Triphosgene: A versatile reagent for the synthesis of azetidin-2-ones

Article abstract of DOI:10.1016/S0040-4020(02)00094-7

An efficient use of triphosgene, as an acid activator, for the synthesis of substituted azetidin-2-ones via ketene-imine cycloaddition reaction using various acids and imines have been described.

Full text of DOI:10.1016/S0040-4020(02)00094-7

TETRAHEDRON
Pergamon
Tetrahedron 58 22002) 2215±2225
Triphosgene: a versatile reagent for the synthesis of
azetidin-2-ones
D. Krishnaswamy, V. V. Govande, V. K. Gumaste, B. M. Bhawal and A. R. A. S. Deshmukhp
Division of Organic Chemistry ꢀSynthesis), National Chemical Laboratory, Pune 411 008, India
Received 28 September 2001; revised 12 December 2001; accepted 17 January 2002
AbstractÐAn ef®cient use of triphosgene, as an acid activator, for the synthesis of substituted azetidin-2-ones via ketene±imine cyclo-
addition reaction using various acids and imines have been described. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Mukaiyama reagent,11 cyanuric chloride12 and several
others5 have been used.
Triphosgene [bis2trichloromethyl)carbonate] has emerged
as a versatile synthetic auxiliary for the synthesis of some
important class of organic compounds.1 This white crystal-
line compound has proved to be safe and advantageous over
its gaseous congener, phosgene. As a part of our on going
program on synthesis2 and development of methodologies
for b-lactams,3 we were interested in developing a mild and
ef®cient acid activator for the construction of b-lactams by
ketene±imine cycloaddition reaction 2Staudinger reaction).
In our recent communication4 we have reported an ef®cient
use of triphosgene as an acid activator in the construction of
b-lactam ring by ketene±imine cycloaddition reaction. In
this paper we wish to report the versatility of triphosgene as
a reagent for the activation of various carboxylic acids and
their utility for the synthesis of substituted azetidin-2-ones
under very mild conditions.
2. Results and discussion
We have successfully employed triphosgene for one-step
cycloaddition reaction 2Staudinger reaction) of acids 21)
and imines 22) to get b-lactams 23). A solution of tri-
phosgene 20.5 molar equivalent) in dichloromethane was
slowly added to a cooled 22408C) mixture of acids 21, 1
molar equivalent), imines 22, 1 molar equivalent), triethyl-
amine 23 molar equivalent) in dichloromethane, and the
reaction mixture was stirred at room temperature for 12 h.
The reaction mixture was washed with water, saturated
NaHCO3, brine and passed through a short silica gel column
to get pure b-lactams 23) in very good yields. We found this
reaction to be very clean and various b-lactams were
prepared in excellent yields 2see Table 1). In fact this
reagent was found to be better than other acid activators
in terms of yields and simplicity of work-up procedure.
Lower yields were obtained when one molar or 1/3 molar
Among the several methods for the synthesis of b-lactams,
the cycloaddition reaction of ketenes with imines
2Staudinger reaction) for the construction of b-lactam ring
has found wide acceptance.5 This is mainly because of its
simplicity, predictability of stereochemical outcome and
proven utility of this method for the synthesis of a large
number of monocyclic, bicyclic, tricyclic, and spirocyclic
b-lactams.6 In the Staudinger reaction, the ketenes are
generated in situ from acid halides by triethylamine or
other tertiary amines5 and reacted with imines to get
b-lactams. In cases where the acid halides are either dif®cult
to prepare or unstable, the acid activating reagents like ethyl
chloroformate,7 tri¯uoroacetic anhydride,8 p-toluene-
sulfonyl chloride,9 phosphorous derived reagents,10
Table 1. Synthesis of azetidin-2-ones 23a±k)
Entry No.
Compound
R1
R2
R3
Yielda 2%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
PhO
PhO
PhO
PhO
PhO
MeO
MeO
MeO
Phth.
Ph
Ph
89
95
83
82
93
87
86
83
78c
65
66
PMPb Ph
Ph
PMP
PMP
PMP
PMP
Ph
PMP
PMP
PMP
Ph
PMP
Styryl
Ph
PMP
PMP
Styryl
Ph
9
10
11
3j
3k
2,4-Cl2PhO
2,4-Cl2PhO
PMP
Keywords: cycloaddition reaction; azetidinones; triphosgene; Staudinger
reaction.
Corresponding author. Fax: 191-20-5893153/5893355; e-mail:
arasd@dalton.ncl.res.in
a
Isolated yield.
PMPˆp-Methoxyphenyl.
b
c
p
The reaction was carried out at 08C.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020202)00094-7

2216
D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
imines, which are sensitive to mineral acids or thionyl
chloride.
Triphosgene was also used as a reagent for the synthesis of
b-lactams in good yields from the potassium salt of azido-
acetic acid12 or Dane's salt13 and various imines 2Scheme 2).
These b-lactams are precursors for 3-aminoazetidin-2-ones,
which are important synthons for a variety of b-lactam
antibiotics.
Scheme 1.
equivalent triphosgene and one molar equivalent acid 21)
were used for the cycloaddition reaction.
A solution of triphosgene in dichloromethane was added to
the suspension of salt, imine and triethylamine in dichloro-
methane at 08C. The reaction mixture was then stirred at
room temperature for 12 h. Usual work-up of the reaction
afforded b-lactams in very good yields. However, the
reaction at lower temperature 22408C) resulted in poor
In all the cases the cycloaddition reaction was found to be
stereoselective and only cis-b-lactam formation was
observed 2Scheme 1, Table 1). This method has also been
applied for the synthesis of b-lactams derived from acids or
Scheme 2.
Scheme 3.
Scheme 4.

D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2217
Table 2. Synthesis of azetidin-2-ones 211a±f) from oxazolidones 210) and
imines 22)
and carene. Camphorsultam derived acid 28) was obtained
in good yield from Oppolzer's sultam in two steps using our
earlier reported procedure.14 The cycloaddition reaction of
ketene derived from the acid 28) with imines in the presence
of triethylamine and triphosgene, as an acid activator, was
found to be stereospeci®c and gave b-lactams 29a±c)
exclusively as a single diastereomer14 2HPLC and 1H
NMR) 2Scheme 3).
Entry No.
Compound
R2
R3
R4
Yield 2%)
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
CH2Ph
PMP
CH2Ph
PMP
PMP
Ph
Ph
Ph
Ph
PMP
Ph
Ph
CH2Ph
CH2Ph
iso-Propyl
iso-Propyl
iso-Propyl
70
67
70
71
72
70
CH2Ph
Scheme 5. Reagents and conditions: 2i) ClCO2Et/H2O2/Na3PO4z, CH2Cl2; 2ii) CH3OH/PTSA, 2 h; 2iii) Na/ClCH2CO2H, toluene.
Scheme 6. Reagents and conditions: 2i) Et3N/triphosgene/dry CH2Cl2, 2408C to rt.
yields of corresponding b-lactams. The formation of only
cis-b-lactams was evident from the 1H NMR spectra of the
reaction product.
Very high selectivity in the b-lactams 211a±f) formation
was observed when triphosgene was used as an acid
activator for cycloaddition reaction of chiral oxazolidinone
derived acids 210) and imines 2Scheme 4). The starting acids
were prepared by N-alkylation of chiral oxazolidinone with
ethyl bromoacetate followed by hydrolysis of the ester using
the reported procedure.15 The cycloaddition reaction was
carried out at 08C using the above acids and imine with
triphosgene as an acid activator. HPLC and 1H NMR
analysis of the reaction mixture revealed the formation of
only one diastereomer in excellent yield 2Table 2).
The acid activator, triphosgene, was also successfully
employed for the synthesis of b-lactams from imines and
chiral acids derived from camphorsultam, oxazolidinones,
Table 3. Synthesis of azetidin-2-ones 220a±g) from dithioglyoxylic acid
219) and imines 22)
Entry No.
Compound
R2
R3
Yield 2%)
1
2
3
4
5
6
7
20a
20b
20c
20d
20e
20f
PMP
Ph
PMP
PMP
Ph
4-Cl-Ph
a-MeCHPh
Ph
70
71
75
70
72
69
69
The 21)-3-carene derived chiral acid 214) was prepared
from naturally occurring monoterpene, 21)-3-carene by
the reaction sequence as shown in Scheme 5. The carene
epoxide, prepared by known method16 from carene, was
regio and stereospeci®cally opened with methanol under
acidic conditions to get methoxy alcohol 213)17 in quanti-
PMP
PMP
Styryl
Ph
Styryl
Ph
20g
Scheme 7.

2218
D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
Table 5. Synthesis of azetidin-2-ones 223a±j) from acid 21) and imines 222)
tative yield. The sodium salt of this alcohol was reacted with
chloroacetic acid to get the required chiral acid 214). This
21)-3-carene derived chiral acid 214) also successfully
underwent cycloaddition reaction with imines using tri-
phosgene as an activator to give a diastereomeric mixture
260:40) of b-lactams 215 and 16) 2Scheme 6). These
diastereomers could not be separated by column chromato-
graphy. However, the major diasteromer could be separated
by crystallization.
Entry No.
Compound
R1
R5
Yield 2%)
1
2
3
4
5
6
7
8
9
10
23a
23b
23c
23d
23e
23f
23g
23h
23i
PhO
PhO
PhO
PhO
PhO
PhO
MeO
MeO
Phth
Phth
Ph
CH2Ph
4-OMePh
CH2CO2Me
CH2CO2Et
CH2Me)CO2Me
CH2CO2Me
CH2CO2Et
CH2CH2CH3
CH2CO2Et
68
65
66
64
62
61
62
60
58
55
Spiro azetidin-2-ones 220) can also be easily obtained by the
cycloaddition reaction of glyoxylic acid derivatives 219)
with imines using triphosgene.
23j
procedure. The reaction of this imine and phenoxyacetic
acid using triphosgene in the presence of triethylamine
gave diastereomeric mixture 270:30) of b-lactams in 60%
yield 2see Table 5, entry 6). Attempt to separate these
diastereomers by column chromatography were
unsuccessful.
Dithioglyoxylic acid 219) was prepared by re¯uxing a
mixture of glyoxylic acid and propanedithiol in benzene
using PTSA18 as a catalyst in very good yield. This dithio-
glyoxylic acid was reacted with various imines using
triphosgene as an acid activator to afford spiro azetidin-2-
ones 220a±g) in excellent yields 2Table 3, Scheme 7). The
cycloaddition reaction of dithioglyoxylic acid with chiral
imine derived from R 21) a-phenylethylamine and benzal-
dehyde gave diastereomeric mixture 250:50) of b-lactams
2see Table 3, entry 7). These diastereomers could not be
separated either by column chromatography or crystalliza-
tion.
3. Conclusion
In summary, we have shown the application and versatility
of triphosgene as an acid activator for the synthesis of
diversely substituted b-lactams under very mild reaction
conditions via ketene±imine cycloaddition reaction.
This method was also extended for the preparation of
protected 4-keto azetidin-2-ones 2Scheme 8). The starting
carbonimidodithioic acid dimethyl esters 222a±g, Table 4)
were prepared by the reaction of various amines with carbon
disulphide in presence of Et3N, followed by methylation
using methyl iodide.19 The cycloaddition reaction of these
dithioesters 222) with acids 21) using triphosgene as an
activator gave good yields of 4,4-bismethylsulfanyl-
azetidin-2-ones 223a±j, Table 5). The chiral imine was
prepared from alanine methyl ester following the above
4. Experimental
4.1. General
1H NMR and 13C NMR Spectra were recorded in CDCl3
solution on a Brucker AC 200 or Bruker MSL 300 spectro-
meters and chemical shifts are reported in ppm down®eld
1
from tetramethylsilane for H NMR. Infrared spectra were
recorded on Perkin±Elmer Infrared Spectrophotometer,
Model 599-B or Shimadzu FTIR-8400 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 standard conditions.
4.2. General procedure for synthesis of b-lactams .3a±k)
A solution of triphosgene 20.148 g, 0.5 mmol), in anhydrous
CH2Cl2 210 ml), was added slowly to a solution of acid
21 mmol), imine 21 mmol) and triethylamine 20.42 ml,
3 mmol) in anhydrous CH2Cl2 210 ml), at 2408C. The
reaction mixture was then allowed to warm upto room
temperature and stirred further for 12 h. The reaction
mixture was then washed with water 220 ml), saturated
sodium bicarbonate solution 22£15 ml) and brine 210 ml).
The organic layer was dried over anhydrous sodium
sulphate and ®ltered through a short silica gel column to
get pure b-lactams 23a±k), which were recrystallized
from methanol.
Scheme 8.
Table 4. Synthesis of carbonimidodithioic acid dimethyl esters 222a±g)
Entry No.
Compound
R5
Yield 2%)
1
2
3
4
5
6
7
22a
22b
22c
22d
22e
22f
Ph
CH2Ph
4-MeOPh
CH2CH2CH3
CH2CO2Me
CH2CO2Et
74
79
72
72
70
76
74
4.2.1. 1-Phenyl-3-phenoxy-4-phenylazetidin-2-one .3a).
White solid; yield 89%; mp184 8C; [found: C, 79.73; H,
22g
CH2Me)CO2Me

D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2219
5.20; N, 4.37. C21H17NO2 requires C, 79.98; H, 5.43; N,
4.44]; nmax 2CHCl3) 1755 cm21; dH 2200 MHz, CDCl3)
5.45 2d, Jˆ4.8 Hz, 1H), 5.60 2d, Jˆ4.8 Hz, 1H), 6.75±
7.50 2m, 15H); dC 250.3 MHz, CDCl31DMSO-d6) 61.61,
80.76, 115.35, 117.26, 121.89, 124.32, 127.81, 128.07,
128.40, 128.88, 128.95, 132.26, 136.60, 156.55, 162.80;
MS 2m/z): 315 2M1).
72.08; H, 6.00; N, 4.94]; nmax2Nujol) 1751 cm21; dH
2200 MHz, CDCl3) 3.20 2s, 3H), 3.80 2s, 3H), 4.80 2d,
Jˆ4.4 Hz, 1H), 5.20 2d, Jˆ4.4 Hz, 1H), 6.80±7.40 2m,
9H); dC 250.3 MHz, CDCl3) 54.98, 58.11, 61.05, 84.46,
113.83, 117.25, 124.09, 124.82, 128.83, 129.01, 136.95,
159.67, 164.23; MS 2m/z): 283 2M1).
4.2.8.
1,4-Di.4-methoxyphenyl)-3-methoxyazetidin-2-
one .3h). White needles; yield 83%; mp114±115 8C
[found: C, 68.84; H, 6.00; N, 4.64. C18H19NO4 requires C,
68.99; H, 6.11; N, 4.47]; nmax 2Nujol) 1747 cm21; dH
2200 MHz, CDCl3) 3.15 2s, 3H), 3.75 2s, 3H), 3.80 2s, 3H),
4.70 2d, Jˆ4.4 Hz, 1H), 5.10 2d, Jˆ4.4 Hz, 1H), 6.70 2d,
Jˆ10 Hz, 2H), 6.85 2d, Jˆ10 Hz, 2H), 7.10±7.40 2m, 4H);
dC 250.3 MHz, CDCl3) 55.02, 55.20, 58.11, 61.19, 84.61,
113.83, 114.13, 118.61, 125.01, 129.09, 130.48, 156.10,
159.67, 163.64; MS 2m/z): 313 2M1).
4.2.2. 1-.4-Methoxyphenyl)-3-phenoxy-4-phenylazetidin-
2-one .3b). White solid; yield 95%; mp186±188 8C; [found:
C, 76.41; H, 5.69; N, 3.93. C22H19NO3 requires C, 76.52; H,
5.51; N, 4.06]; nmax 2Nujol) 1743 cm21; dH 2200 MHz,
CDCl3) 3.74 2s, 3H), 5.35 2d, Jˆ4 Hz, 1H), 5.55 2d,
Jˆ4 Hz, 1H), 6.70±7.40 2m, 14H); dC 250.3 MHz, CDCl3)
55.20, 61.90, 80.98, 114.16, 115.47, 118.67, 121.92, 127.92,
128.14, 128.48, 129.00, 132.43, 156.27, 156.50, 163.00; MS
2m/z): 345 2M1).
4.2.9. 1-.4-Methoxyphenyl)-3-phthalimido-4-styrylazeti-
din-2-one .3i). White solid; yield 78%; mp189±190 8C
2Lit.21 mp192±194 8C); [found: C, 73.36; H, 4.92; N,
6.35. C26H20N2O4 requires C, 73.57; H, 4.75; N, 6.60];
nmax 2Nujol) 1728, 1743 cm21; dH 2200 MHz, CDCl3) 3.75
2s, 3H), 5.00 2dd, Jˆ5.8, 8.45 Hz, 1H), 5.70 2d, Jˆ5.8 Hz,
1H), 6.4 2dd, Jˆ8.45, 16.1 Hz, 1H), 6.80±7.90 2m, 14H); dC
250.3 MHz, CDCl3) 55.52, 57.84, 61.11, 114.52, 118.67,
123.01, 123.78, 126.80, 128.71, 131.35, 131.57, 134.55,
135.54, 137.64, 156.57, 160.69, 167.34; MS 2m/z): 424
2M1).
4.2.3. 4-.4-Methoxyphenyl)-1-phenyl-3-phenoxyazetidin-
2-one .3c). White solid; yield 83%; mp150 8C 2Lit.20 mp
149±1508C); [found: C, 76.33; H, 5.61; N, 4.23. C22H19NO3
requires C, 76.52; H, 5.51; N, 4.06]; nmax 2CHCl3)
1739 cm21; dH 2200 MHz, CDCl3) 3.75 2s, 3H), 5.4 2d,
Jˆ4.9 Hz, 1H), 5.60 2d, Jˆ4.9 Hz, 1H), 6.70±7.40 2m,
14H,); dC 250.3 MHz, CDCl3) 55.06, 61.64, 81.19, 113.87,
115.71, 117.54, 122.10, 124.42, 129.01, 129.16, 129.31,
136.99, 157.02, 159.85, 163.16; MS 2m/z): 345 2M1).
4.2.4. 1,4-Di.4-methoxyphenyl)-3-phenoxyazetidin-2-one
.3d). White crystalline solid; yield 82%; mp166±167 8C;
[found: C, 73.37; H, 5.81; N, 3.84. C23H21NO4 requires C,
73.58; H, 5.68; N, 3.73]; nmax 2Nujol) 1740 cm21; dH
2200 MHz, CDCl3) 3.80 2s, 6H), 5.40 2d, Jˆ5.2 Hz, 1H),
5.50 2s, Jˆ5.2 Hz, 1H), 6.70±7.50 2m, 13H); dC
250.3 MHz, CDCl3) 54.95, 55.19, 61.59, 81.04, 113.63,
114.13, 115.48, 118.70, 121.87, 124.28, 129.01, 129.21,
130.27, 156.22, 156.81, 159.63, 162.33; MS 2m/z): 375
2M1).
4.2.10. 1-.4-Methoxyphenyl)-3-.2,4-dichlorophenoxy)-4-
phenylazetidin-2-one .3j). White solid; yield 65%; mp
148±1508C; [found: C, 63.57; H, 4.06; N, 3.27; Cl, 17.31.
C22H17NO3Cl2 requires C, 63.77; H, 4.11; N, 3.38; Cl,
17.16]; nmax 2CHCl3) 1731 cm21; dH 2200 MHz, CDCl3)
3.75 2s, 3H), 5.40 2d, Jˆ4.9 Hz, 1H) 5.55 2d, Jˆ4.9 Hz,
1H), 6.80±7.50 2m, 12H); dC 250.3 MHz, CDCl3) 55.18,
61.28, 81.38, 114.21, 116.34, 118.69, 123.91, 127.15,
127.88, 128.25, 128.69, 129.68, 130.02, 132.04, 151.22,
156.41, 161.48; MS 2m/z): 413 2M1).
4.2.5. 1-.4-Methoxyphenyl)-3-phenoxy-4-styrylazetidin-
2-one .3e). White solid; yield 93%; mp178±180 8C;
[found: C, 77.46; H, 5.82; N, 3.93 C24H21NO3 requires C,
77.61; H, 5.70; N, 3.77]; nmax 2CHCl3) 1749 cm21; dH
2200 MHz, CDCl3) 3.75 2s, 3H), 5.00 2dd, Jˆ4.4, 5.1 Hz,
1H), 5.50 2d, Jˆ4.4 Hz, 1H), 6.35 2dd, Jˆ5.1, 16.1 Hz, 1H),
6.75±7.50 2m, 15H); dC 250.3 MHz, CDCl3) 57.68, 63.36,
83.72, 116.63, 117.96, 121.04, 124.55, 124.92, 128.90,
130.61, 130.83, 131.74, 133.00, 138.80, 139.17, 158.00,
159.63, 164.90; MS 2m/z): 371 2M1).
4.2.11. 1-Phenyl-3-.2,4-dichlorophenoxy)-4-.4-methoxy-
phenyl)azetidin-2-one .3k). White solid; yield 66%; mp
164±1658C; [found: C, 63.84; H, 4.39; N, 3.22; Cl, 17.31.
C22H17NO3Cl2 requires C, 63.77; H, 4.11; N, 3.38; Cl,
17.16]; nmax 2Nujol) 1747 cm21; dH 2300 MHz, CDCl3)
3.75 2s, 3H), 5.35 2d, Jˆ4.4 Hz, 1H), 5.50 2d, Jˆ4.4 Hz,
1H), 6.8±7.40 2m, 12H); dC 275.48 MHz, CDCl3) 55.01,
60.93, 81.35, 113.79, 116.32, 117.21, 123.65, 123.95,
124.53, 127.19, 128.96, 129.23, 129.78, 136.59, 151.27,
159.84, 142.13; MS 2m/z): 413 2M1).
4.2.6. 1-.4-Methoxyphenyl)-3-methoxy-4-phenylazetidin-
2-one .3f). White solid; yield 87%; mp160±161 8C; [found:
C, 72.32; H, 6.12; N, 5.15. C17H17NO3 requires C, 72.08; H,
6.01; N, 4.94]; nmax 2Nujol) 1741 cm21; dH 2200 MHz,
CDCl3) 3.15 2s, 3H), 3.75 2s, 3H), 4.80 2d, Jˆ5 Hz, 1H),
5.20 2d, Jˆ5 Hz, 1H), 6.75 2d, Jˆ8.8 Hz, 2H), 7.20±7.40
2m, 7H); dC 250.3 MHz, CDCl3) 57.63, 60.61, 64.04, 87.03,
116.53, 120.98, 130.16, 130.78, 132.81, 135.59, 158.54,
166.40; MS 2m/z): 283 2M1).
4.3. General procedure for synthesis of b-lactams .5a,b
and 7a±c) from potassium salt 4 and 6
A solution of triphosgene 20.148 g, 0.5 mmol), in anhydrous
CH2Cl2 210 ml), was added slowly to a mixture of potassium
salt 21 mmol), imine 21 mmol) and triethylamine 20.42 ml,
3 mmol) at 08C. After the addition, the reaction mixture was
allowed to warm upto room temperature and stirred for
12 h. The reaction mixture was then washed with water
220 ml), saturated sodium bicarbonate solution 22£15 ml)
and brine 210 ml). The organic layer was dried over
4.2.7. 1-Phenyl-3-methoxy-4-.4-methoxyphenyl)azetidin-
2-one .3g). White solid; yield 86%; mp129±130 8C
[found: C, 71.88; H, 5.80; N, 4.93. C17H17NO3 requires C,

2220
D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
anhydrous sodium sulphate and concentrated to get crude
product, which was puri®ed by column chromatography to
give pure b-lactams 25a,b and 7a±c).
4.4. General procedure for the synthesis of b-lactams
.9a±c) from camphorsultam derived acid .8)
A similar general procedure, as for compounds 3a±k, was
employed for the synthesis of b-lactams 29a±c) from acid 8
and imines 2.
4.3.1. 3-Azido-4-.4-methoxyphenyl)-1-phenylazetidin-2-
one .5a). White solid; yield 68%; mp120±122 8C; [found:
C, 68.42; H, 5.12; N, 15.10 C16H14N3O2 requires C, 68.56;
H, 5.03; N, 14.99]; nmax 2CHCl3) 1740 cm21; dH 2200 MHz,
CDCl3) 3.80 2s, 3H), 5.00 2d, Jˆ5.4 Hz, 1H), 5.35 2d,
Jˆ5.4 Hz, 1H), 6.90±7.50 2m, 9H); dC 250.3 MHz,
CDCl3) 55.31, 60.61, 67.66, 114.57, 117.62, 124.45,
124.75, 128.94, 129.23, 136.99, 160.48, 161.84; MS 2m/z):
413 2M1).
4.4.1. .2R,3S,6R,30R,40S)-N-[10-.p-Anisyl)-40-phenylaze-
tidin-20-one-30-yl]-2,10-camphorsultam .9a). White crys-
talline solid; yield 90%; mp238±240 8C 2Lit.15 mp242±
2438C); [found: C, 66.62; H, 6.19; N, 5.83; S, 6.70.
C26H30N2O4S requires C, 66.93; H, 6.48; N, 6.00; S, 6.87];
nmax 2CHCl3) 1753 cm21; dH 2200 MHz, CDCl3) 0.15 2s,
3H), 0.70 2s, 3H), 1.25±1.50 2m, 2H), 1.60±1.90 2m, 5H),
2.80 2d, Jˆ13.7 Hz, 1H), 3.10 2d, Jˆ13.7 Hz, 1H), 3.70 2t,
Jˆ7.5 Hz, 1H), 3.75 2s, 3H), 5.30 2m, 2H), 6.85 2d,
Jˆ10 Hz, 2H), 7.25±7.50 2m, 7H); dC 250.3 MHz, CDCl3)
18.75, 19.78, 26.51, 32.35, 37.24, 44.74, 47.13, 48.19,
49.70, 55.21, 59.92, 61.09, 65.28, 114.17, 118.40, 127.48,
127.99, 128.36, 130.64, 133.47, 156.26, 160.34; MS 2m/z):
4.3.2. 3-Azido-1-.4-methoxyphenyl)-4-styrylazetidin-2-
one .5b). White solid; yield 83%; mp115±116 8C; [found:
C, 67.72; H, 5.34; N, 17.66 C18H16N4O2 requires C, 67.48;
H, 5.03; N, 17.49]; nmax 2CHCl3) 1739 cm21; dH 2200 MHz,
CDCl3) 3.80 2s, 3H), 4.90 2dd, Jˆ5.30, 8.30 Hz, 1H), 5.00
2d, Jˆ5.30 Hz, 1H), 6.30 2dd, Jˆ8.30, 15.95 Hz, 1H), 6.80±
7.50 2m, 10H); dC 275.48 MHz, CDCl3) 55.27, 59.75, 67.26,
114.26, 118.50, 122.40, 126.70, 128.59, 130.53, 135.27,
137.04, 156.47, 160.56; MS 2m/z): 320 2M1).
466 2M1); [a]25 ˆ137.60 2c 1.0, CH2Cl2).
D
4.4.2. .2R,3S,6R,30R,40S)-N-[10-.p-Anisyl)-40-p-anisylaze-
tidin-20-one-30-yl]-2,10-camphorsultam .9b). White crys-
talline solid; yield 90%; mp210±212 8C 2Lit.15 mp215±
2168C); [found: C, 65.42; H, 6.37; N, 5.86; S, 6.26.
C27H32N2O5S requires C, 65.30; H, 6.49; N, 5.64; S, 6.46];
nmax 2CHCl3) 1753 cm21; dH 2200 MHz, CDCl3) 0.20 2s,
3H), 0.75 2s, 3H), 1.20±1.50 2m, 2H), 1.60±1.85 2m, 5H),
2.90 2d, Jˆ13.7 Hz, 1H), 3.10 2d, Jˆ13.7 Hz, 1H), 3.70 2t,
Jˆ7.5 Hz, 1H), 3.80 2s, 6H), 5.25 2two merged doublets,
2H), 6.80±7.00 2m, 4H), 7.15±7.40 2m, 4H); dC
250.3 MHz, CDCl3) 18.75, 19.74, 26.54, 32.35, 37.28,
44.74, 47.16, 48.23, 49.74, 55.21, 59.55, 60.98, 65.28,
113.88, 114.17, 118.40, 125.35, 128.66, 130.64, 156.22,
4.3.3. 1-.4-Methoxyphenyl)-3-.a-methyl-b-ethoxycar-
bonylamino)-4-phenyl-azetidin-2-one .7a). White solid;
yield 70%; mp140 8C; [found: C, 69.50; H, 6.45; N, 7.20.
C22H24N2O4 requires C, 69.46; H, 6.36; N, 7.36]; nmax
2CHCl3) 1753 cm21; dH 2200 MHz, CDCl3) 1.10 2t,
Jˆ7.1 Hz, 3H), 1.85 2s, 3H), 3.75 2s, 3H), 3.90 2q,
Jˆ7.1 Hz, 2H), 4.40 2s, 1H), 5.15 2dd, Jˆ4.9, 8.8 Hz, 1H),
5.35 2d, Jˆ4.9 Hz, 1H), 6.80 2d, Jˆ9.3 Hz, 2H), 7.20±7.50
2m, 7H), 8.60 2d, Jˆ8.8 Hz, 1H); dC 250.3 MHz, CDCl3)
14.19, 19.45, 55.21, 58.23, 61.61, 63.30, 86.27, 114.21,
118.55, 127.00, 128.69, 128.91, 131.00, 132.77, 156.22,
158.21, 163.24, 169.13; MS 2m/z): 380 2M1).
159.50, 160.41; MS 2m/z): 496 2M1); [a]25 ˆ158.40 2c
D
1.0, CH2Cl2).
4.3.4. 1-.4-Methoxyphenyl)-3-.a-methyl-b-ethoxycar-
bonylamino)-4-.4-methoxyphenyl)azetidin-2-one .7b).
White solid; yield 65%; mp118±120 8C; [found: C, 67.60;
H, 6.48; N, 6.59. C23H26N2O5 requires C, 67.30; H, 6.39; N,
6.83]; nmax 2CHCl3) 1747 cm21; dH 2200 MHz, CDCl3) 1.17
2t, Jˆ7.1 Hz, 3H), 1.87 2s, 3H), 3.76 2s, 3H), 3.80 2s, 3H),
3.95 2q, Jˆ7.1 Hz, 2H), 4.39 2s, 1H), 5.14 2dd, Jˆ5.4,
8.8 Hz, 1H) 5.23 2d, Jˆ5.4 Hz, 1H), 6.60±7.40 2m, 8H),
8.60 2d, Jˆ8.8 Hz, 1H); dC 250.3 MHz, CDCl3) 14.19,
19.41, 55.03, 55.18, 58.19, 61.20, 63.30, 86.16, 114.17,
114.47, 116.16, 118.58, 124.57, 128.36, 130.46, 156.19,
159.94, 163.32, 169.16; MS 2m/z): 410 2M1).
4.4.3. .2R,3S,6R,30R,40S)-N-[10-.p-Anisyl)-40-styrylazetidin-
20-one-30-yl]-2,10-camphorsultam .9c). White crystalline
solid; yield 82%; mp204±206 8C 2Lit.15 mp208±210 8C);
[found: C, 68.23; H, 6.66; N, 5.97; S, 6.49. C28H32N2O4S
requires C, 68.27; H, 6.55; N, 5.69; S, 6.51]; nmax 2CHCl3)
1751 cm21; dH 2200 MHz, CDCl3) 0.90 2s, 3H), 1.00 2s,
3H), 1.30±1.65 2m, 2H), 1.75±2.00 2m, 5H), 3.20 2q,
Jˆ14 Hz, 2H), 3.70 2dd, Jˆ4.9, 7.3 Hz, 1H), 3.80 2s, 3H),
4.90 2m, 1H), 5.10 2d, Jˆ5.3 Hz, 1H), 6.35 2dd, Jˆ5.3,
16.1 Hz, 1H), 6.60 2d, Jˆ16.1 Hz, 1H), 6.90 2d, Jˆ8.8 Hz,
2H), 7.25±7.50 2m, 7H); dC 250.3 MHz, CDCl3) 19.73,
20.06, 26.49, 32.38, 38.00, 44.69, 47.37, 48.66, 50.13,
55.20, 58.18, 60.53, 65.90, 114.16, 118.28, 123.83, 126.44,
127.80, 128.24, 130.96, 133.61, 135.74, 156.25, 159.71; MS
4.3.5. 1-.4-Methoxyphenyl)-3-.a-methyl-b-ethoxycar-
bonylamino)-4-styrylazetidin-2-one .7c). White solid;
yield 73%; mp115±116 8C; [found: C, 71.10; H, 6.75; N,
7.03 C24H26N2O4 requires C, 70.92; H, 6.45; N, 6.89]; nmax
2CHCl3) 1749 cm21; dH 2200 MHz, CDCl3) 1.17 2t,
Jˆ7.1 Hz, 3H), 1.87 2s, 3H), 3.76 2s, 3H), 3.80 2s, 3H),
3.95 2q, Jˆ7.1 Hz, 2H), 4.39 2s, 1H), 5.14 2dd, Jˆ5.4,
8.8 Hz, 1H) 5.23 2d, Jˆ5.4 Hz, 1H), 6.60±7.40 2m,
8H), 8.60 2d, Jˆ8.8 Hz, 1H); dC 275.48 MHz, CDCl3)
13.95, 19.17, 54.87, 58.03, 59.96, 62.53, 85.91, 113.83,
118.05, 122.38, 122.47, 126.38, 128.06, 134.41, 135.17,
136.69, 155.86, 158.97, 162.56, 169.41; MS 2m/z): 405
2M1-1).
2m/z): 492 2M1); [a]25 ˆ159.0 2c 1.0, CH2Cl2).
D
4.5. General procedure for synthesis of b-lactams from
acids derived from oxazolidinone
A similar general procedure, as for compounds 5a,b and
7a±c, was used for the synthesis of b-lactams 211a±f) start-
ing from the acids 10 and imines 2.
4.5.1.
methyl)-30-azetidinyl]-4-phenyl-2-oxazolidinone .11a).
.4R,30R,40R)-3-[20-Oxo-40-.phenyl)-10-.phenyl-

D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2221
White solid; yield 70%; mp220±222 8C 2Lit.16 mp228±
2308C); [found: C, 75.15; H, 5.45; N, 7.32. C25H22N2O3
requires C, 75.36; H, 5.56; N, 7.03]; nmax 2Nujol)
1750 cm21; dH 2200 MHz, CDCl3) 3.87±4.02 2m, 2H),
4.10±4.38 2m, 2H), 4.42 2d, Jˆ4.6 Hz, 1H), 4.55 2d,
Jˆ4.6 Hz, 1H), 4.95 2d, Jˆ14.7 Hz, 1H), 7.00±7.50 2m,
15H); dC 250.3 MHz, CDCl3) 44.96, 59.40, 60.43, 63.48,
69.92, 127.22, 127.52, 127.63, 128.36, 128.58, 129.17,
132.96, 134.65, 136.34, 156.63, 163.10; MS 2m/z):
124.39, 128.66, 130.86, 156.11, 157.36, 159.50, 160.38; MS
2m/z): 410 2M1); [a]30 ˆ224.4 2c 1.0, CHCl3).
D
4.5.6.
.4R,30R,40R)-3-[20-Oxo-40-.phenyl)-10-.phenyl-
methyl)-30-azetidinyl]-4-isopropyl-2-oxazolidinone .11f).
