Copper-mediated selective C-H activation and cross-dehydrogenative C-N coupling of 2′-aminoacetophenones

Article abstract of DOI:10.1021/ol402750r

Isatins were obtained by cross-dehydrogenative C-N annulation and dealkylative C-N annulation of 2′-N-aryl/alkylaminoacetophenones and 2′-N,N-dialkylaminoacetophenones respectively in the presence of Cu(OAc)₂·H₂O/NaOAc/air. However, on reaction with CuBr, 2′-N-benzylaminoacetophenones underwent selective oxidation of an α-methylene group of amine rather than the 2-acetyl group to provide corresponding benzamides exclusively. Base played an important role in selective oxidation by lowering the temperature and time.

Full text of DOI:10.1021/ol402750r

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5726–5729
Copper-Mediated Selective CꢀH
Activation and Cross-Dehydrogenative
CꢀN Coupling of 20‑Aminoacetophenones
Andivelu Ilangovan* and Gandhesiri Satish
School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India
ilangovanbdu@yahoo.com
Received September 24, 2013
ABSTRACT
Isatins were obtained by cross-dehydrogenative CꢀN annulation and dealkylative CꢀN annulation of 20-N-aryl/alkylaminoacetophenones
and 20-N,N-dialkylaminoacetophenones respectively in the presence of Cu(OAc)2 H2O/NaOAc/air. However, on reaction with CuBr,
3
20-N-benzylaminoacetophenones underwent selective oxidation of an R-methylene group of amine rather than the 2-acetyl group to provide
corresponding benzamides exclusively. Base played an important role in selective oxidation by lowering the temperature and time.
Organic transformations via transition-metal-catalyzed
CꢀH bond activation have emerged as an exciting strategy
for construction of CꢀC and Cꢀheteroatom bonds.1
Consequently, the processes concerning cross-coupling
between Csp3ꢀH and NꢀH centers and dealkylation reac-
tions have received much consideration.2 However, such
examples are only few.
Conversion of readily available tertiary amines into sec-
ondary amines and amides is considered as an important
value addition process in the synthesis of pharmaceuticals
and fine chemicals.3 For demethylation of tertiary amine cata-
lytic systems, such as Ruꢀ and Irꢀpolypyridyl complexes,4a
CuCl/TBHP,4b and Fe(II)-mediated Polonovski-type re-
action,4c were found to be better over conventional
methods.5 Very recently, FeCl2/TBHP was used as catalyst
for intermolecular dealkylative amidation between tertiary
amine and anhydride6 or aldehyde.7 However, to the best
of our knowledge, intramolecular equivalents of such a
reaction are not yet known. Similarly, oxidation of the
R-methylene group of amine to primary amide was re-
ported using catalysts such as RuCl3,8 Ru(OH)x/Al2O3/air
(5 bar),9 CuBrꢀK2CO3/air,10 manganese oxide octahedral
molecular sieves (OMS-2),11 and ZnBr2/TBHP or FeCl3/
TBHP.12 The majority of these reports deal with the
coversion of benzylamine derivatives to the corresponding
benzamides, and chemoselectivity is not addressed. This
may be due to the requirement of high temperature/
pressure or use of strong co-oxidant. Chemoselective
(1) For a review, see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. For references, see: (b)
Zheng, Q. J.; Feng, P.; Liang, Y. F.; Jiao, N. Org. Lett. 2013, 15, 4262. (c)
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Org. Lett. 2013, 15, 2274. (c) Nishioka, Y.; Uchida, T.; Katsui, T. Angew.
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Fronert, J. ACS catal. 2012, 2, 2810. (b) Qian, L.; Juan, C. Chem Res.
Chin. Univ. 2009, 25, 861. (c) Kok, G. B.; Scammells, P. J. Bioorg. Med.
Chem. Lett. 2010, 20, 4499.
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(7) Li, Y.; Jia, F.; Li, Z. Chem.;Eur. J. 2013, 19, 82.
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Commun. 2012, 48, 2642.
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M. Chem. Commun. 2012, 48, 12237.
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Csutoras, C.; Zhang, A.; Bidlack, J. M.; Neumeyer, J. L. Bioorg. Med.
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r
10.1021/ol402750r
Published on Web 11/05/2013
2013 American Chemical Society

oxidation of the CꢀH bond adjacent to nitrogen against the
easily oxidizable acetophenone group is a challenging task.
Isatins are privileged structural motifs found in pharma-
ceuticals and dyes,13 find applications as precious synthetic
intermediates,14,15 and signal several promising applica-
tions. Two major approaches are followed for the synthesis
of isatins. One involves the reaction of aniline with suitable
carbonyl precursors,16ꢀ18 and the other involves oxidation
of a preexisting aromatic ring.19 These methods are gen-
erally associated with harsh and tedious synthetic proce-
dures. Although strategies such as reaction between 2-oxo-
2-(arylamino)acetates and -arynes20 and intramolecular
oxidative cyclization of formyl-N-arylformamide21 or N-aryl-
acetamides22 (Scheme 1) did provide access to N-arylisatins,
typical starting materials which are difficult to prepare were
needed.
Our optimization studies began with the examination of
compound 1a as a typical substrate for CꢀH bond activation.
In the presence of Cu(OAc)2 H2O (0.5 equiv)/air at 80 °C
3
isatin was formed in low yield (Table 1, entry 1). It was
envisaged that a base could be used for removal of proton
from either acetyl group or amine.
Scheme 1. Methods for the Synthesis of Isatin
During the final stages of preparing this manuscript,
Cheng et al.23 and Deng et al.24 have independently
reported the conversion of 20-N-aryl/alkylaminoacetophe-
nones into isatins using CuI and SeO2, respectively. The
former method requires very high temperature (140 °C), high
boiling solvent (o-dichlorobenzene), and 2,20-bipyridine li-
gand. SeO2, which was used in the later method, is considered
to be harmful even at residual level in pharmaceuticals.
Moreover, both procedures studied only the CꢀN bond
formation of 20-N-aryl/alkylaminoacetophenones and did
not consider the functionalization of 20-N,N-dialkylaminoace-
tophenones, chemoselective oxidation of CꢀH bond adjacent
to nitrogen, and the role of amine in the oxidation process.
In the present study, we observed a facile cross dehy-
drogenative and delalkylative CꢀN coupling of 20-N-aryl/
alkylaminoacetophenones and 20-N,N-dialkylaminoaceto-
phenones respectively in the presence of Cu(OAc)2.H2O
(0.5 equiv)/NaOAc (1.5 equiv)/air at relatively low tem-
perature (80 °C). Thus isatins were produced in very good
yield. It was also observed that secondary amines can be
selectively oxidized to amides in the presence 2-acetyl
group using catalytic quantity of CuBr. Further, this study
provided clear evidence for the role of amine group in the
CꢀH activation process. Herein, we portray our approach
toward selective funtionalization of 20-aminoacetophe-
nones using Cu(II) and Cu(I) catalysts (Scheme 1).
Among a set of bases screened, NaOAc furnished good
yield (Table 1, entry 4), while use of K2CO3 and K3PO4
resulted only in moderate yield (Table1, entry 2 and 3).
Et3N asa base produced a complex mixture of products. In
the absence of copper source, no product was obtained
(Table 1, entry 5). Other copper catalysts such as Cu(NO3)2,
Cu(ClO4)2, CuCl2, CuBr2, CuSO4, CuI, and CuBr provided
isatin only in low yield. This preliminary result indicates that
Cu(II) catalysts are better than Cu(I) for isatin formation.
DMSO was more effective among all the solvents such as
toluene, DMF, DMA, CH3CN, and IPA studied. It was
found that 0.5 equiv of Cu(OAc)2 H2O and 1.5 equiv of
NaOAc in DMSO at 80 °C are a superlative combination to
provide isatin in high yield (82%, entry 4).
3
Under the above optimized conditions the substrate
scope was examined. As summarized in Table 2, the
substrates 1aꢀh with no substitution on the 20-aminoace-
tophenone ring afforded isatins 3aꢀh in good yield. Com-
pounds 1dꢀg with N-alkyl substituents reacted slowly
compared to N-benzyl substituent. However, compound
1i, a primary amine, afforded the desired product 3i only in
traces even after a long time. Notably, substrate 1h with a
phenyl group attached to amine gave a very high yield of
the product 3h in the shortest time, indicating that the
electronic factor has significant influence in the reaction.
Halogen substituents on the phenyl ring are well tolerated,
and 5-halo-N-substituted isatins 3jꢀp were obtained in
good yields. There was an increase in the rate of the
reaction and yield when electron-donating substituents
such as 3,5-dimethoxy and 3,4,5-trimethoxy groups are
present on the phenyl ring (3qꢀu). Compounds 1v and 1w
with acetyl and benzoyl amide groups did not undergo
reaction to give expected products 3v and 3w. Overall, this
method has been prove to be versatile for the synthesis of
N-alkyl- as well as N-aryl-substituted isatins.
(13) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104.
(14) (a) Anshu, D.; Vijay, P.; Anuj Kumar, J.; Kuldeep, S. R. Green
Chem. 2011, 13, 2135. (b) Anand Kumar, A.; Kumar, M. Green Chem.
2011, 13, 1332.
(15) (a) Rajasekaran, T.; Karthik, G.; Sridhar, B.; Subba Reddy,
B. V. Org. Lett. 2013, 15, 1512. (b) Jiang, B.; Wang, X.; Xu, H. W.; Tu,
M. S.; Tu, S. J.; Li, G. Org. Lett. 2013, 15, 1540.
(16) Bonnefoy, J.; Martinet, J. Compt. Rend. 1921, 172, 220.
ꢀ
(17) Stolle, R. J. Prakt. Chem. 1922, 106, 137.
(18) Pinto, A. C.; Lapis, A. A. M.; da Silva, B. V.; Bastos, R. S.;
Dupont, J.; Neto, B. A. D. Tetrahedron Lett. 2008, 49, 5639.
(19) Yadav, J. S. Synthesis 2007, 693.
(20) Rogness, D. C.; Larock, R. C. J. Org. Chem. 2011, 76, 4980.
(21) Tang, B. X.; Song, R. J.; Wu, C. Y.; Liu, Y.; Zhou, M. B.; Wei,
W. T.; Deng, G. B.; Yin, D. L.; Li, J. H. J. Am. Chem. Soc. 2010, 132,
8900.
(22) Sun, J.; Liu, B.; Xu, B. RSC Adv. 2013, 3, 5824.
(23) Huang, P. C.; Gandeepan, P.; Cheng, C. H. Chem. Commun.
2013, 49, 8540.
(24) Liu, Y.; Chen, H.; Hu, X.; Zhou, W.; Deng, G. J. Eur. J. Org.
Chem. 2013, 4229.
Org. Lett., Vol. 15, No. 22, 2013
5727

Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Synthesis of Highly Substituted N-Alkyl- and
N-Arylisatins Using Copper(II) Catalyst from Secondary and
Tertiary Aminesa
entry
Cu catalyst
base
solvent time (h) yieldb (%)
1
Cu(OAc)2 H2O
DMSO
K2CO3 DMSO
K3PO4 DMSO
24
15
15
4
55
3
2
Cu(OAc)2 H2O
69
3
3
Cu(OAc)2 H2O
56
3
4
Cu(OAc)2 H2O NaOAc DMSO
82
3
5
NaOAc DMSO
24
20
20
20
20
20
12
16
16
12
12
12
12
ndc
52
6
Cu(OAc)2 H2O
NaOAc DMF
NaOAc DMA
NaOAc CH3CN
NaOAc toluene
NaOAc IPA
3
7
Cu(OAc)2 H2O
54
3
8
Cu(OAc)2 H2O
trace
ndc
ndc
63
ndc
ndc
58
3
9
Cu(OAc)2 H2O
3
10
11
12
13
14
15
16
17
Cu(OAc)2 H2O
3
Cu(NO3)2
Cu(ClO4)2
CuSO4
CuCl2
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
NaOAc DMSO
CuBr2
CuI
70
64
CuBr
68
a Reaction conditions: 1-(2-benzylaminophenyl)ethanone 1a (1 mmol),
[Cu] (0.5 mmol), base (1.5 mmol) in solvent (2 mL) at 80 °C under air
atmosphere. b Isolated yield. c Not determined.
As a part of the study the reactivity of different tertiary
amines such as 2d, 2l, 2q, and 2x was examined under the
optimized reaction conditions (Scheme 2). Remarkably,
compound 2d underwent facile dealkylative CꢀN bond
formation to provide isatin 3d in good yield (70%). To
the best of our knowledge, this is the first example of
intramolecular CꢀN bond cleavage and CꢀN bond for-
mation taking place in single step in the presence of
copper catalyst. Further, 4-bromo- and 3,5-dimethoxy-
substituted 20-aminoaectophnones 2l and 2q, respectively,
underwent reaction to provide isatin 3l and 3q in good
yield. Notably, compound 2x afforded N-methylisatin 3d
in 68% yield, indicating debenzylation takes place faster
than demethylation. During the course of formation of
3d from 2x, intermediate 1d was isolated indicating that
the reaction proceeds via mono-demethylation followed
by oxidative cyclization. This study proves that even
tertiary amines can be used as starting materials for isatin
synthesis.
Next, we examined the effect of copper(I) catalyst on
20-N-benzylaminoacetophenones in CH3CN and air oxi-
dant (Scheme 3). Compound 1aunderwent selective oxida-
tion of benzylic CꢀH bond adjacent to amine, over
another easily oxidizable acetyl group, in the presence of
CuBr (20 mol %) in CH3CN solvent and air oxidant at
relatively low temperature (80 °C)22,23 to produce N-(2-
acetylphenyl)benzamide (4a) in 52% isolated yield. There
was no need for the use of base and co-oxidant.10
a Reaction conditions: 1aꢀw (1 mmol), Cu(OAc)2 H2O (0.5 mmol),
3
NaOAc (1.5 mmol), DMSO (2 mL). b Isolated yield. c,d Tertiary amine as
starting material.
were converted into the corresponding amides 4b, 4c, 4n,
4s, and 4u, respectively, in good yield. None of these
reactions produced isatin at all. Under the same reaction
conditions, simple a benzylamine underwent oxida-
tion to benzamide, only slowly in low yield (15%, 15 h),
which indicates that the acetyl group plays a role in
oxidation step. As expected, 1-(2-(ethylamino)phenyl)-
ethanone (1e) did not undergo reaction under the same
conditions.
To deepen our understanding on the role of the amine
group in the reaction mechanism, substrates 5a, 5b, 5c, and
6 containing substituents H, 2-OH, 4-OMe, and 4-NH2,
respectively, were identified and subjected to oxidation
using Cu(OAc)2 H2O (0.5 equiv)/NaOAc (1.5 equiv)/air
3
in DMSO at 80 °C (Scheme 4). Except for compound 6
undergoing oxidation to compound 7, no other substrate
underwent oxidation of the acetyl group. This result and
dealkylative CꢀN bond-forming reactions of tertiary
Considering the importance of converting amine
to amide,13,14 other benzyl amines 1aꢀc, 1n, 1s, and 1u
5728
Org. Lett., Vol. 15, No. 22, 2013

Scheme 3. Copper-Catalyzed Oxidation of N-Benzyl-20-
Scheme 5. Plausible Mechanism for Cu(II)-Catalyzed CꢀN
aminoacetophenonesa,b
Bond Formation
catalysts, are key intermediates in various organic trans-
formations.4 As shown in Scheme 5, on reaction with basic
and electron-rich amine, Cu(II) undergoes reduction to
Cu(I) and substrate activation takes place.25 Further, the
deprotonation of acetyl group by a base helps the forma-
tion of CꢀN bond faster. Cu(I) formed in the process is
reoxidized to Cu(II) in the presence of air, and this forms a
comfortable catalytic cycle.
a Reaction conditions: 1aꢀu (1 mmol), CuBr (20 mol %), CH3CN
(2 mL). b Isolated yields based on conversion (70% conversion).
In conclusion, we have successfully developed an effi-
cient copper(II)-catalyzed cross-dehydrogenative intramo-
lecular CꢀN coupling of an acetyl group and an amine to
furnish isatins at relatively lower temperature. We have
also observed for the first time that tertiary amines under-
go intramolecular CꢀH bond oxidation, CꢀN bond clea-
vage, as well as CꢀN bond formation to produce isatins in
the presence of Cu(II) catalysts. Cu(I) in the presence of air
selectively oxidized benzyl amines over acetophenone to
the corresponding amides in CH3CN solvent. Application
of copper catalysts for oxidative transformations in or-
ganic synthesis is currently underway in our laboratory.
Scheme 4. Cu(OAc)2 H2O-Catalyzed Oxidation of Some
Acetophenones
3
amines confirms that the amine group plays an important
role and the 2-amino group may provide anchiomeric
assistance during the CꢀH bond activation. This also
confirms the role of a base.
Acknowledgment. G.S. thanks UGC, New Delhi, for
the award of a fellowship. We thank DST-FIST for the
use of the NMR facility at the School of Chemistry,
Bharathidasan University.
Considering the role of amine and base, a suitable
mechanism is proposed. It has recently been established
that the imines or iminium ions, generated by oxidation of
CꢀH bonds adjacent to nitrogen using transition-metal
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(25) (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2011, 50, 11062. (b) Yu, J.; Yang, H.; Jiang, Y.; Fu, H. Chem.;
Eur. J. 2013, 19, 4271.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5729