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Thermal [3 + 2] cycloaddition of phthalazinium dicyanomethanide with allenoates
Tetrahedron 73 (2017) 5926e5931
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Thermal [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with allenoates Bo Wang a, Honglei Liu a, Qijun Wang a, Chunhao Yuan a, Hao Jia a, Chunxiao Liu a, Hongchao Guo a, b, * a b
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 June 2017 Received in revised form 15 August 2017 Accepted 18 August 2017 Available online 24 August 2017
The thermal [3 þ 2] cycloaddition reaction of phthalazinium dicyanomethanide with various allenoates worked efficiently under mild reaction conditions to give functionalized tetrahydropyrrolo[2,1-a] phthalazine derivatives in good to excellent yields and excellent diastereoselectivities. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Cycloaddition Allenoate Phthalazinium dicyanomethanide Heterocycle Tetrahydropyrrolophthalazine
1. Introduction 1,3-Dipolar cycloaddition reactions represent an important class of synthetic methods for the convergent synthesis of a wide range of heterocycles.1 Numerous 1,3-dipoles such as nitrone, azomethine ylide, azomethine imine, nitrile oxide, carbonyl ylide, azide, nitrile imine, carbonyl oxide, diazoalkane and diazoacetate have been exploited for research on cycloaddition chemistry.1 Compared with high-profile dipoles such as nitrone, azomethine ylide, azomethine imine, phthalazinium dicyanomethanide has received little attention although it has several salient features including stability, easy preparation, and high reactivity. In limited examples, it has been used as 1,3-dipole in some thermal, metal-catalyzed and organocatalytic cycloadditions. In 2011, with the use of chiral imidazolidinone as catalyst, the catalytic enantioselective [3 þ 2] cycloaddition between enals and phthalazinium dicyanomethanide was achieved to give highly substituted chiral pyrrolophthalazines in high yields and excellent diastereo- and enantioselectivities.2 In 2015, we reported the Cu(I)-catalyzed highly enantioselective [3 þ 3] cycloaddition
* Corresponding author. Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. E-mail address: [email protected] (H. Guo). http://dx.doi.org/10.1016/j.tet.2017.08.036 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
between phthalazinium dicyanomethanides and iminoester-derived azomethine ylides, providing novel chiral heterocyclic compounds, 2,3,4,11b-tetrahydro-1H-pyrazino[2,1-a]phthalazine derivatives, in high yields with excellent diastereo- and enantioselectivies.3 In the same year, we also developed the Sc(OTf)3-catalyzed diastereoselective [3 þ 3] cycloaddition of phthalazinium dicyanomethanides with cyclopropane 1,1-diesters, affording a variety of 3,4dihydro-1H-pyrido[2,1-a]phthalazine derivatives in high yields with excellent diastereoselectivities.4 Recently, we developed the phosphine-catalyzed [3 þ 2] cycloaddition between phthalazinium dicyanomethanides and allenoates, in which double bond between Cß and Cg of allenoates underwent stepwise cycloaddition with dipole to afford a broad range of novel heterocyclic compounds 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives in excellent yields (Scheme 1a).5 In addition to these catalytic cycloadditions, the thermal [3 þ 2] cycloaddition reactions of phthalazinium dicyanomethanide with alkenes,6 alkynes,6,7 phosphaalkynes,8 or thiones9 have extensively been studied and the [4 þ 3] cycloaddition reaction of phthalazinium dicyanomethanide with azoalkenes formed in situ was recently reported.10 However, thermal cycloaddition of phthalazinium dicyanomethanide with allenoates has never been explored although the electron-deficient allenes have similar reaction activity as alkenes and alkynes. In our previous work, we have investigated the thermal [3 þ 2] cycloaddition reactions of various azomethine
B. Wang et al. / Tetrahedron 73 (2017) 5926e5931
Scheme 1. The [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with allenoates.
imines with allenoates, providing a variety of dinitrogen-fused heterocycles in moderate to excellent yields.11 We also achieved sequential [3 þ 2] cycloaddition/rearrangement reaction of imidazolone nitrones with allenoates, affording the methylene imidazolidinone derivatives in high yields.12 As a continuous interest in cycloaddition reactions,13 herein, employing phthalazinium dicyanomethanide as 1,3-dipole, we describe thermal [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with several types of allenoates, in which double bond between Ca and Cb of allenoate performed [3 þ 2] cycloaddition with dipole to provide functionalized tetrahydropyrrolo[2,1-a]phthalazine derivatives (Scheme 1b). 2. Results and discussions Initially, the [3 þ 2] cycloaddition was investigated with phthalazinium-2-dicyanomethanide (1) and allenoate (2a) as model substrates (Table 1). The reaction was performed at the room temperature. Several solvents were first screened. Treatment of the phthalazinium-2-dicyanomethanide (1) with the allenoate (2a) in THF for 48 h afforded the cycloadduct 3a in 68% yield with excellent diastereoselectivity (entry 1). With the use of dichloromethane as the solvent, the yield was remarkably increased to 76% yield (entry 2). Protic solvents such as H2O and MeOH could not help improve the yields (entries 3, 4). To our delight, the polar solvent acetonitrile demonstrated excellent compatibility, leading to the product 3a in 89% yield (entry 5). When the reaction temperature was increased to 40 C, the reaction time was shortened to 24 h and the yield was still excellent 90% (entry 6). Higher reaction temperature such as 60 C did not further improve the result, on the contrary, resulted in the deterioration of the yield. Based on the above results, the [3 þ 2]
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cycloaddition reactions were next performed in MeCN at 40 C for 24 h. With the optimized conditions in hand, the scope of a-substituted allenoates were next evaluated. As shown in Table 2, the [3 þ 2] cycloaddition reaction of phthalazinium-2-dicyanomethanide (1) with various a-arylmethyl-substituted allenoates (2) proceeded smoothly to provide the cycloadducts in good to excellent yields (80e94%) with excellent diastereoselectivities (entries 1e13). The allenoates bearing both electron-donating and electronwithdrawing substituents on the benzene ring could perform the reaction to give the corresponding product (entries 1e12). Moreover, the substitution pattern had no remarkable influence on the reactivity and stereoselectivity, probably due to the long distance between the aryl group and the reactive center. Particularly, allenoates containing electron-withdrawing groups seemed to produce the corresponding products in higher yields, compared with those allenoates with electron-donating group (entries 2e9 vs 10e12). Additionally, 2-naphthyl substituted allenaote 2m also worked well to afford the cycloadduct 3m in 88% yield (entry 13). The a-methylsubstituted allenoate 2n was also a compatible substrate, performing the [3 þ 2] cycloaddition reaction with phthalazinium-2dicyanomethanide (1) to afford the corresponding product 3n in 82% yield (entry 14). The ethoxycarbonyl substituted allenoate 2o underwent the reaction to afford the cycloadduct 3o in 90% yield (entry 15). The relative configuration of these products has been determined through X-ray crystallographic data of the product 3h.14 The regioselectivity that the double bond between Ca and Cb of allenoate performs cycloaddition with dipole might be the consequence of thermodynamic control. As shown in Table 3, ethyl buta-2,3-dienoate and g-substituted allenoates have also been investigated in this thermal [3 þ 2] cycloaddition reaction with phthalazinium-2-dicyanome-thanide, providing the cycloadducts in good to excellent yields and excellent diastereoselectivities. Ethyl buta-2,3-dienoate performed the reaction to produce the product 3p in 88% yield (entry 1). The reactions of several g-alkyl substituted allenoates (2qe2t) with phthalazinium-2-dicyanome-thanide (1) proceeded smoothly in
Table 2 [3 þ 2] cycloaddition of phthalazinium-2-dicyanome-thanide with a-substituted allenoatesa.
Table 1 Screening of the reaction conditionsa.
Entry
Solvent
Temp. ( C)
t (h)
Yieldb (%)
1 2 3 4 5 6 7
THF CH2Cl2 MeOH H2O MeCN MeCN MeCN
25 25 25 25 25 40 60
48 48 48 48 48 24 24
68 76 74 56 89 90 85
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2a in 2 mL of solvent. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
Entry
R
3
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Ph (2a) 2-FC6H4 (2b) 3-FC6H4 (2c) 4-FC6H4 (2d) 3-ClC6H4 (2e) 4-ClC6H4 (2f) 3-BrC6H4 (2g) 4-BrC6H4 (2h) 3-CF3C6H4 (2i) 3-MeC6H4 (2j) 4-MeC6H4 (2k) 3,5-(OMe)2C6H3 (2l) 2-naphthyl (2m) H (2n) CO2Et (2o)
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o
90 92 86 93 89 94 88 91 86 85 83 80 88 82 90
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2 in 2 mL of MeCN. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
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B. Wang et al. / Tetrahedron 73 (2017) 5926e5931
Table 3 [3 þ 2] cycloaddition of phthalazinium-2-dicyanome-thanide with ethyl buta-2,3dienoate and g-substituted allenoatesa.
