Allylation heterocyclic aldehydes

A chemoenzymatic methodology has been developed using indium-mediated allylation (and propargylation) of heterocyclic aldehydes under aqueous conditions followed by Pseudomonas cepacia lipase-catalyzed enantioselective acylation of racemic homoallylic and homo-propargylic alcohols in organic media.192... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

In addition, silver-catalyzed asymmetric aza-Diels-Alder reactions provide a useful route to optically active nitrogen-heterocyclic compounds such as piperidines or pyrid-azines. Substituted dihydrobenzofurans can also be enantioselectively prepared through silver-promoted allylation of aldehydes. Other types of silver-mediated cyclizations can also be used in the synthesis of tetrahydrofnrans, tetrahydropyrans, 1,2-dioxetanes, 1,2-dioxolanes, medium-sized lactones, dihydroisoqninolines, and so on. Silver salts can also be used as cocatalysts with other transition metals. Unique activity was observed for these silver-based systems in several cases. Conseqnently, the use of silver can enrich several available heterocyclization methods, and fnrther developments in the application of chiral silver complexes will hopefnlly appear in the near future. 

Since the introduction of this reagent in 1983 (/2), it has been utilized in key steps in several syntheses. The reagent can be prepared by the treatment of allyl Grignard reagent with either B-chlorodiisopinocampheylborane (DIP-Chloride M) 34, 35) or B-methoxydiisopinocampheylborane 12). A variety of aldehydes, including perfluoroalkyl 36) and heterocyclic aldehydes (57) have been tested with this reagent to demonstrate its capability. In all of the cases examined thus far the product homoallyl alcohols were obtained in >92% ee (Scheme 2). It has been established that in the case of chiral aldehydes, the reagent controls the diastereoselectivity 38). 

Recently, the intramolecular asymmetric a-allylation of aldehydes has also been accomplished by the MacMillan group via SOMO catalysis. As outlined in Scheme 36.13, this new enantioselective a-formyl cyclization can be employed to build five-, six-, and seven-membered carbocyclic rings 46 from aldehydes 45 in good yields and with a high level of stereocontrol. Heterocycles such as tetrahydropyran 48a and piperidine 48b could also be obtained from substrates 47 in a similar way [19]. 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

Abstract The purpose of this chapter is to present a survey of the organometallic chemistry and catalysis of rhodium and iridium related to the oxidation of organic substrates that has been developed over the last 5 years, placing special emphasis on reactions or processes involving environmentally friendly oxidants. Iridium-based catalysts appear to be promising candidates for the oxidation of alcohols to aldehydes/ketones as products or as intermediates for heterocyclic compounds or domino reactions. Rhodium complexes seem to be more appropriate for the oxygenation of alkenes. In addition to catalytic allylic and benzylic oxidation of alkenes, recent advances in vinylic oxygenations have been focused on stoichiometric reactions. This review offers an overview of these reactions... 

The construction of the heterocycle 3 started with enantiomerically-pure ethyl lactate. Protection, reduction and oxidation led to the known aldehyde 6. Chelation-controlled allylation gave the monoprotected-diol 7. Formation of the mixed acetal with methacrolein followed by intramolecular Grubbs condensation then gave 3. The dihydropyran 3 so prepared was a 1 1 mixture at the anomeric center. 

Under the conditions of alcohol (1.93 mmol), PEG6000-(TEMPO)2 (2.5 mol %), CuCl (5 mol %), 1-methylimidazole (5 mol%), 02 (1 MPa), C02 (6 MPa), benzylic (yield 62-94 %), allylic (yield 95 %), heterocyclic (yield 91 %), and aliphatic alcohols (yield 26 %) are selectively converted into their corresponding aldehydes or ketones, and the over oxidized products are rarely detected (Table 3.1). 

The direct hydrozincation of olefins14 is possible using Et2Zn in the presence of catalytic amount of Ni(acac)2 and 1,5-cyclooctadiene (COD). The resulting diorganozincs can be used for asymmetric additions to aldehydes. The best hydrozincation reactions are obtained with allylic alcohols or amines. In these cases the raction is driven to completion by the formation of a zinc-heterocycle of type 7 (Scheme 5.10). 

The synthesis of silicon-containing heterocycles was reported employing Si-C bond-forming <01JOM160> or aldehyde allylation <01TL581> reactions to prepare the metathesis substrates (Scheme 54). 

We can illustrate the synthesis of allylic alcohols from allylic sulfoxides with this synthesis of the natural product nuciferal. We mentioned this route on p. 1257 because it makes use of a heterocyclic allyl sulfide to introduce an alkyl substituent regioselectively. The allyl sulfide is oxidized to the sulfoxide, which is converted to the rearranged allylic alcohol with diethylamine as the thiophile. Nuciferal is obtained by oxidizing the allylic alcohol to an aldehyde with manganese dioxide. 

Furthermore, the choice of enyne substrates can lead to cyclized products that contain other functionalities than dienes. Very recently, Muller and Kressierer [148] have shown that yne allyl alcohols 200 can be rapidly cyclo-isomerized by a Pd2dba3-W-acetyl phenyl alanine catalyst system to furnish heterocyclic enals 202 in excellent yields (Scheme 82). The intermediate product of the enyne cycloisomerization in this case is the enol 201, which rapidly tautomerizes to the aldehyde 202. 

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