until 2013, no catalytic asymmetric R-azidation of carbo-
nyl compounds had been reported, and the only method to
access enantiopure products was based on a chiral aux-
iliary approach.4
benziodoxole 2 in different solvents, with the best yield
(82% by 1H NMR) obtained in toluene.12 The better result
obtained with benziodoxole 2 is probably due to the higher
basicity of the alcoholate generated after azide transfer.
To solve this challenge, we decided to make use of the
exceptional stability of benziodoxol(on)e-based hypervalent
iodine reagents.7 Our group has recently demonstrated the
exceptional properties of this class of reagents for acetylene
transfer onto dicarbonyl compounds,8 and we wondered if
similar azido reagents would be equally successful. In fact,
Zhdankin and co-workers have described the synthesis of
azido benziodoxol(on)e compounds, which were surpris-
ingly stable.9 The reactivity of these reagents was studied for
the radical-based azidation of aliphatic CÀH bonds.9,10
During completion of our work, Gade and co-workers
reported the first catalytic asymmetric method for the
azidation of β-keto esters and oxindoles using a chiral iron
catalyst together with an azidobenziodoxole reagent.11 This
major breakthrough motivated us to report our own pre-
liminary results in the area, including the very efficient
azidation of cyclic β-keto esters with azidobenziodoxole 2
in the absence of any catalyst and the zinc-catalyzed azidation
of less reactive linear keto esters and silyl enol ethers using the
same reagent (Scheme 1). Our results demonstrated that
the potential of azidobenziodoxole reagents as electrophilic
azidation reagents is not limited to cyclic β-keto esters.
Scheme 2. Azidation of Keto Ester 1a
Table 1. Azidation of Cyclic β-Keto Esters with Benziodoxole 2
Scheme 1. Azidation of Keto Esters and Silyl Enol Ethers
We started our studies with the azidation of keto ester 1a
with benzidoxol(on)e reagents 2 and 6 (Scheme 2).
Whereas no reaction was observed with benziodoxolone
6, a complete conversion to azide 3a was observed with
(6) (a) Fowler, F. W.; Hassner, A.; Levy, L. A. J. Am. Chem. Soc.
1967, 89, 2077. (b) Moriarty, R. M.; Vaid, R. K.; Ravikumar, V. T.;
Vaid, B. K.; Hopkins, T. E. Tetrahedron 1988, 44, 1603. (c) Magnus, P.;
Barth, L. Tetrahedron Lett. 1992, 33, 2777. (d) Magnus, P.; Lacour, J.
J. Am. Chem. Soc. 1992, 114, 767. (e) Magnus, P.; Hulme, C.; Weber, W.
J. Am. Chem. Soc. 1994, 116, 4501. (f) Magnus, P.; Barth, L. Tetrahedron
1995, 51, 11075. (g) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.;
Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406. (h) Magnus, P.; Lacour, J.;
Evans, P. A.; Rigollier, P.; Tobler, H. J. Am. Chem. Soc. 1998, 120,
12486. (i) Tohma, H.; Egi, M.; Ohtsubo, M.; Watanabe, H.; Takizawa,
S.; Kita, Y. Chem. Commun. 1998, 173. (j) Lee, J. C.; Kim, S.; Shin, W. C.
Synth. Commun. 2000, 30, 4271. (k) Pedersen, C. M.; Marinescu, L. G.;
Bols, M. Org. Biomol. Chem. 2005, 3, 816. (l) Kumar, D.; Sundaree, S.;
Rao, V. S. Synth. Commun. 2006, 36, 1893. (m) Telvekar, V. N.; Patile,
H. V. Synth. Commun. 2011, 41, 131. (n) Harschneck, T.; Hummel, S.;
Kirsch, S. F.; Klahn, P. Chem.;Eur. J. 2012, 18, 1187.
a Isolated yields with keto ester 1 or enol ether 4a (0.40 mmol),
benziodoxole 2 (0.52 mmol), toluene (0.4 mL), 1À3 h at rt.
With this simple protocol for the azidation of keto esters
in hand, we investigated the scope of the reaction (Table 1).
On a 0.40 mmol scale, azide 3a could be isolated in 94%
yield (entry 1). The azidation proceeded in good yields
independent of the electronic properties of the substituent
(7) (a) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121. (b) Brand,
J. P.; Fernandez Gonzalez, D.; Nicolai, S.; Waser, J. Chem. Commun.
2011, 47, 102.
(8) Fernandez Gonzalez, D.; Brand, J. P.; Waser, J. Chem.;Eur. J.
2010, 16, 9457.
B
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