A Protocol for the Synthesis of CF2H-Containing

Apr 7, 2018 - multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, m = multiplet), co...
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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

A Protocol for the Synthesis of CF2H‑Containing Pyrazolo[1,5‑c]quinazolines from 3‑Ylideneoxindoles and in Situ Generated CF2HCHN2 Wen-Yong Han,* Jian-Shu Wang, Jia Zhao, Lin Long, Bao-Dong Cui, Nan-Wei Wan, and Yong-Zheng Chen* Generic Drug Research Center of Guizhou Province, Green Pharmaceuticals Engineering Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China S Supporting Information *

ABSTRACT: Herein is disclosed a selective and facile approach for the construction of CF2H-containing pyrazolo[1,5-c]quinazolines from easily accessible 3-ylideneoxindoles and in situ generated CF2HCHN2. The reaction involving a [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade proceeded smoothly at room temperature in the absence of catalyst and additive. Moreover, this metal-free process along with mild conditions is desirable and valuable for the pharmaceutical industry. Importantly, this reaction features a broad substrate scope, good functional group tolerance, and gram-scale synthesis.

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INTRODUCTION

Pyrazolo[1,5-c]quinazolines, a class of N-fused heterocycles bearing pyrazole and quinazoline moieties, have attracted tremendous interest among researchers due to the important bioactivities associated with these compounds (Figure 1), such

The installation of fluorine atoms or fluorinated groups on organic molecules is recognized as a general strategy in drug design and discovery.1 Compared to their parent compounds, the physical, chemical and biological properties of fluorinecontaining molecules, such as lipophilicity, binding affinity, reactivity and metabolic stability, can be dramatically altered.2 In this regard, numerous strategies for the construction of the fluorine-containing molecules have been established, including nucleophilic, electrophilic, radical and transition metal-mediated pathways.3 Among them, much attention has been paid to the fluorination, perfluoroalkylation, trifluoromethylation and trifluoromethylthiolation, while the difluoromethylation has been less explored. The selective introduction of CF2H group into organic molecules is still a challenging task and remains underdeveloped.4 In recent years, significant progress has been achieved on difluoromethylation based on two major strategies. One is the direct difluoromethylation, in which CF2H group is directly transferred into organic molecules usually involving a CF2Hmetal intermediate.5 Another is a stepwise difluoromethylation, transferring a functionalized fluoromethyl moiety, followed by a subsequent transformation, to give a CF2H group.6 Alternatively, a new strategy for the preparation of difluoromethylated compounds through cyclization of CF2H-containing building blocks with other coupling partners has also been elegantly developed.7 Despite the significant progress made for the difluoromethylation, strategies for direct syntheses of difluoromethylated fused-heterocycles are scarce, especially starting from readily accessible reagents.8 © XXXX American Chemical Society

Figure 1. Some biologically active compounds containing a pyrazolo[1,5-c]quinazoline skeleton.

as AMPA receptors,9 Gly/NMDA antagonist,10 benzodiazepine/adenosine receptor,11 and phosphodiesterase 10 A inhibitors.12 Accordingly, substantial effort has been devoted to the development of synthetic methods for the pyrazolo[1,5c]quinazoline derivatives.13,14 However, most of them are mainly limited to the use of complex starting materials, multistep reaction strategy, harsh reaction conditions or tedious Received: April 7, 2018

A

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1. Divergent Syntheses of CF2H-Containing N-Heterocycles with 3-Ylideneoxindoles and CF2HCHN2

Table 1. Investigation of Reaction Conditionsa

yield (%) entry

solvent

Fb

CCc

total yield

1 2 3 4d 5d,e 6e,f

Et2O MTBE CPME Et2O Et2O MTBE

15 − − 34 68 −

3 12 10 5 8 trace

18 12 10 39 76 trace

a

Unless otherwise noted, all reactions were carried out with difluoroethylamine (1, 6.6 mmol, 3.0 equiv), tert-butyl nitrite (7.92 mmol, 3.6 equiv), and AcOH (1.32 mmol, 0.6 equiv) in 15.0 mL of solvent at 35 °C for 10 min. The mixture was cooled to room temperature followed by addition of 3a (2.2 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 7 days. bThe yield was obtained after filtration. cThe yield from the filtrate was obtained by column chromatography. dThe reaction was performed for 14 days. eUnder O2 atmosphere (balloon). fThe reaction was performed at 50 °C for 24 h. MTBE = methyl tert-butyl ether. CPME = cyclopentyl methyl ether.

processes. Herein we wish to report our preliminary studies on this subject.

isolation procedure. From the standpoint of atom- and stepeconomy, the development of facile and practical methods with easily accessible precursors for the construction of pyrazolo[1,5-c]quinazolines is still desirable. In our recent studies, we have shown that in situ generated difluoromethyl diazomethane (2, CF2HCHN2) from difluoroethylamine and tert-butyl nitrite is a highly effective 1,3-dipole. As shown in Scheme 1, CF 2 H-containing spirocyclic dihydropyrazoleoxindoles (4) were constructed through an efficient [3 + 2] cycloaddition of isatin-derived 3-ylideneoxindoles (3) with CF2HCHN2 (2).15a In addition, CF2Hcontaining spirocyclopropyloxindoles (5) were also obtained via a [3 + 2] cycloaddition followed by a ring contraction.15b During our ongoing studies on the reactivity of CF2HCHN2, we discovered that pyrazolo[1,5-c]quinazolines (6) can be efficiently synthesized through a [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade process starting from easily available 3-ylideneoxindoles and CF2HCHN2 (Scheme 1). Importantly, the preparative scale experiment proceeded smoothly, and the product can be purified by simple filtration followed by washing with diethyl ether and drying

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RESULTS AND DISCUSSION Preliminary optimization experiments were carried out with in situ generated CF2HCHN2 (2) and isatin-derived 3-ylideneoxindole 3a. The reaction could proceed smoothly in diethyl ether at room temperature for 7 days, delivering the desired product 6a in 15% yield by filtration and an additional 3% yield by further column chromatography from the filtrate (Table 1, entry 1). The structure of the product 6a was unambiguously determined by X-ray crystallographic analysis.16,17 Other ethereal solvents, such as MTBE and CPME, were also examined; however, no precipitation was observed, only 10− 12% yields of 6a were afforded by column chromatography (Table 1, entries 2 and 3). Additionally, extending the reaction time from 7 to 14 days led to 6a in an improved yield after filtration (34%) (Table 1, entry 4). Given that an oxidative aromatization process might be involved in this cascade reaction, one experiment was performed under O2 atmosphere.18 As expected, 68% yield after filtration was obtained (Table 1, entry 5). In order to accelerate the reaction rate, the B

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 2. Substrate Scopea

reaction was performed at 50 °C for 24 h. Unfortunately, the reaction was complicated as monitored by thin layer chromatography (TLC) analysis and trace amount of 6a was obtained. Simultaneously, the dinitrogen extrusion of the [3 + 2] cycloadduct was achieved, mainly giving a spirocyclopropyl oxindoles (46%), which was caused by the relatively high reaction temperature (50 °C).15b With the optimized reaction conditions in hand (Table 1, entry 5), the scope and generality of this novel procedure using various 3-ylideneoxindoles as the substrates were subsequently investigated. As shown in Table 2, regardless of the electronic nature or positions of the substituents, all substrates could be smoothly transformed into the corresponding CF2H-containing pyrazolo[1,5-c]quinazolines (6b−m) in moderate to good yields (44−74%) (Table 2, entries 2−13). The reaction was also compatible with disubstituted 3-ylideneoxindoles (3n and 3o) that contain electron-donating and -withdrawing substituents at different positions on the phenyl ring, affording 6n in 64% and 6o in 61% yields, respectively (Table 2, entries 14− 15). For the 3-ylideneoxindoles bearing different ester groups, such as methyl and n-propyl, could also undergo this [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade process, leading to the corresponding products in moderate to good yields (Table 2, entries 16−17). In addition, the unprotected 3-ylideneoxindole (3r) also reacted well with in situ generated CF2HCHN2 (2) (Table 2, entry 18). Moreover, diverse N-protecting groups were also successfully employed in the cascade reaction, giving the corresponding products 6t−w with satisfactory results (Table 2, entries 20− 23), while 6s was obtained in a deprotection fashion (Table 2, entry 19).19 Generally, diazo compounds are potentially explosive and extremely difficult to handle on a large scale. However, we found that difluoromethyl diazomethane (2) was generated slowly from difluoroethylamine (1) and tert-butyl nitrite during the reaction process, which was determined by 19 F NMR. Accordingly, this cascade reaction was conducted in a gram scale. Delightedly, under the standard conditions, 6a could be smoothly obtained in an improved yield (80%) after filtration from the mixture (Scheme 2). This demonstrates the good scalability of the reaction and the potential value in pharmaceutical industry. To gain insights into the mechanism of this cascade reaction, the progress of the template reaction was monitored by 1H NMR. And it was found that after 4 days, compound 3a was completely consumed, and intermediate (±)-4a and (±)-7a as well as product 6a were detected (Figure 2).17 To further study the reaction mechanism based on the key intermediates (±)-4a and (±)-7a, two control experiments were performed. As shown in Scheme 3, 6a was obtained in 84% yield from (±)-4a under the O2 atmosphere (Scheme 3a). While (±)-7a could be also transformed into 6a in high yield (Scheme 3b). These results suggest that compounds (±)-4a and (±)-7a are possible intermediates for the construction of 6a. On the basis of the above results and previous studies on the synthesis of N-heterocycles with diazo compounds,15,20 a plausible reaction pathway is proposed in Scheme 4. First, [3 + 2] cycloaddition of in situ generated CF2HCHN2 (2) with 3ylideneoxindoles (3) occurred, giving intermediate (±)-4, followed by a 1,3-H shift process to form the intermediate (±)-7. Subsequently, 1,5-sigmatropic rearrangement and 1,2-H shift occurred to afford the intermediate 9. Further oxidative aromatization took place under the O2 atmosphere to deliver product 6. Additionally, considering the conjugated system

a

Reaction conditions: difluoroethylamine (1, 6.6 mmol, 3.0 equiv), tert-butyl nitrite (7.92 mmol, 3.6 equiv), AcOH (1.32 mmol, 0.6 equiv), 3 (2.2 mmol, 1.0 equiv), Et2O (15 mL), O2 atmosphere (balloon), rt, 14 days. bCombined yield of product 6 based on 3. In the parentheses, the former is the yield obtained by direct filtration, while the latter is the one afforded by column chromatography from the filtrate. c2-fold in scale was carried out.

presented in compound 6, the dehydrogenation step might act as driving force for the transformation of intermediate (±)-7 into fused heterocycles 6. On the other hand, intermediate C

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Preparative-Scale Experiment

Scheme 3. Control Experiments

(±)-7 was surmised to undergo dehydrogenation and subsequent [l,5]-σ rearrangement to give the product 6.14f Although starting from the same materials (2 and 3), different kinds of products (4−6) were obtained under different reaction conditions. The 1,3-dipolar cycloaddition of CF2HCHN2 (2) with 3-ylideneoxindoles (3) proceeded smoothly, affording the spirooxindole (±)-4 in up to 84% yield and 99:1 trans/cis in CH2Cl2 under N2 atmosphere at room temperature for 24 h.15a Simultaneously, a small quantity of side product, spirocyclopropyloxindoles (±)-5, was obtained. We supposed that a dinitrogen extrusion was achieved during this process. Consequently, after the [3 + 2] cycloaddition between CF2 HCHN 2 (2) with 3-ylideneoxindoles (3), subsequent ring contraction in refluxing toluene was conducted, giving spirocyclopropyloxindoles (±)-5 in good to excellent results (up to 99% yield and >99:1 trans/cis).15b In this work, a cascade reaction involving a [3 + 2] cycloaddition/1,3-H shift/

rearrangement/dehydrogenation occurred in Et2O under O2 atmosphere, leading to pyrazolo[1,5-c]quinazolines in up to 85% yield. The reaction provided a divergent and efficient access to CF2H-containing N-Heterocycles under different reaction conditions.

