Oxidative Rearrangement of 2-(2-Aminobenzyl)furans: Synthesis of Functionalized Indoles and Carbazoles

Article abstract of DOI:10.1002/ejoc.202001608

2-(2-Acylvinyl)indoles obtained by oxidative rearrangement of substituted 2-(2-aminobenzyl)furans could be used to construct structural analogues of antifungal alkaloids caulindoles A?D as well as other indole-derived molecules and substituted carbazoles by introducing new reaction centers into the structure of starting materials or by synthetic manipulation with functional groups of the obtained compounds.

Full text of DOI:10.1002/ejoc.202001608

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Oxidative Rearrangement of 2-(2-Aminobenzyl)furans:
Synthesis of Functionalized Indoles and Carbazoles
Anton A. Merkushev,[a] Anton S. Makarov,[a] Pavel M. Shpuntov,[b] Vladimir T. Abaev,[c, d]
Igor V. Trushkov,[e, f] and Maxim G. Uchuskin*[a]
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2-(2-Acylvinyl)indoles obtained by oxidative rearrangement of
substituted 2-(2-aminobenzyl)furans could be used to construct
structural analogues of antifungal alkaloids caulindoles AÀ D as
well as other indole-derived molecules and substituted carba-
zoles by introducing new reaction centers into the structure of
starting materials or by synthetic manipulation with functional
groups of the obtained compounds.
Introduction
The oxidative transformation of furans into various functional-
ized compounds is a powerful instrument in modern organic
chemistry.[1] A strong interest in studying such processes is
certified by
a number of diverse pathways developed
annually,[2] being stimulated, among others, by availability of
starting furans through biomass processing.[3] Due to the
combination of accessibility and versatile reactivity under
oxidative conditions, substituted furans serve as convenient
and inexpensive building blocks for the synthesis of a broad
range of valuable products.
The most studied oxidative transformation of furans is their
conversion into 2,3-unsaturated 1,4-dicarbonyl compounds
(Scheme 1a), which are widely applied in modern synthetic
organic chemistry for the preparation of various acyclic,
alicyclic, and heterocyclic molecules, including natural products.
Usually the construction of the desired molecules proceeds in a
stepwise manner and includes: a) synthesis of a starting furan,
b) its oxidation to the corresponding enedione, c) cyclization, d)
subsequent functionalization. However, the use of this se-
quence not only requires the isolation of multiple intermediary
Scheme 1. Oxidative transformations of furans.
products, but can also be accompanied by diverse side
processes.
The effective solution to this problem is based on the
design of a starting furan containing a nucleophilic moiety at
the appropriate position aiming for the interception of the
unsaturated 1,4-dicarbonyl compound formed during the furan
oxidation. This strategy was for the first time applied 50 years
ago when Achmatowicz et al. reported the oxidation of furfuryl
alcohols affording, after subsequent acidic treatment, substi-
tuted dihydropyran-3-ones (Scheme 1b).[4] Multiple investiga-
tions of this reaction made the Achmatowicz rearrangement a
well-studied oxidative transformation of substituted furans into
functionalized heterocycles such as pyran and pyridine
derivatives.[5]
In the Achmatowicz rearrangement, a nucleophile, located
at the α-position of a side chain at the C(2) atom of the furan
ring, attacks the distal carbonyl group of the intermediate
enedione, furnishing a six-membered heterocycle. Oppositely,
the intramolecular nucleophilic attack on the proximal carbonyl
group, resulted from the oxidation of substituted furan, is
represented only by scarce transformations affording the
[a] Dr. A. A. Merkushev, Dr. A. S. Makarov, Dr. M. G. Uchuskin
Perm State University, Bukireva St. 15, Perm, 614990, Russian Federation
E-mail: mu@psu.ru
[b] P. M. Shpuntov
Kuban State Technological University, Moskovskaya St. 2, Krasnodar,
350072, Russian Federation
[c] Prof. Dr. V. T. Abaev
North-Ossetian State University, Vatutina St. 46, Vladikavkaz, 362025,
Russian Federation
[d] Prof. Dr. V. T. Abaev
North Caucasus Federal University, Pushkin St. 1a, Stavropol, 355009,
Russian Federation
[e] Prof. Dr. I. V. Trushkov
D. Rogachev National Medical Research Center of Pediatric Hematology,
Oncology and Immunology, Samory Mashela St. 1, Moscow, 117997,
Russian Federation
[f] Prof. Dr. I. V. Trushkov
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky Pr. 47, Moscow, 119991, Russian Federation
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corresponding spirocyclic ketals or hemiaminals.[6] Recently we
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described an oxidative rearrangement of 2-(2-amino-benzyl)
furans 1 into 2-(2-acylvinyl)indoles 2 that proceeded in high
yields and excellent stereocontrol affording exclusively either E-
or Z-arrangement of substituents at C=C bond (Scheme 1c).[7]
Herein, we present the continuation of our research of the
oxidative rearrangement of substituted furans and further
transformations of the obtained products into important
heterocyclic motifs.
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Results and Discussion
Unlike Achmatowicz rearrangement, in our approach the furan
core provides only one carbon atom for the construction of a
new heterocycle, while the remaining carbons are released as
the reactive α,β-unsaturated ketone moiety. In the combination
with high reactivity of the indole scaffold toward diverse
reagents, this ensures a wide synthetic value of the obtained 2-
(2-acylvinyl)indoles 2.[8]
We started this work by exploring the reactivity of indoles 2
aiming to demonstrate their potential as versatile building
blocks for the synthesis of various indole-containing molecules.
We found that the quantitative isomerization of (Z)-2a into (E)-
2a could be achieved by heating in the presence of molecular
iodine (Scheme 2). Subsequent treatment of (E)-2a with meth-
anolic KOH led to the NH-indole 3 in a near quantitative yield;
the sequential treatment of the obtained 3 with Oxone/NH4Br
in MeOH and HCl in CHCl3 afforded brominated product 4 in
high yield. The reduction of (Z)-2a with NaBH4 in EtOH afforded
the corresponding alcohol in quantitative yield, further depro-
tection of which produced N-unsubstituted allyl alcohol 5 in
high yield.
Scheme 3. Synthesis of indoles 6–9. a) NaOH, Br2, H2O, 1,4-dioxane, rt; b)
°
°
MeI, Cs2CO3, acetone, 60 C; c) LiAlH4, AlCl3, Et2O, 0 C; d) MnO2, CH2Cl2, rt; e)
°
°
KOH, MeOH, 60 C; f) EtOCOCl, TEA, THF, 0 C then NaBH4.
in the synthesis of analogues of antilipidemic fluvastatin.[9] We
also found that the quantitative deprotection of acrylic acid 6,
its transformation to a mixed anhydride followed by reduction
with NaBH4 led to the corresponding (E)-allyl alcohol 9 in high
yield.
Finally, treatment of indole (E)-2a with Vilsmeier-Haack
reagent provided indolyldienal 10 in excellent yield (Scheme 4).
This compound could be involved in a large variety of trans-
formations furnishing diverse useful polycyclic compounds.[10]
In 2004 Nkunya and co-workers isolated caulindoles AÀ D
from the Isolona cauliflora (Figure 1).[11] These dimeric indoles
showed antifungal and mild antimalarial activity. The isolated
caulindoles AÀ D could be accessed through the Diels–Alder
reaction of corresponding (E)-5-(3-methylbuta-1,3-dien-1-yl)-1H-
indoles.[12] We suggested that the obtained indole (E)-2a could
be smoothly converted into the corresponding diene, which
should afford [4+2]-cyclodimers that can be considered as
caulindoles analogues.
Next, we oxidized (E)-2a with NaBrO to the corresponding
β-(2-indolyl)acrylic acid 6 in quantitative yield (Scheme 3). This
acid was smoothly converted to the corresponding α,β-
unsaturated aldehyde 7, which could be a convenient precursor
Reaction of (E)-2a with MeMgI furnished tertiary allyl
alcohol 11. The sequential treatment of allyl alcohol 11 with
MsCl and TEA led to the corresponding diene 12 in high yield
(Scheme 5). The key Diels–Alder reaction of the obtained diene
12 in the presence of Cu(OTf)2 in CH2Cl2 afforded the mixture of
dimeric indoles 13 in 45% yield.[13]
°
Scheme 2. Synthesis of indoles 2–5. a) I2, toluene, 150 C, MW; b) KOH,
°
°
MeOH, 60 C; c) Oxone, NH4Br, MeOH 20 C; d) HCl, CHCl3, rt; e) NaBH4, EtOH.
Scheme 4. Synthesis of indolyldienal 10.
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Table 1. Optimization of reaction conditions for the Michael addition of 2-
methylfuran 15 to chalcone 14a[a].
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Entry
Solvent
Cat. [% mol]
Yield, [%][b]
1
2
3
DCE
DCE
DCE
CuBr2 (20)
Cu(OTf)2 (20)
I2 (20)
CuBr2 (20)
I2 (20)
Cu(OTf)2 (20)
TMSCl (20)
HCl (20)
TsOH (20)
TMSCl (20)
TsOH (20)
TMSCl (20)
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35
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4[c]
5[c]
6
CH3CN
CH3CN
CH3CN
DCE
CH3CN
DCE
CH3CN
DCE
CH3CN
Figure 1. Antifungal alkaloids caulindoles AÀ D and known approach for their
synthesis.
–
20
70
65
99
99
89[e]
95[e]
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11[d]
12[d]
Carbazoles form an important class of nitrogen-containing
heterocycles; this tricyclic scaffold is an integral part of diverse
natural products and a wide range of bioactive compounds
including approved drugs. Moreover, carbazoles are frequently
used as building blocks for the preparation of a variety of
functional organic materials.[14] Many approaches for the syn-
thesis of functionalized carbazoles have been developed up to
now.[15] The commonly used route is based on various processes
of the benzene ring fusion to readily available indoles.[16] Having
obtained the efficient method for the synthesis of 3-substituted
indoles bearing α,β-unsaturated ketone moiety at the C(2)
atom, we designed a new simple approach to functionalized
carbazole derivatives. To implement this idea, a substituent at
the C(3) atom of the indole ring should have a CH-acid moiety
at the α-position that can be involved into aldol condensation
with unsaturated ketone functionality at the indole C(2) atom.
Retrosynthetic analysis revealed that the appropriate substrates
could be synthesized by Michael addition of 2-alkylfurans to 2-
aminochalcones (Scheme 6).
[a] All reactions performed at 0.1 mmol scale. [b] NMR yields. [c]
Decomposition. [d] Reaction performed at 0.5 mmol scale at 50 C for
24 h. [e] Isolated yield.
°
benzyl)furan 16a were observed when we used TMSCl in DCE
and HCl in CH3CN (Table 1, entries 7,8). Finally, we found that
the desired product 16a was formed in quantitative yield when
TsOH in DCE and TMSCl in CH3CN were applied (Table 1,
entries 9,10). In both cases, the reaction can be efficiently scaled
up; the yield of 16a being slightly dropped to 89% using TsOH
in DCE (Table 1, entry 11), while TMSCl provided the target
product in 95% yield (Table 1, entry 12). Oppositely, the use of
TfOH in DCE led to the partial cyclisation of the starting
chalcone 14a affording 2-substituted quinoline via Friedländer-
like reaction.[17]
We began this part of our work by searching for the optimal
reaction conditions for Michael addition of 2-methylfuran 15 to
2-(tosylamino)chalcone 14a as model compounds (Table 1). We
found that CuBr2, Cu(OTf)2 and I2 in DCE or CH3CN were barely
effective (Table 1, entries 1–6). The good yields of 2-(2-amino-
Using the optimized reaction conditions, we synthesized a
series of substituted 2-(2-aminobenzyl)furans 16a–h in high
yields and studied their oxidative rearrangement (Table 2). We
found that the desired indoles 17a–h were formed in high
Scheme 5. Synthesis of dimeric indole 13. a) MeMgI, Et2O, toluene, rt; b)
Scheme 6. The retrosynthetic scheme for the synthesis of 3,4-substituted
carbazoles.
°
MsCl, TEA, THF, 60 C; c) Cu(OTf)2, CH2Cl2, reflux.
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elimination mechanism. Triflic acid and copper(II) triflate induce
Table 2. Scope of the Oxidative Rearrangement of 2-(2-Aminobenzyl)
furans 16 to 2-(2-Acylvinyl)indoles 17.[a]
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E1 reaction via the carbocation generation from the intermedi-
ate I; this cation can eject either proton or acyl cation.
Oppositely, acetic acid has too weak acidity and can promote
only E2 dehydration.
Fortunately, aldol condensation could be induced not only
by acids but also by bases. We found that heating of the
starting indole with methanolic KOH resulted in the formation
of a mixture of the desired product 18a and the corresponding
NH-carbazole 20a with a total yield of 45% and a ratio of ca.
1:1 (Table 4, entry 1). A prolonged heating of the reaction
mixture led exclusively to NH-carbazole 20a in moderate yield
(Table 4, entry 2). The reaction time could be significantly
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R1
Yield, [%][b]
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a
b
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d
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Ph
92
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84
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89
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4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-FC6H4
°
reduced by heating the indole 20a in methanolic KOH at 110 C
under microwave irradiation; however, the yield of NH-
carbazole 20a was significantly lower (Table 4, entry 3). On the
other hand, the treatment of 17a with methanolic KOH at room
temperature produced carbazole 18a in quantitative yield
(Table 4, entry 4). In other words, the intramolecular aldol
condensation itself should be performed under mild reaction
conditions while N-deprotection required elevated temperature.
Indeed, one-pot version of the total process including aldol
condensation at room temperature overnight followed by
heating the reaction mixture under microwave irradiation
provided desired carbazole 20a in high yield (Table 4, entry 5).
It should be noted that the (E)-17a was used as the starting
material for intramolecular aldol condensation; however, it is
obvious that the Z-isomer 17a enters the aldol condensation,
which was formed through isomerization of the E-isomer 17a.
Thus, the Z/E-isomerization is the important act of the
developed process.
f
85
84
g
h
2-naphthyl
2-thienyl
89
82
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85
°
[a] Reaction conditions: a) 2-methylfuran 15, TMSCl, CH3CN, 50 C; b) m-
CPBA, CH2Cl2, 0 C, 1 h; c) 10% TFA, rt, 20 h. [b] Isolated yields.
°
yields, the substituents at the carbonyl group had no influence
on the reaction outcome.[13] Remarkably, (E)-isomers were
exclusively formed in all reactions.
Finally, we optimized the reaction conditions for the intra-
molecular aldol condensation of the obtained 2-(2-acylvinyl)
indoles 17 aiming to synthesize the desired carbazoles. Initially
screened Cu(OTf)2 and TfOH (Table 3, entries 1,2) gave rise to
the formation of the mixture of the anticipated product 18a
and unexpected carbazole 19a with a 1:1 ratio in ca. 80% total
yield. Both were formed from the same intermediate hydrox-
yketone I via elimination of water or benzoic acid, respectively.
Heating the solution of the starting indole 17a in acetic acid
led to the formation of the desired carbazole 18a exclusively in
high yield (Table 3, entry 3). Supposingly, the different chemo-
selectivity of these reactions resulted from the change of the
Next, we studied the scope of this tandem intramolecular
aldol condensation/deprotection under the optimized reaction
conditions (Table 5). We found that the aryl substituent in the
aroylmethyl moiety had not influence the reaction efficiency;
Table 4. Optimization of reaction conditions for the intramolecular aldol
condensation[a].
Table 3. Optimization of reaction conditions for intramolecular aldol
condensation[a].
Entry
Reaction conditions
KOH, MeOH,
Yield, [%][b]
18a
20a
1
2
3
4
5
24
21
°
60 C, 4 h
KOH, MeOH,
traces
traces
95
47
°
60 C, 50 h
KOH, MeOH
Entry
Reaction conditions
Yield, [%][b]
18a
27
°
110 C, MW, 1 h
19a
KOH, MeOH,
rt, 12 h
–
°
1
2
3
Cu(OTf)2 (5 mol%), DCE, 85 C
TfOH (5 mol%), toluene, 85 C
AcOH, 120 C
40
41
89
38
39
traces
°
KOH, MeOH,
–
93 (89)
°
°
rt, 12 h, then 110 C, MW, 1 h
[a] All reactions performed at 0.1 mmol scale. [b] Yields determined by
NMR using internal standard.
[a] All reactions performed at 0.1 mmol scale. [b] NMR yields. Isolated yield
is given in parentheses.
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To expand the scope of the oxidative rearrangement, we
Table 5. Scope of tandem intramolecular aldol condensation/deprotection
affording carbazoles 20.
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9
studied the transformation of 2-benzylfurans bearing a nucleo-
philic moiety separated from the phenyl group by one or more
atoms. We were pleased to find that the oxidative rearrange-
ment of the benzohydrazide 21 and subsequent cyclodehydra-
tion afforded pyridazino[1,6-b]isoquinoline 22, whilst in low
yield (Scheme 8). The reduced yield of 22 is presumably
associated with the competitive oxidation of hydrazide moiety.
To overcome this problem, we protected the compound 21
with Boc group and used the obtained hydrazide 23 for the title
rearrangement. Indeed, the oxidation of 23 provided the target
pyridazino[1,6-b]isoquinoline 22 in 83% yield.
17,20
R1
Yield of 20, [%][a]
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a
b
c
Ph
89
86
85
91
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
d
f
82
Conclusion
g
h
2-naphthyl
2-thienyl
83
84
We showed that the oxidative transformation of benzylfurans
developed by us earlier could be used to access various
heterocyclic scaffolds via simple structural modifications of
starting materials or manipulations with acylvinyl substituent at
C(2) of obtained products.
[a] Isolated yields.
the functionalized carbazoles 20a–d,f–h were formed invariably
in high yields.
It should be noted that the intramolecular aldol condensa-
tion and deprotection of indole 17e afforded carbazole 20c in Experimental Section
a high yield as a result of competing nucleophilic aromatic
substitution (Scheme 7).
General information
1H and 13C NMR spectra were recorded with a «Bruker Avance III
HD 400» (400 MHz for H and 100 MHz for 13C NMR) spectrometer
1
at room temperature; the chemical shifts (δ) were measured in
ppm with respect to the solvent (CDCl3, 1H: δ= 7.26 ppm, 13C: δ=
77.16 ppm; [D6] DMSO, 1H: δ=2.50 ppm, 13C: δ=39.52 ppm).
Coupling constants (J) are given in Hertz. Splitting patterns of an
apparent multiplets associated with an averaged coupling
constants were designated as s (singlet), d (doublet), t (triplet), q
(quartet), sept (septet), m (multiplet), dd (doublet of doublets)
and br (broadened). IR spectra were measured in nujol or CaF2
using a «FSM 1202» spectrophotometer. High-resolution mass
measurements were carried out using a BrukermicroTOF-QTM
ESI-TOF (Electro Spray Ionization/Time of Flight) mass spectrom-
eter. GC/MS analysis was performed on an «Agilent 7890B»
interfaced to an «Agilent 5977A» mass selective detector. Melting
points were determined with a «Stuart SMP 30. Data sets for X-
Ray diffraction were collected with a «New Xcalibur, Ruby»
diffractometer. All reactions under microwave radiation were
performed in Anton Paar® Microwave Synthesis Reactor «Mono-
wave 300». Column chromatography was performed on silica gel
Macherey Nagel (40–63 μm). All the reactions were carried out
using freshly distilled and dry solvents from solvent stills.
Scheme 7. Tandem Intramolecular aldol condensation and deprotection
affording carbazoles 18e and 20c.
(Z)-4-(3-Phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (2a) was syn-
thesized according to the reported procedure.[7]
(E)-4-(3-Phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one
((E)-2a)[18]
was synthesized according to the reported procedure.[7]
Synthesis of (E)-4-(3-Phenyl-1H-indol-2-yl)but-3-en-2-one (3). To
a stirred solution of indole (E)-2a (528 mg, 1.22 mmol) in MeOH
(12 mL) was added KOH (276 mg, 4.9 mmol). The reaction mixture
was stirred at room temperature until full dissolution of the solid.
Then the reaction mixture was stirred at 60 C in the aluminium
block for 48 hours (The same result might be achieved by heating
°
°
Scheme 8. Synthesis of pyridazino[1,6-b]isoquinoline 22. a) Boc2O, CH2Cl2, rt;
b) m-CPBA, CH2Cl2, 0 C, 1 h; c) HCl, rt, 20 h.
of the reaction mixture at 110 C for 5 hours under microwave
irradiation). After that, the reaction mixture was concentrated in
°
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vacuo and the residue was purified by flash column chromatog-
raphy (silica gel, eluent – ethyl acetate/petroleum ether=1:10) to
methyl iodide (44 μL, 1 equiv.), and the formed suspension was
1
2
3
4
5
6
7
8
9
°
stirred at 50 C in the aluminium block for 4 h (TLC control). Upon
afford the compound 3. Yield: 302 mg, 95%; pale beige solid; mp
completion, the reaction mixture was poured into water (50 mL),
extracted with ethyl acetate (2×50 mL), washed with water
(50 mL), brine (20 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo to afford the ester. To a suspension of LiAlH4
(30 mg, 1.12 equiv., 0.8 mmol) in Et2O (20 mL) was added AlCl3
[19]
°
°
216–217 C (CH2Cl2/hexane=1:9), lit 218–219 C;
1H NMR
(400 MHz, DMSO-d6): δ=11.80 (s, 1H), 7.60–7.40 (m, 8H), 7.31–7.28
3
(m, 1H), 7.11–7.07 (m, 1H), 6.89 (d, J=16.1 Hz, 1H), 2.28 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6): δ=197.1, 137.6, 133.5, 131.1,
130.1, 129.8 (2 C), 128.9 (2 C), 127.0, 126.7, 125.3, 124.9, 122.8,
120.3, 119.7, 111.7, 27.7 ppm.
