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Article

Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates

by
Rowan I. L. Meador
,
Nilamber A. Mate
and
John D. Chisholm
*
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, NY 13244, USA
*
Author to whom correspondence should be addressed.
Organics 2022, 3(2), 111-121; https://doi.org/10.3390/org3020009
Submission received: 21 March 2022 / Revised: 11 April 2022 / Accepted: 28 April 2022 / Published: 24 May 2022
(This article belongs to the Collection Advanced Research Papers in Organics)
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Abstract

:
N-Alkyl pyrazoles are important heterocycles in organic and medicinal chemistry, demonstrating a wide range of biological activity. A new method for the N-alkylation of pyrazoles has been developed using trichloroacetimidate electrophiles and a Brønsted acid catalyst. These reactions provide ready access to N-alkyl pyrazoles which are present in a variety of medicinally relevant lead structures. Benzylic, phenethyl and benzhydryl trichloroacetimidates provide good yields of the N-alkyl pyrazole products. Unsymmetrical pyrazoles provide a mixture of the two possible regioisomers, with the major product being controlled by sterics. This methodology provides an alternative to other alkylation methods that require strong base or high temperature.

1. Introduction

Pyrazoles are aromatic 5-membered carbocyclic rings with two adjacent nitrogen atoms. These heterocycles play an important role in organic and medicinal chemistry. For example, pyrazoles have been utilized as directing groups for C-H bond functionalization [1,2,3]. Recently it was shown that pyrazoles may be converted to amides via ozonolysis [1], further expanding the utility of the heterocycle. Pyrazoles are often incorporated into biologically active systems as a bioisostere for amides [4,5,6], phenols [7] or other aromatic rings [8]. Derivatives of pyrazole also show significant biological activity, with the heterocycle being the basis of molecules that have anti-infective, anti-oxidant and anti-dementia properties [9,10,11,12]. Pyrazoles are especially common in anti-tumor agents, such as the ones shown in Figure 1 [13]. Substituted pyrazoles also have found applications in many other fields including new energetic materials [14,15], sensors [16,17] and batteries [18].
Given the common nature of pyrazole-based structures researchers have been active in defining new methods for the synthesis and modification of this heterocycle. Typically, in the case of N-alkyl pyrazoles, the substituent at the nitrogen is installed under basic conditions which deprotonate the nitrogen followed by the addition of an electrophile such as an alkyl halide [19,20,21]. Alternative methods based on the Mitsunobu reaction [22,23], transition metal catalysis [24,25,26,27,28] and enzymes [29] have also been advanced. Trichloroacetimidates have recently been recognized as excellent participants in a number of amination reactions [30,31,32,33,34]. Our recent studies on the substitution reactions of anilines [35], sulfonamides [36] and isatins [37] with trichloroacetimidate electrophiles led us to speculate that imidates may be efficient electrophiles for use in pyrazole alkylation.

