Palladium(II)-catalyzed direct ortho-C-H acylation of anilides by oxidative cross-coupling with aldehydes using tert-butyl hydroperoxide as oxidant

Article abstract of DOI:10.1002/adsc.201100472

An efficient palladium-catalyzed C-H acylation with aldehydes using tert-butyl hydroperoxide (TBHP) transforms various anilides into synthetically useful 2-aminobenzophenone derivatives under mild conditions (40°C, 3 h). The acylation reaction exhibits ex

Full text of DOI:10.1002/adsc.201100472

FULL PAPERS
DOI: 10.1002/adsc.201100472
À
Palladium(II)-Catalyzed Direct ortho-C H Acylation of Anilides
by Oxidative Cross-Coupling with Aldehydes using tert-Butyl
Hydroperoxide as Oxidant
Chun-Wo Chan,a Zhongyuan Zhou,a and Wing-Yiu Yua,*
a
State Key Laboratory of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax : (+852)-2364-9932; e-mail: bcwyyu@inet.polyu.edu.hk
Received: June 16, 2011; Revised: July 29, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100472.
À
Abstract: An efficient palladium-catalyzed C H acy- ic aldehydes are effective coupling partners. The acy-
lation with aldehydes using tert-butyl hydroperoxide lation reaction is probably initiated by a rate-limiting
+
À
(TBHP) transforms various anilides into synthetical- electrophilic C H cyclopalladation (kH/kD =3.6; 1 =
ly useful 2-aminobenzophenone derivatives under À0.74) to form an arylpalladium complex, followed
mild conditions (408C, 3 h). The acylation reaction by acyl radical functionalization.
exhibits excellent regioselectivity and functional
À
group tolerance, and simple aromatic aldehydes, Keywords: acylation; 2-aminobenzophenones; C H
functionalized aliphatic aldehydes and heteroaromat- activation; Friedel–Crafts reaction; palladium
Introduction
ACHTUNGTRENNUNG
2-Aminobenzophenones are important precursors to ally, 2-aminobenzophenones are prepared by Friedel–
many medicinally useful heterocycles such as fluoren- Crafts acylation reactions of anthranilic acids with
Scheme 1. Some medicinally useful heterocycles derived from 2-aminobenzophenones.
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Chun-Wo Chan et al.
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Scheme 2. Synthesis of 2-aminobenzophenones.
arenes.[1b] However, the Friedel–Crafts acylations excellent regiocontrol and functional group tolerance;
suffer from poor regioselectivity using an over-stoi- aliphatic, aromatic and heteroaromatic aldehydes are
chiometric amount of Lewis acid catalyst (Scheme 2). effective coupling partners to generate structurally di-
While the direct Friedel–Crafts acylation of anilines verse 2-aminobenzophenone derivatives.
with acyl chlorides is problematic, 2-aminobenzophe-
nones can be prepared by directly reacting anilines
with benzonitriles promoted by stoichiometric Results and Discussion
amounts of BCl3 and AlCl3 (the Sugasawa reaction).[3]
Notwithstanding, with the growing demand for sus- Reaction Optimization
À
tainable chemical synthesis, the direct catalytic C H
functionalization of anilines by employing non-haz- With reference to our earlier work,[14a] we began by
ardous acylating reagents under mild conditions is examining the reaction of 3,4-dimethyl-N-pivalanilide
highly desirable.[4]
(1a,
0.25 mmol)
and
4-chlorobenzaldehyde
Catalytic dehydrogenative cross-coupling (CDC) (0.75 mmol) in the presence of TBHP (0.5 mmol),
À
reactions of two simple C H bonds are an attractive TFA (0.25 mmol) and Pd
and yet challenging approach for C C bond forma- gassed DCE (1 mL) at 1008C for 3 h. We were grati-
(TFA)2 (10 mol%) in unde-
À
tion.[5] In this regard, recent advances have been fied to find that 2a was obtained in 50% yield
À
made in Pd-catalyzed regioselective direct C H func- (Table 1, entry 1), and its structure has been estab-
tionalizations.[6,7] With the assistance of a donor group lished by X-ray crystallography (see Supporting Infor-
(e.g., pyridyl, imino, amido, carboxylato), highly re- mation). Under our experimental conditions, no
À
gioselective C H bond couplings with arenes (biaryl ortho-arylation of the anilide was observed.
formation)[8,14e], alkenes (Heck-type vinylation)[9] and
In the absence of PdACTHNGUTER(NNUG TFA)2 or TFA, 2a was not ob-
alkynes (cycloaddition)[10] have been accomplished. tained with full recovery of the starting materials (en-
À
Yet, the analogous direct C H acylations with alde- tries 2 and 3). Notably, no 2a formation was observed
hydes are far less established. In 2009, Cheng and co- without TBHP as oxidant (entry 4). Yet, other oxi-
workers described the intermolecular Pd-catalyzed dants such as tert-butyl peroxide, benzoyl peroxide,
oxidative coupling of 2-arylpyridines with benzalde- H2O2, K2S2O8, benzoquinone and CuACTHNUGTRNE(UNG OAc)2 failed to
hydes to aromatic ketones.[11] Recently, the analogous effect any significant product formation (see Support-
coupling with aliphatic aldehydes was also accom- ing Information). With TBHP as oxidant, 2a was pro-
plished by Li and co-workers.[12] Nevertheless, exam- duced in 90% yield when the reaction was performed
ples of the direct coupling of anilines with aldehydes at 408C under an N2 atmosphere (entry 5). Compara-
have limited precedents in the literature. Notably, Li ble results were obtained when toluene was employed
and co-workers reported the Cu-catalyzed cyclization as solvent (entry 9).
of formyl-N-arylformamides for the synthesis of indo-
However, donor solvents such as 1,4-dioxane, DME
and CH3CN afforded poor results (ca. 40%; entries 6–
line-2,3-diones under an O2 atmosphere.[13]
À
With an interest to develop catalytic C H bond 8). After several trials, 2a was obtained reproducibly
cross-coupling reactions,[14] here we describe a highly in 86% yield (entry 9) under the optimized reaction
versatile 2-aminobenzophenone synthesis[15] by Pd- conditions: 1a, 4-chlorobenzaldehyde (3 equiv.),
À
catalyzed oxidative ortho-C H bond cross-coupling of TBHP (2 equiv.), TFA (1 equiv.) and Pd
anilides with aldehydes using TBHP as oxidant.[16] (5 mol%) in toluene at 408C under N2.
ACHTUNGTRENNUNG(OAc)2
Unlike the Friedel–Crafts reactions, the catalytic ani-
We found that effective coupling of 1a with 4-
lide coupling reactions proceed at 408C and exhibit chloroAHCTUNGTRbEUNNNG enzaldehyde would also occur even at room
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Palladium(II)-Catalyzed Direct ortho-C H Acylation of Anilides
Table 1. Reaction optimization.[a,b]
being formed in 28% yield. After several attempts, ef-
fective cross-coupling of 1c was achieved to furnish 2c
in 74% yield when TBHP was added in a batchwise
fashion (Method B). Similarly, other substituted piva-
lanilides [Y=3-OCHF2, 4-C(O)Me and 4-Br] would
undergo facile cross-coupling with Method B: 2d
(70%), 2e (52%), 2f (45%). Acetamido, benzamido
and tertiary amide groups are capable directing
Entry Pd (mol%)
Solvent Acid
(equiv.)
Yield
[%]
À
groups for the ortho-C H coupling reactions to give
aryl ketones 2g–k in 64–55% yields.
1[c]
2[c]
3[c]
4[d]
5
6
7
8
9
Pd
–
G
DCE
DCE
DCE
DCE
DCE
TFA (0.5) 50
As expected, other substituted benzaldehydes are
effective coupling partners for the Pd-catalyzed acyla-
tion of pivalanildes, and the ketones 2l–n were pro-
duced in 87–72% yields. Likewise, the coupling with
aliphatic aldehydes such as pentanal, cyclohexanecar-
boxyaldehyde, 3-phenylpropanal and phenylacetalde-
hyde furnished ketones 2o (72%), 2p (76%), 2q
(70%) and 2r (48%), respectively. In this work, facile
coupling of cyclopropanecarboxyaldehyde with acet-
anilide afforded exclusively the cyclopropyl aryl
ketone 2s in 64% yield; the ring opened products
were not obtained. The lack of ring opened products
observed in this work resembles an analogous study
on acyl radical addition to fullerenes.[17] Furthermore,
the reaction of a-tert-butyldimethylsilyloxylacetalde-
hyde with acetanilde gave 2t in 61% yield, and the si-
lyloxy group was tolerated. Similarly N-Cbz-protected
2-aminopropanal reacted with pivalanilide to afford
2u in 64% yield. It was reported that amino-function-
alized ketones such as 2u are useful precursors for the
N-alkylaminoethylcamptothecin analogues.[18] Accord-
ing to the literature, the amino-functionalized aryl ke-
tones were prepared in four steps involving Freidel–
Crafts acylation and Michael addition with appropri-
ate alkylamines in 7–44% yields.[19]
TFA (0.5)
–
TFA (0.5)
0
0
0
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
(5)
PdCl
PdCl
Pd
Pd
Pd
TFA (0.5) 90
dioxane TFA (0.5) 34
DME TFA (0.5) 56
CH3CN TFA (0.5) 31
toluene TFA (0.5) 94
toluene TFA (1)
toluene TFA (1)
10
11[f]
12
86[e]
77
67
13
14
15
16
17
<5
39
toluene AcOH (1) <5
toluene PivOH(1)
toluene TsOH (1)
0
48
[a]
General conditions: 1a (0.25 mmol), 4-ClC6H4CHO
(3 equiv.), Pd catalyst, TBHP (2 equiv.), acid (0.5–
1 equiv.), solvent (1 mL) at 408C under N2 for 3 h.
