Rhodium-catalyzed oxidative ortho-acylation of aryl ketone O-methyl oximes with aryl and alkyl aldehydes

Article abstract of DOI:10.1002/adsc.201200401

The rhodium-catalyzed oxidative ortho-acylation of aryl ketone O-methyl oximes with aryl and alkyl aldehydes via C-H bond activation is described. The cross-coupling reaction exhibits high functional group tolerance and regioselectivity under relatively m

Full text of DOI:10.1002/adsc.201200401

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DOI: 10.1002/adsc.201200401
Rhodium-Catalyzed Oxidative ortho-Acylation of Aryl Ketone
O-Methyl Oximes with Aryl and Alkyl Aldehydes
Yaxi Yang,a Bing Zhou,a,* and Yuanchao Lia,*
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park,
Shanghai 201203, Peopleꢀs Republic of China
Fax : (+86)-21-5080-7288; phone: (+86)-21-5080-6600ꢁ3502; e-mail: zhoubing2012@hotmail.com or ycli@mail.shcnc.ac.cn
Received: May 8, 2012; Revised: July 23, 2012; Published online: October 30, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200401.
Abstract: The rhodium-catalyzed oxidative ortho-
acylation of aryl ketone O-methyl oximes with aryl
and alkyl aldehydes via C H bond activation is de-
The transition metal-catalyzed direct transforma-
tion of inactive C H bonds has emerged as an effi-
À
À
cient, atom-economical, and environmentally friendly
scribed. The cross-coupling reaction exhibits high
functional group tolerance and regioselectivity
under relatively mild conditions and constitutes
a versatile route to a diverse library of diaryl ke-
tones, which are difficult to obtain by the classical
Friedel–Crafts acylation. Moreover, this reaction
proceeds via an unprecedented Rh-catalyzed oxida-
tive ortho-acylation of aryl ketone O-methyl oximes
with highly electron-deficient aryl aldehydes fol-
tool in organic synthesis.[5] Recently, the transition
À
metal-catalyzed addition of C H bonds to alkene and
alkyne derivatives has been extensively investigated.[6]
À
However, successful examples of direct aryl C H ad-
dition to C/O[7] or C/N[8] multiple bonds are rarely re-
ported. Particularly, cross-coupling reactions between
À
À
aryl C H and aldehyde C H bonds to form the corre-
sponding aryl ketones remain relatively unexplored.
In 2009, Cheng reported a palladium-catalyzed cou-
pling reaction of 2-arylpyridines and aryl aldehydes to
afford aryl ketones through a pyridine-directing
group.[9] In 2010, Yu developed a Pd-catalyzed cou-
pling reaction of aryl ketone oximes and aldehydes
using tert-butyl hydroperoxide as oxidant.[10] Deng
and Li also demonstrated a palladium-catalyzed oxi-
dative acylation reaction of 2-arylpyridines and ben-
zylic or aliphatic alcohols in the presence of tert-butyl
hydroperoxide as an oxidant.[11] Several studies on
Pd-catalyzed oxidative acylation of anilides with ben-
À
lowed by a direct addition of the second ortho C H
bond to aldehydes in a one-pot reaction, to gener-
À
ate two C C bonds simultaneously.
Keywords: acylation; aldehydes; aryl ketone O-
À
methyl oximes; C H activation; rhodium catalysis
Aryl ketones are very important motifs in organic zylic alcohols or aldehydes have been reported.[12] De-
synthesis as well as an important functionality found spite these advances, the development of novel cata-
in several natural products and in various pharma- lysts is still necessary to achieve such elusive intermo-
ceutical compounds.[1] In particular, 1,2-diacylben- lecular reactivity, especially with respect to selectivity,
zenes have been of great interest primarily as fluores- reaction conditions, and substrate scope. Recently,
cence reagents for both qualitative and quantitative Kim and co-workers described the first rhodium-cata-
high-sensitivity analyses of amines and amino acids.[2] lyzed coupling reaction of benzamides with aryl alde-
Moreover, 1,2-diacylbenzenes are useful precursors to hydes.[13] More recently, we developed a Rh-catalyzed
quinone derivatives, isobenzofurans, indenes, hydroxy- oxidative C-2 acylation of indoles with aryl and alkyl
phenylindanones, N-arylphthalimidines, phthalazines, aldehydes.[14] Inspired by these results and given the
isoindoles and isoindolines, which are scaffolds for importance of 1,2-diacylbenzenes in synthetic chemis-
