Efficient bakers yeast-catalyzed multicomponent synthesis of α-aminophosphonates in one pot

Article abstract of DOI:10.1080/00397911.2012.721918

Utilizing bakers yeast (Saccharomyces cerevisiae) as a biocatalyst, synthesis of α-aminophosphonates in one pot has been accomplished by the three-component reaction of an aldehyde, an amine, and diethyl phosphite in moderate to good yields under solvent-

Full text of DOI:10.1080/00397911.2012.721918

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Efficient Bakers’ Yeast-Catalyzed
Multicomponent Synthesis of α-
Aminophosphonates in One Pot
Asish K. Bhattacharya a & Mohammad Mujahid a
a Division of Organic Chemistry, CSIR-National Chemical Laboratory ,
Pune , Maharashtra , India
Published online: 26 Jun 2013.
To cite this article: Asish K. Bhattacharya & Mohammad Mujahid (2013): Efficient Bakers’ Yeast-
Catalyzed Multicomponent Synthesis of α-Aminophosphonates in One Pot, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:19, 2583-2589
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Synthetic Communications1, 43: 2583–2589, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.721918
EFFICIENT BAKERS’ YEAST–CATALYZED
MULTICOMPONENT SYNTHESIS
OF a-AMINOPHOSPHONATES IN ONE POT
Asish K. Bhattacharya and Mohammad Mujahid
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune,
Maharashtra, India
GRAPHICAL ABSTRACT
Abstract Utilizing bakers’ yeast (Saccharomyces cerevisiae) as a biocatalyst, synthesis of
a-aminophosphonates in one pot has been accomplished by the three-component reaction of
an aldehyde, an amine, and diethyl phosphite in moderate to good yields under solvent-free
reaction conditions.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Aldehydes; amines; a-aminophosphonates; green chemistry; Saccharomyces
cerevisiae; solvent-free conditions
INTRODUCTION
In recent years, a-aminophosphonate has emerged as novel pharmacophore
moiety[1–5] because of their intrinsic biological activities. As a result, several synthetic
methodologies have been reported in the recent past.[6,7] However, most of these
reported methods have their own inherent limitations as water that is generated dur-
ing the course of reaction decomposes or deactivates the Lewis acid[8] and hence
these reactions could not be carried out in one pot (from a carbonyl compound,
an amine, and a phosphite). Also, involvement of stoichiometric amount of catalysts,
expensive reagents,[6a] and harmful organic solvents[7b] renders them unacceptable in
terms of ‘‘green chemistry.’’ We have been interested in exploring biological proper-
ties of aminophosphonates and recently reported aminophosphonates as novel
cysteine protease inhibitors[9a,b] and their anti-HIV activities.[9c] Recently, we have
Received June 29, 2012.
Address correspondence to Asish K. Bhattacharya, Division of Organic Chemistry, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411 008, Maharashtra, India. E-mail:
ak.bhattacharya@ncl.res.in
2583

2584
A. K. BHATTACHARYA AND M. MUJAHID
reported two methods utilizing bismuth nitrate pentahydrate[10] and Amberlite-IR
120[11] as efficient and environmentally benign catalysts for the synthesis of a-amino-
phosphonates in one pot under solvent-free reaction conditions, circumventing some
of the limitations posed by the earlier reported methods. Because a-aminophospho-
nate synthesis via three-component reactions is among the most important reactions,
we opined that there could still be a demand for the development of a three-
component reaction in one-pot that uses enzymes as biocatalysts in organic synthesis
considering the ‘‘green chemistry’’ approach.
Application of bakers’ yeast (Saccharomyces cerevisiae) as a biocatalyst in
organic synthesis is well documented.[12] Several transformations employing bakers’
yeast have been reported, including asymmetric reduction of nitro olefins to nitroalk-
anes,[13] reduction of aryl azides to aryl amines,[14] reduction of nitro group to the
corresponding amine,[15] reduction of ketones to furnish optically active alcohols,[16]
reduction of carbon–carbon double bonds,[17] oxidative coupling of thiols to disul-
fides,[18] biooxidative conversion of a thio group to an oxo functionality,[19] oximes
to chiral amines,[20] oxidation of sulfides to chiral sulfoxides,[21] and acyloin-type
condensations.[22] Also, bakers’ yeast has been employed for the preparation of pyr-
idylethanol N-oxides[23] and isoquinoline.[24] Recently, bakers’ yeast-catalyzed Bigi-
nelli[25] and Hantzsch reactions[26] have also been reported.
RESULTS AND DISCUSSION
Herein, we report development of a synthetic protocol for the synthesis of a-
aminophosphonates in one pot catalyzed by bakers’ yeast (Scheme 1). In an initial
study,[25] bakers’ yeast (500 mg) was taken in 0.01 M phosphate buffer (pH 7.0,
5 mL) in which D-glucose (750 mg) was added and the resulting solution was stirred
overnight. Then carbonyl compound (1 mmol), amine (1 mmol), and diethylpho-
sphite (1 mmol) were added for the required time (as mentioned in Table 1). After
completion of the reaction as indicated by thin-layer chromatography (TLC), it
was filtered over celite. The filtrate was extracted with ethyl acetate (3 ꢀ 50 mL),
dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue
was chromatographed over silica-gel column (100–200 mesh) and eluted with solvent
system petroleumether–ethyl acetate (15–30%) to afford the corresponding pure
a-aminophosphonates.
To study the catalytic efficiency of bakers’ yeast, we carried out control reac-
tions without bakers’ yeast following the procedure described previosly, and to
our surprise, we could not observe even a trace amount of the desired product by
thin-layer chromatography (TLC). Hence, it was clear that bakers’ yeast is necessary
to catalyze this three-component reaction in one pot. Therefore, we decided to
Scheme 1. Reagents and conditions: (i) Baker’s yeast, D-glucose, phosphate buffer (pH 7.0), rt, 36–48 h.

SYNTHESIS OF a-AMINOPHOSPHONATES
2585
Table 1. Bakers’ yeast–mediated one-pot synthesis of a-aminophosphonatesa
Entry
1
R-CHO
R1-NH2
Product
Time (h)
48
Yield (%)b
83
4a
4b
4c
4d
48
48
48
74
81
68
2
3
4
5
4e
4f
48
48
71
66
6
7
8
4 g
4 h
48
48
66
61
4i
4j
48
48
59
9
67
10
(Continued )

2586
A. K. BHATTACHARYA AND M. MUJAHID
Table 1. Continued
Entry
11
R-CHO
R1-NH2
Product
Time (h)
48
Yield (%)b
68
4k
4 l
4 m
4n
48
36
36
78
55
63
12
13
14
15
16
4o
4p
36
48
69
66
4q
48
65
17
4r
—
—
48
72
72
61
—
—
18
19
20
aAll products were characterized by 1H NMR, 13C NMR, and mass spectral data.
bIsolated yields of the corresponding a-aminophosphonates.

SYNTHESIS OF a-AMINOPHOSPHONATES
2587
generalize our developed protocol. Several structurally diverse carbonyl compounds
and aniline=substituted anilines were subjected to this novel procedure to furnish the
corresponding a-aminophosphonates in moderate to good yields. The results are
summarized in Table 1. In all the cases, three-component reaction went smoothly
and the corresponding a-aminophosphonates were obtained in moderate to good
yields. The presence of electron-donating groups on the aldehyde resulted in the cor-
responding products in poor yields and the reaction was sluggish; however, aldehydes
possessing electron-withdrawing groups afforded the corresponding a-aminopho-
sphonates in shorter reaction times as well as in good yields. Also, amines possessing
electron-donating groups gave the corresponding products in good yields. However,
in the case of cyclohexanone (entry 19) and diene aldehyde (entry 20) respectively, the
traces of the corresponding products could not be observed on TLC even after 72 h. It
is pertinent to mention here that the present method is tolerant towards various func-
tional groups including alkoxy, halides, nitro, methylenedioxy, and hydroxy groups.
SELECTED SPECTRAL DATA OF NEW COMPOUNDS
Compound 4k
1
Syrupy liquid; H NMR (200 MHz, CDCl3, TMS): d 8.21–6.24 (m, 8H), 4.86
1
(d, JPH ¼ 25.0 Hz, 1H), 4.18–3.83 (m, 4H), 1.32–1.18 (m, 6H); 13C NMR
(50 MHz, CDCl3, TMS): d 147.5, 147.3, 144.3, 144.2, 135.7, 135.4, 128.6, 123.7,
2
120.9, 118.4, 111.0, 109.7, 63.6 (d, JPC ¼ 6.9 Hz, -OCH2CH3), 55.8 (d,
3
1JPC ¼ 148.9 Hz, -CHP), 55.6, 16.4 (d, JPC ¼ 7.3 Hz, -OCH2CH3); MS (ESI): m=z
395 [M þH]þ, 417 [M þNa]þ.
Compound 4n
1
Syrupy liquid; H NMR (200 MHz, CDCl3, TMS): d 7.37–6.39 (m, 8H), 4.74
1
(d, JPH ¼ 23.8 Hz, 1H), 4.14–3.75 (m, 4H), 2.30 (m, 3H), 1.30–1.12 (m, 6H); 13C
NMR (50 MHz, CDCl3, TMS): d 147.3, 137.5, 136.5, 136.2, 132.9, 132.8, 129.3,