2. Results and Discussion

Initially, we explored the alkylation of pyrazoles under promoter free conditions. Heating 4-choropyrazole 6 and phenethyl trichloroacetimidate 7 in refluxing 1,2-DCE for 24 h showed only a trace of alkylation product, so the use of acid catalysts was investigated (Table 1). Of the Lewis and Brønsted acids evaluated, camphorsulfonic acid (CSA) gave the best yield of N-alkylated product (77%). Other solvents were then evaluated, but did not show improved yields. The reaction time could be shortened to 4 h with little loss in yield, so these conditions were adopted for further studies on the reaction scope.
A number of different trichloroacetimidate electrophiles were then evaluated in the pyrazole N-alkylation using 4-chloropyrazole as the nucleophile (Table 2). Replacement of the benzene ring of the phenethyl group with a 4-methoxyphenyl or a 2-naphthyl group gave good yields of the substitution products 12 and 14. (entries 2 and 3). Diphenylmethyl imidates such as 15 were of special interest, as these systems have shown activity as opioid receptor ligands which can be used to treat addiction and other disorders [38]. Benzhydryl imidates provided the respective N-alkyl pyrazoles in good yields (entries 4–10) except for the nitro-substituted benzhydryl imidate 23 (entry 8). The poor reactivity of imidate 23 in the reaction appears to implicate a carbocation intermediate in the mechanism, as incorporation of a powerful electron withdrawing group such as the nitro group makes formation of a carbocation more difficult, and therefore this reaction did not provide any product. This trend was also apparent when benzyl imidates were investigated (entries 11–13), as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), while the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, allyl and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only returning the starting materials under these reaction conditions. The methyl imidate cannot form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 37 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may compete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimination in the presence of acids, and special conditions are often needed for N-alkylation of this substrate [40].
The new alkylation conditions were also evaluated with regard to the pyrazole nucleophile (Table 3). A number of pyrazoles substituted at the 4-position with halogens, alkyl groups, aryl groups, and esters could be employed with good to moderate results (entries 1–5). The 3,5-disubstituted pyrazoles 53 and 55 were also successfully employed, although the yields for these reactions were generally lower than for 3-substituted pyrazoles. This may be due to steric effects with the groups next to the nitrogen slowing the alkylation. Unsubstituted pyrazole 57 was also utilized in the alkylation, providing a 45% yield. Indazole 59 also participated in the alkylation, providing the N1-alkyl product in 41% yield. None of the regioisomeric N2-alkyl indazole was detected.
Unsymmetrical pyrazoles can provide two different regioisomers depending on which nitrogen reacts with the imidate. To evaluate the selectivity of the imidate alkylation, 3-methyl-5-phenyl-1H-pyrazole 61 was subjected to the transformation with phenethyl trichloroacetimidate (Scheme 1). This provided the two regioisomers, pyrazoles 62 and 63, in 40% and 16% yield, respectively (a 2.5:1 ratio). The position of alkylation was verified by NOESY experiments on the two compounds, with compound 62 showing an interaction between the pyrazole methyl group and the phenethyl group, while isomer 63 lacked this signal. The position of alkylation appears to be the result of steric effects, which favor alkylation at the less hindered nitrogen of the pyrazole ring. We also attempted to determine the selectivity of the alkylation with regard to an alcohol functional group, as alcohols are common and imidates are known to react with them under similar conditions [41,42,43,44]. Using the commercially available 1H-pyrazole-4-methanol 64 as a substrate, treatment of this bifunctional compound with one equivalent of imidate 23 under the alkylation conditions gave the dialkylated product 65 as the only product in 30% yield, with none of the monoalkylation products being detected. While puzzling at first, this result can be rationalized by the poor solubility of 64 in DCE, and the increase in solubility that occurs when the first alkylation takes place. Once the substrate is monoalkylated, it becomes significantly more soluble in the solvent, leading to the selective formation of the dialkylation product. The yield could be increased to 64% by increasing the amount of imidate to 2.5 equivalents. As the alkylation requires a nonpolar solvent to proceed in good yield (Table 1), conditions where selective monoprotection occurs will require further study.
These results may be rationalized by the mechanism presented in Figure 2 below. Initially, the imidate 7 is protonated by the CSA, which then ionizes to form the acetamide B and the carbocation C. The carbocation is then trapped with the pyrazole, resulting in the protonated pyrazole D. This intermediate can then react with another equivalent of imidate to provide alkylated pyrazole and regenerate the protonated imidate A.

3. Materials and Methods

3.1. General Experimental Information

All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column [45]. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Tetrahydrofuran (THF) was freshly distilled from Na/benzophenone still before use. Ethyl acetate (EA) and hexanes were used as received from the manufacturer. Silica gel column chromatography was performed using 60 Å silica gel (230−400 mesh). Melting points are uncorrected. Copies of spectra are available in the supplementary material.

3.2. Preparation of Trichloroacetimidates

Most of the trichloroacetimidates (7 [46], 11 [47], 13 [36], 15 [43], 17 [48], 19 [49], 21 [48], 23 [47], 25 [48], 27 [37], 33 [50], and 35 [51]) were synthesized from the corresponding alcohols as reported previously. Trichloroacetimidates 29, 31, 37, 39 and 41 were purchased from commercial sources.

3.3. General Procedure for the Synthesis of N-Alkyl Pyrazoles

A round-bottom flask was charged with imidate (1 equiv), pyrazole (1 equiv), and CSA (0.2 equiv) and put under an atmosphere of argon. Dry DCE was added to form a 0.25 M solution. The reaction was left to stir at room temperature for 4 h. After 4 h, the reaction mixture was diluted with EA, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel flash column chromatography to provide the N-alkyl pyrazole product. The alkylations were typically performed on a 1 mmol scale.

3.4. Tabulated Characterization Data for N-Alkyl Pyrazoles

4-Chloro-1-(1-phenylethyl)-1H-pyrazole (8). Yield 77%; TLC Rf = 0.37 (5% EA/95% hexanes); IR (ATR) 3129, 3030, 2936, 1493, 1310, 960, 696, 617 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.39–7.30 (m, 4H), 7.24 (d, J = 7.6 Hz, 2H), 5.48 (q, J = 7.0 Hz, 1H), 1.89 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.1, 137.5, 128.9, 128.2, 126.4, 126.0, 109.9, 61.9, 21.1; Anal Calcd for C11H11ClN2: C, 63.93; H, 5.36; N, 13.55; Found: C, 63.86; H, 5.00; N, 13.57.
4-Chloro-1-[1-(p-methoxyphenyl)ethyl]-1H-pyrazole (12). Yield 97%; TLC Rf = 0.26 (5% EA/95% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.20 (s, 1H), 7.05 (d, J = 8.4 Hz), 6.75 (d, J = 8.4 Hz, 2H), 5.27 (q, J = 7.4 Hz, 1H), 3.65 (s, 3H), 1.71 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 137.3, 133.0, 127.8, 125.8, 114.2, 109.7, 61.4, 55.3, 21.1. This compound has been reported previously [52].
4-Chloro-1-[1-(2-naphthyl)ethyl]-1H-pyrazole (14). Yield 67%; mp = 92–94 °C; TLC Rf = 0.28 (5% EA/95% hexanes); IR (ATR) 3112, 3047, 2991, 2952, 1388, 1313, 838, 747 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 3H), 7.56 (s, 1H), 7.38–7.35 (m, 3H), 7.26 (s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 5.48 (q, J = 7.2 Hz, 1H), 1.83 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.3, 137.6, 133.2, 133.0, 128.8, 128.1, 127.7, 126.5, 126.4, 126.1, 125.3, 124.3, 110.0, 62.0, 21.1; Anal Calcd for C17H13ClN2O2: C, 70.18; H, 5.10; N, 10.91; Found: C, 70.14; H, 5.05; N, 10.87.
1-Benzhydryl-4-chloro-1H-pyrazole (16). Yield 59%; mp = 100–103 °C; TLC Rf = 0.35 (5% EA/95% hexanes); IR (ATR) 3108, 3027, 2927, 1520, 726, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (s,1H), 7.26–7.22 (m, 6H), 7.13 (s, 1H), 7.00–6.99 (m, 4H), 6.61 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.8, 138.2. 128.8, 128.4, 128.2, 127.6, 110.0, 70.3; Anal Calcd for C16H13ClN2: C, 71.51; H, 4.88; N, 10.42; Found: C, 71.58; H, 4.82; N, 10.19.
4-Chloro-1-[(p-methoxyphenyl)phenylmethyl]-1H-pyrazole (18). Yield 71%; TLC Rf = 0.30 (5% EA/95% hexanes); IR (ATR) 3132, 3030, 2835, 1610, 1510, 1247, 730 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24–7.22 (m, 3H), 7.13 (s, 1H), 6.97–6.95 (m, 4H), 6.79–6.77 (m, 2H), 6.55 (s, 1H), 3.69 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 139.4, 138.2, 130.8, 129.7, 128.8, 128.2, 127.8, 127.5, 114.2, 109.9, 69.8, 55.3; Anal Calcd for C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38; Found: C, 68.39; H, 4.97; N, 9.41.
4-Chloro-1-[phenyl(p-tolyl)methyl]-1H-pyrazole (20). Yield 98%; mp = 70–72 °C; TLC Rf = 0.35 (5% EA/95% hexanes); IR (ATR) 3129, 3055, 2919, 1512, 1293, 990, 735 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24–7.22 (m, 3H), 7.13 (s, 1H), 7.06 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 6.9 Hz, 2H), 6.91 (d, J = 7.6 Hz, 2H), 6.57 (s, 1H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.1, 138.3, 138.2, 135.8, 129.5, 128.8, 128.3, 128.2, 128.0, 127.5, 109.9, 70.1, 21.2; Anal Calcd for C17H15ClN2: C, 72.21; H, 5.35; N, 9.91; Found: C, 71.20; H, 5.20; N, 9.74.
4-Chloro-1-[(p-chlorophenyl)phenylmethyl]-1H-pyrazole (22). Yield 76%; TLC Rf = 0.46 (5% EA/95% hexanes IR (ATR) 3133, 3096, 1490, 967, 735 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.27–7.21 (m, 5H), 7.14 (s, 1H), 7.01–6.99 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 138.5, 138.3, 137.5, 134.3, 129.5, 129.0, 128.9, 128.7, 128.3, 127.6, 110.6, 69.6; Anal Calcd for C16H12ClN2: C, 63.39; H, 3.99; N, 9.24; Found: C, 63.19; H, 3.94; N, 9.59.
4-Chloro-1-[phenyl(o-tolyl)methyl]-1H-pyrazole (26). Yield 85%; mp = 89–92 °C; TLC Rf = 0.36 (5% EA/95% hexanes); IR (ATR) 3099, 3029, 2920, 1488, 1299, 964, 708 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.39–7.37 (m, 3H), 7.30–7.16 (m, 4H), 7.09–7.07 (m, 2H), 6.90 (s, 1H), 6.72 (d, J = 7.4 Hz, 1H), 2.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.3, 138.2, 137.2, 136.6, 130.9, 128.9, 128.4, 128.3, 128.1, 127.7, 126.4, 109.9, 67.6, 29.7, 19.2; Anal Calcd for C17H15ClN2: C, 72.21; H, 5.35; N, 9.91; Found: C, 71.94; H, 5.44; N, 9.81.
1-[(2H-1,3-Benzodioxol-5-yl)phenylmethyl]-4-chloro-1H-pyrazole (28). Yield 98%; TLC Rf = 0.30 (5% EA/95% hexanes); IR (ATR) 3134, 3062, 2893, 1501, 1487, 1235, 1035 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.25–7.23 (m, 3H), 7.16 (s, 1H), 6.98 (d, J = 6.6 Hz, 2H), 6.67 (d, J = 7.7 Hz, 1H), 6.49 (m, 3H), 5.86 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.1, 147.7, 139.0, 138.3, 132.6, 128.8, 128.3, 127.9, 127.5, 122.1, 109.9, 108.8, 108.4, 101.4, 69.9; Anal Calcd for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96; Found: C, 65.27; H, 4.14; N, 8.63.
1-Benzyl-4-chloro-1H-pyrazole (30). Yield 73%; TLC Rf = 0.31 (10% EA/90% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.37–7.33 (m, 4H), 7.24–7.22 (m, 2H), 5.23 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.9, 135.8, 130.0, 128.4, 127.9, 127.3, 110.3, 56.7. This compound has been reported previously [53].
4-Chloro-1-[(p-methoxyphenyl)methyl]-1H-pyrazole (32). Yield: 92%; TLC Rf = 0.32 (10% EA/90% hexanes); IR (ATR) 3124, 2999, 2933, 2834, 1612, 1511, 1244 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.32 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.19 (s, 2H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 137.7, 129.5, 127.6, 126.9, 114.3, 110.2, 56.3, 56.3; Anal Calcd for C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58; found: C, 59.44; H, 4.92; N, 12.83.
4-Chloro-1-[(p-chlorophenyl)methyl]-1H-pyrazole (34). Yield 37%; mp = 52–55 °C; TLC Rf = 0.27 (5% EA/95% hexanes); IR (ATR) 3129, 3045, 2943, 1492, 970, 755 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.25–7.22 (m, 4H), 7.05 (d, J = 8.3 Hz, 2H), 5.11 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.2, 134.4, 134.3, 129.1, 128.9, 127.2, 110.6, 55.9; Anal Calcd for C10H8Cl2N2: C, 52.89; H, 3.55; N, 12.34; found: C, 52.81; H, 3.54; N, 12.17.
2-[(4-Chloro-1H-pyrazol-1-yl)methyl]-1,3-isoindolinedione (36). Yield 62%; mp = 164–168 °C; TLC Rf = 0.30 (30% EA/70% hexanes); IR (ATR) 3135, 2963, 1771, 1717, 1401, 1323 cm−1; 1H NMR (400 MHz, (CD3)2SO) δ 8.13 (s, 1H), 7.95–7.88 (m, 4H), 7.58 (s, 1H), 5.85 (s, 2H); 13C{1H} NMR (100 MHz, (CD3)2SO) δ 167.2, 138.7, 135.5, 131.6, 129.5, 124.1, 109.2, 52.8; Anal Calcd for C12H8ClN3O2: C, 55.08; H, 3.08; N, 16.06; Found: C, 54.73; H, 2.88; N, 16.40.
4-Bromo-1-(1-phenylethyl)-1H-pyrazole (44). Yield: 70%. IR (ATR) 3124, 3028, 2980, 2933, 1304, 987, 696 cm−1; TLC Rf = 0.37 (5% EA/95% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.25–7.17 (m, 4H), 7.10 (d, J = 6.7 Hz, 2H), 5.35 (q, J = 7.0 Hz, 1H), 1.75 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.1, 139.6, 128.9, 128.2, 128.1, 126.4, 93.1, 61.9, 21.2; Anal Calcd for C11H11BrN2: C, 52.61; H, 4.42; N, 11.16; Found: C, 52.51; H, 4.46; N, 11.28.
4-Iodo-1-(1-phenylethyl)-1H-pyrazole (46). Yield: 70%. IR (ATR) 3109, 2978, 1493, 960, 696 cm−1; TLC Rf = 0.37 (5% EA/95% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.44 (s, 1H), 7.39–7.23 (m, 5H), 5.53 (q, J = 7.0 Hz, 1H), 1.90 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.2, 141.1, 132.4, 128.9, 128.2, 126.4, 61.7, 56.2, 21.3; Anal Calcd for C11H11IN2: C, 44.32; H, 3.72; N, 9.40; Found: C, 44.02; H, 3.44; N, 9.03.
4-Methyl-1-(1-phenylethyl)-1H-pyrazole (48). Yield: 62% IR (ATR) 3085, 2980, 1493, 1340, 1156, 990 cm−1; TLC = Rf 0.63 (30% EA/70% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.36–7.27 (m, 4H), 7.21–7.18 (m, 3H), 5.48 (q, J = 7.3 Hz, 1H), 2.07 (s, 3H), 1.88 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.1, 139.2, 128.7, 127.7, 126.7, 126.3, 116.0, 60.9, 21.4, 8.9; Anal Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04; Found: C, 77.28; H, 7.55; N, 14.92.
Ethyl 1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (50). Yield: 50%. IR (ATR) 2981, 1708, 1551, 1408, 1217, 1024 cm−1; TLC Rf = 0.34 (20% EA/80% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.89 (s, 1H), 7.37–7.30 (m, 3H), 7.22 (d, J = 7.2 Hz, 2H), 5.52 (q, J = 7.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 140.8, 140.6, 131.2, 128.9, 128.3, 126.4, 115.0, 61.7, 60.1, 21.3, 14.4; Anal Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47; Found: C, 68.80; H, 6.56; N, 11.58.
4-(p-Nitrophenyl)-1-(1-phenylethyl)-1H-pyrazole (52). Yield: 43%. mp = 119–123 °C; IR (ATR) 3068, 2943, 1597, 1500, 1333, 1112 cm−1; TLC Rf = 0.35 (25% EA/75% hexanes); 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.74 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.39–7.34 (m, 3H), 7.29–7.27 (m, 2H), 5.57 (q, J = 7.1 Hz, 1H), 1.96 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.0, 141.0, 139.4, 137.1, 128.9, 128.2, 126.4, 125.9, 125.5, 124.4, 121, 61.7, 21.3; Anal Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33; Found: C, 69.66; H, 5.25; N, 14.42.
3,5-Dimethyl-1-(1-phenylethyl)-1H-pyrazole (54). Yield: 52%. TLC Rf = 0.22 (5% EA/95% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.20–7.15 (m, 2H), 7.13–7.09 (m 1H), 6.99 (d, J = 7.4 Hz, 2H), 5.73 (s, 1H), 5.24 (q, J = 7.0 Hz, 1H), 2.18 (s, 3H), 1.99 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 143.0, 138.9, 138.6, 127.2, 125.9, 105.6, 57.3, 21.8, 13.8, 11.2. This compound has been reported previously [1].
Dimethyl 1-(1-phenylethyl)-1H-pyrazole-3,5-dicarboxylate (56). Yield: 44%. mp = 74–77 °C; IR (ATR) 3141, 2988, 1719, 1456, 1218, 1086 cm−1; TLC Rf = 0.69 (20% EA/80% hexanes); 1H NMR (400 MHz, acetone-d6) δ 7.32–7.24 (m, 6H), 6.67 (q, J = 7.0 Hz, 1H), 3.86 (d, J = 3.8 Hz, 6H), 1.91 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, acetone-d6) δ 161.5, 159.3, 142.0, 141.9, 133.4, 128.5, 127.7, 126.4, 113.8, 59.8, 51.7, 51.2, 21.8; Anal Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72; Found: C, 62.42; H, 5.60; N, 9.79.
1-(1-Phenylethyl)-1H-pyrazole (58). Yield: 45%; TLC Rf = 0.33 (20% EA/80% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.56–7.55 (s, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.35–7.27 (m, 3H), 7.20–7.18 (m, 2H), 6.27 (t, = 2.0 Hz, 1H), 5.55 (q, = 7.1 Hz, 1H), 1.90 (d, J = 7.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.9, 139.0, 128.7, 127.8, 127.7, 126.3, 105.4, 61.0, 21.5. This compound has been previously reported [54].
1-(1-Phenylethyl)-1H-indazole (60). Yield: 41%. mp = 91–93 °C; IR (ATR) 3067, 2983, 1626, 1513, 1448, 1167, 1010 cm−1; TLC Rf = 0.65 (25% EA/75% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.36–7.27 (m, 6H), 7.07 (t, J = 7.5 Hz, 1H), 5.86 (q, J = 7.0 Hz, 1H), 2.06 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.1, 140.8, 128.9, 128.2, 126.6, 126.2, 121.8, 121.6, 121.5, 120.2, 117.4, 62.7, 21.6; Anal Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60; Found: C, 81.07; H, 6.12; N, 12.46.
5-Methyl-3-phenyl-1-(1-phenylethyl)-1H-pyrazole (62). Yield: 16%. IR (ATR) 3060, 2981, 2932, 1603, 1453, 1260, 764 cm−1; TLC Rf = 0.41 (10% EA/90% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.31–7.28 (m, 3H), 7.25–7.21 (m, 1H), 7.18 (d, J = 7.3 Hz, 2H), 6.36 (s, 1H), 5.47 (q, J = 7.0 Hz, 1H), 2.17 (s, 3H), 1.98 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.5, 142.6, 139.6, 133.9, 128.6, 128.5, 127.3, 126.2, 126.0, 125.6, 103.2, 58.1, 21.9, 11.3; Anal Calcd for C18H18N2: C, 84.41; H, 6.92; N, 10.68; Found: C, 82.37; H, 6.88; N, 10.70.
3-Methyl-5-phenyl-1-(1-phenylethyl)-1H-pyrazole (63). Yield: 40%. IR (ATR) 3060, 2978, 1494, 1444, 1256 759 cm−1; TLC Rf = 0.34 (10% EA/90% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.38–7.36 (m, 3H), 7.29–7.27 (m, 2H), 7.24–7.20 (m, 3H), 7.13 (d, J = 7.7 Hz, 2H), 6.09 (s, 1H), 5.45 (q, J = 7.0 Hz, 1H), 2.37 (s, 3H), 1.89 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 147.8, 144.6, 143.1, 131.2, 129.1, 128.5, 128.4, 128.3, 127.1, 126.1, 106, 57.2, 22.1, 13.8; Anal Calcd for C18H18N2: C, 84.41; H, 6.92; N, 10.68; Found: C, 82.36; H, 6.86; N, 10.64.
1-Benzhydryl-4-[(benzhydryloxy)methyl]-1H-pyrazole (65). Yield: 61%. IR (ATR): 3060, 3027, 2866, 1493, 1451, 1060, 694 cm−1; TLC Rf = 0.47 (30% EA/70% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.35–7.29 (m, 15H), 7.23 (bs, 2H), 7.12–7.10 (m, 4H), 6.77 (s, 1H), 5.40 (s, 1H), 4.43 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.9, 139.6, 139.3, 129.4, 128.7, 128.4, 128.3, 128.1, 127.5, 127.1, 118, 82.1, 69.6, 61.6; Anal Calcd for C18H18N2: C, 83.69; H, 6.09; N, 6.51; Found: C, 83.59; H, 6.19; N, 6.49.

4. Conclusions

In conclusion, a new method for the N-alkylation of pyrazoles has been developed utilizing trichloroacetimidates and camphorsulfonic acid as a Brønsted acid catalyst. This method provides ready access to N-alkyl pyrazoles which are present in a variety of medicinally relevant structures. Benzylic, phenethyl and benzhydryl trichloroacetimidates provide moderate to good yields of the N-alkyl pyrazole products. Unsymmetrical pyrazoles provide a mixture of the two possible regioisomers, with sterics controlling the which isomer is the major product. This method is differentiated from past N-alkylations in that it does not depend on transition metal catalysts or the use of strong base, instead proceeding under mild acid-catalyzed conditions.

Supplementary Materials

Supporting information (copies of 1H NMR, 13C NMR and NOESY spectra) can be downloaded at: https://www.mdpi.com/article/10.3390/org3020009/s1.

Author Contributions

Conceptualization, J.D.C., R.I.L.M. and N.A.M.; investigation, R.I.L.M. and N.A.M.; formal analysis, R.I.L.M., N.A.M. and J.D.C.; writing—original draft preparation, J.D.C., R.I.L.M. and N.A.M.; writing—review and editing, J.D.C., R.I.L.M. and N.A.M.; supervision, J.D.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Organics 03 00009 g001 550
Figure 1. Examples of Anti-Tumor N-Alkyl Pyrazoles.
Figure 1. Examples of Anti-Tumor N-Alkyl Pyrazoles.
Organics 03 00009 g001
Organics 03 00009 sch001 550
Scheme 1. Selectivity Studies on the Alkylation.
Scheme 1. Selectivity Studies on the Alkylation.
Organics 03 00009 sch001
Organics 03 00009 g002 550
Figure 2. Proposed Reaction Mechanism.
Figure 2. Proposed Reaction Mechanism.
Organics 03 00009 g002
Table
Table 1. Optimization of pyrazole N-alkylation conditions.
Table 1. Optimization of pyrazole N-alkylation conditions.
Organics 03 00009 i001
EntryCatalystSolventTemp. (°C)TimeYield
1none1,2-DCErt240
2none1,2-DCEreflux243
320 mol% TMSOTf1,2-DCE232461
420 mol% BF3•OEt21,2-DCE232468
520 mol% CSA 11,2-DCE232476
620 mol% CSAtoluene232469
720 mol% CSADCM232470
820 mol% CSAMeCN232429
910 mol% CSA1,2-DCE232462
1020 mol% CSA1,2-DCE231877
1120 mol% CSA1,2-DCE23875
1220 mol% CSA1,2-DCE23670
1320 mol% CSA1,2-DCE23471
1420 mol% CSA1,2-DCE23245
1520 mol% CSA1,2-DCEreflux471
1650 mol% CSA1,2-DCE232454
1 CSA = camphorsulfonic acid.
Table
Table 2. N-Alkylation of 4-chloropyrazole 6 with trichloroacetimidates.
Table 2. N-Alkylation of 4-chloropyrazole 6 with trichloroacetimidates.
Organics 03 00009 i002
EntryImidateProductYield (%)
1 Organics 03 00009 i003 Organics 03 00009 i00471
2 Organics 03 00009 i005 Organics 03 00009 i00697
3 Organics 03 00009 i007 Organics 03 00009 i00867
4 Organics 03 00009 i009 Organics 03 00009 i01059
5 Organics 03 00009 i011 Organics 03 00009 i01271
6 Organics 03 00009 i013 Organics 03 00009 i01498
7 Organics 03 00009 i015 Organics 03 00009 i01676
8 Organics 03 00009 i017 Organics 03 00009 i0180
9 Organics 03 00009 i019 Organics 03 00009 i02085
10 Organics 03 00009 i021 Organics 03 00009 i02298
11 Organics 03 00009 i023 Organics 03 00009 i02473
12 Organics 03 00009 i025 Organics 03 00009 i02692
13 Organics 03 00009 i027 Organics 03 00009 i02837
14 Organics 03 00009 i029 Organics 03 00009 i03062
15 Organics 03 00009 i031 Organics 03 00009 i0320
16 Organics 03 00009 i033 Organics 03 00009 i0340
17 Organics 03 00009 i035 Organics 03 00009 i0360
Table
Table 3. Pyrazole alkylations with phenethyl imidate 7.
Table 3. Pyrazole alkylations with phenethyl imidate 7.
Organics 03 00009 i037
EntryPyrazoleProductYield (%)
1 Organics 03 00009 i038 Organics 03 00009 i03971
2 Organics 03 00009 i040 Organics 03 00009 i04170
3 Organics 03 00009 i042 Organics 03 00009 i04359
4 Organics 03 00009 i044 Organics 03 00009 i04562
5 Organics 03 00009 i046 Organics 03 00009 i04750
6 Organics 03 00009 i048 Organics 03 00009 i04943
7 Organics 03 00009 i050 Organics 03 00009 i05150
8 Organics 03 00009 i052 Organics 03 00009 i05344
9 Organics 03 00009 i054 Organics 03 00009 i05545
10 Organics 03 00009 i056 Organics 03 00009 i05741
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MDPI and ACS Style

Meador, R.I.L.; Mate, N.A.; Chisholm, J.D. Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates. Organics 2022, 3, 111-121. https://doi.org/10.3390/org3020009

AMA Style

Meador RIL, Mate NA, Chisholm JD. Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates. Organics. 2022; 3(2):111-121. https://doi.org/10.3390/org3020009

Chicago/Turabian Style

Meador, Rowan I. L., Nilamber A. Mate, and John D. Chisholm. 2022. "Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates" Organics 3, no. 2: 111-121. https://doi.org/10.3390/org3020009

APA Style

Meador, R. I. L., Mate, N. A., & Chisholm, J. D. (2022). Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates. Organics, 3(2), 111-121. https://doi.org/10.3390/org3020009

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