Sequential alkylation/cyclization/isomerization of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters: A new route to 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles

Article abstract of DOI:10.1016/j.tet.2013.08.048

The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters with ethyl iodoacetate or α-bromoacetophenone in the presence of K ₂CO₃ in DMSO provides a new simple access to 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles.

Full text of DOI:10.1016/j.tet.2013.08.048

Tetrahedron 69 (2013) 9494e9498
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequential alkylation/cyclization/isomerization of ethyl 3-(o-
trifluoroacetamidoaryl)-1-propargylic esters: a new route to 2-acyl-
and 2-ethoxycarbonyl-3-alkenyl indoles
Ilaria Ambrogio a, Antonio Arcadi b, Sandro Cacchi a, Giancarlo Fabrizi a,
,
b
Antonella Goggiamani a , Fabio Marinelli
*
a
ꢀ
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
Dipartimento di Scienze Fisiche e Chimiche, Universita di L’Aquila, Via Vetoio, 67010 L’Aquila, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 2 August 2013
Accepted 19 August 2013
Available online 30 August 2013
The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters with ethyl iodoacetate or
bromoacetophenone in the presence of K2CO3 in DMSO provides a new simple access to 2-acyl- and 2-
ethoxycarbonyl-3-alkenyl indoles.
a-
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Propargylic carbonates
Indoles
Sequential reactions
Cyclization
Intramolecular SN20
1. Introduction
During our continuing studies on this research area,5 we had
occasion to examine the utilization of the propargylic carbonate 3a
Propargylic compounds are versatile building blocks in organic
synthesis.1 Cyclization reactions of functionalized propargylic
compounds with a variety of nucleophiles have been reported to
produce both carbocyclic and heterocyclic compounds.2 In partic-
ular, many palladium-catalyzed cyclizations of propargylic de-
rivatives bearing a proximate nucleophilic center have been
developed.3 In this context, we have shown that ethyl 3-(o-tri-
fluoroacetamidoaryl)-1-propargylic carbonates 1, bearing a nitro-
gen nucleophile close to the propargylic moiety, are useful
synthetic intermediates for the preparation of a variety of 2-(ami-
nomethyl)indoles 2 through a palladium-catalyzed cyclization/
amination process (Scheme 1).4
as possible precursor of quinoline derivatives through a related
palladium-catalyzed cyclization/amination reaction (Scheme 2a).
However, when 3a was treated with N-ethylpiperazine under the
conditions shown in Scheme 2, 2-ethoxycarbonyl-3-vinylindole 5a
was isolated in 85% yield and none of the quinoline product 4a was
observed. Although we did not obtain the desired product, the
formation of the indole derivative appeared to us of interest and
Scheme 1. Palladium-catalyzed cyclization-amination of 3-(o-trifluoroacetamidoaryl)-
1-propargylic carbonates.
* Corresponding author. Tel.: þ39 06 4991 2795; fax: þ39 06 4991 2780; e-mail
Scheme 2. Reaction of 3a with N-ethylpiperazine.
address: antonella.goggiamani@uniroma1.it (A. Goggiamani).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.048

I. Ambrogio et al. / Tetrahedron 69 (2013) 9494e9498
9495
decided to investigate this reaction. The development of a synthetic
protocol based on this transformation would add to known pro-
cedures based on the cyclization of o-alkynylanilines and o-alky-
nylanilides6 a new simple approach for the assembly of the
functionalized indole nucleus.
A brief investigation of the role of solvents revealed that traces
or poor yields could be obtained in THF and MeCN. Thus, the fol-
lowing conditions were chosen when the reaction was extended to
other propargylic carbonates: 0.5 mmol of 3, 1.5 mmol of K2CO3 in
3 mL of DMSO at 40 ꢀC. As shown in Table 1, a variety of 2-acyl- and
2-ethoxycarbonyl-3-alkenyl indoles 5 were isolated in moderate to
high yields from primary propargylic carbonates. A moderate yield
was obtained with the secondary propargylic carbonate 3c (Table 1,
entry 3).
Herein we wish to report the results of this study.
2. Results and discussion
Very likely, as shown in Scheme 4 for 3a, the reaction proceeds
via the formation of the anionic species A9 that undergoes an
intramolecular SN20 substitution10 to give the allenyl intermediate
B. A subsequent isomerization step, preceded or/and followed by
the hydrolysis of the trifluoroacetamido group, affords the free
NeH indole derivative.
The starting propargylic carbonates 3ael were prepared as
shown in Scheme 3.
To make this approach to indoles more attractive from a syn-
thetic standpoint, we explored their formation from 1 through
a process that omits the isolation of N-alkyl derivatives 3. Pleas-
ingly, good to high yields of the desired indoles could be obtained
by treating primary and secondary propargylic carbonates 1 with
ethyl iodoacetate or
a-bromoacetophenone in the presence of
K2CO3 in DMSO (Table 2).
We next turned our attention to tertiary 3-(o-trifluoro
acetamidoaryl)-1-propargylic carbonates. However, their synthesis
via esterification of the corresponding propargylic alcohols using the
same protocol used for the preparation of primary and secondary
propargylic carbonates failed to give the desired products. Treatment
of tertiary propargylic alcohols with ethyl chlorocarbonate in the
presence of triethylamine or N,N-dimethylaminopyridine led to the
recovery of the starting materials, usually in almost quantitative yield.
Thus, tertiary 3-(o-trifluoroacetamidoaryl)-1-propargylic acetates,
readily available via reaction of tertiary propargylic alcohols with
acetic anhydride and pyridine, were used as the starting materials.
After some experimentation, we found that best results could be ob-
Scheme 3. Synthesis of propargylic carbonates 3ael.
Control experiments on the reaction shown in Scheme 2
revealed that the same result could be obtained omitting N-ethyl-
piperazine (85% yield) and both N-ethylpiperazine and the palla-
dium catalyst (80% yield). Next, we found that a similar yield could
be obtained lowering the temperature to 40 ꢀC, although a longer
reaction time (3 h) was required. Further investigations ruled out
the possibility that the presence of adventitious palladium,
resulting from the palladium-catalyzed Sonogashira cross-coupling
used for the preparation of the starting material, might be involved
in the ‘Pd-free’ formation of 5a.7 SmopexTM fibers were used to
reduce the concentration of the residual palladium in 3a from
20 ppm to <1 ppm.8 Subjecting this propargylic carbonate to K2CO3
in DMSO at 40 ꢀC led to the isolation of 5a in 86% yield, suggesting
that the formation of the 3-vinylindole 5a is a base-promoted
process. Kinetic evidences (Fig. 1) also support this view. Indeed,
no significant variations of the reaction rate were observed when
the cyclization of 3a was performed without added palladium or
with 1 or 5 mol % palladium.
tained by treating them with ethyl iodoacetate or a-bromoacetophe-
none in the presence of K2CO3 in DMSO at 40 ꢀC and, after completion
of the alkylation step, increasing the temperature to 80 ꢀC (Table 3).
In conclusion, we have shown that the sequential base-
promoted alkylation/cyclization/isomerization of readily available
Table 1
Synthesis of 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles 5ael from propargylic
carbonates 3aela
Entry
R1
R2
R3
R4
R5
Time
(h)
5 (Yieldb
(%))
1
2
3
4
5
6
7
8
H
H
H
Cl
H
H
H
H
H
H
H
Me
Me
Cl
F
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
Ph
OEt
OEt
Ph
OEt
Ph
OEt
Ph
3
5
3
2
4
6
4
5
3
4
5
5
5a (86)
5b (67)
5c (50)c
5d (85)
5e (77)
5f (80)
5g (76)
5h (71)
5i (52)
5j (66)
5k (59)
5l (62)
Cl
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
Ph
OEt
Ph
F
a
Reactions were carried out on a 0.5 mmol scale in 3 mL of DMSO at 40 ꢀC using
1 equiv of 3 and 3 equiv of K2CO3.
b
Fig. 1. Cyclization of 3a (K2CO3, DMSO, 40 ꢀC) (C) without added palladium (<1 ppm);
(-) with 1 mol % palladium; (:) with 5 mol % palladium.
Yields are given for isolated products.
c
Isolated as the E isomer.

9496
I. Ambrogio et al. / Tetrahedron 69 (2013) 9494e9498
Table 3
Synthesis of 2-acyl-3-alkenyl indoles through base-promoted alkylation/cyclization/
isomerization of tertiary propargylic acetates
,
Entry R1
R2 R3
R4
R5
X
Time1 Time2 Yielda b (%)
(h)
(h)
1
2
3
4
5
6
7
H
H
Me
CN
Me
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
OEt
Ph
OEt
OEt
Ph
I
Br
I
1
1
1
1
1
1
1
4
5
10
10
10
2
5n (78)
5o (75)
5p (86)
5q (51)
5r (80)
5s (85)
5t (71)
I
Scheme 4. Proposed mechanism for the formation of 2-acyl- and 2-ethoxycarbonyl-3-
alkenyl indoles from 3-(o-trifluoroacetamidoaryl)-1-propargylic esters.
C5H9
C5H9
Br
Br
Br
C6H11 C6H11 Ph
C5H9 C5H9 Ph
Cl
1
a
ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters 1 repre-
sents a simple straightforward approach to free NeH 2-acyl- and 2-
ethoxycarbonyl-3-alkenyl indoles. The reaction occurs under mild
conditions and indole products are formed in good to high yields.
Furthermore, preliminary results suggest that combining the indole
synthesis with the Heck reaction may provide a new access to the
functionalized indole skeleton. Work along this line is in progress.
Reactions were carried out on 0.5 mmol scale using 1 equiv of 1, 1.5 equiv of
-bromoacetophenone, and 3 equiv of K2CO3 in 3 mL of DMSO.
Yields are given for isolated products.
ethyl iodoacetate or
a
b
3.2. General procedures and methods
3.2.1. General procedure for the alkylation of propargylic carbonates
(1ael): synthesis of ethyl 2-(N-(2-(3-(ethoxycarbonyloxy)prop-1-
ynyl)phenyl)-2,2,2-trifluoroacetamido)acetate (3a). To a stirred so-
3. Experimental section
3.1. General conditions
lution of 1a (0.158 g, 0.5 mmol) and ethyl 2-iodoacetate (89
ml,
0.75 mmol) in MeCN (4 mL), K2CO3 (0.207 g, 1.5 mmol) was added.
The reaction mixture was warmed at 40 ꢀC and stirred for 2 h. After
cooling, the reaction mixture was diluted with Et2O and washed
with brine. The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (SiO2, 50 g; n-hexane/ethyl acetate 85:15 v/
v) to give 3a (0.174 g, 87%) as an oil. IR (KBr): 1749, 1706, 1255, 1006
All the starting materials, catalysts, bases, solvents and eluents are
commercially available and were used as purchased, without further
purification. 1H NMR (400.13 MHz), 13C NMR (100.6 MHz), 19F NMR
(376.5 MHz), were recorded with a Bruker Avance 400 spectrometer.
Infrared spectra were recorded on a Jasco FT/IR-430 spectropho-
(cmꢁ1); 1H NMR (CDCl3):
d 7.61e7.53 (m, 2H), 7.44e7.38 (m, 2H),
€
tometer. Melting points were determined with a Buchi B-545 appa-
5.03 (d, J¼17.1 Hz, 1H), 4.93 (s, 3H), 4.31e4.19 (m, 4H), 3.86 (d,
J¼17.1 Hz, 1H),1.35e1.25 (m, 6H); 13C NMR (CDCl3):
d 167.5, 157.4 (q,
ratus and are uncorrected. Primary and secondary propargylic
carbonates (1ael) and tertiary propargylic acetates (1nes) were
prepared, usually in high yields, according to literature.4
J¼37 Hz), 154.6, 140.9, 133.3, 130.1, 129.8, 129.5, 121.6, 116.1 (q,
J¼288 Hz), 89.3, 82.1, 64.8, 61.8, 55.5, 51.9, 14.3, 14.2; 19F NMR
(CDCl3):
d
: ꢁ68.3. Anal. Calcd for C18H18F3NO6 C, 53.87; H, 4.52; N,
3.49; found C, 53.77; H, 4.53; N, 3.46.
Table 2
Synthesis of 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles through base-
promoted alkylation/cyclization/isomerization of primary and secondary prop-
argylic carbonatesa
3.2.2. General procedure for the synthesis of 2-acyl- and 2-
ethoxycarbonyl-3-alkenyl indoles (5ael) through base-promoted cy-
clization/isomerization of propargylic carbonates derivatives (3ael):
synthesis of ethyl 3-vinyl-1H-indole-2-carboxylate (5a). A solution
of 3a (0.205 g, 0.5 mmol) and K2CO3 (0.207 g, 1.5 mmol) in DMSO
(3 mL) was stirred at 40 ꢀC for 3 h. After cooling, the reaction
mixture was diluted with Et2O and washed with brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(SiO2, 50 g; n-hexane/ethyl acetate 90:10 v/v) to give 5a (0.092 g,
86%) as a yellow solid. Mp: 104e106 ꢀC. IR (KBr): 3320, 2984, 1676,
Entry R1
R2
R3 R4
R5
X
I
Temperature Time 5 (Yieldb
(ꢀC)
(h)
(%))
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
OEt
Ph
80
12
3
5a (80)
1250, 737 (cmꢁ1); 1H NMR (CDCl3):
d 9.11 (br s, 1H), 8.05 (d,
H
H
Cl
Cl
Br rt
5b (67)
5c (40)c
5d (71)
5e (77)
5f (80)
OEt
OEt
Ph
OEt
Ph
I
I
40
80
12
4
5
5
5
5
2
24
J¼4.2 Hz, 1H), 7.58 (dd, J1¼18.1 Hz, J2¼11.6 Hz, 1H), 7.45e7.35 (m,
2H), 7.25e7.21 (m, 1H), 6.00 (d, J¼18.1 Hz, 1H), 5.54 (d, J¼11.6 Hz,
1H), 4.50 (q, J¼6.5 Hz, 2H), 1.47 (t, J¼6.5 Hz, 3H); 13C NMR (CDCl3):
Br 40
80
Br 40
80
Br 40
40
Me
Me
Me Me
Me Me
I
d
162.3, 136.4, 129.6, 125.8, 123.9, 122.5, 121.7, 121.3, 120.9, 116.7,
5g (76)
5h (65)
5i (52)
112.2, 61.3, 14.6. Anal. Calcd for C13H13NO2 C, 72.54; H, 6.09; N, 6.51;
found C, 72.62; H, 6.07; N, 6.54.
OEt
Ph
I
H
H
Me OEt
I
5m (68)d
a
Reactions were carried out on 0.5 mmol scale at 40 ꢀC in 3 mL of DMSO using
3.2.3. General procedure for the synthesis of 2-acyl- and 2-
ethoxycarbonyl-3-alkenyl indoles (5aem) through base-promoted al-
kylation/cyclization/isomerization of primary and secondary prop-
argylic carbonates (1aem): synthesis of ethyl 3-vinyl-1H-indole-2-
carboxylate (5a). To a stirred solution of 1a (0.158 g, 0.5 mmol) and
1 equiv of 1, 1.5 equiv of ethyl iodoacetate or a-bromoacetophenone, and 3 equiv of
K2CO3.
b
Yields are given for isolated products.
Isolated as the E isomer.
Isolated as an approximately 1:1 E/Z mixture.
c
d

I. Ambrogio et al. / Tetrahedron 69 (2013) 9494e9498
9497
ethyl 2-iodoacetate (89
m
l, 0.75 mmol) in DMSO (3 mL), K2CO3
120.7, 117.5, 113.3. Anal. Calcd for C17H12ClNO C, 72.47; H, 4.29; N,
4.97; found C, 72.56; H, 4.30; N, 5.00.
(0.207 g, 1.5 mmol) was added. The reaction mixture was stirred at
80 ꢀC for 12 h. After cooling, the reaction mixture was diluted with
Et2O and washed with brine. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2, 50 g; n-hexane/
ethyl acetate 90:10 v/v) to give 5a (0.086 g, 80%) as a yellow solid.
3.3.6. Ethyl 5-methyl-3-vinyl-1H-indole-2-carboxylate (5f). White
solid. Mp: 170e172 ꢀC. IR (KBr): 3321, 2985, 1673, 1251, 1051
(cmꢁ1); 1H NMR (CDCl3):
d 9.03 (br s, 1H), 7.83 (s, 1H), 7.57 (dd,
J1¼16.2 Hz, J2¼11.5 Hz, 1H), 7.32 (d, J¼8.4 Hz, 1H), 7.20 (d, J¼8.4 Hz,
1H), 5.98 (dd, J1¼16.2 Hz, J2¼1.5 Hz, 1H), 5.52 (dd, J1¼11.6 Hz,
J2¼1.5 Hz, 1H), 4.47 (q, J¼7.1 Hz, 2H), 2.5 (s, 3H), 1.47 (t, J¼7.1 Hz,
3.2.4. General procedure for the synthesis of 2-acyl- and 2-
ethoxycarbonyl-3-alkenyl indoles (5net) through base-promoted alkyl-
ation/cyclization/isomerization of tertiary propargylic acetates (1net):
synthesis of ethyl 3-(2-methylprop-1-enyl)-1H-indole-2-carboxylate
(5n). To a stirred solution of 1n (0.157 g, 0.5 mmol) and ethyl 2-
3H); 13C NMR (CDCl3):
d 162.2,134.6, 130.5, 129.6, 127.6, 126.1,123.8,
121.8, 120.3, 116.3, 111.6, 61.1, 21.7, 14.4. Anal. Calcd for C14H15NO2 C,
73.34; H, 6.59; N, 6.11; found C, 73.26; H, 7.01; N, 6.08.
iodoacetate (89
m
l, 0.75 mmol) in DMSO (3 mL), K2CO3 (0.207 g,
3.3.7. 2-Benzoyl-5-methyl-3-vinyl-1H-indole (5g). Pale yellow solid.
Mp: 110e112 ꢀC. IR (KBr): 3313, 2983, 1614, 1261, 1056, 732 (cmꢁ1);
1.5 mmol) was added. The reaction mixture was stirred at 40 ꢀC for 1 h
and then warmed at 80 ꢀC for 4 h. After cooling, the reaction mixture
was diluted with Et2O and washed with brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2, 50 g; n-
hexane/ethyl acetate 90:10 v/v) to give 5n (0.095 g, 78%) as white solid.
1H NMR (CDCl3):
d 9.28 (br s, 1H), 7.85e7.80 (m, 3H), 7.62e7.58 (m,
1H), 7.51 (t, J¼7.7 Hz, 2H), 7.36 (d, J¼8.4 Hz, 1H), 7.26e7.24 (m, 1H),
6.74 (dd, J1¼18.0 Hz, J2¼11.6 Hz, 1H), 5.83 (dd, J1¼18.0, Hz, J2¼1.5 Hz,
1H), 5.33 (dd, J1¼11.6 Hz, J2¼1.5 Hz, 1H), 2.50 (s, 3H); 13C NMR
(CDCl3): d 189.1,139.1,135.5,132.44,132.41,131.8,130.9,129.9,129.6,
128.4, 126.6, 122.0, 121.0, 116.8, 111.9, 21.8. Anal. Calcd for C18H15NO
C, 82.73; H, 5.79; N, 5.36; found C, 82.62; H, 5.77; N, 5.32.
3.3. Characterization
3.3.1. Ethyl 3-vinyl-1H-indole-2-carboxylate (5a). Yellow solid. Mp:
104e106 ꢀC. IR (KBr): 3320, 2984, 1676, 1250, 737 (cmꢁ1); 1H NMR
3.3.8. Ethyl 5,7-dimethyl-3-vinyl-1H-indole-2-carboxylate
(5h). White solid. Mp: 118e120 ꢀC. IR (KBr): 3341, 2919, 1681,
(CDCl3):
d
9.11 (br s, 1H), 8.05 (d, J¼4.2 Hz, 1H), 7.58 (dd, J1¼18.1 Hz,
1235, 1015, 783 (cmꢁ1); 1H NMR (CDCl3):
d 8.76 (br s, 1H), 7.67 (s,
J2¼11.6 Hz, 1H), 7.45e7.35 (m, 2H), 7.25e7.21 (m, 1H), 6.00 (d,
1H), 7.55 (dd, J1¼17.9 Hz, J2¼11.6 Hz, 1H), 7.01 (s, 1H), 5.98 (d,
J¼18.1 Hz, 1H), 5.54 (d, J¼11.6 Hz, 1H), 4.50 (q, J¼6.5 Hz, 2H), 1.47 (t,
J¼17.9 Hz, 1H), 5.51 (d, J¼11.6 Hz, 1H), 4.49 (q, J¼7.1 Hz, 2H), 2.50 (s,
J¼6.5 Hz, 3H); 13C NMR (CDCl3):
d
162.3, 136.4, 129.6, 125.8, 123.9,
3H), 2.48 (s, 3H), 1.48 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3):
d 162.3,
122.5, 121.7, 121.3, 120.9, 116.7, 112.2, 61.3, 14.6. Anal. Calcd for
C13H13NO2 C, 72.54; H, 6.09; N, 6.51; found C, 72.62; H, 6.07; N, 6.54.