2
127.8, 127.68, 121.0, 117.6, 111.2, 109.6, 63.3 (d, JPC ¼ 7.0 Hz, -OCH2CH3), 57.1,
1
3
55.6 (d, JPC ¼ 152.0 Hz, -CHP), 21.2, 16.3 (d, JPC ¼ 6.2 Hz, -OCH2CH3); MS
(ESI): m=z 364 [M þH]þ, 386 [M þNa]þ.
Compound 4o
Syrupy liquid; 1H NMR (200 MHz, CDCl3, TMS): d 7.33–7.15 (m, 9H),
1
4.12–3.75 (m, 4H), 3.53 (d, JPH ¼ 13.4 Hz, 1H), 2.35 (m, 3H), 1.31–1.10 (m, 6H);
13C NMR (50 MHz, CDCl3, TMS): d 139.3, 137.7, 137.6, 132.5, 132.4, 129.3,
2
1
129.2, 128.4, 127.1, 62.9 (d, JPC ¼ 7.3 Hz, -OCH2CH3), 59.1 (d, JPC ¼ 154.06 Hz,
-CHP), 51.1, 16.4 (d, JPC ¼ 5.8 Hz, -OCH2CH3); MS (ESI): m=z 348 [M þH]þ.
3
Compound 4p
Syrupy liquid; 1H NMR (200 MHz, CDCl3, TMS): d 7.37–6.47 (m, 8H), 4.83 (d,
1JPH ¼ 24.9 Hz, 1H), 4.31–3.59 (m, 4H), 2.25 (s, 3H), 1.29 (t, J ¼ 7.1 Hz, 3H), 1.13 (t,

2588
A. K. BHATTACHARYA AND M. MUJAHID
J ¼ 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3, TMS): d 145.3, 137.5, 137.5, 132.6, 129.3,
129.2, 128.0, 127.9, 119.9, 118.3, 114.4, 112.2, 64.0 (d, 2JPC ¼ 6.9 Hz, -OCH2CH3), 55.8
(d, 1JPC ¼ 154.8 Hz, -CHP), 21.1, 16.4 (d, 3JPC ¼ 5.8 Hz, -OCH2CH3); MS (ESI): m=z
350 [M þH]þ, 372 [M þNa]þ, 388 [M þK]þ.
Compound 4q
Syrupy liquid; 1H NMR (200 MHz, CDCl3, TMS): d 7.36–6.24 (m, 8H), 6.40–6.24
(m, 3H), 5.07 (t, 1H), 4.68 (dd, 1JPH ¼ 24.1 Hz, 1H), 4.16–3.60 (m, 4H), 2.30 (s, 3H), 1.29
(t, J¼ 7.1 Hz, 3H), 1.12 (t, J ¼ 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3, TMS): d 166.3,
161.4, 148.6, 148.4, 148.3, 148.0, 137.8, 132.3, 130.3, 130.1, 129.4, 129.3, 127.6, 109.7,
104.9, 104.5, 100.9, 100.4, 63.3 (d, 2JPC ¼ 7.3Hz, -OCH2CH3), 55.6 (d, 1JPC ¼ 151.8Hz,
Hz, -CHP), 21.1, 16.4 (d, 3JPC ¼ 5.5 Hz, -OCH2CH3); MS (ESI): m=z 352 [M þH]þ, 374
[M þNa]þ, 390 [M þK]þ.
Complete experimental details are available online in the Supplementary
Materials.
CONCLUSION
In summary, we have described baker’s yeast–mediated one-pot reaction of
aldehydes, amines, and diethyl phosphite to afford a-aminophosphonates in moder-
ate to good yields. The main advantages of the present procedure are use of biocata-
lyst, solvent-free conditions, easy reaction workup procedure, and tolerance toward
various functionalities present in the substrates.
ACKNOWLEDGMENTS
A. K. B. is grateful to the Department of Biotechnology (DBT), Government
of India, New Delhi, India, for financial support. Authors are grateful to the late
M. I. Khan, senior principal scientist, Division of Biochemical Sciences, for fruitful
discussions.
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