Entry
R
3
Yieldb (%)
1 2 3 4 5 6
H (2p) Me (2q) Et (2r) i-Pr (2s) t-Bu (2t) Bn (2u)
3p 3q 3r 3s 3t 3u
88 91 87 90 92 86
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2 in 2 mL of MeCN. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
MeCN at 40 C, providing the corresponding products (3qe3t) in 87e92% yields (entries 2e5). The g-benzyl-substituted allenoate 2u could also carry out the reaction to give the product 3u in 86% yield. The relative configuration of these products has been determined through X-ray crystallographic data of the product 3t.14 3. Conclusion In summary, the thermal [3 þ 2] cycloaddition reaction of phthalazinium dicyanomethanide with several types of allenoates has been explored. The reaction is operationally simple and worked efficiently to afford a broad range of functionalized tetrahydropyrrolo[2,1-a]phthalazine derivatives in good to excellent yields with excellent diastereoselectivities. 4. Experimental section All reactions were performed in air in oven-dried glassware with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. All solvents were purified and dried according to standard methods prior to use. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200e300 mesh). 1 H and 13C NMR spectra were recorded in CDCl3 using a 300 MHz Bruker NMR instrument. Accurate mass measurements were performed using an Agilent instrument with the ESI-MS technique. Xray crystallographic data were collected using a MM007HF Saturn 724þ. 4.1. Preparation of phthalazinium dicyanomethanide 1 Phthalazinium dicyanomethanide was synthesized by adding phthalazine or phthalazine derivative (14.58 mmol) to a solution of TCNEO (4.86 mmol) in THF (50 mL) at 0 C. The reaction was stirred at this temperature for 2 h. Then, the formed solid was isolated by filtration and washed with cold THF (3 25 mL) to give the product in nearly quantitative yield. 4.2. Preparation of allenoates 2 The alkyl halide (1.1 equiv) was added to a stirred solution of (carbethoxymethylene)triphenylphosphorane in CHCl3 (80 mL) at room temperature. The mixture was heated under reflux until all of the (carbethoxymethylene)triphenylphosphorane had been
consumed (monitored using TLC). The solvent was evaporated under reduced pressure. CH2Cl2 (100 mL) and triethylamine (8.4 mL, 2.2 equiv) were added to the resulting phosphonium salt. After stirring for 1 h, AcCl (1.96 mL, 1.0 equiv) was added dropwise over 30 min using a syringe pump. The mixture was stirred overnight and then passed through a Buchner funnel packed with silica gel and washed several times with CH2Cl2. The combined filtrates were carefully concentrated and the residue was subjected to a flash column chromatography isolation (eluent: 10e15% EtOAc in hexane) to afford the corresponding allenoate 2. 4.3. General procedure for [3 þ 2] cycloaddition Phthalazinium dicyanomethanide 1 (0.1 mmol) and allenoate 2 (0.15 mmol) were dissolved in 2 mL of MeCN and then stirred at 40 C for about 24 h. Once starting material was consumed (monitored by TLC), the mixture was concentrated to dryness. The residue was purified through flash column chromatography (eluent: 8% EtOAc in hexane) to afford the corresponding cycloaddition product.
4.3.1. Ethyl 1-benzyl-3,3-dicyano-2-methylene-1,2,3,10btetrahydro-pyrrolo[2,1-a]phthalazine-1-carboxylate (3a) 90% yield. White solid. M.P. 155e157 C. IR (film) nmax 2983, 1731, 1496, 1454, 1369, 1223, 1196, 1148, 1113, 1018, 927, 873, 794, 762, 703, 591. 1H NMR (300 MHz, CDCl3) d 7.51 (s, 1H), 7.29e7.06 (m, 8H), 6.84e6.75 (m, 1H), 6.05 (d, J ¼ 3.0 Hz, 1H), 5.81 (d, J ¼ 3.0 Hz, 1H), 4.52 (s, 1H), 3.92 (m, J ¼ 7.1, 2.3 Hz, 2H), 3.61 (d, J ¼ 14.5 Hz, 1H), 3.40 (d, J ¼ 14.5 Hz, 1H), 0.82 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.3, 145.1, 143.1, 134.6, 131.8, 131.3, 130.7, 128.8, 128.5, 127.7, 126.4, 125.4, 123.3, 118.6, 113.1, 111.3, 62.0, 60.7, 58.7, 57.4, 40.6, 13.4; HRMS (ESI) calcd for C24H20N4O2Hþ (M þ H)þ 397.1659, found 397.1664.
4.3.2. Ethyl 3,3-dicyano-1-(2-fluorobenzyl)-2-methylene-1,2,3,10bte-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3b) 92% yield. White solid. M.P. 156e158 C. IR (film) nmax 2989, 2318, 1731, 1492, 1456, 1276, 1261, 1116, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.41e7.21 (m, 5H), 7.14e7.08 (m, 2H), 7.00e6.93 (m, 1H), 6.14 (d, J ¼ 3.0 Hz, 1H), 5.92 (d, J ¼ 3.0 Hz, 1H), 4.58 (s, 1H), 4.01 (q, J ¼ 7.1 Hz, 2H), 3.79 (d, J ¼ 14.8 Hz, 1H), 3.51 (d, J ¼ 14.7 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.5, 161.7 (d, J ¼ 245.6 Hz), 160.1, 145.3, 142.6, 133.0 (d, J ¼ 3.8 Hz), 132.1, 131.4, 129.7 (d, J ¼ 8.5 Hz), 128.6, 126.4, 125.4, 124.7 (d, J ¼ 3.5 Hz), 123.2 (d, J ¼ 1.8 Hz), 121.5 (d, J ¼ 14.9 Hz), 118.8, 115.9, 115.6, 113.2, 111.0, 62.1, 60.5, 60.5, 58.7, 57.1, 33.6, 33.1, 13.4; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1568.
4.3.3. Ethyl 3,3-dicyano-1-(3-fluorobenzyl)-2-methylene-1,2,3,10bte-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3c) 86% yield. White solid. M.P. 148e150 C. IR (film) nmax 2984, 1726, 1588, 1487, 1450, 1259, 1145, 923, 763, 704. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.40e7.30 (m, 2H), 7.30e7.16 (m, 2H), 7.02e6.91 (m, 3H), 6.87e6.84 (m, 1H), 6.14 (d, J ¼ 3.0 Hz, 1H), 5.87 (d, J ¼ 3.0 Hz, 1H), 4.57 (s, 1H), 4.05e3.95 (m, 2H), 3.66 (d, J ¼ 14.5 Hz, 1H), 3.47 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 162.8 (d, J ¼ 247.1 Hz), 145.3, 143.0, 137.0 (d, J ¼ 7.3 Hz), 131.7, 131.4, 130.4 (d, J ¼ 8.4 Hz), 128.7, 126.6, 126.5 (d, J ¼ 3.0 Hz), 125.4, 123.1, 118.7, 117.9, 117.6, 115.0, 114.7, 113.0, 111.3, 62.2, 60.8, 58.8, 57.3, 40.5, 13.4; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1565.
B. Wang et al. / Tetrahedron 73 (2017) 5926e5931
4.3.4. Ethyl 3,3-dicyano-1-(4-fluorobenzyl)-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3d) 93% yield. White solid. M.P. 159e160 C. IR (film) nmax 2987, 1731, 1569, 1454, 1369, 1275, 1260, 1222, 1197, 1082, 928, 891, 764, 750, 708. 1H NMR (300 MHz, CDCl3) d 7.63 (s, 1H), 7.40e7.13 (m, 6H), 7.10e7.06 (m, 1H), 6.90e6.80 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.85 (d, J ¼ 3.0 Hz, 1H), 4.56 (s, 1H), 4.04e3.96 (m, 2H), 3.63 (d, J ¼ 14.5 Hz, 1H), 3.45 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.3, 143.0, 136.7, 134.7, 131.6, 131.4, 130.5 (d, J ¼ 53.9 Hz), 128.8 (d, J ¼ 15.2 Hz), 128.1, 126.6, 125.4, 123.1, 118.7, 112.2 (d, J ¼ 127.6 Hz), 62.2, 60.8, 58.8, 57.3, 40.5, 13.42; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1571. 4.3.5. Ethyl 1-(3-chlorobenzyl)-3,3-dicyano-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3e) 89% yield. White solid. M.P. 151e152 C. IR (film) nmax 2989, 1731, 1454, 1276, 1261, 1223, 1197, 1113, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.42e7.16 (m, 6H), 7.10e7.06 (m, 1H), 7.01e6.76 (m, 1H), 6.16e6.12 (m, 1H), 5.86e5.84 (m, 1H), 4.56e4.55 (m, 1H), 4.05e3.95 (m, 2H), 3.70e3.58 (m, 1H), 3.47e3.40 (m, 1H), 0.89 (t, J ¼ 7.1, 3H); 13C NMR (75 MHz, CDCl3) d 145.3, 143.0, 136.7, 134.7, 131.6, 131.4, 130.8, 130.1, 128.9, 128.7, 128.7, 126.6, 125.4, 123.1, 118.7, 113.0, 111.3, 76.6, 62.2, 60.8, 58.8, 57.3, 40.4, 16.1, 13.4; HRMS (ESI) calcd for C24H19ClN4O2Hþ (M þ H)þ 431.1270, found 431.1276. 4.3.6. Ethyl 1-(4-chlorobenzyl)-3,3-dicyano-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3f) 94% yield. White solid. M.P. 159e161 C. IR (film) nmax 2989, 1731, 1491, 1276, 1261, 1222, 1197, 1095, 1016, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (d, J ¼ 0.6 Hz, 1H), 7.39e7.10 (m, 7H), 6.83e6.80 (m, 1H), 6.13 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.55 (s, 1H), 4.03e3.95 (m, 2H), 3.65 (d, J ¼ 14.6 Hz, 1H), 3.43 (d, J ¼ 14.5 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.2, 143.1, 133.9, 133.2, 132.0, 131.6, 131.4, 129.0, 128.7, 126.6, 125.4, 123.2, 118.6, 113.0, 111.5, 62.2, 60.9, 58.8, 57.3, 40.2, 13.4; HRMS (ESI) calcd for C24H19ClN4O2Hþ (M þ H)þ 431.1270, found 431.1280. 4.3.7. Ethyl 1-(3-bromobenzyl)-3,3-dicyano-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3g) 88% yield. White solid. M.P. 152e154 C. IR (film) nmax 2989, 1731, 1454, 1276, 1261, 1222, 1197, 1074, 764, 750, 707. 1H NMR (300 MHz, CDCl3) d 7.62 (d, J ¼ 0.6 Hz, 1H), 7.43e7.25 (m, 5H), 7.16e7.10 (m, 2H), 6.86e6.82 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.55 (s, 1H), 4.04e3.96 (m, 2H), 3.62 (d, J ¼ 14.6 Hz, 1H), 3.44 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.3, 143.0, 137.0, 133.7, 131.6, 131.4, 131.0, 130.3, 129.4, 128.7, 126.6, 125.4, 123.2, 122.9, 118.7, 113.0, 111.3, 62.3, 60.8, 58.8, 57.3, 40.4, 13.4; HRMS (ESI) calcd for C24H19BrN4O2Hþ (M þ H)þ 475.0764, found 475.0773. 4.3.8. Ethyl 1-(4-bromobenzyl)-3,3-dicyano-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3h) 91% yield. White solid. M.P. 153e154 C. IR (film) nmax 2985, 1731, 1488, 1454, 1275, 1260, 1222, 1196, 1114, 1072, 1012, 925, 790, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.65e7.58 (m, 1H), 7.44e7.23 (m, 5H), 7.15e7.04 (m, 2H), 6.80 (d, J ¼ 7.0 Hz, 1H), 6.13 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.54 (s, 1H), 4.03e3.95 (m, 2H), 3.63 (d, J ¼ 14.5 Hz, 1H), 3.41 (d, J ¼ 14.5 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.2, 143.1, 133.7, 132.3, 132.0, 131.6, 131.4, 128.7, 126.6, 125.4, 123.2, 122.0, 118.6, 113.0, 111.5, 62.2, 61.0, 58.8, 57.2, 40.3, 13.4; HRMS (ESI) calcd for C24H19BrN4O2Hþ (M þ H)þ 475.0764, found 475.0772.
5929
4.3.9. Ethyl 3,3-dicyano-2-methylene-1-(3-(trifluoromethyl) benzyl)-1,2, 3,10b-tetrahydropyrrolo[2,1-a]phthalazine-1carboxylate (3i) 86% yield. White solid. M.P. 127e129 C. IR (film) nmax 2988, 1728, 1452, 1332, 1276, 1261, 1165, 1124, 1075, 750, 706. 1H NMR (300 MHz, CDCl3) d 7.63 (d, J ¼ 0.6 Hz, 1H), 7.57e7.47 (m, 2H), 7.43e7.23 (m, 5H), 6.82e6.72 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.85 (d, J ¼ 3.0 Hz, 1H), 4.54 (t, J ¼ 0.8 Hz, 1H), 4.06e3.95 (m, 2H), 3.73 (d, J ¼ 14.5 Hz, 1H), 3.52 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.1, 145.4, 143.0, 135.7, 134.2, 131.4, 131.4, 129.3, 128.8, 127.5 (q, J ¼ 3.7 Hz), 126.7, 125.3, 124.7 (q, J ¼ 3.8 Hz), 123.1, 118.8, 112.9, 111.3, 62.3, 61.0, 58.9, 57.3, 40.8, 13.4; HRMS (ESI) calcd for C25H19F3N4O2Hþ (M þ H)þ 465.1533, found 465.1542. 4.3.10. Ethyl 3,3-dicyano-1-(3-methylbenzyl)-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3j) 85% yield. White solid. M.P. 157e159 C. IR (film) nmax 2983, 1730, 1607, 1454, 1369, 1222, 1197, 1148, 1113, 937, 786, 763, 709, 590. 1H NMR (300 MHz, CDCl3) d 7.59 (d, J ¼ 0.6 Hz, 1H), 7.37e7.23 (m, 3H), 7.17e6.88 (m, 5H), 6.15 (d, J ¼ 2.9 Hz, 1H), 5.91 (d, J ¼ 2.9 Hz, 1H), 4.56 (s, 1H), 4.06e3.95 (m, 2H), 3.64 (d, J ¼ 14.5 Hz, 1H), 3.46 (d, J ¼ 14.5 Hz, 1H), 2.26 (s, 3H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.3, 138.7, 134.6, 132.0, 131.3, 131.2, 128.7, 128.5, 127.7, 126.4, 125.4, 123.4, 118.6, 113.3, 111.5, 62.1, 60.7, 58.8, 57.6, 40.5, 21.3, 13.4; HRMS (ESI) calcd for C25H22N4O2Hþ (M þ H)þ 411.1816, found 411.1823. 4.3.11. Ethyl 3,3-dicyano-1-(4-methylbenzyl)-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3k) 83% yield. White solid. M.P. 165e165 C. IR (film) nmax 2924, 1731, 1454, 1275, 1260, 1222, 1196, 1116, 924, 790, 764. 1H NMR (300 MHz, CDCl3) d 7.59 (s, 1H), 7.37e7.21 (m, 3H), 7.06 (s, 4H), 6.95e6.85 (m, 1H), 6.12 (d, J ¼ 2.9 Hz, 1H), 5.88 (d, J ¼ 2.9 Hz, 1H), 4.59 (s, 1H), 4.00 (m, 2H), 3.64 (d, J ¼ 14.6 Hz, 1H), 3.44 (d, J ¼ 14.6 Hz, 1H), 2.28 (s, 3H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.2, 137.5, 131.9, 131.5, 131.3, 130.5, 129.5, 128.5, 126.4, 125.4, 123.4, 118.5, 113.2, 111.5, 62.0, 60.7, 58.7, 57.5, 40.2, 21.0, 13.4; HRMS (ESI) calcd for C25H22N4O2Hþ (M þ H)þ 411.1816, found 411.1822. 4.3.12. Ethyl 3,3-dicyano-1-(3,5-dimethoxybenzyl)-2-methylene1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3l) 80% yield. White solid. M.P. 141e142 C. IR (film) nmax 3006, 1731, 1597, 1456, 1276, 1261, 1204, 1153, 1072, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.60 (s, 1H), 7.36e7.24 (m, 3H), 6.98e6.94 (m, 1H), 6.39e6.29 (m, 3H), 6.15 (d, J ¼ 2.9 Hz, 1H), 5.91 (d, J ¼ 2.9 Hz, 1H), 4.58 (d, J ¼ 0.9 Hz, 1H), 4.00 (qd, J ¼ 1.2, 7.1 Hz, 2H), 3.69 (s, 6H), 3.60 (d, J ¼ 14.5 Hz, 1H), 3.44 (d, J ¼ 14.5 Hz, 1H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.3, 161.0, 145.0, 143.6, 136.7, 131.9, 131.3, 128.6, 126.5, 125.4, 123.4, 118.5, 113.3, 111.7, 108.9, 99.4, 62.1, 60.8, 58.8, 57.5, 55.2, 40.8, 13.4; HRMS (ESI) calcd for C26H24N4O4Hþ (M þ H)þ 457.1870, found 457.1879. 4.3.13. Ethyl 3,3-dicyano-2-methylene-1-(naphthalen-2-ylmethyl)1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3m) 88% yield. Pale-yellow solid. M.P. 160e161 C. IR (film) nmax 2988, 1730, 1454, 1275, 1261, 1222, 1196, 1112, 933, 860, 822, 751. 1H NMR (300 MHz, CDCl3) d 7.81e7.66 (m, 4H), 7.57 (d, J ¼ 0.6 Hz, 1H), 7.47e7.40 (m, 2H), 7.36e7.21 (m, 4H), 6.96e6.92 (m, 1H), 6.19 (d, J ¼ 3.0 Hz, 1H), 5.95 (d, J ¼ 3.0 Hz, 1H), 4.65 (s, 1H), 4.08e4.97 (m, 2H), 3.85 (d, J ¼ 14.6 Hz, 1H), 3.68 (d, J ¼ 14.5 Hz, 1H), 0.93 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.4, 133.4, 132.7, 132.2, 131.8, 131.3, 129.7, 128.6, 128.6, 128.2, 127.7, 127.6, 126.5, 126.3, 126.1, 125.4, 123.4, 118.7, 113.2, 111.6, 62.2, 61.1, 58.8, 57.7, 40.9, 13.5; HRMS (ESI) calcd for C28H22N4O2Hþ (M þ H)þ 447.1816, found 447.1815.
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4.3.14. Ethyl 3,3-dicyano-1-methyl-2-methylene-1,2,3,10btetrahydro-pyrrolo[2,1-a]phthalazine-1-carboxylate (3n) 82% yield. Pale-yellow solid. M.P. 138e140 C. IR (film) nmax 2985, 1732, 1454, 1373, 1344, 1275, 1261, 1192, 1113, 1025, 937, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.64 (s, 1H), 7.45e7.37 (m, 2H), 7.37e7.20 (m, 2H), 6.00 (d, J ¼ 3.0 Hz, 1H), 5.74 (d, J ¼ 3.0 Hz, 1H), 4.54 (s, 1H), 3.99 (qd, J ¼ 0.9, 7.1 Hz, 2H), 1.80 (s, 3H), 0.93 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.5, 145.5, 144.4, 131.6, 131.1, 128.9, 126.7, 125.4, 123.0, 117.6, 113.2, 112.8, 64.6, 62.0, 58.6, 53.1, 22.6, 13.5; HRMS (ESI) calcd for C18H16N4O2Hþ (M þ H)þ 321.1346, found 321.1347. 4.3.15. Ethyl 3,3-dicyano-1-(2-ethoxy-2-oxoethyl)-2-methylene1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3o) 90% yield. Pale-yellow solid. M.P. 138e140 C. IR (film) nmax 2985, 1732, 1454, 1373, 1344, 1275, 1261, 1192, 1113, 1025, 937, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.44e7.35 (m, 2H), 7.32e7.19 (m, 2H), 6.04 (d, J ¼ 3.1 Hz, 1H), 5.84 (d, J ¼ 3.1 Hz, 1H), 5.15 (s, 1H), 4.24e4.13 (m, 2H), 4.05e3.92 (m, 2H), 3.41 (d, J ¼ 16.7 Hz, 1H), 3.17 (d, J ¼ 16.7 Hz, 1H), 1.26 (t, J ¼ 7.1 Hz, 3H), 0.95 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 169.5, 169.1, 143.8, 142.8, 131.5, 130.8, 128.9, 126.6, 125.4, 123.3, 118.6, 113.3, 112.7, 62.5, 61.6, 61.7, 59.1, 54.8, 38.7, 14.1, 13.4; HRMS (ESI) calcd for C21H20N4O4Hþ (M þ H)þ 393.1557, found 493.1561. 4.3.16. Ethyl 3,3-dicyano-2-methylene-1,2,3,10b-tetrahydropyrrolo [2,1-a]phthalazine-1-carboxylate (3p) 93% yield. White solid. M.P. 108e110 C, IR (film) nmax 2988, 1734, 1454, 1373, 1276, 1261, 1181, 1109, 936, 764, 750, 587. 1H NMR (300 MHz, CDCl3) d 7.65 (d, J ¼ 0.6 Hz, 1H), 7.49e7.23 (m, 3H), 7.19e7.16 (m, 1H), 6.05 (dd, J ¼ 1.5, 2.6 Hz, 1H), 5.90 (dd, J ¼ 1.5, 2.6 Hz, 1H), 4.82 (dt, J ¼ 0.8, 6.0 Hz, 1H), 4.19 (dt, J ¼ 1.5, 6.0 Hz, 1H), 4.06 (q, J ¼ 7.1 Hz, 2H), 1.05 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.0, 144.6, 138.8, 131.7, 131.0, 129.0, 126.7, 125.2, 124.1, 120.2, 112.9, 112.6, 61.9, 59.0, 58.2, 49.4, 13.7; HRMS (ESI) calcd for C17H14N4O2Hþ (M þ H)þ 307.1193, found 307.1190. 4.3.17. Ethyl (E)-3,3-dicyano-2-ethylidene-1,2,3,10btetrahydropyrrolo-[2,1-a]phthalazine-1-carboxylate (3q) 91% yield. Pale-yellow solid. M.P. 123e125 C. IR (film) nmax 2984, 1733, 1454, 1373, 1260, 1178, 1112, 886, 764, 585. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.47e7.33 (m, 2H), 7.33e7.17 (m, 2H), 6.47 (qd, J ¼ 1.8, 7.1 Hz, 1H), 4.76 (d, J ¼ 6.1 Hz, 1H), 4.24e4.22 (m, 1H), 4.04 (q, J ¼ 7.1 Hz, 2H), 1.92 (dd, J ¼ 1.0, 7.1 Hz, 3H), 1.03 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.2, 144.4, 132.4, 131.7, 131.1, 130.8, 129.0, 126.6, 125.2, 124.0, 113.5, 113.2, 61.7, 59.0, 58.4, 46.9, 14.9, 13.8; HRMS (ESI) calcd for C18H16N4O2Hþ (M þ H)þ 321.1346, found 321.1350. 4.3.18. Ethyl (E)-3,3-dicyano-2-propylidene-1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3r) 87% yield. Pale-yellow solid. M.P. 142e144 C. IR (film) nmax 2983, 1713, 1455, 1373, 1276, 1261, 1156, 1115, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.48e7.16 (m, 4H), 6.37 (td, J ¼ 1.8, 7.6 Hz, 1H), 4.77 (d, J ¼ 6.1 Hz, 1H), 4.22 (d, J ¼ 6.1 Hz, 1H), 4.03 (qd, J ¼ 1.3, 7.1 Hz, 2H), 2.38e2.20 (m, 2H), 1.10 (t, J ¼ 7.3 Hz, 3H), 1.03 (t, J ¼ 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.4, 144.4, 138.8, 131.6, 131.1, 129.5, 128.9, 126.6, 125.3, 124.0, 113.6, 113.3, 61.7, 59.0, 58.4, 47.0, 22.9, 13.8, 12.6; HRMS (ESI) calcd for C19H18N4O2Hþ (M þ H)þ 335.1503, found 335.1508. 4.3.19. Ethyl (E)-3,3-dicyano-2-(2-methylpropylidene)-1,2,3,10btetra-hydropyrrolo[2,1-a]phthalazine-1-carboxylate (3s) 90% yield. Pale-yellow solid. M.P. 150e151 C. IR (film) nmax 2989, 2347, 1727, 1455, 1276, 1261, 1113, 764, 750, 663. 1H NMR (300 MHz,
CDCl3) d 7.62 (s, 1H), 7.46e7.33 (m, 2H), 7.32e7.19 (m, 2H), 6.18 (dd, J ¼ 1.7, 10.4 Hz, 1H), 4.77 (d, J ¼ 6.1 Hz, 1H), 4.23 (dd, J ¼ 1.7, 6.1 Hz, 1H), 4.08e3.97 (m, 2H), 2.74e2.62 (m, 1H), 1.11 (d, J ¼ 6.6 Hz, 3H), 1.07e0.99 (m, 6H); 13C NMR (75 MHz, CDCl3) d 168.6, 144.3, 143.5, 131.6, 131.1, 128.9, 128.0, 126.6, 125.3, 124.1, 113.6, 113.3, 61.7, 59.0, 58.4, 47.0, 29.4, 21.8, 21.3, 13.8; HRMS (ESI) calcd for C20H20N4O2Hþ (M þ H)þ 349.1659, found 349.1664. 4.3.20. Ethyl (E)-3,3-dicyano-2-(2,2-dimethylpropylidene)1,2,3,10b-te-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3t) 90% yield. Pale-yellow solid. 1H NMR (300 MHz, CDCl3) d 7.61 (s, 1H), 7.44e7.36 (m, 3H), 7.30 (s, 1H), 6.31 (s, 1H), 4.81 (d, J ¼ 5.8 Hz, 1H), 4.44 (d, J ¼ 5.8 Hz, 1H), 4.10e3.99 (m, 2H), 1.23 (s, 9H), 1.08 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.4, 146.3, 143.7, 131.2, 130.2, 128.7, 127.6, 126.3, 124.9, 124.7, 113.7, 113.6, 61.5, 59.7, 59.6, 46.9, 34.3, 29.1, 13.5; HRMS (ESI) calcd for C21H22N4O2Hþ (M þ H)þ 363.1816, found 363.1812. 4.3.21. Ethyl (E)-3,3-dicyano-2-(2-phenylethylidene)-1,2,3,10btetra-hydropyrrolo[2,1-a]phthalazine-1-carboxylate (3u) 86% yield. Pale-yellow solid. 1H NMR (300 MHz, CDCl3) d 7.67 (s, 1H), 7.50e7.24 (m, 7H), 7.22e7.16 (m, 2H), 6.62 (td, J ¼ 1.7, 7.7 Hz, 1H), 4.85 (d, J ¼ 6.1 Hz, 1H), 4.45e4.32 (m, 1H), 4.03 (qd, J ¼ 1.0, 7.1 Hz, 2H), 3.66 (dd, J ¼ 3.5, 7.7 Hz, 2H), 1.03 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 167.9, 144.3, 136.6, 135.2, 131.4, 130.8, 130.7, 128.7, 128.6, 127.9, 126.7, 126.4, 124.9, 123.8, 113.1, 112.8, 61.6, 58.8, 58.2, 46.9, 34.8, 13.43. HRMS (ESI) calcd for C24H20N4O2Hþ (M þ H)þ 397.1659, found 397.1658. Acknowledgments This work is supported by the NSFC (21372256 and 21572264), and the National S&T Pillar Program of China (2017YFD0200504). Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.08.036. References 1. For selected reviews, see: (a) Gothelf KV, Jørgensen KA. Chem Rev. 1998;98: 863; (b) Gothelf KV. In: Kobayashi S, Jorgensen KA, eds. Cycloaddition Reactions in Organic Synthesis. Wiley-VCH: Weinheim; 2002:211e247; (c) Padwa A, Pearson WH. In: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistrydtoward Heterocycles and Natural Products. Hoboken, NJ: John Wiley and Sons; 2003; (d) Pellissier H. Tetrahedron. 2007;63:3235; (e) Stanley LM, Sibi MP. Chem Rev. 2008;108:2887; (f) Hashimoto T, Maruoka K. In: Ma S, ed. Handbook of Cyclization Reactions. Weinheim, Germany: Wiley-VCH; 2009:87e168 Chapter 3; (g) Engels B, Christl M. Angew Chem Int Ed. 2009;48:7968; (h) Kissane M, Maguire AR. Chem Soc Rev. 2010;39:845; (i) Narayan R, Potowski M, Jia Z-J, Antonchick AP, Waldmann H. Acc Chem Res. 2014;47:1296; (j) Najera C, Sansano JM, Yus M. Org Biomol Chem. 2015;13:8596; (k) Hashimoto T, Maruoka K. Chem Rev. 2015;115:9653. ndez N, Carrillo L, Vicario JL, Badía D, Reyes E. Chem Commun. 2011;47: 2. Ferna 12313. 3. Yuan C, Liu H, Gao Z, et al. Org Lett. 2015;17:26. 4. Liu H, Yuan C, Wu Y, Xiao Y, Guo H. Org Lett. 2015;17:4220. 5. (a) Yuan C, Zhou L, Sun Z, Guo H. RSC Adv. 2016;6:77931. For selected reviews on phosphine-promoted annulations, see:; (b) Lu X, Zhang C, Xu Z. Acc Chem Res. 2001;34:535; (c) Methot JL, Roush WR. Adv Synth Catal. 2004;346:1035; (d) Ye LW, Zhou J, Tang Y. Chem Soc Rev. 2008;37:1140; (e) Cowen BJ, Miller SJ. Chem Soc Rev. 2009;38:3102; (f) Marinetti A, Voituriez A. Synlett. 2010:174; (g) Wang SX, Han XY, Zhong FR, Wang YQ, Lu YX. Synlett. 2011:2766; (h) Zhao QY, Lian Z, Wei Y, Shi M. Chem Commun. 2012;48:1724; (i) Fan YC, Kwon O. Chem Commun. 2013;49:11588;
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(j) Wang Z, Xu X, Kwon O. Chem Soc Rev. 2014;43:2927; (k) Xiao Y, Sun Z, Guo H, Kwon O. Beilstein J Org Chem. 2014;10:2089; (l) Xie P, Huang Y. Org Biomol Chem. 2015;13:8578; (m) Xiao Y, Guo H, Kwon O. Aldrichim Acta. 2016;49:3; (n) Wang T, Han X, Zhong F, Yao W, Lu Y. Acc Chem Res. 2016;49:1369; (o) Li W, Zhang J. Chem Soc Rev. 2016;45:1657. (a) Butler RN, Coyne AG, Burke LA. J Chem Soc Perkin Trans. 2001;2:1781; (b) Butler RN, Coyne AG, Cunningham WJ, Moloney EM, Burke LA. Helv Chim Acta. 2005;88:1611; (c) Beare KD, Yuen AKL, Masters AF, Maschmeyer T, McErlean CSP. Chem Commun. 2013;49:8347. (a) Butler RN, Coyne AG, McArdle P, Cunninghama D, Burke LA. J Chem Soc Perkin Trans. 2001;1:1391; (b) Butler RN, Coyne AG, Cunningham WJ, Burke LA. J Chem Soc Perkin Trans. 2002;2:1807; (c) Butler RN, Coyne AG, Moloney EM. Tetrahedron Lett. 2007;48:3501; (d) Butler RN, Coyne AG, Cunningham WJ, Moloney EM. J Org Chem. 2013;78: 3276; (e) Butler RN, Coyne AG. J Org Chem. 2015;80:1809. ۧer U, Hoffmann A, Regitz M. Tetrahedron Lett. 1992;33:1049. Bergstra Butler RN, Coyne AG, McArdle P, Sibley LM, Burke LA. Tetrahedron Lett. 2007;48:6684.
