Acid Catalyzed N-Alkylation of Pyrazoles with Trichloroacetimidates

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.


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].

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.

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. 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.

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 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][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), while the 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][12][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]. incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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]. incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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]. incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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]. incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elim nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40].  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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40].  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][12][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].   incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylation of this substrate [40].  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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  Organics 2022, 3, FOR PEER REVIEW incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elim nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].   incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylation of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elim nation in the presence of acids, and special conditions are often needed for N-alkylatio of this substrate [40]. 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][12][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].  incorporation of a powerful electron withdrawing group such as the nitro group make formation of a carbocation more difficult, and therefore this reaction did not provide an product. This trend was also apparent when benzyl imidates were investigated (entrie [11][12][13], as the best yield was obtained with the 4-methoxybenzyl imidate 31 (92%), whil the 4-chlorobenzyl imidate 33 only gave 37% of the pyrazole product 34. The methyl, ally and tert-butyl imidates failed to provide any of the N-alkyl pyrazole products, only re turning the starting materials under these reaction conditions. The methyl imidate canno form a requisite carbocation, so its lack of reactivity is not unexpected. Allyl imidate 3 can rapidly rearrange to the acetamide via a [3,3]-sigmatropic process, which may com pete with alkylation [39]. The tert-butyl imidate has been shown to undergo rapid elimi nation in the presence of acids, and special conditions are often needed for N-alkylation of this substrate [40]. 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][12][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. Table 3. Pyrazole alkylations with phenethyl imidate 7.
FOR PEER REVIEW 4 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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.
Organics 2022, 3, FOR PEER REVIEW 5 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.

Scheme 1. Selectivity Studies on the Alkylation.
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.

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.
Organics 2022, 3, FOR PEER REVIEW 5 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.

Scheme 1. Selectivity Studies on the Alkylation.
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.

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.

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.

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. NaHCO 3 and brine, dried (Na 2 SO 4 ) 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.

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.