Palladium-phosphinous acid-catalyzed cross-coupling of aliphatic and aromatic acyl chlorides with boronic acids

Article abstract of DOI:10.1016/j.tetlet.2008.07.115

The cross-coupling of aromatic and aliphatic acyl chlorides with arylboronic acids in the presence of 2.5 mol % of (t-Bu₂POH)₂PdCl₂ (POPd) provides rapid access to ketones that are obtained in up to 93% yield. This palladium-phosphinous acid-catalyzed reaction is completed within 10 min when microwave irradiation is used, and it overcomes typical drawbacks of Friedel-Crafts acylation procedures such as harsh reaction conditions, untunable regiocontrol, and low substrate scope.

Full text of DOI:10.1016/j.tetlet.2008.07.115

Tetrahedron Letters 49 (2008) 5773–5776
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-phosphinous acid-catalyzed cross-coupling of aliphatic
and aromatic acyl chlorides with boronic acids
*
Kekeli Ekoue-Kovi, Hanhui Xu, Christian Wolf
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The cross-coupling of aromatic and aliphatic acyl chlorides with arylboronic acids in the presence of
2.5 mol % of (t-Bu2POH)2PdCl2 (POPd) provides rapid access to ketones that are obtained in up to 93%
yield. This palladium-phosphinous acid-catalyzed reaction is completed within 10 min when microwave
irradiation is used, and it overcomes typical drawbacks of Friedel–Crafts acylation procedures such as
harsh reaction conditions, untunable regiocontrol, and low substrate scope.
Received 2 July 2008
Accepted 21 July 2008
Available online 25 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
In recent years, phosphinous acid ligands have been success-
fully introduced to a wide range of transition metal-catalyzed
transformations.1 In particular, nickel and palladium complexes
bearing phosphinous acids have proved to be very powerful cata-
lysts for carbon–carbon and carbon-heteroatom bond formation,
but their use in coupling reactions with acyl chlorides has re-
mained unexplored.2–4 While most Stille, Negishi and Suzuki cou-
plings involve aryl halides, the introduction of acyl halides further
extends the application spectrum of these reactions. The cross-
coupling of acyl chlorides with organometallic reagents provides
convenient access to ketones that can often not be prepared other-
wise, for example, via Friedel–Crafts acylation methods. Few tran-
sition metal-catalyzed coupling reactions of acyl halides with
stannanes,5 boronic acids6 and organozinc,7 arylbismuth,8 and
Grignard reagents9 are known. Typical disadvantages of previously
reported procedures include (1) incompatibility with several func-
tionalities, including aryl halide bonds that compete with the acyl
halide group for oxidative addition to the transition metal catalyst
and subsequent carbon–carbon bond formation, (2) the use of toxic
reagents, and (3) the need for high reaction temperatures and long
reaction times.
t
-Bu
P
t
-Bu
P
t
-Bu
t
-Bu
OH
Cl
Cl
P
Cl
P
O
Cl
Pd
P(O)Ht-Bu
Pd
P(O)Ht-Bu
HO
Cl
Cl
t
-Bu
t
-Bu
PXPd
t
-Bu
t
-Bu
POPd
O
2
1
O
P(O)H
O
t-Bu
P(O)H
t
-Bu
P(O)H
t
-Bu
O
O
4
3
5
Figure 1. Structures of palladium catalysts used in this study.
R
R'
O
L
P
L
PdL2
P
OH
HO
P
R'
Pd
H
R'
HO
R'
R
P
R
R
Scheme 1. Formation of palladium-phosphinous acids from phosphine oxides.
Initially, we compared the catalytic activity of palladium-phos-
phinous acid, POPd, and its chlorophosphine analog PXPd, as well
as complexes formed in situ from Pd(dba)2 and phosphine oxides
1–5 (Fig. 1). Phosphine oxides are well known to rapidly tautomer-
ize to the corresponding phosphinous acids that form active palla-
dium catalysts after stirring with a palladium source, such as
Pd(dba)2, at room temperature for 2–4 h (Scheme 1).
phenone, 8, with superior yields and shorter reaction time. Further
screening of catalyst loading, solvent, temperature, and base re-
vealed that 8 can be obtained in 93% yield within 1 h when
2.5 mol % of POPd and stoichiometric amounts of K2CO3 are used
in a toluene-dioxane solvent mixture heated to 80 °C (Table 1, en-
try 1).10
We found that POPd is most effective in catalyzing the coupling
of benzoyl chloride, 6, and phenylboronic acid, 7, providing benzo-
Under these conditions, a wide range of electron-rich and elec-
tron-deficient benzoyl chloride derivatives were successfully con-
verted to benzophenones 10, 12, 15, 16, 18, 20, and 21 (entries
2–8). It is noteworthy that this procedure tolerates the presence
of aryl chloride and bromide bonds in both the acyl halide
substrate and the arylboronic acid (entries 9–13). For example,
* Corresponding author. Tel.: +1 202 687 3468; fax: +1 202 687 6209.
E-mail address: cw27@georgetown.edu (C. Wolf).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.115

5774
K. Ekoue-Kovi et al. / Tetrahedron Letters 49 (2008) 5773–5776
Table 1
POPd-catalyzed Suzuki-Miyaura cross-coupling of acyl chlorides and boronic acidsa
O
B(OH)2
O
POPd
(2.5 mol%)
R
+
R
Cl
K2CO3
Δ
R'
R'
Entry
1
Acyl chloride
Boronic acid
Product
Yield (%)
93
OH
O
O
B
OH
Cl
7
6
8
O
O
OH
B
2
84
81
83
Cl
OH
9
7
10
MeO
MeO
O
O
OH
B
3b
Cl
OH
7
11
12
O
O
OH
OMe
MeO
B
4
Cl
OH
13
15
14
NC
NC
O
O
OH
OMe
MeO
B
5
6
7
8
85
86
87
80
Cl
OH
6
14
16
O
OH
O
17
O
B
Cl
Cl
OH
7
18
O
OH
B
O
O
O
O
OH
7
19
O
20
O
OH
B
OMe
MeO
O
O
O
O
Cl
OH
19
14
21
O
OH
O
Br
B
9
80
90
OH
Cl
23
6
22
Br
O
O
OH
B
10
Cl
Cl
OH
7
24
25
Br
Cl
Br
O
O
OH
B
11
12
88
82
OH
7
27
26
Cl
Cl
O
O
OH
B
Cl
28
OH
29
7
Cl
Cl
O
OH
B
O
Cl
13
14
87
73
Cl
OH
7
30
31
O
O
OH
B
OH
Cl
6
33
32

K. Ekoue-Kovi et al. / Tetrahedron Letters 49 (2008) 5773–5776
5775
Table 1 (continued)
Entry
Acyl chloride
Boronic acid
Product
Yield (%)
75
OH
O
O
O
15
16
B
Cl
Cl
OH
7
34
35
37
OH
O
B
78
65
OH
7
36
OH
O
O
B
17
OH
Cl
7
38
39
a
All reactions were carried out with 150 mg of acyl chloride, 1.3 equiv of boronic acid, 2.5 mol % of POPd, 1.6 equiv of K2CO3 in 1.75 mL of toluene: 1,4-dioxane (2:1, v/v) at
80 °C for 1 h.
coupling of 6 with 3-bromophenylboronic acid, 22, and 4-bromo-
fords significantly better results with aliphatic acyl chlorides than
previously reported Suzuki-type coupling procedures (entries 16
and 17).6
The POPd-catalyzed cross-coupling of acyl chlorides and boro-
nic acids also proceeds upon microwave irradiation, providing
biaryl ketones in yields that are similar to those obtained by con-
ventional heating (Table 2). Under otherwise identical conditions,
the formation of benzophenones and acetophenones was
benzoyl chloride, 24, with boronic acid 7 gave 3-bromoacetophe-
none, 23, and 4-bromoacetophenone, 25, in 80 and 90% yield,
respectively. Unsaturated ketones can be prepared in good yields
either from a styrylboronic acid, such as 32, or from cinnamoyl
chloride, 34, and its analogs (entries 14 and 15). In addition to
the successful synthesis of benzophenone derivatives from benzoyl
chlorides and arylboronic acids, our POPd-catalyzed method af-
Table 2
Microwave-assisted POPd-catalyzed cross-coupling of acyl chlorides with boronic acidsa
O
B(OH)2
POPd
(2.5 mol%)
O
R
+
R
Cl
K2CO3
MW
R'
R'
Entry
1
Acyl chloride
Boronic acid
Product
Yield (%)
90
O
OH
B
O
Cl
OH
7
6
8
O
O
OH
B
2
3
81
80
Cl
OH
9
7
10
MeO
O
MeO
O
OH
B
Cl
OH
7
11
12
O
OH
B
O
Br
4
5
6
73
84
OH
Cl
23
6
22
Br
Cl
O
O
OH
B
Cl
Cl
OH
7
30
31
OH
B
O
O
72
61
Cl
OH
7
36
37
OH
B
O
O
7
OH
Cl
7
38
39
a
All reactions were carried out with 150 mg of acyl chloride, 1.3 equiv of boronic acid, 2.5 mol % of POPd, and 1.6 equiv of K2CO3 in 1.75 mL of toluene: 1,4-dioxane (2:1, v/
v) at 80 °C in the microwave (100 W) for 10 min.

5776
K. Ekoue-Kovi et al. / Tetrahedron Letters 49 (2008) 5773–5776
cle can be found, in the online version, at doi:10.1016/j.tetlet.
2008.07.115.
O
O
B(OH)2
OMe
POPd
OMe
Cl
+
NC
NC
References and notes
13
14
15, 83%
1. (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516; (b) Li, G. Y. J. Organomet.
Chem. 2002, 653, 63–68; (c) Wolf, C.; Lerebours, R.; Tanzini, E. H. Synthesis
2003, 2069–2073; (d) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077–7084;
(e) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7551–7554; (f) Wolf, C.;
Lerebours, R. Org. Lett. 2004, 6, 1147–1150; (g) Wolf, C.; Lerebours, R. Org.
Biomol. Chem. 2004, 2, 2161–2164; (h) Lerebours, R.; Wolf, C. Synthesis 2005,
2287–2292; (i) Bigeault, J.; Giordano, L.; Buono, G. Angew. Chem., Int. Ed. 2005,
44, 4753–4757; (j) Wolf, C.; Ekoue-Kovi, K. Eur. J. Org. Chem. 2006, 1917–1925;
(k) Wolf, C.; Xu, H. J. Org. Chem. 2008, 73, 162–167.
O
OMe
O
O
OMe
FCA
NC
Cl
+
+
NC
OMe
NC
41
42
13
40
Scheme 2. Comparison of the POPd-catalyzed synthesis of 15 with traditional FCA.
2. For a recent review, see: Ackermann, L. Synthesis 2006, 1557–1571.
3. Examples of Pd(II)phosphinous acid-catalyzed reactions: (a) Lerebours, R.;
Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052–13053; (b) Ekoue-Kovi, K.; Wolf, C.
Org. Lett. 2007, 9, 3429–3432.
4. Selected examples of asymmetric catalysis with palladium-phosphinous acids:
(a) Jiang, X.-B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.;
Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5, 1503–1506; (b)
Dai, W.-M.; Yeung, K. K. Y.; Leung, W. H.; Haynes, R. K. Tetrahedron: Asymmetry
2003, 14, 2821–2826.
5. (a) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634–4642; (b)
Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129–6137; (c) Bumagin,
N. A.; Ponomaryov, A. B.; Beletskaya, I. P. J. Organomet. Chem. 1985, 291, 129–
132; (d) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1–5; (e)
Thibonnet, J.; Abarbri, M.; Parrain, J.-L.; Duchêne, A. J. Org. Chem. 2002, 67,
3941–3944; (f) Davis, J. L.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int. Ed.
2004, 43, 590–594; (g) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126,
15666–15667; (h) Lerebours, R.; Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005,
70, 8601–8604.
6. (a) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109–3112; (b)
Chen, H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649–1651; (c) Urawa, Y.; Ogura, K.
Tetrahedron Lett. 2003, 44, 271–273; (d) Nishihara, Y.; Inoue, Y.; Fujisawa, M.;
Takagi, K. Synlett 2005, 2309–2312; (e) Bandgar, B. P.; Patil, A. V. Tetrahedron
Lett. 2005, 46, 7627–7630; (f) Polackova, V.; Toma, S.; Augustinova, I.
Tetrahedron 2006, 62, 11675–11678; (g) Xin, B.; Zhang, Y.; Cheng, K. J. Org.
Chem. 2006, 71, 5725–5731; (h) Xin, B.; Zhang, Y.; Cheng, K. Synthesis 2007,
1970–1978.
completed in very short reaction times. For example, benzoyl chlo-
ride and phenylboronic acid gave 8 in 90% yield in 10 min.
The synthetic usefulness of transition metal-catalyzed ketone
formation from readily available boronic acids becomes apparent
through a comparison with traditional Friedel–Crafts acylation
(FCA). Using our method, 4-cyano-30-methoxybenzophenone, 15,
can be prepared in 83% yield in a single step. By contrast, Lewis
acid-promoted acylation of anisole, 40, with 4-cyanobenzoyl chlo-
ride, 13, would favor the formation of regioisomers 41 and 42. Sim-
ilarly, FCA with benzonitrile, 43, and 3-methoxybenzoyl chloride,
44, would be sluggish and produce 15 only in minor amounts
(Scheme 2). Nucleophilic additions of Grignard reagents or organo-
copper, lithium, and cadmium analogs to carboxylic acid deriva-
tives provide other viable synthetic alternatives toward ketones
such as 15.11 However, these methods generally show limited
functional group compatibility and often afford low yields due to
significant formation of tertiary alcohols.
In summary, we have introduced a palladium-phosphinous
acid-catalyzed Suzuki-type cross-coupling method that furnishes
benzophenone and acetophenone derivatives in good to high yields
from aromatic and aliphatic acyl chlorides, respectively. The POPd-
catalyzed ketone formation utilizes readily available boronic acids
and is generally completed within 10 min when it is conducted in a
microwave. This approach overcomes typical drawbacks of proce-
dures based on Friedel–Crafts acylation or nucleophilic addition of
organometallic reagents to carboxylic acid derivatives such as
harsh reaction conditions, limited substrate scope, reduced func-
tional group tolerance and synthetic limitations due to substitu-
ent-directing effects inherent to electrophilic aromatic
substitution.
7. (a) Evans, P. A.; Nelson, J. D.; Stanley, A. L. J. Org. Chem. 1995, 60, 2298–2301; (b)
Østergaard, N.; Skjaerbaek, N.; Begtrup, M.; Vedso, P. J. Chem. Soc., Perkin Trans.
1 2002, 428–433; (c) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964–
15965.
8. (a) Rao, M. L. N.; Venkatesh, V.; Jadhav, D. N. Tetrahedron Lett. 2006, 47, 6975–
6978; (b) Rao, M. L. N.; Venkatesh, V.; Banerjee, D. Tetrahedron 2007, 63,
12917–12926.
9. Wang, X.-J.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.; Senanayake, C. H. Org.
Lett. 2005, 7, 5593–5595.
10. General procedure for the synthesis of 4-cyano-30-methoxybenzophenone 15: 4-
Cyanobenzoyl chloride 13 (174 mg, 1.05 mmol), 3-methoxyphenylboronic acid
14 (213 mg, 1.4 mmol), POPd (2.5 mol %) and K2CO3 (241 mg, 1.7 mmol) were
dissolved in 1.75 mL of toluene: 1,4-dioxane (2:1, v/v). The reaction mixture
was heated to 80 °C for 1 h, quenched with 1 mL of water and extracted with
methylene chloride. The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. Purification by flash chromatography using
hexanes:methylene chloride (1:2, v/v) as mobile phase gave 175.1 mg of 15 as
a white powder (0.79 mmol, 83%). 1H NMR: d 3.88 (s, 3H), 7.17 (dd, J = 3.6 Hz,
6.6 Hz, 1H), 7.18–7.30 (m, 2H), 7.21 (dd, J = 4.5 Hz, 6.6 Hz, 1H), 7.81 (d,
J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H). 13C NMR: d 55.5, 114.3, 115.6, 118.0,
119.7, 122.8, 129.5, 130.2, 137.5, 141.2, 159.8, 194.7. Anal. Calcd for
Acknowledgement
We thank Combiphos Catalysts, Inc. for providing POPd and
PXPd.
C
15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.60; H, 4.36, N, 5.72.
11. (a) Cason, J.; Fessenden, R. J. Org. Chem. 1960, 25, 477–478; (b) Mathey, F.;
Savignac, P. Tetrahedron 1978, 34, 649–654; (c) Sato, F.; Inoue, M.; Oguru, K.;
Sato, M. Tetrahedron Lett. 1979, 20, 4303–4306; (d) Eberle, M. K.; Kahle, G. G.
Tetrahedron Lett. 1980, 21, 2303–2304; (e) Rubbottom, G. M.; Kim, C. J. Org.
Chem. 1983, 48, 1550–1552; (f) Föhlisch, B.; Flogaus, R. Synthesis 1984, 734–
736; (g) Burkhardt, E. R.; Rieke, R. D. J. Org. Chem. 1985, 50, 416–417.
Supplementary data
Synthesis and characterization of all products including NMR
spectra are available. Supplementary data associated with this arti-