Preparation of N-aryl-substituted spiro-β-lactams via staudinger cycloaddition

Article abstract of DOI:10.1139/v99-212

The interest in the study of β-lactams continues due to their therapeutic importance as antibiotics. In this work, six spiro-β-lactams (7a-7c, 8a-8c) have been prepared using the [2+2] cycloaddition of isomaleimides to acid chlorides. The heterobicyclic structures obtained have been characterized by mass spectrometry, IR, NMR spectroscopy, and for compounds 7a, 7b, and 8b the X-ray crystallographic study showed a nearly planar arrangement for the β-lactam ring.

Full text of DOI:10.1139/v99-212

2025
Preparation of N-aryl-substituted spiro-␤-
lactams via Staudinger cycloaddition
Victor Barba, Cecilia Hernández, Susana Rojas-Lima, Norberto Farfán,
and Rosa Santillan
Abstract: The interest in the study of β-lactams continues due to their therapeutic importance as antibiotics. In this
work, six spiro-β-lactams (7a–7c, 8a–8c) have been prepared using the [2+2] cycloaddition of isomaleimides to acid
chlorides. The heterobicyclic structures obtained have been characterized by mass spectrometry, IR, NMR spectroscopy,
and for compounds 7a, 7b, and 8b the X-ray crystallographic study showed a nearly planar arrangement for the
β-lactam ring.
Key words: β-lactams, azetidinone, isomaleimides, ketenes, X-ray crystallography.
Résumé : L’intérêt dans l’étude des β-lactames se maintient en raison de leur importance thérapeutique comme
antibiotiques. Dans ce travail, on a préparé six spiro-β-lactames (7a–7c, 8a–8c) en faisant appel à une cycloaddition
[2+2] d’isomaléimides sur des chlorures d’acyles. Les structures hétérobicycliques obtenues ont été caractérisées par
spectrométrie de masse, IR, spectroscopie RMN et, pour les composés 7a, 7b et 8b, une étude par diffraction des
rayons X montre que le cycle β-lactame existe dans un arrangement pratiquement plan.
Mots clés : β-lactames, azétidinone, isomaléimides, cétènes, diffraction des rayons X.
[Traduit par la Rédaction] Barba et al. 2032
Introduction
new spiro-β-lactams (7c, 8a–8c) derived from isomalei-
mides (4a–4c) with acid chloride 5 or 6 by using the
Staudinger reaction. Furthermore, the X-ray analysis for 8b
and two previously reported spiro-β-lactams (7a, 7b) (13)
was obtained.
Although a number of pharmacologically active mono-
and bicyclic β-lactams are known (1–3), the interest in the
synthesis of these types of heterocycles continues and vari-
ous elegant preparative methods have been developed (4–7).
Among the numerous methods for the synthesis of
monocyclic β-lactams, the ketene–imine cycloaddition or its
equivalent, the acid chloride – imine method, has proven to
be an exceedingly effective route for the asymmetric con-
struction of the azetidinone nuclei (8–11); specially, the β-
lactams with defined stereochemistry represent an important
synthetic target for a number of biologically active com-
pounds containing this heterocyclic framework (12).
Experimental
Instrumentation
1H- and 13C NMR spectra, in CDCl3 and DMSO-d6, were
recorded on Jeol GSX-270 MHz and Jeol Eclipse +400 MHz
NMR spectrometers. Special techniques (COSY, HETCOR,
NOESY) were applied when necessary to assign the spectra
adequately. Chemical shifts (ppm) are relative to (CH3)4Si.
Coupling constants are quoted in Hz. Infrared spectra were
recorded on a Perkin–Elmer 16F-PC FT-IR spectrophoto-
meter. Melting points were obtained on a Gallenkamp MFB-
595 apparatus and are uncorrected. Ultraviolet spectra were
recorded on a Perkin–Elmer UV–vis λ 2S spectrophotometer
from ethanol solutions. Mass spectra were recorded on a
Hewlett–Packard 5989A spectrometer. Elemental micro-
analyses were determined by Oneida Research Services,
Whitesboro, New York. Crystals suitable for X-ray diffrac-
tion of compounds 7a, 7b, and 8b were obtained when the
products were recrystallized from a mixture of ethyl ether –
hexane.
In the search for new 2-azetidinone nuclei, several spiro-
β-lactams derived from [2+2] cycloaddition reaction of
iminolactones with ketenes have been recorded in the litera-
ture (13–16). In this work we report the synthesis of four
Received June 18, 1999.
V. Barba, C. Hernández, N. Farfán, and R. Santillan.1
Departamento de Química, Centro de Investigación y de
Estudios Avanzados del IPN, Apdo. postal 14-740, 07000,
México D.F., México.
S. Rojas-Lima. Universidad Autónoma del Estado de
Hidalgo, Centro de Investigaciones Químicas, Carretera
Pachuca-Tulancingo Km. 4.5, Ciudad Universitaria, Pachuca
de Soto, Hidalgo, C.P. 42076, México.
X-ray diffraction studies of monocrystals were determined on
an Enraf–Nonius CAD4 diffractometer (λMoK = 0.71073 Å,
monochromator: graphite, T = 293 K, ω-2θ αscan). Crystals
were generally mounted in Lindeman tubes. Absorption cor-
rection was not necessary; corrections were made for
1Author to whom correspondence may be addressed.
Telephone: 52-5-747-3800, ext. 4055. Fax: 52-5-747-7113.
e-mail: rsantill@mail.cinvestav.mx
Can. J. Chem. 77: 2025–2032 (1999)
© 1999 NRC Canada

2026
Can. J. Chem. Vol. 77, 1999
Lorentz and polarization effects. Solution and refinement:
direct methods (SHELXS-86) for structure solution and
SHELXS (version 1.8, 1993) software package for refine-
ment and data output. Hydrogen atoms were determined by
difference Fourier maps and their positions as well as one
overall isotropic thermal parameter were refined.
141.1 (C-1′), 130.8 (C-2), 124.7 (C-2′,6′), 121.9 (C-3′,5′),
21.1 (CH3) ppm.
General procedure for the preparation of -lactams
7a–7c and 8a–8c
To a stirred solution of isomaleimide 4a–4c in anhydrous
dichloromethane at –78°C was added dropwise a solution of
acid chloride in 10 mL of dry dichloromethane, followed by
dropwise addition of a solution of triethylamine in dichloro-
methane. The reaction mixture was maintained at –78°C for
2 h, the resulting suspension was left to warm to room tem-
perature and stirred for 36 additional hours.
Reagents
All starting materials were commercially available. Sol-
vents were used without further purification, but single crys-
tals were grown from spectrophotometric-grade solvents.
The reaction mixture was brought to neutral pH and
poured into dichloromethane and washed with water, the or-
ganic layer was separated, dried over magnesium sulfate,
and evaporated under reduced pressure. The resulting crude
product was purified by column chromatography using silica
gel and hexane – ethyl acetate, 8:2, as the eluent. The prepa-
General procedure for the preparation of arylmaleamic
acids 3a–3c
To prepare the arylmaleamic acids 3a–3c, equimolar quan-
tities of the corresponding arylamine with maleic anhydride
were mixed in 30 mL of dry THF at 0°C and stirred for 2 h
at room temperature. The solvent was removed by filtration
and the solid washed with THF; the product obtained was
used without further purification. The preparation and spec-
troscopic data have already been published (17–18).
1
ration and spectroscopic data (IR, H NMR) of 7a and 7b
have been reported (16).
3-Chloro-1-phenyl-5-oxa-1-azaspiro[3,4]oct-7-en-2,6-dione
(7a): Compound 7a was prepared from 0.5 g (2.9 mmol) of
compound 4a and 0.8 mL (10 mmol) of chloroacetyl chlo-
ride. The resulting product obtained was a colorless solid
(0.24 g, 0.96 mmol) mp 132–133°C (lit (16) = 127–128°C),
33% yield. EI (70 eV) m/z (%): 249 (M+, 6), 130(8.4), 119(100),
4-(Phenylamino)-4-oxo-(Z)-2-butenoic acid (3a): mp 220–
221°C (lit (17) = 196°C).
4-(4′-Methoxy-phenylamino)-4-oxo-(Z)-2-butenoic acid (3b):
mp = 213−214°C (lit (18) = 181–182°C).
117(2), 102(9), 91(19), 77(11), 51(10); UV (EtOH) λ max
:
245 nm (log ⑀ = 4.1); 13C NMR (100 MHz, CDCl3) δ:
167.53 (C-6), 157.77 (C-2), 149.93 (C-8), 134.84 (C-1′),
129.61 (C-3′,5′), 127.89 (C-7), 126.73 (C-4′), 118.46 (C-2′,6′),
96.34 (C-4), 64.66 (C-3) ppm.
4-(4′-Hydroxy-phenylamino)-4-oxo-(Z)-2-butenoic acid (3c):
mp = 220−223°C (lit (17) = 210°C).
General procedure for the preparation of isomaleimides
4a–4b
3-Chloro-1-p-methoxyphenyl-5-oxa-1-azaspiro[3,4]oct-7-en-2,6-
dione (7b): Compound 7b was prepared from 0.5 g (2.5 mmol)
of compound 4b and 0.51 mL (6.4 mmol) of chloroacetyl
chloride. The product obtained was a colorless solid (0.23 g,
0.82 mmol) mp 128–130°C (lit (16) 132–133°C), 33% yield.
EI (70 eV) m/z (%) : 279 (M+., 7), 203 (2), 188 (2), 160 (2),
Arylmaleamic acids 3a–3b were dissolved in 50 mL of
dry dichloromethane, and dicyclohexylcarbodiimide was
added with magnetic stirring at –78°C. The solution was
stirred for 3−4 h at room temperature and the solvent was
evaporated under reduced pressure; the solid obtained was
washed with dry dichloromethane and used without further
purification. The preparation and spectroscopic data have al-
ready been published (16, 19).
149 (100), 134 (37), 106 (13), 78 (11). UV (EtOH) λ max
:
258 nm (log ⑀ = 4.1); 13C NMR (100 MHz, CDCl3) δ:
167.62 (C-6), 158.28 (C-2), 157.71 (C-4′), 149.81 (C-8),
127.79 (C-7), 127.37 (C-1′), 120.97 (C-2′,6′), 114.76 (C-3′,5′),
96.62 (C-4), 64.58 (C-3), 55.52 (OMe) ppm.
N-Phenylisomaleimide (4a): mp 61−62°C (lit (19) = 57−62oC).
N-P-Methoxy-phenylisomaleimide (4b): mp 70−73°C (lit (16)
= 73–74°C).
3-Chloro-1-p-acetoxyphenyl-5-oxa-1-azaspiro[3,4]oct-7-en-2,6-
dione (7c): Compound 7c was prepared from 0.5 g (2.16 mmol)
of compound 4c and 0.51 mL (6.4 mmol) of chloroacetyl
chloride. The product obtained was a colorless solid (0.22 g,
0.72 mmol) mp 118–119°C, 33% yield. EI (70 eV) m/z (%) :
307 (M+, 3), 265 (13), 135 (100), 107 (6), 52 (2), 43 (13);
UV (EtOH) λ max: 249 nm (log ⑀ = 4.1); IR (KBr): 3110,
N-P-Acetoxy-phenylisomaleimide (4c): A solution contain-
ing 3 g (14 mmol) of compound 3c and 10 mL (105 mmol)
of acetic anhydride in 20 mL of dry dichoromethane was
stirred at –78°C for 1 h, followed by the addition of 6 g
(29 mmol) of dicyclohexylcarbodiimide. The mixture was
stirred for 24 h at room temperature to give, after work-up, a
yellow solid (2.35 g, 10 mmol) mp 127–129°C, 70% yield.
EI (70 eV) m/z (%): 231 (M+, 10), 190 (12), 189 (100), 145
(15), 119 (24), 99 (1), 77 (2), 54 (21); IR (KBr): 3082, 1792,
1
1790, 1514, 1394 cm–1; H NMR (270 MHz, CDCl3), δ:
7.56 (1H, d, J = 5.7, H-8), 7.28 (2H, d, J = 8.6, H-2′,6′), 7.05
(2H, d, J = 8.6, H-3′,5′), 6.58 (1H, d, J = 5.7, H-7), 5.32
(1H, s, H-3), 2.27 (3H, s, OCOCH3) ppm; 13C NMR
(67.8 MHz, CDCl3) δ: 169.2 (C-6), 167.4 (OCO), 157.7
(C-2), 149.8 (C-8), 148.8 (C-4′), 132.3 (C-1′), 128.1 (C-7),
122.9 (C-3′,5′), 119.7 (C-2′,6′), 96.3 (C-4), 64.8 (C-3), 21.0
(CH3) ppm. Anal. calcd. for C14H10ClNO3: C 54.72, H 3.25,
N 4.56; found: C 54.71, H 3.18, N 4.57.
1
1680, 1198 cm–1; H NMR (270 MHz, CDCl3) δ: 7.43 (2H,
d, J = 9.0, H-2′,6′), 7.34 (1H, d, J = 5.5, H-3), 7.08 (2H, d,
J = 9.0, 3′,5′), 6.63 (1H, d, J = 5.5, H-2), 2.26 (3H, s,
CO—CH3) ppm; 13C NMR (67.8 MHz, CDCl3) δ: 169.3 (C-
1), 167.1 (OCO), 150.1 (C-4), 148.2 (C-4′) 143.3 (C-3),
© 1999 NRC Canada

Barba et al.
2027
Scheme 1. Reagents: (i) THF, RT, 2 h. (ii) Dicyclohexylcarbodiimide (DCC), CH2Cl2, RT, 3 h, for 4c 1 equiv. of acetic anhydride was
used. (iii) CH2Cl2, triethylamine, –70°C, 2 h to RT 30–36 h.
3-o-Chlorophenoxy-1-phenyl-5-oxa-1-azaspiro-[3,4]oct-7-en-2,6-dione
(8a): Compound 8a was prepared from 0.5 g (2.9 mmol) of
compound 4a and 1.2 g (5.85 mmol) of o-chlorophenoxy-
acetyl chloride. The product obtained was a colorless solid
(0.29 g, 0.85 mmol) mp 181–182°C, 30% yield. EI (70 eV)
m/z (%): 341 (M+, 13), 306 (2), 278 (3), 224 (25), 222 (74),
187 (100), 159 (16), 131 (14), 119 (16), 91 (20), 77 (36);
UV (EtOH) λ max: 241 nm (log ⑀ = 4.20); IR (KBr): 3110,
7.33–7.39 (4H, m, H-2′,3′,5′,6′), 7.26 (1H, m, H-4′), 7.24
(1H, ddd, J = 8.0, 7.7, 1.4, H-5″), 7.09 (1H, dd, J = 8.0, 1.4,
H-6″), 7.04 (1H, ddd, J = 8.0, 7.7, 1.4, H-4″), 6.49 (1H, d,
J = 5.7, H-7), 5.74 (1H, s, H-3) ppm; 13C NMR (100 MHz,
CDCl3) δ: 168.1 (C-6), 159.4 (C-2), 152.2 (C-1″), 150.1
(C-8), 135.0 (C-1′), 128.2 (C-4′), 129.6 (C-3′,5′), 130.8 (C-
3″), 127.7 (C-7), 126.6 (C-5″), 124.2 (C-4″), 123.3 (C-2″),
118.5 (C-2′,6′), 115.7 (C-6″), 97.0 (C-4), 88.5 (C-3) ppm.
Anal. calcd. for C18H12ClNO4: C 63.34, H 3.51, N 4.10;
found: C 63.32, H 3.65, N 4.12.
1
1782, 1588, 1514 cm–1; H NMR (400 MHz, CDCl3) δ: 7.70
(1H, d, J = 5.7, H-8), 7.38 (1H, dd, J = 8.0, 1.4, H-3″),
© 1999 NRC Canada

2028
Can. J. Chem. Vol. 77, 1999
3-o-Chlorophenoxy-1-p-methoxyphenyl-5-oxa-1-azaspiro[3,4]oct-
7-en-2,6-dione (8b): Compound 8b was prepared from 0.5 g
(2.46 mmol) of compound 4b and 1.2 g (5.85 mmol) of
o-chlorophenoxyacetyl chloride. The product obtained was a
colorless solid (0.26 g, 0.7 mmol) mp 136–137°C, 28%
yield. EI (70 eV) m/z (%): 371 (M+, 9), 224 (2), 222 (7), 203
(9), 187 (18), 149 (100), 134 (23), 106 (8), 77 (8); UV
(EtOH) λ max: 252 nm (log ⑀ = 4.21); IR (KBr): 3104, 1780,
(Scheme 1). The structure of these compounds was
confirmed by mass spectrometry where molecular ions were
detected in all cases.
The structures of β-lactams 7a–7c and 8a–8c were estab-
1
1
lished by H and 13C NMR spectroscopy. H NMR analysis
of products 7a–7c and 8a–8c showed a singlet in the range
of 5.31–5.74 ppm corresponding to H-3 of the β-lactam ring.
1
Comparison of the H NMR data for this signal shows that
1
1718, 1248 cm–1; H NMR (400 MHz, CDCl3) δ: 7.66 (1H,
in the case of compounds 8a–8c the signal is shifted to
higher field (∆δ ≈ 4 ppm) than for 7a–7c. These differences
are due to the presence of electron-donating or -withdrawing
substituents at the C-3 position (chlorine for 7a–7c and oxy-
gen for 8a–8c). All of them display signals for vinylic pro-
tons (AB system) between 6.54 and 7.59 ppm for 7a–7c and
6.49 and 7.70 ppm for 8a–8c, with a coupling constant from
5.6 to 5.8 Hz; this AB system remained intact in the course
of the cyclization.
d, J = 5.7, H-8), 7.36 (1H, dd, J = 8.0, 1.4, m, H-3″), 7.25
(1H, d, J = 8.8, H-2′,6′), 7.22 (1H, ddd, J = 8.0, 7.3, 1.4, H-
5″), 7.07 (1H, ddd, J = 8.0, 1.4, 1.0, H-6″), 7.01 (1H, ddd, J
= 8.0, 7.3, 1.4, H-4″), 6.84 (1H, d, J = 8.8, H-3′,5′), 6.49
(1H, d, J = 5.7, H-7), 5.71 (1H, s, H-3), 3.77 (3H, s, OMe)
ppm; 13C NMR (100 MHz, CDCl3) δ: 168.2 (C-6), 159.3 (C-
2), 158.1 (C-4′), 152.2 (C-1″), 150.0 (C-8), 130.7 (C-3″),
128.1 (C-5″), 127.6 (C-7), 124.1 (C-4″), 123.3 (C-1′), 122.0
(C-2″), 121.0 (C-2′, 6′), 115.6 (C-6″), 114.7 (C-3′, 5′), 97.2
(C-4), 88.3 (C-3), 55.5 (OMe) ppm. Anal. calcd. for
C19H14ClNO5: C 61.45, H 3.77, N 3.77; found C 61.08, H
3.72, N 3.74.
The 13C NMR spectra exhibited two carbonyl signals at
167–169 and 157–159 ppm for C-6 and C-2, respectively.
The most interesting observation is the extreme high-field
shift of the C-3 (88.5, 88.3, 88.4 ppm, for 8a–8c) compared
with the downfield shift for the same carbon in 7a–7c (64.7,
64.6, 64.8 ppm). The susbtituent effects may explain these
differences.
The relative configuration at C-3 and C-4 was established
on the basis of evidence from NMR spectra and NOE stud-
ies. Thus, the proton attached to C-8 in 7b showed NOE in-
teraction with H-2′ in the 400 MHz NOESY spectrum. The
fact that no effect was observed between H-8 and H-3 sup-
ports the conclusion that the chlorine atom at C-3 and the
oxygen atom at C-4 have a trans relationship.
3-o-Chlorophenoxy-1-p-acetoxyphenyl-5-oxa-1-azaspiro[3,4]oct-
7-en-2,6-dione (8c): Compound 8c was prepared from 0.5 g
(2.16 mmol) of compound 4c and 1.2 g (5.85 mmol) of o-
chlorophenoxyacetyl chloride. The product obtained was a
colorless solid (0.30 g, 0.75 mmol) mp 122–123°C, 34%
yield. EI (70 eV) m/z (%): 399 (M+, 7), 356 (18), 224 (24),
222 (68), 189 (25), 187 (68), 159 (10), 135 (73), 107 (10),
77 (10), 69 (20), 43 (100); UV (EtOH) λ max: 245 nm (log ⑀
1
= 4.19); IR (KBr): 3088, 1766, 1516, 1482 cm–1; H NMR
(400 MHz, CDCl3), δ: 7.67 (1H, d, J = 5.6, H-8), 7.36
(1H, dd, J = 8.0, 1.6, H-3″), 7.33 (2H, d, J = 8.9, H-2′,6′),
7.23 (1H, ddd, J = 8.0, 7.3, 1.6, H-5″), 7.06 (2H, d, J = 8.9,
H-3′,5′), 7.02 (2H, ddd, J = 8.0, 7.3, 1.4, H-4″,6″), 6.54 (1H,
d, J = 5.6, H-7), 5.73 (1H, s, H-3), 2.28 (3H, s, OCOCH3)
ppm; 13C NMR (100 MHz, CDCl3) δ: 169.2 (C-6), 167.0
(OCO), 159.2 (C-2), 152.1 (C-1″), 149.9 (C-8), 132.4 (C-1′),
148.5 (C-4′), 130.7 (C-3″), 128.1 (C-5″), 127.8 (C-7), 124.2
(C-4″), 123.2 (C-2″), 122.8 (C-3′,5′), 119.6 (C-2′,6′), 115.6
(C-6″), 96.9 (C-4), 88.4 (C-3), 21.0 (CH3) ppm. Anal. calcd.
