Reactivity of allenoates towards aziridines: Synthesis of functionalized methylenepyrrolidines and pyrroles

Article abstract of DOI:10.1016/j.tet.2010.09.081

The reactivity of buta-2,3-dienoates towards aziridines is reported. Typically, allenoates react as the 2π-component in the [3+2] cycloaddition with azomethine ylides generated from aziridines, affording 4- methylenepyrrolidines in a site-, regio- and stereoselective fashion. However, N-cyclohexyl- or N-tert-butyl-2-benzoyl-3-phenylaziridines showed a different reactivity in the reaction with buta-2,3-dienoates. Pyrrole derivatives were obtained as single or major products resulting from a formal [3+2] cycloaddition via C-N bond cleavage of the three-membered ring heterocycle leading to functionalized pyrroles. From the reaction with allenoates bearing bulkier C-4 substituents 4-methylenepyrrolidines were also formed as minor products.

Full text of DOI:10.1016/j.tet.2010.09.081

Tetrahedron 66 (2010) 8815e8822
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactivity of allenoates towards aziridines: synthesis of functionalized
methylenepyrrolidines and pyrroles
a
a
b
b
ꢀ
Fernanda M. Ribeiro Laia , Ana Lucia Cardoso , Ana Matos Beja , Manuela Ramos Silva ,
Teresa M.V.D. Pinho e Melo a
,
*
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2010
Received in revised form 20 September 2010
Accepted 22 September 2010
Available online 29 September 2010
The reactivity of buta-2,3-dienoates towards aziridines is reported. Typically, allenoates react as the
2
p
-component in the [3þ2] cycloaddition with azomethine ylides generated from aziridines, affording
4-methylenepyrrolidines in a site-, regio- and stereoselective fashion. However, N-cyclohexyl- or N-tert-
butyl-2-benzoyl-3-phenylaziridines showed a different reactivity in the reaction with buta-2,3-dien-
oates. Pyrrole derivatives were obtained as single or major products resulting from a formal [3þ2]
cycloaddition via CeN bond cleavage of the three-membered ring heterocycle leading to functionalized
pyrroles. From the reaction with allenoates bearing bulkier C-4 substituents 4-methylenepyrrolidines
were also formed as minor products.
Keywords:
Aziridines
Allenes
Pyrroles
Ó 2010 Elsevier Ltd. All rights reserved.
Methylenepyrrolidines
[3þ2] cycloaddition
Formal [3þ2] cycloaddition
Microwave assisted synthesis
1. Introduction
nitrones, carbonyl ylides, nitrile imines, azides and diazomethanes
but the 1,3-dipolar cycloaddition with azomethine ylides is an al-
Nitrogen-containing five-membered heterocycles are among
the most common structures in biologically active compounds
making them important target molecules. In fact, pyrroles repre-
sent an important class of heterocycles due to their broad distri-
bution in nature as constituents of the framework of a range of
natural products and also of synthetic bioactive molecules.1 Poly-
pyrroles also find applications in materials science, nonlinear
optics and supramolecular chemistry as molecular sensors and
devices.2 Pyrrolidine derivatives are also present in many bioactive
compounds. The development of synthetic routes to methyl-
enepyrrolidine derivatives are of particular interest since the
presence of an unsaturated bond allows further elaboration.3
We have recently described preliminary results on the study of
the reactivity of buta-2,3-dienoates towards aziridines.4 Our aim
was to explore the cycloaddition of azomethine ylides generated
from aziridines via conrotatory electrocyclic ring opening with
buta-2,3-dienoates. Allenes can participate in cycloadditions as
dipolarophiles with a variety of 1,3-dipoles namely nitrile oxides,
most unexplored research topic.5e9 Nevertheless, the enantiose-
lective synthesis of 3-methylenepyrrolidine via catalytic 1,3-dipolar
cycloaddition of allenoates and azomethine ylides generated in situ
from aldehydes and amino esters has been reported.10
Our preliminary results showed that the substitution pattern of
the aziridine determines the chemical behaviour of allenoates to-
wards these three-membered heterocycles.4 Allenoates can react as
the 2
p
-component in the [3þ2] cycloaddition with the azomethine
ylide generated from aziridines affording 4-methylenepyrrolidines
but they can also react via formal [3þ2] cycloadditions leading to
functionalized pyrroles. In this paper, we describe full details of the
study on the reactivity of aziridines in the presence of allenoates.
2. Results and discussion
The reaction of cis-1-benzyl-2-benzoyl-3-phenylaziridine (1)
with allenoates was explored (Scheme 1). Aziridine 1 was prepared
following a known synthetic procedure11a and its X-ray structure
determined in order to unambiguously establish the cis stereo-
chemistry (Fig. 1). Thermolysis of aziridine 1 in the presence of
benzyl buta-2,3-dienoate12 (3a) in refluxing toluene for 24 h did not
lead to the target cycloadduct. However, 4-methylenepyrrolidine 4a
* Corresponding author. Tel.: þ351 239854475; e-mail address: tmelo@ci.uc.pt
(T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.081

8816
F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
The geometry of the carbonecarbon double bond of compound
Bn
N
•
Bn
N
4b was assigned based on the NOESY spectrum. In fact, in this
spectrum methyl protons (H-7) show connectivity with H-3 but no
connectivity was observed with H-5. On the other hand, H-2 shows
connectivity with H-3 and H-5 shows connectivity with H-6. The
structure of methylenepyrrolidine 4d was determined by X-ray
crystallography allowing the complete stereochemistry assignment
(Fig. 2). In the 1H NMR spectrum of compound 4d the coupling
between H-2 and H-3, which are in a cis configuration, is charac-
terized by a coupling constant of 8.0 Hz.
3a
CO2Bn
Ph
BnO2C
COPh
Δ
Ph
H
Toluene, Δ or MW
COPh
2
4a
Bn
N
Reaction conditions 4a Yield
Ph
COPh
MW, 150 ºC, 15 min
1
Reflux, 1.5 h
31.5%
----
Toluene
Reflux, 24 h
R
MW, 120 ºC, 15 min
MW, 150 ºC, 10 min
MW, 150 ºC, 15 min
MW, 150 ºC, 20 min
MW, 160 ºC, 5 min
MW, 160 ºC, 15 min
19%
59%
73%
60%
58%
67%
•
CO2Bn
3b R = Me
3c R = t-Bu
3d R = Ph
Bn
1
2
N
Ph
COPh
5
3
4
6
BnO2C
4b R = Me 59%
R
4c R = t-Bu 46%
4d R = Ph 43%
7
Scheme 1. Synthesis of 4-methylenepyrrolidine 4aed via [3þ2] cycloaddition of
azomethine ylide 2 and allenoates 3aed.
Fig. 2. X-ray structure of 4-methylenepyrrolidine 4d.
A different outcome was observed from the reaction of aziridine
1 with benzyl 5-phenylpenta-2,3-dienoate (3e)12 (Scheme 2). The
expected 4-methylenepyrrolidine 4e was obtained in 30% yield
together with the formation of pyrrole 5a in 23% yield resulting
from a formal [3þ2] cycloaddition (see below).
Fig. 1. X-ray structure of 2-benzoyl-1-benzyl-3-phenylaziridine (1). Selected bond
ꢀ
ꢁ
distances (A): C2eN1 1.451, C2eC3 1.511, C3eN1 1.459. Selected bond angles ( ):
N1eC2eC3 59.0; N1eC3eC2 58.5, C2eN1eC3 62.6.
could be obtained as single stereoisomer in moderate yield (31.5%)
when a significantly shorter reaction time was used (1.5 h). These
results indicate the lack of stability of compound 4a to prolonged
heating. The stuctural assignment of compound 4a was supported
by two-dimensional COSY, NOESY, HMQC, and HMBC spectra
(400 MHz).4 We have previously reported that the microwave
methodology for the conrotatory ring opening of an aziridine,
leading to the corresponding 1,3-dipole and the subsequent cyclo-
addition is more efficient than the conventional heating.13 Thus, the
microwave-assisted 1,3-dipolar cycloaddition of azomethine ylide 2
with benzyl buta-2,3-dienoate (3a) was carried out under different
reaction conditions in order to optimize the synthetic procedure.
We observed that the 1,3-dipolar cycloadduct 4a was obtained in
73% yield in a site-, regio- and stereoselective fashion under mi-
crowave irradiation at 150 ꢀC for 15 min.
The work was extended to the microwave induced reaction of
aziridine 1 with benzyl penta-2,3-dienoate (3b), benzyl 5,5-dime-
thylhexa-2,3-dienoate (3c)12 and benzyl 4-phenylbuta-2,3-dien-
oate (3d).12 Using the optimized reaction conditions, the target
molecules 4bed were also selectively obtained (Scheme 1). Under
conventional heating (reflux, 1.5 h) the reaction of allene 3d with
1,3-dipole 2 also afforded 4-methylenepyrrolidine 4d in 43% yield.
