Uma Pathak*,
Shubhankar Bhattacharyya and
Sweta Mathur
Synthetic Chemistry Division, Defence R & D Establishment, Jhansi Road, Gwalior-474002, M. P., India. E-mail: sc_drde@rediffmail.com; Fax: +91 751 2341148; Tel: +91 751 2390189
First published on 5th December 2014
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.
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
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).
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 cyclodehydrosulfurisation6b 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).
Entry | R | Amine | Temp (°C)/time (h) | Thioamide | Temp (°C)/time (h) | Thiazoline | mp/bp °Cref | Yielda% |
---|---|---|---|---|---|---|---|---|
Step A | Step B | |||||||
a Isolated yield.b Thioamide: amine. HBr: free amine 1![]() ![]() ![]() ![]() |
||||||||
1 | Ph | ![]() |
60–70/5.5 | ![]() |
— | — | Oil10a | 91 |
2 | Ph | ![]() |
60–70/5 | ![]() |
— | — | Oil10a | 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 | ![]() |
Oil11a | 89 |
15b | ![]() |
![]() |
80–90/6 | — | 90–95/10 | ![]() |
41–42 (ref. 11a) | 80 |
16b | ![]() |
![]() |
80–90/9 | — | 90–95/10 | ![]() |
43–44 (ref. 11b) | 76 |
17b | ![]() |
![]() |
80–90/7 | — | 90–95/12 | ![]() |
90–92 (ref. 11c) | 78 |
18 | ![]() |
![]() |
— | — | — | — | — | — |
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.
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.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13097a |
This journal is © The Royal Society of Chemistry 2015 |