Gold(I)-catalyzed dynamic kinetic enantioselective intramolecular hydroamination of allenes

Article abstract of DOI:10.1021/ja0760731

Treatment of benzyl 6-methyl-2,2-diphenyl-4,5-octadienyl carbamate (2a) with a catalytic 1:2 mixture of [(S)-3,5-t-Bu-4-MeO-MeOBIPHEP]Au₂Cl₂ [(S)-1] and AgClO₄ (5 mol %) led to isolation of a 3.1:1 mixture of (R,Z)-3a and (R,E)-3a in 94% combined yield with 96 and 76% ee, respectively. Analyses of concentration versus time and/or conversion plots for the reaction of both racemic and enantiomerically enriched 2a with 1 were consistent with conversion of (R)-2a to (R,Z)-3a in the matched reaction manifold and conversion of (S)-2a to (R,E)-3a in the mismatched reaction manifold via the net anti-addition of Au and N across the internal C=C bond of 2a. Copyright

Full text of DOI:10.1021/ja0760731

Published on Web 10/30/2007
Gold(I)-Catalyzed Dynamic Kinetic Enantioselective Intramolecular
Hydroamination of Allenes
Zhibin Zhang, Christopher F. Bender, and Ross A. Widenhoefer*
French Family Science Center, Duke UniVersity, Durham, North Carolina 27708-0346
Received August 12, 2007; E-mail: rwidenho@chem.duke.edu
Table 1. Dynamic Kinetic Enantioselective Hydroamination
(DKEH) of N-(γ-Allenyl) Carbamates Catalyzed by a Mixture of
(S)-1 (2.5 mol %) and AgClO4 (5 mol %) in m-Xylene at 23 °C
Dynamic kinetic asymmetric transformations (DYKATs) con-
stitute a powerful class of reactions with the potential to convert
both enantiomers of a racemic starting material into a single
enantiomerically pure product with concomitant increase in mo-
lecular complexity.1 Although numerous DYKATs have been
reported,1 few form a C-X (X ) C, N, O) bond at a stereogenic
center, and absent are DYKATs that involve addition across a Cd
C bond.2 Because a number of transition metals catalyze the
functionalization3 and/or racemization4,5 of allenes, axially chiral
allenes represent attractive substrates for the development of
DYKATs that involve both C-X bond formation and CdC bond
functionalization. Nevertheless, DYKATs that employ axially chiral
allenes as substrates remain exceedingly rare.6,7
We recently reported the Au(I)-catalyzed enantioselective in-
tramolecular hydroamination of N-(γ-allenyl) carbamates catalyzed
by mixtures of [(S)-3,5-t-Bu-4-MeO-MeOBIPHEP]Au2Cl2 [(S)-1]
and AgClO4.8,9 Although cationic Au(I) complexes racemize
allenes,5 hydroamination of N-(γ-allenyl) carbamates that con-
tained a 1,3-disubstituted allenyl moiey catalyzed by (S)-1/AgClO4
occurred with high diastereoselectivity/low enantioselectivity in a
substrate-controlled process (eq 1).8 We reasoned that employment
of trisubstituted allenes might both attenuate substrate stereocontrol
and retard the rate of C-N bond formation relative to racemization,
leading to dynamic kinetic enantioselective hydroamination (DKEH).
Indeed, here we report the gold(I)-catalyzed DKEH of N-(γ-allenyl)
carbamates that possess trisubstituted allenyl groups.
yield (Z)-3
+
(Z)-3/
(E)-3
ee (Z)-3
ee (E)-3
entry
allene
(E)-3 (%)a
(%)
(%)
1
2a (X ) CPh2, R1 ) Me,
R2 ) Et)
94
3.1:1
10.1:1
2.6:1
96
91
87
95
2
76
9
2
2b (X ) CPh2, R1 ) Me,
R2 ) n-hexyl)
99
99
94
52
86
87
3b
4
2c (X ) CPh2, R1 ) Me,
R2 ) i-Bu)
54
67
-
2d (X ) CPh2, R1 ) Me,
R2 ) i-Pr)
2.0:1
5c
6
2e (X ) CPh2, R1 ) Me,
R2 ) t-Bu)
e1:25
4.3:1
2f (X ) CPh2, R1 ) Et,
R2 ) n-hexyl)
84
75
47
45
7
2g (X ) CH2, R1 ) Me,
R2 ) n-hexyl)
2.4:1
a Yield of isolated material of >95% purity. b Reaction run at 0 °C for
24 h followed by 23 °C for 24 h. c Reaction run at 60 °C for 212 h followed
by 100 °C for 48 h.
(S)-2a ) 45.8:48.1; 2.4% ee] and remained deficient throughout
95% conversion (Figure 1).10,11 This behavior is indicative of a
dynamic kinetic process in which (R)-2a (matched) is converted
to product more rapidly than is (S)-2a (mismatched) and is
continually replenished via racemization.
Mass balance requires formation of (R,Z)-3a from (R)-2a in the
matched reaction manifold in the reaction of 2a with (S)-1/AgClO4.
To determine whether (R,E)-3a was formed in the matched or
mismatched reaction manifold, we analyzed the (R,Z)-3a/(R,E)-3a
ratio as a function of conversion. If both (R,Z)-3a and (R,E)-3a
were formed in the matched reaction manifold, the (R,Z)-3a/(R,E)-
3a ratio should remain constant with increasing conversion.
Conversely, if (R,Z)-3a and (R,E)-3a were formed in matched and
mismatched reaction manifolds, respectively, the (R,Z)-3a/(R,E)-
3a ratio should decrease from its initial value due to deviation from
true Curtin-Hammett conditions.12 In support of this latter scenario,
the (R,Z)-3a/(R,E)-3a ratio decreased from an initial value of 3.8
to 3.5 at complete conversion (Figure 1).
Analysis of concentration versus time plots for the hydroami-
nation of enantiomerically enriched (R)-2a (44% ee) catalyzed by
either (S)-1/AgClO4 (matched) or (R)-1/AgClO4 (mismatched)
confirmed rapid racemization of 2a under the reaction conditions
(Figure 1).11 Furthermore, these experiments supported our assign-
ment of the major products formed in the matched and mismatched
reaction manifolds in the DKEH of 2a. In the case in which the
Treatment of a number of N-(γ-allenyl) carbamates that possessed
an axially chiral trisubstituted allenyl group with a catalytic mixture
of (S)-1/AgClO4 led to predominant formation of one of four
possible 2-vinyl pyrrolidine stereoisomers (Table 1). For example,
reaction of benzyl 6-methyl-2,2-diphenyl-4,5-octadienyl carbamate
(2a) with a catalytic 1:2 mixture of (S)-1 (2.5 mol %) and AgClO4
(5 mol %) in m-xylene at room temperature for 24 h led to isolation
of a 49:14:1.9:1 mixture of (R,Z)-3a/(R,E)-3a/(S,E)-3a/(S,Z)-3a in
94% combined yield (Table 1, entry 1).10,11 The formation of (R,Z)-
3a as 74% of the reaction mixture pointed to the dynamic nature
of enantioselective hydroamination. Accordingly, when the reaction
of 2a with (S)-1/AgClO4 was monitored periodically by HPLC
equipped with chiral stationary phase, the resulting concentration
versus time plot revealed that the relative concentration of (R)-2a
fell below that of (S)-2a within the first 6% conversion [(R)-2a/
9
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10.1021/ja0760731 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
bond with retention of configuration13 would form (R,Z)-3a. In the
major pathway of the mismatched reaction manifold, outer-sphere
cyclization of gold-allene complex (Si,S)-I followed by deproto-
nation/protonolysis would form (R,E)-3a. Analogous outer-sphere
pathways have been proposed on the basis of stereochemical
analysis for the gold(I)-catalyzed addition of nucleophiles to C-C
multiple bonds.14 Although the mechanism of racemization remains
unclear,5 the formation of (R,Z)-3a and (R,E)-3a in discrete reaction
manifolds argues strongly against racemization of 2a in the C-N
bond forming manifold.
In summary, we have presented the first examples of the dynamic
kinetic enantioselective hydroamination (DKEH) of axially chiral
allenes, and we provide experimental evidence for the dynamic
nature and mechanism of these transformations.
Acknowledgment. Acknowledgment is made to the NSF (CHE-
0555425), NIH (GM-080422), and Johnson&Johnson for support
of this research. We thank Dr. David Pham for determining the
X-ray crystal structure of (R,S)-S13.
Supporting Information Available: Experimental procedures,
spectroscopic data, and scans of NMR spectra and HPLC traces (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Figure 1. Plots of concentration versus time (left-hand column, minor
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Scheme 1
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matched enantiomer was initially present in excess [(R)-2a/(S)-1],
the (R,Z)-3a/(R,E)-3a ratio decreased rapidly from 4.5 to 3.9 early
in the reaction (0-20% conversion), whereas in the reaction in
which the mismatched enantiomer was initially present in excess
[(R)-2a/(R)-1], the (S,Z)-3a/(S,E)-3a ratio increased from 3.1 to 3.6
early in the reaction (0-20% conversion) (Figure 1). In both cases,
the product ratio mirrored the rapidly changing (R)-2a/(S)-2a ratio
early in the reaction.
The experiments described above support the mechanism for the
DKEH of rac-2a catalyzed by (S)-1/AgClO4 depicted in Scheme
1. In the major pathway of the matched reaction manifold,
complexation of gold to the Si face of the internal CdC bond of
(R)-2a followed by outer-sphere cyclization of gold-allene complex
(Si,R)-I would form alkenyl gold σ-complex (R,E)-II (Scheme 1).
Deprotonation of (R,E)-II followed by protonolysis of the Au-C
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