Asymmetric carbon - Carbon coupling of phenols or anilines with aryllead triacetates

Article abstract of DOI:10.1021/ja012287l

The asymmetric coupling of various phenol or aniline derivatives with bulky aryllead triacetates was thoroughly investigated using optically active amines, including strychnine and brucine. We found that conformationally restricted tertiary amines, as wel

Full text of DOI:10.1021/ja012287l

Published on Web 04/19/2002
Asymmetric Carbon-Carbon Coupling of Phenols or Anilines
with Aryllead Triacetates
Taichi Kano, Yuki Ohyabu, Susumu Saito, and Hisashi Yamamoto*
Contribution from the Graduate School of Engineering, Nagoya UniVersity, SORST,
Japan Science and Technology Corporation (JST), Chikusa, Nagoya 464-8603, Japan
Received October 3, 2001
Abstract: The asymmetric coupling of various phenol or aniline derivatives with bulky aryllead triacetates
was thoroughly investigated using optically active amines, including strychnine and brucine. We found that
conformationally restricted tertiary amines, as well as lithium aryloxides and molecular sieves, are essential
for accelerating the rate of phenol coupling. Consequently, the reaction can be carried out at a low
temperature (-40 to -20 °C) and gives a high degree of diastereo- and enantioselectivity. In contrast to
the effectiveness of lithiation in phenol coupling, magnesation of anilines was a critical technique for aniline
coupling with aryllead triacetates. Using these coupling methods, a diverse set of di-, tri, and polyaryl
compounds with axial chirality can be easily obtained, and these should be useful for the construction of
a variety of aryl-aryl frameworks involved in metal ligands, natural products, and artificial helical polymers.
Introduction
tether, and this enables the coupling between two different
aromatics to give the asymmetrical biaryls.8 In contrast, the
The optically pure biaryl axis has been the subject of
increasing interest due to its role as a pivotal element in a rapidly
growing number of not only pharmacologically potent natural
products1 (e.g., vancomycin, steganone, etc.) but also chiral
catalysts2 (e.g., BINAL-H, BINAP, etc.) and artificial helical
polymers.3 Despite a broad spectrum of classical4 and modern5
procedures for connecting aromatic moieties, the development
of efficient aryl-coupling methods that enable the directed
construction of even highly sterically demanding bi and poly-
aryls in optically active form6 has become very important.
The major methods for the synthesis of these compounds can
be divided into four categories: (1) Ullmann coupling of aryl
halides,7 (2) oxidative coupling of electron-rich phenols,8 (3)
nucleophilic aromatic substitution on electron-deficient arenes
with arylmetal compounds,9 and (4) transition-metal-catalyzed
cross-coupling between aryl halides and arylmetal species.10
Optically active biaryls are often prepared by the intramo-
lecular Ullmann coupling of two aryl halides linked by a chiral
intermolecular oxidative coupling of aromatic alcohols using
metal salts ligated by optically active amines gives symmetrical
biaryls, such as BINOL, with high enantioselectivity.8c-f
Moreover, the successful extension of this class of reactions to
the catalytic process, which involves cross-coupling between
two different arenes8h in the presence of molecular oxygen,8i,j
has recently been reported.
With the use of arylmetal reagents, nucleophilic aromatic
substitution of aromatic compounds9 that have both activating
group and leaving groups was extensively studied by Meyers
and co-workers.9a-d Using chiral oxazolines or chiral esters,9f,g
accompanied by specific leaving groups such as menthol,9e
asymmetrical biaryls in an optically active form can be
synthesized diastereoselectively. Unfortunately, however, a very
high atropisomeric excess is obtained with a pair of aromatic
compounds in which the substituents ortho to the coupling
position significantly differ in size.
The cross-coupling reactions between aryl halides or triflates
and aryl boronic acids (Suzuki-Miyaura coupling)5b or Grignard
* To whom correspondence should be addressed. E-mail: yamamoto@
nucc.cc.nagoya-u.ac.jp.
(1) (a) Evans, D. A.; Wood, M. R.; Trotter, W.; Richardson, T. I.; Barrow, J.
C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700. (b) Nicolaou, K.
C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.; Solomon, M. E.;
Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2708. (c) Meyers, A. I.; Willemsen, J. J. Chem.
Commun. 1997, 1673. (d) Chau, P.; Czuba, I. R.; Rizzacasa, M. A.;
Bringmann, G.; Gulden, K.-P.; Scha¨ffer, M. J. Org. Chem. 1996, 61, 7101.
(e) Tomioka, K.; Ishiguro, T.; Koga, K. Tetrahedron Lett. 1980, 21, 2973.
For recent review, see: (f) Lloyd-Williams, P.; Giralt, E. Chem. Soc. ReV.
2001, 30, 145.
(2) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis; Springer-Verlag: Berlin Heidelderg, 1999. (b)
Noyori, R., Ed. Asymmetric Catalysis in Organic Synthesis; John Wiley &
Sons: New York, 1994.
(3) For recent examples: (a) Takata, T.; Furusho, Y.; Murakata, K.; Endo, T.;
Matsuoka, H.; Hirasa, T.; Matsuo, J.; Sisido, M. J. Am. Chem. Soc. 1998,
120, 4530 and references therein. (b) Nozaki, K.; Terakawa, T.; Takaya,
H.; Hiyama, T. Angew. Chem., Int. Ed. 1998, 37, 131. (c) Ito, Y.; Miyake,
T.; Ghima, R.; Ohara, T.; Suginome, M. J. Am. Chem. Soc. 1998, 120,
11880.
(4) (a) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, N.; Fujioka, A.;
Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn.
1976, 49, 1958. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508.
(5) (a) Knochel, P.; Singer, R. Chem. ReV. 1993, 93, 2117. (b) Miyaura, A.;
Suzuki, A. Chem. ReV. 1995, 95, 2457. For recent advances in this field,
see: (c) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722. (d) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387.
(6) For recent reviews, see: (a) Bringmann, G.; Breuning, M.; Tasler, S.
Synthesis 1999, 525. (b) Bringmann, G.; Walter, R.; Weirich, R. In Methods
of Organic Chemistry (Houben Weyl), 4th ed.; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol.
E21a, p 567. (c) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 977.
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Chem. Soc. Jpn. 1988, 61, 3249. (b) Lipshutz, B. H.; Kayser, F.; Liu, Z.-
P. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842. (c) Sugimura, T.; Yamada,
H.; Inoue, S.; Tai, A. Tetrahedron: Asymmetry 1997, 8, 649. (d) Lin, G.-
Q.; Zhong, M. Tetrahedron: Asymmetry 1997, 8, 1369.
9
10.1021/ja012287l CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 5365-5373
5365

A R T I C L E S
Kano et al.
Scheme 1
Scheme 3
Scheme 2
Table 1. Effect of Amine in the Ligand Coupling of 1a with 2aa
entry
amine
yield (%)b
dl-3a:meso-3ac
reagents (Kumada-Tamao coupling)4a with metal catalysts has
been shown to be very useful for obtaining various biaryls.10
Among the most outstanding examples to date are the use of
Hayashi’s chiral Ni catalysts10a,b and the method recently
reported by Buchwald.10c However, the use of sterically con-
gested substrates has frequently resulted in a significant decrease
in yield, and thus these methods have shown limited scope. This
is an inherent disadvantage, since axially chiral compounds are
required to have steric bulk proximal to the chiral axis, around
which conformational rotation is highly restricted. Uemura
reported that Suzuki coupling using planar chiral arene chro-
mium complexes gave relatively bulky biaryls in good yields
with high diastereoselectivity.10e,f
1
2
3
4
5
6
i-PrNH2
(i-Pr)2NH
(i-Pr)2Et
Et3N
DABCO
quinuclidine
75(7)
0(31)
0(10)
0(11)
78
>99:<1
-
-
-
>99:<1
>99:<1
95
a The reaction was performed using 1a (1.0 equiv), aryllead compound
2a (3.0 equiv) and amine (3.0 equiv) at rt for 2 h. Refer to Scheme 3. For
experimental details, see Supporting Information. b Yields are of isolated,
purified 3a, and those in parentheses are of mono-coupling product 4a.
c The ratio of diastereomers of 3a.
have wide-ranging applications. Despite the obvious usefulness
of these methods, there is still a need for enantioselective cross-
coupling using an external source of chirality, such as asym-
metric catalysts.
Entirely different approaches have also been used to create
optically active biaryl frameworks. The kinetic resolution of
racemates with enzymes,11 desymmetrization,12 and the asym-
metric ring-opening of achiral lactones6a,c have been shown to
Barton reported that the ligand coupling of phenols with
arylleads is a powerful tool for synthesizing sterically hindered
products under mild conditions.13 The reaction using arylleads
as an equivalent of aryl cation was originally devised by Pinhey,
who demonstrated that the use of excess pyridine accelerated
the reaction rate (Scheme 1).14
(8) (a) Tomioka, K.; Ishiguro, T.; Iitaka, Y.; Koga, K. Tetrahedron 1984, 40,
1303. (b) Feldman, K. S.; Smith, R. S. J. Org. Chem. 1996, 61, 2606. (c)
Arisawa, M.; Utsumi, S.; Nakajima, M.; Ramesh, N. G.; Tohma, H.; Kita,
Y. Chem. Commun. 1999, 469. (d) Feringa, B.; Wynberg, H. J. Org. Chem.
1981, 46, 2547. (e) Brussee, J.; Jansen, A. C. A. Tetrahedron Lett. 1983,
24, 3261. (f) Yamamoto, K.; Fukushima, H.; Nakazaki, M. Chem. Commun.
1984, 1490. (g) Osa, T.; Kashiwagi, Y.; Yanagisawa, Y.; Bobbitt, M. Chem.
Commun. 1994, 2535. (h) Smrcˇina, M.; Pol´ıvkova´, J.; Vyskocˇil, Sˇ.;
Kocˇovsky, P. J. Org. Chem. 1993, 58, 4534. (i) Nakajima, M.; Miyoshi,
I.; Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J. Org. Chem. 1999,
64, 2264. (j) Irie, R.; Masutani, K.; Katsuki, T. Synlett 2000, 1433. (k)
Smrcˇina, M.; Vyskocˇil, Sˇ.; Pol´ıvkova´, J.; Pola´kova´, J.; Kocˇovsky, P. Collect.
Czech. Chem. Commun. 1996, 61, 1520. (l) Vyskocˇil, Sˇ.; Smrcˇina, M.;
Lorenc, M.; Hanusˇ, V.; Pola´sek, M.; Kocˇovsky, P. Chem. Commun. 1998,
585. (m) Barrett, A. G. M.; Itoh, T.; Wallace, E. M. Tetrahedron Lett.
1993, 34, 2233. For recent review, see: (n) Elliott, G. I.; Konopelski, J. P.
Tetrahedron 2001, 57 5683.
In marked contrast, anilines and anilides do not undergo either
C- or N-arylation with aryllead triacetates.15 Barton16 and
others17 later reported that Cu(OAc)2-catalyzed N-arylation of
anilines using aryllead triacetates, which gave various N,N-
diarylamines but did not lead to C-arylation (Scheme 2). On
the basis of these findings, we report here that the asymmetric
aryl-aryl coupling reaction with aryllead triacetate proceeded
(9) (a) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. (b) Gant, T.
G.; Meyers, A. I. Tetrahedron 1994, 50, 2297. (c) Meyers, A. I.; Lutomski,
K. A. J. Am. Chem. Soc. 1982, 104, 879. (d) Meyers, A. I.; Himmelsbach,
R. J. J. Am. Chem. Soc. 1985, 107, 682. (e) Wilson, J. M.; Cram, D. J. J.
Am. Chem. Soc. 1982, 104, 881. (f) Hattori, T.; Hotta, H.; Suzuki, T.;
Miyano, S. Bull. Chem. Soc. Jpn. 1993, 66, 613. (g) Hattori, T.; Koike,
N.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 2273. (h) Baker, R.
W.; Pocock, G. R.; Sargent, M. V. Chem. Commun. 1993, 1489. (i) Baker,
R. W.; Pocock, G. R.; Sargent, M. V.; Twiss, E. Tetrahedron: Asymmetry
1993, 4, 2423. (j) Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc.
1992, 114, 8732.
(10) (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988,
110, 8153. (b) Hayashi, T.; Hayashizaki, K.; Ito, Y. Tetrahedron Lett. 1989,
30, 215. (c) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
(d) Cammidge, A. N.; Cre´py, V. L. Chem. Commun. 2000, 1723. (e)
Uemura, M.; Kamikawa, K. Synlett 2000, 938. (f) Kamikawa, K.; Watanabe,
T.; Uemura, M. J. Org. Chem. 1996, 61, 1375. (g) Nelson, S. G.; Hilfiker,
M. A. Org. Lett. 1999, 1, 1379.
(11) (a) Miyano, S.; Kawahara, K.; Inoue, Y.; Hashimoto, H. Chem. Lett. 1987,
355. (b) Tamai, Y.; Nakano, T.; Koike, S.; Kawahara, K.; Miyano, S. Chem.
Lett. 1989, 1135.
(12) (a) Matsumoto, T.; Konegawa, T.; Nakamura, T.; Suzuki, K. Synlett 2002,
122. (b) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y.
J. Am. Chem. Soc. 1995, 117, 9101.
(13) Barton, D. H. R.; Donnelly, D. M. X.; Guiry, P. J.; Finet, J.-P. J. Chem.
Soc., Perkin Trans. 1 1994, 2921.
(14) (a) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32, 1551.
(b) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353. (c) Pinhey, J. T. Pure
Appl. Chem. 1996, 68, 819. (d) Pinhey, J. T. In ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 11, p 461.
(15) (a) Barton, D. H. R.; Yadav-Bhanagar, N.; Finet, J.-P.; Khamsi, J.
Tetrahedron Lett. 1987, 28, 3111.
(16) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J. J. Chem.
Soc., Perkin Trans. 1 1991, 2095.
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5366 J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002

Phenol or Aniline Coupling with Aryllead Triacetates
A R T I C L E S
Table 2. Effect of Chiral Amine in the Asymmetric Coupling of 1a with 2a or 2aa
entry
aryllead
amine
yield (%)b
ee (%)c
entry
aryllead
amine
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2b
2b
2b
2b
5
6
7
8
99
48
22
55
49
99
16
36
55
0
0
9
3
5
6
0
0
3
10
11
12
13
14
15
16
17
18
2b
2b
2b
2a
2a
2a
2a
2a
2a
9
68
99
99
14d
16d
2d
4
15
14
4
0
6
0
20
40
strychnine
brucine
9
10
11
sparteine
dehydroabietylamine
ajmalicine
eburnamonine
(DHQD)2PHAL
12
3d
strychnine
brucine
32
92
a The reaction was performed using 1a (1.0 equiv), aryllead compound 2a or 2b (2.5 equiv), and amine (3.0 equiv) in toluene at rt. Refer to Scheme 3.
For experimental details, see Supporting Information. b Unless otherwise specified, yields are of isolated, purified di-coupling product 3a or 3b. c Determined
by HPLC analysis. d Of isolated, purified mono-coupling product 4a.
Table 3. Effect of Solvent in the Asymmetric Coupling of 1a with
corresponding chiral acetate. Thus, the coupling reaction of
3,5-dimethylphenol (1a) with 2-isopropylphenyllead triacetate
2ba
yield (%)b
dl-3b:meso-3b
ee (%)c
(2a)21 was carried out in the presence of various amines (Scheme
3 and Table 1). The rate-enhancing effect was moderate with a
primary amine (entry 1), but less efficient with a second-
ary amine (entry 2) or tertiary amines, including i-Pr2NEt and
NEt3 (entries 3 and 4). Surprisingly, this process using tertiary
amines such as DABCO or quinuclidine exhibited good-to-
excellent reactivity and high dl-selectivity (entries 5 and 6).22,23
These results indicate that conformationally restricted amines
may be useful for the rate enhancement.
entry
solvent
time (h)
1
2
3
4
CH2Cl2
THF
toluene
hexane
2
1
1
99
99
97
55
8:1
11:1
10:1
12:1
14
25
30
11
12
a The reaction was performed using 1a (1.0 equiv), aryllead compound
2b (3.0 equiv), and brucine (10 equiv) at rt. Refer to Scheme 3. For
experimental details, see Supporting Information. b Yields are of isolated,
purified 3b. c (R,R)-3b is the major enantiomer.
Table 4. Effect of Metallation of 1a and Additive in the
Asymmetric Coupling with 2aa
We next investigated an asymmetric version of this process
using optically active bases (Table 2). The use of bidentate
amines led to slower reactions and incomplete consumption of
starting phenol 1a (entries 3-5, 7, 8, and 16). Poor yields were
also obtained when quinuclidine derivatives with an oxygen
functional group at the â-position were used (entries 9, 10, 13,
and 14). In contrast, brucine, which has a conformationally
restricted tertiary amine moiety, was essential to achieve rate
enhancement in addition to high diastereoselectivity. Moreover,
we obtained the best enantiomeric excess (ee) thus far (entries
12 and 18).24 Despite the structural resemblance of strychnine
to brucine, use of the former gave a lower yield as well as a
lower ee (entry 17).
yield (%)b
ee (%)
brucine
(equiv)
conditions
(°C, h)
entry
M
additive
3a
4a
3a 4a
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1a
1a
1a
1a
2.0
3.0
3.0
3.0
3.0
3.0
3.0
6.0
2.0
1.0
0.2
-
-
-
-
-
rt, 12
92
-
-
40
-
-
-20, 1
-20, 2
-20, 1
-20, 1
8
47
22 25 60 52
11
8
64 54
12 15 58 54
MS 4 Å, 0.3 g/mmol -20, 16 64
MS 13X, 0.3 g/mmol -20, 16 47
MS 4 Å, 1.5 g/mmol -20, 24 99
MS 4 Å, 1.5 g/mmol -20, 21 88
MS 4 Å, 1.5 g/mmol -20, 21 75 20 66 58
MS 4 Å, 1.5 g/mmol -20, 28 40 30 61 61
8
6
-
7
63 56
62 56
61
-
64 48
10 1a
11 1a
a The reaction was performed using 1a-1d (1.0 equiv), aryllead
compound 2a (2.5 equiv), and brucine with or without additive in toluene.
For M, refer to Scheme 3. For experimental details, see Supporting
Information. b Yields are of isolated, purified products.
effectively at the ortho-position of phenols18 and anilines19 by
simple metallation of the corresponding hydroxy and amino
groups.
Phenol Coupling: Results and Discussion
Amine Survey. Pinhey suggested that the coupling reaction
of phenols with aryllead triacetates is facilitated by the
participation of excess pyridine or analogous bases in CHCl3.14
Thereafter, Barton carefully optimized the reaction conditions,
particularly for the use of aryllead compounds that incorporated
electron-rich aryl groups.13 Our initial plan was guided by a
reconsideration of an alternative base additive that could lead
to the future discovery of a chiral analogue, with a goal of
efficient asymmetric synthesis. We started with a search
regarding the efficient synthesis of 2,6-bis(2-isopropylphenyl)-
3,5-dimethylphenol (3a) by this ligand coupling using chiral
amines instead of pyridine, since chiral phenol 3a has been
demonstrated to be an effective chiral auxiliary in the diaste-
reoselective aldol20a and Mannich-type reactions20b,c of the
Optimization of Reaction Conditions. With the superior
enantioselectivity exhibited by the combination of phenol 1a,
(17) (a) Lo´pez-Alvarado P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 1995,
60, 5678. (b) Lo´pez-Alvarado P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org.
Chem. 1996, 61, 5865.
9
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A R T I C L E S
Kano et al.
Table 5. Asymmetric Ligand Coupling With Various Arylleadsa
a Unless otherwise specified, reactions were performed using lithiated phenol (1 equiv), aryllead (2.5 equiv), MS 4 Å (3 g/mmol), brucine (6 equiv) in
toluene. b All these reactants were mixed at -78 °C and reacted under each reaction condition(s). For experimental details, see Supporting Information. For
entries 3, 6, and 7, reaction temperature was gradually increased as specified. c Of isolated, purified major coupling product. d Enantiomeric excess of
phenols, which was determined by chiral HPLC analysis. e The absolute configuration of the major enantiomer, which was determined in comparison with
that in the literature 3a-b: ref. 20d: 3l: ref. 38. Others are not assigned. f aryllead:brucine ) 1.25:3 equiv. g aryllead:brucine ) 1:1 equiv. h Mono-
coupling products were also obtained (entry 3, 4b, 26%, 38% ee; entry 5, 4c, 16%, 70% ee; entry 7, 4d, 25%, 29% ee).
2-methylphenyllead triacetate (2b), and brucine (Table 2, entry
12), a study was initiated to survey solvent effects for this
reaction (Table 3). The use of solvents such as CH2Cl2, THF,
and toluene gave comparable yields of 3,5-dimethyl-2,6-bis(2-
methylphenyl)phenol (3b) (entries 1-3); however, the reaction
in hexane gave a lower yield, presumably due to the poor
solubility of brucine (entry 4). Among the solvents examined,
toluene gave the highest ee (entry 3).
(18) (a) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem.
Soc. 1999, 121, 8943. See also ref 8n.
(19) Saito, S.; Kano, T.; Ohyabu, Y.; Yamamoto, H. Synlett 2000, 1676.
(20) (a) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem., Int.
Ed. 1998, 37, 3378. (b) Saito, S.; Hatanaka, K.; Yamamoto, H. Org. Lett.
2000, 2, 1891. (c) Saito, S.; Hatanaka, K.; Yamamoto, H. Tetrahedron
2001, 57, 875. For preliminary preparation of 3a,b, see: (d) Saito, S.; Kano,
T.; Hatanaka, K.; Yamamoto, H. J. Org. Chem. 1997, 62, 5651.
(21) (a) Bell, H. C.; Kalman, J. R.; Pinhey, J. T. Aust. J. Chem. 1979, 32, 1521.
(b) Kozyrod, R. P. Morgan, J.; Pinhey, J. T. Aust. J. Chem. 1985, 38, 1147.
For the preparation of aryllead compounds 2a-e, see: (c) Morgan, J.;
Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990, 715.
To illustrate the effect of acetyl groups of arylleads on the
enantioselectivity, 2-isopropylphenyllead tribenzoate (13) was
prepared from lead tetrabenzoate25 by the procedure described
by Pinhey.21c The reaction between aryllead tribenzoate 13 and
(22) The diastereoselectivity (dl:meso) was unambiguously ascertained by 1H
NMR and HPLC analysis. See ref 20d.
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Phenol or Aniline Coupling with Aryllead Triacetates
A R T I C L E S
Table 6. Effect of Substituent on Brucine in the Asymmetric
Coupling of 1a with 2aa
Scheme 4
yield (%)b
ee (%)
entry
brucine derivative
3a
4a
3a
4a
1
2
3
brucine
14
15
99
86
38
-
-
33
61
60
60
-
-
75
coupling reaction reached completion faster using an excess (6
equiv) amount of brucine (entry 8). Despite lower conversions
and slower reaction rates, no decrease of enantioselectivity was
achieved using smaller quantities of brucine (entries 9-11).
These results indicate that a catalytic amount of brucine could
facilitate the reaction, and in fact an improved turnover number
(5.5) was realized using 0.2 equiv of brucine (entry 11).
Reaction Scope. The procedure described above was ex-
tended to the synthesis of various chiral phenols (Table 5). In
general, the coupling of phenols with aryllead triacetates
proceeded in high yield with moderate-to-high enantioselectivity,
along with excellent diastereoselectivity. In particular, (2-
phenyl)phenyllead triacetate (2c) was generally suitable in terms
of high ee (entries 3, 5, 7, and 12). Subsequent simple
recrystallization from cyclohexane or hexane led to enantio-
merically pure phenols 3a, 3c, and 3e.
The kinetic resolution of mono-arylated phenols was observed
in the second coupling leading to terphenols. For instance, the
coupling of 3,5-dimethoxyphenol (1f) with aryllead 2c gave di-
coupling product 3g with high enantiomeric excess (93% ee),
along with mono-coupling product 4d with 29% ee (entry 7).
Further investigation indicated that the coupling of racemic
mono-arylated phenol 4d with aryllead 2c gave di-coupling
product 3g with 71% ee in 8% yield, demonstrating kinetic
resolution despite the low conversion (eq 2).
a The reaction was performed using 1b (1.0 equiv), aryllead compound
2a (2.5 equiv), and brucine deriviative (3-6 equiv) in the presence of MS
4 Å in toluene at -20 °C. Refer to Scheme 3. For experimental details, see
Supporting Information. b Of isolated, purified product.
phenol 1a using brucine gave a comparable yield of 3a, albeit
with a lower enantioselectivity (eq 1).
When the reaction was performed at a lower temperature
(-20 °C), only mono-coupling product 4a was obtained in a
low yield, albeit with slightly higher enantioselectivity (Table
4, entry 2). To accelerate the reaction rate, we next examined
the effect of the metallation of phenols (Table 4). With lithium
phenoxide, prepared by treatment of phenol 1a with n-BuLi at
0 °C in toluene, di-coupling product 3a was obtained in a higher
yield under similar conditions (entry 3). This may be due not
only to the higher reactivity of the metal phenoxide with aryllead
triacetates but also to the decreased amount of byproduct, acetic
acid, which might concomitantly form a salt with brucine, which
subsequently retards reaction rates. An even more significant
problem is that another equivalent of acetic acid is formed during
the second coupling. Attempts to remove acetic acid by the
known inclusion effect of molecular sieves (4 Å or 13X) resulted
in higher yields (entries 6 and 7). Finally, we found that the
(23) 2,6-Dibromo-3,5-dimethylanisole (37) and boronic acids 38a-c were
subjected to Suzuki coupling to give the corresponding terphenyl adducts
39a-c with moderate yields and diastereoselectivities as shown below.
Brucine Derivatives. Strychnine, which lacks methoxy
substituents on the aromatic ring, is a structural analogue of
brucine. Because the coupling reaction with strychnine gave a
lower enantioselectivity than that with brucine (Table 2, entries
17 and 18), we speculated that the methoxy group on the
aromatic ring could affect enantioselectivity. Therefore, further
studies to improve the enantioselectivity were carried out using
two other brucine derivatives (Table 6). Benzyloxy-substituted
(24) The ee % of each adduct was determined by chiral HPLC analysis.
(25) Hey, D. H.; Stirling, C. J. M.; Williams, G. H. J. Chem. Soc. 1954, 2747.
9
J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002 5369

A R T I C L E S
Kano et al.
Scheme 5
Table 7. Calculated Rotational Barriera
a These values were calculated by AM1 semiempirical computations, which were carried out using the Cerius 2 program (ver. 2.38) with full geometry
optimization.
brucine 14 had little effect on the enantioselectivity of the
reaction between lithium phenoxide 1b and aryllead 2a (entry
2). In contrast, the reaction with silyl-protected brucine 15
resulted in incomplete conversion of the starting substrate but
an increase in the ee of the mono-coupling product 4a (entry
3).
Plausible Mechanistic Model. Since brucine plays a critical
role in the high diastereo- and enantioselectivity, it presumably
coordinates to the Pb center to promote ligand coupling. With
this in mind and as suggested by Pinhey26a-c and Moloney,26d,e
a plausible mechanism for asymmetric ligand coupling can be
proposed (Scheme 4).
First, the lithium phenoxide coordinates to an apical position
of lead, and the resulting lithium acetate might undergo ligand
exchange with brucine. Subsequently, the configuration and
conformation of this complex are thought to be controlled by
the steric effect of brucine during pseudorotation. Finally,
oxidative coupling occurs to give (R)-4a as the major isomer.
The formation of a C-C bond between a phenol and an
aryllead, as a phenyl cation equivalent, initially affords R-sub-
stituted dienones with a chiral center at their R-positions
(Scheme 5). We envisioned that the axial chirality of the
resulting phenol is not transferred from this central chirality of
the initially formed dienone but rather arises from the chiral
axis linking the dienone and its aryl group. The validity of this
mechanism which involves the tautomerization of an axially
chiral ketone to the corresponding phenol with no loss of axial
chirality was demonstrated by comparing several energy barriers
of rotation. These were determined by semiempirical calcula-
tions (AM1) as well as some calculated results in the literature.27
Since the rotational barrier around the chiral axis at the
R-position of the ketone (minimum value: >11.2 kcal/mol, for
rotation in the direction of CdO, see Scheme 5 and Table 7) is
much higher than the energy barrier between phenol and 2,4-
cyclohexadien-1-one (ca. 6 kcal/mol),27a tautomerism of a
dienone to the phenol is likely to be much faster than rotational
isomerism. In this mechanism, whether the initially formed
central chirality is S or R is not important for inducing axial
chirality. Rather, a (pseudo)axial chirality appended primarily
on the sp3 carbon should be translated accurately into a chiral
axis on the sp2 carbon, either aS or aR, although other possible
chiral transfer pathways could not be ruled out.28
On the basis of the above consideration and the high dia-
stereoselectivity (dl over meso) generally observed for di-
coupling products, the second coupling might be impaired by
steric constraints between the ortho substituents of the two arene
(27) Energy barrier: between phenol and 2,4-cyclohexadien-1-one, see: (a)
Shiner, C. S.; Vorndam, P. E.; Kass, S. R. J. Am. Chem. Soc. 1986, 108,
5699; between cyclohexen-1-ol and cyclohexanone, see: (b) Zhang, X.-
M. J. Org. Chem. 1998, 63, 5314.
(28) Another possibility would be a tautomerization of the aryloxylead to a 2,4-
cyclohexadienone with lead in the 6-position followed by subsequent
reductive elimination, or by further tautomerization-reductive elimination.
See also below. In fact, the C-bound, rather than O-bound, lead was isolated
as a single-crystal structure of a ketone enolate, see: Morgan, J.; Buys, I.;
Hambley, T. W.; Pinhey, J. T. J. Chem. Soc., Perkin Trans 1 1993, 1677.
One of the reviewers suggested that the effects of ligands and additives
could be understood in terms of promoting the tautomerization equilibrium
or the reductive elimination.
(26) (a) Morgan, J.; Hambley, T. W. Pinhey, J. T. J. Chem. Soc., Perkin Trans.
1 1996, 2173. A free-radical process seems highly unlikely, see: (b)
Hambley, T. W.; Holmes, R. J.; Parkinson, C. J.; Pinhey, J. T. J. Chem.
Soc., Perkin Trans. 1 1992, 1927. (c) Morgan, J.; Parkinson, C. J.; Pinhey,
J. T. J. Chem. Soc., Perkin Trans. 1 1994, 3361, and references therein.
(d) Buston, J. E. H.; Compton, R. G.; Leech, M. A.; Moloney, M. G. J.
Organomet. Chem. 1999, 585, 326. Ligand influence on the reactivity of
aryllead triacetates: (e) Moloney, M.; Oaul, D. R.; Prottey, S. C.;
Thompson, R. M.; Wright, E. J. Organomet. Chem. 1997, 534, 195.
9
5370 J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002

Phenol or Aniline Coupling with Aryllead Triacetates
A R T I C L E S
Scheme 6
Table 8. Coupling Reactions of Aryllead with Metal Anilides
Table 9. Coupling Reactions of Aryllead with Dimetal Anilides
dimetal anilide
M
amine
solvent
% of yield 17a
1
2
3
16b
16c
16d
MgCl
Li
TMS
quinuclidine
brucine
quinuclidine
toluene
THF
toluene
28 (8)
14
0
a Yield in the parenthesis indicates the yields of di-coupling product 18.
yield (%)
entry
RML
mono (17)
di (18)
n
of aniline 16a with t-BuMgCl, with aryllead 2a gave aniline
17 in 55-65% yield, along with di-arylated aniline 18 (entry
2). In contrast, metallating agents other than t-BuMgCl led to
a significant decline in yield (entries 3-6).
To achieve more effective ligand exchange, the effect of di-
metallated anilines, which would be expected to be more
nucleophilic, was examined (Table 9). Dimagnesium, dilithium,
and disilyl anilides 16b-d were prepared as described in the
literature.29,30 Disappointingly, this dimetallation strategy proved
to be less effective, even though dimagnesium anilide 16b had
higher potential than the others (Table 9, entry 1).
1
2
3
4
5
6
BuLi
10-20
55-66
24
-
4-10
2
t-BuMgCl
MeMgCl
MeMgBr
MeMgI
<5
-
<5
-
MeZnCl
<5
-
rings in aryllead and mono-arylated products to give dl-
terphenols (Scheme 6). However, the steric effect of brucine is
nonnegligible in the second coupling, since in some cases kinetic
resolution proceeded.
Optimization. With the superb productivity exhibited by the
combination of t-BuMgCl (1 equiv) and aniline 16a (1 equiv),
we next examined the solvent effects. The use of Et2O (17, 43%;
18, 5%) or dioxane (17, 39%; 18, 4%) gave rather lower yields,
while the use of other solvents, such as DME (17, 55-66%;
18, 4-10%), THF (17, 55-66%; 18, 2-10%), t-BuOMe (17,
55-70%; 18, 9-12%), or toluene (17, 55-66%; 18, 2-10%),
led to comparable yields. Toluene was eventually chosen as a
suitable solvent with regard to both productivity and reproduc-
ibility.
Finally, we found that the mixing ratio of the starting sub-
strates (aryllead 2a:aniline 16a:t-BuMgCl:DABCO ) 1.0:1.3:
1.3:1.0) was even more critical for high productivity. The mono-
arylated product 17 was obtained in 85-88% yield based on
the initial amount of Pb reagent under these optimal conditions.
Quinuclidine, which has a structure analogous to that of
DABCO, was also examined as a base to give 17 in a similar
yield. Even more interesting is the fact that the reaction pro-
ceeded smoothly without a base to give 17 in 74% yield. This
result indicates that the reaction could be autocatalyzed by
primary amines that were generated as the reaction proceeded.
Aniline Coupling: Results and Discussion
Effect of Metalation. We were next interested in further
developing this coupling method using aryllead triacetates to
achieve C-(ortho-)arylation of anilines. Barton pointed out that
no reaction occurred between amines and organolead derivatives
alone.15 We speculated that anilines alone could not undergo
ligand exchange with an acetoxy group of aryllead triacetates.
Thus, our initial plan was to investigate the metallation of aniline
nitrogen, which might promote effective ligand exchange and
subsequent arylation with aryllead triacetate (Table 8). Since
not only the lithiation of phenols but also the use of DABCO
or quinuclidine facilitates the aryl-aryl coupling of aryllead
triacetate with phenols, we first tested the effect of lithiation
and a base additive on aniline coupling. The reaction of
2-isopropylphenyllead triacetate 2 with the lithium anilide
(which was prepared from 3,5-dimethylaniline 16a and n-BuLi)
in the presence of DABCO in DME afforded only a small
amount of the desired ortho-arylated product 17 (Table 8, entry
1). We next examined a magnesium anilide that would be
expected to promote the ligand exchange by abstraction of an
acetoxy group due to the greater Lewis acidity of magnesium.
Treatment of magnesium anilide, prepared in situ by the reaction
(29) Dilithiated anilines: Ooi, T.; Tayama, E.; Yamada, M.; Maruoka, K. Synlett
1999, 729.
(30) Abel E. W.; Willey, G. R. J. Chem. Soc. 1964, 1528.
9
J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002 5371

A R T I C L E S
Kano et al.
Table 10. Coupling of Anilines With Aryllead Triacetatea,b
a The reaction was performed using aniline (1.3 equiv), t-BuMgCl (1.3 equiv), aryllead (1.0 equiv) in toluene. The yield in parenthese is of dicoupling
product. For experimental details, see Supporting Information. b Yields are of isolated, purified product.
Scheme 7
Reaction Scope. Given the optimal reaction conditions, a
wide variety of ortho-arylanilines were readily synthesized, as
shown in Table 10. This new reaction is characterized by several
features: (1) Various aromatic amines were selectively arylated
at the ortho position. (2) The reactive arylleads with electron-
donating groups on their aromatic rings gave generally high
yields. (3) o-Methoxyarylleads 2f and 2i13 showed novel
reactivity with 16a, and the second ortho arylation proceeded
further to give significant amounts of the di-coupling products
24 and 35, respectively. (4) In contrast, the reaction of
phenyllead triacetate 2h was sluggish due to its poor reactivity,
resulting from the greater electron-deficient nature of the
aromatic ring.14
Asymmetric Coupling. Since biarylamines bearing axial
chirality are readily obtained by this aryl-aryl coupling reaction,
an enantioselective version of this reaction was investigated.
The use of brucine is essential for the asymmetric coupling
reaction of phenols with aryllead compounds, and this method
was applied to the synthesis of chiral aromatic amines (Scheme
7). When brucine was used instead of DABCO, the coupling
reaction of â-naphthylamine 16f with 2-methylnaphthyllead
triacetate 2e or 2-methoxynaphthyllead triacetate 2g proceeded
even at a lower temperature (-78 to -40 °C) to give the desired
axially chiral biaryls 29 (41% ee) and 32 (46% ee). These results
indicate that brucine participates in the asymmetric process of
9
5372 J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002

Phenol or Aniline Coupling with Aryllead Triacetates
A R T I C L E S
C-C bond formation, and therefore the coordination of brucine
to Pb may accelerate the reaction rate. However, the enanti-
oselectivity might be lowered by concomitant autocatalyzation
with primary amines that were generated as the reaction
proceeded.
Acknowledgment. We are grateful to Mr. S. Komai and H.
Choshi (Nagoya University) for performing the high-resolution
mass spectrometric analysis. T.K. also acknowledges a JSPS
Fellowship for Japanese Junior Scientists.
Supporting Information Available: Spectral and analytical
data for all new compounds, and typical experimental pro-
cedures for the coupling of phenols and anilines (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Conclusions
This work describes a new method for preparing a variety
of optically active biphenyls and terphenyls with axial chi-
rality by the coupling of phenols with aryllead compounds.
Quinuclidine, which acts as a base ligand on a lead center,
was shown to promote the ligand coupling. This observation
was successfully extended to the use of brucine, which also
has a conformationally restricted tertiary amine moiety, to
give the desired axially chiral phenols with moderate-to-high
enantioselectivity and excellent diastereoselectivity. This new
method can be applied to the sterically hindered substrates,
which are difficult to be cross-coupled by transition-metal
catalysts.
Magnesium anilides, prepared from anilines with t-BuMgCl,
showed great synthetic potential to achieve the C-arylation of
anilines with aryllead triacetates in the presence of tertiary
amines such as DABCO and quinuclidine. In this reaction,
major products are mono-arylated anilines at their ortho po-
sitions, which are directly accessible from various aromatic
amines. This is in contrast to the preferential ortho,ortho-di-
arylation of phenols with aryllead derivatives. This method is
also advantageous with regard to the substitution pattern,
since anilines are otherwise prone to electrophilic substitution
at their para positions. Further examination indicated that the
use of less than 1 equiv of t-BuMgCl is critical for pro-
ducing mono-arylation, since mono-arylated anilines should not
be further metallated under these conditions, which would re-
sult in desirable retardation of the second coupling. However,
highly reactive lead reagents such as 2-methoxyphenyllead
triacetate and 2,4,6-trimethoxyphenyllead triacetate sometimes
gave considerable amounts of doubly arylated products. The
significance of axially chiral anilines is manifold, since liga-
tion of an aniline structure is frequently found in metal cat-
alysts that have recently been revolutionizing selective trans-
formations.31-37
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