Facile synthesis of 4-acylamino and 4-sulphonamido β-lactams

Article abstract of DOI:10.1016/S0040-4020(00)00699-2

The cycloaddition reaction of trisubstituted amidines (7a-f) with acid chlorides in presence of triethylamine gave 4-acylamino and 4-sulphonamido-trans-β-lactams (9a-h) in very good yields. Similarly N,N'-diarylamidines (5a-d) on reaction with 2 equiv. of acid chlorides (8a,b) gave 4-acylamino-trans-β-lactams (10a-e) via in situ generated acylamidines followed by cycloaddition reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00699-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7811±7816
Facile Synthesis of 4-Acylamino and 4-Sulphonamido b-lactams
K. Thiagarajan,a V. G. Puranik,b A. R. A. S. Deshmukha and B. M. Bhawala,
*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDivision of Physical Chemistry, National Chemical Laboratory, Pune 411 008, India
Received 16 March 2000; revised 19 July 2000; accepted 3 August 2000
AbstractÐThe cycloaddition reaction of trisubstituted amidines (7a±f) with acid chlorides in presence of triethylamine gave 4-acylamino
and 4-sulphonamido-trans-b-lactams (9a±h) in very good yields. Similarly N,N0-diarylamidines (5a±d) on reaction with 2 equiv. of acid
chlorides (8a,b) gave 4-acylamino-trans-b-lactams (10a±e) via in situ generated acylamidines followed by cycloaddition reaction. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
b-lactams have been synthesized by the reaction of
N-protected cyclic amidines either with ketenes9 or
carbene10 chromium complexes.
In continuation of our efforts towards the synthesis of substi-
tuted b-lactams1 and their utility as a synthon2 for the
synthesis of various biologically important compounds,
we were interested in synthesis of 4-amino-b-lactams.
Although, the ®rst synthesis of 4-amino-b-lactams has
been reported by the reaction of b,b-disubstituted enamines
with arylisocyanate3 as early as 1962 from Eli Lilly group,
very few reports4±7 have been appeared for the synthesis of
these b-lactams. This is mainly due the fact that these
b-lactams are highly susceptible towards moisture and
undergo ring opening3a during aqueous work-up or on
storage. Moreover, there is only one report wherein
4-substituted amino b-lactams have been prepared8 by the
reaction of highly reactive diphenylketene with various
trisubstituted amidines. However, very few b-lactams
could be isolated in the pure form as these compounds
undergo ring cleavage mainly by the ®ssion of C3±C4
bond leading to 2,2-diphenylacetanilides. Bicyclic
It has also been shown that 4-(N,N-alkyl/aryl)-b-lactams
with hydrogen on C3 (3-mono substituted b-lactams)
undergo rapid ring opening via N1±C4 bond cleavage to
give enamino amides.3 We also made similar observation
in the reaction of ketene derived from phenoxyacetyl
chloride with N,N0-di-(p-anisyl)-N0-methylamidine (1)
followed by aqueous work-up gave enamino amide (4) in
62% isolated yield instead of the expected b-lactam 2
(Scheme 1). The formation of enaminoamide (4) is presum-
ably due to the N1,C4 cleavage of initially formed b-lactam
(2) assisted by the participation of nitrogen lone pair of
4-amino group via intermediate 3. We envisaged that this
problem could be addressed by arresting the availability of
lone pair with electron withdrawing group on amino
nitrogen. We herein report an ef®cient synthesis of stable
4-substituted amino-b-lactams via cycloaddition reaction of
Scheme 1.
Keywords: cycloaddition reaction; azetidinones; Staudinger reaction.
* Corresponding author. Tel.: 191-20-5893153; fax: 191-20-5893355; e-mail: bhawal@dalton.ncl.res.in
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00699-2

7812
K. Thiagarajan et al. / Tetrahedron 56 (2000) 7811±7816
Table 1. Synthesis N-substituted amidines 7a±f.
Sr.No.
Amidines 7
R1
R2
Yield (%)
Mp (oC)
1.
2.
3.
4.
5.
6.
7a
7b
7c
7d
7e
7f
Ph
Ph
Ph
PhCO±
4±NO2C6H4CO±
Ts
Ts
Ts
Ts
91
84
98
93
81
93
129±30
77±78
209±210
178±179
118±119
100±101
4-ClC6H4±
3-MeC6H4±
4-MeOC6H4±
trans stereochemistry for b-lactam protons is based on
observed low vicinal coupling constant (,1±1.5 Hz). As
anticipated these b-lactams (9a±h) were found to be very
stable to aqueous work-up and did not undergo any decom-
position even after keeping for several months at room
temperature.
The reaction of two equivalents of substituted acetyl
chloride with N,N0-diarylamidines (5) should also undergo
cycloaddition reaction to give stable b-lactams via in situ
generation of acylated amidines, structurally similar to
amidines 7. Thus, cycloaddition reaction of N,N0-diphenyl-
amidine (5a) with two equivalent of phenoxyacetyl chloride
(8a) in presence of triethylamine gave trans-b-lactam (10a)
in very good yield. Similarly, other b-lactams (10b±e) were
also prepared by the reaction of N,N0-diarylamidines (5a±d)
with two equivalents acid chlorides (8a,b) in presence of
triethylamine (Scheme 4, Table 3). The trans stereo-
chemistry of b-lactam ring protons was further con®rmed
from single crystal X-ray analysis of compound 10a (Fig. 1).
Scheme 2.
ketenes with trisubstituted amidines bearing electron-with-
drawing substituent on enamino nitrogen.
Results and Discussion
The starting trisubstituted amidines, N0-benzoyl-N,N0-diaryl-
amidines (7a,b) and N0-sulphonyl-N,N0-diarylamidines
(7c±f) were prepared by reacting N,N0-diarylamidines
(5a±d) with aryloyl chloride (6a,b) or p-toluene sulphonyl
chloride (6c) in presence of triethylamine (Scheme 2). The
trisubstituted amidines 7a±f on cycloaddition reaction with
ketenes derived from acid chloride (8a,b) in presence of
triethylamine afforded exclusively trans-b-lactams (9a±h)
in very good yields (Scheme 3, Table 2). The assignment of
Conclusion
In summary, we have demonstrated that 4-substituted
amino-b-lactams could be synthesized from trisubstituted
amidines via cycloadditon reaction with ketenes. We have
also shown that putting electron withdrawing substitutent on
4-amino group could increase the stability of b-lactams.
Scheme 3.
Table 2. Synthesis of 4-(N,N-disubstituted amino)azetidin-2-one (9a-h) from amidines 7
Sr.No.
Compd 9
R1
R2
R3
Yield (%)
Mp (8C)
1
2
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
Ph
Ph
Ph
PhCO-
4-NO2C6H4CO-
PhO±
PhO±
PhO±
PhO±
PhO±
PhO±
PhthN±
PhthN±
72
68
80
87
86
82
82
89
140±141
96±97
Ts-
Ts-
Ts-
Ts-
Ts-
Ts-
179±180
199±200
161±162
191±192
239±240
248±249
4-ClC6H4±
3-MeC6H4±
4-MeOC6H4±
Ph
9g
9h
4-MeOC6H4±

K. Thiagarajan et al. / Tetrahedron 56 (2000) 7811±7816
7813
Scheme 4.
Table 3. Synthesis 4-(N-acyl-N-arylamino)azetidin-2-ones (10a±e) from
amidines 5
standard conditions. Methylene chloride was distilled over
P2O5 under argon.
Sr. No. Compd.10
R1
R2
Yield (%) Mp (8C)
Preparation of N,N0-di-(p-anisyl)-N0-methylamidine 1.
To a stirred mixture of N,N0-di-(p-anisyl)amidine (1.28 g,
0.005 mol), K2CO3 (1.38 g) and acetone (25 ml), iodo-
methane (1.06 g, 0.0074 mol) was added at room tempera-
ture and stirred further for 12 h. The reaction mixture was
®ltered and ®ltrate was distilled to remove acetone. The
residue so obtained was crystallized from chloroform:pet.
ether to give pure title compound 1 (1.24 g, 91.8%) as a
yellow crystalline solid, mp 114±1168C [lit.,11 mp 110±
1128C]; [Found: C, 70.85; H, 6.86; N, 10.14. C16H18N2O2
requires C, 71.09; H, 6.71; N, 10.36]; nmax(Nujol) 1620,
1500 cm21; dH (200 MHz, CDCl3) 3.45 (s, 3H), 3.75 (s,
3H), 3.80 (s, 3H), 6.70±7.15 (m, 8H), 7.95 (s, 1H); MS
(m/z): 270 (M1).
