Synthesis of New Pyrazolo[1,5-α]Quinazoline Derivatives

Article abstract of DOI:10.1080/00397911.2015.1040511

(Chemical Equation Presented). The reaction of various anthranilic acid derivatives or their esters with 4-oxotetrahydrothiophene-3-carbonitrile 2, 2-oxocyclopentanecarbonitrile (9, n = 1) or 2-oxocyclohexanecarbonitrile (9, n = 2) in ethanol under reflux

Full text of DOI:10.1080/00397911.2015.1040511

This article was downloaded by: [University of California, San Diego]
On: 12 June 2015, At: 09:50
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of New
Pyrazolo[1,5-α]quinazoline Derivatives
Dániel Kovácsa, Judit Molnár-Tótha, Gábor Blaskóa, Imre Fejesa &
Miklós Nyergesa
a Servier Research Institute of Medicinal Chemistry, Budapest,
Hungary
Accepted author version posted online: 22 Apr 2015.Published
online: 22 Apr 2015.
Click for updates
To cite this article: Dániel Kovács, Judit Molnár-Tóth, Gábor Blaskó, Imre Fejes & Miklós Nyerges
(2015) Synthesis of New Pyrazolo[1,5-α]quinazoline Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 45:14, 1675-1680,
DOI: 10.1080/00397911.2015.1040511
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1040511
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 45: 1675–1680, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1040511
SYNTHESIS OF NEW PYRAZOLO[1,5-a]QUINAZOLINE
DERIVATIVES
Dániel Kovács, Judit Molnár-Tóth, Gábor Blaskó,
Imre Fejes, and Miklós Nyerges
Servier Research Institute of Medicinal Chemistry, Budapest, Hungary
GRAPHICAL ABSTRACT
Abstract The reaction of various anthranilic acid derivatives or their esters with
4-oxotetrahydrothiophene-3-carbonitrile 2, 2-oxocyclopentanecarbonitrile (9, n ¼ 1) or
2-oxocyclohexanecarbonitrile (9, n ¼ 2) in ethanol under reflux conditions giving rise the
formation of single products isolated in each case after simple filtration. The products
were characterized as pyrazolo[1,5-a]quinazolin-5-ones
4 instead of the expected
pyrazol-3-amines 3. These cascade condensation–intramolecular acylation processes
generated in one-step reactions from simple starting materials novel heterocyclic scaffolds
ready for further functionalization. The present synthetic protocol provides acceptable
yields of new tetracyclic products in high purity.
Keywords Cascade reactions; heterocycles; pyrazoles
INTRODUCTION
During one of our ongoing medicinal chemistry programs, we intended to
prepare a small library of 2-aryl-4,6-dihydrothieno[3,4-c]pyrazol-3-amine derivatives
(3) using the known nucleophilic addition: cyclization domino reaction between
the appropriate aryl-hydrazine derivatives (1) and 4-oxotetrahydrothiophene-3-
carbonitrile (2) (Scheme 1).[1] A large number of derivatives of this heterocycle are
well described in the patent literature because of their interesting pharmacological
Received February 12, 2015.
Address correspondence to Miklós Nyerges, Servier Research Institute of Medicinal Chemistry, 7
Záhony utca., H-1031 Budapest, Hungary. E-mail: miklos.nyerges@hu.netgrs.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1675

1676
D. KOVÁCS ET AL.
Scheme 1. General synthesis of pyrazole amines.
properties that allow them to function as P2X7 receptor antagonists,[2] inhibitors of
PDE4[3] or the TrkA kinase,[4] antivirials,[5] or modulators of nicotinic acetylcholine
receptors.[6] However, to date there is no example described for the reaction of
2-hydrazino-benzoic acids (1, R1¼COOH), or their esters (1, R1¼COOR) and 4-
oxotetrahydrothiophene-3-carbonitrile 2 in such processes.
RESULTS AND DISCUSSION
The starting 2-hydrazino-benzoic acids or their esters 1 are commercially avail-
able; however, because of their relatively high price all of them were prepared in house
from the corresponding anthranilic acid derivatives according to the procedures
described in the literature.[7,8] These acids or their esters were reacted with 4-
oxotetrahydrothiophene-3-carbonitrile 2 in ethanol under reflux. After 3 h heating
a single product was isolated (via 6, 7 and 8) in each case after simple filtration. These
products were characterized as 6,7-dihydro-5H,9H-thieno[3040:3,4]pyrazolo[1,5-a]
quinazolin-5-ones 4 instead of the expected thieno[3,4-c]pyrazol-3-amines 3 on the
1
basis of their elemental analysis as well as infrared (IR), H NMR, 13C NMR, and
mass spectral (MS) analysis. The IR spectrum of 4 revealed the presence of a
carbonyl stretching vibration band around 1680 cmꢀ1, for the lactam carbonyl group,
and in the NMR spectra a newly formed amide was visible instead of the amine. This
lactam 4 was later reduced to the corresponding amine 5, which become the key
compound for further diversification of this small compound library in our medicinal
Scheme 2. Reagents and conditions: (i) ethanol, reflux; (ii) BH3, THF.

NEW PYRAZOLO[1,5-a]QUINAZOLINE DERIVATIVES
1677
Table 1. The synthesized thieno[30,40.3,4]pyrazolo[1,5-a]quinazoline derivatives
Entry Hydrazine
R1
R2
R3
R4
R5 Product Yield (%) Product Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
CO2H
CO2H
CO2H
CO2H
CO2CH3 CH3
CO2CH3
CO2CH3 Br
H
H
H
H
H
H
CH3
H
H
OCH3
H
H
H
H
CH3
H
H
H
CH3
H
H
H
4a
4b
4c
4d
4e
4f
74
9
5a
5b
5c
5d
5e
5f
51
—
95
—
—
85
—
43
49
15
56
9
H
H
H
1 g
H
4 g
5 g
chemistry program (Scheme 2, Table 1). Among the products 5a, 5c, and 5f were
successfully prepared. In other cases, a complex mixture was observed during the
reduction that lacked the desired products (5b, 5d, 5e, and 5g).
The formation of the pyrazole ring in the reaction of a keto-cyanide 1 and
arylhydrazine 2 is well documented in the literature. However, the intramolecular
acylation of the pyrazolamine 8 usually requires more activated acid derivatives such
as chloride in the presence of base (Scheme 3).
In the same way, refluxing a solution of 2-oxocyclopentanecarbonitrile (9, n ¼ 1)
or 2-oxocyclohexanecarbonitrile (9, n ¼ 2) in ethanol with arylhydrazines 1 afforded a
series of novel tetracyclic pyrazolo[1,5-a]quinazoline 10 derivatives in a single step
(Scheme 4, Table 2). Then the lactam 10 was reduced to the corresponding amine
11 under the same conditions described previously. Besides the successful reactions
of 11a–c, 11e, and 11f (Table 2), the products 11d, 11 g, and 11 h were not observed,
probably due to the decomposition of the proper lactams under the applied reaction
conditions.
Scheme 3. Proposed reaction mechanism of the formation of the new thieno[30,40.3,4]pyrazolo[1,5-a]
quinazoline derivatives.

1678
D. KOVÁCS ET AL.
Scheme 4. Reagents and conditions: (i) ethanol, reflux; (ii) BH3, THF.
In conclusion, we report a cascade condensation–intramolecular acylation
process generated in the reaction of cyclic ketocyanides 2 and 2-hydrazino-benzoic
acids or their esters 1 (R1 ¼ CO2H or CO2Me accordingly) to afford novel
heterocycles. The present synthetic protocol provides acceptable yields of new
tetracyclic products in good purity. The bioactivity of the newly synthesized
compounds will be published elsewhere.
EXPERIMENTAL
Preparation of 2-Hydrazino-benzoic Acids
The corresponding anthranilic acid (1 mmol) was suspended in hydrochloric acid
(6 M, 2.4 ml) and cooled to ꢀ5°C. Sodium nitrite (1.1 mmol) was dissolved in water
(0.4 ml) and added dropwise. The reaction mixture was stirred for 1 h at ꢀ5°C and
then SnCl2 · 2H2O was added (0.451 g, 2 mmol dissolved in 0.6 ml of 6 M aqueous
HCl). The product was precipitated, filtered, washed with water, and dried in vacuo.
The product was used without any further purification (yield 64–100%).
Reaction of Hydrazines with a-Oxo-cyanides
The corresponding 2-hydrazino-benzoic acid or methyl-2-hydrazino-benzoate
(1.1 mmol) and the a -oxo-cyano compound (1 mmol) were suspended in dry ethanol
(5.5 ml) and refluxed for 3 h. After cooling, the product was precipitated, filtered,
and dried in vacuo to yield (51–85%) the title products.
Table 2. The synthesized novel tetracyclic pyrazolo[1,5-a]quinazolines
Entry Hydrazine
n
R1
R2
R3
R4 R5 Product Yield (%) Product Yield (%)
1
2
3
4
5
6
7
8
1a
1c
1f
1 g
1a
1c
1f
1
1
1
1
2
2
2
2
CO2H
CO2H
CO2CH3
CO2CH3 Br
CO2H
CO2H
H
H
H
H
CH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10a
10b
10c
10d
10e
10f
54
44
30
8
55
47
52
3
11a
11b
11c
11d
11e
11f
87
87
57
—
26
44
—
—
H
H
H
H
CH3
OCH3
H
CO2CH3
CO2CH3 Br
10 g
10 h
11 g
11 h
1 g

NEW PYRAZOLO[1,5-a]QUINAZOLINE DERIVATIVES
1679
6,7-Dihydro-5H,9H-thieno[3’,4’.3,4]pyrazolo[1,5-a]quinazoline-5-
one (4a)
1
White powder, 0.180 g (74%); H NMR (500 MHz, DMSO-d6): 12.28 (s, 1H,
NH), 8.11 (d, 1H, J ¼ 7.5 Hz, Ar-40H), 7.97 (d, 1H, J ¼ 8.0 Hz, Ar-10H), 7.84
(t, 1H, J ¼ 8.4 Hz, Ar-20H), 7.45 (t, 1H, J ¼ 7.5 Hz, Ar-30H), 4.02 (s, 2H, H-9),
3.83 (s, 2H, H-7); 13C NMR (125 MHz, DMSO-d6): 161.3 (q), 158.8 (q), 138.5 (q),
135.6 (CH), 132.7 (q), 128.6 (CH), 125.5 (CH), 116.2 (q), 114.6 (CH), 104.7 (q),
28.9 (CH2), 26.8 (CH2); IR (KBr, cmꢀ1): 2820, 1667. HRMS m=z calcd. for
C12H9N3OS (M þ H)þ 244.0546; found 244.0541.
Lactam Reduction
The corresponding indazolo[2,3-a]qinazoline-5(6H)-one or pyrazolo[1,5-a]
quinazoline-5-one (1 mmol) was dissolved in dry tetrahydrofurane (30 ml) and at
ꢀ5°C under a nitrogen atmosphere. BH3 · THF solution (1 M, 7 ml) was added
dropwise. The mixture was stirred at room temperature for 4 h, and then aqueous
hydrochloric acid solution (6 M, until no more gas evolved) was added. The pH
was adjusted to 13 with 2 M sodium hydroxide solution, and the mixture was
extracted with dichloromethane (2 × 200 ml), dried over sodium sulfate, and evapo-
rated. The crude product was purified by column chromatography over silica (eluent:
heptane–ethyl acetate 3:1) to yield (26–87%) the product.
6,7-Dihydro-5H,9H-thieno[3’,4’.3,4]pyrazolo[1,5-a]quinazoline (5a)
Yield 0.117 g (51%); white powder; 1H NMR (500 MHz, DMSO-d6): 7.45 (dm,
1H, J ¼ 8.0 Hz, Ar-10H), 7.29 (m, 1H, Ar-20H), 7.23 (dm, 1H, J ¼ 7.3 Hz, Ar-40H),
7.09 (m, 1H, Ar-30H), 6.75 (brs, 1H, NH), 4.34 (brs, 2H, H-5), 3.85 (brt, 2H, H-9),
3.68 (brt, 2H, H-7); 13C NMR (125 MHz, DMSO-d6): 160.3 (q), 140.8 (q), 135.9
(q), 128.7 (CH), 126.8 (CH), 124.6 (CH), 121.5 (q), 113.7 (CH), 102.5 (q), 42.8
(CH2), 28.9 (CH2), 26.7 (CH2). IR (KBr, cmꢀ1): 3280, 2916. HRMS m=z calcd. for
C12H11N3S (M þ H)þ 230.0754; found 230.0741.
SUPPLEMENTAL MATERIAL
Full experimental details, assignment, the 1H and 13C NMR spectra, IR
spectra, and HRMS details for this article can be accessed on the publisher’s website.
REFERENCES
1. Baraldi, P. G.; El-Kashef, H.; Manfredini, S.; Pineda de las, I., Maria, J.; Romagnoli, R.;
Spalluto, G. Synthesis 1998, 1331–1334.
2. Carroll, W. A.; Perez-Medrano, A.; Li, T. PCT Int. Appl. WO 2007056091, 2007.
3. Govek, S. P.; Oshiro, G.; Noble, S. A.; Malecha, J. W.; Shiau, A. K. PCT Int. Appl. WO
2008045664, 2008.
4. Allen, S.; Andrews, S. W.; Blake, J. F.; Condroski, K. R.; Haas, J.; Huang, L.; Jiang, Y.;
Kercher, T.; Kolakowski, G. R.; Seo, J. PCT Int. Appl. WO 2012158413, 2012.

1680
D. KOVÁCS ET AL.
5. (a) Padmanabhan, R.; Pattabiraman, N.; Mueller, N.; Nagarajan, K. PCT Int. Appl. WO
2010039538, 2010; (b) Gu, B.; Block, T.; Cuconati, A. PCT Int. Appl. WO 2007005541,
2007; (c) Gu, B.; Ouzunov, S.; Wang, L.; Mason, P.; Bourne, N.; Cuconati, A.; Block,
T. M. Antiviral Res. 2006, 70, 39–50.
6. Ernst, G. E.; Frietze, W. E.; Simpson, T. R. PCT Int. Appl. WO2006068591, 2006.
7. Pfannstiel, K.; Janecke, J. Ber. Chem. Gesellsch. 1942, 75B, 1096–1107.
8. Stephenson, E. F. M. Org. Synth. 1949, 29, 54–58.