Synthetic studies on KF-alumina-catalysed reaction of substituted and unsubstituted aryl-oxoketene dithioacetals and 1H-pyrazone-5(4H)-one: a convenient synthesis of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1016/j.tetlet.2009.04.020

The procedures described herein provide a facile method for the synthesis of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine by reacting N-substituted or unsubstituted-pyrazol-5(4H)-one, aryl-oxoketene dithioacetals and alkyl amide. The products wer

Full text of DOI:10.1016/j.tetlet.2009.04.020

Tetrahedron Letters 50 (2009) 3088–3091
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies on KF-alumina-catalysed reaction of substituted and
unsubstituted aryl-oxoketene dithioacetals and 1H-pyrazone-5(4H)-one:
a convenient synthesis of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine
*
Pushpak Mizar, Bekington Myrboh
Department of Chemistry, North-Eastern Hill University, Mawlai-Mawkynroh, Shillong 793 022, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 February 2009
Revised 2 April 2009
Accepted 8 April 2009
Available online 11 April 2009
The procedures described herein provide a facile method for the synthesis of pyrazolo[3,4-b]pyridine and
pyrazolo[1,5-a]pyrimidine by reacting N-substituted or unsubstituted-pyrazol-5(4H)-one, aryl-oxoketen-
e dithioacetals and alkyl amide. The products were obtained in moderate to good yield. The effects of the
solvents and substitution have also been described.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component
KF-Alumina
Fused pyrimidine
Fused pyridines
1. Introduction
1,4,5,6 tetrasubstituted pyrazolo[3,4-b] pyridine and a semi-
conventional method for the synthesis of 5,6,7 trisubstituted
pyrazolo[1,5-a] pyrimidines. The principal advantages, scope and
limitations of the method are discussed.
The functionalized pyrazolo[3,4-b]pyridine and pyrazolo[1,5-
a]pyrimidine are attractive compounds for drug discovery since
many of these scaffolds exhibit excellent biological activities. For
example, pyrazolo[3,4-b]pyridine derivatives have been evaluated
for various biological applications ranging from being good vasodi-
lators to hypotensive, anti-inflammatory, analgesics and antipy-
retic agents.1 The pyrazolo[1,5-a] pyrimidines structural motif is
found in a large number of pharmaceutical agents which exhibit
diverse range of physiological activities such as antiepileptic
agents,2 anxiolytics3 anti depressants4 and as agents for treatment
of sleep disorders5 and oncolytics.6 Therefore the development of
simple methodologies for the synthesis of these highly functional-
ized derivatives is highly challenging in organic synthesis.
To address this challenge, the development of multi-component
reaction method for the synthesis of these derivatives is of great
interest owing to its high efficiency and selectivity. Although there
are a wide range of methods available for the synthesis of pyrazol-
o[1,5-a] pyrimidines7 and pyrazolo [3,4-b] pyridines,8 very few of
these procedures provide a simple method that could yield com-
pounds with more structural diversities. In this Letter, we report
a successful multi-component procedure for the synthesis of
The general method to prepare (1,4,6 tri-substituted-1H-pyraz-
olo[3,4-b]pyridi-6-yl) (aryl) methanone 4a–j involves a three-com-
ponent reaction between 1-substituted-1H-pyrazone-5(4H)-one 1,
substituted aryl-oxoketene dithioacetals 2 and alkyl amides 3 in
presence of KF-alumina.9 The reaction presumably involves Mi-
chael addition and condensation to yield the desired products.
These reactions were attempted in range of solvents such as
DMA, acetonitrile, DMF, THF and 1,4 dioxane. However, the desired
products were obtained in DCM under refluxing conditions. The
reactions studied took between 8 and 16 h for completion (Scheme
1). The reaction time increases when the steric demand of the reac-
tant 1 increases (Table 1).
O
O
SMe
KF-Alumina
DCM, reflux
R2
H2N
R3
R2
+
N
+
O
N
N
R3
N
4a-j
O
MeS
SMe
N
R1
R1
2
3
1
* Corresponding author. Tel.: +91 3642722612; fax: +91 3642228213.
E-mail address: bmyrboh@nehu.ac.in (B. Myrboh).
Scheme 1. Synthesis of (1,4,6 tri-substituted-1H-pyrazolo[3,4-b]pyridi-6-yl) (aryl)
methanone.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.020

P. Mizar, B. Myrboh / Tetrahedron Letters 50 (2009) 3088–3091
3089
Table 1
Substituted fused pyridine and pyrimidines.
