Four tandem C-H activations: A sequential C-C and C-O bond making via a Pd-catalyzed cross dehydrogenative coupling (CDC) approach

Article abstract of DOI:10.1021/ol302438z

An unprecedented aroylation at the ortho C-H bond with respect to a directing group has been accomplished via a Pd(II)-catalyzed cross dehydrogenative coupling approach using alkylbenzene as the synthetic equivalent of an aroyl moiety. The reaction proceeds through sequential C-C and C-O bond making at the expense of four consecutive C-H bond cleavages (three sp ³ benzylic C-H's and one sp² arene C-H) to selectively install an aroyl functionality at the proximal site of substrates containing various directing groups.

Full text of DOI:10.1021/ol302438z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Four Tandem CÀH Activations: A
Sequential CÀC and CÀO Bond Making via
a Pd-Catalyzed Cross Dehydrogenative
Coupling (CDC) Approach
Srimanta Guin, Saroj Kumar Rout, Arghya Banerjee, Shyamapada Nandi, and
Bhisma K. Patel*
Department of Chemistry, Indian Institution of Technology Guwahati,
Guwahati 781 039, India
patel@iitg.ernet.in
Received September 6, 2012
ABSTRACT
An unprecedented aroylation at the ortho CÀH bond with respect to a directing group has been accomplished via a Pd(II)-catalyzed cross
dehydrogenative coupling approach using alkylbenzene as the synthetic equivalent of an aroyl moiety. The reaction proceeds through sequential
CÀC and CÀO bond making at the expense of four consecutive CÀH bond cleavages (three sp3 benzylic CÀH’s and one sp2 arene CÀH) to
selectively install an aroyl functionality at the proximal site of substrates containing various directing groups.
The modern era of organic chemistry has brought about
many appealing results pertaining to transition-metal-
catalyzed CÀH bond activations with subsequent func-
tionalizations.1 Foundations to most CÀH activation
processes generally rely on the strategies of directing
group assisted CÀH bond functionalization2 and cross
dehydrogenative coupling (CDC).3 These two techniques
are highly appreciable due to being atom and step econom-
ic. Pertinent to these seminal achievements, protocols for
the direct conversion of CÀH bonds to CÀC bonds stand
out to be the key pillar in providing a great impetus to
modern synthetic chemistry, as CÀC bond formation is
regarded as the “holey grail” of organic chemistry.4 Oxi-
dative CÀH bond functionalizations have been success-
fully applied to construct CÀC bonds involving sp, sp2, or
sp3 hybridized carbons asmutual cross-coupling partners.5
(1) (a) Dyker, G. Handbook of CÀH Transformations: Applications in
Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Yu, J.-Q.; Shi, Z.-J.
CÀH Activation; Springer: Berlin, Germany, 2010. (c) Activation and
Functionalization of CÀH Bond; Goldberg, K. I., Goldman, A. S., Eds.;
ACS Symposium Series 885; American Chemical Society: Washington, DC,
2004. (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008,
41, 1013. (e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J. -Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Commun. 2010, 46, 677. (g) Gunay, A.; Theopold, K. H. Chem. Rev.
2010, 110, 1060. (h) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (i) Sun, C. -L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(j) Ackermann, L. Chem. Rev. 2011, 111, 1315.
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Chem. Res. 1995, 28, 154.
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C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (c) Yoo,
W. J.; Li, C. -J. Top. Curr. Chem. 2010, 292, 281. (d) Lie, B. J.; Shi, Z. J.
Chem. Soc. Rev. 2012, 41, 5588.
(6) (a) Deng, G.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47,
6278. (b) Deng, G.; Chen, W.; Li, C.-J. Adv. Synth. Catal. 2009, 351, 353.
(c) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J. Chem.;Eur.
J. 2009, 15, 333. (d) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171. (e) Guo,
(2) (a) Chatani, N. Directed Metallation; Springer: Berlin, Germany,
2008. (b) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624.
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X.; Li, C.-J. Org. Lett. 2011, 13, 4977. (f) Liegault, B.; Fagnou, K.
(3) (a) Li, C. -J. Acc. Chem. Res. 2009, 42, 335. (b) Ashenhurst, J. A.
Chem. Soc. Rev. 2010, 39, 540. (c) Scheuermann, C. J. Chem.;Asian J.
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r
10.1021/ol302438z
XXXX American Chemical Society

Despite the significant progress made in this area the more
challenging areneÀalkane couplings remain scarce which
is due to the inertness of sp3 CÀH bonds;6 thus muchofit is
yet to be explored. Very specifically pertaining to the
substrate directed areneÀalkane coupling there is only a
single precedence where 2-phenylpyridine or analogous
substrates have undergone direct CÀH alkylation using
unreactive cycloalkane as the other coupling partner (path
a, Scheme 1).6a However, the susceptibility of benzylic
CÀH bonds toward radical promoted functionalizations
by a single electron transfer (SET) have led to them being
the subject of further exploration.7
donor atoms. The first invokes a CDC approach8 that
usesaldehydesor alcoholsastheacylating equivalent(path
b, Scheme 1) while the second strategy proceeds through a
substrate-directed decarboxylation of R-keto carboxylic
acids.9 However, the present protocol (path c, Scheme 1)
demonstrates an unprecedented areneÀalkane coupling
(CÀC bond formation) with a subsequent CÀO bond
formation via four tandem CÀH bond activations to
selectively install an aroyl moiety at the proximal site of
directing group containing substrates.
Table 1. Screening of Reaction Conditions
Scheme 1. CDC Approaches for CÀC Bond Forming Reactions
via CÀH Bond Cleavage
entry
catalyst (mol %)
oxidant
temp (°C)
yield (%)a,b
1
Pd(OAc)2 (5)
Pd(TFA)2 (5)
PdCl2 (5)
TBHPc,f
TBHPc,f
TBHPc,f
TBHPc,f
TBHPc,f
TBHPc,g
TBHPd,g
120
120
120
120
120
120
120
120
100
120
120
53
15
30
42
73
85
20
00
77
00
00
2
3
4
PdBr2 (5)
5
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
nil
6
7
e,g
8
H2O2
9
TBHPc,g
Nil
In light of the above-mentioned, an initial foray was
intended toward CÀH benzylation using 2-phenylpyridine
(1) (1 equiv) and toluene (a) (10 equiv) as the prototypical
substrates using Pd(OAc)2 (5 mol %) and TBHP in decane
(5À6 M) (1 equiv). Interestingly, the reaction of the afore-
mentioned combinations at 120 °C resulted in an unpre-
cedented formation of phenyl(2-(pyridine-2-yl)phenyl)-
methanone (1a), an aroylated product (53%) instead of
the expected benzylated product (Table 1, entry 1). Thus,
toluene could be perceived as a new synthetic equivalent or
surrogate of the benzoyl functionality. In this case, incor-
porating a benzoyl functionality at the proximal site is at
the expense of four consecutive CÀH bond (three sp3
benzylic CÀH bonds and one sp2 arene CÀH bond)
cleavages. Prior to this report, the directed CÀH ortho-
acylation has been accomplished via two distinct ap-
proaches with substrates possessing various N and O
10
11
TBHPc
a Isolated yield. b Reaction time: 1.5 h. c Decane solution (5À6 M).
d 70% aqueous solution. e 30% aqueous solution. f 1 equiv. g 2 equiv.
Further optimizations were carried out by varying the
reaction parameters in a quest to improve the overall yield.
Other potential Pd catalysts such as Pd(TFA)2, PdCl2, and
PdBr2 wereevaluated(Table 1, entries2À4), and Pd(OAc)2
was the most effective catalyst giving superior results
(Table 1, entry 1). The use of Pd(TFA)2 gave poor con-
version (15%) along with the formation of multitudes of
side products (Table 1, entry 2). Although the reactions
withPdCl2 andPdBr2 (Table1, entries 3À4) wereclean and
smooth, the yields were modest as compared to that for
Pd(OAc)2 (Table 1, entry 1). An increase in the catalyst
loading to 10 mol % and in the TBHP quantity by 2-fold
provided substantial improvement in the isolated yield
(85%) (Table 1, entry 6). The nature of peroxides and their
medium of storage had a marked influence on the pro-
duct yield. For instance the use of either aqueous TBHP
or aqueous H2O2 as the oxidants proved to be ineffec-
tive (Table 1, entries 7À8). A decrease in the reaction
temperature (100 °C) reduced the product yield to 77%
(Table 1, entry 9). Control experiments carried out in the
absence of either Pd(OAc)2 or TBHP failed to give the
desired product (Table 1, entries 10À11) suggesting the
(7) (a) Fructos, M. R.; Trofimenko, S.; Mar Dıaz- Requejo, M.;
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Perez, P. J. J. Am. Chem. Soc. 2006, 128, 11784. (b) Bhuyan, R.;
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Robert-Peillard, F.; Muller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem.
Soc. 2008, 130, 343. (d) Fan, H.; Powell, D. A. J. Org. Chem. 2010, 75,
2726. (e) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2011, 133, 16382. (f) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.;
Zhang, H.; Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51, 1244.
(8) (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett.
2009, 11, 3120. (b) Basle’, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv. Synth.
