An improved catalyst for the asymmetric arylation of ketone enolates

Article abstract of DOI:10.1021/ja011122+

A new catalyst system for the enantioselective α-arylation of ketones is reported. This catalyst, prepared from Pd₂(dba)₃ and a bulky dialkylphosphino-binaphthyl ligand, is able to effect the asymmetric arylation of ketone enolates w

Full text of DOI:10.1021/ja011122+

Published on Web 01/26/2002
An Improved Catalyst for the Asymmetric Arylation of Ketone
Enolates
Takayuki Hamada,† Andre´ Chieffi, Jens Åhman, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received May 4, 2001
Abstract: A new catalyst system for the enantioselective R-arylation of ketones is reported. This catalyst,
prepared from Pd2(dba)3 and a bulky dialkylphosphino-binaphthyl ligand, is able to effect the asymmetric
arylation of ketone enolates with aryl bromides utilizing NaOtBu as base. These new catalysts enjoy much
higher reactivity than previous systems; arylation reactions could be effected at room temperature with
only 2 mol % of the Pd catalyst. The coupling of R-alkyl-R′-protected cyclopentanones proceeded in high
yield, and the resulting quaternary stereogenic center was installed in up to 94% ee.
Introduction
Several years ago, we reported a method for the synthesis of
R-aryl ketones from ketones and aryl bromides using catalytic
amounts of Pd and either BINAP or tol-BINAP.1 This process
represents an excellent complement to existing methods2 to form
R-aryl ketones since the advantages of this new method include
experimental simplicity, good functional group tolerance, and
high regioselectivity for ketones with two enolizable positions
(arylation occurs preferentially at the least-hindered R-carbon).
More recently, bulky, dialkylphosphinobiaryl ligands have been
discovered which allow for the efficient generation of highly
active catalysts for the R-arylation of ketones (Figure 1).3 Aryl
chlorides and bromides may be efficiently coupled with enolates,
often with as little as 0.1 mol % Pd, and the anions of malonate
esters, cyclic 1,3-diketones, nitroalkanes, and esters4 can be used
as nucleophilies under modified conditions. These commercially
available5 ligands are air stable as solids as well as in solution,
and they can be prepared by a simple, one-pot procedure.6
Figure 1. Bulky dialkylphosphino biaryl ligands.
bromides or iodobenzene with Pd/1,1′-bis (di-o-tolylphosphino)-
ferrocene.8a More recently, the Yale group has disclosed that
aryl chlorides, bromides, and in one case, an aryl tosylate could
be coupled with ketone enolates or malonate esters using tri-
(tert-butyl)phosphine, (1,1′-bis-(di-tert-butylphosphino)fer-
rocene), or 1-diphenylphosphino-2-(di-tert-butylphosphino)-
ethylferrocene.8b Hartwig’s group has also reported catalytic
systems for the formation of R-aryl amides,8c,d R-arylcyanoace-
tates,8e esters,8f and R-amino esters.8f Additionally, Miura and
co-workers have shown that PdCl2 is an effective catalyst for
the arylation of benzyl ketones.9
The asymmetric arylation of enolates is an attractive means
to prepare optically active carbonyl compounds that possess a
quaternary asymmetric center R to the carbonyl group. Optically
active 2-methyl-2-arylcyclopentanones are known to be impor-
tant intermediates for natural product synthesis (Scheme 1). For
example, Ogasawara and co-workers reported the total synthesis
of (-)-Aphanorphine by using (S)-2-methyl-2-p-methoxyphe-
nylcyclopentanone as a key intermediate.10 Additionally, Srikrish-
na and Reddy used (R)-2-methyl-2-p-methylphenylcyclopen-
tanone to synthesize tochiunyl acetate, a marine natural product.11
The preparation of these chiral 2-methyl-2-arylcyclopentanones,
however, were quite lengthy. For example, an enzymatic
resolution was used to introduce optical activity in the synthesis
of (-)-Aphanorphine. Thus, new catalytic, enantioselective
Contemporaneously with our work, other groups have also
developed Pd-catalysts for the formation of R-aryl ketones.7-9
In particular, Hartwig reported the coupling of ketones and aryl
† Present address: AJINOMOTO Co., Inc. ALF-1, 1-1 Suzuki-cho,
Kawasaki-shi, Kawasaki-ku, Kanagawa, Japan 210-8681. E-mail:
takayuki_hamada@ajinomoto.com.
(1) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(2) For a survey of methods to prepare R-arylcarbonyl compounds, see
references within ref 3.
(3) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
(4) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(5) From Strem Chemicals, Inc.
(6) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5334.
(7) For a related process for the intermolecular coupling of phenol with aryl
halides to give biaryls, see: Hennings, D. D.; Iwasa, S.; Rawal, V. H. J.
Org. Chem. 1997, 62, 2.
(8) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382. (b)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (c)
Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1998, 63, 6546. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(e) Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 4641. (f) Lee, S.; Beare, N. A.; Hartwig, J. F. J.
Am. Chem. Soc. 2001, 123, 8410.
(9) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740. (b) Satoh, T.; Inoh, J.; Kawamura, Y.; Kawamura,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239.
(10) Takano, S.; Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K. J. Chem.
Soc., Chem. Commun. 1990, 290.
(11) Srikrishna, A.; Reddy, T. J. Tetrahedron 1998, 54, 8133.
9
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J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002 1261

A R T I C L E S
Hamada et al.
Scheme 1
Table 1. Asymmetric Ketone Arylation with a (S)-BINAP/Pd
Catalysta
Scheme 2
a Reaction conditions: 1.0 equiv ketone, 2.0 equiv ArBr, 2.0 equiv
NaOtBu, 0.25 M toluene at 100 °C. Ligand/Pd ) 1.25/1. b Isolated yield.
c % ee determined by HPLC (Daicel CHIRALCEL OD).
be easily installed in high yield.14 Formylation of 2-methylcy-
clopentanone, followed by condensation with N-methylaniline,
cleanly provided 1a in 82% yield (eq 1).
methods for the formation of quaternary stereocenters remain
at the forefront of organic synthesis.12
A few years ago, we communicated that the asymmetric
arylation of ketone enolates could be effected using a (S)-
BINAP/Pd/catalyst13 (Scheme 2), affording 2-aryl-2-methyl-5-
benzylidenecyclopentanones in good yield and high enantio-
meric excess. However, the reactions required high temperatures
(100 °C) and catalyst loadings (10-20 mol % Pd/12-24 mol
% (S)-BINAP). Additionally, it was not possible to remove the
benzylidene blocking group from the products in good yield.
In this contribution, we report a significantly more active and
general catalytic system for the asymmetric arylation of enolates.
This new system allows the arylation reaction to proceed at room
temperature and with much lower catalyst loadings (2 mol %
Pd). In addition, we disclose a more efficient blocking-group
strategy for the preparation of R-aryl-R-alkylcyclopentanones
in high yield and with good-to-excellent levels of enantiomeric
purity.
With the proper protecting-group strategy established, we set
out to determine the effectiveness of the asymmetric arylation
of ketone 1a with 4-bromo-tert-butylbenzene using a number
of commercially available chiral ligands such as BINAP, MOP,
QUINAP, PFFA.4,15 Among all these ligands, only BINAP gave
good levels of enantioselectivity. We found that an excess of
aryl bromide was necessary to ensure complete conversion of
the ketone at 100 °C due to competitive aryl bromide homo-
coupling to yield 4,4′-di-tert-butylbiphenyl as well as reduction
to form 4-tert-butylbenzene. A survey of different solvents and
bases revealed that toluene and sodium tert-butoxide were most
efficient in these reactions utilizing BINAP. There was only a
slight difference in yield and enantioselectivity when the
palladium source was changed from Pd(OAc)2 to Pd2(dba)3.
Under the best conditions, the arylation of 1a with 4-bromo-
tert-butylbenzene was complete within 3 h at 100 °C to furnish
the desired product 2a in 70% yield and 89% ee.
Results
To create a 2-aryl-2-alkylcyclopentanone using the Pd-
catalyzed ketone arylation reaction, it is necessary to prevent
arylation from occurring at the less substituted R-carbon of the
2-alkylcyclopentanone.1,3,8b Thus, we chose to install a 2-methyl-
5-N-methyl-anilinomethylene moiety, a blocking group that can
The (S)-BINAP/Pd catalyzed asymmetric arylation of 1a with
several aryl bromides is summarized in Table 1. The highest
enantioselectivity in this reaction was observed in the coupling
of 1a and 4-bromo-tert-butylbenzene, which proceeded in 89%
ee. Aryl bromides possessing electron-donating methoxy groups
(12) Several elegant Pd-catalyzed methods for the enantioselective formation
of quaternary centers have been reported. Allylation: (a) Trost, B. M.;
Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879. (b) Trost,
B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759. (c) Trost, B.
M.; Schroeder, G. M. J. Org. Chem. 2000, 65, 1569. (d) Hayashi, T.;
Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113.
Heck reaction: (e) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S.
P.; Overman, L. E. J. Am. Chem. Soc. 1998, 120, 6488. (f) Overman, L.
E.; Poon, D. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 518. (g) Ashimori,
A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58,
6949.
(14) (a) Birch, J.; Robinson. R. J. Chem. Soc. 1944, 501. (b) Woodward, R. B.;
Sondheimer, F.; Taub, D, Heusler, K.; McLamore, W. M. J. Am. Chem.
Soc. 1947, 74, 4223. (c) Lin, C. H. Handbook of Reagents for Organic
Synthesis. Reagents, Auxiliaries and Catalysts for C-C bonds; Coates, R.
M., Denmark, S. E., Eds.; Wiley: New York, 1999; p. 509.
(15) For the details of these initial ligand screening experiments, consult the
Supporting Information.
(13) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J.
Am. Chem. Soc. 1998, 120, 1918.
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1262 J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002

Catalyst for Asymmetric Arylation of Ketone Enolates
A R T I C L E S
Table 2. Asymmetric Ketone Arylation Using Monodentate
Table 3. Other Aryl Bromides in the Asymmetric Arylation Using
Ligands 4a
Ligandsa
yield
(%)b
ee
(%)c
ligand
R
R′
Pd source
conditions
(S)-3a Cy NMe2 2.5 mol % Pd2(dba)3 rt, 18 h
93
99
80
78
66
68 (R)
67 (R)
70 (S)
60 (S)
39 (S)
8 (R)
(S)-3a Cy NMe2 2 mol % Pd(OAc)2
(R)-3b iPr NMe2 1 mol % Pd2(dba)3
1 mol % Pd2(dba)3
(R)-3d Cy SiMe3 1 mol % Pd2(dba)3
(R)-3e Cy PCy2 1 mol % Pd2(dba)3
rt, 18 h
rt, 18 h
rt, 3 h
(R)-3c Cy nBu
rt, 8 h
50 °C, 18 h 22
a Reaction conditions: 1.0 equiv ketone, 2.0 equiv ArBr, 2.0 equiv
NaOtBu, 0.25 M toluene, 3/Pd ) 1.25/1. b Isolated yield. c % ee detemined
by HPLC (Daicel Chiralcel OD).
were tolerated in the reaction to furnish the coupled product in
moderate to good enantioselectivity. Although the reaction of
4-bromoanisole with 1a proceeded in only 57% ee, the reaction
of the 3-substituted isomer proceeded in 85% ee. Poor reactivity
and enantioselectivity were observed in the reaction with
2-bromotoluene; coupled product 2b was isolated in 52% yield
and 10% ee.
a Reaction conditions: 1.0 equiv ketone, 2.0 equiv ArBr, 2.0 equiv
NaOtBu, 0.25 M toluene, 3/Pd ) 1.25/1. b Isolated yield. c % ee detemined
by HPLC (Daicel Chiralcel OD).
screened in the reaction displayed in Table 2. In general, it was
found that replacing the cyclohexyl groups bound to phosphorus
with isopropyl groups gave superior results, as did replacing
the methyl ether of 4a with an aryl methylene ether. Of the
ligands reported here, (R)-2-(diisopropylphosphino)-2′-(1-naph-
thylmethoxy)-1,1′-binaphthyl (4e) consistently furnished desired
products with the highest enantiomeric excesses. Ligand 4e is
an air stable, finely crystalline solid. For the reaction of 1a with
3-bromotoluene, (R)-2-(diisopropylphosphino)-2′-(9-phenanth-
ylmethoxy)-1,1′-binaphthyl (4g) gave a catalyst that was almost
as selective as that derived from 4e, but its use necessitated a
much longer reaction time. In addition, (R)-2-(diisopropylphos-
phino)-1,1′-binaphthyl (4h) was prepared and tested in the
arylation of 1a with 3-bromotoluene. The desired product was
produced in low yield (24%) and moderate enantiomeric excess
(57% ee).
It should be noted that the preparation of 2-alkoxy-2′-
dialkylphosphino-1,1′-binaphthyl ligands allowed substantial
flexibility as well as increased modularity in their preparation
since varying the dialkylphosphino and alkoxy groups were
straightforward.22 These phosphines bear an obvious structural
resemblance to the MOP ligands prepared and studied in the
elegant and seminal work of Hayashi,23 except that the phos-
phines introduced here possess alkyl groups and are therefore
more electron-rich. Thus, the series of new ligands 4a-4h were
prepared in analogy to Hayashi’s method.23 The desired ligands
were obtained in up to 61% overall yield (Scheme 3).
We recently reported that(S)-2-(dimethylamino)-2′-N,N-di-
cyclohexylphosphino-1,1′-binaphthyl (3a) was an efficient
ligand for the asymmetric vinylation of enolates16 and the
asymmetric Suzuki cross-coupling reaction.17 The diphenyl
analogue of 3a has been independently developed and utilized
by Kocˇovskoy´, Lloyd-Jones, and co-workers,18 by Mikami and
co-workers19 and by Noyori and co-workers.20 After testing a
variety of ligands and conditions, we found that the use of
ligands such as 3a allows for the reaction illustrated in Table 2
to be performed at room temperature and with smaller quantities
of catalyst (2% Pd/3a vs 10% Pd/BINAP). Thus, the catalyst
derived from electron-rich monophosphine ligand 3a proceeded
with faster rates than did those derived from BINAP.21 As
before, similar results were obtained when either Pd(OAc)2 or
Pd2(dba)3 was used as the palladium source. Toluene was the
most suitable solvent for these arylation procedures, while the
use of ethereal solvents either lowered reaction rates or
enantioselectivities. Because of its structural similarity to both
MOP and 3a, (S)-2-dicyclohexylphosphino-2′-methoxy-1,1′-
binaphthyl (4a) was prepared first and tested in the reaction of
3-bromotoluene with 1a. The enantiomeric excess of the product
(82% ee) was higher than that obtained when ligand (S)-3a was
used (58% ee).21 The groups on phosphorus and oxygen were
then systematically varied, and the resulting ligands were
Table 3 shows the results of the reactions of a series of aryl
bromides with 1a using phosphines 4b, 4d, or 4e. In every
coupling reaction involving meta- or para-substituted aryl
bromides that was studied, the best enantiomeric excesses were
observed using 4e. Unfortunately, ortho-substituted aryl bro-
(16) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Org.
Lett. 2001, 3, 1897.
(17) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12501.
(18) (a) Vyskocˇil, S.; Smrcˇina, M.; Hanus V.; Pola´sek P.; Kocˇovsky´, P. J. Org.
Chem. 1998, 63, 7738. (b) Kocˇovsky´, P.; Vyskocˇil, Sˇ.; C´ısarˇova´, 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. (c)
Lloyd-Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocˇil, Sˇ.;
Kocˇovsky´, P. Chem. Eur. J. 2000, 6, 4348.
(22) For an elegant study applying a modular approach to ligand screening in
the Pd-catalyzed allylation, see: Trost, B. M.; Van Vranken, D. L.; Bingel,
C. J. Am. Chem. Soc. 1992, 114, 9327.
(23) (a) Uozumi, Y.; Suzuki, N.; Ogiwara, A.; Hayashi, T. Tetrahedron 1994,
50, 4293. (b) Hayashi, T.; Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi,
Y.; Miki, M.; Yanagi, K. J. Am. Chem. Soc. 1994, 116, 775. (c) Hayashi,
T. Acc. Chem. Res. 2000, 33, 354.
(19) Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.; Okubo, Y.;
Mikami, K. Chem. Eur. J. 1999, 5, 1734.
(20) Sumi, K.; Ikariya, T.; Noyori, R. Can. J. Chem. 2000, 78, 697.
(21) For reactions between 1a and other aryl halides using the 3a/Pd catalyst,
see the Supporting Information.
9
J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002 1263

A R T I C L E S
Hamada et al.
Scheme 3
Scheme 4
Table 4. Different Ketones in the Asymmetric Arylation: A Ligand
Comparisona
utility of these two catalyst systems, however, efficient arylation
protocols capable of utilizing ortho-substituted aryl bromides
have yet to be developed.
Removing the Blocking Group and Determination of
Absolute Configuration. The use of ethylformate and N-methyl
aniline is a well-known method for blocking the R-position of
a ketone.14 After the arylation reaction, the blocking group could
be removed by hydrolysis with aqueous HCl followed by a retro-
Claisen reaction of the formylated ketone under basic conditions
(Scheme 4). Removal of the blocking group afforded the
arylated cyclopentanones in good yield and without loss of
enantiopurity as determined by HPLC analysis. The absolute
configuration of 2-methyl-2-phenylcyclopentanone 5 was de-
termined by comparison of its optical rotation to the literature
value.24 Notably, the sense of asymmetric induction in the
arylation reaction with (S)-4e was the same as that observed in
the asymmetric vinylation reaction using ligands (S)-3a-d.
a Reaction conditions: 1.0 equiv ketone, 2.0 equiv aryl bromide, 2.0
equiv NaOtBu, 0.25 M toluene, ligand/Pd2(dba)3 ) 2.5:1. b Isolated yield.
c % ee was determined by HPLC (Daicel Chiralcel OD). d 2.5 mol %
Pd2(dba)3 was used. e 10 mol % Pd(OAc)2 was used.
Discussion
The results described here for the asymmetric arylation of
ketones increase the scope of our previously described meth-
odology. The use of a protecting-group strategy provides access
to R-aryl-R-alkylcyclopentanones in good yield and with high
levels of enantiopurity. BINAP has an advantage in that it is
commercially available and can induce high enantioselectivity
for a limited range of substrate combinations. The preliminary
indication is that BINAP is particularly effective when substrates
of type 1b or 1c are used. However, the enantioselectivity is
consistently higher for a wider range of aryl halides and ketones
when 4e is used in the ketone arylation reactions. Furthermore,
palladium catalysts based on the monodentate dialkyl phosphines
such as 3 and 4 are more active than Pd/BINAP systems in
ketone arylations. These catalysts are effective at room tem-
perature, in contrast to the Pd/BINAP catalyst, which requires
heating to 100 °C. Moreover, it was possible to lower catalyst
loadings when dialkylphosphinobinaphthyl ligands were used.
This increase in catalyst activity correlates with our previous
observations in ketone arylations,3 Pd-catalyzed amination
reactions,25,26 Suzuki reactions,27 and Pd-catalyzed diaryl ether-
forming reactions using dialkylphosphinobiphenyl ligands.28
mides such as 2-bromotoluene reacted with 1a with low
enantioselectivities (22-42% ee) and low yields with all three
of the monodentate ligands studied.
The effect of the ketone R-substituent on the enantioselectivity
was also examined (Table 4). The size of the R-substituent of
the ketone was important for the enantioselectivity of the
arylation reaction catalyzed by Pd/(S)-BINAP. The highest
enantioselectivity was observed when the reaction was per-
formed with the largest R-alkyl substituent (n-pentyl > n-propyl
> methyl). For example, the coupling between m-bromotoluene
and R-methyl-substituted ketone 1a afforded the desired product
in 80% ee. The same reaction with the R-n-propyl ketone 1b
gave the desired product in 91% ee. With the R-n-pentyl ketone
1c, the product was afforded in 93% ee. The enantiomeric
excesses observed were less sensitive to the size of the R-alkyl
substituent of the ketone 1 when either ligand 4d or 4e was
used. It should be noted that methyl-substituted 1a was arylated
with the highest enantiomeric excess with these new monoden-
tate ligands (94% ee).
(24) Hoffman, T. D.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 1000.
(25) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158.
(26) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413.
(27) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550.
(28) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
From the results given in Tables 3 and 4 it can be seen that
a single ligand, 4e, is highly effective for a wide variety of
substrate combinations. This ligand, in combination with
BINAP, provides a means to successfully generate quaternary
stereogenic centers with high enantioselectivity. Despite the
9
1264 J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002

Catalyst for Asymmetric Arylation of Ketone Enolates
A R T I C L E S
Although ligands 3a,b and 4a-g could plausibly form P-N
and P-O chelate structures, respectively, several experiments
suggest that these modes of coordination are not important for
the asymmetric arylation reaction. For the reaction displayed
in Table 2, the product is obtained in only slightly lower ee
(60% vs 68) when the dimethylamino group of 3a was replaced
by a hydrogen (4h). It should be noted that both ligands induce
the same sense of asymmetry [(R)-ligand yields (S)-2]. For the
bis-phosphine ligand BINAP, however, the correlation between
the antipode of the binaphthyl moiety of the ligand and the
absolute configuration of the product is reversed [(S)-BINAP
furnished (S)-2a]. These observations suggest that the mecha-
nism of asymmetric induction is significantly different when a
bis-phosphine is used and are consistent with the proposal that
BINAP chelates and that the amine and alkoxy functions of
3a,b and 4a-g, respectively, do not bind to Pd. Hence, reactions
with chelating and monodentate ligands provide the products
of opposite absolute configuration. We note that Overman and
co-workers found in their elegant studies of the intramolecular
asymmetric Heck reaction that reactions employing (R)-BINAP
gave products that were enantiomeric to those formed when
either (R)-i-PrO-MOP or (R)-2-(diphenylmethyl)-2′-diphe-
nylphosphino-1,1′-binaphthyl were used as ligands. This finding
was in accord with additional evidence that led the authors to
conclude that BINAP forms a chelate structure in the step that
determines the absolute stereochemistry.12e,f,g We also note that
Kocˇovskoy´ and co-workers have crystallographically determined
the structure of the complex (MOP)Pd(η3-C3H5)+ OTf-, and
found that the distal naphthyl ring (relative to P) binds to the
Pd center.18b In our laboratories, η2-binding of the distal aromatic
ring of dialkylphosphinobiphenyl ligands has been characterized
by X-ray crystallography for Pd(0) complexes.29 While con-
sideration should be given to Kocˇovskoy´’s comments on the
possible significance of P-C coordination,18b the caveat remains
that there is still no evidence that these modes of binding bear
relevance to any catalytic process.
It is likely that the mechanism for the asymmetric processes
reported here parallel those proposed in our previous studies.3
With either BINAP or ligands 3 and 4a-h, it is probable that
the ratio of ligand:Pd is 1:1 for Pd(II) intermediates in the
catalytic cycle; the reasoning has been discussed previously3
and is supported by the observation that, with either BINAP or
4e, the relationship between the ee of arylation product 2c and
the ee of the ligand is linear. As with the nonasymmetric ketone
arylation reaction, it was found that the effectiveness of the
catalyst was dramatically altered by subtle perturbations in the
structure of the ligand.30 Therefore, the development of the
ligand synthesis illustrated in Scheme 3 is significant, since it
provides a short and efficient means for the preparation of
variety of 2-alkoxy-2′-phosphino-1,1′-binaphthyl ligands from
an inexpensive, enantiomerically pure precursor. The coupling
reaction of dialkylphosphines with BINOL-bis-triflate (Scheme
3) is noteworthy. Although numerous examples of Pd-catalyzed
couplings of aryl triflates and halides with diarylphosphine
oxides have been reported,31 the analogous process with
dialkylphosphine oxides is less studied. The C-P bond forming
reaction between aryl bromides and dialkylphosphine oxide in
the presence of NaNH2 was reported by Raynal and co-
workers.32 Saa´ et al. described a similar reaction where
diethylphosphine was presumably oxidized in situ by exogenous
oxygen prior to the C-P bond forming reaction.33 Additionally,
several groups have utilized diaryl- and alkylarylphosphine
boranes34 as well as triaryl phosphines35 in these Pd-catalyzed
couplings. Direct access to triarylphosphines has also been
achieved by Ni-catalyzed couplings using diarylphosphines36
or chlorodiarylphosphines37 and aryl bromides triflates. We
anticipate that the small library of ligands introduced here, along
with variants prepared by further alteration of the ether and
phosphine substituents, should find excellent utility in the future
development of catalytic asymmetric processes.
Conclusions
A series of new ligands which are useful in the Pd-catalyzed
asymmetric arylation reaction of enolates have been reported.
(R)-2-(Diisopropylphosphino)-2′-(1-naphthylmethoxy)-1,1′-bi-
naphthyl (4e) was the best of all ligands used in this study.
Compared with our previous report, the catalyst derived from
4e and Pd2(dba)3 not only delivers the desired products in higher
enantioselectivity but also reacts under milder conditions.
Experimental Section
General Considerations. THF and Et2O were distilled under argon
from sodium/benzophenone ketyl, and toluene was distilled under
nitrogen from molten sodium. Alternatively, these solvents were
purchased from J.T. Baker in CYCLE-TAINER solvent-delivery kegs
and vigorously purged with argon for 2 h. The solvents were further
purified by passing them under argon pressure through two packed
columns of neutral alumina (for Et2O and THF) or through neutral
alumina and copper (II) oxide (for toluene).38 Aryl bromides and
2-methylcyclopentanone were purchased from Aldrich Chemical Co.
Tris(dibenzylideneacetone) dipalladium (0), (S)-BINAP, (R)-QUINAP,
(S)-MOP, (-)-PPFA, and (rac)-2,2′-dibromo-1,1′-binaphthyl were
acquired from Strem Chemicals, Inc. (R)- and (S)-BINOL were
purchased from Kankyo Kagaku Center Co., Ltd. Ookawa, Kanazawa-
ku, Yokohama, Japan. NaOtBu was purchased from Aldrich; the bulk
of this material was stored in an nitrogen-filled glovebox. Small portions
(1-2 g) were removed from the glovebox in glass vials, stored in the
air in desiccators filled with anhydrous calcium sulfate, and weighed
in the air. All other reagents were available from commercial sources
(31) (a) Kurz, L.; Lee, G.; Morgans Jr., D.; Waldyke, M. J.; Ward, T.
Tetrahedron Lett. 1990, 31, 6321. (b) Uozumi, Y.; Tanahashi, A.; Lee,
S.-Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945. (c) Horiuchi, T.; Ohta,
T.; Stephan, M.; Takaya, H. Tetrahedron: Asymmetry 1994, 5, 325. (d)
Doucet, H.; Brown, J. M. Tetrahedron: Asymmetry 1997, 8, 3775.
(32) Bergeret, W.; Gautier, J. C.; Raynal, S. Phosphorus Sulfur 1986, 27, 275.
(33) Martorell, G.; Garc´ıas, X.; Janura, M.; Saa´, J. M. J. Org. Chem. 1998, 63,
3463.
(34) (a) Oshiki, T.; Imamoto, T. J. Am. Chem. Soc. 1992, 114, 3975. (b)
Imamoto, T. Pure Appl. Chem. 1993, 65, 655. (c) Gaumont, A.-C.;
Hursthouse, M. B.; Coles, S. J.; Brown, J. M. Chem. Commun. 1999, 63.
(d) Lipshutz, B. H.; Buzard, D. J.; Yun, C. S. Tetrahedron Lett. 1999, 40,
201. (e) Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T. J. Org. Chem.
2000, 65, 4776.
(35) (a) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19, 2058. (b) Kwong,
F. Y.; Chan, K. S. Organometallics 2001, 20, 2570.
(36) (a) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1994, 59, 7180. (b) Cai, D.; Payack, J. F.;
Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Organic
Synthesis 1999, 76, 6. (c) Sollewijn, A. E.; Kooijman, H.; Spek, A. L.;
Hiemstra, H. Chem. Eur. J. 1999, 5, 2472.
(37) Ager, D. J.; East, M. B.; Eisenstadt, A.; Laneman, S. A. Chem. Commun.
1997, 2359. (b) Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron
2000, 56, 8893.
(38) (a) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518. (b) Alaimo, P. J.; Peters,
D. W.; Arnold, J.; Bergman, R. G. J. Chem. Educ. 2001, 78, 64.
(29) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. Submitted for
publication.
(30) Plausible intermediates for the asymmetric arylation reaction were modeled
using molecular mechanics and the MacSpartan program. Unfortunately,
our attempts to rationalize the enantioselectivity of the process were
inconclusive.
9
J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002 1265

A R T I C L E S
Hamada et al.
and were used without further purification. Flash chromatography was
performed on Silicycle ultrapure silica gel (230-400 mesh) unless
otherwise noted. Yields refer to isolated yields of compounds of greater
1493, 1268, 1212, 1181; Anal. Calcd for C18H25NO: C, 79.66; H, 9.28.
Found: C, 79.84; H, 9.30.
Experimental Procedures for the Preparation of 2-(Dialkylphos-
phino)-2′-alkoxy-1,1′-binaphthyls.23 To a mixture of (S)-2,2′-bis-
((trifluoromethanesulfonyl)oxy)-1,1′-binaphthyl (2.75 g, 5.00 mmol),
diisopropylphosphine oxide (1.34 g, 10.0 mmol), palladium diacetate
(112 mg, 0.50 mmol), and 1,4-bis(diphenylphosphino)butane (dppb,
213 mg, 0.50 mmol) were added toluene (8 mL), dimethyl sulfoxide
(15 mL), and diisopropylethylamine (3.50 mL, 20.0 mmol). The mixture
was heated with stirring at 110 °C for 14 h. After cooling to room
temperature, the solvent and excess amine were removed under reduced
pressure (0.1-0.2 mmHg). The residue was diluted with EtOAc, washed
with water and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel chromatography
(elution with EtOAc) to give (S)-2-(diisopropylphosphinyl)-2′-[(tri-
fluoromethanesulfonyl)oxy]-1,1′-binaphthyl as a white solid (2.14 g,
80%).
To a solution of (S)-2-(diisopropylphosphinyl)-2′-((trifluoromethane-
sulfonyl)oxy)-1,1′-binaphthyl (2.14 g, 4.00 mmol) in a 2:1 mixture of
1,4-dioxane and MeOH (30.0 mL) was added aqueous NaOH solution
(3 M, 15.0 mL). The reaction mixture was stirred for 14 h at room
temperature, acidified (pH ) 1) with concentrated HCl, and extracted
with EtOAc. The organic phase was dried over MgSO4 and concentrated
under reduced pressure to give (S)-2-(diisopropylphosphinyl)-2′-hy-
droxy-1,1′-binaphthyl as a pale yellow solid, which was used in the
next step without purification.
To a mixture of (S)-2-(diisopropylphosphinyl)-2′-hydroxy-1,1′-
binaphthyl (502 mg, 1.25 mmol), obtained as described above, and
K2CO3 (690 mg, 5.00 mmol) in acetone (6 mL) was added MeI (712
mg, 5.00 mmol). The mixture was stirred at 50 °C for 12 h. After
cooling to room temperature, the mixture was filtered through Celite,
and the solid was washed with Et2O. The organic phases were combined
and concentrated in vacuo. The residue was purified by silica gel
chromatography (elution with EtOAc) to give 505 mg (97%) of (S)-
2-(diisopropylphosphinyl)-2′-methoxy-1,1′-binaphthyl.
To a mixture of (S)-2-(diisopropylphosphinyl)-2′-methoxy-1,1′-
binaphthyl (500 mg, 1.20 mmol) and Et3N (5.60 mL, 40.0 mmol) in
toluene (20 mL) was added Cl3SiH (1.35 g, 10.0 mmol) at 0 °C. The
reaction mixture was stirred at 110 °C for 12 h. After cooling to room
temperature, the mixture was diluted with Et2O (20 mL) and quenched
with a small amount of saturated NaHCO3 (2 mL). The resulting
suspension was filtered through Celite and the solid washed with Et2O.
