CuI-Catalyzed Coupling Reactions of 4-Iodopyrazoles and Alcohols: Application toward Withasomnine and Homologs

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.


Introduction
Owing to their diverse bioactivities, both natural and synthetic pyrazoles and pyrazolefused heterocycles have been widely exploited as pharmaceutical or pesticide active ingredients [1][2][3][4]. Therefore, the efficient synthesis of substituted pyrazoles possessing characteristic functionalities at specific positions is an important objective in organic and medicinal chemistry, as well as in drug discovery. In this context, we recently reported palladium-or copper-catalyzed C-N coupling reactions at the C-4 positions of pyrazoles [5]. Although metal-catalyzed C-O coupling reactions have been widely reported, owing to their wide-ranging potentials [6][7][8][9][10][11][12], the direct C4-O-functionalization of pyrazoles has not yet been studied satisfactorily [13,14] despite the important bioactivities that have been demonstrated for several 4-alkoxypyrazoles, as presented in Figure 1.

Investigation of 4-O-Allylation of 4-Iodopyrazole
Initially, we attempted the Pd(dba) 2 -catalyzed reaction between 2a and allyl alcohol (2 equivalent (equiv)) in the presence of tBuDavePhos as a ligand and potassium tert-butoxide ( t BuOK) as a base under the reaction conditions in our previous report [5]; however, none of the desired coupling product was obtained (Table 1, entry 1). The corresponding 4-bromo-1H-1-tritylpyrazole was not effective in the palladium-catalyzed coupling reaction. Then, the CuI-catalyzed reaction between 4-iodo-1H-1-tritylpyrazole 2a and allyl alcohol was examined; the results are summarized in Table 1. All reactions were performed using 2a (50 mg) in a solvent (2.0 mL). In the presence of ligand 2-isobutyroylcyclo-hexanone (L2) or 1,10-phenanthroline (L3) in N,N-dimethylformamide (DMF) [5], reactions of 2a and allyl alcohol (2 equiv) did not afford 4a (entries 2 and 3, respectively). However, when allyl alcohol was used as a solvent for this reaction with L3 at 100 • C overnight, the desired C4-O-allylation product 4a was obtained in 51% yield (entry 4). Next, microwave (MW) assistance was applied to reduce the reaction time (entries 5-9). In these experiments, the reaction time was fixed at 1 h and the ligand was changed to 3,4,7,8-tetramethyl-1,10-phenanthroline (L4). From entry 6, the optimum reaction temperature was determined to be 130 • C, giving 4a in 66% yield. At 160 • C, the reaction mixture turned black with a poor yield of 4a (16%, entry 8). In addition, shortening the reaction time (30 min) or reducing the amount of CuI to 10 mol% afforded 4a in lower yields (entry 7:24%; entry 9:37%, respectively). Based on these results, the optimum conditions obtained in entry 6 were applied in the following coupling reactions of 4-iodopyrazoles with various alcohols. performed using 2a (50 mg) in a solvent (2.0 mL). In the presence of ligand 2-isobutyroylcyclo-hexanone (L2) or 1,10-phenanthroline (L3) in N,N-dimethylformamide (DMF) [5], reactions of 2a and allyl alcohol (2 equiv) did not afford 4a (entries 2 and 3, respectively). However, when allyl alcohol was used as a solvent for this reaction with L3 at 100 °C overnight, the desired C4-O-allylation product 4a was obtained in 51% yield (entry 4) Next, microwave (MW) assistance was applied to reduce the reaction time (entries [5][6][7][8][9] In these experiments, the reaction time was fixed at 1 h and the ligand was changed to 3,4,7,8-tetramethyl-1,10-phenanthroline (L4). From entry 6, the optimum reaction temperature was determined to be 130 °C, giving 4a in 66% yield. At 160 °C, the reaction mixture turned black with a poor yield of 4a (16%, entry 8). In addition, shortening the reaction time (30 min) or reducing the amount of CuI to 10 mol% afforded 4a in lower yields (entry 7:24%; entry 9:37%, respectively). Based on these results, the optimum conditions obtained in entry 6 were applied in the following coupling reactions of 4-iodopyrazoles with various alcohols.
In these experiments, the reaction time was fixed at 1 h and the ligand was changed to 3,4,7,8-tetramethyl-1,10-phenanthroline (L4). From entry 6, the optimum reaction temperature was determined to be 130 °C, giving 4a in 66% yield. At 160 °C, the reaction mixture turned black with a poor yield of 4a (16%, entry 8). In addition, shortening the reaction time (30 min) or reducing the amount of CuI to 10 mol% afforded 4a in lower yields (entry 7:24%; entry 9:37%, respectively). Based on these results, the optimum conditions obtained in entry 6 were applied in the following coupling reactions of 4-iodopyrazoles with various alcohols.

C4-Alkoxylation of 4-iodopyrazole with Alcohols Using CuI-Catalyzed Coupling
To study the scope and limitations of this transformation, the CuI-catalyzed reactions of iodopyrazoles 2 (50 mg) with various alcohols (2.0 mL, excess amount) were carried out under the optimal conditions (Table 1, entry 6). The results are summarized in Table 2. The reactions of 2a with linear short-chain primary alcohols (methanol, ethanol, and n-propanol) afforded the corresponding products 4c, 4d, and 4e in moderate yields (61-76%, entries 1-3), while the reaction with a longer-chain primary alcohol (n-butanol) resulted in a lower yield (33%, entry 4). The reactions of 2a with branched primary alcohols (isobutyl and isoamyl alcohols) provided 4i (45%) and 4k (37%), respectively (entries 7 and 9), but with secondary isopropanol, gave 4g in only 9% yield (entry 5). The presence of secor tert-butyl groups in the alcohol was not compatible with the present reaction conditions (entries 6 and 8), probably due to steric hindrance. In contrast, the reactions with cyclic secondary alcohols did proceed (entries 10, 11, and 12), but the respective isolated yields of the coupled products 4l, 4m, and 4n were 59%, 18%, and 25%, respectively. In these reactions, 1.0 mL of cyclic alcohol was used with respect to substrate 2a (50 mg); the high boiling points (cyclobutanol: 123 • C/733 mmHg; cyclopentanol: 139-140 • C; cyclohexanol: 160-161 • C) of these materials complicated product isolation by chromatography. Furthermore, when 2 equivalents of the cyclic alcohols and acetonitrile (2.0 mL) as a co-solvent were used, no coupled products could be detected. Although the reaction with benzyl alcohol (bp: 205 • C) was also difficult, the use of benzyl alcohol (1.0 mL) and toluene as a co-solvent (1.0 mL) afforded the corresponding product (4o) in poor yield (12%, entry 13). With phenols, no desired coupling products were obtained under various reaction conditions (entries 14 and 15). In the case of p-methoxyphenol (entry 15), a detailed analysis of the reaction mixture revealed a trace amount of 5,5 -dimethoxy-2,2 -biphenyldiol, which has been reported to have radical scavenging or antibacterial activities [32,33]. The initially formed dihydroxybiphenyls [34] might inhibit the attempted C-O coupling reaction. Table 2. CuI-catalyzed coupling reaction between iodopyrazoles and various alcohols. cyclic secondary alcohols did proceed (entries 10, 11, and 12), but the respective isolated yields of the coupled products 4l, 4m, and 4n were 59%, 18%, and 25%, respectively. In these reactions, 1.0 mL of cyclic alcohol was used with respect to substrate 2a (50 mg); the high boiling points (cyclobutanol: 123 °C/733 mmHg; cyclopentanol: 139-140 °C; cyclohexanol: 160-161 °C) of these materials complicated product isolation by chromatography. Furthermore, when 2 equivalents of the cyclic alcohols and acetonitrile (2.0 mL) as a co-solvent were used, no coupled products could be detected. Although the reaction with benzyl alcohol (bp: 205 °C) was also difficult, the use of benzyl alcohol (1.0 mL) and toluene as a co-solvent (1.0 mL) afforded the corresponding product (4o) in poor yield (12%, entry 13). With phenols, no desired coupling products were obtained under various reaction conditions (entries 14 and 15). In the case of p-methoxyphenol (entry 15), a detailed analysis of the reaction mixture revealed a trace amount of 5,5′-dimethoxy-2,2′-biphenyldiol, which has been reported to have radical scavenging or antibacterial activities [32,33]. The initially formed dihydroxybiphenyls [34] might inhibit the attempted C-O coupling reaction. 2a The direct introduction of the allyloxy group at the C4 position of N-alkenyl-4-iodo-1H-pyrazoles (2b, 2c, 2d) by CuI-mediated reaction afforded the expected products 4r, 4s, The direct introduction of the allyloxy group at the C4 position of N-alkenyl-4-iodo-1H-pyrazoles (2b, 2c, 2d) by CuI-mediated reaction afforded the expected products 4r, 4s, and 4t in moderate yields (entries [17][18][19]. These products were subsequently applied in the synthesis of withasomnine and its analogs (Scheme 2). Neither the C-O coupling reaction of 2a with water nor of N-nonprotected iodopyrazole 1 with allyl alcohol was successful (entries 20 and 21).
In preliminary experiments, the Pd(dba) 2 -catalyzed coupling of 2a with four types of alcohols (methanol, ethanol, n-propanol, and tert-butyl alcohol) under the same conditions as mentioned above was examined; however, these trials did not give the desired coupling products, yielding only hydrogenated 1H-1-tritylpyrazole in 52, 63, 64, and 8% yields, respectively. action of 2a with water nor of N-nonprotected iodopyrazole 1 with allyl alcohol was successful (entries 20 and 21).
In preliminary experiments, the Pd(dba)2-catalyzed coupling of 2a with four types of alcohols (methanol, ethanol, n-propanol, and tert-butyl alcohol) under the same conditions as mentioned above was examined; however, these trials did not give the desired coupling products, yielding only hydrogenated 1H-1-tritylpyrazole in 52, 63, 64, and 8% yields, respectively. Scheme 2. Application to improved synthesis of withasomnine (7).

Application to Improved Synthesis of Withasomnine and Six-and Seven-Membered Cyclic Homologs
A modified synthesis of withasomnine and its homologs using the products described above was performed to demonstrate the usefulness of the present method. The improved synthesis of withasomnine (7) is summarized in Scheme 2. 4-Iodo-1H-pyrazole (1) was treated with allyl bromide under basic conditions to give N-allylated compound 2c in 97% yield. The double bond in the N-allyl group in 2c was migrated by treatment with a ruthenium hydride catalyst (RuClH(CO)(PPh3)3) to give an E/Z mixture of 2b in 96% yield, which was transformed to 4r by CuI-catalyzed coupling, as described above ( Table 2, entry 17). The Claisen rearrangement of 4r gave (E/Z)-12 (87%), which was subsequently O-triflated by treatment with trifluoromethanesulfonic anhydride (Tf2O) in the presence of triethylamine at −20 °C to yield ring-closing metathesis (RCM) substrate 13 in 90% yield. Treatment of 13 with Grubbs 2nd catalyst in toluene at 100 °C under MW irradiation gave the desired RCM product 14 in 0-58% yields with unsatisfied reproducibility.
Alternatively, CuI-assisted RCM [24,35] of 13 in CH2Cl2 under milder conditions using MW-aided heating at 80 °C for 1 h successfully afforded pyrrole-[1,2-b] pyrazole 14 (63%), which was immediately hydrogenated under a hydrogen gas atmosphere with Pd/C in MeOH to give penultimate product 6 in 90% yield. As the transformation from 6 to 7 via a Suzuki-Miyaura coupling reaction has already been reported [22,23], the present approach constitutes a formal total synthesis of withasomnine (7). The overall yield of 7 in this case was 24% over nine steps from commercially available pyrazole, whereas that of our previous method was 8% in 13 steps. Therefore, the current synthesis realizes a four-step reduction and nearly threefold improvement in overall yield [22,23].
The syntheses of the six-and seven-membered cyclic homologs 11 and 15 are summarized in Scheme 3. The total yield of 11 was improved by ~1.6-fold over our former synthesis based on the yields of transformations from 1 to 2c (seen in Scheme 2) and 2c to 4s ( Table 2, entry 18) [24]. Our synthesis of another withasomnine homolog, 15, previously achieved by Allin via radical cyclization [25,26], began with the transformation of 1 to 2d Scheme 2. Application to improved synthesis of withasomnine (7).

Application to Improved Synthesis of Withasomnine and Six-and Seven-Membered Cyclic Homologs
A modified synthesis of withasomnine and its homologs using the products described above was performed to demonstrate the usefulness of the present method. The improved synthesis of withasomnine (7) is summarized in Scheme 2. 4-Iodo-1H-pyrazole (1) was treated with allyl bromide under basic conditions to give N-allylated compound 2c in 97% yield. The double bond in the N-allyl group in 2c was migrated by treatment with a ruthenium hydride catalyst (RuClH(CO)(PPh 3 ) 3 ) to give an E/Z mixture of 2b in 96% yield, which was transformed to 4r by CuI-catalyzed coupling, as described above (Table 2, entry 17). The Claisen rearrangement of 4r gave (E/Z)-12 (87%), which was subsequently O-triflated by treatment with trifluoromethanesulfonic anhydride (Tf 2 O) in the presence of triethylamine at −20 • C to yield ring-closing metathesis (RCM) substrate 13 in 90% yield. Treatment of 13 with Grubbs 2nd catalyst in toluene at 100 • C under MW irradiation gave the desired RCM product 14 in 0-58% yields with unsatisfied reproducibility.
Alternatively, CuI-assisted RCM [24,35] of 13 in CH 2 Cl 2 under milder conditions using MW-aided heating at 80 • C for 1 h successfully afforded pyrrole-[1,2-b] pyrazole 14 (63%), which was immediately hydrogenated under a hydrogen gas atmosphere with Pd/C in MeOH to give penultimate product 6 in 90% yield. As the transformation from 6 to 7 via a Suzuki-Miyaura coupling reaction has already been reported [22,23], the present approach constitutes a formal total synthesis of withasomnine (7). The overall yield of 7 in this case was 24% over nine steps from commercially available pyrazole, whereas that of our previous method was 8% in 13 steps. Therefore, the current synthesis realizes a four-step reduction and nearly threefold improvement in overall yield [22,23].
The syntheses of the six-and seven-membered cyclic homologs 11 and 15 are summarized in Scheme 3. The total yield of 11 was improved by~1.6-fold over our former synthesis based on the yields of transformations from 1 to 2c (seen in Scheme 2) and 2c to 4s (Table 2, entry 18) [24]. Our synthesis of another withasomnine homolog, 15, previously achieved by Allin via radical cyclization [25,26], began with the transformation of 1 to 2d in 88% yield. Compound 2d was O-allylated using the present method to 4t, as described previously (Table 2, entry 19). Then, 4t was rearranged into 16 (81% yield) under MW-assisted heating, and subsequent O-triflation afforded 17 (83% yield). RCM substrate 17 was similarly cyclized to seven-membered intermediate 18 in 72% yield, which was then subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford 19 in 87% yield. The synthesis of 15 was completed in 92% yield by the Pd-C-catalyzed hydrogenation of 19. An alternative route to 15 comprised the transformation of 1 to 4b in 52% yield via a five-step process, and subsequent N-butenylation to give the common intermediate 4t in 69% yield. Therefore, the present route to 15 using the CuI-catalyzed coupling achieved a 1.6-fold increase in overall yield compared to the prior procedure.
was similarly cyclized to seven-membered intermediate 18 in 72% yield, which was then subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford 19 in 87% yield. The synthesis of 15 was completed in 92% yield by the Pd-C-catalyzed hydrogenation of 19. An alternative route to 15 comprised the transformation of 1 to 4b in 52% yield via a five-step process, and subsequent N-butenylation to give the common intermediate 4t in 69% yield. Therefore, the present route to 15 using the CuI-catalyzed coupling achieved a 1.6-fold increase in overall yield compared to the prior procedure.

Conclusions
In this study, a range of 4-alkoxy-1H-pyrazoles was synthesized using the CuI-catalyzed coupling reaction of 4-iodopyrazoles with an excess amount of alcohol. Improved syntheses of withasomnine and its homologs were achieved using the products obtained with the present method. The current withasomnine synthetic route was reduced by four steps with a threefold-improvement in the overall yield compared to our previous report [22,23]. However, reducing the amounts of catalysts, ligands, and alcohols will be required to increase the practicality of this reaction in the future.

Conclusions
In this study, a range of 4-alkoxy-1H-pyrazoles was synthesized using the CuIcatalyzed coupling reaction of 4-iodopyrazoles with an excess amount of alcohol. Improved syntheses of withasomnine and its homologs were achieved using the products obtained with the present method. The current withasomnine synthetic route was reduced by four steps with a threefold-improvement in the overall yield compared to our previous report [22,23]. However, reducing the amounts of catalysts, ligands, and alcohols will be required to increase the practicality of this reaction in the future.