Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min.

On the other hand, pyrazole-fused heterocycles have been recently synthesized because they exhibit diverse important biological activities; they could not be synthesized from substituted monocyclic pyrazole derivatives [15]. Sildenafil citrate, a well-known clinically approved erectile dysfunction improving drug Viagra ® , is one of the representative example possessing a pyrazole-fused bicyclic structure ( Figure 1) [15,16]. Pyraclonil is also well known as an excellent pesticide or herbicide with a similar structural feature [17]. Several examples exhibiting important biological activities are also shown in Figure 1 [18][19][20][21][22][23]. Thus, synthesis of novel pyrazole-fused heterocycles is extremely important for drug discovery and is a great challenge in organic chemistry.

Claisen Rearrangement of 4-Allyloxy-1H-pyrazoles in 1,2-Dimethoxyethane
As mentioned in our previous paper, Claisen rearrangement of 1a in 1,2-dimethoxyethane (DME) showed improved regioselectivity for 2a (65%): 3a (1%) compared to the same reaction in N,N-diethylaniline (DEA) (2a (61%): 3a (3%)) [14]. Another merit of using DME as a solvent is easier purification of the reaction products. DEA must be removed by chromatography, whereas DME can be removed by evaporation. First, the regioselectivity in the Claisen rearrangement of other substrates 1b-e with DME under microwave (MW) irradiation was investigated. The results are summarized in Table 1. The MW reaction conditions were 200 • C and 30 min. In the reaction of substrate 1b (R = benzyl), 5-allylated product 2b was obtained exclusively in a similar yield (98%, entry 2) as DEA (2b: 92%) reported previously [13,14]. Improved regioselectivity was observed for substrate 1d bearing an n-butyl group, affording 5-allylate 2d as the sole product in 97% yield (entry 4), whereas a mixture of 2d (65%) and 3d (20%) was obtained in the MW reaction with DEA. Surprisingly, reversed regioselectivity was observed in the reaction of substrate 1c bearing a p-toluenesulfonyl substituent at the N1 position in DME, giving 3-allylated 3c (55%, entry 3), whereas 2c was formed as the major product (65%) and as the minor product (20%) in the MW-assisted Claisen rearrangement in DEA in our previous study [14]. However, we do not have a plausible explanation for this reversed selectivity. purification of the reaction products. DEA must be removed by chromatography, whereas DME can be removed by evaporation. First, the regioselectivity in the Claisen rearrangement of other substrates 1b-e with DME under microwave (MW) irradiation was investigated. The results are summarized in Table 1. The MW reaction conditions were 200 °C and 30 min. In the reaction of substrate 1b (R = benzyl), 5-allylated product 2b was obtained exclusively in a similar yield (98%, entry 2) as DEA (2b: 92%) reported previously [13,14]. Improved regioselectivity was observed for substrate 1d bearing an n-butyl group, affording 5-allylate 2d as the sole product in 97% yield (entry 4), whereas a mixture of 2d (65%) and 3d (20%) was obtained in the MW reaction with DEA. Surprisingly, reversed regioselectivity was observed in the reaction of substrate 1c bearing a ptoluenesulfonyl substituent at the N1 position in DME, giving 3-allylated 3c (55%, entry 3), whereas 2c was formed as the major product (65%) and as the minor product (20%) in the MW-assisted Claisen rearrangement in DEA in our previous study [14]. However, we do not have a plausible explanation for this reversed selectivity.  [13,14]; b no reaction.
Furthermore, we investigated the relationship between the Claisen rearrangement and the subsequent pattern in the allylic system of substrate 1, having a substituent at R, R', and R" positions.
When R' positions are occupied by methyl group (entries 6 and 9), the Claisen rearrangement did not proceed. Similar results are obtained on the substrates 1e (R' = Me) and 1g (R' = Ph) having Tr group at R position (entries 5 and 7). Meanwhile, reactions of 1h (R = Bn, R' = Me, and R" = H) and 1j (R = Bn, R' = Ph, and R" = H) with a benzyl group at the N1 position provide rearranged products 2h and 2j in 64% and 54% yields, respectively.
In cases of the substrates with Tr groups (entries 5-7) as well as with a Me group at R" position (entry 9), severe steric repulsions in those transition states may inhibit the Claisen rearrangement.
From results summarized in Table 1, appearance of the Claisen rearrangement would depend on the substituent pattern in the allylic system of the substrates 1.
Furthermore, we investigated the relationship between the Claisen rearrangement and the subsequent pattern in the allylic system of substrate 1, having a substituent at R, R', and R" positions.
When R' positions are occupied by methyl group (entries 6 and 9), the Claisen rearrangement did not proceed. Similar results are obtained on the substrates 1e (R' = Me) and 1g (R' = Ph) having Tr group at R position (entries 5 and 7). Meanwhile, reactions of 1h (R = Bn, R' = Me, and R" = H) and 1j (R = Bn, R' = Ph, and R" = H) with a benzyl group at the N1 position provide rearranged products 2h and 2j in 64% and 54% yields, respectively.
In cases of the substrates with Tr groups (entries 5-7) as well as with a Me group at R" position (entry 9), severe steric repulsions in those transition states may inhibit the Claisen rearrangement.
From results summarized in Table 1, appearance of the Claisen rearrangement would depend on the substituent pattern in the allylic system of the substrates 1.

Synthesis of 5-or 3-Allyl-4-allyloxy-1H-pyrazoles
Next, O-allylation of the 4-hydroxyl group in 2 or 3 was investigated (Scheme 2). Substrates 2 or 3 reacted with allyl bromide under basic condition at ambient temperature, affording 5-allyl-4-allyloxy-1H-pyrazoles (4a-d,h,j) and 3-allyl-4-allyloxy-1H-pyrazoles (5a,c) as shown in Scheme 2a,b, respectively. Most of the substrates were O-allylated in good yields except 2c and 3c bearing a toluenesulfonyl substituent at the N1 position. The toluenesulfonyl group at the N1 position seems unstable under the basic reaction condition, resulting in a lower yield of 4c or 5c. Thus, the RCM substrates for the formation of a seven-membered ring were obtained.

Synthesis of 5-or 3-Allyl-4-allyloxy-1H-pyrazoles
Next, O-allylation of the 4-hydroxyl group in 2 or 3 was investigated (Scheme 2). Substrates 2 or 3 reacted with allyl bromide under basic condition at ambient temperature, affording 5-allyl-4-allyloxy-1H-pyrazoles (4a-d,h,j) and 3-allyl-4-allyloxy-1H-pyrazoles (5a,c) as shown in Scheme 2a,b, respectively. Most of the substrates were O-allylated in good yields except 2c and 3c bearing a toluenesulfonyl substituent at the N1 position. The toluenesulfonyl group at the N1 position seems unstable under the basic reaction condition, resulting in a lower yield of 4c or 5c. Thus, the RCM substrates for the formation of a seven-membered ring were obtained.

Synthesis of 5-or 3-Allyl-4-allyloxy-1H-pyrazoles
Next, O-allylation of the 4-hydroxyl group in 2 or 3 was investigated (Scheme 2). Substrates 2 or 3 reacted with allyl bromide under basic condition at ambient temperature, affording 5-allyl-4-allyloxy-1H-pyrazoles (4a-d,h,j) and 3-allyl-4-allyloxy-1H-pyrazoles (5a,c) as shown in Scheme 2a,b, respectively. Most of the substrates were O-allylated in good yields except 2c and 3c bearing a toluenesulfonyl substituent at the N1 position. The toluenesulfonyl group at the N1 position seems unstable under the basic reaction condition, resulting in a lower yield of 4c or 5c. Thus, the RCM substrates for the formation of a seven-membered ring were obtained.

Synthesis of Dihydro-1H-1-Trityloxepino[3,2-c]pyrazoles
Using the prepared substrates, the synthesis of dihydro-1H-or 2H-oxepino[3,2-c]pyrazoles was investigated. First, three types of Grubbs catalysts-Grubbs 1st , Grubbs 2nd , and Hoveyda-Grubbs 2ndwere used in the RCM of substrate 4a ( Table 2). The reaction conditions-solvent, temperature, and amount of ruthenium catalyst-were fixed as CH 2 Cl 2 , room temperature, and 10 mol %, respectively [29,30]. The results are summarized in Table 1. All the reactions afforded the desired 5,8-dihydro-1H-1-trityloxepino[3,2-c]pyrazole (6a), and Grubbs 2nd gave the best yield (entry 2, 74% yield). Then, all the following RCMs were carried out using Grubbs 2nd as the catalyst.  Hoveyda-Grubbs 2nd 150 66 As described above, the RCM reactions using Grubbs 2nd at room temperature took 120-150 min for the complete consumption of starting material 4a. To shorten the reaction time, next, MW-assisted RCM was investigated. The reaction at a high temperature of 140 °C in CH2Cl2 as the solvent was achieved using sealed vials as the MW reactor. The results are summarized in Table 3. Interestingly, the ring-closed products with double-bond migration 9a and 10a were obtained from substrate 4a as the major products in various ratios along with a small amount of 6a, as shown in entries 2-4 [31][32][33][34]. As the best overall yield was obtained in a reaction time of 10 min (entry 4), this condition was applied in the following MW reactions. For reference, the RCM of 4a at room temperature overnight also provided the isomerized products in a small amount in addition to 6a as the major product. To complete the isomerization, overnight reflux (40 °C) was required as noted in entry 1 for comparison. Geometries of the double bond of all the products 6a, 9a, and 10a generated in the RCM were assigned as Z configuration based on the coupling constant <12 Hz of olefinic protons in their 1 H-Nucler Magnetic Resonance (NMR) spectra.  Hoveyda-Grubbs 2nd 150 66 As described above, the RCM reactions using Grubbs 2nd at room temperature took 120-150 min for the complete consumption of starting material 4a. To shorten the reaction time, next, MW-assisted RCM was investigated. The reaction at a high temperature of 140 • C in CH 2 Cl 2 as the solvent was achieved using sealed vials as the MW reactor. The results are summarized in Table 3. Interestingly, the ring-closed products with double-bond migration 9a and 10a were obtained from substrate 4a as the major products in various ratios along with a small amount of 6a, as shown in entries 2-4 [31][32][33][34]. As the best overall yield was obtained in a reaction time of 10 min (entry 4), this condition was applied in the following MW reactions. For reference, the RCM of 4a at room temperature overnight also provided the isomerized products in a small amount in addition to 6a as the major product. To complete the isomerization, overnight reflux (40 • C) was required as noted in entry 1 for comparison. Geometries of the double bond of all the products 6a, 9a, and 10a generated in the RCM were assigned as Z configuration based on the coupling constant <12 Hz of olefinic protons in their 1 H-Nucler Magnetic Resonance (NMR) spectra.  Hoveyda-Grubbs 2nd 150 66 As described above, the RCM reactions using Grubbs 2nd at room temperature took 120-150 min for the complete consumption of starting material 4a. To shorten the reaction time, next, MW-assisted RCM was investigated. The reaction at a high temperature of 140 °C in CH2Cl2 as the solvent was achieved using sealed vials as the MW reactor. The results are summarized in Table 3. Interestingly, the ring-closed products with double-bond migration 9a and 10a were obtained from substrate 4a as the major products in various ratios along with a small amount of 6a, as shown in entries 2-4 [31][32][33][34]. As the best overall yield was obtained in a reaction time of 10 min (entry 4), this condition was applied in the following MW reactions. For reference, the RCM of 4a at room temperature overnight also provided the isomerized products in a small amount in addition to 6a as the major product. To complete the isomerization, overnight reflux (40 °C) was required as noted in entry 1 for comparison. Geometries of the double bond of all the products 6a, 9a, and 10a generated in the RCM were assigned as Z configuration based on the coupling constant <12 Hz of olefinic protons in their 1 H-Nucler Magnetic Resonance (NMR) spectra. Similarly, the reactions of 4b (R = Bn) and 4c (R = Ts) at room temperature gave the desired RCM products 6b (entry 6) and 6c (entry 8), respectively, whereas the corresponding MW reactions gave the isomerized products 9b (25%)/10b (63%) (entry 7) and 9c (21%)/10c (50%) (entry 9), respectively. The reaction of 4d (R = n-Bu) proceeded in the same manner, but the reaction product 6d obtained at room temperature, which was almost pure in the crude 1 H-NMR spectrum, was partially isomerized to an inseparable mixture of 9d and 10d during the purification using a preparative thin layer chromatography (TLC) plate (entry 10). The corresponding MW reaction of 6d afforded a mixture of 9d and 10d, as observed in the 1 H-NMR spectrum of the crude residue, in 77% combined yield in the ratio ca. 1:3 (entry 11).

Double-Bond Migration of Dihydro-1H-1-Trityloxepino[3,2-c]pyrazoles Catalyzed by Ruthenium Hydride Species
Double-bond migration during the RCM of medium-sized rings has been reported [30][31][32][33]. Previous studies showed the participation of a small amount of ruthenium hydride species present in the used catalyst as the impurity or produced during the RCM process. Then, the reaction of 6a with carbonylchlorohydrotris(triphenylphosphine)ruthenium (II) (RuClH(CO)(PPh3)3) was investigated as shown in Scheme 3. The MW reaction at 70 °C for 10 min gave the isomerized products 9a and 10a in 3% and 19% yields, respectively, along with the recovery of 6a (63%), whereas no isomerization was observed in the reaction at 40 °C. The same reaction at 140 °C gave the isomerized products 9a and 9a in 45% and 13% yields, respectively. These experiments indicated the participation of ruthenium hydride species in the double-bond isomerization of 6 to 9 or 10 as observed in the RCMs at a higher temperature in this study.

Double-Bond Migration of Dihydro-1H-1-Trityloxepino[3,2-c]pyrazoles Catalyzed by Ruthenium Hydride Species
Double-bond migration during the RCM of medium-sized rings has been reported [30][31][32][33]. Previous studies showed the participation of a small amount of ruthenium hydride species present in the used catalyst as the impurity or produced during the RCM process. Then, the reaction of 6a with carbonylchlorohydrotris(triphenylphosphine)ruthenium (II) (RuClH(CO)(PPh 3 ) 3 ) was investigated as shown in Scheme 3. The MW reaction at 70 • C for 10 min gave the isomerized products 9a and 10a in 3% and 19% yields, respectively, along with the recovery of 6a (63%), whereas no isomerization was observed in the reaction at 40 • C. The same reaction at 140 • C gave the isomerized products 9a and 9a in 45% and 13% yields, respectively. These experiments indicated the participation of ruthenium hydride species in the double-bond isomerization of 6 to 9 or 10 as observed in the RCMs at a higher temperature in this study. Similarly, the reactions of 4b (R = Bn) and 4c (R = Ts) at room temperature gave the desired RCM products 6b (entry 6) and 6c (entry 8), respectively, whereas the corresponding MW reactions gave the isomerized products 9b (25%)/10b (63%) (entry 7) and 9c (21%)/10c (50%) (entry 9), respectively. The reaction of 4d (R = n-Bu) proceeded in the same manner, but the reaction product 6d obtained at room temperature, which was almost pure in the crude 1 H-NMR spectrum, was partially isomerized to an inseparable mixture of 9d and 10d during the purification using a preparative thin layer chromatography (TLC) plate (entry 10). The corresponding MW reaction of 6d afforded a mixture of 9d and 10d, as observed in the 1 H-NMR spectrum of the crude residue, in 77% combined yield in the ratio ca. 1:3 (entry 11).

Double-Bond Migration of Dihydro-1H-1-Trityloxepino[3,2-c]pyrazoles Catalyzed by Ruthenium Hydride Species
Double-bond migration during the RCM of medium-sized rings has been reported [30][31][32][33]. Previous studies showed the participation of a small amount of ruthenium hydride species present in the used catalyst as the impurity or produced during the RCM process. Then, the reaction of 6a with carbonylchlorohydrotris(triphenylphosphine)ruthenium (II) (RuClH(CO)(PPh3)3) was investigated as shown in Scheme 3. The MW reaction at 70 °C for 10 min gave the isomerized products 9a and 10a in 3% and 19% yields, respectively, along with the recovery of 6a (63%), whereas no isomerization was observed in the reaction at 40 °C. The same reaction at 140 °C gave the isomerized products 9a and 9a in 45% and 13% yields, respectively. These experiments indicated the participation of ruthenium hydride species in the double-bond isomerization of 6 to 9 or 10 as observed in the RCMs at a higher temperature in this study.