A one-pot process for palladium catalyzed direct C-H acylation of anilines in water using a removable ortho directing group

Article abstract of DOI:10.1039/c3ra45160g

A new mild, practical method for the synthesis of aminobenzophenone derivatives through a three step one-pot reaction sequence involving acylation of anilines, palladium catalyzed cross-dehydrogenative coupling of the formed anilides and the hydrolytic cleavage is reported. The full reaction sequence was performed under aqueous conditions.

Full text of DOI:10.1039/c3ra45160g

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A one-pot process for palladium catalyzed direct
C–H acylation of anilines in water using a
removable ortho directing group†
Cite this: RSC Adv., 2014, 4, 3883
Received 16th September 2013
Accepted 4th December 2013
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Fruzsina Szabo, Daniel Simko and Zoltan Novak
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DOI: 10.1039/c3ra45160g
www.rsc.org/advances
A
new mild, practical method for the synthesis of amino- ketocarboxylic acids8 or toluene9 derivatives. In these homoge-
benzophenone derivatives through a three step one-pot reaction nous organic reactions Pd(TFA)2 or Pd(OAc)2/TFA was the most
sequence involving acylation of anilines, palladium catalyzed cross- effective catalyst, and TBHP as oxidant provided the best yields.
dehydrogenative coupling of the formed anilides and the hydrolytic
cleavage is reported. The full reaction sequence was performed under palladium-catalyzed coupling in aqueous media.10 We per-
Recently, our group reported a mild implementation of this
aqueous conditions.
formed the reaction in water at RT in the presence of catalytic
amount of SDS (sodium dodecylsulfate). The surfactant additive
highly accelerates the reaction.11 Taking advantage of these
conditions we synthesized several N-(2-benzoylphenyl) acet-
amide derivatives from N-phenylacetamides.
Oxidative C–H bond activation is one of the most important
topics in recent synthetic organic chemistry.1 Compared to
cross coupling reactions, the preactivation of the substrate is
not needed for the introduction of new functional groups and
the formation of by-products can be reduced. Using oxidative C–
H couplings, a wide range of biaryl structures can be synthe-
sized2 that can potentially be the building blocks of biologically
active natural products.3 A key challenge in C–H activation
chemistry is controlling the regioselectivity. The presence of a
directing group in arenes ensures selective activation of C–H
bond through interaction with the transition metal catalyst
during the reaction.4
Although, the large part of the C–H activation reactions takes
place in organic media, there are several examples for reactions
which are conducted in more environmentally benign solvent
such as water.5
In the past few years, several synthetic methodologies were
developed for the synthesis of benzophenone derivatives via
palladium catalyzed ortho selective cross dehydrogenative C–H
coupling. For these transformations O-phenylcarbamates,
2-arylpiridines, and mostly acetanilides are the substrates,
which can be acylated with aldehydes,6 carboxylic acids,7
N-Phenylacetamide substrates can be prepared from anilines
with acetic anhydride in organic solvents.12 However, Patel et al.
showed that the protection of anilines took place straightfor-
wardly under aqueous conditions with the support of SDS at
room temperature.13 Based on this aqueous N-acylation proce-
dure and our previously developed palladium catalyzed
coupling, we supposed that the aniline protection step and the
C–H acylation step can be carried out successively in one pot
using SDS/water as a solvent. This strategy would enable the
one-pot ortho acylation of anilines via protection-coupling
sequence under aqueous conditions, and also offers the possi-
bility for the nal deprotection of the anilides aer the coupling
to provide aminobenzophenones. In this three step synthesis,
the acetyl group serves as a removable ortho directing group for
C–H activation.
To demonstrate the compatibility of the procedures for
aniline protection and the palladium-catalyzed ortho acylation,
we treated aniline (1a) with 1.5 equivalents of acetic anhydride
in SDS/water at room temperature. The acylation took place
with full conversion aer 0.5 hours providing the acetanilide as
suitable substrate for C–H activation. Then we added 5 mol%
Pd(OAc)2 catalyst, 26 mol% TFA, 2 eq. benzaldehyde (3a) and
2 eq. TBHP (Scheme 1) as the most efficient oxidant in this
coupling.
