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

• transformations of the γ,δ-unsaturated 1,4-adducts were successfully performed: an oxidative cleavage afforded for example ketoester 52 (Scheme 15). Moreover, the in situ trapping of the addition product with acetic anhydride led to the regeneration of the lithium enolate, which was allylated and submitted to

• combination of copper(II) naphthenate (CuNaph) and SimplePhos L16 as the catalytic system [40]. The reported methodology involved a regioselective 1,4 ACA of trimethylaluminium followed by the trapping of the aluminium enolate intermediate with (n-butoxymethyl)diethylamine. An oxidation–elimination sequence

Recent developments in copper-catalyzed radical alkylations of electron-rich π-systems

• Kirk W. Shimkin and
• Donald A. Watson

Beilstein J. Org. Chem. 2015, 11, 2278–2288, doi:10.3762/bjoc.11.248

• alkenylation reactions. However, the product of addition of a secondary bromo keto ester possesses an acidic α-proton. This proton can be deprotonated by diisopropylamine, and the resulting enolate cyclizes onto the newly formed benzylic halide to form the dihydrofuran (Scheme 14). This method is formally a [3

SmI₂-mediated dimerization of indolylbutenones and synthesis of the myxobacterial natural product indiacen B

• Nils Marsch,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2015, 11, 1700–1706, doi:10.3762/bjoc.11.184

• ][28]. Thus, the indole NH group (pKa about 21 in DMSO) should be able to serve as a stoichiometric proton source that, after β,β'-coupling, would convert one of the Sm(III) enolates to the ketone. Attack of the remaining Sm(III) enolate would lead to Dieckmann-type ring closure, followed by

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

• , and finally, an intramolecular Michael addition to provide benzannulated large ring compounds 31 and 33. In this regard, substituted methyl 2-alkenyl-2-siloxycyclopropanecarboxylate 29 was converted into the alkylation product and further react with the ester enolate dibromide to yield vinyl

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• comprised three consecutive flow steps including a low-temperature enolisation of buspirone (7). The subsequent reaction of the enolate with gaseous oxygen in a trickle-bed reactor was coupled to a direct in-line quench of the reaction mixture to yield 6-hydroxybuspirone (Scheme 1). This approach

DBU-promoted carboxylative cyclization of o-hydroxy- and o-acetamidoacetophenone

• Wen-Zhen Zhang,
• Si Liu and
• Xiao-Bing Lu

Beilstein J. Org. Chem. 2015, 11, 906–912, doi:10.3762/bjoc.11.102

• -acetamidoacetophenone with carbon dioxide is proposed as shown in Scheme 1. The reaction can evolve along two pathways: in path A, deprotonation of o-acetamidoacetophenone by DBU gives enolate I, which undergoes an acyl migration from nitrogen to carbon [25][26] similar to the Baker–Venkataraman O to C acyl migration

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

• the oxygen of the resulting enolate of the CA reaction. This chelation to the magnesium would retard the 1,2-addition reaction from occurring. Since the Mukaiyama publication, there have been many chiral auxiliaries studied in DCA reactions of α,β-unsaturated amides [35]. Figure 2 highlights a few of

Attempts to prepare an all-carbon indigoid system

• Şeref Yildizhan,
• Henning Hopf and
• Peter G. Jones

Beilstein J. Org. Chem. 2015, 11, 363–372, doi:10.3762/bjoc.11.42

• at its exocyclic double bond. Indeed, when 9 was first metalated with LDA and the resulting enolate quenched with acetone, the resulting ketol could be dehydrated in situ by treatment with diethyl chlorophosphate to yield 13 [18]. Derivative 13 is a crystalline solid that can be kept in 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

• condensation [20]. Therefore, it is rationalized that an α,β-unsaturated monoester-derived enolate should react preferentially with the keto group in the keto ester to yield the alkoxide, which further lactonizes with an intramolecular ester group to form the lactone. It should provide a novel three-step

• -lactone with a γ-exo-ester group, in 90% yield (Table 1, entry 1). Since the existing methyl methacrylate may also compete as the enolate acceptor, the high yield of 3aa indicate that lactonization of the aldolization alkoxide B proceeded much faster than metathesis of B with a silane, which gave γ

Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

• Bin Yin,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2015, 11, 85–91, doi:10.3762/bjoc.11.12

• in the solution, and consequently the C–S bond cleavage seems to take place more favorably than a deprotonation. A similar effect on the suppression of defluorination of CF3-enolate anion in the presence of a large amount of fluoride ions has been reported [38]. On the other hand, it is known that

One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates

• Joshua P. Barham,
• Matthew P. John and
• John A. Murphy

Beilstein J. Org. Chem. 2014, 10, 2981–2988, doi:10.3762/bjoc.10.316

• catalysts are used in combination with various stoichiometric oxidants including oxygen [16][21]. However, nucleophilic trappings of resultant iminium salts are typically exemplified with highly stabilised carbon nucleophiles such as cyanides, nitronates, enolate equivalents and heterocycles (Scheme 1) [14

Morita–Baylis–Hillman reaction of acrylamide with isatin derivatives

• Radhey M. Singh,
• Kishor Chandra Bharadwaj and
• Dharmendra Kumar Tiwari

Beilstein J. Org. Chem. 2014, 10, 2975–2980, doi:10.3762/bjoc.10.315

• positive. In order to find the best conditions, several reactions were carried out. Increasing the reaction time to 5 days resulted in 56% yield (Table 1, entry 2). An increase in the loading of acrylamide (2 equiv, in order to generate more enolate) was helpful and resulted in 71% yield (Table 1, entry 3

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• with alkyl halides virtually yield single stereoisomers, in which the configuration of the newly formed stereogenic center at C-2 of the amino acid moiety is the same as that in the proline moiety of the chiral auxiliary in the starting material. In reactions of the enolate of this chiral glycine

• acetophenone in only four steps in an overall yield of 30%. A similar protocol for the synthesis of 3-alkylphenylalanines was independently developed by Soloshonok et al. [56]. These authors used sodium hydroxide for the deprotonation of 10 and 1-phenylalkyl bromides for the alkylation of the enolate. Once

Microsolvation and sp²-stereoinversion of monomeric α-(2,6-di-tert-butylphenyl)vinyllithium as measured by NMR

• Rudolf Knorr,
• Monika Knittl and
• Eva C. Rossmann

Beilstein J. Org. Chem. 2014, 10, 2521–2530, doi:10.3762/bjoc.10.263

• decayed at or above +3 °C through proton transfer from the solvent that was cleaved into ethylene and the enolate LiO–CH=CH2 [the latter identified through δH = 6.93 ppm (dd) and confirmed by δC = 81.9 and 158.9 ppm]. In t-BuOMe as the solvent, a purified sample of [6Li]4&TMEDA (entry 5, Table 1

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• construction of building blocks bearing quaternary carbon and fully substituted tertiary centers [1][2]. A recent addition developed by our laboratory is the allylic alkylation of nonstabilized enolate precursors to form α-quaternary carbonyl compounds (Scheme 1) [3]. Once the key stereocenter is set by this

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• ethyl acetate to afford the adduct 19. Diastereoselective methylation of the ester enolate moiety of 19 with MeI afforded only the anti-product 20 [32][33], which was then subjected to the deprotection of the TBDPS group with HF·pyridine, followed by cleavage of the ethyl ester group in 21 to give the

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• summarized splendidly in several reviews, we do not cover these transformations, except for selected examples related to other reactions. Review 1 Chiral phosphine catalysts Nucleophilic phosphine catalysis often involves the formation of Lewis adducts, namely phosphonium (di)enolate zwitterions, as reaction

• -RC reaction between the α,β-unsaturated imine and the enolate, followed by an SN2 reaction. 2.14 Annulations through double-Michael additions The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient alkynes provides an efficient approach for the synthesis of

• bond between the amide NH proton and the enolate oxygen atom assisted the Michael addition from the si-face of the enolate. The alternative re-face attack was blocked by the 3,5-bistrifluoromethylphenyl group (Scheme 55). 2.17 γ-Umpolung additions of allenes or alkynes In the phosphine-catalyzed

