Rapid analogue synthesis of C-5 substituted 1,2,3-triazolo[1,5-a]quinazolines

Article abstract of DOI:10.1016/S0040-4020(02)01351-0

A rapid analogue synthetic strategy has been developed to allow easy variation of the C-5 position of 1,2,3-triazolo[1,5-a]quinazolines. A range of directly linked and carbon tethered aromatic heterocyclic groups have been introduced utilising palladium c

Full text of DOI:10.1016/S0040-4020(02)01351-0

Tetrahedron 58 (2002) 9973–9981
Rapid analogue synthesis of C-5 substituted 1,2,3-triazolo-
[1,5-a]quinazolines
*
Philip Jones and Mark Chambers
Department of Medicinal Chemistry, Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre,
Terlings Park, Harlow CM20 2QR, UK
Received 4 July 2002; revised 23 September 2002; accepted 17 October 2002
Abstract—A rapid analogue synthetic strategy has been developed to allow easy variation of the C-5 position of 1,2,3-triazolo[1,5-a]-
quinazolines. A range of directly linked and carbon tethered aromatic heterocyclic groups have been introduced utilising palladium catalysed
cross-coupling reactions on an imino tosylate. q 2002 Elsevier Science Ltd. All rights reserved.
As part of an ongoing medicinal chemistry programme
directed towards the identification of subtype selective
ligands for the benzodiazepine binding site of GABA-A
receptors, we were interested in preparing a series of novel
1,2,3-triazolo[1,5-a]quinazolines bearing a variety of sub-
stituents at the C-5 position,1 in particular, directly linked
aromatic heterocycles (A) and heterocyclic groups linked by
a short carbon chain (B) (Fig. 1).
are references in the literature describing compounds
substituted at the C-5 position with O-linked functionality,3
there are few references describing triazoloquinazolines
substituted at C-5 with nitrogen4–6 or carbon linked
groups.7,8 Indeed, the only examples described for C-5
carbon linked triazoloquinazolines are those bearing simple
alkyl and aryl groups which are introduced prior to the
formation of the core triazoloquinazoline from ortho-azido-
phenylketones. This method is not suitable for rapid
analogue synthesis and thus could not be employed to
rapidly establish structure activity relationships for this
class of compound. Herein, we describe our strategy and
solution for the synthesis of C-5 carbon linked triazolo-
quinazolines enabling structural changes to be made simply
and efficiently.
Although the first synthesis of 1,2,3-triazolo[1,5-a]quinazo-
lines was reported 36 years ago,2 this class of compounds
has subsequently received little attention. Although there
The triazoloquinazolinone framework was prepared by the
method of Tennant.2 Anthranilic acid (1) was readily
converted into 2-azidobenzoic acid (2) by diazotisation
and displacement with sodium azide (Scheme 1). Treatment
of an equimolar mixture of the aryl azide with the isoxazole
acetonitrile 3 in the presence of sodium ethoxide at 808C
leads to the desired core skeleton 4. The reaction proceeds
by deprotonation of the acetonitrile followed by addition
Figure 1.
Scheme 1.
Keywords: triazoloquinazolines; nitrogen heterocycles; coupling reactions; imidic acids and derivatives.
*
Corresponding author. Fax: þ44-1279-440187; e-mail: philip_jones@merck.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01351-0

9974
P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
Scheme 2.
onto the azido group. Subsequent 5-exo-cyclisation onto the
nitrile group furnishes the triazole group after proton
migration. Ring closure to the triazoloquinazolinone then
occurs readily.
Due to the ready availability of the imino tosylate 6 a
speculative cross-coupling reaction was attempted
(Scheme 4). Despite literature precedent, tosylates are not
used routinely in palladium catalysed couplings.11 Although
the Ni-catalysed Suzuki coupling of aryl tosylates has been
reported,11a there is only one example of the successful
cross-coupling of an imino tosylate reported in the patent
literature,12 despite the widespread use of imino triflates in
synthesis.13 When the imino tosylate 6 was treated with
2 equiv. of 2-tributylstannyl-N-methylimidazole the
coupled product 7e was obtained in 52% yield, the same
as the corresponding reaction on the imino chloride. Other
reactions using heteroarylstannanes yielded similar results.
A control reaction was carried out in the absence of CuI to
ascertain whether the palladium was undergoing oxidative
addition into the imino tosylate or whether initial reaction
between the CuI and the imino tosylate yielded an imino
iodide which in turn reacted. When the tosylate was reacted
with 2-tributylstannylthiophene in the presence of
Pd(PPh3)4 we were delighted to find that cross-coupling
occurred, albeit in longer reaction time, affording 91%
isolated yield of 7a in 8 h compared to 78% yield in 1 h with
CuI. Similar findings were obtained with 2-tributylstannyl-
furan, 87% yield of 7b in 1 h in the presence of CuI,
compared to 73% in 8 h in the absence of CuI. This clearly
demonstrates the potential of imino tosylates for cross-
coupling reaction. At this stage, the rate enhancement due to
CuI could be attributed to either in situ formation of an
imino iodide, thereby allowing faster oxidative insertion
into the C–I bond, or to the formation of a more active
With the core ring system to hand it was then necessary to
elaborate the C-5 position into a suitable leaving group to
enable rapid functionalisation at this position (Scheme 2).
Although attempts to prepare the imino chloride 5 using
SOCl2 gave the desired material on small scale, the reaction
proved not to be reproducible. Likewise, other chlorinating
agents such as POCl3 also gave unsatisfactory results.
However, treatment of the lactam with CCl4 and PPh3 in the
presence of iPr2NEt gave the imino chloride in a modest, but
reproducible, 30–40% yield. In an attempt to prepare other
suitable leaving groups at the C-5 position it was discovered
that the imino tosylate 6 could be readily prepared in
excellent yield by treatment of the lactam with tosyl
chloride in the presence of Et3N.
With the imino chloride 5 to hand cross-coupling reactions
were readily carried out with a range of heteroaromatic
stannanes using Stille conditions,9 resulting in the coupled
products 7 in modest to high yields (Scheme 3). Delighted
with this result, a Negishi cross-coupling was attempted
using 5-(1-N-methylpyrazole)zinc chloride, prepared by
lithiation of N-methylpyrazole at 2788C followed by
transmetallation with ZnCl2.10 The cross-coupling reaction
occurred readily under palladium catalysis to give triazolo-
quinazoline 7f in 40% yield.
Scheme 3.

P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
9975
Scheme 4.
palladium species by the removal of a PPh3 from the
Pd(PPh3)4 as has been described by Liebeskind.14
at coupling 2-ethynylpyridine with 6 under a variety of
Sonogashira–Hagihara coupling conditions failed.15 How-
ever, 6 coupled readily to trimethylsilylacetylene 8 in the
presence of Pd(PPh3)2Cl2 and CuI to give 9 in 88% yield
(Scheme 5). The reaction necessitated the use of Et3N, as
iPr2NH and other secondary amines resulted in rapid
cleavage of the imino tosylate to the lactam 4. Deprotec-
tion of 9 with TBAF in MeOH/CH2Cl2 gave the unsubsti-
tuted alkyne 10 in good yield. However, subsequent
As well as triazoloquinazolines linked directly to hetero-
aromatic groups there was also interest in preparing a series
of compounds linked by an ethynyl, ethenyl or ethanyl
spacer. In the interest of efficiency, it was decided to try to
prepare the ethynyl-linked derivative and then perform
stepwise reductions to yield the other products. All attempts
Scheme 5.

