The nickel/copper-catalyzed direct alkylation of heterocyclic C-H bonds

Article abstract of DOI:10.1002/anie.200907040

(Figure Presented) Too selective: A general and straightforward protocol for the cross-coupling of non-activated alkyl halides with heterocyclic C-H bonds has been developed. The transformation is chemo- and regioselective and many functional groups on both coupling partners are tolerated. The method employs cheap nickel/copper catalysts, and expands significantly the scope of C-H functionalization (see scheme).

Full text of DOI:10.1002/anie.200907040

Angewandte
Chemie
DOI: 10.1002/anie.200907040
À
C H Activation
À
The Nickel/Copper-Catalyzed Direct Alkylation of Heterocyclic C H
Bonds**
Oleg Vechorkin, Valꢀrie Proust, and Xile Hu*
Aromatic heterocycles are an important class of molecules
which have been widely used as synthetic building blocks, bio-
active molecules, pharmaceuticals, and organic materials.[1–3]
There are now many methods available for the preparation of
aromatic heterocycles that are substituted with aryl, alkenyl,
alkynyl, and even activated alkyl groups, the most recent
these reagents. Furthermore, additional chemical transforma-
tions are required for the preparation of the organometallic
reagents. Therefore, the direct cross-coupling of aromatic
À
heterocyclic C H bonds with non-activated alkyl halides
(path C, Figure 1) represents an attractive alternative. How-
ever, this coupling technology is underdeveloped—conse-
quence of the difficulties involved in the coupling of non-
activated alkyl halides.[22–24] Alkyl halides are resistant to
oxidative addition; when they do undergo oxidative addition,
the resulting metal alkyl intermediates are prone to unpro-
ductive b-hydride elimination. To date, the only reported
example of a successful coupling was the palladium-catalyzed
reaction between ethyl oxazole-4-carboxylate with nbutyl
bromide (2 equiv) that afforded ethyl 2-butyloxazole-4-car-
boxylate in 60% yield.[25]
[4–13]
À
method involves C H functionalization.
However, the
synthesis of heterocyclic compounds substituted by non-
activated alkyl groups containing b-hydrogen atom remains
challenging. Traditional methods such as Friedel–Crafts[14]
and radical alkylation reactions[15] pose severe limitations on
the electronic properties of the heterocycles, and are often
incompatible with sulfur containing heterocycles. Addition-
ally, the Friedel–Crafts alkylation requires strong acids, and
suffers from side reactions such as multiple alkylation and
isomerization. Likewise, the method of deprotonation by
strong bases, for example nBuLi, and subsequent electrophilic
trapping requires cryogenic conditions, active electrophiles,
the protection of acidic and/or electrophilic groups, and
special bases.[16–18]
In the course of developing catalysts based on inexpensive
and readily available first-row transition metals, we identified
a nickel complex, [(MeNN2)NiCl] (1), as an active precatalyst
The development of cross-coupling catalysis provides new
opportunities in heterocycle synthesis.[19] The alkylated aro-
matic heterocycles can be produced either by the coupling of
a heterocyclic halide with an alkyl organometallic nucleophile
(path A, Figure 1),[20] or by the coupling of a heterocyclic
organometallic nucleophile with an alkyl halide (path B,
Figure 1).[21] Both methods employ organometallic nucleo-
philes, and are constrained by the stability and availability of
for the coupling of non-activated alkyl halides.[21,26–28,29]
Herein, we show that the combination of this complex and
a copper salt leads to the efficient coupling of aromatic
heterocycles with non-activated alkyl halides containing a b-
hydrogen atom. Notably, not only alkyl iodides and bromides,
but also alkyl chlorides can be used. The catalysis tolerates a
wide range of functional groups in both coupling partners, and
has excellent chemo- and regioselectivity.
Figure 1. Cross-coupling methods for the synthesis of alkylated
aromatic heterocycles; X=halide, M=metal.
The cross-coupling of benzoxazole with nbutyl iodide was
used as a model reaction. After investigating various exper-
imental parameters,[30] we found that 2-nbutyl benzoxazole
could be produced in high yields (ca. 80%) using 1 (5 mol%)
as the precatalyst and CuI (7.5 mol%) as the co-catalyst
[Eq. (1), Scheme 1]. A temperature of 1408C and a reaction
time of 16 hours were required for full conversion. A suitable
base was also needed. The most effective bases were tBuONa
in toluene or tBuOLi in dioxane. Other base/solvent combi-
nations gave lower yields. The coupling proceeded even in the
absence of the copper co-catalyst, however, with a small
amount of CuI, the yields were higher. The yields were nearly
constant when the loadings of CuI were varied from 2 to
7.5 mol%. The nickel complex 1 was essential for achieving
high efficiency. In the absence of 1, no coupling occurred. The
[*] O. Vechorkin, V. Proust, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis
Catalysis Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
ISIC-LSCI, BCH 3305, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9305
E-mail: xile.hu@epfl.ch
Homepage: http://isic.epfl.ch/lsci
[**] This work was supported by the EPFL and the Swiss National
Science Foundation (project no. 126498). We thank Profs. Jꢀrꢁme
Waser and Karl Gademann for insightful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907040.
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replacement of 1 with another soluble NiII compound such as
[NiCl2(dme)] and [NiCl2(PPh3)2], led to diminished yields
(20–30%; dme = 1,2-dimethoxyethane).
was tolerated (Table 1, entry 1). The coupling of alkyl
chloride was selective in the presence of the aryl–Cl bond
(Table 1, entry 3). Potentially coordinating groups such as
ether, thioether, and nitrile groups did not pose problem
(Table 1, entries 4–6). The acetal group was also tolerated
