Angewandte
Chemie
tion.[14,15] For the system at hand we note that running the ing diverse functionalities of relevance to medicinal, materi-
reaction neat is nearly as effective as running it on water. This als, and natural products chemistry. In addition, the reaction is
suggests that a substantial increase in the effective concen- carried out under conditions substantially milder than those
tration of reactants and catalyst system is the main driving commonly found in the literature for heteroarene arylation.
force for rate acceleration in an on-water reaction. Examining Future work will look to apply this methodology to the
the relative ratio of water/MeCN in the reaction showed that synthesis of complex molecules.
whilst small amounts of MeCN were well tolerated, increasing
the proportion of organic solvent led to a rapid decrease in
yield, underlining the requirement for heterogeneity (Fig-
Experimental Section
ure 1B). Pending detailed mechanistic investigation, we hold
this concentration effect as our principal hypothesis. From the
point of view of synthetic expediency, the on-water method is
to be recommended over running the reaction neat in all
cases, owing to benefits of reproducibility and safety.
Having established high-yielding on-water arylation con-
ditions for 2-aryl thiazoles, we were interested in exploring
the scope of the methodology with alternative heterocyclic
substrates. Initial results point to a versatile process for high-
yielding direct arylation (Scheme 3). 2-Alkyl-substituted
5-(4-Chlorophenyl)-2-phenylthiazole (3a):Representative procedure
for cross-coupling in organic solvents: Ag2CO3 (342.1 mg,
1.240 mmol, 2 equiv), [Pd(dppf)Cl2]·CH2Cl2 (25.3 mg, 0.031 mmol,
5.0 mol%), PPh3 (16.3 mg, 0.062 mmol, 10 mol%), 4-chloroiodoben-
zene (177.5 mg, 0.744 mmol, 1.2 equiv), and 2-phenylthiazole
(100 mg, 0.620 mmol,1 equiv) were combined and dissolved in
MeCN (5 mL) under N2. The reaction was heated at 608C for 72 h
and filtered through a pad of celite, washed with acetone (5 mL) and
CH2Cl2 (5 mL), and concentrated under vacuum. The title compound
is obtained following purification by column chromatography in 10%
EtOAc/hexane as a colorless solid (136.5 mg, 81% yield). mp (Et2O):
1378C; 1H NMR (360 MHz, CDCl3): d = 7.92 (1H, s), 7.90–7.87 (2H,
m), 7.47–7.45 (2H, m), 7.39–737 (3H, m), 7.32–7.30 ppm (2H, m);
13C NMR (90 MHz, CDCl3): d = 167.49, 139.44 (CH), 137.94, 134.10,
133.45, 130.16 (CH), 129.88, 129.28 (2CH), 128.99 (2CH), 127.77
(2CH), 126.36 ppm (2CH); IR (thin film): n˜max = 3054, 2986, 1265,
1095, 896, 739, 705 cmÀ1
; HRMS (ES + ve): calculated for
[C15H1035ClNS+H]+: 272.0295, found: 272.0293.
Representative procedure for cross-coupling on water: Ag2CO3
(342.1 mg, 1.240 mmol, 2 equiv), [Pd(dppf)Cl2]·CH2Cl2 (25.3 mg,
0.031 mmol, 5.0 mol%), PPh3 (16.3 mg, 0.062 mmol, 10 mol%), and
4-chloroiodobenzene (177.5 mg, 0.744 mmol, 1.2 equiv) were com-
bined and thoroughly mixed in the bottom of a quickfit testtube. 2-
Phenylthiazole (100 mg, 0.620 mmol, 1 equiv) was added, followed by
deionized water (5 mL), and the suspension heated to 608C for 24 h.
The reaction mixture was then filtered through a pad of celite,
washing the pad with acetone (10 mL) and CH2Cl2 (10 mL), and the
organic solvents removed under vacuum. The resultant slurry was
partitioned between CH2Cl2 (10 mL) and brine (5 mL), and the
phases separated. The aqueous phase was extracted with CH2Cl2
(10 mL) and the combined organic phases concentrated under
vacuum. The crude product was purified by column chromatography
in 10% EtOAc/hexane to afford 3a as a colorless solid (159.7 mg,
95% yield).
Representative procedure for cross-coupling neat: Ag2CO3
(342.1 mg, 1.240 mmol, 2 equiv), [Pd(dppf)Cl2]·CH2Cl2 (25.3 mg,
0.031 mmol, 5.0 mol%), PPh3 (16.3 mg, 0.062 mmol, 10 mol%), and
4-chloroiodobenzene (295.8 mg, 1.240 mmol, 2 equiv) were combined
and shaken to mix thoroughly. 2-Phenylthiazole (100 mg, 0.620 mmol,
1 equiv) was then added and the mixture heated to 608C for 24 h. The
reaction is a melt for the first several hours but as more product forms
it begins to set into a solid cake. CH2Cl2 (10 mL) was added to
suspend the reaction mixture which was mechanically broken down
and filtered through a pad of celite, washed with CH2Cl2 (5 mL) and
acetone (5 mL), then concentrated under vacuum. The crude product
was purified by column chromatography in 10% EtOAc/hexane to
afford 3a as a colorless solid (162.5 mg, 96% yield).
Scheme 3. Direct arylation of five-membered heterocycles on water.
thiazoles were arylated in excellent yield (6) along with the
more sterically hindered 2,4-disubstituted thiazoles (7 and 8)
and the versatile 2-acyl thiazole (9). Moving away from
thiazoles, the three parent benzazole heterocycles were
effectively phenylated at the 2-position, with the benzimida-
zole and benzothiazole affording quantitative yields of
product (12 and 10). 2-Phenyloxazole and 2-methoxythio-
phene were likewise efficiently functionalized at the 5-
position (13 and 14).
Received: May 15, 2007
Revised: July 6, 2007
Published online: September 18, 2007
In conclusion, we have developed the first direct arylation
methodology that takes place on water. The procedure is
highly efficient, user-friendly, and has excellent generality, Keywords: direct arylation · heterocycles ·
.
having been applied to the synthesis of heterocycles display- homogeneous catalysis · palladium · water chemistry
Angew. Chem. Int. Ed. 2007, 46, 7996 –8000
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim