Efficient suzuki-miyaura coupling of deactivated aryl chlorides catalyzed by an oxime palladacycle

Article abstract of DOI:10.1055/s-0029-1218285

Aryl chlorides are efficiently cross-coupled with aryl boronic acids using 0.25 mol% of 4,4-dichlorobenzophenone oxime derived palladacycle as precatalyst in the presence of 1 mol% of [HP(t-Bu)₃]BF₄ as ligand, K₂CO₃ as base, TBAOH as additive, and DMF as solvent under conventional thermal or MW irradiation conditions. Under these simple reaction conditions a wide array of deactivated and hindered aryl chlorides react cleanly to afford in high yields functionalized biaryl derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218285

LETTER
3011
Efficient Suzuki–Miyaura Coupling of Deactivated Aryl Chlorides Catalyzed
by an Oxime Palladacycle
SuzukiCoupling
o
i
f
A
ryl
eChlorides go A. Alonso,* J. F. Cívicos, Carmen Nájera*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Alicante University,
Apdo. 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: diego.alonso@ua.es; E-mail: cnajera@ua.es
Received 21 August 2009
DMF–H2O as solvent at 130 °C with TONs of up to
Abstract: Aryl chlorides are efficiently cross-coupled with aryl bo-
ronic acids using 0.25 mol% of 4,4¢-dichlorobenzophenone oxime
derived palladacycle as precatalyst in the presence of 1 mol% of
[HP(t-Bu)3]BF4 as ligand, K2CO3 as base, TBAOH as additive, and
4700.11 Unfortunately, palladacycle 1 (0.5 mol% Pd) has
shown very low reactivity with unactivated aryl chlorides
such as 4-chlorotoluene and 4-chloroanisole affording
DMF as solvent under conventional thermal or MW irradiation con- low yields (28% and 40%, respectively) even working un-
der harsh reaction conditions (DMF, 160 °C).11b On the
ditions. Under these simple reaction conditions a wide array of de-
other hand, catalysts 212a,b and 312c are very active precat-
alysts for the coupling of arylboronic acids with aromatic
and heteroaromatic bromides and chlorides in water under
reflux conditions or at room temperature in aqueous
activated and hindered aryl chlorides react cleanly to afford in high
yields functionalized biaryl derivatives.
Key words: palladacycles, boronic acids, cross-coupling, biaryls,
Suzuki reaction
MeOH. Here, as a part of our ongoing research program
on Suzuki coupling reactions catalyzed by oxime pallada-
Biaryl derivatives are important substructures in fine
chemistry and are of industrial interest in a wide range of
applications, including the synthesis pharmaceuticals,
herbicides, polymers, materials, liquid crystals, and effi-
cient ligands for catalysis.1 The palladium-catalyzed Su-
zuki–Miyaura coupling is certainly one of the most
attractive methods for preparing biaryl compounds thanks
to the functional-group tolerance of the reaction, the use
of stable and nontoxic organoborane reagents, and the
possibility of using water or aqueous solvents as reaction
medium.2 Despite their lack of reactivity, aryl chlorides
are very interesting substrates from an industrial point of
view as they are cheaper and readily accessible. Nowa-
days, a plethora of Pd-catalyst systems are accessible for
achieving the Suzuki reaction with activated aryl chlo-
rides. However, few catalytic systems are capable of per-
forming the Suzuki coupling of challenging deactivated
aryl chlorides in good yields under low-catalyst-loading
conditions. Among them, those involving electronically
rich and sterically hindered trialkyl- and aryl-
dialkylphosphanes3,4 and heterocyclic or carbocyclic
carbenes5,6 have been the most employed catalytic sys-
tems so far. Palladacycles7 have also been shown to be
efficient precatalysts for the Suzuki coupling of aryl chlo-
rides, especially in combination with phosphanes8 or N-
heterocyclic carbenes9 as ancillary ligands. We recently
described the high catalytic activity of palladacycles 1–3
in different Pd-catalyzed cross-coupling reactions in or-
ganic and aqueous solvents.10 In particular, palladacycle 1
is a very active precatalyst for the Suzuki reaction of aryl
bromides and activated aryl chlorides in a 95:5 mixture of
cycles, we report a large improvement of the catalytic ac-
tivity of oxime palladacycle 1 in the Suzuki coupling of
aryl chlorides with aryl boronic acids in organic solvents
by using tetrabutylammonium hydroxide as cocatalyst
and tri-tert-butylphosphane as ancillary ligand under ther-
mal and microwave13 irradiation conditions.
