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 Conditionsa
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
–
H2 O2
–
–
10
–
MCPBA
–
–
11
–
TBPB
–
20
12
–
CHP
–
16
13
–
TBHP (aq)
–
25
14
–
I2
–
–
15
–
K2 S2 O8
–
15
16
–
Ag2 CO3
–
–
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 Aldehydesa
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.
