Unprecedented intramolecular [3 + 2] cycloadditions of azido-ketenimines and azido-carbodiimides. Synthesis of indolo[1,2-a]quinazolines and tetrazolo[5,1-b]quinazolines

Article abstract of DOI:10.1039/c1ob05745f

N-(2-Azidomethyl)phenyl ketenimines and N-(2-azidomethyl)phenyl-N′- alkyl(aryl) carbodiimides undergo, under mild thermal conditions, intramolecular [3 + 2] cycloaddition reactions between the azido group and either the CC or the distal CN double bonds of the ketenimine and carbodiimide functions respectively. The reaction products are indolo[1,2-a]quinazolines and/or indolo[2,1-b]quinazolines in the case of azido-ketenimines, and tetrazolo[5,1-b]quinazolines in the case of azido-carbodiimides. The formation of the two classes of indoloquinazolines implies the ulterior dinitrogen extrusion from the non-isolated, putative [3 + 2] cycloadducts between the azide and ketenimine functions, whereas in the case of azido-carbodiimides the initial cycloadducts, tetrazoloquinazolines, were cleanly isolated and further converted into 2-aminoquinazolines by thermally induced dinitrogen extrusion.

Full text of DOI:10.1039/c1ob05745f

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PAPER
Unprecedented intramolecular [3 + 2] cycloadditions of azido-ketenimines and
azido-carbodiimides. Synthesis of indolo[1,2-a]quinazolines and
tetrazolo[5,1-b]quinazolines†
Mateo Alajarin,a Baltasar Bonillo,a Maria-Mar Ortin,a Raul-Angel Orenesb and Angel Vidal*a
Received 12th May 2011, Accepted 28th June 2011
DOI: 10.1039/c1ob05745f
N-(2-Azidomethyl)phenyl ketenimines and N-(2-azidomethyl)phenyl-N¢-alkyl(aryl) carbodiimides
undergo, under mild thermal conditions, intramolecular [3 + 2] cycloaddition reactions between the
azido group and either the C C or the distal C N double bonds of the ketenimine and carbodiimide
functions respectively. The reaction products are indolo[1,2-a]quinazolines and/or indolo[2,1-b]-
quinazolines in the case of azido-ketenimines, and tetrazolo[5,1-b]quinazolines in the case of
azido-carbodiimides. The formation of the two classes of indoloquinazolines implies the ulterior
dinitrogen extrusion from the non-isolated, putative [3 + 2] cycloadducts between the azide and
ketenimine functions, whereas in the case of azido-carbodiimides the initial cycloadducts,
tetrazoloquinazolines, were cleanly isolated and further converted into 2-aminoquinazolines by
thermally induced dinitrogen extrusion.
diazo compounds,5 azides,6 acylnitrenes,7 aziridines,8 tiiranes,9
Introduction
oxaziridines10 or heterocyclic carbine-derived 1,3-dipoles.11 In-
Cycloaddition reactions are an important class of chemical
terestingly, the presence of phosphanyl groups at the terminal
transformations having found extensive use in the construction
carbon atom of ketenimines promotes new reactivity patterns,
of structurally simple molecules as well of elaborated molecular
these species being able of behaving as 1,3-dipoles towards alkynes,
frameworks.1 In this context, dipolar [3 + 2] cycloaddition
reactions (1,3-dipolar cycloadditions) have become an appreciated
method for the preparation of a great variety of heterocyclic
compounds bearing a five-membered ring embedded into their
structures.2
Ketenimines are nitrogenated heterocumulenes showing a very
rich and diverse chemistry prone to participate in pericyclic
processes such as electrocyclic ring closures, [n + 2] cycloadditions
and sigmatropic rearrangements.3 Whereas no intramolecular
examples of dipolar [3 + 2] cycloadditions of ketenimines have
been disclosed up to now, a few examples of the intermolecular
version are known. In most of such cases, the ketenimine plays
the role of the dipolarophile contributing with two atoms to the
resulting five-membered ring. The reactive double bond can be
either its cumulated C C or C N double bond. In these reac-
tions the 1,3-dipolar reagents are N-aminopyridininium ylides,4
isocyanates or isothiocyanates.12
Carbodiimides are another class of nitrogenated heterocumu-
lenes with a versatile chemical behaviour,13 also participating in
cycloaddition reactions. Several articles dealing with intermolec-
ular [3 + 2] cycloadditions of carbodiimides can be found in the
chemical literature. In these reports, carbodiimides usually act
as the two-electron component when reacting with 1,3-dipolar
reagents such as 1-aza-14 and 1,3-diaza-2-azoniallenes,15 or with
nitrile oxides and imines.16 However, examples of intramolecular
[3 + 2] cycloadditions involving carbodiimides have not yet been
reported.
For years we have been involved in studying the chemistry of het-
erocumulenes, especially that of ketenimines and carbodiimides.17
A recent publication of Feldman, Lopez and co-workers summa-
rizing their works on the intramolecular [3 + 2] cycloaddition
reactions between allenes and azides18 captured our attention
and directed our interest to testing comparable intramolecular
reactions between azides and heterocumulenes such as ketenimines
or carbodiimides. In a first approach we targeted the preparation of
a series of azido-ketenimines and azido-carbodiimides with their
two functionalities built up on an ortho-benzylic scaffold, more
specifically the azido group placed at the benzylic carbon atom
whereas the heterocumulene function is N-linked to the ortho
position of the aromatic nucleus. We here disclose the results of
our experimental study showing that such azido-heterocumulenes
aDepartamento de Quimica Organica, Facultad de Quimica, Universidad de
Murcia, Campus de Espinardo, 30100, Murcia, Spain. E-mail: vidal@um.es;
Fax: + 34-868 364149; Tel: + 34-868887418
bServicio Universitario de Instrumentacion Cientifica, Universidad de Mur-
cia, Campus de Espinardo, 30100, Murcia, Spain. E-mail: raorenes@um.es
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 2, 4, 5, 12, 14 and 15. 31P NMR spectra of
compounds 2. Cif files of 4a and 12. CCDC reference numbers 824784
and 824785. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob05745f
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Table 1 Azido-ketenimines 3, indolo[1,2-a]quinazolines 4 and indolo[2,1-b]quinazolines 5
Entry
R1
R2
R3
R4
R5
3 Yield (%)
4 Yield (%)
5 Yield (%)
a
b
c
d
e
f
g
h
i
H
H
Br
Cl
Cl
Cl
C4H4
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
Me
H
Ph
Ph
Ph
Ph
Me
Et
Ph
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
99
57
99
98
92
80
97
92
96
95
89
78
61
—
45
69
16
20
40
50
25
35
51
55
—
66
—
—
—
—
—
—
40
—
—
—
H
H
H
H
j
k
l
Cl
Me
C4H4
H
H
undergo, under mild thermal conditions, the presumed [3 + 2]
cycloaddition reactions converting into fused heterocyclic systems,
either indolo[1,2-a]quinazolines and indolo[2,1-b]quinazolines.
Both these products are formed following the N2 extrusion
in the presumed primary cycloadducts between the azide and
ketenimine functions, or tetrazolo[5,1-b]quinazolines in the case
of azido-carbodiimides, in which a further N2 extrusion yielding
2-aminoquinolines took place.
Results and discussion
The slow addition of one equivalent of triphenylphosphine,
dissolved in anhydrous diethyl ether, to a solution of bis(azides)
1 in the same solvent at room temperature provided the azido-
iminophosphoranes 2, through a chemoselective Staudinger re-
action of the phosphine with the more electrophilic azido group,
the one N-linked to the benzene ring. The aza-Wittig reaction
of azido-iminophosphoranes 2 with ketenes, in dichloromethane
solution at room temperature, yielded the azido-ketenimines 3
(Table 1), which were separated from the triphenylphosphine oxide
by short column chromatography on silica gel and immediately
submitted to the next reaction step for avoiding its partial
hydrolysis. Although compounds 3 were not fully characterized,
their formation was guaranteed by recording an IR spectrum
of each one after the purification step. These spectra showed
two very strong absorption bands around 2100 and 2000 cm-1,
respectively, attributable to the azide and ketenimine functional
groups. The heating at reflux temperature of toluene solutions
of azido-ketenimines 3 afforded, in most of the studied cases,
indolo[1,2-a]quinazolines 4 as the unique reaction products
(Scheme 1), isolated from the reaction mixture in low to moderate
yields (Table 1). Interestingly, the thermal treatment of azido-
ketenimines 3b and 3i, in which R3 = Me, provided the isomeric
fused systems indolo[2,1-b]quinazolines 5 as the unique or major
products.
Scheme 1 Reagents and conditions: (a) PPh3, Et2O, r.t., 12 h; (b)
R4(4-R5-C6H4)C
O, CH2Cl2, r.t., 15 min; (c) Toluene, reflux, 2–4 h.
C
C6 resonating at d = 92.7–93.7 ppm. Moreover, the structure of
compound 4a (R1 = R2 = R3 = H; R4 = Ph; R5 = H) was determined
by X-ray crystal diffraction (see Fig. S1 in the ESI†).
The transformation 3 → 4 and/or 5 most probably proceeds
through an intramolecular [3 + 2] cycloaddition of the azido
moiety with the carbon–carbon double bond of the ketenimine
function to give the respective [1,2,3]triazolo[5,1-b]quinazoline
6 (Scheme 2). Following this, dinitrogen extrusion from the
triazoloquinazoline 6 would afford the diradical 7, which is
resonance stabilized. Cyclization of the diradical 7 through the
canonical structure 7C, forming a C–N bond, should lead to the
tetracyclic intermediate 8, which, after a final dehydrogenation
step, would yield the fully aromatic indoloquinazoline 4. Ring-
closure of the canonical structure 7D should give compound
9, which after prototropic equilibration should convert into the
indoloquinazoline 5.
Indoloquinazolines 4 and 5 were characterized according to
1
their spectral data (IR, H and 13C NMR) and high-resolution
mass spectra. In the 1H NMR spectra of indolo[1,2-a]quinazolines
4 the C(5)H proton resonates as a singlet at d = 8.31–8.96 ppm,
and their 13C NMR spectra show the signal of the methine carbon
C5 at d = 148.1–152.1 ppm. Relevant 1H and 13C NMR data of the
indolo[2,1-b]quinazolines 5 are the chemical shifts of the C(12)H
protons appearing at d = 5.18–5.25 ppm, of the methylene carbon
C12 at d = 42.9–43.0 ppm and that of the quaternary carbon
The experimental data presented in Table 1 indicate that, in
most cases, the cyclization of the diyl intermediates 7 occur
6742 | Org. Biomol. Chem., 2011, 9, 6741–6749
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preference for its cyclization via the canonical form D leading to
the linear indoloquinazolines 5.
Evidences for the intermediacy of the biradicals 7 in the
formation of indoloquinazolines 4 and 5 were then sought
by trapping experiments with 1,4-cyclohexadiene. When azido-
ketenimine 3a was heated at 88–89 ◦C for 5 h in 1,4-cyclohexadiene
as solvent, the indolo[1,2-a]quinazoline 4a (40% yield) and 2-
(diphenylmethyl)quinazoline 10 (20% yield) were isolated from the
final reaction mixture (Scheme 3). The abstraction of two hydrogen
atoms from 1,4-cyclohexadiene by the biradical 7a would afford
the 3,4-dihydroquinazoline 11, which under the thermal reaction
conditions seems to convert into the aromatic quinazoline 10 by a
subsequent 3,4-dehydrogenation.
Scheme 3 Reagents and conditions: (a) 1,4-Cyclohexadiene, reflux, 5 h.
On the other hand, in attempts to improve the yield of
conversion 3 → 4 we assayed the thermal treatment of 3 under
deoxygenated reaction conditions, in order to avoid the association
of the putative biradical intermediates with oxygen. In these
experiments we obtained an unexpected, worthy of mentioning,
result. When a strictly deoxygenated toluene solution of azido-
ketenimine 3a was heated at reflux temperature for 2 h the
indoloquinazoline 4a (20% yield) and 6-phenyl-6-hydroxy-6,12-
dihydroindolo[2,1-b]quinazoline 12 (50% yield) were obtained
(Scheme 4). It seems reasonable to postulate that the 6-hydroxy
Scheme 2 Proposed mechanism for the conversion 3 → 4 + 5.
regioselectively to furnish the angular heterocyclic system 4, except
for diradicals 7b and 7i, which rather undergo cyclization to
the linearly fused indoloquinazoline system 5. It seems that the
presence of a methyl substituent (R3 = Me) at the ortho position
of the keteniminic nitrogen in the azido-ketenimines leading to
7b and 7i has a significant influence on directing the product
selectivity toward compounds 5. Probably, there are repulsive
steric interactions originated by such Me group in the transition
states of the cyclizations of the biradical intermediates 7b and
7i via the resonance structure C. These repulsions increase the
Scheme 4 Reagents and conditions: (a) Toluene (deoxygenated), reflux,
2 h.
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derivative 12 should form during the purification stage by oxi-
dation of the corresponding indolo[2,1-b]quinazoline 5a by the
1
action of atmospheric oxygen. In fact, in the H NMR and 13C
NMR spectra of the crude material obtained after this thermal
treatment of the azido-ketenimine 3a we observed, besides others,
the signals expected for 5a [C(12)H singlet at d = 5.28 ppm; C2 d =
42.9 ppm], whereas those corresponding to compound 12 did not
appear.
A single-crystal X-ray analysis of compound 12 shows that its
tetracyclic fused system presents a planar geometry, the main
˚
deviation from plane being 0.0512 A (see Fig. S2 in the ESI†),
and the angle between the mean planes of the indoloquina-
zoline system and that of the benzene ring attached to C9
(crystallographic numbering) is 79.9◦. The main feature of this
structure is that the molecules of 12 in the crystal are linked by
two intermolecular O1–H1 ◊ ◊ ◊ N2 (crystallographic numbering)
hydrogen bonds, thus resulting in the formation of dimers (see
Fig. S3 in the ESI†). Although the overlapping of the benzene
rings of the two molecules forming each dimer is not complete,
it may be stabilized by pi ◊ ◊ ◊ pi stacking interactions, the distance
Scheme 5 Reagent and conditions: (a) R4-N
C
O, CH2Cl2, r.t., 30 min;
(b) Toluene, reflux, 2–5 h; (c) Toluene, sealed tube, 150–180 ◦C, 5–12 d.
Table 3 2-Aminoquinazolines 15
Compound
R1
R2
R3
R4
Yield (%)
15a
15b
15c
15d
H
H
Cl
Me
H
H
H
H
H
Me
H
PhCH2CH2
4-Br-C6H4
4-Me-C6H4
PhCH2
70
63
40
95
˚
between the centroids of the two benzene rings being 3.637 A.
The dimers are further interconnected through C24–H24 ◊ ◊ ◊ O1
(crystallographic numbering) contacts, giving rise to the formation
of ribbons along the c axis (see Fig. S4 in the ESI†).
H
The tetrazolo[5,1-b]quinazolines 14 are thermally stable in
refluxing toluene solutions. Nevertheless, under harsher reaction
conditions (heating of their toluene solutions at 150–180 ◦C in a
sealed tube for long periods of time ranging from 5 to 12 days) the
tetrazoloquinazolines 14 converted into the 2-aminoquinazolines
15 with concomitant dinitrogen extrusion (Scheme 5 and Table 3).
It is reasonable to assume that such extrusion of dinitrogen from
compounds 14 gives, in the first instance, the aminyl biradicals
16, which would then undergo a subsequent hydrogen transfer
from C4 to the exocyclic aminyl center ultimately providing the
2-aminoquinazolines 15 (Scheme 6).
For the study of the azide-carbodiimide intramolecular
+ 2] cycloaddition, the aza-Wittig reaction of azido-
[3
iminophosphoranes 2 with alkyl and aryl isocyanates easily
allowed us the synthesis of a series of the appropriate starting
materials. Thus, treatment of 2, with phenethyl isocyanate, ben-
zyl isocyanate and several aryl isocyanates, in dichloromethane
solution at room temperature, provided azido-carbodiimides 13,
isolated in moderated yields after a short column chromatography
on silica gel (Table 2). The heating at reflux temperature during
2–5 h of toluene solutions of heterocumulenes 13 gave good yields
of the tetrazolo[5,1-b]quinazolines 14 (Scheme 5 and Table 2)
The determination of the structure of the tetrazoloquinazolines
14 was essentially based on their 1H and 13C NMR spectroscopic
data and high-resolution mass spectra. In their 1H NMR spectra
the C(9)H benzylic protons appear at d = 5.50–5.66 ppm. Their 13
C
NMR spectra show the signal due to the C9 carbon atom at d =
56.7–48.0 ppm. In their mass spectra the peak due to the losing of
dinitrogenwas observed, inaddition to the expectedmolecular ion.
It seems obvious that the more plausible mechanism explain-
ing the formation of the tetrazolo[5,1-b]quinazolines 14 is the
intramolecular [3 + 2] cycloaddition between the azido group
and the distal carbon–nitrogen double bond of the carbodiimide
function, C NR.4
Scheme 6 Proposed mechanism for the conversion 14 → 15.
Table 2 Azido-carbodiimides 13 and tetrazolo[5,1-b]quinazolines 14
Entry R1
R2
R3
R4
13 Yield (%) 14 Yield (%)
Conclusions
a
b
c
d
e
f
H
H
H
Cl
Me
Me
Me
C4H4
H
H
H
H
H
H
H
H
H
4-Me-C6H4
PhCH2CH2
75
50
54
75
57
74
87
61
63
93
98
67
95
99
99
99
We have experimentally scrutinized two new types of intramolec-
ular [3 + 2] cycloadditions between an azido group (3-atom
component) and ketenimine and carbodiimide functions (as 2-
atom components). Appropriate substrates for these tests were
N-aryl heterocumulenes bearing a 2-azidomethyl lateral chain at
the aryl nucleus. These species were easily available by applying
Me 4-Br-C6H4
H
H
H
H
H
4-Me-C6H4
4-Cl-C6H4
3-MeO-C6H4
PhCH2
g
h
4-MeO-C6H4
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aza-Wittig chemistry on an azido-iminophosphorane, prepared
in turn by a chemoselective Staudinger Ph3P-azidation reaction
of the adequate bisazide. The [3 + 2] cyloaddition reactions of
the azido-ketenimines occurred in refluxing toluene solution, but
the initial cycloadducts underwent in situ dinitrogen extrusion
converting into members of two isomeric (linear and angular)
heterocyclic systems, indolo[1,2-a]quinazolines and indolo[2,1-
b]quinazolines. One of the presumable biradical intermediates of
these extrusion reactions could be captured, before its final cycliza-
tion, by double H abstraction from 1,4-cyclohexadiene. Whereas
the angular isomers are commonly the products of these tan-
dem cycloaddition/dinitrogen extrusion/cyclization sequences, a
methyl group placed at the ortho position to the N-linked aryl
carbon plays a fundamental role in promoting the appearance of
the linear isomer in the reaction mixture. This effect is rationalized
by a presumable steric biasing at the cyclization step. In contrast
to these results, the [3 + 2] cycloadducts resulting from the azido-
carbodiimides, tetrazolo[5,1-b]quinazolines, proved to be stable
under similar reaction conditions, in refluxing toluene solutions,
and could be thus isolated and characterized. Only under harsh
thermal activation (150–180 ◦C, days) they extruded dinitrogen for
converting into 2-aminoquinazolines. These results are useful for
confirming that the ortho-benzylic scaffolding is an adequate tether
in this type of [3 + 2] cycloaddition reaction, and also disclosed the
relative thermal stability of the respective cycloadducts resulting
from azido-ketenimines and -carbodiimides.
(vs), 1593 (s), 1481 (vs), 1450 (s), 1437 (s), 1348 (vs), 1148 (vs), 1115
(s), 1022 (m), 752 (s), 715 (s), 694 (s); dH(300 MHz, CDCl3) 4.66 (2
H, s), 6.46 (1 H, d, J 7.6), 6.64 (1 H, t, J 7.3), 6.86 (1 H, td, J 7.6,
1.7), 7.19–7.23 (1 H, m), 7.40–7.52 (9 H, m), 7.72–7.79 (6 H, m);
dC(75 MHz, CDCl3) 52.7, 117.1, 121.1 (d, J 10.2), 128.6, 128.7 (d,
J 12.0), 129.4 (d, J 22.8) (s), 129.8 (d, J 2.4), 131.2 (d, J 99.8) (s),
131.7 (d, J 2.9), 132.6 (d, J 9.7), 150.2 (s); dP(121.4 MHz, CDCl3,
H3PO4) 2.8; HRMS (ESI): Calcd for C25H21N4P [M]+ 408.1504,
found 408.1517.
Azido-triphenyliminophosphorane 2b (R1 = R2 = H; R3 = Me).
◦
(4.20 g, 66%); mp 92–93 C (from Et2O); nmax(Nujol)/cm-1 2098
(vs), 1591 (m), 1466 (vs), 1435 (vs), 1350 (m), 1111 (s), 748 (s),
713 (vs), 694 (vs); dH(400 MHz, CDCl3) 1.90 (3 H, s), 4.18 (2 H,
s), 6.73 (1 H, td, J 7.2, 2.0), 7.01 (1 H, d, J 7.2), 7.05 (1 H, d, J
7.2), 7.41-7.45 (6 H, m), 7.50-7.54 (3 H, m), 7.57-7.62 (6 H, m);
dC(100 MHz, CDCl3) 21.3, 53.3, 118.9 (d, J 3.2), 127.0 (d, J 1.9),
128.5 (d, J 11.9), 130.2 (d, J 8.4) (s), 130.4 (d, J 2.7), 131.5 (d, J
2.7), 132.3 (d, J 9.6), 132.7 (d, J 100.9) (s), 133.5 (d, J 5.4) (s), 147.4
(s); dP(161.9 MHz, CDCl3, H3PO4) -4.2; HRMS (ESI): Calcd for
C26H23N4P [M]+ 422.1660, found 422.1674.
Azido-triphenyliminophosphorane 2c (R1 = Br; R2 = R3 = H).
(5.10 g, 70%); mp 106–107 ◦C (from Et2O); nmax(Nujol)/cm-1 2098
(vs), 1581 (m), 1477 (vs), 1437 (s), 1404 (m), 1350 (s), 1288 (m),
1109 (m), 1022 (w), 881 (w), 759 (s), 692 (s); dH(300 MHz, CDCl3)
4.61 (2 H, s), 6.29 (1 H, dd, J 8.5, 1.0), 6.91 (1 H, dd, J 8.5, 2.6),
7.31 (1 H, t, J 2.6), 7.42–7.48 (6 H, m), 7.51–7.54 (3 H, m), 7.69–
7.76 (6 H, m); dC(75 MHz, CDCl3) 52.1, 108.8 (s), 122.2 (d, J 10.3),
128.8 (d, J 12.1), 130.6 (d, J 100.1) (s), 131.2, 131.5 (d, J 23.1) (s),
131.9 (d, J 3.0), 132.0, 132.5 (d, J 9.7), 149.2 (s); dP(121.4 MHz,
CDCl3, H3PO4) 4.2; HRMS (ESI): Calcd for C25H20BrN4P [M]+
486.0609, found 486.0615.
