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

• catalysts is reported. The corresponding products containing a tetrasubstituted carbon center attached to a nitrogen atom at the C-3 position of the oxindole were obtained in high yields and with up to 98% ee. Keywords: 3-aminooxindoles; asymmetric catalysis; phosphine catalyst; tetrasubstituted

• organocatalytic processes. In the field of metal catalysis, Shibasaki et al. reported the reaction between C3-substituted oxindole and azodicarboxylates, using homodinuclear or monometallic Ni-Schiff base complexes as catalysts [13]; Feng et al. also developed a similar procedure with chiral N,N’-dioxide-Sc(III

• -substituted oxindole catalyzed by chiral amino acid-derived organophosphine catalysts, in which the zwitterions in situ generated from the phosphine and azodicarboxylates serve as highly efficient catalysts [44] (Scheme 1). Results and Discussion Initially, the reaction between 3-phenyloxindole 1a and DEAD

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

• catalyst would activate the resulting enolized oxindole reagent 39 via deprotonation. Thus, 39 would be disposed to attack by its Re face to the Si face of the nitroethene derivative 40. Simultaneously, the latter would be fixed and activated by a hydrogen-bonding interaction with the hydroxy moiety of the

(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

• malononitriles 104 and α,α-dicyanoalkenes 105. The process yielded highly functionalized spiro-oxindole dienes 106. The products were obtained in good to excellent yields (up to 97%) and enantioselectivities (up to 96%), but the diastereoselectivities were moderate (up to 7.9:1) (Scheme 34) [53]. In 2015, Soós

• , when a different derivative of L-diphenylprolinol is used, a different diastereomer of the product is obtained. When along with N-Boc-substituted oxindole 218, substituted derived nitro-alkene 82 and substituted unsaturated aldehyde 154, a bifunctional quinine-derived thiourea 57 and L-diphenylprolinol

• to be employed in order to obtain spiro-dihydropyran-oxindole derivatives 231 in good to excellent yields, using catalyst 232 (Scheme 72) [91]. The mechanistic studies showed that the 3,5-bis(trifluoromethyl)phenyl group was an essential component of the thiourea catalyst. After the optimization of

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

• , all these cases suffered from low reactivity and long reaction times were always required (usually > 48 h) for better conversions. 7-Azaisatins bearing an additional nitrogen atom at the 7-position of the 2-oxindole scaffold might be better electrophiles than isatins owing to the electron-withdrawing

Fates of imine intermediates in radical cyclizations of N-sulfonylindoles and ene-sulfonamides

• Hanmo Zhang,
• E. Ben Hay,
• Stephen J. Geib and
• Dennis P. Curran

Beilstein J. Org. Chem. 2015, 11, 1649–1655, doi:10.3762/bjoc.11.181

• the original substrates 1 by swapping the locations of the radical precursor (halide) and the radical acceptor (ene-sulfonamide). The expected products of these reactions, imines like 19, could possibly be used to make spirocyclic oxindole natural products like coerulescine [18], horsfiline [19][20

• identified by 1D and 2D NMR experiments, IR and HRMS as 3-(2-formamidoethyl)-2-oxindole 25. The cyclizations of 23 and 24 gave comparable results. The corresponding formamides 26 and 27 were isolated in 42% and 54% yields, respectively. All three formamides are white solids with high melting points (>200 °C

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

• molecular structure of spiro compound 1k (Figure 1), it can be seen that the four carbon atoms and the nitrogen atom in the newly formed 1,4-dihydropyridyl ring exist nearly in one plane, while the C-4’ atom slightly deviates in this plane (0.318(4) Å). The phenyl group of the oxindole moiety and the 1

• '-picolinamido group exist in the same side of the 1,4-dihydropyridyl plane. By observing the crystal structure of spiro compound 1k, we could conclude that the 1'-picolinamido group might exist in cis- or trans-position of the phenyl group of the oxindole moiety. Thus, the cis/trans-conformations are in a

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

• , however, to transformations involving isatin-derived alkenes as substrates, resulting in very poor diastereoselectivities and enantioselectivities. For these oxindole derivatives, the use of the chiral dipeptide-derived phosphine H12 in toluene at room temperature provided the corresponding [4 + 2

