Bicyclo- -heptane-2-carboxylic

A primary halide, 1-bromooctane, reacted as expected to give 100% yield in 10 min and was converted to pivalic acid in 52% yield after 1 hr of reaction. l-Chlorobicyclo[2.2.1]heptane reacted slowly at room temperature, so this was rerun in refluxing THF. Again, the Grignard preparation was slow, giving 74% yield after 6 hr of reflux. The Grignard was then quenched with CO2 to give l-bicyclo[2.2.1]heptane-carboxylic acid in 63% yield. Bixler and Niemann [64] prepared l-bicyclo[2.2.1]-heptanecarboxylic acid from l-chlorobicyclo[2.2.l]heptane by conversion of the chloride to the lithium salt, followed by CO2 quench. The Rieke method appears to be superior, since it obviates the preparation of the lithium salt used in the procedure of Bixler and Niemann. 

It has been pointed out earlier that the anti/syn ratio of ethyl bicyclo[4.1,0]heptane-7-carboxylate, which arises from cyclohexene and ethyl diazoacetate, in the presence of Cul P(OMe)3 depends on the concentration of the catalyst57). Doyle reported, however, that for most combinations of alkene and catalyst (see Tables 2 and 7) neither concentration of the catalyst (G.5-4.0 mol- %) nor the rate of addition of the diazo ester nor the molar ratio of olefin to diazo ester affected the stereoselectivity. Thus, cyclopropanation of cyclohexene in the presence of copper catalysts seems to be a particular case, and it has been stated that the most appreciable variations of the anti/syn ratio occur in the presence of air, when allylic oxidation of cyclohexene becomes a competing process S9). As the yields for cyclohexene cyclopropanation with copper catalysts [except Cu(OTf)2] are low (Table 2), such variations in stereoselectivity are not very significant in terms of absolute yields anyway. 

Rh(II) pivalate is, however, still not efficient in producing more of the syn than of the anti isomer of ethyl bicyclo[4.1.0]heptane-7-carboxylate from cyclohexene and ethyl diazoacetate 87 98>. It needs a rhodium(III) porphyrin 47 to be successful in this case... 

Trichloroacetyl fluoride, 45, 6 2-(Trichloromethyl)bicyclo[3.3.0]octane, from reaction of chloroform and cib,o i-l,5-cyclooctadiene, 47,10 hydrolysis with phosphoric acid to c.ro-m-bicyclo[3.3.0]octane-2-carboxylic acid, 47, 11 1,1,3-Trichloro- -nonane, 46,104 Tricyclo[2.2.1,02 6]heptan-3-ol, 46,... 

The cation-radicals depicted in Scheme 3.28 form on oxidation of e t(( -2-(2-hydroxy-2-methyl-ethyl)-enr/o-6-(methylthio)-bicyclo[2.2.1]heptane and e t(( -2-(carboxyl)-enr((9-6-(methylthio)-bicyclo[2.2.1]heptane, respectively. Asmus (1990) underlined that only the sulfur atom responds to the one-electron oxidation. This is understandable since sulfur is less electronegative than oxygen. Meanwhile, the onium state is more stable than the sulfonium one. 

Scheme 3.30 depicts an intriguing case, when one-electron oxidation of the conformationally constrained exo-2-(carboxy)-en(i(9-2-(ammo)-en(i(9-6-(methylthio)-bicyclo[2.2.1]heptane gives rise to a cation-radical in which an amino- and not a carboxylate group participates in the three-electron bond with sulfur (Glass 1995). 

In the absence of solvent, only syn stereoselectivity and not stereospecificity was observed for the nucleophilic addition of secondary amines such as dimethylamine, diethylamine, piperidine and morpholine to bicyclo[1.1.0]butane-l-carbonitrile. However, similar addition to 3-methylbicy-clo[l. 1.0]butane-l-carbonitrile was more stereoselective.22 However, the addition of sodium methancthiolate to 3-methylbicyclo[1.1.0]butane-l-carbonitrile, methyl bicyclo[l.l.0]butane-1-carboxylate, methyl 3-mcthylbicyclo[1.1.0]butane-l-carboxylate and methyl tricyclo[4.1.0.02 7]-heptane-l-carboxylate also afforded mixtures of cis- and p-rms-cyclobutancs in > 50% yield, with methyl bicyclo[1.1.0]butane-l-carboxylate showing greater anti stereoselectivity.23,24... 

As expected, delocalizing substituents such as carbomethoxyl and cyano should decrease the barrier to inversion and perhaps may even convert the rapidly inverting g radical to a linear n radical. The net result should be a loss of configuration. Ando and coworkers have shown this to be the case in the tri-n-butyltin hydride reduction of the isomeric exo- (38) and n io-7-chloro-7-carbomethoxybicyclo[4.1.0]heptane (39). Both isomers gave the same (7 93) ratio of exo- (40) and emio-methyl bicyclo[4.1.0]heptane-7-carboxylate (41). 

A Wagner-Meerwein rearrangement via a bridged carbenium ion has been observed in the electrodecarboxylation of bicyclo[2.2.1]heptane-2-carboxylic acids (CXVIIa, CXVIIb, and CXVIIc), leading to the formation of the same products (CXVIII and CXIX) [Eq. (58)] [174]. This method has been successfully applied to synthesis of useful intermediates for natural product synthesis. Some examples are given in Eqs. (59) and (60) [175-179]. 

A ring enlargement involving rupture of a cyclopropane ring on anodic oxidation is exemplified in the transformation of bicyclo[4.1.0]heptane-7-carboxylic acid in methanol to 3-methoxycycloheptene [23]. 

Reaction. with Lithium Thiocyanate. To LiSCN (153 mg, 2.3 mmol) in anhyd Et O (1 mL) was added exo-7,8-epoxybicyclo[4.2.0]octane (166 mg, 1.3 mmol). The flask was stoppered and stirred at 4L C for 34 h. Workup as described above gave the product yield 150 mg (90%), whose H NMR spectrum was consistent with that of known bicyclo[4.1.0]heptane-en<7o-7-carbaldehyde and displayed no cxo-aldchyde signal at 5 = 9.1. Air oxidation of the carbaldehyde gave an acid identical with authentic bicyclo[4.1.0]hep-tane-enrfo-7-carboxylic acid. ... 

A solution of 3,4-dibromo-7-hydroxy-c/s-bicyclo[4.1.0]heptane-exo-7-carboxylic acid (1.25 g, 3.97 mmol) in 0.75% aq NaOH (30 mL) was stirred at 20 C under Nj for 24 h. Acidification to pH 1 with 1 M HCl and continuous extraction with EtjO gave a colorless crystalline product yield 0.95 g (93%) mp 149-150°C (sublimation). 

Decarboxylation of bicyclo[4.1.0]heptane-7,7-dicarboxylic acid (16) affords exo- and endo-hi-cyclo[4.1.0]heptane-7-carboxylic acid (17) in a relatively poor yield together with cyclohex-2-eneacetic acid (18). ... 

Various 7-carboxylic acid derivatives of bicyclo[4.1.0]heptane and -ene were reduced using a two-step procedure starting with generation of anhydride derivatives which were not isolated, but reduced directly with sodium borohydride - for example reduction of... 

When both bridgehead carbon atoms in the bicyclo[4.1.0]heptane system 23 were furnished with carboxylate functions, the central bond was cleaved to produce a seven-membered ring. ... 

Sodium benzenethiolate reacted with 6,6-dimethyl-2-vinyl-5,7-dioxaspiro[2.5]octane-4,8-dione (16) to give the 1,5-addition product only. When ethyl trani-6-(l-heptenyl)-2-oxo-bicyclo[3.1.0]heptane-l-carboxylate (18, R = Et) was treated with potassium benzenethiolate it was converted stereospecifically to the corresponding trawj -cyclopentanone derivative 19 (R = Et) with a defined configuration at the a-carbon atom of the side chain. This reaction proved to be useful for the stereoselective synthesis of prostaglandins. ... 

Pyrolysis of 2-methyl-2-(bicyclo[4.1.0]hex-l-yl)propanoic acid gave a good yield of a mixture of isopropyhdenecycloheptane and 2-methyl-l-isopropylidenecyclohexane. Methyl syn-2-azatricyclo[4.1.0.0 ]heptane-2-carboxylate (16) rearranged to a dihydroazepine (17) on mild thermolysis. ... 

Fig. 11.6 Structures of bridged bicyclic proline mimetics (22) 2-aza-bicyclo[2.2.1]hep-tane-3-carboxylic acid, (23) 2-aza-bicy-clo[2.2.1]hept-5-ene-3-carboxylic acid, (24) 7-aza-bicyclo[2.2.1]heptane-l-carboxylic acid, (25) 2-aza-bicyclo[2.2.1]hexane-l carboxylic acid, (26) 2-aza-bicyclo[2.2.1]hexane-...

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