1
2
3
4
5
10a
10b
10c
10d
10e
Ph
4-ClC6H4±
3-MeC6H4±
4-MeOC6H4± PhO±
Ph
PhO±
PhO±
PhO±
77
82
81
73
146±147
144±145
131±132
142±143
279±280
PhthN± 79
Enamino amide 4. To a mixture of N,N0-di-(p-anisyl)-N0-
methylamidine (1, 1 g, 3.7 mmol), triethylamine (1.8 mL,
13 mmol), CH2Cl2 (20 mL), a solution of phenoxyacetyl
chloride (8a, 0.75 g, 4.4 mmol) in CH2Cl2 (20 mL) was
added over a period of 30 min at 08C with stirring. The
reaction mixture was allowed to warm-up to room tempera-
ture and stirred further for 12 h. The reaction mixture was
diluted with CH2Cl2 (20 mL) and washed successively with
water (15 mL), satd. NaHCO3 (20 mL), brine (10 mL) and
dried over Na2SO4. The solution was passed through short
column (silica gel, 60±120). The removal of solvent by
distillation under reduced pressure gave crude product,
which was puri®ed by crystallization from methanol to
give 0.926 g (61.8%) of pure enamino amide 4 as pale
yellow crystalline solid, mp 137±1398C; [Found: C,
70.95; H, 6.18; N, 6.96. C24H24N2O4 requires C, 71.27; H,
5.98; N, 6.93]; nmax(Nujol) 1650, 1580 cm21; dH (200 MHz,
CDCl3) 3.30 (s, 3H), 3.75 (s, 3H), 3.80 (s, 3H), 6.75±6.85
(m, 4 H), 6.90±7.10 (m, 5 H), 7.25±7.45 (m, 4 H), 7.65 (s,
2H); MS (m/z): 404 (M1).
Figure 1. ORTEP diagram of 10a without solvent.
Experimental
General
1H NMR Spectra were recorded in CDCl3 solution on a
Bruker AC 200 spectrometer at 200 MHz and chemical
shifts are reported in ppm down®eld from tetramethylsilane.
13C NMR spectra were recorded in CDCl3 solution on a
Bruker AC 200 instrument and chemical shifts are reported
in ppm relative to the center line of CDCl3 (77.0 ppm).
Infrared spectra were recorded on a Perkin±Elmer Infracord
Spectrophotometer Model 599-B using sodium chloride
optics. Melting points were determined on a Thermonik
Campbell melting point apparatus and were uncorrected.
The microanalyses were performed on a Carlo-Erba,
CHNS-O EA 1108 Elemental analyzer. Optical rotations
were recorded on a JASCO-181 digital polarimeter under
General procedure for N,N0-diaryl-N0-benzoylamidine
7a,b
To a mixture of N,N0-diarylamidine (5a, 6 mol), triethyl-
amine (2 ml, 15 mmol), CH2Cl2 (20 mL), a solution of
benzoyl chloride (6a,b, 0.93 g, 6.6 mmol) in CH2Cl2
(20 mL) was added over a period of 10 min at 08C. The
reaction mixture was then allowed to warm-up to room
temperature and stirred further for 4 h. The reaction mixture
was then diluted with CH2Cl2 (20 mL) and washed succes-
sively with water (15 mL), satd. NaHCO3 (10 mL), brine
(10 mL) and dried over Na2SO4. It was then ®ltered and

7814
K. Thiagarajan et al. / Tetrahedron 56 (2000) 7811±7816
®ltrate on distillation under reduced pressure gave crude
product (7a,b), which was puri®ed by crystallization from
chloroform:pet. ether.
N,N0-Di(4-methoxyphenyl)-N0-(p-toluenesulphonyl)ami-
dine 7f. The title compound 7f (93%) was obtained from
N,N0-di-(4-methoxyphenyl)amidine (5d) as a white crystal-
line solid, mp 101±1038C [lit.,13 mp 1048C]; Found: C,
64.62; H, 5.53; N, 7.02; S, 7.57. C22H22N2O4S requires C,
64.37; H, 5.40; N, 6.82; S, 7.81; nmax(Nujol) 1620, 1450,
1390 cm21; dH (200 MHz, CDCl3) 2.5 (s, 3H), 3.80 (s, 3H),
3.90 (s, 3H), 6.80±7.80 (m, 12 H), 8.70 (s, 1H); MS (m/z):
410 (M1). (Table 1)
N,N0-Diphenyl-N0-benzoylamidine 7a. The title com-
pound 7a was obtained from N,N0-diphenylamidine (5a),
as a white crystalline solid in 91% yield, mp 129±1308C
[lit.,12 mp 129±1308C]; [Found: C, 79.69; H, 5.46; N, 9.16.
C20H16N2O requires C, 79.98; H, 5.37; N, 9.33]; nmax(Nujol)
1630, 1570 cm21; dH (200 MHz, CDCl3) 6.90±7.50 (m,
15H), 9.00 (s, 1H); MS (m/z): 300 (M1).
General procedure for the preparation of b-lactams 9a±h
N,N0-Diphenyl-N0-(p-nitrobenzoyl)amidine 7b. The title
compound 7b was obtained from N,N0-diphenylamidine
(5a), as a pale yellow crystalline solid, yield 84%, mp
77±788C; [Found: C, 69.38; H, 4.23; N, 12.05.
