Synthesis of indole-2-, 3-, or 5-substituted propargylamines via gold(III)-catalyzed three component reaction of aldehyde, alkyne, and amine in aqueous medium

Article abstract of DOI:10.1016/j.tet.2013.06.098

A simple and efficient route to indole-2-, 3-, or 5-substituted propargylamines by three component-coupling of substituted indole carboxaldehydes, terminal alkyne, and secondary amine in the presence of AuBr₃ catalyst in aqueous medium, is described. This protocol provides a concise and effective route toward the synthesis of a variety of indole-2-, 3-, or 5-substituted propargylamines in excellent yields.

Full text of DOI:10.1016/j.tet.2013.06.098

Tetrahedron 69 (2013) 8025e8033
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of indole-2-, 3-, or 5-substituted propargylamines via
gold(III)-catalyzed three component reaction of aldehyde, alkyne,
and amine in aqueous medium
*
Venu Srinivas, Mamoru Koketsu
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2013
Received in revised form 22 June 2013
Accepted 27 June 2013
Available online 4 July 2013
A simple and efficient route to indole-2-, 3-, or 5-substituted propargylamines by three component-
coupling of substituted indole carboxaldehydes, terminal alkyne, and secondary amine in the presence
of AuBr3 catalyst in aqueous medium, is described. This protocol provides a concise and effective route
toward the synthesis of a variety of indole-2-, 3-, or 5-substituted propargylamines in excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Water
Gold-catalysis
Propargylamine
Three component reaction
1. Introduction
as gold salts, organic gold complexes, and other metal salts.5,6 After
a careful study of these reactions, it was found that the cationic gold
Propargylamines are considered as useful intermediates in the
organic synthesis and they are key elements present in many nat-
ural products.1 These compounds traditionally synthesized by the
reaction of lithium acetylides or Grignard reagents with imine
derivatives. However, it requires the usage of stoichiometric
amount of reagent and harsh reaction conditions. Moreover these
reagents must be carefully handled under inert conditions, which
make this method less important in the organic synthesis. An al-
ternative atom-economic approach to their synthesis to perform
this type of reaction by a catalytic coupling of alkyne, aldehyde, and
amine (A3 coupling) via CeH activation.2 The alkyne CeH bond can
be activated by employing various homogeneous metal catalysts,
such as silver salts, InBr3/InCl3, Ir-complexes, Hg2Cl2, zirconium,
and rhenium.3 However, many of these three-component coupling
reactions involve the use of expensive metal salts in excess
amounts. Thus, the development of improved synthetic methods
for the preparation of propargylamines remains an active research
area. Gold-catalyzed reactions have lately emerged as a very pow-
erful tool in organic synthesis.4 Recent progress in this area
(A3 coupling) has been reported using homogeneous catalysts, such
complexes displayed excellent catalytic activity than other metal
catalysts.7 Li and his co-workers first recognized the gold-catalyzed
coupling synthesis of propargylamines by employing an alkyne,
aldehyde, and amine as substrates in aqueous medium.2a Later,
Che’s research group was reported that gold-salen complex could
be employed as the catalyst for the synthesis of propargylamines
in diastereoselective manner.2b A wide variety of 4,6,7,8,8a,9-
hexahydropyrrolo[1,2-a][1,2,3]-triazolo[1,5-d]pyrazines were also
constructed by employing the gold-catalyzed three component A3
coupling strategy as the key step.2e
Water is a green solvent because it is inexpensive, safe, and
environmentally friendly.8 However, the development of synthetic
methodologies under aqueous conditions has significant limita-
tions associated either with the low solubilities of organic com-
pounds or with their hydrolysis. A key strategy to solve these
problems involves the use of solubilizing agents, or water-tolerant
reagents, in what is a research area of current interest.
As a part of our research and ongoing investigations on gold
catalyzed reactions, herein we describe the one pot synthesis of
indole-based propargylamines via gold(III)-catalyzed three com-
ponent coupling of corresponding substituted indole carbox-
aldehydes, alkyne, and secondary amine, in aqueous medium.
Indoles and their derivatives are important heteroaromatic com-
pounds that are found in nature as well as in several bioactive
* Corresponding author. Tel.: þ81 58 293 2619; fax: þ81 58 293 2794; e-mail
address: koketsu@gifu-u.ac.jp (M. Koketsu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.098

8026
V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
molecules.9 They are good precursors for the construction of
pharmaceutically important skeletons.10 To the best of our knowl-
edge, the synthesis of propargylamines having indole moiety was
not described so far. Hence, our attention devoted toward the re-
actions involving substituted indole-carboxaldehyde compounds
as the precursors. The starting materials 1e5 used for the three
component coupling study are depicted in Chart 1.
Under the similar conditions, by using AuBr3 (5 mol %) as the
catalyst enhanced the desired product 6a yield up to 95% (entry 5).
After obtaining good yield from the above reaction, we studied the
solvent role in this reaction. As we discussed above, the reaction
was performed in water as the solvent. Interestingly, the reaction
was completed smoothly in the presence of catalyst AuBr3
(5 mol %) and product 6a was formed in excellent yield (99%, entry
6). It is noteworthy that, decreasing the catalyst loading to
1.0 mol % also afforded the product in excellent yield (95%, entry
7). The reaction was completed in short period (4 h, entry 6) at
60 ꢀC. This is the advantage of this reaction over the gold-
catalyzed three component reactions described so far.11 Hence,
we chose this condition as optimal for the construction of a variety
of indole substituted propargylamines (see Table 2). To compare
the solvent effect on this reaction, various organic solvents were
used as summarized in Table 1 (entries 8e11). Under these con-
ditions by using the solvents THF, DCM, DMF, toluene did not in-
crease the yield. Moreover the reaction time is also longer
(8e18 h) than compared with reaction in water as solvent. Hence,
all the reactions were performed in water as the solvent. The in-
corporation of other metal catalysts like FeCl3 or CuI did not
produce the product (entries 12e13). On the basis of these results,
we have used the AuBr3/water/60 ꢀC was the optimal conditions
for the formation of propargylamine 6a. Hence, we have continued
our journey toward the preparation of several corresponding
propargylamines by using different substituted indole carbox-
aldehydes, alkynes, and secondary amines.
Chart 1. List of starting materials.
We then examined the substrate scope (see Table 2) under the
optimized conditions by using various substrates. The desired
propargylamines 6aec were formed in excellent isolated yields
(85e94%, entries 1e3), when we employed the substrates 1a,
phenylacetylene 4a, and the amines 5aec as the coupling partners.
All these reactions were conducted in water and under mild re-
action conditions. Encouraged by these results, the methodology
was also extended to the terminal alkyne 4b. More interestingly, by
employing the alkyne 4b, the reaction was completed in short time
(3 h, entry 4) compared with the reactions involved alkyne 4a as
the starting material. The yields of the products 6def (entries 4e6)
were excellent (94e98%). Furthermore, this protocol also assessed
the 6-chloro substituted aldehyde 1b (3,6-dichloro-1H-indole-2-
carboxaldehyde) as one of the coupling partner. Gratifyingly, we
found that the reactions by using aldehyde 1b, alkyne 4a, and
amines 5aec gave the corresponding coupling products 6gei in
good yields at 60 ꢀC (88e92%, Table 2, entries 7e9). Analogously,
the employment of alkyne 4b in place of alkyne 4a, afforded the
products 6jel in excellent yields (94e99%, Table 2, entries 10e12).
Even though the reagents are insoluble in water, the reaction pro-
ceeded smoothly over 3e4 h at 60 ꢀC and the coupling products
were isolated in good to excellent yields (Table 2). All these prod-
ucts were well characterized by 1H and 13C NMR spectra. The for-
mation of the products was also supported by high resolution mass
spectrometric (HR-MS) data.
2. Results and discussion
In an initial investigation, the coupling reaction of 3-chloro-in-
dole-2-carboxaldehyde (1a), phenylacetylene (4a), and piperidine
(5a) in the presence of AuCl as a catalyst and 1,2-dichloroethane as
the solvent successfully resulted the propargylamine 6a (Scheme 1).
However, the yield of the product was low (20%, Table 1, entry 2). The
use of PPh3AuCl as the catalyst also gave the compound in low
yield (10%, entry 3). Hence we changed the catalyst to gold complex
AuCl3. Under these conditions the product was formed in good yield
(80%, entry 4).
Scheme 1. Approach toward indole-2-substituted propargylamine 6a via gold-
catalyzed coupling of 1a, 4a, and 5a.
Table 1
Optimization studies on reaction shown in Scheme 1
Entry
Catalyst (mol %)
Solvent
Temp (ꢀC)
Time (h)
Yield (%)a
In addition to chlorine substituted aldehyde 1b, the reactivity of
bromine substituted aldehyde 1c and indole-2-carboxaldehyde
(1d) (Chart 1) have also been investigated in this reaction (Table
2, entries 13e20). As seen by inspection of the data displayed in
Table 2, a variety of terminal alkynes (4), and secondary amines (5)
participate in these reactions that produce the corresponding
propargylamines (6mep) in high yields (87e94%, Table 2, entries
13e16). The incorporation of the aldehyde 1d in this reaction did
result the products 6qet, but in moderate yields (55e64%, Table 2,
entries 17e20). It might be possible that, no substitution at the
second position of the aldehyde 1d making starting material more
reactive to form side products. Unfortunately the side products
formed in this reaction were inseparable by column chromatogra-
phy, due to their closeness in TLC.
1
2
3
4
5
6
7
8
d
DCE
DCE
DCE
DCE
DCE
H2O
H2O
THF
DCM
DMF
Toluene
H2O
H2O
80
60
60
60
60
60
60
70
40
100
100
100
100
18
18
12
6
7
8
NRb
20
10
80
95
99
95
89
80
AuCl (5)
PPh3AuCl (5)
AuCl3 (5)
AuBr3 (5)
AuBr3 (5)
AuBr3 (1)
AuBr3 (5)
AuBr3 (5)
AuBr3 (5)
AuBr3 (5)
FeCl3 (10)
CuI (10)
4
8
9
12
18
14
18
18
10
11
12
13
50
60
NRb
NRb
a
1H NMR yield based on the aldehyde 1a.
NR: no reaction.
b

V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
8027
Table 2
Substrate scope of the three component reaction shown below: formation of products 6e8a
Entry
Aldehyde
Alkyne
Amine
Product
Yieldb
1
85
2
92
3
94c
4
98
5
94
(continued on next page)

8028
V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
Table 2 (continued )
Entry
Aldehyde
Alkyne
Amine
Product
Yieldb
6
98
7
92
8
90d
9
88
10
99
11
94
12
96

V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
8029
Table 2 (continued )
Entry
Aldehyde
Alkyne
Amine
Product
Yieldb
13
90d
14
94
15
90e
16
87
17
59
18
60
19
55
(continued on next page)

8030
V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
Table 2 (continued )
Entry
Aldehyde
Alkyne
Amine
Product
Yieldb
20
21
22
64
99
96
23
99
a
Reaction conditions: aldehyde (1 mol equiv), alkyne (2 mol equiv), amine (2 mol equiv), AuBr3 (1 mol% equiv), H2O (2 mL) at 60 ꢀC for 3e4 h.
Isolated yield.
Reaction time 3 h.
Reaction time 6 h.
Reaction time 8 h.
b
c
d
e
Next, indole-3-carboxaldehyde (2) and indole-5-carboxaldehyde
indole-substituted propargylamines (Scheme 2). Initial reaction of
aldehyde 1a and secondary amine 5a affords the imine ion I for-
mation. Then gold-catalyst activates the CeH bond of phenyl-
acetylene 4a to form a goldacetylide complex II. Subsequent
nucleophilic attack of goldacetylide complex II on the imine ion
intermediate I results the formation of the propargylamine 6a
(3) were employed as substrates in the three-component coupling
reaction as depicted in Table 2 (entries 21e23). As expected, under
the optimized conditions, the coupling reaction of compound 2 with
acetylene 4b and piperidine (5a) furnished the corresponding
propargylamine 7 in excellent yield (99%, entry 21, Table 2). In the
similar manner, the reaction of indole-5-carboxaldehyde (3) with
acetylene 4b and piperidine (5a) also accomplished the desired
propargylamine 8a (96%, entry 22, Table 2). Finally, the reaction with
pyrrolidine (5b) also produced the corresponding coupling product
8b in almost quantitative yield (99%, entry 23, Table 2).
