Novel domino approach to fluorescent pyrimido[1,6-a]indolones

Article abstract of DOI:10.1055/s-0029-1217807

Easily accessible N-ethoxycarbonyl-2-alkynylindoles undergo, in the presence of primary aryl amines and under TiCl₄/t-BuNH₂ catalysis, domino hydroamination-annulation reactions giving rise to pyrimido[1,6-a]indolones in good to exce

Full text of DOI:10.1055/s-0029-1217807

LETTER
2273
Novel Domino Approach to Fluorescent Pyrimido[1,6-a]indolones
D
omino
A
pproac
h
i
to Fluo
e
rescent Py
g
rimidoindolo
o
nes Facoetti,a Giorgio Abbiati,a Laura d’Avolio,a Lutz Ackermann,b Elisabetta Rossi*a
a
DISMAB, Sezione di Chimica Organica ‘Alessandro Marchesini’, Università degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
Fax +39(02)50314476; E-mail: elisabetta.rossi@unimi.it
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Goettingen, Tammannstr. 2, 37077 Goettingen, Germany
b
Received 21 May 2009
b
Abstract: Easily accessible N-ethoxycarbonyl-2-alkynylindoles
undergo, in the presence of primary aryl amines and under TiCl4/
t-BuNH2 catalysis, domino hydroamination–annulation reactions
giving rise to pyrimido[1,6-a]indolones in good to excellent yields.
The reaction involves an initial highly regio- and chemoselective
hydroamination reaction. The obtained compounds show interest-
ing fluorescence properties and could represent a new class of use-
ful markers for bioanalytical purpose.
b
n
O
R
O
R
a
NH3
NuH
N
b
N
a
b
A
B
Figure 1
Key words: alkynes, titanium, hydroaminations, domino reactions,
heterocycles, fluorescence
During recent years, catalyzed hydroamination reactions
became a valuable tool for the synthesis of nitrogen het-
erocycles and complex molecules.8 Among various cata-
lysts employed, titanium-based catalysts are particularly
attractive in terms of costs, functional group tolerability,
and regioselectivities.9 In particular, the inexpensive and
user-friendly TiCl4/t-BuNH2 catalytic system has been
described for the regioselective intermolecular anti-
Markovnikov hydroamination of alkynes.10
Domino reactions are now widely used to assemble sim-
ple or polyfunctionalized organic molecules.1 Thus, dom-
ino reactions allow the formation of several new covalent
bonds in a one-pot fashion, can accomplish the coupling
of three or more simple building blocks in a modular ap-
proach, and, in several cases, match well also with Trost’s
atom-economy concept.2 Moreover, they offer an attrac-
tive, economical, and ecologically benign alternative to
classical organic transformations. In this context, transi-
tion-metal catalysis has proven to play a pivotal role for
the direct construction of complicated heterocyclic and
heteropolycyclic molecules from readily accessible start-
ing materials under mild conditions.
N-Ethoxycarbonyl-2-alkynylindoles 2a–g were synthe-
sized in excellent yields starting from 2-trifluoromethane-
sulfonyloxy-indole-1-carboxylic acid ethyl ester (1) and
terminal alkynes following the Sonogashira protocol (Ta-
ble 1).11
On these bases, we investigated a domino sequence in-
volving hydroamination–annulation of N-ethoxycarbon-
yl-2-alkynylindoles with primary amines. Thus,
depending on the regiochemistry and the chemoselectivi-
ty of the process (Scheme 1) pyrimido[1,6-a]indol-1-ones
(path 1 and path 2a), imidazo[1,5-a]indol-3-ones (path 2b
and path 3a) or (path 3b) 3H-pyrrolo[1,2-a]indol-3-ones
should be obtained.
