Preparation of tetrahydro-1H-xanthen-1-one and chromen-1-one derivatives via a Morita-Baylis-Hillman/oxa-Michael/elimination cascade

The Morita-Baylis-Hillman (MBH) reaction is a carbon-carbon bond forming transformation between an electrophile, typically an aldehyde, and an activated olefin. MBH adducts obtained from 2-hydroxy- benzaldehydes and cyclic enones are potential substrates for the synthesis of xanthenone and chromenone derivatives. In this work, we investigated conditions to obtain tetrahydro-1H-xanthen-1-ones and chromen- 1-ones directly via a Morita-Baylis-Hillman/oxa-Michael/elimination cascade catalyzed by a bifunctional, bicyclic imidazolyl alcohol (BIA), which proved to be an effective catalyst for this transformation. The reactions were performed at room temperature in water to give the products in 10-74 % yield

Unveiling the mechanism of N‐methylation of indole with dimethylcarbonate using either DABCO or DBU as catalyst

B.R.V.F., P.H.V. and M.N.E. acknowledge the São Paulo State Science Foundation (FAPESP) and the Brazilian National Science Council (CNPq) for financial support. L.A.Z. thanks CNPQ for his PhD scholarship (142476/2018-8), R.A.C. thanks SDumont and CESUP. M.B. thanks the School of Chemistry and EaStCHEM for support and for access to a computer cluster maintained by Dr. H. Früchtl.Depending on the catalyst used, N‐methylation of indole with dimethylcarbonate (DMC) ‐ an environmentally friendly alkylation agent – yields different products. With 1,4‐diazabicyclo[2.2.2]octane (DABCO), the reaction forms only N‐methylated indole but with or 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), both N‐methylated and N‐methoxycarbonylated indole are formed. Using direct ESI(+)‐MS monitoring to collect actual snapshots of the changing ionic composition of the reaction solution, we report on the interception and characterization of key intermediates for such reactions. Although a mechanism has been proposed with methoxycarbonylated base as the key intermediate for both DBU and DABCO, the ESI(+)‐MS data as well as B3LYP‐D3/6‐311+G** calculations suggest that the reaction of DMC with indole under either DABCO or DBU catalysis follow contrasting mechanisms.PostprintPeer reviewe

One-pot organocatalyzed synthesis of tricyclic indolizines

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone- derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends

Origin of the diastereoselectivity of the heterogeneous hydrogenation of a substituted indolizine

The authors are grateful to FAPESP for the financial support of this research. The authors also thank FAPESP for the fellowships to R.A.C. (#2018/03910-1) and F.C. (#2013/07600-3 and #2018/02611-3) and for a scholarship to H.S. (#2015/09205-0) and CNPq for a scholarship to L.A.Z. and a research fellowship for F.C, (307840/2014-0, 422890/2016-2 and 301330/2016-2). L.A.Z. also thanks Capes for a scholarship.In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto–enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity.Publisher PDFPeer reviewe

An Improved Method For The Regioselective Synthesis Of Highly Substituted Quinolines From Morita-baylis-hillman Adducts

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The synthesis of highly substituted quinolines was accomplished through a Heck reaction of substituted iodoanilines with Morita-Baylis-Hillman (MBH) adducts employing Najera N-oxime derived palladacycle as catalyst. The reaction is completely regioselective and gives the products with good to excellent yields (up to 89%) with low catalyst loading and TONs of up to 89. (C) 2015 Elsevier Ltd. All rights reserved.562228712874Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)RGCFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [FAPESP-2013/07600-3]FAPESP [FAPESP 2012/24783-1

Conformational signature of Ishikawa´s reagent using NMR information from diastereotopic fluorines

The active species of the Ishikawa´s reagent [N,N-diethyl-(1,1,2,3,3,3-hexafluoropropyl)amine] is a fluorinating hexafluoropropylamine used to convert alcohols into alkyl fluorides. On the other hand, it is also an example of model compound useful to probe conformational preferences using spectroscopic information from diastereotopic fluorines. Moreover, the possibility of experiencing both the generalized anomeric and gauche effects makes the Ishikawa´s reagent an ideal choice to study the governing stereoelectronic interactions of the conformational equilibrium of organofluorine compounds. The conformational equilibrium of the Ishikawa´s reagent was analyzed using NMR 3JH,F coupling constant data in different solvents, since the orientation of the diastereotopic fluorines relative to H-2 and F-2 changes with the medium. In nonpolar cyclohexane solvent, the preferred conformation experiences a weaker steric and electrostatic repulsion. The conformational behavior changes in the more polar pyridine solution, where the double fluorine gauche effect takes place, since F-2 is preferably gauche to both diastereotopic fluorines. An analysis of the rotation around the N–C(F2) bond indicates the manifestation of anomeric interactions (nN → σ*C–F), which can be demonstrated by means of 19F chemical shifts. The results were rationalized with the aid of theoretical calculations and natural bond orbital (NBO) analysis, allowing for the evaluation of competing steric, electrostatic and hyperconjugative interactions

1,6-Addition of Indolizines to para-Quinone Methides with Indium(III) Chloride as Catalyst

A 1,6-addition of a wide variety of indolizines to para-quinone methides was developed using only 2 mol% indium chloride as a catalyst. The method successfully allows the regioselective addition of indolizines at positions 1 and 3 to p-quinone methides, leading to the formation of the desired products in excellent yields in most cases (up to 99%) under mild conitions and in short reaction time

Palladium-mediated oxidative annulation of δ-indolyl-α,β-unsaturated compounds toward the synthesis of cyclopenta[b]indoles and heterogeneous hydrogenation to access fused indolines

The cyclopenta[b]indole moiety represents a key skeletal unit in several natural and synthetic compounds that exhibit diverse biological properties. We described herein a two-step sequence for synthesizing cyclopenta[b]indoles with great structural diversity in overall yields up to 37%. The key step was a palladium-catalyzed oxidative annulation of 3-alkylindoles (Fujiwara-Moritani reaction). The obtained cyclopenta[b]indoles were used as substrates in heterogeneous hydrogenation reactions to afford new fused indolines in moderate yields. An acid-catalyzed intramolecular cyclization of three such indolines gave tetracyclic lactams in 89, 90, and 61% yields84955645581CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP307840/2014-0; 422880/2016-22013/07600-3; 2013/10449-5; 2018/02611-

Origin of the diastereoselectivity of the heterogeneous hydrogenation of a substituted indolizine

In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto–enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity