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Synthesis
DOI: 10.1055/s-0043-1773546
paper

Pyrazol-3-yldiazonium Salts as Key Reagents for C–C Bond Formation and Pyrazole-Containing Heterocycle Synthesis

Oksana V. Barabash
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine
,
Mary Y. Ostapiuk
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine
,
Mykola Kravets
b   Institute of Physical Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
,
Mykola D. Obushak
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine
,
Andreas Schmidt  ∗
c   Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
,
Yurii V. Ostapiuk∗
a   Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya Str. 6, 79005 Lviv, Ukraine
› Author Affiliations

This work was supported in part by the Simons Foundation (Award Number: 00014574) and by the Ministry of Education and Science of Ukraine, for which we would like to express our sincere thanks.
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Abstract

A novel application of 1-methylpyrazol-3-yldiazonium salts in the Meerwein reaction was introduced. These diazonium salts reacted with α,β-unsaturated functionalized compounds under Meerwein reaction conditions to yield pyrazole-containing building blocks, which subsequently allowed cyclization reactions with bisnucleophiles for the synthesis of pyrazol-3-yl-containing heterocyclic systems. In this way, pyrazole-containing heterocyclic compounds with 2-aminothiazole, 2-aminoselenazole, thiazolidin-4-one, selenazolidin-4-one, 3-hydroxythiophene, and 3-aminothiophene rings were efficiently prepared.


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Key words

3-aminopyrazoles - pyrazolyldiazonium salts - Meerwein reaction - thiazoles - selenazoles - thiophenes - C–C bond formation

Undoubtedly, pyrazoles[1] belong to the most important heterocyclic compounds, as pyrazole derivatives have found numerous applications as biologically active compounds or as partial structures of new materials.[2] [3] [4] Thus, pyrazoles proved to be active as antimalarial,[5] anti-tumor (Crizotinib, Ruxolitinib),[6–8] anti-inflammatory,[9] analgetic (Celecoxib, Difenamizole),[6] and antifungal compounds,[10] [11] insecticides (Penthiopyrad),[12] [13] and antibacterials.[14] Concerning materials chemistry, chemosensors,[15] dyes,[16] thermally stable energetic materials,[17] as well as fluorescent compounds[18] on the basis of pyrazole derivatives have been described.

Among the substituted pyrazoles, compounds linked to the 3-position of the pyrazole have recently attracted considerable attention.[4] [5] [6] , [8] , [9] [10] [11] [12] [13] [14] [15] , [18b] The formation or introduction of the 3-pyrazolyl moiety into the target molecule can be realized by the formation of one, two, or three bonds from a suitable starting materials by cyclizative condensations, cycloadditions, or functionalization of an existing pyrazole ring (Scheme [1]). Typically, 3-substituted pyrazoles are obtained by two-component reactions from 1,3-dicarbonyl compounds I [19] or their synthetic equivalents II and III [10] [11] [20] with hydrazines. Other approaches include modification of the existing pyrazole ring and starting from 3-pyrazolylboronic acids IV in Suzuki–Miyaura couplings,[21] [22] or from 3-halopyrazoles V in Sonogashira[23] or Suzuki[24] couplings.

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Scheme 1 C–C bond formations to C3 of pyrazole

Also, 3-halopyrazoles are precursors for the preparation of organolithium compounds,[25] [26] Grignard reagents,[26] and organostannanes[27] as intermediates VI for the introduction of substituents onto the 3-position of the pyrazole (Scheme [1]). Only few syntheses of N1-substituted pyrazoles possessing carbon substituents in position 3 have been described that use 3-halopyrazoles V in Ni-catalyzed cross couplings,[28] whereas they have been prepared by cycloadditions of hydrazones with dimethyl acetylenedicarboxylate VII,[29] or are available by N-alkylation of 1H-pyrazoles VIII.[30] Interestingly, even 3-halopyrazoles are mostly obtained from the corresponding 3-aminopyrazoles, pyrazol-3-ones, or pyrazol-3-yllithium compounds. However, the direct use of 3-aminopyrazoles or the corresponding pyrazol-3-yldiazonium salts for the formation of a C–C bond at the 3-position of the pyrazole cycle has not been previously described to our knowledge, although the methods described above have serious drawbacks. First, they are limited to suitable and accessible precursors, in particular functionalized acyclic building blocks or pyrazolylboronates, or expensive catalysts. For example, there is very limited possibility to functionalize 1,3-dicarbonyl compounds or their synthetic equivalents to obtain functionalized pyrazoles. Second, these methods are not suitable for introducing polyfunctional substituents on the 3-position of the pyrazole, which are useful for the construction of other heterocycles.

The Meerwein reaction can overcome these difficulties. It enables the preparation of arene-containing building blocks[31] [32] that are suitable precursors for the design of various heterocycles. In our previous work, we described the synthesis of some heterocycles, such as thiazole and thiophene derivatives, via the arylation of α,β-unsaturated functionalized compounds under Meerwein conditions.[33–36] In the present case, 3-pyrazolyldiazonium salts, which are formed from 3-aminopyrazoles as precursors, enable the preparation of pyrazol-3-yl-substituted bifunctional compounds that are suitable for use in heterocyclization reactions (Scheme [1]). Although 1H-pyrazol-3(5)-yldiazonium salts have been used for syntheses before,[37] 1-substituted-3-pyrazolyldiazonium salts have not yet been well examined. According to a recent literature research, only a few articles describe their use in Sandmeyer reactions, azo couplings, phenol O-arylations, aryl-/hetaryl sulfonylation reactions, and the synthesis of pyrazolylsulfinylamines.[25] , [38] [39] [40] [41] [42] However, pyrazolyldiazonium salts have apparently not been described in Meerwein reactions before. In continuation of our studies,[33] [34] [35] [36] , [38] we report here the preparation of pyrazol-3-yl derivatives of thiazoles, selenazole, selenazolone, and thiophene, which are obtained in two steps from functionalized α,β-unsaturated compounds and 3-pyrazolyldiazonium salts. The first Meerwein reactions described here using pyrazolyldiazonium salts can overcome the disadvantages of the previously described, often costly and complicated syntheses and expand the synthetic accessibility of substituted pyrazoles.

We began our investigation by reacting 1-methylpyrazol-3-yldiazonium bromide with methyl vinyl ketone in the presence of copper(II) bromide. It turned out that 1-methylpyrazol-3-yldiazonium bromide is easy to prepare and suitable for further conversions. First, aminopyrazole 1a was added to an aqueous solution of hydrogen bromide (Scheme [2]). After the solution had cooled to –5 °C, sodium nitrite was added to the resulting pyrazolyl ammonium bromide. After 5 minutes in the temperature range of –5 to 0 °C, the resulting 1-methylpyrazol-3-yldiazonium bromide (2a) was treated without prior isolation with methyl vinyl ketone (3a) in acetone in the presence of copper(II) bromide. The mixture was then vigorously stirred until no more nitrogen was evolved. The resulting ketone 4a was extracted from the reaction mixture with dichloromethane and distilled under reduced pressure (0.2 torr). The desired product 4a was obtained in 75% yield (Scheme [2]).

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Scheme 2 Meerwein arylation of functionalized ethenes 3a–e with pyrazol-3-yldiazonium salts

Diazonium bromide 2b was also easily synthesized from pyrazole 1b and reacted efficiently with methyl vinyl ketone in the presence of Cu2+ to form pyrazole 4b in 72% yield (Scheme [2]). Under analogous conditions, the bromopyrazolation of other functionalized unsaturated compounds 3b–e with diazonium bromides 2a,b was continued. The resulting compounds 5a–8b were purified by distillation under reduced pressure (0.2–0.5 torr). Distillation under slightly higher pressure (~2–5 torr) resulted in partial decomposition of the product and the formation of a resinous residue. The use of 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-3-diazonium bromide (2b) in the bromopyrazolylation reaction of α,β-unsaturated functionalized compounds should lead to the formation of tetrahydropyrano[4,3-c]pyrazoles 9,[43] but this was not achieved. The structures of the synthesized compounds and the yields are shown in Scheme [2].

