An improved protocol for ligandless Suzuki-Miyaura coupling in water

Article abstract of DOI:10.1016/j.tetlet.2006.04.039

Using a reverse order of addition of reagents, PdCl₂ and Pd(OAc)₂ are efficient catalysts for the Suzuki-Miyaura reactions in water. The ligandless and mild conditions, the high stability of the catalytic system, short reaction time and good to excellent yields are important features of this protocol.

Full text of DOI:10.1016/j.tetlet.2006.04.039

Tetrahedron Letters 47 (2006) 4225–4229
An improved protocol for ligandless Suzuki–Miyaura coupling
in water
Dmitrii N. Korolev and Nikolay A. Bumagin*
Lomonosov MSU, Department of Chemistry, 119992, GSP-2, Moscow, Leninskie Gori, Russian Federation
Received 24 December 2005; revised 29 March 2006; accepted 10 April 2006
Abstract—Using a reverse order of addition of reagents, PdCl2 and Pd(OAc)2 are efficient catalysts for the Suzuki–Miyaura reac-
tions in water. The ligandless and mild conditions, the high stability of the catalytic system, short reaction time and good to excellent
yields are important features of this protocol.
Ó 2006 Published by Elsevier Ltd.
Hal
+
Ar
The palladium-catalyzed cross-coupling of aryl halides
with arylboronic acids, the Suzuki–Miyaura reaction,1
represents a straightforward and highly effective method
for carbon–carbon bond formation in the synthesis of
biaryl compounds. Although many efficient palladium
catalysts with novel P- and N-ligands have been discov-
ered for the reaction,2 also of great importance are the
protocols that utilize ‘ligandless’ Pd-catalysts in water
or aqueous media.3 Water has clear advantages as a
solvent for use in this type of reactions because it is cheap,
readily available, and nontoxic.4 There are, however,
problems associated with low stability of ligandless cat-
alytic systems. To the best of our knowledge, the effi-
ciency of ligandless Pd catalysts for the coupling of
sterically hindered arylboronic acids and aryl halides
has not been investigated sufficiently.5 It is known that
the cross-coupling of sterically hindered arylboronic
acids proceeds slowly and gives lower yields due to steric
hindrance and hydrolytic deboronation.6 It is also note-
worthy that the cross-coupling of sterically hindered
substrates7 can be used as a very sensitive test for the
efficiency of catalytic systems.
0.1 mol% Pd(OAc)2, H2O
KOH, 20 75 oC, 0.5-5 h
R
Ar B(OH)2
R
ð1Þ
Hal = I, Br; R = COOH, COOMe
74-97 %
Continuing our investigations on the application of
ligandless palladium catalysts, we initially studied the
reaction of mesitylboronic acid [MesB(OH)2] with 4-iodo-
benzoic acid in water as a model system under gradual
heating from 20 to 75 °C in the presence of 0.1 mol %
of PdCl2 (0.1 M water solution) and 3 equiv of various
bases [Na2CO3, K2CO3, K3PO4, Ba(OH)2, NaOH and
KOH]. In the presence of bases, 4-iodobenzoic acid
was converted into the corresponding water soluble benz-
oate and the reactions proceeded under homogeneous
conditions. An important observation made during a
control experiment (no catalyst present) was that Mes-
B(OH)2 decomposed quantitatively to mesitylene under
the reaction conditions after 1.5–2 h. The results are
recorded in Table 1, and show that the bases used have
dramatic effects on the yields of the cross-coupling prod-
uct. Of the bases tested, only NaOH and KOH resulted
in high coupling yields after 1 h (entries 1–6). Presum-
ably the increase of the reaction yields in the presence
of strong bases can be attributed to the easy formation
of the trihydroxyarylboronate [MesB(OH)3]ꢀ—the key
intermediate at the transmetallation step.1a,8 All reac-
tion mixtures became dark, a precipitate of Pd-black
began to deposit in the early stages of the reactions,
and the reactions stopped before full conversion. A large
excess of MesB(OH)2 did not improve the yield of
coupling product (entries 9 and 10). It was shown that
the cross-coupling of MesB(OH)2 did not proceed in
We report herein that it is possible to increase the stability
of ligandless Pd-catalysts by simply changing the order of
addition of the reagents and perform the Suzuki–Miyaura
reactions of water soluble and insoluble substrates in neat
water under comparatively mild conditions (Eq. 1).
Keywords: Suzuki–Miyaura reaction; Ligandless palladium; Biaryls;
Catalysis.
*
Corresponding author. Tel.: +7 495 939 1383; fax: +7 495 932
8846; e-mail: bumagin@org.chem.msu.su
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.04.039

4226
D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 47 (2006) 4225–4229
Table 1. Cross-coupling of mesitylboronic acid with 4-iodobenzoic
conditions oxidative addition of ArI to Pd(0) with the
formation of an [ArPd(II)I]-complex proceeds revers-
ibly, and, if a transmetallation step is fast, equilibrium
shifts towards the Pd(II)-species thereby suppressing
Pd-black formation.
acida
Entry
Catalyst
Base
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(dppf)
Pd-black
Na2CO3
K2CO3
K3PO4
Ba(OH)2
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
2
2
2
2
1
1
2
1
2
2
1
1
1
0.5
1
1
2
2
1
2
0
0
49
55
88
79
44
84
74
A considerable improvement in the yield, up to quanti-
tative, was obtained when the reaction was carried out
in the presence of 0.1 mol % of PdCl2 and 1 mol % of
palmitic acid (entry 11) or 0.1 mol % of Pd(OAc)2 (entry
15). The reverse order of addition of reagents, when base
was added after arylboronic acid, aryl halide, water and
catalyst,11 also resulted in a quantitative product yield in
the presence of PdCl2 (entry 13). The reaction proceeded
smoothly without Pd-black formation even at higher
catalyst loading (1 mol % of PdCl2) (entry 14). The facts
that neither Pd-black was observed, nor did the reaction
stop halfway, indicated that the stability of the ligand-
less catalytic system increased considerably in these
cases. When the solution of PdCl2 was stirred with sus-
pension of 4-iodobenzoic acid in water, the yellow-
brown colour of the mixture disappeared in 5 min and
the palladium salt adsorbed on the surface of the aryl
iodide to form presumably the PdCl2(ArI)n complexes.
We may suppose that after addition of arylboronic acid
and base a reduction of Pd(II) by the trihydroxyarylbor-
onate [MesB(OH)3]ꢀ results in the formation of
Pd(0)(ArI)n particles. Subsequent intramolecular oxida-
tive addition in these complexes proceeds rapidly and
aggregation of Pd(0)-species to form inactive Pd-black
is suppressed. Under these conditions, in the presence
of Pd(OAc)2, 3-iodobenzoic acid also reacted smoothly
to give the cross-coupling product in high yield (entry
16). 4-Bromobenzoic acid was found to be inactive
under the conditions studied (entry 18). It is interesting
to note that the complex PdCl2(dppf) afforded a quanti-
tative yield in 1 h (entry 19).
c
d
8
9e
10f
11
12
13i
14i
15
16i,k
17i,l
18i,m
19
20
81
g
100
59
100j
97
100
100
43
14
100
0
h
c
a 1 mmol of ArI, 1.05 mmol of MesB(OH)2, 3 mmol of base, 5 mL of
water, 0.1 mol % PdCl2 (0.1 M water solution), gradual heating from
20 to 75 °C, argon.
b Determined from the 1H NMR spectra of the crude samples.
c 1 mol % PdCl2.
d 0.01 mol % PdCl2.
e 1.5 equiv of MesB(OH)2.
f 2.5 equiv of MesB(OH)2.
g Solution of PdCl2 (0.1 M) and palmitic acid (1 M) in acetic acid.
h Solid.
i Base was added after reagents and catalyst.
j Isolated yield was 96%.
k 3-IC6H4COOH was used.
l 2-IC6H4COOH was used.
m 4-BrC6H4COOH was used.
the presence of Pd-black as catalyst (entry 20). Earlier,
we reported that Pd-black was an active catalyst for
the Suzuki–Miyaura reaction of sterically unhindered
substrates in water.9 The reaction can be carried out at
lower catalyst loading. For example, the coupling in
the presence of 0.01 mol % of PdCl2 for 1 h provided
an 84% yield of the product.10 However, high catalyst
loading (1 mol %) reduced the coupling yield (entries 7
and 8). In this case, the formation of Pd-black was
clearly visible. A similar effect of Pd-loading on product
yield and palladium black precipitation was recently
observed in a Heck reaction in the presence of ligandless
palladium10c,d and was explained in terms of the equi-
librium between Pd(0)-species, soluble palladium clus-
ters and Pd-black: low Pd concentrations suppress the
aggregation of palladium into inactive Pd-black and
keep the majority of the metal available for catalysis.