Scheme 2. Reaction of aziridine 1 with allene 3e.
trans-2-Benzoyl-1-cyclohexyl-3-phenylaziridine
6 was also
synthesized by a known procedure14 and its reactivity towards
buta-2,3-dienoates studied (Table 1). Carrying out the reaction with
benzyl buta-2,3-dienoate (3a) in refluxing toluene, pyrrole 5b was
obtained in 55.5% yield as single product (entry 1). A significantly
lower yield was obtained when the reaction was carried out with
longer reaction time. From the reaction of aziridine 6 with allene 3b
under conventional heating pyrrole 5c was the major product (62%)
and 4-methylenepyrrolidine 4f was isolated in 19% yield (entry 2).
Similar chemical behaviour was observed when aziridine 6 was
reacted with allene 3d under microwave irradiation giving pyrrole
5d and pyrrolidine 4g in 64% yield and 10% yield, respectively
(entry 3). The reaction of N-cyclohexylaziridine 6 with allene 3e
was also carried out. Heating a solution of these compounds in
refluxing toluene pyrrole 5e (26%) and pyrrolidine 4h (23%) were
obtained, whereas the microwave induced reaction led to the iso-
lation of pyrrole 5e as the only product (entries 4 and 5). However,
no reaction was observed using 5,5-dimethylhexa-2,3-dienoate
(3c) as dipolarophile.

F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
8817
Table 1
In order to support this rationalization, cis-2-benzoyl-3-phe-
nylaziridine 9, bearing a bulky N-tert-butyl substituent, was pre-
pared11 and its reactivity studied (Scheme 3). As expected, the
reaction of aziridine 9 with allene 3a gave pyrrole 10a. The opti-
mized reaction conditions for the conventional thermolysis (80 ꢀC,
4 h) allowed the isolation of pyrrole 10a in 65% yield. Under mi-
crowave irradiation compound 10a was obtained in poor yield
(10e11%). The reaction of aziridine 9 with allene 3b also afforded
the corresponding formal [3þ2] cycloadduct 10b. No reaction
was observed between allene 3d and cis-2-benzoyl-1-tert-butyl
3-phenylaziridine 9.
Synthesis of pyrroles and pyrrolidines from the reaction of aziridine
allenoates
6 with
Cy
R
N
5b R = H
5c R = Me
5d R = Ph
5e R = Bn
Cy
N
Toluene
BnO2C
Ph
R
Cy
N
Ph
COPh
•
6
Ph
COPh
CO2Bn
3a R = H
3b R = Me
3d R = Ph
3e R = Bn
4f R = Me
4g R = Ph
4h R = Bn
BnO2C
R
Entry
Allene
Reaction conditions
Product (Yield %)
1
2
3
4
5
3a
3b
3d
3e
3e
Reflux, 1.5 h
5b (55.5%)
5c (62%)
5d (64%)
5e (26%)
5e (65%)
d
Reflux, 1.5 h
4f (19%)
4g (10%)
4h (23%)
d
MW, 150 ꢀC, 15 min
Reflux, 1.5 h
MW, 150 ꢀC, 15 min
Aiming to find out whether the stereochemistry of the starting
aziridine had a role in determining the outcome of the reaction
with allenoates the reactivity of cis-2-benzoyl-1-cyclohexyl-
3-phenylaziridine 711a was also studied (Table 2). It was observed
that aziridine 7 reacted with benzyl buta-2,3-dienoate (3a) under
conventional thermolysis affording pyrrole 5b in 54% yield (entry
1). Pyrrole 5c was isolated in high yield (86%) from the reaction of
aziridine 7 with allene 3b (entry 2). The reaction with allenoate 3d
gave the corresponding pyrrole 5d as the major product with the
simultaneous formation of pyrrolidine 8a, either under conven-
tional heating or under microwave irradiation (entries 3 and 4).
Finally, the reactivity of aziridine 7 towards benzyl 5-phenylpenta-
2,3-dienoate (3e) was explored. Under conventional heating pyr-
role 5e (43%) and pyrrolidine 8b (33%) were obtained, whereas the
microwave induced reaction gave pyrrole 5e (75%) as single prod-
uct (entry 6).
Scheme 3. Synthesis of pyrroles 10 via formal [3þ2] cycloaddition of aziridine 9 and
allenoates.
The formation of pyrroles 5 and 10 can be explained as outlined
in Scheme 4. Nucleophilic addition of the aziridine to the activated
allene double bond giving intermediate 11 followed by the
intramolecular attack of the carbanion center on the aziridine
ring, affords the five-membered heterocycles 12 via CeN bond
cleavage. Tautomerisms and the subsequent aromatization lead to
pyrrole 13 bearing a hydroxybenzyl sidechain, which is converted
into the final product and benzaldehyde via retro-aldol type
fragmentation.15
Table 2
Synthesis of pyrroles and pyrrolidines from the reaction of aziridine
allenoates
7 with
Cy
R
N
5b R = H
5c R = Me
5d R = Ph
5e R = Bn
R1
COPh
R1
R2
N
R2
N
Cy
N
Tolu
BnO2C
Ph
•
R
Cy
N
Ph
Ph
COPh
R1
Ph
COPh
BnO2C
R1
BnO2C
•
11
7
Ph
COPh
CO2Bn
3a R = H
R2
N
R2
N
R2
N
3b R = Me
3d R = Ph
3e R = Bn
8a R = Ph
8b R = Bn
R1
OH
OH
Ph
BnO2C
COPh
R
Ph
BnO2C
Ph
BnO2C
Ph
BnO2C
Ph
Entry
Allene
Reaction Conditions
Product (Yield %)
12
13
1
2
3
4
5
6
3a
3b
3d
3d
3e
3e
Reflux, 1.5 h
Reflux, 1.5 h
5b (54%)
5c (86%)
5d (41%)
5d (53%)
5e (43%)
5e (75%)
d
R2
N
H
R2
N
d
R1
O
R1
Reflux, 1.5 h
8a (35%)
8a (12%)
8b (33%)
d
MW, 150 ꢀC, 15 min
Reflux, 1.5 h
- PhCHO
Ph
retro-aldol type
fragmentation
MW, 150 ꢀC, 15 min
BnO2C
Ph
BnO2C
Ph
Scheme 4. Mechanism proposal of the formal [3þ2] cycloaddition of aziridines and
These results allowed us to conclude that the nature of the
N-substituent of the 2-benzoyl-3-phenylaziridines determines
the chemical behaviour of these three-membered heterocycles in
the presence of allenoates. The bulkier cyclohexyl N-substituent
seems to hinder the 1,3-dipolar cycloaddition favouring the formal
[3þ2] cycloaddition. However, this reaction pathway becomes less
favourable with allenoates with a bulkier C-4 substituent. Fur-
thermore, the unsuccessful attempt to promote the reaction of
N-cyclohexylaziridine 6 with 5,5-dimethylhexa-2,3-dienoate (3c)
mentioned above is in accordance with these observations.
allenoates.
The reactivity of aziridines participating in formal [3þ2] cyclo-
additions via CeN bond cleavage with activated acetylene de-
rivatives has been reported.16 Mattay and Gaebert demonstrated
that the dipolar intermediate formed from N-butyl-2-phenyl-
aziridine and diethyl acetylenedicarboxylate could be trapped by
carrying out the reaction in methanol.16a Therefore, the reaction
of aziridine 6 with allene 3a in methanol was also performed.
However, we were unable to trap intermediate 11 since at room

8818
F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
temperature no reaction was observed and the reaction in refluxing
methanol gave only pyrrole 5b in 31% yield.
compound 17b shows connectivity of H-6 with H-5 and H-7, H-7
shows connectivity with H-3, and H-2 shows connectivity with H-3,
but no connectivity was observed between H-2 and H-5 or between
H-3 and H-5. On the other hand, methylenepyrrolidines 18 are
characterized by a coupling constant between H-2 and H-3 in the
range of 7.6e8.4 Hz. A similar chemical behaviour was observed
between ethyl N-cyclohexyl-cis-3-phenylaziridine-2-carboxylate
(19) and benzyl buta-2,3-dienoate (3a). Under microwave irradiation
methylenepyrrolidine 20 was obtained in 62% yield, whereas the
conventional thermolysis afforded the same product in lower yield.
Then, the reactivity of trans-2,3-dibenzoyl-1-benzylaziridine
(14)17 in the presence of buta-2,3-dienoate 3a was studied
(Scheme 5). From the thermolysis at 80 ꢀC no product could be
isolated. However, when the reaction was carried out in refluxing
toluene for 3 h, methylenepyrrolidine 15 was obtained in 39% yield.
With a longer reaction time (5.5 h) compound 15 was obtained in
52% together with the formation of methylenepyrrolidine 16 in 4%
yield. The stereochemistry assignment was based on 1H NMR data.
