Heteroaromatic dithioacetals part I: The preparation of unsymmetrical dithioacetals from heteroaromatic thiols

Article abstract of DOI:10.1055/s-1998-1636

The preparation of unsymmetrical dithioacetals derived from heteroaromatic thiols and alkyl thiols is described. Insights into the rich potential of this new class of thioacetals is exemplified with the conversion to various derivatives.

Full text of DOI:10.1055/s-1998-1636

March 1998
SYNLETT
289
Heteroaromatic Dithioacetals Part I: The Preparation of Unsymmetrical Dithioacetals
from Heteroaromatic Thiols
Jacques Yves Gauthier*, Nicolas Zajac , Darrin L. Mayhew , Gregory J. Hughes , Evelyn Martins1d, Daniel Guay, Robert N. Young and Robert J.
1
a
1b
1c
Zamboni
Medicinal Chemistry Department, Merck Frosst Centre For Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Québec, CANADA,
H9R 4P8
E-mail : jacquesyves_gauthier@merck.com
Received 2 December 1997
Abstract: The preparation of unsymmetrical dithioacetals derived from
heteroaromatic thiols and alkyl thiols is described. Insights into the rich
potential of this new class of thioacetals is exemplified with the
conversion to various derivatives.
The discovery of a method for preparing unsymmetrical dithioacetals
from which (i) the sulfur atom substituents can be varied at will and (ii)
2
optically pure asymmetric acetals can be readily obtained has been
pivotal to the development of Venzair® (MK 679), a drug candidate
which validated the hypothesis that leukotriene D antagonists are of
benefit in the treatment of asthma. In addition to the interest generated
4
3
Scheme 1
in this area of medicinal chemistry, the results obtained with the
preparation of unsymmetrical dithioacetals have raised some
fundamental questions concerning the factors which influence the
condensation of acyl thiols and alkyl thiols with aldehydes. Initially we
hypothesized and verified that the condensation of 1 on aldehydes
produces only 2 but the hypothesis was based only on kinetic
considerations: the initial attack of the more nucleophilic alkyl-
substituted thiol followed by an intramolecular cyclization with the less
nucleophilic thiol acid group (Scheme 1).
However, the fact that virtually no traces of 3 and 4 were observed lead
us to suspect the existence of other factors such as thermodynamics,
which contribute to the exclusive formation of 2. From these
considerations emerged the discovery that only unsymmetrical
dithioacetals 5 are produced when stoichiometric amounts of thiol acids
and alkyl thiols are allowed to react with aldehydes (Lewis acid

2
90
LETTERS
SYNLETT
catalysis). A number of explanations were proposed to explain this
remarkable selectivity. Kinetic arguments were raised based on the large
difference in the nucleophilicity of an alkyl thiol compared to an acyl
Under such conditions, the kinetically favoured bis-aliphatic
dithioacetals are formed. Furthermore, nearly statistical mixtures are
obtained if the difference in inductive effects is not large enough. Thus,
the reaction of 4-chlorobenzaldehyde with 4-chlorothiophenol and
benzyl mercaptan yielded an inseparable mixture of the 3 possible
4
thiol , thus supporting a kinetic control during the condensation
reaction. Others considered the existence, in the product, of electronic
effects -best described as push-pull effects- resulting in a stabilizing
hyperconjugation through the acetal carbon.5 Intuitively, these orbital
interactions should be maximized when the inductive effects of an
electron-withdrawing substituent (the acyl group) and an electron-
donating substituent (the alkyl group) are combined in the
acylthioalkylthioacetals. This is in agreement with the work of others
about conformational preferences in 2-(arylseleno)-1,3-dithianes and
dithioacetals. Presumably, with heterocycles containing
a basic
nitrogen, complexation with the acid used (BF •OEt and/or TFA) may
3
2
serve to enhance the inductive effects. The purity of commercially
available thiols is variable, especially for aromatic thiols. They are
relatively easy to purify, if required, but for practical reasons we chose
to use an excess of the aromatic thiols (c.a. 2 equiv.) and the aliphatic
thiols (1.1-1.2 equiv.). This stoichiometry invariably produced the
unsymmetrical dithioacetals in high yields. No traces of the bis-aromatic
dithioacetals, but residual amounts (5-10%) of the bis-aliphatic
dithioacetals, were typically observed. As demonstrated with the variety
of aldehydes, alkyl thiols and aryl thiols used in this study, the reaction
is quite general. However, some difficulties were encountered in
attempting to prepare unsymmetrical dithioacetals derived from 2-
mercapto-N-methyl-imidazole and 2-mercaptothiazole (entries 11 and
15). Benzyl mercaptan is the aliphatic component in each case.
Although these pair of thiols initially produced the desired S,S-acetals
6
related systems. Mechanistic studies are required to definitely account
for the origin of these results but it remains that dithioacetals where one
sulfur atom bears an electron-withdrawing group and the other an
electron-donating group are formed preferentially over the
corresponding symmetrical dithioacetals. From this, we deduced that
the replacement of the acyl group by other electron-withdrawing
substituents, such as aromatic groups, would allow a similar control
(Figure 1).
(NMR examination of reacting mixtures and of freshly isolated
compounds) they somewhat unpredictably rearranged to the
unsymmetrical S,N-acetals, 8 and 10. These novel acetals are best
characterized by their 13C NMR with resonances for the thiocarbonyls
at 163.8 and 161.3 p.p.m., respectively. Preliminary experiments seem
to indicate that the rearrangement occurs more readily with aromatic
aldehydes where the intermediacy of a benzylic carbocation would be
stabilized by resonance. Furthermore, the rearrangement from isolated
S,S-acetals could be thermally induced and occurred at 80 °C and 140
Figure 1
We wish to report that this hypothesis was successfully verified and
provides an entry into a new class of dithioacetals with an exceptionally
rich potential for synthesis. Using the model system of 4-
chlorobenzaldehyde (1 equiv.), 4-mercaptopyridine (1.5 equiv.; the
commercial material is c.a. 85% pure) and benzyl mercaptan (1.1
equiv.) we observed that the condensation, catalyzed by a Lewis acid
such as boron trifluoride etherate, yields nearly exclusively the
alkylthioarylthioacetal, 6, when the reaction is worked up after 8-16
hours (scheme 2).
°
C for 7 and 9 respectively (Scheme 3).
Scheme 2
Scheme 3
Therefore the scope of the reaction was explored and similar results
were obtained with various aromatic or aliphatic aldehydes and thiols
As well as being fundamentally of interest, the preparation of this new
class of dithioacetals offers a rich potential in synthetic organic
chemistry. Preliminary accounts of some of the most obvious
transformations are illustrated in scheme 4.
(
Table). The following general comments summarize our observations
7
while experimental details are given in the References section. The
distribution of the products appears not to be affected by the nature of
the aldehyde, the catalyst, or the solvent, although the condensation is
faster and the product is obtained in higher yield with a strong Lewis
acid such as boron trifluoride etherate. The heteroaromatic thiols are
usually more soluble in a solvent such as acetronitrile. Trifluoroacetic
acid may be needed as a co-solvent (or co-catalyst eventually) for that
purpose. Typically, the reactants are mixed at 0 °C, the catalyst is added,
and the mixture is allowed to warm to 25 °C at which temperature the
aldehyde is rapidly consumed and produces the desired unsymmetrical
dithioacetal within 8-16 hours. If the reaction is quenched at 0 °C, even
after a few hours, the product distribution is dramatically affected.
For example, we have already verified that 11 is metallated with a base
as mild as NaH (0 °C, DMF) and the resulting anion reacted smoothly
with an electrophile such as allyl bromide to produce the dithioketal (92
%). Under the same conditions, 2-phenyl-1,3-dithiane is recovered
unchanged. In addition, the presence of a basic nitrogen in the
dithioacetal moiety allows a smooth regeneration of the carbonyl group
with no requirement for heavy metal salts or oxidizing agents. Thus, 4-
chlorobenzaldehyde was recovered nearly quantitatively from 12 upon
treatment with MeI in aqueous DMF at 25 °C. A number of nucleophilic

March 1998
SYNLETT
291
(
2) a) Young, R. N.; Gauthier, J. Y.; Thérien, M.; Zamboni, R.
Heterocycles, 1989, 28, 967 and references therein. b) Gauthier, J.
Y.; Jones, T.; Champion, E.; Charette, L.; Dehaven, R.; Ford-
Hutchinson, A. W.; Hoogsteen, K.; Lord, A.; Masson, P.;
Piechuta, H.; Pong, S.S.; Springer, J. P.; Thérien, M.; Zamboni,
R.; Young, R. N. J. Med. Chem. 1990, 33, 2841.
(
3) Margolskee, D.; Bodman, S.; Dockhorn, R.; Israel, E.; Kemp, J.;
Mansmann, H.; Minotti, D. A.; Spector, R.; Stricker, W.;
Tinkelman, D.; Townley, R.; Winder, J.; Williams, V. J. Allergy
Clin. Immunol. 1991, 87, 309.
(4) Barnett, R. E.; Jencks, W. P. J. Am. Chem. Soc. 1969, 91, 6758.
(
5) For a review on the anomeric effect, see: Deslongchamps, P.
Stereoelectronic Effects in Organic Chemistry,; Pergamon:
Oxford, 1983.
(6) Pinto, B. M.; Johnston, B. D.; Sandoval-Ramirez, J.; Dev Sharma,
R. J. Org. Chem. 1988, 53, 3766.
Scheme 4
(
7) Dithioacetalisation. Conditions A. 4-[[(4-chlorophenyl)-
type displacements at the acetal carbon can also be envisaged. Among
them, the replacement of the thiopyridine group in 12 by hydrogen
occurs readily with a reducing metal such as zinc in acetic acid (95 %
[(phenylmethyl)-thio]methyl]thio]-pyridine, 6: to a 0 °C sus-
pension of p-chlorobenzaldehyde (3.0 mmol, 422 mg), benzyl
mercaptan (3.3 mmol, 390 uL) and 4-mercaptopyridine (6 mmol,
yield) or with the NaBH CN/ZnI system (90 % yield). This reduction
3
2
7
80 mg) in 1,2-dichloroethane (12 mL) was added trifluoroacetic
acid (3 mL). The cold bath was removed and the mixture stirred at
5 °C for 16 hours. The suspension was poured slowly into ice-
is of interest in view of the overall transformation which constitutes a
non-basic alkylation of a thiol.
2
cold 10 % aqueous NaHCO3 under vigourous stirring and then
extracted with EtOAc (3X). The combined organic extracts were
In conclusion, a new and fundamentally intriguing behaviour in the
thioacetalization of aldehydes has been discovered. The chemistry of
dithioacetals is already rich in variants. It is likely that the potential
offered by unsymmetrical dithioacetals will also be diversified.
Mechanistic aspects of this condensation reaction will be discussed in a
Letter to follow soon, while the chemistry of these novel unsymmetrical
dithioacetals will be the subject of future reports.
washed with brine and dried with Na SO . The residue from
2
4
8
evaporation of the solvents was purified by chromatography with
EtOAc:hexanes, 3:1, to yield the title compound (870 mg, 81 %).
Conditions B: to a 0 °C suspension of 4-chlorobenzaldehyde (5.0
mmol, 703 mg), benzyl mercaptan (5 mmol, 587 uL) and 4-
mercaptopyridine (10 mmol, 1.23 g) in acetonitrile (25 mL) was
added BF •OEt (20 mmol, 2.46 mL). The cold bath was removed
3
2
and the mixture stirred at 25 °C for 16 hours. Work-up was as
described for Conditions A to yield 6 (1.39 g, 78 %). Conditions
C : 4-[[(4-chlorophenyl)[cyclohexyl)thio]methyl]thio]-pyridine,
entry 2 : to a 0 °C suspension of 4-chlorobenzaldehyde (2.2
mmol, 281 mg), cyclohexyl mercaptan (2.2 mmol, 269 uL) and
purified 4-mercaptopyridine ( 2.2 mmol, 245 mg) in acetonitrile
Acknowledgements: The authors are grateful to a number of colleagues
for help and encouragement during this work, to L. Trimble for N.M.R.
experiments and to the management of MFCTR for the liberty to
explore and invest time in explorative chemistry.
References and Notes:
(10 mL) were added successively trifluoroacetic acid (2 mL) and
BF •OEt (6 mmol, 737 uL). The cold bath was removed and the
3
2
mixture stirred at 25 °C for 16 hours. Work-up was as described
for Conditions A to yield the title compound (583 mg, 84 %).
(
1) Undergraduate Research Participants from (a) Université de
Sherbrooke, Sherbrooke, Québec, (b) University of Waterloo,
Waterloo, Ontario, (c) Université du Nouveau-Brunswick,
Frédéricton, Nouveau-Brunswick, (d) McGill University,
Montréal, Québec.
(8) Wood, W. W. In Organosulfur Chemistry; Page, P. Ed.;
Academic: London, 1995; , p 133.