for C20H14ClNO6: C 60.15, H 3.50, N 3.50; found C 59.97,
H 3.54, N 3.50.
The structures of 7a, 7b, and 8a were determined by
X-ray crystallography, which confirmed the structures and
stereochemistries of these compounds. The molecular struc-
tures of 7a, 7b, and 8a are shown in Figs. 1–3. The crystal
data are summarized in Table 1. Selected bond angles, inter-
atomic distances, and torsion angles are given in Tables 2
and 3 and have been deposited.2
The X-ray analysis shows that the arrangement of bonds
around the nitrogen atom is approximately planar. The
C(12)—N(1) bond distances are 1.416(4)/1.412(4), 1.415(3)/
1.414(3), and 1.426(6) Å for 7a, 7b, and 8b, respectively
,
and are considerably shorter than the usual value of 1.47 Å,
and indicate double bond character. Similar bond lengths
(1.41(1) and 1.409(4) Å) have been reported for two similar
β-lactams, 9 and 10 (20, 21) (Scheme 2). Additionally, the
Results and discussion
When the arylamines 1a–1c are treated with maleic anhy-
dride (2), the arylmaleamic acids (3a–3c) are formed in
excellent yields (17–18). The reaction of these acids with
dicyclohexylcarbodiimide affords isomaleimides 4a–4c in
good yields (16, 19). In no case was the formation of
N-arylmaleimides observed under these conditions.
The isomaleimides 4a–4c underwent [2+2] cycloaddition
reaction (Staudinger reaction) with two acid chlorides (5, 6)
in the presence of triethylamine to give regioselectively the
spiro-β-lactams (7a–7c and 8a–8c) in 27–34% yields
C(2)—N(1)
bond
distances
of
1.383(4)/1.375(4),
1.377(3)/1.374(3), and 1.369(6) Å for 7a, 7b, and 8b, re-
spectively, are consistent with N=C double bonding. These
results are in accordance with the observation than the
C(12)-N(1)-C(2) bond angle is 3° larger than the correspond-
ing bond angle for the C(12)-N(1)-C(4) fragment, which can
be attributed to π-delocalization between the amide group
and the aromatic ring.
The high ring strain can be seen from the internal angles,
which show that the larger bond angle is C(2)-N(1)-C(4),
2 Suplementary material may be purchased from: The Depository of Unpublished Data, Document Delivery, CISTI, National Research Coun-
cil of Canada, Ottawa, Canada, K1A 0S2. These have also been deposited with the Cambridge Crystallographic Data Center, and can be ob-
tained on request from: The Director, Cambridge Crystallographic Data Center, University Chemical Laboratory, 12 Union Road,
Cambridge, CB2 1EZ, U.K.
© 1999 NRC Canada

Barba et al.
2029
Fig. 1. Molecular structure of compound 7a; the thermal ellipsoid probability level is 25%.
Fig. 2. Molecular structure of compound 7b; the thermal ellipsoid probability level is 25%.
Fig. 3. Molecular structure of compound 8b; the thermal
ellipsoid probability level is 25%.
94.6(2)/94.9(2), 94.8(2)/95.0(2), and 95.2(3)° and the smaller
bond angle is C(2)-C(3)-C(4), 86.2(2)/85.6(2), 86.0(2)/85.6(2),
and 85.7(3)° for 7a, 7b, and 8b, respectively.
The internal torsion angles indicate the nonplanarity of
the β-lactam ring, in agreement with literature data on struc-
tural analogues (12, 20−22). The torsion angles in the β-
lactam ring range from 4.6 to 9.1° (in absolute values). The
dihedral angles between the plane of the phenyl ring and the
β-lactam ring are 3.4/1.2, –1.2/7.5, and 2.9° for C(2)-N(1)-
C(12)-C(13) and –2.3/7.9, –7.9/11.9, and –4.2° for C(4)-
N(1)-C(12)-C(17), corresponding to 7a, 7b, and 8b, respec-
tively.
© 1999 NRC Canada

2030
Can. J. Chem. Vol. 77, 1999
Table 1. Crystallographic data of compounds 7a, 7b, and 8b.a
7a
7b
8b
Formula
C12H8ClNO3
0.40 × 0.30 × 0.20
Triclinic
249.64
P1
C13H10ClNO4
0.24 × 0.24 × 0.18
Triclinic
279.67
P1
C19H14ClNO5
0.3 × 0.3 × 0.24
Monoclinic
371.76
Crystal size (mm)
Crystal system
fw (g mol–1)
Space group
P21/c
Cell parameters
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (Å3)
Z
7.393(1)
9.005(2)
17.681(4)
94.63(3)
95.07(3)
102.75(3)
1137.5(4)
4
7.635(2)
10.061(2)
18.019(4)
96.25(3)
101.01(3)
110.83(3)
1246.1(5)
4
7.397(1)
6.774(1)
33.924(7)
90.00
92.15(3)
90.00
1698.6(5)
4
µ (mm–1)
ρcalcd (g cm–3)
0.330
1.458
0.316
1.491
0.256
1.454
Data collection
2θmax (°)
44
46
44
Total reflections
Unique reflections
Rmerge
2744
2514
0.0128
1903
6904
3452
0.02
2541
4023
2079
0.07
1490
Refl. with I > 4σ(I)
Refinement
R/Rw(F)b,d
0.0343/0.0868
0.0567/0.0962
307
0.035/0.0892
0.0572/0.1002
343
0.0521/0.1306
0.0816/0.1420
235
R/Rw(F2) (all data)c
No. of variables
Gofd
0.999
1.027
1.188
Max ∆/σ (final cycle)
∆ρmin (e Å–3)
∆ρmax (e Å–3)
0.001
–0.224
0.208
0.001
–0.254
0.309
0.001
–0.216
0.420
aTemperature 293 K, Enraf Nonius CAD4 diffractometer, MoKα (λ = 0.71073) radiation, graphite monochromator.
bR(F) = Σ||Fo| – |Fc|| / Σ|Fo|, Rw(F) = [Σ w(|Fo| – |Fc|)2 / Σ w|Fo|2]1/2
.
2
2
2
2 2
cR(F2) = Σ||Fo | – |Fc2|| / Σ|Fo |, Rw(F2) = [Σ w(|Fo | – |Fc2|)2 / Σ w|Fo | ]1/2
.
dValues given for R, Rw, and gof are based on those reflections with I > 4σ(I).
Scheme 2.
The mean values of the internal bond angles in the β-
lactam ring are 89.6/89, 89.85/ 89.87, and 89.82° for 7a, 7b,
and 8b, respectively, indicating that the ring strain is very
similar in these heterocycles.
In conclusion, the regioselective synthesis of four new
spiro-β-lactams with a trans stereochemistry was shown by
NOE experiments and X-ray diffraction analysis. The molec-
ular perspective of these compounds shows a nearly planar
arrangement for the β-lactam ring and the N-phenyl group.
Acknow ledgments
Financial support from Consejo Nacional de Ciencia y
Tecnología (CONACYT) is acknowledged.
© 1999 NRC Canada

Barba et al.
Table 2. Selected bond lengths and bond angles of compounds 7a, 7b, and 8b.
2031
7a/7a′
7b/7b′
8b
Bond lengths (Å)
N(1)—C(12)
N(1)—C(4)
N(1)—C(2)
C(2)—C(3)
C(3)—C(4)
C(4)—O(5)
O(5)—C(6)
C(6)—C(7)
C(7)—C(8)
C(8)—C(4)
C(3)—Cl(10)a
C(2)—O(9)
C(6)—O(11)
1.416(4)/1.412(4)
1.457(4)/1.454(4)
1.383(4)/1.375(4)
1.514(5)/1.510(4)
1.541(4)/1.560(4)
1.418(3)/1.429(3)
1.383(4)/1.380(4)
1.453(5)/1.452(4)
1.307(4)/1.306(4)
1.482(4)/1.485(4)
1.755(3)/1.757(3)
1.200(4)/1.207(4)
1.196(4)/1.199(3)
1.415(3)/1.414(3)
1.460(3)/1.456(3)
1.377(3)/1.374(3)
1.510(4)/1.512(4)
1.552(3)/1.559(3)
1.419(3)/1.424(3)
1.388(3)/1.384(3)
1.459(4)/1.453(4)
1.311(3)/1.312(3)
1.484(3)/1.493(4)
1.754(3)/1.761(3)
1.207(3)/1.201(3)
1.185(3)/1.194(3)
1.426(6)
1.463(6)
1.369(6)
1.531(7)
1.546(7)
1.428(6)
1.380(6)
1.463(8)
1.313(7)
1.483(7)
1.409(6)
1.191(6)
1.200(6)
Bond angles (°)
C(12)-N(1)-C(2)
C(12)-N(1)-C(4)
N(1)-C(2)-C(3)
N(1)-C(2)-O(9)
N(1)-C(4)-C(3)
N(1)-C(4)-O(5)
N(1)-C(4)-C(8)
C(2)-N(1)-C(4)
C(2)-C(3)-Cl(10)a
C(2)-C(3)-C(4)
C(3)-C(2)-O(9)
C(3)-C(4)-O(5)
C(3)-C(4)-C(8)
C(3)-O(10)-C(20)
134.0(3)/133.8(3)
131.3(3)/131.0(2)
90.7(2)/91.8(2)
132.1(3)/132.3(3)
86.9(2)/86.9(2)
114.2(2)/113.1(2)
116.8(3)/119.0(2)
94.6(2)/94.9(2)
117.8(2)/115.6(2)
86.2(2)/85.6(2)
137.1(3)/135.8(3)
114.6(2)/113.9(2)
119.0(3)/118.6(3)
—
134.1(2)/134.3(2)
131.0(2)/130.6(2)
91.7(2)/91.9(2)
132.4(3)/132.6(3)
86.9(2)/87.0(2)
113.7(2)/113.2(2)
117.4(2)/118.1(2)
94.8(2)/95.0(2)
115.9(2)/115.5(2)
86.0(2)/85.6(2)
135.8(3)/135.5(2)
114.0(2)/113.5(2)
119.0(2)/119.8(2)
—
133.8(4)
130.9(4)
91.2(4)
133.1(5)
87.2(3)
113.3(4)
117.6(4)
95.2(3)
111.8(4)
85.7(3)
135.7(5)
114.1(4)
119.4(4)
117.3(4)
aO(10) for 8b.
Table 3. Selected torsion angles (°) for compounds 7a, 7b, and 8b.a
7a
7b
8b
C(12)-N(1)-C(2)-O(9)
7.9/–4.9
5.7/–3.5
2.3
C(12)-N(1)-C(2)-C(3)
C(12)-N(1)-C(4)-C(3)
C(2)-N(1)-C(12)-C(13)
C(4)-N(1)-C(12)-C(17)
N(1)-C(2)-C(3)-C(4)
C(2)-C(3)-C(4)-N(1)
–173.6/178.7
173.6/–178.6
3.4/1.2
–2.3/7.9
–9.1/6.3
–177.5/178.0
177.5/–178.0
–1.2/7.5
–7.9/11.9
–5.9/4.9
–176.9
176.8
2.9
–4.1
–6.7
6.2
8.6/–6.0
5.6/4.6
aA positive rotation is counterclockwise from atom 1, when viewed from atom 3 to atom 2.
9. R.C. Thomas. Tetrahedron Lett. 30, 5239 (1989).
10. I. Ojima, T. Komata, and X.J. Qui. J. Am. Chem. Soc. 112,
770 (1990).
11. C. Palomo, F.P. Cossío, and C. Cuevas. Tetrahedron Lett. 32,
3109 (1991).
12. G. Barbaro, A. Battaglia, A. Guerrini, C. Bertucci, and
S. Geremia. Tetrahedron Asymm. 9, 3041 (1998), and refs.
therein.
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© 1999 NRC Canada