C6H4(4-Cl)
Me
N
N
OH
OH
Pd
Pd
Cl
HO
2
2
Cl
Cl
Cl
1
2
OH
Pd
N
NO2
PS
3
Figure 1 Oxime palladacycles
The assessment of the efficiency of a catalytic system is
its performance with challenging substrates. Thus, opti-
mization of the reaction conditions were performed under
MW irradiation conditions (40 W, 130 °C, 20 min) with
the exigent 4-chloroanisole and phenylboronic acid using
0.25 mol% of catalyst 1 (Scheme 1, Table 1).
Cl
Ph
B(OH)2
Pd catalyst (0.5 mol% Pd)
ligand (1 mol%), TBAX
+
K2CO3, DMF
MW (40 W, 130 °C), 20 min
OMe
OMe
4a
SYNLETT 2009, No. 18, pp 3011–3015
x
x
.x
x
.2
0
0
9
Advanced online publication: 09.10.2009
DOI: 10.1055/s-0029-1218285; Art ID: G27309ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Suzuki coupling of 4-chloroanisole with phenylboronic
acid

3012
D. A. Alonso et al.
LETTER
Using the same reaction conditions as for aryl bromides conversion of 4-methoxybiphenyl was obtained in both
and activated aryl chlorides,11 that is, K2CO3 as base, tet- cases (Table 1, entries 6 and 7). However, the employ-
rabutylammonium bromide (TBAB) as additive in DMF ment of tri-tert-butyl phosphane led to a significant in-
as solvent, palladacycle 1 was not so efficient and 4-meth- crease of the catalyst efficiency affording a 32%
oxybiphenyl was obtained in only 19% conversion conversion in the process (entry 8). This conversion could
(Table 1 entry 1). The presence of Ph3P as ligand (1 be greatly improved by using the more robust and stable
mol%) was even deleterious for the process since no tri-tert-butylphosphonium tetrafluoroborate14 as ligand,
cross-coupled product was observed after 20 minutes which, under the basic reaction conditions, afforded 4a in
(Table 1, entry 2). The catalytic activity of palladacycle 1 a 40% isolated yield (Table 1, entry 9). In contrast, biden-
was also studied in the presence of different dialkylbiaryl tate phosphane ligands such as 1,1¢-bis(diisopropylphos-
phosphane ligands such as 2-(biphenyl)dicyclohexyl- phino)ferrocene
(DIPPF)
and
4,5-bis(diphenyl-
phosphane, 2-dicyclohexylphosphino-2¢,4¢,6¢-triisopro- phosphino)-9,9-dimethylxanthene (Xantphos) gave prod-
pylbiphenyl (Xphos), and 2-dicyclohexylphosphino-2¢- uct 4a in very low conversions under the same reaction
(N,N-dimethylamino)biphenyl (DavePhos)3b (Table 1, conditions (Table 1, entries 10 and 11). Very low conver-
entries 3–5), obtaining the best result with the latter as an- sions were also obtained when other types of ligands such
cillary ligand (21% conversion, entry 5). The reaction as tris(2,4-di-tert-butylphenyl)phosphite and 1,3-bis(2,6-
seemed to fail under MW heating when bulky and elec- diisopropylphenyl)imidazolinium chloride were used, af-
tron-rich ligands, since when using 1,3,5-triaza-7-phos- fording compound 4a in very low conversions (Table 1,
phadamantane and tricyclohexyl phospane less than 10% entries 12 and 13).
