Mechanistic insights of the copper(I)-catalysed reaction between chlorohydrazones and terminal alkynes

Abstract

Deuterium incorporation in the 5-substituted pyrazoles arising from the copper(I)-catalysed reaction between chlorohydrazones and terminal acetylenes suggests the intermediacy of copper(I)-complexed alkynylhydrazones. Since the efficiency of such a complexation depends on both the chlorohydrazone and the solvent, the obtainment of the pyrazoles and/or the corresponding alkynylhydrazones is variable depending on the reaction conditions. Copper(I)-complexed alkynylhydrazone intermediates should play a pivotal role in the proposed catalytic cycle.

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Introduction

The main interest in the synthesis of variously substituted pyrazoles lies in their pharmaco-clinical properties¹ as analgesic,^2a antifungal,^2b antibacterial^2c and antiviral^2d,e agents. Many pyrazole derivatives have already found their clinical application as nonsteroidal anti-inflammatory^2f and anti-pyretic drugs,^2f and there are also a number of market drugs containing the pyrazole moiety.¹

Access to the pyrazole ring can be pursued via 1,3-dipolar cycloaddition of the nitrilimine intermediate on the carbon–carbon triple bond. Unfortunately, the cycloaddition between nitrilimines and unsymmetrically substituted alkynes very often yields mixtures of regioisomeric pyrazoles. The poor regioselectivity of the reaction applies to both the classical thermal cycloadditions according to Huisgen³ and the more recently introduced metal-catalysed cycloadditions.⁴

The regioselective synthesis of the pyrazole ring from chlorohydrazones in which the formation of the nitrilimine intermediate is avoided was first performed by us⁵ and disclosed the copper(I)-catalysed reaction between chlorohydrazones and terminal alkynes as a fruitful, regioselective route to 5-substituted pyrazoles.

The present paper is focused on the mechanistic aspects of such a reaction that can be deduced from the behaviour of chlorohydrazones 1a–c and the deuterated one D-1a towards terminal acetylenes 2 and deutero-phenylacetylene D-2a (Fig. 1).

Fig. 1 Chlorohydrazones and terminal acetylenes used as reactants.

Results and discussion

Briefly considering the synthetic point of view, optimisation of the reaction conditions has been carried out in our previous papers^5,6 by examining the behaviour of hydrazonoyl chloride 1a towards methyl propiolate⁵ and homopropargylic alcohols⁶ in the presence of salts or oxides of group 1B metals in their lowest (+1) oxidation state. The best reaction conditions involved the use of a 0.25 M solution of chlorohydrazone in the presence of a catalytic amount of CuCl (0.05 mol. equiv.) and triethylamine (1 mol. equiv.) at room temperature. These conditions have been successfully applied to the regioselective synthesis of a number of 5-substituted pyrazoles, including 1,5-diphenyl-3-methoxycarbonyl pyrazole 3aa.⁵ Three novel examples are proposed here with alkynes whose substituents have different electronic demands, and the corresponding results are outlined in Table 1. As expected, these reactions were completely regioselective, yielding pyrazoles 3 in 10–60 minutes in good yield. Due to its usefulness in the following discussion, the literature reaction between 1a and phenylacetylene⁵ is also shown in Table 1 (entry 1). As far as the isolation of the pyrazole products is concerned, in the most favourable case (entries 1 and 2) this was carried out by simple filtration of the reaction crude on Celite, while in the presence of small amounts of by-products, chromatographic treatment on a silica gel column became necessary.

Table 1 Reaction between chlorohydrazone 1a and terminal alkynes 2a–d

Entry	R^1	Product	Time (min)	Yield^a (%)
a Isolation yields. b Data from ref. 5.
1	Ph	3aa	35	88^b
2	COMe	3ab	10	92
3	Cyclopentyl	3ac	40	78
4	CH2Ph	3ad	60	68

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Alongside the synthetic aspects just mentioned, the extent of deuterium incorporation in pyrazole 3aa was determined. For this purpose, deuterated chlorohydrazone D-1a and deutero-phenylacetylene D-2a were prepared. Both deuterated reagents were obtained in an analytically pure form; the former by exchange with D₂O of the hydrazonic proton of 1a, the latter by treatment of phenylacetylene with n-butyllithium, followed by addition of D₂O (Scheme 1).

