One-Pot Multicomponent Domino Synthesis of 4-Aminothiazole-2(3H)-thiones

Abstract

A new multicomponent domino reaction has been developed for the synthesis of 4-aminothiazole-2(3H)-thiones. Carbon disulfide was successfully used in the preparation of 4-aminothiazole-2(3H)-thione derivatives through reaction with primary amines and 2-bromo-2-arylacetonitriles in the presence of sodium carbonate and a catalytic amount of sodium iodide.

Key words

amines - catalysis - heterocycles - multicomponent reactions - domino reactions - cyclizations

Multicomponent reactions and domino reactions are among the most effective and straightforward methods for the diversity-oriented synthesis of heterocycles.[1] [2] [3] [4] [5] [6] [7] [8] The use of multicomponent domino reactions is effective in reducing amounts of chemical waste produced, with shorter reaction times, higher overall yields, and clean syntheses compared with multistep syntheses.

Thiazole-2(3H)-thione and its derivatives are important building blocks in various pharmaceutical and biologically active compounds.[9] Several synthetic methodologies are available for the synthesis of the thiazole-2(3H)-thione skeleton.[10] One general method for preparing thiazole-2(3H)-thiones involves the reaction of chloroacetaldehyde,[11] chloroacetone,[12] or phenacyl bromide[12] with ammonium dithiocarbamate. The reaction of cis- or trans-2,3-dialkylaziridines with carbon disulfide has also been successfully used to synthesize thiazole-2(3H)-thiones.[13] Thiazole-2(3H)-thiones have also been prepared by the reaction triethylammonium salts of dithiocarbamates with 2-(4-nitrophenyl)oxirane followed by dehydrogenation of the thiazolidine ring.[14] However, all these methods suffer from drawbacks such as extended reaction times, low yields, the use of toxic solvents or reagents, requirements for excess reagents or catalysts, difficult workup procedures, or harsh reaction conditions. We therefore wished to develop a convenient, one-pot, practical method for the preparation of fully substituted 4-aminothiazole-2(3H)-thiones.

As part of our ongoing studies on the construction of sulfur-containing heterocycles,[15] [16] [17] we report a novel one-pot, three-component, domino synthesis of 4-aminothiazole-2(3H)-thiones by the reaction of carbon disulfide with a primary aliphatic amine and an aryl(bromo)aceto­nitrile in the presence of sodium carbonate and a catalytic amount of sodium iodide in ethanol (Scheme [1]).

Scheme 1

At the outset of our studies, we chose benzylamine (1a) as a substrate, and we treated it with bromo(phenyl)acetonitrile (2a) and carbon disulfide in the presence of sodium carbonate and a catalytic amount of sodium iodide in ethanol. As shown in Table [1], sodium iodide has a vital role in the reaction, and only a very small yield of product 3a (10%) was obtained in its absence (Table [1], entry 1). The yield increased dramatically when a catalytic amount of sodium iodide was added to the mixture (entries 2 and 3). However, the yield fell on increasing the temperature to 50 or 70 °C (entries 6 and 7, Table [1]), possibly due to unwanted side reactions. Finally, we optimized various reaction parameters such as the amount of catalyst, the type of solvent, and the temperature, and we found that 0.5 equivalents of sodium iodide at 25 °C in ethanol gave the desired product 3a in excellent yield (94%; entry 3).

Table 1Screening of Reaction Conditions in the Synthesis of  4-Amino-3-benzyl-5-phenyl-1,3-thiazole-2(3H)-thione (3a)^a

Entry	NaI (equiv)	Solvent	Temp (°C)	Yieldb (%)
1	–	EtOH	r.t.	10
2	0.25	EtOH	r.t.	85
3	0.5	EtOH	r.t.	94
4	1.0	EtOH	r.t.	93
5	0.5	MeCN	r.t.	47
6	1.0	EtOH	50	75
7	1.0	EtOH	70	62

^a Reaction conditions: 1a (1.0 mmol), 2a (1 mmol), CS₂ (1.2 mmol), Na₂CO₃ (1.2 mmol), NaI, solvent (5 mL).

^b Isolated yield.

Next, we examine the scope of our method for a range of primary amines and bromo(phenyl)acetonitriles, and the results are summarized in Table [2].

Table 2Synthesis of Various 4-Aminothiazole-2(3H)-thiones^a

Entry	R1	R2	Product	Yieldb (%)
1	Bn	Ph	3a	94
2	CH2-4-MeC6H4	Ph	3b	90
3	CH2-3,4-(MeO)2C6H3	Ph	3c	84
4	Bn	4-ClC6H4	3d	79
5	CH2-4-MeC6H4	4-ClC6H4	3e	85
6	CH2-3,4-(MeO)2C6H3	4-ClC6H4	3f	81
7	CH2-2-ClC6H4	Ph	3g	78
8	CH2-2-ClC6H4	4-ClC6H4	3h	88
9	CH2-2,4-Cl2C6H3	Ph	3i	87
10	CH2-2,4-Cl2C6H3	4-ClC6H4	3j	76
11	CH2-4-FC6H4	Ph	3k	72
12	CH2-4-FC6H4	4-ClC6H4	3l	70
13	t-Bu	Ph	3m	69
14	t-Bu	4-ClC6H4	3n	73

^a Reaction conditions: R²CH(Br)CN (1 mmol), R¹NH₂ (1 mmol), CS₂ (1.2 mmol), Na₂CO₃ (1.2 mmol), NaI (0.5 mmol), EtOH, r.t.

^b Isolated yield.

A plausible mechanism for the reaction is shown in Scheme [2]. Dithiocarbamate 5 formed by the initial reaction of amine 1a with carbon disulfide, activated by sodium carbonate, undergoes nucleophilic attack on iodo(phenyl)acetonitrile (4), formed by displacement of bromine from nitrile 2a by iodine. Subsequent cyclization of intermediate 6 and tautomerism affords product 3a.

Scheme 2

In summary, we have developed a novel and efficient three-component protocol for the synthesis of 4-aminothiazole-2(3H)-thiones. Significant advantages of this method include the use of simple and readily available precursors, easy workup, and very short reaction times.

Acknowledgment

The authors are grateful to the University of Isfahan Research Council for financial support of this work.

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• 18 4-Aminothiazole-2(3H)-thiones 3a–n; General ProcedureNa₂CO₃ (1.2 mmol, 128 mg) and NaI (0.5 mmol, 75 mg) were added to a mixture of the appropriate aryl(bromo)acetonitrile (1 mmol), primary amine (1mmol), and CS₂ (1.2 mmol, 73 µL) in EtOH (5 mL), and the mixture was stirred at r.t. for 10 min while the progress of the reaction was monitored by TLC (hexane–EtOAc, 5:1). When the reaction was complete, the mixture was filtered and concentrated in vacuo to give a crude product that was purified by recrystallization from a suitable solvent to afford the pure product as a yellow solid.