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Article

Synthesis of Dihydropyrano[3,2-c]pyrazoles via Double Bond Migration and Ring-Closing Metathesis

by
Yoshihide Usami
*,
Kodai Sumimoto
,
Azusa Kishima
,
Yuya Tatsui
,
Hiroki Yoneyama
and
Shinya Harusawa
Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(2), 296; https://doi.org/10.3390/molecules24020296
Submission received: 25 December 2018 / Revised: 9 January 2019 / Accepted: 11 January 2019 / Published: 15 January 2019
(This article belongs to the Section Organic Chemistry)
Browse Figures
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Abstract

:
Three types of pyrazole-fused heterobicycles, i.e., 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-c]pyrazoles, were synthesized from 4-allyloxy-1H-pyrazoles. A sequence of the Claisen rearrangement of 4-allyloxy-1H-pyrazoles, ruthenium-hydride-catalyzed double bond migration, O-allylation, and ring-closing metathesis was employed in this study.

Graphical Abstract

1. Introduction

The synthesis of substituted or functionalized pyrazoles has been studied extensively thus far because they show or are expected to show important and diverse bioactivities [1,2]. Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a representative pyrazole-containing compound, which acts through selective cyclooxygenase (COX)-2 inhibition. Whereas the late-stage construction of a pyrazole ring through some cycloadditions of already-substituted components is the basis for most syntheses of substituted pyrazoles [3,4], direct functionalization of pyrazoles has not been investigated satisfactorily to date. As investigations on it seem rare, we have been interested in and studied the direct functionalization of pyrazoles through coupling reactions of halogenated analogues derived from commercially available pyrazole [5,6,7,8]. In addition, pyrazole-fused heterocycles have recently been synthesized for reasons similar to those described above or because of characteristic activities not seen in monocyclic substituted pyrazoles [9]. Many pyrazole-fused heterocyclic compounds possess unique and important biological activities [10]. Some examples of pyrano[2,3-c]pyrazoles [11,12,13,14], pyrano[3,2-c]pyrazoles [15,16], and furo[3,2-c]pyrazoles [17,18] are presented in Figure 1.
The Claisen rearrangement followed by ring-closing metathesis (RCM) is an effective sequence for constructing various polycyclic systems [19,20]. On the basis of our previous work on the synthesis of withasomnines [21,22], we recently reported the synthesis of dihydrooxepino[3,2-c]pyrazoles (4 and its isomers) via a combination of the Claisen rearrangement of 4-allyloxy-1H-pyrazoles (1a–d), O-allylation of Claisen rearrangement product 2 into 3, and subsequent RCM of 3 [23]. This realized the construction of pyrazole-containing 5,7-bicyclic system 4, shown in Scheme 1.
After the migration of the double bond in the side chain of intermediate 2 in Scheme 1, expected product 5 can be O-allylated to 6. The subsequent RCM of 6 may provide a pyrazole-containing 5,6-bicyclic system, i.e., a dihydropyrano[3,2-c]pyrazole. These are expected to show various types of activities. There have been many reports of syntheses of pyrano[2,3-c]pyrazoles [10,11,12,13,14], but very few for pyrano[3,2-c]pyrazoles [15,16,24,25]. In addition, the development of a new synthetic method for furo[3,2-c]pyrazoles, which are extremely important as mentioned above, seems possible if both double bond migration and dehydrohalogenation occur on a 5-allyl-4-(2-haloethyl)oxy-1H-1-tritylpyrazole. Described herein is a new and selective synthesis of three types of dihydropyrano[3,2-c]pyrazoles, namely 7, 8, and 20, with pyrazole-fused heterocyclic skeletons from 1 via the combination of Claisen rearrangements and RCM, along with efforts toward furo[3,2-c]pyrazoles (17).

2. Results

2.1. Synthesis of 1,5-Dihydropyrano[3,2-c]pyrazoles

Our initial efforts in the synthesis of 1,5-dihydropyrano[3,2-c]pyrazoles (7) are presented in Scheme 1 and Table 1. In our earlier efforts for double bond migration for the conversion of 2a to 5a with potassium tert-butoxide (t-BuOK) as a base, every trial under microwave (MW) irradiation in a different solvent (tetrahydrofuran (THF), EtOH, MeCN, acetone, 1,2-dimethoxyethane (DME), toluene, THF-toluene) failed to give the desired product 5a [20,26]. Alternatively, carbonylchlorohydridotris(triphenylphosphine)ruthenium(II) [(RuClH(CO)(PPh3)3] was applied to the double bond migration for the conversion of 2 to 5, as shown in Scheme 1 [27]. MW irradiation of the reaction mixture of 2 and 5 mol% of the ruthenium hydride catalyst in toluene gave the desired product 5, whereas the same reaction at room temperature (rt) did not occur. Starting compounds 2a–d are known compounds [21,22,23], and 1-benzyl-4-hydroxy-5-((1-methoxycarbonyl)-2-propen-1-yl)-1H-pyrazole (2e) is the Claisen rearrangement product of 1e, which was newly prepared from 1-benzyl-4-iodo-1H-pyrazole for this work and already contained a small part of 5e (see Experimental section).
Then, the C4-hydroxyl groups in 4-hydroxy-5-(1-propenyl)-1H-pyrazoles 5a and 5b were treated with aqueous NaOH followed by alkenyl halides in order to prepare the RCM substrates 6a and 6b. Conversion of 5c and 5d, which have a substituent, to 6c and 6d using the same condition took a long time with poor yields. So, alternative transformation of 5c and 5d to 6c and 6d was carried out using K2CO3 in acetone under MW irradiation, respectively. The reactions proceeded smoothly and the chemical yields of 6c and 6d are presented in Scheme 1a. In a separate experiment, compound 2e, which already contains a small part of 5e as noted above, was transformed directly to 6e through treatment with K2CO3 and allyl bromide in acetone under MW irradiation in 63% yield, since the yield from 2e to 5e was not satisfactory. The yield of the MW-aided transformation of 2e to 6e was improved to 85% by applying acetone-water (9:1) as the solvent system (Scheme 1b).
RCM substrates 6 were treated with 5 mol% Grubbs′ second-generation catalyst (Grubbs2nd) in CH2Cl2. The results of the RCM reactions are summarized in Table 1. With substrate 6a, reaction at rt afforded the desired RCM product 7a within 30 min (entry 2). A shorter reaction time also led to 7a, but with an inseparable trace amount of 6a (entry 1). In contrast, extended reaction times led to reduced product yields (entries 3 and 4). The MW-aided reaction was also examined in an attempt to reduce the reaction time (entries 5–7). In these trials, only 7a was formed and double bond migration product 8a could not be detected [23]. Moreover, higher temperatures above 100 °C reduced the reaction yield (entry 7). The optimal reaction conditions in entries 2 and 5 for substrate 6a were applied to the RCM of 6b and gave similar results producing 7b (entries 8 and 9, respectively). The MW reaction of 6b at a higher temperature of 140 °C led to partial double bond migration to produce 8b (entry 10). When the substrate had an R′ substituent, different results were obtained, as shown by the following entries. Substrates 6d and 6e did not react at rt (entries 13 and 15, respectively).
The MW-aided reaction (140 °C) of 6c afforded RCM product 7c as a minor product (24%) and 9c (45%) with an exomethylene moiety as the major product (entry 12). The structure of 9c was determined through the heteronuclear single quantum coherence (HSQC) correlations between a carbon signal at δ 107.2 ppm and two proton signals at δ 4.78 and 4.96 ppm. Generally, endo-cyclic alkene is considered to be more stable than the corresponding exo-alkene. But in this case, 7c is thought to be less stable than exo-diene 9c due to the strain caused by 6-membered endo-diene structure in the thermodynamic condition.
However, the same MW conditions applied to substrate 6d did not result in 7d, but dimeric 10d formed through intermolecular metathesis in 30% yield (entry 14). Mass spectrometry (MS) revealed that compound 10d had an m/z of 632 (M+), which corresponds to C42H42N4O2. The 1H nuclear magnetic resonance (NMR) spectrum of 10d suggested the presence of a =CHCH3 moiety through the signals at δ 6.29 (q, J = 7.1 Hz) and 1.51 ppm (d, J = 7.1 Hz) in a 1:3 integral ratio and the lack of an exomethylene from the starting 6d. These data suggest that the intermolecular metathesis product 10d formed by expelling an ethylene molecule [339 (6d) × 2 − 28 (CH2=CH2) = 632 ((M+) for 10d)]. The presence of a bulky R′ substituent may lead to serious repulsion in the transition state for RCM. When the substrate had a methoxycarbonyl group as R′, the results were confusing. The MW reaction of 6e at 140 °C gave a complex mixture and only 7e was isolated in 15% yield (entry 18). The MW reactions of 6e at lower temperatures (80 and 100 °C) gave 10e in similar yields (29% and 30%, respectively) with 7e as a minor product (entries 16 and 17). In both of these entries, 11e, which is a metathesis product of 6e and the Grubbs catalyst, was also isolated as a minor product. The structure of 11e was confirmed through detailed NMR analysis and an M+ peak at m/z 388.1785 (C24H24N2O3) in the high-resolution MS (HRMS) spectrum. However, our attention was focused on increasing the yields of 7e and decreasing the yields of 10e by increasing the reaction temperature (entries 16–18). Then, we hypothesized that 10e transforms into 7e; 10e may be the initial product at lower reaction temperatures. Therefore, the MW reaction of pure 10e with Grubbs2nd at 140 °C was examined independently in an attempt to observe the formation of 7e as the major product in the reaction mixture.

2.2. Synthesis of 1,7-Dihydropyrano[3,2-c]pyrazoles

We attempted to expand this methodology to the syntheses of different types of pyrazole-fused heterobicycles, i.e., 1,7-dihydropyrano[3,2-c]pyrazoles (8) and furo[3,2-c] pyrazoles (17), as illustrated in Scheme 2. In order to realize this, 4-O-vinylation was required. First, the 4-hydroxyl group of 2a was treated with 1,2-dichloroethane to obtain a pyrazole with a 2-chloroethoxy group at C4, 12Cl. However, dehydrochlorination of 12Cl did not occur under basic conditions. Then, 2-bromoethylation of the 4-hydroxyl group was examined, aimed at improving the leaving ability. Desired 5-allyl-4-(2-bromoethyl)oxy-1H-1-tritylpyrazole (12a) was smoothly prepared through the MW-aided reaction of 2a. The examination of the dehydrobromination of 12a is summarized in Table 2. Whereas treatment of 12a with t-BuOK in toluene resulted in no reaction (entry 1), application of THF-MeOH (4:1) led to the desired dehydrobromination (entries 2–5). The MW reaction at 100 °C for 30 min afforded only double bond migration product (E/Z)-5-allyl-4-vinyloxy-1H-1-tritylpyrazole (13a) but in 14% yield (entry 2). Increasing the reaction time to 60 min resulted in an inseparable mixture of 13a and 5-(1-propenyl)-4-vinyloxy-1H-1-tritylpyrazole (14a) in 19% combined yield (entry 3). A higher temperature of 130 °C resulted in only 14a in 30% yield (entry 4). A similar MW reaction at 80 °C produced 13a in a similar yield (entry 5). In these trials (entries 2–5), the chemical yields of desired 13a and 14a were not satisfactory. Close inspection of entries 4 and 5 led us to isolate and elucidate the structures of side product 15 (28% yield), which should have formed via SN2 attack by a methoxide on 12a, and 16 (17% yield) (see footnotes of Table 2). To improve the chemical yields, inhibition of the SN2 attack on 12a by a nucleophile formed from the solvent under basic conditions was required. Hence, t-BuOH was applied instead of MeOH as a co-solvent. Although the MW reaction at 80 °C afforded only a trace amount of desired product 13a (entry 6), the same reaction at 130 °C afforded only 13a in 87% yield (entry 7). Inspired by the result in entry 4, the MW reaction was attempted at a higher temperature of 180 °C and afforded 14a selectively in 67% yield (entry 8). Treatment of the N-benzyl derivative 12b with t-BuOK at 130 °C resulted in only 14b (72%) (entry 9). Then, the dehydrobromination of 12b was examined at a lower temperature (entry 10), but resulted in an inseparable mixture of 12b and 14b.
The RCM of prepared substrates 13a, 14a, and 14b were examined. Treatment of 13a with Grubbs2nd (5 mol%) at rt gave the desired product 8a in 95% yield. However, the corresponding reactions of 14a and 14b did not afford the desired products 17a and 17b, even with MW assistance. Further examinations of 14a with alternative catalysts, such as the Grubbs1st, Hoveyda-Grubbs, and Schrock catalysts, also did not lead to 17a. Our synthesis of 17 will be continued in a future study.

2.3. Synthesis of 2,5-Dihydropyrano[3,2-c]pyrazoles

The synthesis of 2,5-dihydropyrano[3,2-c]pyrazoles (20) was examined and the results are summarized in Scheme 3. For this purpose, selective preparation of 3-alkenyl-4-allyloxy-1H-pyrazoles 19 is required since 3-allyl-4-hydroxy-1H-1-tritylpyrazole is a minor Claisen rearrangement product of 1a, and the corresponding 3-allyl-1-benzyl-4-hydroxy-1H-pyrazole could not be obtained by heating 1b [21,22]. Hence, an alternative method of preparing 19 via a deprotection-reprotection sequence was examined. 4-Allyloxy-5-(1-propenyl)-1H-1-tritylpyrazole (6a) was deprotected with aqueous HCl to give 18, which was then treated with trityl chloride or benzyl bromide under basic conditions. An E/Z mixture of 4-allyloxy-3-(1-propenyl)-1H-1-tritylpyrazole (19a) was obtained exclusively owing to the steric repulsion between the propenyl group on the pyrazole ring and an introduced bulky trityl group. However, N-benzylation of 18 afforded a mixture of 19b and 6b in a ca. 4:1 ratio in 60% combined yield, and separation gave pure 19b in 25% yield. The obtained substrates 19a and 19b were independently treated with 5 mol% Grubbs2nd at rt to afford the desired RCM products 20a and 20b, respectively, in good yields.

3. Conclusions

We synthesized 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-c]pyrazoles (7, 8, and 20) from 5-allyl-4-hydroxy-1H-1-tritylpyrazoles via a combination of the Claisen rearrangement, ruthenium-hydride-catalyzed double bond isomerization, O-alkenylation, and RCM. In the synthesis of 1,5-dihydropyrano[3,2-c]pyrazoles 7, the presence of a substituent on the 5-alkenyl group inhibited smooth RCM through steric hindrance. In these cases, MW-aided reactions were effective, but gave various products. Towards the selective synthesis of 1,7-dihydro-1-tritylpyrano[3,2-c]pyrazole 8a, temperature-dependent selective dehydrobromination was effective for preparing the RCM substrate 13b. For the synthesis of 2,5-dihydropyrano[3,2-c]pyrazoles 20, a deprotection-reprotection sequence was applied to obtain the RCM substrate 19.

4. Materials and Methods

Infrared (IR) spectra were obtained using a Perkin Elmer 1720X FT-IR spectrometer (Perkin Elmer, Wattham, MA, USA). HRMS was performed using a JEOL JMS-700 (2) mass spectrometer (JEOL, Tokyo, Japan). NMR spectra were recorded at 27 °C using Agilent 300, 400-MR-DD2, and 600-DD2 spectrometers in CDCl3 using tetramethylsilane (TMS) as the internal standard. Liquid column chromatography was conducted using silica gel BW127ZH (Fuji Silysia Chemical Ltd., Tokyo, Japn). Analytical and preparative thin layer chromatography (TLC) analyses were performed using pre-coated Merck glass plates (silica gel 60 F254), and the compounds were visualized by dipping the plates in an ethanol solution of phosphomolybdic acid followed by heating (Merk & Co., Inc., Darmstadt, Germany). MW-assisted reactions were carried out using a Biotage Initiator® (Basel, Switzerland). Anhydrous CH2CH2 was purchased from Wako Pure Chemical Industries (Osaka, Japan).

4.1. Synthesis of (E)-Methyl 4-((1-Benzyl-1H-pyrazol-4-yl)oxy)but-2-enoate (1e)

To 1-benzyl-4-formyl-1H-pyrazole (200 mg, 1.07 mmol) in CH2Cl2 (5 mL) was added 70% meta-chloroperoxybenzoic acid (397.6 mg, 1.61 mmol) at 0 °C. After it was stirred overnight at room temperature, the mixture was quenched by adding aqueous NaHCO3 and then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and evaporated to give a crude residue. The crude material was dissolved in t-BuOH-CH2Cl2 (5 mL/5 mL) at 40 °C, and then potassium tert-butoxide (428.6 mg, 3.82 mmol) was added to the solution. After it was stirred overnight at 40 °C, the mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:3) to afford (E/Z)-1e (128.1 mg, 44%): oil; IR (film) vmax 1724 (C=O), 1574 (C=C), 1437 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 3.74 (3H, s, -COOMe), 4.52 (2H, dd, J = 4.1, 1.9 Hz, -OCH2CH=CH-), 6.13 (1H, br d, J = 15.9 Hz, -COCH=CH-), 6.99 (1H, dt, J = 15.9, 4.1 Hz, -CH2CH=CH-), 7.05 (1H, d, J = 0.6 Hz, pyrazole-H), 7.18 (2H, br d, J = 8.0 Hz, Bn-H), 7.30–7.35 (4H, m, Bn-H, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 51.6, 56.6, 70.0, 115.1, 121.4, 127.2, 127.5, 128.0, 128.7, 136.3, 142.5, 145.2, 166.4; high-resolution electron ionization mass spectrometry (HREIMS) m/z calcd. for C15H16N2O3 (M+) 272.1161, found 272.1163.
*(E)-Methyl 4-((1-trityl-1H-pyrazol-4-yl)oxy)but-2-enoate (1f) was synthesized in a similar manner as 1e, but it was not rearranged under the thermal condition described below. 1f: colorless crystals (CH2Cl2); mp 155–158 °C; IR (film) vmax 1725 (C=O), 1572 (C=C), 1492 (C=C), 1442 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 3.76 (3H, s, -COOMe), 4.53 (2H, dd, J = 4.1, 2.0 Hz, -OCH2CH=CH-), 5.20 (2H, s, ArCH2Ph), 6.14 (1H, dt, J = 15.9, 1.9 Hz, -COCH=CH-), 7.00 (1H, dt, J = 15.9, 4.1 Hz, -CH2CH=CH-), 7.05 (1H, s, pyrazole-H), 7.13–7.18 (6H, m, Tr-H), 7.30–7.35 (9H, m, Tr-H), 7.42 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 51.7, 70.0, 78.7, 118.4, 121.5, 127.68, 127.71, 127.9, 130.1, 142.5, 143.0, 143.8, 166.4; HREIMS m/z calcd. for C27H24N2O3 (M+) 424.1786, found 424.1779.