Yields determined by NMR using dibromomethane as in-
ternal standard.
Temperature is 1008C, undegassed.
Without TBHP as oxidant.
Isolated yield=80%.
Room temperature for 12 h.
[b]
[c]
[d]
[e]
[f]
Heteroaromatic rings such as indoles are important
scaffolds for many pharmaceutically active com-
temperature with 2a being obtained in 77% yield pounds;[20] 1-aroylindoles can be readily prepared by
À
(entry 11). Among a panel of common Pd catalysts in- direct acylation of the N H free indole precursors.
cluding Pd
G
PdCl2A(Ph3P)2, Pd
G
E
coupling reaction (entries 10–14). While TFA is the PDC oxidation.[21] In this work, when pivalanilide 1a
most effective additive; other carboxylic acids (e.g., was treated with ethyl 5-formyl-1H-indole-1-carboxyl-
AcOH, PivOH and TsOH) failed to afford better ate under the Pd-catalyzed conditions, ketone 2v was
product yields (entry 14–16).
exclusively isolated in 60% yield. The couplings with
furfural, 5-chloro-2-thiophenecarboxyaldehyde and 2-
benzothiophenecarboxyaldehyde were also accom-
plished: 2w (62%), 2x (75%) and 2y (76%). In all
cases, no significant oxidation to the heterocycles was
Substrate Scope Study
Scheme 3 depicts the substrate scope of the Pd-cata- observed under our experimental conditions.
lyzed oxidative coupling reaction. Treating 4-chloro-
benzaldehyde (3 equiv.) and 3-methoxypivalanilide
(1b) in the Pd-catalyzed conditions [PdACHTNUGTRENUNG(OAc)2 Mechanistic Considerations
(5 mol%), TBHP (2 equiv.), TFA (1 equiv.), N2, tolu-
ene, 408C, 3 h (Method A)] afforded 2b in 71% yield. The oxidative acylation of anilides is probably initiat-
À
However, Method A was less effective for the analo- ed by arene C H bond palladation to form the cyclo-
gous reaction of 3-tosyloxypivalanilide (1c) with 2c palladated complex (Scheme 4).[16a,b] In this work, we
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Scheme 3. Substrate scope study for the Pd-catalyzed cross coupling reaction of anilides with aldehydes. The reported yields
are of isolated product.
prepared the cyclopalladated complex 1g-Pd by react- primary kinetic isotope effect (kH/kD)=3.6 was ob-
ing acetanilide 1g with Pd
petitive experiments with 1g and 1g-d5 as substrates, a mining C H activation step.
ACHTUNGETRN(NUNG OAc)2 in toluene. By com- served; this value is compatible with the rate-deter-
[22]
À
A Hammett correla-
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Palladium(II)-Catalyzed Direct ortho-C H Acylation of Anilides
Scheme 4. Proposed mechanism.
tion study on a series of meta-substituted pivalanilides interaction with the Pd(II) center with little positive
(Y=OMe, Me, Ph, H, Cl and Br) revealed a linear charge development on the arene. The agostic interac-
À
free energy relationship (R=0.96) with the Hammett tion enhances the acidity of the ortho-C H bond,
+
constant sp and the 1+ value was found to be À0.74 which was subsequently deprotonated by the coordi-
(Figure 1). It should be noted that this 1+ value is too nated carboxylate. Recently, Fagnou and co-workers
small to support a carbocation intermediate corre- proposed
a
concerted metallation deprotonation
À
sponding to an electrophilic aromatic substitution (CMD) pathway for the Pd-mediated direct C H ary-
(chlorination of benzene in acetic acid=À9 to À10). lations.[24] For our Pd-catalyzed C H acylation reac-
À
À
Our KIE and Hammett study on the nature of the C
tions, the CMD pathway may not be tenable since
H cleavage steps seems to favour a transition state in- this pathway was characterized by a positive Ham-
volving the build-up of partial positive charge mett correlation manifesting the building up of nega-
(Scheme 4). According to a computational study on tive charge on the arene ring.
the cyclopalladation of N,N-dimethylaminobenzene
Regarding the nature of the anilide-aldehyde cou-
by Davies and Macgregor,[23] the C H palladation pling reaction, a direct nucleophilic-type reaction of
À
À
may proceed by the rate-limiting agostic C H bond the arylpalladium complex with aldehyde can be
ruled out since treatment of 1g-Pd with aldehyde
without TBHP did not produce any coupled ketones.
Indeed, significant ketone 2g formation (59%, compa-
rable to the catalytic results) was only achieved by re-
acting 1g-Pd (1 equiv.) with 4-chlorobenzaldehyde
(3 equiv.) in the presence of 1g (1 equiv.), TBHP
(2 equiv.), and TFA (1 equiv.) (see Supporting Infor-
mation).[25] Since decomposition of TBHP is known to
generate the reactive t-BuOC radical, which would
react with aldehyde by hydrogen atom abstraction to
give reactive acyl radicals,[26,27] we hypothesize that
the acyl radicals[28] would react with the palladacycle
to afford the product ketones via either Pd(IV)[29] or
Figure 1. Hammett correlation studies.
dimeric PdACTHNGUTERNNUG
(III)[25a,30] intermediates (Scheme 4).
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Conclusions
meta-Y-substituted pivalanilide (Y=MeO; Me; Ph; Cl; Br;
0.1 mmol), PdACTHUNRGTNEUNG(OAc)2 (1.8 mg, 0.008 mmol), 4-chlorobenzal-
dehyde (0.084 mg, 0.6 mmol). The reaction tube was stop-
pered, then evacuated and charged with N2 (repeated three
times). Subsequently, dry toluene (1 mL), TFA (0.0154 mL,
0.2 mmol), and TBHP (5M in DCE, 0.08 mL, 0.4 mmol)
were added under a flow of N2. The reaction mixture was
stirred at 408C for 4 min. The reaction mixture was cooled
with ice/water and quenched by saturated sodium bisulfate
solution (2 mL). Then the combined organic solution was
dried with Na2SO4 and concentrated under vaccum. The re-
sulting residue was analyzed by GC/FID for the determina-
tion of conversion using a calibration curve (3 points) with
tetradecane (0.1 mmol) as the internal standard. Each result
was run in triplicate.
In summary, we have developed an intermolecular
cross-coupling of simple aldehydes with anilides via
À
C H bond activation. The cross-coupling reaction ex-
hibits high functional group tolerance and regioselec-
tivity under relatively mild conditions using TBHP as
a benign terminal oxidant. It is noteworthy that heter-
oaromatic aldehydes would effectively couple with
anilides to afford structurally diverse 2-aminobenzo-
phenone derivatives. In view of the synthetic utility of
2-aminobezophenones, this reaction would be of
broad interest to synthetic chemistry.
Experimental Section
Acknowledgements
General Procedure for Pd-Catalyzed Acylation of
Anilides
We thank the financial support from The Hong Kong Re-
search Grants Council (PolyU 5031/09P, SEG PolyU01).
A 10-mL Schlenk-type test tube (with a Quick-fit stopper
and side arm) equipped with a magnetic stir bar was
charged with the anilides substrate (0.25 mmol), PdACTHNUTRGNEUNG(OAc)2
(2.8 mg, 0.0125 mmol), aldehyde (0.75 mmol). The reaction
tube was stoppered, then evacuated and charged with N2
(repeated three times). Subsequently, dry toluene (1 mL),
TFA (0.0192 mL, 0.25 mmol), and TBHP (5M in DCE,
0.1 mL, 0,5 mmol) were added under a flow of N2. The reac-
tion mixture was stirred at 408C for 3 h. The reaction mix-
ture was filtered over a plug of celite and the solvent was re-
moved under vacuum. The resulting residue was purified by
silica gel flash column chromatography using hexanes/
EtOAc as the eluent.
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A 10-mL Schlenk-type test tube (with a Quick-fit stopper
and side arm) equipped with a magnetic stir bar was
charged with acetanilide (1g, 0.1 mmol) and 1g-d5
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times). Subsequently, dry toluene (1 mL), TFA (0.0154 mL,
0.2 mmol), and TBHP (5M in DCE, 0.08 mL, 0.4 mmol)
were added under a flow of N2. The reaction mixture was
stirred at 408C for 30 min. The reaction mixture was cooled
with ice water and quenched by saturated sodium bisulfate
solution (2 mL). Then the combined organic solution was
dried with Na2SO4 and concentrated under vaccum. The re-
sulting residue was purified by a plug of silica gel flash
column chromatography using hexanes/EtOAc (1:1) as the
eluent. Both the recovered starting materials and the isolat-
ed products were analyzed by NMR for determination of
conversion and yield with dibromomethane (0.1 mmol, 2H)
as the internal standard.
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À
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2999 – 3006