Room-temperature palladium-catalyzed and copper(I)-mediated coupling reactions of acid chlorides with boronic acids under neutral conditions

Article abstract of DOI:10.1055/s-2005-872661

The palladium-catalyzed cross-coupling reactions of acid chlorides with arylboronic acids in the presence of copper(I) thiophene-2-carboxylate (CuTC) as an activator under strictly non-basic and mild reaction conditions afford the unsymmetrical ketones in moderate to excellent yields. A wide range of substrates bearing an electron-donating or an electron-withdrawing substituent on the aromatic ring is compatible. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872661

LETTER
2309
Room-Temperature Palladium-Catalyzed and Copper(I)-Mediated Coupling
Reactions of Acid Chlorides with Boronic Acids under Neutral Conditions
C
Y
opper(I)-Mediate
a
d
Coupling
s
Reaction
u
s
of
A
cid Ch
s
lorides
w
i
h
th Boronic
A
i
cids Nishihara,* Yoshiaki Inoue, Mamoru Fujisawa, Kentaro Takagi
Department of Chemistry, Faculty of Science, Okayama University, 3-1-1 Tsushimanaka, Okayama 700-8530, Japan
Fax +81(86)2517855; E-mail: ynishiha@cc.okayama-u.ac.jp
Received 24 June 2005
thiophene-2-carboxylate (CuTC)15 under strictly non-
basic and mild (room temperature) reaction conditions.
Abstract: The palladium-catalyzed cross-coupling reactions of
acid chlorides with arylboronic acids in the presence of copper(I)
thiophene-2-carboxylate (CuTC) as an activator under strictly non- We first carried out the cross-coupling reaction of phenyl-
basic and mild reaction conditions afford the unsymmetrical
ketones in moderate to excellent yields. A wide range of substrates
bearing an electron-donating or an electron-withdrawing substi-
tuent on the aromatic ring is compatible.
boronic acid (1a, 0.1 mmol) with benzoyl chloride (2a,
0
.15 mmol) in the presence of CuTC (0.1 mmol) as an
activator and 5 mol% of Pd(dba) (dba = dibenzylidene-
2
acetone) plus 10 mol% of PPh as the catalyst in THF (1
3
Key words: palladium, cross-coupling reaction, boronic acid,
copper, ketones
mL) at 65 °C for 12 hours: conditions similar to those for
couplings with thioesters.1 The desired coupling prod-
uct, benzophenone (3a) was obtained in 53% yield, based
on 1a. However, the reaction mixture contained 4-chlo-
robutyl benzoate (18%, based on 2a) and biphenyl (4; 7%,
based on 1a), presumably derived from homocoupling of
2b
Among a large number of methods developed for the syn-
1,2
thesis of ketones, the carbonylative Suzuki–Miyaura
3
reactions of organic halides in the presence of carbon
1
a (confirmed by GC and NMR). Formation of 4-chlo-
4
monoxide is most notable. To replace carbonylative
robutyl benzoate was attributed to Pd-mediated reaction
couplings with the use of toxic carbon monoxide, there
has been recent progress in palladium-catalyzed cross-
16
of 2a with THF as the reactant. The similar boiling point
and polarity of 4-chlorobutyl benzoate to the desired ke-
tones would be a drawback for isolation of 3a. Thus, we
screened other solvents for the reactions of 1a with 2a and
found that the solvents employed had a considerable influ-
ence on the yield of 3a. Reactions proceeded in ethereal
solvents such as 1,2-dimethoxyethane (DME) at 65 °C
5
coupling reactions of organoboron compounds with
6
various carboxylic acid derivatives. The reactions of
carboxylic acids or acid anhydrides independently re-
7
8
ported by Gooßen and Yamamoto, have been applied to
the synthesis of ketones. Additionally, although it was
9
,10
11,12
found that activated esters and thioesters
are also
(
59%), tetrahydropyran (THP) at 80 °C (72%), and 1,4-
suitable substrates for cross-coupling reactions with
boronic acids, both substrates need to be prepared from
the corresponding acid chlorides.
dioxane at 100 °C (72%). In addition, with these solvents,
reducing the reaction temperature to room temperature
(
25 °C) had no significant effect on yields of 3a. In partic-
From the point of view of the wide range of availability, ular, diethyl ether as the solvent significantly suppressed
acid chlorides are still preferred as the substrates. In gen- the side reactions and the reaction was completed within
eral, however, acid chlorides are too reactive to be broadly one hour even at room temperature to afford 3a as the sole
useful, and the cross-coupling reactions with boronic product (97% GC yield), as shown in Equation 1.
acids are limited to acid chlorides that can survive under
the basic conditions inherent in Suzuki–Miyaura coupling
cat. Pd(dba)2, PPh3
1
3,14
reactions.
