Activation Substitution

A series of optically active substituted l,2-dihydro-6-oxo-6//-pyr-rolo[3,2,l-j ]quinoline-5-carboxylic acids were prepared (95CPB1678). 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

Optically active substituted alkylidene cyclohexanes were prepared from sulfinyl esters (obtained by carboxylation of sulfinyl anions) by thermolytic elimination of the sulfinyl group65. 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

Most of the other silylation-activation-substitution reactions reported in this review are mechanistically related. Several new reactions (such as those discussed in Sections 7.1, 7.2, and 7.4) have been discovered by following these hnes of thinking about activation of functional groups by O-silylation and subsequent or concomitant reaction with nucleophiles giving the expected products and hexamethyldisiloxane 7. It can thus be expected that current and new silylation-activation reactions will be more commonly used in preparative chemistry in the future. 

Hydrazides also containing a metasulfonamide function are known to exhibit diuretic activity. Substitution of an N-aminodihydroindole for the hydrazine is consistent with this activity. Preparation of one such agent is carried out by reaction of 2-methyl-N-aminoindoline (44) with 3-sulfamoyl-4-chlorobenzoyl chloride (45), leading to the diuretic indapamide (46). ... 

With [2](l,9)anthraceno[2](2,5)furanophane (45) the reaction takes a different course. Here, the intramolecular Diels—Alder reaction in the primary adduct 136 does not take place with the activated, substituted double bond as in the case of 42 and [2.2](2,5)furanophane (43), whose reactions with 133 have also been investigated 66 b>, but with the deactivated double bond functioning as dienophile. Spectroscopic findings indicate the structure 137 for the 1 2 adduct obtained when an excess of 133 is employed. 

Another effective way of staying clear of the thermodynamic barriers of C-H activation/substitution is the use of the c-bond metathesis reaction as the crucial elementary step. This mechanism avoids intermediacy of reactive metal species that undergo oxidative additions of alkanes, but instead the alkyl intermediate does a o-bond metathesis reaction with a new substrate molecule. Figure 19.13 illustrates the basic sequence [20],... 

Changes in R, and X had very similar effects whether these changes were in the imidazoisoindoles, the dihydroimidazo-isoindoles or the benzoates. Optimum activity was associated with = CH and R = CHCCH ) There was nevertheless still considerable activity in compounds in which R,, R2 were methyl, methyl or methyl, ethyl or methyl, cyclopropyl. Other combinations of Rj and R2 usually resulted in compounds with lower levels of activity. Substitution in the aromatic ring also reduced biological activity. 

As Beak and coworkers have established several years ago, A-rert-butoxycarbonyla-mines are sufficiently acidic to be deprotonated adjacent to the nitrogen atom . When applying 5-BuLi/(—(-sparteine (11) to A-Boc-pyrrolidine, asymmetric deprotonation (149), onepro-S-H is removed with high selectivity, furnishing the configurationally stable 2-lithio derivative 150 which was trapped with several electrophiles to form the optically active substitution products 151 (equation 33) A prescription in Organic Syntheses is... 

The 6-phenyldihydrodiazepinium cation is readily brominated at room temperature to give the 6-p-bromophenyl derivative [81JCS(P1)726]. At a naive level this result would seem to indicate the unusual feature of activated substitution at the p-position of a benzene ring brought about by a substituent onium group, but the present onium group is in fact an electron-rich species. Analogs with substituents at the l-,2-,3, or 4-... 

For a series of biologically active substituted 3-phenylsydnones, quantitative structure-activity relationships have been described. ... 

Amino Acid Substitution The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino add is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH]... 

The 1,4-DHP ring is essential for bioactivity the use of reduced (pyridine) or oxidized (piperidine) ring systems reduces activity substitution at the N1 position reduces activity... 

A substituted phenyl ring at the C4 position optimizes activity substitution with heteroaromatic rings (e.g., pyridine) produces similar efficacy but enhances toxicity substitution with nonplanar alkyl or cycloalkyl groups reduces activity... 

TABLE 9. Reactants and products of MMC-activated substitution reactions... 

The partially resolved cobalt acetylacetonate was found to be optically stable in solution or in the solid state for long periods. However, slow crystallization of this substance always produced racemic crystals (14). Several of the optically active substituted cobalt chelates exhibited the same strange phenomenon. Removal of the solvent from solutions of optically active cobalt acetylacetonate with a slow stream of air yielded a solid which showed little apparent crystalline character under a polarizing microscope but dissolved to form a solution of about the same specific rotation as the starting solution. 

Niobium and tantalum dialkylamides can easily undergo substitution or insertion reactions, as well as C—H activation. Substitution reactions have been used to obtain dialkylamides262 or dithiolenes.275 Aminolysis reactions, for instance, were assumed to occur via a simple associative mechanism (equation 6).276... 

The active Pt(IV) compounds are octahedrally coordinated and possess axial bound chloride or—to improve the solubility—hydroxo ligands, i.e., two Y ligands in the trans orientation. These compounds are far more inert than the corresponding Pt(II) compounds that lack these axial ligands. Most likely the Pt(IV) compexes are reduced in vivo to the corresponding Pt(II) complexes, which are in fact the active species (17-19). They can therefore be considered as a type of prodrug that requires in vivo activation (substitution and reduction) to the square-planar Pt(II) compounds to exhibit antineoplastic activity. This hypothesis is supported by the observation that platinum(IV) compounds are unable to react with DNA under ambient conditions (19), and that appreciable amounts of Pt(II) derivatives can be detected in the urine of Pt(IV)-treated patients(fS). 

The d10 system, dominated by Ni(CO)4, sticks closely to the rule that substitution is dissociative. Very little had been done since the early days85-95-108 apart from the reaction between, inter alia, Ni(CO)4 and bidentate ligands where the interest was in the mechanism of chelation,109 and a volume of activation study110 that confirmed the assignment of mechanism. With ligands other than CO it is possible to include Pd(0) and Pt(0) reaction centres. M(PF3)4 (M = Ni, Pt)111 and M[P(OEt3)]4112 undergo dissociatively activated substitution. 

The way to achieve direct iodination in the absence of powerful activating substitutent groups is to convert molecular iodine to some more active species (perhaps H2OI or I ) with an oxidizing agent such as nitric acid or hydrogen peroxide ... 

Under these conditions the carbocation, which is the active substituting agent, is generated by protonation of the alkene ... 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

Table 3 Preparation of Optically Active Substituted 5-Oxoalkanoates (155 Scheme 55)...

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