1,3-Dipolar cycloaddition of azomethine ylides generated from aziridines in supercritical carbon dioxide

Article abstract of DOI:10.1016/j.tetlet.2006.05.179

The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is reported. The photolysis reaction conditions were optimized with a suitable adjustment of pressure, temperature, irradiation time and co-solvent concentration

Full text of DOI:10.1016/j.tetlet.2006.05.179

Tetrahedron Letters 47 (2006) 5475–5479
1,3-Dipolar cycloaddition of azomethine ylides generated
from aziridines in supercritical carbon dioxide
´
Paulo J. S. Gomes, Claudio M. Nunes, Alberto A. C. C. Pais,
Teresa M. V. D. Pinho e Melo* and Luis G. Arnaut
Department of Chemistry, Coimbra University, 3004-535 Coimbra, Portugal
Received 8 March 2006; revised 26 May 2006; accepted 30 May 2006
Abstract—The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is reported. The photo-
lysis reaction conditions were optimized with a suitable adjustment of pressure, temperature, irradiation time and co-solvent concen-
tration leading to a more efficient reaction than in neat acetonitrile. Similar results were observed using thermal reaction conditions.
Supercritical carbon dioxide with a minute co-solvent addition is shown to be a very efficient medium for promoting this type of
cycloadditions.
Ó 2006 Elsevier Ltd. All rights reserved.
Over the last decade, supercritical fluids (SCF) received
significant attention as a new class of environmentally
friendly solvents for organic synthesis. Supercritical flu-
ids have properties intermediate between the gas and the
liquid phases that can be tuned simply by changing the
pressure and temperature. In particular, changes of pres-
sure close to the critical point enable drastic changes in
density and viscosity. Supercritical carbon dioxide
(scCO2) has received special attention since it is readily
accessible with low critical temperature (Tc = 31 °C)
and moderate critical pressure (Pc = 75.8 bar). Super-
critical carbon dioxide is also a desirable organic solvent
replacement because it is abundant, inexpensive, non-
toxic, non-flammable and easily separated from the
reaction mixture.1
ology for the synthesis of nitrogen-heterocyclic
compounds. We chose the 1,3-dipolar cycloaddition
of azomethine ylides generated from aziridines as the
model reaction. Aziridines (1) undergo electrocyclic ring
opening in a disrotatory manner upon irradiation and
conrotatory ring opening upon thermolysis, giving
azomethine ylides (2), which participate in 1,3-dipolar
cycloadditions (Scheme 1).
As the first objective we decided to study the photolysis
of aziridine 3 in the presence of dimethyl acetylene-
dicarboxylate (DMAD) using conventional reaction
conditions (Scheme 2). Ethyl 3-phenylaziridine-2-
carboxylate 3 was prepared as described in the litera-
ture.4 We found that irradiation of a solution of 3 and
DMAD in acetonitrile using a Hg lamp (20 °C,
k = 254 nm, 1 h) affords 5-phenyl-2,3-dihydro-1H-pyr-
role-2,3,4-tricarboxylate 45 in 69% yield. Thus, the ini-
tially formed 1,3-dipolar cycloadduct isomerizes giving
the final product. A 42 min irradiation in acetonitrile
with the fourth harmonic (266 nm) of the Nd:YAG laser
also gave 4 in 69% yield. Dicyano-sensitized photoreac-
tion of aziridine 3 with DMAD was also carried out
leading to compound 4 in 68% (20 °C, k = 380 nm,
25 min).
The study of model reactions is an efficient strategy to
get knowledge on the chemical reactivity in scCO2. That
is the case of the 1,3-dipolar cycloaddition, an important
and general route to the construction of five-membered
heterocyclic ring systems.2 However, 1,3-dipolar cyclo-
addition in scCO2 is an area almost unexplored and only
reports on the cycloaddition of mesonitrile oxide and of
3-phenylsydnone are known.3 The cycloaddition of
azomethine ylides is a particularly powerful method-
The optimization of the cycloaddition reaction in scCO2
requires the control of one additional variable, pressure,
in addition to temperature and irradiation time. Cursory
experiments revealed that the maximum efficiency
Keywords: Supercritical carbon dioxide; 1,3-Dipolar cycloaddition;
Azomethine ylides; Aziridines.
*
Corresponding author. Tel.: +351 239 854475; fax: +351 239
826068; e-mail: tmelo@ci.uc.pt
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.179

