DOI: 10.1002/chem.201405102
Communication
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Synthetic Methods
Copper-Mediated/Catalyzed Oxyalkylation of Alkenes with
Alkylnitriles
Ala Bunescu, Qian Wang, and Jieping Zhu*[a]
Abstract: A copper-promoted oxyalkylation of alkenes
with alkylnitriles has been developed. The protocol pro-
vides rapid access to phthalides (g-lactones) or isochroma-
nones (d-lactones) via the formation of a C(sp3)ÀC(sp3)
and a C(sp3)ÀO bond with the generation of up to two
quaternary carbon atoms. Mechanistic studies suggest
that this reaction is initiated by the formation of the
C(sp3)ÀC(sp3) bond rather than the C(sp3)ÀO bond. Cata-
lytic conditions were subsequently developed using car-
boxylic acid as an internal nucleophile.
The difunctionalization of alkenes represents a domain of
Scheme 1. Functionalization of alkenes with alkylnitriles.
major interest in organic synthesis due to the availability of
the starting materials and the possibility to attain molecular
tionalization,[12,13] we report herein a copper mediated/cata-
complexity and diversity in one single step. Among the avail-
able methods, metal-catalyzed transformations have emerged
as a powerful tool for this purpose.[1] However, C(sp3)ÀC(sp3)
bond formation remains challenging, mainly due to the com-
petitive b-hydride elimination process.[2] In recent years,
copper has gained much popularity as a catalyst for two im-
portant processes: the C(sp3)ÀC(sp3) cross-dehydrogenative
coupling (CDC)[3] and the difunctionalization of alkenes.[4–6] Re-
gardless of remarkable achievements realized in the field, ex-
amples of copper-mediated/catalyzed difunctionalization of al-
kenes with generation of a C(sp3)ÀC(sp3) bond remain rare.[7,8]
The formation of organometallic complexes (Ln, Rh, Fe, Ru)
by activating a-CÀH bond of acetonitrile has been document-
ed in the past.[9] Nevertheless, the use of nitrile with synthetic
purpose is limited mainly to its enolate form[10,11] requiring
a strong base [pKa (MeCN)ꢀ31.3, DMSO] for its formation or
the use of activated nitriles like b-cyanocarbonyls (pKa ꢀ13–14,
DMSO) or a-arylacetonitriles (pKa ꢀ21.9, DMSO). Recently, Liu
and co-workers reported an elegant Pd-catalyzed oxidative
arylalkylation of alkenes involving an a-CH activation of aceto-
nitrile using PhI(OCOtBu)2 (1.1 equiv) and AgF (4.0 equiv) as co-
promoters [Scheme 1, Eq. (1)].[2a] As a continuation of our on-
going project dealing with the metal-catalyzed C(sp3)ÀH func-
lyzed oxyalkylation of alkenes using alkylnitriles as reaction
partners leading to functionalized phthalides and isochroma-
nones [Scheme 1, Eq. (2)]. Phthalides are widely present in nat-
ural products[14] and pharmaceuticals,[15] and have proved
useful as building blocks in organic synthesis.[16]
Using N-(tert-butyl)-2-(prop-1-en-2-yl)benzamide (1a, X=
NHtBu) and acetonitrile as test substrates, conditions were sur-
veyed by varying the copper salts, the oxidants, the ligands,
the bases,[17] and the temperature. The initial conditions, which
led to reasonable yield of 2a, were as follows: Cu(OTf)2
(2.0 equiv), 1,10-phenanthroline (1.0 equiv), K3PO4 (2.0 equiv)
and di-tert-butylperoxide (DTBP; 2.0 equiv) at 1408C (for de-
tails, see the Supporting Information). Under these conditions,
two oxyalkylation products, at the expense of isoindolinone re-
sulting from the aminoalkylation process, were formed in 58%
yield (by NMR spectroscopy; 2a/2b=1:1; Table 1, entry 1).
Gratifyingly, by adding water (11.0 equiv) into the reaction mix-
ture, the yield of oxyalkylation products increased with an im-
proved ratio of 2a to 2b (isolated in 65% yield; 2a/2b=1.5:1;
Table 1, entry 2). Further fine-tuning of the reaction conditions
indicated that 2,2’-bipyridine was the ligand of choice (Table 1,
entries 4–7). In these preliminary experiments, we also isolated
nitrile 3, which could have important mechanistic implications
(see below). Finally, the nature of the amide group (X=NHtBu,
NHMe, or NMe2) impacted significantly the product yield
(Table 1, entries 7–9). Using N,N-dimethylamide 1c (X=NMe2)
as starting material, phthalide 2a was isolated as a sole prod-
uct in 86% yield (Table 1, entry 10). The yield of 2a decreased
significantly when Cu/ligand ratio was reduced to 1:1 (Table 1,
entry 10).
[a] A. Bunescu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Product
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405102.
Chem. Eur. J. 2014, 20, 1 – 5
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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