During the last years, we focused our attention on the
catalyzed and uncatalyzed domino addition–annulation
reactions of 2-acyl-N-propargylindoles and 2-acyl-3-
alkynyl(or propargyl)indoles for the synthesis of a- or b-
fused polycyclic indole systems, respectively. Thus, using
this synthetic approach, b-carbolines,3 pyrazino[1,2-a]-
indoles,4 [1,4]oxazino[4,3-a]indoles,5 pyrrolo[1,2-a]indol-
2-carbaldehydes,6 1-aminocarbazoles,7 and 9-amino-pyri-
do[1,2-a]indoles7 have been obtained. Most of the report-
ed reactions3–5,7 involve in the second step, step b of the
domino reaction, a nucleophilic attack onto a carbon–car-
bon triple bond that allows the annulation onto an existing
ring (Figure 1, A). Furthermore, we reversed the sequence
by performing a domino reaction involving in the first
step, step a, a TiCl4/t-BuNH2-catalyzed hydroamination
of the carbon–carbon triple bond followed by nucleophilic
attack of the enamine intermediate at the carbon–oxygen
double bond (Figure 1, B).6
The reactivity of compounds 2 under hydroamination
reaction conditions was then probed with primary
anilines, along with TiCl4/t-BuNH2 as catalytic system, in
dry toluene at 105 °C (Table 2). Under these conditions
we were pleased to isolate, after chromatographic purifi-
cation on silica gel, the pyrimido[1,6-a]indol-1-ones 3a–r
as the sole reaction products.12
Thus, the reactions proceeded in very good to excellent
yields with complete chemo- and regioselectivity giving
rise to compounds 3 in the presence of anilines bearing ei-
ther electron-donating or electron-withdrawing groups
(Table 2, entries 1–3, 5–7, 11–13). Only the reactions per-
formed on 2-alkynylindole 2g gave the corresponding py-
rimido[1,6-a]indol-1-ones 3o–p in very low yields (Table
2, entries 15, 16). In this case, beside the desired com-
SYNLETT 2009, No. 14, pp 2273–2276
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1217807; Art ID: G15909ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2274
D. Facoetti et al.
LETTER
R1
R1
NHR2
and/or
R1
and/or
R1
NHR2
N
N
N
N
R2NH2
O
O
R2HN
O
O
EtO
EtO
EtO
path 1
path 2b
path 3b
path 2a
path 3a
H
N
R1
R2
N
N
N
R1
and/or
and/or
N
R2
R1
N
R2
O
O
O
Scheme 1
Table 1 Synthesis of N-Ethoxycarbonyl-2-alkynylindoles 2a–g
Table 2 Synthesis of Pyrimido[1,6-a]indol-1-ones 3a–n
R2NH2
H
R
R1
TiCl4, t-BuNH2
Pd(PPh3)4, CuI, Et3N
DMF, r.t.
OSO2CF3
COOEt
R
N
N
R1
toluene, 105 °C, 24 h
N
N
COOEt
N
R2
COOEt
2a–g
3a–n
1
Product
2a
2a–g
O
R
Yield (%)a
Entry Product R1
R2
Yield (%)a,b
Ph
97
92
92
99
92
93
88
1
2
3a
3b
3c
3d
3e
3f
Ph
4-MeC6H4
89
87
81
–
2b
4-MeC6H4
3-F3CC6H4
4-MeOC6H4
C5H11
Ph
4-MeOC6H4
4-ClC6H4
n-Bu
2c
3
Ph
2d
4
Ph
2e
5
3-F3CC6H4
3-F3CC6H4
3-F3CC6H4
3-F3CC6H4
3-F3CC6H4
4-MeOC6H4
C5H11
4-MeC6H4
4-MeOC6H4
4-ClC6H4
n-Bu
85
81
87
–
2f
C6H13
6
2g
TMS
7
3g
3h
3i
a Reaction were carried out on a 2.0 mmol scale in 12 mL of dry
DMF–Et3N (8:4) under nitrogen atmosphere using the following mo-
lar ratios: 1/Pd(0)/CuI = 1:0.03:0.015.
8
9
Bn
–
10
11
12
13
14
15
16
3j
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
n-Bu
93
86
83
79
–
pounds, starting material was recovered in 55% and 57%
yield, respectively. Instead, any attempt to perform these
reactions in the presence of aliphatic amines failed, and
indoles 2 were recovered unreacted even after prolonged
heating at high temperature (170 °C instead of 105 °C;
Table 2, entries 4, 8, 9, 14).
3k
3l
C5H11
3m
3n
3o
3p
C6H13
C6H13
The reaction mechanism probably involves the regio-
selective hydroamination of the triple bond followed by
intramolecular attack of the nitrogen nucleophile at the
carbon–oxygen double bond and subsequent loss of etha-
nol (Scheme 1, path 1). An alternative route based on the
reverse sequence, (Scheme 1, path 2a) can be ruled out by
experimental evidence. Thus, the reaction of indole 2f
with 4-chloroaniline performed under otherwise identical
reaction conditions at ambient temperature for four hours
gave rise to a mixture of pyrimido[1,6-a]indol-1-one 3m
(38%) and ethyl 2-(2-oxooctyl)-1H-indole-1-carboxylate
4 (52%) after aqueous workup (Scheme 2).
TMS
4-MeC6H4
4-MeOC6H4
13
24
TMS
a Yields are referred to a single run.
b Reactions were carried out on a 0.60 mmol scale in 6 mL of dry tol-
uene under nitrogen atmosphere using the following molar ratios: 2/
amine/TiCl4/t-BuNH2 = 1:1.2:0.2:1.
of TiCl4 to activate carbonyl groups towards nucleophiles
is well documented. Thus, an activating role of this cata-
lyst also in the second step of the domino reaction is like-
ly.13
The TiCl4-catalyzed hydroamination–hydrolysis se-
quence of alkynes for the regioselective synthesis of ke-
tones has been reported elsewhere.9d Moreover, the ability
Although several routes are available for the preparation
of pyrimido[1,6-a]indol-1-ones, there are no reports on
general methods for the synthesis of these derivatives.
Synlett 2009, No. 14, 2273–2276 © Thieme Stuttgart · New York

LETTER
Domino Approach to Fluorescent Pyrimidoindolones
2275
heteroatom
4-ClC6H4NH2
TiCl4, t-BuNH2
4-ClC6H4HN
annulation reaction
C6H13
C6H13
N
toluene, r.t., 4 h
N
N
COOEt
2f
COOEt
aryl or
NH
heteroaryl
O
H13C6
Figure 2
O
aq workup
+
3m
These reactions are now under investigations in our labo-
ratories.
N
4
COOEt
Scheme 2
In conclusion, we reported a new efficient domino reac-
tion involving a highly regio- and chemoselective TiCl4-
catalyzed addition of anilines onto carbon–carbon triple
bonds followed by intramolecular annulation reaction,
which allowed for the synthesis of a new class of fluores-
cent pyrimidoindolones.
The reported protocols involve reactions of iminophos-
phoranes with heterocumulenes,14 olefination reactions of
2-formylindole with the N-Cbz Schmidt reagents,15 phos-
gene-mediated cyclization of 2-(1H-indol-2-yl)benzen-
amine,16 palladium-mediated cyclization of N-(2-bromo-
phenyl)- or N-allyl-1H-indole-1-carboxamide,17 and plat-
inum-catalyzed cascade dehydroalkoxylation–cyclization
of ortho-alkynylphenylureas.18
References and Notes
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.;
Brasche, G.; Gericke, K. In Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
Importantly, pyrimido[1,6-a]indol-1-ones 3a–c,e–g,i,j
bearing an aryl substituent in position 4, show interesting
fluorescence properties with maximum absorption and
emission wavelengths ranging from 308–320 and 420–
445 nm in methanol, respectively.19 In recent years, many
heterocyclic fluorescent compounds have been utilized
for labeling amino acids, peptides, proteins, DNA, and
other organic biomolecules for bioanalytical purposes.20
Detection and measurement of protein–protein, as well as
peptide–peptide and peptide–protein interactions based
on fluorescence techniques have received special atten-
tion, and notable progress has been made in both fluores-
cence instrumentation and synthesis of new fluorophores.
The linked organic fluorophores may form covalent or
noncovalent linkages with the sample to be analyzed, pro-
ducing the respective conjugates or complexes that can
show fluorescence from short to very long wavelengths,
depending on the marker used. Thus, the development of
new fluorophores with absorption and emission at appro-
priate wavelengths is of utmost importance. Using our
synthetic methodology a new class of heterocyclic fluoro-
phores could be assembled and utilized as specific probe
in biological studies. In particular, the structure of com-
pounds 3 could be modified by deprotection of N-2, there-
by creating useful functionality for the linkage to the
target bioactive molecule (peptide, oligonucleotide, etc.).
However, since the removal of the N-aryl substituent from
3 could be a complicated task an aliphatic substituent
would be introduced running the reaction of 2 in the pres-
ence of an alkylamine (i.e., benzylamine) and a suitable
catalytic system.8 Moreover, in order to vary the fluores-
cence properties, different aryl or heteroaryl rings could
be introduced in position 3 on the heteroaromatic scaffold,
the core indole nucleus could be modified by the introduc-
tion of other heteroatoms and the fundamental tricyclic
compound could be transformed into a polycyclic deriva-
tive by annulation reactions in 3,4-position (Figure 2).
(2) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259.
(3) Abbiati, G.; Beccalli, E.; Marchesini, A.; Rossi, E. Synthesis
2001, 2477.
(4) (a) Abbiati, G.; Beccalli, E.; Arcadi, A.; Rossi, E.
Tetrahedron Lett. 2003, 44, 5331. (b) Abbiati, G.; Arcadi,
A.; Bellinazzi, A.; Beccalli, E.; Rossi, E.; Zanzola, S. J. Org.
Chem. 2005, 70, 4088.
(5) Abbiati, G.; Canevari, V.; Caimi, S.; Rossi, E. Tetrahedron
Lett. 2005, 46, 7117.
(6) Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E.
Org. Lett. 2006, 8, 4839.
(7) Facoetti, D.; Abbiati, G.; Rossi, E. Eur. J. Org. Chem. 2009,
2872.
(8) Müller, T. E.; Kai, C.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795.
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(b) Doye, S. Synlett 2004, 1653. (c) Odom, A. Dalton
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Inorg. Chem. 2007, 2243.
(10) (a) Ackermann, L. Organometallics 2003, 22, 4367.
(b) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45,
9541. (c) Kaspar, L. T.; Fingerhut, B.; Ackermann, L.
Angew. Chem. Int. Ed. 2005, 44, 5972. (d) Ackermann, L.;
Kaspar, L. T. J. Org. Chem. 2007, 72, 6149.
(e) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 2824. (f) Ackermann, L.; Sandmann, R.;
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(11) Rossi, E.; Abbiati, G.; Canevari, V.; Celentano, G.; Magri,
E. Synthesis 2006, 299.
(12) Representative Procedure - Synthesis of 3a
In a 25 mL Schlenk tube, a solution of t-BuNH2 (49.83 mg,
71.6 mL, 0.673 mmol) in dry toluene (3 mL) was stirred at
0 °C under nitrogen. To the cooled solution TiCl4 (25.53 mg,
14.76 mL, 0.135 mmol) was added dropwise via syringe. The
obtained mixture was stirred at 0 °C for 15 min, and then a
solution of 2a (194.5 mg, 0.673 mmol) and 4-methylaniline
(86.5 mg, 0.808 mmol) in dry toluene (3 mL) was slowly
added via cannula under a nitrogen atmosphere. The reaction
mixture was warmed at 105 °C and stirred overnight. After
cooling the reaction mixture was poured in 0.1 N HCl (20
mL), the organic layer was separated and the aqueous phase
extracted with EtOAc (3 × 20 mL). The collected organic
Synlett 2009, No. 14, 2273–2276 © Thieme Stuttgart · New York

2276
D. Facoetti et al.
LETTER
phases were dried over Na2SO4 and concentrated at reduced
pressure. The resulting crude material was purified by flash
chromatography on SiO2 (EtOAc–hexane, 1:9) to afford 210
mg (89% yield) of pyrimido[1,6-a]indol-1-one 3a. White
solid; mp 199–200 °C. IR (KBr): 3366, 1692, 1634, 1390,
1366, 781, 754 cm–1. 1H NMR (200 MHz, CDCl3): d = 8.69
(dd, J = 0.7, 7.0 Hz, 1 H), 7.65–7.71 (m, 1 H), 7.31–7.44 (m,
2 H), 7.21 (s, 5 H), 7.10 (s, 4 H), 6.61 (s, 1 H), 6.54 (s, 1 H),
2.30 (s, 3 H). 13C NMR (50.3 MHz, APT, CDCl3): d = 149.3
(Cq), 140.9 (Cq), 138.0 (Cq), 135.7 (Cq), 135.5 (Cq), 134.5
(Cq), 133.7 (Cq), 131.1 (Cq), 129.7 (CH), 129.6 (CH), 129.2
(CH), 128.5 (CH), 128.2 (CH), 124.2 (CH), 123.0 (CH),
120.0 (CH), 116.6 (CH), 101.3 (CH), 98.8 (CH), 21.4 (CH3).
ESI-MS: m/z (%) = 351 (100) [MH+]. ESI-MS/MS: m/z
(%) = 351 (64) [MH+], 259 (100). Anal. Calcd for
C24H18N2O: C, 82.26; H, 5.18; N, 7.99. Found: C, 82.24; H,
5.14; N, 8.03.
(13) (a) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem. 2003, 68,
7915. (b) Kabalka, G. W.; Ju, Y.; Wu, Z. Org. Lett. 2002, 4,
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A.; Rizzoli, C. Chem. Ber. 1996, 129, 1361.
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1063.
(15) Carlier, P. R.; Lam, P. C.-H.; Wong, D. M. J. Org. Chem.
2002, 6256.
(16) Bergman, J.; Engqvist, R.; Stålhandske, C.; Wallberg, H.
Tetrahedron 2003, 59, 1033.
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(19) UV and fluorescence spectra were recorded at 25 °C in
MeOH. As an example both absorption and emission spectra
of compound 3c are reported in Figure 3.
Figure 3
(20) Goncalves, M. S. T. Chem. Rev. 2009, 109, 190.
Synlett 2009, No. 14, 2273–2276 © Thieme Stuttgart · New York