Design and Synthesis of Fluorescent 1,3-Diaryl-β-carbolines and 1,3-Diaryl-3,4-dihydro-β-carbolines.

The 1,3-diaryl-β-carboline derivatives, including 3,4-dihydro variants, were synthesized via a multiple-step approach. These compounds possess rigid and twisted configurations, which are expected to exhibit unique optical properties. The absorption and fluorescence properties of the newly synthesized compounds were investigated. These synthetic 1,3-diaryl-β-carbolines displayed strong emission in the range of 387-409 nm and exhibited absolute photoluminescence quantum yields of up to 74%. Density functional theory calculations were performed to better elucidate the geometric, electronic, and optical properties of these novel 1,3-diaryl-β-carbolines.

Introduction

The β-carbolines are a large family of natural products possessing a tricyclic pyrido[3,4-b]indole ring system.[1] These alkaloids are further categorized into three groups based on the saturation level of the pyridine ring: compounds with a fully aromatic pyridine ring are referred to simply as β-carbolines, whereas 3,4-mono- and di-unsaturated congeners are known as dihydro-β-carbolines (DHBCs) and tetrahydro-β-carbolines, respectively (Figure ). The β-carboline family exhibits a diverse array of pharmacological properties, including anticancer,[2] antibacterial,[3] anxiolytic,[4] antifungal,[5] antiviral,[6] anti-Alzheimer,[7] antimalarial,[8] and anticonvulsant activities.[9] Due to the relative ease of synthesis and vast range of potential biological activities, the β-carboline scaffold has long been a valuable platform in drug discovery efforts. The intriguing photoluminescence properties of the β-carbolines[10] and structural analogues[11] have also elicited interest for potential applications in material chemistry, organic light-emitting diodes (OLEDs),[12] and optical sensing agents for selective quantitative analysis of chemical entities.[13]

Figure 1

Parent frameworks for β-carbolines and partially saturated analogues.

There are limited reports describing the synthesis of β-carbolines with aryl substitution at the C1 and C3 positions. In most cases, the resulting modified β-carbolines were arylated exclusively at either C1[14] or C3;[15] in only a few cases were 1,3-diphenyl-β-carbolines successfully synthesized (Scheme ).[16] The structure–activity relationship analyses revealed that 1-aryl-substitution on a β-carboline bearing a carbohydrazide moiety at C3 enhanced the antitumor activity.[17] Heteroaryl substitution (1,2,3-triazolo or pyridine moieties) on the C1 position of the β-carboline nucleus exerts a significant DNA-binding ability to the scaffold.[18] The photophysical properties of C1/C3 mono- and diarylated β-carbolines, however, are underexplored. Chen and co-workers recently described the palladium-catalyzed synthesis and photoemissive properties of several structurally related 1,3-diarylbenzofuro[2,3-c]pyridines (Scheme ).[11] Herein, a synthetic route involving 2-azaallyl anions toward the construction of 3,4-dihydro and fully aromatic β-carbolines with both C1 and C3 aryl substitutions is described. The photophysical properties of the resulting collection of alkaloid-inspired fluorophores were explored and compared using molecular orbital calculations.

Scheme 1

Previous Synthesis of 1,3-Diphenyl β-carbolines, (a) Rossi’s Approach to 1,3-Diphenyl-β-carboline and (b) Donohoe’s Synthesis of N-Benzyl-1,3-diphenyl-β-carboline

Scheme 2

Chen and co-Worker’s Synthesis of Fluorescent 1,3-Diarylbenzofuro[2,3-c]pyridines

Results and Discussion

The 2-azaallyl anion is one of the earliest proposed synthetic intermediates in organic chemistry.[19] Within the past two decades, 2-azaallyl anions have received significant renewed attention due to their ability to serve both as nucleophilic imine umpolungs and as super-electron-donors (SEDs).[20] As part of a broader campaign focused on the decarboxylative generation and functionalization of 2-azaallyl anions, Fields and Chruma reported the Pd-catalyzed decarboxylative benzylation of benzyl 2,2-diphenylglycinate imines.[21] Notably, N-tosyl-3-methyleneindolyl esters of 2,2-diphenylglycinate aryl imines were viable substrates, allowing for the construction of α-aryltryptimines 1, which served as advanced precursors for the synthesis of 1,3-diaryl-β-carbolines and the 3,4-dihydro congeners (Scheme ). A collection of later collaborative studies by Walsh and co-workers revealed that 2-azaallyl anions can serve as anionic SEDs.[22] This strategy of using 2-azaallyl anions as SEDs to reduce organic halides which then couple with the intermediate 2-azaallyl radicals was developed to afford transition-metal-free couplings with vinyl, aryl, and alkyl halides.[22,23] Based on this and other precedent studies,[24] we proposed that direct alkylation of a base-generated 2-azaallyl anion with a 3-(bromomethylene)indole, either by SN2 or radical mechanisms, would be a more flexible route toward α-aryltryptimines 1 and thus 1,3-diaryl-β-carbolines and related DHBCs (Scheme ). In particular, we posited that selective hydrolysis of benzophenone imine in 1 followed by a traditional Bischler–Napieralski cyclization protocol would provide access to 1,3-diarylated DHBCs 4, and after oxidation, the corresponding β-carbolines 5.

Scheme 3

α-Aryltryptimines 1 via Pd-Catalyzed Decarboxylative Benzylation

Scheme 4

Proposed Strategy for the Construction of 1,3-Diaryl DHBCs and β-Carbolines

Our studies began with exploring the alkylation of 2-azaallyl anions with N-tosyl-3-(bromomethylene)indole (7). Since we were interested in exploring how aryl substitution at C1 and C3 of the DHBC/β-carboline scaffold impacted the photophysical properties, we sought to incorporate both electron-deficient and electron-rich aromatic groups. Toward this end, electron-withdrawing 4-cyanobenzaldimine 6a and electron-donating 4-methoxybenzaldimine 6b were both individually converted to the corresponding 2-azaallyl anions following previously reported conditions[23] and combined with bromide 7 (Scheme ). Following this protocol, α-(4-cyanophenyl)tryptimine 1a could be obtained from imine 6a in multigram quantities in a 62% average isolated yield. Coupling of bromide 7 with the 2-azaallyl anion generated by deprotonation of 6b, however, did not generate the expected N-tosylated indole product. Instead, the corresponding free indole 1b was isolated in 14% yield. Murphy and co-workers developed a series of neutral SEDs capable of reductively cleaving a variety of N-sulfamide bonds, including those between tosyl groups and indole nitrogens.[25] Since 2-azaallyl anions can also act as SEDs,[22,23] we suspect that the electron-rich 2-azaallyl anion generated from 4-methoxybenzaldimine 6b had sufficient reducing power to cleave the N-tosyl group preferentially over nucleophilic (or reductive) substitution with the alkyl bromide 7. The electron-withdrawing nitrile moiety in 6a, on the other hand, sufficiently discouraged the reductive cleavage of the sulfamide group. Based on these interesting observations, we opted to focus on nitrile 1a exclusively for further development into the desired 1,3-diaryl DHBCs and β-carbolines.

Scheme 5

Generation and Alkylation of 2-Azaallyl Anions

Selective hydrolysis of benzophenone imine in 1a was achieved with HCl in THF on a multigram scale in an average of 85% isolated yield (Scheme ). Since the primary goal was to explore possible photoelectronic communication between aryl substituents on the 1 and 3 positions of the DHBC and β-carboline frameworks and we were committed to an electron-deficient p-cyanophenyl moiety at C3, electron-neutral and electron-rich aryl groups were desired for the C1 substituent. Accordingly, amine 2a was condensed with benzoyl chloride and p-methoxybenzoyl chloride to obtain amides 3a and 3b in 94 and 92% yields, respectively. To investigate the influence of the electron-withdrawing N-tosyl group on the photoemissive properties of the resultant carbolines, the sulfamides were hydrolyzed with KOH to afford free indoles 3c and 3d in excellent yields. Additionally, the N-methyl indoles 3e and 3f were obtained in 83 and 78% yields, respectively, under phase-transfer catalytic methylation conditions. It should be noted that attempts to synthesize N-methyl-3-(bromomethylene)indole (the N-methyl analogue of 7) in high yield and quantity were not successful, thus necessitating the synthesis of 3e and 3f via the corresponding N-tosyl indoles 3a and 3b, respectively, instead of direct alkylation of the 2-azaallyl anion of 6a.

Scheme 6

Synthesis of Amides 3a–f

With a collection of requisite amides in hand, attention was turned toward identifying appropriate conditions to initiate a Bischler–Napieralski dehydrative cyclization toward the desired 1,3-diaryl-DHBCs. Initial studies with N-tosylated indole 3a suggested that Movassaghi’s conditions (triflic anhydride and 2-chloropyridine in dichloromethane)[26] consistently provided the corresponding DHBC 4a in the highest yield and purity (Scheme ). Dihydropyridine 4a proved to be sensitive toward aerobic and/or photo-oxidative aromatization; extensive attempts to purify the reaction product using various chromatographic techniques always lead to contamination of the product with the corresponding fully aromatic β-carboline 5a. Gratifyingly, DHBC 4a could be purified simply by trituration from a CH2Cl2 solution with ethyl acetate. This sensitivity toward auto-oxidation was most extreme for unprotected indoles 3c and 3d, which directly converted to β-carbolines 5c and 5d in 78 and 28%, respectively, under Movassaghi’s conditions without any of the intermediate DHBCs being detected. The remaining amides 3b, 3e, and 3f, however, transformed into the desired DBHCs in good to quantitative yields; in most cases, the final products were purified by trituration with optimized solvent mixtures.

Scheme 7

Bischler–Napieralski Cyclization of Amides 3 under Movassaghi’s Conditions

After exhaustively exploring a variety of previously disclosed oxidation conditions, we determined that DHBC 4a could be converted rapidly to the fully aromatic β-carboline 5a in 95% with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CH2Cl2 at room temperature (Scheme ). Similarly, DHBC 4b was oxidized with DDQ to β-carboline 5b in a good isolated yield (70%). Oxidation of N-methylated indole 4f, however, was not as successful, affording β-carboline 5f in only 42% average yield. Alternatively, we determined that N-methylation of indole 5c was a more efficient and higher yielding approach to β-carboline 5e than oxidation of DHBC 4e.

Scheme 8

Synthesis of β-Carbolines 5

Photophysical Properties

UV–visible optical absorption studies of the novel DHBCs 4 and 1,3-diaryl-β-carbolines 5 were performed in CH2Cl2 at a concentration of 2.5 × 10–5 M (Figure ). N-Tosyl β-carboline 5b had the highest molar extinction coefficient (ε) at 272 nm, whereas the N-tosyl DHBC 4a displayed the lowest molar extinction coefficient at 315 nm (Table ). Similar UV–vis absorption spectra were produced by compounds with the same skeletal framework and either a phenyl or 4-methoxyphenyl group at C1. For example, the absorption spectra of N-methyl-1-phenyl-β-carboline 5e exhibited absorption maxima at 290 and 333 nm, while the C1-(4-methoxyphenyl)-substituted counterpart 5f displayed nearly identical absorption peaks at 289 and 337 nm. The main distinction between the C1-phenyl and 4-methoxyphenyl congeners was the overall molar absorptivity of the species. In the case of N-tosyl and N-H 1,3-diaryl-β-carbolines, the molar extinction coefficients of the C1-phenyl-substituted compounds (5a and 5c, respectively) were less than those of the corresponding C1-(4-methoxyphenyl)-substituted counterparts 5b and 5d, respectively. In contrast, the absorption spectra of N-methyl 1,3-diaryl-β-carbolines displayed the opposite trend; the molar absorptivity of C1-phenyl-substituted 5e was greater than that of 5f, which possessed a 4-methoxyphenyl group at C1.

Figure 2

Normalized UV–vis absorption spectra of 1,3-diaryl-DHBCs 4 (left) and 1,3-diaryl-β-carbolines 5 (right) in CH2Cl2 (2.5 × 10–5 M).

Table 1

Photophysical Properties of DHBCs 4 and 1,3-Diaryl-β-carbolines 5

compound	λabsa (nm)	λemsb (nm)	intensity (a.u.)	τc (ns)	εd (M–1 cm–1)	stokes shift (nm)	quantum yielde (φ)
4a	315	387	4.26	2.47	12,300	72	0.01
4b	308	391	5.89	2.19	21,800	83	0.01
4e	324	409	20.08	1.20	15,000	85	0.05
4f	324	408	11.45	1.00	13,600	84	0.04
5a	267 and 337	388	42.24	1.65	50,100 (@ 267 nm)	51	0.12
5b	272 and 325	408	23.43	2.16	61,700 (@ 272 nm)	83	0.04
5c	292 and 327	387	277.70	1.95	30,900 (@ 292 nm)	60	0.61
5d	289 and 330	389	377.77	2.02	39,000 (@ 289 nm)	59	0.74
5e	290 and 333	403	275.09	0.93	37,300 (@ 290 nm)	70	0.45
5f	289 and 337	407	316.22	0.98	34,400 (@ 289 nm)	70	0.62

Absorption maximum values obtained from the spectra recorded in CH2Cl2 at 2.5 × 10–5 M.

Emission maximum values from the fluorescence spectra measured in CH2Cl2 at 25 °C.

Photoluminescence decay profiles analyzed in CH2Cl2 at 25 °C using a 280 nm LED source.

Molar extinction coefficients (ε) calculated at a concentration of 2.5 × 10–5 M and a path length of 1 cm.

Absolute photoluminescence quantum yields were measured using a Horiba FluoroMax-4 spectrofluorometer with an integrating sphere.

The fluorescence emission spectra were recorded at different excitation wavelengths ranging from 308–337 nm in CH2Cl2 (Table and Figure ). Overall, the solution-state maximum fluorescence emission wavelengths for the 10 compounds studied fit within a relatively small range of 389–409 nm. The N-H 1-(4-methoxyphenyl)-β-carboline 5d showed both the most intense fluorescence emission, with a global maximum at 389 nm, and the highest quantum yield (74%). The C1-phenyl counterpart 5c showed similar fluorescence emission, albeit with a weaker intensity at 387 nm and a lower quantum yield (61%). The N-Me-1-phenyl-β-carboline 5e showed strong fluorescence emission (λmax = 403 nm) and good quantum yield (45%), and the 1-(4-methoxyphenyl) counterpart 5f showed strong fluorescence emission with a similar maximum (407 nm) and a superior quantum yield (62%). The photophysical properties of 1,3-diaryl-β-carbolines 5 were very similar to those reported by Chen and co-workers for the corresponding benzofuro[2,3-c]pyridines (Scheme ),[11] although the emission wavelengths for the latter (484–492 nm in CHCl3) were red-shifted relative to 5 (see the Supporting Information for comparison of the fluorescence properties of 5 vs other emissive β-carboline derivatives).

Figure 3

Top: comparison of the normalized fluorescence emission spectra of DHBCs 4a and 4b with corresponding β-carbolines 5a and 5b (CH2Cl2, 2.5 × 10–5 M, and λex = 308–337 nm); bottom: normalized fluorescence emission spectra of remaining DHBCs 4e and 4f and β-carbolines 5c and 5d (CH2Cl2, 2.5 × 10–5 M, and λex = 308–337 nm).

In general, the fully conjugated compounds 5 exhibited much stronger fluorescence emission than their unsaturated counterparts 4. For example, the emission from 5a was 10 times more intense than the corresponding DBHC 4a (Figure ; top). Presumably due to the lack of conjugation and electron-withdrawing tosyl group, DHBCs 4a and 4b displayed the weakest fluorescence emissions and the lowest quantum yield (1%). Interestingly, DBHCs 4 exhibited relatively long intrinsic fluorescence lifetimes (τ/φ). For example, the intrinsic fluorescence lifetime of 4a is 247 ns compared with 14 ns for the corresponding fully conjugated 5a. Such a dramatic difference is a key indication that 4a and other 1,3-diaryl-DBHCs are heavily involved in a charge-separated excited state, leading to possible triplet involvement and photo-oxidation. Indeed, the initial impetus for these efforts was to generate new phosphorescent materials. Nevertheless, in contrast to encouraging earlier studies with less pure samples,[27] DHBC 4a did not exhibit any appreciable room temperature phosphorescence in either solution or solid state. This was also the case for purified samples of the other newly synthesized DHBCs 4 and β-carbolines 5 in this report (data not shown).

Computational Studies

To better elucidate the geometric, electronic, and optical properties of these novel 1,3-diaryl-β-carbolines 5 and corresponding DHBCs 4, density functional theory (DFT) calculations were performed using the B3LYP/6–31 + G* method (Figure ). The resultant highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) values are in the range of −5.48 to −6.03 eV and −1.52 to −1.78 eV, respectively. The band gaps for each 1,3-diarylated compound were calculated to fall within the range of 3.93 to 4.26 eV. This range is similar to the range of 3.83–4.64 eV determined empirically from the λabs values of the UV–vis absorption spectra. Moreover, these HOMO–LUMO energy gap calculations predict that N-Ts 1-phenyl-β-carboline 5a will have the highest energy of excitation (ΔEcalc = 4.26 eV), whereas N-Me DHBCs 4e (ΔEcalc = 3.93 eV) and 4f (ΔEcalc = 3.98 eV) would require the lowest energies of excitation. These predictions were confirmed empirically in which the maximum absorption wavelength for 5a in the UV–vis absorption spectra was the highest in energy (λabs = 267 nm), whereas 4e and 4f had the lowest energy maximum absorption (λabs = 324 nm) of the 10 compounds studied.

Figure 4

HOMO–LUMO energy level diagram of compounds 4 and 5 calculated using the B3LYP/6–31 + G* method.

Conclusions

In summary, inspired by previous studies involving 2-azaallyl anions, a multiple-step protocol involving the alkylation of 2-azaallyl anions was developed to synthesize a collection of novel 1,3-diaryl-3,4-DHBCs and 1,3-diaryl-β-carbolines. This approach provided access to 1,3-diaryl-DHBCs and β-carbolines, which possess unique structures and exhibited pronounced photophysical properties. The aryl groups attached to the C1 and C3 positions of the β-carboline skeleton and the nature of the group on the indole nitrogen all affected the emissive performance of the molecule. We obtained compounds with either electron-neutral phenyl or electron-rich 4-methoxyphenyl on the C1 position and electron-deficient 4-cyanophenyl on the C3 position of the DHBC/β-carboline framework. Moreover, compounds possessing either a hydrogen, methyl, or tosyl group on the indole nitrogen of the β-carboline framework were generated. Assessment of the photophysical properties of these novel compounds showed that the fully aromatic compounds 5 exhibited much stronger fluorescence emission than their DHBC counterparts 4. Among these candidate compounds N-H 1,3-diaryl-β-carbolines 5c and 5d displayed the strongest fluorescence emission and exhibited the highest quantum yields (up to 74%). The N-methyl 1,3-diaryl-β-carbolines 5e and 5f also displayed strong fluorescence emission and high quantum yields (up to 62%). DFT calculations were performed to better elucidate the photoluminescence properties at the molecular level. These results suggest that this series of novel fluorophores could have potential application in OLEDs and organic electronics.

Experimental Section

General

All nonaqueous reactions were performed in oven-dried flasks or vials under an atmosphere of dried and deoxygenated argon with dry solvents and magnetic stirring, unless stated otherwise. All solvents were dried by storing over activated 4 Å molecular sieves for at least 48 h and sparged with argon for at least 30 min.[28] All reagents were purchased from commercial sources without any further purification, unless stated otherwise. Bromide 7 was obtained in three steps from commercially available 1H-indole-3-carbaldehyde following literature procedures.[29] All chromatography techniques were performed with indicated solvents and a 300–400 mesh silica gel (solvent abbreviation: PE = petroleum ether). The reaction progress was monitored using a TLC plate under a UV light (254 nm). Melting points were determined with INESA melting point apparatus and were uncorrected. The compound characterizations (nuclear magnetic resonance (NMR), infrared (IR), and high-resolution mass spectrometry (HRMS)) were performed by the Comprehensive Specialized Laboratory Training platform, College of Chemistry, Sichuan University. IR spectra were obtained with a NEXUS 670 FTIR using a thin film deposited on freshly made KBr discs; only strong and specific functional groups were reported (in cm–1). All 1H NMR and 13C NMR spectra were recorded using a Bruker Ascend 400 at 300 K, as indicated. Chemical shifts were reported in δ (ppm) units using residual solvent peaks (1H/13C: CDCl3 δ 7.26/77.16, DMSO-d6 δ 2.50/39.52) as a standard or an internal standard of tetramethylsilane (1H δ 0.00) if the residual solvent peak overlapped with compound signals. UV–vis absorption spectra were recorded using a PerkinElmer Lambda 465 UV–vis spectrometer in CH2Cl2 at a concentration of 2.5 × 10–5 M. Steady-state emission spectra were recorded using a Horiba FluoroMax-4 spectrofluorometer (Horiba Scientific). Fluorescence lifetime data were acquired with a 1 MHz LED laser with the excitation peak at 285 nm. The absolute photoluminescence quantum yields were measured using a Horiba FluoroMax-4 spectrofluorometer (Horiba Scientific) with an integrating sphere (Labsphere Inc.).

Synthetic Procedures

4-((Benzhydrylimino)methyl)benzomitrile (6a)

To an oven-dried flask was added 4-formylbenzonitrile (5.25 g, 40 mmol, 1 equiv) and diphenylmethanamine (8.3 mL, 48 mmol, 1.2 equiv) under an Ar atmosphere. The reaction mixture was heated at 60 °C under Ar for 1 h and then under a reduced pressure (oil-pump vacuum) for an additional 1 h. The reaction mixture was dissolved in EtOAc (50 mL) and recrystallized from EtOAc/hexane to give a white solid (9.8 g, 33 mmol, 83%). The spectroscopic data matched those from previous literature reports.[22c]1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.93 (app d, J = 8.4 Hz, 2H), 7.68 (app d, J = 8.4 Hz, 2H), 7.41–7.36 (m, 4H), 7.36–7.30 (m, 4H), 7.28–7.21 (m, 2H), 5.64 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.1, 143.4, 140.1, 132.5, 129.0, 128.7, 127.7, 127.4, 118.7, 114.1, 78.1.

N-Benzyhydryl-1-(4-methoxyphenyl)methanimine (6b)

To an oven-dried flask was added 4-methoxybenzaldehyde (4.85 mL, 40 mmol, 1 equiv) and diphenylmethanamine (8.3 mL, 48 mmol, 1.2 equiv) under an Ar atmosphere. The reaction mixture was heated at 60 °C under Ar for 2 h and then under a reduced pressure (oil-pump vacuum) for an additional 1 h. The reaction mixture was dissolved in EtOAc (50 mL) and recrystallized from EtOAc/hexane to give 6b as a white solid (10.37 g, 34.5 mmol, 86%). The spectroscopic analysis was conducted as reported in literature reports.[22c]1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.81–7.74 (m, 2H), 7.39 (dd, J = 8.1, 1.0 Hz, 4H), 7.34–7.27 (m, 4H), 7.24–7.19 (m, 2H), 6.95–6.88 (m, 2H), 5.56 (s, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.8, 160.1, 144.2, 130.1, 129.4, 128.4, 127.7, 126.9, 114.0, 55.4.

4-(1-((Diphenylmethylene)amino-2-(1-tosyl-1H-indol-3-yl)ethyl)benzomitrile (1a)

To a flame-dried glass flask charged with imine 6a (8.89 g, 30 mmol, 3 equiv) and bromide 7 (3.64 g, 10 mmol, 1 equiv) in dimethyl sulfoxide (DMSO, 120 mL) at room temperature (rt) was added LiN(SiMe3)2 (1 M in THF, 25 mL, 2.5 equiv) dropwise under an Ar atmosphere. The reaction mixture was stirred for 20 h, quenched with sat aq NH4Cl (120 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine, dried (NaSO4), and concentrated by rotary evaporation. The crude product was purified by flash chromatography (1% Et3N in 10% EtOAc/PE) to give imine 1a as a yellow solid (3.6 g, 6.2 mmol, 62%). The spectroscopic analysis was conducted as reported in literature reports.[21]Rf = 0.25 (10% EtOAc/PE). Mp = 199–201 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 1H), 7.64–7.56 (m, 4H), 7.51 (d, J = 8.3 Hz, 2H), 7.44 (ddd, J = 6.4, 3.8, 1.3 Hz, 1H), 7.41–7.35 (m, 4H), 7.30–7.22 (m, 2H), 7.16 (s, 1H), 7.10–6.97 (m, 4H), 6.92 (d, J = 8.1 Hz, 2H), 6.28 (br d, J = 4.5 Hz, 2H), 4.70 (dd, J = 8.3, 5.1 Hz, 1H), 3.20 (dd, J = 14.1, 8.3 Hz, 1H), 3.06 (dd, J = 14.0, 5.0 Hz, 1H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 149.7, 144.9, 139.4, 135.9, 135.9, 135.2, 135.0, 132.3, 130.9, 130.6, 129.8, 128.7, 128.34, 128.25, 128.0, 127.1, 126.7, 124.6, 124.3, 123.0, 119.4, 119.1, 119.0, 113.7, 110.8, 65.5, 35.2, 21.6. IR (thin film): νmax 3432, 3057, 2227, 1607, 1446, 1373, 1176, 976, 669, 572. HRMS calcd for C37H30N3O2S+ [M + H]+ 580.2053; found 580.2058.

N-(2-(1H-Indol-3-yl)-1-(4-methoxyphenyl)ethyl)-1,1-diphenylmethanimine (1b)

To a dry glass vial charged with imine 6b (451.7 mg, 1.5 mmol, 3 equiv) and bromide 7 (181.5 mg, 0.5 mmol, 1 equiv) in DMSO (5 mL) at rt was added LiN(SiMe3)2 (1 M in THF, 1.25 mL, 2.5 equiv) under an Ar atmosphere. The reaction mixture was stirred for 10 h, quenched with sat aq NH4Cl (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried (NaSO4), and concentrated by rotary evaporation. The crude product was purified by flash chromatography (1% Et3N in 10% EtOAc/PE) to give imine 1b as a yellow solid (30.4 mg, 0.07 mmol, 14%). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.55 (d, J = 7.0 Hz, 2H), 7.21 (tt, J = 11.5, 5.7 Hz, 8H), 7.05 (dd, J = 16.1, 8.2 Hz, 3H), 6.86 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 1.3 Hz, 1H), 6.46 (t, J = 9.6 Hz, 2H), 4.56 (dd, J = 7.6, 5.8 Hz, 1H), 3.70 (s, 3H), 3.31–3.04 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 166.3, 158.4, 140.0, 137.1, 136.8, 136.0, 129.7, 128.5, 128.3, 128.0, 127.9, 127.9, 127.5, 122.7, 121.6, 119.0, 113.6, 113.4, 110.8, 66.3, 55.3, 35.3. HRMS calcd for C30H27N2O+ [M + H]+ 431.2118; found 431.2116.