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CONCLUSION In conclusion, we have developed a facile approach involving a sequential [3 + 2] cycloaddition/1,3-H shift/rearrangement/ dehydrogenation process, giving a variety of pyrazolo[1,5c]quinazoline derivatives in good to high yields. Additionally, a plausible pathway for the reaction was also tentatively brought

Figure 2. 1H NMR determination of the possible intermediates. D

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 4. Proposed Reaction Mechanism

chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give 6a (56.5 mg, 8% yield) (76% total yield). Ethyl 2-(difluoromethyl)-6-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6a). White solid, 537.2 mg, 76% yield, mp 179.4−181.2 °C; 1H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 9.0 Hz, 1H), 7.72−7.67 (m, 1H), 7.45−7.39 (m, 2H), 7.11 (td, J = 2.4, 53.4 Hz, 1H), 4.48 (qd, J = 2.4, 7.2 Hz, 2H), 3.86 (s, 3H), 1.46 (td, J = 2.4, 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 150.6 (t, J = 26.2 Hz, 1C), 144.8, 142.1, 136.6, 132.6, 128.3, 124.2, 114.7, 112.6, 110.3 (t, J = 238.2 Hz, 1C), 108.8, 62.0, 31.9, 14.1; 19F NMR (376 MHz, CDCl3) δ −116.72 (dd, J = 12.6, 53.0 Hz, 2F); HRMS (ESITOF) Calcd for C15H14F2N3O3 [M + H]+: 322.0998, found 322.0998. Ethyl 10-chloro-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6b). White solid, 399.1 mg, 51% yield, mp 136.3−138.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.73−7.69 (m, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 52.8 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSOd6) δ 162.6, 147.6 (t, J = 26.8 Hz, 1C), 143.9, 138.9, 136.8, 132.3, 130.4, 125.5, 114.9, 111.3, 110.7, 110.3 (t, J = 236.2 Hz, 1C), 61.6, 32.3, 13.8; 19F NMR (376 MHz, DMSO-d6) δ −115.09 (d, J = 52.8 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13ClF2N3O3 [M + H]+: 356.0608, found 356.0601. Ethyl 2-(difluoromethyl)-9-methoxy-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6c). Yellow solid, 502.4 mg, 65% yield, mp 198.7−199.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.7 Hz, 1H), 7.53−7.49 (m, 1H), 7.40 (t, J = 53.1 Hz, 1H), 7.32 (dd, J = 2.8, 9.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.66 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 154.9, 149.3 (t, J = 24.2 Hz, 1C), 143.9, 141.4, 130.8, 119.8, 117.0, 112.7, 110.3, 110.1 (t, J = 227.2 Hz, 1C), 107.8, 61.7, 55.6, 31.7, 13.8; 19F NMR (376 MHz, DMSO-d6) δ −116.55 (d, J = 53.1 Hz, 2F); HRMS (ESI-TOF) Calcd for C16H16F2N3O4 [M + H]+: 352.1103, found 352.1106. Anal. Calcd for C16H15F2N3O4: C, 54.70; H, 4.30; N, 11.96. Found: C, 54.67; H, 4.55; N, 11.22. Ethyl 2-(difluoromethyl)-9-fluoro-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6d). White solid, 507.6 mg, 68% yield, mp 203.8−205.6 °C; 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 2.8, 10.0 Hz, 1H), 7.45−7.36 (m, 2H), 7.12 (td, J = 1.4, 53.5 Hz, 1H), 4.49 (qd, J = 1.4, 7.2 Hz, 2H), 3.86 (s, 3H), 1.46 (td, J = 1.4, 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6) δ 160.3, 156.6 (d, J = 240.7 Hz, 1C), 148.6 (t, J = 25.0 Hz, 1C), 142.7, 139.7 (d, J = 3.1 Hz, 1C), 132.0 (d, J = 2.0 Hz, 1C), 118.7 (d, J = 23.6 Hz, 1C), 115.9 (d, J = 8.4 Hz, 1C), 112.3 (d, J = 27.3 Hz,

forward based on the premilinary mechanistic investigations. In particular, this reaction could be easily scaled up, and the product (6a) was purified by simple filtration in high yield (80%, 2.83 g). Although a prolonged period of time (14 days) was required, this strategy can construct concisely the potential biological CF2H-containing pyrazolo[1,5-c]quinazolines from easily accessible 3-ylideneoxindoles and CF2HCHN2 without the need for multistep parallel synthesis as well as without using column chromatography for isolation in some cases. We expect that insights gained from our present study are helpful for providing a valuable synthetic tool for the discovery of drugs.

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EXPERIMENTAL SECTION

General Experimental Information. Unless otherwise noted, all commercially available reagents were used without further purification. All of the solvents were treated according to known methods. Column chromatography was performed on silica gel (200−400 mesh). 1H NMR (400 MHz) chemical shifts were reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard. 13C{1H} NMR (100 MHz) chemical shifts were reported in ppm (δ) from tetramethylsilane (TMS) with the solvent resonance as the internal standard. 19F NMR (376 MHz) chemical shifts were reported in ppm (δ) (CFCl3 as an external standard and low field is positive). Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, m = multiplet), coupling constants (Hz) and integration. HRMS measurements were obtained on a TOF analyzer. Melting points were uncorrected. 3-Ylideneoxindoles were prepared according to the reported procedures.21 Representative Procedure for the Synthesis of Compound 6a. A 50 mL flask with a stir bar was charged with difluoroethylamine (1, 535.0 mg, 6.6 mmol, 3.0 equiv), tert-butyl nitrite (816.7 mg, 7.92 mmol, 3.6 equiv), and AcOH (79.3 mg, 1.32 mmol, 0.6 equiv) in 15.0 mL of diethyl ether at 35 °C for 10 min. The mixture was cooled to room temperature followed by addition of 3-ylideneoxindole 3a (508.8 mg, 2.2 mmol, 1.0 equiv). After the mixture was stirred under O2 atmosphere (balloon) at room temperature for 14 days, white precipitate was appeared. Compound 6a as a white solid (480.6 mg, 68% yield) was obtained by simple filtration followed by washing with cooled diethyl ether (4 × 5 mL) and drying processes. Additionally, the filtrate was further concentrated, and purified by flash column E