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MTA-ELTE “Lendulet” Catalysis and Organic Synthesis Research Group, Institute of
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Chemistry, Eotvos University, Pazmany Peter stny. 1/a, H-1117 Budapest, Hungary.
E-mail: novakz@elte.hu; Fax: +36-1-372-2592; Tel: +36-1-372-2500#1610
† Electronic supplementary information (ESI) available: Results of the
optimization studies, experimental procedures and the characterization data for
the products are available. The identity and purity of the known products was
conrmed by 1H and 13C NMR spectroscopic analysis, and the new products
were fully characterized. See DOI: 10.1039/c3ra45160g
To our delight, at room temperature we observed the trans-
formation of acetanilide (2a) to N-(2-benzoylphenyl)acetamide
(4a) with 77% conversion aer 4 hours, and complete reaction
aer 24 hours. This reaction sequence demonstrated the
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Scheme 1 One-pot ortho acylation of anilines via N protection and
ortho C–H activation.
compatibility of the N and C acylation, therefore we aimed to
explore the substrate scope of this reaction sequence for the
preparation of acetamido benzophenones. It is of note that the
acetic acid formed from anhydride during the acylation and
hydrolysis does not disturb the following palladium catalyzed
step (acidic media is benecial for the C–H activation).
2-Acetamido benzophenone was prepared from aniline using
the two step one-pot procedure, and compound 4a was obtained
in 68% yield (Scheme 2.). Methyl substituted acetanilides gave
N-(2-benzoylphenyl)acetamides (4b and 4c) in good yields (76%
and 69% yield respectively), while the dimethyl product 4d was
obtained in 50% yield. The bulky isopropyl group in the para
position did not affect the reaction signicantly (55%)
compared to methyl group. In the presence of halogens (F, Cl,
Br) the sequential reaction also worked, and the appropriate
products were isolated with 54%, 42% and 40% yield respec-
tively aer two reaction steps.
Scheme 3 Reaction conditions: (a) step 1: acetanilide (1.0 mmol), SDS
(0.05 mmol), water (4 mL), acetic anhydride (1.5 mmol) at RT; step 2:
Pd(OAc)2 (0.05 mmol), TFA (0.26 mmol), benzaldehyde (2.0 mmol),
TBHP (2 mmol, 70 wt% in water), at RT, 24 h. (b) Step 1: acetanilide (1.0
mmol), SDS (0.075 mmol), water (4 mL), acetic anhydride (1.5 mmol) at
RT; step 2: Pd(OAc)2 (0.075 mmol), TFA (0.39 mmol), benzaldehyde
(2.0 mmol), TBHP (2 mmol, 70 wt% in water), at 40 ꢀC, 24 h. Yields of
isolated product.
presence of ester function on the aniline part and the appro-
priate benzophenone derivative (4j) was obtained.
The reaction under the applied conditions readily tolerated
the presence of a free hydroxyl group, and we obtained N-
(2-benzoyl-4-(2-hydroxyethyl)-phenyl)acetamide (4i) in high
yield (84%). The sequential reaction could be achieved in the
Substituents on the aromatic ring of the aldehyde substrate
slightly inuenced the isolated yields of the product (yield
varied in the range of 62–86%, Scheme 3.). Ortho, meta and para
halogenated benzaldehydes, as well as methoxy benzaldehyde
resulted in good yields (4k–4p). Aliphatic and heterocyclic
aldehydes are also compatible with the reaction conditions, but
their transformation required higher palladium catalyst loading
(7.5 mol%) and 40 ꢀC (4q, 4r). Electron rich anilines such as
para anisidine and 4-isopropyl aniline were also acylated in
position 2 with substituted aromatic aldehydes aer the
protection of free amino group, and the appropriate products
(4s and 4t) were obtained with 33% and 36% yield.
We have demonstrated that anilines are reasonable starting
materials for the palladium catalyzed C–H acylation coupling
under aqueous conditions in a two steps one-pot process at
room temperature. The conditions of N-acylation of the free
amino group and the cross-dehydrogenative coupling are
compatible. Moreover, during the synthesis of more complex
structures, the protecting group is usually removed aer several
synthetic steps providing the desired functional group in target
molecules.
