Synthesis of 2-Tetrazolyl-Substituted 3-Acylpyrroles via a Sequential

Sep 14, 2018 - from readily available enynals 1, primary amines 2, isocyanides 3, and ... 2-tetrazolyl-substituted 3-acylpyrroles by a Ag(I)-catalyzed...
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Note Cite This: J. Org. Chem. 2018, 83, 12921−12930

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Synthesis of 2‑Tetrazolyl-Substituted 3‑Acylpyrroles via a Sequential Ugi-Azide/Ag-Catalyzed Oxidative Cycloisomerization Reaction Han-Han Kong, Hong-Ling Pan, and Ming-Wu Ding* Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University, Wuhan 430079, People’s Republic of China

J. Org. Chem. 2018.83:12921-12930. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/19/18. For personal use only.

S Supporting Information *

ABSTRACT: A new efficient Ag-catalyed cascade cycloisomerization/aerobic oxidation reaction of a Ugi-azide adduct for the preparation of 3-acylpyrroles using molecular oxygen as the terminal oxidant has been developed. A series of 2-tetrazolyl-substituted 3-acylpyrroles were obtained in 62−89% yields from readily available enynals 1, primary amines 2, isocyanides 3, and trimethylsilyl azide 4 in the presence of a catalytic amount of AgNO3 and DMAP under an O2 atmosphere.

P

Metal-catalyzed cyclization of alkynes (or alkenes) with nucleophiles has been used extensively to prepare various heterocycles.21 In some cases, the consecutive cycloisomerization/aerobic oxidation reaction will take place to give acylsubstituted heterocycles as a transition-metal catalyst involving Au, Cu, Pd, or Ag was used (Scheme 1a). Such amino-

yrroles represent one of the most important classes of heterocycles that can be found in a wide range of natural products, pharmaceutical molecules, and synthetic materials.1 Some medicines such as atorvastatin and zomepirac contain the core skeleton of pyrroles.2 Many other pyrrole derivatives, especially 3-acylpyrroles, have been proved to exhibit good antipsychotics,3 anti-inflammatory,4 heat shock protein 90 inhibitive,5 antiproliferative,6 calcium channel activatory,7 and cannabinoid type I (CB1) antagonistical activities.8 Due to the significant bioactive and therapeutic properties of the pyrrole moiety, many efforts have been devoted to the preparation of pyrroles. The classical Knorr reactions, Paal−Knorr reactions, and Hantzsch reactions are the often used synthetic methods for preparation of multisubstituted pyrroles.9 Some other efficient approaches, including cycloisomerization10 and multicomponent reactions,11 have been developed to access 3-acylpyrroles starting from β-enaminones,12 1,3-diketones,13 ynones,14 and enones.15 However, most of these synthetic methods require extensive preconstruction of the carbonyl backbone and the method access to 3-acylpyrroles with the acyl group generated in situ is rare.16 1,5-Disubstituted tetrazoles are also a class of heterocycles that may be regarded as bioisosteres of the cisamide bond of peptides and have exhibited good biological activities, including antifungal, antitubercular, and anticancer activities.17 Unfortunately, 2-tetrazolyl-substituted pyrroles are seldom investigated previously probably due to the fact that they are not easily obtained by routine synthetic methods. The four-component Ugi reaction has gained great attention in organic chemistry due to its high versatility, exceptional efficiency, high atom economy, and convenient one-pot operation.18 The so-called Ugi-azide reaction produces 1,5disubstituted tetrazole by utilizing hydrazoic acid (generated in situ from NaN3 or TMS-N3) instead of the carboxylic acid component used in the classical Ugi reaction.19 The sequential Ugi-azide/cyclization strategy has been recently used extensively to form various tetrazolyl-substituted heterocyclic compounds.20 © 2018 American Chemical Society

Scheme 1. Metal-Catalyzed Cycloisomerization/Aerobic Oxidation Reaction

oxygenation22 (or dioxygenation,23 carbo-oxygenation24) reaction often occurs through a 5-exo-dig cyclization reaction between the amino (or hydroxyl or alkenyl) group and the pendant alkyne (or alkene) group, followed by aerobic oxidation of the vinyl-metal intermediate. However, there is no report on the aminooxygenation reaction involving a 5-endo-dig cyclization and aerobic oxidation. Continuing our interests in synthesis of heterocycles via post-Ugi and metal-catalyzed reactions,25 Received: August 2, 2018 Published: September 14, 2018 12921

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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The Journal of Organic Chemistry

entry 7 in Table S1 was optimal for the formation of aminooxygenation product 6a. With the optimized conditions, various Ugi-azide adducts 5 were employed for the cycloisomerization/aerobic oxidation reaction (Table 1). Most of the reactions were carried out

herein we wish to report a new efficient and cascade synthesis of 2-tetrazolyl-substituted 3-acylpyrroles by a Ag(I)-catalyzed aminooxygenation reaction of an azido-Ugi adduct, involving a 5-endo-dig cyclization and aerobic oxidation (Scheme 1b). The Ugi-azide reactions of enynals 1, primary amines 2, aliphatic isocyanides 3 (R3 = alkyl), and trimethylsilyl azide 4 proceeded smoothly, and the products 5 were obtained in 62− 87% yields (Scheme 2). However, as the low reactive aromatic isocyanides 3 (R3 = aryl) were used, the Ugi-azide reactions took place very slowly and no product was obtained.

Table 1. Synthesis of 2-Tetrazolyl-Substituted 3-Acylpyrroles 6

Scheme 2. Ugi-Azide Reaction for the Preparation of Compounds 5

6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r 6s 6t 6u

Compound 5a was selected initially as the starting material to optimize the reaction conditions (Table S1 in Supporting Information). When the cyclization of 5a was performed in the presence of AgNO3 (0.1 equiv) in CH3CN at 80 °C under air, a mixture of acylpyrrole 6a and pyrrole 7a was finally obtained with 21% and 71% yields (Table S1, entry 1). Using PdCl2 as the catalyst (entry 2) also resulted in a mixture of acylpyrrole 6a (12%) and pyrrole 7a (63%). However, only a low yield of 6a (15%) was obtained as Pd(OAc)2 was utilized (entry 3). In cases where CuI and PdCl2(PPh3)2 were used as the catalysts, no product 6a or 7a was formed (entry 4 and 5). Considering the aminooxygenation product 6a was produced in a minor amount under the above condition, the cyclization of 5a under an O2 atmosphere was then investigated. When AgNO3 was used as the catalyst under an O2 atmosphere, aminooxygenation compound 6a was still obtained as a minor product (entry 6, 31%), but the yield was slightly higher than that in entry 1. We were then pleased to find that, as a suitable base was added to the reaction mixture, the yield of the aminooxygenation compound 6a was increased dramatically. As the catalyst AgNO3 and base DMAP were utilized under an O2 atmosphere, the aminooxygenation compound 6a was obtained in 85% yield with no pyrrole 7a formation (entry 7). Using NEt3 as the base also resulted in the acylpyrrole 6a (entry 8, 77%) as predominant product. However, no product 6a was produced in case that the strong basic DBU was utilized (entry 9). Then we screened different Ag salts, solvents, and temperatures in the presence of DMAP (Table S1, entry 10−17). As the catalyst was changed to AgOAc or AgOTf, 69−73% yields of the sole product 6a were also resulted (Table S1, entries 10 and 11). Ag2CO3 was inactive to the reaction, and no product was obtained (entry 12). Changing the solvent to 1,4-dioxane, toluene, or THF gave no improvement to the yields of product 6a (45−79%, entries 13−15). Decreasing the reaction temperature to 50 °C or room temperature resulted in a low yield of the product 6a (0−42%, entries 16 and 17). No product was detected in the absence of the Ag catalyst (entry 18). Therefore, the reaction condition of

Ar

R1

R2

R3

yielda (%)

Ph Ph Ph Ph Ph Ph 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-FC6H4 4-FC6H4 Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

Ph Ph Ph 4-MeC6H4 Ph 4-MeC6H4 Ph Ph Ph 4-FC6H4 4-FC6H4 Ph n-Bu n-Bu Ph Ph Ph n-Pr n-Pr Ph H

Ph 4-MeC6H4 4-ClC6H4 4-NO2C6H4 4-ClC6H4 4-BrC6H4 4-MeC6H4 Ph 4-FC6H4 4-BrC6H4 4-MeC6H4 3-ClC6H4 4-ClC6H4 Ph PhCH2 4-ClC6H4CH2 n-Pr n-Pr n-Bu 2-ClC6H4 Ph

t-Bu t-Bu t-Bu t-Bu n-Bu n-Bu n-Bu c-C6H11c t-Bu t-Bu t-Bu t-Bu t-Bu c-C6H11c t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu

85(74b) 86 82 76 81 85 87 85 79 72 74 82 62 67 87 86 89 74 77 0 0(78d)

a Yields based on the Ugi-azide adducts 5. bYield based on 1a as the reaction performed in one pot without purification of the Ugi adduct 5a. cCyclohexyl. dAs the Me3Si-protected 5ua (R1 = Me3Si) is utilized.

smoothly to give the corresponding 2-tetrazolyl-substituted 3acylpyrroles 6 in good yields. The yields of products were related to R1 and R2 groups. As R1 is an aromatic group (Table 1, compounds 6a−6l and 6o−6q), the products were obtained in 72−89% yields. However, moderate yields (62−77%) were reached in the case that R1 is an alkyl group (Table 1, compounds 6m, 6n, 6r, and 6s). When R2 is an aromatic group (Table 1, compounds 6a−6l), good yields (72−87%) were obtained with different electro-releasing or electro-withdrawing substituents (Me, Cl, Br, F, NO2) on the benzene ring. However, no product was obtained in the case that R2 is an orthosubstituted phenyl group (Table 1, compounds 6t, R2 = 2ClC6H4), probably due to the steric effect of the 2-chlorophenyl group. Better yields of the products (86−89%) were reached as R2 is an alkyl group (Table 1, compounds 6o−6q). The reaction did not work if compound 5u (R1 = H) bearing a terminal alkyne was used, probably due to its formation of silver alkynyl salt instead of activation of the alkyne group in the presence of AgNO3. However, as the trimethylsilyl-protected 5ua (R1 = 12922

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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ments in Scheme 4c showed that product 6a was not directly generated from the oxidation of compound 7a or 10a. In Scheme 4d, the control experiment with labeled 18O2 was performed, and product 6a with 18O incorporation was observed, showing O2 involved in the oxidation reaction. On the basis of the above results and previous literature,22 a plausible reaction mechanism for the Ag-catalyzed aminooxygenation reaction was proposed as depicted in Scheme 5.

Me3Si) was utilized, the detrimethylsilyl product 6u was obtained in 78% yield (Table 1, compounds 6u). The reaction can be performed also in one pot with a slightly higher yield, without purification of the Ugi adduct 5. For example, compound 6a was obtained in 74% overall yield in one pot, compared with 72% overall yield after stepwise operation. As the reaction is not only applied for the Ugi-azide tetrazole adducts 5, the cyclization is also carried out smoothly for compound 8a, and product 9a is obtained in 84% yield under the same reaction conditions (Scheme 3).

Scheme 5. Plausible Mechanism of Silver-Catalyzed Aminooxygenation of 5

Scheme 3. Preparation of Compound 9a from Compound 8a

To gain some insights into the mechanism of this Ag(I)catalyzed aminooxygenation reaction, some control experiments were carried out (Scheme 4). As indicated in Scheme 4a, the Scheme 4. Some Control Experiments

The reaction might involve a double Ag-catalyzed process. The triple bond of compound 5 coordinates first to the silver nitrate to give the intermediate 11. Then 5-endo-dig cyclization of 11 generates the vinylsilver species 12, which undertakes protonolysis of the C−Ag bond to provide dihydropyrrole 13 bearing an exocyclic double bond. In the presence of a suitable base (DMAP), dihydropyrrole 13 is transformed into the silver species 14. A suitable base is necessary for such transformation. Then the addition of oxygen to 14 generates organosilver(II) peroxide intermediate 15, which is subsequently isomerized to give intermediate 16.22 Elimination of AgOH species of 16 produces the aerobic oxidation product 6. AgOH is finally transformed to Ag+ by reaction with the initially formed H+-base salt, with the release of the free base. Compound 7 might be formed from intermediate 13 by isomerization of dihydropyr-

reaction gave the best yield (85%) of the aminooxygenation product 6a under an O2 atmosphere, whereas the yield was reduced to 71% in air and 18% under an argon atmosphere, implying an aerobic oxidation reaction. The 18% yield of 6a obtained under an argon atmosphere may be due to some traces of O2 still in the solvent, indicating that the reaction was very sensitive to O2, similar to a literature report.22b The reaction took place in the presence of H2O18 to give product 6a with no O18 incorporating in the molecule (Scheme 4b), indicating no H2O involved in the oxidation reaction. The control experi12923

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H26ClN5Na 490.1769, found 490.1764. (E)-N-(2-Benzylidene-1-(1-butyl-1H-tetrazol-5-yl)-4-(p-tolyl)but3-yn-1-yl)-4-bromoaniline (5f): white solid (yield 0.45 g, 83%), mp 137−138 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.89 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.37−7.22 (m, 8H), 6.88−6.81 (m, 3H), 5.98 (d, J = 9.0 Hz, 1H), 4.51 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.83−1.76 (m, 2H), 1.28−1.25 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13 C{1H} NMR (DMSO, 150 MHz) δ (ppm) 154.0, 145.6, 139.0, 135.8, 135.0, 131.3, 131.0, 129.3, 128.8, 128.5, 128.4, 118.8, 118.1, 115.5, 108.5, 97.8, 86.2, 52.9, 46.9, 30.8, 20.9, 19.0, 13.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H28BrN5Na 548.1420, found 548.1410. (E)-N-(1-(1-Butyl-1H-tetrazol-5-yl)-2-(4-chlorobenzylidene)-4phenylbut-3-yn-1-yl)-4-methylaniline (5g): white solid (yield 0.404 g, 84%), mp 116−117 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.90 (d, J = 8.4 Hz, 2H), 7.52−7.43 (m, 7H), 7.25 (s, 1H), 6.95 (d, 2H, J = 7.8 Hz), 6.80 (d, 2H, J = 7.8 Hz), 6.35 (d, J = 9.0 Hz, 1H), 5.94 (d, J = 9.0 Hz, 1H), 4.51 (t, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.82−1.76 (m, 2H), 1.28−1.24 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 154.2, 143.8, 134.5, 133.9, 133.1, 131.2, 130.0, 129.3, 129.1, 128.6, 128.5, 126.2, 121.7, 119.4, 113.7, 98.0, 86.6, 53.2, 46.8, 30.8, 19.9, 19.0, 13.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H28ClN5Na 504.1925, found 504.1923. (E)-N-(2-(4-Chlorobenzylidene)-1-(1-cyclohexyl-1H-tetrazol-5yl)-4-phenylbut-3-yn-1-yl)aniline (5h): white solid (yield 0.428 g, 87%), mp 139−140 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.92 (d, J = 6.0 Hz, 2H), 7.53−7.43 (m, 7H), 7.33 (s, 1H), 7.16−6.68 (m, 5H), 6.56 (d, J = 7.8 Hz, 1H), 6.10 (d, J = 7.8 Hz, 1H), 4.76−4.70 (m, 1H), 2.05−1.22 (m, 10H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 154.0, 146.7, 135.2, 134.4, 133.7, 131.7, 130.5, 129.6, 129.3, 129.1, 129.0, 122.2, 120.0, 118.1, 114.1, 98.6, 87.0, 57.6, 53.6, 33.0, 32.9, 25.1, 25.0, 24.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H28ClN5Na 516.1925, found 516.1926. (E)-N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(4-chlorobenzylidene)-4-phenylbut-3-yn-1-yl)-4-fluoroaniline (5i): light yellow solid (yield 0.412 g, 85%), mp 69−70 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.91 (d, J = 8.4 Hz, 2H), 7.52−7.42 (m, 7H), 7.17 (s, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.89−6.87 (m, 2H), 6.69 (d, J = 8.4 Hz, 1H), 5.85 (d, J = 7.8 Hz, 1H), 1.77 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 155.2 (d, 1JF−C = 232.1 Hz), 153.6, 142.6, 134.0, 133.5, 133.0, 131.1, 130.3, 129.0, 128.7, 128.5, 121.8, 119.5, 115.5, 115.3, 114.1, 97.7, 87.3, 61.8, 54.4, 29.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H25ClFN5Na 508.1675, found 508.1675. (E)-4-Bromo-N-(1-(1-(tert-butyl)-1H-tetrazol-5-yl)-2-(4-fluorobenzylidene)-4-(4-fluorophenyl)but-3-yn-1-yl)aniline (5j): yellow solid (yield 0.476 g, 87%), mp 181−182 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.96 (t, J = 6.0 Hz, 2H), 7.50 (t, J = 6.0 Hz, 2H), 7.32− 7.28 (m, 6H), 7.15 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 5.87 (d, J = 7.8 Hz, 1H), 1.76 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 162.2 (d, 1JF−C = 247.1 Hz), 162.0 (d, 1JF−C = 246.2 Hz), 153.7, 145.5, 133.9, 133.6, 131.7, 130.8, 130.7, 118.4, 118.0, 116.3, 116.1, 115.7, 115.6, 115.1, 108.6, 96.3, 87.2, 62.0, 53.7, 29.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H24BrF2N5Na 570.1075, found 570.1075. (E)-N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(4-fluorobenzylidene)4-(4-fluorophenyl)but-3-yn-1-yl)-4-methylaniline (5k): light yellow solid (yield 0.377 g, 78%), mp 145−146 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.94−7.50 (m, 4H), 7.30−7.29 (m, 4H), 7.17 (s, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 6.61 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 2.16 (s, 3H), 1.76 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 162.2 (d, 1JF−C = 247.2 Hz), 161.9 (d, 1 JF−C = 245.3 Hz), 153.9, 143.8, 133.7, 131.8, 130.7, 130.6, 129.6, 126.2, 118.5, 116.2, 116.1, 115.7, 115.5, 113.2, 103.5, 96.2, 87.4, 61.9, 54.1, 29.3, 20.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H27F2N5Na 506.2127, found 506.2121. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenylbut-3-yn-1-yl)-3-chloroaniline (5l): white solid (yield 0.379 g, 81%), mp 168−169 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.83 (d, J = 7.2 Hz, 2H), 7.35−7.25 (m, 8H), 7.10−6.66 (m, 5H), 5.80 (d, J = 8.4 Hz, 1H), 5.36 (br, 1H), 1.81 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ

role 13 through 1,3-H shift, similar to the result we reported previously.25a Intermediate 13 is reactive under the reaction condition, and we have not isolated it from the reaction mixture. In summary, we have developed a novel and efficient method for the preparation of 2-tetrazolyl-substituted 3-acylpyrroles derivatives via a Ag-catalzyed cascade cycloisomerization/ aerobic oxidation reaction of an Ugi-azido adduct, starting from easily accessible enynals, amines, isocyanides, and trimethylsilyl azide (TMSN3). This protocol features a broad substrate scope and provides a novel synthetic strategy for the construction of polysubstituted acylpyrroles, which would be of great importance for drug discovery in terms of the structure diversity of pyrroles derivatives.

