Synthesis of β-lactams: α-chloro and α-cyano β-lactams by condensation of imines with titanium ester enolates derived from chloro and cyano ethyl acetates

Article abstract of DOI:10.1080/00397910500181947

α-Cyano and α-chloro β-lactams are obtained in a one-step reaction at a temperature of less than -78°C by condensation of imines with ester enolates derived from ethyl α-cyano and α-chloro acetates. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500181947

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Synthesis of β‐Lactams:
α‐Chloro and α‐Cyano
β‐Lactams by Condensation
of Imines with Titanium Ester
Enolates Derived from Chloro
and Cyano Ethyl Acetates
Seema Kanwar a & S. D. Sharma a
a Department of Chemistry and Centre of Advanced
Studies in Chemistry , Punjab University ,
Chandigarh, India
Published online: 18 Aug 2006.
To cite this article: Seema Kanwar & S. D. Sharma (2005) Synthesis of β‐Lactams:
α‐Chloro and α‐Cyano β‐Lactams by Condensation of Imines with Titanium Ester
Enolates Derived from Chloro and Cyano Ethyl Acetates, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:16, 2149-2155
To link to this article: http://dx.doi.org/10.1080/00397910500181947
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Synthetic Communicationsw, 35: 2149–2155, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500181947
Synthesis of b-Lactams: a-Chloro and
a-Cyano b-Lactams by Condensation of
Imines with Titanium Ester Enolates
Derived from Chloro and Cyano
Ethyl Acetates
Seema Kanwar and S. D. Sharma
Department of Chemistry and Centre of Advanced Studies in Chemistry,
Punjab University, Chandigarh, India
Abstract: a-Cyano and a-chloro b-lactams are obtained in a one-step reaction at a
temperature of less than 2788C by condensation of imines with ester enolates
derived from ethyl a-cyano and a-chloro acetates.
Keywords: a-Cyano-b-lactams, a-chloro-b-lactams, titanium enolates, ester enolate–
imine condensation
The development of efficient approaches to the stereocontrolled synthesis of
b-lactams continues to be of crucial importance within the context of the
most-employed class of antimicrobial agents, the b-lactam antibiotics.[1–3]
As a result of long-standing interest of b-lactams in medicine, biology, and
chemistry, many approaches to their stereoselective synthesis have been
developed.[4–7] Reaction classes such as metalloester enolate–imine conden-
sations and ketene–imine cycloadditions (Staudinger reaction) are just two
examples that have been used extensively. Direct stereospecific approach
Received in India April 25, 2005
Address correspondence to S. D. Sharma, Department of Chemistry and Centre
of Advanced Studies in Chemistry, Punjab University, Chandigarh 160 014, India.
Tel.: 91-172-2541435; Fax: 91-172-2545074; E-mail: sdsharmapu@yahoo.com
2149

2150
S. Kanwar and S. D. Sharma
could provide a general route to a greater diversity of b-lactams and would
reduce the dependence on other known nonstereospecific methods.
In connection with a series of b-lactams syntheses,[8–13] elaborated in our
laboratory in the past few years, especially with those involving condensation
of lithium ester enolates and imines,[14] we were interested in the condensation
of titanium enolates derived from a-chloro/a-cyano ethylacetates and imines.
For this purpose, the ethyl ester of 2-chloro propanoic acid and 2-cyano
propaonic acid were converted into the corresponding enolates and treated
with Schiff’s base. In the first experiment, ester 1a was transformed with
TiCl4 at 2788C into enolate 2a and on condensation with aryl aldimines
afforded the a-cyano-b-lactam 3a (Table 1, entry 1). Although it had
already been reported[15] that such enolates exist in equilibrium with the
ketene 5 or generate carbene 6 through an elimination process (Scheme 1),
we observed the formation of b-lactams in moderate yields. This can be attrib-
uted to the reactions being performed at 2788C where the titanium ester
enolates are quite stable for the pathway favoring b-lactam formation.
From these results it is clear that enolizable as well as nonenolizable
imines may be used. As the cyclization takes place at a temperature below
2788C, titanium enolates are quite stable with regard to decomposition and
self-condensation. An interesting feature of this reaction is the complete
Table 1. a-Cyano and a-chloro-b-lactams from ester enolate–imine
condensation reaction
Entry
X
R1
R2
R3
3a
3b
3c
3d
3e
3f
CN
CN
CN
CN
CN
CN
Cl
C6H5
C6H4OCH3(p)
piperonyl
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
CH2CH(OH)CH3
CH2CH(OH)CH3
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
C6H4OCH3(p)
CH2CH(OH)CH3
CH2CH(OH)CH3
CH2CH2C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
CH¼CHC6H5
C6H4OCH3(p)
C6H5
3g
3h
3i
C6H5
C6H4OCH3(p)
piperonyl
Cl
Cl
3j
Cl
Cl
CH¼CHC6H5
C6H4OCH3(p)
C6H5
3k
3l
Cl
Cl
3m
C6H4OCH3(p)

Synthesis of b-Lactams
2151
Scheme 1.
absence from the reaction mixture of products containing the aziridine ring 7,
an outcome of a faster addition–elimination reaction (path b) versus the intra-
molecular nucleophilic displacement of the halogen atom (path a), as shown in
Scheme 1. In strong contrast to the previous report,[16] the present trichloro
titanium enolate effected the formation of 3-cyano and 3-chloro-2-azetidinone
in a stereospecific manner. This unprecedented selectivity is quite noteworthy
and can be explained reasonably in terms of the relatively weak ionic but
moderate Lewis acid character of the intermediary titaniumamide 4. Accord-
ingly, preferential attack of titanium amide to the ester part was smoothly
achieved chemoselectively. It can also be argued that the success of this
reaction is the result of the difference in the electrophilicity of carbons of
the titanium enolate involved as well as the stability of the product formed.
Although there is possibility of formation of two isomers, the reaction is
highly cis-stereoselective and no traces of trans isomer were detected. These
facts are consistent with a Zimmerman–Traxler transition state[17] of the
addition of the ester enolate to Schiff’s base, followed by ring closure via
elimination of the acyclic intermediate. In the proposed mechanism, the
geometry of enolate[18] and of the Schiff’s base is assumed to be E.

2152
S. Kanwar and S. D. Sharma
EXPERIMENTAL PROCEDURE
All melting points (mp, 8C) are uncorrected. The FT-IR spectra were recorded
on a Perkin-Elmer model 1430 spectrophotometer and were calibrated against
polystyrene. Only the principal peaks of interest are reported and expressed in
cm21. 1H NMR spectra were recorded on a 300-MHz Bruker AC 300F spec-
trometer. Chemical shifts are expressed as d values (ppm) downfield from
tetramethylsilane (TMS). Elemental analysis (C, H, N) was recorded using
a Perkin-Elmer 2400 (C, H, N) elemental analyzer. Thin-layer chromato-
graphy was performed using TLC-grade silica gel (G) and was developed in
an atmosphere of iodine vapors.
Typical Procedure for Preparation of b-Lactams (3a–3m)
Titanium tetrachloride (0.1 mmol) was added to the appropriate ethyl ester
(0.1 mmol) in dry THF (10 mL) under a nitrogen atmosphere, and the
reaction mixture was cooled to 2788C. After 15 min, triethylamine
(0.11 mmol) was added and stirred for 30 min at 2788C, followed by
addition of Schiff’s base (0.05 mmol) in dry THF (5 mL). The reaction
mixture was stirred for 5–6 h and then at rt overnight, quenched by the
addition of saturated ammonium chloride solution, and filtered. The organic
layer was dried over anhydrous sodium sulphate, filtered, and concentrated
to obtain oily material, which was purified by column chromatography on
silica gel by using ethyl acetate:hexane (20 : 80).
1-(4-Methoxy-phenyl)-2-oxo-4-phenyl-azetidine-3-carbonitrile (3a). Oil
1
(45%); IR: n ¼ 1770 cm21; b-lactam (C55O); H NMR (CDCl3; d/ppm):
3.75 (s, 3H, OCH3), 5.01 (d, 1H, C3H, J ¼ 4.5 Hz), 6.23 (d, 1H, C4H,
J ¼ 4.5 Hz), 6.85–7.51 (m, 9H, ArH). Anal. calcd. for C17H14N2O2: C,
73.38; H, 5.04; N, 10.07. Found: C, 73.05; H, 4.95; N, 10.39.
1,2-Bis-(4-methoxy-phenyl)-4-oxo-azetidine-3-carbonitrile (3b). Oil (48%);
IR: n ¼ 1775cm21; b-lactam (C55O); 1H NMR (CDCl3; d/ppm): 3.79 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 4.96 (d, 1H, C3H, J ¼ 4 Hz), 5.23 (d, 1H, C4H,
J ¼ 4 Hz), 6.72–7.25 (m, 8H, ArH). Anal. calcd. for C18H16N2O3: C, 70.3;
H, 5.19; N, 9.09. Found: C, 70.00; H, 4.99; N, 9.29.
2-Benzo[1,3]dioxol-5-yl-1-(4-methoxy-phenyl)-4-oxo-azetidine-3-carbonitrile
(3c). Oil (36%); IR: n ¼ 1772 cm21; b-lactam (C55O); 1H NMR (CDCl3;
d/ppm): 3.85 (s, 3H, OCH3), 5.11 (d, 1H, C3H, J ¼ 4.3 Hz), 5.25 (d, 1H, C4H,
J ¼ 4.3Hz), 6.16 (s, 2H, OCH2O), 7.12–7.34 (m, 7H, ArH). Anal. calcd. for
C18H14N2O4: C, 67.08; H, 4.35; N, 8.70. Found: C, 66.99; H, 4.15; N, 8.89.
1-(4-Methoxy-phenyl)-2-oxo-4-styryl-azetidine-3-carbonitrile (3d). Solid
(35%), mp 141–1428C; IR: n ¼ 1777 cm21; b-lactam (C55O); 1H NMR

Synthesis of b-Lactams
2153
(CDCl3; d/ppm): 3.73 (s, 3H, OCH3), 4.85 (d, 1H, C3H, J ¼ 4.5 Hz), 5.01 (dd,
1H, C4H, J ¼ 4.5 Hz and 7 Hz), 6.19 (dd, 1H, NCHCH, J ¼ 7 Hz and 15 Hz)
6.53 (d, 1H, CHC6H5, J ¼ 15 Hz), 6.82–7.51 (m, 9H, ArH). Anal. calcd. for
C19H16N2O2: C, 75.00; H, 5.26; N, 9.21. Found: C, 74.89; H, 5.12; N, 9.51.
1-(2-Hydroxy-propyl)-2-(4-methoxy-phenyl)-4-oxo-azetidine-3-carbonitrile
1
(3e). Oil (39%); IR: n ¼ 1760cm21; b-lactam (C55O); H NMR (CDCl3;
d/ppm): 1.21 (d, 3H, CH3), 3.51–3.82 (m, 2H, NCH2), 3.73 (s, 3H, OCH3),
4.02 (m, 1H, CHOH), 4.20 (d, 1H, C3H, J ¼ 3.9 Hz), 4.51 (d, 1H, C4H,
J ¼ 3.9 Hz) 6.91–7.25 (m, 4H, ArH). Anal. calcd. for C14H16N2O3: C, 64.62;
H, 6.15; N, 10.76. Found: C, 64.11; H, 5.89; N, 10.95.
1-(2-Hydroxy-propyl)-2-oxo-4-phenyl-azetidine-3-carbonitrile (3f). Oil
1
(40%); IR: n ¼ 1772 cm21; b-lactam (C55O)]; H NMR (CDCl3; d/ppm):
1.23 (s, 3H, CHCH3), 3.51 (m, 2H, NCH2), 4.21 (m, 1H, CHOH), 4.25
(d, 1H, C3H, J ¼ 4.32 Hz), 4.65 (d, 1H, C4H, J ¼ 4.32 Hz), 7.12–7.34
(m, 5H, ArH). Anal. calcd. for C13H14N2O2: C, 67.83; H, 6.09; N, 12.17.
Found: C, 67.56; H, 5.81; N, 12.35.
3-Chloro-1-(4-methoxy-phenyl)-4-phenyl-azetidin-2-one (3g). Solid (42%),
1
mp 116–1188C; IR: n ¼ 1750cm21; b-lactam (C55O); H NMR (CDCl3;
d/ppm): 3.78 (s, 3H, OCH3), 4.55 (d, 1H, C3H, J ¼ 4.4 Hz), 4.95 (d, 1H,
C4H, J ¼ 4.4 Hz), 6.95–7.45 (m, 9H, ArH). Anal. calcd. for C16H14NO2Cl:
C, 66.78; H, 4.87; N, 4.87. Found: C, 66.52; H, 4.56; N, 4.96.
3-Chloro-1,4-bis-(4-methoxy-phenyl)-azetidin-2-one (3h). Solid (38%),
1
mp 125–1268C; IR: n ¼ 1755 cm21; b-lactam (C55O); H NMR (CDCl3;
d/ppm): 3.75 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.78 (d, 1H, C3H,
J ¼ 4.5 Hz), 5.28 (d, 1H, C4H, J ¼ 4.5 Hz), 6.87–7.51 (m, 8H, ArH). Anal.
calcd. for C17H16NO3Cl: C, 64.25; H, 5.03; N, 4.40. Found: C, 64.11;
H, 4.89; N, 4.61.
4-Benzo[1,3]dioxol-5-yl-3-chloro-1-(4-methoxy-phenyl)-azetidin-2-one (3i).
Solid (37%), mp 140–1428C; IR: n ¼ 1754cm21; b-lactam (C55O); 1H
NMR (CDCl3; d/ppm): 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.52 (d, 1H,
C3H, J ¼ 3.9 Hz), 4.90 (d, 1H, C4H, J ¼ 3.9 Hz), 5.95 (s, 2H, OCH2O),
7.01–7.55 (m, 8H, ArH). Anal. calcd. for C17H17N2O4Cl: C, 60.99; H, 5.08;
N, 4.18. Found: C, 60.78; H, 4.89; N, 4.36.
3-Chloro-1-(4-methoxy-phenyl)-4-styryl-azetidin-2-one (3j). Solid (42%),
;
mp 148–1498C; IR: n ¼ 1760 cm21; b-lactam (C55O); n¼1620 cm21
1
(C ¼ C); H NMR (CDCl3; d/ppm): 3.83 (s, 3H, OCH3), 4.59 (d, 1H, C3H,
J ¼ 4 Hz), 4.89 (dd, 1H, C4H, J ¼ 4 Hz and 6 Hz), 6.19 (dd, 1H, NCHCH,
J ¼ 9 Hz and 14 Hz), 6.53 (d, 1H, CHC6H5, J ¼ 14 Hz), 6.99–7.53 (m, 9H,
ArH). Anal. calcd. for C18H16NO2Cl: C, 68.90; H, 5.10; N, 4.47. Found:
C, 68.61; H, 4.93; N, 4.72.

