Palladium-Catalyzed Carbonylative Cross-Coupling Reaction of Arylboronic Acids with Aryl Electrophiles: Synthesis of Biaryl Ketones

Article abstract of DOI:10.1021/jo980417b

The carbonylative cross-coupling reaction of arylboronic acids with aryl electrophiles (ArI, ArBr, and ArOTf) to yield unsymmetrical biaryl ketones was carried out in anisole at 80°C in the presence of a palladium catalyst and a base. The reaction selectively proceeded under an atmospheric pressure of carbon monoxide when PdCl₂(PPh₃)₂ (3 mol %)/K₂CO₃ (3 equiv) were used for aryl iodides and PdCl₂(dppf) (3 mol %)/K₂CO₃ (3 equiv)/KI (3 equiv) for the bromides or the triflates. The carbonylation of arylboronic acids with benzyl halides gave aryl benzyl ketones.

Full text of DOI:10.1021/jo980417b

4726
J . Org. Chem. 1998, 63, 4726-4731
P a lla d iu m -Ca ta lyzed Ca r bon yla tive Cr oss-Cou p lin g Rea ction of
Ar ylbor on ic Acid s w ith Ar yl Electr op h iles: Syn th esis of Bia r yl
Keton es
Tatsuo Ishiyama, Hiroe Kizaki, Takahiro Hayashi, Akira Suzuki,† and Norio Miyaura*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, J apan
Received March 4, 1998
The carbonylative cross-coupling reaction of arylboronic acids with aryl electrophiles (ArI, ArBr,
and ArOTf) to yield unsymmetrical biaryl ketones was carried out in anisole at 80 °C in the presence
of a palladium catalyst and a base. The reaction selectively proceeded under an atmospheric
pressure of carbon monoxide when PdCl2(PPh3)2 (3 mol %)/K2CO3 (3 equiv) were used for aryl iodides
and PdCl2(dppf) (3 mol %)/K2CO3 (3 equiv)/KI (3 equiv) for the bromides or the triflates. The
carbonylation of arylboronic acids with benzyl halides gave aryl benzyl ketones.
Ta ble 1. Ca r bon yla tive Cou p lin g of P h en ylbor on ic Acid
w ith 4-Iod oa cetop h en on ea
The transition metal-catalyzed three-component cross-
coupling reaction between arylmetal reagents, carbon
monoxide, and aryl electrophiles is a straightforward and
convenient route for the synthesis of unsymmetrical
biaryl ketones. Various arylmetal reagents including
magnesium,1 aluminum,2 silicon,3 and tin compounds4
have been reported to undergo the carbonylative cou-
pling, but the development of the protocol to electron-
deficient aryl electrophiles is severely limited due to a
side reaction that gives a direct coupling product without
carbon monoxide insertion.
We previously reported the palladium-catalyzed cross-
coupling reaction5 of organoboron compounds with or-
ganic electrophiles and the carbonylative cross-coupling
reaction of 9-alkyl-9-borabicyclo[3.3.1]nonane derivatives
(9-alkyl-9-BBN) with aryl, 1-alkenyl, benzyl, and alkyl
halides.6 In this paper, we wish to report the synthesis
of biaryl ketones (3) via the palladium-catalyzed carbo-
nylative cross-coupling of arylboronic acids (1) with aryl
iodides, bromides, or triflates (2) (eq 1).7 The use of a
yieldb (%)
entry
catalyst
base
solvent
anisole
3
4
1
2
3
4
5
6
7
8
9
PdCl2(PPh3)2
K2CO3
Cs2CO3
Tl2CO3
K3PO4
K2CO3
84
69
38
43
82
71
74
68
63
6
11
23
24
23
9
4
7
11
8
0
PdCl2(dppf)c
PdCl2(CH3CN)2
Pd(PPh3)4
PdCl2(PPh3)2
toluene
dioxane
DMF
10
a
Reactions between phenylboronic acid (1.1 mmol), CO (1 atm),
and 4-iodoacetophenone (1.0 mmol) were carried out at 80 °C for
5 h in the presence of catalyst (3 mol %), base (3 mmol), and solvent
b
(6 mL). GLC yields based on 4-iodoacetophenone. c Dppf: 1,1′-
bis(diphenylphosphino)ferrocene.
dppf ligand for the palladium catalyst and the addition
of NaI or KI were requisite to achieve a selective coupling
for aryl bromides or triflates, though various palladium
complexes were effective for aryl iodides in the absence
of metal iodides.
† Current address: Department of Applied Chemistry, Okayama
University of Science, Okayama 700, J apan.
(1) Yamamoto, T.; Kohara, T.; Yamamoto, A. Chem. Lett. 1976, 1217.
(2) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P. Tetrahedron
Lett. 1985, 26, 4819.
(3) (a) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Tetrahedron 1992,
48, 2113. (b) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (c) Hatanaka,
Y.; Hiyama, T. Chem. Lett. 1989, 2049.
(4) (a) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J . Org.
Chem. 1996, 61, 9082. (b) Davies, S. G.; Pyatt, D.; Thomson, C. J .
Organomet. Chem. 1990, 387, 381. (c) Echavarren, A. M.; Stille, J . K.
J . Am. Chem. Soc. 1988, 110, 1557. (d) Stille, J . K. Angew. Chem., Int.
Ed. Engl. 1986, 25, 508. (e) Kikukawa, K.; Idemoto, T.; Katayama, A.;
Kono, K.; Wada, F.; Matsuda, T. J . Chem. Soc., Perkin Trans. 1 1987,
1511. (f) Bumagin, N. A.; Bumagina, I. G.; Kashin, A. N.; Beletskaya;
I. P. Dokl. Akad. Nauk SSSR 1981, 261, 1141. (g) Tanaka, M.
Tetrahedron Lett. 1979, 20, 2601.
(5) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Suzuki, A. Pure Appl. Chem. 1994, 66, 213. (c) Suzuki, A. Pure Appl.
Chem. 1991, 63, 419. (d) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
(e) Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
(6) (a) Ishiyama, T.; Murata, M.; Suzuki, A.; Miyaura, N. J . Chem.
Soc., Chem. Commun. 1995, 295. (b) Ishiyama, T.; Miyaura, N.; Suzuki,
A. Tetrahedron Lett. 1991, 32, 6923. (c) Ishiyama, T.; Miyaura, N.;
Suzuki, A. Bull. Chem. Soc. J pn. 1991, 64, 1999. (d) Wakita, Y.;
Yasunaga, T.; Akita, M.; Kojima, M. J . Organomet. Chem. 1986, 301,
C17.
Resu lts a n d Discu ssion
Rea ction Con d ition s. The reaction of phenylboronic
acid (1.1 equiv) with 4-iodoacetophenone was examined
at 80 °C for 5 h under an atmospheric pressure of carbon
monoxide to optimize the reaction conditions (Table 1).
(7) The preliminary results were reported in: Ishiyama, T.; Kizaki,
H.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1993, 34, 7595.
S0022-3263(98)00417-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/23/1998

Synthesis of Biaryl Ketones
J . Org. Chem., Vol. 63, No. 14, 1998 4727
Ta ble 2. Ca r bon yla tive Cou p lin g of P h en ylbor on ic Acid
w ith 4-Br om oa cetop h en on e or 4-Acetylp h en yl Tr ifla tea
A comparison of various phenylboron derivatives in the
reaction with 4-iodoacetophenone gave the following
order of yields: PhB(OH)2 (3/4 ) 84%/11%), the phenyl-
boronic acid 1,3-propanediol ester (3/4 ) 17%/0%), and
the phenylboronic acid pinacol ester (3/4 ) 3%/0%), 9-Ph-
9-BBN (3/4 ) 69%/7%). The carbonylative coupling of
4-bromoacetophenone with phenylboron derivatives in
the presence of KI (Table 2, entry 4) also afforded a
similar order of reactivity; thus, suggesting the superior-
ity of boronic acids.
yieldb (%)
entry
X
catalyst
additive
3
4
1
2
3
4
5
6
7
8
9
Br
PdCl2(PPh3)2
none
KI
none
KI
NaI
LiI
KI
KI
KI
KI
none
KI
55
64
66
81
80
52
73
67
24
16
3
36
22
18
3
2
1
6
6
6
6
PdCl2(dppf)c
Pd(dba)2/dppfc
Pd(dba)2/dppbc
Pd(dba)2/dpppc
Pd(dba)2/dppec
PdCl2(PPh3)2
PdCl2(dppf)c
Syn th esis of Un sym m etr ica l Bia r yl Keton es. The
carbonylative cross-coupling reaction between various
arylboronic acids and aryl electrophiles was carried out
in anisole at 80 °C under an atmospheric pressure of
carbon monoxide in the presence of PdCl2(PPh3)2 (3 mol
%)/K2CO3 (3 equiv) for the iodides (Table 1, entry 1) or
PdCl2(dppf) (3-5 mol %)/K2CO3 (3 equiv)/KI (3 equiv) for
the bromides and the triflates (Table 2, entries 4 and 12).
The method provides a quite general route for the
synthesis of unsymmetrical biaryl ketones having various
functionalities. Although the iodide afforded better
results in shorter reaction times, good yields of ketones
were similarly obtained from aryl bromides and triflates.
Representative results are summarized in Table 3.
10
11
12
OTf
83
8
78
a
Reactions between phenylboronic acid (1.1 mmol), CO (1 atm),
and 4-bromoacetophenone or 4-acetylphenyl triflate (1.0 mmol)
were carried out at 80 °C for 16 h in the presence of catalyst (3
mol %), K2CO3 (3 mmol), and additive (3 mmol) in anisole (6 mL).
b
GLC yields based on aryl electrophiles. c Dppf, dppe, dppp, and
dppb: 1,1′-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphoshi-
no)ethane, 1,3-bis(diphenylphosphino)propane, and 1,4-bis(diphe-
nylphosphino)butane, respectively.
The bases affected the selectivity of the reaction (entries
1-4). Cs2CO3, K3PO4, and Tl2CO3, which have been
utilized in the cross-coupling reaction of organoboron
compounds,5 had a strong tendency to produce a direct
coupling product, 4-acetylbiphenyl (23-24%). K2CO3 (3
equiv) suspended in anisole is very efficient to yield
4-acetylbenzophenone (82-84%) in the presence of PdCl2-
(PPh3)2 or PdCl2(dppf) (3 mol %), which, however, was
still accompanied the biaryl (9∼11%) (Table 1, entries 1
and 5). Most of the representative palladium catalysts,
including the triphenylphosphine complexes, the dppf
complex, and the phosphine-free complex PdCl2(CH3CN)2,
smoothly catalyzed the reaction, but the choice of less
polar solvents was essential to achieve high yields (Table
1, entries 8-10). The reaction worked well in anisole,
dioxane, or toluene, but low yields resulted in polar
solvents such as DMF, presumably due to another side
reaction leading to 4-acetylbenzoic acid (Table 1, entry
10).8
The presence of a strong electron-attracting substituent
such as NO2 is known to promote the direct coupling
giving biaryl 4. For example, the carbonylative coupling
reaction of triphenylalane with 4-iodonitrobenzene was
reported to provide a 41% yield of 4-nitrobenzophenone
and a 55% yield of 4-nitrobiphenyl,2 and an analogous
reaction with tributyltin hydride resulted in only a 9%
yield of 4-nitrobenzaldehyde with an accompanying 84%
yield of nitrobenzene.10 Indeed, the reaction of phenyl-
boronic acid with 4-iodonitrobenzene with PdCl2(PPh3)2
resulted in 3/4 ) 50%/35%, but the phosphine-free
palladium catalyst of PdCl2(MeCN)2 gave a high yield of
ketone (3/4 ) 89%/6%) (Table 3, entry 1). Other aryl
halides and triflates having an electron-withdrawing
group were successfully carbonylated and coupled with
arylboronic acids with PdCl2(PPh3)2 or PdCl2(dppf) (Table
3, entries 3-8). The bromo group in phenylboronic acid
remained intact during the reaction with iodobenzene
(Table 3, entry 9).
The results prompted us to investigate the reaction of
aryl bromides or triflates (Table 2), but these substrates
resulted in low yields under the conditions optimized for
the iodides. The addition of NaI or KI (3 equiv) and the
use of a dppf ligand for the palladium catalyst remark-
ably enhanced the selectivity of ketone (Table 2, entries
2-5 and 12). Although various palladium complexes
were effective for iodides, the dppf complex was appar-
ently better than the triphenylphosphine complexes for
the bromide and the triflate (Table 2, entries 1-4, 11,
and 12). The selectivity of ketone decreased in the order
of dppf > dppb . dppp > dppe (Table 2, entries 7-10),
thus suggesting the superiority of bidentate phosphine
ligands with a large bite angle.9
The reaction of mesitylboronic acid with 2-iodotoluene
and that of o-tolylboronic acid with iodomesitylene took
a longer reaction time due to their large steric hindrance
(Table 3, entries 17 and 19). A more sterically hindered
combination of mesitylboronic acid and iodomesitylene
was further decelerated, but the reaction still yielded a
35% yield of dimesityl ketone.
