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Synthesis and reactions of substituted nitro-allylating reagents
Tetrahedron Letters,Vo1.23,No.38,pp Prmted m Great Brltam
SYNTHESIS
AND REACTIONS
3897-3900,1982
OF SUBSTITUTED
Paul Knochel') Laboratonum
fur Organlsche
SUmmary achieved
Nztro-cyclohexenylatlon
We recently multi-coupling
reagent4).
give nltro-compounds vity (alkyl-,
vinyl-,
233)
Technlschen
Zurich
plvalates
Hochschule,
of nucleophlllc
that NPP 1 (2-nltro-3-plvaloyloxy-propene)
of type a and 7 (R=R'=H). arylllthlum)
RI R __ _*
centres
2 and 2, and with the chloride -
are
L, which
respectively.
It reacts selectively 2r
ETH-Zentrum,
(Switzerland)
and cr-phenyl-nltro-allylatlon
from the dlols -9 and z,
reported
REAGENTS
and Dieter Seebach
16, CH-8092
(see -11-16) with the nltroallyl
are in turn prepared
NITRO-ALLYLATING
Chemle der Eldgenosslschen
Unlversltatstrasse
0040-4039/82/383897-Od$O3.00/0 01982 Pergamon Press Ltd.
with two different The nucleophlle
can be used as a
nucleophlles
Nu' and Nu2 to
Nu' can be of very high reacti-
, of moderate reactivity (lithium ketone or ester enol-
R
R’
X
1
Ii
H
o-co+
2
-&Hz),
-
o-co+
3
-fCH,),
-
4
-@Hz)
a-
5 _
C,'+,
6
3897
H
Cl OH o-co-j-
3898
ates)3),
as well as of low reactivity
group 1s amenable
to transformation
sponds to the a2/a2'-synthon
The original
in order
avallable5b)
(III)
to obtain
and some reactions
(1) to extend
information
first with DCC to give flwhlch
merlcally
(2) 1s obtained
from which
(R*,R*)-or plvallc
preparation,
the scope of the method,
about the mechamsm
Since the nitro
, the reagent corre-
with
from -4 and thionyl
acid 1s smoothly
_10a
the sluggish
group as present
in 2 and 3,
of the nltro-allylatlon
pivalic
from the dlol 7) 2 by treatment
anhydnde
chloride
Finally,
The 2-nitro-3-chlorothe open-chain,
(2) 1s prepared
If 1s estenfled
eliminated
and analogues 2, 3_, but they are now
(ii) to see whether
by a leaving
-2 1s synthesized
1s estenfied
L-nltrodlol')
and physical
groups 5a)
were unsuccessful,
pure E-2-nltro-1-phenyl-3-plvaloyloxy-propene
avallable8)
132)
amines)
of the NPP denvatlves
to prepare these compounds
The 2-nltro-3-plvaloyloxy-cyclohexene
cyclohexene
secondary
into many other functional
nltrocyclohexene 6) could be activated
electrophlle and
attempts
indoles,
8, R=R'=H
We now report the synthesis and 2
(thlols,
with plvaloyl
with sodium acetate
data of -2-5 and lo, and of the products
diastereo-
from the readily chloride
For yields,
to give lOJ,
conditions
of
from them, see the accom-
panying table Our experience lsed as follows.
with the three new nltro-allylatlng
(1) The plvaloyloxy-nltro-cyclohexene
such as alkylllthlums
(see lJ), aryllithiums
reagents 2, 3, and 5 may be summar-2 reacts well with strong nucleophiles
(see l2_), and lithio-dithianes
(see x),
16
6)
and also
3899
with N-methyl-aniline cyclohexene
(-+14), while -
butylllthlum
to the phenyl-derivative
the addltlon/ellmlnation phile or further
mechanism
a 3 2 mixture
5 yields
proposed
functlonallsatlons
of the nitroolefin
the nitroolefin
earlier 1-4y11).
of the products
1s the nltroketone
(11) The chloro-nitro-
the above mentioned
metal
in high yield
-18 obtained
16, a result compatible
of with
(IV) Addition of a second nucleo-
of type a 1s possible
-16 with 2,3-dlmethylbutadlene
of two diastereoisomers
multi-coupling
to nltro-allylate
the adduct -15 with N-methylindole 6). (iii) Addition
but it furnishes
der~vatlves1-3y10)
heating
indoles do not add even at 80°C.
2 on the other hand 1s not expected
produces
Another
l-3,5,12)
the m&s-Alder
example
Thus, adduct -17 as
of a product
arising
from
13)
from -16 and tnmethylsilyloxy-cyclohexene
Table
Compounds -2-5, -10 and products -11-18 of type fi and 1 given are those of materials purified by flash-chromatography 14) from 10 mmolar runs
The yields
Recrystalllsatlon troscopic
or bulb to bulb distillation
data are compatible
ing points,
m p
with the structures
as well as the 'H-NMR shifts
of the olefinic
(0) or single allylic
22'C, b p
l10°C/10-5
plvallc anhydnde,
thlonyl
chloride
50°C/10-5
mp
69°C;60=
(1 5 equlv.) -lob m p
69"C,
excess
6("-C6H5)
pivaloyl
benzene,
s, 82% from -4 and excess
1 h s, 70% from 2 and 1 1 equiv.
amount Cu(I)Cl,
24 h, r t
,
dlcyclohexylcarbodl-
cf 5b)
s, 95% from -lob and dry powdered
sodium acetate
18 h, r t.
in refluxlng
= 4.19, d, J = 6 Hz, 95% from E,
CH2C12.
-11
b p
-12
m p
58'C, 6. = 7 40, t, J = 4 Hz, 89% from 2 and bromobenzene, -
-13
m p
155'C, 6. = 7 08, t, J = 4 Hz, 63% from 2 and phenyldlthlane,
-14
yellow
-15
m p
68'C/O
points, boll-
multlpllclties
amount BF3 EtOEt.
= 6 16, d, J = 10 Hz, 6(2H,a-0)
chloride
Melting
J[Hzl,and
are listed
mm, 60 = 7 36, m; 6a = 5 21, br
8 35, s, 6, = 5 18, br in dry ether,
constants
All spec-
mm, 6. = 7 51, t, J = 4 Hz, 6a = 5.87, m, 95% from -4 and excess
in refluxlng
cat
pure samples
shown in the formulae
(a) hydrogen(s)
6. = 7 32, t, J = 4 Hz, 6a = 4 75, br lmlde (DCC) in dloxane,
analytically
(6Ippml),coupllng
100°C, 0 75 h, cat
m.p. 23 5'C; b p
furnished
02 mm, 6. = 7 10, t, J = 3 Hz, 92% from 2 and n-BuLl -
in THF at -1OO'C for 1 h,
cf 2,
011; 6a = 5 00, m, 66% from 2 and N-methyl-anlllne, -
cf 2) cf 3) , -lOO'C, 3 h, THF
6 d, in THF, 50°C
71°C, 6, = 7 25, t, J = 4 Hz, 47% from 2 and N-methyllndole,
40 h In refluxing
benzene -16
7o"c/10-5 -1oooc,
-17
mm,
to N02) = 6.4,
14D°C/10V4
do(trans)
= 5 5, br
s, 92% from n-BuLi, THF, 1 h,
refluxlng
2,3-dimethyl-1,3-butadlene
and a trace
40 h
mm, 45%
dlastereomers, benzyllc
m,
cf 2,
170°C/0 05 mm, 89% from -16 and excess hydroquinone,
-18
C~~(CIS
from%
main isomer
and cyclohexanone 'H-NMR benzyllc
CH 6=3 50 (t, 7 Hz), cf 13).
sllyl enolether/SnC14/-78'C, CH 6=3 65 (t, 7 Hz),
3
1 mixture of
minor isomer 'H-NMR
3900
REFERENCES
1) 2)
Part of the Ph.D. thesis of P. Knochel,
3)
P. Knochel
4)
A multi-coupling
P
Knochel and D
Seebach,
the sequential
reagent formation
ETH-Zurich
Tetrahedron
and D. Seebach,
Nouv. J
AND FOOTNOTES (1982).
Lett. 22, 3223 (1981)
Chim
5, 75 (1981).
("Verknupfungsreagenz")ls
a reagent whose
of two or more new carbon-carbon
reactivity
allows
bonds.
2) B 3) (FG -FG')
A,B
nucleophlles
and (or) electrophlles;
the pattern of which
It should have a simple carbon-skeleton, molecules.
