MnO2 promoted sequential C-O and C-N bond formation via C-H activation of methylarenes: A new approach to amides

Article abstract of DOI:10.1021/ol4023886

A novel and efficient approach for the synthesis of amides has been developed through manganese dioxide promoted nondirected C-H activation of methylarenes under mild reaction conditions employing N-chloroamines as effective coupling partners.

Full text of DOI:10.1021/ol4023886

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
MnO2 Promoted Sequential CÀO and
CÀN Bond Formation via CÀH Activation
of Methylarenes: A New Approach to Amides
Rajeshwer Vanjari, Tirumaleswararao Guntreddi, and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science,
Banaras Hindu University, Varanasi-221005, India
knsinghbhu@yahoo.co.in; knsingh@bhu.ac.in
Received August 20, 2013
ABSTRACT
A novel and efficient approach for the synthesis of amides has been developed through manganese dioxide promoted nondirected CÀH activation
of methylarenes under mild reaction conditions employing N-chloroamines as effective coupling partners.
The development of novel chemical reactions and re-
cuperating the reaction conditions to maximize product
selectivity, energy efficiency, and environmental safety
remains the main thrust of current chemical research.
Hydrocarbons, derived from oil and natural gas, constitute
the most inexpensive and readily available feed stocks for
chemical industries. Therefore, direct formation of CÀC
and CÀX linkage via carbonÀhydrogen (CÀH) bond
activation of hydrocarbons is of immense importance
and has currently emerged as a challenging goal. This idea
has been mainly realized by means of chelation-assisted
CÀH activation1 and cross-dehydrogenative coupling
(CDC)2 strategy. Although these advances have been
extensively explored for CÀC and CÀO bond forma-
tion,3,4 there is still a dearth of information on CÀN bond
creation.5 In this perspective, CÀN bond formation and
eventual synthesis of amides involving CÀH bond activa-
tion of alkylarenes remains the cherished target.
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The amide is one of the most important functional
groups in chemistry, forming the basic building block of
a number of natural products, pharmaceuticals, and
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r
10.1021/ol4023886
XXXX American Chemical Society

polymers.6 Amides are commonly formed via reactions of
a carboxylic acid with an amine. A number of alternative
methods for amide bond formation have been developed
including Beckmann rearrangement,7 aminocarbonyla-
tion of aryl halides and alkynes,8 cross-coupling of for-
mamide with alkyl/aryl halides,9 oxidative amidation of
aldehydes/alcohols,10 and transamidation.11 However,
more economical, environmentally friendly, resource effi-
cient, and highly selective methods are in demand.12
Recent developments in the utilization of benzylic CÀH
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Figure 1. Amide synthesis through CÀH activation.
Table 1. Optimization of Reaction Conditionsa
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entry
promoter
MnO2
oxidant
temp (°C)
yield (%)b
1
2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
80
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
75
65
50
15
30
15
trace
trace
20
55
0
A-MnO2
Cu(OAc)2
CuI
3
4
ꢀ
(8) (a) Lopez, B.; Martinez, M.; Ortega, L.; Rodriguez, A.; Santos, D.
5
CuBr2
FeCl3
Organometallics 2013, 32, 649. (b) Xie, P.; Xia, C.; Huang, H. Org. Lett.
2013, 15, 3370. (c) Ueda, T.; Konishi, H.; Manabe, K. Org. Lett. 2012,
14, 5370. (d) Nordeman, P.; Odell, L. R.; Larhed, M. J. Org. Chem. 2013,
77, 11393.
6
7
MnCl2 4H2O
3
8
Mn(OAc)2 4H2O
3
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Chem. 2002, 67, 6232. (b) Schnyder, A.; Beller, M.; Mehltretter, G.;
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J. M. J. Angew. Chem., Int. Ed. 2012, 51, 1383. (c) Nguyen, T. B.; Sorres,
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9
NiCl2 6H2O
3
10
11
12
13
14
15
16
17
18
TBAI
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
0
K2S2O8
AgNO3
TBHP
TBHPc
TBHP
TBHP
0
0
0
80
60
100
65
40
75
a Reaction conditions: N-chloroamine (0.5 mmol), alkylarene (5 mmol),
oxidant (4 equiv), promoter (1 equiv), and acetonitrile (1.5 mL). b Isolated
yields after column chromatography. c Two equivalent.
bonds13 inspired us to look into the CÀH bond activation
of easily available and inexpensive methylarenes to accom-
plish direct formation of amides. Consequently and as a
part of our interest in developing useful synthetic protocols
for amides14 and other systems,15 we report herein, for the
first time, anefficient manganese oxide promoted synthesis
of amides via nondirected CÀH activation of methylben-
zenes (Figure 1).
(12) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
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Angew. Chem., Int. Ed. 2012, 51, 7250. (c) Zhou, W.; Zhang, L.; Jiao, N.
Angw. Chem., Int. Ed. 2009, 48, 7094. (d) Guin, S.; Rout, S. K.; Banerjee,
A.; Nandi, S.; Patel, B. K. Org. Lett. 2012, 14, 5294.
To fulfill the aim to activate the methyl CÀH bond of
toluene, an initial study using toluene and benzylamine as
reactants was made using CuBr2 and TBHP in acetonitrile
at 80 °C for 24 h, which gave rise to 40% yield of the
amidation product. Other copper salts were also screened
to improve the yield, but they did not surpass CuBr2. How-
ever, when CuBr2 was applied to the reactions involving
(14) (a) Vanjari, R.; Allam, B. K.; Singh, K. N. RSC Adv. 2013, 3,
1691. (b) Vanjari, R.; Allam, B. K.; Singh, K. N. Tetrahedron Lett. 2013,
54, 2553.
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15, 4202. (b) Singh, N.; Allam, B. K.; Raghuvanshi, D. S.; Singh, K. N.
Adv. Synth. Catal. 2013, 355, 1840. (c) Guntreddi, T.; Allam, B. K.;
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A. K.; Singh, K. N. Org. Lett. 2012, 14, 4326. (e) Guntreddi, T.; Allam,
B. K.; Singh, K. N. Synlett 2012, 2635.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Substrate Scope of the Reactiona
a Reaction conditions: N-chloroamine (0.5 mmol), alkylarene (5 mmol), oxidant (4 equiv), MnO2 (1 equiv), and acetonitrile (1.5 mL). Isolated yields
reported after column chromatography. b Second recycle. c Third recycle.
secondary amines such as morpholine and piperidine, it
failed to provide the corresponding amides. Considering
the oxidation activity16 of manganese salts, it was then
thought to be worthwhile to attempt Mn salts. The repla-
cement of CuBr2 with MnO2 for the reaction of morpho-
line with toluene succeeded well, giving the corresponding
amide, but that of benzylamine witnessed formation of
benzamide as a byproduct. Considering the high reactivity
of the nitrogenÀhalogen bond,17 we next envisioned to
employ N-chloroamines as a source of amine partner. To
our utmost pleasure, we obtained the desired amides from
N-chloroamines of both benzylamine and morpholine
without the formation of any byproduct. Now a detailed
investigation was carried out to optimize the reaction
conditions by varying different parameters such as pro-
moter, oxidizing agent, and temperature using a model
reaction of toluene and N-chlorobenzylamine, and the
findings are given in Table 1.
The screening was initiated using different metal salts
such as Cu(OAc)2, CuBr2, CuI, FeCl3, and NiCl2 6H2O
3
using TBHP asanoxidant. All of these trialsled us to finish
off MnO2 as the most suitable promoter for successful
activation of benzylic CÀH bonds to give the targeted
amide in reasonably high yield. CuI, CuBr2, and FeCl3
gave poor yields (entries 4À6), but Cu(OAc)2 performed
satisfactorily (entry 3). The use of amorphous MnO2
(A-MnO2) was less effective (entry 2) as compared to
(16) (a) Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem. Commun. 2005,
1321. (b) Sithambaram, S.; Ding, Y.; Li, W.; Shen, X.; Gaenzler, F.;
Suib, S. L. Green Chem. 2008, 10, 1029. (c) Firouzabadi, H.; Abbasi, M.
Synth. Commun. 1999, 29, 1485. (d) Taylor, R. J. K.; Reid, M.; Foot, J.;
Raw, S. A. Acc. Chem. Res. 2005, 38, 851. (e) Cao, H.; Suib, S. L. J. Am.
Chem. Soc. 1994, 116, 5334. (f) Iyer, A.; Del-Pilar, J.; King’ondu, C. K.;
Kissel, E.; Garces, H. F.; Huang, H.; El-Sawy, A. M.; Dutta, P. K.; Suib,
S. L. J. Phys. Chem. C 2012, 116, 6474. (g) Yu, X.; Liu, C.; Jiang, L.; Xu,
Q. Org. Lett. 2011, 13, 6184. (h) Wang, Y.; Kobayashi, H.; Yamaguchi,
K.; Mizuno, N. Chem. Commun. 2012, 48, 2642.
MnO2, whereas other manganese salts such as MnCl2 4H2O
and Mn(OAc)2 4H2O proved worthless (entries 7 and 8).
3
3
(17) (a) Kovacic, P.; Lowery, M. K.; Field, K. W. Chem. Rev. 1970,
70, 639. (b) Minakata, S. Acc. Chem. Res. 2009, 42, 1172. (c) Gassman,
P. G.; Dygos, D. K.; Trent, J. E. J. Am. Chem. Soc. 1970, 92, 2084.
After identification of MnO2 as the most effective promo-
ter, the studies were next directed toward the optimization
Org. Lett., Vol. XX, No. XX, XXXX
C

of molar proportion of TBHP and reaction temperature.
The reaction temperature of 80 °C and 4 equiv of TBHP
were found to be appropriate to bring about the utmost
conversion. Decreasing the molar ratio of TBHP resulted
in decrease of the yield. Changing TBHP to other oxidizing
agents such as K2S2O8 and AgNO3 was also unsuccessful.
TBHP in decane solution gave similar yields, but on
prolongation, it gave rise to the formation of carboxylic
acid, too. Effects of solvent on the reaction were not
studied in detail.
After having establishedthe reaction conditions, various
alkylarenes and N-chloroamines were subjected to the re-
action to assess the scope and versatility of the methodol-
ogy, and the outcome is summarized in Scheme 1. Toluene
derivatives such as p-xylene, m-xylene, o-chlorotoluene,
p-chlorotoluene, m-chlorotoluene, p-bromotoluene, p-
nitrotoluene, and mesitylene worked well and were effec-
tively converted into the corresponding amides in high
yields. Doubly methyl-substituted arenes such as p-xylene
and m-xylene and triply methyl-substituted mesitylene
were selectively converted to their corresponding mono-
substituted amides. With regard to N-chloroamines, cyclic
amines like morpholine and piperidine N-chloroamines
underwent the reaction smoothly, giving tertiary
amides. N-Chloroamines derived from aliphatic primary
amines, such as n-hexylamine, n-butylamine, benzylamine,
2-phenethylamine, and 1-phenethylamine, as well as those
obtained from aliphatic secondary amines such as N-
methylbenzylamine also reacted nicely to afford the corre-
sponding secondary and tertiaryamides. Steric effects were
not predominant, and their effect on the reaction yield was
minimal. While recyclable studies were conducted, MnO2
being heterogeneous in nature was recovered simply by
filtration and was recycled up to three times without any
significant loss in its activity after washing with acetone.
The XRD patterns of fresh and recycled MnO2 match well
with each other (Supporting Information).
Figure 2. Proposed mechanism.
oxidized by TBHP/MnO2 to benzaldehyde, which by
subsequent action of TBHP generates an acyl radical.18
Chloroamine on decomposition gives a nitrogen-centered
radical,17a which then reacts with the acyl radical to afford
the amide eventually.
In summary, we have developed a novel MnO2 pro-
moted approach for the synthesis of amides through a
nondirected CÀH bond activation of alkylarenes using
N-chloroamines as suitable amine partners.
Acknowledgment. We are thankful to the Department
of Science and Technology, New Delhi, for providing
financial support (Grant No. SR/S1/OC-78/2012).
Supporting Information Available. General information,
experimental procedure, spectral data, and copies of 1H and
13C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Based on literature survey and isolation of products, a
plausible mechanism is outlined (Figure 2). Toluene is
(18) Cadoni, R.; Porcheddu, A.; Giacomelli, G.; Luca, L. D. Org.
Lett. 2012, 14, 5014.
The authors declare no competing financial interest.
D
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