3-(2-Alken-1-one-2-yl)indoles through the palladium-catalyzed reaction of 2-alkynyltrifluoroacetanilides with cyclic α-iodoenones

Article abstract of DOI:10.1016/j.tet.2010.01.096

α-Iodoenones can be efficiently employed as organic electrophiles in the Pd-catalyzed synthesis of 2,3-disubstituted indoles from 2-alkynyltrifluoroacetanilides. Best results were obtained using the weak ligand As(Ph)₃. The methodology reported provides an efficient entry to indoles bearing a 2-alkenon-2-yl moiety linked in the 3-position, that possesses a scarcely reported substitution pattern.

Full text of DOI:10.1016/j.tet.2010.01.096

Tetrahedron 66 (2010) 2378–2383
Contents lists available at ScienceDirect
Tetrahedron
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3-(2-Alken-1-one-2-yl)indoles through the palladium-catalyzed reaction
of 2-alkynyltrifluoroacetanilides with cyclic
a-iodoenones
*
Antonio Arcadi, Roberto Cianci, Giovanni Ferrara, Fabio Marinelli
`
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita dell’Aquila, via Vetoio, I-67100 L’Aquila, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2009
Received in revised form 17 December 2009
Accepted 27 January 2010
Available online 2 February 2010
a
-Iodoenones can be efficiently employed as organic electrophiles in the Pd-catalyzed synthesis of 2,
3-disubstituted indoles from 2-alkynyltrifluoroacetanilides. Best results were obtained using the weak
ligand As(Ph)3. The methodology reported provides an efficient entry to indoles bearing a 2-alkenon-2-yl
moiety linked in the 3-position, that possesses a scarcely reported substitution pattern.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
functionalizationof the indolering can beobtainedinsome instances,
with remarkable improvement in terms of scope and application.7
The indole ring system is one of the most widely distributed het-
erocycles found in nature, and occurs in many biologically active
compounds.1 Due to their relevance, the development of new and
efficient procedures for building up indoles from acyclic precursors is
a current challenge in organic synthesis.2 Besides classical method-
ologies, the transition metal mediated cyclization of functionalized
alkynes3 has gained increasing attention, allowing the use of mild
reaction conditions and, consequently, the introduction of a wide
range of functionalities in the target heterocycle. One of the most
popular strategies in this context is the cyclization of 2-alkynylaniline
derivatives 1 to give 2-substituted indoles 2. Although this reaction
can be carried out in the presence of various reagents, including
bases4 and ammonium fluoride,5 many procedures rely on the use
of transition metal salts3,6 (Scheme 1, a). Sequential C-3
In the search for strategies towards C-3 functionalized indoles
from alkynylanilines, attention was turned to a variety of approaches
involving the coordination of the carbon–carbon triple bond by s-
organopalladium(II) complexes, generated in situ through oxidative
addition of organic electrophiles R1-X to Pd(0).3,8 Sequential ami-
nopalladation/reductive elimination of Pd(0) affords indoles 4,
bearing the R1 group in the 3-position (Scheme 1, b). This process
requires the use of trifluoroacetanilides 3, able to generate an anionic
nitrogen nucleophile in the presence of carbonate bases. The use of
suitable electrophiles allowed the introduction of various R1 frag-
ments including aryl/heteroaryl/vinyl,9 alkyl,10 alkynyl,11 allyl12 and
(running the reaction under a CO atmosphere) acyl groups.13
In connection with our current research interests in this area14
and in order to widen the scope and generality of the methodology,
we decided to develop a procedure for the preparation of 3-(2-alken-
1-on-2-yl)-indoles 6 through the palladium-catalyzed reaction of
R
[M]
2-alkynyltrifluoroacetanilides with
a-iodoenones 5 (Scheme 2).
R
a)
N
H
NH2
O
2
n
1
R
O
R1
I
R1
R1
Pd(0), ligand
base
R3
R
+
Pd cat.
R
R1-X
N
H
+
b)
NHCOCF3
R
R3
n
K2CO3
R2
R2
N
H
NHCOCF3
5
3
6
4
3
R = Ar, vinyl, alkyl; R3 = Me, H;
n = 0-2.
R1 = Ar, vinyl, alkyl, alkynyl, allyl.
X = -I, -Br, -Cl, -OTf.
Scheme 2.
Scheme 1.
a
-Iodoenones 5 represent an interesting class of organic elec-
trophile.15 In spite of their sluggish reactivity and limited stability,
these substrates have been successfully employed in some Pd-
catalysed cross-coupling reactions16 with organostannanes,17
* Corresponding author. Tel.: þ39 0862 433752; fax: þ39 0862 433753.
