Reaction alkylation-cyclization

A highly stereoselective synthetic strategy for disubstituted piperidines 247 with cis appendages was reported recently. A one-pot intermolecular imino aldol reaction of a-arylmethylidine 244 or a-alkylidine p-keto ester 248 with aldimine 246 followed by intramolecular aza-Michael reaction (alkylative cyclization) in a domino fashion afforded the corresponding piperidines 247 in high yields and excellent stereoselectivity (er, dr >99%) (Scheme 40.54). ... 

Vinylic sulfones undergo the same reaction especially when allylic, benzylic or t-alkylithium reagents are employed. One case of a vinyl sulfone deserves special mention - . When phenyl trans-3-bromopropenyl sulfone is treated with certain Grignard reagents it undergoes an alkylating cyclization ... 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

Thus, the best compromises for Boc and Fmoc chemistries seem to be cyclohexyl and 2,4-dimethylpent-3-yl (Dmpn), which is of intermediate stability, and the removal of which by trifluoromethanesulfonic acid with the aid of thioanisole (see Section 6.22) leads to minimal imide formation (see Section 6.13). Points to note are that acidolysis of esters by hydrogen fluoride can lead to fission at the oxy-car-bonyl bond instead of the alkyl-oxy bond, thus generating acylium ions that can react with nucleophiles (see Sections 6.16 and 6.22), and that benzyl esters may undergo transesterification if left in methanol. The side reactions of cyclization (see Section 6.16) and acylation of anisole (see Section 6.22) caused by acylium ion formation do not occur at the side chain of aspartic acid.47-51... 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

Palladium-monophosphine complexes catalyse trans-selective arylative, alkenyla-tive, and alkylative cyclization reactions of alkynals [e.g. (68)] and alkynones with organoboronic reagents. These reactions afford six-membered allylic alcohols (69) (g) and/or their five-membered counterparts (70), whose ratios are dramatically affected... 

The direct synthesis of a phosphetane ring by the alkylation-cyclization method using dilithium phosphide and 1,3-dihalopropane resulted in a low yield (13%), because of thermally favored chain-forming side reactions and the instability of the final product in the reaction mixture (Equation 25) <1996OM1301>. 

In summary, the construction of phosphetane or arsetane rings is usually carried out by McBride synthesis or alkylation-cyclization methods. These methods are quite useful, with a good selectivity in most cases. [2+2] Cycloaddition reactions are also available, but this method is limited to particular cases. In addition to these methods, other useful methods based on the transformation from another ring system have been developed. These methodologies are described in Section 2.10.10. 

Another method for the preparation of these pyrazino[2,3-d][l,3]oxazines (169) is the alkylation-cyclization of an appropriate aminocarboxylic acid (170) and an acetanhydride <90JMC464,93UP 719-01). This one-step reaction is an extremely simple way to pyrazino[2,3-d][l,3]oxazines (Equation (23)). 

We end this chapter with a simple commercial synthesis of a drug molecule described as a dopaminergic antagonist. It uses four reactions that you have met conjugate addition of an enolate to acrylonitrile reduction of CN to a primary amine alkylation and reduction of the amide. There is another reaction involved—cyclization to an amide—but this occurs spontaneously. These reactions may be simple but they are important. 

Cyclizations. Cyclization of hydroxylated propargyl sulfones may involve isomerization to the corresponding allenyl sulfones which should behave as Michael acceptors. Access to the indolizidine skeleton by an intramolecular Michael reaction of 5-tosyl-4-pentenamide and subsequent alkylation at nitrogen and carbon is quite efficient. A synthesis of resorcinols from dimethyl acetonedicarboxylate and alkyl alkynoates involves a Michael reaction-Dieckmann cyclization sequence. 

The alkylating-cyclization method may be extended to the enantioselective introduction of an alkyl chain, if a chiral alcohol is used as starting material. The tributyltin hydride mediated radical cyclization of the bromoacetal of 18,19-bisnor-9/i-podocarp-l 3-en-12-one gives a tetracyclic d-lactone, the characteristic structural feature of quassinoids, a complex family of degraded triterpenes82. The hydrogen abstraction in the last step of the reaction has to occur stereoselectively, because only two C-16 diastereomers are formed during the reaction. 

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