Efficient synthesis of allylic amines from α-aminoalkyl cuprates and enol triflates

Full text of DOI:10.1021/jo960272d

2930
J . Org. Chem. 1996, 61, 2930-2931
(Et2O, -78 °C, 0.5 M in carbamate)17 in the presence of
sparteine or TMEDA and added to 0.5 equiv of CuCN
suspended in THF. The solution was warmed to -55 °C
(30 min) to ensure cuprate formation and then cooled to
-78 °C. The cuprate reagent underwent a substitution
reaction (-78 °C to room temperature) with 1-cyclohexen-
1-yl trifluoromethanesulfonate to afford the allylic amine
in 57% (sparteine) and 77% (TMEDA) yield (Table 1,
entries 1 and 2). Coaddition of chlorotrimethylsilane and
the enol triflate resulted in a slightly higher yield (Table
1, entry 3) in contrast to the conjugate addition reac-
tions.15
Preparation of the organolithium reagent by direct
deprotonation or by transmetalation via the organostan-
nane appears to make little difference (Table 1, entries
5 and 6). Deprotonation of the tert-butyl carbamate of
pyrrolidine requires use of sparteine since the presence
of TMEDA has a deleterious effect upon either the
cuprate formation, stability, or reactivity (Table 1, entries
11 and 17).15b Reaction of the mixed dialkyl cuprates
[RLi, MeLi, CuCN, entry 7 (Table 1) and RCuMeLi, entry
8 (Table 1)] with the enol triflate of cyclohexanone affords
the substitution product. Reaction of a mixed dialkyl
cuprate prepared from CuCN with the enol triflate
derived from 4-phenylcyclohexanone (Table 1, entry 13)
reveals that the diminished yield (Table 1, entries 2 vs 7
and 12 vs 13) is due in large part to competitive transfer
of the methyl ligand. This suggests that R-aminoalkyl
ligands have reactivities roughly comparable to the
methyl ligand and lower than other alkyl ligands. In our
hands preparation of the phosphido18 mixed cuprate from
CuI gave significantly higher yields than that obtained
by preparation from CuBr‚Me2S (Table 1, entries 9 and
10). Although CuBr‚Me2S is often superior to CuI for
cuprate preparations,18,19a the observation is consistent
with higher product yields sometimes observed with
cuprates prepared from CuI than from CuBr.19
Efficien t Syn th esis of Allylic Am in es fr om
r-Am in oa lk yl Cu p r a tes a n d En ol Tr ifla tes
R. Karl Dieter,* J anice W. Dieter,
Christopher W. Alexander, and
Naseema S. Bhinderwala
Hunter Laboratory, Department of Chemistry, Clemson
University, Clemson, South Carolina 29634-1905
Received February 9, 1996
Allylic amines1 are an important class of compounds
in organic synthesis as evidenced by the continuing
development of numerous methods for their prepa-
ration.2-12 A characteristic feature of these methods is
the narrow range of applicability for generating a wide
array of substitution patterns in both cyclic and acyclic
amines. It appears that a simple, regioselective synthetic
route to allylic amines of diverse substitution patterns
is unavailable. We now report that R-aminoalkyl cu-
prates prepared from CuCN and 2 equiv of tert-butoxy-
carbonyl-protected R-amino organolithium reagents un-
dergo substitution reactions with enol triflates to afford
a direct and efficient synthesis of allylic amines.
Organocopper reagents are a powerful tool in the
arsenal of synthetic organic chemists, and innovative
developments continue to emerge.13 The reaction of enol
triflates with organocuprates14a,b has recently been ex-
tended to allylcuprate14c reagents. Recently, we re-
ported15 the development of R-aminoalkyl cuprates as
useful reagents for conjugate addition reactions and now
report that these reagents undergo substitution reactions
with enol triflates to afford allylic amines in good to
excellent yields (eq 1). The enol triflates used in this
study were readily prepared by established procedures.16
This methodology provides an opportunity to control
olefin regiochemistry in the product allylic amine as
illustrated for the regioisomeric enol triflates generated
from 2-methylcyclohexanone (Table 1, entries 14 and 15).
The more highly alkyl-substituted enol triflate was
obtained as a 90:10 mixture contaminated with the less
substituted regioisomer and this same ratio was retained
in the resultant allylic amines (Table 1, entry 15).
The enol triflate derived from 2-cyclohexenone gave
excellent yields with R-aminoalkyl cuprates derived from
N,N-dimethylamine and pyrrolidine (Table 1, entries 16
and 17) while the triflate derived from camphor (Table
1, entry 18) gave low yields of substitution product.
These yields in conjunction with those obtained with the
regioisomeric enol triflates of 2-methylcyclohexanone
Initially, the tert-butyl carbamate derivative of N,N-
dimethylamine was deprotonated with sec-butyllithium
(1) For a review on the synthesis of primary allylic amines see:
Cheikh, R. B.; Chaabouni, R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis
1983, 685.
(2) (a) Fischetti, W.; Mak, K. T.; Stakem, F. G.; Kim, J .-I.; Rheingold,
A. L.; Heck, R. F. J . Org. Chem. 1983, 48, 948. (b) Narula, C. K.; Mak,
K. T.; Heck, R. F. J . Org. Chem. 1983, 48, 2792. (c) Shimizu, I.; Tsuji,
J . Chem. Lett. 1984, 233. (d) Tamura, R.; Hayashi, K.; Kai, Y.; Oda,
D. Tetrahedron Lett. 1984, 25, 4437. (e) Murahashi, S.-I.; Imada, Y.;
Taniguchi, Y.; Kodera, Y. Tetrahedron Lett. 1988, 29, 2973. (f) Hayashi,
T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J . Am.
Chem. Soc. 1989, 111, 6301.
