Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• -aminophosphonate 26 in 99% yield (Scheme 7) [34]. The reaction of isatin (27) with diethyl phosphite and benzylamine under similar conditions gave the corresponding α-aminophosphonate 28 in 90% yield together with small amounts of α-hydroxyphosphonate 29 as a side product (Scheme 8). The one-pot reaction of

• and the structure of the dialkyl phosphite and isatin (Scheme 9) [35]. In this way a one-pot three-component reaction between 1-tosylpiperidine-4-one (34), aromatic amines 35 and diethyl phosphonate in the presence of magnesium perchlorate as a catalyst, under neat conditions at 80 °C afforded α

• ZnO nanorods-catalyzed reaction of isatin derivatives 144 with malononitrile (145) and dialkyl or diphenyl phosphonates 146 has been performed to give 2-oxindolin-3-ylphosphonates 147 (Scheme 31) [56]. The products were obtained in good to excellent yields using 10 mol % of the catalyst under solvent

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• (Scheme 1) [14]. 3-Allyl-3-hydroxyoxindoles were obtained in 89–98% yield and with 32–86% ee when the reactions were carried out at −60 °C using 5 mol % of CNN pincer Pd complex (cat. 1). Substituents attached to the isatin aromatic ring and N-protecting groups were important in controlling the

• stereoselectivity. Products bearing electron-donating groups on the isatin core were obtained with high enantioselectivities. When the R2 group was 1-naphthylmethyl, trityl (Tr) or hydrogen, low ee values were observed. This protocol was successfully applied to the synthesis of 3-aminooxindoles, affording the

• reaction times may cause the decomposition of products in the presence of K2CO3. In 2014, Wang et al. designed the chiral tridentate Schiff-base/Cu complex (cat. 3) for the asymmetric Friedel–Crafts alkylation of pyrrole with isatins (route a, Scheme 5) [17]. For N-protected isatin substrates, the final

(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

• aminoaldehyde product. Finally, the N-protected aminoaldehyde product can now be cyclized under the reactions’ conditions. Another stereoselective reaction was attempted by Kotsuki’s group presenting an organocatalytic hetero-Diels–Alder reaction between isatin 229 with substituted diene 230. High pressure had

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

• adduct. A variety of trifluoromethylated α-aminoketones could be synthesised in enantiomerically pure form using this method (Scheme 25). Isatin derived ketimines 41 were employed as electrophiles in the NHC-catalysed chemo- and stereoselective cross-aza-benzoin reaction with enals by Chi. The reaction

• -benzoin reaction of aldehydes with N-PMP-imino esters. NHC-catalysed coupling reaction of acylsilanes with imines. Thiazolium salt-mediated enantioselective cross-aza-benzoin reaction. Aza-benzoin reaction of enals with activated ketimines. Isatin derived ketimines as electrophiles in cross aza-benzoin

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

• this work, Shi, Li and co-workers partnered the isatin derived N-Boc ketimines 8 with MVK (6, Scheme 3a) to obtain the corresponding adducts 9 with very good selectivity [22]. Interestingly, replacing the Boc group with an ethyl carbamate decreased the yield and enantioselectivity dramatically, as did

• utility of the adducts obtained was demonstrated through their conversion to a number of useful constructs (e.g., 16 and 17). In reactions very much related to the MBH process, isatin derivatives have also proven to be particularly suited to the reaction of MBH-like products [26][27][28]. In these

• ; elimination of the catalyst then generates the exo-methylene adduct. For example, Lu and co-workers have used β-ICPD to react isatin-derived MBH carbonates 18 with nitroalkanes 19 [29]. The resulting adducts 20 could be converted to the corresponding spiroxindole 21 via a Zn/HOAc mediated reduction of the

Application of 7-azaisatins in enantioselective Morita–Baylis–Hillman reaction

• Qing He,
• Gu Zhan,
• Wei Du and
• Ying-Chun Chen

Beilstein J. Org. Chem. 2016, 12, 309–313, doi:10.3762/bjoc.12.33

• acrolein catalyzed by β-isocupreidine (β-ICD) was reported by the Zhou group [5], isatin derivatives, as highly activated electrophiles, have been utilized by other groups for similar transformations with acrylates or acrylamides, affording the 3-hydroxyoxindole derivatives with moderate to excellent

• stereocontrol [6][7][8][9][10][11][12]. Maleimides are also good nucleophilic precursors in the MBH reactions and in 2013, Chimni developed an asymmetric MBH reaction of isatins and maleimides with excellent enantioselectivity [13]. Later, the same group expanded this strategy to isatin-derived ketimines under

A new and convenient synthetic way to 2-substituted thieno[2,3-b]indoles

• Roman A. Irgashev,
• Arseny A. Karmatsky,
• Gennady L. Rusinov and
• Valery N. Charushin

Beilstein J. Org. Chem. 2015, 11, 1000–1007, doi:10.3762/bjoc.11.112

• –Knorr cyclization, thus affording tricyclic thieno[2,3-b]indoles. Keywords: aldol-crotonic condensation; isatin; Lawesson’s reagent; methyl ketones; Paal–Knorr reaction; thieno[2,3-b]indole; Introduction 8H-Thieno[2,3-b]indole is a fused heterocyclic system, which has attracted a considerable

• indoline-2-ones 11 from isatins and methyl ketones has previously been realized [32][33]. In particular, preparation of 2-methyl-8H-thieno[2,3-b]indole from unsubstituted isatin and acetone in 15% yield has been reported [32] (Scheme 2). Although it seems to be a very harmonious strategy, it has hardly a

• means of the Paal–Knorr reaction. Compound 9a has also been treated with the Lawesson's reagent in toluene to give the title product 12a via intermediacy of 10a in a low 10% yield, based on the starting isatin 7a (Path A). Also the one-pot synthesis (Path D) of compound 12a has been realized through

Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo

• Alireza Shakoori,
• John B. Bremner,
• Mohammed K. Abdel-Hamid,
• Anthony C. Willis,
• Rachada Haritakun and
• Paul A. Keller

Beilstein J. Org. Chem. 2015, 11, 481–492, doi:10.3762/bjoc.11.54

• were modest, and oxidative isatin byproducts were significant [4]. Thus these reactions of indigo (1) with allylic halides were further explored, not only in an effort to gain better control over reaction pathways, but to optimise the synthesis of known polycyclic ring systems to practicable yields

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

• Abstract The Morita–Baylis–Hillman reaction of acrylamide, as an activated alkene, has seen little development due to its low reactivity. We have developed the reaction using isatin derivatives with acrylamide, DABCO as a promoter and phenol as an additive in acetonitrile. The corresponding aza version

• with acrylate and acrylonitrile has also been developed resulting in high product yields. Keywords: acrylamide; isatin; ketimine; Morita–Baylis–Hillman; phenol; Introduction The Morita–Baylis–Hillman (MBH) reaction is an important carbon–carbon bond-forming reaction [1][2][3]. It involves the

• appending other functionalities/groups for intramolecular transformations. Other reports have used this feature for the development of an intramolecular MBH reaction: Corey et al. (total synthesis) [29], Pigge et al. (ruthenium complexes as an electrophile) [30], and Basavaiah et al. [31][32]. Isatin has

One-pot four-component reaction for convenient synthesis of functionalized 1-benzamidospiro[indoline-3,4'-pyridines]

• Chao Wang,
• Yan-Hong Jiang and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2014, 10, 2671–2676, doi:10.3762/bjoc.10.281

• reactions [19][20][21]. Recently, we and Perumal have demonstrated that the four-component reaction of arylamine, acetylenedicarboxylate, isatin and malononitrile can afford the spiro[indoline-3,4’-pyridine] derivatives in satisfactory yields [22][23][24]. We envisioned that functionalized spiro[indoline

• -3,4’-pyridine] derivatives can be synthesized by employing other nitrogen-containing nucleophiles such as hydrazine and imines in the similar four-component reactions. In fact, the four-component reaction of hydrazine, acetylenedicarboxylate, isatin and malononitrile for the formation of spiro

• [indoline-3,4'-pyrano[2,3-c]pyrazoles] have been developed very recently by several groups [25][26][27]. Against this background and in continuation of our efforts toward the development of practical multicomponent reactions based on the reactivity of isatin and its derivatives [28][29][30][31][32][33][34

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

• activated isatin-based alkenes (Scheme 39) [76]. The reactions, performed in chloroform in the presence of molecular sieves at room temperature, provided biologically important 3-spirocyclopentene-2-oxindoles with two contiguous quaternary centers in very high yields and with good enantioselectivities; they

• tolerated a wide range of MBH carbonates featuring different electronic properties for their aromatic and heteroaromatic moieties at the allylic position (e.g., phenyl, 4-cyanophenyl, 4-methylphenyl, 2-naphthyl, 3-furyl) as well as diverse isatin-derived alkenes having substituents on their phenyl rings. Of

• alkenes and MBH adducts, albeit in slightly diminished yields. Shi and co-workers also studied this reaction, but using the chiral bifunctional thiourea-phosphine catalyst G7. The [3 + 2] annulation of MBH carbonate with an activated isatin-based alkene in toluene at room temperature gave the

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• , Italy Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, 20133 Milano, Italy 10.3762/bjoc.10.141 Abstract An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid

• subjected to post-Ugi transformations, paving the way to application as peptidomimetics. Keywords: isatin; multicomponent; oxindole; peptidomimetics; Ugi; Introduction Isatin and its derivatives have drawn considerable and renewed interest due to their peculiar chemistry and wide range of bioactivities

• . This led to the development of stereoselective methodologies and the synthesis of compounds with various biological properties [1]. In particular, the high reactivity of the C-3 prochiral carbonyl group allows the easy transformation of isatin into 2-oxindole derivatives, mostly by nucleophilic

Novel indolin-2-one-substituted methanofullerenes bearing long n-alkyl chains: synthesis and application in bulk-heterojunction solar cells

• Irina P. Romanova,
• Andrei V. Bogdanov,
• Inessa A. Izdelieva,
• Vasily A. Trukhanov,
• Gulnara R. Shaikhutdinova,
• Dmitry G. Yakhvarov,
• Shamil K. Latypov,
• Vladimir F. Mironov,
• Vladimir A. Dyakov,
• Ilya V. Golovnin,
• Dmitry Yu. Paraschuk and
• Oleg G. Sinyashin

Beilstein J. Org. Chem. 2014, 10, 1121–1128, doi:10.3762/bjoc.10.111

• crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase. Keywords: bulk heterojunction; fullerenes; isatin; phosphorus; photovoltaics; Introduction Organic photovoltaics are a rapidly growing field of research due to its potential for production

• series of N-alkylisatins A 1–9 were used for the synthesis of AIMs 1–9 (Scheme 1). The isatins A 1–9 were obtained by reaction of isatin sodium salt with the corresponding N-bromoalkanes [11][12][13][14]. The reactions of A 1–9 with fullerene C60 and tris(diethylamino)phosphine were conducted in o

Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

• Akshay Kumar and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91

• time of 6 days (Table 5, entry 13). The R absolute configuration of Michael adducts was assigned by comparing the HPLC chromatograms of Michael adducts with that reported in the literature [23][24]. Next, we studied the multicomponent version of this reaction. Acetone, isatin and malononitrile react in

• one pot providing Michael product 4a in a good yield of 80% and a high enantioselectivity of 98% ee (Scheme 3). The slightly lower yield of the one-pot process compared to the stepwise process was due to the competing reaction of isatin and acetone to form aldol adduct 5 (8% yield). The reaction

• involves the initial formation of isatylidenemalononitrile by Knoevenagel condensation of isatin with malononitrile followed by the addition of acetone to provide Michael adduct 4a. Thus, catalyst 1a also finds its successful application in the multicomponet version of this reaction without compromising

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles

• Antonio Arcadi,
• Emanuela Pietropaolo,
• Antonello Alvino and
• Véronique Michelet

Beilstein J. Org. Chem. 2014, 10, 449–458, doi:10.3762/bjoc.10.42

• of 3,3-difluoro-2-oxindoles to give the corresponding 3,3-difluoroindoines when electron-withdrawing groups were present as substituents in the benzene nucleus. The 3,3-difluoro-2-oxindoles were prepared by the reaction of appropriately substituted isatin derivatives with DAST [18]. Anodic

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

• activities and their applications for pharmaceutical lead discovery. These compounds are the central skeleton of numerous alkaloids [1][2][3][4][5][6][7][8] and have found wide biological applications, e.g., as potent p53–MDM2 inhibitors [9][10][11][12][13][14][15]. Usually, isatin and its derivatives were

• employed as starting materials to conduct 1,3-dipolar cycloadditions to yield spirooxindole core structures [16][17][18][19][20]. Owing to the ease of preparation, the azomethine ylides generated from isatin with α-amino acids or amines were frequently chosen as important 1,3-dipolar intermediates to react

• , chalcone derivatives are the most widely used dipolarophiles. Sarrafi and co-workers reported a 1,3-dipolar cycloaddition reaction of isatin, benzylamine and chalcone derivatives [31], and only one single regioisomer was obtained in high yield, in which the benzoyl group was connected to C-3 of the newly

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

• ’(6’-CH) and 2’-CCH3. Also, multiplets for 7a’-CH and 2’-(6’-CH) and singlet for 2’-CCH3 show correlation signals to the neighboring methylene groups. Additionally, the absence of the NOE cross peak of 4-CH of the isatin nucleus and 2’(6’-CH) or 2’-CCH3 of the pyrrolizidine moiety was indicative for

• signals of 2’-CH and doublet at 7.30 ppm (J =1.8 Hz) for 2-CH of the aroyl acrylic acid moiety. In addition, the absence of NOE cross peaks between 4-CH of the isatin core and 2’-CH of the pyrrolizidine fragment supports the assignment. The NH-proton of the oxindole moiety and the 1’-COOH proton of the

• 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

Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

• Ouldouz Ghashghaei,
• Consiglia Annamaria Manna,
• Esther Vicente-García,
• Marc Revés and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2014, 10, 12–17, doi:10.3762/bjoc.10.3

• nitrilium intermediate, in agreement with a Sorensen report (Scheme 4, route iii) [21]. Finally, the imino-nitrilium cation can be trapped by an aromatic ring when using isatin imines, leading to bis(imino)tetrahydroquinoline 8, (Scheme 4, route iv). In a reaction using a large isocyanide excess, a triple

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• less efficient because it needs heating and/or long reaction time to complete the fluorination [48][49]. Nevertheless by the use of a flow microreactor device, isatin underwent gem-difluorination to give the corresponding difluoride in 73% yield (residence time in the reactor: within 1 h). Reactions

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

• -alkyl groups and without N-substituent in the presence of potassium carbonate as a base catalyst. When two equivalents phenacyl bromides were used in the reaction, the N-substitution reaction of isatin also finished with the formation of spiro-oxirane-oxindoles. Keywords: Darzens reaction; isatin

• . Isatins, phenacyl bromide and other reagents are commercial reagents and were used as received. Solvents were purified by standard techniques. All reactions were monitored by TLC. Typical procedure for the preparation of spiro[indoline-3,2'-oxiran]-2-ones 3a–h: A mixture of isatin (1.0 mmol), phenacyl

• C16H11NNaO3, 288.0631; found, 288.0628. Typical procedure for the preparation of spiro[indoline-3,2'-oxiran]-2-ones 4a–e: A mixture of isatin (1.0 mmol), phenacyl bromide (2.2 mmol) and potassium carbonate (2.6 mmol) in 20.0 mL of chloroform was stirred at 50 °C for 10–24 h (TLC analysis). After cooling, the

Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions

• Li-Juan Zhang,
• Qun Wu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 846–851, doi:10.3762/bjoc.9.97

• Li-Juan Zhang Qun Wu Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.97 Abstract In the presence of triethylamine as catalyst, the one-pot four-component reactions of arylamines, methyl propiolate, isatin and

• arylamines and other primary amines. Keywords: 1,4-dihydropyridine; electron-deficient alkyne; four-component reaction; isatin; one-pot reaction; spiro compound; Introduction β-Enaminones and β-enamino esters represent important synthetic building blocks for the development of versatile carbon–carbon bond

• [12][13][14][15][16][17][18][19][20][21][22][23]. Recently, Perumal and we have both developed an efficient synthetic procedure for functionalized spiro[indoline-3,4’-pyridines] by domino reactions of in situ generated β-enamino esters, isatin and malononitrile with triethylamine as the base catalyst

Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach

• Sandeep Kumar,
• Ramendra Pratap,
• Abhinav Kumar,
• Brijesh Kumar,
• Vishnu K. Tandon and
• Vishnu Ji Ram

Beilstein J. Org. Chem. 2013, 9, 809–817, doi:10.3762/bjoc.9.92

• only recently been reported. There are plenty of literature reports available on the construction of 3-alkenylindolin-2-ones [21]. The widely used highly facile protocol for the alkenylation of indolin-2-ones is through aldol condensation [22] of isatin with compounds containing an active methylene

Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

• Yan Sun,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 8–14, doi:10.3762/bjoc.9.2

• -component reactions of arylamine, isatin and cyclopentane-1,3-dione in acetic acid at room temperature. On the other hand the condensation of isatin with two equivalents of cyclopentane-1,3-dione gave 3,3-bis(2-hydroxy-5-oxo-cyclopent-1-enyl)oxindole in high yields. The reaction mechanism and substrate

• scope of this novel reaction is briefly discussed. Keywords: arylamine; cyclopentanedione; isatin; multicomponent reaction; spiro compound; Introduction The spirooxindole is among the most important class of naturally occurring substances, characterized by highly pronounced biological properties, and

• [3][4][5][6]. Isatin and its derivatives may be the most useful starting materials or precursors in the synthesis of a wide number of spirocyclic oxindoles [7][8]. Due to its simple process, easy operation, efficiency and high atomic economy, the multicomponent reaction based on isatin and its

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• with the aldehyde carbonyl in the transition state (TS 3). Under ball-milling conditions, thiodipeptide VI catalyses the enantioselective aldol reaction of acetone (1d) with isatin derivatives 4 to provide 3-substituted-3-hydroxyoxindole derivatives 5 in moderate yield (54–68%) and moderate to good

• of (A) ketones with aldehydes and (B) acetone with isatin derivatives. Enantioselective Michael reaction of aldehydes with nitroalkenes catalysed by pyrrolidine-derived organocatalysts. Chiral squaramide catalysed asymmetric Michael reaction assisted by ball-milling. Asymmetric organocatalytic

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• enantioenriched 3-hydroxyoxindoles [22][23][24]. For the synthesis of chiral 3-aminooxindoles, we developed the first example of catalytic asymmetric addition of nucleophiles to isatin-derived ketoimines using TMSCN [25] and the amination of unprotected 3-prochiral oxindoles using di-tert-butyl azodicarboxylate