Transition-Metal-Free Access to Pyridocarbazoles from 2-Alkynylindole-3-carbaldehydes via Azomethine Ylide

Article abstract of DOI:10.1021/acs.joc.8b00980

An efficient approach for the synthesis of functionalized tetrahydro-pyrido/quinolinocarbazoles from 2-alkynylindole-3-carbaldehydes and l-proline utilizing a metal-free decarboxylative cyclization, ring expansion, and ring contraction strategy via the ge

Full text of DOI:10.1021/acs.joc.8b00980

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Article
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
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00980 • Publication Date (Web): 23 May 2018
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Transition-Metal-Free Access to Pyridocarbazoles
from 2-Alkynylindole-3-carbaldehydes via
Azomethine Ylide
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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: Email: averma@acbr.du.ac.in
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ABSTRACT: An efficient approach for the synthesis of functionalized tetrahydro-
pyrido/quinolinocarbazoles from 2-alkynylindole-3-carbaldehydes and L-proline utilizing a metal-free
decarboxylative cyclization, ring expansion, and ring contraction strategy via the generation of
azomethine ylide has been 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 hetero-annulated carbazoles can be synthesized efficiently.
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INTRODUCTION
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Hetero-annulated carbazole framework is an important core motifs present in the wide range of natural
products and pharmaceutically derived drugs.1 Among them, pyridocarbazoles is an integral part of
numerous natural products, bioactive alkaloids, and pharmaceuticals.2 Analogs of the pyridocarbazoles
such as 6H-pyridocarbazole (ellipticine, olivacine, elliprabin and ratelliptine) and 7H-pyridocarbazole
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exhibit prospective antitumor activity as an efficient DNA intercalating agents3 (Figure 1). Furthermore
metallo-pyridocarbazoles have been used as protein kinase inhibitors.4
,
Figure 1 Biologically important pyridocarbazoles derived anticancer agents
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 co-worker have explored the synthesis
of functionalized annulated carbazoles using ruthenium/copper/ palladium catalysts by heteroannulation
and intramolecular arylation.6 In 2005, 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 Das group.9a In
the same year, Kundu and co-worker reported the synthesis of annulated poly-heterocycles by exploiting
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decarboxylative cyclization under metal-free condition.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
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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-metal-catalyzed 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 analogs containing
fused tetrahydro-pyrido/quinoline ring from 2-alkynylindole-3-carbaldehydes which has not been much
explored and are still challenging.
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Scheme 1. Synthesis of Pyridocarbazoles Derivatives
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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 condition (Scheme 1c).
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RESULTS AND DISCUSSION
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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 accommodated a large variety of functional
groups and provided the coupling products 4a–v and 5a–b in good to excellent yields.
Scheme 2. Preparation of ortho-Alkynylaldehydes
In order to determine the optimal reaction conditions, a variety of additive and solvents were
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 perform the reaction of 4a with 6a using
DMF as a solvent, 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
o
screened using DMF as a solvent. Addition of 4 Å molecular sieves at 120 C provided the desired
o
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 9-10). Drop in the yield of product 7a was observed in the
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absence of molecular sieves (entry 11). Further increase in temperature, declined the yield of 7a (entry
12). Inferior results were obtained when acetic acid was used as an additive (entry 13). The product 7a
was fully characterized by 1H, 13C NMR, and HRMS.
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Table 1. Optimization of Reaction Conditionsa
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yield(%)b
7a
entry
additive (equiv)
solvent
T oC
time (h)
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DMF
DMA
DMSO
NMP
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
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120
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8 c
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10 c
11 d
12 c
13 c
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PhCOOH (0.2)
PhCOOH (0.3)
PhCOOH (0.4)
PhCOOH (0.2)
PhCOOH (0.2)
CH3COOH (0.2)
aReactions were performed using 0.5 mmol of 4a, 0.6 mmol of 6a in 2.0 mL
of solvent. bIsolated yield, c4 Å MS, dWithout molecular sieves
With the optimized reaction condition in hand, scope and generality of the reaction were
explored (Table 2). The N-protected substrates 4b–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 electron-donating and electron- withdrawing substituents. The o-
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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 9–10). Thiophene substituted o-alkynylaldehydes
4k-l were compatible to afford the products 7k and 7l in 75 and 80% yields respectively (entries 11–12).
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 was
successfully provided the desired product 7n–q in 54–62% yields (entries 14–17).
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Table 2. Scopes of Tetrahydropyridocarbazolesa,b
entry
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substrate
amine
product
yieldb (%)
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4b
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7b
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4g
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7g
7h
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6a
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7j
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4l
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4o
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4p
4q
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aReactions 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.
We further extended the scope of proline derivative such as L-hydroxyproline 6b with various
functionalized 2–alkynylindole–3–carbaldehydes under standard reaction condition (Table 3). Halogen-
containing substrates 4r,s were also found viable for the reaction and furnished the desired products 8a–
b in 58-60% yields (entries 1–2). The reaction of substrates 4b, 4a, 4d, 4k and 4s with L-
hydroxyproline 6b furnished the desired product 8c–g in 70–80% yield (entries 3–7).
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Table 3. The Scope of ortho-Alkynylaldehydes and Prolinea,b
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entry
substrate
amine
product
yieldb (%)
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4r
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8b
8c
6a
6a
HN
2
3
Cl
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N
H
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aReactions 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 1h. bIsolated yield.
Encouraged by the above results (Tables 2-3), 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 proline 6a and hydroxyproline 6b provided the
desired products 9a–c in 78 85% yield (Scheme 3).
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Scheme 3. Synthesis of Tetrahydroquinolino[7,8-b] carbazolesa,b
aReactions condition: o-alkynylaldehyde 4 (0.5 mmol), 6a-b (0.6 mmol) and benzoic acid (0.2 equiv) in
2.0 mL of DMF at 130 °C for 1-2 h. bIsolated yield.
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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).
Scheme 4. Ring Expansion vs Elimination
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aReaction Condition: This reaction performed using 0.5 mmol of 4, benzoic acid (0.2
o
b
equiv) and thioproline 6c (0.6 mmol) in 2.0 mL of solvent at 130 C for 4 h. Isolated
yield.
With this chemistry, we have synthesized γ-carbolines 10a–b in 78-80% yields under metal-free
condition. The electron-releasing and electron-withdrawing substrates were well tolerated to afford the
desired product 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–h in 70-78% yields. In addition, the reaction of 4n
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bearing aliphatic alkynes with 6c also allowed an easy access to the synthesis of γ-carbolines 10i in
moderate yield.
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Based on the enormous biological activity of pyridocarbazoles, we have achieved the synthesis of
pyrido [3,2-c]carbazoles 11a–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).
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Scheme 5. Synthesis of Pyrido/Quinolino Carbazoles
Based on the previous reports,8,9b,13 a plausible mechanism has been 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 intermediate C, D and E. In path a, B undergoes cyclopropane formation to furnish
intermediate C which subsequently undergoes ring expansion to generate intermediate D. 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 favourable 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.
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Scheme 6. Proposed Reaction Mechanism
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To find out the application of these compounds we have performed the molecular docking study of
eight compounds (8c–e, 9a–c, and 11a–b) and ellipticine18 (as standard) was done for finding their
binding modes with double-stranded DNA (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 rest of
molecules and ellipticine (-7.49). The presence of hydroxyl groups increases the hydrogen bonding
possibility with nucleotides along with Vander Waals interactions and pi-stacking in case of 9c.
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CONCLUSION
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In summary, we have developed an efficient, metal and 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 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-phenyl-2,3,4,8-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.
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General Experimental
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General Method.
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1H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded in CDCl3/DMSO-d6. Chemical
shifts for protons and carbons are reported in ppm from tetramethylsilane and are referenced to the
carbon resonance of the solvent. Data has been 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 electrospray
mass spectrometer. Crystal structure analysis was accomplished on single needles 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.
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Reagents: All reagents were used directly as obtained commercially unless otherwise noted. Anhydrous
forms of dimethylformamide, dimethylacetamide, dimethylsulfoxide, 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-b were readily
prepared by standard Sonogashira cross–coupling reaction of commercially available and readily
accessible o–haloaldehydes substrates with terminal alkynes (Scheme 2). This coupling procedure has
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-b were confirmed
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by comparison of their physical and spectral data (1H NMR and C NMR) with those 4b15a , (4i, 4l, 4u,
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4v) 15b and (5a-b)15c reported in the literature.
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2-(Phenylethynyl)-1H-indole-3-carbaldehyde (4a).The product was obtained as yellow needle (91.8 mg,
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75%): mp: 160–165 °C: H NMR (400 MHz, CDCl3) δ: 10.25 (s, 1H), 9.20 (brs, 1H), 8.27 (d, J = 7.3
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Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H) , 7.36–7.22 (m, 6H); C NMR (100 MHz, CDCl3) δ: 185.7, 135.8,
131.8, 129.7, 129.4, 128.6, 125.4, 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 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); 13C 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 pale yellow
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needle (107.2 mg, 78%): mp 145–150 °C: H 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–
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7.22 (m, 1H), 7.03 (t, J = 6.1 Hz, 2H), 3.80 (s, 3H); C 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 pale yellow
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needle (103.7 mg, 76%): mp 185–190 °C: H 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, 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.
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2-((4-tert-Butylphenyl)ethynyl)-1H-indole-3-carbaldehyde (4f). The product was obtained as pale yellow
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needle (123.4 mg, 82%) : mp 135–140 °C: H NMR (400 MHz, DMSO–d6) δ: 12.73(s, 1H), 10.19 (s,
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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
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(t, J = 7.6 Hz, 1H), 1.22 (s, 9H); C NMR (100 MHz, DMSO–d6) δ: 184.4, 152.9, 136.3, 131.5, 129.0,
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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 pale yellow
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needle (120.4 mg, 80%): mp 130–135 °C: H 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
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= 7.8 Hz, 2H), 1.49–1.43 (m, 2H), 1.26–1.21(m, 2H), 0.82 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
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 off-white
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needle (95.9 mg, 78%): mp 159–164 °C: H 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); 13C 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
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 (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.
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2-(Thiophen-3-ylethynyl)-1H-indole-3-carbaldehyde (4k).The product was obtained as 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.
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2-(Pyridin-2-ylethynyl)-1H-indole-3-carbaldehyde (4m). The product was obtained as 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 off white needle
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(93.4 mg, 75%) : mp 115–120 °C: H 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–
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6.41 (m, 1H), 2.27–2.15 (m, 4H), 1.65–1.55 (m, 4H); C 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 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.
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2-(Cyclopropylethynyl)-1H-indole-3-carbaldehyde (4q).The product was obtained as pale yellow needle
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(75.2 mg, 72%) : mp 100–105 °C: H NMR (400 MHz, DMSO–d6) δ: 12.50 (s, 1H), 9.99 (s, 1H), 8.04
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(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),
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1.01–0.96 (m, 2H), 0.91–0.88 (m, 2H); C NMR (100 MHz, DMSO–d6) δ: 184.3, 135.9, 130.2, 124.6,
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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 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 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 = 7.8Hz, 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 Brown
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needle (102.9 mg, 82%): mp 150–155 °C: H 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); 13C 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), L-proline 6 (0.6 mmol)
with benzoic acid (0.2 equiv) in 2.0 mL of dry DMF were added under inert atmosphere. The resulting reaction
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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).
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5-Phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7a). The product was obtained as off white
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needle, mp: 165–170 °C (96.2 mg, 65%), H 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,
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2H), 2.76 (t, J = 5.9 Hz, 2H), 2.00–1.95 (m, 2H); C 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
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yellow needle (109.2 mg, 70%); mp 185–190 °C; H 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,
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2H), 2.78 (t, J = 6.4 Hz, 2H), 2.02–1.96 (m, 2H); C 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 brown
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needle (112.0 mg, 60%); mp 180–185 °C; H 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,
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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.
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5-(4-Methoxyphenyl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7d). The product was obtained as
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),
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1.82–1.77 (m, 2H); C 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
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yellow needle (127.0 mg, 78%); mp 115–120 °C; H 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,
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2H), 2.75–2.68 (m, 4H),1.96–1.91 (m, 2H), 1.29 (t, J = 7.8 Hz, 3H); C 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
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off-white needle (125.6 mg, 71%); mp210–215 °C; H 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),
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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); C 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 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),
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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.
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5-m-Tolyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7h). The product was obtained as 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-1H-pyrido[3,2-c]carbazole
(7i).
The
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product was obtained as off–white needle (123.0 mg, 62%); mp 150–155 °C; H 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 [3,2-c]carbazole (7j). The product was
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obtained as red brown needle (99.6 mg, 60%); mp 115–120 °C; H 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,
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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); 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,
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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.
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5-(Thiophen-3-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (7k). The product was obtained as red
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brown needle (114 mg, 75%) ; mp 105–110 °C; H NMR (400 MHz, CDCl3) δ: 7.85–7.83(m, 2H),
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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 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
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brown needle (97.0 mg, 65%); mp 180–185 °C; H 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),
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2.71 (t, J = 5.9 Hz, 2H), 1.82–1.76 (m, 2H); C 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
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as off-white needle (102.0 mg, 60%); mp 125–130 °C; H 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,
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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
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brown needle (93.6 mg, 62%); mp 115–120 °C; H NMR (400 MHz, DMSO–d6) δ: 10.81 (s, 1H), 8.13
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(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,
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2H),1.71–1.63 (m, 4H); C 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 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 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
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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); C 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
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brown needle (109.0 mg, 58%); mp 110–115 °C; H NMR (400 MHz, CDCl3) δ: 7.94 (s, 1H), 7.86 (s,
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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).
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10-Chloro-5-phenyl-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazole (8b). The product was obtained as
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 dark brown needle (121.3 mg, 74%); mp 130–135 °C;1H NMR (400 MHz, CDCl3) 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
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 (ESI-TOF) 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
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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.
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(R)-5-(Thiophen-3-yl)-2,3,4,7-tetrahydro-1H-pyrido[3,2-c]carbazol-3-ol (8f). The product was obtained
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as brown needle (124.8 mg, 78%); mp 100–105 °C; H 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–
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3.51 (m, 1H), 3.17–3.12 (m, 1H), 2.82–2.83 (m, 1H), 2.73–2.48 (m, 1H); C 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
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obtained as dark brown needle (111.6 mg, 64%); mp 110–115°C; H 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 round bottom flask, a solution of o-alkynylheteroarylaldehyde 5a-b (0.5 mmol), L-proline 6
(0.6mmol), benzoic acid (0.2 equiv) and 4Å molecular sieves in 2.0 mL in dry DMF were added under inert
atmosphere. The resulting reaction mixture was heated at 130°C for 3-4h. The reaction mixture was diluted
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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:ethylacetate; 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).
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8-Ethyl-5-phenyl-2,3,4,8-tetrahydro-1H-quinolino[7,8-b] carbazole (9a). The product was obtained as a
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yellow solid (150.6 mg, 85%); mp 275–280 °C; H 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[7,8-b]carbazoles (9b).The product was
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obtained as a yellow needle (160.1 mg, 82%); mp 270–275 °C; H 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,
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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.
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General Procedure for the Synthesis of Functionalized γ-Carbolines 10a-i.
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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 4Å molecular sieves in 2.0 mL dry DMF were added under inert
atmosphere. The resulting reaction mixture was heated at 130°C for 2−4h. 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:ethylacetate; 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); 13C 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
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mg, 78%); mp 120−125 °C; 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,
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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.
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(111.1 mg, 82%); mp 121–126 °C; H NMR (400 MHz, CDCl3) δ: 9.29 (s, 1H), 8.11 (d, J = 7.92 Hz,
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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, 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
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needle (117 mg, 75%); mp 124–129 °C; H NMR (400 MHz, DMSO-d6) δ: 11.89 (s, 1H), 9.44 (s, 1H),
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Hz, 1H),7.49 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 6.9 Hz, 1H); C 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
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brown needle (128.4 mg, 79%): mp 124−129 °C; H 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); 13CNMR (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,
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