Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet–Spengler reaction

• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2023, 19, 991–997, doi:10.3762/bjoc.19.74

• Elena Y. Mendogralo Maxim G. Uchuskin Perm State University, Bukireva st. 15, Perm, 614990, Russian Federation 10.3762/bjoc.19.74 Abstract A semi-one-pot method for the synthesis of 4-substituted tetrahydrofuro[3,2-c]pyridines by the Pictet–Spengler reaction was developed. The method is based on

• of some of the products was investigated and selected synthetic transformations of the obtained tetrahydrofuro[3,2-c]pyridines were shown. Keywords: acid hydrolysis; 1,4-diketone; tetrahydrofuro[3,2-c]pyridines; Paal–Knorr reaction; Pictet–Spengler reaction; Introduction Hydrogenated furo[3,2-c

• rearrangement to a more stable benzhydryl-type cation resulting in the formation of isomeric products. In an alternative group of methods, more accessible 2-substituted furans are used as starting compounds. For example, a construction of tetrahydrofuro[3,2-c]pyridines based on the Pictet–Spengler reaction [17

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• and co-workers reported that the ring closure of the Pictet−Spengler reaction between 2-(1H-indol-4-yl)ethanamine (10) and secologanin (11) in potassium phosphate buffer (KPi) at 70 °C regioselectively took place at the indole C3 position, resulting in unstable 4β-(R)-1H-azepino[3,4,5-cd

• tolerates a variety of substituents in both 22 and 23. From a mechanistic point of view, the reaction proceeds through a domino azomethine ylide formation/allylation/Pictet–Spengler reaction sequence. Recently, An and Xiao and co-workers disclosed high-yielding syntheses of a wide range of indole-3,4-fused

• [4,3,2-cd]indoles via indole C3 regioselective aza-Michael addition/cyclization/dehydration sequence. Indole C3 regioselective Pictet−Spengler reaction of 2-(1H-indol-4-yl)ethanamines. Indole C3 regioselective hydroindolation of cis-β-(α′,α′-dimethyl)-4′-methindolylstyrenes. Indole C3 regioselective

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• relationships in this chemotype. Keywords: acyl Pictet–Spengler reaction; alkaloids; antiproliferative activity; benzyltetrahydroisoquinolines; ion channels; protective group; total synthesis; Introduction The benzylisoquinoline alkaloids are a large and diverse class of plant secondary metabolites including

• arylacetaldimines of phenylethylamines [2] (Figure 1). Especially the Pictet–Spengler reaction has attracted considerable interest in chemistry and drug development in recent years, and modern methods like enantioselective approaches, organocatalysis, and enzymatic methods have been introduced by numerous groups [3

• [15]. In this work we took advantage of the hitherto less explored N-acyl-Pictet–Spengler reaction and related chemistry based on the seminal work of Speckamp [16], where an N-acyl residue at the arylethylamine building block leads to enhanced cyclization rates due to the acid-mediated formation of

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• -workers reported in 2004 an asymmetric Pictet–Spengler reaction of tryptamine-derived imines 4 in the presence of acetyl chloride and 2,6-lutidine, where the chiral thiourea catalyst 6 was employed to enable good yields and enantioselectivities (Scheme 2a) [32]. The initial motivation of their first

• HCl co-catalyzed oxa-Pictet–Spengler reaction employing bisthiourea catalyst 72 bearing two aliphatic groups at one of the nitrogen atoms of one thiourea (Scheme 15) [51]. The key intermediate in this reaction system is the contact ion pair of the thiourea catalyst with the in situ-generated

• participating directly as the nucleophile. First proposed anion-binding mechanism in the thiourea-catalyzed acetalization of benzaldehyde. a) Thiourea-catalyzed enantioselective acyl-Pictet–Spengler reaction of tryptamine-derived imines 4. b) Equilibrium between the ionic (SN1-type mechanism) and neutral form

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• alkaloid ingenine B [20]. The iodine-catalyzed [3 + 3] cycloaddition of indolyl alcohol to enaminones [21] and the thiourea-catalyzed iso-Pictet–Spengler reaction of isotryptamine with aldehydes [22], are some noteworthy contributions to the field. A cascade or domino reaction is an interesting approach

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• oxidative dehydrogenation in the synthesis of β-carboline natural products norharmine (111), harmane (112) and eudistomin U (113) [101]. The general synthetic scheme involved the synthesis of the respective tetrahydro-β-carboline precursors of the said natural products by Pictet–Spengler reaction of

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• developed another CPA-catalyzed three-component cascade Michael/Pictet–Spengler reaction of 3-indolylmethanols and azomethine ylides, in which isatins were used in place of aldehydes (Scheme 55) [72]. Based on this method, they obtained structurally novel and complex bisspirooxindoles in excellent

Synthesis of constrained analogues of tryptophan

• Elisabetta Rossi,
• Valentina Pirovano,
• Marco Negrato,
• Giorgio Abbiati and
• Monica Dell’Acqua

Beilstein J. Org. Chem. 2015, 11, 1997–2006, doi:10.3762/bjoc.11.216

• from the biological evaluation to the chemistry of tryptophan analogues, the above described two categories were synthesized according to the Pictet–Spengler reaction or by Fischer indole synthesis [11][12][13][14]. However, Fischer indolization suffers from the lack of regioselectivity depending on

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• analogues. The α-methoxy cyclic amines were treated with tryptamine (or analogues) and a camphorsulfonic acid (CSA)-mediated Pictet–Spengler reaction afforded the desired Nazlinine and structural variants in one pot. Conclusion In this review article we have highlighted the scope of the Shono-type

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• oxa-Pictet–Spengler reaction from 2,6-dihydroxybenzoic acid 173 and ketal aldehyde 174 as key building blocks (Figure 10). The 2,6-dihydroxybenzoic acid 173 is accessible by opening of epoxide 175 as chiron with a suitable nucleophile. The ketal aldehyde 174 would be derived from butenolide 176

• with DIBAL-H gave ketal aldehyde 181, which was then condensed with 2,6-dihydroxybenzoic acid 173 in a oxa-Pictet–Spengler reaction to form the tetracyclic core of berkelic acid. Treatment of the obtained tetracyclic salicylic acid with allyl bromide and desilyation with TBAF/AcOH provided 182. The

First synthesis of meso-substituted pyrrolo[1,2-a]quinoxalinoporphyrins

• Dileep Kumar Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2014, 10, 808–813, doi:10.3762/bjoc.10.76

• ]quinoxalinoporphyrins; Pictet–Spengler reaction; synthesis; Introduction Many natural porphyrins are known to play essential roles in a number of biological processes including oxygen transport [1], solar energy conservation [2][3][4] and photosynthesis [5]. Owing to the expanded π-conjugation system as well as good

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• –Spengler reaction of dopamine (99) with 4-hydroxyphenylacetaldehyde (100), both derived from L-tyrosine (98) (Scheme 11). After oxidation and O-methylation, which is carried out by S-adenosylmethionine (SAM), (S)-reticuline (101) is obtained. Oxidation of the N-methyl group to the iminium ion and

• ], the isoquinoline nuevamine (96) [77] and the benzazocine magallanesine (97) [79] were isolated from different Berberidaceae species (Figure 6). Chilenine (93) was the first isoindolobenzazepine alkaloid isolated from Berberis empetrifolia in 1982. The biogenesis proceeds most likely via a Pictet

Mild and efficient cyanuric chloride catalyzed Pictet–Spengler reaction

• Ashish Sharma,
• Mrityunjay Singh,
• Nitya Nand Rai and
• Devesh Sawant

Beilstein J. Org. Chem. 2013, 9, 1235–1242, doi:10.3762/bjoc.9.140

• Pictet–Spengler reaction catalyzed by cyanuric chloride (trichloro-1,3,5-triazine, TCT) is described. The 6-endo cyclization of tryptophan/tryptamine and modified Pictet–Spengler substrates with both electron-withdrawing and electron-donating aldehydes was carried out by using a catalytic amount of TCT

• (10 mol %) in DMSO under a nitrogen atmosphere. TCT catalyzed the Pictet–Spengler reaction involving electron-donating aldehydes in excellent yield. Thus, it has a distinct advantage over the existing methodologies where electron-donating aldehydes failed to undergo 6-endo cyclization. Our methodology

• provided broad substrate scope and diversity. This is indeed the first report of the use of TCT as a catalyst for the Pictet–Spengler reaction. Keywords: β-carboline; cyanuric chloride; 6-endo cyclization; Pictet–Spengler; TCT; Introduction The Pictet–Spengler reaction is an important class of name

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• synthesis of peptidomimetic 1a (Scheme 1). Starting from L-tryptophan methyl ester and N-Cbz-aminoacetaldehyde dimethyl acetal [43], tetrahydro-β-carboline 2 was obtained in good yield and high diastereoselectivity (dr 70% from 1H NMR) by means of Pictet–Spengler reaction [44] and subsequent chromatographic

Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

• Piyush K. Agarwal,
• Meena D. Dathi,
• Mohammad Saifuddin and
• Bijoy Kundu

Beilstein J. Org. Chem. 2012, 8, 1901–1908, doi:10.3762/bjoc.8.220

• oxidized product (Scheme 5). After successfully establishing the strategy on 2a-c, we then decided to replace the indole nucleus by another activated nucleus such as trimethoxy- and dimethoxybenzene and designed a substrate 18 (Scheme 6) for the Pictet–Spengler reaction using a similar approach as was used

• on natural products. Structure of meridianins A–G. Synthesis of functionalized meridianin with an amino group at position 5. Synthesis of a functionalized meridianin with an amino group at position 5. Synthesis of substrate for the modified Pictet–Spengler reaction. The Pictet–Spengler reaction

• involving substrate 2a. Reagents and conditions: (i) RCHO, 2% triflic acid in DMF, 120 °C, 16 h. Synthesis of dihydropyrimido-β-carbolines: (i) R-CHO, 2% triflic acid in DMF, 120 °C, 16 h. Synthesis of substrates 18a–c for the modified Pictet–Spengler reaction. General strategy for the Pictet–Spengler

Synthesis and in silico screening of a library of β-carboline-containing compounds

• Kay M. Brummond,
• John R. Goodell,
• Matthew G. LaPorte,
• Lirong Wang and
• Xiang-Qun Xie

Beilstein J. Org. Chem. 2012, 8, 1048–1058, doi:10.3762/bjoc.8.117

• } under acidic conditions to produce the corresponding products in yields ranging from 54–89%. A range of aldehydes were accommodated in the Pictet–Spengler reaction, including formaldehyde (Table 1, entry 1), alkyl aldehydes (Table 1, entries 2 and 3), aryl aldehydes with electron-withdrawing and

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• methyl ester to form the indolopiperidine motif 135 via a Pictet–Spengler reaction followed by a double condensation to install the additional diketopiperazine ring (Scheme 28) [38][39]. To achieve the high levels of cis selectivity required from the Pictet–Spengler reaction, an extensive investigation

A short synthesis of (±)-cherylline dimethyl ether

• Bhima Y. Kale,
• Ananta D. Shinde,
• Swapnil S. Sonar,
• Bapurao B. Shingate,
• Sanjeev Kumar,
• Samir Ghosh,
• Soodamani Venugopal and
• Murlidhar S. Shingare

Beilstein J. Org. Chem. 2009, 5, No. 80, doi:10.3762/bjoc.5.80

• moderate yield. Immediate reduction of the isocyanate 10 by lithium aluminium hydride in tetrahydrofuran gave N-methylamine 6 in 90% yield. The crude amine 6, on Pictet–Spengler reaction with formaldehyde in acetic acid, gave (±)-cherylline dimethyl ether [15] 5 in 45% yield. In short, we have devised a