Pyrazine lithiation

Lithiation of compounds 8.110 generally takes place at the 2-position [as, e.g., in thieno[3,2-b]pyridine (84JHC785), furo[3,2-c]pyridine (83T1777), and thieno[2,3-b]pyridine (74JHC355)]. However, in thie-no[2,3-6]pyrazine lithiation occurs at the 5- and 6-positions in a 17 83 ratio (80JHC1019). Compounds of type 8.111 undergo lithiation as follows imidazo[l,2-[Pg.236]

The titaniated (25)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazines derived from cyclo(L-Val, Gly) or cyclo(L-Val, Ala) (1, R1 = H, CH3) react with a,/I-unsaturatcd aldehydes exclusively by 1.2-addition (cf. nearly exclusive 1,4-addition of ,//-unsaturated ketones with cuprate complexes of 2,5-dialkoxy-3,6-dihydropyrazines, see Section D. 1.5.2.3.1.4.) in a highly diastereoselective mode to give virtually only the (l S,2R)-diastereoniers 2 ". In reactions with the corresponding lithiated pyrazines both regioselectivity and diastereofacial differentiation at C-2 are also remarkably high (dc 95 %), but the diastereomeric excess at C-l is substantially smaller (30 50%) ... 

Qudguiner s group lithiated a sym-disubstituted pyrazine, 2,6-dimethoxypyrazine (43), with lithium 2,2,6,6-tetramethylpiperidine (LTMP). The resulting lithiated intermediate was quenched with h to give 3-iodo-2,6-dimethoxypyrazine (44) and 3,5-diiodo-2,6-dimethoxypyrazine (45) [35]. Iodide 44 was then coupled with phenylacetylene to provide adduct 46. 

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). ... 

Examples of the 3-lithiation of both 2- and 2,6-disubstituted chloro- and methoxypyrazines, as well as 2-thiomethylpyrazine are known (88S881 90JOC3410 91JHC765, 91JOM(412)301] (Scheme 117). As with pyridazine, LiTMP has so far been the only base employed, and this same base system has also recently been used for the directed metalation of pyrazine... 

The lithio derivatives 63 are converted into deuteriopyrazines 64, and their yields can be equivalent to those of the hydrogen/lithium exchange (Scheme 15). As a result, the lithiation of chloropyrazines and pyrazinethiocarboxamide is optimized at —70 to —75°C, whereas that of methoxy- or acylamino-pyrazines at 0°C. Conversely,... 

Table 1 Lithiation of substituted pyrazines and subsequent quenching with deuterated soivents...

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. 

Directed ort o-metalations are also applied to quinoxalines possessing 2-chloro, 2-methoxy, and pivaloylamino substituents <1993JHC1491>, but successful syntheses via the lithio intermediates are far fewer compared to pyrazines. In fact, no example of metalation on aromatic carbons can be found in the literature since 1994. However, lithiation on benzene carbons of 6-chloro-2,3-dimethoxyquinoxaline was reported <1999T5389>. 

Efforts in the 1990s toward the lithiation/trapping sequence for pyrazines and quinoxalines have been reviewed <2001T4489, B-2002MI2>. 

With chiral racemic oxiranes one enantiomer reacts faster than the other the degree of kinetic resolution is very high for L-valine/alanine-based dialkoxydihydropyrazines. For example, in the reaction of one equivalent of (2.S )-2,5-dihydro-2-isopropyl-3,6-dimethoxy-5-methyl-pyrazine (1, R1 = CH3) with two equivalents of fW-(//,/ )-2,3-dimethyloxirane (R2,R4 = CH3 R = H) virtually only the (2//,3/ )-oxirane enantiomer reacts with the lithiated dihydropyrazine to give exclusively the (l /, 2/, 2 / )-configuratcd adduct i.e., (2/ ,5S)-2,5-dihydro-5-isopropyl-3,6-dimethoxy-2-[(l/ ,2/ )-2-(2-methoxyethoxymethoxy)-l-methylpropyl]-2-methylpyrazine, entry 7. Likewise, kinetic resolution (intramolecular) occurs upon reaction with rac-7-oxabicy-clo[4.1.0]heptane (entry 8). 

The usually very powerfully orthodirecting groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithiation of 386 and 387, for example, takes place principally (at least kinetically) at the meta and para positions.339 340... 

Lithiation of pyrazines <(CHEC-III(7.03.5.5)> can be achieved without ortho-assistance for example, pyrazine itself can be lithiated with four equivalents of LiTMP at 75"C <1995JOC3781>. 4-Methoxy-l,2,3-triazine metallates with LiTMP at 100 C to produce a mixture of the 5- and 6-lithiotriazines <1998SP119>. 

Dichloro-3-(3,4-dibenzyloxy-5-benzyloxymethyltetrahydrofuran-2-yl)pyrazine (66, R = H) gave ethyl 3,5-dichloro-6-(3,4-dibenzyloxy-5-benzyloxymethylte-trahydrofuran-2-yl)-2-pyrazinecarboxylate (66, R = C02Et) [lithiated substrate (generated in situ), IMF then Et02CCN j, 1 h 78%].667... 

Dimethylpyrazine gave 2-methyl-6-trimethylsilylmethylpyrazine (335) [Pr, NLi (made in situ), THF, -78°C then MejSlCl, -78°C, 3 h 70%] somewhat similarly, 2-[(but-3-ynyl)oxymethyl]pyrazine (336, R = H) gave 2-[(4-trimethylsilylbut-3-ynyl)oxymethyl]pyrazine (336, R = SiMcj) (lithiation with PhLi etc. 74%). ... 

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