J. Am. Chem. Soc. 1999, 121, 6761-6762
6761
Table 1. Counter-Ion Effect on Regioselectivity in the
Rh-Catalyzed Allylic Amination Reaction
Enantiospecific Synthesis of Allylamines via the
Regioselective Rhodium-Catalyzed Allylic Amination
Reaction
P. Andrew Evans,* John E. Robinson, and Jade D. Nelson
Brown Laboratory
Department of Chemistry and Biochemistry
UniVersity of Delaware
entry
counterion Ma
ratio 2j/3jb
time (hrs)
yield (%)c
Newark, Delaware 19716
1
2
3
Li
Na
K
3:1
2.5:1
10:1
1.5
3.5
2.0
84
71
59
ReceiVed April 6, 1999
a All of the reactions were carried out on a 0.5 mmol reaction scale.
b Ratios determined by capillary GLC. c Isolated yields.
The transition metal-catalyzed allylic amination reaction pro-
vides a powerful method for the construction of chiral non-racemic
allylamines that represent important building blocks for target-
directed synthesis.1 The allylic amination of cyclic and acyclic
substrates, which proceeds through a symmetrical η3-intermediate
to circumvent potential regiochemical problems, furnish the
requisite allylamine in high yield and with excellent enantio-
selectivity.2 Racemic allylic epoxides also provide useful sub-
strates for this type of transformation, affording amino alcohol
derivatives with excellent regio- and enantioselectivity.3 However,
a recent survey of the metal-catalyzed allylic amination revealed
a surprising paucity of methods that can facilitate the regio- and
enantiospecific amination of unsymmetrical acyclic allylic alcohol
derivatives.1
We recently demonstrated that Wilkinson’s catalyst [Rh(PPh3)3-
Cl] may be modified in situ with triorganophosphites to furnish
a catalyst that facilitates the regioselective alkylation of acyclic
unsymmetrical allylic carbonates.4a In the course of these
investigations we established that the reaction proceeds with
overall retention of absolute configuration Via the proposed
intermediacy of an enyl (σ + π) organorhodium intermediate.4b,5
Herein, we describe the first regioselective rhodium-catalyzed
allylic amination of a series of unsymmetrical acyclic enantio-
merically enriched carbonates 1a-i with the lithium anion of
N-tosyl benzylamine to afford the secondary allylamines 2a-i
in high yield and with retention of absolute configuration (eq 1).
These enantiomerically enriched intermediates represent useful
synthons for the preparation of R-amino acids and nitrogen
containing heterocycles (vide infra).
Preliminary studies with classical nitrogen nucleophiles and the
trimethyl phosphite modified Wilkinson’s catalyst furnished the
allylic amination products in poor yield, and with modest
regioselectivity.6 The ability to balance the nucleophilicity and
basicity of the nucleophile was expected to moderate the reactivity
of the nucleophile, and thus improve catalytic activity and reduce
competitive elimination of the organometallic intermediate. The
N-toluenesulfonyl benzylamine, prepared from benzylamine and
p-toluenesulfonyl chloride, was anticipated to provide an improved
nitrogen nucleophile. Hence, the effect of the counter-ion on
solubility, turnover, and selectivity was examined. Treatment of
the allylic carbonate rac-1j with the alkali metal-salt of N-
toluenesulfonyl benzylamine and trimethyl phosphite modified
Wilkinson’s catalyst, furnished the corresponding allylic amination
products rac-2j/3j, as outlined in Table 1. The nature of the
counterion proved crucial, in which lithium was superior to both
sodium and potassium, in terms of reaction rate and regioselec-
tivity. The poor results obtained with sodium and potassium
counterions were again attributed to low solubility and high
basicity.
Table 2 summarizes the application of this transformation to a
variety of enantiomerically enriched carbonates 1a-i. The excel-
lent regioselectiVities and reaction rates represent a unique
solution to the metal-catalyzed allylic amination reaction. The
substituents examined indicate a high degree of tolerance in terms
of the regioselective outcome. Interestingly, the degree of
conservation of enantiomeric excess (cee)7 from the carbonate to
product appears to be independent of the regioselectivity (entries
3, 4, and 6). However, the enantiopurity of the allylic carbonates
does influence the degree of cee in the amination product (entry
1).8 The amination reaction proceeds with overall retention of
absolute configuration,9 which is consistent with a double
(1) For a recent review on allylic amination, see: Johannsen, M.; Jørgensen,
K. A. Chem. ReV. 1998, 98, 1689 and references therein. For a recent example
of an enantioselective approach to allylamines, see: Donde, Y.; Overman, L.
E. J. Am. Chem. Soc. 1999, 121, 2933.
(2) For leading references on transition metal-catalyzed allylic amination
reactions that proceed through symmetrical η3-intermediates, see: (a) von Matt,
P.; Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.; Feucht, T.; Helmchen, G.
Tetrahedron: Asymmetry 1994, 5, 573. (b) Togni, A.; Burckhardt, U.;
Gramlich, V.; Pregosin, P. S.; Salzmann, T. J. Am. Chem. Soc. 1996, 118,
1031. (c) Burckhardt, U.; Baumann, M.; Trabesinger, G.; Gramlich, V,; Togni,
A. Organometallics 1997, 16, 5252. (d) Trost, B. M.; Bunt, R. C J. Am. Chem.
Soc. 1994, 116, 4089. (e) Trost, B. M.; Radinov, R. J. Am. Chem. Soc. 1997,
119, 5962 and references therein.
(6) The poor results obtained with the hard nitrogen nucleophiles (Nu )
PhthNK; 4a/b ) 2:1; TsNHLi; 4a/b ) 3:1), were attributed, at least in part,
to their low solubility and high basicity which resulted in competitive
elimination. Conversely, the softer nitrogen nucleophiles (Nu ) PhNH2; 4a/b
) 10:1; Ph2NH.; 4a/b ) 1:9) provided homogeneous reaction mixtures that
furnished the allylic amination adducts with improved regioselectivity.
However, despite the improved selectivity the poor turnover rates and modest
yields of 4a/b deemed them unsuitable for preparative work, which was
presumably due to competitive coordination of the nucleophile with the metal
center. The crossover in regioselectivity for these nucleophiles is also rather
interesting, and most likely a steric effect.
(3) For leading references to transition metal-catalyzed allylic amination
using racemic vinyl epoxides, see: Trost, B. M.; Bunt, R. C. Angew Chem.,
Int. Ed. Engl. 1996, 35, 99.
(4) (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 38, 1725. (b)
Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(5) Enyl complexes can be defined as those having a discrete σ- and π-metal
carbon component within a single ligand. For definitions and examples, see:
(a) Sharp P. R. In ComprehensiVe Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: New York, 1995,
Chapter 2, p 272. (b) Lawson, D. N.; Osborn, J. A.; Wilkinson, G. J. Chem.
Soc. (A) 1966, 1733. (c) Tanaka, I.; Jin-no, N.; Kushida, T.; Tsutsui, N.;
Ashida, T.; Suzuki, H.; Sakurai, H.; Moro-oka, Y.; Ikawa, T. Bull. Chem.
Soc. Jpn. 1983, 56, 657 and references therein.
(7) The term conservation of enantiomeric excess {cee ) (product
ee/starting material ee) × 100} provides a convenient method of describing
the enantiopecificity of the reaction
(8) The loss in enantiopurity for the conversion of 1a to 2a is not specific
to this substrate, and was observed with other carbonates of similar
enantiomeric purity (96% ee).
(9) The retention of absolute configuration in the rhodium-catalyzed
amination, was assigned on the conversion of allylic carbonate 1e to (R)-
homophenylalanine, as outlined in Scheme 1.
10.1021/ja991089f CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999