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A novel and efficient method for the preparation of asymmetric dithioacetals
Tetrahedron Letters,Vol.29,No.Sl,pp 6729-6732,1988 Printed in Great Britain
0040-4039/88 $3.00 + .OO Pergamon Press plc
A NOVEL AND EFFICIENT METHOD FOR THE PREPARATION OF ASYMMETRIC DITHIOACETALS J.Y. Gauthier*. T. Henien, L. Lo, M. Therien and R.N. Young* Merck Frosst Center for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Abstract: Aldehydes and ketones react with one equivalent each of thiols and thiolacetic acid under acid catalysis to yield almost exclusively the mixed alkylthio-(or arylthio-) acvlthioacetals. Reaction of the mixed thioacetal with a nucleoohile (such as NaOMe) liberates the thiolate anion which can be trapped with a variety'of electrophiles to provide asymmetric dithioacetals in high yields. Thioacetals protecting
and thioketals
groups
are an important
for aldehydes
and ketones
can serve as acyl anion equivalents. the medicinal
chemistry
served as mimetics
This unit has also recently
of leukotriene
of the diacid
class of functional
groups
best known as
and, in the case of thioacetals,
antagonists
polar portion
as units which
found considerable
where bis-thioalkanoic
(Cl-C61 of leukotriene
use in
acid acetals
have
Cl4 or leukotriene
'V2'3 The derivatives of this type reported to date have been generally symmetrical E4' dithioacetals prepared in the normal manner from a thiol and an aldehyde or equivalent. have recently
developed
an unsymmetrical
dithioacetal
To facilitate and versatile
method
greatly
Several which
authors
in reactivity.
alkylation
procedures8
The preparation
activity
studies
in this area we sought a simple.
of dithioacetals
unsymmetrical
have reported in moderate
(particularly
Reaction
of dithioesters
can provide
unsymmetrical
(or thiolesters). ""'
dithioacetals
the stepwise
yield
of mixed acylthioalkylthioacetals
or a-halothioethers
D4 antagonists
could be varied at will and thus rendered
to prepare
can proceed
leukotriene
We
bearing
(I14.
for the preparation chains
A number of methods literature.
moiety
our structure
where the two acetal
ketones5'6
a series of potent and specific
aryldithioacetals) asymmetric.
have been reported
addition
especially
of thiols
reagents'
dithioacetals
in moderate
has also been reported
6729
in the
to aldehydes
and
when the two thiols differ
with grignard
by reductive
efficient
acylation
or under reductive to good yields.
from a-alkoxy-'
of dithioesters'
and
6730
by alkylation procedures
promoted
exchange
were investigated
from symmetrical
but were deemed
dithioacetals."
A number of these
to lack the facility
and versatility
which we
required. As an extension
of our earlier
with thiols or thiolacids observation
of the quantitative
p-mercaptothiolpropionic to examine
formation
system of an aldehyde,
We have found that equivalent to give the mixed
dithioacetals
can subsequently
variety of electrophiles the preparation
of the cyclic dithianone
acid (with zinc iodide catalyst
the three component
acid catalysis
work on the acid catalyzed reaction of activated alcohols 12,13 or thiolesters and based on the initial
to give thioethers
amounts
be deacylated
to give asymmetric
of III are presented
1 R
K
(III)
yield.
thiolate
alkylated
(IV) (Scheme
1).
SCOCH, *
R
HSR’
H(K)
-
Entry
Aldehyde
b>
for
H(R’) t
SR’
of aldehydes
SR’
IV
and ketones
HSR'
(Ketone)
with thiols
(HSR') and
Conditionsa
Yield of III
benzaldehyde
HSCH2CH2CON(CH3)2
A
a4
benzaldehyde
HSCH2CH2CON(CH3)2
I3
73
p-chlorobenzaldehyde
HSC6H5
6
71
p-chlorobenzaldehyde
HSC6H4pOCH3
B
86
p-chlorobenzaldehyde
HSC6H4pN02
B
72
B
a7
p-chlorobenzaldehyde
a)
The results
R 2) R2X
f
acid cat.
reaction
with a wide
SR2
1) Nu:
III Table 1: Acid catalyzed thiolacetic acid
react under
The mixed
in Table I.