Table 1 Optimization of the Reaction Conditionsa
Entry
1
Pd catalyst
Ligand
Cocatalyst (20 mol%)
TBAB
Conversion (%)b
1
–
19
<5
2
1
Ph3P
TBAB
3
1
2-(biphenyl)dicyclohexylphosphane
TBAB
<5
4
1
Xphos
TBAB
19
5
1
Davephos
TBAB
21
6
1
1,3,5-triaza-7-phosphadamantane
TBAB
<5
7
1
PCy3
TBAB
5
8
1
P(t-Bu)3
TBAB
32
9
1
[HP(t-Bu)3]BF4
TBAB
81 (40)
8
10
11
12
13
14
15
16
17
18
19
1
DIPPF
TBAB
1
Xantphos
TBAB
<5
1
tris(2,4-di-tert-butylphenyl)phosphite
1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride
[HP(t-Bu)3]BF4
TBAB
22
1
TBAB
14
1
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
TBAOH
>95 (74)
(60)
>95 (93)
17
1c
1d
1e
2d
[HP(t-Bu)3]BF4
[HP(t-Bu)3]BF4
[HP(t-Bu)3]BF4
[HP(t-Bu)3]BF4
(57)
(47)
d
Pd(OAc)2
[HP(t-Bu)3]BF4
a A 10 mL microwave vessel was charged with K2CO3 (1.5 mmol, 207 mg), TBAOH (0.15 mmol, 120 mg), PhB(OH)2 (1.88 mmol, 225 mg),
Pd catalyst (0.0019 mmol, 0.5 mol% Pd), [HP(t-Bu)3]BF4 (0.00375 mmol, 11 mg), 4-chloroanisole (0.75 mmol, 92 mL), and DMF (1.5 mL).
The vessel was sealed with a pressure lock, and the mixture was heated in air at 130 °C by a MW irradiation of 40 W for 20 min.
b Conversion to coupled product determined by GC using decane as internal standard. In parentheses, isolated yield after recrystallization in
MeOH–H2O (3:1).
c The reaction was carried out under conventional heating conditions at 160 °C for 24 h.
d Conditions: 0.1 mol% of Pd and 0.2 mol% of [HP(t-Bu)3]BF4.
e Conditions: 0.01 mol% of Pd and 0.02 mol% of [HP(t-Bu)3]BF4.
Synlett 2009, No. 18, 3011–3015 © Thieme Stuttgart · New York

LETTER
Suzuki Coupling of Aryl Chlorides
3013
Once determined that tri-tert-butylphosphonium tetraflu- demonstrated by performing the cross-coupling under
oroborate was the ligand of choice for the Suzuki coupling conventional heating conditions at 160 °C obtaining, after
of 4-chloroanisol and phenylboronic acid, further reac- 24 hours, a 60% isolated yield of 4a (entry 15). In order to
tion-conditions optimization was carried out in order to test the limits of the system under the optimized reaction
improve the efficiency of the catalytic system. Quantita- conditions, the precatalyst loading was decreased to 0.1
tive conversion and a 74% isolated yield after recrystalli- mol% of Pd affording an excellent 93% isolated yield of
zation were obtained when a 20 mol% of tetra- 4-methoxybiphenyl after 20 minutes at 130 °C (Table 1,
butylammonium hydroxide (TBAOH) was used instead entry 16). Unfortunately, only a 17% conversion could be
of TBAB as additive (Table 1, compare entries 9 and achieved reducing the loading down to 10–2 mol% of Pd
14).15 At this point, the efficiency of the MW protocol was (Table 1, entry 17). The catalytic activity of palladacycle
Table 2 Suzuki Synthesis of Biaryls from Aryl Chlorides Catalyzed by 1 under MW (A) and Thermal (B) Reaction Conditions
Entry
ArCl
Product
No.
