Synthesis of Indolo-and Benzothieno[2,3-b]quinolines by a Cascade Cyclization of o-Alkynylisocyanobenzene Derivatives

Article abstract of DOI:10.1021/acs.joc.9b02081

A new synthetic approach for the synthesis of indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines has been developed by employing the freshly prepared o-alkynylisocyanobenzenes derived from o-alkynylformamide derivatives as substrates. The synthetic transformations involved chloride-ion-triggered 6-endo cyclization of o-alkynylisocyanobenzenes to generate 2-chloroquinolines in situ, which further cyclized intramolecularly with nitrogen or sulfur atom via a cascade process to provide the corresponding indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines, respectively, in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.9b02081

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Article
Synthesis of Indolo- and Benzothieno[2,3-b]quinolines by a
Cascade Cyclization of o-Alkynylisocyanobenzene Derivatives
Onnicha Khaikate, Natthamon Inthalaeng, Jatuporn Meesin, Kritchasorn Kantarod, Manat
Pohmakotr, Vichai Reutrakul, Darunee Soorukram, Pawaret Leowanawat, and Chutima Kuhakarn
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02081 • Publication Date (Web): 30 Oct 2019
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Synthesis of Indolo- and Benzothieno[2,3-b]quinolines
by a Cascade Cyclization of o-Alkynylisocyanobenzene
Derivatives
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Onnicha Khaikate, Natthamon Inthalaeng, Jatuporn Meesin, Kritchasorn Kantarod, Manat Pohmakotr,
Vichai Reutrakul, Darunee Soorukram, Pawaret Leowanawat, and Chutima Kuhakarn*
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty
of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand.
E-mail: chutima.kon@mahidol.ac.th
Table of Contents (TOC) Graphic
ABSTRACT: A new synthetic approach for the synthesis of indolo[2,3-b]quinolines and
benzothieno[2,3-b]quinolines has been developed by employing the freshly prepared o-
alkynylisocyanobenzenes derived from o-alkynylformamide derivatives as substrates. The
synthetic transformations involved chloride ion triggered 6-endo cyclization of o-
alkynylisocyanobenzenes to generate 2-chloroquinolines in situ, which further cyclized
intramolecularly with nitrogen or sulfur atom via a cascade process to provide the corresponding
indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines, respectively, in moderate to excellent
yields.
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1. INTRODUCTION
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As important intermediates in organic synthesis, isocyanides are the versatile building
blocks being employed in multicomponent reactions (MCRs), and have been widely applied to
access N-heterocycles with delicate molecular complexity.1 Isocyanides can also react with
various radical and anion species to generate the respective imidoyl radical and anion
intermediates for further transformations.2 Synthetic applications have been widely demonstrated
on the synthesis of N-containing heterocycles through the intramolecular addition to alkene,3
alkyne,4 or arene5 moieties to access various substituted indole, quinoline, isoquinoline, and
phenanthridine derivatives.
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Heteroaryl[b]quinolines are important scaffolds found in naturally occurring
compounds,6 and organic materials.7 In particular, indoloquinolines bearing an indole ring fused
to the [b] side of a quinoline ring are privileged structural motifs and explicitly exhibit a broad
spectrum of biological activities as anticancer, antimalarial, antiplasmodial, and antibacterial
agents.8 Given their significant properties in various fields, numerous synthetic approaches have
been continually reported for the preparation of such the indoloquinoline skeletons.9
In recent years, we and others studied nucleophile triggered cyclization of o-
alkynylisocyanobenzenes.10 Widely used by several research groups including us, 2-alkynyl-
N,N-dialkylanilines are synthetically useful substrates employed for preparation nitrogen-
containing heterocycles.11 As a part of our program on the construction on N-heterocycles, we
envisioned that o-alkynylisocyanobenzenes 2 and 5 could undergo a cascade cyclization
mediated by a nucleophile and would provide an access to highly functionalized indolo[2,3-
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b]quinolines and benzothieno[2,3-b]quinolines12 in a single step, involving the formation of
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C−C, and C−X (X = N, S) bonds via a cascade strategy (Scheme 1).
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Scheme 1. Design Synthetic Approach to Indolo[2,3-b]quinolines and Benzothieno[2,3-
b]quinolines
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2. RESULTS AND DISCUSSION
We employed o-alkynylisocyanobenzene 2a as a model substrate to screen for the
optimized reaction conditions. Compound 2a was readily obtained from its corresponding
formamide 1a upon treatment with POCl3, i-Pr2NEt in CH2Cl2 at 0 C.10a,b Compound 2a is
o
inherently unstable therefore, after aqueous work-up, it was employed in the next step without
purification. It is worth mentioning that in contrast to our recently published articles,10a,b in this
work, prior filtration of the freshly prepared isocyanides through alumina column was not
performed. Several reaction parameters including solvents, temperature and time were screened
and the results are summarized in Table 1. On the basis of our previous works on isocyanide
chemistry, we first exposed 2a [prepared from 1a (0.5 mmol)] in DMF (2 mL, 0.25 M) at room
temperature for overnight (16 h).10b Gratifyingly, the reaction readily took place and the desired
indolo[2,3-b]quinoline 3a was obtained in moderate yield (62% yield) (Table 1, entry 1). Slightly
lower yield was observed when the reaction was shortened from 16 h to 1 h (Table 1, entry 2).
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The reaction proceeded more efficiently and gave 90% yield of 3a when the reaction was carried
out in DMF at 80 oC for 1 h (Table 1, entry 3). Next, a variety of solvents were evaluated (Table
1, entries 3−10). Among the organic solvents (DMSO, EtOAc, toluene, CH3CN, THF, and
MeOH) and water screened, DMF gave optimum results. It is worth to emphasize that, after
aqueous work-up, if 2a was filtered through a short-path column packed with Aluminium oxide,
Type E10a,b or Florisil prior to the reaction in step (2), the desired product 3a was obtained in
lower yields (Table 1, entries 11−12).
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Table 1. Optimization of the Reaction Conditionsa
entry
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solvent
DMF
DMF
DMF
DMSO
EtOAc
Toluene
CH3CN
THF
tempb (oC)
time (h)
yieldc (%)
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MeOH
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DMF
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DMF
aReaction conditions: Step (1): 1a (0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv), (i-Pr)2NEt (0.70
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mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 C, 1 h, followed by aqueous work-up. Step (2): The crude
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mixture of 2a from Step (1) was diluted in the solvent (2 mL, 0.25 M) under various reaction conditions. Oil-bath
temperature. cIsolated yields after column chromatography (SiO2). d2a was filtered through a short-path Aluminium
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oxide-Type E column and was eluted with EtOAc. 2a was filtered through a short-path Florisil column and was
eluted with EtOAc.
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After the optimal reaction conditions were identified (Table 1, entry 3), the substrate
scope and limitation of the reaction were evaluated. Substrates 2b‒2n with different substituted
patterns and electronic properties on the aniline moiety (R1) and the isocyanoaryl moiety (R2)
toward the indolo[2,3-b]quinoline formation were investigated and the results are summarized in
Scheme 2. Compounds 2b‒2g bearing different substituent groups on the aniline moiety (R1),
including 4-Me, 4-CF3, 4-F, 4-Cl, 4-Br and 5-Cl, smoothly provided the corresponding products
3b‒3g in good to excellent yields (71−78% yields). Next, substrates 2h‒2n with different
substituted patterns and electronic properties on the isocyanoaryl moiety (R2), including 4-Me, 4-
CF3, 4-F, 4-Cl, 4-Br, 4-NO2 and 5-Cl, were well accommodated and yielded products 3h‒3n in
good yields (70−88% yields). Using substrates 2o and 2p bearing diethyl and dibenzyl moieties
on the aniline nitrogen provided the respective N-ethyl and N-benzyl products 3o and 3p in good
yields (85‒99% yields). The free NH2 substrate 2q gave product 3q in low yield (45% yield).
Noteworthy, the monoethyl and monobenzyl aniline substrates 2o′ and 2p′ also delivered, after
deprotonation, products 3o and 3p in moderate yields (64‒77% yields). Compound 2r bearing
NHTs at the aniline moiety gave 3r in 89% yield. The steric effect in the dealkylation step was
also briefly evaluated. Substrate 1s bearing ethyl and methyl groups at the nitrogen atom was
employed as a substrate to study the influence of the alkyl groups on product distribution after
dealkylation. Under the standard reaction conditions, 1s provided a mixture of 3b and 3o which
can be readily separated. After chromatographic purification, compounds 3b and 3o were
isolated in 21% and 57% yields, respectively. This observation emphasized that the dealkylation
preferably took place at the less steric methyl group. Finally, when cyclic aniline derivatives 1t
and 1u were employed as starting compounds, products 3t and 3u were obtained in 53% and
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78% yields, respectively. The yields of 3t and 3u can be slightly improved to 66% and 84%
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yields, respectively, when the reactions were carried out in the presence of n-Bu4NCl (0.5 mmol,
1.0 equiv). These implied the role of the chloride ion (Cl−) in assisting the dealkylation in the
mechanistic pathway.
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Scheme 2. Scopes of Compounds 2a
3a, R1 = H (90%)
3b, R1 = Me (72%)
3c, R1 = CF3 (78%)
3d, R1 = F (74%)
3e, R1 = Cl (76%)
3f, R1 = Br (71%)
3g (71%)
3h, R2 = Me (84%)
3i, R2 = CF3 (77%)
3j, R2 = F (79%)
3k, R2 = Cl (85%)
3l, R2 = Br (82%)
3m, R2 = NO2 (88%)
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3n (70%)
3o, R = Et (85%)b (77%)c
3p, R = Bn (99%)d (64%)e
3q, R = H (45%)
3r (89%)
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3t (53%) (66%)f
3u (78%) (84%)f
aReaction conditions: Step (1): 1 (0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv), (i-Pr)2NEt (0.70
mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 C, 1 h, followed by aqueous work-up. Step (2): The crude
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mixture of 2 from step (1) was diluted in DMF (2 mL, 0.25 M), 80 C, 1 h. In parenthesis: isolated yields after
column chromatography (SiO2). bFrom 1o. cFrom 1o´. dFrom 1p. eFrom 1p´. fIn the presence of n-Bu4NCl (0.1390 g,
0.5 mmol, 1 equiv).
The synthetic utility of the current protocol was further extended to the synthesis of
benzothieno[2,3-b]quinolines 6.12 Pleasingly, the established protocol can also be applied to
access 6 and the results are shown in Scheme 3.13 The reaction of 5, prepared from the
corresponding formamide substrates 4, readily proceeded in DMF at room temperature to yield
the products 6 in good yields (67−89% yields). Ultimately, efforts were also extended to the
substrate of oxygen analogs in order to access benzofurano[2,3-b]quinolines, unfortunately
without success.
Scheme 3. Scopes of Compounds 5a
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aReaction conditions: Step (1): 4 (0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv), (i-Pr)2NEt (0.70
mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 C, 1 h, followed by aqueous work-up. Step (2): The crude
mixture of 5 from Step (1) was diluted in DMF (2 mL, 0.25 M), room temperature, 1 h. In parenthesis: isolated
yields after column chromatography (SiO2).
o
To demonstrate the synthetic utility of the present reaction, a gram-scale reaction was
evaluated. Under standard reaction conditions, 1a (1.32 g, 5 mmol) and 4a (1.34 g, 5 mmol) were
efficiently converted into 3a (0.9832 g, 85% yield) and 6a (0.8552 g, 73% yield), respectively
(Scheme 4).
Scheme 4. Gram-Scale Synthesis of 3a and 6a
To gain a better understanding on the reaction mechanism, a series of control experiments
were carried out as shown in Scheme 5. Neither TEMPO nor BHT affected the reactions of 2a
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[Scheme 5, (a)]. These results implied that the reaction should proceed through a non-radical
pathway. As previously mentioned, filtration of the prepared isocyanide 2a through aluminium
oxide, Type E or Florisil column deteriorated the reaction efficiency (Table 1, entries 11−12).
However, when the reaction of 2a, pre-filtered with Florisil column, was carried out in the
presence of n-Bu4NCl (0.1390 g, 0.5 mmol, 1.0 equiv), the product yield of 3a improved
considerably (from 76% yield to 93% yield) [Scheme 5, (b)]. These results suggested that
chloride ion might facilitate the present transformation. While substrates 2 bearing N,N-
dialkylaniline moiety smoothly underwent the reaction to give the corresponding indolo[2,3-
b]quinolines 3, the reaction of -NHBn analog 2p′, in the presence of n-Bu4NCl (0.1390 g, 0.5
mmol, 1.0 equiv) gave the desired product 3p (33% yield) along with the 2-chloroquinoline 7
(34% yield) [Scheme 5, (c)]. Exposure of 7 to the standard reaction conditions (DMF, 80 oC, 1 h)
yielded 3p in quantitative yield [Scheme 5, (d)], suggesting that 2-chloroquinoline adduct might
be an intermediate in the present reaction. Worthily to emphasize, when cyclic anilines, for
example, 2t was employed as a substrate, 3t was isolated in 53% yield [Scheme 5, (e)]. This
observation emphasized the role of chloride ion (Cl−) in the mechanistic pathway. Additionally,
the reaction of isocyanide 9 was also evaluated. Thus, compound 8 was treated with POCl3, i-
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Pr2NEt in CH2Cl2 at 0 C for 1 h. After aqueous work up followed by evaporation to dryness, 9
was diluted with DMF and the solution was stirred at room temperature for 4 h. After
chromatographic purification, 2-chloro-3-phenylquinoline (10) and 3-phenylquinolin-2(1H)-one
(11) were obtained in 71% and 10% yields, respectively [Scheme 5, (f)]. This observation
implied that there were chloride ion and water, possibly in the crude isocyanide substance and
moisture in DMF, serving as nucleophiles. Finally, when D2O (0.018 mL, 1.0 mmol, 2.0 equiv)
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was introduced into the reaction, a mixture of products [d1]-3a and 3a ([d1]-3a:3a = 9:1, H
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NMR analysis; see Supporting Information) was obtained [Scheme 5(g)]. The results obtained
implied that the proton source from water served as a proton donor in the mechanistic pathway
during quinoline ring formation.
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Scheme 5. Control Experiments
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On the basis of the experimental results (Table 1 and Schemes 2‒3), control evidences
(Scheme 5) as well as the previously reported literature, a plausible reaction mechanism is
outlined as shown in Scheme 6. Explanation of the reaction mechanism was described employing
2 as the model substrates. Initially, chloride ion (Cl−) which most possibly stems from the step of
isocyanide preparation, acts as a nucleophile and adds to the isocyano carbon leading to the
corresponding imidoyl anion intermediate A. Next, A undergoes 6-endo cyclization followed by
protonation, possibly from moisture in DMF or water in the crude isocyanide substance, leading
to 2-chloroquinoline adduct B. Subsequent intramolecular nucleophilic aromatic substitution
(SNAr) readily take place to provide cationic intermediate C. Dealkylation (dialkylanilines and
methyl sulfides) or the loss of HCl (monosubstituted anilines) with the aid of chloride ion and
aromatization finally leads to the observed products 3. The reaction mechanism for the
conversion of 5 to 6 should also follow a similar pathway.
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Scheme 6. Plausible Reaction Mechanism
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3. CONCLUSIONS
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In summary, we have developed metal-free, rapid, and convenient synthetic route to
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access indolo[2,3-b]quinolines and benzothieno[2,3-b]quinolines via cascade reactions of the
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respective
2-[(2-isocyanoaryl)ethynyl]anilines
2
and
{2-[(2-
isocyanoaryl)ethynyl]aryl}(methyl)sulfanes 5. The reaction involves chloride ion triggered 6-
endo cyclization followed by intramolecular nucleophilic aromatic substitution (SNAr). The
established reaction offers ease of experimentation without the need to perform the reaction
under air- and moisture-free conditions and can accommodate a wide range of substrate scopes to
provide the products in moderate to excellent yields. Further investigation on optical properties
and pharmacological evaluation of new indolo- and benzothieno[2,3-b]quinoline analogs are
currently on going and will soon be reported. We are at the moment expanding this protocol to
access other nitrogen- and sulfur-containing polycycles.
