New and versatile syntheses of 3-alkyl- and 3-aryl-1,2,4-benzotriazine 1,4-dioxides: Preparation of the bioreductive cytotoxins SR 4895 and SR 4941

Article abstract of DOI:10.1016/S0040-4039(02)02417-6

Palladium-mediated coupling of 3-chloro-1,2,4-benzotriazine 1-oxide with a variety of stannanes in the presence of Pd(PPh₃)₄ gives 3-alkyl derivatives in good yields. Suzuki reaction of the 3-chloro compound with phenylboronic acids gives 3-aryl-1,2,4-benzotriazine 1-oxides. Oxidation of 1-oxides with trifluoroperacetic acid gives the 1,4-dioxides. This method provides a better route to the potential anti-cancer agents SR 4895 and SR 4941.

Full text of DOI:10.1016/S0040-4039(02)02417-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9569–9571
New and versatile syntheses of 3-alkyl- and
3-aryl-1,2,4-benzotriazine 1,4-dioxides: preparation of the
bioreductive cytotoxins SR 4895 and SR 4941
Michael P. Hay* and William A. Denny
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland, New Zealand
Received 15 September 2002; revised 12 October 2002; accepted 25 October 2002
Abstract—Palladium-mediated coupling of 3-chloro-1,2,4-benzotriazine 1-oxide with a variety of stannanes in the presence of
Pd(PPh3)4 gives 3-alkyl derivatives in good yields. Suzuki reaction of the 3-chloro compound with phenylboronic acids gives
3-aryl-1,2,4-benzotriazine 1-oxides. Oxidation of 1-oxides with trifluoroperacetic acid gives the 1,4-dioxides. This method provides
a better route to the potential anti-cancer agents SR 4895 and SR 4941. © 2002 Elsevier Science Ltd. All rights reserved.
Tirapazamine 1 (TPZ, 3-amino-1,2,4-benzotriazine 1,4-
cal candidates for TPZ 1.8 The 3-ethyl-1,4-dioxide (SR
4895) 2 and the 3-(2-methoxyethyl)-1,4-dioxide (SR
4941) 3 showed increased aqueous solubility, increased
electron affinity and equivalent in vivo activity com-
pared to TPZ 1. Synthesis of these 3-alkyl derivatives
via the Bamberger synthesis9 required the preparation
and cyclization of appropriately substituted formazans
to give 1,2,4-benzotriazines, which were then oxidized
to the corresponding dioxides.10 This approach required
a separate synthesis for each derivative.
dioxide, Tirazone™) is a bioreductive drug1 undergo-
ing clinical trials as
a cytotoxic agent for the
potentiation of radiotherapy and chemotherapy. TPZ
1 is currently in Phase II trials in combination with
radiotherapy and in Phase III trials with cisplatin.2
TPZ is activated by one-electron reductases3 to form a
radical anion. This radical anion may be oxidized by
molecular oxygen under aerobic conditions, generating
superoxide radical, which mediates aerobic toxicity.
Under hypoxic conditions the radical anion may be
protonated4 and species derived from the radical anion
interact with DNA, although the exact mechanism is
unclear.5 TPZ causes DNA double-strand breaks
under anoxic conditions5a and these correlate with
cytotoxicity.6 Thus, one-electron reduction of TPZ,
reversible in the presence of oxygen, results in selective
cytotoxicity to hypoxic cells, often found in solid
tumours and considered responsible for relapse after
radiotherapy.7
The application of palladium-mediated Stille11 and
Suzuki12 couplings to heterocyclic chemistry has grown
rapidly in recent years,13 leading us to consider the
1,2,4-benzotriazine 1-oxide system as a useful substrate
for such chemistry, directed towards the synthesis of
3-alkyl- and 3-aryl-derivatives.
We wish to report a novel, versatile, and efficient
synthesis of 3-alkyl 1,2,4-benzotriazine 1,4-dioxides that
utilizes Stille coupling with a key 3-chloro-1,2,4-benzo-
triazine 1-oxide intermediate 6. Further elaboration
gives access to a range of derivatives exemplified by the
An analogue development programme identified several
second-generation analogues suitable as ‘backup’ clini-
Keywords: antitumour compounds; Stille reaction; Suzuki reaction; benzotriazoles.
* Corresponding author. Tel.: 64-9-3737599 ext.6598; fax: 64-9-3737502; e-mail: m.hay@auckland.ac.nz
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02417-6

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M. P. Hay, W. A. Denny / Tetrahedron Letters 43 (2002) 9569–9571
Scheme 1. Reagents and conditions: (a) NH2CN, cHCl, 100°C; (b) 30% aq. NaOH, 100°C; (c) NaNO2, HCl; (d) POCl3, PhNMe2,
80°C; (e) SnR4 or n-Bu3SnR, Pd(PPh3)4, DME, 85°C; (f) CF3CO3H, DCM; (g) RC6H4B(OH)2, Pd(PPh3)4, Cs2CO3, DME, water,
85°C.
Scheme 2. Reagents and conditions: (a) O3, DCM/MeOH; (b) NaBH4, EtOH; (c) TMSCH2N2, HBF4, DCM; (d) CF3CO3H,
DCM.
synthesis of 2 and 3. Thus, conversion of 2-nitroaniline
4 to 3-amino-1,2,4-benzotriazine 1-oxide 5 using the
method of Mason and Tennant14 and subsequent diazo-
tization and chlorination of the intermediate phenol
gave the key chloride 615 in 68% overall yield (Scheme
1).
Suzuki coupling of 6 with a variety of phenylboronic
acids to give 3-aryl 1,2,4-benzotriazine 1-oxides extends
the utility of this approach. Biological evaluation of
these derivatives will be reported in a forthcoming
publication.
Chloride 6 was sufficiently activated to undergo Stille
coupling readily with a variety of stannanes in the
presence of Pd(PPh3)4 in DME at 85°C to give good
yields (66–86%) of 3-alkyl 1-oxides 7a–d. Oxidation of
3-methyl-1-oxide 7a and 3-ethyl-1-oxide 7b with tri-
fluoroperacetic acid gave the dioxides 8 and 2,16 respec-
tively. Further elaboration of the 3-vinyl-1-oxide 7c and
the 3-allyl-1-oxide 7d17 gave access to a range of substi-
tuted derivatives. In particular, ozonolysis of 7d, fol-
lowed by a reductive workup gave the 3-(2-hydroxy-
ethyl)-1-oxide 11 that was methylated18 to give 12 and
oxidized to 319 with trifluoroperacetic acid (Scheme 2).
Acknowledgements
The authors acknowledge support from National Can-
cer Institute Program Project Grant 1PO1-CA82566-
01A1 (M.P.H.) and the Auckland Division of the
Cancer Society of New Zealand (W.A.D.), and would
like to thank Dr. Brian Palmer and Dr. Jeff Smaill for
helpful discussions.
References
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85°C gave the 3-aryl-1-oxides 9a–c in good (56–65%)
yields20 (Scheme 1). Oxidation of 9a with trifluoroper-
acetic acid gave dioxide 10.
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1
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