White solid; yield 70%; mp185 8C; [found: C, 72.33; H,
6.53; N, 7.76. C22H24N2O3 requires C, 72.51; H, 6.64; N,
7.69]; nmax 2Nujol) 1747 cm21; dH 2200 MHz, CDCl3) 0.40
2d, Jˆ6.8 Hz, 3H), 0.75 2d, Jˆ6.8 Hz, 3H), 1.60±1.90 2m,
1H), 3.40±3.50 2m, 1H), 3.65±3.75 2dd, Jˆ8.8, 11.5 Hz,
1H), 3.85±3.95 2dd, Jˆ8.8, 4.4 Hz, 1H), 4.15 2d,
Jˆ14.7 Hz, 1H), 4.70 2d, Jˆ4.9 Hz, 1H), 4.90 2d,
Jˆ4.9 Hz, 1H), 5.05 2d, Jˆ14.7 Hz, 1H), 7.10±7.50 2m,
10H); dC 250.3 MHz, CDCl3) 13.46, 17.57, 28.20, 45.14,
58.71, 60.54, 62.97, 63.92, 127.33, 127.70, 128.21,
128.32, 128.62, 133.29, 134.72, 157.22, 163.61; MS 2m/z):
2M12133); [a]30 ˆ273.4 2c 1.0, CHCl3).
D
4.5.2. .4R,30R,40R)-3-[20-Oxo-40-.phenyl)-10-.4-methoxy-
phenyl)-30-azetidinyl]-4-phenylmethyl-2-oxazolidinone
.11b). White solid; yield 67%; mp194 8C; [found: C, 72.67;
H, 5.63; N, 6.52. C26 H24 N2O4 requires C, 72.88; H, 5.65; N,
6.54]; gmax 2CHCl3) 1753 cm21; dH 2200 MHz, CDCl3) 1.80
2dd, Jˆ13.2, 10.3 Hz 1H), 2.95 2dd, Jˆ13.2, 3.9 Hz, 1H),
3.60±3.90 2m, 2H), 3.75 2s, 3H), 4.00±4.25 2m, 1H), 5.20 2d,
Jˆ4.9 Hz, 1H), 5.40 2d, Jˆ4.9 Hz, 1H), 6.85±7.50 2m,
14H); dC 250.3 MHz, CDCl3) 39.96, 55.29, 55.36, 60.58,
63.08, 67.60, 114.28, 118.40, 127.00, 127.30, 128.25,
128.40, 128.73, 130.82, 133.03, 135.09, 156.41, 157.47,
364 2M1); [a]30 ˆ240 2c 1.0, CHCl3).
D
4.5.7. 4-Methoxy-4,7,7-trimethyl-bicyclo[4.1.0]heptan-3-
ol .13). To a solution of 21)-3-carene oxide 12 21.0 g,
6.5 mmol) in methanol 225 ml), a catalytic quantity of
PTSA 230 mg) was added at 08C and stirred for 2 h. The
solvent was evaporated under reduced pressure and the resi-
due was extracted with EtOAc 23£20 ml). The combined
extracts were washed with brine 22£20 ml), dried over
Na2SO4. It was ®ltered and the ®ltrate was concentrated to
give the crude product 13 which on puri®cation by column
chromatography 2silica gel, 60±120, 5% EtOAc in pet.
ether) gave colourless oil 21.1 g, 90%) of pure methoxy
alcohol 213); [found: C, 71.54; H, 11.16. C11H20O2 requires
C, 71.69; H, 10.93]; nmax 2Neat) 3461 cm21; dH 2200 MHz,
CDCl3) 0.60±0.70 2m, 2H); 0.95±1.25 2m, 1H), 0.96 2s, 3H),
0.99 2s, 3H), 1.16 2s, 3H), 1.62±1.80 2m, 1H), 2.00±2.20 2m,
2H), 2.50 2bs, 1H), 3.21 2s, 3H), 3.35±3.50 2m, 2H). MS
160.34; MS 2m/z): 428 2M1); [a]30 ˆ280.20 2c 1.0,
D
CHCl3).
4.5.3.
.4R,30R,40R)-3-[20-Oxo-40-.phenyl)-10-.phenyl-
methyl)-30-azetidinyl]-4-phenylmethyl-2-oxazolidinone
.11c). White solid; yield 70%; mp151 8C; [found: C, 75.56;
H, 5.81; N, 6.82. C26H24N2O3 requires C, 75.71; H, 5.87; N,
6.79]; nmax2Nujol) 1745 cm21; dH 2200 MHz, CDCl3) 1.90
2dd, Jˆ13.1, 9.7 Hz, 1H), 2.95 2dd, Jˆ13.1, 3.9 Hz, 1H),
3.60±3.80 2m, 2H), 3.80±4.10 2m, 1H), 4.25 2d, Jˆ14.7 Hz,
1H), 4.80 2d, Jˆ5.3 Hz, 1H), 5.00 2d, Jˆ5.3 Hz, 1H), 5.10
2d, Jˆ14.7 Hz, 1H), 7.00±7.50 2m, 15H); dC 250.3 MHz,
CDCl3) 39.87, 45.68, 55.53, 60.28, 64.10, 67.44, 127.03,
127.25, 127.95, 128.28, 128.46, 128.79, 133.75, 134.60,
2m/z): 184 2M1); [a]28 ˆ25.8 2c 1.5, CHCl3).
D
135.11, 157.39, 163.71; MS 2m/z): 412 2M1); [a]30 ˆ244
4.5.8. .4-Methoxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-
yloxy)-acetic acid .14). To a solution of 13 21.84 g,
10 mmol) in dry toluene 225 ml), clean sodium pieces
20.5 g) were added and gently re¯uxed for 15 h. The solu-
tion was cooled and the excess of sodium was removed by
®ltration through glass wool. The ®ltrate was heated to 85±
908C with stirring and a solution of chloroacetic acid
20.470 g, 5 mmol) in dry toluene 230 ml) was added in
such a way that the re¯uxing should not be vigorous. A
heavy precipitate of sodium chloroacetate was formed
immediately. The reaction mixture was re¯uxed under stir-
ring for an additional 48 h. The reaction mixture was diluted
with toluene 230 ml) and extracted with water 23£25 ml)
and the aqueous layer was acidi®ed with 20% HCl. The
crude product, which collects as brown oil on the top, was
extracted with diethylether. The organic extract was dried
over Na2SO4 and the solvent was removed under reduced
pressure to give crude product as oil, which was puri®ed by
fractional distillation under reduced pressure to afford pale
yellow oil 21.5 g, 62%) of the acid 214). Bp90±95 8C/5 mm;
[found: C, 64.26; H, 9.26. C13H22O4 requires C, 64.43; H,
9.15]; nmax 2Neat) 1731, 3600±2600 cm21; dH 2200 MHz,
CDCl3), 0.95 2s, 3H, CH3), 1.05 2s, 3H, CH3), 1.25 2s, 3H,
CH3), 3.38 2s, 3H, OCH3), 1.20±2.40 2m, 7H, CH2 and CH),
3.90 2d, Jˆ17.6 Hz, 1H), 4.35 2d, Jˆ17.6 Hz, 1H), 9.30
D
2c 1.0, CHCl3).
4.5.4. .4R,30R,40R)-3-[20-Oxo-40-.phenyl)-10-.4-methoxy-
phenyl)-30-azetidinyl]-4-isopropyl-2-oxazolidinone .11d).
White solid; yield 71%; mp215±217 8C; [found: C, 69.19;
H, 6.13; N, 7.16. C22H24N2O4 requires C, 69.47; H, 6.36; N,
7.36]; nmax2CHCl3) 1747 cm21; dH 2200 MHz, CDCl3) 0.40
2d, Jˆ6.8 Hz, 3H), 0.75 2d, Jˆ6.8 Hz, 3H), 1.60±1.90 2m,
1H), 3.60±3.80 2m, 1H), 3.75 2s, 3H), 3.85±3.95 2m, 2H),
5.00 2d, Jˆ5.4 Hz, 1H), 5.30 2d, Jˆ5.4 Hz, 1H), 6.80±7.50
2m, 9H); dC 250.3 MHz, CDCl3) 13.20, 17.72, 28.67, 55.18,
58.67, 61.09, 63.04, 63.19, 114.10, 118.33, 127.30, 128.21,
128.47, 130.82, 132.70, 156.19, 157.44, 160.27; MS 2m/z):
380 2M1); [a]30 ˆ217.27 2c 1.0, CHCl3).
D
4.5.5. .4R,30R,40R)-3-[20-Oxo-40-.4-methoxyphenyl)-10-
.4-methoxyphenyl)-30-azetidinyl]-4-isopropyl-2-oxazoli-
dinone .11e). White solid; yield 72%; mp200±202 8C;
[found: C, 67.21; H, 6.42; N, 6.75; C23H26N2O5 requires
C, 67.30; H, 6.39; N, 6.83]; nmax 2CHCl3) 1753 cm21; dH
2200 MHz, CDCl3) 0.50 2d, Jˆ6.9 Hz, 3H), 0.75 2d,
Jˆ6.9 Hz, 3H), 1.60±1.90 2m, 1H), 3.60±3.80 2m, 1H),
3.75 2s, 3H), 3.80 2s, 3H), 3.85±3.95 2m, 2H), 5.00 2d,
Jˆ5.4 Hz, 1H), 5.30 2d, Jˆ5.4 Hz, 1H), 6.80±7.50 2m,
8H); dC 250.3 MHz, CDCl3) 13.42, 17.68, 28.45, 55.03,
55.18, 58.78, 60.84, 62.97, 63.19, 113.92, 114.06, 118.36,
2bs, 1H). MS 2m/z): 242 2M1); [a]28 ˆ258.48 2c 1.05,
D
CHCl3).

