Suzuki-Miyaura reactions of the soluble guanylate cyclase inhibitor NS2028: A non-product specific route to C-8 substituted analogues

Article abstract of DOI:10.1016/j.tet.2011.04.003

Both soluble guanylate cyclase (sGC) inhibitors ODQ 1 and NS2028 2 are synthesized via improved protocols. In the former case treating 3,4-dihydroquinoxalin-2(1H)-one oxime 8, which can be prepared in two steps from 1,2-benzenediamine, with 1,1′-carbonyldiimidazole (CDI) gives the dihydro-ODQ 10 that in the presence of KMnO₄ oxidises to give ODQ 1 in an overall yield of 46% starting from 1,2-benzenediamine. In the latter case, the synthesis affords NS2028 2 from 2-amino-4-bromophenol 3 in three steps with an overall yield of 85% and avoids the need for chromatography. Furthermore, Suzuki-Miyaura reaction conditions are described that enable the preparation of 8-aryl and 8-heteroaryl derivatives of NS2028 directly from NS2028 2. Finally, demethylation of the 8-(methoxyphenyl) substituted analogues afforded the 8-(hydroxyphenyl) derivatives 40-42. All new products are fully characterised.

Full text of DOI:10.1016/j.tet.2011.04.003

Tetrahedron 67 (2011) 4069e4078
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SuzukieMiyaura reactions of the soluble guanylate cyclase inhibitor NS2028:
a non-product specific route to C-8 substituted analogues
*
Andrey A. Berezin, Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
Both soluble guanylate cyclase (sGC) inhibitors ODQ 1 and NS2028 2 are synthesized via improved pro-
tocols. In the former case treating 3,4-dihydroquinoxalin-2(1H)-one oxime 8, which can be prepared in two
steps from 1,2-benzenediamine, with 1,10-carbonyldiimidazole (CDI) gives the dihydro-ODQ 10 that in the
presence of KMnO4 oxidises to give ODQ 1 in an overall yield of 46% starting from 1,2-benzenediamine. In
the latter case, the synthesis affords NS2028 2 from 2-amino-4-bromophenol 3 in three steps with an
overall yield of 85% and avoids the need for chromatography. Furthermore, SuzukieMiyaura reaction
conditions are described that enable the preparation of 8-aryl and 8-heteroaryl derivatives of NS2028 di-
rectly from NS2028 2. Finally, demethylation of the 8-(methoxyphenyl) substituted analogues afforded the
8-(hydroxyphenyl) derivatives 40e42. All new products are fully characterised.
Received 3 February 2011
Received in revised form 15 March 2011
Accepted 4 April 2011
Available online 9 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
O
O
1
2
O
N
2
O
N
1
1. Introduction
9
6
9
6
10 N
Br
8
10 N
3
3
8
7
Soluble guanylate cyclase (sGC) is the only known physiolog-
ical receptor for nitric oxide (NO). On binding to NO the activity of
sGC increases 400-fold, promoting the conversion of guanosine
50-triphospate (GTP) to the second messenger guanosine 30,50-
cyclic monophosphate (cGMP) and pyrophosphate. cGMP acts to
regulate various effector proteins, including protein kinases,
phosphodiesterases and ion channels.1 As such inhibitors of sGC
can be used to regulate NO related signalling processes and to
lower cGMP activity.2
1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, (ODQ) 1, and 8-
bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]-benzoxazin-1-one (NS2028)
2 are specific inhibitors of soluble guanylate cyclase (sGC). Recent
applications of NS2028 2 include the development of inhibitors for
lymphangiogenesis that can help prevent the metastasis of solid
tumours,3 for the treatment of dermatological diseases and in cos-
metic skin care,3,4 Furthermore, NS2028 has been used for neural
thermoprotection against heat stroke or hyperthermia via inhibition
of the PKG pathway,5 and for the prevention and treatment of dental
disorders.6
4
7
4
N
O
5
5
2 (NS2028)
1 (ODQ)
While ODQ 1 and NS2028 2 were known for approximately 15
years, their synthesis was only fully reported recently.7 Not surpris-
ingly, only a few analogues have been prepared and as such the
pharmacophore structure of these compounds remains unclear.
Neverthelessreplacingthe8-bromosubstituentby4-methoxyphenyl
or by 3-trifluoromethylphenyl gave analogues with interesting bi-
ologicalprofiles.7 Assuch, modifyingtheC-8position canbeastarting
point for studying structure activity relationships (SARs).
Since NS2028 2 bears a bromine substituent at C-8 it would seem
rational to target a non-product specific route to preparing a library
of analogues for elucidating SARs via transition metal catalysed CeC
coupling reactions. Interestingly, previous efforts to perform Suzu-
kieMiyaura reactions led to decomposition of the oxadiazole ring
affording the oxime. To bypass this, the desired SuzukieMiyaura
coupling reaction was performed at an earlier stage of the synthesis,
leading to a product specific synthesis.7 During the time of the above
disclosure we were working on a similar strategy and had also
encountered problems with the late stage SuzukieMiyaura
* Corresponding author. Tel.: þ357 22 892783; fax: þ357 22 892809; e-mail
address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.003

4070
A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
coupling. In light of these difficulties, we examined the stability of
NS2028 2 in acetonitrile (MeCN) towards various bases and identi-
Br
NH2
OH
Br
NH2
O
i
€
fied SuzukieMiyaura conditions using Hunig’s base that afforded
CN
several 8-aryl and 8-heteroaryl substituted derivatives in moderate
to high yields. Furthermore, alternative routes to both ODQ 1 and
NS2028 2 were developed providing these sGC inhibitors in higher
overall yields than previously reported.
3
9
O
O
H
N
2. Results and discussion
N
Br
NOH
Br
N
ii
iii
2.1. Synthesis of ODQ 1 and NS2028 2
O
O
The recently reported four step synthesis of NS2028 2 started
from available 2-amino-4-bromophenol 3 and gave the target
compound in 64% overall yield.7 The synthesis involved treatment
of 2-amino-4-bromophenol 3 with 2-chloroacetyl chloride to afford
the 1,4-benzoxazinone 4, which was then sequentially converted
into the thione 5, then the oxime 6 and finally cyclised to afford the
NS2028 2 (Scheme 1). Furthermore, the last three steps of this
synthesis required chromatography.
6
2
Scheme 2. Reagents and conditions: (i) ClCH2CN (1.1 equiv), K2CO3 (2.2 equiv), MeCN,
reflux, 12 h, 93%; (ii) NH2OH$HCl (2 equiv), NaHCO3 (2 equiv), H2O/EtOH (17:25), reflux,
48 h, 91%; (iii) CDl (1.2 equiv), THF, reflux, 5 h, 100%.
dihydroquinoxalin-2(1H)-one oxime 8 with the milder reagent CDI
in THF at reflux for 5 h we obtained the dihydro-ODQ 10 cleanly and
in relatively good yield (67%).
The subsequent oxidation of dihydro-ODQ 10 to ODQ 1 using
diethylazodicarboxylate (DEAD)was known9 but failed in ourhands,
as such we considered alternative oxidants MnO2 and KMnO4. The
use of MnO2 (10 equiv) in MeOH at ca. 20 ꢀC, led to incomplete
conversion of the dihydro-ODQ 10 even after several days. While the
reaction of dihydro-ODQ 10 with KMnO4 (1.1 equiv) in MeCN at ca.
20 ꢀC after 5 min gave ODQ 1 in good yield (88%) (Scheme 3).
H
N
H
N
Br
NH2
OH
Br
O
Br
S
i
ii
O
O
3
4
5
O
O
H
N
N
Br
NOH
Br
N
O
O
iii
iv
O
O
N
N
O
O
N
N
i
ii
8
6
2
N
H
N
Scheme 1. Reagents: (i) ClCH2COCl; (ii) Lawesson’s reagent; (iii) NH2OH$HCl; (iv) CDl;
overall yield 64%.7
10
1 (ODQ)
We required an efficient and chromatography free route to
NS2028 2 that avoided the use of thionating agents. Aware of the
reported cyclisation of 2-(2-aminophenylamino)acetonitrile 7 with
hydroxylamine hydrochloride to give directly 3,4-dihydroquinox-
alin-2(1H)-one oxime 8,8 we considered a similar strategy for the
preparation of NS2028 2.
Scheme 3. Reagents and conditions: (i) CDl (1.1 equiv), THF, reflux, 5 h, 67%; (ii)
KMnO4 (1.1 equiv), MeCN, ca. 20 ꢀC, 5 min, 88%.
By comparison with the recently reported two step synthesis of
ODQ 1 from relatively expensive 2-chloroquinoxaline with an
overall yield of 32%,7 the above synthesis of ODQ 1 has an overall
yield of ca. 46% starting from the comparatively cheap 1,2-dia-
minobenzene; n.b., cyanomethylation of 1,2-benzenediamine can
be achieved in high yield (87%) by treating the diamine with
formaldehyde, potassium cyanide in the presence of aqueous HCl.10
NH2OH.HCl, NaHCO3
EtOH/H2O, reflux, 48 h
H
N
NH2
NOH
N
H
CN
N
H
2.2. SuzukieMiyaura coupling reactions of NS2028 2
7
8 (78%)
As reported above, attempted Suzuki reactions with NS2028 2
led to decomposition of the oxadiazolone ring and recovery of the
oxime 6,7 presumably due to base catalysed hydrolysis of the labile
oxadiazolone. We considered a careful study of the reaction con-
ditions, focussing initially on the choice of an appropriate base. As
such, the stability of NS2028 2 in MeCN towards various bases was
examined: at room temperature treating an MeCN solution NS2028
2 with aqueous NaOH or DBU rapidly led to decomposition, while
As such, cyanomethylation of 2-amino-4-bromophenol 3 using
chloroacetonitrile gave 2-(2-amino-4-bromophenoxy)acetonitrile 9
in 93% yield, which on treatment with hydroxylamine hydrochloride
gave the desired oxime 6 again in high yield (91%). Similar to the
previous reported synthesis the final cyclisation using 1,10-carbon-
yldiimidazole (CDI) gave the target NS2028 2 in near quantitative
yields. This three step synthesis required no chromatography and
gave an overall yield of 85% (Scheme 2).
Interestingly, the related conversion of 3,4-dihydroquinoxalin-
2(1H)-one oxime 8 into 4,5-dihydro-1H-[1,2,4]oxadiazolo[4,3-a]
quinoxalin-1-one 10 (dihydro-ODQ) has been reported using ethyl
chloroformate and suffers from over ethylformylation of the
remaining NH groups at the quinoxaline N3, furthermore no yields
or experimental procedures were reported.8 By treating 3,4-
€
with K2CO3, KHCO3, KOAc, KF and Hunig’s base, NS2028 2 was
stable at least for 12 h. This stability was also seen when the mix-
tures were heated to ca. 50 ꢀC for 1 h, however, at ca. 90 ꢀC after 1 h
NS2028 2 decomposed in the presence of K2CO3.
Withthisinformationinhand,wepartiallyoptimizedthecoupling
by preparing a known compound, 8-(4-methoxyphenyl)-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazin-1-one 11 that did not co-run with
the NS2028 2 on TLC (SiO2). Using Pd(OAc)2 (5 mol %) as catalyst and

A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
4071
4-MeOC6H4B(OH)2 (1.5 equiv), several bases that were tolerated by
NS2028atelevatedtemperatures and solvent systemswere screened.
An early observation showed that the SuzukieMiyaura reaction
proceeded to completionfasterwhenaqueous solutionsof dioxane or
MeCN were used, regardless of the base chosen (Table 1). Attempts to
use dry solvents, with or without the use of phase transfer catalysts
inseparable by chromatography the target compound could not be
isolated (entry 13). With pyrid-3-yl and pyrid-4-ylboronic acids no
reaction was observed in either solvent systems affording only re-
covered NS2028 2 (entries 16 and 17).
The conditions identified above led to the desired Suzu-
kieMiyaura coupling but depend on the choice of aryl or hetero-
Table 1
The SuzukieMiyaura reaction of NS2028 2 (0.186 mmol) with 4-MeOC6H4B(OH)2 (1.5 equiv) in the presence of base (3 equiv) and Pd(OAc)2 (5 mol %) in solvent (0.5 mL) at reflux
O
O
MeO
O
O
N
N
Br
N
N
4-MeOC6H4B(OH)2
+
+
2
(4-MeOC6H4)2
O
O
2 (NS2028)
Solvent
12
11
Entry
Base
Time (h)
Yields (%)
12a
2
11
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
KHCO3
KOAc
KOAc
KF
KF
KF
KF
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Py
Dioxane
MeCN
2
2
0.75
2
1.50
2
2
61
27
82
32
61
32
73
83
88
71
57
67
40
50
70
66
43
28
6
0
6
0
0
24
0
20
0
10
22
6
51
38
58
42
44
25
60
65
58
73
71
67
62
60
85
82
9
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
PhMe (18-C-6, 10 mol %)
MeCN
2
18
18
2
2
2
MeCN/H2O (9:1)
Dioxane/H2O (4:1)
Dioxane
MeCN
2
6
0
0
66
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
Dioxane/H2O (4:1)
0.33
0.33
18
a
Yields of biaryl 12 based on 4-MeOC6H4B(OH)2 not converted into compound 11.
led to slow reactions. Furthermore, the reactions were always ac-
companied by moderate amounts of 4,40-dimethoxybiphenyl 12 and
attempts to overcome the formation of this side product by reducing
the amount of 4-methoxyphenylboronic acid used (1.5/1 equiv) led
to incomplete reactions and low product yields.
More important was the choice of base; inorganic bases, such as
K2CO3, KHCO3 and KOAc gave moderate yields of desired product
(entries 1e8), while with KF the yields could be improved to a rea-
sonable 67e73% depending on the choice of solvent system (entries
arylboronic acid. Since aryltrifluoroborates are more stable
alternatives to arylboronic acids11 we also investigated a selection
with reaction of NS2028 2 under similar conditions (Table 3).
The reaction of NS2028
2 with the 2-methoxyphenyltri-
fluoroborates gave an exceptionally highyield of coupled product 26
(93%) in relatively short reaction time (10 min) (entry 1) which was
not dissimilar to that obtained using 2-methoxyphenylboronic acid
(91%, 20 min Table 2, entry 3). Similar high yielding reactions,
however, were not forthcoming with other aryltrifluoroborates. In
particular the simple phenyltrifluoroborate led to only a 51% yield of
8-phenylsubstituted NS2028 28 (entry 4). Similarly, no significant
advantage could be observed when 3-nitrophenyltrifluoroborate
was used instead of 3-nitrophenylboronic acid (17 vs 26%). Allowing
longer reaction times did result in the complete consumption of
additional NS2028 2 but unfortunately did not lead to higher yields
of desired 8-substituted NS2028 derivatives.
€
10e12). Switching to the sterically hindered organic Hunig’s base
(pKb 2.6) was more fruitful, affording the desired product 11 rapidly
(20 min) in good yields (82 and 85%) in either aqueous MeCN or
€
dioxane (entries 16 and 15). Replacing Hunig’s base by a less basic
arylamine pyridine (pKb 8.8) led to a poor conversion of starting
NS2028 2 and low yields of product (entry 17). Furthermore, in the
€
presence of Hunig’s base running the reactions at reflux in two
solvent systems dioxane/water (4:1) and MeCN/water (9:1) was
compatible affording short reaction times, high conversions of
NS2028 2 and moderate to good yields of coupled product.
With these conditions at hand we examined a variety of aryl,
and heteroarylboronic acids as coupling partners for NS2028 2
(Table 2). Both aryl and most heteroarylboronic acids reacted with
NS2028 2 to provide the 8-substituted NS2028 analogues 11, 25e36
in moderate to good yields. With phenylboronic acid and the het-
eroarylboronic acids the MeCN/water (9:1) solvent mixture led to
higher SuzukieMiyaura product yields.
When nitrophenylboronic acid was used the reaction could not
be driven to completion and at best the target compound 27 could
be obtained in 50% based on 52% consumed NS2028 2 (entry 4).
While with thien-2-ylboronic acid the reaction could not be driven
to completion and since both the product and NS2028 2 were
2.3. Further functionalisation of NS2028 and its derivatives
With the SuzukieMiyaura coupling of NS2028 2 with various aryl
and heteroarylboronic acids partially optimized the possibility of
further modifications that can provide additional analogues was in-
vestigated. With readyaccesstothemethoxyphenyl derivatives11, 25
and 26 we attempted demethylation using TMSCl (5 equiv), NaI
(3 equiv) in refluxing MeCN, however, after 2 h only traces of
unreacted starting material, iodine and baseline material could be
observed by TLC. Nevertheless, treating an ice-cold DCM solution of
the 8-methoxyphenyl substituted derivatives 11, 25 and 26 dropwise
with a 1 M solution of boron tribromide in DCM (3 equiv) and leaving
the mixture to stir at ca. 20 ꢀC for 6 h afforded the corresponding
phenols40e42ingoodyields93, 90and91%, respectively(Scheme 4).

4072
A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
Table 2
The SuzukieMiyaura reaction of NS2028 2 (0.186 mmol) with ArB(OH)2 in the presence of i-Pr2NEt (3 equiv) and Pd(OAc)2 (5 mol %) in solvent (0.5 mL) at reflux
O
O
O
O
N
N
Br
N
Ar
N
ArB(OH)2
Ar-Ar
+
2
+
O
O
12-24
11, 25-36
2 (NS2028)
Entry
ArB(OH)2 (equiv)
Solvent system
Time (min)
Yields (%)
12e24a
2
11, 25e36
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-MeOC6H4B(OH)2 (1.5)
3-MeOC6H4B(OH)2 (1.5)
2-MeOC6H4B(OH)2 (1.5)
3-O2NC6H4B(OH)2 (1.5)
PhB(OH)2 (1.5)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
Dioxane/H2O (4:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
20
20
20
60
60
90
60
60
60
90
90
90
90
30
30
30
30
12 (70)
13 (60)
14 (51)
15 (57)
16 (61)
16 (78)
17 (75)
18 (78)
19 (40)
20 (trace)
0
0
8
48
52
2
0
0
0
8
11 (85)
25 (74)
26 (91) (99)b
27 (26) (50)b
28 (46) (97)b
28 (75)
PhB(OH)2 (2)
4-ClC6H4B(OH)2 (1.5)
3-ClC6H4B(OH)2 (1.5)
2-ClC6H4B(OH)2 (1.5)
Fur-2-ylB(OH)2 (2)
Fur-3-ylB(OH)2 (1.5)
Thien-2-ylB(OH)2 (2)
Thien-3-ylB(OH)2 (2)
Indol-5-ylB(OH)2 (2)
Indol-6-ylB(OH)2 (2)
Pyrid-3-ylB(OH)2 (2)
Pyrid-4-ylB(OH)2 (2)
29 (54)
30 (57)
31 (66)
32 (52)
21 (5)
4
33 (38)
c
c
c
22 (59)
23 (58)d
24 (58)d
0
2
34 (47)
35 (65)
36 (65)
0
Traces
Traces
97
0
97
0
a
Yields of biaryls 12e24 based on ArB(OH)2 not converted into 8-aryl substituted NS2028s.
Yield based on recovered NS2028 2.
Incomplete and inseperable reaction mixture.
Indole observed (traces).
b
c
d
Table 3
The SuzukieMiyaura reaction of NS2028 2 (0.186 mmol) with ArBF3K (1.5 equiv) in the presence of i-Pr2NEt (3 equiv) and Pd(OAc)2 (5 mol %) in dioxane/H2O (4:1) (0.5 mL) at
reflux
O
O
O
O
N
N
Br
N
Ar
N
ArBF3K
Ar-Ar
+
2
+
O
O
26-28, 39
2 (NS2028)
14-16, 37,38
Entry
ArBF3K
Time (min)
Yields (%)
AreAra
2
26e28, 39
1
2
3
4
5
6
7
8
2-MeOC6H4BF3K
3-O2NC6H4BF3K
3-O2NC6H4BF3K
PhBF3K
2,6-(MeO)2C6H3BF3K
2,6-(MeO)2C6H3BF3K
2-BrC6H4BF3K
10
150
180
120
20
60
30
10
14 (44)
15 (27)
15 (40)
16 (35)
37 (53)
37 (53)
38 (traces)
0
Traces
32
4
26 (93)
27 (21) (30)b
27 (17)
28 (50)
39 (25)
39 (25)
0
0
60
0
90
40
VinylBF3K
0
a
Yields of biaryls 14e16, 37 and 38 based on ArBF3K not converted into 8-aryl substituted NS2028s.
Yield based on recovered NS2028 2.
b
O
O
N
O
N
O
N
1M BBr3 in CH2Cl2 (3 equiv)
CH2Cl2, 0-20 oC, 6 h
MeO
HO
N
O
O
11 (4-MeO)
40 (4-HO), 91%
25
(3-MeO)
41
(3-HO), 90%
(2-HO), 93%
26
(2-MeO)
42
Scheme 4.

A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
4073
However, attempts to reduce the 8-(3-nitrophenyl) substituted
NS2028 28 to access the anilino analogue using either Pd/C, H2 inTHF
at ca. 20 ꢀC for 15 min, or Zn dust in AcOH at ca. 20 ꢀC, gave only
complex mixtures.
1269w, 1217w, 1161w, 1121m, 1082w, 1069w, 988m, 934w, 883w,
785w, 766m; dH (300 MHz, CDCl3) 8.04 (1H, d, J 9.0, Ar H), 7.11
(1H, dd, J 7.5, 7.5, Ar H), 6.92 (1H, dd, J 7.5, 7.5, Ar H), 6.82 (1H, d, J 9.0,
Ar H), 4.38 (2H, s, CH2), 4.24 (1H, br s, NH); dC (75 MHz, CDCl3) 154.9
(Cq), 152.3 (Cq), 134.7 (Cq), 127.4 (Ar CH), 120.5 (Ar CH), 120.0 (Cq),
116.5 (Ar CH), 115.5 (Ar CH), 38.5 (CH2); m/z (EI) 189 (Mþ, 69%), 144
(97), 118 (100), 105 (5), 91 (33), 77 (9), 63 (12), 51 (13).
3. Conclusion
Two modified synthetic routes to both ODQ 1 and NS2028 2
have been developed that give these two sGC inhibitors in relatively
good yields. In the latter case the synthesis affords NS2028 2 from
2-amino-4-bromophenol (3) in three steps with an overall yield of
85% and avoids the need for chromatography. Furthermore, con-
ditions have been developed that enable the 8-aryl and 8-hetero-
aryl derivatives of NS2028 to be prepared directly from NS2028 2
using SuzukieMiyaura reaction. The biological properties of these
20 new NS2028 analogues are currently under investigation.
4.2.2. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one 1. To a stirred
solution of 4,5-dihydro-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
10 (314 mg, 1.66 mmol) in MeCN (10 mL) at ca. 20 ꢀC was added
KMnO4 (288 mg, 1.82 mmol). After 5 min no starting material
remained (TLC), the colour of the reaction mixture changed from
yellow to colourless and some brown precipitate appeared. The
reaction mixture was poured into water (50 mL), extracted with
DCM (3ꢁ20 mL), and the combined organic phases dried (Na2SO4),
filtered and the volatiles evaporated in vacuo. Recrystallization of
the residue gave the title compound 1 (273 mg, 88%) as colourless
prisms, mp (DSC) onset: 162 ꢀC, peak max: 163 ꢀC (from EtOH) (lit.,7
164e166 ꢀC), Rf (DCM) 0.49; (found: C, 57.9; H, 2.6; N, 22.5.
C9H5N3O2 requires C, 57.8; H, 2.7; N, 22.5%); lmax (DCM)/nm 234
4. Experimental
4.1. General methods and materials
DCM was freshly distilled from CaH2 under argon. Reactions
were protected from atmospheric moisture by CaCl2 drying tubes.
Anhydrous Na2SO4 was used for drying organic extracts, and all
volatiles were removed under reduced pressure. All reaction mix-
tures and column eluents were monitored by TLC using commercial
glass backed thin layer chromatography (TLC) plates (Merck Kie-
selgel 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 us-
ing Merck Silica Gel 60 (less than 0.063 mm). Melting and de-
composition points were determined using either a PolyTherm-A,
Wagner & Munz, Koefler-Hotstage Microscope apparatus or using
a TA Instrument DSC Q1000 with samples hermetically sealed in
aluminium pans under an argon atmosphere; using heating rates of
5 ꢀC/min. Solvents used for recrystallization are indicated after the
melting point. UV spectra were obtained using a PerkineElmer
Lambda-25 UV/vis spectrophotometer and inflections are identi-
fied by the abbreviation ‘inf’. IR spectra were recorded on a Shi-
madzu FTIR-NIR Prestige-21 spectrometer with a Pike Miracle Ge
ATR accessory and strong, medium and weak peaks are represented
by s, m and w, respectively. 1H and 13C NMR spectra were recorded
on a Bruker Avance 300 machine (at 300 and 75 MHz, respectively).
Deuterated solvents were used for homonuclear lock and the sig-
nals are referenced to the deuterated solvent peaks. Low resolution
(EI) mass spectra were recorded on a Shimadzu Q2010 GC/MS with
direct inlet probe. 2-Amino-4-bromophenol 3,12 8-bromo-4H-
[1,2,4]oxadiazolo[3,4-c][1,4]-benzoxazin-1-one (NS2028) 2,7 and
3,4-dihydro-2(1H)-quinoxalinone oxime 88 were prepared using
literature procedures.
(log e 3.29), 254 inf (2.95), 287 inf (2.83), 296 (2.87), 310 (2.79), 331
inf (2.70), 345 (2.72), 360 inf (2.53); nmax/cmꢂ1 3115w, 3084w and
3057w (Ar CH), 1782s, 1769s (C]O), 1614w, 1591w, 1574s, 1543w,
1487w, 1462s, 1423w, 1418w, 1360w, 1348m, 1192w, 1159m, 1117s,
1092w, 1084w, 991w, 986w, 959w, 912m, 901w, 874w, 858m, 775s,
758s; dH (300 MHz, CDCl3) 8.70 (1H, s, H-4), 8.56 (1H, dd, J 8.1, 1.2,
H-6 or 9), 7.94 (1H, dd, J 8.1,1.5, H-6 or 9), 7.67 (1H, ddd, J 7.8, 7.8,1.5,
H-7 or 8), 7.56 (1H, ddd, J 8.1, 8.1, 1.5, H-7 or 8); dC (75 MHz, DMSO-
d6) 155.1 (Cq), 147.8 (Cq), 143.4 (Cq), 135.2 (Ar CH), 132.2 (Ar CH),
130.6 (Ar CH), 128.1 (Ar CH), 125.6 (Cq), 114.8 (Ar CH); m/z (EI)
187 (Mþ, 59%), 143 (100), 116 (63), 102 (12), 89 (20), 75 (13), 63 (26),
51 (13).
4.3. Preparation of NS2028 precursors
4.3.1. 2-(2-Amino-4-bromophenoxy)acetonitrile 9. To
a
stirred
mixture of 2-amino-4-bromophenol 3 (20.1 g, 107 mmol) and
K2CO3 (32.5 g, 235 mmol) in dry MeCN (300 mL) was added
chloroacetonitrile (8.88 g, 7.43 mL, 117.6 mmol) and the suspension
was stirred and heated at reflux for 12 h. After cooling to ca. 20 ꢀC,
the suspension was filtered (Celite) and the Celite rinsed with ac-
etone. The filtrate and acetone rinses were combined, the volatiles
removed in vacuo and the solid residue was dissolved in DCM,
passed through a thin layer of silica and rinsed with DCM to give
a light yellow solution. Removal of the volatiles in vacuo and re-
crystallization of the residue gave the title compound 9 (22.5 g, 93%)
as tawny plates, mp (DSC) onset: 108 ꢀC, peak max: 109 ꢀC (from
CHCl3), Rf (DCM) 0.49; (found: C, 42.4; H, 3.1; N, 12.4. C8H7BrN2O
requires C, 42.3; H, 3.1; N, 12.3%); lmax (DCM)/nm 243 (log e 2.75),
296 (2.48); nmax/cmꢂ1 3472w and 3377m (NH2), 3206w, 3067w (Ar
CH), 2913w, 2264w (C^N), 1630m, 1593w, 1504s, 1439w, 1420w,
1375w, 1296w, 1275w, 1248w, 1207s, 1144w, 1092w, 1065w, 1045m,
1007w, 949w, 887w, 854m, 799w, 779s; dH (300 MHz, acetone-d6)
6.97e6.88 (2H, m, H-3 and 6), 6.73 (1H, dd, J 8.5, 2.5, H-5), 5.05 (2H,
s, CH2O), 4.86 (2H, br s, NH2); dC (75 MHz, acetone-d6) 144.0 (Cq),
141.3 (Cq),119.5 (Ar CH),118.0 (Ar CH),116.7 (Cq),116.3 (Cq),115.7 (Ar
CH), 55.0 (CH2); m/z (EI) 228 (Mþþ2, 34%), 226 (Mþ, 36), 188 (100),
186 (99), 160 (54), 158 (56), 145 (2), 131 (3), 107 (10), 90 (5), 78 (32),
63 (8), 52 (34).
4.2. Preparation of ODQ 1
4.2.1. 4,5-Dihydro[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one 10. A stir-
red mixture of 3,4-dihydro-2(1H)-quinoxalinoneoxime 8 (499 mg,
3.06 mmol) and 1,10-carbonyldiimidazole (CDI) (550 mg, 3.39 mmol)
in dry THF (30 mL) was refluxed for 5 h. The reaction mixture was
cooled to ca. 20 ꢀC, and the volatiles removed in vacuo. The resulting
solid was dissolved in DCM (50 mL), washed with water (2ꢁ25 mL),
dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Re-
crystallization of the residue gave the title compound 10 (388 mg,
67%) as pale yellow needles, mp (DSC) onset: 146 ꢀC, peak max:
163 ꢀC (decomp.) (from EtOH) (lit.,8 149e150 ꢀC), Rf (DCM) 0.36;
(found: C, 57.2; H, 3.6; N, 22.2. C9H7N3O2 requires C, 57.1; H, 3.7; N,
22.2%); nmax/cmꢂ1 3379w and 3345br w (NH), 1776m, 1757s (C]O),
1713w, 1626m, 1599m, 1504s, 1454w, 1433s, 1348w, 1331s, 1314m,
4.3.2. 6-Bromo-2H-1,4-benzo[b][1,4]oxazin-3(4H)-one oxime 6. A
mixture of hydroxylamine hydrochloride (12.4 g, 178 mmol) and
NaHCO3 (15.0 g, 178 mmol) in water (85 mL) was stirred at ca. 20 ꢀC
for 30 min. To this mixture a solution of 2-(4-bromo-2-amino-
phenoxy)-acetonitrile 9 (20.2 g, 89.0 mmol) in EtOH (125 mL) was

4074
A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
added and the resulting mixture was heated at reflux for 48 h. After
cooling to ca. 3e5 ꢀC the precipitate that formed was filtered off,
washed (cold water), dried under vacuum at ca. 60 ꢀC and recrys-
tallized to give the title compound 6 (19.7 g, 92%) as tawny prisms,
mp (DSC) onset: 177 ꢀC, peak max: 184 ꢀC (decomp.) (from EtOH/
H2O) (lit.,7 196e198 ꢀC); Rf (Et2O) 0.75; (found: C, 39.6; H, 2.8; N,
11.5. C8H7BrN2O2 requires C, 39.5; H, 2.9; N, 11.5%); lmax (DCM)/nm
C, 64.8; H, 3.9; N, 9.6. C16H12N2O4 requires C, 64.9; H, 4.1; N, 9.5%);
lmax (DCM)/nm 230 (log 3.61), 262 (3.32), 286 inf (3.15); nmax
e
/
cmꢂ1 3015w, 2997w, 2916w, 2832w, 1776s (C]O), 1634m, 1599m,
1582w, 1510m, 1489m, 1472m, 1447w, 1429w, 1404w, 1342w,
1283w, 1267w, 1250w, 1225s, 1190w, 1161w, 1150w, 1123m, 1092m,
1053vw, 1036m, 1020m, 1005w, 899w, 883w, 874m, 866w, 833m,
814w, 795m, 783s, 762w, 752w; dH (300 MHz, CDCl3) 8.31 (1H, d, J
2.1, H-9), 7.45 (1H, dd, J 8.5, 2.3, H-7), 7.37 (1H, dd, J 7.9, 7.9, Ar H),
7.17 (1H, d, J 8.5, H-6), 7.18e7.13 (1H, m, Ar H), 7.09 (1H, dd, J 2.3, 2.3,
Ar H), 6.92 (2H, ddd, J 8.3, 2.4, 0.8, Ar H), 5.14 (2H, s, CH2O), 3.87 (3H,
s, CH3O); dC (75 MHz, CDCl3) 160.1 (Cq), 154.1 (Cq), 150.8 (Cq), 144.0
(Cq), 140.7 (Cq), 137.2 (Cq), 130.0 (Ar CH), 126.4 (Ar CH), 121.4 (Cq),
119.5 (Ar CH), 118.1 (Ar CH), 115.0 (Ar CH), 113.1 (Ar CH), 112.9 (Ar
CH), 60.2 (CH2O), 55.4 (CH3O); m/z (EI) 296 (Mþ, 100%), 252 (55),
222 (9), 209 (26),195 (10),182 (5),169 (13),155 (9),153 (9),140 (17),
127 (25), 114 (6), 101 (5), 89 (4), 77 (11), 63 (11), 51 (5).
229 (log
e
3.17), 261 (2.95), 299 (2.55); nmax/cmꢂ1 3366m (NH),
3103br w, 2804br w, 1670s, 1603s, 1495s, 1439m, 1385m, 1358m,
1302w, 1279m, 1250w, 1198s, 1119m, 1072w, 1030w, 1007m, 945s,
887m, 856m, 824s, 777s; dH (300 MHz, DMSO-d6) 10.04 (1H, s, NH),
9.58 (1H, s, OH), 7.24 (1H, d, J 2.1, H-5), 6.88 (1H, dd, J 8.5, 2.1, H-7),
6.81 (1H, d, J 8.5, H-8), 4.48 (2H, s, CH2O); dC (75 MHz, DMSO-d6)
143.4 (Cq), 140.9 (Cq), 130.7 (Cq), 122.5 (Ar CH), 118.1 (Ar CH), 117.5
(Ar CH), 113.7 (Ar CH), 63.6 (CH2); m/z (EI) 244 (Mþþ2, 97%), 242
(Mþ, 100), 226 (37), 224 (33), 213 (9), 211 (8), 199 (46), 197 (50), 184
(4), 172 (62), 170 (75), 158 (14), 144 (9), 132 (6), 117 (16), 104 (20), 90
(34), 78 (48), 63 (100), 51 (68).
4.4.3. 8-(2-Methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 26. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 2-methox-
yphenylboronic acid (42.3 mg, 0.279 mmol) in dioxane/water (4:1)
4.4. Suzuki coupling of NS2028 with arylboronic acids
[dioxane/water (4:1) solvent system]
(0.5 mL) with N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and
4.4.1. 8-(4-Methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 11 (typical procedure, see Table 2). To a stirred mixture
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 20 min gave on
chromatography (DCM) 2,20-dimethoxybiphenyl 14 as colourless
needles (6 mg, 51%), mp 154e155 ꢀC (lit.,13 156e157 ꢀC), Rf (DCM)
0.62; identical to an authentic sample. Further elution (DCM) gave
unreacted starting material 2 (NS2028) (4 mg, 8%) followed by the
title compound 26 (50.1 mg, 91%) as colourless prisms, mp (DSC)
onset: 164 ꢀC, peak max: 165 ꢀC (from 1,2-dichloroethane), Rf
(DCM) 0.42; (found: C, 64.7; H, 4.0; N, 9.5. C16H12N2O4 requires C,
of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]-benzoxazin-1-one
2
(50.0 mg, 0.186 mmol) and 4-methoxyphenylboronic acid (42.3 mg,
0.279 mmol) in dioxane/water (4:1) (0.5 mL) was added dropwise
N-ethyldiisopropylamine (96.4
mL, 0.557 mmol). The stirred re-
action mixture was then immersed into a preheated oil bath at ca.
110 ꢀC until all the solids dissolved and then Pd(OAc)2 (2.09 mg,
9.30
m
mol) was added in one portion. The reaction mixture was
64.9; H, 4.1; N, 9.5%); lmax (DCM)/nm 231 (log e 3.47), 289 (3.07);
then allowed to stir at ca. 110 ꢀC for 20 min and then cooled to ca.
20 ꢀC. The volatiles were removed in vacuo and the residue dis-
solved in DCM (5 mL), adsorbed onto silica and chromatographed
(DCM) to give 4,40-dimethoxybiphenyl 12 as colourless needles
(9 mg, 70%), mp 170e171 ꢀC (lit.,13 173e174 ꢀC), Rf (DCM) 0.62;
identical to an authentic sample. Further elution (DCM) gave the
title compound 11 (46.8 mg, 85%) as colourless prisms, mp (DSC)
onset: 207 ꢀC, peak max: 209 ꢀC (from 1,2-dichloroethane) (lit.,7
209 ꢀC), Rf (DCM) 0.42; (found: C, 64.8; H, 4.0; N, 9.4. C16H12N2O4
nmax/cmꢂ1 3076w (Ar CH), 2949w, 2905w, 2835w, 1778s (C]O),
1634m, 1607w, 1510w, 1487s, 1472s, 1454m, 1439w, 1404m, 1342w,
1296w, 1256s, 1240m, 1221w, 1184w, 1152m, 1119s, 1088m, 1061w,
1036m, 1024s, 891w, 885w, 849w, 831m, 810w, 783w; dH
(300 MHz, CDCl3) 8.28 (1H, d, J 1.9, H-9), 7.40 (1H, dd, J 8.5, 2.1, H-7),
7.38e7.28 (2H, m, Ar H), 7.15 (1H, d, J 8.5, H-6), 7.07e6.97 (2H, m, Ar
H), 5.12 (2H, s, CH2O), 3.84 (3H, s, CH3O); dC (75 MHz, CDCl3) 156.3
(Cq), 154.1 (Cq), 150.9 (Cq), 143.5 (Cq), 134.5 (Cq), 130.6 (Ar CH), 129.2
(Ar CH), 128.9 (Ar CH), 128.6 (Cq), 120.9 (Ar CH), 120.7 (Cq), 117.5 (Ar
CH), 117.4 (Ar CH), 111.2 (Ar CH), 60.1 (CH2O), 55.5 (CH3O); m/z (EI)
296 (Mþ, 100%), 251 (9), 223 (13), 209 (29), 196 (8), 183 (51), 169
(13), 155 (32), 140 (9), 127 (23), 115 (8), 101 (5), 89 (4), 77 (14), 63
(11), 51 (5).
requires C, 64.9; H, 4.1; N, 9.5%); lmax (DCM)/nm 242 (log e 3.40),
273 (3.43); nmax/cmꢂ1 3078w (Ar CH), 3015w, 2957w, 2934w,
2914w, 2833w, 1769s (C]O), 1634m, 1609m, 1499s, 1474s, 1443w,
1425m, 1393w, 1344m, 1300m, 1275m, 1256m, 1240s, 1227m,
1182m, 1152m, 1121s, 1092w, 1043m, 1026m, 1018s, 893w, 880w,
843w, 822s, 787w; dH (300 MHz, CDCl3) 8.26 (1H, d, J 2.3, H-9), 7.51
(2H, d, J 9.0, Ar H), 7.41 (1H, dd, J 8.5, 2.3, H-7), 7.15 (1H, d, J 8.5, H-6),
6.98 (2H, d, J 9.0, Ar H), 5.12 (2H, s, CH2O), 3.85 (3H, s, CH3O); dC
(75 MHz, CDCl3) 159.5 (Cq), 154.1 (Cq), 150.8 (Cq), 143.4 (Cq), 137.1
(Cq), 131.7 (Cq), 128.0 (Ar CH), 125.8 (Ar CH), 121.4 (Cq), 118.1 (Ar CH),
114.4 (Ar CH), 114.3 (Ar CH), 60.1 (CH2O), 55.4 (CH3O); m/z (EI) 296
(Mþ, 79%), 252 (35), 237 (100), 209 (58), 182 (7), 169 (5), 155 (9), 153
(10),140 (10),127 (28),114 (7),101 (7), 89 (6), 77 (17), 63 (14), 51 (6).
4.4.4. 8-(3-Nitrophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-
1-one 27. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-
c][1,4]benzoxazin-1-one
phenylboronic acid (46.5 mg, 0.279 mmol) in dioxane/water (4:1)
(0.5 mL) with N-ethyldiisopropylamine (96.4 L, 0.557 mmol) and
Pd(OAc)2 (2.09 mg, 9.30
mol) at ca. 110 ꢀC for 1 h gave on chro-
2
(50.0 mg, 0.186 mmol), 3-nitro-
m
m
matography (DCM) 3,30-dinitrobiphenyl 15 as yellow plates (16 mg,
57%), mp 200e201 ꢀC (lit.,13 mp 201e202 ꢀC), Rf (DCM) 0.80;
identical to an authentic sample. Further elution (DCM) gave
unreacted starting material 2 (NS2028) (24.0 mg, 48%) and then the
title compound 27 (15.1 mg, 26%) as colourless cotton needles, mp
(DSC) onset: 220 ꢀC, peak max: 221 ꢀC (from DCM/pentane), Rf
(DCM) 0.53; (found: C, 57.9; H, 3.0; N, 13.4. C15H9N3O5 requires C,
4.4.2. 8-(3-Methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 25. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 3-methox-
yphenylboronic acid (42.3 mg, 0.279 mmol) in dioxane/water (4:1)
(0.5 mL) with N-ethyldiisopropylamine (96.4
m
L, 0.557 mmol) and
57.9; H, 2.9; N, 13.5%); lmax (DCM)/nm 238 (log e 3.59), 257 inf
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 20 min gave on
(3.49); nmax/cmꢂ1 3107w, 3082w, and 3011w (Ar CH), 2943w,
2862w, 1775s (C]O), 1622w, 1607w, 1530s, 1512s, 1483s, 1437m,
1396w, 1352s, 1314w, 1298m, 1269w, 1260m, 1244m, 1233m,
1159w, 1126m, 1088m, 1049w, 1022s, 907w, 883s, 837m, 829m,
804s; dH (300 MHz, CDCl3) 8.41 (1H, dd, J 2.0, 2.0, Ar H), 8.35 (1H, d, J
2.3, H-9), 8.22 (1H, ddd, J 8.3, 2.1, 0.9, Ar H), 7.90 (1H, ddd, J 7.7, 0.9,
0.9, Ar H), 7.63 (1H, dd, J 8.1, 8.1, Ar H), 7.50 (1H, dd, J 8.6, 2.2, H-7),
chromatography (DCM) 3,30-dimethoxybiphenyl 13 as a colourless
oil (9 mg, 60%) (lit.,14 oil), Rf (DCM) 0.62; m/z (EI) 214 (Mþ, 100%),
171 (67), 154 (31), 141 (31), 139 (28), 128 (55), 115 (29); identical to
an authentic sample. Further elution (DCM) gave the title compound
25 (40.8 mg, 74%) as colourless prisms, mp (DSC) onset: 171 ꢀC,
peak max: 173 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.42; (found:

A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
4075
7.25 (1H, d, J 8.6, H-6), 5.18 (2H, s, CH2O); dC (75 MHz, DMSO-d6)
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 1 h gave on chro-
154.0 (Cq), 151.4 (Cq), 148.4 (Cq), 145.0 (Cq), 140.2 (Cq), 132.9 (Ar CH),
132.8 (Cq), 130.7 (Ar CH), 126.1 (Ar CH), 122.4 (Ar CH), 121.9 (Cq),
120.8 (Ar CH), 118.4 (Ar CH), 113.8 (Ar CH), 59.9 (CH2O); m/z (EI) 311
(Mþ, 100%), 267 (68), 240 (7), 221 (20), 209 (14), 193 (52), 167 (59),
153 (14), 139 (80), 126 (15), 113 (8), 100 (4), 89 (7), 75 (7), 70 (6), 63
(10), 50 (4).
matography (DCM) 2,20-dichlorobiphenyl 19, as colourless needles
(7 mg, 40%), mp 55e56 ꢀC (lit.,13 57e58 ꢀC), Rf (DCM) 0.82; identical
to an authentic sample. Further elution (DCM) gave the title com-
pound 31 (36.9 mg, 66%) as colourless prisms, mp (DSC) onset:
180 ꢀC, peak max: 180 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.67;
(found: C, 60.1; H, 3.0; N, 9.2. C15H9ClN2O3 requires C, 59.9; H, 3.0;
N, 9.3%); lmax (DCM)/nm 232 (log e
3.51), 281 inf (2.81); nmax/cmꢂ1
4.4.5. 8-(4-Chlorophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 29. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 4-chlor-
ophenylboronic acid (43.6 mg, 0.279 mmol) in dioxane/water (4:1)
3051w (Ar CH), 2911w, 1769s (C]O), 1632m, 1609w, 1510m, 1485s,
1464w, 1433m, 1402m, 1358w, 1346w, 1294w, 1277w, 1256w,
1240w, 1221m, 1161w, 1123m, 1090m, 1070m, 1036m, 1020s, 993w,
966w, 955w, 891w, 881w, 847m, 833w, 808w, 766s; dH (300 MHz,
CDCl3) 8.17 (1H, d, J 2.1, H-9), 7.52e7.44 (1H, m, Ar H), 7.36e7.29
(4H, m, Ar H and H-7), 7.19 (1H, d, J 8.5, H-6), 5.16 (2H, s, CH2O); dC
(75 MHz, CDCl3) 1 Ar CH missing 154.0 (Cq), 150.7 (Cq), 144.0 (Cq),
138.5 (Cq), 135.3 (Cq), 132.4 (Cq), 131.2 (Ar CH), 130.0 (Ar CH), 129.1
(Ar CH), 129.0 (Ar CH), 127.0 (Ar CH), 120.7 (Cq), 117.5 (Ar CH), 60.1
(CH2O); m/z (EI) 302 (Mþþ2, 34%), 300 (Mþ, 100), 258 (26), 256
(73), 229 (19), 216 (5), 202 (51), 177 (6), 164 (13), 153 (20), 139 (76),
126 (14), 113 (8), 101 (7), 87 (8), 75 (15), 69 (9), 63 (16), 51 (8).
(0.5 mL) with N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 60 min gave on
chromatography (DCM) 4,40-dichlorobiphenyl 17 as colourless
needles (15 mg, 75%), mp 141e143 ꢀC (lit.,13 149e154 ꢀC), Rf (DCM)
0.82; identical to an authentic sample. Further elution (DCM) gave
the title compound 29 (30.2 mg, 54%) as colourless prisms, mp (DSC)
onset: 210 ꢀC, peak max: 211 ꢀC (from 1,2-dichloroethane), Rf (DCM)
0.67; (found: C, 59.9; H, 3.0; N, 9.4. C15H9ClN2O3 requires C, 59.9; H,
3.0; N, 9.3%); lmax (DCM)/nm 241 (log e
3.52), 266 (3.41); nmax/cmꢂ1
3065w (Ar CH), 2997w, 2928w, 1773s (C]O), 1636m, 1609w,
1520w, 1487s, 1445w, 1420m, 1389w, 1373w, 1346w, 1292w, 1283w,
1269w, 1256w, 1248w, 1234m, 1153w, 1117s, 1092m, 1040w, 1016s,
895w, 881w, 856w, 822s, 808m; dH (300 MHz, CDCl3) 8.28 (1H, d, J
2.1, H-9), 7.50 (2H, d, J 8.7, Ar H), 7.45e7.38 (3H, m, Ar H & H-7), 7.19
(1H, d, J 8.5, H-6), 5.14 (2H, s, CH2O); dC (75 MHz, DMSO-d6) 153.9
(Cq), 151.4 (Cq), 144.4 (Cq), 137.4 (Cq), 133.8 (Cq), 132.5 (Cq), 129.0 (Ar
CH), 128.1 (Ar CH), 125.5 (Ar CH), 121.7 (Cq), 118.2 (Ar CH), 113.4 (Ar
CH), 59.9 (CH2); m/z (EI) 302 (Mþþ2, 30%), 300 (Mþ, 86), 258 (31),
256 (82), 229 (17), 216 (4), 202 (46), 200 (20), 188 (5), 174 (8), 164
(12), 153 (19), 139 (100), 126 (16), 113 (10), 101 (12), 87 (9), 75 (17),
69 (8), 63 (17), 51 (8).
4.5. Suzuki coupling of NS2028 with arylboronic acids [MeCN/
H2O (9:1), solvent system]
4.5.1. 8-Phenyl-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one 28
(typical procedure, see Table 2). To a stirred mixture of 8-bromo-
4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
2
(50.0 mg,
0.186 mmol) and phenylboronic acid (45.3 mg, 0.372 mmol) in
MeCN/water (9:1) (0.5 mL) was added dropwise N-ethyl-
diisopropylamine (96.4
ture was then immersed into a preheated oil bath at ca. 110 ꢀC until
all the solids dissolved and then Pd(OAc)2 (2.09 mg, 9.30 mol) was
mL, 0.557 mmol). The stirred reaction mix-
m
added in one portion. The reaction mixture was then allowed to stir
at ca. 110 ꢀC for 1.5 h and then cooled to ca. 20 ꢀC. The volatiles were
removed in vacuo and the residue dissolved in DCM (5 mL),
adsorbed onto silica and chromatographed (DCM) to give biphenyl
16 as colourless prisms (14 mg, 78%), mp 65e67 ꢀC (lit.,13 mp
67e69 ꢀC), Rf (DCM) 0.78; identical to an authentic sample. Further
elution (DCM) gave crude product, which co-ran with small amount
of unreacted starting material (ca. 2% based on 1H NMR data). Re-
crystallization of crude product gave title compound 28 (37.1 mg,
75%) as colourless prisms, mp (DSC) onset: 176 ꢀC, peak max: 177 ꢀC
(from 1,2-dichloroethane), Rf (DCM) 0.67; (found: C, 67.6; H, 3.7; N,
10.4. C15H10N2O3 requires C, 67.7; H, 3.8; N, 10.5%); lmax (DCM)/nm
4.4.6. 8-(3-Chlorophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 30. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 3-chlor-
ophenylboronic acid (43.6 mg, 0.279 mmol) in dioxane/water (4:1)
(0.5 mL) with N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 1 h gave on chro-
matography (DCM) 3,30-dichlorobiphenyl 18 as a colourless oil
(15 mg, 78%) (lit.,15 oil), Rf (DCM) 0.82; m/z (EI) 222 (Mþ, 100%), 186
(7), 152 (90); identical to an authentic sample. Further elution gave
the title compound 30 (31.9 mg, 57%) as colourless prisms, mp (DSC)
onset: 143 ꢀC, peak max: 145 ꢀC (from 1,2-dichloroethane), Rf
(DCM) 0.67; (found: C, 60.0; H, 2.9; N, 9.3. C15H9ClN2O3 requires C,
236 (log e
3.54), 258 inf (3.35); nmax/cmꢂ1 3063w and 3034w (Ar
CH), 2907w, 1775s (C]O), 1634m, 1609w, 1576w, 1508w, 1485s,
1474m, 1445m, 1400m, 1368w, 1341w, 1287w, 1275w, 1258w,
1246w, 1227m, 1148m, 1111s, 1090m, 1076w, 1043m, 1018s, 1001w,
989w, 889w, 883w, 841m, 827m, 808w, 760s; dH (300 MHz, CDCl3)
8.33 (1H, d, J 2.1, H-9), 7.62e7.55 (2H, m, Ar H), 7.50e7.42 (3H, m, Ar
H and H-7), 7.41e7.34 (1H, m, Ar H), 7.19 (1H, d, J 8.5, H-6), 5.14 (2H,
s, CH2O); dC (75 MHz, CDCl3) 154.1 (Cq), 150.8 (Cq), 143.9 (Cq), 139.1
(Cq), 137.3 (Cq), 129.0 (Ar CH), 127.9 (Ar CH), 127.0 (Ar CH), 126.3 (Ar
CH), 121.4 (Cq), 118.2 (Ar CH), 114.9 (Ar CH), 60.2 (CH2O); m/z (EI)
266 (Mþ, 100%), 222 (71), 195 (17), 182 (6), 168 (43), 166 (27), 153
(9), 139 (74), 127 (27), 115 (9), 111 (10), 102 (9), 89 (8), 77 (18), 70
(13), 63 (20), 51 (15).
59.9; H, 3.0; N, 9.3%); lmax (DCM)/nm 232 (log e 3.51), 262 inf (3.31);
nmax/cmꢂ1 3061w (Ar CH), 2909w, 1778s (C]O), 1632w, 1611w,
1597w, 1564w, 1508w, 1477s, 1439w, 1429w, 1389w, 1342w, 1288w,
1260w, 1240w, 1223w, 1152w, 1113m, 1097w, 1047m, 1020m,
1007w, 995w, 964w, 897w, 885w, 853w, 839m, 810w, 787s, 762m;
dH (300 MHz, CDCl3) 8.29 (1H, d, J 2.1, H-9), 7.55 (1H, dd, J 1.6, 1.6, Ar
H), 7.47e7.32 (4H, m, Ar H and H-7), 7.20 (1H, d, J 8.5, H-6), 5.15 (2H,
s, CH2O); dC (75 MHz, CDCl3) 154.1 (Cq), 150.6 (Cq), 144.3 (Cq), 141.0
(Cq),135.9 (Cq),134.9 (Cq),130.2 (Ar CH),127.9 (Ar CH),127.0 (Ar CH),
126.4 (Ar CH), 125.2 (Ar CH), 121.5 (Cq), 118.4 (Ar CH), 114.9 (Ar CH),
60.2 (CH2O); m/z (EI) 302 (Mþþ2, 36%), 300 (Mþ,100), 258 (30), 256
(85), 229 (18), 216 (5), 202 (48), 200 (16), 188 (4), 177 (5), 164 (12),
153 (19), 139 (78), 126 (14), 113 (9), 101 (9), 87 (7), 75 (16), 69 (11),
63 (17), 51 (8).
4.5.2. 8-(Fur-2-yl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
32. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]
benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), fur-2-ylboronic acid
(41.6 mg, 0.372 mmol) in MeCN/water (9:1) (0.5 mL) with N-eth-
4.4.7. 8-(2-Chlorophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 31. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 2-chlor-
ophenylboronic acid (43.6 mg, 0.279 mmol) in dioxane/water (4:1)
yldiisopropylamine (96.4 mL, 0.557 mmol) and Pd(OAc)2 (2.09 mg,
9.30 m
mol) at ca. 110 ꢀC for 1.5 h gave on chromatography (DCM)
2,20-bifuran 20 (trace) as a volatile colourless oil (lit.,16 oil), m/z (EI)
(0.5 mL) with N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and
134 (Mþ, 100%), 105 (32), 78 (58), 51 (31), 77 (14), 52 (14), 50 (11) 39

4076
A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
(17), identical to an authentic sample. Further elution (DCM) gave
unreacted starting material (NS2028) (4 mg, 8%) and then the title
compound 28 (25.3 mg, 53%) as brown needles, mp (DSC) onset:
185 ꢀC, peak max: 187 ꢀC (from DCM/pentane), Rf (DCM) 0.67;
(found: C, 61.0; H, 3.0; N, 10.8. C13H8N2O4 requires C, 60.9; H, 3.2; N,
127.5 (Ar CH), 125.8 (Ar CH), 125.0 (Ar CH), 121.6 (Cq), 121.1 (Ar CH),
118.0 (Ar CH), 112.8 (Ar CH), 59.8 (CH2O); m/z (EI) 272 (Mþ, 100%),
228 (69), 200 (29), 188 (4), 174 (27), 172 (20), 160 (4), 146 (20), 134
(5), 116 (9), 102 (33), 89 (10), 75 (5), 69 (7), 63 (8), 51 (5).
10.9%); lmax (DCM)/nm 238 (log
e
3.32), 289 (3.43); nmax/cmꢂ1
4.5.5. 8-(1H-Indol-5-yl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-
1-one 35. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 1H-indol-5-ylbor-
onic acid (59.8 mg, 0.372 mmol) in MeCN/water (9:1) (0.5 mL) with
3009w (Ar CH),1798m,1780s (C]O),1645w,1632m,1614m,1557w,
1539w, 1514m, 1495s, 1470s, 1410m, 1344m, 1288m, 1261m, 1246w,
1227m, 1148m, 1111m, 1092m, 1049m, 1016s, 995m, 912w, 883m,
829m, 818m, 812m, 800m, 760s; dH (300 MHz, CDCl3) 8.36 (1H, d, J
1.9, H-9), 7.53 (1H, dd, J 8.7,1.9, H-7), 7.48 (1H, d, J 1.1, Ar H), 7.13 (1H,
d, J 8.5, H-6), 6.68 (1H, d, J 3.4, Ar H), 6.48 (1H, dd, J 3.4, 1.9, Ar H),
5.12 (2H, s, CH2O); dC (75 MHz, CDCl3) 154.0 (Cq), 152.1 (Cq), 150.7
(Cq), 143.5 (Cq), 142.5 (Ar CH), 127.2 (Cq), 123.0 (Ar CH), 121.4 (Cq),
118.2 (Ar CH), 111.9 (Ar CH), 111.7 (Ar CH), 105.7 (Ar CH), 60.1
(CH2O); m/z (EI) 256 (Mþ, 100%), 212 (32), 183 (41), 172 (3), 156 (39),
130 (26), 116 (9), 106 (6), 102 (54), 89 (17), 75 (17), 63 (20), 51 (17).
N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and Pd(OAc)2
(2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 30 min gave on chromatogra-
phy (DCM) indole (trace), then 5,50-biindole 23 as grey needles
(17 mg, 58%), mp 198e200 ꢀC (lit.,19 mp 200e202 ꢀC), Rf (DCM) 0.56;
identical to an authentic sample. Further elution (DCM) gave the title
compound 35 (36.9 mg, 65%) as tawny needles, mp (DSC) onset:
240 ꢀC, peak max: 247 ꢀC (decomp.) (from DCM/pentane), Rf (DCM)
0.44; (found: C, 66.7; H, 3.5; N, 13.6. C17H11N3O3 requires C, 66.9; H,
3.6; N, 13.8%); lmax (DCM)/nm 245 (log e 3.70), 284 inf (3.28); nmax/
4.5.3. 8-(Fur-3-yl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
33. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]
benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), fur-2-ylboronic acid
(41.6 mg, 0.372 mmol) in MeCN/water (9:1) (0.5 mL) with N-ethyl-
cmꢂ1 3379br w (NH), 3134w and 3115w (Ar CH), 1786s (C]O),
1634m, 1607w, 1578w, 1520w, 1504m, 1474s, 1454w, 1427w, 1402w,
1346m, 1312w, 1300w, 1258w, 1238w, 1221m, 1179w, 1155w, 1142w,
1117s, 1103m, 1092m, 1042w, 1034w, 1024w, 1013m, 997w, 897w,
883m, 874m, 808s, 773s; dH (300 MHz, acetone-d6) 10.33 (1H, br s,
NH), 8.32 (1H, d, J 1.9, H-9), 7.83 (1H, br s, Ar H), 7.57 (1H, dd, J 8.7, 2.3,
H-7), 7.53 (1H, d, J 8.7, Ar H), 7.43e7.35 (2H, m, Ar H), 7.22 (1H, d, J 8.7,
H-6), 6.56 (1H, br s, Ar H), 5.33 (2H, s, CH2O); dC (75 MHz, acetone-d6)
155.2 (Cq), 152.6 (Cq), 144.5 (Cq), 139.1 (Cq),136.9 (Cq),131.7 (Cq),129.7
(Cq), 126.7 (Ar CH), 126.5 (Ar CH), 122.9 (Cq), 121.4 (Ar CH), 119.3 (Ar
CH), 118.7 (Ar CH), 115.0 (Ar CH), 112.7 (Ar CH), 102.9 (Ar CH), 61.0
(CH2O); m/z (EI) 305 (Mþ, 100%), 261 (58), 233 (33), 205 (15), 192 (6),
178 (22),164 (4),152 (11),139 (4),131 (6),117 (3),104 (14), 89 (13), 76
(10), 70 (5), 63 (7), 58 (5).
diisopropylamine (96.4
mL, 0.557 mmol) and Pd(OAc)2 (2.09 mg,
9.30
m
mol) at ca.110 ꢀC for 1.5 h gave on chromatography (DCM) 3,30-
bifuran 21 as colourless needles (1 mg, 5%), mp 41e43 ꢀC (lit.,17
44e45 ꢀC), Rf (DCM) 0.82; identical to an authentic sample. Fur-
ther elution (DCM) gave unreacted starting material (NS2028) (2 mg,
4%) and then the title compound 33 (18.1 mg, 38%) as yellow cotton
needles, mp (DSC) onset: 183 ꢀC, peak max: 185 ꢀC (from DCM/
pentane), Rf (DCM) 0.67; (found: C, 60.8; H, 3.0; N, 10.9. C13H8N2O4
requires C, 60.9; H, 3.2; N, 10.9%); lmax (DCM)/nm 231 (log e 3.42),
263 inf (2.99), 298 (2.48); nmax/cmꢂ1 3157w (Ar CH), 1776s (C]O),
1632m, 1611w, 1585w, 1558w, 1512m, 1495w, 1477m, 1449w, 1414w,
1373w, 1362w, 1341w, 1300w, 1269w, 1248w, 1227m, 1155m, 1121m,
1092m, 1057w, 1026m, 1009w, 932w, 883w, 874m, 837w, 818w,
799m, 787s; dH (300 MHz, CDCl3) 8.17 (1H, d, J 2.1, H-9), 7.73 (1H, dd,
J 1.1, 1.1, furyl H), 7.48 (1H, dd, J 1.7, 1.7, furyl H), 7.33 (1H, dd, J 8.5, 2.1,
H-7), 7.11 (1H, d, J 8.5, H-6), 6.68 (1H, dd, J 1.7, 0.9, furyl H), 5.10 (2H, s,
CH2O); dC (75 MHz, CDCl3) 154.1 (Cq), 150.7 (Cq), 144.0 (Ar CH), 143.4
(Cq), 138.8 (Ar CH), 128.8 (Cq), 125.1 (Ar CH), 125.0 (Cq), 121.4 (Cq),
118.2 (Ar CH), 113.6 (Ar CH), 108.7 (Ar CH), 60.1 (CH2O); m/z (EI) 256
(Mþ, 100%), 212 (49), 183 (28), 172 (3), 158 (16), 156 (25), 140 (3), 129
(14), 116 (10), 102 (51), 89 (20), 75 (20), 63 (24), 51 (18).
4.5.6. 8-(1H-Indol-6-yl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-
1-one 36. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 1H-indol-6-ylbor-
onic acid (59.8 mg, 0.372 mmol) in MeCN/water (9:1) (0.5 mL) with
N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and Pd(OAc)2
(2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 30 min gave on chromatogra-
phy (DCM) indole (trace), then 6,60-biindole 24 as grey needles
(17 mg, 58%), mp 281e284 ꢀC (from acetone/pentane) (lit.,20 285 ꢀC),
Rf (DCM) 0.56; identical to an authentic sample. Further elution
(DCM) gave the title compound 36 (36.9 mg, 65%) as tawny needles,
mp (DSC) onset: 234 ꢀC, peak max: 239 ꢀC (decomp.) (from DCM/
pentane), Rf (DCM) 0.44; (found: C, 67.0; H, 3.7; N, 13.6. C17H11N3O3
4.5.4. 8-(Thien-3-yl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-
one 34. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), 3-thienylboronic
acid (47.5 mg, 0.372 mmol) in MeCN/water (9:1) (0.5 mL) with N-
requires C, 66.9; H, 3.6; N, 13.8%); lmax (DCM)/nm 240 (log e 3.71),
294 (3.54); nmax/cmꢂ1 3341br w (NH), 1761s (C]O), 1634m, 1609w,
1566w, 1522w, 1508w, 1477m, 1458w, 1433w, 1418m, 1352m, 1315w,
1261w, 1244m, 1231w, 1196w, 1161w, 1132m, 1123m, 1105m, 1094m,
1038m,1022m,1003w, 897w, 887w, 878w, 856m, 835w, 822w, 806s,
779w, 764m; dH (300 MHz, acetone-d6) 10.35 (1H, s, NH), 8.33 (1H, d,
J 1.9, H-9), 7.72e7.63 (2H, m, Ar H), 7.58 (1H, dd, J 8.5, 2.1, H-7), 7.40
(1H, dd, J 2.5, Ar H), 7.32 (1H, d, J 8.3, Ar H), 7.22 (1H, d, J 8.5, H-6),
6.50 (1H, br s, Ar H), 5.33 (2H, s, CH2O); dC (75 MHz, acetone-d6)
155.2 (Cq), 152.6 (Cq),144.7 (Cq),138.8 (Cq),137.8 (Cq),133.7 (Cq), 128.8
(Cq), 126.8 (Ar CH), 126.5 (Ar CH), 122.9 (Cq), 121.6 (Ar CH), 119.2 (Ar
CH), 118.8 (Ar CH), 114.9 (Ar CH), 110.2 (Ar CH), 102.3 (Ar CH), 61.0
(CH2O); m/z (EI) 305 (Mþ, 84%), 261 (59), 233 (29), 205 (14), 192 (5),
178 (22), 164 (4), 151 (9), 140 (4), 131 (5), 126 (3), 114 (3), 104 (14), 89
(11), 76 (10), 63 (6), 58 (30).
ethyldiisopropylamine (96.4
mL, 0.557 mmol) and Pd(OAc)2
(2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 1.5 h gave on chromatography
(DCM) 3,30-bithiophene 22 as colourless needles (14 mg, 59%), mp
129e130 ꢀC (lit.,18 130e131 ꢀC), Rf (DCM) 0.84; identical to an au-
thentic sample. Further elution (DCM) gave unreacted starting
material 2 (NS2028) (1 mg, 2%) and then the title compound 34
(23.8 mg, 47%) as colourless needles, mp (DSC) onset: 197 ꢀC, peak
max: 198 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.58; (found: C,
57.5; H, 2.8; N, 10.2. C13H8N2O3S requires C, 57.4; H, 3.0; N, 10.3%);
lmax (DCM)/nm 232 (log e
3.54), 270 (3.24); nmax/cmꢂ1 3117w and
3011w (Ar CH), 2990w, 2930w, 1773s (C]O), 1630w, 1609w, 1537w,
1504m, 1474m, 1449w, 1420m, 1400w, 1364w, 1354w, 1337w,
1271w, 1244w, 1229m, 1196m, 1148w, 1121m, 1092w, 1084w,
1042m, 1022m, 1003w, 870m, 839w, 827m, 814w, 777s; dH
(300 MHz, CDCl3) 8.31 (1H, d, J 2.1, H-9), 7.48e7.44 (2H, m, Ar H and
H-7), 7.41 (1H, dd, J 5.1, 3.0, thienyl H-5), 7.37 (1H, dd, J 5.1, 1.2,
thienyl H-2), 7.14 (1H, d, J 8.7, H-6), 5.13 (2H, s, CH2O); dC (75 MHz,
DMSO-d6) 153.9 (Cq), 151.5 (Cq), 143.7 (Cq), 139.9 (Cq), 130.4 (Cq),
4.6. Suzuki coupling of NS2028 with potassium
trifluoroborates
4.6.1. 8-(2,6-Dimethoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]ben-
zoxazin-1-one 39 (typical procedure, see Table 3). To a stirred solution

A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
4077
of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c]-[1,4]benzoxazin-1-one
(50.0 mg, 0.186 mmol) and potassium (2,6-dimethoxyphenyl)-tri-
fluoroborate (68.1 mg, 0.279 mmol) in dioxane/water (4:1) (0.5 mL)
2
(24.8 mg, 50%) as colourless prisms, mp (DSC) onset: 176 ꢀC, peak
max: 177 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.67; identical to
the sample described above.
was added dropwise N-ethyldiisopropylamine (96.4 mL, 0.557 mmol).
The stirred reaction mixture was then immersed into a preheated oil
4.7. Demethylation of 8-(methoxyphenyl)-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazin-1-ones
bath ca. 110 ꢀC until all the solids dissolved and then in one portion
was added Pd(OAc)2 (2.09 mg, 9.30 mmol). The reaction mixture was
then allowed to stir at ca. 110 ꢀC for 1 h. On cooling to ca. 20 ꢀC the
volatiles were removed in vacuo and the residue dissolved in DCM
(5 mL), adsorbed onto silica and chromatographed (DCM) to give
2,20,6,60-tetramethoxybiphenyl 37 as colourless needles (17 mg, 53%),
mp 173e175 ꢀC (lit.,13 175e177 ꢀC), Rf (DCM) 0.78; identical to an
authentic sample. Further elution (DCM) gave the title compound 39
(15.2 mg, 25%) as colourless needles, mp (DSC) onset: 178 ꢀC, peak
max: 179 ꢀC (from 1,2-dichloroethane), Rf (DCM) 0.58; (found: C,
62.6; H, 4.3; N, 8.5. C17H14N2O5 requires C, 62.6; H, 4.3; N, 8.5%); lmax
4.7.1. 8-(4-Hydroxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 40 (typical procedure, see Scheme 4). To a stirred ice-
cold solution of 8-(4-methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-one 11 (150 mg, 0.506 mmol) in DCM (5 mL) was
added dropwise
a 1 M solution of BBr3 in DCM (1.52 mL,
1.52 mmol). The reaction mixture was then allowed to stir at ca.
20 ꢀC for 6 h and then adsorbed onto silica and chromatographed
(Et2O) to give the title compound 40 (130 mg, 91%) as colourless
plates, mp (DSC) onset: 218 ꢀC, peak max: 224 ꢀC (decomp.) (from
acetone/pentane), Rf (Et2O) 0.62; (found: C, 64.0; H, 3.4; N, 9.8.
C16H12N2O4 requires C, 63.8; H, 3.6; N, 9.9%); lmax (DCM)/nm 242
(DCM)/nm 229 (log e
3.40), 239 inf (3.29), 270 inf (2.93); nmax/cmꢂ1
3103w and 3017w (Ar CH), 2967w, 2837w, 1778s (C]O), 1632w,
1607w, 1593w, 1582w, 1510w, 1487w, 1468m, 1433w, 1404w, 1341w,
1298w, 1281w, 1244s, 1225m, 1173w, 1152w, 1119m, 1105s, 1088m,
1036w, 1020m, 887w, 835w, 827m, 806w, 789m; dH (300 MHz,
CDCl3) 8.07 (1H, d, J 1.9, H-9), 7.30 (1H, dd, J 8.4, 8.4, Ar H), 7.20 (2H,
dd, J 8.4, 1.8, H-7), 7.14 (1H, d, J 8.5, H-6), 6.65 (2H, d, J 8.3, Ar H), 5.12
(2H, s, CH2O), 3.75 (6H, s, CH3O); dC (75 MHz, CDCl3) 157.6 (Cq), 154.2
(Cq), 151.1 (Cq), 143.3 (Cq), 130.6 (Ar CH), 130.2 (Cq), 129.3 (Ar CH),
120.6 (Cq), 119.1 (Ar CH), 117.4 (Cq), 117.2 (Ar CH), 104.1 (Ar CH), 60.1
(CH2O), 55.9 (CH3O); m/z (EI) 326 (Mþ, 100%), 281 (4), 267 (3), 253
(8), 239 (15), 224 (10), 213 (30), 196 (9),185 (19), 170 (13), 159 (6),155
(6), 140 (13), 127 (11), 114 (12), 101 (6), 88 (7), 77 (11), 63 (11), 55 (7).
(3.47), 271 (log e
3.47); nmax/cmꢂ1 3356br w (OH), 3063w (Ar CH),
1784m, 1759s (C]O), 1634m, 1611m, 1593m, 1499s, 1474m, 1441s,
1402w, 1366w, 1348m, 1298w, 1265s, 1240m, 1217s, 1180m, 1163m,
1124s,1092m,1043m,1022s, 995w, 974w, 883m, 858w, 845m, 827s,
818m, 804m; dH (300 MHz, acetone-d6) 8.52 (1H, s, OH), 8.21 (1H, d,
J 2.3, H-9), 7.52e7.45 (3H, m, Ar H and H-7), 7.20 (1H, d, J 8.7, H-6),
6.94 (2H, d, J 8.7, Ar H), 5.33 (2H, s, CH2O); dC (75 MHz, acetone-d6)
158.3 (Cq), 155.2 (Cq), 152.5 (Cq), 144.7 (Cq), 137.3 (Cq), 131.6 (Cq),
128.7 (Ar CH), 125.9 (Ar CH), 122.9 (Cq), 118.8 (Ar CH), 116.8 (Ar CH),
114.3 (Ar CH), 61.0 (CH2O); m/z (EI) 282 (Mþ, 100%), 238 (85), 210
(35), 184 (17), 182 (29), 170 (4), 155 (18), 140 (10), 128 (37), 115 (17),
102 (10), 89 (12), 77 (18), 63 (15).
4.6.2. 8-(2-Methoxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 26. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo
[3,4-c][1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), potassium 2-
methoxyphenyltrifluoroborate (59.7 mg, 0.279 mmol) in dioxane/
4.7.2. 8-(3-Hydroxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 41. Similar treatment of 8-(3-methoxyphenyl)-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazin-1-one 25 (150 mg, 0.506 mmol)
with BBr3 (1.52 mL, 1.52 mmol) at ca. 20 ꢀC for 6 h gave the title
compound 41 as colourless prisms (129 mg, 90%), mp (DSC) onset:
241 ꢀC, peak max: 243 ꢀC (from acetone/pentane), Rf (Et2O) 0.62;
(found: C, 64.0; H, 3.5; N,10.0. C16H12N2O4 requires C, 63.8; H, 3.6; N,
water (4:1) (0.5 mL) with N-ethyldiisopropylamine (96.4
mL,
0.557 mmol) and Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for
10 min gave on chromatography (DCM) 2,20-dimethoxybiphenyl 14
as colourless needles (5 mg, 44%), mp 154e155 ꢀC (lit.,13 156e157 ꢀC),
Rf (DCM) 0.62; identical to an authentic sample. Further elution
(DCM) gave the title compound 26 (51.3 mg, 93%) as colourless prisms,
mp (DSC) onset: 164 ꢀC, peak max: 165 ꢀC (from 1,2-dichloroethane),
Rf (DCM) 0.42; identical to the sample described above.
9.9%); lmax (DCM)/nm 233 (log
e 3.48), 262 (3.26), 284 inf (3.11);
nmax/cmꢂ1 3464w (OH), 1755s (C]O), 1636w, 1614w, 1591w, 1578w,
1512w, 1489m,1466m, 1408m, 1352w, 1317w,1302m, 1288w, 1269w,
1244w, 1225w, 1194m, 1153m, 1124m, 1096w, 1047w, 1020s, 966w,
903w, 885w, 862w, 841m, 818w, 802m, 783s; dH (300 MHz, acetone-
d6) 8.50 (1H, s, OH), 8.26 (1H, d, J 2.1, H-9), 7.53 (1H, dd, J 8.5, 2.3, H-
7), 7.30 (1H, dd, J 8.1, 8.1, Ar H), 7.23 (1H, d, J 8.5, H-6), 7.13e7.07 (1H,
m, Ar H), 6.86 (1H, ddd, J 8.1, 2.3, 0.8, Ar H), 5.35 (2H, s, CH2O); dC
(75 MHz, acetone-d6) 158.9 (Cq), 155.2 (Cq), 152.4 (Cq), 145.4 (Cq),
141.7 (Cq), 137.2 (Cq), 131.0 (Ar CH), 126.5 (Ar CH), 122.9 (Cq), 118.9 (Ar
CH), 118.7 (Ar CH), 115.6 (Ar CH), 114.9 (Ar CH), 114.3 (Ar CH), 61.0
(CH2O); m/z (EI): 282 (Mþ, 100%), 238 (80), 211 (15), 184 (31), 170 (3),
155 (19), 140 (9), 127 (34), 115 (17), 102 (10), 89 (10), 77 (17), 63 (15),
51 (13).
4.6.3. 8-(3-Nitrophenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-
1-one 27. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c]
[1,4]benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), potassium 3-nitro-
phenyltrifluoroborate (63.8 mg, 0.279 mmol) in dioxane/water (4:1)
(0.5 mL) with N-ethyldiisopropylamine (96.4
mL, 0.557 mmol) and
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 3 h gave on chro-
matography (DCM) 3,30-dinitrobiphenyl 15 as colourless cotton
needles (12 mg, 40%), mp 200e201 ꢀC (lit.,13 mp 201e202 ꢀC), Rf
(DCM) 0.80; identical to an authentic sample. Further elution (DCM)
gave unreacted starting material 2 (NS2028) (2 mg, 4%) followed by
the title compound 27 (9.8 mg, 17%) as colourless needles, mp (DSC)
onset: 220 ꢀC, peak max: 221 ꢀC (from DCM/pentane), Rf (DCM) 0.53;
identical to the sample described above.
4.7.3. 8-(2-Hydroxyphenyl)-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzox-
azin-1-one 42. Similar treatment of 8-(2-methoxyphenyl)-4H-[1,2,4]
oxadiazolo[3,4-c][1,4]benzoxazin-1-one 26 (150 mg, 0.506 mmol)
with BBr3 (1.52 mL, 1.52 mmol) at ca. 20 ꢀC for 6 h gave the title
compound 42 as colourless needles (133 mg, 93%), mp (DSC) onset:
166 ꢀC, peak max: 167 ꢀC (from DCM/pentane), Rf (Et2O) 0.62;
(found: C, 64.0; H, 3.5; N, 9.9. C16H12N2O4 requires C, 63.8; H, 3.6; N,
4.6.4. 8-Phenyl-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
28. Similar treatment of 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]
benzoxazin-1-one 2 (50.0 mg, 0.186 mmol), potassium phenyl-
trifluoroborate (51.3 mg, 0.279 mmol) in dioxane/water (4:1)
9.9%); lmax (DCM)/nm 232 (log e
3.45), 287 (3.04); nmax/cmꢂ1 3354br
(0.5 mL) with N-ethyldiisopropylamine (96.4
m
L, 0.557 mmol) and
w (OH), 3076w and 3032w (Ar CH), 1748s (C]O), 1628w, 1603w,
1508w, 1495m, 1470m, 1450m, 1398w, 1346m, 1294w, 1279m,
1267w, 1236m, 1196w, 1161w, 1126m, 1107w, 1092w, 1051w, 1034w,
1022m, 997w, 887w, 878w, 858w, 847w, 831m, 814w, 799w, 752s;
dH (300 MHz, CDCl3) 8.33 (1H, d, J 1.9, H-9), 7.46 (1H, dd, J 8.5, 1.9,
Pd(OAc)2 (2.09 mg, 9.30
m
mol) at ca. 110 ꢀC for 2 h gave on chro-
matography (DCM) biphenyl 16 as colourless prisms (5 mg, 35%),
mp 65e67 ꢀC (lit.,13 mp 67e69 ꢀC), Rf (DCM) 0.78; identical to an
authentic sample. Further elution (DCM) gave the title compound 28

4078
A.A. Berezin, P.A. Koutentis / Tetrahedron 67 (2011) 4069e4078
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