Bakers' yeast catalyzed synthesis of benzothiazoles in an organic medium

Article abstract of DOI:10.1016/j.tetlet.2009.01.032

The cyclocondensation of 2-aminothiophenol and aldehydes has been carried out in dichloromethane using bakers' yeast as a catalyst for obtaining 2-aryl/heteryl benzothiazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2009.01.032

Tetrahedron Letters 50 (2009) 1352–1354
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bakers’ yeast catalyzed synthesis of benzothiazoles in an organic medium
Umesh R. Pratap, Jyotirling R. Mali, Dhanaji V. Jawale, Ramrao A. Mane *
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004 (MS), India
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclocondensation of 2-aminothiophenol and aldehydes has been carried out in dichloromethane
using bakers’ yeast as a catalyst for obtaining 2-aryl/heteryl benzothiazoles in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 October 2008
Revised 22 December 2008
Accepted 10 January 2009
Available online 14 January 2009
Keywords:
Bakers’ yeast
Cyclocondensation
Organic medium
2
-Aryl benzothiazole
1
. Introduction
their own respective cofactors are frequently more
advantageous.
1
6
Benzothiazoles bearing substituents at C
2
position are of great
The use of bakers’ yeast (whole-cell biocatalyst) to perform
functional group transformations of compounds has become a well
established and valuable methodology in organic syntheses.17 Bak-
ers’ yeast (Saccharomyces cerevisiae) is a very effective biocatalyst
interest as these structural frameworks have proved to be an
important class of privileged bicyclic substructures owing to their
potent utility as imaging agents for b-amyloid, antituberculotic,
chemiluminescent agents, calcium channel antagonists, antitu-
mour, antiparasitics and photosensitizers.1
18
for the reduction of ketones to optically active alcohols, reduc-
–6
19
tion of the C–C double bond, regioselective reduction of nitro
2
0
21
Numerous methods have been reported for the synthesis of
benzothiazoles. The most commonly used method involves the
condensation of 2-aminothiophenol with substituted nitriles, car-
compounds, reduction of b-ketoester to b-hydroxy esters, oxi-
2
2
dation of sulfide to sulfoxide, acyloin condensation reaction,
2
3
etc.
7
boxylic acids, aldehydes, acyl chlorides or esters. A number of cat-
Bakers’ yeast has been extensively used to carry out various or-
ganic transformations and can be used in the synthesis of hetero-
8
9
10
11
12
alysts, namely, (pmIm)Br,
I
2
,
ZrOCl
2
Á8H
2
O, TMSCl,
2
H O,
1
3
14
24
25
27
PCC and CAN have been used in the cyclocondensation of 2-
aminothiophenol and aldehydes. The other route is based on Jacob-
son’s cyclization of thiobenzanilides.1 But this route requires a
multistep reaction sequence. Many of these methods have disad-
vantages such as drastic reaction conditions, tedious work-up, pos-
sibility of side reactions and generation of acidic/metallic wastes.
Therefore, it was felt that there is an urgent need to overcome
the above limitations by developing an efficient and convenient
methodology for the synthesis of benzothiazoles.
cyclic compounds such as isoxazolines, 1,4-dihydropyridines,
2
6
3,4-dihydro-pyrimidine-2-(1H)-ones and polyhydroquinolines.
5
Csaba and co-workers reported the formation of 2-furylbenzo-
thiazoles from furylthioanilides by employing bakers’ yeast.28
The majority of bakers’ yeast-mediated organic reactions have
been conducted in an aqueous medium to retain its activity. An
aqueous medium is not applicable for dehydration reactions and
therefore the use of enzymes in organic solvents is gaining much
2
9
importance.
Biocatalysis in organic solvents have numerous
Biocatalysis represents an effective and preferable alternative to
the standard synthesis of fine chemicals and optically active com-
pounds. Biocatalysts are excellent catalysts as they can perform re-
gio- and stereo-specific reactions under mild conditions and can
accept non-natural compounds as substrates. Biocatalyzed conver-
sions with living cells (whole-cell) with the ability to regenerate
advantages such as (i) high solubility of most organic compounds
in organic solvents, (ii) ability to carry out reactions which are
impossible in water, (iii) relative ease of product recovery from or-
ganic solvents and (iv) insolubility of enzymes in organic solvents
which permits their easy recovery and reuse, thus eliminating the
need for immobilization.
Considering all the above facts, we turned our attention to
developing an efficient methodology for the cyclocondensation of
2-aminothiophenol with aldehydes in non-aqueous media (organic
*
Corresponding author. Tel.: +91 240 240311.
E-mail address: manera@indiatimes.com (R.A. Mane).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.032

U. R. Pratap et al. / Tetrahedron Letters 50 (2009) 1352–1354
1353
solvents) under relatively mild reaction conditions by using an eas-
HS
S
Bakers' Yeast
CH Cl , R.T.
ily available, cheaper biocatalyst, that is, bakers’ yeast. To the best
of our knowledge, the synthesis of benzothiazoles by the cyclocon-
densation of 2-aminothiophenol and aldehydes mediated by bak-
ers’ yeast has not been previously reported.
Ar-CHO
+
Ar
2
2
N
H N
2
1
(a-m)
2
3(a-m)
2
. Results and discussion
Scheme 1.
Herein, we report an efficient and economic synthesis of 2-aryl-
benzothiazoles under relatively milder reaction conditions by
employing yeast. It was interesting to observe that benzothiazoles
were synthesized in good yields catalyzed by dry bakers’ yeast in
dichloromethane. In order to get the best experimental condition,
we have considered the reaction of p-anisaldehyde and 2-amino-
thiophenol in the presence of bakers’ yeast as a standard model
reaction.
Table 2
Synthesis of 2-arylbenzothiazole derivatives catalyzed by bakers’ yeast
Productb
Yieldsa (%)
Entry
Ar
Ref.
1
2
3
4
5
6
7
8
9
4-OCH
3
C
6
H
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
75
79
67
69
72
84
82
74
71
77
51
57
11
11
11
6
–C H
5
4-N(CH
3
)
2
C
6
H
4
4-CH
3
C
6
H
H
4
30c
30d
30a
30b
30b
30b
30a
30a
11
2-OH C
6
4
To evaluate the effect of the solvent, we carried out the model
2-ClC
4-ClC
6
H
4
reaction in different solvents namely water (H
2
O), ethanol/water,
6
H
4
ethanol (EtOH), methanol (MeOH), 1,4-dioxane, acetonitrile
4-BrC
6 4
H
(
(
ACN), N,N-dimethylformamide (DMF) and dichloromethane
DCM). The use of water or water/ethanol as solvent gave poor
4-FC H4
6
10
3-NO
4-NO
2
C
C
6
H
H
4
3j
3k
3l
11
12
13
2
6
4
yields. (Table 1, entries 1 and 2). Solvents like ethanol, methanol,
,4-dioxane, acetonitrile, DMF gave moderate yields (Table 1, en-
2-pyridyl
2-furyl
1
3m
28
tries 3–7). When the reaction was run in dichloromethane, the
yield of benzothiazole was found relatively better (Table 1, entry
a
Isolated yields.
b
Products were characterized by comparison of their 1H NMR, MS31 and melting
8
). Therefore, dichloromethane was selected as a solvent for this
reaction.
To examine the catalytic efficiency of bakers’ yeast, the model
points with those reported in the literature.
reaction was run in the absence of yeast in dichloromethane. There
was no conversion even after 40 h.
To generalize our methodology with respect to aldehydes, we
have synthesized several 2-arylbenzothiazoles by the reactions of
various aldehydes and 2-aminothiophenol using bakers’ yeast in
dichloromethane, Scheme 1 (Table 2).
dinucleotide-dependent oxidoreductase available in bakers’
yeast, may be catalyzing the aromatization of 4 by dehydrogena-
28
tion involving hydride ion transfer and the subsequent abstraction
of a proton (Scheme 2). The second step could be a rate determin-
ing step. The intermediate 4 may have better solubility in DCM
compared to other solvents, thus permitting better interaction
with the cofactors resulting in high yields of the benzothiazoles.
A variety of aldehydes containing electron-donating and elec-
tron-withdrawing groups were successfully employed to prepare
corresponding benzothiazoles. No significant substituent effect
was observed on the yields of the products. It can be seen further
that 2-arylbenzothiazole bearing nitro functionality on the aryl
ring was obtained in good yields (Table 2, entries 10 and 11). Under
the reaction conditions, no expected reduction of nitro functional-
ity was observed. Encouraged by these results, we have also carried
out the cyclocondensation of some heterocyclic aldehydes, that is,
pyridine-2-carboxaldehyde and furfuraldehyde with 2-aminothio-
phenol to obtain the respective benzothiazoles (Table 2, entries 12
and 13) in moderate yields.
Bakers’ yeast is a known source of extracellular enzymes. These
enzymes might be accelerating the cyclocondensation of 2-amino-
thiophenol and aldehydes by forming either an initial enzyme–2-
aminothiophenol non-covalent complex or an enzyme–aldehyde
complex, resulting in intermediate benzothiazolines 4. The coen-
zymes, nicotinamide adenosine dinucleotide /flavin adenosine
3
. Conclusion
In summary, here we can claim that for the first time bakers’
yeast has been successfully employed to catalyze the condensation
of 2-aminothiophenol and aldehydes in DCM to yield 2-substituted
benzothiazoles in moderate to good yields under mild reaction
condition. This protocol is user-friendly and could be an attractive
S
H
SH
Enzyme
+
Ar-CHO
Ar
N
H
NH2
Enzyme
Table 1
(
4)
Effect of solvent on the synthesis of 2-(4-methoxy phenyl)-benzothiazole catalyzed
by bakers’ yeast
Entry
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
H
2
O
22
30
57
59
55
62
71
80
FAD
EtOH:H
EtOH
MeOH
1,4-Dioxane
ACN
2
O
S
Ar
FADH2
+ Enzyme
DMF
DCM
N
a
Isolated yields.
Scheme 2.

1
354
U. R. Pratap et al. / Tetrahedron Letters 50 (2009) 1352–1354
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Acknowledgement
8
U.R.P. is thankful to the University Grants Commission, New
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2
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