Studies towards C-3 functionalization of β-lactams using substituted allylsilanes

Article abstract of DOI:10.1007/s12039-016-1161-6

An effective and stereoselective synthesis of 3-(1^′-methyl/phenylallyl)-3-phenylthio-β-lactams (3/4) using substituted allylsilane and Lewis acid is described. The reaction leads to the formation of a mixture of C-3 substituted allyl β-Lactams.

Full text of DOI:10.1007/s12039-016-1161-6

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1161-6
Studies towards C-3 functionalization of β-lactams using substituted
allylsilanes
RENU THAPARa,∗, RESHMAb and S S BARIc
aU I ET, Panjab University, Chandigarh 160014, India
bD A V College, Sector 10, Chandigarh 160010, India
cDepartment of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh
160014, India
e-mail: renuarorachem_pu@yahoo.co.in
MS received 17 April 2016; revised 1 August 2016; accepted 17 August 2016
Abstract. An effective and stereoselective synthesis of 3-(1ꢁ-methyl/phenylallyl)-3-phenylthio-β-lactams
(3/4) using substituted allylsilane and Lewis acid is described. The reaction leads to the formation of a mixture
of C-3 substituted allyl β-Lactams. However, these compounds on desulphurisation using tri-n-butyltinhydride
and Raney Ni provide two separable diastereomers of the reduced product.
Keywords. Allylsilane; β-Lactams; Lewis acid; desulphurisation; crotylsilane; cinnamylsilane.
1. Introduction
employs the Lewis acid promoted addition of substi-
tuted allylsilane to β-lactam carbocation equivalents of
type 2.
The presence of β-lactam moiety in several widely
used families of antibiotics has stimulated considerable
activity directed at their stereocontrolled synthesis.1
In recent years, various natural monocyclic β-lactams
have been shown to exhibit high antibacterial activ-
ity, suggesting that a suitably substituted monocyclic
β-lactam might perhaps be the minimum requirement
for biological activity. Besides, the ever growing new
applications of β-lactam in various fields ranging from
enzyme inhibition2 to the use of these products as start-
ing materials to develop new synthetic methodology,3,4
justify a renewed interest in these compounds.5,6 In
the β-lactam chemistry, introduction of allyl group at
C-3 is of special interest.7 As olefins are considered
as masked ketones,8 so the allylated β-lactams can
be convenient intermediates for a variety of hetero-
cyclic compounds. A limited number of approaches
to densely functionalized α-allyl-β-lactams have been
reported so far.9 These employ appropriate substrate
having carbonyl functionality at C-3 for their reac-
tions with organometallics in organic as well as aque-
ous media.10 Alternate methods to introduce allyl group
at β-lactam are of immense interest even today. As a
part of our ongoing research and in continuation of
earlier work,11 here we report a methodology capable
of providing 3-substituted allyl/propyl β-lactams. This
2. Experimental
2.1 General Information
Melting points (uncorrected) were determined with
a Thomas-Hoover capillary melting point apparatus.
Infrared spectra (IR) were recorded using Perkin-Elmer
Model 1430 spectrophotometer. Only principal absorp-
1
tion bands of interest are reported in cm−1. H NMR
spectra were recorded using JEOL FT NMR Sys-
tem AL 300 (300 MHz) in the Department of Chem-
istry and Centre of Advance Studies in Chemistry and
BRUKER AVANCE II 400 (400 MHz) in the Sophisti-
cated Analytical Instrumentation Facility (SAIF), Pan-
jab University, Chandigarh. The chemical shift values
are expressed in δ values (ppm) using tetramethylsi-
lane (TMS) as internal standard. The coupling con-
stant J values are given in Hertz (Hz). While reporting
1H NMR data, following abbreviations have been used:
s-singlet; br s-broad singlet; d-doublet; t-triplet; q-
quartet and m-multiplet. Thin layer chromatography
(TLC) was performed using TLC grade silica gel ‘G’
(Acme Synthetic Chemicals). The spots were made
visible by exposing plates to iodine vapor. Column
chromatography was performed with silica gel (Acme
Synthetic Chemicals, 60–120 mesh) and eluted with
ethyl acetate:hexanes mixture unless otherwise stated.
All commercially available compounds or reagents
∗For correspondence

Renu Thapar et al.
were used without further purification. All solvents 21.2, 14.1, 13.8. Analysis: calcd. for C26H24ONSCl: C,
used were of LR grade. Where necessary, the solvents 72.03; H, 5.58; N, 3.23%; Found: C, 72.17; H, 5.67; N,
were distilled and dried prior to use, when this seemed 3.34%.
necessary by standard methods.
2.2c 1-(4ꢁ-Bromophenyl)-3-(1ꢁ-methylallyl)-3-phenyl-
thio-4-phenylazetidin-2-one (3c): Oil; yield 81%; IR
2.2 General procedure for the synthesis of
cis-3-(1ꢁ-methyl/phenylallyl)-3-phenylthio-β-lactams
(3 and 4)
1
νmax (CCl4): 1756.9 (C=O), 1637.5, 1590.9 cm−1; H
NMR (400 MHz, CDCl3): δ 7.14-7.63 (m, 28H, Ph,
both isomers), 6.29–6.40 (m, 1H, for minor isomer),
5.95–6.07 (m, 1H, major isomer), 5.12–5.22 (m, 4H,
both isomers), 5.01 (s, 1H, C4-H, major isomer), 4.98
(s, 1H, minor isomer), 2.64–2.78 (m, 2H, both iso-
mers), 1.35 (d, J = 8.7 Hz, 3H, CH3, major isomer),
1.28 (d, J = 9.6 Hz, 3H, CH3, minor isomer); 13C
NMR (100 MHz, CDCl3): δ 166.4, 166.1, 138.0, 137.4,
136.2, 136.1, 135.5, 135.4, 135.3, 133.2, 133.0, 132.3,
132.2, 130.5, 130.4, 128.8, 128.5, 128.4, 128.2, 128.1,
128.0, 118.9, 118.3, 117.0, 116.9, 116.3, 70.8, 70.1,
60.1, 60.3, 38.2, 37.1, 14.2, 13.7. Analysis: calcd. for
C25H22ONSBr: C, 64.78; H, 4.79; N, 3.02%; Found: C,
To a stirred solution of trans-3-chloro-3-phenylthio-β-
lactam 2 (1 mmol) and crotyl/ cinnamylsilane (2 mmol)
in dry methylene chloride (15 mL) at 0◦C was added
TiCl4 (2 mmol) rapidly under a nitrogen atmosphere.
The resulting solution was stirred for additional 2 h
at the same temperature. The reaction mixture was
quenched with water, extracted with methylene chlo-
ride, washed with 5% NaHCO3 solution, dried over
Na2SO4 and filtered. The residue after solvent evapora-
tion was purified by column chromatography.
2.2a 1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-methylallyl)-3-phenyl- 64.87; H, 4.83; N, 3.10%.
thio-4-phenylazetidin-2-one (3a): Oil; yield 96%; IR
1
νmax (CHCl3): 1752 (C=O), 1636.7, 1512.8 cm−1; H
2.2d 1-Phenyl-3-(1ꢁ-methylallyl)-3-phenylthio-4-phenyl-
NMR (400 MHz, CDCl3): δ 6.74–7.65 (m, 28H, Ph,
both isomers), 6.24–6.39 (m, 1H, minor isomer), 5.95–
6.05 (m, 1H, major isomer), 5.15–5.30 (m, 4H, both
isomers), 5.00 (s, 1H, C4-H, major isomer), 4.97 (s, 1H,
minor isomer), 3.75 (s, 6H, OCH3, both isomers),
2.65–2.80 (m, 2H, both isomers), 1.40 (d, J = 8.8 Hz,
major isomer, 3H), 1.25 (d, J = 9.6 Hz, minor isomer,
3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 165.5,
156.3, 156.2, 138.4, 137.8, 135.4, 135.2, 133.8, 133.7,
130.9, 127.8, 118.6, 117.8, 116.0, 114.5, 114.4, 70.5,
69.9, 60.7, 60.2, 55.2, 38.3, 37.3, 14.3, 13.8. Analysis:
calcd. for C26H25O2NS: C, 75.15; H, 6.06; N, 3.37%;
Found: C, 75.27; H, 6.17; N, 3.42%.
azetidin-2-one (3d): Oil; yield 85%; IR νmax (CHCl3):
1
1757.4 (C=O), 1600.7 cm−1; H NMR (400 MHz,
CDCl3): δ 7.01–7.64 (m, 20H, Ph both isomers), 6.30–
6.42 (m, 1H, minor isomer), 5.95–6.05 (m, 1H, major
isomer), 5.16–5.31 (m, 4H, both isomers), 5.04 (s, 1H,
C4-H, major isomer), 5.01 (s, 1H, C4-H, minor isomer),
2.66–2.81 (m, 2H, both isomers), 1.35 (d, J = 8.7 Hz,
3H, CH3, major isomer), 1.25 (d, J = 9.6 Hz, 3H, CH3,
minor isomer); 13C NMR (100 MHz, CDCl3): δ 166.3,
166.0, 138.2, 137.6, 137.3, 137.2, 135.4, 135.3, 133.6,
133.5, 130.7, 130.6, 129.2, 129.1, 128.7, 128.6, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 124.0, 123.9,
117.9, 116.0, 70.5, 69.8, 60.6, 60.1, 38.4, 37.2, 14.2,
13.9. Analysis: calcd. for C25H23ONS: C, 77.89; H,
6.01; N, 3.63%; Found: C, 77.97; H, 6.10; N, 3.70%.
2.2b 1-(4ꢁ-Methylphenyl)-3-(1ꢁ-methylallyl)-3-phenyl-
thio-4-(4ꢁ-chlorophenyl)azetidin-2-one (3b): Oil; yield
65%; IR νmax (CCl4): 1757.1 (C=O), 1637.2, 2.2e 1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-phenylallyl)-3-phenyl-
1615.2 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.00–7.64 thio-4-phenylazetidin-2-one (4a): Oil; yield 62%; IR
1
(m, 28H, Ph, both isomers), 6.29–6.40 (m, 1H, minor νmax (CCl4): 1754 (C=O) cm−1; H NMR (400 MHz,
isomer), 5.95–6.07 (m, 1H, major isomer), 5.13–5.33 CDCl3): δ 6.95–7.58 (m, 38H, Ph, both isomers), 6.50–
(m, 4H, both isomers), 4.99 (s, 1H, C4-H, major iso- 6.70 (m, 2H, both isomers), 5.20–5.57 (m, 6H, both
mer), 4.96 (s, 1H, C4-H, minor isomer), 2.61–2.81 (m, isomers), 4.15–4.20 (m, 2H, both isomers), 3.98 (s,
2H, both isomers), 2.34 (s, 6H, CH3, both isomers), 3H, OCH3, major isomer), 3.94 (s, 3H, OCH3, minor
1.35 (d, J = 8.8 Hz, CH3, major isomer, 3H), 1.23 (d, isomer); 13C NMR (100 MHz, CDCl3): δ 165.2, 164.8,
J = 9.5 Hz, CH3, minor isomer, 3H); 13C NMR (100 156.2, 156.0, 138.8, 138.4, 136.2, 135.5, 135.4, 135.1,
MHz, CDCl3): δ 165.8, 165.5, 138.1, 137.6, 135.9, 133.8, 130.8, 130.5, 129.7, 128.6, 128.5, 128.4, 128.3,
135.2, 135.1, 135.0, 134.6, 134.5, 133.5, 133.4, 132.4, 128.2, 128.1, 128.0, 118.9, 118.6, 118.4, 114.5, 114.3,
132.2, 130.5, 130.4, 129.8, 129.7, 129.6, 129.5, 129.3, 70.5, 70.1, 61.8, 61.4, 55.1, 55.0, 51.7, 51.2. Analysis:
129.2, 129.1, 129.0, 128.9, 128.8, 128.5, 128.4, 118.0, calcd. for C31H27O2NS: C, 77.95; H, 5.69; N, 2.93%;
117.5, 117.3, 116.2, 70.6, 69.8, 60.1, 59.1, 38.5, 37.2, Found: C, 78.08; H, 5.77; N, 2.99%.

β-lactams using substituted allylsilanes
2.2f 1-(4ꢁ-Methylphenyl)-3-(1ꢁ-phenylallyl)-3-phenyl-
thio-4-(4ꢁ-chlorophenyl)azetidin-2one (4b): Oil; yield
of AIBN. The reaction mixture was refluxed and
progress of the reaction was monitored by TLC. After
completion of reaction, the reaction mixture was cooled
to RT and concentrated under vacuum. The residue was
redissolved in DCM (20 mL) and washed with water.
The residue obtained after evaporation of solvent was
purified by silica gel column chromatography.
1
71%; IR νmax (CCl4): 1761 (C=O) cm−1; H NMR
(400 MHz, CDCl3): δ 7.45–8.00 (m, 36H, Ph, both
isomers), 6.56–6.75 (m, 2H, both isomers), 5.45 (s, 2H,
C4-H, both isomers), 5.23–5.66 (m, 4H, both isomers),
4.17–4.22 (m, 2H, both isomers), 2.54 (s, 3H, CH3,
major isomer), 2.43 (s, 3H, CH3, minor isomer); 13C
NMR (100 MHz, CDCl3)δ 165.2, 164.8, 138.6, 138.2,
136.4, 135.5, 135.2, 135.1, 133.6, 130.7, 130.2, 129.5,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 118.7,
118.5, 118.4, 114.4, 114.1, 70.3, 70.1, 61.9, 61.5, 51.5,
51.3, 21, 20.9. Analysis: calcd. for C31H26ONSCl: C,
75.13; H, 5.29; N, 2.83%; Found: C, 75.18; H, 5.37;
N, 2.90%.
2.3a cis-1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-methylallyl)-4-
phenylazetidin-2-one (5a, 6a): The fast moving
diastereomer 5a was characterized by the following
data: White solid; yield 24%; M.p. 125–127◦C; IR νmax
1
(KBr): 1749 (C=O), 1513 cm−1; H NMR (400 MHz,
CDCl3): δ 7.08–7.29 (m, 9H, Ph), 5.11–5.25 (m, 1H),
5.05 (d, J = 7.6 Hz ,1H), 4.58 (d, J = 12 Hz 1H), 4.25
(d, J = 17 Hz , 1H), 3.69 (s, 3H, OCH3), 3.28-3.35 (m,
1H), 2.23-2.30 (m, 1H), 1.23 (d, J = 6 Hz 3H); 13C
NMR (100 MHz, CDCl3): δ 165.5, 155.8, 140.5, 135.4,
131.4, 128.5, 128.4, 123.2, 118.3, 114.3, 113.9, 59.2,
58.7, 55.1, 34.7, 18.4. Analysis: calcd. for C20H21O2N:
C, 78.14; H, 6.88; N, 4.56%; Found: C, 78.27; H, 6.99;
N, 4.69%.
2.2g 1-(4ꢁ-Bromophenyl)-3-(1ꢁ-phenylallyl)-3-phenyl-
thio-4-phenylazetidin-2-one (4c): Oil; yield 71%;
1
IR νmax (CCl4): 1760 (C=O), 1656 cm−1; H NMR
(400 MHz, CDCl3): δ 7.00–7.98 (m, 38H, Ph, both
isomers), 6.52–6.72 (m, 2H, both isomers), 5.40 (s, 2H,
C4-H, both isomers), 5.20–5.60 (m, 4H, both isomers),
4.17–4.22 (m, 2H, both isomers); 13C NMR (100
MHz, CDCl3): δ 166.4, 166.1, 139.1, 138.7, 136.5,
136.4, 136.3, 136.1, 135.8, 135.7, 135.6, 133.8, 133.0,
132.9, 132.7, 132.5, 131.1, 131.0, 130.6, 130.3, 132.9,
132.7, 132.5, 131.1, 131.0, 130.6, 130.3, 130.2, 130.0,
129.8, 129.5, 129.3, 129.1, 129.0, 128.9, 128.8, 128.7,
128.6, 128.5, 128.3, 128.2, 127.9, 127.7, 120.6, 119.8,
119.7, 119.5, 119.4, 119.2, 118.4, 117.6, 117.4, 71.5,
70.9, 69.4, 62.6, 62.0, 52.4, 51.6. Analysis: calcd. for
C30H24ONSBr: C, 68.56; H, 4.60; N, 2.66%; Found: C,
68.59; H, 4.67; N, 2.73%.
The slow moving diastereomer 6a was characterized
by following data: Solid; yield 54%; M.p. 105–107◦C;
1
IR νmax (KBr): 1749 (C=O), 1513.3 cm−1; H NMR
(400 MHz, CDCl3): δ 7.11–7.36 (m, 9H, Ph), 5.95–6.16
(m, 1H), 5.07 (d, J = 8 Hz ,1H), 4.89–5.02 (m, 2H),
3.72 (s, 3H, OCH3), 3.28–3.35 (m, 1H), 2.20–2.26 (m,
1H), 0.6 (d, J = 4.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 165.0, 155.9, 140.2, 135.5, 131.4, 128.7,
128.5, 128.3, 127.9, 127.5, 126.9, 118.3, 114.4, 114.3,
60.6, 58.5, 55.1, 34.3, 17.6.
2.3b cis-1-Phenyl-3-(1ꢁ-methylallyl)-4-phenylazetidin-
2-one (5d, 6d): The fast moving diastereomer 5d was
characterized by following data: White solid; yield
28%; M.p. 86–88◦C; IR νmax (KBr): 1750 (C=O),
2.2h 1-Phenyl-3-(1ꢁ-phenylallyl)-3-phenylthio-4-
phenylazetidin-2-one (4d): Oil; yield 70%; IR νmax
(CCl4): 1755 (C=O) cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.00–7.90 (m, 40H, Ph, both isomers),
6.60 (m, 2H, both isomers), 5.49 (s, 2H, C4-H, both
isomers), 5.18–5.68 (m, 4H, both isomers), 4.16 (m,
2H, both isomers); 13C NMR (100 MHz, CDCl3): δ
166.8, 166.4, 160.8, 140.0, 138.9, 137.2, 136.5, 135.9,
135.7, 134.3, 138.7, 131.5, 131.3, 131.2, 130.5, 130.3,
122.5, 121.9, 121.5, 121.4, 117.5, 117.1, 80.7, 71.2,
70.8, 69.5, 62.5, 62.2, 52.3, 52.0. Analysis: calcd. for
C30H25ONS: C, 80.50; H, 5.63; N, 3.13%; Found: C,
80.55; H, 5.69; N, 3.23%.
1
1512 cm−1; H NMR (400 MHz, CDCl3): δ 6.86–7.24
(m, 10H, Ph), 5.05–5.15 (m, 1H), 5.03 (d, J = 7.6
Hz, 1H), 4.54 (d, J = 12 Hz, 1H), 4.20 (d, J = 17.2
Hz, 1H), 3.26–3.32 (m, 1H), 2.22–2.27 (m, 1H), 1.17
(d, J = 6 Hz), 3H); 13C NMR (100 MHz, CDCl3): δ
166.1, 140.8, 140.4, 139.8, 137.7, 135.1, 129.2, 129.1,
129.0, 128.4, 128.3, 123.2, 128.1, 126.1, 126.0, 123.4,
117.1, 116.9, 115.5, 113.9, 65.1, 59.1, 58.6, 34.6, 18.4.
Analysis: calcd. for C19H19ON: C, 82.26; H, 6.90; N,
5.05%; Found: C, 82.32; H, 6.97; N, 5.11%.
The slow moving diastereomer 6d was characterized
by following data: White solid; yield 56%; M.p. 126–
1
128◦C; IR νmax (KBr): 1750 (C=O), 1514 cm−1; H
2.3 General procedure for n-Bu3SnH reduction
NMR (400 MHz, CDCl3): δ 6.87–7.30 (m, 9H, Ph),
To a solution of 3/4 (1 mmol) in dry toluene (10 mL) 5.93–6.06 (m, 1H), 5.10 (d, J = 8 Hz, 1H), 4.84–5.07
were added n-Bu3SnH (1 mmol) and catalytic amount (m, 2H), 3.26–3.33 (m, 1H), 2.23–2.28 (m, 1H), 0.56

Renu Thapar et al.
(d, J = 4.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
2.4 General procedure for Raney-Ni reduction
165.70, 140.1, 137.8, 135.2, 129.0, 128.7, 128.6, 127.8,
123.6, 117.1, 114.4, 60.5, 58.4, 34.3, 17.6.
To a suspension of Raney–Ni (15 mmol, 100% acti-
vated) in dry ethanol (20 mL) was added 3/4 (1 mmol).
The suspension was refluxed for 1 h. The progress of
reaction was checked by TLC. After disappearance
of spot for the starting substrate and appearance of
a new spot, suspension was filtered and solvent was
evaporated in vacuo, extracted with methylene chloride
(3 × 20 mL) and dried over anhydrous Na2SO4. The
residue so obtained was purified by silica gel column
chromatography.
2.3c cis-1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-phenylallyl)-4-
phenylazetidin-2-one (7a, 8a): The fast moving
diastereomer 7a was characterized by following data:
Solid; yield 49%; M.p. 112–114◦C; IR νmax (KBr):
1745 (C=O), 1515 cm−1; 1H NMR (400 MHz, CDCl3):
δ 6.53–7.29 (m, 14H, Ph), 6.25–6.27 (m, 1H), 5.05 (d,
J = 5 Hz, 1H), 4.98 (d, J = 5.4Hz , 1H), 4.62–4.68
(m, 1H), 4.04–4.10 (m, 1H), 3.70 (s, 3H), 3.36–3.40
(m, 1H);13C NMR (100 MHz, CDCl3): δ 165, 156.1,
137.8, 137.4, 136, 135.5, 135.4, 135.1, 133.5, 130.4,
130.2, 129.5, 128.6, 128.2, 128.7, 128.3, 128.2, 128.1,
128.0, 118.8, 118.6, 118, 114.5, 114.2, 61, 60, 55.1,
50. Analysis: calcd for C25H23O2N: Calcd. C, 81.27; H,
6.27; N, 3.79%; Found: C, 81.38; H, 6.39; N, 3.89%.
The slow moving diastereomer 8a was characterized
by following data: Solid; yield 25%; M.p. 182–184◦C;
IR νmax (KBr): 1749 (C=O), 1512 cm−1; 1H NMR (400
MHz, CDCl3): δ 6.66–7.27 (m, 14H, Ph), 5.47-5.59 (m,
1H), 5.18 (d, J = 8 Hz, 1H), 4.74-4.78 (m, 1H), 4.46-
4.52 (m, 1H), 3.96–4.02 (m, 1H), 3.69 (s, 3H), 3.36–
3.38 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 165.2,
156.0, 138.8, 138.4, 136.2, 135.5, 135.4, 135.1, 133.8,
130.8, 130.5, 129.7, 128.6, 128.5, 128.4, 128.3, 128.2,
128.1, 128.0, 118.9, 118.6, 118.4, 114.5, 114.3, 61.2,
60.5, 55.0, 51.5.
2.4a cis-1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-methylpropyl)-4-
phenylazetidin-2-one (9a): Oil; yield 100%; IR νmax
1
(CCl4): 1745.6 (C=O) cm−1; H NMR (400 MHz,
CDCl3): δ 6.67–7.35 (m, 9H, Ph), 5.04 (d, J = 8 Hz,
1H), 3.69 (s, 3H), 3.00–3.20 (m, 1H), 1.06 (d, J = 6
Hz, 3H), 0.84 (t, J = 10 Hz, 2H), 0.60–0.70 (m, 1H),
0.40–0.50 (m, 3H); 13C NMR (100 MHz, CDCl3): δ
166.1, 155.7, 135.6, 131.4, 129.1, 128.6, 128.3, 127.8,
127.2, 125.9, 118.2, 117.7, 114.2, 60.8, 60.1, 58.6,
55.1, 31.6, 31.5, 27.5, 26.7, 16.9, 16.7, 10.7. 10.4.
Analysis: calcd. for C20H23O2N: C, 77.63; H, 7.49; N,
4.52%; Found: C, 77.77; H, 7.62; N, 4.61%.
2.4b cis-1-Phenyl-3-(1ꢁ-methylpropyl)-4-phenylazetidin-
2-one (9d): Oil; yield 80%; IR νmax (CCl4): 1745
1
(C=O) cm−1; H NMR (400 MHz, CDCl3): δ 6.80–
7.25 (m, 10H, Ph), 5.00 (d, J = 8 Hz, 1H), 3.00–3.23
(m, 1H), 1.00 (d, J = 6 Hz, 3H), 0.74 (t, J = 10 Hz,
2H), 0.60–0.71 (m, 1H), 0.41–0.50 (m, 3H); 13C NMR
(100 MHz, CDCl3): δ 166, 135.4, 131.2, 129.4, 128.5,
128.2, 127.5, 127.2, 125.7, 118.2, 117.6, 114.5, 60.6,
60.2, 58.4, 55, 31.7, 31.5, 27.4, 26.5, 16.6, 16.5, 10.8.
10.5. Analysis: calcd. for C19H20ON: C, 81.96; H, 7.24;
N, 5.03%; Found: C, 81.99; H, 7.30; N, 5.13%.
2.3d cis-1-Phenyl-3-(1ꢁ-phenylallyl)-4-phenylazetidin-
2-one (7d, 8d): The fast moving diastereomer 7d was
characterized by following data: Oil; yield 44%; IR
1
νmax (CCl4): 1750 (C=O), 1512 cm−1; H NMR (400
MHz, CDCl3): δ 6.97–7.30 (m, 15H, Ph), 6.27–6.29
(m, 1H), 5.03 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 5 Hz,
1H ), 4.65–4.70 (m, 1H), 4.04–4.10 (m, 1H), 3.35–3.40
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 166.8, 139.0,
138.6, 137.1, 136.5, 135.8, 135.7, 134.1, 132.7, 131.5, 2.4c cis-1-(4ꢁ-Methoxyphenyl)-3-(1ꢁ-phenylpropyl)-4-
131.1, 131.0, 130.5, 130.2, 122.2, 121.7, 121.6, 121.3, phenylazetidin-2-one (10a, 11a): The fast moving
117.3, 117.1, 61.7, 60.5, 51.0. Analysis: calcd. for diastereomer 10a was characterized by following data:
C24H21ON: Calcd C, 84.91; H, 6.24; N, 4.13%; Found: Oil; yield 32%; IR νmax (CCl4): 1745.3 (C=O) cm−1;
C, 84.97; H, 6.30; N, 4.19%.
1H NMR (400 MHz, CDCl3): δ 6.35–7.21 (m, 14H,
The slow moving diastereomer 8d was characterized Ph), 4.83 (d, J = 7.6 Hz, 1H), 3.86 (dd, J = 8, 16 Hz,
by following data: Solid; yield 29%; M.p. 153–160◦C; 1H), 3.63 (s, 3H), 2.40–2.49 (m, 1H), 2.24–2.32 (m,
IR νmax (KBr): 1752 (C=O), 1513 cm−1; 1H NMR (400 1H), 1.40–1.50 (m, 1H), 0.55 (t, J = 10 Hz, 3H); 13C
MHz, CDCl3): δ 6.45–7.32 (m, 10H, Ph), 5.43–5.52 (m, NMR (100 MHz, CDCl3): δ 165.9, 155.8, 141.5, 135.0,
1H), 5.22 (d, J = 8 Hz, 1H), 4.73–4.77 (m, 1H), 4.45– 131.3, 129.1, 128.7, 128.4, 128.2, 128.1, 127.8, 127.7,
4.51 (m, 1H), 3.95–4.02 (m, 1H), 3.35–3.37 (m, 1H); 127.5, 127.0, 125.9, 118.3, 118.1, 114.3, 114.2, 65.9,
13C NMR (100 MHz, CDCl3): δ 166.2, 139.0, 138.4, 59.3, 58.3, 55.1, 47.1, 44.4, 27.9, 26.0, 12.3, 11.3.
137, 136.2, 135.8, 135.2, 134.4, 132.7, 131.7, 131.3,
The slow moving diastereomer 11a was character-
131.0, 130.8, 130.6, 122.4, 121.5, 121.3, 121.1, 117.2, ized by following data: Solid; yield 45%; M.p. 187–
1
117, 61.9, 60.2, 51.3.
189◦C; IR νmax (KBr): 1746.1 (C=O) cm−1; H NMR

β-lactams using substituted allylsilanes
(400 MHz, CDCl3): δ 6.72–7.40 (m, 14H, Ph), 5.23 of the same methodology employing the use of sub-
(d, J = 7.6 Hz, 1H), 3.82–3.88 (m,1H), 2.40–2.52 (m, stituted silanes. The starting substrates for Lewis acid
1H), 1.34–1.40 (m, 2H), 0.39 (t, J = 9.6 Hz, 3H) ; 13C mediated C-3 functionalization, i.e., trans-3-chloro-
NMR (100 MHz, CDCl3): δ 165.5, 155.7, 141.3, 135.0, 3-phenylthio-β-lactams 2 were prepared by reacting
131.3, 128.6, 128.3, 128.2, 127.6, 126.5, 118.2, 114.2, phenylthioacetyl chloride or potassium phenylthioac-
60.0, 58.9, 55.3, 44.4, 27.8, 11.2. Analysis: calcd. for etate with Schiff base in the presence of a triethylamine8
C25H25O2N: C, 81.83; H, 6.78; N, 3.77%; Found: C, and phoshphorus oxychloride, followed by stereospe-
81.95; H, 6.90; N, 3.89%.
cific chlorination9,10 at C-3 using SO2Cl2 (Scheme 1).
Two silanes, namely, crotylsilane and cinnamylsi-
lane have been used for this study. It was envisaged
that use of cinnamylsilane may lead to the forma-
tion of 3-(3ꢁ-phenylallyl) β-lactams very similar to bio-
logically active ezetimibe (Zeita). Similarly, the use
of crotyl silane could provide 3-(3ꢁ-methylallyl) β-
lactams, another type of densely functionalized β-
lactams. The studies were initiated with preparation
of substituted silanes which were prepared by cou-
pling reactions of Grignard reagent of the correspond-
ing halide with chlorotrimethylsilane according to the
procedure reported in literature.14
The reaction of crotyl magnesium chloride with
chlorotrimethylsilane resulted in the formation of
mixture of trans- and cis-crotyltrimethylsilanes and
trimethyl-α-methylallylsilanes in the ratio 80:20. How-
ever, the reaction of cinnamyl chloride with magnesium
and trimethylsilylchloride resulted in the formation
of only trans-cinnamyltrimethylsilane with a trace of
cis-isomer. These silanes were purified by distillation.
However, these silanes could not be fractionated and
were used for further reaction as such. The structures of
these silanes were confirmed by comparison of 1H-NMR
data of products with the reported data in literature
(Schemes 2 and 3).14
2.4d cis-1-Phenyl-3-(1ꢁ-phenylpropyl)-4-phenylazetidin-
2-one (10d, 11d): The fast moving diastereomer 10d
was characterized by following data: Oil; yield 39%;
IR νmax (CCl4): 1745.3 (C=O) cm−1; H NMR (400
1
MHz, CDCl3): δ 6.36–7.25 (m, 15H, Ph, both isomers),
4.87 (d, J = 7.6 Hz, 1H), 3.86 (dd, J = 8, 16 Hz,
1H), 2.41–2.50 (m, 1H), 2.25–2.33 (m, 1H), 1.41–1.51
(m, 1H), 0.54 (t, J = 10 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 166.5, 141.5, 137.7, 134.9, 129.2,
129.0, 128.9, 128.7, 128.4, 128.3, 127.9, 127.8, 127.5,
127.1, 126.0, 125.9, 123.6, 117.2, 117.1, 116.9, 59.4,
58.3, 47.1, 44.4, 27.9, 27.0, 11.3. Analysis: calcd. for
C24H23ON: C, 84.41; H, 6.79; N, 4.10%; Found: C,
84.45; H, 6.84; N, 4.15%.
The slow moving diastereomer 11d was character-
ized by following data: Solid; yield 64%; M.p. 173–
175◦C; IR νmax (KBr): 1745 (C=O) cm−1; H NMR
1
(400 MHz, CDCl3): δ 6.90–7.37 (m, 15H, Ph), 5.21 (d,
J = 7.6 Hz, 1H), 3.82–3.87 (m, 1H), 2.42–2.53 (m,
1H), 1.35–1.42 (m, 2H), 0.40 (t, J = 9.6 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): δ 166.2, 141.0, 137.0, 134.7,
128.2, 127.8, 127.6, 126.9, 126.4, 122.7, 116.2, 59.6,
57.7, 30.8, 26.8, 15.9, 9.6.
