Nitrostyrenes

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

Soderberg and coworkers have developed a palladium-phosphine-catalyzed reductive iV-het-eroannuladon of 2-nitrostyrenes forming indoles in good yields For example, reaction of 6-bromo-2-nitrostyrene with carbon monoxide in the presence of a catalytic amount of palladium diacetate (6 mol% and triphenylphosphine 124 mol% in acetonitrile at 30 gives 4-bromoindole in 86% yield fEq 10 62 Several functional groups, such as esters, ethers, bromides, tnflates, and additional nitro groups, have been shown to be compatible with the reaction conditions... 

This procedure has been used in the preparation of other nitrostyrenes in the following yields o-nitrostyrene (40%),2 / -nitrostyrene (41%),2 and 3-nitro-4-hydroxystyrene (60%).2 A better procedure for more volatile styrenes involves simultaneous decarboxylation and codistillation with quinoline from the reaction flask. This method has been used to prepare the following styrenes o-chlorostyrene (50%),3 4 m-chlorostyrene (65%),4 -chlorostyrene (51%),4 m-bromostyrene (47%),4 o-methoxystyrene (40%),4 -methoxystyrene (76%),4 m-cyano-styrene (51%),3 and j -formylstyrene (52%).9... 

Inter [4+2]/inter [3+2] The tandem intermolecular [4+2]/intermolecular [3+2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers, which can be controlled by the choice of the stereochemistry of each component and the Lewis acids. The nitronate derived from 2-nitrostyrene and 1-trimethylsilyloxycyclohexene reacts with methyl acrylate to give the nitroso acetal in good yield and high diastereoselectivity (Eq. 8.107).154... 

Another classical case with respect to ort/zo-effects is found for 2-nitrostyrene78. The conceivable regio- and stereo-specifically labelled 2-nitrostyrenes have, in addition to the ring-labelled isotopomer, been studied by collision activation mass spectrometry79. Undoubtedly, the most striking result was the nearly equal contribution of both (in the neutral molecule diastereotopic) hydrogens of the fi-carbon. 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

This pressure effect was also observed in the tandem cycloaddition nitroalkene. Combination of methyl acrylate with 2-nitrostyrene and ethyl vinyl ether proceeds at 15 kbar over 1 h to produce a mixmre of diastereomeric nitroso acetals (Eq. 2.24) (83,235,236). 

Selenium has now been added to the growing list of transition metals shown capable of catalyzing the reductive A/-heterocyclization of 2-nitrostyrenes to indoles with carbon monoxide <99TL5717>. Utilizing the palladium-phosphine catalyzed methodology, Soderberg achieved the synthesis of several 4-substituted 2-methylindole natural products isolated from TricMoma... 

The eclipsed tetra-BINAP porphyrin 171 was conveniently synthesized by condensation of the meso-tetrakis(2,6-dihydroxyphenyl)porphyrin 173 with the (S)-BINAP derivative 174 in the presence of K2C03. After removal of the staggered isomer iron was inserted by addition of Fe(CO)5/I2, and the resulting Fe(III)-complex 171 was used as a catalyst (0.2%) to epoxidize a series of six styrene derivatives in the presence of an excess of PhIO. In every case the corresponding (R)-epoxides were preferentially formed in yields up to 72%. The best ee-values were obtained for the electron deficient substrates 2-nitrostyrene (80% ee) and pentafluorostyrene (74% ee), [114],... 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

This crop contained 5% 6-benzyloxy-B-dimethylamino-2-nitrostyrene (by NMR). Pure 6-benzyloxy-2-nitro-B-pyrrolidinostyrene melts at 91.5-92.5°C. 

This crop contained 15% 6-benzyloxy-P-dimethylamino-2-nitrostyrene (by NMR). 

This compound may contain varying amounts of 6-benzyloxy- -dimethylam1no-2-nitrostyrene. 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

Reductive cyclization of nitrostyrene precursors has also proven to be a useful route to 5,6-dihydroxyindole and its derivatives, as illustrated by the efficient preparation of the system 32 (Scheme 18) <1999S793>. A general synthetic approach to indoles involves a palladium-catalyzed reductive cyclization of 2-nitrostyrenes <1997JOC5838>. This procedure was used in the synthesis of several natural products, e.g., 4-(methoxymethyl)-2-methylindole 33 (Scheme 19), a constituent of a tricholoma species <1999JOC9731, CHEC-III(3.03.2)282>. 

SYNTHESIS OF INDOLES BY PALLADIUM-CATALYZED REDUCTIVE N-HETEROANNULATION OF 2-NITROSTYRENES METHYL INDOLE-4-CARBOXYLATE... 

Alkynones and indoles. Stitching of the aryl group of an iodonium salt with a 1 -alkyne by CO furnishes alkynones. On the other hand, CO serves as a reducing agent in the cyclization of 2-nitrostyrenes which results in the formation of indoles ... 

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

Indoles. 2-Nitrostyrenes afford indoles in the Se-catalyzed cyclization. The substrates include 2-nitrostyrene itself and various a- and -substituted homologues. 

Using supported rhodium as catalyst, 2-nitrostyrene is converted in benzene into skatole in 70y. yield, with CO/H2 (160 atm) at 160"CD2ll. However this reaction, conducted under hydrotormi1 ation conditions, involves -formation o-f 2-homogeneous catalysis, reduction o-f the nitro group by heterogeneous catalysis, then ring closure and thermal dehydration ... 

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