Application of Suzuki–Miyaura and Buchwald–Hartwig Cross-coupling Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides Related to the Antitumor Agent Tirapazamine

Article abstract of DOI:10.1002/jhet.2559

Many 1,2,4-benzotriazine 1,4-dioxides display the ability to selectively kill the oxygen-poor cells found in solid tumors. As a result, there is a desire for synthetic routes that afford access to substituted 1,2,4-benzotriazine 1-oxides that can be used as direct precursors in the synthesis of 1,2,4-benzotriazine 1,4-dioxides. Here we describe the use of Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions for the construction of various 1,2,4-benzotriazine 1-oxide analogs bearing substituents at the 3-position, 6-position, and 7-position.

Full text of DOI:10.1002/jhet.2559

Month 2015
Application of Suzuki–Miyaura and Buchwald–Hartwig Cross-coupling
Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides
Related to the Antitumor Agent Tirapazamine
Ujjal Sarkar,a† Roman Hillebrand,a† Kevin M. Johnson,a Andrea H. Cummings,a Ngoc Linh Phung,a
Anuruddha Rajapakse,a Haiying Zhou,a Jordan R. Willis,a Charles L. Barnesa, and Kent S. Gatesa,b
*
aDepartment of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, MO 65211, United States
bDepartment of Biochemistry, University of Missouri, 125 Chemistry Building, Columbia, MO 65211, United States
*
E-mail: gatesk@missouri.edu
†These authors contributed equally to the work.
Additional Supporting Information may be found in the online version of this article.
Received July 1, 2015
DOI 10.1002/jhet.2559
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Many 1,2,4-benzotriazine 1,4-dioxides display the ability to selectively kill the oxygen-poor cells found
in solid tumors. As a result, there is a desire for synthetic routes that afford access to substituted 1,2,4-
benzotriazine 1-oxides that can be used as direct precursors in the synthesis of 1,2,4-benzotriazine
1,4-dioxides. Here we describe the use of Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions
for the construction of various 1,2,4-benzotriazine 1-oxide analogs bearing substituents at the 3-position,
6-position, and 7-position.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
analogs with improved efficacy [18–27]. Accordingly,
there is a continuing need for the development of synthetic
routes that afford access to tirapazamine analogs.
Tirapazamine (1) and many other 1,2,4-benzotriazine
1,4-dioxides are selectively toxic to the oxygen poor (hyp-
oxic) cells found within solid tumors [1–3]. These com-
pounds undergo intracellular enzymatic one-electron
reduction to yield a radical that undergoes relatively harm-
less back-oxidation to starting material in normally oxy-
genated cells. On the other hand, under hypoxic
conditions, the neutral radical intermediate decomposes to
release a highly oxidizing secondary radical that causes cy-
totoxic DNA damage [1–16]. Promising preclinical results
led to the examination of tirapazamine in a large number of
clinical trials, but thus far, the results of these studies have
not earned FDA approval for the drug [17]. As a result,
there have been substantial efforts to prepare tirapazamine
A variety of methods have been developed for the syn-
thesis of tirapazamine and related analogs. Tirapazamine
can be prepared by the reaction of benzofuroxan with
sodium cyanamide [28]. Alternatively, condensation of
2-nitroaniline with cyanamide yields 1,2,4-benzotriazine
1-oxide (2; Scheme 1), which can be oxidized to
tirapazamine using H2O2/HOAc, mCPBA, or HOF-
© 2015 HeteroCorporation

U. Sarkar, R. Hillebrand, K. M. Johnson, A. H. Cummings, N. L. Phung, A. Rajapakse, H. Zhou, Vol 000
J. R, Willis, C. L. Barnes, and K. S. Gates
Scheme 1. Synthesis of halogenated tirapazamine derivatives for use in
Pd-mediated coupling reactions.
preparation of 3-alkyl, aryl, vinyl and allyl 1,2,4-
benzotriazine 1-oxides from 3a [25,33]. In addition, there is
a single report in which the Suzuki–Miyaura reaction was
used to prepare 3-aryl-1,2,4-benzotriazine 1,4-dioxides from
3-halo-1,2,4-benzotriazine 1-oxide precursors [25]. The re-
sults described herein expand the use of the Suzuki–Miyaura
reaction and provide the first uses of the Buchwald–Hartwig
reaction for the preparation of 1,2,4-benzotriazine 1-oxide
analogs related to the antitumor agent tirapazamine.
RESULTS AND DISCUSSION
Six halogenated 1,2,4-benzotriazine 1-oxides were prepared
for use in palladium-catalyzed coupling reactions. Compounds
3 were prepared via reaction of 2 with sodium nitrite in aque-
ous sulfuric acid, followed by treatment with the appropriate
phosphorus oxyhalide (Scheme 1) [33,34]. Analogs 4 bearing
halogens on the benzo-ring were prepared by a well-
established route involving condensation of cyanamide
with the appropriately substituted 2-nitroaniline [14,29,30].
The halogen derivatives 3 were employed as substrates in
Suzuki coupling reactions with aryl and cyclopropyl boronic
acids (Table 1). In these reactions, compound 3, the boronic
acid (1.2 equiv), and the ligand tricyclohexylphosphine or 2-
dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (PCy3 or
SPhos, 10 mol%) [43] were mixed with Pd(OAc)2 (5mol%)
in a mixture of toluene or toluene-water (3:1 v/v) containing
potassium phosphate or cesium carbonate and heated in a
sealed tube at 110°C for 24h. Reactions of the chlorinated
substrate 3a with cyclopropylboronic acid and 4-
cyanophenylboronic acid proceeded in reasonable yields to
give the coupling products 5 and 9, respectively [44,45].
Use of the brominated derivative 3b did not substantially al-
ter the yields in these cases. Reactions of 3a with 4-
bromophenylboronic acid and 4-nitrophenylboronic acid
gave very low and modest yields of the products 6 and 7, re-
spectively (Table 1). In these cases, use of the brominated
substrate 3b improved the yields of the desired coupling
products 6 and 7. This was not unexpected because aryl bro-
mides typically are better substrates than the analogous
chlorides in Suzuki coupling reactions [41,42]. The reaction
between quinolin-2-ylboronic acid and 3a or 3b employing
the PCy3 ligand proceeded in very low yields even with the
brominated substrate 3b, but use of the electron-rich SPhos
ligand [46] afforded improved yields of the coupling prod-
uct 8 (Table 1). Use of the SPhos ligand did not improve
the yield of 6 obtained from the coupling of 3b with 4-
bromophenylboronic acid using the PCy3 ligand (Table 1).
The aryl bromide residue in 6 could be a useful handle for
further elaboration via palladium-catalyzed reactions. Reac-
tion of 4-(N-Boc-amino)phenylboronic acid with 3b using
the SPhos ligand afforded a reasonable yield of the coupling
product 10.
CH3CN [14,29–31]. The reaction of 1-fluoro-2-
nitrobenzene or 1,2-dinitrobenzene with guanidine base
provides another route to 2 [32]. Condensation of various
2-nitroaniline derivatives with cyanamide provides access
to a large number of tirapazamine derivatives bearing sub-
stituents on the benzo ring [18,20,26,33]. Analogs of 2
bearing sulfur or alkoxy substitutents (rather than NH2) at
the 3-position have been prepared by diazotization and hy-
drolysis of 2 to afford the 3-hydroxy-1,2,4-benzotriazine 1-
oxide analog, followed by reaction with phosphorus
oxyhalide to give the 3-chloro-1,2,4-benzotriazine 1-oxide
or 3-bromo-1,2,4-benzotriazine 1-oxide (3a and b), and
finally treatment with an appropriate oxygen or sulfur nu-
cleophile [34]. Similarly, a variety of tirapazamine analogs
bearing alkyl and aryl groups on the 3-amino substituent
have been prepared by nucleophilic aromatic substitution
involving attack of amines on 3a, followed by oxidation
to give the di-N-oxides [35,36]. Photochemical methods
also may enable preparation of 3-(arylamino)-1,2,4-
benzotriazine 1,4-dioxide derivatives from 3-acetamido-
1,2,4-benzotriazine 1,4-dioxide [37].
There is interest in 3-alkyl- and 3-aryl-1,2,4-
benzotriazine 1,4-dioxides because these compounds dis-
play hypoxia-selective DNA-cleaving properties and cy-
totoxicities that are comparable to tirapazamine [8,38].
In addition, these analogs may possess superior pharma-
cokinetic properties [19,20]. The analogs, 3-methyl- and
3-phenyl-1,2,4-benzotriazine oxide, have been prepared
by BF3-catalyzed cyclization of formazan precursors
[39] or PtO2-catalyzed cyclization of the 2-
nitrophenylhydrazone of pyruvic acid [40], followed by
N-oxidation using H2O2/TFAA [38].
Palladium-catalyzed cross-coupling reactions such as
the Suzuki–Miyaura, Buchwald–Hartwig, and Stille
reactions are powerful synthetic methods that may
enable the synthesis of many diverse tirapazamine ana-
logs [41,42]. Along these lines, the palladium-mediated
Stille coupling reactions have been employed for the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Substituted 1,2,4-benzotriazine 1-oxides
Table 1
Preparation of 3-aryl and 3-cyclopropyl derivatives of 1,2,4-benzotriazine 1-oxide.
Aryl halide
R2, product
4-cyanophenyl, 5
4-bromophenyl, 6
4-nitrophenyl, 7
Yield [%]
Ligand
Base
Solvent
Toluene
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3b
66
74
trace
57
42
65
29
40
76
80
SPhos
SPhos
PCy3
PCy3
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
Cs2CO3
Cs2CO3
K3PO4
K3PO4
Cs2CO3
Cs2CO3
K3PO4
K3PO4
Cs2CO3
Cs2CO3
K3PO4
Toluene
MeCN/water
MeCN/water
Toluene
Toluene
quinolin-2-yl, 8
Toluene/water
Toluene/water
Toluene
Toluene
Toluene/water
cyclopropyl, 9
4-N-Boc-aminophenyl, 10
61
Column chromatography of the reaction between 3a and
cyclopropylboronic acid with PCy3 as ligand for palla-
dium, produced a fraction that, upon slow evaporation,
gave a low yield (~1%) of pale yellow crystals that were
characterized by X-ray diffraction. Interestingly, the mate-
rial proved to be a dinuclear triazine-bridged palladium
complex resulting from oxidative addition of 3a to the pal-
ladium catalyst. The C1-carbon and N2-nitrogen atoms
of two benzotriazine 1-oxides and the two palladium
centers form a six-membered ring in a boat conforma-
tion, in which the nitrogens are trans to the phosphine
ligands and carbons are trans to the chlorides (Fig. 1).
The Pd-Pd interatomic distance is 3.1709(4)Å. This struc-
ture is analogous to that of a product previously obtained
from the addition of Pd(PPh3)4 to 2-bromopyridine [47,48].
The success of Suzuki coupling reactions employing 3
led us to extend this reaction to the aryl halides 4a and
4b. In these reactions, 4a or 4b, the boronic acid (1.2 equiv-
alent), and the ligand (PCy3 or SPhos, 10 mol%) were com-
bined with Pd(OAc)2 (5 mol%) in a mixture of toluene or
toluene-water (3:1 v/v) containing potassium phosphate or
cesium carbonate and heated in a sealed tube at 110°C for
24h. These reactions afforded reasonable yields (up to
72%) of the products 11-14 (Table 2). Analogous reactions
refluxed under nitrogen gas gave yields that were substan-
tially lower than those obtained by heating in sealed tubes.
As part of these studies, we examined whether the
boronic acid components of these reactions were stable
in the presence of the N-oxide starting materials. We
were motivated to examine this issue because Zhu
Figure 1. Crystal structure of a complex resulting from oxidative addition
of 3a to palladium.
et al. previously showed that alkyl-oxide and aryl-N-ox-
ide have the potential to convert boronic acids and
boronic acid pinacol esters to the corresponding
alcohols [49]. Under our reaction conditions, however,
we did not observe significant decomposition of 4-(N-
Boc-amino)phenylboronic acid or cyclopropylboronic
acid when these materials were heated at 110°C for
3 days in toluene/water (3:1) with 3a, 3b, 4, or 4b (2
equivalent, in the absence of palladium catalyst).
We next examined whether the Buchwald–Hartwig
reaction could be applied the construction of substituted
1,2,4-benzotriazine 1-oxides [50]. In these reactions, 4a
or c, the ligand 2-dicyclohexylphosphino-2′,4′,6′-triiso-
propylbiphenyl (X-Phos, 10mol%), Pd(OAc)2 (5 mol%),
K3PO4, and the desired amine (1.2 equivalent) was
dissolved in a solvent mixture composed of t-BuOH/
water (3:1 v/v), placed in a sealed tube, and stirred for
Journal of Heterocyclic Chemistry
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U. Sarkar, R. Hillebrand, K. M. Johnson, A. H. Cummings, N. L. Phung, A. Rajapakse, H. Zhou, Vol 000
J. R, Willis, C. L. Barnes, and K. S. Gates
Table 2
Preparation of 7-aryl derivatives of tirapazamine.
Aryl halide
R2, product
Yield [%]
Ligand
Base
Solvent
Toluene
Toluene
Toluene/water
Toluene
4a
4b
4b
4b
4b
4-methoxyphenyl, 11
46
72
30
60
27
SPhos
SPhos
PCy3
SPhos
PCy3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
K3PO4
4-aminophenyl, 12
4-cyanophenyl, 13
2-Naphtyl-6′-methoxy, 14
Toluene/water
Table 3
Preparation of 6-aminoaryl tirapazamine derivative and 7-aminoaryl tirapazamine derivative.
Aryl halide
Amine (R3, R4)
R3 = H, R4 = Ph
Product (R5, R6)
Yield [%] reflux
Yield [%] microwave
4c
4a
4c
4a
4a
4c
R5 = H, R6 = NHPh, 15
R5 = NHPh, R6 = H, 16
R5 = H, R6=6-aminoquinoline, 17
R5=6-aminoquinoline, R6=H, 18
R5 = NPh2, R6 = H
58
81
73
70
0
76
75
61
45
0
R3 = H, R4 = Ph
R3 = H, R4 = quinoline
R3 = H, R4 = quinoline
R3 = Ph, R4 = Ph
R3 = H, R4 = Ph
R5=H, R6 = NPh2
0
0
24h or subjected to microwave irradiation for 45min
(300 W, 60 PSI). Reactions of aniline or 6-
aminoquinoline with 4a or 4c gave good yields of the
coupling products 15–18 using either conventional or mi-
crowave heating (Table 3). Microwave heating has been
used successfully in other palladium-mediated reactions
[51] and, in this case, allowed the use of shorter reaction
times. Diphenylamine gave no product under these reaction
conditions, presumably because of steric crowding. These
palladium-catalyzed C-N bond forming reactions offer a
useful alternative to the previously described nucleophilic
aromatic substitution reactions involving the reaction of
amines with 6-flour and 7-fluoro derivatives of
tirapazamine that give low yields in some cases [12,18].
CONCLUSION
In summary, we examined the utility of palladium-
mediated reactions for the synthesis of 1,2,4-benzotriazine
derivatives related to the antitumor agent tirapazamine.
Our work expands the use Suzuki–Miyaura–type reactions
for the construction of 3-aryl-1,2,4-benzotriazines and
presents the first use of Suzuki–Miyaura and Buchwald–
Hartwig reactions for the functionalization of the
6-position and 7-position of the 1,2,4-benzotriazine ring
system. Given the large number of commercially available
aryl boronic acids and arylamines, our results should
enable the preparation of many structurally diverse
tirapazamine
analogs.
Nitrogen-rich
heterocycles
Journal of Heterocyclic Chemistry
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Month 2015
Substituted 1,2,4-benzotriazine 1-oxides
1.36–1.31 (2H, m), 1.22–1.16 (2H, m); 13C-NMR
(125MHz, CDCl3): δ 167.7, 146.9, 134.7, 133.5, 128.4,
127.6, 119.4, 16.0, 10.42; HRMS (ESI) m/z calc for
C10H10N3O (M+H+) 188.0824, found 188.0823.
sometimes present challenges in palladium-catalyzed cou-
pling reactions [52,53] perhaps because of their propensity
to coordinate the palladium catalyst. Indeed, we isolated
and crystallographically characterized
a
dinuclear
triazine-bridged palladium complex resulting from oxida-
tive addition of 3a to the palladium catalyst. Nonetheless,
the yields of the coupling products obtained here are of
practical utility in the short, 3–4 step synthetic routes used
to prepare the 1,2,4-benzotriazine 1,4-dioxide antitumor
agents.
Representative procedure for coupling of 6- halo-1,2,4-
benzotriazine 1-oxide and 7-halo-1,2,4-benzotriazine 1-oxide
with arylamines: 7-aminophenyl-1,2,4-benzotriazine 1-oxide
(15).
The compound 7-chloro-1,2,4-benzotriazine
1-oxide (80 mg, 0.4 mmol), Pd(OAc)2 (5mol%,
0.02 mmol, 4.6 mg), XPhos (10 mol%, 0.04 mmol),
K3PO4 (3 equiv, 1.2 mmol, 254 mg), and aniline (75 mg,
0.8 mmol, 2 equivalent) were placed in a sealed tube
equipped with a stir bar and suspended in a solvent
mixture composed of t-butanol:water (20 mL, 9:1). The
mixture was stirred while heated at 110°C for 24h. The
mixture was evaporated to dryness, taken up in methanol
or tetrahydrofuran, filtered through celite, slurried with
silica gel, evaporated, and the resulting powder dry-
loaded on top of a silica gel column. Elution with a
gradient of 0–50% ethyl acetate in hexane gave 15 as a
EXPERIMENTAL
Representative procedure for the synthesis of 6-halo-1,2,4-
benzotriazine 1-oxide and 7-halo-1,2,4-benzotriazine 1-oxide:
6-chloro-1,2,4-benzotriazine 1-oxide (4c). The compound
4-chloro-2-nitroaniline (3.02 g, 36 mmol) and cyanamide
(6.20 g, 72 mmol) were mixed, melted by heating at 100°
C, and then cooled to room temperature. Concentrated
HCl (30 mL) was added dropwise and the resulting
mixture heated to 100°C and stirred for 2 h (Caution:
exotherm). The red–orange solution was then cooled to
room temperature, and NaOH (30 mL of a 16 M solution
in water) was added over 15 min with stirring. The
reaction mixture was heated to 100°C for 3.5 h and then
cooled to room temperature. Water (25 mL) was added
and the resulting solid collected by filtration and washed
with a solution of ethyl acetate-hexane (3:1) to give 6 in
38% yield. In cases where purification was required,
column chromatography on silica gel eluted with a
gradient of 5–20% methanol in CH2Cl2. 1H-NMR
(DMSO-d6, 300 MHz): δ 8.12 (d, J = 2 Hz, 1H), 7.77 (dd,
J = 9 Hz, J = 2 Hz, 1H), 7.54 (d, J = 9 Hz, 1H), 7.47 (s,
2H); 13C-NMR (DMSO-d6, 300 MHz): δ 160.4, 147.7,
136.1, 130.0, 128.3, 128.0, 119.0. HRMS [ESI (M + H+)]
m/z calcd for C10H10N3O 197.0230, found 197.0228.
Representative procedure for coupling of 3-halo-1,2,4-
benzotriazine 1-oxides with boronic acids: 3-cyclopropyl-
1,2,4-benzotriazine 1-oxide (9). The compound 3-chloro-
1,2,4-benzotriazine 1-oxide [33,34] (3a, 60mg,
0.33mmol), cyclopropyl boronic acid (1.2 equiv, 34mg),
potassium phosphate (203mg), PCy3 (10mol%), and Pd
(OAc)2 (5mol%) were placed in a nitrogen-purged flask,
dissolved in a mixture of toluene (2mL) and water
(100μL), and refluxed for 24h. The reaction was cooled
to room temperature, water was added (5mL), the mixture
extracted with dichloromethane, the combined organic
extracts dried over Na2SO4, and rotary evaporated.
Column chromatography on silica gel eluted with a
gradient of 5–25% ethyl acetate in hexane gave 9 as a pale
1
red solid in 78% yield. H-NMR (500 MHz, DMSO-d6) δ
6.94 (s, 2 H) 7.00 (t, J= 7 Hz, 1 H) 7.21 (d, J = 8 Hz, 2 H)
7.36 (t, J = 9 Hz, 2 H) 7.50 (d, J = 9Hz, 1H) 7.58 (d,
J = 9Hz, 2H) 7.63 (s, 1H) 8.77 (s, 1 H); 13C-NMR
(126 MHz, DMSO-d6) δ 159.3, 144.6, 142.1, 141.9,130.6
129.8, 129.5, 127.4, 122.1, 118.9, 98.4; HRMS(ESI) m/z
calc for C13H11N3O 254.1036, found 254.1046.
Acknowledgments. We are grateful to the National Institutes of
Health for the support of this work (CA 100757). We thank
Steven R. Tannenbaum and John S. Wishnok for the access to
the ESI-TOF mass spectrometer (Agilent Technologies) in the
Department of Biological Engineering, Massachusetts Institute
of Technology.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet