On the effect of ring substituents in the carbonylation of aziridines

Article abstract of DOI:10.1016/S0040-4020(00)01152-2

The effect of ring substituents on the cobalt carbonyl-catalyzed carbonylation of functionalized aziridines to β-lactams has been investigated. A variety of aziridines with different substituents and stereochemistry has been synthesized and subjected to carbonylation. The ring expansion to β-lactam takes place in the absence of an electron-withdrawing substituent and higher yields are always obtained for cis-aziridines. Moreover, the regioselectivity of the reaction is affected by the nature of substituents at ring carbon atoms.

Full text of DOI:10.1016/S0040-4020(00)01152-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1801±1812
On the effect of ring substituents in the
carbonylation of aziridines
Paolo Davoli, Arrigo Forni, Irene Moretti, Fabio Pratip and Giovanni Torre
Á
Dipartimento di Chimica, Universita di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Received 26 September 2000; revised 20 November 2000; accepted 7 December 2000
AbstractÐThe effect of ring substituents on the cobalt carbonyl-catalyzed carbonylation of functionalized aziridines to b-lactams has been
investigated. A variety of aziridines with different substituents and stereochemistry has been synthesized and subjected to carbonylation.
The ring expansion to b-lactam takes place in the absence of an electron-withdrawing substituent and higher yields are always obtained for
cis-aziridines. Moreover, the regioselectivity of the reaction is affected by the nature of substituents at ring carbon atoms. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Synthesis of aziridines
Cobalt carbonyl-catalyzed carbonylative ring expansion of
aziridines has proved to be a versatile reaction for the
stereospeci®c synthesis of b-lactams in excellent yields.1,2
The reaction proceeds through nucleophilic ring opening of
the aziridine by the in situ-generated tetracarbonylcobaltate
anion [Co(CO)4]2, followed by CO insertion and ®nal ring
closure to b-lactam. The reaction is reported to proceed via
a SN2-like mechanism with inversion of con®guration at the
stereocenter which undergoes CO insertion and shows
stereospeci®city and high regioselectivity: from cis-aziri-
dines trans-b-lactams are obtained, whereas cis-b-lactams
are isolated from trans-aziridines.1,2
Aziridines 3a±e, 4b,d, 5d and 6d were synthesized from the
parent N-benzyl-2-alkoxycarbonylaziridines 1a±e follow-
ing the procedure already described for 1b and reported in
Scheme 1.1 Aziridines 1a±e were obtained by benzylamine
aminative cyclization of the dibromoderivatives prepared
by bromine addition to the appropriate commercially avail-
able a,b-unsaturated esters. Aziridines 1b±d were obtained
as a mixture of cis/trans isomers and aziridine 1e as the only
trans isomer. Reduction of 1a±e with lithium aluminium
hydride afforded the corresponding hydroxymethyl deriva-
tives 2a±e, which were protected as TBDMS-ethers 3a±e or
as acetyl esters cis-4b,d by treatment with tert-butyl-
dimethylsilylchloride (TBDMSCl) or by esteri®cation with
acetic acid in the presence of dicyclohexylcarbodiimide
(DCC) and 4-(dimethylamino)pyridine (DMAP), respec-
tively. Amidation of cis-1d with aqueous ammonia,
followed by reduction with lithium aluminium hydride in
THF, afforded the corresponding 2-aminomethyl derivative
cis-5d. Reduction of aziridine cis-1d with DIBAL-H at
2788C yielded the corresponding 2-formylderivative cis-
6d.
Previous results have shown that substituents at the aziridine
ring carbon atoms, as well as at nitrogen, have a strong effect
on the Co-catalyzed carbonylation reaction.2 More recently,
with the aim of obtaining appropriate functionalized b-
lactams, we applied this procedure to 2-alkoxycarbonyl-
aziridines and 2-hydroxymethylaziridines, obtaining the
corresponding b-lactams only from the latter.1
These results prompted us to investigate in greater detail the
effect of ring substituents on the Co-catalyzed carbonylation
of functionalized aziridines: for this purpose a range of aziri-
dines bearing appropriate substituents on the ring carbon
atoms as well as on the ring nitrogen atom were synthesized
and subjected to carbonylation.
N-Benzyl-2-acetyl-3-phenylaziridine 7d was synthesized in
analogy with aziridine 1d, by bromination of commercially
available 4-phenyl-3-buten-2-one, followed by aminative
cyclization.
Symmetric N-benzyl-2,3-bis-(tert-butyldimethylsilyloxy)-
methylaziridine (cis-3f) was obtained by treating the corre-
sponding N-H aziridine 8, synthesized as described in the
literature,3 with benzyl bromide and potassium carbonate in
re¯uxing acetonitrile (Scheme 2).
Keywords: aziridines; b-lactams; carbonylation; cobalt.
Corresponding author. Tel.: 139-59-2055056; fax: 139-59-373543;
e-mail: prati.fabio@unimo.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01152-2

1802
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
Scheme 1. (i) LiAlH4, THF; (ii) TBDMSCl, DMAP, CH2Cl2; (iii) HOAc, DCC, DMAP, CH2Cl2; (iv) aq NH3; (v) LiAlH4, THF; (vi) DIBAL-H, CH2Cl2.
monoxide (500 psi) and Co2(CO)8 for 14 h at 1008C in a
stainless steel pressure vessel, using a 12:1 ratio of aziridine/
catalyst. After removal of the catalyst by ®ltration on silica
gel, the crude residue was puri®ed by column chroma-
tography. When the carbonyl insertion occurred into both
the two ring carbon±nitrogen bonds, two regioisomers were
isolated.
Scheme 2. (i) PhCH2Br, K2CO3, CH3CN (81%).
Carbonyl insertion was con®rmed by 13C NMR spectro-
scopy, with the carbonyl carbon occurring at 168±
171 ppm. The relative stereochemistry of b-lactam regioi-
somers was determined by 1H NMR spectroscopy
(3JH,Hcis.3JH,Htrans) and the ring substitution pattern was
assigned according to the cross-cleavage MS fragmen-
tation.1 The spectroscopic data of compounds 14±23 were
in close agreement with the structures.
2-(tert-Butyldimethylsilyloxy)methyl-3-phenylaziridine4
(cis-11) was synthesized starting from 2-methoxycarbonyl-
3-phenylaziridine (cis-9), prepared by aminative cyclization
of methyl 2,3-dibromo-3-phenylpropanoate with ammonia.
Reduction of cis-9 with LiAlH4 gave aziridine 10 which was
protected as TBDMS-ether 11 by treatment with tert-butyl-
dimethylsilylchloride. N-Acetyl derivative cis-12 was
obtained by reaction of 11 with acetyl chloride and triethyl-
amine. Treatment of N-H aziridine 11 with ethyl bromo-
acetate afforded aziridine cis-13 (Scheme 3).
2.3. Carbonylation of aziridines 3a±f: effect of
substituent at C3 ring carbon atom
Spectroscopic data of compounds 1±13 were in close agree-
ment with the structures. The relative cis/trans stereo-
Carbonylation of N-benzyl-2-(tert-butyldimethylsilyloxy)-
methylaziridine 3a and 3-phenyl substituted aziridine 3d
afforded solely one b-lactam, 14a and 14d, respectively,
while carbonylation of 3-alkyl substituted aziridines 3b,c
gave two b-lactam regioisomers 14b,c and 15b,c, the
former being signi®cantly predominant. All attempts at
carbonylation of trans-3e failed, whereas aziridine cis-3f,
which does not present any problem in terms of regio-
speci®city, afforded stereospeci®cally b-lactam trans-14f.
The results are shown in Table 1.
1
chemistry was assigned on the basis of H NMR spectral
analysis (3JH,Hcis.3JH,Htrans).5 Moreover, 1H NMR spectra of
trans-aziridines 1(b±d)±3(b±d), in particular, showed the
presence of two invertomers at nitrogen, due to slow nitro-
gen inversion on the NMR scale.6
2.2. Carbonylation of aziridines
Following a well-established protocol,1 aziridines were
dissolved in freshly distilled and oxygen-free anhydrous
1,2-dimethoxyethane (DME) and treated with carbon
As already observed for 3b,1 the carbonylation reaction on
Scheme 3. (i) LiAlH4, THF (68%); (ii) TBDMSCl, DMAP, THF (97%); (iii) AcCl, NEt3, CH2Cl2 (85%); (iv) BrCH2COOEt, K2CO3, CH3CN (52%).

P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
1803
Table 1. Carbonylation of aziridines 3a±f
Aziridines
R
b-Lactams
No.
Stereochemistry
No.
Stereochemistry
Relative ratio 14/15
Yield (%)
3a
3ba
3ba
3c
H
14a
±
100
92:8
88:12
83:17
73:27
100
100
±
100
40
99.8a
63a
98
60
95
40
±
90
cis
trans
cis
trans
cis
trans
trans
cis
CH3
CH3
C2H5
C2H5
Ph
Ph
CF3
CH2OTBDMS
14b 15b
14b 15b
14c 15c
14c 15c
14d
14d
±
14f
trans
cis
trans
cis
trans
cis
±
trans
3c
3d
3d
3e
3f
a
From Ref. 1.
aziridines 3a±f is stereospeci®c: from cis aziridines trans
b-lactams are obtained, whereas cis b-lactams are isolated
from trans aziridines.
the presence of an alkoxycarbonyl group on the ring, gave
preferential elimination to an a,b-unsaturated system
instead of CO insertion, while aziridine 3b, bearing a silyl-
ated 2-hydroxymethyl group, was successfully carbonyl-
ated.1 These results led us to investigate more thoroughly
the compatibility of the carbonylation reaction with
the nature of substituents at C2 ring carbon atom for N-
benzyl-3-phenylaziridines, taking into account the high
regio- and stereospeci®city observed in the case of aziri-
dines 3d (Table 1). Functional groups at C2, such as a
carboxylate group (1d), a formyl (6d), an acetyl (7d)
or an aminomethyl (5d) as well as a free or protected
hydroxymethyl group (2d±4d) were chosen. The results of
carbonylation reactions for 3-phenylderivatives 1d±7d are
reported in Table 2 and compared with derivative 3d.
Moreover, carbonylation reactions show regioselectivity
regardless of the relative stereochemistry of the aziridine
ring: (i) for aziridines 3a and 3d, CO insertion occurs exclu-
sively into the ring C3 carbon±nitrogen bond, affording only
one b-lactam regioisomer, 14a and 14d, respectively; (ii)
for aziridines 3b and 3c on the other hand two b-lactam
regioisomers are obtained, namely 14b,c and 15b,c. Their
relative ratio shows, yet again, the preferential carbonyl
insertion into the alkyl-bearing ring C3 carbon±nitrogen
bond (regioisomer 14) rather than into the O-protected
hydroxymethyl-bearing ring C2 carbon±nitrogen bond
(regioisomer 15). These results indicate that the regioselec-
tivity of carbonylation is driven by electronic and steric
effects: CO insertion occurs preferentially on the ring
carbon atom displaying the higher electrophilic character
or the lower steric hindrance. For aziridines 3a,d, bearing
a primary or a benzylic ring C2 atom, respectively, the elec-
tronic effects seem to predominate and only one b-lactam
regioisomer is obtained. In the case of aziridines 3b,c,
having both ring-C atoms as secondary carbons, CO inser-
tion occurs on both nitrogen±carbon ring bonds, with
preferential insertion on the less sterically hindered N±C3
bond. In particular, higher regioselectivity (Me.Et) is
observed in relation to a lesser steric hindrance of the sub-
stituent. Nevertheless, sterically hindered symmetric aziri-
dine cis-3f gives carbonylation in very high yield.
As already observed for aziridine cis-1b,1 the presence of a
carboxylate or a carbonyl group directly linked to the aziri-
dine ring C2 carbon atom in compounds 1d, 6d and 7d
is detrimental for carbonylation and no b-lactams are
recovered from the reaction mixture.
Table 2. Carbonylation of aziridines 1d±7d
Aziridines
R
b-Lactams
No. Stereochemistry
No. Stereochemistry Yield (%)
With regard to the relative ring stereochemistry, the car-
bonylation of cis-aziridines 3b,c displays higher regioselec-
tivity and affords remarkably higher yields by comparison
with the corresponding trans derivatives.
1d cis
7d cis
6d cis
2d cis
3d cis
4d cis
5d cis
2d trans
3d trans
COOCH3
COCH3
CHO
±
±
±
±
±
±
±
±
±
CH2OH
CH2OTBDMS 14d trans
16 trans
79
96
86
68
±
CH2OAc
CH2NH2
CH2OH
17 trans
18 trans
2.4. Carbonylation of aziridines 2b±4b and 1d±7d: effect
of substituent at C2 ring carbon atom
±
±
CH2OTBDMS 14d cis
40
Previous results showed that aziridine 1b, characterized by

1804
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
Table 3. Carbonylation of aziridines 2b±4b
Aziridines
R
b-Lactams
Stereochemistry
No.
Stereochemistry
No.
Relative ratioa
Yield (%)
2b
cis
cis
cis
trans
trans
CH2OH
19
14b 15b
trans
trans
trans
±
cis
100
92:8
86:14
±
88:12
84
3bb
4b
CH2OTBDMS
CH2OAc
CH2OH
99.8b
82
20
21
c
c
c
c
2b
3bb
±
14b 15b
±
CH2OTBDMS
63b
a
Relative ratio between the regioisomers (14b/15b or 20/21).
From Ref. 1.
The product of the carbonylation reaction is the trans lactone 4-benzylamino-3-methyltetrahydrofuran-2-one (22) in 64% yield.
b
c
Carbonylation of unprotected hydroxymethylaziridine cis-
2d as well as its acetate ester cis-4d proceeded stereo- and
regiospeci®cally, affording only one b-lactam, trans-16 and
trans-17, respectively, in high yields: CO insertion occurs
exclusively on the C3±N bond as observed for the O±
TBDMS analogue cis-3d. Carbonylation of cis-4d, afford-
ing b-lactam 17, underlines the compatibility of a carbonyl
group as substituent when isolated from the ring system.
This result seems to suggest the presence of an intramol-
ecular hydrogen bond between the hydroxy group and the
nitrogen, favouring for CO insertion and thus for regio-
speci®city. Carbonylation of the trans isomer 2b on
the other hand, proceeds to the stereo- and regioselective
formation of trans-lactone 4-benzylamino-3-methyltetrahy-
drofuran-2-one (22) in good yield. The structure and trans
stereochemistry of lactone 22 was con®rmed by NOESY
and COSY NMR spectroscopy. By assuming the same
mechanism reported for carbonylation to b-lactams,1
lactone formation could be explained through the initial
[Co(CO)4]2 nucleophilic opening of the aziridine ring
followed by CO insertion into the Co±C3 bond. The cycli-
zation to the ®ve-membered lactone 22 indicates the nucleo-
philic attack of alcoholic oxygen on the carbonyl through a
proton migration from O to N, promoted by an intramol-
ecular hydrogen bond (Scheme 4).
Furthermore, N-benzyl-2-aminomethyl-3-phenylaziridine
(cis-5d) gave regio- and stereospeci®c carbonylation, yield-
ing trans-b-lactam 18 in good yield.
Surprisingly, when moving to trans-hydroxymethylaziri-
dines, carbonylation of free aziridine trans-2d did not
occur, whereas the corresponding protected trans-3d was
carbonylated albeit in low yield.
The in¯uence of the hydroxymethyl group protection was
evaluated also for the 3-methyl analogues 2b±4b. The
results of carbonylation reactions are collected in Table 3.
2.5. Carbonylation of aziridines cis-11±13: effect of
substituent at the ring nitrogen atom
Since cis-N-benzyl-2-(tert-butyldimethylsilyloxy)methyl-3-
phenylaziridine 3d gave the best results in terms of regio-
and stereoselectivity, as reported above, N-H, N-acetyl and
N-(ethoxycarbonyl)methyl aziridines, cis-11±13, respect-
ively, were chosen and subjected to the carbonylation con-
ditions in order to investigate the in¯uence of substituents at
the ring nitrogen atom. The results are reported in Table 4
and compared with derivative cis-3d.
Aziridine cis-2b, bearing a free hydroxymethyl group on
the C2 ring carbon atom, and its acetate ester cis-4b
were successfully and stereospeci®cally carbonylated to
b-lactams, as already observed for the corresponding O±
TBDMS derivative 3b (Table 3). Carbonylation of acetyl
derivative cis-4b affords two b-lactam regioisomers trans-
20 and trans-21 in good yield and without affecting regio-
selectivity, when compared with the OTBDMS analogue
cis-3b.
The nature of the substituent on ring nitrogen is signi®cant
for carbonylation. N-unsubstituted aziridine cis-11, as well
as N-acetylaziridine cis-12, did not show any reactivity: no
b-lactams were recovered, only the unreacted aziridines. In
the case of cis-12, the presence of an acetyl group on nitro-
gen, which is known to increase the reactivity towards
Interestingly, unlike derivatives cis-3b and 4b, carbonyl-
ation of unprotected hydroxymethyl aziridine cis-2b is
regiospeci®c, yielding only one b-lactam trans-19, indi-
cative of CO insertion exclusively on the C3±N bond.
Scheme 4.

P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
1805
Table 4. Carbonylation of cis aziridines 3d, 11±13
The syntheses of compounds cis- and trans-1b±3b, cis- and
trans-9b, 10b are described elsewhere.1 Tri¯uorinated azir-
idine trans-1e was prepared from the corresponding
dibromo derivative as reported in the literature.9 Compound
8 was synthesized following the procedure already
described.3
Aziridines
R
b-Lactams
4.1.1. 1-Benzyl-2-methoxycarbonylaziridine (1a).10
A
No. Stereochemistry
No. Stereochemistry Yield (%)
solution of commercial methyl 2,3-dibromopropanoate
(2.6 mL, 20.48 mmol) in methanol (50 mL) was slowly
added dropwise at 08C to a stirred solution of benzylamine
(7.83 mL, 71.68 mmol) in methanol (100 mL) and left to
warm to rt overnight. The reaction mixture was rotary
evaporated, diluted with ether (100 mL), washed with
water (200 mL) and the aqueous phase extracted with
ethyl ether (3£50 mL). The combined organic phases
were dried (MgSO4), concentrated in vacuo and chromato-
graphed (ethyl ether/light petroleum 60:40) to afford 1a as a
pale yellow liquid (3.30 g, 84% yield), which was used
11 cis
3d cis
12 cis
13 cis
H
Bn
COCH3
±
14d trans
±
±
95
±
±
CH2COOEt 23 trans
±
63
nucleophiles,7 decreases the basicity with respect to cis-3d:
the basicity of the ring nitrogen atom is reported to play an
important role in the formation of the [Co(CO)4]2 anion, as
well as in the ring closure of the nucleophilic ring-opening
intermediate to b-lactam.2
1
without further puri®cation. H NMR (200 MHz): d 1.74
(1H, dd, Jˆ1.0, 6.5 Hz, CH2), 2.20 (1H, dd, Jˆ3.0,
6.5 Hz, CH2), 2.26 (1H, dd, Jˆ1.0, 3.0 Hz, CHCOOMe),
3.54 (2H, s, CH2Ph), 3.71 (3H, s, COOCH3), 7.20±7.40
(5H, m, aromatic). MS, m/z: 191 (2, M1), 190 (18), 176
(20), 132 (50), 104 (26), 91 (100), 65 (21%).
More interesting is the carbonylation of aziridine cis-13:
trans-b-lactam 23, bearing a carboxymethyl group on nitro-
gen, a typical substituent in the framework of several b-
lactam antibiotics,8 was regio- and stereospeci®cally
obtained in good chemical yield.
4.1.2. cis- and trans-1-Benzyl-3-ethyl-2-methoxycarbonyl-
aziridine (1c). Methyl 2,3-dibromopentanoate (7.65 g,
27.94 mmol), prepared by bromination of methyl trans-2-
pentenoate11 in CCl4 at rt, was dissolved in methanol
(70 mL) and slowly added at 08C to a stirred solution
of benzylamine (12.6 mL, 115.35 mmol) in methanol
(200 mL). The reaction mixture was stirred overnight, leav-
ing to warm to rt. After rotary evaporation of the solvent, the
residue was dissolved in ethyl ether (180 mL), washed with
water (360 mL) and the aqueous phase extracted with ethyl
ether (3£90 mL). The combined organic phases were dried
(MgSO4) and concentrated to give a crude brown-yellowish
oil which was chromatographed on SiO2 (light petroleum/
ethyl ether 80:20 and then 60:40) to afford aziridine cis-1c
(4.02 g) and aziridine trans-1c (1.81 g), both as yellowish
oils, in a 69:31 ratio and in 95% total yield. Aziridine cis-1c
was further puri®ed by in vacuo distillation on a Vigreux
3. Conclusions
These results broaden the range of aziridines that can
be used as substrates for the cobalt carbonyl-catalyzed
carbonylation, thus making available a variety of func-
tionalized b-lactams that might be used as suitable pre-
cursors of antibiotic drugs.
Even though the presence of electron-withdrawing sub-
stituents on ring carbon atoms, such as a tri¯uoromethyl
or an alkoxycarbonyl group, proved incompatible with
carbonylation, a hydroxymethyl (protected or unprotected)
and an aminomethyl group as ring carbon substituents, as
well as an alkoxycarbonylmethyl group on the ring nitrogen
allowed us to perform the carbonylative ring-expansion to
b-lactams, whilst at the same time retaining the possibility
of a further reactivity on the ring substituents.
1
column: colourless oil, bp 1028C (0.6 mm Hg). H NMR
spectroscopy showed compound trans-1c as a 72:28 mixture
of two invertomers at nitrogen, due to slow nitrogen inver-
sion on the NMR scale.
4. Experimental
cis-1c. 1H NMR (200 MHz): d 0.88 (3H, t, Jˆ7.5 Hz,
CH3CH2), 1.39±1.77 (2H, m, CH3CH2), 1.87 (1H, q,
Jˆ6.5 Hz, CH3CH2CH), 2.26 (1H, d, Jˆ6.5 Hz,
CHCOOCH3), 3.53 (1H, d, Jˆ13.5 Hz, CH2Ph), 3.62 (1H,
d, Jˆ13.5 Hz, CH2Ph), 3.72 (3H, s, COOCH3), 7.22±7.36
(5H, m, aromatic). MS, m/z: 219 (6, M1), 204 (1), 190 (1),
160 (21), 146 (3), 131 (3), 128 (2), 91 (100), 68 (8), 65
(13%). Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N,
6.39. Found: C, 71.02; H, 7.98; N, 6.45.
4.1. General procedure
1H and 13C NMR spectra were recorded in CDCl3 solution
on a Bruker DPX-200 MHz and a Bruker AMQ 400 MHz
spectrometers; chemical shifts are reported in d values from
TMS as internal standard; coupling constants (J) are given
in Hz. For mass spectral determinations a Finnigan MAT
SSQ A mass spectrometer was used (EI, 70 eV). Elemental
analyses were performed with a Carlo Erba Elemental
Analyzer 1110. All organic solvents were dried and distilled
by standard methods prior to use and all reactions were
carried out using oven-dried glassware. Chromatographic
puri®cation of compounds was performed on silica gel
(particle size 0.05±0.20 mm). The metal catalyst
Co2(CO)8 was purchased from Merck.
1
trans-1c. H NMR (400 MHz): major invertomer: d 0.87
(3H, t, Jˆ7.5 Hz, CH3CH2), 1.38±1.59 (2H, m, CH3CH2),
2.27 (1H, dt, Jˆ2.5, 6.0 Hz, CH3CH2CH), 2.51 (1H, d,
Jˆ2.5 Hz, CHCOOCH3), 3.69 (3H, s, COOCH3), 3.91
(1H, d, Jˆ13.5 Hz, CH2Ph), 3.99 (1H, d, Jˆ13.5 Hz,

1806
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
CH2Ph), 7.29±7.41 (5H, m, aromatic); minor invertomer: d
1.09 (3H, t, Jˆ7.5 Hz, CH3CH2), 1.59±1.83 (2H, m,
CH3CH2), 2.05 (1H, m, CH3CH2CH), 2.49 (1H, m,
CHCOOCH3), 3.72 (3H, s, COOCH3), 3.65 (1H, d,
Jˆ14.0 Hz, CH2Ph), 3.92 (1H, d, Jˆ14.0 Hz, CH2Ph),
7.22±7.29 (5H, m, aromatic). MS, m/z: 219 (6, M1), 204
(1), 190 (1), 160 (21), 146 (3), 131 (3), 128 (2), 91 (100), 68
(8), 65 (13%). Anal. Calcd for C13H17NO2: C, 71.21; H,
7.81; N, 6.39. Found: C, 70.97; H, 8.05; N, 6.55.
4.2.1. 1-Benzyl-2-hydroxymethylaziridine (2a). Column
chromatography (ethyl ether/light petroleum 90:10)
afforded 2a as a white solid (70% yield), mp 64±668C
1
(lit.,13 84±858C, optically pure). H NMR (200 MHz): d
1.53 (1H, m, CHCH2OH), 1.81±1.91 (2H, m, NCH2CH),
2.25 (1H, br, CH2OH), 3.44 (1H, dd, Jˆ5.0, 11.5 Hz,
CH2OH), 3.46 (1H, d, Jˆ13.0 Hz, CH2Ph), 3.56 (1H, d,
Jˆ13.0 Hz, CH2Ph), 3.81 (1H, dd, Jˆ3.0, 11.5 Hz,
CH2OH), 7.25±7.39 (5H, m, aromatic). MS, m/z: 164 (8,
[M11]1), 163 (7), 162 (7), 132 (6), 91 (100), 72 (75), 65
(32%).
4.1.3. cis- and trans-1-Benzyl-2-methoxycarbonyl-3-
phenylaziridine (1d). Benzylamine (3.56 mL, 32.59 mmol)
was added dropwise at 08C to a stirred solution of methyl 2,3-
dibromo-3-phenylpropanoate12 (3 g, 9.32 mmol) in methanol
(120 mL). After 9 days the reaction mixture was rotary evapo-
rated, the residue dissolved in water (110 mL) and extracted
with ethyl ether (3£50 mL). The combined organic phases
were dried (MgSO4), concentrated in vacuo and chromato-
graphed on SiO2 (light petroleum/ethyl ether 80:20 and ®nally
50:50) to afford aziridine cis-1d (white solid, 1.70 g) and
aziridine trans-1d (light yellow viscous liquid, 493 mg) in a
78:22 ratio and in 88% total yield. By crystallization from
CH2Cl2/n-pentane, aziridine cis-1d was obtained as white
4.2.2. cis-1-Benzyl-3-ethyl-2-hydroxymethylaziridine
(cis-2c). After chromatography (ethyl ether/light petroleum
80:20 and ®nally pure ethyl ether) cis-2c was obtained as a
1
light pink sticky oil (86% yield). H NMR (200 MHz): d
0.88 (3H, t, Jˆ7.5 Hz, CH3CH2), 1.42 (2H, m, CH3CH2),
1.62 (1H, q, Jˆ6.5 Hz, CH3CH2CH), 1.84 (1H, dt, Jˆ5.0,
6.5 Hz, CHCH2OH), 2.38 (1H, br, CH2OH), 3.45 (1H, d,
Jˆ13.0 Hz, CH2Ph), 3.48 (1H, dd, Jˆ11.5, 7.0 Hz,
CH2OH), 3.55 (1H, d, Jˆ13.0 Hz, CH2Ph), 3.71 (1H, dd,
Jˆ11.5, 5.0 Hz, CH2OH), 7.22±7.36 (5H, m, aromatic). MS,
m/z: 190 (1, [M21]1), 160 (1), 146 (1), 117 (1), 100 (16), 91
(39), 72 (100), 65 (59%). Anal. Calcd for C12H17NO: C,
75.35; H, 8.96; N, 7.32. Found: C, 75.19; H, 9.07; N, 7.46.
1
crystals, mp 64±688C. H NMR spectroscopy showed broad
and poorly resolved signals for aziridine trans-1d, indicating
the presence of two invertomers at nitrogen.
4.2.3. trans-1-Benzyl-3-ethyl-2-hydroxymethylaziridine
(trans-2c). Column chromatography (ethyl ether/light
petroleum 90:10 and ®nally pure ethyl ether) afforded
trans-2c (68% yield; light yellow sticky oil) as a 77:23
mixture of two invertomers at nitrogen, due to slow nitrogen
1
cis-1d. H NMR (200 MHz): d 2.69 (1H, d, Jˆ7.0 Hz,
CHCOOMe), 3.11 (1H, d, Jˆ7.0 Hz, PhCH), 3.52 (3H, s,
COOCH3), 3.71 (1H, d, Jˆ13.5 Hz, CH2Ph), 3.97 (1H, d,
Jˆ13.5 Hz, CH2Ph), 7.20±7.51 (10H, m, aromatic). MS,
m/z: 267 (2, M1), 266 (4), 236 (3), 208 (3), 176 (75), 144
(18), 117 (42), 116 (100), 91 (51), 77 (15), 65 (16%). Anal.
Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.21; H, 6.32; N, 5.15.
1
inversion on the NMR scale. H NMR (400 MHz): major
invertomer: d 1.09 (3H, t, Jˆ7.5 Hz, CH3CH2), 1.56±1.82
(3H, m, CH3CH2 and EtCH), 2.05 (1H, ddd, Jˆ7.5, 6.0,
3.5 Hz, CHCH2O), 2.62 (1H, br, CH2OH), 3.42 (1H, dd,
Jˆ11.0, 4.5 Hz, CH2OH), 3.58 (1H, d, Jˆ13.5 Hz,
CH2Ph), 3.74 (1H, br d, Jˆ11.0 Hz, CH2OH), 3.87 (1H, d,
Jˆ13.5 Hz, CH2Ph), 7.33±7.45 (5H, m, aromatic); minor
invertomer: d 0.87 (3H, t, Jˆ7.5 Hz, CH3CH2), 1.43±1.53
(3H, m, CH3CH2 and EtCH), 2.12 (1H, dt, Jˆ8.5, 3.5 Hz,
CHCH2O), 2.40 (1H, br, CH2OH), 3.65 (1H, d, Jˆ14.0 Hz,
CH2Ph), 3.80 (1H, m, CH2OH), 3.88 (1H, d, Jˆ14.0 Hz,
CH2Ph), 3.94 (1H, m, CH2OH), 7.26±7.32 (5H, m,
aromatic). MS, m/z: 190 (1, [M21]1), 160 (2), 146 (1),
130 (2), 100 (19), 91 (40), 77 (6), 72 (100), 65 (55%).
Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32.
Found: C, 75.09; H, 8.82; N, 7.51.
trans-1d. 1H NMR (200 MHz): d 2.87 (1H, br d, Jˆ2.0 Hz,
CHCOOMe), 3.41 (1H, br s, PhCH), 3.77 (3H, br s,
COOCH3), 4.17 (1H, br d, Jˆ14.0 Hz, CH2Ph), 4.34 (1H,
d, Jˆ14.0 Hz, CH2Ph), 7.29±7.47 (10H, m, aromatic). MS,
m/z: 267 (2, M1), 266 (5), 236 (3), 208 (2), 176 (75), 144
(18), 116 (100), 91 (56), 77 (15), 65 (17%). Anal. Calcd for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.02; H,
6.67; N, 5.09.
4.2. Synthesis of hydroxymethyl aziridines 2a,c±e.
General procedure
4.2.4. cis-1-Benzyl-2-hydroxymethyl-3-phenylaziridine
(cis-2d). Chromatography (ethyl ether/light petroleum
50:50) afforded cis-2d as a light yellow sticky oil (99%
yield). 1H NMR (200 MHz): d 1.69 (1H, br, CH2OH),
2.22 (1H, dt, Jˆ6.0, 6.5 Hz, CHCH2OH), 2.94 (1H, d,
Jˆ6.5 Hz, PhCH), 3.34 (1H, dd, Jˆ7.0, 11.5 Hz,
CHCH2OH), 3.50 (1H, dd, Jˆ6.0, 11.5 Hz, CHCH2OH),
3.70 (1H, d, Jˆ13.5 Hz, CH2Ph), 3.80 (1H, d, Jˆ13.5 Hz,
CH2Ph), 7.20±7.50 (10H, m, aromatic). MS, m/z: 239 (5,
M1), 238 (19), 208 (2), 162 (100), 148 (53), 118 (13), 105
(8), 91 (24), 77 (12%). Anal. Calcd for C16H17NO: C, 80.30;
H, 7.16; N, 5.85. Found: C, 80.23; H, 7.34; N, 5.91.
A 1.0 M LiAlH4 solution in THF (2 mmol) was slowly
added dropwise through a dropping funnel to a stirred
solution of aziridines 1a,c±e (1 mmol) in freshly distilled
anhydrous THF (5 mL) at room temperature, under nitrogen
¯ow (for aziridine 1a the reaction was carried out at 2408C
to avoid ring opening). When TLC analysis showed total
disappearance of the starting material, the reaction mixture
was cooled to 08C and carefully quenched by dropwise
addition of water (100 mL), followed by an aqueous
0.15N NaOH solution (100 mL). The white inorganic pre-
cipitate was ®ltered off and washed with abundant ethyl
ether: the ®ltrate was dried (MgSO4) and the solvent evapo-
rated under reduced pressure to give a residue which was
subjected to column chromatography on SiO2.
4.2.5. trans-1-Benzyl-2-hydroxymethyl-3-phenylaziridine
(trans-2d). Chromatography (ethyl ether/light petroleum

P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
1807
t
80:20) gave trans-2d as pale yellow viscous liquid (83%
1
tBuMe2Si), 0.94 (9H, s, BuMe2Si), 0.96 (3H, t, Jˆ7.0 Hz,
CH3CH2), 1.29±1.63 (3H, m, CH3CH2 and CH3CH2CH),
1.81 (1H, q, Jˆ6.0 Hz, CHCH2O), 3.48 (1H, d,
Jˆ13.5 Hz, CH2Ph), 3.59 (1H, d, Jˆ13.5 Hz, CH2Ph),
3.62 (1H, dd, Jˆ6.5, 11.0 Hz, CH2O), 3.81 (1H, dd,
Jˆ6.0, 11.0 Hz, CH2O), 7.24±7.42 (5H, m, aromatic).
MS, m/z: 305 (5, M1), 290 (3), 276 (8), 248 (53), 214
(23), 206 (13), 174 (3), 160 (8), 158 (16), 91 (100), 75
(19), 73 (87%). Anal. Calcd for C18H31NOSi: C, 70.76; H,
10.23; N, 4.58. Found: C, 70.67; H, 10.31; N, 4.49.
yield). H NMR spectroscopy showed compound trans-2d
as a 79:21 mixture of two invertomers at nitrogen. 1H NMR
(400 MHz): major invertomer: d 2.43±2.49 (1H, m,
CHCH2OH), 2.83 (1H, br, CH2OH), 3.19 (1H, d,
Jˆ13.5 Hz, CH2Ph), 3.34 (1H, d, Jˆ3.5 Hz, PhCH), 3.46
(1H, d, Jˆ13.5 Hz, CH2Ph), 3.55±3.65 (1H, m,
CHCH2OH), 3.83±3.90 (1H, m, CHCH2OH), 7.20±7.60
(10H, m, aromatic); minor invertomer: d 2.11 (1H, br,
CH2OH), 2.53 (1H, d, Jˆ3.5 Hz, PhCH), 2.56±2.62 (1H,
m, CHCH2OH), 3.90±3.98 (2H, m, CH2OH and CH2Ph),
4.01±4.10 (2H, m, CH2OH and CH2Ph), 7.20±7.60 (10H,
m, aromatic). MS, m/z: 239 (3, M1), 238 (9), 208 (2), 162
(39), 148 (17), 118 (6), 105 (6), 91 (100), 77 (12%). Anal.
Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.15; H, 7.28; N, 6.02.
4.3.3. trans-1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
3-ethylaziridine (trans-3c). Aziridine trans-3c was
prepared in close analogy with the cis analogue (78%
yield; pale yellow oil). 1H NMR spectroscopy showed
trans-3c as a 53:47 mixture of two invertomers at nitrogen.
1H NMR (400 MHz): major invertomer: d 0.058 (3H, s,
tBuMe2Si), 0.063 (3H, s, tBuMe2Si), 0.92 (9H, s, tBuMe2Si),
1.11 (3H, t, Jˆ7.5 Hz, CH3CH2), 1.40±1.85 (3H, m,
CH3CH2 and CHCH2O), 1.90 (1H, ddd, Jˆ7.5, 6.0,
3.5 Hz, CH3CH2CH), 3.55 (1H, dd, Jˆ6.0, 11.0 Hz,
CH2O), 3.57 (1H, d, Jˆ13.0 Hz, CH2Ph), 3.68 (1H, dd,
Jˆ6.0, 11.0 Hz, CH2O), 4.03 (1H, d, Jˆ13.0 Hz, CH2Ph),
7.30±7.40 (5H, m, aromatic); minor invertomer: d 0.11 (3H,
s, tBuMe2Si), 0.12 (3H, s, tBuMe2Si), 0.86 (3H, t, Jˆ7.5 Hz,
4.2.6. trans-1-Benzyl-2-hydroxymethyl-3-tri¯uoromethyl-
aziridine (trans-2e). The crude residue was chromato-
graphed (ethyl ether/light petroleum 60:40), to provide
1
trans-2e as a pale yellow sticky liquid (92% yield). H
NMR spectroscopy showed broad and poorly resolved
signals, indicating the presence of two invertomers at nitro-
gen. H NMR (200 MHz): d 1.60 (1H, br, OH), 2.10±2.90
1
(2H, br m, CF3CH and CHCH2OH), 3.89 (4H, m,
CHCH2OH and CH2Ph), 7.23±7.40 (5H, m, aromatic).
MS, m/z: 231 (5, M1), 213 (2), 200 (10), 181 (2), 160 (1),
140 (33), 112 (30), 104 (10), 91 (100), 77 (12), 65 (18%).
Anal. Calcd for C11H12F3NO: C, 57.14; H, 5.23; N, 6.06.
Found: C, 57.28; H, 5.38; N, 6.23.
t
CH3CH2), 0.95 (9H, s, BuMe2Si), 1.40±1.85 (3H, m,
CH3CH2 and CH3CH2CH), 2.14 (1H, dt, Jˆ7.5, 3.5 Hz,
CHCH2O), 3.50 (1H, d, Jˆ14.0 Hz, CH2Ph), 3.86 (1H, d,
Jˆ14.0 Hz, CH2Ph), 3.92 (1H, dd, Jˆ7.5, 12.0 Hz, CH2O),
4.04 (1H, dd, Jˆ3.5, 12.0 Hz, CH2O), 7.30±7.40 (5H, m,
aromatic). MS, m/z: 305 (3, M1), 290 (1), 248 (50), 214
(26), 174 (2), 144 (2), 129 (2), 91 (100), 83 (6), 75 (20%).
Anal. Calcd for C18H31NOSi: C, 70.76; H, 10.23; N, 4.58.
Found: C, 70.51; H, 10.39; N, 4.42.
4.3. Synthesis of protected hydroxymethyl aziridines
3a,c±e. General procedure
The hydroxymethylaziridine (1 mmol) was dissolved in
anhydrous dichloromethane (6 mL): DMAP (2.5 mmol)
and TBDMSCl (1.2 mmol) were added at rt under magnetic
strirring and nitrogen ¯ow (for the synthesis of aziridine 3a,
the parent hydroxymethylaziridine 2a was cooled to 2208C,
in order to avoid the easy opening of the aziridine ring).
After disappearance of the starting material, the reaction
mixture was then diluted with CH2Cl2 (12 mL), washed
with water (2£20 mL) and brine (20 mL), dried over
MgSO4 and rotary evaporated. The residue was then
chromatographed to afford the desired TBDMS-derivative
in pure form.
4.3.4. cis-1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
3-phenylaziridine (cis-3d). The residue was chromato-
graphed (light petroleum/ethyl ether 90:10) to afford cis-
1
3d as a light yellow oil (86% yield). H NMR (200 MHz):
d 20.12 (3H, s, BuMe2Si), 20.10 (3H, s, BuMe2Si), 0.84
t
t
t
(9H, s, BuMe2Si), 2.16 (1H, dt, Jˆ5.5, 6.5 Hz, CHCH2O),
2.85 (1H, d, Jˆ6.5 Hz, PhCH), 3.32 (1H, dd, Jˆ6.5,
11.0 Hz, CHCH2O), 3.62 (1H, dd, Jˆ5.5, 11.0 Hz,
CHCH2O), 3.64 (1H, d, Jˆ13.5 Hz, CH2Ph), 3.85 (1H, d,
Jˆ13.5 Hz, CH2Ph), 7.20±7.49 (10H, m, aromatic). MS,
m/z: 353 (36, M1), 338 (4), 296 (38), 262 (100), 206 (25),
130 (11), 115 (12), 91 (58), 73 (79%). Anal. Calcd for
C22H31NOSi: C, 74.73; H, 8.84; N, 3.96. Found: C, 74.66;
H, 8.99; N, 4.07.
4.3.1. 1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
aziridine (3a). Chromatography (light petroleum/ethyl
ether 80:20) afforded 3a as a pale yellow liquid (98%
1
t
4.3.5. trans-1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
3-phenylaziridine (trans-3d). After puri®cation by chro-
matography (light petroleum/ethyl ether 80:20), trans-3d
yield). H NMR (200 MHz): d 0.11 (6H, s, BuMe2Si),
t
0.94 (9H, s, BuMe2Si), 2.97 (1H, quintet, Jˆ5.5 Hz,
CHCH2O), 3.62±3.80 (4H, m, NCH2CH and CHCH2O),
3.85 (1H, d, Jˆ13.0 Hz, CH2Ph), 3.94 (1H, d, Jˆ13.0 Hz,
CH2Ph), 7.26±7.39 (5H, m, aromatic). MS, m/z: 277 (1,
M1), 262 (3), 220 (100), 146 (4), 91 (88), 73 (27%). Anal.
Calcd for C16H27NOSi: C, 69.26; H, 9.81; N, 5.05. Found:
C, 69.03; H, 9.98; N, 5.20.
1
was obtained as a light yellow oil (90% yield). H NMR
spectroscopy showed trans-3d as a 57:43 mixture of two
invertomers at nitrogen. 1H NMR (400 MHz): major invert-
t
t
omer: d 0.17 (6H, s, BuMe2Si), 1.01 (9H, s, BuMe2Si),
2.50±2.52 (1H, m, CHCH2O), 2.70 (1H, d, Jˆ2.5 Hz,
PhCH), 3.79±3.85 (2H, m, CHCH2O), 3.87 (1H, d,
Jˆ14.5 Hz, CH2Ph), 4.25 (1H, d, Jˆ14.5 Hz, CH2Ph),
7.20±7.50 (10H, m, aromatic); minor invertomer: d 0.14
4.3.2. cis-1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
3-ethylaziridine (cis-3c). After chromatography (light
petroleum/ethyl ether 90:10) cis-3c was obtained as a light
yellow oil (91% yield). 1H NMR (200 MHz): d 0.09 (6H, s,
t
t
(6H, s, BuMe2Si), 0.98 (9H, s, BuMe2Si), 2.50±2.52 (1H,
m, CHCH2O), 3.19 (1H, d, Jˆ14.0 Hz, CH2Ph), 3.24 (1H, d,

1808
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
Jˆ3.0 Hz, PhCH), 3.49 (1H, d, Jˆ14.0 Hz, CH2Ph), 4.16
(1H, dd, Jˆ3.0, 12.0 Hz, CHCH2O), 4.21 (1H, dd, Jˆ7.0,
12.0 Hz, CHCH2O), 7.20±7.50 (10 H, m, aromatic). MS, m/
z: 353 (2, M1), 296 (5), 262 (42), 206 (9), 130 (10), 115
(13), 91 (63), 73 (100%). Anal. Calcd for C22H31NOSi: C,
74.73; H, 8.84; N, 3.96. Found: C, 74.53; H, 9.06; N, 4.13.
solution of aziridine cis-2d (154 mg, 0.64 mmol) in anhy-
drous dichloromethane (11 mL) and the mixture was stirred
at rt for 3 h. DCU was ®ltered off, the ®ltrate was concen-
trated in vacuo and puri®ed by chromatography (ethyl ether/
light petroleum 70:30) to give cis-4d as a pale yellow oil
1
(179 mg, 99% yield). H NMR (200 MHz): d 1.95 (3H, s,
COCH3), 2.26 (1H, ddd, Jˆ7.5, 6.5, 5.0 Hz, CHCH2OAc),
2.93 (1H, d, Jˆ6.5 Hz, PhCH), 3.69 (1H, d, Jˆ13.5 Hz,
NCH2Ph), 3.77 (1H, dd, Jˆ12.0, 7.5 Hz, CH2OAc), 3.80
(1H, d, Jˆ13.5 Hz, NCH2Ph), 3.96 (1H, dd, Jˆ12.0,
5.0 Hz, CH2OAc), 7.22±7.49 (10H, m, aromatic). MS,
m/z: 222 (2, [M259]1), 190 (66), 148 (92), 130 (13), 120
(23), 91 (100), 77 (11), 65 (19), 43 (57%). Anal. Calcd for
C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.69; H,
6.96; N, 5.11.
4.3.6. trans-1-Benzyl-2-(tert-butyldimethylsilyloxymethyl)-
3-tri¯uoromethylaziridine (trans-3e). Column chroma-
tography (light petroleum/ethyl ether 95:5) gave trans 3e
1
as a pale reddish liquid (88% yield). As for trans 2e, H
NMR spectroscopy showed broad and poorly resolved
signals, indicating the presence of two invertomers at nitro-
1
t
gen. H NMR (200 MHz): d 0.07 (6H, s, BuMe2Si), 0.90
(9H, s, tBuMe2Si), 2.40 (1H, m, ring H), 2.58 (1H, br m, ring
H), 3.72 (1H, d, Jˆ14.0 Hz, CH2Ph), 3.97 (2H, s, CH2O),
4.01 (1H, d, Jˆ14.0 Hz, CH2Ph), 7.22±7.39 (5H, m,
aromatic). MS, m/z: 345 (1, M1), 330 (1), 288 (33), 276
(1), 241 (1), 200 (2), 168 (1), 144 (4), 91 (100), 77 (12),
65 (6%). Anal. Calcd for C17H26F3NOSi: C, 59.10; H, 7.59;
N, 4.05. Found: C, 59.23; H, 7.81; N, 4.23.
4.3.10. cis-2-Aminomethyl-1-benzyl-3-phenylaziridine
(cis-5d). A stirred solution of aziridine cis-1d (400 mg,
1.50 mmol) in aqueous ammonia (40 mL) was re¯uxed for
6 h. After removal of the solvent, the crude residue was
chromatographed (ethyl acetate/ethyl ether 80:20) affording
cis-1-benzyl-2-carbamoyl-3-phenylaziridine as
a white
4.3.7. cis-1-Benzyl-2,3-bis-(tert-butyldimethylsilyloxy-
methyl)aziridine (cis-3f). Aziridine cis-83 (886 mg,
2.67 mmol) was dissolved in anhydrous acetonitrile
(22 mL). Potassium carbonate (1.11 g, 8.01 mmol) and
benzyl bromide (318 mL, 2.67 mmol) were added at rt to
the stirred solution and the mixture was re¯uxed for 1 h.
After addition of water (50 mL) and extraction with ethyl
ether (3£30 mL), the combined phases were dried (MgSO4)
and concentrated in vacuo. Chromatography on silica gel
(light petroleum/diisopropyl ether 95:5) gave N-benzylaziri-
solid (176 mg, 47% yield). By close analogy with reduction
of aziridine6 1, the amide was reduced with LiAlH4 in THF
at 2108C to the corresponding amino derivative. After chro-
matography (ethyl acetate/ethyl ether 80:20), cis-5d was
recovered as a sticky yellow liquid in 49% yield.
cis-1-Benzyl-2-carbamoyl-3-phenylaziridine. 1H NMR
(200 MHz): d 2.63 (1H, d, Jˆ7.0 Hz, CHCO), 3.20 (1H,
d, Jˆ7.0 Hz, PhCH), 4.43 (1H, d, Jˆ13.0 Hz, NCH2Ph),
4.51 (1H, d, Jˆ13.0 Hz, NCH2Ph), 5.14 (1H, br, CONH2),
6.09 (1H, br, CONH2), 7.20±7.45 (10H, m, aromatic). MS,
m/z: 252 (2, M1), 251 (6), 208 (1), 207 (1), 175 (45), 161
(32), 120 (8), 118 (9), 106 (6), 104 (10), 91 (100), 77 (9), 65
(12), 51 (7%).
1
dine cis-3f as a light yellow oil (912 mg, 81% yield). H
NMR (200 MHz): d 0.08 (2£6H, s, tBuMe2Si), 0.93 (2£9H,
s, ButMe2Si), 1.83±1.93 (2£1H, m, CHCH2O), 3.57 (2H, s,
PhCH2), 3.66±3.76 (2£2H, m, CH2O), 7.26±7.44 (5H, m,
aromatic). MS, m/z: 421 (7, M1), 364 (51), 276 (30), 206
(99), 147 (13), 115 (11), 91 (100), 73 (62%). Anal. Calcd for
C23H43NO2Si2: C, 65.50; H, 10.28; N, 3.32. Found: C,
65.71; H, 10.40; N, 3.18.
cis-5d. 1H NMR (200 MHz): d 1.62 (2H, br, CH2NH2), 2.23
(1H, m, CHCH2), 2.94 (1H, d, Jˆ6.5 Hz, PhCH), 3.34 (1H,
dd, Jˆ7.0, 11.5 Hz, CHCH2NH2), 3.50 (1H, dd, Jˆ6.0,
11.5 Hz, CHCH2NH2), 3.70 (1H, d, Jˆ13.5 Hz, CH2Ph),
3.80 (1H, d, Jˆ13.5 Hz, CH2Ph), 7.23±7.47 (10H, m,
aromatic). MS, m/z: 239 (1, [M11]1), 161 (100), 147
(14), 105 (43), 91 (96), 77 (8%). Anal. Calcd for
C16H18N2: C, 80.63; H, 7.61; N, 11.75. Found: C, 80.33;
H, 7.86; N, 11.48.
4.3.8. cis-2-Acetoxymethyl-1-benzyl-3-methylaziridine
(cis-4b). Aziridine cis-2b (200 mg, 1.13 mmol) was
dissolved in anhydrous dichloromethane (20 mL) and
DCC (279 mg, 1.35 mmol), acetic acid (71 mL, 1.2 mmol)
and few crystals of DMAP were added and the mixture was
stirred at rt for 3 h. DCU was removed by ®ltration, the
®ltrate was concentrated under reduced pressure and puri-
®ed by chromatography (ethyl ether/light petroleum 70:30)
to give cis-4b as a pale yellow oil (232 mg, 94% yield). 1H
NMR (200 MHz): d 1.25 (3H, d, Jˆ5.5 Hz, CH3CH), 1.69±
1.82 (1H, m, CH3CH), 1.83±1.91 (1H, m, CHCH2OAc),
2.01 (3H, s, OCOCH3), 3.45 (1H, d, Jˆ13.5 Hz,
NCH2Ph), 3.65 (1H, d, Jˆ13.5 Hz, NCH2Ph), 4.07 (1H,
dd, Jˆ11.5, 7.0 Hz, CH2OAc), 4.18 (1H, dd, Jˆ11.5,
5.5 Hz, CH2OAc), 7.27±7.38 (5H, m, aromatic). MS, m/z:
218 (2, [M21]1), 160 (12), 128 (13), 91 (65), 86 (100), 77
(3), 65 (14%). Anal. Calcd for C13H17NO2: C, 71.21; H,
7.81; N, 6.39. Found: C, 71.05; H, 7.93; N, 6.58.
4.3.11. cis-1-Benzyl-2-formyl-3-phenylaziridine (cis-6d).
A 20% DIBAL-H solution in hexane (1.4 mL, 1.97 mmol)
was slowly added dropwise through a dropping funnel to a
stirred solution of aziridine cis-1d (250 mg, 0.94 mmol) in
anhydrous CH2Cl2 (3 mL) at 2788C, under nitrogen ¯ow.
After 15 min, NaF (0.83 g, 19.7 mmol) and H2O (0.6 mL)
were added and the reaction mixture allowed to reach rt. The
white inorganic precipitate was ®ltered off and washed with
ethyl ether. The ®ltrate was dried (MgSO4) and the solvent
evaporated under reduced pressure. The crude residue was
chromatographed on SiO2 (light petroleum/ethyl ether
90:10) to afford cis-6d as a pale yellow liquid in 52%
yield, as well as cis-2d in trace amounts.
4.3.9. cis-2-Acetoxymethyl-1-benzyl-3-phenylaziridine
(cis-4d). DCC (160 mg, 0.78 mmol), acetic acid (40 mL,
0.70 mmol) and few crystals of DMAP were added to a
cis-6d. 1H NMR (200 MHz): d 2.49 (1H, t, Jˆ6.5 Hz,
CHCHO), 3.28 (1H, d, Jˆ6.5 Hz, PhCH), 3.74 (1H, d,

P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
1809
Jˆ13.5 Hz, NCH2), 3.94 (1H, d, Jˆ13.5 Hz, NCH2), 7.27±
7.48 (10H, m, aromatic), 8.97 (1H, d, Jˆ6.5 Hz, CHO). MS,
m/z: 195 (27, [M242]1), 194 (27), 178 (1), 152 (2), 139 (1),
117 (10), 104 (5), 91 (100), 77 (9), 65 (21%). Anal. Calcd
for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.83;
H, 6.51; N, 5.75.
(3), 90 (36), 77 (5), 65 (6%). Anal. Calcd for C10H11NO2: C,
67.78; H, 6.26; N, 7.90. Found: C, 67.51; H, 6.45; N, 7.78.
trans-9. 1H NMR (200 MHz) d 1.96 (1H, br, NH), 2.63 (1H,
d, Jˆ2.0 Hz, CHCOOMe), 3.30 (1H, d, Jˆ2.0 Hz, PhCH),
3.83 (3H, s, COOCH3), 7.25±7.46 (5H, m, aromatic). MS,
m/z: 177 (1, M1), 176 (2), 162 (46), 118 (71), 117 (9), 104
(13), 91 (100), 77 (6). 74 (18), 65 (8%). Anal. Calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.92; H,
6.47; N, 8.08.
4.3.12. cis- and trans-2-Acetyl-1-benzyl-3-phenylaziridine
(7d). 3,4-Dibromo-4-phenylbutan-2-one (5 g, 16.3 mmol),
obtained by bromination of commercially available 4-
phenyl-3-buten-2-one in CCl4 at rt, was dissolved in DMF
(35 mL) and slowly added at 08C to a stirred solution of
benzylamine (6.25 mL, 53.1 mmol) in DMF (15 mL). The
reaction mixture was stirred for 30 min, leaving to warm to
rt. After rotary evaporation of the solvent, the residue was
diluted with water (125 mL) and extracted with petroleum
ether (5£50 mL). The combined organic phases were dried
(MgSO4) and concentrated to give a crude oil which
was chromatographed on SiO2 (light petroleum/ethyl ether
80:20) to afford aziridine cis-7d (1.11 g, reddish-yellow oil)
and aziridine trans-7d (1.33 g, dark yellow oil) in 61% total
4.3.14. cis-2-Hydroxymethyl-3-phenylaziridine (cis-10).
Following the general procedure described for aziridines
2, reduction of cis-9 at 2108C gave cis-10 (ethyl acetate/
light petroleum 70:30) as a white solid, mp 92±948C (68%
yield); 1H NMR (200 MHz): d 1.74 (2H, br s, OH and NH),
2.69 (1H, m, CHCH2OH), 3.29 (1H, dd, Jˆ7.0, 12.0 Hz,
CH2OH), 3.47 (1H, d, Jˆ6.5 Hz, PhCH), 3.49 (1H, dd,
Jˆ5.5, 12.0 Hz, CH2OH), 7.24±7.43 (5H, m, aromatic).
MS, m/z: 149 (3, [M11]1), 148 (13), 130 (60), 118 (44),
105 (56), 104 (100), 91 (42), 77 (35), 65 (17%). Anal. Calcd
for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.30;
H, 7.49; N, 9.43.
1
yield. For trans-7d H NMR spectroscopy showed broad
and poorly resolved signals, indicating the presence of
two invertomers at nitrogen.
4.3.15. cis-2-(tert-Butyldimethylsilyloxymethyl)-3-phenyl-
aziridine (cis-11). Following the above described protocol
for aziridines 3, protection of hydroxymethylaziridine 10
gave cis-11 (ethyl acetate/light petroleum 50:50) as a pale
1
cis-7d. H NMR (200 MHz): d 1.75 (3H, s, COCH3), 2.67
(1H, d, Jˆ7.0 Hz, CHCOMe), 3.42 (1H, d, Jˆ7.0 Hz,
PhCH), 3.74 (1H, d, Jˆ13.5 Hz, NCH2Ph), 3.84 (1H, d,
Jˆ13.5 Hz, NCH2Ph), 7.22-7.49 (10H, m, aromatic). MS,
m/z: 251 (5, M1), 223 (18), 208 (1), 174 (1), 160 (1), 132
(1), 118 (5), 104 (100), 91 (53), 78 (5), 65 (9%). Anal. Calcd
for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.48;
H, 6.95; N, 5.36.
1
yellow liquid (97% yield); H NMR (200 MHz): d 20.11
t
t
(3H, s, BuMe2Si), 20.09 (3H, s, BuMe2Si), 0.84 (9H, s,
tBuMe2Si), 2.58±2.63 (1H, q, Jˆ6.5 Hz, CHCH2O), 3.25
(1H, dd, Jˆ6.5, 10.5 Hz, CH2O) 3.39 (1H, d, Jˆ6.5 Hz,
PhCH), 3.57 (1H, dd, Jˆ5.5, 10.5 Hz, CH2O), 7.21±7.43
(5H, m, aromatic). MS, m/z: 263 (1, M1), 248 (2), 206
(62), 176 (33), 131 (69), 104 (100), 91 (18), 75 (23%).
Anal. Calcd for C15H25NOSi: C, 68.38; H, 9.56; N, 5.32.
Found: C, 68.25; H, 9.67; N, 5.44.
trans-7d. 1H NMR (200 MHz): d 2.25 (3H, s, COCH3), 3.01
(1H, br, CHCOMe), 3.42 (1H, br, PhCH), 3.99 (1H, br d,
Jˆ13.5 Hz, NCH2Ph), 4.28 (1H, br d, Jˆ13.5 Hz,
NCH2Ph), 7.25±7.35 (10H, m, aromatic). MS, m/z: 251
(6, M1), 223 (26), 118 (5), 104 (100), 91 (61), 78 (8), 65
(9%). Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57.
Found: C, 81.51; H, 7.03; N, 5.29.
4.3.16. cis-1-Acetyl-2-(tert-butyldimethylsilyloxymethyl)-
3-phenylaziridine (cis-12). Triethylamine (1.22 mL,
8.8 mmol) and a solution of acetyl chloride (46 mL,
0.65 mmol) in CH2Cl2 (10 mL) were added sequentially to
a solution of aziridine cis-11 (150 mg, 0.57 mmol) in
CH2Cl2 (10 mL) cooled at 2108C. After 30 min at rt, the
reaction mixture was diluted with CH2Cl2, washed with
water (2£25 mL) and aqueous NaHCO3 (2£25 mL). The
organic phase was dried (MgSO4) and rotary evaporated.
After chromatography (light petroleum/ethyl ether 70:30)
cis-12 was obtained as a pale yellow liquid (150 mg, 85%
4.3.13. cis-2-Methoxycarbonyl-3-phenylaziridine (cis-9)4.
Gaseous ammonia (3.52 g, 207 mmol) was bubbled into
anhydrous acetonitrile (150 mL) cooled at 2108C in a
four-necked round bottom ¯ask, until the desired weight
was reached. A solution of methyl 2,3-dibromo-3-phenyl-
propanoate (7.5 g, 24 mmol) in CH3CN (45 mL) was then
added dropwise under vigorous magnetic stirring, keeping
the temperature at 2108C. The mixture was then left to react
in the dark at rt and after 14 days triethylamine (3.25 mL,
1 mol) was added. After a further 6 days the precipitate was
removed by ®ltration and the ®ltrate concentrated in vacuo.
The crude residue was puri®ed by chromatography on silica
gel (light petroleum/ethyl ether 60:40) to afford trans-2-
methoxycarbonyl-3-phenylaziridine 9 (1.949 g), as a light
yellow oil, and cis-9 (0.890 g) as white crystals (mp 71±
738C), in 70% overall yield.
1
t
yield). H NMR (200 MHz): d 20.07 (3H, s, BuMe2Si),
t
t
20.11 (3H, s, BuMe2Si), 0.85 (9H, s, BuMe2Si), 2.26
(3H, s, COCH3), 2.97 (1H, q, Jˆ6.0 Hz, CHCH2O), 3.34
(1H, dd, Jˆ6.0, 11.0 Hz, CH2O), 3.60 (1H, dd, Jˆ6.0,
11.0 Hz, CH2O), 3.77 (1H, d, Jˆ6.0 Hz, PhCH), 7.29±
7.38 (5H, m, aromatic). MS, m/z: 305 (1, M1), 262 (24),
248 (76), 218 (72), 206 (100), 177 (14), 144 (42), 131 (49),
115 (26), 104 (41), 91 (42), 75 (34), 73 (98%). Anal. Calcd
for C17H27NO2Si: C, 66.84; H, 8.91; N, 4.59. Found: C,
66.71; H, 9.05; N, 4.72.
cis-9. 1H NMR (200 MHz) d 1.48 (1H, br, NH), 3.06 (1H, d,
Jˆ6.5 Hz, CHCOOMe), 3.52 (1H, d, Jˆ6.5 Hz, PhCH),
3.55 (3H, s, COOCH3), 7.25±7.45 (5H, m, aromatic). MS,
m/z: 177 (3, M1), 176 (2) 162 (9), 146 (19), 117 (100), 104
4.3.17. cis-2-(tert-Butyldimethylsilyloxymethyl)-1-ethoxy-
carbonylmethyl-3-phenylaziridine (cis-13). Aziridine
cis-11 (250 mg, 0.95 mmol) and ethyl bromoacetate

1810
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
(164 mL, 1.42 mmol) were dissolved in anhydrous aceto-
nitrile (15.2 mL) and potassium carbonate (394 mg,
2.85 mmol) was added. The mixture was re¯uxed for 7 h,
cooled to rt and diluted with water (50 mL). The solution
was extracted with ethyl ether (3£50 mL) and the combined
organic phases were dried (MgSO4) and rotary evaporated.
After chromatography (light petroleum/ethyl ether 90:10)
cis-13 was obtained as a pale yellow liquid (174 mg, 52%
4.09 (1H, d, Jˆ15.0 Hz, CH2Ph), 4.70 (1H, d, Jˆ15.0 Hz,
CH2Ph), 7.25±7.36 (5H, m, aromatic). 13C NMR: d 24.86
(tBuMe2Si), 24.84 (tBuMe2Si), 12.3 (CH3CH2), 18.9
(Me3CMe2Si), 21.9 (CH3CH2), 26.5 (Me3CMe2Si), 45.5
(CH2Ph), 54.5 (CH3CH2CH), 58.8 (CHCH2O), 64.4
(CH2O), 128.2, 128.9, 129.3, 137.2, 170.8 (carbonyl). MS,
m/z: 333 (1, M1), 332 (1), 318 (1), 305 (1), 288 (1), 276 (3),
248 (2), 207 (15), 206 (100), 188 (1), 143 (17), 91 (46), 75
(18), 73 (8%). Anal. Calcd for C19H31NO2Si: C, 68.42; H,
9.37; N, 4.20. Found: C, 68.36; H, 9.44; N, 4.31.
1
t
yield). H NMR (200 MHz): d 20.14 (3H, s, BuMe2Si),
t
t
20.11 (3H, s, BuMe2Si), 0.83 (9H, s, BuMe2Si), 1.29
(3H, t, Jˆ7.0 Hz, COOCH2CH3), 2.09 (1H, m, CHCH2O),
2.83 (1H, d, Jˆ6.5 Hz, PhCH), 3.22 (1H, dd, Jˆ7.5,
11.0 Hz, CHCH2O), 3.24 (1H, d, Jˆ16.0 Hz, CH2COOEt),
3.49 (1H, d, Jˆ16.0 Hz, CH2COOEt), 3.75 (1H, dd, Jˆ5.0,
11.0 Hz, CHCH2O), 4.24 (2H, q, Jˆ7.0 Hz, COOCH2CH3),
7.24±7.46 (5H, m, aromatic). MS, m/z: 349 (51, M1), 292
(62), 276 (68), 262 (100), 234 (50), 206 (57), 204 (97), 144
(48), 115 (31), 101 (41), 91 (56), 73 (92%). Anal. Calcd for
C19H31NO3Si: C, 65.29; H, 8.94; N, 4.01. Found: C, 65.20;
H, 9.10; N, 4.13.
1
t
trans-15c. H NMR (400 MHz): d 0.06 (6H, s, BuMe2Si),
t
0.87 (3H, t, Jˆ7.5 Hz, CH2CH3), 0.88 (9H, s, BuMe2Si),
1.34±1.46 (1H, m, CH2CH3), 1.66±1.84 (1H, m, CH2CH3),
2.92 (1H, dddd, Jˆ0.5, 2.0, 3.5, 6.0 Hz, OCH2CH), 3.42
(1H, ddd, Jˆ2.0, 4.0, 9.0 Hz, CHCH2CH3), 3.87 (1H, dd,
Jˆ3.5, 11.0 Hz, OCH2), 3.91 (1H, dd, Jˆ6.0, 11.0 Hz,
OCH2), 4.10 (1H, d, Jˆ15.5 Hz, CH2Ph), 4.65 (1H, d,
Jˆ15.5 Hz, CH2Ph), 7.25±7.35 (5H, m, aromatic). 13C
NMR:
d
24.8 (tBuMe2Si), 24.7 (tBuMe2Si), 10.3
(CH2CH3), 19.0 (Me3CMe2Si), 25.7 (CH2CH3), 26.5
(Me3CMe2Si), 44.4 (CH2Ph), 57.2 (CHCH2CH3), 58.5
(OCH2CH), 60.6 (OCH2), 128.2, 128.8, 129.3, 136.8,
168.4 (carbonyl). MS, m/z: 334 (1, [M11]1), 333 (1), 332
(1), 318 (3), 304 (1), 277 (19), 276 (100), 246 (3), 219 (1),
184 (4), 143 (5), 129 (1), 91 (38), 75 (13), 73 (4%). Anal.
Calcd for C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found:
C, 68.21; H, 9.63; N, 3.94.
4.4. General procedure for the dicobalt octacarbonyl-
catalyzed carbonylation of aziridines
The aziridine (1 mmol) was dissolved in freshly distilled
and oxygen-free anhydrous DME (10 mL) in a stainless
steel autoclave, equipped with a glass liner and a stirring
bar, and the metal catalyst Co2(CO)8 (1/12 mmol) was
added. After purging with CO, the autoclave was charged
with 500 psi of carbon monoxide and placed in an oil bath at
1008C for 14 h. The work-up of the reaction mixture was
carried out as previously reported,1 giving a crude residue
which was puri®ed by chromatography on silica gel, using
the eluent indicated below [in square brackets].
4.4.3. cis-1-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-
3-ethylazetidin-2-one (cis-14c) and cis-1-benzyl-3-(tert-
butyldimethylsilyloxymethyl)-4-ethylazetidin-2-one (cis-
15c). From aziridine trans-3c, b-lactams cis-14c and
cis-15c (73:27) were isolated [light petroleum/ethyl ether
70:30] as yellow oils in 60% overall yield.
4.4.1. 1-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-
azetidin-2-one (14a). From aziridine 3a, b-lactam 14a
[light petroleum/ethyl ether 50:50] was obtained in 40%
1
t
cis-14c. H NMR (200 MHz): d 0.054 (3H, s, BuMe2Si),
0.056 (3H, s, tBuMe2Si), 0.91 (9H, s, tBuMe2Si), 1.09 (3H, t,
Jˆ7.5 Hz, CH3CH2), 1.57±1.89 (2H, m, CH3CH2), 3.11
(1H, dt, Jˆ5.0, 8.0 Hz, CH3CH2CH), 3.63 (1H, dt, Jˆ5.0,
5.5 Hz, CHCH2O), 3.73 (1H, dd, Jˆ5.5, 10.5 Hz,
CHCH2O), 3.79 (1H, dd, Jˆ5.5, 10.5 Hz, CHCH2O), 4.19
(1H, d, Jˆ15.0 Hz, CH2Ph), 4.70 (1H, d, Jˆ15.0 Hz,
CH2Ph), 7.25±7.39 (5H, m, aromatic). MS, m/z: 333 (1,
M1), 248 (4), 206 (100), 143 (17), 91 (67), 75 (31%).
Anal. Calcd for C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20.
Found: C, 68.26; H, 9.58; N, 4.02.
1
yield as a dark yellow liquid; H NMR (200 MHz): d 0.07
t
t
(6H, s, BuMe2Si), 0.92 (9H, s, BuMe2Si), 2.73 (1H, dd,
Jˆ1.5, 14.5 Hz, ring CH2), 2.94 (1H, dd, Jˆ5.0, 14.5 Hz,
ring CH2), 3.58±3.79 (3H, m, CHCH2O and CHCH2O), 4.18
(1H, d, Jˆ15.0 Hz, CH2Ph), 4.71 (1H, d, Jˆ15.0 Hz,
CH2Ph), 7.26±7.42 (5H, m, aromatic). MS, m/z: 305 (1,
M1), 304 (1), 290 (1), 262 (1), 249 (1), 248 (4), 207 (17),
206 (100), 132 (2), 115 (3), 91 (53), 73 (7), 59 (6%). Anal.
Calcd for C17H27NO2Si: C, 66.84; H, 8.91; N, 4.59. Found:
C, 67.13; H, 9.12; N, 4.67.
1
cis-15c. H NMR (400 MHz): d 0.06 (6H, s, BuMe2Si),
t
t
0.87 (3H, t, Jˆ7.5 Hz, CH2CH3), 0.89 (9H, s, BuMe2Si),
4.4.2. trans-1-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-
3-ethylazetidin-2-one (trans-14c) and trans-1-benzyl-3-
(tert-butyldimethylsilyloxymethyl)-4-ethylazetidin-2-one
(trans-15c). From aziridine cis-3c, b-lactams trans-14c and
trans-15c (83:17) were isolated [light petroleum/ethyl ether
70:30] in 98% overall yield, both as a light yellow oil.
1.32±1.43 (1H, m, CH2CH3), 1.68±1.83 (1H, m, CH2CH3),
2.94 (1H, dt, Jˆ3.5, 5.5 Hz, OCH2CH), 3.40 (1H, ddd,
Jˆ4.0, 5.5, 9.0 Hz, CHCH2CH3), 3.85 (1H, dd, Jˆ3.5,
11.0 Hz, OCH2), 3.90 (1H, dd, Jˆ5.5, 11.0 Hz, OCH2),
4.11 (1H, d, Jˆ15.5 Hz, CH2Ph), 4.63 (1H, d, Jˆ15.5 Hz,
CH2Ph), 7.22±7.40 (5H, m, aromatic). MS, m/z: 318 (3,
[M215]1), 276 (100), 246 (3), 184 (7), 143 (7), 129 (3),
91 (98), 75 (40%). Anal. Calcd for C19H31NO2Si: C, 68.42;
H, 9.37; N, 4.20. Found: C, 68.20; H, 9.61; N, 3.95.
1
trans-14c. H NMR (400 MHz): d 0.04 (6H, s, BuMe2Si),
t
t
0.89 (9H, s, BuMe2Si), 0.97 (3H, t, Jˆ7.5 Hz, CH3CH2),
1.60 (1H, ddq, Jˆ9.0, 14.0, 7.5 Hz, CH3CH2), 1.79 (1H,
ddq, Jˆ5.5, 14.0, 7.5 Hz, CH3CH2), 2.84 (1H, dddd,
Jˆ0.5, 2.0, 5.5, 9.0 Hz, CH3CH2CH), 3.24 (1H, ddd,
Jˆ2.0, 4.5, 5.5 Hz, CHCH2O), 3.65 (1H, dd, Jˆ5.5,
11.0 Hz, CH2O), 3.69 (1H, dd, Jˆ4.5, 11.0 Hz, CH2O),
4.4.4. trans-1-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-
3-phenylazetidin-2-one (trans-14d). From aziridine cis-3d,
b-lactam trans-14d [light petroleum/ethyl ether 80:20] was

P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
1811
1
obtained as a clear yellow liquid in 95% yield; H NMR
(200 MHz): d 0.11 (6H, s, tBuMe2Si), 0.95 (9H, s,
tBuMe2Si), 3.63 (1H, dt, Jˆ2.5, 4.5 Hz, CHCH2O), 3.81
(1H, dd, Jˆ4.5, 11.0 Hz, CHCH2O), 3.88 (1H, dd, Jˆ4.0,
11.0 Hz, CHCH2O), 4.18 (1H, d, Jˆ2.5 Hz, PhCH), 4.23
(1H, d, Jˆ15.0 Hz, CH2Ph), 4.84 (1H, d, Jˆ15.0 Hz,
CH2Ph), 7.24±7.39 (10H, m, aromatic). 13C NMR: d 24.81
(tBuMe2Si), 24.76 (tBuMe2Si), 18.9 (Me3CMe2Si), 26.5
(Me3CMe2Si), 45.8 (CH2Ph), 57.4 (PhCH), 61.6
(CHCH2O), 63.4 (CHCH2O), 128.1, 128.2, 128.4, 129.0
129.5, 136.1, 136.9, 168.7 (carbonyl). MS, m/z: 381 (5,
M1), 366 (1), 324 (6), 248 (28), 206 (23), 191 (100), 117
(43), 91 (40), 73 (12), 59 (3%). Anal. Calcd for
C23H31NO2Si: C, 72.39; H, 8.19; N, 3.67. Found: C,
72.16; H, 8.31; N, 3.85.
obtained [ethyl ether/light petroleum 60:40] as a sticky
yellow liquid in 86% yield; H NMR (200 MHz): d 2.07
1
(3H, s, OCOCH3), 3.73 (1H, ddd, Jˆ5.0, 3.5, 2.5 Hz,
CHCH2O), 4.15 (1H, dd, Jˆ12.0, 5.0 Hz, CHCH2O), 4.20
(1H, d, Jˆ2.5 Hz, PhCH), 4.28 (1H, d, Jˆ5.0 Hz, CH2Ph),
4.45 (1H, dd, Jˆ12.0, 3.5 Hz, CHCH2O), 4.77 (1H, d,
Jˆ15.0 Hz, CH2Ph), 7.23±7.45 (10H, m, aromatic); 13C
NMR: d 21.0, 45.6, 57.7, 58.6, 63.4, 127.7, 128.1, 128.3,
128.7, 129.29, 129.33, 134.9, 136.2, 167.9, 170.8. MS, m/z:
310 (1, [M11]1), 267 (1), 206 (1), 176 (100), 134 (65), 133
(50), 116 (38), 91 (76%). Anal. Calcd for C19H19NO3: C,
73.77; H, 6.19; N, 4.53. Found: C, 73.56; H, 6.26; N, 4.46.
4.4.9. trans-4-Aminomethyl-1-benzyl-3-phenylazetidin-
2-one (18). From aziridine cis-5d, b-lactam trans-18 was
obtained [ethyl acetate/light petroleum 60:40] as a pale
1
4.4.5. cis-1-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-
3-phenylazetidin-2-one (cis-14d). From aziridine trans-
3d, b-lactam cis-14d [light petroleum/ethyl ether 80:20]
yellow solid in 68% yield; H NMR (200 MHz): d 1.96
(2H, br, CH2NH2), 3.65 (1H, dt, Jˆ2.5, 3.5 Hz, CHCH2),
3.74 (1H, dd, Jˆ4.0, 12.0 Hz, CH2NH2), 3.84 (1H, dd,
Jˆ3.5, 12.0 Hz, CH2NH2), 4.27 (1H, d, Jˆ2.5 Hz, PhCH),
4.44 (1H, d, Jˆ15.0 Hz, NCH2Ph), 4.65 (1H, d, Jˆ15.0 Hz,
NCH2Ph), 7.24±7.46 (10H, m, aromatic). MS, m/z: 267 (1,
[M11]1), 236 (5), 133 (22), 105 (13), 91 (100%). Anal.
Calcd for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found:
C, 76.38; H, 7.02; N, 10.78.
1
was obtained as yellow sticky liquid in 40% yield; H
t
NMR (200 MHz): d 0.09 (6H, s, BuMe2Si), 0.91 (9H, s,
tBuMe2Si), 3.59 (1H, dt, Jˆ5.5, 4.0 Hz, CHCH2O), 3.83
(1H, dd, Jˆ4.5, 11.0 Hz, CHCH2O), 3.86 (1H, dd, Jˆ4.0,
11.0 Hz, CHCH2O), 4.21 (1H, d, Jˆ5.5 Hz, PhCH), 4.23
(1H, d, Jˆ15.5 Hz, CH2Ph), 4.84 (1H, d, Jˆ15.5 Hz,
CH2Ph), 7.25±7.45 (10H, m, aromatic). MS, m/z: 324 (50,
[M257]1), 248 (9), 191 (100), 135 (33), 117 (20), 91 (56),
73 (29), 59 (10%). Anal. Calcd for C23H31NO2Si: C, 72.39;
H, 8.19; N, 3.67. Found: C, 72.11; H, 8.36; N, 3.90.
4.4.10. trans-1-Benzyl-4-hydroxymethyl-3-methylazetidin-
2-one (19). From aziridine cis-2b, b-lactam trans-19 was
obtained [ethyl acetate 100%] as a sticky yellow liquid soli-
1
difying at 48C in 84% yield; H NMR (200 MHz): d 1.30
4.4.6. trans-1-Benzyl-3,4-bis-(tert-butyldimethylsilyloxy-
methyl)azetidin-2-one (trans-14f). From aziridine cis-3f,
b-lactam trans-14f was obtained [light petroleum/ethyl
(3H, d, Jˆ7.5 Hz, CH3CH), 1.73 (1H, br, OH), 3.06 (1H, dq,
Jˆ2.0, 7.5 Hz, CH3CH), 3.26 (1H, ddd, Jˆ4.5, 3.5, 2.0 Hz,
CHCH2OH), 3.62 (1H, dd, Jˆ12.0, 4.5 Hz, CHCH2OH),
3.72 (1H, dd, Jˆ12.0, 3.5 Hz, CHCH2OH), 4.38 (1H, d,
Jˆ15.0 Hz, CH2Ph), 4.51 (1H, d, Jˆ15.0 Hz, CH2Ph),
7.28±7.44 (5H, m, aromatic); 13C NMR: d 13.0, 45.3,
46.7, 61.1, 62.0, 128.1, 128.6, 129.1, 129.2, 136.7, 171.6.
MS, m/z: 205 (2, M1), 133 (18), 132 (33), 118 (6), 105 (13),
91 (100), 72 (21), 65 (15), 57 (35%). Anal. Calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.02;
H, 7.28; N, 6.94.
1
ether 70:30] as a pale yellow oil in 90% yield; H NMR
t
(200 MHz): d 0.06 (2£3H, s, BuMe2Si), 0.08 (2£3H, s,
t
t
tBuMe2Si), 0.89 (9H, s, BuMe2Si), 0.91 (9H, s, BuMe2Si),
3.06±3.19 (1H, m, CHCHCH2O), 3.62±3.81 (2H, m,
CHCH2O), 3.69 (1H, ddd, Jˆ6.5, 5.0, 2.0 Hz,
CHCHCH2O), 3.86 (1H, dd, Jˆ11.0, 3.5 Hz, CHCH2O),
3.97 (1H, dd, Jˆ11.0, 5.0 Hz, CHCH2O), 4.15 (1H, d,
Jˆ15.5 Hz, CH2Ph), 4.74 (1H, d, Jˆ15.5 Hz, CH2Ph),
7.27±7.34 (5H, m, aromatic). MS, m/z: 448 (1, [M21]1),
434 (3), 392 (100), 362 (1), 336 (1), 304 (1), 264 (1), 260
(4), 248 (3), 206 (57), 149 (2), 147 (16), 133 (3), 91 (46), 73
(19%). Anal. Calcd for C24H43NO3Si2: C, 64.09; H, 9.64; N,
3.11. Found: C, 63.88; H, 9.90; N, 3.38.
4.4.11. trans-4-Acetoxymethyl-1-benzyl-3-methylazetidin-
2-one (20) and trans-3-acetoxymethyl-1-benzyl-4-methyl-
azetidin-2-one (21). From aziridine cis-4b, b-lactams
trans-20 and trans-21 (86:14) were obtained [ethyl ether
100%] as a yellowish oily unresolvable mixture in 82%
yield.
4.4.7. trans-1-Benzyl-4-hydroxymethyl-3-phenylazetidin-
2-one (16). From aziridine cis-2d, b-lactam trans-16 was
obtained [ethyl ether 100%] as a white solid, mp 92±948C,
1
trans-20. H NMR (400 MHz): d 1.31 (3H, d, Jˆ7.5 Hz,
1
in 79% yield; H NMR (200 MHz): d 1.62 (1H, br, OH),
CH3CH), 2.02 (3H, s, OCOCH3), 3.02 (1H, dq, Jˆ2.0,
7.5 Hz, CH3CH), 3.31 (1H, ddd, Jˆ5.5, 3.5, 2.0 Hz,
CHCH2O), 4.00 (1H, dd, Jˆ12.0, 5.5 Hz, CHCH2O), 4.18
(1H, d, Jˆ15.0 Hz, CH2Ph), 4.30 (1H, dd, Jˆ12.0, 3.5 Hz,
CHCH2O), 4.63 (1H, d, Jˆ15.0 Hz, CH2Ph), 7.26±7.43
(5H, m, aromatic). MS, m/z: 219 (6, [M228]1), 205 (3),
192 (1), 187 (1), 174 (1), 160 (12), 133 (8), 132 (18), 114
(27), 105 (13), 104 (13), 91 (100), 72 (40%). Anal. Calcd for
C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.72; H,
7.26; N, 5.85.
3.67 (1H, dt, Jˆ4.0, 2.5 Hz, CHCH2OH), 3.80 (2H, m,
CH2OH), 4.26 (1H, d, Jˆ2.5 Hz, PhCH), 4.49 (1H, d,
Jˆ15.0 Hz, CH2Ph), 4.62 (1H, d, Jˆ15.0 Hz, CH2Ph),
7.20±7.45 (10H, m, aromatic); 13C NMR: d 45.5, 56.5,
61.4, 61.9, 127.8, 127.9, 128.4, 128.8, 129.3, 129.4, 135.5,
136.5, 169.1. MS, m/z: 268 (100, [M11]1), 240 (2), 134
(67), 115 (9), 105 (20), 91 (88), 78 (17), 65 (14%). Anal.
Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.22; H, 6.29; N, 5.12.
1
4.4.8. trans-4-Acetoxymethyl-1-benzyl-3-phenylazetidin-
2-one (17). From aziridine cis-4d, b-lactam trans-17 was
trans-21. H NMR (400 MHz): d 1.31 (3H, d, Jˆ7.5 Hz,
CHCH3), 2.02 (3H, s, OCOCH3), 3.02 (1H, dq, Jˆ2.0,

1812
P. Davoli et al. / Tetrahedron 57 (2001) 1801±1812
7.5 Hz, CHCH3), 3.31 (1H, ddd, Jˆ6.0, 3.5, 2.0 Hz,
OCH2CH), 4.03 (1H, d, Jˆ15.0 Hz, CH2Ph), 4.31 (1H, dd,
Jˆ12.0, 6.0 Hz, OCH2CH), 4.39 (1H, dd, Jˆ12.0, 3.5 Hz,
OCH2CH), 4.74 (1H, d, Jˆ15.0 Hz, CH2Ph), 7.26±7.43
(5H, m, aromatic). MS, m/z: 219 (1, [M228]1), 205 (1),
192 (1), 187 (1), 174 (1), 160 (10), 133 (10), 132 (25),
114 (88), 105 (15), 104 (14), 91 (100), 72 (62%). Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 68.23; H, 6.81; N, 5.89.
Acknowledgements
Á
The authors thank the Ministero della Universita e della
Ricerca Scienti®ca e Tecnologica (Rome) for ®nancial
support and the Centro Interdipartimentale Grandi
Á
Strumenti (Universita di Modena e Reggio Emilia) for
instrumental measurements.
References
4.4.12. trans-4-Benzylamino-3-methyltetrahydrofuran-
2-one (22). From trans-aziridine 2b, trans-lactone 22 was
obtained [ethyl ether/ethyl acetate 50:50] as an amber sticky
1. Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999,
64, 518.
1
2. Piotti, E. M.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111.
3. Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y. Tetrahedron
Lett. 1990, 31, 6663.
oil in 82% yield. H NMR (200 MHz): d 1.33 (3H, d,
Jˆ7.0 Hz, CH3CH), 1.61 (1H, br, NHCH2), 2.47 (1H, quin-
tet, Jˆ7.5 Hz, CH3CH), 3.31 (1H, dt, Jˆ8.0, 7.0 Hz,
CHNH), 3.86 (2H, d, Jˆ2.5 Hz, NHCH2), 3.90 (1H, dd,
Jˆ9.0, 7.0 Hz, OCH2), 4.39 (1H, dd, Jˆ9.0, 6.5 Hz,
OCH2), 7.26±7.43 (5H, m, aromatic). MS, m/z: 205 (25,
M1), 190 (1), 149 (24), 132 (11), 120 (17), 118 (4), 91
(100), 77 (4), 65 (13%). Anal. Calcd for C12H15NO2: C,
70.22; H, 7.37; N, 6.82. Found: C, 70.11; H, 7.43; N, 6.90.
4. Legters, J.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 1.
5. Chervin, I. I.; Fomichev, A. A.; Moskalenko, A. S.;
Zaichenko, N. L.; Aliev, A. E.; Prosyanik, A. V.;
Voznesenskii, V. N.; Kostyanovsky, R. G. Izv. Akad. Nauk
SSSR, Ser. Khim. 1998, 1110.
6. The inversion energy barrier for compounds 1b±d (DG# 16±
17 kcal/mol) was calculated by 1H DNMR technique as
described in: Sandstrom, J. Dynamic NMR Spectroscopy;
Academic: London, 1982.
4.4.13. trans-4-(tert-Butyldimethylsilyloxymethyl)-1-
ethoxycarbonylmethyl-3-phenylazetidin-2-one (23).
From aziridine cis-13, b-lactam trans-23 was obtained
[light petroleum/ethyl ether 70:30] as a yellow sticky oil
in 63% yield; 1H NMR (400 MHz): d 0.10 (3H, s,
7. Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G.
Tetrahedron: Asymmetry 1995, 6, 2073.
t
t
tBuMe2Si), 0.12 (3H, s, BuMe2Si), 0.93 (9H, s, BuMe2Si),
1.33 (3H, t, Jˆ7.0 Hz, COOCH2CH3), 3.88 (1H, dd,
Jˆ11.5, 7.5 Hz, CH2O), 3.92 (1H, d, Jˆ18.0 Hz,
CH2COOEt), 3.97±4.03 (2H, m, CHCH2O and CHCH2O),
4.05 (1H, d, Jˆ2.5 Hz, PhCH), 4.26 (2H, q, Jˆ7.0 Hz,
COOCH2CH3), 4.42 (1H, d, Jˆ18.0 Hz, CH2COOEt),
7.30±7.41 (5H, m, aromatic). 13C NMR: d 25.1, 14.6,
18.5, 26.1, 30.1, 30.7, 42.9, 57.6, 61.9, 62.5, 64.1, 128.0,
128.2, 129.2, 135.2, 168.7, 168.8. MS, m/z: 377 (2, M1),
320 (6), 304 (4), 248 (19), 244 (6), 202 (58), 191 (100), 117
(59), 115 (14), 75 (12), 73 (14%). Anal. Calcd for
C20H31NO4Si: C, 63.62; H, 8.28; N, 3.71. Found: C,
63.48; H, 8.07; N, 3.56.
8. Mukerjee, A. K.; Singh, A. K. Tetrahedron 1978, 34, 1731.
9. Davoli, P.; Forni, A.; Franciosi, C.; Moretti, I.; Prati, F.
Tetrahedron: Asymmetry 1999, 10, 2361.
È
10. Haner, R.; Olano, B.; Seebach, D. Helv. Chim. Acta 1987, 70,
1676.
11. Gastaminza, A. E.; Ferracutti, N. N.; Rodriguez, N. M. J. Org.
Chem. 1984, 49, 3859. Buchta, E.; Burger, K. Liebigs Ann.
Chem. 1952, 576, 155.
12. Michael, A. Berichte 1901, 24, 3640.
13. Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem.
1997, 62, 736.