report a series of isomerically enriched triazolines 1-4
and their stereospecific conversion to aziridines 5-6 con-
sistent with mechanistic pathway A f B f C.
Our study commenced with the outline in Figure 1 and
the hypothesis that relative stereochemistry could be used as
a tool to probe the pathways describedby consideration of a
trans-triazoline (A) as a possible precursor to intermediate
B. Fragmentation of the triazoline15 core by Brønsted
acid16,17 could occur by protonation at oxygen, followed
by amino diazonium ion (D) formation and ring closure to
the trans-aziridinium salt (E). Alternatively, triazoline pro-
tonation at N3 in A would provide proper polarization for
formation of alkyl diazonium intermediate B.18
The ester regioisomers of triazoline A and each trans-
diastereomer were prepared by nonselective thermal cy-
cloaddition of (R)-R-methyl benzyl azide19 to ethyl methyl
fumarate. The four isomers (1-4) could be separated by
preparative HPLC to homogeneity (>98%). The use of
Figure 1. Mechanistic outline connecting aza-Darzens and tria-
zoline decomposition reactions in the presence of Brønsted acid.
R-diazonium β-amino ester intermediate (B), as outlined in
Figure 1.13 Use of the Brønsted acid-catalyzed reaction to
study the mechanism provides an advantage over Lewis
acid/metal-catalyzed variants in that direct reaction of the
diazoalkane with the latter can ultimately lead to an
azomethine ylide intermediate, whose stereochemical
fate might vary from catalyst to catalyst,9,14 whereas
protonation of the diazoalkane cannot lead to products
of carbon-carbon bond formation. In this study, we
(7) Johnston, J. N.; Muchalski, H.; Troyer, T. L. Angew. Chem., Int.
Ed. 2010, 49, 2290–2298.
Figure 2. Selected GOESY enhancements.
(8) Selected examples: (a) Rasmussen, K. G.; Jørgensen, K. A. J.
Chem. Soc., Perkin Trans. 1 1997, 1287–1292. (b) Casarrubios, L.; Perez,
J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358–
8359. (c) Pellicciari, R.; Amori, L.; Kuznetsova, N.; Zlotsky, S.; Gioiello,
A. Tetrahedron Lett. 2007, 48, 4911–4914. (d) Bartnik, R.; Mloston, G.
Acta Biochim. Biophys. Acad. Sci. Hung. 1981, 106, 309–312. (e) Bartnik,
R.; Mloston, G. Tetrahedron 1984, 40, 2569–2576.
bothtriazoline regioisomerswasintentionalsoastorelyon
coupling constants (instead of chemical shift alone) to
assign aziridine stereochemistry. Assignment of the triazo-
line regioisomers was accomplished by a GOESY experi-
ment to reveal long distance enhancements between the
benzylic methine and both ethyl ester methyl (1.7%) and
R-amino methine (2.2%) at C4 in 3 (Figure 2).20
(9) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 676–678.
(10) Another highly successful variant uses both metallocarbene and
ylide intermediates: Aggarwal, V. K. Synlett 1998, 329–336.
(11) (a) Lu, Z. J.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007,
129, 7185–7194. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed.
2000, 39, 4518–4521. (c) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc.
1999, 121, 5099–5100. (d) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356–5357. (e) Dahl, R.; Baldridge, K. K.; Finney, N. S.
Synthesis 2010, 2292–2296. (f) Dahl, R. S.; Finney, N. S. J. Am. Chem.
Soc. 2004, 126, 8356–8357. (g) Hashimoto, T.; Nakatsu, H.; Watanabe,
S.; Maruoka, K. Org. Lett. 2010, 12, 1668–1671.
(15) Early studies, largely thermal triazoline decomposition: (a)
Broeckx, W.; Overberg, N.; Samyn, C.; Smets, G.; L’Abbe, G. Tetra-
€
hedron 1971, 27, 3527–3534. (b) Huisgen, R.; Szeimies, G.; Mobius, L.
Chem. Ber. 1966, 99, 475–490.
(16) For a kinetic study of unsubstituted (achiral) triazoline decom-
position in aqueous buffer over a broad pH range, see: Smith, R. H.;
Wladkowski, B. D.; Taylor, J. E.; Thompson, E. J.; Pruski, B.; Klose,
J. R.; Andrews, A. W.; Michejda, C. J. J. Org. Chem. 1993, 58, 2097–
2103.
(17) (a) Hong, K. B.; Donahue, M. G.; Johnston, J. N. J. Am. Chem.
Soc. 2008, 130, 2323–2328. (b) Donahue, M. G.; Hong, K. B.; Johnston,
J. N. Bioorg. Med. Chem. Lett. 2009, 19, 4971–4973. (c) Muchalski, H.;
Hong, K. B.; Johnston, J. N. Beilstein J. Org. Chem. 2010, 6, 1206–1210.
(18) The intermediacy of a [1,2,4]-triazole has been noted by
Aggarwal (ref 6a), as well as its conversion to a trans-aziridine.
(19) Ramanathan, S. K.; Keeler, J.; Lee, H.-L.; Reddy, D. S.;
Lushington, G.; Aube, J. Org. Lett. 2005, 7, 1059–1062.
(20) Complete details, including 1H NMR spectra for crude reaction
mixtures, are provided in the Supporting Information. Additional
control experiments are provided as well.
(12) For an exception just reported, see: Vetticatt, M. J.; Desai, A. A.;
Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104–13107.
(13) Although they are not acid catalyzed, sulfonium ylide additions
to carbonyl or azomethine have mechanistic considerations similar to
those described here, and have been investigated extensively, including
via computational methods. Leading references: (a) Lindvall, M. K.;
Koskinen, A. M. P. J. Org. Chem. 1999, 64, 4596–4606. (b) Aggarwal,
V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747–
5756. (c) Silva, M. a. A.; Bellenie, B. R.; Goodman, J. M. Org. Lett. 2004,
6, 2559–2562. (d) Robiette, R. J. Org. Chem. 2006, 71, 2726–2734.
(14) Thermal- and solvent-assisted azomethine ylide formation from
aziridine: (a) Padwa, A.; Dean, D.; Oine, T. J. Am. Chem. Soc. 1975, 97,
2822–2829. (b) Huisgen, R.; Martinra, V; Scheer, W. Tetrahedron Lett.
1971, 477–480.
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