Isatin-3-imines

Sect. 3.2). However, this approach is limited to the few trialkylboranes that are easily available and cheap since only one of the three alkyl group is transferred. By using a triethylborane as a chain transfer reagent, the reaction could be extended to alkyl iodides as radical precursors. Bertrand [94,114] and Naito [95,97] reported both the use of triethylborane for the tin-free addition of alkyl iodides to imines. A typical example for a tentative of asymmetric addition to a glyoxylate imine is depicted in Scheme 50 (Eq. 50a). More recently additions to isatin imines were reported (Eq. 50b) as well as addition to 2H-aziridine-3-carboxylates by Lemos [100] and Somfai [101] (Eq. 50c). 

Grigg and co-workers described a novel three-component indium-palladium-mediated allylation reaction [67]. As exemplified by Eq. 14.16, 3,3-disubstituted oxi-ndole derivative 133 was obtained smoothly from phenyl iodide, the easily available isatin imine 132 and 1,2-propadiene (131). Excellent levels of diastereoselectivity were obtained in this cascade reaction employing imines derived from enantiopure sulfmamides. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

In 2012, Ye, Jiao, and co-workers described the first application of iV-aryl isatin imines as the electrophiles in NHC-catalyzed homoenolate additions, providing a simple and efficient approach to spirocyclic y-lactam oxindoles. Utilizing the catalyst with free hydroxyl group first developed in the Ye group, an asymmetric variant of this reaction was demonstrated in a moderate enantioselective manner (80% yield, 6 1 dr, 74% ee) (Scheme 7.48). 

Scheme 7.48 NHC-catalyzed cross-annulation of cinnamaldehydes and N-aryl isatin imines reported by Ye and Jiao.

Scheme 7.49 NHC-catalyzed asymmetric cross-annulation of enals and N-Boc isatin imines reported by Chi.

A simple, inexpensive, environment-friendly, and high-yielding protocol was described for the synthesis of 3,3-di(5-methylfuran-2-yl)oxindoles. This was achieved by the reaction of 2-methylfuran with isatin or isatin imine in the presence of catalytic amount of FeCls.The protocol allows the direct introduction of 2-methylfuran (or 2-methylthiophene) onto isatin at its 3-position with complete regioselectivity (14TL4705). 

The regioselectivity and reactivity of the 1,3-dipolar cycloaddition reactions of nitril-imines with acrylonitrile and methyl acrylate have been investigated. The 1,3-dipolar cycloaddition reactions of nitrilimines with isatin imines yielded spiro[indolin-3,3 -1,2,4-triazol] derivatives under classical and microwave conditions/ An extensive study of the 1,3-dipolar cycloaddition reactions of nitrilimines with a,/ -unsaturated lactones, thiolactones, and lactams has been presented. In all cases, regioisomeric mixtures were obtained with the 5-substituted pyrazole as the major cycloadduct. me5 o-Tetrakis(pentafluorophenyl)porphyrin (51) reacts with iminonitriles (52) yielding pyrazolin-fused chlorines (53) via a 1,3-dipolar cycloaddition reaction (Scheme 17). ... 

Spiro[3H-indole-3,5(4.H)-(l,2,4)triazoline]-2-one derivatives 204 have been obtained using microwave irradiation in the reaction between imines of isatin 203 and nitrile imines generated in situ from the corresponding hydrazonyl chlorides 199 (Scheme 9.63). The yields are in the range 85-95% and the reaction is complete within 5 min [110]. Similar reactions performed under thermal conditions were complete in 6-10 h and yields decreased to 20-30%. However, when the reaction was performed at ambient temperature, the products were obtained in excellent yields but only after a prolonged reaction time (30 h). 

A large variety of aromatic amines react with isatins to give anils (132).169,232,269,305,312,411 413 The imine from isatin and o-hydroxy-aniline forms complexes with copper acetate and zinc iodide.413 Reaction of these anils (132) with phenylhydrazine gives the isatin-3-phenylhydrazone.411 The imine 132 (R = 5-Me, R = H, Ar = p-tolyl)... 

Primary aliphatic amines are also reported to give imines of the type 132 (where Ar now is aliphatic) with isatin,92,170,431 433 although the... 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

The isatins 7 and 54 react with the imines 203 in boiling dioxane with the formation of the products from aldol condensation 204, which recyclize when heated in ethylene glycol or glycerol to the amides of 4-quinolinecarboxylic acids 205 [179],... 

Isatin-3-imines also react with hydrazine derivatives such as heteroarylhydrazines264, thiosemicarbazides265 and acylhydrazides266, resulting in a substitution reaction at the C-3 position. Substitution reactions are also described to occur when O-methylisatin is treated with thiosemicarbazines, furnishing isatin-2-thiosemicarbazones91. 

These findings can be rationalised by consideration of a common intermediate. An intermediate carbinolamine could undergo either a nucleophilic substitution reaction, probably through an ionisation step facilitated by the high temperature and by assistance from the nitrogen lone pair to form the spiro compound in dimethylacetamide, or the intermediate may suffer dehydration in apolar solvents to form the corresponding isatin-3-imine. This imine can undergo facile syn-anti isomerisation upon protonation in acetic acid and thus yields the indoloquinoxaline derivative... 

Isatin-3-imines are hydrolyzed to isatin and the corresponding amine. A ring opened intermediate is proposed to be involved in the process as it was detected by polarography353. 

On the other hand, the reaction of this chloride with anilines always led to isatin-3-imines. In an attempt to rationalize these contradictory results, it was proposed that 2-chloro-3H-indol-3-one was the substrate but that this compound, which reacts with nucleophiles at the C-2 position, readily hydrolyzed in solvents containing water, thus yielding isatin and products resulting from attack at C-3. Sir John Comforth revisited the chemistry of this... 

Isatin, due to its cis a-dicarbonyl moiety, is a potentially good substrate for the synthesis of metal complexes, either alone or with other ligands. Their derivatives, mostly those substituted at C-3, such as isatin-3-hydrazones and isatin-3-imines bearing an extra heteroaromatic ring are also generally employed as ligands. In this manner, Schiff bases... 

Thionation of quinazolinones and then reaction with anthranilic acid derivatives gave 57 A regioselective reaction of isatoic anhydride with isatin-3-imines gave 58". Selfpolymerization of isatoic anhydride, doped over montmorillonite yielded... 

LiBr/Et3N, 9.33 is obtained with a high selectivity, while the use of Ti(0/-Pr)3Cl leads selectively to 934. The chiral auxiliary is removed with LiAlH4 (Figure 9.12). According to the absolute configuration of the chiral alcohol, either enantiomer of the final product is obtained. The 1,3-dipole is introduced on the least hindered face of the acrylate. The reaction has been extended to imines of isatin, but it is less selective [1544],... 

Some ring-expanding reactions leading to annelated pyrimidines will now be considered. The transformation of isatin-3-oxime (120) to 4-amino-quinazoline was described in Section VI,A,4. Isatin-2-oxime, when heated in dilute sodium hydroxide, rearranged to quinazoline-2,4-dione.383 Isatin-3-imine in alkaline hydrogen peroxide was converted to the same substance in excellent yield.384... 

Silvani and coworkers have converted isatin to the chiral imines 94 and 97 that were employed as electrophiles for the diastereoselective addition of Grignard reagents [60]. As illustrated in Scheme 26, addition of allyl Grignard to 94 or 97 afforded the amino-substituted quaternary oxindoles 95 or 98 with good diastereos-electivity (80 20 and 89 11 dr, respectively). Grignard adducts 95 and 98 were further manipulated to afford the enantiomeric pair of 3-amino-3-allyloxindoles (5)-96 and (R)-99, respectively. 

Indoloquinoxaline 693 was obtained in 83-90% yield by irradiating a mixture of isatin with o-phenylenediamine in acetic acid in an MW oven in either an open flask or closed Teflon vessel for 1-2 min. Carbethoxymethylation of isatin with ethyl chloroacetate in the presence of K2CO3 and Nal was carried out under MWI to give compound 694 in 70% yield within 4min. It could be converted into 695 by reaction with o-phenylenediamine in acetic acid in either an open flask (2 min) or closed Teflon vessel (Imin) (Scheme 134). Alternatively, carbethoxymethylation of 693 under MWI for 6 min afforded a 53% yield of 695. Reaction of 695 with hydrazine hydrate in ethanol under MWI gave the hydrazide 696 in 84% yield. MWI has been also used to condense 696 with aromatic aldehydes and monosaccharides to yield the hydrazone derivatives 697 in 58-99% yields (Scheme 134) (05JCR(S)299). 

Isatin-3-imines 822 are versatile precursors for the synthesis of spiroheterocycles. They were prepared by grinding together an equimolar mixture of isatin and aromatic or heterocyclic amine. Subsequent treatment with mercaptoacetic acid using inorganic supports such as montmorillonite KSF, alumina, or silica gel in an open vessel upon MWI gave spiro compounds 823 within 5-7 min. The montmorillonite KSF is the best solid support, giving the best yields (92-97%) in the shortest time and easiest work-up (Scheme 156) (030PP401). 

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