A general palladium-catalyzed method for alkylation of heteroarenes using secondary and tertiary alkyl halides

Article abstract of DOI:10.1002/anie.201408355

A general alkylation of heterocycles using a simple palladium catalyst is reported. Most classes of heterocycles, including indoles and pyridines, efficiently coupled with unactivated secondary and tertiary alkyl halides. An alkyl radical addition to neutral heteroarenes is most likely involved.

Full text of DOI:10.1002/anie.201408355

Angewandte
Chemie
DOI: 10.1002/anie.201408355
Heterocycles
A General Palladium-Catalyzed Method for Alkylation of
Heteroarenes Using Secondary and Tertiary Alkyl Halides**
Xiaojin Wu, Jessica Wei Ting See, Kai Xu, Hajime Hirao, Julien Roger, Jean-Cyrille Hierso, and
Jianrong (Steve) Zhou*
Abstract: A general alkylation of heterocycles using a simple
palladium catalyst is reported. Most classes of heterocycles,
including indoles and pyridines, efficiently coupled with
unactivated secondary and tertiary alkyl halides. An alkyl
radical addition to neutral heteroarenes is most likely involved.
A
lkylated heteroarenes are commonly used in medicines
and materials. In recent years, transition-metal-catalyzed
alkylations of heteroarenes[1] have emerged as useful alter-
natives to Friedel–Crafts alkylation,[2] Minisci-type radical
additions,[3] and metal-catalyzed hydroheteroarylation of
olefins.[4] Many metal-catalyzed alkylations using unactivated
alkyl halides have focused on 1,3-azoles, which have rather
acidic hydrogen atoms,[5] and heterocycles carrying directing
groups.[6] Other families of heterocycles are less explored.
Furthermore, secondary and tertiary alkyl halides have been
rarely used.
In 2010, Miura et al. reported a palladium-catalyzed
alkylation of 1,3-azoles and primary alkyl halides succesfully
coupled (Scheme 1a).[5b] Mechanistically, the key C C bond
À
was formed through reductive elimination on palladium
centers. Later, Hu et al. realized the copper-catalyzed cou-
pling of 1,3-azoles with secondary alkyl halides and a radical
pathway was deduced (Scheme 1b).[7] Recently, Fu et al.
successfully applied a palladium-catalyzed alkylation to
pyridine N-oxides.[8] Both secondary and tertiary alkyl halides
were used, but only C2-substituted pyridine N-oxides reacted
efficiently and C2-substituents were necessary to prevent
double alkylation. The alkyl groups were introduced as
radicals onto the electron-poor azines with low-lying
LUMOs (Scheme 1c). Herein, we report a simple [Pd/dppp]
catalyst which allows regioselective alkylation of various
Scheme 1. Metal-catalyzed alkylation of heterocycles with alkyl halides.
families of heteroarenes using secondary and tertiary alkyl
halides.
Initially, we attempted a model transformation between
1,3-benzoxazole and cyclohexyl iodide by applying the
reaction conditions described in Schemes 1a and c. Unfortu-
nately, only 5% and 30% yields were obtained, respectively.
Gratifyingly, a simple catalyst derived from [Pd(PPh3)4] and
dppp catalyzed the model reaction in high yield (Table 1). The
diphosphine dppp proved to be optimal among many added
phosphines and gave 88% yield. When it was omitted,
[Pd(PPh3)4] alone gave a much lower yield (entry 1). Other
[*] X. Wu, J. W. T. See, K. Xu, Prof. Dr. H. Hirao, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
added
bisphosphines
(entries 3–9),
monophosphines
21 Nanyang Link, 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
(entries 14–19), and an N-heterocyclic carbene, IMes
(entry 20), were less effective. For example, dppf afforded
only 56% yield in this reaction (entry 8). Our efforts to use
other robust ferrocene-derived di-, tri-, and tetraphosphines,
which were developed by Hierso et al. for palladium-cata-
lyzed arylations, did not lead to further improvement
(entries 10–13).[9] If the molar ratio of the heterocycle and
CyI was changed to 2:1, the yield decreased to 60%. For other
reaction condition optimizations, see the Supporting Infor-
mation.
Dr. J. Roger, Prof. Dr. J.-C. Hierso
Institut de Chimie Molꢀculaire (UMR-CNRS 6302)
Universitꢀ de Institut Universitaire de France (IUF)
103 Bd. Saint Michel, 75005 Paris Cedex 5 (France)
[**] We thank the Singapore Singapore Ministry of Education Academic
Research Funding (MOE2013-T2-2-057) and Nanyang Technolog-
ical University for financial support. The work at ICMUB (Universitꢀ
de Bourgogne) is supported by the Rꢀgion Bourgogne and CNRS
(PARI-II-DS2-CDEA and 3MIM program).
The [Pd/dppp] catalyst was applied to couplings of 1,3-
benzoxazole with various secondary and tertiary alkyl iodides
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408365.
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Table 1: Effect of supporting ligands in the model alkylation of 1,3-
benzoxazole.[a]
Entry
Added L
Conv. [%]
Conv. to product [%][b]
1
2
3
4
5
6
7
8
9
none
dppp
dppe
dppb
XantPhos
DPEPhos
(R)-binap
dppf
58
97
97
93
76
90
76
79
94
32
88
63
70
57
68
70
56
56
dippf
10
96
69
Scheme 2. Couplings of 1,3-benzoxazole and various alkyl iodides.
11
12
82
87
50
42
13
70
20
14
15
16
17
18
19
20
PCy3
PtBu2Me
PtBu3
P(p-MeOC6H4)3
JohnPhos
SPhos
51
82
63
70
89
53
76
21
52
33
68
65
36
57
IMes
Scheme 3. Couplings of 1,3-benzoxazole and alkyl bromides (yields are
those of the isolated products).
[a] Reactions were run on a 0.1 mmol scale. [b] Determined by GC
analysis. binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl,
dippf=1,1’-bis(diisopropylphosphino)ferrocene, dppb=1,4-bis(diphe-
nylphosphino)butane, dppe=1, 2-bis(diphenylphosphino) ethane,
DPEPhos=bis(2-diphenylphosphinophenyl)ether, dppp=1, 3-bis(di-
phenylphosphino) propane, IMes=1,3-dimesityl-1,3-dihydro-2H-imid-
azol-2-ylidene, JohnPhos=2-(di-tert-butylphosphino)biphenyl,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, XantPhos=
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
Without NaI, the yield was less than 10% in the reaction with
cyclohexyl bromide. When an isomeric mixture of 4-bromo-2-
pentyltetrahydropyran (trans/cis ratio: 1:2) was used, the
trans isomer was consumed faster and the coupling product
was predominantly cis (trans/cis ratio: 1:17). In the reaction of
exo-2-bromonorbornane, the product was predominantly exo.
A small amount of alkyl iodides were detected during
palladium catalysis, which suggests that alkyl iodides were
probably actual reactants.
This palladium-catalyzed alkylation can be applied to
most major families of azacycles. Not only 1,3-azoles but also
6-membered azines can be alkylated (Scheme 4). 2-Methyl-
pyridine N-oxide coupled efficiently. Without the C2 sub-
stituent, its reactivity decreased dramatically. Interestingly,
our method can be used for regioselective alkylation of
electron-deficient pyridines. The substrate scope of substi-
tuted pyridines and regioselectivity are very different from
that of many existing metal-catalyzed alkylation proce-
dures.[10]
(Scheme 2). Both cyclic and acyclic halides reacted well. The
reaction of CyI was scaled up to 10 mmol using a Schlenk
manifold to afford 72% yield. When an isomeric mixture of 4-
tert-butylcyclohexyl iodide (trans/cis ratio: 2:1) was used, the
cis isomer was preferentially consumed and the trans product
was formed selectively with a trans/cis ratio of 8:1. Impor-
tantly, both 1-adamantyl and tert-butyl iodides gave good
yields. 1,3-Benzoxazole also coupled diastereoselectively with
an estrone-derived halide in a satisfactory yield.
The catalytic system was also successfully applied to
couplings of secondary and tertiary alkyl bromides when two
equivalents of NaI were used as an additive (Scheme 3).
2
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Scheme 4. Alkylation of five- and six-membered electron-poor aza-
cycles with CyI (yields are those of the isolated major isomers).