2222
D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
4.5.9. 3-.4-Methoxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-
3-yloxy)-4-styryl-1-.4-methoxyphenyl) azetidin-2-one
.15 and 16). solution of triphosgene 20.148 g,
16.40]; nmax 2CHCl3) 1745 cm21; dH 2200 MHz, CDCl3)
1.80±2.30 2m, 2H), 2.60±2.90 2m, 2H), 3.50±3.90 2m,
2H), 3.75 2s, 3H), 3.80 2s, 3H), 4.90 2s, 1H), 6.70±7.40
2m, 8H); dC 250.3 MHz, CDCl3), 25.11, 27.76, 28.16,
55.03, 55.25, 60.58, 66.46, 113.66, 114.28, 118.47,
123.58, 128.91, 130.71, 156.19, 160.19, 164.38; MS 2m/z):
3872M1).
A
0.5 mmol) in anhydrous CH2Cl2 210 ml) was added slowly
to a solution of the acid 14 20.242 g, 1 mmol), imine 2
20.237 g, 1 mmol) and triethylamine 20.42 ml, 3 mmol) in
anhydrous CH2Cl2 210 ml) at 2408C. The reaction mixture
was allowed to warm upto room temperature and stirred for
12 h. It was then diluted with CH2Cl2 and washed succes-
sively with water 22£20 ml), saturated NaHCO3 22£20 ml),
brine 220 ml), dried 2anhyd. Na2SO4). The solvent was
removed under reduced pressure and the residue was passed
through a short silica-gel column to afford the b-lactams 15
and 16 20.30 g, 65%) as the diastereomeric mixture 260:40).
The major diastereomer was separated by crystallization
from petroleum ether/acetone, which showed following
spectral and analytical data. White solid; mp 232±2348C;
[found: C, 75.72; H, 7.51; N, 3.14. C29H35O4N requires C,
75.46; H, 7.64; N, 3.03]; nmax 2Nujol) 1740 cm21; dH
2200 MHz, CDCl3) 0.50±0.65 2m, 2H), 0.71 2s, 3H), 0.87
2s, 3H), 0.90±1.10 2m, 1H), 1.27 2s, 3H), 1.55±2.20 2m, 3H),
3.27 2s, 3H), 3.20±3.40 2m, 1H), 3.75 2s, 3H), 4.70 2dd,
Jˆ4.4, 8.7 Hz, 1H), 5.42 2d, Jˆ4.4 Hz, 1H), 6.37 2dd,
Jˆ8.7, 16.0 Hz, 1H), 6.75±6.95 2m, 3H), 7.15±7.55 2m,
7H); dC 250.3 MHz, CDCl3) 14.80, 15.50, 17.60, 19.10,
20.50, 26.20, 28.20, 29.70, 48.90, 55.40, 61.50, 78.20,
81.90, 84.20, 114.20, 118.50, 125.10, 126.50, 128.20,
128.60, 131.50, 135.50, 135.90, 156.10, 164.00;
4.6.4.
2-.4-Methoxyphenyl)-3-styryl-5,9-dithia-2-aza-
spiro[3,5]nonan-1-one .20d). White solid; yield 70%; mp
122±1248C; [found: C, 65.50; H, 5.68; N, 3.40; S, 16.64.
C21H21NO2S2 requires C, 65.79; H, 5.48; N 3.65; S, 16.72];
n
max 2CHCl3) 1745 cm21; dH 2200 MHz, CDCl3) 1.80±2.30
2m, 2H), 2.60±2.90 2m, 2H), 3.50±3.90 2m, 2H), 3.75 2s,
3H), 4.50 2d, Jˆ8.3 Hz, 1H), 6.40 2dd, Jˆ8.3, 16 Hz, 1H),
6.75±7.50 2m, 10H); dC 275.48 MHz, CDCl3) 25.27, 27.56,
28.11, 55.33, 60.58, 65.77, 114.26, 118.38, 121.96, 126.81,
128.36, 128.58, 130.93, 135.26, 137.46, 156.20, 163.98; MS
2m/z): 383 2M1).
4.6.5. 2,3-Diphenyl-5,9-dithia-2-aza-spiro[3,5]nonan-1-
one .20e). White solid; yield 72%; mp173±174 8C 2Lit.22
mp175±176 8C); [found: C, 65.90; H, 5.43; N, 4.31; S,
19.73. C18H17NOS2 requires C, 66.02; H, 5.23; N, 4.28; S,
19.58]; nmax 2CHCl3) 1740 cm21; dH 2200 MHz, CDCl3)
1.80±2.30 2m, 2H), 2.60±2.90 2m, 2H), 3.50±3.90 2m,
2H), 5.00 2s, 1H), 7.00±7.75 2m, 10H); dC 250.3 MHz,
CDCl3) 24.96, 27.72, 28.16, 60.07, 66.35, 117.04, 124.02,
127.44, 128.18, 128.91, 131.49, 137.11, 159.46, 164.68; MS
2m/z): 357 2M1).
[a]23 ˆ23.3 2c 1.2, CH2Cl2).
D
4.6. General procedure for synthesis of b-lactams
.20a±g) from dithioglyoxylic acid .19)
4.6.6. 2-.4-Chlorophenyl)-3-styryl-5,9-dithia-2-aza-spiro-
[3,5]nonan-1-one .20f). White solid; yield 69%; mp
1548C; [found: C, 62.19; H, 4.83; N, 3.39; S, 16.28.
C20H18NOS2Cl requires C, 61.92; H, 4.68; N, 3.61; S,
16.53]; nmax 2CHCl3) 1751 cm21; dH 2200 MHz, CDCl3)
1.80±2.40 2m, 2H), 2.70±2.90 2m, 2H), 3.55±3.90 2m,
2H), 4.50 2d, Jˆ8.3 Hz, 1H), 6.30 2dd, Jˆ8.3, 16.1 Hz,
1H), 6.90 2d, Jˆ16.1 Hz, 1H), 7.25±7.50 2m, 9H); dC
275.48 MHz, CDCl3) 25.27, 27.65, 28.23, 60.89, 65.80,
118.29, 121.38, 126.90, 128.67, 129.16, 129.31, 135.17,
136.15, 137.86, 164.41; MS 2m/z): 387 2M1).
A similar general procedure, as for compounds 5a,b and
7a±c, was used for the synthesis of b-lactams 220a±g)
starting from the acid 19 and imines 2.
4.6.1. 2-.4-Methoxyphenyl)-3-phenyl-5,9-dithia-2-aza-
spiro[3,5]nonan-1-one .20a). White solid; yield 70%; mp
1868C; [found: C, 63.62; H, 5.50; N, 3.73; S, 18.04.
C19H19NO2S2 requires C, 63.83; H, 5.36; N, 3.92; S,
17.94]; nmax 2Nujol) 1735 cm21; dH 2200 MHz, CDCl3)
1.80±2.30 2m, 2H), 2.60±2.90 2m, 2H), 3.50±3.90 2m,
2H), 3.70 2s, 3H), 4.90 2s, 1H), 6.75±7.50 2m, 9H); dC
275.48 MHz, CDCl3) 25.39, 28.18, 28.56, 55.63, 60.55,
66.86, 114.60, 118.75, 127.90, 128.54, 126.38, 130.89,
131.99, 156.47, 164.62; MS 2m/z): 357 2M1).
4.6.7. 2-.10-Phenylethyl)-3-phenyl-2-aza-5,9-dithiaspiro-
[3,5]nonan-1-one .20g). 2Mixture of 2 diastereomers, 3R,
10R and 3S, 10R) Yellow oil; yield 69%; [found: C, 67.45; H,
5.86; N, 3.80; S, 17.91. C20H21NOS2 requires C, 67.61; H,
5.92; N, 3.94; S, 18.03]; nmax 2CHCl3) 1751 cm21; dH
2200 MHz, CDCl3) 1.50 and 1.90 22d, Jˆ7.4, 6.9 Hz, 3H),
1.50±2.25 2m, 2H), 2.50±2.90 2m, 2H), 3.40±3.90 2m, 2H),
4.22 and 4.27 22S, 1H), 4.35 and 5.00 22 q, 1H), 7.00±7.50
2m, 9H); MS 2m/z): 355 2M1).
4.6.2. 2-Phenyl-3-.4-methoxyphenyl)-5,9-dithia-2-aza-
spiro[3,5]nonan-1-one .20b). White solid; yield 71%; mp
155±1568C; [found: C, 63.65; H, 5.60; N, 4.10; S, 17.75.
C19H19NO2S2 requires C, 63.83; H, 5.36; N, 3.92; S, 17.94];
nmax 2Nujol) 1737 cm21; dH 2200 MHz, CDCl3) 1.80±2.30
2m, 2H), 2.60±2.90 2m, 2H), 3.50±3.90 2m, 2H), 3.70 2s,
3H), 4.90 2s, 1H), 6.75±7.50 2m, 9H); dC 250.3 MHz,
CDCl3) 25.33, 28.02, 28.42, 55.33, 60.66, 66.43, 113.92,
117.41, 123.55, 124.28, 129.17, 137.44, 160.42, 165.12;
MS 2m/z): 357 2M1).
4.7. General procedure for the synthesis of carbonimido-
dithioic acid dimethyl esters .22a±g) from amines and
aminoacid esters
To a solution of amine 210 mmol) and carbon disul®de
210 mmol) in dichloromethane 250 ml), triethylamine
210 mmol) was added slowly at 208C and the reaction
mixture was stirred for 30 min. Methyl iodide 212 mmol)
was then added dropwise and the resulting mixture was
re¯uxed for 2±3 h. The reaction mixture was then cooled
4.6.3. 2,3-Di.4-Methoxyphenyl)-5,9-dithia-2-aza-spiro-
[3,5]nonan-1-one .20c). White solid; yield 75%; mp
1308C; [found: C, 61.60; H, 5.72; N, 3.40; S, 16.54.
C20H21NO3S2 requires C, 61.90; H, 5.46; N, 3.61; S,

D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2223
to room temperature and triethylamine 212 mmol), methyl
iodide 212 mmol) were successively added dropwise. The
reaction mixture was again re¯uxed for 2±3 h. After
complete conversion of dithiocarbamate to carbonimido-
dithioate 2TLC), the reaction mixture was washed with
water 22£20 ml), brine 220 ml), dried 2anhyd. Na2SO4)
and concentrated under vacuum to get crude product,
which was puri®ed by column chromatography to get the
desired product 222a±g) in 70±79% yield.
N, 6.78; S, 30.81. C7H13NO2S2 requires C, 40.55; H, 6.32;
N, 6.75; S, 30.93]; nmax 2Neat) 1573, 1745 cm21; dH
2200 MHz, CDCl3) 1.40 2d, Jˆ6.8 Hz, 3H), 2.40 2s, 3H),
2.55 2s, 3H), 3.72 2s, 3H), 4.50 2q, Jˆ6.8 Hz, 1H); dC
250.3 MHz, CDCl3) 14.14, 14.36, 18.04, 51.38, 59.50,
160.70, 172.35; MS 2m/z): 207 2M1).
4.8. General procedure for the preparation of 4-keto
protected b-lactams .23a±j)
4.7.1. N-Phenyl carbonimidodithioic acid dimethyl ester
.22a). Pale yellow oil; yield 74%; [found: C, 54.67; H, 5.44;
N, 7.12; S, 32.23. C9H11NS2 requires C, 54.78; H, 5.61; N,
7.09; S, 32.49]; nmax 2CHCl3) 1587 cm21; dH 2200 MHz,
CDCl3) 2.34 2s, 3H), 2.45 2s, 3H), 7.00±7.30 2m, 5H); dC
250.3 MHz, CDCl3) 14.44, 119.90, 123.35, 128.46, 149.50,
162.02; MS 2m/z): 197 2M1).
A similar general procedure, as for compounds 5a,b and
7a±c, was used for the synthesis of b-lactams 223a±j)
starting from the acids 1 and imines 22.
4.8.1. 4,4-Bis-methylsufanyl-3-phenoxy-1-phenylazetidin-
2-one .23a). White solid; yield 68%; mp142 8C; [found: C,
61.92; H, 5.40; N, 4.29; S, 19.10. C17H17NO2S2 requires C,
61.61; H, 5.17; N, 4.23; S, 19.35]; nmax 2CHCl3) 1766 cm21
;
4.7.2. N-Benzyl carbonimidodithioic acid dimethyl ester
.22b). Pale yellow oil; yield 79%; [found: C, 56.64; H, 6.08;
N, 6.74; S, 30.56. C10H13NS2 requires C, 56.83; H, 6.20; N,
6.62; S, 30.33]; nmax 2CHCl3) 1590 cm21; dH 2200 MHz,
CDCl3) 2.40 2s, 3H), 2.55 2s, 3H), 4.60 2s, 2H), 7.00±7.30
2m, 5H); dC 250.3 MHz, CDCl3) 14.52, 56.06, 126.45,
127.33, 128.14, 140.09, 158.76; MS 2m/z): 211 2M1).
dH 2200 MHz, CDCl3) 2.20 2s, 3H), 2.23 2s, 3H), 5.49 2s,
1H), 7.05±7.50 2m, 8H), 8.00 2d, Jˆ8.3 Hz, 2H); dC
250.3 MHz, CDCl3), 17.32, 18.23, 114.87, 119.72, 122.96,
124.28, 128.73, 129.83, 137.22, 140.60, 141.04, 156.0,
159.57; MS 2m/z): 3312M1).
4.8.2. 1-Benzyl-4,4-bis-methylsulfanyl-3-phenoxyazetidin-
2-one .23b). White crystalline solid; yield 65%; mp79±
808C 2Lit.23 mp78±79 8C); [found: C, 62.43; H, 5.60; N,
4.12; S, 18.36. C18H19NO2S2 requires C, 62.58; H, 5.54;
4.7.3. N-.4-Methoxyphenyl) carbonimidodithioic acid
dimethyl ester .22c). Pale yellow oil; yield 72%; [found:
C, 52.68; H, 5.54; N, 6.32; S, 28.05. C10H13NOS2 requires
C, 52.83; H, 5.76; N, 6.16; S, 28.20]; nmax 2Neat)
1585 cm21; dH 2200 MHz, CDCl3) 2.43 2s, 3H), 2.49 2s,
3H), 3.78 2s, 3H), 6.75±7.00 2m, 5H); dC 250.3 MHz,
CDCl3) 14.62, 55.02, 113.67, 121.22, 142.72, 155.99,
161.71; MS 2m/z): 227 2M1).
N, 4.05; S, 18.56]; nmax 2CHCl3) 1770 cm21
; dH
2200 MHz, CDCl3) 2.00 2s, 6H), 4.50 2q, Jˆ15.2 Hz, 2H),
5.33 2s, 1H), 7.05±7.60 2m, 10H); dC 250.3 MHz, CDCl3)
23.16, 24.13, 54.01, 91.16, 98.94, 126.37, 133.09, 138.31,
138.95, 139.32, 139.93, 145.69, 167.55, 173.65; MS 2m/z):
330 2M1215).
4.7.4. N-Propylcarbonimidodithioic acid dimethyl ester
.22d). Pale yellow oil; yield 72%; [found: C, 43.98; H, 7.97;
N, 8.69; S, 39.08. C6H13NS2 requires C, 44.13; H, 8.02; N,
8.57; S, 39.26]; nmax 2Neat) 1590 cm21; dH 2200 MHz,
CDCl3) 1.00 2t, Jˆ7.2 Hz, 3H), 1.65 2m, 2H), 2.35 2s,
3H), 2.55 2s, 3H), 3.40 2t, Jˆ7.2 Hz, 2H); dC 250.3 MHz,
CDCl3) 11.53, 13.96, 14.07, 23.70, 54.25, 156.14; MS 2m/z):
163 2M1).
4.8.3.
1-.4-Methoxyphenyl)-4,4-bis-methylsulfanyl-3-
phenoxyazetidin-2-one .23c). White crystalline solid;
yield 66%; mp147±149 8C 2Lit.23 mp148±149 8C);
[found: C, 59.59; H, 5.56; N, 3.83; S, 17.53. C18H19NO3S2
requires C, 59.81; H, 5.30; N, 3.87; S, 17.74]; nmax 2CHCl3)
1760 cm21; dH 2200 MHz, CDCl3) 2.20 2s, 3H), 2.22 2s,
3H), 3.83 2s, 3H), 5.46 2s, 1H), 6.95±7.90 2m, 9H); dC
250.3 MHz, CDCl3) 12.75, 14.18, 55.35, 79.61, 88.21,
114.38, 115.96, 120.23, 122.73, 128.83, 129.56, 157.13,
157.39, 160.59; MS 2m/z): 361 2M1).
4.7.5. N-[Bis.methylthio) methylene] glycine methyl
ester .22e). Pale yellow oil; yield 70%; [found: C, 37.58;
H, 5.63; N, 7.51; S, 33.39. C6H11NO2S2 requires C, 37.28;
4.8.4.
