Catalytic asymmetric vinylation of ketone enolates.

Article abstract of DOI:10.1021/ol0159470

[see reaction]. A protocol for the catalytic asymmetric vinylation of ketone enolates has been developed. Key to the success of this process was the development of new electron-rich chiral monodentate ligands.

Full text of DOI:10.1021/ol0159470

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1897-1900
Catalytic Asymmetric Vinylation of
Ketone Enolates
Andre´ Chieffi, Ken Kamikawa, Jens Åhman, Joseph M. Fox, and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received April 5, 2001
ABSTRACT
A protocol for the catalytic asymmetric vinylation of ketone enolates has been developed. Key to the success of this process was the development
of new electron-rich chiral monodentate ligands.
We recently reported the catalytic asymmetric arylation of
ketone enolates employing Pd(0)/(S)-BINAP as catalyst. This
reaction, in several instances, proceeded in good yields and
with high levels of enantioselectivity.1,2 When we attempted
an analogous coupling reaction using a vinyl bromide, the
desired product was formed in low yield and low ee.
Catalysts derived from the aminophosphine ligand 2-(N,N-
dimethylamino)-2′-(dicyclohexylphosphino)-biphenyl (1a)2b
as well as the simpler desamino ligands (1b-e)3 are
extremely active for a number of palladium-catalyzed cross-
coupling reactions, including the R-arylation of ketones.2b,c
As such, we focused our efforts on the preparation of
enantiomerically pure analogues of these (Figure 1)4,5 and
investigated their use in the asymmetric vinylation of ketone
enolates.6
To develop a useful protocol, we first studied the reaction
of 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone
(4a)7 with trans-1-bromopropene under a variety of condi-
tions. Using 2.5 mol % Pd2(dba)3/6.5 mol % 2a with
NaOtBu as base, the desired product (5a) was produced in
high yield (95%) with high enantioselectivity (90% ee) when
the reaction was performed in toluene at room temperature.8,9
We also found that we could increase the enantioselectivity
by lowering the reaction temperature. At 0 °C the ee
increased to 94%, and at -20 °C the ee was 96%. However,
(1) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 1918.
(2) For a racemic version, see: (a) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108. (b) Old, D. W.; Wolfe, J. P.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 9722. (c) Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. (d) Hamann, B.
C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382. (e) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. For catalytic intramo-
lecular vinylations of ketones, see: (f) Piers, E.; Renaud, J. J. Org. Chem.
1993, 58, 11. (g) Sole´, D.; Piedro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225.
(h) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057.
(3) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Wolfe, J. P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (c) Wolfe, J. P.;
Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9550.
Figure 1.
10.1021/ol0159470 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/18/2001

at temperatures below 0 °C the reaction was quite slow
(Table 1, entries 1-3). Using 0.1 mol % Pd2(dba)3 the
2a provides a general method for obtaining a variety of
R-vinyl cyclopentanones in good yields and with moderate
to high levels of enantioselectivity.
The enantioselectivity of the coupling process was strongly
influenced by the structure of the vinyl bromide. The
coupling of vinyl bromide and trans-bromoalkenes proceeded
with high enantioselectivity (>90% ee). When cis-1-bromo-
propene was used as a substrate, the enantiomeric excess
dropped to 76% (Table 2, entry 6). The coupling of a 2,2-
disubstituted alkene, 1-bromo-2-methylpropene (entry 4),
showed approximately the same level of enantioselectivity
as that of cis-1-bromopropene (entry 6). We also briefly
examined the reaction using vinyl chlorides. Under the same
conditions as those described for 1-bromo-2-methylpropene,
use of the corresponding chloride provided the product in
lower yield but with the same enantiomeric excess (entry
5). In contrast to what was observed for the asymmetric
ketone arylation reactions with BINAP, the size of the
R-alkyl substitutent of 4 did not significantly influence the
reaction rate or enantioselectivity (entries 2, 7, and 8).
The vinylation of 1-methylindanone and 1-methyltetralone
with vinyl bromide and trans-1-bromopropene also pro-
ceeded in very good yield and with good enantioselectivity
(Table 2, entries 10 and 11). In these cases, similar results
were obtained in the coupling of a cyclohexanone and
cyclopentanone derivative. However, a considerable differ-
ence in the enantioselectivity was observed when 4a and the
corresponding cyclohexanone derivative 4d were coupled
with trans-1-bromopropene under identical conditions
(entries 1 and 9). While the reaction of 4a proceeded in very
high yield in a highly enantioselective fashion (90% ee), the
product from 4d was formed in lower yield and considerably
lower enantiomeric purity (50% ee). Similar differences in
enantioselectivity were observed for the reactions of five-
and six-membered-ring cyclic ketones in the asymmetric
arylation of ketones.1
Table 1a
entry
ligand
temp
rt
time
conversionb
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2a
2a
2a
2b
2c
2d
2d
2e
2f
3 h
24 h
24 h
2 h
24 h
24 h
3 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
100%
98%
75%
100%
40%
<10%
100%
93%
90%
60%
trace
trace
<10%
85%
90
94
96
74
56
ndd
65
80
82
35
nd
nd
nd
56
0 °C
-20 °C
40 °C
rt
rt
rt
0 °C
0 °C
0 °C
rt
50 °C
rt
3a
3a
3b
3b
50 °C
a Reactions were run at 0.2 M (4a), with 2 equiv of 1-bromopropene
and NaOt-Bu. b Conversion was determined by GC. c The ee was determined
by chiral HPLC. d Not determined.
reaction proceeded to 90% conversion after 2 days at room
temperature with the enantioselectivity of the reaction still
high (86% ee). Upon increasing the temperature to 50 °C,
the coupling product was obtained in 83% yield after 24 h,
but the enantioselectivity was lower (74% ee). However, at
50 °C with Pd:L 1:3 (0.1 mol % Pd2(dba)3), 5a was formed
in 71% yield and 85% ee.10
Next, we extended our investigation to a series of
R′-blocked R-alkylcycloalkanones. As illustrated in Table
2, the asymmetric vinylation of cyclic ketones using Pd2(dba)3/
When 2-alkyl-5-(N-methyl-anilinomethylene)cycloalkanones
were used as coupling partners, the corresponding R-vinyl
ketones were obtained after hydrolysis of the coupled product
followed by a retro-Claisen reaction (Figure 2).11 This
(4) Ligands 2a-2c were prepared in several steps from (rac)-2, 2′-
dibromo-1,1′-binaphthyl. Ligands 2d-2f were prepared in several steps from
(R)-(+)-2,2′-diiodo-1,1′-binaphthyl. Ligand 2a has recently been used in
catalytic asymmetric Suzuki couplings to give axially chiral biaryls: Yin,
J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
(8) Typical Procedure. An oven-dried Schlenk tube was capped with a
rubber septum and cooled under argon. The tube was then charged with
tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol, 1 mol %),
2a (12.4 mg, 0.025 mmol, 2.5 mol %), and 2-methyl-5-(N-methyl-
anilinomethylene)-cyclopentanone (216 mg, 1.0 mmol). Toluene (2 mL)
was added, and the mixture was stirred for 15 min at room temperature.
1-Bromopropene (0.17 mL, 2.0 mmol) and sodium tert-butoxide (192 mg,
2.0 mmol) were added, and the tube was capped with the septum and purged
with argon. Additional toluene (4 mL) was added through the septum, and
the mixture was stirred at room temperature until the starting ketone had
been completely consumed, as judged by GC analysis. The reaction mixture
was quenched with saturated aqueous NH4Cl (10 mL) and diluted with ether
(20 mL). The layers were separated, the aqueous layer was extracted with
ether (20 mL), and the combined organics were washed with brine (20 mL),
dried (MgSO4), filtered, and concentrated. Chromatography gave 242 mg
(95%) of the desired compound, which was judged to be 90% ee by chiral
HPLC analysis.
(5) Three groups have prepared optically pure 2b by methods different
than the one reported here: (a) Vyskocˇil, Sˇ.; Smrcˇina, M.; Hanusˇ, V.;
Pola´sˇek, P.; Kocˇovsky´, P. J. Org. Chem. 1998, 63, 7738. (b) Sumi, K.;
Ikariya, T.; Noyori, R. Can. J. Chem. 2000, 78, 697. (c) Ding, K.; Wang,
Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.; Okubo, Y.; Mikami, K. Chem.
Eur. J. 1999, 5, 1734. In addition, the racemic form of 2a was reported:
216th Meeting of the American Chemical Society, August 23-27, 1998,
Buchwald, S. L.; Wagaw, S.; Yang B. H. ORGN-004. For applications of
2b, see: (d) Kocˇovsky´, P.; Vyskocˇil, Sˇ.; C´ısaˇrova´, I.; Sejbal, J.; Tisˇlerova´,
I.; Smrcˇina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray,
M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714. (e) Kocˇovsky´, P.;
Malkov, A.; Vyskocˇil, Sˇ.; Lloyd-Jones, G. C. Pure Appl. Chem. 1999, 71,
1425. (f) Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.;
Vyskocˇil, Sˇ.; Kocˇovsky´, P. Chem. Eur. J. 2000, 6, 4348.
(6) For the Pd-catalyzed asymmetric alkylation of ketone enolates: (a)
Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759. (b)
You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001, 3, 149.
(7) 2-Methyl-5-(N-methyl-anilinomethylene)cyclopentanone was prepared
in 82% yield by the Claisen condensation of 2-methylcyclopentanone with
ethyl formate followed by reaction with N-methylaniline.
(9) Although we optimized the conditions using toluene as solvent and
Pd2(dba)3 as the palladium source, similar results were obtained using Pd2-
(dba)3 in Et2O and Pd(OAc)2 in toluene.
(10) For the reaction at room temperature, neither the yield nor the
enantioselectivity of the reaction is very sensitive to the Pd:L ratio; the
same result was obtained using ratios of 1/1.25, 1/2, or 1/3.
(11) The lower yields of 6c and 6d are due to difficulties during the
isolation and purification steps due to their high volatility.
1898
Org. Lett., Vol. 3, No. 12, 2001

Table 2. Coupling between Ketone Enolates and Vinyl Halides Catalyzed by Pd2(dba)3/(R)-(-)-2aa
a Reactions were run at 0.2 M (ketone), with 2 equiv of 1-bromopropene and NaOt-Bu and with Pd/L ratio ) 1:1.25. b Yields are an average of two
isolated yields of >95% purity as determined by GC, 1H NMR, and elemental analysis. c The ee was determined by chiral HPLC. d Reactions were run with
1 mol % Pd2(dba)3. e Reactions were run with 2.5 mol % Pd2(dba)3. f 4:1 mixture of E/Z isomers of the vinyl bromide was used. g Yield is for a mixture of
E/Z isomers. h Enantiomeric excess reported is for the E isomer. i (S)-(-)-2a was used.
provides the first general route to cyclopentanone derivatives
of this sort in highly enantiomerically enriched form.12
The absolute configurations of the new ligands introduced
here, and of R-vinyl ketones 6a and 6b, were determined as
follows. Levorotatory 2a and 2c and dextrorotatory 2-bromo-
2′-N,N-(dimethylamino)-1,1′-binaphthyl were shown to have
the (R)-configuration, as the last compound, when treated
with n-BuLi and Ph2PCl, gives (R)-(-)-2b.5a The (R)-
configuration was also assigned to the quaternary chiral
carbons of dextrorotatory 6a and 6b, both of which were
obtained from reactions of (S)-(+)-2a.13 The same sense of
chirality was induced by monophosphines that lack the
(12) For a review on the preparation of chiral quaternary centers, see:
Fuji, K. Chem. ReV. 1993, 93, 2037.
(13) Upon treatment with O3/Me2S, 6a and 6b gave (+)-2-formyl-2-
methylcyclpentanone. Subsequent reaction with trimethylphosphono acetate/
NaH gave (+)-2-methyl-2-(2-trans-methoxycarbonyl-1-ethenyl)cyclopen-
tanone, which is known to have the (R)-configuration. See: (a) Tori, M.;
Miyake, T.; Hamaguchi, T.; Sono, M. Tetrahedron Asymmetry 1997, 8,
2731. (b) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem.
Soc. 1985, 107, 273.
Figure 2.
Org. Lett., Vol. 3, No. 12, 2001
1899

dimethylamino group of 2b; ligands 2d-f with the (R)-
configuration gave (S)-(+)-5a.
Acknowledgment. We thank the National Institutes of
Health (GM 34917) for funding this research. Additional
unrestricted support from Pfizer, Merck, and Novartis is also
gratefully acknowledged. We thank Strem Chemical for
providing (R)-(+)-2,2′-diiodo-1,1′-binaphthyl. A.C. was sup-
ported by a FAPESP postdoctoral fellowship. K.K. thanks
Japan Society for the Promotion of Science for a postdoctoral
fellowship. J. A° . was a Wallenberg Foundation Postdoctoral
Fellow. J.M.F. thanks the NIH for a postdoctoral fellowship.
We are indebted to Professor S. K. Kang for experimental
assistance.
The mechanism of the vinylation reaction presumably
follows a pathway similar to the one proposed for the
nonasymmetric arylation of ketones.2 It is not clear at this
time which step in the catalytic cycle determines the
enantioselectivity of the process. Our view is that the
dimethylamino moiety of 2a does not bind to the Pd complex
to form a four-coordinate intermediate or that, if it does, this
binding is not necessary for an efficient reaction. This belief
is due to several findings. First, we have recently disclosed
that reactions utilizing 1b-e as ligands are similar in
efficiency to those which use 1a.2c,3 Second, reactions that
employed monodentate ligands such as 2d and 2e provided
only slightly lower levels of enantioselectivity than those
using 2a.14,15 In contrast, bidentate ligands such as 3b
produced the coupled product with significantly lower ee.
In summary, we have prepared a class of chiral electron-
rich monodentate phosphines and have used them for the
catalytic asymmetric vinylation of ketones. This reaction
proceeds in very good yields and with high enantioselectivity.
Work on the application of these and related novel ligands,
including P chiral ligands, in a variety of catalytic asymmetric
processes is currently in progress.
Supporting Information Available: Complete experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0159470
(14) It is likely that the enantioselectivity induced by 2a is greater than
that by 2d or 2e because the dimethylamino group is larger than either Me
or n-Bu. That changing the size of the R1 substituent of ligands 2 can
dramatically alter the enantioselectivity is further illustrated by the low ee
that is obtained with ligand 2f. Unfortunately, our efforts to prepare the
isopropyl analogue of these ligands (which would be similar to 2a in terms
of sterics) have thus far been unsuccessful.
(15) For the use of chiral monodentate phosphine MOP-ligands in
asymmetric catalysis: (a) Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
1900
Org. Lett., Vol. 3, No. 12, 2001