Terminal aryl alkenes and alkynes as arylcarboxy surrogates toward o -Benzoxylation of 2-phenylpyridine catalyzed by copper

Article abstract of DOI:10.1021/ol500224e

A variety of styrenes and phenylacetylenes serve as excellent arylcarboxy sources in bringing about substrate directed o-benzoxylation of 2-phenylpyridine derivatives catalyzed by Cu(II) in the presence of TBHP. This reaction proceeds via formation of phenylglyoxal followed by decarbonylation to benzoyl radical/benzaldehyde which acts as the arylcarboxy source.

Full text of DOI:10.1021/ol500224e

Letter
pubs.acs.org/OrgLett
Terminal Aryl Alkenes and Alkynes as Arylcarboxy Surrogates
toward o‑Benzoxylation of 2‑Phenylpyridine Catalyzed by Copper
Saroj Kumar Rout,† Srimanta Guin,† Anupal Gogoi, Ganesh Majji, and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati-781039, India
S
* Supporting Information
ABSTRACT: A variety of styrenes and phenylacetylenes serve as excellent arylcarboxy sources in bringing about substrate
directed o-benzoxylation of 2-phenylpyridine derivatives catalyzed by Cu(II) in the presence of TBHP. This reaction proceeds via
formation of phenylglyoxal followed by decarbonylation to benzoyl radical/benzaldehyde which acts as the arylcarboxy source.
a b
,
Table 1. Screening of Reaction Conditions
he combination of transition metal catalysts and
Tchelation-assisted groups has brought about a renaissance
in organic chemistry providing unprecedented results through
selective functionalizations of unreactive ortho C−H bonds
particularly for the construction of C−C and C−heteroatom
bonds.1 Thus C−H bond activation is one of the most alluring
approaches in organic synthesis that obviates substrate
prefunctionalization, thereby reducing the number of synthetic
steps and making the method atom economic. Recently, our
group has paid substantial attention to C−C and C−O bond
formations via activation of sp2 C−H and sp3 C−H bonds2,3
using a combination of transition metal catalysts and oxidants.
Through sp3 C−H activation, the inert alkylbenzenes have been
found to be surrogates of ArCH2O−,3a ArCO−,3b,c Ar-
COO−,3e and ArCH2−3e equivalents.
Vinylations of substrates possessing directing groups have
been successfully achieved using expensive metal catalysts such
as Rh, Ru, and Pd.4 Thus, it would be desirable and appreciable
if the same can be achieved using less expensive and more
environmentally benign metals such as Cu, albeit its use is so far
unfamiliar in this forum. To check the efficacy of a copper
catalyst toward radically induced o-alkenylation of 2-phenyl-
pyridine (1) an initial reaction was performed using p-methoxy
styrene (e) as the alkenyl source in the presence of Cu(OAc)2
(10 mol %) and oxidant TBHP (3 equiv) in chlorobenzene at
100 °C (Table 1, entry 1). Instead of the expected o-alkenylated
product the reaction interestingly provided o-benzoxylated
product (1e) exclusively. This result is rather surprising as
styrene is not known to be the synthetic equivalent for the
benzoxy (ArCOO−) group. Related to the similar oxidation of
alkenes, styrenes are reported to undergo Wacker type
oxidation to give phenylacetaldehyde5 while stilbenes are
reported to yield 1,2-diketones.6 Irrespective of the nature of
the mechanism the current o-benzoxylation of 2-phenylpyridine
(1) from styrene which is serving as ArCOO− surrogate via
loss of one carbon atom is unprecedented in the literature.
c
entry
catalyst (mol %)
oxidant (equiv)
temp (°C)
yield (%)
1
Cu(OAc)2 (10)
CuBr (10)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (4)
TBHP (5)
TBHP (5)
TBHP (5)
TBHP (5)
100
100
100
100
100
100
100
100
100
100
100
120
46
27
21
28
35
15
33
55
62
71
72
78
2
3
CuBr2 (10)
4.
5.
6.
7
CuCl (10)
CuCl2 (10)
Cu(OTf)2 (10)
CuI (10)
8
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (20)
Cu(OAc)2 (30)
Cu(OAc)2 (20)
9
10
11
12
a
Reaction conditions: 2-phenylpyridine (1) (0.5 mmol), p-methoxy
styrene (e) (1 mmol), in chlorobenzene (1 mL), time 10 h. Isolated
b
c
yield. Decane solution (5−6 M).
Acetoxylation7 and hydroxylation7d−f,8 are two common
forms of C−O bond formation via C−H bond activation;
however reports on benzoxylation are relatively fewer in
numbers. Prior to this observation, o-benzoxylation of 2-
phenylpyridine (1) has been achieved using benzoate iodonium
salts by the Sanford group.9 The same has been demonstrated
using either the carboxylic acid/salt10 or its derivatives such as
anhydride,11 acid chloride,12 or peroxide13 as the arylcarboxy
sources using various metal catalysts (path-a, Scheme 1).
Further, aldehyde (ArCHO) and alkylbenzene (ArCH3) have
been used as alternative sources of the ArCOO− group during
o-benzoxylation of 2-phenylpyridine by Huang et al. (path-b,
Scheme 1).14 While for some other directing groups such as
ketoxime ether15 and acetanilides,16 o-benzoxylation has been
Received: January 22, 2014
© XXXX American Chemical Society
A
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Letter
a
,b
Scheme 1. Various Approaches to o-Benzoxylation
Scheme 2. Substrate Scope for o-Benzoxylation
achieved using carboxylic acid in the presence of Pd and Ru
catalysts respectively. Thus the present method using the Cu
catalyst and styrene as the benzoxy surrogate is novel and
unparalleled in the literature (path-c, Scheme 1).
Encouraged by this unique result, further optimizations were
carried out to attain a better yield of the desired product.
Among several catalysts screened, Cu(OAc)2 (Table 1, entry 1)
was found to be superior to various Cu(I) [CuBr, CuCl, and
CuI] and Cu(II) [CuBr2, CuCl2, Cu(OTf)2] salts (Table 1,
entries 2−7). Subsequently by increasing the TBHP (5−6 M)
quantity from 3 to 4 equiv, the product yield was enhanced to
55% (Table 1, entry 8) while a further improvement of 7%
(Table 1, entry 9) was observed using 5 equiv of the same. The
use of 6 equiv of TBHP did not make any further augmentation
in the yield. A 2-fold increase in the catalyst loading led to a
better yield (71%, Table 1, entry 10), while no significant
change in yield occurred with a 3-fold excess of the catalyst
loading. The yield was increased by an additional 7% (Table 1,
entry 12) upon performing the reaction at 120 °C. Solvents
toluene (68%) and THF (38%) were less efficient compared to
the use of chlorobenzene (78%), whereas other solvents such as
dioxane, DMSO, DMF, and DCE were completely ineffective
in bringing about this transformation. The use of aq. TBHP in
lieu of a decane solution of TBHP (5−6 M) was found to be far
less effective giving only a 27% yield of the desired product
under identical reaction conditions. The reaction failed to
proceed in the absence of either the catalyst or the oxidant
suggesting their combination as an essential requirement. Thus
the use of Cu(OAc)2 (20 mol %) and TBHP (5 equiv) in
chlorobenzene at 120 °C was found to be the optimized
conditions for our subsequent exploration to extend the scope
of this transformation.
The above optimized conditions were then executed for o-
benzoxylation of 2-phenylpyridine (1) using various substituted
styrenes. The electron neutral −H (a) and electron-donating
substituents on styrenes viz. o-Me (b), p-Me (c), 2,4,6-
trimethyl (d), and p-OMe (e) served as excellent benzoxy
surrogates toward o-benzoxylation of 2-phenylpyridine (1)
providing their respective products (1a−1e) in moderate yields
as shown in Scheme 2. Moderately electron-withdrawing
substituents in styrenes such as p-Cl (f) and p-Br (g) also
acted as their respective benzoxy sources yielding correspond-
ing o-benzoxylated products (1f and 1g) but in slightly lesser
yields compared to styrenes possessing electron-donating
substituents. However styrene possessing a strongly electron-
withdrawing group such as m-NO2 failed to give an o-
benzoxylated product with 1. The styrene analogue of
naphthalene such as 2-vinylnaphthalene (h) were also effective
in bringing about the naphthylcarboxylation of 1 giving 1h in a
a
Reaction conditions: arenes (1−2) (0.5 mmol), alkenes (a−h) (1
mmol), Cu(OAc)2 (0.1 mmol), TBHP (5−6 M) (5 mmol), 120 °C, in
chlorobenzene (1 mL), time 10−16 h. b Yield of isolated pure product.
moderate yield. In addition to 1, o-benzoxylation of 2-(p-
tolyl)pyridine (2) was also investigated with various styrenes
and the results are depicted in Scheme 2. The trends in the
reactivity of substituted styrenes were found to be identical to
those observed for 1. Nevertheless, the yields of the o-
benzoxylated products (2a−2f) obtained were marginally better
with 2 than 1, which is perhaps due to better chelation of the
metal catalyst with the electron-rich o-tolyl ring in 2.
Surprisingly, terminal aliphatic alkene 1-methyl 4-butene failed
to undergo any o-acetoxylation with either 1 or 2 under the
present reaction conditions.
Terminal alkynes have been used for the alkynylation of sp2
and sp3 C−H bonds via metal catalyzed cross dehydrogenative
coupling (CDC).1l,17 Specifically in the directing group-assisted
C−H activation process, phenylacetylenes are reported to
undergo regio- and/or stereoselective alkenylation.17c To
explore their utility in C−H activation processes we intended
to investigate whether phenylacetylene (a′) can act as a possible
alkynyl source or as a benzoxy surrogate similar to styrene.
Thus, 1 and a′ were reacted in the presence of Cu(OAc)2 and
TBHP under the aforementioned reaction conditions. To our
surprise and delight the product was again found to be o-
benzoxylated product 1a obtained in a moderate yield of 67%.
This is yet another noteworthy observation where a′ is found to
be the benzoxy surrogate (path-c, Scheme 1).
To check the practicality of this methodology a set of
arylalkynes having electron-donating groups such as m-Me (b′),
p-tBu (c′), 3,5-diMe (d′), and 3,4-diOMe (e′) were
investigated as the potential benzoxy sources for the o-
benzoxylation of 1. Each of these alkynes (b′−e′) served as
excellent surrogates of the benzoxy group providing o-
B
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Letter
benzoxylated products (1b′−1e′) in moderate yields (Scheme
reacting 1 with a divulges the presence of intermediates such as
phenylglyoxal, benzaldehyde, and benzoic acid in the medium.
Surprisingly instead of styrene any one of these intermediates
provided the desired product (1a). Under the oxidative
conditions, the conversion of benzaldehyde to benzoic acid is
not surprising but the formation of phenylglyoxal from styrene
and a further loss of one C-atom to form benzaldehyde
(possibly from phenylglyoxal) were rather puzzling. The
detection of CO in the reaction mixture accounts for the loss
of one carbon possibly from phenylglyoxal. In a control
experiment when phenylglyoxal was treated under the identical
reaction conditions, detection of CO and formation of
benzaldehyde were observed reconfirming our assumption
(see Supporting Information (SI)).18 This reaction is most
probably proceeding via a radical mechanism. To ascertain this,
a reaction was performed in the presence of radical quencher
TEMPO. Substantial rate retardation giving only traces of
desired product 1a and isolation of TEMPO ester (H) confirms
our presumption (Scheme S1, SI). The observed intermediates
were identical even when a′ was used instead of a suggesting
the identical reaction path and mechanism leading to o-
benzoxylation.
3). Alkynes possessing electron-withdrawing substituents such
a
,b
Scheme 3. Substrate Scope for o-Benzoxylation
Parallel to the observations of the above-mentioned experi-
ments a mechanism is proposed composed of three paths as
shown in Scheme 4. In path-I, styrene (a) possibly forms a
Scheme 4. Proposed Mechanism for ortho-Benzoxylation
a
Reaction conditions: arenes (1−2) (0.5 mmol), alkynes (a′−i′) (1
mmol), Cu(OAc)2 (0.1 mmol), TBHP (5 mmol), 120 °C, in
chlorobenzene (1 mL), time 11−22 h. b Yield of isolated pure product.
as p-Cl (f′) and p-Br (g′) when treated with 1 gave o-
benzoxylated products 1f and 1g in 48% and 59% yields
respectively. o-Naphthylcarboxylation (1h′) was achieved
successfully in 60% yield using 1-naphthylalkyne (h′) as the
benzoxy counterpart. The yields of the products obtained using
substituted phenylacetylenes followed similar trends as those
with substituted styrenes.
As in the case of 1, o-benzoxylation of 2 was achieved
successfully using unsubstituted or substituted phenylacety-
lenes. Treatment of 2 with a′ under the present reaction
conditions gave o-benzoxylated product 2a in 70% isolated
yield. For substituted phenylacetylenes possessing electron-
donating m-Me (b′), p-tBu (c′), 3,5-diMe (d′), and p-OMe (i′)
and electron-withdrawing group p-Br (g′), their reactivity and
yield trends were found to be similar to those from their
reactions with 1 as shown in Scheme 3.
This elegant and unprecedented transformation is a
mechanistic enigma to us, and hence systematic investigations
were carried out to depict a plausible mechanism. Two possible
intermediates, viz. styrene epoxide and 1-phenyl-1,2-ethanediol,
could be generated in the reaction medium when styrene (a) is
treated in the presence of Cu/TBHP. So in lieu of styrene two
independent reactions were performed, one with styrene
epoxide and the other using 1-phenyl-1,2-ethanediol, but both
reactions failed to offer the expected product (1a), thus ruling
out the involvement of either of them as possible intermediates.
A careful examination of the reaction mixture obtained by
four-membered cyclic intermediate, 3-phenyl-1,2-dioxetane
(A), upon reaction with TBHP. Intermediate A then undergoes
oxidative dehydrogenation to generate intermediate 3-phenyl-
1,2-dioxete (B). The formation of similar intermediates under
oxidative conditions has been proposed by Jiao et al.19 On the
other hand, phenylacetylene (a′) upon reaction with oxidant
TBHP affords the same intermediate (B) directly (path-II,
Scheme 4). The ring fragmentation of B provides phenylglyoxal
(C) which ultimately heads to the formation of benzaldehyde
(D) via a benzoyl radical (D′) through radically induced
decarbonylation. The effect of TBHP on D or D′ forms tert-
butyl benzoperoxate (E). In path-III, Cu(II) undergoes
t
chelation with 1 to give the complex F. Loss of the BuO
radical from E with subsequent ligation of the benzoxy radical
with F gives the Cu(III) intermediate G. Successful
C
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Letter
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identical reaction conditions supports their intermediacy in this
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In conclusion, this methodology illustrates the use of
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arylcarboxy group (ArCOO−), which has been employed
intriguingly for the o-benzoxylation of 2-phenylpyridine
derivatives. Based on the reaction intermediates detected, a
plausible mechanism has been proposed which accounts for
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral and analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: patel@iitg.ernet.in.
Author Contributions
†These authors contributed equally.
Notes
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(13) Sit, W. N.; Chan, C. W.; Yu, W. Y. Molecules 2013, 18.
(14) Bian, Y.-J.; Xiang, C.-B.; Chen, Z.-M.; Huang, Z.-Z. Synlett 2011,
16, 2407.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
B.K.P. acknowledges the support of this research by the
Department of Science and Technology (DST) (SB/S1/OC-
53/2013), New Delhi, and the Council of Scientific and
Industrial Research (CSIR) (02(0096)/12/EMR-II). S.G. and
S.K.R. thank CSIR.
(15) Sun, C.-L.; Liu, J.; Wang, Y.; Zhou, X.; Li, B.-J.; Shi, Z.-J. Synlett
2011, 7, 883.
DEDICATION
■
(16) Padala, K.; Jeganmohan, M. Chem. Commun. 2013, 49, 9651.
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This manuscript is dedicated to Prof. Bijay Kumar Mishra on
the occasion of his 60th Birthday.
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