p-Nitrophenyl carbonate promoted ring-opening reactions of DBU and DBN affording lactam carbamates

• Madhuri Vangala and
• Ganesh P Shinde

Beilstein J. Org. Chem. 2016, 12, 2086–2092, doi:10.3762/bjoc.12.197

• products [12]. Subsequently, Ma and Dolphin isolated chlorin-e6 lactams from the reaction of methyl pheophorbide with DBU and DBN promoted by trialkyl triflates [13]. Additionally, the conjugate addition reaction of DBU to diarylpyrone [14] and Baylis–Hillman acetates [15] also gave caprolactam products. A

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• they differ by a central, annelated furan-3-one moiety instead of an acrylate unit (Scheme 25) [149]. Their biosynthesis proceeds from chalcones by an oxidation–conjugate addition cascade catalysed by plant phenol oxidases (PPOs) [150][151]. The PPO aureusidin synthase plays a central role in aurone

• biosynthesis in Antirrhinum majus [152][153]. It catalyses the oxidation of phenols 180 and o-catechols 181 to o-quinones 182 and concomitant conjugate addition of a phenolic hydroxy group, leading to the formation of the central furan-3-one unit [154]. This enzyme is flavin-dependent and acts under

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

• are further classified according to whether catalysis is achieved with chiral Lewis acids, organocatalysts, or transition metals. Keywords: asymmetric catalysis; conjugate addition; enantioselective protonation; enolate; Introduction Due to their ubiquity in natural products and drugs, many

• -stereoselective step allows for the generation of a prochiral enolate intermediate that then undergoes enantioselective protonation (Figure 1). Two general strategies can be used when applying a conjugate addition–enantioselective protonation manifold. In the first strategy, a chiral enolate can be protonated by

• an achiral proton source (pathway A). In the second, an achiral enolate can be protonated by a chiral proton source (pathway B). Both strategies have been harnessed by various research groups for conjugate addition–enantioselective protonation reactions. This review covers the many conjugate addition

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

• )-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

• published [73]. This study shows that α’-oxyenones are very efficient key enoate equivalents in Brønsted base-catalyzed asymmetric conjugate addition of a range of soft nucleophiles such as α-substituted oxindoles, cyanoesters, oxazolones, azlactones and thiazolones to afford the corresponding

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

• % of this compound was employed in the enantioselective conjugate addition of the hydroxylamine derivatives 31 to the enoates 30, affording the final products 32 with good yield (up to 98%) and high enantiomeric excess (up to 98% ee). This provided an efficient method that allows the preparation of

(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

• Mannich–Michael pathway instead of the more “reasonable” Michael–Mannich pathway. In 2012, Wang and co-workers reported a novel domino Friedel–Crafts alkylation (via conjugate addition)-hemiacetalization catalyzed by rosin-derived tertiary amine-thiourea 187 (Scheme 61) [82]. Reagent 87 was successfully

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

• cyclopropanation using dimethyl bromomalonate (57) and some form of Michael acceptor. In this process, the enolate resulting from the initital conjugate addition attacks the C–Br bond to form a three-membered ring. In our work in this area, we designed a new cupreine derived catalyst HCPN-59 to add dimethyl

• nitroolefins, and (b) Lin’s similar process with α-nitroesters using the symmetric hydrocupreidine system HCPD-44. A diastereodivergent sulfa-Michael addition developed by Melchiorre and co-workers. Melchiorre’s vinylogous Michael addition. Simpkins’s TKP conjugate addition reactions. Hydrocupreine catalyst

Synthesis and reactivity of aliphatic sulfur pentafluorides from substituted (pentafluorosulfanyl)benzenes

• Norbert Vida,
• Jiří Václavík and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 110–116, doi:10.3762/bjoc.12.12

• transformations: electrophilic aromatic hydroxylation to the intermediate 6, oxidation to ortho-benzoquinone 7, Baeyer–Villiger (BV) oxidation, hydrolysis to muconic acid derivative 8, and finally intramolecular conjugate addition affording 3. Under certain conditions, small amounts of intermediates 6 and 8 were

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• already at that time the great potential of modern synthetic organic chemistry. More than 20 years later, in 1984, Oishi and co-workers reported a different strategy which culminated in the total synthesis of racemic β-caryophyllene (22) (Scheme 5) [34]. Their synthesis commenced with conjugate addition

• allenic sulfone [44] which, upon conjugate addition of diethyl amine followed by hydrolysis afforded a β-ketosulfone. For the following ring closure, the primary alcohol was desilylated and converted to the corresponding allylic carbonate 71. The cyclononene structure 72 was then assembled via a palladium

• -catalyzed conjugate addition of silyl ketene acetal 81a to enone ent-80. Deprotonation and trapping of the resulting enolate with formaldehyde furnished lactone 82 in a regio- and stereoselective fashion. Introduction of the exocyclic double bond proved to be challenging and therefore salt-free, highly

Copper-catalyzed stereoselective conjugate addition of alkylboranes to alkynoates

• Takamichi Wakamatsu,
• Kazunori Nagao,
• Hirohisa Ohmiya and
• Masaya Sawamura

Beilstein J. Org. Chem. 2015, 11, 2444–2450, doi:10.3762/bjoc.11.265

• Takamichi Wakamatsu Kazunori Nagao Hirohisa Ohmiya Masaya Sawamura Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan 10.3762/bjoc.11.265 Abstract A copper-catalyzed conjugate addition of alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of

• alkenes with 9-BBN-H) to alkynoates to form β-disubstituted acrylates is reported. The addition occurred in a formal syn-hydroalkylation mode. The syn stereoselectivity was excellent regardless of the substrate structure. A variety of functional groups were compatible with the conjugate addition

• . Keywords: alkylborane; alkynoate; conjugate addition; copper; multisubstituted alkene; Introduction Copper-mediated conjugate additions of organometallic reagents to alkynoates are powerful tools for the synthesis of multisubstituted alkenes [1][2][3][4][5][6][7][8]. Because of their broad availability

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• Chimie, 8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France 10.3762/bjoc.11.263 Abstract The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as

• ; sequential addition; Introduction Amongst the variety of synthetic methods available for the formation of C–C or C–heteroatom bonds, the asymmetric conjugate addition (ACA) of nucleophiles to electron-deficient alkenes is one of the most relevant and versatile for the synthesis of complex chiral molecules

• compound to an extended Michael acceptor was reported independently as early as 1972, by the Näf [4] and Corey [5] groups, who studied the reactivity of pentadienyl methyl ester (1, Figure 2). In both cases, the 1,6-conjugate addition of a stoichiometric amount of a Gilman reagent proceeded in a selective

Copper-catalyzed arylation of alkyl halides with arylaluminum reagents

• Bijay Shrestha and
• Ramesh Giri

Beilstein J. Org. Chem. 2015, 11, 2400–2407, doi:10.3762/bjoc.11.261

• form triorganoaluminate species in the presence of anions in solution [52][53][54][55][56][57]. In addition, organoaluminum reagents have been demonstrated to undergo transmetalation with Cu salts based on their participation in allylic and conjugate addition reactions [11][15][43]. Similar Cu

Copper catalysis in organic synthesis

• Sherry R. Chemler

Beilstein J. Org. Chem. 2015, 11, 2252–2253, doi:10.3762/bjoc.11.244

• . Some of the most highly cited papers of all time on this topic are reviews on conjugate addition, cross-coupling, and [3 + 2] “Click” reaction applied to bioconjugation. The growth in copper-catalyzed organic reactions may be driven by a couple of factors. First, copper chemistry is incredibly diverse

Chiral Cu(II)-catalyzed enantioselective β-borylation of α,β-unsaturated nitriles in water

• Lei Zhu,
• Taku Kitanosono,
• Pengyu Xu and
• Shū Kobayashi

Beilstein J. Org. Chem. 2015, 11, 2007–2011, doi:10.3762/bjoc.11.217

• Lei Zhu Taku Kitanosono Pengyu Xu Shu Kobayashi Department of Chemistry, School of Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan 10.3762/bjoc.11.217 Abstract The promising performance of copper(II) complexes was demonstrated for asymmetric boron conjugate addition to α,β

• ]. Enantioselective boron conjugate addition to α,β-unsaturated nitriles provides one of the most efficient routes to chiral β-boryl nitriles. Several straightforward methods have been developed that rely on chiral Cu(I) complexes with air-sensitive phosphine ligands [11][12][13][14][15]. In contrast, Cu(II)-based

• catalysis, which has been reported recently for asymmetric boron conjugate addition, is characterized by the effective and thermodynamically stable catalysis in water. Furthermore, a broad range of α,β-unsaturated acceptors, including one example of an α,β-unsaturated nitrile, are applicable, and the

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

• Jingjing Wang,
• Samuel Z. Y. Ting and
• Joanne E. Harvey

Beilstein J. Org. Chem. 2015, 11, 1815–1822, doi:10.3762/bjoc.11.197

• the methyl ester 14 [48]. Cuprate-mediated conjugate addition of a methyl nucleophile to the ynoate 14 provided the Z-enoate 15. Our attempts to directly reduce the ester 15 to the aldehyde 8 were unsuccessful due to competitive over-reduction to the corresponding alcohol. Therefore, a two-step

Reaction of allene esters with Selectfluor/TMSX (X = I, Br, Cl) and Selectfluor/NH₄SCN: Competing oxidative/electrophilic dihalogenation and nucleophilic/conjugate addition

• A. Srinivas Reddy and
• Kenneth K. Laali

Beilstein J. Org. Chem. 2015, 11, 1641–1648, doi:10.3762/bjoc.11.180

• ) is diminished in allenoates, most significantly in reactions with TMSCl, and essentially disappearing in reactions with NH4SCN, in favor of nucleophilic/conjugate addition. The study underscores the contrasting reactivity patterns in 1-arylallenes and allenoates toward electrophilic and nucleophilic

• additions in halofunctionalization with TMSX/Selectfluor and thiocyanation reactions with NH4SCN/Selectfluor. These competing pathways are influenced by the nature of the anion, allene structure, and the choice of solvent. Keywords: allene esters; oxidative electrophilic dihalogenation/conjugate addition

• /Selectfluor in MeCN, DMF, as well as in [BMIM][PF6] and [BMIM][NTf2]. The isomeric conjugate addition products 1l and 1m were isolated, with 1l as the major isomer. Unlike previous findings with 1-arylallenes [18], no dithiocyanation products were found irrespective of the choice of solvent (Scheme 4). In

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• provided acrylate 226, which was subjected to enantioselective copper-catalyzed conjugate addition with a methyl Grignard reagent involving (R)-tol-BINAP ligand to generate ester 227 in good yield and high enantiopurity. This intermediate was then converted to the key metathesis precursor involving a three

One-pot odourless synthesis of thioesters via in situ generation of thiobenzoic acids using benzoic anhydrides and thiourea

• Mohammad Abbasi and
• Reza Khalifeh

Beilstein J. Org. Chem. 2015, 11, 1265–1273, doi:10.3762/bjoc.11.141

• reaction of thiourea with benzoic anhydrides, which were subjected to conjugate addition with electron-deficient alkenes or a nucleophilic displacement reaction with alkyl halides. Keywords: benzoic anhydride; Michael addition; nucleophilic displacement; thioester; thiourea; Introduction Thioesters have

• -based reactions have a foul smell, making them unpleasant. Thioesters can also be prepared through the conjugate addition and nucleophilic displacement reactions using thioacid nucleophiles. Nevertheless, the reactions of thioacids have not been widely studied because they are not sufficiently available

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• Katherine M. Byrd Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive Lawrence, Kansas 66045-7582, USA 10.3762/bjoc.11.60 Abstract The conjugate addition reaction has been a useful tool in the formation of carbon–carbon bonds. The utility of this reaction has been

• demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain

• underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams. Keywords: α,β-unsaturated amides; α,β-unsaturated lactams; conjugate addition

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• Patchornik [20]. As a complicating factor, unlike other side-chain derivatives of hydroxyamino acids, the O-acrylic derivatives are powerful acceptors for conjugate addition and must be kept strictly in salt form to avoid decomposition through self-addition. The problem is exacerbated in proline derivatives

• propylene oxide in lower alcohols [46]. The acrylic derivatives, however, must be kept in salt form to avoid decomposition by conjugate addition. Acylation of hydroxyproline with aliphatic acyl chlorides in CF3CO2H gave a near quantitative yield of product (although the total yield was eroded by the

Copper-catalyzed cascade reactions of α,β-unsaturated esters with keto esters

• Zhengning Li,
• Chongnian Wang and
• Zengchang Li

Beilstein J. Org. Chem. 2015, 11, 213–218, doi:10.3762/bjoc.11.23

• not suitable for some acid-sensitive or base-sensitive intermediates. Alternatively, the lactone is also formed through the reaction of a carbonyl with an enolate that can be generated from a metal-catalyzed conjugate addition of an α,β-unsaturated diester. As shown in Figure 1, it involves a

• of γ-carboxy-γ-lactones via a copper-catalyzed cascade reaction. Considering that the reported conjugate addition–aldolization–lactonization cascade reactions proceed via the key intermediate A in Figure 1, we envisioned that the conjugate reduction of a methacrylate and the following aldol reaction

• esters and a silane was developed. The reaction involves conjugate addition of copper hydride, generated in situ, to α,β-unsaturated esters, followed by the aldolization with a keto ester and lactonization. It gives γ-carboxymethyl-γ-lactones and δ-carboxymethyl-δ-lactones in high yields, and provides a

Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides

• Zsolt Szakonyi,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2014, 10, 2738–2742, doi:10.3762/bjoc.10.289

• -butyl perillate (3), however the saturation of the isopropenyl function at position 4 proved to have no effect on the stereoselectivity of the reaction (Scheme 3). When N-benzyl-N-α-methylbenzylamine was applied as a chiral nucleophile in the conjugate addition, the steric effect of the α-methyl

• synthesis of β-peptides and 1,3-heterocycles in three steps. The steric effects of the isopropyl group at position 4 and of the α-methyl substituent of (R)-N-benzyl-N-α-methylbenzylamine on the reactivity were also studied and, upon application of a chiral amine, excellent stereoselectivity of the conjugate

• addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale. Keywords: asymmetric synthesis; β-amino acid; chiral; Michael addition; monoterpene; Introduction In the past decade, cyclic β-amino acids

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• summarized, as well as an overview of the synthesis of the employed phosphonamide reagents. Keywords: conjugate addition; cyclopropanation; olefination; organophosphorus; phosphonamide; total synthesis; Introduction Chiral non-racemic and achiral cyclic phosphonamide reagents 1–7 (Figure 1) have been

• in 28–64% ee [5]. In a similar fashion, Denmark’s oxazaphosphorinane cis-44a yielded keto esters 46a–c in high optical purities via conjugate addition to enones 41 followed by ozonolysis and oxidative esterification. Using diastereomer trans-44b on the other hand provided ketoesters 46a–c with only

• used for limited exploratory studies. Cyclopropanation and aziridination The cyclopropanation of α,β-unsaturated esters and lactones using chiral phosphonamide reagents is a special case of the conjugate addition–enolate alkylation sequence. The application of chloroallyl phosphonamides such as (trans

A tandem Mannich addition–palladium catalyzed ring-closing route toward 4-substituted-3(2H)-furanones

• Jubi John,
• Eliza Târcoveanu,
• Peter G. Jones and
• Henning Hopf

Beilstein J. Org. Chem. 2014, 10, 1462–1470, doi:10.3762/bjoc.10.150

• economic and most importantly eco-friendly [1][2]. Conjugate addition is a very efficient tool used by synthetic chemists for the construction of carbon–carbon or carbon–heteroatom bonds [3]. Much effort has been invested to develop different variants of conjugate additions, both in catalyzed and non

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• Pd(II)-catalyzed Miyaura 1,4-conjugate addition of phenylboronic acid to cyclohexenone [39]. The resulting ketone 25 was reduced to the axial [40][41] and equatorial [40] alcohols 26 and 27 with excellent diastereoselectivity thanks to steric control of the hydride source. After column chromatography