Allyl carbonate synthesis

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

The reaction can be applied to the synthesis of q, /3-unsaturated esters and lactones by treatment of the ketene silyl acetal 551 with an allyl carbonate in boiling MeCN[356]. The preparation of the q,, 3-unsaturated lactone 552 by this method has been used in the total synthesis of lauthisan[357]. 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

A combination of a Tsuji-Trost and a Michael addition was used for the synthesis of (+)-dihydroerythramine 6/1-269, as reported by Desmaele and coworkers [128]. The Pd-catalyzed reaction of the allylic acetate 6/1-267 with the nitromethylarene 6/1-266 in the presence of Cs2C03 as base led to the domino product 6/1-268 as a 4 1 mixture of two diastereomers in 79% yield. Further manipulation of 6/l-268a yielded the desired dihydroerythramine 6/1-269 (Scheme 6/1.70). Interestingly, using the corresponding allylic carbonate without additional base gave the mono-alkylated product only. 

Besides the formation of carbenes from diazo compounds and the hydroformyla-tion, rhodium (as described previously for palladium) has also been used as catalyst in domino processes involving cycloadditions. Thus, Evans and coworkers developed a new Rh(I)-catalyzed [4+2+2] cycloaddition for the synthesis of eight-membered rings as 6/2-105 using a lithium salt of N-tosylpropargylamines as 6/2-104, allyl carbonates and 1,3-butadiene (Scheme 6/2.22) [221]. The first step is an al-... 

Selenium dioxide is also an oxygen donor to alkenes. In this case, however, the initial reaction of the double bond is with the selenium center followed by two pericyclic steps. After hydrolysis of the organo-selenium intermediate, the result is a hydroxylation at the allylic carbon position65. Thus, limonene (2) yields racemic p-mentha-l,8(9)-dien-4-ol66. The high toxicity of selenium intermediates and prevalence of many rearrangements has limited the widespread use of the reagent in synthesis. 

In 1981, it was demonstrated (70) that anions of nitro compounds can be involved in C,C-coupling with allyl acetates at the allylic carbon atom with the use of metal complex catalysis. For many years, this observation did not come to the attention of chemists interested in the synthesis of cyclic nitronates. However, Trost demonstrated (71) that this process can be used in the synthesis of five-membered cyclic nitronates from olefins (18) containing two acyl groups in the different allylic positions (Scheme 3.21). 

A diverse group of secondary and tertiary amines are readily synthesized from the reaction of primary and secondary amines with allylic carbonates in the presence of preformed iridium metalacycles, but the direct synthesis of primary amines via iridium-catalyzed allylic amination requires the use of ammonia as a nucleophile. The asymmetric allylation of ammonia had not been reported until very recently, and it is not a common reagent in other metal-catalyzed reactions. Nonetheless, Hartwig and coworkers developed the reactions of ammonia with allylic carbonates in the presence of la generated in situ [89]. Reactions conducted in the initial work led exclusively to the products from diallylation (Scheme 16). Further advances in... 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

Rhodium-catalyzed allylic alkylation provides an expeditious entry into a variety of useful synthons for asymmetric synthesis. For example, the application of this reaction to a range of enantiomerically enriched allylic carbonates with the sodium salt of methyl phenylsulfonylacetate provides products that represent important synthons for target-directed synthesis (Tab. 10.1) [17]. 

The synthesis of (S)-ibuprofen (S)-34 utilizing allylic alkylation was undertaken to determine the stereochemical course of this process. The reaction of the enantiomeri-cally enriched allylic carbonate (S)-32 (95% ee) with the requisite aryl zinc bromide (Scheme 10.7) [32], under optimized reaction conditions, furnished the 3-aryl propenyl derivative (R)-33 in 90% yield (2° 1°=10 1) with inversion of configuration (100% cee). The synthesis of (S)-ibuprofen (S)-34 was then completed through the oxidative cleavage of the aUcene (R)-33 in 74% yield [33]. 

Tab. 10.6 summarizes the application of this transformation to a variety of racemic secondary allylic carbonates using the lithium anion of 4-methoxy-N-(p-toluidine)-benzene sulfonamide. The excellent regioselectivity obtained for this type of substitution provided an important advance in the synthesis of N-(arylsulfonyl)anihnes using the metal-catalyzed allyhc amination reaction. The allyhc alcohol derivatives examined... 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

The Tsuji-Trost reaction, more commonly applied to carbocyclic nucleoside synthesis, has been used in the synthesis of famciclovir 21 (Scheme 5) <2000T4589>. Reaction of 2-amino-6-chloropurine with allylic carbonate 22 in the presence of Pd2DBA3 and bis(diphenylphosphino)ethane (DPPE) gave a 1 1 ratio of 23 to 24 after 1 h (DBA = dibenzylideneacetone). However, a ratio of >95 5 in favor of the thermodynamically favored N-9 isomer 23 was subsequently obtained upon further stirring, highlighting the reversibility of the reaction in this specific instance. 