9976
P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
Table 1. Isolated yields for cross-coupling/reduction/oxidation reactions
(5-Methylisoxazol-3-yl)acetonitrile (3),17 2-tributylstannyl-
N-methylimidazole,18 and 5-tributylstannyl-N-methyl-
[1,2,4]-triazole19 were prepared according to published
methods.
No.
Het
Yield 12
(%)
Yield 13
(%)
Yield 14
(%)
a
b
c
d
e
2-Furyl
80
95
28
94
66
56
67
53
59
63
88
82
N/A
27
2-Pyridyl
3-Pyridyl
2-(N-Methylimidazole)
1.1.1. 2-Azidobenzoic acid (2). A solution of sodium nitrite
(4.75 g, 69 mmol) in H2O (63 mL) was added to a solution
of anthranilic acid (10 g, 73 mmol) in H2O (125 mL) and
conc. HCl (125 mL) at 58C under N2 and then stirred for
10 min. The mixture was then filtered through a chilled frit
into a flask cooled in a 2788C bath. This solution was then
added dropwise over 25 min to a stirred solution of sodium
azide (4.2 g, 65 mmol) and sodium acetate trihydrate
(105 g, 0.77 mol) in H2O (125 mL) at 258C under N2.
The resulting mixture was stirred at 08C for 5 min and then
warmed to room temperature and stirred for a further
90 min. The resulting precipitate was filtered and washed
with H2O (200 mL) and hexanes (200 mL) and dried under
reduced pressure to yield the desired azide (8.68 g, 73%).
1H NMR (CDCl3, 400 MHz) d 8.14 (1H, d, J¼7.4 Hz),
7.61 (1H, t, J¼8.1 Hz), 7.30–7.22 (2H, m). 13C NMR
(d6-DMSO, 90 MHz) d 168.7 (s), 141.0 (s), 135.3 (d), 133.4
(d), 127.2 (d), 126.3 (s), 123.1 (d).
5-(N-Methyl-[1,2,4]-triazole)
67
Sonogashira–Hagihara cross-coupling reactions on 10 with
iodobenzene failed to give any of the desired 5-phenylethyl-
ene-[1,2,3]-triazolo[1,5-a]quinazoline.
In order to circumvent the problems of the failed
Sonogashira reactions attempts were made to convert the
acetylene into a vinyl iodide. Having observed the high
reactivity of 6 it was proposed that the acetylene may
behave in a similar manner to a propionate and undergo
conjugate addition with NaI in a manner similar to that
described by Taniguchi.16 Addition of NaI to a solution of
10 in TFA gave the desired E-vinyl iodide 11 exclusively, in
high yield. Unfortunately, when the conditions reported to
prepare the Z-vinyl iodide were tried (NaI, AcOH) only the
E-isomer 11 could be detected.
1.1.2. 3-(5-Methylisoxazol-3-yl)-4H-[1,2,3]-triazolo[1,5-a]-
quinazolin-5-one (4). Sodium (1.77 g, 77 mmol) was added
portionwise to EtOH (200 mL) at room temperature under
N2. Upon complete disappearance of the sodium, the nitrile
3 (4.14 g, 33.9 mmol) was added and the solution stirred for
15 min. A solution of the azide 2 (5.02 g, 30.8 mmol) in
EtOH (20 mL) was added and the reaction stirred at room
temperature for 1 h and then warmed to 808C and heated at
reflux for 5 h. After cooling to room temperature, the EtOH
was removed under reduced pressure and H2O (250 mL)
added. This mixture was acidified with 1 M citric acid
solution (100 mL) and filtered. The solid was then washed
with H2O (200 mL) and toluene (2£100 mL), and dried
under reduced pressure to yield the desired lactam (4.96 g,
60%). 1H NMR (d6-DMSO, 400 MHz) d 12.15 (1H, s), 8.36
(1H, d, J¼7.9 Hz), 8.24 (1H, d, J¼7.9 Hz), 8.02 (1H,
t, J¼7.9 Hz), 7.71 (1H, t, J¼7.9 Hz), 6.82 (1H, s), 2.50
(3H, s). 13C NMR (d6-DMSO, 90 MHz) d 172.2 (s), 161.2
(s), 156.6 (s), 137.8 (d), 136.7 (s), 135.2 (s), 130.7 (d), 130.5
(d), 122.0 (s), 119.7 (s), 117.5 (d), 102.6 (d), 14.1 (q). MS
(ESþ) C13H9N5O2 requires 267, found: 268 (MþHþ,
100%).
The vinyl iodide 11 proved to be a useful synthetic
intermediate and further Stille cross-coupling reactions
were carried out in excellent yield to give the ethenyl
products 12 (Table 1). Reduction of these compounds into
their saturated counterparts 14 proved troublesome, and
most methods gave a complex mixture of products. A
satisfactory resolution proved to be reduction of both the
double bond and the triazoloquinazoline core in tandem to
yield the 4,5-dihydro-[1,2,3]-triazolo[1,5-a]quinazolines 13
in high yield, further demonstrating that the CvN double
bond of the triazoloquinazoline can function as an isolated
imine rather than as part of an aromatic heterocyclic system.
In turn, this compound could be oxidised efficiently to the
desired triazoloquinazolines 14 by addition of DDQ.
In summary, we have devised a short and flexible strategy
for the synthesis of a variety of C-5 substituted 1,2,3-tri-
azolo[1,5-a]quinazolines from the key imino tosylate 6.
Selective variation of the heterocycle and linking group is
possible using this approach. This is the first demonstration
that imino tosylates may have wide application in palladium
catalysed cross-coupling reactions.
1.1.3. 5-Chloro-3-(5-methylisoxazol-3-yl)-[1,2,3]-tria-
zolo[1,5-a]quinazoline (5). A mixture of the triazolo-
quinazolinone 4 (500 mg, 1.75 mmol), PPh3 (981 mg,
i
3.7 mmol), Pr2NEt (648 mL, 3.7 mmol) in CCl4 (15 mL)
and 1,2-DCE (15 mL) was heated at 908C for 10 min and
then cooled to room temperature. The resulting mixture was
filtered through a pad of silica and the pad washed with
DCM. The filtrate was concentrated under reduced pressure
and dry loaded onto silica. Column chromatography on
silica using 5% MeOH/DCM yielded the desired chloride
(200 mg, 37%). 1H NMR (CDCl3, 400 MHz) d 8.75 (1H, d,
J¼8.1 Hz), 8.40 (1H, d, J¼8.1 Hz), 8.11 (1H, t, J¼8.1 Hz),
7.85 (1H, t, J¼8.1 Hz), 6.81 (1H, s), 2.56 (3H, s). 13C NMR
(d6-DMSO, 90 MHz) d 169.9 (s), 154.8 (s), 154.5 (s), 136.5
(s), 136.2 (d), 133.8 (s), 129.6 (s), 128.9 (d), 128.6 (d), 117.5
(s), 116.1 (d), 100.7 (d), 11.3 (q). MS (ESþ) C13H8N5OCl
1. Experimental
1.1. General
1H NMR spectra were recorded at 360 or 400 MHz. Flash
column chromatography was carried out on silica gel
(E. Merck Art 7734). Reagents and dry solvents were
purchased from Sigma Aldrich or Frontier Scientific Europe
Ltd. and used without purification. Glassware was dried
prior to use and reactions were performed under a nitrogen
atmosphere unless otherwise specified. Organic solvents
were evaporated on a rotary evaporator at reduced pressure.

P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
9977
requires 285, found: 286, 288 (3:1) (MþHþ, 100%). HRMS
(ESþ) m/z 286.0495, C13H9N5O35Cl requires 286.0496.
12.3 (q). MS (ESþ) C17H11N5O2 requires 317, found: 318
(MþHþ, 100%). [Found: C, 63.9; H, 3.5; N, 21.7.
C17H11N5O2 requires C, 64.3; H, 3.5; N, 22.1]. HRMS
(ESþ) m/z 318.0991, C17H12N5O2 requires 318.0991.
1.1.4. Toluene-4-sulfonic acid 3-(5-methylisoxazol-3-yl)-
[1,2,3]-triazolo[1,5-a]quinazolin-5-yl ester (6). Tosyl
chloride (1.32 g, 6.89 mmol) was added portionwise over
5 min to a stirred solution of the triazoloquinazolinone 4
(0.92 g, 3.44 mmol) and Et3N (0.95 mL, 6.89 mmol) in
DCM (30 mL) at room temperature under N2. The resulting
mixture was then stirred overnight, during which period a
precipitate formed, this was subsequently filtered off and
washed with DCM (20 mL). After drying under reduced
pressure the desired tosylate was obtained (1.29 g, 89%) as
1.2.3. 3-(5-Methylisoxazol-3-yl)-5-(pyridin-2-yl)-[1,2,3]-
triazolo[1,5-a]quinazoline (7c). The reaction was carried
out as described for 7a using the chloroimidate 5
(87 mg, 0.31 mmol) and 2-tributylstannylpyridine (449 mg,
1.2 mmol) overnight at 708C to yield the desired triazolo-
quinazoline (37 mg, 37%) after recrystallisation from
1
DCM/EtOAc. H NMR (CDCl3, 400 MHz) d 9.04 (1H, d,
J¼7.8 Hz), 8.85–8.80 (2H, m), 8.34 (1H, d, J¼8.0 Hz),
8.10–7.96 (2H, m), 7.77 (1H, t, J¼8.2 Hz), 7.55–7.48 (1H,
m), 6.86 (1H, s), 2.56 (3H, s). 13C NMR (CDCl3, 90 MHz) d
169.5 (s), 159.6 (s), 155.9 (s), 155.1 (s), 148.5 (d), 137.5 (d),
134.7 (d), 134.1 (s), 130.7 (d), 130.3 (s), 128.0 (d), 127.9 (s),
125.8 (d), 124.7 (d), 117.5 (s), 115.7 (d), 100.8 (d), 12.3 (q).
MS (ESþ) C18H12N6O requires 328 found: 329 (MþHþ,
100%). [Found: C, 65.7; H, 3.7; N, 25.3. C18H12N6O
requires C, 65.8; H, 3.7; N, 25.6]. HRMS (ESþ) m/z
329.1146, C18H13N6O requires 329.1151.
1
a pale yellow solid. H NMR (CDCl3, 360 MHz) d 8.68
(1H, d, J¼8.3 Hz), 8.43 (2H, d, J¼8.2 Hz), 8.31 (1H, d, J¼
8.1 Hz), 8.06 (1H, t, J¼8.2 Hz), 7.77 (1H, t, J¼8.2 Hz), 7.44
(2H, d, J¼8.2 Hz), 6.79 (1H, s), 2.59 (3H, s), 2.49 (3H, s).
13C NMR (d6-DMSO, 90 MHz) d 172.2 (s), 161.1 (s), 157.8
(s), 149.0 (s), 147.9 (s), 139.8 (s), 137.6 (d), 136.7 (s), 132.3
(s), 132.0 (s), 130.8 (d), 130.4 (d), 130.3 (d), 127.8 (d),
117.6 (d), 102.5 (d), 13.1 (q), 14.3 (q). MS (ESþ)
C20H15N5O4S requires 421, found: 422 (MþHþ, 100%).
[Found: C, 55.8; H, 3.7; N, 16.2. C20H15N5O4S·0.5H2O
requires C, 55.8; H, 3.7; N, 16.3].
1.2.4. 3-(5-Methylisoxazol-3-yl)-5-(pyridin-3-yl)-[1,2,3]-
triazolo[1,5-a]quinazoline (7d). The reaction was carried
out as described for 7a using the chloroimidate 5
(79 mg, 0.28 mmol) and 3-tributylstannylpyridine (408 mg,
1.1 mmol) overnight at 708C to yield the desired triazolo-
quinazoline (18 mg, 20%) after recrystallisation from
1.2. Method 1: cross-coupling with the chloroimidate 5
1.2.1. 3-(5-Methylisoxazol-3-yl)-5-(thiophen-2-yl)-
[1,2,3]-triazolo[1,5-a]quinazoline (7a). A solution of the
chloroimidate 5 (87 mg, 0.31 mmol) and 2-(tributyl-
stannyl)thiophene (387 mL, 1.2 mmol) in DMF (5 mL)
was degassed with a stream of N2 for 10 min. Pd(PPh3)4
(40 mg, 10 mol%) and CuI (6 mg, 10 mol%) were added
and the reaction heated at 708C overnight. The resulting
mixture was cooled to room temperature and concentrated
under reduced pressure and then azeotroped with xylene
(2£10 mL), prior to absorbing onto silica with DCM and
MeOH. The resulting residue was purified by column
chromatography on silica eluting with 0.5% MeOH in DCM
1
DCM/EtOAc. H NMR (d6-DMSO, 360 MHz) d 9.02 (1H,
s), 8.88 (1H, d, J¼3.6 Hz), 8.80 (1H, d, J¼8.1 Hz), 8.33–
8.21 (2H, m), 8.11 (1H, d, J¼8.0 Hz), 7.89 (1H, t, J¼
8.0 Hz), 7.71 (1H, dd, J¼7.8, 4.9 Hz), 6.95 (1H, s), 2.53
(3H, s). 13C NMR (CDCl3, 90 MHz) d 169.8 (s), 166.2 (s),
164.9 (s), 154.2 (s), 151.2 (d), 150.3 (d), 148.3 (s), 145.1 (s),
137.4 (d), 135.2 (d), 128.9 (d), 128.3 (d), 123.6 (d), 118.7
(s), 118.3 (s), 116.3 (d), 100.8 (d), 12.3 (q). MS (ESþ)
C18H12N6O requires 328, found: 329 (MþHþ, 100%).
HRMS (ESþ) m/z 329.1138, C18H13N6O requires 329.1151.
1
to yield the desired triazoloquinazoline (79 mg, 78%). H
NMR (CDCl3, 400 MHz) d 8.85 (1H, d, J¼7.9 Hz), 8.60
(1H, d, J¼8.1 Hz), 8.07 (1H, t, J¼7.8 Hz), 7.85–7.75 (2H,
m), 7.70 (1H, d, J¼4.9 Hz), 7.30–7.25 (1H, m), 6.88 (1H,
s), 2.56 (3H, s). 13C NMR (CDCl3, 90 MHz) d 169.6 (s),
156.8 (s), 154.9 (s), 139.9 (s), 134.9 (d), 133.8 (s), 131.9 (s),
131.4 (d), 130.9 (d), 129.1 (s), 128.8 (d), 128.3 (d), 128.2
(d), 117.2 (s), 116.4 (d), 100.8 (d), 12.4 (q). MS (ESþ)
C17H11N5OS requires 333, found: 334 (MþHþ, 100%).
HRMS (ESþ) m/z 334.0773, C17H12N5OS requires
334.0763.
1.2.5. 5-(1-Methyl-1H-imidazol-2-yl)-3-(5-methylisoxa-
zol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline (7e). The
reaction was carried out as described for 7a using the
chloroimidate 5 (79 mg, 0.28 mmol) and 2-tributylstannyl-
N-methylimidazole (205 mg, 0.56 mmol) at 708C for 1 h to
yield the desired triazoloquinazoline (51 mg, 55%) after
recrystallisation from DCM/hexanes. 1H NMR (CDCl3,
400 MHz) d 9.58 (1H, d, J¼8.2 Hz), 8.78 (1H, d, J¼
8.0 Hz), 8.03 (1H, t, J¼7.8 Hz), 7.80 (1H, t, J¼7.9 Hz), 7.34
(1H, s), 7.21 (1H, s), 6.81 (1H, s), 4.28 (3H, s), 2.56 (3H, s).
13C NMR (CDCl3þ10% CD3OD, 90 MHz) d 169.8 (s),
155.0 (s), 151.4 (s), 136.6 (s), 135.0 (d), 133.8 (s), 131.0 (d),
130.1 (s), 129.0 (d), 128.4 (d), 125.7 (s), 125.0 (s), 117.6 (d),
115.3 (d), 100.4 (d), 36.5 (q), 12.0 (q). MS (ESþ)
C17H13N7O requires 331, found: 332 (MþHþ, 100%).
[Found: C, 59.9; H, 3.8; N, 28.4. C17H13N7O·0.5H20
requires C, 60.0; H, 4.1; N, 28.1]. HRMS (ESþ) m/z
332.1241, C17H14N7O requires 332.1260.
1.2.2. 5-(Furan-2-yl)-3-(5-methylisoxazol-3-yl)-[1,2,3]-
triazolo[1,5-a]quinazoline (7b). The reaction was carried
out as described for 7a using the chloroimidate 5 (87 mg,
0.31 mmol) and 2-tributylstannylfuran (384 mL, 1.2 mmol)
at 708C for 30 min to yield the desired triazoloquinazoline
1
(20 mg, 20%). H NMR (CDCl3, 400 MHz) d 9.07 (1H, d,
J¼8.2 Hz), 8.83 (1H, d, J¼8.1 Hz), 8.04 (1H, t, J¼8.1 Hz),
7.84–7.74 (2H, m), 7.64 (1H, d, J¼3.1 Hz), 6.86 (1H, s),
6.72 (1H, d, J¼3.1 Hz), 2.56 (3H, s). 13C NMR (CDCl3,
90 MHz) d 169.4 (s), 155.0 (s), 152.3 (s), 150.1 (s), 145.9
(d), 137.0 (s), 134.6 (d), 133.9 (s), 129.6 (s), 128.9 (d), 128.2
(d), 117.0 (d), 116.4 (s), 115.9 (d), 112.6 (d), 100.7 (d),
1.2.6. 3-(5-Methylisoxazol-3-yl)-5-(2-methyl-2H-pyra-
zol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline (7f). A solu-
tion of BuLi (1.54 mmol) in hexane (1.6 M, 0.96 mL) was
i
added to a stirred solution of Pr2NH (215 mL, 1.54 mmol)

9978
P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
in THF (2 mL) at 08C under N2. The resulting solution was
stirred for 20 min and then cooled to 2788C and N-methyl
pyrazole (116 mL, 1.4 mmol) was added. The mixture was
stirred for 1 h at 2788C and then a solution of ZnCl2
(210 mg, 1.54 mmol) in THF (2 mL) was added and then the
reaction was allowed to warm to room temperature. DMF
(5 mL) was added, followed by a slurry of the chloroimidate
(150 mg, 0.53 mmol) in DMF (3 mL) and then Pd(PPh3)4
(40 mg, 6 mol%). The reaction was then heated at 508C for
45 min, cooled to room temperature and concentrated under
reduced pressure and azeotroped with xylene (20 mL). The
crude residue was dissolved in DCM (70 mL) and washed
with 1N HCl (30 mL), dried (MgSO4) and absorbed onto
silica under reduced pressure. The residue was purified by
column chromatography on silica eluting with 5–10%
EtOAc in DCM to yield the desired triazoloquinazoline
(100 mg, 0.24 mmol) and 2-tributylstannylthiophene
(178 mg, 0.48 mmol) to yield the desired triazoloquinazo-
line (62 mg, 78%).
1.3.4. 5-(Furan-2-yl)-3-(5-methylisoxazol-3-yl)-[1,2,3]-
triazolo[1,5-a]quinazoline (7b). The reaction was carried
out as described for 7e using the tosylate 6 (100 mg,
0.24 mmol) and 2-tributylstannylfuran (170 mg, 0.48 mmol)
to yield the desired triazoloquinazoline (66 mg, 87%).
1.4. Method 3: by coupling with the imino tosylate 6 in
the absence of CuI
1.4.1. 3-(5-Methylisoxazol-3-yl)-5-(thiophen-2-yl)-
[1,2,3]-triazolo[1,5-a]quinazoline (7a). A suspension of
the tosylate 6 (100 mg, 0.24 mmol) and 2-tributyl-
stannylthiophene (178 mg, 0.48 mmol) in DMF (5 mL)
was degassed with a stream of N2 for 10 min. The mixture
was then warmed to 708C. At 408C the solids dissolved and
Pd(PPh3)4 (40 mg, 10 mol%) was added. The reaction was
heated at 708C for 8 h. The resulting mixture worked up as
previously to yield the desired triazoloquinazoline (72 mg,
91%).
1
(69 mg, 40%). H NMR (CDCl3, 400 MHz) d 8.77 (1H, d,
J¼8.2 Hz), 8.29 (1H, d, J¼8.2 Hz), 8.02 (1H, t, J¼8.2 Hz),
7.71 (1H, t, J¼8.2 Hz), 7.60 (1H, d, J¼1.8 Hz), 6.74 (1H, s),
6.71 (1H, d, J¼1.8 Hz), 4.17 (3H, s), 2.48 (3H, s). 13C NMR
(CDCl3þ10% CD3OD, 100 MHz) d 170.0 (s), 154.6 (s),
153.4 (s), 138.1 (d), 136.8 (s), 136.6 (s), 135.6 (d), 133.8 (s),
130.3 (s), 128.8 (d), 128.6 (d), 118.0 (s), 116.0 (d), 110.9
(d), 100.6 (d), 38.6 (q), 12.1 (q). MS (ESþ) C17H13N7O
requires 331, found: 332 (MþHþ, 100%). HRMS (ESþ) m/z
332.1268, C17H14N7O requires 332.1260.
1.4.2. 5-(Furan-2-yl)-3-(5-methylisoxazol-3-yl)-[1,2,3]-
triazolo[1,5-a]quinazoline (7b). The reaction was carried
out as described directly above for 7a using the tosylate 6
(100 mg, 0.24 mmol) and 2-tributylstannylfuran (170 mg,
0.48 mmol) to yield the desired triazoloquinazoline (55 mg,
73%).
1.3. Method 2: by coupling with the imino tosylate 6
1.3.1. 5-(1-Methyl-1H-imidazol-2-yl)-3-(5-methylisoxa-
zol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline (7e). A sus-
pension of the tosylate 6 (100 mg, 0.24 mmol) and
2-tributylstannyl-N-methylimidazole (176 mg, 0.48 mmol)
in DMF (5 mL) was degassed with a stream of N2 for
10 min. The mixture was then warmed to 708C. At 408C, the
solids dissolved and Pd(PPh3)4 (40 mg, 10 mol%) and CuI
(6 mg, 10 mol%) were added. The reaction was heated at
708C for 1 h. The resulting mixture worked up as previously
to yield the desired triazoloquinazoline 7e (41 mg, 52%)
after recrystallisation from DCM/hexanes.
1.5. Alternative linkers at the C-5 position
1.5.1. 3-(5-Methylisoxazol-3-yl)-5-(trimethylsilanyl-
ethynyl)-[1,2,3]-triazolo[1,5-a]quinazoline (9). A solution
of the tosylate 6 (5.0 g, 11.9 mmol), trimethylsilylacetylene
(5.0 mL, 35.7 mmol), Pd(PPh3)2Cl2 (416 mg, 5 mol%) and
CuI (339 mg, 15 mol%) in DMF (300 mL) at 608C was
degassed with a stream of N2 for 15 min and then Et3N
(4.1 mL, 29.8 mmol) was added and the reaction heated at
608C for 30 min. The resulting mixture was concentrated
under reduced pressure while azeotroping with xylene
(200 mL). The residue was taken up in DCM (300 mL) and
washed with H2O (2£150 mL), dried (MgSO4), and
concentrated under reduced pressure while dry loading
onto silica. The residue was purified by column chroma-
tography on silica eluting with 2% MeOH in DCM to yield
the desired triazoloquinazoline (3.62 g, 88%). 1H NMR
(CDCl3, 360 MHz) d 8.73 (1H, d, J¼8.2 Hz), 8.45 (1H, d,
J¼8.1 Hz), 8.05 (1H, t, J¼8.1 Hz), 7.81 (1H, t, J¼8.1 Hz),
6.85 (1H, s), 2.56 (3H, s), 0.40 (9H, s). 13C NMR (CDCl3,
90 MHz) d 169.6 (s), 154.8 (s), 146.5 (s), 137.5 (s), 135.2
(d), 133.1 (s), 130.4 (s), 128.9 (d), 128.4 (d), 119.2 (s), 115.6
(d), 106.5 (s), 100.9 (d), 99.3 (s), 12.3 (q), 20.6 (q). MS
(ESþ) C18H17N5OSi requires 347, found: 348 (MþHþ,
100%). HRMS (ESþ) m/z 348.1280, C18H18N5OSi requires
348.1281.
1.3.2. 3-(5-Methylisoxazol-3-yl)-5-(2-methyl-2H-[1,2,4]-
triazol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline (7g). The
reaction was carried out as described directly above for 7e
using the tosylate 6 (100 mg, 0.24 mmol) and 5-tributyl-
stannyl-N-methyl-[1,2,4]-triazole (176 mg, 0.48 mmol) to
yield the desired triazoloquinazoline (55 mg, 69%) after
recrystallisation from DCM/hexanes. 1H NMR (CDCl3,
400 MHz) d 9.40 (1H, d, J¼8.3 Hz), 8.84 (1H, d, J¼
8.1 Hz), 8.13 (1H,s), 8.09 (1H, t, J¼8.2 Hz), 7.84 (1H, t,
J¼8.1 Hz), 6.82 (1H, s), 4.49 (3H, s), 2.57 (3H, s). 13C NMR
(CDCl3þ10% CD3OD, 90 MHz) d 170.1 (s), 154.8 (s),
150.0 (d), 149.6 (s), 149.0 (s), 136.0 (s), 135.7 (d), 133.7 (s),
130.8 (s), 130.0 (d), 128.7 (d), 117.2 (s), 115.5 (d), 100.4
(d), 39.0 (q), 11.9 (q). MS (ESþ) C16H12N8O requires 332,
found: 333 (MþHþ, 100%). [Found: C, 57.3; H, 3.6; N,
33.0. C16H12N8O·0.25H2O requires C, 57.0; H, 3.7; N,
33.3]. HRMS (ESþ) m/z 333.1206, C16H13N8O requires
333.1212.
1.5.2. 5-Ethynyl-3-(5-methylisoxazol-3-yl)-[1,2,3]tri-
azolo[1,5-a]quinazoline (10).
A solution of TBAF
1.3.3. 3-(5-Methylisoxazol-3-yl)-5-(thiophen-2-yl)-
[1,2,3]-triazolo[1,5-a]quinazoline (7a). The reaction was
carried out as described for 7e using the tosylate 6
(2.4 mmol) in THF (1.0 M, 2.4 mL) was added to a stirred
solution of the TMS–acetylene 9 (554 mg, 1.6 mmol) in
DCM (10 mL) and MeOH (5 mL) and the mixture was

P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
9979
stirred at room temperature for 10 min. H2O (20 mL) was
added and the organics were extracted with DCM
(2£50 mL). The organic extracts were washed with brine
(25 mL), dried (MgSO4), and concentrated under reduced
pressure while dry loading onto silica. The residue was
purified by column chromatography on silica eluting with
2% MeOH in DCM to yield the desired triazoloquinazoline
(393 mg, 90%). 1H NMR (CDCl3, 400 MHz) d 8.75 (1H, d,
J¼8.2 Hz), 8.48 (1H, d, J¼8.2 Hz), 8.07 (1H, t, J¼8.2 Hz),
7.82 (1H, t, J¼8.1 Hz), 6.85 (1H, s), 3.78 (1H, s), 2.56 (3H, s).
13C NMR (CDCl3, 90 MHz) d 169.6 (s), 154.5 (s), 145.9 (s),
135.4 (d), 134.5 (s), 132.8 (s), 128.9 (s), 128.5 (d), 128.4 (d),
127.8 (s), 118.8 (s), 115.6 (d), 100.7 (d), 78.8 (d), 12.2 (q). MS
(ESþ) C15H9N5O requires 275, found: 276 (MþHþ, 100%).
HRMS (ESþ) m/z 276.0888, C15H10N5O requires 276.0885.
tion was carried out as described for 12a using the vinyl
iodide 11 (185 mg, 0.46 mmol) and 2-tributylstannyl-
pyridine (337 mg, 0.92 mmol) to yield the desired triazolo-
quinazoline (154 mg, 95%). 1H NMR (CDCl3, 360 MHz) d
8.85–8.80 (1H, m), 8.75–8.68 (1H, m), 8.60–8.50 (2H, m),
8.27 (1H, d, J¼14.9 Hz), 8.05 (1H, t, J¼8.2 Hz), 7.85–7.72
(2H, m), 7.58 (1H, d, J¼7.7 Hz), 7.37–7.30 (1H, m), 6.89
(1H, s), 2.59 (3H, s). 13C NMR (CDCl3, 90 MHz) d 169.4
(s), 157.1 (s), 154.9 (s), 153.5 (s), 150.0 (d), 139.1 (d), 138.3
(s), 138.0 (d), 134.7 (d), 133.1 (s), 129.1 (s), 128.0 (d), 126.6
(d), 125.4 (d), 124.0 (d), 123.7 (d), 118.4 (s), 116.1 (d),
100.9 (d), 12.3 (q). MS (ESþ) C20H14N6O requires 354,
found: 355 (MþHþ, 100%). HRMS (ESþ) m/z 355.1292,
C20H15N6O requires 355.1307.
1.5.6. (E)3-(5-Methylisoxazol-3-yl)-5-[2-(pyridin-3-yl)-
vinyl]-[1,2,3]-triazolo[1,5-a]quinazoline (12c). The reac-
tion was carried out as described for 12a using the vinyl
iodide 11 (185 mg, 0.46 mmol) and 3-tributylstannyl-
pyridine (337 mg, 0.92 mmol) to yield the desired triazolo-
quinazoline (46 mg, 28%) after recrystallisation from
1.5.3. (E)5-(2-Iodovinyl)-3-(5-methylisoxazol-3-yl)-
[1,2,3]-triazolo[1,5-a]quinazoline (11). NaI (90 mg,
0.6 mmol) was added in one portion to a stirred solution
of the acetylene 10 (150 mg, 0.55 mmol) in TFA (1 mL) and
the resulting mixture was stirred at room temperature for
30 min and then H2O (25 mL) was added. The organics
were extracted with DCM (75 mL), dried (MgSO4), and
concentrated under reduced pressure while dry loading onto
silica. The residue was purified by column chromatography
on silica eluting with 5% EtOAc in DCM to yield the
desired triazoloquinazoline (190 mg, 86%). 1H NMR
(CDCl3, 360 MHz) d 8.80 (1H, d, J¼8.1 Hz), 8.35 (1H, d,
J¼14.2 Hz), 8.27 (1H, J¼8.1 Hz), 8.22 (1H, d, J¼14.2 Hz),
8.06 (1H, t, J¼8.1 Hz), 7.80 (1H, t, J¼8.1 Hz), 6.82 (1H, s),
2.56 (3H, s). 13C NMR (d6-DMSO, 90 MHz) d 172.3 (s),
159.0 (s), 156.3 (s), 140.1 (d), 139.8 (s), 138.7 (s), 138.0 (d),
135.1 (s), 130.6 (d), 129.7 (d), 118.9 (s), 117.7 (d), 103.4
(d), 99.8 (d), 14.3 (q). MS (ESþ) C15H10IN5O requires 403,
found: 404 (MþHþ, 100%). HRMS (ESþ) m/z 404.0018,
C15H11N5O127I requires 404.0008.
1
DCM/hexanes. H NMR (CDCl3, 360 MHz) d 9.00 (1H,
s), 8.83–8.78 (1H, m), 8.65 (1H, d, J¼4.8 Hz), 8.43 (1H, d,
J¼7.8 Hz), 8.29 (1H, d, J¼15.5 Hz), 8.10–8.03 (2H, m),
7.92 (1H, d, J¼15.5 Hz), 7.82 (1H, t, J¼8.2 Hz), 7.40 (1H,
dd J¼7.7, 4.7 Hz), 6.87 (1H, s), 2.56 (3H, s). MS (ESþ)
C20H14N6O requires 354, found: 355 (MþHþ, 100%).
[Found: C, 63.8; H, 3.9; N, 22.7. C20H14N6O·1.1H2O
requires C, 64.2; H, 4.3; N, 22.5]. HRMS (ESþ) m/z
355.1297, C20H15N6O requires 355.1307.
1.5.7. (E)5-[2-(1-Methyl-1H-imidazol-2-yl)-vinyl]-3-(5-
methylisoxazol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline
(12d). The reaction was carried out as described for 12a
using the vinyl iodide 11 (200 mg, 0.5 mmol) and 2-tri-
butylstannyl(N-methylimidazole) (368 mg, 0.99 mmol) to
yield the desired triazoloquinazoline (167 mg, 94%). 1H
NMR (CDCl3, 360 MHz) d 8.78 (1H, d, J¼8.2 Hz), 8.53
(1H, d, J¼8.2 Hz), 8.36 (1H, d, J¼14.8 Hz), 8.19 (1H, d,
J¼14.8 Hz), 8.05 (1H, t, J¼8.2 Hz), 7.80 (1H, t, J¼8.2 Hz),
7.25 (1H, s), 7.05 (1H, s), 6.83 (1H, s), 3.92 (3H, s), 2.57
(3H, s). MS (ESþ) C19H15N7O requires 357, found: 358
(MþHþ, 100%). HRMS (ESþ) m/z 358.1403, C19H16N7O
requires 358.1416.
1.5.4. (E)5-(2-Furan-2-ylvinyl)-3-(5-methylisoxazol-3-
yl)-[1,2,3]-triazolo[1,5-a]quinazoline (12a). A solution of
the vinyl iodide 11 (190 mg, 0.47 mmol) and 2-(tributyl-
stannyl)furan (297 mL, 0.94 mmol) in DMF (10 mL) was
degassed with a stream of N2 for 10 min. Pd(PPh3)4 (40 mg,
10 mol%) and CuI (6 mg, 10 mol%) was added and the
reaction heated at 708C for 1 h. The resulting mixture was
cooled to room temperature and concentrated under reduced
pressure and then azeotroped with xylene (2£15 mL), prior
to absorbing onto silica with DCM. The resulting residue
was purified by column chromatography on silica eluting
with 8% EtOAc in hexanes to yield the desired triazolo-
quinazoline (129 mg, 80%) which was recrystallised from
DCM/hexanes. 1H NMR (CDCl3, 360 MHz) d 8.78 (1H, d,
J¼8.2 Hz), 8.42 (1H, d, J¼8.2 Hz), 8.12 (1H, d, J¼
15.1 Hz), 8.04 (1H, t, J¼8.2 Hz), 7.85–7.73 (2H, m), 7.56
(1H, s), 6.86 (1H, s), 6.80–6.75 (1H, m), 6.58–6.53 (1H, m),
2.57 (3H, s). 13C NMR (CDCl3, 90 MHz) d 169.4 (s), 157.0
(s), 155.4 (s), 152.3 (s), 144.5 (d), 138.1 (s), 134.4 (d), 133.4
(s), 129.1 (s), 127.9 (d), 127.3 (d), 126.0 (d), 117.9 (s), 117.3
(d), 116.1 (d), 115.2 (d), 112.7 (d), 100.8 (d), 12.3 (q). MS
(ESþ) C19H13N5O2 requires 343, found: 344 (MþHþ, 100%).
HRMS (ESþ) m/z 344.1154, C19H14N5O2 requires 344.1147.
1.5.8. (E)3-(5-Methylisoxazol-3-yl)-5-[2-(2-methyl-2H-
[1,2,4]-triazol-3-yl)-vinyl]-[1,2,3]-triazolo[1,5-a]quinazo-
line (12e). The reaction was carried out as described
for 12a using the vinyl iodide 11 (200 mg, 0.50 mmol)
and 5-tributylstannyl(1-N-methyl-[1,2,4]-triazole) (369 mg,
0.99 mmol) to yield the desired triazoloquinazoline
1
(118 mg, 66%). H NMR (CDCl3, 360 MHz) d 8.84 (1H,
d, J¼8.2 Hz), 8.49 (1H, d, J¼8.2 Hz), 8.48 (1H, d, J¼
14.8 Hz), 8.17 (1H, d, J¼14.8 Hz), 8.08 (1H, t, J¼8.2 Hz),
7.99 (1H, s), 7.83 (1H, t, J¼8.2 Hz), 6.84 (1H, s), 4.13 (3H,
s), 2.58 (3H, s). MS (ESþ) C18H14N8O requires 358, found:
359 (MþHþ, 100%). HRMS (ESþ) m/z 359.1383,
C18H15N8O requires 359.1369.
1.5.9. 5-[2-(Furan-2-yl)ethyl]-3-(5-methylisoxazol-3-yl)-
4,5-dihydro-[1,2,3]-triazolo[1,5-a]quinazoline
(13a).
NaBH4 (40 mg, 1.0 mmol) was added to a stirred suspension
of the alkene (70 mg, 0.20 mmol) in EtOH (6 mL) and the
1.5.5. (E)3-(5-Methylisoxazol-3-yl)-5-[2-(pyridin-2-yl)-
vinyl]-[1,2,3]-triazolo[1,5-a]quinazoline (12b). The reac-

9980
P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
mixture was heated at reflux for 90 min. The resulting
mixture was cooled to room temperature, quenched with 2N
HCl (5 mL) and concentrated under reduced pressure to
remove the EtOH. The aqueous solution was neutralised
with 2N NaOH (5 mL), extracted with DCM (3£30 mL),
dried (MgSO4), and concentrated under reduced pressure
while dry loading onto silica. The residue was purified by
column chromatography on silica eluting with 1.5% MeOH
in DCM to yield the desired dihydrotriazoloquinazoline
(40 mg, 56%). 1H NMR (CDCl3, 360 MHz) d 7.61 (1H, s),
7.32–7.20 (2H, m), 7.07 (1H, t, J¼7.6 Hz), 6.95 (1H, d,
J¼8.0 Hz), 6.59 (1H, s), 6.21 (1H, dd, J¼3.1, 1.9 Hz),
6.03–5.95 (2H, m), 2.80–2.52 (4H, m), 2.50 (3H, s), 2.40–
2.28 (1H, m). 13C NMR (CDCl3, 90 MHz) d 169.3 (s), 156.7
(s), 154.0 (s), 141.1 (d), 135.3 (s), 134.9 (s), 129.2 (d), 127.5
(d), 122.9 (d), 118.3 (s), 117.8 (s), 115.4 (d), 110.1 (d),
105.5 (d), 99.2 (d), 57.3 (d), 36.6 (t), 23.0 (t), 12.2 (q). MS
(ESþ) C19H17N5O2 requires 347, found: 348 (MþHþ,
100%).
5.92 (1H, m), 3.76 (3H, s), 2.88–2.70 (3H, m), 2.50 (3H, s),
2.50–2.40 (1H, m). MS (ESþ) C18H18N8O requires 362,
found: 363 (MþHþ, 100).
1.5.14. 5-[2-(Furan-2-yl)ethyl]-3-(5-methylisoxazol-3-
yl)-[1,2,3]-triazolo[1,5-a]quinazoline (14a). DDQ (39 mg,
0.17 mmol) was added in one portion to a stirred solution of
the dihydrotriazoloquinazoline 13a (40 mg, 0.12 mmol) in
DCM (4 mL) and then stirred at room temperature for 1 h.
The resulting mixture was then concentrated under reduced
pressure while dry loading onto silica and purified by
column chromatography on silica eluting with 2% MeOH/
DCM to yield the desired triazoloquinazoline (35 mg, 88%)
which was recrystallised from DCM/hexanes. 1H NMR
(CDCl3, 360 MHz) d 8.78 (1H, d, J¼8.1 Hz), 8.18 (1H, d,
J¼8.1 Hz), 8.01 (1H, t, J¼8.1 Hz), 7.74 (1H, t, J¼8.1 Hz),
7.35–7.32 (1H, m), 6.84 (1H, s), 6.31–6.25 (1H, m), 6.15–
6.08 (1H, m), 3.69 (2H, t, J¼8.2 Hz), 3.38 (2H, t, J¼
8.2 Hz), 2.56 (3H, s). 13C NMR (CDCl3þ10% CD3OD,
90 MHz) d 169.8 (s), 165.8 (s), 154.5 (s), 153.4 (s), 140.9
(d), 134.6 (d), 132.6 (s), 128.8 (s), 128.0 (d), 126.3 (d),
118.0 (s), 117.1 (s), 115.7 (d), 110.0 (d), 105.5 (d), 100.4
(d), 33.1 (t), 25.4 (t), 11.8 (q). MS (ESþ) C19H15N5O2
requires 345, found: 346 (MþHþ, 100%). HRMS (ESþ) m/z
346.1304, C19H16N5O2 requires 346.1304.
1.5.10. 3-(5-Methylisoxazol-3-yl)-5-[2-(pyridin-2-yl)-
ethyl]-4,5-dihydro-[1,2,3]-triazolo[1,5-a]quinazoline
(13b). The reaction was carried out as described for 13a
using the alkene 12b (125 mg, 0.35 mmol) to yield the
desired dihydrotriazoloquinazoline (85 mg, 67%). 1H NMR
(CDCl3, 360 MHz) d 8.48–8.40 (1H, m), 7.68–7.03 (7H,
m), 6.95 (1H, d, J¼8.0 Hz), 6.55 (1H, s), 6.00 (1H, dd, J¼
5.6, 3.3 Hz), 2.84–2.65 (3H, m), 2.55–2.40 (1H, m), 2.48
(3H, s). MS (ESþ) C20H18N6O requires 358, found: 359
(MþHþ, 100). HRMS (ESþ) m/z 3579.1622, C20H19N6O
requires 359.1622.
1.5.15. 3-(5-Methylisoxazol-3-yl)-5-[2-(pyridin-2-yl)-
ethyl]-[1,2,3]-triazolo[1,5-a]quinazoline (14b). The reac-
tion was carried out as described for 14a using the dihydro-
triazoloquinazoline 13b (85 mg, 0.24 mmol) to yield the
desired triazoloquinazoline (70 mg, 82%). 1H NMR
(CDCl3, 360 MHz) d 8.76 (1H, d, J¼8.2 Hz), 8.55 (1H, d,
J¼4.8 Hz), 8.31 (1H, d, J¼8.2 Hz), 7.99 (1H, t, J¼8.2 Hz),
7.74 (1H, t, J¼7.7 Hz), 7.65–7.55 (1H, m), 7.38 (1H, d,
J¼7.7 Hz), 7.20–7.10 (1H, m), 6.81 (1H, s), 3.86 (2H, t,
J¼7.5 Hz), 3.53 (2H, t, J¼7.5 Hz), 2.57 (3H, s). 13C NMR
(CDCl3þ10% CD3OD, 100 MHz) d 169.7 (s), 165.2 (s),
160.1 (s), 154.9 (s), 148.7 (d), 143.2 (s), 137.1 (d), 134.8 (d),
132.9 (s), 128.7 (s), 128.3 (d), 126.9 (d), 124.1 (d), 121.7
(d), 118.3 (s), 115.9 (d), 100.7 (d), 34.8 (t), 34.4 (t), 12.1 (q).
MS (ESþ) C20H16N6O requires 356, found: 357 (MþHþ,
100%). HRMS (ESþ) m/z 357.1474, C20H17N6O requires
357.1464.
1.5.11. 3-(5-Methylisoxazol-3-yl)-5-{2-(pyridin-3-yl)-
ethyl]-4,5-dihydro-[1,2,3]-triazolo[1,5-a]quinazoline
(13c). The reaction was carried out as described for 13a
using the alkene 12c (61 mg, 0.17 mmol) to yield the
desired dihydrotriazoloquinazoline (33 mg, 53%). 1H NMR
(CDCl3, 360 MHz) d 8.48–8.30 (2H, m), 7.73–6.95 (7H,
m), 6.59 (1H, s), 6.02 (1H, t, J¼4.5 Hz), 2.78–2.22 (4H, m),
2.50 (3H, s). MS (ESþ) C20H18N6O requires 358, found:
359 (MþHþ, 100).
1.5.12. 5-[2-(1-Methyl-1H-imidazol-2-yl)-ethyl]-3-(5-
methylisoxazol-3-yl)-4,5-dihydro-[1,2,3]-triazolo[1,5-a]-
quinazoline (13d). The reaction was carried out as
described for 13a using the alkene 12d (128 mg,
0.36 mmol) to yield the desired dihydrotriazoloquinazoline
(77 mg, 59%). 1H NMR (CDCl3, 360 MHz) d 7.71 (1H, s),
7.35 (1H, d, J¼7.7 Hz), 7.26 (1H, t, J¼7.7 Hz), 7.07 (1H, t,
J¼7.7 Hz), 6.95 (1H, d, J¼7.7 Hz), 6.89 (1H, s), 6.75 (1H,
s), 6.58 (1H, s), 5.99 (1H, dd, J¼6.6, 3.5 Hz), 3.49 (3H, s),
2.88–2.70 (1H, m), 2.67 (2H, t, J¼8.0 Hz), 2.49 (3H, s),
2.53–2.35 (1H, m). MS (ESþ) C19H19N7O requires 361,
found: 362 (MþHþ, 100).
1.5.16. 5-[2-(1-Methyl-1H-imidazol-2-yl)-ethyl]-3-(5-
methylisoxazol-3-yl)-[1,2,3]-triazolo[1,5-a]quinazoline
(14d). The reaction was carried out as described for 14a
using the dihydrotriazoloquinazoline 13d (77 mg, 0.21 mmol)
and DDQ (120 mg, 0.52 mmol) to yield the desired tri-
azoloquinazoline (21 mg, 27%). 1H NMR (CDCl3,
360 MHz) d 8.68 (1H, d, J¼8.2 Hz), 8.45 (1H, d, J¼
8.2 Hz), 8.01 (1H, t, J¼8.2 Hz), 7.82 (1H, t, J¼8.2 Hz), 7.18
(1H, s), 7.01 (1H, s), 6.77 (1H, s), 4.41 (2H, br s), 4.16 (3H,
s), 3.70 (2H, br s), 2.56 (3H, s). MS (ESþ) C19H17N7O
requires 359, found: 360 (MþHþ, 100%). HRMS (ESþ) m/z
360.1579, C19H18N7O requires 360.1573.
1.5.13. 3-(5-Methylisoxazol-3-yl)-5-[2-(2-methyl-2H-
[1,2,4]triazol-3-yl)-ethyl]-4,5-dihydro-[1,2,3]-triazolo-
[1,5-a]quinazoline (13e). The reaction was carried out as
described for 13a using the alkene 12e (95 mg, 0.27 mmol)
to yield the desired dihydrotriazoloquinazoline (57 mg,
63%). 1H NMR (CDCl3, 360 MHz) d 7.76 (1H, s), 7.69 (1H,
s), 7.33 (1H, d, J¼7.7 Hz), 7.28 (1H, t, J¼7.7 Hz), 7.08 (1H,
t, J¼7.7 Hz), 6.97 (1H, d, J¼7.7 Hz), 6.58 (1H, s), 6.00–
1.5.17. 3-(5-Methylisoxazol-3-yl)-5-[2-(2-methyl-2H-
[1,2,4]-triazol-3-yl)-ethyl]-[1,2,3]-triazolo[1,5-a]quinazo-
line (14e). The reaction was carried out as described for
14a using the dihydrotriazoloquinazoline 13e (57 mg,
0.16 mmol) and DDQ (88 mg, 0.39 mmol) to yield the
desired triazoloquinazoline (38 mg, 67%). 1H NMR

P. Jones, M. Chambers / Tetrahedron 58 (2002) 9973–9981
9981
10. Yagi, K.; Ogura, T.; Numata, A.; Ishii, S.; Arai, K.
Heterocycles 1997, 45, 1463–1466.
(CDCl3, 360 MHz) d 8.71 (1H, d, J¼8.3 Hz), 8.27 (1H, d,
J¼8.3 Hz), 8.00 (1H, t, J¼8.3 Hz), 7.76 (1H, t, J¼8.3 Hz),
7.73 (1H, s), 6.67 (1H, s), 4.04 (3H), 3.96 (2H, t, J¼6.7 Hz),
3.54 (2H, t, J¼6.7 Hz), 2.53 (3H, s). 13C NMR (CDCl3þ
10% CD3OD, 100 MHz) d 169.7 (s), 163.6 (s), 154.9 (s),
149.3 (d), 149.2 (s), 136.8 (s), 135.0 (d), 132.6 (s), 128.9 (s),
128.4 (d), 126.5 (d), 118.2 (s), 115.7 (d), 100.5 (d), 35.1 (q),
31.3 (t), 21.2 (t), 11.8 (q). MS (ESþ) C18H16N8O requires
360, found: 361 (MþHþ, 100%). HRMS (ESþ) m/z
361.1529, C18H17N8O requires 361.1525.
11. For use in Ni-catalysed Suzuki couplings see: (a) Zim, D.;
Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3,
3049–3051. (b) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org.
Chem. 1995, 60, 1060–1065. For use in Pd-catalysed Stille
couplings see: (c) Badone, D.; Cecchi, R.; Guzzi, U. J. Org.
Chem. 1992, 57, 6321–6323. For use in Ni-catalysed coupling
with Grignard reagents see: (d) Wenkert, E.; Michelotti, E. L.;
Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49,
4894–4899.
12. Chikashi, N.; Minoru, M.; Shigeki, S. (Mitsubishi Chem.
Corp.). JP 9124687, 1997.
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