Lithium-Promoted Cycloaddition of Indole-2,3-dienolates and Carbon Disulfide as a One-Pot Route to Thiopyrano[4,3- b]indole-3(5 H)-thiones

Article abstract of DOI:10.1021/acs.joc.1c01200

A new approach for the annulation of a thiopyrane ring to an indole core under mild conditions was developed. Treating 2-methyl-3-acylindoles with lithium diisopropyl amide leads to the elimination of a proton from the 2-methyl group. The lithium indole-2,3-dienolates obtained were found to react with CS2 to give the corresponding thiopyrano[4,3-b]indole-3(5H)-thiones. The mechanism represents a stepwise addition through ion-pair formation, according to PCM/B3LYP/6-311++G**, PBE1PBE/6-311++G**, and MP2//HF/6-311++G*? quantum chemical calculations. AIM calculations revealed the essential role of the Li atom at all stages of the process.

Full text of DOI:10.1021/acs.joc.1c01200

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Article
Lithium-Promoted Cycloaddition of Indole-2,3-dienolates and
Carbon Disulfide as a One-Pot Route to Thiopyrano[4,3‑b]indole-
3(5H)‑thiones
Konstantin F. Suzdalev, Julia V. Vyalyh,* Valery V. Tkachev, Ekaterina A. Lysenko, Oleg N. Burov,
Anton V. Lisovin, Mikhail E. Kletskii, and Sergey V. Kurbatov
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ABSTRACT: A new approach for the annulation of a thiopyrane
ring to an indole core under mild conditions was developed.
Treating 2-methyl-3-acylindoles with lithium diisopropyl amide
leads to the elimination of a proton from the 2-methyl group. The
lithium indole-2,3-dienolates obtained were found to react with
CS2 to give the corresponding thiopyrano[4,3-b]indole-3(5H)-
thiones. The mechanism represents a stepwise addition through
ion-pair formation, according to PCM/B3LYP/6-311++G**,
PBE1PBE/6-311++G**, and MP2//HF/6-311++G** quantum
chemical calculations. AIM calculations revealed the essential role of the Li atom at all stages of the process.
Compounds of the thiopyrano[4,3-b]indole series 9−11 are
INTRODUCTION
■
of particular interest for medicinal chemistry. As sulfur-
containing analogues of tubastatin A (γ-carboline derivative),
substances 9 are the selective inhibitors of the histone
deacetylases HDAC68 and HDAC109 (HDACs are anticancer
targets as they regulate the expression and activity of numerous
proteins involved in both cancer initiation and cancer
progression).10 S,S-Dioxides of compounds 9 (tubatians) are
the most active. Compounds of type 10 (R1−R5 = alkyl, alkoxy,
or halogen) possess in vivo activity against the fungus
Rhizoctonia solani and are applied to the prevention and
treatment of rice sheath blight.11 Substance 11 is recom-
mended for the treatment of septic shock.12
The indole core is an important pharmacophore in a wide
range of biologically active molecules. Numbers of b-fused
indole derivatives are used mainly as pharmaceuticals.1 The
attractive approach for cycle annulation to the indole core is [4
+ 2] cycloaddition reactions of indole-2,3-quinodimethanes
and dienophiles.2 Herein, we investigate the properties of
lithium indole-2,3-dienolates 2 generated from 3-acyl-2-
methylindoles 1. These compounds are of particular interest
because of the increased electron density in their diene
structure, which leads to high reactivity toward electron-
deficient dienophiles. For example, the reaction with dimethyl
acetylenedicarboxylate (DMAD) leads to the carbazole
derivatives 3.3a Reactions with unsaturated aldehydes, which
also allow the formation of a carbazole nucleus, are
described.3b
As we have investigated earlier, reactions of compounds 2
with nitriles lead to γ-carbolines 4.4 Thus, lithium indole-2,3-
dienolates 2 react with molecules containing CC, CC,
and CN fragments via cycloaddition reactions. The reactions
of compounds 2 with dienophiles containing a CS bond are
unknown. In the present work, CS2 is used as a molecule
containing this fragment. It is expected that its addition to the
lithium indole-2,3-dienolates 2 will lead to the formation of
thiopyrano[b]indoles 5 (Scheme 1).
To obtain the thiopyranoindoles, the Fischer reaction is
used.8a,b,9,13 An alternative method is the cycloaddition
reaction of DMAD and indole-3-dithiocarboxylic acid deriva-
tives,14 as well as other dienophiles and 3-thioacetylindole.15
The above methods have some disadvantages. Starting
compounds of the tetrahydro-4H-thiopyran-4-one series for
the Fischer reaction are obtained by multistage synthesis; the
method using DMAD requires unstable thiocarbonyl com-
pounds.
Received: May 23, 2021
Thiopyrano[b]indole derivatives are of interest due to their
biological activity. For example, thiopyrano[2,3-b]indoles 6
and 7 are antibacterial5 and analgesic6 agents, respectively. The
thiopyrano[3,4-b]indole derivative 8 (tandamine) is an
antidepressant7 (Figure 1).
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© XXXX American Chemical Society
A

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Scheme 1. Cycloaddition Reactions of Lithium Indole-2,3-Dienolates
Figure 1. Significant compounds of the thiopyrano[b]indole series.
Monocyclic thiopyrans are obtained when CS2 reacts with
electron-rich dienes: dienamines 1216 or cobalt compounds
1317 (Scheme 2). 2H-Thiopyran-2-thiones 14 are formed in
both cases.
Scheme 3. Reaction of 1,4-Dilithium-1,3-dienes with
Carbon Disulfide
Scheme 2. Cycloaddition Reactions of Carbon Disulfide and
Dienes
The object of this work was the synthesis of thiopyrano[4,3-
b]indoles 5 from lithium indole-2,3-dienolates 2 and CS2 and
the quantum chemical study of the reaction mechanism.
RESULTS AND DISCUSSION
■
When 1,4-dilithium-1,3-dienes 15 react with CS2, along with
the formation of 2H-thiopyran-2-thione 16, thiophenes 17, and
cyclopentadiene derivatives 18 are also formed (Scheme 3).18
The above reactions of diene systems with CS2 have not
previously been used to obtain compounds of the thiopyrano-
[4,3-b]indole series.
The required diene system 2 was generated by the elimination
of a proton from the methyl group of 3-acyl-2-methylindoles 1.
Compounds 1 were obtained by Vilsmeier acylation of 2-
methylindole 19 followed by alkylation of 2-methyl-3-
acylindoles 20 (Scheme 4).
B
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Scheme 4. Synthesis of Starting Compounds*
*
**
Yields of recrystallized products. Yield of the crude product, oil.
Scheme 5. Reaction of Carbon Disulfide and Lithium Indole-2,3-dienolates
To synthesize thiopyranoindoles, we treated sequentially 3-
acyl-2-methylindoles 1 with lithium diisopropylamide (LDA),
CS2, and water (Scheme 5). The red crystals were isolated.
addition, and the formation of product 17 corresponds to
thiophilic addition.
Herein, depending on the orientation of the CS2 molecule
relative to the structures 2, the formation of isomeric products
5 (path A, carbophilic addition) or 22 (path B, thiophilic
addition) is expected (Scheme 5). In addition, the formation of
both products 5 and 22 proceeds either by a concerted or a
stepwise path, as shown in Scheme 5. We carried out quantum-
chemical calculations of possible reaction variants using three
methods: PCM/DFT/B3LYP/6-311++G**, PBE1PBE/6-
311++G**, and MP2//HF/6-311++G**. Geometries of
stationary points on the potential energy surface (PES) are
given in Tables S2−S4, respectively.
1
The H NMR, 13C{1H} NMR, and mass spectra of the
compounds obtained do not make it possible to establish
unambiguously the structure of the products formed, since two
reaction paths for the addition of CS2 to organolithium
reagents are possible. The traditional path involves the attack
of the negatively charged carbon atom of the organolithium
reagent at the CS2 carbon atom (carbophilic addition) by
analogy with CO2. However, because of the specificity of the
sulfur atom, the addition of the carbanion at the sulfur atom
can proceed (thiophilic addition). Both of these paths are well-
known (see ref 18a and references therein). For example, in
Scheme 3, product 18 is obtained as the result of carbophilic
Path A Calculations (Carbophilic CS2 Addition).
According PCM/DFT/B3LYP/6-311++G** calculations, tak-
ing into account the solvation effects,19 a stable ion pair 24a is
C
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Figure 2. Minimum energy paths (MEPs) of the reaction of carbon disulfide and lithium indole-2,3-dienolate 5a, according to PCM/B3LYP/6-
311++G** (a), PBE1PBE/6-311++G** (b), and MP2//HF/6-311++G** (c) quantum-chemical calculations. ΔG: relative values of Gibbs free
energies in kcal/mol. Subscripts A and B correspond to paths A and B (Scheme 5). Unchanging fragments of molecules are shown as colorless.
D
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formed (Figure 2a, Figure S1). The choice of temperature
conditions and solvent is justified below. This process is an
electrophilic addition of the positively charged carbon of CS2
to the negatively charged methylene carbon of the organic
substrate.
The ion-pair 24a is nonrigid, and the Li atom can move with
a small barrier into the space between the sulfur and oxygen
atoms. This leads to the system 24a′ (Figure 2b,c, Figure
S2)where the Li atom forms two bonds of equal energy with
the oxygen and nitrogen atoms in an eight-membered cycle
(ρ(rc) = 0.028). The system 24a′ is energetically less favorable
compared to system 24a by only 3.2 kcal/mol (PCM/DFT
calculation results).
According to the gas-phase calculations PBE1PBE/6-311+
+G** and MP2//HF/6-311++G**, a similar mechanism of
the first stage was found (Figure 2b,c). In the DFT
calculations, for the first stage the energy barrier value is
14.8 kcal/mol, while in the PBE and MP2/HF calculations
these barriers are extremely small. At the next stage, S−C
binding proceeds leading to the six-membered cycle formation,
but in PCM/DFT calculations (Figure 2a) structure 23a
(Figure 2b,c, Figure S3) does not correspond to a minimum on
the PES.The barriers of stage 24a → 23a in PBE and MP2/HF
calculations (where structure 23a was localized) are quite
close: 20.7 and 21.4 kcal/mol, respectively (Figure 2b,c). It
should be noted, that other possibilities of interaction between
−OLi and sulfur atom, even they form nonstrained six-
membered rings analogous to 23a, in all calculation schemes
do not correspond to the stationary points at the PESs and
optimize into 24a′.
unusual multicenter structure 25a (Figure 2c, Figure S5),
corresponding nevertheless to the minimum on the PES, is an
endothermic process and counters the charge distribution in
the initial reagents. Incidentally, in the DFT and PBE
calculations, the stationary points on the PES do not
correspond to the intermediate 25a. Thus, only the
synchronous [4 + 2] cycloaddition processes 2a + CS2 →
21a are possible.
Along the energetically less favorable path B, the
coordinating role of the lithium atom is also significant. In
intermediate 25a (localized only by MP2/HF calculations),
the lithium atom is coordinated with both the oxygen atom
and the CS2 fragment carbon atom forming an eight-
membered ring, as shown in Scheme 5. This makes it spatially
difficult for the further transformation of system 25a into
system 21a (Figure 2a−c). In this case, the binding of a lithium
atom to a carbon atom is stronger than with the carbonyl
group oxygen atom (ρ(rc) = 0.033 and ρ(rc) = 0.026,
respectively).
According to the AIM/PBE calculations, in the intermediate
21a (Figure S6) lithium atoms form bonds with both oxygen
and sulfur atoms (ρ(rc) = 0.056 and ρ(rc) = 0.024,
respectively).
In the transition state TS2B (Figure S7), which is on the
minimum energy path (MEP) of system 21a formation, the
lithium atom is also bound simultaneously to the oxygen and
sulfur atoms (ρ(rc) = 0.031 and ρ(rc) = 0.026, respectively). In
this case, the bond formation between the indole C(3) carbon
atom and the CS2 fragment carbon atom (ρ(rc) = 0.017) is
observed.
It is probable that isomeric products 5a and 22a are formed
after LiOH elimination from structures 23a and 21a,
respectively (partial crystallization of the product 5a before
the addition of water serves as indirect experimental evidence).
In all cases, product 5a is thermodynamically more stable than
product 22a, both in the gas phase and in THF (Table 1). In
According to the quantum-chemical data, the concerted
cycloaddition pathway 2a + CS2 → 23a does not in any case
exist.
Therefore, along Path A the reaction of CS2 with lithium
indole-2,3-dienolates proceeds via a stepwise mechanism:
initially the C−C bond is formed leading to ion-pair 24a,
and then the six-membered cycle is formed because of S−C
binding.
It should be noted that the Li atom plays a significant role in
the calculated mechanism of the 1a → 2a → 24a → 23a → →
5a transformation along path A. Previously, we discovered the
similar effects of Li polycoordination.4 The Li ion stabilizes
structurally the S−C−S triad at the 2a → 24a stage according
to AIM/PBE analysis. The Li atom is binded to both sulfur
atoms in the structure 24a with equal energy (ρ(rc) = 0.190).
At the same time, in the transition state TS1A (Figures 2a,b,
Figure S4) is triple-coordinated and forms bonding paths with
the oxygen, indole carbon C(2), and sulfur atoms (ρ(rc) =
0.037, ρ(rc) = 0.021, ρ(rc) = 0.014, respectively).
In the intermediate 23a the Li atom forms bonds with
oxygen and carbon C(9a) atoms only (ρ(rc) = 0.051 and ρ(rc)
= 0.014, respectively) despite the overlap of the van der Waals
radii of the Li and S atoms (Figure 2b,c, Figure S3).
Consequently, at stage 24a → 23a, simultaneous con-
vergence of the S−C and Li−O atom pairs occurs. The second
stage of the formation of structure 23a is closer to a diotropic
process than to a simple two-center interaction of sulfur and
carbon atoms.
Table 1. Relative Gibbs Energies ΔG (in kcal/mol) of
a
System 22a and 5a
ΔG
B3LYP (THF, −
78 °C)
PBE1PBE (gas
phase)
MP2//HF (gas
phase)
structure
22a
5a
0.0
−8.1
0.0
−7.0
0.0
−5.1
a
Energy system 22a as a zero point.
summary, the addition of CS2 to the lithium indole-2,3-
dienolates proceeds via stepwise Path A. The results of
quantum chemical calculations agree with the X-ray analysis of
product 5a (Figure 3).
Atomic coordinates, full tables of bond lengths, bond angles,
and thermal parameters for system 5a have been deposited at
the Cambridge Crystallographic Data Center (deposition no.
2064018). Bond lengths and bond angles are similar in both
experimental (X-ray) and quantum chemical studies (Figure
S8).
To optimize the reaction conditions, we investigated the
effect of solvent, temperature, and molar ratio on the product
yield using 3-benzoyl-1,2-dimethylindole 1a, LDA, and CS2
(Table 2). Compound 1a was reacted with LDA at the
indicated temperature for 3 h, treated with CS2, and left
overnight at room temperature.
Path B Calculations (Thiophilic CS2 Addition). For a
different intermolecular orientation along Path B, two
cycloaddition mechanisms are also possible: synchronous and
stepwise. However, in the gas-phase MP2//HF/6-311++G**
calculations, the formation of an intermediate ion-pair with an
E
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substituents R at position 5, in yields of up to 87%. The α
carbonyl carbon of starting compound 1 must have no
hydrogens. An attempts to obtain products 5 bearing R1 = H, t-
Bu failed. The reactions resulted in resinification of the
reaction mixture, apparently because of the reduced stability of
enolates 2 with R1 = H, t-Bu compared to aryl-substituted
analogues 2 (R1 = Ar).The presence of an aminoalkyl
substituent at the nitrogen atom did not affect product yield
(example 5i).
CONCLUSIONS
■
In summary, a new synthetic approach was proposed for a one-
pot synthesis of thiopyrano[4,3-b]indol-3(5H)-thiones starting
from readily available 3-aroyl-2-methylindoles 1 and CS2.
According to the quantum-chemical calculations, the reaction
is a stepwise addition of CS2 to lithium indole-2,3-dienolates 2
via ion-pair 24 formation.
EXPERIMENTAL SECTION
■
General Information. Tetrahydrofuran was refluxed over CaH2,
distilled, and then redistilled directly into the reaction vessel from
sodium benzophenone ketyl under argon atmosphere. Benzene was
first distilled from P2O5 and then from sodium. N,N-Dimethylar-
ylamides were synthesized according to the known methods from acid
chlorides and dimethylamine.23 2-Methylindole 13, NaH (Alfa
Aesar), and LDA (Acros Organics) were used as received. Carbon
disulfide (Acros Organics) was distilled from anhydrous CuSO4. For
reactions that require heating, an electric stove was used as the heat
source. To reach a temperature of −25 °C, a reaction vessel was
placed in a household freezer. For cooling to −78 °C, a bath
containing a mixture of ethyl acetate and liquid nitrogen or dry ice
and acetone was used. NMR spectra were recorded on Bruker
Avance-600 (600 MHz for 1H, 151 MHz for 13C{1H}), Varian Unity-
Figure 3. Molecular structure of compound 5a with ellipsoid shown
at the 30% contour percent probability level.
Table 2. Optimization of the Reaction Conditions
temp
(°C)
isolated yield of 5a molar ratio 1a/LDA/
entry
solvent
(%)
CS2
1
2
3
4
5
6
benzene
benzene
THF
THF
THF
+25
+25
−32
−32
−78
−78
8
0
56
0
46
0
1:2:2
1:1:1
1:2:2
1:1:1
1:2:2
1:1:1
1
1
THF
300 (300 MHz for H), and Bruker DPX-250 (250 MHz for H, 63
MHz for 13C{1H}) spectrometers. All resonances are reported relative
to TMS. Spectra were calibrated relative to the solvents’ residual
A 2-fold excess of LDA and CS2 is required for product 5a
obtaining. An attempt to use equimolar ratio of reagents results
in starting compound 1a isolation in all cases.
1
proton and carbon chemical shifts: CHCl3 (δ = 7.26 ppm for H
NMR and δ = 77.16 ppm for 13C{1H} NMR). Carbon types and
structure assignments were determined from APT-NMR or CPD-
NMR and two-dimensional experiments (HMQC and HMBC,
COSY, and NOESY). NMR spectra were analyzed using MestReNova
NMR data processing software (www.mestrelab.com). Coupling
constants (J) are reported in hertz (Hz). The multiplicity of the
signals is given as s (singlet), d (doublet), t (triplet), and m
(multiplet). Copies of 1H NMR and 13C{1H} NMR spectra are
provided in the Supporting Information. Thin-layer chromatography
(TLC) was performed on silica gel or Al2O3 plates, and components
were visualized under UV light and/or by treating the plates with
iodine. Elemental analysis was performed on an Elemental Vario
Micro cube CHNS analyzer. The chlorine content was determined
A choice of solvent is limited to hydrocarbons and ethers
owing to LDA reactivity.20 Initially, the experiment was carried
out in anhydrous benzene at 25 °C, since these conditions are
optimal for a similar reaction of compound 1a with nitriles in
the γ-carbolines synthesis.4 The yield of thiopyranoindole 5a in
this case was 8%. Hexane and Et2O are also applicable for
reactions using LDA; however, starting compounds 1 are not
soluble in these solvents. THF is a common media because of
its ability to act as a ligand for lithium. It causes LDA
depolymerization and increases the reactivity of the C−Li
bond.21 An effective cooling of the reaction mixture is
necessary to inhibit THF cleavage induced by deprotonation
in the α position of the ether.22 That is why in this work only
benzene and THF were tested. When anhydrous THF was
used as a solvent, the yield of the product 5a was found to be
significantly higher: the best result was achieved at −32 °C
(Table 2).
With the optimized reaction conditions in hand, we
synthesized the series of thiopyrano[4,3-b]indol-3(5H)-thiones
5a−i (Scheme 5). When obtaining product 5i, the starting
compound was reacted as the hydrochloride 1i using an
additional LDA equivalent. Hydrochloride 1i was formed when
1j was treated with a solution of HCl in propan-2-ol (see the
Experimental Section).
̈
separately by the Schoniger method. MS data (EI, 70 eV) were
recorded on a Finnigan MAT INCOS 50. The unit cell parameters
and reflection intensities for 5a (a three-dimensional set) were
measured on an ‘Xcalibur, Eos’ autodiffractometer (MoK\α
irradiation, graphite monochromator, 100 K). DFT calculations
were performed using B3LYP24 and PBE25 exchange-correlation
functionals together with the standard 6-311++G** basis set. Ab
initio calculations on the same basis were performed and second-
order Møller−Plesset perturbation (MP2) theory taken into account.
Geometry optimization was carried out using Bemy’s analytical
gradient optimization method. Stationary points of the MEPs were
characterized by frequency calculations, and MEPs were obtained via
the gradient descent method from the transition states in both direct
and reverse directions of the transition vectors. Solvent effects were
considered in the context of a polarizable continuum model (PCM).
All computations were carried out using the Gaussian 09 suite of
programs26 using the Silver cluster of the Research Institute of
Our method is suitable for synthesis of products 5 with
aromatic substituents R1 at position 1 and aliphatic
F
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Physical and Organic Chemistry at Southern Federal University. We
also performed a topological analysis of electron density distribution
function according to the Atoms in Molecules (AIM) model.27
General Procedure for the Synthesis of Indoles 20a−d
(GP1). POCl3 (1 equiv) was added dropwise to arylamide (1.6 equiv).
2-Methylindole 19 (0.8 equiv) was added into the reaction vessel, and
the components were stirred at 85 °C for 2 h. After being cooled, the
resulting mixture was neutralized by NaOH (6 equiv) as a 20% water
solution. The solid product was filtered and purified by recrystalliza-
tion.
using (2-methyl-1H-indol-3-yl)(phenyl)methanone 20a (4.00 g,
17.00 mmol), NaH (1.02 g of 60% suspension in mineral oil, 25.50
mmol), and benzyl chloride (3.23 g, 25.50 mmol). Yellow solid, 89%
1
isolated yield (4.92 g); mp 124−125 °C (propan-2-ol). H NMR
(CDCl3, 250 MHz): δ 7.75−7.84 (m, 2H, CHarom), 7.51−7.61 (m,
1H, CHarom), 7.42−7.51 (m, 2H, CHarom), 7.25−7.38 (m, 5H,
CHarom), 7.12−7.21 (m, 1H, CHarom), 6.99−7.12 (m, 3H, CHarom),
5.40 (s, 2H, CH2), 2.55 (s, 3H, CH3) ppm. 13C{1H} NMR (CDCl3,
63 MHz): δ 193.2, 144.6, 141.5, 136.5, 136.3, 131.7, 129.3, 129.1,
128.4, 127.9, 127.4, 126.1, 122.5, 121.7, 121.2, 114.3, 109.8, 46.8, 12.6
ppm. Anal. Calcd for C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found:
C, 84.72; H, 5.80; N, 4.23.
(2-Methyl-1H-indol-3-yl)(phenyl)methanone (20a). Compound
20a was synthesized according to GP1. Weight, yield, melting point,
and spectral characteristics are the same as described.4
(1,2-Dimethyl-1H-indol-3-yl)(p-tolyl)methanone (1d). Com-
pound 1d was obtained according to GP2 using (2-Methyl-1H-
indol-3-yl)(p-tolyl)methanone 20b (10.37 g, 41.59 mmol), KOH
(4.66 g, 83.18 mmol), and dimethyl sulfate (10.49 g, 83.18 mmol).
Colorless solid, 82% isolated yield (8.98 g); mp 123−125 °C
(2-Methyl-1H-indol-3-yl)(p-tolyl)methanone (20b). Compound
20b was obtained according to GP1 using POCl3 (9.30 mL, 0.10
mol), 4-methyl-N,N-dimethylbenzamide (26.12 g, 0.16 mol), and 2-
methylindole 19 (10.49 g, 0.08 mol). Colorless solid, 55% yield
(11.00 g); mp 202−206 °C (butanol-1) (lit.28 mp 208−209 °C).
(4-Chlorophenyl)(2-methyl-1H-indol-3-yl)methanone (20c).
Compound 20c was obtained according to GP1 using POCl3 (5.58
mL, 60.00 mmol), 4-chloro-N,N-dimethylbenzamide (17.62 g, 96.00
mmol) and 2-methylindole 19 (6.29 g, 48.00 mmol). Colorless solid,
74% yield (9.53 g); mp 175−177 °C (propan-2-ol) (lit.29 mp 190−
(ethanol) (lit.31 mp 123−124 °C (n-hexane/chloroform)). H NMR
1
(CDCl3, 300 MHz): δ 7.64−7.73 (m, 2H, CHarom), 7.29−7.37 (m,
2H, CHarom), 7.16−7.26 (m, 3H, CHarom), 7.07 (t, J = 7.50 Hz, 1H,
CHarom), 3.75 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.44 (s, 3H, CH3)
ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 192.8, 144.4, 142.2, 138.7,
136.6, 129.5, 129.0, 127.3, 122.1, 121.4, 121.2, 113.9, 109.2, 29.8,
21.8, 12.6 ppm. Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N,
5.32. Found: C, 82.21; H, 6.50; N, 5.30.
1
193 °C (methanol)). H NMR (CDCl3, 250 MHz): δ 8.91 (s, 1H,
NH), 7.66−7.79 (m, 2H, CHarom), 7.40−7.49 (m, 2H, CHarom), 7.27−
7.40 (m, 2H, CHarom), 7.04−7.22 (m, 2H, CHarom), 2.55 (s, 3H, CH3)
ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 192.0, 144.0, 139.6, 137.9,
134.8, 130.6, 128.8, 127.5, 122.7, 121.9, 120.9, 113.8, 110.9, 14.6
ppm. Anal. Calcd for C16H12ClNO C, 71.25; H, 4.48; Cl, 13.14; N,
5.19. Found: C, 71.31; H, 4.48; Cl, 13.02; N, 5.18.
(4-Chlorophenyl)(1,2-dimethyl-1H-indol-3-yl)methanone (1e).
Compound 1e was obtained according to GP2 using (4-
chlorophenyl)(2-methyl-1H-indol-3-yl)methanone 20c (5.00 g,
18.55 mmol), KOH (2.08 g, 37.11 mmol), and dimethyl sulfate
(4.68 g, 37.11 mmol). Colorless solid, 86% isolated yield (2.73 g); mp
1
(4-(tert-Butyl)phenyl)(2-methyl-1H-indol-3-yl)methanone (20d).
Compound 20d was obtained according to GP1 using POCl3 (4.82
mL, 51.80 mmol), 4-tert-butyl-N,N-dimethylbenzamide (17.00 g,
82.90 mmol), and 2-methylindole 19 (5.44 g, 41.50 mmol). Colorless
solid was obtained in 92% isolated yield (7.15 g); mp 213-215 °C
(butanol-1). 1H NMR (CDCl3, 250 MHz): δ 8.84 (s, 1H, NH),
7.69−7.77 (m, 2H, CHarom), 7.43−7.52 (m, 3H, CHarom), 7.27−7.33
(m, 1H, CHarom), 7.03−7.21 (m, 2H, CHarom), 2.52 (s, 3H, CH3),
1.37 (s, 9H, t-Bu) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 193.2,
155.4, 143.4, 138.4, 134.8, 129.2, 127.8, 125.3, 122.5, 121.6, 121.1,
114.3, 110.8, 35.2, 31.4, 14.6 ppm. Anal. Calcd for C20H21NO C,
82.44; H, 7.26; N, 4.81. Found: C, 81.31; H, 7.30; N, 4.80.
General Procedure for the Synthesis of Indoles 1a−h, 1j
(GP2). Compound 14 (1 equiv) and powdered KOH (2 equiv) in dry
DMSO were stirred at 70 °C for 1 h. Alkyl sulfate (2 equiv) was
added, and the reaction mixture was left overnight. Water was added,
and product was extracted with ethyl acetate (3 × 20 mL). The
combined organic extract was dried over anhydrous Na2SO4 and
concentrated under vacuum. Solid product was purified by
recrystallization.
155−157 °C (propanol-2). H NMR (CDCl3, 250 MHz): δ 7.65−
7.79 (m, 2H, CHarom), 7.38−7.49 (m, 2H, CHarom), 7.18−7.37 (m,
3H, CHarom), 7.03−7.14 (m, 1H, CHarom), 3.75 (s, 3H, CH3), 2.61 (s,
3H, CH3) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 191.5, 145.1,
139.8, 137.8, 136.7, 130.7, 128.6, 127.0, 122.3, 121.7, 120.9, 113.4,
109.4, 29.9, 12.6 ppm. Anal. Calcd for C17H14ClNO: C, 71.96; H,
4.97; Cl, 12.49; N, 4.94. Found: C, 71.73; H, 5.01; Cl, 12.70; N, 4.89.
(4-Chlorophenyl)(1-ethyl-2-methyl-1H-indol-3-yl)methanone
(1f). Compound 1f was obtained according to GP2 using (4-
chlorophenyl)(2-methyl-1H-indol-3-yl)methanone 20c (2.50 g, 9.27
mmol), KOH (1.04 g, 18.54 mmol), and diethyl sulfate (2.85 g, 18.54
mmol). Colorless solid, 69% isolated yield (1.89 g); mp 107−109 °C
1
(propan-2-ol). H NMR (CDCl3, 250 MHz): δ 7.67−7.76 (m, 2H,
CHarom), 7.39−7.47 (m, 2H, CHarom), 7.32−7.38 (m, 1H, CHarom),
7.16−7.26 (m, 2H, CHarom), 7.02−7.12 (m, 1H, CHarom), 4.23 (q, J =
7.26 Hz, 2H, CH2CH3), 2.63 (s, 3H, CH3), 1.42 (t, J = 7.25 Hz, 3H,
CH2CH3) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 191.6, 144.3,
139.9, 137.8, 135.6, 130.7, 128.7, 127.2, 122.3, 121.6, 121.0, 113.5,
109.5, 38.2, 14.9,12.4 ppm. Anal. Calcd for C18H16ClNO: C, 72.60;
H, 5.42; Cl, 11.90; N, 4.70. Found: C, 72.51; H, 5.47; Cl, 11.73; N,
4.80.
(1,2-Dimethyl-1H-indol-3-yl)(phenyl)methanone (1a). Com-
pound 1a was synthesized according to known method. Weight,
yield, melting point and spectral characteristics are the same as
described.4
(4-(tert-Butyl)phenyl)(1,2-dimethyl-1H-indol-3-yl)methanone
(1g). Compound 1g was obtained according to GP2 using (4-(tert-
butyl)phenyl)(2-methyl-1H-indol-3-yl)methanone 20d (5.00 g, 17.18
mmol), KOH (1.92 g, 34.36 mmol), and dimethyl sulfate (4.32 g,
34.36 mmol). Colorless solid, 86% isolated yield (4.50 g); mp 179−
181 °C (propanol-2). 1H NMR (CDCl3, 250 MHz): δ 7.69−7.78 (m,
2H, CHarom), 7.43−7.50 (m, 2H, CHarom), 7.37−7.43 (m, 1H,
CHarom), 7.28−7.36 (m, 1H, CHarom), 7.17−7.25 (m, 1H, CHarom),
7.04−7.14 (m, 1H, CHarom), 3.74 (s, 3H, CH3), 2.58 (s, 3H, CH3),
1.38 (s, 9H, t-Bu) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 192.7,
155.3, 144.4, 138.6, 136.6, 129.3, 127.2, 125.2, 122.1, 121.4, 121.2,
113.9, 109.2, 35.2, 31.4, 29.8, 12.7 ppm. Anal. Calcd for C21H23NO:
C, 82.58; H, 7.59; N, 4.59. Found: C, 82.41; H, 7.62; N, 4.51.
(4-(tert-Butyl)phenyl)(1-ethyl-2-methyl-1H-indol-3-yl)-
methanone (1h). Compound 1h was obtained according to GP2
using (4-(tert-butyl)phenyl)(2-methyl-1H-indol-3-yl)methanone 20d
(1.50 g, 5.15 mmol), KOH (0.57 g, 10.30 mmol), and diethyl sulfate
(1.59 g, 10.30 mmol). Colorless solid, 47% isolated yield (0.77 g); mp
(1-Ethyl-2-methyl-1H-indol-3-yl)(phenyl)methanone (1b). Com-
pound 1b was obtained according to GP2 using (2-methyl-1H-indol-
3-yl)(phenyl)methanone 20a (7.70 g, 32.74 mmol), KOH (3.67 g,
65.48 mmol), and diethyl sulfate (10.10 g, 65.48 mmol). Colorless
solid was obtained in 82% isolated yield (7.07 g); mp 105−107 °C
(propanol-2) (lit.30 mp 103−104 °C (ethyl ether)). 1H NMR
(CDCl3, 600 MHz): δ 7.75−7.78 (m, 2H, CHarom), 7.53−7.56 (m,
1H, CHarom), 7.43−7.48 (m, 2H, CHarom), 7.28−7.35 (m, 2H,
CHarom), 7.19−7.22 (m, 1H, CHarom), 7.04−7.08 (m, 1H, CHarom),
4.22 (q, J = 7.28 Hz, 2H, CH2), 2.61 (s, 3H, CH3), 1.42 (t, J = 7.28
Hz, 3H, CH2CH3) ppm. 13C{1H} NMR (CDCl3, 151 MHz): δ 193.1,
144.0, 141.7, 135.6, 131.5, 129.2, 128.3, 127.5, 122.1, 121.4, 121.2,
113.9, 109.3, 38.1, 14.9, 12.3 ppm. Anal. Calcd for C18H17NO: C,
82.10; H, 6.51; N, 5.32. Found: C, 81.93; H, 6.49; N, 5.30.
(1-Benzyl-2-methyl-1H-indol-3-yl)(phenyl)methanone (1c).
Compound 1c was synthesized according to the known method4
1
123−125 °C (propanol-2). H NMR (CDCl3, 250 MHz): δ 7.68−
G
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7.79 (m, 2H, CHarom), 7.42−7.50 (m, 2H, CHarom), 7.31−7.41 (m,
2H, CHarom), 7.16−7.25 (m, 1H, CHarom), 7.03−7.14 (m, 1H,
CHarom), 4.22 (q, J = 7.24 Hz, 2H, CH2CH3), 2.60 (s, 3H, CH3), 1.42
(t, J = 7.25 Hz, 3H, CH2CH3), 1.37 (s, 9H, t-Bu) ppm. 13C{1H}
NMR (CDCl3, 63 MHz): δ 192.8, 155.3, 143.6, 138.6, 135.5, 129.3,
127.5, 125.2, 122.0, 121.3, 121.3, 114.0, 109.3, 38.1, 35.2, 31.4, 15.0,
12.4 ppm. Anal. Calcd for C22H25NO: C, 82.72; H, 7.89; N, 4.38.
Found: C, 82.57; H, 7.89; N, 4.44.
(2-Methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-indol-3-yl)(phenyl)-
methanone (1j). Compound 1j was synthesized according to known
method4 using (2-methyl-1H-indol-3-yl)(phenyl)methanone 20a
(1.06 g, 4.52 mmol), NaH (0.22 g of 60% suspension in mineral
oil, 5.42 mmol), and 1-(3-chloropropyl)pyrrolidine32 (1.00 g, 6.77
mmol). Oil, 92% isolated yield (1.44 g). 1H NMR (CDCl3, 250
MHz): δ 7.62−7.72 (m, 2H, CHarom), 7.40−7.50 (m, 1H, CHarom),
7.27−7.39 (m, 3H, CHarom), 7.05−7.24 (m, 2H, CHarom), 6.91−7.01
(m, 1H, CHarom), 4.15 (t, J = 7.18 Hz, 2H, CH2), 2.52 (s, 3H, CH3),
2.34−2.45 (m, 6H, CH2), 1.84−1.97 (m, 2H, CH2), 1.65−1.77 (m,
4H, CH2) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 193.0, 144.6,
141.6, 136.1, 131.5, 129.1, 128.3, 127.3, 122.0, 121.3, 121.0, 113.7,
109.6, 54.1, 52.9, 41.3, 28.9, 23.6,12.5 ppm. Anal. Calcd for
C23H26N2O: C, 79.73; H, 7.56; N, 8.09. Found: C, 79.54; H, 7.59;
N, 8.19.
1-(3-(3-Benzoyl-2-methyl-1H-indol-1-yl)propyl)pyrrolidin-1-ium
Chloride (1i). The crude (2-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-
indol-3-yl)(phenyl)methanone 20a (1.44 g, 4.16 mmol) in dry
benzene was treated with the saturated solution of HCl in anhydrous
propan-2-ol until acidic to give product 1j as colorless solid in 78%
isolated yield (1.24 g), mp 223−225 °C (benzene). 1H NMR
(CDCl3, 250 MHz): δ 12.68 (s, 1H, NH), 7.68−7.79 (m, 2H,
CHarom), 7.51−7.62 (m, 1H, CHarom), 7.28−7.49 (m, 4H, CHarom),
7.16−7.25 (m, 1H, CHarom), 7.02−7.14 (m, 1H, CHarom), 4.39 (t, J =
6.87 Hz, 2H, CH2), 3.54−3.96 (m, 2H, CH2), 2.97−3.14 (m, 2H,
CH2), 2.58 (s, 3H, CH3), 2.53−2.87 (m, 2H, CH2), 2.38−2.52 (m,
2H, CH2), 1.91−2.30 (m, 4H, CH2) ppm. 13C{1H} NMR (CDCl3, 63
MHz): δ 193.1, 143.6, 141.1, 135.9, 131.9, 129.2, 128.5, 127.3, 122.7,
121.9, 121.4, 114.6, 109.2, 53.9, 52.9, 40.7, 26.0, 23.5, 12.8 ppm. Anal.
Calcd for C23H27ClN2O: C, 72.14; H, 7.11; Cl, 9.26; N, 7.32. Found:
C, 72.02; H, 7.01; Cl, 9.28; N, 7.44.
General Procedure for the Thiopyrano[4,3-b]indole-3(5H)-
thiones 5a−h Synthesis (GP3). All reactions were carried out in
flame-dried glassware under a slightly positive pressure of dry,
prepurified argon. Compound 1a−1h (1 equiv) was dissolved in
THF, cooled to −32 °C, and treated with lithium diisopropylamide (2
equiv, 2 M sol in THF/n-heptane/ethylbenzene). The reaction
mixture was kept for 3 h. Carbon disulfide (2 equiv) was added, and
the reaction mixture was left overnight at room temperature. The
reaction was quenched by water addition, and product 5a−h was
precipitated and purified by crystallization (see below).
Hz, 1H, CHarom), 6.98 (t, J = 7.56 Hz, 1H, CHarom), 4.20 (q, J = 7.29
Hz, 2H, CH2), 1.45 (t, J = 7.29 Hz, 3H, CH3) ppm. 13C{1H} NMR
(CDCl3, 151 MHz): δ 191.8, 157.4, 148.6, 142.6, 133.9, 130.8, 129.5,
129.5, 128.8, 123.5, 122.9, 122.5, 121.6, 114.9, 109.5, 38.2, 13.0 ppm.
Anal. Calcd for C19H15NS2: C, 70.99; H, 4.70; N, 4.36; S, 19.95.
Found: C, 70.81; H, 4.73; N, 4.32; S, 19.76.
5-Benzyl-1-phenylthiopyrano[4,3-b]indole-3(5H)-thione (5c).
Compound 5c was obtained according to GP3 using (1-benzyl-2-
methyl-1H-indol-3-yl)(phenyl)methanone 1c (0.70 g, 2.15 mmol),
LDA (2.15 mL of 2 M solution, 4.30 mmol), and CS2 (0.26 mL, 4.30
mmol). Red solid, 41% isolated yield (0.34 g); mp 243−245 °C (1,2-
dichloroethane). 1H NMR (CDCl3, 250 MHz): δ 7.73 (s, 1H,
CHarom), 7.51−7.69 (m, 5H, CHarom), 7.18−7.48 (m, 7H, CHarom),
6.96−7.16 (m, 2H, CHarom), 5.38 (s, 2H, CH2) ppm. 13C{1H} NMR
(CDCl3, 63 MHz): δ 192.6, 157.6, 149.4, 143.3, 134.3, 133.9, 130.9,
129.6, 129.6, 129.4, 128.8, 128.5, 126.5, 123.5, 122.8, 122.8, 121.6,
115.5, 110.1, 46.9 ppm. Anal. Calcd for C24H17NS2: C, 75.16; H, 4.47;
N, 3.65; S, 16.72. Found: C, 75.31; H, 4.44; N, 3.70; S, 16.70.
5-Methyl-1-(p-tolyl)thiopyrano[4,3-b]indole-3(5H)-thione (5d).
Compound 5d was obtained according to GP3 using (1,2-dimethyl-
1H-indol-3-yl)(p-tolyl)methanone 1d (1.00 g, 3.81 mmol), LDA
(3.81 mL of 2 M solution, 7.62 mmol), and CS2 (0.46 mL, 7.62
mmol). Red solid, 49% isolated yield (0.6 g); mp 257−261 °C
1
(toluene); 252−253 °C (acetone). H NMR (CDCl3, 600 MHz): δ
7.66 (s, 1H, CHarom), 7.43−7.46 (m, 1H, CHarom), 7.35−7.41 (m, 4H,
CHarom), 7.26−7.28 (m, 1H, CHarom), 7.13−7.15 (m, 1H, CHarom),
6.99−7.02 (m, 1H, CHarom), 3.68 (s, 3H, CH3), 2.49 (s, 3H, CH3)
ppm. 13C{1H} NMR (CDCl3, 151 MHz): δ 192.0, 157.8, 149.6,
143.5, 141.3, 130.9, 130.2, 129.4, 128.7, 123.2, 122.7, 122.5, 121.5,
115.0, 109.5, 29.7, 21.7 ppm. Anal. Calcd for C19H15NS2: C, 70.99; H,
4.70; N, 4.36; S, 19.95. Found: C, 70.80; H, 4.67; N, 4.39; S, 20.01.
1-(4-Chlorophenyl)-5-methylthiopyrano[4,3-b]indole-3(5H)-thi-
one (5e). Compound 5e was obtained according to GP3 (4-
chlorophenyl)(1,2-dimethyl-1H-indol-3-yl)methanone 1e (1.00 g,
3.52 mmol), LDA (3.52 mL of 2 M solution, 7.05 mmol), and CS2
(0.43 mL, 7.05 mmol). Red solid, 46% isolated yield (0.55 g); 249−
1
250 °C (toluene). H NMR (CDCl3, 250 MHz): δ 7.65−7.72 (m,
1H, CHarom), 7.53−7.62 (m, 2H, CHarom), 7.43−7.53 (m, 3H,
CHarom), 7.27−7.32 (m, 1H, CHarom), 6.98−7.13 (m, 2H, CHarom),
3.70 (s, 3H, CH3) ppm. 13C{1H} NMR (CDCl3, 63 MHz): δ 192.1,
155.4, 149.4, 143.6, 137.2, 132.2, 130.2, 129.9, 129.8, 123.6, 122.7,
122.6, 121.1, 115.2, 109.7, 29.8 ppm. Anal. Calcd for C18H12ClNS2:
C, 63.24; H, 3.54; Cl, 10.37; N, 4.10; S, 18.76. Found: C, 63.39; H,
3.59; Cl, 10.42; N, 4.08; S, 18.84.
1-(4-Chlorophenyl)-5-ethylthiopyrano[4,3-b]indole-3(5H)-thione
(5f). Compound 5f was obtained according to GP3 ((4-
chlorophenyl)(1-ethyl-2-methyl-1H-indol-3-yl)methanone 1f (0.70
g, 2.35 mmol), LDA (2.35 mL of 2 M solution, 4.70 mmol), and
CS2 (0.28 mL, 4.70 mmol). Red solid, 46% isolated yield (0.38 g); mp
216−218 °C (CH3CN). 1H NMR (CDCl3, 250 MHz): δ 7.69 (s, 1H,
CHarom), 7.42−7.62 (m, 5H, CHarom), 7.26−7.33 (m, 1H, CHarom),
6.97−7.16 (m, 2H, CHarom), 4.20 (q, J = 7.25 Hz, 2H, CH2CH3), 1.45
(t, J = 7.23 Hz, 3H, CH2CH3) ppm. 13C{1H} NMR (CDCl3, 63
MHz): δ 191.8, 155.6, 148.5, 142.7, 137.2, 132.3, 130.2, 129.9, 129.7,
123.7, 122.8, 122.7, 121.4, 115.0, 109.7, 38.2, 13.0 ppm. Anal. Calcd
for C19H14ClNS2: C, 64.12; H, 3.97; Cl, 9.96; N, 3.94; S, 18.02.
Found: C, 64.03; H, 3.99; Cl, 10.01; N, 3.07; S, 17.96.
1-(4-(tert-Butyl)phenyl)-5-methylthiopyrano[4,3-b]indole-3(5H)-
thione (5g). Compound 5g was obtained according to GP3 using (4-
(tert-butyl)phenyl)(1,2-dimethyl-1H-indol-3-yl)methanone 1g (1.00
g, 3.27 mmol), LDA (3.27 mL of 2 M solution, 6.55 mmol), and CS2
(0.40 mL, 6.55 mmol). Red solid, 87% isolated yield (1.03 g); mp
250−252 °C (toluene). 1H NMR (CDCl3, 250 MHz): δ 7.70 (s, 1H,
CHarom), 7.55−7.62 (m, 2H, CHarom), 7.41−7.52 (m, 3H, CHarom),
7.26−7.31 (m, 1H, CHarom), 7.15−7.22 (m, 1H, CHarom), 6.98−7.08
(m, 1H, CHarom), 3.70 (s, 3H, CH3), 1.42 (s, 9H, t-Bu) ppm. 13C{1H}
NMR (CDCl3, 63 MHz): δ 192.0, 158.0, 154.5, 149.6, 143.5, 130.9,
129.4, 128.6, 126.5, 123.2, 122.8, 122.6, 121.5, 115.1, 109.5, 35.2,
31.4, 29.7 ppm. Anal. Calcd for C22H21NS2: C, 72.69; H, 5.82; N,
3.85; S, 17.64. Found: C, 82.23; H, 7.60; N, 4.55.
5-Methyl-1-phenylthiopyrano[4,3-b]indole-3(5H)-thione (5a).
Compound 5a was obtained according to GP3 using (1,2-dimethyl-
1H-indol-3-yl)(phenyl)methanone 1a (2.00 g, 8.03 mmol), LDA
(8.02 mL of 2 M solution, 16.06 mmol) and CS2 (0.97 mL, 16.06
mmol). Red solid, 56% isolated yield (1.37 g); mp 209−210 °C
(acetonitrile). 1H NMR (CDCl3, 250 MHz): δ 7.69 (s, 1H, CHarom),
7.40−7.65 (m, 6H, CHarom), 7.30 (s, 1H, CHarom), 6.94−7.10 (m, 2H,
CHarom), 3.70 (s, 3H, CH3) ppm. 13C{1H} NMR (CDCl3, 63 MHz):
δ 191.8, 157.2, 149.4, 143.4, 133.7, 130.8, 129.5, 129.4, 128.7, 123.3,
122.6, 122.5, 121.3, 115.0, 109.6, 29.7 ppm. MS (EI) m/z calcd for
C18H13NS2 M+ 307; found 307. Anal. Calcd for C18H13NS2: C, 70.32;
H, 4.26; N, 4.56; S, 20.86. Found: C, 70.43; H, 4.36; N, 4.42; S,
20.99.
5-Ethyl-1-phenylthiopyrano[4,3-b]indole-3(5H)-thione (5b).
Compound 5b was obtained according to GP3 using (1-ethyl-2-
methyl-1H-indol-3-yl)(phenyl)methanone 1b (1.00 g, 3.83 mmol),
LDA (3.83 mL of 2 M solution, 7.66 mmol), and CS2 (0.46 mL, 7.66
mmol). Red solid, 59% isolated yield (720 mg); mp 182−184 °C
1
(propanol-2). H NMR (CDCl3, 600 MHz): δ 7.69 (s, 1H, CHarom),
7.55−7.62 (m, 3H, CHarom), 7.49−7.53 (m, 2H, CHarom), 7.42−7.45
(m, 1H, CHarom), 7.27 (d, J = 8.13 Hz, 1H, CHarom), 7.04 (d, J = 7.71
H
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1-(4-(tert-Butyl)phenyl)-5-ethylthiopyrano[4,3-b]indole-3(5H)-
thione (5h). Compound 5h was obtained according to GP3 (4-(tert-
butyl)phenyl)(1-ethyl-2-methyl-1H-indol-3-yl)methanone 1h (0.60 g,
1.88 mmol), LDA (1.88 mL of 2 M solution, 3.76 mmol), and CS2
(0.23 mL, 3.76 mmol). Red solid, 42% isolated yield (0.30 g); 278−
Anton V. Lisovin − Department of Chemistry, Southern
Federal University, Rostov-on-Don 344090, Russia
Mikhail E. Kletskii − Department of Chemistry, Southern
Federal University, Rostov-on-Don 344090, Russia
Sergey V. Kurbatov − Department of Chemistry, Southern
Federal University, Rostov-on-Don 344090, Russia
1
280 °C (CH3CN). H NMR (CDCl3, 250 MHz): δ 7.67−7.74 (m,
1H, CHarom), 7.53−7.63 (m, 2H, CHarom), 7.40−7.51 (m, 3H,
CHarom), 7.26−7.33 (m, 1H, CHarom), 7.14−7.21 (m, 1H, CHarom),
6.96−7.08 (m, 1H, CHarom), 4.21 (q, J = 7.24 Hz, 2H, CH2CH3), 1.46
(t, J = 7.23 Hz, 3H, CH2CH3), 1.42 (s, 9H, t-Bu) ppm. 13C{1H}
NMR (CDCl3, 63 MHz): δ 158.0, 154.4, 148.6, 142.4, 130.9, 129.3,
128.5, 126.4, 123.3, 122.8, 122.5, 121.6, 114.8, 109.5, 38.1, 35.1, 31.3,
13.0 ppm. Anal. Calcd for C23H23NS2: C, 73.17; H, 6.14; N, 3.71; S,
16.98. Found: C, 72.93; H, 6.17; N, 3.68; S, 17.07.
1-Phenyl-5-(3-(pyrrolidin-1-yl)propyl)thiopyrano[4,3-b]indole-
3(5H)-thione (5i). 1-(3-(3-Benzoyl-2-methyl-1H-indol-1-yl)propyl)-
pyrrolidin-1-ium chloride 1i (0.60 g, 1.57 mmol) was reacted with
lithium diisopropylamide (2.50 mL of 2 M solution, 5.00 mmol) in
dry THF at −32 °C for 3 h. Carbon disulfide (0.19 mL, 3.13 mmol)
was added, and the reaction mixture was left overnight at room
temperature. The reaction was quenched by water addition, and
product 5i was precipitated and purified by crystallization from
CH3CN. Red solid was obtained in 63% isolated yield (0.40 g); mp
163−165 °C (CH3CN). 1H NMR (CDCl3, 250 MHz): δ 7.84 (s, 1H,
CHarom), 7.32−7.70 (m, 7H, CHarom), 6.89−7.09 (m, 2H, CHarom),
4.27 (t, J = 6.72 Hz, 2H, CH2), 2.34−2.69 (m, 6H, CH2), 1.95−2.13
(m, 2H, CH2), 1.73−1.93 (m, 4H, CH2) ppm. 13C{1H} NMR
(CDCl3, 63 MHz): δ 191.6, 157.2, 149.2, 143.3, 134.0, 130.8, 129.5,
129.4, 128.8, 123.5, 122.7, 122.4, 121.5, 115.5, 110.1, 54.1, 52.5, 41.2,
27.3, 23.8 ppm. Anal. Calcd for C24H24N2S2: C, 71.25; H, 5.98; N,
6.92; S, 15.85. Found: C, 71.35; H, 6.08; N, 6.97; S, 15.93.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01200
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
X-ray analysis was carried out by Valery V. Tkachev as a part of
state task No. AAAA-A19-119092390076-7.
■
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01200.
■
sı
X-ray single crystal data of 5a; copies of 1H and 13C{1H}
NMR spectra; Cartesian coordinates, attractive forces,
and relative Gibbs energies of all stationary points
(PDF)
Accession Codes
CCDC 2064018 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
Julia V. Vyalyh − Department of Chemistry, Southern Federal
University, Rostov-on-Don 344090, Russia; orcid.org/
0000-0002-2826-6025; Email: gcarboline@gmail.com
■
Authors
Konstantin F. Suzdalev − Department of Chemistry, Southern
Federal University, Rostov-on-Don 344090, Russia;
orcid.org/0000-0003-4879-0577
Valery V. Tkachev − Institute of Problems of Chemical
Physics, Russian Academy of Sciences, Chernogolovka
142432, Russia
Ekaterina A. Lysenko − Department of Chemistry, Southern
Federal University, Rostov-on-Don 344090, Russia
Oleg N. Burov − Department of Chemistry, Southern Federal
University, Rostov-on-Don 344090, Russia
I
https://doi.org/10.1021/acs.joc.1c01200
J. Org. Chem. XXXX, XXX, XXX−XXX

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