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Reactions of carbonyl compounds with (monohalo) methyleniminium salts (vilsmeier reagents)
O+iO-4020/92 $S.OO+.OO PergamonPressLtd
Tetrahedron Vol. 48, No. 18.pp.3659-3726.1992 Rited in Great Britain
TETRAHEDRON REPORT NUMBER 312
REACTIONS OF CARBONYL COMPGUNDS WITH (MONOHALO) METHYLENIMINIUM SALTS (VILSMEIER REAGENTS)
Department
Charles M. Marson of Chemistry, The University,
Sheffield,
S3 7HF
(Received 29 October 1991)
Contents 1. Introduction 1.1 scope 1.2 Formation and Structure of Halomethyleniminium (Vilsmeier Reagents) 2. Reactions of Aldehydes with Halomethyleniminium
Salts
Salts
3661 3662
3. Reactions of Ketones with Halomethyleniminium Salts 3.1 General Remarks and Mechanistic Considerations 3.2 Acyclic Ketones 3.2.1 Acyclic Ketones with Two sp3 Carbon Atoms adjacent to the Carbonyl group 3.2.2 Acyclic Alkyl Vinyl Ketones 3.2.3 Aryl Alkyl Ketones 3.3 Saturated Monocarbocyclic Ketones 3.3.1 Unsuhstituted Cycloalkanones 3.3.2 Monosubstituted Cycloalkanones 3.3.3 Steroidal Cycloalkanones 3.4 a&Unsaturated Carbocyclic Ketones 3.4.1 2Cycloalken l-ones 3.4.2 a$-Unsaturated Steroidal Ketones 3.4.3 Benzo-Fused Cycloalkanones 3.4.4 Cycloalkanones fused to Heteroaromatic Rings 3.5 Cyclic Ketones with One or Mom Heteroatoms in the Ketone Ring 3.5.1 Monocyclic Systems 3.5.2 Bicyclic Systems 3.5.3 Polycyclic Systems 3.6 Diketones 3.6.1 Acyclic 1,3-Diketones 3.6.2 Cyclic 1,3-Diketones 3.6.3 1,4- and 1,5-Diketones
3663 3663 3665
4. Reactions of Amidic Carbonyl Compounds 4.1 Amides 4.2 Monocyclic Lactams 4.3 Lactams Fused to Carbocyclic Rings 4.4 Lactams with Benzo-Fusion 4.5 Lactams with Two or Mote Heteroatoms 4.5.1 Five-membered Heterocycles 4.5.2 Six-membered Heterocycles 4.5.3 Seven-membered Heterocycles 4.6 Imides
3698 3698 3702 3704 3705 3708 3708 3710 3713 3714
5. Reactions of Carboxylic Acids
3715
6. Reactions of Esters and Lactonic Carbonyl Compounds
3717
7. Conclusion
3720 3659
3665 3668 3670 3674 3674 3675 3676 3678 3678 3684 3685 3687 3688 3688 3690 3693 3694 3694 3695 3697
3660
c. M. MAILSON
1. INTRODUCTION Scope
I.1
Halomethyleniminium chloride,2
[Me2NCHCll+
generated
in,
the
formylating
activated amide,
frequently The
aromatic typically
potential
rings.
for
‘formylation’ salts
containing
a C=O
linkage
otherwise
inaccessible
compounds
surveyed
and often essential, The reaction
one
as reagents
though
activated
is
well-illustrated
reagent
compounds
to a lesser
of Vilsmeier
produced
extent,
aromatic
nuclei.
in
which
of
when
a
phosgene. reactions536
is by no means their
have
are chiefly
the Vilsmeier
is
methods
(DMF), is treated with an acid
acetone 1. by virtue
e.g.
common
bond-forming
synthesis
of
for, or intermediates
of the most
Vilsmeier
carbon-carbon
in this Report during
A
oxychloride,
salts in organic
halomethyleniminium
best known
reaction,3
NJ-dimethylformamide4
phosphorus
halomethyleniminium Haack-Arnold
e.g. N,N-dimethylchloromethylenammonium
Vilsmeier-Haack
disubstituted halide,
salts,’
Cl-, are perhaps
confined
The
synthetic
value
with
compounds
reactions
of the number
been
of
to Vilsmeier-
of varied,
prepared.
The
those for which enolisation
of and
carbonyl
is possible,
reaction.
reagents
with ketones
containing
methyl
or methylene
groups adjacent to the carbonyl group, reported in the late 1950’s by Arnold and coworkers,798 affords substituted P-chloroacrylaldehydes, such as 2 (Scheme 1). This Report
emphasises
far beyond
the
carbon-carbon
bonds
that the course temperature. somewhat
the
wide-ranging
formylation
of an
to be formed
of such reactions Although
unexpected
Vilsmeier
reactivity5 activated in many
other
can often reagents
transformations,
of Vilsmeier
aromatic
contexts.
be controlled are known
considerable
reagents
nucleus.
which
The Recent
work
by substrate,
to be capable
rationalisation
extends
reagents
allow
has shown
conditions,
or
of a variety
of the
products
of is
now possible. The containing having here:
scope
been (i)
electrophilic aldehydeslO cyclisations compounds
of this
Report
is confined
to the reaction
a C=O double bond with reagents of the Vilsmeier discussed
and reviewed
Vilsmeier-Haack-Arnold formylating (common
agents
products
elsewhere,
will
of organic
type.
not be considered
formylation of activated in general9 (iii) the chemistry
of the reaction
of Vilsmeier
compounds
The following
topics,
in any
detail
aromatic rings3 (ii) of p-chlorovinyl-
reagents
with ketones)
(iv)
involving carbonyl under Vilsmeier conditions * 1 (although such cyclisations will be considered). The importance of g-chlorovinylaldehydes, owing to
their considerable
synthetic
versatility
and generality
of preparation
is worthy
of note.
3661
Reactions of carbonyl compounds with methyleniminium salts
1.2
Formation
and Structure
(Vilsmeier
Reagents)
It is well-known
that inorganic
with NJ-dimethylformamide Haack
reagentstz-15
dehydroxylating
of ffalomethyleniminium
acid halides
(e.g. SOC12, COC12 and POCl3) react
(DMF) to form active complexes,
which
reagents.16
have found
extensive
DMF has been
referred
use as formylating,
to as Vilsmeierhalogenating
and
shown to react with SOC12 at room
1
2
Me,N_+c’ H Me’
Salts
Me,.
-
‘Cl
H
N=C’
Me’
‘Cl xo-
xo-
4
3
a X=POCl, b X=SOCl
Me,+
p
Me,+
N=C, Me’ cl- OP(O)Cl~
N=C,
Me’
,H X
Y6 X=Br 7 X=Br 8 X=1
5
Y=Br Y=OP(0)Br2 Y=I
Scheme 1
temperature
giving a 1:l complex
give the crystalline the latter
complex
[Me2NCHOS(O)CIl+
[Me2NCHCl]+
has been used frequently
Cl- which loses SO2 reversibly
Cl-; both salts have been characterised,l2
in organic
synthesis.
to and
c. M.
3662
The
generally
accepted
representationl7-20
from N,N-dimethylformamide corresponds to the respective phosphoryliminium
chloride
htARSON
phosphate
4a,
Raman
have been
held22 to establish
spectra
Raman
active.
an equilibrium
The alternative
However,
mixture
of those
reagent
derived
thionyl chloride However, the B-
5 has been suggested21 as being more
chloroiminium
DMF with POC13.
of the Vilsmeier
and phosphorus oxychloride or structures 3al4a and 3b/4b.
reactive than the B-
salts
being
generated.
the structure 5, formed in the reaction
of
structure 4a (formed from DMF and COCl2) was not
this claim for structures
other than 4 has been considered
to
be erroneous.1 1 The
mechanism
of
formation
and
the
structures
of
the
Vilsmeier
reagents
(derived from DMF and POC13. SOC12 or COC12) have been studied by 1H NMR23-25 and 3lP
NMR23~24
determined selenophen
and
For
the
commonly although Arnold
spectroscopy.
for formylation generation the
phosgene
of
acid
and thionyl a number
working
are normally
have
and
prepared
agent required.
DMF
usually
use.
is
the
been
amide
phosphorus
most
oxychloride,
As with the Vilsmeier-Haack-
amides
may be used, including
Solvents
commonly
0-lOO’C,
70-80°C
N-
include
employed1 1 are
(e.g. CH2Cl2, CHC13 or CH2Cl.CH2Cl),
iodoformylation
DMF
by
salts,
of DMF27 over N-methylformanilide
in the range
does
not
procedures react
bromide
bromomethylenedimethyliminium treating
the
gaseous HBr or HI, respectively. DMF with either
parameters
in CHC13 of furan, thiophen,
being
or POC13. a satisfactory
1
temperature.1
chloroformylation.
usually
also find
Advantages
Bromoformylation for
activation
is
or aryldialkyl
or chloroalkene
used
employed
chloride
of dialkyl
the cost and weight of formylating DMF, a chloroalkane general
and
halomethyleniminium chloride
phenyl-N-methylformamide.
Temperatures
constants
tellurophen.26
used;
reaction,
Rate
by the complex HCONMe2-COC12
with
are
usually
carbonyl
6 and the analogous
chloromethyleniminium
Salt 8 exhibits
similar
bromide;
to those
the
desired
iodo compound
salt
in
the same properties
8 are
chloroform
with
as the adducts of
POBr3 or PBr3, 28.29 the structure 7 having been proposed
for the latter
adduct. 2.
REACTIONS OF ALDEHYDES WITH HALOMETHYLENIMINIUM The literature
not
extensive.
concerning Arnold
and
(dimethylaminomethylene)butanal workers32
described
an improved
the reaction
of aldehydes
Zemlicka7.30.31 from procedure
with
described
DMF-POC13 (5 1% yield)
SALTS
Vilsmeier
the
and butanal; using
reagents
preparation Barton
of
is 2-
and co-
1,l -diethoxybutane.
Reactions of carbonyl compounds with methyleniminium salts
Aminoformylation conversion,
of
although
I-formylcyclohexene
acetals
react reacts
triformylmethane
Aliphatic
dialdehydes,
intermediates.
and
reagents,
hydrolysis
of
the
malondialdehyde anils.3Ja l3chlorovinylaldehydes35h 3.
with
with
iminium
rapidly
Dimethylaminoacrylaldehyde (84%).34
proceeds
with
DMF-COC12
Phenylacetaldehydes
in
upon
reaction usually
General
Remarks and Mechanistic
The reaction extensively explored, No unambiguous
R’ /v CH;
although R2
HCl =
Pa
Vilsmeier
arylamines,
lead
to
the (E) -
SALTS
Considerations
course for the reaction
of ketones
the mechanisms of these processes OH 0 DMF-l’OCla R’ +
with Vilsmeier which usually
’
DMF-I’OC13 I
Cl
R’
A -
14
with
ggiving
predominantly
11 R2
Cl
10%
salts.33
chloroform
with
afford
than
of Vilsmeier reagents with simple enolisable ketones has been unlike the action of Vilsmeier reagents on a-hydroxyketones.36
mechanistic
has been developed, 0
less
reaction
REACTIONS OF KETONES WITH HALOMETHYLENIMINIUM 3.1
3663
13 Scheme 2
R’ 12
NMe2 +
2HCl
reagents involve
c. M. htAR.WN
3664
chloroformylation the ketone the
fact
Scheme
have been
enolises that
only
2 outlines
Electrophilic oxygen
atom
substitution
of
the source
prior to reaction sufficiently a currently attack ketone
9a
nucleophilic accepted
by
speculation.
the
alkenes
reaction
Vilsmeier
slowly
forms
of salt 10 by the Vilsmeier
The key role in this reaction
of much
with the Vilsmeier
reagent; are
Arnold7
suggested
that
this is consistent
with
formylated
by
this
reagent.
mechanism.* reagent
salt 10
reagent
on and
the HCl
weakly
carbonyl
2).
Further
(Scheme
to give the dication
is thought to be the liberation
basic
12 is improbable.
of HCl during
the conversion
of ketone 9a into salt 10. HCl catalyses the equilibrium between tautomers 9a and 9b; the latter undergoes rapid substitution by the Vilsmeier reagent giving the P-N, Ndimethylaminovinylketone may formylate autocatalytic
11 which is isolable
the enol 9b giving acceleration
11.
ketone
of the reaction
in certain cases. With increasing
is observed.
Reaction
Additionally, concentration of ketone
salt 10 of HCl,
11 with the
Vilsmeier reagent gives the labile bisiminium chloride 12 which readily collapses to the iminium precursor 13 of the g-chloroacrylaldehyde 14. The perchlorate analogues of salts 13 have been isolated
in very high yield. 37
In the chloroformylation Cl
0
DMF-FOCI, * 16
15 0
Cl R2
DW-POQ,
OHC
R*
Cl
0
23 X=O,S Scheme 3
of enolisable
3665
Reactions of carbonyl compounds with methyleniminium salts
ketones,
molar ratios of iminium
with or without exothermic
to ketone
are frequently
between
of induction
is frequently
observed
4:l
and 5:1,
prior
to an
reaction.
Chlorotrienes3*-41 dienones) which
species
A period
a solvent.
(obtained
can be converted
are
derived
from
during
the
by the Vilsmeier the
steroidal
chloroformylation
reagent
dienones
of
some
steroidal
into the same chloroformyltrienes
themselves.
However,
it
appears
are the primary intermediates in the process of unlikely that chloroalkenes chloroformylation; Arnold showed that a-chlorostyrene does not react with Vilsmeier reagents.7 Typical acyclic
patterns
of regioselectivity
monosubstitution
ketones,
for ketones
generally
are illustrated
favourslc
in Scheme
the regioisomer
3.
For
16, a course
predominantly governed by the relative thermodynamic stability of the two possible enol intermediates. However, a,a-disubstitution is found to block formylation at the asite so that only the aldehyde Karlsson
and Frejd42
only a moderate
and that is usually
have shown that the methyl
effect on the regioselectivity
The usual product further formylation
of monoformylation is sometimes
the sole product.
group of 3-methylcyclohexanone
has
(20:21=10:90). of ketones
can arise only if deprotonation,
Polyformylation
is possible.
18 can be formed,
is the salt 13 7*37(Scheme
involving
observed
(e.g.
2);
the R* group of the cation, as for cyclopentanone,
section
3.3.1). 3.2
ACYCLIC KETONES 3.2. I Acyclic Ketones with Two sp 3 Carbon Atom
adjacent to the Carbonyl
Group. Many converted
methyl
by Vilsmeier
are well-covered of the ketone employed reaction
as well
ketones,
reagents
in previous
to control
and
cyclic
3-haloacrylaldehydes
reagent
the exothermic,
(2.5-5
es.),
and sometimes
methylene
(Scheme
reviews. 1~4~10 The usual procedure
to the Vilsmeier
has subsided,
into
as acyclic
violent
reaction.
slow addition
Solvent
is usually
After the initial
the mixture
neut’ralised by cold aqueous
may be heated, prior to being quenched with ice and B-Haloacrylaldehydes sodium acetate or sodium carbonate.
of low molecular mass are lachrymatory oils which decompose spontaneously Acyclic g-bromoacrylaldehydes2g are few hours, sometimes violently. preparable
are
4); these reactions
involves
with cooling.
ketones,
from complexes
of DMFPOBr3.
within a generally
3666
c. M.
0
Vilsmeier
R*
R’
MARSON
-
R’(CW reagent (E)-14b
(Z)-14a
In
the
simplest
formation
of a mixture
afforded
3-chlorobut-2-enal
Scheme 4 monochloroformylation
cases,
14a
of the (Z)-isomer
occurs,
and
usually 14b.
and the @)-isomer
in 39% yield. 7 However,
acetone
and methyl
with the Acetone
ethyl
ketone,
derivatives.43 with the DMFCOC12 or DMF-POC13 complex, can give triformyl Formylation usually occurs at the more substituted a-carbon atom, giving, for example, the aldehyde
25 (Scheme
5-methylhex-2-enal
5).7
However,
27 predominantly
4-methylpentan-Zone
as the (Z)-isomer44
gives
chiefly
3-chloro-
owing to the steric bulk of Cl
i)DMF-POCls, 60°C ii) NaOAc, H20
24
0
-+
CHO
25
nr
H
Vilsmeier reagent
26
27 Scheme 5
I 28
DMF-POC13
0
cl 30
29 Me2 NaOH
i) 3 h, 65 “C, CHCls CI-INMQ
ii) NaC104, H20 31
0
Cl ClOi
50%
Scheme 6
32
+HX
3661
Reactions of carbonyl compounds with methyleniminium salts
the isopropyl subsequent iminium
Isopropyl
group.
deprotonation species
giving
the pentadienal Related
7).46
the substitution, gives
a
units)
and
and
mixture
hence
hydrolysis
a tetrasubstituted
methoxy-3-methylisoquinoline
HX i
(derived
compounds
ph6ph
Hz0 + 37
atom, but
attack
by the
acetoacetate
gives
containing
(Scheme
depending
Phenylacetone
ring. from
product 35 ring-closure
salt 37
or pyrimidines,
3-methoxyphenylacetone
benzene;
36
Methyl
of the pyrylium
of the benzene
pyrimidines
and three
MIl&ph
6).
further
R2=C02Me).45
isoquinolines
the reactivity
substituted
allows
only a double formylation, the to be formed by a 6x-electrocyclic
can afford either
of
atom
salt 31 (Scheme
and subsequent
35
ketones
28 reacts at the methyl carbon
carbon
the (Z)-form, 14a (Rt=Me;
ketone 33 undergoes 38 being considered
Dibenzyl diphenyl-4-pyrone
ketone
methine
the trimethinium
only one isomer, apparently
of
methyl
at the
upon itself
chloromethyleniminium gives
a mixture
a pyrimidine
of 6-
ring.47
-_&ph
X 38
Scheme 7 In 1968, Koyama cr-acyl-a-arylacetonitriles Scheme
8).4s
revealing Vilsmeier into either
that
and co-workers reported a synthesis of isoquinolines Vilsmeier 39 and formamide-POC13 (modified
The formation
of isoquinolines
MeCONH2-POC13
reagent
was
isoquinolines
shown49
pyrimidines
was further
can afford 4-(3H)-pyrimidinones.
However,
to convert
or naphthalenes,
versus certain
depending
alkoxy-substituted upon
the substitution.
40 from reaction; studied:9 the same
acetophenones
3668
C.M. MARSON
CN
CN
R
H*NCHO, POCls
Me0 40 R=H, Me, Et, Ph Scheme 8 Acyclic
3.2.2 Methyl
Alkyl Vinyl Ketones
propenyl
ketones
dimethylamino-3-penten-2-one
including
afford
the
3-penten-2-one, respective
mesityl
oxide
and
4-
43a, 43 b
isophthaldialdehydes
and 43c.50.51 For the related reaction of the methyl ether of acetylacetone, the formation of 3-chloroanisole (42%) can be rationalised by assuming a 6x electrocyclic ring-closure. unsaturated reactivity,
The simplest ketones
is
and the steric
one to five carbon may be formally
44
explanation
a ring-closure demands
atoms derived
represented
x-
of the formation of
associated
a
1,3,5-triene,
which,
with its substituents,
from the Vilsmeier
as iminium
of arenes
moieties
45
Scheme 9
reagent,
(Scheme
3x-
9).
from
acyclic
depending may
of which
contain
a,Son
its from
zero to three
3669
Reactions of carbonyl compounds with methyleniminium salts
Extensions unsaturated mono-,
to
the
allcenones
di-,
illustrative.52
and
above
have
been
of
iminium
by Vilsmeier
reagents
of
into
2-hexen-4-one
chlorobenzene lo).53
54 are formed 54 by the action of DMF-POC13 on the salt Acetylferrocenes
salts 55 and 56.57
react
converted
The reaction
with aqueous
of a formyl
with Vilsmeier
perchlorate,
into
at the methyl at 0°C giving
Benzylideneacetone
of DMF-POC13
coloured,
with crotonophenone
the salt 57 (65%) (Scheme
11).5s
CHO
reagent
’
group reagents
the respective
Vilsmeier
-p
Cl
=I 48 CHO
47 i) DMF-POCls RCH=CHCOMe
*
RCH=CH-CClX!H-CHO
ii) HC104 iii) NaHCOs
49 R= C6F5, C6H5
a.P-
47 into 48 is
49 reacted giving 50 and 51 (Scheme
are smoothly
0L
Several
reported.
2-formyl-l-chlorovinylferrocenes.55.56
cinnamylideneacetone after treatment
been
the lack of introduction
atom is notable. yields
have
Conversion
Benzalacetophenones
2-Acyl-Gaminofulvenes
high
converted
tri-carboxaldehyde.
