Synthesis of vicinal bis(alkylthio) derivatives by reductive coupling of dithioacetals derived from aromatic aldehydes with low valent titanium iodide species

Article abstract of DOI:10.1246/cl.2001.640

Reduction of dithioacetals derived from aromatic aldehydes with low valent titanium iodide species in situ formed by treatment of titanium(IV) iodide with zinc in a mixed solvent of dichloromethane and pivalonitrile at room temperature afforded coupling products, vicinal bis(alkylthio) derivatives, in good to high yields.

Full text of DOI:10.1246/cl.2001.640

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40
Chemistry Letters 2001
Synthesis of Vicinal Bis(alkylthio) Derivatives by Reductive Coupling of Dithioacetals Derived
from Aromatic Aldehydes with Low Valent Titanium Iodide Species
Naritoshi Yoshimura, Koji Igarashi, Setsuo Funasaka, and Teruaki Mukaiyama*
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received April 23, 2001; CL-010375)
Reduction of dithioacetals derived from aromatic aldehydes
with low valent titanium iodide species in situ formed by treatment
of titanium(IV) iodide with zinc in a mixed solvent of dichloro-
methane and pivalonitrile at room temperature afforded coupling
products, vicinal bis(alkylthio) derivatives, in good to high yields.
Synthesis of pinacols by reductive coupling of carbonyl
compounds is an important tool for the formation of vicinal
diols. Of various reducing reagents, low valent titanium com-
pounds proved to be particularly effective and are being studied
intensively.1 Recently, it was reported from our laboratory that
a newly utilized low valent titanium iodide species in situ
formed by treating titanium(IV) iodide with copper was an
effective reductant to afford various vicinal diols from various
aromatic and aliphatic aldehydes in good to high yields with
2
good to high diastereoselectivities under mild conditions. Also
3
from our laboratory in 1978, it was reported that various vici-
nal dialkoxy derivatives or olefins were obtained by treating
acetals, which were usually considered as protected aldehydes
4
under basic conditions, with low valent titanium chloride
species prepared from titanium(IV) chloride and lithium alu-
minum hydride in THF at room temperature.
In order to apply the newly utilized low valent titanium
iodide species to various synthetic reactions, a reductive coupling
4
of dithioacetals, the protected aldehydes, was focused as our next
target. Meanwhile, Takeda and co-workers reported a prepara-
tive method of titanium-carbene complexes generated by reduc-
tive desulfurization of the two alkylthio groups of the dithioac-
5
etals with low valent titanocene species Cp Ti[P(OEt) ] . The
2
3 2
above complexes have effectively been employed to date in
many useful synthetic reactions. To the best of our knowledge,
however, there are no examples reported on the formation of
coupling products, vicinal bis(alkylthio) derivatives, from
1–7). To improve the reactivity of low valent titanium iodide
species, more reliable preparative method was then investigat-
ed. The reaction proceeded successfully to afford the corre-
sponding coupling product in high yield when zinc was added
anew to the supernatant solution of zinc-treated low valent tita-
nium iodide species. The resulted solution was then applied to
6
dithioacetals by desulfurization of one of the alkylthio groups.
In this communication, we would like to report an efficient
method for the preparation of various vicinal bis(alkylthio)
derivatives by reductive coupling of dithioacetals derived from
aromatic aldehydes with low valent titanium iodide species.
At first, reductive coupling of benzaldehyde diethyl
dithioacetal was tried by using reactive low valent titanium
iodide species which were generated by treating titanium(IV)
8
the reductive coupling, and consequently, the double molar
amounts of the respective initial and additional zinc with titani-
um(IV) iodide promoted the reaction most effectively (entries 8
9
7
–13). When other metals were used in place of the additional
zinc, however, the yields of vicinal bis(alkylthio) derivative
remained rather low (entries 14–16). Concerning temperatures,
the reaction proceeded smoothly at 0 °C or above (entries
17–19).
7
iodide with copper or zinc in a mixed solvent of
dichloromethane and pivalonitrile at room temperature (sum-
marized in Table 1). In the case of using copper, the desired
vicinal bis(alkylthio) derivative, 1,2-bis(ethylthio)-1,2-
diphenylethane, was not obtained at all, while it afforded the
desired products in moderate to good yields by way of reduc-
tive elimination of one alkylthio group when low valent titani-
um iodide species generated from more than double molar
amounts of zinc and titanium(IV) iodide were used (entries
Next, reductive coupling reactions of various other
dithioacetals derived from aromatic aldehydes using low valent
titanium iodide reducing system were examined based on the
above results (summarized in Table 2). With regard to the sub-
stituents on phenyl group of dithioacetals, para-substituted
dithioacetals except CF -substituted one coupled smoothly to
3
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
641
coupling of aldehydes.2a,b On the other hand, meso-isomer is
considered to be preferentially produced when symmetry of
