Transition-Metal-Free Regiospecific Aroylation of Nitroarenes Using Ethyl Arylacetates at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.7b03882

A novel regiospecific C(sp³)-C(sp²) coupling between ethyl arylacetates and nitroarenes has been developed to deliver biaryl ketones in excellent yields. The protocol is metal-free, mild, and compatible with a number of functional groups on both of the reacting partners.

Full text of DOI:10.1021/acs.orglett.7b03882

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Regiospecific Aroylation of Nitroarenes Using
Ethyl Arylacetates at Room Temperature
Promod Kumar, Anup Kumar Sharma, Tirumaleswararao Guntreddi, Rahul Singh,
and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi-221005, India
S
* Supporting Information
ABSTRACT: A novel regiospecific C(sp3)−C(sp2) coupling between
ethyl arylacetates and nitroarenes has been developed to deliver biaryl
ketones in excellent yields. The protocol is metal-free, mild, and
compatible with a number of functional groups on both of the reacting
partners.
Scheme 1. Recent Reports and Our Contribution
ransition-metal-catalyzed coupling reactions have trans-
Tformed the construction of carbon−carbon and carbon−
heteroatom bonds in contemporary organic synthesis. Extensive
research in this rapidly evolving field has traversed well beyond
organic synthesis up to biology, materials science, and
engineering.1 Nevertheless, the current challenge in the field
of coupling reactions remains the development of innovative
protocols under transition-metal-free conditions.2
Biaryl ketones constitute an important class of organic
compounds, which are prevalent in biologically active
molecules, photosensitizers, advanced organic materials, and
natural products.3 Traditionally, such ketones are synthesized
by a Friedel−Crafts type reaction of active arenes with acyl
halides in the presence of a Lewis acid,4 or by using three-
component cross-coupling of aryl halides (or pseudohalides),
organometallic reagents, and carbon monoxide (CO) in the
presence of transition metal catalysts.5 In this course, some fine
contributions involving Pd/Cu/Ag-catalyzed decarboxylative
cross-coupling of α-oxocarboxylic acids with aryl halides or
arylboronic acids have lately appeared.6 Recently, some
important reactions involving directing group assisted ortho-
acylation using α-oxocarboxylic acids or aldehydes or toluene
derivatives have also been described.7 Recently, Szostak et al.
have accomplished the synthesis of biaryl ketones using
Suzuki−Miyaura cross-coupling of amides via site selective
N−C bond cleavage by synergistic catalysis of a Lewis base and
palladium,8a whereas Newman et al. have reported the NHC-
based Pd catalyzed synthesis of ketone containing products by
coupling of the aryl esters with aryl boronic acids (Scheme 1).8b
Although these metal catalyzed transformations represent a
powerful tool in organic synthesis, they suffer from the use of
expensive or toxic transition metals and ligands, high
temperature, prolonged reaction time, and generation of
metal waste. Also, certain functional groups are intolerant to
the transition metal systems, which limit their potential
applications. Therefore, the development of practical protocols
to achieve the synthesis of biaryl ketones without using
transition metal catalysts is demanding and challenging.9
Nitroarenes are versatile and common aromatic building
blocks in organic synthesis10 and can be readily obtained by
nitration of the parent arenes. They readily undergo
nucleophilic substitution mediated by strong bases, in which
the NO2 group serves as an activator.11
In light of the above and as a part of our ongoing interest in
metal-free reactions12 we disclose herein an efficient KOtBu
mediated regiospecific aroylation of nitroarenes using ethyl
arylacetates to afford the biaryl ketones at room temperature
(Scheme 1).
In order to optimize the reaction conditions, a model
reaction using ethyl phenylacetate (1A) and nitrobenzene (2a)
was investigated in detail by varying different parameters, and
the findings are summarized in Table 1. The study commenced
with the reaction of equivalent quantities (1.0 mmol) of 1A and
2a in the presence of KOtBu (2.0 equiv) in DMSO at room
temperature for 3 h, which led to the formation of the desired
product (4-nitrophenyl)(phenyl) methanone (3Aa), albeit in
Received: December 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope and Versatility of the Reaction
b
entry
base
KOtBu
solvent
temp (°C)
yield 3Aa (%)
c
1
2
DMSO
DMSO
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
20
−
0
c
3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
LiOtBu
NaOtBu
other bases
10
c
4
CH3CN
toluene
EtOH
18
d
5
30
6
0
75
62
54
0
7
benzene
benzene
benzene
benzene
8
9
e
10
a
Conditions: 1A (1.0 mmol), 2a (1.0 mmol), base (2.0 mmol), solvent