5476
P. J. S. Gomes et al. / Tetrahedron Letters 47 (2006) 5475–5479
R3
N
R3
N
R3
N
R1
H
R1
R2
h
Δ
ν
R1
R2
2
R
H
1
2b
2a
Scheme 1.
MeO2C
Ph
CO2Me
CO2Et
MeO2C
Ph
CO2Me
CO2Et
4 68%
H
N
MeO2C
CO2Me
MeO2C
CO2Me
hν 380 nm
MeCN, 25 min
DCB
N
H
hν 254 nm
MeCN, 1 h
N
Ph
CO2Et
H
4 69%
3
Scheme 2.
Table 1. The four factors in the 24 factorial design and the respective
yield
approached 43% at 110 bar, 45 °C and an irradiation
time of 42 min with the fourth harmonic (266 nm) of
the Nd:YAG laser. Clearly, the maximum yield in
scCO2 is much less than in acetonitrile. Further
improvement of the yield required the use of acetonitrile
as co-solvent, which introduces a fourth variable in the
optimization procedure. This optimization was con-
ducted, as a first approach, resorting to a full 2k factorial
planning, with k = 4 factors. These comprise pressure
(P), temperature (T), irradiation time (It) and the vol-
ume of acetonitrile (V) as co-solvent. The initial objec-
tive function has the form
MeO2C
Ph
CO2Me
CO2Et
H
DMAD
N
hν scCO
2
N
H
Ph
CO2Et
4
3
It/min
V/mLa
T/°C
P/bar
Yield/%6
20
20
40
20
20
20
40
40
40
20
40
40
20
20
40
40
0.1
0.1
0.1
0.2
0.2
0.1
0.2
0.1
0.2
0.1
0.2
0.2
0.2
0.2
0.1
0.1
35
45
35
45
35
35
35
45
45
45
35
45
35
45
45
35
110
110
140
110
110
140
140
110
140
140
110
110
140
140
140
110
42
63
43
54
31
35
21
21
27
18
28
34
44
28
27
32
yield ð%Þ ¼ cte þ aI It þ aV V þ aT T þ aP P
t
þ aI V ItV þ ꢀ ꢀ ꢀ þ aI VT ItVT þ ꢀ ꢀ ꢀ
t
t
þ aI VTP ItVTP
ð1Þ
t
A summary of factor levels and yields can be found in
Table 1, while Table 2 summarizes the values of coeffi-
cients determined using a standard approach7,8 in which
a normalization to ꢁ1 and +1 of the lower and upper
level values was performed. Results in Table 2 suggest
a discrimination of effects based on the interaction
terms. In fact, all power 1 coefficients are negative, but
interaction terms vary signal. Also, a significant number
of interaction terms are, for the ranges used, of the same
order of magnitude as the direct effect of each factor.
One of the most substantial terms reveals a strong inter-
action between pressure and temperature. Conse-
quently, pressure and temperature were transformed
into density, and this variable was taken as the most sig-
nificant one to characterize scCO2. The original 16
experiments were then transformed in a corresponding
23 full factorial planning, without conducting further
experiments. The results indicate that the reaction yield
is higher for low density values of the reactant mixture.
This allows the use of an additionally simplified form of
Eq. 1, which includes only the irradiation time and the
volume of added acetonitrile. Again, for normalized val-
ues of the levels, we obtain Eq. 2 that can be used to
maximize yield. This function is represented in Figure
1 imposing a yield of 100%. It possesses a singularity
for ꢂ15 min irradiation time; also, on the right branch,
the zone It < 34 min corresponds to unphysical negative
a Volume of acetonitrile.
Table 2. Values of coefficients for a full 24 factorial design (Eq. 1)
(cte = 0.3425)
i
ai
ij
aij
ijk
aijk
It
V
T
P
ꢁ0.053
ꢁ0.0096
ꢁ0.003
ꢁ0.0385
ItÆV
VÆT
TÆP
ItÆT
ItÆP
VÆP
ꢁ0.0071
0.0261
ꢁ0.0511
ꢁ0.0155
0.0422
ItÆVÆT
VÆTÆP
ItÆVÆP
ItÆTÆP
0.0223
0.003
0.0446
0.0443
0.0055
volumes. A direct search for It > 34 min lead to yields as
high as 75% (t = 42 min and V = 25 lL; Fig. 2). The
accuracy of the model was tested conducting experi-
ments in conditions anticipated to be less than ideal,
and in all cases the yield was less than for the combina-
tion of parameters recommended by the model. The
actual search along the set of variables anticipated to