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

• 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

• additions or spiroannulation [2][3]. Oxindoles represent a common structural element in various natural products and biologically active compounds. Diverse oxindole derivatives act as non-peptide scaffolds [4] in peptidomimetic chemistry, either as enzyme inhibitors or as ligands of G-protein-coupled

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

• substitution between fluoromalonate systems [52] and appropriate aryl substrates have not been reported previously. Recently, various routes to fluorooxindoles have been discussed involving enantioselective fluorination of appropriate oxindole substrates by electrophilic fluorinating agents [53][54][55][56][57

• various polyfunctional 2-fluoroacetic acid and 3-fluorooxindole systems. Fluorooxindoles are relatively rare fluorinated heterocyclic systems, even though several derivatives have useful biological activity, and current literature syntheses only involve fluorination of appropriate hydroxy and oxindole

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

• Michael acceptors, the oxindole-based Michael acceptors (Figure 1) are considered as valuable electrophiles for catalytic Michael reactions, as these provide a viable approach to procure 3,3'-disubstituted oxindole frameworks [9][10][11][12][13][14][15][16]. The oxindole framework bearing a tetra

• component process involving a domino Knoevenagel–Michael sequence was developed. 3,3'-Disubstituted oxindole could be transformed into spirooxindoles by reduction with NaBH4. Oxindole based Michael acceptors. Primary-tertiary diamine organocatalysts. Diamine catalyzed Michael addition of acetone to

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• (DMAPP) through 28 to yield 29, (Scheme 6) [40][41][42] the spiro-oxindole 30 was synthesized. The system underwent a cis-aryl-vinyl-cyclopropane rearrangement [43] to give 31 followed by rearomatization in 4–12 hours at room temperature yielding tricycle 32. The formation of the obtained tricyclic

• cyclohepta[cd]oxindole core 32 proved the synthetic versatility of a [3,3]-sigmatropic rearrangement for direct C–C-bond formation at the C4 position of the indole nucleus, and thus provides experimental evidence for the biosynthetic proposal. Applications to natural product synthesis Fatty acid metabolites

• oxindole was crucial for the stereochemical control of the spiro-indolinone system in 138, it was removed in the next step using radical conditions. Horner–Wadsworth–Emmons olefination on the carbonyl moiety followed by protection of the oxindole gave intermediate 139. Conjugate addition of methylamine and

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

• commutatа [4], mitraphylline from Uncaria tomentosa [5] and spirotryprostatines A and B from the secondary metabolites of Aspergillus fumigatus [6][7][8]. In particular, oxindole derivatives are well known as powerful anti-tumor agents due to their kinase inhibitory properties, especially as tyrosine kinase

• the assigned relative stereochemistry. Therefore, the relative stereochemistry could be as shown in Figure 1. The NH-proton of the oxindole moiety appeared as a singlet between 10.38–10.86 ppm. The 13C NMR spectra of compounds 4a–4g showed characteristic peaks at 71–73 ppm due to the spiro carbon

• 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

A construction of 4,4-spirocyclic γ-lactams by tandem radical cyclization with carbon monoxide

• Mitsuhiro Ueda,
• Yoshitaka Uenoyama,
• Nozomi Terasoma,
• Shoko Doi,
• Shoji Kobayashi,
• Ilhyong Ryu and
• John A. Murphy

Beilstein J. Org. Chem. 2013, 9, 1340–1345, doi:10.3762/bjoc.9.151

• azides with CO was achieved. The reaction of iodoaryl allyl azides, TTMSS and AIBN under CO pressure (80 atm) in THF at 80 °C gave the desired 4,4-spirocyclic indoline, benzofuran, and oxindole γ-lactams in moderate to good yields. Keywords: 4,4-spirocyclic indol γ-lactams; carbon monoxide; free radical

• ; iodoaryl allyl azides; tandem radical cyclization; Introduction 4,4-Spirocyclic oxindole γ-lactams containing a quaternary carbon center are key structures for the synthesis of biologically active natural products and the related analogues [1][2][3][4]. Therefore, the development of an efficient synthesis

• of this spiro structure is of continued interest for synthetic chemists. Recently, Comesse and Daïch reported the synthesis of 4,4-spirocyclic oxindole γ-lactams by tandem spirocyclization via nucleophilic halide displacement and amide coupling [4]. Shaw and co-workers reported the synthesis of 4,4

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

• ; oxindole; oxirane; spiro-epoxyoxindole; spirooxindole; Introduction The spirooxindole unit is a privileged heterocyclic motif that forms the core structure of a large family of natural alkaloids and many pharmacological agents with important bioactivity and interesting structural properties [1][2][3][4][5

• clearly displayed that the trans-isomer existed mainly with ratios of cis/trans isomers of 1:14 and 1:8, respectively. From Figure 1 and Figure 2 it is seen that the phenyl group of the oxindole unit and the benzoyl group existed in the cis-position. This result also indicated that the thermodynamic

• ratios. It is known that the closure of the epoxy ring would form cis/trans isomers in the Darzens reaction process. Here the N-benzyl and the N-butyl group in the oxindole moiety may decrease the steric effect of formation of the epoxy ring and lead to the easier formation of the relatively unstable cis

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

• molecular structure of the spiro compound 3b shown in Figure 4, we could clearly see that the cyano group and the phenyl group of oxindole moiety in the newly formed dihydropyridinone ring exist in cis-configuration. 1H NMR spectra of 3a–3n all display one singlet at about 5.40 ppm for the one proton in the

• dihydropyridinone ring, which indicated that only one isomer exists in each product. Based on the single crystal structure and 1H NMR data we could tentatively conclude that the spiro[indoline-3,4’-pyridinones] 3a–3n have cis-configuration of the cyano group and the phenyl group of the oxindole moiety. To explain

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

• protocol for the direct alkenylation of 2-oxindole by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3 to deliver 3-alkenyl-2-oxindoles 8 in moderate yield. This procedure is quite efficient, noncatalytic, economical and easy in workup. Moreover, it opens a new avenue for the synthesis of 3-alkenyl-2

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

• Yan Sun Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.2 Abstract A fast and convenient protocol for the synthesis of novel spiro[dihydropyridine-oxindole] derivatives in satisfactory yields was developed by the three

• -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

• cyclopentane-1,3-dione. Under similar conditions various arylamines and isatins with different substituents reacted with cyclopentane-1,3-dione in acetic acid at room temperature for 8–10 hours to afford the corresponding spiro[dihydropyridine-oxindole] compounds 1a–1k in good yields. The results are shown in

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

• because of the wide occurrence of this structural motif in natural products and pharmaceutically active compounds [1][2][3]. In addition, structure–activity relationship studies have revealed that the absolute configuration and the substituent of the C3 position of oxindole greatly influenced the

• be a powerful strategy for the α-arylation of β-ketoesters and aldehydes. Inspired by their work, we anticipated that the catalytic asymmetric addition of 3-aryloxindoles to quinones would possibly install a hydroquinone moiety at the C3 position of oxindole to furnish the desired chiral 3,3

• -diaryloxindoles. It also came to our attention that, while the addition of 3-prochiral oxindole to a variety of Michael acceptors had been studied [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], the use of quinones as the Michael acceptor had not been realized. Therefore, in this letter we are going

Organocatalytic asymmetric allylic amination of Morita–Baylis–Hillman carbonates of isatins

• Hang Zhang,
• Shan-Jun Zhang,
• Qing-Qing Zhou,
• Lin Dong and
• Ying-Chun Chen

Beilstein J. Org. Chem. 2012, 8, 1241–1245, doi:10.3762/bjoc.8.139

• oxindoles as nucleophiles in the reactions with azodicarboxylates or nitrosobenzene provides a very simple and direct approach for the synthesis of optically active 3-amino-2-oxindole derivatives [7], either by the catalysis of chiral metal complexes [8][9][10] or organic catalysts [11][12][13][14][15]. On

• of intermediate 6 happened to afford a spirocyclic oxindole 7 without loss of enantiopurity [37]. Conclusion We have developed a highly enantioselective allylic amination of Morita–Baylis–Hillman carbonates of isatins with N-silyloxycarbamates by the catalysis of a modified β-ICD derivative, which

Expanding the chemical diversity of spirooxindoles via alkylative pyridine dearomatization

• Chunhui Dai,
• Bo Liang and
• Corey R. J. Stephenson

Beilstein J. Org. Chem. 2012, 8, 986–993, doi:10.3762/bjoc.8.111

• development [9][10][11]. To our knowledge, most studies of these types of molecules focus on spirooxindoles bearing a pyrrolidine ring at the 3-position of the oxindole core, while few reports expand to formulate the syntheses of other spiro rings. As part of our ongoing reaction-screening objective [12][13

• exclusively in 74% yield (Table 1, entry 10). We predict that the formation of 6j by dehydration is due to the electron deficiency of the oxindole ring and subsequent stability gained from the ene–trione moiety. The structure of compound 6b was established by single-crystal X-ray analysis (Figure 1). Having

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• existing indole framework. In general, applications of this construction sequence fall into two major camps, namely condensations routed through a 2-aminoindole synthon [49][50][51][52][53][54][55][56], and those targeting pyridine closures onto a 2-oxindole [57][58]. In addition, intramolecular Hartwig

Complete transfer of chirality in an intramolecular, thermal [2 + 2] cycloaddition of allene-ynes to form non-racemic spirooxindoles

• Kay M. Brummond and
• Joshua M. Osbourn

Beilstein J. Org. Chem. 2011, 7, 601–605, doi:10.3762/bjoc.7.70

• complexes were resolved based upon the resonances at δ 3.98 and δ 3.87 ppm, which are peaks that correspond to the methyl in the MOM group on the oxindole nitrogen. For the enantiomerically enriched compound 9, only a single resonance is observed at δ 4.05 ppm in the presence of the chiral shift reagent

Total synthesis of (±)-coerulescine and (±)-horsfiline

• Mukund G. Kulkarni,
• Attrimuni P. Dhondge,
• Sanjay W. Chavhan,
• Ajit S. Borhade,
• Yunnus B. Shaikh,
• Deekshaputra R. Birhade,
• Mayur P. Desai and
• Nagorao R. Dhatrak

Beilstein J. Org. Chem. 2010, 6, 876–879, doi:10.3762/bjoc.6.103

• rearrangement protocol was applied to obtain 3-allyl oxindole. This oxindole was then converted to (±)-coerulescine and (±)-horsfiline. Keywords: alkaloids; Claisen rearrangement; Jones oxidation; spiro-oxindole; Wittig olefination; Introduction The spiro[pyrrolidin-3,3′-oxindole] ring system is a widely

• . The majority of these alkaloids have interesting biological activities and pharmacological properties [9]. However, a crucial observation, reported by Danishefsky et al. [10], found that the unnatural analogous 3 and 4 (Figure 1) of the spiro[pyrrolidin-3,3′-oxindole] possessed significant activity

• protocols. Several synthetic approaches have been developed for the synthesis of the spiro[pyrrolidin-3,3'-oxindole] framework for horsfiline and coerulescine [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], both in racemic and enantiomeric forms. These

A thermally-induced, tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition approach to carbocyclic spirooxindoles

• Kay M. Brummond and
• Joshua M. Osbourn

Beilstein J. Org. Chem. 2010, 6, No. 33, doi:10.3762/bjoc.6.33

• Spirooxindoles are structural motifs containing a heterocycle or carbocycle at the C3 position of an oxindole. Particularly well known are the pyrrolidinyl-spirooxindoles 1 which have been classified as a privileged motif due to their presence in a large number of heterocyclic alkaloids (Figure 1) [1

• ]. Spirotryprostatin B (2) is just one example of many natural products from this class exhibiting interesting biological activity [2]. Compounds possessing a carbocycle at the C3 position of the oxindole, such as 3, are less common and spirooxindoles containing a four carbon spirocycle are rare. One notable natural

• allenyl acetate in intermediate 11 which in turn arises from the thermal [3,3]-sigmatropic rearrangement of 9a (Figure 3). We have briefly investigated the scope and limitations of this tandem cycloaddition reaction by varying the protecting group on the oxindole nitrogen, altering the substitution on the

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• reaction pathway leading to the formation of oxindole via an intramolecular N-arylation process was not observed under these conditions [25][26][27]. The preferential formation of compound 1a indicated that cyclization via palladium-catalyzed CH functionalization could be, under appropriate conditions, a