Base-mediated selective synthesis of diversely substituted N-heterocyclic enamines and enaminones by the hydroamination of alkynes

Article abstract of DOI:10.1021/jo300782n

Regio- and stereoselective alkynylation of various N-heterocycles 1a-l using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-l and 5a-i in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs₂CO₃ selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines.

Full text of DOI:10.1021/jo300782n

Article
pubs.acs.org/joc
Base-Mediated Selective Synthesis of Diversely Substituted N-
Heterocyclic Enamines and Enaminones by the Hydroamination of
Alkynes
Megha Joshi,† Monika Patel,† Rakesh Tiwari,†,‡ and Akhilesh K. Verma*,†
†Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
‡Department of Biomedical & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
02881, United States
S
* Supporting Information
ABSTRACT: Regio- and stereoselective alkynylation of
various N-heterocycles 1a−l using potassium and cesium
salts in DMSO is described. Terminal alkynes 2a−k and
internal alkynes 4a−f provided the kinetically stable Z-
enamines 3a−l and 5a−i in good to excellent yields using
KOH at 120 °C. Addition of heterocyclic amines to 1,3- and
1,4-diethynylbenzene 6a−b provided the mixture of E/Z
isomers with KOH; however, with Cs2CO3 selectively Z-
isomers 7ab−db were obtained by the hydroamination at one
triple bond. This developed methodology also provides an easy
and novel access for the synthesis of enaminones 10a−c. The
detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular
C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines.
isoquinolines6 or isoindoles, isoquinolines, and imidazoles
INTRODUCTION
The addition of amines onto C−C multiple bonds is rising as a
powerful technique for the synthesis of imines, enamines, or
■
have also attracted much interest.7
In our recent report on copper-catalyzed tandem synthesis of
indolo- and pyrrolo[2,1-a]isoquinolines, the reaction was
other nitrogen-containing molecules used in diverse biological
activities.1 Despite the development of a variety of effective
proposed to undergo via formation of a hydroaminated
intermediate H (Scheme 1, eq 2).8 With these successful
strategies, the hydroamination of alkynes has been reported by
reports on the synthesis of biologically important molecules via
hydroamination and strong demand for the development of
general, flexible, and regioselective methodologies motivated us
to explore the addition of heterocyclic amines onto alkynes.
Among the number of intermolecular hydroamination reactions
reported to date, significant progress has been made on
addition reactions of primary amines9 and secondary amines10
to alkenes and alkynes.
both catalytic and noncatalytic methods to overcome the high
activation energy required for this process.2 The products
formed not only can be used in a number of synthetically useful
transformations but also can be reduced to stable secondary
amines.3 Several natural products are well-known to involve
hydroamination of alkynes for their synthesis (Figure 1).4
In 1999, the first report on the addition of amines and
alcohols onto alkynes was made by Knochel using CsOH·H2O
in NMP (Scheme 2, eq 1).11 Later, in 2004, a phosphazene base
t-Bu-P4 was used for the addition of pyrrole and other
nucleophiles onto phenyl- and diphenylacetylene by Kondo and
co-workers (Scheme 2, eq 2).12 With this limited work on this
area and as a part of our ongoing research on alkyne
chemistry,13 very recently, we communicated a direct and
more economical synthetic method for the synthesis of an array
of styryl and vinyl enamines.14 Herein, we wish to report the
full details of our study on the base-mediated regio- and
Figure 1. Natural products synthesized via hydroamination.
A significant progress has been made by Knochel5a,b and
Ackermann5c−g for the synthesis of diversely substituted indoles
using inter- or intramolecular hydroamination of alkynes
(Scheme 1, eq 1). Recent developments in the metal-catalyzed
hydroamination of alkynes to synthesize complex biologically
important molecules like indolo- or pyrrolo[1,2-a]-
Received: April 20, 2012
© XXXX American Chemical Society
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Scheme 1. Applications of Inter- or Intramolecular Hydroamination in the Synthesis of Heterocycles
Scheme 2
Scheme 3. Stereoselective Addition of N-Heterocycles onto Alkynes and Alkynones
stereoselective hydroamination of terminal and internal alkynes
for the confirmation of the mechanistic pathway of tandem
synthesis of [2,1-a]isoquinolines (Scheme 3).8 Present method-
ology also provides for the first time an effective route for the
addition of N-heterocycles onto 1,3- and 1,4-diethynylbenzenes
and substituted alkynones to yield the corresponding addition
products in good yields.
RESULTS AND DISCUSSION
■
Hydroamination of Terminal Alkynes. Our preliminary
investigation revealed that the optimal reaction condition for
the synthesis of diversely substituted Z-styryl enamines was 20
mol % of KOH in DMSO at 120 °C.14a Addition of N-
heterocycles 1a−l on terminal alkynes 2a−k provided the
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a
Table 1. Synthesis of Z-Styrylenamines
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Table 1. continued
a
The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0 mmol of the alkyne 2, and 0.2 equiv of KOH in 1.5 mL of DMSO at 120 °C
b
c
d
for 0.5−1 h unless otherwise noted. Yield of isolated product. Time = 15 min. Time = 2 h.
corresponding Z-addition products 3a−l in good to excellent
yields (Table 1, entries 1−17). During the course of reaction, it
was noticed that the nature of the heteroarenes and the
substituents attached to the aryl group of triple bond were
responsible for the success of the process. The reaction
tolerates a wide range of substituents (comprising electron-
donating and electron-withdrawing groups) both in the N-
heterocycles and acetylenes, thus demonstrating a general
character of the synthesis. Heterocyclic amines with an
electron-donating group such as 3-methylindole 1a and 2-
methylindole 1b afforded the addition products with Z-
stereoselectivity in good yields (Table 1, entries 1−8). When
the scope of various alkynes was checked with 1a, it was found
that electron-donating groups affected the yield of the product
formed (Table 1, entries 1 and 2). Electron-withdrawing
substituents attached to the alkyne substrate 2c and 2d
enhanced the rate of reaction and sped up the conversion of
desired isomer to more stable E-isomer lowering the yield of
the product (Table 1, entries 3 and 4). No reaction was
observed with aliphatic alkynes 2e and 2f with 1a (Table 1,
entries 5 and 6). Heterocycle 1b also afforded the desired
product with alkyne 2g and 2h in 80 and 82% yields,
respectively (Table 1, entries 7 and 8). 5-Bromoindole 1c
afforded the hydroaminated product 3g in 86% yield (Table 1,
entry 9). Modification in the indole ring by substituting a
phenyl ring made no appreciable change in the reactivity of
these substrates with the corresponding alkynes (Table 1,
entries 10 and 11). Pyrrole 1e being more nucleophilic afforded
the hydroaminated product 3j in lesser reaction time in 92%
yield (Table 1, entry 12).
It is interesting to note that electron-deficient heterocycle 1f
and 1g reacted well with terminal alkynes 2b and 2l and
afforded the hydroaminated products 3k and 3l in longer time
(Table 1, entries 13 and 14). Heterocycles substituted with
electron-withdrawing groups −CHO and −COOH in the
indole moiety, i.e., 1H-indole-3-carbaldehyde 1h and 1H-
indole-2-carboxylic acid 1i, did not react under the given
conditions with 2a, which might be due to decrease in
nucleophilicity (Table 1, entries 15 and 16). A cyclic secondary
amine, pyrrolidine 1j, did not react in the presence of KOH
with 2a (Table 1, entry 17).
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a
Table 2. Synthesis of Z-Styrylenamines
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Table 2. continued
a
The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0 mmol of the alkyne 4, and 2.5 equiv of KOH in 1.5 mL of DMSO at 120 °C
b
c
d
for 24 h unless otherwise noted. Yield of isolated product. Time = 18−20 h. CuI (5 mol %) and ligand/BtCH2OH (10 mol %).
a
Table 3. Optimization of Reaction Conditions for the Hydroamination of Dialkynes
product
b
entry
base
t/°C
time/min
7aa
7ab
8aa
8ab
8ac
yield (%)
1
2
3
4
5
KOH
120
120
80
30
15
15
20
10
45
75
70
50
10
50
5
25
10
62
78
80
75
KOH
KOH
20
50
90
Cs2CO3
Cs2CO3
80
120
68
a
b
The reactions were performed using N-heterocycle 1a (3.0 equiv), 1.0 mmol of the alkyne 6a, and 0.2 equiv of base in 1.5 mL of DMSO. Yield of
mixture of isolated product.
Hydroamination of Internal Alkynes. Similarly, hydro-
amination of internal alkynes 4a−f to form Z-vinyl enamines
5a−i was selectively done using 2.5 equiv of KOH in 65−79%
yields in 18−24 h (Table 2, entries 1−12). Substituents
attached in the N-heterocycle exerted a similar effect on the
progress of the reaction as observed with terminal alkynes.
Electron-rich heterocycles afforded the addition products with
diphenylacetylene 4a in good yields in comparison to electron-
deficient substrates (Table 2, entries 1−6). Heterocycle 1a and
1b provided the Z-isomer selectively in 70 and 69% yields,
respectively (Table 2, entries 1 and 2). Pyrrole 1e being more
nucleophilic afforded the hydroaminated product 5c in lesser
reaction time in 76% yield (Table 2, entry 3). 1c afforded the
hydroaminated product 5d in 74% yield (Table 2, entry 4).
No reaction was observed with electron-deficient N-hetero-
cycles like imidazole 1f and 1g with alkyne 4a (Table 2, entries
5 and 6). Electron-rich alkynes 4b and 4c yielded the
corresponding addition products in 76−79% yields, respectively
(Table 2, entries 7−9). Sterically hindered and electron-rich
alkynes 1, 2-di-o-tolylethyne 4d and 1,2-di(thiophen-3-yl)-
ethyne 4e did not react in the presence of KOH. However,
addition of catalytic amount of CuI (5 mol %) and ligand (1H-
benzo[d][1,2,3]triazol-1-yl)methanol (BtCH2OH) (10 mol %)
in the reaction yielded the hydroaminated product 5h and 5i in
52 and 62% yields, respectively (Table 2, entries 10 and 11).
Aliphatic internal alkyne, 3-hexyne 4f, did not react with 1a
(Table 2, entry 12).
Hydroamination of Dialkynes. Next, we sought to
investigate the possibility of the reaction with a dialkyne.
More interestingly, when 1,3-diethynylbenzene 6a was reacted
with 1a using 0.2 equiv of KOH at 120 °C, a complex mixture
of three isomers was obtained in 30 min (Table 3, entry 1).
Reaction monitoring at continuous interval of time showed that
the addition of the amine to the alkyne occurred very fast,
leading to the conversion of kinetically stable Z-isomer to
thermodynamically stable E-isomer followed by the attack on
another alkyne present in the substrate. Decrease in reaction
time and temperature did not show any major change and
provided a mixture of addition products 7aa and 8ab in 78 and
80% yield, respectively (Table 3, entries 2 and 3). Use of
Cs2CO3 (0.2 equiv) yielded a mixture of two stereoisomers 7aa
and 7ab by the addition of 1a only at one position of the
dialkyne (Table 3, entry 4). Increase in temperature provided
the product 7ab in 68% yield (Table 3, entry 5).
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a
Table 4. Hydroamination of 1,3- and 1,4-Diethynylbenzene
a
The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0 mmol of the alkyne 6, and 0.2 equiv of Cs2CO3 in 1.5 mL of DMSO at 120 °C
b
for 10 min. Yield of isolated product.
Under the optimized reaction conditions (Table 3, entry 5),
selective hydroamination of dialkynes 6a and 6b was done
(Table 4, entries 1−5). 6a provided the 1,3-bis((Z)-2-(1H-
indol-1-yl)vinyl)benzene 8bc with 1l in 42% yield (Table 4,
entry 2). 1,4-Diethynylbenzene 6b yielded the mixture of E:Z
isomers with 1a and 1l in 64 and 57% yield, respectively (Table
4, entries 3 and 4). 1e provided Z-isomer in 54% yield along
with a complex mixture of other isomers (Table 4, entry 5).
Synthesis of Enaminones. For decades, enaminones are
known to be prepared by the general reaction of amines and
1,3-diketones and are established substrates in heterocyclic
chemistry15 and possess important biological activities.16 The
current strategy also proved to be efficient for the synthesis of
corresponding enaminone derivatives by the reaction of
heterocyclic amines and alkynones (Scheme 4).
4). Longer reaction time led to the decomposition of product.
Intermolecular addition of heterocycle 1a and alkynone, 1-
phenyl-3-p-tolylprop-2-yn-1-one 9b, yielded 10c a mixture of Z-
and E-hydroaminated products in 25:75 stereoisomeric ratios in
56% yield (Scheme 4).20c The stereochemistry of the products
formed by the addition of amines onto alkynes was determined
by NMR spectroscopy.14a
Hydroamination of Haloarylalkynes. In our ongoing
efforts to synthesize heterocyclic compounds via hydro-
amination and coupling reactions,17 we extended this work
using haloarylalkynes 11a,b (Table 5). Under the catalytic
conditions, it was observed that the addition of N-heterocycles
1l and 1a onto 11a,b was preferred over the N-arylation, and
products 12a−c were obtained in appreciable yields with E-
stereochemistry (Table 5, entries 1−3).14b
During the course of reaction of 1a and 9a, it was observed
that at high temperatures a highly polar unidentified complex
was formed. Thus, we carried out the reaction by using 0.2
equiv of KOH at 80 °C. It was motivating to find that reaction
of heterocycles 1a and 1l with alkynone 1-phenyl-3-
(trimethylsilyl)prop-2-yn-1-one 9a provided E-isomers 10a
and 10b as major products with the in situ hydrolysis of
TMS within 10 min in 81 and 76% yields, respectively (Scheme
Under the given catalytic conditions, internal alkyne 11c
provided the mixture of hydroaminated products in 68% yield
(Table 5, entry 4). Formation of the cyclized product, 6-(4-
ethylphenyl)-12-methylindolo[2,1-a]isoquinoline 12e, from 1-
bromo-2-((4-ethylphenyl)ethynyl)benzene 11d supports the
formation of addition product with Z-stereoselectivity. These
results suggest that the copper-catalyzed tandem synthesis of
indolo- and pyrrolo[2,1-a]isoquinolines undergoes base medi-
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Scheme 4. Hydroamination of Alkynones
chromatography (TLC) was performed on silica gel GF254 plates.
Visualization of spots on TLC plate was accomplished with UV light
ated stereo- and regioselective intermolecular addition of N-
heterocycle 1a onto ortho-haloarylakyne 11d and followed by
intramolecular C2 cyclization in the presence of metal and
ligand (Scheme 5).
We believe that this approach to a variety of enamines and
enaminones is quite useful for the synthesis of additional more
highly substituted indolo- and pyrroloisoquinolines, particularly
when one considers that there are many ways to transform the
halide functional group into other substituents. For example, 5d
produced by this strategy can be further functionalized by
applying palladium-catalyzed Suzuki,18 Heck,19 and Sonoga-
shira20a coupling reactions to afford the corresponding products
14, 16, and 17 in 85, 81, and 70% yields, respectively (Scheme
6).
1
(254 nm) and staining over I2 chamber. H and 13C NMR spectra
were recorded at 300 and 75 MHz or 400 and 100 MHz, respectively.
Thin layer chromatography was performed using commercially
prepared 60 F254 silica gel plates, and visualization was effected with
short wavelength UV light (254 nm). All melting points are
uncorrected. High resolution mass spectra were recorded on a double
focusing magnetic sector mass spectrometer.
General Procedure for the Synthesis of Internal Alkynes.
The 1,2-diarylalkynes and alkynones were prepared by the Sonogashira
coupling reaction of corresponding aryl-iodide or benzoyl chloride
with terminal alkynes using reported procedures.20 The structure and
purity of known starting materials 4a−d and 11a−d were confirmed
by comparison of their physical and spectral data (1H NMR, 13C
NMR, and HRMS) with those reported in literature.20b
1,2-Di(thiophen-3-yl)ethyne (4e).20a The product was obtained
CONCLUSION
1
■
as a brown solid (158.4 mg, 90% yield): mp 110−115 °C; H NMR
(400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.30−7.28 (m, 2H), 7.17
(dt, J = 1.4, 2.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 129.8, 128.5,
125.4, 122.2, 83.9; HRMS (ESI) [M]+ Calcd for [C10H6S2] 189.9911,
found 189.9910.
In summary, we have described a versatile and efficient regio-
and stereoselective synthetic method to produce a broad range
of functionalized vinyl and styryl enamines that are useful and
versatile synthetic intermediates for the synthesis of biologically
active compounds. This metal- and ligand-free methodology
utilizes a simple and economical bases such as KOH and
Cs2CO3 for the addition of N-heterocycles not only onto
terminal and internal alkynes but also for 1,3- and 1,4-dialkynes.
Addition of heterocyclic nucleophiles onto alkynones has also
been reported under mild conditions. Current work also
supports and confirms the mechanistic pathway for the copper-
catalyzed tandem synthesis of indolo- and pyrrolo[2,1-
a]isoquinolines via formation of Z-stereoisomer by hydro-
amination of ortho-haloarylalkyne followed by oxidative
addition in the presence of metal and ligand.
1-Phenyl-3-(trimethylsilyl)prop-2-yn-1-one (9a).20c The prod-
1
uct was obtained as an orange oil (189.5 mg, 92% yield): H NMR
(400 MHz, CDCl3) δ 8.14−8.12 (m, 2H), 7.60 (td, J = 2.2, 5.1 Hz,
1H), 7.51−7.45 (m, 2H), 6.30 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 177.7, 136.4, 134.2, 129.6, 128.5, 100.8, 100.6, −0.7; HRMS (ESI)
[M]+ Calcd for [C12H14OSi] 202.0814, found 202.0814.
1-Phenyl-3-(p-tolyl)prop-2-yn-1-one (9b).20c The product was
1
obtained as a yellow semisolid (168.8 mg, 89% yield): H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 7.4 Hz, 2H), 7.65−7.58 (m, 3H), 7.53 (t,
J = 7.4 Hz, 2H), 7.25 (t, J = 5.8 Hz, 2H), 2.41 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 178.1, 141.5, 136.9, 133.9, 133.1, 129.5, 129.4,
128.6, 116.9, 93.8, 86.8, 21.8; HRMS (ESI) [M]+ Calcd for [C16H12O]
220.0888, found 220.0887.
General Procedure for the Addition of N-Heterocycles with
Terminal Alkynes. The compounds were synthesized as per the
previously reported procedure.14a To a solution of N-heterocycle (2.0
equiv) in DMSO and finely crushed KOH (0.2 equiv), 100 mg of
alkyne (1.0 mmol) was added. Resulting mixture was heated at 120 °C.
EXPERIMENTAL SECTION
■
General Method. All the reactions were performed in an oven-
dried Schlenk flask under an argon atmosphere. Column chromatog-
raphy was performed using silica gel (100−200 mesh). Thin layer
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a
Table 5. Preferential Addition of Haloarylalkynes over N-arylation
a
Reactions were carried out using 1 (2.0 equiv), 11 (1.0 mmol), CuI (10 mol %), BtCH2OH (20 mol %), and KOH (2.0 equiv) in DMSO (1.5 mL)
b
c
at 120 °C for 20−30 min. Isolated yield. Time = 10−12 h.
Scheme 5. Tandem Synthesis of Indolo[2,1-a]isoquinolines by Addition of N-Heterocycle onto o-Haloarylalkyne Followed by
Intramolecular C2 Arylation
Progress of the reaction was monitored by TLC. After the complete
consumption of alkynes, reaction mixture was brought to room
temperature. The reaction mixture was extracted with ethylacetate (5
mL × 3) and evaporated under reduced pressure. The crude reaction
mixture was purified using silica gel column chromatography.
(Z)-3-Methyl-1-(4-methylstyryl)-1H-indole (3a). The product
was obtained as a white solid (195.8 mg, 92% yield): mp 115−117 °C;
1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J = 0.6, 7.2 Hz, 1H), 7.33−
7.29 (m, 1H), 7.24−7.22 (m, 1H), 7.19−7.12 (m, 2H), 7.10 (s, 1H),
7.04 (d, J = 8.1 Hz, 2H), 6.85 (m, 2H), 6.13 (d, J = 9.3 Hz, 1H), 2.31
(s, 3H), 2.24 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 137.2, 136.3,
132.3, 129.1, 129.06, 128.6, 124.5, 122.7, 122.4, 120.3, 118.9, 118.1,
113.2, 109.4, 21.3, 9.6; HRMS (ESI) [M]+ Calcd for [C18H17N]
247.1361, found 247.1362.
(Z)-1-(4-(tert-Butyl)styryl)-3-methyl-1H-indole (3b). The prod-
uct was obtained as orange crystals (142.7 mg, 78% yield): mp 110−
115 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.3 Hz, 1H), 7.32
(d, J = 8.0 Hz, 1H), 7.28−7.24 (m, 2H), 7.22 (dd, J = 1.4 Hz, 1H),
7.19−7.15 (m, 3H), 6.88 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H),
6.15 (d, J = 9.5 Hz, 1H), 2.25 (s, 3H), 1.30 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 149.7, 135.9, 133.5, 129.6, 129.3, 125.9, 125.7,
125.2, 122.9, 122.7, 121.1, 120.3, 119.2, 114.6, 112.3, 109.4, 34.5, 31.3,
I
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Scheme 6. Palladium-Catalyzed Diversification of 5d
9.7; HRMS (ESI) [M]+ Calcd for [C21H23N] 289.1830, found
289.1831.
90−95 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.64 (dd, J =
1.5, 8.0 Hz, 2H), 7.51−7.40 (m, 4H), 7.32 (td, J = 1.5, 8.0 Hz, 1H),
7.12 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.8 Hz,
1H), 6.35 (s, 3H), 6.24 (d, J = 9.5 Hz, 1H), 3.63 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 160.6, 142.2, 136.6, 135.4, 134.2, 129.0, 128.7,
127.9, 127.3, 126.5, 123.5, 122.2, 119.6, 119.4, 110.4, 106.5, 104.3,
100.3, 55.2; HRMS (ESI) [M]+ Calcd for [C24H21NO2] 355.1572,
found 355.1568.
(Z)-1-(2-(6-Methoxyphenanthren-2-yl)vinyl)-5-phenyl-1H-in-
dole (3i). The product was obtained as light brown crystals (150.3
mg, 82% yield): mp 130−135 °C; 1H NMR (400 MHz, CDCl3) δ 7.83
(s, 1H), 7.68−7.61 (m, 5H), 7.56 (d, J = 8.8 Hz, 1H), 7.52−7.42 (m,
5H), 7.33 (d, J = 7.3 Hz, 1H), 7.20 (dd, J = 2.2, 7.3 Hz, 1H), 7.11−
7.07 (m, 3H), 7.02 (d, J = 9.5 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 6.44
(d, J = 9.5 Hz, 1H), 3.91 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
157.9, 142.2, 135.4, 134.2, 133.9, 130.1, 129.5, 129.1, 128.7, 128.6,
127.9, 127.8, 127.3, 126.9, 126.8, 126.4, 122.9, 122.2, 120.1, 119.4,
119.1, 110.4, 105.7, 104.2, 55.3; HRMS (ESI) [M]+ Calcd for
[C31H23NO] 425.1780, found 425.1778.
(Z)-3-Methyl-1-(4-nitrostyryl)-1H-indole (3c). The product was
obtained as yellow needles (122.9 mg, 65% yield): mp 142−145 °C;
1H NMR (400 MHz, CDCl3) δ 7.95 (dt, J = 2.2, 9.5 Hz, 1H), 7.62−
7.56 (m, 2H), 7.19−7.14 (m, 2H), 7.12−7.07 (m, 1H), 7.04−6.97 (m,
1H), 6.91−6.86 (m, 2H), 6.73 (t, J = 8.8 Hz, 1H), 6.43 (s, 1H), 2.34
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.5, 141.6, 136.2, 134.4,
130.9, 130.2, 127.9, 123.7, 121.3, 119.4, 119.3, 116.4, 115.6, 111.7,
111.6, 108.2, 9.8; HRMS (ESI) [M]+ Calcd for [C17H14N2O2]
278.1055, found 278.1051.
(Z)-3-Methyl-1-(4-(trifluoromethoxy)styryl)-1H-indole (3d).
The product was obtained as a yellow oil (126.8 mg, 68% yield):
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.4 Hz, 1H), 7.31−7.29
(m, 1H), 7.25−7.21 (m, 3H), 7.19−7.16 (m, 1H), 7.09 (d, J = 8.1 Hz,
2H), 6.94 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 6.12 (d, J = 8.8
Hz, 1H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.1, 136.2,
134.0, 130.0, 129.2, 126.5, 124.0, 123.9, 122.6, 120.7, 120.4, 119.0,
116.0, 113.9, 109.9, 9.6; HRMS (ESI) [M]+ Calcd for [C18H14F3NO]
317.1027, found 317.1025.
(Z)-1-(4-Ethylstyryl)-1H-pyrrole (3j). The product was obtained
1
as a white semi-solid (139.4 mg, 92% yield): H NMR (400 MHz,
(Z)-2-Methyl-1-(4-methylstyryl)-1H-indole (3e). The product
CDCl3) δ 7.24−7.19 (m, 4H), 6.80−6.78 (m, 3H), 6.26 (t, J = 2.2 Hz,
2H), 6.18 (d, J = 9.5 Hz, 1H), 2.74 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 7.3
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.7, 132.21, 128.7, 127.8,
125.8, 120.8, 118.7, 109.2, 28.6, 15.4; HRMS (ESI) [M]+ Calcd for
[C14H15N] 197.1204, found 197.1204.
was obtained as off-white crystals (170.4 mg, 80% yield): mp 120−125
1
°C; H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 1.5 Hz, 1H), 7.13
(dd, J = 1.5 Hz, 1H), 7.08 (td, J = 1.4, 5.1 Hz, 2H), 6.94 (d, J = 8.0 Hz,
2H), 6.79 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.8
Hz, 1H), 6.36 (s, 1H), 2.24 (s, 3H), 2.22 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 138.0, 136.4, 135.8, 131.6, 129.3, 129.2, 128.7, 128.5,
121.8, 120.9, 120.0, 119.4, 110.5, 101.7, 21.2, 13.0; HRMS (ESI) [M]+
Calcd for [C18H17N] 247.1361, found 247.1362.
(Z)-1-(4-(tert-Butyl)styryl)-1H-imidazole (3k). The product was
obtained as a colorless oil (103.0 mg, 72% yield): 1H NMR (400 MHz,
CDCl3) δ 7.51 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 7.01 (d,
J = 8.8 Hz, 2H), 6.92 (s, 1H), 6.69 (d, J = 9.5 Hz, 1H), 6.35 (d, J = 9.5
Hz, 1H), 1.29 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 151.7, 136.9,
130.4, 129.1, 128.3, 127.9, 125.8, 125.7, 124.3, 121.6, 118.6, 34.8, 31.2;
HRMS (ESI) [M]+ Calcd for [C15H18N2] 226.1470, found 226.1469.
(Z)-2-Ethyl-1-(4-methoxystyryl)-4-methyl-1H-imidazole (3l).
The product was obtained as a off-white semi-solid (150.3 mg, 82%
(Z)-2-Methyl-1-(4-phenoxystyryl)-1H-indole (3f). The product
was obtained as yellow crystals (137.4 mg, 82% yield): mp 130−135
1
°C; H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 2.2, 2.9 Hz, 1H),
7.29 (t, J = 7.7 Hz, 2H), 7.12−7.03 (m, 4H), 6.92 (dd, J = 2.2, 7.3 Hz,
2H), 6.83 (dt, J = 2.6, 8.8 Hz, 2H), 6.73 (dt, J = 2.9, 8.8 Hz, 2H), 6.68
(d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.35 (s, 1H), 2.25 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 157.1, 156.5, 136.2, 135.6,
130.1, 129.7, 129.4, 128.7, 128.5, 123.6, 121.7, 120.9, 120.1, 119.5,
119.3, 118.3, 110.6, 101.8, 13.0; HRMS (ESI) [M]+ Calcd for
[C23H19NO] 325.1467, found 325.1465.
1
yield): H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 8.8 Hz, 2H), 6.72
(d, J = 9.5 Hz, 2H), 6.45 (s, 1H), 6.39 (d, J = 3.6 Hz, 2H), 3.73 (s,
3H), 2.61 (q, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.23−1.18 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.9, 148.3, 139.3, 130.2, 125.1, 119.2,
115.4, 114.2, 55.3, 20.1, 14.1, 12.1; HRMS (ESI) [M]+ Calcd for
[C15H18N2O] 242.1419, found 242.1419.
(Z)-5-Bromo-1-styryl-1H-indole (3g). The product was obtained
1
as white crystals (251.1 mg, 86% yield): mp 130−135 °C; H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 1.4, 6.6
Hz, 1H), 7.26−7.19 (m, 4H), 7.12 (dd, J = 2.2, 5.1 Hz, 2H), 7.01 (d, J
= 2.9 Hz, 1H), 6.89 (d, J = 9.5 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 6.35
(d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 134.5, 134.4,
130.2, 128.6, 128.5, 128.3, 127.8, 125.2, 123.4, 122.9, 121.2, 113.9,
111.6, 103.4; HRMS (ESI) [M]+ Calcd for [C16H12BrN] 297.0153,
found 297.0150.
General Procedure for the Addition of N-Heterocycles with
Internal Alkynes. To a solution of N-heterocycle (2.0 equiv) in
DMSO and finely crushed KOH (2.5 equiv), 100 mg of alkyne (1.0
mmol) was added. Resulting mixture was heated at 120 °C. Progress of
the reaction was monitored by TLC. After the complete consumption
of alkynes, reaction mixture was brought to room temperature. The
reaction mixture was extracted with ethylacetate (5 mL × 3) and
evaporated under reduced pressure. The crude reaction mixture was
purified using silica gel column chromatography. For the synthesis of
(Z)-1-(3,5-Dimethoxystyryl)-5-phenyl-1H-indole (3h). The
product was obtained as brown crystals (186.3 mg, 85% yield): mp
J
dx.doi.org/10.1021/jo300782n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5h and 5i, CuI (5.0 mol %) and ligand BtCH2OH (10.0 mol %) were
also added.
(Z)-1-(1,2-Diphenylvinyl)-3-methyl-1H-indole (5a). The prod-
1H), 6.52 (s, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 138.9, 137.7, 137.4, 136.2, 135.3, 134.8, 130.8,
130.2, 129.9, 129.5, 128.8, 128.1, 127.2, 125.7, 125.6, 121.8, 121.3,
119.8, 119.4, 118.5, 113.1, 111.8, 20.4, 19.7, 9.6; HRMS (ESI) [M]+
Calcd for [C25H23N] 337.1830, found 337.1832.
uct was obtained as white crystals (121.6 mg, 70% yield): mp 109−112
1
°C; H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.3 Hz, 1H), 7.33−
7.28 (m, 4H), 7.25−7.22 (m, 2H), 7.13−7.09 (m, 4H), 7.03−6.99 (m,
2H), 6.85 (d, J = 8.0 Hz, 1H), 6.84−6.81 (m, 1H), 6.77 (s, 1H), 2.35
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.7, 136.2, 135.7, 134.9,
129.4, 128.7, 128.3, 127.6, 126.3, 125.8, 124.2, 122.0, 119.5, 118.7,
113.1, 111.7, 9.7; HRMS (ESI) [M]+ Calcd for [C23H19N] 309.1517,
found 309.1514.
(Z)-1-(1,2-Diphenylvinyl)-2-methyl-1H-indole (5b). The prod-
uct was obtained as a brown oil (119.8 mg, 69% yield): 1H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.31−7.29 (m, 4H), 7.20−
7.18 (m, 2H), 7.12−7.09 (m, 3H), 7.06 (dd, J = 1.5, 6.6 Hz, 1H),
6.97−6.96 (m, 2H), 6.76−6.74 (m, 2H), 6.46 (s, 1H), 2.08 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 138.4, 136.4, 136.2, 134.7, 134.2,
128.8, 128.6, 128.1, 127.5, 125.4, 121.2, 120.0, 119.5, 110.8, 102.0,
12.7; HRMS (ESI) [M]+ Calcd for [C23H19N] 309.1517, found
309.1517.
(Z)-1-(1,2-Diphenylvinyl)-1H-pyrrole (5c). The product was
obtained as a white semi-solid (104.6 mg, 76% yield): 1H NMR
(400 MHz, CDCl3) δ 7.36−7.33 (m, 3H), 7.29−7.27 (m, 2H), 7.25−
7.18 (m, 3H), 6.85−6.82 (m, 3H), 6.58 (t, J = 2.2 Hz, 2H), 6.30 (t, J =
2.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 138.8, 134.8, 130.5,
129.1, 128.8, 128.5, 128.3, 127.7, 126.3, 122.9, 121.4, 120.7, 117.9,
109.7; HRMS (ESI) [M]+ Calcd for [C18H15N] 245.1204, found
245.1203.
(Z)-1-(1,2-Di(thiophen-3-yl)vinyl)-3-methyl-1H-indole (5i).
The product was obtained as a dark yellow oil (104.8 mg, 62%
yield): 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 1H), 7.31−
7.29 (m, 1H), 7.18 (dd, J = 1.5 Hz, 1H), 7.16 (s, 1H), 7.13 (td, J = 1.5,
6.6 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 7.02−6.99 (m, 2H), 6.85 (s,
1H), 6.79−6.73 (m, 2H), 6.22 (d, J = 5.1 Hz, 1H), 2.39 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 140.9, 135.7, 130.6, 128.9, 127.5, 126.4,
125.3, 125.2, 124.9, 122.4, 122.2, 119.5, 119.0, 118.8, 112.8, 111.1, 9.8;
HRMS (ESI) [M]+ Calcd for [C19H15NS2] 321.0646, found 321.0645.
General Procedure for the Addition of N-Heterocycles with
Dialkynes. To a solution of N-heterocycle (2.0 equiv) in DMSO and
finely crushed Cs2CO3 (0.2 equiv), 100 mg of alkyne (1.0 mmol) was
added. Resulting mixture was heated at 120 °C. Progress of the
reaction was monitored by TLC. After the complete consumption of
alkynes, reaction mixture was brought to room temperature. The
reaction mixture was extracted with ethylacetate (5 mL × 3) and
evaporated under reduced pressure.
1-(3-Ethynylstyryl)-3-methyl-1H-indole (7ab). The product
1
was obtained as a yellow oil (138.7 mg, 68% yield): H NMR (400
MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.35−7.30 (m,
2H), 7.24 (t, J = 9.5 Hz, 1H), 7.19−7.16 (m, 3H), 6.94 (d, J = 9.5 Hz,
1H), 6.77 (s, 1H), 6.08 (d, J = 8.8 Hz, 1H), 3.03 (s, 1H), 2.23 (s, 3H);
13C NMR (CDCl3, 100 Hz) δ 136.7, 135.7, 132.4, 130.9, 129.2, 128.9,
128.4, 124.1, 123.9, 122.6, 122.2, 120.4, 119.0, 115.7, 113.8, 109.9,
83.3, 77.3, 9.6; HRMS (ESI) [M]+ Calcd for [C19H15N] 257.1204,
found 257.1201.
(Z)-5-Bromo-1-(1,2-diphenylvinyl)-1H-indole (5d). The prod-
uct was obtained as yellow crystals (155.4 mg, 74% yield): mp 130−
1
132 °C; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 2.2 Hz, 1H),
1,3-Bis((Z)-2-(1H-indol-1-yl)vinyl)benzene (8bc). The product
7.34−7.29 (m, 3H), 7.23−7.19 (m, 2H), 7.14−7.09 (m, 5H), 6.99 (d, J
= 3.6 Hz, 1H), 6.80−6.76 (m, 3H), 6.60 (d, J = 2.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 137.9, 135.7, 134.4, 134.1, 130.5, 129.7,
128.9, 128.8, 128.6, 128.5, 128.0, 126.0,125.2, 125.1, 123.3, 113.6,
113.1, 103.4; HRMS (ESI) [M + 1]+ Calcd for [C22H16BrN]
373.0466, found 373.0465.
1
was obtained as a yellow oil (120.0 mg, 42% yield): H NMR (400
MHz, CDCl3) δ 7.67 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H),
7.30 (td, J = 5.8, 1.5 Hz, 2H), 7.26−7.22 (m, 2H), 7.15−7.13 (m, 2H),
7.08−7.04 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 2.9 Hz, 2H),
6.20 (d, J = 9.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 135.8, 135.2,
129.1, 128.5, 128.4, 127.6, 126.9, 123.6, 122.4, 120.9, 120.7, 118.9,
110.1, 104.0; HRMS (ESI) [M]+ Calcd for [C26H20N2] 360.1626,
found 360.1625.
(Z)-1-(1,2-Di-m-tolylvinyl)-5-methoxy-1H-indole (5e). The
product was obtained as an off-white solid (125.1 mg, 73% yield):
1H NMR (300 MHz, CDCl3) δ 7.24−7.08 (m, 4H), 7.02−6.91 (m,
5H), 6.79 (d, J = 9.0 Hz, 1H), 6.69−6.58 (m, 3H), 6.48 (d, J = 6.9 Hz,
1H), 3.83 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 154.4, 138.6, 138.3, 137.8, 136.3, 134.7, 130.7, 129.9, 129.6,
129.3, 129.2, 128.6, 128.5, 128.2, 125.5, 124.6, 123.5, 112.6, 112.2,
103.4, 102.3, 55.7, 21.5, 21.4; HRMS (ESI) [M]+ Calcd for
[C25H23NO] 353.1780, found 353.1781.
(Z)-1-(1,2-Bis(3-methoxyphenyl)vinyl)-3-methyl-1H-indole
(5f). The product was obtained as a yellow semi-solid (117.8 mg, 76%
yield): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.3 Hz, 1H), 7.26−
7.21 (m, 2H), 7.11−7.00 (m, 3H), 6.91−6.82 (m, 4H), 6.78 (s, 1H),
6.65 (dd, J = 2.2, 5.9 Hz, 1H), 6.57 (d, J = 10.2 Hz, 1H), 6.04 (s, 1H),
3.76 (s, 3H), 3.29 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 159.8, 159.3, 140.1, 136.1, 135.9, 135.7, 129.6, 129.2, 129.0, 125.6,
124.6, 122.1, 122.0, 119.6, 118.9, 118.6, 114.9, 114.1, 113.0, 111.9,
111.6, 55.3, 54.6, 9.7; HRMS (ESI) [M]+ Calcd for [C25H23NO2]
369.1729, found 369.1728.
1-(4-Ethynylstyryl)-3-methyl-1H-indole (7bb). The product
1
was obtained as a light yellow semi-solid (130.5 mg, 64% yield): H
NMR (400 MHz, CDCl3) δ 7.60 [d, J = 14.6 Hz, 0.17H; (for minor)],
7.47 [d, J = 8.1 Hz, 1.0H; (for major)], 7.43−7.39 [m, 0.5H; (for
minor)], 7.30 [d, J = 8.3 Hz, 2.4H; (2.0H for major +0.4H for
minor)], 7.24−7.22 [m, 1.2H; (1.0H for major +0.4H for minor)],
7.19−7.17 [m, 3.5H; (3.0H for major +0.5H for minor)], 6.86 [d, J =
8.8 Hz, 1.0H; (for major)], 6.72 [s, 1H; (for major)], 6.46 [d, J = 13.9
Hz, 0.22H; (for minor)], 6.04 [d, J = 8.8 Hz, 1.0H; (for major)], 3.04
[s, 0.17H; (17% for minor regioisomer)], 3.02 [s, 1.0H; (83% for
major regioisomer)], 2.29 [s, 0.58H; (for minor)], 2.17 [s, 3H; (for
major)]; 13C NMR (CDCl3, 100 MHz) δ 135.9, 132.1, 128.6, 125.2,
124.1, 124.0, 122.6, 120.4, 119.0, 116.4, 113.9, 109.9, 83.6, 77.7, 9.6
(for major regioisomer); 136.2, 132.6, 129.2, 123.0, 120.8, 120.6,
119.4, 111.2, 109.4, 9.8 (for minor regioisomer); HRMS (ESI) [M]+
Calcd for [C19H15N] 257.1204, found 257.1202.
1-(4-Ethynylstyryl)-1H-indole (7cb). The product was obtained
as a brown oil (109.9 mg, 57% yield): 1H NMR (400 MHz, CDCl3) δ
7.71 [d, J = 14.6 Hz, 0.5H; (for minor)], 7.61 [d, J = 8.1 Hz, 1.5H;
(1.0H for major +0.5H for minor)], 7.55 [d, J = 8.0 Hz, 0.5H; (for
minor)], 7.52−7.48 [m, 1.5H; (1.0H for major +0.5H for minor)],
7.40 [d, J = 8.1 Hz, 1H; (for major)], 7.37−7.35 [m, 3H; (2.0H for
major +1.0H for minor)], 7.31−7.30 [m, 0.6H; (for minor)], 7.22−
7.21 [m, 1H; (for major)], 7.19−7.13 [m, 2H; (for major)], 7.00−6.98
[m, 2H; (for major)], 6.69−6.63 [m, 1H; (for minor)], 6.50 [d, J = 2.9
Hz, 1.0H; (for major)], 6.24 [d, J = 8.8 Hz, 1.0H; (for major)], 3.13 [s,
0.3H; (30% for minor regioisomer)], 3.09 [s, 1H; (70% for major
regioisomer)]; 13C NMR (CDCl3, 100 MHz) δ 136.7, 135.7, 132.6,
129.2, 125.4, 124.4, 123.6, 122.9, 121.3, 121.2, 120.2, 112.9, 110.9,
109.6, 105.9, 83.7, 77.7 (for major regioisomer); 128.6, 123.9, 121.9,
(Z)-1-(1,2-Bis(3-methoxyphenyl)vinyl)-1H-pyrrole (5g). The
product was obtained as a dark brown oil (101.3 mg, 79% yield): H
1
NMR (400 MHz, CDCl3) δ 7.28−7.25 (m, 1H), 7.14 (t, J = 7.3 Hz,
1H), 6.92−6.88 (m, 2H), 6.86 (s, 1H), 6.83−6.81 (m, 1H), 6.75 (dd, J
= 2.9, 5.1 Hz, 1H), 6.60 (t, J = 2.2 Hz, 3H), 6.30 (t, J = 2.2 Hz, 2H),
6.19 (t, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 159.8, 159.4, 140.2, 138.2, 135.9, 129.5, 129.1, 123.3,
122.1, 121.4, 118.7, 114.7, 114.3, 112.2, 111.8, 109.8, 55.3, 54.9;
HRMS (ESI) [M]+ Calcd for [C20H19NO2] 305.1416, found 305.1411.
(Z)-1-(1,2-Di-o-tolylvinyl)-3-methyl-1H-indole (5h). The prod-
uct was obtained as yellow crystals (85.1 mg, 52% yield): mp 110−115
1
°C; H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.29 (dd, J = 1.5,
5.9 Hz, 1H), 7.15−7.12 (m, 3H), 7.04−6.99 (m, 2H), 6.90 (d, J = 8.0
Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 7.7 Hz, 2H), 6.59 (s,
K
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120.7, 119.8, 110.9, 102.6 (for minor regioisomer); HRMS (ESI) [M]+
Calcd for [C18H13N] 243.1048, found 243.1048.
(Z)-1-(4-Ethynylstyryl)-1H-pyrrole (7db). The product was
obtained as white needles (82.7 mg, 54% yield): mp 115−119 °C;
1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.1 Hz, 2H), 7.06 (d, J =
δ 135.8, 133.9, 131.6, 130.2, 128.6, 126.9, 123.9, 122.6, 121.3, 120.9,
120.8, 118.2, 110.1, 104.3; HRMS (ESI) [M]+ Calcd for [C16H12BrN]
297.0153, found 297.0153.
(E)-1-(3-Bromostyryl)-1H-indole (12b). The product was
obtained as white crystals (89.5 mg, 76% yield): mp 122−125 °C;
1H NMR (400 MHz, CDCl3) δ 7.67−7.62 (m, 2H), 7.59 (t, J = 1.5
Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 7.37−7.34
(m, 2H), 7.30 (td, J = 1.5, 5.9 Hz, 1H), 7.24−7.17 (m, 2H), 6.68 (d, J
= 3.7 Hz, 1H), 6.59 (d, J = 13.9 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 138.4, 135.7, 130.3, 129.6, 129.2, 128.3, 124.6, 124.3, 123.5,
122.9, 121.3, 121.2, 112.1, 109.6, 105.9; HRMS (ESI) [M]+ Calcd for
[C16H12BrN] 297.0153, found 297.0153.
8.8 Hz, 2H), 6.67 (d, J = 9.5 Hz, 1H), 6.56 (t, d, J = 2.2 Hz, 2H), 6.08
(t, d, J = 2.2 Hz, 2H), 5.98 (d, J = 9.5 Hz, 1H), 3.02 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 136.3, 132.5, 127.8, 125.5, 120.3, 119.1, 113.3,
110.8, 83.6, 77.7; HRMS (ESI) [M]+ Calcd for [C14H11N] 193.0891,
found 193.0891.
General Procedure for the Addition of N-Heterocycles with
Alkynones. To a solution of N-heterocycle (2.0 equiv) in DMSO and
finely crushed KOH (0.2 equiv), 100 mg of alkyne (1.0 mmol) was
added. Resulting mixture was heated at 80 °C. Progress of the reaction
was monitored by TLC. After the complete consumption of alkynes,
reaction mixture was brought to room temperature. The reaction
mixture was extracted with ethylacetate (5 mL × 3) and evaporated
under reduced pressure. The crude reaction mixture was purified using
silica gel column chromatography.
1-(4-Bromostyryl)-2-ethyl-4-methyl-1H-imidazole (12c). The
1
product was obtained as a yellow oil (79.4 mg, 69% yield): H NMR
(400 MHz, CDCl3) δ 7.45 [d, J = 8.0 Hz, 1H; (for major)], 7.34 [d, J
= 8.1 Hz, 2H; 1.0H (for major) and 1.0H (for minor)], 7.26−7.29 [m,
1.5H; 1.0 H (for major), 0.5 H (for minor)], 6.93−6.91 [m, 0.5 H;
(for minor)], 6.88 [d, J = 8.8 Hz, 2H; 1.0 H (for major) and 1.0 H (for
minor)], 6.61 [d, J = 9.5 Hz, 1H; (for major)], 6.49 [t, J = 13.9 Hz, 0.5
H; (34% for minor regioisomer)], 6.38 [s, 1H; (for major)], 6.27 [d, J
= 9.5 Hz, 1 H; (66% for major regioisomer)], 2.78−2.77 [m, 1H; (for
minor)], 2.59 [q, J = 7.3 Hz, 2H; (for major)], 2.20 [s, 2H; (for
minor)], 2.14 [s, 3H; (for major)], 1.32 [t, J = 6.5 Hz, 1.5H; (for
minor)], 1.24−1.21 [m, 3H; (for major)]; 13C NMR (100 MHz,
CDCl3) δ 148.5, 136.9, 133.9, 131.9, 131.7, 130.2, 127.4, 124.5, 122.6,
114.5, 20.5, 13.3, 12.2 (for major regioisomer); and 137.4, 132.5,
132.3, 125.7, 122.3, 116.8, 111.7, 20.4, 13.3, 12.3 (for minor
regioisomer); HRMS (ESI) [M + 1]+ Calcd for [C14H15BrN2]
290.0419, found 291.0419.
(Z)-1-(2-(4-Bromophenyl)-1-p-tolylvinyl)-1H-indole (12d).
This compound was obtained as a white semi-solid (97.4 mg, 68%
yield): 1H NMR (400 MHz, CDCl3) δ 7.59 [d, J = 8.0 Hz, 1.5H; 1.0 H
(for major) + 0.5 H (for minor)], 7.35 [d, J = 8.0 Hz, 0.5H; 0.5 H (for
minor)], 7.13 [d, J = 8.0 Hz, 2.0H; 1.0 H (for major) + 1.0 H (for
minor)], 7.05 [s, 5H; 4.0 H (for major) + 1.0 H (for minor)], 7.02−
7.00 [m, 0.75H (for minor)], 6.98−6.94 [m, 2H (for major)], 6.88−
6.82 [m, 4.5H; 3.0 H (for major) + 1.5 H (for minor)], 6.60−6.58 [m,
2H (for major)], 6.53[d, J = 8.0, 2.5H; 2.0 H (for major) + 0.5 H (for
minor)]), 2.28 [s, 5.2H; 3.0 H (58% for major regioisomer) + 2.2 H
(42% for minor regioisomer)]; 13C NMR (100 MHz, CDCl3) δ 139.3,
137.0, 135.4, 133.9, 131.9, 131.5, 130.2, 129.5, 128.8, 128.3, 126.2,
122.6, 122.3, 121.6, 120.9, 120.4, 111.9, 104.3, 21.3 (for major
regioisomer); 135.3, 129.2, 128.9, 127.6, 125.6, 111.7 (for minor
regioisomer); HRMS (ESI) [M]+ Calcd for [C23H18BrN] 387.0623,
found 387.0623.
(E)-3-(3-Methyl-1H-indol-1-yl)-1-phenylprop-2-en-1-one
(10a). The product was obtained as yellow crystals (104.6 mg, 81%
1
yield): mp 110−112 °C; H NMR (400 MHz, CDCl3) δ 8.39 (d, J =
13.9 Hz, 1H), 7.93 (dd, J = 7.4, 1.4 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H),
7.51−7.47 (m, 2H), 7.45−7.39 (m, 2H), 7.26 (t, J = 8.1 Hz, 1H),
7.23−7.17 (m, 2H), 6.89 (d, J = 13.2 Hz, 1H), 2.25 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 189.6, 138.7, 137.6, 136.8, 132.5, 132.4, 130.9,
128.5, 128.0, 124.8, 124.2, 122.5, 120.7, 119.6, 119.4, 111.2, 102.3, 9.8;
HRMS (ESI) [M]+ Calcd for [C18H15NO] 261.1154, found 261.1153.
(E)-3-(1H-Indol-1-yl)-1-phenylprop-2-en-1-one (10b). The
product was obtained as light brown crystals (92.9 mg, 76% yield):
mp 105−108 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 13.9 Hz,
1H), 8.02 (d, J = 6.6 Hz, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.0
Hz, 1H), 7.58 (dt, J = 7.4, 2.2 Hz, 1H), 7.54−7.50 (m, 3H), 7.37 (t, J =
7.3 Hz, 1H), 7.28−7.24 (m, 1H), 7.09 (d, J = 13.2 Hz, 1H), 6.78 (d, J
= 3.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 189.9, 138.6, 137.8,
136.4, 132.6, 129.9, 128.6, 128.1, 124.2, 123.6, 122.8, 121.6, 110.4,
109.4, 104.6; HRMS (ESI) [M]+ Calcd for [C17H13NO] 247.0997,
found 247.0997.
3-(3-Methyl-1H-indol-1-yl)-1-phenyl-3-(p-tolyl)prop-2-en-1-
one (10c). The product was obtained as a yellow oil (89.4 mg, 56%
yield): 1H NMR (400 MHz, CDCl3) δ 7.91 [dd, J = 7.3, 1.5 Hz, 0.7H;
(for minor)], 7.70 [dt, J = 7.4, 1.5 Hz, 2.0H; (for major)], 7.40 [d, J =
7.3 Hz, 2.0H; 1.0 H (for major) + 1.0 (for minor)], 7.37−7.32 [m, 2H;
1.0 H (for major) + 1.0 (for minor)], 7.27−7.16 [m, 6H; 5.0 H (for
major) + 1.0 (for minor)], 7.06 [t, J = 7.3 Hz, 1H; (for major)], 7.03−
6.99 [m, 1H; (for major)], 6.81−6.76 [m, 3H; (for major)], 2.42 [s,
3H; (75% for major regioisomer)], 2.39 [s, 1H; (25% for minor
regioisomer)], 2.29 [s, 1H; (25% for minor regioisomer)], 2.18 [s, 3H;
(75% for major regioisomer)]; 13C NMR (100 MHz, CDCl3) δ 190.7,
152.0, 148.8, 141.5, 139.1, 138.5, 136.7, 134.1, 132.4, 132.1, 130.1,
129.6, 129.3, 128.6, 128.4, 127.9, 127.8, 125.8, 122.3, 120.4, 118.9,
114.4, 112.9, 21.5, 9.6 (for major regioisomer); and 190.8, 140.6,
138.5, 136.7, 132.2, 131.6, 130.3, 127.0, 123.0, 121.4, 119.4, 115.3,
114.1, 112.5, 21.4, 9.5 (for minor regioisomer); HRMS (ESI) [M]+
Calcd for [C25H21NO] 351.1623, found 351.1622.
6-(4-Ethylphenyl)-12-methylindolo[2,1-a]isoquinoline (12e).
The product was obtained as yellow crystals (82.3 mg, 70% yield): mp
130−132 °C; 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 7.8 Hz, 1H),
7.79 (d, J = 8.1 Hz, 1H), 7.53−7.52 (m, 2H), 7.50−7.41 (m, 3H),
7.38−7.35 (m, 2H), 7.28−7.18 (m, 1H), 6.90 (t, J = 8.4 Hz, 1H), 6.44
(d, J = 7.5 Hz, 2H), 2.89 (s, 3H), 2.81 (q, J = 7.5 Hz, 2H), 1.36 (t, J =
7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 145.5, 138.5, 134.2, 131.4,
130.9, 130.2, 130.0, 129.1, 128.3, 127.2, 126.6, 126.5, 126.2, 124.4,
121.0, 120.2, 118.0, 114.4, 110.7, 105.4, 28.8, 15.5, 11.8; HRMS (ESI)
[M]+ Calcd for [C25H21N] 335.1674, found 335.1674.
General Procedure for the Addition of N-Heterocycles with
Haloarylalkynes. To a solution of N-heterocycle (2.0 equiv) in
DMSO, finely crushed KOH (2.0 equiv), CuI (5.0 mol %), ligand
BtCH2OH (10.0 mol %) and 100 mg of alkyne (1.0 mmol) were
added. Resulting mixture was heated at 120 °C. Progress of the
reaction was monitored by TLC. After the complete consumption of
alkynes, reaction mixture was brought to room temperature. The
reaction mixture was extracted with ethylacetate (5 mL × 3) and
evaporated under reduced pressure. The crude reaction mixture was
purified using silica gel column chromatography.
(E)-1-(4-Bromostyryl)-1H-indole (12a). The product was
obtained as a colorless oil (84.8 mg, 72% yield): 1H NMR (400
MHz, CDCl3) δ 7.69−7.63 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.51−
7.47 (m, 3H), 7.33−7.28 (m, 3H), 7.18 (t, J = 8.8 Hz, 1H), 6.68 (d, J =
2.9 Hz, 1H), 6.61 (d, J = 14.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
(Z)-5-(2,5-Dimethoxyphenyl)-1-(1,2-diphenylvinyl)-1H-in-
dole (14). The product was obtained as an orange semi-solid (98.0
1
mg, 85% yield): H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.35−
7.33 (m, 3H), 7.29−7.28 (m, 2H), 7.23 (dd, J = 1.4 Hz, 1H), 7.15−
7.13 (m, 3H), 7.06 (s, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.97 (d, J = 2.9
Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 4.4 Hz, 1H), 6.87−6.84
(m, 2H), 6.83−6.80 (m, 1H), 6.69 (d, J = 3.7 Hz, 1H), 3.81 (s, 3H),
3.75 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.7, 150.8, 138.3,
136.3, 134.7, 132.6, 130.4, 128.9, 128.8, 128.6, 128.4, 127.8, 126.3,
124.8, 124.1, 121.5, 117.0, 112.6, 112.4, 111.7, 104.3, 56.3, 55.8;
HRMS (ESI) [M]+ Calcd for [C30H25NO2] 431.1885, found 431.1885.
(E)-Methyl 3-(1-((Z)-1,2-diphenylvinyl)-1H-indol-5-yl)acrylate
(16). The product was obtained as white crystals (82.2 mg, 81% yield):
1
mp 130−135 °C; H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 1.6,
15.6 Hz, 2H), 7.37−7.33 (m, 3H), 7.28−7.24 (m, 3H), 7.16−7.14 (m,
L
dx.doi.org/10.1021/jo300782n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4H), 7.05 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.83−6.80 (m,
2H), 6.73 (d, J = 3.2 Hz, 1H), 6.39 (d, J = 14.0 Hz, 1H), 3.82 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 167.9, 146.4, 144.9, 137.9, 136.7,
135.7, 134.4, 130.3, 129.7, 129.1, 129.0, 128.9, 128.8, 128.6, 128.5,
128.0, 126.9, 126.0, 125.3, 122.4, 121.8, 117.8, 114.8, 112.2, 104.7,
51.5; HRMS (ESI) [M]+ Calcd for [C26H21NO2] 379.1572, found
379.1572.
Am. Chem. Soc. 1999, 121, 3633. (d) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101.
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A.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
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(Z)-1-(1,2-Diphenylvinyl)-5-(thiophen-3-ylethynyl)-1H-in-
dole (17). The product was obtained as a brown oil (75.1 mg, 70%
1
yield): H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.47 (d, J = 2.2
Hz, 1H), 7.35−7.33 (m, 2H), 7.29−7.22 (m, 5H), 7.19−7.16 (m, 1H),
7.13−7.10 (m, 3H), 7.02 (d, J = 3.7 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H),
6.79−6.77 (m, 2H), 6.71 (s, 1H), 6.66 (d, J = 2.9 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 138.1, 135.8, 135.3, 134.6, 129.9, 129.4, 128.9,
128.7, 128.6, 128.4, 127.9, 127.8, 126.1, 125.8, 125.2, 125.1, 124.6,
122.9, 116.2, 114.7, 111.8, 104.1, 90.2, 82.3; HRMS (ESI) [M]+ Calcd
for [C28H19NS] 401.1238, found 401.1238.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H 13C NMR and HRMS spectra for selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: averma@acbr.du.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Council of Scientific and
Industrial Research [01(2466)/11/EMR-II] for financial
support and USIC, University of Delhi for providing
instrumentation facilities. M.J. is thankful to UGC and CSIR,
New Delhi for a fellowship.
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dx.doi.org/10.1021/jo300782n | J. Org. Chem. XXXX, XXX, XXX−XXX