Diels-Alder cycloaddition of 2-azadienes to methyl 2-(2,6-dichlorophenyl)- 2H-azirine-3-carboxylate in the synthesis of methyl 4-oxo-1,3-diazabicyclo[4.1. 0]heptane-6-carboxylates

Article abstract of DOI:10.1016/j.tet.2004.06.004

A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by Diels-Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to isomerization of the cycloadducts 7 and 8 or by isomerization of the CN bond of the diene during the reaction. The isomer 10 is formed from diene 2e, and a single diastereoisomer structure 4a-i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been hydrolyzed leading to functionalised aziridines 12, 13 and 15.

Full text of DOI:10.1016/j.tet.2004.06.004

Tetrahedron 60 (2004) 6541–6553
Diels–Alder cycloaddition of 2-azadienes to methyl
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate in the synthesis
of methyl 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates
*
M. Jose Alves, M. Miguel Dura˜es and A. Gil Fortes
´
´
Departamento de Quımica, Universidade do Minho, Campus de Gualtar, 4700-320 Braga, Portugal
Received 7 January 2004; revised 10 May 2004; accepted 3 June 2004
Available online 19 June 2004
Abstract—A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by
Diels–Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and
regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to
isomerization of the cycloadducts 7 and 8 or by isomerization of the CvN bond of the diene during the reaction. The isomer 10 is formed
from diene 2e, and a single diastereoisomer structure 4a–i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been
hydrolyzed leading to functionalised aziridines 12, 13 and 15.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
literature contains examples of the cycloaddition of electron
poor 2-azadienes to simple imines and to an azirine15 but
this work represents the first examples of normal electron
demanding cycloadditions between 2-azadienes and an
azirine.
Methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 6
has been reacted with dienes 1, 21 and 4. It had been
obtained before by pyrolysis of the methyl 3-(2,6-dichloro-
phenyl) a-azidopropenate2 and used in [4þ2] p cyclo-
addition with commercial dienes. Reactions occur at room
temperature with excellent stereoselectivity, being endo3 to
carbodienes and exo4 to furan and diphenylisobenzofuran.
The 2-azadienes were obtained according to methodology
developed by Ghosez5 from acylimidates and tert-butyl-
dimethylsilyl triflates for compounds 1 and 2, and from
LiHMDS, trimethylsilyl chloride and triethylamine in one
pot reaction for compounds 4.5 Nucleophilic 2-azadienes of
this type had been combined with a range of electron poor
dienophiles, such as aldehydes,6a,b nitroso compounds,7–9
olefinic compounds,10 naphthoquinones,11 quinones,12
activated acetylenic dienophiles,12,13 and activated
nitriles,12 in order to obtain the 6 membered ring
compounds or their hydrolysis derivatives. A chiral nitroso
compound was employed giving cycloadducts with high
facial selectivity.9 Also, activated olefinic dienophiles were
used together with nucleophilic 2-azadienes in the presence
of a chiral copper(II) complex to give enantiomerically pure
piperidones.14 The results we now report were obtained
by Diels–Alder cycloaddition between electrophilic 2H-
azirine 6 and the nucleophilic 2-azadiens 1, 2 and 4. The
2. Results and discussion
2.1. Synthesis of 2-azadienes
2.1.1. From imidates. The 2-azadienes 1 and 2 were
obtained in two steps according to the procedure devised by
Ghosez et al. for this type of compound. Commercial
imidates and acid chlorides were mixed together in dry
DCM and over N2, to form the acylimidates 3 as
intermediates. The acylimidates were further silylated in
ether in the presence of tert-butyldimethylsilyl chloride.
Products were obtained in good yields (Scheme 1)
1
contaminated with N-acylimidate, according to H NMR
spectra, and were used without purification in the synthesis
of cycloadducts.
Compounds 1a and 1b have been prepared previously.
Compound 1b was shown to have the Z configuration for the
C-3 to C-4 bond.5 Compounds 1c and 1d are new
compounds and the same configuration is assigned. In
solution compounds 1b–d were found to consist of
mixture of stereomers in relation to C-1. The major isomers
were deduced to have the EZ configuration, based on
Keywords: 2-Azadienes; 2H-Azirines; Diels–Alder cycloaddition.
*
Corresponding author. Fax: þ351-2-53-678983;
e-mail address: mja@quimica.uminho.pt
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.004

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M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
analogous compounds obtained before.5 Three examples are
shown below (Fig. 1):
Figure 1. Some examples of EZ configuration of 2-azadienes reported in
the literature.
Scheme 1. Preparation of 2-azadienes 1 and 2.
The minor compound in series i is assumed to have the EE
configuration according to other cases reported in literature
for the same type of dienes.5 Due to the instability of the
2-azadienes 4, they were identified by 1H NMR
spectroscopy and were used without purification in the
cycloadditions.
spectroscopic evidence for cycloadducts obtained as
discussed later. Stereomer 2 is formed in the series e
together with stereomer 1. Compounds 1e and 2e are formed
in 1:4 ratio when neat TBDMSOTf is added to the
acylimidate solution, and a 1:1 ratio of isomers when
TBDMSOTf is added dropwise diluted in ether. This result
led us to assume the diene 2e to be the kinetic product of
silylation of the acylimidate with TBDMSOTf. Stereomer
2e was assigned as EE configuration on the basis of the
spectroscopic data of cycloadduct 10 obtained along with
the adduct 7e in the reaction of 1e/2e to azirine 6.
2.2. Cycloadditions of 2-azadienes 1 and 2 to 2H-azirine
6
2-Azadienes of type 1a–d react at room temperature with
the azirine 6 to give the cycloadducts 7 and 8 (Scheme 3).
Usually, the desilylated compound precipitated out of the
reaction mixture as a solid that was obtained by filtration.
After repeating these reactions in several conditions, we find
that the better yields correspond to reactions performed in
very small amounts of diethyl ether. As an alternative
procedure after the consumption of the azirine the reaction
material was redissolved in DCM, stirred with SiO2
followed by dry flash chromatography. Poorer yields of
products 7/8 were obtained in all cases. Also treatment of
2.1.2. From aldehydes. 2-Azadienes 4 were obtained in one
pot reaction by combination of 4–5 fold excess of
LiHMDS, freshly distilled aldehyde and trimethylsilyl
chloride to produce the imine 5, that was further acylated
in the presence of an acid chloride and triethylamine,
according to Scheme 2.
This is a modified method of one initially used by Ghosez
to generate azadienes of type 4.5 Excellent yields were
obtained in most cases. All 2-azadienes 4 referred to here
are new compounds that were shown to be single isomers in
solution, with the exception of 4i, where a second isomer is
observed (isomeric ratio 10:1). The EZ stereochemistry for
the compounds is assigned in accordance with a range of
Scheme 2. Preparation of 2-azadienes 4.
Scheme 3. Preparation of the pyrimidinones 7 and 8.

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
6543
the reaction mixture with tetramethylammonium fluoride
gave compound 7b in a poorer yield (41%). The primary
silyloxy cycloadduct could never be isolated or even
7-H to be on the same side of 2-Me, which would be
explained for the same endo approach of the less crowded
face of the azirine to the minor diene isomer ZZ (Fig. 2).
Further support for the difference between the diastereomers
7 and 8 in 2-C is obtained by hydrolysis of compounds 7c
and 8c which gave the same product 12 as seen ahead
(Scheme 6).
1
observed by H NMR analysis.
The solid obtained from reaction of 1a (one stereomer) with
the azirine 6 was a mixture (1:1 ratio) of 7a/8a in 53% yield.
Redissolution of the solid in DCM and stirring the solution
with SiO2 for 24 h gave 7a quantitatively. A single isomer
7b was obtained from 1b in 51% yield after filtration. The
starting diene contained only traces of a minor isomer.
Reaction of 1c (4:1 mixture of stereomers) produced an oil
that was treated with DCM and SiO2 for 3 days. The crude
showed two diastereomers 7c and 8c in a 1:1 ratio. After
flash chromatography the isomer 7c was partially separated
(25%), together with a fraction containing the mixture of
both isomers (33%), in total yield of 58%. Curiously the
diastereomeric ratio after chromatography changed to 4.5
(7c): 1 (8c). Reaction of 1d (2:1 ratio of stereomers) with the
azirine 6 gave an oil which was treated with SiO2 in DCM
for 7 days. 1H NMR spectrum of the reaction mixture
showed a 3:1 mixture of diastereomers that were fully
separated after flash chromatography as two solids, 7d
(27%) and 8d (11%).
Figure 2. Compounds 7c and 8c showing the interaction through space
(NOESY).
On reacting a mixture of dienes 1e and 2e (1:4 ratio) with
the azirine 6 a white solid formed after stirring the reaction
mixture for 7 days at room temperature. The solid was
analysed by 1H NMR showing it to be a mixture of
diastereomers identified as 7e and 10, in 1.2 (7e): 1 (10)
ratio. This is another case besides a and b where a solid is
isolated, without previous contact with silica. As in case a
the isomeric ratio of dienes does not match with the
isomeric ratio of cycloadducts. So the observations made for
the case a can now be used to explain to case e. Flash
chromatography partially separated 7e (30%) as a white
solid together with a mixture of 7e and 10 (21%) also as a
solid, total yield 51%. The NOESY spectrum of 7e showed
the methoxy group at 2-C in the proximity of 7-H and the
methyl group at 5-C close in space to 7-H. On the other hand
the NOESY spectrum of the minor isomer 10 showed
proximity between 5-H and 7-H, which would rule out
structure 8 and strongly suggests structure 10 instead
(Fig. 3).
Unexpectedly no relationship is observed between the
diastereomeric ratio of the adducts 7/8 and the stereomeric
ratio of the precursor dienes. In cases where the products
were obtained after treatment with SiO2 a possible
explanation is the isomerization of products 8 into 7. It is
also relevant that the diastereomeric ratio difference
between a mixture of 7c and 8c that was enriched in 7c
after flash chromatography. In series a two isomers 7 and 8
(1:1 ratio) precipitated out of the reaction mixture before
treatment with SiO2, having started the cycloaddition from
1a as a single isomer. In this case it is more plausible that the
CvN bond rotation between the EZ and ZZ isomer forms
can explain the isomeric ratio of adducts. Possibly a
chemical equilibrium between the EZ and ZZ forms, that
is not observable in CDCl3 solution, occurs during the
cycloaddition giving the respective adducts.
Another possibility is that a step-wise mechanism rather
than a concerted Diels–Alder process could operate in this
case. The same could not be said about the cycloaddition of
1b where a single diene isomer gave a single cycloadduct
(Scheme 4).
Figure 3. Compounds 7e and 10 showing the interaction through space
(NOESY).
Structure 10 should be formed from attack of the less
hindered face of the azirine on the less stable diene
configuration EE. The hydrolysis product of compound 10
confirms a different configuration of the stereocentre 5-C of
this compound related to structures 7 and 8 as seen later.
Cycloaddition preparations of series e showed that starting
with a mixture of dienes 1e and 2e (ca. 1:1 ratio) and with a
mixture of dienes 1e and 2e (ca. 1:4 ratio) isomers 7e and 10
formed in the same isomeric ratio (1:1). This leads us to
propose that an isomerization takes place about 3-C to 4-C
in the diene during the course of the reaction.
Scheme 4. Possible isomerization mechanism between compounds 8 and 7.
A crystal structure confirmed the structure of compound 7c.1
This shows that the reaction goes through an endo approach
of the azirine 6 from its less hindered face to EZ
configuration of the diene 1. Also, NOESY spectra for 7c
show that the 5-H and 2-Me were on the same side of the
molecule. On the other hand the minor isomer 8c showed
1H NMR spectra of compounds 7c and 8c showed the
influence of the ethoxyl group through space on protons 5-H

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M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
and 7-H. When this proximity is observed the 5-H and 7-H
protons suffer a shift to lower field in the spectra. In
compound 7c 7-H suffer a shift to lower field (þ0.31 ppm)
when compared to 7-H in compound 8c. On the other hand,
5-H in compound 8c shows up at lower field (þ0.35 ppm)
compared to 5-H in compound 7c. Comparison of 1H NMR
chemical shifts of 5-H and 7-H obtained to the series c apply
to the diastereomeric pair in series d, but not in series a
(Table 1).
was obtained by filtration. In other cases the product was
obtained as an oil (a, c, h, i) that was subjected to dry flash
chromatography (a, h, i) resulting in a drop in the yield of
the reaction. In case c a polymer formed together with an oil.
The oil crystallized after addition of diethyl ether. The
primary silylated cycloadduct could never be observed by
1H NMR analysis of the products. In accordance with results
obtained for the cycloaddition of 7 and 8 the approach of
reactants is proposed to take place from the less hindered
face of the azirine.
Table 1. Some data for pyrimidones 7, 8 and 11
Major features of the 1H NMR spectra for compounds 11 are
the 5-H and 7-H chemical shifts, comparable to 5-H and 7-H
chemical shifts of compounds 7. Namely the 5-H in the 2,5-
diphenyl disubstituted compounds 11d and 7d are,
respectively, 4.63 and 4.41 ppm. Also the two 5-H of the
monosubstituted 11c and 7a showed similar chemical shift
values: 3.57/3.16 ppm (11c) and 3.40/3.16 ppm (7a).
Compounds 8 showed chemical shifts somewhat further
apart: 3.34/3.08 (8a) and 5.09 (8d). 2-H Chemical shifts in
structures 11 are all around the same chemical shifts
between 5.86 and 6.52 ppm, showing the influence of the
nitrogen atoms and an aromatic ring attached to the 2-C.
Compound
Mp (8C)
1H NMRa, dH in ppm, J in Hz
7a
8a
173.5–176.0
176.0–177.5
5-H 3.16 (d, J¼18.3, 1H), 3.40 (d,
J¼18.3, 1H); 7-H 3.32 (s, 1H)
5-H 3.08 (d, J¼18.3, 1H), 3.34 (d,
J¼18.3, 1H); 7-H 3.58 (s, 1H)
5-H 3.19 (q, J¼7.2, 1H); 7-H 3.59 (s, 1H)
5-H 4.40 (s, 1H,);
7b
7c
140.5–146.5
181.2–183.2
7-H 4.13 (s, 1H)
5-H 4.75 (s, 1H);
7-H 3.82 (s, 1H)
5-H 4.41 (s, 1H);
7-H 3.80 (s, 1H)
5-H 5.09 (s, 1H);
7-H 3.66 (s, 1H)
8c
7d
8d
134.5–137.5
175.5–177.5
189.1–190.1
7e
10
11a
11b
11c
212.0–214.0
187.0–188.4
166.6–169.7
168.6–171.1
189.6–191.2
5-H 2.59 (q, J¼6.9, 1H); 7-H 3.77 (s, 1H)
5-H 3.82 (q, J¼7.2, 1H); 7-H 3.48 (s, 1H)
5-H 3.40 (q, J¼6.9, 1H); 7-H 3.74 (s, 1H)
5-H 3.42 (q, J¼6.9, 1H); 7-H 3.76 (s, 1H)
5-H 3.57 (d, J¼18.3, 1H), 3.16 (d,
J¼18.3, 1H); 7-H 3.75 (s, 1H)
5-H 4.63 (s, 1H);
7-H 4.24 (s, 1H)
5-H 4.63 (s, 1H);
7-H 4.26 (s, 1H)
5-H 4.61 (s, 1H);
7-H 4.22 (s, 1H)
5-H 4.61 (s, 1H);
7-H 4.22 (s, 1H)
5-H 4.50 (s, 1H);
7-H 4.16 (s, 1H)
5-H 3.39 (q, J¼6.9, 1H); 7-H 3.72 (s, 1H)
2.4. Hydrolysis of the cycloadducts
Heating an ether solution of 7a afforded the hydrolysis
product in trace amounts. Compound 12a could be obtained
pure in 74% yield when a solution of 8a in THF was treated
with aq. HCl (1 equiv.) diluted in THF. Also, a mixture of 7c
and 8c was treated the same way to give product 12c in 87%
yield (Scheme 6). As both diastereomers 7c and 8c gave the
same hydrolysis product this confirms the stereochemistry
of adducts discussed above.
11d
11e
11f
210.2–213.6
195.1–196.8
152.4–153.3
208.1–210.3
173.5–173.9
213.4–215.0
11g
11h
11i
a
Selected peaks.
2.3. Cycloadditions of 2-azadienes 4 to 2H-azirine 6
2-Azadienes of type 4a–i react at room temperature with
the azirine 6 to give the cycloadducts 11 as single isomers.
Products were generally obtained in good yields (Scheme 5).
In most cases the desilylated compound precipitated out of
the reaction as a solid practically pure (b, d, e, f and g) that
Scheme 6. Hydrolysis of compounds 7, 8 or mixture of 7/8.
The hydrolysis of the mixture of 7e/10 (1.2:1 ratio)
produced a different result. In this case two products 12e
and 13 (Fig. 4) were obtained (1.2:1) that were characterized
after separation by dry flash chromatography.
A possible mechanism for the hydrolysis can be envisaged
Scheme 5. Preparation of pyrimidones 11.
Figure 4. Structure of compound 13.

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
6545
Scheme 7. Hydrolysis of compound 11d.
masked a-aminoesters with functionalised side chains.
Specially structure 15, where a b-amido group makes it a
potential interesting compound after some minor manipula-
tions. Introducing chirality both in the azirine and the diene
in order to turn the reactions enantioselective are currently
underway.
Table 2. Some data for aziridines 12, 13 and 15
Compound
Mp (8C)
Yield (%)
1H NMR (CH and
NH of the aziridine
ring), dH in ppm, J in Hz
12aa
12bb
12cc
12dd
12ee
13e
164.3–165.1
116.3–117.4
191.1–191.6
180.2–181.2
189.3–190.0
139.5–139.9
167.5–167.7
74
42
87
68
29f
25f
67
CH 3.21 (d, J¼8.4, 1H); NH 2.87
(br d, J¼8.4, 1H)
CH 3.37 (d, J¼9, 1H); NH 2.85
(d, J¼9, 1H)
4. Experimental
4.1. General
CH 2.40 (d, J 9.9, 1H); NH 3.08
(d, J 9.9, 1H)
CH 2.51 (d, J¼9.9, 1H); NH 3.02
(d, J¼9.9, 1H)
1H NMR spectra were recorded on a Varian Unity Plus 300
(300 MHz) spectrometer Multiplicities are recorded as
broad peaks (br), singlets (s), doublets (d), triplets(t),
doublet of doublets (dd) quartets (q) doublet of quartets
(dq) and multiplets (m). J values are in Hz. Infrared spectra
were recorded on a Bomem MB 104 or on a Perkin–Elmer
1600 FT-IR spectrometer. Solid samples were run as nujol
mulls, and liquids as thin films. Mass spectra were recorded
on a VG Autospec M. spectrometer as electron impact
spectra (70 eV). Microanalyses were performed in a LECO-
CHNS-932 analyser. Melting points (mp) were determined
on a Gallenkamp block and are uncorrected. Dry column
flash chromatography was carried out using Kieselgel 60
and water pump vacumm. Thin layer chromatography
(TLC) was carried out on 0.25 mm silica gel layer 60DC-
Ferigplatter Durasil-25 UV254. Diethyl ether and tetra-
hydrofuran were dried over sodium using benzophenone as
indicator. Triethylamine and the acid chlorides were freshly
distilled prior to use. The aldehydes were purified by
crystallization if solids or by distillation if liquids. Dry flash
chromatography was performed on silica gel 60,0.063 mm
for columm chromatography. Petroleum ether 40–60 8C
was distilled before use.
CH 3.39 (d, J¼9.3, 1H); NH 2.83
(d, J¼9.3, 1H)
CH 3.38 (d, J¼9.0, 1H), NH 2.97
(d, J¼9.0, 1H)
15
CH 2.42 (d, J¼8.7, 1H), NH 3.04
(d, J¼8.7, 1H)
a
Obtained from hydrolysis of compound 8a.
Obtained from hydrolysis of compound 7b.
Obtained from hydrolysis of an isomeric mixture (1:1) of compounds 7c
and 8c.
Obtained from hydrolysis of compound 7d.
12e and 13 were obtained from hydrolysis of a mixture of compound 7e
b
c
d
e
and 10.
Partially separated after flash chromatography; total yield of 12e and 13 is
75%.
f
from conversion of compounds 8a into 7a, through 9 as the
intermediate (Scheme 4). On the other hand, compound 11d
would form the imine 14 in the presence of excess of HCl to
generate the final product 15 (Scheme 7).
Major features for assignment of structures 12, 13 and 15
are the two doublets due to the NH–CH moiety of the
aziridine ring coupling J ca. 9 Hz at 2.5–3.5 ppm (Table 2).
Addition of D2O exchanged the mobile proton and the CH
then shows up as a sharp singlet.
4.2. General procedure for the synthesis of the N-
acylimidates
3. Conclusion
Triethylamine recently dried was added in one portion to a
solution of the imidate hydrochloride in dry DCM, stirred at
room temperature under nitrogen. The acid chloride was
added dropwise to the reaction mixture. Stirring was
continued for another 30 min, and dried petroleum ether
40–60 8C (40 mL) was added. The reaction mixture was
filtered over celite and the filtrate concentrated to a residual
oil that was redissolved in dry petroleum ether 40–60 8C
(20 mL) and passed again over a pad of celite. The filtrate
was concentrated to give a pale yellow oil that was
identified as the respective acylimidate by 1H NMR
spectroscopy.
Fused systems containing 2-oxocarbonylaziridines have
been obtained with excellent diastereoselectivity by Diels–
Alder cycloaddition between an electrophilic 2H-azirine
and nucleophilic 2-azadienes. The reaction occurs at room
temperature in the absence of catalysis producing moderate
to good yields of products. Since the purification of the
intermediate compounds were avoided in all steps, the
yields may be considered good even in compounds 7 and 8
and some 11 where the results are poorer. The pyrimidone
compounds 7, 8 and 11 are by themselves compounds with
potential biological interest, but the same could be said
about the hydrolysis products 12, 13 and 15 which are also
4.2.1. Ethyl N-acetylacetimidate 3a. Reaction mixture:

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M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
ethyl acetimidate hydrochloride (1.00 g, 8.10 mmol,
1 equiv.) in DCM (25 mL), triethylamine (2.46 mL,
17.8 mmol, 2.2 equiv.), acetyl chloride (0.58 mL,
8.10 mmol, 1 equiv.). Yield 0.82 g (84%). 1H NMR
(300 MHz, CDCl3), d¼0.93 (t, J¼7.2 Hz, 3H), 1.68 (s,
3H), 1.89 (s, 3H), 3.82 (q, J¼7.2 Hz, 2H) ppm.
(25 mL), triethylamine (1.05 mL, 7.59 mmol, 1.1 equiv.),
tert-butyldimethylsilyl triflate (1.58 mL, 6.90 mmol,
1 equiv.), diluted in dry diethyl ether (10 mL). Yield
1.28 g (65%) contaminated with starting imidate (16%) in
accordance with the H NMR data. H NMR (300 MHz,
CDCl3), d¼0.16 (s, 6H), 0.91 (s, 9H), 1.06 (t, J¼7.2 Hz,
3H), 2.01 (s, 3H), 3.42 (s, 1H), 3.70 (s, 1H), 4.08 (q,
J¼6.9 Hz, 2H) ppm.
1
1
4.2.2. Ethyl N-propionyl acetimidate 3b. Reaction
mixture: ethyl acetimidate hydrochloride (2.00 g,
16.2 mmol, 1 equiv.) in DCM (25 mL), triethylamine
(5.42 mL, 39.2 mmol, 2.2 equiv.), propionyl chloride
4.3.2. 2-Ethoxy-4-(tert-butyldimethylsilyloxy)-3-aza-2,4-
hexadiene 1b. Reaction mixture: ethyl N-propionyl aceti-
midate 3b (1.47 g, 10.30 mmol, 1 equiv.), dry diethyl ether
(25 mL), triethylamine (1.57 mL, 11.30 mmol, 1.1 equiv.),
tert-butyldimethylsilyl triflate (2.36 mL, 10.30 mmol,
1 equiv.), diluted in dry diethyl ether (10 mL). Yield
2.90 g (87%), contaminated with starting acylimidate
(20%) in accordance with the 1H NMR data. 1H NMR
(300 MHz, CDCl3), d¼0.12 (s, 6H), 0.90 (s, 9H), 1.26 (t,
J¼6.9 Hz, 3H), 1.57 (d, J¼6.6 Hz, 3H), 1.98 (s, 3H), 3.78
(q, J¼6.6 Hz, 1H), 4.10 (q, J¼6.9 Hz, 2H) ppm.
1
(1.41 mL, 16.20 mmol, 1 equiv.). Yield 1.47 g (66%). H
NMR (300 MHz, CDCl3), d¼1.12 (t, J¼7.2 Hz, 3H), 1.27
(t, J¼7.5 Hz, 3H), 1.98 (s, 3H), 2.41 (q, J¼7.5 Hz, 2H), 4.08
(q, J¼7.2 Hz, 2H) ppm.
4.2.3. Ethyl N-phenylacetyl acetimidate 3c. Reaction
mixture: ethyl acetimidate hydrochloride (0.58 g,
4.70 mmol, 1 equiv.) in DCM (25 mL), triethylamine
(1.42 mL, 10.33 mmol, 2.2 equiv.), phenylacetyl chloride
(0.62 mL, 4.70 mmol, 1 equiv.). Yield 0.95 g (98%). 1H
NMR (300 MHz, CDCl3), d¼1.25 (t, J¼7.2 Hz, 3H), 1.77
(s, 3H), 3.72 (s, 2H), 4.07 (q, J¼7.2 Hz, 2H), 7.30–7.40 (m,
5H, ArH) ppm.
4.3.3. 4-Ethoxy-1-phenyl-2-(tert-butyldimethylsilyloxy)-
3-aza-1,3-pentadiene 1c. Reaction mixture: ethyl N-
acetylphenyl acetimidate 3c (0.95 g, 4.63 mmol, 1 equiv.),
dry diethyl ether (25 mL), triethylamine (0.71 mL,
5.10 mmol, 1.1 equiv.), tert-butyldimethylsilyl triflate
(1.10 mL, 4.63 mmol, 1 equiv.), diluted in dry diethyl
ether (10 mL). Yield 1.46 g (86%), contaminated with
starting imidate (13%) in accordance with the 1H NMR data.
Mixture of isomers (4:1). Major isomer 1H NMR (300 MHz,
CDCl3), d¼0.21 (s, 6H), 1.01 (s, 9H), 1.33 (t, J¼7.2 Hz,
3H), 2.11 (s, 3H), 4.18 (q, J¼7.2 Hz, 2H), 4.77 (s, 1H),
7.20–7.30 (m, 3H), 7.75 (d, J¼7.2 Hz, 2H) ppm. Minor
isomer (some peaks) 0.22 (s, 6H), 0.98 (s, 9H), 1.91 (s, 3H),
4.30 (q, J¼7.5 Hz, 2H), 5.26 (s, 1H) ppm.
4.2.4. Methyl N-phenylacetyl benzimidate 3d. Reaction
mixture: methyl benzimidate hydrochloride (0.70 g,
4.08 mmol, 1 equiv.) in DCM (25 mL), triethylamine
(1.24 mL, 8.98 mmol, 2.2 equiv.), phenylacetyl chloride
(0.54 mL, 4.08 mmol, 1 equiv.). Yield 0.74 g (55%),
contaminated with methyl benzimidate hydrochloride
1
23%. H NMR (300 MHz, CDCl3), d¼3.66 (s, 2H), 3.82
(s, 3H), 7.04–7.04 (m, 10H, ArH) ppm.
4.2.5. Methyl N-propionyl benzimidate 3e. Reaction
mixture: methyl benzimidate hydrochloride (1.00 g,
5.83 mmol, 1 equiv.) in DCM (25 mL), triethylamine
(1.77 mL, 12.80 mmol, 2.2 equiv.), propionyl chloride
(0.51 mL, 5.83 mmol, 1 equiv.). Yield 0.82 g (74%). 1H
NMR (300 MHz, CDCl3), d¼1.06 (t, J¼7.5 Hz, 3H), 2.34
(q, J¼7.5 Hz, 2H), 3.87 (s, 3H), 7.24–7.62 (m, 5H, ArH)
ppm.
4.3.4. 1-Methoxy-1,4-diphenyl-3-(tert-butyldimethyl-
silyloxy)-2-aza-1,3-butadiene 1d. Reaction mixture: ethyl
N-acetylphenyl benzimidate 3d (0.74 g, 2.93 mmol,
1 equiv.), dry diethyl ether (25 mL), triethylamine
(0.45 mL, 3.22 mmol, 1.1 equiv.), tert-butyldimethylsilyl
triflate (0.67 mL, 2.93 mmol, 1 equiv.), diluted in dry
diethyl ether (10 mL). Yield 1.05 g (88%), contaminated
1
4.3. General procedure for the synthesis of the
2-azadienes 1 and 2
with starting acylimidate (10%) in accordance with the H
NMR data. Mixture of isomers (2:1). Major isomer (some
1
peaks): H NMR (300 MHz, CDCl3), d¼0.27 (s, 6H), 1.00
Triethylamine recently dried was added in one portion to a
solution of the acylimidate in dry ether stirred at room
temperature and under N2. tert-Butyldimethylsilyl triflate
diluted in dry ether was added dropwise. After the
addition was complete the reaction mixture was placed in
the freezer for 10 min. The reaction mixture was allowed to
reach room temperature and the ethereal phase was
separated and the lower phase washed with dry ether
(2£25 mL). The organic layers were combined, dried and
the ether evaporated. A pale brown oil was obtained that
(s, 9H), 3.93 (s, 3H), 4.63 (s, 1H). Minor isomer (some
peaks), 0.12 (s, 6H), 0.95 (s, 9H), 3.73 (s, 3H), 5.22 (s, 1H).
4.3.5. (1E, 3Z) 1-Methoxy-1-phenyl-3-(t-butyldimethyl-
silyloxy)-2-aza-1,3-pentadiene 1e and (1E, 3E) 1-meth-
oxy-1-phenyl-3-(t-butyldimethylsilyloxy)-2-aza-1,3-pen-
tadiene 2e. Reaction mixture: methyl N-propionyl
benzimidate 3e (0.82 g, 4.29 mmol, 1 equiv.), dry diethyl
ether (25 mL), triethylamine (0.65 mL, 4.72 mmol,
1.1 equiv.), tert-butyldimethylsilyl triflate (0.99 mL,
4.29 mmol, 1 equiv.), diluted in dry diethyl ether (10 mL).
Yield 1.14 g (82%), contaminated with starting acylimidate
1
was shown by H NMR to be the respective 2-azadienes
expected, contaminated with a variable amount of the
starting acylimidate.
1
(18%) in accordance with the H NMR data. Mixture of
isomers (4:1). Major isomer (2e): 1H NMR (300 MHz,
CDCl3), d¼0.20 (s, 6H), 0.95 (s, 9H), 1.44 (d, J¼6.6 Hz,
3H), 3.66 (q, J¼6.6 Hz, 1H), 3.86 (s, 3H), 7.30–7.40 (m,
3H), 7.50–7.70 (m, 2H) ppm. Minor isomer (1e): 0.14 (s,
4.3.1. 4-Ethoxy-2-(tert-butyldimethylsilyloxy)-3-aza-1,3-
pentadiene 1a. Reaction mixture: ethyl N-acetyl aceti-
midate 3a (0.82 g, 6.82 mmol, 1 equiv.), dry diethyl ether

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
6547
6H), 0.88 (s, 9H), 1.25 (d, J¼6.6 Hz, 3H), 3.88 (s, 3H), 3.90
(q, J¼6.6 Hz, 1H) ppm.
(0.40 mL, 0.29 g, 2.91 mmol, 1.1 equiv.), propionyl
chloride (0.30 mL, 0.32 g, 3.44 mmol, 1.3 equiv.) in dry
ether (3 mL). Yield of a yellow solid 0.61 (ca. 83%) in
accordance with H NMR. H NMR (300 MHz, CDCl3),
d¼0.28 (s, 9H, SiMe3), 1.81 (d, J¼7.5 Hz, 3H), 5.43 (q,
J¼7.5 Hz, 1H, 4-H), 7.94 (d, J¼9.0 Hz, 2H, ArH), 8.27 (d,
J¼9.0 Hz, 2H, ArH), 8.32 (s, 1H, 1-H) ppm.
1
1
4.4. Synthesis of 2-azadienes 4
Method A. To 1,1,1,3,3,3-hexamethyldisilazane (1 equiv.)
was added n-butyllithium (1.6 M in hexanes, 0.9 equiv.)
over a 5 min period. The reaction solution was kept under
magnetic stirring for 15 min at room temperature and then
cooled in an ice/water bath. Dry THF (the amount needed
for 0.6 M of LiHMDS) was added and the mixture stirred
further for 20 min. A solution of the aldehyde (1 equiv.)
freshly distilled in dry THF was added over a 7 min period
and the resulting solution stirred for 30 min. Trimethylsilyl
chloride (0.9 equiv.) was added in one portion and the
stirring continued for 30 min. Triethylamine (1.1 equiv.)
was added followed by the acid chloride (1.3 equiv.) in dry
ether. The cooling bath was removed and the mixture was
stirred at room temperature for 2 h. The inorganic salts were
filtrated off over celite and the ether was removed in the
rotary evaporator to give the crude product, as a solid or an
oil.
4.4.3. 1-(4-Fluorophenyl)-3-trimethylsilyloxy-2-aza-1,3-
butadiene 4c. Reaction mixture: lithium 1,1,1,3,3,3-hexa-
methyldisilazanate (3.75 mL, 2.70 g, 16.12 mmol, 5 equiv.)
in dry ether (16 mL), 4-fluorobenzaldehyde (0.35 mL,
0.40 g, 3.22 mmol, 1 equiv.) in dry ether (3 mL), trimethyl-
silyl chloride (0.60 mL, 0.53 g, 4.84 mmol, 1.5 equiv.),
triethylamine (0.49 mL, 0.36 g, 3.55 mmol, 1.1 equiv.),
acetyl chloride (0.30 mL, 0.33 g, 4.19 mmol, 1.3 equiv.) in
dry ether (4 mL). Yield of a yellow oil 0.64 g (65%),
contaminated with the starting aldehyde (25%) in accord-
1
1
ance with H NMR data. H NMR (300 MHz, CDCl3)†,
d¼4.31 (s, 1H, 4-H), 4.65 (s, 1H, 4-H), 8.25 (s, 1H, 1-H)
ppm.
4.4.4. 1,4-Diphenyl-3-trimethylsilyloxy-2-aza-1,3-buta-
diene 4d. Reaction mixture: lithium 1,1,1,3,3,3-hexa-
Method B. To lithium 1,1,1,3,3,3-hexamethyldisilazanate
(4–5 equiv.) in dry ether, cooled at 0 8C and in N2
atmosphere was added the aldehyde (1 equiv.) freshly
distilled in dry ether over a 5 min period. The cooling
bath was removed and the reaction mixture was stirred for
3 h at room temperature. Then the reaction mixture was
cooled to 0 8C again and trimethylsilyl chloride (1.3 equiv.)
added in one portion. After stirring the reaction mixture at
0 8C for 5 min, the bath was removed and the mixture stirred
at room temperature for 1 h 15 min. After this time,
triethylamine (1.1 equiv.) was added in one portion
followed by dropwise addition of the acid chloride
(1.3 equiv.) in dry ether. The reaction mixture was
transferred to an water bath at 30 8C and the stirring was
continued for another 2 h. The inorganic salts were filtrated
off over celite and the ether was removed to give the crude
product as a solid or an oil.
methyldisilazanate
(4.38 mL,
3.15 g,
18.85 mmol,
5 equiv.) in dry ether (19 mL), benzaldehyde (0.38 mL,
0.40 g, 3.77 mmol, 1 equiv.) in dry ether (4 mL), trimethyl-
silyl chloride (0.56 mL, 0.49 g, 4.52 mmol, 1.2 equiv.),
triethylamine (0.57 mL, 0.42 g, 4.15 mmol, 1.1 equiv.),
phenylacetyl chloride (0.65 mL, 0.76 g, 4.90 mmol,
1.3 equiv.) in dry ether (5 mL). Yield of a orange oil
1
1
1.19 g (ca. 100%) in accordance with H NMR data. H
NMR (300 MHz, CDCl3), d¼0.24 (s, 9H, SiMe3), 5.90
(s, 1H, 4-H), 7.18 (t, J¼7.5 Hz, 1H, ArH), 7.33 (t, J¼7.5 Hz,
3H, ArH), 7.42–7.50 (m, 2H, ArH), 7.63 (d, J¼7.5 Hz,
2H, ArH), 7.82–7.85 (m, 2H, ArH), 8.51 (s, 1H, 1-H)
ppm.
4.4.5. 1-(4-Nitrophenyl)-4-phenyl-3-trimethylsilyloxy-2-
aza-1,3-butadiene 4e. Reaction mixture: lithium
1,1,1,3,3,3-hexamethyldisilazanate
(3.08 mL,
2.22 g,
4.4.1. 1-Phenyl-3-trimethylsilyloxy-2-aza-1,3-pentadiene
4a. Reaction mixture: lithium 1,1,1,3,3,3-hexamethyl-
disilazanate (3.94 mL, 2.84 g, 16.97 mmol, 4.5 equiv.) in
dry ether (20 mL), benzaldehyde (0.39 mL, 0.4 g,
3.77 mmol, 1 equiv.) dissolved in dry ether (1 mL),
trimethylsilyl chloride (2.10 mL, 0.53 g, 16.97 mmol,
4.5 equiv.), triethylamine (0.57 mL, 0.42 g, 4.15 mmol,
1.1 equiv.), phenylacetyl chloride (0.33 mL, 0.35 g,
3.77 mmol, 1 equiv.) in dry ether (4 mL). Yield of a yellow
solid 0.73 g (ca. 60%), contaminated with the starting
aldehyde, in accordance with 1H NMR data. 1H NMR
(300 MHz, CDCl3), d¼0.28 (s, 9H, SiMe3), 1.77 (d,
J¼7.2 Hz, 3H), 5.25 (q, J¼7.2 Hz, 1H), 7.25–7.35 (m,
ArH, 1H), 7.38–7.50 (m, 2H, ArH), 7.78–7.82 (m, 2H,
ArH), 8.35 (s, 1H, 1-H) ppm.
13.24 mmol, 5 equiv.) in dry ether (13 mL), 4-nitrobenzal-
dehyde (0.40 g, 2.65 mmol, 1 equiv.), trimethylsilyl
chloride (0.39 mL, 0.35 g, 3.18 mmol, 1.2 equiv.), tri-
ethylamine (0.40 mL, 0.29 g, 2.91 mmol, 1.1 equiv.),
phenylacetyl chloride (0.46 mL, 0.53 g, 3.44 mmol,
1.3 equiv.) in dry ether (3 mL). Yield of a red solid 0.90 g
(ca. 99%) in accordance with 1H NMR data. 1H NMR
(300 MHz, CDCl3), d¼0.29 (s, 9H, SiMe3), 6.17 (s, 1H,
4-H), 7.35 (t, J¼7.5 Hz, 2H, ArH), 7.63 (d, J¼7.5 Hz, 2H,
ArH), 8.01 (d, J¼8.7 Hz, 2H, ArH), 8.31 (d, J¼8.7 Hz, 2H,
ArH), 8.52 (s, 1H, 1-H) ppm.
4.4.6. 1-(4-Fluorophenyl)-4-phenyl-3-trimethylsilyloxy-
2-aza-1,3-butadiene 4f. Reaction mixture: lithium
1,1,1,3,3,3-hexamethyldisilazanate
(3.75 mL,
2.7 g,
16.12 mmol, 5 equiv.) in dry ether (16 mL), 4-fluoro-
benzaldehyde (0.35 mL, 0.40 g, 3.22 mmol, 1 equiv.)
dissolved in dry ether (3 mL), trimethylsilyl chloride
(0.6 mL, 0.53 g, 4.84 mmol, 1.5 eq), triethylamine
(0.49 mL, 0.36 g, 3.55 mmol, 1.1 equiv.), phenylacetyl
4.4.2. 1-(4-Nitrophenyl)-3-trimethylsilyloxy-2-aza-1,3-
pentadiene 4b. Reaction mixture: lithium 1,1,1,3,3,3-
hexamethyldisilazanate (3.08 mL, 2.22 g, 13.24 mmol,
5 equiv.) in dry ether (13 mL), 4-nitrobenzaldehyde
(0.40 g, 2.65 mmol, 1 equiv.), trimethylsilyl chloride
(0.39 mL, 0.35 g, 3.18 mmol, 1.2 equiv.), triethylamine
†
Only some peaks have been observed in the crude oil.