Surprisingly, we have found that the formation of Pd-
black also depends on the reactivity of arylboronic acid
during transmetallation step. For example, the reaction
of 4-iodobenzoic acid with the more reactive 4-meth-
oxyphenylboronic acid in the presence of 1 mol % of
PdCl2 proceeded without Pd-black formation up to full
conversion of the aryl iodide (20 °C, 5 min, 100% yield
by 1H NMR). We can hypothesize that under ligandless
To verify the effectiveness of this procedure, the reac-
tions of various arylboronic acids with 2-iodobenzoic
acid were examined using 0.1 mol % of Pd(OAc)2 as cat-
alyst, H2O as solvent, and KOH as base (the base was
added after the reagents, water and catalyst) and grad-
ual heating from 20 to 75 °C (Table 2). Previously, there
have been no reported cross-coupling reactions of 2-
iodo(bromo)benzoic acids in high yields.3e,12 As shown
in Table 2 (entries 1–5), the reactions of 2-iodobenzoic
acid with 2-, 3- and 4-methylphenyl- and 2- and 4-meth-
oxyphenyl-boronic acids gave the cross-coupling prod-
ucts in high yields in 4–5 h. Even sterically hindered
MesB(OH)2 reacted with 2-iodobenzoic acid in 2 h,
yielding 36% of 2-mesitylbenzoic acid (entry 6). In a
control experiment, where the catalyst was added after
reagents, water and base, reaction of 4-methoxyphenyl-
boronic acids and 2-iodobenzoic acid stopped before full
1
conversion (1 h—58%, 6 h—62% yield by H NMR). A
considerable improvement in the yield in the case of
mesitylboronic acid was obtained when the reaction
was carried out with methyl 2-iodobenzoate (entry 8).
Since methyl 2-iodobenzoate was insoluble in water,
hence the reaction proceeded heterogeneously (how-
ever, the addition of TBAB was not required3f), and
hydrolysis of the ester was minimal. The reactions of

D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 47 (2006) 4225–4229
Table 2. Synthesis of 2-arylbenzoic acids and their methyl estersa
4227
Entry
ArI
Ar0B(OH)2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOH
2-IC6H4COOMe
2-IC6H4COOMe
2-IC6H4COOMe
2-IC6H4COOMe
2-IC6H4COOMe
2-MeC6H4B(OH)2
3-MeC6H4B(OH)2
4-MeC6H4B(OH)2
2-MeOC6H4B(OH)2
4-MeOC6H4B(OH)2
MesB(OH)2
4-CF3C6H4B(OH)2
MesB(OH)2
2-MeC6H4B(OH)2
2-MeC6H4B(OH)2
4-FC6H4B(OH)2
4-FC6H4B(OH)2
5
4
4.5
4
5
2
4
2
1
78
93
84
95
93
36 (43)c
92
(75)c
94
97
93
9
10d,e
11
12d
0.5
1
0.5
89
13d
2-IC6H4COOMe
2-IC6H4COOMe
1
1
94
95
B(OH)2
O
B(OH)2
14d
OHC
S
a 1 mmol of ArI, 1.05 mmol of ArB(OH)2, 0.1 mol % Pd(OAc)2, 5 mL of water, 3 mmol of KOH, gradual heating from 20 to 75 °C, argon.
b Isolated yield.
c 1H NMR yield.
d 0.1 mol % PdCl2(dppf).
e After alkaline hydrolysis in ethanol solution, pure acid was isolated in 88% yield.
Table 3. Cross-coupling reactions under the improved protocola
Entry
ArHal
Ar0B(OH)2
Time (h)
Yieldb (%)
1
2
4-IC6H4COOH
4-IC6H4COOH
MesB(OH)2
2-MeOC6H4B(OH)2
1
1
77
95
3
4
4-IC6H4COOH
4-IC6H4COOH
n-C5H11
B(OH)2
1
2
81
79
OHC
B(OH)2
O
5
6
3-IC6H4COOH
3-IC6H4COOH
MesB(OH)2
2-MeOC6H4B(OH)2
1.5
1
82
92
B(OH)2
7c
3-IC6H4COOH
1
97
S
8
9
4-BrC6H4COOH
4-BrC6H4COOH
3-MeC6H4B(OH)2
4-MeC6H4B(OH)2
1
1
90
86
COOH
10
4-CF3C6H4B(OH)2
2
83
Br
11
12
4-MeC6H4B(OH)2
4-MeC6H4B(OH)2
40 min
1
74
92
COOH
Br
Br
O
S
COOH
a 1 mmol of ArHal, 1.05 mmol of Ar0B(OH)2, 0.1 mol % Pd(OAc)2, 5 mL of water, 3 mmol of KOH, gradual heating from 20 to 75 °C, argon.