HSCOCH3 H(R’)
acid.
a thiol and a thiolacid
dithioacetals
and
we were prompted
in excellent
and the resulting
0
Scheme
in CH2C12),
thiol and thiolacetic
of an aldehyde,
acyldithioacetals
(II) from benzaldehyde
p-chlorobenzaldehyde
HSC9H19 HSC(CH3)3
B
91
n-nonylaldehyde
HSC(CH3)3
B
64
P-butanone
HSCH2C6H5pOCH3
C
14
Reaction conditions A: 0.1 eq. pTSOH, ClCH2CH2C1, 2 hr. reflux; B: 0.2 eq ZnI2. CH2Cl2, 2 hr. reflux; C: 0.7 eq., BF3*0Etz, ClCH2CH2C1, O"C, 18 hr. Isolated yields, all new products gave satisfactory elemental analysis.
The normal solvent
reaction
conditions
such as dichloroethane
N2 for l-4 hours at ZO-60°C. dithioacetals
are observed
involve mixing
and then adding Generally
thiol,
thiolacid
the catalyst
and aldehyde
and stirring
only traces of the corresponding
and are readily
removed
by chromatography.
in an inert
the mixture
under
symmetrical As can be seen from
6731
the table,
reactions
nucleophilicity Alkyl
thiols. forcing
with benzaldehydes
aldehydes
conditions
low temperature
and even then proceeded
of the thioacyl
in the presence
nethoxide
followed
by addition
presented
in Table
II.
Oeacylation
nucleophiles
using potassium
R*X
in
entry 7) of the more
yield. can be achieved
carbonate
at
in methanol
or preferrably
Some representative
of mixed acyldithioacetals
(III)
by variations
(entry 9) required
alkylation
such as methyllithium
of the electrophile.
and alkylation
Mixed Thioacetal
Entry
unaffected
(entry 6 versus
in only moderate
group and its subsequent
of an electrophile
by -treatment first with stronger
Table II:
in high yields
also react well (entry 8) but alkyl ketones
(BF3eOEt2)
The deacylation
proceed
entry 5) or steric hindrance
(entry 4 versus
results
or
sodium are
(III+IV)
1
R=pClC6H4
R'=C6H5
BrCH2CON2(CH3)2
A
Yield (IV)b (X) 40
2
R=pClC6H4
R1=C6H5
BrCH2CON2(CH3)2
B
50
3
R=pClC6H4
R1=C6H5
8rCH2CON2(CH3)2
C
69
4
R=pClC6H4
R1=CgHlg
BrCH2CON(CH3)2
A
94
5
R=pClC6H4
R1=CgHlg
BrCH2CON(CH3)2
C
93
6
R=pClC6H4
R1=C(CH3)3
BrCH2CON(CH3)2
A
97
7
R=pC1C6H4
R'=CgHlg
BrCH2CH3
C
95
8
R=pClC6H4
R1=CgHlg
C1CH2CH2COOCH3
C
87
9
R=pClC6H4
R'=CH2CH2CON(CH3)3
CH2=CHCOOCH3
A
87
10
R=C7H15
R1=C(CH3)3
CH2=CHCOOCH3
C
75
11
R=CH2CH3
R'=CH2C6H4pOCH3
BrCH2COOCH3
C
86
a)
b)
R'=CH3
Conditionsa
Reaction conditions A: RZX, K2CO3, CH30H, 2-butanone, -lO"C, 1.5 hr.; B: CH3Li, THF. -80°C. 5 min; RX, 1 hr. -8O"C-RT; C: 1 eq. 1M NaOCH3 in CH3OH. -8O"C, 5 min.; RZX. 20 min., -8O"C-RT. Isolated yields; all new compounds gave satisfactory elemental analysis.
Alkylations various
of arylthioacylthioacetals
conditions
due to competing
thioaldehyde
and arylthiolate
(Scheme 2).
However
even by relatively
Scheme 2
(entries
cleavage
1,2,3) proceed
of the intermediate
anion which may then compete
alkylthioacylthioacetals
poor electrophiles
(entries
in moderate
thiolate
for reaction
IV
R*SPh
yields
under
anion to liberate
with the electrophile
4-11) are alkylated
such as bromoethane.
THF,
in high yields
6732
Conclusions: The method described in this report provides a versatile and simple method for the synthesis of asymmetric dithioacetals. The preferential formation of the mixed thioacylthioalkylacetalin the first step suggests that this is the thermodynamicallyfavored product. Strong evidence for this was obtained by an experiment monitored by NMR and tic in parallel flasks. p-Chlorobenzaldehydewas reacted with ZnI2 and either 1 eq. of t-BUSH or
1 eq. of CH3COSH. Within 30 min. NMR and tic indicated complete consumption of the thiol or thiolacid to form 0.5 equivalents of the corresponding symmetrical dithioalkyl- or dithioacylacetals(indicated by NMR signals at ca. 5.0 and ca. 6.2 ppm respectively). To each reaction was added a further 1 eq. of original thiol or thiolacid and then the two reactions were mixed. Within 15 min. at RT, NMR (and tic) indicated essentially complete conversion to m
the mixed dithioacetal (III;R=pC1C6H4, R'=C(CH3)3) showing
characteristicmethine absorption at 5.7 ppm.
Further studies on the mechanism of this
unusual reaction will be the subject of a full account to be published later. Acknowledgements: Helpful discussions and suggestions of Dr. J.G. Atkinson are greatfully acknowledged. References 1. C.D. Perchonock, M.E. McCarthy, K.F. Erhard, J.G. Gleason, M.A. Wasserman, R.M. Muccitelli, J.F. DeVan, S.S. Tucker, L.M. Vickery, T. Kerchner. B.M. Weichman, S. Mong, S.T. Crooke and J.F. Newton. J. Med. Chem., 2, 1145 (1985). 2. A.K. Saksena. M.J. Green. P. Mangiaracina, J.K. Wang. W. Kreutner and A.R. Gulbenkian, Tetrahedron Lett., 26, 6427 (1985). 3.
R.N. Young and J.Y. Gauthier, U.K. Patent Application #2190377. November 18. 1987.
4.
R.N. Young, R. Zamboni and S. Leger. European Patent Application #233,763, Aug. 26, .1988.
5.
T. Posner. Chem. Ber., 3,
6.
D.T. Gibson. J. Chem. Sot.. 2637 (1931).
7.
D. Paquer, Bul. Sot. Chim. France, 1439 (1975).
8.
L. Kristenbrugger and J. Voss, Liebigs Ann. Chem., 472 (1980).
9.
M. Martin and L. Bassery, C.R. Acad. Sci. Paris Ser. C., 281, 571 (1975).
296 (1903).
10. P. Dubs and R. Stussi, Helv. Chim. Acta. 61, 2351 (1978). 11. H. Bohme. H. Bezzenberger and 0. Muller, Arch. Pharmaz.. 3.!X,268 (1973). 12. Y, Guindon, R. Frenette, R. Fortin and J. Rokach, J. Org. Chem.. 4, 13. J.Y. Gauthier, F. Bourdon and R.N. Young. Tetrahedron Lett., a,
(Received in USA 15 August 1988)
1357 (1984).
15 (1986).
0040-4039/88 $3.00 + .OO Pergamon Press plc
A NOVEL AND EFFICIENT METHOD FOR THE PREPARATION OF ASYMMETRIC DITHIOACETALS J.Y. Gauthier*. T. Henien, L. Lo, M. Therien and R.N. Young* Merck Frosst Center for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Abstract: Aldehydes and ketones react with one equivalent each of thiols and thiolacetic acid under acid catalysis to yield almost exclusively the mixed alkylthio-(or arylthio-) acvlthioacetals. Reaction of the mixed thioacetal with a nucleoohile (such as NaOMe) liberates the thiolate anion which can be trapped with a variety'of electrophiles to provide asymmetric dithioacetals in high yields. Thioacetals protecting
and thioketals
groups
are an important
for aldehydes
and ketones
can serve as acyl anion equivalents. the medicinal
chemistry
served as mimetics
This unit has also recently
of leukotriene
of the diacid
class of functional
groups
best known as
and, in the case of thioacetals,
antagonists
polar portion
as units which
found considerable
where bis-thioalkanoic
(Cl-C61 of leukotriene
use in
acid acetals
have
Cl4 or leukotriene
'V2'3 The derivatives of this type reported to date have been generally symmetrical E4' dithioacetals prepared in the normal manner from a thiol and an aldehyde or equivalent. have recently
developed
an unsymmetrical
dithioacetal
To facilitate and versatile
method
greatly
Several which
authors
in reactivity.
alkylation
procedures8
The preparation
activity
studies
in this area we sought a simple.
of dithioacetals
unsymmetrical
have reported in moderate
(particularly
Reaction
of dithioesters
can provide
unsymmetrical
(or thiolesters). ""'
dithioacetals
the stepwise
yield
of mixed acylthioalkylthioacetals
or a-halothioethers
D4 antagonists
could be varied at will and thus rendered
to prepare
can proceed
leukotriene
We
bearing
(I14.
for the preparation chains
A number of methods literature.
moiety
our structure
where the two acetal
ketones5'6
a series of potent and specific
aryldithioacetals) asymmetric.
have been reported
addition
especially
of thiols
reagents'
dithioacetals
in moderate
has also been reported
6729
in the
to aldehydes
and
when the two thiols differ
with grignard
by reductive
efficient
acylation
or under reductive to good yields.
from a-alkoxy-'
of dithioesters'
and
6730
by alkylation procedures
promoted
exchange
were investigated
from symmetrical
but were deemed
dithioacetals."