compounds of biological or pharmaceutical interest.[3] try, we became interested in exploring the synthesis of
However, only few general synthetic methods for 1,2- 1,2-diacylbenzene oximes via Rh-catalyzed oxidative
diacylbenzenes have been reported to date.[4] There- arene C H bond coupling with aldehydes, the devel-
À
fore, it is highly desirable to develop more versatile opment of which is reported herein. Unlike the Frie-
and efficient methodologies to synthesize 1,2-diacyl- del–Crafts reactions, which suffer from poor regiose-
benzenes with fewer synthetic steps and readily avail- lectivity, this catalytic oxidative coupling reaction ex-
able starting materials.
hibits excellent regioselectivity and functional group
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Rhodium-Catalyzed Oxidative ortho-Acylation of Aryl Ketone O-Methyl Oximes
tolerance; aromatic, heteroaromatic and aliphatic al- toluene, t-BuOH and chlorobenzene was less effective
dehydes are effective coupling partners for this reac- (Table 1, entries 10–12). Finally, the best results were
tion.
obtained by adding 3ꢃ molecular sieves to afford the
We initiated our investigation by exploring the cou- desired 3a in 82% yield, as shown in entry 14.
pling of acetophenone O-methyl oxime (1a) with ben-
zaldehyde (2a) (Table 1). To our delight, the cationic
À
Table 2. Rh-catalyzed oxidative C H bond coupling with al-
dehydes.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry
Oxidant
Solvent
Yield [%][b]
1
Ag2CO3
Ag2CO3
Ag2CO3
THF
THF
THF
THF
30
0
0
20
2[c]
3[d]
4
Cu
A
5
6
7
8
K2S2O8
THF
THF
THF
THF
<10
<10
<10
15
benzoquinone
t-BuO2H
AgOAc
–
9
THF
0
10
11
12
13
14[e]
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
PhMe
t-BuOH
chlorobenzene
CH2Cl2
CH2Cl2
<10
<10
<10
57
82
[a]
Conditions: 1a (1 equiv.), 2a (2.5 equiv.), [Cp*RhCl2]2
(0.05 equiv.), AgSbF6 (0.2 equiv.) and oxidant (2.5 equiv.)
were dissolved in the solvent (0.2M) and heated at the
858C for 24 h in a sealed tube.
[b]
[c]
Yield isolated by column chromatography.
Using Cp*RhACHTUNGTRENNUNG(MeCN)3AHCUTNGTRENN(UGN SbF6)2 (0.05 equiv.) as the cata-
lyst.
[d]
[e]
Using [Cp*RhCl2]2 as the catalyst.
3ꢃ molecular sieves were added.
rhodium complex, derived from [Cp*RhCl2]2 and
AgSbF6, was found to catalyze the coupling in the
presence of Ag2CO3 to produce the desired adduct 3a
in 30% yield (Table 1, entry 1). Use of the complex
Cp*RhACHTUNGTRENNUNG(MeCN)3ACHTUNGTRENNUNG(SbF6)2 and a related non-cationic
catalyst, [Cp*RhCl2]2, did not promote the coupling
reaction (Table 1, entries 2 and 3). The use of other
oxidants, such as CuACHTUNGTRNENUG(OAc)2, K2S2O8, benzoquinone, t-
BuO2H and AgOAc, was relatively ineffective in the
coupling of 1a and 2a (Table 1, entries 4–8). In the ab-
sence of Ag2CO3, no product was observed with full
recovery of the starting materials (Table 1, entry 9).
Solvent screening showed that an improved chemical
yield could be obtained using CH2Cl2 as a solvent,
providing the product 3a in 57% yield (Table 1,
entry 13), whereas the use of other solvents such as
[a]
[b]
Conditions:
[Cp*RhCl2]2
(0.05 equiv.),
AgSbF6
(0.2 equiv.), 1 (1 equiv.), 2 (2.5 equiv.), 3ꢃ molecular
sieves and Ag2CO3 (2.5 equiv.) were dissolved in the
CH2Cl2 (0.2M) and heated at the 858C for 24 h in sealed
tubes. Isolated yields are reported.
38% yield based on recovered starting material.
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À
Table 3. Rh-catalyzed oxidative C H bond coupling with
As shown in Table 2, a range of substrates under-
went this Rh-catalyzed oxidative coupling reaction of
acetophenone oximes and aldehydes. Using benzalde-
hyde or 4-methylbenzaldehyde, the substituted aceto-
phenone oximes were transformed to the correspond-
ing ketones 3b–3h. It was found that the electronic
nature of the substituents on the phenyl ring did not
play key roles (3b to 3g). Acetophenone oximes bear-
ing both electron-donating (OMe, Me) and electron-
withdrawing (CF3, F, COOMe) substituents were
readily converted to the corresponding products in
good yields. But an ortho-methyl-substituted aryl
oxime resulted in poor yield (3h), likely due to steric
congestion between the directing group and the
methyl substituent.[15] The substrate scope was also in-
vestigated with respect to the aldehyde. Compared to
benzaldehyde, this coupling reaction showed slightly
lower yields when using heterocyclic furfural and 2-
thiophenecarboxyaldehyde (3i and 3j). The aliphatic
cyclohexanal (3k) was further tested, but the reaction
gave relatively lower yields. Meanwhile, different
phenyl electron-donating or electron-withdrawing
groups on the aldehyde were explored. For examples,
with a methyl group (3l–3n) and a methoxy group
(3o), the reactions showed good reactivity. In addi-
tion, a bromo substitution (3p) was also tolerated
which offers the opportunity for further transforma-
tions. Relatively electron-deficient m-trifluoromethyl-
benzaldehyde and p-trifluoromethylbenzaldehyde
highly electron-deficient benzaldehyde.[a]
[a]
Conditions: [Cp*RhCl2]2 (0.1 equiv.), AgSbF6 (0.4 equiv.),
1a (1 equiv.), 2 (4 equiv.), 3ꢃ molecular sieves and
Ag2CO3 (2.5 equiv.) were dissolved in the CH2Cl2 (0.2M)
and heated at the 858C for 24 h in sealed tubes. Isolated
yields are reported.
were also converted to the corresponding products 3q oxidized in the presence of a silver(I) salt to regener-
and 3r, respectively. Noteworthy, different from all ate Rh(III).
the previous results,[9–14] with highly electron-deficient
In summary, we have developed an Rh-catalyzed
AHCTUNGTRENNUNG
benzaldehydes as reagent, the monoacylated products intermolecular oxidative cross-coupling of simple al-
À
readily proceeded to an Rh-catalyzed addition reac- dehydes with acetophenone O-methyl oxime via C H
tion[7e,f] of the second ortho C H bond to aldehydes bond activation. In this transformation, both electron-
À
to afford product 4 and no mono-acylation products poor and electron-rich aryl and alkyl aldehydes are
were observed by 1H NMR or GC-MS analysis effective. The cross-coupling reaction exhibits high
(Table 3). After optimization, the best results were functional group tolerance and regioselectivity under
obtained using 400 mol% of aldehyde, 10 mol% of relatively mild conditions and constitutes a versatile
[Cp*RhCl2]2, 40 mol% of AgSbF6 and 250 mol% of route to a diverse library of diaryl ketones, which are
Ag2CO3, in the presence of 3ꢃ molecular sieves in difficult to obtain by the classical Friedel–Crafts acy-
CH2Cl2 at 858C for 24 h, affording the corresponding lation. In view of the synthetic utility of 1,2-diacylben-
aryl ketones 4a–4e in good yields (40–60%).
zenes, this reaction would be of broad interest to syn-
The easy removal of the oxime group to generate thetic chemistry.
the 1,2-diacylbenzenes led us to realize the full syn-
thetic utility of this method. The deprotection of
oximes for 3a, 4b and 4e in HCl/dioxane gave prod-
Experimental Section
ucts 5a, 5b and 5e respectively (Scheme 1).
The postulated mechanism is presented in
Scheme 2. First, coordination of the N atom of 1a to
RhACHTUNGTRENNUNG(III) and the subsequent directed cyclorhodation
affords a rhodacycle A. The aldehyde can then coor-
dinate to the rhodium center, after which migratory
insertion occurs, producing intermediate B. Subse-
quent b-hydrogen elimination occurs to release the
product and the resulting Cp*Rh(I) species may be
Typical Procedure
In a N2-filled glovebox, [Cp*RhCl2]2 (2.3 mg, 0.0075 mmol),
AgSbF6 (10.2 mg, 0.03 mmol), substrate 1a (22.3 mg,
0.150 mmol), 2a (40 mg, 0.375 mmol, 2.5 equiv.), 3ꢃ molecu-
lar sieves (50 mg) and Ag2CO3 (102 mg, 0.375 mmol) were
added to a screw-capped vial followed by addition of a stir
bar and CH2Cl2 (0.75 mL). The vessel was sealed and heated
at 858C (oil bath temperature) for 24 h. The resulting mix-
ture was cooled to room temperature, filtered through
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Adv. Synth. Catal. 2012, 354, 2916 – 2920

Rhodium-Catalyzed Oxidative ortho-Acylation of Aryl Ketone O-Methyl Oximes
Scheme 1. The oxime deprotection of 3a, 4b and 4e.
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Scheme 2. Postulated mechanism.
a short silica gel pad and transferred to silica gel column di-
rectly to give product 3a; yield: 31.3 mg (82%).
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