Fused mesoionic heterocycles: Synthesis of [1,2,3]triazolo[1,5-a]quinoline, [1,2,3]triazolo[1,5-a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline and [1,2,3]triazolo[5,1-c]benzotriazine derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00269-7

General methods are descibed for the synthesis of mesoionic derivatives of [1,2,3]triazolo[1,5-a]quinoline, [1,2,3]triazolo[1,5-a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline and [1,2,3]triazolo[5,1-c]benzotriazine.

Full text of DOI:10.1016/S0040-4020(02)00269-7

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3185±3198
Fused mesoionic heterocycles:
synthesis of [1,2,3]triazolo[1,5-a]quinoline,
[1,2,3]triazolo[1,5-a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline
and [1,2,3]triazolo[5,1-c]benzotriazine derivativesq
Phillip A. Abbott, Roger V. Bonnert, Moya V. Caffrey, Peter A. Cage, Andrew J. Cooke,
David K. Donald, Mark Furber,p Steve Hill and Jane Withnall
Department of Medicinal Chemistry, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leics LE11 5RH, UK
Received 13 December 2001; revised 5 February 2002; accepted 28 February 2002
AbstractÐGeneral methods are descibed for the synthesis of mesoionic derivatives of [1,2,3]triazolo[1,5-a]quinoline, [1,2,3]triazolo[1,5-
a]quinazoline, [1,2,3]triazolo[1,5-a]quinoxaline and [1,2,3]triazolo[5,1-c]benzotriazine. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
suppressive agents,4 we describe in this work a concise
entry into mesoionic [1,2,3]triazolo[1,5-a]quinolinium (1),
[1,2,3]triazolo[1,5-a]quinazolinium (2), [1,2,3]triazolo[1,5-
a]quinoxalinium (3) and [1,2,3]triazolo[5,1-c]benzotri-
azinium (4) ring systems (Fig. 1).
Many routes are available for the synthesis of monocyclic
mesoionic compounds,2 but reported methods for the
preparation of ring fused analogues are more limited.3 As
part of a programme to develop Th2 selective immuno-
Cyclodehydration procedures are often used for the
Figure 1.
q See Ref. 1.
Keywords: fused mesoionic heterocycles; [1,2,3]triazolo[1,5-a]quinoline;
[1,2,3]triazolo[1,5-a]quinazoline; [1,2,3]triazolo[5,1-c]benzotriazine; aryl
hydrocarbon receptor (AhR).
p
Corresponding author. Tel.: 144-1509-644880; fax: 144-1509-645520;
e-mail: mark.furber@astrazeneca.com
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00269-7

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P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
Scheme 4.
which the key ring fusion step is either formation of the
triazolium ring (1) and (2) (Schemes 1 and 2) or formation
of the quinazolium/triazinium ring (3) and (4) (Schemes 3
and 4). Compounds of this type are of interest because they
are found to possess potent immunosuppressive properties
and as such were of potential value for application in
diseases known to possess an immune component.4
Scheme 2.
synthesis of mesoionic compounds and the few reported
examples of mesoionic 1,3-dialkyl- and 1,3-diaryl-substi-
tuted 1,2,3-triazoles have been prepared by this general
approach.5 Analogous ring fused systems corresponding to
(1)±(4) have not been previously described. We report
herein preparative methods for these ring systems in
2. Results and discussion
For the preparation of the [1,2,3]triazolo[1,5-a]quinolinium
ring system of (1), tetrahydroquinaldic acid (5)6 was reacted
with an aryl diazonium (prepared in situ from the
corresponding aniline and sodium nitrite) to afford an inter-
mediate triazine, which was isolated but then immediately
treated with acetic anhydride in pyridine to effect cycliza-
tion to the triazolium hydroxide inner salt (6). Partially
saturated compounds (6) could then be dehydrogenated by
treatment with DDQ or MnO2 or, more preferably, by treat-
ment with palladium on charcoal in dimethylacetamide at
1608C. The choice of conditions for the dehydrogenation
was determined by the presence or absence of groups sensi-
tive to hydrogenolysis during treatment with palladium on
charcoal. Whilst a hydrogen scavenger (cyclohexene) was
added to the reaction, some substrates were still problematic
(e.g. aromatic chlorides) and MnO2 or DDQ proved a more
suitable oxidant. Using one or other of these methods a
range of analogues of (1) possessing various R1±R4 sub-
stituents was prepared in overall yields ranging from
10±30% (from 5). The corresponding quinazolinium salts
(2) were prepared by an analogous route starting from
4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylic acid (7).
Surprisingly, this simple compound (or related analogues)
had not been reported previously, but could be simply
accessed from anthranilamide and glyoxylic acid.4 After
cyclization, the resulting amide (8) can be converted into
a chloroimine (9) by reaction with phosphorus oxychloride,
and then reacted with nucleophiles to afford compounds (2).
This reaction sequence was successful with sodium boro-
hydride and also with amines, but less so with a Grignard
Scheme 3.

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3187
reagent; iso-propylmagnesium chloride affording only a
15% yield of product (2b).
[1,2,3]Triazolo[1,5-a]quinoxalinium (3) and [1,2,3]tri-
azolo[5,1-c]benzotriazinium (4) ring systems were most
expediently prepared from a preexisting 1,3-diaryl substi-
tuted triazolium hydroxide, making use of the nucleo-
philicty of this ring system to effect cyclization onto a
pendant electrophilic substituent on the N1 aryl group
(Schemes 3 and 4). Thus hydrogenation of acylated
2-nitroaniline (10) in the presence of glyoxylic acid
gave an almost quantitative yield of the differentially func-
tionalized phenylenediamine (11), through a sequence of
steps involving reduction of the nitro group and in situ
formation of the imine with glyoxylic acid, followed by
hydrogenation of the imine. This reaction was routinely
carried out on a 50 g scale. The carboxylic acid itself proved
relatively unstable7 but could be conveniently isolated and
stored as a stable lithium salt. Treatment of this compound
under the standard conditions with an aryl diazonium salt
followed by acetic anhydride/pyridine gave the triazolium
hydroxide (12). A variety of conditions were investigated
for cyclization but the most successful and simplest to carry
out was re¯uxing with p-toluenesulphonic acid in toluene.
Scheme 5.
Grignard reagent, or by conversion into an intermediate
chloroimine and further reaction with a nucleophile, such
as an amine. In general, because the yields for both Grignard
addition to the amide and for the nucleophilic displacement
of chloride are low (12±18%), this process is less ef®cient
than the direct route through intermediates (10)±(12).
An X-ray structure determination for compound 3b
illustrates the expected planar arrangement of the ring
system (Fig. 2).8,9 The C±O bond distance of 1.23A8 is
intermediate between a carbonyl CvO bond distance
(1.20A8) and a carboxylate C±O2distance (1.25A8) in
accordance with the proposed mesoionic nature of the tri-
azolium oxide ring system.
The facile reactivity of the intermediate triazolium
hydroxides with electrophiles is re¯ected in the reactivity
of the [1,2,3]triazolo[1,5-a]quinolinium hydroxides (1)
(R3ˆH) (Scheme 6). Treatment with bromine effects clean
bromination at the 5-position. In fact, treatment of the
dihydro analogue (6) with excess bromine (6 equiv.) and
pyridine (2 equiv.) results in the one-pot oxidation/bromina-
tion to give compound (18) cleanly (Scheme 7).
By an analogous sequence of steps triazolium hydroxide
(16) was prepared, with the aniline group being installed
by a Curtius rearrangement in t-butanol solvent (Scheme
4). Diazotization of this aniline resulted in immediate
cyclization to afford the [1,2,3]triazolo[5,1-c]benzotriazi-
nium system of (4).
If the Curtius rearrangement is carried out in a non-nucleo-
philic solvent such as toluene, the intermediate isocyanate is
trapped by the triazolium ring system to give the cyclic
amide (17) (Scheme 5). Amide (17) can itself be converted
into compounds of type (3) either by direct reaction with a
Scheme 6. R2ˆH, m-F, p-F, p-Cl, m-CF3, p-CF3, p-OCF3, 6-Cl-(3-pyri-
dinyl), 6-Me-(3-pyridinyl). R4ˆH, Me. XˆMe, OMe, 1-azetidinyl,
1-morpholinyl, Me2CHOH, NH(CH2)2OMe. YˆNO2, SO2azetidine.
Figure 2. X-Ray structure of compound 3b.

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P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
added and the solution extracted with ethyl acetate (twice),
dried over magnesium sulphate and concentrated in vacuo.
To the residue was added pyridine (90 ml) then acetic
anhydride (10 ml) and the solution was stirred for 1 h. The
reaction mixture was diluted with diethyl ether and ®ltered
to give the title compound (12.25 g, 50%) as a yellow solid;
mp 216±2188C; [Found: C, 61.43; H, 3.67; N, 12.66.
C17H12F3N3O requires: C, 61.63; H, 3.65; N, 12.68%];
nmax (neat) 1656, 1610, 1491, 1418, 1320, 1105, 1062,
845, 755 cm21; dH (CDCl3) 8.40 (2H, d, Jˆ8.7 Hz), 8.02
(1H, m), 7.76 (2H, d, Jˆ8.7 Hz), 7.41 (3H, m), 3.08 (4H,
m); dC (CDCl3) 155.4, 139.1, 132.8, 130.0, 129.7, 129.3,
128.0, 126.3, 120.7 (2C), 117.0, 114.8, 24.8, 17.6, 126.3;
m/z APCI (1ve) 332 ([M1H]1).
Scheme 7. R2ˆp-CF3, R4ˆH 50%. R2ˆp-CF3, R4ˆMe 50%.
The bromo compound itself can be lithiated and quenched
with electrophiles, or can be subjected to palladium
catalyzed coupling reactions (Scheme 6). Nitration of (1)
(R3ˆH) can also be effected cleanly by treatment with
nitronium tetra¯uoroborate in dichloromethane, and
(although not illustrated) the nitro compound can be readily
reduced and derivatized on the resulting aniline nitrogen. In
a similar manner, chlorosulfonation and trapping of the in
situgenerated sulfonyl chloride with an amine affords the
corresponding sulfonamide, as illustrated by the preparation
of the azetidine sulfonamide in 32% yield.
4.2.2. 4,5-Dihydro-3-hydroxy-2-phenyl-[1,2,3]triazolo-
[1,5-a]quinolinium hydroxide, inner salt (6a). Prepared
by the general procedure described above using 1,2,3,4-
tetrahydroquinoline-2-carboxylic acid (12 g, 0.067 mol)
and aniline (6.31 g, 67.8 mmol) to give, after crystallization
from ethyl acetate, the title compound (4.9 g, 28%) as a
brown solid; mp 145±1468C; [Found: C, 72.74; H, 4.85;
N, 15.96. C16H13N3O requires: C, 72.99; H, 4.98; N,
15.96%]; nmax (neat) 1649, 1484, 1313, 1178, 1078, 1065,
754 cm21; dH (CDCl3) 8.14 (2H, m), 8.01 (1H, m), 7.53
(2H, t, Jˆ8 Hz), 7.40 (4H, m), 3.14 (2H, m), 3.08 (2H,
m); dC (CDCl3) 154.7, 136.1, 132.9, 129.8, 129.7, 129.4,
129.2, 128.1, 128.0, 121.5, 117.0, 114.9, 24.9, 17.9; m/z
APCI (1ve) 264 ([M1H]1).
3. Conclusion
In summary, concise routes are provided to fused tricyclic
mesoionic triazolium hydroxide inner salts, many of which
can be prepared on large scale and in relatively few steps.
Examples of functionalization of these ring systems are
provided and these intermediates can themselves provide
the basis for further derivatization.
4.2.3. 4,5-Dihydro-2-(4-¯uorophenyl)-3-hydroxy-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (6b).
Prepared by the general procedure described above using
1,2,3,4-tetrahydroquinoline-2-carboxylic
acid
(23 g,
4. Experimental1
4.1. General
0.13 mol) and 4-¯uoroaniline (13.4 ml, 0.14 mol) to give
the title compound (18.3 g, 50%) as a yellow solid; mp
144±1468C; [Found: C, 68.57; H, 4.33; N, 14.70.
C16H12FN3O requires: C, 68.32; H, 4.30; N, 14.94%]; nmax
(neat) 1635, 1617, 1603, 1509, 1489, 1216, 1151, 835,
759 cm21; dH (CDCl3) 8.18 (2H, m), 7.99 (1H, m), 7.42
(3H, m), 7.18 (2H, m), 3.07 (4H, s); m/z APCI (1ve) 282
([M1H]1).
Melting points are uncorrected. Infrared spectra were
recorded on a Perkin±Elmer 2000 FT spectrometer and
spectra were recorded over the range 400±4000 cm21 by
Attenuated Total Re¯ectance (ATR). 1H and 13C NMR
spectra were recorded on a Varian Unity Inova 300 spectro-
meter in the indicated solvent using TMS as internal
standard. Mass spectra were recorded on an Agilant 100
MSD instrument.
4.2.4. 4,5-Dihydro-3-hydroxy-2-(3-tri¯uoromethylphe-
nyl)-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (6d). Prepared by the general procedure described
above using 1,2,3,4-tetrahydro-quinoline-2-carboxylic acid
(6.0 g, 40 mmol) and 3-tri¯uoromethylaniline (5.46 g,
40 mmol) to give the title compound (2.21 g, 20%) as a
yellow solid; mp 182±1848C; [Found: C, 61.69; H, 3.60;
N, 12.47. C17H12F3N3O requires: C, 61.63 H, 3.65; N,
12.68%]; nmax (neat) 1655, 1489, 1462, 1338, 1289, 1116,
1070, 898, 802, 763 cm21; dH (CDCl3) 8.57 (1H, m), 8.46
(1H, s), 8.05 (1H, m), 7.64 (2H, m), 7.43 (3H, m), 3.08 (4H,
s); dC (CDCl3) 155.4, 136.9, 132.8, 131.6 (C, q,
JC±Fˆ33 Hz), 129.9, 129.7, 129.7, 129.3, 128.0, 124.1
(CH, q, JC±Fˆ4 Hz), 123.9, 122.6, 117.6, 117.1 (CH, q,
JC±Fˆ4 Hz), 114.6, 24.8, 17.7; m/z APCI (1ve) 332
([M1H]1).
4.2. Representative procedure for the preparation of 4,5-
dihydro-3-hydroxy-2-aryl-[1,2,3]triazolo[1,5-a]quino-
linium hydroxide, inner salts (6a±g)
4.2.1. 4,5-Dihydro-3-hydroxy-2-[4-(tri¯uoromethyl)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (6c). To a stirred solution of 4-(tri¯uoromethyl)aniline
(12.08 g, 75 mmol) in a mixture of water (150 ml), tetra-
hydrofuran (60 ml) and concentrated hydrochloric acid
(20 ml) at 0 to 258C was added portionwise a solution of
sodium nitrite (5.43 g, 78 mmol) in water (50 ml). The solu-
tion was stirred 15 min at 0 to 258C and then was added
portionwise to a solution of 1,2,3,4-tetrahydro-quinoline-2-
carboxylic acid (13.3 g, 75 mmol) in pyridine (150 ml) at 0
to 258C. The solution was stirred for 1 h at 0 to 258C and
then was allowed to warm to room temperature. Water was
4.2.5. 4,5-Dihydro-3-hydroxy-2-[4-(tri¯uoromethoxy)-
phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (6e). Prepared by the general procedure described

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3189
above using 1,2,3,4-tetrahydroquinoline-2-carboxylic acid
(12 g, 67.8 mmol) and (4-tri¯uoromethoxy)aniline
(12.01 g, 67.8 mmol) to give the title compound (8.44 g,
36%) as a cream solid; mp 163±1658C; [Found: C, 58.79;
H, 3.30; N, 12.03. C17H12F3N3O2 requires: C, 58.79; H,
3.48; N, 12.10%]; nmax (neat) 1653, 1506, 1491, 1254,
1219, 1149, 752 cm21; dH (CDCl3) 8.27 (2H, m), 8.00 (1H,
m), 7.40 (5H, m), 3.07 (4H, s); dC (CDCl3) 155.2, 148.1, 134.8,
132.9 129.83 129.7, 129.36, 128.0, 122.5, 121.6, 117.0, 114.6,
24.8, 17.7, 17.7; m/z APCI (1ve) 348 ([M1H]1).
hexene (100 ml) was heated in an oil bath at 1408C for 48 h.
After allowing to cool, the solution was diluted with a
mixture of water and ethyl acetate and ®ltered through
Celite. The organic layer was separated, dried over magne-
sium sulphate and concentrated in vacuo. Puri®cation by
chromatography on silica gel (ethyl acetate) gave the title
compound (5.54 g, 58%) as a yellow solid; mp 174±1768C;
nmax (neat) 1659, 1611, 1313, 1107, 1086, 1064, 839,
749 cm21
; [Found: C, 62.20; H, 3.14; N, 12.59.
C17H10F3N3O requires: C, 62.01; H, 3.06; N, 12.76%]; dH
(CDCl3) 8.48 (3H, m), 7.80 (1H, dd, Jˆ7.9, 1.3 Hz), 7.77
(2H, d, Jˆ8.7 Hz), 7.73±7.64 (2H, m), 7.63 (1H, d,
Jˆ9.1 Hz), 7.24 (1H, d, Jˆ9.1 Hz); m/z APCI (1ve) 330
([M1H]1).
4.2.6. 6,9-Di¯uoro-4,5-dihydro-3-hydroxy-2-[4-(tri¯uoro-
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hy-
droxide, inner salt (6f). Prepared by the general
procedure described above using 5,8-di¯uoro-1,2,3,4-tetra-
hydroquinoline-2-carboxylic acid (5.325 g, 25 mmol) and
4-(tri¯uoromethyl)aniline (4.03 g, 25 mmol) to give the
title compound (2.65 g, 24%) as a tan solid; mp.2608C;
[Found: C, 55.26; H, 2.77; N, 11.53. C17H10F5N3O requires:
C, 55.59; H, 2.74; N, 11.44%]; nmax (neat) 1655, 1610,
1508, 1320, 1240, 1121, 1107, 849, 814 cm21; dH
(CDCl3) 8.39 (2H, d, Jˆ8.7 Hz), 7.77 (2H, d, Jˆ8.7 Hz),
7.20 (2H, m), 3.06 (4H, m); dC (CDCl3) 156.5, 154.5,
4.3.2. 3-Hydroxy-2-phenyl-[1,2,3]triazolo[1,5-a]quino-
linium hydroxide, inner salt (1a). Prepared from 4,5-
dihydro-3-hydroxy-2-phenyl-[1,2,3]triazolo[1,5-a]quino-
linium hydroxide, inner salt (6a, 4.1 g, 15.5 mmol) to give
the title compound (1.7 g, 41%) as a yellow solid; mp 153±
1558C; [Found: C, 73.78; H, 4.33; N, 16.12. C16H11N3O
requires: C, 73.55; H, 4.24; N, 16.08%]; nmax (neat) 1655,
1492, 1460, 1401, 1319, 1136, 761 cm21; dH (CDCl3) 8.53
(1H, dd, Jˆ8, 1.3 Hz), 8.12 (2H, m), 7.81 (1H, dd, Jˆ7.6,
1.8 Hz), 7.68 (2H, m), 7.67 (1H, d, Jˆ9.3 Hz), 7.36 (2H, d,
Jˆ8.3 Hz), 7.24 (2H, d, Jˆ9.2 Hz); dC (CDCl3) 153.4,
136.5, 130.3, 129.2, 129.2 (2C), 129.0, 128.7, 127.7,
127.6, 121.2 (2C), 119.7, 118.8, 117.1, 115.8; m/z APCI
(1ve) 262 ([M1H]1).
149.84(C, d, JC±Fˆ255 Hz), 138.8, 129.7 (C, q, JC±F
ˆ
36 Hz), 126.4 (C, d, JC±Fˆ4 Hz), 124.9, 122.7, 121.6 (C,
dd, JC±Fˆ8, 6 Hz), 120.9, 120.4 (C, d, JC±Fˆ23.5 Hz),
117.2 (C, dd, JC±Fˆ16, 8 Hz), 117.0 (C, dd, JC±Fˆ16,
8 Hz), 114.9, 18.6, 17.05; m/z APCI (1ve) 368 ([M1H]1).
4.2.7. 4,5-Dihydro-2-(6-chloro-3-pyridinyl)-3-hydroxy-
4-methyl-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (6g). To a solution of 3-amino-6-chloropyridine
(23.9 g, 0.188 mol) in tetrahydrofuran (100 ml), water
(200 ml) and concentrated hydrochloric acid (40 ml) at
08C was added a solution of NaNO2 (13.0 g, 0.188 mol) in
water (100 ml) dropwise maintaining a temperature of
08C. 30 min after complete addition the mixture was
added to a solution of 3-methyl-1,2,3,4-tetrahydroquino-
line-2-carboxylic acid (30 g, 0.157 mol) in pyridine
(150 ml) at 08C maintaining the temperature below 58C.
After 1.5 h the mixture was partitioned between ethyl
acetate and water. The organic layer was collected and
dried over magnesium sulphate. The solution was partially
concentrated in vacuo, diluted with further pyridine (50 ml)
and treated with acetic anhydride (30 ml). The mixture was
allowed to stand for 3 days. The solid which separated was
washed with ethyl acetate then diethyl ether, then dried to
afford the title compound (14.74 g, 30%); [Found: C, 60.99;
H, 4.22; N, 16.68. C16H13ClN4O requires: C, 61.25; H, 4.19;
N, 16.91%]; dH (CDCl3) 9.20 (1H, m), 8.70 (1H, m), 8.01
(1H, m), 7.37±7.50 (4H, m), 3.46 (1H, m), 3.18 (1H, m),
2.85 (1H, m), 1.43 (3H, m); m/z APCI (1ve) 313 ([M1H]1).
4.3.3. 2-(4-Fluorophenyl)-3-hydroxy-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (1b). Prepared from
4,5-dihydro-2-(4-¯uorophenyl)-3-hydroxy-[1,2,3]triazolo-
[1,5-a]quinolinium hydroxide, inner salt (6b, 1 g, 3.5 mmol)
to give the title compound (0.615 g, 62%) as a yellow solid;
mp 184±1868C; nmax (neat) 1671, 1505, 1405, 1222, 1134,
1097, 838, 795, 764, 750 cm21; [Found: C, 68.76; H, 3.60;
N, 15.06. C16H10F3N3O requires: C, 68.81; H, 3.61; N,
15.05%]; dH (CDCl3) 8.53 (1H, m), 8.26 (2H, m), 7.83
(1H, m), 7.70 (3H, m), 7.26 (3H, m); dc (CDCl3) 153.6,
139.3, 130.1, 129.5, 129.4, 128.8, 127.9, 126.4, 126.3,
126.3, 126.3, 120.6, 120.2, 119.0, 116.9, 115.9; m/z APCI
(1ve) 280 ([M1H]1).
4.3.4. 3-Hydroxy-2-[3-(tri¯uoromethyl)phenyl]-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (1d).
Prepared from 4,5-dihydro-3-hydroxy-2-(3-tri¯uoromethyl
phenyl)-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (6d, 4.08 g, 12.3 mmol) to give the title compound
(1.78 g, 44%) as a yellow solid; mp 168±1698C; nmax
(neat) 1656, 1464, 1342, 1112, 1070, 802, 753 cm21
;
[Found: C, 62.44; H, 3.11; N, 12.68. C17H10F3N3O requires:
C, 62.01; H, 3.06; N, 12.76%]; dH (CDCl3) 8.64 (1H, dt,
Jˆ6.7, 1.9 Hz), 8.56 (2H, m), 7.84 (1H, dd, Jˆ7.7, 1.5 Hz),
7.70 (5H, m), 7.29 (1H, d, Jˆ8.7 Hz); dc (CDCl3) 153.5,
137.0, 131.7 (C, q, JC±Fˆ33 Hz), 130.2, 129.8, 129.5, 129.3,
128.8, 127.9, 123.9 (C, q, JC±Fˆ4 Hz), 123.8, 120.2, 119.0,
117.6 (C, q, JC±Fˆ4 Hz), 116.9, 116.0,131.7; m/z APCI
(1ve) 330 ([M1H]1).
4.3. Representative procedure for the preparation of 3-
hydroxy-2-aryl-[1,2,3]triazolo[1,5-a]quinolinium
hydroxide, inner salts (1) using palladium on charcoal
4.3.1. 3-Hydroxy-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (1c). A
solution of 4,5-dihydro-3-hydroxy-2-[4-(tri¯uoromethyl)
phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (6c, 9.6 g, 28.9 mmol) and 10% palladium on carbon
(1 g) in a mixture of dimethylacetamide (100 ml) and cyclo-
4.3.5. 3-Hydroxy-2-[4-(tri¯uoromethoxy)phenyl]-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (1e).
Prepared from 4,5-dihydro-3-hydroxy-2-[4-(tri¯uoro-

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P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
methoxy) phenyl)-[1,2,3]triazolo[1,5-a]quinolinium hy-
droxide, inner salt (6e, 5 g, 14.4 mmol) to give the title
compound (4.3 g, 86%) as a yellow solid. Mp 155±1568C;
aniline (16.1 g, 0.1 mol) in a mixture of water (145 ml),
tetrahydrofuran (65 ml) and concentrated hydrochloric
acid (35 ml) at 0 to 258C was added portionwise a solution
of sodium nitrite (7.25 g, 0.105 mol) in water (80 ml). The
solution was stirred 15 min at 08 to 258C and then was
added portionwise to a solution of 4-oxo-1,2,3,4-tetrahydro-
quinazoline-2-carboxylic acid (19.2 g, 0.1 mol) in pyridine
(145 ml) and water (100 ml) at 08 to 258C. The solution was
stirred for 1 h then allowed to warm to room temperature.
The solid was ®ltered, washed with water and then azeo-
troped with toluene. To the residue was added pyridine
(180 ml) then acetic anhydride (25 ml) and the solution
was stirred for 1 h. The reaction mixture was diluted with
diethyl ether and ®ltered to give the title compound (6.8 g,
20%) as a yellow solid; mp.2508C; [Found: C, 55.50; H,
2.75; N, 15.79. C16H13N3O requires: C, 55.47; H, 2.62; N,
16.18%]; nmax (neat) 1709, 1661, 1610, 1516, 1319, 1304,
1119, 848, 759 cm21; dH (DMSO-d6) 12.90 (1H, br s), 8.50
(2H, m), 8.33 (1H, m), 8.28 (1H, m), 8.03 (3H, m), 7.83 (1H,
m); m/z APCI (1ve) 347 ([M1H]1).
n
max (neat) 1675, 1500, 1402, 1259, 1215, 1153, 1102, 796,
751 cm21
;
[Found: C, 59.34; H, 3.00; N, 12.36.
C17H10F3N3O2 requires: C, 59.14; H, 2.92; N, 12.17%]; dH
(CDCl3) 8.54 (1H, m), 8.36 (2H, m), 7.84 (1H, m), 7.70 (3H,
m), 7.40 (2H, m), 7.28 (1H, m); dc (CDCl3) 153.3, 147.9,
135.0, 130.2, 129.4, 129.2, 128.8, 127.8, 122.4, 121.7,
121.5, 120.1, 119.4, 118.9, 117.0, 115.9; m/z APCI (1ve)
346 ([M1H]1).
4.3.6. 6,9-Di¯uoro-3-hydroxy-2-[4-(tri¯uoromethyl)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinolinium, hydroxide inner
salt (1f). A solution 6,9-di¯uoro-4,5-dihydro-3-hydroxy-2-
[4-(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quino-
linium hydroxide, inner salt (6f, 2 g, 5.4 mmol) and DDQ
(1.86 g, 8.2 mmol) in toluene (150 ml) was re¯uxed for
14 h. Puri®cation by chromatography on silica gel (ethyl
acetate/iso-hexane 2:1) followed by recrystallization from
ethyl acetate gave the title compound (0.98 g, 49%) as
yellow needles; mp 243±2458C; [Found: C, 55.52; H,
2.18; N, 11.65. C17H8F5N3O requires: C, 55.90; H, 2.21;
N, 11.50%]; dH (CDCl3) 8.49 (2H, m), 7.81 (2H, m), 7.75
(1H, m), 7.37 (3H, m); m/z APCI (1ve) 366 ([M1H]1).
4.3.10. 5-Chloro-3-hydroxy-2-[4-(tri¯uoromethyl)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinazolinium hydroxide, inner
salt (9). A solution of 4,5-dihydro-3-hydroxy-5-oxo-2-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium
hydroxide, inner salt (8, 1.76 g, 5 mmol) in phosphorus
oxychloride (20 ml) was re¯uxed for 2 h before being
concentrated in vacuo. The residue was quenched with
water then basi®ed with solid sodium hydrogen carbonate.
The solution was extracted with ethyl acetate (twice), dried
over magnesium sulphate and concentrated in vacuo. The
solid was washed with ethyl acetate to give the title
compound (1.48 g, 80%) as a yellow solid; mp.2508C;
[Found: C, 52.66; H, 2.15; N, 15.18. C16H8ClF3N3O requires:
C, 52.69; H, 2.21; N, 15.36%]; nmax (neat) 1600, 1556, 1327,
1166, 1122 cm21; dH (CDCl3) 8.39 (1H, m), 8.12 (2H, m),
8.00 (3H, m), 7.69 (1H, m), 7.64 (1H, m); dC (CDCl3) 165.4,
143.5, 136.6, 134.1 (C, q, JC±Fˆ33 Hz), 132.7, 130.2, 129.4,
127.3, 126.2 (2C), 124.2, 122.0, 121.6, 114.5, 112.3; m/z
APCI (1ve) 365 ([M1H]1).
4.3.7. 2-(6-Chloro-3-pyridinyl)-3-hydroxy-4-methyl-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (1g).
4,5-Dihydro-2-(6-chloro-3-pyridinyl)-3-hydroxy-4-methyl-
[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner salt (6g,
11.2 g, 35.8 mmol) was dissolved in chloroform (50 ml) and
manganese dioxide (11 g) was added. The mixture was
re¯uxed for 24 h. Further manganese dioxide (10 g,
115 mmol) was added and the mixture re¯uxed for a further
30 h. The mixture was ®ltered through Celite and concen-
trated in vacuo to give the title compound (10.2 g, 91%); mp
250±2518C; nmax (neat) 1655, 1459, 1384, 1332, 1120,
1100, 1067, 831, 749 cm21; [Found: C, 61.59; H, 3.58; N,
17.76. C16H11ClN4O requires: C, 61.84; H, 3.57; N,
18.03%]; dH (CDCl3) 9.31 (1H, dd, Jˆ2.8, 0.5 Hz), 8.76
(1H, dd, Jˆ8.7, 2.7 Hz), 8.48 (1H, m), 7.74 (1H, m), 7.65
(2H, m), 7.50 (1H, dd, Jˆ8.8, 0.6 Hz), 7.00 (1H, s), 2.78
(3H, s); m/z APCI (1ve) 311([M1H]1).
4.3.11. 3-Hydroxy-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]-
triazolo[1,5-a]quinazolinium hydroxide, inner salt (2a).
To a solution of 5-chloro-3-hydroxy-2-[4-(tri¯uoromethyl)-
4.3.8. 4-Oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylic
acid (7). To a stirred solution of anthranilamide (45 g,
0.33 mol) in methanol (900 ml) was added glyoxylic acid
monohydrate (30.6 g, 0.33 mol) and the reaction mixture
was re¯uxed for 1 h. The solution was cooled to 0 to
258C for several hours, then ®ltered to give the title
compound (28.1 g) as a white solid; mp 184±1858C;
[Found: C, 56.25; H, 3.99; N, 14.64. C9H8N2O3 requires:
C, 56.25; H, 4.20; N, 15.58%]; nmax (neat) 1710, 1687,
1603, 1606, 1518, 1237 cm21; dH (DMSO-d6) 7.57 (1H, d,
Jˆ7.9 Hz), 7.24 (1H, ddd, Jˆ8.3, 7.1, 1.4 Hz), 7.16 (1H, s),
6.78 (1H, d, Jˆ7.7 Hz), 6.68 (1H, dd, Jˆ14.9, 1.1 Hz), 4.96
(1H, dd, Jˆ4.2, 2.7 Hz); dC (DMSO-d6) 172.1, 163.1,
147.06, 133.2, 127.2, 117.3, 114.9, 114.4, 63.4; m/z APCI
(1ve) 193 ([M1H]1).
phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium
hydroxide,
inner salt (9, 1 g, 2.7 mmol) in ethanol (150 ml) was
added sodium borohydride (1.04 g, 27 mmol) and the reac-
tion mixture was stirred for 2 h. The solution was quenched
with ammonium chloride solution, extracted with ethyl
acetate (twice), dried over magnesium sulphate and concen-
trated in vacuo. The residue was recrystallized from metha-
nol to give the title compound (0.33 g, 37%) as a yellow
solid; mp.2508C; [Found: C, 58.28; H, 2.89; N, 16.76.
C16H9F3N4O requires: C, 58.19; H, 2.75; N, 16.96%]; nmax
(neat) 1606, 1556, 1421, 1323, 1171, 1115 cm21; dH
(DMSO-d6) 9.08 (1H, s), 8.40 (2H, m), 8.28 (2H, m), 8.16
(2H, m), 7.95 (1H, m), 7.79 (1H, m); m/z APCI (1ve) 331
([M1H]1).
4.3.12.
3-Hydroxy-5-(1-methylethyl)-2-[4-(tri¯uoro-
4.3.9. 4,5-Dihydro-3-hydroxy-5-oxo-2-[4-(tri¯uoromethyl)-
phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium hydroxide,
inner salt (8). To a stirred solution of 4-(tri¯uoromethyl)-
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium hy-
droxide, inner salt (2b). To a solution of 5-chloro-3-
hydroxy-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3191
a]quinazolinium hydroxide, inner salt (9, 1 g, 2.7 mmol) in
tetrahydrofuran (150 ml) was added dropwise isopropyl
magnesium chloride (3.4 ml, 2 M solution in tetrahydro-
furan) and the solution was stirred overnight. The solution
was quenched with ammonium chloride solution, extracted
with dichloromethane (twice), dried over magnesium
sulphate and concentrated in vacuo. Puri®cation by chroma-
tography on silica gel (acetone/methanol 10:1) followed by
recrystallization from ethyl acetate gave the title compound
(0.15 g) as a white solid; mp 2558C; [Found: C, 61.02; H,
4.04; N, 14.81. C19H15F3N4O requires: C, 61.29; H, 4.06; N,
15.05%]; dH (DMSO-d6) 8.27 (1H, m), 8.17 (3H, m), 8.10
(2H, m), 7.90 (1H, m), 7.77 (1H, m), 2.99 (1H, m), 1.41 (6H,
m); m/z APCI (1ve) 373 ([M1H]1).
17.54%]; dH (DMSO-d6) 8.56 (1H, m), 8.12 (1H, m), 8.06
(2H, m), 7.92 (2H, m), 7.79 (1H, m), 7.69 (1H, m), 3.56 (4H,
m), 1.91 (4H, m); m/z APCI (1ve) 400 ([M1H]1).
4.3.16. [2-(Acetylamino)phenyl]amino acetic acid,
lithium salt (11a). A solution of 2-nitroacetanilide (50 g,
0.277 mol) in methanol (1 l) was stirred with 10% palla-
dium on charcoal (10 g) under an atmosphere of hydrogen
(5 bar). Once hydrogen uptake had ceased a solution of
glyoxylic acid monohydrate (26.2 g, 0.28 mol) in water
(100 ml) was added and the mixture rehydrogenated at
5 bar. Once hydrogen uptake had ceased the mixture was
®ltered rapidly and lithium hydroxide monohydrate
(11.96 g, 0.28 mol) in water (100 ml) was added. The solu-
tion was concentrated to a volume of ca 100 ml in vacuo.
The lithium salt was precipitated by addition of acetone and
dried in vacuo to afford the title compound as a colourless
powder (56.2 g); dH (DMSO-d6) 7.06 (2H, m), 6.55 (2H, m),
3.37 (2H, s), 2.08 (3H, s); dC (MeOH-d4/D20) 202.4, 173.8,
144.6, 129.1, 128.2, 124.1, 118.1, 113.4, 23.4; m/z APCI
(1ve) 209 ([M1H]1).
4.3.13. 3-Hydroxy-5-(morpholinyl)-2-[4-(tri¯uoromethyl)-
phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium
hydroxide,
inner salt (2c). A solution of 5-chloro-3-hydroxy-2-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quinazo-
linium hydroxide, inner salt (9, 0.5 g, 1.37 mmol) in
morpholine (10 ml) was re¯uxed for 30 min. The solution
was concentrated in vacuo and chromatographed on silica
gel (acetone/methanol 10:1) followed by recrystallization
from ethyl acetate gave the title compound (0.25 g, 44%)
as a pale yellow solid; mp.2508C; [Found: C, 57.76; H,
3.93; N, 16.34. C20H16F3N5O2 requires: C, 57.83; H, 3.88;
N, 16.86%]; nmax (neat) 1611, 1602, 1554, 1508, 1323,
4.3.17. [2-(Propionylamino)phenyl]amino acetic acid,
lithium salt (11b). A solution of 2-nitrophenylpropiona-
mide (25 g, 0.129 mol) in methanol (500 ml) was stirred
with 10% palladium on charcoal (5 g) under an atmosphere
of hydrogen (5 bar). Once hydrogen uptake had ceased a
solution of glyoxylic acid monohydrate (12.2 g, 0.13 mol)
in water (100 ml) was added and the mixture rehydro-
genated at 5 bar. Once hydrogen uptake had ceased the
mixture was ®ltered rapidly and lithium hydroxide mono-
hydrate (5.55 g, 0.13 mol) in water (100 ml) was added. The
solution was concentrated to a volume of ca 50 ml in vacuo.
The lithium salt was precipitated by addition of acetone and
dried in vacuo to afford the title compound as a colourless
powder (28 g); dH (DMSO-d6) 9.25 (1H, s), 6.47 (2H, t,
Jˆ8.1 Hz), 6.42 (2H, d, Jˆ8.5 Hz), 7.04±6.94 (2H, m),
5.10 (1H, s), 3.21 (2H, s), 2.32 (2H, q, Jˆ7.6 Hz), 1.10
(3H, t, Jˆ7.6 Hz); dC (DMSO-d6) 172.5, 171.7, 143.2,
126.7, 126.5, 123.0, 114.5, 110.7, 48.1, 28.8, 10.0; m/z
APCI (1ve) 223 ([M1H]1).
1132, 1110, 752 cm21
; dH (CDCl3) 8.44 (1H, d,
Jˆ8.0 Hz), 8.14 (2H, m), 7.97(2H, m), 7.93 (1H, d,
Jˆ8.0 Hz), 7.69 (1H, m), 7.64 (1H, m), 3.74 (4H, m),
3.43 (4H, m); dC (CDCl3) 165.4, 140.5, 137.9, 133.2 (C,
q, JC±Fˆ33 Hz), 133.1, 132.9, 132.3, 131.9, 129.6, 129.4,
127.1, 125.2 (2C), 124.3, 122.1, 121.5, 114.2, 66.6, 50.1,
133.2; m/z APCI (1ve) 416 ([M1H]1).
4.3.14. 3-Hydroxy-5-(piperidinyl)-2-[4-(tri¯uoromethyl)-
phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium hydroxide,
inner salt (2d). A solution of 5-chloro-3-hydroxy-2-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium
hydroxide, inner salt (9, 0.5 g, 1.37 mmol) in piperidine
(10 ml) was re¯uxed for 30 min. The solution was concen-
trated in vacuo and chromatographed on silica gel (dichloro-
methane/methanol 15:1). The product was stirred in diethyl
ether and ®ltered to give the title compound (0.42 g, 74%) as
a pale yellow solid; mp.2508C; [Found: C, 60.72; H, 4.37;
N, 16.94. C21H18F3N5O requires: C, 61.01; H, 4.39; N,
16.94%]; nmax (neat) 1612, 1601, 1502, 1451, 1324, 1164,
1132, 1105, 855, 751 cm21; dH (CDCl3) 8.49 (1H, d,
Jˆ8.0 Hz), 8.13 (2H, m), 8.09 (1H, d, Jˆ8.0 Hz), 7.76
(1H, m), 7.94 (2H, m), 3.35 (4H, m), 7.68 (1H, m), 1.57
(6H, m); m/z APCI (1ve) 414 ([M1H]1).
4.3.18. 1-(2-Acetylamino)phenyl-3-(4-¯uorophenyl)-4-
hydroxy-[1,2,3]triazolium hydroxide, inner salt (12a).
To a solution of 4-¯uoroaniline (9.47 ml, 0.1 mol) in
water (120 ml), tetrahydrofuran (60 ml) and concentrated
hydrochloric acid (30 ml) at 258C was added a solution
of NaNO2 (7.25 g, 0.105 mol) in water (60 ml) dropwise
maintaining a temperature of less than 08C. Once addition
was complete the solution was stirred for a further 30 min at
08C then added portionwise to a solution of 2-(acetyl-
amino)phenylamino acetic acid, lithium salt (21.4 g,
0.1 mol) in pyridine (200 ml) at 258C maintaining a
temperature of less than 08C. The mixture was stirred
below 08C for 2 h before being partitioned between ethyl
acetate and water. The layers were separated and the
aqueous extracted with ethyl acetate. The combined
organics were dried over magnesium sulphate then concen-
trated in vacuo until only pyridine remained (ca 30 ml
volume). To the pyridine solution was added acetic
anhydride (50 ml) and the solution was allowed to stir for
1 h. The reaction mixture was concentrated in vacuo and
azeotroped with toluene. The resulting semi-solid was
4.3.15. 3-Hydroxy-5-(pyrrolidinyl)-2-[4-(tri¯uoromethyl)-
phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium hydroxide,
inner salt (2e). A solution of 5-chloro-3-hydroxy-2-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quinazolinium
hydroxide, inner salt (9, 0.5 g, 1.37 mmol) in pyrrolidine
(10 ml) was re¯uxed for 30 min. The solution was concen-
trated in vacuo and chromatographed on silica gel (dichloro-
methane: methanol/15:1). The product was stirred in diethyl
ether and ®ltered to give the title compound (0.47 g, 86%) as
a pale yellow solid; mp.2508C; [Found: C, 60.28; H, 4.04;
N, 17.36. C20H16F3N5O requires: C, 60.15; H, 4.09; N,

3192
P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
triturated with ether and collected, then washed with diethyl
ether and dried in vacuo to afford the title compound (8.0 g,
26%); mp 228±2308C; [Found: C, 60.65; H, 4.18; N, 17.94.
C16H13FN4O2 requires: C, 60.53; H, 4.20; N, 17.94%]; nmax
br), 8.09 (1H, ddd, Jˆ11.1, 7.3, 2.6 Hz), 7.91 (1H, m), 7.59
(1H, m), 7.46 (1H, dd, Jˆ8.1, 1.5 Hz), 7.32 (2H, m), 7.00
(1H, s), 2.36 (2H, q, Jˆ7.6 Hz), 1.18 (3H, t, Jˆ7.6 Hz); m/z
APCI (1ve) 345([M1H]1).
(neat) 1661, 1600, 1541, 1498, 1299, 1227, 832, 773 cm21
;
dH (CDCl3) 8.90 (1H, s), 8.34 (1H, d, Jˆ7.5 Hz), 8.00 (2H,
m), 7.56 (1H, t, Jˆ7.9 Hz), 7.45 (1H, m), 7.30 (1H, m), 7.13
(2H, m), 6.96 (1H, s), 2.19 (3H, s); dC (CDCl3) 169.3, 162.9,
160.9, 157.4, 132.4, 131.6, 127.3, 125.1, 125.0, 123.0,
122.9, 116.1, 116.0, 109.1, 24.3; m/z APCI (1ve)
313([M1H]1).
4.3.21. 2-(3,4-Di¯uorophenyl)-4-ethyl-3-hydroxy-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3b).
To 3-(3,4-di¯uorophenyl)-4-hydroxy-1-(2-propionylamino)-
phenyl-[1,2,3]triazolium hydroxide, inner salt (12b, 1.56 g,
4.5 mmol) in toluene (120 ml) was added p-toluenesul-
phonic acid monohydrate (0.95 g, 5 mmol) and the mixture
was heated with azeotropic removal of water for 40 h. The
reaction mixture was concentrated in vacuo and partitioned
between dichloromethane and sodium hydrogen carbonate
solution. The organic layer was collected and dried over
magnesium sulphate then concentrated in vacuo. Chromato-
graphy on silica eluting with 49:1 dichloromethane/
methanol followed by recrystallization from ethyl acetate
gave the title compound (0.79 g, 53%) as pale yellow
crystals; mp 160±1628C; [Found: C, 62.56; H, 3.44; N,
17.08. C17H12F2N4O requires: C, 62.58; H, 3.71; N,
17.17%]; nmax (neat) 1672, 1509, 1500, 1262, 1113, 864,
859, 755 cm21; dH (CDCl3) 8.35 (1H, d, Jˆ8.2 Hz), 8.19
(1H, ddd, Jˆ11.4, 7.1, 2.4 Hz), 8.03 (1H, m), 7.74 (1H, t,
Jˆ7.7 Hz), 7.99 (1H, d, Jˆ8.4 Hz), 7.63 (1H, t, Jˆ7.7 Hz),
7.32 (1H, q, Jˆ9.1 Hz), 3.31 (1H, q, Jˆ7.5 Hz), 1.47 (3H, t,
Jˆ7.5 Hz); dC (CDCl3) 160.4, 153.3, 150.2 (C, dd,
JC±Fˆ250, 13 Hz), 149.5 (C, dd, JC±Fˆ250, 13 Hz), 140.1,
132.2 (C, dd, JC±Fˆ8, 4 Hz), 131.0, 129.7, 128.3, 123.9,
117.9, 117.7, 116.7 (C, dd, JC±Fˆ6, 4 Hz), 114.8, 112.8,
110.6, 110.4, 27.7, 12.2, 116.7; m/z APCI (1ve)
327([M1H]1).
4.3.19. 2-(4-Fluorophenyl)-3-hydroxy-4-methyl-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3a).
To 1-(2-acetylamino)phenyl-3-(4-¯uorophenyl)-4-hydroxy-
[1,2,3]triazolium hydroxide, inner salt (12b, 7.47 g,
24 mmol) in toluene (200 ml) was added p-toluenesul-
phonic acid monohydrate (4.83 g, 25 mmol) and the mixture
was heated with azeotropic removal of water for 8 h. The
reaction mixture was concentrated in vacuo and partitioned
between dichloromethane and sodium hydrogen carbonate
solution. The organic layer was collected and dried over
magnesium sulphate, then concentrated in vacuo. Chroma-
tography on silica eluting with 49:1 dichloromethane/
methanol followed by recrystallization from ethyl acetate
gave the title compound (3.58 g, 51%) as pale yellow
needles. Mp 1988C; [Found: C, C, 65.22; H, 3.75; N,
18.86. C16H11FN4O requires: C, 65.30; H, 3.77; N,
19.04%]; nmax (neat) 1677, 1500, 1227, 1131, 1095, 832,
765 cm21; dH (CDCl3) 8.30 (1H, m), 8.16 (2H, m), 7.94
(2H, m), 7.71 (1H, m), 7.60 (1H, m), 7.21 (2H, m), 2.92
(3H, m); dC (CDCl3) 162.8, 160.8, 155.5, 153.7, 139.9,
132.0 (C, d, JC±Fˆ3 Hz), 130.9, 129.4, 128.2, 124.0,
123.0, 122.9, 116.3, 116.1, 114.8, 113.0, 20.9; m/z APCI
(1ve) 295([M1H]1).
4.3.22. 1-(2-Acetylamino)phenyl-3-(4-¯uoro-3-methyl-
phenyl)-4-hydroxy-[1,2,3]triazolium hydroxide, inner
salt (12c). Prepared from 4-¯uoro-3-methylaniline (6.26 g,
50 mmol) in water (60 ml), tetrahydrofuran (30 ml),
concentrated hydrochloric acid (15 ml), NaNO2 (3.63 g,
52 mmol) in water (30 ml), 2-(acetylamino)phenylamino
acetic acid, lithium salt (10.7 g, 50 mmol) in pyridine
(100 ml), and acetic anhydride (25 ml) to afford the title
compound (9.02 g, 55%); mp 201±2028C; [Found: C,
62.30; H, 4.65; N, 16.89. C17H15FN4O2 requires: C, 62.57;
H, 4.63; N, 17.17%]; nmax (neat) 1708, 1685, 1649, 1540,
1491, 1467, 1287, 1243, 761, 735 cm21; dH (CDCl3) 8.97
(1H, s, br), 8.34 (1H, d, br, Jˆ7.9 Hz), 7.80 (2H, m), 7.57
(1H, m), 7.44 (1H, dd, Jˆ8.1, 1.5 Hz), 7.26 (1H, m), 7.26
(1H, s), 7.06 (1H, t, Jˆ8.9 Hz), 6.95 (1H, s), 2.29 (3H, d,
Jˆ1.9 Hz), 2.20 (3H, s); m/z APCI (1ve) 327 ([M1H]1).
4.3.20. 3-(3,4-Di¯uorophenyl)-4-hydroxy-1-(2-propionyl-
amino)phenyl-[1,2,3]triazolium hydroxide, inner salt
(12b). To
a solution of 3,4-di¯uoroaniline (2.83 g,
22 mmol) in water (15 ml) and concentrated hydrochloric
acid (8 ml) at 258C was added a solution of NaNO2 (1.59 g,
23 mmol) in water (15 ml) dropwise maintaining a tempera-
ture of less than 08C. Once addition was complete the solu-
tion was stirred for a further 15 min at 08C then added
portionwise to a solution of 2-(propionylamino) phenyl-
amino acetic acid, lithium salt (5 g, 22 mmol) in pyridine
(50 ml) at 258C maintaining a temperature of less than 08C.
The mixture was stirred below 08C for 1 h then allowed to
warm to room temperature. The mixture was partitioned
between ethyl acetate and water, the layers separated and
the aqueous extracted with ethyl acetate. The combined
organics were dried over magnesium sulphate then concen-
trated in vacuo until only pyridine remained (ca 25 ml
volume). To the pyridine solution was added acetic
anhydride (8 ml) and the solution was allowed to stir for
14 h. The reaction mixture was concentrated in vacuo and
azeotroped with toluene. The resulting semi-solid was
triturated with ether and collected, then washed with ethyl
acetate and dried in vacuo to afford the title compound
(1.76 g, 23%); mp 178±1808C; [Found: C, 59.42; H, 4.17;
N, 16.28. C16H13FN4O2 requires: C, 59.30; H, 4.10; N,
16.27%]; nmax (neat) 1655, 1600, 1518, 1474, 1289, 1270,
755 cm21; dH (CDCl3) 8.39 (1H, d, Jˆ8.7 Hz), 8.31 (1H, s,
4.3.23. 2-(4-Fluoro-3-methyl)phenyl-3-hydroxy-4-methyl-
[1,2,3]triazolo[1,5-a]quinoxalinium hydroxide, inner salt
(3c). Prepared from 12c (6.60 g, 20 mmol) and p-toluene-
sulphonic acid (4.10 g, 21 mmol) in toluene (200 ml) to
give, after recrystallization from ethyl acetate, the title
compound (1.00 g, 16%) as a yellow solid. Mp 203±2058C;
[Found: C, 66.16; H, 4.27; N, 18.25. C17H13FN4O requires: C,
66.23; H, 4.25; N, 18.17%]; nmax (neat) 1665, 1496, 1224,
1120, 826, 761, 754 cm21; dH (CDCl3) 8.36 (1H, dd, Jˆ8.3,
1.3 Hz), 8.05 (1H, dd, Jˆ6.8, 2.4 Hz), 7.97 (1H, dd, Jˆ8.3,
1.2 Hz), 7.94 (1H, m), 7.74 (1H, ddd, Jˆ8.3, 7.2, 1.3 Hz),
7.63 (1H, m), 2.96 (3H, s), 7.17 (1H, t, Jˆ8.9 Hz), 2.39 (3H,
s); m/z APCI (1ve) 309 ([M1H]1).

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3193
4.3.24. 1-(2-Acetylamino)phenyl-3-(4-ethylphenyl)-4-hy-
droxy-[1,2,3]triazolium hydroxide, inner salt (12d).
Prepared from 4-ethylaniline (6.05 g, 50 mmol) in water
(60 ml), tetrahydrofuran (20 ml), concentrated hydrochloric
acid (15 ml), NaNO2 (3.63 g, 52 mmol) in water (30 ml),
2-(acetylamino) phenylamino acetic acid, lithium salt
(10 g, 47 mmol) in pyridine (100 ml), and acetic anhydride
(15 ml) to afford the title compound (4.3 g, 28%); mp 162±
1638C; [Found: C, 67.20; H, 5.50; N, 17.18. C18H18N4O2
requires: C, 67.07; H, 5.63; N, 17.38%]; nmax (neat) 1686,
1649, 1638, 1473, 1294, 770, 761 cm21; dH (CDCl3) 9.17
(1H, s, br), 8.33 (1H, d, Jˆ8.5 Hz), 7.83 (2H, d, Jˆ8.4 Hz),
7.55 (1H, m), 7.42 (1H, m), 7.26 (3H, m), 6.90 (1H, s), 2.66
(2H, q, Jˆ7.6 Hz), 2.19 (3H, s), 1.25 (3H, t, Jˆ7.6 Hz); m/z
APCI (1ve) 323([M1H]1).
4.3.28. 1-(2-Acetylamino)phenyl-3-(3,4-di¯uorophenyl)-
4-hydroxy-[1,2,3]triazolium hydroxide, inner salt (12f).
Prepared from 3,4-di¯uoroaniline (12.9 g, 0.1 mol) in water
(120 ml), tetrahydrofuran (60 ml), concentrated hydro-
chloric acid (30 ml), NaNO2 (7.25 g, 0.105 mol) in
water (60 ml), 2-(acetylamino)phenylamino acetic acid,
lithium salt (21.4 g, 0.1 mol) in pyridine (200 ml), and
acetic anhydride (25 ml) to afford the title compound
(7.05 g, 21%); mp 2098C; [Found: C, 57.94; H, 3.67;
N, 16.71. C16H12F2N4O2 requires: C, 58.18; H, 3.66; N,
16.96%]; nmax (neat) 1706, 1656, 1599, 1514, 1283,
1273, 848, 760 cm21; dH (CDCl3) 9.76 (1H, s), 8.24
(1H, ddd, Jˆ12.1, 7.5, 2.5 Hz), 7.94 (1H, m), 7.88 (1H,
d, Jˆ8.2 Hz), 7.66 (1H, m), 7.70 (1H, m), 7.40 (1H,
m), 7.48 (1H, s), 2.00 (3H, s); m/z APCI (1ve)
331([M1H]1).
4.3.25. 2-(4-Ethylphenyl)-3-hydroxy-4-methyl-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3d).
Prepared from 12d (4.0 g, 12.4 mmol) and p-toluenesul-
phonic acid (2.6 g, 13.7 mmol) in toluene (150 ml) to give
the compound title compound (1.265 g, 34%) as a yellow
solid; mp 176±1788C; [Found: C, 71.28; H, 5.09; N, 18.12.
C18H16N4O requires: C, 71.04; H, 5.30; N, 18.41%]; nmax
(neat) 1577, 1502, 1314, 1132, 1111, 832, 773 cm21; dH
(CDCl3) 8.34 (1H, d, Jˆ8.5 Hz), 8.04 (2H, m), 7.88 (1H,
d, Jˆ7.9 Hz), 7.65 (1H, t, Jˆ7.8 Hz), 7.54 (1H, t,
Jˆ7.8 Hz), 7.36 (2H, m), 2.89 (3H, s), 2.73 (2H, m), 1.29
(3H, t, Jˆ7.8 Hz); dC (CDCl3) 155.6, 153.7, 144.4, 139.8,
133.6, 130.6, 129.3, 128.6, 128.0, 124.2, 121.1, 114.8,
113.0, 28.5, 20.9, 15.4; m/z APCI (1ve) 305 ([M1H]1).
4.3.29. 2-(3,4-Di¯uorophenyl)-3-hydroxy-4-methyl-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3f).
Prepared from 12f (6.50 g, 19.7 mmol) and p-toluene-
sulphonic acid (4.12 g, 21.7 mmol) in toluene (500 ml).
Recrystallization of the product from ethyl acetate to gave
the title compound (3.65 g, 59%) as pale yellow needles; mp
2018C; [Found: C, 60.95; H, 3.15; N, 17.77. C16H10F2N4O
requires: C, 61.04; H, 3.23; N, 17.94%]; nmax (neat) 1668,
1505, 1435, 1376, 1340, 1266, 1119, 828, 770, 762 cm21
;
dH (CDCl3) 8.37 (1H, m), 8.19 (1H, m), 8.06 (1H, m), 7.99
(1H, m), 7.79 (1H, m), 7.66 (1H, m), 7.35 (1H, m), 2.96 (3H,
s); dC (CDCl3) 155.4, 153.6, 150.2 (C, dd, JC±Fˆ250,
14 Hz), 149.5 (C, dd, JC±Fˆ250, 14 Hz), 140.0, 132.2,
131.1, 129.5, 128.3, 123.9, 116.7 (C, dd, JC±Fˆ6, 4 Hz),
114.8, 113.2, 110.5, 110.36, 20.9; m/z APCI (1ve) 313
([M1H]1).
4.3.26. 1-(2-Acetylamino)phenyl-4-hydroxy-[3-(3-pyridi-
nyl)-1,2,3]triazolium hydroxide, inner salt (12e).
Prepared from 3-aminopyridine (9.40 g, 0.1 mol) in water
(120 ml), tetrahydrofuran (60 ml), concentrated hydro-
chloric acid (30 ml), NaNO2 (7.25 g, 0.105 mol) in water
(60 ml), 2-(acetylamino) phenylamino acetic acid, lithium
salt (21.4 g, 0.1 mol) in pyridine (200 ml), and acetic anhy-
dride (25 ml) to afford the title compound (5.8 g, 20%); mp
1908C; [Found: C, 60.24; H, 4.10; N, 23.45. C15H13N5O2
requires: C, 60.01; H, 4.44; N, 23.72%]; nmax (neat) 1703,
1656, 1637, 1601, 1546, 1468, 1424, 1366, 759 cm21; dH
(DMSO-d6) 9.77 (1H, s), 9.25 (1H, m), 8.64 (1H, m), 8.44
(1H, m), 7.90 (1H, m), 7.71 (1H, m), 7.63 (2H, m), 7.50
(1H, s), 7.40 (1H, m), 2.02 (3H, s); dC (CDCl3) 169.7,
157.7, 148.8, 141.5, 132.6, 132.4, 131.7, 127.6, 127.5,
125.4, 125.1, 123.5, 109.5, 24.1; m/z APCI (1ve) 296
([M1H]1).
4.3.30. 3-Hydroxy-4-methyl-2-(4-methylphenyl)-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3g).
Prepared from 4-toluidine (10 g, 93 mmol) and 2-(acetyl-
amino) phenyl amino acetic acid, lithium salt (20 g,
93 mmol) to give the title compound (5.31 g, 19%) as a
beige solid; mp 192±1938C; [Found: C, 70.27; H, 4.78; N,
19.50. C17H14N4O requires: C, 70.33; H, 4.86; N, 19.30%];
n
max (neat) 1675, 1578, 1505, 1475, 1440, 1395, 1373, 820,
760 cm21; dH (DMSO-d6) 8.34 (1H, m), 7.98 (2H, m), 7.92
(1H, m), 7.90 (1H, m), 7.70 (1H, m), 7.38 (2H, d,
Jˆ8.2 Hz), 2.75 (3H, s), 2.38 (3H, s); dC (CDCl3) 155.7,
153.8, 139.9, 138.1, 133.5, 130.7, 129.8, 129.4, 128.1,
124.3, 121.1, 114.9, 113.1, 21.2, 20.9; m/z APCI (1ve)
291 ([M1H]1).
4.3.27. 3-Hydroxy-4-methyl-2-(3-pyridinyl)-[1,2,3]tria-
zolo[1,5-a]quinoxalinium hydroxide, inner salt (3e).
Prepared from 12e (5.40 g, 18 mmol) and p-toluenesul-
phonic acid (6.60 g, 35 mmol) in toluene (300 ml) to give,
after recrystallization from ethyl acetate the title compound
(2.31 g, 45%) as pale orange crystals; mp 2058C; [Found: C,
64.67; H, 3.79; N, 24.96. C15H11N5O requires: C, 64.97; H,
4.00; N, 25.26%]; dH (CDCl3) 9.40 (1H, m), 8.66 (1H, m),
8.62 (1H, m), 8.34 (1H, d, Jˆ8.2 Hz), 7.96 (1H, d,
Jˆ8.2 Hz), 7.74 (1H, t, Jˆ7.3 Hz), 7.64 (1H, t,
Jˆ7.3 Hz), 7.49 (1H, dd, Jˆ8.2, 4.7 Hz), 2.97 (3H, s); dC
(CDCl3) 155.4, 154.0, 148.8, 142.0, 140.0, 132.8, 131.2,
129.5, 128.4, 127.8, 124.0, 123.7, 114.9, 112.9, 20.9; m/z
APCI (1ve) 278 ([M1H]1).
4.3.31. 2-(2-Fluoro-5-methylphenyl)- 3-hydroxy-4-meth-
yl-[1,2,3]triazolo[1,5-a]quinoxalinium hydroxide, inner
salt (3h). Prepared from 2-¯uoro-5-methylaniline
(1.58 ml, 14 mmol) and 2-(acetylamino)phenylamino acetic
acid, lithium salt (3.0 g, 14 mmol) to give the title
compound (0.95 g, 22%) as a yellow solid; mp 231±
2328C; [Found: C, 66.16; H, 3.98; N, 18.20. C17H13FN4O
requires: C, 66.23; H, 4.25; N, 18.17%]; nmax (neat) 1677,
1500, 1371, 1128, 821, 765 cm21; dH (CDCl3) 8.29 (1H, d,
Jˆ8.2 Hz), 7.96 (1H, d, Jˆ8.2 Hz), 7.72 (1H, t, Jˆ7.7 Hz),
7.59 (1H, t, Jˆ7.7 Hz), 7.47 (1H, m), 7.29 (1H, m), 7.21
(1H, t, Jˆ9.0 Hz), 2.96 (3H, s), 2.43 (3H, s); dC (CDCl3)
155.7 (C), 140.0 (C), 134.7 (C), 132.0 (CH), 131.0 (CH),
129.5 (CH), 128.4 (CH), 128.2 (CH), 116.8 (CH), 115.0

3194
P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
(CH), 20.9 (CH3), 20.7 (CH3); m/z APCI (1ve) 309
([M1H]1).
(1H, m), 7.96(2H, d, Jˆ8.7 Hz), 7.88±7.77 (3H, m), 7.66
(1H, d Jˆ1.3 Hz); m/z APCI (1ve) 350 ([M1H]1).
4.3.32. 3-Hydroxy-4-methyl-2-(4-methylthiophenyl)-[1,2,3]-
triazolo[1,5-a]quinoxalinium hydroxide, inner salt (3i).
Prepared from 4-methythioaniline (1.74 ml, 12.7 mmol)
and 2-(acetylamino) phenylamino acetic acid, lithium salt
(3.0 g, 14 mmol) to give the title compound (0.99 g, 22%) as
a yellow solid; mp 198±1998C; [Found: C, 63.53; H, 4.18;
N, 17.37; S, 9.95. C17H14N4OS requires: C, 63.34; H, 4.38;
N, 17.38; S, 9.95%]; nmax (neat) 1662, 1491, 1396, 1376,
821, 769 cm21; dH (CDCl3) 8.36 (1H, m), 8.12 (2H, m),
7.98(1H, m), 7.74 (1H, m), 7.63 (1H, m), 7.40 (2H, m),
2.96 (3H, s), 2.55 (3H, s); dC (CDCl3) 155.6, 153.7,
139.9, 138.9, 133.0, 130.8, 129.4, 128.1, 126.8, 126.8,
124.1, 121.2, 114.8, 113.0, 76.9, 20.9, 15.7; m/z APCI
(1ve) 323 ([M1H]1).
4.3.35.
1-(2-Aminophenyl)-4-hydroxy-3-(4-tri¯uoro-
methylphenyl)-3H-[1,2,3]triazolium hydroxide, inner
salt (16). To 1-(2-carboxyphenyl)-4-hydroxy-3-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolium hydroxide, inner
salt (15, 1 g, 2.86 mmol) in t-butanol (50 ml) was added
triethylamine (0.94 ml, 6.7 mmol) and diphenylphosphoryl
azide (1.29 g, 4.7 mmol). The mixture was heated to 808C
for 18 h. The reaction mixture was concentrated in vacuo
and suspended in dichloromethane (10 ml), then tri¯uoro-
acetic acid (10 ml) was added. After 30 min the mixture was
concentrated in vacuo and partitioned between ethyl acetate
and aqueous sodium hydrogen carbonate solution. The
organics were collected and dried over magnesium sulphate
then concentrated in vacuo. The resulting yellow solid was
recrystallized from ethyl acetate to give the title compound
(0.461 g, 50%); mp 1988C; [Found: C, 55.42; H, 3.15; N,
17.05. C15H11F3N4O requires: C, 56.25; H, 3.46; N,
17.49%]; nmax (neat) 1652, 1633, 1614, 1320, 1110, 1069,
846, 743 cm21; dH (CDCl3) 8.31 (2H, m), 7.75 (2H, m), 7.34
(2H, m), 7.03 (1H, s), 6.90 (2H, m), 4.46 (2H, br s); dC
(CDCl3) 157.89, 140.53, 138.67, 131.77, 126.45 (C, q,
JC±Fˆ7 Hz), 124.91, 122.49, 120.73, 118.71, 117.92,
108.51; m/z APCI (1ve) 321 ([M1H]1).
4.3.33. 4-Hydroxy-1-(2-methoxycarbonylphenyl)-3-[4-
(tri¯uoromethyl)phenyl]-[1,2,3]triazolium hydroxide,
inner salt (14). To a stirred solution of 4-(tri¯uoromethyl)-
aniline (4.2 g, 26 mmol) in a mixture of water (50 ml), tetra-
hydrofuran (20 ml) and concentrated hydrochloric acid
(10 ml) at 0 to 258C, was added portionwise a solution of
sodium nitrite (1.91 g, 27 mmol) in water (20 ml). The solu-
tion was stirred 15 min at 0 to 258C and was then added
portionwise to a solution of methyl 2-(carboxymethyl-
amino)benzoate (13, 5 g, 24 mmol) in pyridine (50 ml)
and water (10 ml) at 0 to 258C. The solution was stirred
for 1 h at 08C and then for 1 h at 0±108C. The mixture was
diluted with ethyl acetate and the organics separated, dried
over magnesium sulphate and concentrated in vacuo to ca
30 ml volume. To the residue was added acetic anhydride
(10 ml) and the solution was stirred for 1 h. The reaction
mixture was concentrated in vacuo, azeotroping twice
with toluene. The product was chromatographed on
silica (ethyl acetate then ethyl acetate/ethanol 10:1).
Crystallization from ethyl acetate/isohexane gave the
title compound (1.50 g, 17%) as a colourless solid; mp
149±1508C; [Found: C, 56.48; H, 3.32; N, 11.58.
C17H12F3N3O3 requires: C, 56.20; H, 3.33; N, 11.57%];
dH (CDCl3) 8.32 (2H, d, Jˆ8.50 Hz), 8.07 (1H, dd, Jˆ7.4,
1.8 Hz), 8.0±7.69 (4H, m), 7.61 (1H, dd, Jˆ7.5, 1.5 Hz),
7.01 (1H, s), 3.79 (3H, s); dC (CDCl3) 164.8, 157.9, 138.7,
135.8, 133.0, 131.7, 131.4, 129.6 (C, q, JC±Fˆ34 Hz),
127.6, 126.4 (C, q, JC±Fˆ4 Hz), 126.2, 123.8 (C, q,
JC±Fˆ272 Hz), 120.7, 109.3, 52.9, 52.9; m/z APCI (1ve)
364 ([M1H]1).
4.3.36. 3-Hydroxy-2-(4-tri¯uoromethylphenyl)-[1,2,3]-
triazolo[5,1-c][1,2,4]benzotriazinium hydroxide, inner
salt (4). To 1-(2-aminophenyl)-4-hydroxy-3-(4-tri¯uoro-
methylphenyl)-3H-[1,2,3]triazolium hydroxide, inner salt
(16, 0.1 g, 0.3 mmol) in water (3.2 ml), tetrahydrofuran
(1 ml) and concentrated hydrochloric acid (0.52 ml) at
258C was added a solution of NaNO2 (21 mg, 0.3 mmol)
in water (0.8 ml) dropwise. After 10 min the mixture was
allowed to warm to room temperature and the resulting solid
was collected by ®ltration. The solid was then stirred in
boiling ethanol (20 ml) for 5 min before being collected
by ®ltration to afford the title compound as a yellow powder
(0.024 g, 23%); mp 317±3188C; [Found: C, 54.32; H, 2.38;
N, 21.04. C15H8F3N5O requires: C, 54.39; H,2.43; N,
21.14%]; nmax (neat) 1700, 1611, 1579, 1483, 1321, 1105,
779 cm21; dH (DMSO-d6) 8.58 (1H, m), 8,51 (1H, m), 8.46
(2H, d, Jˆ8.5 Hz), 8.12 (1H, dd), 8.09 (1H, m), 8.06 (2H, d,
Jˆ8.5 Hz); m/z APCI (1ve) 332([M1H]1).
4.3.37. 3-Hydroxy-4-oxo-2-[4-(tri¯uoromethyl)phenyl]-
4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxalinium hydrox-
ide, inner salt (17). To a stirred solution of 1-(2-carboxy-
phenyl)-4-hydroxy-3-[4-(tri¯uoromethyl)phenyl]-[1,2,3]-
triazolium hydroxide, inner salt (15, 1.2 g, 3.4 mmol) in
anhydrous toluene (40 ml) and triethylamine (1.2 ml,
8.6 mmol) was added diphenylphosphorylazide (1.2 ml,
5.5 mmol) and the mixture stirred at room temperature for
14 h. The mixture was then heated at 758C for 20 min.
Dichloromethane (40 ml) was added and the mixture
allowed to cool. The precipitate was ®ltered and washed
with dichloromethane followed by ethyl acetate then diethyl
ether, and dried in vacuo to give the title compound (1.05 g)
as a colourless solid; mp.3008C; [Found: C, 55.10; H, 2.39;
N, 15.59. C16H9F3N4O2 requires: C, 55.50; H, 2.62; N,
16.18%]; dH (DMSO-d6) 11.68 (1H, s), 8.40 (2H, d,
Jˆ8.7 Hz), 8.25 (1H, dd, Jˆ8.7, 1.3 Hz), 8.01(2H, d,
4.3.34. 1-(2-Carboxyphenyl)-4-hydroxy-3-[4-(tri¯uoro-
methyl)phenyl]-[1,2,3]triazolium hydroxide, inner salt
(15). To a stirred solution of 4-hydroxy-1-(2-methoxycarbo-
nyl phenyl)-3-[4-(tri¯uoromethyl)phenyl]-[1,2,3]triazolium
hydroxide, inner salt (14, 4.55 g, 12.5 mmol) in tetrahydro-
furan (50 ml) and methanol (15 ml) was added a solution of
sodium hydroxide (0.60 g, 15 mmol) in water (15 ml). After
30 min the solution was acidi®ed with aqueous potassium
hydrogen sulphate solution and extracted with ethyl acetate.
The organics were concentrated in vacuo and azeotroped to
dryness with toluene to give the title compound (3.8 g, 87%)
as a colourless solid; mp.2658C; [Found: C, 54.48; H, 2.62;
N, 11.49. C16H10F3N3O requires: C, 55.02; H, 2.89; N,
12.03%]; dH (DMSO-d6) 8.32 (2H, d, Jˆ8.7 Hz), 8.01

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3195
Jˆ8.7 Hz), 7.64 (1H, td, Jˆ7.8, 1.5 Hz), 7.36 (2H, m); m/z
APCI (1ve) 347 ([M1H]1).
H, 3.55; N, 18.18. C19H14F3N5O requires: C, 59.22; H, 3.66;
N, 18.17%]; dH (DMSO-d6) 8.36 (2H, d), 8.19 (1H, m), 7.79
(2H, m), 7.64 (1H, m), 7.56 (1H, m), 7.27 (1H, m), 4.55 (4H,
m), 2.45 (2H, m); m/z APCI (1ve) 386 ([M1H]1).
4.3.38. 4-Ethyl-3-hydroxy-2-[4-(tri¯uoromethyl)phenyl]-
[1,2,3]triazolo[1,5-a]quinoxalinium hydroxide, inner salt
(3j). To a stirred suspension of 3-hydroxy-4-oxo-2-[4-
(tri¯uoromethyl)phenyl]-4,5-dihydro-[1,2,3]triazolo[1,5-a]-
quinoxalinium hydroxide, inner salt (17, 0.90 g, 2.6 mmol)
in toluene (150 ml) at 758C was added a solution of ethyl-
magnesium chloride (3 M in diethyl ether, 3 ml). After
5 min the reaction was quenched with water (3 ml) and
the product extracted with ethyl acetate and concentrated
in vacuo. Chromatography on silica (dichloromethane/
diethyl ether, 4:1) followed by recrystallization from ethyl
acetate: isohexane gave the title compound (0.109 g) as
colourless needles; mp 1818C; [Found: C, 60.20; H, 3.34;
N, 15.50. C18H13F3N4O requires: C, 60.34; H, 3.66; N,
15.64%]; nmax (neat) 1674, 1328, 1103, 1509, 851,
765 cm21; dH (CDCl3) 8.42 (2H, d, Jˆ8.8 Hz), 8.36 (1H,
m), 8.00 (1H, m), 7.80 (2H, d, Jˆ8.8 Hz), 7.76 (1H, m), 7.74
(1H, m), 3.33 (2H, q, Jˆ7.5 Hz), 1.47 (3H, t, Jˆ7.5 Hz); dC
(CDCl3) 160.4, 153.6, 140.3, 138.7, 131.1, 129.8, 129.6 (C,
q, JC±Fˆ33 Hz), 129.5, 128.3, 126.5 (C, q, JC±Fˆ4 Hz),
124.0, 123.7 (C, q, JC±Fˆ272 Hz), 120.5, 114.9, 112.9,
27.7, 12.2; m/z APCI (1ve) 359 ([M1H]1).
4.3.41. 5-Bromo-3-hydroxy-2-phenyl-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (18a). To a solution
of 3-hydroxy-2-phenyl-[1,2,3]triazolo[1,5-a]quinolinium
hydroxide, inner salt (1a, 1.2 g, 4.6 mmol) in dichloro-
methane (100 ml) was added pyridine (0.36 ml, 4.6 mmol)
then bromine (0.48 ml, 9.3 mmol) and stirred for 1 h. The
reaction mixture was partitioned between ethyl acetate and
sodium hydrogen carbonate solution. The organic layer was
separated, dried over magnesium sulphate and concentrated
in vacuo. Puri®cation by chromatography on silica gel
(dichloromethane/ethyl acetate 8:1 then ethyl acetate)
followed by a diethyl ether wash gave the title compound
(1.0 g, 64%) as a yellow solid; mp 246±2498C; [Found: C,
56.88; H, 2.98; N, 12.34. C16H10BrN3O requires: C, 56.49;
H, 2.96; N, 12.35%]; nmax (neat) 1656, 1648, 1492, 1461,
1404, 810, 749 cm21; dH (CDCl3) 8.55 (1H, m), 8.19 (3H,
m), 7.99 (1H, s), 7.77 (2H, m), 7.58 (2H, m), 7.44 (1H, m);
dC (CDCl3) 152.5, 136.3, 130.6, 130.3, 129.8, 129.2, 128.8,
127.9, 126.4, 121.3, 120.3, 118.7, 116.0, 113.1; m/z APCI
(1ve) 340, 342 ([M1H]1).
4.3.39.
3-Hydroxy-4-(1-methylethyl)-2-[4-(tri¯uoro-
4.3.42. 5-Bromo-2-(4-¯uorophenyl)-3-hydroxy-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (18b).
Prepared from 2-(4-¯uorophenyl)-3-hydroxy-[1,2,3]tria-
zolo[1,5-a]quinolinium hydroxide, inner salt (1b, 3 g,
10.7 mmol) to give the title compound (1.0 g, 26%) as a
yellow solid; mp.2508C; [Found: C, 53.38; H, 2.48; N,
11.77. C16H9BrFN3O requires: C, 53.65; H, 2.53; N,
11.73%]; nmax (neat) 1677, 1668, 1507, 1404, 1226, 1141,
831, 776 cm21; dH (CDCl3) 8.53 (1H, m), 8.20 (3H, m), 7.98
(1H, s), 7.78 (2H, m), 7.23 (2H, m); m/z APCI (1ve) 358,
360 ([M1H]1).
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinoxalinium hy-
droxide, inner salt (3k). To a stirred suspension of
3-hydroxy-4-oxo-2-[4-(tri¯uoromethyl)phenyl]-4,5-dihydro-
[1,2,3]triazolo[1,5-a]quinoxalinium hydroxide, inner salt
(17, 0.30 g, 0.87 mmol) in toluene (25 ml) at 808C was
added a solution of isopropylmagnesium chloride (2 M in
diethyl ether, 2.5 ml). After 10 min the reaction was
quenched with water and the product extracted with ethyl
acetate and concentrated in vacuo. Chromatography on
silica (diethyl ether/isohexane, 1:1) and washing with
ether gave the title compound (0.05 g) as a yellow powder;
mp 1678C; [Found: C, 61.35; H, 4.43; N, 14.76.
C19H15F3N4O requires: C, 61.29; H, 4.06; N, 15.05%];
4.3.43. 5-Bromo-2-(4-chlorophenyl)-3-hydroxy-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (18c).
Prepared from 2-(4-chlorophenyl)-3-hydroxy-[1,2,3]tria-
zolo[1,5-a]quinolinium hydroxide, inner salt (3.8 g,
12.9 mmol) to give the title compound (3.67 g, 79%) as a
yellow solid; mp 238±2408C; [Found: C, 57.30; H, 2.33; N,
10.96. C16H9BrClN3O requires: C, 57.30; H, 2.42; N,
11.22%]; nmax (neat) 1664, 1493, 1401, 1332, 834, 812,
763 cm21; dH (CDCl3) 8.55 (1H, m), 8.22 (3H, m), 7.99
(1H, s), 7.78 (2H, m), 7.51 (2H, m); m/z APCI (1ve) 374,
376, 378 ([M1H]1).
nmax (neat) 1672, 1612, 1502, 1316, 1068, 845, 761 cm21
dH (DMSO-d6) 8.43 (3H, m), 8.02 (3H, m), 7.86 (1H, m),
7.78 (1H, m), 3.94 (1H, m), 1.37 (6H, d, Jˆ6.9 Hz); m/z
APCI (1ve) 373 ([M1H]1).
;
4.3.40. 4-Azetidinyl-3-hydroxy-2-[4-(tri¯uoromethyl)-
phenyl]-[1,2,3]triazolo[1,5-a]quinoxalinium hydroxide,
inner salt (3l). A solution of 3-hydroxy-4-oxo-2-[4-
(tri¯uoromethyl)phenyl]-4,5-dihydro-[1,2,3]triazolo[1,5-a]-
quinoxalinium hydroxide, inner salt (17, 2.17 g, 6.3 mmol)
in phosphorus oxychloride (30 ml) was re¯uxed for 2 h
before being concentrated in vacuo. The residue was
quenched with aqueous sodium hydrogen carbonate solu-
tion and extracted with dichloromethane, dried over magne-
sium sulphate and concentrated in vacuo to give crude 4-
chloro-3-hydroxy-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]tria-
zolo[1,5-a]quinoxalinium hydroxide, inner salt (1.80 g). To
a stirred solution of this compound (0.5 g) in dichloro-
methane (10 ml) was added azetidine (1 ml). The mixture
was stirred for 1 h at room temperature then concentrated in
vacuo. Chromatography on silica followed by crystalliza-
tion from ethyl acetate/isohexane gave the title compound
as ®ne needles (0.10 g); mp 216±2178C; [Found: C, 58.92;
4.3.44. 5-Bromo-3-hydroxy-2-(3-tri¯uoromethylphenyl)-
[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner salt
(18d). Prepared from 3-hydroxy-2-(3-tri¯uoromethylphe-
nyl)-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (1e, 0.85 g, 2.46 mmol) to give the title compound
(0.39 g, 37%) as a yellow solid; mp 205±2068C; [Found:
C, 50.15; H, 2.18; N, 10.15. C17H9BrF3N3O requires: C,
50.02; H, 2.22; N, 10.29%]; nmax (neat) 1665, 1452, 1445,
1341, 1324, 1169, 1112, 795, 761 cm21; dH (CDCl3)
8.59 (2H, m), 8.52 (1H, s), 8.22 (1H, m), 7.97 (1H, s),
7.83 (2H, m), 7.64 (2H, m); dC (CDCl3) 152.5, 136.8,
131.7 (C, q, JC±Fˆ33 Hz), 130.5, 130.4, 130.1, 129.9,
128.9, 126.5, 124.2 (C, q, JC±Fˆ4 Hz), 123.8, 123.6 (C, q,

3196
P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
JC±Fˆ272 Hz), 120.1, 118.8, 117.6 (C, q, JC±Fˆ4 Hz),
116.1, 113.7, 131.7, 123.6, 124.2; m/z APCI (1ve) 408,
410 ([M1H]1).
4.3.48. 5-(1-Azetidinyl)-3-hydroxy-4-methyl-2-[4-(tri¯uoro-
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide
inner salt (19b). A solution of 5-bromo-3-hydroxy-4-
methyl-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (18e, 0.7 g, 1.7 mmol),
tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol),
(R)-(1)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (62 mg,
0.1 mmol), azetidine (0.34 ml, 5 mmol) and sodium tertiary
butoxide (0.22 g, 2.3 mmol) in toluene (20 ml) was heated in
a sealed tube at 808C overnight. Puri®cation by chromato-
graphy on silica gel (dichloromethane/ethyl acetate 4:1)
followed by recrystallization from ethyl acetate gave the
title compound (0.30 g, 46%) as an orange solid; [Found:
C, 63.11; H, 4.42; N, 14.09. C21H17F3N4O requires: C,
63.31; H, 4.30; N, 14.06%]; nmax (neat) 1648, 1610, 1409,
1320, 1098, 844, 767 cm21; dH (CDCl3) 8.49 (2H, d,
Jˆ8.5 Hz), 8.43 (1H, dd, Jˆ7.8, 1.1 Hz), 7.98 (1H, dd,
Jˆ8.2, 1.2 Hz), 7.75 (2H, d, Jˆ8.5 Hz), 7.56 (2H, m), 4.33
(4H, s, br), 2.78 (3H, s), 2.34 (2H, quin, Jˆ7.4 Hz); dC
(CDCl3) 153.8, 140.6, 139.6, 129.2, 128.6 (C, q,
JC±Fˆ33 Hz), 128.0, 127.6, 126.1, 124.9, 124.0 (C, q,
JC±Fˆ273 Hz), 123.3, 120.5, 119.6, 116.2, 113.0, 58.2,
17.8, 12.7; m/z APCI (1ve) 399([M1H]1).
4.3.45. 5-Bromo-3-hydroxy-2-[4-(tri¯uoromethyl)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (18e). (a) Prepared from 3-hydroxy-2-[4-(tri¯uoro-
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (1c, 1.0 g, 3 mmol) to give the title compound
(0.56 g, 45%) as a yellow solid.
(b) Prepared from 4,5-dihydro-3-hydroxy-2-(4-tri¯uoro-
methylphenyl)-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (6c, 8.7 g, 26 mmol), bromine (8.1 ml, 157 mmol)
and pyridine (4.25 ml, 53 mmol) to give the title compound
as a yellow solid (5.30 g, 50%); mp 187±1888C; [Found: C,
49.88; H, 2.06; N, 10.09. C17H9BrF3N3O requires: C, 50.02;
H, 2.22; N, 10.29%]; nmax (neat) 1676, 1615, 1514, 1321,
1112, 1104, 1065, 843, 758 cm21; dH (CDCl3) 8.57 (1H, m),
8.47 (2H, m), 8.21 (1H, m), 7.99 (1H, s), 7.80 (4H, m); dC
(CDCl3) 152.6, 139.0, 130.5, 130.4, 130.1, 129.3 (C, q,
JC±Fˆ33 Hz), 128.9, 126.5, 126.4, 126.4 (C, q,
JC±Fˆ4 Hz), 124.9, 123.8 (C, q, JC±Fˆ275 Hz), 122.7,
120.5, 120.1, 118.9, 116.0, 113.7; m/z APCI (1ve) 408,
410 ([M1H]1).
4.3.49.
3-Hydroxy-5-(4-morpholinyl)-2-[4-(tri¯uoro-
methoxy)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hy-
droxide, inner salt (19c). Prepared from 5-bromo-3-
hydroxy-2-[4-(tri¯uoromethoxy) phenyl]-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (1.4 g, 3.3 mmol) to give
the title compound (0.602 g, 42%) as a yellow solid; mp 231±
2328C; [Found: C, 58.31; H, 3.90; N, 13.18. C21H17F3N4O3
requires: C, 58.61; H, 3.98; N, 13.02%]; nmax (neat) 1655,
1505, 1256, 1151, 901, 768, 761 cm21; dH (CDCl3) 8.56 (1H,
m), 8.35 (2H, m), 8.14 (1H, m), 7.73 (2H, m), 7.39 (2H, d,
Jˆ9.0 Hz), 7.26 (1H, s), 3.99 (4H, m), 3.12 (4H, m); m/z
APCI (1ve) 431 ([M1H]1).
4.3.46. 5-Bromo-3-hydroxy-2-[4-(tri¯uoromethoxy)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (18f). Prepared from 3-hydroxy-2-[4-(tri¯uoromethoxy)-
phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (1e, 2.3 g, 6.6 mmol) to give the title compound (1.0 g,
38%) as a yellow solid; mp 202±2048C; [Found: C, 47.98; H,
1.99; N, 9.91. C17H9BrF3N3O2 requires: C, 48.14; H, 2.14; N,
9.91%]; nmax (neat) 1671, 1501, 1249, 1218, 1156, 858,
764 cm21; dH (CDCl3) 8.55 (1H, m), 8.33 (2H, m), 8.21
(1H, m), 7.98 (1H, s), 7.78 (2H, m), 7.40 (2H, m); dC
(CDCl3) 152.5, 148.1, 134.7, 130.6, 130.5, 130.0, 129.0,
126.5, 122.5, 121.8, 120.4 (C, q, JC±Fˆ257 Hz), 120.2,
118.8, 116.0, 113.6; m/z APCI (1ve) 424, 426 ([M1H]1).
4.3.50. 3-Hydroxy-5-(2-methoxyethylamino)-2-[4-(tri-
¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium
hydroxide, inner salt (19d). A solution of 5-bromo-3-
hydroxy-2-[4-(tri¯uoromethyl) phenyl]-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (18e, 1.0 g, 2.4 mmol),
tris(dibenzylideneacetone)dipalladium (0.045 g, 0.05 mmol),
(R)-(1)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.092 g,
0.15 mmol), 2-methoxyethylamine (0.55 g, 7.3 mmol) and
sodium tertiary butoxide (0.33 g, 3.4 mmol) in toluene
(20 ml) was heated at 808C overnight. Puri®cation by
chromatography on silica gel (dichloromethane/ethyl acetate
1:1±1:3) followed by a diethyl ether wash gave the title
compound (0.59 g, 60%) as a yellow solid; mp.2508C;
[Found: C, 59.48; H, 4.36; N, 13.81. C20H17F3N4O2
requires: C, 59.70; H, 4.26; N, 13.92%]; nmax (neat)
1643, 1604, 1555, 1510, 1419, 1330, 1107, 846,
764 cm21; dH (CDCl3) 8.58 (1H, d, Jˆ8.4 Hz), 8.51
(2H, d, Jˆ8.5 Hz), 7.87 (1H, d, Jˆ7.7 Hz), 7.78 (2H,
d, Jˆ8.5 Hz), 7.76 (1H, t, Jˆ7.5 Hz), 7.70 (1H, t,
Jˆ7.5 Hz), 3.78 (2H, s), 3.47 (3H, s); m/z APCI
(1ve) 403 ([M1H]1).
4.3.47. 3-Hydroxy-5-methoxy-2-[4-(tri¯uoromethyl)phe-
nyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (19a). A solution of 5-bromo-3-hydroxy-2-[4-(tri¯uoro-
methyl)phenyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (18e, 1.5 g, 3.7 mmol), tris(dibenzylideneacetone)-
dipalladium (67.5 mg, 0.07 mmol), (R)-(1)-2,2-bis(di-
phenylphosphino)-1,1-binaphthyl (0.138 g, 0.22 mmol),
7 M ammonia in methanol (10 ml) and sodium t-butoxide
(0.5 g, 5.2 mmol) in toluene (30 ml) was heated at 808C in a
sealed tube for 14 h. Puri®cation by chromatography on
silica gel (dichloromethane/ethyl acetate 3:1) followed by
recrystallization from ethyl acetate gave the title compound
(0.25 g, 19%) as a yellow solid; mp 212±2138C; [Found: C,
60.19; H, 3.30; N, 11.62. C18H12F3N3O2 requires: C, 60.17;
H, 3.37; N, 11.70%]; nmax (neat) 1655, 1610, 1560, 1515,
1416, 1319, 1100, 840, 763 cm21; dH (CDCl3) 8.48 (2H, d,
Jˆ8.7 Hz), 8.45 (1H, d, Jˆ8.4 Hz), 8.17 (1H, d, Jˆ8.0 Hz),
7.76 (2H, d, Jˆ8.7 Hz), 7.73 (1H, d, Jˆ7.4 Hz), 7.67 (1H, t,
Jˆ7.6 Hz), 6.87 (1H, s), 4.02 (3H, s); dC (CDCl3) 153.2,
150.0, 139.5, 130.5, 130.1, 129.0, 128.9, 128.8, 126.2 (C, q,
JC±Fˆ4 Hz), 123.9, 123.9 (C, q, JC±Fˆ274 Hz), 122.7,
120.6, 119.3, 115.8, 92.4, 56.2; m/z APCI (1ve) 360
([M1H]1).
4.3.51. 2-(4-Chlorophenyl)-3-hydroxy-5-methyl-1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (19e).
A solution of 5-bromo-2-(4-chlorophenyl)-[3-hydroxy
1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner salt

P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
3197
(18c, 0.438 g, 1.17 mmol), trans-benzyl(chloro)bis (tri-
phenylphosphine)palladium (II) (30 mg, 0.04 mmol) and
tetramethyltin (5 ml) in anhydrous dimethylformamide
(30 ml) was heated under nitrogen at 608C for 14 h. The
mixture was cooled, diluted with ethyl acetate, washed
with water and dried over magnesium sulphate. Concentra-
tion in vacuo and chromatography on silica afforded the title
compound (0.294 g, 32%); mp 2138C; [Found: C, 65.89; H,
3.67; N, 13.48. C17H12ClN3O requires: C, 65.92; H, 3.91; N,
13.57%]; nmax (neat) 1672, 1491, 1408, 1326, 1146, 1094,
824, 752 cm21; dH (CDCl3) 8.55 (1H, m), 8.27 (2H, m), 7.94
(1H, m), 7.69±7.76 (2H, m), 7.50 (3H, m), 2.60 (3H, s); dC
(CDCl3) 135.2, 133.0, 130.1, 129.3, 129.2, 129.1, 128.1,
127.5, 125.7, 122.2, 118.7, 116.2, 116.0, 18.8; m/z APCI
(1ve) 310/312 ([M1H]1).
nyl]-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner salt
(1d, 0.25 g, 0.76 mmol) in dichloromethane (20 ml) and
0.5 M nitronium tetra¯uoroborate solution in sulfolane
(4 ml). Recrystallization from ethyl acetate afforded the
title compound (0.182 g, 64%); mp.2508C; [Found: C,
54.16; H, 2.49; N, 14.75. C17H9F3N4O3 requires: C, 54.55;
H, 2.42; N, 14.97%]; nmax (neat) 1681, 1592, 1536,
1495, 1445, 1307, 1108, 801, 771 cm21; dH (CDCl3) 8.89
(1H, m), 8.74 (1H, s), 8.68 (1H, m), 8.57 (1H, m), 8.44 (1H,
s), 7.89 (2H, m), 7.70 (2H, m); m/z APCI (1ve) 375
([M1H]1).
4.3.55.
2-(4-Chlorophenyl)-3-hydroxy-5-nitro-[1,2,3]-
triazolo[1,5-a]quinolinium hydroxide, inner salt (20c).
Prepared from 2-(4-chlorophenyl)-3-hydroxy-[1,2,3]tri-
azolo[1,5-a]quinolinium hydroxide, inner salt (1.0 g,
3.38 mmol) in dichloromethane (75 ml) and 0.5 M
nitronium tetra¯uoroborate solution in sulfolane (12 ml).
Chromatography on silica gel (dichloromethane/ethyl
acetate 5%) and recrystallization from dichloromethane
afforded the title compound (0.655 g, 57%); mp 2858C;
[Found: C, 56.25; H, 2.56; N, 16.59. C16H19ClN4O3
requires: C, 56.40; H, 2.66; N, 16.44%]; dH (CDCl3) 8.83
(1H, m), 8.66 (2H, m), 8.23 (2H, m), 7.93 (2H, m), 7.58 (2H,
m); m/z APCI (1ve) 340/342 ([M1H]1).
4.3.52. 3-Hydroxy-5-[(1-hydroxy-1-methyl)ethyl]-2-[4-
(tri¯uoromethyl)phenyl]-1,2,3]triazolo[1,5-a]quinolinium
hydroxide, inner salt (19f). To a stirred solution of 5-bromo-
3-hydroxy-2-[4-(tri¯uoromethyl)phenyl]-[1,2,3]triazolo[1,5-
a]quinolinium hydroxide, inner salt (18e, 0.50 g, 1.2 mmol)
in anhydrous tetrahydrofuran (60 ml) at 2708C, was added
n-butyllithium solution (2.5 M, 1.1 ml). After 10 min acetone
(0.1 ml, 1.4 mmol) was added and the solution allowed to
warm to room temperature. The solution was quenched
with 1N aq. hydrochloric acid solution and extracted with
ethyl acetate. The extracts were dried (magnesium sulphate),
concentrated and chromatographed on silica gel (dichloro-
methane/ethyl acetate, 10%) to afford the title compound
as a yellow powder (0.040 g, 9%); mp 205±68C; [Found:
C, 61.77; H, 3.99; N, 10.84. C20H16F3N3O2 requires:
C, 62.01; H, 4.16; N, 10.85%]; dH (CDCl3) 8.54 (1H, m),
8.46 (2H, d, Jˆ8.5 Hz), 7.82 (3H, m), 7.71 (2H, m), 7.17
(2H, d, Jˆ9.0 Hz), 1.77 (6H, s); m/z APCI (1ve) 388
([M1H]1).
4.3.56. 3-Hydroxy-4-methyl-2-(6-methylpyridin-3-yl)-5-
nitro-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (20d). Prepared from 3-hydroxy-4-methyl-2-(6-methyl-
3-pyridinyl)-[1,2,3]triazolo[1,5-a]quinolinium hydroxide,
inner salt (0.30 g, 1 mmol) in dichloromethane (10 ml)
and 0.5 M nitronium tetra¯uoroborate solution in sulfolane
(4 ml). Chromatography on silica (dichloromethane/metha-
nol 2%) and recrystallization from ethyl acetate afforded the
title compound as an orange powder (0.15 g, 43%); mp
202±2048C; [Found: C, 60.55; H, 3.87; N, 20.62.
C17H13N5O3 requires: C, 60.89; H, 3.91; N, 20.89%]; dH
(CDCl3) 9.25 (1H, d, Jˆ2.5 Hz), 8.55 (1H, m), 8.48
(1H, dd, Jˆ8.5, 2.5 Hz), 7.80 (3H, m), 7.35 (1H, d,
Jˆ8.5 Hz), 2.84 (3H, s), 2.66 (3H, s); m/z APCI (1ve)
336 ([M1H]1).
4.3.53. 2-(6-Chloropyridin-3-yl)-3-hydroxy-4-methyl-5-
nitro-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (20a). To a stirred suspension of 2-(6-chloropyridin-3-
yl)-3-hydroxy-4-methyl-[1,2,3]triazolo[1,5-a]quinolinium
hydroxide, inner salt (1g, 13.2 g, 42.6 mmol) in dichloro-
methane (500 ml) was added 0.5 M nitronium tetra¯uoro-
borate solution in sulfolane (85 ml) at room temperature
over a period of 1 min. After 1 h additional nitronium tetra-
¯uoroborate solution (9 ml) was added. After a further 1 h
the mixture was poured into sodium hydrogen carbonate
solution and extracted with dichloromethane. The combined
organic extracts were washed with aqueous sodium hydro-
gen carbonate solution, dried and concentrated in vacuo.
The residue was diluted with water and the precipitated
solid ®ltered and dried. Chromatography on silica (dichloro-
methane/methanol 1%) and recrystallization from acetone
afforded the title compound as a yellow powder (12.60 g,
82%); mp 230±2328C; [Found: C, 53.98; H, 3.03; N, 19.67.
C16H10ClN5O3 requires: C, 54.02; H, 2.83; N, 19.69%]; dH
(CDCl3) 9.25 (1H, d, Jˆ2.7 Hz), 8.68 (1H, dd, Jˆ8.8,
2.8 Hz), 8.56 (1H, m), 7.81 (3H, m), 7.53 (1H, d,
Jˆ8.8 Hz), 2.84 (3H, s); m/z APCI (1ve) 356/358
([M1H]1).
4.3.57. 5-(Azetidin-1-ylsulfonyl)- 2-(3-¯uorophenyl)-3-
hydroxy-[1,2,3]triazolo[1,5-a]quinolinium
hydroxide,
inner salt (20e). A solution of 2-(3-¯uorophenyl)-3-hy-
droxy-[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner
salt (0.50 g, 1.8 mmol) in chlorosulphonic acid (5 ml) was
stirred at room temperature for 60 h. The mixture was
dripped onto ice and the precipitated product ®ltered and
dried. The product was redissolved in tetrahydrofuran (5 ml)
and treated with azetidine (5 ml). The solution was stirred at
room temperature for 30 min then concentrated in vacuo.
Chromatography on silica eluting with ethyl acetate,
followed by recrystallization (ethyl acetate) gave the title
compound as a yellow solid (0.20 g, 32%); mp.2508C;
[Found: C, 57.18; H, 3.88; N, 13.65,
S
8.06.
C19H15FN4O3S requires: C, 57.28; H, 3.80; N, 14.06, S
8.05%]; nmax (neat) 1655, 1492, 1451, 1416, 1345, 1164,
822, 664 cm21; dH (CDCl3) 8.98 (1H, s), 8.14 (2H, m), 8.08
(1H, dd, Jˆ8.4, 1.3 Hz), 8.01 (1H, d, Jˆ9.2 Hz), 7.82 (1H,
d, Jˆ9.2 Hz), 7.54 (1H, m), 7.30 (1H, d, Jˆ9.2 Hz), 7.14
(1H, m), 3.93 (4H, t, Jˆ7.0 Hz), 2.16 (2H, quintet,
Jˆ7.7 Hz); m/z APCI (1ve) 399 ([M1H]1).
4.3.54. 3-Hydroxy-2-[3-(tri¯uoromethyl)phenyl]-5-nitro-
[1,2,3]triazolo[1,5-a]quinolinium hydroxide, inner salt
(20b). Prepared from 3-hydroxy-2-[3-(tri¯uoromethyl)phe-

3198
P. A. Abbott et al. / Tetrahedron 58 (2002) 3185±3198
References
1. It should be noted that many of the compounds described in this
paper have been found to be very potent ligands for the aryl
hydrocarbon receptor. The aryl hydrocarbon receptor (AhR) is a
ligand-activated transcription factor that mediates many of the
biological and toxicological effects of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD, dioxin) and related chemicals.
Given the known toxic potential of such ligands, extreme
caution should be exercised when handling compounds within
this and related series of compounds. An example where AhR
mediated toxicity has been observed with related compounds
can be found in: MacKenzie, A. R.; Brooks, S. Chem. Ber 1998,
34 (12), 18.
7. Cyclization of the parent carboxylic acid occurs on standing to
afford 2-methyl-[1H]-benzimidazol-1-acetic acid.
2. (a) Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965.
(b) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron
1985, 41, 2239.
8. X-Ray crystal data for 3b: space group: triclinic, P-1, (No. 2).
The compound is crystallized from ethylacetate with two
molecules in the unit-cell. Unit-cell parameters: aˆ8.091(1),
Ê
bˆ9.445(1), cˆ9.873(1) A, aˆ78.31(1), bˆ81.79(1),
3. (a) Araki, S.; Hattori, H.; Yamamura, H.; Kawai, M. J. Hetero-
cycl. Chem. 2000, 37 (5), 1129±1134. (b) Lo, ChokW.; Chan,
W. L.; Szeto, Y. S.; Yip, C. W. Heterocycles 1999, 51 (6),
1433±1436. (c) Nagamatsu, T.; Hantani, Y.; Sasaki, K.;
Ohtomo, H.; Nakayama, T.; Hirota, T. J. Heterocycl. Chem.
1993, 30 (1), 233±240. (d) Molina, P.; Lorenzo, A.; Claramunt,
R. M.; Elguero, J. Tetrahedron Lett. 1984, 25 (47), 5427±5428.
(e) Talukdar, P. B.; Sengupta, S. K.; Datta, A. K. Indian J.
Chem., Sect. B 1984, 23B (4), 316±320. (f) Masuda, K.; Adachi,
J.; Shibata, T.; Nomura, K. Chem. Pharm. Bull. 1979, 27 (7),
1688±1690. (g) Nagano, E.; Yoshida, R. Eur. Pat. Appl. 17 pp.
EP 116928, 1984. (h) Abu-El-Haj, Marwan J.; McFarland, J.W.
Ger. Offen. 21 pp. DE 2239400, 1984.
Ê 3
gˆ79.58(1)8, Vˆ722.2(2) A , Zˆ2. Dxˆ1.501(1) g/cm3,
F(000)ˆ336. m(Mo Ka)ˆ1.16 cm21
.
Crystal dimensions
0.11£0.17£0.26 mm. A total of 2403 independent re¯ections
[F2.4s(F2)] was re®ned to give Rˆ0.040, Rwˆ0.044 for 218
2
2
parameters (wˆ1/(s2Fo 1(0.0300)Fo ). (D/s)maxˆ0.0004,
Ê 23
Ê 23
Ê 23
Drmaxˆ0.16 eA
,
Drminˆ20.15 eA
,
Drmeanˆ0.04 eA
.
GOFˆ0.882. The X-ray intensity data of AR-C124721XX
were collected at room temperature with an Enraf±Nonius
k-CCD diffractometer equipped with graphite monochromator
and Mo Ka radiation. The Denzo-SMN Software Package was
used for the unit-cell determination and reduction of the data
set. The structure was solved by direct methods and re®ned with
full-matrix least squares based on F, taking advantage of the
MaXus software package. The non-H atoms were re®ned aniso-
tropically whereas the H-atom positions were veri®ed from
Fourier electron density calculations and supplied with iso-
4. Cooke, A.; Bonnert, R.; Cage, P.; Donald, D.; Furber, M.; With-
nall, J. PCT Int. Appl., 169 pp. WO 9902528, 1999.
5. (a) Potts, K. T.; Hussain, S. J. Org. Chem. 1970, 35, 3451.
(b) Potts, K. T.; Hussain, S. J. Org. Chem. 1972, 37, 2049.
(c) Abu-El-Haj, Marwan J.; McFarland, J.W. U.S. 6 pp. U.S.
3,894,036, 1977. (d) Abu-El-Haj, Marwan J.; McFarland, James
W. U.S. 7 pp. US 3933843, 1976.
Ê 2
tropic thermal displacement factors, U(iso)ˆ0.05 A . No
absorption correction was applied.
9. All X-ray crystallographic data has been deposited with the
Cambridge Crystallographic Data Centre as deposition No.
CCDC-178446.
6. The preparation of tetrahydroquinaldic acids (5) is illustrated by
the following synthetic sequence: