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An efficient one-pot three-component process for the synthesis of highly substituted perfluoroalkylated cyclopentadienes
Tetrahedron 69 (2013) 4205e4210
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An efficient one-pot three-component process for the synthesis of highly substituted perfluoroalkylated cyclopentadienes You Lv a, Xufeng Yan a, Lijun Yan a, Zewei Wang a, Jie Chen a, Hongmei Deng d, Min Shao d, Hui Zhang a, *, Weiguo Cao a, b, c, * a
Department of Chemistry, Shanghai University, Shanghai 200444, PR China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China d Instrumental Analysis and Research Center of Shanghai University, Shanghai 200444, PR China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2013 Received in revised form 18 March 2013 Accepted 25 March 2013 Available online 28 March 2013
A series of highly substituted perfluoroalkylated cyclopentadiene derivatives were efficiently synthesized in moderate to excellent yields by isocyanides, methyl 2-perfluoroalkynoates and electrophilic alkenes via a one-pot three-component reaction under mild condition. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Isocyanide Methyl 2-perfluoroalkynoate Electrophilic alkene Highly substituted perfluoroalkylated cyclopentadiene
1. Introduction In recent years, the development of new methods that provide synthetic efficiency and atom economy has been an important goal of synthetic chemistry.1 Multicomponent reactions (MCRs), by virtue of their convergence, productivity, facile execution and generally high yields of products, are good candidates for this target as they embody ideal synthesis.2 Among the MCRs, those with isocyanides (IMCRs) have attracted enormous attention from organic chemists,3 and thus isocyanides have proved themselves to be irreplaceable building blocks in modern organic chemistry. From an organic view of point, methods starting from isocyanides often have distinct advantages including enhanced convergence, inherent atom economy and the great variety of readily available isocyanides for use. Cyclopentadienes are useful not only as a reactive diene component in the DielseAlder reaction4 but also as a precursor for the preparation of transition-metal complexes with Cp-type ligands.5 However, though the introduction of substituents into the cyclopentadienyl (Cp) backbone is well-known to dramatically affect the reactivity of transition metals containing these ligands,6 the preparation of well-defined, highly substituted cyclopentadienes is not
* Corresponding authors. Fax: þ86 21 66134856; e-mail addresses: wgcao@ staff.shu.edu.cn, [email protected] (W. Cao). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.03.093
necessarily easy owing to the absence of general methods7 and also to the facile migration of the endocyclic double bonds.8 Furthermore, due to the strong electronegativity, the small size and low polarizability of fluorine atom, perfluoroalkyl (RF) moieties exhibit properties of great interest (chemical and thermal stability, low surface energy, self organization ability) for a wide variety of applications.9 Therefore, there has been considerable interest in developing an efficient method for the synthesis of highly substituted perfluoroalkylated cyclopentadiene derivatives.10 Zwitterionic species derived from isocyanides and DMAD can be efficiently trapped by dipolarophiles, such as aryl aldehydes, N-tosylimines and activated alkenes, leading to a facile synthesis of furan, pyrrole derivatives and highly substituted cyclopentadienes, respectively.11 Against this background, we envisaged that the zwitterions derived from isocyanides and methyl 2-perfluoroalkynoates might undergo cycloaddition to activated alkenes, thus constituting a synthesis of highly substituted perfluoroalkylated cyclopentadienes. Our preliminary results validating this idea are presented in this paper.
2. Results and discussion Highly substituted perfluoroalkylated cyclopentadienes 4 were obtained via a one-pot three-component reaction (MCR) by using
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On the basis of the previous reports,5 the proposed mechanism is shown in Scheme 2. First, isocyanide 1 attacks methyl 2-perfluoroalkynoate 2 nucleophilically to generate the zwitterion
isocyanides 1, methyl 2-perfluoroalkynoates 2 and electrophilic alkenes 3 (Scheme 1). The structures of products were confirmed by IR, 1H NMR, 13C NMR, 19F NMR, MS and HRMS as well.
R1 N C
RF
CO2 Me 2
1
H
CN
DCM
Ar
CN
r.t.
1b: R1 = cyclohexyl; 2b: RF = C2F5;
Ar
R1 HN NC
3 1a: R1 = t-butyl; 2a: RF = CF3;
CO2Me
RF
CN 4
2c: RF = n-C3F 7;
Scheme 1. Preparation of highly substituted perfluoroalkylated cyclopentadienes 4.
Initially, we carried out the reaction of tert-butyl isocyanide 1a (1.2 equiv), methyl 4,4,4-trifluorobut-2-ynoate 2a (1.2 equiv) and 2-benzylidenemalononitrile 3a (1.0 mmol) in dry DCM (5 mL) at room temperature for 8 h and the desired product 4a was obtained in excellent yield (90%). Further screening of the reaction conditions was carried out and the results were summarized in Table 1. The role of the solvent in this reaction was studied by performing the same reaction in other various solvents, such as tetrahydrofuran (THF), chloroform, ethanol and toluene. It is worth mentioning that dichloromethane (DCM) is the most suitable solvent for the synthesis (Table 1, entries 1 vs 2e5). A lower yield was obtained when the reaction was performed at 40 or 0 C (Table 1, entries 1 vs 6 or 7). Table 1 Optimization of the reaction conditions Entry
Solvent
Temp ( C)
4a Yielda (%)
1 2 3 4 5 6 7
DCM THF CHCl3 EtOH Toluene DCM DCM
rt rt rt rt rt 0 40
90 73 82 0 57 83 72
Table 2 Preparation of highly substituted perfluoroalkylated cyclopentadienes 4a Entry
1
2
Ar
Time (h)
Product
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1a 1a 1a 1a 1a 1a
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2c 2c
Ph 4-CH3C6H4 4-MeOC6H4 2-NO2C6H4 2-ClC6H4 2-BrC6H4 1-Naphthalene 2-CH3C6H4 3-CH3C6H4 2-CH3C6H4 2-ClC6H4 2-BrC6H4 2-NO2C6H4 2-CH3C6H4 2-ClC6H4 2-BrC6H4 2-NO2C6H4 2-CH3C6H4 2-ClC6H4
8 13 24 7 10 12 24 15 13 15 6 6 6 15 8 8 8 18 7
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s
90 75 61 86 95 93 50 70 73 86 92 96 95 69 96 90 95 63 87
a Reaction conditions: isocyanide 1 (1.2 equiv), methyl 2-perfluoroalkynoate 2 (1.2 equiv), electrophilic alkene 3 (1.0 mmol), dry DCM (5 mL), room temperature. b Isolated yield.
Bold signifies the best result under different reaction conditions. a Isolated yield.
After optimization of the reaction conditions, a variety of electrophilic alkenes 3 containing electron donating or electron withdrawing groups in the aromatic ring were reacted with various 2-perfluoroalkynoates 2 and isocyanides 1. In all cases, the corresponding perfluoroalkylated cyclopentadiene derivatives were obtained in good to excellent yields under similar reaction conditions, which are summarized in Table 2. From these successful results, we concluded that alkenes 3 with electron withdrawing groups on the Ar ring had a shorter reaction time as compared to those with electron donating groups and provided a better yield (Table 2, entries 2, 3 vs 4e6). Only 50% yield of product was obtained when 2-(naphthalen-2-ylmethylene)malononitrile was used (Table 2, entry 7). This might be due to its steric hindrance in the reaction process. However, interestingly, it was found that 3 with an ortho substituent on benzene ring gave good yields of products (Table 2, entries 4e6 and 8). Both tert-butyl isocyanide and cyclohexyl isocyanide are suitable partners in this reaction. The variability of the reaction with respect to the alkyne was also tested. C2F5- or n-C3F7 substituted 2-perfluoroalkynoates also worked well. The structure of the final product was further confirmed by X-ray diffraction analysis of 4c (Fig. 1).12 From the crystal structure, it is clear that C2 of methyl 2-perfluoroalkynoate is attached to C1 of isocyanide and C3 of methyl 2-perfluoroalkynoate is attached to C4 of alkene. The dihedral angle of benzene ring and plane C5C1C2C3 is 87.8 . The dihedral angle of plane C5C1C2C3 and plane C3C4C5 is 20.9 , which shows that the cyclopentadiene ring has an envelope conformation.
Fig. 1. X-ray diffraction of compound 4c.
A. Subsequent nucleophilic addition of A to alkene 3 occurs, affording imine B as the pivotal intermediate, which then undergoes cyclization to deliver the adduct C. The latter isomerizes to give the final product 4 via a [1,5]-H shift. 3. Conclusion We have developed a novel and efficient route for the preparation of highly substituted perfluoroalkylated cyclopentadienes
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Scheme 2. Mechanism for the formation of product 4.
via a three-component reaction of isocyanide, methyl 2-perfluoroalkynoate and activated alkene. The generality of this threecomponent reaction has been demonstrated. A possible reaction mechanism is proposed. Further synthetic applications of highly substituted perfluoroalkylated cyclopentadienes are in progress in our laboratory.
4.2.5. 2-(2-Chlorobenzylidene)malononitrile 3e.14d Pale red solid; yield: 89%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.44e7.47 (m, 1H), 7.55e7.56 (m, 2H), 8.18e8.19 (m, 1H), 8.27 (s, 1H). 4.2.6. 2-(2-Bromobenzylidene)malononitrile (3f).14e Pale yellow solid; yield: 84%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.44e7.51 (m, 2H), 7.74e7.75 (m, 1H), 8.11e8.13 (m, 1H), 8.22 (s, 1H).
