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Stereoselective synthesis of indenone-fused heterocyclic compounds via a one-pot four-component reaction
Tetrahedron 73 (2017) 1196e1204
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Stereoselective synthesis of indenone-fused heterocyclic compounds via a one-pot four-component reaction Mohammad Bayat a, *, Fahimeh Sadat Hosseini a, Behrouz Notash b a b
Chemistry Department, Imam Khomeini International University, Qazvin, Iran Department of Chemistry, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 November 2016 Received in revised form 29 December 2016 Accepted 9 January 2017 Available online 12 January 2017
A one-pot multi-component synthesis of indenone-fused heterocyclic derivatives from readily available starting materials including diamines, 1,1-bis(methylthio)-2-nitroethene, 1,3-indandione and aromatic aldehydes in excellent yields is described. The sequence of cascade reactions include Knoevenagel condensation, enamine formation, Michael addition, imine-enamine tautomerization and cyclization. The diastereoselective synthesis of cis-indenohydropyridine have been definitively proven by X-ray crystallography. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Diamines 1,1-bis(methylthio)-2-nitroethene 1,3-indandione Aromatic aldehydes Multi-component synthesis
1. Introduction The development of new synthetic methods in the research of novel bioactive compounds, such as natural products and analogous, drugs, diagnostics and agrochemicals, in academic and industrial chemistry is closely connected to the efficient synthesis of such compounds. Thus, the view of synthesis has altered in recent years; the development of new, highly selective methods will still be an important task, but the main focus of today's chemists is on efficiency.1 A general way to improve synthetic efficiency, which in addition also gives access to a multitude of diversified products, is the development of multicomponent domino reactions which allow the preparation of complex molecules starting from simple substrates. Domino reactions are defined as processes of two or more bond-forming reactions in one-pot, in which the subsequent transformation occurs at the functionalities obtained in the former transformation; thus, it is a time-resolved process.2 The conventional methods for the synthesis of complex compounds involve many synthetic operations, including extraction and purification processes for each step, that cause synthetic inefficiency and the production of large amounts of waste. Multi
* Corresponding author. E-mail addresses: [email protected], [email protected] (M. Bayat). http://dx.doi.org/10.1016/j.tet.2017.01.024 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
component reactions (MCRs) allow the creation of several bonds in a single operation and offer remarkable advantages like convergence, operational simplicity, facile automation, reduction in the number of workups, extraction and purification processes. Thus, MCRs and their improvement are of considerable interest in the current research. As a one-pot reaction, MCRs permit rapid access to combinatorial libraries of complex molecules especially in drug discovery.3 Indenone frameworks are in a large number of natural and synthetic drugs. Indenone-fused heterocycles have attracted the attention of chemists and pharmacologists4 because of their broad range of bioactivities, such as topoisomerase I inhibitor TAS-1035 (Fig. 1). The indenopyridine skeleton is present in the 4azafluorenone group of alkaloids, represented by its simplest member onychnine6 (Fig. 1). 4-Azafluorenones, a privileged molecular scaffold ubiquitously found in natural products,7 display various biological activities including antimicrobial, antimalarial, and DNA damaging activities.8 The strategies reported for the synthesis of 4-azafluorenones classify in three categories7: intramolecular Friedel-Crafts acylation on 2-arylpyridines containing a carboxylic acid9,10 or an ester group,11 diaryl linkage formation by intramolecular Heck reactions on 3-aroylpyridines,12 and a three-component reaction,13 Remarkably, Mohammadi et al. reported a one-pot four-component reaction for the synthesis of hydroazafluorenones.14
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
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Fig. 1. Bioactive and medicinally important compounds containing an indenone-fused skeleton.
During the last few years, the use of enamines and dienamines from nitro ketene dithioacetal in organic chemistry has attracted great attention of many chemists.15 They have been used for the synthesis of a wide variety of heterocyclic systems and natural products,16 and precursors of chiral amines in asymmetric transformations.17
Fig. 2. X-ray crystal structure (ORTEP) of 5b.
2. Result and discussions The one-pot multicomponent condensation reactions of diamines 1 with 1,1-bis(methylthio)-2-nitroethene 2 and aromatic aldehydes 3 in the presence of 1,3-indandione 4 in EtOH as a solvent under reflux condition leads to corresponding cis-indenohydropyridine heterocyclic systems 5a-5s, in excellent yields (Scheme 1). The cis-indenohydropyridine 5 possesses three chiral centers and there are 8 possible stereoisomers, one of which was prepared in a highly stereo controlled fashion. Clearly the sequential use of two highly stereoselective reactions providing three new chiral centers, is an extremely powerful strategy for asymmetric synthesis. Herein, we report a simple one-pot reaction for the synthesis of cis-indenohydropyridine derivatives in high yields. To the best of our knowledge, there are no reports on the synthesis of these compounds in the literature yet. The structures of compounds 5a-5s were assigned from their elemental analyses and IR, mass, 1H NMR, and 13C NMR spectra (see the Supporting Information) and by single-crystal X-ray analysis of 5b (Fig. 2).18 1 H and 13C NMR spectra of the crude products clearly indicated the formation of heterocyclic compounds 5a-5s. For example, the 1 H NMR spectrum of 5b showed four singlets identified as amino (d 8.74, Hf), hydroxy (d 6.44, He), methine protons (d 4.96, Hd and d 3.26, Hc), along with characteristic multiplets for two CH2 groups (3.17e3.22, 3.44e3.46, 3.64e3.66, 3.90e3.96, 2Ha and 2Hb), and multiplets for the aromatic region (7.07e7.65) (Fig. 3). We didn't see coupling constants between Hc and Hd for all of the products (because of two hydrogens are orthogonal). The X-ray data gave the actual dihedral angle between H (7)-C (7)-C (13)-H (13) is 87. The mass spectra of compounds 5a-5s displayed molecular ion peaks at appropriate m/z values. Initial fragmentations involved loss from or complete loss of the side chains and scission of the heterocyclic system. The 1H-decoupled 13C NMR spectrum of 5b showed 18 distinct resonances, which confirmed the proposed
Scheme 1. Synthetic scheme for the indenone-fused heterocycle 5.
Fig. 3. The 1H NMR spectrum of 5b.
structure. The IR spectrum of 5b displayed characteristic absorption bands (3400, 3326, 1722, 1523, 1380, 1218, 1134 cm1) due to OH, NH, C¼O, NO2, CeN, CeO groups. During the investigation of this work, a similar method for the synthesis of indenofurans and indenopyridines through a one pot, three-component protocol from heterocyclic ketene aminals, ophthalaldehyde and 1,3-diketones was recently reported.19 In this report, Shao and coworkers focus on the reaction behaviors of sixmembered heterocyclic ketene aminals, which nitro group act as leaving group. An examination of the literature showed that ethanol was often used as a compatible solvent.20 The reaction proceeds with excellent yields when ethanol was used as the solvent. We explored the scope of this reaction by varying the structure of the primary diamine 1 and aromatic aldehyde 3 components. The reaction proceeds cleanly to afford a series of cis-indenohydropyridine derivatives 5 in 65e95% yields. The results are shown in Table 1. A plausible mechanism for the formation of cis-indenohydropyridine systems 5 is shown in Scheme 2, on the basis of wellestablished chemistry of 1,1-bis(methylthio)-2-nitroethene.21,22 The process represents a typical cascade reaction in which the reaction between diamine 1 and 1,1-bis(methylthio)-2-nitroethene 2 affords nitroketene aminal 6. The second step involves condensation of 1,3-indandione 4 with aldehyde 3 to afford Knoevenagel adduct 7. Then, the ene-component nitroketene aminal 6 and the Knoevenagel adduct 7 undergo a Michael addition to give the intermediate 8, which undergoes successive imine-enamine tautomerization, followed by nucleophilic addition of the secondary amino group to the carbonyl group, leads to the formation of product 5.
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Table 1 One-pot, four-component synthesis of indenone-fused derivatives 5a-5s. ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
1
5a
1
80
2
5b
1
84
3
5c
1
90
4
5d
2
92
5
5e
2
88
6
5f
1
93
7
5g
3
65
8
5h
3
70
Structure of product
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Table 1 (continued ) ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
9
5i
3
68
10
5j
2
87
11
5k
3
88
12
5l
3
90
13
5m
1
86
14
5n
1
89
15
5o
2
95
Structure of product
(continued on next page)
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M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
Table 1 (continued ) ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
16
5p
2
91
17
5q
2
89
18
5r
3
72
19
5s
3
70
20
5t
e
e
e
21
5u
e
e
e
22
5v
e
e
e
a
Structure of product
Equal amounts (1 mmol) of the reactants were used. The reactions were run in EtOH at 80 C, without any catalyst.
3. Conclusions We have developed a simple and novel four-component one-pot synthesis of cis-indenohydropyridine compounds, through sequential enamine formation, Knoevenagel condensation, Michael addition, imine-enamine tautomerization and cyclization sequences in ethanol. This class of compounds is not only prepared by a one-pot reaction for the first time but also to our knowledge, there is no other report for their synthesis. This reaction includes some important aspects like simple operation under mild conditions, easy accessibility of reactants and workup procedure, absence of catalysts, high atom economy and the use of ethanol as a
green reaction medium. 4. Experimental section 4.1. General The diamines, 1,1-bis(methylthio)-2-nitroethene, 1,3indandione, and aldehydes were obtained from Merck and Aldrich and were used without further purification. NMR spectra were recorded with a Bruker DRX-300 Avance instrument (300 MHz for 1H and 75.4 MHz for 13C) with CDCl3 and DMSO as solvents. Chemical shifts are given in ppm (d) relative to internal
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
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Scheme 2. Mechanistic rationalization for the formation of 5.
TMS, and coupling constant (J) are reported in hertz (Hz). Melting points were measured with an electrotherma1 9100 apparatus. Mass spectra were recorded with an Agilent 5975C VL MSD with Triple-Axis Detector operating at an ionization potential of 70 eV. IR spectra were measured with, Bruker Tensore 27 spectrometer. Elemental analyses: Heraeus CHNO-Rapid analyzer. 4.2. General procedure for the synthesis of 5-(4-chlorophenyl)1,2,3,5-tetrahydro-10b-hydroxy-4-nitro-6H-imidazo[1,2-a]indeno [2,1-e]pyridin-6-one (5b) A mixture of ethylene diamine (66 mL, 1 mmol), 1,1- bis(methylthio)-2-nitro ethylene (0.165 g, 1 mmol) and 10 mL EtOH in a 50 mL flask was refluxed for 6 h. After completion of the reaction (monitored by TLC, ethyl acetate/n-hexane, 6:4), p-chlorobenzaldehyde (0.140 g, 1 mmol), 1,3-indandione (0.146 g, 1 mmol) were added to the reaction mixture, and it was stirred under reflux for 1 h. Then, the reaction mixture was cooled to room temperature and filtered to give the crude product. The solid was washed with ethanol to give product 5b in 84% yield. The crude product recrystallized from methanol to afford the pure product (for CHN analyses and X-ray crystallography).
(%) ¼ 397 (Mþ, 0.13), 374 (14), 267 (23), 233 (18), 176 (19), 119 (87), 91 (40), 69 (31), 54 (71), 43 (100). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.17e3.22 (1H, m, CH), 3.26 (1H, s, CH), 3.44e3.46 (1H, m, CH), 3.64e3.66 (1H, m, CH), 3.90e3.96 (1H, m, CH), 4.94 (1H, s, CH), 6.44 (1H, s, OH), 7.07 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.23 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.36e7.65 (4H, m, 4CH of Ind.), 8.74 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.6, 42.6, 43.8, 63.6, 86.0, 104.2, 123.9, 125.2, 128.5, 130.0, 130.9, 131.2, 133.4, 135.4, 142.3, 151.5, 154.5, 198.6; Anal. Calcd for C20H35 16 ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found C, 60.2; H, 3.9; N, 10.5. Crystal data for 5b: C20H35 16 ClN3O4 (CCDC No. 1486209): M ¼ 397.81, monoclinic system, space group P21/c, a ¼ 8.4393 (17) Å, b ¼ 16.741 (3) Å, c ¼ 15.119 (5) Å, b ¼ 122.58 (2) , V ¼ 1799.9 (9) Å3, Z ¼ 4, Dc ¼ 1.468 mg/m3, F (000) ¼ 824, crystal dimension 0.25 0.2 0.15 mm, radiation: Mo Ka (l ¼ 0.71073 Å). The X-ray diffraction measurement was made on a STOE IPDS-II diffractometer with graphite monochromated Mo-Ka radiation. The structure was solved by using SHELXS. The Data reduction and structure refinement was carried out with SHELXL using the X-STEP32 crystallographic software package. The non-hydrogen atoms were refined anisotropically by full matrix least-squares on F2 values to final R1 ¼ 0.0955, wR2 ¼ 0.0948 and S ¼ 1.047 with 253 parameters using 3122 independent reflection (q range ¼ 2.49e24.99 ).
4.3. 10b-hydroxy1,2,3,5-tetrahydro-4-nitro-5-phenyl-6H-imidazo [1,2-a]indeno[2,1-e]pyridin-6-one (5a) White solid, mp: 212e214 C (dec.), 0.290 g, yield: 80%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3355 (NH), 1724 (C¼O), 1590 (Ar), 1534 and 1350 (NO2), 1222 (CeN), 1133 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.18e3.28 (1H, m, CH), 3.37 (1H, s, CH), 3.42e3.55 (1H, m, CH), 3.65e3.77 (1H, m, CH), 3.93e4.05 (1H, m, CH), 5.02 (1H, s, CH), 6.19 (1H, s, OH), 7.04e7.67 (9H, m, Ar), 8.78 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 37.1, 42.6, 43.8, 63.9, 86.1, 104.5, 123.9, 125.2, 126.6, 128.1, 128.6, 130.9, 133.4, 135.5, 143.3, 151.6, 154.6, 198.9; Anal. Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found C, 65.9; H, 4.6; N, 11.5. 4.4. 5-(4-chlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5b) White solid, mp: 208e210 C (dec.), 0.333 g, yield: 84%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3326 (NH), 1722 (C¼O), 1600 (Ar), 1523 and 1380 (NO2), 1218 (CeN), 1134 (CeO). MS (EI, 70 eV): m/z
4.5. 5-(4-bromophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5c) White solid, mp: 206e208 C (dec.), 0.398 g, yield: 90%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3319 (NH), 1721 (C¼O), 1599 (Ar), 1522 and 1379 (NO2), 1220 (CeN), 1136 (CeO). MS (EI, 70 eV): m/z (%) ¼ 442 (Mþ, 0.22), 391 (11), 376 (28), 313 (93), 268 (12), 233 (100), 205 (26), 176 (74), 151 (20), 129 (37), 104 (56), 88 (15), 76 (64), 50 (24). 1H NMR (300 MHz, DMSO): d 3.18e3.24 (1H, m, CH), 3.44e3.51 (1H, m, CH), 3.51 (1H, s, CH), 3.61e3.67 (1H, m, CH), 3.92e3.98 (1H, m, CH), 4.84 (1H, s, CH), 6.99 (1H, s, OH), 7.27 (2H, d, 3 JHH ¼ 8.5 Hz, 2CH of Ar), 7.46 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.73e7.87 (4H, m, 4CH of Ind.), 9.07 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 31.2, 42.7, 43.8, 63.0, 86.0, 104.0, 119.0, 123.9, 125.2, 130.4, 130.9, 131.4, 133.4, 135.5, 142.7, 151.5, 154.5, 198.5. Anal. Calcd for C20H79 16 BrN3O4: C, 54.31; H, 3.65; N, 9.50. Found C, 54.5; H, 3.7; N, 9.4.
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4.6. 10b-hydroxy-1,2,3,5-tetrahydro-4-nitro-5-(4-nitrophenyl)-6Himidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5d) White solid, mp: 204e206 C (dec.), 0.375 g, yield: 92%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3341 (NH), 1715 (C¼O), 1597 (Ar), 1510 and 1342 (NO2), 1205 (CeN), 1127 (CeO). MS (EI, 70 eV): m/z (%) ¼ 408 (Mþ, 0.03), 279 (80), 262 (81), 232 (100), 205 (16), 176 (75), 165 (20), 151 (28), 129 (33), 104 (35), 76 (35), 54 (15). 1H NMR (300 MHz, DMSO): d 3.18e3.23 (1H, m, CH), 3.49e3.51 (1H, m, CH), 3.60 (1H, s, CH), 3.61e3.69 (1H, m, CH), 3.96e3.99 (1H, m, CH), 5.02 (1H, s, CH), 7.07 (1H, s, OH), 7.58 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 8.16 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.63e7.88 (4H, m, 4CH of Ind.), 9.12 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 37.2, 42.7, 43.9, 63.3, 85.9, 103.5, 123.8, 124.0, 125.1, 129.4, 131.0, 133.4, 135.5, 146.6, 151.3, 151.5, 154.5, 198.1. Anal. Calcd for C20H16N4O6: C, 58.82; H, 3.95; N, 13.72. Found C, 58.9; H, 4.0; N, 13.6. 4.7. 10b-hydroxy-1,2,3,5-tetrahydro-4-nitro-5-(2-nitrophenyl)-6Himidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5e) Yellow solid, mp: 198e200 C (dec.), 0.359 g, yield: 88%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3329 (NH), 1728 (C¼O), 1599 (Ar), 1513 and 1353 (NO2), 1200 (CeN), 1141 (CeO). 1H NMR (300 MHz, DMSO): d 3.18e3.24 (1H, m, CH), 3.46e3.52 (1H, m, CH), 3.55 (1H, s, CH), 3.62e3.71 (1H, m, CH), 3.96e4.02 (1H, m, CH), 5.28 (1H, s, CH), 7.08 (1H, s, OH), 7.43e7.91 (8H, m, 8CH of Ar), 9.09 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 33.0, 42.8, 43.9, 62.0, 85.8, 104.1, 124.0, 124.4, 125.0, 128.3, 128.4, 130.5, 131.0, 133.3, 135.5, 137.6, 149.8, 151.4, 154.7, 197.3. Anal. Calcd for C20H16N4O6: C, 58.82; H, 3.95; N, 13.72. Found C, 58.7; H, 3.9; N, 13.7. 4.8. 5-(3-chlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5f) Brown solid, mp: 210e212 C (dec.), 0.329 g, yield: 83%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3331 (NH), 1723 (C¼O), 1588 (Ar), 1531 and 1394 (NO2), 1222 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO): d 3.12e3.23 (1H, m, CH), 3.42e3.52 (1H, m, CH), 3.56 (1H, s, CH), 3.60e3.72 (1H, m, CH), 3.90e4.03 (1H, m, CH), 4.90 (1H, s, CH), 7.06 (1H, s, OH), 7.29e7.84 (8H, m, 8CH of Ar), 9.08 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.9, 42.7, 43.9, 63.5, 86.0, 103.9, 123.9, 125.1, 126.7, 127.0, 127.8, 130.4, 130.9, 133.2, 133.4, 135.5, 145.9, 151.4, 154.5, 198.4. Anal. Calcd for C20H35 16 ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found C, 60.3; H, 4.1; N, 10.6. 4.9. 5-(4-fluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5g) Pale pink solid, mp: 208e210 C (dec.), 0.247 g, yield: 65%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3358 (NH), 1725 (C¼O), 1594 (Ar), 1540 and 1350 (NO2), 1224 (CeN), 1135 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.18e3.27 (1H, m,CH), 3.31 (1H, s, CH), 3.45e3.55 (1H, m, CH), 3.68e3.72 (1H, m, CH), 3.92e4.03 (1H, m, CH), 5.00 (1H, s, CH), 6.40 (1H, s, OH), 6.80e7.80 (8H, m, 8CH of Ar), 8.80 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 30.9, 42.0, 43.0, 65.0, 89.0, 105.0, 114.9, 118.0, 124.1, 129.3, 129.4, 130.4, 134.0, 135.0, 143.0, 155.0, 168.3, 203.0. Anal. Calcd for C20H16FN3O4: C, 62.99; H, 4.23; N, 11.02. Found C, 63.1; H, 4.4; N, 10.9. 4.10. 5-(3-fluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5h) Pink solid, mp: 212e214 C (dec.), 0.267 g, yield: 70%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3300 (NH), 1727 (C¼O), 1591 (Ar),
1534 and 1350 (NO2), 1226 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.13e3.16 (1H, m, CH), 3.26 (1H, s, CH), 3.41e3.44 (1H, m, CH), 3.62e3.64 (1H, m, CH), 3.91e3.94 (1H, m, CH), 4.93 (1H, s, CH), 6.47 (1H, s, OH), 6.67e7.62 (8H, m, 8CH of Ar), 8.73 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 30.9, 42.2, 43.7, 63.9, 85.8, 104.6, 113.2, 114.6, 123.6, 124.1, 129.6, 130.4, 133.4, 134.6, 145.0, 150.7, 155.02, 163.0, 198.0. Anal. Calcd for C20H16FN3O4: C, 62.99; H, 4.23; N, 11.02. Found C, 62.9; H, 4.1; N, 11.1. 4.11. 5-(3,4-difluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5i) Pale brown solid, mp: 204e206 C (dec.), 0.271 g, yield: 68%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3300 (NH), 1726 (C¼O), 1595 (Ar), 1533 and 1394 (NO2), 1223 (CeN), 1135 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.22e3.31 (1H, m, CH), 3.34 (1H, s, CH), 3.48e3.58 (1H, m, CH), 3.70e3.80 (1H, m, CH), 4.00e4.12 (1H, m, CH), 5.03 (1H, s, CH), 6.55 (1H, s, OH), 6.90e7.80 (7H, m, 7CH of Ar), 8.80 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 37.0, 42.2, 43.8, 63.0, 85.9, 95.1, 116.7, 116.9, 124.0, 124.2, 127.4, 130.4, 133.5, 134.6, 139.0, 144.5, 151.0, 151.2, 154.0, 197.1. Anal. Calcd for C20H15F2N3O4: C, 60.15; H, 3.79; N, 10.52. Found C, 60.3; H, 3.9; N, 10.5. 4.12. 5-(2,6-dichlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5j) Pink solid, mp: 295e297 C (dec.), 0.375 g, yield: 87%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3347 (NH), 1727 (C¼O), 1600 (Ar), 1527 and 1382 (NO2), 1226 (CeN), 1140 (CeO). MS (EI, 70 eV): m/z (%) ¼ 432 (Mþ, 0.10), 267 (100), 176 (23), 129 (13), 76 (22), 54 (14). 1 H NMR (300 MHz, DMSO): d 3.19e3.25 (1H, m, CH), 3.42 (1H, s, CH), 3.39e3.48 (1H, m, CH), 3.66e3.68 (1H, m, CH), 3.93e3.98 (1H, m, CH), 5.63 (1H, s, CH), 6.99 (1H, s, OH), 7.19e7.88 (7H, m, 7CH of Ar), 9.14 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 34.8, 42.7, 43.7, 62.1, 85.2, 102.1, 124.1, 124.7, 128.9, 129.5, 130.8, 133.2, 134.0, 135.5, 135.9, 136.7, 151.8, 155.7, 197.2. Anal. Calcd for C20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72. Found C, 55.4; H, 3.4; N, 9.8. 4.13. 10b-hydroxy-1,2,3,5-tetrahydro-5-(4-hydroxyphenyl)-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5k) Tan solid, mp: 183e185 C (dec.), 0.333 g, yield: 88%. IR (KBr) (nmax/cm1): 3200e3400 (OH), 3317 (NH), 1722 (C¼O), 1596 (Ar), 1517 and 1350 (NO2), 1210 (CeN), 1127 (CeO). 1H NMR (300 MHz, DMSO): d 3.24e3.50 (2H, m, CH2), 3.62 (1H, s, CH), 3.60e3.72 (1H, m, CH), 3.90e4.05 (1H, m, CH), 4.82 (1H, s, CH), 6.91 (1H, s, OH), 6.64 (2H, d, 3JHH ¼ 7.0 Hz, 2H of Ar), 7.10 (2H, d, 3JHH ¼ 7.0 Hz, 2H of Ar), 7.61e7.84 (4H, m, 4CH of Ind.), 9.02 (1H, s, OH), 9.17 (1H, s, NH). 13 C NMR (75.4 MHz, DMSO): d 36.4, 42.6, 43.8, 64.1, 86.2, 105.1, 115.2, 123.8, 125.2, 129.1, 131.5, 133.3, 133.5, 135.5, 151.7, 154.6, 156.1, 199.2. Anal. Calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found C, 63.1; H, 4.4; N, 10.9. 4.14. 10b-hydroxy-1,2,3,5-tetrahydro-5-(2,5-dihydroxyphenyl)-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5l) Pale brown solid, mp: 228e230 C (dec.), 0.355 g, yield: 90%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3340 (NH), 1714 (C¼O), 1596 (Ar), 1512 and 1387 (NO2), 1225 (CeN), 1125 (CeO). 1H NMR (300 MHz, DMSO): d 3.16e3.93 (4H, m, 2CH2), 3.57 (1H, s, CH), 5.14 (1H, s, CH), 6.74 (1H, s, OH), 6.29 (1H, s, 1H of Ar), 6.38 (2H, d, 3 JHH ¼ 8.0 Hz, 2H of Ar), 6.57 (2H, d, 3JHH ¼ 8.0 Hz, 2H of Ar), 7.61e7.80 (4H, m, 4CH of Ind.), 8.52 (1H, s, OH), 8.83 (1H, s, OH),
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
9.08 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.5, 42.7, 43.8, 62.1, 86.1, 103.5, 113.6, 114.6, 115.8, 123.7, 125.1, 129.2, 130.7, 133.6, 135.2, 147.5, 149.9, 151.8, 155.2, 199.2. Anal. Calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found C, 60.8; H, 4.5; N, 10.6. 4.15. 6-(4-chlorophenyl)-2,3,4,6,6a,11b-hexahydro-11b-hydroxy-5nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5m) White solid, mp: 177e179 C (dec.), 0.353 g, yield: 86%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3196 (NH), 1723 (C¼O), 1597 (Ar), 1540 and 1364 (NO2), 1247 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO): d 1.66e1.83 (2H, m, CH2), 3.16e3.83 (4H, m, 2CH2), 3.58 (1H, s, CH), 5.05 (1H, s, CH), 7.07 (1H, s, OH), 7.28e7.96 (8H, m, 8CH of Ar), 11.47 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 31.2, 36.4, 38.1, 62.2, 88.4, 106.8, 123.7, 125.6, 128.5, 129.9, 131.0, 131.2, 133.5, 135.6, 141.2, 151.8, 152.2, 199.1. Anal. Calcd for C21H35 18 ClN3O4: C, 61.24; H, 4.41; N, 10.20. Found C, 61.4; H, 4.6; N, 10.1. 4.16. 6-(4-bromophenyl)-2,3,4,6,6a,11b-hexahydro-11b-hydroxy-5nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5n) White solid, mp: 180e182 C (dec.), 0.406 g, yield: 89%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3196 (NH), 1723 (C¼O), 1600 (Ar), 1597 and 1364 (NO2), 1249 (CeN), 1140 (CeO). MS (EI, 70 eV): m/z (%) ¼ 456 (Mþ, 0.08), 313 (82), 267 (50), 233 (100), 205 (20), 176 (65), 143 (24), 104 (44), 76 (55), 56 (23). 1H NMR (300 MHz, DMSO): d 1.66e1.81 (2H, m, CH2), 3.16e3.82 (4H, m, 2CH2), 3.58 (1H, s, CH), 5.036 (1H, s, CH), 7.06 (1H, s, OH),7.24 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.46 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.60e7.95 (4H, m, 4CH of Ind.), 11.46 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 24.8, 41.0, 43.5, 43.9, 66.9, 93.0, 111.8, 124.8, 128.6, 129.4, 134.5, 135.3, 136.0, 138.4, 139.5, 145.7, 156.4, 156.6, 202.8. Anal. Calcd for C21H79 18 BrN3O4: C, 55.28; H, 3.98; N, 9.21. Found C, 55.1; H, 3.9; N, 9.1. 4.17. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(4nitrophenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5o) Pale yellow solid, mp: 193e195 C (dec.), 0.401 g, yield: 95%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3227 (NH), 1721 (C¼O), 1599 (Ar), 1516 and 1353 (NO2), 1244 (CeN), 1132 (CeO). 1H NMR (300 MHz, DMSO): d 1.68e1.83 (2H, m, CH2), 3.22e3.24 (2H, m, CH2), 3.79e3.84 (2H, m, CH2), 3.69 (1H, s, CH), 5.18 (1H, s, CH), 7.11 (1H, s, OH), 7.56 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 8.16 (2H, d, 3 JHH ¼ 8.5 Hz, 2CH of Ar), 7.61e8.03 (4H, m, 4CH of Ind.), 11.44 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 37.1, 43.0, 44.0, 62.0, 88.2, 106.1, 123.7, 125.6, 129.4, 131.1, 133.5, 134.6, 135.5, 136.7, 150.1, 151.9, 152.1, 198.5. Anal. Calcd for C21H18N4O6: C, 59.71; H, 4.30; N, 13.26. Found C, 59.8; H, 4.2; N, 13.2. 4.18. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(2nitrophenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5p) Pale brown solid, mp: 156e160 C, 0.384 g, yield: 91%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3132 (NH), 1731 (C¼O), 1597 (Ar), 1507 and 1357 (NO2), 1264 (CeN), 1153 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 1.65e1.78 (2H, m, CH2), 2.93e3.01 (2H, m, CH2), 3.26e3.40 (1H, m, CH), 3.53 (1H, s, CH), 3.76e3.80 (1H, m, CH), 5.47 (1H, s, CH), 6.53 (1H, s, OH), 7.12e7.71 (8H, m, 8CH of Ar), 11.65 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 24.8, 37.9, 43.9, 45.9, 65.2, 93.0, 113.0, 128.6, 129.2, 129.6, 132.4, 134.9, 135.3, 137.6, 138.5, 139.2, 142.1, 154.0, 156.2, 156.7, 201.5. Anal. Calcd for C21H18N4O6: C, 59.71; H, 4.30; N, 13.26. Found C, 60.1; H, 4.4; N, 13.1.
1203
4.19. 6-(2,6-dichlorophenyl)-2,3,4,6,6a,11b-hexahydro-11bhydroxy-5-nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5q) Yellow solid, mp: 178e180 C, 0.396 g, yield: 89%. IR (KBr) (nmax/ cm ): 3000e3400 (OH), 3184 (NH), 1723 (C¼O), 1595 (Ar), 1558 and 1377 (NO2), 1221 (CeN), 1145 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 1.60e1.70 (2H, m, CH2), 2.80e3.79 (4H, m, 2CH2), 3.28 (1H, s, CH), 5.59 (1H, s, CH), 6.39 (1H, s, OH), 6.81e7.59 (7H, m, 7CH of Ar), 11.87 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 34.7, 38.1, 41.4, 60.4, 87.6, 105.3, 123.9, 125.5, 128.8, 129.5, 130.8, 133.4, 133.9, 135.2, 136.4, 152.2, 152.6, 197.3. Anal. Calcd for C21H35 17 Cl2N3O4: C, 56.52; H, 3.84; N, 9.42. Found C, 56.7; H, 3.7; N, 9.3. 1
4.20. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(4trifluoromethylphenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin7(1H)-one (5r) White solid, mp: 187e189 C (dec.), 0.320 g, yield: 72%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 33183 (NH), 1721 (C¼O), 1597 (Ar), 1543 and 1324 (NO2), 1249 (CeN), 1139 (CeO). 1H NMR (300 MHz, DMSO): d 1.60e190 (2H, m, CH2), 3.17e3.86 (4H, m, 2CH2), 3.61 (1H, s, CH), 5.15 (1H, s, CH), 7.06 (1H, s, OH), 7.49e7.93 (8H, m, 8CH of Ar), 11.52 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 19.9, 36.8, 42.0, 43.0, 62.1, 88.3, 106.3, 122.8, 123.7, 125.5, 125.7, 127.4, 128.9, 131.1, 133.5, 135.6, 147.2, 151.8, 152.1, 198.9; Anal. Calcd for C22H18F3N3O4: C, 59.33; H, 4.07; N, 9.43. Found C, 59.5; H, 4.0; N, 9.6. 4.21. 6-(3,4-difluorophenyl)-2,3,4,6,6a,11b-hexahydro-11bhydroxy-5-nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5s) White solid, mp: 163e165 C, 0.289 g, yield: 70%. IR (KBr) (nmax/ cm1): 3000e3400 (OH), 3236 (NH), 1724 (C¼O), 1601 (Ar), 1515 and 1360 (NO2), 1246 (CeN), 1139 (CeO). 1H NMR (300 MHz, DMSO): d 1.70e1.86 (2H, m, CH2), 3.17e3.81 (4H, m, 2CH2), 3.57 (1H, s, CH), 5.07 (1H, s, CH), 7.08 (1H, s, OH), 7.13e8.19 (7H, m, 7CH of Ar), 11.51 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 31.1, 36.2, 38.1, 62.0, 88.3, 106.7, 116.9, 117.1, 117.3, 123.7, 124.6, 125.4, 130.8, 133.6, 135.3, 139.7, 151.4, 151.7, 152.0, 198.6. Anal. Calcd for C21H17F2N3O4: C, 61.02; H, 4.15; N, 10.17. Found C, 61.2; H, 4.3; N, 10.3. Acknowledgments Financial support of this research from Imam Khomeini International University, Iran is gratefully acknowledged. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.01.024. References 1. Hulme C. In: Zhu J, Bienayme H, eds. Multicomponent Reactions. Weinheim: Wiley-VCH; 2005:121. 2. (a) Tietze LF, Modi A. Med Res Rev. 2000;20:304e322; (b) Poli G, Giambastiani G, Heumann A. Tetrahedron. 2000;56:5959e5989. 3. Samai S, Nandi GC, Kumar R, Singh MS. Tetrahedron Lett. 2009;50:7096e7098. 4. (a) Chen XB, Liu XM, Huang R, Yan SJ, Lin J. Eur J Org Chem. 2013:4607e4613; b) Duan YJ, Liu JL, Wang CL. Chin J Org Chem. 2010;30:988e996; c) Evdokimov NM, Slambrouck SV, Heffeter P, et al. J Med Chem. 2011;54: 2012e2021. 5. Utsugi T, Aoyagi K, Asano T, et al. Jpn J Cancer Res. 1997;88:992e1002. 6. Manpadi M, Uglinskii PY, Rastogi SK, et al. Org Biomol Chem. 2007;5:
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3865e3872. 7. Laha JV, Jethava KP, Patel S. Org Lett. 2015;17:5890e5893. 8. (a) Mueller D, Davis RA, Duffy S, Avery VM, Camp D, Quinn RJ. J Nat Prod. 2009;72:1538e1540; (b) Kraus GA, Kempema A. J Nat Prod. 2010;73:1967e1968. 9. Stauffer KJ, Williams PD, Selnick HG, et al. J Med Chem. 2005;48:2282e2293. 10. (a) Rebstock AS, Mongin F, Trecourt F, Queguiner G. Tetrahedron. 2003;59: 4973e4977; (b) DuPriest MT, Schmidt CL, Kuzmich D, Williams SB. J Org Chem. 1986;51: 2021e2023. 11. (a) Sreekumar R, Rugmini P, Padmakumar R. Synth Commun. 1998;28: 2071e2075; (b) Zhang S, Liao LY, Zhang F, Duan XF. J Org Chem. 2013;78:2720e2725. 12. (a) Dhara S, Ahmed A, Nandi S, Baitalik S, Ray JK. Tetrahedron Lett. 2013;54: 63e65; (b) Marquise N, Dorcet V, Chevallier F, Mongin F. Org Biomol Chem. 2014;12: 8138e8148; (c) Marquise N, Harford PJ, Chevallier F, et al. Tetrahedron Lett. 2013;54: 3154e3157; (d) Marquise N, Harford PJ, Chevallier F, et al. Tetrahedron. 2013;69: 10123e10133; (e) Marquise N, Chevallier F, Nassar E, et al. Tetrahedron. 2016;72:825e836. 13. (a) Tu S, Jiang B, Jiang H, et al. Tetrahedron. 2007;63:5406e5414; (b) Tu S, Jiang B, Jia R, Zhang J, Zhang Y. Tetrahedron Lett. 2007;48:1369e1374. 14. Mohammadi AA, Taheri S, Amouzegar A. J Heterocycl Chem. 2015;53:805e808.
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15. (a) Alizadeh A, Rezvanian A, Mokhtari J. Synthesis. 2011;21:3491e3495; (b) Alizadeh A, Mokhtari J. Tetrahedron. 2011;67:3519e3523. 16. (a) Stanovnik B, Svete J. Chem Rev. 2004;104:2433e2480; (b) Rueping M, Parra A. Org Lett. 2010;12:5281e5283; (c) Neumann JJ, Suri M, Glorius F. Angew Chem Int Ed. 2010;49:7790e7794; (d) Rakshit S, Patureau FW, Glorius F. J Am Chem Soc. 2010;132:9585e9587; (e) Khan AT, Parvin T, Choudhury LH. J Org Chem. 2008;73:8398e8402. 17. (a) MukherJee S, Yang JW, Hoffmann S, List B. Chem Rev. 2007;107:5471e5569; (b) Enders D, Niemeier O, Henseler A. Chem Rev. 2007;107:5606e5655; (c) Melchiorre P, Marigo M, Carlone A, Bartoli G. Angew Chem Int Ed. 2008;47: 6138e6171. 18. Complete crystallographic data for compounds 5b has been deposited with the Cambridge Crystallographic Data Center as supplementary publication No. CCDC 1486209. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: 0044 1223 336 033, email:[email protected] 19. Sun F, Shao X, Li Z. RSC Adv. 2016;6:15382e15389. 20. Zhang L, Dong J, Xu X, Liu Q. Chem Rev. 2016;116:287e322. 21. (a) Diego PS, Arlene GC. J Braz Chem Soc. 2010;21:795e799; (b) Rao HSP, Geetha K. Tetrahedron Lett. 2009;50:3836e3839; (c) Coustard JM. Tetrahedron. 1995;51:10929e10940; (d) Coustard JM. Tetrahedron. 1996;52:9509e9520. 22. (a) Srinivasachari R. Tetrahedron. 1999;55:7065e7389; (b) Kearney T, Joule JA, Jackson A. Heterocycles. 1992;33:757e762.
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of indenone-fused heterocyclic compounds via a one-pot four-component reaction Mohammad Bayat a, *, Fahimeh Sadat Hosseini a, Behrouz Notash b a b
Chemistry Department, Imam Khomeini International University, Qazvin, Iran Department of Chemistry, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 November 2016 Received in revised form 29 December 2016 Accepted 9 January 2017 Available online 12 January 2017
A one-pot multi-component synthesis of indenone-fused heterocyclic derivatives from readily available starting materials including diamines, 1,1-bis(methylthio)-2-nitroethene, 1,3-indandione and aromatic aldehydes in excellent yields is described. The sequence of cascade reactions include Knoevenagel condensation, enamine formation, Michael addition, imine-enamine tautomerization and cyclization. The diastereoselective synthesis of cis-indenohydropyridine have been definitively proven by X-ray crystallography. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Diamines 1,1-bis(methylthio)-2-nitroethene 1,3-indandione Aromatic aldehydes Multi-component synthesis
1. Introduction The development of new synthetic methods in the research of novel bioactive compounds, such as natural products and analogous, drugs, diagnostics and agrochemicals, in academic and industrial chemistry is closely connected to the efficient synthesis of such compounds. Thus, the view of synthesis has altered in recent years; the development of new, highly selective methods will still be an important task, but the main focus of today's chemists is on efficiency.1 A general way to improve synthetic efficiency, which in addition also gives access to a multitude of diversified products, is the development of multicomponent domino reactions which allow the preparation of complex molecules starting from simple substrates. Domino reactions are defined as processes of two or more bond-forming reactions in one-pot, in which the subsequent transformation occurs at the functionalities obtained in the former transformation; thus, it is a time-resolved process.2 The conventional methods for the synthesis of complex compounds involve many synthetic operations, including extraction and purification processes for each step, that cause synthetic inefficiency and the production of large amounts of waste. Multi
* Corresponding author. E-mail addresses: [email protected], [email protected] (M. Bayat). http://dx.doi.org/10.1016/j.tet.2017.01.024 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
component reactions (MCRs) allow the creation of several bonds in a single operation and offer remarkable advantages like convergence, operational simplicity, facile automation, reduction in the number of workups, extraction and purification processes. Thus, MCRs and their improvement are of considerable interest in the current research. As a one-pot reaction, MCRs permit rapid access to combinatorial libraries of complex molecules especially in drug discovery.3 Indenone frameworks are in a large number of natural and synthetic drugs. Indenone-fused heterocycles have attracted the attention of chemists and pharmacologists4 because of their broad range of bioactivities, such as topoisomerase I inhibitor TAS-1035 (Fig. 1). The indenopyridine skeleton is present in the 4azafluorenone group of alkaloids, represented by its simplest member onychnine6 (Fig. 1). 4-Azafluorenones, a privileged molecular scaffold ubiquitously found in natural products,7 display various biological activities including antimicrobial, antimalarial, and DNA damaging activities.8 The strategies reported for the synthesis of 4-azafluorenones classify in three categories7: intramolecular Friedel-Crafts acylation on 2-arylpyridines containing a carboxylic acid9,10 or an ester group,11 diaryl linkage formation by intramolecular Heck reactions on 3-aroylpyridines,12 and a three-component reaction,13 Remarkably, Mohammadi et al. reported a one-pot four-component reaction for the synthesis of hydroazafluorenones.14
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
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Fig. 1. Bioactive and medicinally important compounds containing an indenone-fused skeleton.
During the last few years, the use of enamines and dienamines from nitro ketene dithioacetal in organic chemistry has attracted great attention of many chemists.15 They have been used for the synthesis of a wide variety of heterocyclic systems and natural products,16 and precursors of chiral amines in asymmetric transformations.17
Fig. 2. X-ray crystal structure (ORTEP) of 5b.
2. Result and discussions The one-pot multicomponent condensation reactions of diamines 1 with 1,1-bis(methylthio)-2-nitroethene 2 and aromatic aldehydes 3 in the presence of 1,3-indandione 4 in EtOH as a solvent under reflux condition leads to corresponding cis-indenohydropyridine heterocyclic systems 5a-5s, in excellent yields (Scheme 1). The cis-indenohydropyridine 5 possesses three chiral centers and there are 8 possible stereoisomers, one of which was prepared in a highly stereo controlled fashion. Clearly the sequential use of two highly stereoselective reactions providing three new chiral centers, is an extremely powerful strategy for asymmetric synthesis. Herein, we report a simple one-pot reaction for the synthesis of cis-indenohydropyridine derivatives in high yields. To the best of our knowledge, there are no reports on the synthesis of these compounds in the literature yet. The structures of compounds 5a-5s were assigned from their elemental analyses and IR, mass, 1H NMR, and 13C NMR spectra (see the Supporting Information) and by single-crystal X-ray analysis of 5b (Fig. 2).18 1 H and 13C NMR spectra of the crude products clearly indicated the formation of heterocyclic compounds 5a-5s. For example, the 1 H NMR spectrum of 5b showed four singlets identified as amino (d 8.74, Hf), hydroxy (d 6.44, He), methine protons (d 4.96, Hd and d 3.26, Hc), along with characteristic multiplets for two CH2 groups (3.17e3.22, 3.44e3.46, 3.64e3.66, 3.90e3.96, 2Ha and 2Hb), and multiplets for the aromatic region (7.07e7.65) (Fig. 3). We didn't see coupling constants between Hc and Hd for all of the products (because of two hydrogens are orthogonal). The X-ray data gave the actual dihedral angle between H (7)-C (7)-C (13)-H (13) is 87. The mass spectra of compounds 5a-5s displayed molecular ion peaks at appropriate m/z values. Initial fragmentations involved loss from or complete loss of the side chains and scission of the heterocyclic system. The 1H-decoupled 13C NMR spectrum of 5b showed 18 distinct resonances, which confirmed the proposed
Scheme 1. Synthetic scheme for the indenone-fused heterocycle 5.
Fig. 3. The 1H NMR spectrum of 5b.
structure. The IR spectrum of 5b displayed characteristic absorption bands (3400, 3326, 1722, 1523, 1380, 1218, 1134 cm1) due to OH, NH, C¼O, NO2, CeN, CeO groups. During the investigation of this work, a similar method for the synthesis of indenofurans and indenopyridines through a one pot, three-component protocol from heterocyclic ketene aminals, ophthalaldehyde and 1,3-diketones was recently reported.19 In this report, Shao and coworkers focus on the reaction behaviors of sixmembered heterocyclic ketene aminals, which nitro group act as leaving group. An examination of the literature showed that ethanol was often used as a compatible solvent.20 The reaction proceeds with excellent yields when ethanol was used as the solvent. We explored the scope of this reaction by varying the structure of the primary diamine 1 and aromatic aldehyde 3 components. The reaction proceeds cleanly to afford a series of cis-indenohydropyridine derivatives 5 in 65e95% yields. The results are shown in Table 1. A plausible mechanism for the formation of cis-indenohydropyridine systems 5 is shown in Scheme 2, on the basis of wellestablished chemistry of 1,1-bis(methylthio)-2-nitroethene.21,22 The process represents a typical cascade reaction in which the reaction between diamine 1 and 1,1-bis(methylthio)-2-nitroethene 2 affords nitroketene aminal 6. The second step involves condensation of 1,3-indandione 4 with aldehyde 3 to afford Knoevenagel adduct 7. Then, the ene-component nitroketene aminal 6 and the Knoevenagel adduct 7 undergo a Michael addition to give the intermediate 8, which undergoes successive imine-enamine tautomerization, followed by nucleophilic addition of the secondary amino group to the carbonyl group, leads to the formation of product 5.
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M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
Table 1 One-pot, four-component synthesis of indenone-fused derivatives 5a-5s. ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
1
5a
1
80
2
5b
1
84
3
5c
1
90
4
5d
2
92
5
5e
2
88
6
5f
1
93
7
5g
3
65
8
5h
3
70
Structure of product
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
1199
Table 1 (continued ) ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
9
5i
3
68
10
5j
2
87
11
5k
3
88
12
5l
3
90
13
5m
1
86
14
5n
1
89
15
5o
2
95
Structure of product
(continued on next page)
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M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
Table 1 (continued ) ArCHOa
Diaminea
Entry
Product
Time (h)
Yield (%)
16
5p
2
91
17
5q
2
89
18
5r
3
72
19
5s
3
70
20
5t
e
e
e
21
5u
e
e
e
22
5v
e
e
e
a
Structure of product
Equal amounts (1 mmol) of the reactants were used. The reactions were run in EtOH at 80 C, without any catalyst.
3. Conclusions We have developed a simple and novel four-component one-pot synthesis of cis-indenohydropyridine compounds, through sequential enamine formation, Knoevenagel condensation, Michael addition, imine-enamine tautomerization and cyclization sequences in ethanol. This class of compounds is not only prepared by a one-pot reaction for the first time but also to our knowledge, there is no other report for their synthesis. This reaction includes some important aspects like simple operation under mild conditions, easy accessibility of reactants and workup procedure, absence of catalysts, high atom economy and the use of ethanol as a
green reaction medium. 4. Experimental section 4.1. General The diamines, 1,1-bis(methylthio)-2-nitroethene, 1,3indandione, and aldehydes were obtained from Merck and Aldrich and were used without further purification. NMR spectra were recorded with a Bruker DRX-300 Avance instrument (300 MHz for 1H and 75.4 MHz for 13C) with CDCl3 and DMSO as solvents. Chemical shifts are given in ppm (d) relative to internal
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
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Scheme 2. Mechanistic rationalization for the formation of 5.
TMS, and coupling constant (J) are reported in hertz (Hz). Melting points were measured with an electrotherma1 9100 apparatus. Mass spectra were recorded with an Agilent 5975C VL MSD with Triple-Axis Detector operating at an ionization potential of 70 eV. IR spectra were measured with, Bruker Tensore 27 spectrometer. Elemental analyses: Heraeus CHNO-Rapid analyzer. 4.2. General procedure for the synthesis of 5-(4-chlorophenyl)1,2,3,5-tetrahydro-10b-hydroxy-4-nitro-6H-imidazo[1,2-a]indeno [2,1-e]pyridin-6-one (5b) A mixture of ethylene diamine (66 mL, 1 mmol), 1,1- bis(methylthio)-2-nitro ethylene (0.165 g, 1 mmol) and 10 mL EtOH in a 50 mL flask was refluxed for 6 h. After completion of the reaction (monitored by TLC, ethyl acetate/n-hexane, 6:4), p-chlorobenzaldehyde (0.140 g, 1 mmol), 1,3-indandione (0.146 g, 1 mmol) were added to the reaction mixture, and it was stirred under reflux for 1 h. Then, the reaction mixture was cooled to room temperature and filtered to give the crude product. The solid was washed with ethanol to give product 5b in 84% yield. The crude product recrystallized from methanol to afford the pure product (for CHN analyses and X-ray crystallography).
(%) ¼ 397 (Mþ, 0.13), 374 (14), 267 (23), 233 (18), 176 (19), 119 (87), 91 (40), 69 (31), 54 (71), 43 (100). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.17e3.22 (1H, m, CH), 3.26 (1H, s, CH), 3.44e3.46 (1H, m, CH), 3.64e3.66 (1H, m, CH), 3.90e3.96 (1H, m, CH), 4.94 (1H, s, CH), 6.44 (1H, s, OH), 7.07 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.23 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.36e7.65 (4H, m, 4CH of Ind.), 8.74 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.6, 42.6, 43.8, 63.6, 86.0, 104.2, 123.9, 125.2, 128.5, 130.0, 130.9, 131.2, 133.4, 135.4, 142.3, 151.5, 154.5, 198.6; Anal. Calcd for C20H35 16 ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found C, 60.2; H, 3.9; N, 10.5. Crystal data for 5b: C20H35 16 ClN3O4 (CCDC No. 1486209): M ¼ 397.81, monoclinic system, space group P21/c, a ¼ 8.4393 (17) Å, b ¼ 16.741 (3) Å, c ¼ 15.119 (5) Å, b ¼ 122.58 (2) , V ¼ 1799.9 (9) Å3, Z ¼ 4, Dc ¼ 1.468 mg/m3, F (000) ¼ 824, crystal dimension 0.25 0.2 0.15 mm, radiation: Mo Ka (l ¼ 0.71073 Å). The X-ray diffraction measurement was made on a STOE IPDS-II diffractometer with graphite monochromated Mo-Ka radiation. The structure was solved by using SHELXS. The Data reduction and structure refinement was carried out with SHELXL using the X-STEP32 crystallographic software package. The non-hydrogen atoms were refined anisotropically by full matrix least-squares on F2 values to final R1 ¼ 0.0955, wR2 ¼ 0.0948 and S ¼ 1.047 with 253 parameters using 3122 independent reflection (q range ¼ 2.49e24.99 ).
4.3. 10b-hydroxy1,2,3,5-tetrahydro-4-nitro-5-phenyl-6H-imidazo [1,2-a]indeno[2,1-e]pyridin-6-one (5a) White solid, mp: 212e214 C (dec.), 0.290 g, yield: 80%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3355 (NH), 1724 (C¼O), 1590 (Ar), 1534 and 1350 (NO2), 1222 (CeN), 1133 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.18e3.28 (1H, m, CH), 3.37 (1H, s, CH), 3.42e3.55 (1H, m, CH), 3.65e3.77 (1H, m, CH), 3.93e4.05 (1H, m, CH), 5.02 (1H, s, CH), 6.19 (1H, s, OH), 7.04e7.67 (9H, m, Ar), 8.78 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 37.1, 42.6, 43.8, 63.9, 86.1, 104.5, 123.9, 125.2, 126.6, 128.1, 128.6, 130.9, 133.4, 135.5, 143.3, 151.6, 154.6, 198.9; Anal. Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found C, 65.9; H, 4.6; N, 11.5. 4.4. 5-(4-chlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5b) White solid, mp: 208e210 C (dec.), 0.333 g, yield: 84%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3326 (NH), 1722 (C¼O), 1600 (Ar), 1523 and 1380 (NO2), 1218 (CeN), 1134 (CeO). MS (EI, 70 eV): m/z
4.5. 5-(4-bromophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5c) White solid, mp: 206e208 C (dec.), 0.398 g, yield: 90%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3319 (NH), 1721 (C¼O), 1599 (Ar), 1522 and 1379 (NO2), 1220 (CeN), 1136 (CeO). MS (EI, 70 eV): m/z (%) ¼ 442 (Mþ, 0.22), 391 (11), 376 (28), 313 (93), 268 (12), 233 (100), 205 (26), 176 (74), 151 (20), 129 (37), 104 (56), 88 (15), 76 (64), 50 (24). 1H NMR (300 MHz, DMSO): d 3.18e3.24 (1H, m, CH), 3.44e3.51 (1H, m, CH), 3.51 (1H, s, CH), 3.61e3.67 (1H, m, CH), 3.92e3.98 (1H, m, CH), 4.84 (1H, s, CH), 6.99 (1H, s, OH), 7.27 (2H, d, 3 JHH ¼ 8.5 Hz, 2CH of Ar), 7.46 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.73e7.87 (4H, m, 4CH of Ind.), 9.07 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 31.2, 42.7, 43.8, 63.0, 86.0, 104.0, 119.0, 123.9, 125.2, 130.4, 130.9, 131.4, 133.4, 135.5, 142.7, 151.5, 154.5, 198.5. Anal. Calcd for C20H79 16 BrN3O4: C, 54.31; H, 3.65; N, 9.50. Found C, 54.5; H, 3.7; N, 9.4.
1202
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
4.6. 10b-hydroxy-1,2,3,5-tetrahydro-4-nitro-5-(4-nitrophenyl)-6Himidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5d) White solid, mp: 204e206 C (dec.), 0.375 g, yield: 92%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3341 (NH), 1715 (C¼O), 1597 (Ar), 1510 and 1342 (NO2), 1205 (CeN), 1127 (CeO). MS (EI, 70 eV): m/z (%) ¼ 408 (Mþ, 0.03), 279 (80), 262 (81), 232 (100), 205 (16), 176 (75), 165 (20), 151 (28), 129 (33), 104 (35), 76 (35), 54 (15). 1H NMR (300 MHz, DMSO): d 3.18e3.23 (1H, m, CH), 3.49e3.51 (1H, m, CH), 3.60 (1H, s, CH), 3.61e3.69 (1H, m, CH), 3.96e3.99 (1H, m, CH), 5.02 (1H, s, CH), 7.07 (1H, s, OH), 7.58 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 8.16 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.63e7.88 (4H, m, 4CH of Ind.), 9.12 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 37.2, 42.7, 43.9, 63.3, 85.9, 103.5, 123.8, 124.0, 125.1, 129.4, 131.0, 133.4, 135.5, 146.6, 151.3, 151.5, 154.5, 198.1. Anal. Calcd for C20H16N4O6: C, 58.82; H, 3.95; N, 13.72. Found C, 58.9; H, 4.0; N, 13.6. 4.7. 10b-hydroxy-1,2,3,5-tetrahydro-4-nitro-5-(2-nitrophenyl)-6Himidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5e) Yellow solid, mp: 198e200 C (dec.), 0.359 g, yield: 88%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3329 (NH), 1728 (C¼O), 1599 (Ar), 1513 and 1353 (NO2), 1200 (CeN), 1141 (CeO). 1H NMR (300 MHz, DMSO): d 3.18e3.24 (1H, m, CH), 3.46e3.52 (1H, m, CH), 3.55 (1H, s, CH), 3.62e3.71 (1H, m, CH), 3.96e4.02 (1H, m, CH), 5.28 (1H, s, CH), 7.08 (1H, s, OH), 7.43e7.91 (8H, m, 8CH of Ar), 9.09 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 33.0, 42.8, 43.9, 62.0, 85.8, 104.1, 124.0, 124.4, 125.0, 128.3, 128.4, 130.5, 131.0, 133.3, 135.5, 137.6, 149.8, 151.4, 154.7, 197.3. Anal. Calcd for C20H16N4O6: C, 58.82; H, 3.95; N, 13.72. Found C, 58.7; H, 3.9; N, 13.7. 4.8. 5-(3-chlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5f) Brown solid, mp: 210e212 C (dec.), 0.329 g, yield: 83%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3331 (NH), 1723 (C¼O), 1588 (Ar), 1531 and 1394 (NO2), 1222 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO): d 3.12e3.23 (1H, m, CH), 3.42e3.52 (1H, m, CH), 3.56 (1H, s, CH), 3.60e3.72 (1H, m, CH), 3.90e4.03 (1H, m, CH), 4.90 (1H, s, CH), 7.06 (1H, s, OH), 7.29e7.84 (8H, m, 8CH of Ar), 9.08 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.9, 42.7, 43.9, 63.5, 86.0, 103.9, 123.9, 125.1, 126.7, 127.0, 127.8, 130.4, 130.9, 133.2, 133.4, 135.5, 145.9, 151.4, 154.5, 198.4. Anal. Calcd for C20H35 16 ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found C, 60.3; H, 4.1; N, 10.6. 4.9. 5-(4-fluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5g) Pale pink solid, mp: 208e210 C (dec.), 0.247 g, yield: 65%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3358 (NH), 1725 (C¼O), 1594 (Ar), 1540 and 1350 (NO2), 1224 (CeN), 1135 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.18e3.27 (1H, m,CH), 3.31 (1H, s, CH), 3.45e3.55 (1H, m, CH), 3.68e3.72 (1H, m, CH), 3.92e4.03 (1H, m, CH), 5.00 (1H, s, CH), 6.40 (1H, s, OH), 6.80e7.80 (8H, m, 8CH of Ar), 8.80 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 30.9, 42.0, 43.0, 65.0, 89.0, 105.0, 114.9, 118.0, 124.1, 129.3, 129.4, 130.4, 134.0, 135.0, 143.0, 155.0, 168.3, 203.0. Anal. Calcd for C20H16FN3O4: C, 62.99; H, 4.23; N, 11.02. Found C, 63.1; H, 4.4; N, 10.9. 4.10. 5-(3-fluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4-nitro6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5h) Pink solid, mp: 212e214 C (dec.), 0.267 g, yield: 70%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3300 (NH), 1727 (C¼O), 1591 (Ar),
1534 and 1350 (NO2), 1226 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.13e3.16 (1H, m, CH), 3.26 (1H, s, CH), 3.41e3.44 (1H, m, CH), 3.62e3.64 (1H, m, CH), 3.91e3.94 (1H, m, CH), 4.93 (1H, s, CH), 6.47 (1H, s, OH), 6.67e7.62 (8H, m, 8CH of Ar), 8.73 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 30.9, 42.2, 43.7, 63.9, 85.8, 104.6, 113.2, 114.6, 123.6, 124.1, 129.6, 130.4, 133.4, 134.6, 145.0, 150.7, 155.02, 163.0, 198.0. Anal. Calcd for C20H16FN3O4: C, 62.99; H, 4.23; N, 11.02. Found C, 62.9; H, 4.1; N, 11.1. 4.11. 5-(3,4-difluorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5i) Pale brown solid, mp: 204e206 C (dec.), 0.271 g, yield: 68%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3300 (NH), 1726 (C¼O), 1595 (Ar), 1533 and 1394 (NO2), 1223 (CeN), 1135 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 3.22e3.31 (1H, m, CH), 3.34 (1H, s, CH), 3.48e3.58 (1H, m, CH), 3.70e3.80 (1H, m, CH), 4.00e4.12 (1H, m, CH), 5.03 (1H, s, CH), 6.55 (1H, s, OH), 6.90e7.80 (7H, m, 7CH of Ar), 8.80 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 37.0, 42.2, 43.8, 63.0, 85.9, 95.1, 116.7, 116.9, 124.0, 124.2, 127.4, 130.4, 133.5, 134.6, 139.0, 144.5, 151.0, 151.2, 154.0, 197.1. Anal. Calcd for C20H15F2N3O4: C, 60.15; H, 3.79; N, 10.52. Found C, 60.3; H, 3.9; N, 10.5. 4.12. 5-(2,6-dichlorophenyl)-1,2,3,5-tetrahydro-10b-hydroxy-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5j) Pink solid, mp: 295e297 C (dec.), 0.375 g, yield: 87%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3347 (NH), 1727 (C¼O), 1600 (Ar), 1527 and 1382 (NO2), 1226 (CeN), 1140 (CeO). MS (EI, 70 eV): m/z (%) ¼ 432 (Mþ, 0.10), 267 (100), 176 (23), 129 (13), 76 (22), 54 (14). 1 H NMR (300 MHz, DMSO): d 3.19e3.25 (1H, m, CH), 3.42 (1H, s, CH), 3.39e3.48 (1H, m, CH), 3.66e3.68 (1H, m, CH), 3.93e3.98 (1H, m, CH), 5.63 (1H, s, CH), 6.99 (1H, s, OH), 7.19e7.88 (7H, m, 7CH of Ar), 9.14 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 34.8, 42.7, 43.7, 62.1, 85.2, 102.1, 124.1, 124.7, 128.9, 129.5, 130.8, 133.2, 134.0, 135.5, 135.9, 136.7, 151.8, 155.7, 197.2. Anal. Calcd for C20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72. Found C, 55.4; H, 3.4; N, 9.8. 4.13. 10b-hydroxy-1,2,3,5-tetrahydro-5-(4-hydroxyphenyl)-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5k) Tan solid, mp: 183e185 C (dec.), 0.333 g, yield: 88%. IR (KBr) (nmax/cm1): 3200e3400 (OH), 3317 (NH), 1722 (C¼O), 1596 (Ar), 1517 and 1350 (NO2), 1210 (CeN), 1127 (CeO). 1H NMR (300 MHz, DMSO): d 3.24e3.50 (2H, m, CH2), 3.62 (1H, s, CH), 3.60e3.72 (1H, m, CH), 3.90e4.05 (1H, m, CH), 4.82 (1H, s, CH), 6.91 (1H, s, OH), 6.64 (2H, d, 3JHH ¼ 7.0 Hz, 2H of Ar), 7.10 (2H, d, 3JHH ¼ 7.0 Hz, 2H of Ar), 7.61e7.84 (4H, m, 4CH of Ind.), 9.02 (1H, s, OH), 9.17 (1H, s, NH). 13 C NMR (75.4 MHz, DMSO): d 36.4, 42.6, 43.8, 64.1, 86.2, 105.1, 115.2, 123.8, 125.2, 129.1, 131.5, 133.3, 133.5, 135.5, 151.7, 154.6, 156.1, 199.2. Anal. Calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found C, 63.1; H, 4.4; N, 10.9. 4.14. 10b-hydroxy-1,2,3,5-tetrahydro-5-(2,5-dihydroxyphenyl)-4nitro-6H-imidazo[1,2-a]indeno[2,1-e]pyridin-6-one (5l) Pale brown solid, mp: 228e230 C (dec.), 0.355 g, yield: 90%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3340 (NH), 1714 (C¼O), 1596 (Ar), 1512 and 1387 (NO2), 1225 (CeN), 1125 (CeO). 1H NMR (300 MHz, DMSO): d 3.16e3.93 (4H, m, 2CH2), 3.57 (1H, s, CH), 5.14 (1H, s, CH), 6.74 (1H, s, OH), 6.29 (1H, s, 1H of Ar), 6.38 (2H, d, 3 JHH ¼ 8.0 Hz, 2H of Ar), 6.57 (2H, d, 3JHH ¼ 8.0 Hz, 2H of Ar), 7.61e7.80 (4H, m, 4CH of Ind.), 8.52 (1H, s, OH), 8.83 (1H, s, OH),
M. Bayat et al. / Tetrahedron 73 (2017) 1196e1204
9.08 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 36.5, 42.7, 43.8, 62.1, 86.1, 103.5, 113.6, 114.6, 115.8, 123.7, 125.1, 129.2, 130.7, 133.6, 135.2, 147.5, 149.9, 151.8, 155.2, 199.2. Anal. Calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found C, 60.8; H, 4.5; N, 10.6. 4.15. 6-(4-chlorophenyl)-2,3,4,6,6a,11b-hexahydro-11b-hydroxy-5nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5m) White solid, mp: 177e179 C (dec.), 0.353 g, yield: 86%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3196 (NH), 1723 (C¼O), 1597 (Ar), 1540 and 1364 (NO2), 1247 (CeN), 1136 (CeO). 1H NMR (300 MHz, DMSO): d 1.66e1.83 (2H, m, CH2), 3.16e3.83 (4H, m, 2CH2), 3.58 (1H, s, CH), 5.05 (1H, s, CH), 7.07 (1H, s, OH), 7.28e7.96 (8H, m, 8CH of Ar), 11.47 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 31.2, 36.4, 38.1, 62.2, 88.4, 106.8, 123.7, 125.6, 128.5, 129.9, 131.0, 131.2, 133.5, 135.6, 141.2, 151.8, 152.2, 199.1. Anal. Calcd for C21H35 18 ClN3O4: C, 61.24; H, 4.41; N, 10.20. Found C, 61.4; H, 4.6; N, 10.1. 4.16. 6-(4-bromophenyl)-2,3,4,6,6a,11b-hexahydro-11b-hydroxy-5nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5n) White solid, mp: 180e182 C (dec.), 0.406 g, yield: 89%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3196 (NH), 1723 (C¼O), 1600 (Ar), 1597 and 1364 (NO2), 1249 (CeN), 1140 (CeO). MS (EI, 70 eV): m/z (%) ¼ 456 (Mþ, 0.08), 313 (82), 267 (50), 233 (100), 205 (20), 176 (65), 143 (24), 104 (44), 76 (55), 56 (23). 1H NMR (300 MHz, DMSO): d 1.66e1.81 (2H, m, CH2), 3.16e3.82 (4H, m, 2CH2), 3.58 (1H, s, CH), 5.036 (1H, s, CH), 7.06 (1H, s, OH),7.24 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.46 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 7.60e7.95 (4H, m, 4CH of Ind.), 11.46 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 24.8, 41.0, 43.5, 43.9, 66.9, 93.0, 111.8, 124.8, 128.6, 129.4, 134.5, 135.3, 136.0, 138.4, 139.5, 145.7, 156.4, 156.6, 202.8. Anal. Calcd for C21H79 18 BrN3O4: C, 55.28; H, 3.98; N, 9.21. Found C, 55.1; H, 3.9; N, 9.1. 4.17. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(4nitrophenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5o) Pale yellow solid, mp: 193e195 C (dec.), 0.401 g, yield: 95%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3227 (NH), 1721 (C¼O), 1599 (Ar), 1516 and 1353 (NO2), 1244 (CeN), 1132 (CeO). 1H NMR (300 MHz, DMSO): d 1.68e1.83 (2H, m, CH2), 3.22e3.24 (2H, m, CH2), 3.79e3.84 (2H, m, CH2), 3.69 (1H, s, CH), 5.18 (1H, s, CH), 7.11 (1H, s, OH), 7.56 (2H, d, 3JHH ¼ 8.5 Hz, 2CH of Ar), 8.16 (2H, d, 3 JHH ¼ 8.5 Hz, 2CH of Ar), 7.61e8.03 (4H, m, 4CH of Ind.), 11.44 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 37.1, 43.0, 44.0, 62.0, 88.2, 106.1, 123.7, 125.6, 129.4, 131.1, 133.5, 134.6, 135.5, 136.7, 150.1, 151.9, 152.1, 198.5. Anal. Calcd for C21H18N4O6: C, 59.71; H, 4.30; N, 13.26. Found C, 59.8; H, 4.2; N, 13.2. 4.18. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(2nitrophenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5p) Pale brown solid, mp: 156e160 C, 0.384 g, yield: 91%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 3132 (NH), 1731 (C¼O), 1597 (Ar), 1507 and 1357 (NO2), 1264 (CeN), 1153 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 1.65e1.78 (2H, m, CH2), 2.93e3.01 (2H, m, CH2), 3.26e3.40 (1H, m, CH), 3.53 (1H, s, CH), 3.76e3.80 (1H, m, CH), 5.47 (1H, s, CH), 6.53 (1H, s, OH), 7.12e7.71 (8H, m, 8CH of Ar), 11.65 (1H, s, NH). 13C NMR (75.4 MHz, DMSO and CDCl3, 3:7): d 24.8, 37.9, 43.9, 45.9, 65.2, 93.0, 113.0, 128.6, 129.2, 129.6, 132.4, 134.9, 135.3, 137.6, 138.5, 139.2, 142.1, 154.0, 156.2, 156.7, 201.5. Anal. Calcd for C21H18N4O6: C, 59.71; H, 4.30; N, 13.26. Found C, 60.1; H, 4.4; N, 13.1.
1203
4.19. 6-(2,6-dichlorophenyl)-2,3,4,6,6a,11b-hexahydro-11bhydroxy-5-nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5q) Yellow solid, mp: 178e180 C, 0.396 g, yield: 89%. IR (KBr) (nmax/ cm ): 3000e3400 (OH), 3184 (NH), 1723 (C¼O), 1595 (Ar), 1558 and 1377 (NO2), 1221 (CeN), 1145 (CeO). 1H NMR (300 MHz, DMSO and CDCl3, 3:7): d 1.60e1.70 (2H, m, CH2), 2.80e3.79 (4H, m, 2CH2), 3.28 (1H, s, CH), 5.59 (1H, s, CH), 6.39 (1H, s, OH), 6.81e7.59 (7H, m, 7CH of Ar), 11.87 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 34.7, 38.1, 41.4, 60.4, 87.6, 105.3, 123.9, 125.5, 128.8, 129.5, 130.8, 133.4, 133.9, 135.2, 136.4, 152.2, 152.6, 197.3. Anal. Calcd for C21H35 17 Cl2N3O4: C, 56.52; H, 3.84; N, 9.42. Found C, 56.7; H, 3.7; N, 9.3. 1
4.20. 11b-hydroxy-2,3,4,6,6a,11b-hexahydro-5-nitro-6-(4trifluoromethylphenyl)-indeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin7(1H)-one (5r) White solid, mp: 187e189 C (dec.), 0.320 g, yield: 72%. IR (KBr) (nmax/cm1): 3000e3400 (OH), 33183 (NH), 1721 (C¼O), 1597 (Ar), 1543 and 1324 (NO2), 1249 (CeN), 1139 (CeO). 1H NMR (300 MHz, DMSO): d 1.60e190 (2H, m, CH2), 3.17e3.86 (4H, m, 2CH2), 3.61 (1H, s, CH), 5.15 (1H, s, CH), 7.06 (1H, s, OH), 7.49e7.93 (8H, m, 8CH of Ar), 11.52 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 19.9, 36.8, 42.0, 43.0, 62.1, 88.3, 106.3, 122.8, 123.7, 125.5, 125.7, 127.4, 128.9, 131.1, 133.5, 135.6, 147.2, 151.8, 152.1, 198.9; Anal. Calcd for C22H18F3N3O4: C, 59.33; H, 4.07; N, 9.43. Found C, 59.5; H, 4.0; N, 9.6. 4.21. 6-(3,4-difluorophenyl)-2,3,4,6,6a,11b-hexahydro-11bhydroxy-5-nitroindeno[20 ,10 :5,6]pyrido[1,2-a]pyrimidin-7(1H)-one (5s) White solid, mp: 163e165 C, 0.289 g, yield: 70%. IR (KBr) (nmax/ cm1): 3000e3400 (OH), 3236 (NH), 1724 (C¼O), 1601 (Ar), 1515 and 1360 (NO2), 1246 (CeN), 1139 (CeO). 1H NMR (300 MHz, DMSO): d 1.70e1.86 (2H, m, CH2), 3.17e3.81 (4H, m, 2CH2), 3.57 (1H, s, CH), 5.07 (1H, s, CH), 7.08 (1H, s, OH), 7.13e8.19 (7H, m, 7CH of Ar), 11.51 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 20.0, 31.1, 36.2, 38.1, 62.0, 88.3, 106.7, 116.9, 117.1, 117.3, 123.7, 124.6, 125.4, 130.8, 133.6, 135.3, 139.7, 151.4, 151.7, 152.0, 198.6. Anal. Calcd for C21H17F2N3O4: C, 61.02; H, 4.15; N, 10.17. Found C, 61.2; H, 4.3; N, 10.3. Acknowledgments Financial support of this research from Imam Khomeini International University, Iran is gratefully acknowledged. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.01.024. References 1. Hulme C. In: Zhu J, Bienayme H, eds. Multicomponent Reactions. Weinheim: Wiley-VCH; 2005:121. 2. (a) Tietze LF, Modi A. Med Res Rev. 2000;20:304e322; (b) Poli G, Giambastiani G, Heumann A. Tetrahedron. 2000;56:5959e5989. 3. Samai S, Nandi GC, Kumar R, Singh MS. Tetrahedron Lett. 2009;50:7096e7098. 4. (a) Chen XB, Liu XM, Huang R, Yan SJ, Lin J. Eur J Org Chem. 2013:4607e4613; b) Duan YJ, Liu JL, Wang CL. Chin J Org Chem. 2010;30:988e996; c) Evdokimov NM, Slambrouck SV, Heffeter P, et al. J Med Chem. 2011;54: 2012e2021. 5. Utsugi T, Aoyagi K, Asano T, et al. Jpn J Cancer Res. 1997;88:992e1002. 6. Manpadi M, Uglinskii PY, Rastogi SK, et al. Org Biomol Chem. 2007;5:
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3865e3872. 7. Laha JV, Jethava KP, Patel S. Org Lett. 2015;17:5890e5893. 8. (a) Mueller D, Davis RA, Duffy S, Avery VM, Camp D, Quinn RJ. J Nat Prod. 2009;72:1538e1540; (b) Kraus GA, Kempema A. J Nat Prod. 2010;73:1967e1968. 9. Stauffer KJ, Williams PD, Selnick HG, et al. J Med Chem. 2005;48:2282e2293. 10. (a) Rebstock AS, Mongin F, Trecourt F, Queguiner G. Tetrahedron. 2003;59: 4973e4977; (b) DuPriest MT, Schmidt CL, Kuzmich D, Williams SB. J Org Chem. 1986;51: 2021e2023. 11. (a) Sreekumar R, Rugmini P, Padmakumar R. Synth Commun. 1998;28: 2071e2075; (b) Zhang S, Liao LY, Zhang F, Duan XF. J Org Chem. 2013;78:2720e2725. 12. (a) Dhara S, Ahmed A, Nandi S, Baitalik S, Ray JK. Tetrahedron Lett. 2013;54: 63e65; (b) Marquise N, Dorcet V, Chevallier F, Mongin F. Org Biomol Chem. 2014;12: 8138e8148; (c) Marquise N, Harford PJ, Chevallier F, et al. Tetrahedron Lett. 2013;54: 3154e3157; (d) Marquise N, Harford PJ, Chevallier F, et al. Tetrahedron. 2013;69: 10123e10133; (e) Marquise N, Chevallier F, Nassar E, et al. Tetrahedron. 2016;72:825e836. 13. (a) Tu S, Jiang B, Jiang H, et al. Tetrahedron. 2007;63:5406e5414; (b) Tu S, Jiang B, Jia R, Zhang J, Zhang Y. Tetrahedron Lett. 2007;48:1369e1374. 14. Mohammadi AA, Taheri S, Amouzegar A. J Heterocycl Chem. 2015;53:805e808.
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