In some cases, the precise amount of
Ph
Cl
CuTC (1 equiv)
Ph
Ph
Ph B(OH)2
+
contaminating water is an important factor for promotion
Et2O
O
O
1
4b,d
of the reaction,
thereby creating problems of repro-
room temperature
1a
2a
3a
ducibility. To the best of our knowledge, there are no
general methods to synthesize ketones by the coupling of Equation 1
stable, functionally rich organoboron compounds with
acid chlorides under neutral conditions. We now describe
an efficient and unprecedented Pd-catalyzed cross-
coupling reaction of acid chlorides with boronic acids,
which provides an efficient route leading to various
ketones. It proceeds in the presence of copper(I)
Diethyl ether seems to play an important role as the low
concentration of CuTC and boronic acids in the reaction
system is favorable to avoid excess amounts of activated
organoboron species leading to homocoupling during the
reaction, thereby giving rise to biaryls as by-products.
Other solvents such as MeCN, N,N-dimethylformamide
(
DMF), and methanol appeared inferior.
Among transition metal catalysts examined in the cou-
pling of 1a with 2a (Table 1), Pd(dba) combined with
SYNLETT 2005, No. 15, pp 2309–2312
Advanced online publication: 08.08.2005
DOI: 10.1055/s-2005-872661; Art ID: U19305ST
1
9
.0
9
.2
0
0
5
2
©
Georg Thieme Verlag Stuttgart · New York

2
310
Y. Nishihara et al.
LETTER
Table 1 CuTC-Mediated Cross-Coupling of 1a with 2a Using
Various Catalystsa
PPh (P/Pd = 2.0; 5 mol%) gave a 97% yield of 3a (run 1).
3
With Pd(PPh ) , 3a was obtained in lower yield (60%, run
3
4
2
). The reason why Pd(PPh ) was not so effective may be
3 4
Run
Catalyst
Yield (%)
due to suppression of the catalytic reaction rate by coordi-
nation of excess PPh ligands. Although P(OPh) and P(2-
3
a
4b
<1
<1
<1
<1
4
3
3
furyl) gave the satisfactory results (runs 3 and 4), other
3
1
2
3
4
5
6
7
8
9
Pd(dba) /2 PPh
97
60
92
72
14
0
2
3
phosphine ligands and Pd(dba) alone gave poor results
2
Pd(PPh3)4
(
runs 5–7). As the catalyst precursor, Pd(OAc) in combi-
2
nation with PPh afforded moderate yields of the product,
3
Pd(dba) /2 P(OPh)
2 3
albeit along with 4 in 8% yield (run 8). In addition,
Pd(dba) /2 P(2-furyl)
Ni(cod) was completely ineffective as the catalyst (run
2
3
2
1
0). Deletion of Pd(dba) yielded no product, confirming
2
Pd(dba) /2 P(t-Bu)
2
3
the requirement for a palladium catalyst. Increasing the
a:2b ratio had a significant effect on yield of 3b: 94%
Pd(dba) /2 PMe
0
1
2
3
yield (2:1), 69% (1.5:1), and 62% (1:1), respectively.
Pd(dba)2
6
<1
8
The reactions of various acid chlorides with arylboronic
acids were conducted and the results are summarized in
Table 2. The use of catalytic (10 mol%) and substoichio-
metric (50 mol%) amounts of CuTC for the reaction of 1a
with 2a afforded 3a in 7% and 44% yields, respectively
Pd(OAc) /2 PPh
71
15
<1
2
3
PdCl (dppf)c
2
6
1
0
Ni(cod)2
0
(
runs 2 and 3), whereas the use of excess (200 mol%)
a
Reaction conditions: Et O (3 mL), 1a (0.2 mmol), 2a (0.1 mmol),
2
amounts of CuTC did not disturb the reaction progress
catalyst (5 mol%), and CuTC (0.1 mmol) at r.t. for 3 h.
b
Yields of 4 were based on 1a.
(
(
entry 4). Thus, we employed a stoichiometric amount
100 mol%) of CuTC as the optimal condition.
c
dppf = 1,1¢-bis(diphenylphosphino)ferrocene.
The reactions of acid chlorides bearing electron-donating
runs 5 and 6) and electron-withdrawing (runs 7–9)
groups with 1a proceeded in good to excellent yields.
