Lewis acid promoted highly stereoselective rearrangement of 2,3-aziridino alcohols: A new efficient approach to β-amino carbonyl compounds

Article abstract of DOI:10.1021/ol0170410

Equation Presented n=0,1 R¹, R² = H, alkyl, aryl A new Lewis acid promoted rearrangement reaction of 2,3-aziridino alcohols was discovered, which involved the highly stereoselective construction of a diastereogenic quaternary carbon

Full text of DOI:10.1021/ol0170410

ORGANIC
LETTERS
2002
Vol. 4, No. 3
363-366
Lewis Acid Promoted Highly
Stereoselective Rearrangement of
2,3-Aziridino Alcohols: A New Efficient
Approach to â-Amino Carbonyl
Compounds
Bao Min Wang, Zhen Lei Song, Chun An Fan, Yong Qiang Tu,* and Yian Shi†
Department of Chemistry and National Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received November 13, 2001
ABSTRACT
A new Lewis acid promoted rearrangement reaction of 2,3-aziridino alcohols was discovered, which involved the highly stereoselective
construction of a diastereogenic quaternary carbon center and efficient formation of â-amino carbonyl compounds in excellent yields. A wide
variety of Lewis acids were proved to be effective for the reaction, and a possible reaction mechanism was also discussed.
In recent years, the chemistry of aziridines has been attracting
much interest of synthetic organic chemists, mainly as a result
of their highly regio- and stereoselective ring-opening
reactions and their great potential as building blocks for the
synthesis of a wide range of biologically significant nitrogen-
containing compounds.1 Many reactions reported involve the
C-N bond cleavage of the aziridines, and few reports
incorporate carbon-carbon migration. The aza-Payne re-
arrangement2 reported by Ibuka merely results in the forma-
tion of 2,3-epoxy amines without any carbon skeleton change
of the substrates. Although the chemistry of 2,3-epoxy
alcohols has been studied extensively,3 the reactions of 2,3-
aziridino alcohols have seldom been investigated. Recently,
our independent research has brought about for the first time
the discovery of a new rearrangement of 2,3-aziridino
alcohols promoted effectively by a variety of Lewis acids,
with zinc bromide being the most effective (Scheme 1). The
Scheme 1
† Visiting professor from Colorado State University.
(1) For a general review of aziridine chemistry, see: (a) Tanner, D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b) Pearson, W. H.; Lian, B.
W.; Bergmeier, S. C. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, 1996; Vol. 1a. (c) Rayner, C. M. Synlett 1997, 11. (d) Osborn, H.
M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693. (e) Atkinson,
R. S. Tetrahedron 1999, 55, 1519.
(2) (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Otaka, A.;
Tamamura, H.; Fuji, N.; Mimura, N.; Miwa, Y.; Taga, T.; Chounan, Y.;
Yamamoto, Y. J. Org. Chem. 1995, 60, 2044. (b) Ibuka, T. Chem. Soc.
ReV. 1998, 27, 145.
synthetic value of this reaction involves the stereoselective
derivation of two adjacent stereocenters, with one being the
quaternary. The stereoselective construction of quaternary
10.1021/ol0170410 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/10/2002

carbon centers, still remaining a crucial aspect of several
areas in organic synthesis, is of particular importance.
Quaternary carbon has long been an important class of
structure, although much progress has been achieved in the
area.4 An additional significant value of this reaction is that
it provides an alternative efficient method for the preparation
of â-amino ketones and aldehydes (Mannich bases), which
are particularly versatile synthetic intermediates and find
great use in medicinal chemistry.5 Generally, the â-amino
carbonyl compounds were prepared by Mannich reaction and
its modern variants6 and by Michael additions of amines to
R,â-unsaturated carbonyl compounds. However, these pro-
cedures sometimes showed poor regio- and stereoselectivity.7
The development of new alternative methods for the
synthesis of â-amino carbonyl compounds is therefore of
considerable synthetic importance.8 In contrast, the procedure
here reported demonstrated excellent regio- and stereo-
selectivity in all examples we examined. Herein, we wish
to report the experimental results of the Lewis acid promoted
rearrangement of 2,3-aziridino alcohols.
Table 1. Rearrangement of 2,3-Aziridino Alcohols Promoted
by ZnBr2 Leading to Spirocyclic â-Amino Ketones
entry
n
m
yield (%)
time (min)
1
2
3
4
5
6
1
1
1
1
0
0
0
1
2
3
2
3
98
95
90
92
91
93
10
30
30
30
30
30
In Table 1, six spirocyclic â-amino ketones were designed
as the target molecules. Although this kind of spiro com-
pound could be prepared via an intramolecular Mannich-
type reaction of benzylic azides with ketones,7b the stereo-
selectivity was very poor and an unremovable phenyl group
was attached to the nitrogen atom instead of a p-toluene-
sulfonyl group. Notably, this kind of chiral spirocyclic
â-amino ketones may have some synthetic utility not only
because they can be easily transformed into 1,3-amino
alcohols but also because spiro compounds have been
investigated recently as possible chiral ligands for catalytic
asymmetric reactions.10 Although the migration of the methyl
group is difficult in many cases,3b-d in entries 1-4 and 6 of
Table 2, however, it seems very easy. Interestingly, in entry
The 2,3-aziridino alcohols we investigated were prepared
in racemic form (except for entry 3 of Table 2) with moderate
yields from the corresponding allylic alcohols via the
aziridination method developed by Sharpless.9 Thus, the 2,3-
aziridino alcohols were subjected to the rearrangement
reaction to afford â-amino ketone or aldehyde in a single
diastereoisomeric form, whose relative configuration was
determined by NOSEY spectrum of the product of entry 1
1
in Table 2 selected as a model and by comparison of H
NMR chemical shifts with that of approximate compounds
in the literature.7b All results were tabulated in Tables 1 and
2 and Scheme 2, from which it can be seen that all reactions
Table 2. Rearrangement of 2,3-Aziridino Alcohols Promoted
by ZnBr2 Leading to â-Amino Ketones and Aldehydes
Scheme 2
were complete in less than 1 h with the exclusive formation
of â-amino ketones and aldehydes stereoselectively in
excellent yields, indicating the convenience and synthetic
value of this reaction.
entry
n
R1
R2
R3
yield (%)
time (min)
1
2
3
4
5
6
7
8
9
1
0
1
1
1
0
1
0
0
Me
Me
Me
Me
Et
Me
Ph
Ph
H
Me
Me
Me
Et
Me
Ph
H
H
H
Me
H
H
H
H
H
H
88
85
78
90
89
85
85
83
85
30
30
60
30
30
30
40
40
40
(3) (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.;
Shimazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827. (b)
Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.; Wrigglesworth,
R.; Edge, S. J. J. Org. Chem. 1993, 58, 5944. (c) Tu, Y. Q.; Sun, L. D.;
Wang, P. Z. J. Org. Chem. 1999, 64, 629. (d) Tu, Y. Q.; Fan, C. A.; Ren,
S. K.; Chan, A. S. C. J. Chem. Soc., Perkin Trans. 1 2000, 3791. (e) Fan,
C. A.; Wang, B. M.; Tu, Y. Q.; Song, Z. L. Angew. Chem., Int. Ed. Engl.
2001, 40, 3877.
H
o-ClC6H4
(4) For recent reviews on stereoselective construction of a quaternary
carbon center, see: (a) Fuji, K.Chem. ReV. 1993, 93, 2037. (b) Seebach,
D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2708. (c) Corey, E. J.; Angel, G.-P. Angew. Chem., Int. Ed. Engl. 1998,
37, 388.
(5) (a) Dimmock, J. R.; Sidhu, K. K.; Chen, M.; Reid, R. S.; Allen, T.
M.; Kao, G. Y.; Truitt, G. A. Eur. J. Med. Chem. 1993, 28, 313. (b) Traxler,
P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer, T.; Mu¨ller, M.; Regenass,
U.; Ro¨sel, N.; Lydon, N. J. Med. Chem. 1995, 38, 2441.
311 the methyl substituent in the cyclohexane ring has no
significant effect on the rearrangement ability of the substrate.
Of particular interest is that secondary 2,3-aziridino alcohols
(entries 7 and 8 in Table 2 and the substrate in Scheme 2)
could also undergo this rearrangement reaction to afford
364
Org. Lett., Vol. 4, No. 3, 2002

