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Synthesis of 3-substituted furans
TetrahedronLetters.Vol. 35. No. 40, pp. 7327-7330.1994 Elsevierscience Ltd Printed in Great Britain
OO40-4039/94 $7.00+0.00 -39(94)01584-8
Synthesis of 3Substituted Gil V. J. da Siia,*
Marcel0 M. M. Pdissen
Av. Bandciitcs, 3900. CEP 14040~901-
Furans. G. Constantine
and Mauri&
Ribci&
F’rcto, SP -Brazil
Abstrocf: A method for the preparation of J-substituted furans starting with the addition of &is~phrnylthio)methyllithium to an ester. followed by a sequence consisting of a Wfttig reaction, a DIBAL-H reduction and an iodine-mediated cycliration is described. Natural They
products
containing
are frequently
carbonyl
compounds
existing
3-substituent’
stereochemistry process
a furan ring substituted
synthesized
by addition
or substitution
on alkyl halides
As part of our studies for furan ring formation
The
method
is
by treatment
Olefination
lack flexibility
in
reaction
4r afforded
alcohol
Sa” (90%,
spontaneously
of these methods,
and is usually
or are plagued
of an the
lost during the
by low yields.
the original configuration
of the 3-substituent
and thus could
ester
equivalents
1. Treatment
the thioacetal
compounds
in the presence
of benzoic
by flash chromatography.
is quite
of
by flash
starting
DIBAL-H
to the homoallylic unstable
isolated
material).
and
by TLC, is
if the reaction
from the reaction. reduction
Treatment
alcohol
also
acid’ leading
monitored
9a and 9b is detected;
will be the main products
of ester
of the allylic
6,13 with 98% yield
isomerizes
during storage or by extending the reaction time in the DIBAL-H 7327
2
ketone 3 was carried out with 60% yield
products
in isomerization Sa
26 with
and 4b.” The reaction,
Ia”
based on the unrecovered
Compound
of
ester 3’ in 80% yield after purification
of the stereocongested
separated
Sa with NaH in THP resulted 4 isomers).
ring.’ In some
elaboration
to
a novel method
of monodesultirization
48 and 4b are readily
of
or by tirther
cuprate
we have developed
scheme
afforded
Compounds
(a mixture
di(3-furyl)
of chiral compounds.
of the E, Z-isomeric
when the presence
since long ago.’
of natural products
time is extended long enough, these compounds
alcohol
of the firan
with methyl (triphenylphosphoranylidene)acetate
to a 1: l-mixture quenched
on the synthesis
depicted
bis(phenylthio)methyllithium’ chromatography.
involved
that preserves
be useful for the preparation
or epoxides,
bearing the furan ring is hard to control,
while in others the reactions
are known
or lithium
of 3-furyllithium’
or even by the construction
of the C-atom
in the 3-position
to
reduction.
6.
either
7328
sche.me 1 1. n-BIG
(1.56M
THF,-78=‘C,
Phs2.
1
+
in hcxanc) 15 min
0
0 3y
OcH’ (0.5 cq.)
2
-+m
O
3
TX-IF,-78T,
30 min
8o?A
3 pkJ-=m
(2.5al.)
PhCQH (0.25 eq.) bcnzcnc,reflux,24h 6@?A -q;+Ty+q-
4p
DIJSL-H,
(2.5 eq., LOM, in m
ether. 0°C. 30 min 90%
6
5a
12(1.5=I.)
12(2 eq.1
6
acuone,42h 54%
S.W&q;);~
(1
67% 8
7
One could
expect
and by elimination the
reduction
isomerization explained
the alkoxide
reaction
to
the
alcohol
goes through
by the Baldwin’s
reaction,
after reduction
to give the target fitran. What is observed
product
12 to
11,
6, which
is
thus, leading to the formation
of ester 4a to cyclise
is a very easy isomerization
resistant
to
ring opening
unfavoured,
cyclization.
sequence
the ring opening
process,
to a dihydrofuran
however,
of 10 to 11 is a 5-exo-tef
ion promotes
a 5-endo-trig of 6.
is quite
a ring closure-
rules. I* Cyclization
to those rules. Then, phenylsulfide reverse
formed
giving
(scheme
process,
Probably
2), which can be
favoured
the alkoxide
the equilibrium
of the
according
12. Since the
is shifted towards
12
7329
scheme2
N*
sa
-6
c,
It was observed to compound treated
later that the alcohol
6 (now
by an allylic
with DIBAL-H
Although
favoured
cyclization.
Sexo-trig
illustrated
in scheme
Therefore,
the mixture
by TLC to afford the rearranged
of compound
by a reaction
of ester 4b also isomerizes
by reduction
rearrangement).
and monitored
the ring closure
can be circumvented
obtained
pathway
6 (5e&o-trig) in which
This condition
is a disfavoured
an intermediate
can be achieved
4a and 4b was
of esters
alcohol
6 directly. process,
formed
this difficulty
from 6 could
by an iodine
slowly
mediated
undergo
ring closure
a as
3.
Scheme 3
L
6
12 )
-
7ors
ECtOlPZ
Accordingly, (phenylthio)furan the presence homoallylic
treatment
of
homoallylic
7.15 Raney-nickel
of a benzyllic-like alcohol
6 with
mediated C-O
iodine
bond,
alcohol
6
with
desulfurization also
in the presence
prone
iodine
in
of 7 to give
furan
to hydrogenolysis.
of Et,N
acetone
afforded
2-
8 is complicated
by
However,
and H,O afforded
treatment
the desired
furan
of 8 in
67% yield.16
AcAnowltdgments: discussions.
Financial
(FAPESP),
Conselho
Coordenacgo
The support
authors came
National
de Aperfeicoamento
are grateful
from FundacBo de
to Professor de Amparo
Desenvolvimento
de Pessoal
Timothy a Pesquisa
Cientifico
de Nivel Superior
e
(CAPES).
J. Brocksom do Estado
Tecnologico
for helpful de Sgo Paulo (CNPq)
and
7330
REFERENCES
AND NOTES
1.
Dean, F. M. NaturaZQ Occuring oxygen Ring Compounds, Butterworth:
2.
Bock, I.; Bomowski,
London, 1963.
H.; Banft, A.; Theis, H. Tetrakerlion 1999, 46, 1199.
3.
Kojima, Y.; Wakitq S.; Kate, N. Tetrahekon
4.
Tanis, S. P.; Heninton, P. M. J. Org. Chem. 1983,48,4572.
5. 6.
Mandai, T.; Takcshita, M.; Mori, IL; Kawada, M.; Otera, J. CJterui~q~ Letters 1983, 1909. Kawaksmi, Y.; Asai, T.; Umeyama, K.; Ysmashita, Y. J. Org. Cbetu. 1982,47, 358 1
7.
Corey, E. J.; Seebach, D. J. Org. Chem. 1966,31,4097.
8.
Compound 3: ‘H NMB (CDCls, 80 MHz) 6 1.34 (s, 6H), 3.86-4.23 (m, 2I-Q 4.75 (dd, J-5.8Hz, J=7_4Hz, lH), 5.40 (a, lH), 7.17-7.54 (m, 1OH); “C NMB (CDCb, 20 MHz) 8 25.3 (GIG), 26.0 (CEt),
60.5 (CH), 66.8 (C&).
Left. 1979, 4577.
78.1 (CH). 111.1 (C), 128.6 (CH), 129.1 (CH), 129.3 (CH), 132.0
(C), 132.8 (C), 133.2 (CH), 133.9 (CH.), 199.8 (C); MS m/z (relative intensity) 360 (5.8) M’, 231 (loo), 9. ,lO.
101 (75.2).
Btkhart,
C.; Eichler, S.; Panse P. Angew. Chem. 1963, 75, 858.
Compound
4r: ‘H NMR (CDCI,, 80 MHz) 6 1.39 (s,3H),
probably dd, 4H), 6.14 (s, III), 6.97 (s, D-I), 7.10-7.57 26.8 (C&),
1.42 (8, 3H), 3.45 (overlap of s and
(m, 1OI-I); “C NMB (CDCla, 20 MHz) 6
27.6 (CH3). 52.6 (CH3), 54.4 (CH), 73.1 (CHz), 76.1 (CH), 110.7 (C), 118.2 (CI-I),
129.0 (CH), 129.8 (CH), 130.3 (CH), 130.4 (CH), 132.5 (CH), 134.4 (C), 135.2 (CI-I), 156.3 (C), 167.5 (C); IB (neat) v,, (89.9), 11.
109 (97.6)
Compound
cm-’ 1713 (GO),
101 (100)
1642 (C=(Z); MS m/z (relative intensity) 307 (53.2),
139
65 (72.6).
4b: ‘H NMR (CDCI,, 80 MHz) 6 1.38 (s, 6H), 3.46 (dd, J=6.4Hz,
(s, 3H), 4.35 (dd, J=8.OHz, J=8.5Hz, 6.23 (d, J=2.OHz, HI), 7.19-7.54
J=8.5Hz,
1H) 5.51 (s, HI), 5.68 (m, J=2.OHz, J=6.4Hz,
lH), 3.65
J-8.OH.2, HI),
(m, 1OH); “C NMB (CDCl3, 20 MHz) 6 24.4 (C&),
25.7 (CHr),
50.7 (CHJ), 54.6 (CH), 69.1 (CH2), 73.7 (CH), 109.4 (C), 119.1 (CH), 127.4, (CH), 127.8 (CH), 128.5 (CH),
128.6 (CH), 131.7 (CH), 132.3 (CH), 132.6 (CH), 133.6 (C), 134.0 (C), 156.7 (C),
165.3 (C); MS m/z (relative intensity) 307 (33.2), 12.
Compound
139 (86.1),
109 (loo),
101 (68.5),
65 (75.8).
Sa: ‘H NMR (CDCl3, 80 MHz) 8 1.40 (s, 6I-I) 3.57 (t, J=8.OHz, lH), 4.06 (d, J-6.7H2,
2H). 4.22 (dd, J=6.OHz, J=8.OHz, lH), 4.77 @r t, lH), 5.23 (s, 1H). 5.98 (t, J=6.7Hz,
lH), 7.17-
7.53 (m, 1OH); ‘“C NMB (CDCb, 20 MHz) 6 25.5 (CH3), 26.3 (CH3), 56.5 (CH), 58.6 (CH2), 70.5 (CH2), 78.1 (CH), 109.0 (C), 128.2 (CH), 128.5 (CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 130.0 (CH), 132.6 (CH), 133.8 (CH), 134.0 (C), 134.1 (C), 137.9 (C). 13.
The product was purified by flash chromatography.
Analysis of the ‘H NMR and ‘“C NMR spectra
showed that it is a mixture of isomers. MS m/z (relative intensity) 388 (11 .O) M’, 279 (27.5) (loo),
111
109 (60.7).
14.
Baldwin, J. E. J. C. S. Gem.
IS.
Compound J=2.1Hz,
Comm. 1976, 734.
7: ‘H NMK (CDCls, 80 MHz) 6 1.36 (s, 3H), 1.39 (s, 3H), 3.55-4.21
IH), 7.06-7.45
(m, 6H); 13C NMB (CD&
(m, 3H), 6.40 (d,
20 MHz) 6 25.8 (CH3), 25.9 (CH3), 42.1
(CH), 65.3 (CHz), 72.7 (C), 109.2 (CH), 114.2 (C), 127.4 (CI-I), 128.9 (CH), 132.6 (CH), 134.2 (C), 141.1 (CH), 155.6 (C). 16.
Compound (dd, J-5.8I-Iz,
8: ‘H NhdR (CDCls, 80 MHz) 6 1.43 (s, 3H), 1.47 (s, 3H), 3.76 (t, J=S.OHz, lH), 4.20 J=8.OHz, lH), 5.03 (dd, J=5.8Hz,
13CNMR(CDC13,20Mhz)G25.6,26.7,
J=8.OHz, lH), 6.39 (m, IH), 7.34-7.47
70.2,70.6,
(Received in USA 20 June 1994; accepted 9 August 1994)
108.6, 109.4, 123.9,
140.1,
143.6.
(m, 2H);
OO40-4039/94 $7.00+0.00 -39(94)01584-8
Synthesis of 3Substituted Gil V. J. da Siia,*
Marcel0 M. M. Pdissen
Av. Bandciitcs, 3900. CEP 14040~901-
Furans. G. Constantine
and Mauri&
Ribci&
F’rcto, SP -Brazil
Abstrocf: A method for the preparation of J-substituted furans starting with the addition of &is~phrnylthio)methyllithium to an ester. followed by a sequence consisting of a Wfttig reaction, a DIBAL-H reduction and an iodine-mediated cycliration is described. Natural They
products
containing
are frequently
carbonyl
compounds
existing
3-substituent’
stereochemistry process
a furan ring substituted
synthesized
by addition
or substitution
on alkyl halides
As part of our studies for furan ring formation
The
method
is
by treatment
Olefination
lack flexibility
in
reaction
4r afforded
alcohol
Sa” (90%,
spontaneously
of these methods,
and is usually
or are plagued
of an the
lost during the
by low yields.
the original configuration
of the 3-substituent
and thus could
ester
equivalents
1. Treatment
the thioacetal
compounds
in the presence
of benzoic
by flash chromatography.
is quite
of
by flash
starting
DIBAL-H
to the homoallylic unstable
isolated
material).
and
by TLC, is
if the reaction
from the reaction. reduction
Treatment
alcohol
also
acid’ leading
monitored
9a and 9b is detected;
will be the main products
of ester
of the allylic
6,13 with 98% yield
isomerizes
during storage or by extending the reaction time in the DIBAL-H 7327
2
ketone 3 was carried out with 60% yield
products
in isomerization Sa
26 with
and 4b.” The reaction,
Ia”
based on the unrecovered
Compound
of
ester 3’ in 80% yield after purification
of the stereocongested
separated
Sa with NaH in THP resulted 4 isomers).
ring.’ In some
elaboration
to
a novel method
of monodesultirization
48 and 4b are readily
of
or by tirther
cuprate
we have developed
scheme
afforded
Compounds
(a mixture
di(3-furyl)
of chiral compounds.
of the E, Z-isomeric
when the presence
since long ago.’
of natural products
time is extended long enough, these compounds
alcohol
of the firan
with methyl (triphenylphosphoranylidene)acetate
to a 1: l-mixture quenched
on the synthesis
depicted
bis(phenylthio)methyllithium’ chromatography.
involved
that preserves
be useful for the preparation
or epoxides,
bearing the furan ring is hard to control,
while in others the reactions
are known
or lithium
of 3-furyllithium’
or even by the construction
of the C-atom
in the 3-position
to
reduction.
6.
either
7328
sche.me 1 1. n-BIG
(1.56M
THF,-78=‘C,
Phs2.
1
+
in hcxanc) 15 min
0
0 3y
OcH’ (0.5 cq.)
2
-+m
O
3
TX-IF,-78T,
30 min
8o?A
3 pkJ-=m
(2.5al.)
PhCQH (0.25 eq.) bcnzcnc,reflux,24h 6@?A -q;+Ty+q-
4p
DIJSL-H,
(2.5 eq., LOM, in m
ether. 0°C. 30 min 90%
6
5a
12(1.5=I.)
12(2 eq.1
6
acuone,42h 54%
S.W&q;);~
(1
67% 8
7
One could
expect
and by elimination the
reduction
isomerization explained
the alkoxide
reaction
to
the
alcohol
goes through
by the Baldwin’s
reaction,
after reduction
to give the target fitran. What is observed
product
12 to
11,
6, which
is
thus, leading to the formation
of ester 4a to cyclise
is a very easy isomerization
resistant
to
ring opening
unfavoured,
cyclization.
sequence
the ring opening
process,
to a dihydrofuran
however,
of 10 to 11 is a 5-exo-tef
ion promotes
a 5-endo-trig of 6.
is quite
a ring closure-
rules. I* Cyclization
to those rules. Then, phenylsulfide reverse
formed
giving
(scheme
process,
Probably
2), which can be
favoured
the alkoxide
the equilibrium
of the
according
12. Since the
is shifted towards
12
7329
scheme2
N*
sa
-6
c,
It was observed to compound treated
later that the alcohol
6 (now
by an allylic
with DIBAL-H
Although
favoured
cyclization.
Sexo-trig
illustrated
in scheme
Therefore,
the mixture
by TLC to afford the rearranged
of compound
by a reaction
of ester 4b also isomerizes
by reduction
rearrangement).
and monitored
the ring closure
can be circumvented
obtained
pathway
6 (5e&o-trig) in which
This condition
is a disfavoured
an intermediate
can be achieved
4a and 4b was
of esters
alcohol
6 directly. process,
formed
this difficulty
from 6 could
by an iodine
slowly
mediated
undergo
ring closure
a as
3.
Scheme 3
L
6
12 )
-
7ors
ECtOlPZ
Accordingly, (phenylthio)furan the presence homoallylic
treatment
of
homoallylic
7.15 Raney-nickel
of a benzyllic-like alcohol
6 with
mediated C-O
iodine
bond,
alcohol
6
with
desulfurization also
in the presence
prone
iodine
in
of 7 to give
furan
to hydrogenolysis.
of Et,N
acetone
afforded
2-
8 is complicated
by
However,
and H,O afforded
treatment
the desired
furan
of 8 in
67% yield.16
AcAnowltdgments: discussions.
Financial
(FAPESP),
Conselho
Coordenacgo
The support
authors came
National
de Aperfeicoamento
are grateful
from FundacBo de
to Professor de Amparo
Desenvolvimento
de Pessoal
Timothy a Pesquisa
Cientifico
de Nivel Superior
e
(CAPES).
J. Brocksom do Estado
Tecnologico
for helpful de Sgo Paulo (CNPq)
and
7330
REFERENCES
AND NOTES
1.
Dean, F. M. NaturaZQ Occuring oxygen Ring Compounds, Butterworth:
2.
Bock, I.; Bomowski,
London, 1963.
H.; Banft, A.; Theis, H. Tetrakerlion 1999, 46, 1199.
3.
Kojima, Y.; Wakitq S.; Kate, N. Tetrahekon
4.
Tanis, S. P.; Heninton, P. M. J. Org. Chem. 1983,48,4572.
5. 6.
Mandai, T.; Takcshita, M.; Mori, IL; Kawada, M.; Otera, J. CJterui~q~ Letters 1983, 1909. Kawaksmi, Y.; Asai, T.; Umeyama, K.; Ysmashita, Y. J. Org. Cbetu. 1982,47, 358 1
7.
Corey, E. J.; Seebach, D. J. Org. Chem. 1966,31,4097.
8.
Compound 3: ‘H NMB (CDCls, 80 MHz) 6 1.34 (s, 6H), 3.86-4.23 (m, 2I-Q 4.75 (dd, J-5.8Hz, J=7_4Hz, lH), 5.40 (a, lH), 7.17-7.54 (m, 1OH); “C NMB (CDCb, 20 MHz) 8 25.3 (GIG), 26.0 (CEt),
60.5 (CH), 66.8 (C&).
Left. 1979, 4577.
78.1 (CH). 111.1 (C), 128.6 (CH), 129.1 (CH), 129.3 (CH), 132.0
(C), 132.8 (C), 133.2 (CH), 133.9 (CH.), 199.8 (C); MS m/z (relative intensity) 360 (5.8) M’, 231 (loo), 9. ,lO.
101 (75.2).
Btkhart,
C.; Eichler, S.; Panse P. Angew. Chem. 1963, 75, 858.
Compound
4r: ‘H NMR (CDCI,, 80 MHz) 6 1.39 (s,3H),
probably dd, 4H), 6.14 (s, III), 6.97 (s, D-I), 7.10-7.57 26.8 (C&),
1.42 (8, 3H), 3.45 (overlap of s and
(m, 1OI-I); “C NMB (CDCla, 20 MHz) 6
27.6 (CH3). 52.6 (CH3), 54.4 (CH), 73.1 (CHz), 76.1 (CH), 110.7 (C), 118.2 (CI-I),
129.0 (CH), 129.8 (CH), 130.3 (CH), 130.4 (CH), 132.5 (CH), 134.4 (C), 135.2 (CI-I), 156.3 (C), 167.5 (C); IB (neat) v,, (89.9), 11.
