Tetrahedron Letters
Oxidative synthesis of benzamides from toluenes and DMF
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Jian-Bo Feng , Duo Wei , Jin-Long Gong , Xinxin Qi , Xiao-Feng Wu
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Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou, Zhejiang Province 310018, People’s Republic of China
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
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a r t i c l e i n f o
a b s t r a c t
Article history:
An interesting oxidative procedure for the synthesis of benzamides has been developed through the
cleavage of sp CAH bond of methyl arenes with N-substituted formamides. Various benzamides were
prepared in low to moderate yields. Even though the yields are moderate in general, this new synthetic
procedure provides another option for benzamide synthesis.
Received 19 June 2014
Revised 17 July 2014
Accepted 22 July 2014
Available online 29 July 2014
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Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Benzamide
Oxidation
Toluene
Formamide
tert-Butyl hydrogen peroxide
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The development of novel chemical approach to improve the
synthetic efficiency, atom economy, and benign environmental
impact is still the main issue in current organic synthesis. Under
this background, the CAH activation of methyl arenes has attracted
cross-coupling of formamides with organohalides, hydration of
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nitriles,
modified Staudinger reaction,
rearrangement of
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oximes, transamidation, and so on. Although many methodolo-
gies of amide synthesis have been published these years, more
economic, environmentally friendly, and efficient strategies still
need to be explored. Herein, we wish to report the development
of an oxidation system for the benzamide synthesis via sp3 CAH
bond activation of methyl arenes with N-substituted formamides.
We employed toluene 1a and N,N-dimethylformamide (DMF)
2a as the initial substrates in the presence of 20 mol % TBAI and
4 equiv TBHP at 80 °C. Fortunately, we got N,N-dimethylbenzamide
3aa in 5% GC yield (Table 1, entry 1). Encouraged by this result, we
proceeded to optimize the reaction conditions. We found that by
decreasing the amount of TBAI to 10 mol %, the yield of amide
product 3aa was raised (Table 1, entry 2). While increasing the
amount of TBHP to 6 equiv or 8 equiv, the 6 equiv gave better yield
(Table 1, entries 3 and 4). The yield has no significant change when
changing the reaction temperature to 100 or 60 °C (Table 1, entries
5 and 6). However, replacing TBHP with a series of oxidants includ-
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a great deal of interest in both academic and industrial research.
Among these, the oxidative cleavage of sp3 CAH bond and subse-
quent coupling has emerged as an efficient strategy to access
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amides, esters, and other carbonyl compounds. In the known pro-
cedures, transition-metal-catalyzed CAH bond functionalization
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approach has made a profound progress, including copper, man-
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ganese, palladium, and so on. On the other hand, the oxidation
system with cheap catalyst or without transition-metal salts is
considered as attractive methodology in organic synthesis and
more and more organic chemists are putting their efforts in this
area. Recently, iodine or tetrabutylammonium iodide (TBAI)-based
catalytic system has drawn much attention for they can avoid the
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usage of transition-metal catalysts. Furthermore, the combination
of TBAI and tert-butyl hydroperoxide (TBHP) was proven to be
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more efficient in oxidation reaction, especially in CAH activation.
The amide is one of the most widely used functional groups in
ing di-tert-butyl peroxide (DTBP), H
acid (mCPBA), benzoyl peroxide (BPO), and O
7–11), the yields were decreased. While employing I
catalyst, only trace amount of product was found (Table 1, entries
12 and 13). Notably, when 10 mol % Zn(OAc) , ZnI , ZnBr , ZnCl
was used as additive, higher conversions were obtained (Table 1,
entries 14–17). We were delighted to find that 20 mol % ZnBr
2
O
2
, meta-chloroperoxybenzoic
(Table 1, entries
or KI as the
chemistry and plays
a
significant role in natural products,
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biomolecules, pharmaceuticals, and agrochemicals. In general,
amides are synthesized by the reaction of carboxylic acids or their
active derivatives, such as acid anhydrides, acyl halides, aldehydes,
and esters with corresponding amine.9 Other alternative methods
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include acylation of amines with aldehydes or alcohols,
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afforded 3aa in the highest yield (Table 1, entry 18). Furthermore,
several typical solvents were screened subsequently and
acetonitrile was found to be the optimal solvent for our oxidation
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040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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