Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

• Yiwen Xiong,
• Haibo Mei,
• Lingmin Wu,
• Jianlin Han,
• Yi Pan and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 653–659, doi:10.3762/bjoc.10.57

• esters [6][7][8][9][10]. Up to now, a series of nucleophilic substrates have been reported to react with α-imino esters, such as enamine [11][12][13][14], carbamate ammonium ylide [15], 1,3-dipolar cycle [16], boronic acid [17], acetylide [18], proparygylic anion [19] and ketene silyl acetal [20]. These

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• respective methyl ester ylide 26 [25][26]. The reaction of phosphorane 24 with 11 under neutral conditions at 50 °C gave the desired diene 9a in very good 88% yield and in nearly perfect E-selectivity. The protection groups were removed from 9a under the previously established conditions to finally give

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• diastereoisomeric 1,2-dihydroisoquinolines 40 (Scheme 22) [60]. Iminium intermediate 28, generated in situ from the aldimine 27 under silver triflate catalysis is the usual electrophilic intermediate, whereas the nucleophile, in this case, is the oxonium ylide 39. The reaction resulted in the synthesis of highly

• substituted 1,2-dihydroisoquinolines 40 characterized by the presence of an α-hydroxy/alkoxy-α-carboxylate carbon pendant. The oxonium ylide 39 was prepared by a well-known procedure involving a rhodium carbenoid intermediate, generated in situ from the corresponding diazoacetate 37 under Rh2(OAc)4 catalysis

• , aldehydes and alkenes in a three-component reaction based on the cascade imine formation, azomethine ylide generation and [3 + 2] cycloaddition reaction for the synthesis of pyrrolidines. However, the adopted method to induce chirality in the final products is rather dissimilar. Thus, in 2006 Garner’s group

Additive-assisted regioselective 1,3-dipolar cycloaddition of azomethine ylides with benzylideneacetone

• Chuqin Peng,
• Jiwei Ren,
• Jun-An Xiao,
• Honggang Zhang,
• Hua Yang and
• Yiming Luo

Beilstein J. Org. Chem. 2014, 10, 352–360, doi:10.3762/bjoc.10.33

• 4-nitrobenzoic acid, respectively. The substituent effects on the regioselectivity were also investigated. Keywords: 1,3-dipolar cycloaddition; azomethine ylide; regioselectivity; spirooxindole; Introduction Spirooxindoles are important synthetic targets due to their significant biological

• -unsaturated enones. Moreover, we envisioned that the additive might effectively tune the regioselectivity of a 1,3-dipolar cycloaddition of azomethine ylide. Herein, we report a three-component 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from isatin derivatives and benzylamine, with

• benzylideneacetone derivatives in the presence of various additives. It was found that the addition of water can significantly improve the regioselectivity and yield of this reaction [45][46][47][48]. More importantly, the regioselectivity of the 1,3-dipolar cycloaddition of azomethine ylide was reversed by the

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

• Fei Wang,
• Lingchun Li,
• Chuanfa Ni and
• Jinbo Hu

Beilstein J. Org. Chem. 2014, 10, 344–351, doi:10.3762/bjoc.10.32

• precursors for organic synthesis, but also act as bioisosteres for enzyme inhibitors. Among various methods for their preparation, the carbonyl olefination with difluoromethylene phosphonium ylide represents one of the most straightforward methods. Results: The combination of (chlorodifluoromethyl

• . Conclusion: Similar to many other Wittig-type gem-difluoroolefination reactions in the presence of PPh3, the reaction of TMSCF2Cl with aldehydes and activated ketones is effective. Keywords: (chlorodifluoromethyl)trimethylsilane; difluorocarbene; gem-difluoroolefin; organo-fluorine; Wittig reaction; ylide

• difluoromethylene phosphonium ylide, which can be generated in situ either by the transformation of a difluorinated phosphonium salt or by the reaction between difluorocarbene (:CF2) and a phosphine (Scheme 1) [19][20][21][22][23][24][25][26]. In 1964, Fuqua and co-workers first reported the difluoromethylenation

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• indolones. Keywords: acrylamides; aroylacrylic acids; azomethine ylide; cyclative rearrangement; cycloaddition; multicomponent; spirooxindoles; Introduction The design of new spirocyclic compounds is intriguing due to their unique non-planar structure and great potential for binding to biomolecules due to

• 22.9° and the shortest distance between carbon atoms (C6…C15) is 3.04 Å). The mechanism of the azomethine ylide formation by a decarboxylative route has been repeatedly described by a number of authors and is depicted in Scheme 1 [35][36]. The reaction between isatin and the α-amino acid affords the

• azomethine ylide, which regioselectively adds to the C=C bond of acrylamide or aroylacrylic acid. Since the stereochemistry of the cycloadducts 4a and 6a was clarified by a single-crystal X-ray analysis, the structures of the reacting systems – the azomethine ylide and dipolarophiles (acrylamide and

Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

• John Li,
• May May Leong,
• Alastair Stewart and
• Mark A. Rizzacasa

Beilstein J. Org. Chem. 2013, 9, 2762–2766, doi:10.3762/bjoc.9.310

• Abstract The total synthesis of the endogenous inflammation resolving eicosanoid resolvin D2 (1) is described. The key steps involved a Wittig reaction between aldehyde 5 and the ylide derived from phosphonium salt 6 to give enyne 17 and condensation of the same ylide with aldehyde 7 to afford enyne 11

• using the common linchpin phosphorus ylide derived from phosphonium salt 6 [21][22] and each of the homochiral aldehydes 5 and 7 [9]. Synthesis of vinyl iodide 4 The synthesis of fragment 4 began with the production of the aldehyde 7 as shown in Scheme 2. A Wittig reaction between hemiacetal 8 [23] and

• the ylide derived from 9 provided the alkene 10 [9] with excellent stereoselectivity. Oxidation of 10 with Dess–Martin periodinane then afforded aldehyde 7. The phosphonium salt 6 [21][22] was produced from propargyl bromide via silylation of the derived sodium salt with TIPSCl followed by reaction

Less reactive dipoles of diazodicarbonyl compounds in reaction with cycloaliphatic thioketones – First evidence for the 1,3-oxathiole–thiocarbonyl ylide interconversion

• Valerij A. Nikolaev,
• Alexey V. Ivanov,
• Ludmila L. Rodina and
• Grzegorz Mlostoń

Beilstein J. Org. Chem. 2013, 9, 2751–2761, doi:10.3762/bjoc.9.309

• react at room temperature with cycloaliphatic thioketones, e.g. 2,2,4,4-tetramethyl-3-thioxocyclobutanе-1-one and adamantanethione, via a cascade process in which the key step is a 1,5-electrocyclization of the intermediate thiocarbonyl ylide leading to tetrasubstituted spirocyclic 1,3-oxathioles. The

• temperature dependence of the main reaction product type obtained from dimethyl diazomalonate and 2,2,4,4-tetramethyl-3-thioxocyclobutanе-1-one as well as to verify reversibility of the thiocarbonyl ylide and 1,3-oxathiole interconversion, the calculations of the energy profile for the transformation of 1,3

• [1][2][3][4] and easily eliminates N2 forming the reactive thiocarbonyl ylide 6. This intermediate, after subsequent 1,5- or 1,3-electrocyclization produces 1,3-oxathioles 3,7 or thiiranes 5 and 8, respectively (Scheme 2, path A) [4][5][6][22]. In some instances, substituted thiiranes undergo

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• one-pot oxidation/Wittig procedure was implemented from 37a; treatment with the Dess–Martin periodinane [41] in the presence of the stabilised ylide afforded a 4:1 E:Z mixture of the product alkene 39a in good (74%) yield. A second purification by column chromatography isolated the E-alkene

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• racemization could be overcome by performing the olefination with AlMe3–Zn–CH2I2 in benzene under non-basic conditions. While looking for non-racemizing conditions for the same reaction, Beaulieu et al. found that the ylide formed from methyltriphenylphosphonium bromide and n-BuLi in THF gave 62 in 69% ee, but

• in low yield (27%) [102]. With a different unstabilized ylide 65, the enantiopurity of the Wittig product increased to >95% ee. The erosion of enantiopurity was attributed to the ylide (Ph3P=CH2) being too basic. It is well known that phosphonium ylides form stable complexes with alkali metals during

• reversed to >10:1 favouring adduct 68 [105]. α,β-Unsaturated esters can be synthesized from stabilized ylides. Reaction of 1 with ylide 69 is E-selective. Depending on the solvent, the E/Z-ratio can vary from 3:1 (in MeOH) [106] to 100:0 (THF [107] or benzene [108]). Since stabilized ylides are less

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

Synthetic scope and DFT analysis of the chiral binap–gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

• María Martín-Rodríguez,
• Luis M. Castelló,
• Carmen Nájera,
• José M. Sansano,
• Olatz Larrañaga,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2013, 9, 2422–2433, doi:10.3762/bjoc.9.280

• the 4e− Pauli repulsion between the reactives in TSNPMdown compared to TSNPMup, and thus an increase of the activation barrier. Moreover, lower energy to deform the initial ylide (strain energy) is required in the latter TS. With that energetic diference, the computed ee is about 99%, in good

• unexpected regioselectivity of the 1,3-DC depicted in Scheme 6, calculations within the DFT framework were performed. In the accepted mechanism of the metal catalyzed 1,3-DC of azomethine ylides and acrylates, the α-carbon atom of the azomethine ylide (C2 in Figure 5) reacts with the β-carbon of the acrylate