Entry
a
Product (4a–j)
Product (6a–j)
Product (9a–j)
Yields (%)
R
R
R
1 = CH3
2 = C6H5
3 = CH3
R1 = CH3
R2 = C6H5
R3 = CH3
R1 = C6H5
R2 = CH3
4a = 80
6a = 83
9a = 78
b
c
R1 = C2H5
R
R
R1 = C2H5
R2 = C6H5
R3 = CH3
R1 = p-Cl–C6H5
4b = 82
6b = 80
9b = 82
2 = C6H5
3 = CH3
R2 = CH3
R1 = p-NO2–C6H5
4c = 81
R1=
R1=
R
R
2 = C6H5
3 = CH3
R2 = C6H5
R3 = CH3
R2 = CH3
6c = 73
9c = 88
CN
CN
d
R1 = p-Br–C6H5
4d = 83
R1=
R1=
R
R
2 = C6H5
3 = CH3
R2 = C6H5
R3 = CH3
R2 = CH3
6d = 75
9d = 85
e
f
R1 = C6H5
4e = 80
R1=
R1=
N
N
R2 = C6H5
R2 = C6H5
R3 = CH3
R1 = CH3
R2 = C2H5
6e = 77
9e = 79
R
3 = CH3
R1 = CH3
R1 = p-Cl–C6H5
4f = 81
6f = 73
9f = 81
R2 = C2H5
R2=
R2=
Br
Br
R3 = C2Hs
R3 = C2H5
R1=
g
R1 = C2H5
R1 = p-NO2–C6H5
4g = 79
R2 = C2H5
6g = 77
9g = 81
4h = 78
R2=
R2=
Br
Br
R3 = CH3
R3 = C2H5
CN
R1=
h
R1 = p-Br–C6H5
R1=
R2=
R2 = C2H5
6h = 67
9h = 83
R2=
Br
Br
R
3 = CH3
R3 = C2H5
CN
R1=
R2=
i
4i = 80
6i = 79
R1=
N
R2=
Br
Br
R
3 = C2H5
R3 = C2H5
j
R1 = CH3
4j = 85
6j = 73
R1=
N
R2 = C6H5
R3 = C2H5
R2=
Br
R3 = C2H5

3090
P. Mizar, B. Myrboh / Tetrahedron Letters 50 (2009) 3088–3091
O
O
O
O
R2
R2
R3
R3
MeS
MeS
N
MeS
N
KF-Alumina
KF-Alumina
R2
R2
H
MeS
SMe
SMe
O
O
N
N
2
5
R1
A
R1
B
O
O
N
N
N
N
R1
R1
1
1
KF-Alumina
KF-Alumina
O
O
R2
R2
O
O
R2
R2
R3
MeS
MeS
MeS
MeS
N
R3
O
O
- H2O
- H2O
R3
H
H
O
O
N
H2N
N
H2N
N
N
R3
N
N
N
3
3
N
R1
N
R1
R1
R1
O
O
O
O
R3
R2
SMe
O
SMe
R3
R2
MeS
N
MeS
R2
- H2O
- H2O
R3
N
N
N
R3
N
4a-j
N
N
O
N
N
O
R2
R1
R1
N
N
N
R1
O
R1
O
Scheme 2. Plausible mechanism for the synthesis (1,4,6 tri-substituted-1H-pyraz-
olo[3,4-b]pyridi-6-yl) (aryl) methanone.
SMe
SMe
R3
R2
R3
R2
-AcOH
N
N
N
N
N
O
SMe
R1
R1
O
6a-j
O
R3
R3
R2
H2N
H3C
KF-Alumina
CHCl3, reflux
R2
SMe
N
+
+
O
N
N
Scheme 4. Synthesis of 5,7,6 trisubstituted pyrazolo[1,5-a] pyrimidines.
O
N
MeS
R1
N
R1
1
5
A plausible mechanism for the formation of 4a–j is outlined
in Scheme 2. The reaction was initiated by Michael addition
reaction between 1 and 2 to give the intermediate A which fur-
6a-j
Scheme 3. Synthesis of 1,4,5,6 tetra-substituted pyrazolo[3,4-b]pyridine.
ther condensed with 3 by abstraction of
a-proton to give the
O
R1
O
SMe
MeS
SMe
R2
R2
NH2
2
N
N
//
N
H
R3
N
4a-j
N
O
O
R1
O
R3
MeS
7
R1
SMe
5
O
N
SMe
toluene
reflux
R1
N
R1
+
N
N
H
O
MeS
SMe
O
O
2
7
8
R2
NH2
KF-Alumina
CCl4, reflux
O
R2
O
N
R1
N
N
SMe
9a-h
Scheme 5.

P. Mizar, B. Myrboh / Tetrahedron Letters 50 (2009) 3088–3091
3091
desired products. This may be concluded from the fact that
References and notes
when condensation of 1-methyl-pyrazol-5(4H)-one and 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one was carried out, 1-
methyl-4-((Z)-1-(methylthio)-3-oxo-3-phenylprop-1-enyl)-pyra-
zol-5(4H)-one was isolated which on further treatment with
acetamide afforded the desired product 4a, thereby indicating
that Michael addition is the first step in the three-component
reaction.
1. (a) Straub, A. S.; Alonso-Alija, J. P. C. Bioorg. Med. Chem. Lett. 2001, 11, 781; (b)
Elnagdi, M. N.; Elmoghayar, M. R. H.; Elgemeie, G. E. H. Adv. Heterocycl. Chem.
1987, 41, 320.
2. Tomcufcik, A. S.; Albright, J. D.; Dusza, J. P. U.S. Patent 4654347, 1987; Chem.
Abstr. 1985, 25, 220889m.
3. (a) Chen, Y. L. JP Patent 2000502723; Chem. Abstr. 1998, 17, 20490s.; (b) Dusza,
J. P.; Albright, J. D.; Tomcufcik, A. S. U.S. Patent 5538977, 1996; Chem. Abstr.
1996, 13, 168011c.
4. Boes, M.; Stadler, H.; Riemer, C. U.S. Patent 6194410, 2001; Chem. Abstr. 1999,
16, 214304z.
In order to study whether a similar type of reaction oc-
curred if the
unavailable, we carried out a three-component reaction of 1,
-substituted aryl oxoketene dithioacetals 5 and acetamide in
a-proton of the aryl oxoketene dithioacetals was
5. O’Donnell, P. B.; Thiele, W. J. U.S. Patent 6384221, 2002; Chem. Abstr. 2001, 15,
212744f.
6. (a) Kendall, R. L.; Rubino, R.; Rutledge, R.; Bilodeau, M. T.; Fraley, M. E.; Thomas,
K. A., Jr.; Hungate, R. W. U.S. Patent 6235741, 2001; Chem. Abstr. 1999, 4,
033028w.; (b) Fraley, M. E.; Hoffman, W. F.; Rubino, R. S.; Hungate, R. W.;
Tebben, A. J.; Rutledge, R. Z.; McFall, R. C.; Huckle, W. R.; Kendall, R. L.; Coll, K.
E.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2002, 12, 2767–2770.
7. (a) Emelina, E. E.; Petrov, A. A.; Firsov, A. V. Russ. J. Org. Chem. 2001, 37, 852–
858; (b) Chern, J.-W.; Lee, C.-C.; Liaw, Y.-C. W.; Andrew, H.-J. Heterocycles 1992,
34, 1133–1145; (c) Balicki, R. Pol. J. Chem. 1983, 57, 1251–1261; (e) Auzzi, G.;
Costanzo, A.; Bruni, F.; Clauser, M.; Guerrini, G.; Selleri, S.; Pecori Vettori, L.
Farmaco 1990, 45, 1193–1205; (f) Bruni, F.; Chimichi, S.; Cosimelli, B.; Costanzo,
A.; Guerrini, G.; Selleri, S. Heterocycles 1990, 31, 1141–1149; (g) Elnagdi, M. H.;
Erian, A. W. Bull. Chem. Soc. Jpn. 1990, 63, 1854–1856; (h) Abdelrazek, F. M. J.
Prakt. Chem. 1989, 331, 475–478; (i) Hussain, S. M.; El-Reedy, A. M.; El-
Sharabasy, S. A. Tetrahedron 1988, 44, 241–246; (j) Ried, W.; Aboul-Fetouh, S.
Tetrahedron 1988, 44, 7155–7162; (k) Ho, Y.-W. J. Chin. Chem. Soc. 1999, 46,
955–962.
a
presence of KF-alumina.10 Interestingly it was observed that
the product obtained was 1,4,5,6 tetra-substituted pyrazolo[3,4
-b]pyridine 6a–j (Scheme 3). The plausible mechanism for the
formation of 6a–j is outlined in Scheme 4. The reaction was
initiated by the Michael addition reaction between 1 and 5 to
give 1,5 dicarbonyl B which further underwent condensation
with acetamide to yield the desired products. The reaction pre-
sumably involves a Michael addition reaction to give 1,5 dicar-
bonyl which further underwent condensation with acetamide to
yield 6a–j (Table 1). The reactions were found to be solvent
dependent and proceded only in CHCl3 under refluxing condi-
tion. The reactions studied took between 12 and 24 h for
completion.
8. (a) Elnagdi, M. H.; Negm, A. M.; Sadek, K. U. Synlett 1995, 27; (b) Quiroga,
J.; Insuasty, B.; Hormaza, A. J. Heterocycl. Chem. 1999, 36, 1311; (c) Quiroga,
J.; Hormaza, A.; Insuasty, A.; Marquez, B. M. J. Heterocycl. Chem. 1998, 35,
409.
It was further observed that the three-component reaction
between 1H-pyrrol-2(3H)-one 7, aryl oxoketene dithioacetal
and acetamide yielded a complex mixture of products. However,
when 7 was refluxed with 2 in toluene an addition product 8
9. Synthesis of 4b: A dry 100 mL flask was charged with 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one
2 (9.9 mmol), acetamides 3 (9 mmol), 1-ethyl-1H-
pyrrol-2(3H)-one 1 (9 mmol), KF-alumina (1 g) and DCM (10 mL). The mixture
was refluxed for 8–16 h. The reaction after completion (monitored by TLC), was
cooled to room temperature, the solvent was evaporated in vacuum, and the
crude product was purified by silica gel column chromatography using
was obtained, which when further refluxed with
3 in CCl4
yielded 5,7,6 trisubstituted pyrazolo[1,5-a] pyrimidines 9a–h11
(Scheme 5).
methanol–DCM (1:20) as eluent to obtain 4b: mp 204–205 °C; IR (KBr)
m
cmÀ1 1685, 1630 and 1592; 1H NMR (CDCl3, 400 MHz) d ppm 1.27 (t, 3H,
J = 14.1 Hz), 2.32 (s, 3H), 2.58 (s, 3H), 3.47 (q, 2H, J = 8.5 Hz), 7.51–7.76 (m, 5H,
aromatic), 8.05 (s, 1H); 13C NMR (CDCl3, 100 MHz) 13.2, 14.7, 18.5, 53.1, 107.6,
127.7, 128.1, 129.1, 132.1, 134.6, 135.7, 150.6, 153.5, 162.9, 195.1. MS (CI) m/
z = 312.10 (M+1). Anal. Calcd for C17H17N3OS: C, 65.57; H, 5.50; N, 13.49.
Found: C, 65.55; H, 5.52; N, 13.51.
In conclusion, we have developed efficient procedures for the
synthesis of biologically active scaffolds by using a three-compo-
nent KF-alumina-catalysed reaction.
10. Compound 6c: mp 174–175 °C; IR (KBr)
m
cmÀ1 1685, 1630 and 1592; 1H NMR
Acknowledgements
(CDCl3, 400 MHz) d ppm 0.99 (d, 6H, J = 6.5 Hz), 1.65–1.68 (m, 1H), 2.21 (s, 3H),
2.36 (s, 3H), 3.42 (d, 2H, J = 8.1 Hz), 7.41–7.85 (m, 5H, aromatic), 8.01 (s, 1H);
13C NMR (CDCl3, 100 MHz) 10.6, 13.7, 21.2, 25.9, 59.7, 103.7, 126.1, 126.7,
127.1, 128.7, 132.8, 134.9, 150.6, 153.9, 157.7.MS (CI) m/z = 312.16 (M+1). Anal.
Calcd for C18H21N3S: C, 69.43; H, 6.80; N, 13.49. Found: C, 69.39; H, 6.80; N,
13.47.
P.M. thanks CSIR for the award of research fellowship; SAIF,
NEHU Shillong and IISc Bangalore for spectral analysis and the
UGC for the ‘Special Assistance Program’.
11. Compound 9a: mp 245–246 °C; IR (KBr)
m
cmÀ1 1685, 1630 and 1592; 1H NMR
(CDCl3, 400 MHz) d ppm 2.24 (s, 3H), 2.41 (s, 3H), 6.74 (d, 1H, J = 9.1 Hz), 7.42–
7.71 (m, 5H, aromatic), 8.12 (d, 1H, J = 9.1 Hz); 13C NMR (CDCl3, 100 MHz) 13.1,
19.2, 98.3, 126.3, 127.3, 129.9, 130.9, 134.6, 135.9, 147.3, 159.8, 166.7, 195.9.
MS (CI) m/z = 284.41 (M+1). Anal. Calcd for C15H13N3OS: C, 63.58; H, 4.62; N,
14.83. Found: C, 63.56; H, 4.60; N, 14.80.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.020.