Mild palladium-catalyzed oxidative direct ortho-C-H acylation of anilides under aqueous conditions

Article abstract of DOI:10.1002/adsc.201200948

Palladium-catalyzed cross-dehydrogenative coupling between anilides and aromatic aldehydes was achieved under aqueous conditions. A wide variety of the desired benzophenone derivatives was isolated in good to excellent yield. The reaction rate acceleration effect of acid and detergent has been demonstrated. Mechanistic insight has been obtained from quantum chemical calculations. Copyright

Full text of DOI:10.1002/adsc.201200948

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DOI: 10.1002/adsc.201200948
À
Mild Palladium-Catalyzed Oxidative Direct ortho-C H Acylation
of Anilides under Aqueous Conditions
Fruzsina Szabꢀ,a Jꢁnos Daru,b Dꢁniel Simkꢀ,a Tibor Zs. Nagy,a Andrꢁs Stirling,c,*
and Zoltꢁn Novꢁka,*
a
MTA-ELTE “Lendꢂlet” Catalysis and Organic Synthesis Research Group, Institute of Chemistry, Eçtvçs University,
Pꢁzmꢁny Pꢃter stny 1/a, H-1117 Budapest, Hungary
E-mail: novakz@elte.hu
Institute of Chemistry, Eçtvçs University, Pꢁzmꢁny Pꢃter stny 1/a, H-1117 Budapest, Hungary
b
c
Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Laboratory of Theoretical Chemistry,
Pusztaszeri fflt 59-67, H-1025 Budapest, Hungary
E-mail: stirling@chemres.hu
Received: October 29, 2012; Revised: November 28, 2012; Published online: && &&, 0000
This paper is dedicated to the memory of Professor rpꢁd Kucsman.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200948.
Abstract: Palladium-catalyzed cross-dehydrogena-
tive coupling between anilides and aromatic alde-
hydes was achieved under aqueous conditions. A
wide variety of the desired benzophenone deriva-
tives was isolated in good to excellent yield. The re-
action rate acceleration effect of acid and detergent
has been demonstrated. Mechanistic insight has
been obtained from quantum chemical calculations.
sides the assessment of the synthetic potential of bi-
metallic complexes in organic chemistry, a thorough
understanding of their working mechanism is also es-
sential.[4]
There are several applications of palladium-cata-
lyzed oxidative transformations for the formation of
new carbon-carbon bonds via functional group-direct-
ed ortho-substitution.[5] Very recently, the synthesis of
aromatic ketones from phenylpyridines[6] or acetani-
lides[7] could be achieved by the palladium-catalyzed
À
Keywords: acylation; aldehydes; C H activation;
palladium; surfactants
oxidative coupling of aldehydes[8] including a C H ac-
tivation step.
À
The recently described methodologies of Zhou,[7a]
Kwong[7b] and Yu[7c] enable the transformation in tolu-
ene at 1208C, 908C, and 408C, respectively
À
Transition metal-catalyzed direct C H bond function- (Scheme 1.). The latter procedure provides the most
alization is one of the most important transformations efficient conditions for the desired coupling due to
in recent organic synthetic strategies.[1] Although cata- the relatively short reaction time under the applied
lytic transformations based on palladium catalysts are conditions (408C, 3 h). Utilization of ketocarboxylic
the most frequently utilized oxidative coupling meth- acids instead of aldehydes enables the formation of
ods in organic syntheses, these reactions usually re- benzophenone derivatives in a similar palladium-cata-
quire harsh conditions (high temperature, long reac- lyzed coupling at room temperature as it was demon-
tion time, necessity of inert atmosphere). Therefore strated by Ge and co-workers.[9] This transformation
the development of efficient palladium-catalyzed oxi- works efficiently at room temperature and it has ex-
dative couplings based on highly active catalyst sys- cellent functional group tolerance.
tems under mild reaction conditions is still highly de-
manded. Regarding the mechanisms of palladium-cat- depicted on Scheme 1., that only Kwongꢄs proce-
alyzed transformations the presence of monometallic
dure[7b] offers possibilities for the transformation of
It is of note, amongst the previous methodologies
AHCTUNGTRENNUNG
palladium complexes in the catalytic cycle is well ac- ortho-substituted acetanilides.
cepted.[2] However, very recently the special role and
Palladium-catalyzed oxidative coupling of acetani-
activity of bimetallic palladium species has been dis- lides with aromatic aldehydes results in 2-acylacetani-
covered and demonstrated in several coupling reac- lides and 2-aminobenzophenone derivatives after hy-
[3]
À
tions involving a C H functionalization step. Be- drolytic cleavage of the amide bond, which are impor-
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Scheme 1. Recently developed couplings.
tant intermediates in the synthesis of many potentially
biologically active heterocycles.[10]
Table 1. Optimization of the reaction conditions.[a]
Our goal was to develop a new palladium-catalyzed
À
C H activation route for the synthesis of aryl ketones
from acetanilides and cheap and readily available al-
dehydes under mild reaction condition in environ-
mentally benign solvent such as water. The utilization
of aqueous media and anionic surfactant enables the
reaction rate acceleration by the “on water”[11] effect
and micellar catalysis.[12] Additionally, we performed
quantum chemical calculations to obtain a possible
mechanistic picture of the transformation.
Entry Catalyst
Solvent Detergent Additive Conv.
[%][b]
Optimization studies were performed with acetani-
lide and benzaldehyde in the presence of 5 mol%
PdACHTUNGTRENNUNG(OAc)2 at room temperature in the presence of tri-
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
DMSO
DMF
MeOH
MeCN
t-BuOH
CHCl3
toluene
DCM
H2O
H2O
H2O
H2O
H2O
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
0
0
0
0
fluoroacetic acid (TFA) and tert-butyl hydroperoxide
(TBHP, 70 wt% in water) as oxidant. For comparison
with literature procedures we examined the applica-
bility of different organic solvents. We found that
only chloroform, dichloromethane and toluene[7] are
suitable solvent for the coupling and we obtained 22,
30 and 24% conversions, respectively, after 3 h. Coor-
dinating solvents such as DMSO, DMF, MeOH,
MeCN gave no reaction and conversion in t-BuOH
was also negligible (Table 1 entries 1–8).
When the reaction was carried out in water instead
of organic media, 60% conversion was obtained
(entry 9.). To ensure better solubility of the reactants
in water we added 0.5 mol% sodium dodecyl sulfate
(SDS) into the reaction, and obtained 67% conver-
sion after 3 h (entry 10).
17
22
24
30
60
67
84
92
93
64
89
16
70
–
–
9
10
11
12
13
14
15
16
17
0.5%,SDS TFA
2%, SDS TFA
5%, SDS TFA
7%, SDS TFA
5%, SMS TFA
5%, SOS TFA
H2O
H2O
H2O
5%, SDS
5%, SDS
–
–
[a]
Reaction conditions: acetanilide (1.0 mmol), benzalde-
hyde (2.0 mmol), Pd(OAc)2 (0.05 mmol), TFA
(0.26 mmol), TBHP (2 mmol), solvent (1 mL) at room
temperataure.
AHCTUNGTRENNUNG
Further addition of the detergent gave up to 93%
conversion (entries 11–13.), showing the importance
[b]
Conversion was determined after 3 h with GC.
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Mild Palladium-Catalyzed Oxidative Direct ortho-C H Acylation of Anilides
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Table 2. Scope of N-acetanilides for Pd-catalyzed C H acy-
of an amphiphilic additive. Examining the effect of
the chain length of alkyl sulfates we performed the re-
actions with sodium methyl and octyl sulfates (SMS
and SOS, respectively). While the former gave a simi-
lar result (64%) to the detergent-free version (com-
pare entries 9 and 14), the latter yielded a similar con-
version (89%) to SDS (compare entries 12 and 15).
These results prove the positive effect of anionic de-
tergents containing long carbon chains on the cou-
pling.[13]
lation.[a]
The presence of TFA was also proved to be essen-
tial. In the absence of the acid the PdACTHNURTGNENG(U OAc)2-cata-
lyzed reaction becomes significantly slower (16% in
3 h, entry 16.). When the catalyst was replaced with
PdACHTUNGTRENNUNG(OTFA)2 without the addition of extra acid the
conversion of the reaction was 70%, showing the im-
portance of TFA anion.
With the optimal conditions in hand next we as-
sessed the scope of the developed methodology. We
achieved the Pd-catalyzed ortho-acylation of differ-
ently substituted acetanilides with benzaldehyde
(Table 2.) in the presence of Pd
ACHTUNGRTEN(NNUG OAc)2 catalyst, TFA
and SDS at room temperature. Application of the
Pd
Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
catalyst system for the synthesis of benzophenone de-
[a]
rivatives.[14]
Reaction conditions: acetanilide (1.0 mmol), benzalde-
hyde
(2.0 mmol),
Pd
(OAc)2
(0.05 mmol),
TFA
The presence of a methyl group in the anilide
slightly affected the yield of the products and 3a-
c were isolated with 48–89%. It is of note that the
ortho-substituted anilides were also successfully trans-
formed into the appropriate products (3a, 3f) in the
(0.26 mmol), TBHP (2 mmol, 70 wt% in water), water
(1 mL) at room temperature, 24 h. Yields [%] of isolated
product.
Reaction conditions: acetanilide (1.0 mmol), aldehyde
(2.0 mmol), PdACTHNUTRGNE(UNG OAc)2 (0.075 mmol), TFA (0.39 mmol),
[b]
À
C H activation reaction, in spite of their lower reac-
TBHP (2 mmol, 70 wt% in water), water (1 mL) at 408C,
24 h.
tivity.
The coupling also took place straightforwardly in
the presence of a methoxy group in the ortho position
and the desired product (3f) was obtained with excel- nitrobenzaldehyde, heterocyclic, conjugated or ali-
lent yield. A methoxy group in a meta-position to the phatic aldehydes. Finally, demonstrating the applica-
amide function afforded the appropriate benzophe- bility of the developed methodology further benzo-
none derivative (3g) in the catalytic transformation.
phenone derivatives 3aa–3ee) bearing functional
We also performed the coupling of anilide deriva- groups in both aromatic rings were synthesized with
tives with benzaldehyde-containing a condensed ring 37–60% yields.
system such as naphthalene or halogen substituents.
In order to support our hypothesis regarding a prob-
The appropriate products (3h–k) were prepared with able mechanism of the reaction, we have performed
similar efficiency using 7.5 mol% palladium catalyst density functional calculations.[15] As a simplified the-
at 408C.
oretical model we have chosen the coupling of acetan-
(OAc)2
After studying the effect of acetanilide substituents ilide and benzaldehyde in the presence of PdACHTUNGTRENNUNG
we examined the effect of functional groups on the al- catalyst in water (Table 1. entry 9.). We have followed
dehyde part (Table 3.). Remarkably, the presence of two different reaction routes featuring mono- and bi-
halogens in any positions of the aromatic ring of the nuclear active Pd species.[16] The corresponding free
aldehyde afforded similar or better yields for products energy profiles are displayed on Figure 1. We propose
3m–t compared to the unsubstituted derivative 3l. that palladium acetate reacts with acetanilide and
The products were obtained with good yields when forms cationic palladium species S1 which is involved
the aldehyde was substituted with electron-donating in the carbopalladation step. The profiles are initiated
groups such as methyl or methoxy group (3u, 3v). at the predicted resting state of the reactants
Larger catalyst loadings and 408C were necessary to (Scheme 2). Both routes start with the carbopallada-
obtain the target products 3w–z constructed from 4- tion step which is the rate-limiting step of the overall
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Table 3. Scope of aldehydes for Pd-catalyzed C H acyla-
ACHTUNGTRENNUNG
Figure 1. Gibbs free energy diagram for the calculated reac-
tion routes.
and enter into its cycle or form bimetallic palladium
complex S3b in a slightly endergonic dimerization
step. In the further calculations the free energy pro-
files of the catalytic cycles based on mono- and binu-
clear palladium species were treated separately. Asso-
ciation of the benzoyl radical formed from TBHP and
aldehyde[17] and the active Pd species is slightly exer-
gonic for the mono- and endergonic for the binuclear
route (S5m and S5b levels, respectively).[18] The next
key step in the reaction is the rapid reductive-elimina-
tion leading to the S6 intermediates. From the S6
states we have assumed fast reaction steps leading to
the products.[19]
Comparison of the two profiles shows that the binu-
clear pathway is more accessible than the mono-
AHCTUNGTREGnNNUN uclear one. This can be attributed to the enthalpical-
ly favourable formation of the binuclear species with
more flexible ligand arrangements which can over-
compensate the entropic loss of the association.
We stress that a complete mechanistic view requires
the consideration of other possibilities. Further exper-
imental and computational studies are now underway
in our laboratories. In particular, we will address the
potential role of different Pd oxidation states in the
mechanism.
In summary, a new and efficient method has been
developed for direct ortho-acylation of anilides with
aromatic aldehydes via C H bond activation. This
[a]
[b]
Reaction conditions: acetanilide (1.0 mmol), aldehyde
(2.0 mmol), Pd(OAc)2 (0.05 mmol), TFA (0.26 mmol),
TBHP (2 mmol, 70 wt% in water), water (1 mL) at room
temperature, 24 h. Yields [%] of isolated product.
Reaction conditions: acetanilide (1.0 mmol), aldehyde
(2.0 mmol), PdACHTUNGTRENNUNG(OAc)2 (0.075 mmol), TFA (0.39 mmol),
ACHTUNGTRENNUNG
À
palladium-catalyzed oxidative coupling reaction was
accomplished between 25-408C in water with the aid
of an anionic surfactant, using TBHP as oxidant. We
demonstrated the rate accelerating effect of long-
chain anionic detergent and trifluoroacetic acid under
aqueous conditions. With the support of quantum
chemical calculations we compared two possible path-
ways and the preference of bimetallic catalysis over
TBHP (2 mmol, 70 wt% in water), water (1 mL) at 408C,
24 h.
process (Figure 1). During this step the aromatic ring the monomeric route was indicated. However, our as-
is deprotonated by the acetate ligand.[19]
sumption regarding the mechanism needs experimen-
After the carbopalladation step the monomeric pal- tal evidence, and consideration of other possible
ladium species S2 can be deprotonated yielding S3m mechanistic pathways is also necessary in the future.
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Mild Palladium-Catalyzed Oxidative Direct ortho-C H Acylation of Anilides
Scheme 2. Mechanistic alternatives proposed for the oxidative coupling of acetanilides and aldehydes.
The developed synthetic procedure has high function- Experimental Section
al group tolerance and ensures easy access to protect-
ed 2-aminobenzophenone derivatives from inexpen- General Procedure
sive and readily available starting materials. Addition-
A screw-capped vial with stir bar was charged with the
5 mol% PdACTHNURGTNEUNG(OAc)2, 5 mol% SDS, acetanilide (1 mmol,
ally, the unique behaviour of bimetallic palladium
complexes and the mild reaction conditions enable
the development of other valuable synthetic tools for
the functionalization of aromatic compounds through
1 equiv.), and water (1 mL). TFA (20 mL, 0.26 mmol,
26 mol%) was added followed by the aldehyde (2 mmol,
2 equiv., and TBHP (250 mL, 2 mmol, 2 equiv., 70 % in
H2O). The reaction vessel was closed, and the reaction mix-
ture was stirred at room temperature. After 24 h, the reac-
tion mixture was washed with EtOAc. The organic phase
was washed with water, dried over magnesium sulfate, and
concentrated. The crude product was purified with column
chromatography (hexane/EtOAc).
À
C H activation.
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Acknowledgements
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This project was supported by the “Lendꢀlet” Research
Scholarship of the Hungarian Academy of Sciences and by
OTKA-NKTH (CK 80763), OTKA K-101115 and TꢁT 10-
1-2011-0245. The help of Prof. K. Torkos and Dr Zs. Eke for
providing the necessary analytical background is gratefully
acknowledged.
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[5] For selected examples, see: a) O. Daugulis, V. G. Zait-
sev, Angew. Chem. 2005, 117, 4114–4116; Angew.
6
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Mild Palladium-Catalyzed Oxidative Direct ortho-C H Acylation of Anilides
[11] a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin,
H. C. Kolb, K. B. Sharpless, Angew. Chem. 2005, 117,
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b) H.-B. Zhang, L. Liu, Y.-J. Chen, D. Wang, C.-J. Li,
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[13] For time-conversion graphs, see Supporting Informa-
tion.
[14] Based on the prices of a chemical supplier PdCAHTUNGTRENNUNG
costs 3 times more than Pd
1 mol of palladium.
ACHTUNGTRENNUNG
[12] a) B. H. Lipshutz, S. Ghorai, Aldrichimica Acta 2008,
41, 59–72; b) B. H. Lipshutz, S. Ghorai , Aldrichimica
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[15] Calculations have been carried out with the G09 pack-
age, applying M06/6-31+G* method (LanL2DZ with
additional diffuse and polarization functions on Pd)
and the SMD water solvent model. Optimizations were
done in the gas phase, the solvent model was applied in
perturbative manner. Further details and the XYZ co-
ordinates of the calculated species are listed in the Sup-
porting Information.
[16] Due to the presence of benzoyl radical and the sup-
posed SET mechanism we have taken into consider-
ation both monometallic and bimetallic pathways.
[17] a) C. Chatgilialoglu, L. Lunazzi, D. Macciantelli, G.
Placucci, J. Am. Chem. Soc. 1984, 106, 5252–5256; b) C.
Walling, M. J. Mintz, J. Am. Chem. Soc. 1967, 89, 1515–
1519.
[18] Due to the endergonic step from S3b to S5b we sup-
pose the addition of only one benzoyl radical to the bi-
metallic complex. Addition of second radical would be
entropically less favourable.
[19] Calculated structures of TS1, TS2m and TS2b can be
found in the Supporting Information.
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