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Article

An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors

by
Terungwa H. Iorkula
,
Bryce A. Tolman
,
Latifat O. Ganiyu
and
Matt A. Peterson
*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(3), 458; https://doi.org/10.3390/molecules30030458
Submission received: 16 November 2024 / Revised: 18 January 2025 / Accepted: 18 January 2025 / Published: 21 January 2025
(This article belongs to the Special Issue Advances in the Synthesis of Heterocyclic Compounds and Their Applications)
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Abstract

:
An efficient method has been developed for the rapid production of diverse arrays of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines. The method utilizes CuI (5 mol%) and carbazole-based ligand L-1 (N-(9H-carbazol-9-yl)-1H-pyrrole-2-carboxamide) (10 mol%) for efficient Ullmann-type coupling of various amines to 5-amino-3-bromopyrazolo[1,5-a]pyrimidine precursors after heating in diethylene glycol (DEG) for only 1 h at 80 °C (microwave heating). 3,5-Bis-aminated products were obtained in good to excellent yields (60–93%, 83% average for 29 examples). 1° and 2° alkylamines, as well as a variety of aryl- or heteroarylamines coupled efficiently, and 1° and 2° alkyl (or aryl) amines at C-5 were well tolerated. The optimized conditions worked well on both the 50 mg and 1.0 g scales and gave products in only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine. Advantages provided by this method include short reaction time, excellent yields, broad substrate scope, and avoidance of toxic reagents commonly utilized for reductive aminations of C-3 NH2 substituted precursors.

Graphical Abstract

1. Introduction

The pyrazolo[1,5-a]pyrimidine scaffold (1) is a versatile template that has been extensively investigated for a number of important medicinal and biologically relevant applications. For example, pyrazolo[1,5-a]pyrimidine derivatives have been investigated as potential therapeutics for diabetes [1], cancer [2], neurodegenerative diseases [3], and various infectious diseases, including viral [4], protozoal [5], fungal [6], trypanosomal [7], and bacterial infections [8]. In addition, pyrazolo[1,5-a]pyrimidines have been used in dyes [9], fluorophores [10], chemosensors [11], tumor imaging [12], and as inhibitors of protein or lipid kinases [13]. Anti-inflammatory [14], anti-anxiolytic [15], and sedative-hypnotic [16] properties have also been reported. The clinical anticancer drugs Larotrectinib [17] and Reprotrectinib [18], along with several other structurally related clinical [19] or preclinical [13] candidates, as well as other promising disease-related enzyme inhibitors [20], have stimulated increased interest in the pyrazolo[1,5-a]pyrimidine scaffold (Figure 1). Of particular interest in recent years has been the synthesis and biological evaluation of C-3 aminated analogs, as underscored by the number of recently reported methodologies for converting C-3 brominated precursors to C-3 aminated derivatives (Figure 2) [21,22,23,24,25,26]. These methods involve transition-metal-catalyzed Buchwald-Hartwig or Ullmann-type coupling reactions, whereas the originally reported method for preparing Larotrectinib involved the reduction of a C-3 nitro group followed by a two-step formation of the urea (Figure 3) [27,28]. The most commonly reported methods for preparing 3,5-bis-aminated
pyrazolo[1,5-a]pyrimidine derivatives have either followed the route originally reported for Larotrectinib or related approaches varying essentially only in the order of C-3 nitration, reduction, and/or C-5 Nucleophilic Aromatic Substitution (SNAr) (Figure 3) [13,20,27,28,29]. Although these methods have provided compound libraries for SAR (Structure Activity Relationship) screening, they suffer from several drawbacks, including low yields, multiple steps, and/or limited synthetic versatility for functionalizing the C-3 NH2 moiety. Indeed, the C-3 NH2 of C-5 aminated derivatives has so far only been converted to ureas or thioureas via two-step carbamoylation/amination or to the N(CH3)2 group via reductive amination utilizing toxic reagents paraformaldehyde and NaBH3CN (Figure 3). Ideally, a synthetic method that avoids these limitations would provide efficient access to a broader array of analogs in short reaction times, high yields, and fewer steps, and it would avoid the use of toxic reagents. Given the considerable biological potential of such derivatives, methods meeting these criteria are highly desirable. Here, we report a new method that achieves these objectives, giving 3,5-bis-aminated products in 83% yield (average from 29 examples), utilizing 5 mol% of CuI catalyst and 10 mol% of carbazole-based ligand (L-1) after heating for only 1 h at 80 °C for C-3 amination. The reaction proceeded in only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (Scheme 1) and provided a broad array of 3,5-bis-aminated products in good to excellent yields (Table 2). Substrates with both 1° alkyl (or aryl) and 2° alkylamines at C-5 were coupled effectively, and efficient C-3 amination was achieved using a variety of 1° or 2° alkylamine as well as aryl- and heteroarylamine C-3 coupling partners. With this method, rapid and efficient access to diverse libraries of 3,5-bis-aminated derivatives consisting of previously unavailable analogs is now readily attainable.

2. Results

2.1. Optimization

2.1.1. Temperature, Solvent, and Base

From the recent report by Huang and co-workers wherein L-1 was shown to promote the efficient N-arylation of cyclopropylamine with arylbromides and a CuI catalyst at room temperature [30], we became interested in the possibility that this novel ligand might prove useful for preparing 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines that were inaccessible via previously published methods (see Figure 2 and Figure 3). Despite the fact that our previous L-proline/CuI method worked well for preparing C-3 mono-aminated derivatives from substrates that lacked a C-5 amino substituent (see Figure 2f) [26], the yields for converting C-5 amino substituted precursors (e.g., 29a or 29b) to 3,5-bis-aminated products 30 were consistently (and unacceptably) low (<35%), with much of the mass balance being attributed to the debrominated byproduct (e.g., 31). In order to determine if the L-1/CuI catalyst system could overcome this limitation, we applied Huang’s conditions, utilizing 29a and morpholine as our model system (Table 1, entry 1). Disappointingly, L-1/CuI failed to produce any detectable amount of 30e, and only unreacted starting material 29a (with trace amounts of 31) were detected, even after 7 days at RT (Table 1, entry 1). Heating the reaction at incrementally higher temperatures (50–70 °C, using an oil bath) for 1–2 days gave a slightly better conversion, but substantial quantities of unreacted starting material (70–92%) remained (Table 1, entries 2–3). Heating at 80 °C was required for the complete conversion of 29a; however, 18% of the debrominated byproduct (31) was also obtained (Table 1, entry 4). Next, microwave heating was examined. Encouragingly, our first attempt with microwave heating (Table 1, entry 5) gave 61.4% 30e, with 1.4% of the debrominated byproduct 31 after heating for only 30 min at 70 °C. Increasing the reaction time (from 30 min to 3h) at 70 °C gave increased conversions, but debromination also increased from 1.8–2.7% (Table 1, entries 5–9). Microwave heating at 80 °C for 1 h gave approximately equivalent results to the reaction run at 70 °C for 3 h (Table 1, entries 9 and 11), while a reaction time of 30 min at 80 °C left 4.4% unreacted 29a (Table 1, entries 10–11). A longer reaction time at 80 °C (1.5 h) gave product with essentially identical conversion to that obtained after only 1 h (Table 1, entries 11–12). At this point, it seemed reasonable to perform a solvent survey in order to confirm that, in keeping with Huang’s observations regarding arylation of cyclopropylamine with L-1/CuI, diethylene glycol (DEG) was the most suitable solvent [30]. Accordingly, six common polar solvents were evaluated (Table 1, entries 13–18). Of these solvents, ethylene glycol and 1,2-propanediol gave comparable results (90–94% conversion), but suffered from higher percentages of debromination (5.7–9.9%, Table 1, entries 13 and 18). NMP gave a lower yield (78%) with 19% debromination (Table 1, entry 17). The reaction in 1,4-dioxane failed to give any detectable C-3 aminated product (entry 16), while n-butanol and DMSO gave only 3.6–10.2% conversion, respectively (Table 1, entries 14–15). Next, a survey of four bases commonly used for transition-metal-catalyzed coupling was conducted (Table 1, entries 19–22). The inorganic base K3PO4 gave inferior conversion (94% compared to 97%), while tBuOK and TMSONa gave product 30e in yields comparable to those obtained with K2CO3 (Table 1, entries 11 and 19–20). DBU afforded the least effective conversion (48.8%; Table 1, entry 22). Based on these data and the relative cost efficiency of K2CO3 compared to TMSONa (which is approx. 55-fold more expensive than K2CO3 on a 100 g basis), we opted to use the conditions in entry 11 (80 °C, 1 h, DEG, K2CO3) for further optimization and substrate scope determination (vide infra).

2.1.2. Ligand and C-3 Halogenated Precursor

A brief survey of structurally related ligands (L-2, L-3, and L-4) further confirmed the suitability of the L-1/CuI catalyst system (Table 1, entries 23–25). Notably, L-2 (which was recently shown to promote the efficient CuI-catalyzed arylation of phenols) [31] gave a nearly 2:1 ratio of debrominated 31:30e, while L-3 and L-4 gave substantially less efficient conversions (12–17%) under our optimized microwave conditions. In order to confirm the suitability of the C-3 brominated precursors, we also screened 3-chloro and 3-iodo derivatives (32a–b) using our optimized conditions (Scheme 2). The reaction for the 3-chloro derivative was markedly inferior (<4% conversion), while the 3-iodo derivative gave excellent yields but suffered from greater dehalogenated byproduct (31) compared to the 3-bromo derivative 29a (5.4 and 2.9%, respectively).

3. Discussion

Using the optimized conditions established in our preliminary experiments (Table 1 and Scheme 2), we applied this methodology to the substrates listed in Table 2. We were pleased to note the broad substrate scope and functional group compatibility exemplified by a variety of 1° alkyl and 2° alkylamines and aryl- or heteroarylamines, with key functionalities such as azides or BOC groups being well tolerated (Table 2). However, amides and ureas did not couple efficiently with our method (and the coupling products from those substrates formed in only trace amounts under our optimized conditions). Notwithstanding, the substrate scope presented in Table 2 is the broadest and most comprehensive scope of 3,5-bis-aminated products yet to be reported for the pyrazolo[1,5-a]pyrimidine scaffold coupled with alkyl- or arylamines [21,22,23,24,25,26,27,28]. Previous methods have been restricted to only C-3 mono-aminated derivates or an extremely limited number of 3,5-bis-aminated products, as illustrated in Figure 3. (The reactions highlighted in Figure 3 are summarized from an exhaustive Scifinder Scholar search conducted in November 2024). These methods were limited to either C-3 ureas, urethanes, or the (CH3)2N group, each of which was obtained via a somewhat circuitous approach requiring C-3 nitration, followed by reduction, with a final step involving either acylation or reductive amination. In our case, C-5 alkylamine- or arylamine-substituted precursors were obtained directly in one step from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (Scheme 1). C-3 amination of both C-5 alkylamine and C-5 arylamine substrates worked equally well, and 29a–b and 29c–e gave 3,5-bis-aminated products in 82.2% and 83.1% (average yields, respectively). Thus, a broad range of 3,5-bis-aminated products, consisting of both 3,5-bis arylamine, 3,5-bis alkylamine, or 3,5-bis alkyl/aryl amine combinations, could be efficiently obtained in only two steps utilizing our method. The functional group tolerance is noteworthy, given the significant potential that derivatives such as 30d, 30g, 30n, and 30z–c’ have for further elaboration into more complex libraries of compounds. Facile TFA-promoted cleavage of the BOC protecting groups or reduction of the azide would provide the corresponding amine products for further functionalization, and the aryl chloride moieties of 30z–c’ could also be used for Suzuki-Miyaura coupling. An additional advantage of azide 30n is its potential use in conventional “click” coupling chemistry for conjugating biologically relevant payloads for biological applications.
3,5-Bis-aminated derivatives with other C-5 amino groups could also be envisioned since model substrates 29a–e establish that a variety of alkyl or aryl amines at this position are well tolerated. Advantages of this method include rapid reaction time (1 h for C-3 amination), high yield (83% average for all 29 substrates examined), avoidance of toxic reagents such as paraformaldehyde and NaBH3CN, and a short reaction sequence (only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine). In addition, our method avoids expensive air- and moisture-sensitive palladium catalysts and provides much greater synthetic versatility than any previously reported method (Figure 2 and Figure 3). Perhaps the most striking drawback of the previous methods for 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines is their limited scope (limited to C-3 ureas or dimethylamine). Our method opens up the possibility of preparing much broader, diversity-rich compound libraries for screening novel and/or enhanced biological, medicinal, or fluorometric properties.
Table 2. Substrate scope for C-3 amination. a,b,c
Table 2. Substrate scope for C-3 amination. a,b,c
Molecules 30 00458 i002
Molecules 30 00458 i003
a Reaction conditions: 29a–e (50 mg, 0.15–0.20 mmol), amine (1.5 equiv.), K2CO3 (2.0 equiv.), CuI (5 mol%), L-1 (10 mol%), diethyleneglycol (DEG) (1.0 mL); b Isolated yields; c Reaction performed on 1.0 g (3.80 mmol) scale.

4. Materials and Methods

4.1. General Experimental

All reactions were performed in either appropriately sized pressure vessels (conventional heating) or in 10 mL microreactor vessels (microwave heating) without previous drying, unless otherwise noted. Conventional heating was performed in an oil bath, and microwave heating was achieved using a CEM Microwave reactor. Reagent-grade solvents and all other reagents were used directly as supplied by commercial suppliers without additional drying or purification. 1H NMR and 13C NMR spectra were determined in CDCl3 or DMSO-d6 using internal references: δ 7.27 or 2.50 (1H) and δ 77.23 or 39.52 (13C), respectively. Abbreviations such as “d”, “t”, or “bs” refer to “apparent doublet”, “apparent triplet”, or “apparent broad singlet”, where such apparent multiplicities represent experimentally observed splitting patterns that result from line-broadening caused by conformational isomerism and/or concentration. High-resolution mass spectra were obtained using fast atom bombardment electrospray (ES) ionization techniques and had errors of less than ±5 ppm.

4.2. Ligand Synthesis

The method for preparing ligands L-1, L-2, L-3, and L-4 is a modification of the method reported by Huang and co-workers [30] (Supplementary Materials, Scheme S1). In our hands, their method for preparing L-1, which employed SOCl2 for generating an acyl chloride from pyrrole 2-carboxylic acid, consistently gave yields <35%, even after rigorous drying of glassware, solvents, and reagents. We employed Ph3P/NIS to generate a reactive acyl iodide intermediate [32,33] and obtained the desired amidation of N-amino-9H-carbazole [34] in higher yields (38–67%; ave = 49%). (Scheme S1).

4.3. 5-Amino-3-Bromopyrazolo[1,5-a]Pyrimidines 29

General Procedure: A solution of 28 (200 mg, 0.86 mmol), pyrrolidine (123 mg, 1.73 mmol, 2.0 equiv), CsF (131 mg, 0.86 mmol, 1.0 equiv), and BnNEt3Cl (20 mg, 0.088 mmol, 10 mol%), in DMSO (6 mL) was stirred in a sealed pressure vessel (15 mL) and heated at 100 °C for 8 h [32,35]. After cooling to ambient temperature, H2O (60 mL) was added. The mixture was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was partitioned with EtOAc (2 × 60 mL) and the combined organic layers were washed with saturated sodium bicarbonate solution (2 × 60 mL) and water (2 × 60 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified using flash chromatography (EtOAc/Hexanes) to give pure 29a (222 mg, 0.83 mmol, 97%).
  • 3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (29a)
3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (200 mg, 0.86 mmol), pyrrolidine (123 mg, 1.73 mmol, 2.0 equiv), CsF (131 mg, 0.86 mmol, 1.0 equiv), BnNEt3Cl (20 mg, 0.088 mmol,10 mol%), DMSO (6 mL); 29a (222 mg, 0.83 mmol, 97%); 1H NMR (DMSO-d6, 500 MHz) δ 8.70 (d, J = 7.7 Hz, 1H), 8.01 (s, 1H), 6.53 (d, J = 7.7 Hz, 1H), 3.62 (“bs”, 4H), 2.06 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 154.5, 145.5, 144.0, 136.2, 99.2, 76.9, 47.2, 25.7, 24.9; HRMS Calcd. for C10H12BrN4 [M + H]: 267.0245; Found: 267.0237 (∆ = 3.0 ppm).
  • 3-Bromo-5-(N-(isopropyl)amino)pyrazolo[1,5-a]pyrimidine (29b)
3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (100 mg, 0.43 mmol), isopropylamine (51 mg, 0.86 mmol, 2.0 equiv), CsF (65 mg, 0.43 mmol, 1.0 equiv), BnNEt3Cl (10 mg, 0.044 mmol,10 mol%), DMSO (3 mL); 29b (105 mg, 0.41 mmol, 96%); 1H NMR (DMSO-d6, 500 MHz) δ 8.42 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.23 (d, J = 7.4 Hz, 1H), 4.15 (“d”, J = 5.0 Hz, 1H), 1.19 (d, J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 155.8, 145.6, 143.5, 135.6, 101.6, 77.5, 42.1, 22.5; HRMS Calcd. for C9H12BrN4 [M + H]: 255.0245; Found: 255.0237 (∆ = 3.1 ppm).
  • 3-Bromo-5-(4-(methoxy)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (29c)
3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (400 mg, 1.73 mmol), 4-methoxyaniline (426 mg, 3.46 mmol, 2.0 equiv), CsF (263 mg, 1.73 mmol, 1.0 equiv), BnNEt3Cl (39 mg, 0.172 mmol,10 mol%), DMSO (12 mL); 29c (473 mg, 1.49 mmol, 86%); 1H NMR (DMSO-d6, 500 MHz) δ 9.73 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 7.6 Hz, 1H), 3.76 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 155.3, 153.9, 144.9, 143.9, 136.4, 133.5, 121.2, 114.5, 102.1, 78.8, 55.7; HRMS Calcd. for C13H12BrN4O [M + H]: 319.0194; Found: 319.0181 (∆ = 4.1 ppm).
  • 3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (29d)
3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (400 mg, 0.43 mmol), 4-isopropylaniline (467 mg, 3.46 mmol, 2.0 equiv), CsF (263 mg, 1.73 mmol, 1.0 equiv), BnNEt3Cl (39 mg, 0.172 mmol,10 mol%), DMSO (12 mL); 29d (525 mg, 1.59 mmol, 92%); 1H NMR (DMSO-d6, 500 MHz) δ 9.82 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 2.83 (sept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 153.9, 144.8, 143.9, 143.2, 138.0, 136.4, 127.0, 119.8, 102.3, 79.0, 33.3, 24.4; HRMS Calcd. for C15H16BrN4 [M + H]: 331.0558; Found: 331.0556 (∆ = 0.6 ppm).
  • 3-Bomo-5-(4-(chloro)anilin-1-yl)-pyrazolo[1,5-a]pyrimidine (29e)
3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (400 mg, 1.73 mmol), 4-chloroaniline (439 mg, 3.46 mmol, 2.0 equiv), CsF (263 mg, 1.73 mmol, 1.0 equiv), BnNEt3Cl (39 mg, 0.172 mmol,10 mol%), DMSO (12 mL); 29e (312 mg, 0.97 mmol, 56%); δ 10.04 (s, 1H), 8.67 (d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 153.7, 144.5, 144.1, 139.3, 136.8, 129.1, 126.5, 121.0, 102.3, 79.4; HRMS Calcd. for C12H9BrClN4 [M + H]: 322.9699; Found: 322.9694 (∆ = 1.5 ppm).

4.4. 3,5-Bis-Aminopyrazolo[1,5-a]Pyrimidines 30

General Procedure: A solution of 3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (29a) (50 mg, 0.19 mmol), morpholine (25 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.) in diethyleneglycol (DEG, 1 mL) was stirred in a 10 mL microwave reactor vessel and heated at 80 °C for 1 h. After cooling to ambient temperature, H2O (5 mL) was added. The mixture was diluted with CH2Cl2 (5 mL) and the organic layer was separated. The aqueous layer was partitioned with CH2Cl2 (2 × 10 mL), and the combined organic layers were washed with brine (2 × 10 mL), followed by water (2 × 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and removed under reduced pressure. The crude product was then purified using flash chromatography (EtOAc/Hexanes or MeOH/CH2Cl2) to give pure product 30e (48 mg, 0.176 mmol, 92%).
  • 3-(N-(Isopropyl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30a)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), isopropylamine (17 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30a (42 mg, 0.171 mmol, 90%); 1H NMR (DMSO-d6, 500 MHz) δ 8.39 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 6.23 (d, J = 7.7 Hz, 1H), 3.47–3.41 (m, 5H), 1.94 (t, J = 6.4 Hz, 4H), 1.07 (d, J = 6.3 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 152.2, 138.7, 136.6, 135.6, 116.3, 97.7, 47.8, 47.0, 25.4, 23.7; HRMS Calcd. for C13H20N5 [M + H]: 246.1719; Found: 246.1712 (∆ = 2.8 ppm).
  • 3-(N-(Cyclohexyl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30b)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), cyclohexylamine (29 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30b (49 mg, 0.172 mmol, 91%); 1H NMR (DMSO-d6, 500 MHz) δ 8.38 (d, J = 7.7 Hz, 1H), 7.50 (s, 1H), 6.22 (d, J = 7.7 Hz, 1H), 3.47 (‘bs’, 4H), 3.12 (t, J = 9.7 Hz, 1H), 1.95 (t, J = 6.3 Hz, 4H), 1.89–1.87 (m, 2H), 1.70– 1.68 (m, 2H), 1.57–1.55 (m, 1H), 1.26–1.09 (m, 5H); 13C NMR (DMSO-d6, 125 MHz) δ 152.1, 138.5, 136.6, 135.6, 115.9, 97.7, 72.7, 60.7, 55.4, 47.0, 33.8, 26.2, 25.4, 25.1; HRMS Calcd. for C16H24N5 [M + H]: 286.2032; Found: 286.2024 (∆ = 2.8 ppm).
  • 3-(N-((Cyclopropyl)methyl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30c)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), cyclopropylamine (21 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30c (29 mg, 0.113 mmol, 60%); 1H NMR (CDCl3, 500 MHz) δ 8.11 (d, J = 7.7 Hz, 1H), 7.61 (s, 1H), 6.04 (d, J = 7.2 Hz, 1H), 3.55 (“bs”, 4H), 2.98 (d, J = 6.9 Hz, 2H), 2.02 (t, J = 6.6 Hz, 4H), 1.17–1.13 (m, 1H), 0.53 (dd, J = 12.6, 5.5 Hz, 2H), 0.23 (dd, J = 10, 4.9 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 152.2, 138.7, 135.3, 134.7, 117.5, 97.2, 54.1, 46.9, 25.5, 11.6, 3.4; HRMS Calcd. for C14H20N5 [M + H]: 258.1719; Found: 258.1704 (∆ = 2.7 ppm).
  • 3-[2-(tert-Butyloxycarbonyl)amino)-1-N-methylamino)ethyl]-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30d)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 1-(tert-butyloxycarbonylamino)-2-(N-methylamino)ethane (51 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30d (60 mg, 0.167 mmol, 88%); 1H NMR (CDCl3, 500 MHz) δ 8.07 (d, J = 7.7 Hz, 1H), 7.67 (s, 1H), 6.42 (s, 1H), 6.02 (d, J = 7.7 Hz, 1H), 3.53 (“bs”, 4H), 3.12–3.09 (m, 2H), 2.97–2.95 (m, 2H), 2.77 (s, 3H), 1.97 (“bs”, 4H), 1.38 (s, 9H); 13C NMR CDCl3, 125 MHz) δ 156.2, 152.7, 141.5, 137.4, 135.1, 119.6, 97.6, 78.5, 57.6, 47.1, 43.0, 38.8, 28.6, 25.5; HRMS Calcd. for C18H29N6O2 [M + H]: 361.2352; Found: 361.2344 (∆ = 2.2 ppm).
  • 3-(Morpholin-1-yl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30e)
(a) 50 mg scale: 3-bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine 29a (50 mg, 0.19 mmol), morpholine (25 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30e (48 mg, 0.176 mmol, 92%); (b) 1.0 g scale: 29a (1.0 g, 3.8 mmol), morpholine (496 mg, 5.7 mmol, 1.5 equiv.), L-1 (105 mg, 0.38 mmol, 10 mol%), CuI (36 mg, 0.19 mmol, 5 mol%), and K2CO3 (1.04 g, 7.6 mmol, 2 equiv.); 30e (913 mg, 3.34 mmol, 88%); 1H NMR (DMSO-d6, 500 MHz) δ 8.45 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 3.74 (t, J = 4.6 Hz, 4H), 3.47 (t, J = 6.6 Hz, 4H), 3.09 (t, J = 4.4 Hz, 4H), 1.95 (“bs”, 4H); 13C NMR (CDCl3, 125 MHz) δ 152.0, 139.4, 134.8, 134.3, 120.6, 97.4, 67.0, 51.5, 46.8, 25.4; HRMS Calcd. for C14H20N5O [M + H]: 274.1668; Found: 274.1659 (∆ = 3.3 ppm).
  • 3-(Piperidin-1-yl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30f)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), piperidine (25 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30f (48 mg, 0.177 mmol, 93%); 1H NMR (DMSO-d6, 500 MHz) δ 8.42 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 6.28 (d, J = 7.7 Hz, 1H), 3.47 (t, J = 6.5 Hz, 4H), 3.05 (t, J = 5.1 Hz, 4H), 1.95 (“bs”, 4H), 1.65–1.61 (m, 4H), 1.51– 1.46 (m, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 151.9, 138.5, 135.7, 134.5, 121.7, 97.9, 52.2, 46.9, 25.9, 25.4, 24.4; HRMS Calcd. for C15H22N5 [M + H]: 272.1875; Found: 272.1875 (∆ = 2.9 ppm).
  • tert-Butyl 4-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperazine-1-carboxylate (30g)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), tert-butyl piperazine-1-carboxylate (54 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30g (45 mg, 0.120 mmol, 64%); 1H NMR (DMSO-d6, 500 MHz) δ 8.44 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 6.29 (d, J = 7.7 Hz, 1H), 3.48–3.30 (m, 8H), 3.04 (t, J = 4.7 Hz, 4H), 1.94 (“bs”, 4H), 1.42 (s, 9H); 13C NMR (DMSO-d6, 125 MHz) δ 154.4, 152.1, 138.8, 135.8, 134.8, 120.2, 98.1, 79.3, 50.9, 47.0, 28.5, 25.4; HRMS Calcd. for C19H29N6O2 [M + H]: 373.2352; Found: 373.2347 (∆ = 1.3 ppm).
  • 3-(4-(tert-Butyl)anilin-1-yl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30h)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 4-tert-butylaniline (43 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30h (56 mg, 0.167 mmol, 88%); 1H NMR (DMSO-d6, 500 MHz) δ 8.53 (d, J = 7.7 Hz, 1H), 7.78 (s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.87 (s, 1H), 6.55 (dd, J = 6.8, 1.9 Hz, 2H), 6.35 (d, J = 7.8Hz, 1H), 3.45 (t, J = 6.4 Hz, 4H), 1.92 (“bs”, 4H), 1.21 (s, 9H); 13C NMR (DMSO-d6, 125 MHz) δ 153.4, 146.7, 143.3, 142.4, 138.8, 136.0, 125.8, 112.7, 108.4, 98.3, 47.2, 33.9, 32.0, 25.4; HRMS Calcd. for C20H26N5 [M + H]: 336.2188; Found: 336.2196 (∆ = 2.4 ppm).
  • 3-(4-(Phenoxy)anilin-1-yl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30i)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 4-phenoxyaniline (54 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30i (59 mg, 0.160 mmol, 84%); 1H NMR (DMSO-d6, 500 MHz) δ 8.54 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.30 (dd, J = 8.4, 7.6 Hz, 2H), 7.10 (s, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 2H), 6.82 (dd, J = 12.2, 3.3 Hz, 2H), 6.66–6.63 (m, 2H), 6.36 (d, J = 7.8 Hz, 1H), 3.46 (t, J = 6.4 Hz, 4H) 1.93 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 159.4, 153.4, 146.3, 145.9, 143.2, 142.3, 136.1, 130.1, 122.2, 121.3, 116.9, 114.1, 108.3, 98.3, 47.2, 25.3; HRMS Calcd. for C22H22N5O [M + H]: 372.1824; Found: 372.1830 (∆ = 1.6 ppm).
  • 3-((4-Methoxy-3-methyl)anilin-1-yl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30j)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 4-methoxy-3-methylaniline (40 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30j (50 mg, 0.156 mmol, 82%); 1H NMR (DMSO-d6, 500 MHz) δ 8.52 (d, J = 7.7 Hz, 1H), 7.76 (s, 1H), 6.66 (d, J = 8.7 Hz, 1H), 6.60 (s, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.7, 2.7 Hz, 1H), 6.34 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H), 3.45 (t, J = 6.4Hz, 4H), 2.03 (s, 3H), 1.93 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 153.3, 149.6, 143.0, 142.8, 142.1, 136.0, 126.3, 116.1, 112.0, 110.9, 109.2, 98.2, 56.1, 47.1, 25.4, 16.7; HRMS Calcd. for C18H22N5O [M + H]: 324.1824; Found: 324.1817 (∆ = 2.2 ppm).
