Alkylation sequencing

The products of these double-alkylation sequences in the j8-carboline series, 2,9-dialkyl-j8-carbolinium salts, react with base to yield the corresponding quaternary hydroxides. Pyrolysis of the salts leads to dealkylation at the pyr-N with the production of the corresponding ind-A-alkyl-j8-carbohnes. ... 

ENONE REDUCTION-ENOLATE ALKYLATION SEQUENCE 2 - ALLYL- 3-METH YLC Y CLOHEX AN ONE... 

It is interesting that fmws-2-allyl-3-methy]cyclohexanone is by far the major product of this reduction-alkylation sequence, being formed in greater than the equilibrium ratio (see Note 13). The lithium cnolate would be expected to exist in the two conformations shown below ... 

A deprotonation-alkylation sequence from tetrahydro-oxazolo[3,4- ]pyridin-5-ones or hexahydro-oxazolo[3,4-r ]pyridin-3-ones is an especially efficient method for diastereoselective functionalization, respectively, via the lactam enolate or... 

Ferrocenylphosphines and their oxides (3) have been prepared by standard routes,7 and the properties of diferrocenylphosphine oxide (3 n = 2) reported.8 Derivatives of diphenyl(ferrocenylmethyl)phosphine oxide (4) have been prepared by a metallation-alkylation sequence,9 as shown for the oxide (5). 

Care must also be taken when choosing the reaction partners within reactions. Nucleophiles that have been reported to be effective in conjugate addition processes can also undergo 1,2-addition reactions and these possibilities must be addressed in reaction design. For example, aldehydes and ketones have been shown to undergo a bis-indole alkylation sequence in the presence of achiral amine 139 (42-84% yield 1-10 mol% catalyst) [189]. This additional reactivity was exploited in the... 

A versatile activating group for the removal of a-protons that are not benzylic is the carbamate fert-butoxycarbonyl, or t-Boc group, developed for this purpose by Beak and Lee in 1989. Its utility derives from the fact that the Boc group is easy to attach to a secondary amine, and easy to remove after a deprotonation/alkylation sequence. Moreover, stannylation affords a-amino-organostannanes that are themselves useful precursors of a-amino-organolithium compounds (Scheme 29) (see Section II). In a chiral pyrrolidine system, it has been shown that both deprotonation (H Li) and methylation (Li Me) occur with retention of configuration. 

Finally, the primary site of reaction with some heterocyclic systems may not be one that is desired for final elaboration, and in these cases blocking of the initial reaction site is necessary. This can often be achieved by a consecutive metalation and alkylation sequence, but as with N—H protection the overall process, including final removal of the blocking group, must be achievable in reasonable yield. Trialkylsiyl groups have so far received the most attention in this area, because of their ready addition, relative stability under metalation conditions, and facile hydrolysis. 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

Related, achiral cc,/ -unsaturated molybdenum-( 2-acyl) complexes, such as 8, have been shown to undergo nucleophilic 1,4-conjugatc addition upon treatment with sodium borohy-dride or methyllithium to generate enolate species, such as 9 (produced by addition of hydride). Subsequent alkylation by iodomethane provides the a-alkylated product 1088. Extension of this tandem Michael addition-alkylation sequence to nonracemic molybdenum species has not yet been reported. 

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

To a first approximation, the chiral discrimination should be independent of the nucleophile. The palladium-catalyzed desymmetrization protocol utilizing a heterocyclic nucleophile provides enantio- and diastereoselective entries to diverse carbo-nucleosides. As shown in Scheme 8E.9, introduction of purine bases rather than the hydroxymethyl synthon also affords high enantioselectivities [61]. A variety of natural and unnatural nucleosides can be flexibly prepared because the simple change of ligand chirality or, alternatively, switching the alkylation sequence leads to opposite enantiomers. The palladium-catalyzed approach sharply contrasts with the chiral-pool method, whose enantiodivergency is limited by the availability of the starting material. 

The less acidic hydroxyl groups being more reactive in this alkylation sequence [1661, the 3-benzyl ethers dominate in the reaction of 2,3-diols, and 4-benzyl ethers in the case of 4,6-diols. Thus, 95 % of methyl 3-0-benzyl-4,6-O-benzylidene-a-D-manno-pyranoside together with 5 % of unreacted starting material have been obtained from methyl 4,6-O-benzylidene-a-D-mannopyranoside. Methyl 2,3-0-isopropylidene-sodium hydride in 1,2-dimethoxy-... 

Reaction of N-substituted bromomethanesulfonamides with 2 equiv of potassium carbonate and an cr-haloketone, ester, or nitrile leads directly to the /3-sultams 187 substituted at the C-3 position by an EWG. This base-promoted condensation can be used with a-halo ketones, esters, and nitriles where a second Sn2 intramolecular displacement can operate in tandem fashion (Scheme 60). This domino alkylation sequence exhibits a reactivity order where ketone > nitrile > ester (Table 14). The process is particularly efficient when diethyl bromomalonate or 3-chloro-2-butanone are involved <2004CJC113>. 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

Scheme 14.2 An intramolecular Reformatsky reaction/alkylation sequence.17...

The minimal tin loadings of the polymer supported tin hydrides 75 were found to be in the range of 0.9-1.4 mmol SnH g 1, which is comparable with the activity of the polymer-supported and —CH2CH2— linked dibutyltin hydride reported by Neumann and coworkers160 169. The advantage of the use of alkyl sequences longer than the —CH2CH2— spacer is the prevention of -elimination in free-radical processes. 

Fig. 17 Total synthesis of methyl curcurbate 76 and methyl epijasmonate 77 via a radical-polar 5-exo cyclization/alkylation sequence...

The stereoelectronic effect of the RO-group is less pronounced, when bulkier electrophiles are employed (Table 3, entries 23,27,28), but is increased when the well solvating agent hexamethyl phosphorous amide (HMPA) is used as an additive 61,68). On the other hand, if one performs the deprotonation/alkylation sequence in the unpolar solvent pentane, a complete reversal of the stereochemical outcome provides the coproduct in excess (Eq. 35)61 Now a coordination of the lithium cation to the siloxy function might favour structures like 109 (or its oligomers) and cause predominant formation of cO-cyclopropanes. 

Although other deprotonated complexes are sometimes not as stable as [CpFe( 5-QMesCF )], they can be generated and used at low temperature to form the desired bonds [27e]. Using the base and electrophile in excess, the reactions can be carried out at room temperature because the deprotonated species immediately reacts with the electrophile in situ. This kind of deprotonation/alkylation sequence underpins the star and dendrimer construction described herein (vide infra). In this way, the complexes [FeCp( s-arene)][PF6] also act as proton reservoirs [33]. 

Hydroxy alkenyl and alkynyl nitriles can be subjected to a one-pot addition-alkylation sequence, leading to polysubstituted products. In the case of open-chain systems, diastereoselectivity from 2.3 1 to 6.6 1 was achieved. Cyclic systems may lead to a highly diastereoselective reaction.234,234a 234c iv-Chloroalkenylmagnesium bromides give bicyclic products (Scheme 77 ) 235>236... 

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