Pd(0)-Catalyzed Intramolecular Heck reaction of 2/3-Aryl(amino)methyl-3/2-bromoindoles: Syntheses of 3,4-Benzo[ c]-β-carbolines, Benzo[4,5]isothiazolo[2,3- a]indole 5,5-Dioxides, and 1,2-Benzo[ a]-γ-carbolines

Article abstract of DOI:10.1021/acs.joc.0c02152

One-pot synthesis of 3,4-benzo[c]-β-carbolines was achieved from 2-aryl(tosylamino)methyl-3-bromoindoles via 10 mol % Pd(OAc)2/PPh3-mediated intramolecular Heck coupling using K2CO3 as a base in DMF at 110 °C with concomitant aromatization through an elimination of tosylsulfinic acid. Under identical conditions, the isomeric 3-aryl(tosylamino)methyl-2-bromoindoles upon intramolecular Heck reaction furnished benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxides instead of the expected γ-carbolines. However, synthesis of the expected γ-carboline framework, 3-tosyl-6,9-dihydro-1,2-benzo[a]-γ-carbolines, could be achieved from 3-aryl(tosylamino)methyl-2-bromoindoles containing a mesitylene sulfonyl unit as a protecting group on the indole nitrogen.

Full text of DOI:10.1021/acs.joc.0c02152

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Pd(0)-Catalyzed Intramolecular Heck reaction of 2/3-
Aryl(amino)methyl-3/2-bromoindoles: Syntheses of 3,4-Benzo[c]‑β-
carbolines, Benzo[4,5]isothiazolo[2,3‑a]indole 5,5-Dioxides, and 1,2-
Benzo[a]‑γ-carbolines
Potharaju Raju,† Velu Saravanan,† Vinayagam Pavunkumar, and Arasambattu K. Mohanakrishnan*
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ABSTRACT: One-pot synthesis of 3,4-benzo[c]-β-carbolines was
achieved from 2-aryl(tosylamino)methyl-3-bromoindoles via 10
mol % Pd(OAc)2/PPh3-mediated intramolecular Heck coupling
using K2CO3 as a base in DMF at 110 °C with concomitant
aromatization through an elimination of tosylsulfinic acid. Under
identical conditions, the isomeric 3-aryl(tosylamino)methyl-2-
bromoindoles upon intramolecular Heck reaction furnished
benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxides instead of the expected γ-carbolines. However, synthesis of the expected γ-
carboline framework, 3-tosyl-6,9-dihydro-1,2-benzo[a]-γ-carbolines, could be achieved from 3-aryl(tosylamino)methyl-2-
bromoindoles containing a mesitylene sulfonyl unit as a protecting group on the indole nitrogen.
arbolines are pyridine-fused indole heterocycles present
in many natural products and bioactive compounds.
C
Among the four regioisomeric α-, β-, γ-, and δ-carbolines, β-
carbolines are most extensively dispersed in nature. β-
Carboline units are present in a wide variety of indole
alkaloids.1 The β-carboline-based alkaloids possess significant
biological activities such as antiplasmodial, antithrombotic,
parasiticidal, anti-HIV, anti-Alzheimer, and antifungal effects.2
These compounds are known for their cytotoxicity, DNA
intercalation, and topoisomerase inhibition.3 Traditionally, β-
carbolines and their derivatives are obtained via Bischler−
Napieralski, Fischer indolization, and Pictet−Spengler cycliza-
tion reactions.4
Some of the recently reported methodologies to access β-
carbolines (Figure 1) involve Pd-catalyzed coupling of 3-iodo-
2-iminoindole with substituted acetylene derivatives followed
by cyclization,5 Bu3SnH-mediated radical cyclization of 3-
bromo-2-aryl-(N-tosylamino)methylindole,6 and regioselective
Buchwald−Hartwig amination followed by Heck-type intra-
molecular arylation of 3-(2-bromophenylamino)quinolines,7
electrocyclization of imino ether precursors,8 Pd(0)-catalyzed
coupling of indole with 1-iodo-2-nitrobenzene followed by
reductive cyclization,9 Pd(II)-catalyzed coupling of 2-iminoin-
dole with acetylene derivatives followed by cyclization,10
Ullmann cross-coupling of 2-iodocyclohex-2-en-1-ones with
3-nitro-4-iodopyrdine followed by Pd-catalyzed sequential
reductive cyclization and dehydrogenation,11 and condensation
of an in situ generated 1,5-diketone with ammonia.12 Apart
from these reports, Mulcahy and co-workers outlined the
synthesis of pyrido[3,4-b]indoles utilizing Rh(I)-catalyzed
cyclization methodology.13 Tilve and Volvoikar reported the
Figure 1. Summary of recent strategies for β-carboline synthesis.
synthesis of indolo[2,3-c]quinoline and indolo[3,2-c]quinoline
salts involving I2/TBHP-mediated intramolecular dehydrogen-
ative coupling reaction.14 Very recently, Vyalyh and co-workers
reported the synthesis of carbolines involving LDA-mediated
Received: September 6, 2020
Published: January 4, 2021
https://dx.doi.org/10.1021/acs.joc.0c02152
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 1925−1937
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cycloaddition of 3-benzoyl-2-methylindole with nitriles.15
Invariably, most of these methods suffer from disadvantages
such as restricted substitution and harsh reaction conditions.
Our strategy is to utilize N-aryltryptamine as well as N-
arylisotryptamine precursors for the construction of cyclo-
fused carbolines via intramolecular Heck coupling of N-((3/2-
bromo-1-(phenylsulfonyl)-1H-indol-2/3-yl)methyl)-4-methyl-
N-arylbenzenesulfonamides. To initiate this work, the known
3-bromo-2-bromomethylindole 16 was reacted with 4-methyl-
N-phenylbenzenesulfonamide 2a in the presence of K2CO3 in
DMF to afford 2-(phenylaminomethyl)-3-bromoindole 3a in
75% yield. Initially, intramolecular Heck coupling of 2-
(phenylaminomethyl)-3-bromoindole 3a using 10 mol %
Pd(PPh3)4 in the presence of K2CO3 in DMF at 100 °C for
12 h led to the isolation of benzo-β-carboline 4a in 36% yield.
Subsequently, the intramolecular coupling reaction employing
an in situ generated zerovalent Pd (10 mol %) using
Pd(OAc)2−PPh3 in the presence of K2CO3 in DMF at 110
°C for 6 h gave the benzo-β-carboline 4a in 78% yield (Scheme
1).
Table 1. Synthesis of Benzo-β-carbolines 4b−i
Scheme 1. Synthesis of Benzo-β-carboline 4a
Having achieved the synthesis of β-carboline 4a, next,
synthesis of β-carboline derivatives having different substitu-
ents on the benzene portion was planned. With that idea in
mind, the required 2-arylaminomethyl-3-bromoindoles 3b−i
were prepared via the reaction of 3-bromo-2-bromomethy-
lindole 1 with substituted 4-methyl-N-arylbenzenesulfona-
mides 2b−i using K2CO3 in DMF at room temperature for
12 h. As expected, 2-arylaminomethyl-3-bromoindole 3b−i
upon reaction with 10 mol % Pd(OAc)2−PPh3(20 mol %) and
K2CO3 in DMF at 110 °C for 6 h underwent intramolecular
coupling followed by a subsequent tosyl group elimination to
furnish the respective β-carbolines 4b−i in 65−90% yields
(Table 1). It should be noted that the Pd-catalyzed
intramolecular coupling of 2-piperonylaminomethyl-3-bro-
moindole 3g furnished β-carboline 4g as an exclusive product
in 78% yield. To our delight, the synthesis of naptho[b]-β-
carboline 4h was also achieved by an intramolecular Heck
coupling of the respective 2-naphthylaminomethyl-3-bromoin-
dole 3h. The 2-phenylaminomethyl-3-bromoindole 3i contain-
ing an electron-withdrawing acetyl unit in the benzene portion
also underwent the Pd-catalyzed intramolecular coupling
reaction followed by aromatization to afford the respective β-
carboline 4i in 65% yield. Except in the case of 3-bromoindole
3i, in all other cases, the 10% Pd(0)-catalyzed intramolecular
cyclization followed by base-mediated elimination of p-
toulenesulfinic acid furnished the corresponding β-carbolines
in very good yields. The structures of the β-carbolines 4a and
4h were confirmed by single-crystal X-ray diffraction analyses
(see the SI).
a
β-Carbolines 4b−i were obtained using 3-bromoindole 3b−i (1
equiv), Pd(OAc)2 (10 mol %), PPh3(20 mol %), and K2CO3 (3
equiv) in DMF at 110 °C under N2 atmosphere for 6 h. Isolated
yield of β-carbolines 4b−i by column chromatography.
b
Based on the facile synthesis of benzo-β-carbolines 4a−i,
next, the synthesis of 4-susbtituted β-carboline was planned by
employing the similar sequence of reactions. As expected, the
reaction of 3-bromo-2-phenylsulfonylaminomethylindole 516
with allyl bromide/cinnamyl bromide using K2CO3 in CH3CN
at reflux led to the formation of 3-bromoindoles 6a and 6b,
respectively. Using the established conditions as mentioned
above, compound 6a/6b underwent smooth Pd(0)-catalyzed
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intramolecular Heck coupling followed by aromatization to
furnish β-carbolines 7a and 7b in 76% and 80% yields,
respectively (Scheme 2).
Table 2. Synthesis of Benzo[4,5]isothiazolo[2,3-a]indole
5,5-dioxides 10b−g
Scheme 2. Synthesis of 4-Substituted β-Carbolines 7a and
7b
Having achieved the synthesis of β-carboline derivatives 4a−
i/7a/7b, next, the synthesis of γ-carboline congeners involving
the Pd-catalyzed intramolecular coupling reaction of isomeric
2-bromoindoles was initiated. Accordingly, the required
starting material, 2-bromo-3-arylaminomethylindole 9a, was
prepared via the reaction of 2-bromo-3-bromomethyl-1-
phenylsulfonylindole 8 with 4-methyl-N-phenylbenzenesulfo-
namide 2a using K2CO3 as base in DMF at room temperature.
However, the Pd-catalyzed intramolecular Heck coupling
reaction of 2-bromo-3-phenylaminomethylindole 9a in the
presence of K2CO3 in DMF at 110 °C for 4 h failed to produce
the expected benzo-γ-carboline 11 (Scheme 3). On the basis of
Scheme 3. Pd-Catalyzed Cyclization of 2-Bromo-3-
phenylaminomethylindole 9a
1
the H and 13C NMR spectral data, the structure of the
unusual product obtained during the Pd-catalyzed intra-
molecular coupling reaction of 9a was assigned as a
sulfonamide 10a. The formation of the sulfonamide 10a
clearly confirmed that the phenyl group of 3-phenyl-
aminomethylindole 9a is not in the proximal position of the
intermediate 2-indolyl-Pd species to induce the required
coupling reaction with the 2-position of N-tosylaniline to
yield the expected γ-carboline 11. Obviously, the 2-indolyl-Pd
species formed underwent facile intramolecular coupling
reaction with the N-phenylsulfonyl group to give the
sulfonamide 10a. A survey of the literature indicated that
Laha and co-workers17 recently observed a similar type of
sulfonamide formation involving Pd-catalyzed CH activation of
N-phenylsulfonylindoles.
Toward unravelling the electronic influence of aryl units on
the observed Pd-catalyzed coupling reaction, a series of 2-
bromo-3-arylaminomethylindoles 9b−g containing different
substituents were prepared from 3-bromomethylindole 8. As
expected, the coupling reaction of 2-bromo-3-arylaminome-
thylindoles 9b−g using Pd(OAc)2−PPh3 in the presence of
K2CO3 as a base in DMF followed by workup afforded, only,
the respective sulfonamides 10b−g as the exclusive products
(Table 2). The 1H and 13C NMR spectral data of sulfonamides
10b−g were consistent with their structures.
a
Indole sulfonamides 10b−g were obtained using 2-bromoindole
9b−g (1 equiv), Pd(OAc)2 (10 mol %), PPh3(20 mol %), and K2CO3
(3 equiv) in DMF at 110 °C under N2 atmosphere for 4 h. Isolated
yield of indole sulfonamides 10b−g by column chromatography.
b
The 2-bromo-3-bromomethyl-1-phenylsulfonylindole 8
upon reaction with 3,4-methylenedioxyanilinylsulfonamide 2g
using K2CO3 in dry DMF gave compound 9h in 78% yield. To
our surprise, intramolecular Heck coupling reaction of 9h
using Pd(OAc)2/PPh3 and K2CO3 in DMF at 110 °C for 6 h
followed by workup furnished sulfonamide 10h and γ-
carboline 12 in 35% and 34% yields, respectively. The
formation of γ-carboline 12 could be realized through the
intramolecular coupling reaction of 9h followed by base-
mediated migration of the tosyl group to give dihydrocarboline
14. The dihydrocarboline 14 uponsubsequent aromatization
could lead to the formation of γ-carboline 12 (Scheme 4). As a
representative case, the structure of sulfonamide 10h could be
confirmed by a single-crystal X-ray diffraction analysis (see SI).
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Scheme 4. Pd-Catalyzed Cyclization of 2-Bromo-3-
piperonylaminomethylindole 9h
Scheme 6. Synthesis of 1-Mesitylenesulfonyl-2-bromo-3-
aryl-N-tosylaminomethylindoles 19a−d
Scheme 7. Pd-Catalyzed Cyclization of 1-
Mesitylenesulfonyl-2-bromo-3-aryl-N-
tosylaminomethylindoles 19a−d
Next, 2-bromo-3-bromomethyl-1-phenylsulfonylindole 8
upon reaction with the 4-methylbenzenesulfonamide in
acetonitrile at reflux gave 2-bromo-3-N-tosylaminomethyl-1-
phenylsulfonylindole 15. Then the subsequent N-alkylation of
compound 15 with allyl bromide afforded allylaminomethy-
lindole 16 in 85% yield. As expected, the Pd(0)-catalyzed Heck
coupling reaction of compound 16 led to the formation of γ-
carboline derivative 17 as an exclusive product in 79% yield
(Scheme 5).
tosylaminomethyl-2-bromoindole 19b using Pd(0) with an
excess of K2CO3 in DMF at 130 °C for 36 h led to the isolation
dihydro-γ-carboline 20c and benzo-γ-carboline 21 in 42% and
26% yields, respectively.
The probable mechanism for the formation of carbolines 4a
and 20a as well as benzo[4,5]isothiazolo[2,3-a]indole 5,5-
dioxide 10a is outlined (see SI Figure 1 [DMH]).
Scheme 5. Pd-Catalyzed Cyclization of 2-Bromo-3-allyl-N-
tosylaminomethylindole 16
Finally, the representative N-sulfonyl-β-carbolines 4a−c
could be hydrolyzed using 30% NaOH in DMSO at room
temperature to give N-free β-carbolines 22a−c (Scheme 8). As
a representative case, gram-scale synthesis of benzo-β-carboline
4a as well as benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxide
10f could be achieved in acceptable yields.
Contrary to the 2-bromo-3-arylaminomethylindoles 9b−g,
the allylaminomethylindole 16 underwent an exclusive intra-
molecular Heck coupling with vinyl unit rather than the
intramolecular coupling reaction with an N-phenylsulfonyl
group.
Scheme 8. Cleavage of the N-Phenylsulfonyl Unit of
Representative β-Carbolines 4a−c [DM2]
To overcome the unexpected intramolecular Heck coupling
of 2-bromoindole with the N-benzenesulfonyl unit, synthesis of
2-bromomethylindoles containing a 2-mesitylenesulfonyl
(Mts) unit at the indole-1-position was initiated. Accordingly,
the required bromomethylindole 18 was prepared via N-
mesitylsulfonylation of 3-methylindole followed by ring
bromination and subsequent benzylic bromination to give 1-
(mesitylenesulfonyl)-2-bromo-3-bromomethylindole 18. The
N-alkylation of bromomethylindole 18 with N-arylbenzene-
sulfonamide 2a,b/2j/2k in the presence of K2CO3 as a base in
DMF at room temperature furnished the 3-arylaminomethyl-2-
bromoindoles 19a−d in 78−90% yields (Scheme 6).
Gratifyingly, the intramolecular Heck coupling reaction of
the 3-phenylaminomethyl-2-bromoindoles 19a−d using Pd(0)
in the presence of K2CO3 in DMF at 110 °C for 24 h gave the
respective dihydro-γ-carbolines 20a−d in 62−76% yields
(Scheme 7). As a representative case, the intramolecular
Heck coupling reaction of the 3-(4-methylphenyl)-
In summary, we have developed an efficient one pot
synthesis of 3,4-benzo[c]-β-carbolines involving the Pd-
catalyzed intramolecular Heck coupling reaction of 2-aryl-
(tosylamino)methyl-3-bromoindoles. The methodology was
found to be useful for accessing 4-substituted β-carbolines as
well. In the case of isomeric 3-aryl(tosylamino)methyl-2-
bromoindoles, the Pd-catalyzed intramolecular Heck coupling
led to the formation of benzo[4,5]isothiazolo[2,3-a]indole 5,5-
dioxides instead of the expected γ-carbolines. However, the 3-
aryl(tosylamino)methyl-2-bromoindoles containing mesityle-
nesulfonyl unit on the indole nitrogen underwent Pd(0)-
mediated intramolecular Heck coupling reaction to furnish the
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135.6, 135.3, 134.0, 131.3, 129.3 (2C), 129.1, 128.8, 128.4, 126.8,
126.4, 124.3, 120.1, 115.3, 107.3, 46.0, 21.5, 21.0 ppm. Anal. Calcd for
C29H25BrN2O4S2: C, 57.14; H, 4.13; N, 4.60; S, 10.52. Found: C,
57.31; H, 3.96; N, 4.81; S, 10.37.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-(4-
chlorophenyl)-4-methylbenzenesulfonamide (3c). The reaction of
3-bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosyl-
4-chloroaniline 2c (196 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) following the general procedure gave
sulfonamide 3c as a colorless solid (249 mg, 68%). Mp: 188−190 °C.
1H NMR (300 MHz, CDCl3): δ 7.99 (d, J = 8.4 Hz, 1H), 7.70 (d, J =
7.8 Hz, 2H), 7.52−7.46 (m, 3H), 7.36 (t, J = 7.35 Hz, 2H), 7.26 (t, J
= 7.35 Hz, 2H), 7.20−7.14 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.65 (d,
J = 8.7 Hz, 2H), 5.23 (s, 2H), 2.35 (s, 3H) ppm. 13C{1H} NMR (75
MHz, CDCl3): δ 144.0, 138.3, 136.6, 136.4, 134.3, 134.2, 134.0,
130.7, 130.4, 129.5, 129.4, 128.6, 128.4, 128.2, 126.7 (2C), 124.4,
120.1, 115.2, 107.4, 45.8, 21.6 ppm. Anal. Calcd for
C28H22BrClN2O4S2: C, 53.38; H, 3.52; N, 4.45; S, 10.18. Found: C,
53.21; H, 3.36; N, 4.58; S, 9.96.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-(4-me-
thoxyphenyl)-4-methylbenzenesulfonamide (3d). The reaction of 3-
bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosyl-4-
methoxyaniline 2d (194 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) adopting the general procedure afforded
sulfonamide 3d as a colorless solid (288 mg, 79%). Mp: 175−177 °C.
1H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 1H), 7.73 (d, J =
required γ-carboline frameworks in reasonable yields. Thus, by
the appropriate choice of protecting group on the indole
nitrogen, the Pd(0)-catalyzed Heck coupling reaction can be
fine tuned to access a wide variety of carboline as well as
benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxide heterocycles.
The structures of the representative benzo[c]β-carbolines
and benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxide were con-
firmed through single-crystal X-ray analyses.
EXPERIMENTAL SECTION
■
General Methods. All melting points were uncorrected. Solvents
were dried by standard procedures. All of the experiments were
carried out under nitrogen atmosphere unless otherwise stated.
Reactions other than room temperature were carried out in an oil
bath. The progression of all of the reactions was monitored by TLC
using a hexanes/ethyl acetate (EA) mixture. Column chromatography
was carried out on silica gel (230−400 mesh, Merck) by increasing
1
the polarity. H, 13C, and DEPT spectra were recorded in CDCl3
using TMS as an internal standard on Bruker 300 and 400 MHz
spectrometers at room temperature. Chemical shift values are quoted
in parts per million (ppm), and coupling constants are quoted in hertz
(Hz). HRMS were recorded on Xevo G2S QTof instrument.
3-Bromo-2-(bromomethyl)-1-(phenylsulfonyl)-1H-indole
(1). To a solution of 3-bromo-2-methyl-1-phenylsulfonylindole (1 g,
2.86 mmol) in CCl4 (30 mL) were added NBS (0.66 g, 3.72 mmol)
and AIBN (0.1 g, 0.28 mmol), and the solution was refluxed for 1 h.
After completion of the reaction (monitored by TLC), the floated
succinimide was filtered off and filtrate was concentrated under
reduced pressure. The crude product was crystallized from methanol
(3 mL) to afford 3-bromo-2-bromomethylindole 1 as a colorless solid
(1.12 g, 92%). Mp: 100−102 °C. 1H NMR (300 MHz, CDCl3): 8.14
(d, J = 8.4 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.60−7.52 (m, 2H),
7.48−7.37 (m, 3H), 7.35−7.32 (m, 1H), 5.14 (s, 2H) ppm. 13C{1H}
NMR (75 MHz, CDCl3)138.5, 136.3, 134.2, 133.3, 129.3, 128.6,
127.1, 124.6, 120.3, 115.0, 106.1, 22.6 ppm.
General Procedure for the Preparation of Compounds 3a−
i. To a solution of 3-bromo-2-bromomethylindole 1 (0.58 mmol) in
DMF (10 mL) were added N-tosylanilines 2a−i (0.70 mmol) and
K2CO3 (1.75 mmol). The reaction mixture was stirred at room
temperature for 12 h. After completion of the reaction (monitored by
TLC), the mixture was poured over crushed ice containing concd
HCl (5 mL). The solid obtained was filtered, washed with water (2 ×
20 mL), and dried (Na2SO4). The crude product was recrystallized
from methanol (5 mL) to afford sulfonamides 3a−i.
7.5 Hz, 2H), 7.50−7.48 (m, 3H), 7.39−7.35 (m, 2H), 7.28−7.17 (m,
5H), 6.59 (d, J = 7.2 Hz, 2H), 6.46 (d, J = 7.8 Hz, 2H), 5.23 (s, 2H),
3.58 (s, 3H), 2.36 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
159.0, 143.6, 138.4, 136.4, 134.8, 134.1, 130.9, 130.7, 130.2, 129.3,
128.5, 128.3, 126.7, 126.5, 124.2, 120.1, 115.2, 113.6, 107.3, 55.2,
45.9, 21.6 ppm. Anal. Calcd for C29H25BrN2O5S2: C, 55.68; H, 4.03;
N, 4.48; S, 10.25. Found: C, 55.58; H, 4.26; N, 4.57; S, 10.01.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-(2,4-di-
methoxyphenyl)-4-methylbenzenesulfonamide (3e). The reaction
of 3-bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-
tosyl-2,4-dimethoxyaniline 2e (215 mg, 0.70 mmol) using K2CO3
(241 mg, 1.75 mmol) in DMF (10 mL) following the general
procedure furnished sulfonamide 3e as a colorless solid (286 mg,
1
75%). Mp: 70−72 °C. H NMR (300 MHz, CDCl3): δ 7.96 (d, J =
8.1 Hz, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.42
(t, J = 7.2 Hz, 1H), 7.32−7.11 (m, 5H), 6.79 (d, J = 8.7 Hz, 1H),
6.11−6.04 (m, 4H), 5.43−5.27 (m, 2H), 3.60 (s, 3H), 3.15 (s, 3H),
2.31 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 160.8, 157.8,
142.6, 138.0, 137.3, 136.4, 134.0, 133.9, 132.1, 129.1, 128.9, 128.7,
128.0, 126.6, 126.3, 124.2, 120.0, 118.5, 115.3, 107.6, 103.7, 98.5,
55.3, 54.4, 45.1, 21.5 ppm. Anal. Calcd for C30H27BrN2O6S2: C,
54.96; H, 4.15; N, 4.27; S, 9.78. Found: C, 55.23; H, 4.43; N, 4.00; S,
10.02.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-4-methyl-
N-phenylbenzenesulfonamide (3a). The reaction of 3-bromo-2-
bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosylaniline 2a
(172 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75 mmol) in DMF
(10 mL) following the general procedure as mentioned above
furnished sulfonamide 3a as a colorless solid (260 mg, 75%). Mp:
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-(3,5-di-
methoxyphenyl)-4-methylbenzenesulfonamide (3f). The reaction
of 3-bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-
tosyl-3,5-dimethoxyaniline 2f (241 mg, 0.70 mmol) using K2CO3
(241 mg, 1.75 mmol) in DMF (10 mL) adopting the general
procedure afforded sulfonamide 3f as a colorless solid (344 mg, 90%).
1
220−222 °C. H NMR (300 MHz, CDCl3): δ 7.97 (d, J = 8.7 Hz,
1H), 7.72 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 7.5 Hz, 3H), 7.35 (t, J = 7.5
Hz, 2H), 7.25−7.13 (m, 5H), 7.00−6.93 (m, 3H), 6.70 (d, J = 7.2 Hz,
2H), 5.26 (s, 2H), 2.33 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 143.7, 138.2, 137.9, 136.4, 134.6, 134.1, 130.8, 129.4,
129.3, 128.5, 128.3, 128.2, 128.1, 126.7, 126.5, 124.2, 120.0, 115.1,
107.3, 45.9, 21.6 ppm. Anal. Calcd for C28H23BrN2O4S2: C, 56.47; H,
3.89; N, 4.70; S, 10.77. Found: C, 56.32; H, 3.65; N, 4.38; S, 10.92.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-4-methyl-
N-p-tolylbenzenesulfonamide (3b). The reaction of 3-bromo-2-
bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosyl-4-
methylaniline 2b (183 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) adopting the above-mentioned general
procedure afforded sulfonamide 3b as a colorless solid (290 mg,
82%). Mp: 185−187 °C. 1H NMR (300 MHz, CDCl3): δ 8.09 (d, J =
8.1 Hz, 1H) 7.82 (d, J = 7.5 Hz, 2H), 7.60−7.55 (m, 3H), 7.47−7.42
(m, 2H), 7.37−7.35 (m, 2H), 7.31−7.26 (m, 3H), 6.86 (d, J = 7.8 Hz,
2H), 6.71 (d, J = 7.8 Hz, 2H), 5.35 (s, 2H), 2.44 (s, 3H), 2.19 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.5, 138.6, 137.9, 136.6,
1
Mp: 110−112 °C. H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 8.1
Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.51 (t, J
= 7.35 Hz, 1H), 7.40−7.19 (m, 7H), 6.88 (d, J = 8.7 Hz, 1H), 6.19−
6.16 (m, 1H), 6.12 (s, 1H), 5.50−5.35 (m, 2H), 3.68 (s, 3H), 3.23 (s,
3H), 2.39 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 160.8,
157.9, 142.6, 138.0, 137.4, 136.4, 134.6, 133.9, 132.2, 129.2, 129.0,
128.8, 128.0, 126.6, 126.3, 124.2, 120.1, 118.6, 115.4, 107.6, 163.7,
98.5, 21.5 ppm. Anal. Calcd for C30H27BrN2O6S2: C, 54.96; H, 4.15;
N, 4.27; S, 9.78. Found: C, 55.23; H, 4.43; N, 4.00; S, 10.02.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-(3,4-
methylenedioxyphenyl)-4-methylbenzenesulfonamide (3g). The
reaction of 3-bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol)
with N-tosyl-3,4-methyledioxyaniline 2g (203 mg, 0.70 mmol) using
K2CO3 (241 mg, 1.75 mmol) in DMF (10 mL) following the general
procedure furnished sulfonamide 3g as a colorless solid (283 mg,
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Note
76%). Mp: 168−170 °C. 1H NMR (300 MHz, CDCl3): δ 8.10 (d, J =
8.1 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.55−
7.54 (m, 1H), 7.45−7.42 (m, 2H), 7.35−7.31 (m, 2H), 7.25−7.21
(m, 2H), 6.41 (d, J = 5.1 Hz, 1H), 6.24−6.23 (m, 1H), 6.21−6.19 (m,
1H), 5.80 (s, 2H), 5.27 (s, 2H), 2.41 (s, 3H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ 147.3, 147.1, 143.8, 138.3, 136.4, 134.6, 134.2,
131.4, 10.7, 129.4 (2C), 128.5, 128.3, 126.7, 126.6, 126.3, 123.1,
120.1, 115.2, 110.7, 107.3, 101.5, 46.0, 21.6 ppm. Anal. Calcd for
C29H23BrN2O6S2: C, 54.46; H, 3.63; N, 4.38; S, 10.03. Found; C,
54.24; H, 3.39; N, 4.51; S, 10.15.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-4-methyl-
N-(naphthalen-1-yl)benzenesulfonamide (3h). The reaction of 3-
bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosyl-1-
naphthylamine 2h (207 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) following the general procedure gave
sulfonamide 3h as a colorless solid (330 mg, 88%). Mp: 70−72 °C.
1H NMR (300 MHz, CDCl3): δ 8.28−8.25 (m, 1H), 7.86 (d, J = 8.1
solid (82 mg, 88%). Mp: 204−206 °C. 1H NMR (300 MHz, CDCl3):
δ 9.96 (s, 1H), 8.55 (d, J = 7.4 Hz, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.37
(s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.69 (t, J =
7.2 Hz, 1H), 7.59−7.54 (m, 2H), 7.46 (t, J = 6.9 Hz, 1H), 7.36−7.28
(m, 2H), 2.67 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
143.5, 138.5, 138.4, 137.9, 137.5, 134.2, 131.7, 130.1, 130.0, 129.3,
128.7, 126.5, 125.9, 125.5, 124.8, 123.5, 123.4, 122.5, 115.5, 22.1
ppm. HRMS (ESI-TOF): m/z calcd [M]+ for C22H16N2O2S
372.0932, found 372.0930.
2-Chloro-7-(phenylsulfonyl)-7H-indolo[2,3-c]quinoline (4c). To a
solution of 3-bromo-2-aminomethylindole 3c (158 mg, 0.25 mmol) in
DMF (8 mL) were added Pd(OAc)2 (6 mg, 0.025 mmol), PPh3(13
mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol), and the mixture
was stirred at 110 °C for 6 h followed by workup and column
chromatographic purification (silica gel, EtOAc−hexane 1:9) afforded
β-carboline 4c as a colorless solid (74 mg, 75%). Mp: 189−190 °C.
1H NMR (300 MHz, CDCl3): δ 9.92 (s, 1H), 8.47−8.44 (m, 2H),
Hz, 1H), 7.72−7.61 (m, 4H), 7.56 (d, J = 7.5 Hz, 2H), 7.45 (d, J =
7.2 Hz, 1H), 7.34−7.20 (m, 8H), 7.17−7.11 (m, 3H), 5.76 (d, J =
13.8 Hz, 1H), 5.37 (d, J = 13.8 Hz, 1H), 2.43 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 143.6, 137.7, 136.6, 135.8, 134.8, 134.3,
133.9, 133.5, 131.3, 129.3, 129.2, 129.1, 129.0, 128.6, 128.3 127.4,
126.5, 126.4, 126.2, 126.0, 124.6, 124.5, 124.4, 120.0, 115.6, 109.3,
47.0, 21.5 ppm. Anal. Calcd for C32H25BrN2O4S2: C, 59.54; H, 3.90;
N, 4.34; S, 9.93. Found; C, 59.42; H, 3.67; N, 4.48; S, 9.76.
N-(2-Acetylphenyl)-N-((3-bromo-1-(phenylsulfonyl)-1H-indol-2-
yl)methyl)-4-methylbenzenesulfonamide (3i). The reaction of 3-
bromo-2-bromomethylindole 1 (250 mg, 0.58 mmol) with N-tosyl-2-
acetylaniline 2i (202 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) following the general procedure afforded
sulfonamide 3i as a colorless solid (278 mg, 75%). Mp: 180−182 °C.
1H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 8.1 Hz, 1H), 7.61−7.52
(m, 5H), 7.44 (t, J = 7.2 Hz, 1H), 7.32−7.25 (m, 6H), 7.22−7.11 (m,
3H), 6.69 (d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 2.56 (s, 3H), 2.38 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 199.9, 143.4, 141.9, 137.2,
137.1, 136.8, 135.8, 133.9, 132.4, 132.2, 130.9, 129.6, 129.3, 129.2,
129.1, 128.6, 128.4, 126.8, 126.5, 124.9, 120.3, 116.2, 110.4, 47.3,
29.8, 21.5 ppm. Anal. Calcd for C30H25BrN2O5S2: C, 56.52; H, 3.95;
N, 4.39; S, 10.06. Found: C, 56.28; H, 4.14; N, 4.18; S, 9.81.
General Procedure for the Preparation of β-Carbolines 4a−
i. To a solution of 3-bromo-2-arylaminomethylindoles 3a−i (0.25
mmol) in DMF (8 mL) were added Pd(OAc)2 (0.025 mmol), PPh3
(0.052 mmol), and K2CO3(0.63 mmol). Then the reaction mixture
was stirred at 110 °C for 6 h. After completion of the reaction
(monitored by TLC), it was filtered through a Celite bed. It was then
washed with ethyl acetate (10 mL). The combined filtrate was diluted
with ethyl acetate (20 mL), washed with brine solution (2 × 10 mL),
and dried (Na2SO4). Removal of solvent followed by column
chromatographic purification (silica gel, EtOAc−hexane) afforded β-
carbolines 4a−i in good yields.
7-(Phenylsulfonyl)-7H-indolo[2,3-c]quinoline (4a). The intra-
molecular cyclization of 3-bromo-2-aminomethylindoles 3a (150
mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3(87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 6 h followed by workup and chromatographic purification
(silica gel, EtOAc−hexane 1:9) furnished β-carboline 4a as a colorless
solid (70 mg, 78%). Mp: 232−234 °C. 1H NMR (300 MHz, CDCl3):
δ 9.96 (s, 1H), 8.55 (d, J = 6.9 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.41
(d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H),
7.67−7.59 (m, 4H), 7.48 (t, J = 7.5 Hz, 1H), 7.27−7.22 (m, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 144.9, 139.5, 138.5, 137.5,
134.2, 131.6, 130.5, 129.3, 128.9, 127.9, 127.7, 126.5, 125.3, 124.9,
123.4, 115.5 ppm. HRMS (ESI-TOF): m/z calcd [M]+ for
C21H14N2O2S 358.0776, found 358.0775.
8.34 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 7.5 Hz,
2H), 7.65−7.58 (m, 3H), 7.49 (t, J = 7.5 Hz, 1H), 7.29−7.24 (m,
2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.2, 139.6, 138.5,
137.4, 134.4, 133.7, 131.9, 130.7, 130.3, 129.8, 129.4, 129.2, 128.7,
127.5, 126.8, 126.5, 125.5, 125.0, 124.0, 123.5, 123.2, 122.5, 115.6
ppm. HRMS (ESI-TOF): m/z calcd [M]+ for C21H13ClN2O2S
392.0386, found 392.0385.
2-Methoxy-7-(phenylsulfonyl)-7H-indolo[2,3-c]quinoline (4d).
The intramolecular Heck reaction of 3-bromo-2-aminomethylindoles
3d (158 mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3
(13 mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8
mL) at 110 °C for 6 h followed by workup and column
chromatographic purification (silica gel, EtOAc−hexane 1.5:8.5)
furnished β-carboline 4d as a colorless solid (77 mg, 79%). Mp:
235−237 °C. 1H NMR (300 MHz, CDCl3): δ 9.79 (s, 1H), 8.45 (d, J
= 8.4 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.78
(d, J = 7.5 Hz, 3H), 7.60 (t, J = 7.2 Hz, 1H), 7.49−7.22 (m, 5H), 3.97
(s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 158.9, 140.8,
138.4, 137.6, 136.8, 134.2, 132.0, 131.9, 129.3, 128.6, 126.5, 125.5
(2C), 124.7, 124.4, 123.0, 119.5, 115.5, 102.5, 55.7 ppm. HRMS
(ESI-TOF): m/z calcd for [M]+ C22H16N2O3S 388.0882, found
388.0880.
2,4-Dimethoxy-7-(phenylsulfonyl)-7H-indolo[2,3-c]quinoline
(4e). The cyclization reaction of 3-bromo-2-aminomethylindole 3e
(165 mg, 0.25 mmol) using Pd(OAc)2(6 mg, 0.025 mmol), PPh3(13
mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at
110 °C for 6 h followed by workup and column chromatographic
purification (silica gel, EtOAc−hexane 2:8) afforded β-carboline 4e as
1
a colorless solid (89 mg, 85%). Mp: 200−202 °C. H NMR (300
MHz, CDCl3): δ 9.87 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.35 (d, J =
8.1 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.71−7.66 (m, 1H), 7.58−7.53
(m, 1H), 7.45−7.28 (m, 4H), 6.77 (s, 1H), 4.13 (s, 3H), 4.06 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 159.9, 157.1, 138.5, 137.6,
135.3, 134.2, 133.0, 132.6, 129.2, 128.6, 126.5, 125.6, 125.2, 124.7,
123.0, 115.5, 99.5, 93.9, 56.2, 55.6 ppm. HRMS (ESI-TOF): m/z
calcd [M]+ for C23H18N2O4S 418.0987, found 418.0985.
1,3-Dimethoxy-7-(phenylsulfonyl)-7H-indolo[2,3-c]quinoline
(4f). The cyclization reaction of 3-bromo-2-aminomethylindole 3f
(165 mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13
mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at
110 °C for 6 h followed by workup and column chromatographic
purification (silica gel, EtOAc−hexane 2:8) afforded β-carboline 4f as
1
a colorless solid (95 mg, 90%). Mp: 228−230 °C. H NMR (300
MHz, CDCl3): δ 9.98 (s, 1H), 8.87 (d, J = 6.3 Hz, 1H), 8.52 (d, J =
6.3 Hz, 1H), 7.79 (d, J = 6 Hz, 2H), 7.64 (t, J = 6 Hz, 1H), 7.45 (m,
2H), 7.31−7.26 (m, 3H), 6.72 (s, 1H), 4.09 (s, 3H), 3.98 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 159.9, 156.4, 148.2, 140.1,
139.8, 138.2, 133.9, 131.4, 129.2, 128.9, 128.0, 127.9, 126.6, 126.2,
124.1, 115.2, 102.4, 100.4, 55.7, 55.4 ppm. HRMS (ESI-TOF): m/z
calcd [M]+ for C23H18N2O4S 418.0987, found 418.0983.
2-Methyl-7-(phenylsulfonyl)-7H-indolo[2,3-c]quinoline (4b). The
cyclization reaction of 3-bromo-2-aminomethylindole 3b (154 mg,
0.25 mmol) using Pd(OAc)2(6 mg, 0.025 mmol), PPh3(13 mg, 0.052
mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110 °C
for 6 h followed by workup and column chromatographic purification
(silica gel, EtOAc−hexane 1:9) afforded β-carboline 4b as a colorless
8-(Phenylsulfonyl)-8H-[1,3]dioxolo[4,5-f ]indolo[2,3-c]quinoline
(4g). The cyclization reaction of 3-bromo-2-aminomethylindoles 3a
(101 mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13
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Note
mg, 0.052 mmol.), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL)
at 110 °C for 6 h followed by workup and chromatographic
purification (silica gel, EtOAc−hexane 2:8) furnished β-carboline 4g
crude product with methanol afforded N-allyl sulfonamide 6a as a
colorless solid (218 mg, 81%). Mp: 168−170 °C. H NMR (300
1
MHz, CDCl3): δ 8.13 (d, J = 8.1 Hz, 1H), 7.86−7.79 (m, 4H), 7.59−
7.54 (m, 2H), 7.51−7.38 (m, 6H), 7.34−7.28 (m, 2H), 5.32−5.23
(m, 1H), 4.91 (s, 2H), 4.84 (d, J = 17.4 Hz, 1H), 4.69 (d, J = 10.2 Hz,
1H), 3.82 (d, J = 6 Hz, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3):
δ 138.9, 137.9, 136.3, 134.2, 132.9, 132.5, 130.8, 129.3, 128.8, 128.7,
126.7, 124.5, 120.9, 117.3, 115.3, 107.9, 51.3, 43.8 ppm. Anal. Calcd
for C25H23BrN2O4S2: C, 53.67; H, 4.14; N, 5.01; S, 11.46. Found; C,
53.42; H, 4.31; N, 5.26; S, 11.72.
1
as a colorless solid (79 mg, 78%). Mp: 202−204 °C. H NMR (300
MHz, CDCl3): δ 9.81 (s, 1H), 9.01 (d, J = 8.1 Hz, 1H), 8.49 (d, J =
8.4 Hz, 1H), 7.91−7.85 (m, 3H), 7.67 (t, J = 8.1 Hz, 1H), 7.49−7.32
(m, 5H), 6.18 (s, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
145.1, 141.7, 139.9, 138.3, 137.8, 137.5, 134.2, 131.4, 129.3, 128.8,
126.5, 125.8, 125.1, 125.0, 124.4, 124.0, 114.8, 111.4, 110.0, 101.6
ppm. Anal. Calcd for C22H14N2O4S: C, 65.66; H, 3.51; N, 6.96; S,
7.97. Found: C, 65.42; H, 3.67; N, 6.86; S, 8.11.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-N-cinna-
mylbenzenesulfonamide (6b). To a solution of 3-bromo-2-amino-
methylindole 5 (250 mg, 0.49 mmol) in acetonitrile (20 mL) were
added cinnamyl bromide (117 mg, 0.59 mmol) and K2CO3 (204 mg,
1.48 mmol), and the reaction mixture was stirred at reflux for 6 h.
Then the usual workup adopting the above-mentioned procedure
furnished 6b as a colorless solid (264 mg, 86%). Mp: 124−126 °C. 1H
NMR (300 MHz, CDCl3): δ 8.06 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.2
Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.58−7.23 (m, 9H), 7.14−7.12 (m,
3H), 6.81−6.80 (m, 2H), 6.01 (d, J = 15.9 Hz, 1H), 5.60−5.50 (m,
1H), 4.99 (s, 2H), 3.90 (d, J = 6.9 Hz, 2H) ppm. 13C{1H} NMR (75
MHz, CDCl3): δ 138.5, 137.8, 136.3, 135.9, 134.0, 132.5, 132.3,
130.5, 129.1, 128.8, 128.4, 127.9, 127.4, 127.2, 126.7, 126.0, 124.3,
123.9, 119.9, 115.1, 107.6, 50.5, 43.8 ppm. Anal. Calcd for
C30H25BrN2O4S2: C, 57.97; H, 4.05; N, 4.51; S, 10.32. Found: C,
58.12; H, 3.80; N, 4.61; S, 10.04.
7-(Phenylsulfonyl)-7H-benzo[h]indolo[2,3-c]quinolone (4h). The
intramolecular cyclization of 3-bromo-2-aminomethylindole 3h (160
mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 6 h followed by workup and column chromatographic
purification (silica gel, EtOAc−hexane 1:9) afforded β-carboline 4h as
1
a colorless solid (91 mg, 90%). Mp: 186−188 °C. H NMR (300
MHz, CDCl3): δ 10.09 (s, 1H), 9.38 (d, J = 6.3 Hz, 1H), 8.56−8.53
(m, 3H), 8.00 (d, J = 6.6 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.85 (d, J
= 6.0 Hz, 2H), 7.79 (t, J = 6 Hz, 1H) 7.70 (t, J = 5.7 Hz, 2H), 7.56 (t,
J = 5.55 Hz, 1H), 7.45 (t, J = 5.55 Hz, 1H), 7.32 (t, J = 5.7 Hz, 2H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 142.4, 138.8, 137.5, 137.0,
134.2, 132.7, 132.4, 131.9, 129.3, 129.1, 129.0, 127.8, 127.7, 127.5,
127.3, 126.5, 125.5, 124.8, 124.7, 123.8, 121.2, 120.9, 115.5 ppm.
HRMS (ESI-TOF): m/z calcd [M]+ for C25H16N2O2S 408.0932,
found 408.0928.
4-Methyl-9-(phenylsulfonyl)-9H-pyrido[3,4-b]indole (7a). The
intramolecular cyclization reaction of 3-bromo-2-phenylaminomethy-
lindole 6a (140 mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025
mmol), PPh3 (13 mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol)
in DMF (8 mL) at 110 °C for 6 h adopting the above-mentioned
general procedure for 4a−i followed by column chromatographic
purification (silica gel, EtOAc−hexane 1:9) afforded β-carboline 7a as
1-(7-(Phenylsulfonyl)-7H-indolo[2,3-c]quinolin-4-yl)ethanone
(4i). The cyclization of 3-bromo-2-aminomethylindole 3i (160 mg,
0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 6 h followed by workup and column chromatographic
purification (silica gel, EtOAc−hexane 1:9) afforded β-carboline 4h as
1
1
a colorless solid (61 mg, 76%). Mp: 208−210 °C. H NMR (300
a colorless solid (66 mg, 65%). Mp: 182−184 °C. H NMR (300
MHz, CDCl3): δ 9.24 (s, 1H) 8.14 (d, J = 7.8 Hz, 2H), 7.85 (d, J =
7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.30−
7.11 (m, 4H), 2.50 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
144.1, 138.5, 136.9, 134.2, 134.0, 131.1, 129.4, 129.2, 126.3, 126.2,
124.8, 124.4, 123.7, 114.7, 17.1 ppm. HRMS (ESI-TOF): m/z calcd
[M]+ for C18H14N2O2S 322.0776, found 322.0775.
MHz, CDCl3): δ 10.01 (s, 1H), 8.71 (d, J = 1.2 Hz, 1H), 8.68 (d, J =
1.2 Hz, 1H), 8.47 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 7.2 Hz, 3H), 7.72−
7.63 (m, 3H), 7.51 (t, J = 8.1 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.29
(t, J = 8.1 Hz, 1H), 2.91 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 204.6, 141.9, 141.1, 139.4, 138.5, 137.5, 134.4, 131.6,
129.4, 129.2, 127.3, 126.9, 126.5, 126.3, 125.1, 124.9, 123.6, 123.5,
115.6, 32.8 ppm. HRMS (ESI-TOF, MeOH): m/z calcd [M]+ for
C23H16N2O3S 400.0882, found 400.0880.
N-((3-Bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-
benzenesulfonamide (5). To a solution of 3-bromo-2-bromomethy-
lindole 1 (2 g, 4.66 mmol) in DMF (15 mL) were added
benzenesulfonamide (0.98 g, 5.59 mmol), and K2CO3 (1.28 g, 9.32
mmol). The reaction mixture was stirred at room temperature for 12
h. After completion of the reaction (monitored by TLC), the mixture
was poured over crushed ice (100 g) containing Conc. HCl (5 mL).
The solid obtained was filtered, washed with water (2 × 30 mL), and
dried (Na2SO4). Purification of the crude product by column
chromatography (silica gel, EtOAc−hexane 2:8) afforded sulfonamide
5 as a colorless solid (1.93 g, 82%). Mp: 140−142 °C. 1H NMR (300
MHz, CDCl3): δ 7.92 (d, J = 7.8 Hz, 1H), 7.76−7.75 (m, 2H), 7.60
(d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.39−7.26 (m, 5H),
7.17−7.16 (m, 3H), 5.75−5.73 (m, 1H), 4.64 (d, J = 6.9 Hz, 2H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 140.2, 137.7, 135.8, 134.4,
132.0, 131.9, 129.6, 128.6, 128.4, 126.8, 126.7, 126.3, 124.8, 120.4,
114.8, 105.9, 39.6 ppm. Anal. Calcd for C21H17BrN2O4S2: C, 49.91;
H, 3.39; N, 5.54; S, 12.69. Found: C, 49.68; H, 3.52; N, 5.49; S,
12.51.
4-Benzyl-9-(phenylsulfonyl)-9H-pyrido[3,4-b]indole (7b). To a
solution of 3-bromo-2-cinnamylaminomethylindole 6b (157 mg, 0.25
mmol) in DMF were added Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13
mg, 0.052 mmol), and K2CO3 (86 mg, 0.62 mmol). The reaction
mixture was then stirred at 110 °C for 6 h. The usual workup
adopting the general procedure as mentioned above followed by
column chromatographic purification (silica gel, EtOAc−hexane 1:9)
furnished β-carboline 7b as a colorless solid (80 mg, 80%). Mp: 192−
194 °C. 1H NMR (300 MHz, CDCl3): δ 9.65 (s, 1H), 8.43 (d, J = 8.4
Hz, 1H), 8.38 (s, 1H), 7.92−7.88 (m, 3H), 7.61 (t, J = 7.5 Hz, 1H),
7.51 (t, J = 7.5 Hz, 1H), 7.40−7.23 (m, 6H), 7.14 (d, J = 7.2 Hz, 2H),
4.51 (s, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 145.4, 138.9,
137.9, 137.4, 135.6, 134.7, 134.2, 131.1, 129.5, 129.3, 129.1, 128.8,
128.4, 126.7, 126.6, 124.5, 124.4, 124.0, 115.0, 36.8 ppm. HRMS
(ESI-TOF): m/z calcd [M]+ for C24H18N2O2S 398.1089, found
398.1088.
2-Bromo-3-(bromomethyl)-1-(phenylsulfonyl)-1H-indole (8). To
a solution of 2-bromo-3-methylindole (1 g, 2.86 mmol) in CCl4(30
mL), NBS (0.66 g, 3.72 mmol), and AIBN (0.1 g, 0.28 mmol) were
added and refluxed for 1 h. After completion of the reaction
(monitored by TLC), the floated succinimide was filtered off and
filtrate was concentrated under reduced pressure. The crude product
was recrystallized from methanol (3 mL) to afford 2-bromo-3-
bromomethylindole 8 as a colorless solid (1.05 g, 86%). Mp: 108−
N-Allyl-N-((3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-
benzenesulfonamide (6a). To a solution of 3-bromo-2-(amino)-
methylindole 5 (250 mg, 0.49 mmol) in acetonitrile (20 mL), allyl
bromide (72 mg, 0.59 mmol), and K2CO3 (204 mg, 1.48 mmol) were
added, and the reaction mixture was stirred at reflux for 6 h. After
completion of the reaction (monitored by TLC), it was concentrated
under reduced pressure. Then the residue was diluted with ethyl
acetate (15 mL), washed with water (2 × 10 mL), and dried
(Na2SO4). Evaporation of the solvent followed by trituration of the
1
110 °C. H NMR (300 MHz, CDCl3): δ 8.14 (d, J = 8.4 Hz, 1H),
7.95 (d, J = 7.8 Hz, 2H), 7.60−7.52 (m, 2H), 7.48−7.37 (m, 3H),
7.35−7.32 (m, 1H), 5.14 (s, 2H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 138.5, 136.3, 134.2, 133.3, 129.3, 128.6, 127.1, 124.6,
120.3, 115.0, 106.1, 22.6 ppm. Anal. Calcd for C15H11Br2NO2S: C,
41.98; H, 2.58; N, 3.26. Found: C, 41.78; H, 2.45; N, 3.42.
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Note
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-4-methyl-
N-phenylbenzenesulfonamide (9a). The reaction of 2-bromo-3-
bromomethylindole 8 (250 mg, 0.58 mmol) with N-tosylaniline 2a
(172 mg, 0.70 mmol) using K2CO3 (241 mg, 1.75 mmol) in DMF
(10 mL) at room temperature stirring for 12 h following the general
procedure furnished sulfonamide 9a as a colorless solid (270 mg,
78%). Mp: 118−120 °C. 1H NMR (300 MHz, CDCl3): δ 8.19−8.16
(m, 1H), 7.99−7.96 (m, 1H), 7.59−7.48 (m, 5H), 7.35−7.26 (m,
6H), 7.12−7.07 (m, 1H), 7.00 (t, J = 7.5 Hz, 2H), 6.59 (d, J = 8.4 Hz,
2H), 4.80 (s, 2H), 2.46 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 143.8, 137.9, 137.7, 137.3, 134.8, 133.9, 131.6, 130.1,
129.6, 129.1, 128.7, 128.5, 128.0, 127.8, 126.6, 125.5, 124.4, 119.8,
119.2, 115.0, 111.5, 46.0, 21.6 ppm. Anal. Calcd for C28H23BrN2O4S2:
C, 56.47; H, 3.89; N, 4.70; S, 10.77. Found: C, 56.42; H, 3.78; N,
4.92; S, 10.56.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-4-methyl-
N-p-tolylbenzenesulfonamide (9b). A mixture of 2-bromo-3-
bromomethylindole 8 (250 mg, 0.58 mmol), N-tosyl-4-methylaniline
2b (183 mg, 0.70 mmol), and K2CO3 (241 mg, 1.75 mmol) in DMF
(10 mL) was stirred at room temperature for 12 h. Then the usual
workup adopting the above-mentioned general procedure afforded
sulfonamide 9b as a colorless solid (319 mg, 90%). Mp: 206−208 °C.
1H NMR (300 MHz, CDCl3): δ 8.09 (d, J = 5.1 Hz, 1H), 7.91 (d, J =
1H), 7.91−7.88 (m, 1H), 7.50 (d, J = 7.5 Hz, 4H), 7.41 (t, J = 7.5 Hz,
1H), 7.26−7.18 (m, 6H), 6.11 (s, 1H), 5.83 (s, 2H), 4.68 (s, 2H),
3.40 (s, 6H), 2.37 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
160.0, 143.8, 139.4, 137.8, 137.3, 134.6, 133.9, 129.5, 129.0, 128.7,
127.9, 126.5, 125.4, 124.4, 119.8, 115.1, 111.5, 106.7, 101.0, 55.2,
46.1, 21.6 ppm. Anal. Calcd for C30H27BrN2O6S2: C, 54.96; H, 4.15;
N, 4.27; S, 9.78. Found: C, 54.81; H, 4.29; N, 4.19; S, 9.52.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(3,4-di-
methoxyphenyl)-4-methylbenzenesulfonamide (9f). A mixture of 2-
bromo-3-bromomethylindole 8 (250 mg, 0.58 mmol), N-tosyl-3,4-
dimethoxyaniline 2j (241 mg, 0.70 mmol), and K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) was stirred at room temperature for 12 h.
Then the usual workup adopting the above-mentioned general
procedure afforded sulfonamide 9f as a colorless solid (305 mg, 80%).
1
Mp: 100−102 °C. H NMR (300 MHz, CDCl3): δ 8.21−8.18 (m,
1H), 8.00−7.97 (m, 1H), 7.58 (d, J = 8.4 Hz, 4H), 7.50 (t, J = 7.5 Hz,
1H), 7.36−7.28 (m, 6H), 6.48 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 8.4
Hz, 1H), 6.21 (s, 1H), 4.81(s, 2H), 3.80 (s, 3H), 3.45 (s, 3H), 2.47
(s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 148.9, 148.6,
143.4, 138.2, 137.6, 135.3, 133.9, 130.7, 129.5, 129.0, 128.9, 128.1,
126.6, 125.5, 124.4, 121.3, 119.9, 119.5, 115.3, 112.8, 111.8, 110.6,
55.9, 55.7, 46.3, 21.5 ppm. Anal. Calcd for C30H27BrN2O6S2: C,
54.96; H, 4.15; N, 4.27; S, 9.78. Found: C, 55.08; H, 4.00; N, 4.52; S,
9.92.
3.6 Hz, 1H), 7.52−7.40 (m, 5H), 7.24−7.19 (m, 6H), 6.71 (d, J = 7.8
Hz, 2H), 6.53 (d, J = 7.8 Hz, 2H), 4.70 (s, 2H), 2.36 (s, 3H), 2.14 (s,
3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.7, 137.9, 137.7,
137.3, 135.0, 134.8, 133.8, 129.5, 129.2, 129.0, 128.7, 128.4, 127.8,
126.6, 125.4, 124.4, 119.8, 119.3, 115.0, 111.5, 46.0, 21.6, 21.1 ppm.
Anal. Calcd for C29H25BrN2O4S2: C, 57.14; H, 4.13; N, 4.60; S, 10.52.
Found: C, 57.03; H, 3.96; N, 4.28; S, 10.37.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(2-ace-
tylphenyl)-4-methylbenzenesulfonamide (9g). The reaction of 2-
bromo-3-bromomethylindole 8 (600 mg, 1.40 mmol) with N-tosyl-2-
acetylaniline 2i (480 mg, 1.69 mmol) using K2CO3 (290 mg, 2.11
mmol) in DMF (10 mL) at room temperature stirring for 12 h
followed by usual workup furnished sulfonamide 9g as a colorless
solid (710 mg, 79%). Mp: 176−178 °C. 1H NMR (300 MHz,
CDCl3): δ 8.25 (d, J = 8.1 Hz 1H), 7.77−7.70 (m, 3H), 7.58−7.51
(m, 3H), 7.43 (d, J = 1.2 Hz, 1H), 7.38−7.27 (m, 7H), 7.11 (t, J = 7.5
Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 5.2 (m, 1H), 4.87 (m, 1H), 2.46 (s,
3H), 2.04 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 199.4,
143.9, 141.5, 138.3, 137.4, 135.9, 135.6, 144.0, 131.1, 130.9, 129.6,
129.4, 129.3, 129.1, 128.5, 128.2, 127.0, 125.6, 124.4, 119.9, 119.7,
115.2, 112.8, 46.5, 29.6, 21.5 ppm. Anal. Calcd for C30H25BrN2O5S2:
C, 56.52; H, 3.95; N, 4.39; S, 10.06. Found; C, 56.68; H, 4.02; N,
4.26; S, 9.87.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(3,4-
methylendioxyphenyl)-4-methylbenzenesulfonamide (9h). The
reaction of 2-bromo-3-bromomethylindole 8 (250 mg, 0.58 mmol)
with N-tosyl-3,4-methylenedioxyaniline 2g (203 mg, 0.70 mmol)
using K2CO3 (241 mg, 1.75 mmol) in DMF (10 mL) at room
temperature stirring for 12 h followed by usual workup furnished
sulfonamide 9h as a colorless solid (290 mg, 78%). Mp: 98−100 °C.
1H NMR (300 MHz, CDCl3): δ 8.22−8.19 (m, 1H), 7.97−7.94 (m,
1H), 7.63−7.49 (m, 5H), 7.36−7.26 (m, 6H), 6.37 (d, J = 8.1 Hz,
1H), 6.25 (d, J = 1.2 Hz, 1H), 6.13 (d, J = 8.4 Hz, 1H), 5.89 (s, 2H),
4.73 (s, 2H), 2.45 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
147.3, 147.2, 143.8, 137.8, 137.3, 134.6, 133.9, 131.3, 129.6, 129.0,
128.7, 127.7, 126.7, 125.5, 124.5, 122.3, 119.7, 119.2, 115.1, 111.6,
109.8, 107.5, 101.4, 46.2, 21.6 ppm. Anal. Calcd for C29H23BrN2O6S2:
C, 54.46; H, 3.63; N, 4.38; S, 10.03. Found; C, 54.58; H, 3.57; N,
4.16; S, 9.87.
N-((5,5-Dioxidobenzo[4,5]isothiazolo[2,3-a]indol-11-yl)methyl)-
4-methyl-N-phenylbenzenesulfonamide (10a). The intramolecular
cyclization reaction of 2-bromo-3-aminomethylindole 9a (150 mg,
0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (90 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 4 h adopting the above-mentioned general procedure for 4a−i
followed by column chromatographic purification (silica gel, EtOAc−
hexane 1:9) afforded sulfonamide 10a as a colorless solid (99 mg,
76%). Mp: 186−188 °C. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J =
8.1 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.60−
7.57 (m, 3H), 7.51−7.48 (m, 2H), 7.32−7.26 (m, 3H), 7.17−7.09
(m, 4H), 6.90−6.87 (m, 2H), 5.10 (s, 2H), 2.47 (s, 3H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 144.0, 138.4, 138.0, 134.8, 134.2,
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(4-me-
thoxyphenyl)-4-methylbenzenesulfonamide (9c). A mixture of 2-
bromo-3-bromomethylindole 8 (250 mg, 0.58 mmol), N-tosyl-4-
methoxyaniline 2d (194 mg, 0.70 mmol), and K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) was stirred at room temperature for 12 h.
Then the workup adopting the above-mentioned general procedure
gave sulfonamide 9c as a colorless solid (291 mg, 80%). Mp: 108−
1
110 °C. H NMR (300 MHz, CDCl3): δ 8.22−8.19 (m, 1H), 7.99−
7.96 (m, 1H), 7.61−7.48 (m, 5H), 7.36−7.28 (m, 6H), 6.65 (d, J = 9
Hz, 2H), 6.52 (d, J = 9 Hz, 2H), 4.81 (s, 2H), 3.73 (s, 3H), 2.47 (s,
3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 159.1, 143.7, 138.3,
137.6, 135.4, 133.8, 130.5, 130.0, 129.6, 129.0, 128.9, 128.0, 126.8,
125.5, 124.5, 119.9, 119.6, 115.2, 113.9, 111.8, 55.3, 46.2, 21.6 ppm.
Anal. Calcd for C29H25BrN2O5S2: C, 55.68; H, 4.03; N, 4.48; S, 10.25.
Found: C, 55.45; H, 4.16; N, 4.32; S, 10.47.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(2,4-di-
methoxyphenyl)-4-methylbenzenesulfonamide (9d). To a solution
of 2-bromo-3-bromomethylindole 8 (250 mg, 0.58 mmol) in DMF
(10 mL), N-tosyl-2,4-dimethoxyaniline 2e (215 mg, 0.70 mmol), and
K2CO3 (241 mg, 1.75 mmol) were added, and it was stirred at room
temperature for 12 h. Then the usual workup produced sulfonamide
1
9d as a colorless solid (297 mg, 78%). Mp: 160−162 °C. H NMR
(300 MHz, CDCl3): δ 8.13−8.10 (m, 1H), 7.91−7.88 (m, 1H), 7.53
(t, J = 8.55 Hz, 4H), 7.44 (t, J = 7.2 Hz, 1H), 7.28−7.23 (m, 4H),
7.18 (t, J = 7.8 Hz, 2H), 6.49 (d, J = 8.4 Hz, 1H), 6.01 (s, 1H), 5.94
(d, J = 8.7 Hz, 1H), 4.97 (d, J = 13.2 Hz, 1H), 4.70 (d, J = 13.2 Hz,
1H), 3.64 (s, 3H), 3.05 (s, 3H), 2.35 (s, 3H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ 160.6, 157.4, 142.8, 137.9, 137.3, 137.2, 133.8,
133.5, 129.0, 127.6, 126.7, 125.2, 124.3, 120.1, 119.9, 117.8, 114.9,
111.6, 104.0, 98.5, 55.3, 54.4, 44.1, 21.5 ppm. Anal. Calcd for
C30H27BrN2O6S2: C, 54.96; H, 4.15; N, 4.27; S, 9.78. Found: C,
55.19; H, 4.38; N, 4.08; S, 10.02.
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(3,5-di-
methoxyphenyl)-4-methylbenzenesulfonamide (9e). A mixture of
2-bromo-3-bromomethylindole 8 (250 mg, 0.58 mmol), N-tosyl-3,5-
dimethoxyaniline 2f (241 mg, 0.70 mmol), and K2CO3 (241 mg, 1.75
mmol) in DMF (10 mL) was stirred at room temperature for 12 h.
Then the usual workup adopting the above-mentioned general
procedure afforded sulfonamide 9e as a colorless solid (309 mg, 81%).
1
Mp: 130−132 °C. H NMR (300 MHz, CDCl3): δ 8.11−8.08 (m,
132.7, 132.1, 131.3, 129.6, 129.2, 129.0, 128.9, 128.5, 128.0, 127.0,
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Note
126.1, 123.7, 123.3, 122.5, 120.7, 111.6, 110.9, 44.8, 21.6 ppm. Anal.
Calcd for C28H22N2O4S2: C, 65.35; H, 4.31; N, 5.44; S, 12.46. Found:
C, 65.14; H, 4.50; N, 5.21; S, 12.35.
107.0, 100.6, 55.1, 44.8, 21.4 ppm. HRMS (ESI-TOF): m/z calcd
[M]+ for C30H26N2O6S2 574.1232, found 574.1231.
N-(3,4-Dimethoxyphenyl)-N-((5,5-dioxidobenzo[4,5]isothiazolo-
[2,3-a]indol-11-yl)methyl)-4-methylbenzenesulfonamide (10f). The
cyclization reaction of 2-bromo-3-aminomethylindole 9f (165 mg,
0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 4 h adopting the above-mentioned general procedure followed
by column chromatographic purification (silica gel, EtOAc−hexane
2:8) afforded sulfonamide 10f as a colorless solid (116 mg, 80%). Mp:
N-((5,5-Dioxidobenzo[4,5]isothiazolo[2,3-a]indol-11-yl)methyl)-
4-methyl-N-(p-tolyl)benzenesulfonamide (10b). The cyclization
reaction of 2-bromo-3-aminomethylindole 9b (154 mg, 0.25 mmol)
using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg, 0.052 mmol),
and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110 °C for 4 h
adopting the above-mentioned general procedure followed by column
chromatographic purification (silica gel, EtOAc−hexane 1:9) afforded
sulfonamide 10b as a colorless solid (109 mg, 82%). Mp: 250−252
°C. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J = 7.8 Hz, 1H), 7.89 (d,
J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.61−7.57 (m, 3H), 7.55−
7.46 (m, 2H), 7.33−7.26 (m, 3H), 7.18 (t, J = 7.5 Hz, 1H), 6.88 (d, J
= 8.1 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 2.47 (s, 3H),
2.17 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.9, 138.5,
138.1, 135.6, 134.9, 134.2, 132.8, 132.1, 131.3, 129.7, 129.6, 129.2,
128.5, 128.0, 127.1, 126.1, 123.8, 123.4, 122.5, 120.9, 111.6, 111.1,
44.8, 21.6, 21.0 ppm. HRMS (ESI-TOF): m/z calcd [M]+ for
C29H24N2O4S2528.1177, found 528.1175.
1
218−220 °C. H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 8.1 Hz,
1H), 7.81 (d, J = 7.8 Hz, 1H), 7.68−7.63 (m, 4H), 7.53−7.47 (m,
2H), 7.36−7.28 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz,
1H), 6.45 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H),
5.12 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 2.48 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 149.5, 149.2, 143.9, 138.5, 135.6, 134.1,
133.0, 131.5, 131.3, 129.6, 129.3, 128.2, 127.3, 126.2, 123.8, 123.5,
122.6, 121.7, 120.9, 113.3, 111.8, 111.4, 111.3, 56.0, 55.9, 45.2, 21.6
ppm. HRMS (ESI-TOF): m/z calcd [M]+ for C30H26N2O6S2
574.1232, found 574.1224.
N-((5,5-Dioxidobenzo[4,5]isothiazolo[2,3-a]indol-11-yl)methyl)-
N-(4-methoxyphenyl)-4-methylbenzenesulfonamide (10c). The
cyclization reaction of 3-bromo-2-aminomethylindole 9c (158 mg,
0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 4 h adopting the above-mentioned general procedure followed
by column chromatographic purification (silica gel, EtOAc−hexane
1.5:8.5) furnished sulfonamide 10c as a colorless solid (117 mg, 85%).
N-(2-Acetylphenyl)-N-((5,5-dioxidobenzo[4,5]isothiazolo[2,3-a]-
indol-11-yl)methyl)-4-methylbenzenesulfonamide (10g). The cyc-
lization reaction of 2-bromo-3-aminomethylindole 9g (310 mg, 0.488
mmol) using Pd(OAc)2 (32 mg, 0.048 mmol), PPh3 (25 mg, 0.097
mmol), and K2CO3 (168 mg, 1.220 mmol) in DMF (8 mL) at 110 °C
for 4 h adopting the above-mentioned general procedure followed by
column chromatographic purification (silica gel, EtOAc−hexane 2:8)
afforded sulfonamide 10g as a colorless solid (179 mg, 66%). Mp:
1
1
Mp: 200−202 °C. H NMR (300 MHz, CDCl3): δ 7.97 (d, J = 8.1
170−172 °C. H NMR (300 MHz, CDCl3): δ 7.81 (d, J = 7.8 Hz,
Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.69−7.60 (m, 4H), 7.55−7.47 (m,
2H), 7.35−7.28 (m, 3H), 7.18 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 9.0 Hz,
2H), 6.60 (d, J = 9.0 Hz, 2H), 5.11 (s, 2H), 3.66 (s, 3H), 2.48 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 159.5, 143.8, 138.4, 135.5,
134.1, 132.9, 132.4, 131.4, 131.0, 130.2, 129.6, 129.2, 128.1, 127.3,
126.1, 123.8, 123.4, 122.5, 120.9, 114.4, 111.7, 111.3, 53.3, 45.0, 21.5
ppm. Anal. Calcd for C29H24N2O5S2: C, 63.95; H, 4.44; N, 5.14; S,
11.77. Found C, 63.72; H, 4.21; N, 5.36; S, 11.92.
N-(2,4-Dimethoxyphenyl)-N-((5,5-dioxidobenzo[4,5]isothiazolo-
[2,3-a]indol-11-yl)methyl)-4-methylbenzenesulfonamide (10d).
The cyclization reaction of 2-bromo-3-aminomethylindole 9d (165
mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg,
0.052 mmol), and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110
°C for 4 h adopting the above-mentioned general procedure followed
by column chromatographic purification (silica gel, EtOAc−hexane
2:8) afforded sulfonamide 10d as a colorless solid (123 mg, 85%). 1H
NMR (300 MHz, CDCl3): δ 7.91 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.5
Hz, 1H), 7.65−7.58 (m, 5H), 7.45 (t, J = 7.5 Hz, 1H), 7.35−7.28 (m,
3H), 7.19 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.17−6.10 (m,
2H), 5.32 (d, J = 12.6 Hz, 1H), 5.08 (d, J = 13.8 Hz, 1H), 3.63 (s,
3H), 3.23 (s, 3H), 2.45 (s, 3H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 160.9, 157.2, 143.0, 138.0, 137.1, 134.0, 133.9, 133.1,
132.1, 131.3, 129.0, 127.7, 127.2, 126.0, 123.6, 123.3, 122.3, 121.2,
118.1, 111.8, 111.4, 104.3, 99.0, 55.3, 54.6, 43.0, 21.5 ppm. HRMS
(ESI-TOF): m/z calcd [M]+ for C30H26N2O6S2574.1232, found
574.1230.
1H), 7.74 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.57 (d, J =
8.4 Hz, 2H), 7.53−7.47 (m, 2H), 7.44−7.39 (m, 2H), 7.35 (t, J = 7.5
Hz, 1H), 7.25−7.22 (m, 3H), 7.17 (d, J = 8.1 Hz, 1H), 7.14−7.07 (m,
1H), 6.55 (d, J = 7.8 Hz, 1H), 5.46 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 200.7, 143.8, 142.0, 138.4,
136.9, 135.1, 133.9, 133.0, 132.9, 132.5, 132.3, 131.3, 129.6, 129.1,
128.9, 128.7, 128.0, 127.1, 126.2, 123.6, 123.5, 122.3, 121.3, 111.8,
111.4, 45.7, 29.6, 21.5 ppm. HRMS (ESI-TOF): m/z calcd [M]+ for
C30H24N2O5S2 556.1127, found 556.1122.
Palladium-Catalyzed Coupling Reaction of N-((2-Bromo-1-
(phenylsulfonyl)-1H-indol-3-yl)methyl)-N-(3,4-methylendiox-
yphenyl)-4-methylbenzenesulfonamide (9h). The cyclization
reaction of 2-bromo-3-aminomethylindole 9h (101 mg, 0.25 mmol)
using Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg, 0.500 mmol.),
and K2CO3 (87 mg, 0.63 mmol) in DMF (8 mL) at 110 °C for 6 h
followed by usual workup and column chromatographic purification
(silica gel, EtOAc−hexane 1:9) furnished γ-carboline 12. Further
elution of the column (EtOAc−hexane 2:8) afforded sulfonamide
10h.
12-(Phenylsulfonyl)-7-tosyl-12H-[1,3]dioxolo[4,5-f ]indolo[3,2-c]-
1
quinoline (12). Colorless solid (48 mg, 34%). Mp: 145−147 °C. H
NMR (300 MHz, CDCl3): δ 7.66−7.62 (m, 1H), 7.58 (d, J = 7.5 Hz,
2H), 7.42 (t, J = 7.5 Hz, 1H), 7.35−7.28 (m, 5H), 7.19−7.16 (m,
2H), 7.03 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 2H), 6.67 (d, J =
8.4 Hz, 1H), 5.68 (s, 2H), 2.17 (s, 3H) ppm. 13C{1H} NMR (75
MHz, CDCl3): δ 146.9, 143.9, 142.8, 139.5, 139.2, 136.1, 133.0,
130.6, 129.5, 129.1, 128.7, 127.4, 126.7, 126.0, 125.3, 124.3, 122.3,
121.0, 118.8, 116.4, 109.6, 107.2, 101.1, 21.4 ppm. HRMS (ESI-
TOF): m/z calcd [M]+ for C29H20N2O6S2 556.0763, found 556.0761.
N-(Benzo[d][1,3]dioxol-5-yl)-N-((5,5-dioxidobenzo[4,5]-
isothiazolo[2,3-a]indol-11-yl)methyl)-4-methylbenzenesulfona-
N-(3,5-Dimethoxyphenyl)-N-((5,5-dioxidobenzo[4,5]isothiazolo-
[2,3-a]indol-11-yl)methyl)-4-methylbenzenesulfonamide (10e).
The intramolecular cyclization reaction of 2-bromo-3-aminomethy-
lindole 9e (165 mg, 0.25 mmol) using Pd(OAc)2 (6 mg, 0.025
mmol), PPh3 (13 mg, 0.052 mmol), and K2CO3 (87 mg, 0.63 mmol)
in DMF (8 mL) at 110 °C for 4 h adopting the above-mentioned
general procedure followed by column chromatographic purification
(silica gel, EtOAc−hexane 2:8) afforded sulfonamide 10e as a
1
mide (10h). Colorless solid (49 mg, 35%). Mp: 216−218 °C. H
NMR (300 MHz, CDCl3): δ 7.90 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.8
Hz, 1H), 7.62−7.53 (m, 4H), 7.44 (t, J = 9.0 Hz, 2H), 7.26−7.19 (m,
3H), 7.09 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 6.37 (s, 1H),
6.20 (d, J = 8.1 Hz, 1H), 5.75 (s, 2H), 4.93 (s, 2H), 2.40 (s, 3H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 147.8, 147.7, 144.1, 138.0, 134.6,
134.3, 132.8, 132.1, 131.9, 131.3, 129.7, 129.3, 128.0, 127.0, 126.1,
123.7, 123.5, 122.6, 122.1, 120.8, 111.6, 110.8, 110.0, 107.9, 101.6,
45.0, 21.7 ppm. HRMS (ESI-TOF): m/z calcd [M]+ for
C29H22N2O6S2558.0919, found 558.0902.
1
colorless solid (123 mg, 85%). Mp: 215−217 °C. H NMR (300
MHz, CDCl3): δ 7.87 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 6.9 Hz, 1H),
7.61−7.55 (m, 5H), 7.42 (t, J = 6.9 Hz, 1H), 7.31−7.28 (m, 3H),
7.16 (t, J = 6.9 Hz, 1H), 6.17 (s, 1H), 6.00 (s, 2H), 4.98 (s, 2H), 3.46
(s, 6H), 2.43 (s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
160.4, 143.9, 140.0, 137.7, 134.7, 133.9, 132.6, 131.8, 131.0, 129.4,
129.1, 127.8, 126.7, 125.9, 123.5, 123.2, 122.1, 120.9, 111.3, 110.9,
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Note
N-((2-Bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-4-methyl-
benzenesulfonamide (15). To a solution of 2-bromo-3-bromome-
thylindole 8 (5 g, 11.60 mmol) in acetonitrile (80 mL), 4-
methylbenzenesulfonamide (2.2 g, 13.90 mmol), and K2CO3 (3.21
g, 23.3 mmol) were added and the reaction mixture was stirred at
reflux for 6 h. After completion of reaction (monitored by TLC), the
usual workup procedure similar to that of 3a−i led to sulfonamide 15
was separated. The aqueous layer was extracted with DCM (2 × 30
mL), and the combined organic extract was dried (Na2SO4). Removal
of the solvent followed by trituration of the crude product with
methanol afforded 1-mesitylenesulfonyl-2-bromo-3-methylindole as a
colorless solid (5.13 g, 82%). Mp: 136−138 °C. 1H NMR (300 MHz,
CDCl3): δ 8.22 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.35−
7.25 (m, 2H), 6.94 (s, 2H), 2.44 (s, 6H), 2.31 (s, 3H), 2.18 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.9, 140.3, 137.8, 134.9,
132.0, 128.7, 124.6, 122.8, 119.1, 118.6, 115.3, 108.2, 22.6, 21.1, 10.0
ppm.
Stage 3: 2-Bromo-3-(bromomethyl)-1-(2-mesitylenesulfonyl)-
1H-indole (18). To a solution of 2-bromo-1-(mesitylenesulfonyl)-3-
methylindole (4.0 g, 10.20 mmol) and AIBN (0.05 g) in dry carbon
tetrachloride (80 mL) was added finely powdered NBS (2.0 g, 11.22
mmol). The reaction mixture was refluxed for 0.5 h and cooled to
room temperature. The floated succinimide was filtered off and
washed with carbon tetrachloride (15 mL). The combined filtrate was
concentrated in vacuo to afford bromo compound 18 as a light brown
solid (3.65 g, 76%). Mp: 118−120 °C. 1H NMR (300 MHz, CDCl3):
δ 8.23 (d, J = 7.8 Hz, 1H), 7.65−7.62 (m, 1H), 7.40−7.31 (m, 2H),
6.96 (s, 2H), 4.58 (s, 2H), 2.43 (s, 6H), 2.32 (s, 3H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 144.4, 140.3, 138.0, 134.4, 132.2, 126.4,
125.3, 123.4, 119.1, 118.7, 115.5, 110.9, 23.1, 22.5, 21.1 ppm. Anal.
Calcd for C18H17Br2NO2S: C, 45.88; H, 3.64; N, 2.97; S, 6.80. Found
C, 45.64; H, 3.52; N, 3.15; S, 6.58.
General Procedure for Preparation of N-Phenylbenzene-
sulfonamides (19a−d). To a solution of 2-bromo-3-bromomethy-
lindole 18 (1 equiv) in DMF (10 mL) were added N-tosylanilines
(2a-c/2k) (1.2 equiv) and K2CO3 (3 equiv). The reaction mixture
was stirred at room temperature for 12 h. After completion of the
reaction (monitored by TLC), it was then poured over crushed ice
containing concd HCl (5 mL). The solid obtained was filtered,
washed with water (2 × 20 mL), and dried (Na2SO4). The crude
product was crystallized from methanol (5 mL) to afford
sulfonamides 19a−d.
N-((2-Bromo-1-(2-mesitylenesulfonyl)-1H-indol-3-yl)methyl)-4-
methyl-N-phenylbenzenesulfonamide (19a). To a solution of 2-
bromo-3-bromomethylindole 18 (300 mg, 0.637 mmol) in DMF (10
mL) were added N-tosylaniline 2a (189 mg, 0.764 mmol) and K2CO3
(263 mg, 1.91 mmol). The reaction mixture was stirred at room
temperature for 12 h. Then the usual workup adopting the above-
mentioned general procedure gave sulfonamide 19a as a colorless
solid (341 mg, 84%). Mp: 194−196. 1H NMR (300 MHz, CDCl3): δ
8.08−8.05 (m, 1H), 7.97−7.94 (m, 1H), 7.54 (d, J = 8.1 Hz, 2H),
7.31−7.25 (m, 4H), 7.10 (t, J = 7.35 Hz, 1H), 7.01 (t, J = 7.5 Hz,
2H), 6.81−6.79 (m, 4H), 4.82 (s, 2H), 2.43 (s, 3H), 2.27 (s, 3H),
2.09 (s, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.7, 143.6,
140.1, 138.1, 138.0, 135.2, 134.9, 131.9, 129.5, 128.9, 128.5, 127.9,
127.8, 127.0, 125.0, 123.4, 119.7, 116.5, 115.0, 111.0, 45.7, 22.1, 21.5,
21.0 ppm. Anal. Calcd for C31H29BrN2O4S2: C, 58.40; H, 4.58; N,
4.39; S, 10.06. Found C, 58.22; H, 4.46; N, 4.52; S, 9.84.
1
as a colorless solid (4.8 g, 80%). Mp: 146−148 °C. H NMR (300
MHz, CDCl3): δ 8.21 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H),
7.64 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.46−7.41 (m, 3H),
7.33 (t,, J = 6.9 Hz, 1H), 7.28−7.23 (m, 1H), 7.19−7.15 (m, 2H),
4.88−4.75 (m, 1H), 4.23 (d, J = 6.0 Hz, 2H), 2.39 (s, 3H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 143.6, 138.5, 137.3, 136.8, 134.3,
129.5, 129.3, 128.3, 127.1, 125.5, 124.2, 119.4, 118.8, 115.1, 110.9,
38.4, 21.4 ppm. Anal. Calcd for C22H19BrN2O4S2: C, 50.87; H, 3.69;
N, 5.39; S, 12.34. Found: C, 51.04; H, 3.42; N, 5.16; S, 12.18.
N-Allyl-N-((2-bromo-1-(phenylsulfonyl)-1H-indol-3-yl)methyl)-4-
methylbenzenesulfonamide (16). To a solution of 2-bromo-3-
aminomethylindole 15 (250 mg, 0.48 mmol) in acetonitrile (20 mL)
were added allyl bromide (70 mg, 0.58 mmol) and K2CO3 (199 mg,
1.44 mmol), and the reaction mixture was stirred at reflux for 6 h.
Then the usual workup adopting the above-mentioned procedure
gave 2-bromo-3-allylaminomethylindole 16 as a colorless solid (228
1
mg, 85%). Mp: 108−110 °C. H NMR (300 MHz, CDCl3): δ 8.28
(d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H),
7.71 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.5 Hz,
1H), 7.38 (d, J = 3.9 Hz, 1H), 7.33−7.26 (m, 4H), 5.26−5.08 (m,
1H), 4.72−4.61 (m, 2H), 4.40 (s, 2H), 3.52 (d, J = 6.0 Hz, 2H), 2.44
(s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.6, 138.1,
137.4, 136.2, 134.2, 131.9, 129.8, 129.1, 128.9, 127.3, 127.0, 125.6,
124.4, 120.0, 119.3, 118.1, 115.1, 111.2, 50.2, 43.6, 21.5 ppm. Anal.
Calcd for C25H23BrN2O4S2: C, 53.67; H, 4.14; N, 5.01; S, 11.46.
Found: C, 53.90; H, 3.93; N, 5.25; S, 11.26.
4-Methylene-5-(phenylsulfonyl)-2-tosyl-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indole (17). To a solution of 2-bromo-3-allylaminome-
thylindole 16 (150 mg, 0.27 mmol) in DMF (8 mL) were added
Pd(OAc)2 (6 mg, 0.027 mmol), PPh3 (14 mg, 0.054 mmol), and
K2CO3 (92 mg, 0.67 mmol). The reaction mixture was then stirred at
110 °C for 6 h followed by workup using the above-mentioned
general procedure gave compound 17 as a colorless solid (101 mg,
79%). Mp: 162−164 °C. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J =
8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.32−7.28 (m, 4H), 7.17−7.11
(m, 7H), 5.86 (s, 1H), 5.40 (s, 1H), 4.23 (s, 2H), 3.87 (s, 2H), 2.28
(s, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.9, 139.4,
136.3, 134.0, 133.9, 133.7, 129.6, 128.6, 128.5, 127.5, 126.5, 126.4,
125.1, 121.3, 118.6, 118.6, 117.9, 51.6, 42.6, 21.4 ppm. HRMS (ESI-
TOF): m/z calcd [M]+ for C25H22N2O4S2478.1021, found 478.1020.
2-Bromo-3-(bromomethyl)-1-(2-mesitylenesulfonyl)-1H-indole
(18). Stage 1: 1-(2-Mesitylenesulfonyl)-3-methyl-1H-indole. To a
solution of 3-methylindole (5 g, 38.16 mmol) in distilled benzene
(100 mL) were added 2-mesitylenesulfonyl chloride (9.15 g, 41.98
mmol) and 60% aqueous NaOH solution (25 g in 40 mL) along with
tetra-n-butylammonium hydrogen sulfate (1.0 g) at room temper-
ature. Then this two-phase system was warmed to 60 °C for 1 h with
continuous stirring. After the reaction was completed (TLC), the
mixture was diluted with water (200 mL), and the organic layer was
separated. The aqueous layer was extracted with benzene (2 × 30
mL), and the combined organic extract was dried (Na2SO4). Removal
of the solvent followed by trituration of the crude product with
MeOH afforded N-mesitylenesulfonylindole as a dull white solid
N-((2-Bromo-1-(2-mesitylenesulfonyl)-1H-indol-3-yl)methyl)-4-
methyl-N-(p-tolyl)benzenesulfonamide (19b). A mixture of 2-
bromo-3-bromomethylindole 18 (300 mg, 0.637 mmol), N-tosyl-4-
methylaniline 2b (199 mg, 0.764 mmol), and K2CO3 (263 mg, 1.91
mmol) in DMF (10 mL) was stirred at room temperature for 12 h.
Then the workup adopting the above-mentioned procedure furnished
sulfonamide 19b as a colorless solid (323 mg, 78%). Mp: 232−234
1
°C. H NMR (300 MHz, CDCl3): δ 8.02−7.99 (m, 1H), 7.94−7.91
(m, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.26−7.18 (m, 4H), 6.74−6.71 (m,
4H), 6.56 (d, J = 8.1 Hz, 2H), 4.70 (s, 2H), 2.36 (s, 3H), 2.21 (s,
3H), 2.16 (s, 3H), 1.99 (s, 6H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 143.7, 143.6, 140.1, 137.9, 137.6, 135.1, 134.9, 134.7,
131.8, 129.5, 129.1, 128.6, 127.9, 126.8, 125.1, 123.4, 119.7, 116.4,
114.9, 110.8, 45.6, 22.2, 21.6, 21.2, 21.1 ppm. Anal. Calcd for
C32H31BrN2O4S2: C, 58.98; H, 4.80; N, 4.30; S, 9.84. Found C, 58.72;
H, 4.76; N, 4.11; S, 9.98.
1
(9.31 g, 78%). Mp: 128−130 °C. H NMR (300 MHz, CDCl3): δ
7.51−7.46 (m, 1H), 7.40−7.34 (m, 1H), 7.31 (d, J = 0.9 Hz, 1H),
7.23−7.17 (m, 2H), 6.92 (s, 2H), 2.53 (s, 6H), 2.56 (s, 6H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 143.8, 140.2, 135.1, 133.3, 132.4,
131.1, 124.2, 123.3, 122.4, 119.5, 115.9, 112.6, 22.7, 21.0, 9.6 ppm.
Stage 2: 2-Bromo-1-(2-mesitylenesulfonyl)-3-methyl-1H-indole.
To a solution of 1-(2-mesitylenesulfonyl)-3-methyl-1H-indole (5 g,
15.97 mmol) in dry DCM (30 mL) at 0 °C was added NBS (3.12 g,
17.57 mmol) in portions (10 times). After the reaction was completed
(TLC), the mixture was poured into ice−water and the organic layer
N-((2-Bromo-1-(2-mesitylenesulfonyl)-1H-indol-3-yl)methyl)-N-
(4-chlorophenyl)-4-methylbenzenesulfonamide (19c). A mixture of
2-bromo-3-bromomethylindole 18 (300 mg, 0.637 mmol), N-tosyl-4-
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Note
chloroaniline 2c (214 mg, 0.764 mmol), and K2CO3 (263 mg, 1.91
mmol) in DMF (10 mL) was stirred at room temperature for 12 h.
Then the usual workup adopting the above-mentioned procedure
afforded sulfonamide 19c as a colorless solid (385 mg, 90%). Mp:
chromatographic purification (silica gel, EtOAc−hexane 1:9) afforded
carboline 20c as a colorless solid (112 mg, 76%). Mp: 156−158 °C.
1H NMR (300 MHz, CDCl3): δ 7.87−7.85 (m, 1H), 7.65 (d, J = 8.4
Hz, 1H), 7.47−7.44 (m, 1H), 7.29−7.12 (m, 7H), 6.95 (s, 2H),
6.84−6.82 (m, 2H), 4.88 (s, 2H), 2.32−2.30 (m, 9H), 2.16 (s, 3H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.9, 143.8, 138.9, 136.7,
135.6, 134.4, 132.5, 132.1, 131.7, 129.5, 129.2, 127.7, 126.7, 126.1,
126.0, 125.9, 125.7, 123.6, 119.9, 119.1, 116.3, 43.2, 22.3, 21.4, 20.9
ppm. HRMS (ESI-TOF): m/z calcd [M]+ for C31H27ClN2O4S2
590.1101, found 590.1098.
2,3-Dichloro-11-(2-mesitylenesulfonyl)-5-tosyl-6,11-dihydro-5H-
indolo[3,2-c]quinolone (20d). A mixture of 2-bromo-3-arylamino-
methylindole 19d (176 mg, 0.25 mmol), Pd(OAc)2 (6 mg, 0.025
mmol), PPh3 (13 mg, 0.05 mmol), and K2CO3 (86 mg, 0.625 mmol)
in DMF (8 mL) was stirred at 110 °C for 24 h. Then the usual
workup and column chromatographic purification (silica gel, EtOAc−
hexane 1:9) afforded carboline 20d as a colorless solid (106 mg,
68%). Mp: 140−142 °C. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, J =
7.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.25−
7.20 (m, 2H), 7.17−7.14 (m, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.87 (s,
2H), 6.76 (dd, J1 = 8.1 Hz, J2 = 2.4 Hz, 1H), 4.80 (s, 2H), 2.45 (s,
3H), 2.26−2.23 (m, 9H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
144.3, 144.2, 140.1, 138.2, 135.1, 134.7, 132.9, 132.7, 132.4, 132.1,
130.5, 130.3, 129.8, 128.7, 128.1, 127.8, 126.0, 124.8, 123.2, 120.2,
113.6, 112.6, 45.8, 22.1, 21.5, 21.0 ppm. HRMS (ESI-TOF): m/z
calcd [M]+ for C31H26Cl2N2O4S2 624.0711, found 624.0704.
1
198−200 °C. H NMR (300 MHz, CDCl3): δ 8.05−8.01 (m, 1H),
7.88−7.85 (m, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.24−7.17 (m, 4H),
6.87 (d, J = 8.4 Hz, 2H), 6.76 (s, 2H), 6.63 (d, J = 8.4 Hz, 2H), 4.70
(s, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 1.97 (s, 6H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ 144.0, 143.9, 140.1, 138.1, 136.6, 134.8, 133.6,
131.8, 130.1, 129.7, 128.6, 127.8, 126.6, 125.2, 123.5, 119.5, 116.0,
115.1, 111.0, 45.5, 22.0, 21.5, 20.9 ppm. Anal. Calcd for
C31H28BrClN2O4S2: C, 55.40; H, 4.20; N, 4.17; S, 9.54. Found C,
55.26; H, 4.04; N, 3.91; S, 9.29.
N-((2-Bromo-1-(2-mesitylenesulfonyl)-1H-indol-3-yl)methyl)-N-
(3,4-dichlorophenyl)-4-methylbenzenesulfonamide (19d). A mix-
ture of 2-bromo-3-bromomethylindole 18 (300 mg, 0.637 mmol), N-
tosyl-3,4-dichloroaniline 2k (241 mg, 0.764 mmol), and K2CO3 (263
mg, 1.91 mmol) in DMF (10 mL) was stirred at room temperature for
12 h. Then the usual workup adopting the above-mentioned
procedure gave sulfonamide 19d as a colorless solid (342 mg,
86%). Mp: 200−202 °C. 1H NMR (300 MHz, CDCl3): δ 8.09 (dd, J1
= 6.1 Hz, J2 = 3.1 Hz, 1H), 7.98 (dd, J1 = 6 Hz, J2 = 3 Hz, 1H), 7.57
(d, J = 8.1 Hz, 2H), 7.34−7.28 (m, 3H), 7.13 (t, J = 7.2 Hz, 1H), 7.04
(t, J = 7.8 Hz, 2H), 6.84−6.82 (m, 3H), 4.85 (s, 2H), 2.45 (s, 3H),
2.30 (s, 3H), 2.12 (s, 6H) ppm. 13C{1H}NMR (75 MHz, CDCl3): δ
143.72, 143.68, 140.1, 138.1, 138.0, 135.2, 134.9, 131.9, 129.5, 128.9,
128.5, 127.9, 127.8, 127.1, 125.0, 123.4, 119.7, 116.5, 115.0, 111.0,
45.7, 22.1, 21.5, 21.0 ppm. Anal. Calcd for C31H27BrC12N2O4S2: C,
52.70; H, 3.85; N, 3.97; S, 9.08. Found C, 52.86; H, 3.97; N, 3.74; S,
9.31.
11-(2-Mesitylenesulfonyl)-5-tosyl-6,11-dihydro-5H-indolo[3,2-c]-
quinolone (20a). To a solution of 2-bromo-3-aminomethylindole 19a
(159 mg, 0.25 mmol) in DMF (8 mL) were added Pd(OAc)2 (6 mg,
0.025 mmol), PPh3 (13 mg, 0.05 mmol), and K2CO3 (86 mg, 0.625
mmol). Then the reaction mixture was stirred at 110 °C for 24 h.
Then the usual workup adopting the above-mentioned procedure for
4a−i followed by column chromatographic purification (silica gel,
EtOAc−hexane 1:9) afforded carboline 20a as a colorless solid (94
mg, 68%). Mp: 184−186 °C. 1H NMR (300 MHz, CDCl3): δ 8.09−
8.06 (m, 1H), 8.00−7.97 (m, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.32−
7.25 (m, 4H), 7.11 (t, J = 7.2 Hz, 1H), 7.01 (t, J = 7.65 Hz, 2H), 6.79
(d, J = 4.8 Hz, 2H), 4.80 (s, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 2.06 (s,
6H) ppm. 13C{1HNMR (75 MHz, CDCl3): δ 143.8, 140.0, 137.9,
137.8, 134.7, 134.6, 131.9, 129.6, 128.8, 128.5, 127.9, 127.8, 126.8,
125.1, 123.4, 119.7, 116.3, 115.0, 110.9, 45.6, 22.2, 21.6, 21.0 ppm.
HRMS (ESI-TOF): m/z calcd [M]+ for C31H28N2O4S2556.1490,
found 556.1496.
11-(2-Mesitylenesulfonyl)-2-methyl-5-tosyl-6,11-dihydro-5H-
indolo[3,2-c]quinolone (20b). To a solution of 2-bromo-3-amino-
methylindole 19b (163 mg, 0.25 mmol) in DMF (8 mL) were added
Pd(OAc)2 (6 mg, 0.025 mmol), PPh3 (13 mg, 0.05 mmol), and
K2CO3 (86 mg, 0.625 mmol). Then the reaction mixture was stirred
at 110 °C for 24 h. Then the usual workup adopting the above-
mentioned procedure followed by column chromatographic purifica-
tion (silica gel, EtOAc−hexane 1:9) afforded carboline 20b as a
colorless solid (88 mg, 62%). Mp: 194−196 °C. 1H NMR (300 MHz,
CDCl3): δ 7.76−7.74 (m, 1H), 7.68−7.65 (m, 1H), 7.46 (d, J = 8.1
Hz, 1H), 7.31−7.29 (m, 4H), 7.14−7.11 (m, 4H), 6.96−6.95 (m,
4H), 4.93 (s, 2H), 2.28 (s, 3H), 2.21 (s, 6H), 2.15 (s, 3H), 2.11 (m,
3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 143.9, 143.3, 138.2,
137.6, 135.6, 135.2, 132.8, 132.2, 132.1, 129.4, 128.4, 127.0, 126.2,
126.1, 125.8, 125.3, 123.7, 123.5, 119.9, 119.7, 42.7, 21.5, 20.9, 20.5,
20.4 ppm. HRMS (ESI-TOF): m/z calcd [M]+ for C32H30N2O4S2
570.1647, found 570.1653.
2-Chloro-11H-indolo[3,2-c]quinoline (21). A mixture of 2-bromo-
3-arylaminomethylindole 19c (150 mg, 0.22 mmol), Pd(OAc)2 (5
mg, 0.022 mmol), PPh3 (13 mg, 0.044 mmol), and K2CO3 (150 mg,
1.11 mmol) in DMF (8 mL) was stirred at 130 °C for 36 h. Then the
usual workup adopting the above-mentioned procedure followed by
column chromatic purification (silica gel, EtOAc−hexane 1:9)
furnished N-tosyldihydrocarboline 20c as a colorless solid (55 mg,
42%). Further elution of the column afforded carboline 21 as a pale
1
yellow solid (15 mg, 26%). Mp: 292−294 °C. H NMR (300 MHz,
CDCl3): δ 12.70 (s, 1H), 9.61 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.33
(d, J = 7.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H),
7.53 (t, J = 7.35 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ 145.2, 143.8, 138.9, 131.6, 129.9, 128.2,
125.9, 121.7, 121.2, 120.8, 120.2, 117.9, 114.9, 112.0 ppm. HRMS
(ESI-TOF): m/z calcd [M]+ for C15H9ClN2252.0454, found
252.0451.
7H-Indolo[2,3-c]quinoline (22a). To a stirred solution of N-
(phenylsulfonyl)carboline 4a (80 mg, 0.22 mmol) in DMSO (5 mL)
was added 30% NaOH (2 mL) and the mixture stirred at room
temperature for 12 h. After the completion of the reaction (TLC), the
mixture was poured over crushed ice (50 g) containing concd HCl (5
mL). The precipitate obtained was filtered and dried (CaCl2).
Trituration of the crude product with MeOH (5 mL) afforded N-free
carboline 22a as a yellow solid (42 mg, 87%). Mp: >300 °C. 1H NMR
(300 MHz, CDCl3): δ 12.19 (s, 1H), 9.29 (s, 1H), 8.80 (d, J = 8.1
Hz, 1H), 8.68 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.79−
7.70 (m, 2H), 7.70−7.57 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 142.2, 139.4, 138.8, 132.7, 129.9,
127.0, 126.7, 125.2, 124.3, 123.2, 122.9, 121.3, 120.3, 119.4, 112.7
ppm. HRMS (ESI-TOF): m/z calcd for [M]+ C15H10N2 218.0844,
found 218.0857.
2-Methyl-7H-indolo[2,3-c]quinolone (22b). To a stirred solution
of N-(phenylsulfonyl)carboline 4b (80 mg, 0.21 mmol) in DMSO (5
mL), 30% NaOH (2 mL) was added. The heterogeneous solution was
stirred at room temperature for 12 h. The usual workup followed by
trituration of the crude product with MeOH (5 mL) gave N-free
carboline 22b as a brown solid (41 mg, 82%). Mp: >300 °C. 1H NMR
(300 MHz, CDCl3): δ 12.10 (s, 1H), 9.20 (s, 1H), 8.71 (d, J = 8.1
Hz, 1H), 8.57 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.75 (t, J = 8.1 Hz,
1H), 7.61−7.56 (m, 1H), 7.51−7.47 (m, 1H), 7.42−7.37 (m, 1H),
2.66 (m, 3H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 140.6, 139.3,
137.7, 136.7, 132.8, 129.7, 127.2, 126.5, 124.2, 123.0, 122.3, 121.3,
120.2, 119.0, 112.6, 21.5 ppm. HRMS (ESI-TOF): m/z calcd [M]+
for C16H12N2 232.1000, found 232.0993.
2-Chloro-11-(2-mesitylenesulfonyl)-5-tosyl-6,11-dihydro-5H-
indolo[3,2-c]quinolone (20c). A mixture of 2-bromo-3-amino-
methylindole 19c (0.168 g, 0.25 mmol), Pd(OAc)2 (6 mg, 0.025
mmol), PPh3 (13 mg, 0.05 mmol), and K2CO3 (86 mg, 0.625 mmol)
in DMF (8 mL) was stirred at 110 °C for 24 h. Then the usual
workup adopting the above-mentioned procedure followed by column
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2-Chloro-7H-indolo[2,3-c]quinolone (22c). The heterogeneous
solution of N-(phenylsulfonyl)carboline 6c (80 mg, 0.20 mmol) in
DMSO (5 mL) and 30% NaOH (2 mL) was stirred at room
temperature for 12 h. Then the usual workup followed by trituration
of the crude product with MeOH (5 mL) gave N-free carboline 22c
Author Contributions
†P.R. and V.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
1
as a brown solid (44 mg, 86%). Mp: >300 °C. H NMR (300 MHz,
ACKNOWLEDGMENTS
CDCl3): δ 12.32 (s, 1H), 9.31 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.70
(d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H),
7.70−7.60 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H) ppm. 13C{1H} NMR (75
MHz, CDCl3): δ 140.5, 139.4, 139.3, 131.9, 131.7, 129.1, 127.0,
125.7, 122.9, 121.9, 120.9, 120.6, 118.5, 112.8 ppm. HRMS (ESI-
TOF): m/z calcd [M]+ for C15H9ClN2252.0454, found 252.0451.
Gram-Scale Synthesis of Benzo-β-carboline (4a). The intra-
molecular cyclization of 3-bromo-2-aminomethylindole 3a (1.17 g,
1.96 mmol) using Pd(OAc)2 (133 mg, 0.196 mmol), PPh3 (103 mg,
0.393 mmol), and K2CO3 (679 mg, 4.9 mmol) in DMF (30 mL) at
110 °C for 8 h followed by workup and chromatographic purification
(silica gel, EtOAc−hexane 1:9) furnished β-carboline 4a (510 mg,
72%).
■
The authors graciously acknowledge the Council of Scientific
and Industrial Research (CSIR) Project (02(0376)/19/EMR-
II) and University Grants Commission (UGC)-Mid Career
Award (F-19-230/20189(BSR)) New Delhi for financial
support. P.R. thanks the University Grants Commission
(UGC) New Delhi for fellowship. V.S. thanks the Council of
Scientific and Industrial Research (CSIR) New Delhi for a
fellowship. The authors thank the Department of Science and
Technology Funds for the Improvement of Science and
Technology (DST-FIST) New Delhi for NMR and HRMS
facilities.
Gram-Scale Synthesis of Benzo[4,5]isothiazolo[2,3-a]indole
5,5-dioxides (10f). The intramolecular cyclization of 2-bromo-3-
aminomethylindole 9f (1.4 g, 2.15 mmol) using Pd(OAc)2 (144 mg,
0.214 mmol), PPh3 (113 mg, 0.428 mmol), and K2CO3 (738 mg, 5.35
mmol) in DMF (30 mL) at 110 °C for 6 h followed by workup and
column chromatographic purification (silica gel, EtOAc−hexane 2:8)
afforded 10f as a colorless solid (940 mg, 76%).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02152.
Copies of 1H and 13C NMR spectra for 1, 3a−i, 4a−i, 5,
6a,b, 7a,b, 8, 9a−h, 10a−h, 12, 15−18, 19a−d, 20a−d,
21, and 22a−c (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Arasambattu K. Mohanakrishnan − Department of Organic
Chemistry, School of Chemical Sciences, University of
Madras, Chennai 600 025, Tamil Nadu, India;
orcid.org/0000-0002-3758-4578;
Email: mohanakrishnan@unom.ac.in, mohan_67@
hotmail.com
Authors
Potharaju Raju − Department of Organic Chemistry, School of
Chemical Sciences, University of Madras, Chennai 600 025,
Tamil Nadu, India
Velu Saravanan − Department of Organic Chemistry, School
of Chemical Sciences, University of Madras, Chennai 600
025, Tamil Nadu, India
Vinayagam Pavunkumar − Department of Organic Chemistry,
School of Chemical Sciences, University of Madras, Chennai
600 025, Tamil Nadu, India
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