Synthesis of novel spiro-β-lactams

Article abstract of DOI:10.1007/s12039-010-0013-z

A new synthetic approach for spiro-β-lactams by cyclization of cis-3-allyl-3-benzylthio-βlactams is presented. The reaction involves step-wise electrophilic addition-dealkylation sequence giving stereospecific synthesis of C-3-spiro-β-lactams. Indian Acad

Full text of DOI:10.1007/s12039-010-0013-z

J. Chem. Sci., Vol. 122, No. 2, March 2010, pp. 125–135. © Indian Academy of Sciences.
Synthesis of novel spiro-β-lactams
RENU ARORA, P VENUGOPALAN and S S BARI*
Department of Chemistry and Centre of Advanced studies in chemistry, Panjab University,
Chandigarh 160 014
e-mail: ssbari@pu.ac.in
MS received 30 April 2009; revised 12 November 2009; accepted 26 November 2009
Abstract. A new synthetic approach for spiro-β-lactams by cyclization of cis-3-allyl-3-benzylthio-β-
lactams is presented. The reaction involves step-wise electrophilic addition-dealkylation sequence giving
stereospecific synthesis of C-3-spiro-β-lactams.
Keywords. β-lactams; spiro; halogen-mediated cyclization; electrophilic; episulfonium ion.
1. Introduction
tance of spiro-β-lactams, we extended our work on
9
C-3 allylation of β-lactams to the synthesis of
Since β-lactam antibiotics are a group of drugs of
unparallel importance in chemotherapy, consider-
able efforts have been made in the development of
novel and biologically more active compounds. The
search for improved antibiotics also includes design-
ing of new methodology for the total synthesis as
well as the semi-synthesis of β-lactam derivatives.
Recently, spiro-β-lactams have become centre of
attraction for many reasons. Primarily this is due to
spiro-β-lactams using halocyclization. The reaction
employs intramolecular addition of nucleophilic sul-
phur to carbon–carbon double bond of allyl group
of
cis-3-allyl-3-phenylthio/benzylthio-azetidin-2-
ones (5/6) in the presence of Br2 or I2 as electro-
10
philic reagent. The reaction proceeds through a
step-wise electrophilic attack and dealkylation se-
quence giving C-3 spiro-β-lactams, 7-halo-5-thia-2-
azaspiro[3,4]octan-1-ones. Since, such type of spiro-
β-lactams are not easily accessible by classical ke-
tene-imine cycloaddition, this reaction serves as an
operationally simple, efficient and better metho-
1 2
their antiviral and antibacterial properties. In addi-
tion, it has been reported that these spiro-β-lactams
3
also acting as cholesterol absorption inhibitors (CAI),
making them potentially useful compounds for de-
velopment of drugs for lowering the high level of
cholesterol. More recently the enzymatic cleavage of
the amyloid precursor protein responsible for the
pathogenesis of Alzheimer’s disease has also been
4
shown to be coupled with cholesterol regulation.
Structure-activity studies have identified 3-spiro-β-
lactams SCH 54016 A and SCH 58053 B as most
5
potent cholesterol absorption inhibitors.
Several approaches for the synthesis of spiro-β-
lactams have been described in literature. Recently
reported synthesis of spiro-β-lactams involves either
intramolecular cyclization of substituted β-lactam
6
enolates or the Staudinger reaction of unsymmetri-
7
cal ketenes as well as halocyclization of cis-3-
(prop-2-ynyloxy/-enyloxy)-β-lactams as reported
8
from our laboratory. Keeping in view, the impor-
Figure 1. Potent cholesterol absorption inhibitors.
*For correspondence
125

126
Renu Arora et al
dology for the formation of heterocyclic ring at C-3 2.1a 1-(4′-Methoxyphenyl)-3-benzylthio-3-(2′,3′-
of β-lactams under very mild conditions.
dibromopropyl)-4-phenyl azetidin-2-one (8a): Oil;
–1
1
yield 9%; IR νmax (CCl4) 1750 (C=O) cm ; H NMR
(400 MHz, CDCl3) δ 6⋅71–7⋅54 (14H, m, Ph), 5⋅42
(1H, s, C4-H), 4⋅49–4⋅56 (1H, m, C2′-H), 3⋅98 (1H,
2. Experimental
Melting points are uncorrected. IR spectra were d, J = 16⋅4 Hz, CH2S), 3⋅91 (1H, d, J = 16⋅4 Hz,
taken on a FTIR spectrophotometer and are reported CH2S), 3⋅71 (3H, s), 3⋅50 (1H, dd, J = 14⋅6 Hz,
–1
1
13
in cm . H and C NMR spectra were recorded on 5⋅6 Hz, C3′-H), 3⋅41 (1H, dd, J = 14 Hz, 10⋅8 Hz,
JEOL 300 and Bruker Avance II 400 NMR spec- C3′-H), 2⋅96 (1H, dd, J = 20 Hz, 2⋅4 Hz, C1′-H),
13
trometers. Chemical shifts are given in parts per mil- 2⋅41(1H, dd, J = 20 Hz, 13⋅2 Hz, C1′-H); C NMR
lion relative to tetramethylsilane as internal standard (100 MHz, CDCl3) δ 164⋅9, 156⋅3, 137⋅6, 133⋅3,
1
(δ = 0) for H NMR and CDCl3 (δ = 77⋅0 ppm) for 130⋅8, 129⋅4, 128⋅8, 128⋅7, 128⋅6, 128⋅1, 127⋅4,
13
C NMR spectra. Mass spectra were recorded on a 118⋅7, 114⋅4, 66⋅2, 63⋅9, 55⋅2, 47⋅7, 40⋅6, 37⋅2, 33⋅2⋅
Shimadzu GCMS-QT 5000 instrument and elemen- Anal. Calcd. For C26H25O2NSBr2: C 54⋅27, H 4⋅38,
tal analysis (C, H, and N) was carried out using a N 2⋅43. Found: C 54⋅21, H 4⋅29, N 2⋅39.
PERKIN-ELMER 2400 elemental analyzer. Column
chromatography was performed using Merck Silica 2.1b 2-(4′-Methoxyphenyl)-3-phenyl-7α-bromo-5-
Gel (100–200 mesh). Thin-layer chromatography thia-2-azaspiro[3,4]octan-1-one (9a): White solid;
(TLC) was performed using Merck Silica Gel. For yield 28%; m.p. 215–217°C; IR νmax (KBr) 1743
–1
1
visualization, TLC plates were stained with iodine (C=O) cm ; H NMR (400 MHz, CDCl3) δ 6⋅73–
vapours. All commercially available compounds/ 7⋅56 (9H, m, Ph), 5⋅01 (1H, s, C3-H), 4⋅11–4⋅20
reagents were used without further purification. Di- (1H, m, C7-H), 3⋅73 (3H, s, OCH3), 3⋅21 (1H, t,
chloromethane and carbon tetrachloride distilled J = 14 Hz, C6-H), 2⋅97–3⋅19 (2H, m, C8-H, and C6-
13
over P2O5 were redistilled over CaH2 before use. H), 2⋅70 (1H, t, J = 17⋅2 Hz, C8-H); C NMR
The melting point of compounds 11 and 12 is not (100 MHz, CDCl3) δ 166⋅0, 156⋅0, 135⋅2, 130⋅7,
reported as most of them have separated as mixture 129⋅0, 128⋅8, 127⋅4, 124⋅6, 118⋅6, 114⋅4, 71⋅0, 70⋅9,
only. Crystallographic data (excluding structure fac- 55⋅0, 48⋅0, 43⋅2, 41⋅00. Anal. Calcd. For C19H18O2
tors) of compound 10e with CCDC-642729 in CIF NSBr: C 56⋅44, H 4⋅48, N 3⋅46. Found: C 56⋅36, H
format have been deposited with the Cambridge 4⋅34, N 3⋅36.
Crystallographic Data Centre. These data can be ob-
2.1c 2-(4′-Methoxyphenyl)-3-phenyl-7β-bromo-5-
thia-2-azaspiro[3,4]octan-1-one (10a): Crystalline
tained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.com.ac.uk/
solid; yield 56%; m.p. 174–176°C; IR νmax (KBr)
data_request/cif.
–1
1
1740 (C=O) cm ; H NMR (400 MHz, CDCl3) δ
6⋅72–7⋅55 (9H, m, Ph), 5⋅17 (1H, s, C3-H), 4⋅75–
4⋅81 (1H, m, C7-H), 3⋅72 (3H, s, OCH3), 3⋅44 (1H,
dd, J = 11⋅8 Hz, 5⋅2 Hz, 6αH–7αH, C6-H), 2⋅97–
3⋅10 (2H, m, C6-H and C8-H), 2⋅85 (1H, dd,
2.1 General procedure for halocyclization
To a stirred solution of cis-3-allyl-3-benzylthio-β-
lactams 6 (1 mmol) in 15 mL of dry methylene chlo-
ride was added bromine/iodine (1⋅1 mmol) at room
temperature. The mixture was allowed to stir (2–3 h)
at the same temperature. The progress of reaction
was monitored by TLC. After completion of reac-
tion, the reaction mixture was poured into aqueous
5% Na2S2O3/Na2S2O5 solution (15 mL) and stirred
until the reddish colouration of bromine/purplish
colouration of iodine dissipated. The aqueous mix-
ture was extracted with methylene chloride (3 × 5 mL)
and the combined organic extracts were washed with
13
J = 13⋅5 Hz, 5⋅65 Hz, 8βH–7αH, C8-H); C NMR
(100 MHz, CDCl3) δ 166⋅7, 156⋅3, 135⋅1, 130⋅6,
129⋅1, 128⋅8, 127⋅4, 118⋅8, 114⋅4, 71⋅9, 68⋅2, 55⋅2,
48⋅6, 47⋅8, 42⋅6. Anal. Calcd. For C19H18O2NSBr: C
56⋅44, H 4⋅48, N 3⋅46. Found: C 56⋅36, H 4⋅34, N
3⋅36.
2.1d 1-(4′-Methoxyphenyl)-3-benzylthio-3-(2′,3′-
dibromopropyl)-4-(4′-methoxy
one (8b): Oil; yield 23%; IR νmax (CCl4) 1748(C=O)
phenyl)azetidin-2-
–1
1
brine and dried over anhydrous Na2SO4. After cm ; H NMR (400 MHz, CDCl3) δ 6⋅71–7⋅38
evaporation of solvent under vacuum, the residue (13H, m, Ph), 5⋅35 (1H, s, C4-H), 4⋅48–4⋅60 (1H, m,
was purified by column chromatography on silica C2′-H), 4⋅05 (1H, d, J = 16⋅4 Hz, CH2S), 3⋅92 (1H,
d, J = 16⋅4 Hz, CH2S), 3⋅76 (3H, s, OCH3), 3⋅74
gel in hexanes/ethyl acetate.

Synthesis of novel spiro-β-lactams
127
(3H, s, OCH3), 3⋅48 (1H, dd, J = 14⋅6 Hz, 5⋅6Hz, 2.1h 2-(4′-Methylphenyl)-3-(4′-chlorophenyl)-7α-
C3′-H), 3⋅38 (1H, dd, J = 14 Hz, 10⋅8 Hz, C3′-H), bromo-5-thia-2-azaspiro[3,4] octan-1-one (9c): Oil;
–1
1
2⋅97 (1H, dd, J = 20 Hz, 2⋅4 Hz, C1′-H), 2⋅44 (1H, yield 15%; IR νmax (CCl4) 1751 (C=O) cm ; H
dd, J = 20 Hz, 13⋅2 Hz, C1′-H)⋅ Anal. Calcd. For NMR (400 MHz, CDCl3) δ 6⋅99–7⋅45 (8H, m, Ph),
C27H27O3NSBr2: C 53⋅57, H 4⋅49, N 2⋅31. Found: C 4⋅95 (1H, s, C3-H), 4⋅00–4⋅10 (1H, m, C7-H), 3⋅30
53⋅51, H 4⋅39, N 2⋅24.
(1H, t, J = 14 Hz, C6-H), 2⋅90–3⋅10 (2H, m, C6-H
13
and C8-H), 2⋅74 (1H, t, J = 17⋅2 Hz, C8-H);
NMR (100 MHz, CDCl3) δ 165⋅0, 136⋅7, 134⋅6,
C
2.1e 2,3-Di-(4′-methoxyphenyl)-7α-bromo-5-thia-
2-azaspiro[3,4]octan-1-one (9b): Oil; yield 36%; IR 133⋅4, 132⋅3, 132⋅0, 129⋅0, 128⋅2, 126⋅8, 119⋅2,
–1
1
νmax (CCl4) 1751 (C=O) cm ; H NMR (400 MHz, 70⋅5, 70⋅0, 48⋅0, 43⋅0, 41⋅2, 21⋅0. Anal. Calcd. For
CDCl3) δ 6⋅71–7⋅24 (8H, m, Ph), 4⋅93 (1H, s, C3-H), C19H17O2NSBrCl: C 51⋅98, H 3⋅90, N 3⋅19. Found:
4⋅09–4⋅15 (1H, m, C7-H), 3⋅79 (3H, s, OCH3), 3⋅73 C 51⋅86, H 3⋅84, N 3⋅12.
