Ru(ii)-catalyzed intermolecular ortho-C-H amidation of aromatic ketones with sulfonyl azides

Article abstract of DOI:10.1039/c3cc41915k

Ru(ii)-catalyzed intermolecular ortho-C-H amidation of weakly coordinating aromatic ketones with sulfonyl azides is reported. The developed reaction protocol can be extended to various substituted aromatic ketones to afford a wide range of desired C-N bond formation products in good yields.

Full text of DOI:10.1039/c3cc41915k

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Ru(II)-catalyzed intermolecular ortho-C–H amidation of
aromatic ketones with sulfonyl azides†‡
Cite this: Chem. Commun., 2013,
49, 5225
M. Bhanuchandra, M. Ramu Yadav, Raja K. Rit, Malleswara Rao Kuram and
Akhila K. Sahoo*
Received 14th March 2013,
Accepted 11th April 2013
DOI: 10.1039/c3cc41915k
www.rsc.org/chemcomm
Ru(II)-catalyzed intermolecular ortho-C–H amidation of weakly
coordinating aromatic ketones with sulfonyl azides is reported. The
developed reaction protocol can be extended to various substituted
aromatic ketones to afford a wide range of desired C–N bond formation
products in good yields.
Following Murai’s pioneering study on Ru-catalyzed C–H activation,1
there has been significant interest in the development of transition-
metal-catalyzed carbonyl-directed aryl ortho-C(sp2)–H functionalization
for C–C and C–X (X = halogen, O, or N) bond formation.2 Particular
attention has been paid to C–N bond formation because of the broad
synthetic potential of nitrogen-bearing compounds.3 Buchwald–
Hartwig amination, for instance, allows for C–N bond induction in
arenes using readily available pre-functionalized haloarenes.4 Interest-
ingly, direct amination of the C–H bond of arenes presents the
advantages of accessing broad scenario of substrate generality and
minimal waste production.5 However, this process requires a strongly
coordinating, i.e., nitrogen-bearing, directing group (DG), which can
be obtained from arene carbonyls/carboxylic acids through multiple
synthetic manipulations.6 Using electrophilic aminating agents, C–H
amination of arenes has successfully been performed in the presence of
a Pd or Rh catalyst (Scheme 1A).7,8 The Chang group demonstrated the
pyridyl and/or oxime directed amidation of arene C–H bonds with
sulfonyl azides under the influence of a Rh-catalyst.8a
Scheme 1 Carbonyl directed ortho-C–N bond formation.
However, to the best of our knowledge, the use of Ru-catalysts for the
C–H amidation of arylketones is unprecedented.9 Recently, our group
demonstrated Ru-catalyzed reusable sulfoximine assisted C(aryl)–N
bond formation with tosyl azides to produce anthranilic acid deriva-
tives.10 The preliminary results inspired us to examine the direct
intermolecular o-C(aryl)–H amidation of weakly coordinating arylk-
etones with tosyl azides (Scheme 1B). In this study, we focus on the
use of inexpensive, easy-to-prepare and air-stable Ru(II) catalysts for
direct intermolecular o-C–H amidation.
Table 1 Optimization of reaction conditionsa
The development of novel methods for the formation of C–N
bonds on readily available precursors would enhance the synthetic
versatility of this strategy. For example, the direct synthesis of ortho-
aminoaryl ketones, which are potential precursors to various biologi-
cally active molecules, from arylketones is therefore desirable.3 An
elegant approach to Pd-catalyzed carbonyl directed amidation of arene
C–H bonds with sulfonamides has been reported by the Liu group.2o
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
—
KOAc
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
Chlorobenzene
CHCl3
CH3CN
Toluene
THF
ClCH2CH2Cl
NR
o5
65
42
08
56
28
o5
o5
o5
08
Cu(OAc)2ꢀH2O
LiOAc
CsOAc
AgOAc
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2Oc
School of Chemistry, University of Hyderabad, Hyderabad 500046, India.
E-mail: akhilchemistry12@gmail.com
9
10
11
12
† Dedicated to Professor Irina P. Beletskaya, for her outstanding contributions to
Organic Chemistry.
74
‡ Electronic supplementary information (ESI) available: Experimental procedures
and 1H and 13C NMR spectra of all new compounds. CCDC 928944. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc41915k
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), [RuCl2(p-cymene)]2
b
c
(5 mol%), base (0.5 mmol). Isolated yields. Cu(OAc)2ꢀH2O (50 mol%).
NR = no reaction.
c
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Table 3 Substrate scope of aryl–alkyl and aryl–aryl ketonesa,b
To find general conditions for the ortho-C(sp2)–H amidation on
aryl-ketones, reaction of acetophenone (1a) with tosylazide (2a) was
conducted in the presence of [RuCl2(p-cymene)]2 (5 mol%), AgSbF6
(20 mol%) and bases in 1,2-dichloroethane (1,2-DCE) at 100 1C for
24 h (Table 1). The reaction did not proceed in the absence of base
(entry 1). Interestingly, a trace amount of desired ortho-amidation
product 3a was noticed, when KOAc was employed in the reaction
(entry 2). However, use of Cu(OAc)2ꢀH2O enhanced the product
formation, affording 3a in 65% yield (entry 3). Another acetate source
CsOAc was ineffective, whereas LiOAc and AgOAc furnished moderate
yield of 3a (entries 4–6). Other solvents such as chlorobenzene yielded
a poor amount of 3a (entry 7), whereas CHCl3, CH3CN, toluene and
THF failed to produce even 10% of 3a (entries 8–11). The less amount
of Cu(OAc)2ꢀH2O (0.5 equiv.) did not affect the reaction efficiency,
producing 74% of 3a (entry 12).
a
Reaction conditions: 1 (1.0 mmol), azide (1.5 mmol), [RuCl2(p-cymene)]2
(5 mol%), AgSbF6 (20 mol%), Cu(OAc)2ꢀH2O (50 mol%), 1,2-DCE (2.0 mL) at
c
100 1C for 24 h. b Isolated yields. Mixture of two regioisomers.
(25%), respectively. The reaction of 2-acetonaphthone (1n) with 2a
furnished a highly regioselective product 3n in good yield. Notably, the
hindered o-C–H was amidated, when 30,40-(methylenedioxy)acetophe-
none (1o) reacted with 2a; the 2-NHTs substituted 3o was produced
albeit in poor yield.2g The ortho-substituted 1p afforded 3p in 39% yield.
Pleasingly, the reaction between chromone (1q) and 2a gave good
amount of 3q, leaving the conjugated double bond unaffected.
Next, we studied the ortho-amidation of various alkyl–aryl ketones
and aryl–aryl ketones with tosyl azides (Table 3). Propyl and n-butyl
substituted ketones, 1r and 1s, independently reacted with 2a to deliver
3r and 3s in 85% and 73% yield, respectively. Amidation product 3t was
obtained from benzophenone in good yield. Similarly, electron-rich
symmetrical 4,40-dimethyl-benzophenone (1u) gave 70% of 3u; whereas
electron deficient Cl-bearing 1v yielded 3v in moderate yield. We next
investigated the reaction of unsymmetrical diarylketones bearing an
electron donating (–Me) (1w) and electron-withdrawing (–Br) group (1x)
at the para-position in one of the aryl moieties with 2a. The inseparable
regioisomeric mixtures of the corresponding amidation products 3w/
3w0 and 3x/3x0 (1.8 : 1) are obtained in moderate yields (see ESI‡).
We next turned our attention to the scope of different sulfonyl
azides in the ortho-amidation on acetophenone (Table 4). Electron
withdrawing arene-sulfonyl azides (2b–e), having NO2, CF3, F or Cl
groups, successfully underwent amidation with 1a, producing the
The optimized conditions in entry 12, Table 1, were screened
examining the scope and functional group tolerance of this transforma-
tion. Table 2 summarizes the results of o-C–H amidation on arylmethyl
ketones with 2a. The o-C–H amidation product 3a was isolated in 72%
yield from the acetophenone (1a). The para-substituted arylmethyl
ketones possessing electron-donating methyl, methoxy, i-butyl substi-
tuents delivered the corresponding ortho-amidation products 3b–d in
good to excellent yields. Interestingly, the OTBS protecting group was
well tolerated, yielding 73% of 3e. Halo groups (F, Cl, Br and I) were
inert under the present reaction conditions, furnishing the desired
products 3f–i in good yields. The tolerance of iodo groups under the
catalytic conditions is notable. The optimized conditions did not
affect the ester-group, producing 3j in 58% yield. The amidations on
meta-substituted arylketones were found to be inferior.2o The regio-
isomeric products 3k and 3k0 were obtained in 8% and 21% yields,
respectively, from the m-methoxyacetophenone 1k. Similarly, the
other meta-substituted acetophenones 1l and 1m gave the corres-
ponding less-hindered o-C–H amidation products 3l (30%) and 3m
Table 2 Substrate scope of aromatic ketonesa,b
Entry
R
Products
1
2
3
4
5
1a (H)
1b (Me)
1c (OMe)
1d (i-butyl)
1e (OTBS)
1f (F)
Table 4 Sulfonyl azide scopea,b
6
7
8
1g (Cl)
1h (Br)
9
10
1i (I)
1j (CO2Me)
a
a
Reaction conditions: 1 (1.0 mmol), azide (1.5 mmol), [RuCl2(p-cym-
ene)]2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2ꢀH2O (50 mol%), 1,2-DCE
Reaction conditions: 1 (1.0 mmol), azide (1.5 mmol), [RuCl2(p-cym-
ene)]2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2ꢀH2O (50 mol%), 1,2-DCE
b
b
(2.0 mL) at 100 1C for 24 h. Isolated yields.
(2.0 mL). Isolated yields.
c
5226 Chem. Commun., 2013, 49, 5225--5227
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Although the detailed mechanism of Ru(II)-catalyzed C–H amida-
tion of arenes is yet to be established, the proposed mechanism is
outlined in Scheme 2.11 The combination of [RuCl2(p-cymene)]2, base,
and AgSbF6 generates the active Ru(II)-catalyst. The coordination of
carbonyl oxygen to the coordinatively unsaturated Ru-catalyst triggers
activation of the o-C–H bond and delivers the metallacycle
intermediate A;6e the deuterium scrambling experiment
supports the reversible cleavage of C–H bonds (see ESI‡).
Coordination of azides to A followed by migratory insertion of
sulfonamido moieties with evolution of N2 gas leads to the
intermediate B. Finally, protonolysis of B provides the desired
product and generates the active ruthenium-complex for the
next catalytic cycle.
In summary, we have developed a ruthenium-catalyzed direct
aryl o-C–H amidation on the readily available aryl–alkyl and aryl–
aryl ketones with sulfonyl azides. The reaction proceeds with the
broad scope of arylketones in good yields. A wide range of sulfonyl
azides were successfully installed on arylketones.
We thank DST (SR/S1/OC-34/2009), UoH, and ACRHEM for
financial support. M.B, M.R.Y, R.K.R and M.R.K thank CSIR,
India, for fellowship.
Notes and references
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2 Selected examples, for keto-directed o-C–H bond alkylation, see:
(a) F. Kakiuchi, T. Kochi, E. Mizushima and S. Murai, J. Am. Chem.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5225--5227 5227