Copper-catalyzed decarboxylative C(sp2)-C(sp3) coupling reactions via radical mechanism

Article abstract of DOI:10.1039/c2cc33203e

We have successfully developed an example of copper-catalyzed decarboxylative C(sp²)-C(sp³) coupling reactions via C-H functionalization for the first time. It is noteworthy that our catalytic system is very stable, low-cost, palladium-free, ligand-free, and easily accessible.

Full text of DOI:10.1039/c2cc33203e

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COMMUNICATION
Copper-catalyzed decarboxylative C(sp2)–C(sp3) coupling reactions via
radical mechanismw
Hailong Yang, Peng Sun, Yan Zhu, Hong Yan, Linhua Lu, Xiaoming Qu, Tingyi Li and
Jincheng Mao*
Received 4th May 2012, Accepted 18th June 2012
DOI: 10.1039/c2cc33203e
We have successfully developed an example of copper-catalyzed
decarboxylative C(sp2)–C(sp3) coupling reactions via C–H functiona-
lization for the first time. It is noteworthy that our catalytic system is
very stable, low-cost, palladium-free, ligand-free, and easily accessible.
Scheme 1 Strategy of coupling via decarboxylative olefination of sp3
C–H bonds.
In the last few decades, radical reactions have been used as
powerful tools for C–C bond formation in synthetic chemistry.1
In this area, carbon radicals, such as aryl, benzyl, acyl, and
carbamoyl radicals, are useful active intermediates. In general,
the key step in all of these reactions is the addition (or cyclization)
of a radical to a multiple bond. Recently, Shi,2a Shirakawa/
Hayashi,2b and Kwong/Lei2c have reported on the construction
of biaryl compounds from unactivated aromatic rings through
homolytic radical aromatic substitution (HAS).2 Many methods
for the generation and reaction of acyl radicals have been
reported.3 Formation of acid amides and their derivatives via
carbamoyl radicals was proved an effective way.4 It could be
easily found that most free radicals are generated from halides,1,5a
hydrazines,5b,c ozonides,5d carboxylic acids5e and phosphites,5f
but examples of the generation of free radicals from alkanes
and arenes are somehow limited.5g,h
Table 1 Copper-catalyzed decarboxylative C(sp2)–C(sp3) coupling of
different cinnamic acids 1 with 2aa
Entry
1
Yield of 3b (trans/cis)c
Entry
6
Yield of 3b (trans/cis)c
2
3
7
8
Recently, another powerful tool for C–C bond formation is the
decarboxylative couplings.6 In 2006, Goossen and co-workers
reported an alternative way to prepare biaryls by decarboxylative
coupling between aryl halides and carboxylic acids.7c Since then,
there have been several more reports of decarboxylative couplings
of carboxylic acids or their salts.7 We, in view of this, wish to
develop a monometallic catalytic system to achieve decarboxy-
lative C–H functionalization. Here we report a copper-catalyzed
decarboxylative C(sp2)–C(sp3) coupling of cinnamic acids with
arenes (Scheme 1).
4
9
5
10
a
After screening various catalytic conditions (see ESIw), the
scope of the reaction with a variety of cinnamic acids 1 bearing
electron-withdrawing and donating substituents was investigated
(Table 1). Generally, moderate to good yields of the desired
Catalytic conditions: Cinnamic acid (1) (0.3 mmol), arene (2a)
b
(2 mL), CuO (10 mol%), DTBP (2 equiv.), 110 1C, 24 h, Ar. Isolated
yield based on cinnamic acid. Determined by H NMR.
c
1
products were obtained (entries 1–9). It is noteworthy that the
configuration of the double bond could be well retained. We
also can see that the electron-releasing methoxyl group (3d) at
the para-position is favorable for the coupling reaction compared
with the electron-withdrawing Cl or F group (3b and 3c) (entry 4
vs. entries 2–3). For the same substituted cinnamic acids, ortho- and
meta- positions afforded the corresponding products in slightly
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou, 215123, P. R. China. E-mail: jcmao@suda.edu.cn
w Electronic supplementary information (ESI) available: Experimental
1
procedures, H, 13C, HRMS spectral data and analytical data for the
products. CCDC 870917. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc33203e
c
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Chem. Commun., 2012, 48, 7847–7849 7847