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10. Yang W, Yuan C, Liu Y, Mao B, Sun Z, Guo H. J Org Chem. 2016;81:7597. 11. (a) Na R, Li Z, Liu H, et al. Tetrahedron. 2012;68:2349; (b) Zhang L, Jing C, Liu H, et al. Synthesis. 2013;45:53; (c) Li Z, Yu H, Zhang L, et al. Lett Org Chem. 2014;11:220; (d) Zhang X, Yuan C, Zhang C, et al. Tetrahedron. 2016;72:8274; (e) For a work from Tong’s group, see: Li FL, Chen JF, Hou YD, Li YJ, Wu XY, Tong XF Org Lett. 2015;17:5376. 12. Wu X, Na R, Liu H, et al. Tetrahedron Lett. 2012;53:342. 13. (a) Na R, Jing C, Xu Q, et al. J Am Chem Soc. 2011;133:13337; (b) Liu J, Liu H, Na R, et al. Chem Lett. 2012;41:218; (c) Jing C, Na R, Wang B, et al. Adv Synth Catal. 2012;354:1023; (d) Guo H, Liu H, Zhu F-L, et al. Angew Chem Int Ed. 2013;52:12641; (e) Li Z, Yu H, Liu H, et al. Chem Eur J. 2014;20:1731; (f) Liu H, Wu Y, Zhao Y, et al. J Am Chem Soc. 2014;136:2625; (g) Li Z, Yu H, Feng Y, et al. RSC Adv. 2015;5:34481; (h) Zhang L, Liu H, Qiao G, et al. J Am Chem Soc. 2015;137:4316; (i) Li Z, Yu H, Liu Y, Zhou L, Sun Z, Guo H. Adv Synth Catal. 2016;358:1880; (j) Yuan C, Zhou L, Xia M, Sun Z, Wang D, Guo H. Org Lett. 2016;18:5644; (k) Zhou L, Yuan C, Zhang C, et al. Adv Synth Catal. 2017;359:2316. 14. Crystallographic data for 3h and 3t have been deposited with the Cambridge Crystallographic Data Centre as deposition number CCDC 1465124 and 1556717, respectively.
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Thermal [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with allenoates Bo Wang a, Honglei Liu a, Qijun Wang a, Chunhao Yuan a, Hao Jia a, Chunxiao Liu a, Hongchao Guo a, b, * a b
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 June 2017 Received in revised form 15 August 2017 Accepted 18 August 2017 Available online 24 August 2017
The thermal [3 þ 2] cycloaddition reaction of phthalazinium dicyanomethanide with various allenoates worked efficiently under mild reaction conditions to give functionalized tetrahydropyrrolo[2,1-a] phthalazine derivatives in good to excellent yields and excellent diastereoselectivities. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Cycloaddition Allenoate Phthalazinium dicyanomethanide Heterocycle Tetrahydropyrrolophthalazine
1. Introduction 1,3-Dipolar cycloaddition reactions represent an important class of synthetic methods for the convergent synthesis of a wide range of heterocycles.1 Numerous 1,3-dipoles such as nitrone, azomethine ylide, azomethine imine, nitrile oxide, carbonyl ylide, azide, nitrile imine, carbonyl oxide, diazoalkane and diazoacetate have been exploited for research on cycloaddition chemistry.1 Compared with high-profile dipoles such as nitrone, azomethine ylide, azomethine imine, phthalazinium dicyanomethanide has received little attention although it has several salient features including stability, easy preparation, and high reactivity. In limited examples, it has been used as 1,3-dipole in some thermal, metal-catalyzed and organocatalytic cycloadditions. In 2011, with the use of chiral imidazolidinone as catalyst, the catalytic enantioselective [3 þ 2] cycloaddition between enals and phthalazinium dicyanomethanide was achieved to give highly substituted chiral pyrrolophthalazines in high yields and excellent diastereo- and enantioselectivities.2 In 2015, we reported the Cu(I)-catalyzed highly enantioselective [3 þ 3] cycloaddition
* Corresponding author. Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. E-mail address: [email protected] (H. Guo). http://dx.doi.org/10.1016/j.tet.2017.08.036 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
between phthalazinium dicyanomethanides and iminoester-derived azomethine ylides, providing novel chiral heterocyclic compounds, 2,3,4,11b-tetrahydro-1H-pyrazino[2,1-a]phthalazine derivatives, in high yields with excellent diastereo- and enantioselectivies.3 In the same year, we also developed the Sc(OTf)3-catalyzed diastereoselective [3 þ 3] cycloaddition of phthalazinium dicyanomethanides with cyclopropane 1,1-diesters, affording a variety of 3,4dihydro-1H-pyrido[2,1-a]phthalazine derivatives in high yields with excellent diastereoselectivities.4 Recently, we developed the phosphine-catalyzed [3 þ 2] cycloaddition between phthalazinium dicyanomethanides and allenoates, in which double bond between Cß and Cg of allenoates underwent stepwise cycloaddition with dipole to afford a broad range of novel heterocyclic compounds 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives in excellent yields (Scheme 1a).5 In addition to these catalytic cycloadditions, the thermal [3 þ 2] cycloaddition reactions of phthalazinium dicyanomethanide with alkenes,6 alkynes,6,7 phosphaalkynes,8 or thiones9 have extensively been studied and the [4 þ 3] cycloaddition reaction of phthalazinium dicyanomethanide with azoalkenes formed in situ was recently reported.10 However, thermal cycloaddition of phthalazinium dicyanomethanide with allenoates has never been explored although the electron-deficient allenes have similar reaction activity as alkenes and alkynes. In our previous work, we have investigated the thermal [3 þ 2] cycloaddition reactions of various azomethine
B. Wang et al. / Tetrahedron 73 (2017) 5926e5931
Scheme 1. The [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with allenoates.
imines with allenoates, providing a variety of dinitrogen-fused heterocycles in moderate to excellent yields.11 We also achieved sequential [3 þ 2] cycloaddition/rearrangement reaction of imidazolone nitrones with allenoates, affording the methylene imidazolidinone derivatives in high yields.12 As a continuous interest in cycloaddition reactions,13 herein, employing phthalazinium dicyanomethanide as 1,3-dipole, we describe thermal [3 þ 2] cycloaddition of phthalazinium dicyanomethanide with several types of allenoates, in which double bond between Ca and Cb of allenoate performed [3 þ 2] cycloaddition with dipole to provide functionalized tetrahydropyrrolo[2,1-a]phthalazine derivatives (Scheme 1b). 2. Results and discussions Initially, the [3 þ 2] cycloaddition was investigated with phthalazinium-2-dicyanomethanide (1) and allenoate (2a) as model substrates (Table 1). The reaction was performed at the room temperature. Several solvents were first screened. Treatment of the phthalazinium-2-dicyanomethanide (1) with the allenoate (2a) in THF for 48 h afforded the cycloadduct 3a in 68% yield with excellent diastereoselectivity (entry 1). With the use of dichloromethane as the solvent, the yield was remarkably increased to 76% yield (entry 2). Protic solvents such as H2O and MeOH could not help improve the yields (entries 3, 4). To our delight, the polar solvent acetonitrile demonstrated excellent compatibility, leading to the product 3a in 89% yield (entry 5). When the reaction temperature was increased to 40 C, the reaction time was shortened to 24 h and the yield was still excellent 90% (entry 6). Higher reaction temperature such as 60 C did not further improve the result, on the contrary, resulted in the deterioration of the yield. Based on the above results, the [3 þ 2]
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cycloaddition reactions were next performed in MeCN at 40 C for 24 h. With the optimized conditions in hand, the scope of a-substituted allenoates were next evaluated. As shown in Table 2, the [3 þ 2] cycloaddition reaction of phthalazinium-2-dicyanomethanide (1) with various a-arylmethyl-substituted allenoates (2) proceeded smoothly to provide the cycloadducts in good to excellent yields (80e94%) with excellent diastereoselectivities (entries 1e13). The allenoates bearing both electron-donating and electronwithdrawing substituents on the benzene ring could perform the reaction to give the corresponding product (entries 1e12). Moreover, the substitution pattern had no remarkable influence on the reactivity and stereoselectivity, probably due to the long distance between the aryl group and the reactive center. Particularly, allenoates containing electron-withdrawing groups seemed to produce the corresponding products in higher yields, compared with those allenoates with electron-donating group (entries 2e9 vs 10e12). Additionally, 2-naphthyl substituted allenaote 2m also worked well to afford the cycloadduct 3m in 88% yield (entry 13). The a-methylsubstituted allenoate 2n was also a compatible substrate, performing the [3 þ 2] cycloaddition reaction with phthalazinium-2dicyanomethanide (1) to afford the corresponding product 3n in 82% yield (entry 14). The ethoxycarbonyl substituted allenoate 2o underwent the reaction to afford the cycloadduct 3o in 90% yield (entry 15). The relative configuration of these products has been determined through X-ray crystallographic data of the product 3h.14 The regioselectivity that the double bond between Ca and Cb of allenoate performs cycloaddition with dipole might be the consequence of thermodynamic control. As shown in Table 3, ethyl buta-2,3-dienoate and g-substituted allenoates have also been investigated in this thermal [3 þ 2] cycloaddition reaction with phthalazinium-2-dicyanome-thanide, providing the cycloadducts in good to excellent yields and excellent diastereoselectivities. Ethyl buta-2,3-dienoate performed the reaction to produce the product 3p in 88% yield (entry 1). The reactions of several g-alkyl substituted allenoates (2qe2t) with phthalazinium-2-dicyanome-thanide (1) proceeded smoothly in
Table 2 [3 þ 2] cycloaddition of phthalazinium-2-dicyanome-thanide with a-substituted allenoatesa.
Table 1 Screening of the reaction conditionsa.
Entry
Solvent
Temp. ( C)
t (h)
Yieldb (%)
1 2 3 4 5 6 7
THF CH2Cl2 MeOH H2O MeCN MeCN MeCN
25 25 25 25 25 40 60
48 48 48 48 48 24 24
68 76 74 56 89 90 85
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2a in 2 mL of solvent. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
Entry
R
3
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Ph (2a) 2-FC6H4 (2b) 3-FC6H4 (2c) 4-FC6H4 (2d) 3-ClC6H4 (2e) 4-ClC6H4 (2f) 3-BrC6H4 (2g) 4-BrC6H4 (2h) 3-CF3C6H4 (2i) 3-MeC6H4 (2j) 4-MeC6H4 (2k) 3,5-(OMe)2C6H3 (2l) 2-naphthyl (2m) H (2n) CO2Et (2o)
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o
90 92 86 93 89 94 88 91 86 85 83 80 88 82 90
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2 in 2 mL of MeCN. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
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Table 3 [3 þ 2] cycloaddition of phthalazinium-2-dicyanome-thanide with ethyl buta-2,3dienoate and g-substituted allenoatesa.
Entry
R
3
Yieldb (%)
1 2 3 4 5 6
H (2p) Me (2q) Et (2r) i-Pr (2s) t-Bu (2t) Bn (2u)
3p 3q 3r 3s 3t 3u
88 91 87 90 92 86
a The reaction was carried out with 0.1 mmol of 1 and 0.15 mmol of 2 in 2 mL of MeCN. b Isolated yield; > 20: 1 dr, determined by 1H NMR data.
MeCN at 40 C, providing the corresponding products (3qe3t) in 87e92% yields (entries 2e5). The g-benzyl-substituted allenoate 2u could also carry out the reaction to give the product 3u in 86% yield. The relative configuration of these products has been determined through X-ray crystallographic data of the product 3t.14 3. Conclusion In summary, the thermal [3 þ 2] cycloaddition reaction of phthalazinium dicyanomethanide with several types of allenoates has been explored. The reaction is operationally simple and worked efficiently to afford a broad range of functionalized tetrahydropyrrolo[2,1-a]phthalazine derivatives in good to excellent yields with excellent diastereoselectivities. 4. Experimental section All reactions were performed in air in oven-dried glassware with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. All solvents were purified and dried according to standard methods prior to use. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200e300 mesh). 1 H and 13C NMR spectra were recorded in CDCl3 using a 300 MHz Bruker NMR instrument. Accurate mass measurements were performed using an Agilent instrument with the ESI-MS technique. Xray crystallographic data were collected using a MM007HF Saturn 724þ. 4.1. Preparation of phthalazinium dicyanomethanide 1 Phthalazinium dicyanomethanide was synthesized by adding phthalazine or phthalazine derivative (14.58 mmol) to a solution of TCNEO (4.86 mmol) in THF (50 mL) at 0 C. The reaction was stirred at this temperature for 2 h. Then, the formed solid was isolated by filtration and washed with cold THF (3 25 mL) to give the product in nearly quantitative yield. 4.2. Preparation of allenoates 2 The alkyl halide (1.1 equiv) was added to a stirred solution of (carbethoxymethylene)triphenylphosphorane in CHCl3 (80 mL) at room temperature. The mixture was heated under reflux until all of the (carbethoxymethylene)triphenylphosphorane had been
consumed (monitored using TLC). The solvent was evaporated under reduced pressure. CH2Cl2 (100 mL) and triethylamine (8.4 mL, 2.2 equiv) were added to the resulting phosphonium salt. After stirring for 1 h, AcCl (1.96 mL, 1.0 equiv) was added dropwise over 30 min using a syringe pump. The mixture was stirred overnight and then passed through a Buchner funnel packed with silica gel and washed several times with CH2Cl2. The combined filtrates were carefully concentrated and the residue was subjected to a flash column chromatography isolation (eluent: 10e15% EtOAc in hexane) to afford the corresponding allenoate 2. 4.3. General procedure for [3 þ 2] cycloaddition Phthalazinium dicyanomethanide 1 (0.1 mmol) and allenoate 2 (0.15 mmol) were dissolved in 2 mL of MeCN and then stirred at 40 C for about 24 h. Once starting material was consumed (monitored by TLC), the mixture was concentrated to dryness. The residue was purified through flash column chromatography (eluent: 8% EtOAc in hexane) to afford the corresponding cycloaddition product.
4.3.1. Ethyl 1-benzyl-3,3-dicyano-2-methylene-1,2,3,10btetrahydro-pyrrolo[2,1-a]phthalazine-1-carboxylate (3a) 90% yield. White solid. M.P. 155e157 C. IR (film) nmax 2983, 1731, 1496, 1454, 1369, 1223, 1196, 1148, 1113, 1018, 927, 873, 794, 762, 703, 591. 1H NMR (300 MHz, CDCl3) d 7.51 (s, 1H), 7.29e7.06 (m, 8H), 6.84e6.75 (m, 1H), 6.05 (d, J ¼ 3.0 Hz, 1H), 5.81 (d, J ¼ 3.0 Hz, 1H), 4.52 (s, 1H), 3.92 (m, J ¼ 7.1, 2.3 Hz, 2H), 3.61 (d, J ¼ 14.5 Hz, 1H), 3.40 (d, J ¼ 14.5 Hz, 1H), 0.82 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.3, 145.1, 143.1, 134.6, 131.8, 131.3, 130.7, 128.8, 128.5, 127.7, 126.4, 125.4, 123.3, 118.6, 113.1, 111.3, 62.0, 60.7, 58.7, 57.4, 40.6, 13.4; HRMS (ESI) calcd for C24H20N4O2Hþ (M þ H)þ 397.1659, found 397.1664.
4.3.2. Ethyl 3,3-dicyano-1-(2-fluorobenzyl)-2-methylene-1,2,3,10bte-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3b) 92% yield. White solid. M.P. 156e158 C. IR (film) nmax 2989, 2318, 1731, 1492, 1456, 1276, 1261, 1116, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.41e7.21 (m, 5H), 7.14e7.08 (m, 2H), 7.00e6.93 (m, 1H), 6.14 (d, J ¼ 3.0 Hz, 1H), 5.92 (d, J ¼ 3.0 Hz, 1H), 4.58 (s, 1H), 4.01 (q, J ¼ 7.1 Hz, 2H), 3.79 (d, J ¼ 14.8 Hz, 1H), 3.51 (d, J ¼ 14.7 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.5, 161.7 (d, J ¼ 245.6 Hz), 160.1, 145.3, 142.6, 133.0 (d, J ¼ 3.8 Hz), 132.1, 131.4, 129.7 (d, J ¼ 8.5 Hz), 128.6, 126.4, 125.4, 124.7 (d, J ¼ 3.5 Hz), 123.2 (d, J ¼ 1.8 Hz), 121.5 (d, J ¼ 14.9 Hz), 118.8, 115.9, 115.6, 113.2, 111.0, 62.1, 60.5, 60.5, 58.7, 57.1, 33.6, 33.1, 13.4; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1568.
4.3.3. Ethyl 3,3-dicyano-1-(3-fluorobenzyl)-2-methylene-1,2,3,10bte-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3c) 86% yield. White solid. M.P. 148e150 C. IR (film) nmax 2984, 1726, 1588, 1487, 1450, 1259, 1145, 923, 763, 704. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.40e7.30 (m, 2H), 7.30e7.16 (m, 2H), 7.02e6.91 (m, 3H), 6.87e6.84 (m, 1H), 6.14 (d, J ¼ 3.0 Hz, 1H), 5.87 (d, J ¼ 3.0 Hz, 1H), 4.57 (s, 1H), 4.05e3.95 (m, 2H), 3.66 (d, J ¼ 14.5 Hz, 1H), 3.47 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 162.8 (d, J ¼ 247.1 Hz), 145.3, 143.0, 137.0 (d, J ¼ 7.3 Hz), 131.7, 131.4, 130.4 (d, J ¼ 8.4 Hz), 128.7, 126.6, 126.5 (d, J ¼ 3.0 Hz), 125.4, 123.1, 118.7, 117.9, 117.6, 115.0, 114.7, 113.0, 111.3, 62.2, 60.8, 58.8, 57.3, 40.5, 13.4; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1565.
B. Wang et al. / Tetrahedron 73 (2017) 5926e5931
4.3.4. Ethyl 3,3-dicyano-1-(4-fluorobenzyl)-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3d) 93% yield. White solid. M.P. 159e160 C. IR (film) nmax 2987, 1731, 1569, 1454, 1369, 1275, 1260, 1222, 1197, 1082, 928, 891, 764, 750, 708. 1H NMR (300 MHz, CDCl3) d 7.63 (s, 1H), 7.40e7.13 (m, 6H), 7.10e7.06 (m, 1H), 6.90e6.80 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.85 (d, J ¼ 3.0 Hz, 1H), 4.56 (s, 1H), 4.04e3.96 (m, 2H), 3.63 (d, J ¼ 14.5 Hz, 1H), 3.45 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.3, 143.0, 136.7, 134.7, 131.6, 131.4, 130.5 (d, J ¼ 53.9 Hz), 128.8 (d, J ¼ 15.2 Hz), 128.1, 126.6, 125.4, 123.1, 118.7, 112.2 (d, J ¼ 127.6 Hz), 62.2, 60.8, 58.8, 57.3, 40.5, 13.42; HRMS (ESI) calcd for C24H19FN4O2Hþ (M þ H)þ 415.1565, found 415.1571. 4.3.5. Ethyl 1-(3-chlorobenzyl)-3,3-dicyano-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3e) 89% yield. White solid. M.P. 151e152 C. IR (film) nmax 2989, 1731, 1454, 1276, 1261, 1223, 1197, 1113, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.42e7.16 (m, 6H), 7.10e7.06 (m, 1H), 7.01e6.76 (m, 1H), 6.16e6.12 (m, 1H), 5.86e5.84 (m, 1H), 4.56e4.55 (m, 1H), 4.05e3.95 (m, 2H), 3.70e3.58 (m, 1H), 3.47e3.40 (m, 1H), 0.89 (t, J ¼ 7.1, 3H); 13C NMR (75 MHz, CDCl3) d 145.3, 143.0, 136.7, 134.7, 131.6, 131.4, 130.8, 130.1, 128.9, 128.7, 128.7, 126.6, 125.4, 123.1, 118.7, 113.0, 111.3, 76.6, 62.2, 60.8, 58.8, 57.3, 40.4, 16.1, 13.4; HRMS (ESI) calcd for C24H19ClN4O2Hþ (M þ H)þ 431.1270, found 431.1276. 4.3.6. Ethyl 1-(4-chlorobenzyl)-3,3-dicyano-2-methylene-1,2,3,10btetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3f) 94% yield. White solid. M.P. 159e161 C. IR (film) nmax 2989, 1731, 1491, 1276, 1261, 1222, 1197, 1095, 1016, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (d, J ¼ 0.6 Hz, 1H), 7.39e7.10 (m, 7H), 6.83e6.80 (m, 1H), 6.13 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.55 (s, 1H), 4.03e3.95 (m, 2H), 3.65 (d, J ¼ 14.6 Hz, 1H), 3.43 (d, J ¼ 14.5 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.2, 143.1, 133.9, 133.2, 132.0, 131.6, 131.4, 129.0, 128.7, 126.6, 125.4, 123.2, 118.6, 113.0, 111.5, 62.2, 60.9, 58.8, 57.3, 40.2, 13.4; HRMS (ESI) calcd for C24H19ClN4O2Hþ (M þ H)þ 431.1270, found 431.1280. 4.3.7. Ethyl 1-(3-bromobenzyl)-3,3-dicyano-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3g) 88% yield. White solid. M.P. 152e154 C. IR (film) nmax 2989, 1731, 1454, 1276, 1261, 1222, 1197, 1074, 764, 750, 707. 1H NMR (300 MHz, CDCl3) d 7.62 (d, J ¼ 0.6 Hz, 1H), 7.43e7.25 (m, 5H), 7.16e7.10 (m, 2H), 6.86e6.82 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.55 (s, 1H), 4.04e3.96 (m, 2H), 3.62 (d, J ¼ 14.6 Hz, 1H), 3.44 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.3, 143.0, 137.0, 133.7, 131.6, 131.4, 131.0, 130.3, 129.4, 128.7, 126.6, 125.4, 123.2, 122.9, 118.7, 113.0, 111.3, 62.3, 60.8, 58.8, 57.3, 40.4, 13.4; HRMS (ESI) calcd for C24H19BrN4O2Hþ (M þ H)þ 475.0764, found 475.0773. 4.3.8. Ethyl 1-(4-bromobenzyl)-3,3-dicyano-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3h) 91% yield. White solid. M.P. 153e154 C. IR (film) nmax 2985, 1731, 1488, 1454, 1275, 1260, 1222, 1196, 1114, 1072, 1012, 925, 790, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.65e7.58 (m, 1H), 7.44e7.23 (m, 5H), 7.15e7.04 (m, 2H), 6.80 (d, J ¼ 7.0 Hz, 1H), 6.13 (d, J ¼ 3.0 Hz, 1H), 5.84 (d, J ¼ 3.0 Hz, 1H), 4.54 (s, 1H), 4.03e3.95 (m, 2H), 3.63 (d, J ¼ 14.5 Hz, 1H), 3.41 (d, J ¼ 14.5 Hz, 1H), 0.89 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.2, 145.2, 143.1, 133.7, 132.3, 132.0, 131.6, 131.4, 128.7, 126.6, 125.4, 123.2, 122.0, 118.6, 113.0, 111.5, 62.2, 61.0, 58.8, 57.2, 40.3, 13.4; HRMS (ESI) calcd for C24H19BrN4O2Hþ (M þ H)þ 475.0764, found 475.0772.
5929
4.3.9. Ethyl 3,3-dicyano-2-methylene-1-(3-(trifluoromethyl) benzyl)-1,2, 3,10b-tetrahydropyrrolo[2,1-a]phthalazine-1carboxylate (3i) 86% yield. White solid. M.P. 127e129 C. IR (film) nmax 2988, 1728, 1452, 1332, 1276, 1261, 1165, 1124, 1075, 750, 706. 1H NMR (300 MHz, CDCl3) d 7.63 (d, J ¼ 0.6 Hz, 1H), 7.57e7.47 (m, 2H), 7.43e7.23 (m, 5H), 6.82e6.72 (m, 1H), 6.15 (d, J ¼ 3.0 Hz, 1H), 5.85 (d, J ¼ 3.0 Hz, 1H), 4.54 (t, J ¼ 0.8 Hz, 1H), 4.06e3.95 (m, 2H), 3.73 (d, J ¼ 14.5 Hz, 1H), 3.52 (d, J ¼ 14.5 Hz, 1H), 0.90 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.1, 145.4, 143.0, 135.7, 134.2, 131.4, 131.4, 129.3, 128.8, 127.5 (q, J ¼ 3.7 Hz), 126.7, 125.3, 124.7 (q, J ¼ 3.8 Hz), 123.1, 118.8, 112.9, 111.3, 62.3, 61.0, 58.9, 57.3, 40.8, 13.4; HRMS (ESI) calcd for C25H19F3N4O2Hþ (M þ H)þ 465.1533, found 465.1542. 4.3.10. Ethyl 3,3-dicyano-1-(3-methylbenzyl)-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3j) 85% yield. White solid. M.P. 157e159 C. IR (film) nmax 2983, 1730, 1607, 1454, 1369, 1222, 1197, 1148, 1113, 937, 786, 763, 709, 590. 1H NMR (300 MHz, CDCl3) d 7.59 (d, J ¼ 0.6 Hz, 1H), 7.37e7.23 (m, 3H), 7.17e6.88 (m, 5H), 6.15 (d, J ¼ 2.9 Hz, 1H), 5.91 (d, J ¼ 2.9 Hz, 1H), 4.56 (s, 1H), 4.06e3.95 (m, 2H), 3.64 (d, J ¼ 14.5 Hz, 1H), 3.46 (d, J ¼ 14.5 Hz, 1H), 2.26 (s, 3H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.3, 138.7, 134.6, 132.0, 131.3, 131.2, 128.7, 128.5, 127.7, 126.4, 125.4, 123.4, 118.6, 113.3, 111.5, 62.1, 60.7, 58.8, 57.6, 40.5, 21.3, 13.4; HRMS (ESI) calcd for C25H22N4O2Hþ (M þ H)þ 411.1816, found 411.1823. 4.3.11. Ethyl 3,3-dicyano-1-(4-methylbenzyl)-2-methylene1,2,3,10b-tetr-ahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3k) 83% yield. White solid. M.P. 165e165 C. IR (film) nmax 2924, 1731, 1454, 1275, 1260, 1222, 1196, 1116, 924, 790, 764. 1H NMR (300 MHz, CDCl3) d 7.59 (s, 1H), 7.37e7.21 (m, 3H), 7.06 (s, 4H), 6.95e6.85 (m, 1H), 6.12 (d, J ¼ 2.9 Hz, 1H), 5.88 (d, J ¼ 2.9 Hz, 1H), 4.59 (s, 1H), 4.00 (m, 2H), 3.64 (d, J ¼ 14.6 Hz, 1H), 3.44 (d, J ¼ 14.6 Hz, 1H), 2.28 (s, 3H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.2, 137.5, 131.9, 131.5, 131.3, 130.5, 129.5, 128.5, 126.4, 125.4, 123.4, 118.5, 113.2, 111.5, 62.0, 60.7, 58.7, 57.5, 40.2, 21.0, 13.4; HRMS (ESI) calcd for C25H22N4O2Hþ (M þ H)þ 411.1816, found 411.1822. 4.3.12. Ethyl 3,3-dicyano-1-(3,5-dimethoxybenzyl)-2-methylene1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3l) 80% yield. White solid. M.P. 141e142 C. IR (film) nmax 3006, 1731, 1597, 1456, 1276, 1261, 1204, 1153, 1072, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.60 (s, 1H), 7.36e7.24 (m, 3H), 6.98e6.94 (m, 1H), 6.39e6.29 (m, 3H), 6.15 (d, J ¼ 2.9 Hz, 1H), 5.91 (d, J ¼ 2.9 Hz, 1H), 4.58 (d, J ¼ 0.9 Hz, 1H), 4.00 (qd, J ¼ 1.2, 7.1 Hz, 2H), 3.69 (s, 6H), 3.60 (d, J ¼ 14.5 Hz, 1H), 3.44 (d, J ¼ 14.5 Hz, 1H), 0.91 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.3, 161.0, 145.0, 143.6, 136.7, 131.9, 131.3, 128.6, 126.5, 125.4, 123.4, 118.5, 113.3, 111.7, 108.9, 99.4, 62.1, 60.8, 58.8, 57.5, 55.2, 40.8, 13.4; HRMS (ESI) calcd for C26H24N4O4Hþ (M þ H)þ 457.1870, found 457.1879. 4.3.13. Ethyl 3,3-dicyano-2-methylene-1-(naphthalen-2-ylmethyl)1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3m) 88% yield. Pale-yellow solid. M.P. 160e161 C. IR (film) nmax 2988, 1730, 1454, 1275, 1261, 1222, 1196, 1112, 933, 860, 822, 751. 1H NMR (300 MHz, CDCl3) d 7.81e7.66 (m, 4H), 7.57 (d, J ¼ 0.6 Hz, 1H), 7.47e7.40 (m, 2H), 7.36e7.21 (m, 4H), 6.96e6.92 (m, 1H), 6.19 (d, J ¼ 3.0 Hz, 1H), 5.95 (d, J ¼ 3.0 Hz, 1H), 4.65 (s, 1H), 4.08e4.97 (m, 2H), 3.85 (d, J ¼ 14.6 Hz, 1H), 3.68 (d, J ¼ 14.5 Hz, 1H), 0.93 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 145.0, 143.4, 133.4, 132.7, 132.2, 131.8, 131.3, 129.7, 128.6, 128.6, 128.2, 127.7, 127.6, 126.5, 126.3, 126.1, 125.4, 123.4, 118.7, 113.2, 111.6, 62.2, 61.1, 58.8, 57.7, 40.9, 13.5; HRMS (ESI) calcd for C28H22N4O2Hþ (M þ H)þ 447.1816, found 447.1815.
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4.3.14. Ethyl 3,3-dicyano-1-methyl-2-methylene-1,2,3,10btetrahydro-pyrrolo[2,1-a]phthalazine-1-carboxylate (3n) 82% yield. Pale-yellow solid. M.P. 138e140 C. IR (film) nmax 2985, 1732, 1454, 1373, 1344, 1275, 1261, 1192, 1113, 1025, 937, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.64 (s, 1H), 7.45e7.37 (m, 2H), 7.37e7.20 (m, 2H), 6.00 (d, J ¼ 3.0 Hz, 1H), 5.74 (d, J ¼ 3.0 Hz, 1H), 4.54 (s, 1H), 3.99 (qd, J ¼ 0.9, 7.1 Hz, 2H), 1.80 (s, 3H), 0.93 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 170.5, 145.5, 144.4, 131.6, 131.1, 128.9, 126.7, 125.4, 123.0, 117.6, 113.2, 112.8, 64.6, 62.0, 58.6, 53.1, 22.6, 13.5; HRMS (ESI) calcd for C18H16N4O2Hþ (M þ H)þ 321.1346, found 321.1347. 4.3.15. Ethyl 3,3-dicyano-1-(2-ethoxy-2-oxoethyl)-2-methylene1,2,3, 10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3o) 90% yield. Pale-yellow solid. M.P. 138e140 C. IR (film) nmax 2985, 1732, 1454, 1373, 1344, 1275, 1261, 1192, 1113, 1025, 937, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.44e7.35 (m, 2H), 7.32e7.19 (m, 2H), 6.04 (d, J ¼ 3.1 Hz, 1H), 5.84 (d, J ¼ 3.1 Hz, 1H), 5.15 (s, 1H), 4.24e4.13 (m, 2H), 4.05e3.92 (m, 2H), 3.41 (d, J ¼ 16.7 Hz, 1H), 3.17 (d, J ¼ 16.7 Hz, 1H), 1.26 (t, J ¼ 7.1 Hz, 3H), 0.95 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 169.5, 169.1, 143.8, 142.8, 131.5, 130.8, 128.9, 126.6, 125.4, 123.3, 118.6, 113.3, 112.7, 62.5, 61.6, 61.7, 59.1, 54.8, 38.7, 14.1, 13.4; HRMS (ESI) calcd for C21H20N4O4Hþ (M þ H)þ 393.1557, found 493.1561. 4.3.16. Ethyl 3,3-dicyano-2-methylene-1,2,3,10b-tetrahydropyrrolo [2,1-a]phthalazine-1-carboxylate (3p) 93% yield. White solid. M.P. 108e110 C, IR (film) nmax 2988, 1734, 1454, 1373, 1276, 1261, 1181, 1109, 936, 764, 750, 587. 1H NMR (300 MHz, CDCl3) d 7.65 (d, J ¼ 0.6 Hz, 1H), 7.49e7.23 (m, 3H), 7.19e7.16 (m, 1H), 6.05 (dd, J ¼ 1.5, 2.6 Hz, 1H), 5.90 (dd, J ¼ 1.5, 2.6 Hz, 1H), 4.82 (dt, J ¼ 0.8, 6.0 Hz, 1H), 4.19 (dt, J ¼ 1.5, 6.0 Hz, 1H), 4.06 (q, J ¼ 7.1 Hz, 2H), 1.05 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.0, 144.6, 138.8, 131.7, 131.0, 129.0, 126.7, 125.2, 124.1, 120.2, 112.9, 112.6, 61.9, 59.0, 58.2, 49.4, 13.7; HRMS (ESI) calcd for C17H14N4O2Hþ (M þ H)þ 307.1193, found 307.1190. 4.3.17. Ethyl (E)-3,3-dicyano-2-ethylidene-1,2,3,10btetrahydropyrrolo-[2,1-a]phthalazine-1-carboxylate (3q) 91% yield. Pale-yellow solid. M.P. 123e125 C. IR (film) nmax 2984, 1733, 1454, 1373, 1260, 1178, 1112, 886, 764, 585. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.47e7.33 (m, 2H), 7.33e7.17 (m, 2H), 6.47 (qd, J ¼ 1.8, 7.1 Hz, 1H), 4.76 (d, J ¼ 6.1 Hz, 1H), 4.24e4.22 (m, 1H), 4.04 (q, J ¼ 7.1 Hz, 2H), 1.92 (dd, J ¼ 1.0, 7.1 Hz, 3H), 1.03 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.2, 144.4, 132.4, 131.7, 131.1, 130.8, 129.0, 126.6, 125.2, 124.0, 113.5, 113.2, 61.7, 59.0, 58.4, 46.9, 14.9, 13.8; HRMS (ESI) calcd for C18H16N4O2Hþ (M þ H)þ 321.1346, found 321.1350. 4.3.18. Ethyl (E)-3,3-dicyano-2-propylidene-1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3r) 87% yield. Pale-yellow solid. M.P. 142e144 C. IR (film) nmax 2983, 1713, 1455, 1373, 1276, 1261, 1156, 1115, 764, 750. 1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.48e7.16 (m, 4H), 6.37 (td, J ¼ 1.8, 7.6 Hz, 1H), 4.77 (d, J ¼ 6.1 Hz, 1H), 4.22 (d, J ¼ 6.1 Hz, 1H), 4.03 (qd, J ¼ 1.3, 7.1 Hz, 2H), 2.38e2.20 (m, 2H), 1.10 (t, J ¼ 7.3 Hz, 3H), 1.03 (t, J ¼ 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.4, 144.4, 138.8, 131.6, 131.1, 129.5, 128.9, 126.6, 125.3, 124.0, 113.6, 113.3, 61.7, 59.0, 58.4, 47.0, 22.9, 13.8, 12.6; HRMS (ESI) calcd for C19H18N4O2Hþ (M þ H)þ 335.1503, found 335.1508. 4.3.19. Ethyl (E)-3,3-dicyano-2-(2-methylpropylidene)-1,2,3,10btetra-hydropyrrolo[2,1-a]phthalazine-1-carboxylate (3s) 90% yield. Pale-yellow solid. M.P. 150e151 C. IR (film) nmax 2989, 2347, 1727, 1455, 1276, 1261, 1113, 764, 750, 663. 1H NMR (300 MHz,
CDCl3) d 7.62 (s, 1H), 7.46e7.33 (m, 2H), 7.32e7.19 (m, 2H), 6.18 (dd, J ¼ 1.7, 10.4 Hz, 1H), 4.77 (d, J ¼ 6.1 Hz, 1H), 4.23 (dd, J ¼ 1.7, 6.1 Hz, 1H), 4.08e3.97 (m, 2H), 2.74e2.62 (m, 1H), 1.11 (d, J ¼ 6.6 Hz, 3H), 1.07e0.99 (m, 6H); 13C NMR (75 MHz, CDCl3) d 168.6, 144.3, 143.5, 131.6, 131.1, 128.9, 128.0, 126.6, 125.3, 124.1, 113.6, 113.3, 61.7, 59.0, 58.4, 47.0, 29.4, 21.8, 21.3, 13.8; HRMS (ESI) calcd for C20H20N4O2Hþ (M þ H)þ 349.1659, found 349.1664. 4.3.20. Ethyl (E)-3,3-dicyano-2-(2,2-dimethylpropylidene)1,2,3,10b-te-trahydropyrrolo[2,1-a]phthalazine-1-carboxylate (3t) 90% yield. Pale-yellow solid. 1H NMR (300 MHz, CDCl3) d 7.61 (s, 1H), 7.44e7.36 (m, 3H), 7.30 (s, 1H), 6.31 (s, 1H), 4.81 (d, J ¼ 5.8 Hz, 1H), 4.44 (d, J ¼ 5.8 Hz, 1H), 4.10e3.99 (m, 2H), 1.23 (s, 9H), 1.08 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.4, 146.3, 143.7, 131.2, 130.2, 128.7, 127.6, 126.3, 124.9, 124.7, 113.7, 113.6, 61.5, 59.7, 59.6, 46.9, 34.3, 29.1, 13.5; HRMS (ESI) calcd for C21H22N4O2Hþ (M þ H)þ 363.1816, found 363.1812. 4.3.21. Ethyl (E)-3,3-dicyano-2-(2-phenylethylidene)-1,2,3,10btetra-hydropyrrolo[2,1-a]phthalazine-1-carboxylate (3u) 86% yield. Pale-yellow solid. 1H NMR (300 MHz, CDCl3) d 7.67 (s, 1H), 7.50e7.24 (m, 7H), 7.22e7.16 (m, 2H), 6.62 (td, J ¼ 1.7, 7.7 Hz, 1H), 4.85 (d, J ¼ 6.1 Hz, 1H), 4.45e4.32 (m, 1H), 4.03 (qd, J ¼ 1.0, 7.1 Hz, 2H), 3.66 (dd, J ¼ 3.5, 7.7 Hz, 2H), 1.03 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 167.9, 144.3, 136.6, 135.2, 131.4, 130.8, 130.7, 128.7, 128.6, 127.9, 126.7, 126.4, 124.9, 123.8, 113.1, 112.8, 61.6, 58.8, 58.2, 46.9, 34.8, 13.43. HRMS (ESI) calcd for C24H20N4O2Hþ (M þ H)þ 397.1659, found 397.1658. Acknowledgments This work is supported by the NSFC (21372256 and 21572264), and the National S&T Pillar Program of China (2017YFD0200504). Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.08.036. References 1. For selected reviews, see: (a) Gothelf KV, Jørgensen KA. Chem Rev. 1998;98: 863; (b) Gothelf KV. In: Kobayashi S, Jorgensen KA, eds. Cycloaddition Reactions in Organic Synthesis. Wiley-VCH: Weinheim; 2002:211e247; (c) Padwa A, Pearson WH. In: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistrydtoward Heterocycles and Natural Products. Hoboken, NJ: John Wiley and Sons; 2003; (d) Pellissier H. Tetrahedron. 2007;63:3235; (e) Stanley LM, Sibi MP. Chem Rev. 2008;108:2887; (f) Hashimoto T, Maruoka K. In: Ma S, ed. Handbook of Cyclization Reactions. Weinheim, Germany: Wiley-VCH; 2009:87e168 Chapter 3; (g) Engels B, Christl M. Angew Chem Int Ed. 2009;48:7968; (h) Kissane M, Maguire AR. Chem Soc Rev. 2010;39:845; (i) Narayan R, Potowski M, Jia Z-J, Antonchick AP, Waldmann H. Acc Chem Res. 2014;47:1296; (j) Najera C, Sansano JM, Yus M. Org Biomol Chem. 2015;13:8596; (k) Hashimoto T, Maruoka K. Chem Rev. 2015;115:9653. ndez N, Carrillo L, Vicario JL, Badía D, Reyes E. Chem Commun. 2011;47: 2. Ferna 12313. 3. Yuan C, Liu H, Gao Z, et al. Org Lett. 2015;17:26. 4. Liu H, Yuan C, Wu Y, Xiao Y, Guo H. Org Lett. 2015;17:4220. 5. (a) Yuan C, Zhou L, Sun Z, Guo H. RSC Adv. 2016;6:77931. For selected reviews on phosphine-promoted annulations, see:; (b) Lu X, Zhang C, Xu Z. Acc Chem Res. 2001;34:535; (c) Methot JL, Roush WR. Adv Synth Catal. 2004;346:1035; (d) Ye LW, Zhou J, Tang Y. Chem Soc Rev. 2008;37:1140; (e) Cowen BJ, Miller SJ. Chem Soc Rev. 2009;38:3102; (f) Marinetti A, Voituriez A. Synlett. 2010:174; (g) Wang SX, Han XY, Zhong FR, Wang YQ, Lu YX. Synlett. 2011:2766; (h) Zhao QY, Lian Z, Wei Y, Shi M. Chem Commun. 2012;48:1724; (i) Fan YC, Kwon O. Chem Commun. 2013;49:11588;
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