C O M M U N I C A T I O N S
Table 1. Asymmetric Induction in the Neber Rearrangement by
Chiral Phase-Transfer Catalysisa
oxime
c
oxime
geometry catalyst
condition yieldb
%ee
1
2
entry
R
R
(°C, h)
(%)
(config)d
1
2
3
4
5
6
7
Ph Ph (1a)
(Z)
5a
5b
5c
5c
5b
5c
5c
0, 72
0, 19
0, 48
0, 48
0, 19
0, 43
0, 68
60
86
80
61
95
90
81
30 (S)
35 (S)
51 (S)
racemic
50
Figure 1. Transition-state model for the asymmetric Neber rearrangement
of (Z)-1b with 5c.
(E)
(Z)
Ph p-F-Ph (1b)
Supporting Information Available: Representative experimental
procedures as well as spectroscopic characterization of catalyst 5 and
all new compounds (PDF). This material is available free of charge
63
70e
a Unless otherwise specified, the reaction was carried out with 1.2 equiv
of p-TsCl and 10 equiv of MeOH in the presence of 5 mol % of 5 in
toluene-50% KOH aq (volume ratio ) 3:1) under the given reaction con-
ditions. b Isolated yield. c Enantiopurity was determined by HPLC analysis
using a chiral column (DAICEL Chiralpak AD) with hexane-2-propanol
as solvent. d Determined, after reduction with NaBH4/MeOH, by comparison
with the optical rotation of N-benzoyl adduct of commercially available
(1S,2R)-(+)-1,2-diphenyl-2-aminoethanol. e Use of mesitylene as solvent.
References
(1) Neber, P. W.; Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449,
109.
(2) Reviews: (a) O’Brien, C. Chem. ReV. 1964, 64, 81. (b) Nair, V. In
Heterocyclic Compounds; Hassner, A., Ed.; John Wiley & Sons: New
York, 1983; Vol. 42.1, Chapter 2. (c) Padwa, A.; Woolhouse, A. D. In
ComprehensiVe Heterocyclic Chemistry; Lowowski, W., Ed.; Pergamon
Press: New York, 1984; Vol. 7, Chapter 5.04.
and 5c enhanced the enantioselectivity to 35% ee and 51% ee,
(3) (a) Cram. D. J.; Hatch, M. J. J. Am. Chem. Soc. 1953, 75, 33. (b) House,
H. O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 307. (c) Parcell, R. F.;
Sanchez, J. P. J. Org. Chem. 1981, 46, 5229. (d) Ueda, S.; Naruto, S.;
Yoshida, T.; Sawayama, T.; Uno, H. J. Chem. Soc., Chem. Commun. 1985,
218.
(4) For example, see: (a) Gordon, E. M.; Natarajan, S.; Pluscec, J.; Weller,
H. N.; Godfrey, J. D.; Rom, M. B.; Sabo, E. F.; Engebrecht, J.; Cushman,
D. W. Biochem. Biophys. Res. Commun. 1984, 124, 148. (b) Lucet, D.; Le
Gall, T.; Mioskowski, C.; Ploux, O.; Marquet, A. Tetrahedron: Asymmetry
1996, 7, 985. (c) Hoffman, R. V.; Tao, J. Tetrahedron 1997, 53, 7119.
(5) House, H. O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 2271.
(6) According to the report by House and Berkowitz (ref 5), we explicitly
illustrate a carbanion from which the azirine can be formed in both ways.
However, a totally concerted process wherein proton removal and
intramolecular displacement occur concomitantly is also conceivable as
an anionic pathway, and our results presented in this manuscript do not
rule out this mechanism. We acknowledge the reviewer for valuable
comments on this point.
respectively (entries 2 and 3).11,12 A noteworthy observation is the
fact that the reaction with (E)-1a under otherwise similar conditions
afforded racemic 4a in 61% yield, suggesting the intervention of
the nitrene pathway rather than the unfavorable syn-displacement
(entry 4). More compelling results were obtained in the rearrange-
ment of the oxime 1b derived from benzyl p-fluorophenyl ketone,
where the corresponding protected amino ketone 4b was obtained
in 95% yield, 50% ee with 5b and 90% yield, 63% ee with 5c,
respectively (entries 5 and 6). It is worthy of comment that use of
mesitylene in place of toluene further increased the enantioselec-
tivity to 70% ee (entry 7).
The effectiveness of the chiral quaternary ammonium bromide
5 in inducing the stereoselectivity can be rationalized by postulating
the transition-state model, in which the conformation of the
catalyst-substrate ion pair would be fixed so that the possible π-π
interactions are fully appreciated (Figure 1). This hypothetical
transition state could explain the beneficial effect of electron-
deficient 3,3′-aromatic substituents of 5 on the enantioselectivity
as well as the absolute configuration of the rearranged product 4.13
Interestingly, use of more electron-rich p-methoxyphenylsulfonyl
chloride in the reaction of (Z)-1b under the influence of 5c led to
the production of more enantioenriched 4b (80% yield, 73% ee).14
In conclusion, we have successfully utilized liquid-liquid phase-
transfer catalysis for the Neber rearrangement of simple ketoxime
sulfonates and unambiguously demonstrated the participation of the
anion pathway by the employment of optically pure, C2-symmetric
chiral quaternary ammonium bromides as catalysts. This provides
not only a new mechanistic insight but also an opportunity for ex-
tending the full synthetic utility of this classical yet useful rear-
rangement along with optimization of the enantioselective reaction.
Acknowledgment. We gratefully appreciate Messrs. Tsutomu
Kaku and Tsutomu Inoue (Nippon Soda Co., Ltd.) for providing
valuable information. This work was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. M.T. is grateful
to the Japan Society for the Promotion of Science for Young
Scientists for a Research Fellowship.
(7) We examined the reaction of (Z)-1a with representative chiral lithium
amides and n-BuLi-chiral diamine complexes, where the desired product
4a was obtained in low yields with 1-5% ee. See the Supporting
Information for details.
(8) A few examples of asymmetric Neber reaction have recently been reported;
(a) For reaction with a chiral auxiliary, see: Piskunova, I. P.; Eremeev,
A. V.; Mishnev, A. F.; Vosekalna, I. A. Tetrahedron 1993, 49, 4671. For
a cinchona alkaloid-mediated reaction, see: (b) Verstappen, M. M. H.;
Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491.
(c) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2000,
41, 5363. (d) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta,
J. M. J. Org. Chem. 2000, 65, 3213. For recent review on 2H-azirines as
synthetic tools, see: Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez de
Marigorta, E.; Manuel de los Santos, J. Eur. J. Org. Chem. 2001, 2401.
(9) For general reviews on phase-transfer reactions, see: (a) Handbook of
Phase Transfer Catalysis; Sasson, Y., Neumann, R., Eds.; Blackie
Academic & Professional: London, 1997. (b) Phase-Transfer Catalysis;
Halpern, M. E., Ed.; ACS Symposium Series 659; American Chemical
Society: Washington, DC, 1997.
(10) (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121,
6519. (b) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (c) Ooi, T.; Kameda, M.; Tannai, H.; Maruoka, K.
Tetrahedron Lett. 2000, 41, 8339.
(11) In the reaction with the catalyst 5c, intermediary optically active methoxy
aziridine 3 was isolated by silica gel column chromatography as a
diastereomeric mixture in a ratio of 1.4:1 after conversion to its N-benzoate.
See the Supporting Information for characterization.
(12) Attempted rearrangement of (Z)-1a with O-allyl-N-(9-anthracenylmethyl)-
cinchonidinium bromide15 as catalyst under otherwise similar conditions
proceeded sluggishly at 0 °C and eventually produced 4a in 35% yield
with 15% ee after stirring at room temperature for 24 h.
(13) Treatment of (Z)-oxime mesylate of benzyl p-fluorophenyl ketone with
5c and MeOH in toluene-50% KOH aqueous solution at 0 °C for 48 h
furnished 4b in 73% yield with 13% ee. The observed substantial decrease
of the enantiomeric excess suggests the importance of the π-π interaction
between tosyloxy moiety of oxime sulfonate and 3,3′-aromatic substituent
of the catalyst to fix the conformation.
(14) Performed in mesitylene-50% KOH aq at 0 °C for 48 h.
(15) For leading references, see: (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am.
Chem. Soc. 1997, 119, 12414. (b) Lygo, B.; Wainwright, P. G. Tetra-
hedron Lett. 1997, 38, 8595. (c) Lygo, B.; To, D. C. M. Tetrahedron
Lett. 2001, 42, 1343. (d) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3,
639.
JA0118791
9
J. AM. CHEM. SOC. VOL. 124, NO. 26, 2002 7641