Catal. 2010, 352, 1145. (c) Xiao, F.; Shuai, Q.; Zhao, F.; Basle’, O.;
Deng, G.; Li, C.-J. Org. Lett. 2011, 13, 1614. (d) Chan, C.-W.; Zhou, Z.;
Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926. (e) Wu, Y.; Li, B.;
Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13, 3258. (f) Li, C.; Wang,
L.; Li, P.; Zhou, W. Chem.;Eur. J. 2011, 17, 10208. (g) Chan, C.-W.;
Zhou, Z.; Yu, W.-Y. Adv. Synth. Catal. 2011, 353, 2999. (h) Park, J.;
Park, E.; Kim, A.; Lee, Y.; Chi, K. W.; Kwak, J. H.; Jung, Y. H.; Kim,
I. S. Org. Lett. 2011, 13, 4390.
(9) (a) Fang, P.; Li, M. Z.; Ge, H. B. J. Am. Chem. Soc. 2010, 132,
11898. (b) Li, M.; Ge, H. Org. Lett. 2010, 12, 3464.
B
Org. Lett., Vol. XX, No. XX, XXXX

Encouraged by this unique areneÀalkane coupling, the
optimized conditions were implemented in the coupling
reactions between a set of substituted alkylbenzenes with
arenes possessing directing groups such as 2-pyridyl,
2-oxopyridyl, and ketoxime ether (Scheme 2). The initial
investigations were focused on the reactions of 2-phenyl-
pyridine (1) with polymethylated benzenes, viz. o-xylene
(b), p-xylene (c), and mesitylene (d). All these coupling
reactions proceeded smoothly providing their respective
ortho-aroylated products (1bÀ1d) in excellent yields. The
lesser yield observed in the case of o-xylene compared to its
para (c) or meta (d) analogues is possibly due to the steric
hindrance of the ortho methyl group in o-xylene (b). The
main features of these reactions were the exclusive forma-
tion of monoaroylated products, with the other methyl
group(s) remaining intact. The reaction with p-methoxy-
toluene (e) afforded the expected product (1e) in an
excellent yield. However, when p-chlorotoluene (f) was
used as the coupling partner the product (1f) yield dropped
considerably (67%). These results imply that the electronic
effects of the substituents in the methylarenes affect the
reaction rates and the product yields. Substituted toluenes
possessing electron-donating groups undergo more facile
coupling with arenes than the substrate having an electron-
withdrawing group. Furthermore, the same optimized
reaction conditions were equally applicable to the 2-ary-
loxypyridine substrate, such as 2-(4-methoxyphenoxy)-
pyridine (2) possessing an additional O-linker between
the pyridyl and the aryl ring. The reaction of 2-(4-
methoxyphenoxy)pyridine (2) with the same set of methyl-
arenes gave moderate to high yields of their respective
monoaroylated products (2aÀ2e). Herein, a similar trend
in reactivity and selectivity were observed for methylarenes
when coupled with 2-(4-methoxyphenoxy)pyridine (2) as
was the case with substrate 2-phenylpyridine (1).
Scheme 2. Substrate Scope for the Synthesis of Ketone via CÀH
Functionalizationa
So far as the ortho-aroylation is concerned, the aryl
ketone oxime ethers as the substrates have significant
prospects. The 1,2-diacylarenes generated upon deprotec-
tion of oxime ether are useful precursors to a number of
biologically important scaffolds such as isoindoles, isoqui-
nolines, N-arylpthalimidines, and pthalazines.10 Thus, a
similar aroylation reaction was attempted with the acet-
ophenone O-methyl oxime (3) and toluene (a) employing
the above optimized conditions. Encouragingly, the reac-
tion provided an excellent yield of the o-aroylated product
(3a). Subsequent reactions were carried out with acetophe-
none O-methyl oxime (3) and other methylarenes as the
coupling partners. The yields of coupled products were
relatively higher (3bÀ3e) with p-chlorotoluene being the
lone exception giving a modest yield of the product (3f).
The effects of substituents present in the acetophenone
O-methyl oxime were investigated. p-Methoxyacetophenone
O-methyl oxime (4) underwent a facile aroylation with
toluene affording a high yield of the desired product (4a).
However with p-bromoacetophenone O-methyl oxime (5),
the product (5a) yield was moderate. The O-methyl oxime
of bicyclic ketones, viz. R-tetralone analogues (6À7),
a Reaction conditions: arenes (1À7) (1 mmol), methylbenzenes (aÀf)
(10 mmol), Pd(OAc)2 (0.1 mmol), TBHP in decane (5À6 M) (2 mmol),
120 °C, time 1À4 h. Reactions were monitored by TLC. Confirmed by
spectroscopic analysis. Yield of isolated pure product reported.
requirement of both the metal catalyst and the oxidant.
Solvent optimizations were not carried out as the methy-
larenes used were liquids which served both the purpose of
reactants and the reaction medium for these oxidative
aroylations. The results for various trial reactions are
summarized in Table 1.
(10) Kotali, A.; Harris, P. A. Org. Prep. Proc. Int. 2003, 35, 583.
Org. Lett., Vol. XX, No. XX, XXXX
C

underwent smooth reactions with toluene furnishing their
corresponding aryl ketones (6aÀ7a) in excellent yields.
Scheme 4. CDC Approaches for CÀC Bond Forming Reactions
via CÀH Bond Cleavage
Scheme 3. Proposed Mechanism for o-Aroylation via Sequential
CÀC and CÀO Bond Formation
Reductiveelimination of the PdcatalystfromIIaffords the
benzylic product (III) which further undergoes rapid oxi-
dation at its benzylic position to generate the keto func-
tionality (1a) via intermediates IV and V.11h All our
attempts to trap the benzylated product failed due to the
fast oxidation kinetics. The benzylic CÀH bond cleavage or
insertion of the benzyl radical might be involved in the rate-
determining step. This fact can be further rationalized from
the observations that the reactions worked better with
methylarenes possessing electron-donating groups com-
pared to those having electron-withdrawing substituents.
In an attempt to isolate the benzylated intermediate and
prevent further oxidation, 1 was reacted with ethylarenes
(ethylbenzene) instead of methylarenes under the standard
conditions (Scheme 4). However, the reaction yielded an o-
hydroxylated product (B) instead of the expected benzy-
lated product (A) leaving a major amount of unreacted
starting material (1) even after 24 h (Scheme 4). Since the
mechanistic picture is currently unclear, the usual acylation
mechanism proceeding via the in situ formation of benzal-
dehyde or benzyl alcohol cannot be completely ruled out.8
In conclusion, an aroylation protocol at the ortho CÀH
bond has been accomplished via sequential CÀC/CÀO bond
formations involving four CÀH bond activations. This is the
first illustration of an areneÀalkane coupling giving an o-
aroylated product involving activations of a nonreactive
benzylic sp3 CÀH of methylarenes and sp2 CÀH bonds of
arenes facilitated by the directing groups. With polymethy-
lated arenes, selective monoaroylated products were formed
without affecting the other methyl groups. Hence by judging
the practicality of the present protocol, it can be an additional
alternative to the existing acylation reactions.
The mechanism for these reactions can be depicted in
keeping with the observations of the control reactions that
were conducted. There was a considerable quenching of
the reaction between 2-phenylpyridine (1) and toluene (a)
in the presence of radical scavenger TEMPO giving <5%
yield of the expected product (1a), suggesting a possible
radical pathway. This observation indicates that TBHP is
possibly playing the role of both an oxidant and a radical
initiator. However, a GC-MS analysisofthe aliquotstaken
during an ongoing reaction of 1 with toluene (a) showed no
presence of either benzaldehyde or benzyl alcohol in the
reaction medium that could possibly form via a radical
oxidation of toluene (a). From these observations and
literature reports, a plausible mechanism has been pro-
posed (Scheme 3).6a,11 Presumably, TBHP generates a
radical at the benzylic carbon that undergoes addition to
the PdÀsubstratecomplex (I) toformthe intermediate(II).
Acknowledgment. B.K.P. acknowledges the support of
this research by the Department of Science and Technology
(DST) (SR/S1/OC-79/2009), New Delhi, and the Department
of Biotechnology (DBT) (BT/P/RC/03). S.G., S.K.R., and
A.B. thank CSIR for fellowships. Thanks are due to Central
Instruments Facility (CIF) IIT Guwahati for NMR spectra.
(11) (a) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319. (b)
Hall, T. L.; Lappert, M. F.; Lednor, P. W. J. Chem. Soc., Dalton Trans.
1980, 1448. (c) Boisvert, L.; Denney, M. C.; Hanson, S. K.; Goldberg, K. I.
J. Am. Chem. Soc. 2009, 131, 15802. (d) Fafard, C. M.; Adhikari, D.;
Foxman, B. M.; Mindiola, D. J.; Ozerov, O. V. J. Am. Chem. Soc. 2007,
129, 10318. (e) Albeniz, A. C.; Espinet, P.; Lopez-Fernandez, R.; Sen, A. J.
Am. Chem. Soc. 2002, 124, 11278. (f) Reid, S. J.; Baird, M. C. Organome-
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L.; Zhang, X.; Zhang, Y. Org. Lett. 2012, 14, 1238.
Supporting Information Available. General informa-
tion, experimental procedures, 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.
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The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX