Copper-catalysed direct radical alkenylation of alkyl bromides

Article abstract of DOI:10.1039/c4ob00813h

A copper-catalysed direct radical alkenylation of various benzyl bromides and α-carbonyl alkyl bromides has been developed. Compared with the recent radical alkenylations which mostly focused on secondary or tertiary alkyl halides, this transformation shows good reactivity to primary alkyl halides and tertiary, secondary alkyl halides were also tolerated. The key initiation step of this transformation is a copper-induced single-electron reduction of C-Br bonds to generate alkyl radical species. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00813h

Organic &
Biomolecular Chemistry
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Copper-catalysed direct radical alkenylation of
alkyl bromides†
Cite this: Org. Biomol. Chem., 2014,
12, 6790
Xu Zhang,‡a Hong Yi,‡a Zhixiong Liao,a Guoting Zhang,a Chao Fan,a Chu Qin,a
Received 20th April 2014,
Accepted 7th July 2014
Jie Liua and Aiwen Lei*a,b
DOI: 10.1039/c4ob00813h
www.rsc.org/obc
A copper-catalysed direct radical alkenylation of various benzyl bromides such as primary alkyl halides is a challenging and
bromides and α-carbonyl alkyl bromides has been developed. important task.
Compared with the recent radical alkenylations which mostly
Copper has been a general catalyst to initiate conversion of
focused on secondary or tertiary alkyl halides, this transformation alkyl halides to alkyl radicals, which have been widely applied
shows good reactivity to primary alkyl halides and tertiary, second- in copper-catalysed atom-transfer radical addition (ATRA)7 and
ary alkyl halides were also tolerated. The key initiation step of this atom-transfer radical polymerization (ATRP).8 Though copper
transformation is a copper-induced single-electron reduction of catalysts can be promising catalysts for the alkyl radical gene-
C–Br bonds to generate alkyl radical species.
ration, the application of copper catalysts in the radical alkenyl-
ation of alkyl halides is very rare. Recently, Takashi Nishikata
and co-workers have reported the first copper-catalysed radical
Heck-type alkenylation reaction.9 However, the alkyl halides
were mostly limited to tertiary alkyl halides and the ligand
used was very special. Herein, we demonstrate our progress in
this copper-catalysed radical mediated direct alkenylation of
various tertiary, secondary and primary alkyl halides using
easily available 1,10-phenanthroline (phen) as the ligand
(Scheme 1).
We commenced our studies with 4-methoxystyrene 1a and
2-(bromomethyl)benzonitrile 2a as model substrates. The best
yield of the desired product 3a could be achieved in the pres-
ence of 20 mol% CuCl, 40 mol% phen, 2 equiv. Na2CO3 and
DMF as the solvent at 100 °C (Table 1, entry 4) and other
selected results are summarized in Table 1. Various copper
catalyst precursors were screened (Table 1, entries 1–4). The
Cu(I) catalysts were effective for this alkenylation transform-
ation in which CuCl was found to be the most effective catalyst
precursor, while the Cu(II) catalyst proved to be ineffective. In
addition, different ligands such as TMEDA and Acac (aceto-
Direct alkenylation of alkyl halides is one of the challenging
fields and has been extensively studied. Although the
palladium-catalysed Heck reaction has been widely applied
in organic synthesis,1 the alkenylation of alkyl halides by
palladium still remains a major challenge.2 In addition to the
oxidative addition pathway for palladium-catalysed alkenyla-
tion of alkyl halides, a radical-mediated approach can serve as
a complementary model for the alkenylation from alkyl
halides because the alkyl halides can be easily activated to
generate the key intermediate alkyl radical species which have
high activity towards alkenyl acceptors.3 Generally, alkyl
halides are divided into primary, secondary and tertiary alkyl
halides. The reactivity of alkyl halides can be correlated with
bond dissociation energy (BDE) and generally depends on the
degree of substitution (primary < secondary < tertiary).4 In the
recently developed radical alkenylations,5 the alkyl halides
were mostly limited to secondary alkyl halides or tertiary alkyl
halides which is attributed to the generation of relatively
stable alkyl radicals.6 The alkenylation of primary halides was
hard to achieve through a radical process because of its low
reactivity. Therefore, the development of radical alkenylation
to expand the application and solve the low reactivity of alkyl
aCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072,
P. R. China. E-mail: aiwenlei@whu.edu.cn; Fax: (+86)-27-68754672;
Tel: (+86)-27-68754672
bNational Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang 330022, Jiangxi, P. R. China
†Electronic supplementary information (ESI) available: General procedures,
spectral data and other ESI. See DOI: 10.1039/c4ob00813h
‡Hong Yi and Xu Zhang contributed equally to this work.
Scheme 1 Copper-catalysed radical alkenylation of alkyl bromides.
6790 | Org. Biomol. Chem., 2014, 12, 6790–6793
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Table 1 Optimization of conditions for the reaction of 4-methoxy-
styrene 1a and 2-(bromomethyl) benzonitrile 2aa
Table 3 Scope of copper-catalysed radical alkenylation of different
benzyl bromides 2 and 4-methoxystyrene 1aa
Entry
[Cu]
L
Yield [%]
1
2
3
4b
5
6
7
8
CuCl2
CuI
CuBr
CuCl
CuCl
CuCl
No
Phen
Phen
Phen
Phen
Acac
TMEDA
Phen
No
5
79
82
83(80)
<5
<5
n.d.c
n.d.c
CuCl
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), catalyst (20 mol%),
ligand (40 mol%), Na2CO3 (1.0 mmol), DMF (2.0 mL), 100 °C, N2, 24 h.
GC yield. b The yield in the parentheses was isolated yield. c n.d. = no
desired product.
a Reaction conditions: 1a (1 mmol), 2 (0.5 mmol), CuCl (20 mol%),
1,10-phen (40 mol%), Na2CO3 (1.0 mmol), DMF (2.0 mL), 100 °C, N2,
24 h. Isolated yield. b NMR yield.
acetonate) were not effective for this reaction, and the product
was in less than 5% yield (Table 1, entries 5 and 6). Finally,
control experiments in the absence of the copper catalyst
(Table 1, entry 7) or the ligand (Table 1, entry 8) confirmed
that these species played a critical role in this transformation.
With the optimal conditions established, various alkenes 1
were tested to react with 2-(bromomethyl)benzonitrile 2a to
form the corresponding alkenylation products 3 (Table 2). This
reaction was successfully amenable to a wide range of substi-
tuted styrenes, and moderate to good yields were achieved
with substrates bearing functional groups such as OMe (3a),
substituents ortho to the olefin (3d) also provided moderate
yield. Interestingly, indene could also be employed to obtain
the target alkenylation product without any difficulties (3e).
Furthermore, the 1,1-disubstituted olefins (3f and 3g) were
suitable for this reaction and the corresponding products were
obtained in good yields.
Next, we investigated the copper-catalysed radical alkenyla-
tion reactions of different benzyl bromides 2 (Table 3). Under
the standard conditions, a wide range of functional groups,
including the C–Br, C–Cl, C–F, CF3 and CN groups, were com-
patible with this method. In addition, the primary α-carbonyl
alkyl bromides were also tested under the optimized reaction
conditions. The bromoacetonitrile (3n) provided the target
product in moderate yield, while the ethyl bromoacetate
afforded a poor yield (3m) because of the low reactivity.
Inspired by the positive results of primary alkyl halides, we
next extended this alkenylation reaction to secondary and
tertiary α-carbonyl alkyl bromides as well (Table 4). Under the
optimized reaction conditions described above, secondary
α-carbonyl alkyl bromides bearing ester and cyano groups were
t
Me (3b) and Bu (3c). In addition, the effect of steric with
Table 2 Scope of copper-catalysed radical alkenylation of different
alkenes 1 and 2-(bromomethyl) benzonitrile 2aa
Table 4 Scope of copper-catalysed radical alkenylation of α-carbonyl
alkyl bromides 2 and 4-methoxystyrene 1aa
a Reaction conditions: 1 (1.0 mmol), 2a (0.5 mmol), CuCl (20 mol%), a Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), CuCl (20 mol%),
1,10-phen (40 mol%), Na2CO3 (1.0 mmol), DMF (2.0 mL), 100 °C, N2, 1,10-phen (40 mol%), Na2CO3 (1.0 mmol), DMF (2.0 mL), 100 °C, N2,
24 h. Isolated yield.
24 h. Isolated yield.
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Table 5 Radical inhibiting experiments
Additive
Yield of 3aa
None
TEMPO (2 equiv.)
BHT (2 equiv.)
80%
0
0
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), CuCl (20 mol%),
1,10-phen (40 mol%), additive (1.0 mmol), Na2CO3 (1.0 mmol), DMF
(2.0 mL), 100 °C, N2, 24 h. GC yield.
Scheme 2 Proposed mechanism.
1 gives the radical intermediate II, which then reacted with Cu(II)
species to form the brominated intermediate III and Cu(I)
species. Meanwhile, Cu(I) species is regenerated to complete
the catalytic cycle. Subsequently, the brominated intermediate
III is eliminated with the base to obtain the desired product 3.
Conclusions
In conclusion, we have demonstrated a copper-catalysed
radical alkenylation of various benzyl bromides and α-carbonyl
alkyl bromides to furnish α-vinyl carbonyls and allylbenzene
derivatives. Specifically, this transformation shows good
regioselectivity to primary alkyl halides and tertiary, secondary
alkyl halides that bear β-hydrides are also tolerated. The key
initiation step of this transformation is copper-induced single-
electron reduction of C–Br bonds to generate alkyl radical
species.
Fig. 1 EPR spectra.
shown to react with 4-methoxystyrene in good yields (3o and
3p). Furthermore, a tertiary α-carbonyl alkyl bromide bearing
ester underwent the alkenylation transformation with 1a
smoothly in 85% yield (3q).
To gather some insights into this radical alkenylation reac-
tion, radical scavengers, such as TEMPO and BHT, were
employed in the reaction (Table 5). As a result, the reactions
were completely shut down, which could indicate that this
transformation involved radical intermediates.
The electron paramagnetic resonance (EPR) was also used
to study this radical process. As shown in Fig. 1(a), no EPR
signal was observed when CuCl, and 1,10-phen were tested in
2.0 mL DMF at 100 °C for 1 hour. However, when a mixture of
CuCl, 1,10-phen and 2a was tested under the same conditions,
a strong Cu(II) EPR signal could be detected (Fig. 1(b)).
In addition, the homo-coupling of 2a was also detected by
GC-MS, which indicated the formation of an alkyl radical.
Therefore, this transformation is Cu(I)-induced single-electron
reduction of C–Br bonds to generate alkyl radical species and
Cu(II) species.
Acknowledgements
This work was supported by the 973 Program (2011CB808600,
2012CB725302), the National Natural Science Foundation
of China (21390400, 21025206, 21272180 and 21302148), the
Research Fund for the Doctoral Program of Higher Education
of China (20120141130002) and the Program for Changjiang
Scholars and Innovative Research Team in University (IRT1030).
The Program of Introducing Talents of Discipline to Universities
of China (111 Program) is also appreciated.
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According to the previous reports and the above results, a
proposed mechanism for this copper-catalysed radical alkenyl-
ation is described in Scheme 2. The alkyl radical I is generated
by the reaction between Cu(I) species and the alkyl bromide 2
through the single-electron transfer process. After the gene-
ration of alkyl radical I, the addition of alkyl radical I to alkene
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