Highly chemoselective Baylis - Hillman and aldol reactions of 2 H-thiopyran-4(3H)-one using tertiary amine catalysts in aqueous media

Article abstract of DOI:10.1021/ol101883g

For the first time, the Baylis - Hillman (BH) reaction of 2H-thiopyran-4(3H)-one is investigated, and surprisingly, the reaction of 2H-thiopyran-4(3H)-one with aldehydes in the presence of different tertiary amines shows excellent chemo- and regioselectiv

Full text of DOI:10.1021/ol101883g

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4568-4571
Highly Chemoselective Baylis-Hillman
and Aldol Reactions of 2H-Thiopyran-
4(3H)-one Using Tertiary Amine
Catalysts in Aqueous Media
Bagher Eftekhari-Sis,*,† Ali Akbari,† and Klaus Harms‡
Department of Chemistry, Faculty of Science, UniVersity of Maragheh, Golshar,
P.O. Box. 55181-83111, Maragheh, Iran, and UniVersitaet Marburg, Fachbereich
Chemie Hans-Meerwein-Str., D-35032, Marburg, Germany
eftekharisis@maragheh.ac.ir; eftekhari.sis@gmail.com
Received August 11, 2010
This paper was withdrawn on November 29, 2010 (Org. Lett. 2010, 12, 5600).
ABSTRACT
For the first time, the Baylis-Hillman (BH) reaction of 2H-thiopyran-4(3H)-one is investigated, and surprisingly, the reaction of 2H-thiopyran-
4(3H)-one with aldehydes in the presence of different tertiary amines shows excellent chemo- and regioselectivity in water. At room temperature,
DBU affords BH adducts, but with DABCO, aldol products were obtained. In the case of DABCO, Et3N, or DMAP, domino aldol-rearrangement
reactions occurred at 45-50 °C.
The organic reactions in aqueous media1 have attracted much
attention in synthetic organic chemistry, not only because
water is one of the most abundant, cheap, and environmen-
tally friendly solvents but also because water exhibits unique
reactivity and selectivity, which is different from those in
conventional organic solvents. Thus, development of novel
reactivity as well as selectivity that cannot be attained in
conventional organic solvents is one of the challenging goals
of aqueous chemistry.2
structural elaboration from relatively simple starting materi-
als,4 it suffers from low reaction rates depending upon the
reactivities of both the activated alkene and aldehyde and
limited substrate scope. To overcome this problem, the
reaction was carried out in a mixture of organic solvents
with water as a cosolvent.5
In this paper, we have carried out the reaction of
2H-thiopyran-4(3H)-one 1 with aldehydes in the presence
of tertiary amines as a catalyst in water. We have observed
that reaction of 1 with aldehydes shows excellent chemo-
and regioselectivity using different tertiary amines as a
catalyst in water. Under the same reaction conditions, when
cyclohex-2-enone 2 was used, only BH adducts 7 were
obtained with any tertiary amines (Figure 1).
The Baylis-Hillman (BH)3 reaction is one of the most
important reactions for C-C bond formation via reaction of
activated alkenes with aldehydes in the presence of a catalytic
amount of tertiary amines. Although the BH reaction
furnishes densely functionalized products amenable to further
In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), BH adduct 3 was obtained as a sole product in short
† University of Maragheh.
‡ Universitaet Marburg.
10.1021/ol101883g  2010 American Chemical Society
Published on Web 09/16/2010

Table 1. DBU-Catalyzed BH Reaction of 1 at Room
Temperature
entry
ArCHO
product
time (h)
yield (%)a
1
2
3
4
5
6
7
C6H5CHO
3a
3b
3c
3d
3e
-
8
6
5
7
68
72
70
67
4-ClC6H4CHO
4-FC6H4CHO
3-ClC6H4CHO
3-BrC6H4CHO
4-MeC6H4CHO
4-NO2C6H4CHOc
6
68
5 days
2
N.R.b
-
Figure 1. Chemo- and regioselectivity of 1 and 2 in reaction with
aldehydes catalyzed with tertiary amines in water.
-
a Yields refer to isolated products. b N.R. ) No reaction. c A complex
mixture of products was obtained.
reaction time (Scheme 1). The scope of the DBU-catalyzed
BH reaction was investigated by reacting 1 with a range of
tified as an isolable product in low yield from a complex
reaction mixture (Figure 2).
Scheme 1. DBU-Catalyzed BH Reaction of 1
Figure 2. Structure of 4.
benzaldehydes in water at room temperature (Table 1). In
the case of strongly electron-withdrawing groups such as
4-nitrobenzaldehyde, the reaction was performed rapidly, and
complex mixtures of products were produced. In the case of
benzaldehydes with electron-releasing groups, the substrates
were recovered without any changes after 5 days (Table 1,
entry 6). Then temperature was raised to 45-50 °C, and
unexpectedly complex mixtures of products were obtained.
Also, the BH reaction of 1 with 4-fluorobenzaldehyde was
investigated at 45-50 °C, and 3-(4-fluorobenzyl)-5-[(4-
fluorophenyl)hydroxymethyl]-4H-thiopyran-4-one 4 was iden-
Due to its easy availability, low cost, and high nucleo-
philicity, 1,4-diazabicyclo[2.2.2]octane (DABCO) is com-
monly used as a catalyst for the BH reaction.3,6
In continution, we were also encouraged to work on
DABCO-catalyzed BH reaction of 1 with aldehydes in water
at room temperature. Surprisingly, as shown in Scheme 2,
in the case of electron-withdraweing substituted benzalde-
hydes, 3-[(4-aryl)hydroxymethyl]-2H-thiopyran-4(3H)-ones
5a-f were obtained as the only product via aldol reaction
in good to high yields with good to excellent syn selectivity
in short reaction times (Table 2, entries 1-6). In the case of
benzaldehydes with electron-releasing groups, there are no
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Org. Lett., Vol. 12, No. 20, 2010
4569

Scheme 2. DABCO-Catalyzed Aldol Reaction of 1
Figure 3. ORTEP representation of the crystal structure of 5d.
Table 2. DABCO-Catalyzed Aldol Reaction of 1
entry
ArCHO
product time (h) yield (%)a
drb
to 45-50 °C, and compounds 6 were obtained in high yields
as sole products, as shown in Scheme 3. Not only electron-
withdrawing substituted benzaldehydes but also electron-
releasing substituted benzaldehydes worked well.
The results persuaded us to investigate chemo- and
regioselectivity in the reaction of cyclohex-2-enone 2, as a
similar structure of 1, with aldehydes catalyzed with tertiary
amines at the same conditions. As shown in Scheme 4, only
1
2
3
4
5
6
7
8
9
4-ClC6H4CHO
4-NO2C6H4CHO
4-CNC6H4CHO
2,4-Cl2C6H3CHO
3-ClC6H4CHO
3-NO2C6H4CHO
C6H5CHO
4-MeC6H4CHO
4-MeOC6H4CHO
n-PrCHO
5a
5b
5c
5d
5e
5f
-
4
5
5
3
8
85
80
77
83
75
73
>99/1
>99/1
60/40
>99/1
95/5
66/34
-
-
-
-
6
24
24
24
24
N.R.c
N.R.c
N.R.c
N.R.c
-
-
-
10
a Yields refer to isolated products. b dr (% syn/anti) was determined by
1H NMR spectroscopy analyses of the crude products. c N.R. ) No reaction.
Scheme 4
.
Tertiary Amine-Catalyzed BH Reaction of 2 in
Water
changes in substrates after 24 h (Table 2, entries 7-9). Then
temperature was raised, and interestingly 3-(arylmethyl)-4H-
thiopyran-4-one derivatives7 6 were obtained via domino
aldol-rearrangement reactions (Scheme 3). Also, the reaction
Scheme 3. Et3N, DMAP, or DABCO-Catalyzed Domino
Aldol-Rearrangement Reactions of 1 at 45-50 °C
BH adducts 7 were obtained in the case of 2 using DBU,
DABCO, Et3N, or DMAP as the catalyst. The results
revealed that DBU and DABCO show similar activity. Et3N
shows good efficiency in the BH reaction of 2 in water at
room temperature.
In the most generally accepted mechanism4,5a of the amine-
catalyzed BH reaction (Scheme 5, Path a), the rate-determin-
of butyraldehyde, an aliphatic aldehyde, with 1 was inves-
tigated at the same conditions, and the starting materials were
recovered after 24 h (Table 2, entry 10).
The X-ray single-crystal structure analysis of 3-[(2,4-
dichlorophenyl)hydroxymethyl]-2H-thiopyran-4(3H)-one 5d
(Figure 3) revealed that the major isomer possesses syn
stereochemistry. The relative configuration of the racemic
title compound is R,R.
Scheme 5
. Effect of the Stability of 8 and Neighboring S Atom
on the Chemo- and Regioselectivity of Reaction
In continution, other tertiary amine catalysts such as
4-(N,N-dimethylamino)pyridine (DMAP) and Et3N were
used. At room temperature, there are no changes in the
starting materials after 24 h. Then, temperature was raised
(7) Abaee, M. S.; Mojtahedi, M. M.; Zahedi, M. M.; Sharifi, R.; Khavasi,
H. Synthesis 2007, 3339.
4570
Org. Lett., Vol. 12, No. 20, 2010

ing step is either the intramolecular proton transfer in the
zwitterionic intermediate 98 or the reaction of zwitterion 8
with aldehydes.9 The rate of the generation of 8 is related to
the nucleophilicity of amine, activity of alkene, and stability
of zwitterion 8. The results of Scheme 4 indicate that in the
case of activated alkene 2 (X ) CH2) nucleophilicity of
amine (DABCO, Scheme 4) works as well as the stability
of 8 (DBU, Scheme 4). DBU is considered to be a non-
nucleophilic hindered base, but because of the stability of
zwitterion 12 through conjugation,9 DBU worked well in
the BH reaction (Figure 4). The results of Tables 1 and 2
products were produced. This can be attributed to, as shown
in Scheme 6, a considerable cyclic conjugation in the enolate
Scheme 6. Plausible Mechanism for Aldol and Domino
Aldol-Rearrangement Reactions of 1
form 11.10 When the zwitterion 8 is not more stable, the
species 11 control the reaction progress, and aldol reaction
occurred.
As the same structure with thiophene, compound 11 with
cyclic conjugation having a hydroxyl group on C-4 undergoes
the reaction with aldehydes at C-5. The plausible mechanism
is shown in Scheme 6. When temperature was raised, a water
molecule was removed, and then by rearrangement of the
double bond, compounds 6 were produced.
Figure 4. Stability of 12 and 13 through conjugation.
In conclusion, for the first time, the BH reaction of 2H-
thiopyran-4(3H)-one 1, a less-activated alkene, was inves-
tigated. Surprisingly the reaction of 1 with aldehydes in the
presence of different tertiary amines shows excellent chemo-
and regioselectivity in water. Also, this study revealed that
the stability of ꢀ-ammonium enolate intermediate 8 plays
an important role in the chemo- and regioselectivity of the
reaction of less-activated alkene 1. According to the stability
of 12 through conjugation, DBU acts as an efficient catalyst
in the BH reaction of 1. However, because of the lower
stability of 8, DABCO, DMAP, and Et3N act as a base, and
an aldol reaction was performed. In the case of activated
alkenes such as 2, the nucleophilicity of amine works as well
as the stability of 8 (X ) CH2), and only a BH reaction
occurred.
revealed that in the case of less activated alkene 1 (X ) S)
the stability of zwitterion 8 is the prominent factor in the
chemo- and regioselectivity of the reaction.
As shown in Scheme 5 (path b), when X ) S, an amine
was removed from 8 by the neighboring sulfur atom
participation. The lower the stability of the zwitterion 8, the
higher the rate of amine removal. Because of the stability
of 12 (X ) S) through conjugation, DBU acts as an efficient
catalyst in the BH reaction of 1. In the case of DMAP,
although there is conjugation stability (Figure 4, 13), the
zwitterion 13 (X ) S) is not more stable, and amine was
removed because of loss of the aromaticity of pyridine. So,
BH adducts were not produced in the DMAP-catalyzed
reaction of 1 with aldehydes in water. Although DABCO is
one of the most nucleophilic amines, the BH reaction did
not occur in the DABCO-catalyzed reaction of 1 because of
the lower stability of the zwitterion 8, and interestingly, aldol
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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OL101883G
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Org. Lett., Vol. 12, No. 20, 2010
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