Scheme 1 Preparation of deuterated reagents D-1 and D-2a.

The copper(I)-catalysed reaction between deutero-phenylacetylene D-2a and chlorohydrazone 1a was pursued in CCl₄ to eliminate undesirable source of hydrogens due to the solvent that could weaken the connection between the results and the reaction mechanism. A mixture of the two pyrazoles 3aa and D-3aa that could not be separated by chromatographic methods was obtained, which showed 30% deuterium incorporation at ¹H NMR (Scheme 2, eqn (1)). The value of deuterium incorporation increases to 65% by reacting deuterated chlorohydrazone D-1a with phenylacetylene (Scheme 2, eqn (2)), and in the reaction between the two deuterated substrates the incorporation reaches 90% (Scheme 2, eqn (3)). The latter value is consistent with similar deuteration experiments. In fact, quantitative deuterium incorporation is quite hard to achieve because of the incomplete purity of all species in the reaction mixture.⁷

Scheme 2 Copper(I)-catalysed reactions involving the deuterated reagents D-1 and D-2a.

The above results are consistent with the catalytic cycle depicted in Fig. 2; for the sake of clarity the behaviour of chlorohydrazone 1a is shown.

Fig. 2 Catalytic cycle proposed for the reaction chlorohydrazones and terminal alkynes.

Consistent with typical azide “click” reactions involving terminal acetylenes in the presence of copper(I),⁸ the first step of the catalytic cycle involves the formation of a copper(I) acetylide, followed by nucleophilic addition to the C=N double bond of chlorohydrazone. The generation of the key intermediate A is fully plausible due to the known propensity of some hydrazones to complexate the copper cation.⁹ This intermediate accounts for the greater degree of deuterium incorporation into the pyrazole adduct from deuterated hydrazonoyl chloride D-1a (65%) than from deutero-phenylacetylene D-2a (30%), which is clearly dictated by the proximity of the deuterium atom to the 4-position of the pyrazole ring upon its closure. In the case of D-2a, one out of three pyrazole molecules must receive the deuterium atom from triethyldeuterammonium chloride, which is present in the reaction medium as it is released in the first step of the catalytic cycle. The same proportion of hydrogen transfer from ammonium cations is observed in the reaction conducted on deuterated chlorohydrazone D-1a; in this case, one in three pyrazole molecules must receive the ¹H atom from triethylammonium chloride. As for the pyrazolium metallated cation B, its intervention has been postulated for the final step of the azide–alkyne “click” cycloaddition⁸ and the cycloaddition of alkynylhydrazones promoted by Au(I) salts.¹⁰

It was not possible to isolate the key intermediate A nor the corresponding alkynylhydrazone 4aa (vide infra) in the reaction between 1a and phenylacetylene. In this regard, it is useful to point out that the attempt to obtain intermediate A by crystallisation of 4aa in the presence of an equimolecular amount of CuCl in dichloromethane yielded the pyrazole 3aa. These results may appear surprising on the basis of a paper published in 2014 in which the facile isolation of alkynylhydrazones from the reaction between C,N-diphenyl chlorohydrazone 1c and terminal alkynes in dimethylformamide is described.¹¹

The contradiction is only apparent as can be seen by comparing the behaviour of chlorohydrazones 1a and 1b, c (Fig. 1) towards phenylacetylene in the presence of catalytic amounts of copper(I) ions.

While the reaction of C-methoxycarbonyl-substituted chlorohydrazone 1a with phenylacetylene in dichloromethane selectively gave the pyrazole 3aa (Table 1, entry 1), mixtures of 3aa and the corresponding alkynylhydrazone 4aa were obtained by using acetonitrile or dimethylformamide as the solvent (Table 2, entries 1 and 2).