Yield (%)a
A
B
Cl
1
2
4b
4c
78
>99
CN
CN
>99c
74b
90
Me
CN
60b
3
4
5
6
7
8
4a
4d
4e
4f
MeO
Cl
MeO
MeO
MeO
Me
93
77
F
83
85
CF3
87b
68b,c
67c
84b
65b
87
Me
Cl
4g
4h
HO
H2N
Cl
HO
H2N
Cl
Me
Me
Me
Me
9
4i
62c
52
Cl
10
11
4j
82d
80d
64d
59d
Cl
Cl
HO2C
HO
HO2C
HO
4k
HO2C
HO2C
12
13
4l
70
77
31
72
N
N
S
Cl
4m
Cl
S
a Isolated yield after flash chromatography.
b Isolated yield after recrystallization in MeOH–H2O (3:1).
c Reaction time: 40 min.
d Isolated yield after recrystallization in Et2O–hexane.
Synlett 2009, No. 18, 3011–3015 © Thieme Stuttgart · New York

3014
D. A. Alonso et al.
LETTER
1 was compared with palladacycle 2 (Figure 1) and 11). Conventional heating afforded the products in signif-
Pd(OAc)2 under the optimized low loading conditions icantly lower yields. The examples illustrated in Table 2
(0.1 mol% Pd). As depicted in Table 1 (entries 18 and 19) with 2-chloropyridine and 2-chlorothiophene (entries 12
both catalysts presented lower activity in the cross-cou- and 13, respectively), clearly show these heterocycles to
pling reaction giving 4a in 57% and 47% isolated yield, be tolerated and compatible with the present method as
respectively.
high yields of the corresponding coupling products (par-
ticularly for MW conditions) were obtained.
Different activated and deactivated aryl chlorides and het-
erocyclic derivatives were cross-coupled with arylboronic In summary, catalyst formed in situ from readily available
acids under the MW optimized reaction conditions and easily handled oxime palladacycle 1 and tri-tert-
(Scheme 2, Table 2, conditions A): palladacycle 1 (0.25 butylphosphonium tetrafluoroborate under basic condi-
mol%) and [HP(t-Bu)3]BF4 (1 mol%) as catalytic mixture, tions shows very good activity in the Suzuki coupling of
TBAOH (20 mol%) as additive, and K2CO3 as base in activated and deactivated aryl chlorides under MW and
DMF at 130 °C (MW, 40 W, 2.41 bar, 20 min). The reac- conventional heating employing TBAOH as cocatalyst
tions were also carried out under conventional heating at and DMF as solvent. Currently, further studies are under
160 °C for 24 hours (Scheme 2, Table 2, conditions B). way addressing extension of this catalytic system to other
With the purpose of comparison, the same catalyst load- palladium-catalyzed transformations.
ing (0.5 mol% Pd) was used under both reaction condi-
tions. The process was very effective for the coupling of
sterically hindered activated aryl chlorides such as 2-chlo-
Acknowledgment
Financial support from the MEC (Projects CTQ2004-00808/BQU,
CTQ2007-62771/BQU and Consolider INGENIO 2010 CSD2007-
00006), from the Generalitat Valenciana (Projects GV/2007/142
and PROMETEO/2009/039), and the University of Alicante is ack-
nowledged.
robenzonitrile (Table 2, entries 1, 2). This substrate react-
ed very efficiently with phenyl- and 4-tolylboronic acids,
producing with the latter 2-cyano-4¢-methylbiphenyl (4c),
a key intermediate in the synthesis angiotensin II receptor
antagonists that are used for the treatment of hyperten-
sion.16
References and Notes
1 (0.5 mol% Pd),
[HP(t-Bu)3]BF4 (1 mol%),
TBAOH (20 mol%), K2CO3, DMF
(1) (a) Littke, A. In Modern Arylation Methods; Ackermann, L.,
Ed.; Wiley-VCH: Weinheim, 2009, 25. (b) Catellani, M.;
Motti, E.; Della Ca’, N.; Ferraccioli, R. Eur. J. Org. Chem.
