Lithium piperidide

The reactions of various halogenopyridines with lithium piperidide and piperidine have been studied by Kauffmann and Boettcher. ... 

By treating 3-bromo- (27, X = Br) or 3-chloropyridine (27, X = Cl) with lithium piperidide (2.2 equivalents) and piperidine (2.8 equivalents) in boiling ether, mixtures of 3- (29, Y = NC5H10) and 4-piper-idinopyridine (34, Y = NC5H10) were obtained in 85-90% total yield. In both reactions the ratio of the 3- to 4-piperidino compounds was 48 52. Support for the hetaryne mechanism as the sole pathway for these reactions comes from the fact that increasing the amounts of lithium piperidide and piperidine to 5 and 10 equivalents, respectively, scarcely changed the composition of the reaction products. If addition-elimination had occurred concomitantly with reaction via the hetaryne, more of the 3-piperidino compound would have been formed, since the reconversion of the hthium intermediate 30 into 27 by piperidine would be accelerated by the enhancement of the concentration of this substance. 

None of the 3-halogenopyridines yield 2-piperidinopyridine. This substance was obtained as the only product from the reaction of 2-fluoropyridine (24, X = F) with lithium piperidide under the same conditions in 97% yield. Finally, it was found that 4-chloropyridine (32, X = Cl) was converted in 95% total yield into a mixture of 0.4% of 3-piperidino- (29, Y = NC5H10) and 99.6% of 4-piperidino-pyridine (34, Y = NCsHio)- Thus, in contrast to the amination with potassium amide, 4-chloropyridine reacts with lithium piperidide almost exclusively via the addition product 33 (X = Cl, Y = NC5H10). 

Those reactions of halogenopyridines with potassium amide and lithium piperidide which proceed via 3,4-pyridyne form the 3- and 4-substituted pyridine derivatives in ratios of 1 2 and 1 1, respectively (see Section II, A, 1). It appears that the ring nitrogen atom has an orienting effect on these additions, but the quantitative divergence of the addition of ammonia and piperidine is not understood at present. 

The four 3-halogenoquinolines were allowed to react with lithium piperidide and piperidine (molar ratio 1 2.2 2.8) in boiling ether. The chloro, bromo, and iodo compound gave, in 45—60% total yield, mixtures of 3- and 4-piperidinoquinoline of the same composition... 

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

Lithium derivatives of dialkylamines react with aryl methyl ethers in refluxing THF by substitution to afford TV-aryldialkylamines (equation 10). Similarly, lithium piperidide and veratrole give 7V-(2-methoxyphenyl)piperidine (15)40. 

The conversion of symmetrical into unsymmetrical thioureas is exemplified by the formation of Af-cyclohexyl-Af -phenylthiourea when yV,iV-diphenyl thiourea is heated with cyclohexylamine and triethylamine in acetonitrile367. Carbonylation of lithium piperidide in the presence of tellurium generates the lithium carbamotellurate 307, which is trapped as the 7V-ethyl carbamotellurate 308 by ethyl bromide368. 

The sensitivity of position 2 in 4-chloroquinazoline for nucleophilic addition was also demonstrated in the reaction with lithium piperidide (73RTC460). Whereas in the amination with potassium amide/liquid ammonia no open-chain intermediate could be isolated, with lithium piperi-dide/piperidine the open-chain compound ort/z6>-(piperidinomethy-leneamino)benzonitrile (78,60%) was obtained, in addition to 4-piperidino-quinazoline (80,19%) (Scheme 11.35). The formation of 80 from 78 involves... 

Temporary protection of an aldehyde by addition of a lithium amide can be used to facilitate lateral lithiation by n-BuLi. The best lithium amide for this purpose is 56 interestingly, lithium piperidide 53 promotes ortho-, rather than lateral, lithiation of 525 (Scheme 206) °, while 56 yields 526. 

