Copper(I)-Catalysed Reaction of Hydrazonyl Chlorides with Homopropargylic Alcohols: Regioselective Synthesis of 5-Substituted Pyrazoles

In memory of Professor Geatano Zecchi. With admiration and gratitude, G.M. remembers his depth of thinking and immense knowledge of heterocyclic chemistry.

Abstract

Fully regioselective synthesis of 5-hydroxyethylpyrazoles was exploited by reacting hydrazonoyl chlorides with homopropargylic alcohols in the presence of catalytic amounts of copper(I) chloride. Good yields of pyrazolic products and mild reaction conditions were experienced notwithstanding the known, poor reactivity of homopropargylic alcohols towards hydrazonoyl chlorides. The role of copper(I) ion and some mechanistic insights for the formation of reaction products are also discussed.

Key words

hydrazonoyl chlorides - copper(I) catalysis - homopropargylic alcohols - pyrazoles - regioselective synthesis

The main feature of hydrazonoyl halide chemistry relies upon their dehydrohalogenation, which occurs easily in the presence of a base.[1] The result of dehydrohalogenation leads to the in situ generation of the corresponding nitril­imine –C≡N⁺–N^––, an unstable and generally non-isolable dipolar intermediate.[2]

Nitrilimine 1,3-dipolar cycloaddition to the C≡C bond represents one of the main methods for accessing the pyrazole ring[3] but, unfortunately, this reaction very often gives mixtures of regioisomeric pyrazole cycloadducts.[4] The poor regioselectivity of the reaction applies both to classical thermal cycloadditions according to Huisgen[5] and to those conducted in the presence of metal cations in stoichiometric or catalytic mode, which have been introduced more recently.[6]

Scheme 1 Literature approaches to 2-hydroxyethylpyrazoles (previous works)

Clearly, the regioselective synthesis of the pyrazole ring from hydrazonoyl chlorides in which the formation of the nitrilimine intermediate is avoided would be an important goal.

The limitation due to the lack of regioselectivity can be removed by reacting hydrazonoyl chlorides in the presence of catalytic amounts of suitable copper(I) salts. This methodology was recently developed by one of us[7] and it allows pyrazole products to be obtained as single 5-substituted regioisomers. This is an undoubtedly synthetic advantage that is the consequence of the reaction mechanism, which is well described by a catalytic cycle involving metallate intermediates.[7] [8]

Beyond the mechanistic features of the copper(I)-catalysed reaction between hydrazonoyl chlorides and terminal alkynes, the main interest in the synthesis of variously substituted pyrazoles lies in their pharmaco-clinical properties as analgesic, antifungal, anti-inflammatory, antibacterial, and antiviral agents.[9] Not by chance, hydrazonoyl halides have been defined as ‘a bubbling fountain of biologically active compounds’.[10]

The C≡C bond of homopropargylic alcohols represents a problematic dipolarophile in the field of nitrilimine 1,3-dipolar cycloadditions (Scheme [1]). In the presence of stoichiometric amounts of silver carbonate as the basic agent, the nitrilimine-alkyne reaction gave very low conversions to the desired 5-hydroxyethyl-substituted pyrazoles.[11] The meticulous study of this reaction revealed the loss of regioselectivity of the cycloaddition, which was also accompanied by the formation of a number of trivial by-products present in traces in the reaction mixture.[11]

An indirect cycloadditive approach involving hydrazonoyl bromides required harsh conditions and the use of furan both as the dipolarophile and the solvent, followed by catalytic hydrogenation and acidic hydrolysis of the corresponding furopyrazole.[12]

In the face of these serious difficulties associated with the cycloadditive approach, it is not surprising that access to 5-hydroxyethylpyrazoles was pursued in a completely different way, that is, by direct lithiation of the pyrazole ring and subsequent reaction with ethylene sulfate.[13]

The present paper involves the study of the behaviour of homopropargyl alcohols 1a,b towards hydrazonoyl chlorides 2a–g in the presence of catalytic amounts of copper(I) salts (Figure [1]).

Figure 1 Homopropargylic alcohols 1a,b and hydrazonoyl chlorides 2a–g used as reactants

Optimisation of the reaction conditions was conducted by examining the behaviour of hydrazonoyl chloride 2a towards 3-butyn-1-ol (1a) in the presence of a metal salt and an organic base. The results are shown in Table [1].

Table 1 Reaction between 3-Butyn-1-ol (1a) and Hydrazonoyl Chloride 2a

Entry	Metal salt (equiv.)	Base (equiv.)	Solvent	Temp (°C)	Time (h)	3aa Yield (%)a
1	–	Et3N (5)	toluene	100	4	17
2	–	Et3N (2)	toluene	20	24	__
3	Ag2CO3 (2)	–	MeCN	20	24	<5b
4	Ag2CO3 (2)	–	MeCN	80	4	17
5	CuCl (0.1)	DBU (1)	CH2Cl2	20	15	56c
6	CuCl (0.1)	Et3N (1)	toluene	20	1.5	35c
7	CuCl (0.1)	Et3N (1)	DMF	20	3	38c
8	CuCl (0.1)	Et3N (1)	MeCN	20	18	65c
9	CuCl (0.1)	Et3N (1)	acetone	20	18	37c
10	CuCl (0.1)	Et3N (1)	MTBE	20	18	35c
11	CuI (0.12)	Et3N (1)	CH2Cl2	20	18	55c
12	Cu2O (0.2)	Et3N (1)	CH2Cl2	20	18	60c
13	CuOAc (0.1)	Et3N (1)	CH2Cl2	20	18	37c
14	CuCl (0.05)	Et3N (1)	CH2Cl2	20	18	56c
15	CuCl (0.1)	Et3N (1)	CH2Cl2	20	18	79c

^a Isolated yields after silica gel column chromatography.

^b Obtained with other unidentified by-products.

^c Obtained with variable amounts of diyne 4a (5–35%).