In our case, removal of the acetyl group from the amino
moiety would provide substituted anilines. This hydrolytic
Scheme 2 Substrate scope of anilines. Reaction conditions: (a) step 1:
acetanilide (1.0 mmol), SDS (0.05 mmol), water (4 mL), acetic anhy- cleavage is usually performed under acidic conditions, which is
dride (1.5 mmol) at RT; step 2: Pd(OAc)2 (0.05 mmol), TFA (0.26 mmol),
benzaldehyde (2.0 mmol), TBHP (2 mmol, 70 wt% in water), at RT, 24 h.
(b) Step 1: acetanilide (1.0 mmol), SDS (0.075 mmol), water (4 mL),
acetic anhydride (1.5 mmol) at RT; step 2: Pd(OAc)2 (0.075 mmol), TFA
(0.39 mmol), benzaldehyde (2.0 mmol), TBHP (2 mmol, 70 wt% in
water), at 40 ꢀC, 24 h. Yields of isolated product.
also compatible with our sequence. Therefore we aimed to
extend our procedure with a hydrolytic reaction step to obtain
amino benzophenones in a three step, one-pot reaction from
anilines using acetyl group as a removable protecting and
directing group for C–H activation.
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compound was isolated with 56% yield. Next, we examined the
substrate scope of the extended three steps sequence. Following
the protection and palladium catalyzed step the nal hydrolysis
completed in 3 hours in all cases (5a–5h, Scheme 4.). Although,
the yield varied in the range of 24–61% the three step one-pot
process provide the desired product with the same efficiency
compared to the step-by-step procedure.
In two cases, we compared the one-pot process to the reac-
tion sequence with full isolation of the intermediate products
(Scheme 5). Starting with aniline, we found that compound 5a
was obtained with 50% overall yield, while the one-pot process
gave the product with similar efficiency (56%). A similar
outcome was observed in the preparation of amino-
benzophenone 5c.
Conclusions
In summary, we developed new sequential methods for the
synthesis of 2- acetamido or 2-amino benzophenone derivatives.
These methods both include the protection of aniline deriva-
tives followed by palladium-catalyzed cross dehydrogenative
coupling of aldehydes under aqueous conditions at room
temperature. Aer the C–H activation step the appropriate
acetamido derivatives can be isolated or hydrolyzed in the same
pot to obtain amino benzophenones, which provide simpler
and faster synthetic routes to the desired target molecules.
Three sequential chemical transformations without the isola-
tion of each intermediate serve as a practical procedure,
producing less waste, and requiring less energy and time for
work up. All reactions were performed in water in the presence
of SDS, which makes the method more attractive with regard to
safety and economic aspects.
Scheme 4 Reaction conditions: (a) step 1: acetanilide (1.0 mmol), SDS
(0.05 mmol), water (4 mL), acetic anhydride (1.5 mmol) at RT; step 2:
Pd(OAc)2 (0.05 mmol), TFA (0.26 mmol), benzaldehyde (2.0 mmol),
TBHP (2 mmol, 70 wt% in water), at RT, 24 h; step 3: 3.5 mL HCl (37 wt%
in water), 125 ꢀC. (b) Step 1: acetanilide (1.0 mmol), SDS (0.075 mmol),
water (4 mL), acetic anhydride (1.5 mmol) at RT; step 2: Pd(OAc)2
(0.075 mmol), TFA (0.39 mmol), benzaldehyde (2.0 mmol), TBHP
(2 mmol, 70 wt% in water), at 40 ꢀC, 24 h. Step 3: 3.5 mL HCl (37 wt% in
water), 125 ꢀC. Yields of isolated product.
¨
This project was supported by the “Lendulet” Research
Accomplishing the protection, coupling and deprotection in
a row without the isolation of the intermediate products
shortens the reaction time and produces less waste. For this
reason, aer the acylation of aniline (1a), and the palladium
catalyzed cross dehydrogenative coupling of the formed acet-
anilide (2a) and benzaldehyde (3a), we treated the reaction
mixture with 37% HCl at 125 ꢀC. To our delight, complete
´
Scholarship of the Hungarian Academy of Sciences, and by TET-
_10-1-2011-0245. The help of Prof. K. Torkos and Dr Zs. Eke for
providing the necessary analytical measurements is gratefully
acknowledged. Thanks to Prof. Tim Peelen for the proofreading
of this manuscript.
hydrolysis took place in 3 hours providing the appropriate Notes and references
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