(3H, s, OCH3), 3⋅20 (1H, t, J = 14 Hz, C6-H), 2⋅09–
3⋅90 (2H, m, C8-H and C6-H), 2⋅75 (1H, t, 2.1i 2-(4′-Methylphenyl)-3-(4′-chlorophenyl)-7β-
13
J = 17⋅2 Hz, C8-H); C NMR (100 MHz, CDCl3) δ bromo-5-thia-2-azaspiro[3,4] octan-1-one (10c):
166⋅6, 160⋅2, 160⋅1, 130⋅7, 128⋅7, 126⋅9, 118⋅9, Crystalline solid; yield 35%; m.p. 211–214°C; IR
–1
1
118⋅7, 118⋅6, 114⋅5, 114⋅4, 114⋅2, 114⋅0, 70⋅7, 69⋅9, νmax (KBr) 1740 (C=O) cm ; H NMR (400 MHz,
55⋅3, 55⋅1, 47⋅0, 43⋅2, 41⋅0. Anal. Calcd. For CDCl3) δ 7⋅01–7⋅37 (8H, m, Ph), 5⋅19 (1H, s, C3-H),
C20H20O3NSBr: C 55⋅30, H 4⋅64, N 3⋅22. Found: C 4⋅79–4⋅81 (1H, m, C7-H), 3⋅48 (1H, dd,
55⋅22, H 4⋅54, N 3⋅14.
J = 11⋅72 Hz, 5⋅1 Hz, 8βH–7αH, C6-H), 2⋅97–3⋅03
(2H, m, C6-H and C8-H), 2⋅82 (1H, dd, J = 13⋅8 Hz,
13
2.1f 2,3-Di-(4′-Methoxyphenyl)-7β-bromo-5-thia-
5⋅6 Hz, 8βH–7αH, C8-H), 2⋅29 (3H, s, CH3);
C
2-azaspiro[3,4]octan-1-one (10b): Oil; yield 28%; NMR (100 MHz, CDCl3) δ 166⋅0, 136⋅7, 134⋅2,
–1
1
IR νmax (CCl4) 1745 (C=O) cm ; H NMR 133⋅2, 133⋅1, 129⋅0, 128⋅9, 128⋅3, 118⋅7, 72⋅0, 68⋅2,
(400 MHz, CDCl3) δ 6⋅70–7⋅52 (8H, m, Ph), 5⋅10 48⋅4, 47⋅8, 42⋅7, 20⋅5⋅ Anal. Calcd. For C19H17O2
(1H, s, C3-H), 4⋅75–4⋅82 (1H, m, C7-H), 3⋅80 (3H, NSBrCl: C 51⋅98, H 3⋅90, N 3⋅19. Found: C 51⋅86,
s, OCH3), 3⋅74 (3H, s, OCH3), 3⋅42 (1H, dd, H 3⋅84, N 3⋅12.
J = 11⋅8 Hz, 5⋅2 Hz, C6-H), 2⋅92 (2H, m, C6-H and
C8-H), 2⋅71 (1H, dd, J = 13⋅5 Hz, 5⋅65 Hz, C8-H); 2.1j 1-Phenyl-3-benzylthio-3-(2′,3′-dibromo-
13
C NMR (100 MHz, CDCl3) δ 166⋅6, 160⋅1, 130⋅7, propyl)-4-phenylazetidin-2-one (8d): Oil; yield 5%;
–1
1
128⋅6, 126⋅9, 118⋅9, 118⋅8, 114⋅4, 114⋅3, 72⋅2, 68⋅0, IR νmax (CCl4) 1750 (C=O) cm ; H NMR
55⋅3, 55⋅1, 48⋅6, 48⋅1, 42⋅7. Anal. Calcd. For (400 MHz, CDCl3) δ 6⋅98–7⋅39 (15H, m, Ph), 5⋅37
C20H20O3NSBr: C 55⋅30, H 4⋅64, N 3⋅22. Found: C (1H, s, C4-H), 4⋅47–4⋅56 (1H, m, C2′-H), 3⋅98 (1H,
55⋅22, H 4⋅54, N 3⋅14.
d, J = 16⋅4 Hz, CH2S), 3⋅91 (1H, d, J = 16⋅4 Hz,
CH2S), 3⋅51 (1H, dd, J = 14⋅6 Hz, 5⋅6 Hz, C3′-H),
3⋅40 (1H, dd, J = 14 Hz, 10⋅8 Hz, C3′-H), 2⋅96 (1H,
2.1g 1-(4′-Methylphenyl)-3-benzylthio-3-(2′,3′-
dibromopropyl)-4-(4′-chlorophenyl)azetidin-2-one
dd, J = 20 Hz, 2⋅4 Hz, C1′-H), 2⋅41 (1H, dd,
13
(8c): Oil; yield 20%; IR νmax (CCl4) 1748 (C=O) J = 20 Hz, J = 13⋅2 Hz, C1′-H); C NMR (100 MHz,
–1
1
cm ; H NMR (400 MHz, CDCl3) δ 6⋅89–7⋅39 CDCl3) δ 164⋅9, 137⋅7, 133⋅3, 130⋅8, 129⋅4, 128⋅8,
(13H, m, Ph), 5⋅34 (1H, s, C4-H), 4⋅43–4⋅50 (1H, m, 128⋅7, 128⋅6, 128⋅1, 127⋅3, 118⋅7, 114⋅4, 63⋅9, 66⋅2,
C2′-H), 3⋅93 (1H, d, J = 16⋅4 Hz, CH2S), 3⋅88 (1H, 47⋅8, 40⋅6, 37⋅2, 33⋅2. Anal. Calcd. For C25H23
d, J = 16⋅4 Hz, CH2S), 3⋅50 (1H, dd, J = 14⋅6 Hz, ONSBr2: C 55⋅06, H 4⋅25, N 2⋅56. Found: C 55⋅01,
5⋅6 Hz, C3′-H), 3⋅39 (1H, dd, J = 14 Hz, 10⋅8 Hz, H 4⋅19, N 2⋅49.
C3′-H), 2⋅86 (1H, dd, J = 20 Hz, 2⋅4 Hz, C1′-H),
2⋅40 (1H, dd, J = 20 Hz, 13⋅2 Hz, C1′-H), 2⋅21 (3H, 2.1k 2,3-Diphenyl-7α-bromo-5-thia-2-azaspiro[3,4]
13
s, CH3); C NMR (100 MHz, CDCl3) δ 165⋅1, octan-1-one (9d): White solid; yield 28%; m.p.
–1
1
136⋅7, 134⋅6, 133⋅2, 132⋅4, 132⋅0, 129⋅0, 128⋅9, 128⋅3, 225–227°C; IR νmax (KBr) 1747⋅8 (C=O) cm ; H
128⋅2, 126⋅8, 119⋅3, 116⋅9, 66⋅2, 63⋅9, 48⋅1, 40⋅0, NMR (400 MHz, CDCl3) δ 7⋅06–7⋅43 (10H, m, Ph),
36⋅0, 34⋅0, 21⋅3. Anal. Calcd. For C26H24O2NSBr2Cl: 5⋅03 (1H, s, C3-H), 4⋅06–4⋅17 (1H, m, C7-H), 3⋅25
C 51⋅21, H 3⋅96, N 2⋅29. Found: C 51⋅11, H 3⋅89, N (1H, t, J = 14 Hz, C6-H), 2⋅98–3⋅10 (2H, m, C6-H
13
2⋅24.
and C8-H), 2⋅71 (1H, t, J = 17⋅2 Hz, C8-H);
C

128
Renu Arora et al
NMR (100 MHz, CDCl3) δ 166⋅4, 136⋅9, 135⋅2, 2.1o 2-(4′-Chlorophenyl)-3-phenyl-7β-bromo-5-
132⋅2, 129⋅1, 129⋅0, 126⋅9, 124⋅5, 119⋅1, 117⋅5, thia-2-azaspiro[3,4]octan-1-one (10e): Crystalline
70⋅8, 70⋅1, 48⋅0, 43⋅5, 41⋅2. Anal. Calcd. For solid; yield 33%; m.p. 133–135°C; IR νmax.(KBr)
–1
1
C18H16ONSBr: C 57⋅76, H 4⋅31, N 3⋅74. Found: C 1739⋅7 (C=O) cm ; H NMR (400 MHz, CDCl3) δ
57⋅66, H 4⋅24, N 3⋅62.
7⋅16–7⋅44 (9H, m, Ph), 5⋅27 (1H, s, C3-H), 4⋅76–
4⋅82 (1H, m, C7-H), 3⋅42 (1H, dd, J = 11⋅72 Hz,
2.1l 2,3-Diphenyl-7β-bromo-5-thia-2-azaspiro[3,4] 5⋅1 Hz, 6α H–7αH, C6-H), 3⋅10–2⋅80 (2H, m, C6-H
octan-1-one (10d): Crystalline solid; yield 66%; and C8-H), 2⋅40 (1H, dd, J = 13⋅8 Hz, 5⋅6 Hz, 8βH-
–1
13
m.p. 142–145°C; IR νmax (KBr) 1745⋅9 (C=O) cm ; 7αH, C8-H); C NMR (100 MHz, CDCl3) δ 167⋅4,
1
H NMR (400 MHz, CDCl3) δ 7⋅03–7⋅42 (10H, m, 135⋅6, 134⋅6, 129⋅6, 129⋅3, 129⋅2, 128⋅9, 127⋅3,
Ph), 5⋅27 (1H, s, C3-H), 4⋅76–4⋅80 (1H, m, C7-H), 118⋅7, 72⋅2, 68⋅3, 48⋅7, 47⋅8, 42⋅7; MS (EI) m/z 409
+
+
+
3⋅44 (1H, dd, J = 11⋅4 Hz, 5⋅1 Hz, 6αH–7αH, C6- (M ), 215 (M -C5H5OSBr), 193 (M -C13H10NCl).
H), 2⋅97–3⋅10 (2H, m, C6-H and C8-H), 2⋅80 (1H, Anal. Calcd. For C18H15ONSBrCl: C 52⋅89, H 3⋅70,
13
dd, J = 13⋅8 Hz, 5⋅7 Hz, 8βH-7αH, C8-H); C NMR N 3⋅40. Found: C 52⋅80, H 3⋅66, N 3⋅35.
(100 MHz, CDCl3) δ 167⋅5, 135⋅9, 134⋅5, 132⋅2,
129⋅2, 129⋅1, 128⋅8, 127⋅3, 119⋅1, 72⋅2, 68⋅2, 48⋅6, 2.1p 2-(4′-Methoxyphenyl)-3-phenyl-7(α,β)-iodo-5-
13
47⋅9, 42⋅7; C NMR (DEPT 135) δ 129⋅2 (+), 129⋅1 thia-2-azaspiro[3,4]octan-1-one (11a, 12a): White
–1
(+), 128⋅8 (+), 127⋅3 (+), 119⋅1 (+), 68⋅2 (+), 48⋅6 solid; yield 80%; IR νmax (KBr) 1749, (C=O) cm ;
1
(–), 47⋅9 (+), 42⋅7 (–). Anal. Calcd. For
H NMR (400 MHz, CDCl3) δ 6⋅69–7⋅34 (18H, m,
C18H16ONSBr: C 57⋅76, H 4⋅31, N 3⋅74. Found: C Ph, both isomers), 5⋅06 (1H, s, for one isomer, C3-
57⋅66, H 4⋅24, N, 3⋅62.
H), 4⋅96 (1H, s, for one isomer, C3-H), 4⋅52–4⋅62
(1H, m, for one isomer, C7-H), 3⋅80–4⋅10 (1H, m,
2.1m 1-(4′-Chlorophenyl)-3-benzylthio-3-(2′,3′-di- for one isomer, C7-H), 3⋅67 (6H, s, both isomers,
bromopropyl)-4-phenyl azetidin-2-one (8e): Oil; OCH3), 3⋅23–3⋅32 (2H, m, both isomers, C6-H),
–1
1
yield 26%; IR νmax (CCl4) 1751 (C=O) cm ; H 3⋅03–3⋅09 (4H, m, both isomers, C6-H and C8-H),
13
NMR (400 MHz, CDCl3) δ 7⋅00–7⋅40 (14H, m, Ph), 2⋅66–2⋅78 (2H, m, both isomers, C8-H); C NMR
5⋅38 (1H, s, C4-H), 4⋅48–4⋅56 (1H, m, C2′-H), (100 MHz, CDCl3) δ 165⋅5, 156⋅4, 135⋅5, 130⋅5,
3⋅99 (1H, d, J = 16⋅4 Hz, CH2S), 3⋅92 (1H, d, 129⋅0, 128⋅8, 127⋅0, 118⋅8, 114⋅4, 72⋅7, 70⋅3, 66⋅7,
J = 16⋅4 Hz, CH2S), 3⋅50 (1H, dd, J = 14⋅6 Hz, 55⋅4, 50⋅8, 50⋅2, 43⋅7, 16⋅6. Anal. Calcd. For
5⋅6 Hz, C3′-H), 3⋅40 (1H, dd, J = 14 Hz, 10⋅8 Hz, C19H18O2NSI: C 50⋅56, H 4⋅02, N 3⋅10. Found: C
C3′-H), 2⋅95 (1H, dd, J = 20 Hz, 2⋅4 Hz, 50⋅47, H 4⋅01, N 3⋅04.
