New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• of organocatalysis. While traditional hydrogen bond donors containing N–H and O–H moieties have been effectively used for electrophile activation, activation based on other types of non-covalent interactions is less common. This mini review highlights recent progress in developing and exploring new

• organic catalysts for electrophile activation through the formation of C–H hydrogen bonds and C–X halogen bonds. Keywords: C–H hydrogen bond; counteranion activation; electrophile activation; halogen bond donor; hydrogen bond donor; organocatalysis; Review Introduction Over the past century chemists

• the near future. Electrophile Activation by Hydrogen Bond Donors [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Early examples of C–H hydrogen bonds and their recent use in supramolecular chemistry [18][19][32][33][34]. Design of 1,2,3-triazole-based catalysts for trityl group transfer

A direct method for the N-tetraalkylation of azamacrocycles

• Andrew J. Counsell,
• Angus T. Jones,
• Matthew H. Todd and
• Peter J. Rutledge

Beilstein J. Org. Chem. 2016, 12, 2457–2461, doi:10.3762/bjoc.12.239

• high levels of over-alkylation to quaternary amine salts observed. Using exactly four equivalents of the electrophile increased the yield to 30%, while adopting a modified Finkelstein procedure by adding catalytic sodium iodide gave a modest further increase in yield, to 39%. Adapting the Tsukube

Chiral ammonium betaine-catalyzed asymmetric Mannich-type reaction of oxindoles

• Masahiro Torii,
• Kohsuke Kato,
• Daisuke Uraguchi and
• Takashi Ooi

Beilstein J. Org. Chem. 2016, 12, 2099–2103, doi:10.3762/bjoc.12.199

• reduced diastereoselectivity (Table 2, entries 1–4). Sterically demanding 2-tolualdehyde-derived imine 3f served as a good electrophile and the corresponding Mannich adduct 4af was isolated as virtually a single stereoisomer (Table 2, entry 5). 3-Thiophenyl aldimine 3g was also well tolerated, but a

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

• nucleophilicity of DBU/DBN and highly electrophile p-nitrophenyl carbonate derivatives. The reactions proceeded even at room temperature and displayed the nucleophilic addition and substitution with the p-nitrophenyl carbonate derivative of 10-bromodecanol. These caprolactam derivatives may find application in

Ionic liquids as transesterification catalysts: applications for the synthesis of linear and cyclic organic carbonates

• Maurizio Selva,
• Alvise Perosa,
• Sandro Guidi and
• Lisa Cattelan

Beilstein J. Org. Chem. 2016, 12, 1911–1924, doi:10.3762/bjoc.12.181

• nucleophile and the electrophile. Scheme 20 shows the proposed mechanisms for the exemplar transesterification of a generic alcohol ROH with DMC using [P8881][MeOCO2] as catalyst. The catalytic cooperative activation also explains the selective formation of cyclic or linear products of Scheme 20, without the

• catalysis by the ionic liquid. This type of ambiphilic catalysis is characterized by the nucleophile and the electrophile both being activated respectively by the anion and by the cation of the ionic liquid. Thirdly, organic carbonates – used as feedstocks or produced by transesterification – are valuable

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• in Supporting Information File 1). The N-iPr product 15a was isolated in only 3% yield. This, therefore, indicates that the electrophile reacts faster with the oxide anion of 13. Repeating the reaction with 15-crown-5 to limit the effect of the sodium cation did not appreciably effect the product

Reactions of N,3-diarylpropiolamides with arenes under superelectrophilic activation: synthesis of 4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones and their derivatives

• Larisa Yu. Gurskaya,
• Diana S. Belyanskaya,
• Dmitry S. Ryabukhin,
• Denis I. Nilov,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2016, 12, 950–956, doi:10.3762/bjoc.12.93

• the large charge on C2 of the protonated carbonyl groups and its substantial contribution into LUMO (Figure 2), this carbon is not reactive, probably, due to steric reasons. A comparison of the electrophilicity indices ω of C1 and D1 (Table 2) revealed that the former is stronger electrophile. Also

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

• enolate or equivalent is fixed due to their cyclic nature, thus facilitating the control of the stereoselectivity; iii) they are substituted at the α-position of the carbonyl and therefore, after reaction with an electrophile, a tetrasubstituted stereocenter is created and, iv) the resulting adducts can

• being necessary for catalyst activity (Figure 4a) [87][88][89]. In 2010 Zhong proposed that the presence of the ortho C–H bond of the aryl group could be the key for success because it could participate together with the thiourea function in the activation of the electrophile [90]. This proposal was in