(3) Overman, L. E.; Freerks, R. L. J . Org. Chem. 1981, 46, 2833.
(4) (a) Schweizer, E. E.; Smucker, L. D.; Votral, R. J . J . Org. Chem.
1966, 31, 467. (b) Marxer, A.; Leutert, T. Helv. Chim. Acta 1978, 61,
1708. (c) Meyers, A. I.; Lawson, J . P.; Carver, D. R. J . Org. Chem. 1981,
46, 3119. (d) Cavalla, D.; Warren, S. Tetrahedron Lett. 1982, 23, 4505.
(5) Moriwake, T.; Hamano, S.; Saito, S.; Torii, S. Chem. Lett. 1987,
2085.
(6) (a) Dolle, R. E.; Li, C.-S.; Novelli, R.; Kruse, L. I.; Eggleston, D.
J . Org. Chem. 1992, 57, 128. (b) Kresze, G.; Mu¨nsterer, H. J . Org.
Chem. 1983, 48, 3561. (c) Natsugari, H.; Whittle, R. R.; Weinreb, S.
M. J . Am. Chem. Soc. 1984, 106, 7867. (d) Shea, R. G.; Fitzner, J . N.;
Frankhauser, J . E.; Spaltenstein, A.; Carpino, P. A.; Peevey, R. M.;
Pratt, D. V.; Tenge, B. J .; Hopkins, P. B. J . Org. Chem. 1986, 51, 5243.
(e) Sharpless, K. B.; Hori, T.; Truesdale, L. K.; Dietrich, C. O. J . Am.
Chem. Soc. 1976, 98, 269. (f) Sharpless, K. B.; Singer, S. P. J . Org.
Chem. 1976, 41, 2504.
(10) Keck, G. E.; Yates, J . B. Tetrahedron Lett. 1979, 4627.
(11) DeShong, P.; Leginus, J . M.; Lander, S. W., J r. J . Org. Chem.
1986, 51, 574.
(12) (a) Murai, T.; Yamamoto, M.; Kato, S. J . Chem. Soc., Chem.
Commun. 1990, 789. (b) Baruah, J . B.; Samuelson, A. G. Tetrahedron
1991, 47, 9449.
(13) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(14) (a) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1980, 21,
4313. (b) Scott, W. J .; McMurry, J . E. Acc. Chem. Res. 1988, 21, 47. (c)
Lipshutz, B. H.; Elworthy, T. R. J . Org. Chem. 1990, 55, 1695.
(15) (a) Dieter, R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33,
5693. (b) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407.
(16) (a) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(b) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1984, 106,
7500.
(17) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(18) Bertz, S. H.; Dabbagh, G. J . Org. Chem. 1984, 49, 1119.
(19) (a) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett.
1987, 28, 4251. (b) Dieter, R. K.; Lagu, B.; Deo, N.; Dieter, J . W.
Tetrahedron Lett. 1990, 31, 4105.
(7) Overman, L. E. J . Am. Chem. Soc. 1976, 98, 2901.
(8) (a) Germon, C.; Alexakis, A.; Normant, J . F. Bull. Chim. Soc.
Fr. 1984, II-377. (b) Germon, C.; Alexakis, A.; Normant, J . F.
Tetrahedron Lett. 1980, 21, 3763.
(9) (a) Fuks, R.; Viehe, H. G. Chem. Ber. 1970, 103, 564. (b)
Barluenga, J .; Aguilar, E.; J oglar, J .; Olano, B.; Fustero, S. J . Chem.
Soc., Chem. Commun. 1989, 1132.
S0022-3263(96)00272-1 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 9, 1996 2931
Ta ble 1. Su bstitu tion Rea ction s of Vin yl Tr ifla tes w ith r-Am in oa lk yl Cu p r a tes
suggest that the reaction is moderately sensitive to steric
hindrance in the triflate.
30%). Consequently, the R-aminoalkyl cuprate/vinyl
triflate and (R-aminoalkyl)lithium/aryl iodide couplings
provide complementary solutions to the coupling of
R-metalated amines with sp2-carbon centers. Although
sensitive to steric factors in the enol triflate and re-
stricted to amines with functional groups compatible with
carbanion formation, the method is extremely versatile
with regard to substitution patterns in both the substrate
and R-aminoalkyl cuprate reagent and should provide a
versatile synthetic route to a wide range of cyclic and
acyclic allylic amines.
These R-aminoalkyl cuprates did not undergo substitu-
tion reactions with the enol triflate derived from ethyl
acetoacetate or with aryl triflates (Table 1, entries 19 and
20). Iodobenzene did undergo reaction with the cuprate
reagent prepared from N,N-dimethylamine to afford the
benzylamine in 10% yield (Table 1, entry 21).
In summary, the reaction of R-aminoalkyl cuprates
with enol triflates affords an efficient synthesis of allylic
amines. Although cuprates containing nontransferable
ligands gave low yields of allylic amines and only a single
group is transferred from the 2 RLi/CuCN reagent, the
unused ligand can be recovered. Regiospecific generation
of enol triflates provides a regiocontrolled route to allylic
amines which may be problematic in Pd-promoted reac-
tions.2 In addition, the Pd/CuCN promoted coupling of
R-aminoalkyl lithium reagents with aryl iodides20a is not
readily extended to vinyl iodides or bromides20b (yield
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation (CHE-
9020793 and 9408912). The 3M Corporation (St. Paul,
MN) graciously provided samples of trifluoromethane-
sulfonic acid and anhydride for which we are grateful.
Su p p or tin g In for m a tion Ava ila ble: Spectra and a pro-
cedure (18 pages).
(20) Dieter, R. K.; Li, S. Tetrahedron Lett. 1995, 36, 3613; (b)
unpublished results.
J O960272D