Palladium-catalyzed selective α-arylation of ortho -bromoacetophenones

Article abstract of DOI:10.1080/00397911.2014.880789

Synthesis of 1-(2-bromophenyl)-2-phenylethanones via an intermolecular Pd-catalyzed α-arylation of 1-(2-bromophenyl)ethanones is presented. The method relies on selective C-H activation (α-arylation) of relatively more reactive external iodo-arenes as cou

Full text of DOI:10.1080/00397911.2014.880789

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Palladium-Catalyzed Selective α-
Arylation of ortho-Bromoacetophenones
Jonnada Krishna a , Alavala Gopi Krishna Reddy a & Gedu
Satyanarayana a
a Department of Chemistry , Indian Institute of Technology (IIT)
Hyderabad, Ordnance Factory Estate Campus , Yeddumailaram ,
India
Accepted author version posted online: 16 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Jonnada Krishna , Alavala Gopi Krishna Reddy & Gedu Satyanarayana (2014)
Palladium-Catalyzed Selective α-Arylation of ortho-Bromoacetophenones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:14, 2103-2111,
DOI: 10.1080/00397911.2014.880789
To link to this article: http://dx.doi.org/10.1080/00397911.2014.880789
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Synthetic Communications1, 44: 2103–2111, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.880789
PALLADIUM-CATALYZED SELECTIVE a-ARYLATION OF
ORTHO-BROMOACETOPHENONES
Jonnada Krishna, Alavala Gopi Krishna Reddy, and
Gedu Satyanarayana
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad,
Ordnance Factory Estate Campus, Yeddumailaram, India
GRAPHICAL ABSTRACT
Abstract Synthesis of 1-(2-bromophenyl)-2-phenylethanones via an intermolecular
Pd-catalyzed a-arylation of 1-(2-bromophenyl)ethanones is presented. The method relies
on selective C-H activation (a-arylation) of relatively more reactive external iodo-arenes
as coupling partners without affecting the bromo-substituent. Moreover, the scope and
generality of the method has been well studied by employing the reaction with iodo-arenes
as coupling partners bearing electron-withdrawing, simple, and electron-donating groups on
the aromatic ring.
Keywords a-Arylation; 1-(2-bromophenyl)ethanones; C-H activation; iodo-arenes;
Pd-catalysis
INTRODUCTION
Synthetic organic chemistry has always faced the challenge of developing
sustainable methods. In this regard, efficient construction of CꢀC bonds has been
achieved by transition-metal catalysis. Among these catalysts, palladium has gained
recognition as one of the most used metals for a wide spectrum of reactions. Heck,[1]
Stille,[2] Suzuki,[3] Sonogashira,[4] and Buchwald–Hartwig[5] coupling transformations
are some of the renowned reactions. Even very recently, reactions of CꢀH activation
via organo-palladium intermediate species have become versatile in this field.[6,7]
Palladium-catalyzed a-arylation on the a-positioned carbon to the carbonyl
has gained immense importance because of several limitations of other classical
methods. The classical procedures known from the literature such as nucleophilic
aromatic substitution (SNAR) reaction of a stabilized enolate with an aryl halide,
Received October 11, 2013.
Address correspondence to Gedu Satyanarayana, Department of Chemistry, Indian Institute of
Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram 502 205, Medak
District, Andhra Pradesh, India. E-mail: gvsatya@iith.ac.in
2103

2104
J. KRISHNA, A. G. K. REDDY, AND G. SATYANARAYANA
Scheme 1. Comparison of the alkyl group directing Pd catalysis.
where the halide partner must possess electron-withdrawing substituents to promote
the reaction or the nucleophilic aromatic substitution (SNAR) through the benzyne
intermediate, which is often regioselective, and even though the SRN1 reaction is
feasible with various aryl halide partners, it is suitable for definite solvents.
Additionally in SRN1 the a-hydrogen of the enolate could react with aryl radicals
formed from aryl halides and lead to the corresponding arene, not the desired a-aryl
ketone. Other problems in making enolates of carbonyl compounds in large quanti-
ties are the number of reagents required and making the corresponding processes
time- and cost-effective. Hence, newer methods are being explored for a-arylation
of ketones, of which palladium-catalyzed transformation by Buchwald and Hartwig
has been the most versatile. In this regard Buchwald and Hartwig contributed a core
part and developed various unusual and active palladium catalytic systems by means
of synthesizing diverse sterically hindered alkyl and electron-rich phosphine ligands
for the selective a-arylation[8] of ketones. As per few reports, a-arylations play a key
step in synthesis of various intermediates present in natural and synthetic products.[9]
In an extension to our ongoing research passion on transition-metal cataly-
sis,[10] particularly in domino one-pot[10f,g] and domino sequential one-pot[10d,e]
processes, we recently reported a novel domino Pd-catalysis for the synthesis of
novel 7-methyl-5H-dibenzo[a,c][7]annulen-5-ones.[10g] Herein, we present selective
a-arylation of 1-(2-bromophenyl)ethanones using external iodo-arenes without
affecting the bromo-substituent of 1-(2-bromophenyl)ethanones under mild reaction
conditions (Scheme 1).
RESULTS AND DISCUSSION
When Pd catalysis of 1b was explored with the external halobenzenes (2a, 2e,
and 6g) as the coupling partners, it did not furnish the expected fused cyclic system
(5ba and 5be) via biaryl formation followed by intramolecular Buchwald–Hartwig

a-ARYLATION OF ORTHO-BROMOACETOPHENONES
2105
coupling; instead, it was impeded just after the a-arylation stage and gave
the ketones 3ba and 3be. It is worth mentioning that the selective a-arylation was
successful only in the case of more reactive external iodo-arenes (2a and 2e), rather
than the corresponding external bromo counterparts (Scheme 2).[10g]
Recently, Willis et al reported a-arylation even by using 1-bromo-2-iodoben-
zenes as coupling partners.[11] Unlike the Willis et al. report, the present work
describes a-arylation wherein the bromo substituent is part of the acetophenone 1
coupling partner (Scheme 2). The study began with the preparation of 2-bromoace-
tophenones 1b under standard reaction conditions (methylmagnesiumiodide
addition to 2-bromobenzaldehydes and oxidation of the resulted secondary alcohol
to the corresponding ketone).[10f,10g] However, after several attempts, we realized
that reported reaction conditions[10g] for longer reaction time were not applicable
for other systems. In most of the cases, the formation of bi-a-arylation products
along with the small amount of other by-products as well was observed. This can
be justified because by the fact that the lesser excesses of iodo-arenes (2a and 2e) than
2-bromoacetophenone 1b would always tend to participate in the second a-arylation.
Therefore, various attempts were made to identify the suitable reaction conditions.
Gratifyingly, it was recognized that the conditions[8a] reported by Buchwald et al.
were suitable for our systems (i.e., with 1 equivalent of iodo-arene and 1.1 equiva-
lents of 2-bromoacetophenone). Moreover, these optimized conditions were broadly
applicable to various iodo-arenes containing electron-withdrawing, simple, and
electron-donating substituents on the aromatic ring. Comparatively, the reaction
was completed in shorter reaction time (i.e., typically 45 min to 3 h) than that
reported previously[10g] and furnished clean a-arylation products 3ac–3cf in very
good yields as shown in Table 1.
Scheme 2. Reported a-arylation of 2-bromoacetophenone 2b.

2106
J. KRISHNA, A. G. K. REDDY, AND G. SATYANARAYANA
Table 1. Pd-catalyzed a-arylation of 2-bromoacetophenones 1a–1c with iodo-arenes 2a–2fa,b,c
aAll reactions are carried out on 0.5-mmol scale of iodo-arenes in 4 mL of toluene (0.12 M).
bYields in the parentheses are isolated yields of chromatographically pure products.
cFor compounds 3ac–3cf the first letter refers to the 2-bromoacetophenes 1a–1c, whereas the second
letter indicates the aromatic ring coming from iodo-arenes 2a–2f.
CONCLUSION
In summary, we have developed a Pd-catalyst selective a-arylation of
1-(2-bromophenyl)ethanones for the synthesis of 1-(2-bromophenyl)-2-phenyletha-
nones. The relatively more reactive external iodo-arenes than bromo-arenes are
identified as suitable coupling partners. Moreover, the scope and generality of the
method have been achieved by employing the reaction with iodo-arene coupling
partners bearing electron-withdrawing, simple, and electron-donating groups on
the aromatic ring.
EXPERIMENTAL
1-(2-Bromophenyl)-2-(3,4-dimethoxyphenyl)ethanone (3ac)
Compound 1 was mixed with with aryliodide 2c (132.0 mg, 0.50 mmol),
ortho-bromoacetophenone 1a (109.4 mg, 0.55 mmol), Pd(OAc)2 (2.2 mg, 2 mol%),
t
xantphos (11.6 mg, 4 mol%), BuOK (72.9 mg, 0.65 mmol), and dry toluene (4 mL)
at 80 ꢁC for 45 min. Silica-gel column chromatography (20g, petroleum ether=ethyl

a-ARYLATION OF ORTHO-BROMOACETOPHENONES
2107
acetate, 85:15 to 80:20) furnished the title compound 3ac (155 mg, 92%) as yellow
solid, recrystallized the solid with dichloromethane=hexane, mp 74–76 ꢁC [TLC
control (petroleum ether=ethyl acetate 90:10), Rf(1a) ¼ 0.55, Rf(2c) ¼ 0.45, and
Rf(3ac) ¼ 0.20, UV detection]. IR (MIR-ATR, 4000–600 cmꢀ1): nmax ¼ 2956, 2923,
1
2852, 1697, 1587, 1512, 1463, 1422, 1259, 1154, 1140, 1025, 791, 757, 678 cmꢀ1. H
NMR (CDCl3, 400 MHz): d ¼ 7.57 (d, 1H, J ¼ 7.8 Hz, Ar-H), 7.35–7.15 (m, 3H,
Ar-H), 6.78 (d, 1H, J ¼ 8.7 Hz, Ar-H), 6.76 (dd, 1H, J ¼ 8.7 and 1.9 Hz, Ar-H),
13
6.74 (d, 1H. J ¼ 1.9 Hz, Ar-H), 4.15 (s, 2H, ArCOCH2), 3.83 (s, 3H, ArOCH3),
=
3.82 (s, 3H, ArOCH3) ppm. C NMR (CDCl3, 100 MHz): 201.8 (s, Ar-C O),
148.9 (s, Ar-C), 148.1 (s, Ar-C), 141.4 (s, Ar-C), 133.5 (d, Ar-CH), 131.4 (d, Ar-CH),
128.6 (d, Ar-CH), 127.2 (d, Ar-CH), 125.8 (s, Ar-C), 121.9 (d, Ar-CH), 118.6
(s, Ar-C), 112.7 (d, Ar-CH), 111.2 (d, Ar-CH), 55.8 (q, 2C, 2 ꢂ ArOCH3), 49.0 (t, Ar-
COCH2) ppm. HR-MS (ESIþ) m=z calculated for [C16H7169 BrO3]þ ¼ [MþH]þ:
335.0277; found 335.0294. [C16H8161 BrO3]þ ¼ [MþH]þ: 337.0259; found 337.0274.
FUNDING
Financial support by the Council of Scientific and Industrial Research [(CSIR),
02(0018)=11=EMR-II], New Delhi, is gratefully acknowledged. J. K. and A. G. K.
thank CSIR, New Delhi, for the award of research fellowships.
SUPPLEMENTARY MATERIAL
1
Copies of H and 13C NMR spectra related to this article can be accessed
on the publisher’s website.
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