Synthesis of some mono- and bis-spiro-β-lactams of benzylisatin

Article abstract of DOI:10.1016/j.tetlet.2007.07.199

Some new mono- and bis-spiro-β-lactams of benzylisatin were prepared by Staudinger's ketene-imine [2+2] cycloaddition reaction. The cycloadducts were characterized by spectral data including ¹H NMR, ¹³C NMR, IR and mass spectra. The

Full text of DOI:10.1016/j.tetlet.2007.07.199

Tetrahedron Letters 48 (2007) 7140–7143
Synthesis of some mono- and bis-spiro-b-lactams of benzylisatin
Aliasghar Jarrahpour* and Dariush Khalili
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 3 July 2007; revised 26 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—Some new mono- and bis-spiro-b-lactams of benzylisatin were prepared by Staudinger’s ketene–imine [2+2] cycloaddi-
tion reaction. The cycloadducts were characterized by spectral data including 1H NMR, 13C NMR, IR and mass spectra. The con-
figuration of benzylisatin and one of mono-spiro-b-lactams (5a) was established by X-ray crystal analysis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The b-lactam skeleton is the key structural unit of b-lac-
tam antibiotics. The importance of b-lactams for the
treatment of bacterial infections have been amply estab-
lished. Although b-lactam derivatives are well known
for their antibiotic activities,1 they have also been used
as synthons for the synthesis of various natural and
unnatural products.2 1,3,4-Trisubstituted b-lactams
were found to be potent cholesterol absorption inhibi-
tors,3 human cytomegalovirus protease inhibitors,4 and
thrombin inhibitors.5 Ojima et al. have shown the utility
of bis-b-lactams for the synthesis of peptides.6 Raghuna-
than et al. have synthesized a series of macrocyclic bis-b-
lactams via a highly stereoselective [2+2] cycloaddition
reaction.7 The rapid emergence of bacterial strains resis-
tant to members of this class of compounds require a
continuous effort for the design and synthesis of novel
derivatives. Spiro compounds represent an important
class of naturally occurring compounds characterized
by pronounced biological properties.8 Spiro-b-lactams
are interesting compounds due to their antiviral9 and
antibacterial properties.10 Several syntheses of spiro-b-
lactams have been described in the literature,11 but to
the best of our knowledge, there have been no reports
of bis-spiro-b-lactams. Therefore in continuation of
our work on the synthesis of novel b-lactams,12 we pres-
ent here the results obtained in the synthesis of isatin-
derived mono- and bis-spiro-b-lactams using the
efficient Staudinger reaction.
Isatin 1 was selected as the starting material because it
has shown a wide variety of biological and pharmaco-
logical activities.13,14 Since isatin is not soluble in the
conventional solvents used for b-lactam synthesis, it
was converted into its benzyl derivative 2 by reaction
with benzyl bromide in the presence of calcium hydride
in DMF.15 The structure of 2 was confirmed by single-
crystal X-ray diffraction. The molecular structure and
labelling scheme are shown in Figure 1.16
Schiff bases 3 and 4a–c were prepared by stirring
2,4-dimethoxyaniline and various aromatic di-amines
with N-benzylisatin in the presence of a catalytic
amount of acetic acid in refluxing ethanol. Crude imines
3 and 4a–cwere treated with different acyl chlorides in
the presence of triethylamine in dichloromethane for
Keywords: Isatin; Benzylisatin; Bis-spiro-b-lactam; Staudinger reaction.
*
Corresponding author. Tel.: +98 711 228 4822; fax: +98 711 228
0926; e-mail addresses: aliasghar6683@yahoo.com; jarrah@susc.ac.ir
Figure 1. An ORTEP-3 drawing of 2, with the atom-numbering
scheme and 50% probability displacement ellipsoids.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.199

A. Jarrahpour, D. Khalili / Tetrahedron Letters 48 (2007) 7140–7143
7141
several hours to give mono- and bis-spiro-b-lactams
5a–d17 and 6a–f in 50–70% yields (Scheme 1), as single
diastereomers.
The reaction progress was monitored by TLC and the
presence of a new compound was confirmed. In addi-
tion, the cycloadducts were characterized by spectral
analysis. For 5a, the IR spectrum shows the characteris-
tic absorption of a b-lactam carbonyl at 1766 and isatin
1
carbonyl at 1728 cmꢀ1. The H NMR spectrum shows
the methoxy protons as two singlets at 3.39 and 3.75,
the benzylic protons as a doublet of doublets at
4.73 ppm (J = 15 Hz) and 5.10 ppm (J = 15 Hz), the
b-lactam H-3 proton as a singlet at 5.64 and aromatic
protons as a multiplet at 6.29–7.93. The 13C NMR spec-
trum exhibited the following signals: CH2 benzylic at
44.2, OMe at 55.2 and 55.5, C-3 of azetidinone ring at
69.9, C-4 (spiro carbon) at 86.0, and aromatic carbons
at 99.5–159.3, the b-lactam carbonyl appeared at 163.4
and the isatin carbonyl at 173.8. The structure of
mono-spiro-b-lactam 5a was further confirmed by a
single-crystal X-ray analysis (Fig. 2). In 5a, the four-
and five-membered rings are nearly planar, the dihedral
angle between these two rings is 86.44ꢁ. The crystal
structure is stabilized by intramolecular C—Hꢁ ꢁ ꢁO
hydrogen-bonding and van der Waals interactions.18
The results for other mono-spiro-b-lactams are shown
in Table 1.
Figure 2. A view of 5a, with the atom-numbering scheme and 30%
probability displacement ellipsoids. All H atoms have been omitted for
clarity.
In the synthesis of mono-spiro-b-lactams, it was found
that the use of alkyloxy acetyl chlorides increase the
yield of cycloaddition products. Furthermore, when this
reaction was performed with phthaloylglycyl and 5-nor-
bornene-2,3-dicarboxyloylglycyl chloride, similar prod-
ucts (5b,c) were obtained but with lower yields.
MeO
O
MeO
O
OMe
R
O
O
N
N
iii
ii
i
OMe
O
O
O
N
N
N
N
H
5a-d
1
3
2
5a: R=PhO
5b: R=
O
iv
N
O
5c: R=PhthN
5d: R=MeO
X
X
O
O
N
N
N
N
R
R
O
O
O
O
v
N
N
N
N
6a-f
6a: X = CH2 (4,4'), R=PhO
6b: X = CH2 (4,4'), R=PhthN
6c: X = CH2 (3,3'), R=PhO
6d: X = CH2 (3,3'), R=PhthN
4a-c
4a: X= CH2 (4,4')
4b: X= CH2 (3,3')
4c: X=
O (4,4')
6e: X =
6f: X =
O
O
(4,4'), R=PhO
(4,4'), R=PhthN
Scheme 1. Reagents and conditions: (i) benzyl bromide, CaH2, DMF, 50 ꢁC; (ii) 2,4-dimethoxyaniline, reflux in EtOH; (iii) RCH2COCl, Et3N,
ꢀ10 ꢁC to rt, CH2Cl2; (iv) Diamine, reflux in EtOH; (v) R0CH2COCl, Et3N, ꢀ10 ꢁC to rt, CH2Cl2.