Table 2 Copper(I)-catalysed reactions between chlorohydrazones 1 and phenylacetylene at 20 °C

Entry	R^1	Solvent	Time (min)	Products	Ratio 3 : 4	Yield (%) 3 + 4
a Literature datum: 91%.^11
1	COOMe	MeCN	45	3aa, 4aa	86 : 14	81
2	COOMe	DMF	45	3aa, 4aa	78 : 22	78
3	2-MeO-C6H4	CH2Cl2	60	3ba, 4ba	91 : 9	70
4	2-MeO-C6H4	MeCN	85	3ba, 4ba	68 : 32	66
5	2-MeO-C6H4	DMF	120	3ba, 4ba	60 : 40	74
6	Ph	CH2Cl2	60	3ca, 4ca	45 : 55	78
7	Ph	MeCN	80	3ca, 4ca	15 : 85	80
8	Ph	DMF	120	3ca, 4ca	0 : 100	84^a

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C-Aryl-substituted chlorohydrazones 1b,c also gave product mixtures (Table 2, entries 3–7) except C-phenyl-substituted 1c in dimethylformamide, which selectively gave the alkynylhydrazone 4ca (Table 2, entry 8). In this latter case the literature datum¹¹ was reproduced in the presence of CuI as the catalyst (see Experimental).

These apparently conflicting results can be rationalised in light of the different complexation extent of copper(I) halides with alkynylhydrazones 4 as a function of solvent. For ease of reading, the three possible intermediates A are illustrated for each hydrazonoyl chloride in Fig. 3, and it can be perceived that the tenacity of the complexation decreases in the order A-1a > A-1b > A-1c, while remaining in the range of a labile complexation.

Fig. 3 Key intermediates A for the catalytic cycle depicted in Fig. 2.

In pathway a of the proposed catalytic cycle (Fig. 2), the copper(I) moiety must move to the carbon at 4- position of the pyrazolium metallated cation B. It is likely that this latter intermediate is more easily formed the more stable the corresponding intermediate A is, thus explaining the experimental results shown in Table 1, entry 1 and Table 2, entries 3 and 6.

Interestingly, the experimental outcome markedly depends on the reaction solvent as can be seen by comparing data of Table 1, entry 1, and Table 2. We interpret this dependence with reference to the complexing ability of organic solvents. This is usually expressed by their “donor number” (DN),¹² and decreases in the order: DMF (26.6) > MeCN (14.1) CH₂Cl₂ (0).¹³

It is plausible that the better complexation of copper(I) chloride by dimethylformamide compared to acetonitrile, and especially dichloromethane, is responsible for the lack of or reduced complexation of the alkynylhydrazone by the copper(I) halide, which necessarily results in greater difficulty in cyclization to the metallated pyrazolium cation B, and thus to the pyrazole product 3. Such competition between solvent and alkynylhydrazone favours the latter over the cyclic product when the solvent has a strong complexing ability towards copper(I) (Fig. 2, pathway b). As can be inferred from the product ratios in entries 1, 4, 7 and 2, 5, 8 of Table 2, the alkynylhydrazone-copper(I) complexation efficiency in acetonitrile and dimethylformamide, respectively, should also decrease in the order A-1a > A-1b > A-1c. In the latter case it must be practically non-existent, effectively preventing the alkynylhydrazone → pyrazole cyclisation, in perfect agreement with the literature data.¹¹ In other words, it is as if the high complexing power of dimethylformamide versus copper(I) halogenide prevented the in situ formation of complex A-1c.

Conclusions

The copper(I)-catalysed reaction between chlorohydrazones and terminal alkynes is a simple and efficient method for the regioselective synthesis of 5-substituted pyrazoles. This paper lays the first mechanistic foundations to elucidate the course of this reaction. In particular, the incorporation of deuterium into the pyrazole adducts is a strong indication in favour of the formation of copper(I)-complexed alkynylhydrazones as key intermediates of the whole catalytic process. The stability of these complexes is strongly influenced by both the structural features of the starting chlorohydrazones and the reaction medium. Complexating solvents towards the Cu⁺ cation limit or prevent its in situ generation affording product mixtures or stopping the reaction at the alkynylhydrazone step, respectively. The results of the present paper are useful in reconciling apparently conflicting literature data. With a view to acquiring more details on the electron flow of the reaction that is the subject of this paper, its in-depth theoretical–computational study is underway.

Experimental

General

Melting points were determined on a Büchi apparatus in open tubes and are uncorrected. IR spectra were recorded on a PerkinElmer 1725 X spectrophotometer. Mass spectra were determined on a VG-70EQ apparatus. ¹H-NMR (300 MHz) and ¹³C-NMR (75 MHz) spectra were taken with a Bruker Avance instrument (in CDCl₃ solutions at room temperature). Chemical shifts are given as parts per million from tetramethylsilane. Coupling constants (J) values are given in hertz and are quoted to ±0.1 Hz consistently with NMR machine accuracy. All solvents and reagents were purified by standard technique or used as supplied from chemical sources as appropriate. Reagent chemicals were purchased from Aldrich Chemical Company Ltd. Solvents were dried and stored over 4 Å molecular sieves prior to use. Deuterium oxide was at 99.95% D grade.

Deutero-phenylacetylene D-2a¹⁴ and chlorohydrazones 1a–c,^15–17 were prepared according to literature procedures.

1,3,5,-Substituted pyrazoles 3aa,¹⁸3ba,¹⁹3ca^3a and alkynylhydrazone 4ca¹¹ are known in the literature.

Reaction between chlorohydrazone 1a and terminal alkynes 2b–d. General procedure. In a clear, colourless solution of the appropriate terminal alkyne 2 (2.0 mmol) and triethylamine (0.20 g, 2.0 mmol) in dry CH₂Cl₂ (4 mL) was added CuCl (10 mg, 0.05 mmol) under vigorous magnetic stirring obtaining a bright yellow subspension. A solution of chlorohydrazone 1a (0.41 g, 2.0 mmol) in dry CH₂Cl₂ (4 mL) was added dropwise to the yellow subspension and the mixture was stirred at 20 °C for the time indicated in Table 1.

In the case of 1-butyn-2-one 2b, Table 1, entry 2, the crude was filtered over a silica gel pad and the solvent was evaporated under reduced pressure. Crystallisation of the residue with iPr₂O gave pure 1-phenyl-3-methoxycarbonyl-5-acetylpyrazole 3ab (0.53 g, 92%) as white powder having mp 109–111 °C; IR (nujol): 1735 (ester [double bond splayed left]C=O), 1710 (ketone [double bond splayed left]C=O) (cm^-1); ¹H-NMR: 7.50 (s, 1H, pyrazole-H4), 7.35–7.46 (m, 5H, aromatics), 3.96 (s, 3H, –COOCH₃), 2.51 (s, 3H, –COCH₃); ¹³C-NMR: 187.2 (s, –COCH₃), 161.9 (s, –COOCH₃), 143.3 (s, pyrazole-C5), 140.9 (s, pyrazole-C3), 140.0 (s, aromatic), 129.3 (d, aromatic), 128.7 (d, aromatic), 126.0 (d, aromatic), 114.8 (d, pyrazole-C4), 52.4 (q, –COOCH₃), 28.7 (q, –COCH₃). MS: 244 m/z (M⁺). Anal. calcd for C₁₃H₁₂N₂O₃: C, 63.93; H, 4.95; N, 11.47. Found: C, 63.89; H, 4.90; N, 11.54.

In the case of cyclopentylacetylene 2c (Table 1, entry 3) and 3-phenoxyprop-1-yne 2d (Table 1, entry 4) the residue was chromatographed on a silica gel column with hexane/EtOAc 1 : 2. First fractions contained starting 1a, further elution followed by crystallisation with iPr₂O gave pure 3.

1-Phenyl-3-methoxycarbonyl-5-cyclopentylpyrazole 3ac (0.42 g, 78%). White powder having mp 90–92 °C, IR (nujol): 1740 ([double bond splayed left]C=O) (cm^-1); ¹H-NMR: 7.41–7.47 (m, 5H, aromatics), 6.76 (s, 1H, pyrazole-H4), 3.91 (s, 3H, –COOCH₃), 2.98–3.02 (m, 1H, cyclopentyl-CH), 1.66–1.80 (m, 2H, cyclopentyl –CH₂CH[double bond splayed right]), 1.66–1.79 (m, 2H, cyclopentyl –CH₂CH[double bond splayed right]), 1.49–1.65 (m, 4H, cyclopentyl –CH₂–CH₂–); ¹³C-NMR: 163.0 (s, –COOCH₃), 150.7 (s, aromatic), 143.3 (s, pyrazole-C3), 139.3 (s, pyrazole-C5), 129.0 (d, aromatic), 128.8 (d, aromatic), 126.2 (d, aromatic), 105.7 (d, pyrazole-C4), 51.8 (q, –COOCH₃), 36.2 (d, –CH₂CH[double bond splayed right]), 33.6 (t, –CH₂CH[double bond splayed right]), 25.1 (t, –CH₂–CH₂–). MS: 270 m/z (M⁺). Anal. calcd for C₁₆H₁₈N₂O₂: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.13; H, 6.68; N, 10.41.

1-Phenyl-3-methoxycarbonyl-5-(phenyl)methylpyrazole 3ad (0.40 g, 68%). Pale yellow powder having mp 96–99 °C, IR (nujol): 1735 (>C=O) (cm⁻¹); ¹H-NMR: 7.08–7.47 (m, 10H, aromatics), 6.72 (s, 1H, pyrazole-H4), 4.00 (s, 2H, –CH₂Ph), 3.94 (s, 3H, –COOCH₃); ¹³C-NMR: 163.0 (s, –COOCH₃), 144.2 (s, aromatic), 143.6 (s, pyrazole-C3), 139.0 (s, aromatic), 137.2 (s, pyrazole-C5), 126.0–129.2 (m, aromatic [double bond splayed left]C–H), 109.6 (d, pyrazole-C4), 52.1 (q, –COOCH₃), 32.4 (t, –CH₂Ph). MS: 292 m/z (M⁺). Anal. calcd for C₁₈H₁₆N₂O₂: C, 73.95; H, 5.52; N, 9.58. Found: C, 74.03; H, 5.47; N, 9.64.

Preparation of deuterochlorohydrazone D-1a. In a solution of chlorohydrazone 1a (1.00 g, 4.7 mmol) in CDCl₃ (30 mL) was added deuterium oxide (1.00 g, 50 mmol). The mixture was stirred at 20 °C for 240 h. The crude was taken up with CDCl₃ (20 mL) and dried over Na₂SO₄. Evaporation of the solvent under reduced pressure gave deuterochlorohydrazone D-1a (0.95 g, 95%) as pale yellow solid having mp 105–106 °C; IR (nujol): 2400 ([double bond splayed left]N–D), 1700 (ester [double bond splayed left]C=O) (cm⁻¹); ¹H-NMR: 7.04–7.39 (m, 5H, aromatics), 3.95 (s, 3H, –COOCH₃), ¹³C-NMR: 160.4 (s, –COOCH₃), 141.5 (s, [double bond splayed left]C=N–), 130.3 (s, aromatic), 129.5 (d, aromatic), 123.3 (d, aromatic), 114.6 (d, aromatic), 53.6 (q, –COOCH₃). MS: 213 m/z (M⁺), exact mass 213.0411. Anal. calcd for C₈H₈DClN₂O₂: C, 50.60; H, 4.72; N, 13.11. Found: C, 50.58; H, 4.70; N, 13.18.

Reaction of chlorohydrazones 1a and D-1a with phenylacetylenes 2a and D-2a. General procedure. In a solution of phenylacetylene 2a or deuterophenylacetylene D-2a (1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) in freshly distilled, dry CCl₄ (3 mL) was added CuCl (10 mg, 0.05 mmol) under vigorous magnetic stirring obtaining a yellow subspension. A solution of the appropriate chlorohydrazone 1a or deuterochloro hydrazone D-1a (1.5 mmol) in dry CCl₄ (3 mL) was added dropwise to the yellow subspension and the mixture was stirred at 20 °C for 20 min. The crude was filtered over a Celite pad and the solvent was evaporated under reduced pressure giving a mixture of 1,5-diphenyl-3-methoxycarbonyl-4-deuteropyrazole D-3aa and 1,5-diphenyl-3-methoxycarbonylpyrazole 3aa.

In the case of the reaction between 1a and D-2a, 355 mg (85% combined yield) were obtained in the ratio D-3aa : 3aa = 30 : 70.

In the case of the reaction between D-1a and 2a, 364 mg (87% combined yield) were obtained in the ratioD-3aa : 3aa = 65 : 35.

In the case of the reaction between D-1a and D-2a, 368 mg (88% combined yield) were obtained in the ratio D-3aa : 3aa = 90 : 10.

Product ratios D-3aa : 3aa were deduced on the basis of the ¹H NMR spectra of the corresponding reaction crudes (see Scheme 2 and ESI†).

Reaction between chlorohydrazones 1a–c and phenylacetylene 2a. General procedure. In a solution of phenylacetylene 2a (0.21 g, 2.0 mmol) and triethylamine (0.20 g, 2.0 mmol) in dry solvent (4 mL, see Table 2) was added CuCl (10 mg, 0.05 mmol) under vigorous magnetic stirring obtaining a bright yellow subspension. A solution of the appropriate chlorohydrazone 1a–c (2.0 mmol) in dry solvent (4 mL) was added dropwise to the yellow subspension and the mixture was stirred at 20 °C for the time indicated in Table 2. The crude was filtered over a Celite pad and the solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column with hexane/EtOAc 1 : 2. First fractions contained pyrazoles 3, further elution gave pure alkynylhydrazones 4. Overall reaction yields (3 + 4) and products ratio (3 : 4) are collected in Table 2.

1-Phenyl-3-methoxycarbonyl-5-phenylpyrazole 3aa¹⁸. ¹H-NMR: 7.20.7.34 (m, 10H, aromatics), 7.06 (1H, s, pyrazole-H̲4), 3.98 (s, 3H, –COOCH₃); ¹³C-NMR: 162.8 (s, –COOCH₃), 144.6 (s, pyrazole C5), 143.9 (s, pyrazole C3), 139.4 (s, aromatic), 128.9 (d, aromatic CH), 128.7 (d, aromatic CH), 125.6 (d, aromatic CH), 109.8 (d, pyrazole C4), 52.0 (q, –COOCH₃). MS: 278 m/z (M⁺).

Methyl 4-phenyl-2-(2-phenylhydrazono)but-3-ynoate 4aa. White powder having mp 86–88 °C (from iPr₂O), IR (nujol): 3320 ([double bond splayed left]N–H), 1735 (ester [double bond splayed left]C=O) (cm⁻¹); ¹H-NMR: 8.55 (br s, 1H, –NH-Ph). 7.19–7.33 (m 10H, aromatics), 3.96 (s, 3H, s, –COOCH₃); ¹³C-NMR: 162.9 (s, –COOCH₃), 143.7 (s, aromatic, C–N), 139.5 (s, [double bond splayed left]C=N–), 135.9 (s, aromatic), 113.6–132.0 (aromatic CH), 103.8 (s, ≡C–), 78.8 (s, ≡C-Ph), 52.2 (q, –COOCH₃). MS 278 m/z (M⁺). Anal. calcd for C₁₇H₁₄N₂O₂: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.31; H, 5.11; N, 10.13.

1-Phenyl-3-(2-methoxy)phenyl-5-phenylpyrazole 3ba¹⁹. ¹H-NMR: 8.12 (d, 1H, J = 8.0, aromatic), 7.31–7.57 (m, 11H, aromatics), 7.09 (s, 1H, pyrazole H4), 7.05 (t, 2H, J = 8.5 Hz, aromatics), 3.97 (s, 3H, s, CH₃O–); ¹³C-NMR: 157.0 (s, aromatic ≥C-OMe), 149.0 (s, pyrazole C3), 143.4 (s, pyrazole C5), 140.3 (s, aromatic ≥C–N), 132.5 (s, aromatic), 131.0 (s, aromatic), 111.3–129.2 (aromatic CH), 109.4 (d, pyrazole C4), 55.5 (q, CH₃O–). MS 326 m/z (M⁺).

1-Phenyl-3-(2-methoxyphenyl)-3-phenylhydrazonopropyne 4ba. Pale yellow powder having mp 93–94 °C (from iPr₂O). IR (nujol): 3330 ([double bond splayed left]N–H), 1735 (ester [double bond splayed left]C=O) (cm⁻¹). ¹H-NMR: 8.96 (br s, 1H, –NH-Ph), 7.80 (d, 1H, J = 4.0 Hz, aromatic), 6.95–7.40 (m, 13H, aromatics), 3.97 (s, 3H, CH₃O–); ¹³C-NMR: 156.6 (s, aromatic ≥C-OMe), 151.6 (s, aromatic ≥C-N–), 141.6 (s, aromatic), 132.9 (s, [double bond splayed left]C=N–), 120.8–131.3 (aromatic CH), 119.6 (s, aromatic), 112.0 (d, aromatic), 106.3 (s, ≡C–), 78.0 (s, ≡C-Ph), 54.9 (q, CH₃O–). MS 326 m/z 326 (M⁺). Anal. calcd for C₂₂H₁₈N₂O₂: C, 80.96; H, 5.56; N, 8.58. Found: C, 81.03; H, 5.55 N, 8.64.

1,3,5-Triphenylpyrazole 3ca^3a. ¹H-NMR: 7.94–7.97 (m, 2H, aromatics), 7.28–7.46 (m, 13H, aromatics), 6.85 (s, 1H, pyrazole H4); ¹³C-NMR: 152.0 (s, pyrazole C3), 144.1 (s, pyrazole C5), 140.2 (s, pyrazole ≥C–N₁), 132.8 (s, aromatic), 130.7 (s, aromatic), 125.3–128.8 (aromatic CH), 105.2 (d, pyrazole C4). MS: 296 m/z (M⁺)

1,3-Diphenyl-3-phenylhydrazonopropyne 4ca¹¹. ¹H-NMR: 8.79 (1H, br s, –NH-Ph), 8.06 (d, 2H, J = 8.0 Hz, aromatics), 7.49 (t, 2H, t, J = 4.0 Hz, aromatics), 7.31–7.47 (m, 10H, aromatics), 7.00 (t, 1H, J = 8.0 Hz, aromatics); ¹³C-NMR: 143.7 (s, aromatic C–N), 139.5 (s, [double bond splayed left]C=N–), 135.9 (s, aromatic), 113.6–132.0 (d, aromatic CH), 103.8 (s, ≡C–), 79.0 (s, ≡C-Ph). MS: 296 m/z (M⁺).

Crystallisation of alkynylhydrazone 4aa in the presence of CuCl. Method a: in a 10 mL tube fitted with a vent needle, a solution of alkynylhydrazone 4aa (8 mg, 29 μmol) and CuCl (3 mg, 29 μmol) in MeCN (0.5 mL) was evaporated at 4 °C in 17 days.

Method b: in a 10 mL test tube fitted with a vent needle, a biphasic mixture of alkynylhydrazone 4aa (8 mg, 29 μmol) and CuCl (3 mg, 29 μmol) in MeCN (0.5 mL) and hexane (0.5 mL) was slowly evaporated at 4 °C in 28 days.

In both methods, the residue was a yellow-green solid of dusty appearance that was not suitable for X-ray analysis. ¹H NMR spectrum of the residue revealed the presence of pyrazole 3aa as the only product.

Author contributions

All authors designed the study. G. M. carried out the experiments and wrote the manuscript with contributions from A. P. and A. S. All authors discussed the results and commented on the manuscript. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Thanks are due to Dr Lara De Benassuti, University of Milan, who accomplished NMR spectra. G. M. was financially supported by the Department of Chemistry of the Università degli Studi di Milano (PSR2021_DIP_005).

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR of all new compounds, IR and MS spectra of deuterated chlorohydrazone D-1a. See DOI: https://doi.org/10.1039/d3nj02712k

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