Aliphatic intramolecular

Ring closure resulting from attack of a heteroatom on a carboxyl group or its equivalent is merely a case of intramolecular esterification or amide formation. The y-butyrolactones or pyrrolidones obtained from such reactions are usually regarded as the province of aliphatic chemistry, so only a few examples are offered by way of illustration in Scheme 15. 

Thus, simple ketones or aliphatic aldehydes may be successfully used as starting materials in the CSIC (Carbanion mediated Sulfonate Intramolecular Cyclization) reaction. Ai-alkylsulfonamides could be also cyclized under CSIC conditions (99T(55)7625) affording the spiroisothiazoline 79. By treatment with TMSCl, Nal in acetonitrile at r.t., hydrolysis of the enamine and formation of the corresponding keto derivative 80 was obtained. 

Although the enantioselective intermolecular addition of aliphatic alcohols to meso-epoxides with (salen)metal systems has not been reported, intramolecular asymmetric ring-opening of meso-epoxy alcohols has been demonstrated. By use of monomeric cobalt acetate catalyst 8, several complex cyclic and bicydic products can be accessed in highly enantioenriched form from the readily available meso-epoxy alcohols (Scheme 7.17) [32]. 

The ionization of (E)-diazo methyl ethers is catalyzed by the general acid mechanism, as shown by Broxton and Stray (1980, 1982) using acetic acid and six other aliphatic and aromatic carboxylic acids. The observation of general acid catalysis is evidence that proton transfer occurs in the rate-determining part of the reaction (Scheme 6-5). The Bronsted a value is 0.32, which indicates that in the transition state the proton is still closer to the carboxylic acid than to the oxygen atom of the methanol to be formed. If the benzene ring of the diazo ether (Ar in Scheme 6-5) contains a carboxy group in the 2-position, intramolecular acid catalysis is observed (Broxton and McLeish, 1983). 

More recently, Beckwith demonstrated that intramolecular Meerwein reactions are also possible if one uses an arenediazonium salt with an aliphatic side-chain in the ortho position containing a double or triple CC bond in 8-position. We will discuss them in Section 10.11. 

There are some reactions in which an aryl radical reacts with an sp2-carbon atom of an aliphatic side chain. In such reactions a carbo- or heteroalicyclic ring fused with a benzene ring is formed (Scheme 10-80). They may be called intramolecular Meerwein reactions. Techniques for these syntheses were developed by Beckwith s group in the 1980s. The majority of Beckwith s investigations were made with 2-(2 -propenyloxy)- and 2[(2 -methyl-2 -propenyl)oxy]benzenediazonium tetrafluoro-... 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Scheme 12.26 Asymmetric intramolecular Stetter reactions with aliphatic aldehydes...

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

An additional example of a cycloamylose-induced rate acceleration which may be reasonably attributed to a conformational effect is the facilitation of the transfer of the trimethylacetyl group from the phenolic oxygen of 9 to the aliphatic oxygen of the adjacent hydroxymethyl group to form 10. This intramolecular transesterification is remarkably enhanced relative to a comparable intermolecular reaction,6 and occurs, at pH 7.0 and 25.5°, with a rate constant of 0.0352 sec-1 (Griffiths and Bender, 1972). An even larger rate enhancement is achieved upon inclusion of this material within the cyclohexaamylose cavity—fc2 = 0.16 sec-1. This fivefold acceleration cannot be satisfactorily explained either by a microsolvent effect which would be expected to depress the rate of the reaction or, at this pH, by covalent... 

Tandem cyclization from [5+1,6+0] atom fragments took place when 3-isothiocyanatobutyraldehyde was reacted with 2-aminobenzylamine 228 (X = NH) to give 229. Based on literature analogies the first step involves the attack of the most nucleophilic aliphatic amino group onto the isothiocyanate and then onto the aldehyde carbon to form 1-(n-aminobenzyl)-6-hydroxytetrahydropyrimidine-2-thione, which undergoes intramolecular cyclocondensation to 229 (Scheme 38) <2005BMC3185>. 

Hultgren, V. M. Atkinson, I. M. Beddoes, R. L. Collison, D. Garner, C. D. Helliwell, M. Lindoy, L. F. Tasker, P. A. Formation of folded complexes retaining intramolecular H-bonding in the extraction of nickel(II) by phenolic oxime and aliphatic diamine ligands. Chem. Commun. 2001, 573-574. 

A similar mechanism of chain oxidation of olefinic hydrocarbons was observed experimentally by Bolland and Gee [53] in 1946 after a detailed study of the kinetics of the oxidation of nonsaturated compounds. Miller and Mayo [54] studied the oxidation of styrene and found that this reaction is in essence the chain copolymerization of styrene and dioxygen with production of polymeric peroxide. Rust [55] observed dihydroperoxide formation in his study of the oxidation of branched aliphatic hydrocarbons and treated this fact as the result of intramolecular isomerization of peroxyl radicals. 

The photocycloaddition of aliphatic and aromatic aldehydes with 2,4,5-trimethyloxazole (131) gave bicyclic oxetanes 132 in almost quantitative yields hydrolitic cleavage led selectively to erytro a-amino-P-hydroxy methyl ketones 133 <00CC589>. The oxazolium salt 134 was converted to the azomethine ylide 136 via electrocyclic ring opening of the oxazoline 135. Intramolecular cycloaddition afforded 137 in 66% overall yield which was transformed into the aziridinomitosene derivative 138 . 

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