Pyrimidines lithiation

Pyrimidines lithiated in the 5-position can be boronated (Scheme 70). Cupration is well established in pyrimidines (86T3981, 87CS519). 

Boronic acids and boronate esters are usually prepared from lithium compounds, for example, from pyrimidines lithiated at the 5-position (Scheme 99). Boronates can also be obtained conveniently by Pd(0)-catalyzed couplings with, for example, pinacol diboron. 

Pyrimidines lithiated in the 5-position can be boronated (299) (Scheme 48). The halogen-metal exchange between 5-bromopyrimidine and butyllithium has to be carried out at low temperature (— 100°C) to avoid 1 1-adduct formation with the lithiated species. The 2,4-di-t-butoxy analogue, however, can be lithiated in the normal manner at — 78°C. Boronation results from addition of tributyl borate with subsequent hydrolysis <90JHC2165>. 

Thieno[2,3-d ]pyrimidin-4(3 H) -one, 3-methyl-synthesis, 4, 1017 Thieno[2,3-d ]pyrimidin-4-ones synthesis, 4, 1017, 1018, 1022 Thieno[2,3-6]pyrrole, 5-aryl-synthesis, 6, 1009 Thieno[2,3-6]pyrrole, N-benzyl- H NMR, 4, 1042 UV spectra, 4, 1044 Thieno[2,3-c]pyrrole, N-ethyl-UV spectra, 4, 1044 Thieno[3,2-6]pyrrole, 5-aryl-synthesis, 6, 1009 Thieno[3,2-6]pyrrole, N-benzyl- H NMR, 4, 1041, 1042 lithiation, 4, 1051 UV spectra, 4, 1044 Thieno[3,2-6]pyrrole, 2,3-dihydro-desulfurization, 6, 984 oxidation, 6, 981... 

Malayamycin A has been synthesised by a lengthy route, starting with the reaction of a protected ribonolactone with a lithiated pyrimidine <06T5201>. A much shorter synthesis of the fused quinazoline asperlicin D involved direct cyclisation of a diamide <06TL693>. 

For the halogen-metal exchange reaction of bulkier halopyrimidines, steric hindrance retards the nucleophilic attack at the azomethine bond. As a consequence, halogen-metal exchange of 5-bromo-2,4-di-r-butoxypyrimidine (43) with n-BuLi could be carried out at -75 °C [20]. The resulting lithiated pyrimidine was then treated with n-butylborate followed by basic hydrolysis and acidification to provide 2,4-di-f-butoxy-5-pyrimidineboronic acid (44). 5-Bromopyrimidine 43 was prepared from 5-bromouracil in two steps consisting of a dehydroxy-halogenation with phosphorus oxychloride and an SnAt displacement with sodium r-butoxide. 

Thermal decarboxylation of pyrimidylcarboxylic organotin esters is another means to prepare the corresponding stannylpyrimidines [33]. This method obviates the intermediacy of lithiated pyrimidine species that would undergo undesired reactions at higher temperatures. The decarboxylation occurs at the activated positions. Therefore, thermal decarboxylation of tributyltin carboxylate 62, derived from refluxing carboxylic acid 61 with bis(tributyltin) oxide, provided 4-stannylpyrimidine 63. Addition of certain Pd(II) complexes such as bis(acetonitrile)palladium(II) dichloride improved the yields, whereas AIBN and illumination failed to significantly affect the yield. 

With even more electrophilic heterocycles, addition of the lithiated species to the starting material can become a problem—for example, LDA will lithiate pyrimidine 181 at — 10°C, but the product, after work up, is the biaryl 182 resulting from ortholithiation and readdition (Scheme 91). By lithiating in the presence of benzaldehyde, a moderate yield of the alcohol 183 is obtainable . Strategies for the lithiation of pyrimidines and other very electrophilic heterocycles are discussed below . 

The protons of pyrimidines, pyrazines and pyridazines are relatively acidic even without halogen activation, and the three simple heterocycles 240-242 have been lithiated (with varying success) with LiTMP (Scheme 120). ... 

Halogen-metal exchange has also been performed in the absence of an N-substituent, as was shown by the lithiation and derivatization of the diaza derivative 5-bromo-4-chloro-7//-pyrrolo[2,3-c(]pyrimidine (Scheme 26K90JMC1984). 

There are several bicyclic compounds with five-membered heterocycles fused to pyridine rings, where metalation occurs in the smaller ring due to activation by the heteroatom. The ring-A lithiation of imidazopyridines and pyrimidines was discussed in Section II,E,6, but in addition, the a-lithio derivatives of thieno[2,3-6]pyridine 119 (74JHC355), thieno[3,2-... 

As with their monocyclic analogs, lithiated derivatives of bicyclic di-azines can be prepared by halogen-metal exchange at low temperature, and examples include the 6-lithiopurine 130 (79JOC4612), and the 5-and 7-lithio-3//-l,2,3-triazolo[4,5-(f pyrimidines 131 and 132 (91CPB2793, 91CPB3037). 

The lithiation of4-chloro-2,6-dimethoxypyrimidine has also been used in a synthesis of inhibitors of lumazine synthase <1999BML39, 1999JOC3838>, and other pyrimidine derivatives to be successfully lithiated and derivatized at the... 

An alternative synthesis of pyrimidine boronic acids, which avoids lithiation chemistry altogether, has been developed <2001SL266>. Thus, reaction of 2,4-dimethoxy-5-iodopyrimidine 352 with cedrane-8,9-diolborane 351 using catalytic amounts of Pd(PPh3)4 and Cul gave the intermediate boronate 353 which could be converted to the free boronic acid 354 in 83% yield by transesterification with diethanolamine, followed by treatment with acid (Scheme 3) <2001SL266>. 

As can be seen also with pyridazines and pyrimidines, the protons of pyrazines are relatively acidic <2001T4489>, and the simple pyrazine is lithiated with 4 equiv of LTMP at —75 °C <1995JOC3781>. Since the lithio intermediate, however, is highly unstable, the subsequent substitution with electrophiles should be carried out within a very short reaction period. 

Direct lithiation of pyridazine 132 followed by trapping with chiral sulfinate esters produced chiral sulfoxides 133, analogous to the pyrimidine reaction covered in Section 6.2.2.2 <99JOC4512>. Queguiner and co-workers demonstrated that a second lithiation/trapping sequence can provide fully substimted pyridazines 134 with high diastereoselectivities. 

There are no reports since 1996, although lithiation of [l,2,3]triazolo[4,5- / pyrimidine at the 7-position followed by reaction with electrophiles was briefly covered in the review by Knowles <1996CHEC-II(7)489>. 

In an ancillary study, the lithiation of triazolo[l,5-c]pyrimidine 522 under a variety of conditions proved to be unsuccessful (Scheme 159) [82 JCS(P 1)967]. 

Organocerium derivatives posses low basicity. 5-Pyrimidylcerium dichlorides (e.g. 881) are available by low-temperature metal-metal exchange using cerium trichloride and 5-lithiated pyrimidines (e.g. 880, R = SMe, R = H). The 5-pyrimidinylcerium dichloride was superior to its 5-lithio analogue in reactions with aldehydes and ketones, especially in reactions with enolizable aldehydes and ketones (89ACS816). 

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