Selective thioacylation of amines in water: a convenient preparation of secondary thioamides and thiazolines

Abstract

Primary thioamides have been utilised directly in water, without any derivatisation, to selectively thioacylate primary amines. By employing 2-hydroxyethylamines, the reaction can be extended to the preparation of 2-thiazolines via formation of β-hydroxythioamides.

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Thioamides and thiazolines are well known organosulfur compounds with diverse applications.¹ Accordingly, various methods have been reported in the literature for their preparation. Thiazolines can be prepared by thionation of oxazolines.² Condensation of β-amino thiols or β-amino alcohols with nitriles, carboxylic acids and esters are the other common methods available for preparation of thiazolines.³ Reactions which employ an amino alcohol as reactant, also require a sulfurating agent for introducing sulfur in the resultant molecule. Thiazolines can also be accessed through cyclisation of β-hydroxy thioamides.⁴ Secondary thioamides are generally prepared by thionation of their oxy analogues.⁵ Thioacylation of amines is another direct route to prepare secondary thioamides but, this approach is limited by the unstability, corrosiveness and non availability of the conventional thioacylating reagents i.e. thioacyl chloride or thionoanhydrides. High reactivity of the thioacylating agents also renders the acylation non selective in presence of other susceptible functionalities such as secondary amine or hydroxyl group, in a multifunctional chemical entity. Due to huge industrial applications of secondary thioamides and thiazolines, there continues to be a demand for their improved methods of preparation in terms of mild reaction conditions, cleaner reactions, and simple isolation of the product. In continuation to our studies on thioamides,^5c,6 herein, we report a simple preparation secondary thioamides and thiazolines via a direct chemo selective thioacylation of primary amines in water.

Primary thioamides are well known synthons to prepare a variety of heterocycles.^1a Advantages associated with primary thioamides are their stability, easy handling and relative ease of preparation. Primary thioamides contain two nucleophilic centres i.e. sulfur and nitrogen and an electrophilic carbon centre (thiocarbonyl). Depending upon the reactant and reaction conditions different compounds have been obtained from thioamides.^1a In general, the reported reaction of primary thioamides exploits either the sulfur or the nitrogen nucleophilic centre to initiate the reaction while the electrophilic carbon centre is less commonly exploited. Utilizing the electrophilicity of thiocarbonyl carbon of primary thioamides, we wished to explore a direct thioacylation of amines by primary thioamides.

Amine/primary thioamides reaction is generally utilized for the preparation of amidine which proceeds with elimination of hydrogen sulfide.^7,8 Though, this reaction has the potential to generate secondary thioamides (Scheme 1), but, it has never been explored extensively though preparation of N-substituted thioacetamides from thioacetamide and corresponding aliphatic amines under solventless condition has been reported.^1a,7

Scheme 1 Thioacylation of amines.

Most of the reported thioamide/amine reactions have been conducted in organic solvents. But, no attempt has been made so far, to investigate the thioamide/amine reaction in aqueous medium. Water as a solvent often modulates behavior of reactants, consequently, leading to either altered reaction products or enhanced rate or selectivity.⁹ Additionally, in this particular reaction water may also assist in suppressing dehydration of primary thioamides to nitriles, which is a commonly occurring side product in thioamide/amine reaction. Considering all these aspects we attempted thioamide/amine reaction in water. To investigate the feasibility of the concept reaction of butylamine with thiobenzamide was studied. Equimolar amount of butylamine and thiobenzamide was reacted at 60–70 °C in water. Formation of N-butylthiobenzamide as expected was observed but, the reaction was limited by simultaneous formation of benzamide, N-butylbenzamide and benzonitrile. This indicated clearly that a thorough optimization of reaction conditions was required.

To optimise the reaction it was investigated under various reaction conditions. Decreasing the reaction temperature was not found helpful, as it only decreased the rate of the reaction without altering the outcome of the reaction. Volume of the solvent was also varied, to optimise the desired product formation. It was noted that with 150–200 μL water per mmol of thioamide, reaction occurred faster but, still formation of undesired products could not be prevented significantly. Next, considering that high basicity of the amine may be responsible for the side products; reaction was attempted with hydrochloride salt of butylamine. But, no reaction took place which may be due to the reduced nucleophilicity of protonated amine. Efforts were then made to progress the reaction by addition of a small amount of the base to the reaction. We assumed that addition of a small amount of base will make a fraction of amine available for the reaction, which upon thioacylation will release of an equivalent amount of ammonia. Ammonia being a proton scavenger may assist the reaction further. Hence, 20 mol% of sodium bicarbonate was added as promoter to initiate the reaction. Indeed, by employing this strategy reaction occurred satisfactorily in the desired direction. Alternatively, we found that a small amount of free reactant amine itself can be utilised for this purpose. An optimised procedure for thioacylation of amine by primary thioamides is as follows: 1 mmol of butylamine in 150 μL of water was neutralised with 5 N HCl, and 1 mmol of thiobenzamide was added to it followed by addition 0.25 mmol of butylamine again. Reaction was heated at 60–70 °C till completion, and contents were neutralised with HCl. N-Butylthiobenzamide separates as an oily layer.

To study the role of water in this reaction, it was conducted without water under various conditions. In toluene at reflux, no appreciable reaction occurred between thiobenzamide and amine hydrochloride (in the presence of base) which may be due to the insolubility of amine salt in toluene. Reaction of thiobenzamide with free amine was also studied both in organic solvents as well as under solvent less condition. Under solvent less condition formation of benzonitrile 27%, thiobenzamide 34%, N,N-dibutylbenzamidine 9% and N-butyl thiobenzamide 30% was observed. Reaction of free amine and thiobenzamide in toluene at reflux after 3 h resulted in benzonitrile 54%, benzamide 17%, thiobenzamide 21%, and N-butylthiobenzamide 8%.

With the optimised reaction in hand scope of the reaction was investigated by employing a variety of amines and primary thioamides. The developed protocol was found applicable to both aromatic as well as aliphatic thioamides. Aromatic thioamides reacted comparatively slower than aliphatic thioamides. Steric factor influenced the reactivity of amine as well as thioamides to a great extent. Primary amines or thioamides with smaller carbon chain (entry 3) reacted faster in comparison to reactants having longer carbon chain (entry 9). When dipropylamine an open chain secondary amines, was investigated for this reaction, no thioacylation was observed. Similar behaviour was exhibited by aniline an aromatic amine. This fact rendered the reaction selective for aliphatic primary amines. To confirm the selective thioacylation of primary amine thiobenzamine was reacted with mixture of propylmine and dipropyl amine and aniline. Exclusive formation of N-propylthiobenzamide was observed and dipropylamine and aniline remained unreacted. Non reactivity with open chain secondary amines may be attributed to the combined effect of steric impositions caused by their alkyl chains and their reduced nucleophilicity in water due to solvation. Similarly, because of resonance and solvation by water molecules aromatic amines also did not have sufficient reactivity to undergo thioacylation. In case of nicotinamide a π deficient heterocycle reaction went well with free amine itself in water. 2,6-Dichlorothiobenzamide in which both of the ortho positions were occupied did not undergo thioacylation due to sterically hindered reaction centre. On further investigation it was observed that alicyclic secondary amine with reduced steric demand i.e. pyrrolidine could be thioacylated conveniently with both aliphatic and aromatic thioamides (entry 3, 7, 9), but, six membered cyclic amines such as morpholine and piperidine reacted only with small chain aliphatic thioamide i.e. thioacetamide (entry 11 and 12) and remained non reactive towards aromatic thioamides. To demonstrate the selective thioacylation among various amine functionalities within the same molecule 2-aminoethyl piperazine (entry 13) was reacted with thiobenzamide. As expected only primary amino group was thioacylated leaving the other amino groups intact (Scheme 2).

Scheme 2 Selective thioacylation of primary amine.

Aminoethanol, a substrate having two potential reaction centres: amino and hydroxyl, was also reacted with thiobenzamide interestingly, thioacylation occurred at amino group to yield N-(2-hydroxy-ethyl)-thiobenzamide exclusively, without considerable subsequent cyclodehydrosulfurisation^6b under the reaction condition. Since β-hydroxythioamides could yield thiazolines upon dehydrocyclisation;⁴ we were curious to know whether this approach can be extended to thiazolines also. A variety of dehydrating agents that have been utilised in organic solvent are reported in the literature for dehydrocyclisation of β-hydroxy thiobenzamides into thiazolines. But, we required a cyclodehydrating agent that can be utilized in aqueous medium in a one pot reaction in continuation with thioacylation. Technically, formation of thiazoline from β-hydroxythioamides is possible through nucleophilic attack of sulfur onto the carbon to which hydroxyl group is attached, followed by cyclodehydration. We reasoned that through protonation, nucleophilicity of the hydroxyl group could be suppressed; as well as it can be turned into a good leaving group. Hence, by exploiting the aforementioned strategy formation of thiazoline may be possible. To achieve this hydrochloric acid, a commonly available protic acid was examined. Indeed, heating N-(2-hydroxy-ethyl)-thiobenzamide with HCl at 90–95 °C resulted in the formation of thiazoline but, a complete reaction could not be achieved. For complete dehydrocyclisation other protic acid such as HBr and phosphoric acid was studied, and HBr was found to produce gratifying results. Faster cyclisation with HBr indicated that N-(2-bromoethyl)-thiobenzamide may be a possible intermediate in the cyclisation process (Table 1).

