Polycyclic N-heterocyclic compounds. Part 84: Reaction of N-(pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-yl)amidines or N-(pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-yl)amidines with hydroxylamine hydrochloride

Article abstract of DOI:10.1002/jhet.2033

The reactions of nine N-(pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-yl)amidines (3) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4-oxadiazole-forming r

Full text of DOI:10.1002/jhet.2033

8
80
Polycyclic N-Heterocyclic Compounds. Part 84: Reaction of N-(pyrido
Vol 52
0
0
0
0
[
3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-yl)amidines or N-(pyrido[2 ,3 :4,5]furo
3,2-d]pyrimidin-4-yl)amidines with Hydroxylamine Hydrochloride
[
a
b
b†
b
Kensuke Okuda, * Ryota Ide, Naoto Uramaru, and Takashi Hirota
a
Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama
00-8530, Japan
Present address: Department of Health Biosciences, Nihon Pharmaceutical University, Saitama 362-0806, Japan
b
7
†
*
E-mail: okuda@gifu-pu.ac.jp
Received January 22, 2013
DOI 10.1002/jhet.2033
Published online 11 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
0
0
The reactions of nine N-(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-yl)amidines (3) with hydroxylamine
hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine
component followed by a 1,2,4-oxadiazole-forming ring closure to give N-[2-([1,2,4]oxadiazol-5-yl)thieno
0 0
[
2,3-b]pyridin-3-yl]formamide oximes (11). Reaction of six N-(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-yl)
amidines (12) with hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized com-
pounds on pentosidine formation were also evaluated.
J. Heterocyclic Chem., 52, 880 (2015).
INTRODUCTION
RESULTS AND DISCUSSIONS
0
0
Addition of a nucleophile to an electron poor heterocycle
can initiate a ring opening/ring closure-like rearrangement
that has proven to be a useful strategy in organic synthesis
First, we examined N-(pyrido[3 ,2 :4,5]thieno[3,2-d]
pyrimidin-4-yl)amidines (3). As shown in Scheme 1, the
requisite amidine 3 starting materials were synthesized
from 2-chloropyridin-3-carbonitrile (4) by several steps.
First, the chlorine substituent was converted to a sulfanyl
group by nucleophilic displacement to give (5),
which was then alkylated by bromoacetonirile to give 2-
(cyanomethylsulfanyl)pyridin-3-carbonitrile (6). Base-
induced cyclization afforded 3-aminothieno[2,3-b]
pyridin-2-carbonitrile (7) [8], which was converted to N,
N-dimethylformamidine derivative (8) by reaction with
N,N-dimethylformamide dimethyl acetal. Cyclization of
[1]. Hydroxylamines are often utilized as 1,2-bidentate nucle-
ophiles for this type of conversion [2–4]. Recently, we have
reported that reaction of N-(quinazolin-4-yl)amidines (2)
with hydroxylamine hydrochloride leads to a pyrimidine
ring opening reaction followed by formation of the
1
5
,2,4-oxadiazole ring to produce N-[2-([1,2,4]oxadiazol-
-yl)phenyl]formamide oximes (1) (Figure 1) [5,6]. We
also reported that some of the products (1) showed signif-
icant inhibitory effects on the formation of pentosidine,
which is one of the representatives of advanced glycation
end products [5,6]. Recognizing that other fused aromatic
derivatives in addition to quinazolines should be suscep-
tible to this transformation [7], we decided to explore re-
actions of hydroxylamine hydrochloride with pyrido
0
0
8 with ammonium acetate gave 4-aminopyrido[3 ,2 :4,5]
thieno[3,2-d]pyrimidine (9) [9]. Amidine 3a was
prepared by the reaction of 9 with commercially available
N,N-dimethylacetamide dimethyl acetal in refluxing tolu-
ene. Other amidines 3b–j were produced by the reaction
of compound 9 with the Vilsmeier reagent prepared from
the corresponding N,N-dimethylamide and phosphoryl
chloride. Because 3b–j were subjects to decomposition
during purification by column chromatography, they were
used as crude amidines for the next reaction.
0
0
0
0
[
3 ,2 :4,5]thieno[3,2-d]pyrimidines and pyrido[2 ,3 :4,5]
furo[3,2-d]pyrimidines as an approach to potential
pharmaceutics. These are aza-analogs of [1]benzofuro[3,2-
d]pyrimidines and [1]benzothieno[3,2-d]pyrimidines [7],
products of rearrangement from which also showed some
inhibitory effects on pentosidine formation. Here, we report
in detail the results of our present investigation.
First, we carried out the reaction of 3a with 1.2 equiv of
hydroxylamine hydrochloride in methanol at room
©
2014 HeteroCorporation

May 2015
Polycyclic N-Heterocyclic Compounds. Part 84
881
at 8.83 ppm (pyrimidine ring proton) present in 3a was
absent in the product. These NMR data indicate that pyrim-
idine ring cleavage, and 1,2,4-oxadiazole ring formation
occurred during reaction of 3a with hydroxylamine hydro-
chloride [10]. Other amidines 3b–i having ethyl group or
aryl group substituted in the amidine moiety needed reflux
conditions with an excess amount of hydroxylamine hydro-
chloride to consume starting materials completely. In ev-
ery case, we did not observe 10, which one can assume is
the probable intermediate in the conversion of 3 to 11
[5,6]. In contrast, reaction of 3j under the same conditions
did not give 11j but led to a decomposition product 9,
which was observed in the reaction mixture by TLC analysis.
Figure 1. Substrates (2) and their rearranged products (1).
temperature. We observed incomplete consumption of 3a
on TLC. However, reaction of 3a with 4.0 equiv of hydroxy-
lamine hydrochloride in methanol led to complete con-
sumption of 3a and gave the 1,2,4-oxadiazole derivative
1
(
11a) in 73% yield. In the H NMR spectrum of 11a, a
characteristic formamide oxime one-proton doublet
J = 10.2 Hz) appeared at 7.88 ppm coupled with an adja-
cent NH proton (J = 10.2 Hz). This NH is exchangeable
and thus the formamide oxime signal changed to a singlet
in the presence of deuterium oxide. The one-proton singlet
0
0
(
Next, we focused our attention on N-(pyrido[2 ,3 :4,5]furo
[3,2-d]pyrimidin-4-yl)amidines (12). As shown in Scheme 2,
the requisite amidine starting materials 12 were prepared from
0
0
4-aminopyrido[2 ,3 :4,5]furo[3,2-d]pyrimidine (13) [11] by
Scheme 1. Synthesis of 11.
Scheme 2. Synthesis of 14.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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82
K. Okuda, R. Ide, N. Uramaru, and T. Hirota
Vol 52
ꢀ
1
1
(
(
potassium bromide) cm : 2224, 2249 (CN); H NMR
the same method as described earlier for amidines 3 except
that phosphorus pentoxide instead of phosphoryl chloride
was employed. The reactivity of each 12 with hydroxylamine
hydrochloride was the same as that of 3. Amidines 12a–f did
not afford isolable amide oximes such as 10 but produced
200 MHz, DMSO-d ): d 4.39 (s, 2H, CH ), 7.46 (dd, 1H,
J = 7.8, 5.0 Hz, H5), 8.34 (dd, 1H, J = 7.8, 1.8 Hz, H4), 8.82 (dd,
H, J = 5.0, 1.8 Hz, H6); FAB-ms m/z: 176 (MH ). Anal. Calcd.
for C S: C, 54.84; H, 2.88; N, 23.98. Found: C, 54.99; H,
.11; N, 24.36.
6
2
+
1
8 5 3
H N
3
1
1
2
1,2,4-oxadiazole derivatives (14a–f) directly by using excess
N ,N -Dimethyl-N -(2-cyanothieno[2,3-b]pyridin-3-yl)
hydroxylamine hydrochloride.
formamidine (8). To a solution of 6 (100mg, 0.571mmol) in dry
Finally, preliminary evaluation of the products on pentosidine
formation was evaluated in vitro. N-[4-Nitro-2-([1,2,4]
DMF (5.0 mL) was added calcium oxide (64.4mg, 1.15 mmol), and
the mixture was stirred at 80 C for 1 h. After filtration to remove
insoluble inorganic material followed by evaporation in vacuo,
the residue was partially purified by recrystallization from ethyl
ꢁ
oxadiazol-5-yl)phenyl]formamide oxime (1, R¼H, R ¼H,
1
R ¼NO ) [5,6] was used as a positive control. We found that
2
2
acetate-n-hexane to give 3-aminothieno[2,3-b]pyridin-2-carbonitrile
11a and 11h had some inhibitory activity (33.8% and 36.7%,
ꢁ
(
7) [8] (88.6 mg, 89%) as yellow feathers, mp 218–219 C;
respectively) against pentosidine formation; however, their
This compound 7 was used without further purification. IR
-
1
potency was lower than 1 (R¼H, R ¼H, R ¼NO )
(potassium bromide) cm : 2199 (CN), 3211, 3344, 3398
1
2
2
1
(94.5%). We are currently exploring their structure–activity
(NH); H NMR (200 MHz, DMSO-d
): d 7.35 (2H, br s,
6
deuterium oxide exchangeable, NH ), 7.53 (dd, 1H, J = 6.2,
relationships for further elucidation of anti-advanced glycation
end products compounds.
2
4
.4 Hz, H5), 8.51 (dd, 1H, J = 6.2, 1.6 Hz, H4), 8.71 (dd, 1H,
J = 4.4, 1.6 Hz, H6).
To a suspension of 7 (100 mg, 0.571 mmol) in dry toluene
(
(
5.0 mL) was added N,N-dimethylformamide dimethyl acetal
90.0 mL, 0.677 mmol), and the mixture was refluxed for 2 h. Af-
EXPERIMENTAL
All melting points were determined on a Yanagimoto (Kyoto,
Japan) micro-melting point apparatus and are uncorrected. Elemental
analyses were performed on a Yanagimoto (Kyoto, Japan) MT-5
CHN Corder elemental analyzer. The ESI-mass spectra were obtained
on a Waters (Milford, MA, USA) ZMD mass spectrometer. FAB
mass spectra were obtained on a Micromass (Manchester, UK)
Autspec-OA-Tof spectrometer and m-nitrobenzyl alcohol was used
as the matrix. The IR spectra were recorded on a Japan Spectroscopic
ter removal of solvent in vacuo, the residue was recrystallized
from ethyl acetate-n-hexane to give 8 (92.6 mg, 62% (2 steps))
as yellow feathers, mp 101–102 C; IR (potassium bromide)
cm : 2198 (CN); H NMR (300 MHz, deuterochloroform): d
3
ꢁ
ꢀ
1
1
.18 and 3.22 (each s, each 3H, NMe
2
), 7.35 (dd, 1H, J = 8.1,
4
.8 Hz, H5), 8.07 (s, 1H, NCH), 8.24 (dd, 1H, J = 8.1, 1.8 Hz,
+
H4), 8.68 (dd, 1H, J = 4.8, 1.8 Hz, H6); ESI-ms m/z: 231 (MH ).
Anal. Calcd. for C11 S: C, 57.37; H, 4.38; N, 24.33. Found:
C, 57.27; H, 4.77; N, 24.31.
4-Aminopyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidine (9) [9]. To a
solution of 8 (1.00 g, 4.34 mmol) in ethanol (15 mL) were added
ammonium acetate (3.70 g, 47.8 mmol) and water (1.0 mL), and the
mixture was then refluxed for 3 h. After cooling to room temperature,
it was made basic with sat. sodium bicarbonate aq. The precipitate
was filtered, washed with water, and then recrystallized from DMF
to give 9 (676.2 mg, 77%) as colorless granules, mp > 300 C; IR
(potassium bromide) cm : 3124, 3294, 3360 (NH); H NMR
(200 MHz, DMSO-d ): d 7.63 (dd, 1H, J=8.0, 4.6Hz, H8), 7.67
(br s, 2H, deuterium oxide exchangeable, NH ), 8.56 (s, 1H, H2),
10 4
H N
(
Hachioji, Japan) FT/IR-200 spectrophotometer with potassium
ꢀ
1
1
0
0
bromide and frequencies are expressed in cm . The H NMR spectra
were recorded on a Varian (Palo Alto, CA, USA) VXR-200
instrument operating at 200MHz or VXR-300 instrument operating
at 300 MHz with tetramethylsilane as an internal standard. Chemical
shifts are given in ppm (d) and J values in Hz, and the signals are
designated as follows: s, singlet; d, doublet; dd, double doublet; t,
triplet; q, quartet; br, broad; and m, multiplet. Column chroma-
tography was performed on silica gel (IR-60-63-210-W, Daiso,
Osaka, Japan). TLC was carried out on Kieselgel 60 F254
ꢁ
ꢀ
1
1
6
(
Merck, Darmstadt, Germany).
-(Cyanomethylsulfanyl)pyridin-3-carbonitrile (6). To a
solution of 2-chloropyridin-3-carbonitrile (4, 10.0 g, 72.1 mmol)
in dry THF (100 mL) were added thioacetamide (16.3 g,
17 mmol) and DBU (32.4 mL, 217 mmol), and the mixture was
then refluxed for 5 h. After evaporation in vacuo, ice water was
added, and the solution was made acidic (pH 1) by addition of
0% hydrochloric acid. The precipitated solid was filtrated to
yield 2-sulfanylpyridin-3-carbonitrile (5) as a yellow solid
2
2
8
.63 (dd, 1H, J= 8.0, 1.8 Hz, H9), 8.83 (dd, 1H, J=4.6, 1.8Hz,
+
H7); ESI-ms m/z: 203 (MH ). Anal. Calcd. for C H N S: C, 53.45;
H, 2.99; N, 27.70. Found: C, 53.26; H, 3.18; N, 28.02.
9
6 4
1
1
2
0
0
2
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4-yl)acetamidine (3a). Compound 9 (200 mg, 0.989 mmol) and
N,N-dimethylacetamide dimethyl acetal (220 mL, 1.50 mmol) in
dry toluene (5.0 mL) was refluxed for 1.5 h. After removal of
solvent, the residue was recrystallized from ethyl acetate-n-
hexane to give 3a (228.1 mg, 85%) as colorless needles, mp
1
(
9.70 g). This intermediate was used without further purification.