4-(1-Amino-2-(1-tosyl-1H-indol-3-yl)ethyl)benzonitrile (2a)

To a flask charged with imine 1a (3.6 g, 6.2 mmol, 1 equiv) dissolved in THF (62 mL) was added 1 N HCl (18.6 mL, 3 equiv). The reaction mixture was stirred for 24 h at rt, quenched with sat aq NaHCO3 (60 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine, dried (NaSO4), and concentrated by rotary evaporation. The crude product was purified by flash chromatography (1% Et3N in CH2Cl2) to give amine 2a as a white solid (2.19 g, 5.26 mmol, 85%). Rf = 0.45 (5% MeOH/CH2Cl2). Mp = 87–89 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1H), 7.71–7.67 (m, 2H), 7.54–7.50 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.35–7.30 (m, 1H), 7.27 (s, 1H), 7.25–7.20 (m, 3H), 4.34 (dd, J = 7.4, 6.2 Hz, 1H), 3.02–2.90 (m, 2H), 2.36 (s, 3H), 1.53 (br s, 2H). 13C NMR (101 MHz, CDCl3) δ 150.8, 145.1, 135.3, 135.2, 132.3, 130.7, 130.0, 127.3, 126.8, 125.0, 124.4, 123.3, 119.4, 119.0, 118.97, 118.94, 114.0, 111.0, 55.5, 35.6, 21.7. IR (thin film): νmax 3381, 2917, 2359, 2227, 1608, 1447, 1365, 1172, 980, 745, 671, 576. HRMS calcd for C24H22N3O2S+ [M + H]+ 416.1427; found 416.1430.

N-(1-(4-Cyanophenyl)-2-(1-tosyl-1H-indol-3-yl)ethyl)benzamide (3a)

To a stirred solution of amine 2a (2.19 g, 5.3 mmol, 1 equiv), i-Pr2NEt (1.75 mL, 10.6 mmol, 2 equiv), and DMAP (0.13 g, 1.06 mmol, 0.2 equiv) in THF (40 mL) at −78 °C was added benzoyl chloride (1.23 mL, 10.6 mmol, 2 equiv). The reaction mixture was allowed to reach rt and stirred for 30 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting crude solid was titurated with CH2Cl2/hexane, and the resulting solid was isolated by filtration and dried under vacuum to give the amide 3a as a white solid (2.58 g, 4.9 mmol, 94%). Rf = 0.32 (30% EtOAc/PE). Mp = 212–213 °C. 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 8.3 Hz, 1H), 7.88–7.84 (m, 3H), 7.81 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.4 Hz, 3H), 7.69 (d, J = 8.3 Hz, 2H), 7.63–7.56 (m, 4H), 7.52–7.48 (m, 2H), 7.36–7.24 (m, 2H), 7.02 (d, J = 8.1 Hz, 2H), 5.55–5.46 (m, 1H), 3.30 (dd, J = 15.3, 10.5 Hz, 1H), 3.18 (dd, J = 15.0, 5.0 Hz, 1H), 2.20 (s, 3H). 13C NMR (101 MHz, DMSO) δ 165.8, 148.9, 145.1, 134.3, 133.95, 133.90, 132.3, 131.5, 130.5, 129.9, 128.4, 127.7, 127.3, 126.3, 124.8, 124.4, 123.3, 119.9, 119.5, 118.9, 113.2, 109.8, 52.4, 30.7, 20.9; IR (thin film): νmax 3325, 2229, 1636, 1365, 1173, 672, 574. HRMS calcd for C31H24N3O3S– [M – H]− 518.1544; found 518.1547.

N-(1-(4-Cyanophenyl)-2-(1-tosyl-1H-indol-3-yl)ethyl)-4-methoxybenzamide (3b)

To a stirred solution of amine 2a (415.5 mg, 1 mmol, 1 equiv), i-Pr2NEt (0.33 mL, 2 mmol, 2 equiv), and DMAP (24.4 mg, 0.2 mmol, 0.2 equiv) in THF (20 mL) at −78 °C was added 4-methoxybenzoyl chloride, and the resulting reaction mixture was allowed to reach rt. After stirring at rt for 24 h, the reaction was quenched with 1 N HCl and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and titrated with CH2Cl2/Et2O to give amide 3b as a white solid (507.4 mg, 0.92 mmol, 92%). Rf = 0.43 (40% EtOAc/PE). Mp = 283–285 °C; 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 8.3 Hz, 1H), 7.88–7.83 (m, 3H), 7.80 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.61 (s, 1H) 7.30–7.24 (m, 2H), 7.07–7.00 (m, 4H), 5.52–5.45 (m, 1H), 3.82 (s, 3H), 3.29 (dd, J = 14.9, 10.2 Hz, 1H), 3.17 (dd, J = 15.0, 5.1 Hz, 1H), 2.20 (s, 3H). 13C{1H} NMR (101 MHz, DMSO) δ 165.3, 161.8, 149.1, 145.0, 134.3, 134.0, 132.3, 131.4, 130.6, 130.0, 129.2, 127.7, 126.3, 126.1, 124.8, 124.4, 123.3, 120.0, 119.6, 118.9, 113.8, 113.6, 113.2, 109.7, 55.4, 52.2, 30.7, 20.9. IR (thin film): νmax 3346, 2362, 2225, 1636, 1506, 1256, 1175, 671, 570. HRMS calcd for C32H27N3NaO4S+ [M + Na]+ 572.1614; found 572.1614.

N-(1-(4-Cyanophenyl)-2-(1H-indol-3-yl)ethyl)benzamide (3c)

To a stirred solution of amide 3a (355.8 mg, 0.68 mmol, 1 equiv) in THF/MeOH (6 mL/3 mL) at rt was added KOH (191.8 mg, 3.5 mmol, 5 equiv). The resulting mixture was heated to 60 °C and stirred at that temperature for 17 h. The solvent was then removed under a reduced pressure and the resulting residue was taken up in water. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL), and the combined organic layer was washed with brine, dried (NaSO4), concentrated in vacuo, and titurated with CH2Cl2/hexane to give free indole amide 3c as a white solid (231.3 mg, 0.63 mmol, 93%). Rf = 0.26 (40% EtOAc/PE). Mp = 269–270 °C. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.97 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.1 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.64 (app dd, J = 7.7, 6.1 Hz, 3H), 7.56–7.48 (m, 1H), 7.45 (dd, J = 7.4, 7.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.09–7.03 (m, 1H), 7.01–6.95 (m, 1H), 5.45–5.34 (m, 1H), 3.32 (dd, J = 14.6, 9.3 Hz, 1H), 3.19 (dd, J = 14.6, 5.9 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 166.0, 149.8, 136.1, 134.2, 132.3, 131.4, 128.3, 127.8, 127.3, 127.2, 123.5, 121.0, 119.0, 118.4, 118.3, 111.4, 110.8, 109.6, 54.1, 31.7. IR (thin film): νmax 3429, 3318, 2224, 1658, 1516, 1481, 745, 709, 566. HRMS calcd for C24H19N3NaO+ [M + Na]+ 388.1420; found 388.1416.

N-(1-(4-Cyanophenyl)-2-(1H-indol-3-yl)ethyl)-4-methoxybenzamide (3d)

To a stirred solution of amide 3b (604 mg, 1.1 mmol, 1 equiv) in THF/MeOH (8 mL/4 mL) was added KOH (308.6 mg, 5.5 mmol, 5 equiv). The reaction mixture was heated at 60 °C and stirred at that temperature for 10 h. The solvent was then removed under a reduced pressure and the resulting residue was taken up in water. The aqueous phase was extracted with CH2Cl2 (3 × 30 mL), and the combined organic layer was washed with brine, dried (NaSO4), and concentrated in vacuo to afford the free indole 3d as a white solid (437.7 mg, 1.1 mmol, quant yield). Rf = 0.25 (40% EtOAc/PE). Mp = 160–161 °C. 1H NMR (400 MHz, DMSO) δ 10.77 (d, J = 1.5 Hz, 1H), 8.81 (d, J = 8.1 Hz, 1H), 7.85–7.80 (m, 2H), 7.79 (app d, J = 8.3 Hz, 2H), 7.66–7.59 (m, 3H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.09–7.03 (m, 1H), 7.01–6.95 (m, 3H), 5.41–5.34 (m, 1H), 3.79 (s, 3H), 3.31 (dd, J = 14.7, 9.3 Hz, 1H), 3.18 (dd, J = 14.6, 6.0 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 165.3, 161.7, 150.0, 136.1, 132.2, 129.2, 127.7, 127.2, 126.4, 123.5, 121.0, 119.0, 118.4, 118.2, 113.5, 111.4, 110.9, 109.5, 55.4, 54.0, 31.7. IR (thin film): νmax 3367, 2930, 2229, 1607, 1505, 1257, 1178, 1027, 843, 744, 574. HRMS calcd for C25H21N3NaO2+ [M + Na]+ 418.1526; found 418.1528.

N-(1-(4-Cyanophenyl)-2-(1-methyl-1H-indol-3-yl)-ethyl)benzamide (3e)

A mixture of amide 3c (291.2 mg, 0.8 mmol, 1 equiv), MeI (1 mL, 16 mmol, 20 equiv), tetrabutylammonium bromide (TBAB, 774 mg, 2.4 mmol, 3 equiv), and 20% aq NaOH solution (10 mL) in CH2Cl2 (15 mL) was stirred at rt for 24 h. The biphasic reaction mixture was then diluted with water, and the resulting aqueous layer was extracted with additional CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography (1% Et3N in 25% EtOAc/PE) to give the N-methylated indole 3e as a white solid (250.5 mg, 0.66 mmol, 83%). Rf = 0.32 (30% EtOAc/PE). Mp = 253–255 °C. 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 8.1 Hz, 1H), 7.84–7.78 (m, 4H), 7.65 (app dd, J = 8.2, 1.7 Hz, 3H), 7.54–7.49 (m, 1H), 7.48–7.42 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.15–7.09 (m, 2H), 7.05–7.00 (m, 1H), 5.38 (ddd, J = 9.3, 8.1, 5.9 Hz, 1H), 3.69 (s, 3H), 3.32 (dd, J = 14.6, 9.3 Hz, 1H), 3.18 (dd, J = 14.6, 5.9 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 166.0, 149.7, 136.5, 134.3, 132.3, 131.4, 128.3, 127.9, 127.8, 127.5, 127.4, 121.1, 119.0, 118.6, 118.5, 110.2, 109.7, 109.6, 54.3, 32.3, 31.6. IR (thin film): νmax 3336, 3050, 2925, 2232, 1632, 1524, 834, 737. HRMS calcd for C25H21N3NaO+ [M + Na]+ 402.1577; found 402.1575.

N-(1-(4-Cyanophenyl)-2-(1-methyl-1H-indol-3-yl)-ethyl)-4-methoxybenzamide (3f)

A mixture of amide 3d (237 mg, 0.6 mmol, 1 equiv), MeI (0.74 mL, 12 mmol, 20 equiv), TBAB (580 mg, 1.8 mmol, 3 equiv), 20% NaOH solution (10 mL), and CH2Cl2 (15 mL) was stirred at rt for 31 h. The reaction mixture was then diluted with water and extracted with additional CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography (1% Et3N in 40% EtOAc/PE) to give the N-methylated indole 3f as a white solid (190.7 mg, 0.46 mmol, 78%). Rf = 0.38 (40% EtOAc/PE). Mp = 253–254 °C. 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 8.1 Hz, 1H), 7.84–7.80 (m, 2H), 7.79 (app d, J = 8.3 Hz, 2H), 7.63 (app d, J = 8.2 Hz, 3H), 7.35 (d, J = 8.2 Hz, 1H), 7.15–7.09 (m, 2H), 7.04–7.00 (m, 1H), 7.00–6.96 (m, 2H), 5.35 (app dd, J = 14.6, 8.5 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.30 (dd, J = 14.6, 9.2 Hz, 1H), 3.17 (dd, J = 14.6, 6.0 Hz, 1H); 13C NMR (101 MHz, DMSO) δ 165.4, 161.7, 149.9, 136.5, 132.2, 129.2, 127.9, 127.8, 127.5, 126.4, 121.1, 119.0, 118.6, 118.5, 113.5, 110.3, 109.6, 109.5, 55.4, 54.2, 32.3, 31.6. IR (thin film): νmax 3333, 2935, 2358, 2228, 1626, 1506, 1261, 1181, 1027, 839, 740. HRMS calcd for C26H23N3NaO2+ [M + Na]+ 432.1682; found 432.1686.

4-(1-Phenyl-9-tosyl-4,9-dihydro-3H-pyrido[3,4-b]indol-3-yl)benzonitrile (4a)

To a stirred mixture of amide 3a (519.2 mg, 1 mmol, 1 equiv) and 2-chloropyridine (0.12 mL, 1.2 mmol, 1.2 equiv) in CH2Cl2 (6 mL) at −78 °C was added Tf2O (0.19 mL, 1.1 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 30 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt at which the reaction mixture stirred for additional 14 h was quenched with sat aq NaHCO3 (30 mL) and was extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and titurated (CH2Cl2/EtOAc) to give dihydro-β-carboline 4a as a white solid (468.2 mg, 0.93 mmol, 93%). Rf = 0.40 (20% EtOAc/PE). Mp = 195–197 °C. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.92–7.87 (m, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.74–7.68 (m, 2H), 7.54–7.43 (m, 5H), 7.36–7.29 (m, 3H), 7.02 (d, J = 8.1 Hz, 2H), 4.58 (dd, J = 15.7, 5.7 Hz, 1H), 3.10 (dd, J = 17.2, 5.7 Hz, 1H), 2.68 (dd, J = 17.1, 15.9 Hz, 1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 149.0, 145.0, 140.0, 134.8, 132.7, 132.5, 129.8, 129.2, 128.9, 128.3, 128.2, 127.7, 127.1, 125.4, 120.5, 119.1, 117.9, 111.0, 61.0, 28.6, 21.7. IR (thin film): νmax 3063, 2224, 1536, 1368, 1177, 667, 575. HRMS calcd for C31H24N3O2S+ [M + H]+ 502.1584; found 502.1585.

4-(1-(4-Methoxyphenyl)-9-tosyl-4,9-dihydro-3H-pyrido[3,4-b]indol-3-yl)benzomitrile (4b)

To a stirred mixture of amide 3b (219.7 mg, 0.4 mmol, 1 equiv) and 2-chloropyridine (0.05 mL, 0.48 mmol, 1.2 equiv) in CH2Cl2 (6 mL) at −78 °C was added Tf2O (0.08 mL, 0.44 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 30 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt. The reaction mixture was stirred at this temperature for an additional 17 h, then quenched with sat aq NaHCO3 (30 mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and titurated with CH2Cl2/Et2O to give dihydro-β-carboline 4b as a yellow solid (134.6 mg, 0.25 mmol, 63%). Rf = 0.31 (20% EtOAc/PE). Mp = 170–172 °C. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H), 7.93–7.88 (m, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.72–7.68 (m, 2H), 7.49 (ddd, J = 8.4, 7.3, 1.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.35–7.28 (m, 3H), 7.02 (d, J = 8.1 Hz, 2H), 7.00–6.96 (m, 2H), 4.55 (dd, J = 15.5, 5.4 Hz, 1H), 3.87 (s, 3H), 3.08 (dd, J = 17.2, 5.6 Hz, 1H), 2.66 (app t, J = 16.4 Hz, 1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.0, 159.2, 149.3, 145.0, 140.1, 134.9, 132.7, 132.5, 129.8, 129.2, 129.1, 128.3, 128.1, 127.1, 125.4, 120.4, 119.2, 118.0, 113.5, 111.0, 60.8, 55.4, 28.7, 21.7. IR (thin film): νmax 3057, 2836, 2360, 2227, 1609, 1510, 1373, 1252, 1175, 574. HRMS calcd for C32H26N3O3S+ [M + H]+ 532.1689; found 532.1693.

4-(9-Methyl-1-phenyl-4,9-dihydro-3H-pyrido[3,4-b]indol3-yl)benzonitrile (4e)

To a stirred mixture of amide 3e (189.6 mg, 0.5 mmol, 1 equiv) and 2-chloropyridine (60 μL, 0.6 mmol, 1.2 equiv) in CH2Cl2 (6 mL) at −78 °C was added Tf2O (0.1 mL, 0.55 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 30 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt. The reaction mixture was stirred for additional 4 h at rt and then was quenched with sat aq NaHCO3 (30 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (1% Et3N in 60% CH2Cl2/PE) to give the dihydro-β-carboline 4e as a yellow solid (139.4 mg, 0.39 mmol, 77%). Rf = 0.53 (20% EtOAc/PE). Mp =198–200 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.69–7.63 (m, 5H), 7.52–7.45 (m, 3H), 7.41–7.33 (m, 2H), 7.21 (ddd, J = 8.0, 6.3, 1.7 Hz, 1H), 4.84 (dd, J = 15.6, 6.1 Hz, 1H), 3.37 (s, 3H), 3.28 (dd, J = 16.2, 6.1 Hz, 1H), 2.93 (app t, J = 15.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.4, 150.2, 139.7, 132.4, 131.4, 130.0, 128.8, 128.38, 128.36, 125.0, 124.5, 120.6, 120.2, 119.3, 110.73, 110.70, 62.9, 33.1, 28.3. IR (thin film): νmax 3697, 3053, 2224, 1522, 1375, 1014, 755. HRMS calcd for C25H20N3+ [M + H]+ 362.1652; found 362.1649.

4-(1-(4-Methoxyphenyl)-9-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-3-yl)benzonitrile (4f)

To a stirred mixture of amide 3f (73.6 mg, 0.18 mmol, 1 equiv) and 2-chloropyridine (0.02 mL, 0.20 mmol, 1.2 equiv) in CH2Cl2 (6 mL) at −78 °C was added Tf2O (0.03 mL, 0.18 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 30 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt. The reaction mixture was stirred for an additional 13 h, quenched with sat aq NaHCO3 (30 mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo, and titurated with Et2O/hexane to afford dihydro-β-carboline 4f as a yellow solid (71 mg, 0.18 mmol, quant yield). Rf = 0.40 (20% EtOAc/PE). Mp = 164–165 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.69–7.59 (m, 5H), 7.38–7.35 (m, 2H), 7.21 (ddd, J = 8.0, 5.7, 2.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.80 (dd, J = 15.4, 6.0 Hz, 1H), 3.88 (s, 3H), 3.42 (s, 3H), 3.26 (dd, J = 16.2, 6.0 Hz, 1H), 2.91 (app t, J = 15.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 161.3, 159.8, 150.2, 139.8, 132.4, 131.5, 131.3, 130.0, 128.4, 125.0, 124.6, 120.6, 120.2, 119.5, 119.3, 114.1, 110.8, 110.7, 62.6, 55.6, 33.2, 28.3. IR (thin film): νmax 3423, 2935, 2837, 2359, 2227, 1608, 1513, 1250, 1170, 1032, 841, 740. HRMS calcd for C26H22N3O+ [M + H]+ 392.1757; found 392.1751.

4-(1-Phenyl-9-tosyl-9H-pyrido[3,4-b]indol-3-yl)benzonitrile (5a)

To a solution of dihydro-β-carboline 4a (100.2 mg, 0.2 mmol, 1 equiv) in CH2Cl2 (4 mL) at rt and open to the air was added DDQ (45.4 mg, 0.2 mmol, 1 equiv). The resulting reaction mixture was stirred open to the air for 24 h, then quenched with sat aq NaHCO3 (20 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined organic layer was washed with brine, dried (NaSO4), filtered through a small pad of silica gel, and concentrated to give β-carboline 5a as a yellow solid (95 mg, 0.19 mmol, 95%). Rf = 0.42 (20% EtOAc/PE). Mp = 315–317 °C. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.5 Hz, 2H), 8.28 (d, J = 8.3 Hz, 1H), 8.22–8.17 (m, 2H), 8.02 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.64–7.59 (m, 1H), 7.55 (app t, J = 7.4 Hz, 2H), 7.51–7.45 (m, 1H), 7.45–7.39 (m, 1H), 7.01 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 2.17 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 151.1, 150.7, 144.8, 143.0, 142.1, 140.9, 139.9, 134.6, 132.7, 132.1, 130.2, 129.1, 129.0, 128.8, 128.3, 127.7, 127.4, 127.0, 126.0, 121.3, 119.7, 119.0, 112.4, 109.2, 21.6. IR (thin film): νmax 3060, 2225, 1612, 1376, 1172, 749, 688, 575. HRMS calcd for C31H21N3NaO2S+ [M + Na]+ 522.1247; found 522.1245.

4-(1-(4-Methoxyphenyl)-9-tosyl-9H-pyrido[3,4-b]indol-3-yl)benzonitrile (5b)

To a solution of dihydro-β-carboline 4b (200.8 mg, 0.38 mmol, 1 equiv) in CH2Cl2 (4 mL) at rt and open to the air was added DDQ (45.4 mg, 1.13 mmol, 3 equiv). The resulting reaction mixture was stirred open to the air for 18 h, quenched with water, and extracted with CH2Cl2 (3 × 30 mL). The combined organic extract was concentrated in vacuo. The resulting residue was first purified by flash chromatography (1% Et3N in 20% EtOAc/PE) and then titurated with CH2Cl2/Et2O to give β-carboline 5b as a white solid (140.7 mg, 0.26 mmol, 70%). Rf = 0.37 (20% EtOAc/PE). Mp = 296–298 °C. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 8.3 Hz, 1H), 8.23–8.18 (m, 2H), 7.95 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.63–7.57 (m, 1H), 7.41 (app t, J = 7.5 Hz, 1H), 7.10–7.04 (m, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 2.17 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.5, 150.9, 150.7, 144.8, 143.1, 142.7, 140.1, 134.3, 133.3, 132.6, 132.0, 130.3, 130.1, 129.0, 127.7, 127.6, 127.1, 126.0, 121.3, 119.8, 119.0, 113.7, 112.4, 108.6, 55.4, 21.6. IR (thin film): νmax 3424, 3064, 2836, 2361, 2226, 1611, 1514, 1364, 1252, 1176, 756, 573. HRMS calcd for C32H23N3NaO3S+ [M + Na]+ 552.1352; found 552.1352.

4-(1-Phenyl-9H-pyrido[3,4-b]indol-3-yl)benzonitrile (5c)

To a stirred solution of amide 3c (227.8 mg, 0.62 mmol, 1 equiv) and 2-chloropyridine (70 μL, 0.75 mmol, 1.2 equiv) in CH2Cl2 (9.3 mL) at −78 °C was added Tf2O (0.11 mL, 0.68 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 10 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt. The reaction mixture was stirred at this temperature for an additional 7 h, quenched with sat aq NaHCO3 (30 mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated by rotary evaporation. The resulting crude product was purified by flash chromatography (1% Et3N in 50% CH2Cl2/PE) to give the fully-oxidized β-carboline 5c as a yellow solid (166.8 mg, 0.48 mmol, 78%). Rf = 0.44 (20% EtOAc/PE). Mp = 349–351 °C. 1H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 8.95 (s, 1H), 8.50 (d, J = 8.4 Hz, 2H), 8.37 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.2 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.67 (app dd, J = 16.4, 8.1 Hz, 3H), 7.57 (app q, J = 7.5 Hz, 2H), 7.32 (app t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 144.2, 143.1, 141.72, 141.67, 138.1, 132.9, 132.6, 130.6, 128.8, 128.5, 126.7, 121.8, 121.8, 121.3, 119.9, 119.2, 112.7, 111.7, 109.8. IR (thin film): νmax 3346, 2926, 2225, 1604, 1445, 1254, 842, 748, 549. HRMS calcd for C24H16N3+ [M + H]+ 346.1339; found 346.1329.

4-(1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)benzonitrile (5d)

To a stirred mixture of amide 3d (139.1 mg, 0.35 mmol, 1 equiv) and 2-chloropyridine (0.04 mL, 0.42 mmol, 1.2 equiv) in CH2Cl2 (6 mL) at −78 °C was added Tf2O (0.07 mL, 0.39 mmol, 1.1 equiv) using a syringe. After stirring at −78 °C for 10 min, the reaction mixture was placed in an ice-water bath and allowed to reach rt. The reaction mixture was stirred at rt for an additional 1 h, quenched with sat aq NaHCO3 (30 mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (1% Et3N in 15 → 30% EtOAc/PE) to give 5d as a yellow solid (37.1 mg, 0.09 mmol, 28%). Rf = 0.40 (20% EtOAc/PE). Mp =292–294 °C. 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 8.89 (s, 1H), 8.49 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.58 (app t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.20 (d, i = 8.7 Hz, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, DMSO) δ 159.9, 144.3, 143.0, 141.7, 141.6, 132.7, 132.6, 130.6, 130.4, 129.8, 128.4, 126.7, 121.8, 121.3, 119.8, 119.2, 114.2, 112.7, 111.1, 109.7, 55.3. IR (thin film): νmax 3356, 2226, 1604, 1512, 1447, 1251, 1179, 1036, 840, 739, 548. HRMS calcd for C25H18N3O+ [M + H]+ 376.1444; found 376.1446.

4-(9-Methyl-1-phenyl-9H-pyrido[3,4-b]indol-3-yl)-benzonitrile (5e)

To a stirred solution of 5c (41.4 mg, 0.12 mmol, 1 equiv) and NaH (14.4 mg, 0.36 mmol, 3 equiv) in dry THF was added MeI (0.03 mL, 0.48 mmol, 4 equiv). The resulting reaction mixture was stirred for 15 h, quenched with ice-cold water, and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine, dried (NaSO4), and concentrated in vacuo. The crude product was purified by flash chromatography (1% Et3N in 10% EtOAc/PE) to afford β-carboline 5e as a white solid (36.2 mg, 0.10 mmol, 84%). Rf = 0.43 (10% EtOAc/PE). Mp = 231–232 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.32–8.27 (m, 2H), 8.24 (d, J = 7.8 Hz, 1H), 7.77–7.69 (m, 4H), 7.67–7.62 (m, 1H), 7.59–7.51 (m, 3H), 7.46 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 7.5, 7.5 Hz, 1H), 3.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.7, 144.3, 144.2, 143.5, 139.8, 135.1, 132.6, 131.2, 129.9, 128.9, 128.8, 128.4, 127.3, 121.6, 121.5, 120.4, 119.5, 110.9, 110.2, 33.2. IR (thin film): νmax 3427, 3056, 2221, 1623, 1456, 841, 744, 547. HRMS calcd for C25H18N3+ [M + H]+ 360.1495; found 360.1485.

4-(1-(4-Methoxyphenyl)-9-methyl-9H-pyrido[3,4-b]indol-3-yl)-benzonitrile (5f)

To a solution of dihydro-β-carboline 4f (156.5 mg, 0.4 mmol, 1 equiv) in CH2Cl2 (4 mL) at rt and open to the air was added DDQ (363.2 mg, 1.6 mmol, 4 equiv). The resulting reaction mixture was stirred open to the air for 16 h, then quenched with water, and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was concentrated in vacuo, and the resulting residue was purified by flash chromatography (1% Et3N in 10% EtOAc/PE) and then titurated with CH2Cl2/EtOAc to give β-carboline 5f as a white solid (66 mg, 0.17 mmol, 42%). Rf = 0.50 (20% EtOAc/PE). Mp = 280–281 °C. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.28 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.64 (app t, J = 8.5 Hz, 3H), 7.45 (d, J = 8.3 Hz, 1H), 7.36 (app t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 3.92 (s, 3H), 3.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.2, 144.6, 144.2, 144.0, 143.6, 135.1, 132.5, 132.1, 131.2, 131.2, 128.9, 127.3, 121.6, 120.4, 119.5, 113.8, 110.9, 110.6, 110.2, 55.6, 33.2. IR (thin film): νmax 3423, 2936, 2360, 2223, 1607, 1509, 1454, 1252, 836, 748. HRMS calcd for C26H20N3O+ [M + H]+ 390.1601; found 390.1599.