Geminal disubstitution

As an illustrating example for the application of the Friedel-Crafts acylation in the synthesis of complex molecules, its use in the synthesis of [2.2.2]cyclophane 13 by Cram and Truesdale shall be outlined. The reaction of [2.2]paracyclo-phane 10 with acetyl chloride gives the acetyl-[2.2]paracyclophane 11, which is converted into the pseudo-geminal disubstituted phane 12 by a Blanc reaction, and further to the triple bridge hydrocarbon 13 ... 

Fig. 2.9 Geminally disubstituted amino acids synthesized to evaluate the preferential conformations of and -peptides...

HSiMe2OTBDPS),43h and benzhydryldimethylsilane (HSiMe2CHPh2).43 As in the racemic variant, efficient cycli-zation generally requires preorganization of the 1,6-diene through homoallylic geminal disubstitution (Scheme 14). 

A strong stabilizing geminal disubstitution effect is also observed for difluoro disubstituted hydrocarbons (e.g. 2MeF CH2F2 + CH4,... 

But if we examine 2, 2 dimethyl cyclopropane-monocarboxylic acid (xxi) it has no plane of symmetry. The molecule contains an asymmetric carbon atom ( ) and exists in (+) and (-) forms and one racemic form. However, a non-geminally disubstituted odd-membered ring provides an... 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Extensive work has been done to determine and understand the factors controlling diastereoselectivity in the cycloaddition of nitrile oxides to alkenes but very little is known about nitrile ylides in this regard. Work on their reactions with alkenes that are geminally disubstituted with electron-withdrawing groups (e.g., 187) has illustrated some of the difficulties in such studies. When the imidoyl chloride-base route was used to generate the nitrile ylides it was found that the products 188 epimerized under the reaction conditions. When the azirine route was used, the reaction was complicated by the photochemical isomerization of the dipolarophiles (96,97). Thus, in both cases, it proved impossible to determine the kinetic product ratio. 

Cascade carbopalladation sequences after attack on an alkene are most commonly terminated by dehydropallada-tion, if a / -hydride is available in a yy//-orientation. The intramolecular carbopalladation starting from the monocyclic diene 122 with a geminally disubstituted alkene terminator leads to a neopentylpalladium intermediate 123, which cannot undergo /J-dehydropalladation, but continue the cascade by a carbopalladation to eventually form the... 

In the second example, the non-geminally disubstituted cyclotriphosphazene N3P3F4(NMe2)2 exist as two isomers, cis (3.10a) and irans (3.10b), that can be distinguished by NMR spectroscopy. For the cis isomer 3.10a, the Fc atoms are related by a plane of symmetry and, therefore, will have the same chemical shifts, whereas the fluorine atoms Fa and Fb are not symmetry related. Therefore, three resonances with relative intensities of 2 1 1 are predicted in the F NMR spectrum. By contrast, the trans isomer 3.10b has a C2 axis that relates the fluorine atoms Fa and Fb the same C2 axis also gives rise to symmetry equivalence for the two Fc atoms. Consequently, two equally intense F NMR resonances will be observed for the trans isomer. 

Phenylsulfonyl)allene and geminal disubstituted dicyanoallenes react with enamines 22 giving 3-alkylidene-l-aminocyclobutanes. The alkylidenecyclobutanes equilibrate via the same zwitter-ionic intermediates.20... 

The geminal disubstituted precursors CF3CH(OH)2 and PhCH(NHCOR)2 were applied in place of trifluoroacetaldehyde134 and benzaldehyde.132 The... 

Substituted cycloalkenes usually react in the ring and not in the side chain. Internal alkenes with CH2 groups in both allylic positions yield a mixture of isomers, whereas terminal alkenes give primary alcohols as a result of allylic rearrangement. Later studies revealed, however, that the reactivity depends on both the structure of the alkene and reaction conditions.674 675 In alcoholic solutions, for example, racemic products are formed. Geminally disubstituted alkenes may exhibit a reactivity sequence CH > CH2 > CH3.675 676... 

Palladium(II) salts, in the form of organic solvent soluble complexes such as PdCl2(RCN)2, Pd(OAc>2 or Li2PdCU, are by far the most extensively utilized transition metal complexes to activate simple (unactivated) alkenes towards nucleophilic attack (Scheme 1). Alkenes rapidly and reversibly complex to pal-ladium(II) species in solution, readily generating alkenepalladium(II) species (1) in situ. Terminal monoalkenes are most strongly complexed, followed by internal cis and trans (respectively) alkenes. Geminally disubstituted, trisubstituted and tetrasubstituted alkenes are only weakly bound, if at all, and intermolecular nucleophilic additions to these alkenes are rare. 

Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe-Ingold effect).56... 

Alkylene chains with geminal dialkyl substitution have been shown to cyclize more readily than the corresponding unsubstituted compounds (Scheme 9.12). This effect can be used to achieve cyclization which might not occur without geminal disubstitution (see, e.g., Scheme 9.21) [32]. The magnitude of this effect is, however, highly dependent on the type of reaction and product, as illustrated by the examples in Scheme 9.12. 

Scheme9.12. Promotion of cyclizations by geminal disubstitution in the chain [33-36],...

When the alkene is neither terminal nor conjugated, addition appears to occur the other way round - to give a (3-alkoxylithium such as 34 - which eliminates Li20 under the conditions of the reaction.26 Cyclic allylic alcohols similarly give alkenes by elimination, and geminally disubstituted allylic alcohols such as 35 are simply unreactive.25... 

With CF3C=CCF3 or olefins with an internal double bond such as cis- or fraras-F-2-pentene, F-cyclobutene, or l,2-dichloro-l,2-difluoro-ethylene, or with a geminally disubstituted olefin such as 1,1-dichloro-2,2-difluoroethylene, only fully fluorinated products were obtained, likely through a nucleophilic fluorination mechanism. This fact, plus the necessity for a Lewis acid catalyst for addition to proceed, is evidence for an electrophilic addition mechanism. Others have suggested polar addition of BF3 to the olefin with RfBF2 as a reactive intermediate (294). 

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