  • 3-(N-(Pyrimidin-2-yl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30k)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 2-aminopyrimidine (28 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30k (45 mg, 0.160 mmol, 84%); 1H NMR (DMSO-d6, 500 MHz) δ 8.53 (d, J = 7.7 Hz, 1H), 8.31 (t, J = 4.7 Hz, 3H), 7.95 (s, 1H), 6.66 (t, J = 4.8 Hz, 1H), 6.35 (d, J = 7.7 Hz, 1H), 3.47 (t, J = 6.6 Hz, 4H), 1.93 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 162.3, 158.5, 153.4, 142.1, 141.6, 135.8, 111.4, 105.9, 98.3, 47.1, 25.4; HRMS Calcd. for C14H16N7 [M + H]: 282.1467; Found: 282.1459 (∆ = 2.8 ppm).
  • 3-(N-(Pyrazol-3-yl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30l)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 3-aminopyrazole (24 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30l (42 mg, 0.156 mmol, 82%); 1H NMR (DMSO-d6, 500 MHz) δ 8.64 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.26 (d, J = 1.8 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 5.65 (s, 2H), 5.41 (d, J = 1.8 Hz, 1H), 3.50 (“bs”, 4H), 1.97 (“bs”, 4H); 13C NMR (DMSO, 125 MHz) δ 153.7, 148.0, 140.4, 139.7, 139.4, 136.6, 108.1, 98.8, 88.7, 47.3, 25.8; HRMS Calcd. for C13H16N7 [M + H]: 270.1467; Found: 270.1460 (∆ = 2.6 ppm).
  • 3-(N-(5-Bromopyrazol-3-yl)amino)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (30m)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 3-amino-5-bromopyrazole (47 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30m (44 mg, 0.127 mmol, 67%); 1H NMR (DMSO-d6, 500 MHz) δ 8.65 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.41 (s, 1H), 6.48 (d, J = 7.8 Hz, 1H), 5.79 (bs, 1H), 5.76 (s, 1H), 3.51 (“bs”, 4H), 1.98 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 153.8, 145.4, 139.9, 139.6, 136.6, 107.6, 99.0, 74.0, 47.4, 25.8, 24.8; HRMS Calcd. for C13H15N7Br [M + H]: 348.0572; Found: 348.0566 (∆ = 1.7 ppm).
  • N-(2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethyl)-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (30n)
3-Bromo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.19 mmol), 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine (63 mg, 0.29 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30n (51 mg, 0.126 mmol, 66%); 1H NMR (CDCl3, 500 MHz) δ 8.02 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 6.04 (d, J = 7.7 Hz, 1H), 3.70–3.66 (m, 12H), 3.54 (“bs”, 4H), 3.37 (t, J = 5.0 Hz, 2H), 3.33 (t, J = 5.3 Hz, 2H), 2.03–2.00 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 152.1, 137.5, 135.6, 134.7, 117.6, 97.8, 70.30, 70.29, 70.23, 70.17, 70.13, 69.7, 50.4, 47.3, 47.0, 25.4; HRMS Calcd. for C18H29N8O3 [M + H]: 405.2363; Found: 405.2382 (∆ = 4.7 ppm).
  • 5-(N-(Isopropyl)amino)-3-(2-N-(thiophen-2-yl)ethylamino)pyrazolo[1,5-a]pyrimidine (30o)
3-Bromo-5-(N-(isopropyl)amino)pyrazolo[1,5-a]pyrimidine (50 mg, 0.20 mmol), 2-(thiophen-2-yl)ethan-1-amine (38 mg, 0.30 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30o (54 mg, 0.180 mmol, 90%); 1H NMR (DMSO-d6, 500 MHz) δ 8.22 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.31 (dd, J = 5.1, 1.2 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.94 (dd, J = 5.1, 3.4 Hz, 1H), 6.90 (dd, J = 3.3 Hz, Jz = 1.0 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 4.12–4.06 (m, 1H), 3.82 (s, 1H), 3.32 (t, J = 7.1 Hz, 2H), 3.02 (t, J = 7.2 Hz, 2H), 1.17 (d, J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 153.1, 142.8, 137.8, 135.0, 134.8, 127.4, 125.4, 124.1, 117.3, 100.3, 49.6, 42.0, 30.5, 22.7; HRMS Calcd. for C15H20N5S [M + H]: 302.1439; Found: 302.1428 (∆ = 3.6 ppm).
  • 3-(4-(tert-Butyl)anilin-1-yl)-5-(N-(isopropyl)amino)pyrazolo[1,5-a]pyrimidine (30p)
3-Bromo-5-(N-(isopropyl)amino)pyrazolo[1,5-a]pyrimidine (50 mg, 0.20 mmol), 4-tert-butylaniline (45 mg, 0.30 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30p (56 mg, 0.173 mmol, 87%); 1H NMR (DMSO-d6, 500 MHz) δ 8.35 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.84 (s, 1H), 6.56 (d, J = 8.7 Hz, 2H), 6.16 (d, J = 7.6 Hz, 1H), 4.06–4.00 (m, 1H), 1.20 (s, 9H), 1.12 (d, J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 154.5, 146.5, 143.1, 141.6, 138.9, 135.5, 125.7, 112.9, 108.9, 100.6, 41.9, 33.9, 31.9, 22.7; HRMS Calcd. for C19H26N5 [M + H]: 324.2188; Found: 324.2174 (∆ = 4.3 ppm).
  • 5-(N-(Isopropyl)amino)-3-(morpholin-1-yl)pyrazolo[1,5-a]pyrimidine (30q)
3-Bromo-5-(N-(isopropyl)amino)pyrazolo[1,5-a]pyrimidine (50 mg, 0.20 mmol), morpholine (26 mg, 0.30 mmol, 1.5 equiv.), L-1 (6 mg, 0.02 mmol, 10 mol%), CuI (2 mg, 0.01 mmol, 5 mol%), and K2CO3 (52 mg, 0.38 mmol, 2 equiv.); 30q (47 mg, 0.180 mmol, 90%); 1H NMR (DMSO-d6, 500 MHz) δ 8.28 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J = 7.0 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 4.06–4.00 (m, 1H), 3.72 (t, J = 4.6 Hz, 4H), 3.08 (“bs”, 4H), 1.17 (d, J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 152.0, 137.5, 134.3, 133.0, 119.8, 99.3, 65.5, 50.6, 41.1, 21.5; HRMS Calcd. for C13H20N5O [M + H]: 262.1668; Found: 262.1656 (∆ = 4.6 ppm).
  • 3-(N-(Isopropyl)amino)-5-(4-(methoxy)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (30r)
3-Bromo-5-(4-(methoxy)anilin-1-yl)-pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), isopropylamine (14 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30r (43 mg, 0.145 mmol, 91%); 1H NMR (DMSO-d6, 500 MHz) δ 9.31 (s, 1H), 8.40 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.55 (s, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.29 (d, J = 7.6 Hz, 1H), 3.74 (s, 3H), 3.65–3.60 (bs, 1H), 3.53 (sept, J = 6.3 Hz, 1H), 1.12 (d, J = 6.2 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 154.6, 150.7, 137.2, 136.3, 135.7, 134.4, 120.5, 117.8, 114.3, 100.7, 55.6, 47.9, 23.7; HRMS Calcd. for C16H20N5O [M + H]: 298.1668; Found: 298.1668 (∆ = 0 ppm).
  • 5-(4-(Methoxy)anilin-1-yl)-3-(morpholin-1-yl)pyrazolo[1,5-a]pyrimidine (30s)
3-Bromo-5-(4-(methoxy)anilin-1-yl)-pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), morpholine (21 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30s (47 mg, 0.145 mmol, 91%); 1H NMR (DMSO-d6, 500 MHz) δ 9.41 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.65 (s, 1H), 6.92 (d, J = 9.1 Hz, 2H), 6.35 (d, J = 7.6 Hz, 1H), 3.78 (t, J = 4.6 Hz, 4H), 3.74 (s, 3H), 3.78 (t, J = 4.6 Hz, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 154.9, 150.7, 137.3, 136.0, 134.3, 134.0, 121.9, 120.7, 114.4, 101.0, 66.6, 55.7, 51.7; HRMS Calcd. for C17H20N5O2 [M + H]: 326.1617; Found: 326.1611 (∆ = 1.8 ppm).
  • 5-(4-(Methoxy)anilin-1-yl)-3-(anilin-1-yl)pyrazolo[1,5-a]pyrimidine (30t)
3-Bromo-5-(4-(methoxy)anilin-1-yl)-pyrazolo[1,5-a] pyrimidine (50 mg, 0.16 mmol), aniline (22 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30t (43 mg, 0.13 mmol, 81%); 1H NMR (DMSO-d6, 500 MHz) δ 9.47 (s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.21 (s, 1H), 7.09 (t, J = 7.6 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 7.9 Hz, 2H), 6.61 (t, J = 7.3 Hz, 1H), 6.41 (d, J = 7.6 Hz, 1H), 3.69 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 154.8, 152.1, 148.5, 141.6, 141.5, 136.2, 133.9, 129.2, 120.9, 116.9, 114.2, 113.6, 109.9, 101.2, 55.6; HRMS Calcd. for C19H18N5O [M + H]: 332.1511; Found: 332.1524 (∆ = 3.9 ppm).
  • 5-(4-(Methoxy)anilin-1-yl)-3-(N-(pyrimidin-2-yl)amino)pyrazolo[1,5-a]pyrimidine (30u)