C20H15N3O3 requires C, 69.56; H, 4.38; N, 12.17]; nmax(Nu-
jol) 1630, 1510 cm21; dH (200 MHz, CDCl3) 7.00±7.45 (m,
10H), 7.54 (d, Jˆ9 Hz, 2H), 8.06 (d, Jˆ9 Hz, 2H), 9.85 (s,
1H); MS (m/z): 345 (M1).
To a mixture of trisubstituted amidine (7a±f, 3 mmol),
triethylamine (1.7 mL, 12 mmol), CH2Cl2 (20 mL), a solu-
tion of acid chloride (8a,b, 4.5 mmol) in CH2Cl2 (20 mL)
was added over a period of 20 min at 08C with stirring. The
reaction mixture was allowed to warm-up to room tempera-
ture and stirred further for 14 h. The reaction mixture was
diluted with CH2Cl2 (20 mL) and washed successively with
water (15 mL), satd. NaHCO3 (20 mL), brine (10 mL) and
dried over Na2SO4. The solution was passed through short
column (silica gel, 60±120). The removal of solvent by
distillation under reduced pressure gave crude product,
which was puri®ed by crystallization from methanol to
give pure b-lactams (9a±h) as white crystalline solids.
General procedure for N,N0-diaryl-N0-(p-toluene-
sulphonyl)amidine 7c±f
To a mixture of N,N0-diarylamidine (2, 5 mol), triethyl-
amine (2 ml, 15 mmol), CH2Cl2 (20 mL), a solution of
p-toluenesulphonyl chloride (6c, 1.045 g, 5.5 mmol) in
CH2Cl2 (20 mL) was added over a period of 10 min at
08C. The reaction mixture was then allowed to warm-up
to room temperature and stirred further for 4 h. The reaction
mixture was then diluted with CH2Cl2 (20 mL) and washed
successively with water (10 mL), satd. NaHCO3 (10 mL),
brine (10 mL) and dried over Na2SO4. It was then ®ltered
and ®ltrate on distillation under reduced pressure gave crude
product (7c±f), which was puri®ed by crystallization from
chloroform:pet. ether.
1-Phenyl-3-phenoxy-4-(N-phenyl-N-benzoylamino)azetidin-
2-one 9a. The title compound 9a was obtained from amidine
7a and acid chloride 8a by using above general procedure as
a white crystalline solid, yield 72%, mp 140±1418C;
[Found: C, 77.13; H, 5.21; N, 6.40. C28H22N2O3 requires
C, 77.40; H, 5.10; N, 6.45]; nmax(Nujol) 1750, 1630,
1510 cm21; dH (200 MHz, CDCl3) 5.05 (d, Jˆ1.2 Hz, 1H),
6.80±8.00 (m, 21H). dc (50.3 MHz, CDCl3) 68.12, 83.73,
116.41, 118.43, 123.15, 125.83, 128.26, 128.66, 129.10,
129.84, 130.09, 130.62, 135.38, 136.25, 137.93, 157.60,
161.50, 172.04; MS (m/z): 341 (M1293).
N,N0-Diphenyl-N0-(p- toluenesulphonyl)amidine 7c. The
title compound 7c was obtained from N,N0-diphenylamidine
(5a), as a white crystalline solid, yield 98%, mp 209±2108C
[lit.,13 mp 2118C]; [Found: C, 68.39; H, 5.36; N, 8.13; S,
9.26. C20H18N2O2S requires C, 68.55; H, 5.18; N, 7.99; S,
9.15]; nmax(Nujol) 1620, 1580, 1440 cm21; dH (200 MHz,
CDCl3) 2.45 (s, 3H), 6.90±7.70 (m, 14 H), 8.72 (s, 1H); MS
(m/z): 350 (M1).
1-Phenyl-3-phenoxy-4-[N-phenyl-N-(4-nitrobenzoyl)-
amino]azetidin-2-one 9b. The title compound 9b was
obtained from amidine 7b and acid chloride 8a by using
above general procedure as a white crystalline solid, yield
68%, mp 96±978C; [Found: C, 69.93; H, 4.34; N, 8.55.
C28H21N3O5 requires C, 70.14; H, 4.41; N, 8.76]; nmax(Nu-
jol) 1760, 1640, 1580 cm21. dH (200 MHz, CDCl3) 4.95 (d,
Jˆ1.1 Hz, 1H), 6.80±7.90 (m, 20H); dc (50.3 MHz, CDCl3)
67.15, 82.90, 115.70, 117.70, 122.60, 122.80, 125.40,
128.80, 129.20, 129.40, 129.60, 129.80, 135.30, 136.10,
140.60, 148.00, 156.80, 160.60, 169.40; MS (m/z): 479
(M1).
N,N0-Di-(4-chlorophenyl)-N0-(p-toluenesulphonyl)amidine
7d. The title compound 7d (93%) was obtained from N,N0-
di-(4-chlorophenyl)amidine (5b) as a white crystalline
solid, mp 178±1798C [lit.,13 mp 1818C]; [Found: C, 57.39;
H, 4.02; N, 6.53; S, 7.88. C20H16 Cl2N2O2S requires C,
57.29; H, 3.85; N, 6.68; S, 7.65]; nmax(Nujol) 1620, 1550,
1440 cm21; dH (200 MHz, CDCl3) 2.45 (s, 3H), 6.90±7.80
(m, 12 H), 8.65 (s, 1H); MS (m/z): 419 (M1).
1-Phenyl-3-phenoxy-4-[N-phenyl-N-(p-toluenesulphonyl)-
amino]azetidin-2-one 9c. The title compound 9c was
obtained from amidine 7c and acid chloride 8a by using
above general procedure as a white crystalline solid, yield
80%, mp 179±1808C; [Found: C, 68.95, H, 4.84, N, 5.97, S,
6.47. C28H24N2O4S requires C, 69.40; H, 4.99; N, 5.78; S,
6.62]; nmax(Nujol) 1750, 1580, 1480 cm21; dH (200 MHz,
CDCl3) 2.45 (s, 3H), 4.95 (d, Jˆ1.1 Hz, 1H), 6.65 (d,
Jˆ1.1 Hz, 1H), 6.70±6.85 (m, 2H), 6.90±7.80 (m, 17H);
dc (50.3 MHz, CDCl3) 21.73, 71.61, 84.73, 116.41,
119.96, 123.31, 127.84, 129.90, 130.10, 130.29, 131.81,
N,N0-Di(3-methylphenyl)-N0-(p-toluenesulphonyl)amidine
7e. The title compound 7e was obtained from N,N0-di-
(3-methylphenyl)amidine (5c) as a white crystalline solid
in 81% yield, mp 118±1198C; [Found: C, 69.67; H, 5.99;
N, 7.26; S, 8.31. C22H22N2O2S requires C, 69.82; H, 5.86; N,
7.40; S, 8.47]; nmax(Nujol) 1620, 1450 cm21; dH (200 MHz,
CDCl3) 2.3 (s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 6.80±7.70 (m,
12 H), 8.70 (s, 1H); MS (m/z): 378 (M1).

K. Thiagarajan et al. / Tetrahedron 56 (2000) 7811±7816
7815
133.21, 134.30, 136.67, 144.95, 157.29, 160.79; MS (m/z):
484 (M1).
and acid chloride 8b by using above general procedure as a
white crystalline solid, yield 89%, mp 248±2498C. [Found:
C, 64.47; H, 4.58; N, 6.93; S, 5.01. C32H27N3O7S requires C,
64.31; H, 4.55; N, 7.03; S, 5.36]; nmax(Nujol) 1750, 1580,
1480 cm21; dH (200 MHz, CDCl3) 2.35 (s, 3H), 3.80 (s, 3H),
3.90 (s, 3H), 5.15 (d, Jˆ1.2 Hz, 1H), 6.65 (d, Jˆ1.2 Hz,
1H), 6.80±8.00 (m, 16H); dc (50.3 MHz, CDCl3) 21.27,
55.35, 55.44, 57.70, 69.00, 114.60, 114.80, 120.10,
123.60, 124.60, 127.30, 129.50, 131.50, 132.80, 134.60,
136.80, 144.00, 157.30, 159.20, 160.50, 166.30; MS (m/z):
448 (M12149).
1-(4-Chlorophenyl)-3-phenoxy-4-[N-(4-chlorophenyl)-N-
(p-toluenesulphonyl)amino]-azetidin-2-one 9d. The title
compound 9d was obtained from amidine 7d and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 87%, mp 199±2008C; [Found: C,
60.50; H, 3.87; N, 4.91. C28H22N2O4Cl2S requires C,
60.76; H, 4.00; N, 5.06]; nmax(Nujol) 1750, 1580,
1475 cm21. dH (200 MHz, CDCl3) 2.45 (s, 3H), 4.95 (d,
Jˆ1.2 Hz, 1H), 6.50 (d, Jˆ1.2 Hz, 1H), 6.60±7.70 (m,
17H); dc (50.3 MHz, CDCl3) 21.73, 71.62, 84.73, 116.41,
119.96, 123.31, 127.89, 129.91, 130.05, 130.29, 131.81,
133.26, 134.30, 136.68, 144.95, 157.34, 160.81; MS (m/z):
399 (M12153).
General procedure for the preparation of b-lactams
10a±e
To a mixture of diarylamidine (5, 3 mmol), triethylamine
(1.7 mL, 12 mmol), CH2Cl2 (20 mL), a solution of acid
chloride (8, 6 mmol) in CH2Cl2 (20 mL) was added over a
period of 30 min at 08C with stirring. The reaction mixture
was allowed to warm-up to room temperature and stirred
further for 14 h. The reaction mixture was diluted with
CH2Cl2 (30 mL) and washed successively with water
(15 mL), satd. NaHCO3 (20 mL), brine (10 mL) and dried
over Na2SO4. The solution was passed through short column
(silica gel, 60±120). The removal of solvent by distillation
under reduced pressure gave crude product, which was puri-
®ed by crystallization from methanol to give pure b-lactams
(10a±e) as white crystalline solids.
1-(3-Methylphenyl)-3-phenoxy-4-[N-(3-methylphenyl)-
N-(p-toluenesulphonyl)amino]-azetidin-2-one 9e. The
title compound 9e was obtained from amidine 7e and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 86%, mp 161±1628C; [Found: C,
70.04; H, 5.38; N, 5.33; S, 5.99. C30H28N2O4S requires C,
70.29; H, 5.51; N, 5.46; S, 6.25]; nmax(Nujol) 1750,
1580 cm21; dH (200 MHz, CDCl3) 2.20 (s, 3H), 2.40 (s,
3H), 4.95 (d, Jˆ1.2 Hz, 1H), 6.60 (d, Jˆ1.2 Hz, 1H),
6.90±7.60 (m, 17H); dc (50.3 MHz, CDCl3) 71.50, 84.34,
116.25, 120.00, 123.00, 126.80, 127.80, 128.20, 129.50,
130.00, 130.80, 132.50, 133.00, 135.50, 136.80, 139.00,
144.80, 157.20, 161.00; MS (m/z): 379 (M12133).
1-Phenyl-3-phenoxy-4-[N-phenyl-N-(phenoxyacetyl)-
amino]azetidin-2-one 10a. The title compound 10a was
obtained from amidine 5a and acid chloride 8a by using
above general procedure as a white crystalline solid, yield
77%, mp 146±1478C; [Found: C, 74.82; H, 5.45; N, 5.78.
C29H24N2O4 requires C, 74.98; H, 5.21; N, 6.03]; nmax(Nu-
jol) 1766, 1693 cm21; dH (200 MHz, CDCl3) 4.25 (d, Jˆ
17.5 Hz, 1H), 4.50 (d, Jˆ17.5 Hz, 1H), 4.95 (d, Jˆ1.2 Hz,
1H), 6.70±7.20 (m, 21H); dc (50.3 MHz, CDCl3) 66.25,
82.80, 114.40, 114.70, 115.90, 118.00, 121.10, 121.60,
122.80, 125.50, 128.70, 128.90, 129.40, 129.70, 130.40,
130.50, 134.00, 135.30, 157.00, 157.60, 160.80, 169.30.
MS (m/z): 464 (M1).
1-(4-Methoxylphenyl)-3-phenoxy-4-[N-(4-methoxylphenyl)-
N-(p-toluenesulphonyl)amino]-azetidin-2-one 9f. The
title compound 9f was obtained from amidine 7f and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 82%, mp 1928C; [Found: C, 65.92;
H, 5.27; N, 5.17. C30H29N2O6S requires C, 66.04; H, 5.36;
N, 5.13]; nmax(Nujol) 1740, 1580, 1500 cm21; dH (200 MHz,
CDCl3) 2.40 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 4.95 (d,
Jˆ1.2 Hz, 1H), 6.70 (d, Jˆ1.2 Hz, 1H), 6.90±7.80 (m,
17H); dc (50.3 MHz, CDCl3) 21.76, 55.66, 71.50, 84.30,
116.20, 120.40, 123.01, 125.10, 127.80, 128.90, 129.90,
132.90, 136.70, 144.40, 157.40, 157.50, 160.70; MS (m/z):
545 (M1).
1-(4-Chlorophenyl)-3-phenoxy-4-[N-(4-chlorophenyl)-
N-(phenoxyacetyl)amino]azetidin-2-one 10b. The title
compound 10b was obtained from amidine 5b and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 82%, mp 144±1458C; [Found: C,
65.21; H, 3.98; N, 4.98. C29H22N2O4Cl2 requires C, 65.30;
H, 4.16; N, 5.25]; nmax(Nujol) 1760, 1680 cm21; dH
(200 MHz, CDCl3) 4.30 (d, Jˆ16.6 Hz, 1H), 4.50 (d,
Jˆ16.6 Hz, 1H), 4.95 (d, Jˆ1.2 Hz, 1H), 6.70±7.70 (m,
19H); dc (50.3 MHz, CDCl3) 66.25, 82.80, 114.40, 115.90,
118.00, 121.10, 121.60, 122.80, 125.50, 128.70, 128.90,
129.40, 129.70, 130.40, 130.50, 134.00, 135.30, 157.00,
157.60, 160.80, 169.30. MS (m/z): 286 (M12246).