Table 1 Preparation of secondary thioamides and thiazolines

Entry	R	Amine	Temp (°C)/time (h)	Thioamide	Temp (°C)/time (h)	Thiazoline	mp/bp °C^ref	Yield^a%
			Step A		Step B
a Isolated yield.b Thioamide: amine. HBr: free amine 1 : 1.5 : 0.25.
1	Ph		60–70/5.5		—	—	Oil^10a	91
2	Ph		60–70/5		—	—	Oil^10a	89
3	CH3		70–80/3		—	—	64–66 (ref. 10b)	89
4	CH3		70–80/5		—	—	48–50 (ref. 10c)	93
5	CH3		70–80/5		—	—	65–66 (ref. 10d)	91
6			70–80/6		—	—	96	93
7	Ph		70–80/8		—	—	73–75 (ref. 10e)	88
8	Ph		70–80/8		—	—	98 (ref. 10f)	87
9	C5H9		70–80/6		—	—	Oil	87
10	Ph		70–80/6		—	—	96 (ref. 10g)	92
11	CH3		70–80/4		—	—	89–91 (ref. 10h)	87
12	CH3		70–80/6		—		55–56	81
13	Ph		70–80/8		—	—	Oil	78
14	Ph		70–80/6	—	90–95/7		Oil^11a	89
15^b			80–90/6	—	90–95/10		41–42 (ref. 11a)	80
16^b			80–90/9	—	90–95/10		43–44 (ref. 11b)	76
17^b			80–90/7	—	90–95/12		90–92 (ref. 11c)	78
18			—	—	—	—	—	—

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To investigate the applicability of this newly developed one pot two step preparation of thiazolines from thioamides and aminoethanol, various substrates were studied. Thiazoline formation was found feasible with both electron donating and electron withdrawing substrates. Preparation of thiazoline from unsubstituted aromatic thioamide (entry 14) was found to be more facile than substituted thioamides. Substituted thioamides required a higher amount of amine and slightly longer reaction time for thiazoline formation. Further, among substituted thioamides, substrates with electron donating group underwent a slow thioacylation in comparison to the substrate having electron withdrawing groups but, cyclodehydration of corresponding thioacylated intermediate was found to occur fast (entry 16). While in case of substrate with electron withdrawing functionalities thioacylation occurred faster but cyclisation was found to be comparatively slower (entry 17). The protocol was not found suitable for substrates containing nitro groups as reaction of aminoethanol with 4-nitro thiobenzamide led to the reduction of nitro group (entry 18).

Based on the above observations a plausible mechanism proposed for this transformation is as follows (Scheme 3): first the electrophilic thiocarbonyl carbon of thioamide undergoes a nucleophilic attack by amine functionality of aminoethanol to yield a β-hydroxy thioamide with the release of ammonia. Upon acidification, the hydroxyl group gets protonated which renders the carbon adjacent to it highly electrophilic. Intermediate 5 is then undergoes cyclisation and simultaneous dehydration via attack of sulfur onto the carbon adjacent to hydroxyl moiety yielding thiazoline 6.

Scheme 3 Plausible mechanism for the formation of 2-thiazolines from thioamides.

In conclusion, a direct water assisted chemoselective thioacylation of primary amines by primary thioamides has been utilized for the preparation secondary thioamides and 2-thiazolines through judicial exploitation of nucleophilicity and electrophilicity of various functionalities in reactants and intermediates. The developed protocol is simple, convenient and applicable to a variety of substrates.

Experimental

Typical experimental procedure for N-butylbenzothioamide: butylamine 2 mmol (156 μL) and water 300 μL were taken in test tube fitted with condenser. Contents were carefully neutralised with 5 N HCl. Thiobenzamide 2 mmol (274 mg) was added followed by addition of 0.5 mmol (36 μL) of butyl amine. Reaction was heated with constant stirring at 60–70 °C with constant reaction for 5.5 hours. Contents were then acidified with dil. HCl. An oily layer separates which was isolated by extraction with DCM. The DCM layer was washed with 5% sodium bicarbonate solution and dried over sodium sulphate. Solvent removal under vacuum yielded N-butylbenzothioamide as yellow oil. If required the compound can be further purified by column chromatography. Data for 1; N-butylbenzothioamide (1): light yellow oil^{1a 1}H NMR (400 MHz, CDCl₃): δ 7.73–7.70 (m, 2H), 7.45 (br, s, 1H), 7.39–7.36 (m, 3H), 3.85–3.79 (m, 2H), 1.78–1.70 (m, 2H), 1.49–1.44 (m, 2H), 1.01–0.97 (m, 3H) EI-MS: m/z 193 [M⁺] (47%), 160 (16), 151 (17), 150 (53), 121 (100), 77 (29), 104 (48); anal. calcd for C₁₁H₁₅NS. C, 68.35; H, 7.82; N, 7.25; S, 16.59. Found C, 68.41; H, 7.69; N, 7.36; S, 16.47.

Acknowledgements

We thank Mr Avik Mazumder, Ajeet Kumar and Mr Ajay Pratap for NMR analysis. We also thank Director, DRDE for his keen interest and encouragement.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13097a

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