3-Aroylindoles via copper-catalyzed cyclization of N-(2-iodoaryl)enaminones

Article abstract of DOI:10.1055/s-0029-1216742

3-Aroylindoles have been prepared via copper-catalyzed cyclization of N-(2-iodoaryl)enaminones, readily available from 2-iodoanilines and α,β-ynones. The reaction tolerates a variety of useful functionalities including ether, keto, cyano, bromo, and chlor

Full text of DOI:10.1055/s-0029-1216742

1480
LETTER
3-Aroylindoles via Copper-Catalyzed Cyclization of
N-(2-Iodoaryl)enaminones
3
-Acylindoles fro
o
m
N
-(2-iodo
b
aryl)enamin
e
a
Dipartimento A.B.A.C., Università della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’,
Via S. Camillo De Lellis, 01100 Viterbo, Italy
b
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 20 January 2009
indoles using 1.5–2.0 equivalents of CuI and NaH as the
base in HMPA at 100–170 °C.
Abstract: 3-Aroylindoles have been prepared via copper-catalyzed
cyclization of N-(2-iodoaryl)enaminones, readily available from 2-
iodoanilines and a,b-ynones. The reaction tolerates a variety of use-
ful functionalities including ether, keto, cyano, bromo, and chloro
substituents. This indole synthesis can also be carried out from 2-
iodoanilines and a,b-ynones through a sequential process that omits
the isolation of enaminone intermediates.
During the past few years there have been remarkable ad-
vances in the use of copper in organic synthesis.6 Particu-
larly, it has been shown that by using appropriate ligands
a large number of reactions can be carried out in the pres-
ence of catalytic amounts of copper, often providing an at-
tractive economic alternative to palladium-catalyzed
reactions. Therefore, because of our continuing interest in
indole synthesis7,8 and our recent studies on the chemistry
of enaminones,9 we became interested in investigating the
feasibility of a copper-catalyzed cyclization of N-(2-
haloaryl)enaminones via substitution of the C–C bond for
the C–halogen bond. Herein we report the results of this
study.
Key words: indoles, enaminones, cyclization, copper, catalysis
3-Acylindoles are useful intermediates for the preparation
of pyridocarbazole alkaloids1 and important therapeutic
agents.2 For example, A-85783 is a potent and selective
antagonist of PAF2e and pravadoline (Figure 1) is a non-
acidic analogue of nonsteroidal anti-inflammatory drugs
(NAID).2a
N-(2-Haloaryl)enaminones 1 were prepared via Sono-
gashira cross-coupling of terminal alkynes with aroyl
chlorides10 followed by the conjugate addition of 2-halo-
anilines with the resultant a,b-ynones4a (Scheme 1). N-(2-
Haloaryl)enaminones 1 have always been isolated as sin-
gle isomers. The Z-stereochemistry of 1a has been as-
signed by NOESY experiments which showed also the
presence of an intramolecular hydrogen bond (N–H···O).
That of the other enaminones has been assigned on the
basis of these data.
MeO
N
S
O
N
Me
O
N
Me
N
N
We started our study by examining the conversion of 1a
into the corresponding indole derivative 2a using CuI as
the precatalyst, K2CO3 as the base at 100 °C, and explor-
ing the influence of solvents and ligands on the reaction
outcome. No indole formation was observed omitting
copper and ligands (Table 1, entry 1) whereas moderate to
good yields were obtained with 0.05 equivalents of CuI
and omitting ligands in DMSO and DMF (Table 1, entries
2 and 3). Utilization of phosphine ligands (Table 1, entries
5–7) showed that 2a could form in high yield with dppp
(Table 1, entry 7) but the best result in terms of yield and
reaction time was achieved using 0.05 equivalents of CuI
and 0.05 equivalents of 1,10-phenanthroline: 2a was iso-
lated in 92% yield after 2.5 hours at 100 °C in DMF
(Table 1, entry 11).
NMe2
F
O
O
pravadoline
A-85783
Figure 1
A variety of methods have been used for their preparation.
The vast majority of them rely on the acylation of pre-
formed indole derivatives.3 Direct construction of the 3-
acylindole skeleton from acyclic precursors has received
less attention. This protocol has been used in the palladi-
um-catalyzed cyclization of 2-(alkynyl)trifluoroacetanil-
ides in the presence of carbon monoxide and aryl halides
or vinyl triflates4 and in the copper-promoted5 cyclization
of N-(2-haloaryl)enaminones. As to the latter, only two N-
(2-haloaryl)enaminones, derived from acyclic b-di-
ketones, were converted into the corresponding 3-acyl-
Using the optimized conditions, we next explored the
scope and generality of the process.11 As shown in
Table 2, a variety of indoles can be prepared in high to ex-
cellent yields. Several useful functionalities are tolerated,
SYNLETT 2009, No. 9, pp 1480–1484
Advanced online publication: 14.05.2009
DOI: 10.1055/s-0029-1216742; Art ID: G01209ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Aroylindoles from N-(2-Iodoaryl)enaminones
1481
PdCl2(PPh3)2
CuI, Et3N
such a competition between C- and O-cyclization was ob-
served with the iodo derivatives that we have investigated.
Ar
Ar
R1
O
+
O
THF, r.t., 1 h
Cl
Table 2 Synthesis of 3-Acylindoles 2 via Copper-Catalyzed
Cyclization of N-(2-Iodoaryl)enaminones 1a
R2
X
R1
Ar
O
R2
X
Entry Product
Time Yield
(h)
NH2
MeOH, 120 °C, 24–48 h
(%)b
N
R1
O
H
Ph
X = I, Br
1
1
2
2a
2b
2.5
92
Scheme 1
Ph
N
H
Table 1 Optimization of Reaction Conditionsa
O
O
Ph
Ph
O
I
5
95
93
F
Ph
Ph
Ph
N
N
H
N
H
Ph
H
O
1a
2a
3
4
2c
3.5
Entry Ligand (equiv)
Solvent
DMF
Time (h) Yield (%)b
CF3
c
1
2
–
7
8
–
N
H
–
DMSO
DMF
51
69
F
O
3
–
8
2d
10
96
d
4
–
dioxane
DMF
8
–
N
H
5
Ph3P (0.05)
dppe (0.05)
dppp (0.05)
TMEDA (0.05)
DMEDA (0.05)
L-proline (0.1)
6
67
47
80
65
69
63
92
OMe
O
6
DMF
7
Ph
5
6
2e
2f
10
3
91
87
7
DMF
7
Cl
N
8
DMF
7
H
O
9
DMF
7
Ph
10
11
DMF
20
n-C5H11
1,10-phenanthroline
(0.05)
DMF
2.5
N
H
a Unless otherwise stated, reactions were carried out at 100 °C on a
0.25 mmol scale using 0.05 equiv of CuI, 2 equiv of K2CO3, in 2.5 mL
of solvent.
O
7
8
9
2g
2h
2i
4
13
8
89
86
88
F
CF3
b Yields are given for isolated products.
c In the absence of CuI.
Ph
Ph
N
H
d Compound 1a was recovered in 93% yield.
O
including ether, keto, cyano, bromo, and chloro substitu-
ents.
F
Me
N
We next explored the extension of this indole synthesis to
bromo-containing enaminones. However, when the N-(2-
bromoaryl)enaminone 1a¢ (R1 = Ar = Ph; R2 = H; X = Br)
was subjected to our standard conditions, we were sur-
prised to find that the formation of the expected indole
product was accompanied by the formation of the benzox-
azepine derivative 3 (Scheme 2). Most probably its for-
mation involves an intramolecular copper-catalyzed
substitution of the C–O bond for the C–Br bond.12 No
H
Cl
O
Me
Ph
N
H
Synlett 2009, No. 9, 1480–1484 © Thieme Stuttgart · New York

1482
R. Bernini et al.
LETTER
Table 2 Synthesis of 3-Acylindoles 2 via Copper-Catalyzed
Cyclization of N-(2-Iodoaryl)enaminones 1a (continued)
Ph
O
Ph
O
1. MeOH, 120 °C, 48 h
2. CuI, phenathroline
K2CO3, DMF, 100 °C, 2 h
I
+
Entry Product
Time Yield
Ph
(h)
(%)b
N
H
NH2
Ph
2a (76%)
O
Scheme 3
10
11
2j
4
96
Me
Me
OMe
Ph
Ph
Ph
als.13 Under these conditions, 2a was isolated in 76%
overall yield (Scheme 3).