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Table 2 Copper-catalyzed decarboxylative C(sp2)–C(sp3) coupling of
1d with different arenes 2a
Entry Yield of 4b (trans/cis)c
Entry Yield of 4b (trans/cis)c
Scheme 2 Copper-catalyzed coupling of 1d with other compounds
containing sp3 C–H bonds.
1
8
These valuable functional groups allow for further functionaliza-
tion. Methyl substituted naphthalenes also showed good activity in
this process (4n and 4o) (entries 13–14).
2
3
9
Subsequently, anisole was employed as the substrate in the
decarboxylative reaction. The desired product was obtained in 36%
yield as shown in Scheme 2. When cyclohexene was investigated,
the allylic oxidation product 4q was acquired in a yield of 66%.
In view of the results above, n-propylbenzene, n-butylbenzene
and methylcyclohexane were employed as the substrates for the
couplings with 4-methoxylcinnamic acid as shown in Scheme 3.
For n-propylbenzene, the two possible desired products were
obtained with a total yield of 70%. More involved was the
easier activated benzyl carbon. For n-butylbenzene which has
three methylene groups, three possible products were obtained
as expected. Here, a similar regioselectivity was found, since the
product from C–H functionalization that is close to the benzene
ring was predominantly obtained, with 39% yield. For methyl-
cyclohexane, two possible products were acquired with a total
yield of 66%, and the methyl moiety is primarily employed.
To gain more understanding of this reaction, we have preformed
some additional experiments in the presence of radical scavengers.
The results showed that TEMPO, AIBN or BQ (1 equiv.)
completely inhibited the reaction (see ESIw), which suggests that
the transformation may proceed via a radical reassembly.
10
4
5
11
12
6
13
14
7
a
Catalytic conditions: 4-methoxylcinnamic acid (1d) (0.3 mmol),
arene (2) (2 mL), CuO (10 mol%), DTBP (2 equiv.), 110 1C, 24 h, Ar.
In addition, we also investigated isotope effect: when toluene
was replaced with [D8]-toluene, product [D]-3d was achieved in
low yield. However, no hydrogen-incorporated product was
observed (Scheme 4a). In the absence of cinnamic acid, the self-
coupling of toluene was observed (Scheme 4b).8 Because it has
been suggested that reactions involving DTBP usually proceed via
a tert-butyl oxygen intermediate,8 we replaced 1d with styrene
butyl ether (5). However, no 3d product was observed
(Scheme 4c), which suggests that the postulated tert-butyl oxygen
intermediate does not exist in the present coupling process.
Moreover, a KIE of 3.0 was determined, which supports the
notion that the C–H bond cleavage is rate limiting (Scheme 4d).
Based on previous observations and literature reports,9,10 we
proposed a plausible catalytic cycle (Scheme 5). The catalytic
cycle starts with abstraction of H from toluene by t-BuOꢀ to give
radical A. The radical could be further oxidized to a benzyl cation
through a single-electron transfer process assisted by a Cu(II) ion.
Subsequently, addition of a benzyl cation to the a-position of the
b
c
Isolated yield based on cinnamic acid. Determined by 1H NMR.
decreased yields (3e and 3f) (entries 5–6). 3-Methylcinnamic acid
gave the desired product in 60% yield (entry 7). However, the
coupling reaction with 4-nitrocinnamic acid was unsuccessful (3j)
(entry 10). When more OMe groups were introduced into the
aromatic ring of cinnamic acid, the decarboxylative coupling could
also be performed efficiently (entries 8–9).
Subsequently, the scope of benzylic hydrocarbons was investi-
gated (Table 2). Moderate to good yields were obtained for several
products (entries 1–14). Different xylenes and mesitylene only
yielded mono-coupling products (4b, 4c, 4d, and 4e) (entries 1–4).
The relative configuration of 4b was confirmed by X-ray diffraction,
it showed that our method could retain the original double-bond
configuration well (Fig. 1). Direct decarboxylative coupling of 1d
with ethylbenzene was also successful (4f) (entry 5). Moreover,
cinnamic acid could also react with tert-butylbenzene to afford the
desired product accompanied by phenyl migration (4g) (entry 6). It
is important to note that chlorine, bromine and even iodine groups
are tolerated in this process (4h, 4i, 4j, 4k, 4l, and 4m) (entries 7–12).
Scheme 3 Copper-catalyzed oxidative decarboxylative C(sp2)–C(sp3)
coupling of 1d with other compounds containing sp3 C–H bounds.
Fig. 1 X-Ray of 4b.
c
7848 Chem. Commun., 2012, 48, 7847–7849
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We are grateful to the grants from the International S&T
Cooperation Program of Jiangsu Province (BZ2010048), the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, State Education Ministry, the Priority Academic
Program Development of Jiangsu Higher Education Institutions,
and the Key Laboratory of Organic Synthesis of Jiangsu Province.
Notes and references
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´
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C(sp2)–C(sp3) coupling reaction of cinnamic acids with
benzylic molecules was developed using di-tert-butyl peroxide
as oxidant under neutral conditions.
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c
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Chem. Commun., 2012, 48, 7847–7849 7849