To a suspension of this crude 5 in dry acetone (150 mL) were
ꢁ
1
6
127–128 C; H NMR (300 MHz, DMSO-d ): d 2.36 (s, 3H,
added bromoacetonitrile (6.0 mL, 86.1 mmol) and potassium car-
bonate (20.0 g, 145 mmol), the reaction mixture was then stirred
at room temperature for 1 h. After filtration to remove insoluble
inorganic material followed by evaporation in vacuo, the residue
was extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous sodium sulfate, and then
evaporated in vacuo. The residue was purified by column chroma-
tography (ethyl acetate/n-hexane, 1:10) to give a white solid,
CMe), 3.20 (s, 6H, NMe ), 7.64 (dd, 1H, J = 7.8, 4.5 Hz, H8),
2
8.66 (dd, 1H, J = 7.8, 1.8 Hz, H9), 8.82 (dd, 1H, J = 4.5, 1.8 Hz,
+
H7), 8.83 (s, 1H, H2); FAB-ms m/z: 272 (MH ). Anal. Calcd.
for C H N S: C, 57.54; H, 4.83, N, 25.81. Found: C, 57.20;
13 13 5
H, 4.88; N, 25.95.
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4-yl)propionamidine (3b). To a solution of 9 (300 mg, 1.48 mmol)
in dry pyridine (40 mL) were added N,N-dimethylpropionamide
(0.200mL, 1.82mmol) and phosphoryl chloride (2.10 g,
13.7mmol), and the mixture was then refluxed for 5 h. After
which was recrystallized from ethyl acetate-n-hexane to give 6
ꢁ
(
8.70 g, 69% (2 steps)) as colorless needles, mp 134–135 C; IR
Journal of Heterocyclic Chemistry
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May 2015
Polycyclic N-Heterocyclic Compounds. Part 84
883
removal of solvent in vacuo, ice water was added to the residue.
The mixture was made basic with sodium carbonate then
extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous sodium sulfate and then
16.5 h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium carbonate
then extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous sodium sulfate, and then
evaporated in vacuo. The brown oily residue (crude 3b) was
evaporated in vacuo. The brown oily residue (crude 3f) was
1
1
used without further purification.
H
NMR (300 MHz,
CH ), 2.84
), 7.48 (dd, 1H,
J = 8.1, 4.5 Hz, H8), 8.72 (br d, 1H, J = 8.1 Hz, H9), 8.78
used without further purification.
H
NMR (300 MHz,
deuterochloroform): d 1.22 (t, 3H, J = 7.5 Hz, CH
q, 2H, J = 7.5 Hz, CH CH ), 3.26 (s, 6H, NMe
2
3
deuterochloroform): d 3.09 and 3.38 (each br s, each 3H, NMe
2
),
0
0
(
2
3
2
3.75 (s, 3H, OMe), 6.89 (dd, 2H, J = 9.0, 1.2 Hz, H3 and 5 ),
0
0
7.33 (br d, 2H, J = 9.0 Hz, H2 and 6 ), 7.47 (dd, 1H, J =7.8,
4.5 Hz, H8), 8.57 (s, 1H, H2), 8.68 (br d, 1H, J = 7.8 Hz, H9),
8.78 (dd, 1H, J =4.5, 1.5Hz, H7).
(
dd, 1H, J = 4.5, 1.8 Hz, H7), 8.83 (s, 1H, H2).
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
1 1 2
0
0
1
1
2
0
0
4
-yl)benzamidine (3c). To a solution of 9 (300 mg, 1.48 mmol)
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-
yl)-4-fluorobenzamidine (3g). To a solution of 9 (200 mg,
in dry pyridine (40 mL) were added N,N-dimethylbenzamide
265.6 mg, 1.78 mmol) and phosphoryl chloride (2.10 g,
3.7 mmol), and the mixture was then refluxed for 18 h. After
(
1
0.989mmol) in dry pyridine (30mL) were added N,N-dimethyl-4-
fluorobenzamide [15] (198.4 mg, 1.19mmol) and phosphoryl
chloride (1.40 g, 9.13 mmol), and the mixture was refluxed for
28h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium carbonate
then extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous sodium sulfate, and then
removal of solvent in vacuo, ice water was added to the residue.
The mixture was made basic with sodium carbonate then
extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous sodium sulfate, and then
evaporated in vacuo. The brown oily residue (crude 3c) was
1
used without further purification.
H
NMR (300 MHz,
evaporated in vacuo. The brown oily residue (crude 3g) was
1
deuterochloroform): d 2.99 and 3.37 (each br s, each 3H, NMe2),
.22–7.26 (m, 5H, Ph), 7.44 (dd, 1H, J = 8.1, 4.8 Hz, H8), 8.58
dd, 1H, J = 8.1, 1.8 Hz, H9), 8.59 (s, 1H, H2), 8.76 (dd, 1H,
J = 4.8, 1.8Hz, H7).
used without further purification.
H
NMR (300MHz,
7
(
deuterochloroform): d 2.99 and 3.36 (each br s, each 3H, NMe ),
2
0
0
0
6.93 (t, 2H, J = 9.0 Hz, H3 and 5 ), 7.24–7.26 (m, 2H, H2 and
6 ), 7.45 (dd, 1H, J = 8.4, 4.8 Hz, H8), 8.60 (dd, 1H, J = 8.4,
0
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
-yl)-4-methylbenzamidine (3d). To a solution of 9 (300 mg,
.48 mmol) in dry pyridine (40 mL) were added N,N-dimethyl-
-methylbenzamide [12] (290.5 mg, 1.78 mmol) and phosphoryl
1.8 Hz, H9), 8.61 (s, 1H, H2), 8.77 (dd, 1H, J = 4.8, 1.8 Hz, H7).
1
1
2
0
0
4
1
4
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4-yl)-4-chlorobenzamidine (3h). To a solution of 9 (300 mg,
1.48 mmol) in dry pyridine (40 mL) were added N,N-dimethyl-
4-chlorobenzamide [14] (326.9 mg, 1.78 mmol) and phosphoryl
chloride (2.10 g, 13.7 mmol), and the mixture was refluxed for
14 h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium carbonate
then extracted with ethyl acetate. The organic phase was
washed with sat. brine, dried over anhydrous sodium sulfate,
and then evaporated in vacuo. The brown oily residue (crude
chloride (2.10 g, 13.7 mmol), and the mixture was then refluxed
for 12 h. After removal of solvent in vacuo, ice water was added
to the residue. The mixture was made basic with sodium
carbonate then extracted with ethyl acetate. The organic phase
was washed with sat. brine, dried over anhydrous sodium
sulfate, and then evaporated in vacuo. The brown oily residue
1
(
crude 3d) was used without further purification. H NMR
1
(
3
300 MHz, deuterochloroform): d 2.26 (s, 3H, CMe), 2.99 and
3h) was used without further purification. H NMR (300 MHz,
0
.35 (each br s, each 3H, NMe
2
), 7.02 (br d, 2H, J = 7.8 Hz, H3
deuterochloroform): d 2.98 and 3.36 (each br s, each 3H,
0
0
0
0 0 0 0
NMe ), 7.20–7.25 (m, 4H, H2 , 3 , 5 , and 6 ), 7.46 (dd, 1H,
2
and 5 ), 7.13 (br d, 2H, J = 7.8 Hz, H2 and 6 ), 7.44 (dd, 1H,
J = 7.8, 4.8 Hz, H8), 8.59 (dd, 1H, J = 7.8, 1.5 Hz, H9), 8.61
J = 8.1, 4.8 Hz, H8), 8.60 (dd, 1H, J = 8.1, 1.8 Hz, H9), 8.61
(s, 1H, H2), 8.77 (dd, 1H, J = 4.8, 1.8 Hz, H7).
(
s, 1H, H2), 8.76 (dd, 1H, J = 4.8, 1.5 Hz, H7).
1 1 2
0
0
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-
yl)-3,4-dimethylbenzamidine (3e). To a solution of 9 (300 mg,
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4-yl)-4-nitrobenzamidine (3i). To a solution of 9 (300 mg,
1
.48 mmol) in dry pyridine (40 mL) were added N,N-dimethyl-3,
1.48 mmol) in dry pyridine (40 mL) were added N,N-dimethyl-
4-nitrobenzamide [14] (345.7 mg, 1.78 mmol) and phosphoryl
chloride (2.10 g, 13.7 mmol), and the mixture was refluxed for
18 h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium carbonate
then extracted with ethyl acetate. The organic phase was
washed with sat. brine, dried over anhydrous sodium sulfate,
and then evaporated in vacuo. The brown oily residue (crude 3i)
4-dimethylbenzamide [13] (315.5 mg, 1.78 mmol) and phosphoryl
chloride (2.10 g, 13.7 mmol), and the mixture was refluxed for
0 h. After removal of solvent in vacuo, ice water was added to
2
the residue. The mixture was made basic with sodium
carbonate then extracted with ethyl acetate. The organic phase
was washed with sat. brine, dried over anhydrous sodium
sulfate, and then evaporated in vacuo. The brown oily residue
1
1
(
(
crude 3e) was used without further purification. H NMR
300 MHz, deuterochloroform): d 2.14 and 2.16 (each s, each
was used without further purification. H NMR (300 MHz,
deuterochloroform): d 2.96 and 3.41 (each br s, each 3H,
3
H, 2 ꢂ CMe), 3.01 and 3.35 (each br s, each 3H, NMe
2
0
), 7.05
NMe
2
), 7.44–7.48 (m, 1H, H8), 7.58 (dd, 2H, J = 9.0, 2.1 Hz,
0
0
0
0
0
0
(
(
br s, 1H, H5 ), 7.12 (br s, 1H, H6 ), 7.25 (br s, 1H, H2 ), 7.44
dd, 1H, J = 8.1, 4.5 Hz, H8), 8.60 (s, 1H, H2), 8.62 (br d, 1H,
H2 and 6 ), 8.27 (dd, 2H, J = 9.0, 2.1 Hz, H3 and 5 ), 8.56
(s, 1H, H2), 8.60 (dd, 1H, J = 7.8, 1.8 Hz, H9), 8.77 (dd, 1H,
J = 4.8, 1.8 Hz, H7).
J = 8.1 Hz, H9), 8.76 (dd, 1H, J = 4.5, 1.8 Hz, H7).
1
1
2
0
0
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-
yl)-4-methoxybenzamidine (3f). To a solution of 9 (200 mg,
.989 mmol) in dry pyridine (30 mL) were added N,N-dimethyl-4-
N ,N -Dimethyl-N -(pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-
yl)nicotinamidine (3j). To a solution of 9 (500 mg, 2.47mmol) in
dry pyridine (60 mL) were added N,N-dimethylnicotinamide
(556.9 mg, 3.71 mmol) and phosphoryl chloride (3.50 g,
22.8 mmol), and the mixture was refluxed for 6.5 h. After removal
0
methoxybenzamide [14] (212.7 mg, 1.19 mmol) and phosphoryl
chloride (1.40 g, 9.13 mmol), and the mixture was refluxed for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

8
84
K. Okuda, R. Ide, N. Uramaru, and T. Hirota
Vol 52
of solvent in vacuo, ice water was added to the residue. The mixture
was made basic with sodium carbonate then extracted with ethyl
acetate. The organic phase was washed with sat. brine, dried over
anhydrous sodium sulfate, and then evaporated in vacuo. The
residue was recrystallized from ethanol to give 3j (383.8 mg, 46%)
oxide exchangeable, NH), 10.85 (s, 1H, deuterium oxide
exchangeable, OH); FAB-msm/z: 338 (MH ). Anal. Calcd. for
+
C
16
H
11
N
5
O
2
S ꢃ 1/2DMF: C, 56.21; H, 3.91; N, 20.60. Found: C,
56.58; H, 3.84; N, 20.81.
N-{2-[3-(4-Methylphenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
ꢁ
1
as yellow granules, mp 200–201 C; H NMR (300 MHz,
deuterochloroform): d 3.02 and 3.42 (each br s, each 3H, NMe ),
.22 (ddd, 1H, J= 7.8, 4.8, 0.6 Hz, H5 ), 7.46 (dd, 1H, J =7.8,
pyridin-3-yl}formamide oxime (11d).
Crude intermediate 3d
was allowed to react with hydroxylamine hydrochloride
(412.3 mg, 5.93 mmol) in dry methanol (30 mL) under reflux for
10 h. Compound 11d (375.3 mg, 72% (2 steps)) from DMF as
2
0
7
4
0
.5 Hz, H8), 7.63 (br d, 1H, J=7.8Hz, H4 ), 8.51–8.55 (m, 2H,
ꢁ
ꢀ
1
0
0
H2 and 6 ), 8.56 (s, 1H, H2), 8.62 (dd, 1H, J = 7.8, 1.8 Hz, H9),
yellow feathers, mp 250–252 C; IR (potassium bromide) cm
:
+
1
8
.78 (dd, 1H, J= 4.5, 1.8 Hz, H7); ESI-ms m/z: 335 (MH ). Anal.
Calcd. for C17 S: C, 61.06; H, 4.22; N, 25.13. Found: C,
1.02; H, 4.49; N, 25.29.
General procedure for the reaction of 3 with hydroxylamine
3211, 3423 (NH and OH); H NMR (300 MHz, DMSO-d
6
):
0
0
H N
14 6
d 2.42 (s, 3H, Me), 7.40 (br d, 2H, J = 8.1 Hz, H3 and 5 ), 7.59
(dd, 1H, J = 8.4, 4.5 Hz, H5), 8.02 (br d, 2H, J = 8.1 Hz, H2 and
6 ), 8.05 (d, 1H, J = 10.2 Hz, changed to singlet after addition of
0
6
0
hydrochloride to give 11. To a solution of amidine (3) in dry
methanol was added hydroxylamine hydrochloride, and the
reaction mixture was stirred at an appropriate temperature. Then, it
was made basic with sat. sodium bicarbonate aq. The precipitate
was filtered, washed with water, and then recrystallized from
methanol or DMF to give 11.
deuterium oxide, NCHNOH), 8.75 (dd, 1H, J = 8.4, 1.5 Hz, H4),
8.79 (dd, 1H, J = 4.5, 1.5 Hz, H6), 10.48 (d, 1H, J = 10.2 Hz,
deuterium oxide exchangeable, NH), 10.80 (s, 1H, deuterium
oxide exchangeable, OH); FAB-ms m/z: 352 (MH ); Anal.
13 5 2
Calcd. for C17H N O S: C, 58.11; H, 3.73; N, 19.93. Found:
+
C, 58.10; H, 4.12; N, 20.10.
N-[2-(3-Methyl[1,2,4]oxadiazol-5-yl)thieno[2,3-b]pyridin-3-
N-{2-[3-(3,4-Dimethylphenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
pyridin-3-yl}formamide oxime (11e). Crude intermediate 3e was
allowed to react with hydroxylamine hydrochloride (412.3mg,
5.93mmol) in dry methanol (30mL) under reflux for 11h.
Compound 11e (357.7mg, 60% (two steps)) from DMF as yellow
yl]formamide oxime (11a).
Compound 3a (200 mg,
0
.737 mmol) was allowed to react with hydroxylamine
hydrochloride (204.9 mg, 2.95 mmol) in dry methanol (20 mL)
at room temperature for 1 h. Compound 11a (148.1 mg, 73%)
ꢁ
ꢁ
ꢀ1
from methanol as colorless feathers, mp 232–233 C; IR
feathers, mp 241–242 C; IR (potassium bromide) cm : 3210,
ꢀ
1
1
1
(
potassium bromide) cm : 3216, 3245, 3405 (NH and OH); H
3406 (NH and OH); H NMR (300MHz, DMSO-d
6
): d 2.32 and
0
NMR (300 MHz, DMSO-d ): d 2.44 (s, 3H, Me), 7.56 (dd, 1H,
2.34 (each s, each 3H, 2 ꢂ Me), 7.34 (d, 1H, J = 8.1 Hz, H5 ), 7.59
6
0
J = 8.4, 4.5 Hz, H5), 7.88 (d, 1H, J = 10.2 Hz, changed to singlet
after addition of deuterium oxide, NCHNOH), 8.63 (dd, 1H,
J = 8.4, 1.5 Hz, H4), 8.86 (dd, 1H, J = 4.5, 1.5 Hz, H6), 9.87
(dd, 1H, J = 8.4, 4.8 Hz, H5), 7.85 (br d, 1H, J = 8.1 Hz, H6 ), 7.87
0
(br s, 1H, H2 ), 8.08 (d, 1H, J = 10.2Hz, changed to singlet after
addition of deuterium oxide, NCHNOH), 8.75–8.79 (m, 2H, H4
and 6), 10.56 (d, 1H, J = 10.2Hz, deuterium oxide exchangeable,
NH), 10.92 (s, 1H, deuterium oxide exchangeable, OH); FAB-
(
(
(
d, 1H, J = 10.2 Hz, deuterium oxide exchangeable, NH), 10.60
s, 1H, deuterium oxide exchangeable, OH); FAB-ms m/z: 276
+
+
MH ). Anal. Calcd. for C11
H
9
N
5
O
2
S: C, 47.99; H, 3.30; N,
ms m/z: 366 (MH ). Anal. Calcd. for C18
H
15
N
5
O
2
S ꢃ 1/2DMF:
2
5.44. Found: C, 47.73; H, 3.60; N, 25.60.
N-[2-(3-Ethyl[1,2,4]oxadiazol-5-yl)thieno[2,3-b]pyridin-3-yl]
formamide oxime (11b). Crude intermediate 3b was allowed
to react with hydroxylamine hydrochloride (263.0 mg,
.78 mmol) in dry methanol (20 mL) under reflux for 18 h.
C, 58.27; H, 4.64; N, 19.17. Found: C, 58.65; H, 4.73; N, 19.28.
N-{2-[3-(4-Methoxyphenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
pyridin-3-yl}formamide oxime (11f). Crude intermediate 3f was
allowed to react with hydroxylamine hydrochloride (274.9mg,
3.96mmol) in dry methanol (20mL) under reflux for 33h.
Compound 11f (7.2 mg, 2% (two steps)) from DMF as yellow
3
Compound 11b (60.1 mg, 14% (two steps)) from methanol as
ꢁ
ꢀ1
ꢁ
1
ꢀ1
yellow feathers, mp 235–236 C; IR (potassium bromide) cm
:
feathers, mp 254–255 C; IR (potassium bromide) cm : 3217,
3423 (NH and OH); H NMR (300 MHz, DMSO-d
1
3
1
188, 3405 (NH and OH); H NMR (300 MHz, DMSO-d ): d
6
): d 3.87
6
0
0
.32 (t, 3H, J = 7.5 Hz, CH
2
CH
3
), 2.82 (q, 2H, J = 7.5 Hz,
(s, 3H, OMe), 7.12 (br d, 2H, J = 8.4 Hz, H3 and 5 ), 7.58
(dd, 1H, J = 8.1, 4.8 Hz, H5), 8.05 (d, 1H, J = 10.2 Hz, changed to
singlet after addition of deuterium oxide, NCH = NOH), 8.08
(br d, 2H, J = 8.4 Hz, H2 and 6 ), 8.73–8.79 (m, 2H, H4 and 6),
10.46 (d, 1H, J = 10.2Hz, deuterium oxide exchangeable, NH),
CH
2
CH ), 7.57 (dd, 1H, J = 8.4, 4.8 Hz, H5), 7.93 (d, 1H,
3
J = 10.2 Hz, changed to singlet after addition of deuterium
oxide, NCHNOH), 8.68 (dd, 1H, J = 8.4, 1.5 Hz, H4), 8.76
dd, 1H, J = 4.8, 1.5 Hz, H6), 10.08 (d, 1H, J = 10.2 Hz,
0
0
(
deuterium oxide exchangeable, NH), 10.64 (s, 1H, deuterium
oxide exchangeable, OH); FAB-ms m/z: 290 (MH ). Anal.
10.82 (s, 1H, deuterium oxide exchangeable, OH); FAB-msm/z:
+
+
368 (MH ). Anal. Calcd. for C17
3.92; N, 18.17. Found: C, 52.92; H, 4.03; N, 17.90.
H
N
O
S ꢃ H
O: C, 52.98; H,
13
5
3
2
Calcd. for C12
Found: C, 48.27; H, 4.05; N, 23.43.
H
11
N
5
O
2
S ꢃ 1/2H
2
O: C, 48.31; H, 4.05; N, 23.48.
N-{2-[3-(4-Fluorophenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
N-[2-(3-Phenyl[1,2,4]oxadiazol-5-yl)thieno[2,3-b]pyridin-3-yl]
formamide oxime (11c). Crude intermediate 3c was allowed to
react with hydroxylamine hydrochloride (355.2 mg, 5.11 mmol) in
dry methanol (20 mL) under reflux for 12h. Compound 11c
pyridin-3-yl}formamide oxime (11g).
Crude intermediate 3g
was allowed to react with hydroxylamine hydrochloride
(219.9 mg, 3.16 mmol) in dry methanol (20 mL) under reflux for
9 h. Compound 11g (179.2 mg, 46% (two steps)) from DMF as
ꢁ
ꢀ1
(
2
230.2mg, 42% (two steps)) from DMF as yellow needles, mp
yellow feathers, mp 258–260 C; IR (potassium bromide) cm
:
ꢁ
ꢀ1
1
40–242 C; IR (potassium bromide) cm : 3211, 3415 (NH and
3212, 3415 (NH and OH); H NMR (300 MHz, DMSO-d
6
): d
1
0
0
OH); H NMR (300MHz, DMSO-d
6
): d 7.57–7.66 (m, 4H, H5,
, 4 , and 5 ), 8.06 (d, 1H, J = 10.2 Hz, changed to singlet after
addition of deuterium oxide, NCHNOH), 8.15 (dd, 2H, J = 7.8,
7.44 (t, 2H, J = 9.0 Hz, H3 and 5 ), 7.60 (dd, 1H, J = 8.4,
4.8 Hz, H5), 8.04 (d, 1H, J = 10.2 Hz, changed to singlet after
addition of deuterium oxide, NCHNOH), 8.19 (dd, 2H, J = 9.0,
5.1 Hz, H2 and 6 ), 8.74–8.80 (m, 2H, H4 and 6), 10.43 (d, 1H,
J = 10.2 Hz, deuterium oxide exchangeable, NH), 10.83 (s, 1H,
0
0
0
3
0
0
0
0
1
1
.5 Hz, H2 and 6 ), 8.74 (dd, 1H, J = 8.4, 1.2 Hz, H4), 8.79 (dd,
H, J = 4.5, 1.2Hz, H6), 10.49 (d, 1H, J = 10.2 Hz, deuterium
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2015
Polycyclic N-Heterocyclic Compounds. Part 84
885
+
1
1
2
0
0
deuterium oxide exchangeable, OH); FAB-ms m/z: 356 (MH ).
Anal. Calcd. for C16
N, 19.66. Found: C, 53.61; H, 3.28; N, 19.85.
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-
yl)-4-methoxybenzamidine (12c). To a solution of 13 (186 mg,
0.999 mmol) in dry pyridine (30 mL) were added N,N-dimethyl-
4-methoxybenzamide [14] (215 mg, 1.20 mmol) and phosphorus
pentoxide (1.42 g, 10.0 mmol), and the mixture was refluxed for
14 h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium
carbonate, then extracted with ethyl acetate. The organic phase
was washed with sat. brine, dried over anhydrous magnesium
sulfate, and then evaporated in vacuo. The brown oily residue
H
10FN
5
O
2
S ꢃ 1/2DMF: C, 53.63; H, 3.47;
N-{2-[3-(4-Chlorophenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
pyridin-3-yl}formamide oxime (11h).
was allowed to react with hydroxylamine hydrochloride
338.1 mg, 4.87 mmol) in dry methanol (20 mL) under reflux for
h. Compound 11h (275.8 mg, 46% (two steps)) from DMF as
Crude intermediate 3h
(
8
ꢁ
ꢀ1
yellow feathers, mp 254–255 C; IR (potassium bromide) cm
3
:
1
211, 3433 (NH and OH); H NMR (300 MHz, DMSO-d
6
): d
1
7
.59 (dd, 1H, J = 8.4, 4.8 Hz, H5), 7.66 (br d, 2H, J = 8.7 Hz,
H3 and 5 ), 8.04 (d, 1H, J = 10.2 Hz, changed to singlet after
addition of deuterium oxide, NCHNOH), 8.13 (br d, 2H,
J = 8.7 Hz, H2 and 6 ), 8.74–8.80 (m, 2H, H4 and 6), 10.42
d, 1H, J = 10.2 Hz, deuterium oxide exchangeable, NH), 10.82
s, 1H, deuterium oxide exchangeable, OH); FAB-ms m/z: 372
(crude 12c) was used without further purification. H NMR
(300 MHz, deuterochloroform): d 3.06, 3.43 (each s, each 3H,
0
0
0
0
NMe ), 3.83 (s, 3H, OMe), 6.73 (d, 2H, J = 8.4 Hz, H3 and 5 ),
2
0
0
0
0
7.31 (d, 2H, J = 8.4 Hz, H2 and 6 ), 7.51 (dd, 1H, J = 8.4,
4.5 Hz, H7), 7.91 (br d, 1H, J = 8.4 Hz, H6), 8.65 (s, 1H, H2),
8.82 (br d, 1H, J = 4.5 Hz, H8).
(
(
(
+
+
1
1
2
0
0
MH ), 374 (MH + 2). Anal. Calcd. for C H ClN O S ꢃ
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-
yl)-4-fluorobenzamidine (12d). To a solution of 13 (186 mg,
0.999 mmol) in dry pyridine (30 mL) were added N,N-dimethyl-
4-fluorobenzamide [15] (201 mg, 1.20 mmol) and phosphorus
pentoxide (1.42 g, 10.0mmol), and the mixture was refluxed for
8 h. After removal of solvent in vacuo, ice water was added to the
residue. The mixture was made basic with sodium carbonate then
extracted with ethyl acetate. The organic phase was washed
with sat. brine, dried over anhydrous magnesium sulfate, and
then evaporated in vacuo. The brown oily residue (crude 12d)
1
6
10
5 2
1
3
/2DMF: C, 51.47; H, 3.33; N, 18.87. Found: C, 51.57; H,
.19; N, 19.05.
N-{2-[3-(4-Nitrophenyl)[1,2,4]oxadiazol-5-yl]thieno[2,3-b]
pyridin-3-yl}formamide oxime (11i). Crude intermediate 3i was
allowed to react with hydroxylamine hydrochloride (362.8mg,
.22 mmol) in dry methanol (20mL) under reflux for 10 h.
5
Compound 11i (340.3 mg, 55% (two steps)) from DMF as a
ꢁ
ꢀ1
yellow powder, mp> 300 C; IR (potassium bromide) cm
:
1
3
218, 3433 (NH and OH); H NMR (300 MHz, DMSO-d
6
): d
1
7
.58 (dd, 1H, J = 8.4, 4.5Hz, H5), 8.04 (d, 1H, J = 10.2Hz,
was used without further purification. H NMR (300MHz,
changed to singlet after addition of deuterium oxide, NCHNOH),
deuterochloroform): d 3.14, 3.48 (each s, each 3H, NMe ), 7.01
2
0
0
0
0
0
0
0
8
6
1
3
.33–8.42 (m, 4H, H2 , 3 , 5 , and 6 ), 8.73–8.79 (m, 2H, H4 and
), 10.44 (d, 1H, J = 10.2 Hz, deuterium oxide exchangeable, NH),
(br t, 2H, J = 8.7Hz, H3 and 5 ), 7.40 (br d, 2H, J = 8.7Hz, H2
0
and 6 ), 7.56 (dd, 1H, J = 8.4, 4.5 Hz, H7), 7.95 (dd, 1H, J = 8.4,
1.2 Hz, H6), 8.57 (s, 1H, H2), 8.83 (dd, 1H, J = 4.5, 1.2 Hz, H8).
0.84 (s, 1H, deuterium oxide exchangeable, OH); FAB-ms m/z:
+
1
1
2
0
0
83 (MH ). Anal. Calcd. for C16
10 6 4
H N O S ꢃ 1/2DMF: C, 50.18;
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-yl)-
4-chlorobenzamidine (12e). To a solution of 13 (186 mg,
H, 3.25; N, 21.73. Found: C, 49.79; H, 3.11; N, 21.87.
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-yl)
0.999 mmol) in dry pyridine (30 mL) were added N,N-
dimethyl-4-chlorobenzamide [14] (220 mg, 1.20 mmol) and
phosphorus pentoxide (1.42 g, 10.0 mmol), and the mixture was
refluxed for 10 h. After removal of solvent in vacuo, ice water
was added to the residue. The mixture was made basic with
sodium carbonate, then extracted with ethyl acetate. The
organic phase was washed with sat. brine, dried over anhydrous
magnesium sulfate, and then evaporated in vacuo. The brown
oily residue (crude 12e) was used without further purification.