P. J. S. Gomes et al. / Tetrahedron Letters 47 (2006) 5475–5479
5477
yield ð%Þ ¼ 0:6511 þ 0:0002It þ 0:0157 V ꢁ 0:0345ItV
ð2Þ
The model leads to the unexpected prediction that the
maximum yield of the cycloaddition should be observed
at low scCO2 densities and minute co-solvent concentra-
tions. This was entirely verified experimentally. In par-
ticular, the yield is maximized when 23 mol of
acetonitrile are present for 1 mol of aziridine and
2.3 mol of DMAD.9 This shows that only a thin solva-
tation layer is required to maximize the yield, and addi-
tional acetonitrile molecules are not necessary.
The work was extended to the study of the reactivity of
aziridine 510 towards photolysis and thermolysis, in the
presence of DMAD (Scheme 3). The irradiation of azi-
ridine 5 in acetonitrile using a Hg lamp (20 °C,
k = 254 nm, 5 h) gave pyrrole 6 (38%) and pyrrole 7
(19%), together with unreacted aziridine 5 (15%). On
the other hand, the cycloaddition of azomethine ylide
generated by the thermolysis of aziridine 5 with DMAD
produced pyrrole 6 in 42% yield as the only product.
Figure 1.
The irradiation with the fourth harmonic (266 nm) of
the Nd:YAG laser of aziridine 5 in the presence of
DMAD in scCO2 led to pyrrole 6 in poor yield (3–5%)
and no improvement was observed using acetonitrile
as co-solvent (Table 3). It is known that 2-benzoylaziri-
dines can undergo a variety of photoinduced transfor-
mations namely intramolecular hydrogen atom, C–N
bond cleavage and C–C bond cleavage.11 The main reac-
tion pathway is determined by the photolysis reaction
conditions. This observation is in agreement with our re-
sults, where different outcomes were observed when the
irradiation was carried out with a Hg lamp and when the
laser irradiation was employed.
The impossibility of achieving an efficient generation of
the azomethine ylide from aziridine 5 using our photolysis
conditions led us to study the thermal electrocyclic ring
opening in the presence of DMAD in scCO2 (Table 4).
Figure 2.
give the highest yields is shown in Figure 2, together
with two points representing experimental conditions
that do not meet the model optimization for the smaller
fraction of acetonitrile employed.
The thermolysis of aziridine 5 using conventional reac-
tion conditions has shown that the C–C bond cleavage
is attainable at 80–85 °C (see Scheme 3). Therefore,
the thermolysis in scCO2 was carried out at 80 °C,
MeO2C
Ph
CO2Me
COPh
MeO2C
Ph
CO2Me
MeO2C
CO2Me
N
N
hν 254 nm, MeCN, 5 h
(15% of 5 recovered)
CH Ph
CH Ph
CH Ph
2
2
2
N
6 38%
7 19%
Ph
COPh
MeO2C
Ph
CO2Me
5
MeO2C
CO2Me
COPh
N
80-85 °C
Toluene, 4.5 h
CH Ph
2
6 42%
Scheme 3.

5478
P. J. S. Gomes et al. / Tetrahedron Letters 47 (2006) 5475–5479
6
Table 3. Photolysis of aziridine 5 in the presence of DMAD in scCO2
C.; Isilda Silva, M.; Arnaut, L. G.; Formosinho, S. J.
Chem. Phys. Lett. 2004, 387, 263–266.
CH2Ph
N
MeO2C
Ph
CO2Me
2. (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863–909; (b) Padwa, A. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, L., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 4, p 1069; (c) Wade, P. A. In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, L., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4, p 1111; (d)
Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2785–
DMAD
hν scCO2
COPh
N
Ph
COPh
CH2Ph
5
6
t/min
Xa
T/°C
P/bar
Yield/%6
´
2809; (e) Najera, C.; Sansano, J. M. Curr. Org. Chem.
300
150
20
—
—
0.005
45
45
45
110
110
110
5
3
0
2003, 7, 1105–1150; (f) Vedejs, E. In Advances in Cyclo-
addition; Curran, D. P., Ed.; JAI Press, 1988; Vol. 1, pp
33–51.
a Of acetonitrile.
3. (a) Totoe, H.; McGowin, A. E.; Turnbull, K. J. Supercrit.
Fluid 2000, 18, 131–140; (b) Lee, C. K. Y.; Holmes, A. B.;
Al-Duri, B.; Leeke, G. A.; Santos, R. C. D.; Seville, J. P.
K. Chem. Commun. 2004, 2622–2623.
4. Gelas-Mialhe, Y.; Touraud, E.; Vessiere, R. Can. J. Chem.
1982, 60, 2830–2851.
Table 4. Thermolysis of aziridine 5 in the presence of DMAD in
6
scCO2
CH2Ph
N
MeO2C
Ph
CO2Me
COPh
5. 2-Ethyl 3,4-dimethyl 5-phenyl-2,3-dihydro-1H-pyrrole-
2,3,4-tricarboxylate 4. The product was purified by flash
chromatography [ethyl acetate–hexane (1:4) then ethyl
acetate–hexane (1:3)] and was obtained as a white solid.
Mp 103–105 °C (from ethyl acetate–hexane). m (KBr)
DMAD
Δ scCO2
N
Ph
COPh
CH2Ph
5
3065, 3006, 1748, 1711, 1703 and 1629 cmꢁ1
;
UV
6
kmax = 254 nm; dH (CDCl3, 300 MHz) 0.95 (3H, t,
t/min
Xa
T/°C
P/bar
Yield/%6
J = 7.1 Hz), 3.26 (1H, d, J = 6.7 Hz), 3.65 (1H, d,
J = 6.7 Hz), 3.79 (3H, s), 3.88 (3H, s), 5.52 (1H, s, NH),
7.29–7.36 (5H, m, Ar–H); dC (CDCl3, 75.5 MHz) 13.8,
45.0, 46.3, 51.8, 53.0, 61.3, 104.7, 127.4, 128.2, 128.3,
132.5, 155.6, 165.1, 165.7; MS (EI) m/z 333 (M+, 8%), 274
(39), 260 (58), 228 (34), 200 (41), 131 (100), 103 (60) and 77
(48). Anal. Calcd for C17H19NO6: C, 61.25; H, 5.75; N,
4.20. Found: C, 61.15; H, 5.43; N, 4.39.
240
240
—
0.005
80
80
110
110
18
53
a Of acetonitrile.
110 bar with a reaction time of 240 min, which gave pyr-
role 6 in 18% yield (Table 4). However, pyrrole 6 could
be obtained in 53% yield when the reaction was carried
out using acetonitrile as co-solvent (X = 0.005). Thus, a
significant improvement was again achieved by perform-
ing the cycloaddition in scCO2 with a minute co-solvent
addition.
6. The yields were determined by HPLC, with a column
Hypersil BDS C18, kept at 40 °C, and a mixture of water–
acetonitrile (50:50) as the mobile phase. In these condi-
tions the retention times are as follows: aziridine 3,
1.83 min; 2,3-dihydro-1H-pyrrole 4, 4.80 min; aziridine 5,
3.59 min; pyrrole 6, 4.33 min and pyrrole 7, 2.89 min. In
all the experiments, a calibration curve was made, to
obtain the concentration of products.
7. Massart, D. L.; Vandeginste, B. G. M.; Deming, S. N.;
Michotte, Y.; Kaufman, L. Chemometrics: a Textbook;
Elsevier, 1998.
8. Peixoto, A. F.; Pereira, M. M.; Pais, A. A. C. C.,
submitted for publication.
9. General procedures for the cycloaddition in supercritical
carbon dioxide. CO2 (airliquide, N48) was passed through
an Alltech charcoal trap and a Matheson Tri-Gas oxygen
absorbing purifier (model 6410), before being allowed into
the high-pressure reactor specifically built in our labora-
tory for these experiments. This reactor was made in
stainless steel, with two sapphire windows 2.00 cm in
diameter and 0.80 cm thick, sealed against the reactor
body with indium wire partially embedded in circular
cages drilled in the stainless steel. A magnetic stirrer
placed inside the reactor kept the solutions homogenized
during the irradiation process. Channels drilled in the
reactor were connected to a Jasco thermostatic bath with
external water circulation to maintain the reactor at the
desired temperature. The high-pressure reactor has two
external connections via 1/1600 stainless steel tubes. One of
them is connected, through a valve, to the high-pressure
line, and the other to a digital pressure indicator (Omega
DP20 and Schaevitz pressure sensor, precision +0.25%).
In a typical experiment, 4.0 mg of aziridine was introduced
in our reactor together with 6 lL of DMAD and the
necessary amount of acetonitrile. The reactor was closed
The use of scCO2 with a minute addition of acetonitrile
as co-solvent leads to cycloaddition yields higher than
those obtained in neat solvents and that are achieved
at lower reaction times. This demonstrates not only
the environmental advantage of using scCO2 in organic
synthesis, but also its cost-effectiveness in photochemical
and thermal cycloadditions.
Acknowledgements
We thank Chymiotechnon and Fundac¸ao para a Cieˆncia
˜
e a Tecnologia (POCI/QUI/55584/2004 and POCTI/
QUI/47267/2002) for financial support.
References and notes
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P. J. S. Gomes et al. / Tetrahedron Letters 47 (2006) 5475–5479
5479
and connected to the high-pressure line. The reactor was
flushed with CO2 to expel the air, and them it was
pressurized with CO2. This procedure was made at low
temperature to avoid evaporation or sublimation. The
samples were irradiated with the fourth harmonic
(266 nm) of a Spectra-Physics Quanta-Ray GCR-130
Nd:YAG laser.
10. Aziridine 5 was prepared as described in Southwick, P. L.;
Christman, D. R. J. Am. Chem. Soc. 1952, 74, 1886–
1891.
11. (a) Padwa, A.; Hamilton, L. J. Am. Chem. Soc. 1967, 89,
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