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First Metallation of Iodo Diazines. Iodo and Nitrogen Directed Metallations

Nelly Plé, Alain Turck, Arnault Heynderickx and Guy Quéguiner*

Laboratoire de Chimie Organique Fine et Hétérocyclique UPRES-A 6014 IRCOF-INSA, B.P. 08, 76131 Mont-Saint-Aignan Cedex (France) Fax + 332(35)522962 E-mail : <guy.qué>

Use of iodine atom as ortho-directing group in the diazine series provides a promising challenge since iodine displays a high reactivity in such useful reactions as halogen-lithium exchange, cross-coupling and trifluoromethylation. We report here the first lithiation of iodopyrazine 1 and 4-iodo-2-methylthiopyrimidine 2 using strong lithium amides as bases. Further reaction of the lithio derivatives with various electrophiles allowed access to functionalized pyrazine or pyrimidines with good yields.

Lithiation of 1 was performed with lithium tetramethylpiperidide LTMP and short reaction time, affording 2-iodo-3-substituted pyrazines with moderate to good yields.

Electrophile E Product Yield Starting material 1
MeCHO MeCH(OH) 3 55 % 9 %
PhCHO PhCH(OH) 4 66 % 12 %
Ph2CO Ph2C(OH) 5 78 % -
PhSSPh SPh 6 82 % -
HCONMe2 CHO 7 26 % 10 %
HCO2Et CHO 7 19 % 9 %
N-Formylpiperidine CHO 7 30 % 10 %
ClSiMe3 SiMe3 8 45 % -
MeI Me 9 56 % 14 %
CO2 COOH 10 24 % -
I2 I 11 73 % -


The metallation of 4-iodo-2-methylthiopyrimidine 2 was achieved with a very hindered base prone to be stronger than LTMP : the lithium N,N-neopentyl-(1-cyclohexyl-2,2-dimethylpropyl)amide symbolized as LB

Electrophile E Compound yield
CH3CHO CH3CH(OH) 12 96%
PhCHO PhCH(OH) 13 63%
Ph2CO Ph2C(OH) 14 72%
MeI Me 15a 50%
Et 15b 24%
ClSiMe3 SiMe3 16 75%
HCO2Et CHO 17 40%
I2 I 18 57%
" I 18 98%*

*Reaction was performed with 120 minutes for reaction time of iodine with lithio derivative

With 4-iodo-2-methylthiopyrimidine 2, an unexpected regioselectivity was observed at the C6 position. In this case it could be noted that iodine and ring nitrogen compete to induce the metallation. The regioselectivity observed at the C6 position can be discussed in terms of kinetic or thermodynamic control of the reaction using semiempirical calculations. The net charges of H5 and H6, determined by the AM1 method, show that H6 is slightly more electropositive than H5, favouring the kinetic deprotonation at C6 .

The heats of formation of lithiated intermediates, determined by semiempirical method Li/PM3 indicate that the C6 lithio derivative is more stable than those at C5, moreover the steric hindrance of the metalling agent could be also in favour of the regioselectivity at C6. These considerations are in agreemant with the unexpected regioselectivity at C6.