Gold(I)-catalyzed enantioselective hydroamination of N-allenyl carbamates

Article abstract of DOI:10.1021/ol071108n

Treatment of the W-4,5-hexadienyl carbamate 2a with a catalytic 1:2 mixture of [(S)-1]Au₂Cl₂ [(S)-1 = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] and AgClO₄ in m-xylene at -40°C for 24 h led to isolation of 2-vinylpyrrolidine 3a in 97% yield with 81% ee. Gold(I)-catalyzed enantioselective hydroamination was effective for a number of carbamate groups and tolerated terminal disubstitutution of the allenyl moiety.

Full text of DOI:10.1021/ol071108n

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2887-2889
Gold(I)-Catalyzed Enantioselective
Hydroamination of N-Allenyl Carbamates
Zhibin Zhang, Christopher F. Bender, and Ross A. Widenhoefer*
Duke UniVersity, French Family Science Center, Durham,
North Carolina 27708-0346
rwidenho@chem.duke.edu
Received May 13, 2007
ABSTRACT
Treatment of the N-4,5-hexadienyl carbamate 2a with a catalytic 1:2 mixture of [(S)-1]Au2Cl2 [(S)-1
)
(S)-3,5-t-Bu-4-MeO-MeOBIPHEP] and
AgClO4 in m-xylene at
−40 °C for 24 h led to isolation of 2-vinylpyrrolidine 3a in 97% yield with 81% ee. Gold(I)-catalyzed enantioselective
hydroamination was effective for a number of carbamate groups and tolerated terminal disubstitutution of the allenyl moiety.
Transition-metal-catalyzed addition of the N-H bond of an
amine or carboxamide derivative across a C-C multiple
bond (hydroamination) is a transformation with potential
application to target-oriented synthesis, pharmaceutical de-
velopment, and large-scale alkene functionalization.1 Al-
though considerable progress has been made in the area of
catalytic hydroamination, effective enantioselective processes
remain scarce.2 Rare earth and group 4 complexes catalyze
the enantioselective hydroamination of alkenes, but asym-
metric induction is typically modest, and the synthetic utility
of these systems is compromised by the excessive oxophi-
licity of the catalysts.3 In comparison, enantioselective
hydroamination catalyzed by late transition-metal complexes
typically suffers from limited scope, modest selectivity, and/
or high catalyst loading.4
the enantioselective, intramolecular hydroalkoxylation7 and
hydroarylation8 of allenes catalyzed by a 1:2 mixture of the
(3) (a) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc.
2003, 125, 14768. (b) O’Shaughnessy, P. N.; Knight, P. D.; Morton, C.;
Gillespie, K. M.; Scott, P. Chem. Commun. 2003, 1770. (c) O’Shaughnessy,
P. N.; Scott, P. Tetrahedron: Asymmetry 2003, 14, 1979. (d) Giardello,
M. A.; Conticello, V. P.; Brard, L.; Gagne, M. R.; Marks, T. J. J. Am.
Chem. Soc. 1994, 116, 10241. (e) Wood, M. C.; Leitch, D. C.; Yeung, C.
S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354. (f)
Riegert, D.; Collin, J.; Meddour, A.; Schulz, E.; Trifonov, A. J. Org. Chem.
2006, 71, 2514. (g) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737.
(h) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006,
128, 3748. (i) Meyer, N.; Zulys, A.; Roesky, P. W. Organometallics 2006,
25, 4179. (j) Collin, J.; Daran, J.-C.; Jacquet, O.; Schulz, E.; Trifonov, A.
Chem. Eur. J. 2005, 11, 3455. (k) Watson, D. A.; Chiu, M.; Bergman, R.
G. Organometallics 2006, 25, 4731. (l) Yu, X.; Marks, T. J. Organometallics
2007, 26, 365. (m) Hong, S.; Marks. T. J. J. Am. Chem. Soc. 2002, 124,
7886.
(4) (a) Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi, N. K.; Gridnev, I. D.;
Yamamoto, Y. J. Org. Chem. 2006, 71, 4270. (b) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 2000, 122, 9546. (c) Dorta, R.; Egli, P.; Zurcher,
F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857. (d) Pawlas, J.; Nakao,
Y.; Kawasura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669. (e)
Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4366.
As part of our ongoing efforts directed toward the
development of new methods for catalytic alkene hydro-
functionalization,5 we recently reported the intramolecular
exo-hydroamination of N-allenyl carbamates catalyzed by a
1:1 mixture of Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf6 and
(5) (a) Widenhoefer, R. A. Pure Appl. Chem. 2004, 76, 671. (b) Liu, C.;
Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700.
(c) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
9536. (d) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070. (e) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747. (f) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (g)
Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143.
(6) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066.
(1) (a) Beller, M.; Tillack, A.; Seayad, J. In Transition Metals for Organic
Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004; pp 403-414. (b) Beller,
M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368.
(c) Han, X.; Widenhoefer, R. A. Eur. J. Org. Chem. 2006, 4555. (d) Pohlki,
F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (e) Hong, S.; Marks, T. J.
Acc. Chem. Res. 2004, 37, 673.
(2) For recent reviews of enantioselective hydroamination, see: (a)
Hultzsch, K. C. Org. Biomol. Chem. 2005, 3, 1819. (b) Hultzsch, K. C.
AdV. Synth. Catal. 2005, 347, 367. (c) Roesky, P. W.; Muller, T. E. Angew.
Chem., Int. Ed. 2003, 42, 2708.
(7) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46,
283.
(8) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935.
10.1021/ol071108n CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/27/2007

bis(gold) phosphine complex [(S)-1]Au2Cl2 and either AgOTs
or AgBF4, respectively.9 On the basis of these results, we
began working toward a protocol for the enantioselective
hydroamination of N-allenyl carbamates. During the course
of these studies, Toste and co-workers reported the enanti-
oselective hydroamination of N-allenyl sulfonamides cata-
lyzed by bis(gold) complexes such as (R)-xylyl-BINAP-
(AuOPNB)2 [OPNB ) p-nitrobenzoate].10,11 Although
enantioselectivities of up to 99% ee were realized with this
system, effective hydroamination was restricted to N-allenyl
sulfonamides that possessed a terminally disubstituted allenyl
moiety. The authors also noted that N-allenyl carbamates
failed to undergo hydroamination under these conditions. We
found this latter limitation peculiar as preliminary results
from our laboratory pointed to the high activity of [(S)-1]-
Au2Cl2 as a precatalyst for the hydroamination of N-allenyl
carbamates. Here we provide an account of our results in
this area.
Table 1. Effect of Silver Source and Temperature on the
Enantioselective Hydroamination of 2a Catalyzed by
[(S)-1]Au2Cl2
Our approach to the development of a catalyst system for
the enantioselective hydroamination of N-allenyl carbamates
targeted the systems optimized for the enantioselective
hydroalkoxylation and hydroarylation of allenes.7,8 Unfor-
tunately, treatment of N-4,5-hexadienyl carbamate 2a with
a catalytic 1:2 mixture of [(S)-1]Au2Cl2 and either AgOTs
or AgBF4 required >6 days to reach completion to form
pyrrolidine 3a with e58% ee (Table 1, entries 1 and 2).
However, subsequent optimization revealed a pronounced
effect of the silver source on the rate of hydroamination
(Table 1). For example, reaction of 2a with a catalytic 1:2
mixture of [(S)-1]Au2Cl2 and AgClO4 was complete within
10 min at room temperature to form 3a as the exclusive
product with 66% ee (Table 1, entry 8). This represents a
1000-fold increase in reaction rate relative to cyclization
employing AgOTs with no deterioration in enantioselectivity.
The high activity of the [(S)-1]Au2Cl2/AgClO4 catalyst
system allowed the reactions to be conducted at low
temperature, which led to a marked increase in enantiose-
lectivity (Table 1, entries 9 and 10). Subsequent optimization
with respect to solvent revealed that substitution of m-xylene
for toluene produced a modest but reproducible increase in
enantioselectivity (Table 1, entry 11). In a preparative-scale
experiment, reaction of 2a with a catalytic mixture of [(S)-
1]Au2Cl2 and AgClO4 in m-xylene at -40 °C for 24 h led
a [2a] ) 0.30 M. b [2a] ) 0.30 M in m-xylene.
to isolation of 3a in 97% yield with 81% ee (Table 2, entry
1).12
Enantioselective hydroamination catalyzed by [(S)-1]-
Au2Cl2/AgClO4 was effective for a number of carbamate
(2b-d) and carboxamide nucleophiles (2e), forming the
corresponding pyrrolidines 3b-e with 73-84% ee (Table
2, entries 2-5).13 Likewise, N-allenyl carbamates that
possessed a terminally disubstituted allenyl moiety (4-6)
underwent gold(I)-catalyzed enantioselective hydroamination
to form the corresponding pyrrolidines 7-9 in good yield
with 76-91% ee (Table 2, entries 6-8). In contrast, gold-
(I)-catalyzed conversion of N-(4,5-undecadienyl)carbamate
10 to 2-(1-hepteny)pyrrolidine 11 occurred with high dias-
tereoselectivity but with negligible enantioselectivity (Table
2, entry 9), which pointed to predominant substrate control
of stereoinduction. Substrate contol of stereoinduction was
also observed for the hydroarylation of axially chiral 2-allenyl
indoles catalyzed by [(S)-1]Au2Cl2/AgBF4.8 In contrast,
stereoinduction in the hydroalkoxylation of axially chiral
γ-hydroxyallenes catalyzed by [(S)-1]Au2Cl2/AgOTs was, to
an overwhelming extent, controlled by the catalyst.7 The
(9) For recent examples of gold-catalyzed hydroamination, see: (a) Liu,
X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (b) Gorin, D. J.;
Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (c)
Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun. 2006,
661. (d) Kang, J.-E.; Kim, H.-B.; Lee, J.-W.; Shin, S. Org. Lett. 2006, 8,
3537. (e) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey,
W. Eur. J. Org. Chem. 2006, 4905. (f) Nishina, N.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 3314. (g) Patil, N. T.; Lutete, L. M.; Nishina, N.;
Yamamoto, Y. Tetrahedron Lett. 2006, 47, 4749. (h) Morita, N.; Krause,
N. Eur. J. Org. Chem. 2006, 4634. (i) Zhang, J.; Yang, C.-G.; He, C. J.
Am. Chem. Soc. 2006, 128, 1798.
(10) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 2452.
(12) Treatment of 2a (0.30 M) with either [(S)-1]Au2Cl2 (2.5 mol %) or
a mixture of (S)-1 (2.5 mol %) and AgClO4 (5 mol %) in m-xylene at rt for
24 h led to no consumption of 2a.
(13) N-Allenyl sulfonamides failed to undergo efficient enantioselective
hydroamination under these conditions. For example, reaction of N-(2,2-
diphenyl-4,5-hexadienyl)-p-toluenesulfonamide (0.30 M) with a catalytic
mixture of [(S)-1]Au2Cl2 (2.5 mol %) and AgClO4 (5 mol %) at -20 °C
for 48 h led to 66% conversion to form 4,4-diphenyl-1-p-toluenesulfonyl-
2-vinylpyrrolidine with 8% ee.
(11) For additional examples of enantioselective transformations catalyzed
by chiral bis(gold) complexes of the form (P-P)Au2X2 (P-P ) bidentate
phosphine; X ) anionic ligand or counterion), see: (a) Munoz, M. P.; Adrio,
J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293.
(b) Gonza´lez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem.
Commun. 2005, 3451. (c) Johansson, M. J.; Gorin, D. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002.
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Org. Lett., Vol. 9, No. 15, 2007

lective hydroamination of N-allenyl sulfonamides catalyzed
by (R)-xylyl-BINAP(AuOPNB)2.7,10 The substrates in these
latter examples differ from 13 both in the nature of the
nucleophile and in the degree of substitution at the terminal
allenyl carbon atom. The possibility that the absolute
configuration of the pyrrolidines formed in the gold(I)-
catalyzed hydroamination of N-allenyl carbamates was
affected by the presence or absence of substitution at the
terminal allenyl carbon atom was firmly ruled out by the
following experiments. Pyrrolidines 3a and 8 were con-
verted separately to the 2-methoxycarbonylpyrrolidine (+)-
16 via oxidative cleavage of the CdC bond followed by
esterification (Scheme 1). Pyrrolidine (+)-16 generated
Table 2. Enantioselective Hydroamination of N-Allenyl
Carbamates and Carboxamides (0.30 M) Catalyzed by a Mixture
of [(S)-1]Au2Cl2 (2.5 mol %) and AgClO4 (5 mol %) in
m-Xylene
Scheme 1
from 3a and (+)-16 generated from 8 possessed the same
absolute configuration as determined by chiral HPLC
analysis.15
In summary, we have developed a gold(I)-catalyzed
protocol for the enantioselective hydroamination of N-allenyl
carbamates. The protocol was effective for a number of
carbamate and carboxamide nucleophiles and tolerated
disubstitution at the terminal allenyl carbon atom. Con-
versely, enantioselective hydroamination was sensitive to
substitution on the alkyl chain that tethered the carbamate
group to the allenyl moiety. We continue to work toward
the identification of more selective and more general catalysts
for enantioselective hydroamination and toward an under-
standing of the mechanisms of stereoinduction in this process
and in related hydrofunctionalization processes.
a Conditions: A ) -40 °C, 24 h; B ) -20 °C, 48 h; C ) -40 °C, 24
h followed by -20 °C, 24 h; D ) -20 °C, 48 h followed by rt, 24 h; E )
0 °C, 24 h followed by rt, 24 h; F ) 0 °C, 24 h; G ) -20 °C, 24 h.
enantioselectivity of hydroamination was sensitive to the
nature of the groups at the C2 position of the 4,5-hexadienyl
chain. For example, gold(I)-catalyzed hydroamination of the
cyclohexyl-substituted N-allenyl carbamate 12 or the unsub-
stituted derivative 13 led to formation of pyrrolidines 14 and
(S)-15,14 respectively, in excellent yield but with e50% ee
(Table 2, entries 10 and 11).
Acknowledgment is made to the NSF (CHE-0304994 and
CHE-0555425) and Johnson & Johnson for support of this
research. We thank Dr. Rudolf Schmid (Hoffmann-La Roche)
for a gift of (S)-1.
It is worth noting that the sense of absolute stereoinduction
in the conversion of 13 to (S)-15 catalyzed by [(S)-1]Au2Cl2
(Table 2, entry 11) is opposite that observed for the
enantioselective hydroalkoxylation of γ-hydroxy allenes
catalyzed by [(S)-1]Au2Cl2/AgOTs and for the enantiose-
Supporting Information Available: Experimental pro-
cedures and scans of chiral HPLC traces and NMR spectra
for pyrrolidines. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) (a) An authentic sample of (S)-15 (98% ee) was prepared from
commercially available Z-L-prolinol in two steps employing published
procedures.14b,c (b) Takeuchi, T.; Yamada, A.; Suzuki, T.; Koizumi, T.
Tetrahedron 1996, 52, 225. (c) Seijas, J. A.; Va´zquez-Tato, P.; Castedo,
L.; Este´vez, R. J.; OÄ nega, M. G.; Ru´ız, M. Tetrahedron 1992, 48, 1637.
OL071108N
(15) A solution of (+)-16 (∼13 mM, 84% ee) in hexane/CH2Cl2 [1:1
(v/v)] in a 10 cm cell displayed an optical rotation of +0.41.
Org. Lett., Vol. 9, No. 15, 2007
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