A number of these
to lack the facility
and versatility
which we
required. As an extension
of our earlier
with thiols or thiolacids observation
of the quantitative
p-mercaptothiolpropionic to examine
formation
system of an aldehyde,
We have found that equivalent to give the mixed
dithioacetals
can subsequently
variety of electrophiles the preparation
of the cyclic dithianone
acid (with zinc iodide catalyst
the three component
acid catalysis
work on the acid catalyzed reaction of activated alcohols 12,13 or thiolesters and based on the initial
to give thioethers
amounts
be deacylated
to give asymmetric
of III are presented
1 R
K
(III)
yield.
thiolate
alkylated
(IV) (Scheme
1).
SCOCH, *
R
HSR’
H(K)
-
Entry
Aldehyde
b>
for
H(R’) t
SR’
of aldehydes
SR’
IV
and ketones
HSR'
(Ketone)
with thiols
(HSR') and
Conditionsa
Yield of III
benzaldehyde
HSCH2CH2CON(CH3)2
A
a4
benzaldehyde
HSCH2CH2CON(CH3)2
I3
73
p-chlorobenzaldehyde
HSC6H5
6
71
p-chlorobenzaldehyde
HSC6H4pOCH3
B
86
p-chlorobenzaldehyde
HSC6H4pN02
B
72
B
a7
p-chlorobenzaldehyde
a)
The results
R 2) R2X
f
acid cat.
reaction
with a wide
SR2
1) Nu:
III Table 1: Acid catalyzed thiolacetic acid
react under
The mixed
in Table I.
HSCOCH3 H(R’)
acid.
a thiol and a thiolacid
dithioacetals
and
we were prompted
in excellent
and the resulting
0
Scheme
in CH2C12),
thiol and thiolacetic
of an aldehyde,
acyldithioacetals
(II) from benzaldehyde
p-chlorobenzaldehyde
HSC9H19 HSC(CH3)3
B
91
n-nonylaldehyde
HSC(CH3)3
B
64
P-butanone
HSCH2C6H5pOCH3
C
14
Reaction conditions A: 0.1 eq. pTSOH, ClCH2CH2C1, 2 hr. reflux; B: 0.2 eq ZnI2. CH2Cl2, 2 hr. reflux; C: 0.7 eq., BF3*0Etz, ClCH2CH2C1, O"C, 18 hr. Isolated yields, all new products gave satisfactory elemental analysis.
The normal solvent
reaction
conditions
such as dichloroethane
N2 for l-4 hours at ZO-60°C. dithioacetals
are observed
involve mixing
and then adding Generally
thiol,
thiolacid
the catalyst
and aldehyde
and stirring
only traces of the corresponding
and are readily
removed
by chromatography.
in an inert
the mixture
under
symmetrical As can be seen from
6731
the table,
reactions
nucleophilicity Alkyl
thiols. forcing
with benzaldehydes
aldehydes
conditions
low temperature
and even then proceeded
of the thioacyl
in the presence
nethoxide
followed
by addition
presented
in Table
II.
Oeacylation
nucleophiles
using potassium
R*X
in
entry 7) of the more
yield. can be achieved
carbonate
at
in methanol
or preferrably
Some representative
of mixed acyldithioacetals
(III)
by variations
(entry 9) required
alkylation
such as methyllithium
of the electrophile.
