moiety also functioned as an effective nucleophile for
gold(I)-catalyzed intramolecular allylic amination,
although the primary amine required 48 h to reach com-
pletion (Table 1, entries 2-4). In comparison, gold(I)-
catalyzed cyclization of benzyl carbamate 2e at room
temperature for 72 h formed pyrrolidine 3e in only 48%
yield (Table 1, entry 5). Substitution of AgClO4 for
AgSbF6 led to a marked increase in the efficiency of the
conversion of 2e to 3e (Table 1, entry 6), although this
transformation was still considerably slower than was the
gold(I)-catalyzed cyclization of substrates 2a-2c.
Scheme 1
We next investigated the effects of substitution, ring size,
and alkene configuration on the efficiency and diastereos-
electivity of gold(I)-catalyzed intramolecular allylic ami-
nation (Table 2). Cyclohexyl-substituted allylic alcohols4a
and 4b that possessed a benzylamine or R-methylbenzyl
amine nucleophile underwent intramolecular allylic ami-
nation to form pyrrolidines 5a and 5b, respectively, in high
yield and in the case of 4b with modest (2:1) diastereos-
electivity (Table 2, entries 1 and 2). gem-Dialkyl substitu-
tion along the alkyl chain that tethered the amino group to
the allylic alcohol moiety facilitated intramolecular allylic
amination but was not required (Table 2, entries 3-5). For
example, 6-amino-2-hexenol derivative 6a that possessed a
C5 phenyl group underwent cyclization at 60 °C to form a
separable 1.3:1 mixture of cis-7a and trans-7a in 95%
combined yield (Table 2, entry 3). Similarly, unsubstituted
6-(N-benzylamino)-2-hexenol (8; Z/E = 7.7:1) underwent
gold(I)-catalyzed cyclization at 60 °C to form 1-benzyl-2-
vinylpyrrolidine (9) in 86% yield (Table 2, entry 5).
Periodic analysisofthe conversion of 8 to 9 by GCrevealed
no significant difference in the rates of cyclization of (E)-8
and (Z)-8.
Gold(I)-catalyzed intramolecular allylic amination was
also effective for the formation of piperidine derivatives
(Table 2, entries 6-8). For example, gold(I)-catalyzed
cyclization of (Z)-6-(N-benzylamino)-2-heptenol (10; Z/E
g50:1) at 60 °C for 16 h led to isolation of 1-benzyl-2-vinyl
piperidine (11) in 91% yield (Table 2, entry 6). Similarly,
gold(I)-catalyzed cyclization of (Z)-8-(N-benzylamino)-3-
octen-2-ol (12) at 100 °C led to isolation of 2-(1-propenyl)
piperidine 13 in 99% yield with g50:1 diastereoselectivity
(Table2, entry 7). Gold(I)-catalyzed cyclizationofdithiane
derivative 14 that possessed a stereogenic center R to the
amino group at 100 °C for 48 h formed cis-2,6-disubsituted
piperidine 15 in 91% yield with 25:1 diastereoselectivity
(Table 2, entry 8). Piperidine 15 represents an advanced
intermediate in the synthesis of a range of naturally
occurring piperidine alkaloids.21
1). Piperidine (R,E)-13 represents a direct precursor to the
naturally occurring alkaloid (S)-(þ)-coniine, and this con-
nection was exploited to determine both the enantiopurity
and absolute configuration of (R,E)-13 generated via gold-
(I)-catalyzed cyclization of (R,Z)-12. To this end, one-pot
hydrogenative cleavage of the benzyl group and reduction
of the exocyclic CdC bond (Pd/C, MeOH, HCOOH)
followed by acidification with aqueous HCl gave (S)-(þ)-
coniine hydrochloridein 90% isolated yield asa white solid
{[R]20 þ6.9° (c 0.1, EtOH); lit. [R]21 þ7.1° (c 1.0,
D
D
EtOH)}.13,22 Chiral phase GC analysis of the correspond-
ing (S)-(þ)-coniine trifluoroacetamide (TFAA, Et3N,
85%) revealed an enantiomeric purity of 96% ee.
Together, these results established the complete transfer
of chirality in the conversion of (R,Z)-12 to (R,E)-13 and
net syn addition of the amine relative to the departing
hydroxyl group.
Although the syn substitution observed in the conver-
sion of (R,Z)-12 to (R,E)-13 is consistent with a concerted
SN20 pathway,23 a mechanism involving σ-activation of the
hydroxyl group appears unlikely given the low oxophilicity
of gold(I). Rather, the pronounced π-acidity of cationic
gold(I) complexes points to a mechanism involving nu-
cleophilic addition/OH-elimination initiated by π-activa-
tion of the allylic CdC bond.24,25 Within this framework,
the net syn-substitution in the conversion of (R,Z)-12 to
(22) For recent examples of the enantioselective synthesis of (S)-(þ)-
coniine, see: (a) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P.
Org. Lett. 2007, 9, 2473. (b) Girard, N.; Pouchain, L.; Hurvois, J.-P.;
Moinet, C. Synlett 2006, 1679. (c) Nagata, K.; Nishimura, K.; Yokoya,
M.; Itoh, T. Heterocycles 2006, 70, 335. (d) Itoh, T.; Nishimura, K.;
Nagata, K.; Yokoya, M. Synlett 2006, 2207. (e) Xu, X.; Lu, J.; Li, R.; Ge,
Z.; Dong, Y.; Hu, Y. Synlett 2004, 122. (f) Gommermann, N.; Knochel,
P. Chem. Commun. 2004, 2324. (g) Passarella, D.; Barilli, A.; Belinghieri,
F.; Fassi, P.; Riva, S.; Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron:
Asymmetry 2005, 16, 2225.
(23) (a) Magid, R. M. Tetrahedron 1980, 36, 1901. (b) Paquette, L. A.;
Stirling, C. J. M. Tetrahedron 1992, 48, 7383.
(24) For a recent review on the mechanisms of gold(I)-catalyzed
transformations, see: Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49,
5232.
To evaluate the selectivity of 1,3-chirality transfer in the
gold(I)-catalyzed intramolecular amination of allylic alco-
hols with secondary alkylamines, we employed enantio-
merically and diastereomerically enriched (R,Z)-12 (96%
ee, 95% de). Treatment of (R,Z)-12 with a catalytic 1:1
mixture of (1)AuCl and AgSbF6 led to isolation of (R,E)-
13 in 99% yield as a single diastereomer (g50:1) (Scheme
(25) For recent examples of cationic, two-coordinate gold π-alkene
complexes, see: (a) Brown, T. J.; Dickens, M. G.; Widenhoefer, R. A. J.
Am. Chem. Soc. 2009, 131, 6350. (b) Brown, T. J.; Dickens, M. G.;
Widenhoefer, R. A. Chem. Commun 2009, 6451. (c) Hooper, T. N.;
Green, M.; McGrady, J. E.; Patel, J. R.; Russell, C. A. Chem. Commun
2009, 3877. (d) Zuccaccia, D.; Belpassi, L.; Tarantelli, F.; Macchioni, A.
ꢀ
(21) Ying, Y.; Kim, H.; Hong, J. Org. Lett. 2011, ASAP; DOI:
10.1020/ol103064f.
J. Am. Chem. Soc. 2009, 131, 3170. (e) de Fremont, P.; Marion, N.;
Nolan, S. P. J. Organomet. Chem. 2009, 694, 551.
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Org. Lett., Vol. 13, No. 6, 2011