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Synlett 2018; 29(11): 1505-1509
DOI: 10.1055/s-0037-1609751
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© Georg Thieme Verlag Stuttgart · New York

Oxidative C–C Bond Cleavage for the Synthesis of Aryl Carboxylic Acids from Aryl Alkyl Ketones

Liang Xu
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Shengpeng Wang
b   Transfar Zhilian Co., Ltd., Xiaoshan Economy & Technology Development Zone, Hangzhou 311215, P. R. of China
,
Bajin Chen
b   Transfar Zhilian Co., Ltd., Xiaoshan Economy & Technology Development Zone, Hangzhou 311215, P. R. of China
,
Meichao Li*
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Xinquan Hu
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Baoxiang Hu
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Liqun Jin
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Nan Sun
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
,
Zhenlu Shen*
a   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: limc@zjut.edu.cn   Email: zhenlushen@zjut.edu.cn
› Author Affiliations

This project was supported by the National Natural Science Foundation of China (21776260, 21773211 and 21376224), Natural Science Foundation of Zhejiang Province (LY17B060007) and Hangzhou ­Qianjiang Distinguished Experts Project.
Further Information

Publication History

Received: 05 March 2018

Accepted after revision: 11 April 2018

Publication Date:
16 May 2018 (online)

 
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Abstract

A metal-free and one-pot two-step synthesis of aryl carboxylic acids from aryl alkyl ketones has been achieved. The reactions were performed with iodine as the catalyst, DMSO and TBHP as the oxidants. Under the optimal reaction conditions, a number of aryl alkyl ketones could be converted into their corresponding aryl carboxylic acids in good to excellent yields (up to 94%).


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Key words

aryl alkyl ketones - aryl carboxylic acids - iodine - dimethyl sulfoxide - tert-butyl hydroperoxide

As a useful intermediate, the carboxylic acids moiety is one of the most important functional groups in organic chemistry and can be easily converted into corresponding esters, acid halides, amides, and anhydrides. Furthermore, the aryl carboxylic acids play an important role as versatile building blocks in the synthesis of natural products, pharmaceuticals, agricultural chemicals, polymers, and dyes.[1] Consequently, the development of efficient methods for the synthesis of aryl carboxylic acids has stimulated considerable interest.

There are many reports on the synthesis of aryl carboxylic acids. The most widely used method involves direct oxidation of methylarenes to aryl carboxylic acids. Stoichiometric amounts of metal oxidants[2] such as Na2Cr2O7, ­KMnO4, and CrO3 and catalytic amounts of transition-metal catalysts[3] have been successfully employed for direct oxidation of methylarenes. Aryl carboxylic acids could also be prepared from various starting materials, such as aromatic aldehydes, benzylic alcohols, 2-oxo-2-arylacetaldehyde, aryl halides, arylolefins, arylalkynes, etc.[4] For example, Wu et al. recently established a new palladium-catalyzed carbonylation procedure for synthesis of aryl carboxylic acids from aryl halides and formic acid.[5]

Aryl alkyl ketones are a stable and readily available class of compounds. Carbon–carbon bond-cleavage reactions between the carbonyl carbon and the α-carbon of aryl alkyl ketones have been reported to successfully produce aryl carboxylic acids. A number of transition-metal-catalyzed C–C bond-cleavage reactions are available for the synthesis of aryl carboxylic acids, including Cu, Hg, W, Mn, and Ru.[6] However, these methods were hampered by the need of transition-metal catalysts, which were not the best choice because of metal contamination. Only a few methods were reported for the synthesis of aryl carboxylic acids from aryl alkyl ketones with transition-metal-free processes.[7] Nevertheless, just moderate yields of aryl carboxylic acids were obtained in most cases. Bjørsvik and co-workers[7a] have provided a simple method for aerobic oxidation of methyl aryl ketones into the corresponding aryl carboxylic acids using 1,3-dinitrobenzene as the catalyst in the presence of stoichiometric amounts of t-BuOH. Seven substrates were tested, but one of them, 3-nitroacetophenone, could not give the corresponding product. Hypervalent iodine reagents [hydroxyl(2,4-dinitrobenzensulfonyloxy)iodo]benzene and pentafluoroiodobenzene bis(trifluoroacetate) have been used as stoichiometric oxidants in the oxidative conversion of aryl ketones into carboxylic acids.[7e] [f] Therefore, it is highly desirable to develop an efficient and metal-free catalytic oxidization protocol for the synthesis of aryl carboxylic ­acids from aryl alkyl ketones.

On the other hand, molecular iodine has attracted much attention as a non-metal, inexpensive, non-toxic, and readily available catalyst or mediator for various organic transformations.[8] It also has been utilized for the synthesis of aryl carboxylic acids. Kalmode and Chaskar et al. have developed a viable protocol for the oxidation of arylacetic acid through cleavage of C–C bond to aryl carboxylic acid in 24–28 h in the presence of stoichiometric amounts of I2 with DMSO as oxidant and solvent.[9] An iodine-catalyzed C–C bond cleavage of aryl alkyl ketones for the synthesis of aryl carboxylic acids with DMSO as oxidant has been reported by Bathula and coworkers.[10] However, 4 equiv of hydroxylamine hydrochloride should be used as promoter and in some cases the yields of aryl carboxylic acids are not satisfactory.

Inspired by the aforementioned work, in continuation of our work on the development of iodine-catalyzed oxidation reactions,[11] we attempted to develop a one-pot two-step oxidation of aryl alkyl ketones to the corresponding aryl carboxylic acids with iodine as the catalyst and DMSO and tert-butyl hydroperoxide (TBHP) as the oxidants (Scheme [1]).

Zoom Image
Scheme 1 The improved method for the synthesis of aryl carboxylic acids via oxidative C–C bond cleavage

Initially, we started to optimize the reaction conditions with acetophenone (1a) as the model substrate (Table [1]). The first-step reaction was carried out with 10 mol% of I2 and 6 equiv of DMSO in chlorobenzene at 120 °C. After 1a was converted into intermediate 1aa completely, 2 equiv of TBHP was added into the mixture. Benzoic acid (2a) could be obtained with 85% GC yield in 13 h of total reaction time (Table [1], entry 1). As outlined in Table [1], the influence of different catalysts was studied. To our surprise, KI, tetrabutylammonium iodide (TBAI), and PhI(OAC)2were ineffective for the formation of the intermediate 1aa (Table [1], entries 2–4). Results in Table [1] showed the solvent can affect this transformation, and chlorobenzene was found to be the most suitable solvent (Table [1], entries 1, 5–9). Then the effect of reaction temperature was further examined. At the beginning, we attempted to reduce the reaction temperature to 110 °C, while the yield of 2a was dramatically dropped into 20% (Table [1], entry 10). When the reaction temperature was increased from 120 °C to 130 °C, the yield of 2a was increased to 92% and the reaction time was shortened to 6 h (Table [1], entry 11).

Table 1 Optimization of Reaction Conditionsa

Entry

Cat. (mol%)

Oxidant (equiv)

Solvent

Temp (°C)

Time (h)b

Yield (%)c

 1

I2 (10)

TBHP (2)

PhCl

120

13 (7)

85

 2

KI (10)

TBHP (2)

PhCl

120

   (7)

NR

 3

TBAI (10)

TBHP (2)

PhCl

120

   (7)

NR

 4

PhI(OAC)2 (10)

TBHP (2)

PhCl

120

   (7)

NR

 5

I2 (10)

TBHP (2)

CH3CN

reflux

18 (13)

69

 6

I2(10)

TBHP (2)

CH2Cl2

reflux

13 (8)

74

 7

I2 (10)

TBHP (2)

toluene

reflux

20 (14)

59

 8

I2 (10)

TBHP (2)

DCE

reflux

10 (6)

54

 9

I2 (10)

TBHP (2)

DMSO

120

12 (6)

67

10

I2 (10)

TBHP (2)

PhCl

110

30 (24)

20

11

I2 (10)

TBHP (2)

PhCl

130

 6 (3)

92

12

I2 (5)

TBHP (2)

PhCl

130

20 (12)

65

13

I2 (15)

TBHP (2)

PhCl

130

 6 (3)

91

14

I2 (20)

TBHP (2)

PhCl

130

 6 (3)

92

15

I2 (10)

DTBP (2)

PhCl

130

 6 (3)

ND

16

I2 (10)

Oxone (2)

PhCl

130

 6 (3)

ND

17

I2 (10)

H2O2 (2)

PhCl

130

 6 (3)

86

18

I2 (10)

TBHP (1.5)

PhCl

130

 6 (3)

84

19

I2 (10)

TBHP (3)

PhCl

130

 4.5 (3)

90

20d

I2 (10)

TBHP (2)

PhCl

130

 6 (3)

58

a Reaction conditions: 1a (1 mmol), DMSO (6 equiv), solvent (2 mL).

b Values in parentheses referred to reaction time of the first step.

c Determined by GC using an internal standard method using biphenyl as the internal standard substance.

d DMSO (4 equiv).

Later on, the loading of I2 was further tested. When the loading of I2was reduced to 5 mol%, 2a was obtained in 65% (Table [1], entry 12). However, the yield of 2a remained almost unchanged by increasing the loadings of I2 from 10 mol% to 15 mol% or 20 mol% (Table [1], entries 13 and 14). Then the different oxidants which were used in the second-step reaction were studied. The results showed that other oxidants like di-tert-butyl peroxide (DTBP) and Oxone were ineffective for the conversion 1aa into 2a. No desired product could be detected in 6 h (Table [1], entries 15 and 16). ­Hydrogen peroxide showed good performance and 86% yield of 2a could be achieved (Table [1], entry 17). Further studies have found that the dosage of 2 equiv of TBHP was appropriate (Table [1], entries 18 and 19). The loading of DMSO has also been tried to reduce. However, 1a could not be transformed into 1aa completely in 6 h, and the yield of 2a was only 58% (Table [1], entry 20). After detailed exploration of the reaction conditions with 1a as the substrate, I2 (10 mol%) with DMSO (6 equiv) in the first step, TBHP (2 equiv) in the second-step and chlorobenzene as the ­solvent at 130 °C were found to be the optimal reaction conditions.

In order to explore the generality of this protocol for the synthesis of aryl carboxylic acids, various aryl methyl ketones were examined under the optimized reaction conditions.[12] The results in Scheme [2] demonstrated that most of the aryl methyl ketones underwent smooth transformations to afford the corresponding aryl carboxylic acids in good to excellent yields (2a–v). The protocol could tolerate various aryl methyl ketones bearing electron-donating and electron-withdrawing groups. The reactions of acetophenones with electron-donating substituents such as 4-methyl, 4-isopropyl, 4-tert-butyl, and 4-methoxy proceeded smoothly to afford the corresponding products 2b–e in 81–94% isolated yields. 3-Methyl- and 2-methylacetophenones were selectively converted into their corresponding benzoic acids 2f and 2g in 82% and 81% isolated yields, respectively. Acetophenones bearing electron-withdrawing groups such as 4-NO2, 4-CN, and 4-COOCH3 could also give the expected products (2h, 2i and 2j) with good yields in 6 h. 3-Nitroacetophenone (1k), which could not converted into 3-nitrobenzoic acid (2k) in Bjørsvik’s work,[7a] could give 2k in 84% isolated yield with this protocol. The substrate scope was further extended to various halogen-substituted acetophenones. As expected, 4-fluoro-, 4-chloro-, 4-bromo-, and 3-chloroacetophenones were smoothly oxidized into their corresponding benzoic acids (2l–o) efficiently in 6–8 h. However, 2-chloroacetophenones showed lower reactivity, only 73% isolated yield of 2p was achieved in 6 h. When 4-acetylbiphenyl was chosen as the substrate, 71% isolated yield of 4-biphenylcarboxylic acid (2q) could be obtained. Under the optimized reaction conditions 1-acetonaphthone and 2-acetonaphthone could afford 1-naphthoic acid (2r) and 2-naphthoic acid (2s) in 84% and 82% isolated yield, respectively. Having established the scope with respect to the aryl methyl ketones, we turned our attention to various heteroaryl methyl ketones such as 2-acetylthiophene and 2-acetylfuran. When 1t and 1u were submitted to the oxidation reactions, the isolated yields of thiophene-2-carboxylic acid (2t) and furan-2-carboxylic acid (2u) were higher than 65%. It should be noted that the reaction temperature was lowered to 110 °C to reduce side reactions. The substrate 1,1′-(1,4-phenylene)diethanone with two acetyl groups was also subjected to this protocol. Terephthalic acid (2v) could be obtained in 75% isolated yield after the reaction time was prolonged to 17 h.

Zoom Image
Scheme 2 Scope of aryl methyl ketone derivatives. a The reactions were carried out with 1 mmol of 1, 10 mol% of I2, 6 equiv DMSO, and 2 equiv of TBHP in 2 mL of chlorobenzene at 130 °C. Isolated yields are given. b Values in parentheses referred to the yield determined by GC using an internal standard method. cReaction temperature: 110 °C.