Five-membered ring annelation in [2.2]paracyclophanes by aldol condensation

• Henning Hopf,
• Swaminathan Vijay Narayanan and
• Peter G. Jones

Beilstein J. Org. Chem. 2014, 10, 2021–2026, doi:10.3762/bjoc.10.210

• the formation of 12 and 15 in the aldol reaction, both containing endo-configurated OH groups only (Scheme 4). The reaction is initiated by proton abstraction from one of the acetyl groups (9→16). The resulting enolate subsequently attacks the vicinal acetyl group, pushing the developing alcoholate

• mechanism is followed during the formation of the main product 15, the only difference between the pathways being the enolate formation, i.e., whether the second five-membered ring is produced by deprotonating a syn- or anti-positioned acetyl group. To learn more about the chemical properties of the above

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

• 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

• ,R,R)-47a in the conjugate addition to enones provides the corresponding fused endo,endo-cyclopropane 50a in high diastereomeric excess [51]. The transformation proceeds via the intermediate Michael adduct 49, which eliminates chloride after stereocontrolled attack of the enolate to afford

• methyl iodide afforded adduct 177 with excellent selectivity (dr > 95:5) (Scheme 22). Ozonolysis with reductive work-up and ensuing protection of the formed hydroxy group as TPDPS ether provided lactone 178. Addition of the enolate of tert-butyl acetate to 178 and ketal formation afforded 179. Reduction

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

• synthesis from imines is similar to that reported for activated alkenes [40]. This tandem protocol has two steps, the first being a Mannich addition of the enolate to the imine. To find out whether Mannich addition is palladium catalyzed, we carried out two reactions of tosylimine 1a with methyl

• propose a plausible mechanism for 3(2H)-furanone synthesis from tosylimines and 4-chloroacetoacetate (Scheme 3). The reaction starts with the Mannich addition of the enolate 15 to the carbon atom of the imine double bond to form intermediate 16. This step is the same for both the catalyzed and the

• closure towards the formation of 3(2H)-furanone is initiated by the abstraction of the acidic proton by the base and consequent ester enolate attack to the end carbon of the oxy-π-allylpalladium intermediate. Having established an efficient method for the synthesis of highly functionalized furanones from

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• 5. The alkylation step was optimized and it can be conducted with an enolate concentration of 4 up to 0.25 M in dioxane (Table 1). The attempt with higher enolate concentration was not smooth due to the increased viscosity of the reaction mixture and thus low efficiency of stirring, even with a

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• prepared using electrophilic fluorination of enolate esters [64][65][66], deoxofluorination [67][68][69] nucleophilic [70] and electrochemical fluorination [71][72] strategies. Attempts to prepare 2-fluoro-2-(2,4-dinitrophenyl)acetic acid by an analogous process led to the isolation of a benzyl fluoride

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• reagent and solvent. Finally, enolate is another nucleophilic species that was engaged in the AT reaction as shown in Scheme 18. In this reaction, an allenylketone was mixed with NaH in THF at −10 °C. After deprotonation (30 min), diethyl phosphite in CCl4 was added dropwise. Treatment with acetic acid

A convenient enantioselective decarboxylative aldol reaction to access chiral α-hydroxy esters using β-keto acids

• Zhiqiang Duan,
• Jianlin Han,
• Ping Qian,
• Zirui Zhang,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2014, 10, 969–974, doi:10.3762/bjoc.10.95

• appears as a common procedure, affording chiral tertiary alcohols which are ubiquitous in the biological sciences and pharmaceutical industry [1][2][3][4][5][6]. The decarboxylative aldol reaction, broadly used for the generation of ester enolate equivalents by the promotion of releasing CO2, has become

Site-selective covalent functionalization at interior carbon atoms and on the rim of circumtrindene, a C₃₆H₁₂ open geodesic polyarene

• Hee Yeon Cho,
• Ronald B. M. Ansems and
• Lawrence T. Scott

Beilstein J. Org. Chem. 2014, 10, 956–968, doi:10.3762/bjoc.10.94

• on the corresponding reaction of fullerenes, the mechanism in Scheme 6 is proposed for the Bingel–Hirsch reaction of circumtrindene. The enolate generated by deprotonation of bromomalonate 18 with DBU functions as a nucleophile; it attacks one of the strongly pyramidalized carbon atoms of