and alkylation
Mixed Thioacetal
Entry
unaffected
(entry 6 versus
in only moderate
group and its subsequent
of an electrophile
by -treatment first with stronger
Table II:
in high yields
also react well (entry 8) but alkyl ketones
(BF3eOEt2)
The deacylation
proceed
entry 5) or steric hindrance
(entry 4 versus
results
or
sodium are
(III+IV)
1
R=pClC6H4
R'=C6H5
BrCH2CON2(CH3)2
A
Yield (IV)b (X) 40
2
R=pClC6H4
R1=C6H5
BrCH2CON2(CH3)2
B
50
3
R=pClC6H4
R1=C6H5
8rCH2CON2(CH3)2
C
69
4
R=pClC6H4
R1=CgHlg
BrCH2CON(CH3)2
A
94
5
R=pClC6H4
R1=CgHlg
BrCH2CON(CH3)2
C
93
6
R=pClC6H4
R1=C(CH3)3
BrCH2CON(CH3)2
A
97
7
R=pC1C6H4
R'=CgHlg
BrCH2CH3
C
95
8
R=pClC6H4
R1=CgHlg
C1CH2CH2COOCH3
C
87
9
R=pClC6H4
R'=CH2CH2CON(CH3)3
CH2=CHCOOCH3
A
87
10
R=C7H15
R1=C(CH3)3
CH2=CHCOOCH3
C
75
11
R=CH2CH3
R'=CH2C6H4pOCH3
BrCH2COOCH3
C
86
a)
b)
R'=CH3
Conditionsa
Reaction conditions A: RZX, K2CO3, CH30H, 2-butanone, -lO"C, 1.5 hr.; B: CH3Li, THF. -80°C. 5 min; RX, 1 hr. -8O"C-RT; C: 1 eq. 1M NaOCH3 in CH3OH. -8O"C, 5 min.; RZX. 20 min., -8O"C-RT. Isolated yields; all new compounds gave satisfactory elemental analysis.
Alkylations various
of arylthioacylthioacetals
conditions
due to competing
thioaldehyde
and arylthiolate
(Scheme 2).
However
even by relatively
Scheme 2
(entries
cleavage
1,2,3) proceed
of the intermediate
anion which may then compete
alkylthioacylthioacetals
poor electrophiles
(entries
in moderate
thiolate
for reaction
IV
R*SPh
yields
under
anion to liberate
with the electrophile
4-11) are alkylated
such as bromoethane.
THF,
in high yields
6732
Conclusions: The method described in this report provides a versatile and simple method for the synthesis of asymmetric dithioacetals. The preferential formation of the mixed thioacylthioalkylacetalin the first step suggests that this is the thermodynamicallyfavored product. Strong evidence for this was obtained by an experiment monitored by NMR and tic in parallel flasks. p-Chlorobenzaldehydewas reacted with ZnI2 and either 1 eq. of t-BUSH or
1 eq. of CH3COSH. Within 30 min. NMR and tic indicated complete consumption of the thiol or thiolacid to form 0.5 equivalents of the corresponding symmetrical dithioalkyl- or dithioacylacetals(indicated by NMR signals at ca. 5.0 and ca. 6.2 ppm respectively). To each reaction was added a further 1 eq. of original thiol or thiolacid and then the two reactions were mixed. Within 15 min. at RT, NMR (and tic) indicated essentially complete conversion to m
the mixed dithioacetal (III;R=pC1C6H4, R'=C(CH3)3) showing
characteristicmethine absorption at 5.7 ppm.
Further studies on the mechanism of this
unusual reaction will be the subject of a full account to be published later. Acknowledgements: Helpful discussions and suggestions of Dr. J.G. Atkinson are greatfully acknowledged. References 1. C.D. Perchonock, M.E. McCarthy, K.F. Erhard, J.G. Gleason, M.A. Wasserman, R.M. Muccitelli, J.F. DeVan, S.S. Tucker, L.M. Vickery, T. Kerchner. B.M. Weichman, S. Mong, S.T. Crooke and J.F. Newton. J. Med. Chem., 2, 1145 (1985). 2. A.K. Saksena. M.J. Green. P. Mangiaracina, J.K. Wang. W. Kreutner and A.R. Gulbenkian, Tetrahedron Lett., 26, 6427 (1985). 3.
R.N. Young and J.Y. Gauthier, U.K. Patent Application #2190377. November 18. 1987.
4.
R.N. Young, R. Zamboni and S. Leger. European Patent Application #233,763, Aug. 26, .1988.
5.
T. Posner. Chem. Ber., 3,
6.
D.T. Gibson. J. Chem. Sot.. 2637 (1931).
7.
D. Paquer, Bul. Sot. Chim. France, 1439 (1975).
8.
L. Kristenbrugger and J. Voss, Liebigs Ann. Chem., 472 (1980).
9.
M. Martin and L. Bassery, C.R. Acad. Sci. Paris Ser. C., 281, 571 (1975).
296 (1903).
10. P. Dubs and R. Stussi, Helv. Chim. Acta. 61, 2351 (1978). 11. H. Bohme. H. Bezzenberger and 0. Muller, Arch. Pharmaz.. 3.!X,268 (1973). 12. Y, Guindon, R. Frenette, R. Fortin and J. Rokach, J. Org. Chem.. 4, 13. J.Y. Gauthier, F. Bourdon and R.N. Young. Tetrahedron Lett., a,
(Received in USA 15 August 1988)
1357 (1984).
15 (1986).