We also carried out a thiocyanate arylation of methyl vinyl ketone (3a) using the methodology described above to give the thiocyanate ketones 11a,b (Scheme [2]). This reaction was carried out with diazonium tetrafluoroborates 10a,b with methyl vinyl ketone 3a and ammonium thiocyanate in acetone/water (1:1) in the presence of Cu(OAc)2 (0.5 mol%). The required pyrazol-3-yldiazonium tetrafluoroborates 10a,b were synthesized in situ from aminopyrazoles 1a,b and used without further purification.

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Scheme 3 Synthesis of 3-(1-methylpyrazol-3-yl)acrylic acids and their nitriles

Since pyrano[4,3-c]pyrazoles 9 are not formed in the bromopyrazolization reaction, we tried to obtain them by treating products 5b and 6b with a solution of KOH, varying the reaction conditions.[43] However, both temperatures of 0 °C and heating at reflux, with variation of the solvent (alcohol, alcohol–water, aqueous dioxane, THF, methanol), only resulted in HBr cleavage to give 3-(pyrazol-3-yl)acrylic acids 12b and 13b (Scheme [3]). Neither chloropyrazolation of 2c of methyl acrylate nor subsequent treatment of the product 5c with KOH solution yielded a tetrahydropyran. The reaction of 5a and 6a with KOH proceeded similarly, forming 12a and 13a respectively. In all cases, the reaction with the base is exothermic and proceeds very rapidly with the cleavage of hydrogen halide, which is probably due to the formation of a thermodynamically favorable conjugated system in compounds 12 and 13. According to the 1H NMR data, elimination of the hydrogen halide mainly leads to the formation of the E isomer, and only compound 13a is formed as a mixture of E and Z isomers (7:3).

We then investigated the synthetic potential of the products obtained in this way for the construction of more complex heterocyclic systems. Firstly, the reaction of 4a,b with thiourea or selenourea yielded the aminothiazoles 14a,b and the 2-aminoselenazoles 15a,b in good yields (Scheme [4]). Thiazolidin-4-ones and selenazolidin-4-ones were also obtained in a similar way by the reaction of α-bromoesters 5a,b with thiourea or selenourea, respectively. Thus, we also obtained thiazolidin-4-ones 16a,b and selenazolidin-4-ones 17a,b as hydrobromides, which crystallized from the reaction mixture when cooled or even while still hot.

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Scheme 4 Syntheses of 2-aminothia(selena)zoles and thia(selena)zolidinones

Further, we subjected nitriles 7 and propanoates 8 to a reaction with thiols 18a,b in the presence of sodium alcoholate in alcohol (Scheme [5]). For compounds 7a and 8a, the reaction with 18a or 18b in methanol in the presence of sodium methylate as a base proceeded smoothly within one hour and yielded the corresponding substituted 3-aminothiophenes 19a or 20a and 3-hydroxythiophenes 21a or 22a. At the same time, the reaction in methanol of compounds 7b and 8b can obviously lead to the transesterification of the ester group at the 4-position of the pyrazole ring.

When nitrile 7b was reacted with ethylthioglycolate (18c) in ethanol, hydrolysis of the ester group in the pyrazole ring and the formation of a mixture of diester 19b and monoester 19c were observed (Scheme [5]). When 7b was reacted with 18b in ethanol in the presence of sodium ethylate, only acid 20b was isolated. On the other hand, the reaction of 7b with 18a or 18b in methanol led to the formation of methyl esters 19d and 20c in good yields as a result of transesterification. The interaction of compound 8b with 18c in ethanol went smoothly to give diethyl ester 21b, but an undesired polymeric material was observed during the interaction of 8b with 18b in an ethanol medium.

At the same time, the reaction of 8b with 18b in methanol yielded methyl ester 22b in good yield (Scheme [5]). It was found that the reaction in the presence of a carboxy group in position 4 of the pyrazole ring yielded poorer yields. Therefore, 3-aminothiophenes and 3-hydroxythiophenes 19a–22b were prepared as stable compounds in moderate to good yields, differing in their substituents at the C2 position and bearing 3-pyrazolyl substituents at the C5 position of the thiophene ring (Scheme [5]).

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Scheme 5 Formation of 3-amino- and 3-hydroxy-5-(pyrazolyl)thiophenes

Additionally, we analyzed the synthetic potential of thiocyanates 11 (Scheme [6]). Thus, we synthesized 2-aminothiazole derivatives with two pyrazole fragments 23, by the interaction of thiocyanato ketones 11a,b with aminopyrazole 1a, and pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-ones 24, by the interaction with aminopyrazole 1b. Since products 23a,b did not crystallize after separation from the reaction mixture, we converted them into their hydrochlorides by the action of an excess of concentrated hydrochloric acid. Yields are presented in Scheme [6]. It is worth noting that substituted N-(pyrazol-3-yl)thiazol-2-amines were identified as antimicrobial and antitrypanosomiasis agents,[44] [45] and derivatives of pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one were found to possess anticancer activities.[46]

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Scheme 6 Cyclization reaction of α-thiocyanato ketones 11 with 3-amino-1-methylpyrazoles 1a and 1b

In summary, we have described the first general method for using the pyrazol-3-yldiazonium salts in the Meerwein­ reaction for the synthesis of difunctional compounds that are suitable building blocks for the preparation of pyrazole-containing derivatives of thiazole, selenazole, and thiophene. A wide range of starting materials, including both aminopyrazoles and unsaturated compounds, allowed us to achieve structural diversity in the 3-position of the pyrazole ring that had not yet been accessible by other routes. Thus, our method provides a smooth and straightforward route to 5-pyrazol-3-ylmethylene-substituted 2-aminothiazoles, 2-aminoselenazoles, thiazolidin-4-ones, and selenazolidin-4-ones, as well as 5-pyrazol-3-yl-substituted 3-aminothiophenes and 3-hydroxythiophenes.

Commercially available reagents and solvents were purchased from Acros, J&K, and TCI and used without further purification unless stated otherwise. TLC was performed on 60 F254 silica-coated aluminum plates from Merck and visualized by using UV light. Melting points are uncorrected and were determined in an apparatus according to Dr. Tottoli (Büchi). The ATR-IR spectra were obtained on a Shimadzu IRSpirit-T in the range of 400 to 4000 cm–1. 1H and 13C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer (400 MHz for 1H, 101 MHz for 13C). Signal orientations in DEPT experiments were described as follows: o = no signal;+ = up (CH, CH3); – = down (CH2). The ESI mass spectra were measured on a Bruker Impact II mass spectrometer, spraying the samples from MeCN. Yields are not optimized.


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3-(2-Bromoalkyl)-Substituted 1-Methyl-1H-pyrazoles 4–8; General Procedure

The appropriate 3-amino-1-methylpyrazole 1 (20 mmol, 1.0 equiv) was added to 46% aq HBr (5.1 mL, 42 mmol, 1.1 equiv). The mixture was then cooled to –5 °C, and sat. aq NaNO2 (1.45 g, 21 mmol, 1.05 equiv) was added dropwise at such rate that the temperature did not exceed 5 °C. Then, a cold solution of freshly prepared diazonium salt 2 was added dropwise under vigorous stirring to a mixture of acetone (20 mL), CuBr2 (20 mg, 0.09 mmol), and functionalized alkene 3 (20 mmol, 1.0 equiv). Then the mixture was stirred at 20 °C until nitrogen no longer evolved. After that, H2O (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The combined organic extracts were dried over MgSO4 and evaporated, and the residue was distilled under reduced pressure.


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3-Bromo-4-(1-methyl-1H-pyrazol-3-yl)butan-2-one (4a)

Yield: 3.468 g (75%); white crystalline solid; bp 92–95 °C/0.2 torr; mp 42–43 °C.

IR (ATR): 1712 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.56 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.09 (d, J = 2.2 Hz, 1 H, H-pyrazole), 4.87 (t, J = 7.4 Hz, 1 H, CH), 3.75 (s, 3 H, CH3), 3.32 (dd, J = 15.3, 7.2 Hz, 1 H, CH2), 3.07 (dd, J = 15.3, 7.6 Hz, 1 H, CH2), 2.31 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 201.3, 147.3, 131.4, 104.5, 52.4, 38.3, 32.0, 26.6.

MS (ESI): m/z = 231.0 [M + H]+.

Anal. Calcd for C8H11BrN2O: C, 41.58; H, 4.80; N, 12.12. Found: C, 41.47; H, 7.72; N, 12.07.


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Ethyl 3-(2-Bromo-3-oxobutyl)-1-methyl-1H-pyrazole-4-carboxylate (4b)

Yield: 4.367 g (72%); white crystalline solid; bp 164–165 °C/0.4 torr; mp 75–76 °C.

IR (ATR): 1698 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H, H-pyrazole), 4.94 (t, J = 7.4 Hz, 1 H,), 4.20 (q, J = 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H, CH3), 3.52 (dd, J = 15.7, 7.3 Hz, 1 H, CH2), 3.39 (dd, J = 15.7, 7.5 Hz, 1 H, CH2), 2.34 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 201.2 (o), 162.6 (o), 149.4 (o), 135.54 (+), 110.9 (o), 59.6 (–), 51.1 (+), 38.7 (+), 31.2 (–), 26.5 (+), 14.2 (+).

MS (ESI): m/z = 303.0 [M + H]+.

Anal. Calcd for C11H15BrN2O3: C, 43.58; H, 4.99; N, 9.24. Found: C, 43.52; H, 4.89; N, 9.20.


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Methyl 2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)propanoate (5a)

Yield: 3.414 g (69%); light-yellow oil; bp 105–107 °C/0.5 torr.

IR (ATR): 1738 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.56 (d, J = 2.0 Hz, 1 H, H-pyrazole), 6.09 (d, J = 2.1 Hz, 1 H, H-pyrazole), 4.70 (t, J = 7.6 Hz, 1 H, CH), 3.75 (s, 3 H, CH3), 3.69 (s, 3 H, CH3), 3.36 (dd, J = 15.0, 8.0 Hz, 1 H, CH2), 3.14 (dd, J = 15.0, 7.1 Hz, 1 H, CH2).

13C NMR (101 MHz, DMSO-d 6): δ = 169.6, 146.9, 131.4, 104.4, 52.7, 44.3, 38.3, 33.6.

MS (ESI): m/z = 247.0 [M + H]+.

Anal. Calcd for C8H11BrN2O2: C, 38.89; H, 4.49; N, 11.34. Found: C, 38.80; H, 4.43; N, 11.24.


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Ethyl 3-(2-Bromo-3-methoxy-3-oxopropyl)-1-methyl-1H-pyrazole-4-carboxylate (5b)

Yield: 4.022 g (63%); light-yellow oil; bp 158–159 °C/0.4 torr.

IR (ATR): 1741 (C=O), 1702 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.22 (s, 1 H, H-pyrazole), 4.80 (t, J = 7.5 Hz, 1 H, CH), 4.20 (q, J = 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H, CH3), 3.69 (s, 3 H, CH3), 3.56 (dd, J = 15.4, 7.7 Hz, 1 H, CH2-pyrazole), 3.43 (dd, J = 15.4, 7.4 Hz, 1 H, CH2-pyrazole), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 169.5, 162.6, 148.9, 135.6, 110.9, 59.6, 52.8, 43.2, 38.7, 32.8, 14.2.

MS (ESI): m/z = 319.0 [M + H]+.

Anal. Calcd for C11H15BrN2O4: C, 41.40; H, 4.74; N, 8.78. Found: C, 41.35; H, 4.66; N, 8.68.


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2-Bromo-3-(1-methyl-1H-pyrazol-3-yl)propanenitrile (6a)

Yield: 3.169 g (74%); light-yellow oil; bp 105–107 °C/0.25 torr.

IR (ATR): 2243 (CN) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.63 (d, J = 2.2 Hz, 1 H, H-pyrazole), 6.22 (d, J = 2.2 Hz, 1 H, H-pyrazole), 5.30 (dd, J = 7.6, 6.9 Hz, 1 H, CH), 3.80 (s, 3 H, CH3), 3.36 (dd, J = 14.9, 7.7 Hz, 1 H, CH2), 3.31 (dd, J = 14.9, 6.9 Hz, 1 H, CH2).

13C NMR (101 MHz, DMSO-d 6): δ = 145.7, 131.6, 118.2, 104.9, 38.4, 34.6, 27.3.

MS (ESI): m/z = 214.0 [M + H]+.

Anal. Calcd for C7H8BrN3: C, 39.28; H, 3.77; N, 19.63. Found: C, 39.19; H, 3.71; N, 19.56.


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Ethyl 3-(2-Bromo-2-cyanoethyl)-1-methyl-1H-pyrazole-4-carboxylate (6b)

Yield: 4.299 g (75%); light-yellow oil; bp 145–147 °C/0.4 torr.

IR (ATR): 2244 (CN), 1698 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.28 (s, 1 H, H-pyrazole), 5.28 (dd, J = 8.3, 6.9 Hz, 1 H, CH), 4.21 (q, J = 7.1 Hz, 2 H, OCH2), 3.85 (s, 3 H, CH3), 3.63 (dd, J = 14.7, 8.3 Hz, 1 H, CH2), 3.56 (dd, J = 14.7, 6.9 Hz, 1 H, CH2), 1.27 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 162.4, 147.4, 135.7, 118.0, 111.4, 59.8, 38.9, 33.9, 26.1, 14.1.

MS (ESI): m/z = 286.0 [M + H]+.

Anal. Calcd for C10H12BrN3O2: C, 41.98; H, 4.23; N, 14.69. Found: C, 41.89; H, 4.20; N, 14.59.


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2-Bromo-2-chloro-3-(1-methyl-1H-pyrazol-3-yl)propanenitrile (7a)

Yield: 3.830 g (77%); off-white crystalline solid; bp 99–101 °C/0.25 torr; mp 66–67 °C.

IR (ATR): 2215 (CN) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.68 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.32 (d, J = 2.2 Hz, 1 H, H-pyrazole), 3.96 (d, J = 15.0 Hz, 1 H, CH2), 3.91 (d, J = 14.9 Hz, 1 H, CH2), 3.83 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 143.7, 131.7, 116.5, 106.3, 49.9, 45.9, 38.5.

MS (ESI): m/z = 247.9 [M + H]+.

Anal. Calcd for C7H7BrClN3: C, 33.83; H, 2.84; N, 16.91. Found: C, 33.75; H, 2.78; N, 16.88.


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Ethyl 3-(2-Bromo-2-chloro-2-cyanoethyl)-1-methyl-1H-pyrazole-4-carboxylate (7b)

Yield: 4.621 g (72%); white crystalline solid; bp 160–161 °C/0.4 torr; mp 57–58 °C.

IR (ATR): 2219 (CN), 1701 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.34 (s, 1 H, H-pyrazole), 4.29 (d, J = 14.9 Hz, 1 H, CH2), 4.23 (d, J = 14.9 Hz, 1 H, CH2), 4.22 (q, J = 7.1 Hz, 2 H, OCH2), 3.88 (s, 1 H, CH3), 1.28 (t, J = 7.1 Hz, 1 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 162.3, 145.1, 135.6, 116.2, 112.5, 59.8, 48.9, 43.7, 39.1, 14.1.

MS (ESI): m/z = 320.0 [M + H]+.

Anal. Calcd for C10H11BrClN3O2: C, 37.47; H, 3.46; N, 13.11. Found: C, 37.42; H, 3.38; N, 13.08.


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Methyl 2-Bromo-2-chloro-3-(1-methyl-1H-pyrazol-3-yl)propanoate (8a)

Yield: 3.998 g (71%); white crystalline solid; bp 118–120 °C/0.25 torr; mp 61–62 °C.

IR (ATR): 1744 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.59 (d, J = 2.2 Hz, 1 H, H-pyrazole), 6.12 (d, J = 2.2 Hz, 1 H, H-pyrazole), 3.89 (d, J = 14.9 Hz, 1 H, CH2), 3.85 (s, 3 H, CH3), 3.77 (s, 3 H, CH3), 3.76 (d, J = 14.8 Hz, 1 H, CH2).

13C NMR (101 MHz, DMSO-d 6): δ = 166.0, 144.8, 131.3, 105.7, 70.9, 54.5, 44.8, 38.4.

MS (ESI): m/z = 281.0 [M + H]+.

Anal. Calcd for C8H10BrClN2O2: C, 34.13; H, 3.58; N, 9.95. Found: C, 34.04; H, 3.51; N, 9.87.


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Ethyl 3-(2-Bromo-2-chloro-3-methoxy-3-oxopropyl)-1-methyl-1H-pyrazole-4-carboxylate (8b)

Yield: 3.902 g (55%); off-white solid; bp 192–196 °C/0.4 torr; mp 37–39 °C.

IR (ATR): 1755 (C=O), 1707 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H, H-pyrazole), 4.29 (d, J = 15.4 Hz, 1 H, CH2), 4.20 (q, J = 7.0 Hz, 2 H, OCH2), 4.12 (d, J = 15.4 Hz, 1 H, CH2), 3.84 (s, 3 H, CH3), 3.79 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 165.9 (o), 162.4 (o), 146.8 (o), 135.1 (+), 112.0 (o), 70.2 (o), 59.6 (–), 54.4 (+), 42.8 (–), 38.9 (+), 14.2 (+).

MS (ESI): m/z = 353.0 [M + H]+.

Anal. Calcd for C11H14BrClN2O4: C, 37.36; H, 3.99; N, 7.92. Found: C, 37.27; H, 3.89; N, 7.87.


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Ethyl 3-(2-Chloro-3-methoxy-3-oxopropyl)-1-methyl-1H-pyrazole-4-carboxylate (5c)

3-Aminopyrazole 1b (1.691 g, 10 mmol, 1.0 equiv) was added to 37% aq HCl (1.77 mL, 21 mmol, 2.1 equiv). The mixture was then cooled to –5 °C, and sat. aq NaNO2 (0.73 g, 10.5 mmol) was added dropwise at such rate that the temperature did not exceed 5 °C. Then, a cold solution of freshly prepared diazonium salt 2 was added dropwise under vigorous stirring to a mixture of acetone (10 mL), CuCl2·2H2O (500 mg, 2.9 mmol), and methyl acrylate (0.90 mL, 10 mmol). Then the mixture was stirred at 20 °C until nitrogen no longer evolved. After that, H2O (50 mL) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (5 × 5 mL). The combined organic extracts were dried over MgSO4 and evaporated, and the residue was distilled under reduced pressure.

Yield: 1.815 g (66%); light-yellow oil; bp 149–151 °C/0.4 torr.

IR (ATR): 1745 (C=O), 1704 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H, H-pyrazole), 4.86 (t, J = 7.3 Hz, 1 H, CH), 4.20 (q, J = 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H, CH3), 3.70 (s, 3 H, CH3), 3.49 (dd, J = 15.0, 7.0 Hz, 1 H, CH2pyrazolyl), 3.41–3.24 (m, 1 H, CH2pyrazolyl), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 169.1, 162.6, 148.2, 135.6, 111.1, 59.6, 55.0, 52.8, 38.7, 32.6, 14.2.

MS (ESI): m/z = 275.1 [M + H]+.

Anal. Calcd for C11H15ClN2O4: C, 48.10; H, 5.50; N, 10.20. Found: C, 47.98; H, 5.43; N, 10.16.


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3-(2-Thiocyanatoalkyl)-Substituted 1-Methyl-1H-pyrazoles 11a,b; General Procedure

The appropriate 3-aminopyrazole 1 (30 mmol, 1.0 equiv) was added to 37% aq HCl (5.6 mL, 66 mmol, 2.2 equiv). The mixture was cooled to –5 °C, and powdered NaNO2 (2.7 g, 33 mmol, 1.1 equiv) was added portionwise at such a rate that the temperature did not exceed 0 °C. After that, 40% aq HBF4 (6.1 mL, 36 mmol, 1.2 equiv) was added to the mixture at 0 °C. The precipitate was filtered off and washed Et2O (3 × 5 mL). The aryldiazonium tetrafluoroborates were processed without further purification. Freshly prepared diazonium tetrafluoroborate 2 (25 mmol, 1.0 equiv) was added portionwise under vigorous stirring to a mixture of Cu(AcO)2·H2O (25 mg, 0.12 mmol, 0.5 mol%), NH4SCN (1.9 g, 25 mmol, 1.0 equiv), MVK (2.6 mL, 25 mmol, 1.0 equiv), H2O (15 mL), and acetone (15 mL). The rate of the addition was selected so that nitrogen evolved at a rate of 2–3 bubbles per second (addition time 0.3–0.5 h). Then the mixture was stirred until nitrogen no longer evolved; H2O (50 mL) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined extract was dried over MgSO4 and evaporated and the residue was purified by column chromatography (silica gel, hexane/EtOAc 1:1).


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4-(1-Methyl-1H-pyrazol-3-yl)-3-thiocyanatobutan-2-one (11a)

Yield: 3.610 g (69%); light yellow oil; Rf = 0.277 (hexane/EtOAc 1:1).

IR (ATR): 2155 (SCN), 1714 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.58 (d, J = 2.2 Hz, 1 H, H-pyrazole), 6.10 (d, J = 2.2 Hz, 1 H, H-pyrazole), 4.69 (t, J = 6.8 Hz, 1 H, CH), 3.76 (s, 3 H, CH3), 3.25 (dd, J = 15.5, 6.5 Hz, 1 H, CH2), 3.13 (dd, J = 15.5, 7.1 Hz, 1 H, CH2), 2.33 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 201.9, 146.4, 131.5, 111.1, 104.8, 54.6, 38.3, 28.8, 27.7.

MS (ESI): m/z = 210.1 [M + H]+.

Anal. Calcd for C9H11N3OS: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.59; H, 5.21; N, 19.99.


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Ethyl 1-methyl-3-(3-oxo-2-thiocyanatobutyl)-1 H-pyrazole-4-carboxylate (11b)

Yield: 5.128 g (73%); white crystalline solid; mp 94–95 °C; Rf = = 0.314 (hexane/EtOAc 1:1).

IR (ATR): 2159 (SCN), 1707 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.24 (s, 1 H, H-pyrazole), 4.70 (t, J = 7.0 Hz, 1 H, CH), 4.21 (q, J = 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H, CH3), 3.57 (dd, J = 15.9, 6.7 Hz, 1 H, CH2), 3.25 (dd, J = 15.9, 7.5 Hz, 1 H, CH2), 2.34 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 201.5, 162.5, 148.8, 135.7, 111.1, 110.8, 59.6, 52.8, 38.8, 28.4, 27.6, 14.2.

MS (ESI): m/z = 282.1 [M + H]+.

Anal. Calcd for C12H15N3O3S: C, 51.23; H, 5.37; N, 14.94. Found: C, 51.15; H, 5.30; N, 14.89.


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3-(1-Methyl-1H-pyrazol-3-yl)acrylic Acids 12a,b and 3-(1-Methyl-1H-pyrazol-3-yl)acrylonitriles 13a,b; General Procedure

A solution of the appropriate 5 or 6 (5 mmol, 1.0 equiv) in EtOH (5 mL) was added dropwise under vigorous stirring to a mixture of KOH (0.98 g, 17.5 mmol, 3.5 equiv), EtOH (5 mL), and H2O (10 mL) at 0 °C. Then the mixture was stirred 1.5 h. After that, the reaction mixture was cooled and poured into a mixture of 37% aq HCl (10 mL) and ice (20 g). The product was filtered off and recrystallized from EtOH or EtOH/H2O.


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(E)-3-(1-Methyl-1H-pyrazol-3-yl)acrylic Acid (12a)

Yield: 0.671 g (88%); light-beige crystalline solid; mp 179–180 °C.

IR (ATR): 1677 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.31 (s, 1 H, COOH), 7.71 (d, J = 2.2 Hz, 1 H, H-pyrazole), 7.42 (d, J = 16.0 Hz, 1 H, = CH), 6.69 (d, J = 2.3 Hz, 1 H, H-pyrazole), 6.37 (d, J = 16.0 Hz, 1 H, = CH), 3.85 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 167.7, 147.0, 136.3, 132.6, 118.9, 105.2, 38.8.

MS (ESI): m/z = 153.1 [M + H]+.

Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.19; H, 5.21; N, 18.33.

Spectroscopic data are in accordance with those reported in the literature.[47]


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(E)-3-(2-Carboxyvinyl)-1-methyl-1H-pyrazole-4-carboxylic Acid (12b)

Yield: 0.935 g (95%); white crystalline solid; mp 270–271 °C.

IR (ATR): 1685 (C=O), 1671 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.55 (s, 1 H, COOH), 8.27 (s, 1 H, H-pyrazole), 7.96 (d, J = 16.1 Hz, 1 H, = CH), 6.56 (d, J = 16.1 Hz, 1 H, = CH), 3.89 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 167.4, 163.8, 146.4, 136.5, 133.8, 120.7, 113.5, 39.3.

MS (ESI): m/z = 197.1 [M + H]+.

Anal. Calcd for C8H8N2O4: C, 48.98; H, 4.11; N, 14.28. Found: C, 48.95; H, 4.03; N, 14.21.


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3-(1-Methyl-1H-pyrazol-3-yl)acrylonitrile (13a)

Yield: 0.826 g (81%); E/Z 7:3; light-beige crystalline solid; mp 48–49 °C.

IR (ATR): 2214 (CN) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.82 (d, J = 2.4 Hz, 0.3 H, H-pyrazole), 7.74 (d, J = 2.3 Hz, 0.7 H, H-pyrazole), 7.47 (d, J = 16.6 Hz, 0.7 H, = CH), 7.28 (d, J = 12.0 Hz, 0.3, = CHH), 6.88 (d, J = 2.4 Hz, 0.3 H, H-pyrazole), 6.67 (d, J = 2.4 Hz, 0.7 H, H-pyrazole), 6.23 (d, J = 16.6 Hz, 0.7 H, = CH), 5.73 (d, J = 12.0 Hz, 0.3 H, = CH), 3.89 (s, 0.9 H, CH3), 3.86 (s, 2.1 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 146.5, 146.0, 142.8, 141.3, 132.8, 118.7, 117.8, 105.4, 105.3, 95.9, 94.1, 38.9.

MS (ESI): m/z = 134.1 [M + H]+.

Anal. Calcd for C7H7N3: C, 63.14; H, 5.30; N, 31.56. Found: C, 63.06; H, 5.29; N, 31.49.


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(E)-3-(2-Cyanovinyl)-1-methyl-1H-pyrazole-4-carboxylic Acid (13b)

Yield: 0.833 g (94%); white crystalline solid; mp 242–243 °C.

IR (ATR): 2220 (CN), 1708 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.79 (s, 1 H, COOH), 8.31 (s, 1 H, H-pyrazole), 7.80 (d, J = 16.8 Hz, 1 H, = CH), 6.45 (d, J = 16.8 Hz, 1 H, = CH), 3.90 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.7, 145.6, 140.1, 136.8, 118.5, 113.4, 98.6, 39.4.

MS (ESI): m/z = 178.1 [M + H]+.

Anal. Calcd for C8H7N3O2: C, 54.24; H, 3.98; N, 23.72. Found: C, 54.15; H, 3.88; N, 23.68.


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3-(Thiazolylmethyl)- and 3-(Selenazolylmethyl)-Substituted 1-Methyl-1H-pyrazoles 14 and 15; General Procedure

A mixture of the appropriate 4 (5 mmol, 1.0 equiv), thiourea (0.380 g, 5 mmol, 1.0 equiv) or selenourea (0.615 g, 5 mmol, 1.0 equiv), and EtOH (5 mL) was stirred under reflux for 2 h. Then hot H2O (50 mL) was added to the mixture, and the aqueous layer was separated and alkalified by a 20% aq solution of NH3 to pH ≈ 11. The mixture was allowed to cool to 20 °C, whereupon a precipitate formed; it was filtered off, dried in air, and recrystallized (hexane/toluene).


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4-Methyl-5-[(1-methyl-1H-pyrazol-3-yl)methyl]thiazol-2-amine (14a)

Yield: 0.732 g (70%); light-beige crystalline solid; mp 152–153 °C.

IR (ATR): 3266 (NH), 3082 (NH) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.52 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.55 (s, 2 H, NH2), 5.95 (d, J = 2.1 Hz, 1 H, H-pyrazole), 3.75 (s, 3 H, CH3), 3.73 (s, 2 H, CH2), 2.02 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 165.2, 150.4, 142.2, 131.2, 115.9, 103.7, 38.2, 24.7, 14.6.

MS (ESI): m/z = 209.1 [M + H]+.

Anal. Calcd for C9H12N4S: C, 51.90; H, 5.81; N, 26.90. Found: C, 51.78; H, 5.76; N, 26.82.


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Ethyl 3-[(2-Amino-4-methylthiazol-5-yl)methyl]-1-methyl-1H-pyrazole-4-carboxylate (14b)

Yield: 1.015 g (72%); light-beige crystalline solid; mp 156–157 °C.

IR (ATR): 3414 (NH), 3293 (NH), 1688 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.17 (s, 1 H, H-pyrazole), 6.55 (s, 2 H, NH2), 4.20 (q, J = 7.1 Hz, 2 H, OCH2), 4.01 (s, 2 H, CH2), 3.79 (s, 3 H, CH3), 2.06 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 165.5, 162.7, 152.1, 142.2, 135.3, 115.2, 110.1, 59.4, 38.7, 23.6, 14.7, 14.3.

MS (ESI): m/z = 281.1 [M + H]+.

Anal. Calcd for C12H16N4O2S: C, 51.41; H, 5.75; N, 19.99. Found: C, 51.33; H, 5.65; N, 19.92.


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4-Methyl-5-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,3-selenazol-2-amine (15a)

Yield: 1.090 g (85%); white crystalline solid; mp 165–166 °C.

IR (ATR): 3305 (NH), 3263 (NH) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.51 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.83 (s, 2 H, NH2), 5.96 (d, J = 2.1 Hz, 1 H, H-pyrazole), 3.77 (s, 2 H, CH2), 3.75 (s, 3 H, CH3), 1.99 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 166.5 (o), 151.1 (o), 142.5 (o), 131.2 (+), 121.5 (o), 103.7 (+), 38.2 (+), 26.9 (–), 15.1 (+).

MS (ESI): m/z = 257.0 [M + H]+.

Anal. Calcd for C9H12N4Se: C, 42.36; H, 4.74; N, 21.96. Found: C, 42.25; H, 4.70; N, 21.88.


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Ethyl 3-[(2-Amino-4-methyl-1,3-selenazol-5-yl)methyl]-1-methyl-1H-pyrazole-4-carboxylate (15b)

Yield: 1.374 g (84%); white crystalline solid; mp 149–150 °C.

IR (ATR): 3340 (NH), 3284 (NH), 1704 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.16 (s, 1 H, H-pyrazole), 6.77 (s, 2 H, NH2), 4.20 (q, J = 7.1 Hz, 2 H, OCH2), 4.04 (s, 2 H, CH2), 3.79 (s, 3 H, CH3), 2.03 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 166.9, 162.7, 152.8, 142.8, 135.3, 120.5, 109.9, 59.4, 38.7, 25.9, 15.3, 14.3.

MS (ESI): m/z = 329.0 [M + H]+.

Anal. Calcd for C12H16N4O2Se: C, 44.04; H, 4.93; N, 17.12. Found: C, 43.96; H, 4.85; N, 17.07.


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3-(Thiazolylmethyl)- and 3-(Selenazolylmethyl)-Substituted 1-Methyl-1H-pyrazoles 16 and 17; General Procedure

A mixture of the appropriate 5 (3 mmol, 1.0 equiv), thiourea (0.228 g, 3 mmol, 1.0 equiv) or selenourea (0.369 g, 3 mmol, 1.0 equiv), and EtOH (3 mL) was stirred under reflux for 3 h. The mixture was allowed to cool to 20 °C, whereupon a precipitate formed, which was filtered off and recrystallized from EtOH.


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2-Imino-5-[(1-methyl-1H-pyrazol-3-yl)methyl]thiazolidin-4-one Hydrobromide (16a)

Yield: 0.550 g (87%); white crystalline solid; mp 235–236 °C.

IR (ATR): 3099 (NH), 1720 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.02–9.67 (m, 2 H, 2NH), 7.59 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.07 (d, J = 2.2 Hz, 1 H, H-pyrazole), 4.66 (dd, J = 10.2, 3.8 Hz, 1 H, CH), 3.75 (s, 3 H, CH3), 3.34 (dd, J = 15.5, 3.8 Hz, 1 H, CH2), 2.98 (dd, J = 15.5, 10.2 Hz, 1 H, CH2).