53 of acetylcyclopentadiene; carbon
ring-closures
50
+
RCH=CH-C(NM~&C!HGI+NMQ 51
Cl0;
Scheme 10 i) DMF-POQ t Na+
Na+
52
53
ii) 3 NaOMe 93%
Cl PhwNM,
Ph&:M% ClO;;
~2C12
57
55 n=l 56 n=2 Scheme 11
and
crystalline affords,
c. M. MARSON
3670
3.2.3
Aryl
Alkyl
Simple acetophenone
Ketones
aryl alkyl ketones and propiophenone
respectively).718 30%.59
However, yields from p-substituted
A
recent
cinnamaldehydeseu DMF-POC13, affords
usually give the chloroformylalkene afford the b-chlorocinnamaldehydes
followed
a mixture
DMF-POC13
procedure
for
from aryl ketones by cooling 12).61
preparation
involves
addition
and treatment
of diastereoisomeric
(Scheme
the
acetophenones of
substituted
with aqueous
NaOH. upon
a Vilsmeier-Haack
DMF--7W
Phqph
+
below
dihydroof
Desoxybenzoin treatment
reaction
(dimethylamino)-desoxybenzoins 61 did not give the anticipated but instead 4-(dimethylamino)-a-halostilbenes 62.62
Ph
are typically
at 70-8O’Y! to a mixture
P-chlorovinylaldehydes
However,
in good yield: (47% and 90%
using
with p- 4-
chloroformylstilbenes,
PhqCl
Ph CHO 60 10%
CHO 59 50%
58
DMF-POQ
62a X=Cl 62b X=Br Scheme 12 Diacetylbenzenes
undergo
diformylation:
when
DMF-COCl2
is used as the
Vilsmeier reagent, a mixture of CHC13 and CH2Cl2 as solvent gave excellent yields of 63 Bis- and tris-(P-chlorovinylaldehydes) 8,8’-dichloro-m-benzenediacrylaldehyde. were
formed
from
1,4_diacetylbenzene
3,4-Dimethoxyacetophenone
and
1,3,5_triacetylbenzene
respectively.52
63a can undergo both mono- and di-formylation,64 Other 63b (Scheme 13). whereas the indene 65 is formed 65 from propioveratrone chloroindenes 67 have been prepared 66 by the action of Vilsmeier reagents on aryl benzyl
ketones.
3671
Reactions of carbonyl compounds with tnethyleniminium salts
MJ@-JJb~=JyyM~~?@J$ HCl -
cl-
63a R=H
NMe2
65
63b R=Me R=H
i) DMF-IQC13 ii) NaOAc. Ha0 I
R’=R2=OMe, R’=H, R2=OMe, F. Br, Cl Scheme 13
OR
HO 68 69 Scheme 14 In Scheme Vilsmeier presumed
14, initial
reagent to occur,
acetophenones
on
the
prior
cyclise
attack on oxygen cannot be excluded, enolised
methylene
to cyclisation in
good
yield
with
group loss
giving
of the
to
give
although
intermediate
methylamine. valuable
attack by the 69
is
o-Hydroxyintermediates,
3-
3672
c. M. h4ARsoN
formylchromones.67-69 phenoxychromones
are
phenoxyacetophenone phenoxychromone hydroxyl
Related catalysed
derivatives derivatives
cyclisation of acetophenone derivatives giving Cyclisation of 2-hydroxyby BF3.OEt2.70
by the Vilsmeier has
been
group has been considered
reagent, catalysed by BF3.OEt2, to 3reported. 70.71 In these cases, initial attack on the
more likely (cf. 72; Scheme
72
71
Vilsmeier reagent
3a-
73
X-
t
R-bkMeZ
74
15).
R-&O
X
75 Scheme 15
Appropriately
substituted
naphthalenes
and
coumarins
react
similarly.67-69
A
variation involves conversion of the 1-acetyl-2-hydroxynaphthalene into a difluoro- 1,3,2dioxaborin with BF3.OEt2, and subsequent formylation, by which the phenalenone 77 can be generated, chloroformylation formation
as well of
as the
expected
I-acetonaphthone
of the same aldehyde
80
chromone 79,
78
migration
as that obtained
(Scheme
During
16).72J3
of the acetyl
group
from 2-acetonaphthone
occurs,
the with
81 (Scheme
17).74
CHO
CHO
76
77 Scheme 16
62%
78
20%
3673
Reactions of carbonyl compounds with methyleniminium salts
79
80
81 Scheme 17 T
82
83
R=Rl=OMe R=H, R’=OMe, OEt, NEtz Scheme 18 A versatile of
the
synthesis
of benzofurans
phenoxyacetophenones
acetylpyrroles
under
chlorovinylpyrroles methylpyrrole
82
Vilsmeier-Haack such
as
83 was accomplished
(Scheme
Treatment of conditions afforded
reaction
84 (Scheme
gave the acetylenic
aldehyde
by the Vilsmeier
l8).75
19).76
Vilsmeier
formylation
85 (34%).77
I
I
il
il
84
85
0
Cl
DMWOC13
f
-
86 Scheme 19
I @ 87
33% CT-IO
reaction
polysubstituted 3the corresponding of
3-acetyl-4-
C. M. h’fARSON
3674
3.3
Saturated 3.3.1
Monocarbocyclic
Unsubstituted
Ketones
Cycloalkanones
P-Chlorovinylaldehydes
are
the
most
abundant
of
the
P-halovinylaldehydes
Vilsmeier reagents, although Arnold and Holy78 showed that prepared using cycloalkanones of five- to eight-membered rings are converted into the corresponding gbromoacrylaldehydes were reported
by DMF-PBr3 complexes.
by Ziegenbein
The corresponding
P-chloroacrylaldehydes
and Lang.7g
0
M
i) DMF-POC13 -Me&+?
zy’
WO+NMez
,, ii) NaC104, Hz0 89 n=l
88
90
t 92
91
93
94
95
Scheme 20
96
3675
Reactions of carbonyl compounds with methyleniminium salts
Cyclobutanone
86 affords the S-chlorovinylaldehyde
87
(Scheme
19).37
No other
product
was reported, even when an excess of formylating agent was used. With DMFcyclopentanone was converted into 2-chlorocyclopentene1-carboxaldehyde POC13, (54%),su
the reaction
Vilsmeier
reagent,
for cyclohexanone
followed
chloropentamethinium could
cyclopentanone aqueous
using
with
illustrates
aqueous
analogously.79.81
of sodium
perchlorate
Work-up
20). carbonate
is evidently
the
important from
afforded
hydrolysed
observations certain
the bromomethyleniminium
afforded
of the reaction the
of
Vilsmeier
effectively
reactions.
salt afforded
salt
the 3-
derivative
mixture
91,
from
which with hot
to 92 and DMF, since a mixture of
95 and the amino ketone 96 is obtained.37
obtained
A large excess of the
solution,
which in the case of the cyclohexanone
Scheme
potassium
carbonate
aldehyde
intermediates
89 (n=l).
to 90 (n=2;
potassium
the amino 96
salts
be hydrolysed
proceeding
by addition
a small
The conversion
of 91 into
thermal deformylations of The reaction of cyclohexanone
quantity
of the doubly
substituted
are formed when cyclopentanone and aldehyde 9 4 .29 The conjugated salts 93 cyclohexanone react with formanilide-POC13. 33 The formation of pentamethinium salts is controlled unit
by the number
are available
compounds
might
deprotonation
Monosubstituted
Cycloalkanones
The
regiochemistry
in
group,
has been a ‘J-methyl
reagent,
present
possessing
methylcycloheptanone the 4-methyl
the
reaction
explored.
substituent
case (Scheme
under
more
little
Karlsson
has
a large
in the cases of six-, seven-,
the five-membered being
and its stability
undergo
3.3.2
Vilsmeier
No other sites of the pentamethinium evidently
prevents
and
hence
further
of
unsymmetrical
isomerisation reaction
into
with
the
reagent.
cycloalkanones small
groups present.
for formylation,
which
Vilsmeier
of alkyl
21).
Vilsmeier-Haack
conformational gave a 1:l
steric
conditions.
mixture
influence
exhibit
mixture
Interestingly, greater
that a relatively
on the rings,
of enols
attack
of the
although
not for
was proposed
the larger
regioselectivity.
of the regioisomers
on the regiochemistry
monosubstituted
showed
and eight-membered
An equilibrium
mobility,
group has little influence
and Frejd42
101 and 102,
of the reaction.
rings,
as
despite
However, showing
4that
C.M. h'iARSON
3676
n=l
60
40
-43
n=2
90
10
52
n=3
95
5
42
n=4
100
0
56
101 50
48%
Scheme 2 1
3.3.3
Cycloalkanones
Steroidal
3-Keto-Sa-steroids thus
afford
the 3-chloro-2-formyi-2-ene
17-acetoxy-Sa-androstan-3-one,
and 5a-pregnan-3.20-diones4 (22-27%) (Scheme
22).
acetoxy-4,4-dimethylandrost-5-en-3-one dimethylandrosta-2,5-diene
with DMF-POC13;
82 17P-acetoxy-l7a-methyl-5a-androstan-3-one,*3 give
The
derivatives
the corresponding
reaction
proceeds
3-chloro-2-formyl
with 4,4-disubstituted
derivatives precursors:
104
17p-
17@-acetoxy-3-chloro-2-formyl-4,4affords (62%) from a reaction with DMF-POC13 at 50-60°C for 4 hours.
Reactions of carbonyl compounds with methyleniminium salts
3677
i) DMF-POClsin DMForCHC!l=C!C12 60°C,3-4h ii) Ha0
OAc i) DMF-POCls, 20°C 0.2 h ii) NaHCQ, Ha0 OAc
106
OAc
HO
107
Scheme 22
The regioselectivity of formylation in ring A is markedly influenced by the relative configuration of the A-B ring junction. Thus, the Sg-androst-3-ene 108 is converted into the 3-chloro-4-formyl derivative 109; 28182 the use of acetyl chloride as the solvent is unusual. Chloroformylation of a steroidal ketone having the carbonyl group at a position other than C-3 usually affords the corresponding g-chlorovinylaldehyde. Thus, 38hydroxyandrost-5-en-17-one
3-acetate
110
is chiefly
converted
with the chloroalkene 111 b being formed as a by-product homosteroidal ketone has been converted by DMF-POCI3 into 112.85
into the aldehyde
llla,
(Scheme 23). A Dthe chlorovinylaldehyde
3678
C. M. MARSON
OAc
llla R=CHO 69% lllb R=H
Me0
Scheme 23
3.4. u&Unsaturated Carbocyclic Ketones. 3.4.1. Of the
2-Cycloaiken-l-ones 2-cycloalken-l-ones
are the most common. The formylmorpholine (NFM)-POC13 which
upon
hydrolysis
25OC for several
gave
reacted exothermic
with
Vilsmeier
reaction
in trichloroethylene
the somewhat
weeks, aerial oxidation
unstable
afforded
of
reagents,
2-cyclohexen-l-ones
2-cyclohexen-l-one
at 20°C afforded dialdehyde
the trialdehyde
123;86 upon 124.
with
N-
a deep red mixture keeping
at
Reactions of carbonyl compounds with methyleniminium salts
3679
117 H+
;W
H
R2
Cl
2
+=H)
124
Scheme reaction
of
cyclohexane-
123
24 provides the
a pathway
1
H20 (&Cl)
12Sa R=Me 12Sb R2=( CH,), Scheme 24 which unifies
3-substituted-2-cycloalken-l-ones
1,3-dione
113d
is discussed
in section
the experimental
(R2=H or Br)
H20
126
observations
or the
113a-113c with Vilsmeier reagents; 3.6.2. There is substantial evidence
C.M. hhRSON
3680
for the involvement
of an enolic
intermediate
than the enol, X=H, or a phosphate
derivative).
of the reaction
apparently
do not involve
the form 121,
stabilised
by extensive
hydrolytic
work-up.
dialdehydes (Rl=H)
125
For the (section
is more susceptible
which is remarkable
delocalisation,
113a-113c,
is considered
to nucleophilic
for 2-cyclohexen-l-one,
intermediate
to be present hydrolysis
129
128 -HCl
I
I
&$.$$;
131
&O
Rl:$l
Cl-
0 Y
0 i) Cl-displacement ii) hydrolysis R
\
Cl ‘I b
CHO 13 2 R=Me, Et, n-Pr, i-Rr Scheme 25
the 12 1
123 is formed,
tautomer.
(y __ml._&+ &NO 127
of
prior to
affords
the intermediate
attack, and the enolic dialdehyde
over the benzenoid
rather
the early stages
A common
113 b and 113d. partial
whereas
for its stability
For ketones
the C=C double bond.
ketones
3.6.2),
114 (in which X may be CH(Cl)NR2
3681
Reactions of carbonyl compounds with methylenitninium salts
For
2-alkyl-2-cyclohexen-l-ones,
evidently
involved
alcohols
because
intermediates
hydrolytic
133 (R#H) are also formed.
observations.
The presence
confirmed
by
alkoxy
the
ethers
allylic
Vilsmeier 133
affords
the
the
species, possibly
reaction
(Rl=alkyl)
mixture
were
fll
“z-_
134
with
132.
The allylic
whereby
The above from
was the
mechanistic
4,4-dimethyl-2-
“nIHNR;z-_
t
136
Hzo
13’
are
with current
alkoxide,
139
1 +NRa X-
-3
137
(~1 =H)
128 or its equivalent,
obtained.87
Nu-
135
NgHNRT
116
aldehydes
features are compatible with the formation of the dialdehyde cyclohexen-l-one 134 and NFM-POC13 (Scheme 26).87.8s
Do
form
Scheme 25 shows a pathway consistent
of a cationic
quenching
corresponding
work-up
of
&Co
t
139
+NR,
29% Scheme 26 A unified lacking and
a methyl
its
(Scheme exocyclic
pathways7 group
5-substituted 28).
148,
thermodynamically Isophorone large excess
derivatives
Although
alkene
several
favoured
an 80% yield of a mixture chlorinated
over
154.
entirely
27.
involving
2-cyclohexen-l-ones
For 3-methyl-2-cyclohexen-l-one
different
Y=Cl
alkenes
their endocyclic
course
analogous isomers
to 148
followeds7-89 moiety
in the
are known
to be
149.
with 2 equiv. of the Vilsmeier iminoalkylation
is
or an oxygenated
to give
reagent,
but with a
the polymethinium
species
during hydrolysis into the 4H-pyran 153 (Scheme 28).87.*s If 151~ with DMF-POC13 (2 equiv.) is quenched after 15 minutes of three chloro-dienes
of (E)- and (Z)-isomers
aldehyde
an
whether
exocyclic
undergoes
processes
in Scheme
147
147~ affords 151cgu
of the reagent
a mixture
typical
it is uncertain
152, which is converted, the reaction of isophorone 151c,
illustrating
at C-3 is given
is obtained.88
was obtained.
From the aldehydes
(IS)-(-)-Verbenone
afforded
151athe
C. M. MARSON
3682
Trialdehydes prepared
146
have been obtained by the Vilsmeier reaction of cyclohexenones The trialdehyde 156 was formed from cyclohexenone in a
by Birch reduction.
Vilsmeier
reaction,
and the dialdehyde
155
from
4-methyl-2-cyclohexen-l-one.91
::I$tE+ ::$?(RlzM:zR 132a
141
140 R2
~~~~~~
R2
I;&
NR2
R’=R’=H $g;
R2=i-F’r
PI
H20
Cl
I1 CHO
OHC
,
R3
’
CHO I
Q
CT-IO
146a R3=OEt 146b R3 =Et Scheme 27
3683
Reactions of carbonyl compounds with methyleniminium salts
goDm--3* gy - -
gy 149
148
147a R’=R’=H
147b R’=H, R’=Me 147~ R’=R’=Me
H20 I
H Cl OHC
151a R’=R’=H 65% 151bR’=H, R*=Me 73% 151~ R’=R’=Me 80% CHO OHCV
fiCo
154
oHc &rHo
155 Scheme 28
156
3684
c. M. bfARSON
3.4.2
a,/MJnsaturated
There
have
Unsaturated
been
steroidal
few
papers
component.
inert
afforded
158b
29).93
Whereas
in this
the corresponding
area
since
and 158~ in equal amounts, enolisation
Vilsmeier
to
methyl
able
attack
of the 3-oxygenated
group
reviewed.r.7
prevents
3-0x0-1,4.6-trienes
further
the
C-4
function reaction
and
a,p-
the
gave
the
157
gave
158a
(Scheme
the
as the first step,93 both for
only in the latter
C-6
by chloride. of
acetate
to the chlorodiene
of the 3-0~0 group was postulated and for the 19-nor-compounds.
displacement
last
19-nortestosterone in addition
the 19-methyl-foxo-enes reagent
it was
3-chloro-3,5dienes;
However,
3-chloro-1,3,5,7-tetraenes.92 aldehydes
Ketones
ketones usually afford a mixture of products of which the halo-diene Thus, 3-oxo-4-ene steroids when heated with DMF-POC13 in an
is the major solvent
Steroidal
series
positions,
prior
The steric
hindrance
3-halo-3.5dienes
with
to
was the
subsequent of the 19-
the
Vilsmeier
reagent. OAc
OAc
o&
;~~:~cl@ R’ R2 158a Rr=R’=H 158b R’=H, R’=CHO 158~ R’=CHO, R2=H
157
Scheme 29
A series
of
steroidal
chloro-2,4,6-trienes
160a,
4,6-dien-3-ones
afforded
with
DMF-POC13 160b,
3-chloro-2-formyl-2,4,6-trienes
and
a mixture
of 3-
3-chloro-3,5,7-
trienes 161 (Scheme 30). The steroid 160a is implicated as an intermediate since it was converted by DMF-POC13 into the aldehyde 160b. 39 In the cases of 17P-acetoxyoestra4,6-dien-3-one
162a
and
17-acetoxy-l9-norpregna-4,6-dien-3,2O-dione
162b,
the
are accompanied by the aromatic expected aldehydes 163a and 163b. respectively, dialdehydes 164a and 164b, formed by oxidation. 39 3p-Acetoxy-5-ene-7-ketosteroids 165
eliminate
acetic
acid
under
Vilsmeier
conditions
giving
the
3,5-dien-7-ones
166
Reactions of carbonyl compounds with methyleniminium salts
which
are
Formylation
then
converted
of triene
attack by Vilsmeier
167a
reagents
into
a mixture
of
chlorinated 167b.38
gives the aldehyde
3685
167a
steroids
and 16 7 b .
3-Alkoxy-3,5-dienes
undergo
at C-6 only.94
DMF-POQ
160a. R’=H 160b, R’=CHO
161
15%?
162a 162b
164b
167b, R’=CHO
Scheme 30 3.4.3
Bento-Fused
Benzo-fused
Cycloalkanones
cycloalkanones
corresponding
chlorovinylaldehydes
Under
conditions,
normal
chlorovinylaldehydes heterocycles.95-98
formylation
are usually
converted
in good yield
by Vilsmeier
and under
of the aromatic
have been used in the synthesis
reagents
mild conditions
ring does not occur. of a wide variety
into
(Scheme
the 31).
The resulting
of polycondensed
c. M.
3686
I-Indanone,
a -tetralone
and
MARSON
benzosuberone
afford
the
corresponding
chlorovinylaldehydes 168a, 168b (77%)7* and 168~ (75%)59 respectively. Derivatives a-tetralone with alkyl groups on either ring afford the expected fi-chlorovinylaldehydes 169.97 present.
No aromatic formylation g -Tetralones usually
carboxaldehyde more readily corresponding
pof
is observed even when 6- or 7-methoxy groups are 2-chloro-3.4-dihydro1 -naphthalenegive the
derivatives [e.g. 170 is formed99 (44%)]. although these decompose much afford the than the isomers such as 169.100 Some g-tetralones The reaction of fl-tetralone 2-chloro-1,3-naphthalenedicarboxaldehydes.
with HCONH2-POC13
168s n=l 168b n=2
168c n=3
afforded 5,6-dihydrobenzoV]quinazolineluI
il 169a R’=R*=H 169b R’=Me, R*=H
169~ R’=H, R*=Me
Scheme 31
in very low yield.
3687
Reactions of carbonyl compounds with methyleniminium salts
Acenaphthenone
with
DMF-POC13
in trichloroethylene
the aldehyde
affords
17 1 a
Other ketones (80%) (50°C. 3 h);79 the methyl derivative 171b was similarly obtained.97 of the a-tetralone type have been converted into the corresponding aldehydes 174-177. The
conversion
probably Using
of
anthrone
the earliest
reported
Vilsmeier
which afforded
172
methodolgy,
the
a convergent
salt 180 (Scheme
into
example
IO-chloro-9-anthracenecarboxaldehyde
of a ‘chloroformylation’
diketone
178 was converted
and unambiguous
173 is
of a methylene into
ketone.102
the dialdehyde
route to the intricate
macrocyclic
179
pyrylium
32).95
178
179
Scheme 32
3.4.4 Cycloalkmonesjbsed to Heteroaromatic Rings The
aldehyde
18 1
indazolecarboxaldehyde reagent
on
the
corresponding
tetrahydroindazoles disubstituted, ketone
183 The
quantities
183
but
the
(Scheme
prepared
from
was also directly ketone.103
were investigated.
chlorovinyl
ketone
the
corresponding
prepared A
ketone.97
The of a Vilsmeier
by the action
number
of
other
4-0x0-4,5,6,7-
Aldehydes were obtained when C-6 was not 184 was formed from the 6,6-gem-dimethyl
33).104
Vilsmeier of aromatised
major products
was
182
(Scheme
formylation
of
products
187,
33).lus
I-ketotetrahydrocarbazoles in addition
185
gave
to the chlorovinylaldehydes
appreciable 186 as the
3688
C. M. htARSON
The four
benzo[b]thiophen-4-one
products
carbonyl
189-192,
188
which
reacts
demonstrates ring (Scheme
group and the thiophene
with the Vilsmeier-Haack competition
181
between
reagent
formylation
giving of
the.
34).106
6
182
184
183
R2np -$%Lp:o~NMe2 0
Cl 186
18Sa R’=H, Me
187
185b R2=H, Cl, Br, C02Et
Scheme 33
3.5
Cyclic Ketones with One or More Heteroatoms in the Ketone Ring
3.5.1
Monocyclic
The containing
principal either
formylthiophenes dependent.107 Vilsmeier intermediates
Systems
reactions a
sulphur
are or
of an
fiveoxygen
and atom
six-membered in
the
ring.
heterocyclic
ketones
Aromatisation
to
Vilsmeier reaction of the keto-ester 194 is temperatureis typical. Some 4-oxo-4,5-dihydrothiophenes 196 have been convertedlo* by
reagents
into
4-chloro-5formylthiophene
in the preparation
of thiophene
derivatives
azo dyes (Scheme
35).
197 which
are
key
c. M.
3690
MARSON
0
Cl DMF-POCls CHCl=CHcl~ 20°C
CHO
24h
22a, X=S 22b, X=0
23a X=S, 52% 23b X=0,44%
0
Cl CHO
DMF-POCls
R 200 R= H, 30% 201 R=Ph, 40%
R 198, R=H
199, R=Ph
&HO &HO 202
203 Scheme 36
3.5.2
Bicyclic Systems
The
reaction
of
3-coumaranone
with
formylbenzo[b]furan 202.t1 1 The aldehyde 203 3-methoxybenzo[b]thiophene with DMF-POC13. The action
of DMF-POC13
the g-chlorovinylaldehyde formylthiachromone involving
oxidation
was
is efficiently
on thiochroman4-one
exclusively 206
DMF-POC13
at temperatures
formed
by the Vilsmeier
in
reagent
205 below
appreciable was tentatively
gave
3-chloro-2-
prepared112
by reacting
was shown59,109 to afford 50°C
quantity.109 proposed
but
at
lOO“C, 3-
A mechanism (Scheme 37).
Cl DMWOCls CHCl=CCla 22’C, 22h 204
205 Scheme 37
206 29% +204 40%
3691
Reactions of carbonyl compounds with methyleniminium salts
The
reaction
expected
of
aldehyde
chroman-4-one
208
207 59*tug being
(chloromethyl)chromone
is
obtained
also at
temperature-dependent,109 The
35°C.
the
formation109
of 3-
209 at 100°C is thought to proceed by isomerisation
to a 3-
cation 213 (Scheme38).
(chloromethyl)benzo[blpyrylium Cl
209
20736%
48%
cl CHCI
00
\+
ti\
cl-
0
212
+H&Me2 Cl-
A
208 I
209
-
210
213 Scheme 38
The
reaction
the importance
of substituted
of intricate
3-carboxaldehydes ones,59.113
but
can
be
a single
2,116,117
formylation
although
dimethyl-2H-chromene steric
and
electronic
dimethylchroman-4-one
from group
is
effect
sufficient
effects
many
derivatives
has
C-2
reagents
illustrates
with ketones.
4-Chloro-
unsubstituted to block
the 4-chlorochromene
is also usually
prevented
of a 7-methoxy
group,
to promote
operating
Vilsmeier
reactions
is sufficient
114 affords of chromenes
the electronic
with
in Vilsmeier
obtained 2-methyl
Methoxy-2-methylchroman-4-one The Vilsmeier
chroman-6ones
steric effects
during been
Vilsmeier
studied.* 15
7-
in high yield.1 15 by substitution
if introduced
6-formylation.117 the
chroman-4-
3-formylation.
at C-
into 2,2-
The interplay formylation
of
of 2,2-
The high degree of solvation
3692
C.M. hiARSON
of the Vilsmeier reaction
reagent
particularly
in the mildly
susceptible
2,2-Dimethylchroman-4-one corresponding
yield of the latter; the
derivatives 39).
2 14
Prolonged
formylation
chlorocarboxaldehydes
by formylation
normally
employed1
gave
high
215 and only a small quantity
216 (Scheme instead,
solvents
216
renders
the
effects.
4-chloro-ZH-chromenes
chlorocarboxaldehydes that
polar
to steric
reaction
of
The results
of 215,
the
(or none) of the
times did not increase
at C-6 of 215 occurred. arise not by formylation
yields
but
the
indicate
presumably
of an enolic precursor.
215
216
Scheme 39
Flavanone
affords the aldehyde
3-formylcoumarin heterocyclic heterocycles
218
has
aldehydes containing
also
217l1* when treated been
and 219b
219a a carbonyl
group
Vilsmeier reagents are rare. 2,3-Dihydro-lZf-pyrrolizin-l-one 222.
depending
detected, converted
on the reaction
and it is surmised into
chloroalkenes,
217
prepared119 have
been
conditions
(Scheme
that enolisabie
occurring
218
The
Reaction
atom in the same ring by DMFPOC13
40).12o
C=O groups
4-Chloro-
reaction.
prepared.59
and a nitrogen
221 is converted
formylation
with DMF-POC13.
by a Vilsmeier
pyrroles
subsequently.
219a X=S 54 8 219b X=0
70 8
with
into 220 and
The chloroalkene
of acylated
of
224 was are first
Reactions of carhonyl compounds with methyleniminium salts
224
OHC 223
3693
CHNMQ
226
&
Cl-IO OHC
227
Cl 228
Scheme 40
3.5.3
Polycyclic
Angularly corresponding
Systems
annellated derivatives S-chlorovinylaldehydes
naphtho[2,3_b]furan
221
naphtho[b]furanone. Vilsmeier reaction trichloroethylene
was
of chroman-Cone 22512*~122 similarly
are also and 226.121
prepared
from
of lO.ll-dihydrohenzo[bJthiepin-lo-one
at 80°C gave the carhoxaldehyde
converted
228 (52%).123
The the
with
into
the
formylated
corresponding DMF-POC13 in
c. M. MARSON
3694
3.6
Diketones
3.6.1
Acyclic
Holy afforded
I ,3-Diketones
and Arnold
showed50
that treatment
2,4-dichlorobenzaldehyde
heptamethinium process,
species
although
Katritzky
and
230
a closure
Marson
the dialkylformamide; the Vilsmeier complex
which of the
showed86
232
undergoes
41).
ring-closure,
229 with
DMF-POC13
The route
involves
probably type
that the course of the reaction
in
cannot
depends
the
a pericyclic be excluded.
on the nature of
4,6-dichloroisophthalaldehyde 233 was the major product when derived from N-formylmorpholine-POC13 was used. The relative
so that further
which then yields
Scheme
Enamine-Exo-6-Exo-Trig
bulk of the R group when R2N = morpholino of the cation 230,
of acetylacetone
231 (84%;
presumably
iminoalkylation
the dialdehyde
reduces
the rate of ring-closure
can occur giving
the dicationic
species
233. -R2NH H20
231
R2N+
NR2
R2N+
NR2 +NR2 2K-
233
232
Scheme 41
A seminal showed steric
that hindrance
study51
of the action
dichlorobenzaldehydes markedly
was formed (Scheme 42).
decreased A terminal
of Vilsmeier
(e.g. 235, 237, the yields
when
reagents and 239)
with acyclic were
S-diketones
formed,
the pentasubstituted
acetyl group appears to be necessary
although
benzene
239
for cyclisation
3695
Reactions of carbonyl compounds with methyleniminium salts
to
Replacement
2,4-dichlorobenzaldehydes.
necessarily
prevented
benzoylacetone A
240
comparative
trisacetylacetonates
the
formation
of
a
of
one
of
substituted
gave the products 241 and 242. study1z4 of the ligand
the
alkyl
benzene reactivity
groups
and at
of Cr(II1) and Co(II1) by means of Vilsmeier-Haack
in
the
by the
phenyl case
3-position
reactions
of of
has been
made.
*w* I
R
I
234
DMP-POQ I
“WC1 *
II
I
I
RWCI-IO 235 R=H, Me
CHO
239 0
0
0 Ph Ph 242
Ph 241
240 Scheme 42
3.6.2
Cyclic 1.3-Diketones
3-Halo-2-cycloalken-
244
1 -ones
reaction of cycloalkane-1,3-diones A mechanism (COC1)2 or (COBr)2. 43).
The absence of formylated
moieties
are usually
introduced.
can
be prepared125
with Vilsmeier involving initial
in excellent
yield
by the
reagents prepared from DMF and attack at oxygen is proposed (Scheme
products is a notable feature since @chlorovinylaldehyde Thus,
the cross-conjugated
dialdehyde
125a
(Scheme
24,
3696
C.M. MARSON
section
3.4.1) was formed (24%) by treating cyclohexane-1,3-dione
at 2WC.t26
The
113b and 113~.
was also by which
The methinium
Scheme 24. investigated;127
heating
249a
observed
for the 3-halo-2-cyclohexen-l-ones
dialdehydes
125 are formed
is outlined
species is thought to be the final product of the reaction
The stability
to hydrolysis. benzene
same reaction The pathway
113d with DMFPOC13
of alkenes
the reaction
(20%) yield.
121 and 125 towards
mixture
under
MNDO calculations
reflux
indicated
aromatisation
afforded an energy
has
in prior been
the pentasubstituted difference
between
125a and 249b of 13 kcal mol-1 in favour of the arene 249b. Reaction of cyclohexane1,3-dione with DMF-POC13 in chloroform at 5O“C afforded 2,4-dichloro- l-formylcyclohexa1,3-diene suggests
117. that
(presumably
This
formation
thermal
by nucleophilic
121) to give 118.
of a less
decomposition
of
attack,
probably
and hence the aldehyde,
referred to in section
substituted
121
(known involving
117.
aldehyde
at higher
to be formed addition
A related
of HCl to the dication
thermal
deformylation
3.3.1.
Me2G=CHX
X-
+q”-q”
+HX
245
HX+DMF
X=Br, Cl
‘CH=&M% X-
,=
248
~
‘$OH
X 247
scheme 43
O\
temperatures
at 2O’C) can occur
CH=+NMe, x-
was
3691
Reactions of carbonyl compounds with methyleniminium salts
The formed 253
general
pathways
by the action could
be derived
nucleophilic
attack
from
leading
beyond the formation
depicted
of DMFPOCl3 the
in
Scheme
on dimedone g em-dimethyl
to dealkylation;
of the gem-dimethyl
24 are 250
consistent
(Scheme
analogue
with
44).t2a
of
the
alternatively, the reaction analogue of the cation 118.
the products
The dialdehyde
dication
12 1 by
might
not proceed
OHC
249a R’=CHO R2= CH2NMe2 24913R’=CH2NM% R2=CH0
b;z_Cl
f
250
bC1
251
+
OHCJ&
CHO
CHO
252
253
Scheme 44
3.6.3
1,4- and l.J-Diketones
Few examples formylmorpholine-POCl3 intermediates methiniam
are species
favoured. keto-aldehyde DMF-POC13.
not
have
been reported. Cyclohexane- 1,4-dione 254 reacts with N to give the phenol 255 (Scheme 45),g6 The probable stabilised by strongly electron-withdrawing groups, as are the
depicted
Chloroformylation 256.
in Scheme
24, so that pathways
of cyclooctane-
The dialdehyde
257
1,%dione
under
is formed129
from
leading mild
to aromatisation
are
conditions
the
cyclooctane-1.5-dione
gave
and
c. M. &‘hRSON
3698
lWM-POC1~ 0 254
Scheme 45
4.
REACTIONS
Similar reagents
mechanistic
as apply
carbonamides will usually
features
to ketones.
as compared initially
apply to ketones). in the reaction reactions
OF AMIDIC CARBONYL COMPOUNDS to the reaction
greater
with ketones
attack the carbonyl
of lactams
in which
with
the amide
Bischler-Napieralski-type
considered
in this Report.
basicity
suggests
atom
that the chloromethyleniminium
in
cation
substantially,
particularly
reagents.
In this Section are emphasised transformation into other functionalities.
undergoes
cyclisations,
extensively
46 outlines
the general
reagents.
attack by chloride ion to give an enamine
enaminoaldehyde so that the iminium
266.
264;
products
involved
by nucleophilic
intermediates
Chlorinated
pathways’
with Vilsmeier stable
with Vilsmeier oxygen
reviewed
elsewhere,
are not
Amides
Scheme
the
carbonyl
the area has grown
Vilsmeier
group
of carbonamides of the
oxygen atom in the former cases (which may also
Since the last reviews,l*s
However,
4.1
apply The
hydrolysis
For some simple
when amides
are derived by initial can
afford
amides,
species 259 may be deprotonated
or lactams
0-acylation,
react
followed
262 which rapidly reacts to give either
chlorinated
an
amide
products
to give 261
265
or
the
are not observed,
followed
by
3699
Reactions of carbonyl compounds with methyleniminium salts
Thus, N,N-dimethylacetamide 267 is converted into the highly acylation. amide 269 (Scheme 47). The dehydrating properties of Vilsmeier functionalised reagents may lead to nitriles. presumably via the iminium species 260. salts 271 using Vilsmeier reagents has been Synthesis of the trimethinium subsequent
extended
from carboxylic
0 R’
0A
DMF-FOCls NR;
258
acids to acetamides
R’ cl-
and thioamides.t30
Cl
+
A
2
-
-DMF
Cl R’
m2
259
260 -HCl
-HCl II
Cl R’ 262
265 Scheme 46
266
3700
C.
M. MARSON
269
268
X
R’C!I$ A
R’
i) R2NCI-I0. =3
*
NH2
R2N-CH=C: ,C=‘NR*
ii) HC!104aq.
H
270 X=0, S
271
Clo;
Scheme 47
Fused pyridin-Zones 273 are formed in low yields by the cyclisation of enamides (Scheme 48).13t Hippuric acid is converted 132 into the oxazole 274 by NMF-POC13.
Cl
DMF-POCl,
0
A, 4 h
273
Me
Scheme 48
Since quinolines
the have
pioneering been
the Vilsmeier
reaction
prepared.135
In certain
49).136
of
Fischer,
Mueller
and
Vilsmeier,l33
prepared
chloro-3-cyanoquinolines,
(Scheme
work
by Vilsmeier reactions of acylanilides; prepared 134 by the action of hydroxylamine Other 2-chloro-3-substituted quinolines mixture. cases, the uncyclised
intermediate
was identified
numerous
these include hydrochloride have
also
2on been
as the salt 276
Reactions of carbonyl compounds with methyleniminium salts
3701
280
Scheme 49 In versatile
syntheses
of quinolines,
by the use of the Vilsmeier chlorinated isolated
heterocycles
reagent
(Scheme
in cases where quinoline
thienopyridines,
under
controlled
50).137 formation
fused
afforded derived
pyridines,
high yields
from 285,
of
can be
is slow.t3*
3 DMF-7 F0Cls W alo
282
283
X-
L
284
286,
A, 1.5h
A, 4 h
iI
conditions
Intermediates
a”uI: 0 281
and related
285
Ii
_I
286
Scheme 50 Carbostyrils substituted
288
acetanilides
generally (Scheme
result 51).
from the action
Electron-donating
of the Vilsmeier groups
reagent
placed meta or para
on aassist
c. M. h’fARSON
3702
the cyclisation group
whereas
deactivates
converted
the same
the ring
by the Vilsmeier
The formylation has been
shown
groups
sufficiently reagent
an excellent
hinder the reaction.
cyclisation;
into the anilide
of N-phenylacetanilides
to provide
ortho
placed
to prevent
the
A p-chloro
acetanilide
289a
is
289 b.131
290
was initially
route 140~141 to
misinterpreted,139
1-phenyl-2-quinolones
but
such
as
292. i) DMFPOC13
-i
287
ii)
-
R’
H,O 288
d
-1
289a, R=H 289b, R=CI
Me
TM”z dH, CH,Cl
/
‘N’
Qx I
290
\
$h
291
Cl
292
Ah x-
hh
Scheme 5 1 3_Acetamidothiophene, HONH2.HC1, rather
than
afforded the
was obtained
expected
when
heated
with
DMF-POC13,
5-chlorothieno[3,2-blpyridine-6-carbonitrile.142 2-formyl
upon Vilsmeier
derivative
formylation
yield
by a one-pot
Monocyclic
4.2
a-Pyrrolones derivativesl45 the ring.
procedure
treated
(Scheme
with
The amidine 294, 293,
52).143 297
have
from 2-indolecarbohydrazides
been
prepared
in
295.144
Lactams
are converted or the
then
of 3-(acetylamino)benzo[b]thiophene
4-0xo-3,4-dihydro-5H-pyridazino[4,5-blindoles excellent
and
by Vilsmeier
2-halo-5-formyl
In some cases, the intermddiate
reagents
into either
derivatives, 146 depending enamines
can be isolated.
the 2-chloro-3-formyl on the substitution The 2-bromopyrrole-
in
Reactions of carbonyl compounds with methyleniminium snlts
294
293
0 ml3
K
NMq
296
cc
mM%!
N R
0
a N
CHCl
0
ILe
Me
299
300
R=$ %, CH0147 =Me, Bu 148
302 X=Cl, Br
H,O, \
/OH.
I Scheme 52
Hz0
3703
3704
C. M.
hiARSON
-5aldehydes so obtained are useful compounds for the synthesis of pyrromethenes. In other cases.147.14* a-pyrrolones afford the dimethylaminomethylene derivatives 298. The
lactams
obtained 14*
299 and 300 were
methyl-e-caprolactam,
respectively,
but were accompanied
2-Chloropyrrole-3-carboxaldehydes pyrrolidin-2-ones
with
from N-methyl-S-valerolactam
have
DMF-POC13
in
Vilsmeier
reagents
smoothly
converted
4.3
has
been
prepared
by
chloroform.145,149 with
studied. 150
treating
The reaction
chlorinated
and
pyrroles
304
(Scheme
A4-
of 4-
brominated
A wide variety of As-pyrrolin-2-ones
into the functionalised
N-
by other products.
been
methoxycarbonyl-5-methyl-A4-pyrrolin-2-one
and
301 are
52).t50,15t
Lactams Fused to Carbocyclic Rings
The enamino-aldehyde pyrrolone and DMF-POC13. from steroidal
lactams
have tolerable
stability
305
has
Vinylogous
such as 306 to acids
been
(Scheme
unless
prepared145
amidines, 53).
aromatisation
e.g. 307
from
the
corresponding
have been prepared1529153
In general, the vinylogous amidines can occur. The chloroformylated
steroid derivatives 308 and 309 are formed’53 by treating the appropriate azacholestanone and aza-homoandrostenone derivatives with DMF-POC13 in refluxing CHC13.
306
307 Scheme 53
Reactions of carbonyl compounds with methyleniminium salts
R
4.4
Lactams
with
308
309
Benzo-Fusion
Early work showed that oxindole 312a
2-chloro-3-formylindole variety into
of
l-substituted
310 (R=H) was converted
(Scheme
oxindoles .t55.
3-chloro-1-methyl-2-quinolinone The
Vilsmeier
either
by the
acylation 5-
or
formylindoles;ts*
7-position however,
has been
converted
conversion
of
1-acyloxindoles
314a
were
also proceeds
and 314b.
converted
with
3 13
into
The products the
oxindoles
substituted
I
II
WV-
I
VN’
II
R’ 313 R’=Me, Et, Pr
eo
A
0
314a R2=H 314b R2=CH0 Scheme 54
-
(Scheme
K=uMe
WC3
WN’ R’
at
2-chloro-3-
differently
31LD
3-
315 had to be
corresponding reacted
the
59.154
VN’
a
1-methyloxindole
Some oxindoles
into
substituted
into the
reported.156
2-chloro-3-formylindole.157 other
by DMFPOC13
The reaction
The remarkable
derivatives of
54).t54
(79%)
reagent
dimethylaminomethylidene prepared
3705
A
315
0
3706
C. M.
Isatin
p -0xime
was
converted
hb%RSON
by
DMF-POC13
into N,N-dimethyl-N-(o-
cyanophenyl)formamidine.l59
MeoyJ$l~Md~;;;~M:&q 320
319 62%H
AH0
B
321 83% Scheme 55
Stable Vilsmeier
vinylogous
reaction
amidines
(Scheme
such
as 323
can
be obtained
from
lactams
in a
56).152.160
322 H
323 Scheme 56
Dihydroisoquinolin-3-ones formylisoquinolines (Scheme
57).161
also
applied
be
(Scheme
58);
326
have
been
of Vilsmeier
The sequence of the Vilsmeier-Haack to
other
blocking
phenylisoquinoline-4-aldehyde enabled
324 by the action
the spirocyclic
dihydroisoquinolinone the
nitrogen
(25%).
chloroketone
converted reagents
reaction
derivatives
into
followed
followed including
3-chloro-4by oxidation
by oxidation
can
327 and 33 0
atom afforded 3-chloro-1,2-dihydro-lBlocking the l-position of the isoquinolone
335 to be obtained.161
3707
Reactions of carbonyl compounds with methyleniminium salts
CHO
326
325
fl
H2S04-KMnOL
& 329
328
327
Scheme 57
332
Ah
Bn
Bn Scheme 58
Benzazepin-2-ones chloroformyl
336
derivatives.59,tQ
react with Vilsmeier Related
reagents
benzazepin-2-thiones
to afford
the corresponding
also react analogously.162
3708
C. M. MARSON
4.5
Lactams with Two or More Heteroatoms
4.5.1
Five-membered
5Pyrazolones pyrazoles.163
Heterocycles
usually
A variety
react
with
Vilsmeier
of other functionalities
reagents
to
may be produced,
substrate and reaction conditions. Formylpyrazole derivatives by treating 5pyrazolones 337 with DMF-POC13 (Scheme 59).