E-mail address: fabio.marinelli@univaq.it (F. Marinelli).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.096

A. Arcadi et al. / Tetrahedron 66 (2010) 2378–2383
2379
organozinc,18 organoboranes,19 organoindium20 and terminal al-
kynes,21 with the aim to achieve challenging
-functionalization of
According to previous findings,9b,14 2-phenyilndole 7 and the
dimer 8 were isolated as significant by-products. Raising the
temperature to 100 ꢀC (conditions used for the less reactive aryl
bromides/triflates9b) afforded 6aa in moderate yield (entries 2
and 3). The use of ligandless Pd2(dba)3 as catalyst resulted in
a
unsaturated carbonyl compounds. However, their efficiency in the
Heck reaction was found to be strongly dependent on the structure:
while 2-iodo-3-methylcyclopentenone reacted in good yield, other
substrates such as 2-iodocyclopentenone (with the 3-position
unblocked) and 2-iodocyclohexenone/cycloheptenone derivatives
gave unsatisfactory results.22 This was attributed to competitive Pd-
catalyzed dehydration/aromatization to give phenols, kinetically
favoured in these cases with respect to the vinylic substitution path.
a
further improvement, although the yield was still un-
satisfactory (entry 4). A screening of some ligands revealed that
tricyclohexyl phosphine and triphenylarsine were the most ef-
fective in promoting the present reaction (entries 6 and 7); the
latter weak ligand has been used in various Stille cross-coupling
of substrates 5.17a–d Good results were also obtained by reducing
AsPh3/Pd ratio to 1:1 (entry 8). Changing the solvent from CH3CN
to ethanol or DMF gave worse results (entries 9 and 10), whereas
lowering the temperature to 80 ꢀC afforded 6a in nearly quanti-
tative amount (entry 11). Omitting AsPh3 at this temperature
afforded 6aa in 75% yield (entry 12), proving that AsPh3 plays
a significative role in determining the reaction outcome, al-
though the process can be carried out also by using ligandless
Pd(0). The presence of the ligand appears more important using
a Pd(II) precatalyst: while in the presence of AsPh3 6aa was
obtained as main product, although in moderate yield (entry 13),
the use of Pd(OAc)2 alone resulted in a very different product
distribution, and 2-phenylindole 7 was isolated in 45% yield
(entry 14).
To date, the use of 5 as precursors of
s-organopalladium (II)
complexes in the aminopalladation/reductive elimination meth-
odology described in Scheme 1,b is still unexplored.
2. Results and discussion
The reaction between trifluoroacetanilide 3a and 2-iodocyclo-
hexenone 5a was chosen as a model (Scheme 3), and some of our
results are reported in Table 1.
O
O
Ph
I
Pd(0), ligand
base
+
+
Ph
NHCOCF3
Finally, we found that under the optimized conditions the use of
K2CO3 as base instead of Cs2CO3 was possible, although the latter
afforded a slightly better yield (entries 11 and 15).
N
H
3a
6aa
5a
We next extended the process to include various 2-alkynylani-
lines/
synthesis of acyclic
on the use of cyclic substrates 5a–d. Our preparative results are
a
-iodoenones; due to the limited stability and troublesome
-iodoenones,15 the present study was centred
NH
Ph
a
+
Ph
reported in Table 2.
N
H
As shown in Table 2, all cyclic
a-iodoenones tested, in-
Ph
N
H
dependent from their ring size, afforded target 3-(2-alken-1-on-
2-yl) indoles 6 in moderate to good yields (entries 1–4); likely,
the lower reactivity observed in the case of 5b (entry 2) is de-
termined by unfavourable steric effect of the methyl group. It is
worth noting that the present reaction tolerates the presence of
various functional groups such as ester (entry 5), keto (entry 6),
nitro and cyano (entry 11). A vinylic substituent at the 2-position
is also allowed, although with moderate results (entry 12).
Moreover, indoles substituted on the benzene ring can be
obtained starting from substituted 2-alkynyltrifluoroacetanilides
(entries 10 and 11).
7
8
Scheme 3.
Table 1
Pd-catalyzed reaction of 3a with 5aa
Entry
Base
Catalyst (equiv %)
T (ꢀC)
Yieldb
6aa
7
8
1
2
3
4
5
6
7
8
K2CO3
K2CO3
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)þttmpp (10)
Pd2(dba)3 (2.5)þP(cy)3 (10)
Pd2(dba)3 (2.5)þAs(Ph)3 (10)
Pd2(dba)3 (2.5)þAs(Ph)3 (5)
Pd2(dba)3 (2.5)þAs(Ph)3 (5)
Pd2(dba)3 (2.5)þAs(Ph)3 (5)
Pd2(dba)3 (2.5)þAs(Ph)3 (5)
Pd2(dba)3
80
100
100
100
100
100
100
100
100
100
80
12
40
44
58
45
71
78
77
27
22
36
16
15
6
32
27
10
12
21
9
11
10
9
22
d
d
5
14
d
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
3. Conclusions
In conclusion, the results reported here widen significantly
the scope of the synthesis of 2,3-disubstituted indoles through
aminopalladation/reductive elimination, proving that
3
5
a-iodoe-
9
50d
52e
95c
75c
51
10
12
d
d
7
nones 5 differing in ring size can be efficiently used as organic
electrophiles in such process. Best results were obtained in the
presence of the weak ligand AsPh3, although ligandless Pd2(dba)3
was also effective. The present reaction allows a straightforward
entry to 3-(2-alken-1-one-2-yl)indoles 6, possessing a scarcely
reported substitution pattern,23 and usefully complements the
well-known reaction of 3-unsubstituted indoles with 1,3-dicar-
bonyl compounds,7b,24 that affords regioisomeric 3-(2-alken-1-
one-3-yl)indoles. Moreover, the 2-alken-1-one-2-yl moiety of 6
could allow further functionalization, opening access to more
complex indole derivatives; for example, the presence of a suit-
able o-substituted phenyl ring at the 2-positition (as in 6da, entry
7) promises to open a new access to polycyclic indole derivatives
through sequential palladium-catalyzed processes. This in-
vestigation is now under way, and the results will be reported in
due course.
10
11
12
13
14
15
80
80
80
80
Pd(OAc)2 (5)þAs(Ph)3 (10)
Pd(OAc)2 (5)
15
45
d
Pd2(dba)3 (2.5)þAs(Ph)3 (5)
88c
a
Reactions were carried out on a 0.3 mmol scale in 1.5 mL of MeCN for 2 h using
the following molar ratios: 3a:5a:base¼1:1.1:1.5.
b
Unless otherwise stated yields were determined by HPLC analysis.
c
Isolated yield.
d
Carried out in ethanol.
Carried out in DMF.
e
Using the reaction conditions that were found suitable for the
palladium-catalyzed reaction of 3 with aryl iodides and vinyl tri-
flates,9c the target indole 6aa was obtained in very low yield (entry 1),
confirming the sluggish reactivity of a
-iodoenones.16

2380
A. Arcadi et al. / Tetrahedron 66 (2010) 2378–2383
Table 2
Pd-catalyzed synthesis of indoles 6 from 2-alkynyltrifluoroacetanilides 3 and cyclic
a
-iodoenones 5a
Entry
2-alkynyltrifluoroacetanilide 3
a
-Iodoenone 5
Indole 6
Yieldb (%)
( )n
R3
O
R
O
R1
R1
I
R
NHCOCF3
R2
R3
N
H
( )n
R2
-R
-R1
H
-R2
H
-R3
n¼
Time (h)
1
2
3
4
3a
3a
3a
3a
Ph
5a
5b
5c
5d
H
CH3
H
1
1
0
2
2
2
2.5
3
6aa
6ab
6ac
6ad
95
58
76
67
H
5
6
3b
3c
H
H
H
H
5a
5a
3.5
2
6ba
6ca
95
67
COOMe
COMe
7
3d
H
H
5a
2
6da
87
Br
8
9
3e
3f
H
H
H
H
5a
5a
2
2
6ea
6fa
95
77
S
n-Butyl
n-Butyl
10
11
3g
3h
F
F
5a
5a
3
6ga
6ha
72
COMe
Ph
NO2
CN
3.5
60c
12
3i
H
H
5a
2
6ia
40
a
Reactions were carried out on a 0.3 mmol scale in 1.5 mL of MeCN using the following molar ratios: 3:5:Cs2CO3:Pd2(dba)3:AsPh3¼1:1.1:1.5:0.025:0.05.
b
c
Isolated yields.
Carried out with 1.5 equiv of 5a.
4. Experimental
DMF (1 mL) and triethylamine (2 mL) were added methyl 3-iodo-
benzoate (1.721 g, 6.57 mmol), PdCl2(PPh3)2 (0.084 g, 0.12 mmol)
and CuI (0.045 g, 0.24 mmol). The mixture was stirred at room
temperature under N2 atmosphere for 5 h, then extracted with HCl
0.1 M (50 mL) and EtOAc (3ꢁ50 mL). The combined organic layers
were washed with 10% NaCl, dried (Na2SO4) and evaporated under
reduced pressure. The residue was connected to a rotary pump for
0.5 h, then dissolved in anhydrous CH2Cl2 (5 mL). The flask was
cooled with an ice bath, then triethylamine (1.25 mL, 8.96 mmol)
and trifluoroacetic anhydride (1.26 mL, 3.47 mmol) were added.
The mixture was stirred under N2 atmosphere for 2 h, then
extracted with HCl 0.1 M (100 mL) and EtOAc (3ꢁ50 mL). The
combined organic layers were washed with 10% NaCl, dried
(Na2SO4) and evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, hexane/EtOAc 90:10 v/
v) to give 3b (1.303 g, 64% yield) as pale brown solid, mp 110–111 ꢀC
4.1. General methods
1H NMR and 13C NMR spectra were recorded in CDCl3 at
200 MHz, unless otherwise stated. IR was recorded with a Perkin–
Elmer 683 or with a Varian 100 FT-IR spectrometer. Only the most
significant IR absorptions are given. EI mass spectra were recorded
with a Saturn 2000T GC/MS apparatus. ESI mass spectra were
recorded with a ThermoFinnigan LCQ Deca XP Plus. CHN analyses
were recorded with an Eager 200 analyser. a-Iodoenones 5 were
obtained according to the literature.15 The synthesis of 2-alkynyl-
trifluoroacetanilides 3a, 3e, 3f and 3i was previously described.13
Compounds 3b, 3c, 3d and 3g were obtained using the following
typical procedure.
4.2. Representative procedure for the synthesis
of 2-alkynyltrifluoroacetanilides 3b–d and 3g from
2-ethynylanilines
(cryst from acetone/hexane). 1H NMR:
d
¼8.84 (br s, 1H, NH), 8.38
(d, J¼7.7 Hz, 1H), 8.22–8.20 (m, 1H), 8.06 (dt, J¼7.9 Hz, J¼1.5 Hz,
1H), 7.69 (dt, J¼7.9 Hz, J¼1.5 Hz, 1H), 7.61–7.52 (m, 1H), 7.50–7.40
(m, 2H), 7.28–7.22 (m, 1H), 3.96 (s, 3H). 13C NMR:
d¼166.3 (C]O),
4.2.1. Methyl 3-({2-[(trifluoroacetyl)amino] phenyl} ethynyl) benzo-
ate (3b). To a solution of 2-ethynylaniline (0.700 g, 5.97 mmol) in
154.6 (q, J¼37.3 Hz, CF3C]O), 136.4, 135.6, 132.8, 132.1, 131.1, 130.4,
129.1, 125.8, 122.4, 120.1, 113.4 (Ar), 97.1, 84.0 (C^C), 52.6. IR (KBr):

A. Arcadi et al. / Tetrahedron 66 (2010) 2378–2383
2381
n
¼3370,1735,1725 cmꢂ1. MS (EI): m/z (%)¼347 (10) [Mþ], 332 (100).
4.4. Representative procedure for the synthesis of indoles 6
4.4.1. 2-(2-Phenyl-1H-indol-3-yl)cyclohex-2-en-1-one (6aa). To
Anal. calcd for C18H12F3NO3: C 62.25, H 3.48, N 4.03. Found: C 62.38,
H 3.50, N 4.01.
a solution of 3a (0.100 g, 0.35 mmol) in MeCN (1.5 mL) were
added 2-iodocyclohex-2-en-1-one 5a (0.085 g, 0.38 mmol),
Cs2CO3 (0.169 g, 0.52 mmol), Pd2(dba)3 (0.008 g, 0.009 mmol)
and AsPh3 (0.006 g, 0.019 mmol). The mixture was stirred at
80 ꢀC under N2 atmosphere for 1.5 h, then extracted with H2O
(50 mL) and EtOAc (3ꢁ40 mL). The combined organic phases
were dried (Na2SO4) and evaporated under reduced pressure.
The residue was purified by flash chromatography (SiO2,
hexane/EtOAc 85:15 v/v) obtaining 0.094 g (95% yield) of 2-(2-
phenyl-1H-indol-3-yl)cyclohex-2-en-1-one 6aa as pale yellow
solid, mp 93–94 ꢀC (cryst from diethyl ether/hexane). 1H NMR:
4.2.2. N-{2-[(4-Acetylphenyl)ethynyl]phenyl}-2,2,2-tri-
fluoroacetamide (3c). Yield¼62%; pale brown solid, mp 141–142 ꢀC
(cryst from acetone/hexane). 1H NMR:
d
¼8.85 (br s, 1H, NH), 8.32
(d, J¼8.2 Hz, 1H), 7.96 (d, J¼8.1 Hz, 2H), 7.60–7.56 (m, 3H), 7.43
(t, J¼7.1 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 2.61 (s, 3H). 13C NMR:
d
¼196.9 (C]O), 154.4 (q, J¼37.4 Hz, CF3C]O), 137.0, 136.2, 131.9,
131.5, 130.3, 128.5, 126.3, 125.6, 119.9, 113.1 (Ar), 96.9, 85.9 (C^C),
26.5. IR (KBr):
n
¼3310, 1710, 1690 cmꢂ1. MS (EI): m/z (%)¼331 (35)
[Mþ], 316 (100). Anal. calcd for C18H12F3NO2: C 65.26, H 3.65, N 4.23.
Found: C 65.11, H 3.65, N 4.24.
d
¼8.58 (br s, 1H, N–H), 7.42–7.34 (m, 4H), 7.30–7.20 (m, 3H),
7.12–7.06 (m, 2H), 7.00 (t, J¼4.2 Hz, 1H), 2.59 (t, J¼6.2 Hz, 2H),
2.53–2.45 (m, 2H), 2.18–2.12 (m, 2H). 13C NMR:
¼198.4 (C]O),
4.2.3. N-{2-[(2-Bromophenyl)ethynyl]phenyl}-2,2,2-tri-
fluoroacetamide (3d)25. Yield¼65%; pale brown solid, mp 109–
d
110 ꢀC (cryst from acetone/hexane). 1H NMR:
d
¼8.88 (br s, 1H,
150.5, 135.8, 135.3, 134.8, 133.0, 129.1, 128.5, 128.3, 127.3, 122.1,
NH), 8.42 (d, J¼8.2 Hz, 1H), 7.68–7.55 (m, 3H), 7.45–7.23 (m,
119.8, 119.2, 111.2, 39.0, 26.6, 23.0. IR (KBr):
n
¼3330, 1670 cmꢂ1
.
4H). 13C NMR:
d
¼154.2 (q, J¼37.5 Hz, CF3C]O), 136.4, 133.3,
MS (EI): m/z (%)¼287 (100) [Mþ], 258 (28), 230 (28). Anal. calcd
for C20H17NO: C 83.59, H 5.96, N 4.87. Found C 83.91, H 5.97,
N 4.89.
132.6, 132.4, 130.3, 130.3, 127.4, 125.6, 125.2, 124.3, 118.6, 113.2
(Ar), 96.0, 87.5 (C^C). IR (KBr):
n
¼3440, 1710, 1680 cmꢂ1. MS
(EI): m/z (%)¼369 (92), 367 (100) [Mþ], 288 (79), 218 (88). Anal.
calcd for C16H9BrF3NO: C 52.20, H 2.46, N 3.80. Found: C 52.06,
H 2.47, N 3.78.
4.4.2. 3-Methyl-2-(2-phenyl-1H-indol-3-yl)cyclohex-2-en-1-one
(6ab). Yield¼58%; 93 mg of pale brown solid, mp 89–90 ꢀC (cryst
from diethyl ether/hexane), were obtained from 154 mg of 3a and
4.2.4. N-{2-[(4-Acetylphenyl)ethynyl]-4,6-difluorophenyl}-2,2,2-tri-
138 mg of 5b. 1H NMR:
d
¼8.52 (br s, 1H, N–H), 7.43–7.35 (m, 2H),
fluoroacetamide (3g)26. Yield¼56%; pale brown solid, mp 172–
7.30–7.23 (m, 4H), 7.21–7.19 (m, 1H), 7.13–7.05 (m, 2H), 2.56 (t,
173 ꢀC (cryst from acetone/hexane). 1H NMR:
d
¼8.13 (br s, 1H, NH),
J¼6.4 Hz, 2H), 2.53–2.45 (m, 2H), 2.20–2.03 (m, 2H), 1.64 (s, 3H). 13C
7.94 (d, J¼8.0 Hz, 2H), 7.53 (d, J¼8.0 Hz, 2H), 7.15–7.08 (m,1H), 7.01–
NMR:
d
¼198.2 (C]O), 160.6, 136.1, 135.3, 133.3, 128.7, 127.9, 127.4,
6.86 (m, 1H), 2.61 (s, 3H). 13C NMR:
d
¼197.2 (C]O), 161.6 (dd,
126.7, 122.3, 119.9, 119.5, 111.1, 38.4, 32.8, 22.4. IR (KBr):
n
¼3320,
J¼252 Hz, J¼13 Hz), 157.7 (dd, J¼241 Hz, J¼14 Hz), 154.3 (q,
J¼37.4 Hz, CF3C]O), 137.3, 131.9, 128.4, 126.1, 115.2 (d, J¼24 Hz),
1660 cmꢂ1. MS (EI): m/z (%)¼301 (100) [Mþ], 258 (31), 230 (22).
Anal. calcd for C21H19NO: C 83.69, H 6.35, N 4.65. Found C 83.99, H
6.37, N 4.64.
106.0 (t, J¼25 Hz) (Ar), 96.7, 85.5 (C^C), 26.6. IR (KBr): ¼3220,
n
1725, 1670 cmꢂ1. MS (EI): m/z (%)¼367 (27) [Mþ], 352 (100). Anal.
calcd for C18H10F5NO2: C 58.86, H 2.74, N 3.81. Found: C 59.00, H
2.73, N 3.81.
4.4.3. 2-(2-Phenyl-1H-indol-3-yl)cyclopent-2-en-1-one
(6ac). Yield¼76%; 79 mg of pale brown solid, mp 175–176 ꢀC (cryst
from diethyl ether/hexane), were obtained from 110 mg of 3a and
4.3. N-(2-Cyano-6-hex-1-ynyl-4-nitrophenyl)-2,2,2-
trifluoroacetamide (3h)
87 mg of 5c. 1H NMR:
d
¼8.54 (br s, 1H, N–H), 7.68 (t, J¼2.5 Hz, 1H),
7.53–7.39 (m, 3H), 7.35–7.25 (m, 4H), 7.20–7,12 (m, 2H), 2.81–2.74
(m, 2H), 2.60–2.55 (m, 2H). 13C NMR:
¼208.3 (C]O), 161.3, 140.5,
d
To a solution of 2-amino-3-bromo-5-nitrobenzonitrile (1.51 g,
6.25 mmol) in DMF (1 mL) and piperidine (2 mL) were added 1-
hexyne (0.912 mL, 8.11 mmol), PdCl2(PPh3)2 (0.087 g, 0.12 mmol)
and CuI (0.047 g, 0.24 mmol). The mixture was stirred at 50 ꢀC
under N2 atmosphere for 3 h, then extracted with HCl 0.1 M
(50 mL) and EtOAc (3ꢁ50 mL). The combined organic layers were
washed with 10% NaCl, dried (Na2SO4) and evaporated under re-
duced pressure. The residue was connected to a rotary pump for
0.5 h, then dissolved in anhydrous CH2Cl2 (7 mL). The flask was
cooled with an ice bath, then triethylamine (1.30 mL, 9.38 mmol)
and trifluoroacetic anhydride (1.33 mL, 9.38 mmol) were added.
The mixture was stirred under N2 atmosphere for 2 h, then
extracted with HCl 0.1 M (50 mL) and EtOAc (3ꢁ50 mL). The
combined organic layers were washed with 10% NaCl, dried
(Na2SO4) and evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, hexane/EtOAc 90:10 v/
v) to give 3h (1.17 g, 55% yield) as pale yellow solid, mp 95–96 ꢀC
136.3, 136.2, 133.2, 128.9, 128.8, 128.2, 127.9, 122.9, 120.6, 120.0,
111.2, 35.2, 27.5. IR (KBr):
n
¼3320, 1680 cmꢂ1. ESI-MS m/z (%): 274
(100) [Mþþ1]. Anal. calcd for C19H15NO: C 83.49, H 5.53, N 5.12.
Found C 83.21, H 5.53, N 5.10.
4 . 4 . 4 . 2 - ( 2 - P h e nyl - 1 H - i n d o l - 3 - yl ) c y c l o h e p t - 2 - e n - 1 -
one(6ad). Yield¼67%; 74 mg of pale yellow oil were obtained from
106 mg of 3a and 95 mg of 5d. 1H NMR:
d¼8.48 (br s, 1H, N–H),
7.47–7.34 (m, 3H), 7.32–7.23 (m, 4H), 7.12–7.05 (m, 2H), 6.78 (t,
J¼6.4 Hz, 1H), 2.72 (t, J¼6.2 Hz, 2H), 2.55–2.46 (m, 2H), 1.94–1.81
(m, 4H). 13C NMR:
d
¼205.3 (C]O), 145.5, 138.3, 135.8, 135.3, 133.1,
129.1, 128.6, 127.7, 127.6, 122.3, 120.1, 119.3, 111.1, 42.9, 28.3, 25.2,
22.1. IR (KBr):
n
¼3350, 1660 cmꢂ1. MS (EI): m/z (%)¼301 (100) [Mþ].
Anal. calcd for C21H19NO: C 83.69, H 6.35, N 4.65. Found C 83.30, H
6.33, N 4.67.
4.4.5. Methyl
3-[3-(6-oxocyclohex-1-en-1-yl)-1H-indol-2-yl]ben-
(cryst from acetone/hexane). 1H NMR:
d
¼8.86 (br s, 1H, NH), 8.48
zoate (6ba). Yield¼95%; 107 mg of yellow solid, mp 142–143 ꢀC
(dd, J¼7.0 Hz, J¼2.5 Hz, 2H), 2.52 (t, J¼6.9 Hz, 2H), 1.65–1.35 (m,
(cryst from diethyl ether/hexane), were obtained from 113 mg of 3b
4H), 0.96 (t, J¼7.2 Hz, 3H). 13C NMR:
d
¼155.1 (q, J¼39.2 Hz,
and 80 mg of 5a. 1H NMR:
d¼9.03 (br s, 1H, N–H), 8.11 (s, 1H), 7.78
CF3C]O), 146.2, 141.9, 131.3, 127.3, 123.7, 111.8 (Ar), 113.9 (C^N),
(d, J¼7.8 Hz, 1H), 7.43–7.35 (m, 2H), 7.09 (t, J¼4.7 Hz, 1H), 7.08–7.04
104.8, 73.3 (C^C), 30.3, 22.3, 19.5, 13.7. IR (KBr):
n
¼3240, 2238,
(m, 4H), 3.88 (s, 3H), 2.65–2.50 (m, 4H), 2.20–2.14 (m, 2H). 13C NMR:
1732, cmꢂ1. MS (EI): m/z (%)¼339 (36) [Mþ], 297 (100). Anal. calcd
for C15H12F3N3O3: C 53.10, H 3.57, N 12.39. Found: C 53.22, H 3.57,
N 12.35.
d
¼198.5 (C]O), 166.9 (C]O), 150.8, 136.1, 134.8, 133.8, 133.3, 131.0,
130.2, 129.1, 128.7, 128.3, 128.1, 122.6, 120.1, 119.2, 111.3, 52.2, 39.1,
26.8, 23.1. IR (KBr):
n
¼3325, 1710, 1680 cmꢂ1. MS (EI): m/z

2382
A. Arcadi et al. / Tetrahedron 66 (2010) 2378–2383
(%)¼345(20) [Mþ], 330 (100). Anal. calcd for C22H19NO3: C 76.42, H
(dec) (cryst from acetone/hexane), were obtained from 106 mg of
3f and 104 mg of 5a. 1H NMR:
5.54, N 4.06. Found C 76.63, H 5.52, N 4.08.
d
¼10.04 (br s, 1H, N–H), 8.40 (s, 1H),
8.29 (s, 1H), 7.11 (t, J¼3.8 Hz, 1H), 2.75–2.64 (m, 6H), 2.29–2.20 (m,
4.4.6. 2-[2-(4-Acetylphenyl)-1H-indol-3-yl]cyclohex-2-en-1-one
(6ca). Yield¼67%; 58 mg of brown solid, mp 194–195 ꢀC (cryst from
acetone/hexane), were obtainedfrom90 mgof3cand67 mgof5a.1H
2H), 1.72–1.60 (m, 2H), 1.41–1.29 (m, 2H), 0.92 (t, J¼7.2 Hz, 3H). 13C
NMR:
d
¼198.1 (C]O), 151.7, 143.6, 141.0, 138.1, 132.5, 129.2, 120.8,
120.2, 115.5, 112.2, 93.5, 38.8, 31.2, 26.7, 26.6, 23.0, 22.4, 13.7. IR
(KBr):
295 (48), 294 (88). Anal. calcd for C19H19N3O3: C 67.64, H 5.68, N
12.46. Found C 67.91, H 5.66, N 12.41.
NMR:
7.34 (d, J¼8.2 Hz, 2H), 7.16 (t, J¼3.9 Hz, 1H), 7.12–7.00 (m, 3H), 2.66–
2.57 (m, 4H), 2.48 (s, 3H), 2.26–2.17 (m, 2H). 13C NMR:
¼198.3,197.6
d¼9.09 (br s,1H, N–H), 7.60 (d, J¼8.2 Hz, 2H), 7.45–7.40 (m,1H),
n
¼3330, 2230, 1670 cmꢂ1. MS (EI): m/z (%)¼337 (100) [Mþ],
d
(C]O),151.0,137.7,136.4,135.5,134.7,133.9,128.7,128.5,126.9,123.0,
120.3, 119.4, 111.2, 39.1, 26.8, 26.5, 23.1. IR (KBr):
n
¼3330, 1670 cmꢂ1
.
4.4.12. 2-[2-(4-Phenylcyclohex-1-en-1-yl)-1H-indol-3-yl]cyclohex-
2-en-1-one (6ia). Yield¼40%; 46 mg of pale grey solid, mp 120–
122 ꢀC (cryst from diethyl ether/hexane), were obtained from
MS (EI): m/z (%)¼329 (100) [Mþ], 286 (17), 272 (72). Anal. calcd for
C22H19NO2: C 80.22, H 5.81, N 4.25. Found C 80.47, H 5.82, N 4.27.
115 mg of 3g and 76 mg of 5a. 1H NMR:
d
¼8.06 (br s,1H, N–H), 7.36–
4.4.7. 2-[2-(2-Bromophenyl)-1H-indol-3-yl]cyclohex-2-en-1-one
(6da). Yield¼87%; 109 mg of pale yellow solid, mp 180–181 ꢀC
(cryst from diethyl ether/hexane) were obtained from 126 mg of 3d
7.21 (m, 7H), 7.17–7.00 (m, 3H), 6.08 (br s, 1H), 2.90–2.75 (m, 1H),
2.65–2.52 (m, 4H), 2.50–2.35 (m, 4H), 2.30–1.95 (m, 4H). 13C NMR:
d
¼198.2 (C]O), 149.3, 146.6, 136.8, 135.4, 135.0, 131.5, 130.6, 129.2,
and 84 mg of 5a. 1H NMR:
d
¼8.23 (br s, 1H, N–H), 7.64 (d, J¼7.7 Hz,
128.4, 126.7, 126.4, 126.2, 122.0, 119.8, 119.0, 110.6, 39.5, 39.1, 33.7,
1H), 7.45–7.30 (m, 3H), 7.24–7.07 (m, 4H), 6.85 (t, J¼4.1 Hz,1H), 2.54
29.9, 28.0, 26.7, 23.2. IR (KBr):
n
¼3335,1660 cmꢂ1. ESI-MS m/z (%):
(t, J¼6.2 Hz, 2H), 2.44–2.35 (m, 2H), 2.11–2.02 (m, 2H). 13C NMR:
368 (100) [Mþþ1]. Anal. calcd for C26H25NO: C 84.98, H 6.86, N 3.81.
d
¼198.0 (C]O), 149.8, 135.5, 134.6, 134.2, 133.3, 132.6, 129.7, 128.9,
Found C 85.23, H 6.89, N 3.80.
128.4, 127.4, 127.2, 123.3, 122.6, 120.2, 120.1, 111.0, 39.0, 26.7, 23.0. IR
(KBr):
n
¼3350, 1650 cmꢂ1. MS (EI): m/z (%)¼367 (87), 365 (87)
Acknowledgements
[Mþ], 286 (100), 272 (72). Anal. calcd for C20H16BrNO: C 65.59, H
4.40, N 3.82. Found C 65.65, H 4.42, N 3.81.
`
This work was financed by the Ministero dell’Universita e della
Ricerca, Rome, and by the University of L’Aquila.
4.4.8. 2-(2-Thien-2-yl-1H-indol-3-yl)cyclohex-2-en-1-one
(6ea). Yield¼95%; 94 mg of brown solid, mp 144–145 ꢀC (cryst
from acetone/hexane), were obtained from 100 mg of 3e and 83 mg
References and notes
of 5a. 1H NMR:
d
¼8.93 (br s, 1H, N–H), 7.31–7.27 (m, 1H), 7.12–7.08
1. Selected current references: (a) Stansfield, I.; Ercolani, C.; Mackay, A.; Conte, I.;
Pompei, M. Bioorg. Med. Chem. Lett. 2009, 19, 627–632; (b) Zhou, N.; Zeller, W.;
Krohn, M.; Anderson, H.; Zhang, J.; Onua, E.; Kiselyov, A. S.; Ramirez, J.; Hall-
dorsdottir, G.; Andre´sson, 5.; Gurney, J.; Singh, M. E. Bioorg. Med. Chem. Lett.
2009, 19, 123–126; (c) Trogden, B. G.; Kim, S. H.; Lee, S.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. Lett. 2009, 19, 485–488; (d) Gurkok, G.; Altanlar, N.; Suzen,
N. S. Chemotherapy 2009, 55, 15–19; (e) Singhl, N.; Kumar Bhati, S.; Kumar, A.
Eur. J. Med. Chem. 2008, 43, 2597–2609; (f) Oslund, R. C.; Cermak, N.; Gelb, M. H.
J. Med. Chem. 2008, 51, 4708–4714.
(m, 2H), 7.04–7.00 (m, 2H), 6.90–6.84 (m, 1H), 6.72–6.70 (m, 1H),
6.62 (t, J¼4.6 Hz, 1H), 2.64 (t, J¼6.2 Hz, 2H), 2.56–2.51 (m, 2H),
2.23–2.10 (m, 2H). 13C NMR:
d
¼198.7 (C]O), 152.2, 135.9, 134.6,
134.4, 129.7, 129.2, 127.3, 124.8, 124.3, 122.5, 119.9, 118.9, 111.1, 39.1,
26.8, 23.0. IR (KBr):
n
¼3320, 1670 cmꢂ1. MS (EI): m/z (%)¼293 (100)
[Mþ], 264 (22), 236 (42). Anal. calcd for C18H15NOS: C 73.69, H 5.15,
N 4.77. Found C 73.43, H 5.13, N 4.77.
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11, 173–176; (b) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11,
221–224; (c) Fuwa, H.; Sasaki, M. J. Org. Chem. 2009, 74, 212–221; (d) Huang, H.;
Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604–606; (e) Goverdhan, G.; Reddy, A.
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2009, 13, 67–72; (f) Barraja, P.; Diana, P.; Carbone, A.; Cirrincione, G. Tetrahedron
2008, 64, 11625–11631; (g) Frayne, G. L.; Green, G. M. Tetrahedron Lett. 2008, 49,
7328–7329; (h) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. Synlett 2008, 3157–
3162; (i) Sanz, R.; Guilarte, V.; Castroviejo, M. P. Synlett 2008, 3006–3010; (j) Xu,
4. 4. 9. 2-(2-Butyl-1H-indol- 3-yl)cyclohex-2-en-1-one
(6fa). Yield¼77%; 81 mg of pale yellow solid, mp 91–93 ꢀC (cryst
from diethyl ether/hexane), were obtained from 106 mg of 3f and
96 mg of 5a. 1H NMR:
7.24–7.19 (m, 1H), 7.09–7.00 (m, 3H), 2.68–2.53 (m, 6H), 2.21–2.09
d
¼8.10 (br s, 1H, N–H), 7.33–7.28 (m, 1H),
¨
Z.; Hu, W.; Zhang, F.; Li, Q.; LU, Z.; Zhang, L.; Jia, Y. Synthesis 2008, 3981–3987;
(m, 2H), 1.65–1.49 (m, 2H), 1.40–1.22 (m, 2H), 0.88 (t, J¼7.2 Hz, 3H).
13C NMR:
d
¼198.5 (C]O), 149.5, 137.5, 135.2, 134.5, 129.0, 128.4,
(k) Li, P.; Wang, L.; Wang, M.; You, F. Eur. J. Org. Chem. 2008, 5946–5951; (l)
Melkonyan, F.; Topolyan, A.; Yurovskaya, M.; Karchava, A. Eur. J. Org. Chem.
2008, 5952–5956; Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61,
4439–4449.
121.0, 119.4, 118.6, 110.5, 39.1, 31.6, 29.7, 26.7, 23.3, 22.4, 13.8. IR
(KBr):
n
¼3310, 1660 cmꢂ1. MS (EI): m/z (%)¼267 (100) [Mþ], 224
¨
3. Recent reviews: (a) KrUger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350,
(98), 196 (41). Anal. calcd for C18H21NO: C 80.86, H 7.92, N 5.24.
Found C 81.11, H 7.88, N 5.22.
2153–2167; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920.
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1170–1173; (b) Yasuhara, A.; Suzuki, N.; Yoshino, T.; Takeda, Y.; Sakamoto, T.
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4.4.10. 2-[2-(4-Acetylphenyl)-5,7-difluoro-1H-indol-3-yl]cyclohex-2-
en-1-one (6ga). Yield¼72%; 95 mg of pale yellow solid, mp 195–
195 ꢀC (cryst from acetone/hexane), were obtained from 132 mg of
3g and 88 mgof 5a.1H NMR:
d
¼8.59 (br s,1H, N–H), 7.93 (d, J¼8.4 Hz,
2H), 7.54 (d, J¼8.4 Hz, 2H), 7.06 (t, J¼4.0 Hz, 1H), 6.84 (d, J¼8.6 Hz,
1H), 6.77–6.67 (m,1H), 2.66–2.52 (m, 4H), 2.60 (s, 3H), 2.22–2.15 (m,
2H). 13C NMR (500 MHz):
d¼197.2, 196.6 (C]O), 156.6 (dd,
J1¼238.1 Hz, J2¼10.0 Hz), 150.7, 147.8 (dd, J1¼247.0 Hz, J2¼13.9 Hz),
135.9, 135.53, 135.49, 133.2, 130.8 (dd, J1¼10.6 Hz, J2¼5.9 Hz), 128.1,
126.2,120.4 (d, J¼13.5 Hz), 99.7 (dd, J1¼23.9 Hz, J2¼4.0 Hz), 97.6 (dd,
J1¼30.2 Hz, J2¼20.3 Hz). IR (KBr):
n
¼3310,1670 cmꢂ1. MS (EI): m/z
(%)¼365 (100) [Mþ], 308 (79). Anal. calcd for C22H17F2NO2: C 72.32, H
4.69, N 3.83. Found C 72.08, H 4.69, N 3.85.
4.4.11. 2-Butyl-5-nitro-3-(6-oxocyclohex-1-en-1-yl)-1H-indole-7-
carbonitrile (6ha). Yield¼60%; 63 mg of yellow solid, mp>230 ꢀC

A. Arcadi et al. / Tetrahedron 66 (2010) 2378–2383
2383
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¨
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