The carbonylative coupling of heteroaromatic halides
or triflates containing sulfur, nitrogen, and oxygen atoms
afforded good yields of the corresponding ketones (Table
3, entries 21-28). PdCl2(dppf) was a good catalyst for
2-bromothiophene or 3-bromoquinoline (Table 3, entries
22 and 28), but the corresponding reaction of 2-bromopy-
ridine or 2-bromofurane (Table 3, entries 24 and 25)
suffered from low yields due to the exclusive formation
of the direct coupling products 4. For these two sub-
strates, Pd(PPh3)4 exceptionally resulted in high yields
of ketone (Table 3, entries 24 and 25).
(8) (a) Soderberg, B. C. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press:
Oxford, 1995; Vol. 12, p 251. (b) Thompson, D. J . In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 3, p 1026. (c) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985; p 348.
(9) (a) Cabri, W.; De Bernardinis, S.; Francalanci, F.; Penco, S.;
Santi, R. J . Org. Chem. 1990, 55, 350. (b) Hayashi, T.; Konishi, M.;
Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J . Am. Chem. Soc.
1984, 106, 158. (c) Steffen, W. L.; Palenik, G. J . Inorg. Chem. 1976,
15, 2432.
(10) (a) Baillargeon, V. P.; Stille, J . K. J . Am. Chem. Soc. 1986, 108,
452. (b) Baillargeon, V. P.; Stille, J . K. J . Am. Chem. Soc. 1983, 105,
7175.

4728 J . Org. Chem., Vol. 63, No. 14, 1998
Ta ble 3. Syn th esis of Un sym m etr ica l Bia r yl Keton esa
Ishiyama et al.

Synthesis of Biaryl Ketones
J . Org. Chem., Vol. 63, No. 14, 1998 4729
Ta ble 3 (Con tin u ed )
a
Reactions between arylboronic acids (1.1 mmol), CO (1 atm), and aryl electrophiles (1.0 mmol) were conducted at 80 °C in the presence
of K2CO3 (3 mmol) in anisole (6 mL) by using PdCl2(PPh3)2 (3 mol %) for iodides and PdCl2(dppf) (3 mol %) with KI (3 mmol) for bromides
b
d
or triflates. Isolated yields based on the halides or triflates. c PdCl2(MeCN)2 was used as catalyst. 5 mol % of catalyst was used.
e Pd(PPh3)4 was used as the catalyst in place of PdCl2(dppf).
A one-pot synthesis of diketone via the sequential
double carbonylation is shown in eq 2. The reaction was
very slow for the bromide, but the carbonylation of
diiodobenzene with 2 equiv of p-tolylboronic acid provided
the diketone in 82% yield after 5 h. On the other hand,
the carbonylation of 4-bromoiodobenzene selectively oc-
curred at the C-I bond in the presence of 2 equiv of
p-tolylboronic acid (eq 3). The subsequent coupling with
the remaining p-tolylboronic acid gave a 90% yield of
biaryl monoketone.
R ea ct ion Mech a n ism . The carbonylative cross-
coupling of arylboronic acid with aryl electrophile may
proceed through a catalytic cycle analogous to that
proposed for other metal reagents (cycle A in Figure 1).1-4
Oxidative addition of ArX to a palladium(0) complex
provides Ar-Pd-X (6), which is followed by migratory
insertion of carbon monoxide giving ArCO-Pd-X (7).
Subsequent transmetalation between 7 and arylboronic
acid with the aid of K2CO3 and reductive elimination of
ketone 3 from ArCO-Pd-Ar′ (8) reproduce the pal-
ladium(0) species. Since 6 is a common intermediate for
the carbonylation (cycle A) and the direct coupling giving
biaryls (cycle B), a large amount of biaryls is often yielded
when the carbon monoxide insertion (6 f 7) is slower
than the transmetalation (6 f 9).
The carbon monoxide insertion into 6 is fast in electron-
rich aryls, and the electron-withdrawing groups slow the
insertion12 by reversely accelerating the rate of trans-
metalation (6 f 9). Thus, low yields and low selectivity
resulted in the reaction of electron-deficient substrates,
especially for the bromides and the triflates. Iodo- and
Syn th esis of Ar yl Ben zyl Keton es. The reaction
failed in other organic electrophiles such as 1-iodo-1-
hexene, 1-iodo-1-hexyne, 1-iodohexane, and 3-bromo-2-
phenyl-1-propene, but benzyl halides readily participated
in the carbonylative cross-coupling reaction (eq 4). Under
the conditions used for aryl iodides, the corresponding
aryl benzyl ketones (5a ,b) were obtained in 76% and 78%
yields in the reaction of benzyl bromide with phenylbo-
ronic acid or [2-(methoxymethoxy)phenyl]boronic acid.