In fact, the coupling constant between protons H-2 and H-3 ob-
served for compound 15 was 8.0 Hz, whereas the value for com-
pound 16 was 4.4 Hz. The microwave induced [3þ2] cycloaddition
of the azomethine ylide generated from aziridine 14 with allene 3a
was also site- and regio-selective but not stereoselective. Carrying
out the reaction at 150 ꢀC for 15 min gave methylenepyrrolidine 15
and methylenepyrrolidine 16 in 49% and 12% yield, respectively.
3. Conclusion
Site-, regio- and stereoselective synthesis of 4-methylenepyr-
rolidines was achieved via [3þ2] cycloaddition of allenoates with
azomethine ylides generated from cis-1-benzyl-2-benzoyl-3-phe-
nylaziridine, N-benzyl- and N-cyclohexyl-cis-3-phenylaziridine-2-
carboxylates.
Reaction of N-cyclohexyl- or N-tert-butyl-2-benzoyl-3-phenyl-
aziridines with buta-2,3-dienoates led to a different outcome. In
these cases pyrroles were obtained as the only or the major product
resulting from formal [3þ2] cycloadditions via aziridine CeN bond
cleavage.
Bn
N
PhOC
COPh
Bn
N
•
3a
BnO2C
15
CO2Bn
Toluene,
Δ
PhOC
COPh
Bn
N
These reactions can be carried out under microwave irradiation
or with conventional heating.
14
PhOC
COPh
Reaction conditions
Products
15
16
BnO2C
16
4. Experimental section
4.1. General
80 ºC 4 h
---
---
Reflux, 3 h
39%
52%
21%
---
Reflux, 5.5 h
4%
6%
MW, 120 ºC, 15 min
MW, 150 ºC, 15 min
49% 12%
1H NMR spectra were recorded on an instrument operating at
400 MHz. 13C spectra were recorded on an instrument operating at
100 MHz. The solvent is deuteriochloroform except where otherwise
indicated. IR spectra were recorded on a PerkineElmer 1720X FTIR
spectrometer. Mass spectra were recorded on a Bruker FTMS APEXIII
instrument under electrospray ionization (ESI) except where in-
dicated otherwise. Melting points were recorded on a Reichert hot
stage and are uncorrected. Flash column chromatography was per-
formed with Merck 9385 silica as the stationary phase.
Scheme 5. Synthesis of 4-methylenepyrrolidines 15 and 16 via [3þ2] cycloaddition.
Finally, the reactivity of N-benzyl- and N-cyclohexyl-cis-3-phe-
nylaziridine-2-carboxylates towards allenoates was explored
(Scheme 6). The microwave induced conrotatory electrocyclic ring
opening of aziridine 17 was followed by 1,3-dipolar cycloaddition of
the in situ generated azomethine ylide with allenoates 3aee in
a
site-, regio- and stereo-selective fashion affording methyl-
enepyrrolidines 18 in good yields. The NOESY spectrum of
4.2. General procedure for the synthesis of ethyl 3-
phenylaziridine-2-carboxylates
Bn
N
Bn
N
A suspension of the appropriated amine (35.7 mmol) and ethyl
2,3-dibromo-3-phenylpropanoate (3.0 g, 8.9 mmol) in ethanol
(12 mL) was stirred at room temperature (for 4.5 days, starting from
benzylamine; for 6 days starting from cyclohexylamine). The re-
action mixture was diluted with water and extracted with
dichloromethane. The organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
crude product was purified by flash column chromatography [ethyl
acetateehexane].
Toluene
2
5
Ph
CO2Et
6
MW, 150 ºC, 15 min
3
4
Ph
CO2Et
R
BnO2C
•
R
7
17
CO2Bn
3a R = H
18a R = H 73%
18b R = Me 50%
18c R = t-Bu 71%
18d R = Ph 48%
18e R = Bn 56%
3b R = Me
3c R = t-Bu
3d R = Ph
3e R = Bn
4.2.1. Ethyl 1-benzyl-3-phenylaziridine-2-carboxylate (17). Purification
by flash column chromatography [ethyl acetateehexane (1:5)] affor-
ded 17 as a white solid in 62% yield. Mp 63.5e66.0 ꢀC (from ethyl
acetateehexane). IR (KBr) 2978, 1734, 1261 and 1163 cmꢁ1; 1H NMR
(CDCl3, 400 MHz) 0.96 (3H, t, J¼7.2 Hz), 2.63 (1H, d, J¼6.8 Hz), 3.06
(1H, d, J¼6.8 Hz), 3.64 (1H, d, J¼13.6 Hz), 3.87e4.02 (3H, m), 7.19e7.43
(10H, m, AreH); 13C NMR (CDCl3, 100 MHz) 13.9, 46.0, 47.7, 60.7, 63.5,
127.3, 127.4, 127.9, 128.0, 128.4, 135.1, 137.7, 168.1; MS (ESI) m/z 282
(MHþ, 100%) and 201 (81). HRMS (ESI) m/z 282.14895 (C18H20NO2
[MHþ], 282.14886).
Cy
N
Cy
N
Toluene, Δ or MW
Ph
CO2Et
•
Ph
CO2Et
CO2Bn
BnO2C
3a
20
19
Reaction conditions
Yield
Reflux, 1.5 h
Reflux, 3 h
27%
40%
MW, 150 ºC, 15 min 62%
4.2.2. Ethyl 1-cyclohexyl-3-phenylaziridine-2-carboxylate (19).
Scheme 6. Synthesis of 4-methylenepyrrolidines 18 and 20 via [3þ2] cycloaddition.
Purification
by
flash
column
chromatography
[ethyl

F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
8819
acetateehexane (1:9)] afforded 19 as a white solid in 59% yield. Mp
34.0e36.0 ꢀC (from ethyl acetateehexane). IR (KBr) 2922, 1738,
J¼12.0 Hz), 4.81 (1H, d, J¼12.0 Hz), 5.04 (1H, s), 5.26 (1H, d, J¼7.6 Hz),
5.40 (1H, s), 7.02 (2H, br s, AreH), 7.17e7.55 (18H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 29.7, 33.7, 50.9, 53.6, 66.4, 66.6, 70.0, 127.0, 128.0,
128.1, 128.2, 128.3, 128.4, 128.6, 129.0, 132.6, 133.2, 135.4, 137.7, 138.2,
138.6, 171.8, 203.7; MS (ESI) m/z 544 (MHþ, 100%). HRMS (ESI) m/z
544.28363 (C37H38NO3 [MHþ], 544.28462).
1250 and 1173 cmꢁ1 1H NMR (CDCl3, 400 MHz) 0.93 (3H, t,
;
J¼7.2 Hz), 1.19e1.30 (3H, m), 1.49e1.61 (4H, m), 1.82e1.84 (4H, m),
2.47 (1H, d, J¼6.8 Hz), 2.93 (1H, d, J¼6.8 Hz), 3.84e3.92
(1H, m), 3.96e4.04 (1H, m), 7.19e7.29 (3H, m, AreH), 7.38e7.40
(2H, m, AreH); 13C NMR (CDCl3, 100 MHz) 13.9, 24.5, 24.5, 26.0,
31.8, 32.3, 44.6, 47.0, 60.5, 68.7, 127.3, 127.8, 127.9, 135.9, 168.7; MS
(ESI) m/z 274 (MHþ, 100%) and 201 (30). HRMS (ESI) m/z 274.18009
(C17H24NO2 [MHþ], 274.18016).
4.3.4. Benzyl 5-benzoyl-1-benzyl-4-benzylidene-2-phenylpyrrolidine-
3-carboxylate (4d). Prepared by methods A or B from aziridine 1
(100 mg, 0.32 mmol) and allene 3d (0.38 mmol). Purification by
flash column chromatography [ethyl acetateehexane (1:9)] affor-
ded 4d as a yellow solid in 43% (method A) or 39% (method B) yield.
4.3. General procedure for [3D2] cycloaddition of aziridines
with allenes
ꢀ
Mp 141.9e143.7 C (from ethyl ether). IR (KBr) 3028, 1737, 1676,
1224 and 1150 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) 3.61 (1H, d,
Method A: A suspension of the appropriated aziridine and allene
in toluene (1 mL) was irradiated in the microwave reactor
(CEMdFocused Synthesis System, Discover S-Class) for 15 min with
the temperature set to 150 ꢀC. The solvent was removed under
reduced pressure and the crude product was purified by crystalli-
zation, by flash column chromatography [ethyl acetateehexane] or
by preparative thin layer chromatography [ethyl acetateehexane
(1:10)] followed by recrystallization, as indicated for each case.
Method B: A solution of the appropriated aziridine and allene in
toluene (6 mL) was heated at reflux for 1.5 h. The solvent was re-
moved under reduced pressure and the crude product was purified
by crystallization or by flash column chromatography [ethyl aceta-
teehexane] followed by recrystallization, as indicated for each case.
J¼13.2 Hz), 3.97 (1H, d, J¼13.2 Hz), 4.12 (1H, d, J¼12.0 Hz), 4.43 (1H,
d, J¼8.0 Hz), 4.63 (1H, d, J¼12.0 Hz), 5.38 (1H, d, J¼8.0 Hz), 5.60 (1H,
s), 6.22 (1H, s), 6.92e6.93 (2H, m, AreH), 7.02e7.04 (2H, m, AreH),
7.10e7.12 (3H, m, AreH), 7.19e7.38 (13H, m, AreH), 7.48e7.49 (3H,
m, AreH), 7.56e7.57 (2H, m, AreH); 13C NMR (CDCl3,100 MHz) 51.2,
54.5, 66.5, 67.1, 70.1, 127.1, 127.2, 127.3, 128.0, 128.0, 128.1, 128.3,
128.3, 128.4, 128.4, 128.6, 129.0, 133.0, 135.4, 136.1, 137.4, 137.9,
138.4, 170.2, 202.2; MS (ESI) m/z 564 (MHþ, 100%) and 201 (74).
HRMS (ESI) m/z 564.25488 (C39H34NO3 [MHþ], 564.25332).
4.3.5. Benzyl 5-benzoyl-1-benzyl-4-phenethylidene-2-phenylpyrrolidine-
3-carboxylate (4e) and benzyl 1-cyclohexyl-2-phenethyl-4-phenyl-1H-
pyrrole-3-carboxylate (5a). Prepared by method A from aziridine 1
(100 mg, 0.32 mmol) and allene 3e (0.48 mmol). Purification by pre-
parative thin layer chromatography [ethyl acetateehexane (1:10)]
afforded 4e as a yellow solid in 30% yield and 5a as a yellow oil in 23%
yield. Benzyl 5-benzoyl-1-benzyl-4-phenethylidene-2-phenylpyrrolidine-
3-carboxylate (4e). Mp 139.9e141.1 ꢀC (from methanol). IR (KBr) 3029,
1735,1680,1235 and 1172 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 3.13 (2H, d,
J¼7.2 Hz), 3.60 (1H, d, J¼13.6 Hz), 3.94 (1H, d, J¼13.6 Hz), 4.17 (1H, d,
J¼8.4 Hz), 4.36 (1H, d, J¼12.0 Hz), 4.76 (1H, d, J¼12.0 Hz), 5.32e5.34
(2H, m), 5.47 (1H, s), 6.87e6.88 (2H, m, AreH), 7.01e7.03 (2H, m,
AreH), 7.18e7.27 (19H, m, AreH), 7.56e7.58 (2H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 35.5, 51.0, 53.7, 65.4, 65.5, 69.1, 125.9, 126.0, 126.5,
127.0, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.8, 129.3, 132.8, 135.3,
137.2, 137.6, 138.2, 138.4, 139.1, 170.9, 202.3; MS (ESI) m/z 578
(MHþ, 100%), 494 (6) and 413 (6). HRMS (ESI) m/z 578.26698
(C40H36NO3 [MHþ], 578.26897); Benzyl 1-cyclohexyl-2-phenethyl-4-
phenyl-1H-pyrrole-3-carboxylate (5a). IR (film) 3028, 1696, 1282 and
1181 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 2.74 (2H, t, J¼7.8 Hz), 3.12 (2H, t,
J¼7.8 Hz), 4.81 (2H, s), 5.18 (2H, s), 6.52 (1H, s), 6.96e6.98 (2H, m,
AreH), 7.02e7.04 (2H, m, AreH), 7.12e7.37 (16H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 28.3, 36.2, 50.4, 65.5, 110.5, 120.9, 126.1, 126.2, 126.7,
127.7, 127.9, 128.3, 128.5, 128.6, 128.7, 129.1, 129.5, 135.9, 136.3, 136.9,
140.2, 141.4, 165.2; MS (ESI) m/z 472 (MHþ, 25%), 429 (17), 301 (29) and
201 (48). HRMS (ESI) m/z 472.22769 (C33H30NO2 [MHþ], 472.22711).
4.3.1. Benzyl 5-benzoyl-1-benzyl-4-methylene-2-phenylpyrrolidine-
3-carboxylate (4a). Prepared by methods A or B from aziridine 1
(100 mg, 0.32 mmol) and allene 3a (0.48 mmol). Crystallization
from methanol afforded 4a as a yellow solid in 73% (method A) or
31.5% (method B) yield. Mp 111.0e113.0 ꢀC (from methanol). IR
(film) 3030, 1734, 1680, 1218 and 1157 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) 3.58 (1H, d, J¼13.2 Hz), 3.84 (1H, d, J¼13.2 Hz), 4.18 (1H,
d, J¼8.0 Hz), 4.41 (1H, d, J¼12.4 Hz), 4.78 (1H, d, J¼12.4 Hz), 4.99
(1H, br s), 5.15 (1H, br s), 5.17 (1H, d, J¼8.0 Hz), 5.35 (1H, s), 7.02 (2H,
br s, AreH), 7.18 (5H, br s, AreH), 7.28e7.36 (8H, m, AreH),
7.46e7.58 (5H, m, AreH); 13C NMR (CDCl3, 100 MHz) 51.5, 55.0,
66.6, 67.2, 68.8, 112.6, 127.1, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6,
129.0, 133.0, 135.4, 136.7, 138.3, 138.5, 144.3, 170.8, 201.3; LCeMS
(ESI) m/z 488 (MHþ, 57%), 470 (35), 396 (100) and 380 (73). HRMS
(ESI) m/z 488.22112 (C33H30NO3 [MHþ], 488.22202).
4.3.2. Benzyl 5-benzoyl-1-benzyl-4-ethylidene-2-phenylpyrrolidine-
3-carboxylate (4b). Prepared by method A from aziridine 1 (100 mg,
0.32 mmol) and allene 3b (0.48 mmol). Crystallization from
methanol afforded 4b as
a yellow solid in 59% yield. Mp
138.8e140.9 ꢀC (from methanol). IR (film) 3030, 1736, 1672, 1217
and 1146 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) 1.40 (3H, d, J¼6.8 Hz),
3.58 (1H, d, J¼13.2 Hz), 3.91 (1H, d, J¼13.2 Hz), 4.07 (1H, d,
J¼8.0 Hz), 4.37 (1H, d, J¼12.0 Hz), 4.79 (1H, d, J¼12.0 Hz), 5.23e5.30
(2H, m), 5.42 (1H, s), 7.01e7.03 (2H, m, AreH), 7.16e7.38 (13H, m,
AreH), 7.44e7.57 (5H, m, AreH); 13C NMR (CDCl3, 100 MHz)
15.0, 51.1, 53.6, 65.3, 66.5, 69.2, 122.3, 127.1, 127.9, 128.0, 128.2,
128.3, 128.3, 128.4, 128.5, 129.0, 132.9, 135.6, 137.3, 138.5, 171.0,
202.2; MS (ESI) m/z 502 (MHþ, 100%). HRMS (ESI) m/z 502.23665
(C34H32NO3 [MHþ], 502.23767).
4.3.6. Benzyl 1-cyclohexyl-2-methyl-4-phenyl-1H-pyrrole-3-carbox-
ylate (5b). Prepared by method B of general procedure from azir-
idine 7 and allene 3a. Purification by preparative thin layer
chromatography [ethyl acetateehexane (1:10)] afforded 5b as
a yellow oil in 54% yield. IR (film) 2932, 1696, 1411, 1272 and
1155 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 1.21e2.01 (10H, m), 2.55 (3H,
s), 3.88 (1H, t, J¼12.0 Hz), 5.14 (2H, br s), 6.61 (1H, s), 7.06 (2H, br s,
AreH), 7.22e7.32 (8H, m, AreH); 13C NMR (CDCl3, 100 MHz) 11.3,
25.4, 25.8, 34.0, 55.3, 65.2, 109.9, 116.0, 126.0, 127.5, 127.6, 127.9,
128.2, 129.3, 135.8, 136.4, 136.5, 165.8; GCeMS (EI) m/z 373 (Mþ,
72%), 283 (25), 282 (100), 200 (55) and 91 (21). HRMS (ESI) m/z
374.21127 (C25H28NO2 [MHþ], 374.21146).
4.3.3. Benzyl
5-benzoyl-1-benzyl-4-(2,2-dimethylpropylidene)-2-
phenylpyrrolidine-3-carboxylate (4c). Prepared by method A from
aziridine 1 (100 mg, 0.32 mmol) and allene 3c (0.48 mmol). Crys-
tallization from methanol afforded 4c as a yellow solid in 46% yield.
Mp 143.0e144.0 ꢀC (from methanol). IR (KBr) 3030, 1732, 1675, 1222
and 1152 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 0.81 (9H, s), 3.54 (1H, d,
J¼13.6 Hz), 3.93 (1H, d, J¼13.6 Hz), 4.20 (1H, d, J¼7.6 Hz), 4.29 (1H, d,
4.3.7. Benzyl 1-cyclohexyl-2-ethyl-4-phenyl-1H-pyrrole-3-carboxyl-
ate (5c) and benzyl 5-benzoyl-1-cyclohexyl-4-ethylidene-2-

8820
F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
phenylpyrrolidine-3-carboxylate (4f). Prepared by method B from
aziridine 6 and allene 3b. Purification by preparative thin layer chro-
matography [ethyl acetateehexane (1:10)] afforded 5c as a yellow oil
in 62% yield and 4f as a yellow oil in 19% yield. Benzyl 1-cyclohexyl-2-
ethyl-4-phenyl-1H-pyrrole-3-carboxylate (5c). IR (film) 2932, 1700,
1281 and 1154 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 1.20 (3H, t, J¼7.2 Hz),
1.38e2.00 (10H, m), 2.99 (2H, q, J¼7.2 Hz), 3.85e3.91(1H, m), 5.14 (2H,
s), 6.60(1H, s), 7.06(2H,brs,AreH), 7.20e7.36 (8H, m, AreH);13CNMR
(CDCl3, 100 MHz) 14.8, 18.5, 25.4, 25.9, 34.6, 55.0, 65.2, 116.2, 126.0,
127.5, 127.6, 128.0, 128.2, 128.3, 128.4, 128.6, 129.3, 136.4, 136.5, 141.6,
165.5; MS (ESI) m/z 388 (MHþ, 100%). HRMS (ESI) m/z 388.22696
(C26H30NO2 [MHþ], 388.22711). Benzyl 5-benzoy-1-cyclohexyl-4-eth-
ylidene-2-phenylpyrrolidine-3-carboxylate (4f). IR (film) 2930, 1735,
1669,1212 and 1148 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 0.80e1.85 (10H,
m), 2.61e2.66 (1H, m), 4.19 (1H, d, J¼8.4 Hz), 4.28 (1H, d, J¼12.0 Hz),
4.64 (1H, d, J¼12.0 Hz), 5.45e5.49 (2H, m), 5.66 (1H, s), 7.04e7.06 (2H,
m, AreH), 7.26e7.50 (11H, m, AreH), 8.09e8.11 (2H, m, AreH); 13C
NMR (CDCl3,100 MHz) 15.3, 25.4, 25.7, 25.9, 30.7, 33.1, 52.6, 56.8, 66.3,
66.9, 122.1, 127.4, 127.7, 127.9, 128.2, 128.6, 128.8, 128.9, 132.9, 135.4,
136.3, 137.0, 139.6, 170.5, 204.0; MS (ESI) m/z 494 (MHþ, 100%),
442 (12), 285 (14) and 254 (24). HRMS (ESI) m/z 494.26825
(C33H36NO3 [MHþ], 494.26897).
[MHþ], 464.25845). Benzyl 5-benzoyl-1-cyclohexyl-4-phenethyli-
dene-2-phenylpyrrolidine-3-carboxylate (4h). IR (film) 2929, 1735,
1670, 1211 and 1149 cmꢁ1 1H NMR (CDCl3, 400 MHz) 0.80e1.89
;
(10H, m), 2.63e2.68 (1H, m), 3.08 (1H, dd, J¼8.0 Hz and 16 Hz), 3.14
(1H, dd, J¼6.4 Hz and 16.0 Hz), 4.23 (1H, d, J¼8.8 Hz), 4.27 (1H, d,
J¼12.4 Hz), 4.63 (1H, d, J¼12.4 Hz), 5.46 (1H, d, J¼8.8 Hz), 5.55 (1H,
approx. t, J¼7.0 Hz), 5.67 (1H, s), 6.78e6.80 (2H, m, AreH),
7.08e7.36 (16H, m, AreH), 8.09e8.11 (2H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 25.5, 25.9, 26.0, 30.9, 33.2, 35.8, 52.8, 57.0, 66.6,
67.2, 126.0, 126.4, 127.7, 127.9, 128.1, 128.2, 128.3, 128.5, 128.6, 128.7,
128.8, 129.0, 133.0, 135.4, 136.6, 137.0, 139.6, 170.6, 207.1; MS (ESI)
m/z 570 (MHþ, 100%), 518 (8), and 254 (4). HRMS (ESI) m/z
570.30053 (C39H40NO3 [MHþ], 570.30027).
4.3.10. Benzyl
2-benzyl-1-cyclohexyl-4-phenyl-1H-pyrrole-3-car-
boxylate (5d) and benzyl 5-benzoyl-4-benzylidene-1-cyclohexyl-2-
phenylpyrrolidine-3-carboxylate (8a). Prepared by methods A or B
from aziridine 7 and allene 3d. Purification by preparative thin
layer chromatography [ethyl acetateehexane (1:10)] afforded by
method B 5d as a yellow oil in 41% yield and 8a as a yellow oil in 35%
yield [method A: 5d (53%) and 8a (35%)]. Compound 5d was iden-
tified by comparison with the specimen previous prepared
(see above). Benzyl 5-benzoyl-4-benzylidene-1-cyclohexyl-2-phe-
nylpyrrolidine-3-carboxylate (8a). IR (film) 2930, 1735, 1669, 1210
4.3.8. Benzyl 2-benzyl-1-cyclohexyl-4-phenyl-1H-pyrrole-3-carbox-
ylate (5d) and benzyl 5-benzoyl-4-benzylidene-1-cyclohexyl-2-phe-
and 1147 cmꢁ1 1H NMR (CDCl3, 400 MHz) 0.86e1.90 (10H, m),
;
nylpyrrolidine-3-carboxylate (4g). Prepared by method
A
from
2.66e2.71 (1H, m), 3.88 (1H, d, J¼12.0 Hz), 4.21 (1H, d, J¼12.0 Hz),
4.69 (1H, d, J¼9.2 Hz), 5.55 (1H, d, J¼9.2 Hz), 6.53 (1H, s), 6.79e6.81
(2H, m, AreH), 7.09e7.53 (16H, m, AreH), 8.18e8.20 (2H, m, AreH);
13C NMR (CDCl3,100 MHz) 25.5, 25.9, 26.0, 31.1, 33.4, 53.5, 57.1, 66.4,
67.9, 126.8, 127.1, 127.6, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6,
128.8, 128.9, 129.0, 133.2, 135.3, 136.3, 136.8, 137.3, 139.9, 169.4,
203.5; MS (ESI) m/z 556 (MHþ, 100%), 504 (6), 466 (8) and 254 (23).
HRMS (ESI) m/z 556.28373 (C38H38NO3 [MHþ], 556.28462).
aziridine 6 and allene 3d. Purification by preparative thin layer
chromatography [ethyl acetateehexane (1:10)] afforded 5d as
a yellow oil in 64% yield and 4g as a yellow solid in 10% yield. Benzyl
2-benzyl-1-cyclohexyl-4-phenyl-1H-pyrrole-3-carboxylate (5d). IR
(film) 2931, 1734, 1696, 1268 and 1149 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) 0.84e1.77 (10H, m), 3.79e3.85 (1H, m), 4.44 (2H, s), 5.13
(2H, s), 6.64 (1H, s), 7.20e7.36 (15H, m, AreH); 13C NMR (CDCl3,
100 MHz) 25.2, 25.8, 31.0, 34.2, 55.4, 65.3, 110.5, 116.8, 126.0, 126.1,
127.5, 127.7, 127.9, 128.0, 128.2, 128.4, 128.5, 128.6, 129.0, 129.3,
129.5, 129.8, 131.8, 133.6, 136.3, 137.1, 139.2, 165.7; MS (ESI) m/z 450
(MHþ, 41%), 342 (7), 273 (27) and 233 (10). HRMS (ESI) m/z
450.24321 (C31H32NO2 [MHþ], 450.24276). Benzyl 5-benzoyl-4-
4.3.11. Benzyl 1-cyclohexyl-2-phenethyl-4-phenyl-1H-pyrrole-3-car-
boxylate (5e) and benzyl 5-benzoyl-1-cyclohexyl-4-phenethylidene-
2-phenylpyrrolidine-3-carboxylate (8b). Prepared by method B from
aziridine 7 and allene 3e. Purification by preparative thin layer
chromatography [ethyl acetateehexane (1:10)] afforded by
method B 5e as a yellow oil in 43% yield and 8b as a yellow oil in
33% yield [method A: 5e (75%)]. Compound 5e was identified by
comparison with the specimen previous prepared (see above).
Benzyl 5-benzoyl-1-cyclohexyl-4-phenethylidene-2-phenylpyrroli-
dine-3-carboxylate (8b). IR (film) 2928, 1732, 1669, 1212 and
benzylidene-1-cyclohexyl-2-phenylpyrrolidine-3-carboxylate
(4g).
Mp 139.0e140.5 ꢀC (from methanol). IR (film) 2930, 1733, 1675,
1267 and 1145 cmꢁ1; 1H NMR (CDCl3, 400 MHz) 0.85e1.59 (8H, m),
1.80e1.90 (2H, m), 2.66e2.71 (1H, m), 3.86 (1H, d, J¼12.4 Hz), 4.19
(1H, d, J¼12.4 Hz), 4.66 (1H, d, J¼8.8 Hz), 5.53 (1H, d, J¼8.8 Hz), 5.81
(1H, s), 6.51 (1H, s), 6.77e6.79 (2H, m, AreH), 7.05e7.35 (13H, m,
AreH), 7.49e7.60 (3H, m, AreH), 8.15e8.17 (2H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 25.5, 25.9, 26.0, 31.1, 33.4, 53.5, 57.1, 66.4, 67.9,
126.7, 127.0, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.5, 128.8,
128.9, 129.0, 133.2, 135.3, 136.3, 136.8, 137.2, 139.9, 169.4, 203.5; MS
(ESI) m/z 556 (MHþ, 100%), 557 (45), 201 (17) and 195 (10). HRMS
(ESI) m/z 556.28482 (C38H38NO3 [MHþ], 556.28462).
1143 cmꢁ1 1H NMR (CDCl3, 400 MHz) 0.82e1.88 (10H, m),
;
2.63e2.68 (1H, m), 3.06 (1H, dd, J¼8.0 and 16.0 Hz), 3.14 (1H, dd,
J¼6.8 and 16 Hz), 4.24 (1H, d, J¼8.8 Hz), 4.27 (1H, d, J¼12.4 Hz),
4.63 (1H, d, J¼12.4 Hz), 5.46 (1H, d, J¼8.8 Hz), 5.55 (1H, approx. t,
J¼7.0 Hz), 5.67 (1H, s), 6.78e6.80 (2H, m, AreH), 7.09e7.36 (16H,
m, AreH), 8.09e8.11 (2H, m, AreH); 13C NMR (CDCl3, 100 MHz)
25.5, 25.9, 26.1, 30.9, 33.2, 35.8, 52.8, 57.0, 66.6, 67.2, 126.0, 126.4,
127.7, 127.9, 128.1, 128.2, 128.3, 128.5, 128.6, 128.7, 128.8, 129.0,
133.0, 135.4, 136.6, 137.0, 139.6, 170.6, 204.0; MS (ESI) m/z 570
(MHþ, 100%), 518 (10) and 254 (7). HRMS (ESI) m/z 570.30060
(C39H40NO3 [MHþ], 570.30027).
4.3.9. Benzyl 1-cyclohexyl-2-phenethyl-4-phenyl-1H-pyrrole-3-car-
boxylate (5e) and benzyl 5-benzoyl-1-cyclohexyl-4-phenethylidene-
2-phenylpyrrolidine-3-carboxylate (4h). Prepared by method B from
aziridine 6 and allene 3e. Purification by preparative thin layer
chromatography [ethyl acetateehexane (1:10)] afforded 5e as
a yellow oil in 26% yield and 4h as a yellow oil in 23% yield. Benzyl 1-
cyclohexyl-2-phenethyl-4-phenyl-1H-pyrrole-3-carboxylate (5e). IR
4.3.12. Benzyl
2,5-dibenzoyl-1-benzyl-4-methylenepyrrolidine-3-
carboxylate (15) and benzyl 2,5-dibenzoyl-1-benzyl-4-methyl-
enepyrrolidine-3-carboxylate (16). Prepared by methods A or B from
aziridine 14 (100 mg, 0.29 mmol) and allene 3a (0.44 mmol).
Compound 15 crystallized from the crude mixture of 15 and 16 as
a white solid in 49% (method A) or 52% (method B; reaction time,
5.5 h) yield. The remaining mixture was purification by flash col-
umn chromatography [ethyl acetateehexane (1:9)] affording 16 as
a yellow oil in 12% (method A) or 4% (method B; reaction time,
5.5 h) yield. Benzyl 2,5-dibenzoyl-1-benzyl-4-methylenepyrrolidine-
(film) 2932, 1696, 1274 and 1168 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
1.11e1.84 (10H, m), 2.90 (2H, t, J¼7.6 Hz), 3.22 (2H, t, J¼7.6 Hz),
3.59e3.65 (1H, m), 5.17 (2H, s), 6.57 (1H, s), 7.09e7.10 (2H, m,
AreH), 7.23e7.36 (13H, m, AreH); 13C NMR (CDCl3, 100 MHz) 25.3,
25.9, 34.3, 36.7, 55.3, 65.3, 109.3, 116.4, 126.0, 126.1, 127.6, 127.9,
128.1, 128.3, 128.5, 128.6, 129.0, 129.4, 129.8, 131.8, 134.5, 136.3,
136.4, 139.2, 141.5, 165.4; MS (ESI) m/z 464 (MHþ, 75%), 303 (11),
287 (80) and 201 (11). HRMS (ESI) m/z 464.25909 (C32H34NO2

F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
8821
3-carboxylate (15). Mp 117.0e118.0 ꢀC (from methanol). IR (film)
3063, 1740, 1675, 1228 and 1151 cmꢁ1 1H NMR (CDCl3, 400 MHz)
171.6, 172.6; MS (ESI) m/z 512 (MHþ, 100%), 201 (76) and 195 (25).
HRMS (ESI) m/z 512.27993 (C33H38NO4 [MHþ], 512.27954).
;
3.63 (1H, d, J¼12.8 Hz), 3.86 (1H, d, J¼12.8 Hz), 4.28e4.30 (1H, m),
4.61 (1H, d, J¼12.4 Hz), 4.85 (1H, d, J¼12.4 Hz), 5.06 (1H, br s), 5.27
(1H, d, J¼8.0 Hz), 5.30 (1H, br s), 5.48 (1H, s), 7.02e7.15 (7H, m,
AreH), 7.22e7.24 (3H, m, AreH), 7.31e7.34 (2H, m, AreH),
7.42e7.46 (2H, m, AreH), 7.49e7.58 (2H, m, AreH), 7.65e7.67 (2H,
m, AreH), 7.92e7.94 (2H, m, AreH); 13C NMR (CDCl3,100 MHz) 51.9,
53.4, 63.4, 66.9, 71.0, 111.6, 127.4, 128.1, 128.2, 128.3, 128.4, 128.5,
129.0, 129.3, 133.0, 133.1, 134.8, 136.4, 137.5, 142.8, 169.0, 199.5,
200.3; MS (ESI) m/z 516 (MHþ, 100%), 517 (35) and 518 (5). HRMS
(ESI) m/z 516.21632 (C34H30NO4 [MHþ], 516.21693); Benzyl 2,5-
dibenzoyl-1-benzyl-4-methylenepyrrolidine-3-carboxylate (16). IR
4.3.16. 4-Benzyl 2-ethyl 1-benzyl-3-benzylidene-5-phenylpyrrolidine-
2,4-dicarboxylate (18d). Prepared by method A from aziridine 17
(100 mg, 0.36 mmol) and allene 3d (0.43 mmol). Crystallization from
methanol afforded 18d as
a white solid in 48% yield. Mp
118.6e119.9 ꢀC (from methanol). IR (KBr) 3031, 1730, 1257 and
1154 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) 1.26 (3H, t, J¼7.2 Hz), 3.59
(1H, d, J¼13.6 Hz), 3.92 (1H, d, J¼13.6 Hz), 4.14e4.21 (3H, m), 4.35
(1H, d, J¼8.0 Hz), 4.54 (1H, s), 4.65 (1H, d, J¼12.4 Hz), 5.13 (1H, d,
J¼8.0 Hz), 6.68 (1H, s), 6.93e6.95 (2H, m, AreH), 7.18e7.35 (16H, m,
AreH), 7.49e7.51 (2H, m, AreH); 13C NMR (CDCl3, 100 MHz) 14.4,
51.1, 54.1, 60.5, 66.5, 67.7, 69.8, 126.7, 127.1, 127.4, 128.0, 128.1, 128.2,
128.3, 128.4, 128.5, 135.4, 136.1, 136.3, 138.0, 138.3, 170.1, 171.9; MS
(ESI) m/z 532 (MHþ, 100%) and 201 (28). HRMS (ESI) m/z 532.24948
(C35H34NO4 [MHþ], 532.24824).
(film) 3063, 1737, 1686, 1228 and 1159 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) 3.78e3.79 (1H, m), 3.85 (1H, d, J¼12.4 Hz), 3.94 (1H, d,
J¼12.4 Hz), 5.04 (1H, br s), 5.15 (2H, s), 5.30 (1H, br s), 5.34 (1H, br
s), 5.53 (1H, d, J¼4.4 Hz), 7.15e7.39 (14H, m, AreH), 7.50e7.56 (2H,
m, AreH), 7.84e7.90 (4H, m, AreH); MS (ESI) m/z 516 (MHþ, 100%),
201 (44), 233 (14) and 207 (15). HRMS (ESI) m/z 516.21749
(C34H30NO4 [MHþ], 516.21693).
