Recyclization reactions of 5-formyl-1,3-dimethyluracil with electron-rich amino heterocycles

Article abstract of DOI:10.1055/s-0029-1216798

Recyclization reactions of 5-formyl-1,3-dimethyluracil with various electron-rich five- or six-membered amino heterocycles led to the formation of a series of fused heterocycles containing a nicotinic acid unit. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216798

1858
PAPER
Recyclization Reactions of 5-Formyl-1,3-dimethyluracil with Electron-Rich
Amino Heterocycles
R
ecyclization Reac
n
tions of 5-F
d
ormyl-1,3-dim
r
ethylur
e
acil y P. Mityuk,a Dmitriy M. Volochnyuk,*a,b Sergey V. Ryabukhin,a,c Andrey S. Plaskon,a,c
Alexander Shivanyuk,*a,c Andrey A. Tolmachevc
a
‘Enamine Ltd.’, 23 A. Matrosova St, 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net; E-mail: A.Shivanyuk@enamine.net
b
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kyiv-94, Ukraine
c
National Taras Shevchenko University, 62 Volodymyrska St, 01033 Kyiv-33, Ukraine
Received 30 October 2008; revised 27 January 2009
synthetic approach towards hetarylo[3,4-b]pyridine-5-
Abstract: Recyclization reactions of 5-formyl-1,3-dimethyluracil
with various electron-rich five- or six-membered amino heterocy-
cles led to the formation of a series of fused heterocycles containing
a nicotinic acid unit.
carboxylic acids through recyclization reactions of 5-
formyl-1,3-dimethyluracil (1) with electron-rich amino
heterocycles.
Key words: 5-formyl-1,3-dimethyluracil, amino heterocycles, As model 1,3-dinucleophilic compounds for the optimiza-
fused pyridines, fused-ring systems, recyclization reactions
tion of synthetic procedures we used readily available and
inexpensive 5-aminopyrazoles 2 and 6-aminouracils 5.
The reaction of 5-formyl-1,3-dimethyluracil (1) with 5-
Derivatives of quinoline-3-carboxylic acid1 and its het-
eroanalogues (hetarylo[3,4-b]pyridine-5-carboxylic ac-
id)2 show a wide spectrum of biological activity.
Hetarylo[3,4-b]pyridine-5-carboxylic acids are usually
obtained through multistep and low-yield synthetic
procedures3 that cannot be used for combinatorial synthe-
sis of diverse compound libraries needed for systematic
QSAR studies. The reaction of readily available 1,3-di-
electrophilic 5-formyl-1,3-dimethyluracil (1) with 1,3-di-
nucleophilic 1,3-dimethyl-6-aminouracil (5a) gives 6-
[(1,3-dimethylureido)carbonyl]-1,3-dimethyl-1,2,3,4-tet-
rahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6a)
in 67% yield (R1 = R2 = Me; Scheme 1).4 We anticipated
that similar recyclization reactions might occur with elec-
tron-rich amino heterocycles to give novel drug-like com-
pounds containing a nicotinic acid unit fused with various
heterocyclic rings. Herein we report a versatile and facile
aminopyrazoles 2a–f and 6-aminouracils 5a–h (AcOH,
reflux) led to compounds 3a–f and 6a–h, respectively, in
84–99% yield (Scheme 1, Table 1). Acid- or base-cata-
lyzed hydrolysis of compounds 3a–f and 6a–h gave the
corresponding acids 4a–f and 7a–h in 71–99% yield
(Scheme 1). Compound 4f could also be obtained through
hydrolysis of sulfolanyl derivative 3e in aqueous sodium
hydroxide (10%). It should be noted that the treatment of
compound 6f with hydrogen chloride in acetic acid also
resulted in hydrolysis of the methyl ether group.
5-Formyl-1,3-dimethyluracil (1) also reacted under the
optimized conditions with aminoisoxazoles 8a–c, isoxa-
thiazole 11, and aminothiophenes 14a–c to give acylureas
9a–c, 12, and 15a–c, respectively (Scheme 2). Unexpect-
edly, 3-dimethyl-5-formyluracil (1) reacted with two
equivalents of aminofuran 17 to form 1,7-dioxa-8-aza-s-
indacene derivative 18 (Scheme 2). It should be noted that
R2
R2
O
R2
N
O
O
N
NH2
N
R1
Me
OH
N
N
N
H
N
R1
Me
O
N
N
R1
N
2a–f
Me
O
3a–f
4a–f
N
O
N
O
O
O
O
O
O
R2
Me
R2
O
Me
R2
O
N
OH
N
N
N
1
N
H
Me
N
R1
N
O
N
N
R1
N
R1
NH2
7a–h
6a–h
5a–h
Scheme 1
SYNTHESIS 2009, No. 11, pp 1858–1864
x
x.
x
x
.
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0
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Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216798; Art ID: P12208SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Recyclization Reactions of 5-Formyl-1,3-dimethyluracil
1859
a very similar reaction has been reported for aminopyra- mental analysis (see Table 1 and Table 2). For example,
1
zoles and aldehydes.5 Acid-catalyzed hydrolysis of com- the H NMR spectra of compounds 4, 7, 10, 13, and 16
pounds 9, 12, and 15 afforded acids 10, 13, and 16, contain two broadened singlets for the protons of the py-
respectively, in nearly quantitative yields (Scheme 2).
ridine ring. The close special proximity of these protons
was confirmed by one-dimensional NOE spectroscopy. In
less viscous chloroform-d, the protons of the pyridine ring
appear as well-resolved meta-coupled doublets (4J = 1.5
Hz).
The structures of the compounds obtained were confirmed
1
by one-dimensional H and 13C NMR, two-dimensional
1
COSY NMR, and H–13C heteronuclear multiple bond
correlation (HMBC) spectroscopy, atmospheric pressure
spray ionization mass spectrometry (APSI-MS), and ele-
Table 1 Yields, Melting Points, and NMR and APSI-MS Data of Compounds 3, 4, 6, and 7d
Starting Producta R1
material
R2
Yieldb Mpc
(%) (°C)
MSd m/z 1H NMRe (d)
[M + 1]
13C NMRf (d)
2a
2b
3a
3b
Me
Me
98
93
146
91
262
276
2.47 (s, 3 H, Me), 2.63 (s, 3 H, Me), 3.17 (s, 12.41, 27.41, 33.80, 34.52,
3 H, Me), 3.95 (s, 3 H, Me), 8.28 (s, 1 H,
NH), 8.33 (s, 1 H, CH), 8.59 (s, 1 H, CH)
113.81, 125.18, 130.18,
141.80, 148.37, 151.03,
156.72, 171.11
i-Pr
H
H
1.50 (d, 3JHH = 7.0 Hz, 6 H, Me), 2.64 (d,
22.31, 27.40, 34.36, 48.79,
3JHH = 4.0 Hz, 3 H, Me), 3,20 (s, 3 H, Me), 114.51, 126.17, 130.59,
5.22 (m, 1 H, CH), 8.26 (s, 1 H, CH), 8.29 133.60, 148.12, 149.39,
(s, 1 H, NH), 8.39 (s, 1 H, CH), 8.65 (s, 1
H, CH)
156.64, 170.81
2c
3c
Bn
Ph
77
97
118
204
324
324
2.63 (d, 3JHH = 4.0 Hz, 3 H, Me), 3.20 (s, 3 27.41, 34.33, 50.62, 114.46,
H, Me), 5.70 (s, 2 H, CH2), 7.26 (d,
126.46, 128.02, 128.07,
3JHH = 6.9 Hz, 2 H, CH), 7.28 (t, 3JHH = 6.9 129.02, 130.79, 134.46,
Hz, 2 H, CH), 7.31 (d, 3JHH = 6.9 Hz, 1 H, 137.57, 148.72, 150.27,
CH), 8.30 (s, 1 H, NH), 8.31 (s, 1 H, CH), 156.61, 170.69
8.44 (s, 1 H, CH), 8.70 (s, 1 H, CH)
2d
3d
Me
2.63 (s, 3 H, Me), 2.65 (d, 3JHH = 4.6 Hz, 3 12.52, 27.39, 34.35, 116.08,
H, Me), 3.22 (s, 3 H, Me), 7.33 (t,
120.61, 126.16, 126,57,
3JHH = 7.6 Hz, 1 H, CH), 7.55 (t, 3JHH = 7.6 129.54, 130.50, 139.23,
Hz, 2 H, CH), 8.23 (d, 3JHH = 7.6 Hz, 2 H, 144.44, 148.78, 150.53,
CH), 8.29 (s, 1 H, NH), 8.51 (s, 1 H, CH), 156.49, 170.54
8.73 (s, 1 H, CH)
2e
2f
3e
3f
sulfolan-
3-yl
Me
Me
88
96
173
163
366
248
2.55 (s, 3 H, Me), 2.64 (d, 3JHH = 4.0 Hz, 3 12.73, 27.41, 29.08, 34.35,
H, Me), 3.19 (s, 3 H, Me), 3.31 (m, 2 H,
CH2), 3.43 (m, 2 H, CH2), 3.58 (m, 2 H,
51.35, 52.00, 54.53, 114.47,
126.23, 130.47, 143.29,
CH2), 5.82 (m, 1 H, CH), 8.28 (s, 1 H, NH), 148.52, 150.69, 156.55,
8.43 (s, 1 H, CH), 8.65 (s, 1 H, CH) 170.69
H
2.51 (s, 3 H, Me), 2.63 (s, 3 H, Me), 3.19 (s, 12.54, 27.36, 34.49, 113.54,
3 H, Me), 8.30 (s, 1 H, NH), 8.36 (s, 1 H,
CH), 8.59 (s, 1 H, CH)
125.09, 129.80, 142.83,
148.30, 152.99, 156.68,
171.12
3a
3b
3c
4a
4b
4c
Me
i-Pr
Bn
Me
H
99
90
88
>350g 192
2.52 (s, 3 H, Me), 3.99 (s, 3 H, Me), 8.70 (s, 12.39, 33.81, 114.25, 120.09,
1 H, CH), 9.02 (s, 1 H, CH)
132.29, 142.20, 150.25,
151.90, 167.29
153
217
206
254
1.47 (d, 3JHH = 6.0 Hz, 6 H, Me), 5.20 (m, 1 22.29, 48.87, 115.15, 120.46,
H, CH), 8.26 (s, 1 H, CH), 8.74 (s, 1 H,
CH), 9.01 (s, 1 H, CH)
133.31, 134.14, 149.98,
150.49, 167.07
H
5.72 (s, 2 H, CH2), 7.26 (t, 3JHH = 6.6 Hz, 2 50.73, 115.15, 120.80, 128.10,
H, CH), 7.28 (t, 3JHH = 6.6 Hz, 1 H, CH),
128.14, 129.07, 133.59,
7.30 (d, 3JHH = 6.6 Hz, 2 H, CH), 8.36 (s, 1 135.04, 137.55, 150.64,
H, CH), 8.83 (d, 4JHH = 1.2 Hz, 1 H, CH), 151.43, 167.05
9.08 (d, 4JHH = 1.2 Hz, 1 H, CH)
Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York

1860
A. P. Mityuk et al.
PAPER
Table 1 Yields, Melting Points, and NMR and APSI-MS Data of Compounds 3, 4, 6, and 7d (continued)
Starting Producta R1
material
R2
Yieldb Mpc
(%) (°C)
MSd m/z 1H NMRe (d)
[M + 1]
13C NMRf (d)
3d
4d
Ph
Me
99
353
254
2.60 (s, 3 H, Me), 7.28 (t, 1 H, 3JHH = 7,0
12.63, 116.56, 120.36, 125.71,
Hz, CH), 7.53 (t, 2 H, 3JHH = 7,0 Hz, CH), 129.05, 129.56, 131.39,
8.29 (d, 2 H, 3JHH = 7,0 Hz, CH), 8.67 (s, 1 139.84, 144.11, 151.13,
H, CH), 9.17 (s, 1 H, CH)
152.15, 169.81
3f
4f
H
Me
Me
76
98
>350g 178
2.53 (s, 3 H, Me), 8.73 (s, 1 H, CH), 8.98 (s, 12.62, 113.98, 119.43, 132.43,
1 H, CH)
143.42, 150.27, 154.04,
167.19
5a
6a
Me
194
274
228
306
292
306
2.61 (s, 3 H, Me), 3.18 (s, 3 H, Me), 3.30 (s, 27.38, 28.59, 29.78, 33.78,
3 H, Me), 3.58 (s, 3 H, Me), 8.18 (s, 1 H,
NH), 8.36 (s, 1 H, CH), 8.78 (s, 1 H, CH)
109.79, 127.62, 136.31,
151.26, 151.84, 153.02,
156.48, 160.87, 168.72
5b
5c
6b
6c
Me
Et
H
H
98
96
2.60 (d, 3JHH = 3.1 Hz, 3 H, Me), 3.18 (s, 3 27.42, 28.94, 33.82, 110.72,
H, Me), 3.50 (s, 3 H, Me), 8.18 (s, 1 H, 127.42, 136.00, 151.00,
NH), 8.31 (s, 1 H, CH), 8.77 (s, 1 H, CH), 153.06, 153.29, 156.53,
11.86 (s, 1 H, NH)
161.32, 168.81
1.20 (t, 3JHH = 6.5 Hz, 3 H, Me), 2.61 (d,
13.43, 27.44, 33.89, 36.99,
3JHH = 3.1 Hz, 3 H, Me), 3.18 (s, 3 H, Me), 110.77, 127.47, 136.18,
4.21 (q, 3JHH = 6.5 Hz, 1 H, CH2), 8.19 (s, 1 150.53, 152.72, 153.26,
H, CH), 8.32 (s, 1 H, CH), 8.78 (s, 1 H,
CH), 11.85 (s, 1 H, NH)
156.53, 161.34, 168.88
5d
5e
5f
6d
6e
6f
Pr
H
97
98
94
96
155
270
188
177
320
318
336
334
0.88 (t, 3JHH = 7.0 Hz, 3 H, Me), 1.63 (m, 2 11.55, 21.18, 27.44, 33.87,
H, CH2), 2.61 (d, 3JHH = 3.0 Hz, 3 H, Me), 43.26, 110.71, 127.52, 136.19,
3.17 (s, 3 H, Me), 4.10 (t, 3JHH = 7.0 Hz, 2 150.77, 152.95, 153.21,
H, CH2), 8.20 (s, 1 H, NH), 8.30 (s, 1 H,
CH), 8.75 (s, 1 H, CH), 11.82 (s, 1 H, NH)
156.55, 161.34, 168.85
cyclopropyl H
0.80 (m, 2 H, CH2), 1.11 (m, 2 H, CH2),
9.78, 25.80, 27.40, 33.80,
2.61 (s, 3 H, CH3), 2.81 (m, 1 H, CH), 3.17 111.07, 127.55, 135.61,
(s, 3 H, CH3), 8.20 (s, 1 H, NH), 8.27 (s, 1 151.13, 152.64, 154.50,
H, CH), 8.77 (s, 1 H, CH), 11.69 (s, 1 H,
NH)
156.52, 161.59, 168.85
(CH2)2
OMe
H
H
2.61 (s, 3 H, Me), 3.18 (s, 3 H, Me), 3.25 (s, 27.41, 33.76, 40.25, 58.50,
3 H, Me), 3.58 (t, 3JHH = 6.0 Hz, 2 H, CH2), 68.93, 110.66, 127.68, 136.10,
4.36 (t, 3JHH = 6.0 Hz, 2 H, CH2), 8.18 (s, 1 150.72, 152.91, 153.07,
H, NH), 8.32 (s, 1 H, CH), 8.77 (s, 1 H,
CH), 11.89 (s, 1 H, NH)
156.52, 161.26, 168.69
5g
6g
i-Bu
0.87 (d, 3JHH = 6.9 Hz, 6 H, CH3), 2.16 (m, 20.33, 27.21, 27.40, 33.83,
1 H, CH), 2.61 (d, 3JHH = 4.4 Hz, 3 H,
48.36, 110.68, 127.53, 136.15,
CH3), 3.17 (s, 3 H, CH3), 4.01 (d, 3JHH = 6.9 151.05, 152.99, 153.22,
Hz, 2 H, CH2), 8.19 (s, 1 H, NH), 8.31 (s, 1 156.51, 161.31, 168.81
H, CH), 8.74 (s, 1 H, CH), 11.83 (s, 1 H,
NH)
5h
6h
H
H
99
>350
278
2.60 (d, 3JHH = 4.5 Hz, 3 H, Me), 3.17 (s, 3 27.54, 34.00, 109.62, 127.71,
H, Me), 8.15 (s, 1 H, NH), 8.25 (d,
136.03, 150.96, 153.88,
4JHH = 2.2 Hz, 1 H, CH), 8.66 (d, 4JHH = 2.2 154.30, 156.69, 162.57,
Hz, 1 H, CH), 11.59 (s, 1 H, NH), 11.94 (s, 169.04
1 H, NH)
6a
6b
7a
7b
Me
Me
Me
H
94
98
290
321
236
222
3.30 (s, 3 H, CH3), 3.59 (s, 3 H, CH3), 8.66 28.63, 29.91, 110.03, 122.00,
(d, 4JHH = 2.2 Hz, 1 H, CH), 9.13 (d,
4JHH = 2.2 Hz, 1 H, CH)
137.84, 151.07, 153.07,
155.02, 160.53, 165.39
3.51 (s, 3 H, Me), 8.62 (d, 4JHH = 2.2 Hz, 1 29.15, 111.05, 121.85, 137.69,
H, CH), 9.12 (d, 4JHH = 2.2 Hz, 1 H, CH), 150.94, 154.58, 155.16,
11.91 (s, 1 H, NH)
161.07, 165.58
Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York

PAPER
Recyclization Reactions of 5-Formyl-1,3-dimethyluracil
1861
Table 1 Yields, Melting Points, and NMR and APSI-MS Data of Compounds 3, 4, 6, and 7d (continued)
Starting Producta R1
material
R2
H
Yieldb Mpc
(%) (°C)
MSd m/z 1H NMRe (d)
[M + 1]
13C NMRf (d)
6c
7c
Et
84
313
236
1.19 (t, 3JHH = 6.5 Hz, 3 H, Me), 4.21 (q,
13.47, 37.23, 111.23, 121.90,
3JHH = 6.5 Hz, 2 H, CH2), 8.60 (s, 1 H, CH), 137.93, 150.52, 154.15,
9.09 (s, 1 H, CH), 11.88 (s, 1 H, NH)
155.30, 161.16, 165.61
6d
7d
Pr
H
H
91
244
250
0.90 (t, 3JHH = 7.3 Hz, 3 H, CH3), 1.64 (m, 11.60, 21.17, 43.43, 111.22,
2 H, CH2), 4.12 (t, 3JHH = 7.3 Hz, 2 H,
CH2), 8.61 (d, 4JHH = 2.2 Hz, 1 H, CH),
121.95, 137.92, 150.76,
154.42, 155.23, 161.19,
9.10 (d, 4JHH = 2.2 Hz, 1 H, CH), 11.90 (s, 165.61
1 H, NH)
6e
7e
c-Pr
99
317
248
0.80 (m, 2 H, CH2), 1.11 (m, 2 H, CH2),
9.88, 26.01, 111.62, 121.96,
2.81 (m, 1 H, CH), 8.50 (d, 4JHH = 2.0 Hz, 137.40, 151.16, 154.77,
1 H, CH), 9.04 (d, 4JHH = 2.0 Hz, 1 H, CH), 156.05, 161.47, 165.69
11.71 (s, 1 H, NH)
6f
7f
(CH2)2OH
H
H
70
92
>350g 252
>350g 264
4.49 (t, 3JHH = 7.3 Hz, 2 H, CH2), 5.19 (t,
3JHH = 7.3 Hz, 2 H, CH2), 8.89 (s, 1 H, CH), 143.37, 147.02, 147.32,
9.67 (s, 1 H, CH), 12.42 (s, 1 H, NH) 152.80, 159.39, 163.09
45.33, 53.64, 112.85, 123.86,
6g
7g
i-Bu
0.86 (d, 3JHH = 7.3 Hz, 6 H, Me), 2.17 (m, 1 20.34, 27.17, 48.14, 110.38,
H, CH), 4.02 (m, 2 H, CH2), 8.67 (s, 1 H, 129.90, 137.47, 151.20,
CH), 9.09 (s, 1 H, CH), 11.70 (s, 1 H, NH) 152.71, 155.44, 161.92,
167.60
6h
7h
H
H
98
>350g 208
8.56 (s, 1 H, CH), 9.02 (s, 1 H, CH), 11.66 110.17, 122.23, 137.82,
(s, 1 H, NH), 12.07 (s, 1 H, NH)
150.96, 155.38, 155.93,
162.48, 165.79
a Unless mentioned otherwise, satisfactory microanalysis data were obtained (C, 0.33; H, 0.45; N, 0.25).
b Yield of pure, isolated product.
c Melting points are uncorrected.
d APSI-MS, Agilent 1100\DAD\MSD VL G1965a instrument.
e 1H NMR (500 MHz, DMSO-d6).
f 13C NMR (125 MHz, DMSO-d6).
g Melting points for hydrochloride salt.
Table 2 Yields, Melting Points, and NMR and APSI MS Data of Compounds 9, 10, 12, 13, 15, 16, and 18d
Starting Producta R1 (R1, Yieldb Mpc
MSd m/z 1H NMRe (d)
[M + 1]
13C NMRf (d)
material
R2)
(%)
(°C)
8a
9a
i-Pr
92
118
277
1.40 (d, 3JHH = 6.8 Hz, 6 H, Me), 2.62 (d,
20.96, 27.23, 27.43, 34.04, 111.51,
3JHH = 3.5 Hz, 3 H, Me), 3.19 (s, 3 H, Me), 129.59, 132.79, 150.27, 156.32, 164.83,
3.46 (m, 1 H, CH), 8.25 (s, 1 H, NH), 8.62 (s, 169.53, 169.75
1 H, CH), 8.72 (s, 1 H, CH)
8b
8c
9b
9c
Me
Tol
87
96
149
174
249
325
2.60 (s, 3 H, Me), 2.63 (d, 3JHH = 4.0 Hz, 3 H, 10.85, 27.41, 34.06, 113.20, 129.70,
Me), 3.19 (s, 3 H, Me), 8.24 (s, 1 H, NH),
8.56 (s, 1 H, CH), 8.72 (s, 1 H, CH)
132.77, 150.15, 156.25, 157.35, 169.48,
169.67
2.38 (s, 3 H, Me), 2.64 (s, 3 H, Me), 3.20 (s, 21.47, 27.41, 34.68, 111.06, 124.95,
3 H, Me), 7.38 (d, 3JHH = 6.8 Hz, 2 H, CH), 127.91, 127.98, 130.44, 133.03, 141.67,
7.90 (d, 3JHH = 6.8 Hz, 2 H, CH), 8.32 (s, 1 150.19, 156.17, 157.71, 169.62, 170.06
H, NH), 8.76 (s, 1 H, CH), 8.79 (s, 1 H, CH)
9a
9b
10a
10b
i-Pr
92
79
169
230
207
179
1.39 (d, 3JHH = 6.7 Hz, 6 H, Me), 3.49 (m, 1 21.00, 27.14, 112.40, 124.06, 135.25,
H, CH), 8.86 (s, 1 H, CH), 9.08 (s, 1 H, CH) 152.60, 165.00, 166.04, 171.14
Me
2.62 (s, 3 H, Me), 8.91 (d, 4JHH = 2.0 Hz, 1 H, 10.84, 113.90, 123.85, 135.38, 152.58,
CH), 9.12 (d, 4JHH = 2.0 Hz, 1 H, CH)
157.63, 165.96, 170.89
Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York

