Highly site- and enantioselective Cu-catalyzed allylic alkylation reactions with easily accessible vinylaluminum reagents

Article abstract of DOI:10.1021/ja0782192

An efficient method for catalytic asymmetric allylic alkylation (AAA) of allylic phosphates with vinylaluminum reagents is reported. The vinylmetal reagents are prepared by reaction of commercially available DIBAL-H and a terminal alkyne. The resulting vi

Full text of DOI:10.1021/ja0782192

Published on Web 12/19/2007
Highly Site- and Enantioselective Cu-Catalyzed Allylic Alkylation Reactions
with Easily Accessible Vinylaluminum Reagents
Yunmi Lee, Katsuhiro Akiyama, Dennis G. Gillingham, M. Kevin Brown, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received October 26, 2007; E-mail: amir.hoveyda@bc.edu
Catalytic enantioselective addition of vinylmetals to activated
alkenes is a potentially versatile but underdeveloped class of trans-
formations.1 Compared to processes with arylmetals2 and, particu-
larly, alkylmetals,1a,b processes with the corresponding vinylic
reagents are of higher synthetic utility but remain scarce, and the
few reported examples are Rh-catalyzed conjugate additions.3 We
have developed an efficient method for catalytic asymmetric allylic
alkylations (AAA) with vinylaluminum reagents that are prepared
and used in situ; stereoselective reactions of commercially available
DIBAL-H with readily accessible terminal alkynes efficiently
deliver the vinylmetals. Alkylations are promoted by 0.5-2.5 mol
% chiral N-heterocyclic carbene (NHC)4 complexes derived from
an air stable Cu salt. To the best of our knowledge, this is the first
report of catalytic AAA reactions involving vinylmetal reagents.5
We began by examining reactions of vinylaluminum 2 with
allylic phosphate 1a, which belongs to a less-examined category
of substrates for catalytic AAA.6 Reagent 2 is generated from
hydroalumination of 1-octyne with DIBAL-H.7 When 2 is used to
alkylate 1a in the presence of 1 mol % CuCN, there is no reaction
(Table 1, entry 1). Alkylation proceeds to 65% conversion with
100 mol % CuCN in 3 h, but nearly all possible isomers are
generated (entry 2); formation of 3a is accompanied by 19% of
1,4-diene 4 as well as the product from transfer of an i-Bu group
(5, 10%). There is <2% conversion after 24 h with 1 mol % CuCl2‚
2H2O (entry 3), and achiral NHC 6 cannot help promote alkylation
(same outcome with (CuOTf)2‚C6H6 and 6). Similarly, in the
presence of chiral NHC‚Ag complexes 74a or 8,4b,8 there is no
reaction (entries 5,6). In a remarkable contrast, with only 0.5 mol
% 9a,9 AAA proceeds to >98% conversion in only 3 h, furnishing
3a in >98% ee and with >98% SN2′ and E selectivity.10 The high
enantioselectivity aside, the data in Table 1 highlight the unique
attributes of the Cu complex derived from 9a, which readily initiates
alkylation with exceptional site (>98% SN2′) and group selectivity
(<2% 5). Direct synthesis of vinylaluminums with DIBAL-H is
an attractive feature of the method and compares favorably with
other protocols. Previous two-step protocols3b involve alkyne
hydrozirconation with the more costly and sensitive11 Cp2ZrHCl
(or hydroboration) followed by transmetallation with Me2Zn, which
is also relatively expensive.12
Various allylic phosphates can be used (Table 2); >98%
conversion is obtained in 2-6 h with 0.5-1 mol % chiral catalyst.
