Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• the decomposition of the second TBHP molecule to tert-butylperoxy radical B. Further, radical A abstracts a hydrogen atom from the starting alcohol 120 to form the α-hydroxy carbon radical C, which added to enyne 119 to form the C-centered radical D. Recombination of radical D with the tert

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• developments and illustrates the influences of copper salt, ligand, and substitution pattern of the substrate on the regioselectivity and stereoselectivity. Keywords: copper-catalysis; copper vinyl allenylidene intermediate; 1,3-enyne; 1,4-enyne; yne-allylic substitution; Introduction Copper is earth

• catalytic center; finally, the selectivity affording E-enyne and Z-enyne product is also an issue to be addressed, and possible side reactions need to be suppressed (Scheme 2). In this review, we summarize the recent development of copper-catalyzed yne-allylic substitutions. It is worth noting that when we

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

• Yukiko Karuo,
• Keita Hirata,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• previous study by Thorand [44], we performed the reaction between fluorine-containing vinyl ether 1a and 1.05 equiv of trimethylsilylacetylene (5a) to afford the corresponding enyne 3a in 55% yield (Table 2, entry 1). Cross-coupling utilizing a palladium(II) catalysts containing phosphine ligands produced

• , respectively, in high yields without byproduct formation (Table 4, entries 15 and 16). Enyne compound 5r and 3-butyn-1-ol 5s also participated in cross-coupling reactions and products 3r and 3s could be obtained in moderate yields of 52 and 53% (Table 4, entries 17 and 18). Then, we attempted the cross

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• ether 39, a ring-closing enyne metathesis (RCEYM) was initiated using the Grubbs second-generation catalyst (G-II) and high temperature to obtain the spiro 2,5-dihydrofuran derivative 40 in 76% yield. Additionally, when a dienophile such as N-phenylmaleimide was directly added to the same pot and

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• IPrAuCl [35]. In arylative cyclisations incomplete reaction was seen with enyne 19 [8][37] but ynone 22 [39] afforded high yield of 24. A quantitative conversion was seen in the intramolecular arylative cyclisation of 25 where 13 outperformed IPrAuCl [36]. Conclusion An L-shaped NHC ligand motif, AImOx

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

• conditions, affording product 61 [60]. On the other hand, reaction with 1,7-enyne 62 affords dihydroquinolinone product 63 via a cascade radical addition/cyclization process [61]. In both transformations, HE serves a dual role by activating the NHPI ester through EDA complex formation and providing a

• 65. Addition of radical 64 to enyne 62 followed by 6-exo-dig cyclization yields radical intermediate 66. Finally, species 65 acts as a hydrogen atom donor, delivering product 63 while forming pyridine 67 as a byproduct. A similar mechanism would in principle account for EDA-complex-mediated Giese

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• -butyldimethylsilyl-protecting group resulted in the corresponding 1,5-enyne only being produced in a 33% yield. Several different norbornene derivatives were explored and gave the anticipated exo,exo-difunctionalized product in good yield. In contrast, when using an ethylene-bridged bicycloalkene to generate the

• the 1,6-enyne 194a producing 196 which undergoes an oxidative cyclization leading to 197. Subsequent β-hydride elimination forms 198 which side-on coordinates with azabenzonorbornadiene 30c forming 199. Migratory insertion of the olefin followed by reductive elimination of the hydride affords the

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

• toluene in the presence of G-II catalyst and provided tetracyclic compound 96 with 50% yield. In this case, the RCM involved a terminal diene and a disubstituted diene. Further oxidation of the secondary alcohol furnished naupliolide (97). 1.2 Enyne ring-closing metathesis The enyne ring-closing

• process [4][8][10]. In 2008, Patrick et al. investigated the access to bicyclic structure 100 mimicking the A-B ring system of the fusicoccane series (Scheme 17) [49]. Starting from lactone 98, enyne 99 was prepared in 23 steps. The EYRCM was planned at the final stage allowing an access to compound 100

• that a less-hindered olefin facilitated the second enyne metathesis of this tandem reaction. The same strategy was applied for the synthesis of the variecolin [5-8-6-5] skeleton (Scheme 20). Dienynes 112 and 113 were first prepared from methyl ketone 111 and subsecuently submitted to the metathesis

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• enynes 25a–e in yields up to 77%. Unfortunately, in the case of nitro-substituted enyne 25d only 4% were isolated due to rapid decomposition and instability issues (Table 1, entry 4). With enynes 25a–e in hand, the influence of solvent, reaction temperature, time, and Pd source on the hydrozirconation

• towards both electron-donating and electron-withdrawing substituents on the phenyl group of the enyne 25. The reaction of 4-methylphenylenyne 25b with benzoyl chloride (26a, Table 4, entry 20) led to the desired product 27ba in only 9% yield. With 4-chlorophenylenyne 25c as well as 4-nitrophenylenyne 25d

• , 17% and 10% yield of product were obtained, respectively (Table 4, entries 21 and 22). In contrast, aliphatic enynes showed promising results. Due to their high volatility, we limited the following experiments to enyne 25e with a long alkyl chain. Reaction of 25e with benzoyl chloride (26a) gave 34

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• functional transformation from 10, which itself would be prepared through methylation and conjugate addition from Pauson–Khand adduct 11. This cyclopentenone could be readily accessed from 1,7-enyne 12 which could be obtained through the reported procedure [35] from the commercially available 5-hexenoic acid

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• . The convergent synthetic strategies feature the utilization of Au(I)-catalyzed cycloisomerizations of a 1,5-enyne and alkynyl ketone substrates, which were prepared by Sonogashira coupling reactions. Keywords: benzo[c]phenanthridine alkaloids; 1,5-enyne; formal total synthesis; gold catalysis

• ) and tert-butyldimethylsilyl chloride (TBSCl) (Scheme 5). To find the best cycloisomerization conditions, the 1,5-enyne substrate 10 was subjected to different reaction conditions as listed in Table 1. It was observed that [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) chloride (IPrAuCl

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• functionalized enyne structure that will be useful in various molecular transformations [27][28][29]. On the basis of a previous report, Sonogashira cross-coupling of 2 with trimethylsilylacetylene was performed with a bis(triphenylphosphine)palladium(II) dichloride. The reaction proceeded smoothly to give

• highly functionalized 7 in 80% yield. Compound 7 contains an enyne motif with both haloalkene and alkenyl ether moieties. Conclusion We have developed a simple method for constructing 1-fluoro-2-bromo-2-chloroalkenyl ethers (2a–p) in moderate to good yields via reactions of phenols and halothane in the

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

• the 1,6-enyne 35 followed by reductive elimination of the carbon nucleophile 38. Interestingly, this reaction proceeds via the cleavage of heteroelements and activated C–C bonds prior to reductive elimination of the metallacyclic ate-complex, resulting in the net formation of two new C–C bonds

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• , Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, 92 Aiguo Road, Nanchang, Jiangxi, 330006, China 10.3762/bjoc.17.163 Abstract Great progress has been made in the tandem annulation of enynes in the past few years. This review only presents the corresponding reactions of 1,3-enyne

• introduce the applications of the products and the reaction mechanisms for the synthesis of corresponding N-heterocycles. Keywords: 1,3-enyne; functionalization; pyridine; pyrrole; tandem annulation; Introduction The pyridine moiety is an important class of six-membered N-heterocycles that is widely found

• powerful nitrogen source for the synthesis of various N-heterocycles, such as isoquinolines, quinolines, pyridines, pyrroles, indoles, azoles, and azepines [40][41][42][43][44][45]. 1,3-Enyne, as a powerful Michael acceptor, is a wonderful synthon for the synthesis of N-heterocycles via tandem addition and

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• )2-catalyzed hydroxylative carbocyclization of 1,6-enyne 156 (Scheme 45) [104]. It was observed that from 1,7-enynes, six-membered rings were formed in low to moderate yield while from 1,8-enynes, uncyclized hydrated products were isolated. as major products along with different byproducts. In a Hg

• acids and alcohol to furan, pyran, and spirocyclic derivatives. Hg(II)-salt-mediated cyclization of 1,4-dihydroxy-5-alkyne derivatives. Six-membered morpholine derivative formation by catalytic Hg(II)-salt-induced cyclization. Hg(OTf)2-catalyzed hydroxylative carbocyclization of 1,6-enyne. a) Hg(OTf)2

• -catalyzed hydroxylative carbocyclization of 1,6-enyne. b) Proposed mechanism. a) Synthesis of carbocyclic derivatives using a catalytic amount of Hg(II) salt. b) Proposed mechanism for dihydronapthanene formation. Cyclization of 1-alkyn-5-ones to 2-methylfuran derivatives. Hg(NO3)2-catalyzed synthesis of 2

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• value of the newly synthesized fragment (+)-82b (see Scheme 12) had a similar magnitude but opposite in sign to that reported by Hatakeyama previously [22]. Thus, the absolute stereochemical assignment of enyne (+)-82b was revised as (3R), which contradicted Hatakeyama’s postulated (3R) configuration of

• enyne (−)-82b (Scheme 10) [22]. Hence, this new total synthesis has claimed to reinstate the originally formulated Zeeck–Taylor (3R)-stereostructure [2][21] for inthomycin C ((+)-3), R. J. K. Taylor’s total synthesis (Scheme 6) and disputes Ryu and Hatakeyama’s (3S)-stereochemical revision of inthomycin

• synthesis of inthomycin A ((+)-1). In the beginning, conversion of enyne 127 to the corresponding (Z,E)-dienylboronic ester 128 was investigated in the presence of rhodium(I)-catalyzed anti-selective hydroboration [72] under several conditions. Unfortunately, the yield of the desired (Z,E)-128 was found to

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• subsequent treatment with Waser’s reagent 116 [61] afforded alkyne 117 in 62% yield over two steps. Enyne 118, which was prepared in two steps from 117, was subjected to rhodium-catalyzed intramolecular [3 + 2] cycloaddition in the presence of carbon monoxide to give tricycle 119 bearing the desired vicinal

• 2017 and 2018, respectively, featuring the rhodium-catalyzed intramolecular [3 + 2] cycloaddition as the key reaction (Scheme 9B and Scheme 9C). Enyne 123, which was prepared from enone 122 in four steps, was subjected to the rhodium-catalyzed intramolecular [3 + 2] cycloaddition under carbon monooxide

• the desired alcohol 133 in 75% yield as a single diastereomer. Allylic oxidation of freshly prepared 133 with SeO2 followed by silylation with TBSOTf/Et3N afforded enyne 134. Enyne 134 was subjected to rhodium-catalyzed intramolecular [3 + 2] cycloaddition with a catalytic amount of [Rh(cod)OH]2 to

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans

• Viola Kolaříková,
• Markéta Rybáčková,
• Martin Svoboda and
• Jaroslav Kvíčala

Beilstein J. Org. Chem. 2020, 16, 2757–2768, doi:10.3762/bjoc.16.226

• ., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic 10.3762/bjoc.16.226 Abstract The prochiral 4-(allyloxy)hepta-1,6-diynes, optionally modified in the positions 1 and 7 with an alkyl or ester group, undergo a chemoselective ring-closing enyne metathesis yielding racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H

• -pyrans. Among the catalysts tested, Grubbs 1st generation precatalyst in the presence of ethene (Mori conditions) gave superior results compared to the more stable Grubbs or Hoveyda–Grubbs 2nd generation precatalysts. This is probably caused by a suppression of the subsequent side-reactions of the enyne

• enantioselective enyne metathesis yielding chiral building blocks for compounds with potential biological activity, e.g., norsalvinorin or cacospongionolide B. Keywords: Diels–Alder reaction; enediyne; enyne metathesis; ring-closing metathesis; ruthenium precatalyst; Introduction Among the plethora of metathetic

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• silyl ether-protected 2-hydroxypropanals 15a and 15b via literature procedures [10], followed by the application of the Still–Gennari Z-selective Horner–Wadsworth–Emmons olefination [11]. Koide’s group [12][13] reported that the asymmetric addition of the enyne 16 to acetaldehyde in the presence of zinc

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• the PKR of enynes containing a fluoride moiety. Keywords: alkene; alkyne; enyne; fluorine; Pauson–Khand; Introduction The prevalence of fluorine-containing molecules in drug-discovery programs is nowadays unquestionable [1][2][3]. The presence of fluorine atoms or fluorine-containing units at

• presence of fluorinated groups on the alkenyl moiety of the 1,6-enyne resulted in low yields (lower than 35%) of the corresponding cyclized products, due to the poor reactivity of the fluorinated olefin (Scheme 6). For example, difluoroalkene-containing compound 1 decomposed and no cyclized product was

• formed. In this NMO-promoted PKR, monofluoroolefinic enyne 2 afforded the defluorinated cyclopentenone 7 in 37% yield. Similarly, trifluoromethyl-substituted olefin 3 also lost the chlorine atom upon cyclization to give 8 as a single diastereoisomer, albeit in a low 14% yield. The reaction of

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• (trifluoromethyl)thiyl radical, which added onto the double bond of 17.1a–d, and finally delivered the desired products 17.5a–d in good yields, through the intermediacy of radicals 17.3·a–d and iminyl radicals 17.4·a–d [85]. The double bond of acrylamides embedded into a 1,7-enyne framework likewise allowed the

Diversity-oriented synthesis of 17-spirosteroids

• Benjamin Laroche,
• Thomas Bouvarel,
• Martin Louis-Sylvestre and
• Bastien Nay

Beilstein J. Org. Chem. 2020, 16, 880–887, doi:10.3762/bjoc.16.79

• Paris, Palaiseau Cedex, France 10.3762/bjoc.16.79 Abstract A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels–Alder reaction on the resulting diene, under

• ; ring-closing enyne metathesis; spirosteroids; steroids; Introduction Diversity-oriented synthesis (DOS) is a powerful approach to access collections of structurally diverse compounds in a few synthetic steps [1][2][3][4][5][6][7]. It can be more relevant when the chemical diversity is centred on

• the propargylic alcohol, the resulting enyne is a good substrate for ring closing enyne metathesis (RCEYM) towards new diene substrates [40][41][42], which can be employed in Diels–Alder reactions with a variety of dienophiles (Figure 1) [43][44][45][46][47][48][49][50][51][52][53][54]. This strategy

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• account surveys the current progress on the application of intra- and intermolecular enyne metathesis as main key steps in the synthesis of challenging structural motifs and stereochemistries found in bioactive compounds. Special emphasis is placed on ruthenium catalysts as promoters of enyne metathesis

• of known, in vivo effective substances but also for designing chemically modified analogs as valid alternatives for further therapeutic agents. Keywords: bioactive compounds; enyne metathesis; ring-closing metathesis; ruthenium catalysts; tandem reactions; Introduction Alkene and alkyne metathesis

• [44]. Among the various embodiments of olefin metathesis, the highly chemoselective enyne metathesis reaction [45][46][47][48][49] has led to some of the most striking advances in the development of modern, efficient synthetic protocols [50][51]. Thus, the present account focuses on the impressive

Controlling alkyne reactivity by means of a copper-catalyzed radical reaction system for the synthesis of functionalized quaternary carbons

• Goki Hirata,
• Yu Yamane,
• Naoya Tsubaki,
• Reina Hara and
• Takashi Nishikata

Beilstein J. Org. Chem. 2020, 16, 502–508, doi:10.3762/bjoc.16.45

• reaction of 3 equivalents of terminal alkyne 1 (aryl substituted alkyne) and an α-bromocarbonyl compound 2 (tertiary alkyl radical precursor) undergoes tandem alkyl radical addition/Sonogashira coupling to produce 1,3-enyne compound 3 possessing a quaternary carbon in the presence of a copper catalyst

• . Moreover, the reaction of α-bromocarbonyl compound 2 and an alkyne 4 possessing a carboxamide moiety undergoes tandem alkyl radical addition/C–H coupling to produce indolinone derivative 5. Keywords: copper catalyst; 1,3-enyne; functionalized quaternary carbon; indolinone; tandem alkyl radical addition

• addition (ATRA) [21] (Scheme 1, i–iii). Therefore, we postulated that if we could control the reactivities of the alkynyl–Cu and ATRA adducts, a tandem tertiary alkylation followed by an alkynylation could occur to produce a 1,3-enyne possessing a quaternary carbon center with good regio- and

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• reaction to achieve spirocyclic pyrrolocyclopentenone derivatives. Specifically, the KA2 reaction was envisaged taking into account cyclic ketones, to install a quaternary carbon atom carrying the required 1,6-enyne moiety for the subsequent Pauson–Khand reaction, thus achieving the corresponding tricylic

• Pauson–Khand (C) reaction. In a dry round bottom flask under a nitrogen flow Co2(CO)8 (0.1 equiv), N,N,N’,N’-tetramethylthiourea (0.6 equiv) and a solution of the enyne compound (1 equiv) were successively added in dry toluene (20 mL/mmol). Then, the reaction mixture was kept under a CO atmosphere and