NaBH4-TMEDA and a palladium catalyst as efficient regio- and chemoselective system for the hydrodehalogenation of halogenated heterocycles

Article abstract of DOI:10.1016/j.molcata.2014.06.012

The pair NaBH₄-TMEDA as hydride source and a palladium catalyst in THF prove to be an efficient system for the hydrodehalogenation of halogenated heterocycles with one or more heteroatoms. In general, Pd(OAc) ₂-PPh₃ rapidly hydrodehalogenates reactive halo-heterocycles such as bromo-pyridines, -quinolines, -thiophenes, -indoles, -imidazoles, etc., at room temperature in very good yields, whereas in most cases PdCl₂(dppf) reduces less reactive halides such as chloro-pyridines, -quinolines, -pyrimidines and bromo-indoles, -benzofurans, etc. Moreover, PdCl₂(tbpf) shows to be even more active removing the 2- and 5-chlorine from both thiophene and thiazole rings. The reaction conditions tolerate various functional groups, allowing highly chemoselective reactions in the presence of halide, ester, alkyne, alkene and nitrile substituents. Moreover, with a proper selection of the catalyst it is also possible to obtain a good control in the regioselective hydrodehalogenation of a variety of polyhalogenated substrates.

Full text of DOI:10.1016/j.molcata.2014.06.012

Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
NaBH4-TMEDA and a palladium catalyst as efficient regio- and
chemoselective system for the hydrodehalogenation of halogenated
heterocycles
Giorgio Chelucci∗, Susanna Figus
Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2014
Received in revised form 5 June 2014
Accepted 11 June 2014
Available online 18 June 2014
The pair NaBH4-TMEDA as hydride source and a palladium catalyst in THF prove to be an efficient
system for the hydrodehalogenation of halogenated heterocycles with one or more heteroatoms. In gen-
eral, Pd(OAc)2-PPh3 rapidly hydrodehalogenates reactive halo-heterocycles such as bromo-pyridines,
-quinolines, -thiophenes, -indoles, -imidazoles, etc., at room temperature in very good yields, whereas in
most cases PdCl2(dppf) reduces less reactive halides such as chloro-pyridines, -quinolines, -pyrimidines
and bromo-indoles, -benzofurans, etc. Moreover, PdCl2(tbpf) shows to be even more active removing the
2- and 5-chlorine from both thiophene and thiazole rings. The reaction conditions tolerate various func-
tional groups, allowing highly chemoselective reactions in the presence of halide, ester, alkyne, alkene
and nitrile substituents. Moreover, with a proper selection of the catalyst it is also possible to obtain a
good control in the regioselective hydrodehalogenation of a variety of polyhalogenated substrates.
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Hydrodehalogenation
Reduction
Haloheterocycles
Palladium catalysts
Sodium borohydride
N,N,Nꢀ,Nꢀ-tetramethylethylenediamine
1. Introduction
could be the halogenation of both positions, followed by selective
removal of the halogen from the more reactive one [6].
The substitution of halogens from aromatic rings by hydrogen is
an important chemical transformation in organic synthesis because
this exchange reaction can constitute a key step in the synthesis of
heteroaryl-based molecules in a number of cases: (i) a halogen sub-
stituent can serve as excellent blocking group for a reactive position
of a heterocycle, thus allowing a reaction to be addressed toward a
less reactive one; then, after having fulfilled its function the halogen
can be removed [1,2]. (ii) In a stereodifferentiating process involv-
ing a heteroaromatic compound the presence of a halogen in the
heterocyclic ring can help to increase the reaction stereoselectivity,
subsequently the removal of the halogen by hydrogen can be pur-
sued [1,3]. (iii) The conversion of a functional group (FG) bonded to
a heteroaromatic ring into a halide substituent and its subsequent
removal from the heterocycle can constitute a way to convert a C-FG
into a C–H bond [4]. (iv) The presence of a halogen on a heterocyclic
ring can activate its ␣-position toward specific reactions, then the
halogen can be removed [5]. Finally, (v) it should be noted that
often it is not possible to directly introduce a halogen on an unre-
active position of a heterocycle as other more reactive free positions
are halogenated more quickly; however, a solution to this problem
A wide variety of hydrodehalogenating systems have been
developed over the years for the hydrodehalogenation of halo-
genated heterocycles [7]. Reduction is usually mediated by a
transition-metal catalyst (Ni, Pd, Rh, Pt) and is performed with
molecular hydrogen, metal hydrides or hydrogen sources such
as formic acid and its salts, hydrazine, alkoxides possessing a ␤-
hydrogen, etc. [7]. A number of hydrogenating systems has been
also extended to halogenated heteroaromatics, although the appli-
cation of several of them to these substrates are rather sporadic. A
recent review cover this subject in some extent [6]. Most hydrode-
halogenations of halogenated heterocycles are often accomplished
by catalytic hydrogenation on metal catalyst, Pd/C or Raney Nickel,
and halogen-metal exchange reaction [6]. These processes are often
troublesome to execute since the former ignites easily and the latter
requires anhydrous conditions and low reaction temperature. For
safety and simplicity of operation, a liquid-phase process without
using molecular hydrogen is more advantageous.
Interestingly, some alternative methods have been recently
described, such as (i) hydrogenolysis of aryl halides with catalytic
Pd/C in the presence of hydrazine hydrochloride [8]; (ii) indium-
mediated dehalogenation of haloheteroaromatics in water [9]; (iii)
reduction of chloroarenes by Pd(OAc)2 in combination with poly-
methylhydrosiloxane and aqueous KF [10], (iv) dehalogenation of
activated and unactivated aryl halides by catalytic Pd-complexes
∗
Corresponding author. Tel.: +39 0 79 229539; fax: +39 0 79 229559.
E-mail address: chelucci@uniss.it (G. Chelucci).
http://dx.doi.org/10.1016/j.molcata.2014.06.012
1381-1169/© 2014 Elsevier B.V. All rights reserved.

192
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
NaBH4, TMEDA
Pd-catalyst, solvent
7c,
4-bromo-2-phenylthiophene
7d,
(4-bromothiophen-
7f,
FG-heterocycle-H
FG-heterocycle-X
2-yl)methanol
7e, 3-bromo-2,5-diphenylthiophene
2-bromo-1-methyl-1H-indole 7i, 2-bromobenzofuran 7j, 2-(5-
bromofuran-2-yl)-1,3-dioxolane 7k, 3-bromobenzo[b]thiophene
X = Br, Cl; FG = CN, C=O, COOR, CONR2, C=C, C
C
7l,
7o,
3-bromo-1-methyl-1H-indole
3-chloroobenzo[b]thiophene
7n,
7q,
3-bromobenzofuran
3,5-dibromo-2-
Scheme 1.
under transfer reaction conditions [11,12], (vi) deiodination [13]
and dechlorination [14] with sodium formate and catalytic palla-
dium catalysts, (vii) Fe(acac)3 catalyzed hydrodehalogenation of
aryl halides with t-BuMgCl as reductant [15], and (viii) hydrode-
halogenation with sodium borohydride (NaBH4) [16,17].
However, most of these methods appear limited to halopy-
ridines, involving other halogenated heterocycles in only some
well-defined cases [6]. Therefore, systematic studies addressing
the application of a single hydrodehalogenating system to a wide
range of halo-heterocycles, also including evidences of chemo- and
regioselective reductions, are missing.
In this paper, we report a complete account on the use of the
pair sodium borohydride/N,N,Nꢀ,Nꢀ-tetramethylethylenediamine
(NaBH4-TMEDA) under palladium catalysts as an efficient system
for the hydrodehalogenation a large variety of halogenated hetero-
cycles (Scheme 1) [17]. Moreover, in this circunstance we also show
that this system allows both highly chemoselective hydrodehalo-
genation in the presence of different functional groups and good
efficiency in the regioselective reduction of a variety of polyhalo-
genated substrates.
phenylthiophene
9a,
2,3-dibromobenzo[b]thiophene
9c,
2,3-dibromobenzofuran 9f, 2,3,6-tribromobenzo[b]thiophene 9 g,
4-bromothiophene-3-carbonitrile 9m, 2-bromo-4-phenylthiazole
11a, 2-chloro-4-phenylthiazole 11b, 5-chloro-5-phenylthiazole
11c, 5-bromo-2-phenylthiazole 11d, 4-bromo-2-phenylthiazole
11e,
1H-imidazole
2-chloro-1-(4-fluorobenzyl)-1H-benzo[d]imidazole
bromo-1-methyl-1H-indazole 11l,
11m, 4-bromo-3,5-dimethylisoxazole
2-bromobenzo[d]thiazole
11i, 3-bromoimidazo[1,2-a]pyridine
11k,
11f,
1-benzyl-4-bromo-
11j,
3-
2-chlorobenzo[d]oxazole
11n, 2-chloro-4-(4-
chlorophenyl)thiazole 11o, 2,5-dichlorobenzo[d]thiazole 11p,
4,5-dibromo-2-phenylthiazole 11q.
2.3. Starting materials prepared according to reported procedures
2-Bromo-3-(1,3-dioxolan-2-yl)pyridine 1c [18], 2-bromo-
6,8-methano-7,7-dimethyl-5,6,7,8-tetrahydroquinoline 1d [17b],
2-chloro-6,8-methano-7,7-dimethyl-5,6,7,8-tetrahydroquinoline
1g [19], 2-bromo-3-(phenylethynyl)pyridine 1o [20], 2-
bromobenzo[h]quinoline 3b [21], 2-bromobenzo[b]thiophene
7h [22], 3-bromo-2-phenylbenzo[b]thiophene 7m [23], 3-
2. Experimental
bromo-1-methyl-1H-indole
7n
[24],
3-bromobenzofuran
7o [25], 2-chloro-5-phenylthiophene 7p [26], 3,5-dibromo-
2-phenylthiophene 9b [27], 2,3-dibromo-1-methyl-1H-indole
2.1. General information
9d
9e
[28],
[29],
methyl
2,3,5-tribromobenzofuran
2,3-dibromo-1H-indole-1-carboxylate
9h [30], methyl
[31],
[32],
All reactions were carried out under nitrogen in oven-dried
glassware with magnetic stirring. Unless otherwise noted, all mate-
rials were obtained from commercial suppliers and were used
without further purification. All solvents were reagent grade. THF
was distilled from sodium-benzophenone ketyl and degassed thor-
oughly with dry nitrogen directly before use. Unless otherwise
noted, organic extracts were dried with Na2SO4, filtered through
a fritted glass funnel, and concentrated with a rotary evaporator
(20–30 mmHg). Flash chromatography was performed with silica
gel (200–300 mesh) using the mobile phase indicated. Melting
points are uncorrected. The NMR spectra were measured on 300
spectrometer at 300 for 1H and 75.4 MHz for 13C in CDCl3 solution
with TMS as an internal standard). Chemical shifts (ı) are given in
parts per million and coupling constants (J) in hertz.
5-bromothiophene-2-carboxylate
(phenylethynyl)benzo[b]thiophene
-2-(4-vinylphenyl)benzo[b]thiophene 9k [33], 3-bromo-2-(3-
cyanophenyl)benzo[b]thiophene 9l [33], 2-chlorobenzo[d]thiazole
11g
2,5-dibromo-4-phenylthiazole 11q [36], 1-benzyl-4,5-dibromo-
1H-imidazole 11r [33], 1-benzyl-4,5-dibromo-1H-imidazole
11s [37], 1-benzyl-2,4,5-tribromo-1H-imidazole 11t [38],
2-bromo-5-chloro-4-phenylthiazole 13a [33], 4-bromo-5-chloro-
2-phenylthiazole 13b [39].
9i
9j
3-bromo-2-
3-Bromo
[34],
1-benzyl-2-bromo-1H-imidazole
11h
[35],
2.4. Commercial products
2-Phenylpyridine 2a, phenyl(pyridin-2-yl)methanol 2b,
2.2. Commercial starting materials
3-(1,3-dioxolan-2-yl)pyridine
2c,
2-ethoxypyridine
2e,
3-phenylpyridine 2f, 5,6,7,8-tetrahydroquinolin-8-ol 2 g, 3-
bromo-5-methylpyridine 2h, 6-methylpyridine-3-carbonitrile
2i, pyridine-2-carbonitrile 2j, N-(pyridin-2-yl)ethanamide 2k,
methyl pyridine-3-carboxylate 2l, 3-(phenylethynyl)pyridine
2-Bromo-6-phenylpyridine
1a,
(6-Bromo-pyridin-2-yl)-
phenyl-methanol 1b, 5-bromo-2-ethoxypyridine 1e, 3-bromo-
5-phenylpyridine 1f, 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol
1h, 5-chloro-2-phenylpyridine 1i, 2-bromo-6-methylpyridine-
2m,
(Z)-3-styrylpyridine
2n1,
(E)-3-styrylpyridine
2n2,
3-carbonitrile
4-chloropyridine-2-carbonitrile 1m, methyl 6-chloropyridine-
3-carboxylate 1n, (6-bromopyridin-2-yl)(phenyl)methanone
1q, 1-(6-bromopyridin-2-yl)ethanone 1r, 2-bromopyridine-
3-carbaldehyde 1s, 2-bromoquinoline 3a„3-bromoquinoline
3c, 2-chloroquinoline 3d, 2-chloro-4-azaphenanthrene 3e, (2-
chloroquinolin-3-yl)methanol 3f, 2-chloro-4-azaphenanthrene
1k,
4-chloropyridine-2-carbonitrile
1l,
phenyl(pyridin-2-yl)methanone 2o, 1-(pyridin-2-yl)ethanone 2p,
pyridine-3-carbaldehyde 2q, quinoline 4a, 7,8-benzoquinoline 4b,
quinolin-3-ylmethanol 4c, isoquinoline 4d, 7-chloroquinoline
4e, 8-chloroquinoline 4f, quinoxaline 6a, quinazoline 6b,
2,4-dimethoxypyrimidine 6c, 4-chloro-5-methoxypyrimidine
6d, 2-phenylthiophene 8a, 2-(thiophen-2-yl)-1,3-dioxolane
8b, thiophen-2-ylmethanol 8c, 2,5-diphenylthiophene 8d,
1-(thiophen-2-yl)ethanol 8e, benzo[b]thiophene 8f, 1-methyl-
1H-indole 8g, benzofuran 8h, 2-(furan-2-yl)-1,3-dioxolane
8i, benzo[b]thiophene 8j, 2-phenylbenzo[b]thiophene 8k, 3-
bromo-2-phenylthiophene 10a, 4-bromo-2-phenylthiophene
3 g,
1-chloroisoquinoline
3h,
4,7-dichloroquinoline
1,3-dichloroisoquinoline
3-chloroisoquinoline
3i,
2,8-
3m,
4-bromoisoquinoline
dichloroquinoline
3j,
3l,
3k,
2-chloroquinoxaline 5a, 4-chloroquinazoline 5b, 4-chloro-2,6-
dimethoxypyrimidine 5c, 2,4-dichloro-5-methoxypyrimidine
5d, 2-bromo-5-phenylthiophene 7a, 2-(5-bromothiophen-
10b,
1-methyl-1H-indole
3,6-dibromobenzo[b]thiophene 10g, 3,5-dibromobenzofuran 10h,
3-bromobenzo[b]thiophene
10c,
2,3-dibromo-
10d, 3-dibromobenzofuran
10f,
2-yl)-1,3-dioxolane
7b,
(5-bromothiophen-2-yl)methanol

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.
2.5. Analytical and spectra data of the products identical to those
reported in the literature
6,8-Methano-7,7-dimethyl-5,6,7,8-tetrahydroquinoline
2d
[19], 3-bromo-2-phenylthiophene 10a [40], methyl thiophene-
2-carboxylate 10i [41], 2-(phenylethynyl)benzo[b]thiophene
3. Results and discussion
10j
[42],
2-(4-vinylphenyl)benzo[b]thiophene
10k
[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
(1.7 equiv) in the presence of the inexpensive catalytic system
formed by Pd(OAc)2 (5 mol%) and PPh3 (20 mol%) in THF (method
A). Under these conditions the substitution of the bromine with
hydrogen in 1a was complete at room temperature in less than
30 min, giving the dehalogenated pyridine 2a in almost quantita-
tive yield (entry 1, Table 1). Similar results were also obtained with
(6-bromopyridin-2-yl)phenylmethanol 1b (entry 2, Table 1). The
more sterically hindered bromide in pyridines 1c and 1d (entries
3 and 4, Table 1) was also removed quantitatively at room tem-
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
use of PdCl2(dppf) was beneficial, allowing the pyridine 2d to be
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).

194
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 1
Hydrodehalogenation of halogenated pyridines.
Entry Halo-heterocycle Product
Methoda
Temp. (◦C)
Time (h)
0.5
Conv.b (%)
100
Yieldc (%)
1
2
Ph
Ph
A
25
95
Br
Ph
Ph
N
1a
N
2a
Br
N
N
A
25
0.5
100
95
OH
OH
2b
1b
O
O
O
O
N
3
4
A
A
25
25
1.5
100
100
95
95
Br
N
N
2c
1c
6
Br
N
1d
2d
Br
Br
5
OEt
A
B
A
C
25
25
60
25
24
24
1
30
45
100
100
nd
nd
83
95
N
N
OEt
Ph
N
2e
1e
2
Ph
6
7
C
25
1.5
100
85
N
1f
2f
A
A
D
25
60
25
48
72
6
0
30
100
–
nd
95
Cl
N
N
1g
2d
Cl
N
N
8
A
B
C
25
60
25
48
18
0.5
40
100
100
nd
85
95
OH
OH
2g
1h
Cl
Ph
N
9
D
C
25
60
48
2.5
17
100
nd
93
Ph
N
2a
1i
a
Method: A = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). B = heterocycle (0.66 mmol), Pd(OAc)2
(10.0 mol%), PPh3 (40.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). C = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv),
THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
c

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
195
Table 2
Hydrodehalogenation of halogenated quinolines and isoquinolines.
Entry
Halo-heterocycle
Product
Methoda
A
Temp. (◦C)
25
Time (h)
0.5
Conv.b (%)
100
Yieldc (%)
N
Br
N
1
95
95
3a
4a
N
Br
N
2
3
A
25
0.5
100
3b
4b
Br
N
C
25
25
48
33
nd
86
N
3c
4a
4a
D
1
100
N
Cl
N
4
C
25
25
48
2
31
nd
87
3d
D
100
Cl
N
N
5
6
D
25
6
100
95
3e
4b
OH
OH
Cl
N
N
A
25
24
40
nd
3f
4c
A
C
60
25
24
3
100
100
65
92
Cl
N
N
7
8
D
C
25
25
2
3
100
100
95
95
4b
3g
N
N
N
Cl
4d
4d
3h
Cl
N
N
9
D
60
60
36
8
100
100
43
82
3i
Dd
Br
10
D
25
1
100
91
N
4d
3j
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
10 mol% PdCl2(dppf) was used.
c
d

196
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 3
Hydrodehalogenation of halogenated pyrazines and and pyrimidines.
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (◦C)
Yieldc (%)
N
N
N
1
A
C
25
25
1
1
100
100
72
52
Cl
N
5a
6a
Cl
N
N
2
C
D
25
25
7
1
100
100
51
58
N
N
6b
5b
OMe
N
OMe
N
3
D
25
7
100
92
OMe
Cl
N
OMe
N
6c
5c
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
c
Hydrodehalogenation of reactive bromides was efficiently per-
formed by Pd(OAc)2-PPh3, whereas PdCl2(dppf) was necessary for
chlorides and bromides in unactivated positions of the hetero-
cycle ring. For the hydrodehalogenation of 1-chloroisoquinoline
method C was required, notwithstanding the chlorine is located
in the very reactive 1-position of the isoquinoline ring (entry 8,
Table 2). The removal of the 3-chlorine from 3-chloroisoquinoline
3i was more problematic even when the reaction was carried out
at 60 ◦C under method D (entry 9, Table 2), but by doubling the
amount of PdCl2(dppf) (10 mol%) a good yield (82%) was obtained.
On the other hand, the 4-bromide in isoquinoline 3j was smoothly
reduced by method D (entry 11, Table 2).
heterocycleswas examined (Table 4). The simple catalyst Pd(OAc)2-
PPh3 was enough reactive to promote the selective removal in
fairly good yield (68%) of the 2-bromine substituent in pyridines
1j, leaving unchanged the bromine in the 5-position (entry 1,
Table 4). 4,7-Dichloroquinoline3k was completely converted under
PdCl2(dppf) catalysis (method D) after 6 h at room temperature,
giving the 7-chloroquinoline as the sole product in 95% yield
(entry 2, Table 4). It should be noted that this result is the
best one among the several methods pursued for this goal [6].
Method D was also able to reduce selectively the 2-chlorine in
2,8-dichloroquinoline 3l, but in this case the yield of the formed
8-dichloroquinoline 4f was lower (75%) (entry 3, Table 4). More
problematic was the regioselective hydrodechlorination of 1,3-
dichloroisoquinoline 3m. Method A after 11 h reacting afforded
the selective removal of the 1-chlorine, but 3-chlororoisoquinoline
3i was isolated in moderate yield (53%). More profitable was
the use of PdCl2(dppf) (method C) by which 3i was formed in
71% yield with 9% of isoquinoline. The hydrodehalogenation of
2,4-dichloro-5-methoxypyrimidine gave a complex mixture from
which 4-chloro-5-methoxypyrimidine was isolated in only 32%
yield (entry 5, Table 4).
3.3. Hydrodehalogenation of halogenated pyrazines and
pyrimidines
Our protocol was next examined for the hydrodehalogenation of
6-membered heterocycles with two nitrogens (Table 3). Since the
reactivity of the 2-chlorine in quinoxaline 5a is expected to be supe-
rior to that of the quinoline [6,46] (entry 4, Table 2), the reduction
of 2-chloroquinoxaline was initially performed with method A at
room temperature. Under these reaction conditions dechlorination
occurred within 1 h, affording quinoxaline 6a in 72% yield (entry
1, Table 3). An attempt to increase the yield by using PdCl2(dppf)
(5 mol%) as the catalyst was unsuccessful giving 6a in lower yield
(52%). The 4-chlorine in 4-chloroquinazoline 5b resulted less reac-
tive than that in 5a, requiring method D to be removed at the
same reaction rate and more with a lower yield (58%) (entry 2,
Table 3). On the other hand, hydrodechlorination of 4-chloro-
2,6-dimethoxypyrimidine under method D occurred in high yield
(92%), but with a longer reaction time (entry 3, Table 3).
3.5. Chemoselective hydrodehalogenation of halogenated
pyridines
Next, the chemoselective reduction of a variety of functional-
ized halogenated pyridines was investigated. The reducing system
showed high functional group tolerance, e.g., nitrile, amide, ester,
alkyne and alkene substituents (Table 5). It should be noted
than when (Z)-2-bromo-3-styrylpyridine 1p was submitted to
hydrodebromination using Pd(OAc)2-PPh3 (5% and 20%, respec-
tively) and NaBH4 (3.4 equiv) and TMEDA (3.4 equiv) (method E),
the reduction of the 2-bromine occurred smoothly, but afforded
in 84% overall yield a 3:1 mixture of two isomeric alkenes, (Z)-
3.4. Regioselective hydrodehalogenation of halogenated
six-membered heterocycles with one or two heteroatoms
On the basis of the above results, the regioselective hydrode-
halogenation of a number of six- membered polyhalogenated
and (E)-3-styrylpyridine, by partial stereoinversion of the C
bond (entry 6, Table 5). The removal of a bromo atom from a
C

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
197
Table 4
Regioselective hydrodehalogenation of halogenated six-membered heterocycles with one or two heteroatoms.
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b
100
Yieldc (%)
Me
Me
Br
Br
1
A
25
0.5
68
N
2h
N
1j
Br
Cl
2
3
D
D
25
25
6
6
100
100
95
75
Cl
N
Cl
N
4e
3k
Cl
Cl
N
N
Cl
Cl
3l
4f
Cl
N
N
4
A
C
25
25
11
2.5
100
100
53
71d
Cl
3m
3i
MeO
Cl
MeO
Cl
N
N
5
D
25
3
100
32
Cl
N
N
5d
6d
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
Isoquinoline (9% yield) was also isolated
c
d
pyridine containing a ketonic carbonyl group was also examined,
notwithstanding the known ability of NaBH4 to reduce the carbonyl
functionality. Surprisingly, the reaction of (6-bromopyridin-2-
yl)(phenyl)methanone 1q under method A gave, by chemoselective
removal of the 2-bromine, phenyl(pyridin-2-yl)methanone 2o in
74% yield (entry 7, Table 5). A similar result was also obtained in
the reduction of the analogue 1-(6-bromopyridin-2-yl)ethanone 1r
(entry 8, Table 5). In both cases, a variable amount (5-20%) of alco-
hols resulting from the reduction of the carbonyl moiety of either
the starting material and the debrominated starting material was
detected by 1H NMR. Thus, when a large excess of NaBH4 (3.4 equiv)
was added to the solution containing the crude phenyl(pyridin-2-
yl)methanone 2o, formed by initial reduction of 1q under method
A (entry 7, Table 5), (phenyl(pyridin-2-yl)methanol was isolated
in 84% yield after a further 2 h reaction time. Thus, this method
appears to allow the one pot consecutive hydrodebromination and
reduction of a pyridine ring containing a bromine and ketonic
carbonyl group. Encouraged by these results, the hydrodehalo-
genation of a bromopyridine containing the very reactive formyl
moiety was also examined. Unfortunately, when 2-bromopyridine-
3-carboxaledehyde 1s was reacted under method A, the reduction
of the carbonyl group to the related alcohol occurred rather than
the removal of the bromine from the pyridine ring (entry 9,
Table 5).
3.6. Hydrodehalogenation of halogenated five-membered
heterocycles with one heteroatom
The good results obtained in the hydrodehalogenation of halo-
genated 6-membered heterocycles prompted us to verify the
potential of this system for the removal of halogens in less reac-
tive heterocycles [6,46] as heteropentalenes with one or more
heteroatoms (Table 6). To assess the reactivity of this kind of hete-
rocycles the hydrodehalogenation of 2-bromo-5-phenylthiophene
7a was examined. Initial experiments were performed at room
temperature with Pd(OAc)2 (5 mol%) and PPh3 (20 mol%) as the
catalytic system and an excess of the couple NaBH4-TMEDA
(1.7 equiv) in THF (entry 1, Table 6). Under these reaction conditions
the substitution of the bromine with hydrogen was incomplete
after 24 h. However, by doubling the amount of NaBH4-TMEDA
(3.4 equiv) (method E) complete conversion was achieved after
2 h and the product, 2-phenylthiophene 8a, was isolated in 94%
yield. Also when PdCl2(dppf) (5 mol%) was used as the catalyst in
combination with 1.7 equiv of the reducing system, incomplete
conversion occurred after 24 h, but by using 3.4 equiv NaBH4-
TMEDA (method D) the reaction was complete in 1 h and 8a
was formed in 92% yield. Similarly, the 2-bromo substitute thio-
phenes 7b and 7c were efficiently hydrodehalogenated under
method D. The known lower reactivity of the ␤-bromine in

198
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 5
Chemoselective hydrodehalogenation of halogenated pyridines.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (%)
Yieldc (%)
CN
CN
1
A
B
B
C
25
25
60
25
48
48
72
6
0
0
30
100
nd
95
Br
N
N
1k
2i
Cl
N
CN
2
3
D
25
2
100
95
N
CN
2j
1l
Br
NHCOCH3
COOMe
N
NHCOCH3
A
A
C
25
60
25
24
1
2
35
100
100
nd
85
95
N
2k
1m
COOMe
Ph
Cl
4
5
A
C
25
25
8
2
100
100
61
62
N
N
N
1n
2l
Ph
A
C
D
25
24
25
24
48
5
55
60
100
nd
nd
82
Br
N
2m
1o
Ph
Ph
Ph
6
E
25
25
3
100
100
84d
Br
N
N
N
2n2 (25%)e
2n1(75%)e
1p
Ph
Ph
Br
N
N
7
8
A
5
7
75
O
O
2o
1q
Br
N
N
A
A
25
25
100
100
74
0
O
O
N
2p
1r
CHO
CHO
9
2
.5
Br
N
2q
1s
a
Method: A = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). B = heterocycle (0.66 mmol), Pd(OAc)2
(10.0 mol%), PPh3 (40.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). C = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv),
THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%),
PPh3 (20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
c
Isolated yields after flash chromatography.
d
Isolated yields of 2n1 (18%) and 2n2 (66%).
eDetermined by 1H NMR of the crude reaction mixture.

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
199
Table 6
Hydrodehalogenation of halogenated five-membered heterocycles with one heteroatom.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (◦C)
Yieldc (%)
Br
Ph
Ph
S
7a
S
8a
1
A
E
C
D
25
25
25
25
24
6
24
1
60
100
66
nd
94
nd
92
100
O
O
Br
Br
S
S
2
3
E
D
25
25
24
20
83
100
nd
87
O
O
7b
8b
HO
HO
S
S
D
25
10
48
100
85
7c
8c
Br
Ph
S
Ph
4
E
D
25
25
24
100
nd
94
S
8a
7d
Br
HO
HO
S
5
D
25
2
7
100
95
S
8c
7e
Br
Ph
Ph
Ph
S
8d
6
D
D
25
65
24
2
64
100
nd
91
Ph
S
7f
Br
OH
CH3
OH
CH3
S
7
D
D
D
25
65
65
20
20
20
20
100
100
nd
74
S
8e
86d
7g
8
E
D
25
25
3
0.5
100
100
92
95
Br
Br
S
7h
S
8f
9
N
Me
N
Me
E
D
25
25
12
0.8
100
100
85
87
7i
8g

200
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 6 (Continued)
Entry
10
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
0.7
Conv.b (◦C)
Yieldc (%)
Br
D
25
100
89
O
O
7j
8h
O
O
Br
O
O
11
A
D
25
25
24
0.2
55
100
0
0
O
O
7k
8i
Br
l2
E
E
D
D
25
65
25
65
84
23
24
3
60
nd
73
85
82
S
S
100
100
100
8j
7l
Br
Ph
Ph
l3
D
D
25
65
48
10
16
100
nd
95
S
S
8k
7m
Br
N
Me
l4
D
25
19
100
93
N
Me
8g
7n
Br
l5
D
E
25
25
6
22
100
100
64
51
O
O
8h
7o
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
Reaction carried out in acetonitrile.
c
d
thiophene was evident since PdCl2(dppf) was necessary to remove
this halide from the thiophene 7d (entry 4, Table 6). Method D
was also able to remove the bromine from the sterically hin-
dered 3-bromo substituted thiophenes 7f and 7g (entries 6 and
7, Table 6), but in these cases the reactions needed to be car-
ried out at 65 ◦C. Interestingly, with the polar thiophene 7g a
better result was obtained when the reaction was carried out in
acetonitrile instead of THF (86% versus 74% yield). The removal
of the 2-bromine of benzothiophene 7h, 1-methylindole 7i and
benzofuran 7j was performed efficiently (85–95 yields) with
both methods E and D, with the second one affording a very
short reaction time. The reduction of the furane derivative 7k
failed to give the expected debrominated compound 8i (entry
11, Table 6), and an intractable reaction mixture was instead
formed.
The reduction of the 3-bromobenzothiophene 7l, was per-
formed efficiently with method D at room temperature, though
a shorter reaction time was obtained in similar yield by carrying
out the reaction at 65 ◦C. Heating and PdCl2(dppf) were instead
imperative to remove the sterically hindered ␤-bromine in ben-
zothiophene 7m (entry 13, Table 6).
Finally, the reduction of the 3-bromo derivatives of 1-
methylindole 7n and benzofuran 7o was performed efficiently with
method D, affording the parent heterocycles in 93% and 64% yields,
respectively.
The removal of the chlorine from a thiophene and benzoth-
iophene rings was also addressed. Initially, the reduction of
2-chloro-5-phenylthiophene 7p was examined since this goal
had been achieved only in some well-defined cases [2b,48].
After several experiments with different catalytic systems we

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
201
Table 7
Hydrodechlorination of 2-chloro-5-phenylthiophene.a
NaBH4, TMEDA
Pd-catalyst, THF
Cl
Ph
Ph
S
S
8i
7p
.
Entry
Catalyst (mol%)a
Temp. (◦C)
rt
Time (h)
48
Conv.b (P/S)
Yieldc (%)
nd
1
2
3
4
5
6
7
8
9
PdCl2(dppf) (5)
30
/70
PdCl2(dppf) (5)
65
65
rt
48
24
48
8
35
/65
Nd
85
Nd
96
78
Nd
PdCl2(dppf) (10)
100
/0
PdCl2(tbpf) (5)
32
/68
PdCl2(tbpf) (5)
65
65
rt
100
/0
Pd2(dba)3/tbpf (2.5/5)
(A.caPhos)PdCl2 (5)d
Pd2(dba)3/DavePhos (2.5/5)e rt
Pd2(dba)3/P(f-Bu)3 (2.5/10) rt
24
48
100
/0
12
/88
48
48
62
/38
nd
nd
56
/44
a
b
c
Reaction conditions: heterocycle (0.66 mmol), catalyst, NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
Determined by 1H NMR as product/starting compound ratio.
Isolated yields.
d
e
(A.caPhos)PdCl2: bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine] palladium(II) chloride.
DavePhos: 2-dicyclohexylphosphino-2ꢀ-(N,N-dimethylamino) biphenyl.
found that the hydrodehalogenation of 7p was more efficiently
obtained by using 5 mol% PdCl2(tbpf) [tbpf = 1,1’-bis(di-tert-
butylphosphino)ferrocene] at 65 ◦C for 8 h (96% yield) (entry 5,
Table 7). On the other hand, the removal of the chlorine from
3-chlorobenzothiophene 7q under these and other reaction con-
ditions failed (Table 8). The very low reactivity of this heteroaryl
chloride is demonstrated by the fact that only very recently has
been discovered that the combination of Pd(OAc)2 and XPhos
(2-dicyclohexylphosphanyl-2ꢀ,4ꢀ,6ꢀ-triisopropylbiphenyl) was able
to catalyze the Suzuki–Miyaura coupling of this substrate.[48]
Inspired by this results we assessed this catalyst for our purpose.
Unfortunately, also in this case no reaction occurred.
1.7 equiv of NaBH4-TMEDA gave only partial conversion, whereas
by increasing the amount of the reducing system to 3.4 equiv total
conversion of the starting material was achieved after 45 minutes,
affording however a mixture of 3-Br-benzofuran 10f (56%) and
benzofuran (31%). On the other hand, the monobromo deriva-
tive 10f, containing only traces of benzofuran, was obtained in
77% yield, by using 2.5 equiv of NaBH4-TMEDA. Thanks to the
results obtained in the reduction of 9c and 9f, the regioselective
hydrodebromination of their tribromoderivative analogues, 2,3,6-
tribromobenzo[b]thiophene 9g and 2,3,5-tribromobenzofuran 9h,
was also examined. However, the regioselective reduction of
these substrates was disappointing. Thus, with compound 9g the
best result of 3,6-dibromobenzo[b]thiophene 10g (52% yield) was
achieved under method C, though the conversion was only 77%.
Increasing the amount of NaBH4-TMEDA to 2.5 equiv, total conver-
sion was obtained after 1 h, but with a reduced yield of 10g (41%).
Still less selective was the reduction of 9h that under the above
reaction conditions afforded a mixture of products (determined by
1H NMR) containing only 44% of 10h.
3.7. Regioselective hydrodehalogenation of halogenated
five-membered heterocycles with one heteroatom
On the basis of the above results, the regioselective hydrode-
halogenation of some polyhalogenated heteropentalenes was
examined (Table 9). The simple catalyst Pd(OAc)2-PPh3 (5% and
20%, respectively) was reactive enough to promote the selective
removal with high yield of the 2-bromo substituent in dibromi-
nated thiophenes 9a and 9b, benzothiophene 9c, N-methylindole
9d and N-methoxycarbonyl indole 9e, leaving unchanged the
bromine in the other positions (entries 1–5, Table 9). Interest-
ingly, by conducing the reduction of 9c under PdCl2(dppf) catalysis
(method D) the same yield than with method E was obtained, but
with the reaction times reduced to 50 min. The reduction of 2,3-
dibromobenzofuran was more complicated. Thus, PdCl2(dppf) and
3.8. Chemoselective hydrodehalogenation of halogenated
five-membered heterocycles
Next, the chemoselective reduction of some haloheteropental-
enes was investigated. The results described in Table 10 show that
the reducing system has high functional group tolerance, e.g., ester,
alkyne, alkene and nitrile substituents (entries 1–5, Table 10).

202
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 8
Hydrodechlorination of 3-chlorobenzo[b]thiophene.a
Cl
NaBH4, TMEDA
Pd-catalyst, THF
S
S
8j
7q
.
Entry
1
Catalyst (mol%)a
PdCl2(dppf) (5)
Temp. (◦C)
rt
Time (h)
48
Conv.b (P/S)
Yieldc (%)
nd
30
/70
2
3
4
5
6
7
8
9
PdCl2(dppf) (5)
65
65
rt
48
24
48
8
35
/65
nd
85
nd
96
78
Nd
PdCl2(dppf) (10)
100
/0
PdCl2(tbpf) (5)
32
/68
PdCl2(tbpf) (5)
65
65
rt
100
/0
Pd2(dba)3/tbpf (2.5/5)
(A.caPhos)PdCl2 (5)d
Pd2(dba)3/DavePhos (2.5/5)e rt
Pd2(dba)3/P(f-Bu)3 (2.5/10) rt
24
48
100
/0
12
/88
48
48
62
/38
nd
nd
56
/44
a
Reaction conditions: heterocycle (0.66 mmol), catalyst, NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
Determined by 1H NMR as product/starting compound ratio.
Isolated yields.
(A.caPhos)PdCl2: bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine] palladium(II) chloride.
DavePhos: 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)-biphenyl
b
c
d
e
3.9. Hydrodehalogenation of halogenated five-membered
benzo[d]oxazole 12h and 3,5-dimethylisoxazole 12i, respectively,
heterocycles with two heteroatoms
was not detected (entries 13 and 14, Table 11).
In the series of the heteropentalenes with two heteroatoms, 2-
bromo-4-phenylthiazole 11a was hydrodehalogenated efficiently
by method E (entry 1, Table 11). Methods E and D were also
successful in the reduction of the low reactive 2-chlorine in the
thiazole 11b, but failed to remove the 5-chlorine from the thi-
azole 11c. On the other hand, this goal was efficiently achieved
by the complex PdCl2(tbpf) that required in any case the heat-
ing at 65 ◦C to afford complete conversion (entry 3, Table 11,
method F). Method D resulted efficient in the removal of the
5- and 4-bromine from thiazoles 11d and 11e, but resulted
relatively inactive in the reduction of 2-bromobenzo[d]thiazole
11f at room temperature. In this case the use of method E
resulted more profitable. Unexpectedly, the removal of the chlorine
in 2-chlorobenzo[d]thiazole 11 g was more effectively obtained
with method D (entry 7, Table 11). The bromine in imidaz-
ole derivatives 11h and 11i was obtained by Pd(OAc)2-PPh3,
whereas PdCl2(dppf) was necessary to dechlorinate 2-chloro-1-
(4-fluorobenzyl)-1H-benzo[d]imidazole 11k (entry 11, Table 11).
3-Bromoimidazo[1,2-a]pyridine 11j was quickly reduced by
the simple method A. 3-Bromo-1-methyl-1H-indazole 11l was
debrominated with both methods E and D, but the latter was more
performing (entry 12, Table 11). Finally, in the reduction of 2-
chlorobenzo[d]oxazole 11m and 4-bromo-3,5-dimethylisoxazole
11n, the disappearance of the starting material was observed
after a short reaction time, but the formation of the expected
3.10. Regioselective hydrodehalogenation of halogenated
five-membered heterocycles with two heteroatoms
The regioselective hydrodehalogenation of two polyhalo-
genated heteropentalenes with two heteroatoms, namely thiazoles
and imidazoles, was studied (Table 12). The removal of the
2-chlorine from the dichlorinated heterocycles, 2-chloro-4-(4-
chlorophenyl)thiazole 11o and 2,5-dichlorobenzo[d]thiazole 11p
was possible with method D, although method E gave higher yield
with the substrate 11p (entries 1 and 2, Table 12).
The simple catalyst Pd(OAc)2-PPh3 (method E) was reactive
enough to promote the selective removal with high yield of the 5-
bromine substituent in 4,5-dibromo-2-phenylthiazole 11q (entry
3, Table 12). On the other hand, the hydrodebromination of 2,5-
dibromo-4-phenylthiazole 11r was less satisfactory. With method
E a mixture of 5-bromo-4-phenylthiazole 12l and 4-phenylthiazole
12a in a 90/10 ratio was obtained. When the reaction was carried
out at 0 ◦C total conversion required 14 h and the 12l/12a ratio was
increased up to 93/7. Several attempts to improve the selectivity
by using different catalytic systems failed. Thus, for instance, the
use of both Pd2(dba)3 (2.5 mol%) and Pd(OAc)2 (5 mol%) in combi-
nation with XantPhos (5 mol%) at 25 ◦C gave a mixture of 12l and
12a in high yield, but with a ratio of only 86/14. A similar result was
obtained by carrying the reaction at 0 ◦C.

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
203
Table 9
Regioselective hydrodehalogenation of halogenated five-membered heterocycles with one heteroatom.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (%)
Yleldc (%)
Br
Br
1
E
25
2
100
89
Br
Br
Ph
S
Ph
S
9a
10a
Br
Br
Br
Br
2
3
E
25
2
100
86
Ph
Ph
S
S
10b
9b
Br
A
C
25
25
4
0.5
100
100
85
85
Br
Br
S
10c
S
9c
Br
4
N
Me
10d
E
C
D
25
25
25
18
0.8
100
55
100
79
N
nd
Me
79e
9d
Br
Br
Br
5
E
25
6
100
85
N
N
COOMe
COOMe
10e
9e
Br
Br
6
7
C
25
25
25
24d
0.7
3
63
100
100
nd
Br
O
O
10f
D
87f
77h
Cg
9f
Br
Br
Br
Br
Br
Br
Ag
B
25
25
25
25
24
5
24
1
20
100
71
nd
31
52i
41
Br
S
S
C
10g
9g
Cg
100
Br
Br
8
Ch
25
1
100
84
Br
j
O
O
9h
10h
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
No further conversion was observed after this time.
Mixture of 3-Br (48%) and 1-methylindole (31%).
Mixture of 3-Br (56%) and benzofuran (31%).
2.5 equiv of NaBH4 and TMEDA were used.
Traces of benzofuran were observed.
c
d
e
f
g
h
i
Yield based on the converted starting material.
j
Mixture of products (determined by 1H NMR) isolated after flash chromatography containing 44% of 10 h.

204
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 10
Chemoselective hydrodehalogenation of halogenated five-membered heterocycles.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
25
Time (h)
3
Conv.b (%)
100
Yieldc (%)
88
Br
MeO2C
S
MeO2C
S
1
E
9i
10i
Br
2
3
D
D
25
25
5
9
100
100
95
91
S
S
9j
Ph
Ph
10j
Br
S
S
10k
9k
Br
CN
CN
S
4
D
25
22
100
85
S
10l
9l
NC
Br
NC
5
E
D
D
25
25
60
24
24
1.5
70/30d
50/50d
10
Nd
nd
42
S
S
10m
9m
a
Method: D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3
(20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
Ratio 9m/10m.
c
d
The selective removal of one of the two bromines in the reduc-
tion of 1-benzyl-4,5-dibromo-1H-imidazole 11s was practically
impossible to achieve with this system despite a number of per-
mutations of conditions have been pursued. By performing the
reduction of 11s with both Pd(OAc)2-PPh3 and PdCl2(dppf) in
combination of 3.4 equiv NaBH4-TMEDA, a mixture of the mono-
bromide 11i and completely debrominated imidazole 12d was
recovered in a 3/1 ratio. When the amount of the reducing sys-
tem was reduced to 1.7 and then to 1.1 under PdCl2(dppf) catalysis,
the conversion of the starting material was uncompleted, but the
11i/12d ratio remained practically unchanged (2.9/1 ÷ 2.7/1)), indi-
cating that the formation of 12d is independent from the conversion
11s into 11i.
3.11. Chemoselective hydrodehalogenation of halogenated
five-membered heterocycles with two heteroatoms
In this circumstance, the selective removal of the bromine
versus chlorine from thiazoles 13a and 13b was examined
(Table 13). The reduction of 2-bromo-5-chloro-4-phenylthiazole
13a occurred smoothly and the 2-bromine was removed selectively
to give 5-chloro-4-phenylthiazole 11c in 79% yield. The chemose-
lectivity in this case is due to two factors working cooperatively,
namely the greater reactivity of the C–Br bond with respect the
C–Cl bond (see for instance entry 1 versus 2 in Table 11) and the
higher reactivity of the 2-position compared to the 5-position of
the thiazole ring toward the metal insertion into C-halogen bonds
(see for instance entries 1 and 2 versus 4 and 5 in Table 11). Such
a situation is to be found in the hydrodehalogenation of 4-bromo-
5-chloro-2-phenylthiazole 13b in which the 4-position appears to
be favoured for both of the above reasons (see for instance entry 4
versus 5 in Table 11). However, the reduction of 13b failed unex-
pectedly under the reaction conditions (method D) that allowed
the removal of the 4- and 5-bromine in thiazoles 11c and 11d
(Table 11). By carrying out the reduction at 60 ◦C partial conver-
sion of 13b was observed, but none of the expected products was
detected. The use of PdCl2(tbpf) that removes efficiently the 5-
chlorine in 5-chloro-4-phenylthiazole 11c (entry 3, Table 11) was
also unsuccessful.
Finally, the hydrodebromination of the more demanding
1-benzyl-2,4,5-tribromoimidazole 11s was examined. Method
E
at room temperature gave a mixture of 1-benzyl-4,5-
dibromoimidazole 11r and 1-benzyl-4-bromoimidazole 11i in a
63/37 ratio, containing also traces (<5%) of 1-benzylimidazole.
Reducing the number of equivalents of the reductant from 3.4 to 2.5
increased only slightly the selectivity (11s/11i = 76/24), whereas a
further decrease to 1.7 equiv gave only partial conversion of the
starting material after 72 h. After a series of optimization exper-
iments, the combination of Pd2(dba)3 (2.5 mol%) and XantPhos
(5 mol%) 3.4 equiv of NaBH4-TMEDA at 0 ◦C (method L) was found
to produce with good yield 11s and 11i in a 87/13 ratio.

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
205
Table 11
Hydrodehalogenation of halogenated five-membered heterocycles with two heteroatoms.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv. b (%)
Yieldc (%)
Ph
Ph
N
N
S
Br
Cl
1
A
E
25
25
48
3
81
100
nd
95
S
11a
12a
Ph
Ph
N
N
2
3
E
D
D
25
25
60
21
20
6
100
100
100
85
93
85
S
S
11b
12a
Ph
Ph
N
N
S
12a
D
D
F
25
65
25
65
24
24
72
20
0
nd
nd
nd
95
S
Cl
11c
20
40
100
F
N
N
S
12b
Ph
Ph
Ph
4
5
E
D
25
25
56
24
100
100
93
94
S
Br
11d
Br
N
S
N
Ph
E
D
25
25
96
30
80
100
nd
95
S
12b
11e
N
N
Br
Cl
6
7
E
D
D
25
25
60
1.5
72
24
100
65
100
92
nd
68
S
11f
S
12c
N
N
S
E
D
D
25
25
60
4
21
6
100
100
100
51
75
55
S
11g
12c
N
N
Br
N
N
8
E
25
1.5
100
95
Ph
Ph
Ph
11h
12d
N
N
N
Br
N
9
E
D
25
25
15
41
100
100
41
65
Ph
11i
12d

206
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 11 (Continued )
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv. b (%)
Yieldc (%)
N
N
Br
10
A
25
2
100
83
N
N
11j
12e
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (%)
Yieldc (%)
Cl
N
N
N
N
11
E
D
25
25
22
22
30
100
nd
95
F
F
12f
11k
Br
N
N
N
12
E
D
25
25
7
3.5
100
100
72
92
N
Me
Me
12g
12h
11l
N
O
N
O
11m
Cl
13
C
A
25
25
1
100
100
0
0
CH3
CH3
Br
N
N
14
0
.3
O
O
H3C
H3C
11n
12i
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). F = heterocycle (0.66 mmol), PdCl2(tbpf) (5.0 mol%),
NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
c
Table 12
Regioselective n of halogenated five-membered heterocycles with two heteroatoms.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (h)
25
Time (h)
22
Conv.b (◦C)
Yieldc (%)
Cl
Cl
N
N
1
D
100
91
Cl
11o
12j
S
S
S
S
Cl
2
A
E
D
25
25
25
24
1.5
16
87
100
100
nd
95
87
N
N
Cl
Cl
11p
12k

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
207
Table 12 (Continued)
Entry
Halo-heterocycle
Product
Methoda
Temp. (h)
25
Time (h)
16
Conv.b (◦C)
Yieldc (%)
Br
Br
Br
N
N
S
Ph
Ph
Ph
3
S
E
100
88
11e
11q
Ph
Br
Ph
Br
N
S
N
N
Br
0/90/10d
0/93/7d
88e
90e
87e
nd
S
4
5
6
S
E
E
G
H
H
25
0
25
25
0
4.5
14
2.3
2.3
7
0/86/14d
0/86/14d
0/83/17d
11r
12l
12a
nd
Br
Br
N
N
N
Br
N
CH2Ph
N
N
E
I
D
C
J
25
0
25
25
25
12
48
2
72
72
0:75/25f
53/31/16f
0:75/25f
18/61/21f
78/16/6f
87g
nd
CH2Ph
CH2Ph
93g
nd
11s
11i
12d
nd
Br
Br
Br
Br
N
N
N
Br
CH2Ph
11t
Br
N
N
CH2Ph
N
E
I
A
E
I
E
C
D
C
D
D
K
L
25
25
25
0
1.5
3.5
72
2
10
48
16
0.75
16
0.75
2
0/63/37h
0/76/24h
23/64/13h
0/81/19h
9/70/21h
7/76/17h
24/62/14h
0/78/22h
24/62/14h
0/78/22h
0/55/45h
0/53/47h
0/87/13h
40/50/10h
nd
nd
nd
nd
nd
nd
nd
87i
nd
87i
nd
nd
83i
nd
CH2Ph
11s
11i
0
23
25
25
25
25
0
25
0
0
0.5
3
48
M
a
Method:A = heterocycle(0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (1.7 equiv), TMEDA(1.7 equiv), THF(13.2 mL). C = heterocycle(0.66 mmol), PdCl2(dppf)
(5.0 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3 (20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). G: heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%),
XantPhos (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). H: heterocycle (0.66 mmol), Pd2(dba)3 (2.5 mol%), XantPhos (5 mol%), NaBH4 (3.4 equiv), TMEDA
(3.4 equiv), THF (13.2 mL). J = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (1.1 equiv), TMEDA (1.1 equiv), THF (13.2 mL). K: heterocycle (0.66 mmol), PdCl2(binap)
(5 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). L: heterocycle (0.66 mmol), Pd2(dba)3 (2.5 mol%), XantPhos (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv),
THF (13.2 mL). M: heterocycle (0.66 mmol), Pd2(dba)3 (2.5 mol%), XantPhos (5 mol%), NaBH4 (1.7 equiv), TMEDA (1.7 equiv), THF (13 equiv).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
Ratio 11r/12l/12a.
Combined yield of 12l and 12a.
Ratio 11s/11i/12d.
Combined yield of 11i and 12d.
Ratio 11t/11s/11i.
Combined yield of 11s and 11i.
c
d
e
f
g
h
i
Table 13
Chemoselective hydrodehalogenation of halogenated five-membered heterocycles with two heteroatoms.a
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (%)
Yieldc (%)
Ph
N
Ph
N
1
E
25
9
100
79
Br
Cl
Cl
S
S
13a
11c

208
G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
Table 13 (Continued)
Entry
Halo-heterocycle
Product
Methoda
Temp. (◦C)
Time (h)
Conv.b (%)
Yieldc (%)
Br
Cl
N
Br(H)
Cl(H)
N
S
Ph
Ph
2
D
D
F
25
60
25
24
24
24
0
26
0
0
0
0
S
13b
a
Method: D = heterocycle (0.66 mmol), PdCl2(dppf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). E = heterocycle (0.66 mmol), Pd(OAc)2 (5.0 mol%), PPh3
(20.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). F = heterocycle (0.66 mmol), PdCl2(tbpf) (5.0 mol%), NaBH4 (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
c
3.12. Mechanism considerations
References
[1] S.S. Capracotta, D.L. Comins, Tetrahedron Lett. 50 (2009) 1806–1808.
[2] (a) R. Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press,
Oxford Elservier Science, 1979, pp. 255;
(b) B. Liégault, I. Petrov, S.I. Gorelsky, K. Fagnou, J. Org. Chem. 75 (2010)
1047–1060.
[3] G. Chelucci, S. Baldino, S. Chessa, Tetrahedron Lett. 62 (2006) 619–626.
[4] G. Chelucci, M. Marchetti, F. Soccolini, C. Botteghi, J. Heterocyclic Chem. 21
(1984) 1717–1719.
[5] (a) C.G. Hartung, V. Snieckus, in: D. Astruc (Ed.), Modern Arene Chemistry,
Wiley–VCH, Germany, Weinheim, 2002, pp. 330–367;
(b) V. Snieckus, Chem. Rev. 90 (1990) 879–933;
(c) F.F. Wagner, D.L. Comins, Eur. J. Org. Chem. (2006) 3562–3565.
[6] G. Chelucci, S. Baldino, G.A. Pinna, G. Pinna, Curr. Org. Chem. 16 (2012)
2921–2945.
[7] (a) F. Alonso, I.P. Beletskaya, M. Yus, Chem. Rev. 102 (2002) 4009–4091;
(b) F.J. Urbano, J.M. Marinas, J. Mol. Catal. A: Chem. 173 (2001) 329–345;
(c) A.R. Pinder, Synthesis (1980) 425–452.
[8] P.P. Cellier, J.F. Spindler, M. Taillefer, H.J. Cristau, Tetrahedron Lett. 44 (2003)
7191–7195.
[9] N. Hirasawa, Y. Takahashi, E. Fukuda, O. Sugimoto, K. Tanji, Tetrahedon Lett. 49
(2008) 1492–1494.
[10] R.J. Rahim Jr., R.E. Maleczka Jr., Tetrahedon Lett. 43 (2002) 8823–9926.
[11] O. Navarro, N. Marion, Y. Oonishi, R.A. Kelly, P. Nolan, J. Org. Chem. 71 (2006)
685–692.
[12] J. Moon, S. Lee, J. Organomet. Chem. 694 (2009) 473–477.
[13] S.H. Leung, D.G. Edington, T.E. Griffith, J.J. James, Tetrahedron Lett. 40 (1999)
7189–7191.
The dehalogenation efficiency of NaBH4-TMEDA arises from
the fact that the addition of a nitrogen-base, especially TMEDA,
considerably enhances the performance of NaBH4 [16c]. On the
base of the generally accepted mechanism based on oxida-
tive addition, hydride transfer (transmetallation) and reductive
elimination, the effect of TMEDA can be three-fold: (a) weak
coordination to the electronically and coordinatively unsat-
urated intermediate in form of [Pd(ligand)(TMEDA)] thereby
stabilizing the catalyst and minimizing catalyst decomposition.
The weak donor ability of TMEDA ensures its cleavage upon
−
entry of the substrate; (b) capture of BH3 from BH4 pro-
vides an extra drive for hydride transfer to the Pd centre
(ArBr + NaBH4 + 1/2TMEDA → ArH + NaBr + 1/2TMEDA•2BH3). The
resultant TMEDA•2BH3 adduct could also serve as an addi-
tional hydride source [49]; (c) alternative debromination pathway
through the elimination of HBr.
4. Conclusions
In conclusion, the pair NaBH4-TMEDA as hydride source and
a palladium catalyst in THF prove to be an efficient system for
the hydrodehalogenation of halogenated heterocycles with one or
more heteroatoms. Since in the heterocycles the reactivity of the
C-halogen bonds varies significantly from one substrate to another,
the rates and yields of the dehalogenation depend critically on the
type of halide (Br > Cl) and on the choice of the catalyst, amount of
the pair NaBH4-TMEDA and temperature. In general, the simple and
inexpensive catalyst Pd(OAc)2-PPh3 rapidly hydrodehalogenates
reactive halo-heterocycles such as bromo-pyridines, -quinolines, -
thiophenes, -indoles, -imidazoles, etc., at room temperature in very
good yields, whereas in most cases PdCl2(dppf) reduces less reac-
tive halides such as chloro-pyridines, -quinolines, -pyrimidines and
bromo-indoles, -benzofurans, etc. Moreover, PdCl2(tbpf) shows to
be even more active removing the 2- and 5-chlorine from both
thiophene and thiazole rings, respectively, which are rather slug-
gish with other reagents. The reaction conditions tolerate various
functional groups, allowing highly chemoselective reactions in the
presence of halide, ester, alkyne, alkene and nitrile substituents.
Moreover, with a proper selection of the catalyst it is also possible
to obtain a good control in the regioselective hydrodehalogenation
of a variety of polyhalogenated substrates. The practical and selec-
tive methodology offers a very powerful, low-cost and safe way for
the hydrodehalogenation of halogenated heteroaromatics and may
constitute a key step in the synthesis of complex molecules.
[14] R. Nakao, H. Rhee, Y. Uozumi, Org. Lett. 7 (2005) 163–165.
[15] W.M. Czaplik, S. Grupe, M. Mayer, A.J. von Wangelin, Chem. Commun. 46 (2010)
6350–6351.
[16] (a) Y. Xie, B. Wu, F. Xue, S.C. Ng, T.C.W. Mak, T.S.A. Hor, Organometallics 17
(1998) 3988–3995;
(b) Y. Xie, S.C. Ng, T.S.A. Hor, H.S.O. Chan, J. Chem. Res. Synop. 3 (1996) 150–151;
(c) B. Wei, T.S.A. Hor, J. Mol. Catal. A 132 (1998) 223–229;
(d) B. Wei, S. Li, H.K. Lee, T.S.A. Hor, J. Mol. Catal. A 126 (1997) L83–L88.
[17] (a) For part of this work, see G. Chelucci, S. Baldino, A. Ruiu, J. Org. Chem. 77
(2012) 9921–9925;
(b) G. Chelucci, Tetrahedon Lett. 51 (2010) 1562–1565.
[18] L. Shukla, A.C. Spivey, J.F. Hayler, Org. Lett. 9 (2007) 891–894.
[19] M. Bella, P. Kocovsky, A.V. Malkov, V. Langer, Org. Lett. 2 (2000) 3047–3049.
[20] Y. Kondo, A. Numata, T. Sakamoto, Synthesis (1999) 306–311.
[21] M. Ballico, W. Baratta, S. Magnolia, P. Rigo, K. Siega, S. Baldino, G. Chelucci, E.
Herdtweck, Chem. Eur. J. 14 (2008) 9148–9160.
[22] W. Chen, Y. Zhang, L. Zhang, M. Wang, L. Wang, Chem. Commun. 47 (2011)
10476–10478.
[23] J.W. Dankwardt, S.G. Koenig, S.P. Singh, H. Zhao, Tetrahedron Lett. 53 (2012)
166–169.
[24] V. Bocchi, G. Palla, Synthesis (1982) 1096–1097.
[25] T. Benincori, E. Brenna, F. Sannicolò, L. Trimarco, P. Antognazza, E. Cesarotti, F.
Demartin, T. Pilati, J. Org. Chem. 61 (1996) 6244–6251.
[26] J.L. Bollige, C.M. Frech, Chem. Eur. J. 16 (2010) 4075–4081.
[27] J. Cai, A. Farha, P.B. Tsitovitch, V. Bodani, R.D. Toogood, R.S. Murphy, J. Pho-
tochem. Photobiol. A 212 (2010) 176–182.
[28] M. Hussain, D.T. Tùng, P. Langer, Synletters (2009) 1822–1826.
[29] O.R. Suárez-Castillo, L. Beiza-Granados, M. Melenéz-Rodriguez, A. Álvarez-
Hernández, M.S. Morales-Ríos, P. Joseph-Nathan, J. Nat. Prod. 69 (2006)
1596–1600.
[30] T. Bach, M. Bartels, Synthesis (2003) 925–939.
[31] T. Suzuki, Y. Ota, Y. Kasuya, H. Tsumoto, H. Nakagawa, N. Miyata, M. Mutsuga,
Y. Kawamura, M.G. Finn, Angew. Chem. 49 (2010) 6817–6820.
[32] V. Lyaskovskyy, R. Froehlich, E.U. Wuerthwein, Chem. Eur. J. 13 (2007)
3113–3119.
[33] G. Chelucci, S. Baldino, A. Ruiu, J. Org. Chem. 77 (2012) 9921–9925.
[34] H.Q. Do, O. Daugulis, Org. Lett. 11 (2009) 421–423.
[35] M.A. Clyne, F. Aldabbagh, Org. Biomol. Chem. 4 (2006) 268–277.
Acknowledgment
We are grateful to the University of Sassari for financial support.

G. Chelucci, S. Figus / Journal of Molecular Catalysis A: Chemical 393 (2014) 191–209
209
[36] M. Walter, Y. von Coburg, K. Isensee, K. Sander, H. Stark, X. Ligneau, J.C. Camelin,
J.C. Schwartz, Bioorg. Med. Chem. Lett. 20 (2010) 5879–5882.
[45] H.P. Lankelma, P.X. Sharnoff, J. Am. Chem. Soc. 53 (1931) 2654–2657.
[46] (a) J.F. Fauvarque, F. Pfleuger, M. Troupel, J. Organomet. Chem. 208 (1981)
419–427;
(b) S.T. Handy, Y.A. Zhang, Chem. Commun. (2006) 299–301.
[47] (a) J. Skramstad, Chem. Scr. 7 (1975) 42–48;
(b) P. Stanetty, E. Puschautz, G. Friedbaeher, Monatsh. Chem. 120 (1989) 53–63.
[48] J. Yang, S. Liu, J.-F. Zheng, J. Zhou &LPKT;Steve&RPKT;, Eur. J. Org. Chem. (2012)
6248–6259.
[37] B. Iddon, N. Khan, J. Chem. Soc., Perkin Trans. 1 (1987) 1445–1452.
[38] B. Iddon, N. Khan, B.L. Lim, J. Chem. Soc., Perkin Trans. 1 (1987) 1437–1443.
[39] M. Begtrup, L.B.L. Hansen, Acta Chem. Scand. 46 (1992) 372–383.
[40] R. Pereira, B. Iglesias, A.R. de Lera, Tetrahedron 57 (2001) 7871–7881.
[41] N. Mori, H. Togo, Tetrahedron 61 (2005) 5915–5925.
[42] A.R. Katritzky, A.A.A. Abdel-Fattah, M. Wane, J. Org. Chem. 67 (2002) 7526.
[43] B. Iddon, N. Khan, B.L. Lim, Chem. Commun. (1985) 1428–1429.
[44] R. Salvio, R. Cacciapaglia, L. Mandolini, J. Org. Chem. 76 (2011) 5438–5443.
[49] B.H. Lipshutz, T. Tomioka, S.S. Pfeiffer, Tetrahedron Lett. 42 (2001)
7737–7740.