°
(35 mg, 0.38 equiv., 0.27 mmol) in one portion at 0 C. The
resulting suspension was stirred for 5 min followed by the
addition of obtained ester (300 mg, 0.71 mmol) portionwise at the
same temperature. The reaction mixture was further stirred until
full consumption of the starting ester (TLC control, ca. 1 h). Upon
completion, the reaction mixture was diluted with water (20 mL)
and extracted with Et2O (2×20 mL). Combined organic fractions
were washed with water (30 mL), brine (30 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. To the solution of
alcohol (300 mg, 0.7 mmol) in CH2Cl2 (30 mL) was added MnO2
(620 mg, 10 equiv., 7 mmol). The resulting suspension was stirred
at room temperature for 24 h (TLC control). Upon completion, the
reaction mixture was filtered through paper filter and concen-
trated to afford the final product with high NMR purity. If needed,
the product could be recrystallized from ethyl acetate/petroleum
Synthesis of (Z)-3-Bromo-4-(3-phenyl-1H-indol-2-yl)but-3-en-2-
one (4). To the solution of indole 3 (131 mg, 0.5 mmol) and NH4Br
(65 mg, 1.2 equiv., 0.6 mmol) in methanol (4 mL) was added
Oxone® (185 mg, 1.2 equiv., 0.6 mmol) in 4 equal portions within
20 min, and the resulting suspension was stirred at room temper-
ature for 3 h (TLC control). After that, the reaction mixture was
diluted with water (30 mL), extracted with ethyl acetate (2×
50 mL), washed with water (3×50 mL), brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue after
concentration was dissolved in CHCl3 (10 mL), treated with HCl
(12 M, 45 μL, 1 equiv., 0.5 mmol) and stirred at room temperature
for 5 min (TLC control). Upon completion, the reaction mixture
was treated with crystalline NaHCO3 (42 mg, 1 equiv., 0.5 mmol)
and concentrated in vacuo. The product was purified by gradient
column chromatography (basic aluminium oxide, eluent – petro-
leum ether/CH2Cl2 10:1 to 2:1). NOTE: partial decomposition was
detected when silica gel was used for column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
ether mixture. Yield: 264 mg, 94%; pale yellow prisms; mp 140–
1
°
141 C (ethyl acetate/petroleum ether=1:10); H NMR (400 MHz,
3
3
CDCl3): δ=9.61 (d, J=7.8 Hz, 1H), 8.32–8.30 (m, 1H), 8.19 (d, J=
16.1 Hz, 1H), 7.60 (AA’BB’-system, 3J=8.2 Hz, 2H), 7.47–7.41 (m,
3
4H), 7.29–7.23 (m, 4H), 7.18 (AA’BB’-system, J=8.2 Hz, 2H), 6.07
°
Yield: 131 mg, 77%; pale green solid; mp 137–138 C (CH2Cl2/
(dd, 3J=16.1 Hz, 3J=7.8 Hz, 1H), 2.34 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ=193.5, 145.5, 141.1, 137.9, 135.1, 133.0, 132.3,
131.2, 131.1, 130.2, 130.0 (2 C), 129.6 (2 C), 129.4 (2 C), 128.8,
127.4, 126.8 (2 C), 124.8, 121.2, 115.9, 21.7 ppm; HRMS (ESI+): m/z
calcd for C24H20NSO3+: 402.1158 [M+H]+; found: 402.1170.
petroleum ether=1:9); 1H NMR (400 MHz, CDCl3): δ=9.98 (br s,
1H), 8.16 (s, 1H), 7.75–7.73 (m, 1H), 7.57–7.42 (m, 6H), 7.42–7.38
(m, 1H), 7.24–7.17 (m, 1H), 2.48 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ=191.5, 137.3, 133.5, 130.6 (2 C), 130.0, 129.0 (2 C), 128.1,
128.0, 127.9, 126.7, 126.4, 121.4, 121.0, 119.7, 112.0, 26.3; HRMS
(ESI+): m/z calcd for C18H15NBrO+: 340.0332 [M+H]+; found:
340.0342.
Synthesis of (E)-3-(3-Phenyl-1H-indol-2-yl)acrylic acid (8). To the
solution of the acrylic acid 6 (417 mg, 1 mmol) in methanol/1,4-
dioxane (1:1, 10 mL) was added KOH (224 mg, 4 equiv., 4 mmol)
Synthesis of (Z)-4-(3-Phenyl-1H-indol-2-yl)but-3-en-2-ol (5). To a
stirred solution of indole (Z)-2a (208 mg, 0.5 mmol) in ethanol
°
The resulting solution was stirred at 60 C in the aluminium block
for 5 h (TLC control). Upon completion, the reaction mixture was
poured into water (50 mL), extracted with ethyl acetate (2×
50 mL), washed with water (50 mL), brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo to afford the acid 8.
°
(20 mL) was added NaBH4 portionwise at 0 C. After addition was
°
complete, the reaction mixture was heated at 80 C in the
aluminium block until yellow color of the solution disappeared
(takes about 5–10 min). Upon completion, the reaction mixture
was poured into water (50 mL), extracted with ethyl acetate (2×
50 mL), washed with water (50 mL), brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
dissolved in methanol (10 mL), and KOH (112 mg, 4 equiv.,
2 mmol) was added at room temperature. The formed suspension
°
Yield: 260 mg, 99%; white solid; mp 226–227 C (ethyl acetate/
petroleum ether=1:10); 1H NMR (400 MHz, DMSO-d6): δ=12.28
(br s, 1H), 11.72 (br s, 1H), 7.57–7.53 (m, 4H), 7.47–7.40 (m, 4H),
7.29–7.25 (m, 1H), 7.10–7.06 (m, 1H), 6.57 (d, 3J=15.9 Hz, 1H) ppm;
13C NMR (100 MHz, DMSO-d6): δ=167.6, 137.3, 133.5, 132.3, 130.0,
129.7 (2 C), 128.8 (2 C), 126.9, 126.6, 124.5, 121.7, 120.1, 119.6,
117.4, 111.5 ppm; HRMS (ESI+): m/z calcd for C17H14NO2+: 264.1019
[M+H]+; found: 264.1020.
°
was stirred at 60 C in the aluminium block for 5 h. Upon
completion, the reaction mixture was poured into water (50 mL),
extracted with ethyl acetate (2×50 mL), washed with water
(50 mL), brine (20 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residue was dissolved in CH2Cl2, passed
through a pad of silica and concentrated in vacuo. Yield: 112 mg,
Synthesis of (E)-3-(3-Phenyl-1H-indol-2-yl)prop-2-en-1-ol (9). To
a solution of acrylic acid 8 (66 mg, 0.25 mmol) in THF (10 mL) was
added TEA (3.5 μL, 1 equiv.) and ethyl chloroformate (24 μL,
1
°
85%; pale beige oil; H NMR (400 MHz, DMSO-d6): δ=11.10 (br s,
1 equiv.) at 0 C. The formed suspension was stirred for 20 min at
1H), 7.57–7.55 (m, 1H), 7.49–7.44 (m, 5H), 7.32–7.29 (m, 1H), 7.18–
the same temperature. Then NaBH4 (30 mg, 3 equiv., 0.75 mmol)
was added in one portion, and the formed suspension was stirred
at room temperature for 20 h (TLC control). Upon completion, the
reaction mixture was diluted with water (20 mL), treated with HCl
(1 M, 3 mL) and extracted with CH2Cl2 (2×30 mL). Combined
organic fractions were washed with water (30 mL), brine (30 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. The
product was purified by column chromatography (silica gel, eluent
3
7.15 (m, 1H), 7.06–7.03 (m, 1H), 6.39 (d, J=12.1 Hz, 1H), 5.75–5.68
(m, 1H), 5.30 (d, 3J=4.6 Hz, 1H), 4.71–4.65 (m, 1H), 1.20 (d, 3J=
6.3 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): δ=137.0, 136.2,
134.7, 131.3, 129.4 (2 C), 128.5 (2 C), 126.5, 126.0, 122.3, 119.7,
118.6, 118.4, 116.2, 111.7, 63.3, 23.6 ppm; HRMS (ESI+): m/z calcd
for C18H18NO+: 264.1383 [M+H]+; found: 264.1381.
(E)-3-(1-Tosyl-3-phenyl-1H-indol-2-yl)prop-2-enoic acid (6) was
1
– CH2Cl2/ethyl acetate, 2:1). Yield: 57 mg, 91%; beige oil; H NMR
synthesized according to the reported procedure.[20]
(400 MHz, DMSO-d6): δ=11.33 (br s, 1H), 7.52–7.44 (m, 5H), 7.40–
7.37 (m, 1H), 7.35–7.31 (m, 1H), 7.16–7.12 (m, 1H), 7.02–6.99 (m,
Synthesis of (E)-3-(3-Phenyl-1-tosyl-1H-indol-2-yl)acrylaldehyde
(7). To a stirred mixture of the acrylic acid 6 (292 mg, 0.7 mmol)
and CsCO3 (228 mg, 1 equiv.) in acetone (20 mL) was added
3
3
2
1H), 6.69 (br d, J=16.1 Hz, 1H), 6.51 (dt, J=16.1 Hz, J=4.8 Hz,
1H), 4.86 (t, J=5.5 Hz, 1H), 4.16 (t, J=4.4 Hz, 2H) ppm; 13C NMR
3
3
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(100 MHz, DMSO-d6): δ=136.4, 134.6, 132.4, 131.0, 129.4 (2 C),
3H), 2.29 (s, 3H), 1.38–1.30 (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H), 1.12–
1.05 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=146.4, 144.5,
144.3, 137.7, 136.8, 136.5, 136.1, 135.9, 135.6, 134.3, 134.2, 133.7,
133.6, 131.9, 130.2 (2C), 129.9 (2C), 129.7 (4C), 128.5 (2C), 127.7,
127.1 (2C), 126.9, 126.7, 126.3 (4C), 124.8, 124.5, 123.9, 123.7,
122.9, 121.7, 120.0, 119.6, 116.2, 115.8, 115.2, 43.4, 40.7, 31.2, 26.6,
24.2, 23.3, 21.7 (2C) ppm; HRMS (ESI+): m/z calcd for
C52H47N2S2O4+: 827.2972 [M+H]+; found: 827.2975.
1
2
3
4
5
6
7
8
9
128.5 (2 C), 127.1, 125.9, 122.3, 119.4, 118.4, 117.9, 115.1, 110.9,
61.3 ppm; HRMS (ESI+): m/z calcd for C17H16NO+: 250.1226 [M+
H]+; found: 250.1225.
Synthesis of (4E)-3-Chloro-5-(3-phenyl-1-tosyl-1H-indol-2-yl)
°
penta-2,4-dienal (10). POCl3 was added to DMF (4 mL) at 0 C, and
the resulting mixture was stirred for 10 min. Indole (E)-2a
(210 mg, 0.5 mmol) was added to the solution of Vilsmeier reagent
°
°
at 0 C, the formed solution was brought to 70 C in the aluminium
block and stirred for 1.5 h (TLC control). Upon completion, the
reaction mixture was diluted with water (5 mL), treated with
saturated aqueous solution of NaHCO3 (1 mL), extracted with ethyl
acetate (2×50 mL), washed with water (3×50 mL), brine (20 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. The
product was purified by column chromatography (silica gel, eluent
– petroleum ether/CH2Cl2 10:1 to 5:1). Yield: 217 mg, 94%; yellow
Synthesis of 2-tosylaminochalcones 14a–h. The 2-tosylamino-
chalcones 14 were synthesized according to the reported
procedures.[17]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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53
54
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56
57
(E)-N-{2-[3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxoprop-1-
en-1-yl]phenyl}-4-methylbenzenesulfonamide
(14f).
Yield:
539 mg, 62%; white solid; mp 151–152 C (CH2Cl2); 1H NMR
(400 MHz, CDCl3): δ=7.45 (d, 3J=15.4 Hz, 1H), 7.35 (AA’BB’-system,
3J=8.1 Hz, 2H), 7.32–7.26 (m, 4H), 7.18–7.14 (m, 1H), 7.12 (br s,
1H), 7.05–7.01 (m, 1H), 6.95–6.89 (m, 3H), 6.71–6.69 (m, 1H), 4.12–
4.10 (m, 2H), 4.08–4.06 (m, 2H), 1.96 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ=188.1, 148.3, 143.9, 143.6, 138.4, 136.3, 135.5,
131.6, 131.1, 131.0, 129.8 (2 C), 127.7, 127.4 (2 C), 127.3, 127.1,
°
1
3
oil; H NMR (400 MHz, CDCl3): δ=10.13 (d, J=7.2 Hz, 1H), 8.33–
8.31 (m, 1H), 8.14 (d, 3J=15.4 Hz, 1H), 7.63 (AA’BB’-system, 3J=
8.2 Hz, 2H), 7.46–7.40 (m, 4H), 7.33–7.25 (m, 4H), 7.19 (AA’BB’-
system, 3J=8.2 Hz, 2H), 6.28 (d, 3J=15.4 Hz, 1H), 5.80 (d, 3J=
7.2 Hz, 1H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=191.1,
148.9, 145.4, 137.7, 135.4, 132.8, 132.2, 131.0, 130.6, 130.0, 129.9
(2 C), 129.5, 129.3 (2 C), 128.5, 128.2, 127.0, 126.9, 126.8 (3 C),
124.7, 120.8, 115.8, 21.7 ppm; HRMS (ESI+): m/z calcd for
C26H21NSClO3+: 462.0925 [M+H]+; found: 462.0926.
124.4, 122.9, 118.2, 117.5, 64.9, 64.3, 21.4 ppm; IR (nujol) νmax
=
3167, 1647, 1610, 1578, 1510, 1329, 1290, 1167 cmÀ 1; HRMS (ESI+):
m/z calcd for C24H22NSO5+: 436.1213 [M+H]+; found: 436.1208.
(E)-4-Methyl-N-{2-[3-(naphthalen-2-yl)-3-oxoprop-1-en-1-yl]
phenyl}benzenesulfonamide (14g). Yield: 632 mg, 74%; white
(E)-2-Methyl-4-(3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-ol (11)
1
°
solid; mp 158–159 C (CH2Cl2); H NMR (400 MHz, CDCl3): δ=8.46
was synthesized according to the reported procedure.[7]
(br s, 1H), 8.03–8.00 (m, 1H), 7.98–7.96 (m, 1H), 7.91–7.88 (m, 1H),
7.87–7.85 (m, 1H), 7.79 (d, 3J=15.5 Hz, 1H), 7.66–7.64 (m, 1H),
7.62–7.53 (m, 4H), 7.49–7.47 (m, 1H), 7.41–7.34 (m, 3H), 7.30–7.27
Synthesis of (E)-2-(3-Methylbuta-1,3-dien-1-yl)-3-phenyl-1-tosyl-
1H-indole (12). To the solution of allyl alcohol 11 (100 mg,
0.24 mmol) and Et3N (0.2 mL, 1.45 mmol) in anhydrous THF
(m, 1H), 7.10 (AA’BB’-system, J=8.0 Hz, 2H), 2.11 (s, 3H) ppm; 13C
3
°
(0.5 mL) at 0 C MsCl (0.05 mL, 0.73 mmol) was slowly added
NMR (100 MHz, CDCl3): δ=190.1, 144.0, 139.3 (2 C), 136.1, 135.7,
135.5, 135.1, 132.7, 131.2 (2 C), 130.4, 129.8 (2 C), 129.7, 128.8,
128.7, 127.9, 127.8, 127.4 (2 C), 127.3, 127.0, 124.6, 124.5,
dropwise. The solution was allowed to warm to room temperature
over 1.5 h and then refluxed for 30 min. The formed precipitate
was filtered off and washed with ethyl acetate. Concentrated
filtrate was purified by flash column chromatography (silica gel,
ethyl acetate/petroleum ether=1:10) to afford the diene 12.
21.4 ppm; IR (nujol) νmax =3188, 1649, 1589, 1330, 1280 cmÀ 1
;
HRMS (ESI+): m/z calcd for C26H22NSO3+: 428.1315 [M+H]+; found:
428.1332.
1
Yield: 81 mg, 82%; pale beige oil; H NMR (400 MHz, CDCl3): δ=
General Procedure for the Synthesis of 2-(2-Aminobenzyl)furans
16. To a solution of corresponding 2-tosylaminochalcone 14
(1 mmol) and 2-methylfuran 15 (265 μL, 3 mmol) in CH3CN (4 mL)
was added TMSCl (25 μL, 0.2 mmol). The resulting solution was
3
8.30–8.28 (m, 1H), 7.62 (AA’BB’-system, J=8.3 Hz, 2H), 7.43–7.39
(m, 2H), 7.35–7.31 (m, 5H), 7.23–7.19 (m, 1H), 7.15 (AA’BB’-system,
3
3
3J=8.3 Hz, 2H), 7.06 (d, J=16.3 Hz, 1H), 6.16 (d, J=16.3 Hz, 1H),
4.96 (s, 1H), 4.69 (s, 1H), 2.33 (s, 3H), 1.97 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ=144.8, 142.1, 139.2, 136.9, 135.7, 134.8, 133.7,
131.3, 130.2 (2 C), 129.7 (2 C), 128.8 (2 C), 127.4, 127.0 (2 C), 125.2,
124.1, 123.7, 119.9, 118.4, 117.9, 115.5, 21.7, 18.4 ppm; HRMS
(ESI+): m/z calcd for C26H24NSO2+: 414.1522 [M+H]+; found:
414.1535.
°
stirred at 50 C in the aluminium block for 24 h (TLC control).
Upon completion, the reaction mixture was concentrated in vacuo.
The product was purified by column chromatography (silica gel,
petroleum ether/CH2Cl2, 3:1). The products were recrystallized
from appropriate solvents mixture.
4-Methyl-N-(2-(1-(5-methylfuran-2-yl)-3-oxo-3-phenylpropyl)
phenyl)benzenesulfonamide (16a). Yield: 422 mg, 92%; white
Synthesis of (E)-2-{2-[1,4-Dimethyl-2-(3-phenyl-1-tosyl-1H-indol-
2-yl)cyclohex-3-en-1-yl]vinyl}-3-phenyl-1-tosyl-1H-indole
(13).
1
°
solid; mp 174–175 C (ethyl acetate); H NMR (400 MHz, CDCl3): δ=
To the solution of diene 12 (104 mg, 0.25 mmol) in CH2Cl2 (5 mL)
was added Cu(OTf)2 (37 mg, 0.5 equiv., 0.125 mmol). The resulting
3
8.36 (br s, 1H), 7.93–7.91 (m, 2H), 7.69 (AA’BB’-system, J=8.2 Hz,
2H), 7.57–7.52 (m, 2H), 7.45–7.41 (m, 2H), 7.25–7.23 (m, 1H), 7.20–
°
mixture was stirred at 40 C in the aluminium block for 120 h (TLC
7.16 (m, 1H), 7.12–7.10 (m, 3H), 5.76 (d, 3J=2.8 Hz, 1H), 5.51 (d,
control). Upon completion, the reaction mixture was dry-loaded
onto silica gel. The product was purified by gradient column
chromatography (silica gel, petroleum ether/CH2Cl2 10:1 to 5:1). If
needed, the product could be recrystallized from benzene/MeOH
3
3
2
3J=2.8 Hz, 1H), 4.59 (dd, J=9.4 Hz, J=3.7 Hz, 1H), 3.72 (dd, J=
3
2
3
18.4 Hz, J=3.7 Hz, 1H), 3.51 (dd, J=18.4 Hz, J=9.4 Hz, 1H), 2.28
(s, 3H), 2.21 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.9,
153.9, 151.2, 143.2, 137.8, 136.4, 136.0, 134.6, 133.8, 129.7 (2 C),
128.8 (2 C), 128.7, 128.4 (2 C), 127.8, 127.3 (2 C), 126.5, 126.4,
107.2, 106.2, 44.6, 33.9, 21.5, 13.6 ppm; IR (nujol) νmax =3244, 1666,
°
mixture. Yield: 93 mg, 45%; colorless plates; mp 258–259 C
(benzene/MeOH). Product was obtained as a mixture of two
diastereomers in 4:1 ratio. NMR data for the major isomer are
1327, 1281, 1221, 1155 cmÀ 1
;
HRMS (ESI+): m/z calcd for
1
given. H NMR (400 MHz, CDCl3): δ=8.18–8.16 (m, 1H), 8.12–8.10
C27H26NSO4+: 460.1577 [M+H]+; found: 460.1578.
3
(m, 1H), 7.66 (AA’BB’-system, J=8.2 Hz, 2H), 7.47 (AA’BB’-system,
3J=8.2 Hz, 2H), 7.36–7.35 (m, 1H), 7.29–7.27 (m, 2H), 7.22–7.20 (m,
2H), 7.19–7.16 (m, 3H), 7.15–7.12 (m, 3H), 7.11–7.06 (m, 1H), 7.03
(AA’BB’-system, 3J=8.2 Hz, 2H), 6.96–6.87 (m, 6H), 6.81–6.79 (m,
1H), 5.91 (d, 3J=16.4 Hz, 1H), 4.82 (br s, 1H), 4.42 (br s, 1H), 2.34 (s,
4-Methyl-N-(2-(1-(5-methylfuran-2-yl)-3-oxo-3-(4-methylphenyl)-
propyl)phenyl)benzenesulfonamide (16b). Yield: 406 mg, 86%;
pale yellow solid; mp 171–172 C (ethyl acetate); 1H NMR
°
(400 MHz, CDCl3): δ=8.47 (br s, 1H), 7.82 (AA’BB’-system, 3J=
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3
3
3
8.2 Hz, 2H), 7.69 (AA’BB’-system, J=8.2 Hz, 2H), 7.54–7.52 (m, 1H),
2.8 Hz, 1H), 4.54 (dd, J=9.6 Hz, J=3.7 Hz, 1H), 4.29–4.28 (m, 2H),
2 3
1
2
3
4
5
6
7
8
9
7.24–7.22 (m, 3H), 7.19–7.16 (m, 1H), 7.12–7.08 (m, 3H), 5.76 (d,
4.25–4.24 (m, 2H), 3.62 (dd, J=18.2 Hz, J=3.7 Hz, 1H), 3.42 (dd,
3J=2.8 Hz, 1H), 5.50 (d, J=2.8 Hz, 1H), 4.57 (dd, J=9.6 Hz, J=
2J=18.2 Hz, J=9.6 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR
3
3
3
3
3.7 Hz, 1H), 3.69 (dd, 2J=18.3 Hz, 3J=3.7 Hz, 1H), 3.49 (dd, 2J=
(100 MHz, CDCl3): δ=197.3, 154.0, 151.1, 148.7, 143.5, 143.1, 137.8,
136.1, 134.6, 130.2, 129.6 (2 C), 128.7, 127.7, 127.3 (2 C), 126.4,
126.3, 122.5, 117.9, 117.4, 107.1, 106.1, 64.9, 64.2, 44.4, 33.9, 21.5,
13.6 ppm; IR (nujol) νmax =3248, 1655, 1603, 1583, 1510, 1489,
1317, 1296, 1213, 1149, 1088, 1067 cmÀ 1; HRMS (ESI+): m/z calcd
for C29H28NSO6+: 518.1632 [M+H]+; found: 518.1642.
3
18.3 Hz, J=9.6 Hz, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ=198.5, 154.0, 151.2, 144.8, 143.2,
137.9, 136.1, 134.6, 133.9, 129.7 (2 C), 129.5 (2 C), 128.7, 128.5
(2 C), 127.7, 127.3 (2 C), 126.5, 126.4, 107.2, 106.1, 44.6, 33.9, 21.8,
21.5, 13.6 ppm; IR (nujol) νmax =3259, 1663, 1607, 1560, 1321,
1283, 1221, 1153 cmÀ 1; HRMS (ESI+): m/z calcd for C28H28NSO4
474.1734 [M+H]+; found: 474.1734.
:
+
4-Methyl-N-{2-[1-(5-methylfuran-2-yl)-3-(naphthalen-2-yl)-3-oxo-
propyl]phenyl}benzenesulfonamide (16g). Yield: 453 mg, 89%;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
white solid; mp 178–179 C (decomp.) (ethyl acetate); 1H NMR
°
N-(2-(3-(4-Methoxyphenyl)-1-(5-methylfuran-2-yl)-3-oxopropyl)-
phenyl)-4-methylbenzenesulfonamide (16c). Yield: 430 mg, 88%;
(400 MHz, CDCl3): δ=8.49 (s, 1H), 8.44 (br s, 1H), 7.98–7.93 (m, 2H),
7.87–7.85 (m, 2H), 7.69 (AA’BB’-system, J=8.2 Hz, 2H), 7.62–7.58
(m, 1H), 7.56–7.53 (m, 2H), 7.29–7.27 (m, 1H), 7.21–7.17 (m, 1H),
pale yellow solid; mp 208–209 C (ethyl acetate); 1H NMR
3
°
(400 MHz, CDCl3): δ=8.58 (br s, 1H), 7.90 (AA’BB’-system, 3J=
3
3
3
8.8 Hz, 2H), 7.69 (AA’BB’-system, J=8.2 Hz, 2H), 7.54–7.52 (m, 1H),
7.14–7.10 (m, 3H), 5.77 (d, J=2.8 Hz, 1H), 5.52 (d, J=2.8 Hz, 1H),
7.23–7.21 (m, 1H), 7.19–7.14 (m, 1H), 7.11–7.07 (m, 3H), 6.89
4.63 (dd, 3J=9.6 Hz, 3J=3.7 Hz, 1H), 3.86 (dd, 2J=18.3 Hz, 3J=
(AA’BB’-system, 3J=8.8 Hz, 2H), 5.75 (d, 3J=2.8 Hz, 1H), 5.49 (d,
3.7 Hz, 1H), 3.66 (dd, J=18.3 Hz, J=9.6 Hz, 1H), 2.27 (s, 3H), 2.23
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.8, 153.9, 151.2,
143.2, 137.7, 136.1, 136.0, 134.5, 133.6, 132.5, 130.3, 129.8, 129.7
(2 C), 129.0, 128.8, 128.7, 127.9, 127.8, 127.3 (2 C), 127.1, 126.6,
126.5, 123.8, 107.3, 106.2, 44.8, 33.9, 21.5, 13.7 ppm; IR (nujol)
νmax =3284, 1670, 1626, 1601, 1582, 1560, 1491, 1323, 1288, 1157,
1090 cmÀ 1; HRMS (ESI+): m/z calcd for C31H28NSO4+: 510.1734 [M+
H]+; found: 510.1743.
2
3
3J=2.8 Hz, 1H), 4.56 (dd, J=9.7 Hz, J=3.6 Hz, 1H), 3.85 (s, 3H),
3.66 (dd, 2J=18.2 Hz, 3J=3.6 Hz, 1H), 3.47 (dd, 2J=18.2 Hz, 3J=
9.7 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ=197.4, 164.2, 154.1, 151.1, 143.1, 137.9, 136.2, 134.6,
130.7 (2 C), 129.6 (2 C), 129.4, 128.7, 127.7, 127.3 (2 C), 126.4,
126.3, 114.0 (2 C), 107.1, 106.1, 55.6, 44.4, 33.9, 21.5, 13.6 ppm; IR
3
3
(nujol) νmax =3225, 1661, 1601, 1319, 1267, 1221, 1173, 1151 cmÀ 1
;
HRMS (ESI+): m/z calcd for C28H28NSO5+: 490.1683 [M+H]+; found:
4-Methyl-N-{2-[1-(5-methylfuran-2-yl)-3-oxo-3-(thiophen-2-yl)
propyl]phenyl}benzenesulfonamide (16h). Yield: 381 mg, 82%;
490.1681.
white solid; mp 170–171 C (ethyl acetate); 1H NMR (400 MHz,
°
N-{2-[3-(4-Chlorophenyl)-1-(5-methylfuran-2-yl)-3-oxopropyl]
phenyl}-4-methylbenzenesulfonamide (16d). Yield: 430 mg,
CDCl3): δ=8.20 (br s, 1H), 7.70 (d, 3J=3.8 Hz, 1H), 7.68 (AA’BB’-
87%; white solid; mp 164–165 C (ethyl acetate); 1H NMR
system, J=8.2 Hz, 2H), 7.63 (d, J=4.8 Hz, 1H), 7.51–7.49 (m, 1H),
3
3
°
(400 MHz, CDCl3): δ=8.22 (br s, 1H), 7.85 (AA’BB’-system, 3J=
7.24–7.22 (m, 1H), 7.19–7.16 (m, 1H), 7.13–7.08 (m, 4H), 5.76 (d,
3
3
3
3
8.5 Hz, 2H), 7.67 (AA’BB’-system, J=8.1 Hz, 2H), 7.51–7.49 (m, 1H),
3J=2.8 Hz, 1H), 5.53 (d, J=2.8 Hz, 1H), 4.57 (dd, J=9.4 Hz, J=
4.1 Hz, 1H), 3.67 (dd, 2J=17.8 Hz, 3J=4.1 Hz, 1H), 3.41 (dd, 2J=
17.8 Hz, 3J=9.4 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ=191.5, 153.6, 151.3, 143.4, 143.2, 137.8, 135.8,
134.5 (2C), 132.7, 129.7 (2 C), 128.7, 128.3, 127.9, 127.3 (2 C), 126.6,
3
7.40 (AA’BB’-system, J=8.5 Hz, 2H), 7.24–7.22 (m, 1H), 7.20–7.16
(m, 1H), 7.12–7.10 (m, 3H), 5.76 (d, 3J=2.8 Hz, 1H), 5.51 (d, 3J=
2.8 Hz, 1H), 4.59 (dd, 3J=9.4 Hz, 3J=4.0 Hz, 1H), 3.69 (dd, 2J=
3
2
3
18.3 Hz, J=4.0 Hz, 1H), 3.47 (dd, J=18.3 Hz, J=9.4 Hz, 1H), 2.29
(s, 3H), 2.21 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=197.7,
153.6, 151.3, 143.3, 140.4, 137.8, 135.9, 134.7, 134.5, 129.8 (2 C),
129.7 (2 C), 129.1 (2 C), 128.7, 127.9, 127.3 (2 C), 126.6, 126.5,
107.3, 106.2, 44.5, 34.0, 21.5, 13.6 ppm; IR (nujol) νmax =3294, 1689,
1595, 1497, 1321, 1209, 1159, 1094 cmÀ 1; HRMS (ESI+): m/z calcd
for C27H25NSClO4+: 494.1187 [M+H]+; found: 494.1189.
126.5, 107.3, 106.2, 45.0, 34.0, 21.5, 13.6 ppm; IR (nujol) νmax
=
3238, 1641, 1412, 1325, 1285, 1153 cmÀ 1; HRMS (ESI+): m/z calcd
for C25H24NS2O4+: 466.1141 [M+H]+; found: 466.1137.
General Procedure for the Synthesis of 2-(2-Acylvinyl)indoles
(17a–h)[7]. m-CPBA (77% w/w, 135 mg, 0.6 mmol) was added to a
solution of a corresponding 2-(2-aminobenzyl)furan 16 (0.5 mmol)
°
N-{2-[3-(4-Fluorophenyl)-1-(5-methylfuran-2-yl)-3-oxopropyl]
phenyl}-4-methylbenzenesulfonamide (16e). Yield: 400 mg, 84%;
in CH2Cl2 (2 mL) at 0 C. The reaction mixture was stirred at the
same temperature for 1 h. Then TFA (3.8 μL, 0.05 mmol) was
added. The reaction mixture was allowed to reach room temper-
ature and stirred for 20 h. Thereafter, the reaction mixture was
white solid; mp 167–168 C (ethyl acetate); 1H NMR (400 MHz,
°
CDCl3): δ=8.29 (br s, 1H), 7.97–7.93 (m, 2H), 7.68 (AA’BB’-system,
3J=8.2 Hz, 2H), 7.52–7.50 (m, 1H), 7.25–7.23 (m, 1H), 7.20–7.16 (m,
cooled to À 10 C for 15 min. This was accompanied by precip-
°
3
3
1H), 7.12–7.08 (m, 5H), 5.76 (d, J=2.8 Hz, 1H), 5.50 (d, J=2.8 Hz,
itation of m-chlorobenzoic acid. Precipitate was filtered off using
rapid vacuum filtration and washed with cooled CH2Cl2 (2×2 mL).
The combined filtrates were concentrated in vacuo and the
residue was purified by flash column chromatography (silica gel,
eluent – petroleum ether/CH2Cl2, 9:1 to 1:1) to afford the
corresponding indoles. The products were recrystallized from
ethyl acetate.
3
3
2
3
1H), 4.58 (dd, J=9.5 Hz, J=3.7 Hz, 1H), 3.70 (dd, J=18.3 Hz, J=
2
3
3.7 Hz, 1H), 3.49 (dd, J=18.3 Hz, J=9.5 Hz, 1H), 2.29 (s, 3H), 2.21
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=197.3, 166.3 (d, JCF
=
=
1
4
256.0 Hz), 153.7, 151.3, 143.3, 137.8, 136.0, 134.6, 132.8 (d, JCF
2.9 Hz), 131.1 (d, JCF =9.4 Hz, 2 C), 129.7 (2 C), 128.7, 127.9, 127.3
(2 C), 126.6, 126.5, 115.9 (d, JCF =21.9 Hz, 2 C), 107.3, 106.2, 44.5,
3
2
34.0, 21.5, 13.6 ppm; IR (nujol) νmax =3275, 1688, 1593, 1489, 1325,
1286, 1238, 1213, 1163, 1092 cmÀ 1; HRMS (ESI+): m/z calcd for
C27H25NSFO4+: 478.1483 [M+H]+; found: 478.1484.
(E)-4-[3-(2-Oxo-2-phenylethyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-
one (17a). Yield: 196 mg, 86%; white solid; mp 168–169 C
(decomp.) (ethyl acetate); H NMR (400 MHz, CDCl3): δ=8.20–8.18
(m, 1H), 8.06 (d, J=16.5 Hz, 1H), 8.00–7.98 (m, 2H), 7.63–7.59 (m,
1H), 7.56 (AA’BB’-system, J=8.2 Hz, 2H), 7.51–7.47 (m, 2H), 7.38–
7.34 (m, 1H), 7.31–7.29 (m, 1H), 7.23–7.21 (m, 1H), 7.16 (AA’BB’-
system, J=8.2 Hz, 2H), 6.26 (d, J=16.5 Hz, 1H), 4.40 (s, 2H), 2.40
(s, 3H), 2.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.2,
195.6, 145.3, 137.4, 136.5, 135.1, 134.2, 133.9, 133.8, 131.7, 130.9,
129.9 (2 C), 129.0 (2 C), 128.4 (2 C), 126.8 (2 C), 126.6, 124.5, 120.2,
°
1
3
N-{2-[3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-(5-methylfuran-
2-yl)-3-oxopropyl]phenyl}-4-methylbenzenesulfonamide (16f).
3
°
Yield: 439 mg, 85%; pale yellow solid; mp 201–202 C (ethyl
1
3
3
acetate/1.4-dioxane=9:1); H NMR (400 MHz, CDCl3): δ=8.50 (br
s, 1H), 7.68 (AA’BB’-system, 3J=8.2 Hz, 2H), 7.54–7.52 (m, 1H),
7.45–7.44 (m, 2H), 7.22–7.20 (m, 1H), 7.18–7.14 (m, 1H), 7.11–7.07
(m, 3H), 6.87–6.85 (m, 1H), 5.75 (d, 3J=2.8 Hz, 1H), 5.48 (d, 3J=
Eur. J. Org. Chem. 2021, 1274–1285
www.eurjoc.org
1281
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202001608
120.1, 115.5, 35.6, 27.0, 21.7 ppm; IR (nujol) νmax =1670, 1618,
(m, 1H), 7.16 (AA’BB’-system, 3J=8.2 Hz, 2H), 6.93–6.91 (m, 1H),
6.26 (d, J=16.5 Hz, 1H), 4.32 (s, 2H), 4.33–4.31 (m, 2H), 4.29–4.27
1
2
3
4
5
6
7
8
9
3
1595, 1362, 1259, 1223, 1171 cmÀ 1; HRMS (ESI+): m/z calcd for
C27H24NSO4+: 458.1421 [M+H]+; found: 458.1421.
(m, 2H), 2.41 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
δ=198.2, 193.9, 148.7, 145.3, 143.7, 137.4, 135.1, 134.1, 134.0,
131.7, 131.0, 130.2, 129.9 (2 C), 126.8 (2 C), 126.6, 124.4, 122.6,
120.6, 120.2, 118.0, 117.6, 115.4, 64.9, 64.3, 35.3, 27.0, 21.7 ppm; IR
(nujol) νmax =1672, 1578, 1506, 1364, 1321, 1286, 1261, 1213, 1175,
1119 cmÀ 1; HRMS (ESI+): m/z calcd for C29H26NSO6+: 516.1475 [M+
H]+; found: 516.1477.
(E)-4-{3-[2-Oxo-2-(p–tolyl)ethyl]-1-tosyl-1H-indol-2-yl}but-3-en-
°
2-one (17b). Yield: 198 mg, 84%; gray solid; mp 141–142 C
1
(decomp.) (ethyl acetate); H NMR (400 MHz, CDCl3): δ=8.19–8.17
3
3
(m, 1H), 8.07 (d, J=16.5 Hz, 1H), 7.89 (AA’BB’-system, J=8.2 Hz,
3
2H), 7.56 (AA’BB’-system, J=8.2 Hz, 2H), 7.37–7.33 (m, 1H), 7.31–
7.27 (m, 3H), 7.22–7.18 (m, 1H), 7.16 (AA’BB’-system, 3J=8.2 Hz,
3
2H), 6.27 (d, J=16.5 Hz, 1H), 4.38 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H),
(E)-4-{3-[2-(Naphthalen-2-yl)-2-oxoethyl]-1-tosyl-1H-indol-2-yl}
but-3-en-2-one (17g). Yield: 212 mg, 83%; pale beige solid; mp
2.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.3, 195.2,
145.3, 144.8, 137.4, 135.0, 134.1, 134.0, 133.9, 131.7, 131.0, 129.9
(2 C), 129.7 (2 C), 128.6 (2 C), 126.8 (2 C), 126.6, 124.4, 120.5, 120.1,
115.4, 35.5, 27.0, 21.8, 21.7 ppm; IR (nujol) νmax =1689, 1663, 1605,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
170–171 C (decomp.) (ethyl acetate); 1H NMR (400 MHz, CDCl3):
δ=8.55 (s, 1H), 8.21–8.19 (m, 1H), 8.10 (d, J=16.5 Hz, 1H), 8.03–
°
3
8.01 (m, 1H), 7.98–7.96 (m, 1H), 7.92–7.88 (m, 2H), 7.65–7.56 (m,
1325, 1250, 1173, 1130 cmÀ 1
;
HRMS (ESI+): m/z calcd for
4H), 7.38–7.34 (m, 2H), 7.24–7.20 (m, 1H), 7.15 (AA’BB’-system, J=
3
C28H26NSO4+: 472.1577 [M+H]+; found: 472.1580.
8.1 Hz, 2H), 6.34 (d, J=16.5 Hz, 1H), 4.55 (s, 2H), 2.42 (s, 3H), 2.31
3
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.4, 195.6, 145.3,
137.3, 136.0, 134.9, 134.1, 134.0, 133.6, 132.6, 131.7, 130.9, 130.3,
129.9 (2 C), 129.8, 129.0, 128.9, 128.0, 127.2, 126.7 (2 C), 126.6,
124.5, 123.9, 120.4, 120.2, 115.4, 35.7, 27.0, 21.7 ppm; IR (nujol)
(E)-4-{3-[2-(4-Methoxyphenyl)-2-oxoethyl]-1-tosyl-1H-indol-2-yl}
but-3-en-2-one (17c). Yield: 217 mg, 89%; pale yellow solid; mp
193–195 C (decomp.) (ethyl acetate); 1H NMR (400 MHz, CDCl3):
°
δ=8.19–8.16 (m, 1H), 8.07 (d, 3J=16.5 Hz, 1H), 7.97 (AA’BB’-
ν
max =1678, 1595, 1358, 1279, 1248, 1167, 1132 cmÀ 1; HRMS (ESI+):
3
3
system, J=8.8 Hz, 2H), 7.56 (AA’BB’-system, J=8.2 Hz, 2H), 7.36–
m/z calcd for C31H26NSO4+: 508.1577 [M+H]+; found: 508.1586.
7.33 (m, 1H), 7.31–7.29 (m, 1H), 7.22–7.18 (m, 1H), 7.16 (AA’BB’-
3
3
system, J=8.2 Hz, 2H), 6.95 (AA’BB’-system, J=8.8 Hz, 2H), 6.28
(E)-4-{3-[2-Oxo-2-(thiophen-2-yl)ethyl]-1-tosyl1H-indol-2-yl}but-
3
°
(d, J=16.5 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 3H), 2.41 (s, 3H), 2.31 (s,
3-en-2-one (17h). Yield: 197 mg, 85%; gray solid; mp 179–180 C
3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.4, 194.1, 164.1, 145.3,
137.3, 135.0, 134.1, 134.0, 131.6, 131.0, 130.8 (2 C), 129.9 (2 C),
129.4, 126.7 (2 C), 126.6, 124.4, 120.7, 120.2, 115.4, 114.2 (2 C),
55.7, 35.3, 27.0, 21.7 ppm; IR (nujol) νmax =1682, 1599, 1576, 1364,
1319, 1248, 1219, 1186, 1175, 1138 cmÀ 1; HRMS (ESI+): m/z calcd
for C28H26NSO5+: 488.1526 [M+H]+; found: 488.1536.
decomp. (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ=8.19–8.17
3
3
(m, 1H), 8.07 (d, J=16.5 Hz, 1H), 7.80 (d, J=3.7 Hz, 1H), 7.68 (d,
3J=4.9 Hz, 1H), 7.55 (AA’BB’-system, J=8.2 Hz, 2H), 7.38–7.34 (m,
3
3
2H), 7.24–7.20 (m, 1H), 7.17–7.15 (m, 3H), 6.35 (d, J=16.5 Hz, 1H),
4.32 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ=198.3, 188.4, 145.4, 143.3, 137.2, 134.9, 134.7, 134.3,
133.9, 132.6, 131.8, 130.8, 130.0 (2 C), 128.5, 126.7 (2 C), 126.6,
(E)-4-{3-[2-(4-Chlorophenyl)-2-oxoethyl]-1-tosyl-1H-indol-2-yl}
but-3-en-2-one (17d). Yield: 226 mg, 92%; pale yellow solid; mp
124.5, 120.2, 119.7, 115.4, 36.3, 27.1, 21.7 ppm; IR (nujol) νmax
=
1657, 1618, 1593, 1558, 1515, 1411, 1364, 1263, 1242, 1227,
1169 cmÀ 1; HRMS (ESI+): m/z calcd for C25H22NS2O4+: 464.0985 [M
+H]+; found: 464.0990.
137–138 C (decomp.) (ethyl acetate); 1H NMR (400 MHz, CDCl3):
°
δ=8.20–8.18 (m, 1H), 8.05 (d, 3J=16.5 Hz, 1H), 7.91 (AA’BB’-
3
3
system, J=8.6 Hz, 2H), 7.55 (AA’BB’-system, J=8.2 Hz, 2H), 7.45
(AA’BB’-system, 3J=8.6 Hz, 2H), 7.38–7.34 (m, 1H), 7.29–7.27 (m,
General Procedure for the Synthesis of (3-Methyl-9-tosyl-9H-
carbazol-4-yl)(aryl)methanones 18. To a solution of (E)-4-[3-(2-
3
1H), 7.23–7.20 (m, 1H), 7.16 (AA’BB’-system, J=8.2 Hz, 2H), 6.23
3
(d, J=16.5 Hz, 1H), 4.36 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H) ppm; 13C
oxo-2-arylethyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one
17
NMR (100 MHz, CDCl3): δ=198.2, 194.5, 145.4, 140.4, 137.4, 135.1,
134.7, 134.2, 133.9, 131.9, 130.8, 130.0 (2 C), 129.8 (2 C), 129.4
(2 C), 126.8 (2 C), 126.7, 124.5, 120.0, 119.8, 115.5, 35.7, 26.9,
(0.2 mmol) in MeOH (4 mL) was added KOH (44.2 mg, 0.8 mmol) at
room temperature. The resulting solution was stirred at the same
temperature overnight (TLC control). After completion of the
reaction, saturated aqueous solution of NH4Cl (1 mL) was added
dropwise. After that, the reaction mixture was concentrated in
vacuo and the residue was purified by flash column chromatog-
raphy (silica gel, eluent – petroleum ether/CH2Cl2, 9:1) to afford
the N-tosylcarbazoles 18.
21.7 ppm; IR (nujol)
νmax =1678, 1587, 1250, 1213, 1173,
1088 cmÀ 1; HRMS (ESI+): m/z calcd for C27H23NSClO4+: 492.1031 [M
+H]+; found: 492.1041.
(E)-4-{3-[2-(4-Fluorophenyl)-2-oxoethyl]-1-tosyl-1H-indol-2-yl}
but-3-en-2-one (17e). Yield: 209 mg, 88%; gray solid; mp 169–
170 C (decomp.) (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ=
(3-Methyl-9-tosyl-9H-carbazol-4-yl)(phenyl)methanone
(18a).
°
3
8.26–8.24 (m, 1H), 8.12 (d, J=16.5 Hz, 1H), 8.09–8.06 (m, 2H), 7.62
Yield: 83 mg, 95% yield; gray oil; 1H NMR (400 MHz, CDCl3): δ=
8.37 (d, 3J=8.5 Hz, 1H), 8.32 (d, 3J=8.5 Hz, 1H), 7.84 (AA’BB’-
(AA’BB’-system, 3J=8.0 Hz, 2H), 7.44–7.41 (m, 1H), 7.36–7.32 (m,
3
3
3
1H), 7.30–7.28 (m, 1H), 7.24–7.19 (m, 4H), 6.30 (d, J=16.5 Hz, 1H),
system, J=7.6 Hz, 2H), 7.69 (AA’BB’-system, J=8.1 Hz, 2H), 7.59–
7.56 (m, 1H), 7.43–7.40 (m, 2H), 7.39–7.37 (m, 2H), 7.35–7.33 (m,
1H), 7.12 (AA’BB’-system, 3J=8.1 Hz, 2H), 7.10–7.06 (m, 1H), 2.29 (s,
3H), 2.26 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=199.0, 145.2,
139.0, 137.0, 136.8, 135.1, 134.3, 133.4, 130.2, 129.9 (2 C), 129.8
(2 C), 129.5, 129.2 (2 C), 127.5, 126.7 (2 C), 124.8, 124.1, 123.3,
122.1, 115.8, 115.2, 21.6, 18.8 ppm; IR (nujol) νmax =1666, 1595,
1421, 1312, 1277, 1219, 1173, 1155 cmÀ 1; HRMS (ESI+): m/z calcd
for C27H22NSO3+: 440.1315 [M+H]+; found: 440.1310.
4.43 (s, 2H), 2.48 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ=198.2, 194.0, 165.3 (d, 1JCF =256 Hz), 145.4, 137.4, 135.1,
134.2, 133.9, 132.9 (d, 4JCF =3.0 Hz), 131.8, 131.1 (d, 3JCF =9.4 Hz,
2 C), 130.8, 130.0 (2 C), 126.8 (2 C), 126.7, 124.5, 120.1, 120.0, 116.2
2
(d, JCF =22.0 Hz, 2 C), 115.5, 35.6, 26.9, 21.7 ppm; IR (nujol) νmax
=
1695, 1663, 1597, 1508, 1364, 1327, 1256, 1232, 1215, 1173,
1132 cmÀ 1; HRMS (ESI+): m/z calcd for C27H23NSFO4+: 476.1326 [M
+H]+; found: 476.1327.
(E)-4-{3-[2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxoethyl]-1-
tosyl-1H-indol-2-yl}but-3-en-2-one (17f). Yield: 216 mg, 84%;
(4-Fluorophenyl)(3-methyl-9-tosyl-9H-carbazol-4-yl)methanone
(18e). Yield: 78 mg, 86%; transparent oil; 1H NMR (400 MHz,
gray solid; mp 171–172 C (decomp.) (ethyl acetate); 1H NMR
(400 MHz, CDCl3): δ=8.18–8.16 (m, 1H), 8.06 (d, J=16.5 Hz, 1H),
7.56–7.51 (m, 4H), 7.36–7.32 (m, 1H), 7.31–7.29 (m, 1H), 7.22–7.18
CDCl3): δ=8.37 (d, J=8.6 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.87–
7.84 (m, 2H), 7.69 (AA’BB’-system, 3J=8.2 Hz, 2H), 7.42–7.37 (m,
2H), 7.32–7.30 (m, 1H), 7.14–7.05 (m, 5H), 2.30 (s, 3H), 2.25 (s, 3H)
3
3
°
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1
+
ppm; 13C NMR (100 MHz, CDCl3): δ=197.4, 166.6 (d, JCF
=
(ESI+): m/z calcd for C21H18NO2
316.1341.
:
316.1332 [M+H]+; found:
1
2
3
4
5
6
7
8
9
4
257.1 Hz), 145.2, 139.1, 137.0, 135.1, 133.3 (d, JCF =2.8 Hz), 133.0,
132.6 (d, JCF =9.6 Hz, 2 C), 130.2, 129.9 (2 C), 129.6, 127.7, 126.7
3
(4-Chlorophenyl)(3-methyl-9H-carbazol-4-yl)methanone (20d).
2
(2 C), 124.7, 124.1, 123.2, 122.0, 116.5 (d, JCF =22.1 Hz, 2 C), 115.9,
1
Yield: 58 mg, 91%; pale yellow oil; H NMR (400 MHz, CDCl3): δ=
115.3, 21.6, 18.8 ppm; HRMS (ESI+): m/z calcd for C27H21FNSO3
458.1221 [M+H]+; found: 458.1220.
:
+
8.17 (br s, 1H), 7.88 (AA’BB’-system, J=8.4 Hz, 2H), 7.44 (d, 3J=
3
8.2 Hz, 1H), 7.41–7.39 (m, 3H), 7.37–7.35 (m, 1H), 7.33–7.31 (m, 1H),
7.29 (d, 3J=8.2 Hz, 1H), 7.00–6.96 (m, 1H), 2.30 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ=198.8, 140.6, 140.2, 138.0, 135.7, 132.7,
131.3 (2 C), 129.5 (2 C), 128.3, 126.2, 125.4, 122.0, 121.6, 120.1,
119.8, 111.7, 110.8, 18.9 ppm; IR (nujol) νmax =3420, 1666, 1649,
1585, 1568, 1398, 1313, 1286, 1256 cmÀ 1; HRMS (ESI+): m/z calcd
for C20H15ClNO+: 320.0837 [M+H]+; found: 320.0842.
Synthesis of 3-Methyl-9-tosyl-9H-carbazole (19a). To the solution
of (E)-4-(3-(2-oxo-2-phenylethyl)-1-tosyl-1H-indol-2-yl)but-3-en-2-
one 17a (0.15 mmol) in DCE (4 mL) was added Cu(OTf)2 (2.7 mg,
0.0075 mmol) at room temperature. The reaction mixture was
°
heated to 85 C in the aluminium block and stirred for 24 h (TLC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
control). After that, the reaction mixture was concentrated in
vacuo and the residue was purified by flash column chromatog-
raphy (silica gel, petroleum ether/CH2Cl2, 25:1) to afford the
carbazole 19a. Yield: 19 mg, 38%; pale gray oil;[21] 1H NMR
(400 MHz, CDCl3): δ=8.31 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.4 Hz,
1H), 7.87–7.85 (m, 1H), 7.68–7.66 (m, 3H), 7.48–7.44 (m, 1H), 7.35–
7.32 (m, 1H), 7.30–7.28 (m, 1H), 7.08 (AA’BB’-system, 3J=8.2 Hz,
2H), 2.48 (s, 3H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=
144.8, 138.9, 136.8, 135.4, 133.8, 129.7 (2 C), 128.7, 127.3, 126.8,
126.7 (3 C), 123.9, 120.2, 120.0, 115.4, 115.1, 21.6, 21.4 ppm.
(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)(3-methyl-9H-carbazol-4-yl)
methanone (20f). Yield: 56 mg, 82%; pale beige oil; 1H NMR
(400 MHz, CDCl3): δ=8.10 (br s, 1H), 7.53–7.45 (m, 3H), 7.39–7.35
(m, 2H), 7.33–7.31 (m, 1H), 7.28 (br s, 1H), 7.00–6.97 (m, 1H), 6.86
(d, 3J=8.4 Hz, 1H), 4.29–4.28 (m, 2H), 4.24–4.23 (m, 2H), 2.31 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ=198.4, 148.9, 143.8, 140.1,
138.0, 133.5, 131.3, 128.2, 126.0, 125.4, 124.3, 122.3, 122.0, 120.2,
119.7, 119.3, 117.8, 111.2, 110.6, 64.9, 64.2, 18.8 ppm; IR (nujol)
3
3
ν
max =3402, 1651, 1599, 1576, 1502, 1310, 1288, 1261, 1175,
General Procedure for the Synthesis of Carbazoles 20. 30 mL
Microwave reaction vessel was charged with corresponding 2-(2-
acylvinyl)indole 17a-h (0.2 mmol), KOH (22.1 mg, 0.4 mmol) and
MeOH (4 mL) at 0 C. The reaction mixture was allowed to reach
room temperature and stirred for 12 h (TLC control). Upon
completion, to a resulting solution was additionally added KOH
1115 cmÀ 1; HRMS (ESI+): m/z calcd for C22H18NO3+: 344.1281 [M+
H]+; found: 344.1290.
(3-Methyl-9H-carbazol-4-yl)(naphthalen-2-yl)methanone (20g).
°
1
Yield: 55 mg, 83%; yellow oil; H NMR (400 MHz, CDCl3): δ=8.29
(br s, 1H), 8.19 (d, 3J=8.6 Hz, 1H), 8.14 (br s, 1H), 7.94 (d, 3J=
3
3
8.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.60–
7.56 (m, 1H), 7.51–7.45 (m, 3H), 7.38–7.33 (m, 2H), 7.30–7.28 (m,
1H), 6.94–6.90 (m, 1H), 2.34 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
δ=199.9, 140.2, 138.1, 136.3, 134.7, 133.5, 133.0, 132.7, 130.0,
129.1, 128.9, 128.3, 128.0, 126.8, 126.1, 125.6, 124.7, 122.3, 121.9,
120.5, 119.8, 111.4, 110.7, 19.0 ppm; IR (nujol) νmax =3238, 1649,
°
(22.1 mg, 0.4 mmol) and stirred at 110 C under microwave
irradiation for 1 hour (TLC control). After completion of the
reaction, saturated aqueous solution of NH4Cl (0.5–1.0 mL) was
added dropwise. After that, the reaction mixture was concentrated
in vacuo and the residue was purified by flash column chromatog-
raphy (silica gel, petroleum ether/CH2Cl2, 9:1) to afford the
carbazoles 20.
1624, 1310, 1265, 1231 cmÀ 1
;
HRMS (ESI+): m/z calcd for
C24H18NO+: 336.1383 [M+H]+; found: 336.1391.
(3-Methyl-9H-carbazol-4-yl)(phenyl)methanone (20a). Yield:
51 mg, 89%; pale yellow oil; 1H NMR (400 MHz, CDCl3): δ=8.16 (br
s, 1H), 7.96–7.94 (m, 2H), 7.59–7.55 (m, 1H), 7.48 (d, 3J=8.0 Hz, 1H),
7.45–7.38 (m, 3H), 7.36–7.28 (m, 3H), 6.98–6.94 (m, 1H), 2.31 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ=200.0, 140.2, 138.1, 137.3,
133.9, 133.3, 130.0 (2 C), 129.1 (2 C), 128.2, 126.1, 125.5, 122.2,
121.8, 120.3, 119.7, 111.4, 110.7, 18.9 ppm; IR (nujol) νmax =3312,
1649, 1319, 1263 cmÀ 1; HRMS (ESI+): m/z calcd for C20H16NO+:
286.1226 [M+H]+; found: 286.1233.
(3-Methyl-9H-carbazol-4-yl)(thiophen-2-yl)methanone
(20h).
Yield: 49 mg, 84%; pale gray oil; 1H NMR (400 MHz, CDCl3): δ=
3
4
3
8.16 (br s, 1H), 7.69 (dd, J=4.9 Hz, J=0.9 Hz, 1H), 7.57 (d, J=
8.0 Hz, 1H), 7.35–7.28 (m, 4H), 7.25–7.23 (m, 1H), 6.99–6.96 (m, 2H),
2.37 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=192.1, 144.8,
140.1, 138.0, 135.9, 135.6, 132.9, 128.7, 128.2, 126.1, 125.5, 122.1,
121.6, 120.1, 119.7, 111.7, 110.8, 18.8 ppm; IR (nujol) νmax =3281,
1630, 1516, 1493, 1410, 1352, 1319, 1265, 1240, 1227 cmÀ 1; HRMS
(ESI+): m/z calcd for C18H14NSO+: 292.0791 [M+H]+; found:
292.0793.
(3-Methyl-9H-carbazol-4-yl)(4-methylphenyl)methanone (20b).
Yield: 51 mg, 86%; pale gray oil; 1H NMR (400 MHz, CDCl3): δ=
Synthesis of 2-[(5-Methylfuran-2-yl)methyl]benzohydrazide (21).
The mixture of 2-[(5-methylfuran-2-yl)methyl]benzoic acid
(200 mg, 0.93 mmol) and K2CO3 (257 mg, 1.86 mmol) in acetone
(5 mL) was reflux for 15–20 minutes. Then the reaction mixture
was cooled to room temperature and MeI (290 μL, 4.65 mmol) was
added dropwise. The resulting solution was stirred at the same
temperature for 3 h (TLC control). Upon completion, the reaction
mixture was concentrated in vacuo. The obtained methyl 2-[(5-
methylfuran-2-yl)methyl]benzoate was purified by column chro-
matography (silica gel, ethyl acetate/petroleum ether, 1:3). The
solution of hydrazine hydrate (1.84 mL, 37.2 mmol) and obtained
3
8.15 (br s, 1H), 7.84 (AA’BB’-system, J=8.0 Hz, 2H), 7.49 (d, 3J=
3
8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.35–7.33 (m, 1H), 7.31–7.27
(m, 2H), 7.22 (AA’BB’-system, 3J=8.0 Hz, 2H), 6.98–6.94 (m, 1H),
2.39 (s, 3H), 2.31 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=200.0,
144.9, 140.2, 138.1, 134.9, 133.6, 130.1 (2C), 129.8 (2C), 128.2,
126.0, 125.4, 122.2, 121.9, 120.2, 119.7, 111.3, 110.7, 21.9,
18.9 ppm; IR (nujol) νmax =3267, 1654, 1599, 1315, 1285, 1261,
1176 cmÀ 1; HRMS (ESI+): m/z calcd for C21H18NO+: 300.1383 [M+
H]+; found: 300.1391.
(4-Methoxyphenyl)(3-methyl-9H-carbazol-4-yl)methanone (20c).
1
Yield: 53 mg, 85%; pale beige oil; H NMR (400 MHz, CDCl3): δ=
methyl
2-[(5-methylfuran-2-yl)methyl]benzoate
(277 mg,
8.10 (br s, 1H), 7.92–7.90 (m, 2H), 7.50 (d, 3J=8.0 Hz, 1H), 7.41–7.39
1.2 mmol) in n-butyl alcohol (1.86 mL, 20.4 mmol) was reflux for
20–30 minutes (TLC control). Upon completion, the reaction
mixture was poured into water (50 mL). The obtained solid
product 21 was filtered under reduced pressure and dried in the
air. Yield: 262 mg, 95%; colorless oil; 1H NMR (400 MHz, CDCl3): δ=
7.45–7.43 (m, 1H), 7.34–7.30 (m, 1H), 7.22–7.20 (m, 1H), 7.17–7.13
3
(m, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.32–7.28 (m, 2H), 6.99–6.95 (m,
3
1H), 6.90 (AA’BB’-system, J=8.9 Hz, 2H), 3.84 (s, 3H), 2.32 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ=198.4, 164.3, 140.1, 138.0,
133.7, 132.4, 130.6, 128.2 (2 C), 126.0, 125.4, 122.3, 122.0, 120.3,
119.8, 114.3 (2 C), 111.2, 110.6, 55.6, 18.8 ppm; IR (nujol) νmax
=
3400, 1647, 1595, 1572, 1493, 1310, 1258, 1169, 1153 cmÀ 1; HRMS
(m, 1H), 6.51 (br s, 3H), 5.83 (d, J=2.8 Hz, 1H), 5.79 (d, J=2.8 Hz,
3
3
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1H), 4.06 (s, 2H), 2.17 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=
2017, 10, 4123–4134; c) T. Montagnon, D. Kalaitzakis, M. Sofiadis, G.
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8
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Vassilikogiannakis, Org. Biomol. Chem. 2016, 14, 8636–8640; d) P.
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50, 15480–15498; f) T. Montagnon, D. Noutsias, I. Alexopoulou, M. Tofi,
G. Vassilikogiannakis, Org. Biomol. Chem. 2011, 9, 2031–2039.
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Ju, C. M. Beaudry, Angew. Chem. Int. Ed. 2019, 58, 6752–6755; d) E.
Hayashi, Y. Yamaguchi, K. Kamata, N. Tsunoda, Y. Kumagai, F. Oba, M.
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170.0, 152.1, 151.3, 137.7, 132.8, 131.1, 130.8, 128.1, 126.9, 107.6,
+
106.3, 31.9, 13.6 ppm; HRMS (ESI+): m/z calcd for C13H15N2O2
231.1128 [M+H]+; found: 231.1127.
:
Synthesis of 2-methyl-10H-pyridazino[1,6-b]isoquinolin-10-one
(22). m-CPBA (77% w/w, 135 mg, 0.6 mmol) was added to a
solution of a 2-[(5-methylfuran-2-yl)methyl]benzohydrazide 21
(115 mg, 0.5 mmol) or tert-butyl 2-{2-[(5-methylfuran-2-yl)methyl]
benzoyl}hydrazine-1-carboxylate 23 (165 mg, 0.5 mmol) in CH2Cl2
°
(2 mL) at 0 C. The reaction mixture was stirred at the same
temperature for 1 h. Then HCl (3.07 μL, 0.1 mmol) was added. The
reaction mixture was allowed to reach room temperature and
stirred for 20 h. Thereafter, the reaction mixture was cooled to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
À 10 C for 15 min. This was accompanied by precipitation of m-
chlorobenzoic acid. Precipitate was filtered off using rapid vacuum
filtration and washed with cooled CH2Cl2 (2×2 mL). The combined
filtrates were concentrated in vacuo and the residue was purified
by flash column chromatography (silica gel, ethyl acetate/petro-
leum ether, 1:3) to afford the corresponding 2-methyl-10H-
pyridazino[1,6-b]isoquinolin-10-one 22. Yield: 42 mg, 40% (for 21),
1
87 mg, 83% (for 23); dark green oil; H NMR (400 MHz, CDCl3): δ=
8.69–8.67 (m, 1H), 7.72–7.68 (m, 1H), 7.63–7.61 (m, 1H), 7.54–7.50
3
(m, 1H), 7.40 (d, J=9.3 Hz, 1H), 6.65 (s, 1H), 6.55 (d, 3J=9.3 Hz,
1H), 2.51 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ=159.5, 152.3,
135.5, 134.0, 133.1, 132.5, 129.1, 126.5, 125.9, 124.2, 120.0, 102.5,
22.7 ppm; HRMS (ESI+): m/z calcd for C13H11N2O+: 211.0866 [M+
H]+; found: 211.0865.
Synthesis
of
tert-butyl
2-{2-[(5-methylfuran-2-yl)methyl]
benzoyl}hydrazine-1-carboxylate (23). The mixture of 2-[(5-meth-
ylfuran-2-yl)methyl]benzohydrazide 21 (230 mg, 1 mmol) and di-
tert-butyl dicarbonate (689 μL, 3 mmol) in CH2Cl2 (5 mL) was reflux
under a argon atmosphere (TLC control). Upon completion, the
reaction mixture was concentrated in vacuo. The product 23 was
purified by column chromatography (silica gel, petroleum ether).
°
Yield: 293 mg, 89%; yellow solid; mp 87–88 C (CH2Cl2/petroleum
ether=1:10); H NMR (400 MHz, CDCl3): δ=7.69 (br s, 1H), 7.54–
1
7.52 (m, 1H), 7.41–7.37 (m, 1H), 7.30–7.27 (m, 2H), 6.61 (br s, 1H),
5.92 (d, 3J=2.8 Hz, 1H), 5.84 (d, 3J=2.8 Hz, 1H), 4.16 (s, 2H), 2.22 (s,
3H), 1.51 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ=168.9, 155.5,
152.2, 151.4, 137.3, 133.4, 131.1, 130.9, 128.2, 126.9, 107.5, 106.3,
82.1, 31.9, 28.3 (3C), 13.6 ppm; HRMS (ESI+): m/z calcd for
C18H23N2O4+: 331.1652 [M+H]+; found: 331.1654.
Acknowledgements
This work was supported by the Russian Science Foundation
(Grant No. 19-73-00093). We thank Dr. Aleksander Rubtsov (Perm
State University) and Dr. Maksim Dmitriev (Perm State University)
for the preparation of single-crystal X-ray data.
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Conflicts of interest
There are no conflicts to declare.
Keywords: Carbazole
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Furans
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Indoles
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Revised manuscript received: January 13, 2021
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