unactivated fragments as the leaving group still remains a
big challenge. Herein, we disclose a novel Mn-promoted
aerobic oxidative CÀC bond cleavage of value for forma-
mide synthesis (Figure 1). The significance of this present
finding is 3-fold: (1) the method realizes CÀC σ-bond
cleavage with an unactivated alkyl chain fragment as
the leaving group; (2) environmentally friendly molecular
oxygen is used as the primary oxidant8,9 and the CÀC bond
cleavage proceeds via a superoxide radical pathway; (3) the
chemistry provides a practical, neutral, and mild synthetic
approach to formamides, which are important units in
biologically active molecules of wide substrate scope.10
Scheme 1. Aerobic Oxidation of Different Amines (1) with 2aa
a Standard reaction conditions; see entry 5, Table S1. b Isolated
yields; the conversions are nearly 100%. c The standard reaction
conditions without Mn(OAc)3 2H2O.
3
Figure 1. Simple synthetic approach to formamides.
57% yield, respectively. The structure of 3qa was further
confirmed by single-crystal X-ray analysis (see Figure S1,
Supporting Information). It is noteworthy that N-substi-
tuted anilines such as N-methyl- and N-ethylanilines could
be smoothly transformed into the desired products (3sa
and 3ta, Scheme 1). Under metal-free conditions, indoline
could be converted into the desired product in moderate
yield (3ua, Scheme 1). Interestingly, alkylamines also
worked well under the standard reaction conditions (3va,
3wa, and 3xa, Scheme 1). Furthermore, the conversions of
all the substituted amines are 100%.
Our studies commenced with the reactions of 4-amino-
benzonitrile (1a) and hexanal (2a) using toluene as solvent
at 90 °C under O2 (1 atm). Interestingly, N-(4-cyano-
phenyl)formamide was produced in 69% yield (entry 1,
Table S1 Supporting Information). Further studies in-
dicated that transition metals could benefit this transfor-
mation. Among these metal salts, Mn(OAc)3 2H2O was
the most effective, promoting the yield of 3aa to 84%
(entry 5, Table S1, Supporting Information).
3
Under these optimized conditions, the scope of substi-
tuted amine (1) was investigated (Scheme 1). Our results
indicate that anilines with both electron-donating and
electron-withdrawing groups operate well in this reaction,
giving moderate to excellent yields. Furthermore, substi-
tuents at different positions of the arene group (para-,
meta-, and ortho-position) do not affect its efficiency.
Notably, even when chloro-, bromo-, and iodo-substituted
aniline were employed as substrates, the desired forma-
mides 3pa, 3qa, and 3ra were formed in 72%, 72%, and
Scheme 2. Aerobic Oxidation of 1a with Different Aldehydes (2)a
(8) Dioxygen has been used as an ideal oxidant; for some reviews, see:
(a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105,
2329. (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (c) Sigman,
M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221. (d) Gligorich, K. M.;
Sigman, M. S. Angew. Chem., Int. Ed. 2006, 45, 6612. (e) Wendlandt,
A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
(f) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381.
(9) For some selected reactions on dioxygen activation in recent
years, see: (a) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010,
132, 7266. (b) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q.
Angew. Chem., Int. Ed. 2011, 50, 5678. (c) Wang, J.; Wang, J.; Zhu, Y.;
Lu, P.; Wang, Y. Chem. Commun. 2011, 47, 3275. (d) King, A. E.;
Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am.
Chem. Soc. 2010, 132, 12068. (e) Decharin, N.; Stahl, S. S. J. Am. Chem.
Soc. 2011, 133, 5732. (f) Campbell, A. N.; White, P. B.; Guzei, L. A.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116. (g) Du, F.-T.; Ji, J.-X.
Chem. Sci 2012, 3, 460. (h) Rolff, M.; Schottenheim, J.; Peters, G.;
a Standard reaction conditions; see entry 5, Scheme 1. b Isolated
yields.
The scope of the aerobic CÀC bond oxidative cleavage
to obtain formamides was further expanded to a variety of
substituted aldehydes (2) (Scheme 2). Our results indicated
thatthe aldehydeswithlongeralkyl chainstendedtoafford
higher yields of product (2aÀ2g, Scheme 2). Interestingly,
substrates withsteric hindrancedid not lower the efficiency
of this transformation (2f, Scheme 2). Furthermore, when
the leaving group was an aryl these substrates also worked
well (2h and 2i, Scheme 2).
As formamides are ubiquitous structural motifs that can
be found in many bioactive componds,10 the present
method provides a simple and easy practical protocol for
the construction of some bioactive compounds under neutral
€
Tuczek, F. Angew. Chem., Int. Ed. 2010, 49, 6438. (i) Schroder, K.; Join,
B.; Amali, A. J.; Junge, K.; Ribas, X.; Costas, M.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 1425. (j) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N.
Angew. Chem., Int. Ed. 2011, 50, 11088.
(10) (a) Miyauchi, M.; Endoh, Y.; Uematsu, T. Bull. Environ. Contam.
Toxicol. 1995, 55, 446. (b) Yuta, K.; Jurs, P. C. J. Med. Chem. 1981, 24, 241.
(c) Popoff, I. C.; Singhal, G. H.; Engle, A. R. J. Med. Chem. 1971, 14, 550.
Org. Lett., Vol. 14, No. 9, 2012
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