N
H
O
On the basis of the recently reported tendency of N-aryl
enaminones to coordinate to palladium(II) electrophiles14
and previous observations on related Cu-catalyzed hetero-
cyclizations involving Caromatic–X bonds,15 a plausible
mechanism for this indole ring formation begins with the
initial coordination of carbon with copper (Scheme 4).
The resulting complex A undergoes an oxidative addition
of the C–X bond to copper to afford the Cu(III) interme-
diate B. Subsequent reductive elimination releases the
product with concomitant regeneration of the Cu(I) spe-
cies. Another possible mechanism involves the formation
of B via oxidative addition of the C–I bond to CuI to pro-
duce a Cu(III) intermediate followed by nucleophilic dis-
placement of iodide by the anionic fragment.
2k
8
88
N
H
O
12
13
2l
3
2
91
93
Cl
Cl
OMe
Ph
N
H
O
Ph
2m
CN
N
H
Br
O
R
R
O
X
R
14
15
2n
2o
6
1
92
73
O
N
Cl
H
2
Ph
N
R
H
N
H
1
Cu(I)X
B
X
O
R
Ph
BH X
O
Cu(III)
R
O
R
Cu(I)
X
O
X
N
H
R
Cu(I)
N
B
N
H
R
N
COMe
H
R
A
a Reactions were carried out at 100 °C on a 0.25 mmol scale using
0.05 equiv of CuI, 0.05 equiv of 1,10-phenathroline, 2 equiv of
K2CO3 in 2.5 mL of DMF.
Scheme 4
b Yields are given for isolated products.
In conclusion, we have shown that N-(2-iodoaryl)enami-
nones can be converted into the corresponding 3-acyl-
indoles in the presence of catalytic amounts of CuI.16,17
The new method tolerates a variety of useful functional-
ities including ether, keto, cyano, bromo, and chloro sub-
stituents. 3-Acylindoles can also be prepared via a
sequential process from a,b-ynones and 2-iodoanilines,
omitting the isolation of the enaminone intermediates.
Since multisubstituted indoles are essentially formed by
This indole synthesis can also be carried out through a
process that omits the isolation of the enaminone interme-
diates. In practice, excellent results can be obtained by
adding CuI, 1,10-phenanthroline, K2CO3, and DMF to the
crude mixture derived from the reaction of 2-iodoanilines
with a,b-ynones after evaporation of the volatile materi-
O
Ph
Ph
CuI
Ph
O
Br
1,10-phenthroline
O
K2CO3
+
Ph
DMF, 100 °C, 1.5 h
N
N
H
N
Ph
H
Ph
2a (30%)
3 (36%)
1a'
Scheme 2
Synlett 2009, No. 9, 1480–1484 © Thieme Stuttgart · New York

LETTER
3-Aroylindoles from N-(2-Iodoaryl)enaminones
1483
Dieguez, M. Chem. Rev. 2008, 108, 2796. (f) Yamada,
K.-i.; Tomioka, K. Chem. Rev. 2008, 108, 2874.
(g) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887.
(h) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
(i) Carril, M.; SanMartin, R.; Dominguez, E. Chem. Soc.
Rev. 2008, 37, 639.
assembling 2-iodoanilines, aroyl chlorides, and terminal
alkynes, a wide variety of indole derivatives can be syn-
thesized by using this protocol that can be particularly
useful for the preparation of libraries.
(7) Cacchi, S.; Fab rizi, G. Chem. Rev. 2005, 105, 2873.
(8) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
(9) (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10,
2629. (b) Bernini, R.; Cacchi, S.; Fabrizi, G.; Sferrazza, A.
Synthesis 2009, 1209.
(10) Karpov, A. S.; Müller, T. J. Org. Lett. 2003, 5, 3451.
(11) Typical Procedure for the Cyclization of N-(2-Iodoaryl)-
enaminones 1 to 3-Acylindoles 2
Acknowledgment
Work carried out in the framework of the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’ sup-
ported by the Ministero dell'’Università e della Ricerca Scientifica
e Tecnologica and by the University ‘La Sapienza’.
References and Notes
To a stirred solution of 1d (118.2 mg, 0.25 mmol) in DMF
(2.5 mL), CuI (2.4 mg, 0.0125 mmol), 1,10-phenanthroline
(2.3 mg, 0.0125 mmol), and K2CO3 (69.0 mg, 0.50 mmol)
were added at r.t. The reaction mixture was warmed at
100 °C and stirred for 10 h. After cooling, the reaction
mixture was diluted with Et2O, washed with 1 N HCl and
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography on
SiO2 [n-hexane–EtOAc, 70:30] to afford 82.8 mg (96%
yield) of 2d: white solid; mp 184–185 °C. IR (KBr): 3423,
2927, 1601, 1562, 1435, 1223 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 12.22 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H),
7.60–7.57 (m, 2 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.27 (t, J = 7.9
Hz, 1 H), 7.18 (t, J = 7.8 Hz, 2 H), 7.04–6.92 (m, 4 H), 6.85
(d, J = 7.6 Hz, 1 H), 3.67 (s, 1 H). 13C NMR (100.6 MHz,
DMSO-d6): d = 191.2, 164.3 (d, JCF = 251 Hz), 159.3, 144.4,
137.1 (d, JCF = 22 Hz), 136.3, 133.2, 132.2 (d, JCF = 9 Hz),
129.7, 128.7, 123.5, 122.5, 122.0, 121.1, 115.4, 115.3, 115.1
(d, JCF = 4 Hz), 112.6, 112.4, 55.6. 19F NMR (376 MHz,
DMSO-d6): d = –108.6. Anal. Calcd for C22H16FNO2: C,
76.51; H, 4.67. Found: C, 76.40; H, 4.58.
(1) Wijsmuller, W. F. A.; Wanner, M. J.; Koomen, G.-J.; Pandit,
U. K. Heterocycles 1986, 24, 1795.
(2) (a) Bell, M. R.; D’Ambra, T. E.; Kumar, V.; Eissenstat,
M. A.; Herrmann, J. L. Jr.; Wetzel, J. R.; Rosi, D.; Philion,
R. E.; Daum, S. J.; Hlasta, D. J.; Kullnig, R. K.; Ackerman,
J. H.; Haubrich, D. R.; Luttinger, D. A.; Baizman, E. R.;
Miller, M. S.; Ward, S. J. J. Med. Chem. 1991, 34, 1099.
(b) D’Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat,
M. A.; Josef, K. A.; Ward, S. J.; Haycock, D. A.; Baizman,
E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.; Grego,
J. D.; Kullnig, R. K.; Daley, G. T. J. Med. Chem. 1992, 35,
124. (c) Sheppard, G. S.; Pireh, D.; Carrera, G. M.; Bures,
M. G.; Heyman, H. R.; Steinman, D. H.; Davidsen, S. K.;
Phillips, J. G.; Guinn, D. E.; May, P. D.; Conway, R. D.;
Rhein, D. A.; Calhoun, W. C.; Albert, D. H.; Magoc, T. J.;
Carter, G. W.; Summers, J. B. J. Med. Chem. 1994, 37,
2011. (d) Lehr, M. J. Med. Chem. 1997, 40, 2694.
(e) Curtin, M. L.; Davidsen, S. K.; Heyman, H. R.; Garland,
R. B.; Sheppard, G. S.; Florjancic, A. S.; Xu, L.; Carrera,
G. M.; Steinman, D. H.; Trautmann, J. A.; Albert, D. H.;
Magoc, T. J.; Tapang, P.; Rhein, D. A.; Conway, R. G.; Luo,
G.; Denissen, J. F.; Marsh, K. C.; Morgan, D. W.; Summers,
J. B. J. Med. Chem. 1998, 41, 74.
(12) Compounds 2a and 3 were isolated in 30% and 60% yield,
respectively, when the reaction was carried out in DMA at
120 °C (3 h).
(13) Typical Procedure for the Preparation of 3-Acylindoles 2
Omitting the Isolation of Enaminone Intermediates
To a stirred solution of 2-iodoaniline (109.5 mg, 0.5 mmol)
in MeOH (1.0 mL), 1,3-diphenylprop-2-yn-1-one (154.5
mg, 0.75 mmol) was added at r.t. The reaction mixture was
warmed at 120 °C and stirred for 48 h. After that period the
volatile materials were evaporated at reduced pressure, and
CuI (4.8 mg, 0.025 mmol), 1,10-phenanthroline (4.5 mg,
0.025 mmol), K2CO3 (138.0 mg, 1.0 mmol), and DMF (4
mL) were added. The reaction mixture was warmed at
100 °C and stirred for 2.5 h. After cooling, the reaction
mixture was diluted with Et2O, washed with1 N HCl and
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography on
SiO2 [n-hexane–EtOAc, 75:25] to afford 106 mg (76%
yield) of 2a: white solid; mp 223–224 °C. IR (KBr): 3055,
1593, 1564, 1450, 1421 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 12.19 (br s, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.54–7.51
(m, 3 H), 7.40–7.35 (m, 3 H), 7.26–7.10 (m, 7 H). 13C NMR
(100.6 MHz, DMSO-d6): d = 192.6, 144.6, 140.3, 136.3,
132.1, 131.8, 130.1, 129.6, 129.0, 128.7, 128.5, 128.3,
123.4, 121.9, 121.1, 112.7, 112.4. Anal. Calcd for
(3) For the acylation of N-protected indoles, see: (a) Ketcha,
D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451. For
the acylation of NH free indoles, see: (b) Ottoni, O.; Neder,
A. de.V.F.; Dias, A. K. D.; Cruz, R. P. A.; Equino, L. B. Org.
Lett. 2001, 7, 1005. For the preparation of 3-acylindoles via
the Vilsmeier–Haack reaction, see: (c) Sundberg, R. J. The
Chemistry of Indoles; Academic Press: New York, 1970.
For the acylation of indole Grignard reagents, see:
(d) Heacock, R. A.; Kasparek, S. Adv. Heterocycl. Chem.
1969, 10, 61. see ref. 3c. For the acylation of 3-indolylzinc
chlorides, see: (e) Bergman, J.; Venemalm, L. Tetrahedron
1990, 46, 6061. (f) Faul, M. M.; Winneroski, L. L.
Tetrahedron Lett. 1997, 38, 4749. For other procedures,
see: (g) Bergman, J.; Bäckvall, J. E.; Lindströn, J. O.
Tetrahedron 1973, 29, 971. (h) Eyley, S. C.; Giles, R. G.;
Heaney, H. Tetrahedron Lett. 1985, 26, 4649. (i) Pindur,
U.; Flo, C.; Akgun, E.; Tunali, M. Liebigs Ann. Chem. 1986,
9, 1621. (j) Pfeuffer, L.; Sody, E.; Pindur, U. Chem.-Ztg.
1987, 111, 84.
(4) (a) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215. (b) Arcadi, A.; Cacchi, S.; Carnicellli,
V.; Marinelli, F. Tetrahedron 1994, 50, 437.
(5) Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031.
(6) For recent reviews, see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem. 2003, 115, 5558. (b) Evano, G.; Blanchard,
N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (c) Deutsch,
C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916.
(d) Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359.
(e) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.;
C21H15NO: C, 84.82; H, 5.08. Found: C, 84.71; H, 5.19.
(14) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008,
130, 3708.
(15) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802.
Synlett 2009, No. 9, 1480–1484 © Thieme Stuttgart · New York

1484
R. Bernini et al.
LETTER
(16) For some recent leading references on the copper-catalyzed
construction of the indole ring, see: (a) Cacchi, S.; Fabrizi,
G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (b) Lu, B.; Ma,
D. Org. Lett. 2006, 8, 6115. (c) Yuen, J.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 653. (d) Chen, Y.; Xie, X.;
Ma, D. J. Org. Chem. 2007, 72, 9329. (e)Tanimori, S.; Ura,
H.; Kirihata, M. Eur. J. Org. Chem. 2007, 3977.
(17) For some recent leading references on the copper-catalyzed
functionalization of indole rings, see: (a) Coste, A.; Toumi,
M.; Wright, K.; Razafimahaléo, V.; Couty, F.; Marrot, J.;
Evano, G. Org. Lett. 2008, 10, 3841. (b) Toumi, M.; Couty,
F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027.
(f) Hiroaki, O.; Yusuke, O.; Shinya, O.; Nobutaka, F.
Angew. Chem. Int. Ed. 2007, 46, 2295. (g) Chen, Y.; Wang,
Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625.
Synlett 2009, No. 9, 1480–1484 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.