0
0
acetamidine (12a). To a suspension of 4-aminopyrido[2 ,3 :4,5]
furo[3,2-d]pyrimidine (13, 186 mg, 0.999 mmol) [11] in dry
toluene (10 mL) was added N,N-dimethylacetamide dimethyl
acetal (160 mg, 1.20 mmol), the mixture was refluxed for 2 h. After
evaporation of solvent in vacuo, the residue was recrystallized
from n-hexane/ethyl acetate to give 12a (227 mg, 89%) as pale
ꢁ
1
yellow needles, mp 125–126 C;
deuterochloroform): d 2.34 (s, 3H, CMe), 3.22, 3.32 (each s, each
H, NMe ), 7.51 (dd, 1H, J = 8.4, 4.8 Hz, H7), 7.94 (dd, 1H,
H
NMR (300 MHz,
1
3
H NMR (300 MHz, deuterochloroform): d 3.03, 3.54 (each s,
2
0 0
each 3H, NMe ), 7.22 (br d, 2H, J = 9.0 Hz, H3 and 5 ), 7.31
2
(br d, 2H, J = 9.0 Hz, H2 and 6 ), 7.52 (dd, 1H, J = 8.4, 4.5 Hz,
H7), 7.92 (dd, 1H, J = 8.4, 1.2 Hz, H6), 8.64 (s, 1H, H2), 8.79
(dd, 1H, J = 4.5, 1.2 Hz, H8).
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-
yl)-4-nitrobenzamidine (12f). To a solution of 13 (186 mg,
J = 8.4, 1.2 Hz, H6), 8.81 (dd, 1H, J =4.8, 1.2Hz, H8), 8.89
+
0
0
(
s, 1H, H2). FAB-ms: m/z 256 (MH ); Anal. Calcd. for
C H N O: C, 61.17; H, 5.13; N, 27.43. Found: C, 60.94; H,
13 13 5
5
.19; N, 27.07.
1 1
2
0
0
1
1
2
0
0
N ,N -Dimethyl-N -(pyrido[2 ,3 :4,5]furo[3,2-d]pyrimidin-4-yl)
benzamidine (12b). To a solution of 13 (186 mg, 0.999 mmol) in
dry pyridine (30 mL) were added N,N-dimethylbenzamide (179 mg,
0.999 mmol) in dry pyridine (30 mL) were added N,N-dimethyl-
4-nitrobenzamide [14] (233 mg, 1.20 mmol) and phosphorus
pentoxide (1.42 g, 10.0 mmol), and the mixture was refluxed for
9 h. After removal of solvent in vacuo, ice water was added to
the residue. The mixture was made basic with sodium carbonate
then extracted with ethyl acetate. The organic phase was
washed with sat. brine, dried over anhydrous magnesium
sulfate, and then evaporated in vacuo. The brown oily residue
1.20 mmol) and phosphorus pentoxide (1.42 g, 10.0 mmol), and the
mixture was refluxed for 6 h. After removal of solvent in vacuo, ice
water was added to the residue. The mixture was made basic with
sodium carbonate then extracted with ethyl acetate. The organic
phase was washed with sat. brine, dried over anhydrous
magnesium sulfate, and then evaporated in vacuo. The brown oily
1
residue (crude 12b) was used without further purification.
H
1
NMR (300 MHz, deuterochloroform): d 3.33, 3.59 (each s, each
(crude 12f) was used without further purification. H NMR
0
0
0
3
H, NMe
J = 9.3, 4.5 Hz, H7), 7.79–7.85 (m, 2H, H2 and 6 ), 8.01 (br d,
H, J = 9.3 Hz, H6), 8.46 (s, 1H, H2), 8.89 (br d, 1H,
J = 4.5 Hz, H8).
2
), 7.19–7.29 (m, 3H, H3 , 4 , and 5 ), 7.62 (dd, 1H,
(300 MHz, deuterochloroform): d 3.07, 3.38 (each s, each 3H,
0
0
0 0
NMe ), 7.41–7.44 (m, 3H, H7, 2 , and 6 ), 7.87 (br d, 1H,
2
0
0
1
J = 7.9 Hz, H6), 8.05 (br d, 2H, J = 7.0 Hz, H3 and 5 ), 8.54
(s, 1H, H2), 8.72 (dd, 1H, J = 4.8, 1.5 Hz, H8).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

8
86
K. Okuda, R. Ide, N. Uramaru, and T. Hirota
Vol 52
General procedure for the reaction of 12 with hydroxylamine
1H, J = 4.5Hz, H5), 8.74 (d, 1H, J= 10.5 Hz, changed to singlet
with addition of deuterium oxide, NCH = NOH), 9.24 (d, 1H,
J = 10.5 Hz, deuterium oxide exchangeable, NH), 10.76 (s, 1H,
hydrochloride to give 14. To a solution of amidine (12) in dry
methanol was added hydroxylamine hydrochloride, and the
reaction mixture was stirred at room temperature for an appropriate
time. After evaporation of solvent in vacuo, the residue was made
basic with sat. sodium bicarbonate aq. The precipitate was
collected on a filter, washed with water, and then recrystallized
from dioxane/methanol to give 14.
N-[2-(3-Methyl[1,2,4]oxadiazol-5-yl)furo[3,2-b]pyridin-3-yl]
formamide oxime (14a). Compound 12a (255mg, 0.999mmol)
was allowed to react with hydroxylamine hydrochloride
+
deuterium oxide exchangeable, OH); FAB-ms: m/z 340 (MH ).
1
6
10
5
3
Anal. Calcd. for C H FN O 1/3dioxane: C, 56.47; H, 3.46; N,
•
19.00. Found: C, 56.60; H, 3.69; N, 19.04.
N-{2-[3-(4-Chlorophenyl)[1,2,4]oxadiazol-5-yl]furo[3,2-b]
pyridin-3-yl}formamide oxime (14e). Crude intermediate 12e
was allowed to react with hydroxylamine hydrochloride (278.0mg,
4.00mmol) in dry methanol (20 mL) at room temperature for 4 h.
Compound 14e (231 mg, 64% (two steps)) as pale green feathers,
ꢁ
ꢀ1
(
278 mg, 4.00 mmol) in dry methanol (20 mL) at room
mp 248–249 C; IR (potassium bromide) cm : 3187, 3339, 3490
1
temperature for 3 h. Compound 14a (210 mg, 79%) as colorless
(NH and OH); H NMR (300 MHz, DMSO-d ): d 7.64–7.72
6
ꢁ
ꢀ1
0
0
0
0
feathers, mp 225–226 C; IR (potassium bromide) cm : 3300,
(m, 3H, H6, 3 , and 5 ), 8.06 (d, 2H, J = 8.4 Hz, H2 and 6 ), 8.26
(dd, 1H, J = 8.7, 1.2 Hz, H7), 8.71 (d, 1H, J = 4.5 Hz, changed to
singlet with addition of deuterium oxide, NCHNOH), 8.72
(dd, 1H, J = 4.5, 1.2 Hz, H5), 9.21, 10.78 (each br, each 1H,
deuterium oxide exchangeable, NH and OH); FAB-ms: m/z 356
1
3
363, 3450 (NH and OH); H NMR (300 MHz, DMSO-d
d 2.32 (s, 3H, Me), 7.65 (dd, 1H, J = 8.4, 4.8 Hz, H6), 8.23
dd, 1H, J = 8.4, 1.2 Hz, H7), 8.70 (d, 1H, J = 10.2 Hz, changed
to singlet with addition of deuterium oxide, NCHNOH), 8.71
dd, 1H, J = 4.8, 1.2 Hz, H5), 8.97 (d, 1H, J = 10.2 Hz,
6
):
(
+
+
(
(MH ), 358 (MH + 2). Anal. Calcd. for C H ClN O 1/4H O:
•
16
10
5
3 2
deuterium oxide exchangeable, NH), 10.65 (s, 1H, deuterium
oxide exchangeable, OH); FAB-ms: m/z 260 (MH ). Anal.