For details
FG, FG'. functlonal
and other examples
of multi-coupling
groups.
1s comnon
reagents
to many target
see
1)
, full papers
are in preparation 5)
a) Review
D
Seebach,
proved procedure D 6)
Seebach,
Synthesis,
7)
all add smoothly
8)
of nltrooleflns
from nitroaldols
with Li-dithianes,
to open chain nltrooleflns.
for other nucleophlles
El-Scherblney,
Chimia 2,
1 (1979), - b) see. P
Knochel
Imand
in print
1924, 1961 (1975), D
F W. Llchtenthaler, A
Lehr, and T. Weller,
does not react with Li-enolates,
Chem. Ber. 108, (1981)),
F
for the preparation
Nltrocyclohexene which
E W. Calvin,
Chem Chem
We thank the Boehrlnger
Ber Ber
Seebach
(D. Seebach,
or with enamines,
H F. Leltz, and V
and 3. Golliiskl, Helv
Chum
Ehng,
Acta 2,
1413
see ref 12) below 96, 845 (1963); F W
101,
Llchtenthaler,
T
Nakagawa,
and
1837 (1968)
AG (Mannhelm)
for a generous
gift of"d1-three-1-phenyl-2-nltro-
-1,3-propanedlol"(lOa) 9)
An unambiguous
specification
Just been proposed
to prevent the growing
D
Seebach
and V
10)
M
Raeber,
Dlplomarbelt
11)
If -16 were formed directly
Prelog, Angew
high yield because 12)
E.J
13)
M. Mlyashlta,
14)
W C
of configurations
ETH-Zurich
16 should
Still, M
(Received
Yanaml,
undergo J
Am
Mltra,
in stereochemlcal
(unlike)]
has
nomenclature
(1981)
further Chem
and A. Yoshlkoshl,
Kahn, and M
confusion
R*,s*f~
, review in press we would
by an SN2'-process,
Corey and H. Ezrelcher, T
Chem
tR*,R*EL(llke),
J. Org
In Germany 6 July 1982)
not expect to obtain
reaction 1~ situ.
Sot
100, 6294 (1978)
J. Am. Chem Chem
Sot
98, 4679 (1976)
43, 2923 (1978).
it in such
SYNTHESIS
AND REACTIONS
3897-3900,1982
OF SUBSTITUTED
Paul Knochel') Laboratonum
fur Organlsche
SUmmary achieved
Nztro-cyclohexenylatlon
We recently multi-coupling
reagent4).
give nltro-compounds vity (alkyl-,
vinyl-,
233)
Technlschen
Zurich
plvalates
Hochschule,
of nucleophlllc
that NPP 1 (2-nltro-3-plvaloyloxy-propene)
of type a and 7 (R=R'=H). arylllthlum)
RI R __ _*
centres
2 and 2, and with the chloride -
are
L, which
respectively.
It reacts selectively 2r
ETH-Zentrum,
(Switzerland)
and cr-phenyl-nltro-allylatlon
from the dlols -9 and z,
reported
REAGENTS
and Dieter Seebach
16, CH-8092
(see -11-16) with the nltroallyl
are in turn prepared
NITRO-ALLYLATING
Chemle der Eldgenosslschen
Unlversltatstrasse
0040-4039/82/383897-Od$O3.00/0 01982 Pergamon Press Ltd.