â-amino aldehydes, which can be easily converted into R,R
geminally disubstituted â-amino acids,12 vital compounds for
the synthesis of â-peptide, via oxidation. Notably, in entries
4 and 5 of Table 2, a pair of separable diastereoisomeric
2,3-aziridino alcohols afforded methyl and ethyl migration
Scheme 3
1
products, respectively, which was verified by the H NMR
spectra of the products. This unusual fact indicates that the
migration priority of two different groups of R1 and R2
(Scheme 1) depends seriously on the configuration of the
carbon bearing a hydroxyl group but not on the migration
ability. Further study led to the discovery that methyl
migrates prior to phenyl in entry 6 (Table 2) and hydride
prior to o-chlorophenyl in entry 9 (Table 2), which further
verified our presumption. This phenomenon is of great
interest and has seldom been reported.
To expand the scope of this rearrangement reaction, we
examined the acyclic substrate (Scheme 2), which was
prepared from 2-bromopropene via a Grignard reaction with
benzaldehyde followed by aziridination of the allylic alcohol
thus formed. The rearrangement of this acyclic 2,3-aziridino
alcohol proceeded smoothly to afford the corresponding
â-amino aldehyde when exposed to the standard condition,
indicating the broad scope of the substrates.
the migrating group in a transition state geometry resembling
that of ordinary nucleophilic substitution proceeding with
inversion of configuration. The five-membered ring structure
resulting from coordination of the Lewis acid to nitrogen
and oxygen prevents the free rotation of the C1-C2 bond,
and thus the group R1 that is anti to the C-N bond migrates.
The rearrangement reaction here reported is therefore highly
stereoselective. The mechanism above interprets very well
why entry 4 in Table 2 gave the methyl migration product
while in entry 5 ethyl migrated. On the basis of this
mechanism and the relative configurations of the products,
the stereochemistry of the diastereomerically pure substrates
in entries 4-9 of Table 2 was assigned as illustrated. There
are no existing methods to determine the relative configura-
tions of such compounds, and the search for experimental
evidence toward this objective is ongoing.
A wide variety of other Lewis acids were also examined
for this reaction, with the 2,3-aziridino alcohol in entry 2 of
Table 1 to be a model substrate, and it was found that many
of them could act as promoter to give good to excellent
product yields in short time (Table 3). Of all the efficient
In summary, we have discovered a new stereoselective
rearrangement reaction of 2,3-aziridino alcohols, which
proceeds under fairly mild conditions with the highly efficient
formation of â-amino carbonyl compounds containing a
quaternary carbon center at the R-position. Although reac-
tions of 2,3-aziridino alcohols with Olah’s reagent have been
reported by Laurent,13 to the best of our knowledge this type
of rearrangement reaction of 2,3-aziridino alcohols has not
Table 3. Effective Lewis Acids for the Rearrangement of
2,3-Aziridino Alcohol
entry
Lewis acid
yield (%)
time (min)
(6) For a general review on Mannich reaction and its modern variants,
see: (a) Blicke, F. F. Org. React. (NY) 1942, 1, 303. (b) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791. (c) Kleinman, E. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 893. (d) Heaney, H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 953. (e) Overmann, L. E.;
Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 1007. (f)
Tramontini, M.; Angiolini, L. Mannich-Bases, Chemistry and Uses; CRC:
Boca Raton, FL, 1994. (g) Arend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1044. (h) Miura, K.; Tamaki, K.; Nakagawa,
T.; Hosomi, A. Angew. Chem., Int. Ed. 2000, 39, 1958.
1
2
3
4
5
6
7
8
9
AlCl3
ZnCl2
Sn(OTf)2
BF3‚Et2O
SnCl4
SmI2
ZnI2
TiCl4
Sc(OTf)3
ZrCl4
40
74
80
82
86
93
82
55
74
76
30
60
60
10
10
40
60
10
60
20
10
(7) (a) Saidi, M. R.; Heydari, A.; Ipaktschi, J. Chem. Ber. 1994, 127,
1761. (b) Wrobleski, A.; Aube´, J. J. Org. Chem. 2001, 66, 886.
(8) Matthew, J.; Jonathan, B. S. Org. Lett. 2001, 3, 25.
(9) Jeong, J. K.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 6844.
(10) (a) Srivastava, N.; Mital, A.; Kumar, A. J. Chem. Soc., Chem.
Commun. 1992, 493. (b) Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.;
Jiang, Y.; Mi, A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J. Am. Chem. Soc.
1997, 119, 9570. (c) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1,
1795.
(11) This chiral 2,3-aziridino alcohol was prepared from R-(+)-pulegone.
For the preparation of the allylic alcohol, see: (a) Neichinasi, E. H. J. Org.
Chem. 1970, 35, 2010. (b) Neidigk, D. D.; Morrison, H. J. Chem. Soc.,
Chem. Commun. 1978, 601.
(12) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1 and references
therein.
Lewis acids investigated, SmI2 gave the best result, while
AlCl3 was found to be too reactive to afford high yield.
On the basis of the abnormal migration mentioned above
and on the relative configurations of the products, a possible
reaction mechanism of this rearrangement of 2,3-aziridino
alcohols was proposed (Scheme 3), in which the Lewis acid
first coordinates to the aziridine nitrogen and the hydroxyl
oxygen, and the cleavage of the activated C-N bond of the
aziridine then occurs concomitantly with 1,2-migration of
Org. Lett., Vol. 4, No. 3, 2002
365

been reported previously. The use of chiral Lewis acids for
the rearrangement and the applications of this synthetically
valuable reaction to other aspects of organic synthesis, such
as synthesis of natural products and preparation of chiral
ligands14 for catalytic asymmetric reactions, are currently
under investigations.
Fund of Ministry of Education (99209). We thank Ms. Wang
Kai Qiu and Mr. Qi Xiu Zhu for their assistance in NMR
and MS studies.
Supporting Information Available: Typical experimen-
tal procedure of the rearrangement reaction and spectra data
of the rearrangement products. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by NSFC
(29972019, 29925205 and QT program), FUKTME of China,
the Young Teachers’ Fund of Ministry of Education and the
OL0170410
(14) (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071. (b) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.;
Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J.
Organomet. Chem. 1990, 19, 382.
(13) Alvernhe, G.; Lacombe, S.; Laurent, A.; Rousset, C. J. Chem. Res.,
Synop. 1983, 246.
366
Org. Lett., Vol. 4, No. 3, 2002