2154
S. Kanwar and S. D. Sharma
3-Chloro-1-(2-hydroxy-propyl)-4-(4-methoxy-phenyl)-azetidin-2-one (3k).
1
Oil (44%); IR n ¼ 1760cm21; b-lactam (C55O); H NMR (CDCl3; d/ppm):
1.33 (d, 3H, CH3), 2.75 (d, 2H, NCH2, J ¼ 7.5 Hz), 3.35 (m, 1H, CHOH),
3.81 (s, 3H, OCH3), 4.11 (d, 1H, C3H, J ¼ 4.1 Hz), 4.71 (d, 1H, C4H,
J ¼ 4.1 Hz), 6.89–7.05 (m, 4H, ArH). Anal. calcd. for C13H16NO3Cl: C,
57.88; H, 5.93; N, 5.19. Found: C, 57.74; H, 5.81; N, 5.35.
3-Chloro-1-(2-hydroxy-propyl)-4-phenyl-azetidin-2-one (3l). Oil (40%);
1
IR: n ¼ 1756.3 cm21; b-lactam (C55O); H NMR (CDCl3; d/ppm): 1.35
(d, 3H, CH3), 2.92 (d, 2H, CH2N), 3.41 (m, 1H, CHOH), 4.09 (d, 1H, C3H,
J ¼ 4.5 Hz), 4.69 (d, 1H, C4H, J ¼ 4.5 Hz), 6.89–7.25 (m, 5H, ArH). Anal.
calcd. for C12H14NO2Cl: C, 60.13; H, 5.85; N, 5.86. Found: C, 60.09; H,
5.79; N, 5.98.
3-Chloro-4-(4-methoxy-phenyl)-1-phenethyl-azetidin-2-one (3m). Oil (41%);
IR: n ¼ 1752.5 cm21; b-lactam (C55O); 1H NMR (CDCl3; d/ppm): 2.56 (t, 2H,
CH2C6H5), 3.13 (t, 2H, NCH2), 3.82 (s, 3H, OCH3), 4.24 (d, 1H, C3H,
J ¼ 4.5 Hz), 4.59 (d, 1H, C4H, J ¼ 4.5 Hz), 7.21 (m, 9H, ArH). Anal. calcd.
for C18H18NO2Cl: C, 68.46; H, 5.71; N, 4.44. Found: C, 68.61; H, 5.46; N, 4.56.
ACKNOWLEDGMENTS
The authors are grateful to CSIR (New Delhi, India) for financial assistance.
REFERENCES
1. Southgate, R.; Elson, S. Progress in the Chemistry of Organic Natural Products;
Herz, W., Grisebach, H., Kirby, G. W., Tam, C., Eds.; Springer Press: Vienna,
1985; Vol. 47, p. 1.
2. Southgate, R.; Branch, C.; Coulton, S.; Hunt, E. Recent Progress in Chemical
Synthesis of Antibiotics and Related Microbial Products; Lukacs, G., Ed.;
Springer Press: Berlin, 1993; Vol. 2, p. 621.
3. Southgate, R. Contemp. Org. Synth. 1994, 1, 417.
4. Georg, G. I Ed. The Organic Chemistry of b-Lactams; VCH Press: New York,
1993.
5. Kingston, D. I. Chem. Commun. 2001, 867.
6. Hayakawa, R.; Shimizu, M. Chem. Lett. 1999, 591.
7. Diez-Barra, E.; Garcia-Martinez, J. C.; Rodriguez-Lopez, J. Synlett 2003, 1587.
8. Sharma, S. D.; Gupta, P. K. Tetrahedron Lett. 1978, 4587.
9. Sharma, S. D.; Bhaduri, S. J. Chem. Research, Synop. 2001, 321.
10. Sharma, S. D.; Kaur, V.; Saluja, A. Indian J. Chem. 1994, 33B, 624.
11. Sharma, S. D.; Bhaduri, S.; Kanwar, S. Indian J. Chem. 2003, 42B, 3152.
12. Sharma, S. D.; Kanwar, S. Indian J. Chem. 1998, 37B, 965.
13. Kanwar, S.; Saluja, A.; Khurana, J. P.S.; Sharma, S. D. J. Indian Chem. Soc. 2001,
78, 137.

Synthesis of b-Lactams
2155
14. Sharma, S. D.; Saluja, A.; Bhaduri, S.; Kanwar, S. Indian J. Chem. 2002,
41B, 1964.
15. Maryanoff, C. A.; Sorgi, K. L.; Zientek, A. M. J. Org. Chem. 1994, 59, 237.
16. Cainelli, G.; Panunzio, M. Tetrahedron Lett. 1991, 32, 121.
17. Heathcock, C. A.; Buse, C. T.; Kleshick, W. A.; Pirrung, M. C.; Sohn, E. J.;
Lampe, J. J. Org. Chem. 1980, 45, 1066.
18. Cainelli, G.; Panunzio, M.; Basile, T.; Bongini, A.; Giacomini, D.; Martelli, G.
J. Chem. Soc. Perkin Trans. 1 1987, 2637.