(Table 1, entry 7). Olefin and ester groups did not interfere
with the coupling (Table 1, entries 8 and 9). Encouragingly, a
substrate containing a base sensitive keto group could be
employed, albeit in modest yield (Table 1, entry 10). The
coupling of substrates containing important heterocyclic
groups such as indole, carbazole, and furan were also
successful (Table 1, entries 11–13). No coupling occurred
with secondary alkyl halides such as cyclohexyl iodide and
cycloheptyl bromide. However, base-induced elimination
from some alkyl halides, for example 2-bromoethylbenzene,
was observed.[30] This side reaction did not pose a problem for
all substrates in Table 1.
The coupling of benzoxazole with noctyl bromide or octyl
chloride was also possible by employing similar reaction
conditions [Eq. (2), Scheme 1]. The best results were
obtained when reactions were carried out in dioxane with
tBuOLi as the base.[30] The addition of NaI (20 mol%) was
beneficial, probably by promoting a halide exchange process.
The optimized reaction conditions are applied to the
coupling of benzoxazole with other non-activated alkyl
halides (Table 1). Branching at the b position of the halide
A similar procedure can be used for the coupling of other
aromatic heterocycles with non-activated alkyl halides
(Table 2). Various 5-aryloxazoles could be readily coupled
at the 2-position (Table 2, entries 1–4). The aryl–Br moiety of
the oxazole did not interfere with the coupling reaction
(Table 2, entry 4). Gratifyingly, the molecules containing
important pharmacophores such as thiazole and thiophene
were also suitable substrates, which gave rise to 2-alkylated
products (Table 2, entries 5–16). In some cases, the more
sterically hindered base Et3COLi was required to achieve
higher yields (Table 2, entries 14–16). The catalysis was
tolerated by carbazole, ether, olefin, ester, indole, NBoc,
aryl and heteroaryl halide groups. For unsubstituted sub-
strates (Table 2, entries 1–4, and 11), no significant amount of
double alkylation product was observed.
Scheme 1. Optimized conditions for the direct alkylation of
benzoxazole.
The mechanism of the coupling reaction might be similar
to those of nickel/copper- and copper-catalyzed direct aryl-
ation and alkynylation of aromatic heterocycles.[10,13,31] Even
though the copper co-catalyst was not necessary for the
coupling reaction, it was needed to achieve satisfactory yields.
We proposed that the copper facilitates the transmetalation of
the anionic azole/thiophene intermediates to nickel. The
existence of an anionic benzoxazole was confirmed, as
quenching of the reaction mixture at partial conversion with
D2O produced 2-deuterated benzoxazole.[30] Almost no iso-
topic effect was observed for the coupling of nBuI with 2-
Table 1: Coupling of benzoxazole with non-activated alkyl halides.[a]
À
À
Entry Alkyl X
Yield Entry Alkyl X
Yield
[%][b]
[%][b]
1
2
79
70
8
9
70
71
À
deuterated benzoxazole, thus suggesting that C H cleavage
might not be the turnover limiting step.[30]
To probe the nature of the nickel catalyst, the catalysis was
followed by 1H NMR spectroscopy (using 20 mol% of nickel
precatalyst). HMeNN2 was detected as the only ligand-
containing species. Thus, precatalyst 1 appeared to degrade
into the active nickel species under the catalytic conditions.
To check whether heterogeneous nickel particles were
responsible for the coupling, a reaction [Eq. (1), Scheme 1]
was conducted in the presence of 100 equivalents of Hg
(relative to nickel).[30] The yield of the coupling reaction
diminished from about 80% to 19%. In addition, filtering off
the insoluble solids from the reaction mixture at partial
conversion led to a lower yield.[30] These results suggest that
the reactions are most likely catalyzed by nickel metal
particles.
3
4
75
84
10
11
44
74
5
6
7
65
56
86
12
13
75
73
[a] Benzoxazole (1.5 mmol) was used. For the coupling of alkyl bromides and
chlorides, NaI (0.3 mmol) was added. [b] Yields of isolated product relative to
the heteroarenes.
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Table 2: Coupling of heterocycles with non-activated alkyl halides.[a]
In conclusion, we have developed a general and versatile
method for the synthesis of alkylated aromatic heterocycles,
which are important organic molecules and materials. The
À
chemistry is based on catalytic C H functionalization using
non-activated alkyl electrophiles—a largely under-explored
reaction type.[25,32–34] The nickel/copper catalysis enables the
coupling of both electron-rich (thiophene) and electron-poor
(oxazole and thiazole) heterocycles which is difficult to
achieve using other synthetic procedures. Various non-
activated alkyl halides containing a b-hydrogen atom, includ-
ing the inexpensive chlorides could be employed. This
method is applicable in the synthesis and derivatization of a
large number of alkylated heterocycles. The coupling protocol
is simple and straightforward, the substrates are readily
available, and the pure products can be isolated in high yields.
Notably, the chemo- and regioselectivities are excellent. Only
alkyl halide bonds are reactive in the presence of aryl and
heteroaryl halide moieties, thus providing more possibilities
for further functionalization. When the alkyl halides possess
heterocyclic groups, no intra- or intermolecular self-coupling
takes place. The coupling occurred exclusively at the 2-
position of the aromatic heterocycles, even when there is
more than one reaction site on the heterocycle. No multiple
alkylation was observed, which is a desirable feature in
comparison to Friedel–Crafts reactions.
À
Entry Alkyl X
Product
Yield
[%][b]
1
74
À
Octyl I
2
3
86
81
4
76
À
Butyl I
5
6
78
74
7
72
Received: December 14, 2009
Revised: January 22, 2010
Published online: March 12, 2010
8
76
85
79
À
Keywords: C H activation · cross-coupling · heterocycles ·
homogeneous catalysis · synthetic methods
.
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