One-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from nitriles and hydrazonoyl chlorides via 1,3-dipolar cycloaddition

Abstract

A one-flask strategy for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles 4a–s and 8a and b from nitriles 5a–i with N-arylhydrazonoyl hydrochlorides 3a–h and 7a and b under basic conditions was developed. The reaction provided the desired 1,2,4-triazoles in moderate to excellent yields (56–98%), and was applicable to aliphatic and aromatic nitriles as well as N-phenylhydrazonoyl hydrochlorides bearing ester and acetyl functionalities. A 1,3-dipolar cycloaddition between imidate and nitrilimine generated from the respective nitrile and N-arylhydrazonoyl chloride in one flask was proposed for the new transformation.

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Introduction

Substituted 1,2,4-triazoles are considered an important class of heterocyclic compounds as they show various biological activities.¹ Among the traditional methods for their preparation,² the dehydrative cyclization of acylamidrazone intermediates,³ formed from the reaction of hydrazides and the activated nitriles with amides including imidates or thioamides at high temperature, are frequently used.⁴ However, the harsh reaction conditions including the use of corrosive POCl₃ or SOCl₂ limit their application to sensitive substrates.^5,6

In our previous study,⁷ we report the synthesis of 1,3,5-trisubstituted 1,2,4-triazole 4 by a new 1,3-dipolar cycloaddition between oxime 2 and hydrazonoyl chloride⁸ 3 under basic conditions (eqn (1) in Fig. 1). In this reaction, compound 2 serves as the dipolarophile and 3 serves as the precursor to 1,3-dipole nitrilimine.⁹ In a further study we present that 1,2,4-triazole 4 can be obtained in “one flask” by reacting aldehyde 1, the precursor to 2, with hydroxylamine hydrochloride following with 3.^7c The two reactions proceed under mild conditions and produce 4 regiospecifically in good to excellent yields. We also demonstrate that triazoles 4 inhibit the proliferation of NCI-H226, NPC-TW01, and Jurkat cancer cells at low micromolar concentrations.^7a

Fig. 1 One-flask 1,3-dipolar cycloaddition strategies for the synthesis of 1,3,5-trisubstituted 1,2,4-triazole 4.

As imidate 6 is electronically analogous to oxime 2, we envisage that 6 could substitute oxime 2 as the dipolarophile for the synthesis of 1,3,5-trisubstituted 1,2,4-triazole 4 (see eqn (2) in Fig. 1). Moreover, due to the preparation of 6 can be achieved by partial alcoholysis (Pinner reaction)¹⁰ of the precedent nitrile 5 under acidic conditions, an “one-flask” synthesis of triazole 4 can thus be achieved from nitrile 5 without the isolation of imidate 6. The use of unstable aldehydes and toxic hydroxylamine as the starting materials can be avoided. Despite direct cycloaddition of nitriles with hydrazonoyl chlorides is also reported to provide 1,2,4-triazoles, the substrates are limited to nitriles such as ethyl carbonocyanidate (EtO₂C–CN), benzyl carbonocyanidate (BnO₂C–CN), and 2,2,2-trichloroacetonitrile (Cl₃C–CN) that bear a strong electron-withdrawing group.¹¹ Herein, we present our investigation on the one-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazoles 4 from nitriles 5 with hydrazonoyl chlorides 3 thorough imidates 6. The reaction provided the desired products in moderate to excellent yields and was applicable to simple aliphatic and aromatic nitriles.

Results and discussion

For the nitrilimine as the 1,3-dipole is generated from hydrazonoyl chloride under basic conditions,⁹ we first screened the suitable base for the new 1,3-dipolar cycloaddition by use of commercially available ethyl acetimidate hydrochloride (6a) with N-phenylhydrazonoyl chloride 3a as the model (Table 1). Reaction of acetonitrile (5a) with HCl(g) and ethanol in CH₂Cl₂, then with 3a in one flask was also studied for comparison.¹² For the reaction of imidate 6a with hydrazonoyl chloride 3a, we observed that the 1,3-dipolar cycloaddition did not take place without a base (entry 1 in Table 1), neither did the use of diethylamine or N,N-diisopropylethylamine or pyridine (entries 2–4). Use of DBU only gave 4a in low yield (23%, entry 5). Among the bases we have tried, only the use of triethylamine displayed a satisfactory result (77% yield, entry 6). For the one-flask transformation from acetonitrile (5a) with hydrazonoyl chloride 3a to 1,2,4-triazole 4a, the reaction provided almost the identical results and the use of triethylamine also provided the best yield of 4a (76%, see entry 6). Triethylamine was thus used as the base for all the following studies.

Table 1 Screening of a suitable base (3.0 equivalents) for the one-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazole 4a via 1,3-dipolar cycloaddition

Entry	Base	Yield (%) of 4a
		From 6a	From 5a
a N.D.: not detectable.
1	—	N.D.^a	N.D.
2	Diethylamine	N.D.	N.D.
3	N,N-Diisopropylethylamine	N.D.	N.D.
4	Pyridine	N.D.	N.D.
5	DBU	23	21
6	Triethylamine	77	76

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In control experiment, 5a was directly reacted with 3a in the presence of Et₃N without being reacted preferentially with HCl to form imidate 6a. The desired 1,3,5-trisubstituted 1,2,4-triazoles 4a was not obtained with the decomposition of starting materials. The result suggested the higher reactivity of imidate 6a than nitrile 5a as the dipolarophile to react with hydrazonoyl chloride 3a.

We then focused on the one-flask 1,3-dipolar cycloaddition strategy for the synthesis of 1,2,4-triazole 4 (eqn (2) in Fig. 1). We prepared various N-phenylhydrazonoyl chlorides 3a–h⁸ bearing different substituents on the phenyl ring and allowed them to react with alkyl nitriles 5a–e (see Table 2). For the reaction of acetonitrile (5a) with hydrazonoyl chlorides 3a–h bearing o-CF₃, m-Br, p-Me, p-CF₃, p-OMe, p-F, and p-Cl on the phenyl group, the reaction readily gave the corresponding 1,2,4-triazoles 4b–h in 56–91% yields (entries 2–8 in Table 2). The use of compound 3h (X = p-Cl) gave the best result (91% yield) nevertheless 3d (X = p-Me) gave a poor result (56% yield).

Table 2 One-flask synthesis of 1,2,4-triazoles 4a–l from alkyl nitriles 5a–e and N-phenylhydrazonoyl chlorides 3a–h via 1,3-dipolar cycloaddition

Entry	Nitrile 5a–e		Hydrazone 3a–h		Triazole 4a–l	Reaction time (h)	Yield (%)
	R	No.	X	No.
1	Me	5a	H	3a	4a	3.0	76
2	Me	5a	o-CF3	3b	4b	3.0	71
3	Me	5a	m-Br	3c	4c	4.0	66
4	Me	5a	p-Me	3d	4d	5.0	56
5	Me	5a	p-CF3	3e	4e	3.0	81
6	Me	5a	p-OMe	3f	4f	2.5	90
7	Me	5a	p-F	3g	4g	3.5	77
8	Me	5a	p-Cl	3h	4h	2.0	91
9	Et	5b	p-Cl	3h	4i	3.5	93
10	i-Pr	5c	p-Cl	3h	4j	2.5	98
11	n-Bu	5d	p-Cl	3h	4k	4.5	76
12	Cyclopentyl	5e	p-Cl	3h	4l	5.0	57

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The one-flask 1,3-dipolar cycloaddition strategy was also applicable to various aliphatic nitriles. Reaction of ethyl, i-propyl, n-butyl, and cyclopentyl nitriles 5b–e with p-chloro-N-phenylhydrazonoyl chloride 3h in the presence of triethylamine provided the corresponding 1,3,5-trisubstituted 1,2,4-triazoles 4i–l in 57–98% yields (see entries 9–12 in Table 2). The results in Table 2 indicated that aliphatic nitriles and N-phenylhydrazonoyl hydrochlorides bearing different substituents on the phenyl group were tolerable in the new 1,3-dipolar cycloaddition. The structures of 1,2,4-triazoles 4a–l were fully characterized by spectroscopic methods and consistent with the data in our previous studies.⁷

We turned to study the reactivity of aromatic nitriles including benzonitrile (5f), 2-furonitrile (5g), thiophene-2-carbonitrile (5h), and 1H-pyrrole-2-carbonitrile (5i) for the one-flask 1,3-dipolar cycloaddition (Table 3). Reaction of compounds 5f–i with N-phenylhydrazonoyl hydrochloride 3h bearing the p-Cl substituent gave the corresponding 1,2,4-triazoles 4m–p in 56–86% yields (entries 1–4 in Table 3). In comparison with the results from aliphatic nitriles 5a–e (entries 8–12 in Table 2), use of aromatic nitriles 5f–i demonstrated slightly poorer results. The lower yields of 4m–p might come from the conjugation of the double bond of imidate with the π-system in the aryl group to alter the HOMO–LUMO interactions of imidate with nitrilimine,¹³ or the instability of π-excessive furyl, thienyl, and pyrrolyl groups in acidic conditions.¹⁴ Reaction of 1H-pyrrole-2-carbonitrile (5i) with N-phenylhydrazonoyl hydrochloride 3b, 3i, or 3e bearing ortho-, meta-, or para-trifluoromethyl group on the phenyl group also provided the corresponding 1,2,4-triazoles 4q–s in 43–75% yields. The experimental results presented in Tables 2 and 3 demonstrated that the one-flask 1,3-dipolar cycloaddition was applicable to aliphatic, cyclic aliphatic, and aromatic nitriles with various N-phenylhydrazonoyl chlorides to synthesize 1,3,5-trisubstituted 1,2,4-triazoles in moderate to excellent yields.

Table 3 Synthesis of 1,2,4-triazoles 4m–s from aromatic nitriles 5f–i with substituted N-phenylhydrazonoyl chlorides 3b, 3e, 3h, and 3i

Entry	Nitrile 5f–i		Hydrazone 3h–e		Triazole 4m–s	Reaction time (h)	Yield (%)
	R	No.	X	No.
1	Phenyl	5f	p-Cl	3h	4m	3.0	86
2	2-Furyl	5g	p-Cl	3h	4n	3.0	61
3	2-Thienyl	5h	p-Cl	3h	4o	4.0	82
4	2-Pyrrolyl	5i	p-Cl	3h	4p	5.0	56
5	2-Pyrrolyl	5i	o-CF3	3b	4q	3.0	43
6	2-Pyrrolyl	5i	m-CF3	3i	4r	2.5	44
7	2-Pyrrolyl	5i	p-CF3	3e	4s	3.5	75

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Table 4 presents the results of the one-flask 1,3-dipolar cycloaddition strategy for the synthesis of 1,2,4-triazoles bearing different C-3 substituents. The reaction of acetonitrile (5a) with N-phenylhydrazonoyl hydrochloride 7a–e was studied using the optimized reaction conditions from Table 1. Not surprisingly, reaction of 5a with 7a bearing ethoxycarbonyl group also provide the corresponding 1,2,4-triazole 8a in 81% yield (see entry 1 in Table 4). Reaction of N-phenylhydrazonoyl hydrochloride 7b bearing acetyl group also gave the corresponding 8b in 79% yield. However, reaction of N-phenylhydrazonoyl hydrochloride 7c with amido group, 7d with ethyl group, and 7e with phenyl group did not give the corresponding 1,2,4-triazole 8c–e (entries 3–5 in Table 4). Decomposition of the starting materials was observed. The results in Table 4 indicated the one-flask 1,3-dipolar cycloaddition strategy was applicable to N-phenylhydrazonoyl hydrochlorides bearing ester and acetyl functionalities.

Table 4 Synthesis of 1,2,4-triazoles 8a–e bearing various C-3 substituents

Entry	Hydrazone 7a–e			Triazole 8a–e	Yield (%)
	X	R	No.
a N.D.: not detectable.
1	CF3	–CO2Et	7a	8a	81
2	H	–(C=O)Me	7b	8b	79
3	H	–CONMe2	7c	8c	N.D.^a
4	H	–Et	7d	8d	N.D.
5	H	–Ph	7e	8e	N.D.

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We proposed a plausible mechanism for the one-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from nitriles and N-arylhydrazonoyl chlorides through a new 1,3-dipolar cycloaddition in Scheme 1. Upon reaction with EtOH in the presence of HCl(g), nitrile 5 was converted to its corresponding imidate 6. N-Arylhydrazonoyl 3 was converted to the corresponding nitrilimine 8 by Et₃N in the same flask, then the 1,3-dipolar cycloaddition between dipolarophile 6 and 1,3-dipole 9 took place to generate cyclic intermediate 10. Aromatization of 10 by releasing EtOH generated 1,2,4-triazole 4 in one flask.

Scheme 1 Proposed mechanism of the one-flask synthesis of 1,2,4-triazole 4 from nitrile 5 and hydrazonoyl chloride 3 via 1,3-dipolar cycloaddition.

Conclusions

We developed a one-flask methodology for the synthesis 1,3,5-trisubstituted 1,2,4-triazoles using nitriles and N-arylhydrazonoyl chlorides as the starting materials. The reaction was applicable to aliphatic and aromatic nitriles with N-arylhydrazonoyl chlorides bearing various substituents on the phenyl group. A plausible 1,3-dipolar cycloaddition mechanism was proposed for the reaction of imidate from nitrile with nitrilimine from hydrazonoyl chloride in one flask to generate the desired 1,2,4-triazole.

Acknowledgements

We are grateful to the China Medical University (CMU100-ASIA-17 and CMU101-S-23), Tsuzuki Institute for Traditional Medicine, and the National Science Council of Republic of China for financial support (NSC-99-2320-B-039-014-MY3 and 102-2113-M-415-005-MY2).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental details, procedures, spectroscopic data for new compounds. See DOI: 10.1039/c4ra00113c

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