G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
193
methyl 2-carboxylate 10i, 2-(phenylethynyl)benzo[b]thiophene
10j, thiophene-3-carbonitrile 10m, 4-phenylthiazole 12a, 2-
phenylthiazole 12b, benzo[d]thiazole 12c, 1-benzyl-1H-imidazole
C13H10BrN: C, 60.02; H, 3.87; N, 5.38. Found: C, 60.66; H, 3.82; N,
5.40.
2.8. Methyl 3-bromo-1H-indole-1-carboxylate (10e)
12d,
imidazo[1,2-a]pyridine
12e,
1-methyl-1H-indazole
3,5-dimethylisoxazole 12i,
1-(4-fluorobenzyl)-1H-
benzo[d]imidazole
benzo[d]oxazole
chlorophenyl)thiazole 12j.
12f,
12h,
12g,
4-(4-
This compound was purified by flash chromatography using
petroleum ether/ethyl acetate = 9:1. Oil; 1H NMR (400.1 MHz,
CDCl3): ı 8.14 (d, 1 H, J = 0.8), 7.63 (s, 1 H), 7.51 (d, 1 H, J = 7.6 Hz),
7.37 (dt, 1H, J = 7.6, 1.2 Hz), 7.31 (dt, 1 H, J = 7.6, 1.2 Hz), 4.01 (s, 3
H); 13C NMR (100.6 MHz, CDCl3): ı 150.6, 134.5, 129.3, 125.6, 124.3,
123.5, 119.5, 115.0, 98.8, 54.0. Anal. calcd. for C10H8BrNO2: C, 47.27;
H, 3.17; N, 5.51. Found: C, 47.65; H, 3.13; N, 5.56.
2d
3. Results and discussion
10j
[42],
[33],
3.1. Hydrodehalogenation of halogenated pyridines
2-(3-cyanophenyl)benzo[b]thiophene 10l [33], 1-benzyl-4-bromo-
1H-imidazole 11i [39], 1-benzyl-4,5-dibromo-1H-imidazole 11s
[43], 1-benzyl-1H-imidazole 12d [44], 6-chlorobenzo[d]thiazole
12k [45], 5-bromo-4-phenylthiazole 12l [33].
Starting our investigation to optimize the reaction conditions,
the reductions were carried out with 2-bromo-6-phenylpyridine
1a as a model substrate. Initial experiments were performed at
room temperature with an excess of the couple NaBH4-TMEDA
A). Under these conditions the substitution of the bromine with
hydrogen in 1a was complete at room temperature in less than
tive yield (entry 1, Table 1). Similar results were also obtained with
(6-bromopyridin-2-yl)phenylmethanol 1b (entry 2, Table 1). The
perature, albeit after a somewhat extended reaction time (1.5
and 6 h, respectively). These reaction conditions were unsatisfac-
tory to hydrodehalogenate the meta-bromide in the pyridine 1e
(entry 5, Table 1), and even increasing the amount of both the
couple NaBH4-TMEDA (1.7–3.4) and catalyst (5–10 mol%) (method
B) only partial conversion was achieved. However, the reduc-
tion was successful when the reaction was carried out at 60 ◦C
under method A, giving the reduced product in good yield (83%).
Impressively, this transformation could take place at room temper-
ature when PdCl2(dppf) [dppf = 1,1ꢀ-bis(diphenylphosphino)] was
used as the catalyst. Thus, 5 mol% PdCl2(dppf), NaBH4 (1.7 equiv)
and TMEDA (1.7 equiv) (method C) converted 1e into the related
hydrohalogenated pyridine 2e in excellent yield (95%) after 2 h at
room temperature. Under these reaction conditions also the meta-
bromide in 3-bromo-5-phenylpyridine 1f was removed in good
yield (85%) after 1.5 h (entry 6).
As expected, chloropyridines resulted less reactive than the
related bromoheterocycles. Thus, for instance, chloropyridine 1g
was unreactive under the conditions in which the related bro-
moropyridine 1d was smoothly reduced (entry 7 versus 4, Table 1),
and only partial conversion was obtained when the reaction was
carried out at 60 ◦C for 72 h. Fortunately, also in this case the
obtained in excellent yield (95%) after 6 h. In this circumstance,
to speed up the reaction 3.4 equiv of the couple NaBH4-TMEDA
(method D) were employed. The 2-chloropyridine 1h behaved
as expected (entry 8, Table 1), whereas the meta-chloride in 5-
chloro-2-phenylpyridine 1i failed to react under method D at room
temperature, but it was converted into 2-phenylpyridine 2a by
heating at 60 ◦C for 2.5 h with 1.7 equiv NaBH4-TMEDA.
2.6. General procedure for the hydrodehalogenation of
halogenated heterocycles
2.6.1. Procedure using in situ formed catalysts
Pd(OAc)2-PPh3,
Pd2(dba)3-tbpf,
Pd2(dba)3-DavePhos
Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos.
Anhydrous THF (13.2 mL) was degassed by bubbling argon for few
minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 mol%) and PPh3
(17.7 mg, 1.132 mmol, 20 mol%) were added and the resulting
mixture stirred at room temperature for 30 min. The halogenated
heterocycle (0.66 mmol), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv)
and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced
in sequence. The mixture was stirred at room temperature or
heated at 65 ◦C under argon for the proper time. The residue
was taken up in brine and extracted with ethyl acetate. The
organic phase was separated, dried, the solvent was evapo-
rated and the residue was purified by flash chromatography
(mixtures of petroleum ether and ethyl acetate) to give pure
hydrodehalogenated heterocycles.
2.6.2. Procedure using preformed catalysts
PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the
halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL)
was degassed by bubbling argon for few minutes. Then, PdCl2(dppf)
(27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol,
1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were
introduced in sequence. The mixture was stirred at room tem-
perature under argon for the proper time and then worked up as
described above.
2.7. (Z)-2-bromo-3-styrylpyridine (1p)
A suspension of the benzyltriphenylphosphonium bromide
(0.76 g, 1.75 mmol), K2CO3 (2.42 g, 17.50 mmol), 2-bromopyridine-
3-carbaldehyde (0.19 g, 1.75 mmol) and
a few milligrams of
18-crown-6 in 50 mL of anhydrous dichloromethane was refluxed
for 12 h. After being washed with water, the organic layer was
dried on anhydrous MgSO4, filtered, and the solvent was evapo-
rated under reduced pressure. The residue was purified by flash
chromatography using petroleum ether/ethyl acetate = 9:1 to give
pure 1p: 0.59 g (82% yield), oil; 1H NMR (400.1 MHz, CDCl3): 8.22 (d,
1 H, J = 4.4 Hz), 7.40 (d, 1 H, J = 7.6 Hz), 7.22–7.17 (m, 3H), 7.14–7.09
(m, 2H), 7.02 (dd, 1 H, J = 4.4, 7.6 Hz), 7.90 (d, 1 H, J = 12 Hz), 5.40 (d,
1 H, J = 12 Hz). 13C NMR (100.6 MHz, CDCl3): ı 148.6, 143.5, 139.0,
135.7, 135.1, 133.1, 129.0, 128.4, 127.8, 127.2, 122.4. Anal. calcd. for
3.2. Hydrodehalogenation of halogenated quinolines and
isoquinolines
The removal of the bromine or chlorine from quinoline deriva-
tives was obtained analogously to the related pyridines (Table 2).