The alkylation procedure was also successfully applied to
furans, thiophenes, pyrroles, and their benzoid-fused deriva-
tives (Scheme 5). The presence of electron-withdrawing
aldehydes, ketones, and nitriles were important for substrate
activation and regiocontrol. Most notably, electron-rich and
electron-neutral indoles bearing N-carbamate groups can also
undergo C2-selective alkylation, which was quite rare in
transition-metal-catalyzed alkylation of indoles.[11] For exam-
ple, Ackermann et al. reported some examples of nickel- and
cobalt-catalyzed directed alkylation of indoles using secon-
dary alkyl halides.[12] However, in those examples, strong
bases or Grignard reagents were used and sensitive polar
groups such as aldehydes and ketones were not tolerated.
Recently, Bach et al. also reported C2-selective alkylation of
indoles and electron-deficient pyrroles using palladium and
norbornene dual catalysis, but only primary alkyl halides were
used.[13]
The new procedure was applied to tert-alkylation of many
families of heterocycles using 1-adamantyl iodide (Scheme 6).
In the case of 3-cyanopyridine, the selectivity was switched
from C6 to C4, probably because of the small size of the nitrile
group. Notably, both electron-neutral and electron-rich
indoles successfully coupled well.
In general, primary alkyl halides containing linear ali-
phatic chains were unsuccessful. The major side reaction was
palladium-catalyzed elimination of alkyl halides to olefins.[14]
However, some branched primary alkyl halides still coupled
in reasonable yields (Scheme 7).
Scheme 5. Alkylation of furans, thiophenes, pyrroles, and their benzo-
fused derivatives with CyI (yields are those of the isolated major
isomers).
halides.[8,15] Similarly under our reaction conditions,
TEMPO trapped the cyclohexyl radical and formed N-
cyclohexyl-TEMPO in significant amounts (Scheme 8a). In
another experiment of indole tert-alkylation, the adamantyl
radical was significantly reduced to adamantane in the
presence of 1,4-cyclohexadiene,
donor (Scheme 8b).
a good hydrogen-atom
Further support for a radical pathway came from DFT
calculations using the B3LYP functional with a 6-31 + G*
basis set. The experimental values of regioselectivity corro-
borated closely the calculated enthalpy gap between two
transition states of cyclohexyl radical addition to major and
minor sites of several heteroarenes (see the Supporting
Information).
Therefore, we propose a possible catalytic cycle in
Scheme 8c. It starts from single electron transfer from
[(dppp)Pd0] to the alkyl halide to give an alkyl radical and
[(dppp)PdIX].[16] Radical addition to a heteroarene, back
electron transfer to [(dppp)PdIX] and deprotonation fur-
nishes the alkylated heteroarene.
In summary, we report a general alkylation of hetero-
cycles using a simple [Pd/dppp] catalyst. Most topical classes
of heterocycles, including indoles and pyridines, efficiently
coupled with unactivated secondary and tertiary alkyl halides.
Previously, alkyl radicals were implicated in other palla-
À
dium-catalyzed C C bond-forming reactions using alkyl
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Scheme 8. Radical trapping and a possible catalytic cycle.
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Scheme 6. Couplings of 1-adamantyl iodide and heterocycles (yields
are those of the isolated major isomers).
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Scheme 7. Palladium-catalyzed alkylation using primary alkyl halides.
An alkyl radical addition to neutral heteroarenes is most
likely involved.
Received: August 19, 2014
Published online: && &&, &&&&
À
Keywords: alkyl radicals · C H activation ·
single electron transfer · heterocycles · palladium
.
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Communications
Heterocycles
X. Wu, J. W. T. See, K. Xu, H. Hirao,
J. Roger, J.-C. Hierso,
J. Zhou*
&&&& — &&&&
A General Palladium-Catalyzed Method
for Alkylation of Heteroarenes Using
Secondary and Tertiary Alkyl Halides
A radical way: The title reaction has been
realized for many unactivated alkyl hal-
ides and a variety of heteroarenes (see
picture; red dots denote the point of
alkylation with secondary and tertiary
alkyl halides). Preliminary mechanistic
studies indicate that the palladium cata-
lyst initiates an alkyl radical addition to
heterocycles.
6
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