A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• ., benzaldehydes) and low-molecular-weight enolate nucleophiles, therefore, temperature regulation is vital for selectivity. This requirement for strict temperature control makes aldol reactions highly suited to flow processing conditions. In 2008, Tanaka et al. [96] disclosed several examples of aldol reaction in

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• -butanesulfinyl ketimine condensation (Scheme 2) [21]. Mechanism of addition of nucleophiles to N-sulfinyl imines The p-toluenesulfinamide 5 was first described by Davis and co-workers in a racemic form [22], and subsequently, the compound was prepared and isolated as a single enantiomer [23][24], becoming an

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• (phosphines, NHC-carbenes, bisoxazolines, pyridine-oxazolines, and miscellaneous) is used. Review Catalytic systems based on phosphine ligands A pioneering work on the enantioselective addition of boron-derived carbon nucleophiles to cyclic enones was published by the group of Miyaura et al. in 2005 [32

• ]. Specifically, they have dealt with the addition of potassium aryltrifluoroborates to conjugated cyclic enones differing in ring size [32]. The catalysts PdL1a,b exhibited great conversion and enantioselectivities (up to 99% and up to 96% ee) for various combinations of nucleophiles and enones (Table 1). The

• of the Pd-catalysed enantioselective addition of boronic acids to cyclic enones [37]. Addition of boron-derived C-nucleophiles to cyclic enones, catalysed by L2/Pd(TFA)2 [37]. Asymmetric addition of arylboronic acids to 2-cyclohexenone catalysed by L3/Pd(dba)2 [39]. Additions to different enones

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• 3100–3400 cm−1 for the N–H bonds vibrations. NMR spectra record specific signals at 6.8–7.5 ppm for the shifts of the protons and 158–165 ppm for the 13C. Biguanides are good nucleophiles and easily carbonated under ambient conditions. They are stable over a wide range of pH. Often, heating in the

• corresponding bisamidinohydrazide product with a moderate 48% yield using the same conditions. Recently, the scope of the transformation was extended to other aminated nucleophiles such as hydroxylamine and methoxyamine. By using methoxyamine hydrochloride as a reactant along with 1 equivalent of pyridine, the

• N1,N5-substituted biguanides, that shows little variation in reactivity. By adapting these conditions, other reactants can be used such as nitrogen-containing heterocycles, other aminated nucleophiles, or ortho-substituted anilines, extending the scope of this reaction to a broader diversity of

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• -nucleophiles were compared under optimized reaction conditions (Table 3). In the case of 2-phenylethanol (2a) as an O-nucleophile, a similar reactivity, yield of mannoside 3a and α-selectivity were observed (Table 3, entries 1–3) among all the halides α-1a–c, although mannosyl chloride α-1b and bromide α-1c

• corresponding chloride α-1b or bromide α-1c. The stability of the latter in liquid SO2 at such a high temperature was unexpected due to their generally established labile nature. Additionally, when competitive glycosylation reactions in the presence of both O- and S-nucleophiles were performed, all mannosyl

• containing an excess of β-anomer β-16 was optimized to 60 °C, while for the more reactive α-anomer α-16 it was decreased to 30 °C. Regardless of the anomeric ratio, the desired O- and S-glucosides 18a–f were isolated in good yields. Besides, glycosylation of primary nucleophiles with benzyl-protected

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• nucleophiles. The second report, by Scheeren [7], working from a bis(phenoxy)chloromethane synthesis reported by Scheibler [8], described the conversion of phenyl orthoformate to bis(phenoxy)chloromethane with acetyl chloride and anhydrous hydrogen chloride, followed by reaction with potassium

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• deallylation of AllMSP is more efficient than its demethylation, which is surprising, because naturally DmdA catalyzes a methyl-group transfer. This finding may reflect the high reactivity of the allyl group towards nucleophiles. Other compounds originating from AllMSP included the di- and trisulfides 2, 26

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• nucleophiles [27][28][29][30]. Thionaphthols, however, are overlooked in sulfa-Michael addition reactions. And to our best knowledge, no study is present concerned with SMAs with naphthalene-1-thiol as the nucleophile for the addition to enones. Encouraged by the good results obtained with enantioselective

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines

• Geetanjali S. Sontakke,
• Rahul K. Shukla and
• Chandra M. R. Volla

Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42

• secondary amines as the nucleophiles [49]. In their protocol, the regioselectivity is controlled by PyBroP catalyst, which acts as the N-oxide activator. Manley and Bilodeau reported the amidation of heterocyclic N-oxides at the C2-position using oxalyl chloride for activating the N-oxides [50]. In addition

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• phosphonodepsipeptides 56 and 57, respectively. The oxidative activation was carried out in the presence of alcohols as nucleophiles so that stoichiometric formation of the phosphonochloridate was avoided and side reactions were minimized (Scheme 9) [25]. The current chlorination is a mild and neutral method for the

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• . A series of substituted products was obtained in SNAr reactions between 2,6-bistriazolylpurine derivatives and O- and C-nucleophiles under mild conditions. The products were isolated in yields up to 87%. The developed C–O and C–C bond forming reactions clearly show the ability of the 1,2,3-triazolyl

• -nucleophiles [12][13][14] and in metal catalyzed reactions of halopurine derivatives [15][16][17][18][19][20]. Modifications of purines with O-nucleophiles are based on SNAr reactions between 6-halopurine derivatives and alcohols [21][22][23][24][25][26][27][28] in the presence of a base. Alcohols are used in

• ][45][46][47][48][49][50]. In the case of C-nucleophiles there are a few precedents of transition-metal-free substitution of chloro [51][52][53][54][55] or 1,2,4-triazolyl [56] moieties as leaving groups at the C6 position of purine. These transformations usually require prolonged time and elevated

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• < T < −40 °C in the presence of aromatic nucleophiles, thiophenes 72-Cl and 72-Br could be converted into 74-Cl and 74-Br derivatives via a side-chain arylation reaction. When the reaction was conducted at −40 °C, the reactivity was shown to be governed by the nature of the halogen atom. For the

• tetralin derivatives 144a and 144b, respectively (Scheme 36). In addition, 144a could be further converted into 146 in the presence of aromatic nucleophiles (e.g., benzene or toluene). Similarly, derivatives 147a–c could also be converted into indanol derivatives 148a–c in high yields (Scheme 36) [95]. Ma

• exploited the reactivity of the trifluoromethylated iminium ion 192 and extended the scope of the reaction to a larger panel of nucleophiles, including alcohols, amines, aromatic and vinyl derivatives, as well as silylated nucleophiles (Scheme 47) [122]. Brigaud and Huguenot also suggested the formation of

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• isomerization [36]. Several nitrogen nucleophiles have been evaluated as catalysts to promote the difluorocarbene formation from TFDA in order to bring about the cyclopropanation of a 2-siloxybuta-1,3-diene derivative; 1,8-bis(dimethylamino)naphthalene (proton sponge) was found to be particularly effective [37

• opposite to the CF2 fragment and the formation of a 2,2-difluorohomoallyl cation. Cleavage of the distal bond. Ring opening of gem-difluorocyclopropyl ketones: The gem-difluorocyclopropyl ketones such as 106 and 108 underwent nucleophilic ring-opening reactions induced by thiolate nucleophiles. A distal

• (Scheme 65) [97][98]. This contrasts with the previously discussed (Scheme 49) distal bond cleavage of ketone 106 in reactions with thiolate nucleophiles. It is likely that an elimination of HF from 106 to form a monofluorocyclopropene intermediate took place under the more strongly basic conditions. This

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• olefins [13][14]. Aziridines are otherwise accessible from a variety of acyclic precursors [15][16][17], even stereoselectively [18][19][20], and through derivatization of 2H-azirines. The reactions using 2H-azirines as electrophiles proceed with several nitrogen, oxygen and sulfur nucleophiles, enabling

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• leaving group in SNAr reactions with S- and N-nucleophiles [19][20][21]. It is worth to note that 2/6-amino-6/2-triazolylpurines possess high levels of fluorescence [19][22][23][24]. Herein, we describe an extension for SNAr reactions that makes use of the 1,2,3-triazole leaving group of 2,6

• analysis. This is similar to the previously observed substitution pattern in SNAr reactions of 2,6-bistriazolylpurine derivatives with simple N- and S-nucleophiles. Experimental General information Commercially available reagents were used as received. The reactions and the purity of the synthesized

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• Sandford group clarified the high potency of these compounds for the conjugate addition of N- as well as O-nucleophiles [21]. On the basis of such an idea, we tried two routes to gain access to 1) 4-substituted 6-(trifluoromethyl)salicylate derivatives (C-nucleophiles) and 2) 6-substituted 4

• -(trifluoromethyl)pyrimidines (N-nucleophiles), both in a concise fashion, with the full details, including the preparation of 2, being reported herein. Results and Discussion Investigations on the reaction conditions were carried out for the oxidation of propargylic alcohols 1, which were readily accessible by our

• structurally similar compounds [29] on the basis of 1) comparison of the chemical shift of the CF3 group and 2) the absence of a coupling between the vinylic and allylic protons. In order to explore other nucleophiles, we employed 1,3-diketones, such as 5-methylhexane-1,3-dione and 5,5-dimethylhexane-1,3-dione

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• perfluoroalkylthiolate nucleophiles. Each of the other BT-SRF reagents (1.25 equiv) was reacted with alcohol 2a and NEt(iPr)2 (2 equiv) in MeCN at −40 °C and, after 2 h, the crude mixture was analysed by 1H and 19F NMR. As shown in Table 1, a significant decrease in the nucleophilic perfluoroalkylthiolation efficiency

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• , Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain 10.3762/bjoc.16.217 Abstract In the present work, arylethynes were studied as new C-nucleophiles in the asymmetric Mannich addition reactions with (S

• yne nucleophiles have never been reported thus far. Accordingly, intrigued by this methodological deficiency, we decided to dedicate a special research project to this objective; herein, we report Mannich reactions between yne nucleophiles and aldimine 1 (Scheme 1c). The results reported in this work

• excellent level (>90% de) of stereocontrol reported for the Mannich additions of aldimine 1 with sp3 [42][55] and sp2 [56] nucleophiles, including lithiated aromatics [57] one would not anticipate such a dramatic drop in the selectivity in the reactions of sp nucleophiles. Accordingly, we considered the

Synthesis of 4-substituted azopyridine-functionalized Ni(II)-porphyrins as molecular spin switches

• Jannis Ludwig,
• Tobias Moje,
• Fynn Röhricht and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2589–2597, doi:10.3762/bjoc.16.210

• . Azopyridines 14, 16 and 18 were prepared by nucleophilic substitution with 2-methylpropane-2-thiol (13) and methyl 3-mercaptopropionate (15) as nucleophiles (Scheme 2). 3-(3-Bromophenylazo)-4-cyanopyridine (20) was directly obtained by conversion of 3-amino-4-cyanopyridine (19) and 3. Alkaline hydrolysis as

Clustering and curation of electropherograms: an efficient method for analyzing large cohorts of capillary electrophoresis glycomic profiles for bioprocessing operations

• Ian Walsh,
• Matthew S. F. Choo,
• Sim Lyn Chiin,
• Amelia Mak,
• Shi Jie Tay,
• Pauline M. Rudd,
• Yang Yuansheng,
• Andre Choo,
• Ho Ying Swan and
• Terry Nguyen-Khuong

Beilstein J. Org. Chem. 2020, 16, 2087–2099, doi:10.3762/bjoc.16.176

• using UPLC-MS The supernatant was purified using Protein A HP SpinTrap (GE Healthcare). The purified glycoprotein obtained was buffer exchanged into water using a 10 kDa molecular weight cut-off filter (Merck Millipore) to eliminate any salts and nucleophiles that could interfere with the subsequent

Efficient [(NHC)Au(NTf₂)]-catalyzed hydrohydrazidation of terminal and internal alkynes

• Maximillian Heidrich and
• Herbert Plenio

Beilstein J. Org. Chem. 2020, 16, 2080–2086, doi:10.3762/bjoc.16.175

• ; Introduction Cationic gold complexes with weakly coordinating counterions (which are often considered to be solvent-separated ions) [1][2][3], render powerful catalysts for the transformation of organic substrates [4][5][6], specifically the reactions of alkynes with a variety of heteroatom nucleophiles

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• variety of nucleophiles to afford products containing a C(CF3)NR2 moiety. In particular C(CF3)NHR and C(CF3)NH2 groups are of interest as pharmacophores in the design of bioactive compounds [10][11][12][13]. Simple α-(trifluoromethyl)iminium salts (RCH(CF3)=N+Me2 X−, R= H, CF3) with weakly nucleophilic or

• non-nucleophilic anions can be isolated [14][15], but in organic synthesis, they are most often generated in situ from suitable precursors and are directly exposed to diverse nucleophiles. Such transformations have been achieved using CH2(CF3)NR2 as the iminium ion precursors [15

A complementary approach to conjugated N-acyliminium formation through photoredox-catalyzed intermolecular radical addition to allenamides and allencarbamates

• Olusesan K. Koleoso,
• Matthew Turner,
• Felix Plasser and
• Marc C. Kimber

Beilstein J. Org. Chem. 2020, 16, 1983–1990, doi:10.3762/bjoc.16.165

• -acyliminium intermediate is provided to explain the addition product distribution. Results and Discussion We began our study by using the iridium catalyst Ir[(ppy)2(dtbbpy)]PF6 (17) and the reaction conditions used in the addition of amine nucleophiles to enamides [48][50]. By exploiting these reaction

• = 2.0 Hz, 1H) ppm, respectively. Crucially, it is apparent that using the photoredox conditions described in Scheme 3, the aniline nucleophile adds primarily at the α-position of the allenamide 15; this is in contrast to the archetypal electrophilic activation modes where comparable nucleophiles add to

• explored oxygen nucleophiles in their photoredox-catalyzed addition to enamides [48]. Consequently, the use of excess methanol provided the addition product 38, resulting from α-addition, in a modest isolated yield. The stability of product 38 was marginal, but an improved stability of the N,O’-allyl

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• nucleophiles [37][38][39]. The assignment of the reaction product to the 5-oxo isomer was made based on 13C NMR spectral analysis: the carbon atoms of the CH=СR fragment (R=CH3, Ph) are represented by a strong signal at δC 101–105 ppm (СН=) and a weak signal at δC 157–158 ppm (=CR). These data coincide with

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• through an olefination reaction with benzothiazoyl sulfones (Scheme 1) [22]. With these fluoroalkylidene-oxetanes in hands, we studied the selectivity of ring-opening reactions with heteroatom nucleophiles in order to access tetrasubstituted fluoroalkenes. A control of the geometry of these reactions

• would allow ready access to novel fluorinated ACN precursors. At the outset the opening of the oxetane ring of 1 by a range of nucleophiles was trialed under acidic conditions. Inspired by Yadav et al. [23], methanol (20 equiv) was used as nucleophile in the presence of camphorsulfonic acid (CSA, 1

• mercaptobenzothiazole (Table 1). However, the reaction was not selective and afforded a mixture of E/Z alkenes 1c. The functionalization of alkene E-1d via displacement of the bromine atom (Scheme 8), with nucleophiles such as CsF and NaN3 was then studied. When the reaction was performed in DMF products E-23 and Z-24