One-Pot Synthesis of Polysubstituted Imidazoles ... - ACS Publications

J. Org. Chem. , 2017, 82 (24), pp 13735–13739 ... 82, 24, 13735-13739 ... Staudinger/aza-Wittig reaction to access N β -protected amino alkyl isoth...
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One-Pot Synthesis of Polysubstituted Imidazoles via Sequential Staudinger/aza-Wittig/Ag(I)-Catalyzed Cyclization/Isomerization Jun Xiong, Xiao Wei, Zi-Ming Liu, and Ming-Wu Ding* Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, P. R. China S Supporting Information *

ABSTRACT: A new one-pot preparation of polysubstituted imidazoles by a Staudinger/aza-Wittig/Ag(I)-catalyzed cyclization/isomerization has been developed. The easily accessible propargylazide derivatives reacted with triphenylphosphine, isocyanates, and amines sequentially to produce the fully substituted imidazoles in good overall yields in the presence of catalytic amount of AgNO3/ DMAP.

P

good functional group compatibility.9 The sequential reaction of allenyl sulfonamides and amines was successfully utilized in regioselective synthesis of highly substituted imidazoles.10 A new, one-pot synthesis of imidazoles was also provided by reaction of imines, acid chlorides, and N-nosyl imines or tethered nitriles, mediated by the phosphonite via regioselective cycloaddition.11 Despite of their many advantages, however, these methods suffer from some drawbacks including harsh reaction condition, acid- or base-sensitive substrates, or multistep operation. Consequently, new and direct synthetic method to imidazoles is still desirable in synthetic organic and pharmaceutical chemistry. Intramolecular cyclization between alkynes and nitrogen nucleophiles is one of the most important methods for the synthesis of N-heterocycles.18 The reaction could be catalyzed by transition metal complexes, such as Pd, Au, Cu, In, Ag, etc.19 Recently, Ag(I) salts are found to be an efficient activator of alkynes and they have received great attention in view of their lower activation energy to obtain target compound in mild condition.20 For example, Van der Eycken disclosed a facile route to 2-imidazolone via a Ag(I)-catalyzed cycloisomerization reaction of secondary propargylamine with isocyanate.21 The aza-Wittig reaction of iminophosphoranes with carbonyl compounds has provided a powerful method for the assembly of CN double bond under mild and neutral conditions.22 It has recently used widely in the synthesis of various heterocyclic compounds.23 The aza-Wittig reactions of iminophosphoranes with isocyanates produce high reactive carbodiimide intermediates, which may be utilized in preparing some heterocycles in further sequential reactions.24 It was reported that 2-amino imidazoles could be prepared by such synthetic approach starting from 2-ethoxycarbonyl azides.25 However, the method included a tedious multistep process involving a first aza-Wittig reaction of 2-ethoxycarbonyl iminophosphorane to give imidazolin-5(4H)-ones, and then DIBAL reduction of

olysubstituted imidozoles are important heterocycles due to their remarkable biological and pharmaceutical activities, which have been found in various natural products and artificial drugs (Figure 1).1 A wide variety of derivatives of this ring

Figure 1. Representative drugs and biologically active imidazoles.

system have recently been used as Janus-associated kinase 2 (Jak2) inhibitors,2 Takeda G-protein-coupled receptor 5 (TGR5) agonists,3 antiviral agents,4 antimicrobial agents,5 anti-Alzheimer’s disease agents,6 and particularly anticancer agents.7 In addition, imidazole rings were also found application in coordination chemistry, or be used as organic catalysts.8 In the past few years, many new methods for synthesis of imidazole have been reported,9−17 including Ag, Rh, Fe, Cucatalyzed reactions, or other metal-free cyclizations. For examples, some 1,2,4-trisubstituted imidazoles were efficiently prepared by silver-promoted [3+2] cycloaddition of azomethine ylides with isocyanides with broad substrate scope and © 2017 American Chemical Society

Received: October 12, 2017 Published: November 17, 2017 13735

DOI: 10.1021/acs.joc.7b02606 J. Org. Chem. 2017, 82, 13735−13739

Note

The Journal of Organic Chemistry imidazolin-5(4H)-ones to 5-hydroxydihydroimidazoles, afterward methanesulfonylation of the hydroxyl group and finally elimination to give 2-amino imidazoles. Continuing our interests in synthesis of heterocycles via aza-Wittig reactions,26 herein we wish to report a new efficient and one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles by Ag(I)-catalyzed intramolecular cyclization of α-alkynylguanidines, which were obtained by aza-Wittig reaction and further reaction of the carbodiimides with amines. Our procedure gave a dexterous one-pot synthesis of 2-amino imidazoles with elaborate substitution patterns from the easily accessible propargyl azides, superior to previous reports. The starting material propargylazides 3 were prepared as illustrated in Scheme 1. Pd-Catalyzed Sonogashina coupling

Table 1. Optimization of the Reaction Conditions entry

catalysta

baseb

1 2 3 4 5 6 7 8 9 10 11

None AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 PdCl2 CuI Pd(OAc)2 AgNO3

DMAP none DMAP t-BuOk NaH DBU Et3N DMAP DMAP DMAP DMAP

condition 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 80 °C/12 r.t. /48 h

h h h h h h h h h h

yieldc (%) 0 0 84 75 53 72 70 26 21 74 0

a c

Scheme 1. Preparation of Propargylazide Derivatives 3

10 %mol amount of the catalyst. b10 %mol amount of the base. Isolated yields.

and 2). Then we screened base, including t-BuOK, NaH, DBU, and Et3N (Table 1, entry 4−7), and found that DMAP was optimal. The suitable basicity of DMAP might be responsible for the relative better yield. As the catalyst was changed to PdCl2 or CuI, low yields (21−26%) of the product were resulted (Table 1, entry 8 and 9). In case that Pd(OAc)2 was utilized, 74% of the product 7a was obtained (Table 1, entry 10). No product was detected when the reaction temperature was decreased to room temperature in the presence of AgNO3/ DMAP system (Table 1, entry 11). Therefore, the optimum reaction condition was identified (Table 1, entry 3). With the optimized condition in hand, we started to examine the scope of the reaction (Scheme 3). As indicated in Table 2,

reaction of aryl halides with commercial available prop-2-yn-1ols gave propargyl alcohols 1.27 Mesylation of compounds 1 with methanesulfonyl chloride in the presence of triethylamine produces the mesylates 2, which were treated with sodium azide in DMF to generate the propargylazides 3.28 Initially, we selected (3-azidoprop-1-yn-1-yl)benzene 3a as the starting material (Scheme 2). As azide 3a was treated with

Scheme 3. Preparation of Compounds 7

Scheme 2. Preparation of Compounds 7a

the yields of products were related to R2 and NR3R4 groups. As aromatic isocyanates were used (R2 are aryl groups), the reaction produced desired products in good overall yields (69− 89%, Table 2, compounds 7a−7p), however, moderate yields (59−62%, Table 2, compounds 7q−7s) were obtained in case that alkyl isocyanates were utilized probably due to their relative lower reactivity toward iminophosphorane 4. In addition, the amino group NR3R4 is also an important influencing factor for the yield of the reaction. When secondary amines and aromatic isocyanates were used as the reaction components, satisfactory yields of the products (71−89%, Table 2, compounds 7a−7i and 7n−7p) were obtained. However, relative lower yields (69−72%, Table 2, compounds 7j−7m) were obtained in case that primary amines were applied. A proposed mechanism for the one-pot formation of the imidazoles 7 is presented in Scheme 4. The triple bond of

triphenylphosphine in CH3CN, iminophosphorane 4a was formed. Reaction of 4a with phenyl isocyanate produced the carbodiimide 5a, which was allowed to react with piperidine to generate the guanidine intermediate 6a. To optimize the reaction conditions, the cyclization of intermediate 6a was chosen as a model reaction. When the reaction was performed in the presence of AgNO3 (0.1 equiv), and DMAP (0.1 equiv) in CH3CN at 80 °C, imidazole 7a was directly obtained in 84% isolated yield (Table 1, Entry 3). However, in the absence of a catalyst or a base, no product 7a was formed (Table 1, entry 1 13736

DOI: 10.1021/acs.joc.7b02606 J. Org. Chem. 2017, 82, 13735−13739

Note

The Journal of Organic Chemistry Table 2. Preparation of Imidazoles 7a 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7q 7r 7s

Ar

R1

R2

NR3R4

yielda (%)

Ph Ph Ph Ph Ph 4-MeC6H4 4-MeC6H4 4-MeC6H4 4-ClC6H4 Ph Ph 4-MeC6H4 4-ClC6H4 Ph Ph Ph Ph 4-MeC6H4 4-ClC6H4

H H H H H H H H H H H H H Me Me Et H H H

Ph 4-MeC6H4 4-MeC6H4 3-MeC6H4 4-ClC6H4 4-ClC6H4 4-FC6H4 4-MeC6H4 Ph 2-ClC6H4 4-CH3OC6H4 Ph 4-MeC6H4 Ph 2-ClC6H4 4-MeC6H4 Bu i-Pr i-Pr

piperidin-1-yl Et2Nmorpholin-4-yl piperidin-1-yl PhCH2(Me)NPr2NPhCH2(Me)Npyrrolidin-1-yl Pr2NPhCH2NH-[b] t-BuNH-[b] BuNH-[b] i-PrNH-[b] Pr2Npiperidin-1-yl Pr2Npiperidin-1-yl piperidin-1-yl PhCH2(Me)N-

84 82 78 82 72 81 82 86 89 72 71 70 69 80 71 74 61 59 62

To a solution of azide 3 (2 mmol) in CH3CN (10 mL) was added PPh3 (0.52 g, 2 mmol), the mixture was stirred at room temperature for 1 h to form iminophosphorane 4 (TLC monitoring). Then isocyanate (2 mmol) was added dropwise at 0 °C. After the reaction mixture was left to stand for 30 min, the amine (2 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h (as R2 is an aryl group) or 80 °C for 12−24 h (as R2 is an alkyl group) to form guanidine 6. Then AgNO3 (0.034 g, 0.2 mmol) and DMAP (0.024 g, 0.2 mmol) was added to the reaction system, and the reaction mixture was heated to 80 °C for another 12−24 h to form 7. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 8:1−4:1, V/V) to give 7. 1-(5-Benzyl-1-phenyl-1H-imidazol-2-yl)piperidine (7a). Light yellow solid (yield 0.533 g, 84%), mp 103−104 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.37−7.13 (m, 7H), 6.97 (d, J = 7.8 Hz, 2H), 6.57 (s, 1H), 3.68 (s, 2H), 2.91 (t, J = 4.8 Hz, 4H), 1.41−1.36 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.3, 138.5, 136.8, 129.0, 128.7, 128.5, 128.1, 127.8, 127.4, 126.0, 123.2, 50.6, 31.3, 25.4, 24.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H24N3 318.1965; Found 318.1975. 5-Benzyl-N,N-diethyl-1-(p-tolyl)-1H-imidazol-2-amine (7b). Light yellow oil (yield 0.524 g, 82%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.20−7.14 (m, 5H), 6.99 (d, J = 7.2 Hz, 2H), 6.94 (d, J = 7.2 Hz, 2H), 6.60 (s, 1H), 3.64 (s, 2H), 2.93 (q, J = 7.2 Hz, 4H), 2.37 (s, 3H), 0.90 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.0, 138.6, 137.8, 134.1, 129.5, 128.7, 128.5, 128.1, 127.6, 126.0, 123.2, 46.0, 31.2, 21.1, 12.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H26N3 320.2121; Found 320.2149. 4-(5-Benzyl-1-(p-tolyl)-1H-imidazol-2-yl)morpholine (7c). Light yellow solid (yield 0.520 g, 78%), mp 90−92 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.68−6.97 (m, 9H), 6.57 (s, 1H), 3.66 (s, 2H), 3.54 (t, J = 4.8 Hz, 4H), 2.96 (t, J = 4.8 Hz, 4H), 2.37 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.9, 138.3, 138.2, 133.6, 132.0, 129.8, 128.5, 128.1, 127.1, 126.1, 122.9, 66.5, 49.6, 31.1, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H24N3O 334.1914; Found 334.1917. 1-(5-Benzyl-1-(m-tolyl)-1H-imidazol-2-yl)piperidine (7d). Light yellow solid (yield 0.544 g, 82%), mp 74−75 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.26−6.96 (m, 8H), 6.88 (s, 1H), 6.56 (s, 1H), 3.67 (s, 2H), 2.91 (t, J = 4.8 Hz, 4H), 2.31 (s, 3H), 1.42−1.38 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.3, 138.9, 138.7, 136.8, 128.8, 128.7, 128.6, 128.5, 128.1, 128.0, 126.1, 124.3, 123.2, 50.6, 31.4, 25.5, 24.1, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26N3 332.2121; Found 332.2137. N,5-Dibenzyl-1-(4-chlorophenyl)-N-methyl-1H-imidazol-2-amine (7e). Light yellow oil (yield 0.559 g, 72%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.31−7.15 (m, 8H), 7.00−6.95 (m, 6H), 6.66 (s, 1H), 4.02 (s, 2H), 3.66 (s, 2H), 2.53 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.1, 138.1, 137.4, 135.0, 134.1, 129.3, 129.2, 128.9, 128.3, 128.2, 128.1, 128.0, 127.1, 126.2, 123.4, 58.4, 39.0, 31.1. HRMS (ESITOF) m/z: [M+H]+ Calcd for C24H23ClN3 388.1575; Found 388.1596. 1-(4-Chlorophenyl)-5-(4-methylbenzyl)-N,N-dipropyl-1H-imidazol-2-amine (7f). Light yellow oil (yield 0.619 g, 81%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.35 (d, J = 8.4 Hz, 2H), 7.02−6.98 (m, 4H), 6.84 (d, J = 7.2 Hz, 2H), 6.64 (s, 1H), 3.57 (s, 2H), 2.86 (t, J = 7.2 Hz, 4H), 2.30 (s, 3H), 1.38−1.34 (m, 4H), 0.71 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.8, 135.8, 134.9, 134.7, 134.2, 129.3, 129.2, 128.9, 128.8, 128.7, 128.2, 53.7, 30.7, 20.9, 20.8, 11.3. HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C23H28ClN3Na 404.1864; Found 404.1845. N-Benzyl-1-(4-fluorophenyl)-N-methyl-5-(4-methylbenzyl)-1Himidazol-2-amine (7g). Light yellow oil (yield 0.632 g, 82%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.21 (d, J = 7.8 Hz, 3H), 7.04− 6.97 (m, 8H), 6.83 (d, J = 7.2 Hz, 2H), 6.66 (s, 1H), 4.05 (s, 2H,), 3.59 (s, 2H), 2.58 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.9, 161.3, 152.5, 137.2, 135.8, 134.7, 132.0, 129.8, 129.7, 129.4, 128.9, 128.2, 128.0, 127.2, 121.9, 116.2, 116.1, 58.2, 39.0, 30.7,

a

Isolated yields based on the propargylazide 3. bPrimary amine was used.

Scheme 4. Proposed Mechanism for the One-Pot Formation of Imidazoles 7

compound 6 coordinates first to the silver nitrate to give the intermediate 8. Then 5-exo-dig cyclization of 8 provides the vinylsilver species 9 in the presence of the base DMAP. Subsequent proton transfer in intermediate 9 with loss of Ag(I) provides dihydroimidazole 10 bearing an exocyclic double bond. Further isomerization of dihydroimidazole 10 through 1,3-H shift takes place to produce imidazole product 7. In summary, we have developed a new method for preparation of 1,2,4,5-tetrasubstituted imidazoles by sequential Staudinger/aza-Wittig/Ag(I)-catalyzed cyclization/isomerization starting from the easily accessible propargylazide derivatives. The method was adapted to the synthesis of various polysubstituted imidazoles in one-pot fashion under mild reaction condition, which makes it useful in synthetic and medicinal chemistry.

■

EXPERIMENTAL SECTION

One-Pot Synthesis of Imidazoles 7 via Sequential Staudinger/aza-Wittig/Ag(I)-Catalyzed Cyclization/Isomerization. 13737

DOI: 10.1021/acs.joc.7b02606 J. Org. Chem. 2017, 82, 13735−13739

Note

The Journal of Organic Chemistry 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25 H25FN3 386.2027; Found 386.2031. 5-(4-Methylbenzyl)-2-(pyrrolidin-1-yl)-1-(p-tolyl)-1H-imidazole (7h). Light yellow oil (yield 0.570 g, 86%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.13 (d, J = 7.2 Hz, 2H), 6.99 (t, J = 7.8 Hz, 4H), 6.88 (d, J = 7.8 Hz, 2H), 6.49 (s, 1H), 3.54 (s, 2H), 3.03 (t, J = 7.2 Hz, 4H), 2.38 (s, 3H), 2.29 (s, 3H), 1.73−1.71 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.1, 137.9, 135.7, 135.4, 134.4, 129.5, 128.7, 128.4, 128.3, 128.2, 122.4, 49.5, 30.7, 25.1, 21.1, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26N3 332.2121; Found 332.2119. 5-(4-Chlorobenzyl)-1-phenyl-N,N-dipropyl-1H-imidazol-2-amine (7i). Light yellow oil (yield 0.655 g, 89%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.36−7.02 (m, 7H), 6.86 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H), 3.61 (s, 2H), 2.83 (t, J = 7.2 Hz, 4H), 1.35−1.30 (m, 4H), 0.68 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.7, 137.0, 136.7, 131.7, 129.7, 128.9, 128.1, 128.0, 127.9, 127.8, 123.3, 53.7, 30.6, 20.8, 11.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H27ClN3 368.1888; Found 368.1873. N,5-Dibenzyl-1-(2-chlorophenyl)-1H-imidazol-2-amine (7j). White solid (yield 0.538 g, 72%), mp 90−91 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.44 (d, J = 7.8 Hz, 1H), 7.34−7.11 (m, 10H), 7.00 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 6.6 Hz, 2H), 6.64 (s, 1H), 4.57− 4.48 (m, 2H), 3.69 (d, J = 16.2 Hz, 1H), 3.56−3.51 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 149.4, 139.2, 138.2, 133.7, 132.5, 130.8, 130.6, 130.5, 128.5, 128.4, 128.0, 127.9, 127.7, 127.2, 126.9, 126.1, 123.0, 47.6, 31.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H21ClN3 374.1419; Found 374.1418. 5-Benzyl-N-(tert-butyl)-1-(4-methoxyphenyl)-1H-imidazol-2amine (7k). Light yellow solid (yield 0.476 g, 71%), mp 108−110 °C; 1 H NMR (CDCl3, 600 MHz) δ (ppm) 7.16−6.87 (m, 9H), 6.56 (s, 1H), 3.83 (s, 3H), 3.60 (s, 2H), 3.26 (s, 1H), 1.33 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 159.5, 148.5, 138.8, 129.5, 128.5, 128.0, 127.6, 126.1, 125.9, 122.5, 114.7, 55.4, 51.7, 31.0, 29.6. HRMS (ESITOF) m/z: [M+H]+ Calcd for C21H26N3O 336.2070; Found 336.2077. N-Butyl-5-(4-methylbenzyl)-1-phenyl-1H-imidazol-2-amine (7l). Light yellow solid (yield 0.447 g, 70%), mp 74−76 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.40−7.07 (m, 5H), 6.96 (d, J = 7.2 Hz, 2H, Ar−H), 6.83 (d, J = 7.2 Hz, 2H), 6.53 (s, 1H), 3.59 (s, 2H), 3.38 (t, J = 5.4 Hz, 1H), 3.31−3.28 (m, 2H), 2.27 (s, 3H), 1.52−1.47 (m, 2H), 1.33−1.27 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 149.8, 135.5, 135.4, 135.1, 129.7, 128.7, 128.6, 128.3, 128.1, 126.7, 122.6, 43.3, 32.0, 30.5, 21.0, 20.1, 13.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H26N3 320.2121; Found 320.2142. 5-(4-Chlorobenzyl)-N-isopropyl-1-(p-tolyl)-1H-imidazol-2-amine (7m). Light yellow oil (yield 0.469 g, 69%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.20 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 6.87 (d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 3.96−3.91 (m, 1H), 3.58 (s, 2H), 3.22 (d, J = 7.8 Hz, 1H), 2.39 (s, 3H), 1.14 (d, J = 6.0 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 149.4, 138.8, 137.2, 132.1, 131.6, 130.3, 129.7, 128.0, 127.7, 125.7, 122.7, 44.9, 30.3, 23.3, 21.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H23ClN3 340.1575; Found 340.1595. 5-Benzyl-4-methyl-1-phenyl-N,N-dipropyl-1H-imidazol-2-amine (7n). Light yellow oil (yield 0.556 g, 80%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.28−6.96 (m, 8H), 6.85 (d, J = 7.8 Hz, 2H), 3.66 (s, 2H), 2.84 (t, J = 7.2 Hz, 4H), 2.23 (s, 3H), 1.36−1.30 (m, 4H), 0.67 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.2, 139.6, 137.1, 130.5, 128.7, 128.1, 128.0, 127.8, 127.7, 125.7, 122.6, 53.7, 29.5, 20.8, 12.8, 11.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H30N3 348.2434; Found 348.2463. 1-(5-Benzyl-1-(2-chlorophenyl)-4-methyl-1H-imidazol-2-yl)piperidine (7o). Light yellow oil (yield 0.519 g, 71%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.39 (d, J = 7.8 Hz, 1H), 7.25−7.04 (m, 5H), 6.91 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 6.6 Hz, 2H), 3.76 (d, J = 16.8 Hz, 1H), 3.52 (d, J = 16.8 Hz, 1H), 2.92 (t, J = 5.4 Hz, 4H), 2.24 (s, 3H), 1.38−1.32 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.1, 139.2, 134.9, 133.2, 130.7, 130.6, 130.1, 129.4, 128.0, 127.9,

127.1, 125.8, 123.1, 51.0, 29.8, 25.6, 24.1, 12.9. HRMS (ESI-TOF) m/ z: [M+H]+ Calcd for C22H25ClN3 366.1732; Found 366.1728. 5-Benzyl-4-ethyl-N,N-dipropyl-1-(p-tolyl)-1H-imidazol-2-amine (7p). Light yellow oil (yield 0.556 g, 74%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.06−6.97 (m, 5H), 6.78−6.74 (m, 4H), 3.58 (s, 2H), 2.75 (t, J = 7.2 Hz, 4H), 2.47 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.26− 1.12 (m, 4H), 0.60 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.3, 139.9, 137.3, 136.6, 134.5, 129.2, 127.9, 127.8, 127.6, 125.6, 121.6, 53.8, 29.4, 20.9, 20.8, 20.5, 14.9, 11.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H34N3 376.2747; Found 376.2764. 1-(5-Benzyl-1-butyl-1H-imidazol-2-yl)piperidine (7q). Light yellow oil (yield 0.363 g, 61%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.27− 7.17 (m, 5H), 6.54 (s, 1H), 3.86 (s, 2H), 3.60 (t, J = 7.2 Hz, 2H), 2.95 (t, J = 6.6 Hz, 4H), 1.64−1.21 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.4, 138.3, 128.3, 128.2, 127.1, 126.3, 123.8, 52.7, 42.4, 32.0, 31.2, 26.0, 23.9, 19.7, 13.5. HRMS (ESITOF) m/z: [M + Na]+ Calcd for C19H27N3Na 320.2097; Found 320.2072. 1-(1-Isopropyl-5-(4-methylbenzyl)-1H-imidazol-2-yl)piperidine (7r). Light yellow solid (yield 0.351 g, 59%), mp 60−62 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.09−7.04 (m, 4H), 6.48 (s, 1H), 4.35− 4.30 (m, 1H), 3.86 (s, 2H), 2.93 (t, J = 6.0 Hz, 4H), 2.31 (s, 3H), 1.66−1.56 (m, 6H), 1.34 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.4, 135.7, 135.4, 128.9, 128.2, 127.2, 124.6, 53.3, 46.5, 31.3, 26.0, 23.9, 21.8, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H28N3 298.2278; Found 298.2256. N-Benzyl-5-(4-chlorobenzyl)-1-isopropyl-N-methyl-1H-imidazol2-amine (7s). Light yellow oil (yield 0.439 g, 62%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.33−7.24 (m, 7H), 7.08 (d, J = 7.8 Hz, 2H), 6.48 (s, 1H), 4.60−4.55 (m, 1H), 4.11 (s, 2H), 3.90 (s, 2H), 2.64 (s, 3H), 1.27 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.0, 138.1, 137.1, 132.1, 129.8, 128.7, 128.4, 128.2, 127.1, 126.6, 125.4, 60.8, 46.4, 42.2, 31.4, 21.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H25ClN3 354.1732; Found 354.1731.

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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.7b02606. 1 H and 13C NMR spectra of compounds 7a−7s (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

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

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 (No. 21572075) and the 111 Project B17019.

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REFERENCES

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