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• face of the enolate, driving the electrophile to attack from the Si face. Conclusion In summary, we have realized enantioselective α-aminations of 3-substitued oxindoles with azodicarboxylates by using amino acid-derived bifunctional phosphine catalysts. These reactions afford a variety of chiral 2

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• on the distal nitrogen atom is likely preventing this nitrogen from attacking the electrophile and triggers an elimination process which would yield a byproduct like 29. Of particular interest, when benzophenone (Ph2CO) was used to trap the α-lithiation product of N-Boc-N’-alkylpiperazines, in

• -piperazine 57. In summary, promising progress has been made in the direct α-lithiation trapping of N-Boc-protected piperazines, including enantioselective versions. So far, these methods are limited by narrow electrophile scopes and often low enantioselectivities rendering further developments necessary

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• nitro-Michael addition; supported catalysts; thioureas; Introduction The use of chiral bifunctional thioureas that allow the simultaneous activation of a electrophile, by hydrogen bonding, and a nucleophile, by deprotonation, plays a major role in the stereoselective formation of C–C bonds in different

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

• % ee) (Scheme 10b) [39]. Based on the experimental results, the authors proposed a bifunctional mode of activation (TS7), where the electrophile is fixed and activated by the thiourea framework through several hydrogen bonds. At the same time, the indole is oriented to attack the Re face of the Michael

• reaction pathway based on previously reported transition states (Figure 6). The catalyst ent-4 would activate and fix the electrophile through several hydrogen-bonding interactions with the NH groups of the thiourea. Simultaneously, the hydroxy group would be involved in the activation of the nucleophile

(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

• ethyl malonate, producing the active nucleophile, while the thiourea group activates the electrophile (Scheme 6). The above catalytic reaction provided products with yields up to 99%, dr up to 93:7 and ee up to 93%. Carter and co-worker utilized a similar primary amine-thiourea, organocatalyst 11, in an

• of the nucleophile, making the diene more nucleophilic, and lowers the LUMO of the electrophile, making the dienophile more electrophilic (Scheme 19), thus the catalyst acts via a bifunctional mode. All these interactions are developed in the transition state through hydrogen-bonding, which controls

• same nucleophile 81, Wang and his group combined it with β,γ-unsaturated α-ketoesters 87, as the electrophile, catalyzed by bifunctional indane-derived thiourea 88, to produce derivatives of 3,4-dihydro-2H-pyran 89 (Scheme 30) [49]. This reaction sequence involved a Michael reaction, followed by a

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

• carbonyl electrophile to afford α-hydroxy ketones (benzoins). It is a 100% atom-economic process wherein a new stereocentre is produced. The reaction is sometimes referred to as acyloin condensation to encompass reactions of aliphatic aldehydes. The assembly of two molecules of the same aldehyde is known

• aldehydes react with an aza electrophile. Imines possessing an electron-withdrawing N-substituent constitute the most commonly used aza electrophile and the reaction affords an α-aminocarbonyl compound as the product. The NHC-mediated addition of aldehyde-derived acyl anions to nitroso compounds leading to

• -2-amino3-hydroxyindanones is catalysed by NHC 31. The imine electrophile is generated in situ from α-sulfonyl-N-Boc amine 33 (Scheme 19). Initial cross-aza-benzoin reaction of one of the aldehyde functionalities with the imine is followed by an intramolecular aldol reaction to furnish the indanone

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

• ]. In this classic process, it was hypothesized that the 6’-OH group was critical in directing the incoming aldehyde electrophile (see Scheme 1 box). Soon after, Shi and co-worker demonstrated the use of β-ICPD in the reaction of imines 5 with methyl vinyl ketone (MVK, 6) using the same catalyst (Scheme

• processes, the tertiary amine adds into the conjugate ester as with the MBH reaction, but instead of the resulting C3-ammonium enolate reacting with an electrophile, an E1cB elimination of the carbonate occurs to generate another conjugated system. This can then undergo an attack by a Michael donor

• hydroxydiketopiperizine system 56 with very high diasterecontrol. Once again, the authors invoke a critical role for the 6’-OH group in the co-ordination and activation of the electrophile in these processes. Cyclopropanations Not unrelated to the Michael addition in a mechanistic sense, is the asymmetric

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

• Ming-Liang Zhang,
• Deng-Feng Yue,
• Zhen-Hua Wang,
• Yuan Luo,
• Xiao-Ying Xu,
• Xiao-Mei Zhang and
• Wei-Cheng Yuan

Beilstein J. Org. Chem. 2016, 12, 295–300, doi:10.3762/bjoc.12.31

• sites, have captured tremendous attention in particular due to their unique ability of the simultaneous activation of the nucleophile and the electrophile in the same transition state [7][8][9][10][11]. Among them, chiral bifunctional thioureas bearing multiple hydrogen-bond donors have been

A convergent, umpoled synthesis of 2-(1-amidoalkyl)pyridines

• Tarn C. Johnson and
• Stephen P. Marsden

Beilstein J. Org. Chem. 2016, 12, 1–4, doi:10.3762/bjoc.12.1

• -amidoalkyl)pyridines that arises from a formally ‘umpoled’ coupling of an α-(amidoalkyl) anion equivalent with a pyridyl electrophile. Results and Discussion Reaction discovery Our research group has a longstanding interest in the synthesis of α,α-disubstituted amino acids [11][12][13][14][15], and in

• pyridylamino acid 9 (Nu = OH) [22][23]. After some minor process optimisation, this product was isolated in 64% yield. We recognised that this constitutes a formally ‘umpoled’ [24] coupling of an α-amino- or amidoalkyl anion [25][26][27] with a pyridyl electrophile and hence would complement existing synthetic

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• isoquinolinium ion 9, and found that improved yields and ee’s can be achieved using this substrate and a CuBr/Quinap catalyst, despite the fact that Quinap had proven inferior to Ph-Pybox in the CDC reaction (Scheme 4) [24]. With this new catalyst and electrophile, the catalyst loading, reaction temperature, and

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

• regiocontrol of the nucleophilic attack, which can occur at three different positions, at least. The regioselectivity outcome of the ACA reaction depends on many parameters, notably the metal/chiral ligand combination, the structure of the electrophile and the nature of the nucleophile. Figure 1 depicts the

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• to produce the RuBisCO substrate 1. A property of RuBisCO with great implications is that it may also accept O2 instead of CO2 as an electrophile in the addition step, thus catalysing a counter-productive reaction, which reduces the photosynthetic output of plants using the Calvin cycle by 25% [48

Molecular-oxygen-promoted Cu-catalyzed oxidative direct amidation of nonactivated carboxylic acids with azoles

• Wen Ding,
• Shaoyu Mai and
• Qiuling Song

Beilstein J. Org. Chem. 2015, 11, 2158–2165, doi:10.3762/bjoc.11.233

• ) superoxide species were reported to be formed under our standard conditions and might act as a nucleophile to attack carbonyl groups in certain cases [30], although it was always reported as an electrophile [32]. Thus, a new intermediate, peroxycarboxylate, will be formed in our case. In order to figure out

Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

• Artem A. Zemtsov,
• Alexander D. Volodin,
• Vitalij V. Levin,
• Marina I. Struchkova and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2015, 11, 2145–2149, doi:10.3762/bjoc.11.231

• difluorocarbene addition to multiple bonds [15]. Recently, we proposed a general method for assembling gem-difluorinated structures from organozinc reagents 1, difluorocarbene, and a terminating electrophile [16][17][18][19][20][21] (Scheme 1). (Bromodifluoromethyl)trimethylsilane [16][17][18] or potassium

Synthesis of quinoline-3-carboxylates by a Rh(II)-catalyzed cyclopropanation-ring expansion reaction of indoles with halodiazoacetates

• Magnus Mortén,
• Martin Hennum and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2015, 11, 1944–1949, doi:10.3762/bjoc.11.210

• -carbenoid in the C3-position of N-methylindole followed by elimination of bromide. The conjugated iminium ion is a very good electrophile and can undergo an electrophilic aromatic substitution in the C3-position of N-methylindole to form the bisindole product. Conclusion We have developed a mild and

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

• catalyst for oxidative functionalization is comparatively less explored [11]. Notable examples of oxidative functionalization by Selectfluor include in situ generation of electrophile equivalents Cl+, Br+, SCN+ and NO2+ and their reactions with aromatics [12], the bromination of representative alkenes with

A new method for the synthesis of α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues

• Anna Kuźnik,
• Roman Mazurkiewicz,
• Mirosława Grymel,
• Katarzyna Zielińska,
• Jakub Adamek,
• Ewa Chmielewska,
• Marta Bochno and
• Sonia Kubica

Beilstein J. Org. Chem. 2015, 11, 1418–1424, doi:10.3762/bjoc.11.153

• derivatives consist in the consecutive formation of two Cα–P bonds between a carbon electrophile (most often an electrophilic imine intermediate) and two identical molecules of the proper phosphorus nucleophile. Another group of methods requires the formation of a Cα–N bond between an easily accessible

• , symmetrical, nucleophilic methylenebisphosphonic acid derivative and a nitrogen electrophile. Both groups of methods result in symmetrical products with the same phosphonyl or dialkoxyphosphonyl groups [10][11][12][13][14][15][16][17][18]. Up until 1989, very little was known about the preparative feasibility