Synthesis of monocyclic β-lactams via cyclodehydration of β-amino acids using POCl3

Article abstract of DOI:10.1081/SCC-120034168

β-Lactams 2 have been synthesized through a convenient use of POCl₃ via cyclodehydration of β-amino acids 1.

Full text of DOI:10.1081/SCC-120034168

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 10, pp. 1855–1862, 2004
Synthesis of Monocyclic b-Lactams via
Cyclodehydration of b-Amino Acids
Using POCl3
*
S. D. Sharma, R. D. Anand, and Gurpreet Kaur
Department Of Chemistry, Panjab University, Chandigarh, India
ABSTRACT
b-Lactams 2 have been synthesized through a convenient use of POCl3
via cyclodehydration of b-amino acids 1.
Key Words: b-Lactams; Cyclodehydration; b-Amino acids; Amide
bond formation.
INTRODUCTION
Development of newer methods for the construction of appropriately sub-
stituted 2-azetidinones continues unawaited because of their therapeutic
importance. There is resurgence of interest, because, this class of compounds
*
Correspondence: S. D. Sharma, Department Of Chemistry, Panjab University, Chan-
digarh 160 014, India; Fax: þ91172-545074; E-mail: sdsharmapu@yahoo.com.
1855
DOI: 10.1081/SCC-120034168
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Sharma, Anand, and Kaur
can effectively inhibit proteases[1–4] and suppress induced inflammation
in animal lungs.[5] They are also capable of offering protection against
human leukemia, prostrate, and head and neck cancer by inducing DNA
damage.[6]
Among many methods for the construction of b-lactam ring, one of the
most useful ones involves dehydration of b-amino acids using various
reagents. The chemistry began with the use of Grignard reagent[7] followed
by thionyl chloride[8–11] in the presence of weak bases for alkyl and aryl sub-
stituted b-lactams. Later, acetic anhydride,[8] acetyl chloride-PCl5,[12] and
alanes[13] were proposed as cyclizing agents. More recently, b-amino acids
have been converted to b-lactams using an array of reagents like ethylpho-
sphorodichloridate,[14] phenylphosphorodichloridate,[15] methanesulfonyl
chloride,[16] N-alkyl-2-benzothiazolylsulfenamide/Ph3P,[17] phosphorodimor-
pholidic halides,[18] N,N-(diethoxyphosphinyl) benzo-1,2,5-thiazolidine-1,
1-dioxide,[19] and 3,30-(phenylphosphoryl)-bis(1,3-thiazolidine-2-thione).[20]
In this paper, we report the synthesis of b-lactams from b-amino acids
using the easily available and comparatively inexpensive reagent phosphorous
oxychloride (Sch. 1). It is worth mentioning here that the use of POCl3 has
already been demonstrated in our laboratory[21–23] for the preparation of a
wide variety of b-lactam compounds using the [2þ2] cycloaddition reaction
of imines and acetic acids in the presence of triethylamine. Besides this, the
dehydrating properties of POCl3 have also been amply demonstrated by us
in a review article.[21] However, use of this reagent for cyclodehydration of
b-amino acids to the corresponding 2-azetidinones seems to be so far unex-
plored and hence, we are pleased to report our successful attempts in this
direction through this communication.
When b-amino acids 1 were treated with POCl3 in dichloromethane in
the presence of triethylamine at low temperature, cyclization proceeded
smoothly to give high yields of b-lactams 2 (Sch. 1). The structures of
the products were confirmed on the basis of IR and 1H NMR spectral
data. IR spectrum showed the characteristic b-lactam carbonyl absorption
peaks in the range generally found for monocyclic b-lactams as reported
under various references cited herein. It may also be emphasized that these
frequencies come in the higher range for more strained bicyclic b-lactam
compounds such as penicillins and cephalosporins. b-Amino acids 1 (entries
a–i) used in this study were prepared[24] by direct addition of the corre-
sponding amine to the appropriate a,b-unsaturated acid in basic solvent
such as pyridine. The b-phenyl b-amino propionic acid (entry 1j) was
synthesized by interaction of benzaldehyde, malonic acid, and ammonium
acetate.[25] This acid was converted into ethyl b-phenyl b-aminopropionate,
which was benzylated and then hydrolyzed to yield b-phenyl b-(benzyl-
amino) propionic acid[26] (entry 1k).

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Synthesis of b-Lactams by Cyclodehydration Method
1857
Scheme 1.

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Sharma, Anand, and Kaur
The POCl3 mediated amide bond formation[27] proceeds via the activation
of the carboxylic acid function as the mixed anhydride rather than via the acti-
vation of amino group, because, the amine intermediates of POCl3 require
drastic conditions for its initial formation and subsequent participation in
coupling reaction. In view of this, the high yields of the b-lactam ring for-
mation under the present conditions employed can probably be explained
by the role of nitrogen electron pair to provide a six-membered transition
state (3) which in the presence of triethylamine undergoes a facile intramole-
cular amide bond formation reaction as shown (Fig. 1).
In conclusion, we can say that the present method is a versatile procedure
for the construction of b-lactam ring from b-amino acids in terms of its
simplicity and high yields.
EXPERIMENTAL PROCEDURE
Typical Procedure for Cyclodehydration
To a cooled solution (08C) of the b-amino acid (1 mmol), triethylamine
(3 mmol) in methylene chloride (25 mL) was added POCl3 (3 mmol) drop-
wise, and the reaction mixture was stirred overnight at room temperature.
The resulting solution was washed with saturated NaHCO3 (25 mL), brine
(25 mL), and water (25 mL ꢀ 3). Drying over anhydrous Na2SO4 and
evaporation of the solvent yielded the desired b-lactams. (Sch. 1)
1-Benzyl-4-methylazetidin-2-one[28] (2a). Oil (83%); IR: n ¼ 1747cm21
(C55O); 1H NMR (CDCl3): 1.18 (d, J ¼ 6.1 Hz, 3H, CH3), 2.50 (dd, J ¼ 14.5,
2.0 Hz, 1H, C3–H), 3.35 (dd, J ¼ 14.6, 5.0 Hz, 1H, C3–H), 3.55 (m, 1H, C4–
H), 4.07 (d, J ¼ 15.3Hz, 1H, benzylic), 4.55 (d, J ¼ 15.3Hz, 1H, benzylic),
7.26 (m, 5H, C6H5). Anal. Calcd for C11H13NO: C, 75.43; H, 7.43; N, 8.00.
Found: C, 75.15; H, 7.29; N, 7.85.
Figure 1. Intramolecular amide bond formation reaction.

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Synthesis of b-Lactams by Cyclodehydration Method
1859
4-Methyl-1-(2-methylpropyl) azetidin-2-one (2b). Oil (77%); IR:
1
n ¼ 1747 cm21 (C55O); H NMR (CDCl3): 0.85, 0.95 (2 ꢀ d, J ¼ 7.0 Hz,
6H, 2 ꢀ CH3), 1.18 (d, J ¼ 6.1 Hz, 3H, CH3), 2.0 (m, 1H, CH), 2.50 (dd,
J ¼ 14.5, 1.9 Hz, 1H, C3–H), 3.1 (m, 2H, –NCH2), 3.35 (dd, J ¼ 14.6,
5.0 Hz, 1H, C3–H), 3.54 (m, 1H, C–H). Anal. Calcd for C8H15NO: C,
68.09; H, 10.64; N, 9.93. Found: C, 67.89; H, 10.52; N, 9.82.
1-(2-Hydroxyethyl)-4-methylazetidin-2-one (2c). Oil (78%); IR: n ¼
1740cm21 (C55O); 1H NMR (CDCl3): 1.71 (bs, 1H, –OH, D2O exchangeable),
1.18 (d, J ¼ 6.5 Hz, 3H, CH3), 2.50 (dd, J ¼ 14.3, 1.9 Hz, 1 H, C3–H), 3.25
(m, 1H, –NCH2), 3.33 (m, 1H, –NCH2), 3.35 (dd, J ¼ 14.6, 5.0 Hz, 1H, C3–
H), 3.54 (m, 1H, C4–H), 3.82 (m, 2H, –OCH2). Anal. Calcd for C6H11NO2:
C, 55.81; H, 8.53; N, 10.85. Found: C, 55.98; H, 8.16; N, 9.80.
1-Butyl-4-methylazetidin-2-one (2d). Oil (76%); IR: n ¼ 1740 cm21
1
(C55O); H NMR (CDCl3): 1.01 (t, 3H, –CH2CH3), 1.18 (d, J ¼ 6.5 Hz,
3H, CH3), 1.8 (m, 4H, –(CH2)2CH3), 2.50 (dd, J ¼ 14.5, 1.9 Hz, 1H, C3–
H), 3.35 (dd, J ¼ 14.6, 5.0 Hz, 1H, C3–H), 3.4 (m, 2H, –NCH2), 3.54
(m, 1H, C4–H). Anal. Calcd for C8H15NO: C, 68.09; H, 10.64; N, 9.93.
Found: C, 67.88; H, 10.52; N, 9.53.
1-(2-Hydroxypropyl)-4-methylazetidin-2-one (2e). Oil (74%); IR: n ¼
1
1740cm21(C55O); H NMR (CDCl3): 1.15 (d, J ¼ 6.5 Hz, 3H, –CHCH3),
1.22 (d, J ¼ 6.6 Hz, 3H, CH3), 2.50 (dd, J ¼ 14.5, 2.0 Hz, 1H, C3–H), 3.18
(d, J ¼ 6.7 Hz, 2H, NCH2) 3.35 (dd, J ¼ 14.6, 5.0 Hz, 1H, C3–H), 3.54
(m, 1H, C4–H), 4.14 (m, 1H, –CHOH). Anal. Calcd for C7H13NO2: C,
58.74; H, 9.09; N, 9.79. Found: C, 58.78; H, 9.19; N, 9.60.
1-(3-Hydroxypropyl)-4-methylazetidin-2-one (2f). Oil (74%); IR:
1
n ¼ 1744 cm21(C55O); H NMR (CDCl3): 1.18 (d, J ¼ 6.4 Hz, 3H, CH3),
1.71 (m, 2H, –CH2), 2.34 (bs, 1H, OH, D2O exchangeable), 2.50 (dd,
J ¼ 14.5, 1.9 Hz, 1H, C3–H), 3.35 (dd, J ¼ 14.5, 5.0 Hz, 1H, C3–H), 3.43
(m, 2H, –NCH2), 3.54 (m, 1H, C4–H), 3.68 (m, 2H, –OCH2). Anal. Calcd
for C7H13NO2: C, 58.74; H, 9.09; N, 9.79. Found: C, 58.70; H, 8.98; N, 9.95.
1-Benzyl-3-methylazetidin-2-one[29] (2g). Oil (82%); IR: n ¼
1
1747cm21(C55O); H NMR (CDCl3): 1.27 (d, J ¼ 7.2 Hz, 3H, CH3), 2.73
(dd, J ¼ 5.2, 2.1 Hz, 1H, C4–H), 3.15 (m, 1H, C3–H), 3.26 (dd, J ¼ 6.0,
5.2 Hz, 1H, C4–H), 4.30 (d, J ¼ 15.1Hz, 1H, benzylic), 4.45 (d, J ¼ 15.1Hz,
1H, benzylic), 7.29 (m, 5H, C6H5). Anal. Calcd for C11H13NO: C, 75.43; H,
7.43; N, 8.00. Found: C, 76.00; H, 7.39; N, 7.82.
3-Methyl-1-(2-methylpropyl) azetidin-2-one (2h). Oil (78%); IR:
1
n ¼ 1743 cm21(C55O); H NMR (CDCl3): 0.9, 0.99 (2 ꢀ d, J ¼ 7.0 Hz, 6H,
2 ꢀ CH3), 1.27 (d, J ¼ 7.4 Hz, 3H, CH3), 2.05 (m, 1H, CH), 2.73 (dd,
J ¼ 5.2, 2.2 Hz, 1H, C4–H), 3.1 (m, 2H, –NCH2), 3.25 (m, 1H, C3–H),
3.36 (dd, J ¼ 6.0, 5.2 Hz, 1H, C4–H). Anal. Calcd for C8H15NO: C, 68.09;
H, 10.64; N, 9.93. Found: C, 67.79; H, 10.58; N, 9.78.

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Sharma, Anand, and Kaur
1-(2-Hydroxyethyl)-3-methylazetidin-2-one (2i). Oil (79%); IR: n ¼
1
1747 cm21 (C55O); H NMR (CDCl3): 1.27 (d, J ¼ 7.3 Hz, 3H, CH3), 1.71
(bs, 1 H, –OH, D2O exchangeable), 2.73 (dd, J ¼ 5.2, 2.2 Hz, 1 H, C4–H),
3.15 (m, 1H, C3–H), 3.25 (m, 1H, –NCH2), 3.36 (dd, J ¼ 6.0, 5.2 Hz, 1H,
C4–H), 3.43 (m, 1H, –NCH2), 3.82 (m, 2H, –OCH2). Anal. Calcd for
C6H11NO2: C, 55.81; H, 8.53; N, 10.85. Found: C, 55.35; H, 8.47; N, 10.88.
4-Phenylazetidin-2-one[30] (2j). Solid (73%), m.p. 114–1168C; IR:
n ¼ 1778 cm21(C55O); 1H NMR (CDCl3): 2.8 (ddd, J ¼ 1.5, 2.7, 15 Hz,
1H, C3–H), 3.42 (ddd, J ¼ 3.0, 4.5, 15 Hz, 1H, C3–H), 4.73 (dd, J ¼ 2.7,
4.5 Hz, 1H, C4–H), 6.6 (br, 1H, –NH), 7.38 (m, 5H, –C6H5). Anal. Calcd
for C9H9NO: C, 73.47; H, 6.12; N, 9.52. Found: C, 73.05; H, 5.95; N, 9.23.
1-Benzyl-4-phenylazetidin-2-one
(2k). Oil
(79%);
IR:
n ¼
1750cm21(C ¼ O); H NMR (CDCl3): 2.88 (dd, J ¼ 14.6, 2.3 Hz, 1H, C3–
H), 3.35 (dd, J ¼ 14.7, 5.1 Hz, 1H, C3–H), 3.76 (d, J ¼ 15.1Hz, 1H, benzylic),
4.41 (dd, J ¼ 5.2, 2.2 Hz, 1H, C4–H), 4.81 (d, J ¼ 15.0Hz, 1H, benzylic), 7.35
(m, 10H, 2 ꢀ C6H5). Anal. Calcd for C16H15NO: C, 81.01; H, 6.32; N, 5.90.
Found: C, 80.99; H, 6.19; N, 5.98.
1
ACKNOWLEDGMENT
Thanks are due to UGC, New Delhi for providing SRF to one of us (G.K.).
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Received in India December 31, 2003

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