3. Results and Discussion
3.1 Studies using crotylsilanes
It has been previously reported that exposure of trans-
3-chloro-3-phenylthio-β-lactams and allylsilane to a Initial studies were carried out using crotyl silanes
Lewis acid promotes a facile and stereoselective C-3 as the nucleophile. Treatment of trans-3-chloro-3-
allylation to give cis-3-allyl-3-phenylthio-β-lactams in phenylthio-β-lactam 2a with crotyl silanes in the pres-
excellent yield.11 13 The present work is an extension ence of TiCl4 at 0◦C in CH2Cl2 was monitored by
11
H
H
PhS
O
R1
R2
PhS
H
1
PhS
O
H
R
O
P
+
Cl
Cl
Base
(Et3N)
+
C
O
:
N
OK
H
N
Cl
1
R2
R1
H
PhS
R1
R2
Cl
H
PhS
O
0oC
+
SO2Cl2
N
N
O
R2
1
2
Scheme 1. Synthesis of starting compounds-3-phenylthioazetidin-2-ones 1 & 3-chloro-3-phenylthioazetidin-2-ones 2.

Renu Thapar et al.
MgCl
Dry Ether
H3C
Cl
H3C
Mg
+
0oC
(CH3)3SiCl
0oC
Si(CH3)3
Si(CH3)3
Si(CH3)3
H3C
+
+
H3C
CH3
Scheme 2. Synthesis of crotyl silanes.
Cl Dry Ether
(CH3)3SiCl
0oC
Si(CH3)3
Ph
Ph
MgCl
Ph
Mg
0oC
Scheme 3. Synthesis of cinnamyl silanes.
Table 1. Preparation of 3-(1ꢁ-methylallyl)-3-phenylthioazetidin-2-ones 3a–d.
Entry
3
R1
R2
Diastereomeric ratio
Yielda (%)
1
2
3
4
a
b
c
C6H5
C6H4Cl(4)
C6H5
C6H4(OMe)(4)
C6H4(Me)(4)
C6H4Br(4)
C6H5
1 : 1
1.33 : 1
1.14 : 1
1.23 : 1
96.15
64.5
80.6
85
d
C6H5
aIsolated yields were determined after work up and chromatographic purification
CH3
H
Cl
H
N
Si(CH3)3
H3C
R1
R1
PhS
PhS
TiCl4
+
0oC
+
Si(CH3)3
N
3
2
R2
O
R2
Scheme 4. Synthesis of 3-α-methylallyl-β-lactams 3.
O
CH3
TLC. The reaction mixture showed the appearance of chromatography, since both isomers showed a single
1
single spot having Rf slightly higher than that of the spot and same Rf in TLC. The comparison of H
1
substrate. The H NMR of the crude product indi- NMR data of this compound with that of cis-3-allyl-3-
cated the formation of 3-(1ꢁ-methylallyl) β-lactams 3 phenylthio-β-lactam,11 whose stereochemistry has been
instead of the expected 3-(3ꢁ-methylallyl) β-lactams. assigned based on X-ray crystallographic data, hinted
This upon purification and complete structural analy- the same stereochemical placement of allyl group at
sis confirmed the formation of compound 3 as mix- C-3. However, as this compound itself could not be
ture of two diastereomers. The diasteromeric ratio was crystallized, so no concrete proof of its stereochemistry
determined by comparing peak area/integral values of can be given. From the types of product obtained, it
multiplet of Cꢁ2–H of attached allyl group which res- can be inferred that in this reaction, out of two isomeric
onated at different chemical shifts δ 6.24–6.39 (minor silanes, only the major one i.e., crotyl silane was found
isomer), 5.95–6.05 (major isomer). But these iso- to be reacting. The reaction was found to be general and
meric diastereomers could not be separated by column results are summarized in Table 1 (Scheme 4).

β-lactams using substituted allylsilanes
stereochemical placement of allyl group could not be
3.2 Studies using cinnamylsilanes
assigned based on this data alone (Scheme 5, Table 2).
The transformation of trans-3-chloro-3-phenylthio-
β-lactam 2 into 3-(1ꢁ-methyl/phenylallyl)-3-phenyl-
thio-β-lactams seems to proceed via intermediate
formed by addition of C-3 carbocation to double bond
facilitating the cleavage of C-Si bond for formation of
vinyl bond in the product as shown below (Scheme 6).
Next, the reaction of 2 with cinnamylsilane under
similar conditions was studied. This reaction also
resulted in formation of the product arising from
allylic shift, namely, 3-(1ꢁ-phenylallyl)-3-phenylthio-β-
lactams. The product of this reaction, 4 was also found
to be a mixture of two inseparable diastereomers, as
1
detected by H NMR spectrum of the crude product.
However, the diastereomeric ratio was obtained from
integration of protons of the substituent attached to the
3.3 Desulphurization studies
benzene ring as all other protons of the two diastere- Further, to prove the synthetic potential of this reaction and
omers resonated at same value of chemical shift. The versatility of the products, all C-3-substituted-β-lactams
Ph
Cl
H
N
H
PhS
R1
PhS
R1
TiCl4
Si(CH3)3
Ph
+
0oC
N
2
4
R2
R2
O
O
Scheme 5. Synthesis of 3-α-phenylallyl-β-lactams 4.
Table 2. 3-(1ꢁ-phenylallyl)-3-phenylthioazetidin-2-ones, 4a–d.
Entry
4
R1
R2
Diastereomeric ratio
Yielda (%)
1
2
3
4
a
b
c
C6H5
C6H4Cl(4)
C6H5
C6H4(OMe)(4)
C6H4(Me)(4)
C6H4Br(4)
C6H5
1.6 : 1
1.5 : 1
62
71
71
70
–
–
d
C6H5
aIsolated yields were determined after work up and chromatographic purification
R
Cl
H
N
H
N
PhS
R1
R1
PhS
TiCl4
0oC
Si(CH3)3
R
+
R = CH3 / Ph
2
R2
O
3/4
R2
O
R
SPh
H
N
R1
(H3C)3Si
R2
O
Scheme 6. Plausible reaction pathway for transformation of substrate 2 to product 3/4.

Renu Thapar et al.
R
H
R1
PhS
Raney Ni
EtOH
n-Bu3SnH, AIBN
Benzene
N
3/4
R2
R = CH3 / Ph
O
R
R
R
R
H
H
N
H
H
N
H
H
N
H
H
N
R1
R2
R1
R2
R1
R2
R1
R2
+
O
O
O
O
10 (R = Ph, fast moving isomer) +
11 (R = Ph, slow moving isomer on TLC)
5 (R = CH3) / 7 (R = Ph)
fast moving isomer on TLC
9 (R = CH3) non-separable
mixture of diastereomers
6 (R = CH3) / 8 (R = Ph)
slow moving isomer on TLC
Scheme 7. Desulphurisation reactions of substrate 3 and 4.
Table 3. Reduction of 3 and 4 using n-Bu3SnH.
bond. Treatment of cis-3-α-methylallyl-β-lactams, 3
with Raney Nickel gave cis-3-α-methylpropyl-β-
lactams 9, whose two diastereomers were inseparable
on TLC and column chromatography. But reaction of 4
with Raney Nickel gave two separable diastereomers of
the product cis-3-α-phenylpropyl-β-lactam, 10 and 11
(Table 4).
Entry
Substrate
Product
Yielda (%)
1
2
3
4
3a
3d
4a
4d
5a, 6a
5d, 6d
7a, 8a
7d, 8d
56, 24
55, 27
49, 25
44, 29
aIsolated yields were determined after work up and chro-
matographic purification.
4. Conclusions
Table 4. Reduction of 3 and 4 using Raney Ni.
In summary, this research work provides a facile and
stereoselective method for the synthesis of cis-3-(1ꢁ-
methyl/phenylallyl)-β-lactams. Although these reactions
could not give the desired products, they have resulted
in the synthesis of new 3-substituted-allyl β-lactams.
Further, reduction using different reagents provides an
easy access to two diastereomers of the products, which
as such were unseparable. The synthetic potential of
these compounds is under research in our lab.
Entry
Substrate
Product
Yielda (%)
1
2
3
4
3a
3d
4a
4d
9a
9d
10a, 11a
10d, 11d
100
80
33, 46
31, 64
aIsolated yields are determined after work up and chromato-
graphic purification.
were subjected to desulphurization reaction. Reduction
of 3 using n-Bu3SnH (1 equiv.) in benzene catalysed by
Azobisisobutyronitrile (AIBN) gave reduced product
cis-3-α-methylallyl-β-lactams 5 and 6. Interestingly,
both the isomers of this reduced product were easily
separable by column chromatography. The reduction
reaction of 4 using the same reagent gave separable
isomers of the reduced products, cis-3-α-phenylallyl-
β-lactams 7 and 8. The stereochemistry at C-3 of
these products was confirmed by the coupling constant
between C3-H and C4-H. However, the relative stereo-
chemistry of the α-group of the allyl substituent to these
isomers could not be assigned on the basis of spectro-
scopic data alone. So, the two isomers were named as
‘slow moving’ and ‘fast moving’ diastereomers based
on their Rf values in TLC profile (Scheme 7, Table 3).
Reduction using Raney Nickel resulted in desulphuri-
sation accompanied by hydrogenation of the double
Supplementary Information (SI)
All additional information pertaining to characteriza-
tion of the representative compounds (3a, 4a, 5a, 6a,
7a, 8a, 9a, 10a and 11a) using 1H NMR and 13C NMR
techniques (Figures S1–S8) are given in the supporting
information. Supplementary Information is available at
www.ias.ac.in/chemsci.
Acknowledgements
We gratefully acknowledge the financial support for this
work from TEQIP-II, UIET, P.U. Chandigarh, India.
References
1. Ojima I 1993 In The Organic Chemistry of β-Lactams
G I George (Ed.) (New York: VCH) p.197

β-lactams using substituted allylsilanes
2. Mascaretti O A, Boschetti C E, Danelon G O, Mata E G
(d) Banik B K, Manhas M S and Bose A K 1995 J. Org.
Chem. 59 4714
and Roveri O A 1995 Current Med. Chem. 1 441
3. Hatanaka N, Abe R and Ojima I 1981 Chem. Lett.
10 1297
4. O’Boyle N, Carr M, Greene L, Bergin O, Nathwani S,
McCabe T, Lloyd D, Zisterer D and Meegan M 2010
J. Med. Chem. 53 8569
5. Sandauayaka V P, Prashad A S, Yang Y, Williamson
R T, Lin Y I and Mausour T S 2003 J. Med. Chem. 46
2569
6. (a) Manhas M S, Banik B K, Mathur A, Vincent J E and
Bose A K 2000 Tetrahedron 56 5587; (b) Bose A K,
Mathur C, Wagle D R and Manhas M S 2000 Tetrahe-
7. Hanessian S and Alpegiani M 1989 Tetrahedron 45 941
8. Tsuji J 1984 Synthesis 369
9. Jayaraman M, Manhas M S and Bose A K 1997 Tetra-
hedron Lett. 38 709
10. Paquette L A, Rothhaar R R, Isaac M, Rogers L M and
Rogers R D 1998 J. Org. Chem. 63 5463
11. Bari S S, Venugopalan P and Arora R 2003 Tetrahedron
Lett. 44 895
12. Arora R, Venugopalan P and Bari S S 2010 J. Chem. Sci.
122 125
13. Reshma Arora R, Hundal G, Bhalla A and Bari S S 2015
J. Chem. Sci. 127 1957
dron 56 5603; (c) Ojima I 1995 Acc. Chem. Res. 28 383; 14. Slutsky J and Kwart H 1973 J. Am. Chem. Soc. 95 8678