Download PDF
Synlett 2019; 30(15): 1782-1786
DOI: 10.1055/s-0039-1690189
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones by Domino Knoevenagel/Hetero Diels–Alder Reactions

Mostafa Kiamehr∗
a   Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 37146-6611, Qom, Iran   Email: m.kiamehr@qom.ac.ir
,
Leyla Mohammadkhani
a   Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 37146-6611, Qom, Iran   Email: m.kiamehr@qom.ac.ir
,
Mohammad Reza Khodabakhshi
b   Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Mollasadra Street, P.O. Box 1435916471, Tehran, Iran
,
Behzad Jafari
c   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Langer  ∗
c   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
d   Leibniz-Institut für Katalyse e.V. an der Universität Rostock, A.-Einstein-Str. 29a, 18059 Rostock, Germany
› Author Affiliations
Further Information

Publication History

Received: 25 June 2019

Accepted after revision: 06 August 2019

Publication Date:
14 August 2019 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

An efficient Lewis acid mediated domino Knoevenagel/hetero Diels–Alder (DKHDA) reaction of pyrazolone derivatives with N-acrylated anthranilic aldehydes was developed, which afforded functionalized tetracyclic tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones. The products were formed in good yields and with excellent regio- and stereoselectivity in favor of the cis-configured isomer.


#

Key words

domino reaction - regioselectivity - cyclizations - heterocycles - Diels–Alder reaction - Knoevenagel reaction

Domino reactions represent an important tool in organic chemistry.[1a] In this context, domino Knoevenagel/hetero Diels–Alder (DKHDA) reactions are of special interest as they proceed by formation of two or more rings in only one synthetic step.[1] Tetra- and pentacyclic heterocycles, containing a pyran or chroman moiety, have been synthesized through DKHDA reactions of internal O-allylated- and O-propargylated salicylic aldehydes with 1,3-dicarbonyl compounds.[2] There have also been reported DKHDA reactions of 2-formylphenyl-N-alkyl-2-phenylethenesulfonamides and 2-formylphenyl-2-phenylethenesulfonates for the synthesis of annelated benzosultams or benzosultones, respectively.[3] Furthermore, DKHDA reactions of O-acrylated salicylic aldehydes and 1,3-dicarbonyl or thiocarbonyl compounds allow the synthesis of polycyclic dihydrocoumarines.[4] We have recently reported the DKHDA reaction of N-acrylated anthranilic aldehydes and indolin-2-thiones, which provides a convenient access to pentacyclic 3,4-dihydroquinolones.[5]

Zoom Image
Figure 1 Biologically active annulated pyrazoles (top) and 3,4-dihydroquinolones (bottom)

The pyrazole moiety represents an important heterocyclic core structure because of its presence in many biologically active compounds,[6] pharmaceuticals,[7] agrochemicals,[8] and natural products.[9] Among pyrazole derivatives, Viagra®,[10] Celebrex®,[11] Acomplia®,[12] and Fipronil® [13] are commercial drugs. Pyrazoles display antimicrobial,[14] antitubercular,[15] antitumor,[16] anticancer,[17] and antihyperglycemic activities, and also inhibit IL-1 synthesis and HIV-1 reverse transcriptase.[18] Likewise, tetrahydropyranopyrazoles represent an important core structure because of their presence in various biologically active compounds (Figure [1], top).[19] On the other hand, functionalized 3,4-dihydroquinolone structures are privileged scaffolds that can be found in many synthetic and natural products (Figure [1], bottom).[20] They show cardiovascular effects and also exhibit phosphodiesterase inhibitory and anti-inflammatory activities.[21] 3,4-Dihydroquinolones have been prepared by Skraup–Doebner–von Miller reactions,[22] Friedlander–Friedel–Crafts cyclizations,[23] radical-mediated reactions,[24] oxidative cyclizations,[25] photochemical reactions,[26] transition-metal-catalyzed reactions,[27] and asymmetric synthetic approaches.[28]

An important concept in medicinal chemistry relies on the synthesis of hybrid molecules containing a combination of known pharmacophores.[29] Tetrahydropyrazolo[4',3':5,6]-pyrano[3,4-c]quinolones combine the structural units of pyrazoles, tetrahydropyranopyrazoles, and 3,4-dihydroquinolones as pharmacophoric core structures. This type of molecule has, to the best of our knowledge, not been reported in the literature so far. Following our general interest in the development of new synthetic methods and their application in heterocyclic chemistry,[30] we herein wish to report a new and convenient synthesis of tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones 3 by DKHDA reaction of pyrazolones 2 with N-acrylated anthranilic aldehydes 1 (Scheme [1]).

Zoom Image
Scheme 1 DKHDA reaction of N-acrylated anthranilaldehydes with pyrazolones

N-Acrylated anthranilic aldehydes 1a–d were synthesized in three steps as shown in Scheme [2]. The alkylation of quinoline with alkyl iodides (1,4-dioxane, reflux) afforded the N-alkylquinolinium salts 5a,b. Oxidation of the latter with H2O2 gave N-alkylanthranilic aldehydes 6a,b.[31] Finally, products 1a–d were obtained by reaction of 6a,b with acryloyl chloride (7a) or (E)-crotonyl chloride (7b) according to a known methodology.[5]

Zoom Image
Scheme 2 Synthesis of 1a–d. Reagents and conditions: (a) R1I, 1,4-dioxane, reflux, 1 h; (b) 1,2-dichloroethane/H2O (1:1), KOH, H2O2, 72 h; (c) NaHCO3, CH2Cl2, 2–5 h.

Table 1 Optimization of the Synthesis of 3a a,b

Entry

Solvent

Additive (mol%)

Temp (°C)

Yieldb(%)

 1

H2O

–

refluxc

13

 2

MeCN

–

refluxc

15

 3

MeOH

–

refluxc

30

 4

EtOH

–

refluxc

32

 5

AcOH

–

refluxc

 5

 6

PhCH3

–

refluxc

18

 7

EtOH

ZnO (100)

refluxd

48

 8

EtOH

ZnCl2 (100)

refluxd

67

 9

EtOH

ZnBr2 (100)

refluxd

85

10

EtOH

NEt3 (100)

refluxd

10

11

EtOH

l-proline (100)

refluxd

20

12

H2O

ZnBr2 (100)

refluxd

25

13

EtOH

ZnBr2 (50)

refluxd

85

14

EtOH

ZnBr2 (40)

refluxd

80

a Reagents and conditions: 1a (0.5 mmol, 1.0 equiv), 2a (0.5 mmol, 1.0 equiv), and solvent (5.0 mL).

b Yields of isolated products.

c Reaction time: 15 h.

d Reaction time: 5 h.

Zoom Image
Scheme 3 Preparative scope. Reagents and conditions: 1 (0.5 mmol, 1.0 equiv), 2 (0.5 mmol, 1.0 equiv), ZnBr2 (0.25 mmol, 0.5 equiv), and EtOH (5.0 mL), reflux, 5 h. Isolated yields are given in parenthesis.

The synthesis of the desired target molecules was next studied. To optimize the conditions of the DKHDA reaction, the synthesis of product 3a by reaction of N-acrylanthranilic aldehyde 1a with N-phenylpyrazolone 2a was investigated (Table [1]). Initially, the effect of the solvent, such as water, acetonitrile, methanol, ethanol, acetic acid, and toluene, was studied. The reactions were carried out under reflux and catalyst-free conditions at a reaction time of 15 hours (entries 1–6, Table [1]). The best yields were obtained in ethanol (32% yield, entry 4). Subsequently, the effect of the Lewis acid, such as ZnO, ZnCl2, and ZnBr2, was studied. In the presence of Lewis acid, the yields were improved to 48, 67, and 85%, respectively, and the reaction time could be reduced to five hours (entries 7-9). In fact, employment of ZnBr2 in ethanol heated to reflux gave the best yields (85%, entry 9). The use of other catalysts, such as the acid l-proline or the base NEt3, was not successful (entries 10 and 11). Likewise, the use of ZnBr2 in water heated to reflux was not successful (entry 12). Reduction of the amount of ZnBr2 to 50 mol% gave equally good yields (85%), but further reduction of the amount of ZnBr2 (40 mol%) gave lower yields (entries 13 and 14). Hence, the optimized reaction conditions involved ethanol at reflux with 50 mol% of ZnBr2 and a reaction time of five hours (entry 13).[32] In all cases, analysis of the 1H NMR spectrum of 3a revealed that the product was selectively obtained as the cis-configured isomer.

By using the optimized conditions, the substrate scope was studied. The cyclization of pyrazolones 2a,b with anthranilic aldehydes 1a–d afforded products 3a–h in 80–90% yield and with very good regio- and diastereoselectivity (Scheme [3]).

Zoom Image
Scheme 4 Possible mechanism of the formation of compounds 3a–h

The structure of the products was confirmed by spectroscopic methods. The coupling constants of the adjacent H atoms clearly indicate the cis configuration of the products (comparison with 1H NMR data of related molecules reported in the literature).[1] [2] [3] [4] [5] For example, in the 1H NMR spectrum of compound 3d, a one-proton double doublet with coupling constants of 7.3 Hz and 5.2 Hz is observed for proton Hb at 2.84 ppm, a three-proton multiplet for the N-CH2 and Ha protons at 3.88–4.03 ppm, and a one-proton doublet with a coupling constant of 5.1 Hz for proton Hc at 4.25 ppm. These data indicate that Ha and Hb are in a trans relationship and Hb and Hc are in a cis relationship (for assignment of the protons, see Scheme [3]). In all compounds, similar coupling constants were observed. In the 1H NMR spectrum of compound 3d, there are also a three-proton triplet, doublet, and a singlet at 1.24, 1.49, and 2.27 ppm, respectively, which can be assigned to the three CH3 groups.

A possible mechanism of the formation of products 3a–h is illustrated in Scheme [4]. The ZnBr2-mediated Knoevenagel condensation of N-acrylanthranilic aldehyde 1 with pyrazolone 2 leads to the formation of an intermediate which can exist in an exo or endo orientation. The stereochemistry of the products depends on the stereochemical orientation of the dienophile in the transition state of the subsequent intramolecular hetero Diels–Alder reaction. The reaction seems to proceed selectively via the endo transition state, as exclusively the formation of the cis-configured isomers was observed. This might be explained by electronic reasons.

In conclusion, we have synthesized what are, to the best of our knowledge, the first tetrahydropyrazolo[4',3':5,6]pyrano[3,4-c]quinolones through DKHDA reaction of pyrazolones with N-acrylated anthranilic aldehydes. The reaction proceeds with excellent regio- and stereoselectivity and in high yields. The reaction was carried out in ethanol heated to reflux as a green and environmentally friendly solvent. The Lewis acid used, ZnBr2, is inexpensive and commercially available.


#

Acknowledgement

Financial support by the State of Mecklenburg-Vorpommern, by the State of Iran, and by the DAAD is gratefully acknowledged.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690189.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Biologically active annulated pyrazoles (top) and 3,4-dihydroquinolones (bottom)
Zoom Image
Scheme 1 DKHDA reaction of N-acrylated anthranilaldehydes with pyrazolones
Zoom Image
Scheme 2 Synthesis of 1a–d. Reagents and conditions: (a) R1I, 1,4-dioxane, reflux, 1 h; (b) 1,2-dichloroethane/H2O (1:1), KOH, H2O2, 72 h; (c) NaHCO3, CH2Cl2, 2–5 h.
Zoom Image
Scheme 3 Preparative scope. Reagents and conditions: 1 (0.5 mmol, 1.0 equiv), 2 (0.5 mmol, 1.0 equiv), ZnBr2 (0.25 mmol, 0.5 equiv), and EtOH (5.0 mL), reflux, 5 h. Isolated yields are given in parenthesis.
Zoom Image
Scheme 4 Possible mechanism of the formation of compounds 3a–h