A convenient method for preparing aromatic ketones from acyl chlorides and arylboronic acids via Suzuki-Miyaura type coupling reaction

Article abstract of DOI:10.1016/S0040-4039(02)02501-7

Aromatic ketones are synthesized efficiently via palladium-catalyzed cross-coupling reaction of boronic acids with acyl chlorides in the presence of K₃PO₄ hydrate in toluene. This allows the use of aliphatic acyl chlorides as the starting material. Hydrated water plays a significant role as an H₂O source to activate the catalytic system.

Full text of DOI:10.1016/S0040-4039(02)02501-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 271–273
A convenient method for preparing aromatic ketones from acyl
chlorides and arylboronic acids via Suzuki–Miyaura type
coupling reaction
Yoshio Urawaa,b,* and Katsuyuki Ogurab,*
aProcess Research Laboratories, Eisai Co., Ltd, 22 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki 314-0255, Japan
bGraduate School of Science and Technology, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
Received 5 October 2002; revised 6 November 2002; accepted 8 November 2002
Abstract—Aromatic ketones are synthesized efficiently via palladium-catalyzed cross-coupling reaction of boronic acids with acyl
chlorides in the presence of K3PO4 hydrate in toluene. This allows the use of aliphatic acyl chlorides as the starting material.
Hydrated water plays a significant role as an H2O source to activate the catalytic system. © 2002 Elsevier Science Ltd. All rights
reserved.
Many synthetic methods have been developed for the
synthesis of aromatic ketones, which are important
building blocks included in a large number of natural
products and active pharmaceutical ingredients (APIs).
Recently, palladium-mediated cross-coupling between a
boronic acid (1) and an activated derivative (2) of an
acid has been reported to be effective for synthesizing
functionalized benzophenones (Eq. (1)).1,2 The acti-
vated derivatives (2) have to be formed either prior to
the reaction or in situ by an activator such as pivalic
anhydride or dimethy dicarbonate.
The former reaction can be performed insofar as the
acid chloride is not susceptible to water. The latter
conditions required an elevated temperature and a
longer reaction time. The yield of the product (3) was
relatively low (19–80%). Here we wish to report that a
hydrated base can accelerate the palladium-catalyzed
reaction of 1 with 4 to provide an efficient route leading
to symmetrical and asymmetric ketones (Eq. (2)).
(2)
Since we needed o-cyanobenzophenone derivatives that
are useful synthetic intermediates for some pharmaceu-
ticals, our initial attempt was to couple benzoyl chlo-
ride with 2-(1,3,2-dioxaborinan-2-yl) benzonitrile (5)
that was selected instead of (o-cyanophenyl)boronic
acid. This is because boronic acids are known to
undergo intermolecular condensation under anhydrous
conditions.5 However, we obtained the expected
product (3a) in 26% yield under the anhydrous condi-
tions reported by Haddach (Cs2CO3, toluene). Under
Bumagin’s aqueous conditions, 3a was formed in 23%
yield (Eq. (3)).
(1)
From the point of view that the reaction is performed
in a large (or industrial) scale, acyl chlorides (4) are
preferred as the activated derivative of an acid because
they are widely available. Haddach3 and Bumagin4
reported the ketone synthesis via palladium-catalyzed
cross-coupling of arylboronic acid (1) and acyl chloride
(4) under aqueous conditions (in acetone–water (3:1))
and anhydrous conditions (in toluene), respectively.
(3)
* Corresponding authors. Tel.: +81-479-46-1155; fax: +81-479-46-
4956; e-mail: y-urawa@hhc.eisai.co.jp
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02501-7

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Y. Urawa, K. Ogura / Tetrahedron Letters 44 (2003) 271–273
Table 1. Palladium-catalyzed reaction of benzoyl chloride
(4a) with 5a
characteristic tendency of hygroscopic bases to aggre-
gate and solidify in the presence of additional water,
as reported previously.6 This is an important factor to
be considered in realizing reproducibility in large-scale
synthesis.
Entry
Base
Solvent
Yield of 3a (%)b
1
2
3
4
5
6
7
8
9
Na2CO3
Na2CO3·H2O
KF
KF·2H2O
K3PO4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NMP
0
2
7
25
Next, we applied the optimized conditions to the
preparation of various ketones from boronic acids (1)
and acyl chlorides (4). To our surprise, various
ketones were formed in from good to excellent yields
as summarized in Table 2. Although K3PO4 hydrate
was used, aliphatic acid chlorides react smoothly to
afford the corresponding ketones in good yields
(entries 7 and 8). Under the present heterogeneous
conditions, competitive hydrolysis of the acyl
chloride is minimized. Probably, the reaction takes
place at the surface of the solid base and the amount
of free water in toluene is controlled to be minimal.
For the synthesis of an ortho-substituted benzophe-
none, the use of the corresponding ortho-substituted
phenylboronic acid gave a better yield (entry 11 versus
entry 4).
11
K3PO4·nH2Oc
K3PO4·nH2Oc
K2CO3·1.5H2O
K3PO4+1.5H2Od
70 (70)e
3
11
53
Toluene
Toluene
a For typical reaction conditions, see Ref. 7.
b Yield was calculated by HPL assay of reaction mixture.
c Actual number of ‘n’ was 1.5 in this lot.
d Water (1.5 mol equiv. to K3PO4) was added to the reaction system..
e Isolation yield after column chromatograph.
In our previous report, the Suzuki–Miyaura reaction
of 5 with an aryl bromide was shown to be promoted
by water.6 Hence, we chose the hydrated bases that
are commercially available, insoluble in organic sol-
vents, and weak in basicity. With these weak bases in
organic solvents, the decomposition of acyl chlorides
and the boronate (5) would be suppressed. As summa-
rized in Table 1, the addition of hydrated bases gave
better results (entries 2, 4, 6 versus entries 1, 3, 5,
respectively). Among the hydrated bases examined
herein, K3PO4 hydrate afforded the best yield in tolu-
ene (entry 6).
The reaction mechanism is thought to be the same as
that of the well-established Suzuki–Miyaura cross-cou-
pling reaction, in which water plays a significant role
as an activator for boronic acid and/or palladium cat-
alyst.8 In the present reaction using K3PO4 hydrate
under heterogeneous conditions, it is concluded that
the hydrated water cannot hydrolyze the acyl chloride,
but activates the boronic acid. In entry 2, the yield of
the ketone decreased to 66% when Pd(OAc)2–PPh3
was used.
In summary, palladium-catalyzed cross-coupling reac-
tion of boronic acids with acid chlorides was achieved
by using K3PO4 hydrate as a base to afford symmetri-
cal and asymmetric ketones in good to excellent yields.
The concept employed herein seems to be applicable
to the Suzuki–Miyaura cross-coupling reactions using
various moisture-sensitive starting materials. Further
studies on the mechanism and the scope of this reac-
tion are in progress.
The use of a polar solvent (1-methyl-2-pyrrolidinone:
NMP) resulted in lowering the yield (entry 7). In this
case, the formation of benzoic acid was detected by
HPLC analysis. It is likely that benzoyl chloride is
easily hydrolyzed with a hydrated base that is more
soluble in NMP than in toluene. It should be noted
that the addition of water to anhydrous K3PO4 low-
ered the yield (entry 9). This is largely due to the
Table 2. Palladium-catalyzed reaction of acyl chlorides (4) with boronic acids (1) in the presence of K3PO4 hydrate
Entry
R
Ar
Temp. (°C)/time (h)
Products
Yield (%)a
1
2
3
4
5
6
7
8
Phenyl
4-Tolyl
3-Tolyl
2-Tolyl
4-Methoxyphenyl
4-Nitrophenyl
Ethyl
Methyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Tolyl
3-Tolyl
2-Tolyl
110/4
110/4
110/4
110/4
110/4
110/4
80/4
Benzophenone
91
95
94
82
90
70
71
68
4-Methylbenzophenone
3-Methylbenzophenone
2-Methylbenzophenone
4-Methoylbenzophenone
4-Nitrobenzophenone
Propiophenone
40/6
Acetophenone
9
10
11
110/4
110/4
110/4
4-Methylbenzophenone
3-Methylbenzophenone
2-Methylbenzophenone
97
Phenyl
Phenyl
91 (90)b
95
a Yield was calculated by HPL assay of the reaction mixture.
b Isolation yield after column chromatograph.

Y. Urawa, K. Ogura / Tetrahedron Letters 44 (2003) 271–273
273
6. Urawa, Y.; Naka, H.; Miyazawa, M.; Souda, S.; Ogura,
K. J. Organomet. Chem. 2002, 653, 269–278.
References
7. Typical procedure: To a mixture of 2-(1,3,2-dioxaborinan-
2-yl)benzonitrile (224 mg, 1.2 mmol), dicholorobis-
(triphenylphosphine)palladium (14 mg, 0.02 mmol) and
hydrated K3PO4 (360 mg, 1.5 mmol) in toluene (5 mL)
under nitrogen was added benzoyl chloride (141 mg, 1.0
mmol). The reaction mixture was heated at 110°C for 4 h
and diluted with toluene (10 mL). The solution was
washed successively with a saturated solution of sodium
bicarbonate, water, and brine, dried over anhydrous mag-
nesium sulfate and concentrated in vacuo. The resulting
material was purified by column chromatography (silica
gel, 1:9 ethyl acetate–hexanes) to give 2-cyanobenzophe-
none (145 mg, 70%) identical with authentic material
purchased from Aldrich.
8. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Miyaura, N. In Advances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; JAI Press: London, 1998; Vol. 6,
pp. 187–243; (c) Suzuki, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998; pp. 49–97.
1. (a) Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, A.
Chem. Lett. 2001, 12, 1242–1243; (b) Gooßen, L. J.;
Ghosh, K. Chem. Commun. 2001, 20, 2084–2085; (c)
Gooßen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40,
3458–3460; (d) Gooßen, L. J.; Winkel, L.; Do¨hring, A.;
Ghosh, K.; Paetzold, J. Synlett 2002, 8, 1237–1240.
2. For other ketone synthesis, the efficient methods using
three-component coupling or organotin compounds were
reported. See: (a) Ishiyama, T.; Kizaki, K.; Hayashi, T.;
Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63, 4726–
4731; (b) Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett.
1977, 1423–1424; (c) Labadie, J. W.; Stille, J. K. J. Am.
Chem. Soc. 1983, 105, 6129–6137.
3. Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40,
3109–3112.
4. Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999,
40, 3057–3060.
5. Cladingboel, D. E. Org. Proc. Res. Dev. 2000, 4,
153–155.