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COMMUNICATION Takeharu Haino et al. Solvent-induced emission of organogels based on tris(phenylisoxazolyl) benzene
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Received 00th January 20xx, Accepted 00th January 20xx
Visible-light induced di- and trifluoromethylation of Nmethacryloyl benzamides with fluorinated sulfones for the synthesis of CF2H/CF3-containing isoquinolinediones†
DOI: 10.1039/x0xx00000x
Guanglong Zou,*a and Xuelin Wangb
www.rsc.org/
A general visible light induced direct difluoromethylation of N-methacryloyl benzamides by using difluoromethyl sulfone was developed. In addition, photoredox-catalyzed trifluoromethylation of N-methacryloyl benzamides with trifluoromethyl sulfone via a similar radical process was also achieved. This method allows for an efficient and practical synthesis of a variety of CF2H/CF3-containing isoquinoline-1,3(2H,4H)-diones in moderate to good yields. The reaction features mild reaction conditions, operational simplicity, and a broad substrate scope.
Introduction The skeleton of isoquinoline-1,3(2H,4H)-dione widely exists in pharmaceutical and bioactive compounds. Isoquinoline1,3(2H,4H)-dione derivatives possess important biological activities such as antitumor activity, HIV-1 integrase inhibitor activity and selective inhibitor activity of cyclin-dependent kinase.1 Consequently, tremendous effort has been focused on the construction of isoquinoline-1,3(2H,4H)-diones and their derivatives.2 Recently, radical addition/tandem cyclization of methacryloyl benzamides has been demonstrated as a fast, effective, and atom-economic approach toward isoquinoline1,3(2H,4H)-dione synthesis, showing its great synthetic capability with various radical precursors, such as carbon-, sulfur-, phosphorus- and nitrogen-containing radicals (Scheme 1a).3-6 For example, Xia and co-workers demonstrated a copper-catalyzed radical aminocyclization of methacryloyl benzamides with N-fluorobenzenesulfonimide (NFSI) as imine radical precursor under heating conditions.3a Afterward, the reaction of methacryloyl benzamides with thiols using molecular oxygen as the sole oxidant was developed by Guo group.3b Since it is generally accepted that incorporation of fluorinated functionalities into molecules could improve its physical, chemical, and biological properties, some attention has been given to the development of efficient methods for the introduction of fluorinated moieties into isoquinoline1,3(2H,4H)-dione skeleton. In 2013, Nevado et al. reported a tetrabutylammonium iodide-induced trifluoromethylation of
a
School of Chemical Engineering,Guizhou Minzu Univeristy, Huaxi Univeristy Town, Guiyang 550025, China. E-mail: [email protected] b School of Graduate Students, Guizhou Minzu University,Ten-li Strand Campus, Guiyang 550025, China. †Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
methacryloyl benzamide with Togni’s reagent to construct isoquinolinediones.4 Subsequently, Liu and Zhang developed the trifluoromethylation of methacryloyl benzamides with TMSCF3 or CF3SO2Cl under metal-free conditions or using a visible light photocatalyst, respectively.5 Shortly after, Tang and Xia reported a similar radical cyclization of methacryloylbenzamide involving difluorobromoacetate as a reaction partner.6 Although the above-mentioned trifluoromethylation and difluoroacetylation of methacryloylbenzamides have been described, the direct difluoromethylation has, to the best of our knowledge, remained elusive, and continues to attract considerable attention from the synthetic community. The difluoromethyl group (CF2H) is an important functional group used for the design of leading compounds in the field of agrochemical and pharmaceutical owing to its unique electronic properties. It is well-known that the CF2H group is a bioisostere of a hydroxyl or thiol group and can act as lipophilic hydrogen bond donor to increase lipophilicity, metabolic stability as well as bioavailability.7 Therefore, it is important to develop synthetic methods for C-CF2H bond formation.8 In this regard, transition-metal-catalyzed difluoromethylation of aryl halides or boronic acids,9 and intermolecular difunctionalization of alkenes10 using different difluoromethylating reagents have been established. However, examples of the preparation of difluoromethylated heterocycles have rare precedents. For example, Dolbier and co-workers have developed the intramolecular difluoroalkylation reactions of unsaturated bonds to access CF2H-substituted oxindoles, azaspirocycles and phenanthridines using HF2CSO2Cl.11 Koike and Akita have described an intramolecular difluoromethylation of aryl-fused cyclo-alkenylalkanols under conditions of photoredox catalysis.12 Hu and Fu groups have reported the difluoromethylation reactions of isocyanides and olefinic amides with difluoromethyl sulfones as the CF2H radial sources, respectively.13 Inspired by these results, we envisioned bringing together the advantages of both strategies by
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DOI: 10.1039/C7OB02226C
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Scheme 1 Radical addition/cyclization of methacryloyl benzamides
Results and discussion We initially chose difluoromethyl sulfones 2a-c as privileged CF2H radical sources. Irradiation of the mixture of Nmethacryloyl-N-methylbenzamide (1a), Na2CO3, and difluoromethyl sulfone 2a in degassed DMSO by 3W blue LED Table 1 Optimization of reaction conditions for 3aa
a Reaction
conditions: 1a (0.20 mmol, 1.0 equiv), 2 (0.30 mmol,View 1.5 Article equiv),Online base (0.30 mmol, 1.5 equiv), and photocatalyst (0.004 mmol, 2.0 mol%) in indicated DOI: 10.1039/C7OB02226C solvent (3.0 mL) was irradiated with a 3 W blue LED for 12 h. b Isolated yield. c Without visible light irradiation.
at rt using 2 mol % of fac-Ir(ppy)3 as photocatalyst, the desired product 3a was obtained in 64% yield after 12 h (Table 1, entry 1). Under the otherwise identical condition, reactions with 2b generated the product in lower reactivity (27%, entry 2). However, no desired product was obtained when 2c was used as the CF2H-transfer reagent (entry 3). With the suitable reagent 2a as the best CF2H-transfer reagent, we continued to optimize other parameters to further improve the yield. A survey of other photocatalysts demonstrated that fac-Ir(ppy)3 is the best choice, which may be attributed to its superior reduction potential in the excited state (entries 4-6). Subsequently, various solvents were evaluated. The yield could be improved by performing the reaction in DMF, while using acetonitrile and acetone led to slightly lower yields (entries7-9). In addition to Na2CO3, we also screened for others inorganic bases, such as Cs2CO3, K2CO3 and K3PO4. However, Na2CO3 gave the best result. Control reactions demonstrated that no desired product 3a was observed when the reaction was carried out in the absence of photocatalyst or light irradiation (entries 13-14). Table 2 Difluoromethylation of methacryloyl benzamides with difluoromethyl sulfone 2a under visible light irradiation
Entry
CF2H Reagent
Catalyst
Base
Solvent
Yieldb (%)
1
2a
fac-Ir(ppy)3
Na2CO3
DMSO
64
2
2b
fac-Ir(ppy)3
Na2CO3
DMSO
27
3
2c
fac-Ir(ppy)3
Na2CO3
DMSO
0
4
2a
Ru(bpy)3Cl2•6H2O
Na2CO3
DMSO
41
5
2a
Ru(bpy)3(PF6)2
Na2CO3
DMSO
43
6
2a
Eosin Y
Na2CO3
DMSO
0
7
2a
fac-Ir(ppy)3
Na2CO3
DMF
76
8
2a
fac-Ir(ppy)3
Na2CO3
CH3CN
55
9
2a
fac-Ir(ppy)3
Na2CO3
acetone
36
10
2a
fac-Ir(ppy)3
Cs2CO3
DMF
65
11
2a
fac-Ir(ppy)3
K2CO3
DMF
71
12
2a
fac-Ir(ppy)3
K3PO4
DMF
58
13
2a
none
Na2CO3
DMF
0
14c
2a
fac-Ir(ppy)3
Na2CO3
DMF
0
Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2a (0.30 mmol, 1.5 equiv), Na2CO3 (0.30 mmol, 1.5 equiv) and fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) in DMF (3.0 mL) was irradiated with a 3 W blue LED for 12 h.
With the optimized reaction conditions established, various substrates were subjected to the reaction and representative results are summarized in Table 2. The reaction of difluoromethyl sulfone 2a with various N-methacryloyl-Nmethylbenzamides afforded the desired CF2H-containing
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combining methacryloyl benzamides with CF2H radicals. Herein, we reported our study on the direct difluoromethylation of methacryloyl benzamides to produce difluoromethylated isoquinoline-1,3(2H,4H)-diones via visible-light photocatalysis. In addition, the present photocatalytic system could also be applicable to the synthesis of attractive trifluoromethylated isoquinoline-1,3(2H,4H)-diones (Scheme 1b).
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isoquinoline-1, 3(2H,4H)-diones 3b−3k in moderate to good yields. The reaction was not sensitive to the electronic nature of substituents on the benzamide moiety. Methyl and methoxyl substituents as well as halogen atoms such as F, Cl and Br on the para-position of the aryl ring can be welltolerated in this system (3b–3f). Furthermore, strong electronwithdrawing groups such as CF3 afforded 3g in slightly lower yield. When the sterically demanding ortho-substituted methacryloyl methylbenzamide was subject to the reaction, lower yield of the product 3h was obtained. In addition, the reaction of meta-substituted 2i with difluoromethyl sulfone 2a proceeded smoothly and readily converted to a mixture of two regioisomers in approximately 6:1 ratio (3i and 3i'). Subsequently, the N-substituents of methacryloyl methylbenzamides were investigated, and no obvious influence on the results was observed upon changing the Me group on N atom to n-butyl or i-butyl (3j-3k). However, no desired product was found in the case of unprotected methacryloyl benzamide (3l). The structures of products 3c and 3d were further confirmed by X-ray crystallographic analysis (Figure 1).14
Fig. 1 X-ray crystal structure of 3c and 3d (from left to right).
Table 3 Trifluoromethylation of methacryloyl benzamides with trifluoromethyl sulfone 4 under visible light irradiation
Encouraged by the successful application of thisView strategy in Article Online DOI: 10.1039/C7OB02226C preparing difluoromethylated isoquinoline-1,3(2H,4H)-diones, we proposed that trifluoromethylated isoquinolinediones could be synthesized by using trifluoromethyl sulfone 4 as trifluoromethyl radical sources through this protocol. We found that a wide range of N-methacryloyl-Nmethylbenzamides with both electron-donating and withdrawing groups gave moderate to good yields of the desired CF3-containing isoquinoline-1,3(2H,4H)-diones 5a−5g, which indicates that there was not obvious electronic effect on the substrate (Table 3). The methacryloyl benzamides having butyl or isobutyl as protecting groups were also compatible in this reaction, and the desired products 5h, 5i were isolated in 71% and 68% yield, respectively. No desired product was observed by the addition of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 1.5 equiv) into the system, which indicates that a free radical process would be involved. Based on the preliminary results discussed above and precedent literatures,3,13 a mechanistic pathway for the [fac-Ir(ppy)3]-catalyzed cyclization process could thus be proposed (Scheme 2). Initially, the excited [facIr(III)(ppy)3*] is formed under the light irradiation. Then, the interaction of fluorinated sulfone 2a or 4 with the excited state [fac-Ir(III)(ppy)3*] triggers the generation of the fluoromethyl radical (·CF2X) A and the strong oxidant [fac-Ir(IV)(ppy)3]. Next, the reaction of fluoromethyl radical (·CF2X) A with methacryloyl benzamides 1 generates radical intermediate B, which undergoes intramolecular cyclization on the aromatic ring, generating intermediate C. The intermediate C is then oxidized by [fac-Ir(IV)(ppy)3]+ to form the cyclohexadienylcation D with the concurrent regeneration of [fac-Ir(III)(ppy)3]. Finally, deprotonation assisted by base leads to the formation of the desired product 3 or 5.