By way of comparison with reactions catalysed by metal salts, the first entry in Table [1] shows the nitrilimine-alkyne reaction pursued in the classical conditions, giving the novel pyrazole 3aa and traces of its 4-(2-hydroxyethyl)-substituted isomer, not shown in the table, in a 9:1 ratio. Since the reaction between hydrazonoyl chloride 2a and 3-butyn-1-ol (1a) does not proceed after 24 hours at 20 °C (Table [1], entry 2), the generation of the nitrilimine intermediate under the same conditions for shorter reaction times can certainly be ruled out. From entry 3 of Table [1] it can be seen that, by stopping the reaction after 24 hours, the presence of silver salts in overstoichiometric amounts leads to the formation of small amounts of pyrazole 3aa. This result appears prima facie rather surprising considering that silver carbonate is capable of increasing the reactivity of hydrazonoyl chlorides towards both ethylenic[14] and allenic[15] dipolarophiles.

Regardless of the different nature of the unsaturated carbon counterpart, the mentioned transformations usually require reaction times well in excess of 24 hours. This uncomfortable picture changes radically by conducting the reaction in the presence of catalytic amounts of copper(I) salts (Table [1], entries 5–15). As can be seen, the best results were obtained using copper(I) chloride at 10 mol% in dichloromethane at 20 °C (entry 15). The influence of the solvent is difficult to consider. Poor results are related to an increased presence of the diyne by-product 4a, which is obtained both with solvents capable of exerting a complexing effect on the Cu⁺ cation (DMF, acetone) and with non-complexing solvents (toluene, MTBE). At this point, the optimised reaction conditions as shown in Table [1], entry 15, were extended to hydrazonoyl chlorides 2b–g and homopropargyl alcohols 1a,b.

All the reactions shown in Table [2] were completely regioselective, yielding pyrazoles 3 in 67–95% yields over 18–40 hours. Due to the presence of conjugated diynes 4 as by-products (5–15%, vide infra), isolation of pyrazoles 3 was pursued by chromatographic treatment on a silica gel column.

Table 2 Reaction between Homopropargylic Alcohols 1a,b and Hydrazonoyl Chlorides 2a–g

Entry	1	R1	2	R2	R3	Pyrazole	Time (h)	Yield (%)a,b
1	1a	H	2a	H	H	3aa	18	79
2	1a	H	2b	H	Me	3ab	18	72
3	1a	H	2c	H	OMe	3ac	19	81
4	1a	H	2d	H	Cl	3ad	18	85
5	1a	H	2e	H	Br	3ae	22	95
6	1a	H	2f	H	CN	3af	26	83
7	1a	H	2g	F	H	3ag	40	67
8	1b	Me	2a	H	H	3ba	18	73
9	1b	Me	2b	H	Me	3bb	18	77
10	1b	Me	2c	H	OMe	3bc	18	69
11	1b	Me	2d	H	Cl	3bd	18	81
12	1b	Me	2e	H	Br	3be	18	88
13	1b	Me	2f	H	CN	3bf	24	85
14	1b	Me	2g	F	H	3bg	36	79

^a Isolated yields after silica gel column.

^b Obtained with variable amounts of diynes 4a,b, which were separated by column chromatography (see Supporting Information).

By-products 4 arise from the Glaser oxidative dimerisation of the alkynylcuprates originating from the corres­ponding homopropargyl alcohols.[16] Since this side reaction competes with the nucleophilic addition of alkynylcuprate to the hydrazonoyl chloride, it proved impossible for us to suppress it. However, Glaser dimerisation was limited to 0–10% by conducting the reactions under nitrogen atmosphere (Scheme [2]).

In order to gain some mechanistic insights about the reaction between homopropargyl alcohols 1 and hydrazonoyl chlorides 2 in the presence of copper(I) salts, it is necessary to consider the reaction between phenylacetylene and hydrazonoyl chloride 2a. Under the same experimental conditions adopted for the homopropargyl alcohols, this latter reaction proceeds in only 35 minutes yielding pyrazole 5 in 88% yield (Scheme [3]).[7] The reaction time is thus very short compared to the analogous reaction with 3-butyn-1-ol. Furthermore, the diyne 6 was not formed as deduced from the ¹H NMR spectrum of the reaction crude.

Scheme 2 Competition between nucleophilic addition to hydrazonoyl chlorides 2 and the Glaser dimerisation of homopropargylic alcohols 1

Scheme 3 Reaction between phenylacetylene and hydrazonoyl chloride 2a [7]

Surprisingly, in the absence of hydrazonoyl chloride, alcohol 1a did not give the expected diyne 4a, although on addition of copper(I) chloride the bright yellow colouration assumed by the reaction mixture indicates that copper(I) acetylide had been formed. Even after 24 hours, chromatographic analysis showed no presence of the diyne 4a. Upon addition of a trace of hydrogen peroxide, however, its almost instantaneous and quantitative formation was realised, while the colour of the reaction mixture turned abruptly from bright yellow to dark green, suggesting a plausible change in the oxidation state of copper. By contrast, under the same reaction conditions the dimerisation of phenylacetylene is completed in 2 hours without the need to add hydrogen peroxide.

In a further experiment, the reaction between hydrazonoyl chloride 2a and tetrahydropyranyl ether 7, prepared as described in the literature,[17] was investigated. The behaviour of this transformation is quite similar to that observed in the case of phenylacetylene. In fact, pyrazole 8 was obtained in 90 minutes, and the corresponding by-product 9 was not detected (Scheme [4]). By contrast, diyne 9 was easily obtained by reacting tetrahydropyranyl ether 7 in the absence of the hydrazonoyl chloride.

Scheme 4 Reaction between tetrahydropyranyl ether 7 and hydrazonoyl chloride 2a

The above experimental facts could be rationalized by considering the involvement of a ‘ladderane’ polymeric structure of the copper(I) phenylacetylide, known in the literature since 2005 and obtained by powder diffraction experiments.[18] However, the involvement of such a complex structure was considered implausible for reactions carried out in solvent, and the intermediacy of dinuclear complex A was proposed (Figure [2]).[19]

Figure 2 Complexed intermediates proposed for phenylacetylene (A)[19] and 3-butyn-1-ol (B)

In the case of homopropargyl alcohols, intramolecular complexation of copper(I) by carbinol oxygen could be at work with the formation of intermediate B (Figure [2]). The distorted tetrahedral geometry around the two copper(I) atoms is consistent with that exhibited by some binuclear copper(I) complexes.[20]

Compared to the intermediate A, the involvement of the complexed one B is able to explain its lower reactivity towards: (i) the hydrazonoyl chlorides, since alcohols 1 react much more slowly than phenylacetylene and, for such prolonged reaction times, the competing reaction of oxidative dimerisation emerges; (ii) the Glaser dimerisation to 4, which for alcohols 1 occurs quickly only in the presence of traces of hydrogen peroxide as the oxidising agent.

If intramolecular complexation is prevented, as is the case of tetrahydropyranyl ether 7, the intervention of an A-like intermediate can be assumed. Similar to what is observed for phenylacetylene, the reaction towards hydrazonoyl chlorides is in fact rather fast and no diyne formation is observed.

In order to extend the applicability of the copper(I)-catalysed reaction between hydrazonoyl chlorides and alkynols, the behaviour of 4-pentyn-1-ol (10) was considered. Pyrazoles 11 and diyne 12 by-products were obtained in comparable yield to homopropargyl alcohols 1 (Table [3]).

As concluding remarks, the present synthetic approach to 5-hydroxyalkylpyrazole is superior to the nitrilimine-alkynol 1,3-dipolar cycloaddition despite the formation of conjugated diyne by-products. It also represents a viable alternative to the protocol based on the lithiation of the pre-formed pyrazole ring, since it does not require the use of low temperatures and hazardous reagents.

Table 3 Reaction between 4-Pentyn-1-ol (10) and Hydrazonoyl Chlorides 2a,b,d

Entry	2	R1	Pyrazole	Time (h)	Yield (%)a,b
1	2a	H	11a	18	77
2	2b	Me	11b	18	80
3	2d	Cl	11c	19	83

^a Isolated yields after silica gel column.

^b Obtained with variable amounts of the corresponding diyne 12 (4–8%, see experimental section).

Furthermore, the three-step sequence involving the protection of the alkynol as a tetrahydropyranyl ether, the subsequent copper(I)-catalysed reaction and the release of the unprotected pyrazole 3aa was also inferior in comparison with the direct alkynol-chlorohydrazone reaction. In fact, 5-hydroxyethyl-pyrazole 3aa was obtained in 79% yield with the direct reaction and 65% in the three-step sequence.

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 (400 MHz), ¹³C NMR (100 MHz), and ¹⁹F NMR (376 MHz) spectra were taken with a Bruker Avance instrument (in CDCl₃ solutions at r.t.). Chemical shifts are given as parts per million from TMS. Coupling constants (J) values are given in hertz (Hz) 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 Fluorochem Ltd. Solvents were dried and stored over 4Å molecular sieves prior to use.

Hydrazonoyl chlorides 2a,c,d,[21a] 2b,e,f,[21b] 2g,[21c] and tetrahydropyranyl ether 7 [17] were prepared according to literature procedures. Diynes 4a,[22a] 4b,[22b] 6,[22c] 12,[22d] and 9 [22e] are known in the literature.

Optimisation procedures listed in Table [1], chromatographic R_f values of pyrazoles 3 and 11, and the experimental details of diyne by-products 4 and 12 are provided in the Supporting Information.

Copper(I)-Catalysed Reaction between Acetylenic Alcohols 1a,b and 10 and Hydrazonoyl Chlorides 2a–g; General Procedure

To a clear, colourless solution of the appropriate acetylenic alcohol 1a,b, or 10 (2.0 mmol) and Et₃N (0.20 g, 2.0 mmol) in anhyd CH₂Cl₂ (4 mL) was added CuCl (10 mg, 0.1 mmol) under vigorous magnetic stirring. A solution of the appropriate hydrazonoyl chloride 2 (2.0 mmol) in anhyd CH₂Cl₂ (4 mL) was added dropwise and the mixture was stirred at 20 °C for the time indicated in Table [2]. The crude mixture was filtered over a Celite pad, which was washed with CH₂Cl₂ (3 × 5 mL). The solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column with CH₂Cl₂/MeOH (95:5). Earlier fractions contained pyrazole products. Crystallisation of the eluate from i-Pr₂O gave the pure pyrazole 3 or 11.

1-Phenyl-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3aa)

Yield: 389 mg (79%); pale yellow solid; mp 110–112 °C.

IR (Nujol): 3450, 1735 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.39 (m, 5 H, C₆H₅), 6.81 (s, 1 H, pyrazole-H4), 3.89 (s, 3 H, CO₂CH₃), 3.78 (t, J = 8.0 Hz, 2 H, CH ₂OH), 2.85 (t, J = 8.0 Hz, 2 H, CH₂), 2.61 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.9 (s, CO₂CH₃), 143.3 (s, pyrazole-C3), 142.5 (s, C_q of Ph attached to pyrazole-N1), 138.6 (s, pyrazole-C5), 129.1–125.8 (d, CH_arom), 108.2 (d, pyrazole-C4), 60.4 (t, CH₂OH), 51.9 (q, CO₂ CH₃), 29.1 (t, CH₂).

MS (EI): m/z = 246 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₃H₁₄N₂O₃: 247.1083; found: 247.1060.

Anal. Calcd for C₁₃H₁₄N₂O₃: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.44; H, 5.70; N, 11.43.

1-(4-Methylphenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3ab)

Yield: 374 mg (72%); pale yellow solid; mp 102–103 °C.

IR (Nujol): 3460, 1730 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.25 (m, 4 H_arom), 6.82 (s, 1 H, pyrazole-H4), 3.92 (s, 3 H, CO₂CH₃), 3.80 (t, J = 8.0 Hz, 2 H, CH ₂OH), 2.87 (t, J = 8.0 Hz, 2 H, CH₂), 2.41 (m, 4 H, overlapping of br s, 1 H, OH, and Ar-CH ₃).

¹³C NMR (100 MHz, CDCl₃): δ = 162.9 (s, CO₂CH₃), 143.3 (s, pyrazole-C3), 142.3 (s, C_q of Ar attached to C-pyrazole-N1), 139.2 (s, pyrazole-C5), 136.3 (s, C_q, ArCH₃), 129.7 (d, CH_arom), 125.7 (d, CH_arom), 108.2 (d, pyrazole-C4), 60.8 (t, CH₂OH), 52.0 (q, CO₂ CH₃), 29.3 (t, CH₂), 21.1 (q, ArCH₃).

MS (EI): m/z = 260 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆N₂O₃: 261.1239; found: 261.1247.

Anal. Calcd for C₁₄H₁₆N₂O₃: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.56; H, 6.17; N, 10.72.

1-(4-Methoxylphenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3ac)

Yield: 447 mg (81%); white solid; mp 112–114 °C.

IR (Nujol): 3435, 1735, 1255 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 8.0 Hz, 2 H_arom), 6.98 (d, J = 8.0 Hz, 2 H_arom), 6.84 (s, 1 H, pyrazole-H4), 3.93 (s, 3 H, CO₂CH₃), 3.86 (s, 3 H, OCH₃), 3.83 (t, J = 8.0 Hz, 2 H, CH ₂OH), 2.86 (t, J = 8.0 Hz, 2 H, CH₂), 2.31 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (s, CO₂CH₃), 159.9 (s, C_q, ArOCH₃), 143.2 (s, pyrazole-C3), 142.5 (s, C_q of Ar attached to pyrazole-N1), 131.7 (s, pyrazole-C5), 127.3 (d, CH_arom), 114.1 (d, CH_arom), 108.0 (d, pyrazole-C4), 60.6 (t, CH₂OH), 55.5 (q, OCH₃), 51.7 (q, CO₂ CH₃), 29.3 (t, CH₂).

MS (EI): m/z = 276 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆N₂O₄: 277.1188; found: 277.1172.

Anal. Calcd for C₁₄H₁₆N₂O₄: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.82; H, 5.81; N, 10.10.

1-(4-Chlorophenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3ad)

Yield: 476 mg (85%); pale yellow solid; mp 127–129 °C.

IR (Nujol): 3455, 1740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.38 (m, 4 H_arom), 6.82 (s, 1 H, pyrazole-H4), 3.91 (s, 3 H, CO₂CH₃), 3.83 (t, J = 8.0 Hz, 2 H, CH ₂OH), 2.86 (t, J = 8.0 Hz, 2 H, CH₂), 2.81 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.7 (s, CO₂CH₃), 143.6 (s, pyrazole-C3), 142.7 (s, C_q of Ar attached to pyrazole-N1), 137.1 (s, pyrazole-C5), 134.7 (s, C_q, ArCl), 129.3 (d, CH_arom), 127.1 (d, CH_arom), 108.4 (d, pyrazole-C4), 60.4 (t, CH₂OH), 52.0 (q, CO₂ CH₃), 23.3 (t, CH₂).

MS (EI): m/z = 280 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆N₂O₄: 281.0693; found: 281.0707.

Anal. Calcd for C₁₃H₁₃ClN₂O₃: C, 55.62; H, 4.67; N, 9.98. Found: C, 54.59; H, 4.63; N, 10.11.

1-(4-Bromophenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3ae)

Yield: 616 mg (95%); yellow solid; mp 109–113 °C.

IR (Nujol): 3455, 1735 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H_arom), 7.68 (d, J = 8.2 Hz, 2 H_arom), 6.88 (s, 1 H, pyrazole-H4), 3.93–3.90 (m, 5 H, overlapping of CO₂CH₃ and CH₂OH), 2.95 (t, J = 8.0 Hz, 2 H, CH₂), 2.32 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.7 (s, CO₂CH₃), 143.8 (s, pyrazole-C3), 142.6 (s, C_q of Ar attached to pyrazole-N1), 137.7 (s, pyrazole-C5), 132.2 (d, CH_arom), 127.4 (d, CH_arom), 122.8 (s, C_q, ArBr), 108.5 (d, pyrazole-C4), 60.8 (t, CH₂OH), 51.8 (q, CO₂ CH₃), 29.2 (t, CH₂).

MS (EI): m/z = 324 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₃H₁₄BrN₂O₃: 325.0188; found: 325.0171.

Anal. Calcd for C₁₃H₁₃BrN₂O₃: C, 48.02; H, 4.03; N, 8.62. Found: C, 47.98; H, 4.00; N, 8.66.

1-(4-Cyanophenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3af)

Yield: 450 mg (83%); white solid; mp 131–135 °C.

IR (Nujol): 3440, 2230, 1735 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 8.0 Hz, 2 H_arom), 7.69 (d, J = 8.0 Hz, 2 H_arom), 6.90 (s, 1 H, pyrazole-H4), 3.94 (s, 3 H, CO₂CH₃), 3.91 (t, J = 8.0 Hz, 2 H, CH ₂OH), 2.95 (t, J = 8.0 Hz, 2 H, CH₂), 2.82 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.5 (s, CO₂CH₃), 144.6 (s, pyrazole-C3), 143.0 (s, C_q of Ar attached to pyrazole-N1), 142.3 (s, pyrazole-C5), 133.1 (d, CH_arom), 126.2 (d, CH_arom), 117.7 (s, C≡N), 112.4 (s, C_q, ArCN), 109.2 (d, pyrazole-C4), 60.9 (t, CH₂OH), 52.1 (q, CO₂ CH₃), 29.3 (t, CH₂).

MS (EI): m/z = 271 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₄N₃O₃: 272.1035; found: 272.1019.

Anal. Calcd for C₁₄H₁₃N₃O₃: C, 61.99; H, 4.83; N, 15.49. Found: C, 62.03; H, 4.80; N, 15.44.

1-(2-Fluorophenyl)-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3ag)

Yield: 354 mg (67%); colourless solid; mp 92–93 °C.

IR (Nujol): 3450, 1735, 1490 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.21 (m, 4 H_arom), 6.85 (s, 1 H, pyrazole-H4), 3.92 (s, 3 H, CO₂CH₃), 3.80 (m, 2 H, CH ₂OH), 2.78 (t, J = 7.6 Hz, 2 H, CH₂), 2.22 (br s, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.7 (s, CO₂CH₃), 156.8 (d, ¹ J _C,F = 334 Hz, C_q, ArF), 144.4 (s, pyrazole-C3), 144.1 (s, pyrazole-C5), 131.4 (d, ³ J _C,F = 10 Hz, CH_arom), 129.4 (d, CH_arom), 126.6 (s, ² J _C,F = 17 Hz, C_q of Ar attached to pyrazole-N1), 124.7 (d, ³ J _C,F = 4 Hz, CH_arom), 116.5 (d, ² J _C,F = 26 Hz, CH_arom), 107.8 (d, pyrazole-C4), 60.2 (t, CH₂OH), 52.0 (q, CO₂ CH₃), 28.8 (t, CH₂).

