Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• hand, the presence of thiourea additives could activate nitroalkenes when used as substrates by double hydrogen bonding, which lead to improved reactivities [24]. Based on these findings, we decided to explore the effect of a Brønsted acid or an achiral thiourea as additive on the reaction between

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• class of sulfur-containing pro-nucleophiles in a highly enantio- and diastereoselective conjugate addition to nitroalkenes, providing α,α-disubstituted α-mercapto carboxylic acids [5]. Since then, several asymmetric variants using 5H-thiazol-4-ones as nucleophiles have been disclosed; such as amination

• activated alkenes, including nitroalkenes, 4-oxo-4-arylbutenones, 4-oxo-4-arylbutenoates and methyleneindolinones [10]. This work elucidated the feasibility of the electrophilic addition to the C2 position of 5H-thiazol-4-ones. More importantly, it provided a direct and convenient approach to synthesize

• chemoselectivity and thus the moderate yield. When the H-bond donor was changed from thiourea to urea (catalyst II), it did not provide better results (Table 1, entry 2) [17][19]. In the [4 + 2] annulation of 5H-thiazol-4-ones with nitroalkenes, dipeptide-based thiourea−amide−tertiary amine III (DP-TAA) was

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• nitroalkenes Organocatalysts In the first reported example of the enantioselective protonation of a nitronate, Ellman and co-workers demonstrated that an N-sulfinylurea organocatalyst could be used to catalyze the addition of α-substituted Meldrum’s acids to terminally unsubstituted nitroalkenes (Scheme 37

• , including alkyl, phenethyl, pendant esters and thioethers, and an α-acetyloxy group (81–98% yield, 95.5:4.5 to 97:3 er). Slightly lower enantioselectivity was observed only when R1 was benzyl (93.5:6.5 er). Methyl, ethyl, n-butyl, and isopentyl R2 substituted nitroalkenes were efficient substrates (84–98

• % yield, 95.5:4.5 to 97:3 er). The resulting nitroalkane adduct 159 could be reduced and cyclized to access α,γ-disubstituted γ-lactams. Ellman and co-workers, in the second example of conjugate addition–enantioselective protonation with nitroalkenes, showed that thioacids 160 could be added in high

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• the pionnering work by Trost in 2004 [26], several examples of the utility of the structurally related oxazol-4(5H)-ones (Figure 1b, X = O) have also been published, which involve mainly Michael additions (to enones [27][28], nitroalkenes [29][30], alkynones [31][32][33] and vinyl sulfones [34]), γ

• )-ones 1 as pronucleophiles in organocatalyzed Michael addition reactions 2-Thio-1H-imidazol-4(5H)-ones 1 (R = SBn) have been reported to be effective equivalents of N-subtituted (alkyl, aryl, allyl) α-amino acids in conjugate addition reactions to both, nitroalkenes and α-silyloxy enones as Michael

• acceptors in reactions promoted by bifunctional Brønsted bases. 1.2.1 Nitroalkenes as acceptors. Investigation of the base-catalyzed Michael addition reaction of 2-thio-1H-imidazol-4(5H)-ones 4 to nitroalkenes 5 [55] revealed that cinchona alkaloids such as quinine, (DHQ)2Pyr or even thiourea tertiary amine

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

• nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes

• the bifunctional organocatalyst structure and reaction conditions will be required for further improvements of the challenging cascade process. Organocatalysts screened in the cascade reaction. Synthesis of catalyst VIII. Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 1–3 with 1,4

• -dithiane-2,5-diol (4) catalyzed by catalysts I–VIII. Solvent screening in the asymmetric Michael/nitroaldol reaction of 2a with 1,4-dithiane-2,5-diol (4) catalysed by amine thiourea VII. Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 2 with 1,4-dithiane-2,5-diol (4) catalysed by amine

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• derivative 4 to develop the first organocatalytic enantioselective Friedel–Crafts (F–C) alkylation of indoles, employing nitroalkenes as versatile electrophiles. In the presence of catalyst 4, the differently functionalized indole derivatives 2 reacted with aryl and alkyl nitroalkenes 3 in dichloromethane at

• of incorporating this scaffold into diverse organocatalysts. In 2008, Seidel’s group published a new example of an asymmetric addition of indoles to nitroalkenes, employing a novel catalyst design [24]. The authors envisioned that a protonated 2-pyridyl substituent could increase the acidity of the

• the compounds 32a–d, being S. Later, He and co-workers reported the use of several chiral multiple hydrogen-bond donating tertiary amine-based organocatalysts in the asymmetric addition of acetylacetone (36a) to the β-nitroalkenes 3. They found the thiourea 37 as a highly suitable catalytic structure

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• wide range of products in excellent yields (up to 95%) and selectivities (87–96% ee), confirming the generality of the protocol. In 2010, Zhong and co-workers demonstated that bifunctional thiourea 56 could catalyze the domino Michael–Henry reaction between nitroalkenes 82 and methyl 2,5

• , Enders and co-workers described the three-component domino Michael–Michael aldol reaction between β-ketoesters 153, nitroalkenes 77 and α,β-unsaturated aldehydes 154, producing heavily substituted cyclohexanes 155 containing six contiguous stereocenters with excellent stereocontrol (Scheme 49) [70]. In

• (Scheme 53). In 2008, Wang and co-workers described a very interesting Michael–Michael cascade of trans-3-(2-mercaptophenyl)-2-propenoic acid ethyl esters 167 and nitroalkenes 82 to produce thiochromane derivatives 168 catalyzed by the bifunctional thiourea 57 (Scheme 54) [75]. The reaction proceeded

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• vinylogous Michael addition reaction [48]. In this process, cyclic enones 52 are added to nitroalkenes 41 using dienamine catalysis (Scheme 13). Although no model is suggested with respect to how the 6’-OH is involved, it is clearly of importance as the analogous 6’-OMe derived cupreine catalyst gives

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

• nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in

• all cases. Keywords: asymmetric diastereodivergent; enantioselective; Michael addition; nitroalkenes; nitroesters; organocatalysis; squaramides; Introduction The absolute stereochemistry of a molecule has a paramount influence on the properties that this compound will have when interacting with

• ][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

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

• Sundaravel Vivek Kumar,
• Shanmugam Muthusubramanian,
• J. Carlos Menéndez and
• Subbu Perumal

Beilstein J. Org. Chem. 2015, 11, 1707–1712, doi:10.3762/bjoc.11.185

• associated with the lack of regioselectivity and difficult isomer separation [23]. Other methods for the synthesis of 2,3-disubsituted thiophenes include the reactions of (i) 1,4-dithiane-2,5-diol with nitroalkenes [24], activated nitriles [25] and cyanoacetamide [26]; (ii) 3-nitrothiophene with Grignard

Cathodic hydrodimerization of nitroolefins

• Michael Weßling and
• Hans J. Schäfer

Beilstein J. Org. Chem. 2015, 11, 1163–1174, doi:10.3762/bjoc.11.131

• Michael Wessling Hans J. Schafer Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität, Correns-Straße 40, 48149 Münster, Germany 10.3762/bjoc.11.131 Abstract Nitroalkenes are easily accessible in high variety by condensation of aldehydes with aliphatic nitroalkanes. They belong to

• 85% to 92% yield at a mercury pool cathode and with slightly lower yields at a graphite cathode [5][6][7][8]. The current controlled reduction of alkyl- and aryl-substituted nitroalkenes in acidic medium affords mixtures of ketones and oximes in yields of 39% to 72% [9] and 55% to 91% [10

• reduction of 1-nitroalkenes was studied by cyclic voltammetry and controlled potential coulometry. The reduction probably proceeds by initial formation of the radical anion, which subsequently dimerizes [17]. Later conditions were described to achieve selectively either a cathodic ß,ß-coupling (cathodic

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• diphenylphosphine to a range of nitroalkenes 56 has been described using a bifuntional Cinchona alkoid/thiourea catalyst 58 [132]. The catalyst 58 is able to simultaneously activate both the electrophilic and nucleophilic reagents. On one hand the thiourea presumably binds the nitro group while on the other hand

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• -workers, which demonstrated that backbone fluorination of bicyclic NHCs improves enantioselectivity in Stetter reactions of heterocyclic aldehydes with nitroalkenes [37][38][39][40]. Finally, one hybrid system was prepared containing both β-fluoroamine classes (7). The trifluoromethylated triazolium salt

Sequential Diels–Alder/[3,3]-sigmatropic rearrangement reactions of β-nitrostyrene with 3-methyl-1,3-pentadiene

• Peter A. Wade,
• Alma Pipic,
• Matthias Zeller and
• Panagiota Tsetsakos

Beilstein J. Org. Chem. 2013, 9, 2137–2146, doi:10.3762/bjoc.9.251

• been the subject of several theoretical investigations [7][8][9][10]. The necessary nitronic ester precursors are readily preparable by Lewis acid-promoted [4 + 2]-cycloaddition reactions of nitroalkenes with appropriate dienes, a general reaction first reported by Denmark and coworkers (Denmark Diels

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO₄

• Leandro Lara de Carvalho,
• Robert Alan Burrow and
• Vera Lúcia Patrocinio Pereira

Beilstein J. Org. Chem. 2013, 9, 838–845, doi:10.3762/bjoc.9.96

• nitroalkenes 5a–c as heterodienes, ethyl vinyl ether (EVE) as a dienophile, and selected electron-deficient alkenes as 1,3-dipolarophiles. The employment of different organic solutions of LiClO4 or LiCl as promoter systems provided the respective nitroso acetals with yields from 34–72% and good levels of

• diffraction experiment. Keywords: chiral heterodiene; hetero-Diels–Alder reaction; pyrrolizidin-3-one; solvent effect; tandem reaction; Introduction Conjugated nitroalkenes play an important role in cycloaddition reactions providing useful nitrogenated cycloadducts with varied synthetic applications (Scheme

•  1) [1][2][3]. These compounds can act as dienophiles or 1,3-dipolarophiles to provide nitrocycloadducts of type 1 or nitroheterocycles of type 2, respectively [4][5]. In addition, nitroalkenes can act as heterodienes reacting with suitable dienophiles, often in the presence of a Lewis acid, to

A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-γ-aminated nitroalkenes derived from L-α-amino acids

• Vera Lúcia Patrocinio Pereira,
• André Luiz da Silva Moura,
• Daniel Pais Pires Vieira,
• Leandro Lara de Carvalho,
• Eliz Regina Bueno Torres and
• Jeronimo da Silva Costa

Beilstein J. Org. Chem. 2013, 9, 832–837, doi:10.3762/bjoc.9.95

• Janeiro, 21941-902, Rio de Janeiro, Brazil Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, 26530-060, Nilópolis, RJ, Brazil 10.3762/bjoc.9.95 Abstract New chiral (S,E)-γ-N,N-dibenzylated nitroalkenes 2a–c were synthesized from natural L-(α)-amino acids in five steps with overall

• alcohol; amino aldehyde; azide addition; Baylis–Hillman reaction; cyanide addition; Michael addition; Introduction Nitroalkenes constitute a class of organic compounds that present exceptional versatility in organic synthesis [1][2][3][4]. They are reactive in Michael reactions with a wide variety of

• nucleophiles [5][6][7][8][9][10], in Friedel–Crafts alkylations [11][12][13][14], and Baylis–Hillman reactions [15][16][17][18]. Furthermore, nitroalkenes can react as dipolarophiles in [3 + 2] cycloadditions [19][20][21][22], as dienophiles in [4 + 2] cycloadditions [23][24][25][26], and as heterodienes in

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

• Ping-An Wang,
• Sheng-Yong Zhang and
• Henri B. Kagan

Beilstein J. Org. Chem. 2013, 9, 265–269, doi:10.3762/bjoc.9.32

• nitroalkenes serves as the key transformation. The chiral ammonium salts 7 have a structure similar to the chiral PTCs of Denmark et al. The substituents in the chiral ammonium salts 7 are easily tunable, which could open a route to various chiral PTCs for organic synthesis. Conclusion In summary, we provide

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• most highly studied and important reactions for the synthesis of valuable chiral molecules [39][40][41][42][43][44]. Recently, Sebesta and co-workers compared the enantioselective organocatalytic Michael addition of aldehydes to nitroalkenes in aqueous solution with the reaction performed under solvent

• ball-milling conditions. O-Lauroyl-trans-4-hydroxyproline (VII) was identified as the best catalyst in aqueous media, whilst α,α-diphenylprolinol trimethylsilyl ether (VIII) turned out to be the best catalyst under ball-milling conditions. Michael reaction of aliphatic aldehydes 6 with nitroalkenes 7

• solvent-free conditions by using a planetary ball mill (Scheme 7) [46]. Cinchona-derived chiral squaramide IX, at low catalyst loading of 0.5 mol %, efficiently catalyses the solvent-free Michael reaction of acetylacetone (9) with various substituted nitroalkenes 7 in a short reaction time (5–30 minutes

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• salicylaldehydes 1 and nitroalkenes 27 employing (S)-1-methyl-2-(pyrrolidin-2-ylmethylthio)-1H-imidazole (VIII) as organocatalyst in the presence of salicylic acid as cocatalyst and in DMSO as solvent (Scheme 14). The reaction was interpreted as following an aromatic iminium activation strategy and provided 2H

• -nitrochromene derivatives 28 with moderate yields and moderate to good enantioselectivities. One of the limitations of this methodology is that only aromatic nitroalkenes tolerate the reaction conditions. Subsequently a closely related reaction of salicylaldehydes 29 with β-nitrostyrene (27) employing

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• organic transformations with hydrogen bond accepting substrates. Recently, we reported the enantioselective ring opening of cyclic meso-anhydrides and asymmetric Michael additions of 1,3-dicarbonyl compounds to nitroalkenes with thiourea-based organocatalysts [48][49]. Based on those studies and in the

Enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes catalyzed by binaphthyl-derived organocatalysts

• Saet Byeol Woo and
• Dae Young Kim

Beilstein J. Org. Chem. 2012, 8, 699–704, doi:10.3762/bjoc.8.78

• Saet Byeol Woo Dae Young Kim Department of Chemistry, Soonchunhyang University, Asan, Chungnam, 336-745, Korea 10.3762/bjoc.8.78 Abstract The highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes, promoted by binaphthyl-modified chiral bifunctional

• organocatalysts is described. This reaction afforded the chiral functionalized naphthoquinones in high yields (81–95%) and excellent enantioselectivities (91–98% ee) under low catalyst loading (1 mol %). Keywords: asymmetric catalysis; Michael addition; 1,4-naphthoquinones; nitroalkenes; organocatalysis

• subjected to rigorous investigation in recent years [16][17][18][19][20][21][22]. The asymmetric Michael addition of various nucleophiles to nitroalkenes is of great interest, because the products obtained are versatile intermediates in organic synthesis [23][24][25][26]. Extensive studies have been devoted

Catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to nitroalkenes by a grinding method

• Zong-Bo Xie,
• Na Wang,
• Ming-Yu Wu,
• Ting He,
• Zhang-Gao Le and
• Xiao-Qi Yu

Beilstein J. Org. Chem. 2012, 8, 534–538, doi:10.3762/bjoc.8.61

• , East China Institute of Technology, Fuzhou, China, 344000; Fax: (+86)794-8258320; Tel:(+86)794-8258320 10.3762/bjoc.8.61 Abstract An environmentally benign, fast and convenient protocol has been developed for the Michael addition of 1,3-dicarbonyl compounds to β-nitroalkenes in good to excellent

• ], Aldol condensation [18], etc. [1][2][19][20]. The Michael addition is one of the most fundamental and important reactions for the formation of carbon–carbon bonds and carbon–heteroatom bonds in organic synthesis. The conjugate Michael addition of carbon nucleophiles to electron deficient nitroalkenes is

• environmentally hazardous residues and undesirable byproducts [25][26][27][28][29][30]. As one part of our continuing efforts toward the development of green synthesis methods for Michael additions of nitroalkenes, we have previously reported an enzymatic tandem reaction to form 5-hydroxyimino-4,5-dihydrofurans

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• of the enantiomers of hindered enone 46 by addition, oxidation and elimination of a sulfenic acid under basic conditions (Scheme 18) [45]. Xiao and co-workers developed an organocatalytic process for the addition of thiols to nitroalkenes [46]. Using thiourea organocatalyst 48, conjugate addition of

• a variety of thiols to a range of nitroalkenes 49 proceeds to give 50 and hence 51 in good yield and good enantioselectivity (Scheme 19). α-Arylthio-β-amino acid 54 was prepared from Michael adduct 52 in three steps (Scheme 20) in good yield and with full conservation of enantiomeric purity. Palomo

• of enone 46. Organocatalytic conjugate addition to nitroalkenes 49. Preparation of β-amino acid 54. Sulfur migration within oxazolidine-2-thiones 56. Preparation of thiols 62 by self-regeneration of stereocentres. Synthesis of (5R)-thiolactomycin. Preparation of tertiary thiols and thioethers via α

One-pot gold-catalyzed synthesis of 3-silylethynyl indoles from unprotected o-alkynylanilines

• Jonathan P. Brand,
• Clara Chevalley and
• Jérôme Waser

Beilstein J. Org. Chem. 2011, 7, 565–569, doi:10.3762/bjoc.7.65

• -alkynylanilines can be followed by 1,4-addition to enones [15][16], iodination [17] or reaction with 1,3-dicarbonyl compounds [18]. Perumal recently demonstrated that aldehydes and nitroalkenes can be used as electrophilic partners [19][20]. Triple bonds can also serve as a second electrophile for the

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• -generation catalyst for the Stetter reaction between aryl aldehydes (e.g. 47) and nitroalkenes (e.g. 48). Superficially, it seems that the bulky isopropyl group of 49 is solely responsible for the enantioselectivity of this reaction. However, the shape of the bicyclic ring system might also play a role and