Scheme 2 Plausible reaction mechanism.
Conclusions Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 4 (0.30 mmol, 1.5 equiv), Na2CO3 (0.30 mmol, 1.5 equiv), and fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) in DMF (3.0 mL) was irradiated with a 3 W blue LED for 12 h.
Early work in the field of radical trifluoromethylation of methacryloyl benzamides employed Togni’s reagent, TMSCF3 or CF3SO2Cl as trifluoromethylating reagents,4-5 but remains associated with certain disadvantages such as high reaction temperatures and use of environmentally unfriendly reagents.
In conclusion, we have developed an efficient and mild photocatalytic radical di- or trifluoromethylation/cyclization cascade of methacryloyl benzamides with difluoromethyl or trifluoromethyl sulfones using visible light. A series of potentially biological CF2H or CF3-containing isoquinoline1,3(2H,4H)-diones could be conveniently and efficiently obtained in moderate to good yields with excellent functional group tolerance. The easy and efficient method for the
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synthesis of isoquinolinediones should attract much attention in synthetic and pharmaceutical chemistry. Further investigations on direct difluoromethylation or trifluoromethylation of alkenes for the synthesis of other heterocycles with privileged structures are underway in our laboratory.
Experimental section
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General All the reactions were conducted using standard Schlenk tube techniques. Solvents were purified or dried in a standard manner. Photo-irradiation was carried out with a 3 W blue LEDs. Column chromatography was performed on silica gel (200−300 mesh). 1H NMR spectra, 13C NMR spectra, and 19F{1H} NMR spectra were measured in CDCl3 and recorded on 500 MHz NMR spectrometers with TMS as an internal standard. Chemical shifts (δ) are reported in ppm downfield from tetramethylsilane. Abbreviations for signal couplings are: s, singlet; d, doublet; t, triplet; m, multiplet. HRMS analyses was recorded on Q-TOF Global mass spectrometer. Methacryloyl benzamides 1,3 difluoromethyl sulfones 2a-c13 and 2((trifluoromethyl)sulfonyl)benzo[d]thiazole 413 were prepared according to the reported literature. General procedure for the synthesis of di- or trifluoromethylated isoquinoline-1, 3(2H,4H)-diones 3a-k a or 5a-i. Methacryloyl benzamides 1 (0.20 mmol), fluorinated sulfones 2a or 4 (0.30 mmol), fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) and Na2CO3 (0.30 mmol) were dissolved in DMF (3.0 mL). Then, the resulting mixture was degassed via ‘freezepump-thaw’ procedure (3 times). After that, the solution was stirred at room temperature under 3 W blue LED irradiation for 12 h. Then the reaction mixture was diluted by adding EtOAc and brine. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 15:1 as the eluant) on silica gel to give the desired isoquinoline-1, 3 (2H, 4H)-diones 3a-k or 5a-i.
Characterization data for the products 3a-k and 5a-i 4-(2,2-Difluoroethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)dione (3a). White solid (38.5 mg, 76% yield). 1H NMR (500 MHz, CDCl3): δ 8.29 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 8.0 Hz, J2 = 1.5 Hz), 7.51-7.46 (m, 2 H), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.0 Hz), 3.40 (s, 3 H), 3.05-2.95 (m, 1 H), 2.56-2.45 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.20, 163.78, 141.33, 134.15, 129.37, 128.01, 125.28, 124.40, 115.05 (t, J = 238.9 Hz), 45.03 (t, J = 21.6 Hz), 43.72 (dd, J1 = 7.0 Hz, J2 = 3.0 Hz), 30.57, 27.35. 19F NMR (470 MHz, CDCl3): δ -115.14 (d, J = 291.4 Hz, 1 F), -116.40 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H14F2NO2: 254.0992, found: 254.0985.
4-(2,2-Difluoroethyl)-2,4,6-trimethylisoquinoline-1,3(2H,4H)View Article Online 1H NMR (500 10.1039/C7OB02226C dione (3b). White solid (42.2 mg, 79%DOI: yield). MHz, CDCl3): δ 8.17 (d, 1 H, J = 8.0 Hz), 7.29 (d, 1 H, J = 8.5 Hz), 7.23 (s, 1 H), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.00-2.96 (m, 1 H), 2.53-2.45 (m, 1 H), 2.48 (s, 3 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.34, 163.79, 145.13, 141.35, 129.39, 129.11, 125.60, 121.93, 115.11 (t, J = 238.8 Hz), 45.08 (t, J = 21.6 Hz), 43.66 (dd, J1 = 7.3 Hz, J2 = 2.8 Hz), 30.51, 27.25, 21.94. 19F NMR (470 MHz, CDCl3): δ -115.09 (d, J = 290.9 Hz, 1 F), -116.48 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1150. 4-(2,2-Difluoroethyl)-6-methoxy-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3c). White solid (42.5 mg, 75% yield). 1H NMR (500 MHz, CDCl3): δ 8.24 (d, 1 H, J = 8.5 Hz), 7.01 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 6.89 (d, 1 H, J = 2.5 Hz), 5.43 (tdd, 1 H, J1 = 56.0 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.92 (s, 3 H), 3.38 (s, 3 H), 3.00-2.96 (m, 1 H), 2.50-2.40 (m, 1 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.27, 164.24, 163.43, 143.52, 131.76, 117.36, 115.06 (t, J = 238.8 Hz), 113.49, 110.76, 55.64, 45.16 (t, J = 21.8 Hz), 43.91 (dd, J1 = 7.1 Hz, J2 = 2.8 Hz), 30.57, 27.20. 19F NMR (470 MHz, CDCl3): δ -115.01 (d, J = 290.9 Hz, 1 F), -116.27 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO3: 284.1098, found: 284.1094. 4-(2,2-Difluoroethyl)-6-fluoro-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3d). White solid (36.9 mg, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.31 (dd, 1 H, J1 = 7.5 Hz, J2 = 5.5 Hz), 7.21-7.13 (m, 2 H), 5.46 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.38 (s, 3 H), 3.05-2.95 (m, 1 H), 2.51-2.40 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.73, 166.31 (d, J = 254.9 Hz), 162.85, 144.45 (d, J = 8.5 Hz), 132.47 (d, J = 9.8 Hz), 120.85 (d, J = 2.5 Hz), 116.00 (d, J = 21.9 Hz), 114.79 (t, J = 239.0 Hz), 112.34 (d, J = 23.0 Hz), 44.98 (t, J = 21.5 Hz), 43.95 (t, J = 4.1 Hz), 30.57, 27.38. 19F NMR (470 MHz, CDCl3): δ 102.71 (s, 1 F), -115.14 (d, J = 291.9 Hz, 1 F), -115.89 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13F3NO2: 272.0898, found: 272.0896. 6-Chloro-4-(2,2-difluoroethyl)-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3e). White solid (44.2 mg, 77% yield). 1H NMR (500 MHz, CDCl3): δ 8.23 (d, 1 H, J = 8.5 Hz), 7.48-7.44 (m, 2 H), 5.46 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.05-2.95 (m, 1 H), 2.53-2.42 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.58, 162.95, 143.15, 140.74, 130.97, 128.65, 125.58, 122.88, 114.80 (t, J = 239.1 Hz), 44.92 (t, J = 21.6 Hz), 43.77 (dd, J1 = 5.9 Hz, J2 = 4.0 Hz), 30.50, 27.43. 19F NMR (470 MHz, CDCl ): δ -115.12 (d, J = 291.9 Hz, 1 F), 3 115.94 (d, J = 291.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13ClF2NO2: 288.0603, found: 288.0597. 6-Bromo-4-(2,2-difluoroethyl)-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3f). White solid (49.1 mg, 74% yield). 1H NMR (500 MHz, CDCl3): δ 8.16 (d, 1 H, J = 8.5 Hz), 7.64 (dd, 1 H, J1 = 8.5 Hz, J2 = 2.0 Hz), 7.61 (d, 1 H, J = 2.0 Hz), 5.47 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.40 (s, 3 H), 3.06-2.96 (m, 1 H), 2.53-2.43 (m, 1 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.51, 163.10, 143.21, 131.61, 131.00, 129.40, 128.55, 123.32, 114.77 (t, J = 239.3 Hz), 44.97 (t, J = 21.5 Hz), 43.73 (dd, J1 = 5.9 Hz, J2 = 3.6 Hz), 30.55, 27.47. 19F NMR (470 MHz, CDCl3): δ -115.14 (d, J = 291.9 Hz, 1 F), -115.97 (d, J =
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291.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13BrF2NO2: 332.0097, found: 332.0090. 4-(2,2-Difluoroethyl)-2,4-dimethyl-6-(trifluoromethyl) isoquinoline-1,3(2H,4H)-dione (3g). White solid (40.5 mg, 63% yield). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, 1 H, J = 8.5 Hz), 7.76 (d, 1 H, J = 8.0 Hz), 7.71 (s, 1 H), 5.48 (tdd, 1 H, J1 = 55.5 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.43 (s, 3 H), 3.11-3.01 (m, 1 H), 2.61-2.50 (m, 1 H), 1.72 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.45, 162.68, 142.32, 135.63 (q, J = 32.8 Hz), 130.28, 127.25, 124.78 (q, J = 3.5 Hz), 123.24 (q, J = 271.5 Hz), 122.50 (q, J = 3.8 Hz), 114.68 (t, J = 239.3 Hz), 44.87 (t, J = 21.4 Hz), 43.86 (t, J = 4.6 Hz), 30.59, 27.57. 19F NMR (470 MHz, CDCl3): δ -63.16 (s, 3 F), -115.35 (s, 1 F), -115.36 (s, 1 F). HRMS (ESI): calcd for [M+H]+ C14H13F5NO2: 322.0866, found: 322.0858. 4-(2,2-Difluoroethyl)-2,4,8-trimethylisoquinoline-1,3(2H,4H)dione (3h). Oil (27.8 mg, 52% yield). 1H NMR (500 MHz, CDCl3): δ 7.54 (t, 1 H, J = 7.8 Hz), 7.35 (d, 1 H, J = 8.0 Hz), 7.30 (d, 1 H, J = 7.5 Hz), 5.42 (tdd, 1 H, J1 = 55.5 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.05-2.95 (m, 1 H), 2.82 (s, 3 H), 2.54-2.43 (m, 1 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.89, 164.31, 143.16. 142.64, 132.90, 132.00, 123.52, 122.80, 115.17 (t, J = 238.6 Hz), 45.37 (t, J = 21.6 Hz), 43.78 (dd, J1 = 7.1 Hz, J2 = 3.0 Hz), 30.91, 27.35, 24.04. 19F NMR (470 MHz, CDCl3): δ -115.0 (d, J = 291.4 Hz, 1 F), -116.39 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1153. 4-(2,2-Difluoroethyl)-2,4,7-trimethylisoquinoline-1,3(2H,4H)dione (3i) and 4-(2,2-difluoroethyl)-2,4,5trimethylisoquinoline-1,3(2H,4H)-dione (3i’) (6:1). Oil (32.6 mg, 61% yield). 1H NMR (500 MHz, CDCl3): δ 8.28 (dd, 0.14 H, J1 = 7.5 Hz, J2 = 1.3 Hz), 8.10 (d, 0.83 H, J = 1.0 Hz), 7.50 (dd, 0.88 H, J1 = 8.0 Hz, J2 = 1.5 Hz), 7.47 (d, 0.11 H, J = 0.5 Hz), 7.41 (t, 0.13 H, J = 8.0 Hz), 7.35 (d, 0.87 H, J = 8.0 Hz), 5.50-5.26 (m, 1 H), 3.42 (s, 0.39 H), 3.40 (s, 2.57 H), 3.03-2.93 (m, 1 H), 2.63 (s, 0.35 H), 2.53-2.42 (m, 1 H), 2.46 (s, 2.55 H), 1.77 (s, 0.36 H), 1.65 (s, 2.67 H). 13C NMR (125 MHz, CDCl3): δ 176.34, 175.39, 164.04, 163.96, 138.69, 138.48, 138.40, 138.04, 135.24, 135.16, 129.44, 128.42, 127.97, 125.58, 125.19, 124.20, 115.44 (t, J = 238.0 Hz), 115.12 (t, J = 238.8 Hz), 45.26 (t, J = 21.5 Hz), 43.47 (dd, J1 = 7.1 Hz, J2 = 2.9 Hz), 41.78 (t, J = 21.5 Hz), 30.90, 30.57, 27.65, 27.35, 22.73, 20.95. 19F NMR (470 MHz, CDCl3): δ -115.20 (d, J = 291.4 Hz), -115.50 (d, J = 290.5 Hz), -116.50 (d, J = 290.9 Hz), -117.30 (d, J = 290.5 Hz). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1144. 2-Butyl-4-(2,2-difluoroethyl)-4-methylisoquinoline1,3(2H,4H)-dione (3j). White solid (46.1 mg, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 7.5 Hz, J2 = 1.5 Hz), 7.50 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.46 (d, 1 H, J = 8.0 Hz), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.5 Hz), 4.06-3.97 (m, 2 H), 3.05-2.97 (m, 1 H), 2.55-2.45 (m, 1 H), 1.67 (s, 3 H), 1.64-1.58 (m, 2 H), 1.43-1.36 (m, 2 H), 0.96 (t, 3 H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.86, 163.48, 141.37, 134.04, 129.43, 127.97, 125.22, 124.56, 115.11 (t, J = 238.9 Hz), 44.89 (t, J = 21.6 Hz), 43.67 (dd, J1 = 6.9 Hz, J2 = 3.3 Hz), 40.54, 30.78, 29.73, 20.24, 13.78. 19F NMR (470 MHz, CDCl ): δ -115.09 (d, J = 291.4 Hz, 1 F), 3 116.07 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C16H20F2NO2: 296.1462, found: 296.1462.
4-(2,2-Difluoroethyl)-2-isobutyl-4-methylisoquinolineView Article Online DOI:mg, 10.1039/C7OB02226C 1,3(2H,4H)-dione (3k). White solid (43.7 74% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.52-7.46 (m, 2 H), 5.44 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.5 Hz), 3.94-3.85 (m, 2 H), 3.07-3.01 (m, 1 H), 2.57-2.47 (m, 1 H), 2.18-2.11 (m, 1 H), 1.67 (s, 3 H), 0.95 (d, 3 H, J = 6.5 Hz), 0.92 (d, 3 H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl ): δ 175.22, 163.83, 141.43, 134.03, 3 129.59, 127.95, 125.19, 124.48, 115.13 (t, J = 238.9 Hz), 47.45, 44.51 (t, J = 21.6 Hz), 43.83 (dd, J1 = 6.5 Hz, J2 = 3.4 Hz), 31.25, 27.17, 20.22, 20.12. 19F NMR (470 MHz, CDCl3): δ -115.08 (d, J = 290.9 Hz, 1 F), -116.01 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C16H20F2NO2: 296.1462, found: 296.1458. 2,4,6-Trimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5a).5a White solid (42.8 mg, 75% yield). 1H NMR (500 MHz, CDCl3): δ 8.19 (d, 1 H, J = 9.0 Hz), 7.31 (d, 1 H, J = 9.5 Hz), 7.21 (s, 1 H), 3.42 (s, 3 H), 3.38-3.31 (m, 1 H), 2.852.77 (m, 1 H), 2.48 (s, 3 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.70, 163.76, 144.71, 140.41, 129.31, 129.15, 125.98, 124.98 (q, J = 277.1 Hz), 121.78, 44.37 (q, J = 27.4 Hz), 43.50 (d, J = 2.1 Hz), 31.18, 27.31, 21.91. 19F NMR (470 MHz, CDCl3): δ -61.65 (s, 3 F). 6-Methoxy-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5b).5a White solid (41.5 mg, 69% yield). 1H NMR (500 MHz, CDCl3): δ 8.25 (d, 1 H, J = 8.5 Hz), 7.01 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 6.87 (d, 1 H, J = 2.5 Hz), 3.92 (s, 3 H), 3.40 (s, 3 H), 3.41-3.31 (m, 1 H), 2.82-2.74 (m, 1 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.62, 163.98, 163.37, 142.58, 131.66, 124.97 (q, J = 277.1 Hz), 117.25, 113.62, 111.13, 55.61, 44.41 (q, J = 27.4 Hz), 43.75 (d, J = 2.0 Hz), 31.25, 27.24. 19F NMR (470 MHz, CDCl3): δ -61.61 (s, 3 F). 6-Fluoro-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5c).5b White solid (42.2 mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.34 (dd, 1 H, J1 = 8.5 Hz, J2 = 6.0 Hz), 7.24-7.20 (m, 1 H), 7.12 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 3.42 (s, 3 H), 3.44-3.35 (m, 1 H), 2.80-2.71 (m, 1 H), 2.20 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.03, 166.14 (d, J = 254.6 Hz), 162.76, 143.38 (d, J = 8.5 Hz), 132.42 (d, J = 9.6 Hz), 124.81 (q, J = 277.1 Hz), 128.74 (d, J = 2.4 Hz), 116.14 (d, J = 21.9 Hz), 112.60 (d, J = 23.3 Hz), 44.49 (q, J = 27.6 Hz), 43.76, 30.98 (d, J = 18.1 Hz), 27.44. 19F NMR (470 MHz, CDCl3): δ -61.72 (s, 3 F), 103.12 (s, 1 F). 6-Chloro-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5d).5a White solid (37.8 mg, 62% yield). 1H NMR (500 MHz, CDCl3): δ 8.25 (d, 1 H, J = 8.5 Hz), 7.49 (dd, 1 H, J1 = 8.5 Hz, J2 = 2.0 Hz), 7.42 (d, 1 H, J = 1.5 Hz), 3.42 (s, 3 H), 3.41-3.34 (m, 1 H), 2.82-2.74 (m, 1 H), 1.69 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 173.90, 162.89, 142.07, 140.52, 130.93, 128.78, 125.89, 124.81 (q, J = 276.8 Hz), 122.78, 44.43 (q, J = 27.5 Hz), 43.57 (q, J = 2.1 Hz), 31.00, 27.50. 19F NMR (470 MHz, CDCl3): δ -61.68 (s, 3 F). 6-Bromo-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5e). White solid (51.0 mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.17 (d, 1 H, J = 8.5 Hz), 7.65 (dd, 1 H, J1 = 7.5 Hz, J2 = 3.5 Hz), 7.59 (d, 1 H, J = 1.5 Hz), 3.42 (s, 3 H), 3.42-3.35 (m, 1 H), 2.83-2.74 (m, 1 H), 1.69 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 173.83, 163.02, 142.12, 131.70, 130.91,
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129.08, 128.88, 124.81 (q, J = 277.0 Hz), 123.20, 44.42 (q, J = 27.5 Hz), 43.52 (q, J = 2.3 Hz), 31.00, 27.51. 19F NMR (470 MHz, CDCl3): δ -61.67 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C13H12BrF3NO2: 350.0003, found: 349.9995. 2,4-Dimethyl-4-(2,2,2-trifluoroethyl)-6(trifluoromethyl)isoquinoline-1,3(2H,4H)-dione (5f). White solid (37.3 mg, 55% yield). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, 1 H, J = 8.5 Hz), 7.76 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (s, 1 H), 3.44 (s, 3 H), 3.47-3.37 (m, 1 H), 2.90-2.81 (m, 1 H), 1.72 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.74, 162.56, 141.15, 135.42 (q, J = 32.8 Hz), 130.21, 127.15, 124.87 (q, J = 3.5 Hz), 124.77 (q, J = 277.0 Hz), 123.23 (q, J = 271.5 Hz), 122.86 (d, J = 3.5 Hz), 44.33 (q, J = 27.6 Hz), 43.68 (d, J = 2.1 Hz), 30.95, 27.59. 19F NMR (470 MHz, CDCl3): δ -61.73 (s, 3 F), -63.27 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C14H12F6NO2: 340.0772, found: 340.0776. 2,4,8-Trimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5g). Oil (28.5 mg, 50% yield). 1H NMR (500 MHz, CDCl3): δ 7.52 (t, 1 H, J = 8.0 Hz), 7.33-7.29 (m, 2 H), 3.423.33 (m, 1 H), 3.40 (s, 3 H), 2.85-2.77 (m, 1 H), 2.82 (s, 3 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.26, 164.24, 143.04. 141.70, 132.57, 132.06, 125.04 (q, J = 277.1 Hz), 123.95, 122.57, 44.66 (q, J = 27.3 Hz), 43.60 (q, J = 2.1 Hz), 31.63, 27.39, 24.10. 19F NMR (470 MHz, CDCl3): δ -61.51 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C14H15F3NO2: 286.1055, found: 286.1059. 2-Butyl-4-methyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5h).5c White solid (44.5 mg, 71% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.68 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.50 (t, 1 H, J = 8.0 Hz), 7.44 (d, 1 H, J = 8.0 Hz), 4.08-3.98 (m, 2 H), 3.43-3.40 (m, 1 H), 2.87-2.78 (m, 1 H), 1.67 (s, 3 H), 1.63-1.58 (m, 2 H), 1.44-1.37 (m, 2 H), 0.97 (t, 3 H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.22, 163.43, 140.41, 133.68, 129.33, 128.00, 125.63, 125.03 (q, J = 277.0 Hz), 124.36, 44.18 (q, J = 27.3 Hz), 43.54 (d, J = 2.0 Hz), 40.62, 31.39, 29.61, 20.21, 13.76. 19F NMR (470 MHz, CDCl3): δ -61.39 (s, 3 F). 2-Isobutyl-4-methyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5i). White solid (42.6 mg, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.31 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.68 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.52-7.49 (m, 1 H), 7.44 (d, 1 H, J = 8.0 Hz), 3.96-3.86 (m, 2 H), 3.47-3.37 (m, 1 H), 2.892.80 (m, 1 H), 2.19-2.10 (m, 1 H), 1.67 (s, 3 H), 0.95 (dd, 6 H, J1 = 21.0 Hz, J2 = 6.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.57, 163.79, 140.41, 133.67, 129.50, 128.01, 125.61, 125.03 (q, J = 277.1 Hz), 124.30, 47.57, 43.85 (q, J = 7.4 Hz), 43.72, 31.85, 27.14, 20.22, 20.08. 19F NMR (470 MHz, CDCl3): δ -61.17 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C16H19F3NO2: 314.1368, found: 314.1365.
We are grateful to the Natural Science FoundationView of Article China for Online DOI: 10.1039/C7OB02226C financial support to this work (No.21363004) and the support from China Scholarship Council Program.
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Conflicts of interest There are no conflicts to declare
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7.
(a) H. Tsou, M. Otteng, T. Tran, M. B. Floyd, M. J. Reich, G. Birnberg, K. Kutterer, S. A. Kaloustian, M. Ravi, R. Nilakantan, M. Grillo, J. P. McGinnis and S. K. Rabindran, J. Med. Chem., 2008, 51, 3507; (b) Y.-L. Chen, J. Tang, M. J. Kesler, Y. Y. Sham, R. Vince, R. J. Geraghty and Z. Wang, Bioorg. Med. Chem., 2012, 20, 467; (c) M. Billamboz, F. Bailly, C. Lion, N. Touati, H. Vezin, C. Calmels, M. L. Andréola, F. Christ, Z. Debyser and P. Cotelle, J. Med. Chem., 2011, 54, 1812; (d) S. K. V. Vernekar, Z. Liu, E. Nagy, L. Miller, K. A. Kirby, D. J. Wilson, J. Kankanala, S. T. Sarafianos, M. A. Parniak and Z. Wang, J. Med. Chem., 2015, 58, 651; (e) M. Billamboz, V. Suchaud, F. Bailly, C. Lion, J. Demeulemeester, C. Calmels, M. Andréola, F. Christ, Z. Debyser and P. Cotelle, ACS Med. Chem. Lett., 2013, 4, 606; (f) H. R. Tsou, X. Liu, G. Birnberg, J. Kaplan, M. Otteng, T. Tran, K. Kutterer, Z. Tang, R. Suayan, A. Zask, M. Ravi, A. Bretz, M. Grillo, J. P. McGinnis, S. K. Rabindran, S. Ayral-Kaloustian and T. S. Mansour, J. Med. Chem., 2009, 52, 2289. (a) Y. J. Pan, C. P. Holmes and D. Tumelty, J. Org. Chem., 2005, 70, 4897; (b) J. Vicente, P. González-Herrero, R. Frutos-Pedreñ o, M.-T. Chicote, P. G. Jones and D. Bautista, Organometallics, 2011, 30, 1079; (c) S. Ozcan, C. Dengiz, M. K. Deliö meroglu, E. Sahin and M. Balci, Tetrahedron Lett., 2011, 52, 1495. (a) X.-F. Xia, S.-L. Zhu, J.-B. Liu, D. Wang and Y.-M. Liang, J. Org. Chem., 2016, 81, 12482; (b) Y.-Q. Yuan, P. S. Kumar, C.-N. Zhang, M.-H. Yang and S.-R. Guo, Org. Biomol. Chem., 2017, 15, 7330; (c) M. Zhang, P. Xie, W. Zhao, B. Niu, W. Wu, Z. Bian, C. U. Pittmann Jr. and A. Zhou, J. Org. Chem., 2015, 80, 4176; (d) W. Zhao, P. Xie,M. Zhang, B. Niu, Z. Bian, C. Pittman Jr. and A. Zhou, Org. Biomol. Chem., 2014, 12, 7690; (e) X. Li, S. Zhuang, X. Fang, P. Liu and P. Sun, Org. Biomol. Chem., 2017, 15, 1821; (f) Y. Tang, M. Zhang, X. Li, X. Xu and X. Du, Chin. J. Org. Chem., 2015, 35, 875; (g) S. Tang, Y.-L. Deng, J. Li, W.-X.Wang, Y.-C. Wang, Z.-Z. Li, L. Yuan, S.-L. Chen and R.-L. Sheng, Chem. Commun., 2016, 52, 4470; (h) S.-L. Zhu, P.-X. Zhou and X.-F. Xia, RSC Adv., 2016, 6, 63325; (i) X.-F. Xia, S.-L. Zhu, C. Chen, H. Wang and Y.-M. Liang, J. Org. Chem., 2016, 81, 1277; (j) C. Pan, C. Chen and J.-T. Yu, Org. Biomol. Chem., 2017, 15, 1096; (k) P. Qian, B. Du, W. Jiao, H. Mei, J. Han and Y. Pan, Beilstein J. Org. Chem., 2016, 12, 301; (l) J. Wu, Y. Gao, X. Zhao, L. Zhang, W. Chen, G. Tang and Y. Zhao, RSC Adv., 2016, 6, 303. W. Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem., Int. Ed., 2013, 52, 13086. (a) L. Li, M. Deng, S. C. Zheng, Y. P. Xiong, B. Tan and X. Y. Liu, Org. Lett., 2014, 16, 504; (b) L. Zheng, C. Yang, Z. Xu, F. Gao and W. Xia, J. Org. Chem., 2015, 80, 5730; (c) C. Liu, W. Zhao, Y. Huang, H. Wang, B. Zhang, Tetrahedron, 2015, 71, 4344. (a) S. Tang, Y.-L. Deng, J. Li, W.-X. Wang, G.-L. Ding, M.-W. Wang, Z.-P. Xiao, Y.-C. Wang and R.-L. Sheng, J. Org. Chem., 2015, 80, 12599; (b) X.-F. Xia, S.-L. Zhu, Y. Li and H. Wang, RSC Adv., 2016, 6, 51703; (c) Y.-L. Deng, S. Tang, G.-L. Ding, M.-W. Wang, J. Li, Z.-Z. Li, L. Yuan and R.-L. Sheng, Org. Biomol. Chem., 2016, 14, 9348. (a) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (b) J. A. Erickson and J. I. McLoughlin, J. Org. Chem., 1995, 60, 1626; (c) F. Narjes, K. F. Koehler, U. Koch, B. Gerlach, S.
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Colarusso, C. Steinkü hler, M. Brunetti, S. Altamura, R. De Francesco and V. G. Matassa, Bioorg. Med. Chem. Lett., 2002, 12, 701; (d) C. Ni and J. Hu, Synthesis, 2014, 46, 842. (a) J. Rong, C. Ni and J. Hu, Asian J. Org. Chem., 2017, 6, 139; (b) A. G. O’Brien, A. Maruyama, Y. Inokuma, M. Fujita, P. S. Baran and D. G. Blackmond, Angew. Chem., Int. Ed., 2014, 53, 11868; (c) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214; (d) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 1494; (e) C. S. Thomoson and W. R., Jr. Dolbier, J. Org. Chem., 2013, 78, 8904; (f) P. S. Fier and J. F. Hartwig, Angew. Chem., Int. Ed., 2013, 52, 2092; (g) G. Liu, X. Wang, X.-H. Xu, X. Lu, E. Tokunaga, S. Tsuzuki and N. Shibata, Org. Lett., 2013, 15, 1044; (h) X. Shen, W. Zhang, C. Ni, Y. Gu and J. Hu, J. Am. Chem. Soc., 2012, 134, 16999; (i) V. V. Levin, A. L. Trifonov, A. A. Zemtsov, M. I. Struchkova, D. E. Arkhipov and A. D. Dilman, Org. Lett., 2014, 16, 6256. (a) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood, J. K. Swabeck and G. A. Olah, Angew. Chem., Int. Ed., 2012, 51, 12090; (b) P. S. Fier and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134, 5524; (c) Y. Gu, X.-B. Leng and Q. Shen, Nat. Commun., 2014, 5, 5405; (d) Z. Feng, Q.-Q. Min and X. Zhang, Org. Lett., 2016, 18, 44; (e) H. Serizawa, K. Ishii, K. Aikawa and K. Mikami, Org. Lett., 2016, 18, 3686; (f) X.-L. Jiang, Z.-H. Chen, X.-H. Xu and F.-L. Qing, Org. Chem. Front., 2014, 1, 774. (g) C. Matheis, K. Jouvin and L. J. Goossen, Org. Lett., 2014, 16, 5984. (a) Z. He, P. Tan, C. Ni and J. Hu, Org. Lett., 2015, 17, 1838; (b) C. S. Thomoson, X.-J. Tang and W. R., Jr. Dolbier, J. Org. Chem., 2015, 80, 1264; (c) Z. Zhang, X. Tang, C. S. Thomoson and W. R., Jr. Dolbier, Org. Lett., 2015, 17, 3528; (d) Q.-Y. Lin, Y. Ran, X.-H. Xu and F.-L. Qing, Org. Lett., 2016, 18, 2419; (e) Y. Ran, Q.-Y. Lin, X.-H. Xu and F.-L. Qing, J. Org. Chem., 2016, 81, 7001. (f) Y. Arai, R. Tomita, G. Ando, T. Koike and M. Akita, Chem. -Eur. J., 2016, 22, 1262. (a) X.-J. Tang, C. S. Thomoson and W. R., Jr. Dolbier, Org. Lett., 2014, 16, 4594; (b) Z. Zhang, X.-J. Tang and W. R., Jr. Dolbier, Org. Lett., 2016, 18, 1048; (c) Z. Zhang, X. Tang and W. R., Jr. Dolbier, Org. Lett., 2015, 17, 4401. N. Noto, T. Koike and M. Akita, J. Org. Chem., 2016, 81, 7064. (a) J. Rong, L. Deng, P. Tan, C. Ni, Y. Gu and J. Hu, Angew. Chem., Int. Ed., 2016, 55, 2743; (b) W. Fu, X. Han, M. Zhu, C. Xu, Z. Wang, B. Ji, X.-Q. Hao and M.-P. Song, Chem. Commun., 2016, 52, 13413. CCDC 1572251 (3c) and CCDC 1572250 (3d) see the ESI† for details.
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Received 00th January 20xx, Accepted 00th January 20xx
Visible-light induced di- and trifluoromethylation of Nmethacryloyl benzamides with fluorinated sulfones for the synthesis of CF2H/CF3-containing isoquinolinediones†
DOI: 10.1039/x0xx00000x
Guanglong Zou,*a and Xuelin Wangb
www.rsc.org/
A general visible light induced direct difluoromethylation of N-methacryloyl benzamides by using difluoromethyl sulfone was developed. In addition, photoredox-catalyzed trifluoromethylation of N-methacryloyl benzamides with trifluoromethyl sulfone via a similar radical process was also achieved. This method allows for an efficient and practical synthesis of a variety of CF2H/CF3-containing isoquinoline-1,3(2H,4H)-diones in moderate to good yields. The reaction features mild reaction conditions, operational simplicity, and a broad substrate scope.
Introduction The skeleton of isoquinoline-1,3(2H,4H)-dione widely exists in pharmaceutical and bioactive compounds. Isoquinoline1,3(2H,4H)-dione derivatives possess important biological activities such as antitumor activity, HIV-1 integrase inhibitor activity and selective inhibitor activity of cyclin-dependent kinase.1 Consequently, tremendous effort has been focused on the construction of isoquinoline-1,3(2H,4H)-diones and their derivatives.2 Recently, radical addition/tandem cyclization of methacryloyl benzamides has been demonstrated as a fast, effective, and atom-economic approach toward isoquinoline1,3(2H,4H)-dione synthesis, showing its great synthetic capability with various radical precursors, such as carbon-, sulfur-, phosphorus- and nitrogen-containing radicals (Scheme 1a).3-6 For example, Xia and co-workers demonstrated a copper-catalyzed radical aminocyclization of methacryloyl benzamides with N-fluorobenzenesulfonimide (NFSI) as imine radical precursor under heating conditions.3a Afterward, the reaction of methacryloyl benzamides with thiols using molecular oxygen as the sole oxidant was developed by Guo group.3b Since it is generally accepted that incorporation of fluorinated functionalities into molecules could improve its physical, chemical, and biological properties, some attention has been given to the development of efficient methods for the introduction of fluorinated moieties into isoquinoline1,3(2H,4H)-dione skeleton. In 2013, Nevado et al. reported a tetrabutylammonium iodide-induced trifluoromethylation of
a
School of Chemical Engineering,Guizhou Minzu Univeristy, Huaxi Univeristy Town, Guiyang 550025, China. E-mail: [email protected] b School of Graduate Students, Guizhou Minzu University,Ten-li Strand Campus, Guiyang 550025, China. †Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
methacryloyl benzamide with Togni’s reagent to construct isoquinolinediones.4 Subsequently, Liu and Zhang developed the trifluoromethylation of methacryloyl benzamides with TMSCF3 or CF3SO2Cl under metal-free conditions or using a visible light photocatalyst, respectively.5 Shortly after, Tang and Xia reported a similar radical cyclization of methacryloylbenzamide involving difluorobromoacetate as a reaction partner.6 Although the above-mentioned trifluoromethylation and difluoroacetylation of methacryloylbenzamides have been described, the direct difluoromethylation has, to the best of our knowledge, remained elusive, and continues to attract considerable attention from the synthetic community. The difluoromethyl group (CF2H) is an important functional group used for the design of leading compounds in the field of agrochemical and pharmaceutical owing to its unique electronic properties. It is well-known that the CF2H group is a bioisostere of a hydroxyl or thiol group and can act as lipophilic hydrogen bond donor to increase lipophilicity, metabolic stability as well as bioavailability.7 Therefore, it is important to develop synthetic methods for C-CF2H bond formation.8 In this regard, transition-metal-catalyzed difluoromethylation of aryl halides or boronic acids,9 and intermolecular difunctionalization of alkenes10 using different difluoromethylating reagents have been established. However, examples of the preparation of difluoromethylated heterocycles have rare precedents. For example, Dolbier and co-workers have developed the intramolecular difluoroalkylation reactions of unsaturated bonds to access CF2H-substituted oxindoles, azaspirocycles and phenanthridines using HF2CSO2Cl.11 Koike and Akita have described an intramolecular difluoromethylation of aryl-fused cyclo-alkenylalkanols under conditions of photoredox catalysis.12 Hu and Fu groups have reported the difluoromethylation reactions of isocyanides and olefinic amides with difluoromethyl sulfones as the CF2H radial sources, respectively.13 Inspired by these results, we envisioned bringing together the advantages of both strategies by
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Scheme 1 Radical addition/cyclization of methacryloyl benzamides
Results and discussion We initially chose difluoromethyl sulfones 2a-c as privileged CF2H radical sources. Irradiation of the mixture of Nmethacryloyl-N-methylbenzamide (1a), Na2CO3, and difluoromethyl sulfone 2a in degassed DMSO by 3W blue LED Table 1 Optimization of reaction conditions for 3aa
a Reaction
conditions: 1a (0.20 mmol, 1.0 equiv), 2 (0.30 mmol,View 1.5 Article equiv),Online base (0.30 mmol, 1.5 equiv), and photocatalyst (0.004 mmol, 2.0 mol%) in indicated DOI: 10.1039/C7OB02226C solvent (3.0 mL) was irradiated with a 3 W blue LED for 12 h. b Isolated yield. c Without visible light irradiation.
at rt using 2 mol % of fac-Ir(ppy)3 as photocatalyst, the desired product 3a was obtained in 64% yield after 12 h (Table 1, entry 1). Under the otherwise identical condition, reactions with 2b generated the product in lower reactivity (27%, entry 2). However, no desired product was obtained when 2c was used as the CF2H-transfer reagent (entry 3). With the suitable reagent 2a as the best CF2H-transfer reagent, we continued to optimize other parameters to further improve the yield. A survey of other photocatalysts demonstrated that fac-Ir(ppy)3 is the best choice, which may be attributed to its superior reduction potential in the excited state (entries 4-6). Subsequently, various solvents were evaluated. The yield could be improved by performing the reaction in DMF, while using acetonitrile and acetone led to slightly lower yields (entries7-9). In addition to Na2CO3, we also screened for others inorganic bases, such as Cs2CO3, K2CO3 and K3PO4. However, Na2CO3 gave the best result. Control reactions demonstrated that no desired product 3a was observed when the reaction was carried out in the absence of photocatalyst or light irradiation (entries 13-14). Table 2 Difluoromethylation of methacryloyl benzamides with difluoromethyl sulfone 2a under visible light irradiation
Entry
CF2H Reagent
Catalyst
Base
Solvent
Yieldb (%)
1
2a
fac-Ir(ppy)3
Na2CO3
DMSO
64
2
2b
fac-Ir(ppy)3
Na2CO3
DMSO
27
3
2c
fac-Ir(ppy)3
Na2CO3
DMSO
0
4
2a
Ru(bpy)3Cl2•6H2O
Na2CO3
DMSO
41
5
2a
Ru(bpy)3(PF6)2
Na2CO3
DMSO
43
6
2a
Eosin Y
Na2CO3
DMSO
0
7
2a
fac-Ir(ppy)3
Na2CO3
DMF
76
8
2a
fac-Ir(ppy)3
Na2CO3
CH3CN
55
9
2a
fac-Ir(ppy)3
Na2CO3
acetone
36
10
2a
fac-Ir(ppy)3
Cs2CO3
DMF
65
11
2a
fac-Ir(ppy)3
K2CO3
DMF
71
12
2a
fac-Ir(ppy)3
K3PO4
DMF
58
13
2a
none
Na2CO3
DMF
0
14c
2a
fac-Ir(ppy)3
Na2CO3
DMF
0
Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2a (0.30 mmol, 1.5 equiv), Na2CO3 (0.30 mmol, 1.5 equiv) and fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) in DMF (3.0 mL) was irradiated with a 3 W blue LED for 12 h.
With the optimized reaction conditions established, various substrates were subjected to the reaction and representative results are summarized in Table 2. The reaction of difluoromethyl sulfone 2a with various N-methacryloyl-Nmethylbenzamides afforded the desired CF2H-containing
2 | J. Name., 2012, 00, 1-3
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combining methacryloyl benzamides with CF2H radicals. Herein, we reported our study on the direct difluoromethylation of methacryloyl benzamides to produce difluoromethylated isoquinoline-1,3(2H,4H)-diones via visible-light photocatalysis. In addition, the present photocatalytic system could also be applicable to the synthesis of attractive trifluoromethylated isoquinoline-1,3(2H,4H)-diones (Scheme 1b).
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isoquinoline-1, 3(2H,4H)-diones 3b−3k in moderate to good yields. The reaction was not sensitive to the electronic nature of substituents on the benzamide moiety. Methyl and methoxyl substituents as well as halogen atoms such as F, Cl and Br on the para-position of the aryl ring can be welltolerated in this system (3b–3f). Furthermore, strong electronwithdrawing groups such as CF3 afforded 3g in slightly lower yield. When the sterically demanding ortho-substituted methacryloyl methylbenzamide was subject to the reaction, lower yield of the product 3h was obtained. In addition, the reaction of meta-substituted 2i with difluoromethyl sulfone 2a proceeded smoothly and readily converted to a mixture of two regioisomers in approximately 6:1 ratio (3i and 3i'). Subsequently, the N-substituents of methacryloyl methylbenzamides were investigated, and no obvious influence on the results was observed upon changing the Me group on N atom to n-butyl or i-butyl (3j-3k). However, no desired product was found in the case of unprotected methacryloyl benzamide (3l). The structures of products 3c and 3d were further confirmed by X-ray crystallographic analysis (Figure 1).14
Fig. 1 X-ray crystal structure of 3c and 3d (from left to right).
Table 3 Trifluoromethylation of methacryloyl benzamides with trifluoromethyl sulfone 4 under visible light irradiation
Encouraged by the successful application of thisView strategy in Article Online DOI: 10.1039/C7OB02226C preparing difluoromethylated isoquinoline-1,3(2H,4H)-diones, we proposed that trifluoromethylated isoquinolinediones could be synthesized by using trifluoromethyl sulfone 4 as trifluoromethyl radical sources through this protocol. We found that a wide range of N-methacryloyl-Nmethylbenzamides with both electron-donating and withdrawing groups gave moderate to good yields of the desired CF3-containing isoquinoline-1,3(2H,4H)-diones 5a−5g, which indicates that there was not obvious electronic effect on the substrate (Table 3). The methacryloyl benzamides having butyl or isobutyl as protecting groups were also compatible in this reaction, and the desired products 5h, 5i were isolated in 71% and 68% yield, respectively. No desired product was observed by the addition of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 1.5 equiv) into the system, which indicates that a free radical process would be involved. Based on the preliminary results discussed above and precedent literatures,3,13 a mechanistic pathway for the [fac-Ir(ppy)3]-catalyzed cyclization process could thus be proposed (Scheme 2). Initially, the excited [facIr(III)(ppy)3*] is formed under the light irradiation. Then, the interaction of fluorinated sulfone 2a or 4 with the excited state [fac-Ir(III)(ppy)3*] triggers the generation of the fluoromethyl radical (·CF2X) A and the strong oxidant [fac-Ir(IV)(ppy)3]. Next, the reaction of fluoromethyl radical (·CF2X) A with methacryloyl benzamides 1 generates radical intermediate B, which undergoes intramolecular cyclization on the aromatic ring, generating intermediate C. The intermediate C is then oxidized by [fac-Ir(IV)(ppy)3]+ to form the cyclohexadienylcation D with the concurrent regeneration of [fac-Ir(III)(ppy)3]. Finally, deprotonation assisted by base leads to the formation of the desired product 3 or 5.
Scheme 2 Plausible reaction mechanism.
Conclusions Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 4 (0.30 mmol, 1.5 equiv), Na2CO3 (0.30 mmol, 1.5 equiv), and fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) in DMF (3.0 mL) was irradiated with a 3 W blue LED for 12 h.
Early work in the field of radical trifluoromethylation of methacryloyl benzamides employed Togni’s reagent, TMSCF3 or CF3SO2Cl as trifluoromethylating reagents,4-5 but remains associated with certain disadvantages such as high reaction temperatures and use of environmentally unfriendly reagents.
In conclusion, we have developed an efficient and mild photocatalytic radical di- or trifluoromethylation/cyclization cascade of methacryloyl benzamides with difluoromethyl or trifluoromethyl sulfones using visible light. A series of potentially biological CF2H or CF3-containing isoquinoline1,3(2H,4H)-diones could be conveniently and efficiently obtained in moderate to good yields with excellent functional group tolerance. The easy and efficient method for the
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synthesis of isoquinolinediones should attract much attention in synthetic and pharmaceutical chemistry. Further investigations on direct difluoromethylation or trifluoromethylation of alkenes for the synthesis of other heterocycles with privileged structures are underway in our laboratory.
Experimental section
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General All the reactions were conducted using standard Schlenk tube techniques. Solvents were purified or dried in a standard manner. Photo-irradiation was carried out with a 3 W blue LEDs. Column chromatography was performed on silica gel (200−300 mesh). 1H NMR spectra, 13C NMR spectra, and 19F{1H} NMR spectra were measured in CDCl3 and recorded on 500 MHz NMR spectrometers with TMS as an internal standard. Chemical shifts (δ) are reported in ppm downfield from tetramethylsilane. Abbreviations for signal couplings are: s, singlet; d, doublet; t, triplet; m, multiplet. HRMS analyses was recorded on Q-TOF Global mass spectrometer. Methacryloyl benzamides 1,3 difluoromethyl sulfones 2a-c13 and 2((trifluoromethyl)sulfonyl)benzo[d]thiazole 413 were prepared according to the reported literature. General procedure for the synthesis of di- or trifluoromethylated isoquinoline-1, 3(2H,4H)-diones 3a-k a or 5a-i. Methacryloyl benzamides 1 (0.20 mmol), fluorinated sulfones 2a or 4 (0.30 mmol), fac-Ir(ppy)3 (0.004 mmol, 2.0 mol%) and Na2CO3 (0.30 mmol) were dissolved in DMF (3.0 mL). Then, the resulting mixture was degassed via ‘freezepump-thaw’ procedure (3 times). After that, the solution was stirred at room temperature under 3 W blue LED irradiation for 12 h. Then the reaction mixture was diluted by adding EtOAc and brine. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 15:1 as the eluant) on silica gel to give the desired isoquinoline-1, 3 (2H, 4H)-diones 3a-k or 5a-i.
Characterization data for the products 3a-k and 5a-i 4-(2,2-Difluoroethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)dione (3a). White solid (38.5 mg, 76% yield). 1H NMR (500 MHz, CDCl3): δ 8.29 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 8.0 Hz, J2 = 1.5 Hz), 7.51-7.46 (m, 2 H), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.0 Hz), 3.40 (s, 3 H), 3.05-2.95 (m, 1 H), 2.56-2.45 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.20, 163.78, 141.33, 134.15, 129.37, 128.01, 125.28, 124.40, 115.05 (t, J = 238.9 Hz), 45.03 (t, J = 21.6 Hz), 43.72 (dd, J1 = 7.0 Hz, J2 = 3.0 Hz), 30.57, 27.35. 19F NMR (470 MHz, CDCl3): δ -115.14 (d, J = 291.4 Hz, 1 F), -116.40 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H14F2NO2: 254.0992, found: 254.0985.
4-(2,2-Difluoroethyl)-2,4,6-trimethylisoquinoline-1,3(2H,4H)View Article Online 1H NMR (500 10.1039/C7OB02226C dione (3b). White solid (42.2 mg, 79%DOI: yield). MHz, CDCl3): δ 8.17 (d, 1 H, J = 8.0 Hz), 7.29 (d, 1 H, J = 8.5 Hz), 7.23 (s, 1 H), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.00-2.96 (m, 1 H), 2.53-2.45 (m, 1 H), 2.48 (s, 3 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.34, 163.79, 145.13, 141.35, 129.39, 129.11, 125.60, 121.93, 115.11 (t, J = 238.8 Hz), 45.08 (t, J = 21.6 Hz), 43.66 (dd, J1 = 7.3 Hz, J2 = 2.8 Hz), 30.51, 27.25, 21.94. 19F NMR (470 MHz, CDCl3): δ -115.09 (d, J = 290.9 Hz, 1 F), -116.48 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1150. 4-(2,2-Difluoroethyl)-6-methoxy-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3c). White solid (42.5 mg, 75% yield). 1H NMR (500 MHz, CDCl3): δ 8.24 (d, 1 H, J = 8.5 Hz), 7.01 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 6.89 (d, 1 H, J = 2.5 Hz), 5.43 (tdd, 1 H, J1 = 56.0 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.92 (s, 3 H), 3.38 (s, 3 H), 3.00-2.96 (m, 1 H), 2.50-2.40 (m, 1 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 175.27, 164.24, 163.43, 143.52, 131.76, 117.36, 115.06 (t, J = 238.8 Hz), 113.49, 110.76, 55.64, 45.16 (t, J = 21.8 Hz), 43.91 (dd, J1 = 7.1 Hz, J2 = 2.8 Hz), 30.57, 27.20. 19F NMR (470 MHz, CDCl3): δ -115.01 (d, J = 290.9 Hz, 1 F), -116.27 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO3: 284.1098, found: 284.1094. 4-(2,2-Difluoroethyl)-6-fluoro-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3d). White solid (36.9 mg, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.31 (dd, 1 H, J1 = 7.5 Hz, J2 = 5.5 Hz), 7.21-7.13 (m, 2 H), 5.46 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.38 (s, 3 H), 3.05-2.95 (m, 1 H), 2.51-2.40 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.73, 166.31 (d, J = 254.9 Hz), 162.85, 144.45 (d, J = 8.5 Hz), 132.47 (d, J = 9.8 Hz), 120.85 (d, J = 2.5 Hz), 116.00 (d, J = 21.9 Hz), 114.79 (t, J = 239.0 Hz), 112.34 (d, J = 23.0 Hz), 44.98 (t, J = 21.5 Hz), 43.95 (t, J = 4.1 Hz), 30.57, 27.38. 19F NMR (470 MHz, CDCl3): δ 102.71 (s, 1 F), -115.14 (d, J = 291.9 Hz, 1 F), -115.89 (d, J = 291.4 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13F3NO2: 272.0898, found: 272.0896. 6-Chloro-4-(2,2-difluoroethyl)-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3e). White solid (44.2 mg, 77% yield). 1H NMR (500 MHz, CDCl3): δ 8.23 (d, 1 H, J = 8.5 Hz), 7.48-7.44 (m, 2 H), 5.46 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.05-2.95 (m, 1 H), 2.53-2.42 (m, 1 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.58, 162.95, 143.15, 140.74, 130.97, 128.65, 125.58, 122.88, 114.80 (t, J = 239.1 Hz), 44.92 (t, J = 21.6 Hz), 43.77 (dd, J1 = 5.9 Hz, J2 = 4.0 Hz), 30.50, 27.43. 19F NMR (470 MHz, CDCl ): δ -115.12 (d, J = 291.9 Hz, 1 F), 3 115.94 (d, J = 291.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13ClF2NO2: 288.0603, found: 288.0597. 6-Bromo-4-(2,2-difluoroethyl)-2,4-dimethylisoquinoline1,3(2H,4H)-dione (3f). White solid (49.1 mg, 74% yield). 1H NMR (500 MHz, CDCl3): δ 8.16 (d, 1 H, J = 8.5 Hz), 7.64 (dd, 1 H, J1 = 8.5 Hz, J2 = 2.0 Hz), 7.61 (d, 1 H, J = 2.0 Hz), 5.47 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.40 (s, 3 H), 3.06-2.96 (m, 1 H), 2.53-2.43 (m, 1 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.51, 163.10, 143.21, 131.61, 131.00, 129.40, 128.55, 123.32, 114.77 (t, J = 239.3 Hz), 44.97 (t, J = 21.5 Hz), 43.73 (dd, J1 = 5.9 Hz, J2 = 3.6 Hz), 30.55, 27.47. 19F NMR (470 MHz, CDCl3): δ -115.14 (d, J = 291.9 Hz, 1 F), -115.97 (d, J =
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291.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C13H13BrF2NO2: 332.0097, found: 332.0090. 4-(2,2-Difluoroethyl)-2,4-dimethyl-6-(trifluoromethyl) isoquinoline-1,3(2H,4H)-dione (3g). White solid (40.5 mg, 63% yield). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, 1 H, J = 8.5 Hz), 7.76 (d, 1 H, J = 8.0 Hz), 7.71 (s, 1 H), 5.48 (tdd, 1 H, J1 = 55.5 Hz, J2 = 6.0 Hz, J3 = 3.5 Hz), 3.43 (s, 3 H), 3.11-3.01 (m, 1 H), 2.61-2.50 (m, 1 H), 1.72 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.45, 162.68, 142.32, 135.63 (q, J = 32.8 Hz), 130.28, 127.25, 124.78 (q, J = 3.5 Hz), 123.24 (q, J = 271.5 Hz), 122.50 (q, J = 3.8 Hz), 114.68 (t, J = 239.3 Hz), 44.87 (t, J = 21.4 Hz), 43.86 (t, J = 4.6 Hz), 30.59, 27.57. 19F NMR (470 MHz, CDCl3): δ -63.16 (s, 3 F), -115.35 (s, 1 F), -115.36 (s, 1 F). HRMS (ESI): calcd for [M+H]+ C14H13F5NO2: 322.0866, found: 322.0858. 4-(2,2-Difluoroethyl)-2,4,8-trimethylisoquinoline-1,3(2H,4H)dione (3h). Oil (27.8 mg, 52% yield). 1H NMR (500 MHz, CDCl3): δ 7.54 (t, 1 H, J = 7.8 Hz), 7.35 (d, 1 H, J = 8.0 Hz), 7.30 (d, 1 H, J = 7.5 Hz), 5.42 (tdd, 1 H, J1 = 55.5 Hz, J2 = 7.0 Hz, J3 = 3.5 Hz), 3.39 (s, 3 H), 3.05-2.95 (m, 1 H), 2.82 (s, 3 H), 2.54-2.43 (m, 1 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.89, 164.31, 143.16. 142.64, 132.90, 132.00, 123.52, 122.80, 115.17 (t, J = 238.6 Hz), 45.37 (t, J = 21.6 Hz), 43.78 (dd, J1 = 7.1 Hz, J2 = 3.0 Hz), 30.91, 27.35, 24.04. 19F NMR (470 MHz, CDCl3): δ -115.0 (d, J = 291.4 Hz, 1 F), -116.39 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1153. 4-(2,2-Difluoroethyl)-2,4,7-trimethylisoquinoline-1,3(2H,4H)dione (3i) and 4-(2,2-difluoroethyl)-2,4,5trimethylisoquinoline-1,3(2H,4H)-dione (3i’) (6:1). Oil (32.6 mg, 61% yield). 1H NMR (500 MHz, CDCl3): δ 8.28 (dd, 0.14 H, J1 = 7.5 Hz, J2 = 1.3 Hz), 8.10 (d, 0.83 H, J = 1.0 Hz), 7.50 (dd, 0.88 H, J1 = 8.0 Hz, J2 = 1.5 Hz), 7.47 (d, 0.11 H, J = 0.5 Hz), 7.41 (t, 0.13 H, J = 8.0 Hz), 7.35 (d, 0.87 H, J = 8.0 Hz), 5.50-5.26 (m, 1 H), 3.42 (s, 0.39 H), 3.40 (s, 2.57 H), 3.03-2.93 (m, 1 H), 2.63 (s, 0.35 H), 2.53-2.42 (m, 1 H), 2.46 (s, 2.55 H), 1.77 (s, 0.36 H), 1.65 (s, 2.67 H). 13C NMR (125 MHz, CDCl3): δ 176.34, 175.39, 164.04, 163.96, 138.69, 138.48, 138.40, 138.04, 135.24, 135.16, 129.44, 128.42, 127.97, 125.58, 125.19, 124.20, 115.44 (t, J = 238.0 Hz), 115.12 (t, J = 238.8 Hz), 45.26 (t, J = 21.5 Hz), 43.47 (dd, J1 = 7.1 Hz, J2 = 2.9 Hz), 41.78 (t, J = 21.5 Hz), 30.90, 30.57, 27.65, 27.35, 22.73, 20.95. 19F NMR (470 MHz, CDCl3): δ -115.20 (d, J = 291.4 Hz), -115.50 (d, J = 290.5 Hz), -116.50 (d, J = 290.9 Hz), -117.30 (d, J = 290.5 Hz). HRMS (ESI): calcd for [M+H]+ C14H16F2NO2: 268.1149, found: 268.1144. 2-Butyl-4-(2,2-difluoroethyl)-4-methylisoquinoline1,3(2H,4H)-dione (3j). White solid (46.1 mg, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 7.5 Hz, J2 = 1.5 Hz), 7.50 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.46 (d, 1 H, J = 8.0 Hz), 5.39 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.5 Hz), 4.06-3.97 (m, 2 H), 3.05-2.97 (m, 1 H), 2.55-2.45 (m, 1 H), 1.67 (s, 3 H), 1.64-1.58 (m, 2 H), 1.43-1.36 (m, 2 H), 0.96 (t, 3 H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.86, 163.48, 141.37, 134.04, 129.43, 127.97, 125.22, 124.56, 115.11 (t, J = 238.9 Hz), 44.89 (t, J = 21.6 Hz), 43.67 (dd, J1 = 6.9 Hz, J2 = 3.3 Hz), 40.54, 30.78, 29.73, 20.24, 13.78. 19F NMR (470 MHz, CDCl ): δ -115.09 (d, J = 291.4 Hz, 1 F), 3 116.07 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C16H20F2NO2: 296.1462, found: 296.1462.
4-(2,2-Difluoroethyl)-2-isobutyl-4-methylisoquinolineView Article Online DOI:mg, 10.1039/C7OB02226C 1,3(2H,4H)-dione (3k). White solid (43.7 74% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.52-7.46 (m, 2 H), 5.44 (tdd, 1 H, J1 = 56.0 Hz, J2 = 6.5 Hz, J3 = 3.5 Hz), 3.94-3.85 (m, 2 H), 3.07-3.01 (m, 1 H), 2.57-2.47 (m, 1 H), 2.18-2.11 (m, 1 H), 1.67 (s, 3 H), 0.95 (d, 3 H, J = 6.5 Hz), 0.92 (d, 3 H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl ): δ 175.22, 163.83, 141.43, 134.03, 3 129.59, 127.95, 125.19, 124.48, 115.13 (t, J = 238.9 Hz), 47.45, 44.51 (t, J = 21.6 Hz), 43.83 (dd, J1 = 6.5 Hz, J2 = 3.4 Hz), 31.25, 27.17, 20.22, 20.12. 19F NMR (470 MHz, CDCl3): δ -115.08 (d, J = 290.9 Hz, 1 F), -116.01 (d, J = 290.9 Hz, 1 F). HRMS (ESI): calcd for [M+H]+ C16H20F2NO2: 296.1462, found: 296.1458. 2,4,6-Trimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5a).5a White solid (42.8 mg, 75% yield). 1H NMR (500 MHz, CDCl3): δ 8.19 (d, 1 H, J = 9.0 Hz), 7.31 (d, 1 H, J = 9.5 Hz), 7.21 (s, 1 H), 3.42 (s, 3 H), 3.38-3.31 (m, 1 H), 2.852.77 (m, 1 H), 2.48 (s, 3 H), 1.67 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.70, 163.76, 144.71, 140.41, 129.31, 129.15, 125.98, 124.98 (q, J = 277.1 Hz), 121.78, 44.37 (q, J = 27.4 Hz), 43.50 (d, J = 2.1 Hz), 31.18, 27.31, 21.91. 19F NMR (470 MHz, CDCl3): δ -61.65 (s, 3 F). 6-Methoxy-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5b).5a White solid (41.5 mg, 69% yield). 1H NMR (500 MHz, CDCl3): δ 8.25 (d, 1 H, J = 8.5 Hz), 7.01 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 6.87 (d, 1 H, J = 2.5 Hz), 3.92 (s, 3 H), 3.40 (s, 3 H), 3.41-3.31 (m, 1 H), 2.82-2.74 (m, 1 H), 1.66 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.62, 163.98, 163.37, 142.58, 131.66, 124.97 (q, J = 277.1 Hz), 117.25, 113.62, 111.13, 55.61, 44.41 (q, J = 27.4 Hz), 43.75 (d, J = 2.0 Hz), 31.25, 27.24. 19F NMR (470 MHz, CDCl3): δ -61.61 (s, 3 F). 6-Fluoro-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5c).5b White solid (42.2 mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.34 (dd, 1 H, J1 = 8.5 Hz, J2 = 6.0 Hz), 7.24-7.20 (m, 1 H), 7.12 (dd, 1 H, J1 = 9.0 Hz, J2 = 2.5 Hz), 3.42 (s, 3 H), 3.44-3.35 (m, 1 H), 2.80-2.71 (m, 1 H), 2.20 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.03, 166.14 (d, J = 254.6 Hz), 162.76, 143.38 (d, J = 8.5 Hz), 132.42 (d, J = 9.6 Hz), 124.81 (q, J = 277.1 Hz), 128.74 (d, J = 2.4 Hz), 116.14 (d, J = 21.9 Hz), 112.60 (d, J = 23.3 Hz), 44.49 (q, J = 27.6 Hz), 43.76, 30.98 (d, J = 18.1 Hz), 27.44. 19F NMR (470 MHz, CDCl3): δ -61.72 (s, 3 F), 103.12 (s, 1 F). 6-Chloro-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5d).5a White solid (37.8 mg, 62% yield). 1H NMR (500 MHz, CDCl3): δ 8.25 (d, 1 H, J = 8.5 Hz), 7.49 (dd, 1 H, J1 = 8.5 Hz, J2 = 2.0 Hz), 7.42 (d, 1 H, J = 1.5 Hz), 3.42 (s, 3 H), 3.41-3.34 (m, 1 H), 2.82-2.74 (m, 1 H), 1.69 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 173.90, 162.89, 142.07, 140.52, 130.93, 128.78, 125.89, 124.81 (q, J = 276.8 Hz), 122.78, 44.43 (q, J = 27.5 Hz), 43.57 (q, J = 2.1 Hz), 31.00, 27.50. 19F NMR (470 MHz, CDCl3): δ -61.68 (s, 3 F). 6-Bromo-2,4-dimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5e). White solid (51.0 mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.17 (d, 1 H, J = 8.5 Hz), 7.65 (dd, 1 H, J1 = 7.5 Hz, J2 = 3.5 Hz), 7.59 (d, 1 H, J = 1.5 Hz), 3.42 (s, 3 H), 3.42-3.35 (m, 1 H), 2.83-2.74 (m, 1 H), 1.69 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 173.83, 163.02, 142.12, 131.70, 130.91,
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129.08, 128.88, 124.81 (q, J = 277.0 Hz), 123.20, 44.42 (q, J = 27.5 Hz), 43.52 (q, J = 2.3 Hz), 31.00, 27.51. 19F NMR (470 MHz, CDCl3): δ -61.67 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C13H12BrF3NO2: 350.0003, found: 349.9995. 2,4-Dimethyl-4-(2,2,2-trifluoroethyl)-6(trifluoromethyl)isoquinoline-1,3(2H,4H)-dione (5f). White solid (37.3 mg, 55% yield). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, 1 H, J = 8.5 Hz), 7.76 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.69 (s, 1 H), 3.44 (s, 3 H), 3.47-3.37 (m, 1 H), 2.90-2.81 (m, 1 H), 1.72 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.74, 162.56, 141.15, 135.42 (q, J = 32.8 Hz), 130.21, 127.15, 124.87 (q, J = 3.5 Hz), 124.77 (q, J = 277.0 Hz), 123.23 (q, J = 271.5 Hz), 122.86 (d, J = 3.5 Hz), 44.33 (q, J = 27.6 Hz), 43.68 (d, J = 2.1 Hz), 30.95, 27.59. 19F NMR (470 MHz, CDCl3): δ -61.73 (s, 3 F), -63.27 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C14H12F6NO2: 340.0772, found: 340.0776. 2,4,8-Trimethyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5g). Oil (28.5 mg, 50% yield). 1H NMR (500 MHz, CDCl3): δ 7.52 (t, 1 H, J = 8.0 Hz), 7.33-7.29 (m, 2 H), 3.423.33 (m, 1 H), 3.40 (s, 3 H), 2.85-2.77 (m, 1 H), 2.82 (s, 3 H), 1.68 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ 174.26, 164.24, 143.04. 141.70, 132.57, 132.06, 125.04 (q, J = 277.1 Hz), 123.95, 122.57, 44.66 (q, J = 27.3 Hz), 43.60 (q, J = 2.1 Hz), 31.63, 27.39, 24.10. 19F NMR (470 MHz, CDCl3): δ -61.51 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C14H15F3NO2: 286.1055, found: 286.1059. 2-Butyl-4-methyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5h).5c White solid (44.5 mg, 71% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.68 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.50 (t, 1 H, J = 8.0 Hz), 7.44 (d, 1 H, J = 8.0 Hz), 4.08-3.98 (m, 2 H), 3.43-3.40 (m, 1 H), 2.87-2.78 (m, 1 H), 1.67 (s, 3 H), 1.63-1.58 (m, 2 H), 1.44-1.37 (m, 2 H), 0.97 (t, 3 H, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.22, 163.43, 140.41, 133.68, 129.33, 128.00, 125.63, 125.03 (q, J = 277.0 Hz), 124.36, 44.18 (q, J = 27.3 Hz), 43.54 (d, J = 2.0 Hz), 40.62, 31.39, 29.61, 20.21, 13.76. 19F NMR (470 MHz, CDCl3): δ -61.39 (s, 3 F). 2-Isobutyl-4-methyl-4-(2,2,2-trifluoroethyl)isoquinoline1,3(2H,4H)-dione (5i). White solid (42.6 mg, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.31 (dd, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.68 (td, 1 H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.52-7.49 (m, 1 H), 7.44 (d, 1 H, J = 8.0 Hz), 3.96-3.86 (m, 2 H), 3.47-3.37 (m, 1 H), 2.892.80 (m, 1 H), 2.19-2.10 (m, 1 H), 1.67 (s, 3 H), 0.95 (dd, 6 H, J1 = 21.0 Hz, J2 = 6.5 Hz). 13C NMR (125 MHz, CDCl3): δ 174.57, 163.79, 140.41, 133.67, 129.50, 128.01, 125.61, 125.03 (q, J = 277.1 Hz), 124.30, 47.57, 43.85 (q, J = 7.4 Hz), 43.72, 31.85, 27.14, 20.22, 20.08. 19F NMR (470 MHz, CDCl3): δ -61.17 (s, 3 F). HRMS (ESI): calcd for [M+H]+ C16H19F3NO2: 314.1368, found: 314.1365.
We are grateful to the Natural Science FoundationView of Article China for Online DOI: 10.1039/C7OB02226C financial support to this work (No.21363004) and the support from China Scholarship Council Program.
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Conflicts of interest There are no conflicts to declare
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7.
(a) H. Tsou, M. Otteng, T. Tran, M. B. Floyd, M. J. Reich, G. Birnberg, K. Kutterer, S. A. Kaloustian, M. Ravi, R. Nilakantan, M. Grillo, J. P. McGinnis and S. K. Rabindran, J. Med. Chem., 2008, 51, 3507; (b) Y.-L. Chen, J. Tang, M. J. Kesler, Y. Y. Sham, R. Vince, R. J. Geraghty and Z. Wang, Bioorg. Med. Chem., 2012, 20, 467; (c) M. Billamboz, F. Bailly, C. Lion, N. Touati, H. Vezin, C. Calmels, M. L. Andréola, F. Christ, Z. Debyser and P. Cotelle, J. Med. Chem., 2011, 54, 1812; (d) S. K. V. Vernekar, Z. Liu, E. Nagy, L. Miller, K. A. Kirby, D. J. Wilson, J. Kankanala, S. T. Sarafianos, M. A. Parniak and Z. Wang, J. Med. Chem., 2015, 58, 651; (e) M. Billamboz, V. Suchaud, F. Bailly, C. Lion, J. Demeulemeester, C. Calmels, M. Andréola, F. Christ, Z. Debyser and P. Cotelle, ACS Med. Chem. Lett., 2013, 4, 606; (f) H. R. Tsou, X. Liu, G. Birnberg, J. Kaplan, M. Otteng, T. Tran, K. Kutterer, Z. Tang, R. Suayan, A. Zask, M. Ravi, A. Bretz, M. Grillo, J. P. McGinnis, S. K. Rabindran, S. Ayral-Kaloustian and T. S. Mansour, J. Med. Chem., 2009, 52, 2289. (a) Y. J. Pan, C. P. Holmes and D. Tumelty, J. Org. Chem., 2005, 70, 4897; (b) J. Vicente, P. González-Herrero, R. Frutos-Pedreñ o, M.-T. Chicote, P. G. Jones and D. Bautista, Organometallics, 2011, 30, 1079; (c) S. Ozcan, C. Dengiz, M. K. Deliö meroglu, E. Sahin and M. Balci, Tetrahedron Lett., 2011, 52, 1495. (a) X.-F. Xia, S.-L. Zhu, J.-B. Liu, D. Wang and Y.-M. Liang, J. Org. Chem., 2016, 81, 12482; (b) Y.-Q. Yuan, P. S. Kumar, C.-N. Zhang, M.-H. Yang and S.-R. Guo, Org. Biomol. Chem., 2017, 15, 7330; (c) M. Zhang, P. Xie, W. Zhao, B. Niu, W. Wu, Z. Bian, C. U. Pittmann Jr. and A. Zhou, J. Org. Chem., 2015, 80, 4176; (d) W. Zhao, P. Xie,M. Zhang, B. Niu, Z. Bian, C. Pittman Jr. and A. Zhou, Org. Biomol. Chem., 2014, 12, 7690; (e) X. Li, S. Zhuang, X. Fang, P. Liu and P. Sun, Org. Biomol. Chem., 2017, 15, 1821; (f) Y. Tang, M. Zhang, X. Li, X. Xu and X. Du, Chin. J. Org. Chem., 2015, 35, 875; (g) S. Tang, Y.-L. Deng, J. Li, W.-X.Wang, Y.-C. Wang, Z.-Z. Li, L. Yuan, S.-L. Chen and R.-L. Sheng, Chem. Commun., 2016, 52, 4470; (h) S.-L. Zhu, P.-X. Zhou and X.-F. Xia, RSC Adv., 2016, 6, 63325; (i) X.-F. Xia, S.-L. Zhu, C. Chen, H. Wang and Y.-M. Liang, J. Org. Chem., 2016, 81, 1277; (j) C. Pan, C. Chen and J.-T. Yu, Org. Biomol. Chem., 2017, 15, 1096; (k) P. Qian, B. Du, W. Jiao, H. Mei, J. Han and Y. Pan, Beilstein J. Org. Chem., 2016, 12, 301; (l) J. Wu, Y. Gao, X. Zhao, L. Zhang, W. Chen, G. Tang and Y. Zhao, RSC Adv., 2016, 6, 303. W. Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem., Int. Ed., 2013, 52, 13086. (a) L. Li, M. Deng, S. C. Zheng, Y. P. Xiong, B. Tan and X. Y. Liu, Org. Lett., 2014, 16, 504; (b) L. Zheng, C. Yang, Z. Xu, F. Gao and W. Xia, J. Org. Chem., 2015, 80, 5730; (c) C. Liu, W. Zhao, Y. Huang, H. Wang, B. Zhang, Tetrahedron, 2015, 71, 4344. (a) S. Tang, Y.-L. Deng, J. Li, W.-X. Wang, G.-L. Ding, M.-W. Wang, Z.-P. Xiao, Y.-C. Wang and R.-L. Sheng, J. Org. Chem., 2015, 80, 12599; (b) X.-F. Xia, S.-L. Zhu, Y. Li and H. Wang, RSC Adv., 2016, 6, 51703; (c) Y.-L. Deng, S. Tang, G.-L. Ding, M.-W. Wang, J. Li, Z.-Z. Li, L. Yuan and R.-L. Sheng, Org. Biomol. Chem., 2016, 14, 9348. (a) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (b) J. A. Erickson and J. I. McLoughlin, J. Org. Chem., 1995, 60, 1626; (c) F. Narjes, K. F. Koehler, U. Koch, B. Gerlach, S.
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Colarusso, C. Steinkü hler, M. Brunetti, S. Altamura, R. De Francesco and V. G. Matassa, Bioorg. Med. Chem. Lett., 2002, 12, 701; (d) C. Ni and J. Hu, Synthesis, 2014, 46, 842. (a) J. Rong, C. Ni and J. Hu, Asian J. Org. Chem., 2017, 6, 139; (b) A. G. O’Brien, A. Maruyama, Y. Inokuma, M. Fujita, P. S. Baran and D. G. Blackmond, Angew. Chem., Int. Ed., 2014, 53, 11868; (c) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214; (d) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 1494; (e) C. S. Thomoson and W. R., Jr. Dolbier, J. Org. Chem., 2013, 78, 8904; (f) P. S. Fier and J. F. Hartwig, Angew. Chem., Int. Ed., 2013, 52, 2092; (g) G. Liu, X. Wang, X.-H. Xu, X. Lu, E. Tokunaga, S. Tsuzuki and N. Shibata, Org. Lett., 2013, 15, 1044; (h) X. Shen, W. Zhang, C. Ni, Y. Gu and J. Hu, J. Am. Chem. Soc., 2012, 134, 16999; (i) V. V. Levin, A. L. Trifonov, A. A. Zemtsov, M. I. Struchkova, D. E. Arkhipov and A. D. Dilman, Org. Lett., 2014, 16, 6256. (a) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood, J. K. Swabeck and G. A. Olah, Angew. Chem., Int. Ed., 2012, 51, 12090; (b) P. S. Fier and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134, 5524; (c) Y. Gu, X.-B. Leng and Q. Shen, Nat. Commun., 2014, 5, 5405; (d) Z. Feng, Q.-Q. Min and X. Zhang, Org. Lett., 2016, 18, 44; (e) H. Serizawa, K. Ishii, K. Aikawa and K. Mikami, Org. Lett., 2016, 18, 3686; (f) X.-L. Jiang, Z.-H. Chen, X.-H. Xu and F.-L. Qing, Org. Chem. Front., 2014, 1, 774. (g) C. Matheis, K. Jouvin and L. J. Goossen, Org. Lett., 2014, 16, 5984. (a) Z. He, P. Tan, C. Ni and J. Hu, Org. Lett., 2015, 17, 1838; (b) C. S. Thomoson, X.-J. Tang and W. R., Jr. Dolbier, J. Org. Chem., 2015, 80, 1264; (c) Z. Zhang, X. Tang, C. S. Thomoson and W. R., Jr. Dolbier, Org. Lett., 2015, 17, 3528; (d) Q.-Y. Lin, Y. Ran, X.-H. Xu and F.-L. Qing, Org. Lett., 2016, 18, 2419; (e) Y. Ran, Q.-Y. Lin, X.-H. Xu and F.-L. Qing, J. Org. Chem., 2016, 81, 7001. (f) Y. Arai, R. Tomita, G. Ando, T. Koike and M. Akita, Chem. -Eur. J., 2016, 22, 1262. (a) X.-J. Tang, C. S. Thomoson and W. R., Jr. Dolbier, Org. Lett., 2014, 16, 4594; (b) Z. Zhang, X.-J. Tang and W. R., Jr. Dolbier, Org. Lett., 2016, 18, 1048; (c) Z. Zhang, X. Tang and W. R., Jr. Dolbier, Org. Lett., 2015, 17, 4401. N. Noto, T. Koike and M. Akita, J. Org. Chem., 2016, 81, 7064. (a) J. Rong, L. Deng, P. Tan, C. Ni, Y. Gu and J. Hu, Angew. Chem., Int. Ed., 2016, 55, 2743; (b) W. Fu, X. Han, M. Zhu, C. Xu, Z. Wang, B. Ji, X.-Q. Hao and M.-P. Song, Chem. Commun., 2016, 52, 13413. CCDC 1572251 (3c) and CCDC 1572250 (3d) see the ESI† for details.
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