The ketone 5b thus obtained is a useful synthetic
intermediate readily convertible to isoflavone (79%) (eq
5).11
(12) The carbonylation of Ar-M-X complexes (M ) Pd, Pt): (a)
Dixon, K. R.; Dixon, A. C. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press:
Oxford, 1995; Vol. 9, p 208. (b) Anderson, G. K. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon Press: Oxford, 1995; Vol. 9, p 460. (c) Alexander,
J . J . In The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Patai,
S., Eds.; Wiley: New York, 1985; Vol. 2, p 349. (d) Cross, R. J .; Gemmill,
J . J . Chem. Soc., Dalton Trans. 1981, 2317. (e) Sugita, N.; Minkiewicz,
J . V.; Heck, R. F. Inorg. Chem. 1978, 17, 2809. (f) Garrou, P. E.; Heck,
R. F. J . Am. Chem. Soc. 1976, 98, 4115.
(11) Bass, R. J .; J . Chem. Soc., Chem. Commun. 1976, 78.

4730 J . Org. Chem., Vol. 63, No. 14, 1998
Ishiyama et al.
F igu r e 1. Catalytic cycle.
phenylboronic acid and trans-PdX(4-MeCOC6H4)(PPh3)2
(X ) I, Br) (eq 7). The carbonylative coupling of the Pd-I
complex with phenylboronic acid resulted in a higher
yield and selectivity (3/4 ) 76%/8%) than that of the Pd-
Br complex (3/4 ) 60%/19%) in accordance with the
selectivity of the catalytic reaction.
4-bromonitrobenzene (Table 3, entries 1 and 2) indeed
exhibited a strong tendency to produce the direct coupling
products.
The palladium-dppf complex is highly effective for the
carbonylative coupling of aryl bromides and triflates. The
order of yields and selectivity observed during the reac-
tion of 4-bromoacetophenone is parallel to the bond
angles of P-Pd-P (dppf > dppb . dppp > dppe, Table
2, entries 7-10).9 The rate of carbon monoxide insertion
is accelerated by bidentate phosphine ligands having a
large bite angle;13 thus, the high catalytic efficiency and
selectivity of PdCl2(dppf) for the bromides and triflates
can be attributed to its large P-Pd-P angle, which
facilitates the CO insertion.
The carbon monoxide insertion to the Ar-Pd-I com-
plexes (6, X ) I) proceeds more readily than that into
the corresponding Ar-Pd-Br complexes.14 Thus, sig-
nificant improvement of the yields and selectivity was
observed by the addition of NaI or KI for aryl bromides
and triflates. Indeed, the reaction of trans-PdBr(4-
MeCOC6H4)(PPh3)2 with a large excess of KI gave trans-
PdI(4-MeCOC6H4)(PPh3)2 in a yield of 70% (eq 6).15 The
superiority of the palladium iodides over the bromides
was demonstrated by a stoichiometric reaction between
Exp er im en ta l Section
Rea gen ts. PdCl2(dppf),9b Pd(dba)2,16 trans-PdBr(4-MeCO-
C6H4)(PPh3)2,17 and trans-PdI(4-MeCOC6H4)(PPh3)2 were
18
prepared. Arylboronic acids19 and 9-phenyl-9-BBN20 were
synthesized by the reported procedures. The reaction of
phenylboronic acid with diols in the presence of MgSO4 in
benzene gave phenylboronates. 4-Iodo-1,2-(methylenedioxy)-
benzene,21 4-iodo-N,N-dimethylaniline,22 2-iodopyridine,15d 3-io-
dobenzothiophene,23 and aryl triflates24 were prepared by the
literature procedures.
Rea ction Con d ition s (Ta bles 1 a n d 2). Palladium
catalyst (0.03 mmol), base (3 mmol), phenylboronic acid (1.1
mmol), and 4-iodoacetophenone (1.0 mmol) were added to a
flask fitted with a reflux condenser, a septum inlet, and a
magnetic stirring bar. The flask was flushed with carbon
monoxide and then charged with solvent (6 mL). The mixture
was stirred at 80 °C for 5 h under an atmospheric pressure of
carbon monoxide. The product was extracted with benzene
(20 mL), washed with water, and dried over MgSO4. The
yields based on 4-iodoacetophenone were determined by GLC
using pentadecane as an internal standard.
In a similar way, the reaction between phenylboronic acid
(1.1 mmol), CO (1 atm), and 4-acetylphenyl bromide and
triflate (1.0 mmol) was carried out in anisole (6 mL) at 80 °C
for 16 h in the presence of palladium catalyst (0.03 mmol),
K2CO3 (3 mmol), and powdered KI or NaI (3 mmol).
(13) The effect of phosphine ligands on the CO insertion of R-Pd-X
complexes: (a) Yu, W.-Y.; Alper, H. J . Org. Chem. 1997, 62, 5684. (b)
Ru¨lke, R. E.; Kaasjager, V. E.; Kliphuis, D.; Elsevier, C. J .; van
Leeuwen, P. W. N. M.; Vrieze, K.; Goubitz, K. Organometallics 1996,
15, 668. (c) van Asselt, R.; Gielens, E. E. C. G.; Ru¨lke, R. E.; Vrieze,
K.; Elsevier, C. J . J . Am. Chem. Soc. 1994, 116, 977. (d) Dekker, G. P.
C. M.; Buijs, A.; Elsevier, C. J .; Vrieze, K.; van Leeuwen, P. W. N. M.;
Smeets, W. J . J .; Spek, A. L.; Wang, Y. F.; Stam, C. H. Organometallics
1992, 11, 1937. (e) Dekker, G. P. C. M.; Elsevier, C. J .; Vrieze, K.; van
Leeuwen, P. W. N. M.; Roobeek, C. F. J . Organomet. Chem. 1992, 430,
357. (f) Dekker, G. P. C. M.; Elsevier, C. J .; Vrieze, K.; van Leeuwen,
P. W. N. M. Organometallics 1992, 11, 1598. The effect of phosphine
ligands on the alkene insertion: (g) Cabri, W.; Candiani, I.; Bedeschi,
A.; Santi, R. J . Org. Chem. 1992, 57, 3558. (h) Cabri, W.; Candiani, I.;
Bedeschi, A.; Penco, S.; Santi, R. J . Org. Chem. 1992, 57, 1481. (i)
Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.; Penco, S.;
Santi, R. J . Org. Chem. 1991, 56, 5796. (j) Cabri, W.; Candiani, I.;
Bedeschi, A.; Santi, R. J . Org. Chem. 1990, 55, 3654.
(14) The effect of halogen ligand on the carbonylation of R-M-X
complexes (M ) Pd, Pt): (a) Cross, R. J . In Comprehensive Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon Press: Oxford, 1995; Vol. 9, p 407. (b) Ankersmit, H. A.;
Witte, P. T.; Kooijman, H.; Lakin, M. T.; Spek, A. L.; Goubitz, K.;
Vrieze, K.; Vankoten, G. Inorg. Chem. 1996, 35, 6053. (c) Stang, P. J .;
Zhong, Z.; Arif, A. M. Organometallics 1992, 11, 1017. (d) Anderson,
G. K.; Cross, R. J . Acc. Chem. Res. 1984, 17, 67. (e) Anderson, G. K.;
Cross, R. J . J . Chem. Soc., Dalton Trans. 1980, 712.
Syn th esis of Un sym m etr ica l Bia r yl Keton es (Ta ble 3).
The synthesis of 4-acetylbenzophenone25 is representative. A
flask equipped with a magnetic stirring bar, a septum inlet,
and a reflux condenser was charged with PdCl2(PPh3)2 (0.03
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65, 253.
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Soc. 1992, 114, 7076.
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(19) (a) Nesmeyanov, A. N.; Sokolik, R. A. Methods of Elemento-
Organic Chemistry; North-Holland: Amsterdam, 1967; Vol. 1. (b)
Mikhailov, B. M.; Bubnov, Y. N. Organoboron Compounds in Organic
Synthesis; Harwood Academic Pub.: Amsterdam, 1983.
(20) Brown, H. C. In Organic Syntheses via Boranes; Wiley: New
York, 1975; p 59.
(21) J anssen, D. E.; Wilson, C. V. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, p 547.
(22) Potts, K. T. J . Chem. Soc. 1953, 3711.
(23) Gaertner, R. J . Am. Chem. Soc. 1952, 74, 4950.
(24) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982,
85.
(25) Zelinski, R. P.; Turnquest, B. W.; Martin, E. C. J . Am. Chem.
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(15) The halogen exchange of Ar-Ni-Br: (a) Smith, A. K. In
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G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 9, p
56. The nickel-catalyzed halogen exchange reaction of aryl halides: (b)
Yang, S. H.; Li, C. S.; Cheng, C. H. J . Org. Chem. 1987, 52, 691. (c)
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Synthesis of Biaryl Ketones
J . Org. Chem., Vol. 63, No. 14, 1998 4731
mmol), K2CO3 (3 mmol), phenylboronic acid (1.1 mmol), and
4-iodoacetophenone (1.0 mmol). The flask was flushed with
carbon monoxide, and anisole (6 mL) was then added. After
being stirred at 80 °C for 5 h under CO (1 atm), the reaction
mixture was cooled to room temperature, diluted with benzene,
washed with water, and finally dried over MgSO4. GC analysis
revealed the formation of a 84% yield of 4-acetylbenzophenone.
The isolation by chromatography over silica gel gave a pure
Syn th esis of Ar yl Ben zyl Keton es (Eq 4). The procedure
is the same as that employed for the reaction of aryl iodides.
Ben zyl 2-(m eth oxym eth oxy)p h en yl k eton e (5b): IR
1
(film) 1680 cm-1
; H NMR δ 3.47 (s, 3 H), 4.31 (s, 2 H), 5.26
(s, 2 H), 7.03 (t, 1 H, J ) 7.4 Hz), 7.18 (d, 1 H, J ) 8.5 Hz),
7.23 (d, 1 H, J ) 7.6 Hz), 7.24 (t, 2 H, J ) 7.3 Hz), 7.29 (d, 1
H, J ) 7.1 Hz), 7.30 (t, 1 H, J ) 7.3 Hz), 7.42 (t, 1 H, J ) 7.9
Hz), 7.64 (d, 1 H, J ) 7.7 Hz); 13C NMR δ 50.10, 56.43, 94.55,
114.82, 121.84, 126.66, 128.40, 129.14, 129.61, 130.38, 133.31,
135.02, 155.87, 200.21; MS m/e 45 (87), 65 (8), 77 (5), 91 (15),
135 (25), 165 (100), 256 (M+, 0.4); exact mass calcd for C16H16O3
256.1099, found 256.1124.
1
compound: IR (Nujol) 1700, 1660 cm-1; H NMR δ 2.67 (s, 3
H), 7.51 (t, 2 H, J ) 7.8 Hz), 7.63 (t, 1 H, J ) 7.4 Hz), 7.81 (d,
2 H, J ) 7.3 Hz), 7.87 (d, 2 H, J ) 8.1 Hz), 8.06 (d, 2 H, J )
8.1 Hz); 13C NMR δ 26.87, 128.14, 128.46, 130.02, 130.07,
132.96, 136.90, 139.55, 141.32, 195.92, 197.49; MS m/e 77 (9),
105 (9), 153 (15), 181 (14), 209 (100), 224 (M+, 31); exact mass
calcd for C15H12O2 224.0838, found 224.0826.
Syn th esis of Isofla von e (Eq 5).27 5b (0.47 mmol) was
treated with 10% HCl in MeOH (5 mL) at room temperature
for 13 h. Benzyl 2-hydroxyphenyl ketone thus obtained was
directly subjected to the further transformation:11 IR (Nujol)
1640 cm-1; 1H NMR δ 7.39 (t, 1 H, J ) 7.2 Hz), 7.43 (t, 1 H, J
) 6.5 Hz), 7.45 (t, 2 H, J ) 6.8 Hz), 7.49 (d, 1 H, J ) 8.5 Hz),
7.58 (d, 2 H, J ) 7.1 Hz), 7.69 (t, 1 H, J ) 7.7 Hz), 8.03 (s, 1
H), 8.33 (d, 1 H, J ) 8.1 Hz); 13C NMR δ 118.04, 124.62, 125.25,
125.44, 126.46, 128.21, 128.52, 128.96, 131.86, 133.61, 153.06,
156.23, 176.21; MS m/e 39 (20), 50 (24), 63 (56), 76 (24), 92
(51), 102 (18), 111 (7), 120 (21), 165 (9), 222 (M+, 100); exact
mass calcd for C15H10O2 222.0681, found 222.0680.
The reaction of arylboronic acids (1.0 mmol) with aryl
bromides or triflates (1.0 mmol) was carried out in anisole (6
mL) at 80 °C for 16 h under CO (1 atm) in the presence of
PdCl2(dppf) (0.03 mmol), K2CO3 (3 mmol), and KI (3 mmol).
1,4-Bis(4-m eth ylben zoyl)ben zen e (Eq 2).26 The double
carbonylative coupling was carried out in anisole (12 mL) at
80 °C for 5 h under CO (1 atm) by the use of PdCl2(PPh3)2
(0.06 mmol), K2CO3 (6 mmol), p-tolylboronic acid (2.2 mmol),
and 1,4-diiodobenzene (1.0 mmol). A similar reaction between
p-tolylboronic acid (2.2 mmol), CO (1 atm), and 1,4-dibro-
mobenzene (1.0 mmol) was carried out at 80 °C for 16 h in
anisole (12 mL) by using of PdCl2(dppf) (0.06 mmol), K2CO3
(6 mmol), and KI (6 mmol): IR (Nujol) 1650 cm-1; 1H NMR δ
2.46 (s, 6 H), 7.31 (d, 4 H, J ) 8.5 Hz), 7.75 (d, 4 H, J ) 8.1
Hz), 7.86 (s, 4 H); 13C NMR δ 21.66, 129.13, 129.51, 130.32,
134.30, 140.83, 143.84, 195.74; MS m/e 65 (14), 91 (38), 119
(100), 195 (7), 223 (21), 314 (M+, 30); exact mass calcd for
tr a n s-P d I(4-MeCOC6H4)(P P h 3)2 (Eq 6). A mixture of
trans-PdBr(4-MeCOC6H4)(PPh3)2 (0.06 mmol), KI (6 mmol),
and anisole (12 mL) was stirred at 80 °C for 3 h under N2.
After removal of KI by filtration, the product was extracted
with benzene, washed with water, and purified by recrystal-
1
lization from benzene: IR (Nujol) 1680 cm-1; H NMR δ 2.28
(s, 3 H), 6.76 (s, 4 H), 7.23 (t, 12 H, J ) 7.4 Hz), 7.32 (t, 6 H,
J ) 7.2 Hz), 7.52 (dd, 12 H, J ) 5.6, 12.7 Hz); 13C NMR δ
26.16, 126.45, 127.82 (t, J ) 5.4 Hz), 129.90, 131.65 (t, J )
23.6 Hz), 134.80 (t, J ) 6.2 Hz), 135.82 (t, J ) 4.1 Hz), 172.47,
198.50; 31P NMR (CDCl3, H3PO4) δ 23.33.
C
22H18O2 314.1307, found 314.1280.
4-Meth yl-4′-(p-tolyl)ben zop h en on e (Eq 3). The carbo-
nylative coupling between p-tolylboronic acid (2.2 mmol), CO
(1 atm), and 4-bromoiodobenzene (1.0 mmol) was conducted
in anisole (12 mL) at 80 °C for 1.5 h in the presence of
PdCl2(PPh3)2 (0.06 mmol) and K2CO3 (6 mmol). After being
cooled to room temperature, the flask was flushed with
nitrogen and charged with H2O (2 mL). The resulting mixture
Effect of Ha logen Liga n d s (Eq 7). The reaction of
phenylboronic acid (0.11 mmol) with trans-PdX(4-MeCOC6H4)-
(PPh3)2 (X ) I, Br) (0.10 mmol) was carried out in the presence
of K2CO3 (0.3 mmol) in anisole (1 mL) at 80 °C for 3 h under
CO (1 atm).
was stirred at 80 °C for 16 h under N2: IR (Nujol) 1650 cm-1
;
1H NMR δ 2.42 (s, 3 H), 2.45 (s, 3 H), 7.29 (d, 2 H, J ) 8.3
Hz), 7.30 (d, 2 H, J ) 8.3 Hz), 7.55 (d, 2 H, J ) 8.3 Hz), 7.68
(d, 2 H, J ) 8.3 Hz), 7.75 (d, 2 H, J ) 8.3 Hz), 7.86 (d, 2 H, J
) 8.3 Hz); 13C NMR δ 21.15, 21.65, 126.63, 127.11, 128.97,
129.67, 130.23, 130.60, 135.10, 136.31, 137.13, 138.09, 143.11,
144.93, 196.10; MS m/e 65 (11), 91 (33), 119 (67), 129 (10), 152
(27), 165 (17), 195 (100), 271 (16), 286 (M+, 86); exact mass
calcd for C21H18O 286.1358, found 286.1380.
Su p p or tin g In for m a tion Ava ila ble: Spectral data and
copies of H NMR spectra of biaryl ketones (18 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
J O980417B
(26) Koelsch, C. F.; Bryan, C. E. J . Am. Chem. Soc. 1945, 67, 2041.
(27) Brady, W. T.; Gu, Y.-Q. J . Org. Chem. 1988, 53, 1353.