7142
A. Jarrahpour, D. Khalili / Tetrahedron Letters 48 (2007) 7140–7143
Table 1. Synthesis of mono-spiro-b-lactams 5a–d from Schiff base 3
and different acyl chlorides in CH2Cl2
References and notes
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Table 2. Synthesis of bis-spiro-b-lactams 6a–f using different acyl
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b-Lactam
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Bisimines 4a–c on reaction with various acid chlorides in
the presence of triethylamine resulted in bis-spiro-b-
lactams 6a–f in moderate to good yields (Scheme 1,
Table 2).
The cycloadducts were characterized by spectral analy-
sis. The IR spectrum of 2-azetidinone 6a shows a
carbonyl peak at 1774 and the isatin carbonyl at
1
1720 cmꢀ1. The H NMR spectrum exhibited the meth-
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ylene protons at d 3.77, the signals in the 4.69–5.02 cor-
related with benzylic protons, the signals in the 5.52
correlated with H(3) and the aromatic protons reso-
nated in the 6.58–7.62 region. The 13C NMR spectrum
exhibited the following signals: Ph–C–Ph at 40.6, benz-
ylic carbons at 44.5, C(3) at 66.9, the spiro carbon at
85.3, the aromatic carbons at 109.8–142.9, the b-lactam
carbonyl at 156.6 and the isatin carbonyl at 161.4. The
mass spectrum shows a peak at m/e 577 corresponding
to C37H27N3O4. Changing the phenoxyacetyl chloride
to the phthaloylglycyl chloride resulted in a lower yield
of cycloaddition product.
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This Letter describes the first examples of bis-spiro-b-
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The authors thank the Shiraz University Research
Council for financial support (Grant No. 85-GR-SC-
23).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
07.199.
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7143
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evaporated to give the crude product, which was purified
by column chromatography over silica gel. Spectral data
of compound 5a: Mp 176 ꢁC. IR (KBr, cmꢀ1): 1728
(COIs), 1766 cmꢀ1 (CO, b-lactam). 1H NMR (CDCl3,
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250 MHz): d 3.39, 3.75 (6H, s, OMe), 4.73 (1H, d, Ha Bn
,
J = 15 Hz), 5.10 (1H, d, Hb Bn, J = 15 Hz), 5.64 (1H, s,
CHlactam), 6.29–7.93 (17H, m, ArH). 13C NMR (CDCl3,
62.9 MHz): d 44.17 (CH2-benzylic), 55.17 and 55.50 (OMe),
69.90 (C3), 85.98 (C4spiro carbon), 99.50–159.25 (aromatic
carbons), 163.44 (COb-lactam), 173.77 (COisatin). MS (m/z
%): 506 (28.8), 372 (16.0), 328 (22.8), 327 (55.7). Spectral
data for 6a: Mp 144 ꢁC, IR (KBr, cmꢀ1): 1720 (COIs),
1774 (CO, b-lactam). 1H NMR (CDCl3, 250 MHz): d 3.77
(2H, s, CH2), 4.69–5.02 (4H, m, HBn), 5.52 (2H, s, Hlactam),
6.58–7.62 (36H, m, ArH). 13C NMR (CDCl3, 62.9 MHz):
d 40.63 (Ph–C–Ph), 44.46 (CH2-benzylic), 66.87 (C3),
85.29 (C4), 109.80–142.91 (aromatic carbons), 156.57
(COb-lactam), 161.41 (COisatin), MS (m/z %): 577 (2.9),
443 (1.6), 327 (18.5).
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¨ ¨
¨
01577.
17. General procedure for the synthesis of mono- and bis-spiro-
b-lactams: A solution of the acid chloride (6.00 mmol) in
dry CH2Cl2 (15 mL) was slowly added to a solution of
Schiff base (1.0 mmol) and triethylamine (9 mmol) in
CH2Cl2 (15 mL) at ꢀ10 ꢁC. The reaction mixture was then
allowed to warm to room temperature and stirred for 15 h.
It was then washed with water (2 · 20 mL), saturated
NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and
18. Pinar, S.; Akkurt, M.; Jarrahpour, A. A.; Khalili, D.;
Buyukgungo¨r, O. Acta. Crystallogr. E 2006, 62, 0804–
¨ ¨
¨
0806.