13C NMR (101 MHz, DMSO-d 6): δ = 183.1, 179.1, 147.8, 131.8, 104.2, 53.7, 38.4, 30.9.

MS (ESI): m/z = 211.1 [M + H]+.

Anal. Calcd for C8H11BrN4OS: C, 33.00; H, 3.81; N, 19.24. Found: C, 32.95; H, 3.73; N, 19.14.


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Ethyl 3-[(2-Imino-4-oxothiazolidin-5-yl)methyl]-1-methyl-1H-pyrazole-4-carboxylate Hydrobromide (16b)

Yield: 0.672 g (79%); white crystalline solid; mp 225–226 °C (decomp).

IR (ATR): 2969 (NH), 1690 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 9.82–9.50 (m, 2 H, 2NH), 8.25 (s, 1 H, H-pyrazole), 4.69 (dd, J = 11.1, 3.6 Hz, 1 H, CH), 4.19 (q, J = 7.1 Hz, 2 H, OCH2), 3.81 (s, 3 H, CH3-pyrazole), 3.69 (dd, J = 16.4, 3.6 Hz, 1 H, CH2), 3.13 (dd, J = 16.4, 11.1 Hz, 1 H, CH2), 1.25 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 183.3, 179.4, 162.5, 150.1, 135.8, 110.8, 59.6, 52.3, 38.8, 30.9, 14.3.

MS (ESI): m/z = 283.1 [M + H]+.

Anal. Calcd for C11H15BrN4O3S: C, 36.37; H, 4.16; N, 15.42. Found: C, 36.26; H, 4.09; N, 15.07.


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2-Imino-5-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,3-selenazolidin-4-one Hydrobromide (17a)

Yield: 0.680 g (88%); white crystalline solid; mp 234–235 °C.

IR (ATR): 3094 (NH), 1712 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.05–9.56 (m, 2 H, NH), 7.60 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.08 (d, J = 2.1 Hz, 1 H, H-pyrazole), 4.84 (dd, J = 10.9, 3.8 Hz, 1 H, CH), 3.75 (s, 3 H, CH3), 3.52 (dd, J = 15.8, 3.8 Hz, 1 H, CH2), 3.06 (dd, J = 15.7, 11.0 Hz, 1 H, CH2).

13C NMR (101 MHz, DMSO-d 6): δ = 183.9, 176.1, 148.6, 131.8, 104.0, 50.9, 38.4, 31.4.

MS (ESI): m/z = 259.0 [M + H]+.

Anal. Calcd for C8H11BrN4OSe: C, 28.42; H, 3.28; N, 16.57. Found: C, 28.33; H, 3.20; N, 16.55.


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Ethyl 3-[(2-Imino-4-oxo-1,3-selenazolidin-5-yl)methyl]-1-methyl-1H-pyrazole-4-carboxylate Hydrobromide (17b)

Yield: 0.822 g (83%); white crystalline solid; mp 250–251 °C (decomp).

IR (ATR): 2972 (NH), 1691 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.11–9.52 (br.s, 2 H, NH), 8.26 (s, 1 H, H-pyrazole), 4.85 (dd, J = 11.7, 3.7 Hz, 1 H, CH), 4.19 (q, J = 7.1 Hz, 2 H, OCH2), 3.88 (dd, J = 16.9, 3.7 Hz, 1 H, CH2), 3.81 (s, 3 H, CH3), 3.21 (dd, J = 16.9, 11.7 Hz, 1 H, CH2), 1.25 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 184.1, 176.3, 162.5, 150.8, 135.9, 110.6, 59.6, 49.2, 38.8, 31.4, 14.3.

MS (ESI): m/z = 331.0 [M + H]+.

Anal. Calcd for C11H15BrN4O3Se: C, 32.21; H, 3.69; N, 13.66. Found: C, 32.16; H, 3.60; N, 13.59.


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Methyl 3-Amino-5-(1-methyl-1H-pyrazol-3-yl)thiophene-2-carboxylates 19a,d and 3-Amino-5-(1-methyl-1H-pyrazol-3-yl)-N-phenylthiophene-2-carboxamide 20a,c; General Procedure A

A solution of propanenitrile 7 (3 mmol, 1.0 equiv) in MeOH (5 mL) was added dropwise under stirring to a mixture of the appropriate thiol 18a or 18b (3.03 mmol, 1.01 equiv) and 1 M MeONa in MeOH (9 mL) at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature and then under reflux for 1 h. The solvent was evaporated under reduced pressure and 2% aq AcOH (20 mL) was added to the residue. The product was filtered off and recrystallized from MeOH.


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Methyl 3-Amino-5-(1-methyl-1H-pyrazol-3-yl)thiophene-2-carboxylate (19a)

Yield: 0.580 g (81%); white crystalline solid; mp 157–158 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 7.75 (d, J = 2.1 Hz, H-pyrazole), 6.86 (s, 1 H, H-thiophene), 6.60 (d, J = 2.2 Hz, H-pyrazole), 6.56 (s, 2 H, NH2), 3.86 (s, 3 H, CH3), 3.72 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 164.1, 155.3, 144.6, 141.2, 132.8, 115.8, 103.3, 95.6, 50.9, 38.7.

MS (ESI): m/z = 238.1 [M + H]+.

Anal. Calcd for C10H11N3OS: C, 50.62; H, 4.67; N, 17.71. Found: C, 50.59; H, 4.59; N, 17.65.


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Methyl 3-[4-Amino-5-(methoxycarbonyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (19d)

Yield: 0.621 g (70%); white crystalline solid; mp 175–176 °C.

IR (ATR): 3461 (NH), 3351 (NH), 1714 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.40 (s, 1 H, H-pyrazole), 7.62 (s, 1 H, H-thiophene), 6.60 (s, 2 H, NH2), 3.89 (s, 3 H, CH3), 3.77 (s, 3 H, CH3), 3.73 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 164.1, 162.5, 154.8, 144.7, 138.5, 137.5, 120.8, 109.9, 97.0, 51.4, 50.9, 39.1.

MS (ESI): m/z = 296.1 [M + H]+.

Anal. Calcd for C12H13N3O4S: C, 48.81; H, 4.44; N, 14.23. Found: C, 48.73; H, 4.35; N14.19.


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3-Amino-5-(1-methyl-1H-pyrazol-3-yl)-N-phenylthiophene-2-carboxamide (20a)

Yield: 0.735 g (82%); white crystalline solid; mp 176–177 °C.

IR (ATR): 3462 (NH), 3345 (NH), 3276 (NH), 1614 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 9.21 (s, 1 H, NH), 7.76 (d, J = 1.9 Hz, 1 H, H-pyrazole), 7.69 (d, J = 7.9 Hz, 2 H, C6H5), 7.29 (t, J = 7.8 Hz, 2 H, C6H5), 7.02 (t, J = 7.3 Hz, 1 H, C6H5), 6.89 (s, 1 H, H-thiophene), 6.65 (s, 2 H, NH2), 6.61 (d, J = 2.0 Hz, 1 H, H-pyrazole), 3.86 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.3, 154.7, 144.8, 139.4, 138.2, 132.8, 128.4, 122.9, 120.6, 116.3, 103.1, 98.9, 38.7.

MS (ESI): m/z = 299.1 [M + H]+.

Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78. Found: C, 60.32; H, 4.62; N, 18.67.


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Methyl 3-[4-Amino-5-(phenylcarbamoyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (20c)

Yield: 0.751 g (70%); white crystalline solid; mp 91–92 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 9.27 (s, 1 H, NH), 8.42 (s, 1 H, H-pyrazole), 7.75–7.63 (m, 3 H, C6H5, H-thiophene), 7.29 (t, J = 7.9 Hz, 2 H, C6H5), 7.03 (t, J = 7.3 Hz, 1 H, C6H5), 6.70 (s, 2 H, NH2), 3.89 (s, 3 H, CH3), 3.79 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.2, 162.6, 154.4, 144.9, 139.4, 137.5, 135.6, 128.4, 122.9, 121.4, 120.6, 109.9, 100.3, 51.4, 39.0.

MS (ESI): m/z = 357.1 [M + H]+.

Anal. Calcd for C17H16N4O3S: C, 57.29; H, 4.53; N, 15.72. Found: C, 57.20; H, 4.43; N, 15.63.


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Ethyl 3-Amino-5-(1-methyl-1H-pyrazol-3-yl)thiophene-2-carboxylates 19b,c and 3-Amino-5-(1-methyl-1H-pyrazol-3-yl)-N-phenylthiophene-2-carboxamide 20b; General Procedure B

A solution of propanenitrile 7 (3 mmol, 1.0 equiv) in absolute EtOH (5 mL) was added dropwise under stirring to a mixture of the appropriate thiol 18c or 18b (3.03 mmol, 1.01 equiv) and 1 M EtONa in EtOH (9 mL) at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature and then under reflux for 1 h. The solvent was evaporated under reduced pressure and 2% aq AcOH (20 mL) was added to the residue. The product was filtered off.

In the case of the reaction with 18c, a mixture of compounds 19b and 19c formed. The mixture was dissolved in CH2Cl2 (30 mL) and the resulting solution was treated with aq NaHCO3 (20 mL, 0.6 g, 7 mmol, 2.038 equiv). The organic phase was separated and dried over Na2SO4 and evaporated under reduced pressure to give 19b. The aqueous layer was acidified with 15% aq HCl and the resulting precipitate was filtered off, washed with distilled H2O, and dried, giving 19c.


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Ethyl 3-[4-Amino-5-(ethoxycarbonyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (19b)

Yield: 0.196 g (20%); white crystalline solid; mp 159–160 °C.

IR (ATR): 3437 (NH), 3347 (NH), 1694 (C=O), 1655 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.39 (s, 1 H, H-pyrazole), 7.61 (s, 1 H, H-thiophene), 6.55 (s, 2 H, NH2), 4.30–4.18 (m, 4 H, 2 °CH2), 1.33–1.22 (m, 6 H, 2CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.8, 162.1, 154.7, 144.7, 138.4, 137.5, 120.8, 110.3, 97.2, 59.99, 59.4, 39.05, 14.5, 14.2.

MS (ESI): m/z = 324.1 [M + H]+.

Anal. Calcd for C14H17N3O4S: C, 52.00; H, 5.30; N, 12.99. Found: C, 51.93; H, 5.25; N, 12.88.


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Ethyl 3-[4-Amino-5-(ethoxycarbonyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (19c)

Yield: 0.436 g (49%); white crystalline solid; mp 115 °C (subl.).

IR (ATR): 3434 (NH), 3345 (NH), 1695 (C=O), 1654 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.77–12.25 (br.s, 1 H, COOH), 8.32 (s, 1 H, H-pyrazole), 7.64 (s, 1 H, H-thiophene), 6.55 (s, 2 H, NH2), 4.19 (q, J = 7.0 Hz, 2 H, CH2), 3.87 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.8, 163.6, 154.8, 144.7, 138.8, 137.7, 120.8, 111.3, 97.2, 59.4, 39.00, 14.5.

MS (ESI): m/z = 296.1 [M + H]+.

Anal. Calcd for C12H13N3O4S: C, 48.81; H, 4.44; N, 14.23. Found: C, 48.75; H, 4.41; N14.13.


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3-[4-Amino-5-(phenylcarbamoyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylic Acid (20b)

Yield: 0.669 g (65%); white crystalline solid; mp 180–181 °C.

IR (ATR): 3448 (NH), 3394 (NH), 3347 (NH), 1681 (C=O), 1648 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.97–12.01 (m, 1 H, COOH), 9.26 (s, 1 H, NH), 8.34 (s, 1 H), 7.74 (s, 1 H), 7.70 (d, J = 7.9 Hz, 2 H), 7.29 (t, J = 7.8 Hz, 2 H), 7.02 (t, J = 7.3 Hz, 1 H), 6.70 (s, 2 H, NH2), 3.88 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.7, 163.3, 154.5, 144.9, 139.4, 137.7, 136.1, 128.4, 122.9, 121.6, 120.6, 111.3, 100.2, 38.9.

MS (ESI): m/z = 343.1 [M + H]+.

Anal. Calcd for C16H14N4O3S: C, 56.13; H, 4.12; N, 16.36. Found: C, 56.05; H, 4.09; N, 16.28.


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3-Hydroxy-5-(1-methyl-1H-pyrazol-3-yl)thiophenes 21a and 22a,b; General Procedure A

A solution of 8 (3 mmol, 1.0 equiv) in MeOH (5 mL) was added dropwise under stirring to a mixture of the appropriate thiol 18a or 18b (3.03 mmol, 1.01 equiv) and 1 M MeONa in MeOH (9 mL) at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature and then under reflux for 1 h. The solvent was evaporated under reduced pressure and 2% aq AcOH (20 mL) was added to residue. The product was filtered off and recrystallized from MeOH.


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Methyl 3-Hydroxy-5-(1-methyl-1H-pyrazol-3-yl)thiophene-2-carboxylate (21a)

Yield: 0.574 g (80%); white crystalline solid; mp 121–122 °C.

IR (ATR): 1647 (C=O) cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.64 (s, 1 H, OH), 7.36 (d, J = 2.3 Hz, 1 H, H-pyrazole), 6.93 (s, 1 H, H-thiophene), 6.48 (d, J = 2.3 Hz, 1 H, H-pyrazole), 3.92 (s, 3 H, CH3), 3.89 (s, 3 H, CH3).

13C NMR (101 MHz, CDCl3): δ = 167.0 (o), 164.7 (o), 145.7 (o), 142.3 (o), 131.9 (+), 114.8 (+), 103.9 (+), 102.0 (o), 51.9 (+), 39.4 (+).

MS (ESI): m/z = 239.0 [M + H]+.

Anal. Calcd for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76. Found: C, 50.33; H, 4.15; N, 4.11.


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3-Hydroxy-5-(1-methyl-1H-pyrazol-3-yl)-N-phenylthiophene-2-carboxamide (22a)

Yield: 0.755 g (84%); white crystalline solid; mp 250–251 °C.

IR (ATR): 3358 (NH), 1650 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 11.99 (s, 1 H, OH), 9.50 (s, 1 H, NH), 7.77 (s, 1 H, H-pyrazole), 7.65 (d, J = 7.9 Hz, 2 H, C6H5), 7.34 (t, J = 7.6 Hz, 2 H, C6H5), 7.09 (t, J = 7.2 Hz, 1 H, C6H5), 7.04 (s, 1 H, H-thiophene), 6.67 (s, 1 H, H-pyrazole), 3.87 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 160.7, 156.6, 144.7, 139.3, 138.4, 132.9, 128.9, 123.5, 119.8, 115.5, 110.0, 103.2, 38.8.

MS (ESI): m/z = 300.1 [M + H]+.

Anal. Calcd for C15H13N3O2S: C, 60.19; H, 4.38; N, 14.04. Found: C, 60.11; H, 4.27; N, 13.94.


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Methyl 3-[4-Hydroxy-5-(phenylcarbamoyl)thiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (22b)

Yield: 0.741 g (69%); white crystalline solid; mp 247–248 °C.

IR (ATR): 3334 (NH), 1720 (C=O), 1610 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.00 (s, 1 H, OH), 9.52 (s, 1 H, NH), 8.42 (s, 1 H, H-pyrazole), 7.87 (s, 1 H), 7.66 (d, J = 7.3 Hz, 2 H), 7.34 (s, 2 H), 7.09 (s, 1 H), 3.91 (s, 3 H, CH3), 3.79 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 162.6, 160.3, 155.5, 144.7, 138.3, 137.6, 136.5, 128.9, 123.6, 120.6, 119.7, 111.9, 109.8, 51.4, 39.1.

MS (ESI): m/z = 358.1 [M + H]+.

Anal. Calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.76. Found: C, 57.07; H, 4.13; N, 11.69.


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Ethyl 3-[5-(Ethoxycarbonyl)-4-hydroxythiophen-2-yl]-1-methyl-1H-pyrazole-4-carboxylate (21b) (by Method B)

A solution of 8b (1.059 g, 3 mmol, 1.0 equiv) in absolute EtOH (5 mL) was added dropwise under stirring to a mixture of 18c (0.33 mL, 3.03 mmol, 1.01 equiv) and 1 M EtONa in EtOH (9 mL) at ambient temperature. The resulting mixture was stirred for 2 h at ambient temperature and then under reflux for 1 h. The solvent was evaporated under reduced pressure and 2% aq AcOH (20 mL) was added to the residue. The product was filtered off and recrystallized from EtOH/H2O.

Yield: 0.496 g (51%); white crystalline solid; mp 149–150 °C.

IR (ATR): 1707 (CN), 1647 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.38 (s, 1 H, OH), 8.41 (s, 1 H, H-pyrazole), 7.73 (s, 1 H, H-thiophene), 4.34–4.15 (m, 4 H, 2CH2), 1.33–1.22 (m, 6 H, 2CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 162.4, 162.1, 160.4, 144.4, 137.8, 137.6, 120.9, 110.3, 104.7, 60.1, 39.1, 14.3, 14.2.

MS (ESI): m/z = 325.1 [M + H]+.

Anal. Calcd for C14H16N2O5S: C, 51.84; H, 4.97; N, 8.64. Found: C, 51.73; H, 4.93; N, 8.55.


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2-(Pyrazol-3-ylamino)-5-(pyrazol-3-ylmethyl)thiazoles 23a,b; General Procedure

A solution of 1a (0.194 g, 2 mmol, 1.0 equiv) and the appropriate 11 (2 mmol, 1.0 equiv) in glacial AcOH (3 mL) was stirred under reflux on a hot plate magnetic stirrer for 2 h. Then H2O (30 mL) was added and the solvent was evaporated under reduced pressure. The glassy residue was dissolved in 37% aq HCl (0.51 mL, 6 mmol, 3 equiv) and the resulting solution was treated with acetone (15 mL). The resulting solid was filtered off and dried in air.


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4-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-5-[(1-methyl-1H-pyrazol-3-yl)methyl]thiazol-2-amine Hydrochloride (23a)

Yield: 0.468 g (72%); white crystalline solid; mp 221–222 °C.

IR (ATR): 3343 (NH) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.74 (d, J = 2.1 Hz, 1 H, H-pyrazole), 7.63 (d, J = 1.8 Hz, 1 H, H-pyrazole), 6.14 (d, J = 2.2 Hz, 1 H, H-pyrazole), 6.11 (d, J = 1.9 Hz, 1 H, H-pyrazole), 3.95 (s, 2 H, CH2), 3.81 (s, 3 H, CH3), 3.78 (s, 3 H, CH3), 2.29 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 160.8 (o), 148.3 (o), 145.4 (o), 133.0 (+), 131.97 (+), 131.6 (o), 118.4 (o), 104.3 (+), 94.9 (+), 38.9 (+), 38.4 (+), 23.8 (–), 11.5 (+).

MS (ESI): m/z = 289.1 [M(C13H16N6S)+H]+.

Anal. Calcd for C13H17ClN6S: C, 48.07; H, 5.28; N, 25.87. Found: C, 47.97; H, 5.23; N, 25.80.


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Ethyl 1-Methyl-3-({4-methyl-2-[(1-methyl-1H-pyrazol-3-yl)amino]thiazol-5-yl}methyl)-1H-pyrazole-4-carboxylate Hydrochloride (23b)

Yield: 0.636 g (80%); white crystalline solid; mp 249–250 °C.

IR (ATR): 2876 (NH), 1714 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 10.04–9.53 (br.s, 1 H, NH), 8.30 (s, 1 H, H-pyrazole), 8.02 (d, J = 2.0 Hz, 1 H, H-pyrazole), 6.58 (d, J = 2.1 Hz, 1 H, H-pyrazole), 4.23 (q, J = 7.1 Hz, 2 H, OCH2), 4.19 (s, 2 H, CH2), 3.90 (s, 3 H, CH3), 3.84 (s, 3 H, CH3), 1.98 (s, 3 H, CH3), 1.27 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 168.3 (o), 162.6 (o), 149.5 (o), 139.6 (o), 135.7 (+), 134.3 (+), 132.0 (o), 114.3 (o), 110.4 (o), 103.8 (+), 59.7 (–), 39.4 (+), 38.8 (+), 23.5 (–), 14.2 (+), 11.8 (+).

MS (ESI): m/z = 361.1 [M + H]+.

Anal. Calcd for C16H21ClN6O2S: C, 48.42; H, 5.33; N, 21.17. Found: C, 48.34; H, 5.28; N, 21.08.


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7-[(1H-Pyrazol-3-yl)methyl]pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidines 24a,b; General Procedure

A solution of 1b (2 mmol, 1.0 equiv) and the corresponding 11 (2 mmol, 1.0 equiv) in glacial AcOH (3 mL) was stirred under reflux on a hot plate magnetic stirrer for 3 h. Then H2O (30 mL) was added to the mixture. The precipitate was filtered off and recrystallized from EtOH.


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2,8-Dimethyl-7-[(1-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (24a)

Yield: 0.537 g (85%); white crystalline solid; mp 234–235 °C.

IR (ATR): 1731 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.64 (s, 1 H, H-pyrazole), 7.63 (d, J = 2.1 Hz, 1 H, H-pyrazole), 6.16 (d, J = 2.1 Hz, 1 H, H-pyrazole), 4.06 (s, 2 H, CH2), 4.06 (s, 3 H, CH3), 3.79 (s, 3 H, CH3), 2.74 (s, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 162.4, 159.4, 147.7, 147.3, 131.9, 131.1, 129.7, 119.6, 105.3, 104.5, 40.2, 38.4, 24.4, 13.4.

MS (ESI): m/z = 315.1 [M + H]+.

Anal. Calcd for C14H14N6OS: C, 53.49; H, 4.49; N, 26.73. Found: C, 53.40; H, 4.41; N, 26.69.


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Ethyl 3-[(2,8-Dimethyl-4-oxo-2,4-dihydropyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-7-yl)methyl]-1-methyl-1H-pyrazole-4-carboxylate (24b)

Yield: 0.675 g (87%); white crystalline solid; mp 265–266 °C.

IR (ATR): 1705 (C=O), 1624 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.45 (s, 1 H, H-pyrazole), 8.26 (s, 1 H, H-pyrazole), 4.36–4.14 (m, 4 H, 2СH2), 4.02 (s, 3 H, CH3), 3.83 (s, 3 H, CH3), 2.73 (s, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).

13C NMR (101 MHz, DMSO-d 6): δ = 163.7 (o), 162.7 (o), 162.6 (o), 149.7 (o), 147.7 (o), 135.7 (+), 130.1 (o), 128.9 (o), 115.9 (o), 110.6 (o), 105.5 (o), 59.7 (–), 39.9 (+), 38.8 (+), 23.6 (–), 14.3 (+), 13.5 (+).

MS (ESI): m/z = 387.1 [M + H]+.

Anal. Calcd for C17H18N6O3S: C, 52.84; H, 4.70; N, 21.75. Found: C, 52.76; H, 4.60; N, 21.69.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0043-1773546.
  • Supporting Information

Corresponding Authors

Andreas Schmidt
Institute of Organic Chemistry, Clausthal University of Technology
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld
Germany   

Yurii V. Ostapiuk
Department of Organic Chemistry, Ivan Franko National University of Lviv
Kyryla i Mefodiya Str. 6, 79005 Lviv
Ukraine   

Publication History

Received: 25 March 2025

Accepted after revision: 30 April 2025

Article published online:
20 May 2025

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Zoom Image
Scheme 1 C–C bond formations to C3 of pyrazole
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Scheme 2 Meerwein arylation of functionalized ethenes 3a–e with pyrazol-3-yldiazonium salts
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Scheme 3 Synthesis of 3-(1-methylpyrazol-3-yl)acrylic acids and their nitriles
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Scheme 4 Syntheses of 2-aminothia(selena)zoles and thia(selena)zolidinones
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Scheme 5 Formation of 3-amino- and 3-hydroxy-5-(pyrazolyl)thiophenes
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Scheme 6 Cyclization reaction of α-thiocyanato ketones 11 with 3-amino-1-methylpyrazoles 1a and 1b