Experimental
All melting points are uncorrected. Infrared (IR) spectra were
recorded neat or as Nujol emulsions. 1H NMR spectra were
recorded at 200, 300 or 400 MHz. 13C NMR spectra were recorded
at 50, 75 or 100 MHz. The chemical shifts are expressed in ppm,
relative to Me4Si at d = 0.00 ppm in the 1H NMR spectra recorded
in CDCl3 and DMSO-d6 and to the signal of the solvent at d =
11.50 ppm when recorded in CF3CO2D. The chemical shifts in the
13C NMR spectra are reported relative to the resonance of CDCl3
at d = 77.1 ppm, DMSO-d6 at d = 39.5 ppm or CF3CO2D at d =
165.4 ppm. J values are given in Hz.
Azido-triphenyliminophosphorane 2d (R1 = Cl; R2 = R3 = H).
(4.90 g, 74%); mp 107–108 ◦C (from Et2O); nmax(Nujol)/cm-1 2100
(vs), 1587 (m), 1473 (s), 1410 (m), 1356 (m), 1182 (w), 1034 (w),
1022 (w), 812 (w), 715 (s), 692 (vs); dH(400 MHz, CDCl3) 4.61 (2
H, s), 6.34 (1 H, dd, J 8.5, 1.1), 6.78 (1 H, dd, J 8.5, 2.7), 7.18 (1 H,
t, J 2.7), 7.43–7.48 (6 H, m), 7.51–7.53 (3 H, m), 7.70–7.75 (6 H,
m); dC(100 MHz, CDCl3) 52.2, 121.5 (s), 121.7 (d, J 10.2), 128.2,
128.8 (d, J 12.0), 129.2, 130.7 (d, J 100.1) (s), 131.0 (d, J 22.7)
(s), 131.9 (d, J 2.6), 132.5 (d, J 9.6), 148.7; dP(161.9 MHz, CDCl3,
H3PO4) 3.6; HRMS (ESI): Calcd for C25H20ClN4P [M]+ 442.1114,
found 442.1118.
2-Azidobenzylazide 1a,19 2-azido-3-methylbenzylazide 1b,19
2-azido-5-bromobenzylazide 1c,19 2-azido-5-chlorobenzylazide
1d,19 2-azido-5-methylbenzylazide 1e,19 3-azido-2-azidomethyl-
naphthalene 1f,19 methylphenylketene,20 ethylphenylketene21 and
diphenylketene22 were prepared following published experimental
procedures.
Azido-triphenyliminophosphorane 2e (R1 = Me; R2 = R3 = H).
(4.56 g, 72%); mp 114–115 ◦C (from Et2O); nmax(Nujol)/cm-1 2106
(s), 1610 (w), 1490 (vs), 1437 (s), 1348 (vs), 1107 (s), 1036 (w), 1024
(w), 814 (w), 737 (s), 715 (s), 694 (s); dH(300 MHz, CDCl3) 2.19
(3 H, s), 4.64 (2 H, s), 6.37 (1 H, d, J 8.0), 6.67 (1 H, d, J 8.0),
7.03 (1 H, s), 7.40–7.52 (9 H, m), 7.72–7.78 (6 H, m); dC(75 MHz,
CDCl3) 20.6, 52.6, 120.8 (d, J 9.9), 126.1 (s), 128.6 (d, J 12.0),
129.1 (d, J 22.6) (s), 129.2, 130.4 (d, J 2.2), 131.3 (d, J 99.6) (s),
131.7 (d, J 2.8), 132.6 (d, J 9.7), 147.4 (s); dP(121.4 MHz, CDCl3,
H3PO4) 2.3; HRMS (ESI): Calcd for C26H23N4P [M]+ 422.1660,
found 422.1180.
Preparation of azido-triphenyliminophosphoranes 2
To a solution of the corresponding 2-azidobenzylazide 1 (15 mmol)
in anhydrous diethyl ether (60 mL), under nitrogen and at room
temperature, a solution of triphenylphosphine (4.19 g, 16 mmol)
in the same solvent (20 mL) was added dropwise during 6–8 h. The
reaction mixture was stirred at room temperature for 12 h. Then,
the solvent was removed under reduced pressure, and the crude
material was purified by column chromatography on silica gel
deactivated with triethylamine, using hexanes/diethyl ether (7 : 3,
v/v) as eluent.
Azido-triphenyliminophosphorane 2f (R1-R2 = C6H4; R3 = H).
(4.74 g, 69%); mp 130–131 ◦C (from Et2O); nmax(Nujol)/cm-1 2094
(vs), 1624 (m), 1595 (m), 1493 (w), 1461 (vs), 1387 (s), 1344 (s),
Azido-triphenyliminophosphorane 2a (R1 = R2 = R3 = H).
◦
(4.28 g, 70%); mp 94–95 C (from Et2O); nmax(Nujol)/cm-1 2092
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1279 (s), 1196 (m), 997 (w), 737 (vs), 694 (vs); dH(400 MHz, CDCl3)
4.88 (2 H, s), 6.74 (1 H, s), 7.15 (1 H, t, J = 7.6), 7.21–7.27 (2 H,
m), 7.47–7.52 (6 H, m), 7.55–7.59 (3 H, m), 7.69 (1 H, d, J 7.6
Hz), 7.75 (1 H, s), 7.83 (6 H, s); dC(100 MHz, CDCl3) 52.9, 114.8,
121.8, 125.4 (d, J 21.1), 127.3 (s), 127.5, 128.1, 128.8 (d, J 47.6),
130.7 (d, J 97.2) (s), 131.9 (d, J 2.3), 132.2 (d, J 23.0) (s), 132.7
(d, J 9.6), 134.9 (s); dP(161.9 MHz, CDCl3, H3PO4) 3.9; HRMS
(ESI): Calcd for C29H23N4P [M]+ 458.1660, found 458.1669.
8.20 (2 H, m), 8.43 (1 H, s); dC(100 MHz; CDCl3) 110.6 (s), 113.9,
115.7 (s), 116.2, 120.5 (s), 120.9, 122.8, 123.7, 126.8, 128.3 (s),
128.7, 129.6 (s), 130.0, 131.3, 133.3 (s), 135.9, 136.8 (s), 138.4 (s),
149.7; HRMS (ESI): Calcd for C21H13BrN2 [M]+ 372.0262, found
372.0262.
3-Chloro-7-phenylindolo[1,2-a]quinazoline 4d. Eluent for col-
umn chromatography: hexanes/diethyl ether (9 : 1, v/v); (0.23 g,
69%); mp 191–192 ◦C (from Et2O); nmax(Nujol)/cm-1 1543;
dH(400 MHz; CDCl3) 7.36–7.40 (1 H, m), 7.43–7.56 (4 H, m),
7.65–7.69 (2 H, m), 7.84–7.87 (2 H, m), 8.13–8.15 (1 H, m), 8.23
(1 H, d, J 8.6), 8.30 (1 H, d, J 8.6), 8.47 (1 H, s); dC(100 MHz;
CDCl3) 110.6 (s), 113.9, 116.1, 120.2 (s), 120.9, 122.8, 123.7, 126.8,
128.2 (s), 128.3, 128.4 (s), 128.7, 129.6 (s), 130.0, 133.2, 133.3 (s),
136.5 (s), 138.5 (s), 149.8; HRMS (ESI): Calcd for C21H13ClN2
[M]+ 328.0767, found 328.0774.
Procedure for the preparation of azido-ketenimines 3a–g
To
a solution of the azido-triphenyliminophosphorane 2
(1.5 mmol) in anhydrous dichloromethane (20 mL) a solution
of the corresponding ketene (2 mmol) in the same solvent (5 mL)
was added. The reaction mixture was stirred at room temperature
under nitrogen for 30 min. Next the solvent was removed under
reduced pressure and the resulting material was purified by column
chromatography on silica gel, using hexanes/diethyl ether (9 : 1,
v/v) as eluent, to afford the azido-ketenimine 3.
3-Chloro-7-methylindolo[1,2-a]quinazoline 4e. Eluent for col-
umn chromatography: hexanes/diethyl ether (7 : 3, v/v); (0.042 g,
16%); mp 183–184 ◦C (from Et2O); nmax(Nujol)/cm-1 1541;
dH(400 MHz; CDCl3) 2.64 (3 H, s), 7.43–7.52 (2 H, m), 7.65–
7.70 (2 H, m), 7.90 (1 H, d, J 8.2), 8.20 (1 H, d, J 8.2), 8.26 (1
H, d, J 8.2), 8.40 (1 H, s); dC(100 MHz; CDCl3) 7.9, 105.5 (s),
113.7, 115.7, 119.9 (s), 120.1, 122.0, 123.3, 127.9 (s), 128.4, 129.3
(s), 129.9 (s), 133.0, 136.9 (s), 138.8 (s), 148.1; HRMS (ESI): Calcd
for C16H11ClN2 [M]+ 266.0611, found 266.0611.
Procedure for the preparation of azido-ketenimines 3h–l
To a solution of bis(4-chlorophenyl)acetyl chloride (0.66 g,
2.2 mmol) in anhydrous diethyl ether (30 mL), cooled at 0 ◦C
and under nitrogen, triethylamine (0.263 g, 2.6 mmol) was added,
and the reaction mixture was stirred at 0 ◦C for 15 min. Then,
the solution containing bis(4-chlorophenyl)ketene was added via
a canula, provided with a cotton filter, to a solution of the
azido-triphenyliminophosphorane 2 (1.1 mmol) in anhydrous
dichloromethane (20 mL). The new reaction mixture was stirred
at room temperature under nitrogen for 30 min. Next the solvent
was removed under reduced pressure and the resulting material
was purified by column chromatography on silica gel, using
hexanes/diethyl ether (9.5 : 0.5, v/v) as eluent, to afford the azido-
ketenimine 3.
3-Chloro-7-ethylindolo[1,2-a]quinazoline 4f. Eluent for col-
umn chromatography: hexanes/diethyl ether (9 : 1, v/v); (0.056 g,
20%); mp 135–136 ◦C (from Et2O); nmax(Nujol)/cm-1 1542;
dH(300 MHz; CDCl3) 1.37 (3 H, t, J 7.5), 3.14 (2 H, q, J 7.5),
7.39–7.49 (2 H, m), 7.61–7.67 (2 H, m), 7.90–7.93 (1 H, m), 8.17–
8.24 (2 H, m), 8.34 (1 H, s); dC(75 MHz; CDCl3) 15.4, 16.6, 111.9
(s), 113.8, 115.6, 119.8 (s), 120.1, 121.9, 123.1, 127.8 (s), 128.2,
129.0 (s), 129.3 (s), 132.8, 136.6 (s), 138.3 (s), 148.1; HRMS (ESI):
Calcd for C17H13ClN2 [M]+ 280.0767, found 280.0772.
7-Phenylindolo[1,2-a]benzo[g]quinazoline 4g. Eluent for col-
umn chromatography: hexanes/diethyl ether (7 : 3, v/v); (0.14 g,
40%); mp 218–219 ◦C (from Et2O); nmax(Nujol)/cm-1 1554;
dH(400 MHz; CDCl3) 7.39–7.43 (1 H, m), 7.44–7.52 (2 H, m),
7.55–7.61 (3 H, m), 7.62–7.65 (1 H, m), 7.89–7.91 (2 H, m), 7.94
(1 H, d, J 8.0), 7.98 (1 H, d, J 8.4), 8.14 (1 H, d, J 8.0), 8.18 (1 H,
s), 8.46 (1 H, d, J 8.4), 8.60 (1 H, s), 8.66 (1 H, s); dC(100 MHz;
CDCl3) 110.9, 112.0 (s), 113.4, 119.6 (s), 120.9, 122.4, 124.0, 125.7,
128.6, 127.6, 128.2 (s), 128.7, 128.8, 128.9, 129.3 (s), 129.8, 130.1,
131.1 (s), 133.4 (s), 134.6 (s), 135.9 (s), 138.4 (s), 152.0; HRMS
(ESI): Calcd for C25H16N2 [M]+ 344.1313, found 344.1312.
Preparation of indolo[1,2-a]quinazolines 4 and
indolo[2,1-b]quinazolines 5
A solution of the corresponding azido-ketenimine 3 (1 mmol) in
anhydrous toluene (20 mL) was heated at reflux temperature under
nitrogen for 2–4 h. After cooling at room temperature, the solvent
was removed under reduced pressure and the resulting material
was chromatographed on a silica gel column.
7-Phenylindolo[1,2-a]quinazoline 4a. Eluent for column chro-
matography: hexanes/diethyl ether (9 : 1, v/v); (0.18 g, 61%); mp
149–150 ◦C (from Et2O); nmax(Nujol)/cm-1 1599; dH(400 MHz;
CDCl3) 7.30 (1 H, t, J 7.5), 7.36 (1 H, t, J 7.5), 7.41–7.49 (2 H,
m), 7.50–7.56 (2 H, m), 7.68–7.72 (2 H, m), 7.87–7.89 (2 H, m),
8.14 (1 H, d, J 7.7), 8.30 (1 H, d, J 8.5), 8.35 (1 H, d, J 8.5), 8.55
(1 H, s); dC(100 MHz; CDCl3) 109.8 (s), 114.1, 114.6, 119.1 (s),
120.6, 122.5, 123.2, 126.5, 128.3 (s), 128.6, 129.1, 129.7 (s), 130.0,
133.4, 133.7 (s), 138.1 (s), 138.8 (s), 151.4; HRMS (ESI): Calcd for
C21H14N2 [M]+ 294.1157, found 294.1164.
10-Chloro-7-(4-chlorophenyl)indolo[1,2-a]quinazoline 4h. Elu-
ent for column chromatography: hexanes/dichloromethane (7 : 3,
v/v); (0.18 g, 50%); mp 273–275 ◦C (from Et2O); nmax(Nujol)/cm-1
1554; dH(400 MHz; CF3CO2D) 7.36–7.44 (5 H, m), 7.60 (1 H, t,
J 7.6), 7.75 (1 H, d, J 8.0), 8.12 (1 H, d, J 8.0), 8.20 (1 H, t, J
8.0), 8.35 (1 H, s), 8.48 (1 H, d, J 8.0), 8.93 (1 H, s); dC(100 MHz;
CF3CO2D) 110.5 (s), 114.2 (s), 116.4, 117.0 (s), 117.7 (s), 117.9,
124.0, 128.6, 128.7, 128.8 (s), 132.3, 132.9, 135.4 (s), 137.2, 138.6
(s), 142.5 (s), 145.1, 152.1; HRMS (ESI): Calcd for C21H12Cl2N2
[M]+ 362.0378, found 362.0376.
3-Bromo-7-phenylindolo[1,2-a]quinazoline 4c. Eluent for col-
umn chromatography: hexanes/diethyl ether (9 : 1, v/v); (0.17 g,
45%); mp 202–204 ◦C (from Et2O); nmax(Nujol)/cm-1 1597;
dH(400 MHz; CDCl3) 7.36–7.50 (3 H, m), 7.52–7.56 (2 H, m),
7.75–7.80 (2 H, m), 7.84–7.86 (2 H, m), 8.12 (1 H, d, J 7.5), 8.17–
10-Chloro-7-(4-chlorophenyl)-1-methylindolo[1,2-a]quinazoline
4i. Eluent for column chromatography: hexanes/diethyl ether
6746 | Org. Biomol. Chem., 2011, 9, 6741–6749
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(9.5 : 0.5, v/v); (0.094 g, 25%); mp 183–184 ◦C (from Et2O);
max(Nujol)/cm-1 1545; dH(300 MHz; CDCl3) 2.57 (3 H, s), 7.36 (1
7.11 (3 H, m), 7.21–7.22 (1 H, m), 7.43–7.50 (5 H, m); dC(75 MHz;
CDCl3) 16.6, 43.0, 92.7 (s), 108.5, 114.3 (s), 117.2, 120.9, 121.4,
121.7 (s), 125.1 (s), 125.2, 126.0 (s), 128.6, 129.8, 131.0 (s), 133.3 (s),
133.4 (s), 133.5 (s), 134.7 (s); HRMS (ESI): Calcd for C22H16Cl2N2
[M]+ 378.0691, found 378.0673.
n
H, dd, J 8.7, 1.8), 7.41 (1 H, t, J 8.0), 7.47–7.50 (2 H, m), 7.61–7.64
(2 H, m), 7.71 (1 H, d, J 1.8), 7.78–7.81 (2 H, m), 7.95 (1 H, d,
J 8.4), 8.54 (1 H, s); dC(75 MHz; CDCl3) 22.2, 108.5 (s), 115.6,
120.8, 121.8 (s), 123.1, 124.7, 125.7 (s), 126.1 (s), 126.3, 127.7 (s),
129.0, 131.1, 131.8 (s), 132.2 (s), 132.6 (s), 135.6 (s), 137.0, 141.1
(s), 152.0; HRMS (ESI): Calcd for C22H14Cl2N2 [M]+ 376.0534,
found 376.0538.
Thermal treatment of azido-ketenimine 3a in 1,4-cyclohexadiene
A solution of azido-ketenimine 3a (0.32 g, 1 mmol) in 1,4-
cyclohexadiene (20 mL), under nitrogen, was heated at reflux
temperature for 5 h. After cooling at room temperature, the
solvent was removed under reduced pressure and the resulting
material was chromatographed on a silica gel column, using hex-
anes/diethyl ether (9 : 1, v/v) as eluent, to give 7-phenylindolo[1,2-
a]quinazoline 4a (0.12 g, 40%) and 2-(diphenylmethyl)quinazoline
1023 (0.059 g, 20%).
3,10-Dichloro-7-(4-chlorophenyl)indolo[1,2-a]quinazoline
4j.
Eluent for column chromatography: hexanes/diethyl ether (9 : 1,
v/v); (0.14 g, 35%); mp 318–319 ◦C (from Et2O); nmax(Nujol)/cm-1
1551; dH(400 MHz; CF3CO2D) 7.42–7.49 (4 H, m), 7.55 (1 H,
d, J 8.4), 7.85 (1 H, d, J 8.4), 8.12–8.16 (2 H, m), 8.39 (1 H, s),
8.51 (1 H, d, J 8.4), 8.96 (1 H, s); dC(100 MHz; CF3CO2D) 111.2
(s), 114.0 (s), 116.0, 118.6 (s), 119.0, 119.7 (s), 124.2, 128.2 (s),
128.5 (s), 128.8, 132.1, 132.8, 134.9 (s), 135.3, 135.8 (s), 138.7 (s),
140.6 (s), 144.3, 151.0; HRMS (ESI): Calcd for C21H11Cl3N2 [M]+
395.9988, found 396.0007.
Thermal treatment of azido-ketenimine 3a under deoxygenated
conditions
A deoxygenated solution of the azido-ketenimine 3a (0.32 g,
1 mmol) in anhydrous toluene (20 mL) was heated at reflux
temperature for 2 h, under atmosphere of nitrogen. After cooling
to room temperature, the solvent was removed under reduced
pressure and the resulting material was chromatographed on a
silica gel column, using hexanes/diethyl ether (9 : 1, v/v) as eluent.
10-Chloro-7-(4-chlorophenyl)-3-methylindolo[1,2-a]quinazoline
4k. Eluent for column chromatography: hexanes/diethyl ether
(9 : 1, v/v); (0.19 g, 51%); mp 303–305 ◦C (from Et2O);
n
max(Nujol)/cm-1 1558; dH(300 MHz; CF3CO2D) 2.44 (3 H, s),
7.33–7.42 (5 H, m), 7.70 (1 H, d, J 8.7), 7.88 (1 H, s), 8.02 (1 H, d,
J 8.7), 8.28 (1 H, s), 8.34 (1 H, d, J 8.7), 8.85 (1 H, s); dC(75 MHz;
CF3CO2D) 21.1, 109.9 (s), 113.7 (s), 116.2, 117.7, 123.9, 128.4,
128.6 (s), 128.7 (s), 128.8 (s), 132.3, 132.7 (s), 132.9, 135.1 (s),
136.4, 138.5 (s), 140.3 (s), 140.5 (s), 146.5, 151.8; HRMS (ESI):
Calcd for C22H14Cl2N2 [M]+ 376.0534, found 376.0545.
7-phenylindolo[1,2-a]quinazoline 4a. (0.06 g, 20%)
6-Hydroxy-6-phenyl-6,12-dihydroindolo[2,1-b]quinazoline 12.
(0.16 g, 50%); mp 205–206 ◦C (from Et2O); nmax(Nujol)/cm-1
3175 (m), 1643 (vs), 1597 (vs), 1573 (s), 1495 (s), 1321 (m), 1219
(m), 1174 (s), 1043 (m), 941 (w), 777 (m), 768 (m), 748 (s), 731
(m); dH(400 MHz, CDCl3) 4.14 (1 H, d, J 13.6), 4.77 (1 H, d, J
13.6), 6.56 (1 H, d, J 7.6), 6.63 (1 H, d, J 7.6), 6.69 (1 H, s), 6.80
(1 H, t, J 7.2), 6.88¢6.90 (1 H, m), 6.97 (1 H, t, J 7.2), 7.12 (1 H,
t, J 7.6), 7.26–7.40 (5 H, m), 7.55 (2 H, d, J 7.2); dC(100 MHz,
CDCl3) 43.2, 79.7 (s), 107.6, 119.1 (s), 123.2, 124.9, 125.4, 125.5,
125.9, 126.0, 127.8, 128.4, 128.5, 129.4, 134.3 (s), 140.6 (s), 142.2
(s), 143.2 (s), 163.9 (s); HRMS (ESI): Calcd for C21H16N2O [M]+
312.1263, found 312.1272.
10-Chloro-7-(4-chlorophenyl)indolo[1,2-a]benzo[g]quinazoline
4l. Eluent for column chromatography: hexanes/diethyl ether
(9 : 1, v/v); (0.23 g, 55%); mp 314–316 ◦C (from Et2O);
n
max(Nujol)/cm-1 1562; dH(300 MHz; CDCl3/CF3CO2H) 7.48 (1
H, dd, J 10.0, 5.2), 7.51–7.54 (2 H, m), 7.61–7.65 (3 H, m), 7.76–
7.80 (1 H, m), 7.91 (1 H, d, J 8.8), 8.06 (1 H, d, J 7.6), 8.13 (1 H,
d, J 7.6), 8.44 (1 H, s), 8.51 (1 H, d, J 1.6), 8.62 (1 H, s), 8.88 (1
H, s); dC(100 MHz; CDCl3/CF3CO2H) 110.6 (s), 112.4, 113.2 (s),
114.0, 115.8 (s), 116.0 (s), 122.4, 125.5, 126.2 (s), 126.9 (s), 128.1,
128.3, 129.9, 130.0 (s), 130.6, 131.3, 131.6 (s), 132.7 (s), 133.1 (s),
133.6, 135.8 (s), 138.9, 139.2 (s), 151.6; HRMS (ESI): Calcd for
C25H14Cl2N2 [M]+ 412.0534, found 412.0550.
Procedure for the preparation of azido-carbodiimides 13
To a solution of the azido-triphenyliminophosphorane 2 (1 mmol)
in anhydrous dichloromethane (20 mL) a solution of the cor-
responding isocyanate (1.1 mmol) in the same solvent (5 mL)
was added. The reaction mixture was stirred at room temperature
under nitrogen for 30 min. Next the solvent was removed under
reduced pressure and the resulting material was purified by column
chromatography on silica gel, using hexanes/diethyl ether (9 : 1,
v/v) as eluent, to afford the azido-carbodiimide 13.
4-Methyl-6-phenyl-5,12-dihydroindolo[2,1-b]quinazoline
5b.
Eluent for column chromatography: hexanes/diethyl ether (9 : 1,
v/v); (0.20 g, 66%); mp 173–174 ◦C (from Et2O); nmax(Nujol)/cm-1
3456, 1579; dH(300 MHz; CDCl3) 2.25 (3 H, s), 5.24 (2 H, s),
6.85–6.90 (2 H, m), 7.09 (2 H, t, J 9.2), 7.14–7.18 (2 H, m),
7.20–7.30 (2 H, m), 7.52 (2 H, t, J 9.2), 7.65 (2 H, d, J 9.2), 7.72 (1
H, d, J 9.2); dC(75 MHz; CDCl3) 16.6, 42.9, 93.7 (s), 108.1, 114.6
(s), 116.8, 119.3, 120.4, 120.9, 121.6 (s), 125.1, 125.2, 127.5, 127.6
(s), 129.5, 129.6, 133.0 (s), 133.9 (s), 134.1 (s), 135.4 (s); HRMS
(ESI): Calcd for C22H18N2 [M]+ 310.1470, found 310.1474.
Preparation of the tetrazolo[5,1-b]quinazolines 14
9-Chloro-6-(4-chlorophenyl)-4-methyl-6-phenyl-5,12-dihydroin-
dolo[2,1-b]quinazoline 5i. Eluent for column chromatography:
hexanes/diethyl ether (9.5 : 0.5, v/v); (0.15 g, 40%); mp 220–221 ◦C
(from Et2O); nmax(Nujol)/cm-1 3398, 1573; dH(300 MHz; CDCl3)
2.24 (3 H, s), 5.18 (2 H, s), 6.71 (1 H, s), 6.90 (1 H, t, J 7.5), 7.07–
A solution of the azido-carbodiimide 13 (1 mmol) in anhydrous
toluene (20 mL) was heated at reflux temperature under nitrogen
for 2–5 h. After cooling to room temperature, the solvent was
removed under reduced pressure, and the resulting material was
chromatographed on a silica gel column.
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3-(4-Methylphenyl)-3,9-dihydrotetrazolo[5,1-b]quinazoline 14a.
Eluent for column chromatography: hexanes/diethyl ether (4 : 1,
v/v); (0.16 g, 63%); mp 158–159 ◦C (from Et2O); nmax(Nujol)/cm-1
1641, 1595; dH(300 MHz; CDCl3) 2.38 (3 H, s), 5.53 (2 H, s), 6.95–
7.00 (2 H, m), 7.11–7.14 (1 H, m), 7.16–7.21 (1 H, m), 7.27–7.30
(2 H, m), 7.96–8.00 (2 H, m); dC(75 MHz; CDCl3) 21.2, 47.7,
115.5 (s), 119.8, 122.8, 124.7, 126.4, 129.2, 129.9, 132.7 (s), 137.4
(s), 143.5 (s), 144.0 (s); HRMS (ESI): Calcd for C15H13N5 [M]+
263.1171, found 263.1177.
3-Benzyl-7-methyl-3,9-dihydrotetrazolo[5,1-b]quinazoline 14g.
Eluent for column chromatography: hexanes/diethyl ether (7 : 3,
v/v); (0.27 g, 99%); mp 139–140 ◦C (from Et2O); nmax(Nujol)/cm-1
1643, 1603; dH(300 MHz; CDCl3) 2.26 (3 H, s), 5.21 (2 H, s), 5.44
(2 H, s), 6.79 (1 H, s), 6.99–7.00 (2 H, m), 7.29–7.37 (3 H, m),
7.42–7.45 (2 H, m); dC(75 MHz; CDCl3) 20.7, 47.6, 48.9, 115.0 (s),
123.8, 126.9, 128.5, 128.6, 128.9, 129.9, 131.9 (s), 134.4 (s), 141.2
(s), 145.2 (s); HRMS (ESI): Calcd for C16H15N5 [M]+ 277.1327,
found 277.1328.
3-(4-Methoxyphenyl)-3,11-dihydrotetrazolo[5,1-b]benzo[g]qui-
nazoline 14h. Eluent for column chromatography: hex-
anes/diethyl ether (9 : 1, v/v); (0.32 g, 99%); mp 209–210 ◦C (from
Et2O); nmax(Nujol)/cm-1 1651, 1614; dH(400 MHz; CDCl3) 3.87
(3 H, s), 5.66 (2 H, s), 7.03–7.07 (2 H, m), 7.28–7.32 (1 H, m),
7.38 (1 H, td, J 6.8, 1.2), 7.49 (1 H, s), 7.55 (1 H, s), 7.67 (1 H,
d, J 8.4), 7.70 (1 H, d, J 8.4), 8.04–8.07 (2 H, m); dC(100 MHz;
CDCl3) 47.6, 55.7, 114.7, 117.3 (s), 120.5, 121.7, 124.4, 125.5,
126.4, 127.1, 127.3, 128.6 (s), 130.2 (s), 134.9 (s), 141.3 (s), 144.1
(s), 159.0 (s); HRMS (ESI): Calcd for C19H15N5O [M]+ 329.1277,
found 329.1290.
3-Phenethyl-3,9-dihydrotetrazolo[5,1-b]quinazoline 14b. Elu-
ent for column chromatography: hexanes/diethyl ether (3 : 7, v/v);
(0.26 g, 93%); mp 130–131 ◦C (from Et2O); nmax(Nujol)/cm-1 1643,
1568; dH(400 MHz; CDCl3) 3.24 (2 H, t, J 8.0), 4.34 (2 H, t, J 8.0),
5.50 (2 H, s), 6.93–6.96 (1 H, m), 6.99–7.01 (1 H, m), 7.11 (1 H, d,
J 8.0), 7.20–7.34 (6 H, m); dC(75 MHz; CDCl3) 34.1, 46.7, 47.6,
115.2 (s), 122.2, 123.9, 126.5, 127.0, 128.7, 128.9, 129.2, 136.9
(s), 143.9 (s), 145.5 (s); HRMS (ESI): Calcd for C16H15N5 [M]+
277.1327, found 277.1334.
3-(4-Bromophenyl)-5-methyl-3,9-dihydrotetrazolo[5,1-b]quina-
zoline 14c. Eluent for column chromatography:◦hexanes/diethyl
ether (9.5 : 0.5, v/v); (0.33 g, 98%); mp 118–119 C (from Et2O);
Preparation of 2-aminoquinazolines 15
n
max(Nujol)/cm-1 1647, 1604; dH(300 MHz; CDCl3) 2.38 (3 H, s),
5.51 (2 H, s), 6.82–6.84 (1 H, m), 6.85–6.90 (1 H, m), 7.09 (1 H, d, J
7.2), 7.58–7.62 (2 H, m), 8.16–8.20 (2 H, m); dC(75 MHz; CDCl3)
17.9, 48.0, 115.2 (s), 120.3, 122.9, 124.0, 130.5, 132.5, 133.0 (s),
134.9 (s), 141.5 (s), 143.1 (s); HRMS (ESI): Calcd for C15H12BrN5
[M]+ 341.0276, found 341.0276.
A solution of the tetrazoloquinazoline 14 (1 mmol) in anhydrous
toluene (20 mL) was heated in a sealed tube at 150–180 ◦C
during 5–12 d. After cooling to room temperature, the solvent
was removed under reduced pressure and the crude material was
chromatographed on a silica gel column.
7-Chloro-3-(4-methylphenyl)-3,9-dihydrotetrazolo[5,1-b]quina-
zoline 14d. Eluent for column chromatography: hexanes/diethyl
ether (9 : 1, v/v); (0.20 g, 67%); mp 145–146 ◦C (from Et2O);
2-Phenethylaminoquinazoline 15a. Eluent for column chro-
matography: hexanes/ethyl acetate (7 : 3, v/v); (0.17 g, 70%); mp
123–124 ◦C (from Et2O); nmax(Nujol)/cm-1 3267 (s), 1620 (vs),
1595 (vs), 1551 (vs), 1240 (w), 1142 (w), 1113 (w), 862 (w), 796
(m), 721 (w), 700 (w); dH(300 MHz, CDCl3) 2.97 (2 H, t, J 6.9),
3.82 (2 H, q, J 6.9), 5.51 (1 H, br s), 7.18–7.32 (6 H, m), 7.58–7.69
(3 H, m), 8.94 (1 H, s); dC(75 MHz, CDCl3) 35.8, 42.9, 120.2 (s),
122.9, 125.3, 126.5, 127.7, 128.7, 129.0, 134.5, 139.3 (s), 159.3 (s),
162.4; HRMS (ESI): Calcd for C16H15N3 [M]+ 249.1266, found
249.1266.
n
max(Nujol)/cm-1 1673, 1593; dH(400 MHz; CDCl3) 2.41 (3 H,
m), 5.54 (2 H, m), 6.99 (1 H, s), 7.08 (1 H, d, J 8.8), 7.15 (1 H, dd,
J 8.8, 1.6), 7.31 (2 H, d, J 8.4), 7.96 (2 H, d, J 8.4); dC(100 MHz;
CDCl3) 21.2, 47.5, 116.8 (s), 119.9, 125.8, 126.2, 127.6 (s), 129.3,
130.0, 132.4 (s), 137.8 (s), 142.1 (s), 144.1 (s); HRMS (ESI): Calcd
for C15H12ClN5 [M]+ 297.0781, found 297.0787.
3-(4-Chlorophenyl)-7-methyl-3,9-dihydrotetrazolo[5,1-b]quina-
zoline 14e. Eluent for column chromatography: hexanes/diethyl
ether (9 : 1, v/v); (0.28 g, 95%); mp 164–165 ◦C (from Et2O);
2-(4-Bromophenyl)amino-8-methylquinazoline 15b. Eluent for
column chromatography: hexanes/diethyl ether (1 : 1, v/v);
(0.20 g, 63%); mp 221–222 ◦C (from Et2O); nmax(Nujol)/cm-1 3269
(s), 1616 (vs), 1603 (s), 1578 (s), 1549 (s), 1489 (s), 1414 (s), 1304
(m), 1254 (m), 1007 (w), 823 (m), 769 (s), 723 (m); dH(200 MHz,
CDCl3, 55 ◦C) 2.70 (3 H, s), 7.27 (1 H, t, J 7.8), 7.46–7.50 (2 H, m),
7.57–7.65 (2 H, m), 7.77–7.81 (2 H, m), 9.06 (1 H, m); dC(50 MHz,
CDCl3, 55 ◦C) 17.3, 114.8 (s), 120.6, 120.9 (s), 124.0, 125.3, 131.9,
134.4 (s), 134.7, 139.0 (s), 149.9 (s), 155.9 (s), 162.4; HRMS (ESI):
Calcd for C15H12BrN3 [M]+ 313.0215, found 313.0218.
n
max(Nujol)/cm-1 1647, 1606; dH(300 MHz; CDCl3) 2.26 (3 H,
s), 5.50 (2 H, s), 6.80 (1 H, s), 7.00–7.04 (2 H, m), 7.43–7.46 (2
H, m), 8.12–8.15 (2 H, m); dC(75 MHz; CDCl3) 20.8, 47.7, 115.3
(s), 120.4, 124.7, 126.9, 129.5, 130.0, 132.6 (s), 132.9 (s), 133.9
(s), 140.5 (s), 143.3 (s); HRMS (ESI): Calcd for C15H12ClN5 [M]+
297.0781, found 297.0793.
7-Methyl-3-(3-methoxyphenyl)-3,9-dihydrotetrazolo[5,1-b]qui-
nazoline 14f. Eluent for column chromatography: hex-
anes/diethyl ether (9 : 1, v/v); (0.29 g, 99%); mp 187–188 ◦C (from
Et2O); nmax(Nujol)/cm-1 1650, 1587; dH(400 MHz; CDCl3) 2.26 (3
H, s), 3.88 (3 H, s), 5.48 (2 H, s), 6.77 (1 H, s), 6.87 (1 H, dd, J 8.4,
2.0), 6.98–7.05 (2 H, m), 7.38 (1 H, t, J 8.4), 7.77 (1 H, d, J 8.4),
7.81 (1 H, s); dC(100 MHz; CDCl3) 20.7, 47.6, 55.5, 104.8, 111.3,
113.0, 115.3 (s), 124.6, 126.8, 129.8, 130.1, 132.5 (s), 136.3 (s),
140.6 (s), 143.4 (s), 160.2 (s); HRMS (ESI): Calcd for C16H15N5O
[M]+ 293.1277, found 193.1280.
6-Chloro-2-(4-methylphenyl)aminoquinazoline 15c. Eluent for
column chromatography: hexanes/dichloromethane (1 : 9, v/v);
(0.11 g, 40%); mp 178–179 ◦C (from Et2O); nmax(Nujol)/cm-1 3253
(s), 1620 (vs), 1603 (vs), 1539 (vs), 1514 (s), 1407 (m), 1356 (s),
1174 (m), 1074 (m), 966 (w), 816 (s), 758 (w), 719 (m), 646 (w);
dH(400 MHz, CDCl3) 2.36 (3 H, s), 7.18–7.20 (2 H, m), 7.64–7.66
(3 H, m), 7.69–7.72 (3 H, m), 9.03 (1 H, s); dC(100 MHz, CDCl3)
21.0, 120.0, 120.9 (s), 126.4, 127.1, 129.2 (s), 129.6, 133.2 (s), 135.7,
6748 | Org. Biomol. Chem., 2011, 9, 6741–6749
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136.2 (s), 156.6 (s), 161.8; HRMS (ESI): Calcd for C15H12ClN3 [M]+
269.0720, found 269.0710.
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2-Benzylamino-6-methylquinazoline 15d. Eluent for column
chromatography: dichloromethane/diethyl ether (9 : 1, v/v);
(0.24 g, 95%); mp 147–148 ◦C (from Et2O); nmax(Nujol)/cm-1 3228
(s), 1629 (m), 1599 (vs), 1544 (vs), 1311 (m), 1259 (m), 1246 (m),
1205 (w), 1143 (m), 1076 (w), 976 (w), 831 (m), 752 (m), 700 (m),
642 (m); dH(300 MHz, DMSO-d6) 2.43 (3 H, s), 4.76 (2 H, d, J
5.7), 6.13 (1 H, s), 7.24–7.34 (3 H, m), 7.38–7.40 (2 H, m), 7.44 (1
H, s), 7.53–7.54 (2 H, m), 8.90 (1 H, s); dC(75 MHz, DMSO-d6)
21.2, 45.8, 120.1 (s), 124.3, 126.6, 127.4, 127.8, 133.0 (s), 137.1,
138.9 (s), 158.6 (s), 162.4; HRMS (ESI): Calcd for C16H15N3 [M]+
249.1266, found 249.1263.
Acknowledgements
This work was supported by the Ministerio de Ciencia e Inno-
vacion of Spain (Project CTQ2008-05827/BQU) and Fundacion
Seneca-CARM (Project 08661/PI/08). B. B. and M.-M. O. thank
Fundacion Seneca-CARM and Fundacion CajaMurcia for their
respective fellowships.
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This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6741–6749 | 6749
©