SCHEME 1. Lewis Acid Catalyzed [3+2]
Cycloaddition
Lewis Acid Catalyzed Dipolar
Cycloadditions of an Activated Imidate
Roy K. Bowman and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
TABLE 1. Evaluation of Mg(II) Catalysts and Reaction
Solvents
Received August 18, 2004
Abstract: An evaluation of simple Lewis acids revealed that
N-malonylimidates undergo catalyzed [3+2] cycloaddition
reactions with aldehydes, imines, and activated olefins to
form oxazolines, imidazolines, and pyrrolines, respectively.
Reactions proceed optimally at ambient temperature with
the addition of 5 mol % of MgCl2 in CH3CN. Experiments
aimed at elucidation of the reactive intermediate undergoing
cycloaddition suggest that the Lewis acid promotes a 1,2-
prototropic shift to give a metal-coordinated azomethine
ylide, rather than ionization and proton transfer to give a
nitrile ylide.
MgX2 (equiv) solvent PhCHO (equiv) time (h)
yield (%)
Mg(OTf)2 (1.1) THF
MgCl2 (1.1) THF
Mg(OTf)2 (1.1) CH2Cl2
2.0
2.0
22.75 not complete
16.5
5
5.5
20
2.25 63
36
2.0
49
MgCl2 (1.1)
MgCl2 (1.1)
MgCl2 (0.2)
MgCl2 (0.1)
MgCl2 (0.1)
MgCl2 (0.1)
CH2Cl2
toluene
CH2Cl2
CH2Cl2
DMF
2.0
60
2.0
not complete
5.0
10.0
10.0
10.0
1
1
76
not complete
CH3CN
1.25 93
Recently, our group reported a Zn(II)-catalyzed het-
erolytic carbon-carbon bond cleavage of aziridines in
which the intermediate azomethine ylide underwent
cycloaddition with electron-rich dipolarophiles.16 A gemi-
nal diester was needed to favor carbon-carbon bond
cleavage relative to scission of the carbon-nitrogen bond,
presumably allowing for stabilization of the nascent
anion and chelation of the Lewis acid. In the context of
this work we became interested in malonic imidate 1,
which, through the work of Bazureau, is known to
undergo thermal dipolar cycloaddition with heterodi-
polarophiles.6,17 The presence of the geminal ester groups
suggested to us that this process may also be amenable
to catalysis. In this Note we document mild, base-free,
Lewis acid-catalyzed [3+2] cycloadditions of 2-(1-ethoxy-
ethylideneamino)malonic acid dimethyl ester 1 and elec-
tron poor dipolarophiles (Scheme 1) and report our
observations germane to the mechanism of this trans-
formation.
Catalyst Evaluation and Scope. An examination of
several Lewis acids (SnCl2, Sn(OTf)2, ZnCl2, Zn(OTf)2,
TiCl4(THF)2, TiCl4, AlCl3, Cu(OTf)2, La(OTf)3, Mg(OTf)2)
revealed magnesium(II) triflate as the most promising
promoter of oxazoline formation in the reaction between
malonic imidate 1 and benzaldehyde (THF, 25 °C).
Further investigation into the impact of the counterion
showed MgCl2 to be a more efficient catalyst. Finally,
examination of reaction solvent demonstrated that CH3-
CN was optimal (Table 1).
Azomethine ylides are important intermediates in
many [3+2] cycloadditions and have enjoyed much suc-
cess in the synthesis of pyrrolidines and other nitrogen-
containing heterocycles.1-3 Continuing interest in such
reactions has prompted a number of research groups to
investigate N-metalated azomethine ylides formed via
“soft enolization” of (imino)glycine esters as alternatives
to ylides generated from the same compounds in the
classic thermal [1,2]-prototropy manifold.4,5 Ylides gener-
ated by the former method require a weak base working
in concert with a metal salt.6-10 Most substrates included
in these cycloadditions are electron poor olefins which
form functionalized pyrrolidines, in some cases with high
levels of enantiocontrol.11-13 [3+2] cycloadditions in which
heterodipolarophiles are employed to intercept reactive
azomethine ylide intermediates represent a useful entry
into functionalized, protected R-amino acids.14,15
(1) Lown, J. W. In 1,3-Dipolar Cycloaddtion Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, pp 653-732.
(2) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, pp 1-177.
(3) Harwood, L. M.; Vickers, R. J. In The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chem-
istry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley and Sons: New York, 2002; Vol. 59, pp 169-252.
(4) Grigg, R.; Kemp, J.; Sheldrick, G.; Trotter, J. J. Chem. Soc.,
Chem. Commun. 1978, 109-111.
(5) Joucla, M.; Hamelin, J. Tetrahedron Lett. 1978, 2885-2888.
(6) Amornraksa, K.; Barr, D.; Donegan, G.; Grigg, R.; Ratananukul,
P.; Sridharan, V. Tetrahedron 1989, 45, 4649-4668.
(7) Ayerbe, M.; Arrieta, A.; Cossio, F. P.; Linden, A. J. Org. Chem.
1998, 63, 1795-1805.
A catalyst loading of 5 mol % of MgCl2 and 10 equiv of
dipolarophile was found to provide convenient reaction
(8) Garcia Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem.
2002, 67, 981-987.
(9) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174-10175.
(14) Pearson, W. H.; Stoy, P.; Mi, Y. J. Org. Chem. 2004, 69, 1919-
1939.
(10) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata,
S.; Komatsu, M. Org. Lett. 2003, 5, 5043-5046.
(15) Harwood, L. M.; Macro, J.; Watkin, D.; Williams, C. E.; Wong,
L. F. Tetrahedron: Asymmetry 1992, 3, 1127-1130.
(16) Pohlhaus, P. D.; Bowman, R. K.; Johnson, J. S. J. Am. Chem.
Soc. 2004, 126, 2294-2295.
(11) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486.
(12) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236-4238.
(13) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400-13401.
(17) Lerestif, J. M.; Toupet, L.; Sinbandhit, S.; Tonnard, F.;
Bazureau, J. P.; Hamelin, J. Tetrahedron 1997, 53, 6351-6364.
10.1021/jo0485536 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/03/2004
J. Org. Chem. 2004, 69, 8537-8540
8537