The scope of this reaction was subsequently extended to several aryl alkyl ketones with varying alkyl chain lengths (Scheme [3]). The reactions with aryl alkyl ketones 3a–d proceeded smoothly to give the benzoic acids 2a, 2b, 2m, and 2a in good yields (71–84%). However, in contrast to the reaction of aryl methyl ketones 1, much longer reaction time (12–17 h) was required for efficient transformation. β-O-4 (3e) is an important fragment of lignin. To our delight, it could transformed smoothly and afford 4-methoxybenzoic acid (2e) in 79% isolated yield. When a branched substrate, phenyl isopropyl ketone, was submitted to the oxidation reaction, it could not be converted into the intermediate 1aa, and no product 2a could be observed.

Zoom Image
Scheme 3 Synthesis of carboxylic acids from aryl alkyl ketones. ­Reagents and conditions: 3 (1 mmol), I2 (10 mol%), DMSO (6 equiv), TBHP (2 equiv), PhCl (2 mL), 130 °C.

Carbinols can be converted into their corresponding ketones under oxidative conditions, thus 1-phenylethanol was also subjected to this protocol. However, no desired product 2a could be obtained.

To understand the mechanism of this transformation, several control experiments were then carried out (Scheme [4]). Acetophenone (1a) could easily be converted into phenylglyoxal (1aa) in high yields in the presence of iodine and DMSO (Scheme [4], eq. 1). When 1aa was treated with 2 equiv of TBHP, 64% GC yield of benzoic acid (2a) and 32% GC yield of tert-butyl benzoate (2aa) were obtained (Scheme [4], eq. 2). We had tried the conversion of 2aa into 2a in the presence of 10 mol% of iodine and 6 equiv of DMSO. As expected, 2a was observed in 92% GC yield (Scheme [4], eq. 3). This result is consistent with the literature reports that tert-butyl esters can be hydrolyzed into acids in the presence of iodine.[13] To further confirm the mechanism, an isotope trace experiment was conducted with dimethyl sulfoxide labeled with 18O (Scheme [4], eq. 4). 18O-Labeled carbon dioxide (CO18O) could be detected with GC-MS after 1a was oxidized with I2/DMS18O/TBHP.

Zoom Image
Scheme 4 Control experiments for mechanism studies

A plausible reaction mechanism for the transformation of aryl methyl ketones into aryl carboxylic acids is shown in Scheme [5]. Initially, substrate 1a reacts with molecular iodine, and α-iodoketone 1ab is formed.[14] Then α-iodoketone 1ab is converted into phenylglyoxal (1aa) which was confirmed by GC-MS and releases HI by a subsequent Kornblum oxidation.[15] Homolytic cleavage of TBHP gives tert-butoxyl radical and hydroxyl radical, which attacks 1aa to form radical 1ac. Radical 1ac can be converted into radical 1ad and formic acid. Formic acid is decomposed under 130 °C, and CO2 is released. Radical 1ad reacts with hydroxyl radical to form 2a directly. Otherwise, 1ad is turned to 2aa in the presence of tert-butoxyl radical. Subsequently, the HI-catalyzed hydrolysis of 2aa gives the product 2a.[13]

Zoom Image
Scheme 5 Plausible reaction pathways

In summary, we have successfully developed a one-pot two-step oxidation of aryl alkyl ketones to the corresponding aryl carboxylic acids with iodine as the catalyst and DMSO and TBHP as the oxidants. The reaction tolerated various aryl alkyl ketones bearing electron-donating and electron-withdrawing groups in ortho, meta, and para positions of the aromatic ring. This catalytic oxidation system displayed high reaction efficiency, and numerous aryl carboxylic acids could be obtained in good to excellent yields. A noteworthy feature of this work is that the protocol is metal free and easy to operate.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1609751.
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Zoom Image
Scheme 1 The improved method for the synthesis of aryl carboxylic acids via oxidative C–C bond cleavage
Zoom Image
Scheme 2 Scope of aryl methyl ketone derivatives. a The reactions were carried out with 1 mmol of 1, 10 mol% of I2, 6 equiv DMSO, and 2 equiv of TBHP in 2 mL of chlorobenzene at 130 °C. Isolated yields are given. b Values in parentheses referred to the yield determined by GC using an internal standard method. cReaction temperature: 110 °C.
Zoom Image
Scheme 3 Synthesis of carboxylic acids from aryl alkyl ketones. ­Reagents and conditions: 3 (1 mmol), I2 (10 mol%), DMSO (6 equiv), TBHP (2 equiv), PhCl (2 mL), 130 °C.
Zoom Image
Scheme 4 Control experiments for mechanism studies
Zoom Image
Scheme 5 Plausible reaction pathways