Inversion of stereochemistry in the Co2(CO)8-catalyzed carbonylation of aziridines to β-lactams. The first synthesis of highly strained trans-bicyclic β-lactams

Article abstract of DOI:10.1021/ja9531586

β-Lactams were synthesized by the carbonylative ring expansion of aziridines catalyzed by dicobalt octacarbonyl under CO pressure. The active catalyst, cobalt tetracarbonyl anion, induces nucleophilic ring opening of the heterocycle, resulting in inversio

Full text of DOI:10.1021/ja9531586

J. Am. Chem. Soc. 1996, 118, 111-116
111
Inversion of Stereochemistry in the Co2(CO)8-Catalyzed
Carbonylation of Aziridines to â-Lactams. The First Synthesis
of Highly Strained trans-Bicyclic â-Lactams
Marcelo E. Piotti and Howard Alper*
Contribution from the Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa,
Ontario, Canada K1N 6N5
ReceiVed September 14, 1995X
Abstract: â-Lactams were synthesized by the carbonylative ring expansion of aziridines catalyzed by dicobalt
octacarbonyl under CO pressure. The active catalyst, cobalt tetracarbonyl anion, induces nucleophilic ring opening
of the heterocycle, resulting in inversion of configuration. The regio- and stereospecificity of this reaction resulted
in the synthesis of the first highly strained trans-7-azabicyclo[4-2-0]octan-8-one derivatives.
Introduction
purity. Another interesting example is the carbonylation of vinyl
aziridines with [Pd2(dba)3‚CHCl3], Ph3P, and CO (1 atm).9 The
carbonyl insertion occurs, as in the above example, at the most
substituted ring carbon-nitrogen bond.
The use of carbon monoxide for the carbonylation of organic
compounds in the presence of transition metal catalysts is an
important method for organic synthesis.1 One facet of this
chemistry involves carbonylation with ring expansion of het-
erocycles, leading to lactams, lactones, or thiolactones.2 Rep-
resentative examples include the carbonylation of azirines,3
azetidines,4 oxetanes, and thietanes,5 pyrrolidines,6 and thiazo-
lidines.7
The ring strain present in three-membered ring compounds
makes them interesting substrates for carbonylation. The facility
to open these rings suggests that carbonylation could take place
under relatively mild conditions. Aziridines,8-10 oxiranes,11 and
thiiranes12 have been subjected to carbonylation affording
different heterocyclic compounds.
There are few examples of the carbonylation and ring
expansion of aziridines. The reaction of 2-aryl-1-alkylaziridines8
with carbon monoxide in the presence of catalytic amounts of
[Rh(CO)2Cl]2 is the most impressive case (eq 1). This reaction,
which affords â-lactams in quantitative yields, is regiospecific,
with carbonyl insertion occurring exclusively into the aryl
bearing carbon-nitrogen bond. The process is stereospecific,
proceeding with retention of stereochemistry of the substituents
on the carbon atoms of the aziridine ring. When the carbony-
lation reaction is carried out in the presence of optically pure
d- or l-menthol, kinetic resolution of the aziridine takes place,
and the aziridine and the lactam are both obtained in high optical
The two noted examples are limited to aziridines bearing
activating groups in the 2-position (phenyl or vinyl), which likely
have a directive effect in the process. Carbonylation of
nonactivated aziridines10 takes place by treating the aziridine
first with LiI and then with Ni(CO)4, followed by workup with
iodine (eq 2). In this case CO inserts into the less substituted
carbon-nitrogen bond with net retention of configuration,
affording moderate yields (40-50%) of â-lactams. Unfortu-
nately excess quantities of the very toxic nickel tetracarbonyl
are required for this reaction.
We now wish to report that nonactivated aziridines can be
carbonylated to â-lactams using catalytic amounts of Co2(CO)8,
with CO insertion occurring into the least substituted ring C-N
bond. Furthermore, these reactions often proceed in high yields
and always with inversion of configuration, complementing the
stereochemistry of the rhodium-catalyzed reaction. This meth-
odology also resulted in the isolation of the trans-7-azabicyclo-
[4.2.0]octan-8-one ring system. This is, to our knowledge, the
first synthesis of these highly strained fused â-lactams.
X Abstract published in AdVance ACS Abstracts, December 1, 1995.
(1) Colquhoun, H. M.; Thompson, D. G.; Twigg, M. V. Carbonylation;
Plenum Press: New York, 1991; pp 191-203.
(2) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res., in press.
(3) Alper, H.; Perera, C. P.; Ahmed, F. R. J. Am. Chem. Soc. 1981, 103,
1289.
(4) Roberto, D.; Alper, H. J. Am. Chem. Soc. 1989, 111, 7539.
(5) Wang, M. D.; Calet, S.; Alper, H. J. Org. Chem. 1989, 54, 20.
(6) Wang, M. D.; Alper, H. J. Am. Chem. Soc. 1992, 114, 7018.
(7) Khumtaveeporn, K.; Alper, H. J. Am. Chem. Soc. 1994, 116, 5662.
(8) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931.
(9) a) Spears, G. W.; Nakanishi, K.; Ohfune, Y. Synlett 1991, 91. b)
Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett. 1993, 3, 2415.
(10) Chamchaang, W.; Pinhas, A. R. J. Org. Chem. 1990, 55, 2943.
(11) (a) Aumann, R.; Ring, H. Angew. Chem., Int. Ed. Engl. 1977, 16,
50. (b) Kamiya, Y.; Kawato, K.; Ohta, H. Chem. Lett. 1980, 1549. (c)
Alper, H.; Calet, S. Tetrahedron Lett. 1988, 29, 1763. (d) Alper, H.;
Arzoumanian, J. F.; Petrignani, J. F.; Saldana-Maldonado, M. J. Chem. Soc.,
Chem. Commun. 1985, 340.
Results and Discussion
Treatment of 1,2-disubstituted aziridines (1a-5a) with carbon
monoxide and dicobalt octacarbonyl in 1,2-dimethoxyethane
(DME) for one day at 100 °C and ∼33 atm of CO gave
â-lactams in up to 95% yield (Table 1). The ratio of aziridine
to Co2(CO)8 was 12/1. The reaction is regiospecific for 1a-
4a, with carbonyl insertion occurring into the less substituted
of the two ring carbon-nitrogen bonds. The isolated yields of
(12) Calet, S.; Petrignani, J. F.; Arzoumanian, H.; Alper, H. Organo-
metallics 1987, 6, 1625.
0002-7863/96/1518-0111$12.00/0 © 1996 American Chemical Society

112 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Piotti and Alper
Table 1. Cobalt-Catalyzed Carbonylation of Monocyclic
Aziridines
As far as a possible mechanism is concerned, the inversion
of configuration resulting from carbonylation indicates that the
ring opening of the aziridine may proceed in a SN2 manner.
The reaction of Co2(CO)8 with N, O, and P donors is known to
induce the cleavage of the Co-Co bond and form the ionic
pair 11 (eq 4).14 Tetracarbonylcobaltate is a nucleophile of
moderate strength,15 useful for effecting reactions such as the
carbonylation of epoxides with added alcohol to form â-hydroxy
esters.16 It has been proposed that the latter reaction proceeds
by anion attack at the less substituted carbon atom of the oxirane
ring. A similar sequence of events may occur for an aziridine,
which, of course, can be regarded as an N-donor.
isolated
yield (%)
R1
R2
Et
n-Bu
Et
t-Bu
H
Me
Me
Ph
R3
R4
product
1a
2a
3a
4a
6a
7a
8a
9a
10a
PhCH2CH2
PhCH2CH2
PhCH2
p-MeOPh
i-Pr
PhCH2CH2
PhCH2CH2
t-Bu
H
H
H
H
Ph
Me
H
Ph
Ph
H
H
H
H
H
H
Me
H
H
1b
2b
3b
4b
6b
7b
8b
9b
10b
94
95
64
50
42
95
95
94
94
i-Pr
Me
-
â-lactams are excellent (>90%) for 1b and 2b, both of which
contain a phenethyl group at nitrogen, but decrease when the
nitrogen substituent is changed to benzyl (3a) or aryl (4a).
Nevertheless, as the p-methoxyphenyl group can easily be
removed by oxidative dearylation using ceric ammonium
nitrate13 to give the unsubstituted 2-azetidinone, this is a useful
tool for the preparation of different â-lactam derivatives.
The effect of a benzoyl group in position 1 (5a) is significant,
since it induces carbonylation of the two C-N bonds, giving a
mixture of isomeric products (5b and 5c) in high combined yield
(eq 3). The aziridine 5a, being an amide, is appreciably less
basic than 1a-4a.
Reaction of an aziridine with Co2(CO)8 can give Co(CO)4
,
which would be the active catalyst for the reaction (Scheme 1).
Nucleophilic ring opening of the aziridine by tetracarbonylco-
baltate would occur at the less substituted carbon of the aziridine,
with inversion of configuration, to give 12. Insertion of CO
into the C-Co bond of 12 should proceed with retention of
configuration to form 13. Ring closure of the acyl complex 13
gives the â-lactam and regenerates the catalyst.
Scheme 1
The participation of tetracarbonylcobaltate anion in the
-
reaction pathway was confirmed by the use of Na+Co(CO)4
as the catalyst. The â-lactam 2b was isolated in 92% yield
from the aziridine 2a, although the reaction time is longer than
when Co2(CO)8 was the catalyst. The lower rate of reaction
could be due to the lower solvation of the Na+ counterion, what
makes the anion less reactive.
Reaction of 1-benzoyl-2-methylaziridine (5a) gives a mixture
of two isomers (5b and 5c) in good combined yield. The lower
regioselectivity here can be explained by considering some
studies done by Stamm et al.17 regarding nucleophilic ring
opening of aziridines. Usually this reaction, under neutral or
basic conditions, proceeds via an SN2 like mechanism. How-
ever, when there is a moderate activating group attached to the
The nature of the substituent at the 2-position of the aziridine
is important. When an alkyl substituent is replaced by a phenyl
group (6a) the regioselectivity changes completely, giving
carbonylation of the phenyl bearing C-N bond in moderate
yield.
The results obtained using 1,2,3-trisubstituted aziridines as
reactants provide some information regarding the possible
mechanism of the reaction. For aziridines containing identical
groups in positions 2 and 3 (7a-9a), carbon monoxide insertion
occurs with inversion of configuration at the reacting carbon,
i.e. starting from a cis-aziridine the product is a trans-â-lactam,
and the cis-â-lactam is formed as the only product by use of a
trans-aziridine. Reaction of 10a, which contains two different
substituents at positions 2 and 3, with Co2(CO)8 and CO, affords
carbonylation only of the benzylic C-N bond.
(14) Kemmit, R. D. W.; Russell, D. R. In ComprehensiVe Organometallic
Chemistry Wilkinson, G., Ed.; Pergamon Press: New York, 1982; Vol. 5,
Chapter 34.2.4.
(15) Dessy, R. E.; Pohl, R. L.; King, R. B. J. Am. Chem. Soc. 1966, 88,
5121.
(16) Heck, R. F. J. Am. Chem. Soc. 1963, 85, 1460.
(17) Stamm, H.; Assithianakis, Buchholz, B.; Weib, R. Tetrahedron Lett.
1982, 23, 5021.
(13) Kronethanl, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.

Synthesis of Highly Strained trans-Bicyclic â-Lactams
J. Am. Chem. Soc., Vol. 118, No. 1, 1996 113
Scheme 2
Table 2. Cobalt-Catalyzed Carbonylation of Bicyclic Aziridines
nitrogen atom, the nucleophile reacts at the most substituted
carbon of the aziridine ring with a single electron transfer
mechanism proposed for the reaction. It is conceivable that a
SET type mechanism (Scheme 2) is competing with the
“normal” process (Scheme 1) in the reaction of Co(CO)4- with
5a. A ketyl radical anion (14) may be formed, which undergoes
ring opening to a secondary radical (15). Radical combination
•
with Co(CO)4 would afford 16 which is then convertible to
5c.
isolated
yield (%)
It is well known that benzylic carbons are more reactive
toward nucleophiles than alkyl carbons. This is reflected in
the carbonylation of 6a, which takes place at the most substituted
carbon to form 6b in moderate yield. No other carbonylation
product was detected in the reaction. The same preference for
the benzylic carbon is observed for 10a, giving 10b in high
yield.
R1
product
19a
20a
21a
22a
23a
PhCH2CH2
PhCH2
cyclohexyl
(CH3)3C
19b
20b
21b
22b
23b
44
28
69
67
80
1-adamantyl
Bicyclic â-Lactams. Bicyclic â-lactams are usually prepared
by cycloaddition of a cycloalkene and chlorosulfonyl isocyan-
ate18 (eq 5). The stereochemistry of this reaction is such that
one can only obtain the trans isomer if a trans cycloalkane is
used as reactant. The smallest isolable trans cycloalkene is
trans-cyclooctene (17), which has been used to prepare the
â-lactam 1819 (eq 5).
relatively low by using DME as the solvent, it increased
significantly when THF was the solvent for the reaction (e.g.
80% yield for 23b in THF, 35% yield using DME, Table 2).
Spectroscopic studies and X-ray analysis of 23b confirm the
trans configuration of the product. While trans-bicyclic aze-
tidines20 are known, to our knowledge this is the first example
of trans-7-azabicyclo[4.2.0]octan-8-ones (â-lactams fused to a
six-membered ring in a trans fashion). Temperature control is
crucial to the success of these reactions, as it must be maintained
between 100 and 105 °C. At T < 100 °C the reaction is too
slow, and at T > 110 °C the decomposition of the product is
faster than its formation, and no lactam can be isolated.
The â-lactams 19b and 21b-23b are white solids while 20b
is a liquid at room temperature. These compounds can be
purified by preparative TLC, column chromatography, or
recrystallization from hexane. Suitable crystals of 23b were
easily obtained from hexane or mixtures of hexane and ether
or methylene chloride and subjected to X-ray analysis. The
ORTEP of 23b (Figure 1) confirms the trans configuration for
the â-lactam, and pertinent crystallographic data are given in
Table 3.
A novel feature of the Co2(CO)8-catalyzed reaction is the
conversion of bicyclic aziridines into highly strained trans
bicyclic â-lactams. Carbonylation of the cis-bicyclic aziridines
19a-23a (7-azabicyclo[4.1.0]heptane derivatives) affords the
â-lactams 19b-23b. While the yield of the trans-â-lactams is
(18) Rasmussen, J. L.; Hassner, A. Chem. ReV. 1976, 76, 389.
(19) Jendralla, H.; Laumen, K. Chem. Ber. 1983, 116, 2136.
(20) Moriconi, E. J.; Mazzochi, P. H. J. Org. Chem. 1966, 31, 1372.

114 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Piotti and Alper
Figure 1. Structure of 23b, showing the atom-labeling scheme. Selected bond distances (Å): N1-C1, 1.395(4); N1-C3, 1.492(4); N1-C8,
1.456(3); C1-O1, 1.215(4); C1-C2, 1.531(4); C2-C3, 1.524(4). Selected bond angles (deg): C1-N1-C3, 91.25(20); C1-N1-C8, 127.09(23);
C3-N1-C8, 127.59(22); N1-C1-C2, 90.62(21); C1-C2-C3, 85.08(20); N1-C1-O1, 131.8(3); C2-C1-O1, 137.6(3).
Table 3. Crystallographic Data for 23b
Table 4. Comparative Structural Parameters of Different Types of
â-Lactams
formula
fw
crystal shape
C17H25NO
259.39
needle
N-CO distance between
sum of bond
bond (Å) N and plane (Å) angles about N (deg)
crystal dimensions, mm
crystal system
lattice parameters
a, Å
b, Å
0.2 × 0.05 × 0.1
23b
1.395
1.37b
1.38b
0.433
0.4b
345.93
monoclinic
penicillinsa
cephalosporinsa
335-343
0.2b
343-351
13.904(6)
6.385(3)
15.793(9)
P21/n
unstrained systemsa 1.347b
∼0
∼360
a Reference 21b. b Average values.
c, Å
space group
Z
4
Table 4 shows comparative structural parameters of 23b,
penicillins, cephalosporins, and unstrained systems. The dis-
tance from the N to the plane formed by the other three members
in the penicillin ring is quite similar to the one observed in 23b.
In addition, the N-CO bond is longer in the latter than the
average in penicillins. In the light of these structural similarities
it is reasonable to believe that this class of bicyclic â-lactams
could find application as acylating agents, and that appropriately
substituted derivatives may exhibit significant physiological
activity.
In conclusion, a new method has been developed for the
synthesis of â-lactams by the carbonylation of a wide range of
aziridines, using Co2(CO)8, an economical catalyst. The yields
are often excellent, and the reaction proceeds with inversion of
configuration. In most cases the reaction begins by nucleophilic
ring opening of the aziridine by in situ-generated tetracarbon-
ylcobaltate anion. A significant result of this research is the
preparation of highly strained bicyclic â-lactams containing the
trans-7-azabicyclo[4.2.0]octan-8-one nucleus. These new com-
pounds present very interesting structural features that resemble
those contained in biologically active â-lactams.
V, Å3
1401.8(13)
1.229
128
Mo KR (0.70930)
0.07
d
calc, g/cm3
T, K
radiation (λ, Å)
µ, mm-1
R (Rw), %
5.1 (5.1)
Usually, the four-membered ring in unstrained â-lactams is
essentially planar. In addition, the substituent at N lies in the
same plane than the ring. These two structural features make
possible an optimum amide resonance between the unpaired N
electrons and the carbonyl group, resulting in a shorter OC-N
bond and a longer CdO bond. This is not the case for 23b.
The X-ray analysis of 23b shows that the trans fusion of the
rings adds considerable strain to the system. The N is out of
the plane formed by the three carbons in the ring. The distance
between the N and the plane is 0.433 Å. In addition the
structure shows a pyramidal conformation of N, as reflected by
the sum of bond angles about N (345.93°). The N-CO length
bond (1.395 Å) is longer than the one present in unstrained
systems. All these facts suggest the amide conjugation in the
ring is considerably inhibited by the strain of the system. This
is a very important property if compared with physiologically
active â-lactams.21a,b It is known that the activity of â-lactam
antibiotics is highly dependent on the deviation of planarity of
the four-membered ring. It increases as the tension in the ring
is higher, and it is absent when there is not enough strain in the
cycle. The acylating power of penicillins and cephalosporins
is due mainly to the strain present in the ring, which facilitates
the cleavage of the amide bond by lowering the amide
resonance.
Experimental Section
General. Spectral data were obtained by use of the following
instruments: Bomem MB-100 (FT-IR), Bruker AMX-500, Varian
XL300 or Gemini 200 MHz (NMR), VG 7070E (MS). The carbony-
lation reactions were run in 45 mL stainless steal autoclaves, containing
a glass liner.
Synthesis of Aziridines. Aziridines 1a-3a, 6a-8a, 19a-23a were
synthesized by reacting their respective amino alcohols with Ph3P‚Br2
and Et3N in acetonitrile22 and purified by distillation in vacuo. Aziridine
4a was prepared by refluxing a toluene solution of p-methoxyphenyl
azide23 and 3,3-dimethyl-1-butene for 48 h. The product was purified
(21) (a) Sweet, R. M. Cephalosporins and Penicillins, Chemistry and
Biology; Flynn, E., H., Ed.; Academic Press: New York and London, 1972;
pp 281-308. (b) Boyd, D. B. Chemistry and Biology of â-Lactam
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New York,
1982; Vol. 1, pp 500-534.
(22) Okada, I.; Ichimura, K.; Sudo, R. Bull. Chem. Soc. Jpn. 1970, 43,
1185.
(23) Mandenhall, G. D.; Smiyh, P. A. S. Organic Synthesis; Baumgartner,
H. E., Ed.; John Wiley and Sons: New York, 1973; Coll. Vol. 5, p 829.

Synthesis of Highly Strained trans-Bicyclic â-Lactams
J. Am. Chem. Soc., Vol. 118, No. 1, 1996 115
by column chromatography. Aziridine 5a was prepared by reacting
benzoyl chloride with 2-methylaziridine.10 Aziridine 9a24 was obtained
from decyl chloride, and 10a25 was prepared from propiophenone, both
following known methodology.
(m, 5H). 13C-NMR: δ 9.2, 25.6, 41.7, 44.6, 52.5, 127.6, 128.1, 128.7,
136.1, 167.2. IR (neat): 1743 cm-1 (CdO). MS: 189 (M+).
2-(1,1-Dimethylethyl)-1-(4-methoxyphenyl)aziridine (4a): 1H-
NMR (200 MHz) δ 0.99 (s, 9H), 1.81 (d, 2H, J ) 2.3 Hz), 2.15 (t, 1H,
J ) 2.3 Hz), 3.74 (s, 3H), 6.75 (d, 2H, J ) 8.9 Hz), 6.90 (d, 2H, J )
8.9 Hz). 13C-NMR: δ 26.8, 30.3, 30.5, 49.9, 55.5, 114.1, 121.2, 149.1,
154.8. MS: 205 (M+). Anal. Calcd for C13H19NO: C, 76.06; H, 9.33;
N, 6.82. Found: C, 75.77; H, 9.01; N, 6.85.
4-(1,1-Dimethylethyl)-1-(4-methoxyphenyl)-2-azetidinone (4b):
white solid, mp: 89-90 °C. 1H-NMR (200 MHz) δ 0.93 (s, 9H), 2.74
(dd, 1H, J ) 15.2 and 2.5 Hz), 2.95 (dd, 1H, J ) 15.2 and 5.5 Hz),
3.76 (s, 3H), 3.97 (dd, 1H, J ) 5.5 and 2.5 Hz), 6.85 (d, 2H, J ) 9
Hz), 7.23 (d, 2H, J ) 9 Hz). 13C-NMR: δ 26.7, 34.6, 38.7, 56.0,
61.4, 114.7, 122.8, 131.6, 157.3, 166.3. IR (KBr): 1730 cm-1 (CdO).
MS: 233 (M+). Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N,
6.00. Found: C, 72.16; H, 8.43; N, 5.73.
1-Benzoyl-2-methylaziridine (5a):10 1H-NMR (200 MHz) δ 1.40
(d, 3H, J ) 5.6 Hz), 2.15 (d, 1H, J ) 3.1 Hz), 2.57 (m, 2H), 7.49 (m,
3H), 8.04 (m, 2H). 13C-NMR: 17.7, 32.1, 34.5, 128.3, 129.0, 132.6,
133.5, 179.2. IR (neat): 1672 cm-1. MS: 161 (M+).
1-Benzoyl-4-methyl-2-azetidinone (5b)29 and 1-Benzoyl-3-methyl-
2-azetidinone (5c): 1H-NMR (200 MHz) δ 1.24 (d, 3H, J ) 6.9 Hz),
1.31 (d, 3H, J ) 6.8 Hz), 2.31 (dd, 1H, J ) 16.1 and 9.5 Hz), 2.64 (m,
1H), 2.68 (dd, 1H, J ) 16.1 and 5.2 Hz), 3.37 (dd, 1H, J ) 16.3 and
12.3 Hz), 3.82 (dd, 1H, J ) 16.3 and 7.0 Hz), 3.91 (m, 1H), 7.38 (m,
6H), 7.94 (m, 4H). 13C-NMR: δ 13.0, 22.1, 33.9, 35.8, 49.6, 50.1,
128.1, 128.2, 129.0, 131.0, 132.3, 153.0, 154.5, 166.7, 170.1. IR
(neat): 1671 and 1786 cm-1 (CdO). MS: 189 (M+).
1-(1-Methylethyl)-2-phenylaziridine (6a):30 1H-NMR (200 MHz)
δ 1.85 (d, 6H, J ) 6.2 Hz), 1.51 (q, 1H, J ) 6.2 Hz), 1.57 (d, 1H, J
) 6.6 Hz), 1.79 (d, 1H, J ) 3.4 Hz), 2.24 (dd, 1H, J ) 6 and 3.4 Hz),
7.2 ppm (m, 5H). 13C-NMR: δ 22.4, 23.0, 37.2, 41.4, 62.5, 127.0,
127.3, 128.8, 141.2. MS: 161 (M+).
1-(1-Methylethyl)-3-phenyl-2-azetidinone (6b):31 1H-NMR (200
MHz) δ 1.13 (d, 3H, J ) 6.8 Hz), 1.15 (d, 3H, J ) 6.8 Hz), 3.12 (dd,
1H, J ) 5.3 and 2.5 Hz), 3.54 (t, 1H, J ) 5.5 Hz), 3.93 (sept, 1H, J )
6.6 Hz), 4.15 (dd, 1H, J ) 5.5 and 2.5 Hz), 7.2 (m, 5H). 13C-NMR:
δ 20.9, 21.2, 43.9, 44.8, 53.5, 127.9, 128.0, 129.4, 136.6, 168.1. IR
(neat): 1739 cm-1 (CdO). MS: 104 (M+ - 65, PhCHdCH2).
cis-2,3-Dimethyl-1-(2-phenylethyl)aziridine (7a): 1H-NMR (200
MHz) δ 1.05 (d, 6H, J ) 6.4 Hz), 1.28 (m, 2H), 2.50 (tr, 2H, J ) 8.5
Hz), 2.85 (tr, 2H, J ) 8.5 Hz), 7.21 (m, 5H). 13C-NMR: δ 13.6, 37.2,
39.3, 63.6, 126.6, 128.9, 129.4, 140.8. MS: 175 (M+). Anal. Calcd
for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found: C, 82.34; H, 9.90;
N, 7.98.
trans-3,4-Dimethyl-1-(2-phenylethyl)-2-azetidinone (7b): 1H-NMR
(200 MHz) δ 1.18 (d, 3H, J ) 6.1 Hz), 1.20 (d, 3H, J ) 7.4 Hz), 2.62
(dq, 1H, J ) 7.4 and 2.0 Hz), 2.88 (m, 2H), 3.06 (dq, 1H, J ) 6.1 and
2.0 Hz), 3.20 (m, 1H), 3.64 (m, 1H), 7.25 (m, 5H). 13C-NMR: δ 12.8,
17.5, 34.6, 41.2, 51.6, 56.0, 126.6, 128.6, 138.7, 138.7, 170.4. IR
(neat): 1738 cm-1 (CdO). MS: 203 (M+). HRMS calcd for C13H17-
NO: 203.1310. Found: 203.1325.
trans-2,3-Dimethyl-1-(2-phenylethyl)aziridine (8a): 1H-NMR (200
MHz) δ 1.05 (s, 4H), 1.18 (d, 3H, J ) 6.4 Hz), 1.72 (dq, 1H, J ) 6.4
and 2.2 Hz), 2.55 (m, 1H), 2.85 (m, 3H), 7.22 (m, 5H). 13C-NMR: δ
11.5, 19.0, 38.0, 39.1, 42.4, 54.4, 126.6, 128.9, 129.4, 141.0. MS: 175
(M+). Anal. Calcd for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found:
C, 82.23; H, 9.95; N, 7.90.
Carbonylation of Monocyclic Aziridines. The following is a
typical procedure: 0.6 mmol of aziridine 1a, 10 mL of dry and O2
free DME, and 0.05 mmol of Co2(CO)8 (17.4 mg) were placed in a
stainless steel autoclave equipped with a stirring bar. The autoclave
was purged three times with carbon monoxide and then was charged
with 500 psi of carbon monoxide. The reaction was placed in an oil
bath at 100 °C and stirred overnight. The autoclave was opened and
left in contact with air for a few hours to induce decomposition of the
catalyst. Addition of a small amount of ether accelerates the process.
A precipitate was formed, the mixture was filtered through a small
column packed with silica gel, using ether as the eluant, to give the
â-lactam in high purity. For analytically pure â-lactam, the product
was further purified by preparative TLC, using hexane/ethyl acetate
65/35 as the developer.
Carbonylation of Bicyclic Aziridines 19a-23a. A 0.6 mmol
amount of aziridine, 6 mL of dry and O2 free THF, and 0.05 mmol of
Co2(CO)8 (17.4 mg) were placed in a stainless steel autoclave equipped
with a stirring bar. The autoclave was purged three times with carbon
monoxide and then was charged with 500 psi of carbon monoxide.
The reaction was placed in an oil bath at 100-105 °C. Conversion of
19a and 20a was complete after 60 h. In the case of 21a-23a, 40 h
was sufficient for complete reaction. Workup was similar to that
described for monocyclic aziridines.
Sodium Tetracarbonylcobaltate. Preparation of sodium tetracar-
bonylcobaltate was effected from Co2(CO)8 and NaOH26 in THF. The
catalyst was kept in THF solution. IR of the solution shows
characteristic metal carbonyl absorption at 1890 cm-1
.
2-Ethyl-1-(2-phenylethyl)aziridine (1a): 1H-NMR (300 MHz) δ
0.99 (tr, 3H, J ) 6.7 Hz) 1.22 (m, 2H), 1.38 (q, 2H, J ) 6.7 Hz), 1.54
(d, 1H, J ) 3.2 Hz), 2.38 (m, 1H), 2.59 (m, 1H), 2.90 (m, 2H), 7.25
(m, 5H). 13C-NMR: δ 12.2, 26.7, 34.3, 37.1, 41.9, 63.8, 126.6, 128.9,
129.3, 140.7. MS: 175 (M+). Anal. Calcd for C12H17N: C, 82.23;
H, 9.78; N, 7.99. Found: C, 81.84; H, 9.79; N, 7.92.
4-Ethyl-1-(2-phenylethyl)-2-azetidinone (1b): 1H-NMR (300 MHz)
δ 0.84 (tr, 3H, J ) 7.5 Hz), 1.30 (m, 1H), 1.68 (m, 1H), 2.42 (dd, 1H,
J ) 2.0 and 14.4 Hz), 2.84 (m, 3H), 3.18 (m, 1H), 3.29 (m, 1H), 3.58
(m, 1H), 7.21 (m, 5H). 13C-NMR: δ 9.25, 25.5, 34.5, 41.4, 41.9, 52.9,
126.5, 128.5, 138.6, 167.0. IR (neat): 1743 cm-1 (CdO). MS: 203
(M+). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89.
Found: C, 76.84; H, 8.25; N, 7.01.
2-Butyl-1-(2-phenylethyl)aziridine (2a): 1H-NMR (200 MHz) δ
0.90 (tr, 3H, J ) 6.9 Hz), 1.18 (d, 1H, J ) 6.1 Hz), 1.31 (m, 7H), 1.51
(d, 1H, J ) 3.1 Hz), 2.48 (m, 2H), 2.88 (m, 2H), 7.24 (m, 5H). 13C-
NMR: δ 14.7, 23.2, 30.3, 33.4, 34.5, 37.1, 40.4, 63.8, 126.6, 128.9,
129.3, 140.7. MS: 203 (M+). Anal. Calcd for C14H21N: C, 82.70;
H, 10.41; N, 6.89. Found: C, 82.41; H, 10.62; N, 6.80.
4-Butyl-1-(2-phenylethyl)-2-azetidinone (2b): 1H-NMR (200 MHz)
δ 0.90 (tr, 3H, J ) 6.8 Hz), 1.28 (m, 5H) 1.70 (m, 1H), 2.47 (dd, 1H,
J ) 2.2 and 14.3 Hz), 2.92 (m, 3H), 3.25 (m, 1H), 3.38 (m, 1H), 3.62
(m, 1H), 7.28 (m, 5H). 13C-NMR: δ 14.6, 23.2, 28.2, 33.1, 35.3, 42.6,
42.7, 52.5, 127.2, 129.2, 139.3, 167.7. IR (neat): 1743 cm-1 (CdO).
MS: 231 (M+). Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N,
6.05. Found: C, 77.69; H, 9.39; N, 5.98.
2-Ethyl-1-(phenylmethyl)aziridine (3a):27 1H-NMR (200 MHz) δ
0.89 (t, 3H, J ) 7.0 Hz), 1.42 (m, 4H), 1.63 (m, 1H), 3.32 (d, 1H, J )
13.2 Hz), 3.53 (d, 1H, J ) 13.2 Hz), 7.3 (m, 5H). 13C-NMR: δ 12.1,
26.7, 34.4, 41.9, 65.6, 127.5, 128.7, 128.8, 140.0. MS: 161 (M+).
4-Ethyl-1-(phenylmethyl)-2-azetidinone (3b):28 1H-NMR (200
MHz) δ 0.82 (tr, 3H, J ) 7.5 Hz), 1.40 (m, 1H), 1.73 (m, 1H), 2.55
(dd, 1H, J ) 14.5 and 2 Hz), 2.98 (dd, 1H, J ) 14.5 and 5 Hz), 3.39
(m, 1H), 4.10 (d, 1H, J ) 14.5 Hz), 4.60 (d, 1H, J ) 14.5 Hz), 7.30
cis-3,4-Dimethyl-1-(2-phenylethyl)-2-azetidinone (8b): 1H-NMR
(500 MHz) δ 1.03 (d, 3H, J ) 6.4 Hz), 1.09 (d, 3H, J ) 7.6 Hz), 2.85
(tr, 2H, J ) 7.4 Hz), 3.13 (dq, 1H, J ) 7.6 and 5.3 Hz), 3.20 (m, 1H),
3.54 (m, 2H), 7.23 (m, 5H). 13C-NMR: δ 9.3, 14.0, 35.2, 41.9, 47.2,
51.7, 127.1, 129.1, 129.2, 139.4, 171.6. IR (neat): 1739 cm-1 (CdO).
MS: 203 (M+). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89. Found: C, 76.44; H, 8.27; N, 7.11.
cis-1-(1,1-Dimethylethyl)-2,3-diphenylaziridine (9a):24 White solid,
mp: 96.5-97 °C. 1H-NMR (200 MHz) δ 1.21 (s, 9H), 3.20 (s, 2H),
(24) Leoppky, R. N.; Smith, D. H. J. Org. Chem. 1976, 41, 1578.
(25) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. J. Org. Chem.
1980, 45, 5319.
(26) Edgel, W. F.; Lyford, J. Inorg. Chem. 1970, 9, 1932.
(27) Suzuki, H.; Tani, H. Chem. Lett. 1984, 12, 2129.
(28) Lee, Y. H.; Lee, C. H.; Lee, J. H.; Choi, W. S. Bull. Korean Chem.
Soc. 1993, 14, 415.
(29) Kricheldorf, H. R. J. Polym. Sci., Polym. Chem. Ed. 1979, 17, 97.
(30) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. J. Org. Chem.
1981, 46, 2079.
(31) Bergmann, H. J.; Mayrhofer, R.; Otto, H. H. Arch. Pharm.
(Weinheim, Ger.) 1986, 319, 203.

116 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Piotti and Alper
7.15 (m, 10H). 13C-NMR: δ 27.4, 42.6, 53.9, 126.9, 128.1, 128.6,
138.3. MS: 251 (M+).
25.0, 25.2, 26.5, 27.7, 33.2, 53.8, 55.9, 56.7, 173.0. IR (KBr): 1735
cm-1 (CdO). MS: 181 (M+). HRMS calcd for C11H19NO: 181.1467.
Found: 181.1464.
trans-1-(1,1-Dimethylethyl)-3,4-diphenyl-2-azetidinone (9b):32 white
solid, mp ) 91-92 °C. 1H-NMR (200 MHz) δ 1.33 ppm (s, 9H),
3.98 (d, 1H, J ) 2.15 Hz), 4.48 (d, 1H, J ) 2.15 Hz), 7.35 (m, 10H).
13C-NMR: δ 28.2, 54.7, 63.1, 63.6, 126.3, 127.2, 127.4, 128.3, 128.7,
128.8, 135.5, 140.3, 168.4. IR (KBr): 1745 cm-1 (CdO). MS (EI):
180 (M+ - 99, PhCHdCHPh). MS (CI): 280 (M + 1).
7-(1-Adamantyl)-7-azabicyclo[4.1.0]heptane (23a): 1H-NMR (200
MHz) δ 1.13 (m, 2H), 1.36 (m, 2H), 1.48 (m, 6H), 1.62 (m, 10H),
1.87 (m, 2H), 2.02 (m, 3H). 13C-NMR: δ 20.6, 25.3, 28.0, 29.6, 36.9,
40.4, 52.4. MS: 231 (M+). Anal. Calcd for C16H25N: C, 83.06; H,
10.89; N, 6.05. Found: C, 83.45; H, 10.61; N, 6.00.
cis-3-Methyl-1-(1-methylethyl)-2-phenylaziridine (10a):25 1H-
NMR (200 MHz) δ 0.81 (d, 3H, J ) 5.7 Hz), 1.08 (d, 3H, J ) 6.2
Hz), 1.09 (d, 3H, J ) 6.4 Hz), 1.63 (m, 2H), 2.41 (d, 1H, J ) 6.8 Hz),
7.2 (m, 5H). 13C-NMR: δ 13.7, 21.9, 22.1, 40.5, 45.9, 61.3, 126.4,
127.8, 127.9, 138.0. MS: 175 (M+).
trans-7-(1-Adamantyl)-7-azabicyclo[4.2.0]octan-8-one (23b): white
solid, mp: 122 °C dec. 1H-NMR (200 MHz) δ 1.40-2.40 (m, 23H),
2.48 (m, 1H), 3.07 (m, 1H). 13C-NMR: δ 25.0, 25.3, 26.5, 29.1, 33.5,
36.3, 40.8, 54.7, 55.8, 172.8. IR (KBr): 1732 cm-1 (CdO). MS: 259
(M+). HRMS calcd for C17H25NO: 259.1947. Found: 259.1936.
Single Crystal Diffraction Study of 23b. Crystals of 23b were
obtained by layering a concentrated solution of 23b in ether with
hexane. One of the crystals having approximate dimensions of 0.2,
0.05, 0.1 mm was mounted on a glass capillary. All the measurements
were made on a Rigaku diffractometer with Mo KR radiation. Cell
constants and an orientation matrix for data collection were obtained
from least-squares refinement using the setting angles of 25 reflections
in the range 40 < θ < 50 corresponded to a monoclinic cell with
dimensions a ) 13.904(6) Å, b ) 6.385(3) Å, c ) 15.793(9) Å, â )
91.43(6). For Z ) 4 and FW ) 259.39, the calculated density is 1.229
g/cm3. Based on the systematic absences, the space group was
determined to be P21/n. The data were collected at a temperature of
-145 °C using the ω-2θ scan technique to a maximum 2θ value of
49.9 degrees.
A total of 2595 reflections was collected. The unique set contains
only 2486 reflections. The standards were measured after every 150
reflections. No crystal decay was noticed. The data were corrected
for Lorentz and polarization effects.36 No absorption correction was
made.
The structure was solved by direct methods. All the atoms were
refined anisotropically except for hydrogen atoms. The hydrogen atoms
were found by difference Fourier map. The final cycle of full matrix
least-squares refinement was based on 1825 observed reflections (I >
2.5σ(I)) and 272 variable parameters. Weights based on counting
statistics were used. The maximum and minimum peaks on the final
difference Fourier map corresponded to 0.220 and -0.220 e/a3,
respectively.
trans-4-Methyl-1-(1-methylethyl)-3-phenyl-2-azetidinone (10b):
1H-NMR (200 MHz) δ 1.18 (d, 3H, J ) 6.8 Hz), 1.22 (d, 3H, J ) 6.8
Hz), 1.39 (d, 3H, J ) 6 Hz), 3.58 (dd, 1H, J ) 6 and 2.1 Hz), 3.66 (d,
1H, J ) 2.2 Hz), 3.85 (sept, 1H, J ) 6.8 Hz), 7.2 (m, 5H). 13C-NMR:
δ 20.8, 21.1, 22.5, 44.5, 56.5, 61.8, 127.9, 129.4, 136.3, 167.6. IR
(neat): 1743 cm-1 (CdO). MS (EI): 118 (M+ - 85, PhCHdCH2-
CH3). MS (CI): 204 (M + 1). Anal. Calcd for C13H17NO: C, 76.81;
H, 8.43; N, 6.89. Found: 76.69; H, 8.52; N, 6.79.
7-(2-Phenylethyl)-7-azabicyclo[4.1.0]heptane (19a):33 1H-NMR
(200 MHz) δ 1.26 (m, 4H), 1.42 (m, 2H), 1.73 (m, 4H), 2.46 (t, 2H,
J ) 7.8 Hz), 2.86 (t, 2H, J ) 7.8 Hz), 7.24 (m, 5H). 13C-NMR: δ
20.6, 24.5, 36.5, 38.3, 63.2, 125.9, 128.3, 128.8, 140.4. MS: 201 (M+).
trans-7-(2-Phenylethyl)-7-azabicyclo[4.2.0]octan-8-one (19b): white
solid, mp: 69-70 °C. 1H-NMR (500 MHz) δ 1.33 (m, 3H), 1.78 (m,
5H), 2.55 (m, 1H), 2.80 (m, 2H), 2.86 (m, 1H), 3.19 (m, 1H), 3.60 (m,
1H), 7.23 (m, 5H). 13C-NMR: δ 25.5, 26.0, 26.8, 32.1, 35.9, 44.7,
57.8, 61.0, 126.8, 128.5, 128.8, 139.7, 174.6. IR (KBr): 1742 cm-1
(CdO). MS: 229 (M+). HRMS calcd for C15H19NO: 229.1467.
Found: 229.1460.
7-(Phenylmethyl)-7-azabicyclo[4.1.0]heptane (20a):34 1H-NMR
(200 MHz) δ 1.31 (m, 4H), 1.63 (m, 2H), 1.83 (m, 4H), 3.48 (s, 2H),
7.31 (m, 5H). 13C-NMR: δ 20.6, 24.5, 38.5, 64.3, 126.5, 127.4, 128.2,
140.0. MS: 187 (M+).
trans-7-(Phenylmethyl)-7-azabicyclo[4.2.0]octan-8-one (20b): 1H-
NMR (200 MHz) δ 1.12-1.88 (m, 8H), 2.58 (m, 1H), 2.78 (m, 1H),
4.14 (d, 1H, J ) 14.5 Hz), 4.31 (d, 1H, J ) 14.5 Hz), 7.20 (m, 5H).
13C-NMR: δ 24.7, 25.5, 26.3, 31.3, 46.9, 57.3, 59.4, 127.4, 128.3, 128.6,
136.7, 174.0. IR (neat): 1752 cm-1 (CdO). MS: 215 (M+). HRMS
calcd for C14H17NO: 215.1310. Found: 215.1330.
All the calculations were performed using the NRCVAX crystal-
lographic software package.37
7-Cyclohexyl-7-azabicyclo[4.1.0]heptane (21a):35 1H-NMR (200
MHz) δ 1.25 (m, 13H), 1.72 (m, 8H). 13C-NMR: δ 20.6, 24.8, 25.1,
26.1, 32.3, 36.9, 69.6. MS: 179 (M+).
trans-7-Cyclohexyl-7-azabicyclo[4.2.0]octan-8-one (21b): white
solid, mp: 43.5-44.5 °C. 1H-NMR (200 MHz) δ 1.0-2.1 (m, 18H),
2.57 (m, 1H), 3.07 (m, 1H), 3.45 (m, 1H). 13C-NMR: δ 24.8, 24.9,
25.0, 25.3, 25.4, 26.4, 30.7, 32.1, 32.5, 51.9, 56.4, 57.1, 173.0. IR
(KBr): 1738 cm-1 (CdO). MS: 207 (M+). HRMS calcd for C13H21-
NO: 207.1623. Found: 207.1629.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for support of
this research. Dr. Corinne Bensimon is gratefully acknowledged
for the X-ray diffraction study of compound 23b.
Supporting Information Available: Experimental details
and tables of crystal structure determination data, atomic
coordinates, thermal parameters, and bond length and angles
for compound 23b (14 pages); listing of structure factors (14
pages). This material is contained in many libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, can be ordered from the ACS, and can
be downloaded from the Internet; see any current masthead page
for ordering information and Internet access instructions.
7-(1,1-Dimethylethyl)-7-azabicyclo[4.1.0]heptane (22a): 1H-NMR
(200 MHz) δ 0.91 (s, 9H), 1.18 (m, 2H), 1.35 (m, 2H), 1.65 (m, 6H).
13C-NMR: 20.6, 25.0, 26.6, 30.1, 52.8. MS: 153 (M+). HRMS calcd
for C10H19N: 153.1517. Found: 153.1516.
trans-7-(1,1-Dimethylethyl)-7-azabicyclo[4.2.0]octan-8-one
(22b): white solid, mp: 57-58 °C. 1H-NMR (200 MHz) δ 1.29 (s,
9H), 1.30-2.15 (m, 8H), 2.50 (m, 1H), 3.01 (m, 1H). 13C-NMR: δ
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