Baker's yeast as an efficient biocatalyst for regioselective 1,4-conjugate addition of indoles to nitroolefins in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2016.04.057

The 1,4-conjugate addition of indoles to nitroolefins was efficiently carried out in aqueous media using baker's yeast as a biocatalyst at room temperature. The merits of the present method are operational simplicity, easy workup, utilization of an inexpensive catalyst, free from hazardous organic solvents and good yields of products. The generality of this method was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives and could be extended for dialkylation of 1,4-bis-(2-nitrovinyl)benzene.

Full text of DOI:10.1016/j.tetlet.2016.04.057

Tetrahedron Letters 57 (2016) 2341–2346
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Digest paper
Baker’s yeast as an efficient biocatalyst for regioselective 1,4-
conjugate addition of indoles to nitroolefins in aqueous medium
⇑
Ananda Mane, Trushant Lohar, Rajashri Salunkhe
Department of Chemistry, Shivaji University, Kolhapur 416004, M.S., India
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,4-conjugate addition of indoles to nitroolefins was efficiently carried out in aqueous media using
baker’s yeast as a biocatalyst at room temperature. The merits of the present method are operational sim-
plicity, easy workup, utilization of an inexpensive catalyst, free from hazardous organic solvents and good
yields of products. The generality of this method was demonstrated by synthesizing an array of diverse 3-
substituted indole derivatives and could be extended for dialkylation of 1,4-bis-(2-nitrovinyl)benzene.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 20 January 2016
Revised 14 April 2016
Accepted 16 April 2016
Available online 19 April 2016
Keywords:
Baker’s yeast
Biocatalyst
Nitroolefins
3
-Substituted indoles
Contents
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
References and notes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
Organic transformations involving biocatalyst in aqueous media
have received great attention from researchers. Biocatalyst has the
potential to achieve regio- and stereo-specific conversions under
mild conditions, no side reaction products and can accept un-nat-
ural compounds as substrates by reducing the use of hazardous
reagents and solvents. Although significant progress has been
made through the use of isolated enzymes, whole-cell biocatalysts
with the ability to regenerate their own respective cofactors are
Indole nuclei are central building blocks for various biologically
active natural products, agrochemicals, and drugs. Indole based
5
framework is a component of complex macromolecules including
6
porphyrins of heme and pigments. Many indole ligands with high
affinity for G-protein coupled receptors have been identified.7 Of
these, the 3-substituted indole has privileged status in medicinal
chemistry due to its recurring presence among antiviral agents.8
For instance, Arbidol (1) is used for the treatment and prophylactic
1
9
frequently more advantageous. Among biocatalysts, bakers’ yeast
prevention of influenza A and B virus, Golotimod (2) shows
(
Saccharomyces cerevisiae) is a renowned catalyst due to its low
potential immunostimulating, antimicrobial and antineoplastic
1
0
cost, easy handling and no requirement of assistance of a specialist
in microbiology for growth. It has the ability to catalyze functional
group conversions and is known to play a vital role in the synthe-
sis of bioactive compounds such as 1,4-dihydropyridines,
activities
and Panobinostat (3) is a non-selective histone
2
deacetylase inhibitor developed for the treatment of Acute Myeloid
3
11
Leukemia (Fig. 1).
4
a
The 3-substituted indoles are assessed by Michael addition of
indoles to Michael acceptors. Among various types of Michael
acceptors, nitroalkenes are undoubtedly the strongest and versatile
4
b
4c
4f
3
,4-dihydropyrimidin-2-(1H)-ones,
polyhydroquinolines,
4
d
4e
benzothiazoles,
1
4H-pyranes,
2,3-diaryl-4-thiazolidinones,
,4-benzothiazines,4 benzimidazoles, quinoxalines, isoindolo
g
4h
4h
one, due to their propensity to undergo facile a-alkylation reactions
4
i
4j
4j
12
[
2,1-a]quinazolines, bisindolyl alkanes, and indolyl chromenes.
and interconversions to other organic functional groups. Consid-
ering the importance of above mentioned transformation, a
plethora of catalysts have been developed for this purpose includ-
⇑
Corresponding author. Tel.: +91 231 260 9169; fax: +91 231 2692333.
E-mail address: rsschem1@gmail.com (R. Salunkhe).
1
3
14
ing tetrabutyl ammonium hydrogen sulfate, boric acid, graphite
http://dx.doi.org/10.1016/j.tetlet.2016.04.057
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

2
342
A. Mane et al. / Tetrahedron Letters 57 (2016) 2341–2346
Table 1
N
H
a
N
Study of catalyst efficiency for the synthesis of 3-substituted indoles
OH
O
Reaction timeb (h)
Yieldc (%)
N
H
O
Entry
Amount of catalyst (mg)
3
1
2
3
4
5
100
200
300
400
500
2.5
2.5
2.5
2.5
2.5
72
80
90
90
89
O
OH
O
N
O
O
N
H
HO
Br
OH
H
2
N
N
S
N
H
a
Reaction conditions: indole (1 mmol), b-nitrostyrene (1 mmol),
D-glucose,
2
1
phosphate buffer (pH 7.0, 5 mL) at room temperature.
b
Reaction progress monitored by TLC.
c
Figure 1. Bioactive compounds containing 3-substituted indole nucleus.
Isolated yield.
oxide,15 metal halide hydrates, silanediol, Zn(II)-oxazoline-imi-
16
17
observed that (3a) was formed in 20% yield after stirring reaction
mixture for 24 h. (V) With inactive yeast: by employing inactivated
baker’s yeast (inactivation of yeast was carried out in boiling water
and dead cells obtained after centrifugation were used instead of
active baker’s yeast) after 24 h, no product formation was observed
by TLC.
dazoline catalyst and HY zeolite. Solvent free,20 catalyst-free
1
8
19
21
22
and ultrasound assisted methods are also reported. Very recently
Bronsted acid, palladium(II) surfactant combined catalyst24 and
2
3
2
5
graphite have been used as catalysts for addition of indoles to
nitroolefins. Although the synthesis of indole derivatives has been
well studied, the area is far from fully explored. The environmental
concerns in the entire research community are increasing with
increase in pressure to reduce pollutants, especially organic sol-
vents whose recovery is mandated by evermore strict laws. In this
context, the synthetic protocols utilizing biomaterial based cata-
lysts in aqueous media are becoming more important due to the
Based upon the results obtained in experiment III, it was con-
firmed that the presence of fermented baker’s yeast was essential
for successful Michael addition of indole to b-nitrostyrene. Table 1
shows the effect of the amount of catalyst on the product yield. The
high yield was achieved with 300 mg of baker’s yeast and increas-
ing its amount further to 500 mg failed to increase the yield.
These encouraging results obtained in the preliminary experi-
ments prompted us to explore the generality of this protocol to var-
ious other substituted indoles 1(a–h) and nitroolefins 2(a–k). As
indicated in Table 2 (Scheme 1), all the reactions uniquely occurred
at the 3-position of indole ring, indicating that the addition reaction
was regioselective and it is remarkable that all products obtained
are in the racemic form. The electron rich indole such as 5-methoxy
indole alkylated with b-nitrostyrene in a shorter time to obtain the
corresponding product, 3e in good yield (entry 5). However, the
electron withdrawing group bearing indoles such as 5-bromo
indole, 6-chloro indole and 6-fluro indole require longer reaction
time to obtain the desired product (entries 6–8). The reaction of
N-methyl indole with b-nitrostyrene underwent smoothly to fur-
nish the corresponding Michael adduct, 3b with excellent yield.
This may be due to the presence of electron releasing methyl group
which activates the indole ring toward the nucleophilic attack. It
was observed that increasing the size of substituent close to the
reaction center, nucleophilicity of the indole was depressed which
causes yield decrement (entries 3, 4). The reactions of nitroolefins
growing interest in sustainable chemistry. As a part of our ongoing
research program on biocatalysts,26 herein we report synthetic
methodology for the conjugate addition of indoles to nitroolefins
in the presence of baker’s yeast as catalyst in aqueous medium.
To the best of our knowledge, the conjugate addition of indoles to
nitroolefins mediated by baker’s yeast has not been previously
reported.
In the beginning, the reaction between indole (1a) and b-nitros-
tyrene (2a) in the presence of baker’s yeast was chosen as a stan-
dard model reaction to optimize the best experimental
conditions (Scheme 1).
The integral role of baker’s yeast has been revealed by examin-
ing model reaction at different reaction conditions as follows; (I)
Control experiment: a control reaction was carried out using indole
(
1 mmol) and b-nitrostyrene (1 mmol) in 5 mL of 0.01 M phos-
phate buffer (pH = 7) and -glucose (Scheme 1). The reaction mix-
D
ture was stirred at room temperature for prolonged time, no
product formation was observed by TLC. (II) With dry yeast: baker’s
yeast,
D-glucose, indole (1 mmol) and b-nitrostyrene (1 mmol)
with electron-withdrawing groups (ANO
entries 11, 12) had a slightly higher reaction rate than the reactions
of nitroolefins with electron-donating groups (AOCH , ACH ) on
2
, ACl) on the phenyl ring
were taken together in 0.01 M phosphate buffer (5 mL, pH = 7)
and stirred for 24 h. After workup and purification, 20% of 3-(2-
nitro-1-phenylethyl)-1H-indole (3a) was obtained. (III) With fer-
(
3
3
the phenyl ring (entries 9, 10). Similarly, other substituted nitroole-
fins (entries 13, 14) reacted to deliver the desired products in mod-
erate to good yields. It is important to note that the heteroaromatic
nitroolefins also reacted with equal ease to furnish Michael adducts
in excellent yields (entries 15, 16). However, the aliphatic nitroalke-
nes gave products with reduced yields under optimized reaction
conditions (entries 17, 18).
mented yeast: baker’s yeast (300 mg) and D-glucose (500 mg) were
taken in 5 mL of 0.01 M phosphate buffer and stirred for 12 h for
fermentation of yeast. To the fermented yeast indole (1 mmol)
and b-nitrostyrene (1 mmol) were added. Surprisingly the yield
of product (3a) was increased to 90% after stirring the reaction
mixture for 2.5 h. (IV) With yeast extract: baker’s yeast was stirred
in distilled water and supernatant solution thus obtained after cen-
trifugation was used as yeast extract for the model reaction. It was
Next, we have extended this protocol for dialkylation of 1,4-bis-
(
2-nitrovinyl)benzene 4. It underwent Michael addition with
indole 1a in presence of baker’s yeast in aqueous medium, to afford
the sterically hindered Michael adduct 5 in 82% yield within 3.5 h
(Scheme 2).
R3
NO
R1
2
Baker’s yeast produces a variety of enzymes during fermenta-
Baker's yeast
R1
R3
NO
2
27,28
R
tion.
Among them, lipase is known to catalyze organic transfor-
R
N
Phosphate buffer
D-glucose, r.t
4e
N
mations. It is known that lipases are functional proteins having
amino acid residues with varied functionalities at particular
locations. These amino acid residues like histidine, serine and
aspartate or glutamate are known to form hydrogen bonding with
oxygen thereby increasing the electrophilicity of atom attached to
R2
.
R2
2(a-k)
1
(a-h)
3
(a-r)
Scheme 1. Michael addition of indoles to nitroolefins in fermented baker’s yeast at
room temperature.

A. Mane et al. / Tetrahedron Letters 57 (2016) 2341–2346
2343
oxygen.4e,4f In our case, amino hydrogen of histidine is likely to be
responsible for enhancing electrophilicity of nitrostyrene at b-
carbon through hydrogen bonding as depicted in Figure 2.
Another amino acid residue, aspartic anion might be responsible
for enhancing nucleophilicity at 3-position of indole ring causing
its facile addition on the nitrostyrene as depicted in Figure 2. We
have also carried out a reaction by employing isolated lipase as a
catalyst and obtained 3-(2-nitro-1-phenylethyl)-1H-indole (3a)
with 70% yield. No product formation was observed by employing
thermally inactivated baker’s yeast, but with active baker’s yeast
3a was obtained in 90% yield. Due to thermal inactivation of
baker’s yeast lipase is inactivated which results in no product
formation. It indicates that, components apart from enzymes
present in baker’s yeast are not responsible to catalyze the
4f
Table 2
a
Baker’s yeast catalyzed synthesis of 3-substituted indoles
Entry
Indole
Nitroolefin
Reaction time (h)
Product
Yieldb (%)
Mp (°C)
NO2
N
H
NO
NO
NO
2
1
1a
2a
2.5
90
[96–98]19
N
H
3
a
NO2
N
CH
3
2
2
a
a
[94–96]21
[92–94]25
[142–144]21
2
3
4
3.0
3.0
3.0
89
84
81
1
b
N
CH
b
3
3
3
NO2
CH3
N
H
2
2
1
c
CH
3
N
H
c
NO2
Ph
N
H
NO
2
2
a
1d
Ph
N
H
3
d
3
H CO
NO2
N
H
NO
2
H CO
[116–118]21
[122–124]21
[Pink liquid]19
3
5
6
7
2a
2.5
3.5
3.5
91
82
88
1
e
N
H
3
e
Br
NO2
N
H
NO
2
Br
2a
2a
1
f
N
H
3
f
NO2
N
H
Cl
NO
2
1
g
N
H
Cl
3
g
NO2
N
F
H
NO
2
2
a
[Brown liquid]19
8
1h
3.5
86
N
H
F
3
h
(
continued on next page)

2
344
A. Mane et al. / Tetrahedron Letters 57 (2016) 2341–2346
Table 2 (continued)
Entry Indole
Nitroolefin
Reaction time (h)
Product
CO
Yieldb (%)
Mp (°C)
NO
2
H
3
N
H
3
H CO
NO
2
[148–150]25
9
1a
2b
6.0
83
N
H
3
i
NO
2
3
H C
N
H
3
H C
2
c
NO
2
[Liquid]21
1
0
1a
1a
4.0
86
N
H
3
j
NO
2
O N
2
N
H
O
2
N
1
1
2d
2.0
NO
2
94
[145–147]21
N
H
3
k
NO
2
Cl
N
H
Cl
2
e
1
a
NO
2
[104–106]25
[142–144]25
[132–134]19
1
1
1
2
3
4
3.0
3.0
2.5
89
83
87
N
H
3
l
NO
2
Cl
N
H
Cl
NO
2
2f
1a
N
H
3
m
Cl
Cl
NO
2
Cl
N
H
Cl
2
g
NO
2
1a
N
H
3
n
NO
2
O
N
H
O
NO
2
2
h
[68–70]25
1
5
2.5
85
1
a
N
H
3
o
NO
2
S
N
H
S
NO
NO
2
1
1
6
7
2i
4.0
6.0
86
70
[92–94]21
1
a
N
H
3
p
NO
2
N
H
2j
2
[Liquid] 22
1a
N
H
3
q

A. Mane et al. / Tetrahedron Letters 57 (2016) 2341–2346
2345
Table 2 (continued)
Entry Indole
Nitroolefin
Reaction time (h)
Product
Yieldb (%)
Mp (°C)
NO
2
N
H
2
k
NO
2
1
8
1a
6.0
74
Liquid
N
H
3
r
a
Reaction conditions: indole (1 mmol), nitroolefin (1 mmol), baker’s yeast (300 mg),
Isolated yield after column chromatography.