4.2. Synthesis of Methyl 2-(1-Benzyl-4-hydroxy-1H-pyrazol-5-yl)but-3-enoate (2e)

A sealed microwave vial containing a solution of 1e (128.1 mg, 0.47 mmol) in 1,2-dimethoxyethane (DME) (2 mL) was heated under microwave irradiation at 200 °C for 30 min. After it had cooled, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:1) to afford 2e with a small amount of the isomer, 5e (53.9 mg, 42%).
2e (major) and 5e (minor) in ca. 2:1 ratio: oil; IR (film) vmax 1716 (C=O), 1497 (C=C), 1435 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.65 (1H, d, J = 7.3 Hz, =CHCH3 of 5e), 3.64 (1H, s, -COOMe of 5e), 3.68 (2H, s, -COOMe of 2e), 4.37 (0.7H, br d, J = 7.0 Hz, ArCH(COOMe)CH=), 4.93 (0.7H, dd, J = 17.0, 1.5 Hz, -CH=CHH), 5.01 (0.6H, s, ArCH2Ph), 5.12 (0.7H, dd, J = 10.3, 1.5 Hz, -CH=CHH of 2e), 5.19 (0.7H, br d, J = 16.1 Hz, ArCHHPh of 2e), 5.25 (0.7H, br d, J = 16.1 Hz, ArCHHPh of 2e), 5.86 (1H, ddd, J = 17.0, 10.3, 6.5 Hz, -CH(COOMe)CH=CH2 of 2e), 6.83 (0.6H, br s, -OH of 2e), 7.03–7.05 (2H, m, Ph-H), 7.19–7.31 (3H, m, Ph-H; 0.3H, m, overlapped, =CHCH3 of 5e), 7.30 (1H, br s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 15.8 (5e), 46.4, 52.3 (5e), 53.2, 54.4 (5e), 54.6, 118.7, 120.6, 122.4 (5e), 122.9 (5e), 126.6, 127.2 (5e), 127.6 (5e), 127.9, 128.2 (5e), 128.40 (5e), 128.44, 129.1, 130.7, 136.9 (5e), 139.8 (5e), 140.9, 147.0, 166.5 (5e), 173.2; HREIMS m/z calcd. for C15H16N2O3 (M+) 272.1161, found 272.1162.

4.3. Double Bond Migration of 5-Allyl-4-hydroxy-1H-pyrazoles (Scheme 1)

General procedure: To a toluene solution (10 mL) of 5-allyl-4-hydroxy-1-trityl-1H-pyrazole (2a) (0.434 g, 1.19 mmol) in a microwave vial (5–20 mL), RuClH(CO)(PPh3)3 (56.6 mg, 0.059 mmol) was added. The reaction vial was sealed and then heated at 150 °C for 15 min under microwave irradiation. The cooled reaction mixture was evaporated to give a crude residue, which was purified using column chromatography (eluent: hexane:EtOAc = 1:1) to afford 4-hydroxy-5-(1-propenyl)-1-trityl-1H-pyrazole (5a) (0.323 g, 74% yield) as an E/Z mixture.
**Pure starting material gave the desired product as described above, but a small contamination inhibited the isomerization. In that case, a toluene-MeOH (9:1) solvent system was effective for isolating the desired product.
5a: oil; IR (film) vmax 3268 (-OH), 1597 (C=C), 1494 (C=C), 1446 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.43 (3H, dd, J = 6.5, 1.2 Hz, =CHCH3), 5.17 (1H, dd, J = 11.4, 1.4 Hz, ArCH=CH-), 5.23 (1H, dq, J = 11.4, 6.6 Hz, -CH=CHCH3), 7.09–7.34 (16H, m, Tr-H, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 14.9, 78.8, 118.3, 126.2, 127.3, 127.4, 127.6, 127.8, 129.6, 130.0, 130.1, 130.28, 130.34, 142.6; HREIMS m/z calcd. for C25H22N2O (M+) 366.1732, found 366.1731.
(E/Z)-1-Benzyl-4-hydroxy-5-(1-propenyl)-1H-pyrazole (5b): E/Z mixture in ca. 5:1 ratio (X); oil; IR (film) vmax 3031 (-OH), 1589 (C=C), 1496 (C=C), 1454 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 1.72 (0.5H, dd, J = 6.8, 1.5 Hz, -CH=CHCH3 of (E)-isomer), 1.83 (2.5H, dd, J = 6.8, 1.8 Hz, -CH=CHCH3 of (Z)-isomer), 5.15 (0.3H, s, -NCH2Ph of (Z)-isomer), 5.24 (1.5H, s, -NCH2Ph of (E)-isomer), 5.93 (0.15H, dq, J = 10.1, 6.8 Hz, -CH=CHCH3 of (Z)-isomer), 5.99 (0.15H, dq, J = 10.1, 1.5 Hz, ArCH=CHCH3 of (Z)-isomer), 6.15 (0.85H, dq, J = 16.1, 1.5 Hz, ArCH=CHCH3 of (E)-isomer), 6.38 (0.85H, dq, J = 16.1, 6.8 Hz, -CH=CHCH3 of (E)-isomer), 7.06–7.09 (6H, m, Tr-H), 7.16 (1H, s, pyrazole-H), 7.22–7.31 (9H, m, Tr-H); 13C NMR of (E)-isomer (150 MHz, CDCl3): δ 19.2, 53.7, 116.7, 126.6, 127.6, 127.9, 128.7, 130.3, 137.1, 138.9 (two carbon signals were deduced to have overlapped); (Z)-isomer: δ 15.4, 54.0, 115.4, 126.8, 126.9, 127.9, 128.6, 133.4, 137.0, 138.4 (two carbon signals were deduced to have overlapped); HREIMS m/z calcd. for C13H14N2O (M+) 214.1106, found 214.1104.
(E/Z)-1-Benzyl-4-hydroxy-5-(1-(1-methyl)propen-1-yl)-1H-pyrazole (5c): E/Z ratio = ca. 1:1; oil; IR (film) vmax 3063 (OH), 1563 (C=C), 1497 (C=C), 1456 (C=C) cm−1; 1H NMR of E/Z mixture (400 MHz, CDCl3): δ 1.41 (1.6H, dd, J = 6.9, 1.5 Hz, -CH=CHCH3), 1.73 (1.4H, dd, J = 6.8, 1.2 Hz, -CH=CHCH3), 1.79 (3H, br s, CqCH3), 4.30 (0.47H, br s, -OH), 4.43 (0.53H, br s, -OH), 5.08 (0.9H, s, -NCH2Ph), 5.15 (1.1H, s, -NCH2Ph), 5.57 (0.47H, qq, J = 6.8, 1.6 Hz, -CCH=CHCH3), 5.78 (0.53H, qq, J = 6.9, 1.6 Hz, -CCH3=CHCH3), 7.03 (0.94H, br d, J = 6.7 Hz, Ph-H), 7.07 (1.06H, br d, J = 6.7 Hz, Ph-H), 7.06–7.09 (6H, m, Ph-H), 7.16–7.36 (3H, m, Ph-H), 7.21 (1H, s, pyrazole-H); 13C NMR of E/Z mixture (100 MHz, CDCl3): δ 14.0, 15.0, 16.2, 32.0, 53.9, 54.1, 124.2, 124.6, 126.8, 127.2, 127.4, 127.5, 127.91, 127.94, 128.46, 128.49, 128.6, 129.8, 130.0, 132.6, 137.3, 137.6, 137.8; HREIMS m/z calcd. for C14H16N2O (M+) 228.1263, found 228.1260.
(E/Z)-1-Benzyl-4-hydroxy-5-(1-(1-phenyl)propenyl)-1H-pyrazole (5d): isomer ratio = ca. 5:1; oil; IR (film) vmax 3031 (OH), 1573 (C=C), 1496 (C=C) cm−1; 1H NMR (100 MHz, CDCl3): δ 1.55 (2.5H, d, J = 7.0 Hz, =CHCH3), 1.85 (0.5H, d, J = 7.3 Hz, =CHCH3), 4.61 (1H, br s, J = 14.8 Hz, -NCHHPh), 4.95 (1H, br s, J = 15.3 Hz, -NCHHPh), 5.94 (0.16H, q, J = 7.2 Hz, Cq=CHCH3), 6.31 (0.84H, br q, J = 7.0 Hz, Cq=CHCH3), 6.87–6.90 (0.66H, m, Ph-H), 6.93–6.96 (1.34H, m, Ph-H), 7.06–7.34 (4H, m, Ph-H), 7.32 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.7, 54.3, 126.2, 127.0, 127.38, 127.45, 127.6, 128.3, 128.4, 128.6, 128.9, 129.3, 131.1, 136.9, 139.9 (minor isomer: 15.4, 54.0, 126.4, 127.68, 127.8); HREIMS m/z calcd. for C19H18N2O (M+) 290.1419, found 290.1417.
(E/Z)-1-Benzyl-4-hydroxy-5-(1-(1-methoxycarbonyl)propenyl)-1H-pyrazole (5e): E/Z mixture in ca. 13:1 ratio; oil; IR (film) vmax 3090 (OH), 1716 (C=O), 1507 (C=C), 1436 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.72 (2.6H, d, J = 7.3 Hz, -CH=CHCH3 of major isomer), 1.83 (0.4H, d, J = 7.2 Hz, -CH=CHCH3 of minor isomer), 3.66 (2.6H, s, -OCH3 of major isomer), 3.71 (0.4H, s, -OCH3 of minor isomer), 4.73 (1H, s, -OH), 5.06 (1.86H, s, -NCH2Ph of major isomer), 5.17 (0.14H, s, -NCH2Ph of minor isomer), 7.04 (2H, br d, J = 6.6 Hz, Ph-H), 7.19–7.30 (4H, m, Ph-H, =CHCH3), 7.33 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.8, 52.3, 54.5, 122.2, 122.9, 127.3, 127.6, 128.1, 128.4, 136.7, 140.0, 147.5, 166.5; HREIMS m/z calcd. for C15H16N2O3 (M+) 272.1161, found 272.1160.

4.4. O-Allylation of 1-Protected 5- or 3-Allyl-4-allyloxy-1H-pyrazoles (Scheme 1)

General procedure: To a solution of an E/Z mixture of 4-hydroxy-5-(1-propenyl)-1H-1-tritylpyrazole (5a) (0.410 g, 1.12 mmol) in acetone (2 mL), 20% aqueous NaOH (1 mL) and allyl bromide (142 μL, 1.68 mmol) were added. The reaction mixture was stirred for 1 h and then quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered, and evaporated. The crude residue was purified with column chromatography (eluent: hexane:EtOAc = 3:1) to afford 4-allyloxy-5-(1-propenyl)-1H-1-tritylpyrazole (6a) (E/Z mixture in ca. 3:1 ratio, 0.334 g, 73% yield).
(E)-6a: mp 152–155 °C; IR (KBr) vmax 1567 (C=C), 1491 (C=C), 1446 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.40 (3H, dd, J = 6.7, 1.5 Hz, CH3CH=), 4.50 (2H, dt, J = 5.3, 1.5 Hz, -OCH2CH=CH2), 5.26 (1H, dq, J = 15.8, 1.4 Hz, -CH2CH=CHH), 5.37 (1H, dq, J = 17.2, 1.5 Hz, -CH2CH=CHH), 5.46 (1H, dq, J = 15.8, 1.4 Hz, ArCH=CHCH3), 6.04 (1H, ddt, J = 17.2, 10.5, 5.3 Hz, -OCH2CH=CH2), 6.14 (1H, dq, J = 15.8, 6.7 Hz, ArCH=CHCH3), 7.07–7.16 (6H, m, Tr-H), 7.24–7.39 (9H, m, Tr-H), 7.32 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 18.9, 72.0, 79.0, 117.5, 120.0, 124.7, 127.3, 127.4, 127.6, 128.5, 130.3, 133.5, 142.9, 143.5; HREIMS m/z calcd. for C28H26N2O (M+) 406.2055, found 406.2047.
(Z)-6a: mp 82–86 °C; IR (KBr) vmax 1567 (C=C), 1491 (C=C), 1446 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.42 (3H, d, J = 5.1 Hz, CH3CH=), 4.47 (2H, dt, J = 5.5, 1.6 Hz, -OCH2CH=CH2), 5.16–5.20 (2H, m), 5.22 (1H, dq, J = 10.6, 1.4 Hz, -CH2CH=CHH), 5.34 (1H, dq, J = 17.2, 1.5 Hz, -CH2CH=CHH), 6.00 (1H, ddt, J = 17.2, 10.6, 5.6 Hz, -OCH2CH=CH2), 7.03–7.17 (6H, m, Tr-H), 7.21–7.32 (9H, m, Tr-H), 7.37 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.4, 72.0, 78.9, 117.4, 117.9, 124.9, 127.2, 127.3, 127.9, 129.8, 130.1, 133.7, 142.6, 142.9; HREIMS m/z calcd. for C28H26N2O (M+) 406.2046, found 406.2050.
(E/Z)-4-Allyloxy-1-benzyl-5-(1-propenyl)-1H-pyrazole (6b) (an inseparable E/Z mixture in a ca. 8:2 ratio, 0.334 g, 73% yield): oil; IR (film) vmax 1566 (C=C), 1495 (C=C), 1452 (C=C) cm−1; HREIMS m/z calcd. for C16H18N2O (M+) 254.1419, found 254.1421. (E)-isomer: 1H NMR (600 MHz, CDCl3): δ 1.82 (3H, d, J = 6.7, 1.8 Hz, CH3CH=), 4.50 (2H, dt, J = 5.4, 1.4 Hz, -OCH2CH=CH2), 5.26 (1H, dq, J = 10.6, 1.4 Hz, -CH2CH=CHH), 5.28 (2H, s, NCH2Ph), 5.39 (1H, ddd, J = 17.3, 3.2, 1.8 Hz, -CH2CH=CHH), 6.05 (1H, ddt, J = 17.3, 10.6, 5.4 Hz, -OCH2CH=CH2), 6.16 (1H, br d, J = 15.8 Hz, ArCH=CHCH3), 6.46 (1H, dq, J = 15.8, 6.7 Hz, -CH=CHCH3), 7.07 (2H, br d, J = 7.6 Hz, Ph-H), 7.24 (1H, br t, J = 7.6 Hz, Ph-H), 7.26 (1H, s, pyrazole-H), 7.30 (2H, br t, J = 7.6 Hz, Ph-H); 13C NMR (150 MHz, CDCl3): δ 19.3, 53.9, 72.2, 116.6, 117.5, 125.8, 126.5, 126.8, 127.5, 128.6, 128.7, 129.6, 133.5, 137.2; (Z)-isomer: 1H NMR (600 MHz, CDCl3): δ 1.72 (3H, dd, J = 6.8, 1.8 Hz, CH3CH=), 4.46 (2H, dt, J = 5.6, 1.5 Hz, -OCH2CH=CH2), 5.18 (2H, s, NCH2Ph), 5.24 (1H, dq, J = 10.5, 1.5 Hz, -CH2CH=CHH), 5.36 (1H, dq, J = 17.1, 1.5 Hz, -CH2CH=CHH), 5.91 (1H, dq, J = 11.2, 6.8 Hz, -CH=CHCH3), 6.01 (1H, ddt, J = 17.1, 10.5, 5.6 Hz, -OCH2CH=CH2), 6.01 (1H, br d, J = 11.2 Hz, ArCH=CHCH3, overlapped), 7.07 (2H, br d, J = 7.6 Hz, Ph-H), 7.24 (1H, br t, J = 7.6 Hz, Ph-H), 7.28 (1H, s, pyrazole-H), 7.30 (2H, br t, J = 7.6 Hz, Ph-H); 13C NMR (150 MHz, CDCl3): δ 15.7, 53.9, 72.4, 115.4, 117.4, 126.59, 126.64, 127.5, 133.2, 137.1, 142.7 (three signals should be overlapped with signals of the (E)-isomer).
(E/Z)-4-Allyloxy-1-benzyl-5-(1-(1-methyl)propenyl)-1H-pyrazole (6c): isomer ratio = ca. 1:1; oil; IR (film) vmax 1562 (C=C), 1496 (C=C), 1455 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.43 (1.6H, dd, J = 6.7, 1.4 Hz, CH3CH=), 1.72 (1.4H, dd, J = 6.9, 1.2 Hz, CH3CH=), 4.414 (1.06H, d, J = 5.5 Hz, -OCH2CH=), 4.417 (0.94H, d, J = 5.5 Hz, -OCH2CH=), 5.08 (0.94H, s, NCH2Ph), 5.19 (1.06H, s, NCH2Ph), 5.19–5.36 (2H, m, =CH2), 5.54 (0.44H, qq, J = 6.9, 1.6 Hz, -C(CH3)H=CH3), 5.75 (0.56H, qq, J = 6.8, 1.6 Hz, -C(CH3)H=CH3), 5.92–6.04 (1H, m, -CH2CH=CH2), 7.02 (0.94H, br d, J = 7.3 Hz, Ph-H), 7.07 (1.06H, br d, J = 7.2 Hz, Ph-H), 7.18–7.29 (3H, m, Ph-H), 7.29 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 13.9, 15.2, 16.0, 23.1, 53.7, 54.0, 72.8, 117.45, 117.54, 125.0, 126.77, 126.86, 127.21, 127.3, 127.5, 128.46, 128.49, 129.0, 129.2, 129.5, 133.2, 133.7, 133.8, 137.3, 137.8, 141.6, 141.7; HREIMS m/z calcd. for C17H20N2O (M+) 268.1576, found 268.1575.
(E/Z)-4-Allyloxy-1-benzyl-5-(1-(1-phenyl)propenyl)-1H-pyrazole (6d): isomer ratio = ca. 7:1; oil; IR (film) vmax 1556 (C=C), 1500 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.55 (2.7H, d, J = 6.9 Hz, CH3CH=), 1.85 (0.3H, d, J = 7.3 Hz, CH3CH=), 4.38 (0.25H, br d, J = 5.5 Hz, -OCH2CH=), 4.44 (1.75H, br d, J = 3.9 Hz, -OCH2CH=CH2), 4.64 (1H, br d, J = 14.9 Hz, NCHHPh), 4.94 (1H, br d, J = 14.8 Hz, NCHHPh), 5.19 (1H, dd, J = 10.5, 1.3 Hz, -CH2CH=CHH), 5.29 (1H, dq, J = 17.2, 1.6 Hz, -CH2CH=CHH), 5.89–6.99 (1H, m, -OCH2CH=CH2 overlaps with 0.12H, m, =CHCH3), 6.31 (0.88H, q, J = 7.0 Hz, =CHCH3), 6.89–6.90 (2H, m, Ph-H), 7.08–7.49 (8H, m, Ph-H), 7.39 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.8, 54.3, 72.7, 117.5, 126.2, 127.0, 127.1, 127.4, 128.27, 128.33, 128.5, 129.2, 129.3, 131.2, 133.7, 137.0, 139.7, 143.3; HREIMS m/z calcd. for C22H22N2O (M+) 330.1732, found 330.1729.
Synthesis of (E/Z)-4-allyloxy-1-benzyl-5-(1-(1-methoxycarbonyl)propenyl)-1H-pyrazole (6e) from 2e: To an acetone solution (4.5 mL) of 2e with a small amount of 5e (121.8 mg, 0.45 mmol) in a microwave vial were added K2CO3 (61.8 mg, 0.45 mmol) in water (0.5 mL) and allyl bromide (0.04 mL, 0.45 mmol). After the reaction vial was sealed, the mixture was heated under microwave irradiation at 60 °C for 1 h. After it had cooled, the reaction was quenched by adding aqueous NH4Cl. Then, the reaction mixture was extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4, filtered, and then evaporated to give a crude residue, which was purified using column chromatography (eluent: hexane:EtOAc = 2:1) to give pure 6e (117.1 mg, 84%).
6e (isomer ratio = ca. 13:1): oil; IR (film) vmax 1717 (C=O), 1500 (C=C) cm−1; 1H NMR: δ 1.54 (2.6H, d, J = 7.2 Hz, CH3CH= of major isomer), 2.12 (0.4H, d, J = 7.2 Hz, CH3CH= of minor isomer), 3.52 (0.4H, s, -OCH3 of minor isomer), 3.60 (2.6H, s, -OCH3 of major isomer), 4.92 (0.93H, br d, J = 15.3 Hz, NCHHPh of major isomer), 5.01 (0.14H, s, NCH2Ph of minor isomer), 5.03 (0.93H, br d, J = 15.3 Hz, NCHHPh of major isomer), 5.11 (0.93H, dq, J = 10.6, 1.4 Hz, -CH2CH=CHH of major isomer), 5.14 (0.07H, dq, J = 10.6, 1.5 Hz, -CH2CH=CHH of minor isomer), 5.22 (0.93H, dq, J = 17.5, 1.6 Hz, -CH2CH=CHH of major isomer), 5.23 (1H, dq, J = 17.4, 1.6 Hz, -CH2CH=CHH of minor isomer), 5.87–5.93 (1H, m, -OCH2CH=CH2), 6.46 (0.07H, q, J = 7.3 Hz, -Cq=CHCH3 of minor isomer), 7.06 (2H, br d, J = 6.6 Hz, Ph-H), 7.17–7.30 (3H, m, Ph-H), 7.20 (0.07H, q, J = 7.2 Hz, -Cq=CHCH3 of major isomer), 7.32 (1H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.7, 52.0, 54.6, 72.5, 117.6, 122.0, 123.2, 126.4, 127.4, 127.6, 128.4, 133.4, 136.7, 143.2, 147.9, 165.9 (minor isomer: 16.2, 51.5, 54.1, 72.8, 121.5, 123.1, 126.6, 127.5, 136.9, 147.7); HREIMS m/z calcd. for C18H20N2O3 (M+) 312.1474, found 312.1467.

