A new method for the synthesis of α-thio aldehydes and alcohols from aldehydes with one-carbon elongation

Article abstract of DOI:10.1016/S0040-4039(00)00087-3

A two-step and high-yield method for the synthesis of α-thio aldehydes from aldehydes with one-carbon elongation is realized by using chloromethyl phenyl sulfoxide as a one-carbon homologating agent. The α-thio aldehydes are easily converted to desulfurized alcohols with Bu₃SnH and AIBN in refluxing benzene in good yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00087-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2121–2124
A new method for the synthesis of α-thio aldehydes and alcohols
from aldehydes with one-carbon elongation
Tsuyoshi Satoh ∗ and Ko-ichi Kubota
Department of Chemistry, Faculty of Sciences, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 29 November 1999; revised 5 January 2000; accepted 7 January 2000
Abstract
A two-step and high-yield method for the synthesis of α-thio aldehydes from aldehydes with one-carbon
elongation is realized by using chloromethyl phenyl sulfoxide as a one-carbon homologating agent. The α-thio
aldehydes are easily converted to desulfurized alcohols with Bu3SnH and AIBN in refluxing benzene in good
yield. © 2000 Elsevier Science Ltd. All rights reserved.
The homologation of carbonyl compounds from lower carbonyl compounds by a carbon–carbon
coupling reaction is an attractive way for obtaining the desired carbonyl compounds.1 In addition, the
produced carbonyl compounds are easily converted to other compounds useful in organic chemistry.
In our laboratory, we have reported some new methods for homologation of carbonyl compounds2 by
using aryl 1-haloalkyl sulfoxides as acyl anion equivalents.3 In continuation of our work, we report herein
a new method for the synthesis of α-thio aldehydes 4 from aldehydes 1 with one-carbon elongation
by using chloromethyl phenyl sulfoxide 2 as a one-carbon homologating agent. Moreover, the α-thio
aldehydes 4 were easily reduced to one-carbon elongated desulfurized alcohols 5 in good yields.
One-carbon elongation of 3-phenylpropanal is described as a specific example (Scheme 1). Treatment
of the lithium carbanion of chloromethyl phenyl sulfoxide with 3-phenylpropanal at −78°C gave the
adduct 6 in quantitative yield as a diastereomeric mixture. In order to obtain the sulfinyloxirane 7, we
first treated 6 with several bases;4 however, because 7 was very unstable, all the attempts gave a complex
mixture. Next, we tried in situ trap of this unstable 7 in the presence of a highly nucleophilic reagent (such
as thiolate, selenolate, and amine). Thus, a solution of 6 in THF was added to a mixture of t-BuOK (7
equiv.) and benzenethiol (5 equiv.) in a mixture of t-BuOH–THF (2:1) at room temperature. Quite a rapid
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00087-3
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reaction took place, and after 10 min the desired α-(phenylthio)aldehyde 8 (R0=Ph) was obtained in 73%
yield (see Table 1, entry 1). This reaction is thought to proceed via a sulfinyloxirane 7.1d We investigated
this reaction with other thiols and found that alkyl thiols gave slightly better yield than benzenethiol. The
best yield (93%) was obtained with benzyl mercaptan at 0°C (see Table 1, entries 2–4).
Scheme 1.
α-Thio aldehydes themselves are very important compounds in organic synthesis;5 however, if the
α-thio group can be reduced easily to hydrogen, these reactions offer a good method for homologation
of aldehydes to one-carbon elongated aldehydes. To this end, reduction of the benzylthio group in 8
(R0_CH2Ph) with Raney–Ni in EtOH under several conditions was investigated; this reaction, however,
only gave a complex mixture. The reduction in acetone gave some amount of 9; however, this reaction
again usually gave a complex mixture. Finally, we found that the reduction was successful in acetone
containing a few drops of acetic acid to give 9 in 81% yield. However, these conditions are still not ideal.
Reproducibility of this reaction was variably poor.
As the desulfurization of the α-thio aldehyde was found to be rather difficult, we changed our target to
a synthesis of one-carbon elongated alcohols 10. After some investigation, reduction of 8 (R0_CH2Ph)
with excess tributyltin hydride in the presence of AIBN6 was found to be the conditions of choice.
Reduction of 8 with 7 equiv. of tributyltin hydride with 1 equiv. of AIBN in refluxing benzene gave the
desired alcohol in 85% yield (Scheme 1 and Table 1, entry 4).
Other representative examples are shown in Table 1, entries 6–12. Entries 1 and 6 show the results with
n-alkyl aldehydes. Entries 7 and 8 show the results of the α-branched alkyl aldehydes. Entries 9 to 11
show the results with aromatic aldehydes and entry 12 shows the result with α,β-unsaturated aldehydes.
The yields of the adducts 3 of all the aldehydes with the lithium carbanion of chloromethyl phenyl
sulfoxide are very high (87–98%). The yields for the reaction with benzyl mercaptan in the presence of
t-BuOK gave again excellent yields of the α-thio aldehydes 4 (89–98%). These results show that this
method is quite useful for a one-carbon elongation of aldehydes to α-thio aldehydes.7
The reduction of the α-thio aldehydes 4 with Bu3SnH was examined and the results are shown in Table
1. The yields of the reduction were shown to be somewhat variable. It is important to note that because
the α-thio aldehyde in entry 12 was the α,β-(dibenzylthio)aldehyde the alcohol was saturated.

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Table 1
One-carbon elongation of aldehydes to α-thio aldehydes and alcohols
We next applied the presented method to two-carbon elongation of aldehydes to α,β-dithio aldehydes
14 and alcohols 15. The overall process and the yields are shown in Scheme 2. All the reactions starting
from 3-phenylpropanal gave over 90% yield and the overall yield was 76%. In contrast to this, the yields
starting from 1-naphthaldehyde were good but not excellent, and the overall yield was reduced to 45%.
This work was supported by a Grant-in-Aid for Scientific Research No. 11640545 from the Ministry
of Education, Science, Sports, and Culture, Japan, which is gratefully acknowledged.

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Scheme 2. Two-carbon elongation of aldehydes 1 to α,β-(dibenzylthio)aldehydes 14 and alcohols 15
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