■

EXPERIMENTAL SECTION

Synthesis of Ugi-Azido Products 5. A mixture of αalkynylcinnamaldehydes 126 (1 mmol), amine 2 (1 mmol), isocyanides 3 (1 mmol), and trimethylsilyl azide (115 mg, 1 mmol) 4 was stirred in methanol (5 mL) at room temperature for 24−48 h. Then the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1−10:1, v/v) to give 5. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenylbut-3-yn-1-yl)aniline (5a): white solid (yield 0.368 g, 85%), mp 126− 127 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.88 (d, J = 6.6 Hz, 2H), 7.44−7.33 (m, 8H), 7.17−7.15 (m, 3H), 6.86 (d, J = 7.2 Hz, 2H), 6.72−6.66 (m, 2H), 5.87 (d, J = 7.8 Hz, 1H), 1.76 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 153.7, 146.1, 135.1, 134.9, 131.0, 129.0, 128.9, 128.7, 128.4, 122.0, 118.6, 117.5, 113.0, 97.1, 87.8, 61.7, 53.9, 29.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H27N5Na 456.2159, found 456.2156. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenylbut-3-yn-1-yl)-4-methylaniline (5b): yellow solid (yield 0.386 g, 86%), mp 135−136 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.85 (d, J = 8.4 Hz, 2H), 7.36−7.26 (m, 8H), 7.04−6.98 (m, 3H), 6.70 (d, J = 7.8 Hz, 2H), 5.83 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 7.2 Hz, 1H), 2.25 (s, 3H), 1.82 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 154.3, 142.9, 136.1, 135.2, 131.4, 130.0, 129.1, 128.8, 128.6, 128.4, 128.2, 122.5, 118.3, 114.2, 103.8, 97.9, 87.4, 61.8, 55.8, 30.2, 20.4; HRMS (ESITOF) m/z [M + Na]+ calcd for C29H29N5Na 470.2315, found 470.2309. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenylbut-3-yn-1-yl)-4-chloroaniline (5c): yellow solid (yield 0.405 g, 87%), mp 76−77 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.89 (d, J = 7.2 Hz, 2H), 7.45−7.35 (m, 8H), 7.20−7.15 (m, 3H), 6.94−6.89 (m, 3H), 5.87 (d, J = 7.8 Hz, 1H), 1.76 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 153.6, 145.0, 135.0, 134.9, 130.9, 128.9, 128.7, 128.6, 128.5, 128.4, 121.9, 121.0, 118.3, 114.5, 97.1, 87.6, 61.8, 53.9, 29.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H26ClN5Na 490.1769, found 490.1763. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-(ptolyl)but-3-yn-1-yl)-4-nitroaniline (5d): yellow solid (yield 0.419 g, 85%), mp 175−176 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.01 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 4.8 Hz, 2H), 7.29−7.03 (m, 8H), 6.78− 6.63 (m, 3H), 5.89 (d, J = 7.2 Hz, 1H), 2.36 (s, 3H), 1.83 (s, 9H); 13 C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 153.1, 150.8, 139.6, 139.4, 135.5, 134.7, 131.2, 129.3, 129.2, 128.9, 128.3, 128.2, 118.9, 116.8, 112.2, 99.0, 86.2, 62.2, 54.7, 30.1, 21.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H28N6O2Na 515.2166, found 515.2161. (E)-N-(2-Benzylidene-1-(1-butyl-1H-tetrazol-5-yl)-4-phenylbut-3yn-1-yl)-4-chloroaniline (5e): white solid (yield 0.38 g, 81%), mp 112−113 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.91 (d, J = 7.8 Hz, 2H), 7.46−7.37 (m, 8H), 7.28 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 8.4 Hz, 1H), 4.54 (t, J = 7.2 Hz, 2H), 1.85−1.79 (m, 2H), 1.30−1.26 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 154.0, 145.2, 136.2, 134.9, 131.1, 129.0, 128.9, 128.6, 128.5, 128.4, 121.8, 121.0, 118.0, 115.0, 97.4, 86.7, 53.0, 46.9, 30.8, 19.0, 13.1; 12924

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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(ESI-TOF) m/z [M + Na]+ calcd for C23H33N5Na 402.2628, found 402.2626. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenylbut-3-yn-1-yl)-2-chloroaniline (5t): yellow solid (yield 0.397 g, 85%), mp 59−60 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.89 (d, J = 7.8 Hz, 2H), 7.46−7.18 (m, 12H), 6.76 (t, J = 7.2 Hz, 1H), 6.15−6.09 (m, 2H), 1.78 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 153.4, 141.3, 137.0, 135.0, 131.2, 129.3, 129.2, 129.1, 128.8, 128.6, 128.5, 128.1, 121.9, 119.4, 119.1, 118.1, 113.9, 97.4, 86.7, 62.2, 54.1, 29.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H26ClN5Na 490.1769, found 490.1767. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4(trimethylsilyl)but-3-yn-1-yl)aniline (5ua): yellow solid (yield 0.374 g, 87%), mp 59−60 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.63 (d, J = 7.6 Hz, 2H), 7.12−6.99 (m, 5H), 6.83 (s, 1H), 6.62−6.54 (m, 3H), 5.57 (d, J = 8.8 Hz, 1H), 4.70 (br, 1H), 1.61 (s, 9H), 0 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 154.1, 145.2, 136.7, 135.0, 129.4, 129.1, 128.9, 128.0, 119.1, 118.0, 113.7, 104.7, 103.0, 61.7, 54.9, 30.2, −0.47; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H31N5SiNa 452.2241, found 452.2239. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)but-3-yn1-yl)aniline (5u): yellow oil (yield 0.286 g, 80%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.78 (d, J = 8.0 Hz, 2H), 7.32−7.27 (m, 5H), 7.01 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 5.76 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 8.8 Hz, 1H), 3.38 (s, 1H), 1.78 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 153.9, 145.1, 137.8, 134.6, 129.5, 129.1, 129.0, 128.2, 119.3, 117.1, 113.8, 86.3, 81.5, 61.9, 55.2, 30.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H23N5Na 380.1846, found 380.1844. Synthesis of Compound 8a. A mixture of (E)-2-benzylidene-4phenylbut-3-ynal (1a) (232 mg, 1 mmol), aniline 2a (93 mg, 1 mmol), t-butylisonitrile 3a (83 mg, 1 mmol), and H3PO4 (20 mg, 0.2 mmol) was stirred in methanol (5 mL) at room temperature for 48 h. Then the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1−10:1, v/v) to give 8a. (E)-3-Benzylidene-N-(tert-butyl)-5-phenyl-2-(phenylamino)pent4-ynamide (8a): white solid (yield 0.348 g, 85%), mp 137−138 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.88−7.86 (m, 2H), 7.52−7.50 (m, 2H), 7.38−6.58 (m, 13H), 4.96 (s, 1H), 4.40 (s, 1H), 1.25 (s, 9H); 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 168.7, 146.2, 137.0, 135.6, 131.4, 129.2, 129.0, 128.9, 128.7, 128.6, 128.2, 122.6, 118.6, 118.0, 113.8, 97.7, 87.4, 65.4, 51.4, 28.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H28N2ONa 431.2094, found 431.2092. Synthesis of 3-Acylpyrroles 6 and 9a. Ugi-azido products 5 (0.5 mmol) or compound 8a (204 mg, 0.5 mmol) and DMAP (31 mg, 0.25 mmol) were added to a Schlenk tube containing 5 mL of acetonitrile. AgNO3 (9 mg, 0.05 mmol) was added to the reaction mixture, and the whole reaction mixture was heated at 80 °C under O2 for 2−6 h; the reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1−10:1, v/v) to give 3-acylpyrroles 6 or 9a. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1,5-diphenyl-1H-pyrrol-3-yl)(phenyl)methanone (6a): white solid (yield 0.190 g, 85%), mp 205− 206 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.89 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 2H), 7.34−7.17 (m, 10H), 6.99 (s, 1H), 1.34 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 189.2, 145.3, 137.8, 136.8, 135.9, 132.4, 130.4, 129.1, 128.9, 128.8, 128.5, 128.4, 128.2, 127.8, 127.7, 125.4, 123.4, 112.3, 62.1, 28.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H26N5O 448.2132, found 448.2127. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-5-phenyl-1-(p-tolyl)-1H-pyrrol-3-yl)(phenyl)methanone (6b): white solid (yield 0.197 g, 86%), mp 210−211 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.90 (d, J = 7.8 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 2H), 7.27−6.98 (m, 9H), 6.98 (s, 1H), 2.23 (s, 3H), 1.35 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 189.3, 145.5, 138.6, 137.9, 136.8, 133.5, 132.6, 130.5, 129.7, 129.0, 128.6, 128.5, 128.4, 127.8, 127.6, 125.3,

(ppm) 153.8, 146.6, 136.2, 135.2, 135.0, 131.4, 130.5, 129.1, 129.0, 128.9, 128.5, 128.3, 122.4, 119.0, 117.7, 113.5, 112.1, 98.2, 87.2, 61.9, 55.3, 30.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H26ClN5Na 490.1769, found 490.1772. (E)-N-(2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)oct-3-yn1-yl)-4-chloroaniline (5m): light yellow solid (yield 0.349 g, 78%), mp 96−97 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.80 (d, J = 7.2 Hz, 2H), 7.37−7.30 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 5.64 (d, J = 7.8 Hz, 1H), 2.36 (t, J = 6.0 Hz, 2H), 1.71 (s, 9H), 1.41−1.39 (m, 2H), 1.28−1.24 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 153.5, 145.1, 135.2, 132.7, 128.7, 128.3, 128.2, 128.1, 120.9, 118.7, 114.3, 99.7, 78.7, 61.6, 54.4, 29.7, 29.2, 21.1, 18.5, 13.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H30ClN5Na 470.2082, found 470.2073. (E)-N-(2-Benzylidene-1-(1-cyclohexyl-1H-tetrazol-5-yl)oct-3-yn1-yl)aniline (5n): light yellow solid (yield 0.348 g, 79%), mp 98−99 °C; 1 H NMR (DMSO, 600 MHz) δ (ppm) 7.81 (d, J = 7.2 Hz, 2H), 7.37− 7.31 (m, 3H), 7.17−7.11 (m, 3H), 6.85 (d, J = 7.2 Hz, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 5.88 (d, J = 7.8 Hz, 1H), 4.71− 4.65 (m, 1H), 2.37 (t, J = 7.2 Hz, 2H), 2.01−1.23 (m, 14H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 153.4, 146.2, 135.1, 134.4, 128.7, 128.5, 128.2, 128.1, 119.0, 117.5, 113.5, 99.9, 77.8, 57.0, 53.6, 32.5, 32.4, 29.7, 24.6, 24.5, 24.4, 21.1, 18.6, 13.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H33N5Na 462.2628, found 462.2625. (E)-N-Benzyl-2-benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4phenylbut-3-yn-1-amine (5o): brown oil (yield 0.290 g, 65%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.91 (d, J = 7.2 Hz, 2H), 7.46−7.22 (m, 13H), 6.74 (s, 1H), 5.02 (s, 1H), 3.95 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 13.8 Hz, 1H), 2.90 (br, 1H), 1.62 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 154.1, 138.4, 136.9, 134.9, 131.2, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.1, 122.3, 119.5, 119.4, 97.8, 87.0, 61.2, 58.3, 50.6, 29.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H29N5Na 470.2315, found 470.2308. (E)-2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-N-(4-chlorobenzyl)-4-phenylbut-3-yn-1-amine (5p): brown oil (yield 0.322 g, 67%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.88 (d, J = 6.6 Hz, 2H), 7.44−7.28 (m, 12H), 6.65 (s, 1H), 4.96 (s, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 2.91 (br, 1H), 1.66 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 154.1, 137.3, 137.1, 135.0, 132.9, 131.5, 129.6, 129.0, 128.8, 128.5, 128.4, 128.3, 122.4, 119.7, 98.0, 87.1, 61.5, 58.7, 50.1, 29.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H28ClN5Na 504.1925, found 504.1924. (E)-2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-4-phenyl-Npropylbut-3-yn-1-amine (5q): brown oil (yield 0.248 g, 62%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.91 (d, J = 7.2 Hz, 2H), 7.45−7.27 (m, 8H), 6.82 (s, 1H), 5.03 (s, 1H), 2.77−2.56 (m, 2H), 2.41 (br, 1H), 1.76 (s, 9H), 1.62−1.57 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 154.5, 136.7, 135.1, 131.3, 128.7, 128.6, 128.2, 128.1, 127.8, 122.4, 119.8, 98.0, 86.9, 61.4, 60.3, 49.3, 29.8, 23.0, 11.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H29N5Na 422.2315, found 422.2316. (E)-2-Benzylidene-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-N-propylhept-3-yn-1-amine (5r): brown oil (yield 0.248 g, 68%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.83 (d, J = 7.2 Hz, 2H), 7.34−7.24 (m, 3H), 6.64 (s, 1H), 4.90 (s, 1H), 2.71−2.52 (m, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.77 (s, 9H), 1.63−1.56 (m, 4H), 1.01−0.92 (m, 6H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 154.5, 135.4, 135.2, 128.4, 128.2, 127.9, 120.5, 99.8, 78.1, 61.3, 60.5, 49.2, 29.7, 22.9, 21.6, 21.5, 13.3, 11.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H31N5Na 388.2472, found 388.2479. (E)-2-Benzylidene-N-butyl-1-(1-(tert-butyl)-1H-tetrazol-5-yl)hept-3-yn-1-amine (5s): brown oil (yield 0.274 g, 72%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.83 (d, J = 7.2 Hz, 2H), 7.34−7.24 (m, 3H), 6.64 (s, 1H), 4.89 (s, 1H), 2.74−2.55 (m, 2H), 2.39 (t, J = 7.2 Hz, 3H), 1.77 (s, 9H), 1.63−1.56 (m, 4H), 1.40−1.35 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 154.5, 135.4, 135.2, 128.4, 128.3, 127.9, 120.5, 99.9, 78.2, 61.3, 60.6, 47.1, 31.8, 29.7, 21.7, 21.6, 20.1, 13.7, 13.3; HRMS 12925

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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The Journal of Organic Chemistry

MHz) δ (ppm) 7.93 (d, J = 8.4 Hz, 2H), 7.38−6.97 (m, 10H), 6.80 (s, 1H), 1.40 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 188.3, 165.3 (d, 1JF−C = 253.8 Hz), 162.3 (d, 1JF−C = 248.0 Hz), 145.2, 136.0, 135.2, 134.3, 132.5, 131.9, 130.5, 129.3, 126.6, 126.3, 123.4, 122.9, 115.8, 115.7, 115.5, 115.4, 112.6, 62.4, 29.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H23BrF2N5O 562.1049, found 562.1034. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-5-(4-fluorophenyl)-1-(p-tolyl)1H-pyrrol-3-yl)(4-fluorophenyl)methanone (6k): light yellow solid (yield 0.184 g, 74%), mp 224−225 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.99 (t, J = 6.0 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.28−7.02 (m, 9H), 2.24 (s, 3H), 1.34 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 187.9, 164.6 (d, 1JF−C = 250.1 Hz), 161.6 (d, 1JF−C = 244.7 Hz), 145.4, 138.8, 135.9, 134.4, 133.3, 132.1, 130.8, 129.8, 127.6, 127.0, 125.0, 123.6, 115.8, 115.7, 115.5, 115.3, 112.3, 62.3, 28.9, 20.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H25F2N5ONa 520.1919, found 520.1919. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-(3-chlorophenyl)-5-phenyl1H-pyrrol-3-yl)(phenyl)methanone (6l): white solid (yield 0.198 g, 82%), mp 250−251 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.90 (d, J = 7.2 Hz, 2H), 7.58−7.44 (m, 3H), 7.27−7.12 (m, 9H), 6.86 (s, 1H), 1.42 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ (ppm) 190.0, 145.4, 138.2, 137.6, 137.1, 134.7, 132.4, 130.5, 130.1, 129.3, 128.9, 128.6, 128.5, 128.3, 128.1, 128.0, 126.7, 126.2, 123.5, 112.9, 62.4, 29.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H24ClN5ONa 504.1562, found 504.1558. (5-Butyl-2-(1-(tert-butyl)-1H-tetrazol-5-yl)-1-(4-chlorophenyl)1H-pyrrol-3-yl)(phenyl)methanone (6m): light yellow solid (yield 0.144 g, 62%), mp 163−164 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.85 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48−7.29 (m, 6H), 6.51 (s, 1H), 2.56−2.39 (m, 2H), 1.51−1.42 (m, 11H), 1.31−1.27 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 190.1, 145.6, 138.5, 137.5, 135.1, 134.2, 132.0, 129.1, 128.1, 125.8, 121.5, 110.4, 62.2, 30.6, 29.5, 26.2, 22.1, 13.6; HRMS (ESITOF) m/z [M + Na]+ calcd for C26H28ClN5ONa 484.1874, found 484.1873. (5-Butyl-2-(1-cyclohexyl-1H-tetrazol-5-yl)-1-phenyl-1H-pyrrol-3yl)(phenyl)methanone (6n): light yellow solid (yield 0.152 g, 67%), mp 134−135 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.85 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.46−7.23 (m, 7H), 6.53 (s, 1H), 4.01−3.96 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 1.83−1.21 (m, 14H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 190.3, 146.8, 138.6, 138.5, 135.9, 132.1, 129.2, 129.1, 128.2, 126.0, 119.1, 110.2, 103.8, 58.2, 32.4, 30.6, 26.3, 25.1, 24.8, 22.1, 13.6; HRMS (ESITOF) m/z [M + Na]+ calcd for C28H31N5ONa 476.2421, found 476.2419. (1-Benzyl-2-(1-(tert-butyl)-1H-tetrazol-5-yl)-5-phenyl-1H-pyrrol3-yl)(phenyl)methanone (6o): white solid (yield 0.201 g, 87%), mp 162−163 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.84 (d, J = 7.2 Hz, 2H), 7.52−6.81 (m, 13H), 6.69 (s, 1H), 5.10 (s, 2H), 1.30 (s, 9H); 13 C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 190.1, 146.1, 138.7, 137.7, 135.7, 132.0, 131.2, 129.7, 129.1, 128.9, 128.8, 128.7, 128.2, 128.0, 127.3, 126.1, 122.2, 112.9, 62.9, 48.8, 29.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H27N5ONa 484.2108, found 484.2109. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-(4-chlorobenzyl)-5-phenyl1H-pyrrol-3-yl)(phenyl)methanone (6p): white solid (yield 0.213 g, 86%), mp 172−173 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.84 (d, J = 6.6 Hz, 2H), 7.52 (d, J = 6.6 Hz, 1H), 7.44−7.37 (m, 7H), 7.15 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 7.2 Hz, 2H), 6.69 (s, 1H), 5.07 (d, J = 15.6 Hz, 1H), 4.90 (d, J = 15.6 Hz, 1H), 1.41 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 190.0, 146.0, 138.5, 137.5, 134.1, 134.0, 132.1, 131.0, 129.7, 129.1, 128.8, 128.7, 128.6, 128.2, 126.1, 122.2, 113.1, 62.9, 29.4, 29.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H26ClN5ONa 518.1718, found 518.1714. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-5-phenyl-1-propyl-1H-pyrrol3-yl)(phenyl)methanone (6q): white solid (yield 0.183 g, 89%), mp 149−150 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.85 (d, J = 7.8 Hz, 2H), 7.52−7.43 (m, 8H), 6.63 (s, 1H), 3.94−3.32 (m, 2H), 1.74−1.44 (d, 11H), 0.64 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 189.9, 146.2, 138.7, 137.0, 131.9, 131.5, 129.3, 129.1, 128.7, 128.5, 128.1, 125.5, 122.1, 113.0, 62.7, 47.6, 29.7, 24.2, 10.9; HRMS

123.6, 112.3, 62.2, 28.9, 20.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H28N5O 462.2289, found 462.2280. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-(4-chlorophenyl)-5-phenyl1H-pyrrol-3-yl)(phenyl)methanone (6c): white solid (yield 0.198 g, 82%), mp 183−184 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.90 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.27− 7.12 (m, 9H), 6.86 (s, 1H), 1.40 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 189.9, 145.4, 138.2, 137.0, 135.0, 134.6, 132.3, 130.5, 129.3, 129.2, 129.1, 128.6, 128.5, 128.3, 128.0, 126.6, 123.4, 113.0, 62.4, 29.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H25ClN5O 482.1742, found 482.1737. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-(4-nitrophenyl)-5-(p-tolyl)1H-pyrrol-3-yl)(phenyl)methanone (6d): light red solid (yield 0.193 g, 76%), mp 226−227 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 8.20 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.2 Hz, 2H), 7.45 (d, J = 6 Hz, 2H), 7.15−7.11 (m, 4H), 7.00 (s, 1H), 2.26 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 189.2, 147.0, 145.0, 141.3, 137.7, 137.6, 137.3, 132.6, 129.3, 129.0, 128.9, 128.6, 128.5, 127.0, 126.1, 124.4, 122.7, 112.5, 62.4, 28.9, 20.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H27N6O3 507.2139, found 507.2139. (2-(1-Butyl-1H-tetrazol-5-yl)-1-(4-chlorophenyl)-5-phenyl-1Hpyrrol-3-yl)(phenyl)methanone (6e): white solid (yield 0.195 g, 81%), mp 114−115 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.88 (d, J = 7.2 Hz, 2H), 7.56−7.15 (m, 12H), 6.91 (s, 1H), 4.14 (t, J = 7.2 Hz, 2H), 1.69−1.11 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 190.2, 147.2, 138.3, 138.1, 135.0, 134.8, 132.5, 130.4, 129.3, 129.2, 128.6, 128.5, 128.3, 128.1, 126.7, 126.0, 120.8, 112.9, 47.8, 30.9, 19.5, 13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H25ClN5O 482.1742, found 482.1735. (1-(4-Bromophenyl)-2-(1-butyl-1H-tetrazol-5-yl)-5-(p-tolyl)-1Hpyrrol-3-yl)(phenyl)methanone (6f): light yellow solid (yield 0.228 g, 85%), mp 110−111 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.87 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.56−7.53 (m, 4H), 7.18−7.12 (m, 6H), 6.95 (s, 1H), 4.14 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.61−1.59 (m, 2H), 1.10−1.07 (m, 2H), 0.75 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 189.4, 147.1, 138.0, 137.8, 137.5, 135.4, 132.5, 132.0, 130.1, 128.9, 128.8, 128.5, 128.4, 127.2, 125.8, 122.2, 120.3, 112.0, 47.0, 30.2, 20.5, 18.8, 13.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H27BrN5O 540.1394, found 540.1387. (2-(1-Butyl-1H-tetrazol-5-yl)-5-phenyl-1-(p-tolyl)-1H-pyrrol-3yl)(4-chlorophenyl)methanone (6g): white solid (yield 0.216 g, 87%), mp 143−144 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.90 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.28−7.24 (m, 5H), 7.13−7.09 (m, 4H), 7.01 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 2.25 (s, 3H), 1.59−1.57 (m, 2H), 1.12−1.09 (m, 2H), 0.75 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 188.2, 147.2, 138.6, 137.9, 137.3, 136.5, 133.4, 130.7, 130.4, 129.4, 128.6, 128.5, 128.2, 127.8, 127.6, 125.2, 120.9, 112.2, 47.0, 30.2, 20.4, 18.8, 13.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H27ClN5O 496.1899, found 496.1897. (4-Chlorophenyl)(2-(1-cyclohexyl-1H-tetrazol-5-yl)-1,5-diphenyl1H-pyrrol-3-yl)methanone (6h): white solid (yield 0.217 g, 85%), mp 163−164 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.94 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.34−7.23 (m, 10H), 7.03 (s, 1H), 4.12−4.06 (m, 1H), 1.66−1.14 (m, 10H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 188.2, 146.4, 137.7, 137.5, 136.4, 136.0, 130.8, 130.3, 129.1, 128.7, 128.4, 128.2, 127.8, 127.7, 125.6, 120.9, 112.1, 57.2, 32.0, 24.3, 24.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H27ClN5O 508.1899, found 508.1898. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-(4-fluorophenyl)-5-phenyl1H-pyrrol-3-yl)(4-chlorophenyl)methanone (6i): light yellow solid (yield 0.197 g, 79%), mp 119−120 °C; 1H NMR (DMSO, 600 MHz) δ (ppm) 7.92 (d, J = 6.6 Hz, 2H), 7.62 (d, J = 6.0 Hz, 2H), 7.29−7.21 (m, 9H), 7.03 (s, 1H), 1.38 (s, 9H); 13C{1H} NMR (DMSO, 150 MHz) δ (ppm) 188.0, 161.5 (d, 1JF−C = 246.5 Hz), 145.1, 137.4, 137.2, 136.4, 132.2, 130.7, 130.1, 130.0, 128.7, 128.5, 128.3, 127.8, 125.1, 123.5, 116.2, 116.0, 112.1, 62.2, 28.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H24ClFN5O 500.1648, found 500.1639. (1-(4-Bromophenyl)-2-(1-(tert-butyl)-1H-tetrazol-5-yl)-5-(4-fluorophenyl)-1H-pyrrol-3-yl)(4-fluorophenyl)methanone (6j): white solid (yield 0.203 g, 72%), mp 199−200 °C; 1H NMR (CDCl3, 600 12926

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

Note

The Journal of Organic Chemistry (ESI-TOF) m/z [M + Na]+ calcd for C25H27N5ONa 436.2108, found 436.2106. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1,5-dipropyl-1H-pyrrol-3-yl)(phenyl)methanone (6r): brown oil (yield 0.140 g, 74%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.78 (d, J = 7.2 Hz, 2H), 7.52−7.40 (m, 3H), 6.37 (s, 1H), 3.80−2.76 (m, 1H), 3.23−3.19 (m, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.79−1.69 (m, 4H), 1.57 (s, 9H), 1.03 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 189.9, 146.3, 138.9, 136.1, 131.6, 128.9, 128.0, 125.0, 120.3, 110.3, 62.5, 46.9, 29.5, 28.0, 24.2, 21.8, 13.7, 11.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H29N5ONa 402.2264, found 402.2269. (1-Butyl-2-(1-(tert-butyl)-1H-tetrazol-5-yl)-5-propyl-1H-pyrrol-3yl)(phenyl)methanone (6s): brown oil (yield 0.152 g, 77%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.78 (d, J = 6.8 Hz, 2H), 7.52−7.40 (m, 3H), 6.36 (s, 1H), 3.82−2.79 (m, 1H), 3.26−3.22 (m, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.75−1.69 (m, 3H), 1.57 (s, 9H), 1.29−1.24 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 189.9, 146.3, 138.9, 136.0, 131.7, 129.0, 128.0, 125.0, 120.4, 110.4, 62.5, 45.1, 32.9, 29.5, 28.1, 21.8, 19.9, 13.8, 13.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H31N5ONa 416.2421, found 416.2420. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (6u): white solid (yield 0.144 g, 78%), mp 131− 132 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.87 (d, J = 7.2 Hz, 2H), 7.57−7.44 (m, 3H), 7.35−7.28 (m, 5H), 7.14 (d, J = 3.2 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 1.32 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 189.9, 145.6, 138.3, 138.0, 132.2, 129.6, 129.3, 128.4, 128.2, 127.5, 124.9, 124.1, 121.6, 113.3, 62.2, 29.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H21N5ONa 394.1638, found 394.1642. 3-Benzoyl-N-(tert-butyl)-1,5-diphenyl-1H-pyrrole-2-carboxamide (9a): white solid (yield 0.178 g, 84%), mp 217−218 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.47 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.60−7.02 (m, 13H), 6.48 (s, 1H), 1.32 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 193.6, 159.8, 139.2, 138.7, 136.1, 133.5, 132.4, 131.3, 129.9, 128.9, 128.6, 128.2, 128.1, 128.0, 127.5, 127.4, 123.1, 113.3, 51.5, 28.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H26N2O2Na 445.1886, found 445.1886. One-Pot Synthesis of 3-Acylpyrrole 6a. A mixture of (E)-2benzylidene-4-phenylbut-3-ynal (1a) (232 mg, 1 mmol), aniline 2a (93 mg, 1 mmol), t-butylisonitrile 3a (83 mg, 1 mmol), and trimethylsilyl azide (115 mg, 1 mmol) 4 was stirred in methanol (5 mL) at room temperature for 48 h, and then the solvent was removed under reduced pressure. To the residue were added DMAP (61 mg, 0.5 mmol), AgNO3 (17 mg, 0.1 mmol). and CH3CN (5 mL). The reaction mixture was heated at 80 °C under O2 for 6 h, and the reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 10:1, v/ v) to give 3-acylpyrroles 6a (yield 0.33 g, 74%). Control Experiments.

acetonitrile. AgNO3 (9 mg, 0.05 mmol) and H2O18 (50 mg, 2.5 mmol) were added to the reaction mixture. The container was sealed, pumped into a vacuum, and flushed with O2 using a balloon three times, and the whole reaction mixture was heated at 80 °C for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1−10:1, v/v) to give 6a: HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H26N5O16 448.2132, found 448.2131; HRMS (ESITOF) m/z [M + H]+ calcd for C28H26N5O18 450.2174; not found. (c) Compound 7a (216 mg, 0.5 mmol) or 10a (224 mg, 0.5 mmol) and DMAP (31 mg, 0.25 mmol) were added to a Schlenk tube containing 5 mL of acetonitrile. AgNO3 (9 mg, 0.05 mmol) was added to the reaction mixture, and the whole reaction mixture was heated at 80 °C under an O2 atmosphere for 20 h. No product 6a was detected by TLC analysis. Compound 10a was prepared by reduction of compound 6a. NaBH4 (75 mg, 2 mmol) was added portionwise to a solution of compound 6a (447 mg, 1 mmol) in methanol (5 mL), and the mixture was cooled with an ice bath. The mixture was stirred for an additional 1 h at room temperature, and the progress was monitored by TLC. The reaction mixture was quenched with a saturated NH4Cl solution. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1, v/v) to give compound 10a. (2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-1,5-diphenyl-1H-pyrrol-3-yl)(phenyl)methanol (10a): white solid (yield 0.358 g, 80%), mp 99−100 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.39−6.91 (m, 15H), 6.54 (s, 0.43H), 6.37 (s, 0.57H), 5.63 (d, J = 4.2 Hz, 1H), 3.11−2.83 (br, 1H), 1.14 (s, 5.22H), 1.01 (s, 3.78H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 146.3, 143.6, 142.9, 137.5, 137.4, 136.6, 136.5, 131.8, 131.7, 131.6, 131.3, 129.1, 128.5, 128.2, 128.0, 127.7, 127.5, 127.4, 127.1, 127.0, 126.7, 125.6, 116.0, 115.1, 110.2, 109.3, 70.4, 69.6, 62.4, 62.1, 29.2, 29.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H27N5ONa 472.2108, found 472.2106. (d) Under an Ar atmosphere, a flask equipped with a magnetic stir bar and reflux condenser was charged with Ugi-azido product 5a (216 mg, 0.5 mmol), DMAP (31 mg, 0.25 mmol), and AgNO3 (9 mg, 0.05 mmol) in acetonitrile (5 mL). The vial was flushed with 18O2 for 1 min, capped with a septum, and stirred at 80 °C for 4 h with an 18O2 balloon through the septum. After the reaction was completed, the mixture was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 20:1−10:1, v/v) to give the 18O-incorporated product 6a: HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H26N518O 450.2174, found 450.2172; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H25N518ONa 472.1994, found 472.1995.

(a) Ugi-azido product 5a (216 mg, 0.5 mmol) and DMAP (31 mg, 0.25 mmol) were added to a Schlenk tube containing 5 mL of acetonitrile. AgNO3 (9 mg, 0.05 mmol) was added to the reaction mixture, and the whole reaction mixture was heated at 80 °C under an Ar, air, or O2 atmosphere for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 40:1−10:1, v/v) to give 6a and 7a.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01984.

5-(3-Benzyl-1,5-diphenyl-1H-pyrrol-2-yl)-1-(tert-butyl)-1H-tetrazole (7a): white solid, mp 125−126 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.18−6.89 (m, 15H), 6.30 (s, 1H), 3.64−3.57 (m, 2H), 0.99 (s, 9H); 13C{1H} NMR (CDCl3, 150 MHz) δ (ppm) 146.4, 140.0, 137.8, 136.4, 132.0, 129.0, 128.7,128.5, 128.4, 128.1, 127.7, 127.4, 127.3, 126.9, 126.1, 115.8, 111.7, 62.0, 32.8, 29.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H27N5Na 456.2159, found 456.2159.

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1 H and 13C NMR spectra of compounds 5a−5u, 6a−6u, 7a, 8a, 9a, and 10a and HRMS spectrum of 6a in the presence of H2O18 or 18O2 (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

(b) Ugi-azido product 5a (216 mg, 0.5 mmol) and DMAP (31 mg, 0.25 mmol) were added to a Schlenk tube containing 5 mL of

Ming-Wu Ding: 0000-0002-3464-4774 12927

DOI: 10.1021/acs.joc.8b01984 J. Org. Chem. 2018, 83, 12921−12930

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The Journal of Organic Chemistry Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (21572075) and the 111 Project B17019.

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