• higher in the carbon in α-position to the carboxy group (C2). Initially, a model azomethine ylide derived from oxazolone 10 was considered (Figure 5). Moreover, an acyclic w-shaped ylide analogue (Ylide-II) was also studied as a reference. We chose this latter 1,3-dipole because it is known that with

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• cycloaddition is shown in Scheme 13. The reaction commences with oxidation of tetrahydroisoquinoline 41 to amine radical cation 48 by the photoexcited state of Ru2+. Subsequently, abstraction of a hydrogen atom α to the nitrogen atom of 48 yields iminium ion 49, which is then converted to azomethine ylide 50 by

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• variety of reactions e.g. cyclopropanation, X–H insertion, cycloaddition and ylide formation [13][15], and more recently, in the synthesis of valuable compound classes such as β-keto esters [16] and β-hydroxy-α-diazocarbonyl compounds [17], we aimed to develop an inherently safe continuous-flow EDA

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• nitrile ylide formation and the 1,3-dipolar cycloaddition. We initially chose to photolyze methyl 4-(1-azidovinyl)benzoate (1a) in the presence of acrylonitrile (4a) (Table 2). A solution of 1a and 4a in the respective solvent was passed through the photochemical flow-reactor with 5.5 mL volume and a

• azodicarboxylate (DIAD, 4e) as the dipolarophile (Scheme 5). Additionally, we found that even electron-deficient alkynes such as 4f can serve as dipolarophiles in these reactions (Scheme 6). However, the resulting pyrrole 5k could only be isolated in 26% yield. Alternatively, the in-situ generated nitrile ylide

• of 2H-azirines 2 under inductive heating and photochemical conditions. The experiments were conducted at a concentration of 0.05 M. Optimization of the photolysis of vinyl azide 1a and trapping of nitrile ylide with acrylonitrile 4a under flow conditions. Supporting Information Supporting

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• ]. Treatment of 20 with the sulfur ylide derived from trimethylsulfoxonium iodide [33][34] led to recovery of starting material at room temperature, but decomposition at elevated temperatures. Instead, the enone was smoothly reduced to the allylic alcohol, and a Furukawa-modified Simmons–Smith reaction [35

Dipolar addition to cyclic vinyl sulfones leading to dual conformation tricycles

• Steven S. Y. Wong,
• Michael G. Brant,
• Christopher Barr,
• Allen G. Oliver and
• Jeremy E. Wulff

Beilstein J. Org. Chem. 2013, 9, 1419–1425, doi:10.3762/bjoc.9.159

• species [13][14][15][16][17][18][19][20][21]) have been less-frequently employed as acceptors in 1,3-dipolar cycloadditions [22][23][24][25]. Indeed, we are only aware of a single prior example of a cyclic alkyl vinyl sulfone participating in a dipolar addition with an azomethine ylide [26]. In part, this

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• cycloaddition, ylide formation, cyclopropanation and C–H insertion reactions [1][2][3]. A generally useful modification of diazo compounds is the substitution of the α-hydrogen for an electrophile. This substitution can be effected in the presence of a base or starting from the metalated diazo compound, and

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

Facile synthesis of functionalized spiro[indoline-3,2'-oxiran]-2-ones by Darzens reaction

• Qin Fu and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 918–924, doi:10.3762/bjoc.9.105

• -dihydrofurans, polysubstituted pyridines, pyrido[1,2-a]benzimidazoles and charge-separated zwitterionic salts [26][27][28][29][30][31]. We envisaged that in situ generated pyridinium ylide might react with the reactive carbonyl group of isatins to afford spiro epoxyoxindoles (Scheme 1). To test this feasibility

• ]+ calcd for C23H17NNaO3, 378.1101; found, 378.1103. Molecular structure of spiro compound 3c. Molecular structure of spiro compound 4a. Molecular structure of spiro compound 5o. Synthesis of spiro-epoxyoxindole with pyridinium ylide. Reaction of 5-methylisatin (1) with phenacyl bromide (2). Synthesis of

4-Pyridylnitrene and 2-pyrazinylcarbene

• Curt Wentrup,
• Ales Reisinger and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 754–760, doi:10.3762/bjoc.9.85

• shift finally converts the nitrile ylide 9 to the open-chain ketenimine 10 (Scheme 2). 3-Pyridylcarbene undergoes analogous Type I ylidic ring opening to an ethynylvinylnitrile imine [6]. Type II ring opening is diradicaloid and proceeds via an open-chain vinylnitrene or biradical 13 in nitrenes such as

• Supporting Information File 1 for computational details). We postulate that the rearrangement to 27 occurs via the unobserved nitrile ylide intermediate 26 (Scheme 4). The calculated IR spectra of the four s-E and s-Z conformers of 26 are shown in Figure S8 and Figure S9 in Supporting Information File 1

• . Related nitrile ylides are known to undergo very facile 1,7-H shifts (see, e.g., Scheme 2) [3][6]. Both the nitrile ylide and the ring-expanded ketenimine were observed in the corresponding benzannelated systems, viz 4-azidoquinoline and 2-diazomethylquinoxaline [17], and the ylidic ring opening is very

3-Pyridylnitrene, 2- and 4-pyrimidinylcarbenes, 3-quinolylnitrenes, and 4-quinazolinylcarbenes. Interconversion, ring expansion to diazacycloheptatetraenes, ring opening to nitrile ylides, and ring contraction to cyanopyrroles and cyanoindoles

• Curt Wentrup,
• Nguyen Mong Lan,
• Adelheid Lukosch,
• Pawel Bednarek and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 743–753, doi:10.3762/bjoc.9.84

• to the formation of glutacononitriles in low yields [12]. In contrast, 3-pyridylnitrene (10) undergoes a different type of ring opening to the observable nitrile ylide 11 and subsequently the ketenimine 12 (Scheme 3) [13]. Nitrile imines [14] and nitrile ylides [15][16] may have either allenic or

• the (s,Z)-nitrile ylide 11 lies 5 kcal/mol above the open shell singlet nitrene S1 10, i.e., the barrier is only 11 kcal/mol above the cyclic ketenimine 16. This is lower than the barrier for direct ring opening of the nitrene 10 itself (16 kcal/mol) (Scheme 4 and Figure 1) [13]. Thus, while both the

• nitrene 10 and the ketenimine 16 may undergo ring opening with rather low activation barriers, the ring opening of the ketenimine has the lowest barrier. Both of these reactions can take place with ease under conditions of FVT. With a low barrier for ring opening, recyclization of the nitrile ylide 11 now

Alkenes from β-lithiooxyphosphonium ylides generated by trapping α-lithiated terminal epoxides with triphenylphosphine

• David. M. Hodgson and
• Rosanne S. D. Persaud

Beilstein J. Org. Chem. 2012, 8, 1896–1900, doi:10.3762/bjoc.8.219

• with Ph3P to provide a new and direct entry to β-lithiooxyphosphonium ylides. The intermediacy of such an ylide is demonstrated by representative alkene-forming reactions with chloromethyl pivalate, benzaldehyde and CD3OD, giving a Z-allylic pivalate, a conjugated E-allylic alcohol and a partially

• deuterated terminal alkene, respectively, in modest yields. Keywords: alkenes; epoxides; lithiation; synthetic methods; ylide; Introduction β-Lithiooxyphosphonium ylides 4 are useful intermediates in synthesis as they react with a variety of electrophiles to provide a convergent entry to alkenes, often

• with high regio- and stereocontrol (Scheme 1) [1][2][3][4][5][6][7][8][9]. These ylide intermediates can be generated by initiating a Wittig reaction between an aldehyde 1 and a phosphorane 2 at low temperature in the presence of lithium salts, which promote ring opening of the initially formed

Synthesis and ring openings of cinnamate-derived N-unfunctionalised aziridines

• Alan Armstrong and
• Alexandra Ferguson

Beilstein J. Org. Chem. 2012, 8, 1747–1752, doi:10.3762/bjoc.8.199

• Alan Armstrong Alexandra Ferguson Department of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, U.K. 10.3762/bjoc.8.199 Abstract tert-Butyl cinnamates are aziridinated with high trans-selectivity by an N–N ylide generated in situ from N-methylmorpholine and O

• carbonyl compounds. Our method produces trans-NH-aziridines from α,β-unsaturated carbonyl compounds in good to excellent yield with high diastereoselectivity (Figure 1) [21]. An N–N ylide (aminimine) is the presumed active intermediate, formed from the reaction of a tertiary amine promoter and an aminating

• agent. Conjugate addition of the ylide, followed by a ring-closure step affords the NH-aziridine. More recently, the methodology has been extended to α,β,γ,δ-unsaturated carbonyl compounds, with excellent regio- and diastereoselectivity [31]. Herein, we report the optimisation of our nucleophilic

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• Fryzuk [62][63][64]. With a coordinatively unsaturated and electron-rich center, this species exhibits some reactivity that is similar to the isoelectronic Vaska's complex [65], such as oxidative addition of methyl iodide. It also reacts in dipolar fashion with an in-situ-generated phosphorus ylide to

• ) imide [42]. Formal [2 + 2] cycloaddition of methyl isocyanate at a ruthenium silylene [58]. Oxygen-atom transfer from phenyl isocyanate to a cationic terminal borylene [60]. Coupling of a phosphorus ylide with an iridium methylene [62]. Reactions of (PNP)Ir═C(H)Ot-Bu with oxygen-containing