C O M M U N I C A T I O N S
Table 1. Effect of Leaving Group and Additivesa
2d in the presence of 1 mol % of total iridium (0.5 mol % of
[Ir(cod)(κ2-L1)(L1)] and 0.25 mol % of Ir(cod)Cl]2) without any
significant change in yield, b:l ratio, or enantioselectivity (entry
11).
Published iridium-catalyzed allylations of aliphatic silyl enol
ethers occurred in only 46-54% yield, and reaction times were
also long (18-40 h).5 In contrast, the allylations of aliphatic
enamines generally occurred in high yield, with high selectivity,
and with much shorter reaction times (Table 2, entries 2, 4-8, and
11). The aliphatic enamine (2d) even coupled with a generally less
reactive straight chain allylic carbonate (1g) in satisfactory yield
and ee at 35 °C (entry 10).12 The allylation of aliphatic ketones
with allylic esters containing aliphatic substituents is rare.1a,6c
In summary, we have developed the first catalytic enantioselec-
tive allylation of ketone enamines to give the products from addition
to the more substituted position of an allyl electrophile, and these
reactions encompass rare examples of the enantioselective allylation
of any acyclic aliphatic ketone.1,13 Notable features of these reactions
include the absence of diallylation products, regioselective allylation
at the less hindered position of the enamine, high yields from
reactions of aliphatic ketone enamines, and high enantioselectivities
with a broad range of enamine nucleophiles and carbonate elec-
trophiles. Studies to extend these methods to the reactions of
prochiral enamines, aldehyde enamines, and 1,1-bis(amino)ethylenes
are ongoing.
entry
R1
OCO2R3
t (h)
additive
yieldb 3 (%)
yieldb 6 (%)
1
2
3
4
5
6
7
8
Ph
OCO2Me
OCO2Et
2
1.5
1.5
2.5
6
21
21
21
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
none
85
88
78
94
91
28
59
66
17
8
15
4
<2
ndc
ndc
ndc
OCO2i-Bu
OCO2i-Pr
OCO2t-Bu
OCO2i-Pr
OCO2i-Pr
OCO2i-Pr
Me
CaCl2
ZnCl2
a See Supporting Information. b NMR yield. c Byproduct 6 is volatile.
Table 2. Ir-Catalyzed Allylation of Enaminesa
Acknowledgment. We acknowledge financial support from the
NIH (NIH-GM58108 to J.F.H. and GM075703 to D.J.W.) and a
gift of IrCl3 from Johnson-Matthey. We thank Mark Pouy, Dr.
Timm Graening, and Dr. Yasuhiro Yamashita for synthesis of
several allylic alcohols used in this work. We thank the Denmark
and Zimmerman groups for the use of their instruments.
entry
R1
R2
3
t (h)
yieldb (%)
3:4c
% eed
1
2
3
Ph
Ph
Ph
Ph
Ph
i-Pre
3a
3b
6
5
3.5
4
2
91
86
86
91
91
75
90
86
68
64
84
>99:1
>99:1
96:4
98:2
97:3
85:15
98:2
98:2
95:5
89:11
98:2
94
95
96
96
96
94
97
77
94
83
95
2-anisyl 3c
4f
5h
6h
7h
8h
i-Bug
i-Bug
3d
3e
3f 11
3g
3h
3i
3j 39
3d 11
4-anisyl
4-(CF3)C6H4 i-Bug
2-furyl
2-anisyl
i-Bug
i-Bug
Ph
2
7.5
4
Supporting Information Available: Detailed experimental pro-
cedures and spectral data for all compounds synthesized. This material
9h,i Me
10 j
11k
Pr
Ph
i-Bug
i-Bug
References
a See Supporting Information. b Isolated yield of 3. c Determined by NMR
and/or GC/MS. d Determined by HPLC. e 95:5 ratio of regioisomers.
f Average of three runs. g 68:32 ratio of regioisomers. h Average of two runs.
i 2 equiv of enamine. j 1.5 equiv of enamine, 35 °C. k Reaction run with
0.5 mol % of Ir(cod)(κ2-L1)(L1) and 0.25 mol % of [Ir(cod)Cl]2.
(1) (a) Braun, M.; Meier, T. Angew. Chem., Int. Ed. 2006, 45, 6952. (b) Braun,
M.; Meier, T. Synlett 2006, 661. (c) Negishi, E.-i.; Liou, S.-y. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.;
John Wiley & Sons, Inc.: New York, 2002; Vol. 2, p 1769.
(2) Using chiral auxilliaries: (a) Hiroi, K.; Abe, J.; Suya, K.; Sato, S.; Koyama,
T. J. Org. Chem. 1994, 59, 203. Using enantioselective catalysis: (b)
Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952. See
Supporting Information for data.
ZnCl2 occurred in slightly higher yield than reactions with added
CaCl2 (Table 1, entries 7 and 8).
(3) Constant, S.; Tortoioli, S.; Mu¨ller, J.; Lacour, J. Angew. Chem., Int. Ed.
The reactions of a variety of enamines (2a-d) with allylic
carbonates (1a-g) were conducted under these optimized conditions
(Table 2). While reactions were nearly complete in as little as 1 h
(entry 5), reactions were allowed to run for several hours. Reaction
rates were similar for reactions of different enamines (entries 1-4),
but varied with the electronic (entries 4-7) and steric (entries 5 vs
8 and 9 vs 10) properties of the allylic carbonate.12
The regioselectivities at the allyl and enamine units were high
in most cases. The reaction of the electron-poor, p-CF3-substituted
cinnamyl carbonate 1c with the enamine of isobutyl methyl ketone
(2d) and the reaction of hexenyl carbonate 1g with enamine 2d
occurred with b:l ratios of 85:15 (entry 6) and 89:11 (entry 10).
All other reactions occurred with b:l ratios greater than 95:5. The
reactions of enamines from methyl alkyl ketones that exist as
mixtures of two regioisomers occurred regioselectively (g99:1) at
the less hindered position. The enantioselectivities were also high
in most cases. All reactions occurred in g94% ee, except for that
of enamine 2d with o-methoxycinnamyl 2-propyl carbonate (1e)10
(77% ee) and that of 2d with hexenyl carbonate 1g (83% ee). In
addition, the fast rates allowed carbonate 1a to react with enamine
2007, 46, 2082.
(4) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
(5) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 17192.
(6) (a) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180. (b) Behenna,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (c) Tunge, J.
A.; Burger, E. C. Eur. J. Org. Chem. 2005, 2005, 1715.
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2003, 125, 14272.
(8) (a) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem.
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J. F. J. Am. Chem. Soc. 2005, 127, 15506.
(9) (a) Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen, R.
Chem. Commun. 2007, 674. (b) Takeuchi, R.; Kezuka, S. Synthesis 2006,
3349. (c) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.;
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Thermodyn. 1982, 14, 125. (b) Hopfinger, C. M. Am. Midland Nat. 1912,
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(12) Thus far, reactions of the more hindered aliphatic allylic carbonate with
branching R to the allyl group (R1 ) i-Pr) have occurred to low
conversions.
(13) Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.; Dai, L.-X.;
Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544.
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