Amino-nitriles Michael addition

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,14 15 cf. the overview given in the Organic Syntheses preparation of nitroacetaldehyde diethyl acetal.16 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.14 18 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),19 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.20 21... 

Michael reactions.1 Various organozinc reagents bearing remote ester, nitrile, or a-amino acid groups undergo Michael addition to a,(3-unsaturated carbonyl compounds in the presence of CuCN, (CH3)3SiCl, and HMPA.1... 

The Timmis reaction makes use of the regioselective condensations of 6-amino-5-nitroso-pyrimidines with aldehydes, ketones, esters, and nitriles under base catalysis. An extension of this principle is seen in the condensation reaction of 6-amino-5-nitroso-(320) and 6-amino-5-phenylazo-1,3-dimethyluracils (321) with dimethyl alkenedicarboxylate and propiolamide, respectively, leading by a Michael addition mechanism to 6,7-bis(methoxycarbonyl)- (322) and 6-carbamoyl-l,3-dimethyllumazine (323) (Scheme 52) <82JHC949>. 

The number of reports on Michael additions of hetero-nucleophiles to enynes bearing an acceptor substituent at the double bond is also rather limited. Bowden and coworkers found that 3-hexen-5-yn-2-one reacts with diethylamine under 1,6-addition to form the 6-amino-substituted dienone (equation 73). Similarly, 1,6-addition products were obtained by Russian groups from reactions of various primary and secondary amines with 2-en-4-ynoates and -nitriles . However, enynoates and nitriles bearing /-hillyI or trimethylsilyl groups at the triple bond were reported to react with methyl- and dimethy-lamine under 1,4-addition, indicating that the regioselectivity of the nucleophihc attack is... 

The Michael addition reaction is commonly recognized as one of the most important carbon-carbon bond-forming reactions in organic synthesis, and major efforts have been made to develop efficient catalytic systems for this type of transformation. In particular, the Michael addition of a carbon nucleophile to nitroalkenes is a useful synthetic method for the preparation of nitroalkanes [76], which are versatile synthetic intermediates owing to the various possible easy transformations of the nitro group into other useful functional groups, such as amino groups and nitrile oxides. 

The amino nitrile 70 is simply and cheaply made (90% yield) and does react with alkyl halides.14 Aldehydes are easily released from 71 with aqueous oxalic acid. After a second alkylation or Michael addition an even milder method of hydrolysis, aqueous Cu(II) salts at near neutrality, releases diketones such as 57. Cyclisation in base gives m-jasmonc13 65. 

The ideal of cascade synthesis was first introduced in 1978 by Vogtle [41] etal., who reported reactions involving Michael additions of an amine to acrylonitrile, followed by reduction of the nitrile group to an amino group. In 1979 [40] a Dow research group reported that a variety of amines could be added to methyl acrylate and the products subsequently amidated with a, co-diaminoalkane to give cascade products . Further work by the Dow group has expanded this area to produce the Starburst system [40]. An in depth review by Tomalia [40] et al. should be consulted. 

All these experiments give dendrons possessing either a vinyl, a primary amino, a bisphosphino, or an azido group at the level of the core. Other functional groups can be incorporated [30,31]. These compounds are useful precursors of multidendritic systems. Various surface-block dendrimers can be prepared from these macromolecules. For instance, a Michael addition between dendron 17c-[G 3] (100% excess) and dendron 15b-[G 3] at 90°C induces the formation of dendrimer 20-[G 3]-[G 3] (Scheme 13). This dendrimer possesses two different faces 16 dimethylamino groups on one side, 16 nitrile groups on the other side. 

Enantioselective synthesis of N-protected aminodiols 235 and 239 via dia-stereoselective inter- and intramolecular cycloaddition of optically active nitrile oxides 233 and 237 followed by cleavage of the isoxazoHnes 234 and 238 has been reported by Enders and co-workers (Schemes 55 and 56) [156]. The nitrile oxides 233 and 237 were generated from nitroalkanes 232 and 236, respectively, which in turn were obtained by diastereoselective oxa-Michael addition of (IR, 2S)-(-)-N-formylnorephedrine 231 to ahphatic nitroalkenes 75b,c. The LiAIH4-mediated cleavage of isoxazolines 234 and 238 to aminoal-cohols 235 and 239, respectively, proceeded with >96% diastereoselectivity. 

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