Palladium-catalyzed oxidative C-H bond acylation of N-nitrosoanilines with toluene derivatives: A traceless approach to synthesize N-alkyl-2-aminobenzophenones

Article abstract of DOI:10.1039/c4cc07440h

A palladium-catalyzed cascade cross-coupling of N-nitroso-anilines and toluene derivatives for the direct synthesis of N-alkyl-2-aminobenzophenones is described. N-nitroso groups in anilines can act as the traceless directing groups while toluene derivatives can serve as effective acyl precursors under mild reaction conditions.

Full text of DOI:10.1039/c4cc07440h

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Palladium-catalyzed oxidative C–H bond
acylation of N-nitrosoanilines with toluene
derivatives: a traceless approach to synthesize
N-alkyl-2-aminobenzophenones†
Cite this:DOI: 10.1039/c4cc07440h
Received 20th September 2014,
Accepted 15th October 2014
Yinuo Wu,a Ling-Jun Feng,a Xiao Lu,a Fuk Yee Kwong*b and Hai-Bin Luo*a
DOI: 10.1039/c4cc07440h
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A
palladium-catalyzed cascade cross-coupling of N-nitroso-
anilines and toluene derivatives for the direct synthesis of
N-alkyl-2-aminobenzophenones is described. N-nitroso groups in
anilines can act as the traceless directing groups while toluene
derivatives can serve as effective acyl precursors under mild reac-
tion conditions.
Transition-metal-catalyzed direct C–H bond functionalization
has been successful as a valuable approach for the modular and
facile synthesis of structurally similar, yet diversified organic
molecules.1 In general, directing groups are necessary for
facilitating the ortho-C(sp2 or sp3)–H bond activation in the Scheme 1 Protocols for the preparation of ortho-aminobenzophenones.
presence of transition metals (e.g., Pd, Ir, Rh, Ru, Cu, Fe,
etc.), leading to a versatile C–H bond functionalization upon
trapping with appropriate electrophiles or nucleophiles under acylation of anthranilic acids with arenes in the presence of AlCl3 or
basic or oxidative conditions, respectively.2 However, it may the reaction between anilines and benzonitriles promoted by a
also need additional steps for the directing group to be stoichiometric amount of BCl3/AlCl3 (Scheme 1A).7 In view of
removed or transformed after the C–H bond functionalization. minimizing the waste/side product formation in aromatic ketone
Recently, traceless directing groups such as N-nitroso and synthesis,8 the oxidative coupling between two C–H bonds from two
N-oxide have emerged and been proved to be efficient in C–H coupling partners is highly attractive.9 In 2010, Ge and co-workers
olefination, alkynylation, etc.3 The removal or transformation disclosed that the ortho-acylation of acetanilides could be carried
of these kinds of groups occurs during the C–H bond coupling, out by employing a-oxocarboxylic acid via a Pd-catalyzed decarb-
affording the desired product directly, which makes them oxylative pathway (Scheme 1B).10 In 2011, our group11 and
attractive alternatives in view of the atom economy.4
others12 independently reported oxidative coupling of alde-
ortho-Aminobenzophenones are frequently found in pharma- hydes with acetanilides. In 2012, Yuan showed that benzyl-
ceuticals, natural products, and biologically active molecules.5 alcohols could also act as acylating agents.13 Very recently, our
In particular, N-alkyl-2-aminobenzophenones are known to be group14 and others15 independently proved the application of
crucial synthetic precursors for a wide range of biologically active toluene derivatives as simple coupling partners in the Pd-
compounds including benzodiazepines, acridones, quinazoli- catalyzed ortho-C–H bond acylation of acetanilides. In fact,
nones, indoles, and indazoles.6 The traditional method for previous literature reports were mainly focused on the C–H bond
the synthesis of 2-aminobenzophenones is the Friedel–Crafts acylation of acetanilides, affording N-acyl-2-aminobenzophenones
as final products. The C–H bond acylation directly providing
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China. E-mail: luohb77@mail.sysu.edu.cn; Fax: +86-20-3994-3000
b State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Kowloon,
Hong Kong. E-mail: fuk-yee.kwong@polyu.edu.hk; Fax: +852-2364-9932
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc07440h
N-alkyl-2-aminobenzophenones has not been reported yet. In
continuation of our previous work on palladium-catalyzed C–H
acylation of acetanilides with toluene derivatives,11,14 herein, we
report a new oxidative approach for accessing N-alkyl-2-amino-
benzophenones by using N-nitroso as the traceless directing
group and toluene derivatives as acyl sources (Scheme 1C).
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Table 2 Scope of N-nitrosoaniline in Pd-catalyzed oxidative ortho-
In our initial trial, toluene was used as the model coupling
partner in the cross-coupling of N-methyl-N-nitrosoaniline
(ESI,† Table S1). The N-alkyl-N-nitrosoanilines were prepared
from commercially available anilines and sodium azide in
quantitative yield at room temperature. We found that this
protocol was viable and the desired product 3ab could be
afforded in 58% yield (entry 1). A screening of metal catalysts
revealed that Pd(OAc)2 and Pd(TFA)2 were applicable catalysts,
while Ni(acac)2 and Rh(PPh3)3Cl were found to be inferior
(entries 1–6). The effectiveness of oxidants was also examined
(entries 7–10). Our results demonstrated that TBHP was the
most suitable oxidant in this reaction. Other oxidants screened
were essentially not effective. Increasing the stoichiometry of
TBHP significantly increased the yield of the desired product
(entries 11–14). Interestingly, lowering the reaction tempera-
ture gave a better yield (entries 14–17) possibly due to the
minimization of reagent decomposition. A reaction tempera-
ture of 80 1C was found to be optimal (entry 15). Further
lowering the reaction temperature decreased the substrate
acylationa
a
Reaction conditions: N-nitrosoaniline 1a–l (1.0 mmol), Pd(OAc)2
(10 mol%), TBHP (12.0 mmol), toluene (4.0 mL) were stirred at 80 1C
conversion. In addition, our results showed that 1,2-dichloro- for 24 h under air. Isolated yields were reported.
ethane, 1,4-dioxane, and trifluoromethylbenzene were not
effective solvents for this reaction (entries 18–20).
The electron-withdrawing para-trifluoromethyl toluene gave
With our optimized reaction conditions in hand, we next
tested the scope of the toluene derivatives as simple acyl sources
(Table 1). 1-Methylnaphthalene gave good yields of the corre-
sponding products (3ac). It is worth noting that ortho-hindered
substrates were feasible coupling partners in this catalytic
system (3ae and 3ai). Strongly electron-donating para-/meta-
methoxytoluene gave a slightly lower yield of the product pre-
sumably due to the difficult C–H bond cleavage of the C(O)–H
bond (3ag and 3ah).16 ortho- and para-Fluoro/chloro substituted
toluenes were compatible substrates (3ai–3al). In particular,
the bromo group remained intact during the course of the reaction
(3ak and 3al). This entry potentially offers further structural fine-
tuning using other traditional cross-coupling reactions.17
moderate product yield (3am).
Various substituted N-nitrosoanilines (1b–l) were also exam-
ined and the results are compiled in Table 2. N-nitrosoanilines
with different alkyl groups (e.g. Me, Et, Bu, and Bn) reacted well
with toluene and generated the corresponding products in
69–81% yields (3ab–3db). A variety of functional groups, including
F, Br, Cl and CF3, were tolerated under these reaction conditions
and no significant electronic effect was found (3eb–3ib). The
trifluoromethyl group was tolerable under this catalytic system
(3ib). meta-Methyl-N-nitrosoanilines gave the corresponding pro-
duct in good yields (3jb) while ortho-methyl-N-nitrosoanilines gave
the product in trace amounts possibly due to the high steric
hindrance (3kb). We also attempted to examine N-phenyl-N-
nitrosoaniline in this reaction, the desired product was obtained
in moderate yield (3lb).
Although the exact reaction mechanism is not clear to date,
we suggest that the reaction mechanism began with aliphatic
C–H bond oxidation to aldehyde by the oxidant in the presence
of the palladium complex at elevated temperature (Scheme 2).18
Control experiments revealed that in the presence of only toluene
and TBHP (i.e. without a Pd catalyst), no significant benzaldehyde
formation was observed as judged by GC-MS analysis.19 The t-BuOꢀ
Table 1 Scope of Pd-catalyzed oxidative ortho-acylation of N-methyl-
N-nitrosoaniline with different toluene derivativesa
a
Reaction conditions: N-nitrosoaniline 1a (1.0 mmol), Pd(OAc)2
(10 mol%), TBHP (12.0 mmol), toluene derivatives 2b–m (4.0 mL or
30 equiv.) were stirred at 80 1C for 24 h under air. Isolated yields were
reported.
Scheme 2 A plausible reaction mechanism.
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radical reacts with TBHP to generate t-BuOOꢀ.20 This species then
abstracts an H atom to give reactive acyl radicals.21,22 Meanwhile,
the N-nitroso group undergoes directed electrophilic palladation
and generates a palladacyclic intermediate (Scheme 2).3a We
hypothesize that the acylradicals react with the palladacycle to
afford the ketone products via either a Pd(IV)23 or a dimeric Pd(III)24
pathway. After the reductive elimination along with the N–N(O)
bond cleavage, the desired product was released and the Pd(II)
species was regenerated to complete the catalytic cycle. Moreover,
we also attempted to add a radical scavenger (e.g. ascorbic acid25)
to the reaction, the rate of reactions was greatly suppressed and
only a trace amount of the product was detected. Thus radical
intermediates may be involved in this reaction.
In conclusion, we have developed a cascade cross-coupling of
N-nitrosoanilines and toluene derivatives for the direct access to
N-alkyl-2-aminobenzophenones. The nitroso group could act as a
traceless directing group while toluene derivatives served as
effective acyl precursors in the oxidative coupling between two
C–H bonds under mild reaction conditions. Fluoro, bromo,
chloro, methoxy, and trifluoromethyl groups at different posi-
tions are compatible in this catalytic system. An array of N-alkyl-
2-aminobenzophenones was obtained in moderate to high
yields. We believe that this synthetic approach will be useful
for generating versatile ortho-amino diaryl ketone motifs.
We thank the National Natural Science Foundation of China
(No. 21402243, 21103234 and 81373258), The Fundamental
Research Funds for the Central Universities (Sun Yat-sen Univer-
sity) (No. 31610013), The Priming Scientific Research Foundation
for the junior teachers of medicine in Sun Yat-sen University
(No. 31101402) and the Medical Scientific Research Foundation of
Guangdong Province (No. B2014105) for financial support.
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