Palladium-Catalyzed Synthesis of Aryl Ketones from Boronic Acid and Carboxylic Acids or Anhysrides

Full text of DOI:10.1002/1521-3773(20010917)40:18<3458::AID-ANIE3458>3.0.CO;2-0

COMMUNICATIONS
system and screened several palladium catalysts under various
conditions (Scheme 1). Selected results are shown in Table 1.
We initially employed anhydrous conditions to prevent
hydrolysis of the anhydrides. However, with various catalytic
systems, only sluggish turnovers and moderate yields were
observed (Table 1, entry 1). Upon the addition of water, the
reaction surprisingly became faster while the competing
hydrolysis of the anhydride remained slow, so that high yields
Palladium-Catalyzed Synthesis of Aryl Ketones
from Boronic Acids and Carboxylic Acids or
Anhydrides **
Lukas J. Gooûen* and K. Ghosh
The acylation of carbon nucleophiles with carboxylic acid
derivatives is an important C�C bond-forming reaction that is
extensively used in the synthesis of natural products and
pharmaceutical compounds. Several carboxylic acid deriva-
tives, for example, nitriles, amides, anhydrides, or acid
chlorides, can be alkylated or arylated with a variety of
organometallic species to produce ketones in moderate to
[11]
of the desired ketone 3a were obtained. The addition of two
equivalents of water with respect to the boronic acid was
found to be optimal (Table 1, entries 1 ± 3).
[
1]
excellent yields.
Carboxylic acids themselves can only be transformed into
the corresponding ketones by treatment with lithium, magne-
sium, or aluminum reagents under rather elaborate conditions
Scheme 1. Coupling of anhydrides with boronic acids (R, Ar: see below).
Table 1. Coupling of hexanoic anhydride with phenylboronic acid.
[
2]
that are intolerant of most functional groups. Various
procedures have been developed to stop the reaction at the
stage of the ketone and avoid the formation of the tertiary
[
3]
Entry
Phosphane
Solvent
Water [mmol]
Yield [%]
alcohols. Milder reagents, for example organotin, -zinc, and
copper compounds or boronic acids, are acylated only by
-
1
2
3
4
5
6
7
8
9
0
1
PPh3
THF
THF
THF
DME
DMF
toluene
0
2.5
10
29
97
38
53
92
77
54
92
91
31
< 5
97
< 5
46
28
more reactive acid derivatives (usually acid chlorides), which
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
have to be generated in an additional reaction step.[4]
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Recently, Liebeskind et al. disclosed a versatile, base-free
synthesis of aryl ketones by the palladium-catalyzed coupling
of thioesters with boronic acids.[5] However, this transforma-
tion requires the preformation of the thioester and calls for a
stoichiometric amount of copper thiophene carboxylate.
Our target was to develop a convenient preparation of
ketones directly from carboxylic acids under mild conditions
and with minimal waste production by using a strategy similar
to the one that Yamamoto and co-workers utilized for the
3
CH CN
[
a]
THF
THF
THF
THF
THF
THF
THF
THF
PCy
3
1
1
P(o-Tol)
3
BINAP
P(p-MeOPh)3
DPPF
P(Fur)
P(tBu)
12
13
4
5
1
1
3
3
[
6]
reduction of carboxylic acids. Boronic acids appeared to be
the carbon nucleophiles of choice, as they are readily
Reagents and conditions: hexanoic anhydride (1 mmol), phenylboronic
acid (1.2 mmol), Pd(OAc) (0.03 mmol), ligand (0.07 mmol; 0.035 mmol for
chelating phosphanes), 16 h. The yields were determined by using GC.
[
7]
2
available, non-toxic, air- and moisture-stable compounds
that tolerate the presence of many sensitive functionalities.
Since most carboxylic acids can easily (and potentially in
[a] The reaction was performed at 208C. DME ˆ 1,2-dimethoxyethane.
[
8]
situ) be converted into their anhydrides, our first goal was
the development of a catalytic system capable of coupling
anhydrides with boronic acids. Although the palladium-
catalyzed coupling of the more reactive acid chlorides with
DMF (N,N-dimethylformamide) and THF proved to be the
most effective solvents (Table 1, entries 2, 4 ± 7). Owing to its
lower toxicity, we considered THF to be more convenient.
The choice of phosphane also has a significant effect on the
reaction outcome (Table 1, entries 9 ± 15). The optimum
reaction temperature was 608C, but reasonable yields were
also obtained at lower temperatures (Table 1, entry 8).
To study the scope of this transformation, we varied both
the boronic acids and the anhydrides. A few representative
results are shown in Table 2. We found that for best results,
different phosphanes need to be chosen with regard to the
steric and electronic properties of the anhydrides. Tri-p-
methoxyphenylphosphane is generally suitable for all carbox-
ylic acid anhydrides and the superior choice for most alkyl
derivatives. For more electron-poor aryl derivatives, however,
triphenylphosphane or diphenylferrocenylphosphane are
more effective.
[
9]
boronic acids is known, no reports have been made on
whether anhydrides are also suitable for this reaction.[ In
principle, a similar catalytic process for anhydrides that
consists of the oxidative addition of the anhydride to an acyl
palladium complex, exchange of the carboxylate for the aryl
group by transmetallation of the boronic acid, and reductive
elimination of the ketone should also be possible.
10]
We chose the reaction of hexanoic anhydride (1a, R ˆ
n-C H ) with phenylboronic acid (2a, Arˆ Ph) as our model
5
11
[
*] Dr. L. J. Gooûen, Dr. K. Ghosh
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax : (‡49)208-306-2985
E-mail: goossen@mpi-muelheim.mpg.de
Most substrates gave excellent yields, and even sensitive
compounds such as furaneboronic acid were smoothly con-
verted. Alkyl, vinyl, and aryl anhydrides are equally suitable
[
**] We thank M. Rössig and L. Winkel for technical assistance, Prof. Dr.
M. T. Reetz for generous support and constant encouragement, and
the DFG for financial support.
3458
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3458 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 18

COMMUNICATIONS
Table 2. Synthesis of aryl ketones according to Scheme 1.
Table 3. Synthesis of aryl ketones from carboxylic acids and aryl boronic
acids.
Entry
R
Ar
Yield [%]
Entry Product[a]
Ligand[b] Yield [%]
1
2
n-C
n-C
n-C
n-C
n-C
n-C
5
5
5
5
5
5
H
H
H
H
H
H
11
11
11
11
11
11
o-tolyl
p-MeO-phenyl
p-CH CO-phenyl
3
m-Cl-phenyl
2-furyl
3-thienyl
phenyl
phenyl
phenyl
phenyl
98
91
96
97
84
88
98
98
71
90
96
0
[
a]
3
4
5
6
7
8
9
0
1
2
1
A
A
A
90
60
65
CH
sec-butyl
-C(CH
3
2[c]
)ˆCH
3
2
[
[
b]
b]
1
1
1
p-MeO-Ph
phenyl
tert-butyl
phenyl
phenyl
3
Reagents and conditions: anhydride (1 mmol), boronic acid (1.2 mmol),
Pd(OAc) (0.03 mmol), P(p-MeOPh) (0.07 mmol), 16 h, 608C; all yields
refer to isolated products. [a] PCy (0.07 mmol) was used as ligand. [b] PPh
0.07 mmol) was used as ligand.
2
3
3
3
(
for this transformation (Table 2, entries 1, 7 ± 11). However,
no reaction was observed for the sterically demanding pivalic
anhydride (Table 2, entry 12).
4
A
81
The low reactivity of pivalic anhydride (5) opened up an
opportunity for achieving an in situ activation of sterically less
hindered carboxylic acids 4 by the generation of the corre-
sponding mixed anhydrides 6 (Scheme 2).
We tested our hypothesis on the reaction of 3-phenyl-
propionic acid (4b) with phenylboronic acid (2a) (Scheme 3,
R ˆ 3-phenylpropyl, Arˆ Ph) and indeed observed the de-
sired conversion exclusively into 3-phenylpropyl phenyl
ketone 3b.
The optimum reaction conditions for the one-pot reaction
were found to be similar to the best conditions for the homo-
anhydrides. The influence of the water content is profound: in
the absence of water, less than 1% of the ketone was
obtained. However, with two equivalents of water more than
5
6
7
C
B
C
68
80
75
9
0% of the ketone was formed, but with ten equivalents less
than 80% was produced. P(p-MeOPh) (65%), PPh (68%),
3
3
8
9
D
B
54
85
DPPF (91%; DPPF ˆ 1,1'-bis(diphenylphosphino)ferrocene),
and PCy (55% yield) were found to be effective ligands on
3
palladium. The scope of the one-pot reaction was investigated
by using different combinations of carboxylic acids and
boronic acids. Selected results are displayed in Table 3. P(p-
MeOPh) is most effective for alkyl carboxylic acids (Table 3,
3
entries 1 ± 5), whereas PPh or DPPF are usually superior for
3
aryl derivatives (Table 3, entries 1 ±
0). For aryl alkyl derivatives such
1
as 3-phenylpropionic acid, the prop-
erties of the boronic acids also have
to be taken into account when choos-
ing the ligand (Table 3, entries 12 ±
18).
Scheme 2. In situ activation of carboxylic acids.
Many functional groups are toler-
ated: carboxylic acids and boronic
acids that contain halo, keto, cyano,
ester, nitro, or protected amino groups were successfully
converted. Some heteroyclic ketones were synthesized as
well. However, alkylboronic acids were not converted under
any of the given conditions.
Scheme 3. One-pot synthesis of aryl ketones.
Angew. Chem. Int. Ed. 2001, 40, No. 18 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3459 $ 17.50+.50/0
3459

COMMUNICATIONS
Table 3. (Continued).
propionic acid (1.50 g, 10 mmol), and phenylboronic acid (1.46 g, 12 mmol).
Subsequently, THF (40 mL), water (45 mg, 2.5 mmol), and pivalic anhy-
dride (2.79 g, 15 mmol) were added through a syringe. The reaction vessel
was purged with argon and the brown reaction mixture was heated at 608C
overnight. After removal of the volatiles under vacuum, the residue was
taken up in a minimum amount of hexane and filtered through aluminum
oxide (10 cm) by using a hexane/MTBE (MTBE ˆ tert-butyl methyl ether)
gradient as eluent. The first fraction contained mainly biphenyl formed
during the reduction of the palladium(ii) precatalyst. The second fraction,
which eluted with 10% MTBE in hexane, contained the almost pure
product. After the removal of the volatiles and crystallization of the residue
from hexane, 3-phenylpropyl phenyl ketone (1.73 g, 83%) was obtained as
Entry
Product[a]
Ligand[b]
D
Yield [%]
48
10
11
12
D
C
55
65
colorless crystals. 1H NMR (200 MHz, CDCl
, 258C, TMS): d ˆ 7.95 (m,
3
3
3
2
6
1
H), 7.61 ± 7.19 (m, 8H), 3.32 (t, J(H,H) ˆ 6 Hz, 2H), 3.13 (t, J(H,H) ˆ
13
Hz, 2H); C NMR (50 MHz, CDCl
3
, 258C, TMS): d ˆ 198.8, 141.0, 136.5,
32.7, 128.3, 128.2, 128.1, 127.7, 125.8, 40.1, 29.8; MS (70 eV): m/z (%): 210
‡
‡
(
53) [M ], 105 (100), 77 (46), 51 (17); HR-MS: calcd for C15
H
14O [M ]:
2
10.104465; found: 210.10447; Elemental analysis calcd for C15
14
H O
(
210.3): C 85.68%, H 6.71%, N 0.00%; found: C 85.37, H 6.67, N 0.00%.
1
1
3
4
C
55
78
The reactions in Tables 1 ± 3 were performed on a 1-mmol scale, with
tetradecane (0.05 mL) as an internal GC standard. The products were
2 3 2
isolated by column chromatography (basic Al O or SiO , ethyl acetate/
hexane 1:30 ± 1:10) and characterized by means of 1H and 13C NMR
spectroscopic analysis as well as by GC-MS and HR-MS.
A
Received: May 3, 2001 [Z17041]
1
1
5
6
D
C
55
75
[
1] a) J. March, Advanced Organic Chemistry, 3rd ed., Wiley, New York,
1
985, pp. 433 ± 435, 824 ± 827; b) R. C. Larock, Comprehensive Organ-
ic Transformations: A Guide to Functional Group Preparations, VCH,
New York, 1989, pp. 685 ± 702; c) D. A. Shirley, Org. React. 1954, 8,
2
8 ± 58; d) B. T. OꢁNeill in Comprehensive Organic Synthesis, Vol. 1
(
Eds.: B. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 397 ± 458.
[
[
[
2] a) M. J. Jorgenson, Org. React. 1970, 18, 1 ± 97; b) C. R. Iwanow, C. R.
Hebd. Seances Acad. Sci. 1928, 186, 442 ± 444; c) A. Meisters, T. Mole,
Aust. J. Chem. 1974, 27, 1665 ± 1672.
3] a) G. M. Rubottom, C. Kim, J. Org. Chem. 1983, 48, 1550; b) Y. Ahn,
T. Cohen, Tetrahedron Lett. 1994, 35, 203 ± 206; c) T. Fujisawa, S. Iida,
H. Uehara, T. Sato, Chem. Lett. 1983, 1267 ± 1270.
4] R. K. Dieter, Tetrahedron 1999, 55, 4177 ± 4236; b) M. P. Sibi, Org.
Prep. Proced. Int. 1993, 25, 15 ± 40; c) V. Farina, V. Krishnamurthy, W.
Scott, Org. React. 1997, 50, 1 ± 652.
1
1
7
8
A
B
72
47
[5] L. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260 ± 11261; b)
P. Zurer, Chem. Eng. News 2000, 78(48), 26.
Reagents and conditions: carboxylic acid (1 mmol), boronic acid
[
6] a) K. Nagayama, F. Kawataka, M. Sakamoto, I. Shimizu, A. Yama-
moto, Chem. Lett. 1995, 367 ± 368; b) K. Nagayama, I. Shimizu, A.
Yamamoto, Chem. Lett. 1998, 1143 ± 1144.
(
1.2 mmol), pivalic anhydride (1.5 mmol), Pd(OAc)
0.07 mmol; 0.035 mmol for DPPF), solvent (4 mL), H
08C, 16 h; all yields refer to isolated products. [a] Aryl groups that
originate from the boronic acids are drawn on the left side of the keto
groups. [b] Ligands: A ˆ P(p-MeOPh) ; B ˆ PPh ; C ˆ DPPF; D ˆ PCy
c] DME was used as solvent.
2
(0.03 mmol), ligand
(
2
O (2.5 mmol),
6
[
7] a) T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508 ±
7
1
510; b) T. Ishiyama, Y. Itoh, T. Kitano, N. Miyaura, Tetrahedron Lett.
997, 38, 3447 ± 3450; c) M. Murata, T. Oyama, S. Watanabe, Y.
3
3
3
.
[
Masuda, J. Org. Chem. 1997, 62, 6458 ± 6459; d) M. Murata, T. Oyama,
S. Watanabe, Y. Masuda, J. Org. Chem. 2000, 65, 164 ± 168.
[
8] a) J. March, Advanced Organic Chemistry, 3rd ed., Wiley, New York,
In summary, the palladium-catalyzed cross-coupling reac-
1
985, p. 355; b) S. G. Burton, P. T. Kaye, Synth. Commun. 1989, 19,
tion disclosed herein represents a one-step, high-yielding
synthesis of aryl ketones directly from the plethora of
available carboxylic acids and boronic acids. The reaction is
easily performed with many functionalized derivatives, re-
quires only commercially available nontoxic chemicals, and
produces a minimum amount of waste. It is thus a valuable
alternative to the standard procedures, especially for applica-
tions in drug discovery or combinatorial chemistry.
3
331 ± 3335.
[
9] a) M. Haddach, J. R. McCarthy, Tetrahedron Lett. 1999, 40, 3109 ±
3112; b) N. A. Bumagin, D. N. Korolev, Tetrahedron Lett. 1999, 40,
3057 ± 3060.
10] For example, anhydrides have been used as substrates for Heck
olefinations: M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl,
J. G. de Vries, Angew. Chem. 1998, 110, 688 ± 690; Angew. Chem. Int.
Ed. 1998, 37, 662 ± 664.
[
[11] We also observed a similar influence of water in other reactions: L. J.
Goossen, Chem. Commun. 2001, 669 ± 670.
Experimental Section
3
b: A 100-mL round-bottomed flask equipped with a pressure equalizer
and a magnetic stirring bar was charged with palladium acetate (67.3 mg,
.30 mmol), diphenylferrocenylphosphane (194 mg, 0.35 mmol), 3-phenyl-
0
3460
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3460 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 18