Transition-Metal-Free Access to Pyridocarbazoles from 2

(1) Among them, pyridocarbazoles are an integral part of numerous natural .... The molecular docking score of −8.39 of compound (R)-8-ethyl-5-phenyl...
1 downloads 0 Views 2MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 6650−6663

pubs.acs.org/joc

Transition-Metal-Free Access to Pyridocarbazoles from 2‑Alkynylindole-3-carbaldehydes via Azomethine Ylide Shalini Verma,†,# Pawan K. Mishra,†,# Manoj Kumar,† Souvik Sur,‡ and Akhilesh K. Verma*,† †

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India

‡

Downloaded via TUFTS UNIV on June 15, 2018 at 06:09:49 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An efficient approach for the synthesis of functionalized tetrahydro-pyrido/quinolinocarbazoles from 2-alkynylindole3-carbaldehydes and L-proline utilizing a metal-free decarboxylative cyclization, ring expansion, and ring contraction strategy via the generation of azomethine ylide was developed. The reaction of 2-alkynylindole-3-carbaldehydes with L-thioproline leads to the formation of γ-carbolines. By virtue of this expedient method, a diverse range of biologically active heteroannulated carbazoles can be synthesized efficiently.

■

INTRODUCTION Heteroannulated carbazole framework is an important core motif present in a wide range of natural products and pharmaceutically derived drugs.1 Among them, pyridocarbazoles are an integral part of numerous natural products, bioactive alkaloids, and pharmaceuticals.2 Analogues of the pyridocarbazoles such as 6H-pyridocarbazole (ellipticine, olivacine, elliprabin, and ratelliptine) and 7H-pyridocarbazole exhibit prospective antitumor activity as an efficient DNA intercalating agents3 (Figure 1). Furthermore, metallo-pyridocarbazoles have been used as protein kinase inhibitors.4 A number of traditional approaches5 have been reported in the literature for the synthesis of pyridocarbazole derivatives. However, these methods have multistep synthetic operations with limited substrate scope. The 7H-pyridocarbazoles and quinolinocarbazoles are synthetically challenging frameworks which have not been much explored. Nagarajan and coworkers explored the synthesis of functionalized annulated carbazoles using ruthenium/copper/palladium catalysts by heteroannulation and intramolecular arylation.6 In 2005, the Bowman group reported7 the synthesis of ellipticine derivatives in a multistep sequence. An elegant approach for the synthesis of polycyclic ring system using L-proline and heteroaldehyde via azomethine ylide intermediate was reported by Seidel et al. (Scheme 1a).8 In 2015, the palladium-catalyzed synthesis of heteroannulated carbazole was reported by the © 2018 American Chemical Society

Figure 1. Biologically important pyridocarbazole-derived anticancer agents.

Das group.9a In the same year, Kundu and coworkers reported the synthesis of annulated polyheterocycles by exploiting decarboxylative cyclization under metal-free conditions.9b Recently, Liu et al. reported the transition-metal-catalyzed synthesis of pyrido[4,3-b]- and quino[4,3-b]-carbazole skeleton via palladium-catalyzed direct C-3 alkenylation of indoles (Scheme 1b).10 Received: April 18, 2018 Published: May 23, 2018 6650

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Scheme 1. Synthesis of Pyridocarbazole Derivatives

Scheme 2. Preparation of ortho-Alkynylaldehydes

accommodated a large variety of functional groups and provided the coupling products 4a−v and 5a−b in good to excellent yields. To determine the optimal reaction conditions, a variety of additives and solvents was examined using 2-(phenylethynyl)1H-indole-3-carbaldehyde 4a and L-proline 6a as our model substrates (Table 1). Inspired from the Kundu conditions, we performed the reaction of 4a with 6a using DMF as a solvent, and the desired product 7a was obtained in 35% yield instead of hexahydropyrrolo[2,1-b]oxazoles16 (entry 1). Other solvents such as DMA, DMSO, NMP, and toluene were capable of promoting the transformation with low yields (entries 2−5). Subsequently, various parameters were screened using DMF as a solvent. Addition of 4 Å molecular sieves at 120 °C provided the desired product 7a in 40% yield (entry 6). Increasing the temperature from 120 to 130 °C improved the yield of the product 7a (entry 7). It was interesting to note that the use of 0.2 equiv of benzoic acid as an additive afforded the desired product 7a in 65% yield (entry 8). Further increase in loading of the additive decreased the yield of product 7a (entries 9 and 10). A drop in the yield of product 7a was observed in the absence of molecular sieves (entry 11). Further increase in temperature declined the yield of 7a (entry 12). Inferior results were obtained when

In recent years, decarboxylative coupling reaction has emerged as a mechanistically distinct strategy for the formation of C−C and C−N bonds. There are several transition-metalcatalyzed decarboxylative reactions have been developed for the construction of a variety of heterocycles.11,12 In continuation of our ongoing efforts for the synthesis of biologically important heterocycles using o-alkynylaldehydes,13,14 we envisioned our effort for the rapid access of carbazole analogues containing fused tetrahydro-pyrido/quinoline ring from 2-alkynylindole3-carbaldehydes which has not been much explored and is still challenging. The striking feature of the present strategy involves the one-step construction of pyridocarbazole derivatives by the sequential formation of one C−N and two C−C bonds via decarboxylation/cyclization followed by ring expansion under transition-metal-free conditions (Scheme 1c).

■

RESULTS AND DISCUSSION Preparation of ortho-Alkynylaldehydes. To probe the viability of the designed tandem strategy, ortho-alkynylaldehydes 4a−v and 5a−b were readily prepared by standard Sonogashira cross-coupling reaction of commercially available and readily accessible ortho-haloaldehydes with terminal alkynes 3a−n (Scheme 2).15a−c This coupling procedure has readily 6651

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

entry 1 2 3 4 5 6c 7c 8c 9c 10c 11d 12c 13c

additive (equiv)

solvent

T (°C)

time (h)

yield(%)b 7a

PhCOOH (0.2) PhCOOH (0.3) PhCOOH (0.4) PhCOOH (0.2) PhCOOH (0.2) CH3COOH (0.2)

DMF DMA DMSO NMP toluene DMF DMF DMF DMF DMF DMF DMF DMF

120 120 120 120 120 120 130 130 130 130 130 140 130

4 4 4 4 4 4 4 1 1 1 1 1 1

35 30 32 32 15 40 48 65 60 56 40 55 42

proline 6a and hydroxyproline 6b provided the desired products 9a−c in 78−85% yield (Scheme 3). Interestingly, when we performed the reaction of substrate 4a with (R)-4-thioproline (6c) under standard reaction (entry 8), no ring expansion product 7a was observed. The formation of another biologically important heterocycle γ-carboline17 10a was observed in 80% yield via elimination reaction (Scheme 4). With this chemistry, we synthesized γ-carbolines 10a and b in 78−80% yields under metal-free conditions. The electronreleasing and electron-withdrawing substrates were welltolerated to afford the desired products 10c−e in good yields. Halogen bearing o-alkynylaldehyde substrate was also successful to furnish the desired product 10f in 81% yield. It was noteworthy that the 2-(thiophen-3-ylethynyl)-1H-indole-3-carbaldehyde provided the product 10g and h in 70−78% yields. In addition, the reaction of 4n bearing aliphatic alkynes with 6c also allowed an easy access to the synthesis of γ-carbolines 10i in moderate yield. Based on the enormous biological activity of pyridocarbazoles, we achieved the synthesis of pyrido [3,2-c]carbazoles 11a and b and quinolino[3,2-c]carbazole 11c by the oxidation of compounds 7a, 8c, and 9b using DDQ at room temperature with excellent yields (Scheme 5). On the basis of previous reports,8,9b,13 a plausible mechanism is proposed in Scheme 6. The mechanism is initiated via condensation of 2-alkynylindole-3-carbaldehydes 4 with proline 6 to produce an imine intermediate A. Further decarboxylation of intermediate A leads to the generation of an azomethine ylide B. The ylide B is then converted into species F either by the path a or path b via formation of intermediates C−E. In path a, B undergoes cyclopropane formation to furnish intermediate C, which subsequently undergoes ring expansion to generate intermediate D. The lone pair of nitrogen migrates to undergo 6-endo dig cyclization to give intermediate E. Further, E rearranges to give F. However, in case of path b, intermediate B undergoes favorable 5-endo dig cyclization followed by the abstraction of proton to generate intermediate C′ which, on ring expansion, leads to the generation of a stable benzyl cation D′. Intermediate D′ readily undergoes ring contraction to yield E′, which further rearranges to gave the final product 7/8. To find out the application of these compounds, we performed a molecular docking study of eight compounds (8c−e, 9a−c, and 11a and b) and ellipticine18 (as standard), and their binding modes with double-stranded DNA were determined (see Table S1, Supporting Information). We found that out of eight selected compounds, six molecules fit more firmly as intercalator than ellipticine.18 The compounds 9c, 11b, 8b, 8c, 8a, and 11a were found to have better docking scores than the rest. Compound 9c having more fused aromatic ring systems with hydroxyl groups shows the most effective stacking interaction with DNA nucleotides with the best docking score of −8.39 as compared with the rest of molecules and ellipticine (−7.49). The presence of hydroxyl groups increases the hydrogen bonding possibility with nucleotides along with van der Waals interactions and π-stacking in case of 9c. Conclusion. In summary, we developed an efficient metaland protection-free protocol for the synthesis of highly functionalized pyrido/quinolino carbazole via in situ generation of azomethine ylide with excellent regioselectivity from easily accessible 2-alkynylindole-3-carbaldehydes starting material. It was established that electron-rich, electron-deficient, and alkyl substituted alkynes can be used for the incorporation of a variety of functional groups in the products. The developed

a

Reactions were performed using 0.5 mmol of 4a and 0.6 mmol of 6a in 2.0 mL of solvent. bIsolated yield. c4 Å MS. dWithout molecular sieves.

acetic acid was used as an additive (entry 13). The product 7a was fully characterized by 1H and 13C NMR and HRMS. With the optimized reaction conditions in hand, scope and generality of the reaction were explored (Table 2). The N-protected substrates 4b and c also gave the desired products 7b and 7c in 70 and 60% yields, respectively (entries 2−3). The structure of pyridocarbazole 7b was further supported by X-ray crystallographic analysis (see Figure S1; Supporting Information). The reaction was well-tolerated with substrates having electrondonating and electron-withdrawing substituents. The o-alkynylaldehydes bearing electron-donating groups such as methoxy (4d), ethyl (4e), tert-butyl (4f), n-butyl (4g), and methyl (4h) on the arene afforded the desired products 7d−h in 71−78% yields (entries 4−8). However, the reaction of electron-deficient substrate 4i−j bearing trifluoromethoxy and trifluoromethyl group at the distal end of the para position of phenyl ring furnished the desired products 7i and 7j in 62 and 60% yields, respectively (entries 9 and 10). Thiophene substituted o-alkynylaldehydes 4k−l were compatible to afford the products 7k and 7l in 75 and 80% yields, respectively (entries 11 and 12). Substrate 4m with an electron-deficient heterocycle (2-pyridyl) provided the product 7m in moderate yield (entry 13). Notably, substrates 4n−q having an aliphatic group attached to triple bond successfully provided the desired product 7n−q in 54−62% yields (entries 14−17). We further extended the scope of proline derivative such as L-hydroxyproline 6b with various functionalized 2-alkynylindole3-carbaldehydes under standard reaction conditions (Table 3). Halogen-containing substrates 4r and s were also found viable for the reaction and furnished the desired products 8a and b in 58−60% yields (entries 1 and 2). The reaction of substrates 4b, 4a, 4d, 4k, and 4s with L-hydroxyproline 6b furnished the desired products 8c−g in 70−80% yield (entries 3−7). Encouraged by the above results (Tables 2 and 3), we further extended the scope of this reaction for the synthesis of novel pentacyclic tetrahydroquinolinocarbazoles (9a−c) which are difficult to synthesize. The reaction of 9-ethyl-2-(phenylethynyl)-9H-carbazole-3-carbaldehyde 5a and 9-ethyl-6-methyl-2-(phenyl ethynyl)-9H-carbazole-3-carbaldehyde 5b with 6652

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Table 2. Scopes of Tetrahydropyridocarbazolesa

6653

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry

a Reactions were performed using 2-alkynylindole-3-carbaldehydes 4 (0.5 mmol), proline 6a (0.6 mmol), and benzoic acid (0.2 equiv) in 2.0 mL of DMF at 130 °C for 1 h. bIsolated yield.

protons and carbons are reported in ppm from tetramethylsilane and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling constants in Hertz, and integration. High-resolution mass spectra were recorded on an electrospray mass spectrometer. Crystal structure analysis was accomplished on a single needle X-ray diffractometer. TLC analysis was performed on commercially prepared 60 F254 silica gel plates and visualized by either UV irradiation or by staining with I2. All purchased chemicals were used as received. All melting points are uncorrected. Reagents. All reagents were used directly as obtained commercially unless otherwise noted. Anhydrous forms of dimethylformamide,

synthetic method also allows for the synthesis of free (NH) γ-carbolines under a metal-free condition. The molecular docking score of −8.39 of compound (R)-8-ethyl-5-phenyl2,3,4,8-tetrahydro-1H-quinolino[7,8-b]carbazol-3-ol (9c) having hydroxyl groups showed better stacking interaction with nucleotides in comparison to the known DNA intercalator drug ellipticine (−7.49). This chemistry is general and expected to find application in a variety of organic synthesis.

■

GENERAL EXPERIMENTAL

General Method. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3/DMSO-d6. Chemical shifts for 6654

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Table 3. Scope of ortho-Alkynylaldehydes and Prolinea

a Reactions were performed using 2-alkynylindole-3-carbaldehydes 4 (0.5 mmol), L-hydroxyproline 6b (0.6 mmol), and benzoic acid (0.2 equiv) in 2.0 mL of DMF at 130 °C for 1 h. bIsolated yield.

dimethylacetamide, dimethyl sulfoxide, dioxane dichloroethane, diethyether, THF, toluene, hexanes, ethyl acetate, and CH2Cl2 were purchased from Merck Chemical Co. Oxindole, N-methyloxindole, N-phenyloxindole, terminal alkynes, palladium(II) chloride, L-prolines, POBr3, 5-chloroisatin, 5-bromoisatin, Et3N, and the palladium salts were purchased from Aldrich Chemical Co., Inc. Preparation of ortho-Alkynylaldehydes. To probe the viability of the designed tandem strategy, o-alkynylaldehydes 4a−v and 5a and b were readily prepared by standard Sonogashira cross-coupling reaction of commercially available and readily accessible o-haloaldehyde substrates with terminal alkynes (Scheme 2). This coupling procedure readily

accommodated a large variety of functional groups and provided the coupling products in good to excellent yields. The structure and purity of known starting materials 4a−v and 5a and b were confirmed by comparison of their physical and spectral data (1H NMR and 13C NMR) with those 4b,15a 4i, 4l, 4u, 4v,15b and 5a and b15c reported in the literature. 2-(Phenylethynyl)-1H-indole-3-carbaldehyde (4a). The product was obtained as a yellow needle (91.8 mg, 75%): mp 160−165 °C: 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 9.20 (brs, 1H), 8.27 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.36−7.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 185.7, 135.8, 131.8, 129.7, 129.4, 128.6, 125.4, 6655

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Scheme 3. Synthesis of Tetrahydroquinolino[7,8-b] Carbazolesa

Reaction conditions: o-alkynylaldehyde 4 (0.5 mmol), 6a and b (0.6 mmol), and benzoic acid (0.2 equiv) in 2.0 mL of DMF at 130 °C for 1−2 h. Isolated yield.

a

Scheme 4. Ring Expansion vs Eliminationa

a

Reaction conditions: This reaction was performed using 0.5 mmol of 4, benzoic acid (0.2 equiv), and thioproline 6c (0.6 mmol) in 2.0 mL of solvent at 130 °C for 4 h. Isolated yield. mp 145−150 °C: 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.18 (s, 1H), 8.10 (dd, J = 2.3 and 8.4 Hz, 1H), 7.65−7.62 (m, 2H), 7.46−7.43 (m, 1H), 7.34−7.28 (m, 1H), 7.27−7.22 (m, 1H), 7.03 (t, J = 6.1 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 184.5, 160.5, 136.3, 133.5, 129.4, 124.8, 124.0, 122.9, 120.7, 119.1, 114.7, 112.4, 112.0, 97.6, 77.7, 55.4 ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C18H14NO2] 276.1025, found 276.1021. 2-((4-Ethylphenyl)ethynyl)-1H-indole-3-carbaldehyde (4e). The product was obtained as a pale yellow needle (103.7 mg, 76%): mp 185−190 °C: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 9.27 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.31−7.29 (m, 1H), 7.26−7.18 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 2.59 (q, J = 7.3 and 7.8 Hz, 2H), 1.17 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 185.7, 146.5, 135.8, 131.8, 129.8, 128.2, 125.3, 124.4, 123.4, 121.9, 120.5,

124.4, 123.5, 122.0, 121.1, 120.7, 111.1, 98.3, 78.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H12NO] 246.0919; found 246.0913. 1-Phenyl-2-(phenylethynyl)-1H-indole-3-carbaldehyde (4c). The product was obtained as a brown needle (120.4 mg, 75%): mp 160− 165 °C: 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.39 (dd, J = 6.9 and 1.5 Hz, 1H),7.60−7.50 (m, 6H),7.44−7.43 (m, 1H),7.35−7.33 (m, 1H),7.32−7.28 (m, 2H),7.26−7.24 (m, 2H),7.02−7.00 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 185.5, 137.8, 136.0, 131.6, 130.6, 129.3, 128.8, 127.1, 125.9, 125.3, 124.3, 123.8, 122.0, 120.5, 120.2, 110.7, 96.0, 77.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C23H16NO] 322.1232, found 322.1210. 2-((4-Methoxyphenyl)ethynyl)-1H-indole-3-carbaldehyde (4d). The product was obtained as a pale yellow needle (107.2 mg, 78%): 6656

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry Scheme 5. Synthesis of Pyrido/Quinolino Carbazoles

Scheme 6. Proposed Reaction Mechanism

CDCl3) δ 185.9, 145.1, 136.1, 131.7, 130.4, 128.6, 125.2, 124.4, 123.4, 121.8, 120.2, 118.2, 111.4, 98.7, 77.8, 35.6, 33.2, 22.2, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H20NO] 302.1545, found 302.1568. 2-((3-(Methyl)phenyl)ethynyl)-1H-indole-3-carbaldehyde (4h). The product was obtained as an off-white needle (95.9 mg, 78%): mp 159−164 °C: 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.90 (s, 1H), 8.26 (d, J = 6.9 Hz, 1H), 7.32−7.21 (m, 7H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 185.6, 138.4, 135.8, 132.3, 130.7, 129.4, 128.9, 128.5, 125.4, 124.4, 123.5, 122.0, 120.9, 120.7, 111.0, 98.6, 77.8, 21.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C18H14NO] 260.1075, found 260.1059. 2-((4-(Trifluoromethyl)phenyl)ethynyl)-1H-indole-3-carbaldehyde (4j). The product was obtained as a pale yellow needle (101.7 mg, 65%): mp 155−160 °C: 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 6.9 Hz, 1H), 7.26

118.2, 111.1, 98.7, 28.9, 15.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C19H16NO] 274.1232, found 274.1251. 2-((4-tert-Butylphenyl)ethynyl)-1H-indole-3-carbaldehyde (4f). The product was obtained as a pale yellow needle (123.4 mg, 82%): mp 135−140 °C: 1H NMR (400 MHz, DMSO-d6) δ 12.73(s, 1H), 10.19 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45− 7.42 (m, 3H), 7.29 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 1.22 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 184.4, 152.9, 136.3, 131.5, 129.0, 125.8, 124.8, 124.0, 122.9, 120.8, 119.4, 117.7, 112.0, 97.4, 78.3, 34.7, 30.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H20NO] 302.1545, found 302.1568. 2-((4-Butylphenyl)ethynyl)-1H-indole-3-carbaldehyde (4g). The product was obtained as a pale yellow needle (120.4 mg, 80%): mp 130− 135 °C: 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.91 (brs, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.3 Hz, 3H), 7.24−7.15 (m, 2H), 7.02 (d, J = 7.8 Hz, 2H), 2.49 (t, J = 7.8 Hz, 2H), 1.49−1.43 (m, 2H), 1.26−1.21(m, 2H), 0.82 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, 6657

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry (t, J = 7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 184.7, 136.4, 132.5, 129.8, 129.4, 127.6, 125.8 (q, J = 3.8 Hz, 1C), 125.2, 125.0, 123.9, 123.1, 122.5, 120.9, 120.0, 112.2, 95.4, 81.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C18H11F3NO] 314.0793, found 314.0807. 2-(Thiophen-3-ylethynyl)-1H-indole-3-carbaldehyde (4k). The product was obtained as an off-white needle (102.9 mg, 82%): mp 150−155 °C: 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.16 (s, 1H), 8.15−8.14 (m, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.73−7.71 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40−7.39 (m, 1H), 7.35−7.29 (m, 1H), 7.27−7.23 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 184.5, 136.3, 132.4, 129.6, 128.9, 127.7, 125.0, 124.0, 123.0, 120.8, 119.6, 119.4, 112.1, 92.8, 78.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C15H10NOS] 252.0483, found 252.0478. 2-(Pyridin-2-ylethynyl)-1H-indole-3-carbaldehyde (4m). The product was obtained as a brown needle (95.9 mg, 78%): mp 145− 150 °C: 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.67 (d, J = 4.6 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.94−7.89 (m,1H), 7.83− 7.81(m, 1H), 7.63−7.58 (m, 1H), 7.55−7.46 (m, 1H), 7.37−7.33 (m, 1H), 7.29−7.25 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 184.4, 150.5, 141.0, 137.1, 136.5, 128.1, 127.5, 125.3, 124.5, 123.9, 123.2, 120.9, 120.3, 112.3, 96.2, 77.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C16H11N2O] 247.0871, found 247.0860. 2-(Cyclohexenylethynyl)-1H-indole-3-carbaldehyde (4o). The product was obtained as an off-white needle (93.4 mg, 75%): mp 115−120 °C: 1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.04 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H), 7.22 (t, J = 6.3 Hz, 1H), 6.43−6.41 (m, 1H), 2.27−2.15 (m, 4H), 1.65−1.55 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 184.2, 138.9, 136.2, 129.5, 124.7, 123.9, 122.9, 120.6, 119.0, 118.9, 112.0, 99.3, 76.3, 28.1, 25.4, 21.6, 20.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H16NO] 250.1232, found 250.1223. 2-(Cyclohexylethynyl)-1H-indole-3-carbaldehyde (4p). The product was obtained as a pale yellow needle (90.3 mg, 72%): mp 120− 125 °C: 1H NMR (400 MHz, CDCl3) δ 10.18(s, 1H), 9.39 (brs, 1H), 8.29 (dd, J = 6.4 and 2.8 Hz, 1H),7.36−7.25 (m, 3H), 2.70−2.65 (m, 1H), 1.90−1.86 (m, 2H), 1.77−1.72 (m, 2H), 1.60−1.52 (m, 3H), 1.40−1.34 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 185.9, 135.5, 130.9, 124.9, 124.3, 123.2, 121.7, 120.0, 111.0, 104.4, 69.9, 32.0, 29.8, 25.6, 24.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H18NO] 252.1388, found 252.1398. 2-(Cyclopropylethynyl)-1H-indole-3-carbaldehyde (4q). The product was obtained as a pale yellow needle (75.2 mg, 72%): mp 100−105 °C: 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.99 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.28−7.24 (m, 1H), 7.22−7.18 (m, 1H), 1.73−1.69 (m, 1H), 1.01−0.96 (m, 2H), 0.91−0.88 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 184.3, 135.9, 130.2, 124.6, 123.9, 122.8, 120.6, 119.1, 111.9, 103.2, 65.2, 9.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C14H12NO] 210.0919, found 210.0938. 5-Bromo-2-(phenylethynyl)-1H-indole-3-carbaldehyde (4r). The product was obtained as a pale yellow needle (121.5 mg, 75%): mp 200−205 °C: 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.21 (d, J = 1.4 Hz, 1H), 7.70−7.68 (m, 2H),7.53−7.48 (m, 4H),7.45−7.39 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 184.5, 135.1, 131.8, 130.2, 129.4,129.0, 127.5, 125.7, 122.8, 120.5, 118.7, 115.7, 114.2, 97.7, 78.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H11BrNO] 324.0024, found 326.0055 (81Br). 5-Chloro-2-(phenylethynyl)-1H-indole-3-carbaldehyde (4s). The product was obtained as a pale yellow needle (100.8 mg, 72%): mp 175−180 °C: 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.02 (s, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.53−7.43 (m, 5H), 7.32−7.30 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 184.4, 134.7, 131.8, 130.2,129.6, 129.0, 127.7, 125.0, 124.9, 120.4, 119.7, 118.8, 113.7, 97.6, 78.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H11ClNO] 280.0529, found 280.0530. 1-Phenyl-2-(thiophen-3-ylethynyl)-1H-indole-3-carbaldehyde (4t). The product was obtained as a brown needle (102.9 mg, 82%): mp 150−155 °C: 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.31− 8.29 (m, 1H), 7.53−7.49 (m, 2H), 7.47−7.42 (m, 3H), 7.37−7.36 (m, 1H), 7.28−7.22 (m, 2H), 7.20−7.17 (m, 2H), 6.94−6.92 (m, 1H);

C NMR (100 MHz, CDCl3) δ 185.7, 137.9, 136.1, 131.5, 129.6, 129.4, 128.8, 128.7, 128.5, 127.3, 125.4, 124.4, 123.9, 122.1, 121.2, 120.6, 110.8, 100.8, 78.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H14NOS] 328.0796, found 328.0810. General Procedure for the Synthesis of Functionalized Tetrahydro Pyridocarbazoles 7a−q and 8a−g. In an oven-dried round-bottom flask, a solution of o-alkynylaldehyde 4 (0.5 mmol) and L-proline 6 (0.6 mmol) with benzoic acid (0.2 equiv) in 2.0 mL of dry DMF was added under inert atmosphere. The resulting reaction mixture was heated at 130 °C for 1−2 h. Progression of the reaction was monitored by TLC analysis; after completion, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). The layers were separated, and the organic layer was washed with saturated brine solution and dried over Na2SO4. Organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on silica gel (100−200) (hexane/ethyl acetate; 95/5). The structure and purity of known starting materials were confirmed by comparison of their physical and spectral data (1 H NMR, 13C NMR, and HRMS). 5-Phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7a). The product was obtained as an off-white needle, mp 165−170 °C (96.2 mg, 65%), 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.47−7.32 (m, 7H), 7.26−7.22 (m, 1H), 6.68−6.67 (m, 1H), 4.72 (brs, 1H), 3.56 (t, J = 3.6 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.00−1.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.7, 141.3, 140.6, 139.2, 138.8, 129.4, 127.8, 126.5, 124.0, 122.7, 120.3, 119.1, 110.0, 109.5, 108.8, 101.1, 42.2, 26.0, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H19N2] 299.1548, found 299.1540. 7-Methyl-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7b). The product was obtained as a yellow needle (109.2 mg, 70%); mp 185−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.48−7.36 (m, 7H),7.25−7.21 (m, 1H), 6.71 (s, 1H), 4.75 (brs, 1H), 3.77 (s, 3H), 3.58 (t, J = 5.7 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.02−1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.0, 141.1, 140.8, 140.7, 140.4, 129.4, 127.9, 126.6, 123.7, 122.3, 120.2, 118.5, 109.2, 107.9, 107.8, 99.2, 42.2, 29.0, 26.0, 22.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H21N2] 313.1705, found 313.1697. 5,7-Diphenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7c). The product was obtained as a brown needle (112.0 mg, 60%); mp 180−185 °C; 1H NMR (400 MHz, CDCl3) δ 7.92, (d, J = 7.8 Hz, 1H), 7.46−7.45 (m, 4H), 7.33−7.17(m, 9H), 6.58 (s, 1H), 4.72 (brs, 1H), 3.52 (t, J = 5.5 Hz, 2H), 2.68 (t, J = 5.9 Hz, 2H), 1.94−1.88 (m, 2H); 13C NMR(100 MHz, CDCl3) δ 142.8, 141.3, 140.8, 140.4, 137.7, 133.6, 130.1, 129.7, 129.5, 129.4, 128.5, 127.8, 127.4, 127.3, 126.6, 124.0, 121.7, 120.3, 119.6, 110.1, 109.2, 100.3, 42.3, 26.0, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C27H23N2] 375.1861, found 375.1894. 5-(4-Methoxyphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7d). The product was obtained as a brown needle (123.0 mg, 75%); mp 180−185 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.31−7.25 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.55 (s, 1H),5.78 (s, 1H),3.79 (s, 3H), 3.44 (t, J = 4.6 Hz, 2H), 2.64 (t, J = 6.5 Hz, 2H), 1.82−1.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 157.9, 140.5,139.9, 139.3, 139.2, 135.0, 130.1, 123.3, 122.2, 121.0, 117.8, 113.3, 109.8, 107.6, 107.4, 100.0, 55.0, 40.1, 26.2, 22.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H21N2O] 329.1654, found 329.1640. 5-(4-Ethylphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7e). The product was obtained as a yellow needle (127.0 mg, 78%); mp 115−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 1H), 7.87(s, 1H), 7.32−7.30 (m, 4H),7.24−7.17 (m, 3H),6.66 (s, 1H), 4.65 (br s, 1H), 3.53 (t, J = 5.5 Hz, 2H), 2.75−2.68 (m, 4H),1.96− 1.91 (m, 2H), 1.29 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.4, 141.3, 140.6, 140.0, 139.2, 138.8, 129.3, 127.3, 123.9, 122.8, 120.3, 119.1, 110.0, 109.7, 108.7, 101.2, 42.2, 28.5, 26.0, 22.5, 15.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C23H23N2] 327.1861, found 327.1884. 5-(4-tert-Butylphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c] carbazole (7f). The product was obtained as an off-white needle (125.6 mg, 13

6658

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry 71%); mp 210−215 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.3 Hz, 1H), 7.80 (s, 1H), 7.36−7.34 (m, 2H), 7.26 (s, 1H), 7.25−7.24 (m, 3H),7.15−7.10 (m, 1H),6.59 (s, 1H), 3.46 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 1.89−1.83 (m, 2H),1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 149.3, 141.2, 140.6, 139.7, 139.2, 138.8, 129.0, 124.7, 123.9, 122.8, 120.2, 119.0, 110.0, 109.7, 108.7, 101.2, 42.2, 34.5, 31.4, 26.1, 22.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C25H27N2] 355.2174, found 355.2191. 5-(4-Butylphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7g). The product was obtained as an off-white needle (134.0 mg, 76%); mp 205−210 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.79(s, 1H), 7.31−7.26 (m, 4H),7.20−7.15 (m, 3H), 6.61(s, 1H), 4.61(brs, 1H), 3.50 (t, J = 5.0 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H), 1.94−1.88 (m, 2H), 1.69−1.61 (m, 2H), 1.45−1.36 (m, 2H), 0.98−0.94 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 141.3, 141.1, 140.6, 139.9, 139.2, 138.8, 129.2, 127.8, 123.9, 122.7, 120.2, 119.0, 110.0, 109.6, 108.7, 101.2, 42.2, 35.4, 33.6, 26.0, 22.5, 22.4, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C25H27N2] 355.2174, found 355.2191. 5-m-Tolyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7h). The product was obtained as a yellow needle (113.8 mg, 73%); mp 100− 105 °C; 1H NMR (400 MHz, CDCl3) δ 7.94−7.91 (m, 2H), 7.40− 7.28 (m, 3H), 7.23−7.21 (m, 2H), 7.19−7.15 (m, 2H), 6.70 (s, 1H), 4.70 (brs, 1H), 3.56 (t, J = 5.5 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.41(s, 3H), 2.00−1.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.7, 141.5, 140.7, 139.2, 138.8, 137.4, 130.1, 127.7, 127.3, 126.4, 123.9, 122.9, 120.3, 119.1, 110.0, 109.6, 108.8, 101.0, 42.2, 26.0, 22.5, 21.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H21N2] 313.1705, found 313.1697. 7-Methyl-5-(4-(trifluoromethoxy)phenyl)-2,3,4,7-tetrahydro-1Hpyrido[3,2-c]carbazole (7i). The product was obtained as an off-white needle (123.0 mg, 62%); mp 150−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 1H), 7.38−7.28 (m, 4H), 7.20−7.14 (m, 3H), 6.57 (s, 1H), 4.69 (s, 1H), 3.69 (s, 3H), 3.49 (t, J = 4.6 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 1.93−1.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.0, 141.7, 140.9, 140.7, 140.4, 139.6, 130.7, 123.9, 122.1, 120.4, 120.3, 118.7, 109.0, 108.1, 107.9, 99.1, 42.2, 29.0, 26.0, 22.4; HRMS (ESI-TOF) m/z: [M + H] + Calcd for [C23H20F3N2O] 397.1528, found 397.1519. 5-(4-(Trifluoromethyl)phenyl)-2,3,4,7-tetrahydro-1H-pyrido [3,2c]carbazole (7j). The product was obtained as a red brown needle (99.6 mg, 60%); mp 115−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.59−7.54 (m, 2H), 7.44− 7.42 (m, 2H), 7.33−7.26 (m, 2H), 7.17−7.12 (m, 1H), 6.58 (s, 1H), 3.49 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 1.92−1.86 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 146.5, 140.8, 139.7, 139.3, 138.8, 133.4, 132.6, 129.7, 124.8 (q, J = 2.9 Hz, 1C), 124.2, 122.6, 120.4, 119.3, 110.1, 109.1, 100.8, 42.1, 25.9, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H18F3N2] 367.1422, found 367.1400. 5-(Thiophen-3-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7k). The product was obtained as a red brown needle (114 mg, 75%); mp 105−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.85−7.83(m, 2H), 7.28−7.23 (m, 3H), 7.14−7.11 (m, 3H), 6.67−6.66 (m, 1H), 3.47 (t, J = 5.9 Hz, 2H), 2.74 (t, J = 5.5 Hz, 2H), 1.93−1.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.0, 140.8, 139.2, 138.8, 135.7, 129.4, 124.4, 124.0, 122.8, 122.3, 120.3, 119.1, 110.1, 109.9, 109.0, 101.0, 42.1, 26.0, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C19H17N2S] 305.1112, found 305.1136. 7-Methyl-5-(thiophen-3-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7l). The product was obtained as a yellow needle (127.2 mg, 80%); mp 100−105 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.31−7.28 (m, 3H), 7.20−7.12 (m, 3H), 6.69 (s, 1H), 3.70 (s, 3H),3.49 (t, J = 5.5 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), 1.95−1.91 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.2, 140.8, 140.7, 140.4, 135.5, 129.4, 124.5, 123.8, 122.31, 122.27, 120.2, 118.6, 109.6, 108.1, 107.9, 99.1, 42.2, 29.0, 26.0, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C20H19N2S] 319.1269, found 319.1260. 5-(Pyridin-2-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7m). The product was obtained as a brown needle (97.0 mg, 65%); mp 180−185 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H),

8.63 (d, J = 4.1 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.84−7.80 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.32−7.25 (m, 2H), 7.09 (t, J = 6.9 Hz, 1H), 6.69 (s, 1H),5.80 (s, 1H), 3.44−3.35 (m, 2H), 2.71 (t, J = 5.9 Hz, 2H), 1.82−1.76 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 160.6, 148.7, 140.6, 139.4, 139.1, 139.0, 136.2, 124.1, 123.6, 122.1, 121.5, 121.2, 117.9, 109.9, 108.4, 107.7, 100.3, 41.4, 25.7, 22.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C20H18N3] 300.1501, found 300.1522. 7-Methyl-5-phenethyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7n). The product was obtained as an off-white needle (102.0 mg, 60%); mp 125−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 1H), 7.33−7.10 (m, 9H), 6.58 (s, 1H), 3.69(s, 3H), 3.45 (t, J = 5.3 Hz, 2H), 2.93−2.88 (m, 4H), 2.82 (t, J = 6.1 Hz, 2H), 2.07−2.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.4, 141.1, 140.6, 140.4, 139.3, 128.42, 128.35, 125.9, 123.4, 122.4, 120.0, 118.4, 109.8, 107.7, 107.5, 98.1, 42.0, 37.3, 36.2, 29.0, 23.8, 22.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C24H25N2] 341.2018, found 341.2009. 5-Cyclohexenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazoles (7o). The product was obtained as a brown needle (93.6 mg, 62%); mp 115−120 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 6.9 Hz, 1H), 6.40 (s, 1H), 5.74 (s, 1H), 5.64 (s, 1H), 3.39 (s, 2H), 2.70 (t, J = 5.3 Hz, 2H), 2.17−2.13 (m, 4H), 1.84−1.83 (m, 2H), 1.71−1.63 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 143.0, 140.2, 139.8, 139.2, 139.1, 124.1, 123.0, 122.3, 120.8, 117.7, 109.6, 107.3, 107.0, 98.4, 54.9, 40.1, 30.0, 24.9, 22.8, 22.1, 21.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H23N2] 303.1861, found 303.1861. 5-Cyclohexyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7p). The product was obtained as a red brown needle (87.8 mg, 58%); mp 110−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.29−7.25 (m, 2H), 7.17−7.12 (m, 1H), 6.68 (s, 1H), 4.55 (brs, 1H), 3.48 (t, J = 5.5 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.81− 2.76 (m, 1H), 2.12−2.07 (m, 2H), 1.87 (d, J = 7.8 Hz, 4H), 1.81−1.77 (m, 1H), 1.50−1.19 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 145.7, 140.8, 139.3, 139.1, 123.5, 123.0, 120.0, 118.8, 109.8, 109.4, 107.9, 97.0, 41.9, 40.0, 34.2, 27.3, 26.5, 23.5, 22.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H25N2] 305.2018, found 305.2018. 5-Cyclopropyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7q). The product was obtained as a yellow needle (70.7 mg, 54%); mp 110−115 °C: 1H NMR (400 MHz, CDCl3) δ 7.81−7.76 (m, 2H),7.26− 7.20 (m, 2H), 7.09 (t, J = 6.9 Hz, 1H), 6.45 (s, 1H), 4.49 (brs, 1H), 3.44 (t, J = 5.27 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.09−2.03 (m, 2H), 1.90−1.83 (m, 1H), 0.88−0.80 (m, 2H), 0.61−0.57 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.8, 140.6, 139.02, 138.99, 123.6, 122.9, 120.1, 118.9, 112.2, 109.9, 108.2, 97.6, 42.0, 24.0, 22.6,14.1, 6.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C18H19N2] 263.1548, found 263.1571 10-Bromo-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (8a). The product was obtained as a brown needle (109.0 mg, 58%); mp 110−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.86 (s, 1H), 7.35−7.27 (m, 6H), 7.16−7.11 (m, 1H), 6.57 (s, 1H), 3.46 (t, J = 5.3 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H), 1.88− 1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.5, 142.1, 140.8, 139.2, 137.8, 129.3, 127.9, 126.7, 126.6, 124.6, 122.9, 111.7, 111.3, 110.0, 108.1, 101.1, 42.2, 26.0, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H18BrN2] 377.0653, found 377.0674 (79Br). 10-Chloro-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (8b). The product was obtained as a red brown needle (99.6 mg, 60%); mp 115−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (s, 1H), 7.33−7.26 (m, 5H), 7.19−7.16 (m, 2H), 6.57 (s, 1H), 4.48 (brs, 1H), 3.45 (t, J = 5.5 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H), 1.89−1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.5, 142.0, 140.7, 139.4, 137.5, 129.3, 127.9, 126.7, 124.3, 123.9, 119.9, 110.8, 109.9, 108.2, 101.1, 42.2, 26.0, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H18ClN2] 333.1159, found 333.1154. (R)-7-Methyl-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8c). The product was obtained as a dark brown needle (121.3 mg, 74%); mp 130−135 °C; 1H NMR (400 MHz, CDCl3) 6659

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry δ 7.94 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 9.2 Hz, 1H), 7.44−7.41 (m, 5H), 7.39−7.31 (m, 3H), 7.22−7.21 (m, 1H), 6.75 (s, 1H), 4.27−4.25 (m, 1H), 3.76 (s, 3H), 3.60−3.58 (m, 1H), 3.51−3.47 (m, 1H), 3.03− 2.99 (m, 1H), 2.81−2.76 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 142.5, 142.0, 140.6, 140.5, 139.6, 134.0, 129.3, 128.9, 128.5, 128.0, 126.8, 124.1, 122.0, 120.3, 118.8, 108.1, 105.8, 100.4, 63.5, 47.7, 34.4, 29.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H21N2O] 329.1654, found 329.1651. (R)-5-Phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8d). The product was obtained as a brown needle (110 mg, 70%); mp 110−115 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.40−7.33 (m, 7H), 7.23−7.19 (m, 1H), 6.72−6.71 (m, 1H), 4.23 (s, 3H), 3.56−3.53 (m, 1H), 3.47−3.43 (m, 1H), 2.99− 2.94 (m, 1H), 2.76−2.71 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 142.2, 142.1, 139.5, 139.2, 139.0, 129.3, 128.0, 126.7, 124.2, 122.4, 120.3, 119.3, 110.2, 108.6, 106.1, 102.3, 63.4, 47.6, 34.4; HRMS (ESITOF) m/z: [M + H]+ Calcd for [C21H19N2O] 315.1497, found 315.1491. (R)-5-(4-Methoxyphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8e). The product was obtained as an off-white needle (137.6 mg, 80%); mp 225−230 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.27−7.24 (m, 1H), 7.17− 7.14 (m, 3H), 6.98−6.94 (m, 1H), 6.86−6.84 (m, 2H), 6.44−6.43 (m, 1H), 5.65−5.62 (m, 1H),4.76 (s, 1H), 3.78−3.73 (m, 1H),3.66 (s, 3H), 3.41−3.39 (m, 1H), 3.00 (t, J = 9.2 Hz, 1H), 2.63−2.59 (m, 1H), 2.52−2.46 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 158.0, 140.3, 139.9, 139.4, 139.3, 134.9, 130.2, 123.4, 122.2, 121.0, 117.9, 113.4, 109.9, 107.5, 106.1, 100.4, 63.2, 55.1, 48.1, 35.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H21N2O2] 345.1603, found 345.1589. (R)-5-(Thiophen-3-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8f). The product was obtained as a brown needle (124.8 mg, 78%); mp 100−105 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.59−7.57 (m, 1H), 7.46− 7.45 (m, 1H),7.38 (d, J = 8.4 Hz, 1H), 7.26−7.23 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 6.67 (s, 1H),5.78 (s, 1H), 4.92−4.91 (m, 1H), 3.93−3.91 (m, 1H), 3.54−3.51 (m, 1H), 3.17−3.12 (m, 1H), 2.82−2.83 (m, 1H), 2.73−2.48 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 143.0, 140.0, 139.3, 135.1, 129.3, 125.2, 123.5, 122.5, 122.1, 121.1, 117.9, 109.9, 107.7, 106.2, 100.3, 63.1, 48.0, 35.5, 27.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C19H17N2OS] 321.1062, found 321.1061. (R)-10-Chloro-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8g). The product was obtained as a dark brown needle (111.6 mg, 64%); mp 110−115 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.34−7.22 (m, 6H), 7.17− 7.15 (m, 1H), 6.46 (s, 1H), 5.83 (s, 1H), 4.77 (d, J = 3.7 Hz, 1H), 3.80−3.73 (m, 1H),3.41−3.38 (m, 1H), 3.01 (t, J = 10.8 Hz, 1H), 2.63−2.57 (m, 1H), 2.51−2.45 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 142.6, 141.3, 140.0, 137.8, 129.0, 128.0, 126.5, 123.4, 123.1, 122.4, 120.4, 110.9, 106.9, 106.1, 100.2, 62.9, 47.7, 35.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H18ClN2O] 349.1108, found 349.1103. General Procedure for the Synthesis of Functionalized Tetrahydro Quinolinocarbazoles 9a−c. In an oven-dried roundbottom flask, a solution of o-alkynylheteroarylaldehyde 5a and b (0.5 mmol), L-proline 6 (0.6 mmol), benzoic acid (0.2 equiv), and 4 Å molecular sieves in 2.0 mL in dry DMF were added under inert atmosphere. The resulting reaction mixture was heated at 130 °C for 3−4 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). The layers were separated, and the organic layer was washed with saturated brine solution and dried over Na2SO4. Organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on silica gel (100−200) (hexane/ethyl acetate; 95/5). The structure and purity of known starting materials were confirmed by comparison of their physical and spectral data (1 H NMR, 13C NMR, and HRMS). 8-Ethyl-5-phenyl-2,3,4,8-tetrahydro-1H-quinolino[7,8-b]carbazole (9a). The product was obtained as a yellow solid (150.6 mg, 85%); mp 275−280 °C; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.55 (s, 1H), 7.49−7.41 (m, 6H), 7.38−7.31 (m, 2H), 7.21−7.16 (m, 1H), 4.32 (q, J = 6.9 and 14.2 Hz, 2H), 3.56

(t, J = 5.5 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1.99−1.93 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 142.4, 140.9, 139.7, 138.9, 133.8, 133.1, 131.7, 129.3, 127.9, 126.7, 126.6, 124.2, 123.2, 120.6, 118.5, 118.1, 110.6, 107.9, 103.7, 42.5, 37.5, 26.4, 22.3, 13.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C27H25N2] 377.2018, found 377.2015. 8-Ethyl-11-methyl-5-phenyl-2,3,4,8-tetrahydro-1H-quinolino[7,8b]carbazoles (9b). The product was obtained as a yellow needle (160.1 mg, 82%); mp 270−275 °C; 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.98 (s, 1H), 7.53 (s, 1H), 7.47−7.40 (m, 4H), 7.37− 7.29 (m, 2H), 7.26−7.21 (m, 2H), 4.31 (q, J = 7.3and 14.2 Hz, 2H), 3.55 (t, J = 4.6 Hz,2H), 2.74 (t, J = 5.9 Hz, 2H), 2.54 (s, 3H), 1.97− 1.91 (m, 2H), 1.40 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.6, 140.9, 140.7, 140.0, 139.4, 131.7, 129.3, 127.8, 126.6, 124.1, 123.4, 120.8, 117.8, 117.6, 110.8, 110.4, 107.7, 103.6, 42.5, 37.6, 26.4, 22.5, 21.3, 13.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C28H27N2] 391.2174, found 391.2175. (R)-8-Ethyl-11-methyl-5-phenyl-2,3,4,8-tetrahydro-1H-quinolino[7,8-b] carbazol-3-ol (9c). The product was obtained as a yellow needle (158.5 mg, 78%); mp 300−305 °C; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.01 (s, 1H), 7.55 (s, 1H), 7.46−7.43 (m, 4H), 7.41−7.33 (m, 3H), 7.26−7.24 (m, 1H), 4.31 (q, J = 7.3 and 14.6 Hz, 2H), 4.26−4.22 (m, 1H), 3.98 (brs 1H), 3.54−3.46 (m, 2H), 3.05− 3.00 (m, 1H), 2.79−2.73 (m, 1H), 2.58 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.0, 141.1, 140.6, 140.0, 138.4, 131.7, 129.5, 128.9, 128.2, 127.9, 127.6, 127.0, 126.4, 124.1, 123.2, 121.1, 118.8, 117.3, 110.9, 108.0, 107.7, 103.8, 63.2, 47.7, 37.5, 34.8, 21.5, 13.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C28H27N2O] 407.2123, found 407.2095. General Procedure for the Synthesis of Functionalized γ-Carbolines 10a−i. In an oven-dried round-bottom flask, a solution of o-alkynylheteroaryl aldehyde 4 (0.5 mmol), L-thioproline 6c (0.6 mmol), benzoic acid (0.2 equiv), and 4 Å molecular sieves in 2.0 mL of dry DMF were added under inert atmosphere. The resulting reaction mixture was heated at 130 °C for 2−4 h. Progression of the reaction was monitored by TLC analysis; after complete consumption of starting material, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). The layers were separated, and the organic layer was washed with saturated brine solution and dried over Na2SO4. Organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on silica gel (100−200) (hexane/ethyl acetate; 80/20). The structure and purity of known starting materials were confirmed by comparison of their physical and spectral data (1H NMR, 13C NMR, and HRMS). 3-Phenyl-5H-pyrido[4,3-b]indole (10a). The product was obtained as a brown needle (97.2 mg, 80%); mp 120−125 °C: 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 9.41 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.3 Hz, 2H), 7.96 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51−7.46 (m, 2H), 7.45−7.39 (m, 2H),7.26 (t, J = 6.9 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 151.3, 145.0, 142.0, 140.3, 139.4, 128.7, 128.5, 126.8, 120.7, 120.6, 120.2, 118.8, 111.6, 102.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H13N2] 245.1079, found 245.1075. 5-Methyl-3-phenyl-5H-pyrido[4,3-b]indole (10b). The product was obtained as a yellow needle (100.6 mg, 78%); mp 120−125 °C; 1 H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.06 (d, J = 7.3 Hz, 1H), 8.02−8.00 (m, 2H), 7.57 (s, 1H), 7.46−7.39 (m, 3H), 7.34−7.31 (m, 2H), 7.26−7.22 (m, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.5, 146.0, 142.2, 141.4, 140.5, 128.7, 128.4, 127.2, 126.6, 121.3, 120.6, 120.5, 118.6, 108.8, 100.5, 29.0; HRMS (EI-TOF) m/z: [M]+ Calcd for [C18H14N2] 258.1157, found 258.1156. 5-Methyl-3-(p-tolyl)-5H-pyrido[4,3-b]indole (10c). This compound was obtained as a yellow needle (111.1 mg, 82%); mp 121− 126 °C; 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.11 (d, J = 7.92 Hz, 1H), 7.97 (d, J = 7.92 Hz, 2H), 7.58 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.96 Hz, 1H), 7.31−7.27 (m, 3H), 3.79 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.5, 146.1, 142.1, 141.4, 138.2, 137.7, 129.4, 127.0, 126.5, 121.3, 120.5, 120.4, 118.4, 108.8, 6660

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry

H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 7.8 Hz, 1H), 9.08−9.06 (m, 1H), 8.54 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.54− 7.40 (m, 8H), 7.33−7.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 150.0, 146.2, 140.2, 139.1, 138.7, 138.6, 135.0, 130.4, 128.5, 127.7, 125.2, 124.2, 124.0, 122.5, 121.0, 118.5, 116.5, 114.0, 110.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H15N2] 295.1235, found 295.1223. 7-Methyl-5-phenyl-7H-pyrido[3,2-c]carbazol-3-ol (11b). The product was obtained as yellow needle (133.0 mg, 82%); mp 153− 158 °C; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.90 (d, J = 7.8 Hz, 1H), 8.75−8.74 (m, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.58−7.57 (m, 4H), 7.52−7.46 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 4.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.2, 142.2, 140.1, 139.8, 139.6, 138.0, 136.7, 130.1, 128.5, 127.5, 124.5, 123.2, 122.3, 122.2, 119.6, 115.8, 114.9, 113.1, 109.5, 29.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C22H17N2O] 325.1341, found 325.1313. 8-Ethyl-11-methyl-5-phenyl-8H-quinolino[7,8-b]carbazole (11c). The product was obtained as yellow needle (131.9 mg, 85%); mp 303−308 °C; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.95− 8.93 (m, 1H), 8.18 (s, 1H), 7.75−7.73(m, 1H), 7.31 (s, 1H), 7.26− 7.23 (m, 2H), 7.17−7.12 (m, 3H),6.98 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.64−6.62 (m, 1H), 6.53 (d, J = 8.2 Hz, 1H), 3.86 (q, J = 7.3 and 14.6 Hz, 2H), 2.51 (s, 3H), 0.81 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.1, 147.8, 141.2, 140.3, 137.5, 135.8, 135.1, 133.8, 132.1, 128.8, 128.6, 128.1, 127.6, 127.1, 126.6, 125.3, 124.3, 124.0, 123.3, 121.5, 120.3, 116.3, 108.0, 104.8, 37.3, 21.4, 13.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C28H23N2] 387.1861, found 387.1870.

100.1, 29.0, 21.2; HRMS (EI-TOF) m/z: [M]+ Calcd for [C19H16N2] 272.1313, found 272.1313. 3-(4-(Trifluoromethyl)phenyl)-5H-pyrido[4,3-b]indole (10d). The product was obtained as a red brown needle (117 mg, 75%); mp 124− 129 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.44 (s, 1H), 8.40 (d, J = 8.4 Hz, 2H),8.25 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H),7.59 (d, J = 8.4 Hz, 1H),7.49 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 149.8, 144.7, 143.6, 142.6, 140.4, 127.3, 127.0, 125.6, 125.5 (q, J = 3.4 Hz, 1C), 120.9, 120.5, 120.3, 119.2, 111.7, 103.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C18H12F3N2] 313.0953, found 313.0952. 5-Methyl-3-(4-(trifluoromethyl)phenyl)-5H-pyrido[4,3-b]indole (10e). The product was obtained as a brown needle (128.4 mg, 79%): mp 124−129 °C; 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.20− 8.14 (m, 3H), 7.72 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.56−7.52 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 6.7 Hz, 1H), 3.87 (s, 3H); 13 CNMR (100 MHz, CDCl3) δ 151.8, 145.9, 143.8, 142.4, 141.6, 127.4, 127.0, 125.6 (q, J = 3.8 Hz, 1C), 121.1, 120.8, 119.2, 109.0, 101.1, 29.2; HRMS (EI-TOF) m/z: [M]+ Calcd for [C19H13F3N2] 326.1031, found 326.1030. 8-Chloro-3-phenyl-5H-pyrido[4,3-b]indole (10f). The product was obtained as a yellow needle (112.6 mg, 81%): mp 122−127 °C: 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.44 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 7.6 Hz, 2H),7.96 (s, 1H),7.57 (d, J = 9.1 Hz, 1H), 7.51− 7.45 (m, 3H),7.42−7.38 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 152.3, 145.4, 143.2, 139.7, 138.7, 128.7, 128.5, 126.8, 126.4, 124.5, 122.1, 120.3, 118.0, 113.0, 102.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H12ClN2] 279.0689, found 279.0696. 5-Methyl-3-(thiophen-3-yl)-5H-pyrido[4,3-b]indole (10g). The product was obtained as a brown needle (92.0 mg, 70%): mp 130− 135 °C; 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.74−7.72 (m, 1H), 7.53−7.48 (m, 2H), 7.41−7.38 (m, 2H), 7.30 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H); 13 CNMR (100 MHz, CDCl3): δ 149.3, 146.0, 142.0, 141.5, 126.7, 126.3, 126.2, 123.0, 121.3, 120.7, 120.6, 118.4, 108.9, 100.2, 29.1; HRMS (EI-TOF) m/z: [M]+ Calcd for [C16H12N2S] 264.0721, found 264.0721. 5-Phenyl-3-(thiophen-3-yl)-5H-pyrido[4,3-b]indole (10h). The product was obtained as a brown needle (127.5 mg, 78%); mp 128−133 °C: 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.82−7.81 (m, 1H), 7.58−7.54 (m, 3H), 7.48−7.45 (m, 3H), 7.38−7.24 (m, 4H), 5.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 150.0, 146.0, 142.9, 142.6, 141.5, 136.4, 130.2, 128.3, 127.0, 126.8, 126.4, 126.0, 123.0, 121.8, 121.4, 120.6, 118.9, 110.2, 101.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C21H15N2S] 327.0956, found 327.0942. 5-Methyl-3-phenethyl-5H-pyrido[4,3-b]indole (10i). This compound was obtained as a yellow needle (42 mg, 50%), mp 124− 128 °C; 1H NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.03 (d, J = 7.32 Hz, 1H), 7.45−7.41 (m, 1H), 7.32 (d, J = 7.96 Hz, 1H), 7.25− 7.19 (m, 2H), 7.18−7.08 (m, 4H), 6.95 (s, 1H), 3.68 (s, 3H), 3.21− 3.17 (m, 2H), 3.10−3.06 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 145.9, 141.7, 141.4, 141.2, 128.5, 128.3, 126.5, 125.8, 121.3, 120.5, 120.5, 117.9, 108.8, 102.6, 40.6, 36.6, 29.0; HRMS (EI-TOF) m/z: [M]+ Calcd for [C20H18N2]: 286.1470, found: 286.1470. General Procedure for the Synthesis of Pyrido/quinolino[3,2-c]carbazoles 11a−c. In an oven-dried round-bottom flask, a solution of 5-phenyl-2,3,4,7-tetrahydro-pyrido[3,2-c]carbazoles 7, 8, and 9 (0.5 mmol) and DDQ in 2.0 mL of benzene was added. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). The layers were separated, and the organic layer was washed with aqueous saturated brine solution and dried over Na2SO4. Organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on silica gel (100−200) (hexane/ethyl acetate; 95/5). The structure and purity of known starting materials were confirmed by comparison of their physical and spectral data (1 H NMR, 13C NMR, and HRMS). 5-Phenyl-7H-pyrido[3,2-c]carbazole (11a). The product was obtained as yellow needle (129.5 mg, 88%); mp 192−197 °C;

1

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00980. Data and spectral copies of 1H, 13C NMR, and HRMS for target compounds (PDF) Crystallographic information for compound 7b (CCDC reference number 1572153) (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Akhilesh K. Verma: 0000-0001-7626-5003 Author Contributions #

S.V. and P.K.M. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was supported by SERB/CSIR and University of Delhi. S.V., M.K., and P.K.M are thankful to CSIR and UGC for fellowships.

■

REFERENCES

(1) (a) Knölker, H.-J.; Reddy, K. R. Isolation and synthesis of biologically active carbazole alkaloids. Chem. Rev. 2002, 102, 4303. and references cited therein. (b) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem. Rev. 2012, 112, 3193. and references cited therein. (c) Reddy, P. N.; Padmaja, P. Applications of aminocarbazoles in heterocyclic synthesis. ARKIVOC 2015, 46, 244. (d) Kumar, V. P.; Gruner, K. K.; Kataeva, O.; Knölker, H.-J. Total Synthesis of the Biscarbazole Alkaloids Murrafoline A−D by a Domino Sonogashira Coupling/Claisen Rearrangement/Electrocyclization Reaction. Angew. Chem., Int. Ed. 2013, 52, 11073. (e) Bashir, M.; Bano,

6661

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry

synthesis of quino[2,3-c] and quino[3,2-b]carbazoles. Tetrahedron 2010, 66, 9650. (d) Prakash, K. S.; Nagarajan, R. A General Method for the Synthesis of 5H-Benzo [b]-Carbazolo [2, 3-b]-and Indolo [2,3b] carbazole Derivatives via Copper (II) Triflate-Catalyzed Heteroannulation. Adv. Synth. Catal. 2012, 354, 1566. (e) Viji, M.; Nagarajan, R. CAN-Catalyzed Regio-selective Synthesis of Pyrido [2, 3-c] carbazoles by the Povarov Reaction. Synthesis 2012, 44, 253. (7) Pedersen, J. M.; Bowman, W. R.; Elsegood, M. R.; Fletcher, A. J.; Lovell, P. J. Synthesis of Ellipticine: A Radical Cascade Protocol to Aryl- and Heteroaryl-Annulated[b]carbazoles. J. Org. Chem. 2005, 70, 10615. (8) Zhang, C.; Das, D.; Seidel, D. Azomethine ylide annulations: facile access to polycyclic ring systems. Chem. Sci. 2011, 2, 233. (9) (a) Reddy, K. R.; Reddy, A. S.; Dhaked, D. K.; Rasheed, S. K.; Pathania, A. S.; Shankar, R.; Malik, F.; Das, P. Palladium-catalyzed arylation of 2H-chromene: a new entry to pyrano [2, 3-c] carbazoles. Org. Biomol. Chem. 2015, 13, 9285. (b) Samala, S.; Singh, G.; Kumar, R.; Ampapathi, R. S.; Kundu, B. Metal-Free Decarboxylative Cyclization/Ring Expansion: Construction of Five-, Six-, and SevenMembered Heterocycles from 2-Alkynyl Benzaldehydes and Cyclic Amino Acids. Angew. Chem., Int. Ed. 2015, 54, 9564. (10) Lin, K.; Jian, Y.; Zhao, P.; Zhao, C.-S.; Pan, W.-D.; Liu, S. A rapid construction of a specific quino[4,3-b] carbazolone system and its application for the synthesis of calothrixin B. Org. Chem. Front. 2018, 5, 590. (11) (a) Ardill, H.; Grigg, R.; Sridharan, V.; Malone, J. A one-pot three carbon decarboxylative ring expansion of cyclic secondary amino acids. X-Ray crystal structure of a substituted 1-azacyclo-octa-2,4diene. J. Chem. Soc., Chem. Commun. 1987, 0, 1296. (b) Rodríguez, N.; Goossen, J. L. Decarboxylative coupling reactions: a modern strategy for C−C-bond formation. Chem. Soc. Rev. 2011, 40, 5030. (c) Bode, J. W.; Fox, R. M.; Baucom, K. D. Chemoselective amide ligations by decarboxylative condensations of N-alkylhydroxylamines and αketoacids. Angew. Chem., Int. Ed. 2006, 45, 1248. (d) Wang, C.; Tunge, J. A. Decarboxylative ring contractions and olefin insertions of vinyl oxazinanones. Org. Lett. 2006, 8, 3211. (e) Yan, Y.; Wang, Z. Metal-free intramolecular oxidative decarboxylative amination of primary α-amino acids with product selectivity. Chem. Commun. 2011, 47, 9513. (f) Wang, C.; Piel, I.; Glorius, F. Palladium-catalyzed intramolecular direct arylation of benzoic acids by tandem decarboxylation/C− H activation. J. Am. Chem. Soc. 2009, 131, 4194. (12) (a) Zuo, Z.; MacMillan, D. W. C. Decarboxylative arylation of α-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J. Am. Chem. Soc. 2014, 136, 5257. (b) Kang, Y.; Seidel, D. Decarboxylative Annulation of α-Amino Acids with γ-Nitroaldehydes. Org. Lett. 2016, 18, 4277. (c) Seidel, D. The azomethine ylide route to amine C−H functionalization: Redoxversions of classic reactions and a pathway to new transformations. Acc. Chem. Res. 2015, 48, 317. and references cited therein’. (d) Wang, H.; Xu, W.; Xin, L.; Liu, W.; Wang, Z.; Xu, K. Synthesis of 1,3Disubstituted Imidazo[1,5-a]pyridines from Amino Acids via Catalytic Decarboxylative Intramolecular Cyclization. J. Org. Chem. 2016, 81, 3681. (e) Wang, Q.; Zhang, S.; Guo, F.; Zhang, B.; Hu, P.; Wang, Z. Natural α-Amino Acids Applied in the Synthesis of Imidazo[1,5-a]Nheterocycles under Mild Conditions. J. Org. Chem. 2012, 77, 11161. (f) Gaddam, V.; Nagarajan, R. An Efficient, One-Pot Synthesis of Isomeric Ellipticine Derivatives through Intramolecular Imino-Diels− Alder Reaction. Org. Lett. 2008, 10, 1975. (13) (a) Mishra, P. K.; Verma, A. K. Metal-free regioselective tandem synthesis of diversely substituted benzimidazo-fused polyheterocycles in aqueous medium. Green Chem. 2016, 18, 6367. (b) Pal, S.; Choudhary, D.; Jainth, M.; Kumar, S.; Tiwari, R. K.; Verma, A. K. Regio- and Stereoselective Domino Synthesis of Oxazolo Fused Pyridoindoles and Benzofurooxazolo Pyridines from ortho-Alkynylarylaldehydes. J. Org. Chem. 2016, 81, 9356. (c) Verma, A. K.; Danodia, A. K.; Saunthwal, R. K.; Patel, M.; Choudhary, D. Palladium-Catalyzed Triple Successive C−H Functionalization: Direct Synthesis of Functionalized Carbazoles from Indoles. Org. Lett. 2015, 17, 3658. (d) Saunthwal, R. K.; Patel, M.; Kumar, S.; Danodia, A. K.; Verma, A.

A.; Ijaz, A. S.; Chaudhary, B. A. Recent developments and biological activities of N-substituted carbazole derivatives: A review. Molecules 2015, 20, 13496. (2) (a) Knölker, H.-J; Reddy, K. R. Chapter 4 - Biological and Pharmacological Activities of Carbazole Alkaloids in The Alkaloids; Cordell, G. A., Ed.; Elsevier Science: New York, 2008, Vol 65, pp 1− 430. (b) Indumathi, T.; Muthusankar, A.; Shanmughavel, P.; Prasad, K. J. R. Synthesis of hetero annulated carbazoles: exploration of in vitro cytotoxicity and molecular docking studies. MedChemComm 2013, 4, 450. (c) Murali, K.; Sparkes, H. A.; Prasad, K. J. R. Synthesis of hetero annulated isoxazolo-, pyrido- and pyrimido carbazoles: Screened for in vitro antitumor activity and structure activity relationships, a novel 2Amino-4-(3′-bromo-4′-methoxyphenyl)-8-chloro-11H-pyrimido[4,5a]carbazole as an antitumor agent. Eur. J. Med. Chem. 2017, 128, 319. (d) Vairavelu, L.; Zeller, M.; Prasad, K. J. R. Solvent-free synthesis of heteroannulated carbazoles: A novel class of anti-tumor agents. Bioorg. Chem. 2014, 54, 12. (e) Le Mée, S.; Pierré, A.; Markovits, J.; Atassi, G.; Jacquemin-Sablon, A.; Saucier, J.-M. S16020−2, a new highly cytotoxic antitumor olivacine derivative: DNA interaction and DNA topoisomerase II inhibition. Mol. Pharmacol. 1998, 53, 213. (3) (a) Léon, P.; Garbay-Jaureguiberry, C.; Barsi, M. C.; Le Pecq, J. B.; Roques, B. P. Modulation of the Antitumor Activity by Methyl Substitutions in the Series of 7H-Pyridocarbazole Monomers and Dimers. J. Med. Chem. 1987, 30, 2074. (b) Lescot, E.; Muzard, G.; Markovits, J.; Belleney, J.; Roques, B. P.; Le Pecq, J. B. Synthesis of 11H-Pyridocarbazoles and Derivatives. Comparison of Their DNA Binding and Antitumor Activity with those of 6H-and 7HPyridocarbazoles. J. Med. Chem. 1986, 29, 1731. (c) Pelaprat, D.; Oberlin, R.; Guen, I. L.; Pecq, J. B. L.; Roques, B. P. DNA Intercalating Compounds as Potential Antitumor Agents. 1. Preparation and Properties of 7H-Pyridocarbazoles. J. Med. Chem. 1980, 23, 1330. (d) Mosher, C. W.; Crews, O. P.; Acton, E. M.; Goodman, L. Preparation and Antitumor Activity of Olivacine and Some New Analogs. J. Med. Chem. 1966, 9, 237. (e) Guillonneau, C.; Pierré, A.; Charton, Y.; Guilbaud, N.; Kraus- Berthier, L.; Léonce, S.; Michel, A.; Bisagni, E.; Atassi, G. Synthesis of 9-O-Substituted Derivatives of 9Hydroxy-5,6-dimethyl-6H- pyrido[4,3-b]carbazole-1-carboxylic Acid (2-(Dimethylamino)ethyl) amide and their 10- and 11-Methyl Analogues with Improved Antitumor Activity. J. Med. Chem. 1999, 42, 2191. (f) Prudent, R.; Moucadel, V.; Nguyen, C.-H.; Barette, C.; Schmidt, F.; Florent, J.-C.; Lafanechère, L.; Sautel, C. F.; DucheminPelletier, E.; Spreux, E.; Filhol, O.; Reiser, J.-B.; Cochet, C. Antitumor Activity of Pyridocarbazole and Benzopyridoindole Derivatives that Inhibit Protein Kinase CK2. Cancer Res. 2010, 70, 9865. (4) (a) Pagano, N.; Wong, E. Y.; Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.; Diamond, S. L.; Meggers, E. From imide to lactam metallo-pyridocarbazoles: distinct scaffolds for the design of selective protein kinase inhibitors. J. Org. Chem. 2009, 74, 8997. (b) Williams, D. S.; Carroll, P. J.; Meggers, E. Platinum complex as a nanomolar protein kinase inhibitor. Inorg. Chem. 2007, 46, 2944. (c) Pagano, N.; Maksimoska, J.; Bregman, H.; Williams, D. S.; Webster, R. D.; Xue, F.; Meggers, E. Ruthenium half-sandwich complexes as protein kinase inhibitors: derivatization of the pyridocarbazole pharmacophore ligand. Org. Biomol. Chem. 2007, 5, 1218. (5) (a) Narasimhan, N. S.; Gokhale, S. M. A New Efficient Synthesis of Pyridocarbazoles. J. Chem. Soc., Chem. Commun. 1985, 0, 86. (b) Manske, R. F.; Kulka, M. Synthesis of some pyridocarbazoles. J. Am. Chem. Soc. 1950, 72, 4997. (c) Gribble, G. W.; Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. Metalated heterocycles in the synthesis of ellipticine analogs. A new route to the 10H-pyrido [2, 3-b] carbazole ring system. J. Org. Chem. 1989, 54, 3264. (6) (a) Gaddam, V.; Nagarajan, R. A one-pot synthetic approach to the functionalized isomeric ellipticine derivatives through an imino Diels−Alder reaction. Tetrahedron Lett. 2009, 50, 1243. (b) Viji, M.; Nagarajan, R. RuCl3/SnCl2 mediated synthesis of pyrrolo[2,3c]carbazoles and consequent preparation of indolo[2,3-c]carbazoles. Tetrahedron 2012, 68, 2453. (c) Sreenivas, D. K.; Nagarajan, R. Palladium-mediated intramolecular O-arylation: a simple route for the 6662

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663

Article

The Journal of Organic Chemistry K. Pd (II)-Catalyzed C-H Activation of Styrylindoles: Short, Efficient, and Regioselective Synthesis of Functionalized Carbazoles. Chem. Eur. J. 2015, 21, 18601. (14) (a) Jha, R. R.; Danodia, A. K.; Kumar, S.; Verma, A. K. Au(III)catalyzed regio- and stereoselective tandem synthesis of oxazolo fused naphthyridines and isoquinolines from o-alkynylaldehydes. Tetrahedron Lett. 2014, 55, 610. (b) Jha, R. R.; Saunthwal, R. K.; Verma, A. K. Stereoselective tandem synthesis of thiazolo fused naphthyridines and thienopyridines from o-alkynylaldehydes via Au(III)-catalyzed regioselective 6-endo-dig ring closure. Org. Biomol. Chem. 2014, 12, 552. (c) Kumar, S.; Saunthwal, R. K.; Aggarwal, T.; Kotla, S. K. R.; Verma, A. K. Palladium meets copper: one-pot tandem synthesis of pyrido fused heterocycles via Sonogashira conjoined electrophilic cyclization. Org. Biomol. Chem. 2016, 14, 9063. (15) (a) Tiano, M.; Belmont, P. Rapid access to amino-substituted quinoline,(di) benzofuran, and carbazole heterocycles through an aminobenzannulation reaction. J. Org. Chem. 2008, 73, 4101. (b) Pal, S.; Choudhary, D.; Jainth, M.; Kumar, S.; Tiwari, R. K.; Verma, A. K. Regio- and Stereoselective Domino Synthesis of Oxazolo Fused Pyridoindoles and Benzofurooxazolo Pyridines from ortho-Alkynylarylaldehydes. J. Org. Chem. 2016, 81, 9356. (c) Chaitanya, T. K.; Nagarajan, R. Synthesis of functionalized ellipticinium and ellipticine derivatives via electrophilic cyclization. Org. Biomol. Chem. 2011, 9, 4662. (16) (a) Rahman, M.; Bagdi, A. K.; Mishra, S.; Hajra, A. Functionalization of an sp3 C−H bond via a redox-neutral domino reaction: diastereoselective synthesis of hexahydropyrrolo [2, 1-b] oxazoles. Chem. Commun. 2014, 50, 2951. (b) Yang, D.; Zhao, D.; Mao, L.; Wang, L.; Wang, R. Copper/DIPEA-Catalyzed, AldehydeInduced Tandem Decarboxylation−Coupling of Natural α-Amino Acids and Phosphites or Secondary Phosphine Oxides. J. Org. Chem. 2011, 76, 6426. (c) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. 1, 3 Dipolar cycloadditions of azomethine ylides with aromatic aldehydes. Syntheses of 1-oxapyrrolizidines and 1, 3oxazolidines. Tetrahedron 1988, 44, 519. (17) (a) Otto, R.; Penzis, R.; Gaube, F.; Winckler, T.; Appenroth, D.; Fleck, C.; Trankle, C.; Lehmann, J.; Enzensperger, C. Beta and gamma carboline derivatives as potential anti-Alzheimer agents: a comparison. Eur. J. Med. Chem. 2014, 87, 63. (b) Zhang, H.; Larock, R. C. Synthesis of Annulated γ-Carbolines by Palladium-Catalyzed Intramolecular Iminoannulation. Org. Lett. 2002, 4, 3035. (18) (a) Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47, 1739. (b) Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening. J. Med. Chem. 2004, 47, 1750.

6663

DOI: 10.1021/acs.joc.8b00980 J. Org. Chem. 2018, 83, 6650−6663