4.5. Ring-Closing Metathesis of 6 to 1H-1,5-Dihydropyrano[3,2-c]pyrazoles 7 (Table 1)

General procedure (Table 1, entry 3): To a solution of 6a (21.8 mg, 0.054 mmol) in CH2Cl2 (2 mL) was added Grubbs2nd (1.7 mg, 2.7 mmol) at rt. The reaction mixture was stirred at rt for 1 h, and then the solvent was removed under reduced pressure, affording a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:3) to afford 7a (16.2 mg, 83%).
*General procedure for MW-aided reaction (Table 1, entry 5): To a solution of 6a (16.4 mg, 0.04 mmol) in CH2Cl2 (2 mL) was added Grubbs2nd (2.3 mg, 2.0 mmol) in a microwave vial. The reaction mixture was heated under microwave irradiation at 80 °C for 3 min. After the reaction mixture had cooled, the solvent was removed under reduced pressure, affording a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:4) to afford 7a (12.8 mg, 87%).
1,5-Dihydro-1-tritylpyrano[3,2-c]pyrazole (7a): oil; IR (film) vmax 1677 (C=C), 1581 (C=C), 1493 (C=C), 1447 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 4.64 (2H, dd, J = 3.8, 1.8 Hz, -OCH2CH=CH-), 5.15 (1H, dt, J = 10.2, 3.7 Hz, -OCH2CH=CH-), 5.28 (1H, dtd, J = 10.2, 1.8, 0.8 Hz, -OCH2CH=CH-), 7.08–7.17 (6H, m, Tr-H), 7.18 (1H, d, J = 0.8 Hz, pyrazole-H), 7.23–7.32 (9H, m, Tr-H); 13C NMR (100 MHz, CDCl3): δ 66.9, 78.0, 117.7, 118.6, 124.3, 127.55, 127.57, 130.1, 141.4, 142.7; HREIMS m/z calcd. for C25H20N2O (M+) 364.1575, found 364.1585.
1-Benzyl-1,5-dihydropyrano[3,2-c]pyrazole (7b): oil; IR (film) vmax 1566 (C=C), 1495 (C=C), 1452 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 4.75 (2H, dd, J = 3.9, 1.8 Hz, -OCH2CH=), 5.21 (2H, s, ArCH2Ph), 5.53 (1H, dt, J = 10.0, 3.9 Hz, -OCH2CH=CH-), 6.34 (1H, br d, J = 10.0 Hz, -OCH2CH=CH-), 7.10 (1H, d, J = 0.8 Hz, pyrazole-H), 7.10–7.14 (2H, d, J = 6.6 Hz, Ph-H), 7.26–7.32 (3H, m, Ph-H); 13C NMR (100 MHz, CDCl3): δ 54.0, 67.2, 115.5, 119.7, 124.5, 127.1, 127.9, 128.8, 136.6, 140.9; HREIMS m/z calcd. for C13H12N2O (M+) 212.0950, found 212.0949.
1-Benzyl-1,5-dihydro-7-methylpyrano[3,2-c]pyrazole (7c): oil; IR (film) vmax 1732 (C=O), 1541 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.96 (3H, br s, CqCH3), 4.64 (2H, dq, J = 3.3, 1.6 Hz, -OCH2CH=), 5.23–5.26 (1H, m, -OCH2CH=), 5.39 (2H, s, NCH2Ph), 7.01 (2H, br d, J = 7.0 Hz, Ph-H), 7.17 (1H, s, pyrazole-H), 7.24–7.32 (3H, m, Ph-H); 13C NMR (100 MHz, CDCl3): δ 18.1, 55.3, 67.6, 116.5, 124.7, 126.0, 127.6, 127.3, 128.7, 137.7, 141.4; HREIMS m/z calcd. for C15H14N2O3 (M+) 270.1004, found 270.1003.
1-Benzyl-1,5-dihydro-7-methoxycarbonylpyrano[3,2-c]pyrazole (7e): oil; IR (film) vmax 1732 (C=O), 1541 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 3.76 (3H, s, -COOCH3), 4.72 (2H, d, J = 4.5 Hz, -OCH2CH=), 5.57 (2H, s, ArCH2Ph), 6.45 (1H, t, J = 4.5 Hz, -OCH2CH=Cq), 6.33 (1H, br d, J = 10.0 Hz, -OCH2CH=CH-), 7.04 (2H, br d, J = 6.5 Hz, Ph-H), 7.23 (1H, s, pyrazole-H), 7.23–7.31 (3H, m, Ph-H); 13C NMR (100 MHz, CDCl3): δ 52.3, 56.4, 66.9, 124.0, 124.7, 127.0, 127.4, 128.4, 128.7, 137.5, 142.4, 163.8; HREIMS m/z calcd. for C15H14N2O3 (M+) 270.1004, found 270.1003.
1-Benzyl-1,7-dihydropyrano[3,2-c]pyrazole (8b): oil; IR (film) vmax 1607 (C=C), 1586 (C=C), 1557 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 3.23 (2H, dd, J = 3.3, 2.0 Hz, ArCH2CH=), 4.77 (1H, dt, J = 6.3, 3.4 Hz, -CH2CH=CH-), 5.17 (2H, s, ArCH2Ph), 6.42 (1H, dt, J = 6.2, 2.0 Hz, =CH=CHO-), 7.06–7.20 (2H, m, Ph-H), 7.22–7.33 (4H, m, Ph-H, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 19.5, 53.8, 97.1, 125.1, 126.4, 127.0, 127.9, 128.8, 129.0, 136.6, 141.3; HREIMS m/z calcd. for C13H12N2O (M+) 212.0950, found 212.0947.
1-Benzyl-1,7-dihydro-7-methylenepyrano[3,2-c]pyrazole (9c): oil; IR (film) vmax 1644 (C=C), 1556 (C=C), 1401 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 2.54 (2H, br t, J = 5.6 Hz, -OCH2CH2Cq), 4.17 (2H, t, J = 5.7 Hz, -OCH2CH2-), 4.78 (1H, br s, CqCHH), 4.96 (1H, br s, CqCHH), 5.43 (2H, s, NCH2Ph), 7.02 (2H, d, J = 7.0 Hz, Ph-H), 7.22–7.32 (4H, m, Ph-H, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 32.2, 55.4, 68.3, 107.2, 124.0, 125.3, 126.2, 127.5, 128.7, 129.7, 136.9, 142.6; HREIMS m/z calcd. for C14H14N2O (M+) 226.1106, found 226.1102.
1,4-Bis((1-benzyl-5-(1-phenylprop-1-en-1-yl)-1H-pyrazol-4-yl)oxy)but-2-ene (10d): oil; IR (film) vmax 1569 (C=C), 1496 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.51 (6H, d, J = 7.1 Hz, =CHCH3), 4.40 (4H, br s, -OCH2CH=), 4.62 (2H, br d, J = 14.8 Hz, ArCHHPh), 4.92 (2H, br d, J = 14.4 Hz, ArCHHPh), 5.82–5.84 (2H, m, -OCH2CH=), 6.29 (2H, q, J = 7.1 Hz, =CHCH3), 6.92–6.95 (4H, m, Ph-H), 7.06–7.25 (6H, m, Ph-H), 7.35 (2H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.8, 54.3, 71.6, 126.1, 127.1, 127.35, 127.42, 128.3, 128.7, 129.1, 129.2, 131.2, 137.0, 140.0, 143.2 (three carbon signals overlapped); HREIMS m/z calcd. for C42H40N4O2 (M+) 632.3151, found 632.3145.
1,4-Bis((1-benzyl-5-(1-(methoxycarbonyl)prop-1-en-1-yl)-1H-pyrazol-4-yl)oxy)but-2-ene (10e): oil; IR (film) vmax 1722 (C=O), 1712 (C=O), 1642 (C=C), 1573 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.54 (5.4H, d, J = 7.0 Hz, =CHCH3 of major isomer), 2.14 (0.6H, d, J = 7.2 Hz, =CHCH3 of minor isomer), 3.61 (0.6H, s, -OCH3 of minor isomer), 3.62 (5.4H, s, =CHCH3 of major isomer), 4.42 (3.6H, br s, -OCH2CH= of major isomer), 4.48 (0.4H, br s, -OCH2CH= of minor isomer), 5.08 (1.8H, br d, J = 13.3 Hz, ArCHHPh of major isomer), 5.11 (0.4H, s, ArCH2Ph of minor isomer), 5.12 (1.8H, br d, J = 13.3 Hz, ArCHHPh of major isomer), 5.77 (3.6H, br t, J = 3.7 Hz, -OCH2CH= of minor isomer), 5.88 (0.4H, br t, J = 3.7 Hz, -OCH2CH= of major isomer), 6.28 (0.2H, q, J = 7.5 Hz, =CHCH3 of minor isomer), 7.08 (4H, d, J = 6.8 Hz, Ph-H), 7.20–7.32 (7.8H, m, Ph-H, =CHCH3 of major isomer), 7.33 (2H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 15.7, 52.1, 54.6, 71.5, 122.1, 123.2, 126.4, 127.4, 127.6, 128.4, 128.5, 136.7, 147.9, 165.9; HREIMS m/z calcd. for C34H36N4O6 (M+) 596.2635, found 596.2634.
Methyl 2-(1-benzyl-4-(cinnamyloxy)-1H-pyrazol-5-yl)but-2-enoate (11e): oil; IR (film) vmax 1716 (C=O), 1644 (C=C), 1574 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 1.58 (3H, d, J = 7.3 Hz, =CHCH3), 3.58 (3H, s, -COOCH3), 4.58 (2H, d, J = 6.2 Hz, -OCH2CH=), 5.02 (1H, br d, J = 15.2 Hz, ArCHHPh), 5.12 (1H, br d, J = 15.2 Hz, ArCHHPh), 6.30 (1H, dt, J = 15.9, 6.2 Hz, -OCH2CH=CH-), 6.62 (1H, d, J = 15.9 Hz, -CH=CHPh), 7.09 (2H, d, J = 7.3 Hz, Ph-H), 7.20–7.38 (8H, m, Ph-H), 7.30 (1H, q, J = 7.3 Hz, -Cq=CHCH3), 7.40 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 15.8, 52.0, 54.7, 72.7, 122.2, 123.6, 124.7, 126.6, 126.9, 127.4, 127.6, 127.9, 128.4, 128.6, 133.1, 136.4, 136.7, 143.2, 147.9, 165.9; HREIMS m/z calcd. for C24H24N2O3 (M+) 388.1787, found 388.1785.

4.6. Synthesis of 5-Allyl-4-(2-haloethoxy)-1H-pyrazoles (12) (Scheme 2)

General procedure: To a solution of 2a (50.8 mg, 0.14 mmol) in acetone (2 mL) in a microwave vial were added 1,2-dibromoethane (0.05 mL, 0.56 mmol), 20% aqueous NaOH (0.11 mL, 0.56 mmol), and a catalytic amount of tetrabutylammonium bromide. The sealed reaction vial was MW irradiated at 140 °C for 30 min. After it had cooled, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude residue. The residue was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:3) to afford 12a (42.9 mg, 65%) as an oil.
5-Allyl-4-(2-bromoethoxy)-1H-1-tritylpyrazole (12a): pale yellow crystals (CH2Cl2); mp 135–140 °C; IR (film) vmax 1581 (C=C), 1491 (C=C), 1446 (C=C) cm−1; 1H NMR (500 MHz, CDCl3): δ 2.85 (2H, dt, J = 6.5, 1.2 Hz, ArCH2CH=CH2), 3.56 (2H, t, J = 6.2 Hz, -OCH2CH2CBr), 4.20 (2H, t, J = 6.2 Hz, -OCH2CH2Br), 4.63 (1H, dq, J = 17.0, 1.6 Hz, -CH=CHH), 4.66 (1H, dq, J = 10.0, 1.4 Hz, -CH=CHH), 4.97 (1H, ddt, J = 17.0, 10.0, 6.5 Hz, -CH2CH=CH2), 7.10–7.13 (6H, m, Tr-H), 7.25–7.30 (9H, m, Tr-H), 7.33 (1H, s, pyrazole-H); 13C NMR (125 MHz, CDCl3): δ 29.4, 31.2, 71.6, 78.7, 115.9, 125.6, 127.4, 127.6, 129.9, 130.1, 132.4, 142.8, 143.6; HREIMS m/z calcd. for C27H25BrN2O (M+) 472.1151, found 472.1149.
5-Allyl-1-benzyl-4-(2-bromoethoxy)-1H-pyrazole (12b): oil; IR (film) vmax 1583 (C=C), 1496 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 3.29 (2H, dd, J = 4.7, 1.7 Hz, ArCH2CH=), 3.56 (2H, br t, J = 6.2 Hz, -OCH2CH2Br), 4.20 (2H, br t, J = 6.2 Hz, -OCH2CH2Br), 5.00 (1H, dd, J = 7.0, 1.4 Hz, -CH=CHH), 5.07 (1H, dd, J = 10.2, 1.4 Hz, -CH=CHH), 5.73–5.83 (1H, m, -CH2CH=CH2), 7.06 (2H, br d, J = 8.1 Hz, Bn-H), 7.25–7.33 (4H, m, Ph-H, pyrazole-H); 13C NMR (100 MHz, CDCl3): δ 27.1, 29.5, 53.9, 72.4, 116.5, 126.7, 127.2, 127.7, 127.8, 128.7, 133.6, 136.9, 141.6; HREIMS m/z calcd. for C15H17BrN2O (M+) 320.0524, found 320.0520.
5-Allyl-4-(2-chloroethoxy)-1H-1-tritylpyrazole (12Cl): white powder (CH2Cl2); mp 120–125 °C; IR (KBr) vmax 1580 (C=C), 1493 (C=C), 1446 (C=C) cm−1; 1H NMR (500 MHz, CDCl3): δ 2.85 (2H, br d, J = 7.6 Hz, ArCH2CH=), 3.72 (2H, t, J = 5.7 Hz, -OCH2CH2Cl), 4.14 (2H, t, J = 5.7 Hz, -OCH2CH2CCl), 4.63 (1H, dq, J = 17.0, 1.6 Hz, -CH=CHH), 4.66 (1H, dq, J = 10.0, 1.4 Hz, -CH=CHH), 4.97 (1H, ddt, J = 17.0, 10.0, 6.7 Hz, -CH2CH=CH2), 7.10–7.14 (6H, m, Tr-H), 7.24–7.31 (9H, m, Tr-H), 7.34 (1H, s, pyrazole-H); 13C NMR (125 MHz, CDCl3): δ 31.2, 42.1, 71.7, 78.6, 115.8, 125.5, 127.3, 127.6, 129.9, 130.0, 132.4, 142.8, 143.7; HREIMS m/z calcd. for C27H25ClN2O (M+) 428.1655, found 428.1654. *MW conditions: 160 °C, 30 min.

4.7. Reaction of 12 with Potassium Tert-Butoxide (Table 2, Scheme 2)

General procedure (Table 2, entry 7): To a solution of 12a (28.8 mg, 0.05 mmol) in anhydrous THF:t-BuOH (2 mL:0.5 mL) in a microwave vial was added potassium tert-butoxide (28.8 mg, 0.26 mmol). The sealed reaction vial was MW irradiated at 130 °C for 1 h. After it had cooled, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude residue. The residue was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:3) to afford 13a (20.8 mg, 87%).
5-Allyl-1-trityl-1H-4-vinyloxypyrazole (13a): white powder (CH2Cl2); mp 75–80 °C; IR (KBr) vmax 1639 (C=C), 1624 (C=C), 1566 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 2.81 (2H, ddd, J = 6.8, 1.5, 1.2 Hz, ArCH2CH=CH2), 4.23 (1H, dd, J = 5.4, 1.8 Hz, -OCH=CHH), 4.50 (1H, dd, J = 13.8, 2.1 Hz, -OCH2=CHH), 4.62 (1H, dq, J = 16.7, 1.5 Hz, -CH2CH=CHH), 4.68 (1H, dq, J = 10.9, 1.5 Hz, -CH2CH=CHH), 4.99 (1H, ddt, J = 16.5, 10.9, 2.1 Hz, -CH2CH=CH2), 6.53 (1H, dd, J = 13.8, 6.5 Hz, -OCH=CH2), 7.12–7.14 (6H, m, Tr-H), 7.25–7.31 (9H, m, Tr-H), 7.40 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 31.1, 77.8, 91.3, 116.1, 127.4, 127.6, 128.3, 130.0, 131.7, 131.9, 140.4, 142.3, 150.7; HREIMS m/z calcd. for C27H24N2O (M+) 392.1888, found 392.1880.
5-(1-Propenyl)-1-trityl-1H-4-vinyloxypyrazole (14a): white powder (CH2Cl2); mp 133–135 °C; IR (KBr) vmax 1639 (C=C), 1560 (C=C), 1492 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 1.39 (3H, dd, J = 6.8, 1.8 Hz, -CH=CHCH3), 4.29 (1H, dd, J = 6.2, 2.0 Hz, -OCH=CHH), 4.59 (1H, dd, J = 13.8, 2.0 Hz, -OCH=CHH), 5.39 (1H, br dq, J = 15.8, 0.8 Hz, -CH=CHCH3), 5.98 (1H, dq, J = 15.8, 6.8 Hz, -CH=CHCH3), 6.56 (1H, dd, J = 13.8, 6.2 Hz, -OCH=CH2), 7.11–7.15 (6H, m, Tr-H), 7.26–7.32 (9H, m, Tr-H), 7.38 (1H, br s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 18.8, 79.8, 92.3, 119.1, 127.38, 127.44, 128.0, 129.1, 130.3, 131.2, 139.5, 142.7, 150.4; HREIMS m/z calcd. for C27H24N2O (M+) 392.1889, found 392.1887.
(E/Z)-1-Benzyl-5-(1-propenyl)-1H-4-vinyloxypyrazole (14b): E/Z ratio = ca. 5:1; oil; IR (film) vmax 1642 (C=C), 1562 (C=C), 1493 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.68 (0.5H, d, J = 6.3 Hz, =CHCH3 of (Z)-isomer), 1.82 (2.5H, dd, J = 6.6, 1.6 Hz, =CHCH3 of (E)-isomer), 4.22 (0.17H, dd, J = 6.3, 2.0 Hz, -CH=CHH of (Z)-isomer), 4.29 (0.83H, dd, J = 6.3, 2.0 Hz, -CH=CHH of (E)-isomer), 4.57 (0.17H, dd, J = 13.7, 2.0 Hz, -CH=CHH of (Z)-isomer), 4.59 (0.83H, dd, J = 13.7, 2.0 Hz, -CH=CHH of (E)-isomer), 5.93 (0.17H, dq, J = 11.0, 6.5 Hz, -CH=CHCH3 of (Z)-isomer), 5.98 (0.17H, br d, J = 11.0 Hz, ArCH=CHCH3 of (Z)-isomer), 6.11 (0.83H, br dq, J = 16.0, 1.6 Hz, ArCH=CHCH3 of (E)-isomer), 6.34 (0.83H, dq, J = 15.8, 6.8 Hz, -CH=CHCH3 of (E)-isomer), 6.49 (0.17H, dd, J = 13.7, 6.3 Hz, -OCH=CH2 of (Z)-isomer), 6.55 (0.83H, dd, J = 13.7, 6.3 Hz, -OCH=CH2 of (E)-isomer), 7.07 (2H, br d, J = 7.0 Hz, Ph-H), 7.23–7.37 (3H, m, Ph-H), 7.33 (1H, br s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 16.0 (minor), 19.3, 53.4 (minor), 54.0, 91.9 (minor), 92.3, 114.7 (minor), 115.9, 126.5, 126.9, 127.7, 128.7, 128.8, 129.0 (minor), 131.5, 134.2 (minor), 136.9, 138.5 (minor), 150.4 (minor), 150.5; HREIMS m/z calcd. for C15H16N2O (M+) 240.1263, found 240.1256.
(E/Z)-4-(2-Methoxy)ethoxy-3-(1-propenyl)-2H-2-tritylpyrazole (15): oil; IR (film) vmax 1492 (C=C), 1446 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.39 (3H, d, J = 6.7 Hz, =CHCH3), 3.65 (0.5H, br t, J = 4.1 Hz, -OCH2CH2Br), 3.7 (1.5H, br t, J = 4.1 Hz, -CH2CH2Br), 4.07 (0.5H, br t, J = 3.9 Hz, -CH2CH2Br), 3.70 (1.5H, br t, J = 4.1 Hz, -OCH2CH2Br), 5.44 (1H, br d, J = 15.8 Hz, (E)-ArCH=CH-), 6.09–6.18 (1H, m, -CH=CHCH3), 7.11–7.20 (6H, m, Tr-H), 7.24–7.29 (9H, m, Tr-H), 7.32 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 18.9, 59.2, 70.6, 71.3, 79.0, 119.9, 124.8, 127.3, 127.4, 127.6, 130.1, 130.4, 142.9, 143.7; HREIMS m/z calcd. for C28H28N2O2 (M+) 424.2151, found 424.2157.
4-(2-Methoxy)ethoxy-3-(2-propenyl)-2H-2-tritylpyrazole (16): oil; IR (film) vmax 1580 (C=C), 1447 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 2.84 (2H, br d, J = 6.5 Hz, ArCH2CH=), 3.41 (3H, s, -OCH3), 3.66 (1H, br t, J = 5.0 Hz, -OCH2CH2O-), 4.05 (2H, br t, J = 5.0 Hz, -OCH2CH2O-), 4.60 (1H, dq, J = 17.0, 1.7 Hz, -CH=CHH), 4.64 (1H, dq, J = 10.5, 1.5 Hz, -CH=CHH), 7.10–7.13 (6H, m, Tr-H), 7.23–7.33 (9H, m, Tr-H), 7.34 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 31.2, 59.2, 71.2, 71.4, 78.5, 115.6, 125.5, 127.3, 127.6, 127.9, 130.1, 132.6, 143.0, 144.4; HREIMS m/z calcd. for C28H28N2O2 (M+) 424.2151, found 424.2157.

4.8. RCM of 13a and 14a and 14b

The RCM reactions of 13a and 14a and 14b in Scheme 2 were carried out as described above.
1,7-Dihydro-1-tritylpyrano[3,2-c]pyrazole (8a): oil; IR (film) vmax 1583 (C=C), 1493 (C=C), 1446 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 2.27 (2H, dd, J = 3.5, 2.0 Hz, ArCH2CH=CH-), 4.49 (1H, dt, J = 6.5, 3.5 Hz, -OCH=CHCH2-), 6.33 (1H, dt, J = 6.4, 2.0 Hz, -OCH=CHCH2-), 7.12–7.15 (6H, m, Tr-H), 7.26–7.32 (9H, m, Tr-H), 7.32 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 22.5, 29.7, 78.6, 98.2, 124.3, 127.6, 127.6, 127.9, 130.4, 140.3, 142.6; HREIMS m/z calcd. for C25H20N2O (M+) 364.1575, found 364.1576.

4.9. Acid-Catalyzed Hydrolysis of 6a (Scheme 3)

To a solution of 6a (121.5 mg, 0.30 mmol) in acetone (10 mL) was added 1 N aqueous HCl (0.6 mL). The reaction mixture was warmed under reflux for 90 min with stirring. After the reaction mixture had cooled, it was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered, and condensed under reduced pressure to give a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:2) to afford (Z)-18 (9.1 mg, 20%) and (E)-18 (14.2 mg, 31%).
(E)-4-Allyloxy-5-(1-propenyl)-1H-pyrazole ((E)-18): oil; IR (film) vmax 1568 (C=C), 1516 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 1.89 (3H, br d, J = 6.0 Hz, CH3CH=), 4.60 (2H, dt, J = 5.5, 1.5 Hz, -OCH2CH=CH2), 4.46 (1H, dq, J = 10.0, 1.5 Hz, -CH=CHH), 5.40 (1H, dq, J = 17.3, 1.5 Hz, -CH=CHH), 6.04 (1H, ddt, J = 17.3, 10.5, 5.5 Hz, -OCH2CH=CH2), 6.34 (1H, d, J = 16.7 Hz, ArCH=CH-), 6.35–6.41 (1H, m, -CH=CHCH3), 7.22 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 18.9, 72.7, 117.7, 118.7, 127.6, 133.4, 142.0; HREIMS m/z calcd. for C9H12N2O (M+) 164.0950, found 164.0950.
(Z)-4-Allyloxy-5-(1-propenyl)-1H-pyrazole ((Z)-18): oil; IR (film) vmax 1570 (C=C), 1524 (C=C), 1450 (C=C) cm−1; 1H NMR (600 MHz, CDCl3): δ 1.98 (3H, dd, J = 7.0, 1.8 Hz, CH3CH=), 3.49 (3H, s, -OCH3), 4.45 (2H, dt, J = 5.2, 1.5 Hz, -OCH2CH=CH2), 5.27 (1H, dq, J = 10.6, 1.5 Hz, -CH=CHH), 5.38 (1H, dq, J = 17.0, 1.5 Hz, -CH=CHH), 5.82 (1H, dq, J = 11.4, 7.0 Hz, -CH=CHCH3), 6.03 (1H, ddt, J = 17.3, 10.6, 5.3 Hz, -OCH2CH=CH2), 6.27 (1H, dq, J = 11.5, 1.5 Hz, ArCH=CHCH3), 7.27 (1H, s, pyrazole-H); 13C NMR (150 MHz, CDCl3): δ 69.1, 69.3, 117.7, 118.7, 127.6, 133.4, 142.0; HREIMS m/z calcd. for C9H12N2O (M+) 164.0950, found 164.0949.

4.10. Reprotection of 18 (Scheme 3)

General procedure: To a stereo mixture of (E/Z)-18 (15.9 mg, 0.10 mmol) in CH2Cl2 (10 mL) were added TrCl (43.0 mg, 0.15 mmol) and Et3N (0.022 mL, 0.15 mmol) at 0 °C. The reaction mixture was stirred at rt overnight, and then quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and condensed under reduced pressure to give a crude residue, which was purified using silica gel column chromatography (eluent: EtOAc:hexane = 1:4) to afford 19a (28.9 mg, 68%) as an oil.
(E/Z)-4-Allyloxy-3-(1-propenyl)-1H-1-tritylpyrazole (19a): oil; IR (film) vmax 1560 (C=C), 1491 (C=C), 1445 (C=C) cm−1; 1H NMR of (E)-isomer (600 MHz, CDCl3): δ 1.90 (3H, dd, J = 7.1, 1.8 Hz, CH3CH=CH-), 4.27 (2H, dt, J = 5.6, 1.5 Hz, -OCH2CH=CH2), 5.20 (1H, ddd, J = 10.6, 3.2, 1.5 Hz, -CH2CH=CHH), 5.28 (1H, ddd, J = 17.0, 3.2, 1.8 Hz, -CH2CH=CHH), 5.75 (1H, dq, J = 11.5, 7.1 Hz, -CH=CHCH3), 5.95 (1H, ddt, J = 17.3, 10.7, 5.6 Hz, -OCH2CH=CH2), 6.29 (1H, dq, J = 11.5, 1.5 Hz, ArCH=CHCH3), 6.84 (1H, s, pyrazole-H), 7.14–7.18 (6H, m, Tr-H), 7.26–7.30 (9H, m, Tr-H); 13C NMR (150 MHz, CDCl3): δ (14.2), 15.6, (60.4), 72.9, 78.6, (117.4), 117.6, 117.7, 127.4, 127.5, (127.6), 127.9, 130.4, 133.3, (138.6), (142.0), 143.4, signals in parentheses correspond to some of those of the (Z)-isomer; HREIMS m/z calcd. for C28H26N2O (M+) 406.2045, found 406.2040.
(E)-4-Allyloxy-1-benzyl-3-(1-propenyl)-1H-pyrazole (19b): oil; IR (film) vmax 1566 (C=C), 1496 (C=C), 1445 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 1.87 (3H, dd, J = 6.3, 1.2 Hz, CH3CH=CH-), 4.35 (2H, dt, J = 5.4, 1.5 Hz, -OCH2CH=CH2), 5.16 (2H, s, ArCH2Ph), 5.24 (1H, dq, J = 10.5, 1.5 Hz, -CH2CH=CHH), 5.36 (1H, dq, J = 17.2, 1.6 Hz, -CH2CH=CHH), 6.00 (1H, ddt, J = 17.2, 10.5, 5.4 Hz, -OCH2CH=CH2), 6.40 (1H, br d, J = 16.3 Hz, ArCH=CHCH3), 6.53 (1H, dq, J = 16.3, 6.3 Hz, ArCH=CHCH3), 6.92 (1H, s, pyrazole-H), 7.18 (2H, br d, J = 8.0 Hz, Ph-H), 7.26–7.35 (3H, m, Ph-H); 13C NMR (100 MHz, CDCl3): δ 18.9, 56.5, 72.6, 114.7, 117.6, 121.4, 127.4, 127.9, 128.7, 133.2, 136.8, 138.4, 143.1; HREIMS m/z calcd. for C16H18N2O (M+) 254.1419, found 254.1416.

4.11. RCM of 19

The RCM reactions of 19 were carried out in a similar manner to that described above to afford 20.
2,5-Dihydro-2-tritylpyrano[3,2-c]pyrazole (20a): oil; IR (film) vmax 1492 (C=C), 1447 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 4.76 (2H, dd, J = 2.9, 1.9 Hz, -OCH2CH=CH-), 5.72 (1H, dt, J = 10.2, 3.5 Hz, -OCH2CH=CH-), 6.62 (1H, br d, J = 10.0 Hz, -OCH2CH=CHAr), 6.80 (1H, s, pyrazole-H), 7.18–7.20 (6H, m, Tr-H), 7.28–7.31 (9H, m, Tr-H); 13C NMR (150 MHz, CDCl3): δ 67.2, 78.0, 116.5, 120.1, 122.7, 126.5, 127.6, 127.7, 137.5, 139.1, 143.3; HREIMS m/z calcd. for C25H20N2O (M+) 364.1575, found 364.1584.
2-Benzyl-2,5-dihydropyrano[3,2-c]pyrazole (20b): oil; IR (film) vmax 1660 (C=C), 1576 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): δ 4.77 (2H, dd, J = 3.5, 1.9 Hz, -OCH2CH=CH-), 5.73 (1H, dt, J = 10.0, 3.5 Hz, -OCH2CH=CH-), 6.63 (1H, dt, J = 10.0, 1.9 Hz, -OCH2CH=CHAr), 6.84 (1H, s, pyrazole-H), 7.18–7.20 (2H, br d, J = 6.5 Hz, Ph-H), 7.27–7.36 (3H, m, Ph-H); 13C NMR (100 MHz, CDCl3): δ 56.4, 67.2, 113.3, 119.5, 122.3, 127.5, 128.0, 128.8, 136.6, 137.2, 140.5; HREIMS m/z calcd. for C13H12N2O (M+) 212.0949, found 212.0950.

Author Contributions

Y.U. and K.S. conceived and designed the experiments; K.S., A.K., Y.T., and Y.U. performed the experiments; Y.U., H.Y., and S.H. wrote the paper.

Funding

This research received no external funding.

Acknowledgments

The authors are grateful to K. Minoura and M. Fujitake for NMR and MS measurements, respectively. Y. Suzuki, R. Nakamura, K. Hashimoto, and H. Matsukawa of our laboratory group are also appreciated for their experimental assistance. We would like to thank Editage (www.editage.jp) for English language editing.

Conflicts of Interest

The authors declare no conflicts of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 24 00296 g001 550
Figure 1. Examples of bioactive pyrano[2,3-c]pyrazoles, pyrano[3,2-c]pyrazoles, and furo[3,2-c]pyrazoles.
Figure 1. Examples of bioactive pyrano[2,3-c]pyrazoles, pyrano[3,2-c]pyrazoles, and furo[3,2-c]pyrazoles.
Molecules 24 00296 g001
Molecules 24 00296 sch001 550
Scheme 1. Preparation of 5-allyl-4-allyloxy-1H-pyrazoles (6) from 4-allyloxy-1H-pyrazoles (2).
Scheme 1. Preparation of 5-allyl-4-allyloxy-1H-pyrazoles (6) from 4-allyloxy-1H-pyrazoles (2).
Molecules 24 00296 sch001
Molecules 24 00296 sch002 550
Scheme 2. Challenges in the syntheses of 1,7-dihydropyrano[3,2-c]pyrazoles (8) and furo[3,2-c]pyrazoles (19).
Scheme 2. Challenges in the syntheses of 1,7-dihydropyrano[3,2-c]pyrazoles (8) and furo[3,2-c]pyrazoles (19).
Molecules 24 00296 sch002
Molecules 24 00296 sch003 550
Scheme 3. Synthesis of 2,5-dihydropyrano[3,2-c]pyrazoles (20).
Scheme 3. Synthesis of 2,5-dihydropyrano[3,2-c]pyrazoles (20).
Molecules 24 00296 sch003
Table
Table 1. Ring-closing metathesis (RCM) of 5-allyl-4-allyloxy-1H-pyrazoles.
Table 1. Ring-closing metathesis (RCM) of 5-allyl-4-allyloxy-1H-pyrazoles.
Molecules 24 00296 i001
EntrySubstrateRR′Temp. (°C)Time (min)Product Yield (%)
16aTrHrt5 7a (89) e
26a rt30 7a (92)
36a rt607a (83)
46a rt1207a (44)
56a 80 (MW)37a (87)
66a 100 (MW)0.57a (71)
76a 140 (MW)107a (65)
86bBnHrt307b (96)
96b 80 (MW)37b (91)
106b 140 (MW)107b (75)8b (15)
11 a6cBnMertovernight7c (10)
126c 140 (MW)607c (24) 9c (45)
136dBnPhrtovernight---
146d 140 (MW)60--10d (30)
15 b6eBnCOOMertovernight---
16 c6e 80 (MW)607e (2) 10e (29)
17 d6e 100 (MW)607e (7) 10e (30)
186e 140 (MW)607e (15)
a. 60% of starting material 6c was recovered. b. 50% of 6e was recovered. c. Undesired 11e (2%) was obtained during the recovery of 6e (21%). d. 11e was obtained (4%). e. A small amount of 6a was detected in the NMR spectrum and was inseparable from 7a.
Table
Table 2. Potassium t-butoxide promoted dehydrohalogenation of 12.
Table 2. Potassium t-butoxide promoted dehydrohalogenation of 12.
EntrySubstrateSolventTime (min)Temp. (°C)Product Yield (%)
112aTHF30100No reaction
212aTHF:MeOH (4:1)3010013a (14)14a (0)
312aTHF:MeOH (4:1)6010013a + 14a (19) a
4 b12aTHF:MeOH (4:1)6013013a (0)14a (30)
5 c12aTHF:MeOH (4:1)608013a (27)14a (0)
612aTHF:t-BuOH (4:1)608013a (trace)14a (0)
712aTHF:t-BuOH (4:1)6013013a (87)14a (0)
812aTHF:t-BuOH (4:1)6018013a (0)14a (67)
912bTHF:t-BuOH (4:1)6013013b (0)14b (72)
10 d12bTHF:t-BuOH (4:1)608013b (0)14b (31) e
a. Combined yield of 13a and 14a. b. Formation of side product 15 (28%) was observed. c. Formation of side product 16 (17%) was observed. d. An inseparable mixture of 12b and 14b was obtained. e. Combined yields of (E)-14b (25%) and (Z)-14b (6%) calculated from the 1H NMR spectrum with unreacted 12b (6%).

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Usami, Y.; Sumimoto, K.; Kishima, A.; Tatsui, Y.; Yoneyama, H.; Harusawa, S. Synthesis of Dihydropyrano[3,2-c]pyrazoles via Double Bond Migration and Ring-Closing Metathesis. Molecules 2019, 24, 296. https://doi.org/10.3390/molecules24020296

AMA Style

Usami Y, Sumimoto K, Kishima A, Tatsui Y, Yoneyama H, Harusawa S. Synthesis of Dihydropyrano[3,2-c]pyrazoles via Double Bond Migration and Ring-Closing Metathesis. Molecules. 2019; 24(2):296. https://doi.org/10.3390/molecules24020296

Chicago/Turabian Style

Usami, Yoshihide, Kodai Sumimoto, Azusa Kishima, Yuya Tatsui, Hiroki Yoneyama, and Shinya Harusawa. 2019. "Synthesis of Dihydropyrano[3,2-c]pyrazoles via Double Bond Migration and Ring-Closing Metathesis" Molecules 24, no. 2: 296. https://doi.org/10.3390/molecules24020296

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