Recent Syntheses of 1,2,3,4-Tetrahydroquinolines,  2,3-Dihydro-4(1H)-quinolinones and 4(1H)-Quinolinones  using Domino Reactions

Nammalwar, Baskar; Bunce, Richard A.

doi:10.3390/molecules19010204

Cited by 117 publications

(39 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the past few years, our efforts have focused on the development of atom-economical, 9,10 cost-efficient, and transition metal-free methods for the synthesis of a wide variety of biologically active structural motifs including benzazepines, 6 dihydro-quinolinones, 11 tetrahydroquinolinones, 12 1,3,4-oxadiazoles, 13 and pyrazoloquinolinones 14 among others. 12 Hence, we sought to develop an efficient route for nucleophilic addition of active methylene compounds as well as amines to electron deficient vinylarenes as a route to heterocycle precursors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nucleophilic additions to polarized vinylarenes

Gnanasekaran

Yoon

Bunce

2016

Tetrahedron Letters

View full text Add to dashboard Cite

a b s t r a c tThe addition of nucleophiles to the terminal double bond carbon of a styrene incorporating an electronwithdrawing group at the ortho or para position has been studied. The conditions for this transformation have been optimized and structural modifications to the substrate have been explored. The structural changes included variation of the activating group on the aromatic ring and positioning substituents on the side chain double bond. The study revealed that nitro substitution gave the best results for addition of carbon and nitrogen nucleophiles. Cyano-substituted systems added carbon nucleophiles, but underwent polymerization or degradation with nitrogen nucleophiles. Ethoxycarbonyl-bearing substrates reacted primarily at the ester carbonyl. The reaction generally proceeded well with methyl on the a carbon of the double bond, but was slowed by methyl at the b position. The yields varied from 50% to 97% for 22 examples.Ó 2016 Elsevier Ltd. All rights reserved.Carbon-carbon and carbon-nitrogen bond formations by Michael 1,2 and S N Ar 3,4 reactions have been important synthetic tools for many years. The Michael reaction involves the addition of a nucleophile to a double bond polarized by conjugation with an electron-withdrawing group and is facilitated by stabilization of the intermediate anion a to the polarizing group. The S N Ar typically involves displacement of an aryl-bound halide by a nucleophile via an addition-elimination mechanism, which is possible when a strong electron-withdrawing group is situated ortho or para to the halide. This process is assisted by delocalization of the negative charge toward the activating group on the aromatic ring in a Meisenheimer complex. In the current reaction, we have explored the addition of nucleophiles to several vinylarenes (styrenes) bearing strong electron-withdrawing groups on the aromatic ring. The effect is to polarize the double bond such that addition of a nucleophile can take place at the side chain double bond terminus. The resulting anion is then stabilized in a Meisenheimer-like complex by delocalization into the aromatic ring.To date, only one report 5 has appeared describing nucleophilic additions to electron deficient styrene double bonds. In this account, the addition of malonate to 2-and 4-nitrostyrene using sodium ethoxide in alcohol (equilibrating conditions) gave moderate yields (72% and 45%, respectively) of the single addition products, and in the latter case, a substantial quantity (34%) of the double addition product. We recently utilized this reaction to prepare 1a, which was converted, using iron in acetic acid, to the ring-fused synthetic building block (±)-ethyl 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-carboxylate (2), but the overall efficiency suffered due to the modest yield of the initial transformation (Fig. 1). 6 Beyond this application, the possible addition of amines to these systems could have potential for the preparation of CDC25 phosphatase inhibitor analogues, such as 3, for the treatment of cancer. 7,8 Th...

show abstract

Section: Introductionmentioning

confidence: 99%

“…12 Hence, we sought to develop an efficient route for nucleophilic addition of active methylene compounds as well as amines to electron deficient vinylarenes as a route to heterocycle precursors. Nucleophiles do not normally react with styrene double bonds.…”

Section: Introductionmentioning

confidence: 99%

Nucleophilic additions to polarized vinylarenes

Gnanasekaran

Yoon

Bunce

2016

Tetrahedron Letters

View full text Add to dashboard Cite

show abstract

“…Our synthetic methods program has recently been focused on the use of nucleophilic aromatic substitution (S N Ar)-terminated domino reactions as a means to prepare heterocyclic compounds [1,2,3,4]. The current project has developed a synthesis of 1-aryl-1 H -indazoles, which are core ring structures in a broad range of biologically active compounds (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

2018

Self Cite

View full text Add to dashboard Cite

An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (SNAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the SNAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation.

show abstract

“…Salsolinol (4), 1-methyl-6,7-dihydroxy-THIQ and its N-methyl-derivative (5) have been identified as endogenous neurotoxins to dopamine neurons [12]. A diverse substitution pattern with respect to 2 on the phenyl ring as in the Cactaceae alkaloids arizonine (6) and gigantine (7) may cause unspecific toxic effects involving the central nervous system [30]. More complex structures, such as protoberberine-type alkaloids (8), display high antiviral activities, but they are also very active against acetylcholinesterase [23].…”

Section: Introductionmentioning

confidence: 99%

“…The 1,2,3,4-tetrahydroisoquinoline (THIQ) skeleton is an important structural motif commonly encountered in naturally-occurring alkaloids of vegetal origin with interesting biological/pharmacological properties, including inhibition of cell proliferation/anticancer activity [1], multiple cardiovascular activities related to different mechanisms of action [2][3][4], anti-inflammatory [5], antimicrobial [6,7], antiplasmodial activities [8,9] and acetylcholinesterase inhibitory effects [10,11]. A variety of THIQ derivatives has been found also in mammals, especially in human brain, suggesting a role of these molecules in neurons under physiological and pathological conditions [12].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of C3/C1-Substituted Tetrahydroisoquinolines

et al. 2015

View full text Add to dashboard Cite

Abstract:A broad biological screening of the natural alkaloid N-methylisosalsoline (2) extracted from Hammada scoparia leaves against a panel of human and parasitic proteases revealed an interesting activity profile of 2 towards human 20S proteasome. This outcome suggests that the 1,2,3,4-tetrahydroisoquinoline skeleton may be exploited as a template for the development of novel anticancer agents. In this article, we report the synthesis and chemical characterization of a new series of isosalsoline-type alkaloids (10-11) with variations at N2 and C3 positions with respect to the natural Compound 2, obtained by a synthetic strategy that involves the Bischler-Napieralski cyclization. The substrate for the condensation to the tetrahydroisoquinoline system, i.e., a functionalized β-arylethyl amine, was obtained through an OPEN ACCESSMolecules 2015, 20 14903 original double reduction of nitroalkene. The synthetic strategy can be directed to the construction of highly substituted and functionalized 1,2,3,4-tetrahydroisoquinolines.

show abstract

Recent Syntheses of 1,2,3,4-Tetrahydroquinolines, 2,3-Dihydro-4(1H)-quinolinones and 4(1H)-Quinolinones using Domino Reactions

Cited by 117 publications

References 117 publications

Nucleophilic additions to polarized vinylarenes

Nucleophilic additions to polarized vinylarenes

Syntheses of 1-Aryl-5-nitro-1H-indazoles and a General One-Pot Route to 1-Aryl-1H-indazoles

Synthesis of C3/C1-Substituted Tetrahydroisoquinolines

Contact Info

Product

Resources

About