.2,2-Bis-methylsulfanyl-4-oxo-3-phenoxy-1-yl)-
H, 5.73; N, 7.24; S, 33.17]; nmax 2Neat) 1579, 1751 cm21
;
acetic acid methyl ester .23d). White crystalline solid;
yield 64%; mp93±94 8C; [found: C, 51.20; H, 5.34; N,
4.36; S, 19.36. C14H17NO4S2 requires C, 51.36; H, 5.23;
N, 4.28; S, 19.58]; nmax 2CHCl3) 1755, 1782 cm21; dH
2200 MHz, CDCl3) 2.21 2s, 3H), 2.33 2s, 3H), 3.81 2s, 3H),
4.11 2dd, Jˆ17.6 Hz, 2H), 5.41 2s, 1H), 7.05±7.40 2m, 5H);
dC 250.3 MHz, CDCl3) 12.72, 13.79, 40.25, 61.68, 80.25,
87.34, 115.61, 122.59, 129.43, 156.78, 162.95, 166.74; MS
2m/z): 327 2M1).
dH 2200 MHz, CDCl3) 2.43 2s, 3H), 2.56 2s, 3H), 3.75 2s,
3H), 4.24 2s, 2H); dC 250.3 MHz, CDCl3) 14.18, 14.51,
51.42, 53.73, 162.79, 170.07; MS 2m/z): 193 2M1).
4.7.6. N-[Bis.methylthio)methylene] glycine ethyl ester
.22f). Pale yellow oil; yield 76%; [found: C, 40.26; H,
6.25; N, 6.87; S, 30.76. C7H13NO2S2 requires C, 40.55; H,
6.32; N, 6.75; S, 30.93]; nmax 2Neat) 1579, 1751 cm21; dH
2200 MHz, CDCl3) 1.28 2t, Jˆ7.3 Hz, 3H), 2.44 2s, 3H),
2.56 2s, 3H), 4.20 2q, J ˆ7.3 Hz, 2H), 4.22 2s, 3H); dC
250.3 MHz, CDCl3) 13.52, 13.85, 14.14, 53.51, 60.05,
162.24, 169.23; MS 2m/z): 207 2M1).
4.8.5.
.2,2-Bis-methylsufanyl-4-oxo-3-phenoxy-1-yl)-
acetic acid ethyl ester .23e). White crystalline solid;
yield 62%; mp99±100 8C 2Lit.23 mp100±101 8C); [found:
C, 52.53; H, 5.74; N, 4.05; S, 18.92. C15H19NO4S2 requires
C, 52.77; H, 5.61; N, 4.10; S, 18.78]; nmax 2CHCl3) 1749,
1780 cm21; dH 2300 MHz, CDCl3) 1.32 2t, Jˆ7.3 Hz, 3H),
4.7.7. N-[Bis.methylthio)methylene] alanine methyl ester
.22g). Pale yellow oil; yield 74%; [found: C, 40.31; H, 6.59;

2224
D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2.20 2s, 3H), 2.33 2s, 3H), 4.00 2dd, Jˆ17.6 Hz, 2H), 4.25 2q,
Jˆ7.3 Hz, 2H), 5.41 2s, 1H), 7.05±7.40 2m, 5H,); dC
250.3 MHz, CDCl3) 12.76, 13.86, 40.29, 61.76, 80.28,
87.34, 115.61, 122.63, 129.46, 156.78, 162.95, 166.81;
MS 2m/z): 341 2M1).
Acknowledgements
The authors 2D. K. and V. V. G.) thank CSIR for the
®nancial support.
4.8.6. .2,2-Bis-methylsulfanyl-4-oxo-3-phenoxy-1-yl)-a-
methylacetic acid methyl ester .23f). Pale yellow oil;
yield 61%; [found: C, 52.90; H, 5.60; N, 4.10; S, 18.43
C15H19NO4S2 requires C, 52.76; H, 5.61; N, 4.10; S,
18.78]; nmax 2CHCl3) 1747, 1776 cm21; dH 2200 MHz,
CDCl3) 2Mixture of two diastereomers) 1.75 and 1.80 22
d, Jˆ7.4, 7.8 Hz, 3H), 2.22, 2.31, 2.27 and 2.30 24 s, 6H),
3.81 2s, 3H), 4.10 and 4.20 22 q, Jˆ7.4, 7.8 Hz, 2H), 5.32
and 5.36 22 s, 1H), 7.05±7.40 2m, 5H); dC 250.3 MHz,
CDCl3) 13.79, 15.18, 17.91, 50.10, 52.46, 80.39, 88.22,
114.98, 115.79, 122.59, 129.39, 162.33, 169.9; MS 2m/z):
341 2M1).
References
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1996, 553±576.
2. 2a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Synlett 1992, 749±750. 2b) Jayaraman, M.; Nandi, M.; Sathe,
K. M.; Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron:
Asymmetry 1993, 4, 609±612. 2c) Jayaraman, M.; Deshmukh,
A. R. A. S.; Bhawal, B. M. J. Org. Chem. 1994, 59, 932±934.
2d) Jayaraman, M.; Srirajan, V.; Deshmukh, A. R. A. S.;
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4.8.7. .3-Methoxy-2,2-bis-methylsulfanyl-4-oxo-azetidin-
1-yl)acetic acid methyl ester .23g). Pale yellow oil; yield
62%; [found: C, 40.60; H, 5.69; N, 5.28; S, 24.16.
C9H15NO4S2 requires C, 40.74; H, 5.69; N, 5.28; S,
24.17]; nmax 2Neat) 1755, 1778 cm21; dH 2200 MHz,
CDCl3) 2.18 2s, 3H), 2.24 2s, 3H), 3.63 2s, 3H), 3.76 2s,
3H), 4.00 2dd, Jˆ17.6 Hz, 2H), 4.67 2s, 1H); dC
250.3 MHz, CDCl3) 16.10, 17.94, 40.66, 51.91, 58.48,
91.53, 149.09, 162.47, 169.82; MS 2m/z): 265 2M1).
4. Krishnaswamy, D.; Bhawal, B. M.; Deshmukh, A. R. A. S.
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b-lactams, Georg, G. I., Ed.; VCH: New York, 1993; p. 295
and references cited therein.
4.8.8. .3-Methoxy-2,2-bis-methylsulfanyl-4-oxo-azetidin-
1-yl)acetic acid ethyl ester .23h). Colourless oil; yield
60%; [found: C, 42.76; H, 6.32; N, 5.20; S, 23.11.
C10H17NO4S2 requires C, 42.99; H, 6.13; N, 5.01; S,
22.95]; nmax 2Neat) 1747, 1782 cm21; dH 2200 MHz,
CDCl3) 1.28 2t, Jˆ7.3 Hz, 3H), 2.18 2s, 3H), 2.25 2s, 3H),
3.64 2s, 3H), 4.00 2dd, Jˆ17.5 Hz, 2H), 4.20 2q, Jˆ7.3 Hz,
2H), 4.67 2s, 1H); dC 275.4 MHz, CDCl3) 16.17, 18.04,
40.74, 51.94, 58.57, 80.08, 91.77, 149.03, 162.45, 169.81;
MS 2m/z): 279 2M1).
6. 2a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles
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J.; Mukkavilli, L.; Ram, B.; Vencent, J. E. Tetrahedron Lett.
1979, 2771±2774.
8. Bose, A. K.; Kapur, J. C.; Sharma, S. D.; Manhas, M. S.
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4.8.9. 3-Phthalimido-4,4-bis-methylsulfanyl-1-propyl-
azetidin-2-one .23i). White crystalline solid; yield 58%;
mp98±100 8C; [found: C, 54.96; H, 5.05; N, 8.08; S,
18.01. C16H18N2O3S2 requires C, 54.84; H, 5.18; N, 7.99;
S, 18.29]; nmax 2Nujol) 1728, 1774 cm21; dH 2200 MHz,
CDCl3) 1.06 2t, Jˆ7.4 Hz, 3H), 1.80 2m, 2H), 2.11 2s,
3H), 2.23 2s, 3H), 3.30 2m, 2H), 5.43 2s, 1H), 7.70±7.90
2m, 4H); dC 250.3 MHz, CDCl3) 11.43, 13.30, 13.57,
21.62, 42.68, 65.84, 81.20, 123.58, 131.19, 134.35,
160.97, 166.30; MS 2m/z): 335 2M1215).
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835.
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4.8.10.
[3-Phthalimido-2,2-bis-methylsulfanyl-4-oxo-
azetidin-1-yl]-acetic acid ethyl ester .23j). White crystal-
line solid; yield 55%; mp112±113 8C; [found: C, 51.84; H,
4.91; N, 6.80; S, 15.93 C17H18N2O5S2 requires C, 51.76; H,
4.60; N, 7.10; S, 16.26]; nmax 2CHCl3) 1778, 1787 cm21; dH
2200 MHz, CDCl3) 1.32 2t, Jˆ7.3 Hz, 3H), 2.09 2s, 3H),
2.30 2s, 3H), 4.10 2dd, Jˆ17.5 Hz, 2H), 4.25 2q,
Jˆ7.3 Hz, 2H), 5.57 2s, 1H), 7.70±8.00 2m, 4H); dC
250.3 MHz, CDCl3) 12.68, 38.78, 40.51, 41.10, 41.50,
61.68, 65.21, 81.50, 123.14, 123.69, 131.15, 132.00,
133.76, 134.50, 160.86, 164.31, 166.22, 166.81, 167.80;
MS 2m/z): 394 2M1).
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D. Krishnaswamy et al. / Tetrahedron 58ꢀ2002) 2215±2225
2225
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