C1′-H), 2⋅41 (1H, dd, J = 20 Hz, 13⋅2 Hz, C1′-H);
C NMR (100 MHz, CDCl3) δ 166⋅1, 135⋅6, 134⋅6, 2.1q 2,3-Di-(4'-methoxyphenyl)-7(α,β)-iodo-5-thia-
13
129⋅6, 129⋅4, 129⋅3, 129⋅2, 129⋅0, 128⋅9, 2-azaspiro[3,4]octan-1-one (11b, 12b): White
–1
127⋅9, 127⋅6, 127⋅3, 118⋅0, 65⋅1, 63⋅2, 47⋅1, 40⋅0, solid; yield 80%; IR νmax (KBr) 1747⋅6, (C=O) cm ;
1
36⋅5, 33⋅6. Anal. Calcd. For C25H22ONSClBr2: C H NMR (400 MHz, CDCl3) δ 6⋅95–7⋅40 (16H, m,
51⋅78, H 3⋅82, N 2⋅41. Found: C 51⋅70, H 3⋅70, N, Ph, both isomers), 5⋅01(1H, s, for one isomer, C3-
2⋅29.
H), 4⋅91 (1H, s, for one isomer, C3-H), 4⋅51–4⋅60
(1H, m, for one isomer, C7-H), 3⋅80–4⋅10 (1H, m,
for one isomer, C7-H), 3⋅72 (12H, s, both isomers,
2.1n 2-(4′-Chlorophenyl)-3-phenyl-7α-bromo-5-
thia-2-azaspiro[3,4]octan-1-one (9e): White solid; OCH3), 3⋅20–3⋅32 (2H, m, both isomers, C6-H),
yield 16%; m.p. 220–223°C; IR νmax (KBr) 1747⋅8 2⋅88–3⋅10 (4H, m, both isomers, C6-H and C8-H),
–1
1
13
(C=O), cm ; H NMR (400 MHz, CDCl3) δ 7⋅10– 2⋅75–2⋅83 (2H, m, both isomers, C8-H); C NMR
7⋅72 (9H, m, Ph), 5⋅29 (1H, s, C3-H), 4⋅10–4⋅20 (100 MHz, CDCl3) δ 160⋅1, 156⋅2, 135⋅4, 130⋅5,
(1H, m, C7-H), 3⋅22 (1H, t, J = 14 Hz, C6-H), 2⋅95– 128⋅4, 128⋅3, 118⋅8, 114⋅6, 114⋅4, 114⋅3, 72⋅0, 70⋅1,
3⋅10 (2H, m, C6-H and C8-H), 2⋅79 (1H, t, 67⋅2, 55⋅3, 55⋅1, 50⋅8, 49⋅1, 43⋅7, 16⋅7. Anal. Calcd.
13
J = 17⋅2 Hz, C8-H); C NMR (100 MHz, CDCl3) δ For C20H20O3NSI: C 49⋅90, H 4⋅18, N 2⋅90. Found:
167⋅4, 135⋅2, 134⋅7, 129⋅6, 129⋅4, 129⋅3, 128⋅62 C 49⋅87, H 4⋅12, N 2⋅81.
127⋅2, 118⋅8, 71⋅0, 70⋅6, 48⋅2, 44⋅4, 41⋅2. Anal.
Calcd. For C18H15ONSBrCl: C 52⋅89, H 3⋅70, N 2.1r 2,3-Di-(4′-Methoxyphenyl)-7α-iodo-5-thia-2-
3⋅42. Found: C 52⋅80, H 3⋅66, N 3⋅35.
azaspiro[3,4]octan-1-one (11b): White solid; yield

Synthesis of novel spiro-β-lactams
129
62%; m.p. 174–175°C; IR νmax (KBr) 1748, (C=O) mers, C6-H), 2⋅85–3⋅14 (4H, m, both isomers, C6-H
–1
1
cm ; H NMR (400 MHz, CDCl3) δ 6⋅68–7⋅18 (8H, and C8-H), 2⋅77–2⋅90 (2H, m, both isomers, C8-H);
13
m, Ph), 4⋅84 (1H, s, C3-H), 3⋅90–3⋅94 (1H, m, C7-
C NMR (100 MHz, CDCl3) δ 168⋅0, 166⋅3, 135⋅4,
H), 3⋅75 (3H, s, OCH3), 3⋅70 (3H, s, OCH3), 3⋅25– 134⋅8, 134⋅5, 129⋅6, 129⋅4, 129⋅2, 129⋅0, 128⋅0,
3⋅30 (1H, m, C6-H), 3⋅10–3⋅20 (1H, m, C6-H), 2⋅95– 127⋅0, 126⋅9, 118⋅8, 118⋅7, 73⋅0, 72⋅6, 70⋅3, 66⋅8,
13
2⋅99 (1H, m, C8-H), 2⋅71–2⋅77 (1H, m, C8-H);
C
50⋅8, 50⋅2, 43⋅8, 43⋅7, 19⋅32, 16⋅3. Anal. Calcd. For
NMR (100 MHz, CDCl3) δ 165⋅7, 160⋅0, 156⋅3, C18H15ONSICl: C 47⋅44, H 3⋅31, N 3⋅07. Found: C
130⋅6, 128⋅3, 127⋅3, 118⋅8, 114⋅37, 96⋅1, 72⋅8, 70⋅0, 47⋅37, H 3⋅23, N 3⋅01.
55⋅4, 55⋅2, 50⋅7, 43⋅7, 16⋅7.
