An efficient synthesis of fused 3-formylpyridines and 5-formylpyrimidines

Article abstract of DOI:10.1055/s-0030-1258139

Cyclization of 2-dimethylaminomethylene-1,3-bis(dimethylimonio)propane diperchlorate with various amino heterocycles led to the formation of a series of fused heterocyclic systems containing a 3-formylpyridine or 5-formylpyrimidine unit. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258139

PAPER
2767
An Efficient Synthesis of Fused 3-Formylpyridines and 5-Formylpyrimidines
S
ynthesis of Fused
n
3-Formylpy
d
ridines and 5
r
-Formyl
e
pyrimidine
y
s
P. Mityuk,a Sergey E. Kolodych,b Sergey A. Mytnyk,b Yuri V. Dmytriv,b Dmitriy M. Volochnyuk,a
Pavel K. Mykhailiuk,*a,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Oleksandra Matrosova Street 23, Kiev 01103, Ukraine
Fax +380(44)2351273; E-mail: Pashamk@gmx.de
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska Street 64, Kiev 01033, Ukraine
b
Received 13 April 2010; revised 20 April 2010
NC
Abstract: Cyclization of 2-dimethylaminomethylene-1,3-bis(di-
methylimonio)propane diperchlorate with various amino heterocy-
cles led to the formation of a series of fused heterocyclic systems
containing a 3-formylpyridine or 5-formylpyrimidine unit.
NH2
NH2
MeO2C
O
NH2
N
MeO2C
S
4
5
Key words: fused pyridines, fused pyrimidines, cyclization reac-
tions, amino heterocycles, 2-dimethylaminomethylene-1,3-
bis(dimethylimonio)propane diperchlorate
3
MeO2C
NH2
N
NH2
MeO2C
S
NH2
O
S
6
7
8
Derivatives of 3-formylpyridine and 5-formylpyrimidine
are valuable building blocks commonly used in medicinal
chemistry.1 These compounds are usually obtained
through multistep and low-yielding synthetic procedures
that can not be applied to combinatorial synthesis of di-
verse compound libraries needed for systematic QSAR
studies.2 The reaction of 2-dimethylaminomethylene-1,3-
bis(dimethylimonio)propane diperchlorate (1) with
amidines gives the corresponding 2-substituted 5-
formylpyrimidines (Scheme 1).3 It is also known that an
analogue of 1, 2-dimethylaminomethylene-1,3-bis(di-
methylimonio)propane bis(tetrafluoroborate) (2), reacts
with electron-rich anilines to provide 3-formylquinolines
(Scheme 1).4 We expected that similar cyclization reac-
tions of the readily available vinamidinium salt 15 might
occur with various five-membered amino heterocycles to
give novel compounds containing a fused 3-formylpyri-
dine or 5-formylpyrimidine unit.
N
N
N
NH2
O
NH2
NH2
O
O
9
11
10
N
NH2
N
N
N
NH2
NH2
N
N
Me
Boc
SO2
12
13
14
CN
CO2Et
N
N
N
NH2
NH2
N
N
H
NH2
N
H
H
15
17
16
Indeed, the reaction of salt 1 with derivatives of 2-ami-
nopyrrole 3, 2-aminofuran 4, 2-aminothiophene 5 and 6,
3-aminothiophene 7, 5-aminoisoxazole 8–11 and 3-ami-
nopyrazole 12 and 13 in the presence of 0.4 N sodium
methoxide in methanol under reflux led to the formation
Ph
N
N
NH2
NH2
N
N
H
18
N
H
19
Figure 1 Structures of the five-membered amino heterocycles 3–19
R
+NMe2
R
of the corresponding fused 3-formylpyridines 3a–13a in
34–99% yield (Figure 1 and Table 1).
