Allylation under neutral conditions

Wylation under neutral conditions. Reactions which proceed under neutral conditions are highly desirable, Allylation with allylic acetates and phosphates is carried out under basic conditions. Almost no reaction of these allylic Compounds takes place in the absence of bases. The useful allylation under neutral conditions is possible with some allylic compounds. Among them, allylic carbonates 218 are the most reactive and their reactions proceed under neutral conditions[13,14,134], In the mechanism shown, the oxidative addition of the allyl carbonates 218 is followed by decarboxylation as an irreversible process to afford the 7r-allylpalladium alkoxide 219. and the generated alkoxide is sufficiently basic to pick up a proton from active methylene compounds, yielding 220. This in situ formation of the alkoxide. which is a 

Since allylation with allylic carbonates proceeds under mild neutral conditions, neutral allylation has a wide application to alkylation of labile compounds which are sensitive to acids or bases. As a typical example, successful C-allylation of the rather sensitive molecule of ascorbic acid (225) to give 226 is possible only with allyl carbonate[l 37]. Similarly, Meldrum s acid is allylated smoothly[138]. Pd-catalyzed reaction of carbon nucleophiles with isopropyl 2-methylene-3,5-dioxahexylcarbomite (227)[I39] followed by hydrolysis is a good method for acetonylation of carbon nucleophiles. 

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]. 

Allylation of the 10-carborane 236 (pKa = 18-22) with diallyl carbonate is possible under neutral conditions to give 237[146], Allylation and rearrangement of the trialkylalkynylborane 238 affords the trisubstituted alkene 239 stereoselectively [ 147], 

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn- 

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Allylation under basic conditions. Allylation can be carried out under basic conditions with allylic acetates and phosphates, and under neutral conditions with carbonates and vinyloxiranes. The allylations under neutral conditions are treated separately in Section 2.2.2.1 from those under basic conditions. However, in some cases, allylations of the same substrates are carried out under both basic and neutral conditions to give similar results. These reactions are treated together in this section for convenience. Allylic acetates are widely used for Pd-catalyzed allylation in the presence of bases tertiary amines or NaH are commonly used[6,7,4l]. As a base, basic alumina or ICF on alumina is conveniently used, because it is easy to remove by filtration after the reaction[42]. Allyl phosphates are more reactive than acetates. The allylation with 40 proceeds stepwise. At first allylic phosphate reacts with malonate and then allylic acetate reacts with amine to give 41(43]. 

However, a variant (Scheme 2) using mixed carbonates 5 has become very popular. The leaving group decomposes into C02 and the alkoxide anion (6), which is itself a strong enough base to subtract the active proton from the pronucleophiles. This variant can be considered an allylation under neutral conditions, since no external base is added and the required alkoxide is generated in situ and never accumulates. 

Allylic carbonates are more reaetive than acetates. In addition, reaction of carbonates proceeds in the absence of bases [6]. Formation of jr-allylpalladium 9 from allyl methyl carbonates 8 proceeds by oxidative addition, followed by decarboxylation, and TT-allylpalladium methoxide 9 is generated at the same time, which abstracts a proton from a pronucleophile to form 10. In situ formation of methoxide is a key in the allylation under neutral conditions. Allylation under neutral conditions is useful for the reaction of base-sensitive compounds. For example, exclusive chemoselective reaction of the carbonate group in 4-acetoxy-2-butenyl methyl carbonate (11) occurred in the absence of a base to yield 12. Similar chemoselective reaction of the allyl carbonate group in the chiral cyclopentenyl methyl carbonate 13 with the jS-keto ester 14 without attacking the allylic acetate group to give 15 was observed even in the presence of NaH. As expected, retention of stereochemistry (see Chapter 4.2.1) was observed in this substitution [7]. 

A convenient one-pot procedure for allylation under neutral conditions. 

Allylic acetates are widely used. The oxidative addition of allylic acetates to Pd(0) is reversible, and their reaction must be carried out in the presence of bases. An important improvement in 7r-allylpalladium chemistry has been achieved by the introduction of allylic carbonates. Carbonates are highly reactive. More importantly, their reactions can be carried out under neutral con-ditions[13,14]. Also reactions of allylic carbamates[14], allyl aryl ethers[6,15], and vinyl epoxides[16,17] proceed under neutral conditions without addition of bases. 

Allylation with allyl borates takes place smoothly under neutral conditions. Allylic alcohols are also used for allylation in the presence of boron oxide by in situ formation of allylic borates[125]. Similarly, arsenic oxide is used for allylation with allylic aleohols[126]. In addition, it was claimed that the allyl alkyl ethers 201. which are inert by themselves, can be used for the allylation in the presence of boron oxide[127]. 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

Phenols arc highly reactive 0-nucleophiles and allylated easily with allylic carbonates under neutral conditions. EWGs on phenols favor the reac-tion[213]. Allylic acetates are used for the allylation of phenol in the presence of KF-alumina as a base[214]. 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Besides allylic substitution reactions it was also shown that [Fe(CO)3(NO)] 76 is catalytically active in transesterification reactions under neutral conditions (Scheme 24) [70]. Various activated acyl donors 97 can be used to give rise to the corresponding carboxylic esters 100 in good to excellent yields. This reaction proceeds in the absence of additional ligands in nonpolar solvents, for example, hexane. Mechanistically, the reaction is assumed to proceed via a Fe-acyl-complex 98 (Scheme 24). 

Allylic hydroxycrotyl-oligoethylene glyco-n-alkanoyl (HYCRON) linker 25 was applied to the synthesis of protected peptides and glycopep-tides [31]. HYCRON is stable to both acidic and basic conditions and is compatible with Boc- and Fmoc-based chemistry. The preparation of this novel linker is only two steps from commercially available materials. H YCRON linker can be cleaved under neutral conditions using Pd catalyst (Scheme 9). 

As the nitro group is removed by radical denitration with Bu3SnH, allylic alkylation of a-nitro ketones with allyl carbonates in the presence of Pd(0) followed by denitration with Bu3SnH provides a new regio-selective allylation of ketones under neutral conditions (Eq. 5.55).79... 

Nitrocycloalkanones can be successfully C-allylated by Pd(0)-catalyzed reaction with various allyl carbonates and 1,3-dienemonoepoxides under neutral conditions, as shown in Eqs. 5.56 and 5.57, respectively.801 The product of Eq. 5.56 is converted into cyclic nitrone via the reduction of nitro group with H2-Pd/C followed by hydrolysis and cyclization.80b... 

Recent papers have disclosed that Pd(0) catalyzed allylic alkylations under neutral conditions are not limited to allylic carbonates or epoxides but also can be extended in many cases to the more popular allylic acetates (Eq. 5.58).sla... 

Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)s under photochemical activation conditions, to give mainly aldol products (Scheme 11).33 This novel tandem iosmerization-aldolization reaction is a process with a perfect atom economy, proceeding under neutral conditions. 

Various nucleophiles other than methanol can be introduced onto the carbonyl carbon. Anodic oxidation of acylsilanes in the presence of allyl alcohol, 2-methyl-2-propanol, water, and methyl /V-methylcarbamate in dichlorometh-ane affords the corresponding esters, carboxylic acid, and amide derivatives (Scheme 24) [16]. Therefore, anodic oxidation provides a useful method for the synthesis of esters and amides under neutral conditions. 

New routes to the alkoxides have been established, starting from the hydrido-, allyl-, or alkynylstannanes. Allyltributyltin and tributyltin hydride react with alcohols in the presence of triflic acid to give the tributyltin alkoxides in good yields,379 and the alkyltrialkynylstannanes are cleaved by alcohols under neutral conditions to give the trialkoxides (Equations (136)—(138)).247... 

The Pd(0)-catalyzed displacement of allylic acetates (297) with various nucleophiles via the allylic Pd(II) complex (298) is a well-established procedure (Scheme 114). Through attack of electrons (+2e ) in place of nucleophiles, (298) is expected to undergo a reductive cleavage providing allylic carbanions (299) and the acetate anion along with Pd(0) complexes. The latter can then be captured by various electrophiles (polarity inversion. Scheme 114) leading to (300) [434]. This procedure is useful for the deprotection of allyl esters under neutral conditions. Recently, a mechanistic study of the Pd-catalyzed reaction of allylic acetate (297), using carbonyl compounds as an electrophile, has been reported [435]. 

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