Synthesis of pyrroles in supercritical carbon dioxide: Formal [3+2] cycloaddition of 2-benzoyl-aziridines and allenoates

Article abstract of DOI:10.1055/s-0030-1260209

The reactivity of N-benzyl- and N-cyclohexyl-2-benzoyl-3-phenylaziridines toward allenoates in supercritical carbon dioxide (scCO₂) is described. The study led to the development of a sustainable and selective approach to pyrrole derivatives an

Full text of DOI:10.1055/s-0030-1260209

3516
PAPER
Synthesis of Pyrroles in Supercritical Carbon Dioxide: Formal [3+2]
Cycloaddition of 2-Benzoyl-Aziridines and Allenoates
S
ynthesis of Pyrro
n
les in Superc
a
ritica
l
Carbon
D
io
L
xide . Cardoso, Rui M. D. Nunes, Luis G. Arnaut, Teresa M. V. D. Pinho e Melo*
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Fax +351(239)827703; E-mail: tmelo@ci.uc.pt
Received 8 July 2011; revised 4 August 2011
Dedicated to Prof. Francisco Palacios on the occasion of his 60th anniversary
tramolecular attack of the carbanion on the aziridine ring
to give the formal 1,3-dipolar cycloaddition product 6
through C–N bond cleavage.3 A sequential SN2/formal
[3+2] cycloaddition approach to indolizines starting from
non-activated aziridines has also been reported.4 After the
initial SN2 reaction of 7-iodo-2-heptynoates 7 and N-un-
substituted aziridines, dipole 8 is formed. The reaction
with iodide anion then leads to the opening of the aziridine
ring5 followed by a third SN2 reaction giving the final
products (Scheme 1).
Abstract: The reactivity of N-benzyl- and N-cyclohexyl-2-ben-
zoyl-3-phenylaziridines toward allenoates in supercritical carbon
dioxide (scCO2) is described. The study led to the development of a
sustainable and selective approach to pyrrole derivatives and gave a
new insight into the mechanism involved in the process.
Key words: cycloaddition, scCO2, aziridines, allenes, pyrroles
Aziridines are valuable strained small heterocycles that
are of interest for preparative organic synthesis. In fact,
chemistry based on the ring opening of aziridines has been
used in an impressive range of synthetic applications.1
Aziridines 1 undergo electrocyclic ring opening upon ir-
radiation or thermolysis, giving azomethine ylides 2
through C–C bond cleavage, which participate in 1,3-di-
polar cycloadditions to give five-membered nitrogen het-
erocycles.1 On the other hand, in the presence of Lewis
acids, N-tosylarylaziridines undergo C–N bond cleavage
leading to zwitterionic 1,3-dipoles 3, which react with alk-
enes, alkynes, ketones, and nitriles to form formal 1,3-di-
polar cycloadducts.2 Mattay et al. reported that the
nonactivated aziridine 4 reacts with acetylenedicarboxy-
lates affording a dipolar intermediate 5, followed by an in-
We have recently described the results of studies on the
reactivity of buta-2,3-dienoates toward aziridines
(Scheme 2).6 It was observed that allenoates can react as
the 2-component in the [3+2] cycloaddition with azometh-
ine ylides generated from aziridines, affording 4-methyl-
enepyrrolidines, but they can also react via formal [3+2]
cycloadditions leading to functionalized pyrroles. The
substitution pattern of the aziridine determines the chem-
ical behaviour of allenoates in the presence of these three-
membered heterocycles. Site-, regio- and stereoselective
synthesis of 4-methylenepyrrolidines 12 was achieved by
[3+2] cycloaddition of allenoates with azomethine ylides
generated from N-benzyl-2-benzoyl-3-phenylaziridine.
X = Ts
1 = H; R2 = Ar
Lewis acid
X
N
R
X
R2 = COR3
dipolarophiles
dipolarophiles
formal [3+2]
cycloadducts
R1
N
COR3
Ts
Ar
[3+2] cycloadducts
N
C–C bond
cleavage
C–N bond
cleavage
R1
R2
3
1
2
Bu
N
Ph
Bu
N
RO2C
RO2C
CO2R
N
RO2C
C–N bond
cleavage
Bu
Ph
RO2C
Ph
CO2R
4
5
6
R1
H
X
X
R1
X
X
I–
N
R1
I
R2
R1
R2
I
N
N
N
R2
R2
C–N bond
cleavage
K2CO3
7
10
8
9
Scheme 1 Aziridines in [3+2] and formal [3+2] cycloadditions
SYNTHESIS 2011, No. 21, pp 3516–3522
x
x.
x
x
.
2
0
1
1
Advanced online publication: 06.09.2011
DOI: 10.1055/s-0030-1260209; Art ID: T68411SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrroles in Supercritical Carbon Dioxide
3517
However, reactions of N-cyclohexyl- or N-t-butyl-2-ben- interactions between substrate and CO2 or from simple
zoyl-3-phenylaziridines with buta-2,3-dienoates led to a solvent effects. In this paper, the study of the reactivity of
different outcome. In these cases, pyrroles 11 were ob- N-benzyl- or N-cyclohexyl-2-benzoyl-3-phenylaziridines
tained as single or major products, resulting from formal toward allenoates in scCO2 is described.
[3+2] cycloadditions through aziridine C–N bond cleav-
age followed by a retro-aldol type fragmentation with
elimination of benzaldehyde. From the reaction with alle-
noates bearing bulkier C-4 substituents, 4-methylenepyr-
It has been previously reported that allenoate 15a reacts as
the 2-component in the [3+2] cycloaddition with azo-
methine ylide 14, generated from cis-1-benzyl-2-benzoyl-
3-phenylaziridine (13), giving 4-methylenepyrrolidine 16
rolidines were also formed as minor products.
selectively (Scheme 3).6 Under conventional reaction
conditions, this heterocycle was obtained as a single ste-
reoisomer in moderate yield (32%). However, micro-
wave-assisted 1,3-dipolar cycloaddition afforded the
R1
R1
N
C–C bond
cleavage
N
R2
R3
[3+2] cycloaddition
R2
R3
target molecule 16 in higher yield (73%).
R4
BnO2C
•
R1
Bn
R4
CO2Bn
Bn
N
N
N
12
Δ
Ph
toluene
Ph
H
R2
R3
•
Ph
COPh
COPh
14
CO2Bn
COPh
R1
13
R4
R4
COPh
N
R1
N
R4
C–N bond
•
CO2Bn
cleavage
15a
R2 = Ph
3 = COPh
via formal
BnO2C
Ph
[3+2] cycloaddition
R
Bn
N
Ph
BnO2C
11
Reaction conditions Yield of 16
reflux, 1.5 h 32%
Scheme 2 Reactivity of aziridines toward allenoates
MW, 150 °C, 15 min 73%
BnO2C
16
This study gave an insight into the chemistry of aziridines
and provided a synthetic approach to nitrogen-containing
five-membered heterocycles, which are among the most
common structures in biologically active compounds,
making them important target molecules.7–9 Therefore, we
decided to further explore the chemistry of aziridines to-
ward allenoates with the aim of finding a more sustainable
approach to this type of heterocycle.
Scheme 3 Aziridine 13 in the [3+2] cycloaddition with allenoate
155
The reactivity of aziridine 13 toward allenoate 15a in
scCO2 was investigated (Table 1). Our study on the 1,3-
dipolar cycloaddition of azomethine ylides generated
from aziridines in scCO2 indicated that the use of small
amounts of co-solvents such as acetonitrile leads to more
efficient processes.21a In fact, it has been demonstrated
that the low polarity of scCO2 can be a disadvantage but
that this can be overcome by addition of very small
amounts of co-solvent.10 Thus, initial experiments were
carried out using acetonitrile as co-solvent (Table 1, en-
tries 1–5). Interestingly, the formation of 4-methylenepyr-
rolidine 16 was not observed. Performing the reaction
with aziridine 13 (1.5 equiv) and allenoate 15a at 90 °C
with a CO2 pressure of 100 bar for 18 hours, provided pyr-
role 17a in 69% yield as a single product (Table 1, entry
1). An improvement was achieved by carrying out the re-
action at 80 °C with a shorter reaction time (4 h), giving
the same pyrrole in 80% yield (Table 1, entry 2). Howev-
er, when the reaction time was reduced to 2 h, pyrrole 17a
was formed as the major product (66%) together with pyr-
role 18, which was isolated in 9% yield (Table 1, entry 3).
The reaction of aziridine 13 with allenoate 15a in scCO2
at 75 bar, 80 °C for four hours also led to the formation of
pyrroles 17a and 18 in 65 and 4% yield, respectively
(Table 1, entry 4). A similar result was obtained using 1.0
equiv of aziridine instead of 1.5 equiv (Table 1, entry 5).
Supercritical carbon dioxide (scCO2) is regarded as an en-
vironmentally friendly solvent for organic synthesis, and
is an attractive alternative to conventional organic sol-
vents. The physical properties of scCO2 are intermediate
between the gas and the liquid phases and can be tuned by
changing pressure and temperature.10 In particular,
changes close to the critical point enable drastic changes
in density, viscosity and diffusion. Among supercritical
fluids (SCF), scCO2 has received special attention since it
is readily accessible at a low critical temperature
(Tc = 31 °C) and moderate critical pressure (Pc = 75.8
bar). Supercritical carbon dioxide is also a desirable or-
ganic solvent replacement because it is abundant, inex-
pensive, non-toxic, non-flammable and can be easily
separated from the reaction mixture.
The use of SCF as a substitute for organic solvents has
been exploited in a variety of organic reactions.11–21 Due
to higher solute diffusivity, lower fluid viscosity and a
more limited solvation of reacting species than in liquid
solvents, different kinetics can be observed in reactions
carried out in scCO2. Thus, the use of scCO2 in processes
under kinetic control can lead to enhanced selectivity.22 In
some cases, an improvement in selectivity can result from
Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York

3518
A. L. Cardoso et al.
PAPER
Table 1 Reaction of Aziridine 13 with Allenoate 15a in scCO2
obtained (Table 1, entries 9 and 10). Attempts were also
made to find reaction conditions that favour the formation
of pyrrole 18, namely, the use of lower temperature. How-
ever, no reaction was observed either at 40 or 60 °C
(Table 1, entries 11 and 12). Thus, in contrast to the reac-
tion in toluene of N-benzyl-2-benzoyl-3-phenylaziridine
(13) with allenoate 15a, which leads to 4-methylenepyrro-
lidine 16 (Scheme 3), the main reaction pathway in scCO2
under the studied reaction conditions afforded pyrrole 17a
(Table 1).
Bn
Bn
OH
6
N
Bn
N
N
5
4
2
3
scCO2
•
Ph
+
BnO2C
Ph
Ph
COPh
BnO2C
Ph
CO2Bn
13
15a
17a
18
Entry 13
MeCN
P
Temp Time Products (%)a
(equiv) (mL)
(bar)
(°C)
90
80
80
80
83
90
80
85
80
80
40
60
(h)
18
4
17a
69
80
66
65
62
79
50
64
64
45
–
18
1
2
1.5
1.5
1.5
1.5
1.0
1.5
1.5
1.0
1.0
1.0
1.0
1.0
520
520
520
520
520
–
100
90
–
Table 2 Reaction of Aziridine 13 with Allenoate 15a
–
Bn
N
Bn
N
•
Bn
N
3
100
75
2
9
Ph
COPh
CO2Bn
15a
+
4
4
4
Ph
COPh
BnO2C
BnO2C
Ph
5
98
4
5
16
17a
13 (1 equiv)
6
85
4
–
Entry
Reaction conditions
Reflux, MeCN, 1.5 h
Products (%)a
7
–
100
90
4
31
–
16
7b
17a
11b
9c
8
–
4
1
2
3
4
5
MW, MeCN, 110 °C, 15 min
12c
28
2
9
–
100
100
100
100
4
3
10b
11
12
–
2
15
–
scCO2, toluene, 90 bar, 80 °C, 4 h
scCO2, toluene, 140 bar, 80 °C, 4 h
scCO2, MeOH, 100 bar, 80 °C, 2 h
22
–
4
48
–
4
–
–
–
63
a Yield of isolated products.
b Starting aziridine and allenoate recovered.
a Yield of isolated products.
b Starting aziridine (47%) recovered.
c Starting aziridine (13%) and allenoate (25%) recovered.
The structural assignment of compound 18 was supported
by two-dimensional, NOESY, HMQC and HMBC spectra
(400 MHz). The HMBC spectrum shows connectivity of
the methyl protons with C-3, and H-6 shows connectivity
with C-4 and C-5, but no connectivity with C-3. In the
NOESY spectrum, H-6 shows connectivity with the meth-
ylenic protons of the N-benzyl group, but no connectivity
with the methylenic protons of the benzyl ester group. On
the other hand, the infrared spectrum clearly shows a
strong broad absorption band at 3450 cm–1, which is char-
acteristic of the hydroxy group.
Bn
N
•
+
Ph
COPh
CO2Bn
13 (1.5 equiv)
15a
scCO2
147 bar, 90 °C, 4 h
Bn
Bn
N
N
Ph
COPh
+
It was important to determine whether the use of a co-sol-
vent was necessary to assure the efficiency of this type of
reaction. The reaction of aziridine 13 (1.5 equiv) with al-
lenoate 15a at 85 bar and 90 °C with a reaction time of
four hours gave pyrrole 17a in 79% yield as a single prod-
uct (Table 1, entry 6). Thus, we could conclude that super-
critical carbon dioxide is a very efficient medium for the
synthesis of pyrrole 17a. However, in the absence of co-
solvent, when the reaction was carried out at 100 bar and
80 °C, pyrroles 17a and 18 were obtained in 50 and 31%
yield, respectively (Table 1, entry 7). We then studied this
reaction without the addition of co-solvent using 1.0 equiv
of aziridine. When the reaction was performed at 90 bar
and 85 °C for four hours, pyrrole 17a was isolated in 64%
yield (Table 1, entry 8), whereas when the reaction was
carried out at 100 bar and 80 °C, pyrroles 17a and 18 were
BnO2C
BnO2C
Ph
16 39%
17a 34%
Scheme 4 Aziridine 13 in the [3+2] and formal [3+2] cycloaddition
with allenoate 15
These results suggest that the nature of the solvent may
have a role in determining the reaction outcome. There-
fore, reactions under conventional thermolysis and under
microwave irradiation were carried out using acetonitrile
as solvent. In both cases, 4-methylenepyrrolidine 16 and
pyrrole 17a were obtained in low overall yield (Table 2,
entries 1 and 2). Thus, on changing the solvent from tolu-
ene to acetonitrile, although the process becomes less ef-
ficient, it was observed that the synthesis of pyrrole 17a
Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrroles in Supercritical Carbon Dioxide
3519
becomes more favourable. The reaction carried out in (Table 3, entry 5). However, pyrrole 17c could only be
scCO2 at 90 bar and 80 °C for four hours using toluene as obtained in low yield (Table 3, entries 3 and 4). In the re-
co-solvent gave 4-methylenepyrrolidine 16 and pyrrole action of aziridine 13 with allenoate 15e, bearing a bulky
17a in 28 and 22% yield, respectively (Table 2, entry 3). C-4 substituent, no reaction was observed (Table 3, en-
It should be mentioned that similar reaction conditions in tries 6 and 7).
scCO2 in the absence of co-solvent or in the presence of
acetonitrile lead to the formation of pyrrole 17a, and pyr-
rolidine 16 was never observed (Table 1, entries 2 and 8).
Aiming to find out whether the nature of the N-substituent
of the 2-benzoyl-3 phenylaziridines plays a role in the
chemical behaviour of these three-membered heterocy-
At higher CO2 pressure (140 bar), pyrrole 17a was formed
cles in the presence of allenoates, cis-2-benzoyl-1-cyclo-
as the major product (48%), whereas pyrrolidine 16 was
hexyl-3-phenylaziridine (19) was synthesized and its
isolated in 2% yield (Table 1, entry 4). Using methanol as
reactivity toward allenoates in scCO2 was studied
co-solvent, pyrrole 17a was obtained in 63% yield as a
(Table 4). Aziridine 19 reacted with allenoate 15a at 100
single product (Table 1, entry 5).
bar and 80 °C for four hours using acetonitrile as co-sol-
vent, giving pyrrole 20a6b in moderate yield; an improve-
Table 3 Synthesis of Pyrroles 17b–d in scCO2 from the Reaction of
Aziridine 13 with Allenoates 15b–d
ment was achieved with a longer reaction time (18 h),
affording the product in 40% yield (Table 4, entries 1 and
Bn
Bn
N
R
2). However, the same pyrrole could be obtained in higher
yield (58%) in the absence of co-solvents at 90 bar and
85 °C for four hours (Table 4, entry 3). It was observed
that the best reaction conditions for the synthesis of pyr-
roles 20b–d6b from the reaction of aziridine 19 and the ap-
propriate allenoate was also the use of scCO2 without co-
solvent as the reaction medium (Table 4, entries 4–8). It
has been reported that aziridines can be converted into 2-
oxazolidinones under scCO2.23 However, adducts of this
type were never detected in the studied reactions of aziri-
dines 13 and 19 with allenoates.
N
R
scCO2
•
+
Ph
COPh
CO2Bn
BnO2C
Ph
13
15b R = Ph
15c R = Me
15d R = Bn
17b R = Ph
17c R = Me
17d R = Bn
15e R = t-Bu
Entry R
13
MeCN P
Temp Time ProductYield
(equiv) (mL) (bar) (°C)
(h)
(%)a
79
63b
7
1
2
3
4
5
6
7
Ph
1.5
1.0
1.0
1.0
1.5
1.0
1.0
520
–
118
100
115
110
95
82
80
80
80
82
80
80
4
17b
17b
17c
17c
17d
–
We have previously proposed that pyrroles can be ob-
tained from aziridines and allenoates via a formal [3+2]
cycloaddition as outlined in Scheme 5.6 Nucleophilic ad-
dition of the aziridine to the activated allenoate double
Ph
2
Me
Me
Bn
520
520
520
520
520
2
4
18
58
–
Table 4 Synthesis of Pyrroles 20 from the Reaction of Aziridine 19
with Allenoates
4
t-Bu
t-Bu
100
100
2
Cy
Cy
N
R
N
R
19
–
–
scCO2
•
+
a Yields of isolated product.
b Starting aziridine and allenoate recovered.
Ph
COPh
CO2Bn
BnO2C
Ph
19
15a R = H
20a R = H
20b R = Ph
20c R = Me
20d R = Bn
15b R = Ph
15c R = Me
15d R = Bn
The described results indicate that the best reaction condi-
tions for selective generation of pyrrole 17a involve the
reaction of aziridine 13 and allenoate 15a in scCO2 at 85
bar and 90 °C (Table 1, entry 6). Interestingly, when the
scCO2 pressure was raised to 147 bar, both cycloaddition
via azomethine ylide 14 and formal [3+2] cycloaddition
took place, affording pyrrolidine 16 and pyrrole 17a in 39
and 34% yields, respectively (Scheme 4). Therefore, the
selectivity towards pyrrole 17a is higher at pressures close
to the critical pressure of scCO2.
Entry
R
MeCN
(mL)
P
(bar)
Temp Time Product Yield
(°C)
80
80
85
80
80
80
80
85
(h)
(%)a
21
40
58
34
51
49
37
70
1
2
3
4
5
6
7
8
H
H
H
520
520
–
100
110
90
4
20a
20a
20a
20b
20b
20c
20d
20d
18
4
Ph
Ph
Me
Bn
Bn
520
–
90
18
4
The work was extended to reactions of aziridine 13 with
allenoates 15b–d in scCO2 (Table 3). Using CO2 pres-
sures between 95 and 118 bar, the corresponding pyrroles
17 were obtained as a single product. Pyrrole 17b was iso-
lated in good yield either using acetonitrile as co-solvent
or in the absence of a co-solvent (Table 3, entries 1 and 2).
The reaction of aziridine 13 with allenoate 15d also effi-
ciently led to the formation of pyrrole 17d6b in 58% yield
110
110
90
–
4
520
–
18
4
90
a Yields of isolated products.
Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York

3520
A. L. Cardoso et al.
PAPER
R2
N
bond giving intermediate 21 followed by intramolecular
attack of the carbanion centre on the aziridine ring, affords
the five-membered heterocycles via C–N bond cleavage.
Tautomerisation leads to the formation of pyrrole 22,
bearing a hydroxybenzyl side-chain, which is converted
into the final product and benzaldehyde via retro-aldol
type fragmentation.
Bn
N
R1
OH
Ph
OH
Ph
R1 = H
R2 = Bn
BnO2C
Ph
BnO2C
Ph
22
18
Scheme 6 Mechanism proposal for the synthesis of pyrrole 18
The isolation of pyrrole 18 from the reaction of aziridine
13 and allenoate 15a (Table 1) supports the mechanistic
proposal. The formation of this derivative can be ex-
plained by considering that the proposed intermediate 22
is formed and undergoes tautomerisation to give the cor-
responding pyrrole containing a hydroxybenzyl substitu-
ent (Scheme 6). On the other hand, the isolation of
benzaldehyde from reactions where pyrroles 17 and 20
were obtained is in agreement with the proposed final step
involving a retro-aldol type fragmentation.
In conclusion, we have described the selective synthesis
of pyrroles in scCO2 from the reaction of 2-benzoyl-azir-
idines with allenoates. In contrast to the reactivity ob-
served in toluene, the main pathway involves a formal
[3+2] cycloaddition starting either from N-benzyl- or N-
cyclohexyl-2-benzoyl-3-phenylaziridines.
The isolation, under selected reaction conditions, of a mi-
nor amount of the pyrrole derivative containing a hydroxy-
benzyl side-chain, which is formed from a proposed
intermediate, reinforced the mechanism proposal. Fur-
thermore, the isolation of benzaldehyde from these reac-
tions is also in agreement with the proposed final step
involving a retro-aldol type fragmentation.
The work reported herein has demonstrated that the use of
scCO2 medium favours this type of formal [3+2] cycload-
dition. In fact, even in cases where aziridines and alle-
noates
participate
exclusively
in
1,3-dipolar
cycloadditions in organic solvents (via the generation of
azomethine ylides in situ) to give 4-methylenepyrro-
lidines (e.g., reaction of aziridine 13 in toluene with alle-
noates 15a–c6), the reaction in scCO2 with pressures
between 75–100 bar allowed the exclusive synthesis of
pyrroles 17 (Table 1 and Table 3). The exclusive forma-
tion of pyrroles 17 and 20 was also observed when the re-
action was conducted in scCO2 using acetonitrile or
methanol as co-solvents. However, using scCO2 with the
addition of minute amounts of toluene in the reaction of
aziridine 13 and allenoate 15a led to the competitive syn-
thesis of 4-methylenepyrrolidine and pyrrole derivatives.
The reaction of aziridine 13 with allenoate 15a at a scCO2
pressure of 147 bar, in the absence of a co-solvent, afford-
ed both pyrrole 17a and pyrrolidine 16. Thus, there is an
1H NMR spectra were recorded with a Bruker Avance III instrument
operating at 400 MHz; 13C spectra were recorded with a Bruker
Avance III instrument operating at 100 MHz. Spectra were recorded
with samples dissolved in CDCl3, except where otherwise indicat-
ed. Mass spectra were recorded under electrospray ionization (ESI)
except where indicated otherwise. Compounds 16, 17d and 20c–d
were prepared following the general procedure described below and
were identified by comparison with specimens previously pre-
pared.6 Buta-2,3-dienoates 15 were prepared through Wittig reac-
tion of benzyl(triphenylphosphoranylidene)acetate with ketenes
following known synthetic procedures.24 cis-1-Benzyl-2-benzoyl-
3-phenylaziridine (13) and cis-2-benzoyl-1-cyclohexyl-3-phenyl-
aziridine (19) were prepared by a known procedure.25,6
Reactions in Supercritical Carbon Dioxide; Reaction Setup and
intrinsic advantage of using scCO2 as solvent near the crit- General Procedure
CO2 (airliquide, N48) was passed through an Alltech charcoal trap
ical pressure. The higher solute diffusivity, lower fluid
viscosity, and limited solvation of reacting species than in
liquid solvents is lost when scCO2 pressure is increased.
These observations indicate that solvent effects near the
critical point can play an important role in determining the
outcome of this type of reaction.
and a Matheson Tri-Gas oxygen absorbing purifier (model 6410),
before being allowed into the high-pressure reactor specifically
built in our laboratory (V = 55 cm3). The reactor body was made of
stainless steel and the upper part was sealed with a Teflon ring and
bolted against the reactor body in a circular cage drilled into the
stainless steel. The reactor was fitted with two external connections
via 1/16¢¢ stainless steel tubes. One was connected through a valve
to the high-pressure inlet system, and the other to a digital pressure
indicator (Omega DP20 and Schaevitz pressure sensor, precision
0.25%). A magnetic stirrer placed inside the reactor kept the solu-
tions homogeneous during the reaction. The temperature was mea-
sured using a thermopar sensor inserted through a hole drilled in the
upper part of the reactor.
R2
R1
OH
Ph
COPh
Ph
R1
R2
N
N
BnO2C
Ph
BnO2C
22
21
In a typical procedure, allene (1 equiv, 0.171 mmol) was introduced
into the reactor together with aziridine (1 or 1.5 equiv) and MeCN
(520 mL), and the reactor was closed and connected to a high-
pressure line. The reactor was cooled to –80 °C and all air was
pumped out during 30 min and then pressurized with CO2. The re-
actor was then placed in a thermostatic bath (water or paraffin) at
the appropriate temperature and the reaction was stirred for 4 h.
R2
N
R1
retro-aldol-type
fragmentation
– PhCHO
BnO2C
Ph
Scheme 5 Mechanism proposal for the formal [3+2] cycloaddition
of aziridines and allenotes
Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrroles in Supercritical Carbon Dioxide
3521
Benzyl 1-Benzyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylate
(17a) and Benzyl 1-Benzyl-5-(1¢-hydroxy-1¢-phenylmethyl)-2-
methyl-4-phenyl-1H-pyrrole-3-carboxylate (18)
13C NMR (100 MHz, CDCl3): d = 14.3, 19.0, 50.3, 65.3, 109.9,
120.5, 126.1, 126.6, 127.6, 127.8, 128.1, 128.2, 128.4, 128.6, 128.7,
128.9, 129.4, 133.8, 135.9, 136.4, 137.0, 165.3.
Prepared by the general procedure from aziridine 13 and allene 15a.
Purification by preparative thin layer chromatography (EtOAc–
hexane, 1:10) afforded 17a (1st eluted compound) and 18 (2nd elut-
ed compound).
MS (ESI): m/z = 396 (100) [M + H]+, 339 (37), 314 (7), 279 (4).
HRMS (ESI): m/z [M + H]+ calcd. for C27H26NO2: 396.19565;
found: 396.19581.
Compound 17a
Yellow oil.
Acknowledgment
IR (film): 1700, 1653, 1522, 1497, 1454 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.47 (s, 3 H), 5.04 (s, 2 H), 5.15
(s, 2 H), 6.56 (s, 1 H), 7.08–7.33 (m, 15 H, ArH).
13C NMR (100 MHz, CDCl3): d = 11.6, 50.6, 65.3, 110.8, 120.5,
125.5, 126.2, 126.4, 126.6, 127.6, 127.8, 128.0, 128.2, 128.9, 129.4,
135.9, 136.4, 136.7, 136.8, 165.6.
Thanks are due to Fundação para a Ciência e a Tecnologia (Grant:
SFRH/BPD/34569/2007) for financial support. We acknowledge
the Nuclear Magnetic Resonance Laboratory of the Coimbra
Chemical Centre (www.nmrccc.uc.pt), University of Coimbra for
obtaining the NMR data.
References
MS (ESI): m/z (%) = 381 (48) [M]+, 290 (29), 272 (45), 91 (100).
HRMS (ESI): m/z [M + H]+ calcd. for C26H24NO2: 382.18072;
found: 382.18016.
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Compound 18
Orange oil.
IR (film): 3450, 1697, 1452 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.22 (s, 3 H), 4.78 (s, 2 H), 4.96
(s, 2 H), 5.98 (s, 1 H), 6.57–6.59 (m, 2 H, ArH), 6.84–6.86 (m, 2 H,
ArH), 7.05–7.19 (m, 16 H, ArH).
13C NMR (100 MHz, CDCl3): d = 11.2, 48.3, 65.2, 67.1, 112.7,
121.0, 125.6, 127.1, 127.8, 127.9, 128.2, 128.3, 128.5, 132.5, 136.3,
138.4, 140.2, 141.7, 165.3.
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(15).
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found: 488.22202.
Benzyl 1,2-Dibenzyl-4-phenyl-1H-pyrrole-3-carboxylate (17b)
Prepared by the general procedure from aziridine 13 and allene 15b.
Purification by preparative thin layer chromatography (EtOAc–
hexane, 1:10) afforded 17b.
Van Speybroeck, V. J. Org. Chem. 2010, 75, 885.
Yellow oil.
IR (film): 1695, 1603, 1496, 1459 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.35 (s, 2 H), 4.90 (s, 2 H), 5.14
(s, 2 H), 6.57 (s, 1 H), 6.98–7.39 (m, 20 H, ArH).
13C NMR (100 MHz, CDCl3): d = 31.0, 50.6, 65.4, 111.9, 121.2,
126.2, 126.3, 126.5, 126.7, 127.6, 127.7, 127.8, 128.0, 128.1, 128.2,
128.6, 128.9, 129.4, 135.8, 136.2, 136.6, 137.9, 138.6, 165.4.
MS (ESI): m/z (%) = 458 (100) [M + H]+, 448 (40), 415 (13), 350
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Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York

3522
A. L. Cardoso et al.
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Synthesis 2011, No. 21, 3516–3522 © Thieme Stuttgart · New York