1-Phenyl-3-phthalimido-4-[N-phenyl-N-(p-toluenesul-
phonyl)amino]azetidin-2-one 9g. The title compound 9g
was obtained from amidine 7c and acid chloride 8b by
using above general procedure as a white crystalline solid,
yield 82%, mp 239±2408C; [Found: C, 66.82; H, 4.46; N,
7.63; S, 6.23. C30H23N3O5S requires C, 67.03; H, 4.31; N,
7.82; S, 5.96]; nmax(Nujol) 1750, 1680, 1480 cm21; dH
(200 MHz, CDCl3) 2.30 (s, 3H), 5.20 (d, Jˆ1.2 Hz, 1H),
6.75 (d, Jˆ1.2 Hz, 1H), 6.90±8.20 (m, 18H); dc
(50.3 MHz, CDCl3) 21.47, 40.00, 57.70, 68.80, 78.70,
79.20, 79.60, 117.90, 123.60, 124.02, 125.80, 127.60,
128.90, 130.00, 130.40, 130.80, 131.30, 131.60, 135.00,
135.40, 144.70, 145.60, 166.30, 166.60, 167.09; MS (m/z):
537 (M1).
1-(3-Methylphenyl)-3-phenoxy-4-[N-(3-methylphenyl)-
N-(phenoxyacetyl)amino]azetidin-2-one 10c. The title
compound 10c was obtained from amidine 5c and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 81%, mp 131±1328C. [Found: C,
75.33; H, 5.49; N, 5.54. C31H28N2O4 requires C, 75.59; H,
1-(4-Methoxylphenyl)-3-phthalimido-4-[N-(4-methoxyl-
phenyl)-N-(p-toluenesulphonyl)-amino]azetidin-2-one
9h. The title compound 9h was obtained from amidine 7f

7816
K. Thiagarajan et al. / Tetrahedron 56 (2000) 7811±7816
5.73; N, 5.69]; nmax(Nujol) 1750, 1670 cm21; dH (200 MHz,
CDCl3) 2.2 (s, 3H), 2.4 (s, 3H), 4.25 (d, Jˆ16.6 Hz, 1H),
4.55 (d, Jˆ16.6 Hz, 1H), 4.95 (d, Jˆ1.2 Hz, 1H), 6.75±7.50
(m, 19H); dc (50.3 MHz, CDCl3) 20.70, 21.10, 82.40,
114.00, 114.70, 115.50, 118.50, 121.10, 122.30, 125.90,
129.00, 129.30, 129.60, 130.60, 133.70, 134.90, 139.30,
140.20, 156.70, 157.30, 160.40, 168.90; MS (m/z): 399
(M1293).
®xed and con®rmed by a difference fourier was held ®xed
during the re®nement. The re®nements were carried out
using SHELXL-97.15
Acknowledgements
One of the authors (K. T.) thanks CSIR for the ®nancial
support.
1-(4-Methoxyphenyl)-3-phenoxy-4-[N-(4-methoxyphenyl)-
N-(phenoxyacetyl)amino]-azetidin-2-one 10d. The title
compound 10d was obtained from amidine 5d and acid
chloride 8a by using above general procedure as a white
crystalline solid, yield 73%, mp 142±1438C; [Found: C,
70.79; H, 5.28; N, 5.13. C31H28N2O6 requires C, 70.98; H,
5.38; N, 5.34]; nmax(Nujol) 1768, 1685 cm21; dH (200 MHz,
CDCl3) 3.85 (s, 3H), 3.88 (s, 3H), 4.25 (d, Jˆ16 Hz, 1H),
4.50 (d, Jˆ16 Hz, 1H), 5.00 (d, Jˆ1.2 Hz, 1H), 6.60±7.50
(m, 19H); dc (50.3 MHz, CDCl3) 55.50, 55.58, 66.30, 66.47,
82.80, 114.50, 115.00, 115.70, 115.90, 119.00, 121.60,
122.80, 126.20, 128.70, 129.50, 129.80, 130.60, 133.90,
157.20, 157.70, 160.40, 160.70, 169.80; MS (m/z): 524
(M1).
References
1. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Synlett 1992, 749. (b) Jayaraman, M.; Nandi, M.; Sathe, K. M.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron: Asymmetry
1993, 4, 609. (c) Jayaraman, M.; Deshmukh, A. R. A. S; Bhawal,
B. M. J. Org. Chem. 1994, 59, 932. (d) Jayaraman, M.; Srirajan, V.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996, 52,
3741. (e) Karupaiyan, K.; Srirajan, V.; Deshmukh, A. R. A. S;
Bhawal, B. M. Tetrahedron Lett. 1997, 38, 4281. (f) Krishna-
swamy, D.; Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron
Lett. 2000, 41, 417.