From these results it can be concluded that the three component
coupling reaction of indole-substituted-carboxaldehydes, terminal
alkyne, and secondary amine in presence of AuBr3 catalyst in
aqueous media at 60 ꢀC (oil bath temperature) shows high
reactivity, versatility, tolerating the functional groups. It is note-
worthy that the reaction time for the formation of the indole-
substituted propargylamines faster (w3e4 h) than the earlier
reports (>18 h) and carried out under mild reaction conditions
(at temperature 60 ꢀC).
On the basis of earlier reports on gold-catalyzed CeH activation
Scheme 2. Proposed reaction mechanism for the formation of indole-based prop-
argylamine 6a via gold catalyzed three component coupling reaction.
reactions,2a we propose a tentative mechanism for the formation of

V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
8031
along with the water as byproduct. The formation of the remaining
products can also be explained by this mechanism.
134.3; HRMS (EI) calcd for C21H19ClN2 [M]þ 334.1237, found
334.1237.
3. Conclusion
4.2.3. 1-(3-Chloro-1H-indol-2-yl)-3-phenyl-N,N-dipropylprop-2-yn-
1-amine (6c). Yield 0.095 g (94%); Rf¼0.67 (EtOAc/hexane 1:19);
gummy liquid; [Found: C, 75.69; H, 6.95; N, 7.64. C23H25ClN2 re-
quires C, 75.70; H, 6.91; N, 7.68%]; IR (CHCl3, cmꢁ1) 3434, 2960,
In conclusion, we have presented an efficient method for the
synthesis of a variety of indole-2-, 3-, or 5-substituted propargyl-
amines by using AuBr3 as the catalyst in water medium via the CeH
activation process. The reactants employed in these reactions are
inexpensive indole-based aldehydes, terminal alkyne, and sec-
ondary amines. By using this strategy one can generate a library of
compounds, which may be utilized further in cyclization reactions.
Overall the present work shows the obvious potential of mecha-
nistic insights and isolation of biologically important molecules by
one pot synthesis, that is, difficult to achieve by other methods
selectively. The utility of these products for the synthesis of het-
erocycles is currently underway.
2932, 2231, 1618, 1597; 1H NMR (400 MHz, CDCl3)
d 0.89 (t,
J¼7.4 Hz, 6H), 1.49e1.58 (m, 4H), 2.51e2.63 (m, 4H), 5.26 (s, 1H),
7.15e7.24 (m, 2H), 7.32e7.36 (m, 4H), 7.49e7.51 (m, 2H), 7.60e7.63
(m, 1H), 8.56 (br, 1H); 13C NMR (100 MHz, CDCl3)
d 12.0, 21.0, 51.1,
53.3, 84.3, 87.0, 104.5, 111.4, 118.2, 120.4, 122.8, 123.0, 126.8, 128.5,
128.6, 131.1, 132.0, 133.6; HRMS (EI) calcd for C23H25ClN2 [M]þ
364.1706, found 364.1721.
4.2.4. 3-Chloro-2-(1-(piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-
yl)-1H-indole (6d). Yield 0.094 g (98%); Rf¼0.44 (EtOAc/hexane
1:9); mp 120e122 ꢀC; [Found: C, 66.49; H, 7.05; N, 8.19.
4. Experimental section
4.1. General
C19H25ClN2Si requires C, 66.15; H, 7.30; N, 8.12%]; IR (CHCl3, cmꢁ1
)
3408, 2934, 2172, 1594, 1454; 1H NMR (400 MHz, CDCl3)
d 0.19 (s,
9H), 1.42e1.43 (m, 2H), 1.59e1.61 (m, 4H), 2.46e2.49 (m, 2H), 2.61
(br, 2H), 4.70 (s, 1H), 7.17e7.25 (m, 2H), 7.35 (d, J¼8.2 Hz, 1H), 7.59
General remarks are given in Supplementary data. The starting
(d, J¼8.3 Hz,1H), 8.45 (br,1H); 13C NMR (100 MHz, CDCl3)
d 0.1, 24.4,
precursors 1aed are prepared by following reported procedures.10b,12
26.1, 51.6, 54.5, 92.0, 100.7, 105.3, 111.4, 118.4, 120.5, 123.3, 126.2,
129.9, 134.1; HRMS (FAB) calcd for C19H25ClN2Si [M]þ 344.1476,
found 344.1487.
4.2. Synthesis of indole-based propargylamines 6e8: General
procedure
4.2.5. 3-Chloro-2-(1-(pyrrolidin-1-yl)-3-(trimethylsilyl)prop-2-yn-
1-yl)-1H-indole (6e). Yield 0.087 g (94%); Rf¼0.33 (EtOAc/hexane
1:19); mp 130e133 ꢀC; [Found: C, 65.63; H, 7.11; N, 8.52.
A mixture of aldehyde 1/2/3 (0.28 mmol) and terminal alkyne 4
(0.56 mmol), secondary amine
5 (0.56 mmol), and AuBr3
(0.0028 mmol) in water (2 mL) were heated at 60 ꢀC for 3e4 h. The
progress of the reaction was monitored by TLC or 1H NMR spectrum
of the reaction mixture. When there was no starting material
(aldehyde) present, the mixture was diluted with ethyl acetate
(10 mL) and excess of water (5 mL) and extracted. The aqueous
layer was washed again with ethyl acetate (10 mL). The combined
organic layer was washed with water (10 mL), saturated brine so-
lution (10 mL), and dried over anhydrous Na2SO4. Subsequent
evaporation of organic solvent by using rotary evaporator afforded
brown colored gummy material. Analytically pure compound 6 was
isolated by using silica-gel flash column chromatography [ethyl
acetate/hexanes mixture]. Since the products 7e8 are sensitive to
silica gel, they are purified by using alumina (neutral) column
chromatography.
C18H23ClN2Si requires C, 65.33; H, 7.01; N, 8.47%]; IR (CHCl3, cmꢁ1
)
3408, 2959, 2923, 2853, 2174, 1594; 1H NMR (400 MHz, CDCl3)
0.18 (s, 9H), 1.78e1.81 (m, 4H), 2.58e2.59 (m, 2H), 2.74e2.75 (m,
d
2H), 4.73 (s, 1H), 7.16e7.19 (m, 1H), 7.21e7.25 (m, 1H), 7.34 (d,
J¼8.2 Hz, 1H), 7.59 (d, J¼8.7 Hz, 1H), 8.49 (br, 1H); 13C NMR
(100 MHz, CDCl3)
d 0.07, 23.5, 51.6, 51.9, 90.6, 101.6, 104.4, 111.5,
118.4, 120.5, 123.4, 125.9, 130.8, 134.3; HRMS (EI) calcd for
C18H23ClN2Si [M]þ 330.1319, found 330.1311.
4.2.6. 1-(3-Chloro-1H-indol-2-yl)-N,N-dipropyl-3-(trimethylsilyl)
prop-2-yn-1-amine (6f). Yield 0.098 g (98%); Rf¼0.70 (EtOAc/hex-
ane 1:20); gummy liquid; [Found: C, 66.74; H, 7.88; N, 7.43.
C20H29ClN2Si requires C, 66.54; H, 8.10; N, 7.76%]; IR (CHCl3, cmꢁ1
)
3443, 2960, 2932, 1621, 1584; 1H NMR (400 MHz, CDCl3)
d 0.22 (s,
9H), 0.86 (t, Jw7.4 Hz, 6H), 1.44 (sextet, Jw7.4, 5.1 Hz, 4H), 2.44 (dt,
Jw7.3, 5.1 Hz, 2H), 2.51 (dt, Jw7.3, 5.1 Hz, 2H), 5.03 (s, 1H), 7.15e7.24
(m, 2H), 7.34 (d, J¼8.3 Hz, 1H), 7.60 (d, J¼7.8 Hz, 1H), 8.44 (br, 1H);
4.2.1. 3-Chloro-2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)-1H-
indole (6a). Yield: 0.083 g (85%); Rf¼0.33 (EtOAc/hexane 1:19); mp
150e152 ꢀC; [Found: C, 75.54; H, 5.99; N, 8.28. C22H21ClN2 requires
C, 75.74; H, 6.07; N, 8.03%]; IR (CHCl3, cmꢁ1) 3420, 2933, 2853,1641,
13C NMR (100 MHz, CDCl3)
d 0.2, 12.0, 20.9, 51.1, 53.1, 91.9, 100.4,
104.5,111.3,118.3,120.4,123.0,126.7,130.8,133.5; HRMS (FAB) calcd
1597; 1H NMR (400 MHz, CDCl3)
d 1.40e1.50 (m, 2H), 1.58e1.68 (m,
for C20H29ClN2Si [M]þ 360.1789, found 360.1815.
4H), 2.53e2.62 (m, 2H), 2.73 (br, 2H), 4.92 (s,1H), 7.15e7.26 (m, 2H),
7.29e7.37 (m, 4H), 7.45e7.48 (m, 2H), 7.61 (d, J¼8.2 Hz, 1H), 8.68
4.2.7. 3,6-Dichloro-2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)-
1H-indole (6g). Yield 0.098 g (92%); Rf¼0.31 (EtOAc/hexane 1:4);
mp 142e144 ꢀC; [Found: C, 68.86; H, 5.48; N, 7.37. C22H20Cl2N2
requires C, 68.94; H, 5.26; N, 7.31%]; IR (CHCl3, cmꢁ1) 3418, 2935,
(br, 1H); 13C NMR (100 MHz, CDCl3)
d 24.3, 26.0, 51.8, 54.4, 84.7,
87.0, 105.2, 111.4, 118.3, 120.4, 122.6, 123.3, 126.0, 128.4, 128.6, 130.0,
131.9, 134.1; HRMS (EI) calcd for C21H21ClN2 [M]þ 348.1393, found
348.1379.
2857, 2340, 1635, 1594; 1H NMR (400 MHz, CDCl3)
d 1.46e1.47 (m,
2H), 1.60e1.65 (m, 4H), 2.54e2.57 (m, 2H), 2.71e2.72 (m, 2H), 4.89
(s, 1H), 7.14 (dd, J¼8.7 Hz, J¼1.8 Hz, 1H), 7.30e7.36 (m, 4H),
7.46e7.48 (m, 2H), 7.51 (d, J¼8.7 Hz, 1H), 8.60 (br, 1H); 13C NMR
4.2.2. 3-Chloro-2-(3-phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-yl)-1H-
indole (6b). Yield 0.086 g (92%); Rf¼0.31 (EtOAc/hexane 1:9); mp
144e146 ꢀC; [Found: C, 75.30; H, 5.45; N, 8.44. C21H19ClN2 requires
C, 75.33; H, 5.72; N, 8.37%]; IR (CHCl3, cmꢁ1) 3376, 2959, 2924,
(100 MHz, CDCl3)
d 24.3, 26.2, 51.8, 54.5, 84.2, 87.3, 104.6, 113.0,
113.8, 121.0, 122.5, 126.3, 127.9, 128.5, 128.7, 131.6, 131.9, 132.7;
2236, 1642, 1597; 1H NMR (400 MHz, CDCl3)
d 1.83 (br, 4H),
HRMS (EI) calcd for C22H20Cl2N2 [M]þ 382.1004, found 382.1034.
2.66e2.67 (m, 2H), 2.82e2.85 (m, 2H), 4.96 (s, 1H), 7.16e7.25 (m,
2H), 7.28e7.35 (m, 4H), 7.44e7.46 (m, 2H), 7.60e7.62 (m, 1H), 8.63
4.2.8. 3,6-Dichloro-2-(3-phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-yl)-
1H-indole (6h). Yield 0.093 g (90%); Rf¼0.35 (EtOAc/hexane 1:9);
mp 137e139 ꢀC; [Found: C, 68.32; H, 4.70; N, 7.55. C21H18Cl2N2
(br, 1H); 13C NMR (100 MHz, CDCl3)
d
23.6, 51.5, 52.0, 85.6, 85.7,
104.3,111.5, 118.4,120.5, 122.6, 123.4, 125.9, 128.4, 128.6, 131.1,131.9,

8032
V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
requires C, 68.30; H, 4.91; N, 7.59%]; IR (CHCl3, cmꢁ1) 3433, 2960,
2932, 2285, 1597, 1455; 1H NMR (400 MHz, CDCl3)
1.87 (br, 4H),
119.3, 121.3, 122.5, 124.8, 126.1, 128.7, 129.7, 131.0, 131.9, 134.3;
HRMS-EI (m/z) [M]þ calcd for C22H20BrClN2 [M]þ 426.0498, found
426.0482.
d
2.71e2.72 (m, 2H), 2.86e2.88 (m, 2H), 4.96 (s, 1H), 7.13e7.16 (m,
2H), 7.31e7.36 (m, 3H), 7.44e7.46 (m, 2H), 7.50 (d, J¼8.7 Hz, 1H),
8.94 (br, 1H); 13C NMR (100 MHz, CDCl3)
d
23.6, 51.5, 52.0, 85.0, 86.1,
4.2.14. 5-Bromo-3-chloro-2-(3-phenyl-1-(pyrrolidin-1-yl)prop-2-
yn-1-yl)-1H-indole (6n). Yield 0.108 g (94%); Rf¼0.36 (EtOAc/hex-
ane 1:4); mp 153e155 ꢀC; [Found: C, 60.74; H, 4.28; N, 6.51.
104.5, 111.5, 119.4, 121.4, 122.4, 124.5, 128.4, 128.7, 129.3, 131.7,
131.9, 134.6; HRMS (EI) calcd for C21H18Cl2N2 [M]þ 368.0847, found
368.0818.
C21H18BrClN2 requires C, 60.96; H, 4.39; N, 6.77%]; IR (CHCl3, cmꢁ1
)
3409, 2969, 2932, 2238, 1643, 1597; 1H NMR (400 MHz, CDCl3)
1.86 (br, 4H), 2.70e2.72 (m, 2H), 2.86e2.87 (m, 2H), 4.98 (s, 1H),
4.2.9. 1-(3,6-Dichloro-1H-indol-2-yl)-3-phenyl-N,N-dipropylprop-2-
yn-1-amine (6i). Yield 0.097 g (88%); Rf¼0.60 (EtOAc/hexane 1:10);
gummy liquid; [Found: C, 69.09; H, 6.29; N, 6.94. C23H24Cl2N2 re-
quires C, 69.17; H, 6.06; N, 7.01%]; IR (CHCl3, cmꢁ1) 3279, 2959,
d
7.22 (d, J¼8.7 Hz, 1H), 7.29e7.33 (m, 4H), 7.44e7.46 (m, 2H), 7.73 (d,
J¼1.8 Hz, 1H), 9.11 (br, 1H); 13C NMR (100 MHz, CDCl3)
d 23.6, 51.4,
52.0, 85.1, 86.0, 103.7, 113.1, 113.8, 121.1, 122.4, 126.3, 127.6, 128.5,
128.8, 131.9, 132.5, 132.9; HRMS (EI) calcd for C21H18BrClN2 [M]þ
412.0342, found 412.0314.
2926,1622,1599; 1H NMR (400 MHz, CDCl3)
d 0.88 (t, Jw7.6 Hz, 6H),
1.52 (sextet, Jw7.6, 5.0 Hz, 4H), 2.52 (dt, Jw7.6, 5.0 Hz, 2H), 2.61 (dt,
Jw7.6, 5.0 Hz, 2H), 5.22 (s,1H), 7.14 (dd, Jw8.5,1.6 Hz,1H), 7.33e7.35
(m, 4H), 7.49e7.52 (m, 3H), 8.56 (br,1H); 13C NMR (100 MHz, CDCl3)
4.2.15. 1-(5-Bromo-3-chloro-1H-indol-2-yl)-3-phenyl-N,N-dipropyl-
prop-2-yn-1-amine (6o). Yield 0.111 g (90%); Rf¼0.43 (EtOAc/hex-
ane 1:10); mp 190e192 ꢀC; [Found: C, 62.05; H, 5.30; N, 6.07.
d
12.0, 21.0, 51.1, 53.3, 84.8, 87.3, 104.6, 111.3, 119.2, 121.3, 122.7,
125.4, 128.5, 128.7, 128.9, 131.9, 132.0, 133.8; HRMS (EI) calcd for
C23H24Cl2N2 [M]þ 398.1317, found 398.1313.
C23H24BrClN2 requires C, 62.25; H, 5.45; N, 6.31%]; IR (CHCl3, cmꢁ1
)
3271, 2959, 2931, 2230, 1654, 1598; 1H NMR (400 MHz, CDCl3)
0.88 (t, Jw7.3 Hz, 6H), 1.53 (sextet, Jw7.3 Hz, 4H), 2.51 (dt,
4.2.10. 3,6-Dichloro-2-(1-(piperidin-1-yl)-3-(trimethylsilyl)prop-2-
yn-1-yl)-1H-indole (6j). Yield 0.104 g (99%); Rf¼0.45 (EtOAc/hexane
1:9); mp 152e154 ꢀC; [Found: C, 60.07; H, 6.15; N, 7.50.
d
Jw7.4 Hz, 2H), 2.62 (dt, Jw6.8 Hz, 2H), 5.24 (s, 1H), 7.22 (d, J¼8.7 Hz,
1H), 7.29e7.35 (m, 4H), 7.49e7.52 (m, 2H), 7.74 (s, 1H), 8.65 (br, 1H);
C19H24Cl2N2Si requires C, 60.15; H, 6.38; N, 7.38%]; IR (CHCl3, cmꢁ1
)
13C NMR (100 MHz, CDCl3)
d 12.0, 21.0, 51.1, 53.3, 83.7, 87.4, 103.9,
3278, 2934, 2286, 1652, 1623; 1H NMR (400 MHz, CDCl3)
d
0.21 (s,
112.9, 113.8 (2C), 120.9, 122.6, 126.0, 128.4, 128.5, 128.7, 132.0, 132.2;
9H), 1.43e1.45 (m, 2H), 1.57e1.63 (m, 4H), 2.47e2.49 (m, 2H),
2.62e2.64 (m, 2H), 4.69 (s, 1H), 7.14 (dd, Jw8.5, 1.6 Hz, 1H), 7.34 (d,
Jw1.6 Hz, 1H), 7.49 (d, Jw8.5 Hz, 1H), 8.53 (br, 1H); 13C NMR
HRMS (EI) calcd for C23H24BrClN2 [M]þ 442.0811, found 442.0790.
4.2.16. 1-(5-Bromo-3-chloro-1H-indol-2-yl)-N,N-dipropyl-3-(trime-
(100 MHz, CDCl3)
d
0.1, 24.3, 26.1, 51.6, 54.6, 92.3, 100.2, 105.4, 111.4,
thylsilyl)prop-2-yn-1-amine (6p). Yield 0.106
g
(87%); Rf¼0.52
119.3, 121.3, 124.8, 129.2, 130.6, 134.3; HRMS (FAB) calcd for
(EtOAc/hexane 1:19); gummy liquid; [Found: C, 54.67; H, 6.43; N,
6.15. C20H28BrClN2Si requires C, 54.61; H, 6.42; N, 6.37%]; IR (CHCl3,
cmꢁ1) 3436, 2959, 2933, 2163, 1593, 1464; 1H NMR (400 MHz,
C19H25Cl2N2Si [MþH]þ 379.1164, found 379.1139.
4.2.11. 3,6-Dichloro-2-(1-(pyrrolidin-1-yl)-3-(trimethylsilyl)prop-2-
yn-1-yl)-1H-indole (6k). Yield 0.096 g (94%); Rf¼0.52 (EtOAc/hex-
ane 1:9); mp 110e112 ꢀC; [Found: C, 59.02; H, 5.81; N, 7.41.
CDCl3) d 0.24 (s, 9H), 0.87 (t, Jw7.6 Hz, 6H), 1.46e1.51 (m, 4H),
2.41e2.52 (m, 4H), 5.02 (s, 1H), 7.22 (d, Jw9.2 Hz, 1H), 7.30 (dd,
Jw9.2 Hz, Jw2.4 Hz, 1H), 7.73 (d, Jw2.4 Hz, 1H), 8.51 (br, 1H); 13C
C18H22Cl2N2Si requires C, 59.17; H, 6.07; N, 7.67%]; IR (CHCl3, cmꢁ1
)
NMR (100 MHz, CDCl3) d 0.2, 12.0, 21.0, 51.2, 53.2, 92.4, 99.8, 103.8,
3434, 2948, 2931, 2147,1589, 1454; 1H NMR (400 MHz, CDCl3)
d
0.19
112.8, 113.7, 120.8, 125.9, 128.4, 132.0, 132.2; HRMS (FAB) calcd for
(s, 9H), 1.78e1.82 (m, 4H), 2.56e2.59 (m, 2H), 2.72e2.75 (m, 2H),
4.70 (s, 1H), 7.13 (dd, J¼8.7 Hz, J¼1.8 Hz 1H), 7.33 (d, J¼1.8 Hz, 1H),
7.48 (d, J¼8.7 Hz, 1H), 8.52 (br, 1H); 13C NMR (100 MHz, CDCl3)
C20H29BrClN2Si [MþH]þ 439.0972, found 439.0993.
4.2.17. 1-(1H-Indol-2-yl)-3-phenyl-N,N-dipropylprop-2-yn-1-amine
(6q). Yield 0.054 g (59%); Rf¼0.60 (EtOAc/hexane 1:19); gummy
liquid; [Found: C, 83.43; H, 7.72; N, 8.26. C23H26N2 requires C, 83.59;
H, 7.93; N, 8.48%]; IR (CHCl3, cmꢁ1) 3456, 2960, 2931, 2226, 1598,
d
0.04, 23.5, 51.6, 51.9, 91.0, 101.1, 104.5, 111.5, 119.4, 121.3, 124.6,
129.3, 131.6, 134.5; HRMS (FAB) calcd for C18H23Cl2N2Si [MþH]þ
365.1008, found 365.0991.
1456; 1H NMR (400 MHz, CDCl3)
d 0.90 (t, Jw7.6 Hz, 6H), 1.47e1.57
4.2.12. 1-(3,6-Dichloro-1H-indol-2-yl)-N,N-dipropyl-3-(trime-
(m, 4H), 2.51e2.55 (m, 4H), 5.16 (s, 1H), 6.69 (s, 1H), 7.09 (t,
Jw7.1 Hz, 1H), 7.16 (t, Jw7.1 Hz, 1H), 7.33e7.36 (m, 4H), 7.53e7.59
thylsilyl)prop-2-yn-1-amine (6l). Yield 0.106
g
(96%); Rf¼0.60
(EtOAc/hexane 1:19); mp 172e174 ꢀC; [Found: C, 60.60; H, 7.17; N,
6.87. C20H28Cl2N2Si requires C, 60.75; H, 7.14; N, 7.08%]; IR (CHCl3,
cmꢁ1) 3275, 2958, 2925, 2295, 1652, 1563; 1H NMR (400 MHz,
(m, 3H), 8.48 (br, 1H); 13C NMR (100 MHz, CDCl3)
d 12.1, 21.5, 52.9,
53.2, 84.6, 86.3, 101.9, 110.9, 119.7, 120.5, 121.8, 123.2, 128.4, 128.5,
128.6, 132.1, 136.1, 137.9; HRMS (EI) calcd for C23H26N2 [M]þ
330.2096, found 330.2078.
CDCl3)
d 0.24 (s, 9H), 0.87 (t, Jw7.6 Hz, 6H), 1.48 (sextet, Jw7.6 Hz,
4H), 2.45 (dt, Jw6.0 Hz, 2H), 2.54 (dt, Jw6.0 Hz, 2H), 5.01 (s,1H), 7.14
(dd, J¼8.7, 1.8 Hz, 1H), 7.36 (d, J¼1.8 Hz, 1H), 7.50 (d, J¼8.7 Hz, 1H),
4.2.18. 2-(1-(Piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-1H-
indole (6r). Yield 0.052 g (60%); Rf¼0.46 (EtOAc/hexane 1:9); mp
108e110 ꢀC; [Found: C, 73.68; H, 8.45; N, 9.03. C19H26N2Si requires
C, 73.49; H, 8.44; N, 9.02%]; IR (CHCl3, cmꢁ1) 3438, 2960, 2933,
8.53 (br, 1H); 13C NMR (100 MHz, CDCl3)
d 0.1, 12.0, 20.9, 51.2, 53.1,
92.4, 99.8, 104.6, 111.3, 119.2, 121.2, 125.4, 128.9, 131.4, 133.8; HRMS
(EI) calcd for C20H28Cl2N2Si [M]þ 394.1399, found 394.1373.
2164, 1623, 1456; 1H NMR (400 MHz, CDCl3)
d 0.25 (s, 9H),
4.2.13. 5-Bromo-3-chloro-2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-
1-yl)-1H-indole (6m). Yield 0.107 g (90%); Rf¼0.29 (EtOAc/hexane
1:4); mp 175e177 ꢀC; [Found: C, 61.45; H, 4.84; N, 6.60.
1.45e1.46 (m, 2H), 1.56e1.62 (m, 4H), 2.49 (br, 4H), 4.76 (s, 1H), 6.57
(s,1H), 7.08 (t, Jw7.6 Hz,1H), 7.15 (t, Jw7.6 Hz,1H), 7.34 (d, Jw7.6 Hz,
1H), 7.57 (d, Jw7.6 Hz, 1H), 8.54 (br, 1H); 13C NMR (100 MHz, CDCl3)
C22H20BrClN2 requires C, 61.77; H, 4.71; N, 6.55%]; IR (CHCl3, cmꢁ1
)
d 0.3, 24.4, 26.3, 50.7, 57.3, 91.9,100.0,102.1, 110.9,119.7, 120.6, 121.9,
3418, 2935, 2854, 2232, 1596; 1H NMR (400 MHz, CDCl3)
1.45e1.47 (m, 2H), 1.59e1.64 (m, 4H), 2.54e2.57 (m, 2H),
128.4, 136.2, 136.4; HRMS (EI) calcd for C19H26N2Si [M]þ 310.1865,
found 310.1860.
d
2.70e2.71 (m, 2H), 4.91 (s, 1H), 7.22 (d, J¼8.7 Hz, 1H), 7.30e7.33 (m,
4H), 7.46e7.49 (m, 2H), 7.74 (d, J¼1.8 Hz,1H), 8.64 (br, 1H); 13C NMR
4.2.19. 2-(1-(Pyrrolidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-1H-
indole (6s). Yield 0.045 g (55%); Rf¼0.58 (EtOAc/hexane 1:19);
(100 MHz, CDCl3)
d
24.3, 26.1, 51.8, 54.5, 84.3, 87.3, 105.4, 111.4,

V. Srinivas, M. Koketsu / Tetrahedron 69 (2013) 8025e8033
8033
gummy liquid; [Found: C, 73.10; H, 7.92; N, 9.50. C18H24N2Si re-
quires C, 72.92; H, 8.16; N, 9.45%]; IR (CHCl3, cmꢁ1) 3273, 2959,
2925, 2340, 1655, 1598; 1H NMR (400 MHz, CDCl3)
0.24 (s, 9H),
NMR (100 MHz, CDCl3)
d
0.4, 23.6, 50.5, 60.0, 90.7, 103.0, 104.3,
110.9, 120.5, 122.9, 124.6, 127.8, 131.0, 135.5; MS (EI) m/z 296 [M]þ
d
1.80 (br, 4H), 2.61e2.65 (m, 4H), 4.92 (s, 1H), 6.54 (d, J¼0.9 Hz, 1H),
Acknowledgements
7.08 (t, J¼7.6 Hz, 1H), 7.16 (t, J¼7.8 Hz, 1H), 7.33 (d, J¼8.2 Hz, 1H),
7.58 (d, J¼7.8 Hz, 1H), 8.54 (br, 1H); 13C NMR (100 MHz, CDCl3)
d 0.3,
This work was supported by The Greater Nagoya Invitation
Program for International Research Scientists in Environmental
Science Field to which we are grateful. We also thank Mr. Masayuki
Ninomiya for assistance in recording HR-MS spectra.
23.7, 50.0, 53.3, 91.3, 100.7, 101.3, 110.9, 119.8, 120.7, 121.9, 128.3,
136.2, 136.9; HRMS (EI) calcd for C18H24N2Si [M]þ 296.1709, found
296.1687.
4.2.20. 1-(1H-Indol-2-yl)-N,N-dipropyl-3-(trimethylsilyl)prop-2-yn-
1-amine (6t). Yield 0.058 g (64%); Rf¼0.66 (EtOAc/hexane 1:20);
gummy liquid; [Found: C, 73.76; H, 9.17; N, 8.37. C20H30N2Si re-
quires C, 73.56; H, 9.26; N, 8.58%]; IR (CHCl3, cmꢁ1) 3460, 2960,
Supplementary data
General remarks and copies of 1H/13C NMR spectra. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.098.
2933, 2167, 1618, 1456; 1H NMR (400 MHz, CDCl3)
d 0.29 (s, 9H),
0.93 (t, Jw7.3 Hz, 6H), 1.49e1.58 (m, 4H), 2.47e2.50 (m, 4H), 4.98 (s,
1H), 6.65 (s, 1H), 7.15 (t, Jw7.8 Hz, 1H), 7.21 (t, Jw7.6 Hz, 1H), 7.38 (d,
Jw7.8 Hz, 1H), 7.63 (d, Jw7.6 Hz, 1H), 8.46 (br, 1H); 13C NMR
References and notes
(100 MHz, CDCl3) d 0.3, 12.0, 21.4, 53.0 (2C), 90.9, 100.7, 101.8, 110.8,
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Chem. 2013, 78, 1463.
119.7, 120.5, 121.7, 128.6, 136.0, 137.7; HRMS (EI) calcd for
C20H30N2Si [M]þ 326.2178, found 326.2176.
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4.2.21. 3-(1-(Piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-1H-
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alumina (neutral) column chromatography. Yield 0.211 g (99%, us-
ing 0.69 mmol of compound 2); Rf¼0.33 (EtOAc/hexane 1:2);
gummy liquid; [Found: C, 73.27; H, 8.34; N, 8.78. C19H26N2Si re-
quires C, 73.49; H, 8.44; N, 9.02%]; IR (CHCl3, cmꢁ1) 3409, 2933,
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2857, 2163, 1599, 1449; 1H NMR (400 MHz, CDCl3)
d 0.23 (s, 9H),
1.39e1.42 (m, 2H), 1.51e1.60 (m, 4H), 2.47e2.58 (m, 4H), 4.87 (s,
1H), 7.10 (td, Jw7.7, 0.9 Hz, 1H), 7.18 (t, Jw7.2, 1.2 Hz, 1H), 7.25e7.26
(m, 1H), 7.34 (d, J¼8.2 Hz, 1H), 7.94 (d, J¼8.2 Hz, 1H), 8.08 (br, 1H);
13C NMR (100 MHz, CDCl3)
d 0.4, 24.8, 26.4, 50.4, 56.0, 89.9,
103.1, 111.1, 114.3, 119.5, 120.9, 122.2, 124.2, 127.0, 136.8; MS (EI) m/z
310 [M]þ.
€
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4.2.22. 5-(1-(Piperidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-1H-
indole (8a). Reaction time: 3 h. This product was purified by using
alumina (neutral) column chromatography. Yield 0.101 g (96%, us-
ing 0.34 mmol of compound 3); Rf¼0.33 (EtOAc/hexane 1:4);
gummy liquid; [Found: C, 73.18; H, 8.11; N, 9.13. C19H26N2Si requires
C, 73.49; H, 8.44; N, 9.02%]; IR (CHCl3, cmꢁ1) 3416, 2934, 2855,
2163, 1582, 1249; 1H NMR (400 MHz, CDCl3)
d 0.26 (s, 9H),
1.35e1.45 (m, 2H), 1.51e1.58 (m, 4H), 2.41e2.52 (m, 4H), 4.66
(s, 1H), 6.54 (br, 1H), 7.19 (br, 1H), 7.33 (d, J¼8.7 Hz, 1H), 7.37 (d,
J¼8.2 Hz, 1H), 7.80 (s, 1H), 8.21 (br, 1H); 13C NMR (100 MHz, CDCl3)
7. (a) Skouta, R.; Li, C. J. Tetrahedron 2008, 64, 4917; (b) Li, C. J. Acc. Chem. Res. 2010,
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d
0.5, 24.7, 26.3, 50.7, 63.0, 91.7, 102.9, 103.5, 110.6, 120.9, 123.2,
124.5, 127.6, 129.8, 135.4; MS (EI) m/z 310 [M]þ.
9. (a) Joule, J. A. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme: Stuttgart,
2000; Vol. 10, pp 361e652; (b) de Sa Alves, F. R.; Barreiroand, E. J.; Fraga, C. A.
M. Mini-Rev. Med. Chem. 2009, 9, 782; (c) Halland, N.; Nazare, M.; Alonso, J.;
R’kyek, O.; Lindenschmidt, A. Chem. Commun. 2011, 1042; (d) Hayashi, K.;
Yoshida, K.; Yanagisawa, A. J. Org. Chem. 2013, 78, 3464.
10. (a) Qiu, Y.; Kong, W.; Fu, C.; Ma, S. Org. Lett. 2012, 14, 6198; (b) Phani Pavan, M.;
Kumara Swamy, K. C. Synlett 2011, 1288; (c) Rama Suresh, R.; Kumara Swamy,
K. C. J. Org. Chem. 2012, 77, 6959.
11. In earlier reports it was observed that long reaction time required for the for-
mation of desired products.
12. For the preparation of aldehydes (1aed) see: (a) Majo, V. J.; Perumal, P. T. J. Org.
Chem. 1996, 61, 6523; (b) Zheng, C.; Lu, Y.; Zhang, J.; Chen, X.; Chai, Z.; Ma, W.;
Zhao, G. Chem.dEur. J. 2010, 16, 5853.
4.2.23. 5-(1-(Pyrrolidin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-1H-
indole (8b). Reaction time: 3 h. This product was purified by using
alumina (neutral) column chromatography. Yield 0.099 g (99%,
using 0.34 mmol of compound 3); Rf¼0.38 (EtOAc/hexane 1:4);
gummy liquid; [Found: C, 72.99; H, 7.97; N, 9.24. C18H24N2Si re-
quires C, 72.92; H, 8.16; N, 9.45%]; IR (CHCl3, cmꢁ1) 3410, 2960,
2165, 1625, 1421; 1H NMR (400 MHz, CDCl3)
d 0.21 (s, 9H), 1.74e1.77
(m, 4H), 2.58e2.64 (m, 4H), 4.70 (s, 1H), 6.53 (br, 1H), 7.18
(t, Jw2.8 Hz, 1H), 7.31e7.36 (m, 2H), 7.76 (s, 1H), 8.26 (br, 1H); 13C