Organocatalytic Three‐Component, One‐Pot Reaction of Highly Substituted Tetrahydropyrano[2, 3‐c]pyrazoles

Abstract

We have developed an efficient synthetic method for the production of substituted tetrahydropyrano[2, 3-c]pyrazoles using (E)-2-nitro-1,3-enynes, 1-aryl-3-substituted pyrazolones and methyl vinyl ketone. The sequential, one-pot reaction proceeded smoothly to give the desired products in high to excellent yields and stereoselectivities in the presence of a quinine-derived squaramide organocatalyst.The use of conjugated 1,3-enynes as dielectrophiles in organic reactions has received considerable attention in recent years. [1] Many chemical transformations have been developed that enable the rapid construction of useful intermediates either in the presence of a metal species or under metal-free conditions. These exemplify the synthetic utility of the electron-deficient 1,3-enynes, which have been widely explored in the synthesis functionalized compounds, and 2-keto/2-ester/sulfonyl-and 1nitro-/(E)-2-nitro-derived 1,3-enynes have been most commonly used. The Zhang group reported the reactions of activated 2keto-1,3-enynes with various nucleophiles to give functionalized carbocycles, heterocycles and tetrasubstituted allenes using metal catalysts. [2] These conjugated 2-keto/2-ester 1,3enynes can also be applied in organocatalytic reactions for the preparation of heterocyclic compounds as well as angularly fused polycycles. [3] Furthermore, the use of 1-nitro-1,3-enynes in sequential catalytic reactions that combine metal catalysis and organocatalysis to generate pyrano-annulated pyrazoles and tetrahydrofuranyl derivatives was reported by Enders [4] and Krause/Alexakis, [5] respectively. The use of (E)-2-nitro-1,3-enynes for the synthesis of highly substituted pyrroles [6] and thiophenes [7] has been reported by Punniyamurthy. The pyranoannulated molecular architectures can be readily assembled by using (E)-2-nitro-1,3-enynes in organocatalytic tandem reactions via in situ formation of an allene (Scheme 1, eqs a and b). [8] These results signify the potential uses of activated conjugated 1,3-enynes in organocatalytic reactions; however, useful protocols remain elusive. [9,10] Herein, we reported a three-component Michael/oxa-Michael/Michael reaction, which uses (E)-2-nitro- [a] Prof.

Asymmetric Organocatalysis of Activated Alkynes and Enynes

“…Contemporarily, Chen and Wu reported a similar one‐pot, three‐component enantioselective tandem reaction involving ( E )‐2‐nitro‐1,3‐enynes, aryl substituted pyrazolones 125 and methyl vinyl ketone 137 under chiral quinine‐derived squaramide 23 h bifunctional catalysis (Scheme 44). [71] This strategy provided functionalized enantioenriched tetrahydropyranopyrazole derivatives 140 with good yields and stereoselectivities (75–98% yield, >20 : 1 dr and 82–95% ee). The described strategy involves Michael addition of pyrazolone, oxa‐Michael initiated 6‐ endo‐dig cyclization and DBU catalysed nitro‐Michael addition to MVK 137 .…”

An Unprecedented Organocascade Synthesis of Functionalized Bicyclic Nitrones from 2‐Aminomalonate Derived Nucleophiles and 1‐Nitro‐1,3‐Enynes via Allenes Formation and Subsequent Rearrangement

“…In continuation of our efforts on organocatalytic reactions on electron deficient alkynes,‐, herein, we report an unprecedented example for synthesis of functionalized bicyclic nitrones 6 from dielectrophilic ethyl 2‐(nitromethylene)‐4‐arylbut‐3‐ynoate 4 and 2‐aminomalonate derived ( E )‐diethyl 2‐((2‐hydroxybenzylidene)amino)malonates 5 . The organocascade process was believed to proceed via conjugate addition, in situ generation of allenes and subsequent rearrangement …”

“…The use of conjugate nitro‐1,3‐enynes and related derivatives in this protocol has received much attention in recent years, including 2‐nitro‐1,3‐enynes ( 1 ), 1‐nitro‐1,3‐enynes ( 2 ) and alkyne‐tethered nitroalkenes ( 3 ) . Numerous chemical scaffolds that include nitrochromans (Xu), pyrano‐annulated derivatives (Chen,, Samanta, Singh), substituted pyrrole/thiophenes (Punniyamurthy),‐ tetrahydrofuranyl ethers (Krause, Alexakis), spirooxindole (Zhou), pyrano‐annulated pyrazoles (Enders), and spiropyrazolones (Schoenebeck, Enders) were prepared using these electron deficient enynes under either organocatalytic reaction conditions or sequential organocatalysis and metal catalysis (Figure ).…”

Synthesis of pyrano[2,3‐c]pyrazoles: A review

“…Research group of Chen and Singh have independently reported the use of N ‐substituted pyrazolinones 17 and nitroolefins 18 for asymmetric synthesis of chiral tetrahydropyrano[2,3‐c]pyazoles 19 , 20 having exocyclic double bonds using quinine/cinchona derived‐squaramide organocatalysts 15 , 16 in different reaction conditions (Figure 3) (Scheme 4). [ 29,30 ]…”