2.2 General procedure for desulphurization
2.1s 2-(4′-Methylphenyl)-3-(4′-chlorophenyl)-7(α,β)-
iodo-5-thia-2-azaspiro[3,4] octan-1-one (11c, 12c):
To a stirred solution of spiro-β-lactams 9 +
Solid; yield 62%; IR νmax (KBr) 1746⋅8, 1707⋅5
10/11 + 12 (1mmol) and catalytic amount of AIBN
–1
1
(C=O) cm ; H NMR (400 MHz, CDCl3) δ 6⋅95–
7⋅30 (16H, m, Ph, both isomers), 5⋅05 (1H, s, for one
isomer, C3-H), 4⋅88 (1H, s, for one isomer, C3-H),
4⋅50–4⋅61 (1H, m, for one isomer, C7-H), 3⋅82–4⋅00
(1H, m, for one isomer, C7-H), 3⋅19–3⋅32 (2H, m,
both isomers, C6-H), 2⋅90–3⋅15 (4H, m, both iso-
mers, C6-H and C8-H), 2⋅61–2⋅80 (2H, m, both iso-
in 5mL of dry benzene was added n-Bu3SnH
(1⋅1 mmol) under nitrogen atmosphere. The reaction
mixture was refluxed for 40 min and progress was
monitored by TLC. Upon completion of the reac-
tion, the solvent was removed under reduced pres-
sure. The residue was dissolved in methylene
chloride and was washed with water, brine, and dried
over anhydrous Na2SO4 and filtered. After evapora-
tion of solvent under vacuum, the residue was puri-
fied by column chromatography on silica gel in
hexanes/ethyl acetate.
13
mers, C8-H), 2⋅17 (6H, s both isomers); C NMR
(100 MHz, CDCl3) δ 165⋅7, 165⋅4, 134⋅9, 134⋅8,
134⋅4, 134⋅3, 134⋅0, 133⋅6, 129⋅7, 129⋅3, 129⋅1,
128⋅5, 128⋅3, 117⋅4, 72⋅6, 72⋅3, 69⋅5, 66⋅3, 50⋅8,
50⋅3, 44⋅1, 43⋅7, 29⋅6, 20⋅9, 26⋅0, 16⋅31. Anal.
Calcd. For C19H17O2NSICl: C 46⋅98, H 3⋅52, N 2⋅88.
Found: C 46⋅88, H 3⋅43, N 2⋅81.
2.2a 2-(4′-Methoxyphenyl)-3-phenyl-5-thia-2-aza-
spiro[3,4]octan-1-one (13a): White flakes; yield
75%; m.p. 185–187°C; IR νmax (KBr) 1736 (C=O)
–1
1
2.1t 2,3-Diphenyl-7(α,β)-iodo-5-thia-2-azaspiro
[3,4]octan-1-one (11d, 12d): Solid; yield 71%; IR
cm ; H NMR (400 MHz, CDCl3) δ 6⋅72–7⋅39 (9H,
m, Ph), 4⋅97 (1H, s, C4-H), 3⋅74 (3H, s, OCH3),
2⋅90–3⋅00 (1H, m, C6-H), 2⋅75–2⋅85 (1H, m, C6-H),
2⋅45–2⋅58 (2H, m, C7-H), 2⋅25–2⋅40 (1H, m, C8-H),
–1
1
νmax (KBr) 1747, (C=O) cm ; H NMR (400 MHz,
CDCl3) δ 7⋅03–7⋅40 (20H, m, Ph, both isomers),
5⋅15 (1H, s, for one isomer, C3-H), 5⋅06 (1H, s, for
one isomer, C3-H), 4⋅52–4⋅60 (1H, m, for one iso-
mer, C7-H), 3⋅82–4⋅00 (1H, m, for one isomer, C7-
H), 3⋅19–3⋅31 (2H, m, both isomers, C6-H), 2⋅90–
3⋅10 (4H, m, both isomers, C6-H and C8-H), 2⋅70–
13
1⋅95–2⋅01 (1H, m, C8-H); C NMR (100 MHz,
CDCl3) δ 168⋅0, 156⋅1, 136⋅5, 131⋅3, 128⋅6, 128⋅3,
127⋅0, 118⋅6, 114⋅4, 74⋅1, 68⋅5, 55⋅2, 39⋅7, 33⋅8,
13
30⋅4; C NMR (DEPT 135) δ 128⋅6 (+), 128⋅3 (+),
127⋅0 (+), 118⋅6 (+), 114⋅4 (+), 68⋅5 (+), 55⋅2 (+),
13
+
2⋅85 (2H, m, both isomers, C8-H); C NMR
39⋅7 (–), 33⋅8 (–), 30⋅4 (–); MS (EI) m/z 325 (M ),
+
+
(100 MHz, CDCl3) δ 160⋅0, 133⋅4, 127⋅1, 126⋅9,
126⋅8, 124⋅8, 124⋅7, 116⋅4, 70⋅4, 68⋅1, 64⋅5, 48⋅8,
48⋅1, 41⋅4. Anal. Calcd. For C18H16ONSI: C 51⋅31,
H 3⋅82, N 3⋅32. Found: C 51⋅24, H 3⋅79, N 3⋅24.
219, 176, 147 (M – C11H12S), 115 (M – C14H13NO).
Anal. Calcd. For C19H19O2NS: C 70⋅12, H 5⋅88, N
4⋅30. Found: C 70⋅04, H 5⋅73, N 4⋅21.
2.2b 2,3-Diphenyl-5-thia-2-azaspiro[3,4]octan-1-
one (13d): White solid; yield 80%; m.p. 200–
2.1u 2-(4′-Chlorophenyl)-3-phenyl-7(α,β)-iodo-5-
thia-2-azaspiro[3,4]octan-1-one (11e, 12e): White
–1
1
202°C; IR νmax (KBr) 1733 (C=O) cm ; H NMR
(400 MHz, CDCl3) δ 7⋅04–7⋅51 (10H, m, Ph), 5⋅02
(1H, s, C4-H), 2⋅92–3⋅00 (1H, m, C6-H), 2⋅71–2⋅81
(1H, m, C6-H), 2⋅40–2⋅50 (2H, m, C7-H), 2⋅28–2⋅40
–1
solid; yield 48%; IR νmax (KBr) 1747⋅5, (C=O) cm ;
H NMR (400 MHz, CDCl3) δ 7⋅12–7⋅43 (18H, m,
1
Ph, both isomers), 5⋅15 (1H, s, for one isomer, C3-
H), 5⋅05 (1H, s, for one isomer, C3-H), 4⋅56–4⋅62
(1H, m, for one isomer, C7-H), 3⋅86–4⋅10 (1H, m,
for one isomer, C7-H), 3⋅20–3⋅34 (2H, m, both iso-
13
(1H, m, C8-H), 2⋅00–2⋅10 (1H, m, C8-H); C NMR
(100 MHz, CDCl3) δ 168⋅8, 135⋅6, 132⋅0, 129⋅0,
127⋅7, 126⋅8, 124⋅0, 118⋅9, 117⋅4, 74⋅2, 68⋅5, 39⋅7,

130
Renu Arora et al
Scheme 1. Synthesis of cis-3-allyl-3-phenylthio/benzylthio β-lactams 5/6.
Table 1. 3-Allyl-3-phenylthio/benzylthioazetidin-2-ones 5 and 6.
1
2
a
Entry
R
R
Substrate (% yield)
1
2
3
4
5
6
C6H5
C6H4⋅OMe (4)
C6H4⋅OMe (4)
C6H4⋅CH3 (4)
C6H4Br (4)
C6H5
5a (86)
5b (85)
5c (88)
5d (85)
–
6a (90)
6b (99)
6c (69)
–
C6H4⋅OMe (4)
C6H4⋅Cl (4)
C6H5
C6H5
6d (99)
6e (95)
C6H5
C6H4Cl (4)
–
a
Isolated yield
13
34⋅0, 30⋅3; C NMR (DEPT 135) δ 132⋅0 (+), 129⋅0 3. Results and discussion
(+), 127⋅7 (+), 126⋅8 (+), 118⋅9 (+), 117⋅4 (+), 68⋅5
The studies start with the preparation of trans-3-
phenylthio/benzylthio-β-lactams (1/2) by reacting
Schiff base and phenylthio/benzylthioacetic acid
(+), 39⋅7 (–), 34⋅0 (–), 30⋅3 (–). Anal. Calcd. For
C18H17ONS: C 73⋅18, H 5⋅80, N 4⋅74. Found: C
73⋅09, H 5⋅73, N 4⋅61.

Synthesis of novel spiro-β-lactams
131
Scheme 2. Cyclization studies of substrate 5 with Br2 and I2.
Scheme 3. Synthesis of spiro-β-lactams 9a–e and 10a–e.
11,12
using reported procedure.
These were trans- afforded cis-3-allyl-3-phenyl/benzylthio-β-lactams
9
formed into their 3-chloro derivatives using SO2Cl2 (5/6) in good yield. The structures of these products
12,13
as chlorinating agent.
The conversion of were established spectroscopically. However, the
3-benzylthio-β-lactams into 3-chloro-3-benzylthio- stereochemistry was assigned on the basis of X-ray
9
β-lactams (4) was done with NCS in the presence of crystallographic studies (scheme 1 and table 1).
AIBN. These trans-3-chloro-β-lactams (3/4) on The halocyclization studies were initially carried
treatment with allylsilane in the presence of TiCl4 out using substrate 5a. Treatment of β-lactam 5a

132
Renu Arora et al
Table 2. 7-Bromo-5-thia-2-azaspiro[3,4]octan-1-ones 9a–e and 10a–e.
Addition product
a,b
(% yield)
α-Bromoisomer β-Bromoisomer
a,b
1
R
2
a,b
Entry
R
(% yield)
(% yield)
1
2
3
4
5
C6H5
C6H4OCH3 (4)
8a (9)
9a (28)
9b (26)
9c (15)
9d (28)
9e (16)
10a (27)
10b (28)
10c (35)
10d (66)
10e (33)
C6H4OCH3 (4) C6H4OCH3 (4)
8b (23)
8c (20)
8d (5)
8e (27)
C6H4Cl (4)
C6H5
C6H4CH3 (4)
C6H5
C6H5
C6H4Cl (4)
a
All new compounds gave satisfactory CHN analysis
13
1
Yields quoted are for the isolated products characterized by IR, H NMR, C NMR
b
Scheme 4. Synthesis of spiro-β-lactams 11a–e and
12a–e.
Figure 2. An ORTEP diagram of compound 10e.
Continuing further, these studies were repeated
using substrate 6a. It was envisaged that since com-
pound 6a has a methylene inserted between sulphur
and phenyl group, this might be having different re-
activity and might prove to be a suitable substrate
for this reaction. Thus addition of Br2 (1 equiv.) to
β-lactam substrate 6a in methylene dichloride at
room temperature initially showed no change in
TLC profile. However, after stirring for 3 h, the
TLC profile showed two new spots having Rf lower
than that of the substrate. Of these three spots, first
one having same Rf as substrate was identified as
acyclic dibromide i.e. 1-(4′-methoxyphenyl)-3-benzyl-
thio-3-(2′,3′-dibromopropyl)-4-phenylazetidin-2-one
with Br2 in methylene dichloride at room tempera-
ture did not provide the anticipated spiro-β-lactam,
rather it produced product 7a from addition of Br2
across the double bond as a mixture of inseparable
diastereomers. However, the reaction when carried
with I2 neither gave spiro nor addition product, as
1
was evident from the H NMR spectra of reaction
mixture.
These results showed that 5a was not suitable
substrate for halocyclization. This might be ascribed
to poor leaving ability of phenyl group. The lone
pair on sulphur might not be fully available for
cyclization due to resonance with phenyl group
(scheme 2).

Synthesis of novel spiro-β-lactams
133
Table 3. 7-Iodo-5-thia-2-azaspiro[3,4]octan-1-ones 11a–e and 12a–e.
α-Iodoisomer
a,b
(% yield)
β-Iodoisomer
a,b
(% yield)
1
R
2
R
Entry
1
2
3
4
5
C6H5
C6H4OCH3 (4)
C6H4OCH3 (4)
C6H4CH3 (4)
C6H5
11a (63)
11b (62)
11c (47)
11d (51)
11e (34)
12a (19)
12b (19)
12c (16)
12d (20)
12e (14)
C6H4OCH3 (4)
C6H4Cl (4)
C6H5
C6H5
C6H4Cl (4)
a
All new compounds gave satisfactory CHN analysis
1 13
Yields quoted are for the isolated products characterized by IR, H NMR, C NMR
b
It is clear that substrate 6 cyclize to give exclu-
sively the five-membered ring via a 5-endo ring clo-
sure process, instead of 4-exo ring closure. The
regiospecificity of these ring closure reactions may
be due to kinetic preference for forming the less
strained five membered ring compared to four-
membered ring.
In continuation to these studies, this reaction was
also studied using I2 as halogenating agent. Thus,
treatment of 6a with I2 (1 equiv.) under similar con-
ditions though did not show any significant change
in TLC profile, but the residue after work up and pu-
rification did show the formation of spiro product
2-(4′-methoxyphenyl)-3-phenyl-7-iodo-5-thia-2-aza-
spiro[3,4]octan-1-one. The product was found to be
a mixture of diastereomers 11a and 12a formed in
Scheme 5. Plausible mechanism for the formation of
spiro-β-lactams 9 and 10.
1
the ratio 3:1 as evident from H NMR of the crude
product (scheme 4). In one compound, the major
α-iodo isomer got separated in pure form from ethyl
acetate-hexanes. The other isomeric cyclized prod-
uct, i.e. β-iodo isomer did not crystallize in pure
form. The reaction was carried out with number of
substrates as given in table 3.
(8a) formed by addition of Br2 across the double
bond. Its structure was assigned on the basis of spec-
troscopic data. A shift in the position of allylic pro-
tons from their original value was indicative of the
formation of additional product.
The second product was identified as spiro com-
pound 2-(4′-methoxyphenyl)-3-phenyl-7α-bromo-5-
thia-2-azaspiro[3,4]octan-1-one (9a) containing five-
membered ring, formed by halocyclization. The
third compound was identified as the second
diastereomer of the above product (9a) i.e. 2-(4′-
methoxyphenyl)-3-phenyl-7β-bromo-5-thia-2-azaspiro
[3,4]octan-1-one (10a). This reaction was tried with
many substrates and was found to be general
(scheme 3 and table 2).
The structures of these products were established
1
by IR, H NMR, C NMR, DEPT-135, H– H
13
1
1
1
13
COSY, H– C COSY and MS. The stereochemistry
at C-4 junction was also assigned on the basis of
1 13
correlation of H NMR and C NMR data of these
products with those of bromo derivatives.
Thus, halocyclisation reaction of β-lactams of
type 6 leads to the formation of both α- and β-
epimers at C-7 of spiro system. The reaction em-
ploying bromine favours the formation of β-epimer,
where as reaction using iodine strongly favours the
The structures of these products were established
1
by spectroscopic studies such as IR, H NMR,
13
C
1
formation of α-epimer as indicated by H-NMR
1
1
1
13
NMR, DEPT-135, H– H COSY, H– C COSY and
MS. These results were further substantiated by
double irradiation studies of spiro-β-lactam 10e. The
stereochemistry was established through single crys-
analysis.
The favoured formation of β-bromo-spiro-β-lactam
during this reaction indicates that bromocyclization
occurs by the pathway in which Br2 adds across the
14
tal X-ray analysis of major isomer 10e (figure 2).

134
Renu Arora et al
Table 4. 5-Thia-2-azaspiro[3,4]octan-1-one 13a,d.
Product
1
2
a,b
Entry
R
R
Reagent
(% yield)
1
2
3
C6H5
C6H5
C6H5
C6H4OCH3 (4)
C6H5
n-Bu3SnH
13a (75)
13d (70)
13a (40)
n-Bu3SnH
C6H4OCH3 (4)
NaBH4–DMSO
a
All new compounds gave satisfactory CHN analysis
1
Yields quoted are for the isolated products characterized by IR, H NMR,
b
13
C
NMR
Scheme 6. Plausible mechanism for the formation of spiro-β-lactams 11 and 12.
double bond. The complete mechanism involves co- the presence of catalytic amount of AIBN in reflux-
ordination by halogen to form π-complex followed ing benzene clearly afforded the dehalogenated
by nucleophilic attack of the sulphide centre as product 13 in good yield (scheme 7 and table 4).
shown in scheme 5.
The bromide retains more stable pseudoequatorial bromination along with desulphurization, via ring
position during the nucleophilic attack of sulphur on opening producing cis-3-propyl-β-lactam. The use
the carbon of olefin–halogen complex. of NaBH4 and DMSO for dehalogenation was found
However, in case of iodocyclization the sulphur to be unsatisfactory because of low yield.
atom is transformed to an electrophilic species first,
which then interacts with olefin followed by nucleo-
philic attack of halide anion to form the five-
Increasing the amount of n-Bu3SnH afforded de-
4. Conclusion
membered spiro ring. The iodide being bigger in In conclusion, a simple and efficient methodology
size perhaps avoids the steric repulsion from phenyl for the synthesis of spiro β-lactams employing halo-
group on C-4 while approaching the cyclopropane cyclization of cis-3-allyl-3-benzylthio-β-lactams has
ring carbon to open it and hence attacks from α-side been developed. The ring closure using Br2 results in
(scheme 6).
the formation of spiro-β-lactams along with a minor
Further, the halospiro-β-lactams were also sub- addition product. However, this reaction favours the
jected to dehalogenation studies. Treatment of these formation of β-bromo epimer. In contrast, the ring
halospiro-β-lactams with n-Bu3SnH (1⋅2 equiv.) in closure using I2 leads to the exclusive formation

Synthesis of novel spiro-β-lactams
135
Scheme 7. Dehalogenation reaction of spiro-β-lactams.
Activators; University of Oxford, UK, April, Abstract
Book p. 6
of spiro-β-lactams as well as favours the formation
of α-epimer.
5. Dugar S, Clader J, Chan T M and Davis H 1995 J.
Med. Chem. 38 4875
6. (a) Gabe E and Lee F 1990 J. Org. Chem. 55 5525;
(b) Mash E A and Sharma M K 1987 Tetrahedron 43
679
Supporting Information
Crystallographic data of compound 10e can be seen
7. Alonso E, del Pozo C and Gonzalez J 2002 J. Chem.
Soc., Perkin Trans. 1 571
in website (www.ccdc.comac.uk/data_request).
8. Bhalla A, Venugopalan P and Bari S S 2006 Eur. J.
Org. Chem. 62 5054
Acknowledgement
9. Bari S S, Venugopalan P and Arora R 2003 Tetrahe-
dron Lett. 44 895
We gratefully acknowledge the financial support for
this work from the University Grants Commission
(UGC), New Delhi, India.
10. Ren X F, Turos E, Lake C H and Churchill M R 1995
J. Org. Chem. 60 6468
11. van der Veen J M, Bari S S, Krishnan L, Manhas M S
and Bose A K 1989 J. Org. Chem. 54 5758
12. Bhalla A, Madan S, Venugopalan P and Bari S S
2006 Tetrahedron 62 5054
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7277
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85⋅37(1), β – 75⋅95(1), γ – 81⋅90(1)°, V – 876⋅52(10) Å ,
3
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–1
Z – 2, D = 1⋅549 mg/m , μ(MoKα) – 2⋅619 mm ,
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2
3. (a) Guangzhong Wu and W Tormos 1997 J. Org.
Chem. 62 6414; (b) Chen L Y, Zarks A, Chack-
alamamil S and Dugar S 1996 J. Org. Chem. 61
8341
full matrix least square on F , R1 = 0⋅0315, wR2 =
0⋅0741 for 2391 reflections [I > 2σ(I)]. Crystallo-
graphic data (excluding structure factors) for the
structure 10e in this paper has been deposited with
the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC-642729
4. Austen B M, Frears E R and Davies H 2000 In Inter-
national Symposium on Proteinase Inhibitors and