Bridgehead alkyl derivs

Grignard syntheses under pressure Bridgehead alkyl derivs. 

Similar intermediates including o-ethoxycarbonyl-, o-cyano- and o-dimethyl-aminomethylene-piperidones or their imines have been used to give partially reduced analogues, e.g. (244), in the [2,3-. 

The bridgehead-amine-derived electrophilic fluorinating reagents l-alkyl-4-fluoro-l,4-di-azoniabicyclo[2.2.2]octane ditriflate 5 a or bis(tetrafluoroborates) 5b and 6 can be prepared from l-alkyl-4-aza-l-azoniabicyclo[2.2.2]octane salts and elemental fluorine. For example, treatment of l-methyl-4-aza-l-azoniabicyclo[2.2.2]octane triflate (4a) and lithium triflate in acetonitrile at — 35CC with neat fluorine over three hours gives l-fluoro-4-methyl-l,4-dia-zoniabicyclo[2.2.2]octane ditriflate (5a).81 The reagents 5b, 6, 7, and 8 can be synthesized in a similar manner.76 83... 

Fluorinations with Silver Fluoride. Reaction of AgF with alkyl and aryl halides often results in the formation of the corresponding fluorides usually under mild conditions. With gemi-nal dihalides, this conversion has been shown to involve a carbo-nium ion intermediate (eq 1). Chloro quinones react with AgF under high pressure and temperature conditions to give partial conversion to the fluoro quinone (eq 2). Cis- and trans-2,3-difluoro-2,3-dihydrobenzofuran can be similarly obtained by the reaction of AgF with trans-2,3-dibromo-2,3-dihydrobenzofuran (eq 3). Bromoadamantanes and l-bromobicyclo[3.3.1]nonan-3-one undergo fluorination with AgF to yield bridgehead fluorine derivatives (eq 4). 

Tertiary alkyl chlorides have been converted to the tertiary nittiles with trimethylsilyl nittile ia dichioromethane ia the presence of SnCl (131). The reaction was appHed to the synthesis of several bridgehead nittiles, such as 1-adamantyl and 1-diamantyl nittiles from the corresponding chloro or bromo derivatives usiag SnCl or AIBr. catalysts (132). 

The enolates derived from racemic 2-(trimethylsiIyI)- or 2-benzyl-3-ethoxy-2,3,3a<4,7,7a-hexa-hydro-1 //-isoindol-l-one (13) react with some haloalkynes. Attack by the electrophile occurs at the bridgehead carbon (7a) from the least hindered side, to afford only one diastereomer of the alkylation product 14, as judged by spectroscopic properties14,15. In some experiments 2-desilylation is effected before product isolation15. 

The two bridgehead hydrogens Ha and Hb in the anisaldehyde dithioace-tal (130) have a large difference in their acidities, as indicated by the NMR chemical-shift difference (4.88 and 5.03 ppm). Preparation of the monocarbanion (1 BuLi in THF at -78°C) and quenching with DC1 removed only the higher field hydrogen. The carbanion can be reacted with electrophiles such as primary halides, acid halides, or aldehydes to produce (135). Carbanion generation and alkylation can be repeated on (135) to yield the disubstituted derivative (136) as shown in Scheme 44. 

Alkyl cyanates are obtained from sterically crowded alcohols or bridgehead derivatives via the corresponding alcoholates by treatment with cyanohalides in quite modest yields (Scheme 27). Higher yields and more stable products may be obtained from polyhalogenated alcohols or certain enols. These cyanates show properties comparable to the aromatic series discussed earlier. 

Treatment of 2-alkyl- or 2-hydroxymethyl-l-aminopyridinium salts with acyl or aroyl chlorides in the presence of base causes cyclization to pyrazolo[l,5-a]pyridine derivatives. If the 3-position is unsubstituted, acylation occurs at this position under the reaction conditions (Eq. 13).18141 There is good evidence that the initial step is acylation of the iV-amino group. This reaction has been extended to the synthesis of various bridgehead nitrogen heterocyclic systems including pyrazolodiazines (11),9 pyrazolo[5,l- ]thiazole (12),142 and imidazo[l,2-h]pyrazole (13).142... 

Sulfonium ions are well-known alkylating agents in view of the electrophilic nature of their a-carbon atoms. Their synthetic and biological applications are extensively studied. Reactions of bicyclic bridgehead sulfonium ions with nucleophiles have been investigated only for the more stable benzo derivative (13 R = Bz). As shown in Equation (11), Sn2 and Sn2 attacks by a range of... 

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