Regiochemical control

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

The regiochemical control of Pd-catalyzed hydnde transfer reacdon is much more effeedve than that of the radical denitradon, as Shown in Eq 7 98 The base-catalyzed reacdon of nitroolefins with aldehydes followed by denitradon provides a new syntbedc method of homoallyl aicohols fEq 7 99 Exomethylene compounds are obtined by denitradon of cyclic allylic nino compounds with PdfO, HGO-,H and Et- N fEq 7 100 ... 

We have found in our studies that the use of the lithium counter ion in the base is essential for successful reaction with regiochemical control and allows cyclization to proceed under mild thermal conditions. In contrast, use of sodium (NaH, NaN(SiMe3)2) or potassium (KH, KN(SiMe3)2) bases require elevated temperatures, and results in poor yields of the desired product, and a mixture of several by-products, including the regioisomeric 4-hydroxymethy-2-oxazolidinone,6 resulting from alternate processes. Thus, the lithium ion plays a very important role in the mechanism of this reaction. 

Hydrozirconation of terminal alkynes R-C=CH (R= aryl, alkyl) with 1 affords terminally ( )-Zr-substituted alkenes with high efficiency and excellent stereochemical and regiochemical control (>98%). These alkenylzirconocene complexes are of particular interest for synthetic use [136, 143, 144]. Moreover, beside the electropositive halogen sources [145] and heteroatom electrophiles [3] used in the pioneering studies to directly cleave the Zr-C bond, ( )-vinyl-Zr complexes were recently transformed into a number of other trans-functionalized alkenes such as ( )-vinyl-sul-fides[146], vinylic selenol esters [147], vinyl-sulfones [148], vinyl-iodonium [149], vinyl-(R0)2P(0) [150], and vinilic tellurides [143]. 

For methyl ketimines good regiochemical control in favor of methyl deprotonation, regardless of imine stereochemistry, is observed using LDA at -78° C. With larger A-substituents, deprotonation at 25° C occurs anti to the nitrogen substituent.115... 

Phenylprop-2-enyl sulfates are cyclized stereospecifically and with Markovnikov regiochemical control. These are endo-6 cyclizations. 

Danishefsky s diene).46 The two donor substituents provide strong regiochemical control. The D-A adducts are trimethylsilyl enol ethers that can be readily hydrolyzed to ketones. The (3-methoxy group is often eliminated during hydrolysis, resulting in formation of cyclohexenones. 

Mitchell, D. Doecke, C. W. Hay, L. A. Koenig, T. M. Wirth, D. D. Ortho-hydroxyl assisted deoxygenation of phenones. Regiochemical control in the synthesis of mono-protected resorcinols and related polyphenolic hydroxyl systems. Terahedron Lett. 1995, 36, 5335-5338. 

The regiochemical control of Pd-catalyzed hydride transfer reaction is much more effective than that of the radical denitration, as shown in Eq. 7.98. The base-catalyzed reaction of nitroolefins with aldehydes followed by denitration provides a new synthetic method of homoallyl alcohols (Eq. 7.99).140 Exomethylene compounds are obtained by denitration of cyclic allylic nitro compounds with Pd(0), HC02H and Et3N (Eq. 7.100).140b... 

Cox AL, Johnston JN (2001) Use of the Vicinal Element Effect for Regiochemical Control of Quinone Substitutions and Its Implication for Convergent Mitomycin Construction. Org Lett 3 3695... 

In broad definition, regio-control over reactivity (regiochemical control) involves the demonstration of locale preferences for a chemical reaction. Generally, regio-control is thought of in terms of through bond separation of reactive sites, as in the resonance forms for the cyclohexanedionyl anion of Figure 6.1. 

Crotti and co-workers work on regiochemical control of ring opening of epoxides by means of chelating agents has continued. Under standard conditions the regio-isomeric C(l) derivatives are the sole products from the trans epoxides (22a) and (22b) and are the predominant products from the cis epoxides (23a) and (23b). Under chelating conditions the cis epoxides unexpectedly show a consistent increase in C(2) selectivity. The results are discussed in terms of electronic and steric effects. 

On the other hand, differential substitution adj acent to equivalently substituted a positions does not afford a good regiochemical control (compare 103 and 104, equation 35) . 

TABLE 18. Cation-dependent regiochemical control in the intra i t tooxygenation of 1- phenyl-3-methyl-2-butene e p o-... 

Thermolysis of a solution of epoxide 79 and l,3-thiazole-5(477)-thione derivative 80 in xylene led to the formation of three cycloadducts in 85% overall yield (22). It was expected that the geminal cyano groups of the epoxide would control the regioselectivity of the ring opening such that the anionic terminus of the dipole would be localized on that carbon. Regiochemical control led to a very selective... 

Piperidines can also be functionalized via the N-chloro derivatives. These are known to give imines when treated with base (76S745). Although there is little regiochemical control, the reaction provides a useful entry into the simple A1 -piperideines (Scheme 6) (80JOC1515). 

The electrolytic oxidation of N- methoxycarbonylpiperidines provides an interesting and potentially valuable method for the functionalization of piperidine derivatives (81JA1172). Anodic oxidation of piperidine (101) gave (102) which reacted, presumably through the acyl imine, with enol ethers to form a carbon-carbon bond a to the nitrogen atom (Scheme 9). The regiochemical control in this reaction is illustrated by the exclusive oxidation at the less substituted carbon atom (55JA439). 

Electrophile-initiated cyclizations of substrates where an existing ring constrains rotation of the vinylic bond which attaches the nucleophile to the double bond generally occur with quite predictable stereochemical and regiochemical control. These reaction types have been used extensively in synthesis and only representative examples and leading references will be presented here. 

The effects on coupling efficiency and regiochemical control in nonsymmetrical allyl complexes as a function of added ligand in these reactions has been determined155,156 (vide infra) and applied in the synthesis of flexibilene and humulene.157... 

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