1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one: Selected chemistry at the C-6, C-7 and C-8 positions

Article abstract of DOI:10.1039/c1ob05410d

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) reacts with tetracyanoethylene (TCNE) or tetracyanoethylene oxide (TCNEO) to give the deep green 2-[1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ylidene]propanedinitrile (11) in 17 and 15% yields, respectively. Nucleophiles such as amines, alkoxides, thiols and Grignard reagents all reacted with the 1,3-diphenylbenzotriazinone 6 regioselectively at C-6, while halogenating agents reacted exclusively at C-8. Furthermore, 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) undergoes palladium-catalysed Suzuki-Miyaura and Stille coupling reactions to give 8-aryl- or heteroaryl-substituted benzotriazinones. By combining both the C-6 and C-8 chemistries 1,3,6,8-tetraphenylbenzo[e][1,2,4]triazin-7(1H)-one (42) and 1,3-diphenyl-6,8-di(thien-2-yl)-benzo[e][1,2,4]triazin-7(1H)-one (43) can be prepared. All new compounds are fully characterized. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05410d

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 5228
www.rsc.org/obc
PAPER
1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one: Selected Chemistry at the C-6,
C-7 and C-8 Positions†
Panayiotis A. Koutentis,* Harry Krassos and Daniele Lo Re
Received 15th March 2011, Accepted 13th April 2011
DOI: 10.1039/c1ob05410d
1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) reacts with tetracyanoethylene (TCNE) or
tetracyanoethylene oxide (TCNEO) to give the deep green 2-[1,3-diphenylbenzo[e][1,2,4]triazin-
7(1H)-ylidene]propanedinitrile (11) in 17 and 15% yields, respectively. Nucleophiles such as amines,
alkoxides, thiols and Grignard reagents all reacted with the 1,3-diphenylbenzotriazinone 6
regioselectively at C-6, while halogenating agents reacted exclusively at C-8. Furthermore,
8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) undergoes palladium-catalysed
Suzuki–Miyaura and Stille coupling reactions to give 8-aryl- or heteroaryl-substituted
benzotriazinones. By combining both the C-6 and C-8 chemistries 1,3,6,8-tetraphenylbenzo[e]-
[1,2,4]triazin-7(1H)-one (42) and 1,3-diphenyl-6,8-di(thien-2-yl)-benzo[e][1,2,4]triazin-7(1H)-one (43)
can be prepared. All new compounds are fully characterized.
1. Introduction
1,2,4-Triazines are a well know class of heterocycle, several of
which are particularly important as agrochemicals.1 Commer-
cial herbicides include 4-amino-6-tert-butyl-3-(methylthio)-1,2,4-
R
triazin-5(4H)-one (1a) (Metribuzin or Sencorꢀ) and 4-amino-
3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one (1b) (Metamitron or
R
Goltixꢀ).2 Several benzo-fused 1,2,4-triazines also show inter-
esting properties: 4-hydroxy-1-oxido-1,2,4-benzotriazin-1-ium-3-
imine (2) (Tirapazamine) is a bioreductive prodrug which attacks
chemo- and radio-resistant hypoxic tumor cells.3 Furthermore,
1,2,4-benzotriazinyls are stable organic radicals (e.g., Blatter’s
radical 3),4 which display a range of magnetic behaviours,5
and were the inspiration behind the preparation of the unusual
zwitterionic biscyanine tetraphenylhexaazaanthracene 4 (TPHA)6
Fig. 1 Some 1,2,4-triazines that display either important biological
(Fig. 1). The synthesis and chemistry of 1,2,4-triazines and their
benzo derivatives has been extensively reviewed.7
and/or physical properties.
We recently developed a high yielding route to a poten-
tially useful 1,2,4-benzotriazine scaffold, 1,3-diphenylbenzo[e]-
[1,2,4]triazin-7(1H)-one (6) from readily available Blatter’s radical
3 or directly from an amidrazone precursor 5 via oxidation using
either MnO2 (20 equiv., 8 d) or KMnO4 (10 equiv., 3 d) in 68
and 82% yields, respectively.4c The benzotriazinone 6, which is a
deep purple in color [lmax(DCM) 544 nm (log e 3.82)], possesses a
quinonimine functionality that renders it redox active (Scheme 1).
Scheme 1 Oxidation of amidrazone 5 to give benzotriazinone 6.
Planar polycyclic quinones can intercalate DNA by binding
strongly between the base pairs through hydrogen bond and p
interactions.8 Several polycyclic quinonimines have interesting
anticancer9 and antibiotic activities.10 For example, Actinomycin
D (7), isolated from Streptomyces parvulus,9c is a strong antitumor
agent but has limited use due to side effects such as myelosuppres-
sion and cardiotoxicity; the synthetic 7-(benzylamino)-1,3,4,8-
tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (8, BA-TPQ) is
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678
Nicosia, Cyprus. E-mail: koutenti@ucy.ac.cy
† Electronic supplementary information (ESI) available: Experimental
procedures, analytical and spectroscopic data for all new compounds. 1H
and 13C NMR spectra of all new compounds, and computational data for
the benzotriazinone 6 are provided. See DOI: 10.1039/c1ob05410d
5228 | Org. Biomol. Chem., 2011, 9, 5228–5237
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
active against a variety of human cancer cell lines through multiple
mechanisms of action (inhibition of MDM2 oncoprotein, induc-
tion of DNA damage response, and induction of endoplasmic
reticulum stress).11 In addition, several polycyclic quinonimines
such as Endophenazine B (9) [lmax(MeOH) 516 nm (log e 3.89)],
isolated from Streptomyces anulatus12 and 10-phenylphenazin-
2(10H)-one (10, aposafranone),13 are highly colored. The latter
have been investigated as dyes and incorporated in organic
photovoltaic devices14 (Fig. 2).
Scheme 2 Important resonance forms of quinonimine 6.
which no stable product could be isolated. As such, alternative
strategies were followed that included treating the benzotriazinone
6 with other dicyanomethylene sources.18 Fortunately, a PhCl solu-
tion of benzotriazinone 6 treated with tetracyanoethylene (TCNE)
at ca. 140 ◦C gave the desired 2-[1,3-diphenylbenzo[e][1,2,4]triazin-
7(1H)-ylidene]propanedinitrile (11) in low yield (17%) (Scheme 3).
Scheme 3 Synthesis of the ylidenemalononitrile 11.
Recrystallisation of the ylidenemalononitrile 11 afforded dark
green plates mp 306–311 ◦C (CHCl3) that gave a deep blue-green
solution lmax(DCM) 702 nm (log e 3.08) supporting a highly
conjugated and possibly charge separated system. Attempts to
improve the yield of this reaction by using additional equivalents
of TCNE or prolonged reaction times led to a drop in yield.
Replacing TCNE for tetracyanoethylene oxide (TCNEO) led
to similar yields (15%). In light of these low yields, further
chemistry on the ylidenemalononitrile 11 was not considered
worthwhile. Nevertheless, the failure to condense malononitrile
onto the carbonyl at C-7 and the lack of any identifiable n(C O)
stretch in the IR spectrum of quinonimine 6 supported the strong
contribution of the charge separated resonance form. As such
it was unlikely that TCNE reacts with benzotriazinone via a
concerted 2 + 2 cycloaddition but rather the benzotriazinone 6
added to the highly electrophilic TCNE in a stepwise manner
to give first the zwitterion 12, which subsequently cyclises to
afford the spirocyclic oxetane 13 that eliminated unstable carbonyl
cyanide to give the ylidene 11 (Scheme 4).
Fig. 2 Selected natural and synthetic quinonimines.
In light of the above, we have been investigating the chemistry of
the readily accessible benzotriazinone 6 to determine its potential
as a new heterocyclic quinonimine scaffold. Below we report the
preparation of the highly colored ylidenemalononitrile and the
regioselective nucleophilic and electrophilic substitution reactions
of benzotriazinone 6 which occur at C-6 and C-8, respectively.
2. Results and discussion
Benzotriazinone 6 was first identified by Huisgen et al.,15 in 1969
as a minor byproduct during the preparation of 1,4-dihydro-
7-methoxy-1,3-diphenyl-1,2,4-benzotriazin-4-yl from diphenyl-
nitrilimine and 4-methoxyphenyliminotriphenylphosphorane.
Later, in 1980, Neugebauer et al.16 attempted a direct synthesis
of benzotriazinone 6 by treating 1,4-dihydro-1,3-diphenyl-1,2,4-
benzotriazinyl (3) (Blatter’s radical) with oxygen in the presence
of active charcoal. Both routes, however, were very low yielding,
preventing the study of this quinonimine. In light of our ability to
access benzotriazinone 6 in multigram quantities we proceeded to
study the chemistry of this potentially useful quinonimine.4c
2.1. Preparation of the (benzotriazinylidene)malononitrile 11
1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) has a deep pur-
ple color presumably owing to a strong contribution of a
zwitterionic resonance form (Scheme 2). In an attempt to build
a “chromophore” with a longer wavelength absorption possibly
extending into the near infrared we considered the synthesis of the
ylidenemalononitrile 11. Furthermore, ylidenemalononitriles are
also useful scaffolds for the preparation of a wide range of other
heteroarenes.17
However, all attempts to condense malononitrile with the benzo-
triazinone 6, led to complex highly colored reaction mixtures, from
Scheme 4 Plausible mechanism for the formation of the ylidenemalonon-
itrile 11.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5228–5237 | 5229
©

View Article Online
In addition, benzotriazinone 6 was reacted with PCl5 (1 equiv.)
in POCl3 at ca. 20 ◦C to give presumably the 7-chloro-1,3-
diphenylbenzo[e][1,2,4]triazin-1-ium in situ. Subsequent treatment
of this cation with aniline (3 equiv.) gave a deep blue compound
that gave a mass spectrum molecular ion peak of m/z 374 Da, po-
tentially corresponding to N-(1,3-diphenylbenzo[e][1,2,4]triazin-
7(1H)-ylidene)benzenamine. However, after chromatographic pu-
1
rification, the H NMR was complex, indicating mixtures that
could not be separated. This work remains on going.
2.2. Regioselective nucleophilic addition
Further chemistry of the benzotriazinone 6 was discovered when
an ethanolic solution of Blatter’s radical 3 treated with MnO2 gave
not only the expected benzotriazinone 6 (14%) but also a deep
red colored [lmax(DCM) 520 nm (log e 2.83)] ethoxy-substituted
1
benzotriazinone 14 in low yield (15%). H NMR spectroscopy
of the ethoxybenzotriazinone 14 identified two clear singlets at
dH 7.01 and 6.31 ppm that tentatively corresponded to the H-5
and H-8 hydrogens, respectively. These assignments were based on
the anticipated shielding effects of the N-1 phenyl which should
lead to H-8 appearing more up-field than H-519 and supported
the structure to be the 6-ethoxy-substituted benzotriazinone 14
and not the isomeric 5-ethoxy-substituted analogue. Additional
support for this tentative assignment came from a comparison of
the structurally related aposafranone 10 which suffers regioselec-
tive nucleophilic addition at C-3,10a and electrophilic substitution
at C-1 (Fig. 3).20 As such, we initiated the “semi-independent”
synthesis of the red 6-ethoxybenzotriazinone 14 followed by a
broader investigation of regioselective nucleophilic substitution
involving N, S and C nucleophiles.
Scheme 5 Preparation of 6-ethoxybenzotriazinone 14.
and phenyl mercaptans reacted readily with the benzotriazinone
6 to give the corresponding 6-substituted analogues 16–18 (Table
1, entries 3–5). A wide range of nitrogen and carbon nucleophiles
could also be introduced with ease (Table 1). Monoalkyl
amino derivative 6-ethylaminobenzotriazinone 20 (entry 7), was
obtained in good yield (72%) using excess 2 N ethylamine in
THF heated to reflux, while 6-anilinobenzotriazinone 21 (entry
8) was prepared in 67% yield using aniline (1.5 equiv.) in the
presence of Hu¨nig’s base (1.5 equiv.) in EtOH heated to reflux.
In both cases the products could be isolated without the need for
chromatography. Several 6-dialkylamino- or 6-alkylarylamino-
substituted benzotriazinones 23–27 were prepared in high yields
(81–99%) using neat amine as solvent (entries 10–14). However,
secondary dialkylamines that are more costly can also be used
in less quantity (2 equiv.) using THF as solvent (entry 9).
More interestingly, powerful carbon nucleophiles as phenyl- and
thien-2-ylmagnesium bromide (entries 15 and 16) also gave the
6-phenyl and 6-thien-2-yl benzotriazinones 28 and 29 in 82 and
63% yields, respectively (Table 1). Both 1,2- and 1,4-additions
of Grignards to 1,4-quinones are known,21 but the high isolated
yields of 6-substituted benzotriazinones further supported the
hypothesis of a strong contribution of the charge separated
resonance form.
The regioselectivity observed was not altogether surprising,
although the C-5, C-6 and C-8 positions are all b to either imine
or carbonyl functionality, making them potentially active towards
nucleophilic attack. However, attack at C-5 would leave an anion
that was stabilized only by the carbonyl oxygen while attack at
either C-6 or C-8 left intermediates that had the anion doubly
stabilized by both the triazine nitrogens N-2 and N-4. The C-6
position was preferred over the C-8 since the latter was strongly
influenced by the electron releasing enamine-like triazine nitrogen
N-1 and was more sterically crowded owing to the N-1 phenyl
substituent (Scheme 6). The regioselectivity was also supported by
computational studies (see the ESI†) which indicated the LUMO
of the benzotriazinone 6 had considerable orbital density at C-6.
Fig. 3 Regioselectivity of aposafranone 10.
Treating benzotriazinone 6 with 2 N EtONa (2 equiv.) in EtOH
at ca. 20 ◦C or at ca. 78 ◦C gave only intractable material
(baseline on TLC); however, treatment in EtOH with Hu¨nig’s
base (20 equiv.) at ca. 78 ◦C gave 6-ethoxybenzotriazinone
14 in moderate yield (44%) identical to that described above.
The compound can also be prepared in somewhat higher yield
via a two-step synthesis. Treating benzotriazinone 6 with KOH
(3 equiv.) in THF/H2O (4 : 1) at ca. 90 ◦C for 18 h gave 6-hydroxy-
1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (15), in good yield
(92%) without the need for chromatographic isolation. Subsequent
O-ethylation using EtI (4 equiv.) and Hu¨nig’s base (8 equiv.) in
refluxing MeCN for 2 d gave the identical 6-ethoxybenzotriazinone
14 in 71% yield (Scheme 5).
In light of the observed regioselectivity, additional
nucleophiles were investigated: attempts to prepare the
6-phenoxybenzotriazinone
failed
since
treatment
of
benzotriazinone 6 with PhONa (1 equiv.) or PhOH/NaH (5 equiv.)
in THF gave only an intractable baseline material. Alkyl, benzyl
5230 | Org. Biomol. Chem., 2011, 9, 5228–5237
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 Regioselective nucleophilic addition reactions of benzotriazinone 6
Entry
NuH (equiv.)
i-Pr2NEt (equiv.)
Solvent
Temp. (◦C)
Time (h)
Yields (%)
1
2
3
4
5
6
7
8
EtOH
KOH (3)
i-BuSH (3)
BnSH (3)
PhSH (3)
NH3(g)
EtNH2 (20)
PhNH2 (1.5)
4-Ph-piperazine (2)
PhNHMe
N-Me-cyclohexylamine
Piperidine
1,2,3,4-Tetrahydroisoquinoline
4-Me-piperazine
PhMgBr (4)
20
—
1.1
1.1
1.1
—
—
1.5
—
—
—
—
—
—
—
—
EtOH
THF/H2O 4 : 1
THF
78
90
20
20
78
120
20
78
20
80
20
20
50
50
20
20
48
18
0.50
0.30
0.50
12
2
12
9
72
14 (44)
15 (92)
16 (91)
17 (83)
18 (100)
19 (64)
20 (72)
21 (67)
22 (91)
23 (93)
24 (87)
25 (99)
26 (81)
27 (84)
28 (82)
29 (63)
THF
EtOH
DMF
THF
EtOH
THF
neat
neat
neat
neat
neat
THF
9
10
11
12
13
14
15
16
20
0.17
0.50
0.25
12
Thien-2-ylMgBr (4)
THF
18
Table 2 C-8 Halogenation of benzotriazinone 6 in DCM at RT
Scheme 6 Resonance structures supporting the regioselective addition of
nucleophiles to C-6.
It is worth noting that the “substitution” at C-6 is in reality
an addition reaction and that oxidation is needed to transform
the adduct back into the quinonimine form via a formal loss
of hydride. Presumably this step is catalysed by oxygen present
in the reaction mixture. Attempts to carry out the reaction of
benzotriazinone 6 with piperidine in either dry deoxygenated
THF under an argon atmosphere or in non-deoxygenated
THF under air atmosphere at ca. 20 ◦C gave the expected 6-
piperidinobenzotriazinone 25 rapidly (3 h) and in high yield (93%),
which indicated that either the oxidation step was very facile and
required only traces of molecular oxygen or that another species
present in the reaction mixture was responsible for the oxidation.
Another interesting feature of substitution at C-6 was the blue
shifts observed in the UV/vis spectra on introducing strongly
donating amino or oxy groups. The lmax of benzotriazinone 6
shifted from 544 nm to 430–504 nm on introduction of an amino
group at C-6 and to 508–520 nm on introduction of hydroxyl or
ethoxy groups, as such all these compounds were colored deep
red. Introduction of alkyl or aryl thiols or phenyl and thien-2-
yl substituents led to a red shift in the UV/vis spectra and the
compounds were either deep purple or brown in color. Presumably,
the electron releasing groups undermined the contribution of the
charge separated zwitterionic resonance form.
Entry R1
Reagent (equiv.)
Time (h) Hal
Yields (%)
1
2
3
4
5
6
H
H
H
H
Ph
NCS(1.1)
NBS(5)
Br2 (2)
NIS (5)
NIS (5)
12
12
0.5
12
12
12
Cl
Br
Br
I
30 (99)
31 (100)
31 (100)
32 (100)
33 (76)
34 (67)
I
I
Thien-2-yl NIS (5)
manner.20 Reaction of benzotriazinone 6 with different sources
of electrophiles such NIS, NBS, Br2 and NCS in DCM at
ca. 20 ◦C afforded the desired 8-halobenzotriazinones 30–32 in
quantitative yields (Table 2, entries 1–4). In addition, regioselective
halogenation of 6-substituted benzotriazinones also occurred in
good yield (Table 2, entries 5 and 6).
The selectivity of substitution at C-8 was supported by the loss
of the up-field H-8 signal in the 1H NMR spectrum. Interestingly,
halogenation at C-8 also led to significant red shifts in the UV/vis
spectroscopy affording in all cases deep blue colored products
(568–602 nm). Furthermore, understanding the regioselectivity of
the electrophilic substitution was less complex than that of the
nucleophilic substitution since the C-8 position was enamine-like
with respect to the N-1 position. The triazine N-1 nitrogen releases
electrondensity toboth the C-8 andthe carbonyl oxygen. However,
only substitution at C-8 readily provides the opportunity for the
loss of the C-8 proton to neutralize the intermediate triazinium
cation (Scheme 7). The rationale is presumably very similar to
2.3. Electrophilic regioselective substitution and Pd coupling on
C-8
Aposafranone chemistry suggests that the benzotriazinone 6
should also react with electrophiles in a very regioselective
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5228–5237 | 5231
©

View Article Online
reaction: treating 8-bromobenzotriazinone 31 with tributyl(furan-
◦
2-yl)stannane (3 equiv.) and Pd(OAc)2 (15%) in DMF at 100 C
for 24 h gave no reaction and the starting 8-bromobenzotriazinone
31 was completely recovered, while under the same conditions,
8-iodobenzotriazinone 32 gave the desired 8-(furan-2-yl)-1,3-
diphenylbenzo[e][1,2,4]triazin-7(1H)-one (39) in 71% yield. In a
similar manner, the 8-(thien-2-yl)- and 8-vinylbenzotriazinones 40
and 41 were obtained in 79 and 51% yields, respectively. Suzuki
and Stille couplings were also successfully achieved on the 6-
substituted benzotriazinones 30 and 31 obtaining 1,3,6,8-tetraaryl
analogues 42 and 43 (entries 7 and 8).
Scheme 7 Rationale for regioselective addition of electrophiles at C-8.
that which governs the analogous electrophilic substitution of
aposafranones at C-1. The regioselectivity was also supported by
computational studies (see the ESI†) which indicated the HOMO
of the benzotriazinone 6 had considerable orbital density at C-8.
With a good leaving group at C-8 we then investigated the
reactivity of the 8-bromo- and 8-iodobenzotriazinones 31 and
32 towards nucleophiles (Table 3). In all cases (entries 1–3)
substitution occurred regioselectively at C-6 and displacement of
the halogen at C-8 was not observed. Nevertheless, the reactions
between the 8-iodobenzotriazinone 32 and the Grignard reagents
(entries 1 and 2) gave slightly more complex reactions and the
desired product can be obtained only in low to moderate yields,
while the reaction with 8-bromobenzotriazinone 31 with the
‘softer’ pyrrolidine nucleophile gave the desired compound 35 in
good yield (entry 3).
These 1,3,6,8-tetraarylbenzotriazinones 42 and 43 could al-
ternatively be prepared from the 8-arylbenzotriazinones via C-6
nucleophilic substitution (Scheme 8).
Despite the preference of nucleophiles to react regioselectively
at C-6 even in the presence of a potentially reactive halo-
gen at C-8, we considered arylation of the C-8 position by
involving Suzuki–Miyaura or Stille coupling chemistry (Table
4). The Suzuki–Miyaura reaction of 8-chlorobenzotriazinone
30 [Pd(dppf)Cl2·DCM (10 mol%), PhB(OH)2 (2 equiv.),
K2CO3 (2 equiv.) dioxane/water 3 : 1, at reflux] gave no
reaction while 8-bromobenzotriazinone 31 only gave 1,3,8-
triphenylbenzo[e][1,2,4]triazin-7(1H)-one (36) in a moderate yield
(51%) and with a considerable amount (34%) of unreacted
bromobenzotriazinone 31. Fortunately, 8-iodobenzotriazinone 32
under similar conditions gave 1,3,8-triphenylbenzotriazinonone
36 in 78% yield (Table 4, entry 1). In a similar manner, 8-
(4-chlorophenyl)- and 8-(3-methoxyphenyl)benzotriazinones 37
and 38 could be prepared in 91 and 96% yield, respectively.
Unfortunately, the use of either 2-bromophenyl- or 2-chloro-
4-(trifluoromethyl)-phenylboronic acids gave only protodehalo-
genated benzotriazinone 6 probably due to steric hindrance.
Similar reactivities were also observed with the Stille coupling
Scheme 8 1,3,6,8-Tetraarylbenzotriazinones via C-6 Substitution Reac-
tions with Aryl Grignards.
With this result in hand there were now three available routes to
the 1,3,6,8-tetraphenylbenzotriazinone 42: Route 1) C-6 Grignard
mediated phenylation followed by C-8 electrophilic iodination and
subsequent Suzuki–Miyaura reaction with phenylboronic acid
to give in 3 steps the 1,3,6,8-tetraphenylbenzotriazinone 42 in
an overall yield of 48%; Route 2) C-8 electrophilic iodination,
followed by Suzuki–Miyaura C-8 arylation and subsequent C-6
Grignard mediated phenylation to give in 3 steps the tetrasubsti-
tuted benzotriazinone 42 in a 62% overall yield; and finally, Route
3) C-8 electrophilic iodination, followed by Grignard mediated
C-6 phenylation and finally Suzuki–Miyaura C-8 arylation that
provided benzotriazinone 42 in the overall lowest yield of 17%.
Similar overall yields were obtained for the 1,3-diphenyl-6,8-
dithien-2-ylbenzotriazinone 43, supporting Route 2 as the most
efficient for the preparation of tetraarylbenzotriazinones.
Table 3 Nucleophilic addition reactions of 8-halobenzotriaziones 31
(Hal = Br) and 32 (Hal = I) at RT
3. Conclusions
1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) on heating with
TCNE affords the ylidinemalononitrile 11 in low yield. Fur-
thermore, benzotriazinone 6 readily undergoes high yielding and
regioselective nucleophilic substitution at C-6 and electrophilic
halogenations at C-8. 8-Iodobenzotriazinones participate in both
Suzuki–Miyaura and Stille coupling reactions to give 1,3,8-
triarylbenzotriazinones. By combining the above chemistries,
1,3,6,8-tetraarylbenzotriazinones can also be prepared. The above
demonstrated the versatility of benzotriazinone 6 as a useful
heterocyclic scaffold that can be used for the preparation of
small libraries of potentially biological active quinonimines. The
biological activity of these new benzotriazinones will be reported
in the near future.
Entry Hal Conditions
R1
Yields (%)
1
2
I
I
PhMgBr (4 equiv.) THF, 18 h Ph
(Thien-2-yl)MgBr (4 equiv.), Thien-2-yl
THF, 18 h
33 (22)
34 (49)
3
Br
Pyrrolidine (2 equiv.) DCM, Pyrrolidinyl
36 h
35 (74)
5232 | Org. Biomol. Chem., 2011, 9, 5228–5237
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 4 Suzuki–Miyaura [Pd(dppf)Cl2·DCM (10 mol %), K2CO3 (2 equiv.), ArB(OH)2 (2 equiv.), dioxane/water 3 : 1, ca. 90 ◦C] and Stille [ArSnBu3
(3 equiv.), Pd(OAc)2 (15 mol %), DMF, ca. 100 ◦C, Ar atmosphere] C–C coupling reactions of 8-iodobenzotriaziones 32–34
Entry
R1
Reaction type
Reagent
Time (h)
R2
Yields (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
Suzuki
Suzuki
Suzuki
Stille
Stille
Stille
PhB(OH)2
2.5
1.5
1
21
25
24
2.5
15
Ph
36 (78)
37 (91)
38 (96)
39 (71)
40 (79)
41 (51)
42 (77)
43 (81)
4-ClC6H4B(OH)2
3-MeOC6H4B(OH)2
Fur-2-ylSnBu3
Thien-2-ylSnBu3
VinylSnBu3
PhB(OH)2
Thien-2-ylSnBu3
4-ClC6H4
3-MeOC6H4
Fur-2-yl
Thien-2-yl
Vinyl
Ph
Thien-2-yl
Ph
Thien-2-yl
Suzuki
Stille
to afford the title compound 11 (6 mg, 17%) as green plates, mp
306–311 ◦C (from CHCl3), Rf 0.61 (t-BuOMe/hexane, 3 : 1);
(found: C, 75.9; H, 3.7; N, 20.1. C22H13N5 requires C, 76.1; H, 3.8;
N, 20.2%); lmax(DCM)/nm 277 (log e 3.06), 345 inf (3.24), 360
(3.37), 377 (3.42), 421 (2.98), 610 inf (2.90), 647 (3.04), 702 (3.08),
774 inf (2.84); vmax/cm-1 3063w (Ar CH), 2203 m (C N), 1612w,
1551w, 1508 s, 1489w, 1472w, 1454w, 1449w, 1427w, 1402w, 1377
m, 1364w, 1341w, 1306 m, 1267 m, 1227w, 1207w, 1188w, 1153w,
1136w, 1069w, 1028w, 1003w, 983w, 989w, 924w, 887w, 860w, 841
m, 833w 816w, 800w, 781w; dH(300 MHz, CDCl3) 8.28–8.25 (2H,
m, Ar H), 7.94 (1H, d, J 9.5, 1.9, H-6), 7.72–7.59 (6H, m, Ar H),
7.52–7.46 (3H, m, Ar H), 6.59 (1H, d, J 2.0, H-8); dH(125 MHz;
CDCl3) 156.5 (s), 154.1 (s), 153.1 (s), 140.7 (s), 137.8 (d), 134.7
(s), 133.3 (s), 131.5 (d), 131.2 (d), 130.6 (d), 130.6, (d), 129.1 (d),
127.2 (d), 125.4 (d), 116.1 (s), 116.0 (s), 95.1 (d); m/z (EI) 348
(M+ + 1, 26%), 347 (M+, 100), 319 (3), 244 (4), 215 (6), 188 (3),
4. Experimental
4.1. General procedures
Acetonitrile was distilled over CaH2 and THF was distilled over
Na before use. Reactions were protected by CaCl2 drying tubes.
Anhydrous Na2SO4 was used for drying organic extracts and
all volatiles were removed under reduced pressure. All reaction
mixtures and column eluents were monitored by TLC using
commercial glass backed thin layer chromatography (TLC) plates
(Kieselgel 60 F254). The plates were observed under UV light at 254
and 365 nm. The technique of dry flash chromatography was used
throughout for all non-TLC scale chromatographic separations
using silica gel 60 (less than 0.063 mm). Melting points were
determined using a hot stage microscope apparatus. Solvents
used for recrystallization are indicated after the melting point.
Inflections in the UV spectra are identified by the abbreviation
“inf”. FTIR spectra were recorded using a Ge ATR accessory
and strong, medium and weak peaks are represented by s, m
and w respectively. 1H NMR spectra were recorded at either 300
or 500 MHz and 13C NMR spectra were recorded at either 75
and 125 MHz, respectively. DEPT 135 NMR studies identified
quaternary and tertiary carbons, which are indicated by (s) and
(d) notations, respectively. Deuterated solvents were used for
homonuclear lock and the signals are referenced to the deuterated
solvent peaks. Low resolution (EI) mass spectra were recorded on
a GCMS with direct inlet probe.
+
139 (16), 112 (11), 103 (6), 91 (6), 77 (C5H5 , 41), 51 (21).
4.3. C-6 substituted benzotriazinones
4.3.1. 6 - Hydroxy - 1,3 - diphenylbenzo[e][1,2,4]triazin - 7(1H) -
one (15). To a stirred solution of 1,3-diphenylbenzo[e][1,2,4]-
triazin-7(1H)-one (6) (29.9 mg, 0.1 mmol) in THF/H2O (4 : 1)
(1 ml), KOH (16.8 mg, 0.3 mmol) was added and the reaction
mixture was heated at 90 ◦C for 18 h. TLC (t-BuOMe) showed
the absence of the starting material and the presence of a very
polar red compound. Conc. HCl was added (51 ml, 0.61 mmol),
followed by an excess of hexane (10 ml) and the precipitate that
formed was filtered, washed (water) and recrystallized to afford
the title compound 15 (28.9 mg, 92%) as light red plates, mp 250–
255 ◦C (from PhH), Rf 0.74 (DCM/MeOH, 5 : 1); (found: C, 72.3;
H, 4.1; N, 13.4. C19H13N3O2 requires C, 72.4; H, 4.2; N, 13.3%);
4.2. Preparation of (benzotriazinylidene)malononitrile
4.2.1. 2-(1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-ylidene)pro-
panedinitrile (11). To
a stirred solution of 1,3-diphenyl-
benzo[e][1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol) in PhCl
(1 ml), TCNE (23 mg, 0.18 mmol) was added and the mixture
heated to ca. 140 ◦C for 18 h. TLC (t-BuOMe/hexane, 2 : 1)
showed the absence of the starting material and the presence of a
new less polar green product. The mixture was diluted with THF
(2 ml) and cooled until ca. 0 ◦C. The precipitate was filtered and
dissolved in DCM (5 ml). To this solution was added silica gel
(100 mg) and the mixture stirred for 10 min and then filtered.
The solvent was evaporated in vacuo and the residue crystallized
l
max(DCM)/nm 251 (log e 3.41), 309 (3.72), 366 inf (2.91), 386 inf
(2.83), 508 (2.82); nmax/cm-1 3161w (OH), 1580 s, 1555 s, 1495 m,
1470 m, 1404 m, 1385 s, 1364 m, 1314 s, 1290 m, 1261w, 1229 m,
1190 m, 1163 m, 1070w, 1026w, 1003w, 984w, 928w, 854 m, 818w,
781 m, 750w, 717m; dH(300 MHz; TFA-d1) OH peak missing 8.32
(2H, d, J 7.7, Ar H), 7.83–7.61 (7H, m, Ar H), 7.53 (2H, dd, J 7.5,
7.5, Ar H), 7.19 (1H, m, Ar H); dC(75 MHz; TFA-d1) 167.1 (Ar
C
O), 161.5 (s), 158.7 (s), 148.5 (s), 142.2 (s), 140.1 (s), 135.4 (d),
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5228–5237 | 5233
©

View Article Online
134.3 (d), 131.7 (d), 130.9 (s), 130.7 (d), 129.3 (d), 126.3 (d), 108.1
(d), 100.2 (d); m/z (EI) 316 (M+ + 1, 24%), 315 (M+, 100), 298 (4),
287 (26), 277 (6), 258 (2), 184 (13), 155 (9), 144 (17), 128 (10), 117
(8), 104 (12), 89 (5), 77 (62), 51 (33).
4.3.4. 6-Amino-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one
(19). To a stirred solution of 1,3-diphenylbenzo[e][1,2,4]triazin-
7(1H)-one (6) (30 mg, 0.1 mmol) in DMF (2 ml) at ca. 120 C,
◦
a steady stream of NH3 (g) was passed through for 6 h. After
an additional 6 h at ca. 120 ◦C TLC (t-BuOMe) showed the
disappearance of the starting material. The mixture was allowed
to cool to ca. 20 ◦C, diluted with DCM (20 ml) and washed with
H2O (15 ml). The organic layer was separated, dried (Na2SO4)
and adsorbed onto silica. Dry flash chromatography (t-BuOMe)
gave the title compound 19 (20 mg, 64%) as a light orange needles,
mp 279–282 ◦C (from PhH); Rf 0.21 (t-BuOMe/hexane, 3 : 1);
(found: C, 72.7; H, 4.4; N, 17.9. C19H14N4O requires C, 72.6; H,
4.5; N, 17.8%); lmax(DCM)/nm 274 (log e 3.49), 302 inf (3.46),
312 (3.48), 332 inf (3.29), 401 inf (3.25), 417 (3.30), 504 (2.60);
4.3.2. 6-Ethoxy-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one
(14) (Method 1). To a stirred solution of 1,3-diphenylbenzo-
[e][1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol) in EtOH (1 ml),
Hu¨nig’s base (342 ml, 2 mmol) was added, and the reaction mixture
was heated at reflux for 48 h. TLC (t-BuOMe) showed the absence
of the starting material and the presence of a new red compound.
The mixture was diluted with DCM (8 ml) and adsorbed onto silica
gel. Dry flash chromatography (t-BuOMe) gave the title compound
14 (15 mg, 44%) as red needles, mp 212–214 ◦C (from PhH), Rf 0.29
(t-BuOMe); (found: C, 73.6; H, 4.9; N, 12.2. C21H17N3O2 requires
C, 73.5; H, 5.0; N, 12.2%); lmax(DCM)/nm 246 (log e 3.39), 311
(3.72), 363 inf (3.03), 381 inf (2.77), 520 (2.83); nmax/cm-1 3107w,
3061w and 3036w (Ar CH), 2990w, 1607 s, 1591 m, 1560 s, 1516 m,
1493 m, 1458w, 1447w, 1408w, 1393w, 1379w, 1352w, 1314w, 1281
m, 1256 m, 1242 m, 1227w, 1206w, 1196w, 1155w, 1136w, 1107w,
1084w, 1067w, 1024 m, 986w, 970w, 926w, 901w, 866w, 849 m,
824m; dH(300 MHz; CDCl3) 8.32–8.29 (2H, m, Ar H), 7.62–7.57
(4H, m, Ar H), 7.51–7.48 (4H, m, Ar H), 7.01 (1H, s, H-5), 6.31
(1H, s, H-8), 4.34 (2H, q, J 6.8, OCH2), 1.62 (3H, t, J 7.0, CH3);
dC(75 MHz; CDCl3) 175.3 (C O), 163.4 (s), 155.3 (s), 151.4 (s),
141.5 (s), 135.2 (s), 134.6 (s), 130.6 (d), 130.2 (d), 130.1 (d), 128.9
(d), 126.9 (d), 125.9 (d), 104.6 (d), 97.3 (d), 65.9 (OCH2), 14.3
(CH3); m/z (EI) 344 (M+ + 1, 10%), 343 (M+, 31), 328 (100), 314
(9), 300 (48), 271 (7), 195 (3), 184 (2), 168 (11), 155 (8), 144 (12),
128 (5), 116 (10), 103 (9), 89 (7), 77 (72), 57 (12), 51 (22).
n
max/cm-1 3416w (Ar NH), 3283w, 3221br w, 3154br w (Ar CH),
1639w, 1581 m, 1566 m, 1555 s, 1541 s, 1491 m, 1449w, 1422w,
1391w, 1360w, 1312w, 1292w, 1275w, 1231w, 1190w, 1173w, 1098w,
1067w, 1026w, 1003w, 980w, 916w, 854w, 835w,m, 824 m, 812w;
dH(300 MHz; TFA-d1) NH peak missing 8.09 (2H, d, J 7.6, Ar H),
7.78–7.64 (7H, m, Ar H), 7.58–7.48 (3H, m, Ar H); dC(75 MHz;
TFA-d1) 161.8 (C O), 158.9 (s), 154.1 (s), 143.7 (s), 142.0 (s),
141.2 (s), 136.8 (d), 134.9 (d), 131.9 (d), 131.4 (d), 129.5 (d), 127.8
(s), 126.5 (d), 101.8 (d), 99.0 (d); m/z (EI) 315 (M+ + 1, 23%), 314
(M+, 100), 297 (3), 286 (12), 183 (9), 155 (9), 143 (7), 116 (8), 104
(13), 89 (7), 77 (100), 67 (9), 63 (5), 51 (61).
4.3.5. 6-(Ethylamino)-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-
one (20). To
a stirred solution of 1,3-diphenylbenzo[e]-
[1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol) in EtNH2 2 M in
THF (1 ml, 20 mmol) was added and the mixture was stirred at
ca. 20 ◦C for 2 h. The solution was cooled to ca. 0 ◦C and filtered
to afford the title compound 20 (24.8 mg, 72%) as orange plates,
mp 297–301 ◦C (from PhH), Rf 0.69 (t-BuOMe); (found: C, 73.6;
H, 5.4; N, 16.2. C21H18N4O requires C, 73.7; H, 5.3; N, 16.4%);
4.3.3. 6-(Isobutylthio)-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-
one (16) (typical procedure). To a stirred solution of 1,3-
diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol)
in THF (1 ml), 2-methylpropane-1-thiol (32 ml, 0.3 mmol)
and Hu¨nig’s base (19 ml, 0.11 mmol) were added. The mixture
was stirred at ca. 20 ◦C for 30 min. TLC (t-BuOMe) showed
the absence of the starting material and the presence of a less
polar brown compound. The mixture was diluted with DCM
(5 ml) and adsorbed onto silica gel. Dry flash chromatography
(t-BuOMe/hexane, 1 : 2) of the residue gave the title compound
16 (35.3 mg, 91%) as brown needles, mp 205–209 ◦C (from
DCM/MeOH, 1 : 2); Rf 0.76 (t-BuOMe/hexane, 3 : 1); (found: C,
71.2; H, 5.3; N, 10.7. C23H21N3OS requires C, 71.3; H, 5.5; N,
10.8%); lmax(DCM)/nm 267 (log e 3.23), 324 (3.37), 341 inf (3.26),
425 (3.15), 519 inf (2.50), 550 (2.55), 603 inf (2.27); nmax/cm-1
2955w, 2922w, 2855w, 1580 s, 1522 s, 1508 s, 1493 m, 1452w,
1429w, 1371w, 1339w, 1314 m, 1287w, 1215w, 1198w, 1171w,
1144w, 1069w, 1024w, 1009 m, 928w, 847 m, 812w; dH(300 MHz,
CDCl3) 8.29–8.26 (2H, m, Ar H), 7.63–7.55 (5H, m, Ar H),
7.47–7.45 (3H, m, Ar H), 7.36 (1H, s, H-5), 6.15 (1H, s, H-8),
2.88 (2H, d, J 6.5, SCH2), 2.13 (1H, hept, J 6.8, CHMe2), 1.16
[6H, d, J 6.8, CH(CH3)2]; dC(75 MHz, CDCl3) 177.4 (C O),
160.5 (s), 151.8 (s), 151.5 (s), 141.5 (s), 136.1 (s), 134.5 (s), 130.6
(d), 130.3 (d), 130.1 (d), 128.9 (d), 126.9 (d), 125.9 (d), 119.9 (d),
95.7 (d), 39.9 (SCH2), 27.6 (CH), 22.6 (2 ¥ CH3); m/z (EI) 387
(M+, 13%), 372 (10), 354 (100), 344 (92), 331 (52), 313 (10), 303
(16), 299 (5), 200 (6), 180 (9), 168 (8), 160 (6), 116 (16), 103 (6), 94
(11), 77 (71), 69 (6), 51 (15).
l
max(DCM)/nm 280 inf (log e 3.44), 287 (3.46), 301 (3.45), 311
inf (3.41), 336 inf (3.06), 352 inf (2.94), 412 inf (3.29), 430 (3.39);
max/cm-1 3240br w (NH), 2980w, 2864w, 1562w, 1547 s, 1518w,
n
1489 m, 1477 m, 1449w, 1383w, 1354w, 1312 m, 1298w, 1271w,
1200w, 1171w, 1134w, 1070w, 1051w, 1024w, 989w, 924w, 866w,
843w, 816w, 806w, 779w; dH(300 MHz; TFA-d1) NH peak missing
7.99 (2H, d, J 8.0, Ar H), 7.70–7.56 (6H, m, Ar H), 7.52–7.47
(2H, m, Ar H), 7.24 (1H, s, H-5 or 8), 6.96 (1H, s, H-5 or 8),
3.75 (2H, q, J 7.1, NCH2), 1.40 (3H, t, J 7.1, CH3); dC(75 MHz;
TFA-d1) 155.8 (C O), 153.4 (s), 144.1 (s), 144.1 (s), 142.0 (s),
141.0 (s), 136.7 (d), 134.7 (d), 132.0 (d), 131.4 (d), 129.4 (d), 127.9
(s), 126.5 (d), 100.9 (d), 95.2 (d), 42.4 (NCH2), 13.1 (CH3); m/z
(EI) 343 (M+ + 1, 24%), 342 (M+, 100), 327 (26), 300 (17), 284 (4),
271 (5), 197 (4), 180 (8), 134 (11), 118 (7), 104 (10), 89 (5), 77 (60),
64 (7), 51 (17).
4.3.6. 1,3,6-Triphenylbenzo[e][1,2,4]triazin-7(1H)-one
(28)
(typical procedure). To a stirred solution of 1,3-diphenylbenzo[e]-
[1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol) in dry THF (0.6 ml)
at ca. 20 ◦C under an Ar atmosphere, PhMgBr 1 M in THF
(0.4 ml, 0.4 mmol) was added and the mixture was stirred for
12 h. TLC (t-BuOMe/hexane, 3 : 1) showed the absence of the
starting material and the presence of a new less polar purple
product. The mixture was diluted with MeOH (1 ml) and stirred
for 10 min. Dry flash chromatography (t-BuOMe) gave the title
◦
compound 28 (30.8 mg, 82%) as purple needles, mp 262–265 C
5234 | Org. Biomol. Chem., 2011, 9, 5228–5237
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(from DCM/MeOH, 1 : 3), Rf 0.60 (t-BuOMe/hexane, 3 : 1);
(found: C, 79.9; H, 4.4; N, 11.1. C25H17N3O requires C, 80.0; H,
4.6; N, 11.2%); lmax(DCM)/nm 253 (log e 3.39), 272 inf (3.32),
327 (3.56), 405 inf (2.73), 568 (2.72), 617 inf (2.54); vmax/cm-1
3061w (Ar CH), 1611w, 1601w, 1585 m, 1541 s, 1520 s, 1489 m,
1456w, 1439w, 1396w, 1373w, 1344w, 1314 m, 1281w, 1267w, 1202
m, 1179w, 1169w, 1157w, 1136w, 1078w, 1067w, 1028w, 1001w,
989w, 930w, 916w, 905w, 849 m, 839 m, 829 m, 785 m, 777 m,
762s; dH(300 MHz; CDCl3) 8.30–8.27 (2H, m, Ar H), 7.84 (1H,
s, H-5 or 8), 7.78–7.75 (2H, m, Ar H), 7.63–7.57 (5H, m, Ar H),
7.48–7.47 (6H, m, Ar H), 6.23 (1H, s, H-5 or 8); dC(75 MHz;
CDCl3) 180.7 (C O), 155.1 (s), 151.6 (s), 151.1 (s), 141.3 (s),
136.1 (s), 135.7 (s), 134.2 (s), 130.6 (d), 130.2 (d), 130.2 (d), 129.8
(d), 129.7 (d), 128.9 (d), 128.4 (d), 126.8 (d), 125.8 (d), 98.4 (d);
m/z (EI) 376 (M+ + 1, 19%), 375 (M+, 72), 374 (M+-1, 100), 347
(4), 270 (9), 243 (8), 188 (4), 166 (7), 139 (14), 103 (3), 89 (7), 77
(42), 63 (4), 51 (13).
m, 1584 m (Ar C-C), 1564 s, 1531 s, 1495 m, 1468 m, 1454 m,
1443w, 1404 m, 1371 m, 1302 s, 1290 m, 1256w, 1225w, 1200w,
1171w, 1157w, 1119w, 1107w, 1092w, 1069w, 1026w, 993w, 937 m,
922w, 905w, 883w, 856w, 843w, 816 m, 782w, 768m; dH(300 MHz;
CDCl3) 8.27≥8.24 (2H, m, Ph CH), 7.50≥7.42 (8H, m, Ph CH),
6.57 (1H, s, Ph CH), 4.335 (2H, s, CH2), 3.533 (2H, s, CH2), 2.00
(4H, s, CH2); dC(75 MHz; CDCl3) 172.0 (C O), 153.1, 152.05,
150.6, 144.2, 135.2, 133.8, 130.5 (d), 129.25 (d), 129.2 (d), 128.9
(d), 127.4 (d), 126.8, 100.15, 27.3 (CH2); m/z (EI) 448 (M++1,
55), 447 (M+, 14), 446 (M+ + 1, 57), 393 (4), 367 (M+ + Br, 4), 339
(M+-C2H4Br, 20), 298 (M+ - C4H8NBr, 4), 238 (13), 180 (7), 167
(5), 152 (5), 140 (7), 116 (7), 103 (12), 91 (13), 77 (100), 70 (12).
4.5.2. 8-Iodo-1,3,6-triphenylbenzo[e][1,2,4]triazin-7(1H)-one
(33) (typical procedure). To a stirred solution of 8-iodo-1,3-
diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) (42.5 mg, 0.1 mmol)
in dry THF (0.6 ml) at ca. 20 ◦C in Ar atmosphere, PhMgBr 1 M
in THF (0.4 ml, 0.4 mmol) was added and the mixture was stirred
for 18 h. TLC (t-BuOMe/hexane, 1 : 1) showed the absence of
the starting material and the presence of a new less polar blue
product. The mixture was diluted with MeOH (1 ml), stirred for
10 min, adsorbed onto silica gel and dry flash chromatography
(EtOAc/hexane, 1 : 2) gave the title compound 33 (11 mg, 22%)
4.4. Halogenation at C-8 using NXS
4.4.1. 8-Chloro-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one
(30) (typical procedure). To a solution of 1,3-diphenylbenzo[e]-
[1,2,4]triazin-7(1H)-one (6) (30 mg, 0.1 mmol) in dry DCM (2 ml),
NCS (15 mg, 0.11 mmol) was added. The mixture was stirred at
ca. 20 ◦C for 12 h or until all the starting material was consumed.
The reaction mixture was then adsorbed onto silica using DCM.
Dry flash chromatography (t-BuOMe) of the residue gave the title
compound 30 (33 mg, 99%) as shiny blue crystals, mp 187–189 ◦C
(from cyclohexane); Rf 0.80 (t-BuOMe/hexane, 3 : 1); (found: C,
68.3; H, 3.7; N, 12.5. C19H12ClN3O requires C, 68.4; H, 3.6; N,
12.6%); lmax(DCM)/nm 241 (log e 3.07), 301 (3.30), 313 inf (3.26),
358 (2.96), 568 (2.55); nmax/cm-1 3054w (Ar CH), 1615 m, 1605 m,
1536w, 1517 s, 1490w, 1455w, 1430w, 1389w, 1376w, 1312w, 1198w,
1175w, 1137w, 1108 m, 1088w, 1073w, 1027w, 1000w, 946w, 921w,
903w, 840 m, 811w, 799w; dH(300 MHz, CDCl3) 8.29–8.26 (2H,
m, Ar H), 7.77 (1H, d, J 9.7, Ar H), 7.54–7.47 (9H, m, Ar H);
dC(75 MHz, CDCl3) 176.2 (C O), 154.8 (s), 150.8 (s), 143.3 (s),
140.5 (d), 133.0 (s), 131.8 (s), 131.8 (d), 130.9 (d), 129.3 (d), 128.8
(d), 126.7 (d), 125.3 (d), 105.4 (C-8); m/z (EI) 335 (M+ + 2, 24%),
333 (M+, 54), 298 (100), 270 (6), 167 (12), 139 (16), 114 (4), 104
(6), 97 (24), 77 (70), 62 (10), 51 (27).
◦
as blue needles, mp 96–101 C (DCM/MeOH, 1 : 3), Rf 0.43 (t-
BuOMe/hexane, 1 : 4), identical to that describe above.
4.6. C–C coupling reactions
4.6.1. Suzuki coupling at C-8.
4.6.1.1. 1,3,8-Triphenylbenzo[e][1,2,4]triazin-7(1H)-one (36)
(typical procedure). To a stirred solution of 8-iodo-1,3-diphenyl-
benzo[e][1,2,4]triazin-7(1H)-one (32) (42.5 mg, 0.1 mmol) in diox-
ane/water 3 : 1 (0.8 ml), Pd(dppf)Cl2·DCM (8 mg, 0.01 mmol),
K2CO3 (27.6 mg, 0.2 mmol) and phenylboronic acid (24.4 mg,
0.2 mmol) were added and the mixture was heated at reflux for
2.5 h. TLC (t-BuOMe/hexane, 1 : 1), showed the absence of the
starting material and the presence of a new slightly more polar blue
product. The mixture was dried (Na2SO4) filtered, adsorbed onto
silica gel and dry flash chromatography (t-BuOMe/hexane, 1 : 2)
gave the title compound 36 (29.4 mg, 78%) as shiny blue needles, mp
219–222 ◦C (from DCM/MeOH 1 : 1); Rf 0.70 (t-BuOMe/hexane
3 : 1); (found: C, 80.1; H, 4.5; N, 11.1. C25H17N3O requires C,
80.0; H, 4.6; N, 11.2%); lmax(DCM)/nm 230 inf (log e 3.46), 240
(3.47), 256 (3.44), 288 (3.58), 309 inf (3.47), 360 (3.28), 584 (2.76);
4.5. Reaction of 8-halobenzotriazinones with nucleophiles
4.5.1. 8-Bromo-1,3-diphenyl-6-(pyrrolidin-1-yl)benzo[e][1,2,4]-
triazin-7(1H)-one (35). To a stirred solution of 8-bromo-1,3-
n
max/cm-1 3055w (Ar CH), 2920w, 2849w, 1624w, 1599w, 1582 m,
diphenylbenzo[e][1,2,4]triazin-7(1H)-one
(31)
(37.8
mg,
1537 m, 1524 m, 1483 m, 1456 m, 1435 s, 1396w, 1373 m, 1321w,
1310 m, 1287w, 1234 m, 1175 m, 1132 m, 1107 m, 1088 m, 1074
m, 1026w, 989w, 951 m, 910w, 891w, 835m; dH(300 MHz, CDCl3)
8.31–8.28 (2H, m, Ar H), 7.78 (1H, d, J 9.7, Ar H), 7.52–7.48 (3H,
m, Ar H), 7.42 (1H, d, J 9.7, Ar H), 7.16–7.11 (2H, m, Ar H),
7.05–6.95 (6H, m, Ar H), 6.92–6.88 (2H, m, Ar H); dC(75 MHz,
CDCl3) 181.2 (C O), 155.9 (s), 150.7 (s), 143.5 (s), 141.6 (d),
133.8 (s), 133.6 (s), 132.6 (s), 132.2 (d), 131.0 (d), 130.7 (d), 128.9
(d), 128.5 (d), 128.1 (d), 127.7 (d), 127.0 (d), 126.7 (d), 124.8 (d),
112.7 (s); m/z (EI) 376 (M+ + 1, 29%), 375 (M+, 100), 346 (38),
330 (5), 298 (23), 284 (6), 271 (42), 243 (15), 215 (14), 187 (6), 180
(9), 166 (9), 139 (26), 114 (9), 104 (11), 89 (22), 77 (54), 63 (10),
51 (21).
0.100 mmol) in DCM (2 ml), at ca. 20 ◦C, protected with a
CaCl2 drying tube, pyrrolidine (18.2 ml, 0.200 mmol) was added
and the reaction mixture was stirred at this temperature for
36 h until no starting material remained (TLC). The reaction
mixture was then diluted (DCM) and washed (5% HCl) to remove
unreacted amine. The organic layer was separated, dried (Na2SO4)
and evaporated to afford the title compound 35 (33.1 mg, 74%)
as red crystals, mp 254–255 ◦C (from cyclohexane); (Found C,
61.9; H, 4.2 N, 12.6. C23H19BrN4O requires C, 61.8; H, 4.3; N,
12.5%); lmax(DCM)/nm 283 inf (log e 3.53), 307 (3.69), 327 inf
(3.53), 354 inf (3.10), 368 inf (3.02), 440 inf (3.49), 459 (3.60);
n
max/cm-1 2968w, 2924w (Ar CH), 2878w (Ar CH), 2849w, 1609
This journal is The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5228–5237 | 5235
©

View Article Online
4.6.2. Stille coupling at C-8.
134.3 (s), 134.1 (s), 132.2 (s), 131.3 (d), 130.6 (d), 130.0 (d), 129.7
(d), 128.9 (d), 128.5 (d), 128.3 (d), 128.1 (d), 127.6 (d), 126.9 (d),
126.8 (d), 125.0 (d), 112.9 (s); m/z (EI) 452 (M+ + 1, 31%), 451
(M+, 100), 450 (M+ - 1, 46), 423 (35), 374 (18), 347 (18), 319 (13),
285 (3), 242 (8), 216 (14), 189 (9), 180 (11), 165 (6), 104 (7), 89
(15), 77 (33), 69 (7), 51 (10).
4.6.2.1. 8-(Furan-2-yl)-1,3-diphenylbenzo[e][1,2,4]triazin-
7(1H)-one (39) (typical procedure). To a stirred solution of 8-
iodo-1,3-diphenylbenzo[e][1,2,4]-triazin-7(1H)-one (32) (42.5 mg,
0.1 mmol) in DMF (2 ml), 2-(tributylstannyl)furan (91 ml,
0.29 mmol) and Pd(OAc)2 (3.4 mg, 0.015 mmol) were added and
the solution was heated at ca. 100 ◦C under an Ar atmosphere
for 21 h. TLC (t-BuOMe/hexane, 1 : 1) showed the absence of
the starting material and the presence of a new more polar
product. The reaction mixture was cooled, filtered, diluted with
EtOAc (10 ml) and washed with water (15 ml). The combined
organic layers were dried (Na2SO4), filtered and the residue dry
flash chromatographed (t-BuOMe/hexane, 1 : 2) to give the title
compound 39 (25.9 mg, 71%) as shiny blue needles, mp 189–192 ◦C
(from cyclohexane); Rf 0.65 (t-BuOMe/hexane, 3 : 1); (found: C,
75.5; H, 4.1; N, 11.4. C23H15N3O2 requires C, 75.6; H, 4.1; N,
11.5%); lmax(DCM)/nm 218 (log e 3.83), 252 (3.11), 298 (3.14),
378 (2.72), 602 (2.53); nmax/cm-1 3140w, 3113w, 3065w (Ar CH),
1626 m, 1599 m, 1585 m, 1539w, 1514 m, 1485w, 1470 m, 1454w,
1437 s, 1391w, 1364 m, 1329 m, 1317 m, 1277w, 1232 m, 1215w,
1188w, 1169 m, 1155 m, 1126 m, 1101 m, 1088w, 1076 m, 1024
m, 1003w, 986w, 949 m, 935w, 883w, 858w, 831s; dH(300 MHz,
CDCl3) 8.33–8.30 (2H, m, Ar H), 7.76 (1H, d, J 9.7, Ar H), 7.54–
7.48 (3H, m, Ar H), 7.41–7.37 (3H, m, Ar H), 7.24–7.17 (3H,
m, Ar H), 6.78–6.77 (1H, m, Ar H), 6.57 (1H, dd, J 3.1, 0.7, Ar
H), 6.11 (1H, dd, J 3.3, 1.9, Ar H); dC(75 MHz, CDCl3) one Ar
CH missing 179.8 (C O), 155.3 (s), 151.5 (s), 145.3 (s), 143.2 (s),
141.8 (d), 141.4 (d), 133.7 (s), 132.2 (d), 131.9 (s), 130.8 (d), 128.9
(d), 128.5 (d), 128.3 (d), 127.0 (d), 123.2 (d), 113.1 (d), 111.3 (d),
102.8 (s); m/z (EI) 366 (M+ + 1, 28%), 365 (M+, 100), 336 (80),
322 (40), 308 (17), 260 (5), 232 (10), 219 (5), 205 (25), 191 (5), 176
(17), 169 (7), 152 (12), 129 (15), 103 (18), 88 (4), 77 (87), 63 (7), 51
(52).
Acknowledgements
The authors wish to thank Dr Georgia Loizou and Miss Marina
Demetriadou for early experiments and the Cyprus Research Pro-
motion Foundation [Grant No. YCEIA/bIOR/0308(bIE)/13]
and the University of Cyprus (Medium Sized Grants) for financial
support. Furthermore, the authors thank the following organiza-
tions in Cyprus for generous donations of chemicals and glassware:
the State General Laboratory, the Agricultural Research Institute,
the Ministry of Agriculture, and Biotronics Ltd. Finally, we thank
the A. G. Leventis Foundation for helping to establish the NMR
facility in the University of Cyprus.
References
1 In The Triazine Herbicides, 50 Years Revolutionizing Agriculture, J. E.
McFarland and O. E. Burnside, ed., H. M. LeBaron, Ed-in-Chief,
Elsevier, Oxford, 2008.
2 H. O. Esser, G. Depuis, E. Ebert, G. Nacro and C. Vogel, in Herbicides
Chemistry, Degradation and Mode of Action, P. C. Kearney and D. D.
Kaufmann, ed., Dekker, New York, 1976, Vol. 3, p 191.
3 Y. Chen and L. Hu, Med. Res. Rev., 2009, 29, 29 and references cited
herein.
4 (a) H. M. Blatter and H. Lukaszewski, Tetrahedron Lett., 1968, 9, 2701;
(b) H. Blatter, U.S. Pat. 3 423 409, 1969; (c) P. A. Koutentis and D. Lo
Re, Synthesis, 2010, 2075; (d) C. P. Constantinides, P. A. Koutentis and
G. Loizou, Org. Biomol. Chem., 2011, 9, 3122.
5 (a) K. Mukai, K. Inoue, N. Achiwa, J. B. Jamali, C. Krieger and F. A.
Neugebauer, Chem. Phys. Lett., 1994, 224, 569; (b) C. Krieger and F. A.
Neugebauer, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1996,
52, 3124; (c) C. P. Constantinides, P. A. Koutentis, H. Krassos, J. M.
Rawson and A. J. Tasiopoulos, J. Org. Chem, 2011, 76, 2798; (d) B. Yan,
J. Cramen, R. McDonald and N. L. Frank, Chem. Commun., 2011, 47,
3201.
4.7. Preparation of 1,3,6,8-tetraarylbenzotriazinones via
Grignard reaction at C-6
6 K. Hutchison, G. Srdanov, R. Hicks, H. Yu and F. Wudl, J. Am. Chem.
Soc., 1998, 120, 2989.
4.7.1. 1,3,6,8-Tetraphenylbenzo[e][1,2,4]triazin-7(1H)-one (42)
(typical procedure). To
a
stirred solution of 1,3,8-
7 (a) V. Charushin, V. Rusinov and O. Chupakhin, in Comprehensive
Heterocyclic Chemistry III, ed. K. Turnbull, (Eds in Chief A. R.
Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor),
Elsevier, Oxford, 2008, vol. 9, ch. 9.02, p. 95-196; (b) H. Neunhoeffer,
in Comprehensive Heterocyclic Chemistry II, ed. A. J. Boulton, (Eds in
Chief A. R. Katritzky, C. W. Rees and E. F. V. Scriven), Elsevier, Oxford,
1996, vol. 6, ch. 6.11, p. 507-573; (c) H. Neunhoeffer, in Comprehensive
Heterocyclic Chemistry, ed. A. J. Boulton and A. McKillop, (Eds in
Chief A. R. Katritzky and C. W. Rees), Elsevier, Oxford, 1984, vol. 3
(part 2B), ch. 2.19, p. 385-456; (d) C. W. Lindsley, M. E. Layton, 1,2,4-
Triazines, in Science of Synthesis, Product Class 2, ed. S. M. Weinreb,
Georg Thieme Verlag, Stuttgart, 2003, vol. 17, ch 17.2, p. 357-448.
8 (a) L. P. G. Wakelin and M. J. Waring, Comprehensive Medicinal
Chemistry, P. G. Sammes, Ed., Pergamon Press, Oxford, U.K., 1990,
Vol. 2, pp 703; (b) B. A. Chabner, C. J. Allegra, G. A. Curt and
P. Calabresi, Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, 9th ed., J. G. Hardman, L. E. Limbird, P. B. Molinoff, R.
W. Ruddon and A. G. Gilman, ed., McGraw-Hill, New York, 1996, pp
1233.
diphenylbenzo[e][1,2,4]triazin-7(1H)-one (28) (37.5 mg, 0.1 mmol)
in dry THF (0.6 ml) at ca. 20 ◦C in Ar atmosphere, PhMgBr 1 M
in THF (0.4 ml, 0.4 mmol) was added and the mixture stirred for
18 h. TLC (t-BuOMe/hexane, 1 : 1) showed the absence of the
starting material and the presence of a new less polar blue product.
The mixture was diluted with MeOH (1 ml) and stirred for 10
min. Dry flash chromatography (EtOAc/hexane, 1 : 2) gave the
title compound 42 (35.5 mg, 79%) as blue needles, mp 205–209 ◦C
(from DCM/MeOH, 1 : 3), Rf 0.37 (t-BuOMe/hexane, 1 : 4);
(found: C, 82.3; H, 4.7; N, 9.2. C31H21N3O requires C, 82.5; H,
4.7; N, 9.3%); lmax(DCM)/nm 230 inf (log e 3.62), 255 (3.70),
285 inf (3.57), 339 (3.76), 585 (2.93); vmax/cm-1 3055w (Ar CH),
2963w, 2916w, 1601 m, 1587 s, 1547 s, 1524 s, 1487 s, 1454w,
1445w, 1431 m, 1369w, 1335w, 1310 m, 1285 s, 1258 m, 1209 m,
1182w, 1146w, 1124w, 1076w, 1069w, 1028w, 1005w, 953w, 920w,
907w, 883w, 839w, 802m; dH(500 MHz; CDCl3) 8.33–8.31 (2H,
m, Ar H), 7.95 (1H, s, Ar H), 7.81–7.82 (2H, m, Ar H), 7.53–7.45
(6H, m, Ar H), 7.20–7.18 (2H, m, Ar H), 7.08–7.04 (3H, m, Ar
H), 7.00–6.94 (5H, m, Ar H); dC(125 MHz; CDCl3) one Ar CH
missing 179.8 (s), 155.9 (s), 151.0 (s), 150.3 (s), 143.6 (s), 136.0 (s),
9 (a) S. J. Ezell, H. Li, H. Xu, X. Zhang, E. Gurpinar, X. Zhang, E.
R. Rayburn, C. I. Sommers, X. Yang, S. E. Velu, W. Wang and R.
Zhang, Mar. Drugs, 2010, 8, 2129; (b) J. W. Ruan, Z. S. Huang, J.
F. Huang, C. J. Du, S. L. Huang, Z. Shi, L. W. Fu and L. Q. Gu,
Chin. Chem. Lett., 2006, 17, 1141; (c) A. Bolognese, G. Correale, M.
Manfra, A. Lavecchia, O. Mazzoni, E. Novellino, V. Barone, A. Pani,
E. Tramontano, P. La Colla, C. Murgioni, I. Serra, G. Setzu and R.
5236 | Org. Biomol. Chem., 2011, 9, 5228–5237
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Loddo, J. Med. Chem., 2002, 45, 5205; (d) A. Bolognese, G. Correale,
M. Manfra, A. Lavecchia, O. Mazzoni, E. Novellino, V. Barone, P. La
Colla and R. Loddo, J. Med. Chem., 2002, 45, 5217; (e) S. Kamitori and
F. Takusagawa, J. Mol. Biol., 1992, 225, 445; (f) U. Hollstein, Chem.
Rev., 1974, 74, 625.
13 (a) A. Sugimoto, Y. Yoshino, R. Watanabe, K. Mizuno and K. Uehara,
J. Heterocycl. Chem., 1999, 36, 1057; (b) F. Kehrmann and H. Burgin,
Ber. Dtsch. Chem. Ges., 1896, 29, 1819.
14 T. Mikayama, H. Matsuoka, M. Ara, A. Sugimoto and K. Mizuno,
Sol. Energy Mater. Sol. Cells, 2001, 65, 133.
15 R. Huisgen and J. Wulff, Chem. Ber., 1969, 102, 1848.
16 F. A. Neugebauer and I. Umminger, Chem. Ber., 1980, 113, 1205.
17 (a) F. Freeman, Chem. Rev., 1969, 69, 591; (b) P. A. Koutentis and C.
W. Rees, J. Chem. Soc., Perkin Trans. 1, 2000, 2601.
18 (a) P. A. Koutentis and C. W. Rees, J. Chem. Soc., Perkin Trans. 1,
1998, 2505; (b) I. C. Christoforou, P. A. Koutentis and C. W. Rees, J.
Chem. Soc., Perkin Trans. 1, 2002, 1236; (c) A. S. Kalogirou and P. A.
Koutentis, Tetrahedron, 2009, 65, 6850.
19 (a) F. Wudl, P. A. Koutentis, A. Weitz, B. Ma, T. Strassner, K. N. Houk
and S. I. Khan, Pure Appl. Chem., 1999, 71, 295; (b) P. A. Koutentis,
Arkivoc, 2002, 5, 175.
20 D. Twomey, J. Heterocycl. Chem., 1986, 23, 615.
21 E. Bamberger and L. Blangey, Justus Liebigs Ann. Chem., 1911, 384,
272.
10 (a) T. K. Pashkevich, I. A. Postovskii, G. B. Afanaseva and L. P.
Ananina, Khim. Geterotsikl. Soedin., 1976, 10, 77; (b) V. C. Barry, M.
L. Conalty and E. E. Gaffney, J. Pharm. Pharmacol., 1956, 8, 1089.
11 (a) F. Wang, S. J. Ezell, Y. Zhang, W. Wang, E. R. Rayburn, D. H.
Nadkarni, S. Murugesan, S. E. Velu and R. Zhang, Invest. New Drugs,
2010, 28, 234; (b) D. H. Nadkarni, F. Wang, W. Wang, E. R. Rayburn, S.
J. Ezell, S. Murugesan, S. E. Velu and R. Zhang, Med. Chem., 2009, 3,
227; (c) W. Wang, E. R. Rayburn, S. E. Velu, D. Chen, D. H. Nadkarni,
S. Murugesan, D. Chen and R. Zhang, Breast Cancer Res. Treat., 2010,
123, 321.
12 (a) K. Gebhardt, J. Schimana, P. Krastel, K. Dettner, J. Rheinheimer,
A. Zeeck and H.-P. Fieldler, J. Antibiot., 2002, 55, 794; (b) P. Krastel,
A. Zeeck, K. Gebhardt, H.-P. Fiedler and J. Rheinheimer, J. Antibiot.,
2002, 55, 801.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5228–5237 | 5237
©