Continuous 4+2 adducts, synthesis

Kappe et al. described a two-step continuous-flow synthesis of 2-amino-4 industrial synthesis of fungicide Boscalid (Scheme 7.46) [177]. Homogeneous palladium-catalyzed Suzuki-Miyaura coupling was accomplished by using an X-Cube reactor. The crude coupling adduct... 

Synthetic activity associated with the carbonyl-ene reaction is extensive. During the past decade, the trend has been to perform these reactions in the presence of a Lewis acid in an enantioselective fashion. Efforts to find a general catalyst that affords homoallylic alcohols in high yields and enantioselectivities are continual. The synthetic utility of this reaction has been validated by its application to the synthesis of a number of natural products (see Section 10.12.6) and many structurally novel motifs that have found a place in drug discovery vide infra). It is the latter application that has resulted in research efforts aimed at large-scale production of carbonyl-ene adducts. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

In the synthesis of carbamates, R NH.C02R, from A iV -dialkylureas, (R NH)2CO, and dialkyl carbonates, (RO)2CO, dibutyltin oxide, Bu2SnO, acted as an efficient catalyst. The proposed mechanism (Scheme 13) involves addition of the dialkyl carbonate to Bu2SnO to give an adduct (43), which is attacked by the urea to yield a new tin complex (44) and one molecule of carbamate. Attack by dialkyl carbonate upon this complex (44) yields a further molecule of carbamate and regenerates the original tin complex (43), which can continue the catalytic cycle.42... 

The intramolecular condensation of ort/ro-(2-oxoalkyl)analines continues to provide reliable access to the indole ring system. Kerr and Jackson prepared the indole core of herbindole B 89 in three steps (80%) via oxidation of the Diels-Alder adduct 81 (Plieninger indolization) as illustrated below <07JOC1405>. A similar strategy was applied by the same group in the total synthesis of ( )-decursivine <07EJOC237>. 

The alkene pseudohalogen adducts (15) of Scheme 8 are also useful intermediates for aziridine synthesis. These adducts are discussed later in Sections 3.S.6.2-4. The iodine azide and bromine azide adducts may be reduced to aziridines with many reagents recent references report use of lidiium aluminum hydride - and dimethylamineborane. The iodine isocyanate aziridination continues to prove useful, as in Scheme Since the recent reviews, - the mechanism of the triphenylphosphine-based... 

The method by which cyclopropenones were first prepared namely the addition of dichloro (or dibromo) carbene to an alkyne and subsequent hydrolysis of the adduct continues to be a good source of cyclopropenones despite the generally low yields involved. In particular, it has provided a convenient synthesis of deltic acid (70) in 13-35% overall yield from di-t-butoxyacetylene (equation 29). The dicyclopropyl... 

Nucleophilic Attack at Other Atoms.- Interest has continued in the synthesis of phosphine-borane adducts. Complexes of tetramethyldiphosphine with borane and various halogenoboranes have been used to generate a series of open-chain and cyclic phosphino-boranes. Adducts of 1,3,5-diazaphosphorinanes involving two... 

Asymmetric induction in synthesis continues to receive attention as in the photoaddition of cyclopentene to the optically active enone esters (74). The (2+2)-cycloadducts obtained are claimed to have substantial enantiomeric excesses. The adducts are diastereoisomeric and two types are obtsuned, the cis-anti-cis (75) and the cis-syn-cis (76). Analysis of the results shows that the yield of the cis-anti-cis isomers diminishes as the size of the ester group increases due to steric interactions. ... 

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