4. Experimental 4.1. General information All reagents were purchased from commercial sources and used without further purification, except that methyl 2perfluoroalkynoates 213 and electrophilic alkenes 314 were prepared according to the known literature. Melting points were recorded on a WRS-1 instrument and uncorrected. 1H, 19F and 13C NMR spectra were recorded on a Bruker DRX-500 MHz spectrometer. All chemical shifts are reported in parts per million downfield (positive) of the standard: C6F6 for 19F, TMS for 1H and 13C NMR spectra. IR spectra were obtained on an AVATAR370 FT-IR spectrometer. LRMS (lower resolution mass spectra) and HRMS (high resolution mass spectra) were obtained on LCMS 2020 and Bruker Daltonics APEXIII 7.0 TESALA FTMS instrument, respectively. X-ray analysis was performed on a Bruker Smart Apex2 CCD spectrometer. All yields reported in this publication referred to isolated ones of compounds and their purity was determined by 1H NMR. 4.2. General procedure for preparation of compound 3 Malononitrile (10.0 mmol) was added to a stirred solution of benzaldehyde (10.0 mmol) and piperidine (1.0 mmol) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 5 h. A precipitate was formed and collected by suction filtration, washed with n-hexane/ethanol (v/v¼10:1), and then dried under high vacuum. 4.2.1. 2-Benzylidenemalononitrile 3a.14b Pale yellow solid; yield: 82%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.53e7.56 (m, 2H), 7.62e7.65 (m, 1H), 7.78 (s, 1H), 7.90e7.92 (m, 2H). 4.2.2. 2-(4-Methylbenzylidene)malononitrile 3b.14b White solid; yield: 64%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.46 (s, 3H), 7.34 (d, J¼8.5 Hz, 2H), 7.72 (s, 1H), 7.81 (d, J¼8.5 Hz, 2H). 4.2.3. 2-(4-Methoxybenzylidene)malononitrile 3c.14b Pale yellow solid; yield: 71%. 1H NMR (CDCl3, 500 MHz, ppm): d 3.91 (s, 3H), 7.01 (d, J¼9.0 Hz, 2H), 7.65 (s, 1H), 7.91 (d, J¼9.0 Hz, 2H). solid; 4.2.4. 2-(2-Nitrobenzylidene)malononitrile 3d.14c Brown yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.79e7.83 (m, 2H), 7.87e7.90 (m, 1H), 8.35e8.37 (m, 1H), 8.45 (s, 1H).
4.2.7. 2-(Naphthalen-1-ylmethylene)malononitrile 3g.14f Yellow solid; yield: 75%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.60e7.71 (m, 3H), 7.95e7.97 (m, 2H), 8.11e8.12 (m, 1H), 8.27e8.29 (m, 1H), 8.66 (s, 1H). 4.2.8. 2-(2-Methylbenzylidene)malononitrile (3h).14g White solid; yield: 68%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.45 (s, 3H), 7.32e7.37 (m, 2H), 7.48e7.51 (m, 1H), 8.08e8.09 (m, 1H), 8.10 (s, 1H). 4.2.9. 2-(3-Methylbenzylidene)malononitrile 3i.14h White solid; yield: 72%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.43 (s, 3H), 7.41e7.45 (m, 2H), 7.69 (s, 1H), 7.72e7.74 (m, 2H). 4.3. General procedure for preparation of compound 4 To a solution of methyl 2-perfluoroalkynoate 2 (1.2 mmol) and electrophilic alkene 3 (1.0 mmol) in dry DCM (5 mL) was added isocyanide 1 (1.2 mmol) and the mixture was stirred at room temperature. After the completion of the reaction (monitored by TLC), the solvent was removed in vacuo to give the crude product, which was purified by silica gel chromatography. 4.3.1. Methyl 4-(tert-butylamino)-3,3-dicyano-2-phenyl-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4a. White solid; mp: 133.3e134.5 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.57 (s, 9H), 3.72 (s, 3H), 5.06 (br s, 1H), 7.29e7.31 (m, 2H), 7.46e7.48 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.2, 60.2, 60.4, 111.3, 113.5, 119.3 (q, 1JCeF¼272.0 Hz, CF3), 128.8, 129.4, 130.4, 131.2, 132.9 (q, 2JCeF¼32.8 Hz, CCF3), 141.6, 148.7, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2977, 2258, 1740, 1661, 1360, 1293, 1270, 1183, 1164, 1148, 1044, 705. MS (EI) m/z (%): 388 [(MH)]þ. HRMS (ESI) calcd for C20H18F3N3O2 [(MH)]þ: 388.1278, found: 388.1275. 4.3.2. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(p-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4b. White solid; mp: 121.0e123.1 C; yield: 75%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 2.38 (s, 3H), 3.72 (s, 3H), 5.02 (br s, 1H), 7.17 (d, J¼7.5 Hz, 2H), 7.25 (d, J¼7.5 Hz, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 21.2, 30.2, 53.2, 60.1, 60.4, 111.5, 113.6, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 128.1, 128.7, 130.2, 132.8 (q, 2JCeF¼32.8 Hz, CCF3), 140.6, 141.7, 148.9, 162.8. 19 F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2986, 2959, 2247, 1738, 1658, 1359, 1292, 1186, 1155, 1088, 828. MS
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(EI) m/z (%): 402 [(MH)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MH)]þ: 402.1435, found: 402.1422.
[(MþNa)]þ. HRMS (ESI) calcd for C24H20F3N3O2 [(MþNa)]þ: 462.1400, found: 462.1410.
4.3.3. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(4-methoxyphenyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4c. White solid; mp: 111.9e113.1 C; yield: 61%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.72 (s, 3H), 3.83 (s, 3H), 5.01 (br s, 1H), 6.96 (d, J¼8.7 Hz, 2H), 7.21 (d, J¼8.7 Hz, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.3, 55.3, 60.0, 60.5, 111.5, 113.6, 114.9, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 122.8, 130.2, 132.7 (q, 2JCeF¼32.8 Hz, CCF3), 141.7, 148.9, 161.1, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2976, 2960, 2250, 1739, 1661, 1515, 1360, 1293, 1184, 1157, 1029, 840. MS (ESI) m/z (%): 418 [(MH)]þ. HRMS (ESI) calcd for C21H20F3N3O3 [(MH)]þ: 418.1384, found: 418.1373.
4.3.8. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(o-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4h. White solid; mp: 154.1e155.3 C; yield: 70%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 2.52 (s, 3H), 3.72 (s, 3H), 5.38 (br s, 1H), 7.06e7.08 (m, 1H), 7.25e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 19.9, 30.2, 53.2, 56.2, 60.6, 111.4, 113.8, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 126.9, 127.8, 130.2, 130.3, 131.5, 133.1 (q, 2JCeF¼32.8 Hz, CCF3), 137.4, 141.6, 149.3, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2975, 2248, 1738, 1671, 1363, 1294, 1192, 1152, 1082, 756. MS (ESI) m/z (%): 426 [(MþNa)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MþNa)]þ: 426.1400, found: 426.1405.
4.3.4. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(2-nitrophenyl)-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4d. White solid; mp: 177.7e178.1 C; yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.57 (s, 9H), 3.75 (s, 3H), 5.66 (br s, 1H), 7.34e7.36 (m, 1H), 7.67e7.71 (m, 1H), 7.75e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.6, 55.5, 61.0, 111.8, 112.9, 119.2 (q, 1 JCeF¼272.0 Hz, CF3), 126.4, 127.6, 129.8, 131.7, 134.4, 135.1 (q, 2 JCeF¼32.8 Hz, CCF3), 140.9, 147.4, 148.6, 162.4. 19F NMR (CDCl3, 470 MHz, ppm): d 62.5 (s, CF3). IR (KBr, cm1): n 2979, 2253, 1743, 1668, 1527, 1365, 1352, 1283, 1190, 1143, 1033, 762. MS (ESI) m/z (%): 433 [(MH)]þ. HRMS (ESI) calcd for C20H17F3N4O4 [(MH)]þ: 433.1129, found: 433.1114.
4.3.9. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(m-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4i. White solid; mp: 106.5e108.0 C; yield: 73%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.58 (s, 9H), 2.40 (s, 3H), 3.72 (s, 3H), 5.03 (br s, 1H), 7.07e7.11 (m, 2H), 7.27e7.36 (m, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 21.4, 30.3, 53.3, 60.4, 60.6, 111.5, 113.7, 119.5 (q, 1JCeF¼272.0 Hz, CF3), 125.7, 129.4, 129.7, 131.2, 131.3, 133.0 (q, 2JCeF¼32.8 Hz, CCF3), 139.5, 141.7, 148.9, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2978, 2250, 1739, 1663, 1361, 1293, 1189, 1157, 1043, 760, 713. MS (ESI) m/z (%): 426 [(MþNa)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MþNa)]þ: 426.1400, found: 462.1408.
4.3.5. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4e. White solid; mp: 169.8e170.4 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.76 (s, 3H), 5.70 (br s, 1H), 7.19e7.21 (m, 1H), 7.34e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.5, 56.4, 60.9, 111.3, 113.3, 119.3 (q, 1JCeF¼272.2 Hz, CF3), 127.7, 129.3, 130.3, 130.6, 131.7, 134.1 (q, 2JCeF¼32.8 Hz, CCF3), 135.4, 141.2, 148.3, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2976, 2250, 1740, 1672, 1364, 1293, 1191, 1157, 1145, 1085, 768. MS (ESI) m/z (%): 422 [(MH)]þ. HRMS (ESI) calcd for C20H17ClF3N3O2 [(MH)]þ: 422.0889, found: 422.0879. 4.3.6. Methyl 2-(2-bromophenyl)-4-(tert-butylamino)-3,3-dicyano-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4f. White solid; mp: 178.4e179.3 C; yield: 93%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.76 (s, 3H), 5.72 (br s, 1H), 7.17e7.19 (m, 1H), 7.31e7.42 (m, 2H), 7.73e7.74 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 58.7, 60.7, 111.2, 113.1, 119.3 (q, 1JCeF¼272.2 Hz, CF3), 126.0, 128.2, 129.4, 131.7, 132.0, 133.8, 133.9 (q, 2JCeF¼32.8 Hz, CCF3), 141.2, 148.3, 162.5. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2969, 2250, 1739, 1672, 1363, 1293, 1192, 1156, 1144, 1084, 761, 594. MS (ESI) m/z (%): 466 [(MH)]þ. HRMS (ESI) calcd for C20H17BrF3N3O2 [(MH)]þ: 466.0384, found: 466.0385. 4.3.7. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(naphthalen-1-yl)5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4g. White solid; mp: 120.1e121.5 C; yield: 50%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.70 (s, 3H), 5.98 (br s, 1H), 7.37e7.38 (m, 1H), 7.51e7.54 (m, 1H), 7.61e7.64 (m, 1H), 7.71e7.74 (m, 1H), 7.95e7.97 (m, 1H), 8.12e8.14 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.4, 55.4, 60.8, 111.3, 114.0, 119.4 (q, 1JCeF¼272.2 Hz, CF3), 122.0, 125.1, 126.8, 127.0, 128.1, 128.2, 129.5, 131.1, 131.6, 133.6 (q, 2 JCeF¼32.8 Hz, CCF3), 134.1, 141.5, 149.3, 163.0. 19F NMR (CDCl3, 470 MHz, ppm): d 62.5 (s, CF3). IR (KBr, cm1): n 2980, 2249, 1732, 1666, 1359, 1290, 1192, 1152, 1086, 779. MS (ESI) m/z (%): 462
4.3.10. Methyl 3,3-dicyano-4-(cyclohexylamino)-2-(o-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4j. White solid; mp: 122.7e123.9 C; yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.34e1.86 (m, 10H), 2.53 (s, 3H), 3.73 (s, 3H), 4.02e4.06 (m, 1H), 5.33 (br s, 1H), 7.07e7.08 (m, 1H), 7.26e7.34 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 19.9, 23.4, 25.3, 31.9, 32.2, 37.3, 53.3, 54.9, 64.1, 109.6, 112.4, 119.2 (q, 1JCeF¼272.2 Hz, CF3), 126.9, 127.9, 130.2, 130.3, 131.5, 131.6 (q, 2JCeF¼32.8 Hz, CCF3), 137.2, 148.4, 151.0, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2934, 2251, 1736, 1664, 1375, 1294, 1201, 1160, 1076, 740. MS (ESI) m/z (%): 452 [(MþNa)]þ. HRMS (ESI) calcd for C23H22F3N3O2 [(MþNa)]þ: 452.1556, found: 452.1557. 4.3.11. Methyl 2-(2-chlorophenyl)-3,3-dicyano-4-(cyclohexylamino)5-(trifluoromethyl)cyclopenta-1,4-diene carboxylate 4k. White solid; mp: 132.3e133.5 C; yield: 92%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.33e1.86 (m, 10H), 3.78 (s, 3H), 4.03e4.06 (m, 1H), 5.62 (br s, 1H), 7.20e7.21 (m, 1H), 7.34e7.44 (m, 2H), 7.56e7.58 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.4, 32.0, 32.2, 37.2, 53.6, 55.0, 64.3, 109.5, 111.9, 119.3 (q, 1JCeF¼272.5 Hz, CF3), 127.8, 129.3, 130.4, 130.6, 131.7, 132.6 (q, 2JCeF¼34.4 Hz, CCF3), 135.2, 148.2, 149.9, 162.4. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2939, 2251, 1742, 1657, 1294, 1199, 1163, 1078, 757. MS (ESI) m/z (%): 472 [(MþNa)]þ. HRMS (ESI) calcd for C22H19ClF3N3O2 [(MþNa)]þ: 472.1010, found: 472.1024. 4.3.12. Methyl 2-(2-bromophenyl)-3,3-dicyano-4-(cyclohexylamino)5-(trifluoromethyl)cyclopenta-1,4-diene carboxylate 4l. White solid; mp: 139.3e140.5 C; yield: 96%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.36e1.86 (m, 10H), 3.77 (s, 3H), 4.03e4.07 (m, 1H), 5.64 (br s, 1H), 7.18e7.20 (m, 1H), 7.31e7.35 (m, 1H), 7.39e7.42 (m, 1H), 7.73e7.75 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.4, 32.0, 32.2, 37.2, 53.6, 57.4, 64.3, 109.5, 111.9, 119.3 (q, 1JCeF¼272.5 Hz, CF3), 125.9, 128.4, 129.5, 131.9, 132.2, 132.6 (q, 2JCeF¼34.4 Hz, CCF3), 133.9, 148.2, 150.1, 162.3. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2938, 2252, 1741, 1656, 1294, 1198, 1162, 1078, 736,
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605. MS (ESI) m/z (%): 516 [(MþNa)]þ. HRMS (ESI) calcd for C22H19BrF3N3O2 [(MþNa)]þ: 516.0505, found: 516.0515.
1174, 1130, 1054, 761. MS (ESI) m/z (%): 507 [(MþNa)]þ. HRMS (ESI) calcd for C21H17F5N4O4 [(MþNa)]þ: 507.1062, found: 507.1054.
4.3.13. Methyl 3,3-dicyano-4-(cyclohexylamino)-2-(2-nitrophenyl)5-(trifluoromethyl)cyclopenta-1,4-dienecar boxylate 4m. Pale yellow solid; mp: 158.5e159.7 C; yield: 95%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.34e1.91 (m, 10H), 3.75 (s, 3H), 4.08e4.11 (m, 1H), 5.56 (s, 1H), 7.35e7.37 (m, 1H), 7.68e7.71 (m, 1H), 7.76e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.3, 31.9, 32.1, 38.5, 53.7, 54.2, 64.3, 110.0, 111.6, 119.2 (q, 1JCeF¼272.5 Hz, CF3), 126.3, 127.5, 130.1, 131.7, 133.5 (q, 2JCeF¼34.4 Hz, CCF3), 134.5, 148.0, 148.6, 149.1, 162.1. 19F NMR (CDCl3, 470 MHz, ppm): d 62.0 (s, CF3). IR (KBr, cm1): n 2937, 2252, 1736, 1660, 1532, 1354, 1288, 1203, 1150, 1072, 724. MS (ESI) m/z (%): 483 [(MþNa)]þ. HRMS (ESI) calcd for C22H19F3N4O4 [(MþH)]þ: 461.1431, found: 461.1436.
4.3.18. Methyl 4-(tert-butylamino)-3,3-dicyano-5-(heptafluoro-propyl)-2-(o-tolyl)cyclopenta-1,4-dienecarboxylate 4r. White solid; mp: 122.3e123.7 C; yield: 63%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 2.52 (s, 3H), 3.70 (s, 3H), 5.40 (br s, 1H), 7.03e7.04 (m, 1H), 7.28e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 20.0, 30.1, 53.2, 56.6, 60.8, 108.9 (m, CF2), 111.4, 113.2 (m, CF2), 113.9, 117.8 (qt, 1 JCeF¼287.8 Hz, 2JCeF¼34.0 Hz, CF3), 127.0, 127.9, 130.3, 130.4, 131.6, 132.8 (t, 2JCeF¼23.2 Hz, CCF2), 137.5, 141.9, 152.6, 163.0. 19F NMR (CDCl3, 470 MHz, ppm): d 80.7 (t, J¼9.4 Hz, CF3), 108.0 (m, CF2), 122.7 (m, CF2). IR (KBr, cm1): n 2983, 2254, 1750, 1363, 1253, 1208, 1187, 1124, 1016, 751. MS (ESI) m/z (%): 526 [(MþNa)]þ. HRMS (ESI) calcd for C23H20F7N3O2 [(MþNa)]þ: 526.1336, found: 526.1355.
4.3.14. Methyl 4-(tert-butylamino)-3,3-dicyano-5-(pentafluoroethyl)2-(o-tolyl)cyclopenta-1,4-dienecarboxylate 4n. White solid; mp: 120.5e121.3 C; yield: 64%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 2.52 (s, 3H), 3.70 (s, 3H), 5.39 (br s, 1H), 7.01e7.03 (m, 1H), 7.26e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 20.0, 30.2, 53.3, 56.5, 60.8, 111.0 (m, CF2), 111.4, 113.9, 118.5 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.3 Hz, CF3), 127.0, 127.9, 130.3, 130.4, 131.6, 132.5 (t, 2JCeF¼23.0 Hz, CCF2), 137.5, 141.7, 152.5, 163.1. 19F NMR (CDCl3, 470 MHz, ppm): d 81.2 (s, CF3), 111.0 (m, CF2). IR (KBr, cm1): n 2983, 2251, 1750, 1657, 1256, 1221, 1174, 1129, 1055, 754. MS (ESI) m/z (%): 476 [(MþNa)]þ. HRMS (ESI) calcd for C22H20F5N3O2 [(MþNa)]þ: 476.1368, found: 476.1385. 4.3.15. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano-5(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4o. White solid; mp: 137.2e137.9 C; yield: 96%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 3.75 (s, 3H), 5.70 (br s, 1H), 7.14e7.15 (m, 1H), 7.35e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 56.6, 60.9, 111.0 (m, CF2), 111.3, 113.3, 118.4 (qt, 1JCeF¼288.0 Hz, 2 JCeF¼36.2 Hz, CF3), 127.8, 129.3, 130.3, 130.5, 131.7, 133.4 (t, 2JCeF¼23.0 Hz, CCF2), 135.4, 141.4, 151.5, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 81.2 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2983, 2253, 1748, 1657, 1257, 1221, 1175, 1046, 751. MS (ESI) m/z (%): 496 [(MþNa)]þ. HRMS (ESI) calcd for C21H17ClF5N3O2 [(MþNa)]þ: 496.0822, found: 496.0825. 4.3.16. Methyl 2-(2-bromophenyl)-4-(tert-butylamino)-3,3-dicyano5-(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4p. White solid; mp: 148.5e149.7 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 3.74 (s, 3H), 5.72 (br s, 1H), 7.11e7.13 (m, 1H), 7.31e7.34 (m, 1H), 7.39e7.43 (m, 1H), 7.73e7.74 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.5, 59.1, 61.0, 111.0 (m, CF2), 111.3, 113.3, 118.4 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.4 Hz, CF3), 126.1, 128.4, 129.4, 131.9, 132.1, 133.3 (t, 2JCeF¼23.0 Hz, CCF2), 133.9, 141.3, 151.6, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 81.1 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2985, 2251, 1739, 1658, 1274, 1205, 1173, 1128, 1050, 766, 598. MS (ESI) m/z (%): 540 [(MþNa)]þ. HRMS (ESI) calcd for C21H17BrF5N3O2 [(MþNa)]þ: 540.0317, found: 540.0339. 4.3.17. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(2-nitrophenyl)-5(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4q. White solid; mp: 154.1e155.3 C; yield: 95%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.55 (s, 9H), 3.74 (s, 3H), 5.66 (br s, 1H), 7.28e7.30 (m, 1H), 7.67e7.71 (m, 1H), 7.76e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.6, 55.8, 61.1, 110.9 (m, CF2), 111.9, 112.9, 118.4 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.1 Hz, CF3), 126.4, 127.6, 129.8, 131.8, 134.4 (t, 2JCeF¼23.0 Hz, CCF2), 134.6, 141.1, 148.7, 150.6, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 80.9 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2985, 2253, 1739, 1657, 1533, 1348, 1272, 1207,
4.3.19. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano5-(heptafluoropropyl)cyclopenta-1,4-dienecarboxylate 4s. White solid; mp: 143.0e143.8 C; yield: 92%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.74 (s, 3H), 5.75 (br s, 1H), 7.18e7.19 (m, 1H), 7.35e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 56.6, 60.9, 108.8 (m, CF2), 111.3, 113.1 (m, CF2), 113.3, 117.6 (qt, 1JCeF¼287.5 Hz, 2JCeF¼34.1 Hz, CF3), 127.8, 129.3, 130.3, 130.6, 131.7, 133.7 (t, 2JCeF¼23.1 Hz, CCF2), 135.4, 141.5, 151.5, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 80.7 (t, J¼9.4 Hz, CF3), 108.1 (m, CF2), 122.8 (m, CF2). IR (KBr, cm1): n 2983, 2254, 1748, 1356, 1255, 1233, 1208, 1189, 1122, 1016, 755. MS (ESI) m/z (%): 546 [(MþNa)]þ. HRMS (ESI) calcd for C22H17ClF7N3O2 [(MþNa)]þ: 546.0790, found: 546.0797. Acknowledgements The authors are grateful to the National Natural Science Foundation of China (Grant No. 21072126, 21272152) and Leading Academic Discipline Projects of Shanghai Municipal Education Commission (Grant No. J50102) for their financial support. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.03.093. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Trost, B. M. Science 1991, 254, 1471. 2. (a) Isonitrile Chemistry; Ugi, I., Ed.; Academic: New York, NY, 1971; (b) Ugi, I.; € DOmling, A.; Horl, W. Endeavour 1994, 18, 115; (c) Multicomponent Reactions; , H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; (d) Zhu, J., Bienayme € DOmling, A. Chem. Rev. 2006, 106, 17; (e) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439; (f) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300; (g) Isambert, N.; Lavilla, R. Chem.dEur. J. 2008, 14, 8444; (h) Ganem, B. Acc. Chem. Res. 2009, 42, 463. 3. For recent examples on isocyanide chemistry, see: (a) Kim, J.; Schneekloth, J. S.; Sorensen, E. J. Chem. Sci. 2012, 3, 2849; (b) Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520; (c) Khoury, K.; Sinha, M. K.; Nagashima, € T.; Herdtweck, E.; DOmling, A. Angew. Chem., Int. Ed. 2012, 51, 10280; (d) € Huang, Y. J.; Khoury, K.; Chanas, T.; DOmling, A. Org. Lett. 2012, 14, 5916; (e) Spisa, F. L.; Feo, A.; Mossetti, R.; Tron, G. C. Org. Lett. 2012, 14, 6044; (f) Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012, 14, 6218; (g) Moliner, F. D.; Hulme, C. Org. Lett. 2012, 14, 1354; (h) Masui, H.; Fuse, S.; Takahashi, T. Org. Lett. 2012, 14, 4090; (i) Sha, F.; Wu, L. L.; Huang, X. J. Org. rez-Labrada, K.; Brouard, I.; Me ndez, I.; Rivera, D. G. Chem. 2012, 77, 3754; (j) Pe J. Org. Chem. 2012, 77, 4660; (k) Terzidis, M. A.; Zarganes-Tzitzikas, T.; Tsimenidis, C.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A.; Kostakis, G. E. J. Org. Chem. 2012, 77, 9018; (l) Sun, H. P.; Zhou, H. Y.; Khorev, O.; Jiang, R. W.; Yu, T.; Wang, X.; Du, Y. L.; Ma, Y.; Meng, T.; Shen, J. K. J. Org. Chem. 2012, 77, 10745; (m) Qiu, G.; Liu, G.; Pu, S. Z.; Wu, J. Chem. Commun. 2012, 2903; (n) Li, J.; Liu, Y. J.; Li, C. J.; Jie, H. H.; Jia, X. S. Green Chem. 2012, 14, 1314; (o) Khan, A. T.; Basha, R. S.; Lal, M.; Mir, M. H. RSC Adv. 2012, 2, 5506; (p) Li, J.; Wang, N.; Li, C. J.; Jia, X. S. Chem.dEur. J. 2012, 18, 9645.
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10. (a) Chambers, R. D.; Mullins, S. J.; Roche, A. J.; Vaughan, J. F. S. J. Chem. Soc., Chem. Commun. 1995, 841; (b) Laganis, E. D.; Lemal, D. M. J. Am. Chem. Soc. 1980, 102, 6633; (c) Burk, M. J.; Arduengo, A. J., III; Calabrese, J. C.; Harlow, R. L. J. Am. Chem. Soc. 1989, 111, 8938. 11. (a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019; (b) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427; (c) Nair, V.; Vinod, A. U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma, L. R.; Viji, S.; Mathew, S.; Srinivas, R. Tetrahedron 2003, 59, 10279; (d) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar, V.; Bindu, S. Org. Lett. 2004, 6, 767. 12. CCDC 890131 (4c) contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/consts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: þ44 1223 336 033; or [email protected]. Unit cell parameters (4c): a: 20.349(14) A; b: 9. 195(7) A; c: 23.382(16) A; a: 90 ; b: 90 ; g: 90 ; space group: Pbca. , M. 13. (a) Hamper, B. C. Org. Synth. 1992, 70, 246; (b) Jeannin, O.; Fourmigue Chem.dEur. J. 2006, 12, 2994. 14. (a) Guo, K.; Thompson, M. J.; Chen, B. J. Org. Chem. 2009, 74, 6999; (b) Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. Chem.dEur. J. 2012, 18, 2423; (c) Wang, X. S.; Zeng, Z. S.; Li, Y. L.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M. Synth. Commun. 2005, 35, 1915; (d) Shi, D. Q.; Wang, X. S.; Yao, C. S.; Mu, L. L. J. Chem. Res., Synop. 2002, 344; (e) Song, Y. Y.; Jing, H. W.; Li, B.; Bai, D. S. Chem.dEur. J. 2011, 17, 8731; (f) Yang, X. H.; Fox, T.; Berke, H. Org. Biomol. Chem. 2012, 10, 852; (g) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Tsadjout, A. Synth. Commun. 2002, 32, 355; (h) € € A.; KUnzel, € Mantri, M.; Graaf, O. D.; Veldhoven, J. V.; GObly Os, J. K. V. F. D.; Mulder-Krieger, T.; Link, R.; Vries, H. D.; Beukers, M. W.; Brussee, J.; IJzerman, A. P. J. Med. Chem. 2008, 51, 4449.
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An efficient one-pot three-component process for the synthesis of highly substituted perfluoroalkylated cyclopentadienes You Lv a, Xufeng Yan a, Lijun Yan a, Zewei Wang a, Jie Chen a, Hongmei Deng d, Min Shao d, Hui Zhang a, *, Weiguo Cao a, b, c, * a
Department of Chemistry, Shanghai University, Shanghai 200444, PR China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China d Instrumental Analysis and Research Center of Shanghai University, Shanghai 200444, PR China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2013 Received in revised form 18 March 2013 Accepted 25 March 2013 Available online 28 March 2013
A series of highly substituted perfluoroalkylated cyclopentadiene derivatives were efficiently synthesized in moderate to excellent yields by isocyanides, methyl 2-perfluoroalkynoates and electrophilic alkenes via a one-pot three-component reaction under mild condition. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Isocyanide Methyl 2-perfluoroalkynoate Electrophilic alkene Highly substituted perfluoroalkylated cyclopentadiene
1. Introduction In recent years, the development of new methods that provide synthetic efficiency and atom economy has been an important goal of synthetic chemistry.1 Multicomponent reactions (MCRs), by virtue of their convergence, productivity, facile execution and generally high yields of products, are good candidates for this target as they embody ideal synthesis.2 Among the MCRs, those with isocyanides (IMCRs) have attracted enormous attention from organic chemists,3 and thus isocyanides have proved themselves to be irreplaceable building blocks in modern organic chemistry. From an organic view of point, methods starting from isocyanides often have distinct advantages including enhanced convergence, inherent atom economy and the great variety of readily available isocyanides for use. Cyclopentadienes are useful not only as a reactive diene component in the DielseAlder reaction4 but also as a precursor for the preparation of transition-metal complexes with Cp-type ligands.5 However, though the introduction of substituents into the cyclopentadienyl (Cp) backbone is well-known to dramatically affect the reactivity of transition metals containing these ligands,6 the preparation of well-defined, highly substituted cyclopentadienes is not
* Corresponding authors. Fax: þ86 21 66134856; e-mail addresses: wgcao@ staff.shu.edu.cn, [email protected] (W. Cao). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.03.093
necessarily easy owing to the absence of general methods7 and also to the facile migration of the endocyclic double bonds.8 Furthermore, due to the strong electronegativity, the small size and low polarizability of fluorine atom, perfluoroalkyl (RF) moieties exhibit properties of great interest (chemical and thermal stability, low surface energy, self organization ability) for a wide variety of applications.9 Therefore, there has been considerable interest in developing an efficient method for the synthesis of highly substituted perfluoroalkylated cyclopentadiene derivatives.10 Zwitterionic species derived from isocyanides and DMAD can be efficiently trapped by dipolarophiles, such as aryl aldehydes, N-tosylimines and activated alkenes, leading to a facile synthesis of furan, pyrrole derivatives and highly substituted cyclopentadienes, respectively.11 Against this background, we envisaged that the zwitterions derived from isocyanides and methyl 2-perfluoroalkynoates might undergo cycloaddition to activated alkenes, thus constituting a synthesis of highly substituted perfluoroalkylated cyclopentadienes. Our preliminary results validating this idea are presented in this paper.
2. Results and discussion Highly substituted perfluoroalkylated cyclopentadienes 4 were obtained via a one-pot three-component reaction (MCR) by using
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On the basis of the previous reports,5 the proposed mechanism is shown in Scheme 2. First, isocyanide 1 attacks methyl 2-perfluoroalkynoate 2 nucleophilically to generate the zwitterion
isocyanides 1, methyl 2-perfluoroalkynoates 2 and electrophilic alkenes 3 (Scheme 1). The structures of products were confirmed by IR, 1H NMR, 13C NMR, 19F NMR, MS and HRMS as well.
R1 N C
RF
CO2 Me 2
1
H
CN
DCM
Ar
CN
r.t.
1b: R1 = cyclohexyl; 2b: RF = C2F5;
Ar
R1 HN NC
3 1a: R1 = t-butyl; 2a: RF = CF3;
CO2Me
RF
CN 4
2c: RF = n-C3F 7;
Scheme 1. Preparation of highly substituted perfluoroalkylated cyclopentadienes 4.
Initially, we carried out the reaction of tert-butyl isocyanide 1a (1.2 equiv), methyl 4,4,4-trifluorobut-2-ynoate 2a (1.2 equiv) and 2-benzylidenemalononitrile 3a (1.0 mmol) in dry DCM (5 mL) at room temperature for 8 h and the desired product 4a was obtained in excellent yield (90%). Further screening of the reaction conditions was carried out and the results were summarized in Table 1. The role of the solvent in this reaction was studied by performing the same reaction in other various solvents, such as tetrahydrofuran (THF), chloroform, ethanol and toluene. It is worth mentioning that dichloromethane (DCM) is the most suitable solvent for the synthesis (Table 1, entries 1 vs 2e5). A lower yield was obtained when the reaction was performed at 40 or 0 C (Table 1, entries 1 vs 6 or 7). Table 1 Optimization of the reaction conditions Entry
Solvent
Temp ( C)
4a Yielda (%)
1 2 3 4 5 6 7
DCM THF CHCl3 EtOH Toluene DCM DCM
rt rt rt rt rt 0 40
90 73 82 0 57 83 72
Table 2 Preparation of highly substituted perfluoroalkylated cyclopentadienes 4a Entry
1
2
Ar
Time (h)
Product
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1a 1a 1a 1a 1a 1a
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2c 2c
Ph 4-CH3C6H4 4-MeOC6H4 2-NO2C6H4 2-ClC6H4 2-BrC6H4 1-Naphthalene 2-CH3C6H4 3-CH3C6H4 2-CH3C6H4 2-ClC6H4 2-BrC6H4 2-NO2C6H4 2-CH3C6H4 2-ClC6H4 2-BrC6H4 2-NO2C6H4 2-CH3C6H4 2-ClC6H4
8 13 24 7 10 12 24 15 13 15 6 6 6 15 8 8 8 18 7
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s
90 75 61 86 95 93 50 70 73 86 92 96 95 69 96 90 95 63 87
a Reaction conditions: isocyanide 1 (1.2 equiv), methyl 2-perfluoroalkynoate 2 (1.2 equiv), electrophilic alkene 3 (1.0 mmol), dry DCM (5 mL), room temperature. b Isolated yield.
Bold signifies the best result under different reaction conditions. a Isolated yield.
After optimization of the reaction conditions, a variety of electrophilic alkenes 3 containing electron donating or electron withdrawing groups in the aromatic ring were reacted with various 2-perfluoroalkynoates 2 and isocyanides 1. In all cases, the corresponding perfluoroalkylated cyclopentadiene derivatives were obtained in good to excellent yields under similar reaction conditions, which are summarized in Table 2. From these successful results, we concluded that alkenes 3 with electron withdrawing groups on the Ar ring had a shorter reaction time as compared to those with electron donating groups and provided a better yield (Table 2, entries 2, 3 vs 4e6). Only 50% yield of product was obtained when 2-(naphthalen-2-ylmethylene)malononitrile was used (Table 2, entry 7). This might be due to its steric hindrance in the reaction process. However, interestingly, it was found that 3 with an ortho substituent on benzene ring gave good yields of products (Table 2, entries 4e6 and 8). Both tert-butyl isocyanide and cyclohexyl isocyanide are suitable partners in this reaction. The variability of the reaction with respect to the alkyne was also tested. C2F5- or n-C3F7 substituted 2-perfluoroalkynoates also worked well. The structure of the final product was further confirmed by X-ray diffraction analysis of 4c (Fig. 1).12 From the crystal structure, it is clear that C2 of methyl 2-perfluoroalkynoate is attached to C1 of isocyanide and C3 of methyl 2-perfluoroalkynoate is attached to C4 of alkene. The dihedral angle of benzene ring and plane C5C1C2C3 is 87.8 . The dihedral angle of plane C5C1C2C3 and plane C3C4C5 is 20.9 , which shows that the cyclopentadiene ring has an envelope conformation.
Fig. 1. X-ray diffraction of compound 4c.
A. Subsequent nucleophilic addition of A to alkene 3 occurs, affording imine B as the pivotal intermediate, which then undergoes cyclization to deliver the adduct C. The latter isomerizes to give the final product 4 via a [1,5]-H shift. 3. Conclusion We have developed a novel and efficient route for the preparation of highly substituted perfluoroalkylated cyclopentadienes
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Scheme 2. Mechanism for the formation of product 4.
via a three-component reaction of isocyanide, methyl 2-perfluoroalkynoate and activated alkene. The generality of this threecomponent reaction has been demonstrated. A possible reaction mechanism is proposed. Further synthetic applications of highly substituted perfluoroalkylated cyclopentadienes are in progress in our laboratory.
4.2.5. 2-(2-Chlorobenzylidene)malononitrile 3e.14d Pale red solid; yield: 89%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.44e7.47 (m, 1H), 7.55e7.56 (m, 2H), 8.18e8.19 (m, 1H), 8.27 (s, 1H). 4.2.6. 2-(2-Bromobenzylidene)malononitrile (3f).14e Pale yellow solid; yield: 84%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.44e7.51 (m, 2H), 7.74e7.75 (m, 1H), 8.11e8.13 (m, 1H), 8.22 (s, 1H).
4. Experimental 4.1. General information All reagents were purchased from commercial sources and used without further purification, except that methyl 2perfluoroalkynoates 213 and electrophilic alkenes 314 were prepared according to the known literature. Melting points were recorded on a WRS-1 instrument and uncorrected. 1H, 19F and 13C NMR spectra were recorded on a Bruker DRX-500 MHz spectrometer. All chemical shifts are reported in parts per million downfield (positive) of the standard: C6F6 for 19F, TMS for 1H and 13C NMR spectra. IR spectra were obtained on an AVATAR370 FT-IR spectrometer. LRMS (lower resolution mass spectra) and HRMS (high resolution mass spectra) were obtained on LCMS 2020 and Bruker Daltonics APEXIII 7.0 TESALA FTMS instrument, respectively. X-ray analysis was performed on a Bruker Smart Apex2 CCD spectrometer. All yields reported in this publication referred to isolated ones of compounds and their purity was determined by 1H NMR. 4.2. General procedure for preparation of compound 3 Malononitrile (10.0 mmol) was added to a stirred solution of benzaldehyde (10.0 mmol) and piperidine (1.0 mmol) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 5 h. A precipitate was formed and collected by suction filtration, washed with n-hexane/ethanol (v/v¼10:1), and then dried under high vacuum. 4.2.1. 2-Benzylidenemalononitrile 3a.14b Pale yellow solid; yield: 82%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.53e7.56 (m, 2H), 7.62e7.65 (m, 1H), 7.78 (s, 1H), 7.90e7.92 (m, 2H). 4.2.2. 2-(4-Methylbenzylidene)malononitrile 3b.14b White solid; yield: 64%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.46 (s, 3H), 7.34 (d, J¼8.5 Hz, 2H), 7.72 (s, 1H), 7.81 (d, J¼8.5 Hz, 2H). 4.2.3. 2-(4-Methoxybenzylidene)malononitrile 3c.14b Pale yellow solid; yield: 71%. 1H NMR (CDCl3, 500 MHz, ppm): d 3.91 (s, 3H), 7.01 (d, J¼9.0 Hz, 2H), 7.65 (s, 1H), 7.91 (d, J¼9.0 Hz, 2H). solid; 4.2.4. 2-(2-Nitrobenzylidene)malononitrile 3d.14c Brown yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.79e7.83 (m, 2H), 7.87e7.90 (m, 1H), 8.35e8.37 (m, 1H), 8.45 (s, 1H).
4.2.7. 2-(Naphthalen-1-ylmethylene)malononitrile 3g.14f Yellow solid; yield: 75%. 1H NMR (CDCl3, 500 MHz, ppm): d 7.60e7.71 (m, 3H), 7.95e7.97 (m, 2H), 8.11e8.12 (m, 1H), 8.27e8.29 (m, 1H), 8.66 (s, 1H). 4.2.8. 2-(2-Methylbenzylidene)malononitrile (3h).14g White solid; yield: 68%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.45 (s, 3H), 7.32e7.37 (m, 2H), 7.48e7.51 (m, 1H), 8.08e8.09 (m, 1H), 8.10 (s, 1H). 4.2.9. 2-(3-Methylbenzylidene)malononitrile 3i.14h White solid; yield: 72%. 1H NMR (CDCl3, 500 MHz, ppm): d 2.43 (s, 3H), 7.41e7.45 (m, 2H), 7.69 (s, 1H), 7.72e7.74 (m, 2H). 4.3. General procedure for preparation of compound 4 To a solution of methyl 2-perfluoroalkynoate 2 (1.2 mmol) and electrophilic alkene 3 (1.0 mmol) in dry DCM (5 mL) was added isocyanide 1 (1.2 mmol) and the mixture was stirred at room temperature. After the completion of the reaction (monitored by TLC), the solvent was removed in vacuo to give the crude product, which was purified by silica gel chromatography. 4.3.1. Methyl 4-(tert-butylamino)-3,3-dicyano-2-phenyl-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4a. White solid; mp: 133.3e134.5 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.57 (s, 9H), 3.72 (s, 3H), 5.06 (br s, 1H), 7.29e7.31 (m, 2H), 7.46e7.48 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.2, 60.2, 60.4, 111.3, 113.5, 119.3 (q, 1JCeF¼272.0 Hz, CF3), 128.8, 129.4, 130.4, 131.2, 132.9 (q, 2JCeF¼32.8 Hz, CCF3), 141.6, 148.7, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2977, 2258, 1740, 1661, 1360, 1293, 1270, 1183, 1164, 1148, 1044, 705. MS (EI) m/z (%): 388 [(MH)]þ. HRMS (ESI) calcd for C20H18F3N3O2 [(MH)]þ: 388.1278, found: 388.1275. 4.3.2. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(p-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4b. White solid; mp: 121.0e123.1 C; yield: 75%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 2.38 (s, 3H), 3.72 (s, 3H), 5.02 (br s, 1H), 7.17 (d, J¼7.5 Hz, 2H), 7.25 (d, J¼7.5 Hz, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 21.2, 30.2, 53.2, 60.1, 60.4, 111.5, 113.6, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 128.1, 128.7, 130.2, 132.8 (q, 2JCeF¼32.8 Hz, CCF3), 140.6, 141.7, 148.9, 162.8. 19 F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2986, 2959, 2247, 1738, 1658, 1359, 1292, 1186, 1155, 1088, 828. MS
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(EI) m/z (%): 402 [(MH)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MH)]þ: 402.1435, found: 402.1422.
[(MþNa)]þ. HRMS (ESI) calcd for C24H20F3N3O2 [(MþNa)]þ: 462.1400, found: 462.1410.
4.3.3. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(4-methoxyphenyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4c. White solid; mp: 111.9e113.1 C; yield: 61%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.72 (s, 3H), 3.83 (s, 3H), 5.01 (br s, 1H), 6.96 (d, J¼8.7 Hz, 2H), 7.21 (d, J¼8.7 Hz, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.3, 55.3, 60.0, 60.5, 111.5, 113.6, 114.9, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 122.8, 130.2, 132.7 (q, 2JCeF¼32.8 Hz, CCF3), 141.7, 148.9, 161.1, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2976, 2960, 2250, 1739, 1661, 1515, 1360, 1293, 1184, 1157, 1029, 840. MS (ESI) m/z (%): 418 [(MH)]þ. HRMS (ESI) calcd for C21H20F3N3O3 [(MH)]þ: 418.1384, found: 418.1373.
4.3.8. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(o-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4h. White solid; mp: 154.1e155.3 C; yield: 70%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 2.52 (s, 3H), 3.72 (s, 3H), 5.38 (br s, 1H), 7.06e7.08 (m, 1H), 7.25e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 19.9, 30.2, 53.2, 56.2, 60.6, 111.4, 113.8, 119.4 (q, 1JCeF¼272.0 Hz, CF3), 126.9, 127.8, 130.2, 130.3, 131.5, 133.1 (q, 2JCeF¼32.8 Hz, CCF3), 137.4, 141.6, 149.3, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2975, 2248, 1738, 1671, 1363, 1294, 1192, 1152, 1082, 756. MS (ESI) m/z (%): 426 [(MþNa)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MþNa)]þ: 426.1400, found: 426.1405.
4.3.4. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(2-nitrophenyl)-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4d. White solid; mp: 177.7e178.1 C; yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.57 (s, 9H), 3.75 (s, 3H), 5.66 (br s, 1H), 7.34e7.36 (m, 1H), 7.67e7.71 (m, 1H), 7.75e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.6, 55.5, 61.0, 111.8, 112.9, 119.2 (q, 1 JCeF¼272.0 Hz, CF3), 126.4, 127.6, 129.8, 131.7, 134.4, 135.1 (q, 2 JCeF¼32.8 Hz, CCF3), 140.9, 147.4, 148.6, 162.4. 19F NMR (CDCl3, 470 MHz, ppm): d 62.5 (s, CF3). IR (KBr, cm1): n 2979, 2253, 1743, 1668, 1527, 1365, 1352, 1283, 1190, 1143, 1033, 762. MS (ESI) m/z (%): 433 [(MH)]þ. HRMS (ESI) calcd for C20H17F3N4O4 [(MH)]þ: 433.1129, found: 433.1114.
4.3.9. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(m-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4i. White solid; mp: 106.5e108.0 C; yield: 73%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.58 (s, 9H), 2.40 (s, 3H), 3.72 (s, 3H), 5.03 (br s, 1H), 7.07e7.11 (m, 2H), 7.27e7.36 (m, 2H). 13C NMR (CDCl3, 125 MHz, ppm): d 21.4, 30.3, 53.3, 60.4, 60.6, 111.5, 113.7, 119.5 (q, 1JCeF¼272.0 Hz, CF3), 125.7, 129.4, 129.7, 131.2, 131.3, 133.0 (q, 2JCeF¼32.8 Hz, CCF3), 139.5, 141.7, 148.9, 162.9. 19F NMR (CDCl3, 470 MHz, ppm): d 62.7 (s, CF3). IR (KBr, cm1): n 2978, 2250, 1739, 1663, 1361, 1293, 1189, 1157, 1043, 760, 713. MS (ESI) m/z (%): 426 [(MþNa)]þ. HRMS (ESI) calcd for C21H20F3N3O2 [(MþNa)]þ: 426.1400, found: 462.1408.
4.3.5. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4e. White solid; mp: 169.8e170.4 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.76 (s, 3H), 5.70 (br s, 1H), 7.19e7.21 (m, 1H), 7.34e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.5, 56.4, 60.9, 111.3, 113.3, 119.3 (q, 1JCeF¼272.2 Hz, CF3), 127.7, 129.3, 130.3, 130.6, 131.7, 134.1 (q, 2JCeF¼32.8 Hz, CCF3), 135.4, 141.2, 148.3, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2976, 2250, 1740, 1672, 1364, 1293, 1191, 1157, 1145, 1085, 768. MS (ESI) m/z (%): 422 [(MH)]þ. HRMS (ESI) calcd for C20H17ClF3N3O2 [(MH)]þ: 422.0889, found: 422.0879. 4.3.6. Methyl 2-(2-bromophenyl)-4-(tert-butylamino)-3,3-dicyano-5(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4f. White solid; mp: 178.4e179.3 C; yield: 93%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.76 (s, 3H), 5.72 (br s, 1H), 7.17e7.19 (m, 1H), 7.31e7.42 (m, 2H), 7.73e7.74 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 58.7, 60.7, 111.2, 113.1, 119.3 (q, 1JCeF¼272.2 Hz, CF3), 126.0, 128.2, 129.4, 131.7, 132.0, 133.8, 133.9 (q, 2JCeF¼32.8 Hz, CCF3), 141.2, 148.3, 162.5. 19F NMR (CDCl3, 470 MHz, ppm): d 62.6 (s, CF3). IR (KBr, cm1): n 2969, 2250, 1739, 1672, 1363, 1293, 1192, 1156, 1144, 1084, 761, 594. MS (ESI) m/z (%): 466 [(MH)]þ. HRMS (ESI) calcd for C20H17BrF3N3O2 [(MH)]þ: 466.0384, found: 466.0385. 4.3.7. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(naphthalen-1-yl)5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4g. White solid; mp: 120.1e121.5 C; yield: 50%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.70 (s, 3H), 5.98 (br s, 1H), 7.37e7.38 (m, 1H), 7.51e7.54 (m, 1H), 7.61e7.64 (m, 1H), 7.71e7.74 (m, 1H), 7.95e7.97 (m, 1H), 8.12e8.14 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.2, 53.4, 55.4, 60.8, 111.3, 114.0, 119.4 (q, 1JCeF¼272.2 Hz, CF3), 122.0, 125.1, 126.8, 127.0, 128.1, 128.2, 129.5, 131.1, 131.6, 133.6 (q, 2 JCeF¼32.8 Hz, CCF3), 134.1, 141.5, 149.3, 163.0. 19F NMR (CDCl3, 470 MHz, ppm): d 62.5 (s, CF3). IR (KBr, cm1): n 2980, 2249, 1732, 1666, 1359, 1290, 1192, 1152, 1086, 779. MS (ESI) m/z (%): 462
4.3.10. Methyl 3,3-dicyano-4-(cyclohexylamino)-2-(o-tolyl)-5-(trifluoromethyl)cyclopenta-1,4-dienecarboxylate 4j. White solid; mp: 122.7e123.9 C; yield: 86%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.34e1.86 (m, 10H), 2.53 (s, 3H), 3.73 (s, 3H), 4.02e4.06 (m, 1H), 5.33 (br s, 1H), 7.07e7.08 (m, 1H), 7.26e7.34 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 19.9, 23.4, 25.3, 31.9, 32.2, 37.3, 53.3, 54.9, 64.1, 109.6, 112.4, 119.2 (q, 1JCeF¼272.2 Hz, CF3), 126.9, 127.9, 130.2, 130.3, 131.5, 131.6 (q, 2JCeF¼32.8 Hz, CCF3), 137.2, 148.4, 151.0, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2934, 2251, 1736, 1664, 1375, 1294, 1201, 1160, 1076, 740. MS (ESI) m/z (%): 452 [(MþNa)]þ. HRMS (ESI) calcd for C23H22F3N3O2 [(MþNa)]þ: 452.1556, found: 452.1557. 4.3.11. Methyl 2-(2-chlorophenyl)-3,3-dicyano-4-(cyclohexylamino)5-(trifluoromethyl)cyclopenta-1,4-diene carboxylate 4k. White solid; mp: 132.3e133.5 C; yield: 92%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.33e1.86 (m, 10H), 3.78 (s, 3H), 4.03e4.06 (m, 1H), 5.62 (br s, 1H), 7.20e7.21 (m, 1H), 7.34e7.44 (m, 2H), 7.56e7.58 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.4, 32.0, 32.2, 37.2, 53.6, 55.0, 64.3, 109.5, 111.9, 119.3 (q, 1JCeF¼272.5 Hz, CF3), 127.8, 129.3, 130.4, 130.6, 131.7, 132.6 (q, 2JCeF¼34.4 Hz, CCF3), 135.2, 148.2, 149.9, 162.4. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2939, 2251, 1742, 1657, 1294, 1199, 1163, 1078, 757. MS (ESI) m/z (%): 472 [(MþNa)]þ. HRMS (ESI) calcd for C22H19ClF3N3O2 [(MþNa)]þ: 472.1010, found: 472.1024. 4.3.12. Methyl 2-(2-bromophenyl)-3,3-dicyano-4-(cyclohexylamino)5-(trifluoromethyl)cyclopenta-1,4-diene carboxylate 4l. White solid; mp: 139.3e140.5 C; yield: 96%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.36e1.86 (m, 10H), 3.77 (s, 3H), 4.03e4.07 (m, 1H), 5.64 (br s, 1H), 7.18e7.20 (m, 1H), 7.31e7.35 (m, 1H), 7.39e7.42 (m, 1H), 7.73e7.75 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.4, 32.0, 32.2, 37.2, 53.6, 57.4, 64.3, 109.5, 111.9, 119.3 (q, 1JCeF¼272.5 Hz, CF3), 125.9, 128.4, 129.5, 131.9, 132.2, 132.6 (q, 2JCeF¼34.4 Hz, CCF3), 133.9, 148.2, 150.1, 162.3. 19F NMR (CDCl3, 470 MHz, ppm): d 62.1 (s, CF3). IR (KBr, cm1): n 2938, 2252, 1741, 1656, 1294, 1198, 1162, 1078, 736,
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605. MS (ESI) m/z (%): 516 [(MþNa)]þ. HRMS (ESI) calcd for C22H19BrF3N3O2 [(MþNa)]þ: 516.0505, found: 516.0515.
1174, 1130, 1054, 761. MS (ESI) m/z (%): 507 [(MþNa)]þ. HRMS (ESI) calcd for C21H17F5N4O4 [(MþNa)]þ: 507.1062, found: 507.1054.
4.3.13. Methyl 3,3-dicyano-4-(cyclohexylamino)-2-(2-nitrophenyl)5-(trifluoromethyl)cyclopenta-1,4-dienecar boxylate 4m. Pale yellow solid; mp: 158.5e159.7 C; yield: 95%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.34e1.91 (m, 10H), 3.75 (s, 3H), 4.08e4.11 (m, 1H), 5.56 (s, 1H), 7.35e7.37 (m, 1H), 7.68e7.71 (m, 1H), 7.76e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 23.5, 25.3, 31.9, 32.1, 38.5, 53.7, 54.2, 64.3, 110.0, 111.6, 119.2 (q, 1JCeF¼272.5 Hz, CF3), 126.3, 127.5, 130.1, 131.7, 133.5 (q, 2JCeF¼34.4 Hz, CCF3), 134.5, 148.0, 148.6, 149.1, 162.1. 19F NMR (CDCl3, 470 MHz, ppm): d 62.0 (s, CF3). IR (KBr, cm1): n 2937, 2252, 1736, 1660, 1532, 1354, 1288, 1203, 1150, 1072, 724. MS (ESI) m/z (%): 483 [(MþNa)]þ. HRMS (ESI) calcd for C22H19F3N4O4 [(MþH)]þ: 461.1431, found: 461.1436.
4.3.18. Methyl 4-(tert-butylamino)-3,3-dicyano-5-(heptafluoro-propyl)-2-(o-tolyl)cyclopenta-1,4-dienecarboxylate 4r. White solid; mp: 122.3e123.7 C; yield: 63%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 2.52 (s, 3H), 3.70 (s, 3H), 5.40 (br s, 1H), 7.03e7.04 (m, 1H), 7.28e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 20.0, 30.1, 53.2, 56.6, 60.8, 108.9 (m, CF2), 111.4, 113.2 (m, CF2), 113.9, 117.8 (qt, 1 JCeF¼287.8 Hz, 2JCeF¼34.0 Hz, CF3), 127.0, 127.9, 130.3, 130.4, 131.6, 132.8 (t, 2JCeF¼23.2 Hz, CCF2), 137.5, 141.9, 152.6, 163.0. 19F NMR (CDCl3, 470 MHz, ppm): d 80.7 (t, J¼9.4 Hz, CF3), 108.0 (m, CF2), 122.7 (m, CF2). IR (KBr, cm1): n 2983, 2254, 1750, 1363, 1253, 1208, 1187, 1124, 1016, 751. MS (ESI) m/z (%): 526 [(MþNa)]þ. HRMS (ESI) calcd for C23H20F7N3O2 [(MþNa)]þ: 526.1336, found: 526.1355.
4.3.14. Methyl 4-(tert-butylamino)-3,3-dicyano-5-(pentafluoroethyl)2-(o-tolyl)cyclopenta-1,4-dienecarboxylate 4n. White solid; mp: 120.5e121.3 C; yield: 64%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 2.52 (s, 3H), 3.70 (s, 3H), 5.39 (br s, 1H), 7.01e7.03 (m, 1H), 7.26e7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz, ppm): d 20.0, 30.2, 53.3, 56.5, 60.8, 111.0 (m, CF2), 111.4, 113.9, 118.5 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.3 Hz, CF3), 127.0, 127.9, 130.3, 130.4, 131.6, 132.5 (t, 2JCeF¼23.0 Hz, CCF2), 137.5, 141.7, 152.5, 163.1. 19F NMR (CDCl3, 470 MHz, ppm): d 81.2 (s, CF3), 111.0 (m, CF2). IR (KBr, cm1): n 2983, 2251, 1750, 1657, 1256, 1221, 1174, 1129, 1055, 754. MS (ESI) m/z (%): 476 [(MþNa)]þ. HRMS (ESI) calcd for C22H20F5N3O2 [(MþNa)]þ: 476.1368, found: 476.1385. 4.3.15. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano-5(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4o. White solid; mp: 137.2e137.9 C; yield: 96%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 3.75 (s, 3H), 5.70 (br s, 1H), 7.14e7.15 (m, 1H), 7.35e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 56.6, 60.9, 111.0 (m, CF2), 111.3, 113.3, 118.4 (qt, 1JCeF¼288.0 Hz, 2 JCeF¼36.2 Hz, CF3), 127.8, 129.3, 130.3, 130.5, 131.7, 133.4 (t, 2JCeF¼23.0 Hz, CCF2), 135.4, 141.4, 151.5, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 81.2 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2983, 2253, 1748, 1657, 1257, 1221, 1175, 1046, 751. MS (ESI) m/z (%): 496 [(MþNa)]þ. HRMS (ESI) calcd for C21H17ClF5N3O2 [(MþNa)]þ: 496.0822, found: 496.0825. 4.3.16. Methyl 2-(2-bromophenyl)-4-(tert-butylamino)-3,3-dicyano5-(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4p. White solid; mp: 148.5e149.7 C; yield: 90%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.54 (s, 9H), 3.74 (s, 3H), 5.72 (br s, 1H), 7.11e7.13 (m, 1H), 7.31e7.34 (m, 1H), 7.39e7.43 (m, 1H), 7.73e7.74 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.5, 59.1, 61.0, 111.0 (m, CF2), 111.3, 113.3, 118.4 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.4 Hz, CF3), 126.1, 128.4, 129.4, 131.9, 132.1, 133.3 (t, 2JCeF¼23.0 Hz, CCF2), 133.9, 141.3, 151.6, 162.7. 19F NMR (CDCl3, 470 MHz, ppm): d 81.1 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2985, 2251, 1739, 1658, 1274, 1205, 1173, 1128, 1050, 766, 598. MS (ESI) m/z (%): 540 [(MþNa)]þ. HRMS (ESI) calcd for C21H17BrF5N3O2 [(MþNa)]þ: 540.0317, found: 540.0339. 4.3.17. Methyl 4-(tert-butylamino)-3,3-dicyano-2-(2-nitrophenyl)-5(pentafluoroethyl)cyclopenta-1,4-dienecarboxylate 4q. White solid; mp: 154.1e155.3 C; yield: 95%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.55 (s, 9H), 3.74 (s, 3H), 5.66 (br s, 1H), 7.28e7.30 (m, 1H), 7.67e7.71 (m, 1H), 7.76e7.79 (m, 1H), 8.22e8.24 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.6, 55.8, 61.1, 110.9 (m, CF2), 111.9, 112.9, 118.4 (qt, 1JCeF¼287.8 Hz, 2JCeF¼36.1 Hz, CF3), 126.4, 127.6, 129.8, 131.8, 134.4 (t, 2JCeF¼23.0 Hz, CCF2), 134.6, 141.1, 148.7, 150.6, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 80.9 (s, CF3), 111.1 (m, CF2). IR (KBr, cm1): n 2985, 2253, 1739, 1657, 1533, 1348, 1272, 1207,
4.3.19. Methyl 4-(tert-butylamino)-2-(2-chlorophenyl)-3,3-dicyano5-(heptafluoropropyl)cyclopenta-1,4-dienecarboxylate 4s. White solid; mp: 143.0e143.8 C; yield: 92%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.56 (s, 9H), 3.74 (s, 3H), 5.75 (br s, 1H), 7.18e7.19 (m, 1H), 7.35e7.43 (m, 2H), 7.55e7.57 (m, 1H). 13C NMR (CDCl3, 125 MHz, ppm): d 30.1, 53.4, 56.6, 60.9, 108.8 (m, CF2), 111.3, 113.1 (m, CF2), 113.3, 117.6 (qt, 1JCeF¼287.5 Hz, 2JCeF¼34.1 Hz, CF3), 127.8, 129.3, 130.3, 130.6, 131.7, 133.7 (t, 2JCeF¼23.1 Hz, CCF2), 135.4, 141.5, 151.5, 162.6. 19F NMR (CDCl3, 470 MHz, ppm): d 80.7 (t, J¼9.4 Hz, CF3), 108.1 (m, CF2), 122.8 (m, CF2). IR (KBr, cm1): n 2983, 2254, 1748, 1356, 1255, 1233, 1208, 1189, 1122, 1016, 755. MS (ESI) m/z (%): 546 [(MþNa)]þ. HRMS (ESI) calcd for C22H17ClF7N3O2 [(MþNa)]þ: 546.0790, found: 546.0797. Acknowledgements The authors are grateful to the National Natural Science Foundation of China (Grant No. 21072126, 21272152) and Leading Academic Discipline Projects of Shanghai Municipal Education Commission (Grant No. J50102) for their financial support. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.03.093. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes 1. Trost, B. M. Science 1991, 254, 1471. 2. (a) Isonitrile Chemistry; Ugi, I., Ed.; Academic: New York, NY, 1971; (b) Ugi, I.; € DOmling, A.; Horl, W. Endeavour 1994, 18, 115; (c) Multicomponent Reactions; , H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; (d) Zhu, J., Bienayme € DOmling, A. Chem. Rev. 2006, 106, 17; (e) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439; (f) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300; (g) Isambert, N.; Lavilla, R. Chem.dEur. J. 2008, 14, 8444; (h) Ganem, B. Acc. Chem. Res. 2009, 42, 463. 3. For recent examples on isocyanide chemistry, see: (a) Kim, J.; Schneekloth, J. S.; Sorensen, E. J. Chem. Sci. 2012, 3, 2849; (b) Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 1520; (c) Khoury, K.; Sinha, M. K.; Nagashima, € T.; Herdtweck, E.; DOmling, A. Angew. Chem., Int. Ed. 2012, 51, 10280; (d) € Huang, Y. J.; Khoury, K.; Chanas, T.; DOmling, A. Org. Lett. 2012, 14, 5916; (e) Spisa, F. L.; Feo, A.; Mossetti, R.; Tron, G. C. Org. Lett. 2012, 14, 6044; (f) Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012, 14, 6218; (g) Moliner, F. D.; Hulme, C. Org. Lett. 2012, 14, 1354; (h) Masui, H.; Fuse, S.; Takahashi, T. Org. Lett. 2012, 14, 4090; (i) Sha, F.; Wu, L. L.; Huang, X. J. Org. rez-Labrada, K.; Brouard, I.; Me ndez, I.; Rivera, D. G. Chem. 2012, 77, 3754; (j) Pe J. Org. Chem. 2012, 77, 4660; (k) Terzidis, M. A.; Zarganes-Tzitzikas, T.; Tsimenidis, C.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A.; Kostakis, G. E. J. Org. Chem. 2012, 77, 9018; (l) Sun, H. P.; Zhou, H. Y.; Khorev, O.; Jiang, R. W.; Yu, T.; Wang, X.; Du, Y. L.; Ma, Y.; Meng, T.; Shen, J. K. J. Org. Chem. 2012, 77, 10745; (m) Qiu, G.; Liu, G.; Pu, S. Z.; Wu, J. Chem. Commun. 2012, 2903; (n) Li, J.; Liu, Y. J.; Li, C. J.; Jie, H. H.; Jia, X. S. Green Chem. 2012, 14, 1314; (o) Khan, A. T.; Basha, R. S.; Lal, M.; Mir, M. H. RSC Adv. 2012, 2, 5506; (p) Li, J.; Wang, N.; Li, C. J.; Jia, X. S. Chem.dEur. J. 2012, 18, 9645.
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