Page 3 of 5
Journal Name
RSC Advances
DOI: 10.1039/C4RA09922B
temperature 120 oC, in chlorobenzene (2 mL), time 14−22 h. bYield of
isolated pure product.
(B). In the presence of excess of TBHP, (B) or (B′) is transformed to
tertꢀbutyl benzoperoxate (C). A loss of tBuO radical from (C) gives
benzoxy radical. The radical species on subsequent ligation with the
Cu(II) complex (D) gives the Cu(III) intermediate (E). The reductive
elimination in the final step leads to the oꢀbenzoxylated product (1a)
while the Cu(I) generated is reoxidised to Cu(II) for next catalytic
cycle.
The optimised conditions were then implemented for oꢀ
benzoxylation of 2ꢀarylpyridines (1−5) using various substituted
benzylamines and the results are summarised in Scheme 2. Initially
benzyl amine (a) and benzyl amines possessing various electronꢀrich
groups viz. oꢀMe (b), pꢀMe (c) and pꢀOMe (d) were treated with 2ꢀ
phenylpyridine (1) for oꢀbenzoxylation at the proximal site of Nꢀ
atom. All the benzyl amines served as their respective ArCOO−
surrogates to provide good to moderate yields of their oꢀ
benzoxylated products (1a−1d) as shown in Scheme 2. Moderately
electronꢀdeficient groups such as pꢀBr (f) and pꢀF (g) when present
in phenyl ring of the benzyl amine coupled with (1) to give oꢀesters
(1e) and (1f) in lower yields of 48% and 29% (Scheme 2).
Arylmethyl amines bearing electronꢀdeficient substituents gave
lower yields compared to substrates possessing electronꢀrich groups
suggesting the importance of their electronic effects on the overall
process. Notably, 1ꢀnaphthylmethylamine (g) having a fused ring
reacted smoothly with (1) yielding naphthylcarboxylated (1g) in
49%. In addition to 2ꢀphenylpyridine (1), oꢀbenzoxylation of 2ꢀ(pꢀ
tolyl)pyridine (2) were also investigated with various arylmethyl
amines (Scheme 2). The selectivity and reactivity trends of
substituted benzyl amines towards oꢀbenzoxylation of (2) were
found to be identical as was observed for (1). Marginally better
yields were obtained for oꢀbenzoxylated products (2a−2f) with (2)
than (1) could be attributed to its better chelation ability with metal
catalyst due to presence of electronꢀdonating oꢀtolyl group. Directing
arene possessing two electron donating groups (–Me and –OMe) as Scheme 3 Proposed Mechanism for orthoꢀBenzoxylation
in 2ꢀ(4ꢀmethoxyꢀ3ꢀmethylphenyl)pyridine (3) showed identical
reactivity and yield trends as that of (2) toward oꢀbenzoxylation
when reacted with various benzylamines (a), (c) and (d) as shown in
Scheme 2. The scope of oꢀbenzoxylation for 2ꢀ(4ꢀ
bromophenyl)pyridine (4) with benzyl amine (a) and substituted
benzyl amines viz pꢀMe (c), and pꢀOMe (d) were also investigated.
All provided oꢀbenzoxylated products (4a−4d) in moderate yields
ranging from 51% to 57% (Scheme 2). Lower yields obtained in 2ꢀ
In conclusion this protocol demonstrates the use of benzyl amines
as an unconventional synthetic equivalent of arylcarboxy groups
(ArCOO−) which has been employed for the oꢀbenzoxylation of 2ꢀ
phenylpyridine derivatives. A plausible reaction mechanism involves
the in situ generation of intermediates such as imine and aldehyde
from arylmethylamine. The radical nature of the reaction has been
established by isolation of TEMPO ester. This protocol shows the
differential selectivities and reactivities of Cu and Pd catalysts for
(4ꢀbromophenyl)pyridine (4) could possibly arise from poor
chelating ability of (4) as compared to its neutral and electronꢀrich
the same reaction.
analogues (1,
chlorophenyl)pyridine (5) with pꢀmethoxybenzylamine (d) afforded
oꢀbenzoxylated products (5d) in modest yield of 39%.
2
and 3). Finally, reaction of 2ꢀ(4ꢀ
B. K. P acknowledges the support of this research by the
Department of Science and Technology (DST) (SB/S1/OCꢀ53/2013),
New Delhi, and the Council of Scientific and Industrial Research
(CSIR) (02(0096)/12/EMRꢀII).
a
Unfortunately, aliphatic amines such as butyl amine and
cyclohexylmethylamine failed to undergo any oꢀacetoxylation with
any of the directing arenes under the optimised condition.
To find out a possible reaction pathway for this protocol
systematic investigations were carried out. Analysis of the reaction 1 (a) G Dyker, Handbook of C−H Transformations: Applications in Organic
Notes and References
Synthesis; WileyꢀVCH: Weinheim, 2005; (b) J.ꢀQ. Yu, and Z.ꢀJ. Shi, C−H
Activation; Springer: Berlin, Germany, 2010; (c) T. Satoh and M. Miura,
Chem. Eur. J., 2010, 16, 11212; (d) X Chen, K. M. Engle, D.ꢀH. Wang
and J. –Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (e) T. W. Lyons
and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (f) L.ꢀM. Xu, B.ꢀJ. Li, Z.
Yang and Z.ꢀJ Shi, Chem. Soc. Rev., 2010, 39, 712; (g) D. A. Colby, R. G.
Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (h) J. Wencelꢀ
Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740;
(i) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011,
40, 5068; (j) C.ꢀL. Sun, B.ꢀJ. Li and Shi, Z.ꢀJ, Chem. Rev., 2011, 111,
1293; (k) L. Ackermann, Chem. Rev., 2011, 111, 1315; (l) A. S. Girard, T.
Knauber and C.ꢀJ. Li, Angew. Chem. Int. Ed., 2013, 52, 2; (m) S. E. Allen,
R. R. Walvoord, R. PadillaꢀSalinas and M. C. Kozlowski, Chem. Rev.,
2013, 113, 6234.
2 (a) S. K. Rout, S. Guin, K. K. Ghara, A. Banerjee and B. K. Patel, Org.
Lett., 2012, 14, 3982; (b) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and
B. K. Patel, Org. Lett., 2012, 14, 5294; (c) S. K. Rout, S. Guin, A.
Banerjee, N. Khatun, A. Gogoi and B. K. Patel, Org. Lett., 2013, 15, 4106;
(d) G. Majji, S. Guin, A. Gogoi, S. K. Rout and B. K. Patel, Chem.
Commun., 2013, 49, 3031.
mixture between (1) and (a) divulges the presence of benzaldehyde
and benzoic acid in the medium suggesting their intermediacy. A
control experiment carried out by reacting (1) with an equimolar
mixture of pꢀmethylbenzyl amine (c) and pꢀmethoxybenzoic acid
under the optimised condition gave product (1a) predominantly
(53%) along with a trace of (1d); suggesting arylcarboxylic acid is
not the main coupling partner. The coupling partner is most likely
tertꢀbutyl benzoperoxate generated in situ by the reaction of
aldehyde and TBHP; similar to our recent oꢀbenzoxylation of (1)
using terminal alkenes and alkynes.3 The aldehyde is obtained by the
hydrolysis of imine which in turn is formed by the oxidation of
benzylamine.4b To ascertain the nature of reaction mechanism a
reaction was performed in the presence of radical inhibitor TEMPO
(see Scheme S2, ESI†). Substantial quenching of product formation
and isolation of TEMPO ester (F) suggest a radical mechanism.
From the above experimental observations a tentative mechanism
has been proposed for this protocol as depicted in Scheme 3. Benzyl
amine oxidises to imine (A) which on hydrolysis gives benzaldehyde
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3