An efficient synthesis of indolo[1,2-c]quinazolines

Article abstract of DOI:10.14233/ajchem.2014.15954

Gold(I)-catalyzed cascade reaction was developed for the synthesis of new fused indolo[1,2-c]quinazolines by using 2-(3-methyl-1Hindol- 2-yl)aniline and alkynes. This reaction provides a variety of biologically important quinazolines from easily available starting materials.

Full text of DOI:10.14233/ajchem.2014.15954

Asian Journal of Chemistry; Vol. 26, No. 10 (2014), 2893-2895
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15954
An Efficient Synthesis of Indolo[1,2-c]quinazolines
*
PEDIREDLA G.V.V. LAKSHMI and NITIN T. PATIL
Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
*Corresponding author: E-mail: p.g.v.v.lakshmi@gmail.com
Received: 25 June 2013;
Accepted: 14 August 2013;
Published online: 10 May 2014;
AJC-15142
Gold(I)-catalyzed cascade reaction was developed for the synthesis of new fused indolo[1,2-c]quinazolines by using 2-(3-methyl-1H-
indol-2-yl)aniline and alkynes. This reaction provides a variety of biologically important quinazolines from easily available starting
materials.
Keywords: Gold(I), Cascade reactions, 2-(3-Methyl-1H-indol-2-yl)aniline, Alkynes, Indolo[1,2-c]quinazolines.
by silica gel column chromatography with hexane/ethyl
acetate as an eluent to afford analytically pure compound 3
(Scheme-I).
INTRODUCTION
Nitrogen containing polycyclic compounds are identified
as attractive templates for drug discovery. Among various
nitrogen containing heterocycles1, fused quinazolines2 are
important structural motifs found in many natural products
and these are pharmaceutically important compounds. General
and convenient methods for the construction of these types of
compounds would be of great interest to the synthetic organic
chemists. The ideal way to access these compounds from easily
available starting materials, without isolating any interme-
diates3 would be of more interest.
Scheme-I
6,12-Dimethyl-6-phenyl-5,6-dihydroindolo[1,2-
c]quinazoline (3a): 80 % yield; liquid; Rf = 0.42 (hexane/
EtOAc = 90/10); 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, J =
7.9 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.64-7.63 (m, 1H),
7.57-7.55 (m, 1H), 7.47-7.44 (m, 1H), 7.40-7.39 (m, 1H), 7.12-
7.09 (m, 1H), 7.01 (t, J = 6.9 Hz, 2H), 6.96-6.92 (m, 1H),
6.80-6.78 (m, 1H), 6.70 (d, J = 6.9 Hz, 1H), 6.23 (d, J = 7.9
Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); 13C NMR (CDCl3, 75 MHz):
δ 143.2, 139.9, 133.1, 130.4, 128.9, 128.6, 128.5, 128.2, 127.5,
127.4, 125.1, 121.3, 119.6, 119.0, 118.2, 115.1, 111.5, 107.2,
73.4, 24.8, 11.0; IR (film): νmax, cm-1, 3393, 3012, 3001, 2999,
2925, 1687, 1649, 1516, 1509, 1320, 1020, 973, 882, 841,
758, 687; HRMS calcd. for C23H21N2 (M+• + H) 325.1705,
found 325.1716.
As a part of our interest in the development of metal cata-
lyzed cascade processes4 that easily produced privileged
scaffolds with molecular complexity5, we recently reported,
Au(I)-catalyzed cascade reaction between aminoaromatics
having tethered nucleophiles and alkynes6. The hypothesis on
which the present work involved the use of 2-(3-methyl-1H-
indol-2-yl)aniline7 with different alkynes in the presence of
catalyst Ph3PAuOTf to produce fused indolo[1,2-c]quinazolines.
EXPERIMENTAL
General method for the synthesis of fused indolo-
quinazolines: To a screw cap vial containing a stir bar, were
added 2-(3-methyl-1H-indol-2-yl)aniline 1 (0.450 mmol),
alkyne 2 (0.540 mmol) and 2 mol % Ph3PAuOTf (Ph3PAuCl/
AgOTf) in toluene (2 mL). The reaction vial was evacuated
and filled with nitrogen and heated with stirring at 100 °C for
24 h. The reaction mixture was cooled to ambient temperature,
diluted with ethyl acetate and filtered through a plug of silica
gel. The filtrate was concentrated and the residue was purified
RESULTS AND DISCUSSION
For the present transformation, the catalyst Ph3PAuOTf
in toluene was found to be optimal. An equimolar mixture of
2-(3-methyl-1H-indol-2-yl)aniline (1) and ethynylbenzene
(2a) in the presence of 2 mol % Ph3PAuOTf was heated in

2894 Lakshmi et al.
Asian J. Chem.
toluene at 100 °C for 24 h. The starting material was completely
consumed and giving the required product 6,12-dimethyl-6-
phenyl-5,6-dihydroindolo[1,2-c]quinazoline (3a) in 78 % yield
(Entry 1, Table-1). The scope of this transformation was further
explored by treating 1 with different terminal alkynes such as
but-3-ynylbenzene (2b) and oct-1-yne (2c), the expected
products 3b and 3c obtained in 71 and 76 % respectively
(Entries 2 and 3, Table-1). Next, the substituents amino and
hydroxyl groups present on the aromatic alkynes are also well
tolerated under the present reaction conditions. Thus when 3-
ethynylaniline (2d) and 3-ethynylphenol (2e) were treated with
1 gave the corresponding products 3d and 3e with 62 and 68 %
respectively (Entries 4 and 5, Table-1). Later sterically hindered
ethynylcyclohexane (2f) on treated with 1 gave 3f in 76 %
yield (Entry 6, Table-1). Unfortunately, the presence of electron
withdrawing group present on the aromatic alkyne, i.e., 1-
ethynyl-4-nitrobenzene (2g) was found to be inert under
present reaction conditions (Entry 7, Table-1). Finally when 1
treated with hex-1-yne (2h) gave 3h with 75 % yield (Entry 8,
Table-1).
Yield
(%)
Entry
Compd. 2
Compd. 3
6
76
7
100
8
75
TABLE-1
SYNTHESIS OF FUSED INDOLO[1,2-c]QUINAZOLINES
Yield
(%)
Entry
Compd. 2
Compd. 3
Conclusion
We developed Au(I)-catalyzed cascade reactions for the
synthesis of new fused indolo[1,2-c]quinazolines from 2-(3-
methyl-1H-indol-2-yl)aniline and alkynes in the presence of
2 mol % Ph3PAuOTf catalyst in toluene at 100 °C for 24 h.
1
80
ACKNOWLEDGEMENTS
The author is thankful to CSIR for Senior Research
Fellowship.
2
71
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