Base-mediated three-component system for the synthesis of S-substituted N-acyl ureas

Abstract

N-Acyl ureas are crucial intermediates in the synthesis of biologically active molecules, and their preparation traditionally relies on multi-step synthesis under reflux conditions. Here, we report a three-component system that combines widespread alkyl halides, thiourea and carbamoyl chlorides. Crucial to this strategy is the synthesis of specific S-substituted N-acyl ureas via the formation of the isothiouronium salt intermediates. This developed three-component system affords scalable and functional group-tolerant reactivity, furnishing the desired products in good to excellent yields under mild conditions.

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Introduction

N-Acyl ureas are important intermediates in a wide range of biologically active molecules.^1–5 For example, the N-acyl urea motif is incorporated in molecules active as anti-cancer,^6–8 anti-inflammatory,^9,10 anti-convulsant¹¹ and anti-diabetic^12,13 agents. Therefore, the advancement of efficient synthetic methods for their preparation is of considerable interest. Over the years, a cascade of strategies for synthesising these motifs has been reported.^14–23 Traditional synthetic methods typically involve the acylation of amides and ureas,^14–17 nucleophilic substitution of acyl carbamates,¹⁸ coupling of carboxylic acids with cyanamides and carbodiimides,^19,20 and the addition of amines to acyl isocyanates.^21,22 However, these approaches require transition-metal catalysts as well as multi-step synthesis.

To overcome these limitations, a few alternative methods have been developed.^24–28 Notably, Kukushkin's group developed a transition metal-free, one-pot stepwise N-acyl urea synthesis using a reactive aminonitrone-isocyanide system. However, substrate scope was limited and reflux conditions were required (Scheme 1a).²⁹ Recently, Irannejad's group reported the use of dibenzoylhydrazine carboxamide and benzylamines under reflux conditions, although this protocol is limited to five N-benzyl-N-acyl ureas (Scheme 1b).³⁰ Clearly, the establishment of more protocols that would provide unique and efficient access to different classes of N-acyl ureas under mild conditions would be highly advantageous.

Scheme 1 (a) Two-step hydrolytic synthesis of N-acyl ureas.²⁹ (b) Reaction of dibenzoylhydrazine carboxamide and benzylamines.³⁰ (c) One-step, three-component strategy for the preparation of S-substituted N-acyl ureas.

Here, we present a one-pot three-component system for the alkylation and carbamoylation of thiourea for the synthesis of S-substituted N-acyl ureas (Scheme 1c). This study draws inspiration from the well-documented S_N2 interaction of alkyl halides and thiourea to generate isothiouronium salts I.^31–36 We posited that a nucleophilic attack of the salt I on the carbamoyl chloride would furnish the desired product under mild reaction conditions (40 °C) (Scheme 1c). The reports that demonstrated the acylation of ureas using acyl halides further supported the feasibility of our plan.^2,37

Results and discussion

We began our investigations with benzyl bromide 1a, N,N-dimethyl carbamoyl chloride 2a, thiourea (A) and sodium carbonate (Na₂CO₃) as a base in tetrahydrofuran (THF) solvent at 40 °C for 12 h (Table 1). The reaction proceeded almost quantitatively, furnishing the desired S-substituted N-acyl urea product 3a in 92% yield (entry 1). Attempts to use other solvents such as acetonitrile (MeCN) and ethanol (EtOH) (entries 2 and 3) as well as H₂O and diethyl ether (Et₂O) (entries 4 and 5) resulted in either diminished 3a yields (69–71%) or no product formation, respectively. Moreover, testing other bases resulted in comparable yields but lower efficiencies (entries 6–9, 81–89%). Further optimisation revealed that reactions conducted for 6 hours (entry 10, 77%) and lowering the temperature to 25 °C (entry 11, 75%) result in good yields, although still in lower efficiencies. Notably, no product was formed in the absence of thiourea and the base (entries 12 and 13). Given the lower effectiveness of greener solvents (entries 3 and 4), THF was selected due to its optimal reactivity.

Table 1 Optimisation and control experiments^a

Entry	Variations	Yield^b (%)
a Optimisation and control experiments. Reactions performed on the scale: 1a (1.5 mmol) and 2a (1 mmol).b Reported yields are isolated yields. DIPEA: N,N-diisopropylethylamine; DBU: 1,8-diazabicyclo [5.4.0]undec-7-ene.
1	None	92
2	MeCN	71
3	EtOH	69
4	H2O	0
5	Et2O	0
6	Et3N	81
7	DIPEA	84
8	DBU	86
9	K3PO4	89
10	6 h	77
11	25 °C	75
12	No thiourea	0
13	No base	0

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With the crystal structure of the desired product 3a obtained from single-crystal X-ray analysis and optimised reaction conditions described in entry 1 of Table 1, we then explored the reaction scope for the S-substituted N-acyl urea synthesis using a diverse range of alkyl halides 1 with N,N dimethylcarbamoyl chloride 2a (Fig. 1). The benzyl halides with different substituents on the phenyl ring; 4-nitro 1b, 2-bromo 1c, and 2,4,6-trimethyl 1d moieties, reacted efficiently to form the corresponding 3b–3d products with good to excellent yields (74–84%). The protocol also exhibited excellent tolerance towards cinnamyl bromide 1e and valuable alkyl halides bearing a 5-membered heterocyclic isoxazole ring 1f–1g,³⁸ furnishing the corresponding products 3e (83%), 3f (88%) and 3g (86%) in excellent yields. Furthermore, straight-chain alkyl halides such as iodomethane 1h, 1-bromobutane 1i, 1-bromopentane 1j and 1-iodohexane 1k efficiently reacted to give the corresponding products 3h–3k in excellent yields (81–91%). However, longer chains such as 1-bromodecane, 1-bromoundecane and 1-bromohexadecane, as well as secondary alkyl halides, failed to produce the corresponding products 3. This is presumably due to the inability of these long-chain and secondary alkyl halides to form the isothiouronium salt I under the identified reaction conditions (Table 1, entry 1). A complete list of failed substrates is reported in Fig. S1 of the SI. Additionally, straight-chain alkyl halides with reactive functional groups, including terminal alkenes 1l–1m, alkyne 1n, and cyano 1o moieties, were suitable substrates, furnishing products 3l–3o in good to excellent yields (77–93%), thus demonstrating the versatility of the developed protocol. Furthermore, the alkoxy group (1p) did not hinder the reaction (3p, 80%).

Fig. 1 S-Substituted N-acyl ureas synthesis substrate scope and gram-scale synthesis. Reactions performed on a 1 mmol scale. Alkyl bromides were used, unless otherwise stated. Reported yields are isolated yields.

We next explored various carbamoyl chlorides 2 with benzyl bromide 1a and thiourea (A), demonstrating the effectiveness of the developed reaction protocol (Fig. 1). For example, increasing the steric bulk around the carbamoyl N-centre did not impede the reaction, as demonstrated by the nearly quantitative product yields obtained in the coupling of carbamoyl chlorides containing N,N-diethyl 2q and N,N-isopropyl 2r moieties to produce products 3q (85%) and 3r (91%). Similarly, unsymmetrical carbamoyl chlorides 2s and 2t furnished products 3s and 3t in good to excellent yields (75–87%). Furthermore, with the abundance of N-cyclic motifs in biologically active molecules,³⁹ carbamoyl chlorides 2u–2w with cyclic moieties were also well-tolerated, furnishing products 3u–3w in excellent yields (82–89%). Finally, it was envisioned that this reaction protocol could be particularly suitable for gram-scale synthesis. Gratifyingly, a yield of 89% of product 3a for a 20 mmol scale was obtained (Fig. 1). This yield is comparable to that observed for small-scale synthesis (1 mmol scale). Additionally, 2D NMR experiments, such as HMBC and HSQC, were conducted on product 3j, and no structural rearrangements of the product were observed (see SI).

The effectiveness of this method was also demonstrated by developing a one-pot two-step telescoped procedure where benzyl bromide 1a could be converted to product 3a (93%). This telescoped procedure did not require any solvent evaporation but sequential addition of reagents (Fig. 2a). Furthermore, given the easy preparation and isolation of stable, odourless isothiouronium salts I,³¹ product 3a was obtained in excellent yield (85%) (see Section 4.5 of the SI). We then envisaged that the same isothiouronium salt I technique could provide reactivity to previously unreactive alkyl halides. Gratifyingly, the long straight-chained alkyl halides furnished the desired products in excellent yields (3x, 91% and 3y, 93%) (Fig. 2b), demonstrating the easy access of the desired S-substituted N-acyl ureas 3x and 3y via isothiouronium salt I utility.

Fig. 2 (a) One-pot, two-step telescoped synthesis. (b) S-Alkyl isothiouronium salt utility. (c) Alkyl alcohols utility as leaving group precursors. (d) Proposed reaction mechanism. Reactions were performed on a 1 mmol scale. Reported yields are isolated yields.

Finally, as a feature of our reaction design, it was anticipated that halides might be substituted by a different leaving group suitable for S_N2 reactivity. In particular, alcohols 4 – abundant feedstock with wide commercial availability – could serve as attractive precursors, a substitute for alkyl halides 1.⁴⁰ To this end, we investigated alkyl mesylates 5 reactivity generated from one-step sulfonation of commercially available benzyl alcohol 4a, 4-methoxybenzyl alcohol 4b, and methanol 4c (Fig. 2c). The reaction of benzyl mesylate 5a with various carbamoyl chlorides furnished the desired products 3a (74%), 3q (79%), 3u (65%), and 3w (62%) in good to excellent yields. Lastly, 4-methoxybenzyl mesylate 5b and methyl mesylate 5c were also suitable electrophiles as demonstrated by the reaction with N,N-dimethylcarbamoyl chloride 2a, furnishing products 3h (60%) and 3z (70%), respectively, in good yields.

From the onset, it was envisioned that, mechanistically, the isothiouronium salt formation via S_N2 reactivity of the alkyl halides 1 and thiourea (A) would be critical for this reaction (Fig. 2d).^34,41 We propose that the nucleophilic attack of the in situ generated isothiouronium salt I on the carbamoyl chloride 2 would follow.⁴² The resulting iminium intermediate II, which, upon hydrolysis, would furnish the desired product 3.

Conclusion

In summary, we report the one-pot, three-component synthesis of S-substituted N-acyl ureas using a combination of alkylation and carbamoylation of the thiourea approach. Isolated product yields of up to 93% were obtained despite the electronic, steric, and structural variations of the alkyl halides and carbamoyl chloride substrates. Furthermore, we disclose the practicality of this protocol by demonstrating the underutilised mesylates as precursors for the in situ formation of the isothiouronium salt I, delivering the desired N-acyl urea products in good to excellent yields. Given the importance of N-acyl ureas in bioactive structures, we anticipate that this protocol will find broad use in the synthetic community.

Author contributions

Conceptualisation, M. P. S., J. L. L., and P. T. M.; methodology, M. P. S., and A. R. N. All authors have read and agreed to this version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2451965 (3a) contains the supplementary crystallographic data for this paper.⁴³

The data supporting this article have been included in the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5ra05563f.

Acknowledgements

Research reported in this work was supported by the University of Johannesburg, Research Centre for Synthesis and Catalysis. We thank the National Research Fund (NRF) for financial support. We also thank Dr Banele Vatsha for X-ray single-crystal analysis, Mutshinyalo Nwamadi for NMR analysis, Dr Madelien Wooding for mass analysis (University of Pretoria), and Blessing Mkhonazi for the helpful discussions.

Notes and references

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