4. EXPERIMENTAL SECTION
General Procedure: The nuclear magnetic resonance (NMR) spectra were recorded in
deuterochloroform (CDCl3) with 400 MHz spectrometer. Chemical shifts for H and 13C{1H}
1
NMR spectra were reported in parts per million (ppm, δ). The chemical shift of 1H NMR spectra
is reported with reference to tetramethylsilane (δ = 0.00 ppm) as the internal reference, while the
chemical shift of 13C{1H} NMR is reported with reference to CDCl3 at 77.0 ppm. Coupling
constants (J) were reported in hertz. Infrared spectra were recorded using an FT-IR spectrometer
and only partial data were reported in cm-1. High-Resolution Mass Spectra (HRMS) were
recorded using time-of-flight (TOF) and electrospray ionization (ESI). Unless otherwise noted,
the commercial grade chemicals were used without prior purification. Column chromatography
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was performed using silica gel 60 (particle size 0.06−0.2 mm; 70−230 mesh ASTM). Analytical
TLC was performed with silica gel 60 F254 aluminum sheets.
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General Procedure for the Synthesis of Compounds 1. To a two-neck flask containing 2-
iodoaniline derivatives (10 mmol, 1.0 equiv), PdCl2(PPh3)2 (91.2 mg, 0.13 mmol, 0.013 equiv),
and CuI (19 mg, 0.1 mmol, 0.01 equiv) was added Et3N (1 mL/mmol) under argon atmosphere.
Next, the reaction was added dropwise with a solution of N-(2-ethynylphenyl)formamide
derivatives (11 mmol, 1.1 equiv) in THF (1 mL/mmol) at room temperature under argon
atmosphere. The reaction mixture was stirred at room temperature under argon atmosphere for
16 h, then quenched with saturated aqueous NH4Cl (20 mL) and the resulting mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20
mL), dried (anh. MgSO4), filtered, and concentrated under reduced pressure (aspirator). The
crude product was purified by column chromatography on silica gel (EtOAc/hexane) to provide
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the corresponding compounds 1. The peaks of H and C NMR spectral data of compounds 1
were observed as the mixture of amide rotamers.4a,c
N-(2-((2-(Dimethylamino)phenyl)ethynyl)phenyl)formamide (1a). Purification by column
chromatography (EtOAc/hexane, 1:19 v/v) afforded 1a (0.9912 g, 75%); pale brown viscous
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liquid; H NMR (CDCl3, 400 MHz): δ 8.86 (br s, 0.66H), 8.73 (br d, J = 10.8 Hz, 0.34H), 8.73
(d, J = 10.8 Hz, 0.34H), 8.49−8.47 (m, 1.32H), 7.51−7.46 (m, 2H), 7.35−7.21 (m, 2.34H),
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7.12−7.05 (m, 2H), 7.01−6.95 (m, 1H), 2.92 & 2.88 (each s, 6H); C{1H} NMR (CDCl3, 100
MHz): δ 161.1, 158.8, 155.9, 155.3, 132.2, 138.1, 132.7, 132.7, 131.6, 130.5, 129.7, 129.4,
129.2, 123.9, 123.6, 122.1, 121.8, 119.7, 118.2, 118.0, 116.2, 115.0, 113.3, 112.4, 96.0, 95.9,
89.3, 88.8, 44.4, 43.9 ppm; IR (neat): 3293, 2203, 1683, 1263 cm-1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C17H16N2ONa 287.1155, found 287.1151.
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N-(2-((2-(Dimethylamino)-5-methylphenyl)ethynyl)phenyl)formamide (1b). Purification by
column chromatography (EtOAc/hexane, 1:9 v/v) afforded 1b (0.9325 g, 67%); pale brown
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viscous liquid; H NMR (CDCl3, 400 MHz): δ 9.07 (br s, 0.68H), 8.95 (d, J = 11.2 Hz, 0.32H),
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8.78 (br d, J = 8.0 Hz, 0.32H), 8.51−8.49 (m, 1.35H), 7.52−7.46 (m, 1H), 7.37−7.30 (m, 2.32H),
7.15−7.08 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 2.89 & 2.86 (each s, 6H), 2.31 & 2.30 (each s, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 161.2, 158.9, 154.7, 153.4, 138.5, 132.9, 131.7, 130.6,
130.4, 129.5, 129.3, 124.0, 123.7, 119.8, 118.4, 118.3, 116.7, 114.8, 113.2, 112.5, 96.4, 92.6,
45.0, 44.3, 20.4 ppm; IR (neat): 3247, 2223, 1693, 1265 cm-1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C18H18N2ONa 301.1311, found 301.1312.
N-(2-((2-(Dimethylamino)-5-(trifluoromethyl)phenyl)ethynyl)phenyl)formamide
(1c).
Purification by column chromatography EtOAc/hexane, 1:4 v/v) afforded 1c (1.3625 g,82%); pale
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yellow solid; mp = 125.4−127.0 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.89 (d, J
= 11.6 Hz, 0.34H), 8.50 (s, 0.66H), 8.46 (d, J = 8.4 Hz, 0.66H), 8.42 (br s, 1H), 7.72 (s, 1H),
7.55−7.49 (m, 2H), 7.39−7.32 (m, 1H), 7.28 (d, J = 8.0 Hz, 0.34H), 7.17−7.10 (m, 1H), 7.03 (d,
J = 8.8 Hz, 1H), 3.023 & 3.016 (each s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.2, 158.8,
157.7, 157.2, 138.0, 137.9, 132.2, 131.1, 130.7 (q, JC,F = 3.7 Hz), 130.6 (q, JC,F = 3.6 Hz), 130.0,
129.8, 126.6 (q, JC,F = 3.8 Hz), 125.37, 125.34, 124.3, 123.99 (q, JC,F = 269.7 Hz), 123.95, 123.0,
122.83 (q, JC,F = 33.0 Hz), 122.6, 120.0, 117.5, 117.3, 115.6, 114.5, 113.7 (q, JC,F = 118.6 Hz),
112.0, 94.93, 94.89, 90.2, 89.9, 43.6, 43.3 ppm; IR (neat): 3248, 2203, 1661, 1273 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C18H15F3N2ONa 355.1029, found 355.1033.
N-(2-((2-(Dimethylamino)-5-fluorophenyl)ethynyl)phenyl)formamide (1d). Purification by
column chromatography (EtOAc/hexane, 1:9 v/v) afforded 1d (0.8893 g, 63%); pale brown
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viscous liquid; H NMR (CDCl3, 400 MHz): δ 9.03 (br s, 0.61H), 8.96 (d, J = 11.2 Hz, 0.39H),
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8.83 (br d, J = 9.2 Hz, 0.39H), 8.52−8.49 (m, 1.22H), 7.52 (d, J = 7.6 Hz, 0.39H), 7.48 (d, J =
7.6 Hz, 0.61H), 7.39−7.29 (m, 1.39H), 7.20−7.16 (m, 1H), 7.13−7.01 (m, 3H), 2.88 & 2.85 (s,
6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.1, 158.0 (d, JC,F = 241.4 Hz), 158.9, 157.8 (d, JC,F
= 240.8 Hz), 138.6, 138.5, 131.7, 130.5, 129.9, 129.7, 123.9, 123.7, 120.0 (d, JC,F = 8.4 Hz),
119.8, 119.7 (d, JC,F = 8.4 Hz), 118.7, 118.48, 118.45 (d, JC,F = 11.6 Hz), 118.6 (d, JC,F = 23.6
Hz), 118.40, 118.39 (d, JC,F = 23.7 Hz), 118.37, 116.52 (d, JC,F = 22.0 Hz), 116.50 (d, JC,F = 22.0
Hz), 114.8, 112.7, 111.8, 94.8, 94.6, 90.1, 89.5, 45.0, 44.4 ppm; IR (neat): 3271, 2329, 1697,
1264 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15FN2ONa 305.1061, found
305.1062.
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N-(2-((5-Chloro-2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1e). Purification by
column chromatography (EtOAc/hexane, 1:9 v/v) afforded 1e (0.9411 g, 63%); pale brown
viscous liquid; 1H NMR (CDCl3, 400 MHz): δ 8.92 (d, J = 11.2 Hz, 1H), 8.65 (br d, J = 8.0 Hz,
0.42H), 8.52 (s, 0.58H), 8.47 (d, J = 8.0 Hz, 0.58H), 7.50−7.45 (m, 2H), 7.37−7.34 (m, 1H),
7.30−7.25 (m, 1.42H), 7.14−7.09 (m, 1H), 7.07−7.00 (m, 1H), 2.93 (s, 6H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 161.1, 158.8, 154.6, 153.9, 138.3, 132.2, 132.0, 131.9, 130.8, 129.9, 129.8,
129.69, 129.68, 127.0, 126.8, 124.1, 123.8, 119.9, 119.5, 119.3, 117.7, 117.6, 115.1, 112.9,
111.9, 94.7, 94.6, 90.3, 89.8, 44.5, 43.9 ppm; IR (neat): 3270, 2209, 1688, 1260 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H15ClN2ONa 321.0765, found 321.0768.
N-(2-((5-Bromo-2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1f). Purification by
column chromatography (EtOAc/hexane, 1:9 v/v) afforded 1f (1.0297 g, 60%); pale brown
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viscous liquid; H NMR (CDCl3, 400 MHz): δ 8.93 (d, J = 11.2 Hz, 0.37H), 8.70 (br s, 0.63H),
8.57 (br d, J = 11.2 Hz, 0.37H), 8.51−8.47 (m, 1.26H), 7.60−7.58 (m, 1H), 7.52−7.47 (m, 1H),
7.42−7.28 (m, 2.37H), 7.16−7.09 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 2.92 & 2.89 (each s, 6H);
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13C{1H} NMR (CDCl3, 100 MHz): δ 161.1, 158.7, 155.0, 154.4, 138.3, 135.1, 135.0, 131.9,
130.8, 130.0, 129.8, 124.1, 123.9, 119.9, 119.7, 119.2, 118.0, 115.1, 114.2, 114.0, 112.0, 94.7,
94.6, 90.5, 89.9, 44.4, 43.9 ppm; IR (neat): 3367, 2204, 1694, 1263 cm-1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C17H15BrN2ONa 365.0260, found 365.0258.
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N-(2-((4-Chloro-2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1g). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1g (1.1204 g, 75%); pale brown
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viscous liquid; H NMR (CDCl3, 400 MHz): δ 8.84 (d, J = 11.2 Hz, 0.37H), 8.68 (br s, 0.63H),
8.52 (br d, J = 10.8 Hz, 0.37H), 8.46−8.42 (m, 1.26H), 7.47−7.43 (m, 1H), 7.36−7.25 (m, 2H),
7.19 (d, J = 8.4 Hz, 0.37H), 7.10−7.04 (m, 1H), 6.95 (d, J =2.4 Hz, 1H), 6.91−6.87 (m, 1H),
2.90 & 2.87 (each s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.1, 158.8, 156.5, 156.0, 138.0,
137.9, 135.4, 133.9, 133.8, 131.8, 130.8, 129.6, 129.5, 124.1, 123.8, 121.8, 121.6, 119.9, 118.5,
118.3, 115.4, 113.9, 113.2, 112.2, 95.1, 94.9, 90.1, 89.6, 44.0, 43.5 ppm; IR (neat): 3295, 2206,
1688, 1267 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15ClN2ONa 321.0765, found
321.0766.
N-(2-((2-(Dimethylamino)phenyl)ethynyl)-4-methylphenyl)formamide (1h). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1h (0.9742 g, 70%); pale brown
viscous liquid; 1H NMR (CDCl3, 400 MHz): δ 8.86 (d, J = 11.2 Hz, 1H), 8.59 (br d, J = 10.4 Hz,
0.31H), 8.48 (s, 0.69H), 8.35 (d, J = 8.4 Hz, 0.69H), 7.50−7.46 (m, 1H), 7.35−7.31 (m, 2.31H),
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7.18−6.97 (m, 3H), 2.94 & 2.92 (each s, 6H), 2.32 (s, 3H); C{1H} NMR (CDCl3, 100 MHz): δ
161.3, 158.8, 144.7, 136.0, 135.8, 133.8, 133.4, 132.93, 132.91, 132.1, 130.9, 130.3, 130.1,
129.8, 129.0, 124.8, 122.0, 119.9, 118.3, 118.2, 116.5, 116.3, 115.36, 115.35, 113.5, 112.3, 95.4,
94.3, 89.3, 89.2, 44.6, 44.0, 20.7, 20.6 ppm; IR (neat): 3270, 2199, 1686, 1265 cm-1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C18H18N2ONa 301.1311, found 301.1315.
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N-(2-((2-(Dimethylamino)phenyl)ethynyl)-4-(trifluoromethyl)phenyl)formamide
(1i).
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pale brown viscous liquid; H NMR (CDCl3, 400 MHz): δ 9.14 (br s, 0.72H), 9.03 (d, J = 10.8
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Hz, 0.28H), 8.95 (br d, J = 9.6 Hz, 0.28H), 8.64 (d, J = 8.8 Hz, 0.72H), 8.55 (d, J = 1.2 Hz,
0.72H), 7.77−7.74 (m, 1H), 7.59−7.54 (m, 1H), 7.51−7.48 (m, 1H), 7.41−7.34 (m, 1.28H), 7.12
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(d, J = 8.4 Hz, 1H), 7.07−7.01 (m, 1H), 2.93 & 2.90 (each s, 6H); C{1H} NMR (CDCl3, 100
MHz): δ 160.7, 159.1, 156.4, 155.7, 141.1, 140.8, 135.1, 132.9, 132.7, 130.4, 128.6, 127.5 (q,
JC,F = 3.6 Hz), 126.3 (q, JC,F = 269.8 Hz), 126.3 (q, JC,F = 3.5 Hz), 125.8 (q, JC,F = 33.8 Hz),
126.09, 126.05, 122.5, 122.3, 119.7, 118.6, 118.3, 116.0, 114.3, 113.4, 112.9, 97.8, 97.4, 88.0,
87.4, 44.7, 44.1 ppm; IR (neat): 3270, 2210, 1703, 1267 cm-1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C18H15F3N2ONa 355.1029, found 355.1029.
N-(2-((2-(Dimethylamino)phenyl)ethynyl)-4-fluorophenyl)formamide (1j). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1j (0.5786 g, 41%); pale brown
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viscous liquid; H NMR (CDCl3, 400 MHz): δ 8.89 (br s, 0.75H), 8.80 (d, J = 11.2 Hz, 0.25H),
8.60 (br d, J = 10.8 Hz, 0.25H), 8.48− 8.44 (m, 1.50H), 7.49−7.46 (m, 1H), 7.36−7.31 (m, 1H),
7.21 (dd, J = 8.4 Hz, J = 3.2 Hz, 0.25H), 7.17 (dd, J = 8.6 Hz, J = 3.0 Hz, 1H), 7.09−6.97 (m,
3H), 2.92 & 2.89 (each s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.3, 159.0 (d, JC,F = 243.0
Hz), 158.7, 158.2 (d, JC,F = 242.7 Hz), 156.2, 155.6, 134.7 (d, JC,F = 2.7 Hz), 134.5 (d, JC,F = 2.7
Hz), 133.0, 132.9, 130.2, 122.4, 121.9, 121.4 (d, JC,F =8.2 Hz), 118.3, 118.2, 118.0 (d, JC,F = 24.0
Hz), 117.0, 116.8 (d, JC,F = 54.8 Hz), 116.7, 116.3 (d, JC,F = 22.1 Hz), 116.0 (d, JC,F = 59.5 Hz),
115.9, 115.3 (d, JC,F = 9.7 Hz), 114.0 (d, JC,F = 9.6 Hz), 97.1, 96.9, 88.4, 88.0, 44.6, 44.0 ppm;
IR (neat): 3272, 2203, 1690, 1259 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H15FN2ONa 305.1061, found 305.1060.
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N-(4-Chloro-2-((2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1k). Purification by
column chromatography (EtOAc/hexane, 1:19 v/v) afforded 1k (0.5975 g, 40%); brown viscous
liquid; 1H NMR (CDCl3, 400 MHz): δ 8.93 (br s, 0.71H), 8.88 (d, J = 11.2 Hz, 0.29H), 8.68 (br
d, J = 8.8 Hz, 0.29H), 8.49 (d, J = 1.6 Hz, 0.71H), 8.45 (d, J = 8.8 Hz, 0.71H), 7.49−7.45 (m,
2H), 7.37−7.31 (m, 1H), 7.29 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.20 (d, J = 8.8 Hz, 0.29H), 7.09
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(d, J = 8.4 Hz, 1H), 7.05−6.98 (m, 1H), 2.92 & 2.89 (each s, 6H); C{1H} NMR (CDCl3, 100
MHz): δ 161.0, 158.9, 156.3, 155.7, 136.9, 133.0, 132.9, 131.2, 130.3, 130.1, 129.5, 129.3,
129.2, 128.7, 125.1, 122.5, 122.1, 121.0, 118.5, 118.3, 116.2, 115.9, 115.1, 114.1, 97.5, 97.2,
88.2, 87.7, 44.7, 44.1 ppm; IR (neat): 3256, 2196, 1689, 1258 cm-1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C17H15ClN2ONa 321.0765, found 321.0763.
N-(4-Bromo-2-((2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1l). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1l (0.9268 g, 54%); brown viscous
liquid; 1H NMR (CDCl3, 400 MHz): δ 8.95 (br s, 0.76H), 8.84 (d, J = 10.8 Hz, 0.24H), 8.72 (br
d, J = 10.8 Hz, 0.24H), 8.47 (d, J = 1.6 Hz, 0.76H), 8.37 (d, J = 8.8 Hz, 0.76H), 7.61 (d, J = 2.0
Hz, 0.24H), 7.58 (d, J = 2.4 Hz, 0.76H), 7.48−7.44 (m, 1H), 7.41 (dd, J = 8.8 Hz, J = 2.4 Hz,
0.76H), 7.37 (dd, J = 8.8 Hz, J = 2.4 Hz, 0.24H), 7.35−7.30 (m, 1H), 7.10−7.06 (m, 1.24H),
7.02−6.96 (m, 1H), 2.90 & 2.87 (each s, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 160.8, 158.8,
156.3, 155.6, 137.3, 134.3, 134.0, 132.94, 132.91, 132.86, 132.3, 132.2, 130.34, 130.28,
124.0,122.4, 122.1, 121.2, 119.6, 118.4, 118.2, 116.4, 116.3, 116.0, 115.9, 115.8, 115.3, 114.4,
97.6, 97.3, 88.0, 87.5, 44.7, 44.1 ppm; IR (neat): 3269, 2196, 1689, 1258 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H15BrN2ONa 365.0260, found 365.0264.
N-(2-((2-(Dimethylamino)phenyl)ethynyl)-4-nitrophenyl)formamide (1m). Purification by
column chromatography (EtOAc/hexane, 2:3 v/v) afforded 1m (0.6032 g, 39%); orange solid; mp
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= 102.12−103.1 °C (CH2Cl2/hexane); 1H NMR (CDCl3, 400 MHz): δ 8.92 (br s, 0.75H), 9.09 (br
d, J = 10.4 Hz, 0.25H), 8.70 (d, J = 9.2 Hz, 0.75H), 8.58 (s, 0.75H), 8.38−8.35 (m, 1.25H), 8.20
(d, J = 9.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1.25H), 7.14 (d, J = 8.0 Hz,
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1H), 7.07 (t, J = 7.4 Hz, 1H), 2.91 (s, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 160.3, 159.0,
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156.8, 155.9, 143.2, 143.1, 132.9, 132.7, 130.8, 126.9, 125.8, 124.9, 124.7, 122.8, 122.6, 119.5,
118.9, 118.5, 115.6, 113.5, 113.3, 99.3, 98.4, 87.2, 86.6, 44.9, 44.3 ppm; IR (neat): 3256, 2187,
1671, 1267 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15N3O3Na 332.1006, found
332.1004.
N-(5-Chloro-2-((2-(dimethylamino)phenyl)ethynyl)phenyl)formamide (1n). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1n (0.8216 g, 55%); pale brown
1
viscous liquid; H NMR (CDCl3, 400 MHz): δ 9.01 (br s, 0.74H), 8.19 (d, J = 10.8 Hz, 0.26H),
8.76 (br d, J = 11.6 Hz, 0.26H), 8.58 (d, J = 2.4 Hz, 0.74H), 8.50 (d, J = 1.6 Hz, 0.74H),
7.49−7.45 (m, 1H), 7.58 (d, J = 8.4 Hz, 0.26H), 7.39 (d, J = 8.4 Hz, 0.74H), 7.36−7.31 (m, 1H),
7.28 (d, J = 1.6 Hz, 0.26H), 7.11−7.07 (m, 2H), 7.05−6.98 (m, 1H), 2.91 & 2.89 (each s, 6H);
13C{1H} NMR (CDCl3, 100 MHz): δ 160.7, 158.9, 156.2, 155.2, 139.3, 139.1, 135.2, 135.0,
132.7, 132.6, 132.4, 131.2, 130.1, 124.1, 124.0, 122.5, 122.2, 120.0, 118.5, 118.3, 116.3, 115.1,
111.7, 110.8, 97.1, 96.9, 88.5, 87.9, 44.7, 44.1 ppm; IR (neat): 3256, 2207, 1690, 1260 cm-1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15ClN2ONa 321.0765, found 321.0765.
N-(2-((2-(Diethylamino)phenyl)ethynyl)phenyl)formamide (1o). Purification by column
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1o (0.7748 g, 53%); pale brown viscous liquid;
1H NMR (CDCl3, 400 MHz): δ 9.22 (br s, 0.70H), 8.95 (br s, 0.60H), 8.55 (s, 0.70H), 8.53−8.52
(m, 0.70H), 7.52−7.47 (m, 2H), 7.36−7.26 (m, 2.30H), 7.16−7.02 (m, 3H), 3.32 (q, J = 7.2 Hz,
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1.20H), 3.22 (q, J = 7.2 Hz, 2.80H), 1.05−0.99 (m, 6H); C{1H} NMR (CDCl3, 100 MHz): δ
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161.0, 158.8, 152.7, 152.1, 138.5, 132.3, 132.3, 131.5, 130.3, 129.32, 129.27, 129.22, 129.15,
123.7, 123.6, 123.2, 122.8, 122.1, 121.8, 119.8, 119.8, 119.6, 114.5, 113.1, 112.4, 96.6, 96.4,
88.5, 88.0, 48.3, 47.8, 12.1, 12.0 ppm; IR (neat): 3248, 2206, 1694, 1252 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H20N2ONa 315.1468, found 315.1469.
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N-(2-((2-(Ethylamino)phenyl)ethynyl)phenyl)formamide (1o′). Purification by column
chromatography (EtOAc/hexane, 1:9 v/v) afforded 1o′ (1.0177 g, 77%); pale brown viscous
liquid; 1H NMR (CDCl3, 400 MHz): δ 8.79 (d, J = 11.6 Hz, 0.27H), 8.53 (d, J = 8.0 Hz, 0.73H),
8.23 (d, J = 1.6 Hz, 0.73H), 7.69 (d, J = 8.0 Hz, 0.73H), 7.66 (d, J = 8.0 Hz, 0.27H), 7.51−7.41
(m, 3H), 7.39−7.28 (m, 3H), 7.26−7.52 (m, 1.27H), 6.56 (s, 0.73H), 6.52 (s, 0.27H), 3.99 (q, J =
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6.8 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 161.1, 158.8, 136.7,
136.1, 134.6, 134.0, 132.2, 131.0, 130.1, 130.0, 128.12, 128.06, 124.5, 124.1, 122.7, 122.29,
122.26, 121.9, 120.9, 120.86, 120.84, 120.2, 116.4, 110.1, 110.0, 103.5, 103.1, 38.6, 15.3 ppm;
IR (neat): 3182, 2115, 1666, 1252 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H16N2ONa 287.1155, found 287.1155.
N-(2-((2-(Dibenzylamino)phenyl)ethynyl)phenyl)formamide (1p). Purification by column
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1p (1.1454 g, 55%); pale brown viscous liquid;
1H NMR (CDCl3, 400 MHz): δ 8.46 (d, J = 11.2 Hz, 0.28H), 8.41 (d, J = 8.0 Hz, 0.72H), 8.14
(br d, J = 11.2 Hz, 0.28H), 8.08 (br s, 0.72H), 7.99 (d, J = 1.2 Hz, 0.72H), 7.58−7.53 (m, 1H),
7.34−7.12 (m, 11H), 7.06 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.4 Hz, 0.72H), 6.93 (t, J = 7.4 Hz,
0.28H), 6.84−6.79 (m, 1.28H), 4.50 (s, 1.12H), 4.42 (s, 2.88H); 13C{1H} NMR (CDCl3, 100
MHz): δ 161.1, 158.9, 152.6, 152,3, 137.9, 137.7, 137.6, 134.0, 133.9, 132.4, 131.5, 129.6,
129.5, 129.3, 128.4, 128.24, 128.22, 127.3, 126.9, 124.3, 123.8, 122.1, 121.7, 121.5, 121.2,
119.9, 116.4, 116.1, 115.6, 113.8, 112.5, 96.2, 96.1, 89.1, 88.6, 56.3, 56.1 ppm; IR (neat): 3164,
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2111, 1685, 1290 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H24N2ONa 439.1781,
found 439.1782.
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N-(2-((2-(Benzylamino)phenyl)ethynyl)phenyl)formamide (1p′). Purification by column
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1p′ (1.2730 g, 78%); pale brown viscous
liquid; 1H NMR (CDCl3, 400 MHz): δ 8.82 (d, J = 11.2 Hz, 0.36H), 8.40 (d, J = 8.0 Hz, 0.64H),
8.29 (s, 0.64H), 7.90 (br s, 1H), 7.51−7.47 (m, 1H), 7.43−7.27 (m, 7.36H), 7.24−7.15 (m, 1H),
7.15 (t, J = 7.6 Hz, 0.36H), 7.10 (t, J = 7.6 Hz, 0.64H), 6.74−6.96 (m, 1H), 6.66 (d, J = 8.4 Hz,
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0.64H), 6.61 (d, J = 8.4 Hz, 0.36H), 5.00 (br s, 1H), 4.47 & 4.44 (each s, 2H); C{1H} NMR
(CDCl3, 100 MHz): δ 161.3, 158.8, 148.8, 138.7, 137.6, 132.9, 132.4, 132.3, 131.2, 130.8, 129.7,
129.6, 128.8, 128.7, 127.5, 127.23, 127.18, 127.1, 124.6, 124.0, 120.2, 116.9, 116.8, 116.4,
112.2, 110.3, 110.2, 106.6, 93.3, 93.2, 89.6, 89.3, 47.8, 47.6 ppm; IR (neat): 3368, 2205, 1685,
1292 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H18N2ONa 349.1311, found 349.1313.
N-(2-((2-Aminophenyl)ethynyl)phenyl)formamide
(1q).14
Purification
by
column
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1q (1.0404 g, 88%); white solid; mp =
1
99.4−100.6 °C (CH2Cl2/hexane) (lit.13b mp 101.0−103.0 °C); H NMR (CDCl3, 400 MHz): δ
8.81 (d, J = 11.2 Hz, 0.34H), 8.49 (s, 0.66H), 8.43 (d, J = 8.4 Hz, 0.66H), 8.05 (br s, 1H),
7.56−7.50 (m, 1H), 7.38−7.32 (m, 2H), 7.26−7.10 (m, 2.34H), 6.77−6.75 (m, 2H), 4.26 (br s,
2H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.5, 159.0, 147.9, 137.7, 137.3, 132.8, 132.3, 132.2,
131.8, 130.53, 130.50, 129.8, 129.6, 124.7, 124.0, 120.2, 118.2, 118.1, 116.6, 114.7, 114.6,
114.0, 112.2, 106.9, 106.8, 93.2, 93.1, 89.0, 88.9 ppm; IR (neat): 3409, 2206, 1643, 1250 cm-1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H12N2ONa 259.0842, found 259.0841.
N-(2-((2-((4-Methylphenyl)sulfonamido)phenyl)ethynyl)phenyl)formamide (1r). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 1r (1.2690 g, 65%); pale brown solid;
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mp = 136.7−138.4 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.53 (d, J = 11.2 Hz,
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0.45H), 8.39 (d, J = 8.4 Hz, 0.55H), 8.35 (d, J = 8.4 Hz, 0.45H), 8.26 (d, J = 8.0 Hz, 0.55H), 8.20
(d, J = 1.6 Hz, 0.55H), 7.55−7.38 (m, 4H), 7.36−7.28 (m, 3H), 7.23 (d, J = 7.6 Hz, 0.45H),
7.18−7.13 (m, 1H), 7.11−7.04 (m, 3H), 6.57 (d, J = 8.8 Hz, 1H), 2.33 & 2.32 (each s, 3H);
13C{1H} NMR (CDCl3, 100 MHz): δ 161.8, 159.9, 158.9, 145.3, 136.4, 135.7, 132.6, 131.6,
130.5, 130.4, 129.9, 129.8, 129.5, 127.0, 126.8, 125.6, 125.5, 124.5, 124.4, 123.9, 122.14,
121.08, 121.0, 118.8, 116.1, 116.0, 114.3, 114.2, 100.0, 94.3, 21.6 ppm; IR (neat): 3305, 2073,
1683, 1256, 1173 (SO2) cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H18N2O3SNa
413.0930, found 413.0936.
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N-(2-((2-(ethyl(methyl)amino)phenyl)ethynyl)phenyl)formamide (1s). Purification by column
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chromatography (EtOAc/hexane, 1:4 v/v) afforded 1s (0.7098 g, 51%); brown viscous liquid; H
NMR (CDCl3, 400 MHz): δ 8.80 (d, J = 11.2 Hz, 0.78H) 8.56 (br d, J = 10.0 Hz, 0.22H),
8.41−8.39 (m, 1.22H), 7.42−7.37 (m, 2H), 7.25−7.13 (m, 2.78H), 7.03−6.98 (m, 2H), 6.97−6.86
(m, 1H), 3.24 (q, J = 6.8 Hz, 0.78H), 3.16 (q, J = 6.8 Hz, 1.22H), 2.77 & 2.73 (each s, 3H),
1.02−0.97 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.1, 158.9, 154.7, 154.4, 138.3,
133.0, 131.9, 130.7, 129.7, 129.5, 129.3, 124.0, 123.7, 122.3, 121.9, 119.8, 119.7, 119.6, 115.1,
113.5, 112.5, 96.4, 96.2, 88.9, 88.4, 50.6, 50.0, 41.3, 40.8, 12.3, 12.0 ppm; IR (neat): 3250, 2207,
1690, 1260 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H19N2O 279.1492, found
279.1494.
N-(2-((2-(Pyrrolidin-1-yl)phenyl)ethynyl)phenyl)formamide (1t). Purification by column
1
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1t (0.8130 g, 56%); brown viscous liquid; H
NMR (CDCl3, 400 MHz): δ 8.82 (d, J = 11.6 Hz, 0.36H), 8.46 (s, 0.64H), 8.43 (d, J = 8.4 Hz,
0.64H), 8.10 (br s, 0.64H), 7.99 (br d, J = 10.4 Hz, 0.36H), 7.50−7.43 (m, 2H), 7.35−7.29 (m,
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1H), 7.27−7.21 (m, 1H), 7.15 (d, J = 7.6 Hz, 0.36H), 7.12−7.08 (m, 1H), 6.75−6.69 (m, 2H),
3.60−3.56 (m, 4H), 1.97−1.84 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.3, 158.9, 150.5,
150.4, 137.6, 135.4, 135.1, 132.2, 131.1, 130.10, 130.08, 129.2, 129.0, 124.5, 123.9, 119.9,
117.3, 117.1, 116.1, 114.6, 114.4, 114.2, 113.1, 107.9, 98.2, 86.8, 50.6, 50.5, 25.64, 25.59 ppm;
IR (neat): 3306, 2202, 1685, 1263 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C19H18N2ONa 313.1311, found 313.1313.
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N-(2-((2-(piperidin-1-yl)phenyl)ethynyl)phenyl)formamide (1u). Purification by column
chromatography (EtOAc/hexane, 1:4 v/v) afforded 1u (0.8827 g, 58%); yellow viscous liquid; 1H
NMR (CDCl3, 400 MHz): δ 8.87 (d, J = 11.6 Hz, 0.27H), 8.53 (s, 0.73H), 8.47 (d, J = 8.4 Hz,
0.73H), 8.43 (br s, 0.73H), 8.25 (br d, J = 10.4 Hz, 0.27H), 7.55−7.49 (m, 3H), 7.36−7.24 (m,
2.27H), 7.15−7.08 (m, 1H), 7.03−6.64 (m, 2H), 3.13−3.10 (m, 4H), 1.76−1.70 (m, 4H),
1.61−1.56 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.0, 158.8, 155.7, 150.4, 137.6,
133.6, 133.5, 132.5, 131.3, 130.0, 129.4, 129.3, 124.2, 123.8, 121.9, 121.6, 119.8, 118.4, 118.3,
116.5, 115.5 112.6, 95.9, 95.8, 88.5, 88.2, 53.3, 53.0, 26.4, 26.2, 24.2, 24.0 ppm; IR (neat): 3325,
2206, 1688, 1229 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H21N2O 305.1648, found
305.1649.
General Procedure for the Synthesis of Compounds 4. To a two-neck flask containing (2-
iodophenyl)(methyl)sulfane (10 mmol, 1.0 equiv), PdCl2(PPh3)2 (91.2 mg, 0.13 mmol, 0.013
equiv), and CuI (19 mg, 0.1 mmol, 0.01 equiv) was added Et3N (1 mL/mmol) under argon
atmosphere. Next, the reaction was added dropwise with a solution of N-(2-
ethynylphenyl)formamide derivatives (11 mmol, 1.1 equiv) in THF (1 mL/mmol) at room
temperature under argon atmosphere. The reaction mixture was stirred at room temperature
under argon atmosphere for 16 h, then quenched with saturated aqueous NH4Cl (20 mL) and the
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resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine (20 mL), dried (anh. MgSO4), filtered, and concentrated under reduced
pressure (aspirator). The crude product was purified by column chromatography on silica gel
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(EtOAc/hexane) to provide the corresponding compounds 4. The peaks of H and 13C NMR
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spectral data of compounds 4 were observed as the mixture of amide rotamers.
N-(2-((2-(Methylthio)phenyl)ethynyl)phenyl)formamide (4a). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4a (1.0024 g, 75%); white solid; mp =
1
89.6−91.5 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.89 (d, J = 11.2 Hz, 0.23H),
8.74 (br s, 0.77H), 8.57 (br d, J = 10.0 Hz, 0.23H), 8.58 (d, J = 1.6 Hz, 0.77H), 8.48 (d, J = 8.4
Hz, 0.77H), 7.56−7.48 (m, 2H), 7.38−7.31 (m, 2H), 7.28 (d, J = 8.0 Hz, 1.23H), 7.20−7.15 (m,
1H), 7.13−7.08 (m, 1H), 2.563 & 2.558 (each s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.8,
159.0, 140.4, 138.4, 132.5, 132.0, 131.9, 131.2, 139.9, 129.8, 129.4, 125.4, 125.2, 125.1, 124.7,
124.2, 123.8, 121.2, 119.8, 115.5, 112.0, 94.4, 90.7, 90.3, 15.8, 15.5 ppm; IR (neat): 3353, 1683,
1277 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H13NOSNa 290.0610, found 290.0618.
N-(2-((2-(Methylthio)phenyl)ethynyl)-4-methylphenyl)formamide (4b). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4b (1.3082 g, 93%); pale yellow solid; mp =
1
75.6−77.3 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.82 (d, J = 11.0 Hz, 0.26H),
8.64 (br s, 0.74H), 8.48 (s, 0.74H), 8.45 (br d, J = 9.6 Hz, 0.26H), 8.34 (d, J = 8.4 Hz, 0.74H),
7.50−7.46 (m, 1H), 7.36−7.30 (m, 2H), 7.27−7.22 (m, 1H), 7.19−7.11 (m, 2.26H), 2.54 (s, 3H),
2.31 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.3, 158.7, 141.6, 140.3, 136.0, 135.8,
134.0, 133.3, 132.7, 131.8, 131.4, 130.6, 130.5, 129.2, 125.4, 125.1, 124.9, 124.6, 121.3, 120.9,
119.7, 115.7, 113.0, 111.8, 93.9, 93.8, 90.8, 90.5, 20.6, 20.5, 15.7, 15.4 ppm; IR (neat): 3349,
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1706, 1232 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15NOSNa 304.0767, found
304.0770.
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N-(2-((2-(Methylthio)phenyl)ethynyl)-4-trifluoromethylphenyl)formamide (4c). Purification by
column chromatography (EtOAc/hexane, 3:7 v/v) afforded 4c (0.8553 g, 51%); pale yellow solid;
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mp = 100.9−102.8 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.97 (d, J = 11.2 Hz,
0.18H), 8.89 (br s, 0.82H), 8.78 (br d, J = 8.0 Hz, 0.18H), 8.61 (d, J = 8.8 Hz, 0.82H), 8.55 (s,
0.82H), 7.79−7.76 (m, 1H), 7.59−7.48 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.29−7.25 (m, 1.18H),
7.19 (d, J = 7.6 Hz, 1H), 2.56 & 2.56 (each s, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 160.6,
13
159.0, 141.8, 141.0, 140.8, 140.5, 132.1, 131.9, 129.7, 129.3, 128.1 (q, JC,F = 3.9 Hz), 126.5 (q,
JC,F = 3.5 Hz), 125.7 (q, JC,F = 35.6 Hz), 125.4, 125.2, 124.8, 123.6 (q, JC,F = 267.9 Hz), 120.5,
120.2, 119.6, 114.5, 112.9, 112.2, 95.7, 95.6, 89.1, 88.7, 15.7, 15.4 ppm; IR (neat): 3325, 1705,
1149 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H12F3NOSNa 358.0484, found
358.0481.
N-(2-((2-(Methylthio)phenyl)ethynyl)-4-fluorophenyl)formamide (4d). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4d (0.9134 g, 64%); white solid; mp =
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117.6−119.0 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.75 (d, J = 10.8 Hz, 0.29H),
8.65 (br s, 0.71H), 8.47 (s, 0.71H), 8.44 (dd, J = 8.8 Hz, J = 5.4 Hz, 1H), 7.50−7.45 (m, 1H),
7.37−7.33 (m, 1H), 7.26−7.21 (m, 1.29H), 7.19−7.13 (m, 2H), 7.04 (td, J = 8.6 Hz, J = 2.7 Hz,
1H), 2.54 & 2.53 (each s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.3, 159.0 (d, JC,F = 243.3
Hz), 158.7, 158.1 (d, JC,F = 242.9 Hz), 141.9, 140.5, 134.7 (d, JC,F = 2.8 Hz), 134.5 (d, JC,F = 3.2
Hz), 132.0, 131.9, 129.6, 125.3 (d, JC,F = 24.3 Hz), 125.0, 124.6, 121.3 (d, JC,F = 8.1 Hz), 120.6,
120.2, 118.6 (d, JC,F = 24.0 Hz), 117.4, 117.3 (d, JC,F = 24.1 Hz), 116.9, 116.8 (d, JC,F = 22.9
Hz), 116.7 (d, JC,F = 22.1), 114.9 (d, JC,F = 9.8 Hz), 113.4 (d, JC,F = 9.5 Hz), 95.0, 89.5, 89.4,
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15.7, 15.4 ppm; IR (neat): 3262, 1662, 1260 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C16H12FNOSNa 308.0516, found 308.0519.
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N-(2-((2-(Methylthio)phenyl)ethynyl)-4-chlorophenyl)formamide (4e). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4e (0.7998 g, 53%); pale yellow solid; mp =
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108.8−109.6 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.86 (d, J = 10.8 Hz, 0.16H),
8.71 (br s, 0.84H), 8.53 (br d, J = 8.0 Hz, 0.16H), 8.50 (d, J = 2.0 Hz, 0.84H), 8.44 (d, J = 8.8
Hz, 0.84H), 7.52−7.48 (m, 2H), 7.37 (td, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.32−7.27 (m, 2H),
7.19−7.13 (m, 1.16H), 2.56 (s, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 160.9, 158.8, 140.5,
13
136.9, 132.1, 132.0, 131.8, 130.5, 129.8, 129.7, 128.6, 125.5, 125.2, 125.1, 124.7, 120.9, 120.7,
116.5, 113.5, 95.3, 89.3, 88.9, 15.8, 15.5 ppm; IR (neat): 3342, 1697, 1255 cm-1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C16H12ClNOSNa 324.0220, found 324.0224.
N-(2-((2-(Methylthio)phenyl)ethynyl)-4-bromophenyl)formamide (4f). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4f (1.6112 g, 93%); white solid; mp =
1
97.5−98.8 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.83 (d, J = 10.8 Hz, 0.20H),
8.69 (br s, 0.80H), 8.53 (br d, J = 11.2 Hz, 0.20H), 8.49 (d, J = 1.2 Hz, 0.80H), 8.37 (d, J = 8.8
Hz, 0.80H), 7.65−7.61 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43 (dd, J = 4.6 Hz, J = 2.4 Hz, 1H),
7.37−7.34 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.19−7.10 (m, 1.20H), 2.54 (s, 3H); C{1H} NMR
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(CDCl3, 100 MHz): δ 160.8, 158.8, 141.9, 140.5, 137.4, 137.3, 134.7, 133.4, 132.6, 132.5, 132.1,
132.1, 131.9, 129.7, 129.7, 125.4, 125.2, 125.1, 124.7, 121.1, 120.7, 116.6, 116.0, 114.8, 113.8,
95.5, 95.4, 89.1, 88.8, 15.8, 15.5 ppm; IR (neat): 3342, 1694, 1256 cm-1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C16H12BrNOSNa 367.9715, found 367.9725.
N-(2-((2-(Methylthio)phenyl)ethynyl)-5-chlorophenyl)formamide (4g). Purification by column
chromatography (EtOAc/hexane, 3:7 v/v) afforded 4g (0.7850 g, 52%); pale yellow solid; mp =
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155.2−156.0 °C (CH2Cl2/hexane); H NMR (CDCl3, 400 MHz): δ 8.88 (d, J = 10.8 Hz, 0.16H),
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8.78 (br s, 0.84H), 8.62 (br d, J = 9.2 Hz, 0.16H), 8.58 (d, J = 2.0 Hz, 0.84H), 8.52 (d, J = 1.6
Hz, 0.84H), 7.52−7.46 (m, 1.16H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 7.6 Hz, J = 1.4 Hz,
1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (td, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.09 (dd, J = 8.4 Hz, J = 2.0
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Hz, 1H), 2.57 (s,3H); C{1H} NMR (CDCl3, 100 MHz): δ 158.8, 140.3, 139.1, 135.7, 131.9,
131.8, 129.5, 125.6, 125.3, 124.0, 121.0, 119.9, 110.3, 95.2, 89.7, 15.9 ppm; IR (neat): 3331,
1685, 1260 cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H12ClNOSNa 324.0220, found
324.0223.
General Procedure for Preparation of Compounds 2, 5 and 9. To a solution of N-(2-((2-
(dimethylamino)phenyl)ethynyl)phenyl)formamides
1,
or
N-(2-((2-
(methylthio)phenyl)ethynyl)phenyl)formamides 4, or N-(2-(phenylethynyl)phenyl)formamide 8
(0.5 mmol, 1.0 equiv) and diisopropylethylamine (0.70 mL, 4.0 mmol, 8.0 equiv) in CH2Cl2 (4
o
mL, 0.125 M) was added dropwise POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv) at 0 C under argon
o
atmosphere. The reaction mixture was stirred at 0 C for 1 h. The reaction was quenched with
NaHCO3 (5 mL) and the resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine (20 mL), dried (anh. MgSO4), filtered, and
concentrated under reduced pressure (aspirator). The crude product was subsequently used in the
next step without prior purification.
General Procedure for the Synthesis of Compounds 3. To a round-bottomed flask filled with
compound 2 {freshly prepared from the corresponding compound 1 (0.5 mmol)} was diluted
o
with DMF (2 mL, 0.25 M). The reaction mixture was stirred at 80 C for 1 h, then diluted with
H2O (5 mL) and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried (anh. MgSO4), filtered, and concentrated
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under reduced pressure (aspirator). The crude product was purified by column chromatography
on silica gel (EtOAc/hexane) to yield the corresponding indolo[2,3-b]quinolines 3.
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6-Methyl-6H-indolo[2,3-b]quinoline (3a).9m Purification by column chromatography
(EtOAc/hexane, 1:4 v/v) afforded 3a (105 mg, 90%); pale yellow solid. mp = 73.2−74.5 °C
(CH2Cl2/hexane) (lit.9m mp 83.0−87.0 °C); 1H NMR (CDCl3, 400 MHz): δ 8.62 (s, 1H), 8.17 (d,
J = 8.4 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.2 Hz, 1H), 7.57
(t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H),
3.95 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 152.5, 146.3, 142.7, 128.9, 128.5, 128.1,
127.5, 127.1, 123.9, 122.9, 121.4, 120.3, 120.0, 118.2, 108.7, 27.8 ppm; IR (neat): 3050, 2921,
1635, 1604, 1490, 1428 cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H13N2 233.1073,
found 233.1074.
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6,9-Dimethyl-6H-indolo[2,3-b]quinoline (3b). Purification by column chromatography
(EtOAc/hexane, 1:9 v/v) afforded 3b (89 mg, 72%); pale yellow solid; mp = 77.9−78.9 °C
(CH2Cl2/hexane); 1H NMR (CDCl3, 400 MHz): δ 8.60 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.95 (d,
J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.69 (t, J = 8.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.4
Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.92 (s, 1H), 2.53 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 152.9, 146.7, 140.9, 129.3, 129.1, 128.7, 128.4, 127.3, 127.1, 124.0, 122.7, 121.5, 120.4, 118.2,
108.3, 27.7, 21.3 ppm; IR (neat): 3050, 2917, 1636, 1609, 1483, 1447 cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C17H15N2 247.1230, found 247.1231.
6-Methyl-9-(trifluoromethyl)-6H-indolo[2,3-b]quinoline (3c). Purification by column
chromatography (EtOAc/hexane, 1:9 v/v) afforded 3c (117 mg, 78%); pale yellow solid; mp =
117.5−118.3 °C (CH2Cl2/hexane); 1H NMR (CDCl3, 400 MHz): δ 8.45 (s, 1H), 8.15 (s, 1H), 8.11
(d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.56 (t, J =
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