Angewandte
Chemie
DOI: 10.1002/anie.200905967
À
C H Activation
À
Room Temperature C H Activation and Cross-Coupling of Aryl Ureas
in Water**
Takashi Nishikata, Alexander R. Abela, and Bruce H. Lipshutz*
Palladium-catalyzed cross-coupling reactions of aryl halides
Optimization studies employed the combination of ani-
lides (1a–f) and 4-iodoanisole (2a, 2 equiv) in the presence of
Pd(OAc)2 (10 mol%), AgOAc (2 equiv) and aqueous HBF4
(5 equiv) in 2 wt% surfactant/water solutions at room
temperature (Table 1). The effectiveness of various directing
À
with aromatic C H bonds have emerged as a powerful
method for the preparation of biaryls.[1,2] Despite substan-
tially increased attention to the field, typical reaction
conditions still require high temperatures (> 1208C) for
À
insertion into aromatic C H bonds, which can be viewed as
a major drawback to this chemistry. Such forcing conditions
[a]
À
Table 1: Optimization of C H arylations at room temperature.
often appear to be critical to overcoming the low reactivity of
À
À
aryl C H bonds. A much milder C H activation reaction at
ambient temperatures would, in particular, likely be more
dependent on activation by the catalyst.[3]
À
Although there are many ortho-directing groups for C H
activation reactions,[1] the amide residue in anilides is
especially attractive as a coupling partner for the synthesis
of valuable aniline derivatives. In 1984, Tremont and co-
Run
X
Surfactant
Yield [%]
À
workers used acetanilides for C H alkylation with alkyl
1
2
3
4
5
6
7
8
COMe
COiPr
COtBu
CSNMe2
COCF3
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
1a
1b
1c
1d
1e
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
PTS
PTS
PTS
PTS
PTS
PTS
Triton X-100
Solutol
Brij 35
Brij 30
TPGS
trace
trace
24
0
iodides, albeit promoted by stoichiometric Pd(OAc)2.[4] Both
the Daugulis[5] and Sanford[6] groups have demonstrated Pd-
catalyzed ortho-arylations of anilides with aryl iodides or
iodonium salts at temperatures above 1008C. Moreover,
trace
67(0,[b] 0,[c] 0,[d] 60[e])
À
ortho-directed C H activation can suffer from double aryla-
73 (47,[f] 20[g])
tions with respect to the directing group.[1,5] C H arylations of
À
65
76
72
73
40
35
reactive indoles have been reported at room temperature,[7]
9
À
but to the best of our knowledge C H arylation of anilide
10
11
12
13
derivatives with aryl halides at ambient temperatures have
not yet been achieved.[1,8] Herein, we describe the first room
Cremophor EL
none
À
temperature mono-C H activation of urea derivatives and
their cross-couplings with aryl iodides in water (Scheme 1).
This methodology provides a convenient route to various
[a] Conducted at room temperature for 20 h in 2 wt% surfactant/water
with 10 mol% Pd(OAc)2, AgOAc (2 equiv), aq. HBF4 (5 equiv), 1
(0.25 mmol), and 2 (2 equiv). [b] AcOH (instead of HBF4). [c] HCl.
[d] TFA. [e] TsOH. [f] 1.2 equiv AgOAc. [g] 3 mol% catalyst.
À
aniline derivatives by means of C H activation under mild
conditions.
groups was initially examined, and among a number of
different anilide derivatives 1a–f explored, only the aromatic
À
urea 1 f smoothly underwent C H arylation at room temper-
ature (Table 1, runs 1–6). Recently, Lloyd-Jones and Booker-
Milburn have also found aryl ureas to be more active coupling
[9]
À
partners for C H functionalizations than other anilides.
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Scheme 1. C H activation at room temperature in water.
Acetanilide 1a reacted with 2a only upon heating to 508C.
Pivaloylanilide 1c has been reported as an effective directing
group at 1308C,[1,2,5] but gave a low yield under these room
temperature conditions (run 3). Generally, acetic acid or
[*] Dr. T. Nishikata, A. R. Abela, Prof. B. H. Lipshutz
Department of Chemistry & Biochemistry, University of California
Santa Barbara, CA 93106 (USA)
À
trifluoroacetic acid (TFA) is required to carry out C H
activation;[1,2] in this case, HBF4 was found to be critical for
generation of biaryl 3 in good yield (run 6).
Fax: (+1)805-893-8265
E-mail: lipshutz@chem.ucsb.edu
Although use of the surfactant PTS[10] gave good yields,
comparable results were realized with several commercially
available amphiphiles. Best yields were obtained using 2 wt%
Brij35 in water (Table 1, runs 7–13). Reduced amounts of
HBF4, silver salt, or palladium catalyst led to lower yields. A
[**] Financial support provided by the NIH (GM 86485) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 781 –784
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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