Polycyclic N-heterocyclic compounds, part 72: Reaction of N-([1]benzofuro (or benzothieno)[3,2-d]pyrimidin-4-yl)formamidine and N-(pyrido[2,3-d]pyrimidin- 4-yl)formamidine derivatives with hydroxylamine hydrochloride

Article abstract of DOI:10.1002/jhet.850

The reactions of N-([1]benzofuro[3,2-d]pyrimidin-4-yl)formamidines with hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4-oxadiazole to give N-[2-([1,2,4]oxadiazol-5-yl)[1]benzofuran-3-yl) formamide oximes. N-([1]Benzothieno[3,2-d]pyrimidin-4-yl)formamidines and N-(pyrido[2,3-d]pyrimidin-4-yl)formamidines with hydroxylamine hydrochloride gave similar results.

Full text of DOI:10.1002/jhet.850

Month 2012 Polycyclic N-Heterocyclic Compounds, Part 72: Reaction of N‐([1]Benzofuro
(or Benzothieno)[3,2‐d]pyrimidin‐4‐yl)formamidine and N‐(Pyrido[2,3‐d]
pyrimidin‐4‐yl)formamidine Derivatives with
Hydroxylamine Hydrochloride
a
b
b
*
Kensuke Okuda, Kiyoko Tsuchie, and Takashi Hirota
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University,
Gifu 501‐1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University, Kita‐ku, Okayama 700‐8530, Japan
*
E-mail: okuda@gifu‐pu.ac.jp
Received January 5, 2011
DOI 10.1002/jhet.850
Published online 00 Month 2012 in Wiley Online Library (wileyonlinelibrary.com).
The reactions of N‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride
gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring
closure of the 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide oximes.
N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamidines and N‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidines
with hydroxylamine hydrochloride gave similar results.
J. Heterocyclic Chem., 00, 00 (2012).
INTRODUCTION
reagent prepared from the corresponding N,N‐dimethy-
lamide and phosphoryl chloride in the presence of
triethylamine.
Addition of a nucleophile to an electron poor heterocycle
can initiate a ring‐opening/ring‐closure (ANRORC)‐like
rearrangement, which has proven to be a useful strategy in
organic synthesis [1]. Hydroxylamines are often utilized
as 1,2‐bidentate nucleophiles for this type of conversion
[2]. Recently, we reported that reaction of N‐(quinazolin‐
4‐yl)formamidines (1) with hydroxylamine hydrochloride
results in a pyrimidine ring‐opening reaction and formation
of the 1,2,4‐oxadiazole ring to give N‐[2‐([1,2,4]oxadiazol‐
5‐yl)phenyl]formamide oximes (2) (Fig. 1) [3]. As this un-
usual reaction should be applicable to other fused aromatic
derivatives such as electron rich benzofuro (or benzothieno)
[3,2‐d]pyrimidines and electron deficient pyrido[2,3‐d]py-
rimidine, we have explored extension of this process to
such systems. Herein, we report in detail the results of these
studies.
When a hydrogen is attached to the amidine moiety
(R = H) the reaction of 4a with 1.2 equiv of hydroxyl-
amine hydrochloride in methanol at room temperature
gave the amide oxime (5a) in 87% yield. Reaction of
5a with 10 equiv of hydroxylamine hydrochloride in a
refluxing methanol containing dioxane to increase the
solubility of 5a produced the 1,2,4‐oxadiazole deriva-
tive (6a) in 34% yield.
In the 1H NMR spectrum of 6a, a characteristic formam-
ide oxime one‐proton doublet (J = 10.5 Hz) appeared at 8.01
ppm coupled with an adjacent NH proton (J = 10.5 Hz).
This NH is exchangeable and, thus, the formamide oxime
signal changed to a singlet in the presence of deuterium ox-
ide. The one‐proton singlet at 8.74 ppm (pyrimidine ring
proton) present in 5a was absent in the product. One
1,2,4‐oxadiazole ring proton was observed in the product
at 9.24 ppm as a singlet. These NMR data indicate that py-
rimidine ring cleavage and 1,2,4‐oxadiazole ring formation
occurred during reaction of 5a with hydroxylamine hydro-
chloride [6].
In similar fashion, we carried out the reaction of 4b (R = Me)
with 1.2 equiv of hydroxylamine hydrochloride in methanol
at room temperature. TLC analysis suggested the formation
of a mixture of 5b and 6b, but we were unable to isolate
the product. However, reaction of 4b with 6.0 equiv of
hydroxylamine hydrochloride in methanol under reflux gave
the 1,2,4‐oxadiazole derivative (6b) in 50% yield. The
RESULTS AND DISCUSSIONS
First, we examined ([1]benzofuro[3,2‐d]pyrimidin‐4‐
yl)amidines (4). As shown in Scheme 1, the requisite
amidine starting materials 4 were synthesized by previ-
ously reported methods [4]. Amidines 4a,b were
prepared by the reaction of 4‐amino[1]benzofuro[3,2‐
d]pyrimidine (3) [5] with commercially available N,N‐
dimethylformamide (or acetamide) dimethyl acetal in
refluxing toluene. Other amidines 4c–g were produced
by the reaction of compound 3 with the Vilsmeier
© 2012 HeteroCorporation

K. Okuda, K. Tsuchie, and T. Hirota
Vol 000
oxime 9a was isolated. Other amidines 8b‐e did not afford
isolable amide oxime but produced 1,2,4‐oxadiazole deri-
vatives (10b‐e) directly by using excess hydroxylamine
hydrochloride. However, conversion of 9a to 1,2,4‐oxadia-
zole derivative (10a) was not successful in contrast to the
behavior of 5a. Reaction with 14 equiv of hydroxylamine
hydrochloride in refluxing methanol was necessary to con-
sume 9a completely, but this produced a complex mixture
of compounds that could not be isolated. This was proba-
bly due to the fact that 10a appears to be contaminated in
the reaction mixture with partly hydrolyzed 5‐(3‐amino[1]
benzothiophen‐2‐yl)‐1,2,4‐oxadiazole and/or 4‐amino[1]
benzothieno[3,2‐d]pyrimidine (7) [7], as judged the 1H
NMR spectrum.
The above reactions were done for fused pyrimidines
that posses electron‐rich aromatics such as benzofuran
and benzothiophene. It is quite interesting that formamide
oximes (5a and 9a) alone were stable and could be iso-
lated. We speculated that fused electron‐deficient aro-
matics such as pyridine could affect this amide oxime
stability. To test this, the requisite formamidine (12a) [8]
and acetamidine (12b) starting materials were synthesized
by the same method as described above from amine 11
(Scheme 3). We examined the reaction of 12a with 1.2
equiv of hydroxylamine hydrochloride in methanol at
room temperature. We observed a possible mixture of
Figure 1. Substrates (1) and their rearranged products (2).
reaction of 4c (R = Et) with 1.2 equiv of hydroxylamine hy-
drochloride in methanol at room temperature gave the 1,2,4‐
oxadiazole derivative (6c) in 56% yield instead of the amide
oxime 5c.