C, 53.35; H, 2.94; N, 19.44. Found: C, 53.64; H, 3.00; N, 19.28.
N-{2-[3-(4-Nitrophenyl)[1,2,4]oxadiazol-5-yl]furo[3,2-b]pyridin-
3-yl}formamide oxime (14f). Crude intermediate 12f was allowed
to react with hydroxylamine hydrochloride (278.0 mg, 4.00 mmol)
in dry methanol (20 mL) at room temperature for 5 h. Compound
14f (256 mg, 66% (two steps)) as pale yellow feathers, mp
+
Calcd. for C11
6.21. Found: C, 50.87; H, 3.67; N, 26.45.
N-[2-(3-Phenyl[1,2,4]oxadiazol-5-yl)furo[3,2-b]pyridin-3-yl]
H
9
N
5
O
3
ꢃ 1/4CH
3
OH: C, 50.56; H, 3.77; N,
2
formamide oxime (14b). Crude intermediate 12b was allowed
to react with hydroxylamine hydrochloride (278.0 mg, 4.00mmol)
in dry methanol (20 mL) at room temperature for 6 h.
Compound 14b (202 mg, 55% (two steps)) as colorless
ꢁ
ꢀ1
229–230 C; IR (potassium bromide) cm : 3110, 3229, 3490
1
(NH and OH); H NMR (300 MHz, DMSO-d ): d 7.68 (dd, 1H,
6
J = 8.7, 4.8 Hz, H6), 8.27 (br d, 1H, J = 8.7 Hz, H7), 8.30
ꢁ
ꢀ1
0
0
0
feathers; mp 246–247 C. IR (potassium bromide) cm : 3073,
(d, 2H, J = 9.0 Hz, H3 and 5 ), 8.44 (d, 2H, J = 9.0 Hz, H2 and
1
0
3
270, 3339 (NH and OH); H NMR (300 MHz, DMSO-d ):
6 ), 8.74 (d, 1H, J = 10.2 Hz, changed to singlet with addition
6
0
0
0
d 7.57–7.63 (m, 3H, H3 , 4 , and 5 ), 7.67 (dd, 1H, J = 8.7,
of deuterium oxide, NCHNOH), 8.76 (br d, 1H, J = 4.8 Hz,
H5), 9.21 (d, 1H, J = 10.2 Hz, deuterium oxide exchangeable,
0
0
4
.8 Hz, H6), 8.09 (dd, 2H, J = 7.5, 2.4 Hz, H2 and 6 ), 8.27
dd, 1H, J = 8.7, 1.2 Hz, H7), 8.72 (dd, 1H, J = 4.8, 1.2 Hz, H5),
.74 (d, 1H, J = 9.0 Hz, changed to singlet with addition of
(
8
NH), 10.81 (s, 1H, deuterium oxide exchangeable, OH); FAB-
+
ms: m/z 367 (MH ). Anal. Calcd. for C H N O
1
6
10
6
5
•
1/4dioxane:
deuterium oxide, NCHNOH), 9.31, 10.75 (each br, each 1H,
C, 52.58; H, 3.11; N, 21.64. Found: C, 52.73; H, 3.24; N, 21.74.
Determination of pentosidine formation in vitro. Test
deuterium oxide exchangeable, NH, OH); FAB-ms: m/z 322
+
(
4
MH ). Anal. Calcd. for C16
H
11
N
5
O
3
ꢃ 1/2dioxane: C, 59.18; H,
compound stock solutions were prepared at 100 mM concentration
in DMSO. The reaction mixture (total volume 200 mL) consisting
of 24 mg/mL bovine serum albumin, 10 mM D-glucose, and
.14; N, 19.17. Found: C, 58.81; H, 4.18; N, 19.05.
N-{2-[3-(4-Methoxyphenyl)[1,2,4]oxadiazol-5-yl]furo[3,2-b]
pyridin-3-yl}formamide oxime (14c). Crude intermediate 12c
was allowed to react with hydroxylamine hydrochloride
278.0mg, 4.00mmol) in dry methanol (20 mL) at room
ꢁ
2.0 mM test compounds was incubated at 37 C for 4 weeks in
100 mM phosphate buffer (pH 7.4). Then, 10% trichloroacetic acid
was added to precipitate proteins. After collecting the precipitate
by centrifugation, 2% protease (Sigma) was added and incubated
(
temperature for 5 h. Compound 14c (207mg, 55% (two steps)) as
ꢁ
ꢀ1
ꢁ
colorless feathers, mp 243–244 C; IR (potassium bromide) cm
:
for 18 h at 37 C followed by 2% aminopeptidase (Sigma) for 18 h
1
ꢁ
3
230, 3350, 3448 (sh.) (NH and OH); H NMR (300 MHz,
DMSO-d ): d 3.90 (s, 3H, OMe), 7.19 (d, 2H, J = 9.0 Hz, H3 and
), 7.71 (dd, 1H, J = 8.7, 4.8 Hz, H6), 8.06 (d, 2H, J = 9.0 Hz, H2
and 6 ), 8.31 (br d, 1H, J = 8.7 Hz, H7), 8.76 (d, 1H, J = 4.8, H5),
.76 (d, 1H, J = 4.2 Hz, changed to singlet with addition of
at 37 C. After digestion, samples were filtered through a 0.22 mm
0
6
filter (Millipore, USA) for ESI/LC/MS analysis. The quantitative
ESI/LC/MS analysis was performed on the basis of a method
described previously [16].
0
0
5
0
8
deuterium oxide, NCHNOH), 9.32, 10.81 (each br, each 1H,
Acknowledgments. The authors are grateful to the SC-NMR
deuterium oxide exchangeable, NH and OH); FAB-ms: m/z 352
1
+
Laboratory of Okayama University for 200 and 300 MHz
H
(
5
MH ). Anal. Calcd. for C H N O ꢃ 1/2H O ꢃ 1/2CH OH: C,
1
7
13
5
4
2
3
NMR experiments. They also thank Dr. K. L. Kirk (NIDDK,
NIH) for the helpful comments on the manuscript.
5.85; H, 4.29; N, 18.61. Found: C, 56.20; H, 4.00; N, 18.35.
N-{2-[3-(4-Fluorophenyl)[1,2,4]oxadiazol-5-yl]furo[3,2-b]
pyridin-3-yl}formamide oxime (14d).
was allowed to react with hydroxylamine hydrochloride (278.0 mg,
.00 mmol) in dry methanol (20 mL) at room temperature for 7 h.
Compound 14d (153 mg, 42% (two steps)) as pale green feathers,
Crude intermediate 12d
REFERENCES AND NOTES
4
[
[
1] van der Plas, H. C. Adv Heterocycl Chem 1999, 74, 1.
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Tetrahedron Lett 2008, 49, 941.
ꢁ
ꢀ1
mp 237–238 C; IR (potassium bromide) cm : 3110, 3280, 3480
1
(
(
(
sh.) (NH and OH); H NMR (300 MHz, DMSO-d ): d 7.40–7.50
6
0
0
m, 2H, H3 and 5 ), 7.67 (dd, 1H, J= 8.4, 4.5Hz, H6), 8.06–8.15
m, 2H, H2 and 6 ), 8.27 (br d, 1H, J= 8.4 Hz, H7), 8.71 (br d,
[
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2015
Polycyclic N-Heterocyclic Compounds. Part 84
887
[
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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