Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• [55] under the same conditions as mentioned in Scheme 25. The presence of an alkyl group on the indole nitrogen led to a Heck cyclization instead of a cycloaminocarbonylation (Scheme 29). In 2019, two different groups independently reported a carbonylative cyclization of o-indolylarylamines. In

• ). The proposed mechanism, shown in Scheme 34, suggested that the process proceeded through a Pd(0) catalysis proceeding through first an intramolecular Heck reaction, followed by CO insertion, N-cyclization (anilines) or O-cyclization (phenols) and final reductive elimination. Carbonylative

• functionalization of indoles to 3-substituted indoles Functionalization through direct C–H alkoxycarbonylation The transition-metal-catalyzed carbonylation of aryl halides, triflates, and tosylates with carbon monoxide and an alcohol was first pioneered by Heck and co-workers in 1974 [64][65]. Since then, this

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• herein an enantioselective palladium-catalyzed Heck–Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation

• commercial drug baclofen as hydrochloride. Keywords: desymmetrization; enantioselective Heck–Matsuda reaction; lactam synthesis; N,N-ligands; palladium; Introduction Desymmetrization reactions consist in the modification of a molecule with the loss of one or more symmetry elements, such as those which

• complexity in a synthetic route. The palladium-catalyzed coupling of arenediazonium salts with olefins, the Heck–Matsuda reaction, has been instrumental in this strategy involving the desymmetrization of cyclic systems [3], especially five-membered substrates [4][5][6][7]. As we have demonstrated previously

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE). Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

• ]quinazolines (Scheme 2D) [40]. There are numbers of Ugi and subsequential Heck (or reductive Heck) reactions that have been developed for the synthesis of poly-heterocyclic compounds [43][44][45][46][47][48][49][50][51]. Reported in this paper is a one-pot Ugi-azide reaction followed by an intramolecular Heck

• used as the isocyanide source, the Ugi-azide reaction gives rise to ring-fused tetrazolo[1,5-a]pyrazin-6(5H)-one adducts 5. The subsequent Pd-catalyzed intramolecular Heck reaction of compounds 5 or 7 then affords 1,2,3,4-tetrohydroisoquinolines 6 and 8, respectively. Results and Discussion Following

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• crossover process [47][48][49][50]. However, activated alkyl halides are not suitable for these carboamination reactions due to the direct nucleophilic substitution of activated alkyl halides with nucleophilic reagents under the necessary alkaline conditions [51]. Recently, a Pd-catalyzed alkyl Heck

• allenes that were never used as substrates in interrupted radical Heck/allylic substitution reactions. As summarized in Scheme 3, unsaturated γ-AA derivatives were observed in this reaction albeit with poor stereoselectivity. Linear amines containing alkyl, hydroxy, and terminal alkenyl groups were

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• -bromo-4-iodotoluene with 1,1-diphenylethylene yields the desired 9-arylphenanthrene 28 via a Heck reaction followed by intramolecular C–H arylation (Scheme 6). However, partial conversion of the starting material was observed. The use of 3 equiv KOPiv and 3 equiv Cs2CO3 as a base mixture increased the

• -arylphenanthrenes 28–30 via Heck reaction followed by intramolecular C–H bond arylation The reaction of the 1,1-diphenylethylene (0.180 g, 1 mmol), 1,2-dihalobenzene (1.5 mmol), KOPiv (0.420 g, 3 mmol) and Cs2CO3 (0.978 g, 3 mmol) in the presence of PdCl(C3H5)(dppb) (30.5 mg, 0.05 mmol) at 150 °C during 16 h in DMA

• -dihalobenzenes. Pd-catalyzed Heck reaction followed by direct arylation of 1,1-diphenylethylene with 1,2-dihalobenzenes. Influence of the conditions on the Pd-catalyzed reaction of 1,8-dibromonaphthalene with 1,2,3,4-tetrafluorobenzene.a Supporting Information Supporting Information File 43: Characterization

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• phthalimidyl anion would generate the aminoalkylation product 119, completing the catalytic cycle. In addition to this aminoalkylation method, the synthetic utility of radical intermediates derived from NHPI esters under photoinduced Pd-catalysis has been demonstrated in Heck-type couplings [81][82] and in the

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• carried out with Cu. The aminocarbonylation reaction which was introduced by Schoenberg and Heck in 1974 is an efficient catalytic route to carboxamides [11]. It was a major step forward and has been amply applied in a number of carbonylation reactions over the years [12]. In 2011, Buchwald and

