Synthesis of novel β-aryl-β-(methylthio)acroleins via Vilsmeier-Haack protocol as potential 1,3-dielectrophilic three-carbon building blocks

Article abstract of DOI:10.1016/j.tetlet.2014.06.065

A new general route for the synthesis of novel β-aryl-β- (methylthio)acroleins, a class of stable potential 1,3-dielectrophilic synthons, has been reported. The overall protocol involves treatment of either β-chloroacroleins or their precursor iminium salts (generated in situ from the corresponding active methylene ketones under Vilsmeier-Haack reaction conditions) with S,S-dimethyldithiocarbonates (DDC)/aqueous KOH in either a one-pot or two-step process. The dimethyldithiocarbonate (DDC)/30% aqueous KOH has been shown to be an excellent source of methylthiolate anion.

Full text of DOI:10.1016/j.tetlet.2014.06.065

Tetrahedron Letters 55 (2014) 4475–4479
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel b-aryl-b-(methylthio)acroleins via
Vilsmeier–Haack protocol as potential 1,3-dielectrophilic
three-carbon building blocks
G. Byre Gowda a,b, T. P. Charanraj b, C. S. Pradeepa Kumara a,b, N. Ramesh b, S. P. Thomas c,
,
M. P. Sadashiva a, , H. Junjappa b,
⇑
⇑
a Department of Studies in Chemistry, University of Mysore, Mysore 570 006, India
b Department of Chemistry, REVA Institute of Science and Management, Yelahanka, Bangalore 560 064, India
c Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new general route for the synthesis of novel b-aryl-b-(methylthio)acroleins, a class of stable potential
1,3-dielectrophilic synthons, has been reported. The overall protocol involves treatment of either b-chlo-
roacroleins or their precursor iminium salts (generated in situ from the corresponding active methylene
ketones under Vilsmeier–Haack reaction conditions) with S,S-dimethyldithiocarbonates (DDC)/aqueous
KOH in either a one-pot or two-step process. The dimethyldithiocarbonate (DDC)/30% aqueous KOH
has been shown to be an excellent source of methylthiolate anion.
Received 13 May 2014
Revised 13 June 2014
Accepted 14 June 2014
Available online 21 June 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
b-Thioacroleins
b-Chloroacroleins
Dimethyldithio
Formylation
Thiolation
The versatile formylation reaction of electron rich aromatics
and heteroaromatics developed by Vilsmeier and Haack in 19271
was successfully extended by Arnold and Zamlicka2 to active
methylene carbonyl compounds yielding the corresponding
b-chloroacroleins3a–h in good to excellent yields. The b-chloroacro-
lein chemistry has since been extensively explored as potential
1,3-dielectrophilic building blocks for the synthesis of a variety
of five and six membered heterocycles.4a–c Additionally, it is
known that the b-chloro group can be replaced by nucleophiles
such as alkoxides and aryloxides to yield the corresponding b-alk-
oxy/aryloxyacroleins in excellent yields.5 However, these chloroac-
roleins are unstable as they rapidly undergo polymerization6 even
at room temperature, though addition of anhydrous sodium ace-
tate (1 g/100 mL) may extend their stability for some time. Thus,
most of these chloroacroleins are generally prepared and used
immediately. Our experience in organosulfur chemistry prompted
us to develop a methodology for the corresponding b-(methyl-
thio)acroleins 6a–r (Scheme 3), which we conceived, would be
more stable and thus assume a positive advantage over the unsta-
ble b-chloroacroleins. To transform these b-chloroacroleins to the
corresponding b-(methylthio)acroleins, methylthiolate (CH3SNa)
anion is required, which is generated by treatment of methylmer-
captan with a base. Since methylmercaptan is a gas, alternatively
its sodium salt is generated by basic hydrolysis of precursors such
as thiolesters or S-methylthiouronium salt etc. Interestingly,
Degani and co-workers7a,b have used a symmetrical S,S-dim-
ethyldithiocarbonate 2 as a new useful source of methylthiolate
anion to prepare the corresponding methylsulfides. The required
S,S-dimethyldithiocarbonate 2 has been reported to be prepared
by rearrangement of easily available dimethyl xanthate 1 in the
presence of tetrabutylammonium salt.8a However in our hands, it
resulted in an uncontrollable spontaneous exothermic reaction.
Alternatively in the present studies, we found that the xanthate 1
undergoes a facile rearrangement in the presence of anhydrous
aluminium chloride in boiling dichloromethane to yield the corre-
sponding dimethyldithiocarbonate 2 in more than 80% yield8b
(Scheme 1). We therefore preferred to follow the aluminium
S
O
KOH
AlCl3
CH2Cl2
2KSMe
MeS
OMe
MeS
SMe
2
1
⇑
Corresponding authors. Tel.: +91 98453 72078.
E-mail address: junjappa_123@rediffmail.com (H. Junjappa).
crystal structure of 6f and 6o.
Scheme 1. Preparation of dimethyldithiocarbonate (DDC).
http://dx.doi.org/10.1016/j.tetlet.2014.06.065
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

