Cyclization/fragmentation process

A route to alkyl-2-deoxy-2-C-formylglucopyranosides by a radical cyclization-fragmentation process is shown in Scheme 9. ... 

As shown in Figure 42 for the Norrish II reactions of a simple ketone, 2-nonanone, not only do the shapes of the products differ from those of the reactant, but so do their molecular volumes [265]. Interestingly, the volume of the fragmentation products, 1-hexene and 2-hydroxypropene (which ketonizes to acetone), are closer in volume to 2-nonanone than is either of the cyclization products. They are also capable of occupying more efficiently the shape allocated by a stiff solvent matrix to a molecule of 2-nonanone in its extended conformation the cross-sectional diameter of either of the cyclobutanols is much larger than that of extended 2-nonanone or the fragmentation products when spaced end-on. Both of these considerations should favor fragmentation processes if isomorphous substitution for the precursor ketone in the reaction cavity is an important requirement for efficient conversion to photoproducts. 

Kilburn has extensively studied radical cascades centered on the use of methylenecyclopropane derivatives. An addition-fragmentation process ap-parented to pathway c opened new routes for the synthesis of carbocycles. In a recent work, a Sml2-promoted cascade of propargyl ether 73 has been used to give bicyclic ether 78 with good diastereoselectivity (Scheme 24), thus providing a short route to the monoterpenoid paeonilactone B. The observed stereoselectivity in the 74 75 cyclization step was shown to be critically dependent on the presence of HMPA [84]. 

A further interesting example is the use of l,l-di(phenylthio)med)yllithium to open an epoxide followed by a Grob fragmentation process as shown in Scheme 56 (entry b). The reaction of 1,1-di-(thio)methyllithium with epoxides has also been used - in the one-pot synthesis of l,l-di(thio)cyclopropanes involving an intramolecular cyclization of the 7-tosyloxydi(phenylthio)alkylli-thium. This intramolecular alkylation reaction proceeds even more efficiently than its intermolecular version, and allows the synthesis of a large variety of l,l-di(thio)cyclopTDpanes from 3-chloro- and 3-phenylthio-l,l-di(thio)alkanes and n-butyllithium in THF (Scheme 57 and Scheme 58). 

Cyanothiazoles 33 are prepared from A -vinyl-l,2,3-dithiazolimines 31, obtained from the reaction of 4,5-dichloro-l,2,3-dithiazolium chloride 29 with aziridines 28 <05H(65)1601>. Thermolysis of imines 31 brings about cyclization to give sulfur, hydrogen chloride and 2-cyanothiazoles 33, possibly by an electrocyclization and fragmentation process. Reaction of allenyl isothiocyanate 34 with a variety of nucleophiles (NuH) leads to... 

On elaboration of l,5-hexadiene-3,4-diol through a 1,3-dioxolane derivative, the RCM delivers a precursor of either exo-brevicomin or endo-brevicomin. A route to (+)-malyngolide also exploits the RCM process. A successful cyclization-fragmentation approach to medium-sized rings is based on the RCM reaction of 2-hydroxycycloalkanones that are substituted with proper alkenyl groups at both a- and a -positions.- ... 

A process involving cyclization-fragmentation of 2-(( )-bromoalkyl)-l,l-dicyanocy-clopropanes is a radical alternative to the Thorpe-Ziegler reaction of dinitriles. Thus,... 

Alkyl triflates can also be used as efficient leaving groups for intramolecular cyclization in the process of generating heterocycles, such as thioindenes, cyclic enones, iV-heterocyclic carbene precursors, or tetrahydropyridines via a Grob fragmentation process (93). They can also be reduced to the corresponding alkane in the presence of a copper catalyst. ... 

SCHEME 25.50. Cyclization upon a vinyl chloride and fragmentation process. 

There are also examples of electrocyclic processes involving anionic species. Since the pentadienyl anion is a six-7c-electron system, thermal cyclization to a cyclopentenyl anion should be disrotatory. Examples of this electrocyclic reaction are rare. NMR studies of pentadienyl anions indicate that they are stable and do not tend to cyclize. Cyclooctadienyllithium provides an example where cyclization of a pentadienyl anion fragment does occur, with the first-order rate constant being 8.7 x 10 min . The stereochemistry of the ring closure is consistent with the expected disrotatory nature of the reaction. 

The fragmentation/cyclization ratio is determined by the relative orientation of the respective molecular orbitals, and thus by the conformation of diradical species 2. The quantum yield with respect to formation of the above products is generally low the photochemically initiated 1,5-hydrogen shift from the y-carbon to the carbonyl oxygen is a reversible process, and may as well proceed back to the starting material. This has been shown to be the case with optically active ketones 7, containing a chiral y-carbon center an optically active ketone 7 racemizes upon irradiation to a mixture of 7 and 9 ... 

Other radicals undergo rearrangement in competition with bimolecular processes. An example is the 5-hexenyl radical (5). The 6-heptenoyloxy radical (4) undergoes sequential fragmentation and cyclization (Scheme 3.8).1S... 

The main primary fragment ions of diaryl sulfoxides 13 and 14 have the structures 16a or 16b(C8H7S02 + m/z 167) and the ion m/z 152 (17) can be obtained from both by the loss of CH3 (equation 5)13. Ions 16a and 16b are formed from the sulfenate ester structure of the molecular ions of 13 and 14 through a cyclization process and a simultaneous loss of the other O Ar part. A similar ortho effect is not possible in 15 and hence its most intense ion is M+ (23% of the total ionization in comparison with 2.7 and 0.6% for 13 and 14, respectively) and its primary fragments are typical for a normal diaryl sulfoxide. 

The selection of the thirty procedures clearly reflects the current interest of synthetic organic chemistry. Thus seven of them illustrate uses of T1(I), T1 (III), Cu(I), and Li(I), and three examples elaborate on the process now termed phase-transfer catalysis. In addition, newly developed methods involving fragmentation, sulfide contraction, and synthetically useful free radical cyclization arc covered in five procedures. Inclusion of preparations and uses of five theoretically interesting compounds demonstrates the rapid expansion of this particular area in recent years and will render these compounds more readily and consistently available. 

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