Highly efficient direct alkylation of activated methylene by cycloalkanes

Article abstract of DOI:10.1002/ejoc.200700686

A simple FeCl₂-catalyzed C-C bond formation by direct alkylation of activated methylene by using simple cycloalkanes was developed. Several kinds of alkanes were found to react with phenyl β-ketone ester and diketone compounds to afford alkylated 1,3-dicarbonyl compounds in 10-88% yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700686

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700686
Highly Efficient Direct Alkylation of Activated Methylene by Cycloalkanes
Yuhua Zhang[a] and Chao-Jun Li*[a,b]
Dedicated to the memory of Professor Yoshihiro Matsumura
Keywords: C–C bond formation / Alkanes / Iron / C–H bond reactions
A simple FeCl2-catalyzed C–C bond formation by direct alky-
lation of activated methylene by using simple cycloalkanes
was developed. Several kinds of alkanes were found to react
with phenyl β-ketone ester and diketone compounds to af-
ford alkylated 1,3-dicarbonyl compounds in 10–88% yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
oxides catalyzed by various iron catalysts.[6] We rationalized
that the process may be tuned toward the formation of C–
C bonds with the interception of intermediates in such reac-
tions. To begin this study, we chose cyclohexane (1a) and
ethyl benzoylacetate (2a) as the standard substrates to se-
arch for suitable reaction conditions in the presence of iron
catalysts (Table 1). To our delight, desired product 3a was
obtained in 30% NMR spectroscopic yield when tert-butyl
peroxybenzoate was used as an oxidant (Table 1, Entry 1).
After numerous unsuccessful optimizations, it was found
that the yield of the desired product could be increased to
52% when the reaction was performed under an atmo-
sphere of nitrogen (Table 1, Entry 3). Then, various oxi-
dants were tested under such conditions and all led to the
desired product with various efficiencies. The only excep-
tion was tert-butyl hydroperoxide (TBHP) with which no
reaction was observed (Table 1, Entries 2–8). The desired
product could be obtained in 79% yield when tert-butyl
peroxide was used as the oxidant (Table 1, Entry 8). On the
basis of this result, various iron catalysts were examined:
FeCl2, FeBr2, FeCl3, and FeCl3·6H2O also gave good yields
for this reaction (Table 1, Entries 9–13). No desired product
was detected by 1H NMR spectroscopic analysis when
Fe(NO)3·9H2O, FeSO4·XH2O, Fe(C2O4)·2H2O, Fe(acac)3,
or other metal salts such as CuCl·5H2O, Cu(OAc)2,
CuSO4·5H2O, or CuCl2 were used as the catalysts (Table 1,
Entries 14–17). Albeit still effective, lowering the reaction
temperature significantly decreased the rate of the reaction
(Table 1, Entry 18). A reduction in the amount of either the
catalyst or tert-butyl peroxide resulted in a marked decrease
in the product yield (Table 1, Entries 19 and 20). Interest-
ingly, in the absence of any iron catalyst, a trace amount of
coupling product 3a was still generated (Table 1, Entry 23).
Subsequently, under the optimized reaction conditions,
various activated methylene substrates were treated with cy-
Introduction
Recently, there has been great interest in the direct trans-
formation of C–H bonds into C–C bonds without prefunc-
tionalizations.[1] Towards such a goal, we[2] and others[3]
have developed various oxidative intermolecular C–C bond
formation reactions by utilizing two different C–H bonds
(Scheme 1). In these cases, the C–H bond adjacent to a het-
eroatom[2a–2g] or a C=C bond[2h,2i] reacts with activated
methylene compounds, alkene, or alkynes to form new C–C
bonds. However, it is a great challenge to use simple alkanes
(without any functional groups) to form C–C bonds by such
an oxidative approach. Traditionally, the alkylation of 1,3-
dicarbonyl compounds represents one of the most common
methods in organic synthesis. As an alternative, herein we
wish to report direct alkylation of 1,3-dicarbonyl compounds
by using simple alkanes.
Scheme 1.
Results and Discussion
The pioneering work of Fenton chemistry[4] and the Gif
processes[5] established the conversion of aliphatic C–H
bonds into C–O bonds under mild conditions by using per-
[a] Department of Chemistry, Tulane University,
New Orleans, Louisiana 70118, USA
[b] Department of Chemistry, McGill University,
801 Sherbrooke St. West, Montreal QC H3A 2K6, Canada
Fax: +1-514-398-3797
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Direct Alkylation of Activated Methylene by Cycloalkanes
Table 1. Optimization of reaction conditions.[a]
bonds in n-hexane. The slightly higher ratio of the product
corresponding to alkylation at the C3 methylene rather than
the one at the C2 methylene could be attributed to the more
stable radical at the C3 position. No product was isolated
due to the reaction of the C–H bonds at the terminal methyl
groups (Scheme 3).
Table 2. FeCl2-catalyzed alkylation of alkane C–H bonds.[a]
[a] Ethyl benzoylacetate (0.2 mmol), cyclohexane (4.0 mmol), 12 h
under N2; unless otherwise noted; TBHP (5–6  in decane). [b]
NMR spectroscopic yields by using an internal standard. [c] Ethyl
benzoylacetate (0.2 mmol), cyclohexane (1.0 mL), 12 h. [d] Not de-
tected by NMR spectroscopy.
clohexane, cyclopentane, cycloheptane, cyclooctane, nor-
bornane, or adamantane. The representative results are
summarized in Table 2. With cyclohexane, various aryl β-
keto esters provided the desired alkylation products, mostly
in good yields (Table 2, Entries 1–7). The use of diketones
led to lower conversions relative to those obtained with the
use of β-keto esters (Table 2, Entries 8 and 9). When a cyclic
diketone was used, a complicated mixture was obtained ow-
ing to the self-reaction of the cyclic diketone. In contrast,
various cyclic alkanes (five-, seven-, or eight-membered
rings) were transformed into the desired products in good
yields when treated with the β-keto esters (Table 2, Entries
10–16). Reaction of norbornane with 2a (and 2g) gave the
alkylation products as a mixture of two diastereoisomers in
a 1:1 ratio (Table 2, Entries 17 and 18). On the basis of the
1H NMR spectrum of the crude reaction mixture, no prod-
uct resulting from the reaction of the bridgehead C–H bond
was detected. Quite the reverse was found when ada-
mantane was treated with ethyl benzoylacetate (2a): a 4:1
mixture of the alkylation products was obtained with the
major isomer corresponding to the coupling at the more-
substituted carbon atom (Scheme 2). It is worth mentioning
[a] Conditions: 1 (10 mmol), 2 (0.5 mmol), tert-butyl peroxide
(1.0 mmol), FeCl2·4H2O (0.1 mmol), 100 °C, 12 h, N2. [b] Isolated
yields are reported; the ratios of two isomers are reported in the
parentheses. [c] 23% of 2a remained after reaction.
A tentative mechanism for this novel C–C bond forma-
that simple n-hexane is also effective in this reaction. Its tion process by the reaction of simple alkane C–H bonds is
alkylation with β-keto ester 2a gave two regioisomers corre- proposed in Scheme 4. Iron(II) could catalyze the decompo-
sponding to the reaction of the two types of methylene C–H sition of the peroxide to give RO· and an RO-Fe(III) species.
Eur. J. Org. Chem. 2007, 4654–4657
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Y. Zhang, C.-J. Li
SHORT COMMUNICATION
Scheme 2. Alkylation of ethyl benzoylacetate with adamantane.
Scheme 3. Alkylation of ethyl benzoylacetate by n-hexane.
The RO· radical species could then react with cyclohexane vestigations including the mechanism, the scope, and syn-
to give a cyclohexyl radical, whereas RO–Fe(III) could react thetic applications of this reaction are in progress.
with the β-keto ester to generate an Fe enolate. The cyclo-
Supporting Information (see footnote on the first page of this arti-
hexyl radical is able to react with the enolate to form the
cle): Experimental details and characterization data for all com-
alkylated β-keto ester to regenerate FeII for further reac-
pounds.
tions. Alternatively, the reaction could be considered as a
simple free-radical addition onto a double bond[7] of an
iron benzoylacetate; albeit no product was observed with
Acknowledgments
other metal salts.
We are grateful to the Canada Research Chair (Tier I) foundation
(to C. J. L) and the US Environmental Protection Agency’s Tech-
nology for Sustainable Environment Program for support of our
research.
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Received: July 25, 2007
Published Online: August 23, 2007
Eur. J. Org. Chem. 2007, 4654–4657
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