109 (97.6)
Compound
cm-’ 1713 (GO),
101 (100)
1642 (C=(Z); MS m/z (relative intensity) 307 (53.2),
139
65 (72.6).
4b: ‘H NMR (CDCI,, 80 MHz) 6 1.38 (s, 6H), 3.46 (dd, J=6.4Hz,
(s, 3H), 4.35 (dd, J=8.OHz, J=8.5Hz, 6.23 (d, J=2.OHz, HI), 7.19-7.54
J=8.5Hz,
1H) 5.51 (s, HI), 5.68 (m, J=2.OHz, J=6.4Hz,
lH), 3.65
J-8.OH.2, HI),
(m, 1OH); “C NMB (CDCl3, 20 MHz) 6 24.4 (C&),
25.7 (CHr),
50.7 (CHJ), 54.6 (CH), 69.1 (CH2), 73.7 (CH), 109.4 (C), 119.1 (CH), 127.4, (CH), 127.8 (CH), 128.5 (CH),
128.6 (CH), 131.7 (CH), 132.3 (CH), 132.6 (CH), 133.6 (C), 134.0 (C), 156.7 (C),
165.3 (C); MS m/z (relative intensity) 307 (33.2), 12.
Compound
139 (86.1),
109 (loo),
101 (68.5),
65 (75.8).
Sa: ‘H NMR (CDCl3, 80 MHz) 8 1.40 (s, 6I-I) 3.57 (t, J=8.OHz, lH), 4.06 (d, J-6.7H2,
2H). 4.22 (dd, J=6.OHz, J=8.OHz, lH), 4.77 @r t, lH), 5.23 (s, 1H). 5.98 (t, J=6.7Hz,
lH), 7.17-
7.53 (m, 1OH); ‘“C NMB (CDCb, 20 MHz) 6 25.5 (CH3), 26.3 (CH3), 56.5 (CH), 58.6 (CH2), 70.5 (CH2), 78.1 (CH), 109.0 (C), 128.2 (CH), 128.5 (CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 130.0 (CH), 132.6 (CH), 133.8 (CH), 134.0 (C), 134.1 (C), 137.9 (C). 13.
The product was purified by flash chromatography.
Analysis of the ‘H NMR and ‘“C NMR spectra
showed that it is a mixture of isomers. MS m/z (relative intensity) 388 (11 .O) M’, 279 (27.5) (loo),
111
109 (60.7).
14.
Baldwin, J. E. J. C. S. Gem.
IS.
Compound J=2.1Hz,
Comm. 1976, 734.
7: ‘H NMK (CDCls, 80 MHz) 6 1.36 (s, 3H), 1.39 (s, 3H), 3.55-4.21
IH), 7.06-7.45
(m, 6H); 13C NMB (CD&
(m, 3H), 6.40 (d,
20 MHz) 6 25.8 (CH3), 25.9 (CH3), 42.1
(CH), 65.3 (CHz), 72.7 (C), 109.2 (CH), 114.2 (C), 127.4 (CI-I), 128.9 (CH), 132.6 (CH), 134.2 (C), 141.1 (CH), 155.6 (C). 16.
Compound (dd, J-5.8I-Iz,
8: ‘H NhdR (CDCls, 80 MHz) 6 1.43 (s, 3H), 1.47 (s, 3H), 3.76 (t, J=S.OHz, lH), 4.20 J=8.OHz, lH), 5.03 (dd, J=5.8Hz,
13CNMR(CDC13,20Mhz)G25.6,26.7,
J=8.OHz, lH), 6.39 (m, IH), 7.34-7.47
70.2,70.6,
(Received in USA 20 June 1994; accepted 9 August 1994)
108.6, 109.4, 123.9,
140.1,
143.6.
(m, 2H);