2007, 4153. (c) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174. (d) Suzuki, A. In Boronic
Acids. Preparation, Applications in Organic Synthesis and
Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005,
123.
Ar1Cl + Ar2B(OH)2
Ar1 Ar2
4a–m
A: MW (40 W, 130 °C), 20 min
B: 160 °C, 24 h
Scheme 2 Suzuki synthesis of biaryls from aryl chlorides
With respect to deactivated aryl chlorides, microwave ir-
radiation and conventional heating afforded, in general,
high yields for the corresponding biaryl derivatives after
purification by flash chromatography or recrystallization
(Table 2, entries 3–10).17 Besides phenylboronic acid,
4-chloroanisole efficiently reacted under MW and con-
ventional heating conditions, with 4-fluorophenyl- and 4-
(trifluoromethyl)phenylboronic acids, affording the corre-
sponding biaryl derivatives in high yields (Table 2, entries
4 and 5). Good yields were also obtained with other elec-
tron-rich aryl chlorides such as 4-chlorotoluene, 4-chlo-
rophenol, and 4-chloroaniline. These deactivated
substrates afforded compounds 4f, 4g, and 4h, respective-
ly with isolated yields ranging from 65% to 87% (Table 2,
entries 6–8). In the more sterically demanding coupling
reaction of 2-chloro-1,3-dimethylbenzene with phenylbo-
ronic acid, the product was obtained in moderate yields
under MW and conventional heating reaction conditions
(Table 2, entry 9). On the other hand, MW heating was
very effective for the synthesis of biphenylacetic and 4-
phenylmandelic acids, very interesting substrates from the
pharmaceutical point of view.18 These derivatives were
prepared from the corresponding chloride precursors in
82% and 80% yield, respectively (Table 2, entries 10 and
(2) For recent selected reviews, see: (a) Alonso, F.; Beletskaya,
I. P.; Yus, M. Tetrahedron 2008, 64, 3047. (b) Miyaura, N.
In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.,
Vol. 1; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004, 41.
(3) For recent reviews, see: (a) Martin, R.; Buchwald, S. L. Acc.
Chem. Res. 2008, 41, 1461. (b) Fu, G. C. Acc. Chem. Res.
2008, 41, 1555.
(4) For representative examples, see: (a) Littke, A. F.; Dai, C.;
Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (b) Zapf, A.;
Ehrentraut, A.; Beller, M. Angew. Chem. Int. Ed. 2000, 39,
4153. (c) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871.
(5) For recent reviews, see: (a) Marion, N.; Nolan, S. P. Acc.
Chem. Res. 2008, 41, 1440. (b) Würtz, S.; Glorius, F. Acc.
Chem. Res. 2008, 41, 1523. (c) Organ, M. G.; Chass, G. A.;
Fang, D.-C.; Hopkinson, A. C.; Valente, C. Synthesis 2008,
2776. (d) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G.
Angew. Chem. Int. Ed. 2007, 46, 2768.
(6) For representative examples, see: (a) Gstöttmayr, C. W. K.;
Böhm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann,
W. A. Angew. Chem. Int. Ed. 2002, 41, 1363.
(b) Herrmann, W. A.; Öfele, K.; Schneider, S. K.;
Herdtweck, E.; Hoffmann, S. D. Angew. Chem. Int. Ed.
2006, 45, 3859. (c) Diebolt, O.; Braunstein, P.; Nolan, S. P.;
Cazin, C. S. J. Chem. Commun. 2008, 3190. (d) Organ, M.
G.; Çalimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew.
Chem. Int. Ed. 2009, 48, 2383.
Synlett 2009, No. 18, 3011–3015 © Thieme Stuttgart · New York

LETTER
Suzuki Coupling of Aryl Chlorides
3015
(7) Palladacycles: Synthesis, Characterization and
Applications; Dupont, J.; Pfeffer, M., Eds.; Wiley-VCH:
Weinheim, 2008.
(8) (a) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001,
1540. (b) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser,
H.-U. Angew. Chem. Int. Ed. 2002, 41, 3668. (c) Bedford,
R. B.; Cazin, C. S. J.; Hazelwood, S. L. Angew. Chem. Int.
Ed. 2002, 41, 4120.
DMF (2.5 mL) and [HP(t-Bu)3]BF4 (110 g, 0.0375 mmol) in
DMF (2.5 mL) were previously prepared and used. A 10 mL
MW vessel was charged with K2CO3 (1.5 mmol, 207 mg),
TBAOH (0.15 mmol, 120 mg), PhB(OH)2 (1.88 mmol, 225
mg), catalyst 1 (250 mL of the stock soln, 0.0019 mmol, 15
mg, 0.5 mol% Pd), [HP(t-Bu)3]BF4 (250 mL of the stock soln,
0.00375 mmol, 11 mg), 4-chloroanisole (0.75 mmol, 92 mL),
and DMF (1.5 mL). The vessel was sealed with a pressure
lock, and the mixture was heated in air at 130 °C by a MW
irradiation of 40 W for 20 min in a CEM Discover MW
reactor. After allowing the reaction to cool down to r.t., the
mixture was filtered through a pad of Celite and poured into
an excess of H2O (5 mL) and extracted with Et2O (3 × 5 mL).
The combined organic phases were washed with H2O (3 × 5
mL), dried (MgSO4), and evaporated. The obtained crude
product was purified by recrystallization in MeOH–H2O
(3:1), yielding 102 mg of pure 4-methoxybiphenyl (4a, 74%)
as a white solid; mp 89–93 °C. 1H NMR (300 MHz, CDCl3):
d = 7.57–7.51 (m, 4 H, ArH), 7.42 (t, J = 7.5 Hz, 2 H, ArH),
7.30 (t, J = 7.2 Hz, 1 H, ArH), 6.98 (d, J = 8.7 Hz, 2 H, ArH),
3.86 (s, 3 H, CHO). MS (EI, 70 eV): m/z (%) = 184 (100)
[M+], 169 (49) [M+ – Me], 141 (49), 139 (13), 115 (35).
(18) (a) p-Biphenylacetic acid(felbinac) and 2-ethyl-4-
biphenylacetic acid with dimethylaminoethanol-
(9) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc.
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2000, 2, 1823. (b) Alonso, D. A.; Nájera, C.; Pacheco, M. C.
J. Org. Chem. 2002, 67, 5588.
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(14) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(15) At this point, the efficiency of the previously tested
phosphane ligands with TBAOH as additive was tested
again, showing in all cases lower activities. For example,
P(t-Bu)3 only led to a 31% isolated yield of 4a.
(16) Goubet, D.; Meric, P.; Dormoy, J.-R.; Moreau, P. J. Org.
Chem. 1999, 64, 4516.
(namoxyrate) are anti-inflamatory and analgesic drugs,
respectively: USP Dictionary of USAN and International
Drugs names. (b) p-Biphenylacetamides have been used as
mesogenic arms in porphyrin thermotropic liquid crystals:
Michaeli, S.; Hugerat, M.; Levanon, H.; Bernitz, M.; Natt,
A.; Neumann, R. J. Am. Chem. Soc. 1992, 114, 3612.
(17) Typical Procedure for the Suzuki Coupling under MW
Irradiation Conditions (Table 2, Entry 3)
A freshly stock soln of catalyst 1 (150 mg, 0.019 mmol) in
Synlett 2009, No. 18, 3011–3015 © Thieme Stuttgart · New York

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