Solvent-free thermal and microwave-assisted [3 + 2] cycloadditions between stabilized azomethine ylides and nitrostyrenes. An experimental and theoretical study

Article abstract of DOI:10.1021/jo062672z

(Chemical Equation Presented)The stereochemical outcomes observed in the thermal and microwave-assisted [3 + 2] cycloaddition between stabilized azomethine ylides and nitrostyrenes have been analyzed using experimental and computational approaches. It has

Full text of DOI:10.1021/jo062672z

Solvent-Free Thermal and Microwave-Assisted [3 + 2]
Cycloadditions between Stabilized Azomethine Ylides and
Nitrostyrenes. An Experimental and Theoretical Study
†
†
†
,†
,‡
Ana Arrieta, Dorleta Otaegui, Aizpea Zubia, Fernando P. Coss ´ı o,* Angel D ´ı az-Ortiz,*
‡
‡
‡
§
Antonio de la Hoz, M. Antonia Herrero, Pilar Prieto, Concepci o´ n Foces-Foces,
¶
¶
Jos e´ L. Pizarro, and Mar ´ı a I. Arriortua
Kimika Organikoa I. Saila, Kimika Fakultatea, UniVersidad del Pa ´ı s Vasco-Euskal Herriko Unibertsitatea,
P.K. 1071, 20080 San Sebasti a´ n-Donostia, Spain, Facultad de Qu ´ı mica, UniVersidad de Castilla-La
Mancha, E-13071 Ciudad Real, Spain, Dpto. Cristalograf ´ı a, Instituto de Qu ´ı mica-F ´ı sica ‘Rocasolano’,
CSIC, Serrano 119, E-28006 Madrid, Spain, and Mineralogia eta Petrologia Saila, Zientzia eta Teknologia
Fakultatea, UniVersidad del Pa ´ı s Vasco-Euskal Herriko Unibertsitatea, P.K. 644 Bilbao, Spain
fp.cossio@ehu.es
ReceiVed December 29, 2006
The stereochemical outcomes observed in the thermal and microwave-assisted [3 + 2] cycloaddition
between stabilized azomethine ylides and nitrostyrenes have been analyzed using experimental and
computational approaches. It has been observed that, in the absence of solvent, three stereoisomers are
formed, both under classical heating conditions and under microwave irradiation. This result contrasts
with that observed in solution under classical thermal conditions. The 4-nitropyrrolidines obtained in
this way can be aromatized under further microwave irradiation to yield mixtures of pyrroles and
4-nitropyrroles. It is found that ground state cycloadditions between imines and nitrostyrenes take place
by three-step mechanisms. The first step involves enolization of the starting imine, and this is followed
by a pseudopericyclic 10-electron [1.4]-hydrogen shift. Finally, the cycloaddition takes place by a relatively
asynchronous aromatic six-electron supra-supra thermal mechanism.
Introduction
consequence of the heating rate, a phenomenon that cannot be
easily reproduced by classical heating. As a result, higher yields,
milder reaction conditions, and shorter reaction times can often
be achieved. Under microwave irradiation, superheating to
temperatures above the conventional boiling point of a solvent
Microwave radiation is an alternative to conventional heating
for the introduction of energy into reactions and has clear
1
benefits in many chemical transformations, including cycload-
2
ditions. Microwave-assisted organic synthesis is known for the
3
can be produced, and decreases in reaction time are not
spectacular accelerations produced in many reactions as a
surprising. Consequently, interest in microwave irradiation as
a technique in organic chemistry has increased considerably in
recent years.
†
Kimika Fakultatea, Universidad del Pa ´ı s Vasco-Euskal Herriko
Unibertsitatea.
‡
Universidad de Castilla-La Mancha.
CSIC.
Zientzia eta Teknologia Fakultatea, Universidad del Pa ´ı s Vasco-Euskal
1
,3-Dipolar cycloadditions represent one of the most versatile
§
4
¶
tools for the construction of five-membered heterocycles.
Herriko Unibertsitatea.
Imines derived from R-aminoesters can be isomerized to
1
0.1021/jo062672z CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/17/2007
J. Org. Chem. 2007, 72, 4313-4322
4313

Arrieta et al.
5
SCHEME 1a
azomethine ylides that undergo 1,3-dipolar cycloadditions with
6
dipolarophiles to afford pyrrolidine derivatives. The effective
and eco-friendly microwave methodology to generate azome-
thine ylides from R-aminoester imines avoids harsh reaction
7
conditions and the use of silver or lithium salts. On classical
heating in the absence of a Lewis acid catalyst, these cycload-
ditions can require long reaction times (24 h) and high
temperatures (toluene reflux) to afford moderate yields (ca.
4
5%).8
9
The importance of substituted prolines in the design of new
1
0
11
catalysts or in the chemical synthesis of pharmacologically
12
or biologically interesting molecules is widely recognized. The
3 + 2] reaction of azomethine ylides and alkenes is one of the
[
most useful methods for the preparation of these molecules in
a convergent manner.13
Attention has recently been directed toward pyrrole-2-
carboxylates as lead structures for the development of effective
(1) (a) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Math e´ , D.
Synthesis 1998, 1213. (b) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225. (c) Varma, R. S. Green Chem. 1999, 1, 43.
(
d) Strauss, C. R. Aust. J. Chem. 1999, 52, 83. (e) MicrowaVes in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2002. (f)
Majetich, G.; Wheless, K. MicrowaVe-Enhanced Chemistry. Fundamentals,
Sample Preparations and Applications; Kingston, H. M. S., Haswell, S. J.,
Eds.; American Chemical Society: Washington, DC, 1997; Chapter 8. (g)
N u¨ tcher, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004,
a
Reagents and conditions: (i) microwaves, 210-270 W, 110-120 °C;
(ii) classical heating, 120 °C; all pyrrolidines are racemic mixtures.
6
, 128. (h) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (i) Hayes,
anticonvulsants,14 but these compounds have long been impor-
B. L.; MicrowaVe Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002. (j) MicrowaVe-Assisted Organic Synthesis;
Lidstr o¨ m, P., Tierney, J. P., Eds.; Blackwell Scientific: Oxford, 2005. (k)
Kappe, C. O.; Stadler, A. In MicrowaVes in Organic and Medicinal
Chemistry. Methods and Principles in Medicinal Chemistry; Mannhold, R.,
Kubinyi, H., Folkers, G., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
Vol. 25. (l) de la Hoz, A.; D ´ı az-Ortiz, A.; Moreno, A. Chem. Soc. ReV.