Transformations of trisubstituted olefins bearing an aryl substituent
are shown in entries 1-8. Substrates bearing sterically demanding
groups (entries 1, 3, 6, and 8), electron-withdrawing aryl units
(entries 2-5) or an unsubstituted phenyl (entry 7) undergo AAA
in 82-94% yield and 87 to >98% ee. The reaction in entry 9 (88%
yield, 77% ee) is an efficient but less selective AAA of a
trisubstituted olefin with an n-alkyl substituent. The only AAA that
affords the undesired chiral SN2 product is one where the aryl
substituent contains an electron donating ortho methoxy group
(entry 6). As the examples in entries 10-12 indicate, alkylations
Table 1. Synthesis of Vinylaluminum Reagents and Use in
Catalytic Allylic Alkylationa
Table 2. Cu-Catalyzed AAA with Vinylaluminum Reagent 2a
NHC; mol %; temp
SN2′
yield
ee
entry
R1
R2
mol % Cu
(°
C) product (%)b (%)c (%)d
1
2
3
4
5
6
7
8
9
o-MeC6H4
o-BrC6H4
o-NO2C6H4 Me 1c 9a; 0.5; 1 -15
p-NO2C6H4 Me 1d 9a; 0.5; 1 -15
m-TsOC6H4 Me 1e 9a; 0.5; 1 -15
o-MeOC6H4 Me 1f
C6H5 Me 1g 9a; 0.5; 1 -15
1-naphthyl Me 1h 9a; 0.5; 1 -15
Ph(CH2)2 Me 1i 9b; 0.5; 1 -15
Me 1a 9a; 0.5; 1 -15
Me 1b 9a; 0.5; 1 -15
3a >98 87 >98
a Conditions: 2.0 equiv of vinyl-Al reagent (vs substrate) under N2. b 1H
NMR analysis (400 MHz). c By chiral HPLC (Supporting Information).
3b >98 84
3c >98 94
3d >98 93
3e >98 82
96
96
89
87
95
92
91
77
79
86
93
9a; 0.5; 1 -15
3f
90 88e
3g >98 84
3h >98 88
3i >98 88
10 C6H5
11 Cy
12 PhMe2Si
H
H
H
10a 9b; 1; 2
10b 9b; 1; 2
10c 9b; 0.5; 1 -15 11c >98 91
-50 11a >98 90
-50 11b >98 92
a Conditions: 2 equiv of vinyl-Al reagent (vs substrate); under N2. b 1H
NMR analysis (400 MHz). c Yield after purification; all conversions >98%.
d By chiral HPLC (Supporting Information). e Yield of pure SN2′ product.
9
446
J. AM. CHEM. SOC. 2008, 130, 446-447
10.1021/ja0782192 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
of disubstituted olefins proceed in high yield but are less selective
unless a sterically demanding group, such as a silyl substituent, is
present (entry 12). The findings in entries 9-12 of Table 2 involve
modified complex 9b, since in such cases, use of 9a leads to lower
selectivities; 1,4-dienes 3i and 11a,b,c are formed in 65%, 56%,
78%, and 90% ee, respectively, when 9a is employed. Reactions
in entries 1-8 proceed with identical degrees of asymmetric
induction when 9a or 9b are used.
bearing versatile alkyl halide substituents13 can be synthesized (19
in 92% ee). Tris(homoallylic) ether 20 and allylsilane 21 are
obtained in 93% and 89% ee, respectively, and exclusively as E
alkene isomers. Allylether 22 is, in contrast, formed with >98% Z
selectivity (80% ee).14 In the latter case, the initial hydroalumination
is likely directed by the proximal Lewis basic, albeit sterically
demanding, t-butoxy ether to generate a cis-vinylaluminum.
The utility of this method is showcased by the one-pot, gram-
scale transformation in eq 1. Treatment of 1-octyne with DIBAL-
H, addition of a mixture of 9a (0.5 mol %) and CuCl2‚2H2O (1
mol %, from a commercial bottle), followed by the addition of 1.42
grams of allylic phosphate 1g, results in the formation of 3g in
94% yield and 92% ee (>98% E). The Cu-catalyzed three-
component enantioselective process was performed on a bench top
without the need to resort to glovebox techniques.
Noteworthy are enantioselective syntheses of acyclic 1,4-diene
12 (91% ee) and bicyclic diene 13 (87% ee; 69% ee with 9a); these
transformations illustrate that catalytic AAA can be used with vinyl
bromides and cyclic alkenes. Other alkynes may be employed to
access products 14-17, bearing different vinyl groups (Table 3;
>98% SN2′ and E selectivity). Alkynes with sizable substituents
can be utilized: 1,4-diene 17 (entry 4, Table 3) is obtained in 93%
yield and 88% ee (82% ee with 9a).
Acknowledgment. Support was provided by the NIH (Grant
GM-47480), NSF (Grant CHE-0715138), Schering-Plough, and
Bristol-Myers Squibb (fellowships to Y.L. and M.K.B., respec-
tively). We thank P. Paredes for valuable experimental assistance.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Table 3. Cu-Catalyzed AAA of Vinylaluminum Reagent Derived
from Various Terminal Alkynesa
References
(1) (a) Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 4435-
4439. (b) Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem.
Commun. 2004, 1779-1785.
(2) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 4554-4558.
(3) For Rh-catalyzed asymmetric conjugate additions of vinylboronates and
vinylzirconocenes, respectively, to enones, see: (a) Hayashi, T.; Yamasaki,
K. Chem. ReV. 2003, 103, 2829-2844. (b) Nicolaou, K. C.; Tang, W.;
Dagneau, P.; Faraoni, R. Angew. Chem., Int. Ed. 2005, 44, 3874-3879.
(4) For other catalytic AAA involving chiral NHC complexes, see: (a) Larsen,
A. O.; Leu, W.; Nieto-Oberhuber, C.; Campbell, J. E.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 11130-11131. (b) Van Veldhuizen, J. J.;
Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 6877-6882. (c) Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto,
S. Tetrahedron Lett. 2004, 45, 5585-5588. (d) Lee, Y.; Hoveyda, A. H.
J. Am. Chem. Soc. 2006, 128, 15604-15605.
yield
(%)c
ee
entry
R
NHC
product
(%)d
1
2
3
4
PhCH2
9b
9a
9a
9b
14
15
16
17
85
90
91
93
91
92
91
88
(cyclopent)CH2
cyclohex
t-Bu
a Conditions: 2 equiv of vinyl-Al reagent (vs substrate); under N2. b 1H
NMR analysis (400 MHz). c Yield after purification; all conversions >98%.
d By chiral HPLC (Supporting Information).
Additional attributes of the method are illustrated by preparation
of 18-22. Enantioselective synthesis of 18 demonstrates that
conjugated enynes can be utilized to access chiral dienes. Products
(5) An example of hydroalumination of an alkyne/Cu-catalyzed asymmetric
conjugate addition to â-methylcyclohexenone has been reported (73%
ee): Vuagnoux-d’Augustin, M.; Alexakis, A. Chem.sEur. J. 2007, 13,
9647-9662.
(6) (a) Falciola, C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem., Int.
Ed. 2006, 45, 5995-5998. (b) Gillingham, D. G.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 3860-3864.
(7) Negishi, E.; Takahashi, T.; Baba, S. Org. Synth., Collect. 1993, 8, 295-
297.
(8) Lee, K. S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem.
Soc. 2006, 128, 7182-7184.
(9) (a) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 1097-1100. (b) Reference 2. (c) Reference 6b.
(10) When the precursor imidazolinium salt of 9a is used, 77% conversion is
observed (24 h, -15 °C) and 3a is formed in >98% ee (>98% E and
SN2′). There is, however, <2% conversion with the BF4‚imidazolinium
salt of 6.
(11) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675-3678.
(12) (a) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 7440-
7441. (b) Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1269-1279. (c)
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355-8361.
(13) For hydrolalumination of halogen-containing alkynes, see: Gardette, M.;
Jabri, N.; Alexakis, A.; Normant, J. F. Tetrahedron 1984, 40, 2741-
2750.
(14) For directed hydroalumination of propargylic t-butyl ethers, see: (a)
Alexakis, A.; Duffault, J. M. Tetrahedron Lett. 1988, 29, 6243-6246.
For a review on directed reactions, see: (b) Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
JA0782192
9
J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 447