(
4
8
-chloromethylbenzophenone (3q) as a sole product in
1% yield within three hours. Substituting K PO for
3
4
Acid chlorides having heteroaromatics such as 2-furyl and
CuTC gave the formation of multiple products including
-benzylbenzophenone.
2
-thienyl groups afforded the corresponding cross-cou-
4
pling products 3g and 3h in 73% and 82% isolated yields,
respectively (runs 10 and 11). Alkyl- and alkenyl acid
chlorides 2i and 2j underwent the reactions to give 3i and
Although a detailed understanding of this cross-coupling
is not currently in hand, we propose a reaction mechanism
as depicted in Scheme 2. Oxidative addition of acid chlo-
rides to Pd(0) generates an acylpalladium(II) chloride 5.17
Subsequent transmetalation of the organic group on
boronic acid to palladium takes place at the Pd–Cl bond.
3
j in moderate yields (runs 12 and 13). On the other hand,
the reactions of 2a with arylboronic acids bearing various
functional groups similarly underwent the cross-coupling
reactions in up to 96% yield (runs 14–19). However, a
sterically hindered arylboronic acid, 2,6-dimethylphenyl- In regard to the transmetalation step, our earlier studies of
boronic acid, completely retarded the reaction of 2a and the Ag O-mediated, palladium-catalyzed couplings of or-
2
gave no desired product.
ganic halides with organosilanols suggested that Ag O
2
may activate intermediate organo(iodo)palladium and sil-
As one example of the advantage of the neutral reaction
conditions, the result of the present reaction of 4-chloro-
methylbenzoyl chloride with 1a was compared with that
of the reported basic condition (Scheme 1). In the pres-
ence of one equivalent of CuTC at room temperature in
anols simultaneously.18 In conjunction with this specula-
1
2
tion and similar proposals by Liebeskind, copper(I)
carboxylate seems to play an important role as a dual
activator: the soft Cu(I) ion accelerates the polarization
of the palladium-chloride bond while the hard
carboxylate counterion activates the boronic acids by
1
4d
Et O, chemoselective cross-coupling occurred to generate
2
cat. Pd(dba)2, PPh3
CuTC (1 equiv)
Cl
sole product
Ph
Et2O
Cl
1a
r.t., 3 h
3q: 81%
O
Cl
PdCl2(PPh3)2 (2 mol%)
K3PO4 (1.5 equiv)
O
Ph
3q: 43%
+
Ph
H2O (2.25 equiv)
toluene
7%
O
110 °C, 4 h
Scheme 1
Synlett 2005, No. 15, 2309–2312 © Thieme Stuttgart · New York

LETTER
Copper(I)-Mediated Coupling Reactions of Acid Chlorides with Boronic Acids
2311
L
and –OCHMeCH CHMeO–] and 2a, but no reaction
2
proceeded even after 48 hours at room temperature. As a
3
2
L
Pd R1
O
result, we found that both CuTC and boronic acids are
critical to the smooth transmetalation, presumably due to
the presence of hydrogen bond between the carbonyl
R2
(HO)2BO2CR
Pd(dba)2, PPh3
CuCl
12c
oxygen and a hydroxy group of a boronic acid. The
H
postulated by-products are CuCl and (HO) BO CR
2
2
R1 B(OH)2
O
B
O
(R = 2-thienyl). The former was unambiguously identi-
fied by XRD analysis, although we could not determine
the fate of a boronic acid. After transmetalation is
completed, the cross-coupling product 3 is formed by
reductive elimination and the Pd(0) is regenerated.
HO
1
2
Pd(Cl)(COR )(PPh3)2
R1
O
R
CuO2CR
R2
Pd
Ln
Cu
5
(
R = 2-thienyl)
Cl
O
In summary, the first palladium-catalyzed cross-coupling
reactions of acid chlorides with boronic acids were
achieved in the presence of CuTC as a neutral activator.19
Scheme 2 Proposed mechanism for cross-coupling
constructing a six-membered ring. Although the reac- Reaction conditions developed for the facile synthetic
tion with other copper salts such as CuCl, CuI, Cu(OAc), method of ketones tolerate the use of both coupling part-
and Cu(OAc) have been examined, no reaction occurred ners with high compatibility. It is remarkable that diethyl
2
under the standard conditions. We also attempted the ether as the solvent effects the transformation of arylbo-
reactions using relatively labile phenylboronates ronic acids into ketones, forming a carbon–carbon bond
PhB(OR) [(OR) = –OCH CH O–, –OCH CMe CH O–, through the cross-coupling by the activation with CuTC.
2
2
2
2
2
2
2
Table 2 Pd(0)-Catalyzed Reactions of Various Acid Chlorides with Boronic Acids in the Presence of CuTCa
Run
1
Boronic acid (R1)
Ph
Acid chloride (R2)
Ph
Time (h)
CuTC (mol%)
Product
Yield (%)b
78 (97)
(7)
(1a)
(2a)
1
48
48
1
100
10
3a
2
3
50
(44)
4
200
100
(97)
5
3-MeC H
(2b)
(2c)
(2d)
(2e)
(2f)
(2g)
(2h)
(2i)
1
3b
3c
3d
3e
3f
78 (94)
87 (98)
76 (89)
93 (94)
75 (89)
73 (88)
82 (90)
47
6
4
6
4-n-BuC H
3
6
4
7
4-O NC H
4
3
2
6
8
4-ClC H
1
6
4
9
4-NCC H
1
6
4
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
2-Furyl
2-Thienyl
n-C H
3
3g
3h
3i
3
3
7
15
(E)-PhCH=CH
(2j)
(2a)
3
3j
52
4-MeC H
(1b)
(1c)
(1d)
(1e)
(1f)
(1g)
Ph
3
3k
3l
87 (91)
71 (94)
76 (76)
82 (90)
80 (93)
96 (99)
6
4
4-MeOC H
3
6
4
4
2-MeOC H
3
3m
3n
3o
3p
6
4-CF C H
4
3
3
6
4-BrC H4
3
6
1
4-MeCOC H
3
6
4
a
The reactions were carried out under the following conditions: Et O (30 mL), boronic acid (2 mmol), acid chloride (1 mmol), Pd(dba) (5
2
2
mol%), PPh (10 mol%), and CuTC (1 mmol) at r.t.
3
b
Isolated yields. GC yields are shown in parentheses.
Synlett 2005, No. 15, 2309–2312 © Thieme Stuttgart · New York

2
312
Y. Nishihara et al.
LETTER
The present coupling reaction is straightforward and
general with great synthetic potential because both
boronic acids and acid chlorides are easily available.
Detailed studies of the mechanism, as well as further in-
vestigation of the scope and limitations of this chemistry,
are in progress.
(9) (a) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc.
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(
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(
(
11) Zeysing, B.; Gosch, C.; Terfort, A. Org. Lett. 2000, 2, 1843.
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000, 122, 11260. (c) Yu, Y.; Liebeskind, L. S. J. Org.
Acknowledgment
Chem. 2004, 69, 3554.
(
13) (a) Cho, C. S.; Itotani, K.; Uemura, S. J. Organomet. Chem.
We are grateful to Professor Hideki Taguchi at Okayama University
for the XRD measurements.
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mg, 0.1 mmol), were added dry Et O (30 mL) and benzoyl
2
chloride (2a, 116 mL, 1 mmol) at r.t. The reddish brown
suspension was stirred for 1 h at r.t. and monitored by GC
and TLC. After completion of the reaction, the reaction
mixture was passed briefly through a Celite pad. Further, the
(
(
7) (a) Gooßen, L. J.; Ghosh, K. Angew. Chem. Int. Ed. 2001,
pad was washed with Et O (2 × 10 mL). The combined
2
40, 3458. (b) Gooßen, L. J.; Ghosh, K. Chem. Commun.
organics were concentrated with a rotary evaporator to give
a viscous oil or solid. The residue was purified by flash
column chromatography on silica gel (hexane–EtOAc = 9:1,
2001, 20, 2084. (c) Gooßen, L. J.; Winkel, L.; Dohring, A.;
Ghosh, K.; Paetzold, J. Synlett 2002, 1237. (d) Gooßen, L.
J.; Ghosh, K. Eur. J. Org. Chem. 2002, 3254.
R = 0.47), compound 3a (142 mg, 0.78 mmol, 78%) was
f
(
8) (a) Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, A.
Chem. Lett. 2001, 12, 1242. (b) Kakino, R.; Narahashi, H.;
Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2002, 75,
1
obtained as a white solid. H NMR (300 MHz, CDCl ): d =
3
7
.46–7.51 (m, 4 H), 7.56–7.62 (m, 2 H), 7.79–7.83 (m, 4 H).
13
1
C{ H} NMR (75 MHz, CDCl ): d = 128.1, 129.9, 132.3,
3
1333.
1
37.4, 196.5.
Synlett 2005, No. 15, 2309–2312 © Thieme Stuttgart · New York