Iodine-catalyzed oxidative C–C bond cleavage for benzoic acids and benzamides from alkyl aryl ketones

Abstract

Iodine-catalyzed oxidative C–C bond cleavage has been performed for the facile synthesis of both benzoic acids and benzamides from readily available alkyl aryl ketones. Additionally benzylidene acetones and phenylacetylenes were also converted to the corresponding aromatic acids under the same conditions. This approach features the use of inexpensive iodine as a catalyst, broad substrate scope and open air conditions.

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Carbon–carbon bond cleavage reactions are gaining prominence in organic chemistry due to their potential applications in developing novel functionalization processes and biodegradation methods.¹ However, achieving such transformations is difficult because of the high C–C bond strength and uncontrollable selectivity.¹ Representative methods of C–C bond cleavage are mostly based on strain² and chelation³ assisted strategies. Furthermore, Cu catalyzed oxidative C(CO)–C(alkyl) bond cleavage methods are also emerging as effective substitutes for such strenuous processes.^4–8 Recently, we too have demonstrated a copper catalyzed aerobic oxidative C(CO)–C bond cleavage reaction for the synthesis of benzoic acids.⁹ However, most of these processes are transition metal mediated. Despite great advantages, transition-metal-catalyzed reactions are often impracticable due to their cost, toxicity and sensitivity to air and moisture.¹⁰ Hence, the development of metal free processes for C–C bond cleavage is highly desirable. Amongst the non-metallic C–C bond cleavage methods, iodine mediated haloform reaction¹¹ is well known for the synthesis of carboxylic acids from methyl ketones (Scheme 1A). In addition, recently, Erick,¹² Wu¹³ and Narendar¹⁴ research groups have independently developed iodine mediated C–C bond cleavage reactions for the synthesis of amides from methyl ketones (Scheme 1B–D). All these processes require stoichiometric (3–6 equiv.) amount of iodine. Therefore, the discovery of catalytic iodine mediated C–C bond cleavage processes are indispensable as well as demanding for environmental friendly processes. Herein, we demonstrate iodine catalyzed aerobic oxidative C–C bond cleavage for benzoic acids and benzamides (Scheme 1E and F). This is complementary to our earlier report of copper catalyzed C–C bond cleavage for benzoic acid.

Scheme 1 Iodine mediated C–C bond cleavage for the synthesis of benzoic acids and benzamides.

In continuation of our efforts on the oxidative C(NOH)–C(alkyl) bond cleavage of aryl alkyl ketones⁹ and inspired by a report from Sandip et al.¹⁵ on molecular iodine catalyzed oxidative C–C bond cleavage of aryl methyl ketones, we aimed for the iodine catalyzed C–C bond cleavage adjacent to oxime.

Our research commenced with the reactions of acetophenone (1a) and 2 equiv. of hydroxylamine hydrochloride in the presence of 10 mol% iodine at 50 °C in DMSO under air (Table 1, entry 1), where we obtained only oxime 2a in 85% yield. Increase of hydroxyl amine to 4 equiv. triggered C(NOH)–CH₃ bond cleavage reaction and led to the formation of 3a in a 12% yield along with 50% of 2a (Table 1, entry 2). Increase of temperature to 80 °C dramatically improved the yield of 3a to 60% together with the formation of 20% oxime 2a (Table 1, entry 3). Further increase of temperature to 100 °C produced 3a as only product in 78% yield (Table 1, entry 4). We next screened reaction in different solvents such as DMF, DCE, EtOH and water (Table 1, entries 5–8). However, no product formation was observed. No product was detected in the absence of iodine and/or hydroxylamine (Table 1, entries 9 and 10), suggesting that both the catalyst and reagent were essential for this reaction.

Table 1 Optimization of hydroxyl amine mediated carbon–carbon bond cleavage reaction conditions^a

Entry	[I2]	NH2OH·HCl	Solvent	Temp (°C)	Yields^b (%)
					2a	3a
a Reaction conditions: 1a (1.0 mmol), NH2OH·HCl (4.0 mmol), I2 (0.1 mmol) in DMSO at 100 °C for 4 h under air.b Isolated yields.c Starting material recovered.
1	0.1 eq.	2 eq.	DMSO	50	85	—
2	0.1 eq.	4 eq.	DMSO	50	50	12
3	0.1 eq.	4 eq.	DMSO	80	20	60
4	0.1 eq.	4 eq.	DMSO	100	—	78
5	0.1 eq.	4 eq.	DMF	100	20	—^c
6	0.1 eq.	4 eq.	EtOH	80	—	—^c
7	0.1 eq.	4 eq.	DCE	100	—	—^c
8	0.1 eq.	4 eq.	H2O	100	—	—^c
9	—	4 eq.	DMSO	100	20	—^c
10	0.1 eq.	—	DMSO	100	—	—^c

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Upon the establishment of viable reaction conditions, a wide range of (het) aryl methyl ketones were employed as substrates in this transformation (Table 2). Substrates bearing electron-donating substituents on benzene ring such as methyl, methoxy, ethoxy and cyclohexyl groups gave their corresponding products (3b–c, 3f, 3j–l and 3p) in excellent yields with high efficiency. Similarly, the reaction proceeded well with good yields when electron-withdrawing groups (EWG) (e.g., –F, –Cl, –Br, –NO₂, and –CN) were substituted at the ortho-, meta-, or para-positions on the benzene ring (3d–e, 3g–i, 3m–o and 3q). 2-Acetylfuran and 2-acetylthiophene also underwent this reaction smoothly to deliver the corresponding heteroaryl products 3r and 3s in 80% and 89% yields, respectively.

Table 2 Synthesis of aromatic acids from aryl methyl ketones^a

a Reaction conditions: 1 (1.0 mmol), NH2OH·HCl (4.0 mmol), I2 (0.1 mmol) in DMSO at 100 °C, under air. Yields are based on isolated products.
	R = H (3a, 5 h, 78%)	R = 4-OMe (3j, 4 h, 93%)
	R = 2-Me (3b, 4 h, 80%)	R = 4-OEt (3k, 4 h, 88%)
	R = 2-OMe (3c, 4 h, 86%)	R = 4-cyclohexyl (3l, 4 h, 65%)
	R = 2-Br (3d, 5 h, 58%)	R = 4-F (3m, 5 h, 62%)
	R = 2-NO2 (3e, 6 h, 61%)	R = NO2 (3n, 6 h, 72%)
	R = 3-OMe (3f, 5 h, 90%)	R = 4-CN (30, 6 h, 61%)
	R = 3-F (3g, 5 h, 64%)	R = 2,4-di Me (3p, 4 h, 87%)
	R = 3-Br (3h, 6 h, 70%)	R = 2,4-di Cl (3q, 5 h, 52%)
	R = 3-NO2 (3i, 6 h, 62%)

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The scope of this reaction was subsequently extended to several aryl ketones with varying alkyl chain lengths. To our delight, reactions with aryl ketones 4a–h proceeded smoothly to give the acids 3a–b, 3j, 3t and 3u in good yields. However, in contrast to the reaction of acetophenones 1, much longer reaction times (9–11 h) were required for efficient transformation. Interestingly, in case of substrates 4g and 4h, both the aryl terminals were converted to the corresponding acids (Table 3).

Table 3 Synthesis of benzoic acids from aryl alkyl ketones^a

a Reaction conditions: 4 (1.0 mmol), NH2OH·HCl (4.0 mmol), I2 (0.1 mmol) in DMSO at 100 °C, under air. Yields are based on isolated products.
4a, R = H, n = 1, 3a, 10 h, 41%	4d, R = 4-Me, n = 1, 3t, 10 h, 55%
4b, R = 2-OMe, n = 1, 3b, 9 h, 52%	4e, R = 4-Br, n = 1, 3u, 10 h, 51%
4c, R = 4-OMe, n = 1, 3j, 9 h, 56%	4f, R = 4-Me, n = 5, 3t, 11 h, 41%

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Encouraged by the results achieved above, we hoped that the substrates of this efficient reaction system could be further extended. Next, benzylideneacetone (5a) was examined under the standard reaction conditions to find whether an alkenyl group can act as a terminator to the above oxidation process. Interestingly, no expected product (cinnamic acid) was obtained but we isolated benzoic acid as a product after cleavage of the C–C double bond of benzylideneacetone. To probe the substrate scope for this reaction, a series of substituted benzylideneacetones 5 were subjected to the optimized reaction conditions (Table 4). The electronic properties of the 5 exerted some influence on this transformation; benzylideneacetones bearing electron-donating groups provided the corresponding acids in better yields (3c, 3j and 3t) than those with electron-withdrawing substituents (3d, 3u–w). This protocol was further extended to fused benzylideneacetones and heteroaromatic vinyl ketones, and the desired products were obtained in moderate to good yields (3r–s, and 3x).

Table 4 Vinyl bond cleavage of vinyl methyl ketones^a

a Reaction conditions: 5 (1.0 mmol), NH₂OH·HCl (4.0 mmol), I₂ (0.1 mmol) in DMSO at 100 °C, under air. Yields are based on isolated product.

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To further expand the substrate scope, terminal aryl alkynes were investigated using the conditions optimized for aromatic ketones. On the basis of previous report,¹⁶ we found that a wide range of terminal aryl alkynes in the presence of I₂ in DMSO could be easily transformed to glyoxal, which further reacted with hydroxylamine to afford the corresponding benzoic acids in one-pot (Table 5). Substrates with electron-rich, and electron-deficient groups were all compatible and provided the corresponding products in moderate to good yields (49–71%; 3a, 3g, 3j, 3m, 3t and 3y).

Table 5 Synthesis of benzoic acids from phenylacetylens^a

a Reaction conditions: 6 (1.0 mmol), NH2OH·HCl (4.0 mmol), I2 (0.1 mmol) in DMSO at 100 °C, under air. Yields are based on isolated products.
	R = H (3a, 8 h, 49%)	R = 4-Me (3t, 7 h, 65%)
	R = 3-F (3g, 8 h, 60%)	R = 4-t-Bu (3y, 8 h, 61%)
	R = 4-OMe (3j, 6 h, 71%)	R = 4F (3m, 8 h, 62%)

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We next turned curious to test the fate of the reaction with the substitution of hydroxylamine hydrochloride with sodium azide. Under the standard conditions, interestingly, we observed the formation of trace amount of benzamide (7a from 1a) as a product (entry 1, Table 6). To improve the yield of the benzamide, we further optimized the reaction conditions as shown in Table 6. Increase of sodium azide to 6.0 equiv. did not change the outcome (16% of 7a, entry 2). Interestingly, addition of water as co-solvent helped to improve the yield of product 7a to 30% (entry 3). Increase of amount of I₂ to 30 mol% could further improve the yield to 46% (entry 4). To our delight, use of AcOH as an additive provided the desired product cleanly in 70% yield (Table 6, entry 5). However, additional increase of the amount of I₂ to 0.5 equivalents did not offer any improvement in the yield (entry 6). The controlled experiments revealed the essentiality of both I₂ and DMSO (entries 7 & 8).

Table 6 Optimization of the reaction conditions for the synthesis of benzamide from acetophenone^a

Entry	[I2] (equiv.)	NaN3 (equiv.)	Solvent (1 : 1)	AcOH	Temp (°C)	Yields^b (%)
a Reaction conditions: 1a (1.0 mmol), NaN3 (6.0 mmol), I2 (0.3 mmol) in DMSO/H2O (1 : 1) and AcOH (4 eq.) at 100 °C for 12 h under air.b Isolated yields.c Starting material recovered.
1	0.1	4	DMSO	—	100	10^c
2	0.1	6	DMSO	—	100	16^c
3	0.1	6	DMSO/H2O	—	100	30^c
4	0.3	6	DMS/H2O	—	100	46
5	0.3	6	DMS/H2O	4 eq.	100	70
6	0.5	6	DMS/H2O	4 eq.	100	64
7	—	6	DMS/H2O	4 eq.	100	—^c
8	0.3	6	H2O	4 eq.	100	—^c

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Under the optimized reaction conditions, a study on the substrate scope was carried out. As shown in Table 7, several substituents, namely –OMe, t-Bt, Cl, Br and NO₂, on the aromatic ring at the acetophenone were well tolerated (7b–h). For example, 4-t-Bt and 2,4-di OMe substituted acetophenones successfully furnished 7b and 7c in 87% and 72% respectively. Halogen groups, Cl and Br, were also compatible with the optimal conditions (7d–f), which will enable subsequent modifications at the halogenated positions. Modest yields (53% and 56%) of 7g and 7h were observed when nitro functionality was present at acetophenone. 2-Acetylthiophene also smoothly furnished corresponding product (7i, 75%) in good yield.

Table 7 I₂-catalyzed synthesis of benzamides from acetophenones^a

a Reaction conditions: 1a (1.0 mmol), NaN3 (6.0 mmol), I2 (0.3 mmol) in DMSO/H2O (1 : 1) and AcOH (4 eq.) at 100 °C for 12 h under air. Yields are based on isolated products.
R = H (7a, 65%)	R = 4-NO2 (7g, 53%)
R = 4-t-Bu (7b, 87%)	R = 4-OMe, 3-NO2 (7h, 56%)
R = 2,4-OMe (7c, 72%)
R = 3-Br (7d, 58%)
R = 4-Br (7e, 62%)
R = 2,4-di Cl (7f, 60%)

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Next, some control experiments were performed to elucidate the mechanism for the iodine catalyzed C–C bond cleavage. When 4-methoxyacetophenone oxime 2j was subjected to the standard conditions, product 3j was obtained in 90% yield (Scheme 2A). However, 2j was not converted to 3j in 12 h in the absence of hydroxylamine (Scheme 2B). Also, glyoxal 8 was smoothly transformed to the corresponding acid 3j in 80% yield (Scheme 2C). Moreover, dioxime 9 furnished 3j in 93% yield under standard conditions (Scheme 2D). Under optimized condition, anisaldehyde 10 was converted to nitrile 11 in 93% yield (Scheme 2E). Furthermore, it was found that 11 could not produce 3j under the standard conditions (Scheme 2F). Taken together, these control experiments clearly demonstrated that 4-methoxyacetophenoneoxime 2j, dioxime 9 and benzoyl cyanide oxime d may be key intermediates in this reaction.

Scheme 2 Control experiments.

According to the aforementioned information and based on previous reports,⁹ we propose a plausible mechanism of this iodine-catalyzed C–C bond cleavage of aryl alkyl ketones for the synthesis of acids (Scheme 3A). Initially, acetophenone reacts with hydroxylamine to produce oxime a and upon Kornblum oxidation a gives α-oxo oxime b by releasing HI. Further condensation of b with second hydroxylamine gives the dioxime c. Subsequent dehydration of dioxime intermediate produces benzoyl cyanide oxime d which after decomposition produces three membered cyclic intermediate oxazirene e along with release of hydrogen cyanide (HCN) via C–C bond cleavage. Finally, oxazirene undergoes a known hydrolysis¹⁷ to deliver the desired acid.

Scheme 3 Proposed mechanism.

We also propose a mechanistic possibility for the formation of amides from acetophenones as depicted in Scheme 3B. In this reaction, acid mediated nucleophilic addition of azide on carbonyl of acetophenone 1 leads to the formation of intermediate I, which on iodination produces intermediate II. This II on coupling with DMSO forms III. Elimination of dimethyl sulfide and formaldehyde form acyl azide V (via IV) which through known conversion affords benzamide 7.¹²

In summary, we have developed a new type of iodine-catalyzed C(CO)–C(alkyl)bond cleavage of aryl/vinyl ketones/phenylacetylenes for the synthesis of benzoic acids and benzamides via an aerobic oxidation and oxygenation process under air. This reaction has many advantages like iodine as the metal free catalyst, air as the sole terminal oxidant, cheap and readily available starting materials and a wide substrate scope. Further studies toward the synthetic utility of this novel C–C bond cleavage reaction are currently underway.

Acknowledgements

This work was supported by CSIR-ORIGIN (CSC0108), New Delhi. We are thankful to NMR, Mass divisions of CSIR-IICT, for providing the analytical facilities. P. S. N, O. R, A. U, and P. R. M. thank UGC and CSIR for the Ph.D. fellowships.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and compound characterization data. See DOI: 10.1039/c6ra02962k

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