4.3.17. 4-Benzyl 2-ethyl 1-benzyl-3-phenethylidene-5-phenylpyrroli-
dine-2,4-dicarboxylate (18e). Prepared by method A from aziridine
17 (100 mg, 0.36 mmol) and allene 3e (0.43 mmol). Crystallization
from methanol afforded 18e as a white solid in 56% yield. Mp
94.3e95.2 ꢀC (from methanol). IR (KBr) 2931, 1722, 1603, 1277 and
4.3.13. 4-Benzyl 2-ethyl 1-benzyl-3-methylene-5-phenylpyrrolidine-
2,4-dicarboxylate (18a). Prepared by method A from aziridine 17
(100 mg, 0.36 mmol) and allene 3a (0.43 mmol). Crystallization
from methanol afforded 18a as a yellow solid in 73% yield. Mp
84.0e86.0 ꢀC (from methanol). IR (KBr) 3026, 1738, 1247 and
1159 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) 1.17 (3H, t, J¼7.2 Hz), 3.23
(2H, d, J¼7.6 Hz), 3.59 (1H, d, J¼14.0 Hz), 3.89 (1H, d, J¼14.0 Hz),
4.08e4.14 (3H, m), 4.38 (1H, d, J¼12.4 Hz), 4.41 (1H, s), 4.75 (1H,
d, J¼12.4 Hz), 5.09 (1H, d, J¼8.0 Hz), 5.84 (1H, t, J¼7.6 Hz)),
7.03e7.05 (4H, m, AreH), 7.20e7.33 (14H, m, AreH), 7.49e7.51
(2H, m, AreH); 13C NMR (CDCl3, 100 MHz) 14.3, 35.6, 51.0, 53.3,
60.4, 65.9, 66.6, 69.1, 125.9, 126.2, 127.1, 127.7, 127.9, 128.1, 128.3,
128.4, 128.7, 135.4, 136.4, 138.0, 138.4, 139.4, 170.8, 172.1; MS (ESI)
m/z 546 (MHþ, 100%), 287 (3) and 201 (6). HRMS (ESI) m/z
546.26447 (C36H36NO4 [MHþ], 546.26389.
1152 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) 1.24 (3H, t, J¼7.2 Hz), 3.55
(1H, d, J¼13.6 Hz), 3.81 (1H, d, J¼13.6 Hz), 4.09 (1H, d, J¼8.4 Hz),
4.13e4.18 (2H, m), 4.38 (1H, s), 4.43 (1H, d, J¼12.4 Hz), 4.77 (1H, d,
J¼12.4 Hz), 4.94 (1H, d, J¼8.4 Hz), 5.23 (1H, br s), 5.39 (1H, br s),
7.01e7.02 (2H, m, AreH), 7.29e7.32 (11H, m, AreH), 7.39e7.41 (2H,
m, AreH); 13C NMR (CDCl3, 100 MHz) 14.3, 51.6, 54.6, 60.6, 66.5,
66.7, 68.6, 112.1, 127.1, 128.0, 128.1, 128.2, 128.3, 128.4, 128.6, 135.4,
138.2, 138.3, 143.7, 170.7, 171.8; MS (ESI) m/z 456 (MHþ, 100%), 201
(17) and 195 (15). HRMS (ESI) m/z 456.21580 (C29H30NO4 [MHþ],
456.21693).
4.3.18. 4-Benzyl 2-ethyl1-cyclohexyl-3-methylene-5-phenylpyrrolidine-
2,4-dicarboxylate (20). Prepared by method A from aziridine 19
(100 mg, 0.37 mmol) and allene 3a (0.44 mmol). Crystallization
from methanol afforded 20 as a white solid in 62% yield. Prepared
by method B hating the toluene solution of aziridine 19 (100 mg,
0.37 mmol) and allene 3a (0.44 mmol) for 3 h. Purification by
flash column chromatography [ethyl acetateehexane (1:8)]
afforded 20 as a yellow oil in 40% yield. Mp 96.5e98.0 ꢀC (from
4.3.14. 4-Benzyl 2-ethyl 1-benzyl-3-ethylidene-5-phenylpyrrolidine-
2,4-dicarboxylate (18b). Prepared by method A from aziridine 17
(100 mg, 0.36 mmol) and allene 3b (0.43 mmol). Purification by
flash column chromatography [ethyl acetateehexane (1:9)] affor-
ded 18b as a white solid in 50% yield. Mp 72.0e74.0 ꢀC (from
methanol). IR (film) 3031, 1733, 1256 and 1151 cmꢁ1
;
1H NMR
methanol). IR (KBr) 2930, 1745, 1237 and 1187 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz) 1.22 (3H, t, J¼7.2 Hz), 1.52 (3H, d, J¼6.8 Hz), 3.55
(1H, d, J¼14.0 Hz), 3.86 (1H, d, J¼14.0 Hz), 3.99 (1H, d, J¼8.0 Hz),
4.14 (2H, q, J¼7.2 Hz), 4.35 (1H, s), 4.40 (1H, d, J¼12.0 Hz), 4.78 (1H,
d, J¼12.0 Hz), 5.04 (1H, d, J¼8.0 Hz), 5.72 (1H, q, J¼6.8 Hz),
7.02e7.03 (2H, m, AreH), 7.23e7.34 (11H, m, AreH), 7.48e7.50 (2H,
m, AreH); 13C NMR (CDCl3, 100 MHz) 14.3, 15.0, 51.1, 53.0, 60.3,
65.9, 66.5, 69.0, 122.0, 127.0, 128.0, 128.2, 128.3, 128.3, 128.4, 128.4,
135.6, 136.1, 138.2, 138.5, 170.8, 172.3; MS (ESI) m/z 470 (MHþ,
100%), 211 (12) and 201 (28). HRMS (ESI) m/z 470.23076
(C30H32NO4 [MHþ], 470.23258).
(CDCl3, 400 MHz) 1.25 (3H, br s), 1.29 (3H, t, J¼7.2 Hz), 1.45e1.48
(1H, m), 1.55e1.62 (3H, m), 1.78e1.86 (3H, m), 2.41e2.46 (1H, m),
4.21 (2H, q, J¼7.2 Hz), 4.25e4.28 (1H, m), 4.54 (1H, d, J¼12.0 Hz),
4.54 (1H, s), 4.76 (1H, d, J¼12.0 Hz), 4.92 (1H, d, J¼8.4 Hz), 5.42
(1H, br s), 5.50 (1H, br s), 7.12e7.13 (4H, m, AreH), 7.20e7.22 (3H,
m, AreH), 7.29e7.31 (3H, m, AreH); 13C NMR (CDCl3, 100 MHz)
14.2, 25.0, 25.4, 25.8, 31.0, 32.5, 52.2, 57.5, 60.9, 66.2, 66.5, 68.1,
112.0, 127.5, 127.9, 128.1, 128.3, 128.4, 135.5, 139.7, 142.5, 169.3,
174.3; MS (ESI) m/z 448 (MHþ, 100%) and 274 (8). HRMS (ESI) m/z
448.24723 (C28H34NO4 [MHþ], 448.24824).
4.3.15. 4-Benzyl 2-ethyl 1-benzyl-3-(2,2-dimethylpropylidene)-5-
phenylpyrrolidine-2,4-dicarboxylate (18c). Prepared by method A
from aziridine 17 (100 mg, 0.36 mmol) and allene 3c (0.43 mmol).
Crystallization from methanol afforded 18c as a white solid in 71%
yield. Mp 138.0e140.0 ꢀC (from methanol). IR (KBr) 2952, 1724,
4.4. General procedure for formal [3D2] cycloaddition of
2-benzoyl-1-tert-butyl-3-phenylaziridine (9) with allenes
A solution of aziridine 9 (100 mg, 0.36 mmol) and the appro-
priated buta-2,3-dienoate (0.54 mmol) in toluene (6 mL) was
heated at 80 ꢀC for 4 h. The solvent was removed under reduced
pressure and the crude product was purified by flash chromatog-
raphy [ethyl acetateehexane (1:9)].
1257 and 1146 cmꢁ1 1H NMR (CDCl3, 400 MHz) 0.96 (9H, s), 1.21
;
(3H, t, J¼7.2 Hz), 3.53 (1H, d, J¼13.6 Hz), 3.88 (1H, d, J¼13.6 Hz),
4.05e4.22 (3H, m), 4.34 (1H, d, J¼12.0 Hz), 4.35 (1H, s), 4.81 (1H, d,
J¼12.0 Hz), 5.03 (1H, d, J¼7.6 Hz), 5.62 (1H, s), 7.02e7.03 (2H, m,
AreH), 7.22e7.34 (11H, m, AreH), 7.46e7.48 (2H, m, AreH); 13C
NMR (CDCl3, 100 MHz) 14.3, 29.8, 33.6, 50.8, 53.1, 60.1, 66.6, 67.1,
69.9, 127.0, 128.1, 128.3, 128.4, 128.5, 131.5, 135.4, 137.1, 138.3, 138.6,
4.4.1. Benzyl 1-tert-butyl-2-methyl-4-phenyl-1H-pyrrole-3-carbox-
ylate (10a). Cycloadduct 10a was obtained as a yellow oil in 65%
yield. IR (film) 2980, 1696, 1209 and 1143 cmꢁ1 1H NMR (CDCl3,
;

8822
F.M. Ribeiro Laia et al. / Tetrahedron 66 (2010) 8815e8822
400 MHz) 1.64 (9H, s), 2.75 (3H, s), 5.12 (2H, s), 6.72 (1H, s),
7.00e7.02 (2H, m, AreH), 7.20e7.30 (8H, m, AreH); 13C NMR
(CDCl3, 100 MHz) 14.7, 30.7, 57.0, 65.3, 112.4, 117.7, 124.3 125.9,
127.5, 127.7, 128.0, 128.2, 129.2, 136.4, 136.5, 166.1; MS (EI) m/z 347
(Mþ, 24%), 256 (14), 201 (14), 200 (100) and 184 (16). HRMS (EI) m/z
347.1894 (C23H25NO2 [Mþ], 347.1885).
1.111 g cmꢁ3, Z¼4,
m
¼0.070 mmꢁ1. R (I>2
(I))¼0.0477andRw¼0.1418
s
for 6657 independent reflections. H atoms were placed at calculated
positions and refined as riding on their parent atoms.
Acknowledgements
Thanks are due to FCT (Project PTDC/QUI/64470/2006; Grant
SFRH/BPD/34569/2007) COMPETE, QREN and FEDER for financial
support. We acknowledge the Nuclear Magnetic Resonance Labo-
ratory of the Coimbra Chemical Centre (www.nmrccc.uc.pt), Uni-
versity of Coimbra for obtaining the NMR data.
4.4.2. Benzyl 1-tert-butyl-2-ethyl-4-phenyl-1H-pyrrole-3-carboxyl-
ate (10b). Cycloadduct 10b was obtained as a colourless oil in 38%
yield. IR (film) 2980, 1696, 1210 and 1145 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) 1.28 (3H, t, J¼7.2 Hz), 1.64 (9H, s), 3.17 (2H, q, J¼7.2 Hz),
5.12 (2H, s), 6.66 (1H, s), 7.01e7.02 (2H, m, AreH), 7.20e7.36 (8H, m,
AreH); 13C NMR (CDCl3, 100 MHz) 15.5, 21.0, 26.1, 31.3, 57.1, 65.2,
67.2, 111.5, 117.6, 124.7, 125.9, 127.5, 127.6, 128.0, 128.2, 128.3, 128.4,
128.6, 129.3, 136.4, 136.6, 143.2, 165.5; MS (EI) m/z 361 (Mþ, 25%),
214 (52),196 (100) and 91 (41). HRMS (EI) m/z 361.2037 (C24H27NO2
[Mþ], 361.2042).
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.09.081.
4.5. Crystal data
References and notes
4.5.1. Crystal data for 2-benzoyl-1-benzyl-3-phenylaziridine (1). The
X-ray data were collected on a Bruker Apex II single crystal
1. For reviews on pyrrole, see: (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, pp 119e206; (b) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Mikhaleva, A. L. Chem. Rev. 2004, 104, 2481e2506; (c) Furstner, A. Angew. Chem.,
Int. Ed. 2003, 42, 3582e3603.
2. (a) Baumgarlen, M.; Tyulyulkor, N. Chem.dEur. J. 1998, 4, 987e989; (b) Higgins,
S. J. Chem. Soc. Rev. 1997, 26, 247e258; (c) Anzenbacher, P., Jr.; Nishiyabu, R.;
Palacios, M. A. Coord. Chem. Rev. 2006, 250, 2929e2938; (d) Jeppesen, J. O.;
Becher, J. Eur. J. Org. Chem. 2003, 3245e3266.
diffractometer, using room temperature using Mo K
a radiation.
The structures were solved by direct methods as implemented
in SHELXS97 and refined by full-matrix least-squares using
SHELXL97.17 All the crystals available were ill-formed and showed
signs of twinning. Examination of the structure with PLATON
revealed a twin law that was used in the last refinements (the BASF
parameter refined to 0.17).
3. Yamazaki, S. Chem.dEur. J. 2008, 14, 6026e6036.
4. Ribeiro Laia, F. M.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2009, 50, 6180e6182.
5. Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2009, 13, 1406e1431.
6. Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; WILEY-VCH GmbH
KgaA: Weinheim, 2004.
7. Ma, S. Chem. Rev. 2005, 105, 2829e2871.
8. Ma, S. Aldrichimica Acta 2007, 40, 91e102.
C22H19NO, M¼313.38, triclinic, P-1 with unit cell, a¼5.7129
(10) A, b¼10.7002(17) A, c¼14.740(2) A,
¼88.373(12)ꢀ,
¼77.814
b
ꢁ
ꢁ
ꢁ
a
3
ꢁ
(13)ꢀ,
g
¼74.337(12) , V¼847.6(2) A . It contains two molecules/unit
ꢀ
cell. rcalcd¼1.228 g cmꢁ3, Z¼2,
m
¼0.075 mmꢁ1. R (I>2
(I))¼0.1228
s
9. Hassan, H. H. A. M. Curr. Org. Chem. 2007, 4, 413e439.
and Rw¼0.3693 for 3226 independent reflections. H atoms were
placed at calculated positions and refined as riding on their parent
atoms.
10. Yu, J.; Long, H.; Chen, X.-H.; Song, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2009, 11,
4946e4949.
11. (a) Aziridine 1 (Mp 105e107 ꢀC; lit. Mp 108 ꢀC), aziridine 7 (Mp 107.5e109 ꢀC;
lit. Mp 107 ꢀC) and aziridine 8 were prepared as described in Cromwell, N. H.;
Badson, R. D.; Harris, C. E. J. Am. Chem. Soc. 1943, 65, 312e315; (b) Aziridine 8,
Mp 100.3e101.8 ꢀC; lit. Mp 106.0e107.0 ꢀC reported in Padwa, A.; Eisenhardt,
W. J. Am. Chem. Soc. 1971, 93, 1400e1408.
4.5.2. Crystal data for benzyl 5-benzoyl-1-benzyl-4-benzylidene-
2-phenylpyrrolidine-3-carboxylate (4d). The X-ray data were col-
lected on a Bruker Apex II single crystal diffractometer, using room
12. (a) Buta-2,3-dienoates were prepared via Wittig reaction of benzyl(triphenyl-
phosphoranylidene)acetate with ketene following the general procedure de-
scribed in: Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Rocha Gonsalves, A. M. d’A.;
temperature using Mo Ka radiation. The structures were solved by
~
Costa Pessoa, J.; Paixao, J. A.; Beja, A. M. Eur. J. Org. Chem. 2004, 4830e4839; (b)
direct methods as implemented in SHELXS97 and refined by full-
matrix least-squares using SHELXL97.18 Examination of the
structure with PLATON revealed voids capable of containing sol-
vent molecules. Such molecules could not be modelled and the
SQUEEZE function was used to account for the extra charge
density.
Lambert, T. H.; MacMillan, D. C. W. J. Am. Chem. Soc. 2002, 124, 13646e13647.
~
13. Lopes, S. M. M.; Beja, A. M.; Silva, M. R.; Paixao, J. A.; Palacios, F.; Pinho e Melo,
T. M. V. D. Synthesis 2009, 2403e2407.
14. Aziridine 5 (Mp 100e102 ꢀC; lit. 101e102 ꢀC) was prepared as described in
Southwick, P. L.; Christman, D. R. J. Am. Chem. Soc. 1952, 74, 1886e1891.
15. Casiraghi, G.; Zanardi, F. Chem. Rev. 2000, 100, 1929e1972.
16. (a) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297e14316; (b) Dalili, S.;
Yudin, A. K. Org. Lett. 2005, 7, 1161e1164; (c) Zhu, W.; Cai, G.; Ma, D. Org. Lett.
2005, 7, 5545e5548.
C39H33NO3, M¼563.66, monoclinic, P21/c with unit cell,
ꢁ
3
ꢁ
ꢁ
ꢁ
a¼11.2176(4) A, b¼15.7551(6) A, c¼19.3159(7) A,
b
¼99.281(2)ꢀ,
17. Turner, A. B.; Heine, H. W.; Irving, J.; Bush, J. B. J. Am. Chem. Soc.1965, 87,1050e1055.
18. Sheldrick, G. M. Acta Crystallogr. 2008, A 64, 112e122.
V¼3369.1(2) A . It contains four molecules/unit cell. rcalcd
¼