Reactivity of allenoates toward aziridines: [3+2] and formal [3+2] cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2009.08.088

The reactivity of buta-2,3-dienoates toward aziridines is reported. Allenoates react as 2π-component in the [3+2] cycloaddition with the azomethine ylide generated from cis-1-benzyl-2-benzoyl-3-phenylaziridine affording 4-methylenepyrrolidines in a site-,

Full text of DOI:10.1016/j.tetlet.2009.08.088

Tetrahedron Letters 50 (2009) 6180–6182
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Tetrahedron Letters
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Reactivity of allenoates toward aziridines: [3+2] and formal [3+2] cycloadditions
*
Fernanda M. Ribeiro Laia, Teresa M. V. D. Pinho e Melo
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactivity of buta-2,3-dienoates toward aziridines is reported. Allenoates react as 2p-component in
Received 19 June 2009
Revised 7 August 2009
Accepted 26 August 2009
Available online 1 September 2009
the [3+2] cycloaddition with the azomethine ylide generated from cis-1-benzyl-2-benzoyl-3-phenylazir-
idine affording 4-methylenepyrrolidines in a site-, regio-, and stereoselective fashion. Under conventional
thermolysis, cis- and trans-2-benzoyl-1-cyclohexyl-3-phenylaziridines showed a different reactivity.
These aziridines participate in formal [3+2] cycloadditions with allenes via C–N bond cleavage of the
three-membered ring leading to functionalized pyrroles.
Keywords:
Aziridines
Ó 2009 Elsevier Ltd. All rights reserved.
Allenes
Pyrroles
Pyrrolidines
[3+2] cycloaddition
Formal [3+2] cycloaddition
Microwave
Allenes are interesting dipolarophiles due to the presence of
two cumulative unsaturations. In fact, both C@C bonds are suitable
positions for dipolar attack which can proceed with two opposite
orientations. Hence, in the 1,3-dipolar cycloadditions of allenes
both site- and regioselectivity can be involved. Allenes participate
in cycloadditions with a variety of 1,3-dipoles, namely, nitrile oxi-
des, nitrones, carbonyl ylides, nitrile imines, azides, and diazome-
thanes. However, the 1,3-dipolar cycloaddition of allenes with
azomethine ylides is an unexplored research topic.1–5 Therefore,
we set out to explore the cycloaddition of azomethine ylides gen-
erated from aziridines via conrotatory electrocyclic ring opening
with buta-2,3-dienoates.
112.6 ppm corresponds to a methylene group since it shows con-
nectivity with two protons with different chemical shifts,
4.99 ppm and 5.15 ppm. In the HMBC spectrum, carbon C-8
(170.8 ppm) correlates with H-2 and H-3. On the other hand, the
carbon C-5 correlates with protons H-10 and H-2. In the NOESY
spectrum 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.
We have recently reported that the microwave methodology for
the conrotatory ring opening of an aziridine leading to the corre-
sponding 1,3-dipole and the subsequent cycloaddition is more effi-
cient than the conventional heating.10 Thus, the microwave-
assisted 1,3-dipolar cycloaddition of azomethine ylide 2 with ben-
zyl buta-2,3-dienoate (3) was carried out under different reaction
Aziridine 1 was prepared following a known synthetic proce-
dure6 and its X-ray structure was determined in order to unambig-
uously establish the stereochemistry.7 Thermolysis of aziridine 1 in
the presence of benzyl buta-2,3-dienoate8 (3) in refluxing toluene
for 24 h did not lead to the target cycloadduct (Scheme 1). How-
ever, 4-methylenepyrrolidine 49 could be obtained as single ste-
reoisomer 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 4 to prolonged heating.
Bn
Bn
N
Δ
Ph
N
H
Ph
COPh
COPh
2
1
•
Toluene
Reaction conditions
Yield
3
CO2Bn
COPh
Bn
N
1H and 13C NMR data for pyrrolidine 4 are given in Table 1
(chemical shifts of the aromatic groups are not included). The
assignment was supported by two-dimensional COSY, NOESY,
HMQC, and HMBC spectra (400 MHz). From the HMQC spectrum,
it was established that the carbon with the chemical shift
Reflux, 1.5 h
Reflux, 24 h
31.5%
----
Ph
MW, 120°C, 15 min
MW, 150°C, 10 min
MW, 150°C, 15 min
MW, 150°C, 20 min
MW, 160°C, 5 min
MW, 160°C, 15 min
19%
59%
73%
60%
58%
67%
BnO2C
4
Scheme 1. Synthesis of 4-methylenepyrrolidine
azomethine ylide 2 and allenoate 3.