When the Pd bears chiral ligands, these reactions can be enantioselective.1448 ir-Allylmo-lybdenum compounds behave similarly.1449 Because palladium compounds are expensive, a catalytic synthesis, which uses much smaller amounts of the complex, was developed. That is, a substrate such as an allylic acetate, alcohol, amine, or nitro compound1450 is treated with the nucleophile, and a catalytic amount of a palladium salt is added. The rr-allylpal-ladium complex is generated in situ. Alkene-palladium complexes (introducing the nucleophile at a vinylic rather than an allylic carbon) can also be used.1451... 

Allyl carbonates can be cleaved by nucleophiles under palladium(O) catalysis. Allyl carbonates have been proposed for side-chain protection of serine and threonine, and their stability under conditions of /VT moc or /V-Boc deprotection has been demonstrated [107]. Prolonged treatment with nucleophiles (e.g., 20% piperidine in DMF, 24 h) can, however, lead to deprotection of Alloc-protected phenols [108,109]. Carbohydrates [110], tyrosine derivatives [107], and other phenols have been protected as allyl ethers, and deprotection could be achieved by palladium-mediated allylic substitution (Entry 9, Table 7.8). 9-Fluorenyl carbonates have been used as protected intermediates for the solid-phase synthesis of oligosaccharides [111]. Deprotection was achieved by treatment with NEt3/DCM (8 2) at room temperature. 

Needless to say, /i-keto esters are important compounds in organic synthesis. Their usefulness has been considerably expanded, based on Pd-catalysed reactions of allyl / -keto carboxylates 399. Cleavage of the allylic carbon-oxygen bond and subsequent facile decarboxylation by the treatment of allyl / -keto carboxylates with Pd(0) catalysts generate the 7i-allylpalladium enolates 400, 401. These intermediates undergo, depending on the reaction conditions, various transformations which are not possible by conventional methods. Thus new synthetic uses of / -keto esters and malonates based on Pd enolates have been expanded. These reactions proceed under... 

In the synthesis of alkylidenecyclobutenes from propargyl alcohols, stoichiometric experiments show that the first step involves [2+2] oxidative head-to-head coupling of the alkynes, leading to an isolable cyclobutadiene-ruthenium complex. Addition of acid generates a cyclobutenyl metal intermediate which undergoes carboxylate addition on the less substituted allylic carbon atom (Scheme 7). 

Nemoto, Yamamoto, and Cai[30a] later modified the preparation of their water-soluble carborane to include the attachment of a tumor seeking uracil moiety (Scheme 5.8). Key transformations allowing the synthesis of this unique dendritic carborane (33) included construction of masked uracil allyl carbonate 34 and its subsequent connection to the benzyl protected o-carborane cascade 35, the intermediate precursor to tetraol 30, via palladium bis(dibenzylideneacetone) [Pd(dba)2] and l,2-bis(diphenylphosphino)ethane (dppe) mediation. 

Ruthenium complexes are also suitable catalysts for carbonylation reactions of a variety of substrates. Indeed, when a reaction leads to C-Ru or het-eroatom-Ru bond formation in the presence of carbon monoxide, CO insertion can take place at the coordinatively unsaturated ruthenium center, leading to linear ketones or lactones. Thus, ruthenium-catalyzed carbonylative cyclization was involved in the synthesis of cyclopentenones by reaction of allylic carbonates with alkenes in the presence of carbon monoxide [124] (Eq. 93). 

Moreno-Manas M, Pleixats R (2002) Palladium-Catalyzed Allylation with Allyl Carbonates. In Negishi E, de Meijere A (eds) Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley, New York, p 1707... 

We have reported on a tandem procedure for the synthesis of 3-allyl-N-(alkoxycarbonyl)indoles 115 via the reaction of 2-(alkynyl)phenylisocyanates 114 and allyl carbonates 5 in the presence of Pd(PPh3)4 (lmol%) and CuCl (4 mol%) bimetallic catalyst [80]. A proposed mechanism is shown in Scheme 35. Initially, the insertion of the isocyanates 114 into the complex 7, formed by the reaction of 5 with Pd(0), would form the 7r-allylpalladium intermediates 117. This intermediate, with Pd - N bonding, could be in equilibrium with the Pd - O bonded intermediates 118, which should more probably be represented as the bis-7r-allylpalladium analogue 119. Insertion of the alkyne then occurs to form the indoles 115 and the Pd(0) species is regenerated. It should be emphasized that no carboamination takes place at all in the absence of CuCl the product 116 was obtained. 

Another rapidly progressing field is that of multistep reactions which occur in ordered sequences chemo-, regio- and stereo-selectively on a transition metal species. To this end, it is necessary to delay release of the desired product until the whole series of steps has been completed competitive terminations (such as hydride elimination) must be prevented or must only occur at low rates compared to the main sequence. An example, reported by Chiusoli in the late 50s, is offered by the nickel-catalyzed synthesis of methyl 2,5-heptadienoate from 2-butenyl chloride, acetylene, CO and methanol. The reaction is chemo-, regio- and stereo-selective the four molecules react in the order shown in Equation A3.4 (chemoselectivity) the butenyl group attacks the terminal allylic carbon rather than the internal one (regioselectivity) and acetylene insertion leads to a Z double bond (stereoselectivity). 

---