Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• ways and 20c is a precursor to an API. Another method for benzothiopene construction is seen in Kumar and co-workers’ report describing a dehydrogenative oxytrifluoromethylation cascade reaction of 1,6-enynes, catalysed by phenanthrene-9,10-dione (PQ) (Ered*(cat/cat•−) +1.6 V vs SCE) using visible

Cationic cobalt-catalyzed [1,3]-rearrangement of N-alkoxycarbonyloxyanilines

• Itaru Nakamura,
• Mao Owada,
• Takeru Jo and
• Masahiro Terada

Beilstein J. Org. Chem. 2018, 14, 1972–1979, doi:10.3762/bjoc.14.172

• -catalysed cascade reaction involving rearrangement via N–O bond cleavage [14]. While divalent copper acetate and copper chloride did not show any catalytic activities (Table 1, entries 1 and 2), more Lewis acidic copper complexes, such as [Cu(MeCN)4](PF6)2 and [Cu(OTf)]2·toluene, afforded the corresponding

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• catalyzed cascade reaction to afford alkylidenefluorenes 49 (Scheme 17) [57]. In terms of mechanism, a Pd(0)/Cu(I)-catalyzed Sonogashira coupling reaction from the iodonium salt 48 delivers a 2-alkynyl-2’-iodoarene 50 that, then, cyclizes to 51 via insertion of the Pd(0) species into the iodoarene moiety

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• easy to recycle [3][4][16][17]. On the other hand, the additional incorporation of the former iodoarene waste into the reaction product via a cascade reaction does not only improve the overall AE of a chemical reaction but also directly leads to highly functionalized target molecules. A rough estimate

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• , namely: (polymer) vesicles, micelles, dendrimers and nanogels. The ability and efficiency of catalytic nanoreactors to carry out organic reactions in water, to perform cascade reaction and their ability to be recycled will be discussed. Keywords: catalysis; dendrimers; green chemistry; nanogels

• reference [67]. Suzuki−Miyaura couplings with, or without, ppm Pd. Conditions: ArI 0.5 mmol 3a, Ar’B(OH)2 (0.75–1.00 mmol, 1.5–2.0 equiv) 3b, *with 200 ppm of Pd(OAc)2. Adapted from reference [70]. Copyright 2016 American Chemical Society. Cascade reaction with GOx and Myo. Adapted from reference [82

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• dehydratase. The dehydrated product is then reduced through a 3-step-cascade reaction (catalysed by 3 different enzymes) giving the final dehydroxylated product. 7-OH epimerization: shift the equilibrium Chemical epimerization of CDCA into UDCA The second step of UDCA synthesis from CA, is the epimerization

• formate is cheap and, because of the gaseous nature of CO2 as product, the equilibrium of the reaction is entropically favoured. Pedrini et al. in 2006 [33] reported the successful epimerization of CDCA to UDCA using a redox-neutral cascade reaction, with two NAD+-dependent dehydrogenases. In this way the

• Fusarium merismoides VKM F-2310. The possibility to access that kind of chemical and chemo-enzymatic reactions pave the way for the design of other unexplored routes for the production of UDCA (example in Figure 8). In addition, other reported enzymes can eventually play a role in the cascade reaction

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• double labeling of the mRNA cap with alkyne moieties could also be achieved based on a recently reported enzymatic cascade reaction [99]. In this system a Se-propargyl-modified AdoMet analogue (SeAdoYn [100]) was prepared enzymatically from the respective methionine analogue and ATP by a methionine

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• was obtained predominantly: the α-aryl-β-trifluoromethyl amide 6. This compound was determined to be issued from a trifluoromethylation/1,4-aryl shift/desulfonylation cascade reaction (Scheme 7). This reaction could be performed on various N-aryl,N-tosylacrylamides with moderate to good yields. The

• species 7 then underwent an aryl migration/desulfonylation cascade reaction to furnish intermediate 8. In the case of an aryl substituted substrate, this nitrogen radical being stabilised, it directly performed an hydrogen abstraction on acetonitrile to lead to the corresponding α-aryl-β-trifluoromethyl

• compound, albeit in low yield and with poor regio- and diastereoselectivity (Scheme 19). Interestingly, the authors proposed a mechanism involving a chain propagation pathway, in contrast to the work of Jung and Han. A similar cascade reaction was also performed on diethyl 2-allyl-2-(3-methylbut-2-en-1-yl

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• (Scheme 11) [30]. Amino- and azotrifluoromethylation of alkenes: Alkene trifluoromethylation was applied to the construction of indole, pyrazole and pyridazinone moieties via a multicomponent cascade reaction developed by Antonchick and Matcha in 2014 [31]. The method was based on the reaction between

• and co-workers reported the use of CF3SO2Na in combination with iodide pentoxide in a similar way to their iodotrifluoromethylation of alkenes (see earlier in the text) [42] (Scheme 29a) [51]. Interestingly, this cascade reaction was also applied to enynes for the synthesis of pyrrolidines 52 (Scheme

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

• Dmitry Yu. Vandyshev,
• Khidmet S. Shikhaliev,
• Andrey Yu. Potapov,
• Michael Yu. Krysin,
• Fedor I. Zubkov and
• Lyudmila V. Sapronova

Beilstein J. Org. Chem. 2017, 13, 2561–2568, doi:10.3762/bjoc.13.252

• -addition by the activated C=C double bond and subsequent intramolecular recyclization of the intermediate with the amino group involved. Keywords: cascade reaction; diaminoimidazoles; HPLC–HRESIMS; imidazo[1,5-b]pyridazines; itaconimides; Introduction Among the numerous bicyclic fused imidazole

• the HPLC–HRESIMS monitoring of the reaction confirm its selectivity. Conclusion In summary, a new regioselective and chemoselective cascade reaction of N-arylitaconimides with 1,2-diamino-4-phenylimidazole as 1,3-C,N-dinucleophile was developed to synthesize tetrahydroimidazo[1,5-b]pyridazines. The

Sustainable synthesis of 3-substituted phthalides via a catalytic one-pot cascade strategy from 2-formylbenzoic acid with β-keto acids in glycerol

• Lina Jia and
• Fuzhong Han

Beilstein J. Org. Chem. 2017, 13, 1425–1429, doi:10.3762/bjoc.13.139

• phthalides in good to excellent yields. Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a catalytic one-pot cascade reaction in glycerol has been accomplished. Keywords: β-keto acid; decarboxylation; glycerol; one-pot cascade

• functional group compatibility and ingenious construction of molecular architectures [11][12][13][14]. Consequently, an efficient synthesis of 3-substituted phthalides via a one-pot cascade reaction is still in high demand. An analogous approach was described involving a catalytic sequence of the aldol

• reaction; phthalide; Introduction The phthalides, also known as isobenzofuran-1(3H)-ones, are an important class of heterocycles which are of continued interest for chemists [1][2]. 3-Substituted phthalides, which are recognized as versatile building blocks found in a large number of bioactive compounds

Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds

• M. Fernanda N. N. Carvalho,
• Rudolf Herrmann and
• Gabriele Wagner

Beilstein J. Org. Chem. 2017, 13, 1230–1238, doi:10.3762/bjoc.13.122

• intermediate in the sulphur-reduction step of the cascade reaction, and the isolated product thus supports our mechanistic considerations. Platinum(II) catalysis applied to camphor-derived dialkynes with two different substituents can thus not only give valuable insight in the mechanism of such

Synthesis of D-manno-heptulose via a cascade aldol/hemiketalization reaction

• Yan Chen,
• Xiaoman Wang,
• Junchang Wang and
• You Yang

Beilstein J. Org. Chem. 2017, 13, 795–799, doi:10.3762/bjoc.13.79

• aldol/hemiketalization reaction of a C4 aldehyde with a C3 ketone provides the differentially protected ketoheptose building block, which can be further reacted to furnish target D-manno-heptulose. Keywords: aldol reaction; cascade reaction; D-manno-heptulose; higher-carbon sugar; ketoheptose

• -selective coupling intermediate 12 underwent in situ cyclization to provide hemiketal 13 as the major product in about 50–60% yield (35% overall yield from compound 11). Notably, trace amounts of a stereoisomer and a minor highly polar unknown byproduct were also observed in this cascade reaction. The

N-Propargylamines: versatile building blocks in the construction of thiazole cores

• S. Arshadi,
• E. Vessally,
• L. Edjlali,
• R. Hosseinzadeh-Khanmiri and
• E. Ghorbani-Kalhor

Beilstein J. Org. Chem. 2017, 13, 625–638, doi:10.3762/bjoc.13.61

• thiazole-2-thiones 3 through the thermal cyclocondensation of N-propargylamines 1 with carbon disulfide as developed by Batty and Weedon [75]. (a) One-pot synthesis of 2-benzylthiazolo[3,2-a]benzimidazoles 6 through a base-catalyzed cascade reaction of internal N-propargylamines 4 and CS2. (b) Synthesis of

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• continuous flow process, however, succinimide precipitation would cause blockage of the system. Attempts at transferring the cascade reaction to a continuous platform began with direct adaptation of the existing batch process (Table 2). The solubility of NCS in toluene was found to be variable and often

• stoichiometry afforded by a continuous platform and offers the possibility to isolate selected intermediates in the cascade reaction using a continuous process, more effectively than in batch and with greater flexibility. Optimization of the cascade process using flow chemistry In all the aforementioned cases

• . Interestingly, during development studies on the conversion of α-thioamide 2 to α-thio-β-chloroacrylamide Z-3 in acetonitrile, by flow or in batch, a new component of the cascade reaction was observed, which was identified as the (E)-α-thio-β-chloroacrylamide E-3. An important feature of the experiments

Diastereoselective synthesis of 3,4-dihydro-2H-pyran-4-carboxamides through an unusual regiospecific quasi-hydrolysis of a cyano group

• Mikhail Yu. Ievlev,
• Oleg V. Ershov,
• Mikhail Yu. Belikov,
• Angelina G. Milovidova,
• Viktor A. Tafeenko and
• Oleg E. Nasakin

Beilstein J. Org. Chem. 2016, 12, 2093–2098, doi:10.3762/bjoc.12.198

• diastereoselective cascade reaction [23]. The crucial stage of the described transformation is the formation of a pyran-4-carboxamide intermediate. A trace amount of it was isolated accidentally and we could not repeat this procedure and characterize the compound by spectra. Results and Discussion In continuation of

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• turn be synthesised by an aminolysis/oxidation/olefination sequence of the terminal alcohol 6, following traceless nitro group removal. 5-Nitropiperidin-2-one 6 in turn could be accessed by a nitro-Mannich lactamisation cascade reaction between Michael adduct 7, formaldehyde and a suitable primary

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

• . Differently, treatment of 3-indolylmethanols with Nazarov reagents with TfOH in MeCN led to the generation of indoles through a cascade reaction in an (E/Z)-selective mode. These unusual reactions may serve as stereoselective and chemodivergent methods for accessing indole-containing scaffolds. Shi and co

• diastereoselectivities (all >95:5 dr) and enantioselectivities (up to >99% ee, Scheme 58) [75]. Mechanistic studies showed that this cascade reaction proceeded via a vinylogous Michael addition/Friedel–Crafts process involving a dual H-bonding activation of substrates. In 2015, Wang and co-workers reported Lewis acid

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• systems rapidly and efficiently, though additional catalyst development is needed. Keywords: bridged rings; carbene; cascade reaction; C–H bond insertion; nitrene; Introduction Bridged polycyclic natural products are an inviting challenge to the synthetic chemist for their rich display of functional

• , without having to preinstall functional groups at those positions (Figure 2). Ideally, the choice of catalyst or reagent would control the product formed. The transformation of 5 to 1 or 3 could occur in a single-bond-forming event, or multiple rings could be synthesized in a cascade reaction (i.e., 6 to

• synthesis of phomoidride B (Scheme 16) [76]. While this strategy was ultimately not productive for the total synthesis of the natural product, it did synthesize the key synthetic intermediate 62 very rapidly by taking advantage of insertion into the ether-activated C–H bond of 61. A carbene cascade reaction

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

• Sara Meninno,
• Chiara Volpe,
• Giorgio Della Sala,
• Amedeo Capobianco and
• Alessandra Lattanzi

Beilstein J. Org. Chem. 2016, 12, 643–647, doi:10.3762/bjoc.12.63

• affording the heterocyclic products in good yields and moderate stereoselectivities. Keywords: cascade reaction; tetrahydrothiophenes; aymmetric synthesis; amine thioureas; organocatalysis; Introduction The interest toward the development of stereoselective methodologies to prepare tetrahydrothiophenes

• /nitroaldol reaction and herein we report our preliminary results. Results and Discussion According to the literature data, low control of the diastereoselectivity was observed in the cascade reaction of 1,4-dithiane-2,5-diol with trans-β-nitrostyrenes, and in the case of (E)-1-aryl-2-nitropropene all four

• predicted relative free energies for 10, 11 and 12 fall within a range of 0.1 kcal/mol. Pleasingly, a solvent screening for the cascade reaction carried out on compound 2a with catalyst VII enabled to improve the diastereoselectivity as only 7a/8a were detected in 75:25 ratio and the enantiocontrol

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• the electrophilic component in a few reactions of NHC-bound aldehydes. The addition of acyl anions occur at the nitrogen atom of the nitroso compound. A NHC-catalysed cascade reaction of o-vinylarylaldehydes with nitrosoarenes afforded functionalised 2,3-benzoxazin-4-ones 45 [44]. The initial

• intermolecular aza-benzoin reaction is followed by an intramolecular oxa-Michael reaction to form the observed product (Scheme 28). Enders reported a cascade reaction which is initiated by an NHC-catalysed aza-benzoin condensation between various aldehydes and nitrosobenzenes to generate the hydroxamic acids 47

• catalyst rapidly shuttles the intermediate δ-keto aldehyde 61 to the final product preventing the erosion of enantioselectivity [54]. This cascade reaction constitutes a fine example of symbiotic dual-catalysis wherein both catalysts perform better together in a one-pot reaction than they do independently

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• -forming carbocation cascade reaction, thereby increasing the likelihood of direct formation of epi-isozizaene over byproducts. Outlook Clearly, non-statistical dynamic effects play important roles in carbocation rearrangement reactions. Neglecting such dynamic effects may lead to incorrect conclusions

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

• Hong-Bo Zhang,
• Yong-Chun Luo,
• Xiu-Qin Hu,
• Yong-Min Liang and
• Peng-Fei Xu

Beilstein J. Org. Chem. 2016, 12, 253–259, doi:10.3762/bjoc.12.27

• [65]. However, substrates with aliphatic R1, R2 or R3 did not produce the desired products (Table 2, entries 21–26). This bifunctional catalysis cascade reaction was also amenable to scale-up. When the reaction was carried out on a 3 mmol scale, the desired product was obtained in 84% yield. Therefore

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• [24][25][26]. In this context, our group recently introduced an interesting asymmetric organo-cascade reaction of 2-cyanobenzaldehyde (5) with malonate 6. This resulted in enantioenriched 2-(1-oxoisoindolin-3-yl)malonate 7 which is supposed to serve as a potentially useful building block for further

• cascade reaction, investigating novel trans-1,2-cyclohexane diamine-based bifunctional ammonium salts 8. These catalysts were recently introduced by our groups in a variety of different reactions [27][28][29], as exemplified by a related aldol-initiated cascade reaction of glycine Schiff base with 2

• -cyanobenzaldehydes [29]. Then we decided to address the asymmetric synthesis of bioactive isoindolinones, identifying the chiral isoindolinone 9 as a very useful, key building block, as shown in Scheme 1. Results and Discussion Asymmetric cascade reaction of 2-cyanobenzaldehyde under phase-transfer conditions As

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• ][25][26]. In this context, we have recently reported a catalytic and enantioselective Michael/Michael cascade reaction in which α-nitro-δ-ketoesters react with nitroalkenes to provide densely functionalized cyclohexanes in excellent yield and stereoselectivity (Scheme 1) [27]. This reaction made use