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• bioactive compounds and natural products such as PB1-5 [74], lixivaptan, and (+)-anthramycin (Figure 5) [73]. Stepwise synthesis of pyrrolo[2,1-a]isoquinolines A stepwise synthesis involving [3 + 2] cycloaddition, N-allylation and Heck reactions has been developed for the synthesis of pyrrolo[2,1-a

• Pd-catalyzed Heck reaction to give products 26 in 65–78% yields (Scheme 16) [75]. The pyrrolo[2,1-a]isoquinoline core installed by this route can be found in some natural products and synthetic compounds with antitumor, antibacterial, antiviral, antioxidizing, and other biological activities (Figure

Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions

• Aaron H. Shoemaker,
• Elizabeth A. Foker,
• Elena P. Uttaro,
• Sarah K. Beitel and
• Daniel R. Griffith

Beilstein J. Org. Chem. 2023, 19, 1615–1619, doi:10.3762/bjoc.19.118

• accessed from tropone (via its η4-diene complex with Fe(CO)3) in a short sequence of steps: 1) nucleophilic amine addition and subsequent Boc-protection, 2) photochemical demetallation of the iron complex, and 3) an intramolecular Heck reaction. Minor modifications to the protocol enabled access to the

• related 2-azabicyclo[4.4.1]undecane system, albeit in lower yield. Keywords: alkaloids; azabicycles; Heck reaction; iron complex; tropone; Introduction Azapolycycles are embedded within numerous biologically active alkaloids [1] and pharmaceuticals [2]. As such, novel approaches to the synthesis of

• ervitsine [10][11] (Figure 1). We reasoned that, with an appropriately functionalized amine side chain and properly disposed unsaturation on the seven-membered ring, an intramolecular Heck reaction could give rise to skeleton 4 in just a few steps from tricarbonyl(tropone)iron (Scheme 1). Herein, we report

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• interconvertible to each other by hydration or dehydration, i.e., a plausible precursor of the allylic alcohol would be the diene, and vice versa [90]. Since both 8 and 10 are easily obtainable from 2 by Mozoroki–Heck coupling with commercially available 2-methyl-3-buten-2-ol, ester hydrolysis (LiOH in THF/H2O

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• Heck cross-coupling [69][70]. However, researchers have developed various methods for the transition-metal-catalyzed C(sp2)–H olefination using various types of alkenes as coupling partners [71][72][73]. This part of the review covers reports for the alkenylation of pyridine with terminal alkynes

• functionalizations under ligand-controlled conditions are underexplored. Hence, differentiating from this co-coordinative model, in 2013, Zeng and co-workers [86] reported the MPAA (mono-N-protected amino acids) ligand-promoted non-chelate-assisted C–H activation via Pd-catalyzed dehydrogenative Heck reactions on

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• . Among these, Heck reaction conditions allowed for the coupling of aryl acrylates 50 to aryl halides 48 and 49, followed by intramolecular Pd-catalysed amination or etherification to give C-10 carboxylates of dibenzo[b,f]azepine 55 and dibenz[b,f]oxepine 54 in good yield (Scheme 11). However, no ring

• -substituted derivatives were reported. The authors used alpha-substituted acrylates to reduce the effect of poor endo/exo regioselectivity in the intramolecular Heck reaction (cf. Scheme 19). Božinović et al. [52] reported the synthesis of symmetrical 5H-dipyridoazepines 60a and unsymmetrical 5H

• –Heck coupling Whereas Arnold et al. [30] reported the preparation of dibenzo[b,f]heteropines via consecutive Heck and Buchwald–Hartwig reactions (Scheme 11), amination may also precede the introduction of the double bond (Scheme 17). The formation of the dibenzo[b,f]heteropine skeleton by means of a

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• -methylphenyl)benzothiophene-fused 2-hydroxy-1-oxa-2-phosphacycloundecane 2-oxide 36 in 83% yield (Scheme 7) [22]. 1.1.2 Synthesis via other C–C bond formations: The palladium-catalyzed intramolecular Heck arylation of 2-bromophenylmethyl alk-1-enylphosphinates 37 provides access to 4-alkylidene-1,4

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• Mizoroki–Heck reaction: construction of the [5-8] bicyclic ring system of brachialactone A study of the versatility of the Mizoroki–Heck reaction in an intramolecular version was recently described by Nishikawa to elaborate the eight-membered ring of brachialactone (7) (fusicoccane series) from an advanced

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• and the aromatic moieties present in these natural products and provided the common synthetic intermediate 70 (Scheme 6). The diverse tetracycles were accessed either via an intramolecular radical cyclization of the reduced congener 73 or through a Heck reaction of intermediate 71. Reaction of 73 with

• conditions of the Heck reaction to common scaffold 70 proved unsuccessful. Screening of several reaction conditions on different analogues led to the conclusion that reduction of the C8-carbonyl side and acetal deprotection to 71 are essential in order to create the 6/6/5/6-carbocycle in the presence of Pd2

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• produced as byproduct in the metathesis reaction. Some subsequent publications include the Pd-complex removal after a Suzuki coupling [126], a Heck catalyst retention with reverse boiling-point-order solvent exchange [127], and a membrane for recovery of the photocatalyst TBADT (tetrabutylammonium

Palladium-catalyzed solid-state borylation of aryl halides using mechanochemistry

• Koji Kubota,
• Emiru Baba,
• Tamae Seo,
• Tatsuo Ishiyama and
• Hajime Ito

Beilstein J. Org. Chem. 2022, 18, 855–862, doi:10.3762/bjoc.18.86

• transformations. Thus far, mechanochemical palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura [34][35][36][37][38][39][40][41][42][43][44][45][46][47], Buchwald–Hartwig [48][49][50][51][52], Sonogashira [53][54][55][56], Negishi [57], Mizoroki–Heck [58][59][60], and C–S bond-forming [61

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• flow conditions. In these reactions, the leaching of palladium was as low as 34 ppm for Suzuki–Miyaura reactions and 100 ppm for Heck reactions. Importantly, the functionalized nanoparticles could be reused several times without observing a decrease in catalytic activity. 3.2.4 Multistep processes: The

Cs₂CO₃-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

• Ol'ga G. Volostnykh,
• Olesya A. Shemyakina,
• Anton V. Stepanov and
• Igor' A. Ushakov

Beilstein J. Org. Chem. 2022, 18, 420–428, doi:10.3762/bjoc.18.44

• transformations. For example, bromoacetylenes were demonstrated to add imidazoles, imidazolines [12], and benzimidazoles [13][14] to give vinyl bromides. Sulfonamides reacted with bromoacetylenes to deliver N-bromovinyl-p-toluenesulfonamides that under Heck reaction conditions afforded N-(p-toluenesulfonyl

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• -phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1H-indol-2-yl)acetate in 55% yield. Keywords: anticancer; Fischer indole synthesis; Heck reaction; heterocyclic compounds; indolobenzazepines; latonduines; paullones; Introduction Indolobenzazepines are fused heterocyclic

• -oxobutanoate (Scheme 1). To construct scaffold C by route (a) we first tried to synthesize 3-(2-nitrophenyl)indole by Heck reaction of indole and o-iodo-nitrobenzene [25]. However, in this case we obtained an isomeric mixture of 3- and 2-(2-nitrophenyl)indole in a 3:1 molar ratio, quite difficult to separate

• by column chromatography. Protection of the indole nitrogen by an ethoxymethyl group (Scheme 2) and the use of protected indole 4 in the subsequent Heck reaction resulted in a significantly lower conversion of 22% vs 64% for the unprotected indole. However, the protection of the indole nitrogen atom

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• co-workers established a Heck/Kumada cross-coupling cascade to construct nitrogen and oxygen-containing cis-heterospirocycles 40 in high yield and diastereoselectivity with inexpensive Fe(acac)3 as the precatalyst (Scheme 8) [73]. Interestingly, this protocol was applicable to substrates bearing

AlBr₃-Promoted stereoselective anti-hydroarylation of the acetylene bond in 3-arylpropynenitriles by electron-rich arenes: synthesis of 3,3-diarylpropenenitriles

• Yelizaveta Gorbunova,
• Dmitry S. Ryabukhin and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2663–2667, doi:10.3762/bjoc.17.180

• way for the synthesis of compounds 2. These compounds can be alternatively obtained by a Pd-catalyzed Heck reaction of 3-arylpropenenitriles with iodoarenes [23] or by a Cu-catalyzed hydroarylation of 3-arylpropynenitriles with arylboronic acid [24][25]. There is one example of use of dicyanoacetylene

A visible-light-induced, metal-free bis-arylation of 2,5-dichlorobenzoquinone

• Pieterjan Winant and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 2315–2320, doi:10.3762/bjoc.17.149

• be a challenging endeavor. As conventional methods, e.g., the Heck reaction are incompatible with quinones [15], a large subset of research recently focused on radical-based CH-arylation reactions. In 2011, Baran published a seminal paper that relied on using a AgNO3/K2S2O8 induced homolytic

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• a reliable strategy in modern organic synthesis. Palladium-catalyzed cross-coupling reactions such as Mizoroki–Heck [5][6][7][8], Suzuki–Miyaura [9][10][11], Buchwald–Hartwig [12][13], Negishi [14][15], Migita–Stille [16], Sonogashira [17], among others [18][19][20], significantly changed the design

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90