The combined organic phases were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (elution: 10% EtOAc in hexane) to give 4b as a white
solid (340 mg, 71%).
1
than 95% purity as estimated by capillary GC, H NMR, and in most
cases elemental analysis. Yields reported in this section refer to a single
experiment, while those reported in the tables are an average of two or
more runs, and therefore, the numbers may differ slightly. Elemental
analyses were performed by Atlantic Microlab, Inc. Infrared (IR) spectra
reported in this paper for neat solids were obtained by placing neat
samples directly on the DiComp probe of an ASI Applied Systems
React IR 1000 in situ IR instrument. Alternatively, IR spectra in this
paper for several compounds were recorded on a Perkin-Elmer FT-IR
1600. Chiral HPLC analyses were performed on a Hewlett-Packard
1100 system with an HP 1100 diode array detector (monitoring at 254
nm) using a Chiralcel OD column (25 cm × 0.46 cm). Racemic
compounds analogous to the enantiomerically enriched compounds
described below were prepared by reaction with (rac)-BINAP. The
HPLC retention times of the racemic products were the same as those
of the enantiomerically enriched products. Optical rotations were
recorded on a Perkin-Elmer 241 Polarimeter.
General Procedure for 2-Alkyl-5-(N-methyl-anilinomethylene)-
cycloalkanones.14,15 Ethylformate (10.0 mL) was added dropwise to a
stirred solution of KOtBu (3.70 g, 33.0 mmol) in THF (25 mL) at 0 °C
(CAUTION: gas evolution occurs.) The mixture was cooled to -10
°C, and the ketone (30.0 mmol) in ethylformate (20.0 mL) was added
via cannula. The resulting mixture was stirred at -10 °C for 30 min,
warmed to room temperature, and stirred for an additional 12 h. The
mixture was transferred to a separatory funnel, acidified to pH ) 1
with HCl (1 M), and extracted with Et2O (3 × 100 mL). The combined
organic extracts were dried with MgSO4, filtered, and concentrated in
vacuo to give the crude formylated ketone.
The crude formylated ketone was dissolved in benzene (60 mL),
and N-methylaniline (4.20 mL, 39.0 mmol) was added. The flask was
fitted with a Dean-Stark trap, and the mixture was refluxed for 3 h
with azeotropic removal of water. The mixture was allowed to cool to
room temperature and concentrated in vacuo. The excess N-methyl
aniline was removed by distillation, and the resulting solid was purified
by recrystallization from hexane.
2-Methyl-5-(N-methyl-anilinomethylene)cyclopentanone (1a). The
general procedure gave 5.31 g (82% yield) of the title compound as a
yellow solid: mp 88-90 °C; 1H NMR (300 MHz, CDCl3) δ 7.55 (t, J
) 1.8 Hz, 1 H), 7.37-7.31 (m, 2H), 7.15-7.10 (m, 3H), 3.49 (s, 3H),
2.52-2.07 (m, 4H), 1.43-1.30 (m, 1H), 1.12 (d, J ) 6.8 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 208.3, 146.2, 141.3, 129.1, 124.4, 121.1,
108.9, 42.8, 40.0, 29.8, 26.2, 15.5; IR (neat, cm-1) 2954, 2867, 1679,
1559, 1497, 1364, 1185; Anal. Calcd for C14H17NO: C, 78.10; H, 7.96.
Found: C, 78.36; H, 8.08.
4a-4g were prepared using the method above.
(R)-(+)-2-(Dicyclohexylphosphino)-2′-methoxy-1,1′-binaphthyl (4a).
Prepared as above in 17% overall yield as a white solid which was
2-Propyl-5-(N-methyl-anilinomethylene)cyclopentanone (1b). The
general procedure gave 5.18 g (71% yield) of the title compound as a
yellow solid: mp 78-79 °C; 1H NMR (300 MHz, CDCl3) δ 7.55 (t, J
) 1.8 Hz, 1H), 7.36-7.31 (m, 2H), 7.15-7.10 (m, 3H), 3.48 (s, 3H),
2.58-2.37 (m, 2H), 2.27-2.05 (m, 2H), 1.87-1.76 (m, 1H), 1.48-
1.16 (m, 4H), 0.92 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
208.1, 146.2, 141.3, 129.0, 124.4, 121.1, 109.3, 48.0, 40.0, 33.0, 27.5,
26.3, 20.9, 14.3; IR (neat, cm-1) 2952, 2925, 2856, 1677, 1559, 1492,
1362, 1216, 1187; Anal. Calcd for C16H21NO: C, 78.97; H, 8.70.
Found: C, 78.99; H, 8.72.
1
judged to be 95% pure by 31P NMR; mp 177-179 °C dec; H NMR
(300 MHz, CD2Cl2) δ 8.04-7.78 (m, 5H), 7.49-7.43 (m, 2H), 7.33-
7.09 (m, 4H), 6.89 (d, J ) 8.4 Hz, 1H), 3.78 (s, 3H), 1.95-0.84 (m,
22H); 13C NMR (75 MHz, CD2Cl2) δ 154.7, 134.4, 134.3, 133.7, 133.4,
133.3, 129.56, 129.53, 128.7, 128.0, 127.9, 126.9, 126.8, 126.5, 126.1,
123.4, 123.4, 112.5, 55.7, 36.0, 35.7, 34.5, 34.3, 31.1, 31.0, 30.8, 30.7,
30.5, 30.3, 28.1, 28.0, 27.9, 27.8, 27.6, 27.5, 27.4, 26.9, 26.7 (observed
complexity due to P-C splitting); 31P NMR (121 MHz, CD2Cl2) δ
-8.90; IR (neat, cm-1) 2950, 1594, 1509, 1463, 1272, 1248, 1084,
814, 746; [R]20Na +65.7 (c 2.5, CH CH2Cl2); HRMS (+)FAB, m/z 481
[M + H]+; HRMS calcd for [M + H]+: +481.2655, Found[M + H]+:
+481.2636.
(S)-(-)-2-(Diisopropylphosphino)-2′-methoxy-1,1′-binaphthyl (4b).
Prepared as above in 55% overall yield as a white solid; mp 133-134
°C; 1H NMR (300 MHz, CDCl3) δ 8.05-7.78 (m, 5H), 7.49-7.42 (m,
2H), 7.32-7.14 (m, 4H), 6.96 (d, J ) 8.4 Hz, 1H), 3.76 (s, 3H), 2.11-
2.07 (m, 2H), 1.14-0.98 (m, 6H), 0.93-0.83 (m, 6H);13C NMR (75
2-Pentyl-5-(N-methyl-anilinomethylene)cyclopentanone (1c). The
general procedure gave 6.18 g (76% yield) of the title compound as a
yellow solid: mp 72-73 °C; 1H NMR (300 MHz, CDCl3) δ 7.55 (t, J
) 1.8 Hz, 1 H), 7.37-7.31 (m, 2H), 7.15-7.10 (m, 3H), 3.49 (s, 3H),
2.52-2.43 (m, 2H), 2.20-2.04 (m, 2H), 1.87-1.81 (m, 1H), 1.48-
1.19 (m, 8H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
208.1, 146.2, 141.2, 129.1, 124.4, 121.1, 109.4, 48.2, 40.0, 32.1, 30.8,
27.5, 27.4, 26.5, 22.7, 14.2; IR (neat, cm-1) 2927, 2858, 1679, 1559,
9
1266 J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002

Catalyst for Asymmetric Arylation of Ketone Enolates
A R T I C L E S
MHz, CDCl3) δ 154.6, 143.5, 134.4, 133.9, 133.4, 129.6, 129.23,
129.19, 128.1, 128.0, 127.2, 126.9, 126.8, 126.2, 126.1, 123.4, 122.6,
122.5, 112.6, 55.7, 26.2, 26.0, 24.9, 24.7, 20.9, 20.7, 20.63, 20.57, 20.45,
20.41, 20.3 (observed complexity due to P-C splitting);31P NMR (121
MHz, CDCl3) δ -0.80; IR (neat, cm-1) 2966, 2950, 1594, 1574, 1495,
25.9, 25.8, 25.6, 25.2, 24.9, 22.9, 21.0, 20.8, 20.7, 20.6, 20.44, 20.37,
20.29, 14.5 (observed complexity due to P-C splitting); 31P NMR (121
MHz, CDCl3) δ -0.73, -0.64, IR (neat, cm-1) 2948, 2863, 1509, 1463,
1268, 1223, 814, 744; [R]20 +17.5 (c 1.0, CHCl3); HRMS (+)FAB
Na
calcd for [M + H]+: +577.2660 Found[M + H]+: +577.2674.
(R)-(-)-2-(Diisopropylphosphino)-1,1′-binaphthyl (4h). Prepared
as above in 55% overall yield from (S)-2-(trifluoromethanesulfonyl)-
oxy-1,1′-binaphthyl21 as a white solid; mp 128-130 °C; 1H NMR (300
MHz, CDCl3) δ 7.91 (q, J ) 8.7 Hz, 3H), 7.75 (dd, J ) 8.7 Hz, 1.5
Hz, 1H), 7.55 (dd, J ) 8.1 Hz, 6.9 Hz, 1H), 7.46-7.33 (m,3H), 7.20
(t, J ) 6.9 Hz, 2H), 7.12(d, 2H), 2.17-1.97(m, 2H), 1.08-0.78 (m,
12H); 13C NMR (75 MHz, CDCl3) δ 147.0, 146.6, 138.4, 134.9, 133.6,
133.5, 133.4, 133.3, 129.41, 129.37, 128.7, 128.4, 128.0, 127.8, 127.6,
127.3, 127.1, 126.5, 126.2, 125.7, 124.9, 26.6, 26.4, 24.7, 24.5, 21.3,
21.1, 20.9, 20.8, 20.7, 20.5, 20.2, 20.1 (observed complexity due to
1208, 885, 748; [R]20 -81.9 (c 3.5, CHCl3); MS (+)FAB, m/z 401
Na
[M + H]+; Anal. Calcd for C27H29OP: C, 80.97; H, 7.30. Found; C,
80.94; H, 7.34.
(S)-(-)-2-(Diisopropylphosphino)-2′-isopropoxy-1,1′-binaphth-
yl (4c). Prepared as above in 24% overall yield as a white solid; mp
48-49 °C;1H NMR (300 MHz, CD2Cl2) δ 8.01-7.78 (m, 5H), 7.50-
7.42 (m, 2H), 7.33-7.11 (m, 4H), 6.90 (d, J ) 8.4 Hz, 1H), 3.76 (s,
3H), 2.11-2.07 (m, 2H), 1.14-0.98 (m, 6H), 0.93-0.83 (m, 6H);13C
NMR (75 MHz, CD2Cl2) δ 150.7, 147.4, 129.9, 129.6, 129.0, 128.7,
127.8, 127.1, 126.2, 125.9, 123.4, 121.7, 120.1 115.4, 22.6, 22.2, 20.7,
20.6, 17.7, 17.2, 15.6, 15.4, 14.0 (observed complexity due to P-C
splitting);31P NMR (121 MHz, CD2Cl2) δ -0.75; IR (neat, cm-1) 2966,
P-C splitting); 31P NMR (121 MHz, CDCl3) δ -2.09; IR (neat, cm-1
)
3053, 2948, 2863, 1505, 1462, 1360, 816, 780, 747; [R]20Na δ -291.4
(c 7.0, CHCl3); MS (+)FAB, m/z 371 [M + H]+; HRMS (+)FAB calcd
for [M + H]+: +371.1923 Found[M + H]+: +371.1920.
2950, 1594; [R]20 -134.5 (c 1.0, CH2Cl2); MS (+)ESI, m/z 429 [M
Na
+ H]+; Anal. Calcd for C29H33OP: C, 81.28; H, 7.76. Found; C, 81.00;
H, 7.85.
General procedure for asymmetric arylation using (S)-BI-
NAP.13,16 An oven-dried Schlenk tube equipped with a rubber septum
was evacuated and backfilled with argon. The tube was charged with
palladium acetate (0.05 mmol), (S)-BINAP (0.12 mmol) and ketone 1
(0.50 mmol). The tube was evacuated and backfilled with argon
(repeated three times). Toluene (2 mL) was added and the mixture was
stirred for 15 min at room temperature. The corresponding aryl halide
(1.00 mmol) and NaOtBu (96 mg, 1.00 mmol) were added to the tube.
The tube was capped with a septum, purged with argon, and additional
toluene (4 mL) was added via syringe. The mixture was stirred at 100
°C until the starting ketone had been completely consumed as judged
by GC analysis (2-3 h). The reaction mixture was quenched with
saturated aqueous ammonium chloride (10 mL) and diluted with ether
(20 mL). The mixture was poured into a separatory funnel and the
layers were separated. The aqueous layer was extracted with ether (20
mL) and the combined organic layers were washed with brine (20 mL),
dried over MgSO4, filtered and concentrated in vacuo. The crude
materials were purified by silica gel chromatography (elution: 10%-
20% EtOAc in hexane).
(S)-(-)-2-(Diisopropylphosphino)-2′-benzyloxy-1,1′-binaphthyl (4d).
Prepared as above in 61% overall yield as a white solid; mp 123 °C
(dec); H NMR (300 MHz, CDCl3) δ 7.92-7.77 (m, 5H), 7.47-6.90
1
(m, 11H), 5.04 (s, 2H), 2.07-2.00 (m, 2H), 1.04-0.98 (m, 6H), 0.92-
0.81 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 153.6, 137.6, 136.0, 134.4,
133.7, 133.3, 133.2, 128.8, 128.2, 128.0, 127.9, 127.2, 127.0, 126.4,
126.0, 123.4, 114.4, 70.1, 25.9, 25.7, 25.0, 24.8, 20.9, 20.7, 20.6, 20.5,
20.3 (observed complexity due to P-C splitting); 31P NMR (121 MHz,
CDCl3) δ -0.88; IR (neat, cm-1) 2966, 2950, 1594, 1509, 1465, 1270,
814, 742; MS (+)FAB, m/z 477 [M + H]+; [R]20 -65.9 (c 1.67,
Na
CHCl3) Anal. Calcd for C33H33OP: C, 83.16; H, 6.98. Found; C, 82.92;
H, 7.00.
(S)-(-)-2-(Diisopropylphosphino)-2′-(1-naphthylmethoxy)-1,1′-bi-
naphthyl (4e). Prepared as above in 61% overall yield as a white solid;
1
mp 94 °C (dec); H NMR (300 MHz, CDCl3) δ 7.96-7.81 (m, 4H),
7.72-7.40 (m, 6H), 7.72-7.40 (m, 6H), 5.45 (m, 2H), 2.02-1.96 (m,
2H), 1.02-0.70 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 153.6, 143.4,
143.0, 136.2, 134.5, 133.7, 133.5, 133.4, 132.7, 130.8, 129.7, 129.0,
128.9, 128.4, 128.2, 128.0, 127.8, 127.1, 126.5, 126.3, 126.0, 125.9,
125.4, 125.2, 123.6, 123.6, 123.4, 114.6, 69.2, 25.9, 25.8, 25.2, 25.1,
21.0, 20.7, 20.6, 20.5, 20.4, 20.3 (observed complexity due to P-C
splitting); 31P NMR (121 MHz, CDCl3) δ -0.67; IR (neat, cm-1) 3054,
General procedure for asymmetric arylation using ligands 3 and
4.16 An oven-dried Schlenk tube equipped with a rubber septum was
evacuated and backfilled with argon. The tube was charged with tris-
(dibenzylideneacetone)dipalladium (0.005 mmol), ligand 3 or 4 (0.0125
mmol) and the ketone 1 (0.50 mmol). The tube was evacuated and
backilled with argon (repeated three times). Toluene (2 mL) was added
and the mixture was stirred for 15 min at room temperature. The
corresponding aryl halide (1.00 mmol) and sodium t-butoxide (96 mg,
1.00 mmol) were added to the tube. The tube was capped with a septum,
purged with argon, and additional toluene (1 mL) was added through
the septum. 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
ammonium chloride (10 mL) and diluted with ether (20 mL). The
mixture was poured into a separatory funnel and the layers were
separated. The aqueous layer was extracted with ether (20 mL) and
the combined organic layers were washed with brine (20 mL), dried
over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
The crude materials were purified by silica gel chromatography
(elution: 10%-20% EtOAc in hexane). See Tables 3 and 4 and the
Supporting Information for yields.
2948, 2865, 1509, 1465, 1455, 1270, 814, 744; [R]20 -6.78 (c 6.0,
Na
CHCl3); MS (+)FAB, m/z 527 [M + H]+; Anal. Calcd for C37H35OP:
C, 84.38; H, 6.70. Found; C, 84.15; H, 6.69.
(R)-(-)-2-(Diisopropylphosphino)-2′-(2-naphthylmethoxy)-1,1′-
binaphthyl (4f). Prepared as above in 49% overall yield as a white
solid; mp 74-76 °C (dec); 1H NMR (300 MHz, CDCl3) δ 7.96-7.00
(m, 19H), 5.19 (s, 2H), 2.07-2.00 (m, 2H), 1.04-0.82 (m, 12H); 13C
NMR (75 MHz, CDCl3) δ 153.5, 135.1, 134.4, 133.8, 133.4, 133.3,
133.2, 132.7, 129.6, 129.1, 128.8, 128.0, 127.9, 127.8, 127.2, 127.1,
126.5, 126.4, 126.1, 126.05, 126.0, 125.8, 125.2, 124.4, 123.6, 114.6,
70.1, 26.0, 25.8, 25.0, 24.8, 20.7, 20.6, 20.4, 20.2 (observed complexity
due to P-C splitting); 31P NMR (121 MHz, CDCl3) δ -1.81; IR (neat,
cm-1) 1509, 1463, 1270, 812, 744; [R]20 -9.08 (c 4.0, CHCl3); MS
Na
(+)FAB, m/z 527 [M + H]+; Anal. Calcd for C37H35OP: C, 84.38; H,
6.70. Found; C, 84.08; H, 6.72.
(R)-(+)-2-(Diisopropylphosphino)-2′-(9-phenanthylmethoxy)-1,1′-
binaphthyl (4 g). Prepared as above in 38% overall yield as a white
1
solid; mp 113-116 °C (dec); H NMR (300 MHz, CDCl3) δ 8.66 (t,
(R)-(+)-2-Methyl-2-(p-tert-butylphenyl)-5-(N-methylanilinometh-
ylene)cyclopentanone (2a).1H NMR (300 MHz, CDCl3) δ 7.63 (t, J
) 1.5 Hz, 1H), 7.33-7.27 (m, 5H), 7.13-7.07 (m, 4H), 3.45 (s, 3H),
2.57-2.36 (m, 3H), 1.91-1.81 (m, 1H), 1.43 (s, 3H), 1.28 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 207.6, 148.7, 146.2, 142.8, 141.1, 129.1,
126.1, 125.2, 124.6, 121.1, 108.2, 52.1, 40.1, 36.7, 34.3, 31.5, 25.2,
25.0; IR (neat, cm-1) 2960, 2927, 2867, 1684, 1605, 920, 841, 752,
J ) 9.3 Hz, 2H), 7.94-6.99 (m, 19H), 5.46 (s, 2H), 2.00 (m, 2H),
1.13-1.01 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 153.5, 143.0, 136.2,
135.9, 134.4, 133.7, 133.6, 133.5, 133.2, 131.5, 131.3, 130.8, 130.3,
130.2, 130.1, 129.8, 129.7, 128.9, 128.7, 128.5, 128.0, 127.9, 127.7,
127.1, 126.8, 126.5, 126.4, 126.3, 126.1, 126.0, 125.8, 125.7, 123.9,
123.6, 123.0, 122.8, 122.7, 122.4, 122.0, 114.8, 114.5, 69.5, 68.9, 31,8,
9
J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002 1267

A R T I C L E S
Hamada et al.
737, 694; [R]20Na +5.39 (c 10.0, CHCl3); MS(EI), m/z 347[M]+; Anal.
Calcd for C23H25NO: C, 82.95; H, 8.41. Found; C, 82.73; H, 8.54.
(R)-(+)-2-Methyl-2-(o-tolyl)-5-(N-methylanilinomethylene)cyclo-
+22.9 (c 10.0, CHCl3); MS(EI), m/z 363[M]+; Anal. Calcd for C23H25-
NO3: C, 82.95; H, 8.41. Found; C, 82.73; H, 8.54.
(R)-(+)-2-Propyl-2-(m-tolyl)-5-(N-methyl-anilinomethylene)cyclo-
1
1
pentanone (2b). H NMR (300 MHz, CDCl3) δ 7.65 (t, J ) 1.5 Hz,
pentanone (2i). H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.33-
1H), 7.38-7.32 (m, 3 H), 7.17-7.12 (m, 6H), 3.53 (s, 3H), 2.63-
2.55 (m, 2H), 2.26 (s, 3H), 2.25-2.16 (m, 1H), 1.85-1.76 (m, 1H),
1.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 208.6, 146.3, 143.0, 136.5,
132.1, 129.3, 129.1, 127.6, 126.7, 125.7, 124.9, 121.7, 107.7, 53.5,
6.99 (m, 9H), 3.43 (s, 3H), 2.56-2.37 (m, 3H), 2.33 (s, 3H), 2.01-
1.82 (m, 2H), 1.67-1.57 (m, 1H), 1.21-1.03 (m, 2H), 0.83 (t, J ) 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 206.7, 146.3, 142.2, 141,5,
137.7, 129.1, 128.1, 127.7, 127.1, 124.6, 123.8, 121.1, 108.6, 56.3,
41.8, 40.0, 32.5, 25.2, 21.9, 18.4, 14.9; IR (neat, cm-1) 2956, 2931,
2871, 1686, 1567, 885, 773, 731; [R]20Na +28.4 (c 10.0, CHCl3); MS-
(EI), m/z 333[M]+, Anal. Calcd for C23H27NO: C, 82.84; H, 8.16.
Found; C, 82.91; H, 8.30.
40.7, 36.5, 25.1, 23.8, 22.5; IR(neat, cm-1) 2964, 1684, 1567, [R]20
Na
+29.3 (c 1.2, CHCl3); MS(EI), m/z 305[M]+, Anal. Calcd for C21H23-
NO: C, 82.58; H, 7.59. Found; C, 82.53; H, 7.68.
(R)-(+)-2-Methyl-2-(m-tolyl)-5-(N-methylanilinomethylene)cyclo-
1
pentanone (2c). H NMR (300 MHz, CDCl3) δ 7.64 (t, J ) 1.5 Hz,
(R)-(+)-2-Pentyl-2-(m-tolyl)-5-(N-methyl-anilinomethylene)cyclo-
1H), 7.34-7.29 (m, 2H), 7.19-7.09 (m, 6H), 7.02-6.98 (m, 1H), 3.47
(s, 3H), 2.51-2.33 (m, 3H), 2.32 (s, 3H), 1.90-1.81 (m, 1H), 1.43 (s,
3H);13C NMR (75 MHz, CDCl3) δ 207.6, 146.2, 144.2, 142.6, 137.8,
129.2, 128.2, 127.3, 127.0, 124.7, 123.4, 121.3, 108.3, 52.7, 40.2, 36.9,
25.4, 25.1, 21.9; IR (neat, cm-1) 2960, 2932, 2863, 1686, 1563, 920,
1
pentanone (2j). H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.31-
6.98 (m, 9H), 3.44 (s, 3H), 2.56-2.43 (m, 3H), 2.32 (s, 3H), 2.02-
1.83 (m, 2H), 1.70-1.60 (m, 1H), 1.20-1.02 (m, 6H), 0.81 (t, J ) 6.6
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 206.6, 146.2, 142.1, 141.5,
137.6, 129.1, 128.0, 127.6, 127.0, 124.5, 123.7, 121.0, 108.6, 56.2,
39.9, 39.4, 32.6, 32.6, 25.1, 24.6, 22.7, 21.9, 14.3; IR(neat) 2954, 2931,
2858, 1686, 1567, 908, 754, 710; [R]25Na +35.4 (c 10.0, CHCl3); MS-
(EI), m/z 361[M]+, Anal. Calcd for C25H31NO: C, 83.06; H, 8.64.
Found; C, 82.81; H, 8.66.
787, 754, 696; [R]20 +9.37 (c 10.0, CHCl3); MS(EI), m/z 305[M]+;
Na
Anal. Calcd for C21H23NO: C, 82.58; H, 7.59. Found; C, 82.40; H,
7.70.
(R)-(+)-2-Methyl-2-(p-tolyl)-5-(N-methyl-anilinomethylene)cyclo-
1
pentanone (2d). H NMR (300 MHz, CDCl3) δ 7.63 (t, J ) 1.5 Hz,
(R)-(+)-2-Methyl-2-phenyl-5-(N-methyl-anilinomethylene)cyclo-
1H), 7.34-7.24 (m, 4H), 7.14-7.08 (m, 5H), 3.47 (s, 3H), 2.51-2.34
(m, 3H), 2.30 (s, 3H), 1.90-1.80 (m, 1H), 1.41 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 207.6, 146.2, 142.5, 141.2, 135.8, 129.2, 129.1, 126.5,
1
pentanone (2k). H NMR (300 MHz, CDCl3) δ 7.64 (t, J ) 1.5 Hz,
1H), 7.40-7.09 (m, 10H), 3.47 (s, 3H), 2.52-2.37 (m, 3H), 1.93-
1.82 (m, 1H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.6, 146.2,
144.3, 142.8, 129.2, 128.4, 126.5, 126.3, 124.9, 121.4, 108.2, 52.7,
40.4, 36.9, 25.3, 25.0; IR (neat, cm-1) 2957, 2862, 1683, 1602, 1569,
124.7, 121.3, 108.3, 52.4, 40.2, 36.7, 25.4, 25.0, 21.2; IR (neat, cm-1
)
2958, 2923, 2863, 1688, 1605, 1563, 920, 818, 802, 754, 694; [R]20
Na
+5.41 (c 10.0, CHCl3); MS(EI), m/z 305[M]+; Anal. Calcd for C23H25-
NO3: C, 82.95; H, 8.41. Found; C, 82.73; H, 8.54, Anal. Calcd for
C21H23NO: C, 82.58; H, 7.59. Found; C, 82.56; H, 7.58.
923, 756, 697; [R]20 +20.0 (c 5.83, CHCl3); MS(EI), m/z 291[M]+;
Na
Anal. Calcd for C20H21NO: C, 82.44; H, 7.26. Found; C, 82.20; H,
(R)-(+)-2-Methyl-2-(m-anisyl)-5-(N-methyl-anilinomethylene)cy-
clopentanone (2e). 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.34-
6.95 (m, 8H), 6.75-6.71 (m, 1H), 3.78 (s, 3H), 3.45 (s, 3H), 2.49-
2.34 (m, 3H), 1.90-1.81 (m, 1H), 1.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 207.2, 159.5, 146.1, 145.9, 142.6, 129.2, 129.1, 124.7, 121.3,
118.9, 112.8, 111.3, 108.1, 55.3, 52.7, 40.2, 36.8, 25.3, 25.0; IR (neat,
cm-1) 2960, 2863, 1686, 1561, 920, 895, 781, 739, 694; [R]20Na +0.30
(c 10.0, CHCl3); MS(EI), m/z 321[M]+; Anal. Calcd for C21H23NO2:
C, 78.47; H, 7.21. Found; C, 78.22; H, 7.22.
7.24.
Procedure for Removing the Blocking Group.16 Ketone 2k (84
mg, 0.29 mmol) was dissolved in THF (8.0 mL) in a round-bottomed
flask. Aqueous HCl (1 M, 6.0 mL) was added and the mixture stirred
at room temperature until 2k had been completely consumed, as judged
by GC analysis (ca. 3 h). The mixture was diluted with water (10 mL)
and ether (10 mL) and was poured into a separatory funnel; the layers
were then separated. The aqueous layer was extracted with ether (10
mL), and the organic layers were combined and concentrated in vacuo.
The residual oil was dissolved in aqueous NaOH solution (1 M, 8 mL)
in a round-bottomed flask equipped with a reflux condenser, and the
resulting solution was stirred at 90 °C for 2 h. The mixture was cooled
to room temperature, neutralized with aqueous HCl (1 M), and diluted
with ether (20 mL). The mixture was poured into a separatory funnel,
and the layers were separated. The aqueous layer was extracted with
ether (10 mL), and the combined organic layers were washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude material was purified by flash chromatography on silica gel to
give (R)-(+)-2-methyl-2-phenylcyclopentanone 522 (46.0 mg, 91%,
(R)-(+)-2-Methyl-2-(p-anisyl)-5-(N-methyl-anilinomethylene)cy-
clopentanone (2f). 1H NMR (300 MHz, CDCl3) δ 7.62 (t, J ) 1.5 Hz,
1H), 7.33-7.29 (m, 4 H), 7.13-7.08 (m, 3H), 6.85-6.80 (m, 2H),
3.75 (s, 3H), 3.45 (s, 3H), 2.56-2.32 (m, 3H), 1.89-1.79 (m, 1H),
1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.5, 157.8, 146.1, 142.4,
136.1, 129.1, 127.4, 124.6, 121.1, 113.6, 108.0, 55.3, 51.9, 40.1, 36.6,
25.4, 24.9; IR (neat, cm-1) 2960, 2836, 1684, 1561 920, 860, 802,
729, 694; [R]20Na +1.53 (c 10.0, CHCl3); MS(EI), m/z 321[M]+; Anal.
Calcd for C21H23NO: C, 82.58; H, 7.59. Found; C, 82.53; H, 7.68.
(R)-(+)-2-Methyl-2-(p-trifluoromethanephenyl)-5-(N-methyl-anili-
1
nomethylene)cyclopentanone (2 g). H NMR (300 MHz, CDCl3) δ
[R]20 +76.6 (c 3.4, EtOH), 93% ee) as a colorless oil.
Na
7.65 (s, 1H), 7.55-7.49 (m, 4H), 7.35-7.30 (m, 2H), 7.16-7.10 (m,
3H), 3.48 (s, 3H), 2.56-2.30 (m, 3H), 1.97-1.87 (m, 1H), 1.45 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 206.4, 148.7, 145.9, 143.3, 128.2,
128.5, 128.1, 127.0, 126.1, 125.2, 125.1, 125.0, 122.5, 121.6, 107.3,
Acknowledgment. This research was funded by the National
Institutes of Health (GM46059) with additional support from
Ajinomoto Co., Inc. We are grateful to Drs. Joseph M. Fox
and Alex R. Muci for helpful discussions as well as assistance
in the preparation of the manuscript.
52.7, 40.5, 36.7, 25.0, 24.8; IR(neat, cm-1) 2964, 1686, 1565; [R]20
Na
+7.7 (c 10.0, CHCl3); MS(EI), m/z 359[M]+, Anal. Calcd for C21H20-
NOF3: C, 70.18; H, 5.61. Found; C, 69.89, H, 5.47.
(R)-(+)-2-(3-[1,3]Dioxolan-2-yl-phenyl)-2-methyl-5-(N-methyl-
anilinomethylene)cyclopentanone (2h). 1H NMR (300 MHz, CDCl3)
δ 7.63 (s, 1H), 7.49 (s, 1H), 7.42-7.27 (m, 4H), 7.14-7.08 (m, 3H),
5.78 (s, 1H), 4.14-3.98 (m, 3H), 3.46 (s, 3H), 2.55-2.37 (m, 3H),
1.92-1.83 (m, 1H), 1.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.1,
146.1, 144.4, 142.7, 141.2, 137.6, 129.3, 129.1, 128.4, 127.6, 124.8,
124.7, 121.4, 108.1, 104.0, 65.4, 52.4, 40.3, 36.7, 25.4, 25.0; IR (neat,
Supporting Information Available: 1H and 31P NMR spectra
of 4a and 4h, and additional results in the arylation of 1a with
other commercially available ligands and reactions with different
aryl halides using 3/Pd-based catalysts (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
cm-1) 2960, 2927, 2887, 1684, 1605, 1565, 920, 802, 756, 696; [R]20
JA011122+
Na
9
1268 J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002