Pd-catalyzed cyclization of 1-allyl-2-indolecarboxamides by intramolecular amidation of unactivated ethylenic bond

Article abstract of DOI:10.1055/s-2005-922788

The intramolecular Pd(II)-mediated cyclization of 1-allyl-2- indolecarboxamides leads to pyrazino[1,2-a]indoles through the conversion of the olefinic C-H bond into a C-N bond by reaction with an amide group. When operating on the allylamide, a domino pro

Full text of DOI:10.1055/s-2005-922788

LETTER
73
Pd-Catalyzed Cyclization of 1-Allyl-2-indolecarboxamides by Intramolecular
Amidation of Unactivated Ethylenic Bond
P
d-Catalyze
d
Cyci
o
of 1-Allyl-2
r
-indolec
g
a
Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, Università di Milano, via Venezian 21, 20133 Milan, Italy
b
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
Fax +39(31)2386449; E-mail: gianluigi.broggini@uninsubria.it
Received 4 October 2005
Both protocols have also become important in the func-
tionalization and synthesis of heterocyclic compounds,3
where in particular the elaboration of the indolyl nucleus
has received significant attention.4 Indole is a versatile
Abstract: The intramolecular Pd(II)-mediated cyclization of 1-al-
lyl-2-indolecarboxamides leads to pyrazino[1,2-a]indoles through
the conversion of the olefinic C–H bond into a C–N bond by
reaction with an amide group. When operating on the allylamide, a
domino process was observed with a double C–H functionalization. and useful tool for the synthesis of a wide range of
biologically important molecules, such as alkaloids and
natural peptides where the indole nucleus constitutes the
core of complex structures.5
Key words: cyclizations, fused-ring systems, indoles, palladium,
domino reactions
One research interest in our group concerns the develop-
ment of Pd-catalyzed processes for the synthesis of indo-
lo-fused polycyclic systems.6 We have previously
described the synthesis of pyrazino[1,2-a]indoles by an
intramolecular amination reaction employing 1-unsub-
stituted 2-indolecarboxylic acid allyl-amides.6c These
synthetically current structures7 constitute a class of
biologically active compounds as serotonin antagonists,8
protein kinase C inhibitors,9 DHFR inhibitors,10 throm-
bolytics,11 antileishmanials,12 GGTase I inhibitors13 and
5-HT2 agonists.14 Here, we report an alternative synthetic
approach to the same targets using N-monosubstituted 1-
allyl-2-indolecarboxamides and exploiting a Pd(II)-cata-
lyzed intramolecular oxidative process which involves the
formation of a C–N bond between the allylic group and
the amidic nitrogen atom.
In recent years there has been increasing interest in palla-
dium-catalyzed C–N bond-forming reactions. As well
documented, the Buchwald–Hartwig amination reaction
(Equation 1) has had a considerable impact in organic
synthesis, despite the need for aryl and vinyl halides as
starting substrates.1 A more versatile methodology, avoid-
ing halogenated compounds, consists of the direct interac-
tion of a nitrogen atom with simple olefins through an
oxidative palladium(II)-catalyzed process (Equation 2).2
RNH2
X
NHR
Pd cat.
Equation 1
R
The title amides were easily prepared by converting 1-al-
lyl-2-indolecarboxylic acid (1)15 into the corresponding
acyl chloride and subsequent reaction with the amines
depicted in Scheme 1.
R'2N
R'2NH
Pd cat.
R
R
or
R'2N
Equation 2
H
i, ii
iii
N
O
CO2H
R
N
N
N
O
N
R
1
2a–h (64–93%)
3a–h
a: R = phenyl
e: R = cyclohexyl
b: R = 4-methyl-phenyl
c: R = 4-methoxy-phenyl
d: R = 4-nitro-phenyl
f: R = (ethoxycarbonyl)methyl
g: R = benzyl
h: R = (2-furyl)methyl
Scheme 1 Amidation process on 1-allyl-2-indolecarboxamides 2a–h. Reagents and conditions: i) SOCl2, toluene, reflux, 4 h; ii) RNH2, TEA,
CH2Cl2, r.t., 2 h; iii) Pd(OAc)2 (5 mol%), Na2CO3, Bu4N+Cl–, 1,4-benzoquinone, DMF, 100 °C, 24 h.
SYNLETT 2006, No. 1, pp 0073–0076
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922788; Art ID: D30505ST
© Georg Thieme Verlag Stuttgart · New York

74
G. Abbiati et al.
LETTER
To realize the Pd-catalyzed intramolecular C–N bond for-
mation, a series of experiments was first screened on the
anilide 2a (Table 1). The best results were observed using
5 mol% of Pd(OAc)2 in the presence of Na2CO3, Bu4NCl
and 1,4-benzoquinone (BQ), in DMF as solvent at 100 °C
for 24 hours (entry b) which gave the total conversion of
the starting amide and the isolation of the pyrazino[1,2-
a]indole 3a in 78% yield.16
Table 1 Reaction Conditions for Cyclization of 2aa
Entry Catalystb
Solvent
Basec
Oxidantd Yield (%)
a
b
c
d
e
f
Pd(OAc)2/PPh3 DMF
Na2CO3 BQ
5
e
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
Na2CO3 BQ
78
THF–DMF t-BuOKe BQ
f
e
Scheme 2 Catalytic cycle for amidation process.
DMF
Na2CO3 MnO2 69
PdCl2(CH3CN)2 MeCN
PdCl2(CH3CN)2 DMF
BQ
Na2CO3 BQ
CuCl2
Na2CO3 BQ
–
e
Table 2 Conversion and Cyclization Yields of the Carboxamides 2
into the Pyrazino[1,2-a]indoles 3
28
–
g
h
Pd(OAc)2
THF
Entry
R
Conversion of 2 Yield of 3 (%)b
e
(%)a
Pd(OCOCF3)2 DMF
23
a Heating at reflux for entries e, g and at 100 °C for other entries for
a
b
c
d
e
f
100
78
83
77
75
28
55
24 h.
*
b 5 mol%.
c 3 Equiv.
90
d 1 Equiv.
*
*
e In the presence of Bu4NCl (1 equiv).
f Only double-bond isomerization was observed.
100
100
37
OMe
NO2
The following facts were established: i) the presence of a
base and tetrabutylammonium chloride were essential for
the cyclization reaction; the chloride anion plausibly acts
as a stabilizing agent in absence of phosphine ligand in the
reaction mixture and the cationic portion might act as ac-
celerating agent;17 ii) the process required the stoichio-
metric amount of an oxidant in order to achieve
reoxidation of the Pd(0) species to Pd(II). The latter
evidence demonstrates the need for a Pd(II) species in the
catalytic cycle and suggests the following mechanistic
sequence. The first formed electrophilic p-olefin palladi-
um(II) complex 4 is able to sustain the intramolecular nu-
cleophilic attack by the deprotonated nitrogen atom of the
tethered amide group to afford the s-complex 5
(Scheme 2). The subsequent b-hydride elimination gener-
ates the primary exomethylenic cyclization product 6,
which undergoes an inside double bond migration to give
3a. This final step produces Pd(0), justifying the need of
its reoxidation to Pd(II) to regenerate the catalytic cycle.
*
*
67
O
*
*
O
g
h
41
60
36
26
*
O
a Conversion determined by 1H NMR on the crude reaction mixture.
b Yield calculated after chromatography on silica gel column.
bases were tried out to improve the cyclization process of
2e–h. Unfortunately, no better results were attained
neither in presence of Pd(O2CCF3)2 or PdCl2(CH3CN)2 as
catalysts nor by using NaH or t-BuONa as base. In the
latter case, only double bond isomerization was observed.
In the light of the result obtained with the anilide 2a, the
same amidation reaction was carried out on the substrates
2b–h. Conversions and yields are collected in Table 2.
While the behavior of the arylamides 2b–d was analogous
to that of 2a, the alkyl and (hetero)benzylic ones were
more reluctant towards the intramolecular C–N bond for-
mation, probably due to the lower NH acidity, and large
amounts of starting material remained. Other catalysts and
When the protocol was applied to 1-allyl-2-indolecarbox-
amides 7 and 9, bearing a pyridyl or allyl group, respec-
tively, a different behavior was observed.
Synlett 2006, No. 1, 73–76 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Cyclization of 1-Allyl-2-indolecarboxamides
75
Refluxing the pyridylamide 7 for 48 hours afforded a In conclusion, we have developed an alternative synthesis
complex mixture from which only the hydroamidation of pyrazino[1,2-a]indoles by using the easily accessible 1-
product 818 was isolated (22% yield) and characterized allyl-2-indolecarboxamides via intramolecular Pd(II)-cat-
(Scheme 3). The mechanism path is undefined, even alyzed C–H functionalization. Such a feature is remark-
though interference of the pyridyl nitrogen in the Pd able because C–N bond formation by the way of an amide
elimination from the s-complex intermediate may be en- group is still rare,21 mostly requiring a powerful electron-
visaged.
withdrawing group (e.g. sulphonyl) on the nitrogen.22 In
the case of the substrate bearing two allylic groups, a
domino process was observed with generation of a tetra-
cyclic product. Further studies on the extension of this
cascade process are currently underway.
O
O
i
N
N
NH
N
N
N
Acknowledgment
We are grateful to MIUR (Cofin 2003) for financial support.
7
8
References and Notes
Scheme
3
Hydroamidation of 1-allyl-2-indolecarboxamide 7.
Reagents and conditions: i) Pd(OAc)2 (5 mol%), Na2CO3, Bu4N+Cl–,
(1) For reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-
F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
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(d) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am.
Chem. Soc. 2003, 125, 12996. (e) Gowan, M.; Caillé, A. S.;
Lau, C. K. Synlett 1997, 1312. (f) Andersson, P. G.;
Bäckvall, J.-E. J. Am. Chem. Soc. 1992, 114, 8696.
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5800.
1,4-benzoquinone, DMF, 100 °C, 48 h.
Under the standard conditions, only unreacted starting
material was recovered on treating allylamide 9.19
A
search for new reaction conditions to obtain the cycliza-
tion path led to an intriguing tetracyclic indole derivative
1020 in 28% yield instead of the typical amidation product,
as depicted in Scheme 4. Gratifyingly, treatment of 9 with
10 mol% of PdCl2(CH3CN)2 as catalyst, a stoichiometric
amount of 1,4-benzoquinone in DMF–THF as solvent at
80 °C for 2 hours resulted in a cascade process involving
in sequence the intramolecular C–N and C–C bond forma-
tions. The Pd-promoted domino process provides for a
double C–H functionalization with an oxidative coupling
triggered afterwards to the initial amidation step. Longer
reaction times led to decomposition of the product.
(3) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
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(4) For recent contributions, see: (a) Cacchi, S.; Fabrizi, G.
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Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem.
Int. Ed. 2005, 44, 3125. (d) Cacchi, S.; Fabrizi, G.; Parisi, L.
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Int. Ed. 2005, 44, 403. (g) Watanabe, T.; Arai, S.; Nishida,
A. Synlett 2004, 907.
NH
O
i
N
N
O
N
9
Cl Pd
(5) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(b) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
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O
O
N
N
N
N
(6) (a) Beccalli, E. M.; Broggini, G.; Marchesini, A.; Rossi, E.
Tetrahedron 2002, 58, 6673. (b) Beccalli, E. M.; Broggini,
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10
Cl Pd
Scheme 4 Domino process on 1-allyl-2-indolecarboxamide 9.
Reagents and conditions: i) PdCl2(CH3CN)2 (10 mol%), 1,4-benzo-
quinone, DMF–THF (1:2), 80 °C, 2 h.
Synlett 2006, No. 1, 73–76 © Thieme Stuttgart · New York

76
G. Abbiati et al.
LETTER
(s). MS: m/z = 274 [M+]. Anal. Calcd for C18H14N2O: C,
78.81; H, 5.14; N, 10.21. Found: C, 78.97; H, 4.99; N, 10.32.
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Cadilhac, C.; Dellac, G. Fr. Patent FR 2 761 073, 1998;
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(16) Experimental Procedure.
(18) 3-Methyl-2-(pyridin-2-yl)-3,4-dihydro-2H-pyrazino[1,2-
a]indol-1-one (8).
Mp 198–199 °C (diisopropyl ether). IR (nujol): 1678 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.46 (3 H, d, J = 6.7 Hz),
4.32 (1 H, d, J = 12.0 Hz), 4.44 (1 H, dd, J = 4.0, 12.0 Hz),
5.43–5.51 (1 H, m), 7.13 (1 H, dd, J = 5.0, 7.0 Hz), 7.18–
7.24 (1 H, m), 7.34–7.44 (2 H, m), 7.45 (1 H, s), 7.71–7.80
(2 H, m), 8.17 (1 H, d, J = 8.4 Hz), 8.47 (1 H, d, J = 4.0 Hz).
13C NMR (100 MHz, CDCl3): d = 19.3 (q), 46.4 (t), 51.5 (d),
107.9 (d), 110.1 (d), 120.1 (d), 120.7 (d), 121.2 (d), 123.2
(d), 125.3 (d), 128.0 (s), 129.2 (s), 137.3 (s), 137.7 (d), 148.1
(d), 152.9 (s), 159.7 (s). MS: m/z = 277 [M+]. Anal. Calcd for
C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.51; H,
5.27; N, 15.01.
(19) Chacun-Lefèvre, L.; Bénéteau, V.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2002, 58, 10181.
(20) 2-Methyl-12,12a-dihydro-1H-pyrrolo[1¢,2¢:4,5]pyr-
azino[1,2-a]indol-5-one (10).
Oil. IR (nujol): 1657 cm–1. 1H NMR (400 MHz, DMSO):
d = 1.83 (3 H, s), 2.59–2.69 (1 H, m), 2.78 (1 H, dd, J = 9.2,
15.9 Hz), 3.97 (1 H, dd, J = 12.1, 12.2 Hz), 4.52–4.65 (1 H,
m), 4.92 (1 H, dd, J = 4.4, 12.1 Hz), 6.80 (1 H, s), 7.08 (1 H,
s), 7.12 (1 H, dd, J = 7.7, 8.3 Hz), 7.31 (1 H, dd, J = 7.7, 8.0
A suspension of 2a (276 mg, 1.0 mmol), Pd(OAc)2 (11 mg,
0.05 mmol), Na2CO3 (318 mg, 3.0 mmol), Bu4NCl (278 mg,
1.0 mmol) and p-benzoquinone (108 mg, 1 mmol) in DMF
(10 mL) was stirred for 24 h at 100 °C. The solution was
washed with brine (25 mL) and extracted with Et2O (2 × 25
mL). The organic layer was dried over Na2SO4 and taken to
dryness under reduced pressure. The residue was
chromatographed on a silica gel column with light PE–
EtOAc 12:1 as eluent to give 3a.
Hz), 7.57 (1 H, d, J = 8.3 Hz), 7.67 (1 H, d, J = 8.0 Hz). 13
NMR (100 MHz, DMSO): d = 14.4 (q), 38.8 (t), 45.9 (t),
C
57.5 (d), 106.6 (d), 109.9 (d), 116.6 (d), 121.1 (d), 122.6 (s),
123.2 (d), 125.0 (d), 128.0 (s), 129.6 (s), 136.8 (s), 169.7 (s).
MS: m/z 238 [M+]. Anal. Calcd for C15H14N2O: C, 75.61; H,
5.92; N, 11.76. Found: C, 75.79; H, 6.01; N, 11.92.
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Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004, 69,
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Int. Ed. 2002, 41, 164. (d) Larock, R. C.; Hightower, T. R.;
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McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
Data for 3-Methyl-2-phenyl-2H-pyrazino[1,2-a]indol-1-
one (3a).
Mp 249–250 °C (diisopropyl ether). IR (nujol): 1682 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.95 (3 H, s), 7.24 (1 H, s),
7.29–7.34 (3 H, m), 7.39–7.45 (2 H, m), 7.48–7.56 (3 H, m),
7.68 (1 H, d, J = 8.2 Hz), 7.85 (1 H, d, J = 8.1 Hz). 13C NMR
(100 MHz, CDCl3): d = 18.7 (q), 103.5 (d), 104.1 (d), 110.8
(d), 122.6 (d), 123.0 (s), 123.1 (d), 124.3 (d), 127.4 (s), 128.0
(s), 129.1 (d), 129.4 (d), 129.9 (d), 132.3 (s), 137.9 (s), 158.4
Synlett 2006, No. 1, 73–76 © Thieme Stuttgart · New York