intermediate B is retained. However, the symmetry is readily
lost before coupling because of the poor electronic repulsion of
alkylthio groups in α-(alkylthio)benzyl radicals different from
the cases shown in the coupling of aldehydes. This considera-
tion explains that a mixture of dl- and meso-diastereomers are
produced by the present reaction.
Thus, reductive coupling reaction of dithioacetals derived
from aromatic aldehydes was effectively achieved by the in situ
formed low valent titanium iodide species in a mixed solvent of
dichloromethane and pivalonitrile under mild conditions.
References and Notes
1
For reviews, see: a) G. M. Robertson, in “Comprehensive Organic
Synthesis,” ed. by B. M. Trost and I. Fleming, Pergamon Press,
Oxford (1991), Vol. 3, p. 563. b) T. Wirth, Angew. Chem., Int. Ed.
Engl., 35, 61 (1996). c) A. Fürstner and B Bogdanovic, Angew.
Chem., Int. Ed. Engl., 35, 2442 (1996).
2
a) T. Mukaiyama, N. Yoshimura, and K. Igarashi, Chem. Lett., 2000,
8
38. b) T. Mukaiyama, N. Yoshimura, K. Igarashi, and A.
Kagayama, Tetrahedron, 57, 2499 (2001). Recent reports of pinacol
coupling reaction by using titanium iodide species, see: c) S.
Talukdar, S. K. Nayak, and A. Banerji, J. Org. Chem., 63, 4925
(
1998). d) R. Hayakawa and M. Shimizu, Chem. Lett., 2000, 724.
H. Ishikawa and T. Mukaiyama, Bull. Chem. Soc. Jpn., 51, 2059
1978).
3
4
(
T. W. Greene and P. G. M. Wuts, in “Protective Groups in Organic
Synthesis, Third Edition,” John Wiley & Sons, New York (1999), p.
2
93.
5
For reviews, see: a) T. Takeda and T. Fujiwara, Yuki Gosei Kagaku
Kyokaishi, 56, 1048 (1998). b) T. Takeda, M. A. Rahim, M.
Takamori, K. Yanai, and T. Fujiwara, Polyhedron, 19, 593 (2000).
And recent reports were as follows: c) T. Takeda, N. Saeki, Y.
Takagi, and T. Fujiwara, Chem. Lett., 2000, 1198. d) T. Fujiwara, K.
Yanai, K. Shimane, M. Takamori, and T. Takeda, Eur. J. Org. Chem.,
2001, 155.
A preparative method of vicinal bis(alkylthio) derivatives was report-
ed by diisopropylamide-induced fragmentation of dibenzyl disulfide,
followed by trapping with alkyl halides, see: a) H. Ikehara and S.
Tanimoto, Bull. Chem. Soc. Jpn., 57, 1423 (1984). b) S. Tanimoto, S.
Nozawa, and Y. Inoue, Bull. Inst. Chem. Res., Kyoto Univ., 68, 193
afford the corresponding vicinal bis(alkylthio) derivatives in
high yields, and also, the ortho- and meta-substituted dithioac-
etals reacted likewise to give the coupling products in good
yields (entries 1–11). Then, the influence of alkylthio group on
the present reaction was examined and the vicinal bis(alkylthio)
derivatives were obtained in high yields irrespective of the sub-
stituents (entries 12–14). Furthermore, the reductive coupling
of dithioketal derived from acetophenone proceeded smoothly
as well to afford the corresponding coupling product in high
yield (entry 15) while dithioacetals derived from aliphatic alde-
hydes did not react under these reaction conditions.
As illustrated in Scheme 1, the reaction is assumed to pro-
ceed as follows: there are two reaction pathways of forming
coupling products, namely, via a titanium-bridged intermediate
A and a titanium-nonbridged intermediate B generated by
reductive desulfurization of an alkylthio group. Of the two pos-
sibilities, the formation of dl-isomer via intermediate A might
not take precedence because the sulfur–titanium–sulfur bridg-
ing interaction (coordination and coordination) is relatively
weak compared with the oxygen–titanium–oxygen bridging
interaction (by σ-bond and coordination) suggested in reductive
6
(1990).
7
8
Copper powder was purchased from Soekawa Chemical Co., Ltd. and
used without any treatment. Zinc powder was activated before use
with 1 mol/L aqueous HCl and washed with H2O and ether, then
dried under vacuum at 100 °C. Manganese was dried under vacuum
at 100 °C.
A typical reaction procedure for the reductive coupling of benzalde-
hyde diethyl dithioacetal corresponding to Table 1, entry 8: to a red-
dish brown suspension of titanium(IV) iodide (1.11 g, 2.0 mmol) and
zinc powder (0.26 g, 4.0 mmol) in dichloromethane (19.11 mL) was
added pivalonitrile (0.89 mL, 8.0 mmol) under argon atmosphere.
The color was changed to dark brown and the mixture was stirred for
3 h at room temperature. Resulted dark brown supernatant solution
(
0
3.0 mL, 0.3 mmol Ti) was added to additional zinc powder (0.039 g,
.6 mmol) and the mixture was stirred for another 30 min. Then, a
solution of benzaldehyde diethyl dithioacetal (0.064 g, 0.3 mmol) in
dichloromethane (1.0 mL) was added. The reaction mixture was
stirred for 1 h, and then phosphate buffer solution (pH = 7) was
added. The mixture was filtered and extracted with CH Cl , and the
2
2
organic layer was washed with saturated aqueous NaCl, dried over
Na SO . After filtration and concentration, the crude product was
2
4
purified by thin layer chromatography to afford the desired vicinal
bis(alkylthio) derivative (0.043 g, 95% yield).
9
When titanium(IV) bromide and titanium(IV) chloride were
employed in place of titanium(IV) iodide using double molar amounts
of the respective initial and additional zinc, the yields of vicinal
bis(alkylthio) derivative a little decreased (82% [dl / meso = 49 / 51]
and 92% [dl / meso = 50 / 50], respectively). On the other hand,
when the procedure of ref 3 was applied, the reaction did not proceed
at all.