¹⁹F NMR (376 MHz, CDCl₃): δ = –110.90.

MS (EI): m/z = 264 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₃H₁₄FN₂O₃: 265.0988; found: 265.0994.

Anal. Calcd for C₁₃H₁₃FN₂O₃: C, 59.09; H, 4.96; N, 10.60. Found: C, 59.05; H, 4.95; N, 10.64.

1-Phenyl-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3ba)

Yield: 380 mg (73%); white solid; mp 94–96 C.

IR (Nujol): 3450, 1740, 1490 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.42 (m, 5 H, C₆H₅), 6.87 (s, 1 H, pyrazole-H4), 4.05–3.95 (m, 1 H, CHOH), 3.92 (s, 3 H, CO₂CH₃), 2.83–2.73 (m, 2 H, CH₂), 2.17 (br s, 1 H, OH) 1.17 [d, J = 7.5 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (s, CO₂CH₃), 143.7 (s, pyrazole-C3), 142.5 (s, C_q of Ph attached to pyrazole-N1), 139.0 (s, pyrazole-C5), 129.2 (d, CH_arom), 129.0 (d, CH_arom), 126.2 (d, CH_arom), 108.8 (d, pyrazole-C4), 66.8 (d, CHOH), 52.0 (q, CO₂ CH₃), 35.5 (t, CH₂), 23.1 [q, CH(OH)CH₃].

MS (EI): m/z = 260 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₇N₂O₃: 261.1239; found: 261.1245.

Anal. Calcd for C₁₄H₁₆N₂O₃: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.63; H, 6.20; N, 10.80.

1-(4-Methylphenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3bb)

Yield: 422 mg (77%); white solid; mp 89–90 °C.

IR (Nujol): 3440, 1725 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.31 (d, J = 8.5 Hz, 2 H_arom), 7.26 (d, J = 8.5 Hz, 2 H_arom), 6.85 (s, 1 H, pyrazole-H4), 4.04–3.99 (m, 1 H, CHOH), 3.92 (s, 3 H, CO₂CH₃), 2.82–2.72 (m, 2 H, CH₂), 2.42 (s, 3 H, ArCH ₃), 2.06 (br s, 1 H, OH) 1.17 [d, J = 5.0 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (s, CO₂CH₃), 143.5 (s, pyrazole-C3), 142.5 (s, C_q of Ar attached to C-pyrazole-N1), 139.1 (s, pyrazole-C5), 136.5 (s, C_q, ArCH₃), 129.7 (d, CH_arom), 126.0 (d, CHarom), 108.7 (d, pyrazole-C4), 66.8 (d, CHOH), 52.0 (q, CO₂ CH₃), 35.5 (t, CH₂), 23.1 [q, CH(OH)CH₃], 21.2 (q, ArCH₃).

MS (EI): m/z = 274 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₉N₂O₃: 275.1396; found: 275.1382.

Anal. Calcd for C₁₅H₁₈N₂O₃: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.71; H, 6.64; N, 10.21.

1-(4-Methoxyphenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3bc)

Yield: 400 mg (69%); white solid; mp 99–102 °C.

IR (Nujol): 3440, 1725, 1255 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36 (d, J = 8.2 Hz, 2 H_arom), 6.99 (d, J = 8.2 Hz, 2 H_arom), 6.87 (s, 1 H, pyrazole-H4), 4.08–4.00 (m, 1 H, CHOH), 3.95 (s, 3 H, CO₂CH₃), 3.88 (s, 3 H, OCH₃), 2.79–2.77 (m, 2 H, CH₂), 1.84 (br s, 1 H, OH) 1.21 [d, J = 5.2 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (s, CO₂CH₃), 159.9 (s, C_q, ArOCH₃), 143.4 (s, pyrazole-C3), 142.5 (s, C_q of Ar attached to C-pyrazole-N1), 132.0 (s, pyrazole-C5), 127.6 (d, CH_arom), 114.3 (d, CH_arom), 108.5 (d, pyrazole-C4), 66.9 (d, CHOH), 55.6 (OCH₃), 52.0 (q, CO₂ CH₃), 35.5 (t, CH₂), 23.1 [q, CH(OH)CH₃].

MS (EI): m/z = 290 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₉N₂O₄: 291.1345; found: 291.1353.

Anal. Calcd for C₁₅H₁₈N₂O₄: C, 62.06; H, 6.25; N, 9.65. Found: C, 62.09; H, 6.23; N, 9.68.

1-(4-Chlorophenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3bd)

Yield: 475 mg (81%); pale yellow solid; mp 116–118 °C.

IR (Nujol): 3435, 1740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.37 (m, 4 H_arom), 6.81 (s, 1 H, pyrazole-H4), 4.03 (dd, J = 8.0, 5.2 Hz, 1 H, CHOH), 3.89 (s, 3 H, CO₂CH₃), 2.73 (d, J = 8.0 Hz, 2 H, CH₂), 2.46 (br s, 1 H, OH) 1.17 [d, J = 5.2 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 162.8 (s, CO₂CH₃), 143.8 (s, pyrazole-C3), 142.8 (s, C_q of Ar attached to pyrazole-N1), 137.4 (s, pyrazole-C5), 134.8 (s, C_q, ArCl), 129.4 (d, CH_arom), 127.4 (d, CH_arom), 109.0 (d, pyrazole-C4), 66.8 (d, CHOH), 52.1 (q, CO₂ CH₃), 35.4 (t, CH₂), 23.2 [q, CH(OH)CH₃].

MS (EI): m/z = 294 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆ClN₂O₃: 295.0849; found: 295.0833.

Anal. Calcd for C₁₄H₁₅ClN₂O₃: C, 57.05; H, 5.13; N, 9.50. Found: C, 57.09; H, 5.15; N, 9.56.

1-(4-Bromophenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3be)

Yield: 595 mg (88%); yellow solid; mp 121–123 °C.

IR (Nujol): 3440, 1730 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.2 Hz, 2 H_arom), 7.36 (d, J = 8.2 Hz, 2 H_arom), 6.86 (s, 1 H, pyrazole-H4), 4.03 (dd, J = 5.4, 5.0 Hz, 1 H, CHOH), 3.94 (s, 3 H, CO₂CH₃), 2.78 (d, J = 5.4 Hz, 2 H, CH₂), 2.16 (br s, 1 H, OH), 1.22 [d, J = 5.0 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 162.8 (s, CO₂CH₃), 144.0 (s, pyrazole-C3), 142.6 (s, C_q of Ar attached to C-pyrazole-N1), 138.0 (s, pyrazole-C5), 132.4 (d, CH_arom), 127.7 (d, CH_arom), 122.9 (s, C_q, ArBr), 109.0 (d, pyrazole-C4), 66.8 (d, CHOH), 52.1 (q, CO₂ CH₃), 35.4 (t, CH₂), 23.3 [q, CH(OH)CH ₃].

MS (EI): m/z = 338 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆BrN₂O₃: 339.0344; found: 339.0331.

Anal. Calcd for C₁₄H₁₅BrN₂O₃: C, 49.57; H, 4.46; N, 8.26. Found: C, 50.01; H, 4.44; N, 8.29.

1-(4-Cyanophenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3bf)

Yield: 485 mg (85%); pale yellow solid; mp 136–139 °C.

IR (Nujol): 3440, 2225, 1730 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.0 Hz, 2 H_arom), 7.69 (d, J = 8.0 Hz, 2 H_arom), 6.91 (s, 1 H, pyrazole-H4), 4.12 (dd, J = 5.2, 5.0 Hz, 1 H, CHOH), 3.94 (s, 3 H, CO₂CH₃), 2.84 (d, J = 5.2 Hz, 2 H, CH₂), 2.02 (br s, 1 H, OH), 1.26 [d, J = 5.0 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 162.6 (s, CO₂CH₃), 144.8 (s, pyrazole-C3), 142.9 (s, C_q of Ar attached to C-pyrazole-N1), 142.5 (s, pyrazole-C5), 133.2 (d, CH_arom), 126.6 (d, CH_arom), 117.8 (s, C≡N), 112.6 (s, C_q, ArCN), 109.7 (d, pyrazole-C4), 67.1 (d, CHOH), 52.2 (q, CO₂ CH₃), 35.4 (t, CH₂), 23.4 [q, CH(OH)CH₃].

MS (EI): m/z = 285 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₆N₃O₃: 286.1192; found: 286.1183.

Anal. Calcd for C₁₅H₁₅N₃O₃: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.11; H, 5.27; N, 14.78.

1-(2-Fluorophenyl)-3-methoxycarbonyl-5-(2-hydroxypropyl)pyrazole (3bg)

Yield: 439 mg (79%); pale yellow solid; mp 136–139 °C.

IR (Nujol): 3450, 1735, 1495 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.18 (m, 4 H_arom), 6.85 (s, 1 H, pyrazole-H4), 3.95 (m, 1 H, CHOH), 3.89 (s, 3 H, CO₂CH₃), 2.70–2.59 (m, 2 H, CH₂), 2.31 (br s, 1 H, OH), 1.11 [d, J = 5.2 Hz, 3 H, CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 162.5 (s, CO₂CH₃), 156.6 (d, ¹ J _C,F = 251 Hz, C_q, ArF), 144.0 (s, pyrazole-C3), 143.9 (s, pyrazole-C5), 131.1 (d, ³ J _C,F = 8 Hz, CH_arom), 129.2 (d, CH_arom), 126.4 (d, ² J _C,F = 12 Hz, C_q of Ar attached to pyrazole N1), 124.5 (d, ³ J _C,F = 4 Hz, CH_arom), 116.3 (d, ² J _C,F = 20 Hz, CH_arom), 108.0 (d, pyrazole-C4), 66.0 (d, CHOH), 51.7 (q, CO₂ CH₃), 34.7 (t, CH₂), 22.6 [q, CH(OH)CH ₃].

¹⁹F NMR (376 MHz, CDCl₃): δ = –110.78.

MS (EI): m/z = 278 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆FN₂O₃: 279.1145; found: 279.1167.

Anal. Calcd for C₁₄H₁₅FN₂O₃: C, 60.42; H, 5.43; N, 10.07. Found: C, 60.40; H, 5.38; N, 10.10.

1-Phenyl-3-methoxycarbonyl-5-(3-hydroxypropyl)pyrazole (11a)

Yield: 400 mg (77%); white solid; mp 83–85 °C.

IR (Nujol): 3440, 1745 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.46–7.40 (m, C₆H₅), 6.76 (s, 1 H, pyrazole-H4), 3.91 (s, 3 H, CO²CH₃), 3.59 (t, J = 6.1 Hz, 2 H, CH ₂OH), 2.72 (t, J = 8.2 Hz, 2 H, CH ₂CH₂CH₂OH), 2.16 (br s, 1 H, OH) 1.81 (dt, 2 H, J = 8.2, 6.1 Hz, CH₂CH ₂CH₂OH).

¹³C NMR (100 MHz, CDCl₃): δ = 163.1 (s, CO₂CH₃), 145.2 (s, pyrazole-C3), 143.5 (s, C_q of Ph attached to pyrazole-N1), 139.1 (s, pyrazole-C5), 129.2 (d, CH_arom), 128.9 (d, CH_arom), 125.8 (d, CH_arom), 107.0 (d, pyrazole-C4), 61.3 (t, CH₂OH), 52.0 (q, CO₂ CH₃), 31.2 (t,
CH₂ CH₂CH₂OH), 22.6 (t, CH₂CH₂CH₂OH).

MS (EI): m/z = 260 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₇N₂O₃: 261.1239; found: 261.1258.

Anal. Calcd for C₁₄H₁₆N₂O₃: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.63; H, 6.20; N, 10.80.

1-(4-Methylphenyl)-3-methoxycarbonyl-5-(3-hydroxypropyl)pyrazole (11b)

Yield: 438 mg (80%); white solid; mp 77–78 °C.

IR (Nujol): 3445, 1740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.24 (m, 4 H_arom), 6.75 (s, 1 H, pyrazole-H4), 3.92 (s, 3 H, CO₂CH₃), 3.60 (m, 2 H, CH ₂OH), 2.70 (t, J = 8.0 Hz, 2 H, CH ₂CH₂CH₂OH), 2.40 (s, 3 H, ArCH ₃), 2.13 (br s, 1 H, OH) 1.81 (t, J = 6.0 Hz, CH₂CH ₂CH₂OH).

¹³C NMR (100 MHz, CDCl₃): δ = 163.1 (s, CO₂CH₃), 145.2 (s, pyrazole-C3), 143.3 (s, C_q of Ar attached to pyrazole-N1), 139.0 (s, pyrazole-C5), 136.6 (s, C_q, ArCH₃), 129.8 (d, CH_arom), 125.7 (d, CH_arom), 107.8 (d, pyrazole-C4), 61.4 (t, CH₂OH), 52.0 (q, CO₂ CH₃), 31.3 (t,
CH₂ CH₂CH₂OH), 22.6 (t, CH₂CH₂CH₂OH).

MS (EI): m/z = 274 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₉N₂O₃: 275.1396; found: 275.1411.

Anal. Calcd for C₁₅H₁₈N₂O₃: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.71; H, 6.57; N, 10.26.

1-(4-Chlorophenyl)-3-methoxycarbonyl-5-(3-hydroxypropyl)pyrazole (11c)

Yield: 488 mg (77%); pale yellow solid; mp 95–97 °C.

IR (Nujol): 3440, 1730 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.39 (m, 4 H_arom), 6.78 (s, 1 H, pyrazole-H4), 3.93 (s, 3 H, CO₂CH₃), 3.65–3.62 (m, 2 H, CH ₂OH), 2.74 (t, J = 8.0 Hz, 2 H, CH ₂CH₂CH₂OH), 1.96 (br s, 1 H, OH) 1.88–1.81 (m, CH₂CH ₂CH₂OH).

¹³C NMR (100 MHz, CDCl₃): δ = 162.9 (s, CO₂CH₃), 145.3 (s, pyrazole-C3), 143.8 (s, C_q of Ar attached to pyrazole-N1), 137.5 (s, pyrazole-C5), 134.8 (C_q, ArCl), 129.4 (d, CH_arom), 127.0 (d, CH_arom), 108.1 (d, pyrazole-C4), 61.3 (t, CH₂OH), 52.1 (q, CO₂ CH₃), 31.1 (t, CH₂ CH₂CH₂OH), 22.6 (t, CH₂CH₂CH₂OH).

MS (EI): m/z = 294 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₆ClN₂O₃: 295.0849; found: 295.0823.

Anal. Calcd for C₁₄H₁₅ClN₂O₃: C, 57.05; H, 5.13; N, 9.50. Found: C, 57.02; H, 5.10; N, 9.55.

Further elution gave the diynes 4 or 12 (see Supporting Information).

Octa-3,5-diyn-1,8-diol (4a)

Undistillable oil.

¹H NMR (400 MHz, CDCl₃): δ = 3.77 (t, J = 6.0 Hz, 4 H, 2 × CH₂OH), 2.56 (t, J = 6.0 Hz, 4 H, 2 × CH₂), 1.83 (br s, 2 H, 2 × OH).

¹³C NMR (100 MHz, CDCl₃): δ = 74.7 (s, C≡), 66.8 (s, ≡CCH₂), 60.8 (t, CH₂OH), 23.6 (t, CH₂).

MS (EI): m/z = 138 [M⁺].

Anal. Calcd for C₈H₁₀O₂: C, 69.54; H, 7.30. Found: C, 69.58; H, 7.33.

Deca-4,6-diyn-2,9-diol (4b)

Undistillable oil.

¹H NMR (400 MHz, CDCl₃): δ = 4.00–3.94 (m, 2 H, 2 × CHOH), 2.44 (d, J = 8.0 Hz, 4 H, 2 × CH₂), 2.39 (br s, 2 H, 2 × OH), 1.28 [d, J = 8.0 Hz, 6 H, 2 × CH(OH)CH ₃].

¹³C NMR (100 MHz, CDCl₃): δ = 74.4 (s, C≡), 67.3 (s, ≡CCH₂), 66.3 (d, CHOH), 29.7 (t, CH₂), 22.5 [q, CH(OH)CH₃].

MS (EI): m/z = 166 [M⁺].

Anal. Calcd for C₁₀H₁₄O₂: C, 72.26; H, 8.49. Found: C, 72.30; H, 8.44.

Deca-4,6-diyn-1,10-diol (12)

Undistillable oil.

¹H NMR (400 MHz, CDCl₃): δ = 3.75 (t, J = 6.2 Hz, 4 H, 2 × CH₂OH), 2.40 (t, J = 8.1 Hz, 4 H, 2 × ≡C-CH₂), 2.02 (br s, 2 H, 2 × OH), 1.79 (dt, J = 8.1, 6.2 Hz, 4 H, CH₂CH₂OH).

¹³C NMR (100 MHz, CDCl₃): δ = 76.9 (s, C≡), 65.7 (s, ≡CCH₂), 61.3 (t, CH₂OH), 31.0 (t, ≡CCH₂), 15.7 (t, 2 × CH ₂CH₂OH).

MS (EI): m/z = 166 [M⁺].

Anal. Calcd for C₁₀H₁₄O₂: C, 72.26; H, 8.49. Found: C, 72.21; H, 8.54.

Copper(I)-Catalysed Reaction between Tetrahydropyranyl Ether 7 and Hydrazonoyl Chloride 2a; 1-Phenyl-3-methoxycarbonyl-5-[2-(2-tetrahydropyrano)oxyethyl]pyrazole (8)

To a clear, colourless solution of tetrahydropyranyl ether 7 [17] (0.31 g, 2.0 mmol) and Et₃N (0.20 g, 2.0 mmol) in anhyd CH₂Cl₂ (4 mL) was added CuCl (10 mg, 0.1 mmol) under vigorous magnetic stirring at 20 °C. A solution of hydrazonoyl chloride 2a (0.42 g, 2.0 mmol) in anhyd CH₂Cl₂ (4 mL) was added dropwise and the mixture was stirred at 20 °C for the time indicated in Table [2]. The crude was filtered over a Celite pad, which was washed with CH₂Cl₂ (3 × 5 mL). The solvent was evaporated under reduced pressure to give 8; yield: 500 mg (76%); thick, undistillable oil.

IR (Nujol): 3440 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.45 (m, 5 H, C₆H₅), 6.87 (s, 1 H, pyrazole-H4), 4.56 (m, 1 H, OCHO), 3.97–3.94 (m, 1 H, tetrahydropyranyl OCH₂), 3.93 (s, 3 H, CO₂CH₃), 3.73 (t, J = 8.0 Hz, 1 H, pyrazole CH₂O), 3.60 (dt, J = 8.0, 6.2 Hz, 1 H, tetrahydropyranyl OCH₂), 3.47 (m, 1 H, pyrazole CH₂O), 2.95 (t, J = 8.0 Hz, 2 H, CH ₂CH₂OTHP), 1.77–1.48 (m, 6 H, tetrahydropyranyl CH₂CH₂CH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (s, CO₂CH₃), 143.7 (s, pyrazole-C3), 142.8 (s, C_q of Ph attached to pyrazole-N1), 139.1 (s, pyrazole-C5), 129.1 (d, CH_arom), 128.9 (d, CH_arom), 126.1 (d, CHarom), 108.5 (d, pyrazole-C4), 98.9 (d, OCHO), 65.7 (t, tetrahydropyranyl OCH₂), 62.2 (t, pyrazole CH₂O), 52.0 (q, CO₂ CH₃), 30.5 (t, CH₂CH₂OTHP), 26.9 (t, tetrahydropyranyl CH₂), 25.3 (t, tetrahydropyranyl CH₂), 19.4 (t, tetrahydropyranyl CH₂).

MS (EI): m/z = 330 [M⁺].

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₈H₂₂N₂O₄: 331.1658; found: 331.1631.

Anal. Calcd for C₁₈H₂₂N₂O₄: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.49; H, 6.77; N, 8.40.

Acidic Cleavage of (Tetrahydropyrano)oxyethylpyrazole 8; 1-Phenyl-3-methoxycarbonyl-5-(2-hydroxyethyl)pyrazole (3aa)

A solution of 8 (330 mg, 1 mmol) in AcOH/THF/H₂O (4:2:1, 3 mL) was stirred at 50 °C for 4 h. The solvent was evaporated in vacuo giving a light-brown oily residue that was taken up with CH₂Cl₂ (10 mL). The clear solution was washed with 5% aq NaHCO₃ (2 × 3 mL) and H₂O (2 × 3 mL). The organic layer was dried (Na₂SO₄) and filtered over a silica gel pad with CH₂Cl₂/MeOH (95:5) to afford the pyrazole 3aa; yield: 216 mg (88%).

Glaser-Type Dimerisation of 3-Butyn-1-ol (1a); Octa-3,5-diyn-1,8-diol (4a)

A solution of 3-butyn-1-ol (1a; 0.28 g, 4.0 mmol) and Et₃N (0.40 g, 4.0 mmol) in anhyd CH₂Cl₂ (8 mL) was treated with CuCl (20 mg, 0.2 mmol) under vigorous magnetic stirring and air bubbling at 20 °C. After 24 h, the TLC analysis of the bright yellow suspension did not show the presence of any product. Aq 30% H₂O₂ (5 μL, 49 μmol) was added, and the resulting dark-green mixture was filtered over a Celite pad, which was washed with CH₂Cl₂ (3 × 5 mL). Evaporation of the solvent under reduced pressure gave octa-3,5-diyn-1,8-diol (4a); yield: 248 mg (90%).

Glaser-Type Dimerisation of Tetrahydropyranylether 7; Octa-3,5-diyn-1,8-diol Bis-Tetrahydropyranyl Ether (9)

A solution of tetrahydropyranyl ether 7 [17] (0.62 g, 4.0 mmol) and Et₃N (0.40 g, 4.0 mmol) in anhyd CH₂Cl₂ (8 mL) was treated with CuCl (20 mg, 0.2 mmol) under vigorous magnetic stirring for 5 h at 20 °C. The crude mixture was filtered over a Celite pad, which was washed with CH₂Cl₂ (3 × 5 mL), and the solvent was removed under reduced pressure to give 9; yield: 529 mg (87%); mixture of unseparable racemic diastereoisomers; thick, undistillable oil.

¹H NMR (400 MHz, CDCl₃): δ = 4.65 (t, J = 4.0 Hz, 2 H, 2 × OCHO), 3.83 (td, J = 10.0, 7.0 Hz, 4 H, 2 × OCH ₂CH₂), 3.55 (ddd, J = 10.0, 3.5, 2.5 Hz, 4 H, 2 × CH ₂OTHP), 2.56 (t, J = 7.5 Hz, 2 H, ≡CCH₂), 2.50 (t, J = 7.5 Hz, 2 H, ≡CCH₂), 1.51–1.85 (m, 12 H, CH₂CH₂CH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 98.9 (d, OCHO), 74.5 (s, C≡), 69.2 (s, ≡CCH₂), 65.2 (t, CH₂OTHP), 62.2 (t, OCH₂CH₂), 30.5 (t, ≡CCH₂), 25.4 (t, THPCH₂), 20.7 (t, THPCH₂), 19.3 (t, THPCH₂).

MS (EI): m/z = 306 [M⁺, 73%].

Anal. Calcd for C₁₈H₂₆O₄: C, 70.56; H, 8.55. Found: C, 70.61; H, 8.50.

No conflict of interest has been declared by the author(s).

• References

• 1 Shawali AS, Párkányi C. J. Heterocycl. Chem. 1980; 17: 833
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Publication History

Received: 07 October 2022

Accepted after revision: 14 November 2022

Article published online:
28 November 2022