Copper-catalysed α-selective allylic alkylation of heteroaryllithium reagents

Article abstract of DOI:10.1039/c4ob01896f

2-Allyl-substituted thiophenes and furans are synthesised efficiently in a direct procedure using 2-heteroaryllithium reagents and allyl bromides and chlorides catalysed by ligand-free copper(i). The reactions take place under mild conditions, with excellent α-selectivity, high functional group tolerance and good yields for the S_N2 products. This journal is

Full text of DOI:10.1039/c4ob01896f

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Copper-catalysed α-selective allylic alkylation of
heteroaryllithium reagents†
Cite this: Org. Biomol. Chem., 2014,
12, 9321
Carlos Vila, Valentín Hornillos, Martín Fañanás-Mastral and Ben L. Feringa*
Received 5th September 2014,
Accepted 13th October 2014
DOI: 10.1039/c4ob01896f
www.rsc.org/obc
2-Allyl-substituted thiophenes and furans are synthesised efficien-
tly in a direct procedure using 2-heteroaryllithium reagents and
allyl bromides and chlorides catalysed by ligand-free copper(I).
The reactions take place under mild conditions, with excellent
α-selectivity, high functional group tolerance and good yields for
the SN2 products.
Introduction
Scheme 1 Different methodologies for allylic alkylation of thiophene.
Heteroarenes such as thiophene and furan have attracted great
attention in the last decades, due to their versatility in syn-
thesis and specific properties.1 These heterocyclic compounds
have been used extensively in material science for organic dyes
and electronic devices,2 in agriculture and pharmaceutical
chemistry3 or as intermediates for the synthesis of natural pro-
ducts or flavours.4 Therefore, the functionalization of furans
and thiophenes at C2 represents an important target for
organic synthesis.1 In this context, the allylic substitution is a
very convenient reaction,5 due to the fact that the incorporated
olefin motif may serve as a latent group for further transform-
ations. There are a number of methods for allylic substitutions
lithium10 reagents in asymmetric allylic substitutions11 and
palladium-catalysed cross-coupling reactions,12,13 we were inter-
ested in the direct allylic alkylation of 2-heteroaryl lithium
reagents. Herein, we present an α-selective allylic alkylation of
2-heteroaromatic lithium reagents using copper as a catalyst.14
In this way, the initial functionalization of the organometallic
reagent is avoided, which allows the synthesis of 2-allyl-substi-
tuted heterocycles in an efficient and straightforward procedure.
with heterocycles (Scheme 1). For example, the Friedel–Crafts6 Results and discussion
reaction represents
a straightforward manner to access
Our studies began with the reaction between 2-thienyllithium15
and cinnamyl bromide, both commercially available. Different
solvents, temperatures and copper sources were evaluated
(Table 1). Initially, solvents such as toluene, TBME and THF
(entries 1–3, respectively), using CuBr·SMe2 as a catalyst at
−80 °C, were tested. Gratifyingly, full conversion and complete
SN2 selectivity (99 : 1, linear : branched) was achieved when
THF was used as solvent. This copper-catalysed allylic
alkylation reaction shows high regioselectivity to the α-substi-
tuted product, independently of the absence or presence of a
ligand.16 Importantly, when copper(I) was not used the conver-
sion dropped significantly (entry 4). We decided for practical
reasons to carry out the reaction at higher temperature, there-
fore the allylic alkylation was tested at 0 °C. A screening of
different copper(I) salts (entries 5–7) revealed that CuBr·SMe2
2-allylheteroarenes, but usually this transformation suffers
from a lack of regioselectivity, both in the heteroarene and
in the allyl electrophile, especially when thiophene is used as
a nucleophile.7 On the other hand, several successful cross-
coupling reactions catalysed by palladium8 and copper9
have been described, but in these cases a pre-functionalised
thiophene or furan is needed. Usually, a boronic, organotin or
organosilicon reagent is used in these cross-coupling reac-
tions. As part of our continuing efforts to employ organo-
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG
Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl; Fax: +31 50 363 4278;
Tel: +31 50 363 4296
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01896f
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Table 1 Optimization of the reaction conditionsa
T
Conv. b 3a + 3a′ b
4 b
(%)
Entry Solvent Copper
(°C) (%)
(l : b)c (yield)d
1
2
3
4
5
6
7
8
9
Toluene CuBr·SMe2 −80 95
90% (99 : 1)
80% (99 : 1)
Full (99 : 1)
25% (99 : 1)
94% (97 : 3)
50% (98 : 2)
60% (98 : 2)
60% (98 : 2)
Full (98 : 2)
(86%)
5
10
0
10
6
TBME
THF
THF
THF
THF
THF
THF
THF
CuBr·SMe2 −80 90
CuBr·SMe2 −80 Full
—
−80 35
CuBr·SMe2
CuCl
CuI
0
0
0
0
Full
55
80
80
5
20
20
0
—
CuBr·SMe2
−5 Full
10e
THF
CuBr·SMe2
−5 Full
Full (98 : 2)
(93%)
0
a Reaction conditions: copper salt (0.01 mmol, 5 mol%), 1.5 eq. of 1a
and 0.2 mmol of 2a in 2 mL of solvent. b Conversions were determined
by 1H NMR. c Linear : branched ratio was determined by GC. d Isolated
yield after column chromatography. e Cinnamyl chloride was used as a
allylic reagent.
Scheme 2 Scope of copper(I)-catalysed allylic alkylation. Reaction con-
ditions: allyl bromide 2 (0.2 mmol) was added to a stirred solution of
CuBr·SMe2 (0.01 mmol) in 2 mL of dry THF at −5 °C; 2-heteroaryllithium
reagent 1 (0.3 mmol) was added dropwise over 1 h. Isolated yield
after column chromatography. Linear : branched ratio determined by
GC. a1.1 eq. of 2-heteroaryllithium reagent 1 was used. b1,2-addition to
the carbonyl group was also observed as a side reaction.
is the most efficient catalyst for this transformation. When the
reaction was run at 0 °C, a small amount of homocoupling
product 4 was still formed (entry 5). Finally, when the reaction
was performed at −5 °C in THF and using CuBr·SMe2, full con-
version was achieved (86% isolated yield of 3a) without the
presence of product 4. When the reaction was carried out at
room temperature, a complex mixture was obtained and the
1H NMR of the crude mixture was difficult to analyse. Interest-
ingly, when cinnamyl chloride was used (entry 12, Table 1),
full conversion and high regioselectivity to the linear product
were also observed and the corresponding product 3a was
obtained in 93% yield.
2-yllithium, easily prepared by direct metallation with
n-BuLi,18 was successfully coupled with (E)-N-allyl-N-(4-bromo-
but-2-en-1-yl)-4-methylbenzenesulfonamide and 3-bromocyclo-
hexene, affording the corresponding products 3k (78%) and 3l
(81%) in high yields. 2-Furanyllithium and 2-benzofuranyl-
lithium, freshly prepared by direct metallation, were also suit-
able partners for this reaction, resulting in products 3m–3o,
with high regioselectivity and good yields.
With the optimised conditions in hand (Table 1, entry 9),
the scope of this reaction was investigated (Scheme 2). It
should be emphasized that high functional group tolerance
was observed and cinnamyl bromides with different substitu-
ents, such as methyl ester, bromide,17 NO2 or CF3 groups in
para position at the aromatic ring can be present, affording
the corresponding products 3b–3e, in good to high yields with
excellent levels of regioselectivity. Other functional groups
such as benzyl ether or a dioxalane ring were allowed and the
corresponding products 3f and 3g, were obtained in 78 and
90% yield, respectively. Also, the presence of N-Ts-protected
amines was tolerated, but in this case 1.1 eq. of organolithium
reagent was used in order to obtain good yield. Furthermore,
multiple coupling of 1a is shown in the twofold alkylation of
(E)-1,4-dibromobut-2-ene, providing the corresponding dialky-
lated product 3j in 70% isolated yield. Next, different hetero-
aryllithium reagents were tested. For example benzo[b]thiophen-
Conclusions
In summary, we have developed a highly regioselective ligand-
free copper-catalysed allylic alkylation using directly 2-hetero-
arylithium reagents. The corresponding α-substituted products
are obtained in good to excellent yields (up to 94%). The
reaction takes place under mild conditions and tolerates a
wide range of functional groups and offers a method for direct
access to various C2-substituted heterocycles.
Acknowledgements
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW), National Research School
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