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

139.5 (d, J = 2.9 Hz, 1C), 124.4 (d, J = 7.2 Hz, 1C), 123.2 (d, J = 8.6 Hz, 1C), 122.1 (d, J = 3.7 Hz, 1C), 118.7 (d, J = 23.0 Hz, 1C), 113.3 (d, J = 2.2 Hz, 1C), 108.5 (t, J = 237.2 Hz, 1C), 107.4, 60.3, 34.5 (d, J = 16.5 Hz, 1C), 12.4; 19F NMR (376 MHz, CDCl3) δ −116.70 (d, J = 53.4 Hz, 2F), (−119.58) to (−119.69) (m, 1F); HRMS (ESI-TOF) Calcd for C15H13F3N3O3 [M + H]+: 340.0904, found 340.0906. Ethyl 7-chloro-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6k). Yellow solid, 446.1 mg, 57% yield, mp 128.2−128.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 53.0 Hz, 1H), 7.39−7.36 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 149.5 (t, J = 24.5 Hz, 1C), 145.6, 140.8, 135.3 (d, J = 27.3 Hz, 1C), 135.2, 125.6, 124.9, 121.2, 116.1, 110.4 (t, J = 210.0 Hz, 1C), 107.8, 61.8, 13.8; 19F NMR (376 MHz, DMSO-d6) δ −117.12 (d, J = 53.1 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13ClF2N3O3 [M + H]+: 356.0608, found 356.0611. Anal. Calcd for C15H12ClF2N3O3: C, 50.65; H, 3.40; N, 11.81. Found: C, 50.67; H, 3.48; N, 11.80. Ethyl 7-bromo-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6l). Yellow solid, 431.4 mg, 49% yield, mp 134.8−135.1 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J = 1.3, 8.1 Hz, 1H), 7.99 (dd, J = 1.3, 7.9 Hz, 1H), 7.41 (t, J = 53.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 149.5 (t, J = 24.7 Hz, 1C), 145.8, 140.9, 138.7, 137.1, 126.0, 125.3, 116.4, 110.4 (t, J = 211.7 Hz, 1C), 109.5, 108.4, 61.8, 40.9, 13.8; 19F NMR (376 MHz, DMSO-d6) δ −117.08 (d, J = 53.0 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13BrF2N3O3 [M + H]+: 400.0103, found 400.0107. Anal. Calcd for C15H12BrF2N3O3: C, 45.02; H, 3.02; N, 10.50. Found: C, 45.14; H, 3.14; N, 10.44. Ethyl 2-(difluoromethyl)-6-methyl-5-oxo-7-(trifluoromethyl)-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6m). White solid, 573.8 mg, 67% yield, mp 153.8−155.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.43 (t, J = 53.0 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.62 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 149.6 (t, J = 24.8 Hz, 1C), 145.4, 140.9, 137.0, 132.1 (q, J = 5.7 Hz, 1C), 130.7, 123.7, 123.6 (q, J = 272.7 Hz, 1C), 117.6, 117.2, 115.7, 110.1 (t, J = 237.2 Hz, 1C), 108.6, 61.8, 13.7; 19F NMR (376 MHz, CDCl3) δ −53.61 (s, 3F), −116.83 (d, J = 53.5 Hz, 2F); HRMS (ESI-TOF) Calcd for C16H13F5N3O3 [M + H]+: 390.0872, found 390.0869. Anal. Calcd for C16H12F5N3O3: C, 49.37; H, 3.11; N, 10.79. Found: C, 49.49; H, 3.26; N, 10.76. Ethyl 2-(difluoromethyl)-6,7,9-trimethyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6n). Red solid, 491.9 mg, 64% yield, mp 156.2−157.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.37 (t, J = 53.2 Hz, 1H), 7.31 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 2.57 (s, 3H), 2.31 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 149.4 (t, J = 24.5 Hz, 1C), 145.7, 141.6, 137.5, 135.6, 132.9, 126.5, 124.2, 113.7, 110.3 (t, J = 237.1 Hz, 1C), 109.6, 107.5, 61.6, 22.6, 20.3, 13.8; 19 F NMR (376 MHz, DMSO-d6) δ −116.94 (d, J = 53.1 Hz, 2F); HRMS (ESI-TOF) Calcd for C17H18F2N3O3 [M + H]+: 350.1311, found 350.1313. Anal. Calcd for C17H17F2N3O3: C, 58.45; H, 4.91; N, 12.03. Found: C, 58.44; H, 4.88; N, 11.96. Ethyl 2-(difluoromethyl)-8,9-difluoro-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6o). White solid, 479.4 mg, 61% yield, mp 197.8−198.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (dd, J = 8.9, 12.2 Hz, 1H), 7.82 (dd, J = 7.0, 12.6 Hz, 1H), 7.39 (t, J = 53.0 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 3.66 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7, 151.3 (dd, J = 13.9, 252.1 Hz, 1C), 149.4 (t, J = 24.2 Hz, 1C), 144.9 (dd, J = 13.3, 242.2 Hz, 1C), 143.9, 140.4, 135.0 (dd, J = 1.5, 9.5 Hz, 1C), 115.3 (d, J = 22.4 Hz, 1C), 110.0 (t, J = 237.6 Hz, 1C), 108.5 (dd, J = 2.9, 8.5 Hz, 1C), 107.8, 105.7 (d, J = 23.4 Hz, 1C), 61.8, 32.3, 13.7; 19F NMR (376 MHz, DMSO-d6) δ −116.92 (d, J = 53.0 Hz, 2F), −128.68 (ddd, J = 9.3, 12.3, 21.6 Hz, 1F), −142.35 (ddd, J = 7.2, 12.1, 23.7 Hz, 1F); HRMS (ESI-TOF) Calcd for C15H12F4N3O3 [M + H]+:

1C), 111.8 (d, J = 10.3 Hz, 1C), 108.5 (t, J = 237.4 Hz, 1C), 107.4, 60.4, 30.7, 12.5; 19F NMR (376 MHz, CDCl3 + DMSO-d6) δ −116.09 (s, 1F), −116.90 (dd, J = 7.6, 53.4 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13F3N3O3 [M + H]+: 340.0904, found 340.0900. Ethyl 9-bromo-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6e). White solid, 449.0 mg, 51% yield, mp 227.2−228.3 °C; 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 2.2, 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.13 (t, J = 53.5 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 151.0 (t, J = 26.2 Hz, 1C), 144.5, 140.8, 135.7, 135.4, 130.9, 117.4, 116.4, 114.2, 110.1 (t, J = 238.5 Hz, 1C), 109.5, 62.3, 32.1, 14.1; 19F NMR (376 MHz, CDCl3) δ −112.79 (d, J = 53.4 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13BrF2N3O3 [M + H]+: 400.0103, found 400.0105. Ethyl 2-(difluoromethyl)-6-methyl-5-oxo-9-(trifluoromethoxy)5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6f). White solid, 659.8 mg, 74% yield, mp 187.5−189.4 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.79−7.73 (m, 2H), 7.43 (t, J = 53.0 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.4, 162.1, 151.0 (t, J = 26.3 Hz, 1C), 145.1 (q, J = 1.8 Hz, 1C), 144.5, 141.1, 135.2, 125.4, 121.0, 120.6 (q, J = 257.2 Hz, 1C), 116.3, 113.7, 110.1 (t, J = 238.6 Hz, 1C), 62.3, 32.3, 14.1; 19F NMR (376 MHz, CDCl3) δ −52.94 (s, 3F), −112.63 (d, J = 53.6 Hz, 2F); HRMS (ESI-TOF) Calcd for C16H13F5N3O4 [M + H]+: 406.0821, found 406.0820. Ethyl 2-(difluoromethyl)-8-fluoro-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6g). White solid, 552.3 mg, 74% yield, mp 159.5−161.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 6.3, 9.1 Hz, 1H), 7.51 (dd, J = 2.2, 11.2 Hz, 1H), 7.39 (t, J = 51.0 Hz, 1H), 7.31−7.26 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.0 (d, J = 249.8 Hz, 1C), 161.8, 149.3 (t, J = 24.3 Hz, 1C), 144.1, 141.1, 139.1 (d, J = 11.8 Hz, 1C), 129.7 (d, J = 10.4 Hz, 1C), 110.9 (d, J = 22.5 Hz, 1C), 110.2 (t, J = 237.3 Hz, 1C), 108.8 (d, J = 2.2 Hz, 1C), 107.4, 103.1 (d, J = 28.0 Hz, 1C), 61.6, 32.0, 13.8; 19F NMR (376 MHz, DMSO-d6) δ (−104.68) to (−104.76) (m, 1F), −117.21 (d, J = 53.1 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13F3N3O3 [M + H]+: 340.0904, found 340.0905. Anal. Calcd for C15H12F3N3O3: C, 53.10; H, 3.57; N, 12.39. Found: C, 53.15; H, 3.66; N, 12.31. Ethyl 8-chloro-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6h). White solid, 344.3 mg, 44% yield, mp 164.1−166.8 °C; 1H NMR (400 MHz, CDCl3) δ 9.34 (dd, J = 0.9, 8.2 Hz, 1H), 7.39 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.10 (t, J = 53.5 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.8, 149.4 (t, J = 24.3 Hz, 1C), 144.1, 140.9, 138.1, 137.2, 128.5, 123.4, 115.5, 110.8, 110.2 (t, J = 237.3 Hz, 1C), 108.0, 61.7, 31.9, 13.8; 19 F NMR (376 MHz, CDCl3) δ −116.87 (d, J = 53.7 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13ClF2N3O3 [M + H]+: 356.0608, found 356.0608. Ethyl 8-bromo-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6i). White solid, 537.0 mg, 61% yield, mp 163.1−165.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 1.5, 8.7 Hz, 1H), 7.38 (t, J = 53.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6) δ 160.3, 148.6 (t, J = 24.6 Hz, 1C), 142.7, 139.9, 136.3, 127.7, 125.2, 125.1, 116.7, 109.7, 108.4 (t, J = 237.5 Hz, 1C), 107.1, 60.3, 30.5, 12.5; 19F NMR (376 MHz, DMSO-d6) δ −116.60 (d, J = 52.8 Hz, 2F); HRMS (ESI-TOF) Calcd for C15H13BrF2N3O3 [M + H]+: 400.0103, found 400.0106. Ethyl 2-(difluoromethyl)-7-fluoro-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6j). White solid, 335.9 mg, 45% yield, mp 156.1−157.3 °C; 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J = 7.9 Hz, 1H), 7.43−7.31 (m, 2H), 7.08 (t, J = 53.5 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.02 (d, J = 9.0 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6) δ 160.3, 148.8 (d, J = 245.5 Hz, 1C), 148.6 (t, J = 24.8 Hz, 1C), 143.3, F

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

yield, mp 152.5−154.3 °C; 1H NMR (400 MHz, CDCl3 + DMSO-d6) δ 9.19 (d, J = 8.1 Hz, 1H), 7.54−7.49 (m, 1H), 7.34−7.23 (m, 7H), 7.16 (td, J = 1.7, 53.6 Hz, 1H), 5.57 (s, 2H), 4.42 (qd, J = 1.5, 7.1 Hz, 2H), 1.40 (td, J = 1.5, 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3 + DMSO-d6) δ 160.9, 149.3 (t, J = 25.0 Hz, 1C), 144.1, 141.0, 134.8, 133.8, 131.5, 127.9, 127.0, 126.8, 125.5, 122.9, 114.8, 111.5, 109.0 (t, J = 237.8 Hz, 1C), 107.7, 60.7, 46.9, 13.0; 19F NMR (376 MHz, CDCl3 + DMSO-d6) δ −112.39 (d, J = 53.3 Hz, 2F); HRMS (ESI-TOF) Calcd for C21H18F2N3O3 [M + H]+: 398.1311, found 398.1308. Anal. Calcd for C21H17F2N3O3: C, 63.47; H, 4.31; N, 10.57. Found: C, 63.63; H, 4.38; N, 10.41. Ethyl 2-(difluoromethyl)-5-oxo-6-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6w). White solid, 615.7 mg, 73% yield, mp 199.8−200.7 °C; 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 8.2 Hz, 1H), 7.67−7.58 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.39−7.35 (m, 3H), 7.12 (t, J = 53.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 150.8 (t, J = 26.6 Hz, 1C), 144.3, 142.6, 138.1, 136.0, 132.2, 130.7, 130.1, 128.9, 128.0, 124.3, 116.7, 112.5, 110.4 (t, J = 238.2 Hz, 1C), 109.2, 62.1, 14.1; 19F NMR (376 MHz, CDCl3) δ −112.45 (dd, J = 4.5, 53.5 Hz, 2F); HRMS (ESI-TOF) Calcd for C20H16F2N3O3 [M + H]+: 384.1154, found 384.1158. Preparative-Scale Experiment of Compound 6a. A 200 mL flask with a stir bar was charged with difluoroethylamine (1, 2675.2 mg, 33.0 mmol, 3.0 equiv), tert-butyl nitrite (4083.6 mg, 39.6 mmol, 3.6 equiv) and AcOH (396.3 mg, 6.6 mmol, 0.6 equiv) in 75.0 mL of diethyl ether at 35 °C for 10 min. The mixture was cooled to room temperature followed by addition of 3-ylideneoxindole 3a (2543.8 mg, 11.0 mmol, 1.0 equiv). After the mixture was stirred under O2 atmosphere (balloon) at room temperature for 14 days, white precipitate was appeared. Compound 6a as a white solid (2827.3 mg, 80% yield) was obtained by simple filtration followed by washing with cooled diethyl ether (4 × 20 mL) and drying processes. Additionally, the filtrate was further concentrated, and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give 6a (459.4 mg, 13% yield) (93% total yield). Synthesis of Compound (±)-4a.15a A 100 mL flame-dried flask with a stir bar was charged with CF2HCH2NH2 (1, 97.3 mg, 1.2 mmol, 3.0 equiv), tBuONO (148.5 mg, 1.44 mmol, 3.6 equiv) and AcOH (14.5 mg, 0.24 mmol, 0.6 equiv) in 15.0 mL of dry CH2Cl2 at 70 °C for 10 min. The mixture was cooled to room temperature followed by addition of 3-ylideneoxindole 3a (92.5 mg, 0.4 mmol, 1.0 equiv), and the mixture was stirred under N2 atmosphere at room temperature for 24 h, concentrated, and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give compound (±)-4a (108.6 mg, 84% yield). Light yellow solid, mp 91.8−93.8 °C; 99:1 trans/cis; 1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.44 (td, J = 4.0, 54.4 Hz, 1H), 5.82−5.73 (m, 1H), 3.90−3.73 (m, 2H), 3.57 (d, J = 8.4 Hz, 1H), 3.32 (s, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 167.9, 144.7, 131.5, 124.9, 123.4, 121.6, 112.9 (t, J = 244.0 Hz, 1C), 109.0, 99.3, 94.0 (t, J = 22.0 Hz, 1C), 61.9, 44.3 (t, J = 3.0 Hz, 1C), 27.2, 13.5; 19F NMR (376 MHz, CDCl3) δ −122.74 (ABdd, J = 8.9, 54.3, 294.8 Hz, 1F), −126.64 (ABdd, J = 16.2, 55.4, 294.6 Hz, 1F); HRMS (ESI-TOF) Calcd for C15H15F2N3NaO3 [M + Na]+: 346.0974, found 346.0971. Synthesis of Compound (±)-7a.22 A 200 mL flame-dried flask with a stir bar was charged with CF2HCH2NH2 (1, 535.2 mg, 6.6 mmol, 3.0 equiv), tBuONO (816.8 mg, 7.92 mmol, 3.6 equiv) and AcOH (79.8 mg, 1.32 mmol, 0.6 equiv) in 50 mL of dry THF at 70 °C for 10 min. The mixture was cooled to room temperature followed by addition of 3-ylideneoxindole 3a (508.7 mg, 2.2 mmol, 1.0 equiv), and the mixture was stirred under N2 atmosphere at room temperature for 72 h, concentrated, and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give compound (±)-7a (483.6 mg, 68% yield). Brown solid, mp 129.1−130.4 °C; 99:1 trans/cis; 1H NMR(400 MHz) δ 7.35 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.61 (td, J = 4.7, 54.7 Hz, 1H), 6.11 (s, 1H), 4.56 (s, 1H), 3.91−3.73 (m, 2H), 3.24 (s, 3H), 0.80 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz)