b
c
d
(4.0 mL), 3 h. Isolated yield. 4Aa as major product. 5Aa as a major
product (47%) in accordance with an earlier observation13a concerned
with the α-C−H hydroxylation of α-substituted carbonyl compounds.
e
Other bases: Na2CO3, K2CO3, Cs2CO3, CH3COONa, KOH, NaOH,
DBU, DABCO.
low yield (20%; Table 1, entry 1). The role of KOtBu was
found to be critical, as the reaction did not proceed at all in its
absence (entry 2). In an attempt to improve the product yield,
several solvents and bases were then screened at different
temperatures. Changing the solvent from DMSO to DMF and
acetonitrile diminished the formation of 3Aa (entries 3 and 4)
and facilitated the α-C−H arylation giving rise to the product
4Aa (50% in DMSO, 44% in DMF and 39% in CH3CN). The
use of toluene as solvent, however, furnished a mixture of
products 3Aa (30%) and 5Aa (47%), whereas use of EtOH
remained completely futile (entries 5 and 6). However, use of
benzene as solvent increased the desired product 3Aa yield
(75%, entry 7). Other bases such as LiOtBu and NaOtBu
afforded the product 3Aa in 62% and 54% yields respectively
(entries 8 and 9). The effect of bases such as Na2CO3, K2CO3,
Cs2CO3, CH3COONa, KOH, NaOH, DBU, and DABCO in
benzene at room temperature was also examined, however did
not afford any product (entry 10).
Having identified KOtBu/benzene as the preferred combi-
nation, other parameters such as the change in the ratio of the
reactants, base, and temperature was studied. The optimized
reaction conditions were found to include the use of KOtBu
(2.0 equiv) in benzene employing equivalent quantities (1.0
mmol) of the reactants 1A and 2a at room temperature for 3 h
(entry 7).
With the established conditions in hand (Table 1, entry 7),
the scope and versatility of the reaction were then examined by
using different ethyl arylacetates 1A−M and nitroarenes 2a−e
as coupling partners (Scheme 2).
Ethyl arylacetates 1 bearing a halogen substituent such as 2-
Cl (1C), 4-Cl (1D), 3,5-dichloro (1E), 2,4-dichloro (1F), 4-Br
(1G), and 4-F (1H), when reacted with nitrobenzene (2a),
gave the corresponding products 3Ca, 3Da, 3Ea, 3Fa, 3Ga, and
3Ha in good yields. Ethyl arylacetates having an electron-rich
substituent at different positions such as 4-OMe (1I), 2-OMe
(1J), 2-Me (1K), and 4-Me (1L) also underwent smooth
aroylation with 2a affording the corresponding products 3Ia,
3Ja, 3Ka, and 3La in 64−80% yield. Ethyl 1-(naphthalen-1-
yl)acetate (1M) also worked well leading to the formation of
a
Conditions: 1 (1.0 mmol), 2 (1.0 mmol), KOtBu (2.0 mmol),
b
c
d
benzene (4.0 mL). DMSO (4.0 mL). DMF (4.0 mL). CH3CN (4.0
mL). Toluene (4.0 mL).
e
the product 3Ma in 72% yield. The adaptability of the reaction
on the nitroarene component having a substituent such as 2-Cl
(2b), 3-Me (2c), 3-Br (2d), and 2-CN (2e) was also checked
with various ethyl arylacetates to give the corresponding biaryl
ketones 3Ib, 3Db, 3Ic, 3Lc, 3Dc, 3Hc, 3Dd, 3Gd, and 3De in
57−75% yields. More importantly, the reaction is highly
regiospecific, as para-aroylation of nitroarenes is exclusively
observed. Employing different para-substituted nitroarenes, viz.
1-fluoro-4-nitrobenzene, 1-chloro-4-nitrobenzene, and 1-iodo-
4-nitrobenzene, in the reaction under the optimized reaction
conditions failed to give the desired products or any ortho
functionalized products.
In order to gain insight into the reaction mechanism, some
control experiments (Scheme 3) were performed using esters
B
DOI: 10.1021/acs.orglett.7b03882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03882.
Experimental procedures and spectroscopic data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: knsingh@bhu.ac.in; knsinghbhu@yahoo.co.in.
ORCID
Krishna Nand Singh: 0000-0001-9147-5463
Notes
other than ethyl phenylacetate, viz. methyl phenylacetate and
iso-propyl phenylacetate, with 2a resulting in the same product
3Aa with marginal difference in yields. When ethyl phenyl-
acetate was allowed to react under the optimized reaction
conditions without nitrobenzene, it furnished potassium 2-
phenylacetate, which eventually failed to give the desired
product on addition of nitrobenzene. This suggests that the
reaction proceeds with α-C−H aroylation followed by the
decarboxylation step. In order to ascertain the role of
atmospheric oxygen, the reaction was also performed under
an inert atmosphere which failed to produce any significant
conversion to the desired product.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the SERB, New Delhi (File No. EMR/
2016/000750) for financial assistance. P.K. thanks UGC, New
Delhi for the award of a DSK−Postdoctoral Fellowship (Award
Letter No. F.4-2/2006 (BSR)/CH/13-14/0165).
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DOI: 10.1021/acs.orglett.7b03882
Org. Lett. XXXX, XXX, XXX−XXX