1862
A. P. Mityuk et al.
PAPER
Table 2 Yields, Melting Points, and NMR and APSI MS Data of Compounds 9, 10, 12, 13, 15, 16, and 18d (continued)
Starting Producta R1 (R1, Yieldb Mpc
MSd m/z 1H NMRe (d)
[M + 1]
13C NMRf (d)
material
R2)
(%)
(°C)
9c
10c
12
Tol
98
256 255
2.28 (s, 3 H, Me), 7.15 (d, 3JHH = 7.5 Hz, 2 H, 21.33, 109.20, 125.14, 126.44, 129.45,
CH), 7.33 (d, 3JHH = 7.5 Hz, 2 H, CH), 7.60 133.16, 138.84, 139.73, 141.08, 152.07,
(s, 1 H, CH), 8.10 (s, 1 H, CH)
160.32, 165.78
11
–
–
91
86
157 265
2.64 (d, 3JHH = 3.5 Hz, 3 H, Me), 2.71 (s, 3 H, 18.17, 27.43, 34.04, 127.03, 129.58,
Me), 3.22 (s, 3 H, Me), 8.30 (s, 1 H, NH),
8.63 (s, 1 H, CH), 8.85 (s, 1 H, CH)
131.79, 149.21, 156.28, 163.77, 169.98,
172.71
12
13
209 195
126 336
2.77 (s, 3 H, Me), 8.94 (s, 1 H, CH), 9.24 (s, 18.25, 124.05, 127.56, 134.28, 151.24,
1 H, CH)
164.16, 166.44, 174.73.
14a
15a
Et, Me 99
1.33 (t, 3JHH = 6.5 Hz, 3 H, Me), 2.64 (d,
13.20, 14.50, 27.39, 34.08, 61.99,
3JHH = 2.5 Hz, 3 H, Me), 2.68 (s, 3 H, Me), 127.38, 129.73, 131.27, 132.76, 139.80,
3.20 (s, 3 H, Me), 4.33 (q, 3JHH = 6.5 Hz, 2 H, 148.42, 156.30, 161.56, 162.51, 170.11
CH2), 8.30 (s, 1 H, NH), 8.45 (s, 1 H, CH),
8.75 (s, 1 H, CH)
14b
14c
15b
15c
Me, H 94
Me, Me 96
171 308
169 322
2.61 (s, 3 H, Me), 3.20 (s, 3 H, Me), 3.91 (s, 27.42, 33.93, 53.45, 129.79, 130.18,
3 H, Me), 8.22 (s, 1 H, NH), 8.25 (s, 1 H,
CH), 8.52 (s, 1 H, CH), 8.75 (s, 1 H, CH)
131.66, 133.17, 133.74, 148.34, 156.39,
162.39, 163.22, 169.84
2.63 (d, 3JHH = 2.5 Hz, 3 H, Me), 2.72 (s, 3 H, 13.25, 27.41, 34.04, 53.10, 126.94,
Me), 3.20 (s, 3 H, Me), 3.89 (s, 3 H, O Me), 129.83, 131.37, 132.73, 140.10, 148.50,
8.28 (s, 1 H, NH), 8.48 (s, 1 H, CH), 8.77 (s, 156.31, 161.53, 162.96, 170.05
1 H, CH)
15a
17
16a
18
Me
–
94
89
>350 238
274 414
2.74 (s, 3 H, Me), 8.72 (s, 1 H, CH), 9.12 (s, 12.99, 123.69, 129.37, 133.42, 133.47,
1 H, CH)
138.98, 150.07, 163.78, 164.02, 166.47
3.34 (s, 3 H, Me), 3.50 (s, 3 H, Me), 3.95 (s,
6 H, O Me), 7.88 (s, 2 H, CH), 8.22 (s, 1 H,
CH)
a Satisfactory microanalysis data were obtained (C, 0.33; H, 0.45; N, 0.25).
b Yield of pure, isolated product.
c Melting points are uncorrected.
d APSI-MS, Agilent 1100\DAD\MSD VL G1965a instrument.
e 1H NMR (500 MHz, DMSO-d6).
f 13C NMR (125 MHz, DMSO-d6).
A possible mechanism for the formation of acylureas 3, 9, cient C=N bond followed by elimination of ammonium
12, and 15 is shown in Scheme 3. The proton-activated al- cation and aromatization lead to compound 18.
dehyde group of 1 is likely to attack the heterocyclic ring
in the position ortho to the amino group. The latter may
In conclusion, the recyclization reaction of 5-formyl-1,3-
dimethyluracil (1) with electron-rich amino heterocycles
undergo an intramolecular Michael addition to the double
is a facile method for the synthesis of drug-like com-
bond of the dimethyluracil fragment to give intermediate
pounds of the hetarylo[3,4-b]pyridine-5-carboxylic acid
type, which are promising building blocks for combinato-
rial synthesis of highly diverse drug-like compounds.
19, which may eliminate water to give intermediate 20
(Scheme 3). The energy gain of the aromatization of the
pyridine ring through the proton transfer seems likely to
drive the opening of the uracil ring and the formation of
All commercially available starting materials were used without ad-
the acylurea.
ditional purification. All solvents were purified by standard meth-
A mechanism for the reaction of 1 with 17 giving 18
(Scheme 2) is also proposed in Scheme 3. The acid-cata-
lyzed Bayer condensation of 1 with two moles of amino-
furan 17 giving bisfurylmethane 21 seems likely to be the
first step of the formation of compound 18. Dehydrogena-
tion of 22 may result in resonance-stabilized cation 23. It
is plausible that the subsequent intermolecular nucleo-
philic addition of the amino group to the electron-defi-
ods. All procedures were carried out in an open atmosphere with no
precautions taken to exclude moisture. 1H NMR (500 MHz) and 13
C
NMR (125 MHz) spectra were recorded on a Bruker Avance DRX
500 spectrometer with TMS as an internal standard. HPLC
APSI-MS spectra were recorded on an Agilent 1100\DAD\MSD
VL G1965a instrument. 5-Formyl-1,3-dimethyluracil (1)6 and the
amino heterocycles (5-aminopyrazoles 2a–f,7 6-aminouracils 5a–
h,8 5-aminoisooxazoles 8a–c,9 2-aminothiophenes 14a–c,10 and 2-
aminofuran 1711) were prepared according to the literature proce-
dures.
Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York

PAPER
Recyclization Reactions of 5-Formyl-1,3-dimethyluracil
1863
O
O
R1
R1
O
R1
Me
N
N
OH
N
H
N
N
Me
NH2
8a–c
O
O
O
N
N
10a–c
9a–c
O
O
O
O
N
NH2
S
Me
Me
11
N
N
N
OH
O
N
H
N
Me
S
S
O
N
N
N
13
12
Me
1
R2
R1OOC
NH2
S
14a–c
O
O
O
R2
R2
MeOOC
NH2
O
Me
N
N
OH
17
R1OOC
H
HOOC
Me
S
S
N
N
O
15a–c
16a
Me
Me
O
N
N
MeOOC
COOMe
O
O
N
18
Scheme 2
Y
Y
Y
a
R
R
R
X
X
X
H
N
N
O
OH
N
H
N
Me
O
O
Me
N
O
O
N
HN
HN
N
Me
O
Me
19
20
Me
b
X
X
X
O
O
O
+
NH3
NH2
+
R
NH4
H
R
++
+
R
NH2
NH2
18
NH2
– H2
NH2
O
O
O
X
X
X
21
22
23
Scheme 3 Possible reaction mechanisms
(1,3-Dimethylureido)carbonyl-Substituted Fused Pyridines 3,
Tables 1 and 2 for characterization data of (1,3-dimethylureido)car-
6, 9, 12, and 15 from 5-Formyl-1,3-dimethyluracil (1) and Ami-
no Heterocycles; General Procedure
bonyl-substituted fused pyridines 3, 6, 9, 12, and 15.
A mixture of the appropriate amino heterocycle (one of 2a–f, 5a–h,
8a–c, 11, or 14a–c) (4 mmol) and 5-formyl-1,3-dimethyluracil (1; 4
mmol) in glacial acetic acid (30 mL) was refluxed for 6 h. After
cooling of the mixture, the solvent was evaporated under reduced
pressure. The analytical samples were obtained by crystallization of
the crude product from an appropriate solvent, usually MeOH. See
Nicotinic Acid Derivatives 4, 7, 10, 13, and 16 from the Corre-
sponding Fused Pyridines 3, 6, 9, 12, and 15
Procedure A
A mixture of the appropriate urea derivative (one of 3a–f, 6a–h, 9a–
c, 12, or 15a–c) (3 mmol) and 10% aq NaOH (25 mL) was heated
and stirred for 2 h at 60 °C. After cooling, the reaction mixture was
Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York

1864
A. P. Mityuk et al.
PAPER
(2) (a) McClure, K. J.; Huang, L.; Arienti, K. L.; Axe, F. U.;
filtered, and the filtrate was acidified with dilute aq HCl. The ob-
tained precipitate was filtered and dried.
Brunmark, A.; Blevitt, J.; Breitenbucher, J. G. Bioorg. Med.
Chem. Lett. 2006, 16, 1924. (b) Nam, G.; Yoon, C. M.; Kim,
E.; Rhee, C. K.; Kim, J. H.; Shin, J. H.; Kim, S. H. Bioorg.
Med. Chem. Lett. 2001, 11, 611. (c) Laborde, E.; Robinson,
L.; Meng, F.; Peterson, B. T.; Villar, H. O.; Anuskiewicz,
S. E.; Ma, W.; Matsumoto, Y.; Baba, K.; Inagaki, H.;
Tanaka, K.; Ishiwata, Y.; Yokochi, S.; Okamoto, M.;
Nakamura, T.; Miyachi, A.; Takeuchi, M.; Matsushima, K.
WO 2002060900 A2, 2002; Chem. Abstr. 2002, 137,
154931.
Procedure B
The appropriate urea derivative (one of 3a–f, 6a–h, 9a–c, 12, or
15a–c) (3 mmol) in a mixture of glacial AcOH (20 mL) and concd
aq HCl (5 mL) was refluxed and stirred for 4 h. After rotary evapo-
ration of the solvent, the obtained residue was crystallized from
MeOH.
See Tables 1 and 2 for characterization data of nicotinic acid deriv-
atives 4, 7, 10, 13, and 16.
(3) (a) Walsh, E. B.; Nai-Jue, Z.; Fang, G.; Wamhoff, H.
Tetrahedron Lett. 1988, 29, 4401. (b) Hirota, K.; Kuki, H.;
Maki, Y. Heterocycles 1994, 37, 563. (c) Rho, K. Y.; Kim,
J. H.; Kim, S. H.; Yoon, C. M. Heterocycles 1998, 48, 2521.
(d) Dias, L. R. S.; Alvim, M. J. F.; Freitas, A. C. C.; Antonio,
C. C.; Barreiro, E. J.; Miranda, A. L. P. Pharm. Acta Helv.
1994, 69, 163. (e) Barker, J. M.; Huddleston, P. R.; Holmes,
D. J. Chem. Res., Miniprint 1985, 2501. (f) Arcadi, A.;
Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Synlett
2002, 453.
(4) Harjit, S.; Dolly, C.; Swapandeep, S.; Kumar, S.
Tetrahedron 1995, 51, 12775.
(5) (a) Henning, L.; Hofmann, J.; Alva-Astudillo, M.; Mann, G.
J. Prakt. Chem. 1990, 332, 351. (b) Esteves-Souza, A.;
Echevarrõ, A.; Vencato, I.; Jimeno, M. L.; Elguero, J.
Tetrahedron 2001, 57, 6147.
Compound 18
A mixture of ethyl 5-amino-2-furoate (17; 0.62 g, 4 mmol), 5-
formyl-1,3-dimethyluracil (1; 0.672 g, 4 mmol), and glacial AcOH
(30 mL) was refluxed for 6 h. After cooling, the solvent was evap-
orated under reduced pressure and the product was recrystallized
from DMSO.
Yield: 89% (based on 17); mp 274 °C.
1H NMR (500 MHz, CF3CO2D): d = 3.92 (s, 3 H, CH3), 4.03 (s, 3
H, CH3), 4.39 (s, 6 H, CH3), 8.15 (s, 2 H, CH), 8.39 (s, 1 H, CH).
13C NMR (125 MHz, CF3CO2D): d = 28.83, 37.92, 53.46, 108.43,
114.04, 117.78, 135.51, 143.94, 145.08, 147.11, 152.80, 160.11,
163.32.
See Table 2 for additional analytical data for 18.
(6) Hirota, K.; Kitade, Y.; Shimada, K.; Maki, Y. J. Org. Chem.
1985, 59, 1512.
(7) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P.
Synlett 1998, 446. (b) Cacchi, S.; Carangio, A.; Fabrizi, G.;
Moro, L.; Pace, P. Synlett 1997, 1400. (c) Hinkle, J. S.;
Lever, O. W. Tetrahedron 1988, 44, 3391.
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Synthesis 2009, No. 11, 1858–1864 © Thieme Stuttgart · New York