An efficient synthesis of benzodiazepinyl phosphonates as clostripain inhibitors via FeCl3 catalyzed four-component reaction

Article abstract of DOI:10.1039/c0ob01102a

A novel one-pot route for the synthesis of benzodiazepinyl phosphonates (BDPs) has been achieved. FeCl₃ efficiently catalyzed four-component condensation of diamines, acetone and phosphites in the presence of molecular sieves to furnish BDPs as novel chemical entities with good yield. The synthesized BDPs have shown significant protease inhibition activity against clostripain, a disease model for gas gangrene, suggesting that these novel chemical entities could be further explored as cysteine protease inhibitors.

Full text of DOI:10.1039/c0ob01102a

Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 9 | Number 15 | 7 August 2011 | Pages 5305–5580
ISSN 1477-0520
PAPER
Asish K. Bhattacharya and co-workers
An efficient synthesis of
benzodiazepinyl phosphonates
as clostripain inhibitors via FeCl3
catalyzed four-component reaction
1477-0520(2011)9:15;1-T

Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 5407
www.rsc.org/obc
PAPER
An efficient synthesis of benzodiazepinyl phosphonates as clostripain
inhibitors via FeCl3 catalyzed four-component reaction†
Asish K. Bhattacharya,*a Kalpeshkumar C. Rana,a Dnyaneshwar S. Raut,a Vaibhav P. Mhaindarkarb and
Mohamad I. Khan‡b
Received 1st December 2010, Accepted 29th March 2011
DOI: 10.1039/c0ob01102a
A novel one-pot route for the synthesis of benzodiazepinyl phosphonates (BDPs) has been achieved.
FeCl3 efficiently catalyzed four-component condensation of diamines, acetone and phosphites in the
presence of molecular sieves to furnish BDPs as novel chemical entities with good yield. The
synthesized BDPs have shown significant protease inhibition activity against clostripain, a disease
model for gas gangrene, suggesting that these novel chemical entities could be further explored as
cysteine protease inhibitors.
otics and pharmacological agents,10 and herbicides.11 Therefore,
Introduction
we opined that benzodiazepinyl phosphonates (BDPs) will be
In recent years, multicomponent reactions (MCRs) have gained
an interesting class of compounds as it combines these two
tremendous attention of medicinal as well as organic chemists for
biologically active moieties and also the synthesis of benzodi-
the generation of compound libraries of novel chemical entities
azepinyl phosphonates could be achieved in one pot utilizing
to satisfy the need of high-throughput screening for new bioactive
molecules having diversified scaffolds. In MCR, more than two
reactants are reacted in a reaction flask to furnish a product
that incorporates substantial portions of all the components.1,2
MCR. Further, a-aminophosphonates are considered to be the
structural analogues of the corresponding a-amino acids and
transition-state mimics of peptide hydrolysis, the phosphonate
group of a-aminophosphonates can act as an electrophile which
is the common requirement of cysteine protease inhibitors.12 This
generates the possibility that BDPs can act as a cysteine protease
inhibitor. Clostripain is one of the cysteine proteases associated
with collagenase, isolated from Clostridium histolyticum, an anaer-
obic rod-shaped, spore-forming bacillus, which belongs to the
group of Clostridium spp,13 and causes deadly gas gangrene, a
severe pathological condition. These Clostridium species are also
responsible for various disorders like pseudomembranous colitis,
food poisoning, tetanus and enteroxemia. Therefore, inhibitors of
clostripain could be utilized in the therapy of gas gangrene.
Recently, we have described the three-component reaction of
aldehydes, amines, and diethyl phosphite catalyzed by Amberlite
IR 120 (acidic)14a or bismuth nitrate14b affording the correspond-
ing a-amino phosphonates in excellent yields. In the literature,
syntheses of benzodiazepines have been accomplished by reacting
o-phenylenediamine and ketones catalyzed by various Lewis acids
(Scheme 1).15 We envisaged that further nucleophilic attack of
phosphite on the imine would result in the formation of BDPs in
one pot in a true MCR fashion (Scheme 2).
In its true form, MCR involves formation of several bonds
in a single operation without the need for isolation of the
intermediates formed, changing the reaction conditions or adding
further reagents. Many important named reactions are MCR in
nature,3 e.g. Strecker, Hantzsch, Biginelli, Mannich, Passirini, Ugi
reactions, etc. Some classes of compounds such as isonitriles
and 1,3-dicarbonyl compounds have found wide applications in
a variety of MCRs. Similarly alkyl/aryl phosphites have also been
utilized as an important participating component in some MCRs.4
The benzodiazepines represent a biologically active class of
compounds which exhibits a wide range of therapeutic and
pharmacological properties5 such as anticonvulsant, anti-anxiety,
analgesic, hypnotic, sedative, antidepressant, anti-inflammatory,
inhibition of hepatitis C NS5B RNA polymerase,6 antago-
nism of platelet-activating factor, psychotropic activity, caspase-
1 inhibitors,7 antitumor agents5 and b-secretase inhibition.5 a-
Aminophosphonates have also shown various biological activities
such as peptide mimics,8 haptens of catalytic antibodies,9 antibi-
aDivision of Organic Chemistry, National Chemical Laboratory (NCL-
CSIR), Dr Homi Bhabha Road, Pune 411 008, India. E-mail: ak.
bhattacharya@ncl.res.in; Fax: +91 20 25902629; Tel: +91 20 25902309
bDivision of Biochemical Sciences, National Chemical Laboratory (NCL-
CSIR), Dr Homi Bhabha Road, Pune 411 008, India
† Electronic supplementary information (ESI) available: Full experimental
procedures and copies of NMR spectra of all the compounds. See DOI:
10.1039/c0ob01102a
‡ Deceased.
Scheme 1 Reported one pot synthesis of benzodiazepine.
Org. Biomol. Chem., 2011, 9, 5407–5413 | 5407
This journal is
The Royal Society of Chemistry 2011
©

Table 2 One-pot synthesis of benzodiazepinyl phosphonate catalyzed by
FeCl3
Scheme 2 Proposed one-pot synthesis of benzodiazepinyl phosphonates.
Results and discussion
Chemistry
Initially the reaction of o-phenylenediamine 1a, acetone 2 and
diethylphosphite 4a was carried out in the presence of silica–
perchloric acid; however, BDP 5aa was obtained in low yield
(12%) even after 2 days. The slow reaction and low yield could
be attributed to the less electrophilic ketimine which results in
the slow attack of the phosphite. To overcome this problem, we
screened several catalysts and reaction conditions as shown in
Table 1.
Catalyst screening revealed that FeCl3 (10 mol%) was the
best catalyst furnishing the product in 43% yield; however, the
reaction was slow (entry 7, Table 1). To circumvent this problem,
reflux or microwave irradiation conditions were employed which
resulted in decomposition (entries 8 and 9, respectively). Since
the reaction proceeds with the initial formation of the imine
with concomitant generation of water which can decompose or
deactivate the catalyst,14 we opined that trapping of the water by
the use of molecular sieves would be beneficial. When the reaction
was carried out in the presence of preactivated molecular sieves
Entry Amine Phosphite Product
Yield (%)a Ratio of isomersb
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
4a
4b
4c
4d
4a
4b
4c
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
5aa
63
63
66
65
42
50
52
59
55
52
51
63
59
57
53
43
42
50
49
—
—
—
—
1 : 6
1 : 8
1 : 5
—
—
—
5ab
5ac
5ad
5ba+5ba¢
5bb+5bb¢
5bc+5bc¢
5ca
9
5cb
10
11
12
13
14
15
16
17
18
19
5cc
5cd
—
5da + 5da¢
5db + 5db¢
5dc + 5dc¢
5dd + 5dd¢
5ea + 5ea¢
5eb + 5eb¢
5ec + 5ec¢
5ed + 5ed¢
1 : 8
0 : 1
0 : 1
1 : 1
3 : 4
1 : 3
1 : 2
1 : 1
a Yields refer to the isolated yields. b Ratio of regioisomers formed are
calculated based on 1H NMR spectra.
˚
(4 A) at room temperature, the reaction was complete within 1 h
with 63% yield of the product (entry 10). After optimizing the
reaction conditions, we carried out generalization of this reaction
by reacting structurally diverse diamines, ketone and phosphites.
The results are summarized in Table 2.
Different substituted diamines underwent one-pot reaction to
yield corresponding benzodiazepinyl phosphonates (Fig. 1). In
the case of substituted benzene-1,2-diamine, two regioisomers
were formed, however, which could not be separated by repeated
chromatography (Scheme 3). Thus, the ratio of the regioisomers
1
was calculated from H NMR, e.g. in the case of 3-methyl-1,2-
diamine 1b, two regioisomers 5ba and 5ba¢ were formed in the
ratio of 1 : 3 (see the Experimental section).
Table 1 Catalyst screening and reaction condition optimization for one-
pot synthesis of benzodiazepinyl phosphonate
Sl. no.
Catalysta,b
Conditions
Time
Yield (%)
Scheme 3 One-pot synthesis of benzodiazepinyl phosphonate from
2,3-diamino toluene.
16
1
2
3
4
5
6
7
8
HClO4–SiO2
RT
RT
RT
RT
RT
RT
RT
Reflux
Microwave
˚
RT, MS 4 A
2 d
2 d
2 d
2 d
2 d
2 d
2 d
6 h
1 min
1 h
12
23
15
15
25
10
43
17
TaCl5–SiO2
Mg(ClO4)2
AlCl3
InCl3
BiCl3
FeCl3
FeCl3
FeCl3
FeCl3
In the case of the reaction of butylphosphite and allylphosphite
with nitro-substituted diamine (entries 13 and 14, respectively)
exclusively one regioisomer was formed. The characterization of
the regioisomers was based on HMBC correlation as shown in
Fig. 2. In compound 5db¢, the aromatic proton at d 7.67 (dd, 1H)
showed HMBC correlation with the carbon at d 139.0, which in
turn did not show any C–P coupling, suggesting a syn-structure
for the regioisomer 5db¢. Similarly, in the case of 5dc¢, the proton
at d 7.66 (dd, 1H) showed HMBC correlation with the carbon at
Decomposition
Decomposition
63
9
10
a For entries 1–2, 10 wt.% of the catalyst was used. b For entries 3–10,
10 mol% of the catalyst was used.
5408 | Org. Biomol. Chem., 2011, 9, 5407–5413
This journal is
The Royal Society of Chemistry 2011
©

Scheme 4 Plausible mechanism for the formation of benzodiazepinyl
phosphonates (major and minor regioisomers).
Fig. 1 Structures of benzodiazepinyl phosphonates synthesized through
one-pot reaction.
is not conjugated with the electron-withdrawing Z group, and
thereby easily donated leading to the intermediate that gives the
syn-regioisomer as the major product. Similarly, the reaction of
the tautomeric form B gives the anti-regioisomer as the minor
product.
Several ketones such as cyclobutanone, ethyl methyl ketone,
isopropyl methyl ketone and acetone were employed; however,
only acetone furnished the corresponding products, BDPs. In
the case of the other ketones, only intermediate ketimines were
formed. This could be due to the steric factor. With higher ketones,
the ketimines formed are so sterically crowded that it could not
allow phosphite to attack even if the reaction was continued for
a prolonged period of time. All the phosphites employed worked
well except triphenyl phosphite and diphenyl phosphite. This can
also be explained on the basis of steric factors.
The synthesized benzodiazepinyl phosphonates were tested for
their in vitro inhibition of clostripain and the results are summa-
rized in Table 3. Compound 5ba + 5ba¢ derived from 2,3-diamino
toluene and diethyl phosphite inhibited the clostripain enzyme
with an IC50 value of 32 mM. When the phosphite was changed to
allyl (5bc + 5bc¢) and butyl (5bb + 5bb¢), the activity dropped to
Fig. 2 HMBC correlations of 5db¢ and 5dc¢.
d 139.1, which also did not show any C–P coupling, suggesting a
syn-structure for 5dc¢. The above results indicate that in the case
of unsymmetrical diamines, the major product formed is the syn-
regioisomer. Further, this could be explained on the basis of the
plausible reaction mechanism shown in the Scheme 4. Initially, di-
imine is formed by the reaction of ketone with diamine catalyzed
by FeCl3. The di-imine exists in two tautomeric forms, A and
B. The tautomeric form A is more reactive than B since the lone
pair of electrons on the nitrogen in B is conjugated with the
electron-withdrawing group Z and therefore not easily available
for donation while the lone pair of electrons on nitrogen in A
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5407–5413 | 5409
©

Table 3 Inhibition activity of synthesized BDPs against clostripain
Entry
Compound code
IC50 values/mM
Entry
Compound code
IC50 values/mM
1
2
3
4
5
6
7
8
9
5aa
ND
780
>300
490
32
278
80
>300
175
>300
11
12
13
14
15
16
17
18
19
5cd
150
>300
ND
165
220
36
140
70
90
5ab
5da + 5da¢
5db + 5db¢
5dc + 5dc¢
5dd + 5dd¢
5ea + 5ea¢
5eb + 5eb¢
5ec + 5ec¢
5ed + 5ed¢
5ac
5ad
5ba + 5ba¢
5bb + 5bb¢
5bc + 5bc¢
5ca
5cb
5cc
10
ND = Not determined.
80 and 278 mM, respectively. A similar trend in the activity profile
was observed in the case of benzodiazepinyl phosphonate obtained
by the reaction of 3,4-diamino benzophenone. Compound 5ea +
5ea¢ showed an IC50 value of 36 mM, which dropped to 70 and
140 mM in the case of 5ec + 5ec¢ and 5eb + 5eb¢, respectively.
The benzodiazepinyl phosphonates derived from symmetrical
diamines (1a and 1c) were found to be comparatively less potent
than their corresponding benzodiazepinyl phosphonates derived
from unsymmetrical diamines (1b, 1d and 1e).
Typical experimental procedure. To
phenylenediamine (1 mmol), acetone (0.5 mL) and molecular
a
mixture of o-
˚
sieves (4 A, 50 mg), FeCl3 (10 mol%) and phosphite (1 mmol)
were added. The reaction mixture was stirred at room temperature
for 1 h. After completion of the reaction (TLC), saturated aq.
NaHCO3 (10 mL) was added to the reaction mixture and the
product was extracted with EtOAc (3 ¥ 20 mL). The combined
organic layer was washed with brine (30 mL), dried over anhydrous
Na2SO4 and concentrated under vacuum to furnish the crude
product which was purified by silica gel column chromatography
(ethyl acetate : pet. ether, 40–60%).
Diethyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo-[b][1,4]-
diazepin-2-ylphosphonate (5aa). Pale yellow syrup; (Found: C,
58.95; H, 8.28; N, 8.63. Calc. for C16H27N2O3P: C, 58.88; H, 8.34;
N, 8.58%); nmax(CHCl3)/cm-1 3420, 3367, 3019, 1604, 1518, 1424,
1216, 1048 and 1031; dH (200 MHz; CDCl3) 1.29-1.36 (12 H, m),
Conclusions
In summary, a four-component reaction of diamines, ketones and
phosphite catalyzed by FeCl3 has been established to generate
novel chemical entities, benzodiazepinyl phosphonates (BDPs).
All the synthesised compounds were assayed in vitro for their
efficacies against clostripain, a disease model for gas gangrene.
Some of the synthesized BDPs showed remarkable cysteine
protease inhibition activities in the micromolar range, thereby
suggesting that these chemical entities could be further explored
for their protease inhibition to obtain a lead compound.
3
1.56 (3 H, d, JPH 17.2), 1.72–1.82 (1 H, m), 2.14–2.37 (1 H, m),
4.08–4.24 (4 H, m) and 6.62–6.81 (4 H, m); dC (50 MHz, CDCl3)
16.5 (d, 3JPC 5.9), 16.6 (d, 3JPC 5.5), 23.5, 30.5, 33.6, 44.0 (d, 2JPC
2.6), 53.2 (d, 3JPC 14.6), 56.2 (d, 1JPC 148.2), 62.5 (d, 2JPC 7.7), 63.2
2
3
(d, JPC 7.0), 121.6, 121.8, 121.9, 122.0, 136.8 (d, JPC 12.4) and
137.5; dP (161 MHz, CDCl3) 29.1; m/z (ESI): 327.29 (M + H)+,
349.28 (M + Na)+.
Dibutyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]-
diazepin-2-ylphosphonate (5ab). Yellow syrup; (Found: C, 62.78;
H, 9.34; N, 7.41. Calc. for C20H35N2O3P: C, 62.80; H, 9.22; N,
7.32%); nmax(CHCl3)/cm-1 3421, 3020, 2972, 1599, 1476, 1423,
1216 and 1030; dH (400 MHz, CDCl3) 0.91 (6 H, t, J 7.3), 1.28
Experimental section
General
The FT-IR spectra were recorded on an FT-IR-8300 Shimadzu
spectrometer and microanalyses were carried out on a Carlo-
Erba instrument. NMR spectra were recorded on Bruker ACF
3
(3 H, s), 1.30 (3 H, s), 1.56 (3 H, d, JPH 17.2), 1.26–1.66 (8 H,
m), 1.72–1.77 (1 H, m), 2.15–2.21 (1 H, m), 4.04–4.14 (4 H, m)
200 and AV200 (200 MHz for H NMR and 50 MHz for 13C
1
and 6.60–6.76 (4 H, m); dC (100 MHz, CDCl3) 13.6, 18.7, 23.6,
3
3
2
NMR) and AV400 (400 MHz for 1H NMR and 100 MHz for 13
C
30.6, 32.6 (d, JPC 5.8), 32.7 (d, JPC 5.5), 33.4, 43.9 (d, JPC 2.6),
53.2 (d, 3JPC 14.6), 56.4 (d, 1JPC 147.8), 66.2 (d, 2JPC 8.0), 66.8 (d,
2JPC 7.3), 121.5, 121.6, 121.8, 121.9, 136.8 (d, 3JPC 11.7) and 137.4;
dP (161 MHz, CDCl3) 29.77; m/z (ESI) 383.32 (M + H)+, 405.31
(M + Na)+.
NMR) spectrometers, using CDCl3 as solvent. Tetramethylsilane
(0.00 ppm) served as an internal standard in 1H NMR and
CDCl3 (77.0 ppm) in 13C NMR, respectively. Chemical shifts are
expressed in parts per million (ppm). In the case of NMR data of
a mixture of regioisomers, the peaks corresponding to the major
isomer are given. Mass spectra were recorded on LC-MS/MS-
TOF API QSTAR PULSAR spectrometer, samples introduced
by infusion method using the Electrospray Ionization Tech-
nique (ESI). Clostripain, N-a-benzoyl-DL-arginine-p-nitroanilide
(BAPNA), dithiothreitol (DTT), dimethoxy sulfoxide (DMSO)
and calcium chloride (CaCl2) were purchased from Sigma Chem.
Co. (USA). All other chemicals were of analytical grade.
Diallyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]-
diazepin-2-ylphosphonate (5ac). Yellow syrup; (Found: C, 61.76;
H, 7.69; N, 7.92. Calc. for C18H27N2O3P: C, 61.70; H, 7.77; N,
7.99%); nmax(CHCl3)/cm-1 3420, 3019, 2934, 1602, 1522, 1424,
1216 and 1045; dH (200 MHz, CDCl3) 1.30 (3 H, s), 1.33 (3 H, s),
3
1.59 (3 H, d, JPH 17.4), 1.74–1.84 (1 H, m), 2.18–2.31 (1 H, m),
4.52–4.65 (4 H, m), 5.14–5.43 (4 H, m), 5.83–6.03 (2 H, m) and
6.61–7.01 (4 H, m); dC (50 MHz, CDCl3) 23.7, 30.6, 33.5, 43.8 (d,
5410 | Org. Biomol. Chem., 2011, 9, 5407–5413
This journal is
The Royal Society of Chemistry 2011
©

2JPC 2.2), 53.2 (d, 3JPC 14.6), 56.6 (d, 1JPC 147.1), 66.9 (d, 2JPC 7.7),
syrup; (Found: C, 48.77; H, 6.44; N, 7.16. Calc. for
C16H25Cl2N2O3P: C, 48.62; H, 6.38; N, 7.09%); nmax(CHCl3)/cm-1
3421, 3019, 1647, 1542, 1489, 1215 and 1048; dH (400 MHz,
2
4
67.4 (d, JPC 6.9), 118.0 (d, JPC 2.2), 121.5, 121.8, 121.8, 122.0,
3
3
3
133.0 (d, JPC 5.9), 133.2 (d, JPC 5.9), 136.5 (d, JPC 11.7) and
137.5; dP (161 MHz, CDCl3): 30.43; m/z (ESI) 351.27 (M + H)+,
373.25 (M + Na)+.
3
CDCl3) 1.32–1.37 (12 H, m), 1.59 (3 H, d, JPH 16.8), 1.77–1.82
(1 H, m), 2.17–2.24 (1 H, m), 4.13–4.25 (4 H, m), 6.72 (1 H, s)
3
Dimethyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo-[b]-
[1,4] diazepin-2-ylphosphonate (5ad). Yellow syrup; (Found: C,
56.42; H, 7.70; N, 9.42. Calc. for C14H23N2O3P: C, 56.37; H, 7.77;
N, 9.39%); nmax(CHCl3)/cm-1 3420, 3019, 2934, 1614, 1502, 1216
and 1054; dH (400 MHz, CDCl3) 1.30 (3 H, s), 1.31 (3 H, s), 1.56
and 6.79 (1 H, s); dC (100 MHz, CDCl3): 16.5 (d, JPC 6.6), 16.6
(d, 3JPC 5.9), 23.8, 30.8, 33.2, 43.3, 53.5 (d, 3JPC 13.9), 56.2 (d, 1JPC
2
2
148.2), 62.7 (d, JPC 8.1), 63.2 (d, JPC 7.3), 121.7, 122.1, 123.7,
123.9, 136.4 (d, 3JPC 11.0) and 137.1; dP (161 MHz, CDCl3): 29.1;
m/z (ESI): 395.12 (M + H)+, 417.10 (M + Na)+.
3
(3 H, d, JPH 17.3), 1.75–1.80 (1 H, m), 2.04–2.37 (1 H, m), 3.79
Dibutyl-7,8-dichloro-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo [b][1,4]diazepin-2-ylphosphonate (5cb). Yellow syrup;
(Found: C, 53.25; H, 7.43; N, 6.24. Calc. for C20H33Cl2N2O3P:
C, 53.22; H, 7.37; N, 6.21%); nmax(CHCl3)/cm-1 3421, 3019, 2964,
1607, 1488, 1385, 1215 and 1028; dH (500 MHz, CDCl3): 0.93 (6
H, 2t, J 7.3), 1.29 (3 H, s), 1.33–1.42 (4 H, m), 1.37 (3 H, s), 1.58 (3
H, d, 3JPH 16.8), 1.62–1.67 (4 H, m), 1.75–1.79 (1 H, m), 2.16–2.21
(1 H, m), 4.05–4.12 (4 H, m), 6.69 (1 H, s) and 6.76 (1 H, s); dC
(125 MHz, CDCl3): 13.6, 18.8, 24.1, 30.9, 32.6 (d, 3JPC 5.5), 32.7
(d, 3JPC 5.5), 33.2, 43.2, 53.5 (d, 3JPC 13.6), 56.5 (d, 1JPC 148.1), 66.5
(d, 2JPC 8.2), 66.8 (d, 3JPC 7.3), 121.5, 122.1, 123.6, 123.9, 136.3 (d,
3JPC 9.9) and 137.0; dP (202 MHz, CDCl3) 28.91; m/z (ESI) 383.32
(M + H)+, 405.31 (M + Na)+.
3
3
(3 H, d, JPH 10.5), 3.81 (3 H, d, JPH 10.5), 6.64–6.66 (1 H, m),
6.72–6.74 (1 H, m) and 6.77–6.80 (2 H, m); dC (100 MHz, CDCl3):
23.5, 30.3, 33.6, 44.0 (d, 3JPC 2.2), 53.1 (d, 3JPC 14.6), 53.2 (d, 2JPC
2
1
8.1), 54.3 (d, JPC 7.3), 56.6 (d, JPC 147.5), 121.6, 121.8, 121.9,
122.2, 136.6 (d, 3JPC 12.5) and 137.5; dP (161 MHz, CDCl3) 32.27;
m/z (ESI) 299.23 (M + H)+, 321.20 (M + Na)+.
Diethyl-2,4,4,9-tetramethyl-2,3,4,5-tetrahydro-1H-benzo[b]
[1,4]diazepin-2-ylphosphonate (5ba + 5ba¢) (1 : 6 regio-isomeric
mixture). Yellow syrup; (Found: C, 59.83; H, 8.63; N, 8.34. Calc.
for C17H29N2O3P: C, 59.98; H, 8.59; N, 8.23%); nmax(CHCl3)/cm-1
3420, 3367, 3019, 1599, 1476, 1421, 1216 and 1029; dH (500 MHz,
CDCl3) 1.29–1.38 (12 H, m), 1.58 (3 H, d, 3JPH 17.9), 1.77–1.81 (1
H, m), 2.13–2.16 (1 H, m), 2.23 (3 H, s), 4.13–4.23 (4 H, m), 6.55
(1 H, d, J 7.6), 6.66–6.69 (1 H, m) and 6.74 (1 H, d, J 7.6); dC
(125 MHz, CDCl3): 16.5 (d, 3JPC 5.5), 18.0, 23.4, 30.4, 33.4, 43.6
(d, 2JPC 1.8), 52.8 (d, 3JPC 15.4), 56.0 (d, 3JPC 148.0), 62.7 (d, 2JPC
Diallyl-7,8-dichloro-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo [b][1,4]diazepin-2-ylphosphonate (5cc). Yellow syrup;
(Found: C, 51.64; H, 6.15; N, 6.74. Calc. for C18H25Cl2N2O3P:
C, 51.56; H, 6.01; N, 6.68%); nmax(CHCl3)/cm-1 3421, 3019, 1611,
1423, 1215 and 1019; dH (400 MHz, CDCl3) 1.29 (3 H, s), 1.36 (3
H, s), 1.61 (3 H, d, 3JPH 17.2), 1.74–1.84 (1 H, m), 2.16–2.35 (1 H,
m), 4.53–4.62 (4 H, m), 5.23–5.38 (4 H, m), 5.83–6.02 (2 H, m),
6.69 (1 H, s) and 6.77 (1 H, s); dC (50 MHz, CDCl3) 24.1, 30.9,
33.2, 43.2 (d, 2JPC 1.1), 53.5 (d, 3JPC 13.9), 56.5 (d, 1JPC 147.1), 67.1
2
2
8.2), 62.8 (d, JPC 7.3), 120.4, 120.9, 124.1, 128.2, 136.0 (d, JPC
10.9 and 137.3; dP (202 MHz, CDCl3) 30.30; m/z (ESI) 341.57
(M + H)+, 363.57 (M + Na)+.
Dibutyl-2,4,4,9-tetramethyl-2,3,4,5-tetrahydro-1H-benzo[b]
[1,4]diazepin-2-ylphosphonate (5bb + 5bb¢) (1 : 8 regio-isomeric
mixture). Yellow syrup; (Found: C, 63.55, H, 9.50; N, 7.10. Calc.
for C21H37N2O3P: C, 63.61; H, 9.41; N, 7.07%); nmax(CHCl3)/cm-1
3420, 3360, 3019, 1599, 1518, 1476, 1424, 1215 and 1022; dH
(200 MHz, CDCl3): 0.88–0.98 (6 H, m), 1.25–1.73 (17 H, m),
1.76–1.83 (1 H, m), 2.08–2.28 (1 H, m), 2.23 (3 H, s), 4.02–4.18 (4
H, m) and 6.53–6.90 (3 H, m); dC (50 MHz, CDCl3): 13.6, 18.1,
2
2
(d, JPC 7.7), 67.4 (d, JPC 7.0), 118.3, 118.4, 121.6, 122.2, 123.5,
124.1, 132.8, 132.9, 135.6 (d, 2JPC 10.6) and 137.1; dP (161 MHz,
CDCl3) 29.68; m/z (ESI) 420.31 (M + H)+.
Dimethyl-7,8-dichloro-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepin-2-ylphosphonate (5cd). Yellow syrup;
(Found: C, 45.83; H, 5.82, N, 7.66. Calc. for C14H21Cl2N2O3P:
C, 45.79; H, 5.76; N, 7.63%); nmax(CHCl3)/cm-1 3421, 3019, 2964,
1622, 1542, 1488, 1385, 1216 and 1031; dH (200 MHz, CDCl3) 1.30
(3 H, s), 1.34 (3 H, s), 1.58 (3 H, d, 3JPH 17.2), 1.73–1.83 (1 H, m),
3
2
18.7, 23.6, 30.5, 32.7 (d, JPC 5.5), 33.3, 43.4 (d, JPC 2.2), 52.8
(d, 3JPC 15.0), 56.3 (d, 1JPC 147.5), 66.5 (d, 2JPC 7.7), 66.6 (d, 2JPC
7.7), 120.5, 120.9, 124.2, 128.2, 136.1 (d, 3JPC 10.6) and 137.1; dP
(161 MHz, CDCl3) 29.94; m/z (ESI) 397.64 (M + H)+, 419.65
(M + Na)+.
3
3
2.05–2.25 (1 H, m), 3.79 (3 H, d, JPH 10.4), 3.82 (3 H, d, JPH
10.3), 6.72 (1 H, s) and 6.81 (1 H, s); dC (50 MHz, CDCl3) 23.9,
30.7, 33.2, 43.4, 53.4(d, 2JPC 7.7), 53.5 (d, 3JPC 13.9), 54.0 (d, 2JPC
7.0), 56.1 (d, 1JPC 148.6), 121.8, 122.2, 123.7, 124.1, 136.2 (d, 3JPC
10.9) and 137.1; dP (202 MHz, CDCl3) 31.33; m/z (ESI) 367.17
(M + H)+, 389.16 (M + Na)+.
Diallyl-2,4,4,9-tetramethyl-2,3,4,5-tetrahydro-1H-benzo[b]
[1,4]diazepin-2-ylphosphonate (5bc + 5bc¢) (1 : 5 regio-isomeric
mixture). Yellow syrup; (Found: C, 62.57; H, 8.09; N, 7.74. Calc.
for C19H29N2O3P: C, 62.62; H, 8.02; N, 7.69%); nmax(CHCl3)/cm-1
3355, 3019, 1599, 1520, 1466, 1384, 1319, 1215 and 1029; dH
(200 MHz, CDCl3) 1.28 (3 H, s), 1.32 (3 H, s), 1.63 (3 H, d,
3JPH 17.6), 1.75–1.85 (1 H, m), 2.12–2.19 (1 H, m), 2.23 (3 H, s),
4.55–4.66 (4 H, m), 5.15–5.44 (4 H, m), 5.86–6.03 (2 H, m) and
6.53–6.90 (3 H, m); dC (50 MHz, CDCl3) 18.1, 23.6, 30.5, 33.3,
Diethyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo-
[b][1,4]diazepin-2-ylphosphonate (5da + 5da¢) (1 : 8 regio-
isomeric mixture). Pale yellow semi-solid; (Found: 51.81; H, 7.17;
N, 11.23. Calc. for C16H26N3O5P: C, 51.75; H, 7.06; N, 11.31%);
3
1
2
43.3, 52.8 (d, JPC 15.0), 56.4 (d, JPC 147.1), 67.1 (d, JPC 7.7),
n
max(CHCl3)/cm-1 3421, 3367, 3019, 1614, 1519, 1216 and 1054;
2
67.2 (d, JPC 7.7), 118.0, 118.1, 120.6, 121.1. 124.3, 128.4, 132.9
dH (200 MHz, CDCl3) 1.26 (6 H, t, J 7.0), 1.39 (3 H, s), 1.59 (3
H, d, 3JPH 16.7), 1.57 (3 H, s), 1.76–1.85 (1 H, m), 2.37–2.53 (1 H,
m), 4.01–4.21 (4 H, m), 6.43 (1 H, d, J 8.7) and 7.58–7.90 (2 H,
m); dC (50 MHz, CDCl3) 16.4 (d, 3JPC 5.5), 16.5 (d, 3JPC 5.5), 25.0,
3
3
3
(d, JPC 5.9), 133.0 (d, JPC 5.9), 135.9 (d, JPC 10.6) and 137.3;
dP (161 MHz, CDCl3) 30.95; m/z (ESI) 365.62 (M + H)+, 387.62
(M + Na)+.
1
1
Diethyl-7,8-dichloro-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-
benzo [b][1,4]diazepin-2-ylphosphonate (5ca). Pale yellow
32.0, 33.5, 43.1, 54.3 (d, JPC 11.7), 55.2 (d, JPC 145.6), 62.5 (d,
2JPC 8.0), 62.7 (d, 2JPC 7.3), 116.5, 117.4, 119.3, 132.3 (d, 3JPC 7.0),
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5407–5413 | 5411
©

138.9 and 145.3; dP (161 MHz, CDCl3) 28.35; m/z (ESI) 372.67
N, 5.68. Calc. for C27H39N2O4P: C, 66.65; H, 8.08; N, 5.76%);
n
max(CHCl3)/cm-1 3421, 3392, 3018, 1641, 1593, 1480, 1320 and
(M + H)+, 394.73 (M + Na)+.
1216; dH (200 MHz, CDCl3) 0.94 (6 H, t, J 7.2), 1.19–1.75 (17 H,
m), 1.82–2.41 (2 H, m), 4.00–4.15 (4 H, m), 6.52 (1 H, d, J 8.6),
7.23–7.30 (2 H, m), 7.40–7.56 (3 H, m) and 7.69–7.74 (2 H, m); dC
(100 MHz, CDCl3): 13.6, 18.7, 24.7, 31.2, 33.4, 32.6 (d, 3JPC 5.8),
32.6 (d, 3JPC 5.5), 43.5, 53.9 (d, 3JPC 13.5), 56.8 (d, 1JPC 146.4), 66.3
(d, JPC 8.0), 66.6 (d, JPC 7.7), 119.2, 123.9, 126.1, 128.1, 128.5,
129.5, 131.3, 135.4, 138.9, 143.0 and 195.5; dP (161 MHz, CDCl3)
28.96; m/z (ESI) 487.94 (M + H)+, 509.95 (M + Na)+.
Dibutyl2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo
[b][1,4]diazepin-2-ylphosphonate (5db¢). Pale yellow semi-solid;
(Found: C, 56.10; H, 8.14; N, 9.96 Calc. for C20H34N3O5P: C, 56.19;
H, 8.02; N, 9.83%); nmax(CHCl3)/cm-1 3420, 3367, 3019, 2964,
1593, 1518, 1319, 1216 and 1024; dH (400 MHz, CDCl3) 0.87–0.95
(6 H, m), 1.27–1.61 (8 H, m), 1.38 (3 H, s), 1.57 (3 H, s), 1.60 (3
H, d, 3JPH 16.5), 1.78–1.83 (1 H, m), 2.40–2.48 (1 H, m), 3.74 (1 H,
bs), 3.94–4.11 (4H, m), 4.18 (1 H, bs), 6.41 (1 H, d, J 8.8), 7.58 (1
H, d, J 2.5) and 7.67 (1 H, dd, J 8.7, 2.4); dC (100 MHz, CDCl3)
2
2
Diallyl-7-benzoyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo
4
3
13.6, 18.7, 18.8, 25.1 (d, JPC 1.10), 32.1, 32.6 (d, JPC 3.3), 32.7
[b][1,4]diazepin-2-ylphosphonate (5ec
+ 5ec¢) (1 : 2 regio-
3
3
1
(d, JPC 3.3), 33.6, 43.0, 54.3 (d, JPC 11.7), 56.9 (d, JPC 145.3),
66.3 (d, 2JPC 7.7), 66.5 (d, 2JPC 7.7), 116.5, 117.5, 119.3, 132.4 (d,
3JPC 6.6), 139.0 and 145.1; dP (161 MHz, CDCl3) 25.7; m/z (ESI):
428.2 (M + H)+, 450.2 (M + Na)+.
isomeric mixture). Yellow syrup; (Found: C, 66.13; H, 6.84;
N, 6.21. Calc. for C25H31N2O4P: C, 66.07; H, 6.87; N, 6.16%);
n
max(CHCl3)/cm-1 3420, 3370, 3019, 1641, 1521, 1476, 1422 and
1215; dH (200 MHz, CDCl3) 1.38 (3 H, s), 1.50 (3 H, s), 1.61 (3 H,
d, 3JPH 17.1), 1.79–1.88 (1 H, m), 2.35–2.51 (1 H, m), 4.43–4.63 (4
H, m), 5.14–5.49 (4 H, m), 5.78–5.97 (2 H, m), 6.51 (1 H, d, J 8.6),
7.23–7.29 (1 H, m), 7.39–7.54 (4 H, m) and 7.67–7.78 (2 H, m); dC
Diallyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo
[b][1,4]diazepin-2-ylphosphonate (5dc¢). Pale yellow semi-solid;
(Found: C, 54.75, 6.53. N, 10.59 Calc. for C18H26N3O5P: C, 54.68;
H, 6.63; N, 10.63%); nmax(CHCl3)/cm-1 3421, 3367, 3020, 1593,
1519, 1484, 1320, 1215 and 1030; dH (500 MHz, CDCl3) 1.38 (3 H,
s), 1.59 (3 H, s), 1.62 (3 H, d, 3JPH 16.6), 1.80–1.84 (1 H, m), 2.47–
2.53 (1 H, m), 4.38–4.58 (4 H, m), 5.20–5.30 (4 H, m), 5.80–5.88 (2
H, m), 6.40 (1 H, d, J 8.7), 7.58 (1 H, d, J 2.5) and 7.66 (1 H, dd,
J 8.7, 2.5); dC (125 MHz, CDCl3): 25.2, 32.0, 33.6, 43.0, 54.2, 57.0
3
(50 MHz, CDCl3) 24.8, 31.9, 33.5, 43.4, 54.0 (d, JPC 12.4), 56.9
1
2
2
(d, JPC 144.9), 66.9 (d, JPC 8.0), 67.2 (d, JPC 7.0), 117.8, 118,1,
118.2, 124.1, 128.2, 128.1, 128.7, 129.5, 131.4, 132.9, 133.2, 138.9,
142.9 and 195.1; dP (161 MHz, CDCl3): 29.79; m/z (ESI) 455.44
(M + H)+, 477.29 (M + Na)+.
Dimethyl-7-benzoyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b][1,4]diazepin-2-ylphosphonate (5ed + 5ed¢) (1 : 1 regio-
isomeric mixture). Yellow syrup; (Found: C, 62.75; H, 6.72;
N, 6.91. Calc. for C21H27N2O4P: C, 62.68; H, 6.76; N, 6.96%);
1
2
2
(d, JPC 143.5), 66.8 (d, JPC 7.3), 67.0 (d, JPC 7.3), 116.4, 117.5,
118.2, 118.4, 119.4, 132.1 (d, 3JPC 5.9), 132.7 (d, 3JPC 5.3), 132.8 (d,
3JPC 5.3), 139.1 and 145.3; dP (202 MHz, CDCl3) 29.1; m/z (ESI)
396.48 (M + H)+, 418.43 (M + Na)+.
n
max(CHCl3)/cm-1 3420, 3018, 2956, 1653, 1641, 1593, 1508, 1338,
Dimethyl-2,4,4-trimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo-
[b][1,4]diazepin-2-ylphosphonate (5dd + 5dd¢) (1 : 1 regio-
isomeric mixture). Yellow syrup; (Found: C, 49.87; H, 6.52; N,
12.22. Calc. for C14H22N3O5P: C, 49.98; H, 6.46; N, 12.24%);
1217, 1132 and 1053; dH (400 MHz, CDCl3) 1.37 (3 H, s), 1.39 (3
H, s), 1.70 (3 H, d, 3JPC 16.6), 1.78–1.88(1 H, m), 2.20–2.40 (1 H,
m), 3.74–3.85 (6 H, m), 6.69 (1 H, d, J 8.6), 7.23–7.27 (2 H, m),
7.43–7.54 (3 H, m) and 7.72–7.82 (2 H, m); dC (100 MHz, CDCl3):
24.6, 30.9, 32.7, 43.1, 53.2 (d, 2JPC 7.3), 53.4, 56.9 (d, 1JPC 149.6),
118.2, 123.9, 125.8, 128.1, 129.6, 130.3, 131.6, 133.4, 138.7, 141.9
and 195.2; dP (161 MHz, CDCl3): 31.5; m/z (ESI): 403.62 (M +
H)+, 425.69 (M + Na)+.
n
max(CHCl3)/cm-1 3420, 3360, 3019, 2923, 1592, 1518, 1318, 1215
and 1046; dH (400 MHz, CDCl3) 1.28 (3 H, s), 1.38 (3 H, s), 1.70
(3 H, d, 3JPH 16.6), 1.79–1.87 (1 H, m), 2.15–2.45 (1 H, m), 3.68 (3
H, d, 3JPH 10.3), 3.79 (3 H, d, 3JPH 10.3), 6.42 (1 H, d, J 8.8) and
7.53–7.64 (2 H, m); dC (100 MHz, CDCl3): 25.1, 31.2, 32.4, 43.2,
53.6 (d, 2JPC 8.1), 54.1 (d, 2JPC 7.3), 53.7 (d, 3JPC 11.0), 57.0 (d, 1JPC
149.7), 116.4, 118.2, 119.4, 135.1, 140.9 and 145.2; dP (161 MHz,
CDCl3): 30.80; m/z (ESI) 344.28 (M + H)+, 366.25 (M + Na)+.
Bioassay of synthesized BDPs. The inhibitory activity of
cysteine protease inhibitor (CPI) against clostripain was assayed
spectrophotometrically.18 Clostripain was activated in 10 mM Tris
HCL buffer, pH 7.4, containing 1 mM CaCl2 and 2.5 mM DTT
for 3 h at 37 ◦C. After activation, clostripain (25 nM) was added
to enzyme buffer (100 mM Tris HCl buffer, pH 7.4) containing
the substrate BAPNA (500 mM) in the presence and absence of
CPI. Formation of product (p-nitroaniline) was monitored by the
increase in absorbance at 410 nm.
Diethyl-7-benzoyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo-
[b][1,4]diazepin-2-ylphosphonate (5ea + 5ea¢) (3 : 4 regio-
isomeric mixture). Yellow syrup; (Found: C, 64.27; H, 7.30;
N, 6.50. Calc. for C23H31N2O4P: C, 64.17; H, 7.26; N, 6.51%);
n
max(CHCl3)/cm-1 3420, 3368, 3019, 1730, 1620, 1515, 1446, 1319
and 1215; dH (200 MHz, CDCl3) 1.24–1.48 (12 H, m), 1.58 (3 H,
d, 3JPH 16.9), 1.77–1.89 (1 H, m), 2.14–2.46 (1 H, m), 4.05–4.24 (4
H, m), 6.52 (1 H, d, J 8.7), 7.21–7.28 (2 H, m), 7.40–7.57 (3 H, m)
and 7.69–7.74 (2 H, m); dC (50 MHz, CDCl3): 16.4 (d, JPC 4.4),
16.6 (d, JPC 4.4), 24.6, 31.9, 33.5, 43.5, 54.0 (d, JPC 13.5), 56.5
(d, JPC 146.7), 62.9 (d, JPC 7.0), 63.4 (d, JPC 7.0), 117.9, 123.9,
126.1, 128.1, 130.0, 129.5, 131.4, 135.5, 138.9, 143.0 and 195.2;
dP (161 MHz, CDCl3) 29.08; m/z (ESI) 431.76 (M + H)+, 453.77
(M + Na)+.
Acknowledgements
3
3
3
AKB is grateful to the Department of Biotechnology (DBT),
Government of India, New Delhi, India for financial support. A
generous book grant from Deutscher Akademischer Austausch-
dienst (DAAD), Germany to one of us (AKB) is gratefully
acknowledged. KCR is grateful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the award of a
Senior Research Fellowship. Authors are thankful to the referees
for their valuable suggestions.
1
2
2
Dibutyl-7-benzoyl-2,4,4-trimethyl-2,3,4,5-tetrahydro-1H-benzo-
[b][1,4]diazepin-2-ylphosphonate (5eb + 5eb¢) (1 : 3 regio-
isomeric mixture). Yellow syrup; (Found: C, 66.70; H, 8.13;
5412 | Org. Biomol. Chem., 2011, 9, 5407–5413
This journal is
The Royal Society of Chemistry 2011
©

10 (a) F. R. Atherton, C. H. Hassall and R. W. Lambert, J. Med. Chem.,
1986, 29, 29; (b) J. G. Allen, F. R. Atherton, M. J. Hall, C. H. Hassal,
S. W. Holmes, R. W. Lambert, L. J. Nisbet and P. S. Ringrose, Nature,
1978, 272, 56; (c) J. G. Allen, F. R. Atherton, M. J. Hall, C. H. Hassall,
R. W. Lambert, L. J. Nisbet and P. S. Ringrose, Antimicrob. Agents
Chemother., 1979, 15, 684; (d) F. R. Atherton, M. J. Hall, C. H. Hassall,
R. W. Lambert and P. S. Ringrose, Antimicrob. Agents Chemother., 1979,
15, 677; (e) F. R. Atherton, M. J. Hall, C. H. Hassall, R. W. Lambert,
W. J. Lloyd and P. S. Ringrose, Antimicrom. Agents Chemother., 1979,
15, 696; (f) D. Skropeta, R. Schwoerer and R. R. Schmidt, Bioorg. Med.
Chem. Lett., 2003, 13, 3351.
Notes and references
1 (a) G. H. Posner, Chem. Rev., 1986, 86, 831; (b) A. Do¨mling and I. Ugi,
Angew. Chem., Int. Ed., 2000, 39, 3168.
2 (a) A. Do¨mling, Chem. Rev., 2006, 106, 17; (b) J. P. Zhu, Eur. J. Org.
Chem., 2003, 7, 1133; (c) R. V. A. Orru and M. De Greef, Synthesis,
2003, 1471; (d) L. Banfi and R. Riva, Org. React., 2005, 65, 1.
3 (a) A. Strecker, Ann. Chem. Pharm., 1850, 91, 349; (b) A. Hantzsch,
Justus Liebigs Ann. Chem., 1882, 215, 1; (c) P. Biginelli, Ber. Dtsch.
Chem. Ges., 1891, 24, 2962; (d) C. Mannich and W. Krosche, Arch.
Pharm., 1912, 250, 647; (e) M. Passerini, Gazz. Chim. Ital., 1922, 52,
126.
4 (a) H. Zhou, H. Jin, S. Ye, X. He and J. Wu, Tetrahedron Lett., 2009,
50, 4616; (b) Z. Miao, B. Wang, G. Zhang and R. Chen, Bioorg. Chem.,
2006, 34, 167; (c) Q. Ding, B. Wang and J. Wu, Tetrahedron, 2007, 63,
12166; (d) A. Alizadeh, N. Zohreh and L. Zhu, Tetrahedron, 2009, 65,
2684; (e) D. L. Fox, N. R. Whitely, R. J. Cohen and R. N. Salvatore,
Synlett, 2003, 2037.
5 (a) H. Schutz, in Benzodiazepines, Springer: Heidelberg, 1982; Vol. 2,
pp. 240; (b) R. K. Smalley, in Comprehensive Organic Chemistry, ed.
D. H. R. Barton and W. E. Ollis, Pergamon, Oxford, 1979; Vol. 4, pp.
600; (c) J. K. Landquist, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. N. Russ, Pergamon, Oxford, 1984; Vol. 1, pp.
166; (d) A. Chimirri, S. Grasso, R. Ortana, G. Romeo and M. Zappala,
J. Heterocycl. Chem., 1990, 27, 371; (e) M. C. Aversa, A. Ferlazzo, P.
Giannetto and F. I. Kohnke, Synthesis, 1986, 3, 230; (f) K. V. V. Reddy,
P. S. Rao and D. Ashok, Synth. Commun., 2000, 30, 1825; (g) R. A.
Mane and D. B. Ingle, Indian J. Chem. Sect. B, 1982, 21B, 973; (h) K. P.
Jadhav and D. B. Ingle, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 1983, 22B, 180; (i) R. J. Reddy, D. Ashok and P. N. Sarma,
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 1993, 32B, 404;
(j) K. Satyanarayana and M. N. A. Rao, Indian J. Pharm. Sci., 1993,
55, 230; (k) G. DeSarro, A. Chimirri, A. DeSarro, R. Gitto and M.
Zappala, Eur. J. Med. Chem., 1995, 30, 925.
6 K. Vandyck, M. D. Cummings, O. E. Nyanguile, C. W. Boutton, S.
Vendeville, D. McGowan, B. Devogelaere, K. Amssoms, S. Last, K.
Rombauts, A. Tahri, P. Lory, L. Hu, D. A. Beauchamp, K. Simmen
and P. Raboisson, J. Med. Chem., 2009, 52, 4099.
7 D. J. Lauffer and M. D. Mullican, Bioorg. Med. Chem. Lett., 2002, 12,
1225.
8 P. Kafarski and B. Leczak, Phosphorus, Sulfur Silicon Relat. Elem.,
1991, 63, 193.
9 (a) R. Hirschmann, A. B. Smith, C. M. Taylor, P. A. Benkovic, S. D.
Taylor, K. M. Yager, P. A. Sprengler and S. J. Benkovic, Science,
1994, 265, 23; (b) A. B. Smith, C. M. Taylor, S. J. Benkovic and R.
Hirschmann, Tetrahedron Lett., 1994, 35, 6853.
11 C. H. Hassall, in Antibiotics, ed. E. F. Hahn, Springer Verlag: Berlin
1983, Vol VI, 1.
12 (a) D. Leung, G. Abbenante and D. P. Fairlie, J. Med. Chem., 2000, 43,
305; (b) H. H. Otto and T. Schirmeister, Chem. Rev., 1997, 97, 133; (c) S.
Hawthorne, R. Hamilton, B. J. Walker and B. Walker, Anal. Biochem.,
2004, 326, 273; (d) B. Walker, S. Wharry, R. J. Hamilton, S. L. Martin,
A. Healy and B. J. Walker, Biochem. Biophys. Res. Commun., 2000,
276, 1235; (e) J. Oleksyszyn and J. C. Powers, Biochemistry, 1991, 30,
485; (f) C. Bergin, R. Hamilton, B. Walker and B. J. Walker, Chem.
Commun., 1996, 1155.
13 (a) J. Jozwiak, A. Komar, E. Jankowska and G. Martirosian, Enzyme
Microb. Technol., 2006, 39, 28; (b) A. M. Gilles and B. Keil, FEBS
Lett., 1984, 173, 58; (c) W. H. Poryper, L. W. Cunniivgham and
W. M. Mitchell, J. Biol. Chem., 1971, 246, 7675; (d) C. T. Supuran,
A. Scozzafava and B. W. Clare, Med. Res. Rev., 2002, 22, 329; (e) I. R.
Lepow, S. Katz, J. Pensky and L. Pillemer, J. Immunol., 1952, 69, 435;
(f) J. D. MacLennan, I. Mandl and E. L. Howes, J. Gen. Microbiol.,
1958, 18, 1.
14 (a) A. K. Bhattacharya and K. C. Rana, Tetrahedron Lett., 2008, 49,
2598; (b) A. K. Bhattacharya and T. Kaur, Synlett, 2007, 745.
15 (a) R. Fazaeli and H. Aliyan, Appl. Catal., A, 2007, 331, 78; (b) M. A.
Alibeik, I. M. Baltork, Z. Zaghaghi and B. H. Yousefi, Catal. Commun.,
2008, 9, 2496; (c) A. Hegedues, Z. Hell and A. Potor, Catal. Lett.,
2005, 105, 3; (d) B. V. S. Reddy, S. Praveenkumar and K. Nagaiah,
Synthesis, 2005, 480; (e) S. K. De and R. A. Gibbs, Tetrahedron Lett.,
2005, 46, 1811; (f) W. Chen and J. Lu, Synlett, 2005, 1337; (g) J. Wu,
F. Xu, Z. Zhou and Q. Shen, Synth. Commun., 2006, 36, 457; (h) R.
Hekmatshoar, S. Sadjadi, S. Shiri, M. M. Heravi and M. S. Beheshtiha,
Synth. Commun., 2009, 39, 2549; (i) S. T. Gao, W. H. Liu, J. J. Ma, C.
Wang and Q. Liang, Synth. Commun., 2009, 39, 3278.
16 A. K. Chakraborti and R. Gulhane, Chem. Commun., 2003, 1896.
17 S. Chandrasekhar, S. J. Prakash, V. Jagadeshwar and C. Narsihmulu,
Tetrahedron Lett., 2001, 42, 5561.
18 H. Gusman, J. Grogan, H. M. Kagan, R. F. Troxler and F. G.
Oppenheim, FEBS Lett., 2001, 489, 97.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5407–5413 | 5413
©