4476
G. Byre Gowda et al. / Tetrahedron Letters 55 (2014) 4475–4479
chloride method for the preparation of 2 in the present studies.
Interestingly, the dimethyldithiocarbonate 2 alone cannot be
hydrolysed by 30% potassium hydroxide solution either in the
presence or in the absence of quaternary ammonium salts. The
reaction occurs only when the electrophilic reagent is present in
the reaction mixture. It is therefore concluded that the hydrolysis
of 2 is a reversible reaction involving methylthiolate anion and 2
which are at equilibrium with very low concentration of the potas-
sium methylthiolate (Scheme 1).
In the present work we have examined the transformation of
b-chloroacroleins 5 or their precursors 4 (generated from corre-
sponding active methylene ketones 3) to b-(methylthio)acroleins
6 through manipulating the Vilsmeier–Haack protocol either in
one pot reaction or in two-step conversion by utilizing S,S-dim-
ethyldithiocarbonate (DDC) 2 as an excellent source of methylthi-
olate anion. We herein report the results of these studies.
With cyclic ketones 3a–d (Table 1) the reaction could be
conducted in a one pot manner by heating intermediate b-chloroi-
minium salts directly with dimethyldithiocarbonate (DDC) 2 in the
presence of 30% potassium hydroxide at 90 °C affording the corre-
sponding cyclic b-(methylthio)acroleins 6a–d in 57–81% overall
yields (Table 1, Scheme 2). Our literature survey at this stage
revealed that b-(methylthio)acroleins 6b9a and 6c9b (Table 1) have
been reported in the literature involving a two step protocol by
treating the corresponding b-chloroacroleins with sodium methyl-
thiolate in comparable yields.
One pot three component reaction
Cl
SMe
O
Cl
N
R1
R1
H
POCl3
DMF
Cl
R1
a
R
b
R
R
R
R1
O
H
O
3
4
5
6
R=Alkyl, hetero aryl,
R1=H
a. NaOAc (sat),b.(Me2S)CO, KOH (30%)
Scheme 2. Synthesis of b-(methylthio)acroleins from ketones.
b-phenyl-b-(methylthio)acrolein 6e in 82% yield (Table 2, entry 1).
The reaction was equally facile with other b-aryl-b-chloroacroleins
bearing either electron donating (5f–h, entries 2–4) or electron
withdrawing groups (5i–j, entries 5 and 6) in the para position of
the aryl ring. On the other hand decreased yield of product 6k was
obtained from chloroacrolein 5k bearing a o-chlorophenyl group
(entry 7). The corresponding b-(m-nitrophenyl)chloroacrolein 5l
also afforded the corresponding b-aryl-(methylthio)acrolein 6l in
67% yield (Table 2, entry 8), however the reaction was not successful
with b-(p-nitrophenyl)chloroacrolein 5m, with no trace of 6m,
yielding only an intractable mixture of products. The corresponding
b-(2-naphthyl)- and b-(2-thienyl)-b-(methylthio)acroleins 6n–o
were also obtained in good yields from the respective b-chloroac-
roleins 5n–o (entries 10 and 11). On the other hand, the
We next examined the methylthiolation of the corresponding
open-chain chloroacrolein precursors. The above single step proce-
dure did not yield the satisfactory results, when applied to iminium
salts 4e–r generated in situ from the corresponding active methy-
lene ketones. Therefore we examined the methylthiolation of the
corresponding open-chain b-chloroacrolein precursors 5, which
were isolated in pure form by treatment of the corresponding
iminium salts 4 with aqueous sodium acetate.7a Thus treatment of
b-chloroacrolein 5e with dimethyldithiocarbonate(DDC) 2/30%
aqueous KOH, as described above, afforded the corresponding
a
-methyl-b-phenylchloroacrolein 5p furnished the respective tet-
rasubstituted b-(methylthio)acrolein 6p only in 47% yield (entry
12), which may be due to release of electron to the chlorocarbon
through hyperconjugation by the methyl group. The reaction could
also be extended to the cyclic and heterocyclic chloroaldehydes
5q–r affording the corresponding (methylthio)aldehydes 6q–r in
moderate to good yields (entries 13 and 14) under the identical
conditions. Degani and co-workers7a,b have invariably used tetrabu-
tylammonium bromide as phase transfer catalyst in transforming
Table 1
Synthesis of b-(methylthio)acroleins from cyclic ketones-one pot protocol
Entry
Ketones
Product
Time (h)
3.5
Yield (%)
57
SMe
O
Cl
N
CHO
CHO
ClH
Cl
1
6a
3a
4a
Cl
SMe
O
N
2
3
3.5
3.5
68
81
6b
4b
3b
SMe
N
O
Cl
CHO
CHO
Cl
6c
3c
4c
MeS
O
Cl
Cl
4
3.5
57
6d
3d
4d
Reaction conditions: POCl3 (15 mmol) was added dropwise to a mixture of DMF (15 mmol) and Toluene (15 mL) at rt. After 30 min ketone (10 mmol) was added dropwise.
The reaction mixture was stirred for 2.55–3.5 h at rt (monitored by TLC). The reaction mixture was cooled to 0 °C and DDC (10 mmol) was added followed by 30% aq KOH until
the reaction mixture is basic and heated to 90 °C for 45 min.

G. Byre Gowda et al. / Tetrahedron Letters 55 (2014) 4475–4479
4477
Table 2
Synthesis of b-(methylthio)acroleins from b-chloroacroleins-two-step protocol
Entrya
Acroleins
Cl
Product
Time (min)
60
Yield (%)
SMe
1
82
58
75
CHO
Cl
CHO
5e
6e
SMe
2
3
60
60
CHO
Cl
CHO
SMe
Me
Me
5f
6f
CHO
CHO
MeO
MeO
6g
5g
Cl
SMe
4
5
90
60
70
79
CHO
CHO
6h
SMe
Br
F
Br
F
5h
Cl
CHO
Cl
CHO
SMe
6i
5i
6
7
60
90
74
40
CHO
CHO
Cl
Cl
6j
SMe
5j
Cl
CHO
CHO
Cl
5k
Cl
6k
Cl
SMe
8
45
67
CHO
CHO
5l
6l
NO2
NO2
Cl
SMe
9
120
90
0
CHO
CHO
SMe
O2N
O2N
5m
6m
6n
Cl
10
70
CHO
CHO
5n
OHC
OHC
11
12
60
90
80
47
S
S
Cl
SMe
5o
6o
Cl
SMe
Me
CHO
Me
CHO
6p
SMe
5p
Cl
CHO
CHO
13
60
62
5q
6q
(continued on next page)

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G. Byre Gowda et al. / Tetrahedron Letters 55 (2014) 4475–4479
Table 2 (continued)
Entrya
Acroleins
Product
Time (min)
Yield (%)
CHO
Cl
CHO
Me
Me
N
N
N
SMe
N
14b
90
52
5r
6r
a
Reaction conditions: Chloroacrolein (10 mmol), DDC (10 mmol) were dissolved in Toluene (15 mL) and 30% KOH (10 mL) was added dropwise at rt. The reaction mixture
is heated at 90 °C for 1-2 h (monitored by TLC).10
b
Tetrabutylammonium bromide (1 mmol) is used.
O
Cl
H
SMe
SMe
O
MeS
SMe
CO2
CO
N
30% KOH
N
N
CHO
O
11
6s
5s
OH
O
N
MeS
O
10
Cl
O
Cl
H
O
N
N
N
O
O
HO
O
9
OH
8
7
MeS
SMe
2
Scheme 3.
active chloro compounds to the corresponding methylthio systems.
Interestingly in the present study, all the b-(methylthio)acroleins
6a–q were obtained in the absence of phase transfer catalyst, how-
ever only 5r required PTC to yield the corresponding (methyl-
thio)acrolein 6r in 52% yield (Table 2, entry 14).
In the course of this investigation we observed an interesting
deviation in the reaction path, when b-chloroacrolein derived from
4-acetylpyridine was subjected to methylthiolation under the
described reaction conditions. The expected (methylthio)acrolein
6s was not formed and the product isolated was characterized as
11 in quantitative yield based on spectral and analytical data.
The mechanism governing this transformation is described in
Scheme 3. The nucleophilic attack of hydroxide ion on aldehyde
carbonyl followed by 1,3-prototropic shift and elimination of chlo-
ride ion through intermediate 7 and 8 afforded enecarboxylate 9.
The resulting enecarboxylate 9 further reacts with 2 to yield an
unstable mixed anhydride 10 followed by methylthio group migra-
tion releasing carbon dioxide and carbon monoxide to yield 11. We
continue to work on this reaction under alternative experimental
protocols to realize the desired product.
6f
6o
Figure 1. X-ray structure; ORTEP diagram of b-(methylthio)acroleins 6f and 6o.
excellent source of methylthiolate anion. It should be noted
that these b-aryl-b-(methylthio)acroleins are stable at room
temperature, whereas b-chloroacroleins are usually unstable as
they rapidly undergo polymerization even at room temperature.
Further work to explore the synthetic application of these novel
intermediates is in progress in our laboratory and will be published
later.
The open chain (Table 2) b-(methylthio)acroleins do exist in E
stereochemistry as confirmed by X-ray diffraction data of acroleins
6f and 6o (Figure 1).
Acknowledgments
In conclusion, we have developed a new general approach to
novel b-aryl-b-(methylthio)acroleins, a class of stable, potential
1,3-dielectrophilic building blocks, via transformation of either
b-chloroacrolein or the corresponding iminium salts (generated
in situ from the respective active methylene ketones), either in a
one pot or two-step process, by treatment with S,S-dimethyldithio-
carbonate (DDC)/aqueous KOH, which has been shown to be an
H.J. is grateful to INSA for the award of Sr. Scientist. We grate-
fully acknowledge the financial support for the project by CSIR,
New Delhi. We express our grateful thanks to Prof. S. Chandrasek-
aran, IISc., Bangalore-12 for the spectral and analytical data. The
authors also express thanks to Mr. P. Shyamaraju, Chairman REVA
Institute of Science and Management, Yelahanka, Bangalore 560
064.

G. Byre Gowda et al. / Tetrahedron Letters 55 (2014) 4475–4479
4479
5. (a) Rappaport, Z.; Gazit, A. J. Org. Chem. 1985, 50, 3184; (b) Rappaport, Z.; Gazit,
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Supplementary data
6. Paquette, L. A.; Johnson, B. A.; Hinga, F. M. Org. Syn. Coll. Vol. 1973, V, 215–217.
and references therein.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.
065.
7. (a) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1983, 630–632; (b) Degani, I.;
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10. General procedure for the synthesis of b-(methylthio)acroleins 6a–d: To a solution
of DMF (15 mmol) in dry toluene (15 mL), POCl3 (15 mmol) was added at room
temperature with stirring for 30 min followed by addition of respective ketone
(10 mmol) in toluene and further stirred for 2.5–3.5 h (monitored by TLC). The
reaction mixture was then cooled in an ice bath, followed by addition of the
dimethyldithiocarbonate (DDC, 10 mmol) and 30% aqueous KOH (10 mL) till
solution becomes basic. It was then heated at 90 °C for 45 min (monitored by
TLC), cooled to room temperature and extracted with petroleum ether, washed
with water until the washings were neutral to litmus. The combined extracts
were dried (Na2SO4) and the solvent was evaporated under reduced pressure
to give crude b-(methylthio)acroleins, which were purified by column
chromatography over silica gel using ethyl acetate–pet ether (5:95) as eluents.
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