with two different The nucleophlle
can be used as a
nucleophlles
Nu' and Nu2 to
Nu' can be of very high reacti-
, of moderate reactivity (lithium ketone or ester enol-
R
R’
X
1
Ii
H
o-co+
2
-&Hz),
-
o-co+
3
-fCH,),
-
4
-@Hz)
a-
5 _
C,'+,
6
3897
H
Cl OH o-co-j-
3898
ates)3),
as well as of low reactivity
group 1s amenable
to transformation
sponds to the a2/a2'-synthon
The original
in order
avallable5b)
(III)
to obtain
and some reactions
(1) to extend
information
first with DCC to give flwhlch
merlcally
(2) 1s obtained
from which
(R*,R*)-or plvallc
preparation,
the scope of the method,
about the mechamsm
Since the nitro
, the reagent corre-
with
from -4 and thionyl
acid 1s smoothly
_10a
the sluggish
group as present
in 2 and 3,
of the nltro-allylatlon
pivalic
from the dlol 7) 2 by treatment
anhydnde
chloride
Finally,
The 2-nitro-3-chlorothe open-chain,
(2) 1s prepared
If 1s estenfled
eliminated
and analogues 2, 3_, but they are now
(ii) to see whether
by a leaving
-2 1s synthesized
1s estenfied
L-nltrodlol')
and physical
groups 5a)
were unsuccessful,
pure E-2-nltro-1-phenyl-3-plvaloyloxy-propene
avallable8)
132)
amines)
of the NPP denvatlves
to prepare these compounds
The 2-nltro-3-plvaloyloxy-cyclohexene
cyclohexene
secondary
into many other functional
nltrocyclohexene 6) could be activated
electrophlle and
attempts
indoles,
8, R=R'=H
We now report the synthesis and 2
(thlols,
with plvaloyl
with sodium acetate
data of -2-5 and lo, and of the products
diastereo-
from the readily chloride
For yields,
to give lOJ,
conditions
of
from them, see the accom-
panying table Our experience lsed as follows.
with the three new nltro-allylatlng
(1) The plvaloyloxy-nltro-cyclohexene
such as alkylllthlums
(see lJ), aryllithiums
reagents 2, 3, and 5 may be summar-2 reacts well with strong nucleophiles
(see l2_), and lithio-dithianes
(see x),
16
6)
and also
3899
with N-methyl-aniline cyclohexene
(-+14), while -
butylllthlum
to the phenyl-derivative
the addltlon/ellmlnation phile or further
mechanism
a 3 2 mixture
5 yields
proposed
functlonallsatlons
of the nitroolefin
the nitroolefin
earlier 1-4y11).
of the products
1s the nltroketone
(11) The chloro-nitro-
the above mentioned
metal
in high yield
-18 obtained
16, a result compatible
of with
(IV) Addition of a second nucleo-
of type a 1s possible
-16 with 2,3-dlmethylbutadlene
of two diastereoisomers
multi-coupling
to nltro-allylate
the adduct -15 with N-methylindole 6). (iii) Addition
but it furnishes
der~vatlves1-3y10)
heating
indoles do not add even at 80°C.
2 on the other hand 1s not expected
produces
Another
l-3,5,12)
the m&s-Alder
example
Thus, adduct -17 as
of a product
arising
from
13)
from -16 and tnmethylsilyloxy-cyclohexene
Table
Compounds -2-5, -10 and products -11-18 of type fi and 1 given are those of materials purified by flash-chromatography 14) from 10 mmolar runs
The yields
Recrystalllsatlon troscopic
or bulb to bulb distillation
data are compatible
ing points,
m p
with the structures
as well as the 'H-NMR shifts
of the olefinic
(0) or single allylic
22'C, b p
l10°C/10-5
plvallc anhydnde,
thlonyl
chloride
50°C/10-5
mp
69°C;60=
(1 5 equlv.) -lob m p
69"C,
excess
6("-C6H5)
pivaloyl
benzene,
s, 82% from -4 and excess
1 h s, 70% from 2 and 1 1 equiv.
amount Cu(I)Cl,
24 h, r t
,
dlcyclohexylcarbodl-
cf 5b)
s, 95% from -lob and dry powdered
sodium acetate
18 h, r t.
in refluxlng
= 4.19, d, J = 6 Hz, 95% from E,
CH2C12.
-11
b p
-12
m p
58'C, 6. = 7 40, t, J = 4 Hz, 89% from 2 and bromobenzene, -
-13
m p
155'C, 6. = 7 08, t, J = 4 Hz, 63% from 2 and phenyldlthlane,
-14
yellow
-15
m p
68'C/O
points, boll-
multlpllclties
amount BF3 EtOEt.
= 6 16, d, J = 10 Hz, 6(2H,a-0)
chloride
Melting
J[Hzl,and
are listed
mm, 60 = 7 36, m; 6a = 5 21, br
8 35, s, 6, = 5 18, br in dry ether,
constants
All spec-
mm, 6. = 7 51, t, J = 4 Hz, 6a = 5.87, m, 95% from -4 and excess
in refluxlng
cat
pure samples
shown in the formulae
(a) hydrogen(s)
6. = 7 32, t, J = 4 Hz, 6a = 4 75, br lmlde (DCC) in dloxane,
analytically
(6Ippml),coupllng
100°C, 0 75 h, cat
m.p. 23 5'C; b p
furnished
02 mm, 6. = 7 10, t, J = 3 Hz, 92% from 2 and n-BuLl -
in THF at -1OO'C for 1 h,
cf 2,
011; 6a = 5 00, m, 66% from 2 and N-methyl-anlllne, -
cf 2) cf 3) , -lOO'C, 3 h, THF
6 d, in THF, 50°C
71°C, 6, = 7 25, t, J = 4 Hz, 47% from 2 and N-methyllndole,
40 h In refluxing
benzene -16
7o"c/10-5 -1oooc,
-17
mm,
to N02) = 6.4,
14D°C/10V4
do(trans)
= 5 5, br
s, 92% from n-BuLi, THF, 1 h,
refluxlng
2,3-dimethyl-1,3-butadlene
and a trace
40 h
mm, 45%
dlastereomers, benzyllc
m,
cf 2,
170°C/0 05 mm, 89% from -16 and excess hydroquinone,
-18
C~~(CIS
from%
main isomer
and cyclohexanone 'H-NMR benzyllc
CH 6=3 50 (t, 7 Hz), cf 13).
sllyl enolether/SnC14/-78'C, CH 6=3 65 (t, 7 Hz),
3
1 mixture of
minor isomer 'H-NMR
3900
REFERENCES
1) 2)
Part of the Ph.D. thesis of P. Knochel,
3)
P. Knochel
4)
A multi-coupling
P
Knochel and D
Seebach,
the sequential
reagent formation
ETH-Zurich
Tetrahedron
and D. Seebach,
Nouv. J
AND FOOTNOTES (1982).
Lett. 22, 3223 (1981)
Chim
5, 75 (1981).
("Verknupfungsreagenz")ls
a reagent whose
of two or more new carbon-carbon
reactivity
allows
bonds.
2) B 3) (FG -FG')
A,B
nucleophlles
and (or) electrophlles;
the pattern of which
It should have a simple carbon-skeleton, molecules.
For details
FG, FG'. functlonal
and other examples
of multi-coupling
groups.
1s comnon
reagents
to many target
see
1)
, full papers
are in preparation 5)
a) Review
D
Seebach,
proved procedure D 6)
Seebach,
Synthesis,
7)
all add smoothly
8)
of nltrooleflns
from nitroaldols
with Li-dithianes,
to open chain nltrooleflns.
for other nucleophlles
El-Scherblney,
Chimia 2,
1 (1979), - b) see. P
Knochel
Imand
in print
1924, 1961 (1975), D
F W. Llchtenthaler, A
Lehr, and T. Weller,
does not react with Li-enolates,
Chem. Ber. 108, (1981)),
F
for the preparation
Nltrocyclohexene which
E W. Calvin,
Chem Chem
We thank the Boehrlnger
Ber Ber
Seebach
(D. Seebach,
or with enamines,
H F. Leltz, and V
and 3. Golliiskl, Helv
Chum
Ehng,
Acta 2,
1413
see ref 12) below 96, 845 (1963); F W
101,
Llchtenthaler,
T
Nakagawa,
and
1837 (1968)
AG (Mannhelm)
for a generous
gift of"d1-three-1-phenyl-2-nltro-
-1,3-propanedlol"(lOa) 9)
An unambiguous
specification
Just been proposed
to prevent the growing
D
Seebach
and V
10)
M
Raeber,
Dlplomarbelt
11)
If -16 were formed directly
Prelog, Angew
high yield because 12)
E.J
13)
M. Mlyashlta,
14)
W C
of configurations
ETH-Zurich
16 should
Still, M
(Received
Yanaml,
undergo J
Am
Mltra,
in stereochemlcal
(unlike)]
has
nomenclature
(1981)
further Chem
and A. Yoshlkoshl,
Kahn, and M
confusion
R*,s*f~
, review in press we would
by an SN2'-process,
Corey and H. Ezrelcher, T
Chem
tR*,R*EL(llke),
J. Org
In Germany 6 July 1982)
not expect to obtain
reaction 1~ situ.
Sot
100, 6294 (1978)
J. Am. Chem Chem
Sot
98, 4679 (1976)
43, 2923 (1978).
it in such