134.4, 130.8, 129.8, 127.9, 125.8, 123.6, 120.8, 120.7, 119.3, 116.3, 61.1,
21.6, 16.5, 14.5. Anal. Calcd for C15H17NO2 C, 74.05; H, 7.04; N, 5.76;
found C, 74.10; H, 7.07; N, 5.72.
3.3.2. 2-Benzoyl-3-vinyl-1H-indole
134e136 ꢀC. IR (KBr): 3300, 2919, 1613, 1262, 1060, 742 (cmꢁ1); 1H
NMR (CDCl3):
(5b). White
solid.
Mp:
3.3.9. 2-Benzoyl-5,7-dimethyl-3-vinyl-1H-indole (5i). Yellow solid.
Mp: 154e156 ꢀC. IR (KBr): 3316, 2916, 1619, 1503, 1262, 1067
d
9.18 (br s, 1H), 8.04 (d, J¼8.2 Hz, 1H), 7.84 (d, J¼7.2 Hz,
2H), 7.63 (d, J¼7.2 Hz, 1H), 7.55e7.37 (m, 4H), 7.27e7.20 (m, 1H), 7.58
(dd, J1¼17.7 Hz, J2¼11.5 Hz, 1H), 5.84 (d, J¼17.7 Hz, 1H), 5.34 (d,
(cmꢁ1); 1H NMR (CDCl3):
d
9.08 (br s, 1H), 7.83 (d, J¼7.0 Hz, 2H),
7.65e7.59 (m, 2H), 7.54e7.48 (m, 2H), 7.06 (s, 1H), 6.65 (dd,
J1¼17.6 Hz, J2¼11.6 Hz, 1H), 5.80 (dd, J1¼17.6 Hz, J2¼1.3 Hz, 1H), 5.29
(dd, J1¼11.6 Hz, J2¼1.3 Hz, 1H), 2.52 (s, 3H), 2.48 (s, 3H); 13C NMR
J¼11.5 Hz,1H); 13C NMR (CDCl3):
d189.1,139.0,137.0,132.6,131.7,129.8,
129.7, 128.5, 126.6, 126.4, 122.8, 121.5, 121.4,117.1, 112.3. Anal. Calcd for
C17H13NO C, 82.57; H, 5.30; N, 5.66; found C, 82.68; H, 5.29; N, 5.63.
(CDCl3):
d 189.1, 139.2, 135.2, 132.3, 131.7, 131.1, 130.0, 129.6, 128.8,
128.4, 126.3, 121.4, 121.2, 119.6, 116.8, 21.7, 16.6. Anal. Calcd for
C19H17NO C, 82.88; H, 6.22; N, 5.09; found C, 82.96; H, 6.20; N, 5.05.
3.3.3. (E)-Ethyl 3-styryl-1H-indole-2-carboxylate (5c). White solid.
Mp: 150e152 ꢀC. IR (KBr): 3295, 2923,1680,1253,1060, 737 (cmꢁ1);
1H NMR (CDCl3):
d
9.01 (br s, 1H), 8.18 (d, J¼8.0 Hz, 1H), 8.10 (d,
3.3.10. 2-Benzoyl-7-chloro-5-methyl-3-vinyl-1H-indole (5j). White
solid. Mp: 129e131 ꢀC. IR (KBr): 3252, 2920, 1619, 1258, 1216, 1059
J¼16.8 Hz, 1H), 7.64e7.60 (m, 2H), 7.45e7.38 (m, 5H), 7.30e7.27 (m,
2H), 4.50 (q, J¼7.2 Hz, 2H), 1.51 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3):
(cmꢁ1); 1H NMR (CDCl3):
d
9.02 (br s, 1H), 7.83 (d, J¼7.6 Hz, 2H),
d
162.1, 138.2, 136.4, 130.9, 128.7, 127.4, 126.3, 125.9, 125.7, 124.0,
7.70e7.62 (m, 2H), 7.55e7.48 (m, 2H), 7.26 (s, 1H), 6.69 (dd,
J1¼18.0 Hz, J2¼11.6 Hz, 1H), 5.80 (d, J¼18.0 Hz, 1H), 5.34 (d,
122.6, 121.9, 121.3, 120.9, 112.1, 61.2, 14.5. Anal. Calcd for C19H17NO2
C, 78.33; H, 5.88; N, 4.81; found C, 78.40; H, 5.86; N, 4.79.
J¼11.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (CDCl3):
d 188.6, 138.6, 132.65,
132.61, 132.0, 131.9, 129.5, 129.4, 128.5, 127.7, 127.1, 121.4, 120.7,
117.3, 117.1, 21.5. Anal. Calcd for C18H14ClNO C, 73.10; H, 4.77; N,
4.74; found C, 73.17; H, 4.77; N, 4.73.
3.3.4. Ethyl 5-chloro-3-vinyl-1H-indole-2-carboxylate (5d). White
solid. Mp: 160e162 ꢀC. IR (KBr): 3318, 2992,1682,1253,1056 (cmꢁ1);
1H NMR (CDCl3):
d
9.08 (br s, 1H), 7.99 (s, 1H), 7.48 (dd, J1¼18.0 Hz,
J2¼11.6 Hz, 1H), 7.35e7.26 (m, 2H), 5.90 (d, J¼18.0 Hz, 1H), 5.52 (d,
3.3.11. Ethyl 7-fluoro-5-methyl-3-vinyl-1H-indole-2-carboxylate
(5k). Pale yellow solid. Mp: 138e140 ꢀC. IR (KBr): 3361, 2920,
J¼11.6 Hz, 1H), 4.47 (q, J¼6.8 Hz, 2H), 1.51 (t, J¼6.8 Hz, 3H); 13C NMR
(CDCl3):
d
161.8, 134.4, 128.9, 126.9, 126.7, 126.2, 124.8, 121.7, 120.2,
1683, 1247, 1018 (cmꢁ1); 1H NMR (CDCl3):
d 8.83 (br s, 1H),
117.0, 113.0, 61.4, 14.4. Anal. Calcd for C13H12ClNO2 C, 62.53; H, 4.84;
N, 5.61; found C, 62.45; H, 4.85; N, 5.59.
7.52e7.43 (m, 2H), 6.94 (d, J¼18.0 Hz, 1H), 5.86 (d, J¼18.0 Hz, 1H),
5.50 (d, J¼11.6 Hz, 1H), 4.47 (q, J¼7.2 Hz, 2H), 2.51 (s, 3H), 1.46 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3):
d
162.0, 158.5 (d, J¼236.4 Hz),
3.3.5. 2-Benzoyl-3-vinyl-5-chloro-1H-indole (5e). Pale yellow solid.
Mp: 171e173 ꢀC. IR (KBr): 3299, 2923, 1611, 1268, 1054 (cmꢁ1); 1H
132.5, 129.3, 125.3 (d, J¼10.4 Hz), 124.7, 122.8 (d, J¼9.2 Hz), 121.0 (d,
J¼5.5 Hz), 116.5, 115.0 (d, J¼26.6 Hz), 104.4 (d, J¼23.9 Hz), 61.3, 16.7,
NMR (CDCl3):
d
9.26 (br s, 1H), 7.98 (s, 1H), 7.80 (d, J¼7.1 Hz, 2H),
14.4. 19F NMR (CDCl3):
d
ꢁ122.1. Anal. Calcd for C18H14FNO2 C,
7.64 (t, J¼7.1 Hz, 1H), 7.55e7.49 (m, 3H), 7.43e7.32 (m, 2H), 7.56 (dd,
J1¼17.9 Hz, J2¼12.5 Hz, 1H), 5.77 (dd, J1¼17.9 Hz, J2¼1.0 Hz, 1H), 5.52
68.00; H, 5.71; N, 5.66; found C, 68.10; H, 5.69; N, 5.63.
(dd, J1¼12.5 Hz, J2¼1.0 Hz, 1H); 13C NMR (CDCl3):
d
188.9, 138.6,
3.3.12. 2-Benzoyl-7-fluoro-5-methyl-3-vinyl-1H-indole (5l). White
solid. Mp: 169e171 ꢀC. IR (KBr): 3331, 2922, 1620, 1254, 742 (cmꢁ1);
135.2, 132.8, 132.6, 129.6, 129.2, 128.6, 127.2, 127.1, 126.9, 122.0,

9498
I. Ambrogio et al. / Tetrahedron 69 (2013) 9494e9498
1H NMR (CDCl3):
d
9.12 (br s, 1H), 7.83 (d, J¼8.1 Hz, 2H), 7.66e7.45
3.3.18. 2-Benzoyl-(3-(cyclohexylidenemethyl)-1H-indole)
(m, 4H), 7.00 (d, J¼9.6 Hz, 1H), 6.60 (dd, J1¼18.0 Hz, J2¼11.2 Hz, 1H),
(5r). White solid. Mp: 151e153 ꢀC. IR (KBr): 3305, 2920, 2850,1618,
5.71 (d, J¼18.0 Hz, 1H), 5.29 (d, J¼11.2 Hz, 1H), 2.55 (s, 3H); 13C NMR
1240 (cmꢁ1); 1H NMR (CDCl3):
d
9.28 (br s, 1H), 7.81 (d, J¼7.5 Hz,
(CDCl3):
d
188.9, 158.7 (d, J¼238.2 Hz), 138.7, 133.2, 132.6, 129.6,
2H), 7.62e7.59 (m, 2H), 7.57e7.35 (m, 4H), 7.16 (t, J¼7.7 Hz,1H), 5.90
129.5, 128.4, 125.8 (d, J¼10.2 Hz), 123.1 (d, J¼9.4 Hz), 121.54, 121.48,
116.9, 115.8 (d, J¼26.5 Hz), 104.5 (d, J¼24.4 Hz), 104.4 (d, J¼23.9 Hz).
(s, 1H), 2.13e1.99 (m, 4H), 1.45e1.20 (m, 6H); 13C NMR (CDCl3):
d
189.4, 145.6, 138.7, 136.7, 131.9, 131.4, 129.7, 128.1, 127.9, 126.5,
19F NMR (CDCl3):
d
ꢁ121.7. Anal. Calcd for C18H14FNO C, 77.40; H,
122.8, 121.8, 120.4, 113.9, 111.9, 36.8, 30.8, 27.9, 27.4, 26.5. Anal.
Calcd for C22H21NO C, C, 83.78; H, 6.71; N, 4.44; found C, 83.86; H,
6.70; N, 4.41.
5.05; N, 5.01; found C, 77.32; H, 5.06; N, 5.05.
3.3.13. Ethyl 3-(prop-1-enyl)-1H-indole-2-carboxylate, (cis, trans 1:1
mixture) (5m). Pale yellow solid. IR (KBr): 3310, 2987, 1676, 1245
3.3.19. 2-Benzoyl-3-(cyclopentylidenemethyl)-1H-indole
(cmꢁ1); 1H NMR (CDCl3):
d
9.17 (br s, 0.5H, cis, NH), 9.17 (br s, 0.5H,
(5s). White solid. Mp: 148e150 ꢀC. IR (KBr): 3303, 2924, 2848,
trans, NH), 8.00 (d, J¼8.0 Hz, 0.5H), 7.60 (d, J¼7.9 Hz, 0.5H),
7.45e7.18 (m, 3.5H), 6.79 (d, J¼11.3 Hz, 0.5H, cis, eCH]CHCH3),
6.60e6.51 (m, 0.5H, trans, eCH]CHCH3), 6.03e5.98 (m, 0.5H, cis,
eCH]CHCH3), 4.49e4.41 (m, 2H), 2.05e2.01 (m, 1.5H), 1.77e1.73
1613, 1267, 1006, 745 (cmꢁ1); 1H NMR (DMSO):
d 11.76 (br s, 1H),
7.71 (d, J¼7.6 Hz, 2H), 7.61 (t, J¼7.2 Hz, 1H), 7.51e7.44 (m, 4H), 7.30
(t, J¼7.6 Hz, 1H), 7.08 (t, J¼7.2 Hz, 1H), 6.10 (s, 1H), 2.17e2.00 (m,
2H), 1.97e1.92 (m, 2H), 1.47e1.43 (m, 4H); 13C NMR (DMSO):
(m, 1.5H), 1.50e1.40 (m, 3H); 13C NMR (CDCl3):
d
(cis/trans mixture,
d 189.1, 148.5, 139.0, 137.3, 132.5, 131.1, 129.6, 128.4, 126.7, 125.9,
unselected signals): 162.4, 136.5, 136.0, 129.0, 128.9, 126.1, 125.7,
125.6, 123.8, 122.8, 122.7, 122.6, 121.7, 121.5, 120.9, 120.4, 120.3,
112.0, 111.9, 61.1, 19.6, 16.0, 14.5. Anal. Calcd for C14H15NO2 C, 73.34;
H, 6.59; N, 6.11; found C, 73.41; H, 6.56; N, 6.08.
122.3, 121.3, 120.4, 113.5, 113.1, 33.9, 31.2, 26.4, 25.7. Anal. Calcd for
C21H19NO C, 83.69; H, 6.35; N, 4.65; found C, 83.60; H, 6.32; N,
4.68.
3.3.20. 2-Benzoyl-5-chloro-3-(cyclopentylidenemethyl)-1H-indole
3.3.14. Ethyl 3-(2-methylprop-1-enyl)-1H-indole-2-carboxylate
(5t). Pale yellow solid. Mp: 160e162 ꢀC. IR (KBr): 3289, 2921, 1619,
(5n). Pale yellow solid. Mp: 135e137 ꢀC. IR (KBr): 3352, 2920,
1263 (cmꢁ1); 1H NMR (DMSO):
d
11.93 (br s, 1H), 7.72 (d, J¼7.6 Hz,
1623, 1257 (cmꢁ1); 1H NMR (CDCl3):
d
8.90 (br s, 1H), 7.58 (d,
2H), 7.63e7.60 (m, 1H), 7.50e7.43 (m, 4H), 7.30 (d, J¼8.4 Hz, 1H),
J¼8.0 Hz, 1H), 7.43e7.31 (m, 2H), 7.17 (t, J¼7.3 Hz, 1H), 6.52 (s, 1H),
6.01 (s, 1H), 2.11e2.08 (m, 2H), 1.95e1.90 (m, 2H), 1.52e1.50 (m,
4.42 (q, J¼7.1 Hz, 2H), 2.03 (s, 3H), 1.73 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H);
4H); 13C NMR (DMSO):
d 189.1, 149.2, 138.6, 135.6, 132.7, 132.3,
13C NMR (CDCl3):
d
162.2, 137.5, 135.8, 127.4, 125.5, 123.3, 122.7,
129.7, 128.5, 127.8, 125.9, 124.9, 121.0, 120.5, 114.9, 112.8, 33.9, 31.1,
26.3, 25.6. Anal. Calcd for C21H18ClNO C, 75.11; H, 5.40; N, 4.17;
found C, 75.02; H, 5.38; N, 4.20.
121.7, 120.2, 116.6, 111.7, 60.8, 26.0, 20.8, 14.4. Anal. Calcd for
C15H17NO2 C, 74.05; H, 7.04; N, 5.76; found C, 74.13; H, 7.01; N, 5.80.
3.3.15. 2-Benzoyl-(3-(2-methylprop-1-enyl)-1H-indole) (5o). White
solid. Mp: 105e107 ꢀC. IR (KBr): 3320, 2927, 1605, 1336, 1266, 734,
Acknowledgements
695 (cmꢁ1); 1H NMR (CDCl3):
d
9.32 (br s, 1H), 7.79 (d, J¼7.6 Hz, 2H),
7.60e7.53 (m, 2H), 7.47e7.35 (m, 4H), 7.17 (t, J¼7.4 Hz, 1H), 6.02 (s,
1H), 1.65 (s, 3H), 1.51 (s, 3H); 13C NMR (CDCl3):
189.5, 138.6, 138.5,
ꢀ
The authors gratefully acknowledge the Universita of L’Aquila
and Sapienza, Universita di Roma for financial support of this
research.
ꢀ
d
136.7, 131.9, 131.1, 129.5, 128.0, 127.7, 126.4, 122.7, 122.1, 120.5, 117.1,
112.0, 25.5, 20.2. Anal. Calcd for C19H17NO C, 82.88; H, 6.22; N, 5.09;
found C, 82.77; H, 6.23; N, 5.06.
References and notes
1. (a) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589e2612; (b)
Geng, L.; Lu, X. Tetrahedron Lett. 1990, 31, 111e114.
2. Sun, P.-S.; Hu, J.; Wang, X.-C.; Liu, L.; Liang, Y.-M. Tetrahedron 2012, 68,
3.3.16. Ethyl 5-methyl-3-(2-methylprop-1-enyl)-1H-indole-2-
carboxylate (5p). Brown solid. Mp: 132e134 ꢀC. IR (KBr): 3327,
1367e1370.
2936, 1672,1259, 1181 (cmꢁ1); 1H NMR (CDCl3):
d 8.84 (br s,1H), 7.35
3. For a recent review, see: Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Acc. Chem. Res.
2011, 44, 111e122.
4. (a) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083e2086; (b)
Ambrogio, I.; Cacchi, S.; Fabrizi, G.; Prastaro, A. Tetrahedron 2009, 65,
8916e8929.
(s, 1H), 7.30 (d, J¼8.4 Hz, 1H), 7.17 (d, J¼8.4 Hz, 1H), 6.50 (s, 1H), 4.41
(q, J¼7.1 Hz, 2H), 2.47 (s, 3H), 2.03 (s, 3H),1.72 (s, 3H),1.43 (t, J¼7.1 Hz,
3H); 13C NMR (CDCl3):
d 162.2, 137.3, 134.3, 129.5, 127.6, 127.4, 123.4,
121.9, 121.2, 116.7, 111.4, 60.7, 26.0, 21.6, 20.7, 14.4. Anal. Calcd for
C16H19NO2 C, 74.68; H, 7.44; N, 5.44; found C, 74.56; H, 7.48; N, 5.42.
5. (a) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 2007, 48, 7721e7725; (b)
Cacchi, S.; Fabrizi, G.; Filisti, E. Synlett 2009, 1817e1821.
6. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,105, 2873e2920; (b) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2011, 111, PR215ePR283 see also: (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Iazzetti, A.; Marinelli, F. Org. Biomol. Chem. 2013, 11, 545e548.
7. (a) Livendall, M.; Espintet, P.; Echavarren, A. M. Platinum Metals Rev. 2011, 55,
212e214; (b) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586e5587; (c) Bedford, R. B.; Nakamura, M.; Gower, N. J.; Haddow, M. F.; Hall,
M. A.; Huwea, M.; Hashimoto, T.; Okopie, R. A. Tetrahedron Lett. 2009, 50,
6110e6111; (d) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161e168.
3.3.17. Ethyl 5-cyano-3-(2-methylprop-1-enyl)-1H-indole-2-
carboxylate (5q). White solid. Mp: 182e184 ꢀC. IR (KBr): 3291, 2914,
16,762, 1260, 1015 (cmꢁ1); 1H NMR (CDCl3):
d 9.25 (br s, 1H), 7.94 (s,
1H), 7.54 (d, J¼8.5 Hz, 1H), 7.47 (d, J¼8.5 Hz, 1H), 6.43 (s, 1H), 4.43 (q,
J¼7.1 Hz, 2H), 2.03 (s, 3H), 1.65 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H); 13C NMR
(CDCl3): d161.6,139.1,137.1,128.6,127.6,127.2,125.3,121.9,120.2,115.3,
8. Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889e900.
9. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 647e649.
10. Yoshida, M.; Komatsuzaki, Y.; Ihara, M. Org. Lett. 2008, 10, 2083e2086.
112.8,103.7, 61.3,25.9, 20.7,14.3.Anal. CalcdforC16H16N2O2 C,71.62;H,
6.01; N, 10.44; found C, 71.70; H, 6.00; N, 10.47.