b Isolated yield.
c 0.1 mol scale, 0.001 mol % Pd(OAc)2.

4228
D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 47 (2006) 4225–4229
3. (a) Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Bull.
Acad. Sci. USSR, Div. Chem. Sci. 1989, 38, 2206; (b)
Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034–
5037; (c) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.;
Naesland, C. G. M. Chem. Commun. 1994, 2395; (d)
Moreno-Manas, M.; Pajuelo, F.; Pleixats, R. J. Org.
Chem. 1995, 60, 6296–6297; (e) Bumagin, N. A.; Bykov, V.
V. Tetrahedron 1997, 53, 14437–14450; (f) Badone, D.;
Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org.
Chem. 1997, 62, 7170–7173; (g) Bumagin, N. A.; Korolev,
D. N. Tetrahedron Lett. 1999, 40, 3057–3060; (h)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68,
4302–4314; (i) Deng, Y.; Gong, L.; Mi, A.; Liu, H.; Jiang,
Y. Synthesis 2003, 337–339; (j) Liu, L.; Zhang, Y.; Wang,
Y. J. Org. Chem. 2005, 70, 6122–6125.
unhindered aryl- and heteroarylboronic acids with
methyl 2-iodobenzoate were also examined. Each reac-
tion proceeded to full conversion of the aryl iodide in
the presence of 0.1 mol % of Pd(OAc)2 or PdCl2(dppf)
in 0.5–1 h giving methyl 2-aryl(heteroaryl)benzoates in
89–97% isolated yields (entries 9–14). A substrate with
the strong base-sensitive CHO-group was also tolerated
(entry 12).
The value of our protocol was illustrated by a one-step
synthesis of 2-(4-trifluoromethylphenyl)benzoic acid
(xenalipin), an active pharmaceutical ingredient which
lowers cholesterol and triglyceride levels in plasma.13
Coupling of 2-iodobenzoic acid with 4-trifluoromethyl-
phenylboronic acid in the presence of 0.1 mol % of
Pd(OAc)2 afforded xenalipin in 92% isolated yield in
4 h (entry 7).
4. (a) Leadbeater, N. E. Chem. Commun. 2005, 2881–2902;
(b) Li, C.-J. Chem. Rev. 2005, 105, 3095–3165.
5. For ligandless-palladium coupling of hindered arylboron
compounds, see: (a) Kang, S.-K.; Lee, H.-W.; Jang, S.-B.;
Ho, P.-S. J. Org. Chem. 1996, 61, 4720–4724; (b) Bumagin,
N. A.; Tsarev, D. A. Tetrahedron Lett. 1998, 39, 8155–
8158.
These standard conditions14 were successfully used in
the reactions of various bromo(iodo)benzoic acids and
their heterocyclic analogs with aryl(heteroaryl)boronic
acids to give cross-coupling products in high yields in
1–2 h (Table 3). For preparative scale synthesis, the cat-
alyst amount was reduced to a 10 ppm level without a
decrease in activity. For instance, 3-iodobenzoic acid
reacted with 3-thienylboronic acid (entry 7) in 97%
isolated yield in 1 h, corresponding to turnover numbers
(TON) up to 97,000 and turnover frequencies (TOF) up
6. Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207–
210.
7. Selected examples of cross-coupling with sterically hin-
dered substrates: (a) Wolfe, J. P.; Singer, R. A.; Yang, B.
H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550–
9561; (b) Griffiths, C.; Leadbeater, N. E. Tetrahedron Lett.
2000, 41, 2487–2490; (c) Littke, A. F.; Dai, C.; Fu, G. C. J.
Am. Chem. Soc. 2000, 122, 4020–4028; (d) Feuerstein, M.;
Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667–
6670; (e) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1162–1163; (f)
Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius,
F. Angew. Chem., Int. Ed. 2003, 42, 3690–3693; (g)
Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 16194–16195; (h) Walker, S. D.; Barder, T.
E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1871–1876; (i) Altenhoff, G.; Goddard, R.;
Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126,
15195–15201; (j) Singh, R.; Viciu, M. S.; Kramareva, N.;
Navarro, O.; Nolan, S. P. Org. Lett. 2005, 7, 1829–1832;
(k) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–
4696; (l) Dai, W.-M.; Zhang, Y. Tetrahedron Lett. 2005,
46, 1377–1381, and references cited therein.
to 97,000 hꢀ1
.
It is important to note that the end of all these reactions
(Tables 1–3) was clearly visualized since palladium metal
precipitated as soon as all of the aryl halide was con-
sumed and pale yellow-brown mixtures turned dark.
Crude products were in most cases sufficiently pure
1
(>97% by H NMR). Pure products were obtained by
simple filtration through silica gel using ether as solvent
to remove traces of Pd-black.
In summary, we have found that under modified condi-
tions ligandless PdCl2 and Pd(OAc)2 are effective cata-
lysts for Suzuki–Miyaura coupling of aryl iodides and
bromides at low palladium loading in water.
8. Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.;
Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151–8156.
9. Kuznetsov, A. G.; Korolev, D. N.; Bumagin, N. A. Russ.
Chem. Bull. 2003, 52, 1882–1883.
Supplementary data
10. For examples of ‘homeopathic’ ligandless palladium as
catalyst, see: (a) De Vries, J. G.; De Vries, A. H. M. Eur. J.
Org. Chem. 2003, 799–811; (b) Alimardanov, A.; Van de
Vondervoort, L. S.; De Vries, A. H. M.; De Vries, J. G.
Adv. Synth. Catal 2004, 346, 1812–1817; (c) De Vries, A.
H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; De Vries, J. G. Org. Lett. 2003, 5,
3285–3288; (d) Reetz, M. T.; De Vries, J. G. Chem.
Commun. 2004, 1559–1563.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
04.039.
References and notes
11. The effect of changing the order of reagent addition in
Suzuki–Miyaura reactions: Song, Q.-B.; Lin, R.-X.; Teng,
M.-Y.; Zhang, J.; Ma, C.-A. Synthesis 2006, 123–127.
12. Examples of coupling of 2-iodo(bromo)benzoic acids: (a)
Bumagin, N. A.; Nikitin, K. V.; Beletskaya, I. P. J.
Organomet. Chem. 1988, 358, 563–565; (b) Bumagin, N.
A.; Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271–
273; (c) Stadler, A.; Kappe, C. O. Org. Lett. 2002, 4, 3541–
3543; (d) Garcia-Martinez, G. C.; Lezutekong, R.;
Crooks, R. M. J. Am. Chem. Soc. 2005, 127, 5097–5103;
1. For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457–2483; (b) Stanforth, S. P. Tetrahedron
1998, 54, 263–304; (c) Suzuki, A. J. Organomet. Chem.
1999, 576, 147–168; (d) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633–9695.
2. For the most recent review on catalyst systems for the
Suzuki–Miyaura reaction, see: Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419–2440, and references cited
therein.

D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 47 (2006) 4225–4229
4229
Examples of coupling of 2-carboxyphenylboronic acid: (e)
Gong, Y.; Pauls, H. W. Synlett 2000, 829–831; (f) Tao, B.;
Goel, S. C.; Singh, J.; Boykin, D. W. Synthesis 2002,
1043–1046.
Pd(OAc)2 was stirred at rt for 5 min under argon, followed
by the addition of 3 mmol (0.168 g) of KOH. The
temperature was gradually (over ꢁ1 h) increased up to
75 °C. The mixture was stirred for the appropriate time
and conditions (Tables 1–3). After the reaction had been
completed the mixture was acidified (in the case of acids)
and the product was extracted by ether. Pure products
were obtained by filtration of the ether solution through
silica gel and evaporation of solvent.
13. Lewis, M. C.; Hodgson, G. L.; Shumaker, T. K.; Namm,
D. H. Atherosclerosis 1987, 64, 27–35.
14. Typical procedure for cross-coupling reactions. A mixture
of 1 mmol of aryl halide, 5 ml of water, 1.05 mmol of
arylboronic acid and 0.001 mmol (0.1 mol %, 0.22 mg) of