Bridgeheads

Bredt s rule A double bond cannot be introduced at the bridgehead carbon of a bridged bicyclic or polocyclic system with small- or medium-sized rings. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

The acylpalladium complex formed from acyl halides undergoes intramolecular alkene insertion. 2,5-Hexadienoyl chloride (894) is converted into phenol in its attempted Rosenmund reduction[759]. The reaction is explained by the oxidative addition, intramolecular alkene insertion to generate 895, and / -elimination. Chloroformate will be a useful compound for the preparation of a, /3-unsaturated esters if its oxidative addition and alkene insertion are possible. An intramolecular version is known, namely homoallylic chloroformates are converted into a-methylene-7-butyrolactones in moderate yields[760]. As another example, the homoallylic chloroformamide 896 is converted into the q-methylene- -butyrolactams 897 and 898[761]. An intermolecular version of alkene insertion into acyl chlorides is known only with bridgehead acid chlorides. Adamantanecarbonyl chloride (899) reacts with acrylonitrile to give the unsaturated ketone 900[762],... 

Another interesting transformation is the intramolecular metathesis reaction of 1,6-enynes. Depending on the substrates and catalytic species, very different products are formed by the intramolecular enyne metathesis reaction of l,6-enynes[41]. The cyclic 1,3-diene 71 is formed from a linear 1,6-enyne. The bridged tricyclic compound 73 with a bridgehead alkene can be prepared by the enyne metathesis of the cyclic enyne 72. The first step of... 

The bicyclic compound decahydronaphthalene, or bicyclo[4.4.0]decane, has two fused six-mem-bered rings. It exists in cis and trans forms (see Fig. 1.10), as determined by the configurations at the bridgehead carbon atoms. Both cis- and rran -decahydronaphthaiene can be constructed with two chair conformations. 

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). 

Adamantylamine is prepared from the corresponding alcohol or bromide by bridgehead cation generation in the presence of acetonitrile (49). Selective hydrolysis of the resultant acetamide to the rigid cycloahphatic amine by acid or base is difficult. 

The symbols f and f correspond to total fraction of and hybridi2ed carbon, respectively, f represents the fraction of carbon in aromatic rings f , the fraction in carbonyls, b > 165 ppm the aromatic fraction that is protonated the aromatic fraction that is nonprotonated f, the phenoHc or phenohc ether carbon, 6 = 150-165 ppm f, the alkylated aromatic carbon, 6 = 135-150 ppm , the aromatic bridgehead carbon f represents the fraction of CH or CH2 aUphatic carbon f, the CH or nonprotonated aUphatic carbon and f, the aUphatic carbon bound to oxygen, b — 50-90 ppm. 

Azonia substitution at a naphthalene bridgehead position gives the quinolizinium ion (16). Oxonia substitution, elsewhere, forms the 1- and 2-benzopyrylium ions (17) and (18). The two most well-known monoaza systems with three aromatie fused rings are aeridine (19), derived structurally from anthraeene, and phenanthridine (20), an azaphenanthrene. The better-known diaza systems inelude phenazine (21) and 1,10-phenanthroline (22), while systems with three linearly fused pyridine rings are ealled anthyridines, e.g. the 1,9,10-isomer (23). 

Since diazaquinones are among the most powerful dienophiles, they undergo [4+2] cycloaddition (Diels-Alder) reactions with a great variety of dienes to give various heterocyclic systems accessible with difficulty by other methods. Diazaquinone reacts with butadiene and substituted butadienes, carbocyclic and heterocyclic dienes, 1-vinylcycloalkenes, polyaromatic compounds and vinylaromatic compounds to afford bicyclic and polycyclic bridgehead diaza systems, including diazasteroids (Scheme 56). 

The UV spectra have been used in studies of protonation and related covalent hydration, structural assignments and tautomerism (see appropriate Sections), as well as in studies of bridgehead addition to 5-deazapterins (79MI21500, 78TL2271) and related 5-deazaflavin derivatives (80JA1092). 

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-. 

Apart from a short section in an early book on phthalazines (53HC(5)198), the only previous general account of significance occurs in a chapter in a now dated volume on fused pyridazines, which covers work up to 1969 (73HC(27)968), and which also includes bridgehead nitrogen derivatives not relevant to this review. A later review (75MI21504) does exist but is in Japanese. 

Both the possible non-bridgehead pyridopyrazines, pyrido[2,3-f ]pyrazine (386) and pyrido[3,4-f ]pyrazine (387), are well known, the numbering being as shown. In the older literature they may be known as pyridino-2, 3 -2,3- and -3, 4 -2,3-pyrazines, as 1,4,5- and 1,4,6-triazanaphthalenes, or as 5- and 6-azaquinoxalines respectively. Some derivatives may also be referred to and numbered as deazapteridines, or as deaza derivatives of various natural products (see Section 2.15.16.3). Of the benzo fused systems, representatives of one angular (388) and two linear (389) and (390) derivatives of the [2,3-f ] system are known, but only the linear benzo fused [3,4-6] system (391). 

A -Bridgehead compounds have been obtained from the photochemical cyclization of cfi-1-styrylimidazoles. For example, irradiation of the imidazole (532) in methanol in the presence of I2 resulted in cyclization at the 2-position of the imidazole ring with the formation of an imidazo[2,l-a]isoquinoline (533) (76JCS(Pl)75). Isomerization of the trans-to the c/i-styrylimidazole was followed by photodehydrocyclization, trans- 1-Styrylbenzimidazole (534) was isomerized under Pyrex-filtered light in the presence of one molar equivalent of I2. The resulting cis isomer on irradiation through quartz gave the benzimidazo[2,l-a]isoquinoline (535) in 53% yield. 

For bicyclic structures the von Baeyer name consists of the prefix bicyclo-, followed in square brackets by the numbers of carbon atoms separating the bridgeheads on the three possible routes from one bridgehead to the other, followed in turn by the name of the alkane (or other homogeneous hydride, or repeating unit hydride) containing the same number of atoms in the chain as the whole bicyclic skeleton (examples 55-57). Replacement nomenclature can be applied to hydrocarbon names (example 58). 

An NOE between the the alkene proton at 3h = 6.22 and the methyl protons at Sh = 1.17 establishes the relative eonfiguration (exo) of the respeetive methyl group. The exo attaehment of the six-membered ring in the stereostrueture I follows, in partieular, from the NOE between the methyl protons at 5h = 1.26 and the bridgehead proton at Sh = 3.22 as well as the absenee of effeets between the alkenyl proton pair with Sh = 5.44/6.22 and the bridgehead proton pair with Sh = 2.85/3.22. 

Assume that the bond dissociation energy of the bridgehead hydrogens in each bicycloalkane is 104kcal/mol. Indicate and discuss any other assumptions you have made. 

The apocamphyl structure is particularly rigid, and bridgehead caibocationa become accessible in more flexible structures. The relative solvolysis rates of the bridgehead bromides 1-bromoadamantane, l-bromobicyclo[2.2.2]octane, and l-bromobicyclo[2.2,l]-... 

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