Highly enantioselective catalytic phenylation of ketones with a constrained geometry titanium catalyst

Article abstract of DOI:10.1021/ol0352963

(Matrix Presented) The catalytic asymmetric addition of phenyl groups from diphenylzinc to ketones is reported. The catalyst, generated from a dihydroxy bis-(sulfonamide) ligand and titanium tetraisopropoxide, gives good to excellent enantioselectivities with a range of substrates.

Full text of DOI:10.1021/ol0352963

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3641-3644
Highly Enantioselective Catalytic
Phenylation of Ketones with a
Constrained Geometry Titanium Catalyst
Celina Garc´ıa and Patrick J. Walsh*
Department of Chemistry, Roy and Diana Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
pwalsh@sas.upenn.edu
Received July 14, 2003
ABSTRACT
The catalytic asymmetric addition of phenyl groups from diphenylzinc to ketones is reported. The catalyst, generated from a dihydroxy bis-
(sulfonamide) ligand and titanium tetraisopropoxide, gives good to excellent enantioselectivities with a range of substrates.
The asymmetric addition of alkyl groups to aldehydes has
been extensively studied, and many catalysts will promote
this addition with high enantioselectivities.1,2 In contrast,
analogous addition reactions to ketones have proven to be a
challenging problem.3-8 This discrepancy is due to the
reduced propensity of ketones to coordinate to Lewis acids,
relative to aldehydes. Furthermore, to achieve high enantio-
selectivities, catalysts must readily distinguish between the
lone pairs of the carbonyl oxygen. Differentiation of aldehyde
lone pairs is simple; little steric hinderence is encountered
on binding syn to the aldehydic hydrogen relative to binding
syn to the alkyl substituent. With ketones, however, dis-
crimination of the lone pairs is difficult due to their similar
environments.
One of the goals of our research has been to develop
catalysts capable of promoting the asymmetric alkylation of
carbonyl groups. To this end, we have had a long-standing
interest in the design of catalysts based on multidentate
dihydroxy bis(sulfonamide) ligands incorporating trans-1,2-
diaminocyclohexane.6,7,9,10 These investigations culminated
in our identification of the dihydroxy bis(sulfonamide) ligand
1 (Figure 1), which formed the first efficient and highly
(1) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856.
(2) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(3) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446.
(4) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239-1242.
(5) Ramo´n, D. J.; Yus, M. Tetrahedron 1998, 54, 5651-5666.
(6) Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 10970-10971.
(7) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-9545.
(8) Yus, M.; Ramo´n, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002,
13, 2291-2293.
Figure 1. Ligand 1 based on the (R,R)-diamine and (S)-camphor.
10.1021/ol0352963 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003

enantioselective catalyst for the addition of alkyl groups to
aryl alkyl ketones6 and R,â-unsaturated cyclic enones.7
Ligand 1 is readily synthesized in two steps from com-
mercially available materials and can be used in as little as
2 mol % loading.6 After our report detailing the synthesis
and application of 1 to the catalytic asymmetric addition of
alkyl groups to ketones,6 Yus and co-workers published a
similar study using the same ligand.8 Our success with ligand
1 in the alkyl additions led us to examine the enantioselective
arylation of ketones with ZnPh2, and we were pleased to
find that the results were again excellent across a range of
substrates. The products of these reactions are tertiary
alcohols that possess chiral quaternary centers. Such stereo-
centers are difficult to install in an asymmetric fashion with
high enantioselectivity. During the preparation of the current
manuscript, Yus published the use of 1 in the arylation of
4′-substituted acetophenones and 4′-bromopropiophenone,11
prompting us to report our independent investigations that
define the scope of the phenyl addition to ketones with ligand
1.
Table 1. Examination of the Effects of Solvents and
Temperature on the Yield and Enantioselectivity of the
Phenylation of 3′-Chloropropiophenone
entry
solvent
T (°C)
yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
toluene/hexanes
toluene/hexanes
toluene
hexanes
Et2O
Et2O/hexanes
THF/hexanes
THF/CH2Cl2
toluene/methanol
22
0
99
57
99
99
81
88
NR
NR
NR
87
65
89
87
92
91
22
22
22
22
22
22
22
a Conditions for all ee determinations are in Supporting Information.
outlined in Table 1. In our initial experiments, we used
conditions similar to those in our asymmetric alkylations of
ketones. Employing 10 mol % 1, 1.2 equiv of titanium
tetraisopropoxide, and 1.6 equiv of diphenylzinc in a mixture
of toluene and hexanes at room-temperature resulted in
formation of the product with 99% isolated yield and in 87%
enantioselectivity after 18 h (entry 1). Unfortunately, lower-
ing the temperature to 0 °C led to significant decrease in
both product ee and yield (entry 2). Use of toluene alone
resulted in a slight increase in the product ee to 89%, while
hexanes alone resulted in no change (entries 3 and 4). Diethyl
ether gave product of 92% ee, but the yield dropped to 81%.
Combination of diethyl ether and hexanes gave higher yield
(88%) with little change in product ee (91%). No reaction
was observed when the Lewis basic THF was employed or
methanol was added in a fashion similar to the report of Dosa
and Fu.3 These studies indicate that the catalyst enantiose-
lectivity remains high with a variety of solvents.
The first catalytic enantioselective phenyl addition to
ketones was reported by Dosa and Fu in 1998.3 In this
pioneering work, these authors employed Noyori’s (+)-DAIB
ligand12,13 and diphenylzinc. Although direct use of diphe-
nylzinc gave low yields, addition of methanol to the
diphenylzinc solution resulted in formation of a mixed alkoxy
phenyl zinc reagent that gave increased yields and enantio-
selectivities, as shown in Figure 2.3 In contrast, diphenylzinc
The next step in our optimization involved variation of
the reagent stoichiometry, as detailed in Table 2. Using
toluene and hexanes, we initially varied the amount of
titanium tetraisopropoxide and ligand 1 (entries 1-7).
Decreasing the titanium tetraisopropoxide to 0.6 equiv led
Figure 2. Results of Dosa and Fu in the asymmetric addition of
phenyl groups to ketones.
and alkyl phenyl zinc reagents can be used in the additions
to aldehydes.14-20
(13) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994.
(14) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444-
In our study, we chose 3′-chloropropiophenone as the test
substrate for optimization of the reaction parameters, as
445.
(15) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew. Chem.,
Int. Ed. 2000, 39, 3465-3467.
(9) Ho, D. E.; Betancort, J. M.; Woodmansee, D. H.; Larter, M. L.;
Walsh, P. J. Tetrahedron Lett. 1997, 38, 3867-3870.
(10) Guo, C.; Qiu, J.; Zhang, X.; Verdugo, D.; Larter, M. L.; Christie,
R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145-4158.
(11) Prieto, O.; Ramo´n, D. J.; Yus, M. Tetrahedron: Asymmetry 2003,
14, 1955-1957.
(16) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norrby, P.-O. Angew. Chem.,
Int. Ed. 2003, 42, 3002-3005.
(17) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41, 145-148.
(18) Zhao, G.; Lib, X.-Z.; Wang, X.-R. Tetrahedron: Asymmetry 2001,
12, 399-403.
(19) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759-3762.
(20) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem.,
Int. Ed. 2001, 40, 3284-3308.
(12) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071-6072.
3642
Org. Lett., Vol. 5, No. 20, 2003

Table 2. Examination of the Effect of Reagent Stoichiometry
on Yield and Enantioselectivity in the Phenylation of
3′-Chloropropiophenone
Table 3. Yields and Enantioselectivities for the Phenylation of
Various Ketone Substrates (Eq 2)
entry mol % 1 equiv Ti(O-i Pr)4 solvent yield (%) ee (%)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
5
0.2
0.4
0.6
1.2
1.8
2.4
0.6
0.6
0.6
tol/hex
tol/hex
tol/hex
tol/hex
tol/hex
tol/hex
tol/hex
Et2O/hex
Et2O
37
66
99
99
97
95
82
80
59
65
87
92
87
85
85
87
91
92
10
10
to the highest yield and product ee (99% yield, 92% ee, entry
3). Reducing the catalyst loading to 5 mol % resulted in a
decrease in the enantioselectivity to 87% (entry 7). Reactions
employing diethyl ether and 0.6 equiv of titanium tetraiso-
propoxide gave excellent enantioselectivities; however, yields
were reduced (entries 8 and 9).
Employing the optimized reaction conditions in entry 3
of Table 2,21 we examined the phenylation of a series of
ketone substrates, as shown in eq 2 and Table 3. A slightly
lower enantioselectivity was observed with 4′-chloropro-
piophenone than with the 3′-chloro derivative. Acetophenone
derivatives are excellent substrates for this catalyst. The
phenyl addition products from 3′-(trifluoromethyl)acetophe-
none, 2′-bromoacetophenone, and 2′-acetonaphthone were
formed with high yields and enantioselectivities of 95-96%
(entries 3-5). It is anticipated that the 2′-bromo benzene
derivative in entry 4 can be further elaborated through cross-
coupling reactions. Impressive enantioselectivities were also
obtained with R,â-unsaturated enones (entries 6 and 7).
1-Acetyl-1-cyclohexene (entry 6) underwent addition with
94% yield and 93% enantioselectivity. The yield of the
addition product with trans-4-phenyl-3-buten-2-one was
58%, but the enantioselectivity remained high (91%). The
allylic alcohol products formed from R,â-unsaturated enones
are useful chiral building blocks that can be readily func-
tionalized at the double bond. Dialkyl ketones also proved
to be good substrates for our catalyst, with cyclohexyl methyl
ketone and 3-methyl-2-butanone giving 87 and 75% ee
(entries 8 and 9, respectively). These data compare favorably
with the results of Dosa and Fu3 illustrated in Figure 2.
formation of the product alcohol in 66% yield and 79%
enantioselectivity. Cyclization proceeded cleanly, affording
the epoxide in 90% yield with no loss of ee, within
experimental error. Such chiral 1,1-diaryl epoxides are
difficult to prepare by catalytic asymmetric methods, despite
extensive research into epoxide-forming reactions.
(21) General Procedure for the Preparation of Tertiary Alcohols.
Preparation of 1-(3-Chlorophenyl)-1-phenyl-1-propanol. The bis(sul-
fonamide) ligand 1 (5.4 mg, 10 mol %) was weighed into a well-dried
Schlenk flask. A solution of diphenylzinc (35.1 mg, 0.16 mmol) in toluene
(1 mL) was added, followed by titanium(IV) isopropoxide (50 µL, 1.2 M
hexanes solution, 0.06 mmol). The homogeneous reaction mixture was
stirred at room temperature for 15 min. 3′-Chloropropiophenone (17.2 mg,
0.1 mmol) was then added as a solution in toluene (0.5 mL). The reaction
mixture was stirred at room temperature until TLC showed complete
consumption of the ketone. The reaction was quenched with a 15% aqueous
tartaric acid and extracted with CH2Cl2. The combined organic phases were
dried using anhydrous sodium sulfate and filtered, and the solvent was
removed under vacuum. The residue was purified by silica gel column
chromatography (hexanes/EtOAc 98:2) to give the tertiary alcohol (24.4
To further expand the scope of the asymmetric phenylation
of ketones, we have investigated the use of an R-halo ketone.
The products of such a reaction can be converted into
epoxides, which are among the most useful chiral building
blocks in organic synthesis. Subjecting R-bromo-2′-aceto-
naphthone to the phenylation conditions in eq 3 resulted in
20
mg, 99% yield, 92% ee) as an oil: [R]D ) +21.4 (c 0.81, CHCl3).
Org. Lett., Vol. 5, No. 20, 2003
3643

ment over those obtained using the more synthetically
challenging DAIB (Figure 2).22,23 Additionally, a methanol
additive is not necessary. Future studies will focus on
expanding the scope of reactions catalyzed by our ligand 1
and studies directed toward understanding the mechanism
of this synthetically useful reaction.
Acknowledgment. This work was supported by the
National Institutes of Health (National Institute of General
Medical Sciences GM58101).
Supporting Information Available: Procedures and full
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we report an efficient and highly enantio-
selective catalyst for the phenylation of ketones. The reaction
employs the readily available ligand 1, a substoichiometric
amount of titanium tetraisopropoxide, and commercially
available diphenylzinc. The reactions are clean, affording
high yields of the tertiary alcohol in less than 24 h at room
temperature. These results represent a significant improve-
OL0352963
(22) White, J. D.; Wardrop, D. J.; Sundermann, K. F. Org. Synth. 2001,
79, 125-129.
(23) White, J. D.; Wardrop, D. J.; Sundermann, K. F. Org. Synth. 2001,
79, 130-138.
3644
Org. Lett., Vol. 5, No. 20, 2003