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K. Lee, P. H. Lee / Tetrahedron Letters 49 (2008) 4302–4305
Our initial study focused on homo-coupling reaction of 3-bro-
In summary, we have developed efficient homo-coupling reac-
tions of heterocyclic aromatic bromides using indium in the pres-
ence of cat-Pd(OAc)2 and LiCl in DMF at 100 °C, producing
exclusively homo-coupling products in good to excellent yields,
in which Csp2–Csp2 bonds were formed.13 It is noteworthy that
protection of aldehyde and ketone group on substrates is not
necessary.
moquinoline (1e) and the results are summarized in Table 1.
Although 4,40-dimethoxy-1,10-biphenyl from homo-coupling reac-
tion of 4-iodoanisole using indium in the presence of cat-Pd/C
was produced in 91% yield,8 the homo-coupling product 2e of
3-bromoquinoline (1e) under the same reaction conditions was
obtained only in 24% yield together with quinoline (38%) and 1e
(21%) even at 100 °C for 20 h in DMF (entry 1). Therefore, new
optimum reaction conditions for biaryls possessing heterocyclic
aromatic ring were highly required. Of the reactions screened,
the best results were obtained with 2.5 mol % Pd(OAc)2 with
indium (0.5 equiv) and LiCl (1.5 equiv) in DMF at 100 °C for 1.5 h
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-2005-
041-C00255) and the Korea Science and Engineering Foundation
(KOSEF) through the National Research Lab. Program funded by
the Ministry of Science and Technology (No. M10600000203-
06J0000-20310). The NMR data were obtained from the central
instrumental facility in Kangwon National University. Dr. Sung
Hong Kim at the KBSI (Daegu) is thanked for obtaining the MS data.
under
a nitrogen atmosphere, producing the homo-coupling
product 2e in 91% yield (entry 3). 2.5 mol % of Pd2dba3CHCl3,
Pd(PPh3)4, and (p-allyl)2PdCl2 gave the desired product 2e in good
yield, while a longer reaction time was needed to complete the
reaction (entries 4–6).
To demonstrate the efficiency and scope of the present method,
we applied the above catalytic reaction system to a variety of het-
erocyclic aromatic bromides. The results are summarized in Table
2. 4-Bromopyridine (1a) produced 4,40-bipyridine (2a) in 71% yield
together with recovered 1a (13%) under the optimum reaction con-
ditions (entry 1), while the use of 1 equiv indium and 5 mol %
Pd(OAc)2 gave 2a in 90% yield (entry 2). 2-Bromo-5-fluoropyridine
(1b) gave the homo-coupling product 2b in 89% yield (entry 3).11
2-Bromo-5-methylpyridine (1c) and 2-bromo-5-methoxypyridine
(1d) were treated with Pd(OAc)2, indium, and LiCl to provide the
desired products 2c and 2d in 94% and 87% yields, respectively
(entries 4 and 5). 4-Bromoisoquinoline (1f) turned out to be com-
patible with the employed reaction conditions (entry 7). The
homo-coupling reaction of 5-bromoindole (1g) having aryl bro-
mide moiety works equally well to give rise to the heterocyclic
biaryl 2g in 80% yield (entry 8). The presence of various carbonyl
groups, such as aldehyde, ketone, and ester groups, on the hetero-
cyclic aromatic rings did not largely affect on the efficiency of the
present reactions. 5-Bromo-2-thiophene-carboxaldehyde (1h) and
5-acetyl-2-bromothiophene (1i) gave the homo-coupling products
2h and 2i in 71% and 76% yields (entries 9 and 10) under the opti-
mum reaction conditions. It is noteworthy that protection of alde-
hyde and ketone group on substrates is not necessary. The use of
ethyl 5-bromo-2-furoate (1j) afforded the symmetric biaryl 2j hav-
ing furan moieties in 85% yield together with recovered 1j in 8%
yield (entry 11). Subjecting 5-bromopyrimidine (1k) to Pd(OAc)2,
indium, and LiCl in DMF for 3 h produced 5,50-bipyrimidine (2k)
in 71% yield (entry 12). In the case of 2-bromothiazole (1l), 2,20-
bithiazole (2l) was obtained in 72% yield (entry 13). However,
a longer reaction time (16 h) at 100 °C in DMF was required to
complete the homo-coupling reaction.
References and notes
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Although the mechanism of the coupling reactions has not been
established, we believe that this transformation most likely pro-
ceeded via a direct electron transfer from indium to palladium(II),
which completed the catalytic cycle (Scheme 2).5b,12 In addition,
potential for single electron transfer to generate radical or aryl-
indium species can be considered.
11.
A mixture of 1b (176.0 mg, 1.0 mmol), Pd(OAc)2 (5.61 mg, 0.025 mmol),
indium (57.4 mg, 0.5 mmol) and lithium chloride (63.5 mg, 1.5 mmol) in dry
DMF (2 mL) was stirred at 100 °C for 1 h under a nitrogen atmosphere. The
reaction mixture was quenched with NaHCO3 (satd aq). The aqueous layer was
extracted with ethyl acetate (3 ꢀ 20 mL) and the combined organic phase was
washed with water (20 mL) and brine (20 mL), dried with MgSO4, and filtered.
The residue was purified by silica gel column chromatography (EtOAc–
hexane = 1:2) to give 2b (85.5 mg, 89%). Mp 153–154 °C; 1H NMR (400 MHz,
CDCl3) d 8.41 (s, 2H), 7.98 (t, J = 7.9 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 164.8, 162.4, 146.0, 145.8, 139.8, 139.7, 130.7, 130.6, 110.2,
109.9; IR (film) 3071,1584, 1466 cmꢁ1; MS(EI) calcd for C10H6F2N2 M+: 192;
found, 192.12.
Ar-X
Pd(0)
Pd(0)
Ar-Pd-X
12. Amatore, C.; Carré, E.; Jutand, A.; Tanaka, H.; Ren, Q.; Torii, S. Chem. Eur. J. 1996,
2, 957.
13. Compound 2a: Kuroboshi, M.; Waki, Y.; Tanaka, H. J. Org. Chem. 2003, 68, 3938;
Compound 2c: (a) Heller, M.; Eschbaumer, C.; Schubert, U. S. Org. Lett. 2000, 2,
3373; (b) De Franca, K. W. R.; De Oliveira, J.; Florencio, T.; Da Silva, A. P.;
Ar-Ar
In
Ar2Pd
PdX2
Scheme 2. Proposed catalytic cycle.