Bakers' yeast-catalyzed reductive cleavage of 3-aryl-2,1-benzisoxazoles and its quaternary salts: An efficient green synthesis of 2-aminobenzophenones

Article abstract of DOI:10.1007/s00706-009-0159-x

3-Aryl-2,1-benzisoxazoles and its salts underwent reductive cleavage of the N-O bond leading to 2-aminobenzophenones with bakers' yeast under non-fermenting conditions in aqueous media. The procedure gives excellent yields of 2-alkylamino- and 2-aminobenzophenones.

Full text of DOI:10.1007/s00706-009-0159-x

Monatsh Chem (2009) 140:1183–1187
DOI 10.1007/s00706-009-0159-x
ORIGINAL PAPER
Bakers’ yeast-catalyzed reductive cleavage of 3-aryl-2,
1-benzisoxazoles and its quaternary salts: an efficient green
synthesis of 2-aminobenzophenones
Kushal C. Lekhok Æ Dipak Prajapati Æ
Ramesh C. Boruah Æ Sharbani Mazumder Æ
Tarun C. Borah
Received: 30 September 2008 / Accepted: 27 January 2009 / Published online: 11 June 2009
Ó Springer-Verlag 2009
Abstract 3-Aryl-2,1-benzisoxazoles and its salts underwent
reductive cleavage of the N–O bond leading to 2-amino-
benzophenones with bakers’ yeast under non-fermenting
conditions in aqueous media. The procedure gives excellent
yields of 2-alkylamino- and 2-aminobenzophenones.
drugs of the 1,4-benzodiazepine class [9]. Thus, chloro-
diazepoxide, proquazone, amfenae, and nitrazepam are
drugs on the market prepared from a 2-aminobenzophe-
none starting material [10]. The key factor in the synthesis
of these substances is the construction of a suitably
substituted 2-aminobenzophenone moiety [11]. Although
several chemical methods have been reported for the syn-
thesis of 2-aminobenzophenones, these have their own
merits as well as limitations [12]. Most of the methods
require appropriately substituted anilines, high temperature
[13], and catalytic reduction using expensive palladium [3],
and also functional groups are susceptible to reduction that
cannot be tolerated [2]. The thionyl chloride-catalyzed
cleavage of 2,1-benzisoxazoles yielded haloaminobenz-
ophenones [14], with the entry of halogen atom into the
carbocyclic ring, which makes the corresponding 1,4-ben-
zodiazepines less pharmacologically active due to the
presence of a chloro substituent in the 9 position [15]. In a
very recent report expensive SmI2 and TiCl3 were also used
for the cleavage of the N–O bond of isoxazoles [16, 17].
Consequently, pursuance of more convenient, selective,
eco-benign, and cost effective synthetic protocols for the
synthesis of 2-aminobenzophenones still remains an active
area of research [18–20].
Keywords Bakers’ yeast Á 2,1-Benzisoxazolium salts Á
2,1-Benzisoxazoles Á 2-(Alkylamino)benzophenones Á
2-Aminobenzophenones
Introduction
The reductive cleavage of isoxazoles is an industrially
important method for the construction of b-diketones, al-
kylaminoketones, b-ketoesters, b-ketoimines, and their
derivatives, and is normally carried out by metal-catalyzed
hydrogenolysis (nickel or palladium) [1]. These methods
fail when other sensitive groups or catalyst poisons are
present in the molecule [2, 3]. The 2-aminobenzophenones
have drawn much attention due to the fact that they are
among the important starting materials for the synthesis of
a wide variety of heterocyclic systems [4–8]. In particular,
it has been reported that 2-aminobenzophenones can be
used as intermediates for the synthesis of numerous CNS
Bakers’ yeast (Saccharomyces cerevisiae BY), the most
popular whole-cell biocatalyst, has been employed [21–23]
since the beginning of the twentieth century and continues to
be of interest [24–27]. A variety of new and novel applica-
tions of bakers’ yeast has been reported [26–29]. Some
examples include the biooxidative conversion of a thio to an
oxo functionality [30], conversion of nitro compounds to
hydroxylamines [26], ester hydrolysis, bioreduction of
PEG–acetoacetate [27], reduction of aromatic nitro [31–33]
and nitroso compounds [34], reduction of aryl azides to aryl
amines [35], oximes to chiral amines [36], Hantsch pyridine
K. C. Lekhok Á D. Prajapati (&) Á R. C. Boruah
Medicinal Chemistry Division,
North East Institute of Science and Technology,
Jorhat 785006, India
e-mail: dr_dprajapati2003@yahoo.co.uk
S. Mazumder Á T. C. Borah
Department of Biotechnology,
North East Institute of Science and Technology,
Assam, Jorhat 785006, India
123

1184
K. C. Lekhok et al.
synthesis [28], and notably the enantioselective reduction of
carbonyl function [37–40]. Bakers’ yeast has also been
extensively used to carry out reductions of aromatic nitro
groups, but there has been little work on the application of
this reagent to the reductive cleavage of heterocycles,
although they have been employed for the reductive cycli-
zation [30]. Herein, in this report we wish to disclose the
reductive N–O bond cleavage of 3-aryl-2,1-benzisoxazoles
1 and its quaternary salts 2, to the corresponding 2-amino-
benzophenones 3 using bakers’ yeast as a new catalyst under
aqueous and non-fermenting conditions. The reaction pro-
ceeds efficiently in excellent yields at ambient temperature
under neutral conditions (Scheme 1).
aminobenzophenones involves either very critical conditions
or requires a multi-step process [42, 43]. But bakers’ yeast
produces 2-(alkylamino)benzophenones from 2,1-ben-
zisoxazolium salts in a one-pot process in excellent yields
without any complications. The structure of 2-methylamino-
5-chlorobenzophenone thus obtained was confirmed through
elemental and spectral analysis. The IR spectrum of 3f
exhibited sharp bands at 3,340 and 1,625 cm-1 due to –NH
and C=O. The 1H NMR spectrum displayed signals at d 2.90
(s, 3H, NCH3), 6.54 (br, 1H, NH), and 7.12–7.58 (m, 8H,
aromatic protons). The mass spectrum of 3f showed a
molecular ion peak at m/z 245 (M?). Similarly, other 3-aryl-
2,1-benzisoxazoles 1b–1e and 2,1-benzisoxazolium salts
2g–2i were reacted, and the corresponding substituted and
unsubstituted 2-aminobenzophenones were isolated in 85–
92% yields (Table 1). All the products thus obtained were
Results and discussion
1
characterized by spectral analyses (IR, H NMR, and MS)
Treatment of 2,1-benzisoxazole 1a (R1=H, R2=Cl,
R3=R4=H) with bakers’ yeast (Saccharomyces cerevisiae
BY), at ambient temperature for 6 h, at pH 7.0, followed by
standard workup yielded the corresponding 2-amino-5-
chlorobenzophenone (3a) in 87% yield without the formation
of any side products. Under identical conditions, the reaction
also proceeds effectively when 2,1-benzisoxazolium salts
2 are reacted, and the corresponding 2-(alkylamino)
benzophenones were isolated in 85–92% yields. The 2,1-
benzisoxazolium salts thus reacted were prepared from the
corresponding 2,1-benzisoxazoles and alkyl sulphates [41] in
good yields. It is to be noted that the synthesis of 2-(alkyl-
amino)benzophenones through selective monoalkylation of
and finally by comparison with authentic samples [10, 15].
The results are shown in Table 1. Rate enhancement of the
reaction was observed when 15 or 20 g of bakers’ yeast was
employed, but relatively lower yields (70 or 65%) were
obtained due to decomposition of the starting material.
Moreover, use of only 5 g of bakers’ yeast led to lower yields
(40–50%) in longer reaction times. We extended the scope of
the reaction using 10 g of the yeast for 6–8 h and obtained
products with 85–92% yields. To study the role of lyophi-
lized yeast cells in catalyzing the reaction, a control reaction
was performed without using any bakers’ yeast under neutral
conditions (pH 7.0). The reaction did not yield any product
even after 7–8 h of reaction time. Further increase of reaction
R1
R2
Scheme 1
R1
R2
NH2
O
NH
OH
R1
N
O
H+
R2
R3
R3
BY
MeOH
R3
3
A
R4
R4
1
R4
R1 = Cl, Br, NO2
R2 = H, CH3
R3 = H, OH
R4 = H
R
N
R
NH
R1
R2
R1
R2
RSO4
R3
O
BY
O
R3
R4
R4
3
R1 = Cl, Br
R2 = H
2
R3 = H, OH
R4 = H, Cl
R = Me, Et
123

Bakers’ yeast-catalyzed reductive cleavage
1185
Table 1 Bakers’ yeast mediated synthesis of 2-aminobenzophenones and 2-(alkylamino)benzophenones 3
Products
R
R1
R2
R3
R4
mp (°C)
Yielda (%)
Reaction timeb (h)
Found
Lit.
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cl
H
98
110
123
152
172
94
99–100 [5]
110–11 [5]
122–24 [5]
152–54 [5]
172–74 [5]
94–95 [10]
97–98 [10]
88–89 [10]
56–57 [10]
87
89
85
87
85
92
90
85
91
6.0
6.0
7.0
6.0
6.0
8.0
7.5
7.5
8.0
H
Br
Me
NO2
Cl
H
H
H
H
H
H
OH
H
Me
Me
Me
Et
Cl
Br
Cl
H
97
H
89
Cl
H
56
a
Yield refers to the yield of pure isolated products
b
Products were identified by the comparison of IR and NMR spectra and melting points with those of authentic samples
time led only to decomposition of starting materials. It is
noteworthy that this reaction also proceeds, but not so
effectively, when carried out either in alkaline conditions
(10% NaOH solution, 10 g yeast) or under fermenting con-
ditions (bakers’ yeast 5 g, benzisoxazole 0.25 g, sucrose
30 g, and water 200 cm3). After 12 h, the corresponding 2-
aminobenzophenones were obtained in 40–50% yields only.
In the present method nitroanthranil 1d was converted to the
corresponding nitroaminobenzophenone 3d without effect-
ing the nitro group, which is in contrast to an earlier report
[44] where bakers’ yeast reduced nitro groups to their cor-
responding amino derivatives in alkaline solution. Also, we
did not observe any dehalogenation or entry of halogen into
the carbocyclic ring as observed by Boruah et al. during
cleavage of 2,1-benzisoxazoles [14]. It is worth mentioning
here that Easton et.al. reported [45] a yeast-catalyzed
cleavage of isoxazole under fermenting conditions (cleavage
of either an aromatic ring or a single bond), where they
employed 75 g of sucrose in 400 cm3 of water for 0.5 g of
substrate, in 24% yield after 24 h of reaction time and iso-
lated the corresponding hydroxyimines. In another report
Bianchi et al. observed the formation of alcohols when they
performed the reduction of ketoisoxazoles by bakers’ yeast in
liquid culture media incubated at 30 °C. Here, the authors did
not observe any ring cleavage of the isoxazole unit; rather,
reduction of carbonyl function occurs [46]. In contrast to
these reports, we reacted various 2,1-benzisoxazoles and its
quaternary salts in the presence of bakers’ yeast under non-
fermenting conditions and isolated exclusively the corre-
sponding ring cleavage product 2-aminobenzophenones in
excellent yields without the formation of any other products.
Although the detailed mechanism of the reaction is not clear
at this stage, a plausible explanation for the reductive
cleavage of the 2,1-benzisoxazole unit on the basis of the
known reductive metabolism of nitroaromatics [47–49] is as
follows: the 2,1-benzisoxazole is first reduced to form the
imine function A (methanol acts as a proton source), which
was then non-enzymatically further stabilized as aminoke-
tone to yield the product (Scheme 1).
Conclusion
We have developed an efficient metal-free method for the
reductive cleavage of the N–O bond of 2,1-benzisoxazo-
lium salts and 2,1-benzisoxazoles to afford medicinally
important building blocks, employing a biocatalyst under
non-fermenting conditions. The method is inexpensive,
nontoxic, and environmentally friendly. It is beneficial that
halogen and nitro groups were not affected under the
reaction conditions. Yeast did not require sucrose or glu-
cose in this reaction, which resulted in appropriate
regulation of the reducing ability of yeast. This biotrans-
formation technique will constitute a useful alternative to
the commonly accepted chemical methods (when other
sensitive groups or catalyst poisons are present in the
molecule) for the synthesis of 2-aminoarylketones.
Experimental
Materials and methods
Melting points were determined by using a Buchi melting
point apparatus. IR spectra were recorded for KBr discs on
a PerkinElmer 240C analyzer. 1H NMR spectra were
recorded on 90-MHz spectrometers, and chemical shift
values were recorded in d units (ppm) relative to Me4Si as
internal standard. Mass spectra were recorded in an AE-
IMS-30 spectrometer. Elemental analyses were performed
123

1186
K. C. Lekhok et al.
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