Room temperature C-H activation and cross-coupling of aryl ureas in water

Article abstract of DOI:10.1002/anie.200905967

(Chemical Equation Present) Just mix in water'n stir: Pd-catalyzed C-H activation/cross-couplings can be carried out at room temperature in water/surfactant mixtures. The combination of Pd-(OAc)₂ and HBF ₄ allowed for reactions of ar

Full text of DOI:10.1002/anie.200905967

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.
À
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
under http://dx.doi.org/10.1002/anie.200905967.
Angew. Chem. Int. Ed. 2010, 49, 781 –784
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
781

Communications
shown to be prone to double arylation. Under these
conditions, couplings are selective for singly arylated products
(3 f, 3r, 3s, 3v). Only reactions of the aryl urea bearing a 4-sec-
butyl group with phenyliodide and 4-tolyl iodide produced
small amounts (10–15% yields) of doubly arylated products.
Reduced aryl iodide loading or reaction time, however,
suppressed double arylation to less than 3% (3t, 3u).
While current reaction conditions were effective for a
variety of substrates, products resulting from sterically
hindered aryl iodides having ortho-substituents, such as 2-
anisyl iodide and 2-tolyl iodide, were not formed (3b, 3n).
The reactivity of N-methyl substituted ureas (e.g., 3x)
appears to be much lower than that of their non-N-methyl-
substituted analogues, possibly due to palladium coordination
Scheme 2. Generation of a cationic palladium(II) species.
plausible rationale for these results involves generation of a
highly active cationic palladium species (Scheme 2).[7c,11]
As illustrated by several representative examples in
Table 2, the scope of this transformation is broad, applying
Table 2: Products from reactions of aryl ureas with aryl iodides.[a]
Product, Yield [%]
À
in the initial C H activation step. Electron-deficient ureas
(e.g., 3q) were also inert, suggesting that electrophilic attack
of cationic palladium may be critical for activating aromatic
À
C H bonds. The reactivity of aryl iodides possessing electron-
rich groups is also much higher than that of more electron-
withdrawing aryl iodides (3a vs. 3e).
Further advantage can also be taken of the reaction
conditions associated with these cross-couplings to allow for
tandem processes. Thus, in the presence of silver nitrate,
arylation afforded a product of type 3 exclusively, following
standard treatment with hydrogen carbonate (Scheme 3).
À
Scheme 3. Tandem C H arylation–electrophilic trapping.
Without exposure to this aqueous workup, nitrated biaryl 4
was isolated. Since use of silver acetate gave only arylated
product 3a regardless of quenching conditions, the potential
for carrying out secondary electrophilic aromatic substitution
could readily be demonstrated. Simple introduction of
bromine prior to workup afforded the C-arylated, regiospe-
cifically brominated adduct 5 in good overall isolated yield
(70%). The identities of products 3a and 4 were confirmed by
X-ray analyses (see Supporting Information).
[a] Conducted at room temperature for 20 h in 2 wt% Brij35/water with
10 mol% Pd(OAc)2, AgOAc (2 equiv), aq. HBF4 (5 equiv), 1 (0.25 mmol),
and 2 (2 equiv). [b] Run for 48 h. [c] Run for 72 h. [d] Run for 96 h.
[e] 1.2 equiv of ArI.
to aryl urea derivatives and aryl iodides bearing a variety of
functional groups with yields in the 70–97% range, all done in
water at room temperature. Under these mild conditions, only
mono-arylated products of net substitution were typically
obtained.
While the exact reaction mechanism is currently unclear,
one possibility involves a cationic PdII complex-catalyzed
[7,11]
À
Especially noteworthy are aniline derivatives lacking
ortho- or meta-substitution, which have previously been
electrophilic C H activation step.
Nevertheless, the
reaction of 1 f and 2a (see Table 2) in the presence of
782
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Angewandte
Chemie
[Pd(MeCN)4](BF4)2, a commercially available cationic palla-
dium(II) complex, did not result in the formation of product
(Scheme 4, top). It was found, however, that adding 40 mol%
Experimental Section
General procedure: Aryl urea
1 (0.25 mmol), aryl iodide 2
(0.5 mmol), AgOAc (0.5 mmol, 83 mg), and Pd(OAc)2 (0.025 mmol,
5.6 mg) were sequentially added in air to a reaction tube equipped
with a stir bar and a septum. The aqueous solution containing the
surfactant (1.0 mL, 2 wt%), and 48 wt% HBF4 solution (1.25 mmol,
0.16 mL) were added by syringe and vigorously stirred for 20 h. After
completion, the contents of the flask were quenched with NaHCO3
and extracted with EtOAc. The solution obtained was filtered
through a plug of silica gel and anhydrous MgSO4, and concentrated
by rotary evaporation. The residue was purified by flash chromatog-
raphy eluting with hexane/EtOAc to afford the product.
Received: October 23, 2009
Published online: December 17, 2009
Scheme 4. Effect of cationic palladium species.
À
Keywords: anilines · aryl urea · C H activation · palladium ·
water
.
MeCN under the standard, optimized, and otherwise success-
ful conditions (cf. Table 2, product 3a; 76% yield), only traces
of product formation was observed (Scheme 4, bottom). This
suggests that the low reactivity of the pre-formed cationic
palladium complex may actually be due to suppression of the
reaction by MeCN coordination to the Lewis acidic PdII.
With the goal of generating a highly active cationic PdII
complex without the aid of strong acid, and in the absence of
coordinating ligands, the combination of Pd(OAc)2 and
AgBF4 was examined (Scheme 5). As expected, these con-
[1] Reviews: a) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem.
Res. 2009, 42, 1074; b) X. Chen, K. M. Engle, D.-H. Wang, J.-Q.
Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed. 2009,
48, 5094; c) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; d) F.
Kakiuchi, T. Kochi, Synthesis 2008, 3013; e) I. V. Seregin, V.
Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173; f) T. Ishiyama, N.
Miyaura, Pure Appl. Chem. 2006, 78, 1369; g) C. Nevado, A. M.
Echavarren, Synthesis 2005, 167, and references therein.
À
[2] Recent reports on C H activation/arylation with aryl halides:
a) B. Join, T. Yamamoto, K. Itami, Angew. Chem. 2009, 121,
3698; Angew. Chem. Int. Ed. 2009, 48, 3644; b) L.-C. Campeau,
D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle, E. Villemure,
H.-Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier, K. Fagnou,
J. Am. Chem. Soc. 2009, 131, 3291; c) F. Yang, Y. Wu, Y. Li, B.
Wang, J. Zhang, Tetrahedron 2009, 65, 914; d) C. C. Scarborough,
R. I. McDonald, C. Hartmann, G. T. Sazama, A. Bergant, S. S.
Stahl, J. Org. Chem. 2009, 74, 2613; e) J. Kim, M. Jo, W. So, Z.
No, Tetrahedron Lett. 2009, 50, 1229; f) S. I. Gorelsky, D.
Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848.
À
[3] C H activation at room temperature is very rare: a) Reaction of
À
Scheme 5. C H activation without acids at room temperature in water.
an arene with benzoquinone: H.-B. Zhang, L. Liu, Y.-J. Chen, D.
Wang, C.-J. Li, Adv. Synth. Catal. 2006, 348, 229; b) Fujiwara–
Moritani reaction in TFA: M. D. K. Boele, G. P. F. van Strij-
donck, A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries,
P. W. N. M. van Leeuwen, J. Am. Chem. Soc. 2002, 124, 1586;
À
ditions led to C H activation. Unlike the reaction with
AgOAc, the reaction with AgBF4 produced the correspond-
ing C H arylated product 3a without assistance of external
acid at room temperature. This result, under such mild
conditions, is indicative of the potential for highly active
cationic palladium species to serve as especially effective
catalysts for C H arylation reactions. The silver salt may not
only weaken the C I bond and/or function as halogen
À
c) C H borylation: T. Ishiyama, J. Takagi, J. F. Hartwig, N.
À
Miyaura, Angew. Chem. 2002, 114, 3182; Angew. Chem. Int. Ed.
2002, 41, 3056; d) reaction of an arene forming multiple bonds:
C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura, Y. Fujiwara,
Science 2000, 287, 1992; e) methoxycarbonylation: see ref. [9].
[4] S. J. Tremont, H. ur Rahman, J. Am. Chem. Soc. 1984, 106, 5759.
[5] a) D. Shabashov, O. Daugulis, J. Org. Chem. 2007, 72, 7720; b) O.
Daugulis, V. G. Zaitsev, Angew. Chem. 2005, 117, 4114; Angew.
Chem. Int. Ed. 2005, 44, 4046.
À
À
scavenger, but may also play an important role in the
generation of cationic palladium(II) species.
[6] D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am.
Chem. Soc. 2005, 127, 7330.
À
In summary, the first room temperature C H arylation of
anilides with aryl iodides to give biaryl derivatives in good
yields is described. These are accomplished using aryl urea
derivatives, and are all done in water in the absence of
[7] a) N. R. Deprez, D. Kalyani, A, Krause, M. S. Sanford, J. Am.
Chem. Soc. 2006, 128, 4972; b) L.-C. Campeau, M. Bertrand-
Laperle, J.-P. Leclerc, E. Villemure, S. Gorelsky, K. Fagnou, J.
Am. Chem. Soc. 2008, 130, 3276; c) N. Lebrasseur, I. Larrosa, J.
Am. Chem. Soc. 2008, 130, 2926; d) J. Zhao, Y. Zhang, K. Cheng,
J. Org. Chem. 2008, 73, 7428.
[8] a) S. A. Ohnmacht, P. Mamone, A. J. Culshaw, M. F. Greaney,
Chem. Commun. 2008, 1241; b) E. F. Flegeau, M. E. Popkin,
M. F. Greaney, Org. Lett. 2008, 10, 2717; c) G. L. Turner, J. A.
Morris, M. F. Greaney, Angew. Chem. 2007, 119, 8142; Angew.
À
phosphine ligands. Further studies of metal-catalyzed C H
activation reactions at room temperature, including both
Heck couplings and mechanistic studies, are currently under
investigation.
Angew. Chem. Int. Ed. 2010, 49, 781 –784
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
783

Communications
Chem. Int. Ed. 2007, 46, 7996; d) C. I. Herrerꢀas, X. Yao, Z. Li,
C.-J. Li, Chem. Rev. 2007, 107, 2546.
2009, 131, 10974; b) L. V. Desai, K. J. Stowers, M. S. Sanford,
J. Am. Chem. Soc. 2008, 130, 13285; c) B. S. Lane, M. A. Brown,
D. Sames, J. Am. Chem. Soc. 2008, 130, 8050; d) D. Garcꢀa-
Cuadrado, P. de Mendoza, A. A. C. Braga, F. Maseras, A. M.
Echavarren, J. Am. Chem. Soc. 2007, 129, 6880; e) M. Lafrance,
K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496; f) M. Lafrance,
C. N. Rowley, T. K. Woo, K. Fagnou, J. Am. Chem. Soc. 2006,
128, 8754; g) D. Garcꢀa-Cuadrado, A. A. C. Braga, F. Maseras,
A. M. Echavarren, J. Am. Chem. Soc. 2006, 128, 1066; h) D. L.
Davies, S. M. A. Donald, S. A. Macgregor, J. Am. Chem. Soc.
2005, 127, 13754.
[9] C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G.
Tyler, M. R. Gagnꢁ, G. C. Lloyd-Jones, K. I. Booker-Milburn,
Angew. Chem. 2009, 121, 1862; Angew. Chem. Int. Ed. 2009, 48,
1830.
[10] For other reactions at room temperature in water, see: a) T.
Nishikata, B. H. Lipshutz, J. Am. Chem. Soc. 2009, 131, 12103;
b) A. Krasovskiy, C. Duplais, B. H. Lipshutz, J. Am. Chem. Soc.
2009, 131, 15592 – 15593; c) B. H. Lipshutz, S. Ghorai, Aldrichi-
mica Acta 2008, 41, 58.
À
[11] The mechanism of C H activation has been well studied:
a) J. M. Racowski, A. R. Dick, M. S. Sanford, J. Am. Chem. Soc.
784
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