Reactions of other amidines 4d–g having an aryl group
substituted in the amidine moiety required an excess
amount of hydroxylamine hydrochloride to consume start-
ing materials completely. In such cases, the reaction did
not produce amide oximes (5d–g) but instead gave the oxa-
diazole 6d–g in reactions with 5–8 equiv of hydroxylamine
hydrochloride.
Next, we focused our attention on the ([1]benzothieno
[3,2‐d]pyrimidin‐4‐yl)amidines (8). As shown in Scheme
2, the requisite amidines 8 starting materials were synthe-
sized by the same method as described above for amidines
4. The reactivity of each 8 with hydroxylamine hydrochlo-
ride was same as that of 4. In the case of 8a (R = H), amide
Scheme 1. Synthesis of 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

Month 2012 Polycyclic N-Heterocyclic Compounds, Part 72: Reaction of Benzofuro (or Benzothieno)
[3,2‐d]pyrimidines and Pyrido[2,3‐d]pyrimidine Derivatives with Hydroxylamine Hydrochloride
Scheme 2. Synthesis of 10.
formamide oxime (13a) and 1,2,4‐oxadiazole derivative
(14a) as indicated by TLC analysis, but no product could
be isolated. In contrast, reaction of 12a with 6.0 equiv of
hydroxylamine hydrochloride in methanol at room temper-
ature gave the 1,2,4‐oxadiazole derivative (14a) in 54%
yield.
This result was quite different compared to the reactions
of N‐(electron rich aromatics‐fused pyrimidin‐4‐yl)forma-
midines (4a and 8a) described above. In those cases, the
amide oximes were isolable when a hydrogen is attached
to the amidine moiety. From these results, we conclude that
the fused pyridine moiety of pyrido[2,3‐d]pyrimidine
affects the reactivity by facilitating the nucleophilic attack
of amide oxime (13a) on the pyrimidine ring. This in-
creased reactivity toward nucleophilic should promote the
ring‐cleavage and ring‐closure reactions that give the
1,2,4‐oxadiazole derivatives (14a). This assumption is sup-
ported by LUMO energy level comparison of 5a, 9a, and
13a. The calculated LUMO energy of 5a is −1.543 eV,
and 9a is −1.474 eV while that of 13a is −1.929 eV [9].
Therefore, increased reactivity toward nucleophilic
attack is a reasonable explanation for our inability to
isolate 13a.
Compound 12b displayed behavior similar to 12a. Thus,
reaction of 12b with 1.2 equiv of hydroxylamine hydro-
chloride in methanol at room temperature did not consume
starting material completely while reaction with 4.0 equiv
of hydroxylamine hydrochloride in methanol at room tem-
perature gave the 1,2,4‐oxadiazole derivative (14b) in 61%
yield.
Many 1,2,4‐oxadiazoles are known to be bioactive com-
pounds [10]. In this regard, we found that 3,5‐disubstituted
1,2,4‐oxadiazoles, the structures of which are related to the
products (6, 10, and 14), have considerable activity as inhi-
bitors of arachidonic acid‐induced platelet aggregation [3,11]
and pentosidine formation [12]. We are currently exploring
Scheme 3. Synthesis of 14.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

K. Okuda, K. Tsuchie, and T. Hirota
Vol 000
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)
propionamidine (4c). A mixture of 3 (500 mg, 2.70 mmol),
N,N‐dimethylpropionamide (360 μL, 3.27 mmol), phosphoryl
chloride (1.50 mL, 16.1 mmol), and triethylamine (2.20 mL,
15.8 mmol) was refluxed for 23 h. After the workup procedure
described above, the brown oily residue was purified by neutral
alumina column chromatography (ethyl acetate/n‐hexane, 1:5),
and the product was recrystallized from n‐hexane to give 4c
(288 mg, 40%) as colorless needles, mp 69–72°C; 1H NMR
(deuterochloroform): δ 1.25 (t, 3H, J = 7.5 Hz, Me), 3.03 (q,
2H, J = 7.5 Hz, CH2Me), 3.38 and 3.42 (each br s, each 3H,
2 × NMe), 7.49–7.58 (m, 1H, H8), 7.69–7.72 (m, 2H, H7 and
9), 8.35 (br d, 1H, J = 7.5, H9), 8.57 (s, 1H, H2); FAB‐ms:
m/z 269 (MH+). Anal. Calcd. for C15H16N4O: C, 67.15; H,
6.01; N, 20.88. Found: C, 67.19; H, 6.30; N, 20.64.
the biological properties of the products prepared in this study
with the goal of developing new pharmaceutical agents.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-
melting point apparatus and are uncorrected. Elemental analyses
were performed on a Yanagimoto MT‐5 CHN Corder elemental
analyzer. The FAB‐mass and EI‐mass spectra were obtained on
a VG 70 mass spectrometer and m‐nitrobenzyl alcohol was used
as the matrix. The IR spectra were recorded on a Japan Spectro-
scopic FTIR‐200 spectrophotometer with potassium bromide,
and frequencies are expressed in cm−1. The 1H NMR spectra were
recorded on a Varian VXR‐200 instrument operating at 200 MHz
with tetramethylsilane as an internal standard. Chemical shifts are
given in ppm (δ) and J values in Hz, and the signals are desig-
nated as follows: s, singlet; d, doublet; dd, double doublet; t, trip-
let; q, quartet; br, broad; m, multiplet. Column chromatography
was performed on silica gel (IR‐60–63‐210‐W, Daiso) or alumi-
num oxide 90 active neutral (101077, 70−230 mesh ASTM,
Merck). TLC was carried out on Kieselgel 60F254 (Merck).
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)
benzamidine (4d). A mixture of 3 (500 mg, 2.70 mmol), N,N‐
dimethylbenzamide (483 mg, 3.24 mmol), phosphoryl chloride
(1.25 mL, 13.4 mmol), and triethylamine (3.10 mL, 22.2 mmol)
was refluxed for 23 h. After the workup procedure described
above, the brown oily residue was purified by neutral alumina
column chromatography (ethyl acetate/n‐hexane, 1:5), and the
product was recrystallized from n‐hexane to give 4d (319 mg,
37%) as colorless needles, mp 137–139°C; 1H NMR
(deuterochloroform): δ 2.99 and 3.41 (each br s, each 3H, 2 ×
NMe), 7.17–7.33 (m, 5H, phenyl‐H), 7.35–7.46 (m, 1H, H8),
7.58–7.64 (m, 2H, H6 and 7), 8.11 (d, 1H, J = 7.6 Hz, H9),
8.58 (s, 1H, H2); FAB‐ms: m/z 317 (MH+). Anal. Calcd. for
C19H16N4O: C, 72.13; H, 5.10; N, 17.71. Found: C, 72.18; H,
5.45; N, 17.67.
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)
formamidine (4a).
To a solution of 4‐amino[1]benzofuro
[3,2‐d]pyrimidine [5] (3, 1.00 g, 5.40 mmol) in dry toluene
(80 mL), N,N‐dimethylformamide dimethyl acetal (900 μL,
6.77 mmol) was added, and the mixture was refluxed for 2 h.
After the removal of solvent in vacuo, the residue was purified
by silica gel column chromatography (ethyl acetate/n‐hexane,
3:2) and recrystallized from cyclohexane to give 4a (710 mg,
55%) as colorless prisms, mp 130–133°C; 1H NMR
(deuterochloroform): δ 3.28 and 3.33 (each s, each 3H, 2 ×
NMe), 7.47 (td, 1H, J = 7.9, 1.5 Hz, H8), 7.60–7.73 (m, 2H,
H6 and 7), 8.24 (d, 1H, J = 7.9 Hz, H9), 8.76 (s, 1H, H2),
8.98 (s, 1H, N CHNMe2); FAB‐ms: m/z 241 (MH+). Anal.
Calcd. for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C,
65.13; H, 5.04; N, 23.26.
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)‐4‐
chlorobenzamidine (4e). A mixture of 3 (500 mg, 2.70 mmol),
N,N‐dimethyl‐4‐chlorobenzamide (596 mg, 3.25 mmol),
phosphoryl chloride (2.00 mL, 21.5 mmol), and triethylamine
(2.70 mL, 19.4 mmol) was refluxed for 28 h. After the workup
procedure described above, the brown oily residue was purified
by neutral alumina column chromatography (ethyl acetate/n‐
1
hexane,1:5) to give 4e (275 mg, 29%) as colorless oil; H NMR
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)
acetamidine (4b). To a solution of 3 (300 mg, 1.62 mmol) in
dry toluene (30 mL), N,N‐dimethylacetamide dimethyl acetal (310
μL, 2.12 mmol) was added, and the mixture was refluxed for 20 h.
After the removal of solvent in vacuo, the residue was purified by
silica gel column chromatography (ethyl acetate/n‐hexane, 2:1),
and recrystallized from cyclohexane to give 4b (187 mg, 45%) as
(deuterochloroform): δ 3.25 and 3.54 (each s, each 3H, 2 ×
NMe), 7.36 (d, 2H, J = 8.5 Hz, H3′ and 5′), 7.50–7.80 (m, 5H,
H6, 7, 8, 2′ and 6′), 8.42 (d, 1H, J = 7.8 Hz, H9), 8.45 (s, 1H,
H2); FAB‐ms: m/z 351 (MH+), 353 (MH+ + 2). HR‐FAB‐ms: m/
z 351.0981 (Calcd. for C19H16ClN4O: 351.1013) [13].
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)‐4‐
fluorobenzamidine (4f). A mixture of 3 (500 mg, 2.70 mmol),
N,N‐dimethyl‐4‐fluorobenzamide (542 mg, 3.24 mmol),
phosphoryl chloride (2.00 mL, 21.5 mmol), and triethylamine
(3.30 mL, 23.7 mmol) was refluxed for 28 h. After the workup
procedure described above, the brown oily residue was purified
by neutral alumina column chromatography (ethyl acetate/
1
a white powder, mp 84–86°C; H NMR (deuterochloroform): δ
2.32 (s, 3H, CMe), 3.23 and 3.32 (each s, each 3H, 2 × NMe),
7.42–7.52 (m, 1H, H8), 7.62–7.68 (m, 2H, H6 and 7), 8.23 (d,
1H, J = 7.7 Hz, H9), 8.80 (s, 1H, H2); FAB‐ms: m/z 255 (MH+).
Anal. Calcd. for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found:
C, 66.11; H, 5.79; N, 22.03.
1
n‐hexane, 1:5) to give 4f (240 mg, 26%) as pale yellow oil; H
General procedure for the preparation of 4c–g.
To a
NMR (deuterochloroform): δ 3.14 and 3.48 (each br s, each 3H,
2 × NMe), 6.99 (t, 2H, J = 8.7 Hz, H3′ and 5′), 7.42–7.56 (m,
3H, H8, 2′ and 6′), 7.64–7.70 (m, 2H, H6 and 7), 8.27 (d, 1H,
J = 8.2 Hz, H9), 8.52 (s, 1H, H2); FAB‐ms: m/z 335 (MH+).
Anal. Calcd. for C19H15FN4O·0.5H2O: C, 66.46; H, 4.70; N,
16.32. Found: C, 66.65; H, 4.84; N, 15.97.
solution of 3 (500 mg, 2.70 mmol) in dry chloroform (200 mL),
N,N‐dimethylamide, phosphoryl chloride, and triethylamine
were added sequentially, and the mixture was then refluxed.
After the removal of solvent in vacuo, water (150 mL) was
added, and the mixture was made basic with sodium carbonate
and then extracted with ethyl acetate (150 mL × 3). The
combined organic phase was washed with sat. brine, dried over
anhydrous sodium sulfate, and then evaporated in vacuo. The
residue was purified by column chromatography and/or
recrystallization to give 4.
N1,N1‐Dimethyl‐N2‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)‐4‐
methylbenzamidine (4g).
A mixture of 3 (500 mg, 2.70
mmol), N,N‐dimethyl‐4‐methylbenzamide (530 mg, 3.25 mmol),
phosphoryl chloride (2.00 mL, 21.5 mmol), and triethylamine
(4.00 mL, 28.7 mmol) was refluxed for 31 h. After the workup
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

Month 2012 Polycyclic N-Heterocyclic Compounds, Part 72: Reaction of Benzofuro (or Benzothieno)
[3,2‐d]pyrimidines and Pyrido[2,3‐d]pyrimidine Derivatives with Hydroxylamine Hydrochloride
procedure described above, the brown oily residue was purified by
neutral alumina column chromatography (ethyl acetate/n‐hexane,
1:5) to give 4g (270 mg, 30%) as pale yellow oil; 1H NMR
(deuterochloroform): δ 2.28 (s, 3H, CMe), 3.18 and 3.49 (each br
s, each 3H, 2 × NMe), 7.10 (d, 2H, J = 8.0 Hz, H3′ and 5′), 7.38
(d, 2H, J = 8.0 Hz, H2′ and 6′), 7.44–7.52 (m, 1H, H8), 7.64–
7.69 (m, 2H, H6, and 7), 8.32 (d, 1H, J = 7.6 Hz, H9), 8.48 (s,
1H, H2); FAB‐ms: m/z 331 (MH+). HR‐FAB‐ms: m/z 331.1525
(Calcd. for C20H19N4O: 331.1559) [13].
General procedure for the reaction of 4c–g with
hydroxylamine hydrochloride to give 6c–g. To a solution
of amidine (4) in dry methanol, hydroxylamine hydrochloride
was added, and the reaction mixture was stirred at room
temperature. The precipitate was filtered and then recrystallized
to give 6.
N‐[2‐(3‐Ethyl[1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide
oxime (6c).
Compound 4c (220 mg, 0.820 mmol) was
allowed to react with hydroxylamine hydrochloride (69.0 mg,
0.993 mmol) in dry methanol (5.0 mL) for 2 h. Compound 6c
(124 mg, 56%) was obtained as colorless needles from
methanol, mp 220–221°C (dec.); IR (potassium bromide):
N‐([1]Benzofuro[3,2‐d]pyrimidin‐4‐yl)formamide oxime
(5a).
To a solution of 4a (500 mg, 2.08 mmol) in dry
methanol (10 mL), hydroxylamine hydrochloride (173 mg,
2.49 mmol) was added, and the reaction mixture was stirred at
room temperature for 10 min. The precipitate was filtered and
then recrystallized from dioxane to give 5a (412 mg, 87%) as
colorless needles, mp 215–217°C; IR (potassium bromide):
1
3110, 3190, and 3280 (NH and OH) cm−1; H NMR (DMSO‐
d6): δ 1.31 (t, 3H, J = 7.5 Hz, Me), 2.83 (q, 2H, J = 7.5 Hz,
CH2Me), 7.41 (br t, 1H, J = 7.6 Hz, H5), 7.62 (br t, 1H, J =
7.6 Hz, H6), 7.76 (d, 1H, J = 8.2 Hz, H7), 8.00 (d, 1H, J =
10.5 Hz, changed to singlet with addition of deuterium oxide,
NCH NOH), 8.25 (d, 1H, J = 8.2 Hz, H4), 9.26 (d, 1H, J =
10.5 Hz, deuterium oxide exchangeable, NH), 10.62 (s, 1H,
deuterium oxide exchangeable, OH); FAB‐ms: m/z 273 (MH+).
Anal. Calcd. for C13H12N4O3: C, 57.35; H, 4.44; N, 20.58.
Found: C, 57.21; H, 4.40; N, 20.49.
1
3040, 3130, and 3180 (NH, OH) cm−1; H NMR (DMSO‐d6):
δ 7.51–7.61 (m, 1H, H8), 7.73–7.84 (m, 1H, H7), 7.89 (d, 1H,
J = 8.3 Hz, H6), 8.09 (d, 1H, J = 9.6 Hz, changed to singlet
with addition of deuterium oxide, NCH NOH), 8.18 (dd, 1H,
J = 7.8, 1.3 Hz, H9), 8.74 (s, 1H, H2), 9.56 (d, 1H, J = 9.6 Hz,
deuterium oxide exchangeable, NH), 10.79 (s, 1H, deuterium
oxide exchangeable, OH); FAB‐ms: m/z 229 (MH+). Anal. Calcd.
for C11H8N4O2: C, 57.89; H, 3.53; N, 24.55. Found: C, 57.78;
H, 3.77; N, 24.50.
N‐[2‐(3‐Phenyl[1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)
formamide oxime (6d). Compound 4d (320 mg, 1.01 mmol)
was allowed to react with hydroxylamine hydrochloride (420 mg,
6.04 mmol) in dry methanol (20 mL) for 2 h. Compound 6d (253
mg, 69%) was obtained as colorless needles from dioxane, mp
219°C (dec.); IR (potassium bromide): 3100, 3200, and 3280
N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide
oxime (6a). To a solution of 5a (200 mg, 0.876 mmol) in dry
methanol (100 mL) and dry dioxane (20 mL), hydroxylamine
hydrochloride (610 mg, 8.78 mmol) was added, and the
reaction mixture was refluxed for 3 h. After the removal of
solvent in vacuo, the residue was purified by silica gel column
chromatography (ethyl acetate/n‐hexane, 1:4) and then
recrystallized from methanol to give 6a (72.0 mg, 34%) as
colorless needles, mp 178–180°C; IR (potassium bromide):
1
(NH and OH) cm−1; H NMR (DMSO‐d6): δ 7.43 (br t, 1H, J =
7.8 Hz, H5), 7.56–7.72 (m, 4H, H6, 3′, 4′, and 5′), 7.79 (d, 1H,
J = 8.3 Hz, H7), 8.07 (d, 1H, J = 10.7 Hz, changed to singlet
with addition of deuterium oxide, NCH NOH), 8.08–8.17 (m,
2H, H2′and 6′), 8.29 (d, 1H, J = 7.8 Hz, H4), 9.53 (d, 1H, J =
10.7 Hz, deuterium oxide exchangeable, NH), 10.77 (s, 1H,
deuterium oxide exchangeable, OH); FAB‐ms: m/z 321 (MH+).
Anal. Calcd. for C17H12N4O3·0.5dioxane: C, 62.63; H, 4.43; N,
15.38. Found: C, 62.40; H, 4.61; N, 15.28.
1
3120, 3200, and 3300 (NH, OH) cm−1; H NMR (DMSO‐d6):
δ 7.42 (br t, 1H, J = 7.6 Hz, H5), 7.63 (br t, 1H, J = 7.6 Hz,
H6), 7.77 (d, 1H, J = 8.3 Hz, H7), 8.01 (d, 1H, J = 10.5 Hz,
changed to singlet with addition of deuterium oxide,
NCH NOH), 8.25 (d, 1H, J = 8.3 Hz, H4), 9.22 (d, 1H, J =
10.5 Hz, deuterium oxide exchangeable, NH), 9.24 (s, 1H,
H3′), 10.66 (s, 1H, deuterium oxide exchangeable, OH); FAB‐
ms: m/z 245 (MH+). Anal. Calcd. for C11H8N4O3: C, 54.10; H,
3.30; N, 22.94. Found: C, 54.26; H, 3.36; N, 22.83.
N‐{2‐[3‐(4‐Chlorophenyl)[1,2,4]oxadiazol‐5‐yl][1]benzofuran‐
3‐yl}formamide oxime (6e).
Compound 4e (470 mg, 1.34
mmol) was allowed to react with hydroxylamine hydrochloride
(745 mg, 10.7 mmol) in dry methanol (40 mL) for 2 h.
Compound 6e (271 mg, 57%) was obtained as colorless
needles from methanol, mp 223–226°C (dec.); IR (potassium
1
bromide): 3140, 3200, and 3320 (NH and OH) cm−1; H NMR
N‐[2‐(3‐Methyl[1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)
formamide oxime (6b). To a solution of 4b (100 mg, 0.393
mmol) in dry methanol (50 mL), hydroxylamine hydrochloride
(165 mg, 2.37 mmol) was added, and the reaction mixture was
refluxed for 2 h. After the removal of solvent in vacuo, water
was added, and then the solution was made basic with sat.
sodium bicarbonate aq. The precipitate was filtered and then
recrystallized from methanol to give 6b (51.0 mg, 50%) as
colorless needles, mp 221°C (dec.); IR (potassium bromide):
(DMSO‐d6): δ 7.43 (br t, 1H, J = 7.6 Hz, H5), 7.60–7.73 (m,
3H, H6, 3′ and 5′), 7.79 (d, 1H, J = 8.0 Hz, H7), 8.06 (d, 1H,
J = 10.3 Hz, changed to singlet with addition of deuterium
oxide, NCH NOH), 8.10 (dd, 2H, J = 8.6 Hz, H2′ and 6′),
8.28 (d, 1H, J = 7.8 Hz, H4), 9.45 (d, 1H, J = 10.3 Hz,
deuterium oxide exchangeable, NH), 10.76 (s, 1H, deuterium
oxide exchangeable, OH); FAB‐ms: m/z 355 (MH+), 357
(MH+ + 2). Anal. Calcd. for C17H11ClN4O3: C, 57.56; H, 3.13;
N, 15.79. Found: C, 57.45; H, 3.37; N, 15.82.
1
3130, 3190, and 3280 (NH, OH) cm−1; H NMR (DMSO‐d6):
N‐{2‐[3‐(4‐Fluorophenyl)[1,2,4]oxadiazol‐5‐yl][1]benzofuran‐
δ 2.45 (s, 3H, Me), 7.41 (br t, 1H, J = 7.6 Hz, H5), 7.62 (br t,
1H, J = 7.8 Hz, H6), 7.76 (d, 1H, J = 8.3 Hz, H7), 8.00 (d, 1H,
J = 10.5 Hz, changed to singlet with addition of deuterium
oxide, NCH NOH), 8.24 (d, 1H, J = 7.8 Hz, H4), 9.14 (d, 1H,
J = 10.5 Hz, deuterium oxide exchangeable, NH), 10.63 (s,
1H, deuterium oxide exchangeable, OH); FAB‐ms: m/z 259
(MH+). Anal. Calcd. for C12H10N4O3: C, 55.81; H, 3.90; N,
21.70. Found: C, 55.60; H, 4.11; N, 21.83.
3‐yl}formamide oxime (6f).
Compound 4f hemihydrate (230
mg, 0.670 mmol) was allowed to react with hydroxylamine
hydrochloride (380 mg, 5.47 mmol) in dry methanol (5.0 mL) for
2 h. Compound 6f (157 mg, 61%) was obtained as colorless
needles from methanol–dioxane, mp 219–221°C (dec.); IR
(potassium bromide): 3080, 3200, and 3270 (NH and OH) cm−1;
1H NMR (DMSO‐d6): δ 7.37–7.52 (m, 3H, H5, 3′and 5′), 7.65
(br t, 1H, J = 7.2 Hz, H6), 7.79 (d, 1H, J = 8.2 Hz, H7), 8.07 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

K. Okuda, K. Tsuchie, and T. Hirota
Vol 000
1H, J = 10.5 Hz, changed to singlet with addition of deuterium
oxide, NCH NOH), 8.11–8.21 (m, 2H, H2′ and 6′), 8.29 (d, 1H,
J = 8.3 Hz, H4), 9.47 (d, 1H, J = 10.5 Hz, deuterium oxide
exchangeable, NH), 10.76 (s, 1H, deuterium oxide exchangeable,
OH); FAB‐ms: m/z 339 (MH+). Anal. Calcd. for
C17H11FN4O3·0.5dioxane: C, 59.69; H, 3.95; N, 14.65. Found:
C, 59.67; H, 3.83; N, 14.92.
then evaporated in vacuo. The brown oily residue was purified
by neutral alumina column chromatography (ethyl acetate/n‐
hexane, 1:5) to give 8c (135 mg, 32%) as colorless oil; 1H
NMR (deuterochloroform): δ 1.19 (t, 3H, J = 7.6 Hz, Me), 2.77
(q, 2H, J = 7.6 Hz, CH2Me), 3.22 (br s, 6H, NMe2), 7.49–7.67
(m, 2H, H7 and 8), 7.90 (dd, 1H, J = 6.8, 1.5 Hz, H6), 8.48
(dd, 1H, J = 7.7, 1.6 Hz, H9), 8.89 (s, 1H, H2); FAB‐ms: m/z
285 (MH+). HR‐FAB‐ms: m/z 285.1127 (Calcd. for C15H17N4S:
285.1174) [13].
N‐{2‐[3‐(4‐Methylphenyl)[1,2,4]oxadiazol‐5‐yl][1]benzofuran‐
3‐yl}formamide oxime (6g).
Compound 4g (260 mg,
N1,N1‐Dimethyl‐N2‐([1]benzothieno[3,2‐d]pyrimidin‐4‐yl)
benzamidine (8d). To a solution of 7 (500 mg, 2.48 mmol) in
dry chloroform (200 mL), N,N‐dimethylbenzamide (445 mg, 2.98
mmol), phosphoryl chloride (2.00 mL, 21.5 mmol), and
triethylamine (3.00 mL, 21.5 mmol) were added sequentially,
and the reaction was then refluxed for 27 h. After the removal
of solvent in vacuo, water (150 mL) was added, and the mixture
was made basic with sodium carbonate and then extracted with
ethyl acetate (150 mL × 3). The combined organic phase was
washed with sat. brine, dried over anhydrous sodium sulfate and
then evaporated in vacuo. The brown oily residue was purified
by neutral alumina column chromatography (ethyl acetate/n‐
hexane, 1:5) to give 8d (121 mg, 15%) as colorless oil; 1H
NMR (deuterochloroform): δ 3.23 and 3.51 (each br s, each 3H,
2 × NMe), 7.33–7.45 (m, 3H, H3′, 4′, and 5′), 7.53–7.74 (m,
4H, H7, 8, 2′ and 6′), 7.97 (br d, 1H, J = 7.4 Hz, H6), 8.44 (s,
1H, H2), 8.58 (br d, J = 7.7 Hz, H9); FAB‐ms: m/z 333 (MH+).
HR‐FAB‐ms: m/z 333.1161 (Calcd. for C19H17N4S: 333.1174)
[13].
0.787mmol) was allowed to react with hydroxylamine
hydrochloride (275 mg, 3.96 mmol) in dry methanol (25 mL)
for 2 h. Compound 6g (93.0 mg, 35%) was obtained as
colorless needles from dioxane, mp 216–218°C (dec.); IR
(potassium bromide): 3100, 3190, and 3300 (NH and OH)
1
cm−1; H NMR (DMSO‐d6): δ 2.42 (s, 3H, Me), 7.37–7.48 (m,
3H, H5, 3′and 5′), 7.65 (t, 1H, J = 7.3 Hz, H6), 7.79 (br d, 1H,
J = 8.3 Hz, H7), 8.00 (d, 2H, J = 8.2 Hz, H2′ and 6′), 8.08 (d,
1H, J = 10.6 Hz, changed to singlet with addition of deuterium
oxide, NCH NOH), 8.29 (br d, 1H, J = 8.0 Hz, H4), 9.56 (d,
1H, J = 10.6 Hz, deuterium oxide exchangeable, NH), 10.77 (s,
1H, deuterium oxide exchangeable, OH); FAB‐ms: m/z 335
(MH+). Anal. Calcd. for C18H14N4O3: C, 64.66; H, 4.22; N,
16.76. Found: C, 65.05; H, 4.09; N, 16.74.
N1,N1‐Dimethyl‐N2‐([1]benzothieno[3,2‐d]pyrimidin‐4‐yl)
formamidine (8a).
To a solution of 4‐amino[1]benzothieno
[3,2‐d]pyrimidine [7] (7, 450 mg, 2.24 mmol) in dry toluene
(40 mL), N,N‐dimethylformamide dimethyl acetal (330 μL,
2.48 mmol) was added, and the mixture was refluxed for 2 h.
After the removal of solvent in vacuo, the residue was purified
by silica gel column chromatography (ethyl acetate/n‐hexane,
3:2), and the product was recrystallized from cyclohexane to
N1,N1‐Dimethyl‐N2‐([1]benzothieno[3,2‐d]pyrimidin‐4‐yl)‐
4‐fluorobenzamidine (8e). To a solution of 7 (400 mg, 1.99
mmol) in dry chloroform (170 mL), N,N‐dimethyl‐4‐
fluorobenzamide (400 mg, 2.39 mmol), phosphoryl chloride
(1.10 mL, 11.8 mmol), and triethylamine (2.70 mL, 19.4 mmol)
were added sequentially, and the reaction was then refluxed for
24 h. After the removal of solvent in vacuo, water (150 mL)
was added, the mixture was made basic with sodium carbonate,
and then extracted with ethyl acetate (150 mL × 3). The
combined organic phase was washed with sat. brine, dried over
anhydrous sodium sulfate, and then evaporated in vacuo. The
brown oily residue was purified by neutral alumina column
chromatography (ethyl acetate/n‐hexane, 1:5) to give 8e (104
1
give 8a (467 mg, 81%) as colorless prisms, mp 124–125°C; H
NMR (deuterochloroform): δ 3.26 and 3.28 (each s, each 3H,
2 × NMe), 7.54–7.67 (m, 2H, H7 and 8), 7.93 (br d, 1H, J =
7.2 Hz, H6), 8.51 (br d, 1H, J = 7.2 Hz, H9), 8.86 (s, 1H, H2),
9.01 (s, 1H, N CHNMe2); FAB‐ms: m/z 257 (MH+). Anal.
Calcd. for C13H12N4S: C, 60.91; H, 4.72; N, 21.86. Found: C,
60.86; H, 4.91; N, 22.25.
N1,N1‐Dimethyl‐N2‐([1]benzothieno[3,2‐d]pyrimidin‐4‐yl)
acetamidine (8b). To a solution of 7 (300 mg, 1.49 mmol) in
dry toluene (30 mL), N,N‐dimethylacetamide dimethyl acetal
(240 μL, 1.64 mmol) was added, and the mixture was refluxed
for 20 h. After the removal of solvent in vacuo, the residue was
purified by silica gel column chromatography (ethyl acetate/n‐
hexane, 5:1) and recrystallized from cyclohexane to give 8b
(275 mg, 68%) as a white powder, mp 108–110°C; 1H NMR
(deuterochloroform): δ 2.33 (s, 3H, CMe), 3.19 (s,6H, NMe2),
7.53–7.73 (m, 2H, H7 and 8), 8.10 (d, 1H, J = 7.9 Hz, H6),
8.34 (dd, 1H, J = 7.9, 1.0 Hz, H9), 8.80 (s, 1H, H2); FAB‐ms:
m/z 271 (MH+). Anal. Calcd. for C14H14N4S: C, 62.20; H, 5.22;
N, 20.72. Found: C, 62.44; H, 4.83; N, 20.62.
1
mg, 15%) as colorless oil; H NMR (deuterochloroform): δ 3.06
and 3.40 (each br s, each 3H, 2 × NMe), 6.96 (t, 2H, J = 8.8
Hz, H3′ and 5′), 7.36 (dd, 2H, J = 8.8, 5.3 Hz, H2′ and 6′),
7.50–7.68 (m, 2H, H7 and 8), 7.93 (br d, 1H, J = 7.5 Hz, H6),
8.48 (br d, 1H, J = 7.5 Hz, H9), 8.57 (s, 1H, H2); FAB‐ms: m/z
351 (MH+). HR‐FAB‐ms: m/z 351.1042 (Calcd. for
C19H16FN4S: 351.1080) [13].
N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamide oxime
(9a).
To a solution of 8a (300 mg, 1.17 mmol) in dry
methanol (30 mL), hydroxylamine hydrochloride (97.0 mg, 1.40
mmol) was added, and the reaction mixture was stirred at room
temperature for 10 min. The precipitate was filtered and then
recrystallized from methanol to give 9a (228 mg, 80%) as
colorless needles, mp 205–211°C; IR (potassium bromide):
N1,N1‐Dimethyl‐N2‐([1]benzothieno[3,2‐d]pyrimidin‐4‐yl)
propionamidine (8c). To a solution of 7 (300 mg, 1.49 mmol)
in dry chloroform (130 mL), N,N‐dimethylpropionamide (200 μL,
1.82 mmol), phosphoryl chloride (1.12 mL, 12.0 mmol), and
triethylamine (3.20 mL, 23.0 mmol) were added sequentially,
and the mixture was then refluxed for 25 h. After the removal
of solvent in vacuo, water (100 mL) was added, and the mixture
was made basic with sodium carbonate and then extracted with
ethyl acetate (100 mL × 3). The combined organic phase was
washed with sat. brine, dried over anhydrous sodium sulfate,
1
3000, 3050, and 3130 (NH and OH) cm−1; H NMR (DMSO‐
d6): δ 7.57–7.81 (m, 2H, H7 and 8), 8.13 (d, 1H, J = 9.2 Hz,
changed to singlet with addition of deuterium oxide,
NCH NOH), 8.20 (d, 1H, J = 8.0 Hz, H6), 8.40 (br d, 1H, J =
7.5 Hz, H9), 8.84 (s, 1H, H2), 9.96 (d, 1H, J = 9.2 Hz,
deuterium oxide exchangeable, NH), 10.78 (s, 1H, deuterium
oxide exchangeable, OH); FAB‐ms: m/z 245 (MH+). Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

Month 2012 Polycyclic N-Heterocyclic Compounds, Part 72: Reaction of Benzofuro (or Benzothieno)
[3,2‐d]pyrimidines and Pyrido[2,3‐d]pyrimidine Derivatives with Hydroxylamine Hydrochloride
Calcd. for C11H8N4OS: C, 54.09; H, 3.30; N, 22.94. Found: C,
53.90; H, 3.54; N, 23.22.
mp 219–222°C (dec.); IR (potassium bromide): 3060, 3130, and
1
3220 (NH and OH) cm−1; H NMR (DMSO‐d6): δ 7.45 (t, 2H, J
= 8.8 Hz, H3′ and 5′), 7.56–7.69 (m, 2H, H5 and 6), 8.02 (d, 1H,
J = 9.8 Hz, changed to singlet with addition of deuterium oxide,
NCH NOH), 8.14 (d, 1H, J = 7.8 Hz, H7), 8.11–8.24 (m, 2H, H2′
and 6′), 8.28 (br d, 1H, J = 7.4 Hz, H4), 10.30 (d, 1H, J = 9.8 Hz,
deuterium oxide exchangeable, NH), 10.79 (s, 1H, deuterium
oxide exchangeable, OH); FAB‐ms: m/z 355 (MH+). Anal. Calcd.
for C17H11FN4O2S: C, 57.62; H, 3.13; N, 15.81. Found: C, 57.31;
H, 3.37; N, 15.79.
N1,N1‐Dimethyl‐N2‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidine
(12a). To a suspension of 4‐aminopyrido[2,3‐d]pyrimidine [8]
(11, 300 mg, 2.05 mmol) in dry toluene (30 mL), N,N‐
dimethylformamide dimethyl acetal (340 mg, 2.85 mmol) was
added, and the mixture was refluxed for 3 h. The solution was
evaporated in vacuo, and the residue was recrystallized from
benzene to give 12a (286 mg, 69%) as a white granule, mp
162–164°C (lit. [8] 164–166°C); 1H NMR (DMSO‐d6): δ 3.24 (s,
3H, NMe), 3.27 (s, 3H, NMe), 7.58 (dd, 1H, J = 8.2, 4.4 Hz, H6),
8.82 (s, 1H, N CHNMe2), 8.83 (dd, 1H, J = 8.2, 2.0 Hz, H5), 8.98
(s, 1H, H‐2), 9.09 (dd, 1H, J = 4.4, 2.0 Hz, H7); FAB‐ms: m/z
202 (MH+).
N‐[2‐(3‐Methyl[1,2,4]oxadiazol‐5‐yl)[1]benzothiophen‐3‐yl]
formamide oxime (10b).
To a solution of 8b (100 mg,
0.370mmol) in dry methanol (50 mL), hydroxylamine
hydrochloride (154 mg, 2.22 mmol) was added, and the
reaction mixture was refluxed for 2 h. Water was added, and
the mixture was then made basic with sat. sodium bicarbonate
aq. The precipitate was filtered, washed with water, and then
recrystallized from methanol to give 10b (58.0 mg, 57%) as
colorless needles, mp 220–222°C; IR (potassium bromide):
1
3050, 3110, and 3200 (NH and OH) cm−1; H NMR (DMSO‐
d6): δ 2.44 (s, 3H, Me), 7.53 (br t, 1H, J = 7.7 Hz, H5), 7.63
(br t, 1H, J = 7.7 Hz, H6), 7.84 (d, 1H, J = 9.8 Hz, changed to
singlet with addition of deuterium oxide, NCH NOH), 8.11 (br
d, 1H, J = 7.9 Hz, H7), 8.20 (br d, 1H, J = 7.9 Hz, H4), 9.72
(d, 1H, J = 9.8 Hz, deuterium oxide exchangeable, NH), 10.55
(s, 1H, deuterium oxide exchangeable, OH); FAB‐ms: m/z 275
(MH+). Anal. Calcd. for C12H10N4O2S: C, 52.54; H, 3.67; N,
20.43. Found: C, 52.72; H, 3.65; N, 20.07.
General procedure for the reaction of 8c–e with
hydroxylamine hydrochloride to give 10c–e. To a solution
of amidine (8) in dry methanol, hydroxylamine hydrochloride
was added, and the reaction mixture was stirred at room
temperature. The precipitate was filtered and then recrystallized
to give 10.
N1,N1‐Dimethyl‐N2‐(pyrido[2,3‐d]pyrimidin‐4‐yl)acetamidine
(12b). To a suspension of 11 (200 mg, 1.37 mmol) in dry toluene
(20 mL), N,N‐dimethylacetamide dimethyl acetal (310 mg, 2.33
mmol) was added, and the mixture was refluxed for 3 h. After the
solution was evaporated in vacuo, the residue was recrystallized
from cyclohexane/benzene to give 12b (170 mg, 58%) as a
N‐[2‐(3‐Ethyl[1,2,4]oxadiazol‐5‐yl)[1]benzothiophen‐3‐yl]
formamide oxime (10c). Compound 8c (200 mg, 0.704 mmol)
was allowed to react with hydroxylamine hydrochloride (391 mg,
5.63 mmol) in dry methanol (5.0 mL) for 2 h. Compound 10c
(112 mg, 55%) was obtained as colorless needles from methanol/
dioxane, mp 220–221°C (dec.); IR (potassium bromide): 3050,
3120, and 3200 (NH and OH) cm−1; 1H NMR (DMSO‐d6): δ
1.32 (t, 3H, J = 7.5 Hz, Me), 2.81 (q, 2H, J = 7.5 Hz, CH2Me),
7.48–7.69 (m, 2H, H5 and 6), 7.89 (d, 1H, J = 10.3 Hz, changed
to singlet with addition of deuterium oxide, NCH NOH), 8.10 (d,
1H, J = 7.7 Hz, H7), 8.22 (d, 1H, J = 8.1 Hz, H4), 9.50 (d, 1H, J
= 10.3 Hz, deuterium oxide exchangeable, NH), 10.58 (1H, s,
deuterium oxide exchangeable, OH); FAB‐ms: m/z 289 (MH+).
Anal. Calcd. for C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43.
Found: C, 53.76; H, 3.97; N, 19.26.
1
brown powder, mp 149–151°C; H NMR (DMSO‐d6): δ 2.31 (s,
3H, C Me), 3.21 (s, 6H, NMe2), 7.53 (dd, 1H, J = 8.0, 4.4 Hz,
H6), 8.61 (dd, 1H, J = 8.0, 2.0 Hz, H5), 8.80 (s, 1H, H2), 9.13
(dd, 1H, J = 4.4, 2.0 Hz, H7); FAB‐ms: m/z 216 (MH+). Anal.
Calcd. for C11H13N5: C, 61.38; H, 6.09; N, 32.54. Found: C,
61.30; H, 6.00; N, 32.56.
N‐[3‐([1,2,4]Oxadiazol‐5‐yl)‐2‐pyridyl]formamide oxime
(14a). Compound 12a (100 mg, 0.497 mmol) was allowed to
react with hydroxylamine hydrochloride (210 mg, 3.02 mmol)
in dry methanol (10 mL) for 4 h. Compound 14a (54.0 mg,
54%) was obtained as a colorless feather, mp 170–172°C (dec.);
IR (potassium bromide): 3080, 3160, and 3230 (NH and OH)
cm−1 1H NMR (DMSO‐d6): δ 7.16 (dd, 1H, J = 7.8, 4.8 Hz,
;
H5), 8.14 (d, 1H, J = 9.4 Hz, changed to singlet after addition
of deuterium oxide, NCH NOH), 8.31 (dd, 1H, J = 4.8, 2.0 Hz,
H6), 8.49 (dd, 1H, J = 7.8, 2.0 Hz, H4), 9.36 (s, 1H, H3′),
10.67 (s, 1H, deuterium oxide exchangeable, OH), 10.80 (d,
1H, J = 9.4 Hz, deuterium oxide exchangeable, NH); FAB‐ms:
m/z 206 (MH+). Anal. Calcd. for C8H7N5O2: C, 46.83; H, 3.44;
N, 34.13. Found: C, 46.61; H, 3.81; N, 34.22.
N‐[2‐(3‐Phenyl[1,2,4]oxadiazol‐5‐yl)[1]benzothiophen‐3‐yl]
formamide oxime (10d). Compound 8d (110 mg, 0.331 mmol)
was allowed to react with hydroxylamine hydrochloride (94.0
mg, 1.35 mmol) in dry methanol (5.0 mL) for 2 h. Compound
10d (73.0 mg, 64%) was obtained as colorless needles from
methanol, mp 207–209°C (dec.); IR (potassium bromide): 3040,
3130, and 3220 (NH and OH) cm−1 1H NMR (DMSO‐d6): δ
;
N‐[3‐(3‐Methyl[1,2,4]oxadiazol‐5‐yl)‐2‐pyridyl]formamide
7.20–7.35 (m, 2H, H5 and 6), 7.55–7.73 (m, 4H, H7, 3′, 4′, and
5′), 8.03 (d, 1H, J = 10.1 Hz, changed to singlet with addition
of deuterium oxide, NCH NOH), 8.15 (m, 2H, H2′ and 6′), 8.29
(br d, 1H, J = 7.8 Hz, H4), 10.34 (br d, 1H, J = 10.1 Hz,
deuterium oxide exchangeable, NH), 10.79 (s, 1H, OH); FAB‐
ms: m/z 337 (MH+). Anal. Calcd. for C17H12N4O2S·0.5H2O: C,
59.12; H, 3.79; N, 16.22. Found: C, 59.30; H, 3.67; N, 15.96.
oxime (14b).
Compound 12b (100 mg, 0.464 mmol) was
allowed to react with hydroxylamine hydrochloride (129 mg,
1.86 mmol) in dry methanol (10 mL) for 3 h. Compound 14b
(62.0 mg, 61%) was obtained as a yellow grain crystal, mp
228–230°C; IR (potassium bromide): 3040, 3140, and 3270
(NH and OH) cm−1; H NMR (DMSO‐d6): δ 2.47 (s, 3H, Me),
1
7.14 (dd, 1H, J = 7.8, 4.8 Hz, H5), 8.13 (d, 1H, J = 9.3 Hz,
changed to singlet after addition of deuterium oxide,
NCH NOH), 8.43 (dd, 1H, J = 7.8, 1.7 Hz, H4), 8.51 (dd, 1H, J
N‐{2‐[3‐(4‐Fluorophenyl)[1,2,4]oxadiazol‐5‐yl][1]benzothiophen‐
3‐yl}formamide oxime (10e). Compound 8e (80.0 mg, 0.228 mmol)
was allowed to react with hydroxylamine hydrochloride (67.0 mg,
0.964 mmol) in dry methanol (2.0mL) for 2 h. Compound 10e
(30.0 mg, 37%) was obtained as colorless needles from dioxane,
=
4.8, 1.7 Hz, H6), 10.63 (s, 1H, deuterium oxide
exchangeable, OH), 10.77 (d, 1H, J = 9.3 Hz, deuterium oxide
exchangeable, NH); FAB‐ms: m/z 220 (MH+). Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850

K. Okuda, K. Tsuchie, and T. Hirota
Vol 000
[6] The reaction mechanism was already proposed in Ref.4(a).
[7] Robba, M.; Touzot, P.; El‐Kashef, H. J Heterocycl Chem
1980, 17, 923.
[8] Verček, B.; Leban, I.; Stanovnik, B.; Tišler, M. J Org Chem
1979, 44, 1695.
C9H9N5O2: C, 49.31; H, 4.14; N, 31.95. Found: C, 49.42; H,
4.46; N, 32.19.
Acknowledgments. The authors are grateful to the SC‐NMR Lab-
oratory of Okayama University for 200 MHz 1H‐NMR
experiments. They also thank Mr. Hideki Muroyama (Laboratory
of Pharmaceutical Chemistry, Faculty of Pharmaceutical
Sciences, Okayama University) for his preliminary experimental
results and Dr. K. L. Kirk (NIDDK, NIH) for helpful comments
on the manuscript.
[9] Data were calculated with B3LYP/6–31G* by Gaussian03W,
R. C.; Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakat-
suji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dap-
prich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al‐Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.; Gauss-
ian, Inc.: Wallingford, CT, 2004.
REFERENCES AND NOTES
[1] van der Plas, H. C. Adv Heterocycl Chem 1999, 74, 1.
[2] For recent reports,see: (a) Buscemi, S.; Pace, A.; Pibiri, I.;
Vivona, N.; Lanza, C. Z.; Spinelli, D. Eur J Org Chem 2004, 2004,
974; (b) Adamo, M. F. A.; Donati, D.; Sarti‐Fantoni, P.; Buccioni,
A. Tetrahedron Lett 2008, 49, 941; (c) Piccionello, A. P.; Pace, A.;
Buscemi, S.; Vivona, N.; Giorgi, G. Tetrahedron Lett 2009, 50,
1472.
[10] Pace, A.; Pierro, P. Org Biomol Chem 2009, 7, 4337.
[11] Okuda, K.; Zhang, Y.‐X.; Ohtomo, H.; Hirota, T.; Sasaki, K. J
Heterocycl Chem 2011, 48, 715.
[3] Okuda, K.; Zhang, Y.‐X.; Ohtomo, H.; Hirota, T.; Sasaki, K.
Chem Pharm Bull 2010, 58, 369.
[12] Okuda, K.; Muroyama, H.; Hirota, T. J Heterocycl Chem
2011, 48, 1407.
[13] This type of viscous oily amidine products did not give satis-
factory elemental analytical data due to their slight instability during col-
umn chromatography purification. We therefore decided to use this
product as a slight crude status.
[4] (a) Sasaki, K.; Zhang, Y.‐X.; Yamamoto, H.; Kashino, S.; Hir-
ota, T. J Chem Res (S) 1999, 92; (b) Zhang, Y.‐X.; Sasaki, K.; Hirota, T. J
Heterocycl Chem 1999, 36, 787; (c) Sasaki, K.; Zhang, Y.‐X.; Okuda, K.;
Hirota, T. J Heterocycl Chem 2001, 38, 425.
[5] Sangapure, S. S.; Agasimundin, Y. S. Indian J Chem Sect B
1976, 14B, 688.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.850