6548
M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
chloride (0.55mL, 0.65 g, 4.19 mmol, 1.3 equiv.) in dry
ether (4 mL). Yield of a yellow solid 1.10 g (ca. 100%), in
accordance with 1H NMR data. 1H NMR (300 MHz,
CDCl3), d¼0.25 (s, 9H, SiMe3), 5.92 (s, 1H, 4-H), 7.17
(m, 3H, ArH), 7.35 (t, J¼7.8 Hz, 2H, ArH), 7.65 (d,
isomer is coincident with the spectrum of the major isomer
except for a peak at d¼1.98 (d, J¼7.2 Hz, 3H) ppm.
4.5. General procedure for the cycloaddition products 7
and 8
0
0
0
J¼7.8 Hz, 2H, ArH), 7.87 (dd, J2 ,3 ¼8.7 Hz, JF,3 ¼5.4 Hz,
2H), 8.48 (s, 1H, 1-H) ppm. 13C NMR (75.5 MHz, CDCl3),
To a solution of the 2-azadiene dissolved in dry ether,
methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate
was added in one portion. The reaction mixture was stirred
at room temperature under N2 for 3 to 7 days, after which
the reaction was complete according to TLC (DCM). In
some cases a white solid precipitated out of the reaction
mixture and was characterized as the cycloadduct 7 or the
cycloadduct 8 or a mixture of 7 and 8. In other cases no
precipitate was formed. The solvent was removed, the
residual oil dissolved in DCM and SiO2 was added. The
mixture was stirred for several days at room temperature,
SiO2 was filtered off, the solvent was removed leaving an oil
that was subject to dry flash chromatography (SiO2, diethyl
ether/petroleum ether 40–60 8C, polarity gradient) to give
the respective cycloadducts 7 and 8, as a white solids.
0
d¼0.7 (SiMe3), 105.3 (4-C), 115.9 (d, JF,3 ¼21.8 Hz, Ar),
0
126.0 (Ar), 128.1 (Ar), 128.5 (Ar), 130.8 (d, JF,2 ¼8.3 Hz,
0
Ar), 132.2 (d, JF,1 ¼3.2 Hz, Ar), 136.3 (Ar), 153.3 (3-C),
0
154.2 (1-C), 164.6 (d, JF,4 ¼252.2 Hz, Ar) ppm.
4.4.7. 1-(4-Methoxyphenyl)-4-phenyl-3-trimethyl-
silyloxy-2-aza-1,3-butadiene 4g. Reaction mixture: lithium
1,1,1,3,3,3-hexamethyldisilazanate
(2.73 mL,
1.97 g,
11.75 mmol, 4 equiv.) in dry ether (15 mL), 4-methoxy-
benzaldehyde (0.36 mL, 0.4 g, 2.94 mmol, 1 equiv.) dis-
solved in dry ether (4 mL), trimethylsilyl chloride (1.45 mL,
1.28 g, 11.75 mmol, 4 eq), triethylamine (0.45 mL, 0.33 g,
3.23 mmol, 1.1 equiv.), phenylacetyl chloride (0.56 mL,
0.68 g, 4.41 mmol, 1.5 equiv.) in dry ether (4 mL). Yield of
an orange oil 0.94 g (71%) contaminated with 28% of the
1
1
starting aldehyde in accordance with H NMR data. H
NMR (300 MHz, CDCl3), d¼0.24 (s, 9H, SiMe3), 3.88 (s,
3H), 5.78 (s, 1H, 4-H), 6.99 (d, J¼9.0 Hz, 2H, ArH), 7.16 (t,
J¼7.5 Hz, 1H), 7.26–8.38 (m, 2H, ArH), 7.62 (d, J¼7.5 Hz,
2H), 7.81 (d, J¼9 Hz, 2H), 8.44 (s, 1H, 1-H) ppm.
4.5.1. Methyl 7-(2,6-dichlorophenyl)-2a-ethoxy-2b-
methyl-4-oxo-1,3-diazabicyclo(4.1.0( heptane-6b-car-
boxylate 7a. 4-Ethoxy-2-(tert-butyldimethylsilyloxy)-3-
aza-1,3-pentadiene 1a (0.67 g, 2.76 mmol, 1 equiv.), methyl
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 6 (0.61 g,
2.48 mmol, 0.9 equiv.), dry diethyl ether (5 mL), 7 days.
Yield 0.50 g (53%). White solid, mixture of two
isomers (1:1): methyl 7-(2,6-dichlorophenyl)-2b-ethoxy-
2a-methyl-4-oxo-1,3-diaza-bicyclo(4.1.0(heptane-6b-car-
boxylate 7a and methyl 7-(2,6-dichlorophenyl)-2a-ethoxy-
2b-methyl-4-oxo-1,3-diazabicyclo(4.1.0(heptane-6b-car-
boxylate 8a. Treatment of the solid with DCM (20 mL),
SiO2 (1 g), 5 days, formed exclusively methyl 7-(2,6-
dichlorophenyl)-2b-ethoxy-2a-methyl-4-oxo-1,3-diaza-
bicyclo(4.1.0(heptan-6b-carboxylate 7a 0.50 g (53%).
White solid, mp 173.5–176.0 8C. 1H NMR (300 MHz,
CDCl3), d¼1.18 (t, J¼6.9 Hz, 3H), 1.85 (s, 2H), 3.16 (d,
J¼18.3 Hz, 1H), 3.32 (s, 1H, 7-H), 3.40 (d, J¼18.3 Hz,
1-H), 3.46 (s, 3H, OMe), 3.65 (dq, J¼9.0, 7.2 Hz, 1H), 3.84
(dq, J¼9.0, 7.2 Hz, 1H), 6.42 (br s, 1H, N H, disappears
after D2O exchange), 7.14 (m, 1H), 7.28 (dd, J¼6.9, 0.9 Hz,
2H) ppm.13C NMR (75.7 MHz, CDCl3), d¼15.3 (Me), 23.5
(Me), 30.3 (CH2), 44.2 (CH), 52.4 (OMe)‡, 58.7 (OCH2),
97.2 (2-C), 128.4 (Ar), 128.7 (Ar), 130.1 (Ar), 135.3 (Ar),
168.9 (CO), 169.8 (CO). IR (nujol), n¼1725, 1750, 3101,
3206 cm21. C16H18Cl2N2O4 (373.2): calcd C 51.45, H 4.82,
N 7.51; found C 51.12, H 4.87, N 7.59.
4.4.8. 1-(3-Furyl)-4-phenyl-3-trimethylsilyloxy-2-aza-
1,3-butadiene 4h. Reaction mixture: hexamethyldisilazane
(0.98 mL, 0.75 g, 4.63 mmol, 1 equiv.), in dry THF (8 mL),
n-butyllithium (1.6 M in hexanes, 2.6 mL, 4.16 mmol,
0.9 equiv.) in dry tetrahydrofuran (8 mL), 3-furaldehyde
(0.35 mL, 0.4 g, 4.16 mmol, 0.9 equiv.) dissolved in dry
tetrahydrofuran (1 mL), trimethylsilyl chloride (0.51 mL,
0.45 g, 4.16 mmol, 1.9 equiv.), triethylamine (0.66 mL,
0.46 g, 4.68 mmol, 1.1 equiv.), phenylacetyl chloride
(0.71 mL, 0.84 g, 5.41 mmol, 1.3 equiv.) in dry ether
(6 mL). Yield of a yellow solid 1.36 g (ca. 100%) in
1
accordance with H NMR data.
1H NMR (300 MHz, CDCl3), d¼0.20 (s, 9H, SiMe3), 5.83
(s, 1H, 4-H), 6.89 (br s, 1H, furyl), 7.16 (t, J¼7.5 Hz, 1H),
7.31 (t, J¼7.5 Hz, 2H), 7.48 (s, 1H, furyl), 7.59 (d,
J¼7.2 Hz, 1H), 7.85 (s, 1H, furyl), 8.44 (s, 1H, 1-H)
ppm.
4.4.9. 1-(4-Fluorophenyl)-3-trimethylsilyloxy-2-aza-1,3-
pentadiene 4i. Reaction mixture: lithium 1,1,1,3,3,3-
hexamethyldisilazanate (3.75 mL, 2.70 g, 16.12 mmol,
5 equiv.) in dry ether (16 mL), 4-fluorobenzaldehyde
(0.35 mL, 0.40 g, 3.22 mmol, 1 equiv.) dissolved in dry
ether (3 mL), trimethylsilyl chloride (0.48 mL, 0.42 g,
3.87 mmol, 1.2 equiv.), triethylamine (0.49 mL, 0.36 g,
3.55 mmol, 1.1 equiv.), propionyl chloride (0.36 mL,
0.39 g, 4.19 mmol, 1.3 equiv.) in dry ether (4 mL). Yield
of a yellow solid 0.75 g (93%) in accordance with 1H NMR
data. The solid is a mixture of isomers in a ratio 10:1
according to 1H NMR data. Major isomer, 1H NMR
(300 MHz, CDCl3), d¼0.27 (s, 9H, SiMe3), 1.76 (d,
J¼7.2 Hz, 3H), 5.23 (q, J¼7.2 Hz, 1H, 4-H), 7.10 (t,
4.5.2. Methyl 7-(2,6-dichlorophenyl)-2b-ethoxy-2a-
methyl-4-oxo-1,3-diaza-bicyclo(4.1.0( heptane-6b-car-
boxylate 8a. 4-Ethoxy-2-(tert-butyldimethylsilyloxy)-3-
aza-1,3-pentadiene 1a (0.63 g, 2.59 mmol, 1 equiv.), methyl
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 6 (0.57 g,
2.33 mmol, 0.9 equiv.), dry diethyl ether (15 mL). Yield
1
0.22 g (25%). White solid, mp 176.0–177.5 8C. H NMR,
(300 MHz, CDCl3), d¼1.24 (t, J¼7.2 Hz, 3H), 1.78 (s, 3H),
3.08 (d, J¼18.3 Hz, 1H, 1-H), 3.34 (d, J¼18.3 Hz, 1H,
1-H), 3.49 (s, 3H, OMe), 3.58 (s, 1H, 7-H), 3.82 (dq, J¼7.2,
9.0 Hz, 1H), 3.96 (dq, J¼9.0, 7.2 Hz, 1H), 5.84 (br s, 1H, N
0
0
1
0
J¼9.0 Hz, 2H, ArH), 7.78 (dd, J2 ,3 ¼9.0 Hz, JF,3 ¼5.7 Hz,
‡
2H,), 8.27 (s, 1H, 1-H) ppm. The H NMR of the minor
6-C May coincide with OMe at d 52.4 ppm.

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
6549
H, disappears after D2O exchange), 7.14 (m, 1H), 7.28 (dd,
J¼9.0, 6.9 Hz, 2H) ppm. 13C NMR (75.7 MHz, CDCl3),
d¼15.4 (Me), 23.9 (Me), 30.5 (CH2), 44.3 (CH), 52.5
(OMe)§, 58.9 (OCH2), 97.2 (2-C), 128.9 (Ar), 129.5 (Ar),
130.1 (Ar), 135.4 (Ar), 168.7 (CO), 168.9 (CO). IR (nujol),
n¼1737, 3182, 3269, 3301 cm21. C16H18Cl2N2O4 (373.2):
calcd C 51.44, H 4.82, N 7.51; found C 51.27, H 4.66, N
7.33.
fractions: (i) mixture of a major and a minor isomers 2 (7c):
1 (8c), 0.72 g (33%), further separated by recrystallization
DCM/petroleum ether giving a major isomer 0.45 g (21%)
and a minor isomer 0.24 g (11%); (ii) 7c, major isomer
0.55 g (25%). Total yield of isomer 4c 1.0 g (46%), white
1
solid, mp 181.2–183.2 8C. H NMR (300 MHz; CDCl3),
d¼1.13 (t, J¼7.2 Hz, 3H), 1.91 (s, 3H), 3.40 (s, 3H), 3.75
(dq, J¼9.0, 7.2 Hz, 1H), 3.94 (dq, J¼9.0, 7.2 Hz, 1H), 4.13
(s, 1H, H-7), 4.40 (s, 1H, H-5), 6.03 (br s, 1H, N H,
disappears after D2O exchange), 7.06–7.13 (m, 1H), 7.23–
7.28 (m, 2H), 7.28–7.37 (m, 3H), 7.41–7.46 (m, 2H) ppm.
13C NMR (75.7 MHz, CDCl3), d¼15.3 (Me), 27.5 (Me),
40.7 (CH), 46.9 (CH), 49.7 (6-C), 52.4 (OMe), 59.2 (OCH2),
96.0 (2-C), 127.9 (Ar), 128.2 (Ar), 128.5 (Ar), 129.4 (Ar),
129.5 (Ar), 130.3 (Ar), 133.3 (Ar), 135.7 (Ar), 167.4 (CO),
4.5.3. Methyl 7-(2,6-dichlorophenyl)-2a-ethoxy-2b,5a-
dimethyl-4-oxo-1,3-diazabicyclo(4.1.0( heptane-6b-car-
boxylate 7b. Method A. 2-Ethoxy-4-(tert-butyldimethyl-
silyloxy)-3-aza-2,4-hexadiene 1b (0.65 g, 2.52 mmol,
1 equiv.), methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-car-
boxylate 6 (0.55 g, 2.23 mmol, 0.9 equiv.), dry diethyl ether
(15 mL), 5 days. Yield 0.44 g (51%). White solid, mp
140.5–146.5 8C.{ 1H NMR (300 MHz, CDCl3), d¼1.18 (t,
J¼7.2 Hz, 3H), 1.56 (d, J¼7.2 Hz, 3H), 1.77 (s, 3H), 3.19
(q, J¼7.2 Hz, 1H, 5-H), 3.56 (s, 3H, OMe), 3.59 (s, 1H,
7-H), 3.76 (dq, J¼8.4, 7.2 Hz, 1H), 3.91 (dq, J¼7.2, 8.4 Hz,
1H), 5.88 (br s, 1H, N H, disappears after D2O exchange),
7.12 (m, 1H), 7.30 (d, J¼6.9 Hz, 2H) ppm.13C NMR
(75.7 MHz, CDCl3), d¼13.0 (Me), 15.1 (Me), 27.9 (Me),
34.4 (CH), 41.1 (CH), 47.6 (6-C), 52.5 (OMe), 59.2 (OCH2),
95.8 (2-C), 128.4 (Ar), 129.0 (Ar), 129.9 (Ar), 135.4 (Ar),
169.0 (CO), 169.6 (CO) ppm. IR (nujol), n¼1667, 1723,
3164 cm21. C17H20Cl2N2O4 (387.3): calcd C 52.73, H 5.21,
N 7.23; found C 52.59, H 5.19, N 7.26.
168.7 (CO) ppm. IR (nujol), n¼1750, 3062, 3167 cm21
.
C22H22Cl2N2O4 (449.3): calcd C 58.76, H 4.89, N 6.23;
found C 58.84, H 4.96, N 6.24. Minor isomer 8c 0.24 g
(11%), white solid, mp 134.5–137.5 8C. 1H NMR,
(400 MHz, CDCl3), d¼1.29 (t, J¼7.2 Hz, 3H), 1.80 (s,
3H), 3.39 (s, 3H), 3.73 (dq, J¼9.0, 7.2 Hz, 1H), 3.82 (s, 1H,
7-H), 4.03 (dq, J¼7.2, 9.0 Hz, 1H), 4.75 (s, 1H, 5-H), 6.29
(br s, N H, disappears after D2O exchange, 1H), 7.07–7.11
(m, 1H), 7.29–7.32 (m, 3H), 7.46 (d, J¼6.9 Hz, 2H) ppm.
13C NMR (75.7 MHz, CDCl3), d¼15.3 (Me), 23.8 (Me),
42.9 (CH), 46.8 (CH), 49.3 (6-C), 52.0 (OMe), 59.1 (OCH2),
97.7 (2-C), 127.7 (Ar), 127.8 (Ar), 128.6 (Ar), 129.0 (Ar),
130.1 (Ar), 131.2 (Ar), 133.9 (Ar), 135.5 (Ar), 168.4 (CO),
169.5 (CO) ppm. IR (nujol), n¼1742, 1757, 3094,
3203 cm21. C22H22Cl2N2O4 (449.3): calcd C 58.76, H
4.89, N 6.23; found C 58.69, H 5.22, N 6.14.
Method B. To a solution of the 2-ethoxy-4-(tert-butyl-
dimethylsilyloxy)-3-aza-2,4-hexadiene 1b (0.68 g,
2.64 mmol, 1 equiv.) dissolved in dry ether (15 mL) methyl
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 6 (0.58 g,
2.37 mmol, 0.9 equiv.) was added in one portion. The
reaction mixture was stirred at room temperature under N2
for 5 days, until complete according to TLC (DCM). The
reaction mixture was evaporated and the residual oil was
dissolved in DCM (10 mL). Tetrabutylammonium fluoride
(1.37 mL, 4.74 mmol, 1.8 equiv.) was added. The mixture
was stirred for 45 min at room temperature and then washed
with water (2£15 mL). The organic layer was dried over
MgSO4 and the solvent removed giving an oil that was kept
in the freezer for 48 h. A white solid was formed and
washed with diethyl ether (0.38 g, 42%), that proved to be
the title compound as shown by a comparison (NMR, TLC)
with the specimen obtained previously.
4.5.5. Methyl 7-(2,6-dichlorophenyl)-2b,5a-diphenyl-
2a-methoxy-4-oxo-1,3-diazabicyclo (4.1.0(heptane-6b-
carboxylate 7d and methyl 7-(2,6-dichlorophenyl)-
2a,5b-diphenyl-2b-methoxy-4-oxo-1,3-diazabicyclo-
(4.1.0(heptane-6b-carboxylate 8d. 1-Methoxy-1,4-di-
phenyl-3-(tert-butyldimethylsilyloxy)-2-aza-1,3-butadiene
1d (1.75 g, 4.76 mmol, 1 equiv.), methyl 2-(2,6-dichloro-
phenyl)-2H-azirine-3-carboxylate 6 (1.04 g, 4.28 mmol,
0.9 equiv.), dry diethyl ether (15 mL), 6 days. Total yield
0.81 g (38%). White solid, mixture of the two isomers 3
(7d): 1 (8d). The major isomer 7d, white solid, mp
1
175.5–177.5 8C. H NMR (300 MHz, CDCl3), d¼3.22 (s,
3H, OMe), 3.35 (s, 3H, OMe), 3.80 (s, 1H, 7-H), 4.41 (s, 1H,
5-H), 6.59 (br s, 1H, N H, disappears after D2O exchange),
7.10–7.18 (m, 1H), 7.24–7.38 (m, 7H), 7.48–7.56 (m, 3H),
7.88–7.93 (m, 2H) ppm. 13C NMR (75.7 MHz, CDCl3),
d¼39.7 (CH), 47.9 (CH), 50.1 (6-C), 52.0 (OMe), 52.2
(OMe), 98.2 (2-C), 127.6 (Ar), 128.0 (Ar), 128.2 (Ar), 128.5
(Ar), 128.6 (Ar), 129.57 (Ar), 129.6 (Ar), 130.4 (Ar), 132.6
135.8 (Ar), 138.8 (Ar), 167.0 (CO), 168.0 (CO) ppm. IR
(nujol), n¼1673, 1735, 3064, 3187, 3278 cm21. HR MS
(EI): calcd for C26H22Cl2N2O4 496.0956 [Mþ]; found
496.0960. The minor isomer 8d, white solid, mp 189.1–
190.1 8C. 1H NMR (300 MHz, CDCl3), d¼3.13 (s, 3H,
OMe), 3.15 (s, 3H, OMe), 3.66 (s, 1H, 7-H), 5.09 (s, 1H,
5-H), 6.37 (br s, NH, disappears after D2O exchange, 1H),
7.03 (m, 1H), 7.13 (m, 2H), 7.24–7.38 (m, 3H), 7.44–7.51
(m, 3H), 7.68–7.74 (m, 2H), 7.78–7.84 (m, 2H) ppm. 13C
NMR (75.7 MHz, CDCl3), d¼43.6 (CH), 47.2 (CH), 50.7
(Me), 51.2 (6-C), 52.0 (OMe), 99.2 (2-C), 127.3 (Ar), 127.4
(Ar), 128.3 (Ar), 128.5 (Ar), 128.8 (Ar), 128.91(Ar), 128.94
4.5.4. Methyl 7-(2,6-dichlorophenyl)-2a-ethoxy-5a-
phenyl-2b-methyl-4-oxo-1,3-diazabicyclo(4.1.0(heptane-
6b-carboxylate 7c and methyl 7-(2,6-dichlorophenyl)-
2b-ethoxy-5a-phenyl-2a-methyl-4-oxo-1,3-diaza-
bicyclo(4.1.0(heptane-6b-carboxylate 8c. 4-Ethoxy-1-
phenyl-2-(tert-butyldimethylsilyloxy)-3-aza-1,3-pentadiene
1c, (1.94 g, 6.05 mmol, 1 equiv.), methyl 2-(2,6-dichloro-
phenyl)-2H-azirine-3-carboxylate 6 (1.18 g, 4.84 mmol,
0.8 equiv.), dry diethyl ether (15 mL), 6 days. Oil was
formed which is a mixture of two diastereomers 1 (7c): 1
(8c) ratio. Flash chromatography (SiO2, diethyl ether/
petroleum ether 40–60 8C, polarity gradient) gave two
§
{ 6-C May coincide with OMe at d 52.5 ppm.
Traces of a second isomer evidence for which are signals at d 1.80 ppm
(s, 3H) and 6.04 (br s, 1H, N H).

6550
M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
(Ar), 130.0 (Ar), 135.5 (Ar), 135.8 (Ar), 136.8 (Ar), 167.0
(CO), 169.2 (CO) ppm. IR (nujol), n¼1674, 1750, 3069,
3177 cm21. HR MS (EI): m/z (%)¼(43) [Mþ2CH3O]:
calcd for C25H19Cl2N2O4 465.0772 [Mþ]; found 465.0767.
and 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate
6
(0.35 g, 1.41 mmol, 0.9 equiv.); reaction was complete in
6 days. Yield 0.13 g (28%) after flash chromatography
(SiO2, diethyl ether/petroleum ether, gradient polarity).
White solid, mp 166.6–169.7 8C. 1H NMR (300 MHz,
CDCl3), d¼1.70 (d, J¼7.2 Hz, 3H), 3.40 (q, J¼6.9 Hz, 1H,
5-H), 3.51 (s, 3H, OMe), 3.74 (s, 1H, 7-H), 5.86 (s, 1H,
2-H), 5.96 (br s, 1H, NH), 7.02–7.20 (m, 3H, ArH), 7.38–
7.52 (m, 5H, ArH) ppm. 13C NMR (75.5 MHz, CDCl3), 13.0
(Me), 35.8 (CH), 37.4 (CH), 48.3 (6-C), 52.4 (OMe), 70.1
(CH), 127.4 (Ar), 128.3 (Ar), 128.5 (Ar), 128.8 (Ar), 129.6
(Ar), 130.4 (Ar), 135.2 (Ar), 136.7 (Ar), 169.1 (CO), 171.5
4.5.6. Methyl 7-(2,6-dichlorophenyl)-2b-phenyl-5a-
methyl-2a-methoxy-4-oxo-1,3-diazabicyclo(4.1.0(hep-
tane-6b-carboxylate 7e and methyl 7-(2,6-dichloro-
phenyl)-2a-phenyl-5a-methyl-2b-methoxy-4-oxo-1,3-
diazabicyclo(4.1.0(heptane-6b-carboxylate 10. 1-Meth-
oxy-1-phenyl-3-(tert-butyldimethylsilyloxy)-2-aza-1,3-
pentadiene 4 (1e): 1 (2e) ratio (0.59 g, 1.93 mmol, 1 equiv.),
methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 6
(0.42 g, 1.74 mmol, 0.9 equiv.), dry diethyl ether (15 mL), 7
days. Total yield 0.39 g (51%) as a mixture of the two
diastereomers 1.2 (7e): 1 (10). Flash chromatography gave
the major product 7e 0.23 g (30%), and a mixture of 7e and
10 (21%) also as a solid. Compound 7e is a white solid, mp
(CO). IR (nujol), n¼1724, 1738, 3083, 3216 cm21
.
C20H18Cl2N2O3 (405.3): calcd C 59.26, H 4.49, N 6.91;
found C 59.12, H 4.64, N 6.93.
4.6.2. Methyl 7-(2,6-dichlorophenyl)-2a-[4-(nitrophe-
nyl)]-5a-methyl-4-oxo-1,3-diazabicyclo[4.1.0]heptane-
6b-carboxylate 11b. 1-(4-Nitrophenyl)-3-trimethylsilyl-
oxy-2-aza-1,3-pentadiene 4b (0.17 g, 0.61 mmol, 1 equiv.)
in ether (10 mL) and 2-(2,6-dichlorophenyl)-2H-azirine-3-
carboxylate 6 (0.14 g, 0.55 mmol, 0.9 equiv.). The reaction
was complete in 1 day. Yield 0.39 g (71%), white solid mp
1
212.0–214.0 8C. H NMR (300 MHz, CDCl3), d¼1.48 (d,
J¼6.9 Hz, 3H), 2.59 (q, J¼6.9 Hz, 1H, 5-H), 3.22 (s, 3H,
OMe), 3.56 (s, 3H, OMe), 3.77 (s, 1H, 7-H), 6.62 (br s, 1H,
N H, disappears after D2O exchange), 7.18 (t, J¼7.8 Hz,
1H), 7.32 (d, J¼7.8 Hz, 2H), 7.38–7.44 (m, 3H), 7.72–7.75
(m, 2H) ppm. 13C NMR (75.7 MHz, CDCl3), d¼12.5 (Me),
35.5 (CH), 40.7 (CH), 47.8 (6-C), 52.3 (OMe), 52.8 (OMe),
98.1 (2-C), 127.3 (Ar), 128.4 (Ar), 128.6 (Ar), 129.0 (Ar),
129.6 (Ar), 130.2 (Ar), 135.5 (Ar), 139.1 (Ar), 168.8 (CO),
169.5 (CO) ppm. IR (nujol), n¼1673, 1731, 1746, 3067,
3176, 3276 cm21. C21H20Cl2N2O4 (435.3): calcd C 57.89,
H 4.59, N 6.43; found C 57.70, H 4.70, N 6.50. The sample
containing the mixture of two isomers was subjected again
to flash chromatography (SiO2, diethyl ether/petroleum
ether, polarity gradient) giving a small amount of the minor
1
168.6–171.1 8C. H NMR (300 MHz, CDCl3), d¼1.58 (d,
J¼6.9 Hz, 3H), 3.42 (q, J¼6.9 Hz, 1H, 5-H), 3.53 (s, 3H,
OMe), 3.76 (s, 1H, 7-H), 5.98 (s, 2H, 2-HþN H), 7.09 (dd,
J¼6.9, 9 Hz, 1H, ArH), 7.17 (d, J¼6.9 Hz, 2H, ArH), 7.70
(d, J¼9 Hz, 2H, ArH), 8.31 (d, J¼9 Hz, 2H, ArH,) ppm. 13C
NMR (75.5 MHz, CDCl3), d¼13.0 (Me), 35.9 (CH), 37.4
(CH), 48.4 (6-C), 52.6 (OMe), 69.3 (CH), 124.0 (Ar), 128.7
(Ar), 128.8 (Ar), 129.8 (Ar), 135.0 (Ar), 143.1 (Ar), 148.5
(Ar), 168.7 (CO), 171.8 (CO) ppm. IR (nujol), n¼1674,
1749, 3223 cm21. C20H17Cl2N3O5 (450.3): calcd C 53.34,
H 3.80, N 9.33; found C 53.36, H 4.13, N 9.19.
1
isomer 10 as a white solid, mp 187.0–188.4 8C. H NMR
(300 MHz, CDCl3), d¼1.65 (d, J¼7.2 Hz, 3H), 3.32 (s, 3H,
OMe), 3.36 (s, 3H, OMe), 3.48 (s, 1H, 7-H), 3.82 (q,
J¼7.2 Hz, 1H, 5-H), 6.37 (br s, 1H, N H, disappears after
D2O exchange), 7.00–7.06 (m, 1H), 7.13 (d, J¼7.5 Hz, 2H),
7.42–7.50 (m, 3H), 7.60–7.68 (m, 2H) ppm. 13C NMR
(75.7 MHz, CDCl3), d¼16.1 (Me), 36.1 (CH), 44.1 (CH),
51.0 (OMe), 51.3 (6-C), 52.0 (OMe), 99.0 (2-C), 127.0 (Ar),
128.5 (Ar), 128.7 (Ar), 128.8 (Ar), 129.9 (Ar), 135.6 (Ar),
136.6 (Ar), 167.5 (CO), 172.7 (CO) ppm. IR (nujol),
n¼1680, 1751, 3063, 3179 cm21. C21H20Cl2N2O4 (435.3):
calcd C 57.89, H 4.59, N 6.43; found C 57.63, H 4.55, N
6.51.
4.6.3. Methyl 7-(2,6-dichlorophenyl)-2a-4-fluorophenyl-
4-oxo-1,3-diazabicyclo[4.1.0]heptane-6b-carboxylate
11c.
1-(4-Fluorophenyl)-3-trimethylsilyloxy-2-aza-1,3-
butadiene 4c (0.50 g, 2.09 mmol, 1 equiv.) in ether
(15 mL) and 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxyl-
ate 6 (0.41 g, 1.67 mmol, 0.8 equiv.). The reaction was
complete in 6 days. Yield 0.11 g (16%), white solid after
washings with ether, mp 189.6–191.2 8C. 1H NMR
(300 MHz, CDCl3), d¼3.16 (d, J¼18.3 Hz, 1H, 5-H), 3.48
(s, 3H, OMe), 3.57 (d, J¼18.3 Hz, 1H, 5-H), 3.75 (s, 1H,
7-H), 5.87 (br s, 1H, N H), 5.89 (s, 1H, 2-H), 7.04–7.19 (m,
5H, ArH), 7.48–7.54 (m, 2H, ArH) ppm. 13C NMR
(75.5 MHz, CDCl3), d¼30.8 (CH2), 39.4 (CH), 45.1 (6-C),
4.6. General procedure for the cycloaddition products 11
0
52.7 (OMe), 70.3 (CH), 115.9 (d, JF,3 ¼22.0 Hz, Ar), 128.4
0
To the crude 2-azadiene in ether was added the methyl
6
(Ar), 128.8 (Ar), 129.5 (d, JF,2 ¼8.4 Hz, Ar), 129.7 (Ar),
0
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate
132.5 (d, JF,1 ¼3.2 Hz, Ar), 135.4 (Ar), 163.4 (d,
0
(0.9 equiv.) at room temperature. The progress of the
reaction was followed by TLC until disappearance of the
starting azirine. In most cases products precipitated pure
(11b, 11c, 11d, 11e, 11f, 11g) and were washed with cold
ether. In cases 11a, 11h and 11i, the reaction mixture gave
an oil or a mixture of an oil and a solid that were combined
and subjected to dry flash chromatography.
JF,4 ¼249.3 Hz, Ar), 168.8 (CO), 168.9 (CO) ppm. IR
(nujol), n¼1686, 1748, 3098, 3257 cm21. C19H15Cl2F N2O3
(409.3): calcd C 55.76, H 3.70, N 6.85; found C 55.73, H
4.12, N 6.77.
4.6.4. Methyl 7-(2,6-dichlorophenyl)-2a,5a-diphenyl-4-
oxo-1,3-diazabicyclo[4.1.0]heptane-6b-carboxylate 11d.
1,4-Diphenyl-3-trimethylsilyloxy-2-aza-1,3-butadiene 4d
(0.62 g, 2.11 mmol, 1 equiv.) in ether (15 mL) and 2-(2,6-
4.6.1. Methyl 7-(2,6-dichlorophenyl)-2a-phenyl-5a-
methyl-4-oxo-1,3-diazabicyclo[4.1.0]heptane-6b-car-
boxylate 11a. 1-Phenyl-3-trimethylsilyloxy-2-aza-1,3-pen-
tadiene 4a (0.37 g, 1.57 mmol, 1 equiv.) in ether (10 mL)
dichlorophenyl)-2H-azirine-3-carboxylate
1.69 mmol, 0.8 equiv.). The reaction was complete in 4
6
(0.41 g,
days. Yield 0.59 g (75%), white solid, mp 210.2–213.6 8C.

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
6551
1H NMR (300 MHz, CDCl3), d¼3.38 (s, 3H, OMe), 4.24 (s,
1H, 7-H), 4.63 (s, 1H, 5-H), 6.04 (s, 1H, 2-H), 6.06 (br s, 1H,
N H), 7.05 (dd, J¼6.9, 9 Hz, 1H, ArH), 7.15 (d, J¼6.9 Hz,
2H, ArH), 7.32–7.38 (m, 3H, ArH) 7.42–7.44 (m, 3H,
ArH), 7.46–7.60 (m, 4H, ArH) ppm. 13C NMR (75.5 MHz,
CDCl3), d¼37.4 (CH), 48.2 (CH), 49.2 (6-C), 52.3 (OMe),
70.2 (CH), 127.0 (Ar), 127.90 (Ar), 127.94 (Ar), 128.5 (Ar),
128.9 (Ar), 129.0 (Ar), 129.6 (Ar), 129.8 (Ar), 131.1 (Ar),
133.1 (Ar), 135.7 (Ar), 136.6 (Ar), 168.4 (CO), 169.4 (CO)
OMe), 4.22 (s, 1H, 7-H), 4.61 (s, 1H, 5-H), 5.99 (s, 1H,
2-H), 6.02 (br s, 1H, N H), 6.94 (d, J¼8.7 Hz, 2H, ArH),
7.04 (dd, J¼9, 6.9 Hz, 1H, ArH), 7.14 (d, J¼6.9 Hz, 2H,
ArH), 7.30–7.37 (m, 3H, ArH), 7.43 (d, J¼8.7 Hz, 2H,
ArH), 8.30 (dd, J¼8.1, 6.3 Hz, 2H, ArH,) ppm. 13C NMR
(75.5 MHz, CDCl3), d¼37.4 (CH), 48.1 (CH), 49.2 (6-C),
52.3 (OMe), 55.3 (OMe), 69.8 (CH), 114.2 (Ar), 127.85
(Ar), 127.88 (Ar), 128.3 (Ar), 128.5 (Ar), 128.86 (Ar),
128.88 (Ar), 129.9 (Ar), 131.1 (Ar), 133.2 (Ar), 135.7 (Ar),
160.3 (Ar), 168.5 (CO), 169.5 (CO). IR (nujol), n¼1675,
1727, 3168 cm21. C26H22Cl2N2O4 (497.4): calcd C 62.78,
H 4.47, N 5.63; found C 62.54, H 4.77, N 5.47.
ppm. IR (nujol), n¼1680, 1735, 3147, 3235 cm21
.
C25H20Cl2N2O3 (467.4): calcd C 64.24, H 4.74, N 5.99;
found C 64.22, H 4.62, N 6.07.
4.6.5. Methyl 7-(2,6-dichlorophenyl)-2a-4-(nitrophenyl)-
5a-phenyl-4-oxo-1,3-diazabicyclo[4.1.0]heptane-6b-car-
boxylate 11e. 1-(4-Nitrophenyl)-4-phenyl-3-trimethylsilyl-
oxy-2-aza-1,3-butadiene 4e (0.20 g, 0.59 mmol, 1 equiv.) in
ether (10 mL) and 2-(2,6-dichlorophenyl)-2H-azirine-3-
carboxylate 6 (0.13 g, 0.53 mmol, 0.9 equiv.). The reaction
was complete in 2 days. Yield 0.17 g (61%). White solid,
4.6.8. Methyl 7-(2,6-dichlorophenyl)-2a-3-furyl-5a-phe-
nyl-4-oxo-1,3-diazabicyclo[4.1.0]heptane-6b-carboxyl-
ate 11h. 1-(3-Furyl)-4-phenyl-3-trimethylsilyloxy-2-aza-
1,3-butadiene 4h (0.65 g, 2.27 mmol, 1 equiv.) in ether
(15 mL) and 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxyl-
ate 6 (0.44 g, 0.82 mmol, 0.8 equiv.). The reaction was
complete in 7 days. Yield 0.23 g (28%) after flash
chromatography (SiO2, diethyl ether/petroleum ether,
polarity gradient). White solid, mp 173.5–173.9 8C. 1H
NMR (300 MHz, CDCl3), d¼3.36 (s, 3H, OMe), 4.16 (s,
1H, 7-H), 4.50 (s, 1H, 5-H), 6.01 (br s, 1H, N H), 6.52 (s, 1H,
2-H), 7.06 (dd, J¼6.9, 9.0 Hz, 1H, ArH), 7.21 (d, J¼6.9 Hz,
2H, ArH), 7.31–7.39 (m, 4H, ArH) 7.43–7.44 (m, 1H,
ArH), 7.47–7.50 (m, 2H, ArH), 7.63 (s, 1H, ArH) ppm. 13C
NMR (75.5 MHz, CDCl3), d¼37.6 (CH), 48.8 (CH), 49.9
(6-C), 52.7 (OMe), 64.5 (CH), 109.3 (furyl), 123.0 (Ar),
128.5 (Ar), 129.0 (Ar), 129.6 (Ar), 130.0 (Ar), 131.2 (Ar),
133.3 (Ar), 136.2 (Ar), 141.1 (Ar), 144.3 (furyl), 168.7
(CO), 169.8 (CO) ppm. IR (nujol), n¼1736, 1753,
3213 cm21. C23H18Cl2N2O4 (457.3): calcd C 60.40, H
3.98, N 6.13; found C 60.42, H 4.22, N 6.06.
1
mp 195.1–196.8 8C. H NMR (300 MHz, CDCl3), d¼3.86
(s, 3H, OMe), 4.26 (s, 1H, 7-H), 4.63 (s, 1H, 5-H), 6.15 (s,
1H, 2-H), 6.25 (br s, 1H, N H), 7.04–7.10 (m, 1H, ArH),
7.14–7.20 (m, 2H, ArH), 7.32–7.42 (m, 3H, ArH) 7.50–
7.58 (m, 2H, ArH), 7.74 (d, J¼9 Hz, 2H, ArH), 8.30 (d,
J¼9 Hz, 2H, ArH) ppm. 13C NMR (75.5 MHz, CDCl3),
d¼37.8 (CH), 48.8 (CH), 49.6 (6-C), 52.8 (OMe), 69.9
(CH), 124.5 (Ar), 128.0 (Ar), 128.4 (Ar), 128.7 (Ar), 129.2
(Ar), 129.4 (Ar), 129.6 (Ar), 131.3 (Ar), 133.1 (Ar), 136.0
(Ar), 143.4 (Ar),148.8 (Ar), 168.5 (CO), 170.5 (CO) ppm.
IR (nujol), n¼1681, 1748, 3092, 3194 cm21
.
C25H19Cl2N3O5 (512.4): calcd C 58.60, H 3.75, N 8.20;
found C 58.61, H 4.01, N 8.24.
4.6.6. Methyl 7-(2,6-dichlorophenyl)-2a-4-fluorophenyl-
5a-phenyl-4-oxo-1,3-diazabicyclo[4.1.0]heptane-6b-car-
boxylate 11f. 1-(4-Fluorophenyl)-4-phenyl-3-trimethyl-
silyloxy-2-aza-1,3-butadiene 4f (0.59 g, 1.97 mmol,
1 equiv.) in ether (15 mL) and 2-(2,6-dichlorophenyl)-2H-
azirine-3-carboxylate 6 (0.43 g, 1.78 mmol, 0.9 equiv.). The
reaction was complete in 2 days. Yield 0.60 g (70%). White
4.6.9. Methyl 7-(2,6-dichlorophenyl)-2a-4-(fluoro-
phenyl)-5a-methyl-4-oxo-1,3-diazabicyclo[4.1.0]hep-
tane-6b-carboxylate
trimethylsilyloxy-2-aza-1,3-pentadiene
11i.
1-(4-Fluorophenyl)-3-
4i (0.29 g,
1.16 mmol, 1 equiv.) in ether (10 mL) and 2-(2,6-dichloro-
phenyl)-2H-azirine-3-carboxylate 6 (0.26 g, 1.05 mmol,
0.9 equiv.). The reaction was complete in 1 day. Yield
0.15 g (96%), brownish oil (very impure). After dry flash
chromatography (diethyl ether/petroleum ether, polarity
gradient) gave a white solid (33%), mp 213.4–215.0 8C. 1H
NMR (300 MHz, CDCl3), d¼1.70 (d, J¼6.9 Hz, 3H), 3.39
(q, J¼6.9 Hz, 1H, 5-H), 3.51 (s, 3H), 3.72 (s, 1H, 7-H), 5.86
(s, 2H, 2-HþN H), 7.04–7.19 (m, 5H, ArH), 7.44–7.50 (m,
2H, ArH) ppm. 13C NMR (75.5 MHz, CDCl3), d¼13.5
(Me), 36.3 (CH), 37.9 (CH), 48.8 (6-C), 52.9 (OMe), 69.9
1
solid, mp 152.4–153.3 8C. H NMR (300 MHz, CDCl3),
d¼3.38 (s, 3H, OMe), 4.22 (s, 1H, 7-H), 4.61 (s, 1H, 5-H),
6.03 (s, 1H, 2-H), 6.09 (br s, 1H, NH), 7.02–7.19 (m, 5H,
ArH), 7.32–7.40 (m, 3H, ArH), 7.44–7.48 (m, 4H, ArH)
ppm. 13C NMR (75.5 MHz, CDCl3), d¼37.8 (CH), 48.6
0
(CH), 49.6 (6-C), 52.7 (OMe), 116.3 (d, JF,3 ¼22.0 Hz),
128.28 (Ar), 128.30 (Ar), 129.0 (Ar), 129.4 (Ar), 129.5 (d,
0
0
JF,2 ¼6.8 Hz), 130.2 (Ar), 131.5 (Ar), 132.0 (d, JF,1
¼
0
3.0 Hz), 133.5 (Ar), 136.1 (Ar), 163.5 (d, JF,4 ¼249.0 Hz),
168.8 (CO), 170.3 (CO). IR (nujol), n¼1688, 1743,
3187 cm21. C25H19FCl2N2O3 (485.4): calcd C 61.86, H
3.95, N 5.77; found C 61.53, H 4.67, N 5.54.
0
(CH), 116.3 (d, JF,3 ¼22.0 Hz), 128.9 (Ar), 129.1 (Ar),
0
0
129.8 (d, JF,2 ¼8.3 Hz), 130.7 (Ar), 133.2 (d, JF,1 ¼3.0 Hz),
0
135.7 (Ar), 163.7 (d, JF,4 ¼249.0 Hz), 169.4 (CO), 171.9
(CO) ppm. IR (nujol), n¼1674, 1751, 3088, 3193 cm21
.
4.6.7. Methyl 7-(2,6-dichlorophenyl)-2a-4-(methoxy-
phenyl)-5a-phenyl-4-oxo-1,3-diazabicyclo[4.1.0]hep-
tane-6b-carboxylate 11g. 1-(4-Methoxyphenyl)-4-phenyl-
C20H17Cl2FN2O3 (423.3): calcd C 56.74, H 4.06, N 6.62;
found C 56.60, H 4.16, N 6.63.
3-trimethylsilyloxy-2-aza-1,3-butadiene
4g
(0.68 g,
4.7. General procedure for the hydrolysis products 12,
13 and 15
2.07 mmol, 1 equiv.) in ether (10 mL) and 2-(2,6-dichloro-
phenyl)-2H-azirine-3-carboxylate 6 (0.40 g, 1.66 mmol,
0.8 equiv.). The reaction was complete in 2.5 days. Yield
0.49 g (60%). White solid, mp 208.1–210.3 8C. H NMR
(300 MHz, CDCl3), d¼3.37 (s, 3H, OMe), 3.84 (s, 3H,
To a solution of the pyrimidone or of the mixture of
diastereomeric pyrimidones in THF was added dropwise
HCl diluted in THF, in an ice/water bath. After the addition
1

6552
M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
was complete the mixture was stirred at room temperature
for 1 h. THF was partially removed to a 1/3 of the original
volume and aq. NaHCO3 (20 mL) was added. The mixture
was vigorously stirred for 15 min. The organic phase was
separated and the aq. phase was washed with DCM
(3£25 mL). The organic phases were combined, washed
with water (25 mL), and dried over MgSO4. The solvent was
removed giving a pale yellow oil that crystallized in the
fridge. The solid was recrystallized from DCM/petroleum
ether 40–60 8C giving the product as a white solid. In one
case (e) the hydrolysis compounds 12 and 13 were shown to
be a mixture of two isomers that were separated by flash
chromatography (SiO2, diethyl ether/petroleum ether,
gradient polarity).
(d, J¼9.9 Hz, 1H, 3-H), 2.43 (s, 3H, Me), 3.08 (br d,
J¼9.9 Hz, 1H, N H aziridine, disappears after D2O
exchange), 3.56 (s, 3H, OMe), 5.02 (s, 1H, 1-H), 7.12 (t,
J¼7.5 Hz, 1H), 7.28 (d, J¼7.5 Hz, 2H), 7.36–7.45 (m, 5H),
7.88 (br s, 1H, N H) ppm. 13C NMR (75.7 MHz, CDCl3),
d¼25.3(Me), 41.5 (CH), 45.5 (2-C), 53.0 (CH), 53.3 (OMe),
127.7 (Ar) 128.9 (Ar), 129.0 (Ar), 129.9 (Ar), 130.5 (Ar),
131.1 (Ar), 131.7 (Ar), 135.5 (Ar), 170.7 (CO), 171.0 (CO),
171.9 (CO) ppm. IR (nujol), n¼1735, 3168, 3242 cm21
.
C20H18Cl2N2O4. 1/2H2O (430.3): calcd C 55.82, H 4.23, N
6.51; found C 55.87, H 4.43, N 6.47.
4.7.4. Methyl 2-((2-benzoylamino)-2-oxoethyl(-1-phenyl-
3-(2,6-dichlorophenyl)aziridine-2-carboxylate
12d.
Methyl 7-(2,6-dichlorophenyl)-2b,5a-diphenyl-2a-meth-
oxy-4-oxo-1,3-diazabicyclo(4.1.0(heptane-6b-carboxylate
7d (0.22 g, 0.44 mmol), THF (10 mL) and conc. HCl
(37 mL) in THF (5 mL). Yield 0.15 g (68%). White solid,
4.7.1. Methyl 2-((2-acetylamino)-2-oxoethyl(-3-(2,6-
dichlorophenyl)aziridine-2-carboxylate 12a. Methyl
7-(2,6-dichlorophenyl)-2b-ethoxy-2a-methyl-4-oxo-1,3-
diaza-bicyclo(4.1.0( heptan-6b-carboxylate 8a (0.21 g,
0.56 mmol), THF (10 mL) and conc. HCl (46 mL) in THF
(5 mL). Yield 0.14 g (74%). White solid, mp 164.3–
165.1 8C. 1H NMR (300 MHz, CDCl3), d¼2.35 (s, 3H,
Me), 2.67 (d, J¼17.1 Hz, 1H), 2.87 (br d, J¼8.4 Hz, 1H, N
H aziridine, disappears after D2O exchange), 3.21 (d,
J¼8.4 Hz, 1H, 3-H), 3.57 (s, 3H, OMe), 3.83 (d, J¼17.1 Hz,
1H), 7.18 (t, J¼7.5 Hz, 1H), 7.27 (d, J¼7.5 Hz, 2H), 8.82
(br s, 1H, N H) ppm. 13C NMR, (75.7 MHz, CDCl3) d¼25.0
(Me), 41.0 (CH2), 42.6 (2-C), 45.5 (CH), 53.0 (OMe), 127.8
(Ar) 128.9 (Ar), 129.5 (Ar), 130.9 (Ar), 135.7 (Ar), 170.5
(CO), 171.0 (CO), 171.3 (CO) ppm. IR (nujol), n¼1725,
1745, 3205, 3255 cm21. C14H14Cl2N2O4 (345.0): calcd C
48.71, H 4.06, N 8.12; found C 48.26, H 4.16, N 8.07. HR
MS (EI): m/z (%)¼(0.1) [M þ]: calcd for C14H14O4N2Cl2
344.0331; found 344.0325.
1
mp 180.2–181.2 8C. H NMR (300 MHz, CDCl3), d¼2.51
(d, J¼9.9 Hz, 1H, 3-H), 3.02 (br d, J¼9.9 Hz, 1H, N H
aziridine, disappears after D2O exchange), 3.55 (s, 3H,
OMe), 5.93 (s, 1H, 1-H), 7.09–7.15 (m, 1H), 7.22–7.62 (m,
10H), 7.75 (d, J¼7.2 Hz, 2H), 8.66 (br s, 1H, N H) ppm. 13C
NMR (75.7 MHz, CDCl3), d¼40.8 (CH), 46.0 (2-C), 52.5
(CH), 53.0 (OMe), 127.7 (Ar) 128.3 (Ar), 128.9 (Ar), 129.0
(Ar), 131.1 (Ar), 131.5 (Ar), 131.7 (Ar), 131.8 (Ar), 132.6
(Ar), 133.2 (Ar), 135.7 (Ar), 164.6 (CO), 171.1 (CO), 173.6
(CO) ppm. IR (nujol), n¼1714, 1731, 3168, 3263 cm21. HR
MS (FAB): calcd 483.0878 [Mþ1]; found 483.0876.
4.7.5. Methyl 2-((2-benzoylamino)-2-oxoethyl(-1-methyl-
3-(2,6-dichlorophenyl)aziridine-2-carboxylate 12e and
13. Methyl 7-(2,6-dichlorophenyl)-2b-phenyl-5a-methyl-
2a-methoxy-4-oxo-1,3-diazabicyclo(4.1.0(heptane-6b-car-
boxylate 7e and methyl 7-(2,6-dichlorophenyl)-2a-phenyl-
5a-methyl-2b-methoxy-4-oxo-1,3-diazabicyclo(4.1.0(hep-
tane-6b-carboxylate 10, mixture 1.2 (7e): 1 (10), (0.37 g,
0.85 mmol), THF (10 mL), conc. HCl (71 mL) in THF
(5 mL). Total yield 0.27 g (75%): two isomers 1.2 (12e): 1
(13). The isomers were partially isolated after flash
chromatography (SiO2, diethyl ether/petroleum ether 40–
60 8C, polarity gradient). Compound 12e (0.1 g, 29%),
white solid, mp 189.3–190.0 8C. 1H NMR, (300 MHz,
CDCl3), d¼1.41 (d, J¼7.2 Hz, 3H), 2.38 (d, J¼9.3 Hz, 1H),
3.39 (d, J¼9.3 Hz, 1H, 3-H), 3.58 (s, 3H, OMe), 4.44 (q,
J¼7.2 Hz, 1H, 1-H), 7.18 (t, J¼8.1 Hz, 1H), 7.30 (br d,
J¼7.5 Hz, 2H), 7.54 (m, 2H), 7.63 (m, 1H), 7.92 (dd, J¼8.4,
1.2 Hz, 2H), 9.25 (br s, 1H, N H) ppm. 13C NMR
(75.7 MHz, CDCl3), d¼12.8 (Me), 41.0 (CH), 46.1 (2-C),
51.1 (OMe), 127.7 (Ar) 128.9 (Ar), 129.3 (Ar), 131.3 (Ar),
132.8 (Ar), 133.2 (Ar), 135.6 (Ar), 165.1 (CO), 171.0 (CO),
175.3 (CO) ppm. IR (nujol), n¼1712, 1735, 3071,
3279 cm21. C20H18Cl2N2O4. 1/2H2O (421.3): calcd C
55.82, H 4.23, N 6.51; found C 55.99, H 4.31, N 6.54.
4.7.2. Methyl 2-((2-acetylamino)-2-oxoethyl(-1-methyl-3-
(2,6-dichlorophenyl)aziridine-2-carboxylate 12b. Methyl
7-(2,6-dichlorophenyl)-2a-ethoxy-2b,5a-dimethyl-4-oxo-
1,3-diazabicyclo(4.1.0(heptane-6b-carboxylate 7b (0.60 g,
2.46 mmol), THF (15 mL) and conc. HCl (200 mL) in THF
(10 mL). Yield 0.37 g (42%). White solid, mp 116.3–
117.4 8C. 1H NMR (300 MHz, CDCl3), d¼1.30 (d,
J¼7.2 Hz, 3H), 2.43 (s, 3H, Me), 2.85 (br d, J¼9.0 Hz,
1H, N H aziridine, disappears after D2O exchange), 3.37 (d,
J¼9.0 Hz, 1H, 3-H), 3.56 (s, 3H, OMe), 3.75 (q, J¼7.2 Hz,
1H), 7.18 (t, J¼8.4 Hz, 1H), 7.28 (d, J¼8.4 Hz, 2H), 8.71
(br s, 1H, N H) ppm. 13C NMR (75.7 MHz, CDCl3), d¼12.9
(Me), 25.5 (Me), 41.2 (CH), 41.8 (CH), 45.8 (2-C), 53.2
(OMe), 127.9 (Ar) 129.1 (Ar), 129.4 (Ar), 130.9 (Ar), 135.5
(Ar), 170.4 (CO), 172.1 (CO), 173.1 (CO) ppm. IR (nujol),
n¼1724, 1741, 3067, 3157, 3211 cm21. C15H16O4N2Cl2
(359.2): calcd C 50.15, H 4.45, N 7.80; found C 50.24, H
4.68, N 7.80.
4.7.3. Methyl 2-((2-acetylamino)-2-oxoethyl(-1-phenyl-3-
(2,6-dichlorophenyl)aziridine-2-carboxylate 12c. Methyl
7-(2,6-dichlorophenyl)-2a-ethoxy-5a-phenyl-2b-methyl-4-
oxo-1,3-diazabicyclo(4.1.0(heptane-6b-carboxylate 7c and
methyl 7-(2,6-dichlorophenyl)-2b-ethoxy-5a-phenyl-2a-
methyl-4-oxo-1,3-diazabicyclo(4.1.0(heptane-6b-carboxyl-
ate 8c (0.21 g, 0.46 mmol), THF (10 mL) and conc. HCl
(38 mL) in THF (5 mL). Yield 0.17 g (87%). White solid,
1
Compound 13, white solid, mp 139.5–139.9 8C. H NMR
(300 MHz, CDCl3), d¼1.58 (d, J¼7.5 Hz, 3H), 2.97 (d,
J¼9.0 Hz, 1H, NH aziridine), 3.38 (d, J¼9 Hz, 1H, 3-H),
3.42 (q, J¼7.5 Hz, 1H, 1-H), 3.64 (s, 3H, OMe), 7.20 (t,
J¼7.8 Hz, 1H), 7.31 (d, J¼7.8 Hz, 1H), 7.40–7.55 (m, 2H),
7.55–7.70 (m, 1H), 7.98 (dd, J¼6.9, 1.5 Hz, 2H), 10.4 (br s,
1H, N H) ppm. 13C NMR (75.7 MHz, CDCl3), d¼14.6
(Me), 44.4 (CH), 44.7 (CH), 46.6 (2-C), 53.3 (OMe), 127.0
1
mp 191.1–191.6 8C. H NMR (300 MHz, CDCl3), d¼2.40

M. J. Alves et al. / Tetrahedron 60 (2004) 6541–6553
2. Knittel, D. Synthesis 1985, 44, 186–188.
6553
(Ar) 127.8 (Ar), 128.5 (Ar), 128.9 (Ar), 129.9 (Ar), 130.4
(Ar), 133.0 (Ar), 135.5 (Ar), 164.9 (CO), 169.9 (CO), 170.8
(CO) ppm. IR (nujol), n¼1725, 1735, 3070, 3295 cm21. HR
MS (FAB): calcd 421.0722 [Mþ1]; found 421.0703.
3. (a) Bhullar, P.; Gilchrist, T. L.; Maddocks, P. Synthesis 1997,
271–272. (b) Alves, M. J.; Gilchrist, T. L. J. Chem. Soc.,
Perkin 1 1998, 299–303. (c) Alves, M. J.; Gilchrist, T. L.
´
Tetrahedron Lett. 1998, 39, 7579–7582. (d) Alvares, Y. S. P.;
Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Gilchrist, T. L.
J. Chem. Soc., Perkin 1 2002, 1911–1919.
4.7.6. Methyl 2-[carbamoyl(phenyl)methyl]-3-(2,6-
dichlorophenyl)aziridine-2-carboxylate 15. Methyl-7-
(2,6-dichlorophenyl)-2a,5a-diphenyl-4-oxo-1,3-diaza-
bicyclo[4.1.0]heptane-6b-carboxylate 11d (0.32 g,
0.68 mmol, 1 equiv.), THF (15 mL), containing conc. HCl
(2.44 mL). Yellow solid 0.17 g (67%), mp 167.5–167.7 8C.
1H NMR (300 MHz, CDCl3), d¼2.42 (d, J¼8.7 Hz, 1H,
3-H), 3.04 (d, J¼8.7 Hz, 1H, NH aziridine), 3.58 (s, 3H,
OMe), 4.88 (s, 1H, 10 H), 5.77 (s, 2H, NH2), 7.10 (t,
J¼7.2 Hz, 1H), 7.22 (d, J¼7.5 Hz, 2H), 7.33–7.40 (m, 3H),
7.48 (d, J¼7.8 Hz, 2H) ppm. 13C NMR (75.7 MHz, CDCl3),
d¼42.0 (CH), 46.1 (2-C), 51.9 (CH), 53.0 (OMe), 127.6
(Ar) 128.3 (Ar), 128.7 (Ar), 129.0 (Ar), 130.2 (Ar), 131.2
(Ar), 133.7 (Ar), 135.5 (Ar), 171.0 (CO), 173.7 (CO). IR
(nujol), n¼1685, 1740, 3171, 3290 cm21. C18H16Cl2N2O3
(379.3): calcd C 57.00, H 4.26, N 7.39; found C 56.99, H
4.48, N 7.20.
4. Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Gil Fortes, A.;
Gilchrist, T. L.; Mendonc¸a, R. J. Chem. Soc., Perkin 1 2001,
1976–2969.
5. Ghosez, L.; Bayard, Ph.; Nshimyumukiza, P.; Gouverneur, V.;
Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain,
A.-M.; Wynants, C. Tetrahedron 1995, 51, 11021–11042.
6. (a) Ntirampebura, D.; Ghosez, L. Tetrahedron Lett. 1999, 40,
7079–7082. (b) Bongini, A.; Panunzio, M.; Bandini, E.;
Campana, E.; Martelli, G.; Spunta, G. Tetrahedron:
Asymmetry 2001, 12, 439–454.
7. Gouverneur, V.; McCarthy, S. J.; Mineur, C.; Belotti, D.;
Dive, G.; Ghosez, L. Tetrahedron 1998, 54, 10537–10554.
8. Gouverneur, V.; Ghosez, L. Tetrahedron 1996, 52,
7585–7598.
9. Gouverneur, V.; Ghosez, L. Tetrahedron Lett. 1991, 32,
5349–5352.
10. Bayard, Ph.; Ghosez, L. Tetrahedron Lett. 1988, 29,
6115–6118.
Acknowledgements
11. Bouammali, B.; Pautet, F.; Fillion, H.; Soufiaoui, M.
Tetrahedron 1993, 49, 3125–3130.
We thank Dr Thomas Gilchrist for reading the manuscript
ˆ
and Fundac¸a˜o Ciencia e Tecnologia for project funding
(POCTI/32723/QUI/2000).
12. Ghosez, L.; Jnoff, E.; Bayard, Ph.; Sainte, F.; Beaudegnies, R.
Tetrahedron 1999, 55, 3387–3400.
13. Bayard, Ph.; Sainte, F.; Beaudegnies, R.; Ghosez, L.
Tetrahedron Lett. 1988, 29, 3799–3802.
14. Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121,
2617–2618.
References and notes
1. Alves, M. J.; Dura˜es, M. M.; Gil Fortes, A. Tetrahedron Lett.
2003, 44, 5079–5082.
15. Steglich, W.; Jeschke, R.; Buschmann, E. Gazz., Chim. Ital.
1986, 116, 361–372.