Direct C-2 Acylation of Thiazoles with Aldehydes via Metal- and Solvent-Free C–H Activation in the Presence of tert-Butyl Hydroperoxide

Abstract

A novel and efficient methodology for the synthesis of heteroaryl ketones by C–H activation of aldehydes and thiazoles is developed. The reaction occurs smoothly, under metal-, acid- and solvent-free conditions using tert-butyl hydroperoxide as the oxidant under an air atmosphere, to afford a wide range of heteroaryl ketones in moderate to good yields. The sp² C–H bonds in the aldehyde and thiazole undergo direct oxidative cross-coupling, resulting in C-2 acylation of the azole.

Key words

acylation - C–H activation - oxidative cross-coupling - metal-free - solvent-free

Azole derivatives are important building blocks in various natural products, agrochemicals and biologically active molecules.[1] In this regard, significant progress has been made in developing efficient methodologies for the synthesis of azoles substituted at C-2. Thus, C–C and C–N bond formation between azoles and various moieties such as alkynyl halides,[2] amines,[3] esters,[4] alkyl halides,[5] mesylates,[6] nitriles,[7] benzyl halides,[8] and alkenyl halides[9] have been achieved with considerable efficiency by cross-­coupling at the C-2 position of azoles.

Acylation of azoles is an important approach to the synthesis of various heteroaryl ketones. Anderson and co-workers have developed C-2 acylations of azoles with acyl chlorides.[10] Benzaldehyde as an acylating reagent has also been explored by various groups,[11] the process requiring lithium metal along with inorganic oxidants. Beller and co-workers have reported carbonylative C–H activation of azoles using aryl halides and carbon monoxide gas.[12] Furthermore, the acylations of 2-phenylpyridine,[13] acetanilide[14] and other moieties,[15] via C–H bond activation with different acyl moieties using noble metal catalysts, have been reported.

Metal-free C–C bond formation by C–H activation using milder reaction conditions is a challenging prospect. In this regard, Wang and co-workers reported metal-free amidation[16] and alkylation[17] through oxidative cross-coupling by C–H activation. In addition, the metal-free acylation of heteroaryl moieties has been explored.[18] Thus, we aimed to develop an efficient and mild protocol for the ­acylation of thiazoles with aldehydes via sp² C–H bond activation at C-2. The present system works efficiently under metal-, acid-, and solvent-free conditions using ­tert-butyl hydroperoxide (TBHP) as an oxidant under an air atmosphere (Scheme [1]).

Scheme 1 Oxidative acylation of thiazoles with aldehydes

Initially, the reaction of 4,5-dimethylthiazole (1a) with benzaldehyde (2a) was chosen as a model reaction, and the effects of various parameters such as the catalyst, solvent, oxidant, temperature and reaction time were studied. At the outset, we screened various transition-metal salts [Pd(OAc)₂, Co(OAc)₂, Fe(OAc)₂ and FeSO₄] for the oxidative cross-coupling of 1a with 2a using tert-butyl hydroperoxide as the oxidant (Table [1], entries 1–4). It was found that palladium acetate [Pd(OAc)₂] and iron(II) sulfate (FeSO₄) provided the desired product 3a in 10% and 38% yield respectively (Table [1], entries 1 and 4). Furthermore, when the reaction was carried out in the absence of a metal salt, an improvement in the yield (45%) was observed (Table [1], entry 5). Next, we investigated the effect of different solvents on the reaction (Table [1], entries 6 and 7). However, when the reaction was carried out in the absence of a catalyst and solvent, the yield of the desired product 3a increased to 73% (Table [1], entry 8).

We next screened various organic and inorganic oxidants under metal- and solvent-free conditions (Table [1], entries 9–16), and observed that hydrogen peroxide and m-chloroperoxybenzoic acid (MCPBA) were ineffective (Table [1], entries 9 and 10), whilst tert-butyl perbenzoate (TBPB), cumene hydroperoxide (CHP) and aqueous tert-butyl hydroperoxide afforded the expected product in poor yields (Table [1], entries 11–13). Inorganic oxidants did not work under the same reaction conditions (Table [1], entries 14–16). When the reaction was carried out using tert-butyl hydroperoxide as the oxidant without an air atmosphere the yield of the desired product decreased (Table [1], entry 17). Performing the reaction under an oxygen atmosphere also led to a lower yield of the acylation product (Table [1], entry 18). Furthermore, the effect of increasing the number of equivalents of benzaldehyde (2a) showed that the yield of 3a was improved when the 1a:2a ratio was 1:4 (Table [1], entries 8 and 19). We also studied the effect of the tert-butyl hydroperoxide loading and found that four equivalents of the oxidant were necessary to obtain acceptable yields (Table [1], entries 8 and 20). Subsequently, the effect of the reaction time and temperature were examined, and it was found that the highest yield of the product 3a was obtained at 100 °C within 16 hours.

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst	Oxidant	Solvent	Yield (%)b
Effect of the catalyst
1	Pd(OAc)2	TBHP	toluene	10
2	Co(OAc)2	TBHP	toluene	–
3	Fe(OAc)2	TBHP	toluene	–
4	FeSO4	TBHP	toluene	38
5	–	TBHP	toluene	45
Effect of the solvent
6	–	TBHP	PhCl	5
7	–	TBHP	MeCN	10
8	–	TBHP	–	73
Effect of the oxidant
9	–	H2O2	–	–
10	–	MCPBA	–	–
11	–	TBPB	–	20
12	–	CHP	–	16
13	–	TBHP (aq)	–	25
14	–	I2	–	–
15	–	K2S2O8	–	15
16	–	Ag2CO3	–	–
17c	–	TBHP	–	58
18d	–	TBHP	–	13
19e	–	TBHP	–	29
20f	–	TBHP	–	61

^a Reaction conditions: 4,5-dimethylthiazole (1a) (1 mmol), benzaldehyde (2a) (4 mmol), oxidant (4 mmol), catalyst (10 mol%) if necessary, solvent (3 ml) if necessary, 100 °C, air atmosphere, 16 h.

^b Yield determined by GC.

^c Without an air atmosphere.

^d Under an oxygen atmosphere.

^e Ratio of 1a/2a = 1:1.

^f TBHP (3 equiv, 5–6 M in decane).

With optimized reaction conditions in hand, the scope of the protocol was extended for the synthesis of various acylated thiazole derivatives. As shown in Table [2], the reaction worked efficiently with different aldehydes to provide a wide range of acylated thiazole derivatives in moderate to good yields. The important feature of the present protocol is that acylation of thiazole 1a with ­ortho-, meta-, and para-substituted aldehyde derivatives proceeded well, and the corresponding 2-acylated thiazole products were obtained in good yields (Table [2], entries 1–11), indicating that the steric and electronic effects of the substituents on the aromatic rings of the aldehydes were negligible. The acylation of thiazole 1a with aldehydes bearing electron-donating substituents proceeded smoothly to afford good yields of the corresponding products (Table [2], entries 2–6).

Aldehydes bearing halide substituents also furnished good yields of the corresponding products (Table [2], entries 7–11). The heteroaromatic aldehyde, thiophene-3-carboxaldehyde (2l) smoothly underwent oxidative cross-coupling and provided a moderate yield of the respective product 3l (Table [2], entry 12). Moreover, an aliphatic aldehyde also reacted under the optimized reaction conditions to give a moderate 47% yield of the coupled product 3m (Table [2], entry 13).[19] When the reaction was carried out using 4-methylthiazole (1b), satisfactory yields of the corresponding products were obtained (Table [2], entries 14–16).[20]

Scheme 2 A plausible reaction mechanism for the acylation of thiazoles with aldehydes

A tentative mechanism to rationalize this transformation is presented in Scheme [2]. The reaction may proceed through the generation of free radicals, the first step involving homolysis of tert-butyl hydroperoxide to generate a hydroxyl radical and an alkoxyl radical. In the next step, these radicals abstract hydrogens from the sp² C–H (C-2) of 4,5-dimethylthiazole and the aldehydic C–H of benzaldehyde, generating the corresponding free radicals. Finally, the free radicals of 4,5-dimethylthiazole and benzaldehyde react with each other to form a new carbon–carbon bond and generate the acylated derivative (3a) as the major product, along with the minor homo-coupled side product through termination of two radicals of 4,5-dimethylthiazole. It should be noted that the reaction was suppressed by a radical scavenger, such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO).

Table 2 Oxidative Acylation of Thiazoles with Various Aldehydes^a

Entry	Thiazole	Aldehyde	Product	Yield (%)b
1	1a	2a	3a	70
2	1a	2b	3b	72
3	1a	2c	3c	78
4	1a	2d	3d	73
5	1a	2e	3e	71
6	1a	2f	3f	80
7	1a	2g	3g	72
8	1a	2h	3h	76
9	1a	2i	3i	65
10	1a	2j	3j	72
11	1a	2k	3k	77
12	1a	2l	3l	56
13	1a	2m	3m	47
14	1b	2a	3n	60
15	1b	2b	3o	63
16	1b	2d	3p	64

^a Reaction conditions: thiazole (1 mmol), aldehyde (4 mmol), TBHP (4 mmol, 5–6 M in decane), 100 °C, 16 h, air atmosphere, neat.

^b Yield of isolated product.

In summary, we have developed an efficient protocol for the direct C-2 acylation of thiazoles with a range of aldehydes, via C–H activation under metal-, acid-, and solvent-free conditions, to give the corresponding acylated thiazole derivatives.[21] Further applications of the present protocol for acylation of various moieties are under progress.

Acknowledgment

A.B.K. is grateful to the Council of Scientific and Industrial Research (CSIR) India for providing a Senior Research Fellowship. The authors thank Dr. C. V. Rode from the National Chemical Laboratory, Pune for providing HRMS analysis of products.

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• 21 (4,5-Dimethylthiazol-2-yl)(phenyl)methanone (3a); Typical Procedure An oven-dried 15 mL glass vial containing a magnetic stir bar was charged with 4,5-dimethylthiazole (1a) (1 mmol) and benzaldehyde (2a) (4 mmol). The vial was then flushed with air and sealed with a cap. Next, TBHP (4 mmol, 5–6 M in decane) was added dropwise with stirring and the mixture was further stirred at 100 °C for 16 h under an air atm. After cooling the mixture to r.t., it was washed with sat. NaHCO₃ solution (1 × 30 mL). The product was extracted with EtOAc (3 × 10 mL) and dried over Na₂SO₄. The solvent was removed under vacuum and the crude residue was purified by column chromatography (silica gel, 60–100 mesh; PE–EtOAc) to afford pure coupled product 3a. ¹H NMR (300 MHz, CDCl₃): δ = 8.44–8.41 (m, 2 H), 7.56–7.51 (m, 3 H), 2.47 (s, 3 H), 2.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 184.08, 162.58, 151.77, 135.92, 133.25, 131.10, 128.68, 124.02, 15.14, 12.02. GC–MS (EI, 70 eV): m/z (%) = 217 (20) [M]⁺, 188 (52), 105 (100), 85 (37), 77 (87), 53 (10), 51 (31). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₂NOS: 218.0640; found: 218.0634. (4,5-Dimethylthiazol-2-yl)(p-tolyl)methanone (3b) ¹H NMR (300 MHz, CDCl₃): δ = 8.34 (d, J = 8.05 Hz, 2 H), 7.29 (d, J = 8.05 Hz, 2 H), 2.46 (s, 3 H), 2.44 (s, 3 H), 2.42 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 183.69, 162.89, 151.60, 144.15, 135.57, 133.01, 131.23, 129.07, 21.80, 15.14, 12.00. GC–MS (EI, 70 eV): m/z (%) = 231 (23) [M]⁺, 202 (55), 119 (100), 91 (55), 89 (13), 86 (27), 65 (29), 45 (30), 44 (23), 39 (11). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄NOS: 232.0796; found: 232.0791. (2,6-Dimethylphenyl)(4,5-dimethylthiazol-2-yl)methanone (3c) ¹H NMR (300 MHz, CDCl₃): δ = 7.52 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 2 H), 2.45 (s, 3 H), 2.35 (s, 3 H), 2.19 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 191.94, 161.71, 152.86, 138.78, 130.63, 129.32, 127.62, 119.38, 19.70, 15.06, 12.22. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆NOS: 246.0953; found: 246.0947. GC–MS (EI, 70 eV): m/z (%) = 245 (38) [M]⁺, 228 (16), 218 (18), 217 (100), 216 (63), 202 (18), 133 (37), 105 (56), 103 (24), 86 (60), 79 (32), 78 (14), 77 (41), 71 (22), 53 16), 39 (13).