favoring formation of R2CuM (M ) Li, MgX) reagents
facilitate formal SN2 substitution, while conditions favoring
formation of RCuXM (X ) Cl, CN; M ) Li, MgX) promote
SN2′ substitution involving allylic rearrangement. Use of
Lewis acid additives enhances SN2′ selectivity.7,8 This general
pattern holds for reactions involving copper(I)-catalyzed
Grignard reagents with allylic esters,8 halides,8c,9 and sulfides
of benzothiozole-2-thiol.10 Reactions of organocopper(I) or
lithium cuprate reagents with allylic halides display the same
general patterns.11 Et2O as a solvent generally favors SN2′
substitution, while THF favors SN2 substitution, although in
Et2O the choice of Cu(X) (X ) Cl, Br, I, CN)8c-d can
determine selectivity. Allylic phosphates12 strongly favor anti
SN2′ substitution with cuprates prepared from CuCN, while
CuOTf and CuSCN favor SN2 substitution. These results
illustrate the sensitivity of organocopper-mediated reactions
to solvent effects,8c-d,13a-c Cu(I) salt,8b,12,13d and the nature
of the reagent.4b,c,5,8b-d
corresponding alkoxides [LDA, -50 °C, THF] with (PhO)2P-
(O)Cl. These allylic phosphates, along with 1e, were unstable
to chromatographic purification (e.g., silica gel, alumina, or
florisil), and the crude preparations were used. The requisite
scalemic allylic alcohols needed for phosphates 2a,b were
obtained by asymmetric addition of 1-(5-phenyl)pentynylzinc
to isobutrylaldehyde (82%, 92% ee)14 followed by reduction
to either the trans15 or cis16 allylic alcohols. trans-Carveol17
was converted to phosphate 3, while cis-carveol18 was
converted to phosphate 4.
Deprotonation of carbamates 5a-c (Scheme 1) according
to Beak’s procedure19 followed by treatment with THF-
Scheme 1
Recent studies suggest that anti SN2′ regioselectivity may
be enhanced by use of allylic phosphates,5a-c,12 allylic
perfluorobenzoates,5d CuCN-derived cuprates5,8c-d,12 or zinc
cuprate5c-d reagents alone or in combination. With these
caveats in mind, the development of regio- and stereo-
selective reactions between allylic phosphates and R-(N-
carbamoyl)alkylcuprates was undertaken. We now report that
R-(N-carbamoyl)alkylcuprates undergo allylic substitution
reactions in high yield and that excellent SN2 or SN2′
regioselectivity can be obtained by judicious choice of
cuprate reagent, R-(N-carbamoyl)alkyl ligand, and reaction
conditions. Utilization of scalemic R-(N-carbamoyl)alkyl-
cuprates or scalemic allylic phosphates affords good to
excellent enantiocontrol.
Allylic phosphates 1a-e (Figure 1) were prepared by
soluble CuCN‚2LiCl afforded either the lithium alkylcyano-
cuprates 6a-c (i.e., RCuCNLi) or the lithium dialkylcuprates
7a-c (i.e., R2CuLi). Formation of scalemic cuprates from
5b required asymmetric deprotonation in Et2O followed by
addition of THF soluble CuCN‚2LiCl to afford a 1:1 Et2O/
THF solvent mixture of the stereogenic cuprate reagent.6 The
reaction of cuprate reagents 6a-c or 7a-c with allylic
phosphates gave homoallylic amines (Scheme 1, Table 1)
in modest to excellent yields.
reaction of the allylic alcohol [THF, Et3N, 25 °C]5a with
Reaction of cuprate reagents with allylic phosphates 1a,b
affords the same substitution product via either reaction
pathway. The alkylcyanocuprates 6a,b gave higher yields
of carbamoyl alkenes 8a,b than the corresponding lithium
dialkylcuprates 7a,b upon reaction with 1a (Table 1, entries
1-4). In the reactions of lithium dialkylcuprates 7a,b with
1a, homocoupling dimers [i.e., Me(Boc)NCH2CH2N(Boc)Me
(37%) and bis-N-Boc-pyrrolidine (22%), respectively] were
Figure 1. Allylic phosphates.
(13) (a) House, H. O.; Lee, T. V. J. Org. Chem. 1978, 43, 4369. (b)
Bertz, S. H.; Dabbagh, G. Tetrahedron 1989, 45, 425. (c) Christenson, B.;
Hallnemo, G.; Ullenius, C. Tetrahedron 1991, 47, 4739. (d) Bertz, S. H.;
Gibson, C. P.; Dabbagh, G. Tetrahedron Lett. 1987, 28, 4251.
(14) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
(15) Andre’s, J. M.; Pedrosa, R. Tetrahedron: Asymmetry 1998, 9, 2493.
(16) Burgstahler, A. W.; Widiger, G. J. Org. Chem. 1973, 38, 3652.
(17) Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437.
(PhO)2P(O)Cl in 65-90% yields after purification. Allylic
phosphates 2a,b, 3, and 4 were prepared by reaction of the
(12) (a) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron 1994,
50, 6017 and references therein. (b) Yanagisawa, A.; Nomura, N.; Noritake,
Y.; Yamamoto, H. Synthesis 1991, 1130.
(18) Ireland, R. E.; Maienfisch, P. J. Org. Chem. 1988, 53, 640.
(19) Beak, P.; Basu, A.; Gallaghar, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552 and references therein.
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Org. Lett., Vol. 6, No. 5, 2004