type reaction. This synthesis fulfills standards to define it as
an atom-economical procedure.8
using chiral N,N-dibenzyl alaninal 7. Hence, crude 3-amino-
1-bromo-1-nitrobutan-2-ol 9 was obtained in quantitative
yield and with good diastereoisomeric excess (de 70%)
(Scheme 4).
Compounds 5 were isolated as a mixture of diastereoiso-
1
mers in approximately a 1:1 ratio, determined by H and
13C NMR analyses of the crude reaction products. These
stereochemical results were similar to those previously
reported in the literature.5,6
Scheme 4. Synthesis of Enantiopure
(1S,2S,3S)-3-Amino-1-bromo-1-nitrobutan-2-ol 9
As expected, the reaction also took place when another
iodide source was used. So, when the reaction was performed
with KI instead of NaI, compound 5a was also obtained in
comparable yield (91%). In this case, longer reaction times
were however required (18 h), probably due to the lower
solubility of KI in THF.
Similarly, the reaction can also be performed using
tetrabutylammonium iodide as a source of iodide. Thus,
compound 5a has also been obtained in high yield (89%);
however, the main drawback in the utilization of (Bu4N)+
I- when compared with NaI is that a purification by column
chromatography was necessary to eliminate completely the
ammonium salt and to isolate 1-bromo-1-nitroalkan-2-ols 5
in a pure form.
Mechanistically, a possible explanation of this transforma-
tion could be based on the high acidity of bromonitromethane
1. Although the iodide is a very weak base in an aqueous
medium, in THF it could be sufficiently strong to abstract
the proton from bromonitromethane. Thus, the abstraction
of a proton of bromonitromethane could generate a bro-
monitronate intermediate 6 that could react with the aldehyde
3 to afford the alcoholate 7 which after protonolysis would
generate the corresponding bromonitroalcohol 5 and the
iodide anion that would continue the process (Scheme 3).
The stereoselectivity of the reaction was determined by
1H NMR spectroscopy (300 MHz) on the crude product 9.
It is noteworthy that in the synthesis of 9 two new stereogenic
centers were generated with good stereoselectivity (70% de).
In addition, after conventional column chromatography, pure
compound 9 was obtained with de > 95%.
The structure of compound 9 was unambiguously estab-
lished by single-crystal X-ray diffraction.10
The absolute configuration of compound 9 was in ac-
cordance with the addition of the bromonitronate anion to
alaninal 8 under a nonchelation control mechanism. This fact
is in agreement with other previously reported additions of
nucleophiles to N,N-dibenzyl R-aminoaldehydes.11
The enantiomeric purity of compound 9 was determined
by chiral HPLC chromatography, showing an enantiomeric
excess (ee) >98%. Racemic mixtures of 9 were prepared
from racemic alaninal 8 to exclude the possibility of coelution
of both enantiomers in HPLC.12
In conclusion, we have described a novel reaction of
bromonitromethane with a variety of aldehydes under very
mild conditions, promoted by catalytic amounts of NaI to
afford 1-bromo-1-nitroalkan-2-ols and with 100% atom
economy. When chiral N,N-dibenzyl alaninal was utilized
as the starting material, the enantiopure (1S,2S,3S)-3-amino-
1-bromo-1-nitrobutan-2-ol was obtained after column chro-
matography purification.
Scheme 3. Mechanistic Proposal
(8) For a discussion on atom economy, see: (a) Trost, B. M. Science
1991, 254, 1471-1477. (b) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34,
259-281.
(9) Preparation of chiral 3-amino-1-bromo-1-nitroalkan-2-ols 9 has not
been reported to date. For the syntheses of the related 3-amino-1-nitroalkan-
2-ols from chiral aminoaldehydes, see: (a) Sohtome, Y.; Takemura, N.;
Iguchi, T.; Hashimoto, Y.; Nagasawa, K. Synlett 2006, 144-146. (b) Klein,
G.; Pandiaraju, S.; Reiser, O. Tetrahedron Lett. 2002, 43, 7503-7506. (c)
Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401-9403. (d)
Misumi, Y.; Matsumoto, K. Angew. Chem., Int. Ed. 2002, 41, 1031-1033.
(e) Corey, E. J.; Zhang, F. -Y. Angew. Chem., Int. Ed. 1999, 38, 1931-
1934. (f) Hanessian, S.; Devasthale, P. V. Tetrahedron Lett. 1996, 37, 987-
990. (g) Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett.
1994, 35, 6123-6126 and ref 7.
(10) CCDC 610565 contains the supplementary crystallographic data for
the bromohydrate derivative of compound 9. These data can be obtained
Cambridge Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax
(+44)1223-336-033; or deposit@ccdc.cam.ac.uk).
The different behavior of the iodide atoms depending on
their cationic partner (Sm+2 or Sm+3 vs Na+) could be
rationalized considering the ionic (NaI) or covalent (SmI2
or SmI3) character of these species. So, iodide from NaI could
be completely dissociated and could abstract acidic hydro-
gens, whereas iodide from SmI2 or SmI3 would be partially
bonded to the samarium center decreasing the basic proper-
ties of these iodide ions.
(11) (a) Reetz, M. T. Chem. ReV. 1999, 99, 1121-1162. (b) Reetz, M.
T. Angew. Chem., Int. Ed. 1991, 30, 1531-1546.
(12) Chiral HPLC analysis for 9 shows an ee > 98 %: Chiracel-OD,
UV detector 210 nm, 0.5 mL/min, 98:2 hexane/i-PrOH, tR 21.2 min; racemic
mixture, tR 21.2 and 26.0 min.
The first application of this method to obtain enantiopure
3-amino-1-bromo-1-nitroalkan-2-ols9 was carried out by
Org. Lett., Vol. 8, No. 26, 2006
5981