4 via [3+2] cycloaddition of
* Corresponding author. Tel.: +351 239 854475; fax: +351 239 826068.
E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.088

F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo / Tetrahedron Letters 50 (2009) 6180–6182
6181
Table 1
1H and 13C NMR data for pyrrolidine 4a
Ph
R
6
Toluene
N
O
N
Reflux, 1.5h
R
N1
5
4
2
3
Ph
O
9
Ph
COPh
Ph
•
BnO2C
Ph
CO2Bn
7
10
8
Ph
O
3
R = H
7
8a R = H
8b R = Me 25%
51.5%
5a R = Me
4
C
1H NMR
13C NMR
51.5
C-6
3.58 (1H, d, J = 13.2 Hz)
3.84 (1H, d, J = 13.2 Hz)
4.18 (1H, d, J = 8.0 Hz)
4.41 (1H, d, J = 12.4 Hz)
4.78 (1H, d, J = 12.4 Hz)
4.99 (1H, br s)
5.15 (1H, br s)
5.17 (1H, d, J = 8.0 Hz)
5.35 (1H, s)
Toluene
N
N
Reflux, 1.5h
Me
BnO2C
8a 54%
C-3
C-7
54.9
66.6
Ph
COPh
•
Ph
CO2Bn
C-10
112.6
9
3
C-2
C-5
C-4
C-8
C-9
68.8
67.2
136.7
170.8
201.3
Scheme 3. Synthesis of pyrroles 8 via formal [3+2] cycloaddition of aziridines and
allenoates.
—
—
—
a
Chemical shifts of the aromatic groups are not included.
to the synthesis of pyrrole 8a in 54% yield (Scheme 3). This result
allowed us to conclude that the nature of N-substituent of the ben-
zoyl-3-phenylaziridines determines the chemical behavior of these
three-membered heterocycles toward allenoates.
conditions in order to optimize the synthetic procedure. We ob-
served that the 1,3-dipolar cycloadduct 4 was obtained in 73%
yield in a site-, regio-, and stereoselective fashion under micro-
wave irradiation at 150 °C for 15 min (Scheme 1).
The work was extended to the reaction of aziridine 1 with ben-
zyl penta-2,3-dienoate (5a)8 and 5,5-dimethylhexa-2,3-dienoate
(5b)8 under microwave irradiation. Using the optimized reaction
conditions the target molecules 6 were also selectively obtained
(Scheme 2). It is worth noting that the isolation of 4-methylene-
pyrrolidines 4 and 6 only requires crystallization from methanol.
The formation of pyrroles 8 can be explained as outlined in
Scheme 4. Nucleophilic addition of aziridines 7 or 9 to the acti-
vated allene double bond giving intermediate 10 followed by the
intramolecular attack of the carbanion center on the aziridine ring
affords the five-membered heterocycles 11 via C–N bond cleavage.
Tautomerisms and the subsequent aromatization lead to pyrrole
13 bearing a hydroxybenzyl sidechain, which is converted into
benzaldehyde and the final product. The conversion of 2-(1-
hydoxybenzyl)thiamin into thiamin and benzaldehyde involves a
similar fragmentation step.13
It is known that trans- and cis-2-benzoyl-1-cyclohexyl-3-
phenylaziridines (7 and 9) undergo thermal ring opening affording
azomethine ylides which participate in [3+2] cycloadditions as di-
pole.14 However, the reactivity of aziridines participating in formal
[3+2] cycloadditions via C–N bond cleavage with activated
acetylene derivatives has been reported.15 Mattay and Gaebert
demonstrated that the dipolar intermediate formed from N-bu-
tyl-2-phenylazirine and diethyl acetylenedicarboxylate could be
trapped by carrying out the reaction in methanol.15a Therefore,
trans-2-Benzoyl-1-cyclohexyl-3-phenylaziridine
7 was also
synthesized by a known procedure11 and its reactivity toward
buta-2,3-dienoate was studied (Scheme 3). The reaction of aziri-
dine 7 with benzyl buta-2,3-dienoate (3) in refluxing toluene led
to an unexpected result. Pyrrole 8a12 was obtained in 51.5% yield.
Carrying out the reaction with longer reaction time leads to signif-
icantly lower yield.
Based on the 1H and 13C NMR spectra we concluded that com-
pound 8a did not retain the benzoyl substituent. In fact, no signal
with the chemical shift expected for a carbonyl carbon of a benzoyl
group could be observed. On the other hand, the 1H NMR spectrum
shows a singlet at 6.61 ppm corresponding to a pyrrolic proton. In
the NOESY spectrum no connectivity was observed between the
protons of the methyl group and the pyrrolic proton, which is in
agreement with the proposed structure.
COPh
R
R
Cy
N
Cy
N
•
Ph
Ph
COPh
R
BnO2C
A similar reactivity was observed when aziridine 7 was reacted
with allene 5a in refluxing toluene. Pyrrole 8b was isolated in 25%
yield (Scheme 3).
BnO2C
10
The reaction of cis-2-benzoyl-1-cyclohexyl-3-phenylaziridine
Cy
N
Cy
N
Cy
R
OH
Ph
R
96 with benzyl buta-2,3-dienoate (3) was carried out and it led
N
COPh
Ph
COPh
H
BnO2C
BnO2C
BnO2C
Ph
Ph
Bn
N
Bn
N
12
11
Toluene
Ph
COPh
R
Cy
N
Cy
MW, 150°C, 15 min
R
OH
Ph
R
Ph
COPh
N
R
BnO2C
- PhCHO
1
•
CO2Bn
6a R = Me 59%
6b R = t-Bu 46%
BnO2C
Ph
BnO2C
Ph
5a R = Me
5b R = t-Bu
13
8
Scheme 2. Synthesis of 4-methylenepyrrolidines 6 via reaction of aziridine 1 and
allenoates 5.
Scheme 4. Mechanism proposal of the formal [3+2] cycloaddition of aziridines and
allenoates.

6182
F. M. Ribeiro Laia, T. M. V. D. Pinho e Melo / Tetrahedron Letters 50 (2009) 6180–6182
Cy
N
References and notes
Ph
COPh
Me
1. Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2009, 13, 1406–1431.
2. Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; WILEY-VCH GmbH &
Co. KgaA: Weinheim, 2004.
Cy
N
Toluene
BnO2C
13 4%
MW, 150 °C, 15 min
3. Ma, S. Chem. Rev. 2005, 105, 2829–2871.
4. Ma, S. Aldrichimica Acta 2007, 40, 91–102.
5. Hassan, H. H. A. M. Curr. Org. Chem. 2007, 4, 413–439.
•
Ph
COPh
Cy
N
CO2Bn
6. Aziridine 1 (mp 105–107 °C; lit. 108 °C) and aziridine 9 (mp 107.5–109 °C; lit.
107 °C) were prepared as described in Cromwell, N. H.; Badson, R. D.; Harris, C.
E. J. Am. Chem. Soc. 1943, 65, 312–315.
7. Crystallography data of aziridine 1 will be disclosed in due time.
8. Buta-2,3-dienoates were prepared via Wittig reaction of benzyl(triphenylphos-
phoranylidene)acetate with ketene following the general procedure described
in (a) Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Rocha Gonsalves, A. M. d’A.; Costa
Pessoa, J.; Paixão, J. A.; Beja, A. M. Eur. J. Org. Chem. 2004, 4830; (b) Lambert, T.
H.; MacMillan, D. C. W. J. Am. Chem. Soc. 2002, 124, 13646–13647.
3
7
Ph
COPh
Me 14 15%
BnO2C
Scheme 5. Microwave-assisted reaction of aziridine 7 and allenoate 3.
9. Benzyl 5-benzoyl-1-benzyl-4-methylene-2-phenylpyrrolidine-3-carboxylate 4.
A
suspension of aziridine 1 (100 mg, 0.32 mmol) and buta-2,3-dienoate 3 (84 mg,
0.48 mmol) in toluene (1 mL) was irradiated in the microwave reactor (CEM-
Focused 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 recrystallized from methanol. Pyrrolidine 4 was obtained as a
yellow solid in 73% yield. Mp 111.0–113.0 °C (methanol). IR (film) 3030, 1734,
the reaction of aziridine 7 with allene 3 in methanol was also
performed. However, we were unable to trap intermediate 10 since
at room temperature no reaction was observed and the reaction in
refluxing methanol gave only pyrrole 8a in 31% yield.
The microwave-induced reaction of aziridine 7 and allene 3
with the temperature set to 150 °C for 15 min afforded pyrrole
14 and dihydropyrrole 13 in 15% and 4% yield, respectively. There-
fore, under these reaction conditions only products resulting from
the 1,3-dipolar cycloaddition of the azomethine ylide generated
in situ from aziridine 7 could be isolated (Scheme 5).
In conclusion, the site-, regio-, and stereoselective synthesis of
4-methylenepyrrolidines was achieved via [3+2] cycloaddition of
allenoates with the azomethine ylide generated from cis-1-ben-
zyl-2-benzoyl-3-phenylaziridine.
This reaction proved to be more efficient under microwave irra-
diation than with conventional heating.
1680, 1218 and 1157 cmÀ1
;
1H NMR (CDCl3, 400 MHz) 3.58 (1H, d, J = 13.2 Hz),
3.84 (1H, d, J = 13.2 Hz), 4.18 (1H, d, J = 8.0 Hz), 4.41 (1H, d, J = 12.4 Hz), 4.78
(1H, d, J = 12.4 Hz), 4.99 (1H, br s), 5.15 (1H, br s), 5.17 (1H, d, J = 8.0 Hz), 5.35
(1H, s), 7.02 (2H, br s, Ar–H), 7.18 (5H, br s, Ar-H), 7.28–7.36 (8H, m, Ar–H),
7.46–7.58 (5H, m, Ar–H); 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; LC–MS (ESI) m/z 488 (MH+, 57%), 470 (35),
396 (100) and 380 (73). HRMS (ESI) m/z 488.22202 (C33H30NO3 [MH+],
488.21810).
10. Lopes, S. M. M.; Beja, A. M.; Silva, M. R.; Paixão, J. A.; Palacios, F.; Pinho e Melo,
T. M. V. D. Synthesis 2009, 2403–2407.
11. Aziridine 7 (mp 100–102 °C; lit. 101–102 °C) was prepared as described in
Southwick, P. L.; Christman, D. R. J. Am. Chem. Soc. 1952, 74, 1886–1891.
12. Benzyl 1-cyclohexyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylate 8a. A solution
of aziridine 7 (80 mg, 0.26 mmol) and buta-2,3-dienoate 3 (54 mg, 0.31 mmol)
in toluene (5 mL) was heated at reflux for 1.5 h. The solvent was removed
under reduced pressure and the crude product was purified by preparative thin
layer chromatography [ethyl acetate/hexane (1:10)]. Pyrrole 8a was obtained
The conventional thermolysis of cis- and trans-2-benzoyl-1-
cyclohexyl-3-phenylaziridines in the presence of buta-2,3-dieno-
ates allows us to report, for the first time, formal [3+2]
cycloadditions of allenes and aziridine via C–N bond cleavage lead-
ing to functionalized pyrroles.
as a yellow oil in 51.5% yield. IR (film) 2932, 1696, 1411, 1272 and 1155 cmÀ1
;
1H NMR (CDCl3, 400 MHz) 1.21–2.01 (10H, m), 2.55 (3H, s), 3.88 (1H, t,
J = 12.0 Hz), 5.14 (2H, br s), 6.61 (1H, s), 7.06 (2H, br s, Ar–H), 7.22–7.32 (8H, m,
Ar–H); 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; GC-
MS (EI) m/z 373 (M+, 72%), 283 (25), 282 (100), 200 (55) and 91 (21). HRMS
(ESI) m/z 374.21146 (C25H28NO2 [MH+], 374.20753).
Acknowledgments
13. Kluger, R. Pure Appl. Chem. 1997, 69, 1957–1967.
14. (a) Amal Raj, A.; Raghunathan, R. Tetrahedron 2003, 59, 2907–2911; (b) Boruah,
A.; Baruah, B.; Prajapati, D.; Sandhu, J. S.; Ghosh, A. Tetrahedron Lett. 1996, 37,
4203–4204; (c) Padwa, A.; Hamilton, L. Tetrahedron Lett. 1965, 48, 4363–4367.
15. (a) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297–14316; (b) Dalili, S.;
Yudin, A. K. Org. Lett. 2005, 7, 1161–1164; (c) Zhu, W.; Cai, G.; Ma, D. Org. Lett.
2005, 7, 5545–5548.
Thanks are due to FCT (Project PTDC/QUI/64470/2006) and FED-
ER 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.