338
give
formylated
depending
upon the
have been prepared
I-Phenyl-3-methyl-5-pyrazolone
340164
when
339 afforded the pyrazole carboxaldehyde when the reaction mixture was added to water and slowly neutralised. However, the mixture was poured into aqueous K2C03, some of the hydroxymethylene
derivative
341
was also obtained.
aminomethylenepyrazolone
342
Working is
dialdehyde
343,165
observed.
3-Amino-1-phenyl-5-pyrazolone
the aldehyde
the formation
of the
has been observed.
3-Methyl-1-phenyl-5-pyrazolone although
at lower temperatures,
simple
converted
by
chloroformylation was
converted
344.166
336a R=H 336b R=Cl
DMF-POCl,
R’, R’=lower alkyl
Scheme 59
a Vilsmeier
reagent
of the pyrazole by a Vilsmeier
has
into
the
also
been
reagent
into
Reactions of carbonyl compounds with methyleniminium salts
Chlorination diformylated
of
a
3-methyl
S-oxopyrazolone
group,
has
system
been
345,
in addition
using
Vilsmeier
observed
When the product derived from a Vilsmeier reaction is treated with NH4C1, 3-chloro-7-formyl-lH-pyrazolo[4,3-clpyridine 60).167
The
five-membered
by Vilsmeier-Haack
heterocyclic
reactions
chloro-aldehydes
on the appropriate
347 X=N, CMe
to an effectively reagents
amides
S
CHO
N
Cl
(Scheme
on 3-methyl-5pyrazolone is obtained.168
347 and 348
heterocyclic
a\
CHO
3709
were
(Scheme
prepared 6O).le9
348 Scheme 60
Rhodanine
349 was
converted
2-Phenyliminothiazolidin-4-one versatile been
derivatives
352
(Scheme
into
4-dimethylaminoformylidene
351 is converted by a Vilsmeier 61) from which several 5,5-fused
rhodanine
350.
reagent into the heterocycles have
made.170 2-Amino-4-thiazolinones
derivatives
by Vilsmeier
reagents
are
transformed
(Scheme
62). 171
into
4-chloro-5-formylthiazole
Oxazine derivatives
356. useful as
c. M. hiARSON
3710
DMP-POQ, 30°C,6h
s
l-f
OHC
0
Cl
Vilsmeier reagent W
NH 351 K NPh
352 HNPh Scheme 61
fungicides the thiazine
and analgesics. analogues
0
were prepared
of 355
e
reaction
on the amide
355;172
similarly.
Cl DMWOCl~, 70°C
N
S 353
reacted
by a Vilsmeier
t
NH2
OHC 354
.HCl 0 i) DMP in PhMe, ii) MesN, EtsN, 4h,50°C
355
356
Scheme 62
4.5.2
Six-membered
Unactivated Vilsmeier
Heterocycles
pyrimidines
reagents.
However,
(e.g.
4,6-dichloropyrimidine)
the unsubstituted
acid, uracils,l73 and 4-hydroxy-6-oxodihydropyrimidines Barbituric accordance with its reactivity as a g-enamide. either
357
or 3 59,
depending
on
the
solvent
do not usually
5-position
of derivatives
react
with
of barbituric
undergoes formylation, in acid derivatives 358 afforded
employed
(Scheme
63).
The
5-
Reactions of carbonyl compounds with methyleniminium salts
acid
dimethylaminomethylenebarbituric
derivatives
359
3711
were hydrolysed
by alkali
to
The Vilsmeier reaction of 1,3-disubstituted uracil 5-formylbarbituric acids 360. Reactive afforded 1,3-disubstituted 5-formyluracil derivatives.173.174 derivatives intermediates 362 (R=Cl, Ph, NMe2, NEt2) for dyes have been prepared175 by Vilsmeier the
reactions; barbituric acid 361 obtained from the corresponding
afforded the aldehyde 362 (R=Cl). barbitmic acid and DMF-POC13.176
Cl DMF-POCl,
OYYO HNNH Ko
,
363 was
Vilsmeier-Haack
reagents
Cl
I N\ N YR 362
_+f
i)6h,50°C ii) 20 h, 85°C R=Cl
361
Aldehyde
364
365
Scheme 63
have
Hydroxytriazolopyrimidines into
chlorovinylaldehydes
prepared
by
the
such
Vilsmeier
as 364 reaction
been
converted
(3 h; 70-8O’C; of
by
85%).177
The amide 365
2-ethoxycarbonylmethylene-3-oxo-
was
1,2,3,4-
tetrahydroquinoxaline.178 Substituted
1-formyl-1.5-benzodiazepines
decreasing the amount of Vilsmeier and 50 ml POC13; Scheme 64).179
reagent
were used (e.g.
prepared
in
improved
10 g of amide 366,
yield
by
50 ml DMF,,
C. M. MARSON
3712
DMF-POCls looOC, lh H
367
366
369a, R=H
368
370 R’=H. Br, Cl, NOZ, OMe, NMe2 R’=HorCHO Scheme 64
Several arylthiazine
thiazinones derivatives
have been reacted 368 afforded
with Vilsmeier
mixtures
369b in ratios depending on the electronegativity substituents (e.g. NMe2) electron-donating withdrawing
ones
(e.g. p-N02)
hydroxy-1,3-thiazin-&ones and by photoelectron determined chloroformyl
lactams.162
A similar reaction
the corresponding
salts
substituents
Vilsmeier
by CND0/2
the product ratios
enamines
period of two days (Scheme 65).164 2H-1,4-Benzoxazin-3-one and iminium
thiazinones
369a
reactions
376 which
(Scheme
form a variety
65).tg2
and
and MND0/3
of 2-aryl-4MO methods,
(R=H or CHO in 369)
are chiefly The
using 4H-1,4-benzothiazin-3-ones but they decomposed
374 to be isolated, its
of 2-
of the p-substituents in the aryl ring; favoured 369b, whereas electron-
369a.lau
were analysed
spectroscopy;
of the chlorinated
A variety
by the energetic and structural parameters of the HOMO.lst derivatives 371 and 372 were formed by the action of DMFPOC13
corresponding enabled
368
favoured
reagents.
derivatives
react
with
of products
with alkali,
on the 373 during a
DMF-POC13
to give
some lacking
chloro-
Reactions of carbonyl compounds with methyleniminium salts
3713
R
:xtHr N
0
i) DMP-FOCls ii) NaHa
S
aq. 374
373
376
375
po2CG Scheme 65
4.5.3
Seven-membered
The action 4.4.
Several
Heterocycles
of Vilsmeier
benzo-fused
reagents
on benzazepin-Zones
1,4-diazepinones
Ph
Cl
was described
in Section
(Scheme 66) have also been subjected
Ph R= Cl 80% R=OMe30% i) DMP-POCI, ii) NH&l
Scheme 66
to
C. M.
3714
Vilsmeier
aminomethylene
4.6
were
derivatives 378, rather than the The pyrido-fused benzodiazepin-2-one
reaction
on
dibenzodiazepinone conditions
377
benzodiazepin-2-ones
converted
corresponding
compounds.la3 Vilsmeier
The
reactions.
hfAR!3ON
the 381
(Scheme
benzodiazepin-2-one
the
380 was produced via a Ring contraction of the
379.184
to the benzimidazole
into
chloroformylated
382
occurred
under
Vilsmeier
67).1*5
Imides
Glutarimides
are
diformyldihydropyridines seven-membered rings chlorovinylaldehydes
converted
by
DMF-POC13
into the lactams
384 can also be obtained.187 DMF-POC13 react with excess
387 (Scheme
383;1*6
the
Imides of five-, six-, and to give the useful di-p-
67).18* NO2
I’ a
DMF-POCla NO2
CONMq
W
ij 382
381
0
lx I
CHO
Cl
L!
384 R=H, Ph
383 R=Me, Et, Pr, Ph
R
‘cl
bH2
c,
387a n=2, R=CH2P h I!,h 388a, n=2 n=O, 1,2; R=CH2Ph, CI-I,CO,Et, Ph Scheme 67
Reactions of carbonyl compounds with methyleniminium salts
The azepines 4 equiv.
386 are converted
of the Vilsmeier
reagent
3715
by excess DMF-POC13 into the aldehydes 387;
diluted
with CHC13 afforded
a mixture
of azepines
387a (10%) and 388a (35%). REACTIONS
5.
A general reaction
method
of derivatives
acids,*93 addition
into
The
of vinamidinium
salts 390189-192 is the
reagents
derivatives
(Scheme
68).
of glycinel95
The action of DMF-POC13 on sodium trifluoroacetate, affords
2-fluoro-3-dimethyiaminoacrylaldehyde
Malonic
also afford followed
by
which
can
be
reaction
of
the
fluoromalondialdehyde.196
acrylaldehydes
corresponding
acetic
Formylation
392
were
acids 391 (Scheme
of 2,4-dienoic
isophthalaldehyde prepared
for the preparation
acid,194 and substituted
salts.
of Et3N,
converted
ACIDS
of acetic acid with Vilsmeier
cyanoacetic
vinamidinium
OF CARBOXYLIC
from
by
with
poor
conditions
selectivity.
DMF-POCls
W
was
M~&~NMQ
389 R= aryl, F, Cl, CO,Et
X-
390 X=Cl, ClO,
Me0
Me0 \
W R
3,5-xylenol
acid.198
R
Meo
gave low yields of
However,
3-methylhexa-2,4-dienoic
RCH,CO,H
Vilsmeier
68).197
acids under Vilsmeier
derivatives,
in 45% yield
prepared
COzH
-
DMF-POCI,
/
*
Meo
\ *
391
CHNMe2 /
CHO
R 392 R=H, Me0
“HO( 393
‘b Scheme 68
Benzimidazole-2-propionic 394 by the Vilsmeier 395 affords
the
reagent
benzofulvene
acid at room
393
is converted
temperature. l 99
into
the enamino-ketone
Benzene-l
396 in low yield (Scheme 69).2cu
,2-diacetic
Benzene-1,3-
acid
3716
C. M.
diacetic
acid
and benzene- 1,4-diacetic
salts in respective 397b, give
and the
opening Upon
acid afford
anhydride
isochroman-1,3-dione and ring-closure
the corresponding
Homophthalic
yields of 65 and 82%.
homophthalic
treatment
MARSON
398 all reacted
399
in excellent
acid 397a,
with
yield.
bistrimethinium its methyl
the Vilsmeier The latter
underwent
with acid or POC13 to give the carboxyisoquinolone
of the Vilsmeier
product
399
with
HCl,
ester
reagent
to
ring-
400.2u1
isocoumarin-4-carboxylic
acid 401 is obtained.202
39713 R=Me
Scheme 69 1,4-Dihydrobenzoic and
acids
tri-carboxaldehydes.
dicarboxaldehyde
403
react This
with
DMF-POC13
procedure
also
to give benzene afforded
naphthalene-
(Scheme 70).203
COZH
o$
e
q$mo
402 Scheme 70
mono-,
91%
di-, 1,3-
Reactions of carbonyl compounds with methyleniminium salts
6.
REACTIONS OF ESTERS AND LACTONIC CARBONYL COMPOUNDS
A two-step group
3717
towards
route
to diazepinoindoles
Vilsmeier
reagents
dimethyl-l.bdihydropyridine
406
(Scheme
depends on the inertness
71).m
was formylated
The 2-methyl
by a Vilsmeier
group
reagent,
of an ester of a 2,6-
leaving
intact
the ester groups at the 3- and 5-positions.205 Vilsmeier 7 1).206
reactions
of benzazoles
Ethyl 2-pyridineacetate
409
407
reacted
generated analogously
the enamines (Scheme
(Scheme
72).
Me
Me 405
407
408
406
408 X=NH, S, 0 Scheme 7 1
The and
pyran-2,4-dione
pharmacologically
active
411,
a useful
compounds,
intermediate was
lactone with DMF and POC13 under cooling.207
Scheme 72
prepared
in the preparation by
treating
of dyes
triacetic
acid
c. M.
3718
Treatment three products (Scheme
of
2-coumaranone
413, 414. and 415,
MARSON
412
with
the Vilsmeier
reagent
afforded
the latter two as mixtures of (I?)- and (Z)-isomers
73).*cs
413 46%
412
415
414 10%
24%
Scheme 73 Vilsmeier-Haack isoxazolones reaction
417.209
reactions
on 5(4H)-isoxazolones
Recently,
new routes to 1,3-oxazin-6-ones
on isoxazolin-5-ones
e
418 have been developed
416 led to dichloromethylby the Vilsmeier
(Scheme 74).*tc
0
DMF-FOCJ
0
Ar
.N’
416
16 k H
418
Cl NM% 419
-HCI
421 Scheme 74
;)f:a)NM% H 420
J
the
Reactions of carbonyl compounds with methyleniminium salts
3719
The Vilsmeier-Haack reaction on 4-alkylideneisoxazolin-5-ones 422 gives 1,3oxazin-&ones 424 which are useful precursors of a-pyrones, 2-pyridones and pyridines
(Scheme
75).2tt
:&@0=
:x0
H423
422
424
Scheme 75
427 71% .
429 428 46% Scheme 76 A excess
reinvestigation212
Vilsmeier
reagents
give 1,3-oxazin-6-ones isoxazolone
of the reaction revealed
of 3-phenyl-5-isoxazolinone
a ring-expansion
at temperatures
around
425 with 80°C
to
(Scheme 76).
425 reacts via
The following rationale has been proposed: the its enol form with the chloromethyleniminium species to
give, after loss of HCI, the dimethylamino-derivative
426,
which under more forcing
conditions reacts with excess Vilsmeier reagent at the ring nitrogen atom (Scheme 77). Ring-opening, subsequent ring-closure, and lastly hydrolysis affords the 1,3-
3720
C. M.
oxaxin-6-one proceeds
4 27.
Formation
via phosphorylation
of
the
hiARSON
5-chloro-4-formylisoxazole
of the exocyclic
428
evidently
oxygen atom of 426.212
0 Me&C!HCl
425
-HX -
Mez
0
0
-427
433
432 Scheme 77
7.
CONCLUSION
In the last decade, reaction of significantly. ketones,
both the synthetic
diketones,
lactones,
have led to the development or less
unexpected
rapidly
gaining
usually
employed
reactions reagents.
potential
and the understanding
lactams,
transformations
both
intelligibility
under
and g-haloenones.
of new reactions
mild
by Vilsmeier and
conditions,
Recent
and compounds. reagents
predictability. and
the
and deserving
of further
mechanistic
insights
The variety
of more
referred The
ease
ensure the continued academic and industrial The products are often g-chlorovinylaldehydes,
synthesis,luv213
of the
salts with carbonyl compounds has grown halomethyleniminium Reactions have been extended, among other classes, to a,g-unsaturated
of
to by Burnsa is
inexpensive scaling
up
reagents, Vilsmeier
importance of Vilsmeier versatile intermediates in
study.
- The author wishes to thank P. R. Giles for his help in preparing Acknowledgements the manuscript, and Professor W. D. Ollis, FRS for helpful suggestions.
Reactions of carbonyl compounds
8. 1. 2. 3. 4. 5.
6.
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
36. 37.
with methyleniminium
salts
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143. 144. 145. 146. 147. 148. 149. 150.
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Chupp, J. P.; Metz, S. J. Heterocycl. Chem. 1979,16, 65. Comforth, J. W. Heterocycl. Comp. 1957.5, 346. Fischer, 0.; Mueller, A.; Vilsmeier, A. J. Prukt. Chem. 1925. 109, 69. Wright, T. L. U. S. Pat. 4,540,786 (1985); Chem. Abstr. 1986,104, 68762~. aMeth-Cohn, 0.; Rhouati, S.; Tamowski, B. Tetrahedron Lert. 1979,50, 4885 hMeth-Cohn, 0.; Rhouati. S.; Tamowski, B.; Robinson, A. J. Chem. Sot., Perkin Trans. I 1981, 1537. Meth-Cohn, 0.; Narine, B.; Tamowski. B. J. Chem. Sot., Perkin Trans. J 1981, 1520. Meth-Cohn, 0.; Narine. B. Tetrahedron Lett. 1978. 2045. Meth-Cohn, 0.; Narine, B.; Tamowski, B. Tetrahedron Left. 1979. 3111. Schulte. K. E.; Bergenthal, D. Arch. Pharm. (Weinheim, Ger.) 1979,312, 265. Hayes, R.: Meth-Cohn, 0.; Tamowski, B. J. Chem. Research (S) 1980, 414. Schulte, K. E.; Bergenthal, D. Arch. Pharm. (Weinheim, Ger.) 1980,313, 890. Wright, T. L. U. S. Par. 4.581,455 (1986); Chem. Abstr. 1986,105, 24271. Bushkov, A. Ya.; Lantsova, 0. I.; Bren, V. A.; Minkin. V. I. Khim. Geterotsikl. Soedin. 1985.4, 565; Chem. Abstr. 1985.103, 37451~. Monge, A.; Aldana. 1.; Lezamiz, I.; Femandez-Alvarez, E. Synthesis, 1984, 160. Schulte, K. E.; Reisch, J. Stoess, LJ. Angew. Chem., Jnt. Ed. Engl. 1965,4, 1081. Dobeneck. H. von; Schnierle, F. Tetrahedron Let?. 1966, 5327. Tomakov, G. P.; Zemlyanova, T. G.: Grandberg, I. I. Khim. Geterorsikl. Soedin. 1984. 1, 56; Chem. Abstr. 1984, 100, 209658y. Tomakov, G. P.; Grandberg, I. I. Jzv. Timiryazevsk. S-kh. Aknd. 1979, 6, 151; Chem. Abstr. 1980.92, 94219c. Schulte. K. E.; Reisch. J. Stoess, U. Arch. Pharm. 1972,305, 523. Messerschmitt, T.; von Specht, U.; von Dobeneck, H. Liebigs Ann. Chem. 1971, 751, 50.
151.
152. 153. 154. 155. 156. 157. 158. 159. 160.
161.
aDobeneck, H. von; Messerschmitt, T. Liebigs Ann. Chem. 1971, 751, 32 bschnierle, F.; Reinhard, H.; Dieter, N.; Lippacher, E.; von Dobeneck. H. Liebigs Ann. Chem. 1968,715, 90. Chandramohan, M. R.; Seshadri, S. Indian J. Chem. 1973, JJ. 1108. Singh, H.; Paul, D. Indian J. Chem. 1974,12, 1210. Seshadri, S.; Sardessai, M. S.; Betrabet, A. M. Jndian J. Chem. 1969. 7, 662. Marchetti, L.; Andreani, A. Ann. Chim. (Rome) 1973,53, 681; Chem. Abstr., 1975, 82, 727236 Andreani, A.: Bonazzi, D.; Rambaldi, M. Boll. Chim. Farm. 1976, JJS, 732; Chem. Abstr. 1978,89, 241074. Andreani, A.: Bonazzi, D; Rambaldi. M.; Mungiovino, G; Greci, L. Fnrmaco, Ed. Sci. 1978.33, 781; Chem. Abstr. 1979.90, 38743r. Andreani, A.; Rambaldi, M.; Bonazzi, D.; Guamieri, A.; Greci, L. Boll. Chim. Furm. 1977.116, 589; Chem. Abstr. 1978, 88, 169876t. Deshpande, M. N.: Seshadri, S. Indian J. Chem. 1973. JJ, 538. Chandramohan, M. R.; Seshadri, S. Indian J. Chem. 1974.12. 940. Bartmann, W.; Konz, E.; Rueger, W. Synthesis, 1988. 680.
Reactions of carbonyl compounds
162. 163.
Aki. 0.; Nakagawa, Y. Chcm. Pharm. Bull. 1972.20, 1325. Kishida. M; Hanaguchi, H.; Akita, T. Jpn. Kokai To&Q0 Kohl Chem.
164.
with methyleniminium
Absrr. 1989,
Chandramohan, 1969,7,
III.
3725
salts
JP
63.267,762;
5772811.
M. R.; Sardessai.
M. S.; Shah, S. R.; Seahadri.
S. Indian
J.
Chem.
1006.
165. 166. 167.
Bamela. S. B.; Pandit. R. S.; Seshadri, S. Indian J. Chem., Sect. B 1976.148, 665. Bamela, S. B.; Pandit, R. S.: Seshadri. S. Indian J. Chem., Sect. B 1976.14B. 668. Awad, I. M. A.; Hassan, K. M.; Phosphorus, Sulfur Silicon Relat. Elem. 1989,44, 135;
168. 169. 170. 171. 172.
Thiruvikraman. S. V.; Seshadri, S. Indian J. Chem., Sect. B 1984,238, 768. Becher, J.; Olesen, P. H.: Knudsen, N. A.: Toftlund, H. Sulfur Lert. 1986.4, 175. Pawar, R. A.; Rajput, A. P. Indian J. Chem., Sect. B. 1989,288. 866. Egli, R. Ger. Offen. 3,015,121 (1980); Chem. Abstr. 1981.94. 158317j. Tomita, K.; Murakami, T. Jpn. Tokkyo Koho 7,920,504 (1979); Chem. Abstr. 1979.91, 157755b. Senda. S.; Hirota. K.; Yang, G.-N.: Shirahashi, M.; Yakugaku Zasshi, 1971.91, 1372; Chem. Abstr. 1972, 76, 126915q. Cherdantseva, N. M.; Nesterov, V. M.; Safonova, T. S.; Khim. Geterorsikl. Soedin.
Chem.
173. 174.
Absrr. 1990,112,
1983.6,
175. 176. 177. 178. 179. 180. 181. 182. 183.
184.
Chem Absrr. 1983.99,
139895h.
Dehnert, J. Ger. Oflen. 3,603,797 (1987); Chem. Absrr. 1988, 108, 75112. Prajapati, D.; Bhuyan, P. Sandhu, J. S. J. Chem. Sot., Perkin Trans. I, 1988, 607. Lippmann, E.; Strauch, P.; Tenor, E.; Thomas, Ger. (East) DD 264,439; Chem. Abstr. 1989,111, 115203~. Kurasawa, Y.; Takada, A. Heterocycles, 1980,14, 281. Kurasawa, Y.; Shimabukuro, S.; Okamoto. Y.; Ogura, K.; Takada, A. J. Heterocycl. Chem. 1985.22, 1135. Mironova, G. A.; Kirillova, E. N.; Kuklin, V. N.; Smorygo, N. A.; Ivin. B. A. Khim.Geterotsikl Soedin. 1984, IO, 1328. Chem. Absrr. 1985.102, 149205c. Yakovlev, I. P.; Mironova, G. A.; Timoshenko, M. M.; Chizhov, Yu. V.; Ivin, B. A.; Zh. Org. Khim. 1987.23, 1556; Chem. Abstr. 1988,108, 111713~. Mazharuddin, M.; Thyagarajan, G. Tetrahedron Lett. 1971, 307. aSolomko. Z. F.; Proshkina, V. N.; Avramenko, V. I.: Plastun, I. A.; Bozhanova, N. Ya.; Khim. Geterotsikl. Soedin. 1984.9, 1262; Chem. Absrr. 1985,102, 6436t bsolomko, Z. F.; Proshkina. V. N.; Bozhanova, N. Ya.; Loban, S. V.; Babichenko, L. N; Khim. Geterorsikl. Soedin. 1984.2, 223; Chem. Absrr. 1984,100. 209762c. Proshkina, V. N.; Solomko, Z. F.; Bozhanova. N. Ya.; Khim. Geterorsikl. Soedin. 1988, 9,
185. 186. 187. 188.
834;
178773~.
1288; Chem.
Abstr. 1989,111,
39322s.
Nagarajan, K.; Shah, R. K. Indian J. Chem., Sect. B 1976.148, Weissenfels, M.; Kaubisch, S. Z. Chem. 1981, 21, 259. Weissenfels,
M.; Kaubisch,
Aubert, T.; Famier,
S. Z. Chem. 1982.22,
M.; Meunier,
1.
23.
1.; Guilard, R. J. Chem. Sot.,
Perkin
Trans.
I, 1989.
2095.
189. 190.
191. 192.
Lloyd, D.; McNab, H.; Angew. Chem., Int. Ed. Engl. 1976. IS, 459. Lloyd, D.: Tucker. K. S.: Marshall. D. M. J. Chem. Sot.. Perkin Trans. 1.1981. 726. Jut;, C.; Kirchlechner, R.; Seidel, H.-J. Chem. Ber. 1969, 102, 2301. aAmold, Z. Collect. Czech. Chem. Commun. 1961,26, 3051 bArnold, Z. Collect. Czech. Chem.
193. 194.
195. 196. 197. 198. 199. 201. 202.
Commun.
1965.30,
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Kucera, J.; Arnold, Z. Collect. Czech. Chem. Commun. 1967.32. 3792. Kucera, J.; Arnold, Z. Collect. Czech. Chem. Commun. 1967.32, 1704. Arnold, Z; Sauliova, J; Krchnak, V. Collect. Czech. Chem. Commun. 1973,38, 2633. Reichardt, C.; Halbritter, K. Liebigs Ann. Chem. 1970, 737, 99. Hardtmann, G. E. V. S. Pat. 1970; Chem. Absrr., 1974. SO. 3261~. Raju, B.; Krishna Rao, G. S. Indian J. Chem., Sect. B, 1987,268, 175. Naik, H. A.: Pumaprajna, V.; Seshadri. S. Indian J. Chem.. Sect. B 1977, ISB, Arnold, Chem. Commun. 1965.30, 2783. Belgaonkar, V. H.; Usgaonkar, R. N. Tetrahedron Letf. 1975. 3849. Belgaonkar. V. H.; Usgaonkar, R. N. Chem. and Ind. (London) 1976, 954.
3726
C. M. MARSON
203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213.
Raju, B.; Rao, G. S. K. Synthesis. 1987, 197. Mange, A.: Palop, J. A.: Goni, T.; Martinez, A.; Femandez-Alvarez, E. J. Heterocycl. Chem. 1985,22, 1445. Flitsch, W.; Lautenvein. J.; Temme. R.; Wibbeling. B. Tetrahedron Lett. 1988.29, 3391. Kate, T.; Chiba, T.; Okada. T. Chem. Pharm. Bull. 1979.27, 1186. Hirsch. B.; Hoefgen, N. Ger. (East) DD 226,892 (1985); Chem. Abstr. 1986,105, 42647. Coppola, G. M. J. Heterocycl. Chem. 1981.18. 845. Kallury. R. K. M. R.; Devi, P. S. U. Tetrahedron Lett. 1977.41. 3655. Beccalli, E. M.; Marchesini. A.; Molinari, H. Tetrahedron Lett. 1986.27, 627. Beccalli. E. M.; Marchesini. A.; Pilati, T. Tetrahedron 1989.45, 7485. Anderson, D. J. J. Org. Chem. 1986.51, 945. Coates. R. M.; Senter, P. D.; Baker, W. R. 1. Org. Chem. 1982.47. 3597.
Tetrahedron Vol. 48, No. 18.pp.3659-3726.1992 Rited in Great Britain
TETRAHEDRON REPORT NUMBER 312
REACTIONS OF CARBONYL COMPGUNDS WITH (MONOHALO) METHYLENIMINIUM SALTS (VILSMEIER REAGENTS)
Department
Charles M. Marson of Chemistry, The University,
Sheffield,
S3 7HF
(Received 29 October 1991)
Contents 1. Introduction 1.1 scope 1.2 Formation and Structure of Halomethyleniminium (Vilsmeier Reagents) 2. Reactions of Aldehydes with Halomethyleniminium
Salts
Salts
3661 3662
3. Reactions of Ketones with Halomethyleniminium Salts 3.1 General Remarks and Mechanistic Considerations 3.2 Acyclic Ketones 3.2.1 Acyclic Ketones with Two sp3 Carbon Atoms adjacent to the Carbonyl group 3.2.2 Acyclic Alkyl Vinyl Ketones 3.2.3 Aryl Alkyl Ketones 3.3 Saturated Monocarbocyclic Ketones 3.3.1 Unsuhstituted Cycloalkanones 3.3.2 Monosubstituted Cycloalkanones 3.3.3 Steroidal Cycloalkanones 3.4 a&Unsaturated Carbocyclic Ketones 3.4.1 2Cycloalken l-ones 3.4.2 a$-Unsaturated Steroidal Ketones 3.4.3 Benzo-Fused Cycloalkanones 3.4.4 Cycloalkanones fused to Heteroaromatic Rings 3.5 Cyclic Ketones with One or Mom Heteroatoms in the Ketone Ring 3.5.1 Monocyclic Systems 3.5.2 Bicyclic Systems 3.5.3 Polycyclic Systems 3.6 Diketones 3.6.1 Acyclic 1,3-Diketones 3.6.2 Cyclic 1,3-Diketones 3.6.3 1,4- and 1,5-Diketones
3663 3663 3665
4. Reactions of Amidic Carbonyl Compounds 4.1 Amides 4.2 Monocyclic Lactams 4.3 Lactams Fused to Carbocyclic Rings 4.4 Lactams with Benzo-Fusion 4.5 Lactams with Two or Mote Heteroatoms 4.5.1 Five-membered Heterocycles 4.5.2 Six-membered Heterocycles 4.5.3 Seven-membered Heterocycles 4.6 Imides
3698 3698 3702 3704 3705 3708 3708 3710 3713 3714
5. Reactions of Carboxylic Acids
3715
6. Reactions of Esters and Lactonic Carbonyl Compounds
3717
7. Conclusion
3720 3659
3665 3668 3670 3674 3674 3675 3676 3678 3678 3684 3685 3687 3688 3688 3690 3693 3694 3694 3695 3697
3660
c. M. MAILSON
1. INTRODUCTION Scope
I.1
Halomethyleniminium chloride,2
[Me2NCHCll+
generated
in,
the
formylating
activated amide,
frequently The
aromatic typically
potential
rings.
for
‘formylation’ salts
containing
a C=O
linkage
otherwise
inaccessible
compounds
surveyed
and often essential, The reaction
one
as reagents
though
activated
is
well-illustrated
reagent
compounds
to a lesser
of Vilsmeier
produced
extent,
aromatic
nuclei.
in
which
of
when
a
phosgene. reactions536
is by no means their
have
are chiefly
the Vilsmeier
is
methods
(DMF), is treated with an acid
acetone 1. by virtue
e.g.
common
bond-forming
synthesis
of
for, or intermediates
of the most
Vilsmeier
carbon-carbon
in this Report during
A
oxychloride,
salts in organic
halomethyleniminium
best known
reaction,3
NJ-dimethylformamide4
phosphorus
halomethyleniminium Haack-Arnold
e.g. N,N-dimethylchloromethylenammonium
Vilsmeier-Haack
disubstituted halide,
salts,’
Cl-, are perhaps
confined
The
synthetic
value
with
compounds
reactions
of the number
been
of
to Vilsmeier-
of varied,
prepared.
The
those for which enolisation
of and
carbonyl
is possible,
reaction.
reagents
with ketones
containing
methyl
or methylene
groups adjacent to the carbonyl group, reported in the late 1950’s by Arnold and coworkers,798 affords substituted P-chloroacrylaldehydes, such as 2 (Scheme 1). This Report
emphasises
far beyond
the
carbon-carbon
bonds
that the course temperature. somewhat
the
wide-ranging
formylation
of an
to be formed
of such reactions Although
unexpected
Vilsmeier
reactivity5 activated in many
other
can often reagents
transformations,
of Vilsmeier
aromatic
contexts.
be controlled are known
considerable
reagents
nucleus.
which
The Recent
work
by substrate,
to be capable
rationalisation
extends
reagents
allow
has shown
conditions,
or
of a variety
of the
products
of is
now possible. The containing having here:
scope
been (i)
electrophilic aldehydeslO cyclisations compounds
of this
Report
is confined
to the reaction
a C=O double bond with reagents of the Vilsmeier discussed
and reviewed
Vilsmeier-Haack-Arnold formylating (common
agents
products
elsewhere,
will
of organic
type.
not be considered
formylation of activated in general9 (iii) the chemistry
of the reaction
of Vilsmeier
compounds
The following
topics,
in any
detail
aromatic rings3 (ii) of p-chlorovinyl-
reagents
with ketones)
(iv)
involving carbonyl under Vilsmeier conditions * 1 (although such cyclisations will be considered). The importance of g-chlorovinylaldehydes, owing to
their considerable
synthetic
versatility
and generality
of preparation
is worthy
of note.
3661
Reactions of carbonyl compounds with methyleniminium salts
1.2
Formation
and Structure
(Vilsmeier
Reagents)
It is well-known
that inorganic
with NJ-dimethylformamide Haack
reagentstz-15
dehydroxylating
of ffalomethyleniminium
acid halides
(e.g. SOC12, COC12 and POCl3) react
(DMF) to form active complexes,
which
reagents.16
have found
extensive
DMF has been
referred
use as formylating,
to as Vilsmeierhalogenating
and
shown to react with SOC12 at room
1
2
Me,N_+c’ H Me’
Salts
Me,.
-
‘Cl
H
N=C’
Me’
‘Cl xo-
xo-
4
3
a X=POCl, b X=SOCl
Me,+
p
Me,+
N=C, Me’ cl- OP(O)Cl~
N=C,
Me’
,H X
Y6 X=Br 7 X=Br 8 X=1
5
Y=Br Y=OP(0)Br2 Y=I
Scheme 1
temperature
giving a 1:l complex
give the crystalline the latter
complex
[Me2NCHOS(O)CIl+
[Me2NCHCl]+
has been used frequently
Cl- which loses SO2 reversibly
Cl-; both salts have been characterised,l2
in organic
synthesis.
to and
c. M.
3662
The
generally
accepted
representationl7-20
from N,N-dimethylformamide corresponds to the respective phosphoryliminium
chloride
htARSON
phosphate
4a,
Raman
have been
held22 to establish
spectra
Raman
active.
an equilibrium
The alternative
However,
mixture
of those
reagent
derived
thionyl chloride However, the B-
5 has been suggested21 as being more
chloroiminium
DMF with POC13.
of the Vilsmeier
and phosphorus oxychloride or structures 3al4a and 3b/4b.
reactive than the B-
salts
being
generated.
the structure 5, formed in the reaction
of
structure 4a (formed from DMF and COCl2) was not
this claim for structures
other than 4 has been considered
to
be erroneous.1 1 The
mechanism
of
formation
and
the
structures
of
the
Vilsmeier
reagents
(derived from DMF and POC13. SOC12 or COC12) have been studied by 1H NMR23-25 and 3lP
NMR23~24
determined selenophen
and
For
the
commonly although Arnold
spectroscopy.
for formylation generation the
phosgene
of
acid
and thionyl a number
working
are normally
have
and
prepared
agent required.
DMF
usually
use.
is
the
been
amide
phosphorus
most
oxychloride,
As with the Vilsmeier-Haack-
amides
may be used, including
Solvents
commonly
0-lOO’C,
70-80°C
N-
include
employed1 1 are
(e.g. CH2Cl2, CHC13 or CH2Cl.CH2Cl),
iodoformylation
DMF
by
salts,
of DMF27 over N-methylformanilide
in the range
does
not
procedures react
bromide
bromomethylenedimethyliminium treating
the
gaseous HBr or HI, respectively. DMF with either
parameters
in CHC13 of furan, thiophen,
being
or POC13. a satisfactory
1
temperature.1
chloroformylation.
usually
also find
Advantages
Bromoformylation for
activation
is
or aryldialkyl
or chloroalkene
used
employed
chloride
of dialkyl
the cost and weight of formylating DMF, a chloroalkane general
and
halomethyleniminium chloride
phenyl-N-methylformamide.
Temperatures
constants
tellurophen.26
used;
reaction,
Rate
by the complex HCONMe2-COC12
with
are
usually
carbonyl
6 and the analogous
chloromethyleniminium
Salt 8 exhibits
similar
bromide;
to those
the
desired
iodo compound
salt
in
the same properties
8 are
chloroform
with
as the adducts of
POBr3 or PBr3, 28.29 the structure 7 having been proposed
for the latter
adduct. 2.
REACTIONS OF ALDEHYDES WITH HALOMETHYLENIMINIUM The literature
not
extensive.
concerning Arnold
and
(dimethylaminomethylene)butanal workers32
described
an improved
the reaction
of aldehydes
Zemlicka7.30.31 from procedure
with
described
DMF-POC13 (5 1% yield)
SALTS
Vilsmeier
the
and butanal; using
reagents
preparation Barton
of
is 2-
and co-
1,l -diethoxybutane.
Reactions of carbonyl compounds with methyleniminium salts
Aminoformylation conversion,
of
although
I-formylcyclohexene
acetals
react reacts
triformylmethane
Aliphatic
dialdehydes,
intermediates.
and
reagents,
hydrolysis
of
the
malondialdehyde anils.3Ja l3chlorovinylaldehydes35h 3.
with
with
iminium
rapidly
Dimethylaminoacrylaldehyde (84%).34
proceeds
with
DMF-COC12
Phenylacetaldehydes
in
upon
reaction usually
General
Remarks and Mechanistic
The reaction extensively explored, No unambiguous
R’ /v CH;
although R2
HCl =
Pa
Vilsmeier
arylamines,
lead
to
the (E) -
SALTS
Considerations
course for the reaction
of ketones
the mechanisms of these processes OH 0 DMF-l’OCla R’ +
with Vilsmeier which usually
’
DMF-I’OC13 I
Cl
R’
A -
14
with
ggiving
predominantly
11 R2
Cl
10%
salts.33
chloroform
with
afford
than
of Vilsmeier reagents with simple enolisable ketones has been unlike the action of Vilsmeier reagents on a-hydroxyketones.36
mechanistic
has been developed, 0
less
reaction
REACTIONS OF KETONES WITH HALOMETHYLENIMINIUM 3.1
3663
13 Scheme 2
R’ 12
NMe2 +
2HCl
reagents involve
c. M. htAR.WN
3664
chloroformylation the ketone the
fact
Scheme
have been
enolises that
only
2 outlines
Electrophilic oxygen
atom
substitution
of
the source
prior to reaction sufficiently a currently attack ketone
9a
nucleophilic accepted
by
speculation.
the
alkenes
reaction
Vilsmeier
slowly
forms
of salt 10 by the Vilsmeier
The key role in this reaction
of much
with the Vilsmeier
reagent; are
Arnold7
suggested
that
this is consistent
with
formylated
by
this
reagent.
mechanism.* reagent
salt 10
reagent
on and
the HCl
weakly
carbonyl
2).
Further
(Scheme
to give the dication
is thought to be the liberation
basic
12 is improbable.
of HCl during
the conversion
of ketone 9a into salt 10. HCl catalyses the equilibrium between tautomers 9a and 9b; the latter undergoes rapid substitution by the Vilsmeier reagent giving the P-N, Ndimethylaminovinylketone may formylate autocatalytic
11 which is isolable
the enol 9b giving acceleration
11.
ketone
of the reaction
in certain cases. With increasing
is observed.
Reaction
Additionally, concentration of ketone
salt 10 of HCl,
11 with the
Vilsmeier reagent gives the labile bisiminium chloride 12 which readily collapses to the iminium precursor 13 of the g-chloroacrylaldehyde 14. The perchlorate analogues of salts 13 have been isolated
in very high yield. 37
In the chloroformylation Cl
0
DMF-FOCI, * 16
15 0
Cl R2
DW-POQ,
OHC
R*
Cl
0
23 X=O,S Scheme 3
of enolisable
3665
Reactions of carbonyl compounds with methyleniminium salts
ketones,
molar ratios of iminium
with or without exothermic
to ketone
are frequently
between
of induction
is frequently
observed
4:l
and 5:1,
prior
to an
reaction.
Chlorotrienes3*-41 dienones) which
species
A period
a solvent.
(obtained
can be converted
are
derived
from
during
the
by the Vilsmeier the
steroidal
chloroformylation
reagent
dienones
of
some
steroidal
into the same chloroformyltrienes
themselves.
However,
it
appears
are the primary intermediates in the process of unlikely that chloroalkenes chloroformylation; Arnold showed that a-chlorostyrene does not react with Vilsmeier reagents.7 Typical acyclic
patterns
of regioselectivity
monosubstitution
ketones,
for ketones
generally
are illustrated
favourslc
in Scheme
the regioisomer
3.
For
16, a course
predominantly governed by the relative thermodynamic stability of the two possible enol intermediates. However, a,a-disubstitution is found to block formylation at the asite so that only the aldehyde Karlsson
and Frejd42
only a moderate
and that is usually
have shown that the methyl
effect on the regioselectivity
The usual product further formylation
of monoformylation is sometimes
the sole product.
group of 3-methylcyclohexanone
has
(20:21=10:90). of ketones
can arise only if deprotonation,
Polyformylation
is possible.
18 can be formed,
is the salt 13 7*37(Scheme
involving
observed
(e.g.
2);
the R* group of the cation, as for cyclopentanone,
section
3.3.1). 3.2
ACYCLIC KETONES 3.2. I Acyclic Ketones with Two sp 3 Carbon Atom
adjacent to the Carbonyl
Group. Many converted
methyl
by Vilsmeier
are well-covered of the ketone employed reaction
as well
ketones,
reagents
in previous
to control
and
cyclic
3-haloacrylaldehydes
reagent
the exothermic,
(2.5-5
es.),
and sometimes
methylene
(Scheme
reviews. 1~4~10 The usual procedure
to the Vilsmeier
has subsided,
into
as acyclic
violent
reaction.
slow addition
Solvent
is usually
After the initial
the mixture
neut’ralised by cold aqueous
may be heated, prior to being quenched with ice and B-Haloacrylaldehydes sodium acetate or sodium carbonate.
of low molecular mass are lachrymatory oils which decompose spontaneously Acyclic g-bromoacrylaldehydes2g are few hours, sometimes violently. preparable
are
4); these reactions
involves
with cooling.
ketones,
from complexes
of DMFPOBr3.
within a generally
3666
c. M.
0
Vilsmeier
R*
R’
MARSON
-
R’(CW reagent (E)-14b
(Z)-14a
In
the
simplest
formation
of a mixture
afforded
3-chlorobut-2-enal
Scheme 4 monochloroformylation
cases,
14a
of the (Z)-isomer
occurs,
and
usually 14b.
and the @)-isomer
in 39% yield. 7 However,
acetone
and methyl
with the Acetone
ethyl
ketone,
derivatives.43 with the DMFCOC12 or DMF-POC13 complex, can give triformyl Formylation usually occurs at the more substituted a-carbon atom, giving, for example, the aldehyde
25 (Scheme
5-methylhex-2-enal
5).7
However,
27 predominantly
4-methylpentan-Zone
as the (Z)-isomer44
gives
chiefly
3-chloro-
owing to the steric bulk of Cl
i)DMF-POCls, 60°C ii) NaOAc, H20
24
0
-+
CHO
25
nr
H
Vilsmeier reagent
26
27 Scheme 5
I 28
DMF-POC13
0
cl 30
29 Me2 NaOH
i) 3 h, 65 “C, CHCls CI-INMQ
ii) NaC104, H20 31
0
Cl ClOi
50%
Scheme 6
32
+HX
3661
Reactions of carbonyl compounds with methyleniminium salts
the isopropyl subsequent iminium
Isopropyl
group.
deprotonation species
giving
the pentadienal Related
7).46
the substitution, gives
a
units)
and
and
mixture
hence
hydrolysis
a tetrasubstituted
methoxy-3-methylisoquinoline
HX i
(derived
compounds
ph6ph
Hz0 + 37
atom, but
attack
by the
acetoacetate
gives
containing
(Scheme
depending
Phenylacetone
ring. from
product 35 ring-closure
salt 37
or pyrimidines,
3-methoxyphenylacetone
benzene;
36
Methyl
of the pyrylium
of the benzene
pyrimidines
and three
MIl&ph
6).
further
R2=C02Me).45
isoquinolines
the reactivity
substituted
allows
only a double formylation, the to be formed by a 6x-electrocyclic
can afford either
of
atom
salt 31 (Scheme
and subsequent
35
ketones
28 reacts at the methyl carbon
carbon
the (Z)-form, 14a (Rt=Me;
ketone 33 undergoes 38 being considered
Dibenzyl diphenyl-4-pyrone
ketone
methine
the trimethinium
only one isomer, apparently
of
methyl
at the
upon itself
chloromethyleniminium gives
a mixture
a pyrimidine
of 6-
ring.47
-_&ph
X 38
Scheme 7 In 1968, Koyama cr-acyl-a-arylacetonitriles Scheme
8).4s
revealing Vilsmeier into either
that
and co-workers reported a synthesis of isoquinolines Vilsmeier 39 and formamide-POC13 (modified
The formation
of isoquinolines
MeCONH2-POC13
reagent
was
isoquinolines
shown49
pyrimidines
was further
can afford 4-(3H)-pyrimidinones.
However,
to convert
or naphthalenes,
versus certain
depending
alkoxy-substituted upon
the substitution.
40 from reaction; studied:9 the same
acetophenones
3668
C.M. MARSON
CN
CN
R
H*NCHO, POCls
Me0 40 R=H, Me, Et, Ph Scheme 8 Acyclic
3.2.2 Methyl
Alkyl Vinyl Ketones
propenyl
ketones
dimethylamino-3-penten-2-one
including
afford
the
3-penten-2-one, respective
mesityl
oxide
and
4-
43a, 43 b
isophthaldialdehydes
and 43c.50.51 For the related reaction of the methyl ether of acetylacetone, the formation of 3-chloroanisole (42%) can be rationalised by assuming a 6x electrocyclic ring-closure. unsaturated reactivity,
The simplest ketones
is
and the steric
one to five carbon may be formally
44
explanation
a ring-closure demands
atoms derived
represented
x-
of the formation of
associated
a
1,3,5-triene,
which,
with its substituents,
from the Vilsmeier
as iminium
of arenes
moieties
45
Scheme 9
reagent,
(Scheme
3x-
9).
from
acyclic
depending may
of which
contain
a,Son
its from
zero to three
3669
Reactions of carbonyl compounds with methyleniminium salts
Extensions unsaturated mono-,
to
the
allcenones
di-,
illustrative.52
and
above
have
been
of
iminium
by Vilsmeier
reagents
of
into
2-hexen-4-one
chlorobenzene lo).53
54 are formed 54 by the action of DMF-POC13 on the salt Acetylferrocenes
salts 55 and 56.57
react
converted
The reaction
with aqueous
of a formyl
with Vilsmeier
perchlorate,
into
at the methyl at 0°C giving
Benzylideneacetone
of DMF-POC13
coloured,
with crotonophenone
the salt 57 (65%) (Scheme
11).5s
CHO
reagent
’
group reagents
the respective
Vilsmeier
-p
Cl
=I 48 CHO
47 i) DMF-POCls RCH=CHCOMe
*
RCH=CH-CClX!H-CHO
ii) HC104 iii) NaHCOs
49 R= C6F5, C6H5
a.P-
47 into 48 is
49 reacted giving 50 and 51 (Scheme
are smoothly
0L
Several
reported.
2-formyl-l-chlorovinylferrocenes.55.56
cinnamylideneacetone after treatment
been
the lack of introduction
atom is notable. yields
have
Conversion
Benzalacetophenones
2-Acyl-Gaminofulvenes
high
converted
tri-carboxaldehyde.
53 of acetylcyclopentadiene; carbon
ring-closures
50
+
RCH=CH-C(NM~&C!HGI+NMQ 51
Cl0;
Scheme 10 i) DMF-POQ t Na+
Na+
52
53
ii) 3 NaOMe 93%
Cl PhwNM,
Ph&:M% ClO;;
~2C12
57
55 n=l 56 n=2 Scheme 11
and
crystalline affords,
c. M. MARSON
3670
3.2.3
Aryl
Alkyl
Simple acetophenone
Ketones
aryl alkyl ketones and propiophenone
respectively).718 30%.59
However, yields from p-substituted
A
recent
cinnamaldehydeseu DMF-POC13, affords
usually give the chloroformylalkene afford the b-chlorocinnamaldehydes
followed
a mixture
DMF-POC13
procedure
for
from aryl ketones by cooling 12).61
preparation
involves
addition
and treatment
of diastereoisomeric
(Scheme
the
acetophenones of
substituted
with aqueous
NaOH. upon
a Vilsmeier-Haack
DMF--7W
Phqph
+
below
dihydroof
Desoxybenzoin treatment
reaction
(dimethylamino)-desoxybenzoins 61 did not give the anticipated but instead 4-(dimethylamino)-a-halostilbenes 62.62
Ph
are typically
at 70-8O’Y! to a mixture
P-chlorovinylaldehydes
However,
in good yield: (47% and 90%
using
with p- 4-
chloroformylstilbenes,
PhqCl
Ph CHO 60 10%
CHO 59 50%
58
DMF-POQ
62a X=Cl 62b X=Br Scheme 12 Diacetylbenzenes
undergo
diformylation:
when
DMF-COCl2
is used as the
Vilsmeier reagent, a mixture of CHC13 and CH2Cl2 as solvent gave excellent yields of 63 Bis- and tris-(P-chlorovinylaldehydes) 8,8’-dichloro-m-benzenediacrylaldehyde. were
formed
from
1,4_diacetylbenzene
3,4-Dimethoxyacetophenone
and
1,3,5_triacetylbenzene
respectively.52
63a can undergo both mono- and di-formylation,64 Other 63b (Scheme 13). whereas the indene 65 is formed 65 from propioveratrone chloroindenes 67 have been prepared 66 by the action of Vilsmeier reagents on aryl benzyl
ketones.
3671
Reactions of carbonyl compounds with tnethyleniminium salts
MJ@-JJb~=JyyM~~?@J$ HCl -
cl-
63a R=H
NMe2
65
63b R=Me R=H
i) DMF-IQC13 ii) NaOAc. Ha0 I
R’=R2=OMe, R’=H, R2=OMe, F. Br, Cl Scheme 13
OR
HO 68 69 Scheme 14 In Scheme Vilsmeier presumed
14, initial
reagent to occur,
acetophenones
on
the
prior
cyclise
attack on oxygen cannot be excluded, enolised
methylene
to cyclisation in
good
yield
with
group loss
giving
of the
to
give
although
intermediate
methylamine. valuable
attack by the 69
is
o-Hydroxyintermediates,
3-
3672
c. M. h4ARsoN
formylchromones.67-69 phenoxychromones
are
phenoxyacetophenone phenoxychromone hydroxyl
Related catalysed
derivatives derivatives
cyclisation of acetophenone derivatives giving Cyclisation of 2-hydroxyby BF3.OEt2.70
by the Vilsmeier has
been
group has been considered
reagent, catalysed by BF3.OEt2, to 3reported. 70.71 In these cases, initial attack on the
more likely (cf. 72; Scheme
72
71
Vilsmeier reagent
3a-
73
X-
t
R-bkMeZ
74
15).
R-&O
X
75 Scheme 15
Appropriately
substituted
naphthalenes
and
coumarins
react
similarly.67-69
A
variation involves conversion of the 1-acetyl-2-hydroxynaphthalene into a difluoro- 1,3,2dioxaborin with BF3.OEt2, and subsequent formylation, by which the phenalenone 77 can be generated, chloroformylation formation
as well of
as the
expected
I-acetonaphthone
of the same aldehyde
80
chromone 79,
78
migration
as that obtained
(Scheme
During
16).72J3
of the acetyl
group
from 2-acetonaphthone
occurs,
the with
81 (Scheme
17).74
CHO
CHO
76
77 Scheme 16
62%
78
20%
3673
Reactions of carbonyl compounds with methyleniminium salts
79
80
81 Scheme 17 T
82
83
R=Rl=OMe R=H, R’=OMe, OEt, NEtz Scheme 18 A versatile of
the
synthesis
of benzofurans
phenoxyacetophenones
acetylpyrroles
under
chlorovinylpyrroles methylpyrrole
82
Vilsmeier-Haack such
as
83 was accomplished
(Scheme
Treatment of conditions afforded
reaction
84 (Scheme
gave the acetylenic
aldehyde
by the Vilsmeier
l8).75
19).76
Vilsmeier
formylation
85 (34%).77
I
I
il
il
84
85
0
Cl
DMWOC13
f
-
86 Scheme 19
I @ 87
33% CT-IO
reaction
polysubstituted 3the corresponding of
3-acetyl-4-
C. M. h’fARSON
3674
3.3
Saturated 3.3.1
Monocarbocyclic
Unsubstituted
Ketones
Cycloalkanones
P-Chlorovinylaldehydes
are
the
most
abundant
of
the
P-halovinylaldehydes
Vilsmeier reagents, although Arnold and Holy78 showed that prepared using cycloalkanones of five- to eight-membered rings are converted into the corresponding gbromoacrylaldehydes were reported
by DMF-PBr3 complexes.
by Ziegenbein
The corresponding
P-chloroacrylaldehydes
and Lang.7g
0
M
i) DMF-POC13 -Me&+?
zy’
WO+NMez
,, ii) NaC104, Hz0 89 n=l
88
90
t 92
91
93
94
95
Scheme 20
96
3675
Reactions of carbonyl compounds with methyleniminium salts
Cyclobutanone
86 affords the S-chlorovinylaldehyde
87
(Scheme
19).37
No other
product
was reported, even when an excess of formylating agent was used. With DMFcyclopentanone was converted into 2-chlorocyclopentene1-carboxaldehyde POC13, (54%),su
the reaction
Vilsmeier
reagent,
for cyclohexanone
followed
chloropentamethinium could
cyclopentanone aqueous
using
with
illustrates
aqueous
analogously.79.81
of sodium
perchlorate
Work-up
20). carbonate
is evidently
the
important from
afforded
hydrolysed
observations certain
the bromomethyleniminium
afforded
of the reaction the
of
Vilsmeier
effectively
reactions.
salt afforded
salt
the 3-
derivative
mixture
91,
from
which with hot
to 92 and DMF, since a mixture of
95 and the amino ketone 96 is obtained.37
obtained
A large excess of the
solution,
which in the case of the cyclohexanone
Scheme
potassium
carbonate
aldehyde
intermediates
89 (n=l).
to 90 (n=2;
potassium
the amino 96
salts
be hydrolysed
proceeding
by addition
a small
The conversion
of 91 into
thermal deformylations of The reaction of cyclohexanone
quantity
of the doubly
substituted
are formed when cyclopentanone and aldehyde 9 4 .29 The conjugated salts 93 cyclohexanone react with formanilide-POC13. 33 The formation of pentamethinium salts is controlled unit
by the number
are available
compounds
might
deprotonation
Monosubstituted
Cycloalkanones
The
regiochemistry
in
group,
has been a ‘J-methyl
reagent,
present
possessing
methylcycloheptanone the 4-methyl
the
reaction
explored.
substituent
case (Scheme
under
more
little
Karlsson
has
a large
in the cases of six-, seven-,
the five-membered being
and its stability
undergo
3.3.2
Vilsmeier
No other sites of the pentamethinium evidently
prevents
and
hence
further
of
unsymmetrical
isomerisation reaction
into
with
the
reagent.
cycloalkanones small
groups present.
for formylation,
which
Vilsmeier
of alkyl
21).
Vilsmeier-Haack
conformational gave a 1:l
steric
conditions.
mixture
influence
exhibit
mixture
Interestingly, greater
that a relatively
on the rings,
of enols
attack
of the
although
not for
was proposed
the larger
regioselectivity.
of the regioisomers
on the regiochemistry
monosubstituted
showed
and eight-membered
An equilibrium
mobility,
group has little influence
and Frejd42
101 and 102,
of the reaction.
rings,
as
despite
However, showing
4that
C.M. h'iARSON
3676
n=l
60
40
-43
n=2
90
10
52
n=3
95
5
42
n=4
100
0
56
101 50
48%
Scheme 2 1
3.3.3
Cycloalkanones
Steroidal
3-Keto-Sa-steroids thus
afford
the 3-chloro-2-formyi-2-ene
17-acetoxy-Sa-androstan-3-one,
and 5a-pregnan-3.20-diones4 (22-27%) (Scheme
22).
acetoxy-4,4-dimethylandrost-5-en-3-one dimethylandrosta-2,5-diene
with DMF-POC13;
82 17P-acetoxy-l7a-methyl-5a-androstan-3-one,*3 give
The
derivatives
the corresponding
reaction
proceeds
3-chloro-2-formyl
with 4,4-disubstituted
derivatives precursors:
104
17p-
17@-acetoxy-3-chloro-2-formyl-4,4affords (62%) from a reaction with DMF-POC13 at 50-60°C for 4 hours.
Reactions of carbonyl compounds with methyleniminium salts
3677
i) DMF-POClsin DMForCHC!l=C!C12 60°C,3-4h ii) Ha0
OAc i) DMF-POCls, 20°C 0.2 h ii) NaHCQ, Ha0 OAc
106
OAc
HO
107
Scheme 22
The regioselectivity of formylation in ring A is markedly influenced by the relative configuration of the A-B ring junction. Thus, the Sg-androst-3-ene 108 is converted into the 3-chloro-4-formyl derivative 109; 28182 the use of acetyl chloride as the solvent is unusual. Chloroformylation of a steroidal ketone having the carbonyl group at a position other than C-3 usually affords the corresponding g-chlorovinylaldehyde. Thus, 38hydroxyandrost-5-en-17-one
3-acetate
110
is chiefly
converted
with the chloroalkene 111 b being formed as a by-product homosteroidal ketone has been converted by DMF-POCI3 into 112.85
into the aldehyde
llla,
(Scheme 23). A Dthe chlorovinylaldehyde
3678
C. M. MARSON
OAc
llla R=CHO 69% lllb R=H
Me0
Scheme 23
3.4. u&Unsaturated Carbocyclic Ketones. 3.4.1. Of the
2-Cycloaiken-l-ones 2-cycloalken-l-ones
are the most common. The formylmorpholine (NFM)-POC13 which
upon
hydrolysis
25OC for several
gave
reacted exothermic
with
Vilsmeier
reaction
in trichloroethylene
the somewhat
weeks, aerial oxidation
unstable
afforded
of
reagents,
2-cyclohexen-l-ones
2-cyclohexen-l-one
at 20°C afforded dialdehyde
the trialdehyde
123;86 upon 124.
with
N-
a deep red mixture keeping
at
Reactions of carbonyl compounds with methyleniminium salts
3679
117 H+
;W
H
R2
Cl
2
+=H)
124
Scheme reaction
of
cyclohexane-
123
24 provides the
a pathway
1
H20 (&Cl)
12Sa R=Me 12Sb R2=( CH,), Scheme 24 which unifies
3-substituted-2-cycloalken-l-ones
1,3-dione
113d
is discussed
in section
the experimental
(R2=H or Br)
H20
126
observations
or the
113a-113c with Vilsmeier reagents; 3.6.2. There is substantial evidence
C.M. hhRSON
3680
for the involvement
of an enolic
intermediate
than the enol, X=H, or a phosphate
derivative).
of the reaction
apparently
do not involve
the form 121,
stabilised
by extensive
hydrolytic
work-up.
dialdehydes (Rl=H)
125
For the (section
is more susceptible
which is remarkable
delocalisation,
113a-113c,
is considered
to nucleophilic
for 2-cyclohexen-l-one,
intermediate
to be present hydrolysis
129
128 -HCl
I
I
&$.$$;
131
&O
Rl:$l
Cl-
0 Y
0 i) Cl-displacement ii) hydrolysis R
\
Cl ‘I b
CHO 13 2 R=Me, Et, n-Pr, i-Rr Scheme 25
the 12 1
123 is formed,
tautomer.
(y __ml._&+ &NO 127
of
prior to
affords
the intermediate
attack, and the enolic dialdehyde
over the benzenoid
rather
the early stages
A common
113 b and 113d. partial
whereas
for its stability
For ketones
the C=C double bond.
ketones
3.6.2),
114 (in which X may be CH(Cl)NR2
3681
Reactions of carbonyl compounds with methylenitninium salts
For
2-alkyl-2-cyclohexen-l-ones,
evidently
involved
alcohols
because
intermediates
hydrolytic
133 (R#H) are also formed.
observations.
The presence
confirmed
by
alkoxy
the
ethers
allylic
Vilsmeier 133
affords
the
the
species, possibly
reaction
(Rl=alkyl)
mixture
were
fll
“z-_
134
with
132.
The allylic
whereby
The above from
was the
mechanistic
4,4-dimethyl-2-
“nIHNR;z-_
t
136
Hzo
13’
are
with current
alkoxide,
139
1 +NRa X-
-3
137
(~1 =H)
128 or its equivalent,
obtained.87
Nu-
135
NgHNRT
116
aldehydes
features are compatible with the formation of the dialdehyde cyclohexen-l-one 134 and NFM-POC13 (Scheme 26).87.8s
Do
form
Scheme 25 shows a pathway consistent
of a cationic
quenching
corresponding
work-up
of
&Co
t
139
+NR,
29% Scheme 26 A unified lacking and
a methyl
its
(Scheme exocyclic
pathways7 group
5-substituted 28).
148,
thermodynamically Isophorone large excess
derivatives
Although
alkene
several
favoured
an 80% yield of a mixture chlorinated
over
154.
entirely
27.
involving
2-cyclohexen-l-ones
For 3-methyl-2-cyclohexen-l-one
different
Y=Cl
alkenes
their endocyclic
course
analogous isomers
to 148
followeds7-89 moiety
in the
are known
to be
149.
with 2 equiv. of the Vilsmeier iminoalkylation
is
or an oxygenated
to give
reagent,
but with a
the polymethinium
species
during hydrolysis into the 4H-pyran 153 (Scheme 28).87.*s If 151~ with DMF-POC13 (2 equiv.) is quenched after 15 minutes of three chloro-dienes
of (E)- and (Z)-isomers
aldehyde
an
whether
exocyclic
undergoes
processes
in Scheme
147
147~ affords 151cgu
of the reagent
a mixture
typical
it is uncertain
152, which is converted, the reaction of isophorone 151c,
illustrating
at C-3 is given
is obtained.88
was obtained.
From the aldehydes
(IS)-(-)-Verbenone
afforded
151athe
C. M. MARSON
3682
Trialdehydes prepared
146
have been obtained by the Vilsmeier reaction of cyclohexenones The trialdehyde 156 was formed from cyclohexenone in a
by Birch reduction.
Vilsmeier
reaction,
and the dialdehyde
155
from
4-methyl-2-cyclohexen-l-one.91
::I$tE+ ::$?(RlzM:zR 132a
141
140 R2
~~~~~~
R2
I;&
NR2
R’=R’=H $g;
R2=i-F’r
PI
H20
Cl
I1 CHO
OHC
,
R3
’
CHO I
Q
CT-IO
146a R3=OEt 146b R3 =Et Scheme 27
3683
Reactions of carbonyl compounds with methyleniminium salts
goDm--3* gy - -
gy 149
148
147a R’=R’=H
147b R’=H, R’=Me 147~ R’=R’=Me
H20 I
H Cl OHC
151a R’=R’=H 65% 151bR’=H, R*=Me 73% 151~ R’=R’=Me 80% CHO OHCV
fiCo
154
oHc &rHo
155 Scheme 28
156
3684
c. M. bfARSON
3.4.2
a,/MJnsaturated
There
have
Unsaturated
been
steroidal
few
papers
component.
inert
afforded
158b
29).93
Whereas
in this
the corresponding
area
since
and 158~ in equal amounts, enolisation
Vilsmeier
to
methyl
able
attack
of the 3-oxygenated
group
reviewed.r.7
prevents
3-0x0-1,4.6-trienes
further
the
C-4
function reaction
and
a,p-
the
gave
the
157
gave
158a
(Scheme
the
as the first step,93 both for
only in the latter
C-6
by chloride. of
acetate
to the chlorodiene
of the 3-0~0 group was postulated and for the 19-nor-compounds.
displacement
last
19-nortestosterone in addition
the 19-methyl-foxo-enes reagent
it was
3-chloro-3,5dienes;
However,
3-chloro-1,3,5,7-tetraenes.92 aldehydes
Ketones
ketones usually afford a mixture of products of which the halo-diene Thus, 3-oxo-4-ene steroids when heated with DMF-POC13 in an
is the major solvent
Steroidal
series
positions,
prior
The steric
hindrance
3-halo-3.5dienes
with
to
was the
subsequent of the 19-
the
Vilsmeier
reagent. OAc
OAc
o&
;~~:~cl@ R’ R2 158a Rr=R’=H 158b R’=H, R’=CHO 158~ R’=CHO, R2=H
157
Scheme 29
A series
of
steroidal
chloro-2,4,6-trienes
160a,
4,6-dien-3-ones
afforded
with
DMF-POC13 160b,
3-chloro-2-formyl-2,4,6-trienes
and
a mixture
of 3-
3-chloro-3,5,7-
trienes 161 (Scheme 30). The steroid 160a is implicated as an intermediate since it was converted by DMF-POC13 into the aldehyde 160b. 39 In the cases of 17P-acetoxyoestra4,6-dien-3-one
162a
and
17-acetoxy-l9-norpregna-4,6-dien-3,2O-dione
162b,
the
are accompanied by the aromatic expected aldehydes 163a and 163b. respectively, dialdehydes 164a and 164b, formed by oxidation. 39 3p-Acetoxy-5-ene-7-ketosteroids 165
eliminate
acetic
acid
under
Vilsmeier
conditions
giving
the
3,5-dien-7-ones
166
Reactions of carbonyl compounds with methyleniminium salts
which
are
Formylation
then
converted
of triene
attack by Vilsmeier
167a
reagents
into
a mixture
of
chlorinated 167b.38
gives the aldehyde
3685
167a
steroids
and 16 7 b .
3-Alkoxy-3,5-dienes
undergo
at C-6 only.94
DMF-POQ
160a. R’=H 160b, R’=CHO
161
15%?
162a 162b
164b
167b, R’=CHO
Scheme 30 3.4.3
Bento-Fused
Benzo-fused
Cycloalkanones
cycloalkanones
corresponding
chlorovinylaldehydes
Under
conditions,
normal
chlorovinylaldehydes heterocycles.95-98
formylation
are usually
converted
in good yield
by Vilsmeier
and under
of the aromatic
have been used in the synthesis
reagents
mild conditions
ring does not occur. of a wide variety
into
(Scheme
the 31).
The resulting
of polycondensed
c. M.
3686
I-Indanone,
a -tetralone
and
MARSON
benzosuberone
afford
the
corresponding
chlorovinylaldehydes 168a, 168b (77%)7* and 168~ (75%)59 respectively. Derivatives a-tetralone with alkyl groups on either ring afford the expected fi-chlorovinylaldehydes 169.97 present.
No aromatic formylation g -Tetralones usually
carboxaldehyde more readily corresponding
pof
is observed even when 6- or 7-methoxy groups are 2-chloro-3.4-dihydro1 -naphthalenegive the
derivatives [e.g. 170 is formed99 (44%)]. although these decompose much afford the than the isomers such as 169.100 Some g-tetralones The reaction of fl-tetralone 2-chloro-1,3-naphthalenedicarboxaldehydes.
with HCONH2-POC13
168s n=l 168b n=2
168c n=3
afforded 5,6-dihydrobenzoV]quinazolineluI
il 169a R’=R*=H 169b R’=Me, R*=H
169~ R’=H, R*=Me
Scheme 31
in very low yield.
3687
Reactions of carbonyl compounds with methyleniminium salts
Acenaphthenone
with
DMF-POC13
in trichloroethylene
the aldehyde
affords
17 1 a
Other ketones (80%) (50°C. 3 h);79 the methyl derivative 171b was similarly obtained.97 of the a-tetralone type have been converted into the corresponding aldehydes 174-177. The
conversion
probably Using
of
anthrone
the earliest
reported
Vilsmeier
which afforded
172
methodolgy,
the
a convergent
salt 180 (Scheme
into
example
IO-chloro-9-anthracenecarboxaldehyde
of a ‘chloroformylation’
diketone
178 was converted
and unambiguous
173 is
of a methylene into
ketone.102
the dialdehyde
route to the intricate
macrocyclic
179
pyrylium
32).95
178
179
Scheme 32
3.4.4 Cycloalkmonesjbsed to Heteroaromatic Rings The
aldehyde
18 1
indazolecarboxaldehyde reagent
on
the
corresponding
tetrahydroindazoles disubstituted, ketone
183 The
quantities
183
but
the
(Scheme
prepared
from
was also directly ketone.103
were investigated.
chlorovinyl
ketone
the
corresponding
prepared A
ketone.97
The of a Vilsmeier
by the action
number
of
other
4-0x0-4,5,6,7-
Aldehydes were obtained when C-6 was not 184 was formed from the 6,6-gem-dimethyl
33).104
Vilsmeier of aromatised
major products
was
182
(Scheme
formylation
of
products
187,
33).lus
I-ketotetrahydrocarbazoles in addition
185
gave
to the chlorovinylaldehydes
appreciable 186 as the
3688
C. M. htARSON
The four
benzo[b]thiophen-4-one
products
carbonyl
189-192,
188
which
reacts
demonstrates ring (Scheme
group and the thiophene
with the Vilsmeier-Haack competition
181
between
reagent
formylation
giving of
the.
34).106
6
182
184
183
R2np -$%Lp:o~NMe2 0
Cl 186
18Sa R’=H, Me
187
185b R2=H, Cl, Br, C02Et
Scheme 33
3.5
Cyclic Ketones with One or More Heteroatoms in the Ketone Ring
3.5.1
Monocyclic
The containing
principal either
formylthiophenes dependent.107 Vilsmeier intermediates
Systems
reactions a
sulphur
are or
of an
fiveoxygen
and atom
six-membered in
the
ring.
heterocyclic
ketones
Aromatisation
to
Vilsmeier reaction of the keto-ester 194 is temperatureis typical. Some 4-oxo-4,5-dihydrothiophenes 196 have been convertedlo* by
reagents
into
4-chloro-5formylthiophene
in the preparation
of thiophene
derivatives
azo dyes (Scheme
35).
197 which
are
key
c. M.
3690
MARSON
0
Cl DMF-POCls CHCl=CHcl~ 20°C
CHO
24h
22a, X=S 22b, X=0
23a X=S, 52% 23b X=0,44%
0
Cl CHO
DMF-POCls
R 200 R= H, 30% 201 R=Ph, 40%
R 198, R=H
199, R=Ph
&HO &HO 202
203 Scheme 36
3.5.2
Bicyclic Systems
The
reaction
of
3-coumaranone
with
formylbenzo[b]furan 202.t1 1 The aldehyde 203 3-methoxybenzo[b]thiophene with DMF-POC13. The action
of DMF-POC13
the g-chlorovinylaldehyde formylthiachromone involving
oxidation
was
is efficiently
on thiochroman4-one
exclusively 206
DMF-POC13
at temperatures
formed
by the Vilsmeier
in
reagent
205 below
appreciable was tentatively
gave
3-chloro-2-
prepared112
by reacting
was shown59,109 to afford 50°C
quantity.109 proposed
but
at
lOO“C, 3-
A mechanism (Scheme 37).
Cl DMWOCls CHCl=CCla 22’C, 22h 204
205 Scheme 37
206 29% +204 40%
3691
Reactions of carbonyl compounds with methyleniminium salts
The
reaction
expected
of
aldehyde
chroman-4-one
208
207 59*tug being
(chloromethyl)chromone
is
obtained
also at
temperature-dependent,109 The
35°C.
the
formation109
of 3-
209 at 100°C is thought to proceed by isomerisation
to a 3-
cation 213 (Scheme38).
(chloromethyl)benzo[blpyrylium Cl
209
20736%
48%
cl CHCI
00
\+
ti\
cl-
0
212
+H&Me2 Cl-
A
208 I
209
-
210
213 Scheme 38
The
reaction
the importance
of substituted
of intricate
3-carboxaldehydes ones,59.113
but
can
be
a single
2,116,117
formylation
although
dimethyl-2H-chromene steric
and
electronic
dimethylchroman-4-one
from group
is
effect
sufficient
effects
many
derivatives
has
C-2
reagents
illustrates
with ketones.
4-Chloro-
unsubstituted to block
the 4-chlorochromene
is also usually
prevented
of a 7-methoxy
group,
to promote
operating
Vilsmeier
reactions
is sufficient
114 affords of chromenes
the electronic
with
in Vilsmeier
obtained 2-methyl
Methoxy-2-methylchroman-4-one The Vilsmeier
chroman-6ones
steric effects
during been
Vilsmeier
studied.* 15
7-
in high yield.1 15 by substitution
if introduced
6-formylation.117 the
chroman-4-
3-formylation.
at C-
into 2,2-
The interplay formylation
of
of 2,2-
The high degree of solvation
3692
C.M. hiARSON
of the Vilsmeier reaction
reagent
particularly
in the mildly
susceptible
2,2-Dimethylchroman-4-one corresponding
yield of the latter; the
derivatives 39).
2 14
Prolonged
formylation
chlorocarboxaldehydes
by formylation
normally
employed1
gave
high
215 and only a small quantity
216 (Scheme instead,
solvents
216
renders
the
effects.
4-chloro-ZH-chromenes
chlorocarboxaldehydes that
polar
to steric
reaction
of
The results
of 215,
the
(or none) of the
times did not increase
at C-6 of 215 occurred. arise not by formylation
yields
but
the
indicate
presumably
of an enolic precursor.
215
216
Scheme 39
Flavanone
affords the aldehyde
3-formylcoumarin heterocyclic heterocycles
218
has
aldehydes containing
also
217l1* when treated been
and 219b
219a a carbonyl
group
Vilsmeier reagents are rare. 2,3-Dihydro-lZf-pyrrolizin-l-one 222.
depending
detected, converted
on the reaction
and it is surmised into
chloroalkenes,
217
prepared119 have
been
conditions
(Scheme
that enolisabie
occurring
218
The
Reaction
atom in the same ring by DMFPOC13
40).12o
C=O groups
4-Chloro-
reaction.
prepared.59
and a nitrogen
221 is converted
formylation
with DMF-POC13.
by a Vilsmeier
pyrroles
subsequently.
219a X=S 54 8 219b X=0
70 8
with
into 220 and
The chloroalkene
of acylated
of
224 was are first
Reactions of carhonyl compounds with methyleniminium salts
224
OHC 223
3693
CHNMQ
226
&
Cl-IO OHC
227
Cl 228
Scheme 40
3.5.3
Polycyclic
Angularly corresponding
Systems
annellated derivatives S-chlorovinylaldehydes
naphtho[2,3_b]furan
221
naphtho[b]furanone. Vilsmeier reaction trichloroethylene
was
of chroman-Cone 22512*~122 similarly
are also and 226.121
prepared
from
of lO.ll-dihydrohenzo[bJthiepin-lo-one
at 80°C gave the carhoxaldehyde
converted
228 (52%).123
The the
with
into
the
formylated
corresponding DMF-POC13 in
c. M. MARSON
3694
3.6
Diketones
3.6.1
Acyclic
Holy afforded
I ,3-Diketones
and Arnold
showed50
that treatment
2,4-dichlorobenzaldehyde
heptamethinium process,
species
although
Katritzky
and
230
a closure
Marson
the dialkylformamide; the Vilsmeier complex
which of the
showed86
232
undergoes
41).
ring-closure,
229 with
DMF-POC13
The route
involves
probably type
that the course of the reaction
in
cannot
depends
the
a pericyclic be excluded.
on the nature of
4,6-dichloroisophthalaldehyde 233 was the major product when derived from N-formylmorpholine-POC13 was used. The relative
so that further
which then yields
Scheme
Enamine-Exo-6-Exo-Trig
bulk of the R group when R2N = morpholino of the cation 230,
of acetylacetone
231 (84%;
presumably
iminoalkylation
the dialdehyde
reduces
the rate of ring-closure
can occur giving
the dicationic
species
233. -R2NH H20
231
R2N+
NR2
R2N+
NR2 +NR2 2K-
233
232
Scheme 41
A seminal showed steric
that hindrance
study51
of the action
dichlorobenzaldehydes markedly
was formed (Scheme 42).
decreased A terminal
of Vilsmeier
(e.g. 235, 237, the yields
when
reagents and 239)
with acyclic were
S-diketones
formed,
the pentasubstituted
acetyl group appears to be necessary
although
benzene
239
for cyclisation
3695
Reactions of carbonyl compounds with methyleniminium salts
to
Replacement
2,4-dichlorobenzaldehydes.
necessarily
prevented
benzoylacetone A
240
comparative
trisacetylacetonates
the
formation
of
a
of
one
of
substituted
gave the products 241 and 242. study1z4 of the ligand
the
alkyl
benzene reactivity
groups
and at
of Cr(II1) and Co(II1) by means of Vilsmeier-Haack
in
the
by the
phenyl case
3-position
reactions
of of
has been
made.
*w* I
R
I
234
DMP-POQ I
“WC1 *
II
I
I
RWCI-IO 235 R=H, Me
CHO
239 0
0
0 Ph Ph 242
Ph 241
240 Scheme 42
3.6.2
Cyclic 1.3-Diketones
3-Halo-2-cycloalken-
244
1 -ones
reaction of cycloalkane-1,3-diones A mechanism (COC1)2 or (COBr)2. 43).
The absence of formylated
moieties
are usually
introduced.
can
be prepared125
with Vilsmeier involving initial
in excellent
yield
by the
reagents prepared from DMF and attack at oxygen is proposed (Scheme
products is a notable feature since @chlorovinylaldehyde Thus,
the cross-conjugated
dialdehyde
125a
(Scheme
24,
3696
C.M. MARSON
section
3.4.1) was formed (24%) by treating cyclohexane-1,3-dione
at 2WC.t26
The
113b and 113~.
was also by which
The methinium
Scheme 24. investigated;127
heating
249a
observed
for the 3-halo-2-cyclohexen-l-ones
dialdehydes
125 are formed
is outlined
species is thought to be the final product of the reaction
The stability
to hydrolysis. benzene
same reaction The pathway
113d with DMFPOC13
of alkenes
the reaction
(20%) yield.
121 and 125 towards
mixture
under
MNDO calculations
reflux
indicated
aromatisation
afforded an energy
has
in prior been
the pentasubstituted difference
between
125a and 249b of 13 kcal mol-1 in favour of the arene 249b. Reaction of cyclohexane1,3-dione with DMF-POC13 in chloroform at 5O“C afforded 2,4-dichloro- l-formylcyclohexa1,3-diene suggests
117. that
(presumably
This
formation
thermal
by nucleophilic
121) to give 118.
of a less
decomposition
of
attack,
probably
and hence the aldehyde,
referred to in section
substituted
121
(known involving
117.
aldehyde
at higher
to be formed addition
A related
of HCl to the dication
thermal
deformylation
3.3.1.
Me2G=CHX
X-
+q”-q”
+HX
245
HX+DMF
X=Br, Cl
‘CH=&M% X-
,=
248
~
‘$OH
X 247
scheme 43
O\
temperatures
at 2O’C) can occur
CH=+NMe, x-
was
3691
Reactions of carbonyl compounds with methyleniminium salts
The formed 253
general
pathways
by the action could
be derived
nucleophilic
attack
from
leading
beyond the formation
depicted
of DMFPOCl3 the
in
Scheme
on dimedone g em-dimethyl
to dealkylation;
of the gem-dimethyl
24 are 250
consistent
(Scheme
analogue
with
44).t2a
of
the
alternatively, the reaction analogue of the cation 118.
the products
The dialdehyde
dication
12 1 by
might
not proceed
OHC
249a R’=CHO R2= CH2NMe2 24913R’=CH2NM% R2=CH0
b;z_Cl
f
250
bC1
251
+
OHCJ&
CHO
CHO
252
253
Scheme 44
3.6.3
1,4- and l.J-Diketones
Few examples formylmorpholine-POCl3 intermediates methiniam
are species
favoured. keto-aldehyde DMF-POC13.
not
have
been reported. Cyclohexane- 1,4-dione 254 reacts with N to give the phenol 255 (Scheme 45),g6 The probable stabilised by strongly electron-withdrawing groups, as are the
depicted
Chloroformylation 256.
in Scheme
24, so that pathways
of cyclooctane-
The dialdehyde
257
1,%dione
under
is formed129
from
leading mild
to aromatisation
are
conditions
the
cyclooctane-1.5-dione
gave
and
c. M. &‘hRSON
3698
lWM-POC1~ 0 254
Scheme 45
4.
REACTIONS
Similar reagents
mechanistic
as apply
carbonamides will usually
features
to ketones.
as compared initially
apply to ketones). in the reaction reactions
OF AMIDIC CARBONYL COMPOUNDS to the reaction
greater
with ketones
attack the carbonyl
of lactams
in which
with
the amide
Bischler-Napieralski-type
considered
in this Report.
basicity
suggests
atom
that the chloromethyleniminium
in
cation
substantially,
particularly
reagents.
In this Section are emphasised transformation into other functionalities.
undergoes
cyclisations,
extensively
46 outlines
the general
reagents.
attack by chloride ion to give an enamine
enaminoaldehyde so that the iminium
266.
264;
products
involved
by nucleophilic
intermediates
Chlorinated
pathways’
with Vilsmeier stable
with Vilsmeier oxygen
reviewed
elsewhere,
are not
Amides
Scheme
the
carbonyl
the area has grown
Vilsmeier
group
of carbonamides of the
oxygen atom in the former cases (which may also
Since the last reviews,l*s
However,
4.1
apply The
hydrolysis
For some simple
when amides
are derived by initial can
afford
amides,
species 259 may be deprotonated
or lactams
0-acylation,
react
followed
262 which rapidly reacts to give either
chlorinated
an
amide
products
to give 261
265
or
the
are not observed,
followed
by
3699
Reactions of carbonyl compounds with methyleniminium salts
Thus, N,N-dimethylacetamide 267 is converted into the highly acylation. amide 269 (Scheme 47). The dehydrating properties of Vilsmeier functionalised reagents may lead to nitriles. presumably via the iminium species 260. salts 271 using Vilsmeier reagents has been Synthesis of the trimethinium subsequent
extended
from carboxylic
0 R’
0A
DMF-FOCls NR;
258
acids to acetamides
R’ cl-
and thioamides.t30
Cl
+
A
2
-
-DMF
Cl R’
m2
259
260 -HCl
-HCl II
Cl R’ 262
265 Scheme 46
266
3700
C.
M. MARSON
269
268
X
R’C!I$ A
R’
i) R2NCI-I0. =3
*
NH2
R2N-CH=C: ,C=‘NR*
ii) HC!104aq.
H
270 X=0, S
271
Clo;
Scheme 47
Fused pyridin-Zones 273 are formed in low yields by the cyclisation of enamides (Scheme 48).13t Hippuric acid is converted 132 into the oxazole 274 by NMF-POC13.
Cl
DMF-POCl,
0
A, 4 h
273
Me
Scheme 48
Since quinolines
the have
pioneering been
the Vilsmeier
reaction
prepared.135
In certain
49).136
of
Fischer,
Mueller
and
Vilsmeier,l33
prepared
chloro-3-cyanoquinolines,
(Scheme
work
by Vilsmeier reactions of acylanilides; prepared 134 by the action of hydroxylamine Other 2-chloro-3-substituted quinolines mixture. cases, the uncyclised
intermediate
was identified
numerous
these include hydrochloride have
also
2on been
as the salt 276
Reactions of carbonyl compounds with methyleniminium salts
3701
280
Scheme 49 In versatile
syntheses
of quinolines,
by the use of the Vilsmeier chlorinated isolated
heterocycles
reagent
(Scheme
in cases where quinoline
thienopyridines,
under
controlled
50).137 formation
fused
afforded derived
pyridines,
high yields
from 285,
of
can be
is slow.t3*
3 DMF-7 F0Cls W alo
282
283
X-
L
284
286,
A, 1.5h
A, 4 h
iI
conditions
Intermediates
a”uI: 0 281
and related
285
Ii
_I
286
Scheme 50 Carbostyrils substituted
288
acetanilides
generally (Scheme
result 51).
from the action
Electron-donating
of the Vilsmeier groups
reagent
placed meta or para
on aassist
c. M. h’fARSON
3702
the cyclisation group
whereas
deactivates
converted
the same
the ring
by the Vilsmeier
The formylation has been
shown
groups
sufficiently reagent
an excellent
hinder the reaction.
cyclisation;
into the anilide
of N-phenylacetanilides
to provide
ortho
placed
to prevent
the
A p-chloro
acetanilide
289a
is
289 b.131
290
was initially
route 140~141 to
misinterpreted,139
1-phenyl-2-quinolones
but
such
as
292. i) DMFPOC13
-i
287
ii)
-
R’
H,O 288
d
-1
289a, R=H 289b, R=CI
Me
TM”z dH, CH,Cl
/
‘N’
Qx I
290
\
$h
291
Cl
292
Ah x-
hh
Scheme 5 1 3_Acetamidothiophene, HONH2.HC1, rather
than
afforded the
was obtained
expected
when
heated
with
DMF-POC13,
5-chlorothieno[3,2-blpyridine-6-carbonitrile.142 2-formyl
upon Vilsmeier
derivative
formylation
yield
by a one-pot
Monocyclic
4.2
a-Pyrrolones derivativesl45 the ring.
procedure
treated
(Scheme
with
The amidine 294, 293,
52).143 297
have
from 2-indolecarbohydrazides
been
prepared
in
295.144
Lactams
are converted or the
then
of 3-(acetylamino)benzo[b]thiophene
4-0xo-3,4-dihydro-5H-pyridazino[4,5-blindoles excellent
and
by Vilsmeier
2-halo-5-formyl
In some cases, the intermddiate
reagents
into either
derivatives, 146 depending enamines
can be isolated.
the 2-chloro-3-formyl on the substitution The 2-bromopyrrole-
in
Reactions of carbonyl compounds with methyleniminium snlts
294
293
0 ml3
K
NMq
296
cc
mM%!
N R
0
a N
CHCl
0
ILe
Me
299
300
R=$ %, CH0147 =Me, Bu 148
302 X=Cl, Br
H,O, \
/OH.
I Scheme 52
Hz0
3703
3704
C. M.
hiARSON
-5aldehydes so obtained are useful compounds for the synthesis of pyrromethenes. In other cases.147.14* a-pyrrolones afford the dimethylaminomethylene derivatives 298. The
lactams
obtained 14*
299 and 300 were
methyl-e-caprolactam,
respectively,
but were accompanied
2-Chloropyrrole-3-carboxaldehydes pyrrolidin-2-ones
with
from N-methyl-S-valerolactam
have
DMF-POC13
in
Vilsmeier
reagents
smoothly
converted
4.3
has
been
prepared
by
chloroform.145,149 with
studied. 150
treating
The reaction
chlorinated
and
pyrroles
304
(Scheme
A4-
of 4-
brominated
A wide variety of As-pyrrolin-2-ones
into the functionalised
N-
by other products.
been
methoxycarbonyl-5-methyl-A4-pyrrolin-2-one
and
301 are
52).t50,15t
Lactams Fused to Carbocyclic Rings
The enamino-aldehyde pyrrolone and DMF-POC13. from steroidal
lactams
have tolerable
stability
305
has
Vinylogous
such as 306 to acids
been
(Scheme
unless
prepared145
amidines, 53).
aromatisation
e.g. 307
from
the
corresponding
have been prepared1529153
In general, the vinylogous amidines can occur. The chloroformylated
steroid derivatives 308 and 309 are formed’53 by treating the appropriate azacholestanone and aza-homoandrostenone derivatives with DMF-POC13 in refluxing CHC13.
306
307 Scheme 53
Reactions of carbonyl compounds with methyleniminium salts
R
4.4
Lactams
with
308
309
Benzo-Fusion
Early work showed that oxindole 312a
2-chloro-3-formylindole variety into
of
l-substituted
310 (R=H) was converted
(Scheme
oxindoles .t55.
3-chloro-1-methyl-2-quinolinone The
Vilsmeier
either
by the
acylation 5-
or
formylindoles;ts*
7-position however,
has been
converted
conversion
of
1-acyloxindoles
314a
were
also proceeds
and 314b.
converted
with
3 13
into
The products the
oxindoles
substituted
I
II
WV-
I
VN’
II
R’ 313 R’=Me, Et, Pr
eo
A
0
314a R2=H 314b R2=CH0 Scheme 54
-
(Scheme
K=uMe
WC3
WN’ R’
at
2-chloro-3-
differently
31LD
3-
315 had to be
corresponding reacted
the
59.154
VN’
a
1-methyloxindole
Some oxindoles
into
substituted
into the
reported.156
2-chloro-3-formylindole.157 other
by DMFPOC13
The reaction
The remarkable
derivatives of
54).t54
(79%)
reagent
dimethylaminomethylidene prepared
3705
A
315
0
3706
C. M.
Isatin
p -0xime
was
converted
hb%RSON
by
DMF-POC13
into N,N-dimethyl-N-(o-
cyanophenyl)formamidine.l59
MeoyJ$l~Md~;;;~M:&q 320
319 62%H
AH0
B
321 83% Scheme 55
Stable Vilsmeier
vinylogous
reaction
amidines
(Scheme
such
as 323
can
be obtained
from
lactams
in a
56).152.160
322 H
323 Scheme 56
Dihydroisoquinolin-3-ones formylisoquinolines (Scheme
57).161
also
applied
be
(Scheme
58);
326
have
been
of Vilsmeier
The sequence of the Vilsmeier-Haack to
other
blocking
phenylisoquinoline-4-aldehyde enabled
324 by the action
the spirocyclic
dihydroisoquinolinone the
nitrogen
(25%).
chloroketone
converted reagents
reaction
derivatives
into
followed
followed including
3-chloro-4by oxidation
by oxidation
can
327 and 33 0
atom afforded 3-chloro-1,2-dihydro-lBlocking the l-position of the isoquinolone
335 to be obtained.161
3707
Reactions of carbonyl compounds with methyleniminium salts
CHO
326
325
fl
H2S04-KMnOL
& 329
328
327
Scheme 57
332
Ah
Bn
Bn Scheme 58
Benzazepin-2-ones chloroformyl
336
derivatives.59,tQ
react with Vilsmeier Related
reagents
benzazepin-2-thiones
to afford
the corresponding
also react analogously.162
3708
C. M. MARSON
4.5
Lactams with Two or More Heteroatoms
4.5.1
Five-membered
5Pyrazolones pyrazoles.163
Heterocycles
usually
A variety
react
with
Vilsmeier
of other functionalities
reagents
to
may be produced,
substrate and reaction conditions. Formylpyrazole derivatives by treating 5pyrazolones 337 with DMF-POC13 (Scheme 59).
338
give
formylated
depending
upon the
have been prepared
I-Phenyl-3-methyl-5-pyrazolone
340164
when
339 afforded the pyrazole carboxaldehyde when the reaction mixture was added to water and slowly neutralised. However, the mixture was poured into aqueous K2C03, some of the hydroxymethylene
derivative
341
was also obtained.
aminomethylenepyrazolone
342
Working is
dialdehyde
343,165
observed.
3-Amino-1-phenyl-5-pyrazolone
the aldehyde
the formation
of the
has been observed.
3-Methyl-1-phenyl-5-pyrazolone although
at lower temperatures,
simple
converted
by
chloroformylation was
converted
344.166
336a R=H 336b R=Cl
DMF-POCl,
R’, R’=lower alkyl
Scheme 59
a Vilsmeier
reagent
of the pyrazole by a Vilsmeier
has
into
the
also
been
reagent
into
Reactions of carbonyl compounds with methyleniminium salts
Chlorination diformylated
of
a
3-methyl
S-oxopyrazolone
group,
has
system
been
345,
in addition
using
Vilsmeier
observed
When the product derived from a Vilsmeier reaction is treated with NH4C1, 3-chloro-7-formyl-lH-pyrazolo[4,3-clpyridine 60).167
The
five-membered
by Vilsmeier-Haack
heterocyclic
reactions
chloro-aldehydes
on the appropriate
347 X=N, CMe
to an effectively reagents
amides
S
CHO
N
Cl
(Scheme
on 3-methyl-5pyrazolone is obtained.168
347 and 348
heterocyclic
a\
CHO
3709
were
(Scheme
prepared 6O).le9
348 Scheme 60
Rhodanine
349 was
converted
2-Phenyliminothiazolidin-4-one versatile been
derivatives
352
(Scheme
into
4-dimethylaminoformylidene
351 is converted by a Vilsmeier 61) from which several 5,5-fused
rhodanine
350.
reagent into the heterocycles have
made.170 2-Amino-4-thiazolinones
derivatives
by Vilsmeier
reagents
are
transformed
(Scheme
62). 171
into
4-chloro-5-formylthiazole
Oxazine derivatives
356. useful as
c. M. hiARSON
3710
DMP-POQ, 30°C,6h
s
l-f
OHC
0
Cl
Vilsmeier reagent W
NH 351 K NPh
352 HNPh Scheme 61
fungicides the thiazine
and analgesics. analogues
0
were prepared
of 355
e
reaction
on the amide
355;172
similarly.
Cl DMWOCl~, 70°C
N
S 353
reacted
by a Vilsmeier
t
NH2
OHC 354
.HCl 0 i) DMP in PhMe, ii) MesN, EtsN, 4h,50°C
355
356
Scheme 62
4.5.2
Six-membered
Unactivated Vilsmeier
Heterocycles
pyrimidines
reagents.
However,
(e.g.
4,6-dichloropyrimidine)
the unsubstituted
acid, uracils,l73 and 4-hydroxy-6-oxodihydropyrimidines Barbituric accordance with its reactivity as a g-enamide. either
357
or 3 59,
depending
on
the
solvent
do not usually
5-position
of derivatives
react
with
of barbituric
undergoes formylation, in acid derivatives 358 afforded
employed
(Scheme
63).
The
5-
Reactions of carbonyl compounds with methyleniminium salts
acid
dimethylaminomethylenebarbituric
derivatives
359
3711
were hydrolysed
by alkali
to
The Vilsmeier reaction of 1,3-disubstituted uracil 5-formylbarbituric acids 360. Reactive afforded 1,3-disubstituted 5-formyluracil derivatives.173.174 derivatives intermediates 362 (R=Cl, Ph, NMe2, NEt2) for dyes have been prepared175 by Vilsmeier the
reactions; barbituric acid 361 obtained from the corresponding
afforded the aldehyde 362 (R=Cl). barbitmic acid and DMF-POC13.176
Cl DMF-POCl,
OYYO HNNH Ko
,
363 was
Vilsmeier-Haack
reagents
Cl
I N\ N YR 362
_+f
i)6h,50°C ii) 20 h, 85°C R=Cl
361
Aldehyde
364
365
Scheme 63
have
Hydroxytriazolopyrimidines into
chlorovinylaldehydes
prepared
by
the
such
Vilsmeier
as 364 reaction
been
converted
(3 h; 70-8O’C; of
by
85%).177
The amide 365
2-ethoxycarbonylmethylene-3-oxo-
was
1,2,3,4-
tetrahydroquinoxaline.178 Substituted
1-formyl-1.5-benzodiazepines
decreasing the amount of Vilsmeier and 50 ml POC13; Scheme 64).179
reagent
were used (e.g.
prepared
in
improved
10 g of amide 366,
yield
by
50 ml DMF,,
C. M. MARSON
3712
DMF-POCls looOC, lh H
367
366
369a, R=H
368
370 R’=H. Br, Cl, NOZ, OMe, NMe2 R’=HorCHO Scheme 64
Several arylthiazine
thiazinones derivatives
have been reacted 368 afforded
with Vilsmeier
mixtures
369b in ratios depending on the electronegativity substituents (e.g. NMe2) electron-donating withdrawing
ones
(e.g. p-N02)
hydroxy-1,3-thiazin-&ones and by photoelectron determined chloroformyl
lactams.162
A similar reaction
the corresponding
salts
substituents
Vilsmeier
by CND0/2
the product ratios
enamines
period of two days (Scheme 65).164 2H-1,4-Benzoxazin-3-one and iminium
thiazinones
369a
reactions
376 which
(Scheme
form a variety
65).tg2
and
and MND0/3
of 2-aryl-4MO methods,
(R=H or CHO in 369)
are chiefly The
using 4H-1,4-benzothiazin-3-ones but they decomposed
374 to be isolated, its
of 2-
of the p-substituents in the aryl ring; favoured 369b, whereas electron-
369a.lau
were analysed
spectroscopy;
of the chlorinated
A variety
by the energetic and structural parameters of the HOMO.lst derivatives 371 and 372 were formed by the action of DMFPOC13
corresponding enabled
368
favoured
reagents.
derivatives
react
with
of products
with alkali,
on the 373 during a
DMF-POC13
to give
some lacking
chloro-
Reactions of carbonyl compounds with methyleniminium salts
3713
R
:xtHr N
0
i) DMP-FOCls ii) NaHa
S
aq. 374
373
376
375
po2CG Scheme 65
4.5.3
Seven-membered
The action 4.4.
Several
Heterocycles
of Vilsmeier
benzo-fused
reagents
on benzazepin-Zones
1,4-diazepinones
Ph
Cl
was described
in Section
(Scheme 66) have also been subjected
Ph R= Cl 80% R=OMe30% i) DMP-POCI, ii) NH&l
Scheme 66
to
C. M.
3714
Vilsmeier
aminomethylene
4.6
were
derivatives 378, rather than the The pyrido-fused benzodiazepin-2-one
reaction
on
dibenzodiazepinone conditions
377
benzodiazepin-2-ones
converted
corresponding
compounds.la3 Vilsmeier
The
reactions.
hfAR!3ON
the 381
(Scheme
benzodiazepin-2-one
the
380 was produced via a Ring contraction of the
379.184
to the benzimidazole
into
chloroformylated
382
occurred
under
Vilsmeier
67).1*5
Imides
Glutarimides
are
diformyldihydropyridines seven-membered rings chlorovinylaldehydes
converted
by
DMF-POC13
into the lactams
384 can also be obtained.187 DMF-POC13 react with excess
387 (Scheme
383;1*6
the
Imides of five-, six-, and to give the useful di-p-
67).18* NO2
I’ a
DMF-POCla NO2
CONMq
W
ij 382
381
0
lx I
CHO
Cl
L!
384 R=H, Ph
383 R=Me, Et, Pr, Ph
R
‘cl
bH2
c,
387a n=2, R=CH2P h I!,h 388a, n=2 n=O, 1,2; R=CH2Ph, CI-I,CO,Et, Ph Scheme 67
Reactions of carbonyl compounds with methyleniminium salts
The azepines 4 equiv.
386 are converted
of the Vilsmeier
reagent
3715
by excess DMF-POC13 into the aldehydes 387;
diluted
with CHC13 afforded
a mixture
of azepines
387a (10%) and 388a (35%). REACTIONS
5.
A general reaction
method
of derivatives
acids,*93 addition
into
The
of vinamidinium
salts 390189-192 is the
reagents
derivatives
(Scheme
68).
of glycinel95
The action of DMF-POC13 on sodium trifluoroacetate, affords
2-fluoro-3-dimethyiaminoacrylaldehyde
Malonic
also afford followed
by
which
can
be
reaction
of
the
fluoromalondialdehyde.196
acrylaldehydes
corresponding
acetic
Formylation
392
were
acids 391 (Scheme
of 2,4-dienoic
isophthalaldehyde prepared
for the preparation
acid,194 and substituted
salts.
of Et3N,
converted
ACIDS
of acetic acid with Vilsmeier
cyanoacetic
vinamidinium
OF CARBOXYLIC
from
by
with
poor
conditions
selectivity.
DMF-POCls
W
was
M~&~NMQ
389 R= aryl, F, Cl, CO,Et
X-
390 X=Cl, ClO,
Me0
Me0 \
W R
3,5-xylenol
acid.198
R
Meo
gave low yields of
However,
3-methylhexa-2,4-dienoic
RCH,CO,H
Vilsmeier
68).197
acids under Vilsmeier
derivatives,
in 45% yield
prepared
COzH
-
DMF-POCI,
/
*
Meo
\ *
391
CHNMe2 /
CHO
R 392 R=H, Me0
“HO( 393
‘b Scheme 68
Benzimidazole-2-propionic 394 by the Vilsmeier 395 affords
the
reagent
benzofulvene
acid at room
393
is converted
temperature. l 99
into
the enamino-ketone
Benzene-l
396 in low yield (Scheme 69).2cu
,2-diacetic
Benzene-1,3-
acid
3716
C. M.
diacetic
acid
and benzene- 1,4-diacetic
salts in respective 397b, give
and the
opening Upon
acid afford
anhydride
isochroman-1,3-dione and ring-closure
the corresponding
Homophthalic
yields of 65 and 82%.
homophthalic
treatment
MARSON
398 all reacted
399
in excellent
acid 397a,
with
yield.
bistrimethinium its methyl
the Vilsmeier The latter
underwent
with acid or POC13 to give the carboxyisoquinolone
of the Vilsmeier
product
399
with
HCl,
ester
reagent
to
ring-
400.2u1
isocoumarin-4-carboxylic
acid 401 is obtained.202
39713 R=Me
Scheme 69 1,4-Dihydrobenzoic and
acids
tri-carboxaldehydes.
dicarboxaldehyde
403
react This
with
DMF-POC13
procedure
also
to give benzene afforded
naphthalene-
(Scheme 70).203
COZH
o$
e
q$mo
402 Scheme 70
mono-,
91%
di-, 1,3-
Reactions of carbonyl compounds with methyleniminium salts
6.
REACTIONS OF ESTERS AND LACTONIC CARBONYL COMPOUNDS
A two-step group
3717
towards
route
to diazepinoindoles
Vilsmeier
reagents
dimethyl-l.bdihydropyridine
406
(Scheme
depends on the inertness
71).m
was formylated
The 2-methyl
by a Vilsmeier
group
reagent,
of an ester of a 2,6-
leaving
intact
the ester groups at the 3- and 5-positions.205 Vilsmeier 7 1).206
reactions
of benzazoles
Ethyl 2-pyridineacetate
409
407
reacted
generated analogously
the enamines (Scheme
(Scheme
72).
Me
Me 405
407
408
406
408 X=NH, S, 0 Scheme 7 1
The and
pyran-2,4-dione
pharmacologically
active
411,
a useful
compounds,
intermediate was
lactone with DMF and POC13 under cooling.207
Scheme 72
prepared
in the preparation by
treating
of dyes
triacetic
acid
c. M.
3718
Treatment three products (Scheme
of
2-coumaranone
413, 414. and 415,
MARSON
412
with
the Vilsmeier
reagent
afforded
the latter two as mixtures of (I?)- and (Z)-isomers
73).*cs
413 46%
412
415
414 10%
24%
Scheme 73 Vilsmeier-Haack isoxazolones reaction
417.209
reactions
on 5(4H)-isoxazolones
Recently,
new routes to 1,3-oxazin-6-ones
on isoxazolin-5-ones
e
418 have been developed
416 led to dichloromethylby the Vilsmeier
(Scheme 74).*tc
0
DMF-FOCJ
0
Ar
.N’
416
16 k H
418
Cl NM% 419
-HCI
421 Scheme 74
;)f:a)NM% H 420
J
the
Reactions of carbonyl compounds with methyleniminium salts
3719
The Vilsmeier-Haack reaction on 4-alkylideneisoxazolin-5-ones 422 gives 1,3oxazin-&ones 424 which are useful precursors of a-pyrones, 2-pyridones and pyridines
(Scheme
75).2tt
:&@0=
:x0
H423
422
424
Scheme 75
427 71% .
429 428 46% Scheme 76 A excess
reinvestigation212
Vilsmeier
reagents
give 1,3-oxazin-6-ones isoxazolone
of the reaction revealed
of 3-phenyl-5-isoxazolinone
a ring-expansion
at temperatures
around
425 with 80°C
to
(Scheme 76).
425 reacts via
The following rationale has been proposed: the its enol form with the chloromethyleniminium species to
give, after loss of HCI, the dimethylamino-derivative
426,
which under more forcing
conditions reacts with excess Vilsmeier reagent at the ring nitrogen atom (Scheme 77). Ring-opening, subsequent ring-closure, and lastly hydrolysis affords the 1,3-
3720
C. M.
oxaxin-6-one proceeds
4 27.
Formation
via phosphorylation
of
the
hiARSON
5-chloro-4-formylisoxazole
of the exocyclic
428
evidently
oxygen atom of 426.212
0 Me&C!HCl
425
-HX -
Mez
0
0
-427
433
432 Scheme 77
7.
CONCLUSION
In the last decade, reaction of significantly. ketones,
both the synthetic
diketones,
lactones,
have led to the development or less
unexpected
rapidly
gaining
usually
employed
reactions reagents.
potential
and the understanding
lactams,
transformations
both
intelligibility
under
and g-haloenones.
of new reactions
mild
by Vilsmeier and
conditions,
Recent
and compounds. reagents
predictability. and
the
and deserving
of further
mechanistic
insights
The variety
of more
referred The
ease
ensure the continued academic and industrial The products are often g-chlorovinylaldehydes,
synthesis,luv213
of the
salts with carbonyl compounds has grown halomethyleniminium Reactions have been extended, among other classes, to a,g-unsaturated
of
to by Burnsa is
inexpensive scaling
up
reagents, Vilsmeier
importance of Vilsmeier versatile intermediates in
study.
- The author wishes to thank P. R. Giles for his help in preparing Acknowledgements the manuscript, and Professor W. D. Ollis, FRS for helpful suggestions.
Reactions of carbonyl compounds
8. 1. 2. 3. 4. 5.
6.
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
36. 37.
with methyleniminium
salts
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3721
3722
C. M. MARSON
40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. ::: 61. 62. 63. ::: 66. 67. 68. 69. 70. 71. 72. 73.
14. 75. 76. 17. 78. 79.
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