The acetal [1,2]-Wittig rearrangement protocol is also applicable to the synthesis of medium-sized cyclic ethers. For example, a reaction of the 9-membered cyclic acetal 37 with lithium piperidide provides the 8-membered ring ether 38 in good yield along with high diastereoselectivity (equation 20) . 

Meyers and Shimano further expanded the scope of this methodology to include lithium amides as the nucleophile. The authors meticulously optimized the reaction conditions and determined the scope of the amide addition. Selected examples are listed in Table 8.32 (Scheme 8.163). The best results were obtained when THF was used as the solvent together with a stoichiometric amount of HMPA, relative to the lithium amide. The reaction was quite sensitive to the steric demand of the amide. Thus, lithium diethylamide give no product whereas lithium methyl n-pentylamide and lithium piperidide gave efficient reaction. Primary amides also failed to react. 

In connection with the substituent effects, the kinetic stability of benzyne is suggested to be increased by electron withdrawal (-/) and decreased by electron release (+/).73 However, the inference cannot be extrapolated to selectivity of substituted arynes in general. For example, in additions involving competition between phenyllithium and lithium piperidide, the methyl substituents (+/) on benzyne increase its selectivity, whereas methoxy groups (-/) decrease it (Scheme 6). On the other hand, in reactions of car-banions derived from acetonitrile in alkylamine solvents both +/ and -/ benzyne substituents lower selectivity and cause predominant amination. Thus, the method was found unsuitable for preparation of many substituted benzyl nitriles.74 In symmetrically disubstituted arynes there is partial cancellation of polarization, and in fact acceptable yields of acetonitrile adducts could be obtained from 3,6-dimethoxy-benzyne.75 The selectivity of substituted arynes varies with the set of nucleophiles in the competition and no comprehensive theory or simple generalization is available on this point. 

The products from the lithium piperidide-catalysed substitution of (173, n=3) by phenyllithium are also compatible with the above picture. 

When 3-chloro- or 3-bromopyridine is heated with lithium piperidide and piperidine in boiling ether, 156 is formed, which reacts further with piperidine to give a mixture of 3- and 4-piperidinopyridine in the ratio of 48 52. No 2,3-pyridyne intermediate is apparently produced under these conditions.388 Such an intermediate is probably involved in the reaction of potassium amide in liquid ammonia with 3-bromo-4-ethoxypyridine, which gives 2-amino-4-ethoxypyridine (55-60%). The reaction is, however, complicated by the fact that 2-amino-5-bromo-4-ethoxypyridine (15-20%) and 4-ethoxypyridine (25%) are also obtained.387 The formation of these two by-products may proceed by the preliminary disproportionation of some 3-bromo-4-ethoxy-pyridine to 3,5-dibromo-4-ethoxypyridine and 4-ethoxypyridine.388 The remarkable observation that both 2-amino-6-ethoxypyridine (157) (85%) and 4-amino-2-ethoxypyridine (158) (15%) are formed during the amination of 2-bromo-6-ethoxypyridine367 still requires explanation. No such rearrangement is observed with lithium piperidide.3880... 

In the attempted preparation of cyclooctyne (14)10) from 1-chlorocyclooctene (12) using lithium piperidide as a base only l-(piperidyl)-cis-cyclooctene (13) was obtained 10). This result was interpreted by assuming (14) as an intermediate which then adds lithium piperidide to yield (13). 

Azine approach. Cyclocondensation between 3-amino-4-hydroxypyridines and carboxylic acids leads to oxazole fusion as in (233) (77CR(C)(284)73>. The 2-phenyl derivative (235) has been obtained via a pyridyne-type reaction 3-benzamido-5-bromopyridine reacts with lithium piperidide via an intermediate which can be visualized as the pyridyne enolate (234) (73CB220). 

Quantitative experiments by Huisgen et cd. on the competition of lithium piperidide and phenyllithium for benzyne originating from different halogenobenzenes show that in these reactions benzyne and not a complex of benzene and a halogen atom is an intermediate. 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write db initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the literature on reactions of halogenopyridines with potassium amide and lithium piperidide involving pyridynes. 

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