Nonbasic, room temperature, palladium-catalyzed coupling of aryl and alkenyl iodides with boronic acids mediated by copper(I) thiophene-2-carboxylate (CuTC)

Article abstract of DOI:10.1021/ol010060p

(Matrix presented) A new protocol for the palladium-catalyzed, copper-mediated coupling of aryl and alkenyl iodides with boronic acids is described. As an alternative to the well-known and widely used Suzuki cross-coupling, this reaction occurs in the absence of a base at room temperature and should be particularly useful for the construction of substrates bearing base-sensitive and thermally sensitive moieties.

Full text of DOI:10.1021/ol010060p

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2149-2152
Nonbasic, Room Temperature,
Palladium-Catalyzed Coupling of Aryl
and Alkenyl Iodides with Boronic Acids
Mediated by Copper(I)
Thiophene-2-carboxylate (CuTC)
Cecile Savarin and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
chemll1@emory.edu
Received April 4, 2001 (Revised Manuscript Received May 30, 2001)
ABSTRACT
A new protocol for the palladium-catalyzed, copper-mediated coupling of aryl and alkenyl iodides with boronic acids is described. As an
alternative to the well-known and widely used Suzuki cross-coupling, this reaction occurs in the absence of a base at room temperature and
should be particularly useful for the construction of substrates bearing base-sensitive and thermally sensitive moieties.
Suzuki-Miyaura cross-coupling reactions of aryl and alkenyl
iodides with boronic acids have been extensively described.1
Various reaction conditions (catalysts, bases, solvents, tem-
perature) have been used to afford the desired product in
good to excellent yields. All of these protocols, however,
require the use of a base, and with only a few exceptions
due to specific palladium/ligand systems,2 high temperature
is needed for efficient reaction rates. We recently described
two CuI carboxylate-mediated, Pd-catalyzed cross-coupling
reactions of boronic acids with thioorganics: reaction with
thiol esters gives ketones3 and reaction with 1-thioalkynes
produces unsymmetrical alkynes.4,5 These mechanistically
novel reactions take place under nonbasic conditions. The
key to the reaction is the chemoselective, copper carboxylate-
mediated transmetalation from the boronic acid to the
organopalladium thiolate intermediate (Scheme 1). Because
Scheme 1. CuTC-Mediated B to Pd Transmetalation
(1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. Pure Appl. Chem. 1994, 66, 2, 213-222. (c) Martin, A. R.;
Yang, Y. Acta Chem. Scand. 1993, 47, 221-230. (d) Li, Y.; Hong, X. M.;
Collard, D. M.; El-Sayed, M. A. Org. Lett. 2000, 2 (15), 2385-2388.
(2) (a) Littke, A.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028. (b) Bei, X.; Turner, H. W.; Weinberrg, W.; Guram, A. S. J. Org.
Chem. 1999, 64, 6797-6803.
(3) Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2000, 122 (45), 11260-
11261.
non-carboxylate CuI salts (CuCl, CuBr, CuI, CuCN) were
ineffective, it appeared that the CuI carboxylate served a dual
role in effecting transmetalation from boron to palladium:
(4) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3 (1), 91-
93.
(5) Related CuI carboxylate-mediated couplings of boronic acids with
heteroaryl thioethers and thioimidates will be disclosed shortly.
10.1021/ol010060p CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/20/2001

Table 1. Room Temperature, Nonbasic Pd-Catalyzed Cross-Coupling of Boronic Acids Mediated by CuTC
it polarized the Pd-S bond through CuI coordination to S
and it simultaneously activated the trivalent boron through
coordination of carboxylate to B (structure I in Scheme 1).
This analysis suggests that CuI carboxylates should
uniquely facilitate boron-based cross-coupling with other
“cuprophilic” reaction partners under nonbasic reaction
conditions. Supporting that notion, we report herein the
efficient, nonbasic,6 room temperature coupling of aryl and
alkenyl iodides with boronic acids mediated by copper(I)
thiophene-2-carboxylate.
Table 1 depicts the room temperature coupling of boronic
acids (1.0-1.2 equiv) with aryl and vinyl iodides in the
presence of catalytic Pd(PPh3)4 and CuI thiophene-2-car-
boxylate (CuTC; 1.0-1.2 equiv). The coupling reaction
proceeded within 2-18 h at room temperature in good to
excellent isolated yields (72-96%) and was compatible with
electron-withdrawing and -donating groups on both the iodo
substrates and the arylboronic acids. This CuI carboxylate-
mediated coupling was very selective under the conditions
studiedsreaction was observed only at the carbon-iodine
bond. Bromo, chloro, and triflate derivatives did not couple,
even up to 50 °C (neither chlorobenzene, 4-bromoacetophe-
none, nor 2-naphthyl trifluoromethylsulfonate gave coupling
product; see also Table 1, entry 8). Neither did aryl thioethers
react (Table 1, entry 5), in contrast to thiol esters3 and
1-thioalkynyl ethers,4 which undergo palladium-catalyzed,
CuTC-mediated coupling with boronic acids. A refractory
oxidative addition of aryl thioethers to palladium is the likely
source of nonreactivity.7
As one example of the benefit of these new, nonbasic
conditions, 2-iodobenzyl chloride was subjected to Pd(PPh3)4-
catalyzed cross-coupling with PhB(OH)2 under three different
conditions (Scheme 2). In the presence of 1.1 equiv of CuTC
at room temperature in THF, iodo-specific coupling occurred
to generate 2-phenylbenzyl chloride in 72% within 12 h.
Substituting K2CO3 (3.3 equiv) for CuTC under the same
(6) The pH of distilled water is unchanged in the presence of a CuTC
slurry.
(7) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei, I.
A. J. Am. Chem. Soc. 1998, 120, 9205-9219.
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Org. Lett., Vol. 3, No. 14, 2001

boron to copper transmetalation or directly from the arylpal-
ladium iodide-CuTC complex (Scheme 3). It was previously
Scheme 2. A Comparison of the CuTC-Mediated Coupling
with Traditional Suzuki Conditions
Scheme 3
conditions gave no reaction; only starting material was
observed by GC/MS analysis. Raising the reaction temper-
ature to 60 °C led to the formation of multiple products
(including 2-phenylbenzyl chloride and 2-benzylbiphenyl)
and some recovered starting material.
pointed out that naphthalene-2-boronic acid suffers rapid (2
h) protodeborylation to naphthalene upon treatment with 1
equiv of CuTC in THF at room temperature.3 This observa-
tion provides strong support for direct boron to copper
transmetalation; however, the absence of any significant
protodeborylation product under the very similar cross-
coupling conditions argues against a simple boron to copper
transmetalation. Rather, we suggest an intimate interaction
of RPdL2I with both CuTC and the boronic acid as depicted
in Scheme 3 (Mori and Hiyama suggested a similar cyclic
transmetalation process for the palladium-catalyzed, Ag2O-
mediated coupling of silanols with aryl and vinyl iodides9).
If prior transmetalation from boron to the Pd-I-bound CuI
does occur, protodemetalation from this intermediate must
be slow relative to a fast internal transfer from copper to
palladium. Alternatively, direct transmetalation from boron
to palladium is feasible. CuI, which is not an effective
cofactor for the coupling (as shown by the previous control
experiment), must be generated during this process and
subsequently precipitates from solution.
Various palladium catalysts were assayed. Among Pd-
(PPh3)4, Pd2dba3 with P(cyclohexyl)3, and Pd2dba3 with TFP,
Pd(PPh3)4 was the most efficient; the other palladium
catalysts afforded complete reactions but required longer time
at room temperature. Both CuI thiophene-2-carboxylate and
CuI 3-methylsalicylate were studied. Although aryl iodides
are known to undergo Ullmann reductive coupling in the
presence of stoichiometric RCOOCu(I) at or below room
temperature,8 the homocoupling byproduct was not observed
with CuI thiophene-1-carboxylate (CuTC); only the cross-
coupling product of the boronic acid was detected. In
contrast, some Ullmann reductive coupling product was
detected with CuI 3-methylsalicylate. Different solvents
(THF, dioxane, N,N-dimethylacetamide, ethanol, toluene)
could be used, although THF and dioxane gave the fastest
reaction at room temperature.
We note again that no reaction took place when CuTC
was substituted with NaTC, even at 50 °C, nor in the
presence of excess K2CO3 at room temperature, which makes
an alternate transmetalation mechanism proceeding by simple
RCO2 -induced nucleophilic activation of the boronic acid
unlikely.
In conclusion, a new, base-free protocol for the coupling
of aryl and alkenyl iodides with boronic acids is reported.
The reaction proceeds within a few hours at room temper-
The unique ability of CuTC to mediate the room temper-
ature cross-coupling is apparent from comparative and
control reactions (and from the reactions depicted in Scheme
2). Palladium-catalyzed reaction of p-iodotoluene with phen-
ylboronic acid in the presence of stoichiometric CuTC led
to quantitative formation of product (no product was
observed if palladium or copper carboxylate was omitted).
Reaction with substoichiometric CuTC led to incomplete
conversion. Both the copper and the counterion are important;
no product was observed when 1 equiv of NaTC was used
in place of CuTC, even at 50 °C. No coupling product was
observed within 14 h using CuCl, CuI, or CuCN at room
temperature.
The mechanism of this process is presumed to begin with
room temperature oxidative addition of the carbon-iodine
bond to palladium to provide an ArPdL2I intermediate. This
intermediate must undergo a CuTC-mediated, room temper-
ature, base-free transmetalation with R1B(OH)2. The trans-
metalation from boron to palladium can occur, either by prior
-
(9) Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.; Nishihara,
Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342-5349.
(10) General experimental procedure. The boronic acid (1.0-1.2
equiv), Pd catalyst (2-5%), CuTC (1.0-1.2 equiv), and aryl or alkenyl
iodide (1.0 equiv) were placed in a 25 mL Schlenk tube. After a vacuum
and argon cycle, dry and degassed THF was added (the use of the Schlenk
tube with dry, degassed solvents is not critical, although yields are higher
with these precautions). When one of the starting materials was an oil, it
was added by syringe after the solvent. The reaction mixture was stirred
for 2-12 h at room temperature. Following the general procedure, dry and
degassed THF (8.0 mL) was added to 4-methyliodobenzene (494 mg, 2.3
mmol, 1.0 equiv), phenylboronic acid (304 mg, 2.5 mmol, 1.1 equiv), Pd-
(PPh3)4 (81 mg, 0.7 mmol, 3%), and CuTC (476 mg, 2.5 mmol, 1.1 equiv).
The reaction was stirred for 3 h at room temperature. After purification by
radial chromatography (hexanes), 1 (348 mg, 2.1 mmol, 90%) was obtained
as a white solid.
(8) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
2312-2313.
Org. Lett., Vol. 3, No. 14, 2001
2151

ature and efficiently generates functionalized molecules in
high yields.10
facilitating this study with a generous supply of boronic acids,
and to Dr. Jiri Srogl for his insight and critical commentary.
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The National Cancer Institute, DHHS,
supported this investigation through Grant CA40157. We are
grateful to Dr. Paul Reider of Merck Pharmaceutical Co. for
his interest in and generous support of this work, to Dr. Gary
Allred of Frontier Scientific, Inc., of Logan, UT, for
OL010060P
2152
Org. Lett., Vol. 3, No. 14, 2001