358.0809, found 358.0813. Anal. Calcd for C15H11F4N3O3: C, 50.43; H, 3.10; N, 11.76. Found: C, 50.51; H, 3.28; N, 11.68. Methyl 2-(difluoromethyl)-6-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6p). White solid, 486.7 mg, 72% yield, mp 163.4−165.1 °C; 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 8.4 Hz, 1H), 7.72−7.68 (m, 1H), 7.45−7.39 (m, 2H), 7.10 (t, J = 53.6 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.6 (t, J = 26.5 Hz, 1C), 144.9, 142.2, 136.7, 132.8, 128.3, 124.3, 114.8, 112.6, 110.3 (t, J = 238.2 Hz, 1C), 108.4, 52.7, 31.9; 19F NMR (376 MHz, CDCl3) δ −117.94 (d, J = 53.6 Hz, 2F); HRMS (ESI-TOF) Calcd for C14H12F2N3O3 [M + H]+: 308.0841, found 308.0836. Propyl 2-(difluoromethyl)-6-methyl-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6q). White solid, 302.5 mg, 41% yield, mp 161.1−162.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.07− 8.99 (m, 1H), 7.76−7.68 (m, 1H), 7.58 (dd, J = 8.6, 20.0 Hz, 1H), 7.43−7.39 (m, 1H), 7.39 (t, J = 53.2 Hz, 1H), 4.33−4.29 (m, 2H), 3.71 (s, 3H), 1.82−1.73 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.0, 149.1 (t, J = 24.2 Hz, 1C), 144.2, 141.4, 136.7, 132.5, 126.8, 123.3, 115.6, 111.8, 110.2 (t, J = 236.7 Hz, 1C), 107.7, 67.1, 31.6, 21.3, 10.4; 19F NMR (376 MHz, CDCl3) δ −117.54 (d, J = 53.6 Hz, 2F); HRMS (ESI-TOF) Calcd for C16H16F2N3O3 [M + H]+: 336.1154, found 336.1149. Ethyl 7-chloro-2-(difluoromethyl)-6-methyl-5-oxo-5,6dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6r). Yellow solid, 466.1 mg, 62% yield, mp 128.2−128.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.94 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 53.1 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 149.4 (t, J = 23.8 Hz, 1C), 143.5, 141.8, 132.9, 132.4, 125.5, 123.8, 119.5, 113.4, 110.3 (t, J = 236.7 Hz, 1C), 108.6, 61.7, 13.8; 19F NMR (376 MHz, DMSO-d6) δ (−116.52) to (−116.69) (m, 2F); HRMS (ESI-TOF) Calcd for C14H11ClF2N3O3 [M + H]+: 342.0452, found 342.0459. Ethyl 2-(difluoromethyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6s). White solid, 1149.1 mg, 85% yield, mp 191.5−193.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 53.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 149.1 (t, J = 24.2 Hz, 1C), 143.5, 142.7, 135.9, 132.3, 126.6, 123.1, 116.1, 111.4 (t, J = 118.6 Hz, 1C), 108.0, 107.9, 61.5, 13.8; 19F NMR (376 MHz, DMSO-d6) δ −116.44 (d, J = 53.2 Hz, 2F); HRMS (ESI-TOF) Calcd for C14H12F2N3O3 [M + H]+: 308.0841, found 308.0846. Ethyl 2-(difluoromethyl)-6-ethyl-5-oxo-5,6-dihydropyrazolo[1,5c]quinazoline-1-carboxylate (6t). Yellow solid, 442.6 mg, 60% yield, mp 181.8−182.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.6 Hz, 1H), 7.78−7.68 (m, 2H), 7.42 (t, J = 53.1 Hz, 1H), 7.41 (dd, J = 6.0, 8.6 Hz, 1H), 4.42−4.33 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 149.3 (t, J = 24.3 Hz, 1C), 143.8, 141.4, 135.6, 132.7, 127.2, 123.3, 115.5, 112.2, 110.3 (t, J = 237.1 Hz, 1C), 107.7, 61.5, 13.8, 12.3; 19 F NMR (376 MHz, DMSO-d6) δ −116.44 (d, J = 53.0 Hz, 2F); HRMS (ESI-TOF) Calcd for C16H16F2N3O3 [M + H]+: 336.1154, found 336.1156. Ethyl 6-allyl-2-(difluoromethyl)-5-oxo-5,6-dihydropyrazolo[1,5c]quinazoline-1-carboxylate (6u). White solid, 626.6 mg, 82% yield, mp 124.2−125.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.41− 7.39 (m, 1H), 7.38 (t, J = 41.4 Hz, 1H), 6.03−5.94 (m, 1H), 5.22 (d, J = 5.6 Hz, 1H), 5.19 (s, 1H), 4.94 (s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.9, 149.3 (t, J = 242.0 Hz, 1C), 144.1, 141.6, 135.9, 132.4, 131.5, 126.9, 123.4, 117.1, 116.1, 112.1, 110.2 (t, J = 235.8 Hz, 1C), 107.9, 61.5, 46.2, 13.7; 19F NMR (376 MHz, CDCl3) δ −117.01 (d, J = 53.1 Hz, 2F); HRMS (ESI-TOF) Calcd for C17H16F2N3O3 [M + H]+: 348.1154, found 348.1159. Ethyl 6-benzyl-2-(difluoromethyl)-5-oxo-5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate (6v). White solid, 533.3 mg, 61% G

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry δ 175.2, 165.9, 143.4, 131.1, 126.0, 124.5, 123.5, 110.6 (t, J = 235.5 Hz, 1C), 110.6, 108.7, 72.9, 61.7, 58.7, 26.9, 13.6; 19F NMR (376 MHz) δ −116.10 (dd, J = 54.8, 311.6 Hz, 1F), −122.02 (dd, J = 54.2, 311.6 Hz, 1F); HRMS (ESI-TOF) Calcd for C15H15N3O3F2Na [M + Na]+: 346.0974, found 346.0969. Synthesis of 6a Starting from (±)-4a. A 50 mL flask with a stir bar was charged with (±)-4a (711.3 mg, 2.2 mmol) in 15.0 mL of diethyl ether under O2 atmosphere (balloon) at room temperature for 14 days, white precipitate was appeared. Compound 6a as a white solid (212.0 mg, 30% yield) was obtained by simple filtration followed by washing with cooled diethyl ether (4 × 5 mL) and drying processes. Additionally, the filtrate was further concentrated, and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give 6a (381.7 mg, 54% yield) (84% total yield). Synthesis of 6a Starting from (±)-7a. A 50 mL flask with a stir bar was charged with (±)-7a (711.3 mg, 2.2 mmol) in 15.0 mL of diethyl ether under O2 atmosphere (balloon) at room temperature for 14 days, white precipitate was appeared. Compound 6a as a white solid (176.7 mg, 25% yield) was obtained by simple filtration followed by washing with cooled diethyl ether (4 × 5 mL) and drying processes. Additionally, the filtrate was further concentrated, and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give 6a (452.4 mg, 64% yield) (89% total yield).

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715−726. (e) Yerien, D. E.; Bonesi, S.; Postigo, A. Fluorination Methods in Drug Discovery. Org. Biomol. Chem. 2016, 14, 8398−8427. (2) (a) O’Hagan, D.; Rzepa, H. S. Some Influences of Fluorine in Bioorganic Chemistry. Chem. Commun. 1997, 645−652. (b) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M. Organofluorine Compounds: Chemistry and Applications; Springer: Berlin, 2000. (c) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006. (d) O’Hagan, D. Understanding Organofluorine Chemistry. An Introduction to the C−F Bond. Chem. Soc. Rev. 2008, 37, 308−319. (3) For selected reviews, see: (a) Chu, L.; Qing, F.-L. Oxidative Trifluoromethylation and Trifluoromethylthiolation Reactions Using (Trifluoromethyl)trimethylsilane as a Nucleophilic CF3 Source. Acc. Chem. Res. 2014, 47, 1513−1522. (b) Merino, E.; Nevado, C. Addition of CF3 Across Unsaturated Moieties: A Powerful Functionalization Tool. Chem. Soc. Rev. 2014, 43, 6598−6608. (c) Ma, J.-A.; Li, S. Catalytic Fluorination of Unactivated C(sp3)−H Bonds. Org. Chem. Front. 2014, 1, 712−715. (d) Li, Y.; Wu, Y.; Li, G.-S.; Wang, X.-S. Palladium−Catalyzed C−F Bond Formation via Directed C−H Activation. Adv. Synth. Catal. 2014, 356, 1412−1418. (e) Ni, C.; Hu, M.; Hu, J. Good Partnership between Sulfur and Fluorine: Sulfur− Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis. Chem. Rev. 2015, 115, 765−825. (f) Shao, X.; Xu, C.; Lu, L.; Shen, Q. Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation. Acc. Chem. Res. 2015, 48, 1227−1236. (g) Campbell, M. G.; Ritter, T. Modern Carbon−Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis. Chem. Rev. 2015, 115, 612−633. (h) Sather, A. C.; Buchwald, S. L. The Evolution of Pd0/PdII-Catalyzed Aromatic Fluorination. Acc. Chem. Res. 2016, 49, 2146−2157. (i) Ni, C.; Hu, J. The Unique Fluorine Effects in Organic Reactions: Recent Facts and Insights into Fluoroalkylations. Chem. Soc. Rev. 2016, 45, 5441−5454. (4) For reviews, see: (a) Chen, B.; Vicic, D. A. Topics in Organometallic Chemistry; Springer International Publishing: Cham, 2014; Vol. 52, pp 113−141. (b) Hu, J.; Zhang, W.; Wang, F. Selective Difluoromethylation and Monofluoromethylation Reactions. Chem. Commun. 2009, 7465−7478. (c) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X. Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers. Chem. - Eur. J. 2015, 21, 12836−12865. (d) Lu, Y.; Liu, C.; Chen, Q.-Y. Recent Advances in Difluoromethylation Reaction. Curr. Org. Chem. 2015, 19, 1638−1650. (e) Xu, P.; Guo, S.; Wang, L.; Tang, P. Recent Advances in the Synthesis of Difluoromethylated Arenes. Synlett 2015, 26, 36−39. (f) Ni, C.; Zhu, L.; Hu, J. Advances in Transition-Metal-Mediated Di-and Monofluoroalkylations. Acta Chim. Huaxue Xuebao 2015, 73, 90− 115. (g) Rong, J.; Ni, C.; Hu, J. Metal-Catalyzed Direct Difluoromethylation Reactions. Asian J. Org. Chem. 2017, 6, 139−152. (5) For selected recent examples on direct difluoromethylation, see: (a) Gu, Y.; Leng, X.-B.; Shen, Q. Cooperative Dual Palladium/Silver Catalyst for Direct Difluoromethylation of Aryl Bromides and Iodides. Nat. Commun. 2014, 5, 5405−5411. (b) Feng, Z.; Min, Q.-Q.; Zhang, X. Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate. Org. Lett. 2016, 18, 44− 47. (c) Fu, W.; Han, X.; Zhu, M.; Xu, C.; Wang, Z.; Ji, B.; Hao, X.-Q.; Song, M.-P. Visible-Light-Mediated Radical Oxydifluoromethylation of Olefinic Amides for the Synthesis of CF2H-Containing Heterocycles. Chem. Commun. 2016, 52, 13413−13416. (d) Deng, Z.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Direct Nucleophilic Difluoromethylation of Carbonyl Compounds. Org. Lett. 2016, 18, 3206−3209. (e) Xu, L.; Vicic, D. A. Direct Difluoromethylation of Aryl Halides via Base Metal Catalysis at Room Temperature. J. Am. Chem. Soc. 2016, 138, 2536−2539. (f) Feng, Z.; Min, Q.-Q.; Fu, X.-P.; An, L.; Zhang, X. Chlorodifluoromethane-Triggered Formation of Difluoromethylated Arenes Catalysed by Palladium. Nat. Chem. 2017, 9, 918−923. (g) Lu, C.; Lu, H.; Wu, J.; Shen, H. C.; Hu, T.; Gu, Y.; Shen, Q. Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and Triflates and Its Applications in the Preparation of Difluoromethylated Derivatives of Drug/Agrochemical Molecules. J. Org. Chem. 2018, 83, 1077−1083. (h) Sheng, J.; Ni, H.-Q.; Bian, K.-J.; Li, Y.; Wang, Y.-N.; Wang, X.-S. Nickel-Catalyzed Direct Difluoromethylation of Aryl Boronic Acids

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00866. Crystal data for compound 6a (CIF) NMR spectra, X-ray crystal structure (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wen-Yong Han: 0000-0001-6236-4238 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21762054), the Science and Technology Department of Guizhou Province (QKHJZ-20152155, QKHRC-2016-4029, QKHPTRC-2016-5801 and QKHRCTD-2014-4002), Program for the Top Talents of Science and Technology in Higher Learning Institutions of Guizhou Province (QJHKYZ-2016-081), National First-Rate Construction Discipline of Pharmacy (YLXKJS-YX-04), the Fifth Batch of Talent Base in Guizhou Province (2016).

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REFERENCES

(1) For selected reviews, see: (a) Filler, R.; Saha, R. Fluorine in Medicinal Chemistry: A Century of Progress and a 60-Year Retrospective of Selected Highlights. Future Med. Chem. 2009, 1, 777−791. (b) Wang, J.; Sanchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506. (c) Harsanyi, A.; Sandford, G. Organofluorine Chemistry: Applications, Sources and Sustainability. Green Chem. 2015, 17, 2081− 2086. (d) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in Drug Design: A Case Study with Fluoroanisoles. ChemMedChem 2015, 10, H

DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.8b00866 J. Org. Chem. XXXX, XXX, XXX−XXX