D-glucose (500 mg), phosphate buffer (pH 7.0, 5 mL) at room temperature.
b
NO
2
NO
2
Baker's yeast
NH
Phosphate buffer
D-glucose, r.t.
N
H
O
2
N
HN
1
a
4
O
2
N
5
Scheme 2. Dialkylation of 1,4-bis-(2-nitrovinyl) benzene in presence of baker’s yeast.
idin
e
References and notes
His
t
1.
2.
3.
Davis, B. G.; Boyer, V. Nat. Prod. Rep. 2001, 81, 618.
Jones, J. B. Tetrahedron 1986, 42, 3351.
(a) Zagozada, M.; Plenkiewicz, J. Tetrahedron: Asymmetry 2007, 18, 1457; (b)
Athanasiou, N.; Smallridge, A. J.; Trewhella, M. A. J. Mol. Catal. B: Enzym. 2001,
11, 893; (c) Li, F.; Cui, J.; Quan, X.; Zhang, R. Chem. Commun. 2004, 2328; (d)
Kostraby, M. M.; Smallridge, A. J.; Trewhella, M. A. Biotechnol. Bioeng. 2002, 77,
N
N
H
O:
N
O
N
H
827.
4. (a) Lee, J. H. Tetrahedron Lett. 2005, 46, 7329; (b) Kumar, A.; Maurya, R. A.
Tetrahedron Lett. 2007, 48, 4569; (c) Kumar, A.; Maurya, R. A. Tetrahedron Lett.
O
O
2007, 48, 3887; (d) Pratap, U. R.; Mali, J. R.; Jawale, D. V.; Mane, R. A.
Tetrahedron Lett. 2009, 50, 1352; (e) Pratap, U. R.; Jawale, D. V.; Netankar, P. D.;
Mane, R. A. Tetrahedron Lett. 2011, 52, 5817; (f) Pratap, U. R.; Jawale, D. V.;
Bhosle, M. R.; Mane, R. A. Tetrahedron Lett. 2011, 52, 1689; (g) Pratap, U. R.;
Jawale, D. V.; Londhe, B. S.; Mane, R. A. J. Mol. Catal. B: Enzym. 2011, 68, 94; (h)
Beheshtiha, Y. S.; Heravi, M. M.; Amrollah, M.; Saeedi, M.; Fallah, A. Chem. Sci.
Trans. 2012, 1, 134; (i) Avalani, J. R.; Patel, D. S.; Raval, D. K. J. Mol. Catal. B:
Enzym. 2013, 90, 70; (j) Singh, N. G.; Nongrum, R.; Kathing, C.; Rani, J. W. S.;
Nongkhlaw, R. Green Chem. Lett. Rev. 2014, 7, 137.
(a) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, 1996; p 113;
(b) Casapullo, A.; Bifulco, G.; Bruno, I. R. J. Nat. Prod. 2000, 63, 447; (c) Horgen, F.
D.; Santos, D. B. D.; Goetz, G.; Sakamoto, B.; Kan, Y.; Nagai, H.; Scheuer, P. J. J.
Nat. Prod. 2000, 63, 152.
Aspartic anion
Figure 2. Activation of indole and b-nitrostyrene by baker’s yeast for 1,4-conjugate
addition.
Michael addition of indole to b-nitrostyrene. Therefore we believe
that the enzyme lipase available in baker’s yeast is likely to be
responsible to accelerate the 1,4-conjugate addition of indoles to
nitroolefins.
5
.
.
6
(a) Saracoglu, N. Top. Heterocycl. Chem. 2007, 11, 1; (b) O’Hagan, D. Nat. Prod.
Rep. 2000, 17, 453.
In conclusion, for the first time we have explored the potential of
baker’s yeast as a biocatalyst for the synthesis of 3-substituted
indoles with simple adoptable procedure. The reactions are remark-
ably tolerant of substituents at different positions of indolyl rings
and benzene ring of nitroolefins. The reactions are carried out in
aqueous medium at room temperature so no side product or
decomposition product was observed. In terms of green chemistry,
the process is of great interest as it avoids the use of corrosive acids,
toxic metallic catalysts and organic volatile solvents. Overall, the
developed methodology using baker’s yeast, turned out to be an
environmentally benign one and it is a good contribution for the
regioselective 1,4-conjugate addition of indoles to nitroolefins.
7. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
8
.
(a) Xu, H.; Lv, M. Curr. Pharm. Des. 2009, 15, 2120; (b) Olgen, S. Rev. Med. Chem.
013, 13, 1700.
2
9
.
Boriskin, Y. S.; Leneva, I. A.; Pecheur, E. I.; Polyak, S. J. Curr. Med. Chem. 2008, 15,
997.
1
1
1
0. Suzuki, H.; Kato, K.; Kumagai, H. J. Biotechnol. 2004, 111, 291.
1. Zhang, M. Z.; Chen, Q.; Yang, G. F. Eur. J. Med. Chem. 2015, 89, 421.
2. (a) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 612; (b) Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
3. Damodiran, M.; Senthil Kumar, R.; Shiva Kumar, P. M.; Doble, M.; Perumal, P. T.
J. Chem. Sci. 2009, 121, 65.
4. Meshram, H. M.; Nageswara Rao, G.; Santosh Kumar, G. Synth. Commun. 2010,
40, 3496.
5. Kumar, A. V.; Rao, K. R. Tetrahedron Lett. 2011, 52, 5158.
6. Schwalm, C. S.; Ceschi, M. A.; Russowsky, D. J. Braz. Chem. Soc. 2011, 22, 623.
7. Tran, N. T.; Wilson, S. O.; Franz, A. K. Org. Lett. 2012, 14, 186.
1
1
1
1
1
Acknowledgements
18. Islam, M. S.; Al Majid, A. M. A.; Al-Othman, Z. A.; Barakat, A. Tetrahedron:
Asymmetry 2014, 25, 245.
1
2
2
9. Jeganathan, M.; Kanagaraj, K.; Dhakshinamoorthy, A.; Pitchumani, K.
We gratefully acknowledge the financial support from the
Department of Science and Technology and University Grants
Commission, New Delhi, India.
Tetrahedron Lett. 2014, 55, 2061.
0. Liang, L.; Liu, Q.; Zhang, J.; Wang, F.; Yuan, Y. Res. Chem. Intermed. 2013, 39,
1957.
1. Habib, P. M.; Kavala, V.; Kuo, C.-W.; Raihan, M. J.; Yao, C.-F. Tetrahedron 2010,
6
6, 7050.
Supplementary data
22. Fu, Z.; Shao, H. Ultrason. Sonochem. 2011, 18, 520.
2
2
2
3. Samet, M.; Buhle, J.; Zhou, Y.; Kass, S. R. J. Am. Chem. Soc. 2015, 137, 4678.
4. Kitanosono, T.; Miyo, M.; Kobayashi, S. Tetrahedron 2015, 71, 7739.
5. Parsekar, S. B.; Naik, S.; Naik, M. M.; Tilve, S. G. Monatsh. Chem. 2015, 146, 691.
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.057.

2
346
A. Mane et al. / Tetrahedron Letters 57 (2016) 2341–2346
2
6. (a) Mane, A.; Salokhe, P.; More, P.; Salunkhe, R. J. J. Mol. Catal. B: Enzym. 2015,
27. Jones, R. C.; Hough, J. S. J. Gen. Microbiol. 1970, 60, 107.
28. Pscheidt, B.; Glieder, A. Microb. Cell Fact. 2008, 7, 25.
1
4
21, 75; (b) Salokhe, P. R.; Rashinkar, G. S.; Salunkhe, R. S. Indian J. Chem. 2010,
9B, 199; (c) More, P.; Patil, A.; Salunkhe, R. RSC Adv. 2014, 4, 63039.