2. (a) Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 5585. (b) Jayaraman, M.; Puranik, V. G.;
Bhawal, B. M. Tetrahedron 1996, 52, 9005. (c) Jayaraman, M.;
Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996, 52,
8989. (d) Srirajan, V.; Deshmukh, A. R. A. S.; Puranik, V. G.;
Bhawal, B. M. Tetrahedron: Asymmetry 1996, 7, 2733.
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(b) Abdulla, R. F.; Fuhr, K. H. J. Med. Chem. 1975, 18, 625.
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5. Nisole, C.; Uriac, P.; Huet, J.; Toupet, L. J. Chem. Res., Synop.
1991, 204.
1-Phenyl-3-phthalimido-4-[N-phenyl-N-(phthalimido-
acetyl)amino]azetidin-2-one 10e. The title compound 10e
was obtained from amidine 5a and acid chloride 8b by using
above general procedure as a white crystalline solid, yield
79%, mp 279±2808C; [Found: C, 69.22; H, 3.67; N, 9.58.
C33H22N4O6 requires C, 69.47; H, 3.89; N, 9.82]; nmax(Nu-
jol) 1764, 1724, 1693 cm21; dH (200 MHz, CDCl3) 3.95 (d,
Jˆ16 Hz, 1H), 4.20 (d, Jˆ16 Hz, 1H), 5.25 (d, Jˆ1.2 Hz,
1H), 7.10 (d, Jˆ1.2 Hz, 1H), 7.2±8.00 (m, 18H); dc
(50.3 MHz, CDCl3) 66.65, 117.97, 123.15, 123.65, 125.21,
129.75, 130.00, 130.50, 130.60, 131.00, 131.70, 132.00,
133.80, 134.10, 134.50, 134.79, 159.90, 166.80, 167.50,
168.00; MS (m/z): 451 (M12119).
6. Nisole, C.; Uriac, P.; Toupet, L.; Huet, J. Tetrahedron 1993, 49,
889.
7. Nisole, C.; Uriac, P.; Huet, J.; Toupet, L. Tetrahedron 1992, 48,
1081.
X-Ray diffraction study. X-Ray structure determination of
10a
8. Bose, A. K.; Kugajevsky, I. Tetrahedron 1967, 23, 957.
9. (a) Bose, A. K.; Kapoor J. C.; Fahey, J. L.; Manhas, M. S. J. Org.
Chem. 1973, 38, 3437. (b) Sharma, S. D.; Arora, S. K.; Mehra, U.;
Indian J. Chem. 1985, 24B, 895.
[C29H24N204.0.5(H2O)]:
Colorless
needles
(0.74X0.2X0.12 mmgrown from methanol). Mˆ473.51,
Ê
monoclinic, space group P21/C, aˆ8.720(5) A, bˆ
Ê
Ê
16.606(7) A, cˆ17.424(1) A, bˆ16.606(1)8, Vˆ
10. (a) Ronan, B.; Hegedus, L. S. Tetrahedron 1993, 49, 5549.
(b) Hsiao, Y.; Hegedus, L. S. J. Org. Chem. 1997, 62, 3586.
11. Oszczapowicz, J.; Osek, J.; Orlinski, R.; Polish J. Chem. 1980,
54, 1191.
Ê 3
2518.8(18) A , Zˆ4, Dˆ1.249 g cm23, mˆ0.689 mm21
,
F(000)ˆ996, Tˆ293 K. Data were collected on Enaraf
Nonius CAD-4 Single Crystal X-ray diffractometer using
Ê
Cu±Ka radiation (lˆ1.5406 A) and v22u scan mode to
12. Ono, M.; Tamura, S. Chem. Pharm. Bull. 1990, 38, 590.
13. Ono, M.; Hayakawa, K.; Tamura, S. Chem. Pharm. Bull. 1990,
38, 1176.
a maximum u range of 658. The structure was solved by
direct methods using MULTAN-80 (NRCVAX-
program).14 Least squares re®nement of scale, positional
and anisotropic thermal parameters for non hydrogen atom
converged to Rˆ0.0776. Rwˆ0.192 for 3340 unique
observed re¯ections. Hydrogen atoms were geometrically
14. Gabe, E. J.; Page, Y-Le.; Charland, J. P.; Lee, F. L.; White,
P. S. J. Appl. Cryst. 1989, 22, 384.
15. Sheldrick, G. M. SHELXL-97, Program for the re®nement of
È
crystal structure, University of Gottingen: Germany, 1997.