A Novel Solid-Phase Synthesis of Carboxypyrrolinones

Abstract

A solid-phase organic synthesis method has been developed for the preparation of 3-carboxypyrrolinones 9. Treatment of polymer-bound malonic acid with amino alcohols afforded the malonamide resin products 6. Benzyl and alkyl amino alcohols were prepared in solution via a two-step procedure without purification and were coupled to the resin directly using a resin capture strategy. Polymer loadings and product conversions were determined by direct cleavage of resin-bound materials and analysis by 1H NMR spectroscopy with an internal standard. Treatment of the polymer-bound malonamides with TFA released the malonamic acids, 10, which underwent further reaction to afford the trifluoroacetate derivatives 11. Secondary amides underwent an additional cyclization to afford oxazoles 12. The malonamide resins 6 can be oxidized to the corresponding ketones 7 by treatment with CrO2(O-t-Bu)2, which can in turn be cyclized in the presence of LDA or LHMDS to afford the carboxypyrrolinones 8. TFA treatment releases the free carboxypyrrolinones, 9, in 43−80% overall yield.

Recent development in the synthesis of pyrrolin‐4‐ones/pyrrolin‐3‐ones

“…TFA is found to be an active additive in the reaction with increases the yield of 64a-i. R 1 = Me,R 2 = CO 2 Me, R 3 = Me,97%, 3E/3Z(%): 100/0 R = -(CH 2 ) 5 -, R 1 = Me,R 2 = CO 2 Me, R 3 = Me,95%, 3E/3Z(%): 100/0 R = -(CH 2 ) 5 -, R 1 = Ph, R 2 = CO 2 Me, R 3 = Me,99%, 3E/3Z(%): 0/100 R = Et, R 1 = Me,R 2 = H, R 3 = Et,98%, 3E/3Z(%): 20/80 R = -(CH 2 ) 5 -, R 1 = Me,R 2 = H, R 3 = Et,95%, 3E/3Z(%): 35/65 R = Et, R 1 = Me,R 2 = CO 2 Me, R 3 =Me,6%, --R = -(CH 2 ) 5 -, R 1 = Ph, R 2 = CO 2 Me, R 3 =Me,56%, --R = Et, R 1 = Me,R 2 = CO 2 Me, R 3 =Me,34%, --R = Et, R 1 = Me, R 2 = CO 2 Me, R 3 =Me,56%, --R = Et, R 1 = Me, R 2 = CO 2 Me, R 3 =Me,73%, --R = -(CH 2 ) 5 -, R 1 = Me,R 2 = CO 2 Me, R 3 This cyclization reaction displays high functional group tolerance and represents a useful methodology for the rapid synthesis of substituted pyrrolin-4-ones 64a-i in higher yields. Enamino amides 63 with a variety of functionality, viz methyl, ethyl, phenyl, and benzyl substituents at the nitrogen atom are well tolerated and exhibit more reactivity as compared to N-unsubstituted enamino amide 63a.…”

“…a, R 1 = H, R 2 = H, R 3 = CO 2 Me,79% b, R 1 = CH 3 , R 2 = H, R 3 = CO 2 Me,88% c, R 1 = Cl, R 2 = H, R 3 = CO 2 Me,87% d, R 1 = H, R 2 = Cl, R 3 = CO 2 Me,74% e, R 1 = OCH 3 , R 2 = H, R 3 = CO 2, 75% f, R 1 = H, R 2 = CH 3, R 3 = CO 2 Me,80% g, R 1 = H, R 2 = H, R 3 = H,79% h, R 1 = CH 3 , R 2 = H, R 3 = H, 88% i, R 1 = Cl, R 2 = H, R 3 30% aqueous H 2 O 2 promoted tandem reactions with variety of both aliphatic or aromatic amines (Scheme 41). 29 Sha et al explored the asymmetric synthesis of 1Hpyrrol-3(2H)-ones 108 using 2,3-diketoesters 105 via combination of aldol condensation and benzilic acid rearrangement.…”

“…Pyrrolin-4-ones/pyrrol-3-ones are prevalent in a vast variety of pharmaceutical active molecules, biologically important natural products, and a variety of vital materials having immense applications. [1][2][3] Functionalized pyrrolin-3/4-ones have received incredible attention, as privileged N-heterocycles, in the development of various molecules having anticancer, antithrombotic, and antimalarial activities. 4,5 The pyrrolin-4-ones are also valuable intermediates in the development of functionalized pyrrolidines and other natural products.…”

In Situ Generated TEMPO Oxoammonium Salt Mediated Tandem Cyclization of β-Oxoamides with Amine Hydrochlorides for the Synthesis of Pyrrolin-4-ones

“…Pyrrolin-4-ones are prevalent in many pharmaceuticals, biologically active natural products, and materials. − Compounds belonging to this class have consequently received remarkable attention as privileged N -heterocycle building blocks, with particular emphasis on the development of potential drugs with interesting biological activities, such as anticancer, antithrombotic, and antimalarial agents . Various synthetic methods have been developed for the construction of pyrrolin-4-one scaffolds, including the transition-metal-catalyzed/mediated cycloisomerization of 1-amino ynones and the dimerization of enaminones or α-diazo-β-oxoamides. , Dong, Guan and other groups recently reported three novel approaches to a series of substituted pyrrolin-4-ones using α-diazo-β-oxoamides and enaminones as starting materials .…”

Solid Phase Synthesis of Substituted 2-Amino-4-Pyrrolinones via Spontaneous Postcleavage Cyclization

“…6 Functionalized derivatives of carboxypyrrolinones, compounds of similar structure to known chemical hybridizing agents, have been prepared using a combination of solution phase and solid phase techniques. 7 The pyrrolinone scaffold has been extensively used in the development of nonpeptidyl peptidomimetics 8 and optically active 3-pyrrolin-2-ones are important synthons for the preparation of various biologically active compounds. 9 The interesting and variable biological activities of compounds containing the 2-substituted-4-pyrrolinone moiety prompted us to develop a new versatile route for the synthesis of optically active pyrrolinones bearing a variety of substituents at positions 2, 3 and 5.…”