+
1
N
N
Me2N
NH2
2 X–
HN
Me2N
Unexpectedly, the N-Boc-protected aminopyrazole 14 un-
der the same reaction conditions afforded two isomeric
products 14a (32%) and 14b (64%), both possessing no
Boc group (Table 1). In contrast, aminopyrazole 15 react-
ed with salt 1 as an N,N bis-nucleophile to provide the
sole isomer 14b. The structure of both isomers 14a/14b
was confirmed by directed synthesis of 14a (Scheme 2).
Cleavage of the N-sulfolanyl protecting group in 13a af-
forded compound 14a, identical to the isomer formed as
the minor product in the reaction of the Boc-protected
aminopyrazole 14 with salt 1.
CHO
CHO
–
1 X– = ClO4
2
2 X– = BF4
–
R
NH2
N
R
Scheme
1
Synthesis of 5-formylpyrimidines and 3-formyl-
quinolines3,4
SYNTHESIS 2010, No. 16, pp 2767–2770
x
x.
x
x
.
2
0
1
0
Advanced online publication: 01.07.2010
DOI: 10.1055/s-0030-1258139; Art ID: Z09110SS
© Georg Thieme Verlag Stuttgart · New York

2768
A. P. Mityuk et al.
PAPER
Table 1 Synthesis of 3-Formylpyridines and 5-Formylpyrimidinesa
Table 1 Synthesis of 3-Formylpyridines and 5-Formylpyrimidinesa
(continued)
Starting amino Product
heterocycle
Yield (%)
Starting amino Product
heterocycle
Yield (%)
CHO
CHO
NC
3
3a
34
N
N
N
N
N
H
14a
14a: 32
14b: 64
14
14a + 14b
CHO
CHO
CHO
4
5
6
4a
5a
6a
38
43
57
N
N
N
N
N
N
MeO2C
MeO2C
O
CHO
14b
S
S
N
N
15
16
14b
16b
44
27
N
MeO2C
S
CHO
CHO
CO2Et
7
7a
64
N
N
N
N
CO2Me
CHO
CHO
CN
8
9
8a
57
52
61
N
N
N
17
18
19
17b
18b
19b
53
80
39
N
O
N
N
CHO
9a
CHO
N
N
N
O
CHO
N
N
10
10a
N
CHO
O
Ph
N
CHO
N
N
11
12
11a
12a
99
80
N
N
N
CHO
O
a Reaction conditions: salt 1, 0.4 N NaOMe, MeOH, reflux, 12 h.
CHO
N
N
N
N
CHO
N
Me
CHO
CHO
N
a
N
N
N
N
84%
N
H
13
13a
76
N
14a
SO2
13a
SO2
Scheme 2 Reagents and conditions: a) 15% aq HCl, heating at
reflux, 6 h.
Synthesis 2010, No. 16, 2767–2770 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused 3-Formylpyridines and 5-Formylpyrimidines
2769
Methyl 5-Formyl-3-methylthieno[2,3-b]pyridine-2-carboxylate
(6a)
Pale brown solid; yield: 1.34 g (57%); mp 197 °C.
1H NMR (500 MHz, CDCl3): d = 2.72 (s, 3 H), 3.91 (s, 3 H), 8.75
(s, 1 H), 9.09 (s, 1 H), 10.20 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.0, 52.8, 127.3, 128.6,
133.2, 133.8, 140.1, 150.2, 162.5, 164.7, 191.8.
Amino heterocycles 16–19 with an a-NH moiety reacted
with salt 1 to give the corresponding fused 5-formylpyri-
midines 16b–19b in 27–80% yield (Figure 1 and Table 1).
In conclusion, the cyclization reaction of 2-dimethylami-
nomethylene-1,3-bis(dimethylimonio)propane diperchlo-
rate (1) with various five-membered amino heterocycles
is a facile method for the synthesis of fused 3-formylpy-
ridines and 5-formylpyrimidines.
MS: m/z = 236 [M + 1]+.
Methyl 6-Formylthieno[3,2-b]pyridine-3-carboxylate (7a)
Brown solid; yield: 1.42 g (64%); mp 169 °C.
1H NMR (500 MHz, CDCl3): d = 3.90 (s, 3 H), 9.10 (d, J = 2.0 Hz,
1 H), 9.21 (s, 1 H), 9.24 (d, J = 2.0 Hz, 1 H), 10.21 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 52.3, 127.3, 127.3, 133.5,
134.0, 147.0, 149.6, 155.4, 161.9, 192.0.
Solvents were purified according to standard procedures. All other
materials were purchased from Aldrich and Enamine Ltd. Melting
points are uncorrected. Analytical TLC was perfomed using Poly-
chrom SI F254 plates. 1H and 13C NMR spectra were recorded on a
Bruker Avance 500 spectrometer (at 499.9 and 124.9 MHz, respec-
tively). Chemical shifts are reported in ppm downfield from TMS
as internal standard. Mass spectra were recorded on an Agilent 1100
LC/MSD SL instrument using chemical ionization (CI). 2-Dimeth-
ylaminomethylene-1,3-bis(dimethylimonio)propane diperchlorate
(1) was prepared according to the literature procedure.5a
MS: m/z = 222 [M + 1]+.
3-Methylisoxazolo[5,4-b]pyridine-5-carbaldehyde (8a)
Pale brown solid; yield: 0.93 g (57%); mp 139 °C.
1H NMR (500 MHz, CDCl3): d = 2.62 (s, 3 H), 8.90 (s, 1 H), 9.15
Fused 3-Formylpyridines and 5-Formylpyrimidines; General
Procedure
(s, 1 H), 10.19 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.8, 114.5, 129.2, 135.0,
154.0, 157.9, 171.2, 191.2.
MS: m/z = 163 [M + 1]+.
A soln of 2-dimethylaminomethylene-1,3-bis(dimethylimonio)pro-
pane diperchlorate (1; 3.82 g, 10 mmol) and an amino heterocycle
3–19 (10 mmol) in 0.4 N NaOMe in anhyd MeOH (50 mL) was
heated at reflux for 12 h. Thereafter, the reaction mixture was
cooled to r.t., which was followed by the addition of H2O (10 mL).
The formed suspension was concentrated under reduced pressure to
remove the MeOH. The obtained residue was extracted with CH2Cl2
(3 × 5 mL). The combined organic phase was dried (Na2SO4) and
concentrated under reduced pressure to provide the crude product
3a–13a, 14a/14b, 14b, 16b–19b. Crystallization (MeOH) afforded
pure 3a–13a, 14b, 16b–19b. The mixture 14a/14b was separated by
flash column chromatography. Elution with CHCl3 provided isomer
14b (1.04 g, 6.4 mmol, 64% yield); further elution with MeOH af-
forded isomer 14a (0.52 g, 3.2 mmol, 32% yield).
3-Isopropylisoxazolo[5,4-b]pyridine-5-carbaldehyde (9a)
Yellow solid; yield: 0.99 g (52%); mp 75 °C.
1H NMR (500 MHz, CDCl3): d = 1.42 (d, J = 6.8 Hz, 6 H), 3.50 (m,
J = 6.8 Hz, 1 H), 9.01 (d, J = 1.0 Hz, 1 H), 9.14 (d, J = 1.0 Hz, 1 H),
10.19 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.9, 27.2, 112.9, 129.1,
135.7, 153.4, 165.3, 171.4, 191.3.
MS: m/z = 191 [M + 1]+.
3-tert-Butylisoxazolo[5,4-b]pyridine-5-carbaldehyde (10a)
Yellow solid; yield: 1.25 g (61%); mp 48 °C.
1H NMR (500 MHz, CDCl3): d = 1.48 (s, 9 H), 9.07 (s, 2 H), 10.19
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 28.8, 34.3, 112.1, 129.0,
136.9, 152.5, 167.2, 171.6, 191.3.
MS: m/z = 205 [M + 1]+.
1-tert-Butyl-5-formyl-1H-pyrrolo[2,3-b]pyridine-3-carboni-
trile (3a)
Yellow solid; yield: 0.77 g (34%); mp 184 °C.
1H NMR (500 MHz, CDCl3): d = 1.77 (s, 9 H), 8.58 (s, 1 H), 8.69
(s, 1 H), 8.92 (s, 1 H), 10.17 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 28.9, 59.6, 84.1, 115.1, 120.9,
126.7, 129.8, 138.7, 145.85, 149.0, 192.2.
MS: m/z = 228 [M + 1]+.
3-(4-Methylphenyl)isoxazolo[5,4-b]pyridine-5-carbaldehyde
(11a)
Yellow solid; yield: 2.36 g (99%); mp 152 °C.
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 7.38 (d, J = 6.6 Hz, 2
H), 7.89 (d, J = 6.6 Hz, 2 H), 9.07 (s, 1 H), 9.14 (s, 1 H), 10.20 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 21.5, 112.2, 124.6, 127.9,
129.6, 130.4, 136.4, 141.8, 153.0, 158.0, 171.7, 191.2.
MS: m/z = 239 [M + 1]+.
Methyl 5-Formylfuro[2,3-b]pyridine-2-carboxylate (4a)
Yellow solid; yield: 0.78 g (38%); mp 193 °C.
1H NMR (500 MHz, CDCl3): d = 3.93 (s, 3 H), 7.91 (s, 1 H), 8.76
(s, 1 H), 9.03 (s, 1 H), 10.18 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 53.2, 114.3, 119.9, 129.9,
134.7, 146.1, 150.8, 158.9, 163.9, 191.8.
MS: m/z = 206 [M + 1]+.
1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde
(12a)
Pale yellow solid; yield: 1.40 g (80%); mp 110 °C.
1H NMR (500 MHz, CDCl3): d = 2.48 (s, 3 H), 3.95 (s, 3 H), 8.55
(s, 1 H), 8.86 (s, 1 H), 10.05 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.2, 33.7, 114.4, 125.4,
132.9, 143.0, 150.3, 152.0, 191.3.
MS: m/z = 176 [M + 1]+.
Methyl 5-Formylthieno[2,3-b]pyridine-2-carboxylate (5a)
Yellow solid; yield: 0.95 g (43%); mp 180 °C.
1H NMR (500 MHz, CDCl3): d = 3.93 (s, 3 H), 8.37 (s, 1 H), 8.91
(s, 1 H), 9.18 (s, 1 H), 10.21 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 53.4, 129.2, 130.0, 132.3,
134.2, 135.5, 150.6, 162.2, 166.3, 192.2.
MS: m/z = 222 [M + 1]+.
Synthesis 2010, No. 16, 2767–2770 © Thieme Stuttgart · New York

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A. P. Mityuk et al.
PAPER
1-(1,1-Dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazo-
lo[3,4-b]pyridine-5-carbaldehyde (13a)
2-Phenyl[1,2,4]triazolo[1,5-a]pyrimidine-6-carbaldehyde (19b)
White solid; yield: 0.88 g (39%); mp 263 °C.
Yellow solid; yield: 2.13 g (76%); mp 138 °C.
1H NMR (500 MHz, CDCl3): d = 7.58 (m, 3 H), 8.25 (m, 2 H), 9.21
1H NMR (500 MHz, CDCl3): d = 2.57 (s, 3 H), 3.38–3.42 (m, 2 H),
3.49–3.56 (m, 2 H), 3.76–3.81 (m, 2 H), 5.82–5.88 (m, 1 H), 8.74
(d, J = 1.4 Hz, 1 H), 8.98 (d, J = 1.4 Hz, 1 H), 10.09 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.8, 29.0, 51.3, 52.1, 54.5,
115.5, 126.4, 133.7, 144.7, 151.0, 152.0, 191.7.
(s, 1 H), 10.00 (s, 1 H), 10.11 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 120.9, 127.6, 129.6, 130.1,
131.7, 142.4, 154.7, 157.2, 167.3, 189.1.
MS: m/z = 225 [M + 1]+.
MS: m/z = 280 [M + 1]+.
3-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (14a)
from 1-(1,1-Dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazo-
lo[3,4-b]pyridine-5-carbaldehyde (13a)
3-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (14a)
Yellow solid; yield: 0.52 g (32%); mp 196 °C.
1H NMR (500 MHz, CDCl3): d = 2.53 (s, 3 H), 8.68 (d, J = 1.5 Hz,
1 H), 8.93 (d, J = 1.5 Hz, 1 H), 10.07 (s, 1 H), 13.67 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.6, 114.3, 125.7, 133.1,
144.3, 150.7, 154.4, 191.8.
A suspension of compound 13a (0.56 g, 2.00 mmol) in 15% aq HCl
(20 mL) was heated at reflux for 6 h. Thereafter, the reaction mix-
ture was cooled to r.t. and neutralized with aq K2CO3 soln to pH 7.
The formed precipitate was collected by filtration to provide pure
14a (0.27 g, 1.68 mmol, 84% yield).
MS: m/z = 162 [M + 1]+.
References
2-Methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (14b)
Yellow solid; yield: 1.04 g (64%); mp 154 °C.
1H NMR (500 MHz, CDCl3): d = 2.45 (s, 3 H), 6.67 (s, 1 H), 8.76
(s, 1 H), 9.61 (s, 1 H), 9.94 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.9, 98.1, 118.2, 142.0,
147.6, 149.9, 159.1, 189.4.
MS: m/z = 162 [M + 1]+.
(1) (a) Yan, H.; Boehm, J. C.; Jin, Q.; Kasparec, J.; Li, H.; Zhu,
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Ethyl 6-Formylpyrazolo[1,5-a]pyrimidine-3-carboxylate (16b)
Yellow solid; yield: 0.59 g (27%); mp 199 °C.
1H NMR (500 MHz, CDCl3): d = 1.32 (t, J = 6.9 Hz, 3 H), 4.32 (q,
J = 6.9 Hz, 2 H), 8.81 (s, 1 H), 9.13 (s, 1 H), 9.93 (s, 1 H), 10.06 (s,
1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.8, 60.4, 103.9, 120.3,
143.4, 148.3, 150.5, 151.4, 161.7, 189.4.
MS: m/z = 220 [M + 1]+.
6-Formylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (17b)
Brown solid; yield: 0.92 g (53%); mp 218 °C.
1H NMR (500 MHz, CDCl3): d = 8.95 (s, 1 H), 9.14 (s, 1 H), 9.97
(s, 1 H), 10.08 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 83.3, 113.0, 121.1, 143.6,
150.7, 151.3, 152.3, 189.2.
MS: m/z = 173 [M + 1]+.
(3) (a) Gupton, J. T.; Gall, J. E.; Riesinger, S. W.; Smith, S. Q.;
Bevirt, K. M.; Sikorski, J. A.; Dahl, M. L.; Arnold, A.
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McDermott, R. E.; Jones, B. P.; Ende, D. J.; Clifford, P. J.;
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(4) Tom, N. J.; Ruel, E. M. Synthesis 2001, 1351.
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(a) Jameleddine, K.; Adnen, H. A. M.; Bechir, B. H.
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4735. (d) Angus, R. O.; Bryce, M. R.; Keshavarz, B.; Wudl,
F. Synthesis 1998, 746.
Pyrimido[1,2-a]benzimidazole-3-carbaldehyde (18b)
Brown solid; yield: 1.58 g (80%); mp 266 °C.
1H NMR (500 MHz, CDCl3): d = 7.56 (t, J = 7.6 Hz, 1 H), 7.66 (t,
J = 7.6 Hz, 1 H), 7.94 (d, J = 7.6 Hz, 1 H), 8.44 (d, J = 7.6 Hz, 1 H),
9.18 (s, 1 H), 10.06 (s, 1 H), 10.26 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 113.4, 117.3, 120.1, 123.1,
127.5, 127.9, 142.7, 144.8, 154.5, 154.7, 188.4.
MS: m/z = 198 [M + 1]+.
Synthesis 2010, No. 16, 2767–2770 © Thieme Stuttgart · New York