Nucleophilic azidation

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs wifii complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show fiiat partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react until water to give product of retained configuratioiL When azide ion is present, dioxane does not efiTectively conqiete for tiie ion-p intermediate, and all of the alcohol arises from tiie inversion mechanism. ... 

The syntheses were effected by selective mesylation of one or two hydroxyl groups and displacement of each mesyloxy group by an azido group, which was reduced to amino. Although attempted SN2 displacement of cyclohexane substituents is often unsuccessful, the powerfully nucleophilic azide ion is usually able to displace an alkylsulfonoxy group, and this route has been exploited in several recent cyclitol syntheses. 

Results such as these have led to recurring discussions about the extent of stabihzation of the transition state for heterolytic cleavage at tertiary carbon by nucleophilic assistance from solvent. The difficulty lies in reconciling studies that suggest that there is a small dependence of obsd (s ) for solvolysis of tert-butyl chloride,and some cumyl derivatives, on solvent nucleophilicity with other work that shows there is no detectable stabilization of the transition state for these reactions by interaction with the strongly nucleophilic azide and hydroxide ions, and the strong neutral nucleophile propanethiol. ... 

The preparation of the allene bis-epoxide 1 started with isovaleraldehyde 9. Addition of the protected propargyl alcohol 10 under the Carreira conditions led to 11 in > 95% . Mesylation followed by displacement with methyl cuprate provided the allene without loss of enantiomeric excess. Oxidation of the allene 12 with dimethyldioxirane could have led to any of the four diastereomers of the spiro bis epoxide. In the event, only two diastereomers were observed, as a 3 1 mixture. That 1 was the major diastereomer followed from its conversion to 3. The configuration of the minor diastereromer was not noted. Exposure of 1 to nucleophilic azide then gave the easily-purified 2. 

The clusters Os3(CO)10L(NNNPhCO) (14) formed by adding PhN3 to Os3(CO)uL (L = MeCN or py) are also related to II and 13. Since Os3(CO)12 does not react with PhN3, the nucleophilic azide does not seem to attack CO directly but only after displacing L which then is recoordinated in product 14 (88,89). 

In papers on the Walden inversion, Ingold s group (Harvey et al., 1960) established that electrostatic forces do not contravene the normal stereochemistry of SN2 reactions. Even in the favorable case of negative nucleophile (azide) and positive substrate (sulfonium salt), exclusive inversion occurs. Obviously, the quantal forces of orbital symmetry and energy obliterate the coulombic factor here. 

However, reaction of acyclic dienamines with hydrazoic acid gives a mixture of products derived by 1,2-, 1,4- and 3,4 + 1,2-addition of HN3 to the diene system. In this case C-protonation is followed immediately by addition of the strongly nucleophilic azide anion, so that equilibrium of the C-protonated enamines cannot occur3c. Treatment of the morpholine dienamine of isophorone with trichloroacetic acid in boiling benzene resulted in decarboxylation and the 1,4-addition of a proton and the trichloromethyl anion. Basic hydrolysis of the adduct gave dienoic acid 54 (Scheme 4). 

Reaction of (284) with an aldehyde, ketone, or enol ether in the presence of acid results in an electrophilic substitution that produces a -ferrocenylalkyl carbocations that may be trapped by nucleophiles (azides, amines, thiols). This chemistry may be used to prepare enantiomerically pure ferrocene derivatives in a maimer that avoids resolution procedures (Scheme 86)." For example, the enol ether from (-)-menthone affords a kinetic carbocation (302) that may be trapped or allowed to rearrange to the more thermodynamically stable cation (303) and then trapped, thus offering a means of controlling the configuration of the stereocenter adjacent to the ferrocene unit. Use of an enantiomerically pure aldehyde derived from Q -pinene (304) affords a 1 1 carbocationic mixture that similarly isomerizes to a single cation. 

The rate constant kgaiv for solvolysis is assumed to reflect the stability and reactivity of (i.e., faster solvolysis gives a more stable cation, which, therefore, reacts more slowly with nucleophiles). The ratio kt /k , measured by product distribution studies, is a measure of selectivity with respect to the nucleophiles azide ion and water. The plot of log k oiv against log (kn/k ) is messy and rather confusing, containing regions of constant selectivity, RSP behavior, and possibly anti-RSP behavior. The present point is that the measures of reactivity and selectivity may affect the conclusions drawn. The role of solvent effects can be important in modifying RSP behavior. ... 

Reaction of a l,3-thiaselenole-2-thione with Meerwein s reagent yields the 2-ethylthio-l,3-thia-selenolylium cation (87) in quantitative yield subsequent reaction with the nucleophilic azide anion (sodium azide) leads to ring transformation via an azido intermediate <84S667> (cf. Scheme 9). 

Experimental studies show that HheC mediates attack at the less substituted carbon of various epoxides with the nucleophiles azide, cyanide, and nitrite. " For azidolysis of styrene oxide, the observed regioselectivity is different from that in solution. While chemical conversion of styrene oxide with azide results in 2% attack at the terminal carbon (C/3), HheC-mediated azidolysis increases this value to 79%. This observation made us interested in studying the regioselectivity of HheC-mediated epoxide opening and to investigate the factors controlling it. 

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