1
5
tant as analgesics and anti-inflammatory agents. Likewise,
some pyrrole-2-carboxylates bearing a substituted phenyl group
16
have found potential applications as glycine antagonists or as
1
7
anti-HIV-1 agents (Delavirdine analogues).
Recently, we reported a preliminary combinatorial chemistry
application of the 1,3-dipolar cycloaddition between imines
derived from R-aminoesters and nitroalkenes under focused
2
005, 34, 164.
2) de la Hoz, A.; D ´ı az-Ortiz, A.; Moreno, A.; Langa, F. Eur. J. Org.
Chem. 2000, 3659.
3) (a) Barghust, D. R.; Mingos, D. M. P. J. Chem. Soc., Chem. Commun.
992, 674. (b) Zhang, X.; Hayward, D. O.; Mingos, D. M. P. J. Chem.
(
18
(
microwaves in the absence of solvent. We wish to report here
a complete study of this reaction. Likewise, we have developed
an efficient process for the aromatization of these pyrrolidines
to give highly substituted pyrroles of potential interest.
1
Soc., Chem. Commun. 1999, 975. (c) Chemad, F.; Esveld, E. Chem. Eng.
Technol. 2001, 24, 735.
(
4) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984; Vols. 1, 2.
5) (a) Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1978, 109.
b) Grigg, R.; Kemp, J. Tetrahedron Lett. 1980, 21, 2461.
(
Results and Discussion
(
(
6) (a) Tsuge, O.; Kanemasa, S. Recent AdVances in Azomethine Ylide
Experimental Studies. In the absence of solvent, microwave
irradiation induces the thermal isomerization of imines 1a-d
to the corresponding azomethine ylides. The subsequent 1,3-
dipolar cycloadditions with substituted â-nitrostyrenes 2a-c,
which occur within 10-15 min, afford the corresponding
pyrrolidines 3 in 81-87% yield (Scheme 1). Three stereoiso-
mers, namely, endo-3, exo-3, and endo′-3, were obtained in each
cycloaddition. The reaction conditions, yields, and stereoisomer
ratios are summarized in Table 1. Reactions were performed in
open vessels at atmospheric pressure in monomode microwave
Chemistry: AdVances in Heterocyclic Chemistry; Katritzky, A. R., Ed.;
Academic Press: San Diego, CA, 1989; Vol. 45, pp 231-349. (b) Grigg,
R. Chem. Soc. ReV. 1987, 16, 89.
(7) Enders, D.; Meyer, I.; Runsink, J.; Raabe, G. Tetrahedron 1998, 54,
1
0733.
8) Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden,
A.; Coss ´ı o, F. P. J. Am. Chem. Soc. 2000, 122, 6078.
9) (a) Pichon, M.; Figad e` re, B. Tetrahedron: Asymmetry 1996, 7, 927.
b) Sharma, R.; Lubell, W. D. J. Org. Chem. 1996, 61, 202. (c) Collado, I.;
(
(
(
Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60, 5011. (d) Mulzen, J.;
Meier, A.; Buschmann, J.; Luger, P. Synthesis 1996, 123.
(10) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publish-
ers: New York, 1993. (b) Nojori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994. (c) Doyle, M. P. Aldrichimica Acta
1
996, 29, 3.
11) See for example: (a) Waid, P. P.; Flynn, G. A.; Huber, E. W.; Sabol,
(14) Liebscher, J.; Knoll, A.; Rolfs, A.; Ushmajew, A.; Lohmann, D.;
Faust, G.; Morgenstern, E.; Scharfenberg, P. EP-OS 0431 371 (12 June
1991); Chemical Abstracts 1991, 115, 92063s.
(15) (a) Doherty, J. B.; Chang, M. N.; Dorn, C. P. EP-OS 72 013 (16
February 1983); Chemical Abstracts 1983, 99, 22311y. (b) Massaroli, G.
G. DE 3415 321 (13 May 1985); Chemical Abstracts 1986, 104, 19507h.
(16) Balsamini, C.; Bedini, A.; Diamantini, G.; Spadoni, G.; Tontini,
A.; Tarzia, G.; Di Fabio, R.; Feriani, A.; Reggiani, A.; Tedesco, G.; Valigi,
R. J. Med. Chem. 1998, 41, 808.
(
J. S. Tetrahedron Lett. 1996, 37, 4091. (b) Khav, V. V.; Martinelli, M. J.
Tetrahedron Lett. 1996, 37, 4323. (c) Koloziej, S. A.; Nikiforovich, G. V.;
Skeean, R.; Lignon, M.-F.; Martinez, J.; Marshall, G. R. J. Med. Chem.
1
995, 38, 137.
12) See for example: (a) Fishwick, C. W. G.; Foster, R. J.; Carr, R. E.
(
Tetrahedron Lett. 1996, 37, 3915. (b) Bianco, A.; Maggini, M.; Scorrano,
G.; Toniolo, C.; Marconi, G.; Villani, C.; Prato, M. J. Am. Chem. Soc.
1
3
3
996, 118, 4072. (c) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991,
0, 1278. (d) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
2, 1244.
(17) Pinna, G. A.; Loriga, G.; Murineddu, G.; Grella, G.; Mura, M.;
Vargiu, L.; Murgioni, Ch.; La Colla, P. Chem. Pharm. Bull. 2001, 49, 1406.
(18) D ´ı az-Ortiz, A.; de la Hoz, A.; Herrero, M. A.; Prieto, P.; S a´ nchez-
Migall o´ n, A.; Coss ´ı o, F. P.; Arrieta, A.; Vivanco, S.; Foces-Foces, C. Mol.
DiVersity 2003, 7, 175.
(13) (a) Huisgen, R. Angew. Chem. 1983, 2, 565. (b) Huisgen, R. J. Org.
Chem. 1976, 41, 403.
4314 J. Org. Chem., Vol. 72, No. 12, 2007

Thermal and MicrowaVe-Assisted [3 + 2] Cycloadditions
TABLE 1. Cycloaddition Reactions between Imines 1a-d and
â-Nitrostyrenes 2a-c under Microwave Irradiation in the Absence
of Solvent
SCHEME 2. Selected Examples of Synthesis of Pyrrolidines
with Substituents at C-2 and C-5 in a trans Relationship
reaction conditions yielda stereoisomer ratiob
reactants products
power/temp/time
210 W/120 °C/10 min 87
-/120 °C/10 min 79
210 W/120 °C/10 min 86
210 W/110 °C/10 min 84
270 W/120 °C/15 min 84
240 W/120 °C/13 min 82
270 W/120 °C/10 min 81
(%) endo-3/exo-3/endo′-3
1a + 2a
1a + 2a
1b + 2b
1c + 2b
1d + 2b
1b + 2c
1c + 2c
3a
3a
3b
3c
3d
3e
3f
38/43/19
33/44/23
33/44/23
31/45/24
39/41/20
31/49/20
37/42/21
a
Combined yield of isolated cycloadducts. b Determined by H NMR
1
spectroscopy.
Our results indicate that both profiles are similar, within the
experimental error. The formation of diastereoisomers endo′-3
is quite surprising, although pyrrolidines having a trans-
relationship between the substituents at C-2 and C-5 are
1
9-21
known
(Scheme 2). However, in these cases, the nitrogen
atoms of the corresponding azomethine ylides have bulky
19
substituents or are conformationally restricted by the presence
20,21
of cyclic chiral structures,
whereas in the present case, only
NH-azomethine ylides are present.
The stereochemistry of adducts endo-3 and exo-3 was easily
deduced by comparison with the products obtained by classical
heating. The stereochemistry of cycloadducts endo′-3 could only
be inferred by X-ray crystallography of derivatives 5 and 7 (see
the Supporting Information) obtained from inseparable mixtures
2
2
of exo-3a,b and endo′-3a,b (Scheme 3).
With cycloadducts 3 in hand, we decided to explore their
aromatization to the corresponding 1H-pyrroles under micro-
wave irradiation.
In recent years, 5-arylpyrrole-2-carboxylates have been
prepared in moderate to good yields from their corresponding
pyrrolidines by treatment with chloranil in refluxing xylene for
FIGURE 1. A [3 + 2] cycloaddition reaction between 1a and 2a:
2
3
24
(
A) microwave irradiation, 210 W, 10 min; (B) classical heating, 10
2-36 h or DBU in hot DMF for 1 h.
min.
After several attempts, we found that pyrrolidines 3 can be
aromatized to the corresponding 3,5-diaryl-1H-pyrrole-2-car-
boxylates 8 and 9 under microwave irradiation by oxidation
with DDQ in refluxing xylene for 45 min (Scheme 4 and Table
reactors with total control of power and temperature by means
of an infrared sensor. Conditions were optimized until complete
disappearance of the imine was achieved.
2). This procedure represents a simple and fast method to obtain
In the absence of any catalyst and using classical heating with
an oil bath, these cycloadditions require refluxing toluene for
excellent yields of a wide range of pyrrole-2-carboxylates with
different substitution patterns by using microwave irradiation.
2
4 h to afford yields below 50%. Moreover, under these
8
conditions, only stereoisomers endo-3 and exo-3 were obtained.
However, when the reaction between imine 1a and nitrostyrene
(19) (a) Harwood, L. M.; Macro, J.; Watkin, D.; Williams, C. E; Wong,
L. F. Tetrahedron: Asymmetry 1992, 3, 1127. (b) Alker, D.; Hamblett, G.;
Harwood, L. M.; Robertson, S. M.; Watkin, D. J.; Williams, C. E.
Tetrahedron 1998, 54, 6089.
2
a was repeated under classical heating, but in the absence of
solvent, the presence of endo′-3a was also observed in the crude
reaction mixture.
In order to determine both the efficiency of the [3 + 2]
cycloaddition reaction between 1a and 2a as well as the
stereoselectivity of the reaction at different temperatures, the
(20) Peyronel, J. F.; Grisoni, S.; Carboni, B.; Courgeon, T.; Carri e´ , R.;
Tetrahedron Lett. 1994, 50, 189.
(
21) Grigg, R.; Sridharan, V. AdV. Cycloaddit. 1993, 3, 161.
(22) Beauseleil, E.; Lubell, W. D. J. Am. Chem. Soc. 1996, 118, 12902.
(23) (a) Sammes, M. P.; Chung, M. W. L.; Katritzky, A. R. J. Chem.
Soc., Perkin Trans. 1 1985, 1773. (b) Lakhlifi, T.; Sedqui, A.; Fathi, T.;
Laude, B.; Robert, J. F. Can. J. Chem. 1994, 72, 1417.
1
a + 2a f 3a transformation was studied under both classical
(
24) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. Synlett 1998, 731.
b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans.
1 2001, 2874.
heating and microwave irradiation at different temperatures
during 10 min. The results obtained are reported in Figure 1.
(
J. Org. Chem, Vol. 72, No. 12, 2007 4315

Arrieta et al.
SCHEME 3. Acetylation and Carbamoylation Reactions of
the Inseparable Mixtures of Stereoisomers exo-3a,b and
endo′-3a,ba
SCHEME 4. Aromatization Reactions of Pyrrolidines 3
with DDQ under Microwave Irradiationa
a
Reagents and conditions: (i) DDQ, xylene, microwaves.
a
28
Reagents and conditions: (i) 3a, OCN-C6H4-4Cl, MeCN, rt; (ii) 3b,
as implemented in the GAUSSIAN 03 suite of programs, was
TFA, Ac2O, rt.
29
used in all cases. Houk et al. have shown that the B3LYP/6-
3
1G* level is a convenient method for the computational study
TABLE 2. Aromatization of Pyrrolidines 3 with DDQ in Refluxing
Xylene under Microwave Irradiation
of pericyclic reactions in terms of computational cost and
accuracy.
products
The synchronicity30 of the reactions was calculated using a
a
substrates
[yield (%)]
31
previously described approach. For a given concerted reaction,
endo-3a + exo-3a + endo′-3a
endo-3b + exo-3b + endo′-3b
endo-3c + exo-3c + endo′-3c
endo-3d + exo-3d + endo′-3d
endo-3e + exo-3e + endo′-3e
endo-3f + exo-3f + endo′-3f
8a (89)
“
synchronicity” (Sy) is quantified as
8b (68) + 9b (15)
8c (74) + 9c (14)
8d (35)
8e (82) + 9e (12)
8f (71)
n
|δB - δB |
i
av
-1
Sy ) 1 - (2n - 2)
(1)
∑
i)1
δBav
a
Isolated yields of pure products.
where n is the number of bonds directly involved in the reaction
and δBi is the relative variation of the bond index Bi at the
When these transformations were carried out under the same
reaction conditions, but with classical heating, at least 90 min
was required to obtain similar yields and product distributions.
Aromatization of pure endo-3b, exo-3b, or a mixture of
stereoisomers exo-3b and endo′-3b gave similar results (products
and yields) in each case. It appears that, under these conditions,
the elimination processes are not sensitive to the relative
stereochemistries of the leaving groups. For this reason, all of
the aromatizations were performed using the mixture of stere-
oisomers obtained in the cycloaddition. In some cases, 1H-
pyrroles 8b, 8c, and 8e were obtained along with a minor
amount of the 4-nitropyrrole. However, with pyrrolidines 3a,
(26) (a) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100,
12974. (b) Becke, A. D. J. Chem. Soc. 1993, 98, 5648. (c) Becke, A. D.
Phys. ReV. A 1988, 38, 3098.
(27) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986; pp 76-87 and
references therein.
(28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
3
d, and 3f, aromatization took place with complete loss of the
nitro group.
Computational Studies. All of the calculations reported
in this paper were performed within Density Functional
2
5
Theory, using the hybrid three-parameter functional com-
26
27
monly denoted as B3LYP. The standard 6-31G* basis set,
0
3, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(29) Guner, V.; Khuong, K. S.; Leach, A. G.; Lee, P. S.; Bartberger, M.
(
25) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
Molecules; Oxford: New York, 1989.
D.; Houk, K. N. J. Phys. Chem. A 2003, 107, 11445.
4316 J. Org. Chem., Vol. 72, No. 12, 2007

Thermal and MicrowaVe-Assisted [3 + 2] Cycloadditions
a
SCHEME 5. Reactants, Intermediates, Cycloadducts, and
Reaction Profiles Included in the Computational Studiesa
TABLE 3. Bond Indices for Reactants, Intermediates, Transition
Structures, and Products Indicated in Scheme 5
structure B1,2
B2,3
B3,4
B4,5
B5,1
B2,6
B6,7
B7,8
B1,8
1
2
a
a
1.03 0.00 0.00 0.00 1.83 0.97 1.74 0.00 0.00
0.00 0.00 1.76 0.00 0.00 0.00 0.00 0.00 0.00
endo-3a 0.98 0.97 0.97 0.95 0.98 0.94 1.75 0.00 0.81
exo-3a 0.99 0.96 0.96 0.94 0.98 0.96 1.76 0.00 0.80
endo′-3a 0.99 0.94 0.98 0.94 0.99 0.96 1.72 0.02 0.79
exo′-3a
1.00 0.96 0.96 0.95 0.97 0.95 1.75 0.01 0.79
1.17 0.00 0.00 0.00 1.66 1.54 1.06 0.66 0.05
1.23 0.00 0.00 0.00 1.39 1.19 1.57 0.03 0.72
1.21 0.00 0.00 0.00 1.37 1.20 1.59 0.00 0.77
1.18 0.00 0.00 0.00 1.54 1.36 1.26 0.35 0.37
0.92 0.00 0.00 0.00 1.68 1.31 1.55 0.01 0.75
1.15 0.39 1.39 0.18 1.35 1.07 1.67 0.02 0.73
1.14 0.41 1.37 0.17 1.36 1.07 1.66 0.02 0.74
1.11 0.45 1.34 0.14 1.37 1.06 1.66 0.00 0.90
1.13 0.41 1.39 0.18 1.34 1.05 1.69 0.00 0.77
1
1
1
0
1
2
TS1
TS2
TS3
TS4
TS5
TS6
a
Calculated at the B3LYP/6-31G(d) level.
SCHEME 6. Electronic Circulations and Orbital
Disconnections in the Pseudopericyclic Transformation of
Enol 10 into Azomethine Ylide 11
a
Reactants and observed products are depicted in blue and red,
respectively. Reaction intermediates and cycloadducts that are not observed
are represented in black.
transition structure (TS) relative to the reactant(s) (R) and
product (P), according to the following expression:
TS
R
Bi - Bi
δB )
(2)
i
P
i
R
i
B - B
The average value of δBi, denoted as δBav, in eq 2 is therefore
n
2
and 3, early and late transition structures will be characterized
-1
δB ) n
δBi
(3)
av
∑
by δBav < 0.5 and δBav > 0.5, respectively.
i)1
Donor-acceptor interactions were also computed using the
NBO method. The energies associated with these two-electron
interactions were computed by means of the second-order pertur-
Wiberg indices Bi were employed;32 these were evaluated
using the natural bond orbital (NBO) method.33 According to
eq 1, for a perfectly synchronous reaction, Sy ) 1 since for
any given bond index δBi ) δBav. Similarly, according to eqs
(2)
bation energy, ∆E , according to the following equation:
φφ*
2
〈
φ*| Fˆ |φ〉
(
2)
∆E
) -nφ ꢀ
(4)
φφ*
(
30) (a) Borden, W. T.; Loncharich, R. J.; Houk, K. N. Annu. ReV. Phys.
Chem. 1988, 39, 213. (b) Moyano, A.; Peric a` s, M. A.; Valent ´ı , E. J. Org.
Chem. 1989, 54, 573.
31) (a) Coss ´ı o, F. P.; Morao, I.; Jiao, H.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1999, 121, 6737. (b) Morao, I.; Lecea, B.; Coss ´ı o, F. P. J. Org. Chem.
997, 62, 7033. (c) Lecea, B.; Arrieta, A.; Roa, G.; Ugalde, J. M.; Coss ´ı o,
F. P. J. Am. Chem. Soc. 1994, 116, 9613. (d) Lecea, B.; Arrieta, A.; Lopez,
X.; Ugalde, J. M.; Coss ´ı o, F. P. J. Am. Chem. Soc. 1995, 117, 12314.
φ* - ꢀ
φ
where φ* and φ are the non-Lewis and Lewis localized orbitals,
Fˆ is the Fock operator, nφ is the occupation of the φ localized
orbital, and ꢀφ* and ꢀφ are the respective energies.
(
1
Nucleus-independent chemical shifts (NICS) as defined by
34
Schleyer were computed using the gauge invariant atomic
(
32) Wiberg, K. B. Tetrahedron 1968, 24, 1083.
(
33) (a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
8
8
99. (b) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
3, 735.
(34) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes,
N. J. R. v. E. J. Am. Chem. Soc. 1996, 118, 6317.
J. Org. Chem, Vol. 72, No. 12, 2007 4317

Arrieta et al.
FIGURE 2. Fully optimized structures [B3LYP/6-31G(d) level of theory] of the stationary points found in the thermal conversion of imine 1a to
azomethine ylides 11 and 12. Bond distances are given in Å. Dipole moments (µ) are reported in Debyes (D). The numbers on the arrows indicate
the relative energies, in kcal/mol, of the stationary points connected by the arrow [B3LYP/6-31G(d)+∆ZPVE level of theory]. Numbers in parentheses
are the relative energies between azomethines 11 and 12, in kcal/mol.
a
orbital35 (GIAO) approach at the GIAO-B3LYP/6-31G*//
B3LYP/6-31G* level.
TABLE 4. Activation Energies (∆Ea, kcal/mol), Reaction
a
a,b
Energies (∆Erxn, kcal/mol), Average Bond Index Changes (δBav),
Synchronicities (Sy), and Nucleus-Independent Chemical Shifts
(NICS, ppm/mol) Associated with the Formation of [3 + 2]
Cycloadducts Indicated in Scheme 5
a,c
d
All of the stationary points were characterized by harmonic
analysis.36 Activation energies (∆Ea) and reaction energies
(
∆Erxn) were computed at the B3LYP/6-31G* level including
NICS NICS
(TS) (3)
reaction
TSe ∆Ea ∆Erxn δBav Sy
zero-point vibrational energy (ZPVE) corrections.
8
In a previous investigation, we studied several model [3 +
1
1 + 2a f endo-3a TS3 5.0 -22.0 0.30 0.74 -16.76 -6.82
2
] cycloadditions involving stabilized azomethine ylides and
11 + 2a f exo-3a
TS4 4.1 -24.6 0.31 0.71 -13.70 -5.70
1
1
2 + 2a f endo′-3a TS5 3.8 -26.0 0.32 0.61 -14.01 -6.09
nitroethylene. It was found that the substitution pattern has a
strong influence on the reaction profiles, and for this reason,
we decided to compute the structures shown in Scheme 5, which
are the most important reactants, cycloadducts, and intermedi-
ates. These stationary points include all of the functional groups
and general substituents included in the experimental studies.
The corresponding Wiberg bond indices are collected in Table
2 + 2a f exo′-3a TS6 7.7 -31.0 0.29 0.66 -12.69 -5.86
a
Computed at the B3LYP/6-31G(d)+∆ZPVE level. b Computed at the
B3LYP/6-31G(d) level according to eqs 2 and 3 and using the bond indices
reported in Table 3. Computed at the B3LYP/6-31G(d) level according
c
to eq 1. d Computed [GIAO-B3LYP/6-31G(d) level of theory] at the ring
point of electron density of the corresponding transition structure or
cycloadduct 3. e Calculated NICS corresponding to transition structures and
cycloadducts are denoted as NICS (TS) and NICS (3), respectively. For
each structure, these NICS were calculated at the ring point of electron
density.
3
.
We studied the generation of azomethine ylides 11 and 12
first. As described previously, formation of these 1,3-dipoles
starts with the enolization of imine 1a to yield the intermediate
imino enol 10, which lies ca. 15 kcal/mol above 1a at the
B3LYP/6-31G(d) level (Figure 2). From this local minimum,
conversion to the azomethine ylide is readily accomplished
through a pseudopericyclic [1,5]-hydrogen shift, as can be seen
by the planar geometry of TS1 and the low activation energy
(35) Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112,
8
2
251.
(36) McIver, J. W., Jr.; Komornicki, A. J. Am. Chem. Soc. 1972, 94,
625.
4318 J. Org. Chem., Vol. 72, No. 12, 2007

Thermal and MicrowaVe-Assisted [3 + 2] Cycloadditions
the five-membered π-array of p AOs and the system formed
by the 1s AO of the migrating hydrogen atom and the lone pairs
of the nitrogen and oxygen atoms (Scheme 6).
We also calculated the synchronicity of this 10-electron
pseudopericyclic hydrogen shift by analyzing the variation of
the bond indices along the 10-TS1-11 sequence. As reported
in Table 3, the bond indices considered were B1,2, B2,6, B6,7,
B7,8, B1,8, and B1,5. According to eq 3, and considering that n )
6
from the data included in Table 3, the value δBav ) 0.41 is
obtained. This means that TS1 is an almost halfway, slightly
early transition structure. The computed synchronicity is 0.87,
which indicates that this pseudopericyclic reaction is quite
synchronous in spite of the large number of electrons and
different bonds and lone pairs involved.
A less stable stereoisomer 12 can be formed from azomethine
ylide 11 by rotation about the C2-C6 bond (Table 3). This
process is easier than the alternative rotation around the C5-
3
8
N1 bond since in 11 B1,5 > B2,6 (Table 3). The activation
energy associated with the formation of 12 from 11 is calculated
to be 24.6 kcal/mol higher than that corresponding to formation
of azomethine ylide 11 from enol 10 (Figure 2). In addition, 11
is calculated to be ca. 4 kcal/mol more stable than its
stereoisomer 12.
FIGURE 3. Formation of azomethine ylide 12 via bimolecular double
hydrogen transfer from imine 1a. Main geometric features of the
Azomethine ylide 12 can also be formed by a bimolecular
mechanism involving a double proton transfer from two
molecules of imine 1a. According to this alternative mechanism,
both protons are transferred in a very asynchronous manner,39
as it can be appreciated in Figure 3, in which the chief geometric
features of the corresponding transition structure TS2′ are
shown. The activation energy for this process is comparable,
although slightly higher, than that computed for the formation
corresponding transition structure TS2′ (B3LYP/6-31G* level). ∆E
is the activation energy for this process, calculated at the B3LYP/6-
1G(d)+∆ZPVE level. See caption of Figure 2 for additional details.
a
3
associated with the 10f11 transformation (Figure 2). The
pseudopericyclic nature of this reaction3 can be readily ap-
preciated considering the two orbital disconnections between
7
FIGURE 4. Main features of transition structures TS3-6. Numbers in parentheses are the relative energies with respect to TS3, calculated at the
B3LYP/6-31G(d)+∆ZPVE level. See caption of Figure 2 for additional details.
J. Org. Chem, Vol. 72, No. 12, 2007 4319

Arrieta et al.
FIGURE 5. Main features of cycloadducts endo-, exo-, endo′-, and exo′-3. Numbers in parentheses are the relative energies with respect to endo-3,
calculated at the B3LYP/6-31G(d)+∆ZPVE level. See caption of Figure 2 for additional details.
of 12 via TS2. It is likely that this bimolecular mechanism,
together with that associated with TS2, contributes to the
formation of an appreciable proportion of azomethine ylide 12
in the absence of solvent. As a consequence, formation of
cycloadduct(s) derived from 12 could be expected under solvent-
free conditions in spite of the large activation energy associated
with this process.
(37) Zhou, C.; Birney, D. M. J. Am. Chem. Soc. 2002, 124, 5231.
We proceeded to study the [3 + 2] cycloaddition reactions
of azomethine ylides 11 and 12 with nitrostyrene 2a to yield
the corresponding cycloadducts 3a. On the basis of our previous
results for this reaction and on our experimental results, only
the regioisomers reported in Scheme 5 were considered since
the reaction paths that lead to the four alternative regioisomers
are of much higher energy. The chief features of the four pos-
sible transition structures and cycloadducts are shown in Figures
(
38) The calculated transition structure associated with rotation around
C5-N1 collapses to that associated with the conrotatory electrocyclic
opening of the corresponding cis-aziridine 10, according to the following
reaction:
All our attempts to locate a genuine TS associated only with rotation about
C5-N1 failed. TS7 was computed to lie 5.7 kcal/mol above TS2 and 25.7
kcal/mol above TS1 at the B3LYP/6-31G(d)+∆ZPVE level. In this saddle
point, the phenyl and methoxycarbonyl groups are inward and outward,
respectively, with respect to the aziridine ring:
4
and 5, respectively. The activation and reaction energies, as
well as synchronicities and NICS, are shown in Table 4.
According to our results, all transition structures TS3-6
correspond to [π4s+π2s] mechanisms. However, the studied
reactions are quite asynchronous, with an average Sy value of
ca. 0.7 (Table 4). These values were obtained from eqs 1-3
and by considering bond indices B1,2, B2,3, B3,4, B4,5, and B5,1
(Table 3) with n ) 5. The activation energies associated with
these cycloadditions are lower than those corresponding to the
formation of the dipoles, thus confirming that this latter reaction
is the limiting step of the whole process, although the kinetic
treatment of the alternative reaction paths is quite complex.
Transformations involving dipole 11 are slightly more synchro-
nous than those involving dipole 12. Within each subset, the
most asynchronous transition structures are of lower energy than
the most synchronous ones.
The high energy associated with TS7, together with its relatively low
calculated polarity (µ ) 2.632 D), indicates that this TS is not associated
with the stereochemical outcome of the reaction. For the stereochemistry
of conrotatory electrocyclizations, see: Niwayama, S.; Kallel, E. A.;
Spellmeyer, D. C.; Sheu, C.; Houk, K. N. J. Org. Chem. 1996, 61, 2813.
(39) The connection between TS2′ and reactants (2 × 1a) and products
(
2 × 12) was verified by IRC computations.
4320 J. Org. Chem., Vol. 72, No. 12, 2007

Thermal and MicrowaVe-Assisted [3 + 2] Cycloadditions
(3, +1) ring point and the i atom, Zi is the corresponding atomic
number (therefore, ZC ) 6 and ZN ) 7 for carbon and nitrogen
atoms, respectively), and a0 is the Bohr radius. The diamagnetic
d
max
at the (3, +1) ring point40 induced by this in-
shielding σ
plane ring current is
2
e µ
d
max
0
-1
av
σ
) -
R
(6)
8
πme
where me and e are the mass and charge of the electron and µ0
is the permeability of vacuum.
d
max
We computed the Rav and σ
values for TS3-6, and the
results are shown in Figure 6. According to these results, the
d
max
computed σ
values are quite close to the previously ob-
tained NICS values (Table 4). This result indicates that the
aromatic character of these asynchronous [π4s+π2s] transition
structures can be almost completely described in terms of
diamagnetic ring currents. Therefore, it can be concluded that
transition states associated with thermal 1,3-dipolar reactions
between azomethine ylides and nitroalkenes exhibit in-plane
aromaticity.
The experimentally observed cycloadduct ratios follow the
relative energies of transition structures TS3-6 and not those
calculated for cycloadducts endo-, exo-, endo′-, and exo′-3
(Figures 4 and 5). Therefore, we conclude that this reaction takes
place under kinetic control, a result compatible with the
exothermicity of the cycloaddition reaction (Table 4). The
energy order found for the transition structures is TS4 < TS3
<
TS5 < TS6, and this is consistent with the exo-3a/endo-3a/
endo′-3a ratios obtained under classical heating and microwave
irradiation. The lower energies of saddle points TS4 and TS3
can be rationalized in terms of steric repulsion and secondary
orbital interactions between the different substituents. Thus, in
TS3, the nitro group has stabilizing two-electron interactions
with the N1-H moiety [∆E(2) ) -0.35 kcal/mol] and with
the phenyl group at C5 [∆E(2) ) -0.75 kcal/mol] since both
moieties are in a cis disposition with respect to the nitro group.
In the case of TS4, the main secondary orbital interactions take
place between the phenyl group at C3 and the carbonyl group,
which are cis with respect to one another, with ∆E(2) ) -0.98
kcal/mol. However, the latter saddle point is earlier than TS3
FIGURE 6. (A) Schematic definition of an in-plane ring current for
transition structures TS3-6. The ring current of radius Rav is shown
by a dashed line. The (3, +1) ring point of electron density and the
radii R
i
are shown in red and black, respectively. Bonds being formed
and participating p AOs are represented in green and blue, respectively.
d
(
B) R
i
, Rav (in Å), and σ
(in ppm/mol) values for transition
max
structures TS3-6.
Our calculations also indicate that saddle points TS3-6 are
(Table 3), and therefore, the destabilizing four-electron interac-
aromatic.3
1a,40,41
Thus, all of these transition structures have large
tions are less important. The final result of this situation is a
lower energy for TS4, which is in good agreement with the
experimental observations. Saddle point TS5 benefits from both
interactions present in TS3 and TS4 since in this case the nitro
group is cis with respect to the N1-H group and the phenyl
group at C5, whereas the phenyl group at C3 is also cis with
respect to the carbonyl group. Therefore, the combined ∆E(2)
terms yield a value of -2.03 kcal/mol. However, the repulsive
four-electron interactions are larger than those in the preceding
cases because this latter saddle point is later than TS3 and TS4
(Table 4). The result is a relative destabilization of TS5 with
respect to TS3 and TS4.
negative NICS values (Table 4), calculated at the (3, +1) ring
points of electron density.3
1a,40,41
In contrast, cycloadducts 3a
have only slightly negative NICS values, probably because of
local diamagnetic effects.
In previous studies,3
1a,41
we reported that transition structures
corresponding to aromatic thermally allowed cycloadditions can
be described by a diamagnetic ring current of radius Rav
according to the following expression:
n
4
-1
Rav ) n
Ri - a0
(5)
∑
(
)
i)1
Z
i
In summary, the stereochemical outcome of this reaction is
the result of a delicate balance between stabilizing and
destabilizing interactions. In addition, as we have previously
mentioned, formation of the endo′-3a cycloadduct can be related
to the bimolecular formation of the more polar azomethine ylide
12, which is the limiting step of the whole reaction.
where n is the number of atoms involved in the electronic
circulation (in our case n ) 5), Ri is the distance between the
(
40) Bader, R. F. W. Atoms in Molecules: A Quantum Theory; Clarendon
Press: Oxford, 1990; pp 13-52.
41) Morao, I.; Coss ´ı o, F. P. J. Org. Chem. 1999, 64, 1868.
(
J. Org. Chem, Vol. 72, No. 12, 2007 4321

Arrieta et al.
Conclusions
into a solid derivative by means of reaction with 4-chloriphenyl
isocyanate (0.47 g, 3 mmol) in CH
temperature and under argon atmosphere. Then CH
was added, and the resulting mixture was filtered through a Celite
pad. The filtrate was washed with saturated aqueous NH Cl solution
(2 × 10 mL) and water (4 × 10 mL). The organic extract was
dried with Na SO , and the organic solvent was evaporated under
reduced pressure. The resulting residue was triturated in Et O (yield
9%), and the isomers were separated by preparative TLC.
3
CN (30 mL) overnight at room
Microwave irradiation induces the 1,3-dipolar cycloaddition
of imines derived from R-aminoesters with â-nitrostyrenes in
the absence of solvent within 10-15 min. The reaction proceeds
to give yields in the range of 81-87%, and three isomeric
pyrrolidines are obtained in the cycloaddition. The stereochem-
ical outcome of the reaction is similar under microwave
irradiation and thermal heating in the absence of solvent.
Thermal cycloadditions between imines and nitrostyrenes take
place by three-step mechanisms. The first step involves eno-
lization of the starting imine, and this is followed by a
pseudopericyclic 10-electron [1.4]-hydrogen shift. Finally, the
cycloaddition takes place by a relatively asynchronous aromatic
six-electron supra-supra thermal mechanism. Formation of a
third stereoisomer is observed in the absence of solvent. It is
proposed that formation of this stereoisomer involves an
azomethine ylide resulting from isomerization of the previous
one or from a double highly asynchronous proton transfer
between two starting imine molecules.
2
2
Cl (30 mL)
4
2
4
2
7
Data for (2S*,3S*,4R*,5S*)-1-(4-Chlorophenylcarbamoyl)-
,5-diphenyl-2-methoxycarbonyl-4-nitropyrrolidine, 4: white
3
solid, mp 229-231 °C; IR 3407, 1748, 1648, 1532, 1341, 1030
-1
1
cm ; H NMR (δ ppm, CDCl ) 3.37 (s, 3H), 4.46 (dd, 1H, J )
3
1
2.0 Hz, J′ ) 9.5 Hz), 5.22 (d, 1H, J ) 9.5 Hz), 5.32 (d, 1H, J )
8.6 Hz), 5.79 (dd, 1H, J ) 12.0 Hz, J′ ) 8.6 Hz), 5.97 (s , 1H),
b
6.82 (d, 2H, J ) 8.8 Hz), 7.13 (d, 2H, J ) 8.8 Hz), 7.24-7.31 (m,
2H), 7.32-7.39 (m, 3H), 7.53-7.60 (m, 3H), 7.89 (d
b
, 2H, J )
) 49.7, 52.1, 63.9, 65.8, 92.9,
20.7, 127.5, 127.7, 128.6, 128.8, 128.9, 129.0, 130.3, 130.7, 130.8,
36.1, 136.3, 152.8, 171.4. Anal. Calcd for C25 Cl: C,
5
1
1
6
.7 Hz); 13C NMR (δ ppm, CDCl
3
22 5 3
H O N
2.57; H, 4.62; N, 8.76. Found: C, 62.57; H, 4.56; N, 8.80.
Data for (2R*,3R*,4S*,5S*)-1-(4-Chlorophenylcarbamoyl)-
,5-diphenyl-2-methoxycarbonyl-4-nitropyrrolidine, 5: white
3
Experimental Section
solid, mp 112-113 °C; IR 3427, 1723, 1673, 1557, 1331, 1095
-
1 1
Imines 1a-d and nitrostyrenes 2a-c were prepared as previously
reported.8 Cycloadducts endo-3a-c and exo-3a-c are also known
compounds. Characterization of these pyrrolidines was performed
by comparison of the physical and spectroscopic properties with
the published ones.8
cm ; H NMR (δ ppm, CDCl ) 3.40 (s, 3H), 4.60 (dd, 1H, J )
3
,42
12.3 Hz, J′ ) 8.69 Hz), 5.00 (d, 1H, J ) 8.7 Hz), 5.76 (d, 1H, J
) 9.31 Hz), 5.99 (s , 1H), 6.23 (dd, 1H, J ) 12.3 Hz, J′ ) 9.4
b
Hz), 6.97 (d, 2H, J ) 8.8 Hz), 7.13 (d, 2H, J ) 8.8 Hz), 7.24-
,42
13
7.28 (m, 2H), 7.32-7.38 (m, 3H), 7.46-7.52 (m, 5H); C NMR
Cycloaddition of Imine 1a with â-Nitrostyrene (2a). A mixture
of methyl N-benzylidene glycinate (1a) (354 mg, 2 mmol) and
â-nitrostyrene (2a) (298 mg, 2 mmol) was irradiated in a focused
microwave reactor (Prolabo MX350), modified to achieve the
measurement and control of power and temperature by infrared
detection, at 210 W for 10 min (final temperature 120 °C) to give
a mixture of three stereoisomers endo-3a, exo-3a, and endo′-3a
3
(δ ppm, CDCl ) 45.8, 52.2, 62.4, 63.8, 87.5, 120.8, 127.5, 127.5,
128.8, 129.0, 129.8, 130.6, 131.4, 133.9, 136.2, 153.1, 171.7. Anal.
Calcd for C25 Cl: C, 62.57; H, 4.62; N, 8.76. Found: C,
62.46; H, 4.61; N, 8.9.
22 5 3
H O N
Aromatization of endo-3a, exo-3a, and endo′-3a. A mixture
of endo-3a, exo-3a, and endo′-3a (653 mg, 2 mmol) and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (681 mg, 3 mmol)
in xylene (20 mL) was irradiated in a focused microwave reactor
(Prolabo MX350), modified to achieve the measurement and control
of power and temperature by infrared detection, at 255 W for 45
min (max temperature 140 °C). After cooling, the resulting brown
solution was concentrated in vacuo. The products were purified
and separated by column chromatography on silica gel using
hexane/ethyl acetate as the eluent to yield pyrrole 8a (494 mg, 89%).
Data for 2-Methoxycarbonyl-3,5-diphenyl-NH-pyrrole, 8a:
(568 mg, 87%, stereoisomer ratios 38/43/19). The crude product
was purified by silica gel flash column chromatography using
hexane/ethyl acetate as the eluent. Three fractions containing
stereoisomers endo-3a, exo-3a, and an inseparable mixture of exo-
3a and endo′-3a were isolated.
Data for (2S*,3R*,4S*,5S*)-3,5-Diphenyl-2-methoxycarbonyl-
-nitropyrrolidine, endo-3a: yellow solid, mp 120-122 °C; IR
4
3
1
-
1 1
3 b
314, 1735, 1545, 1370 cm ; H NMR (δ ppm, CDCl ) 3.35 (s ,
-1 1
H), 3.80 (s, 3H), 4.14 (d, 1H, J ) 7.4 Hz), 4.21 (dd, 1H, J ) 7.6
white solid, mp 179-180 °C; IR 3427, 3306, 1666 cm ; H NMR
(δ ppm, CDCl ) 3.77 (s, 3H), 6.61 (d, 1H, J ) 3.3 Hz), 7.33 (m,
2H), 7.41 (m, 4H), 7.59 (m, 4H), 9.51 (s
CDCl ) 51.3, 109.9, 118.2, 124.7, 125.8, 127.1, 127.7, 127.9, 128.9,
129.0, 129.3, 129.4, 130.9, 133.6, 1135.0, 135.5, 161.6; MS m/z
Hz, J′ ) 3.1 Hz), 4.91 (d, 1H, J ) 6.6 Hz), 5.27 (dd, 1H, J ) 6.5
3
1
3
13
Hz, J′ ) 3.2 Hz), 7.25-7.44 (m, 10H); C NMR (δ ppm, CDCl
3
)
b
, 1H); C NMR (δ ppm,
52.6, 55.3, 67.3, 67.7, 96.9, 126.4, 127.4, 128.0,128.7, 129.2, 134.4,
138.5, 171.7. Anal. Calcd for C18 : C, 66.24; H, 5.57; N,
8.58. Found: C, 66.41; H, 5.74; N, 8.58.
3
18 4 2
H O N
+
(EI) 321 (M ). Anal. Calcd for C18
15 2
H O N: C, 77.96; H, 5.45; N,
Data for (2S*,3S*,4R*,5S*)-3,5-Diphenyl-2-methoxycarbonyl-
-nitropyrrolidine, exo-3a: yellow solid, mp 113-115 °C; IR
5.05. Found: C, 77.65; H, 5.39; N, 4.96.
4
3
1
-
1
1
Acknowledgment. We thank the Ministerio de Educaci o´ n
y Ciencia of Spain (Projects CTQ2004-06816/BQU), the Go-
bierno Vasco-Eusko Jaurlaritza (Grants 9/UPV 00170.215-
13548/2001 and BIOFAMIP-SAIOTEK), and Junta de Comu-
nidades de Castilla-La Mancha (Projects PAI-05-019 and PBI06-
0020) for financial support. Thanks are also due to Prof. M. L.
Rodr ´ı guez for the use of the X-ray facilities.
3 b
355, 1743, 1544, 1347 cm ; H NMR (δ ppm, CDCl ) 2.73 (s ,
H), 3.27 (s, 3H), 4.37 (t, 1H, J ) 7.7 Hz), 4.50 (d, 1H, J ) 9 Hz,
J′ ) 3.1 Hz), 4.75 (d
b
, 1H, J ) 8.2 Hz), 5.21 (dd, 1H, J ) 8.0 Hz),
.20-7.58 (m, 10H); 1 C NMR (δ ppm, CDCl
3
7
6
1
3
) 51.8, 53.7, 64.2,
7.6, 95.0, 126.8, 127.8, 128.1,128.7, 128.9, 129.0, 135.8, 137.6,
71.8. Anal. Calcd for C18 : C, 66.24; H, 5.57; N, 8.58.
18 4 2
H O N
Found: C, 66.70; H, 5.56; N, 8.58.
Data for (2R*,3R*,4S*,5S*)-3,5-Diphenyl-2-methoxycarbonyl-
Supporting Information Available: Complete Experimental
Section with the characterization of all compounds, copy of H and
C spectra of all new compounds, X-ray crystallographic data for
compounds 5 and 7, Cartesian coordinates and energies (including
zero-point vibrational energies) of all reactants, intermediates,
products, and transition structures discussed in this work can be
found in the Supporting Information. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
4
1
(
7
-nitropyrrolidine, endo′-3a: H NMR (δ ppm, CDCl
3 b
) 2.68 (s ,
1
H), 3.28 (s, 3H), 4.53 (dd, 1H, J ) 11.3 Hz, J′ ) 7.8 Hz), 4.74
13
d, 1H, J ) 8.2 Hz), 5.46 (d, 1H, J ) 8.0 Hz), 5.64 (dd, 1H, J )
.7 Hz, J′ ) 6.4 Hz), 7.17-7.44 (m, 10H).
Synthesis of Carbamoyl Derivatives 4 and 5. A mixture of
exo-3a and endo′-3a cycloadducts (1.0 g, 3 mmol) was transformed
(42) Ayerbe, M.; Arrieta, A.; Coss ´ı o, F. P.; Linden, A. J. Org. Chem.
1
999, 63, 1795.
JO062672Z
4322 J. Org. Chem., Vol. 72, No. 12, 2007