3-Bromo-5-(4-(methoxy)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), 2-aminopyrimidine (23 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30u (42 mg, 0.13 mmol, 81%); 1H NMR (DMSO-d6, 500 MHz) δ 9.48 (s, 1H), 8.63 (s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 4.7 Hz, 2H), 8.04 (s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 6.71 (t, J = 4.7 Hz, 1H), 6.41 (d, J = 7.6 Hz, 1H), 3.72 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 166.9, 163.2, 159.6, 156.9, 145.7, 145.4, 140.8, 138.7, 125.7, 119.0, 116.3, 112.4, 106.0; HRMS Calcd. for C17H16N7O [M + H]: 334.1416; Found: 334.1421 (∆ = 1.5 ppm).
  • 3-(N-(Isopropyl)amino)-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (30v)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.15 mmol), isopropylamine (14 mg, 0.23 mmol, 1.5 equiv.), L-1 (4 mg, 0.015 mmol, 10 mol%), CuI (1.4 mg, 0.007 mmol, 5 mol%), and K2CO3 (41 mg, 0.30 mmol, 2 equiv.); 30v (42 mg, 0.136 mmol, 90%); 1H NMR (DMSO-d6, 500 MHz) δ 8.10 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.19 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.58 (bs, 1H), 6.13 (d, J = 7.6 Hz, 1H), 3.38 (sept, J = 6.3 Hz, 1H), 2.84 (sept, J = 6.9 Hz, 1H), 1.20 (d, J = 6.9 Hz, 6H), 1.15 (d, J = 6.3 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 150.8, 142.2, 138.8, 137.2, 136.5, 135.8, 126.9, 119.0, 117.9, 100.9, 48.0, 33.3, 24.5, 23.6; HRMS Calcd. for C18H24N5 [M + H]: 310.2032; Found: 310.2027 (∆ = 1.6 ppm).
  • 5-(4-(Isopropyl)anilin-1-yl)-3-(morpholin-1-yl)pyrazolo[1,5-a]pyrimidine (30w)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.15 mmol), morpholine (20 mg, 0.23 mmol, 1.5 equiv.), L-1 (4 mg, 0.015 mmol, 10 mol%), CuI (1.4 mg, 0.007 mmol, 5 mol%), and K2CO3 (41 mg, 0.30 mmol, 2 equiv.); 30w (44 mg, 0.13 mmol, 87%); 1H NMR (DMSO-d6, 500 MHz) δ 9.52 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 7.6 Hz, 1H), 3.77 (t, J = 4.6 Hz, 4H), 3.13 (t, J = 4.5 Hz, 4H), 2.84 (sept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 150.7, 142.5, 138.5, 137.4, 136.0, 134.4, 126.9, 119.2, 101.2, 66.5, 51.6, 33.3, 24.5; HRMS Calcd. for C19H24N5O [M + H]: 338.1981; Found: 338.1984 (∆ = 0.9 ppm).
  • 5-(4-(Isopropyl)anilin-1-yl)-3-(anilin-1-yl)pyrazolo[1,5-a]pyrimidine (30x)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.15 mmol), aniline (21 mg, 0.23 mmol, 1.5 equiv.), L-1 (4 mg, 0.015 mmol, 10 mol%), CuI (1.4 mg, 0.007 mmol, 5 mol%), and K2CO3 (41 mg, 0.30 mmol, 2 equiv.); 30x (41 mg, 0.12 mmol, 80%); 1H NMR (DMSO-d6, 500 MHz) δ 9.56 (s, 1H), 8.54 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H), 7.10 (t, J = 7.2 Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 8.1 Hz, 2H), 6.61 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 2.78 (sept, J = 6.8 Hz, 1H), 1.14 (d, J = 6.8 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 152.1, 148.3, 142.5, 141.5, 141.4, 138.3, 136.2, 129.2, 126.7, 119.5, 117.0, 113.6, 110.1, 101.3, 33.2, 24.4; HRMS Calcd. for C21H22N5 [M + H]: 344.1875; Found: 344.1865 (∆ = 2.9 ppm).
  • 5-(4-(Isopropyl)anilin-1-yl)-3-(N-(pyrimidin-2-yl)amino)pyrazolo[1,5-a]pyrimidine (30y)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.15 mmol), 2-aminopyrimidine (22 mg, 0.23 mmol, 1.5 equiv.), L-1 (4 mg, 0.015 mmol, 10 mol%), CuI (1.4 mg, 0.007 mmol, 5 mol%), and K2CO3 (41 mg, 0.30 mmol, 2 equiv.); 30y (36 mg, 0.104 mmol, 69%); 1H NMR (DMSO-d6, 500 MHz) δ 9.54 (s, 1H), 8.64 (s, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.36 (d, J = 4.7 Hz, 2H), 8.05 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.71 (t, J = 4.7 Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 2.83 (sept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 162.1, 158.5, 152.1, 142.4, 140.9, 140.6, 138.4, 136.1, 126.8, 119.5, 111.6, 107.8, 101.3, 33.3, 24.5; HRMS Calcd. for C19H20N7 [M + H]: 346.1780; Found: 346.1784 (∆ = 1.2 ppm).
  • 5-(4-(Chloro)anilin-1-yl)-3-(N-isopropylamino)pyrazolo[1,5-a]pyrimidine (30z)
3-Bromo-5-(4-(chloro)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), isopropylamine (14 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30z (42 mg, 0.14 mmol, 87%); 1H NMR (DMSO-d6, 500 MHz) δ 9.60 (s, 1H), 8.47 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 7.0 Hz, 2H), 7.59 (s, 1H), 7.36 (d, J = 8.9 Hz, 2H), 6.33 (d, J = 7.6 Hz, 1H), 3.70 (bs, 1H), 3.54 (m, 1H), 1.13 (d, J = 6.3 Hz, 6H); 13C NMR (DMSO-d6, 125 MHz) δ 150.3, 140.1, 136.5, 136.23, 136.18, 128.9, 125.3, 120.4, 118.5, 100.7, 47.8, 23.7; HRMS Calcd. for C15H17ClN5 [M + H]: 302.1172; Found: 302.1179 (∆ = 2.3 ppm).
  • 5-(4-(Chloro)anilin-1-yl)-3-(morpholin-1-yl)pyrazolo[1,5-a]pyrimidine (30a’)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), morpholine (21 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30a’ (48 mg, 0.146 mmol, 91%); 1H NMR (DMSO-d6, 500 MHz) δ 9.75 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.69 (s, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.40 (d, J = 7.6 Hz, 1H), 3.77 (t, J = 4.5 Hz, 4H), 3.12 (t, J = 4.4 Hz, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 150.4, 139.7, 136.9, 136.4, 134.4, 129.0, 125.7, 122.4, 120.6, 101.2, 66.5, 51.6; HRMS Calcd. for C16H17ClN5O [M + H]: 130.1122; Found: 330.1118 (∆ = 1.2 ppm).
  • 5-(4-(Chloro)anilin-1-yl)-3-(anilin-1-yl)pyrazolo[1,5-a]pyrimidine (30b’)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a] (50 mg, 0.16 mmol), aniline (22 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30b’ (39 mg, 0.12 mmol, 75%); 1H NMR (DMSO-d6, 500 MHz) δ 9.77 (s, 1H), 8.63 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.29 (s, 1H), 7.16 (d, J = 7.0 Hz, 2H), 7.11 (dd, J = 8.3, 7.4 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 6.63 (t, J = 7.3 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 151.6, 148.1, 141.5, 140.8, 139.6, 136.7, 129.2, 128.8, 125.6, 120.7, 117.1, 113.8, 110.6, 101.3; HRMS Calcd. for C18H15ClN5 [M + H]: 336.1016; Found: 336.1009 (∆ = 2.1 ppm).
  • 5-(4-(Chloro)anilin-1-yl)-3-(N-(pyrimidin-2-yl)amino)pyrazolo[1,5-a]pyrimidine (30c’)
3-Bromo-5-(4-(isopropyl)anilin-1-yl)pyrazolo[1,5-a]pyrimidine (50 mg, 0.16 mmol), 2-aminopyrimidine (23 mg, 0.24 mmol, 1.5 equiv.), L-1 (4.4 mg, 0.016 mmol, 10 mol%), CuI (1.5 mg, 0.008 mmol, 5 mol%), and K2CO3 (44 mg, 0.32 mmol, 2 equiv.); 30c’ (40 mg, 0.12 mmol, 75%); 1H NMR (DMSO-d6, 500 MHz) δ 9.77 (s, 1H), 8.76 (s, 1H), 8.62 (d, J = 7.5 Hz, 1H), 8.37 (d, J = 4.7 Hz, 2H), 8.12 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 6.73 (t, J = 4.7 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 161.9, 158.5, 151.7, 140.8, 139.9, 139.7, 136.4, 128.8, 125.6, 120.8, 111.6, 108.4, 101.4; HRMS Calcd. for C16H13ClN7 [M + H]: 338.0921; Found: 338.0912 (∆ = 2.7 ppm).
  • 5-(Pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (31)
Similar to the method for preparing 29a–e. 5-chloropyrazolo[1,5-a]pyrimidine (1.0 g, 6.5 mmol), pyrrolidine (925 mg, 13 mmol, 2.0 equiv), CsF (988 mg, 6.5 mmol, 1.0 equiv), and BnNEt3Cl (148 mg, 0.65 mmol,10 mol%), in DMSO (30 mL) was stirred in a sealed pressure vessel (350 mL) and heated at 100 °C for 8 hrs. After cooling to ambient temperature, H2O (300 mL) was added. The mixture was diluted using ethyl acetate, and the organic layer was separated. The aqueous layer was partitioned with EtOAc (2 × 300 mL), and the combined organic layers were washed with saturated sodium bicarbonate solution (2 × 300 mL) and then water (2 × 300 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure. The crude product was purified using flash chromatography (EtOAc/Hexanes) to give pure 31 (1.13 g, 6.0 mmol, 92%); 1H NMR (DMSO-d6, 500 MHz) δ 8.59 (dd, J = 7.7, 0.5 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 7.7 Hz, 1H), 5.98 (d, J = 1.5 Hz, 1H), 3.48 (t, J = 6.5 Hz, 4H), 1.95 (“bs”, 4H); 13C (DMSO, 125 MHz) δ 154.0, 148.8, 144.5, 135.6, 98.3, 91.1, 47.1, 25.4; HRMS Calcd. for C10H13N4 [M + H]: 189.1140; Found: 189.1132 (∆ = 4.2 ppm).

4.5. 3-Halo-5-(Pyrrolidin-1-yl)Pyrazolo[1,5-a]Pyrimidines 32

General Procedure: To a stirred solution of 5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (31) (100 mg) in CH3CN:CH2Cl2 (1:3, 2 mL) chilled to 0 °C was added N-halosuccinimide (1.0 equiv in 0.5 mL CH3CN), over 30 min. The mixture was stirred while slowly warming to ambient temperature (approx. 2 h). The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography (20% EtOAc/CH2Cl2).
  • 3-Chloro-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (32a)
5-(Pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.53 mmol) in 2 mL (CH3CN:CH2Cl2, 1:3), N-chlorosuccinimide (70 mg, 0.53 mmol) in 0.5 mL CH3CN; 32a (110 mg, 0.49 mmol, 93%); 1H NMR (DMSO-d6, 500 MHz) δ 8.59 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.52 (“bs”, 4H), 1.96 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 154.3, 144.2, 142.2, 136.2, 99.2, 92.1, 47.2, 25.7, 24.9; HRMS Calcd. for C10H12ClN4 [M + H]: 223.0750; Found: 223.0761 (∆ = 4.9 ppm).
  • 3-Iodo-5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (32b)
5-(Pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.53 mmol) in 2 mL (CH3CN:CH2Cl2, 1:3); N-iodosuccinimide (119 mg, 0.53 mmol) in 0.5 mL CH3CN; 32b (160 mg, 0.51 mmol; 96%); 1H NMR (DMSO-d6, 500 MHz) δ 8.60 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 6.40 (d, J = 7.7 Hz, 1H), 3.52 (“bs”, 4H), 1.96 (“bs”, 4H); 13C NMR (DMSO-d6, 125 MHz) δ 154.7, 148.2, 148.0, 136.2, 99.1, 47.2, 43.3, 25.7, 24.9; HRMS Calcd. for C10H12IN4 [M + H]: 315.0107; Found: 315.0096 (∆ = 3.5 ppm).

5. Conclusions

We have developed an efficient method for rapid generation of diverse arrays of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidine derivatives. The reaction proceeds in only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine and features efficient copper catalyzed C-3 amination of C-5 aminated precursors. 3,5-bis-aminated products consisting of both 3,5-bis arylamine, 3,5-bis alkylamine, or 3,5-bis alkyl/aryl amine combinations were efficiently obtained in only two steps utilizing our method. This represents the most comprehensive substrate scope for 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines ever reported. Advantages of this method include rapid reaction time (1 h for C-3 amination), high yield, avoidance of toxic reagents such as NaBH3CN commonly used for reductive amination, and utilization of inexpensive CuI catalyst (5 mol%) in place of more expensive and/or less efficient air and moisture-sensitive palladium catalysts previously utilized for C-3 amination (Figure 2). With these advantages now in hand, access to broad, diversity-rich libraries of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines for screening novel or enhanced biological, medicinal, or fluorometric properties is now readily available.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30030458/s1, Experimental procedures for preparing L-1–L-4; Scheme S1: Synthesis of ligands L-1–L-4; spectral data for compounds 29a–e, 30a–c’, 31, 32a–b; and representative conversion-optimization data. References [30,32,33,34] are cited the supplementary materials.

Author Contributions

Conceptualization, T.H.I. and M.A.P.; methodology, T.H.I., B.A.T. and L.G; compound characterization, T.H.I., B.A.T. and L.O.G.; writing—original draft preparation, M.A.P.; writing—review and editing, T.H.I. and M.A.P.; supervision, T.H.I. and M.A.P.; project administration, M.A.P.; funding acquisition, M.A.P. All authors have read and agreed to the published version of the manuscript.

Funding

Generous support from the Simmons Center for Cancer Research and the College of Computational, Mathematical, and Physical Sciences at Brigham Young University is gratefully acknowledged.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Acknowledgments

We gratefully acknowledge Matthew Eli Stecher for technical support in preparing bulk quantities of starting materials.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 30 00458 g001
Figure 1. Clinical and preclinical biologically active pyrazolo[1,5-a]pyrimidines.
Figure 1. Clinical and preclinical biologically active pyrazolo[1,5-a]pyrimidines.
Molecules 30 00458 g001
Molecules 30 00458 g002
Figure 2. Buchwald-Hartwig or Ullmann-type coupling methods for C-3 amination. a [21], b [22], c [23], d [24], e [25], f [26].
Figure 2. Buchwald-Hartwig or Ullmann-type coupling methods for C-3 amination. a [21], b [22], c [23], d [24], e [25], f [26].
Molecules 30 00458 g002
Molecules 30 00458 g003
Figure 3. Synthesis of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines. a [27], b [13], c [29], d [20].
Figure 3. Synthesis of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines. a [27], b [13], c [29], d [20].
Molecules 30 00458 g003
Molecules 30 00458 sch001
Scheme 1. Two-step preparation of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines 30.
Scheme 1. Two-step preparation of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines 30.
Molecules 30 00458 sch001
Molecules 30 00458 sch002
Scheme 2. C-3 amination with 3-chloro or 3-iodo precursors. a (2.0 equiv).
Scheme 2. C-3 amination with 3-chloro or 3-iodo precursors. a (2.0 equiv).
Molecules 30 00458 sch002
Table 1. Optimization. a–e
Table 1. Optimization. a–e
Molecules 30 00458 i001
EntryTemp. (°C)LigandTimeSolventBase cProducts d
1RTL-17 daysDEGK2CO330e (---) 31 (---) e 29a (100%)
250 aL-12 daysDEGK2CO330e (7.7%) 31 (---) e 29a (92.3%)
370 aL-124 hDEGK2CO330e (27.3%) 31 (2.8%); 29a (69.9%)
480 aL-12 daysDEGK2CO330e (82.4%) 31 (17.6%); 29a (---)
570 bL-130 minDEGK2CO330e (61.4%) 31 (1.8%); 29a (36.8%)
670 bL-11 hDEGK2CO330e (78.7%) 31 (2.4%); 29a (18.9%)
770 bL-11.5 hDEGK2CO330e (87.2%) 31 (2.1%); 29a (10.7%)
870 bL-12 hDEGK2CO330e (96.7%) 31 (2.5%); 29a (0.8%)
970 bL-13 hDEGK2CO330e (97.3%) 31 (2.7%); 29a (---)
1080 bL-130 minDEGK2CO330e (93.7%) 31 (1.9%); 29a (4.4%)
1180 bL-11 hDEGK2CO330e (97.1%) 31 (2.9%); 29a (---)
1280 bL-11.5 hDEGK2CO330e (97.0%) 31 (3.0%); 29a (---)
1380 bL-11 hEthylene GlycolK2CO330e (90.1%) 31 (9.9%); 29a (---)
1480 bL-11 hDMSOK2CO330e (10.2%) 31 (5.1%); 29a (84.7%)
1580 bL-11 hn ButanolK2CO330e (3.6%) 31 (6.3%); 29a (90.1%)
1680 bL-11 hDioxaneK2CO330e (---) 31 (7.2%); 29a (92.8%)
1780 bL-11 hNMPK2CO330e (78%) 31 (19%); 29a (3%)
1880 bL-11 h1,2-PropanediolK2CO330e (94.3%) 31 (5.7%); 29a (---)
1980 bL-11 hDEGtBuOK30e (95.2%) 31 (4.8%); 29a (---)
2080 bL-11 hDEGTMSONa30e (97.1%) 31 (2.9%); 29a (---)
2180 bL-11 hDEGK3PO430e (94.3%) 31 (5.7%); 29a (---)
2280 bL-11 hDEGDBU30e (48.8%) 31 (1.4%); 29a (49.8%)
2380 bL-21 hDEGK2CO330e (21%) 31 (39%); 29a (40%)
2480 bL-31 hDEGK2CO330e (17.4%) 31 (0.7%); 29a (81.9%)
2580 bL-41 hDEGK2CO330e (12.3%) 31 (---); 29a (87.7%)
a Conventional oil bath heating; b Microwave heating; c 2.0 equiv.; d Percent conversion as determined by 1HNMR; e Trace amounts (1H NMR signal detected, but barely distinguishable from baseline noise).
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Iorkula, T.H.; Tolman, B.A.; Ganiyu, L.O.; Peterson, M.A. An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors. Molecules 2025, 30, 458. https://doi.org/10.3390/molecules30030458

AMA Style

Iorkula TH, Tolman BA, Ganiyu LO, Peterson MA. An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors. Molecules. 2025; 30(3):458. https://doi.org/10.3390/molecules30030458

Chicago/Turabian Style

Iorkula, Terungwa H., Bryce A. Tolman, Latifat O. Ganiyu, and Matt A. Peterson. 2025. "An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors" Molecules 30, no. 3: 458. https://doi.org/10.3390/molecules30030458

APA Style

Iorkula, T. H., Tolman, B. A., Ganiyu, L. O., & Peterson, M. A. (2025). An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors. Molecules, 30(3), 458. https://doi.org/10.3390/molecules30030458

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