One-pot nitrodebromination and methyl bi-functionalization of 5-bromo 6-methylpyrimidines: a unique simultaneous transformation

A unique one-pot, simultaneous nitrodebromination and methyl bromonitration occurred upon treatment of 5-bromo-2,4-di-tert-amino-6-methylpyrimidine derivatives with a cold mixture of concentrated H2SO4–HNO3 in moderate yields. It is actually a facile and rapid transformation that has been reported neither on pyrimidines nor simultaneously on other organic compounds.


Introduction
Organic compounds containing nitro and/or halogen functionalities are considerably important intermediates in organic and total syntheses of natural products [1][2][3]. Besides their structure-induced properties that have given them a broad range of biological and industrial applications, they can undergo further valuable transformations and; thus, are considered as potential precursors in multistep synthesis [4][5][6].
In contrast to the frequently reported aromatic C-H nitration, investigation of aliphatic C-H nitration has largely been overlooked, as the latter may require rather challenging and perplexed operation. In this regard, reports on α-nitration of heterocycles mainly involve the use of alkylnitrites at − (30-78) °C in the presence of strong bases, such as LDA [7,8] or KNH 2 [9], AgNO 2 under oxidative conditions [10], and use of concentrated neat nitric acid [11], or in In memory of professor Mehdi Bakavoli, who was skilled, mastered, and proficient at pyrimidine chemistry.

Results and discussion
In our previous study on 5-halopyrimidines, we found that under metal/catalyst-free conditions, halogen atom could easily be displaced with S/N nucleophiles through S N Ar mechanism [37][38][39][40][41], as well as with radicals [42], or even with electrophilic hydrogen (H + ) through electrophilic aromatic substitution mechanism (EAS) [34], to give the ipsosubstituted product. This interesting achievement leading to the formation of hydrodehalogenated product, prompted us to examine the possible substitution of halogen with other electrophilic species. To the purpose, a series of 2,4-ditert-amino-5-bromo-6-methylpyrimidine derivatives 1a-1i were synthesized according to the previously published work (Scheme 1) [42]. Initially, 5-bromo-2,4-dimorpholino-6-methylpyrimidine 1f, as the model derivative, was treated with a mixture of concentrated sulfuric and fuming nitric acids at 0 °C. Interestingly, the elemental and spectral analysis revealed that instead of ipso-product, the product contains two nitro groups and the bromine atom still present in, as the mass spectrum showed a molecular ion peak at m/z = 432. 1 H NMR spectrum of this compound exhibited a singlet signal at 7.66 ppm for − CH group; 13 C NMR spectrum showed two signals at 78.01 ppm and 120.22 ppm attributed to − C(NO 2 )(Br) and aromatic C-NO 2 groups respectively. Considering of elemental and spectral analysis, the following structure is given to 2f as illustrated in Scheme 1.
Worthy to mention that the formation of other possible isomer, the corresponding 5-bromo-6-dinitromethylpyrimidine 2f', was ruled out by comparison of calculated 13 C NMR values for 2f and 2f' with the corresponding experimental data, as depicted in Fig. 1 [42][43][44].
As shown in Fig. 1, a comparison of Gibbs energy difference between 2 and 2f', indicates that the former is 15.12 kJ mol −1 more stable thermodynamically. Moreover, although the largest difference between unscaled calculated and experimental chemical shifts of structure 2f is only 6.0 ppm for C-6 atom of pyrimidine ring, the calculated chemical shift of carbon atom attached to the two nitro groups in 2f' deviates 31.6 ppm from the experimental value. It should be noted that there is a well-known heavy-atom effect which is reported without relativistic and spin-orbit coupling corrections. Due to this effect, the results for computed chemical shifts of carbon atoms attached to the halogens, other atoms of the third row or greater, will always be obtained downfield [45]. Accordingly, the de-shielded computed chemical shift value for brominated carbon atom in 2f (12.0 ppm) is normal, while for C-5 of pyrimidine ring attached to Br atom in 2f', is abnormally 10.2 ppm smaller than the experimental one, despite being de-shielded by the heavy atom. These results clearly rule out the likely formation of 2f' and cross-validate the results of experimental data for the formation of 2f.
To establish the generality of this strategy for bi-functionalization of methyl group at position 6 of pyrimidine, a wide range of 2-and 4-substituted pyrimidines 1a-1i were successfully examined to afford 2a-2i in satisfactory yields (Scheme 1).
Based on the obtained results, a reasonable mechanism for the observed simultaneous nitrodebromination-bromonitration of 6-methylpyrimidine derivatives is proposed as illustrated in Scheme 2. Accordingly, the reactive electrophile NO 2 + is generated upon treatment of concentrated sulfuric Scheme 1 acid with fuming nitric acid at 0 °C. The reaction begins by an initial attack of the known electron-rich C-5 atom of pyrimidine to reactive NO 2 + to generate ipso-intermediate A and its mesomeric contributor B. The latter loses a hydrogen atom in the presence of HSO 4 − to create enamine C bearing an exo-methylene group. Subsequent attack of the activated   [46], affords the gem-bromonitrated product 2.
As could be expected from our previous findings, it seems that 5-halopyrimidenes can still undergo EAS reaction at C-5 to afford the ipso-substituted product. In the case of 5-bromo-6-methylpyrimidines the reaction proceeds further, giving rise to the methyl bi-functionalized product.
It is worthy to note that the formation of the stabilized enamine seems crucial to the formation of products, as the reaction yields were poor with 2,4-dimethylamino and 2,4-diethoxy derivatives. This observation obviously confirms the acidity of methyl group hydrogens in position 6 of certain pyrimidine derivatives.

Conclusion
A series of novel gem-bromonitromethyl pyrimidines were synthesized from their corresponding 5-bromo-6-methylpyrimidine derivatives through a unique onepot, nitrodebromination and bromonitration reaction in satisfactory yields. The reaction was simply performed in a cold mixture of H 2 SO 4 (conc) − HNO 3(fum) in the absence of any catalyst or other reagents and additives. Short reaction time, easy work-up procedure, and readily availability of reagents were other merits of this approach. To the best of our knowledge, this is the first report of nitrodebromination and α-methyl bi-functionalization reactions in pyrimidines, as well as first example of one-pot simultaneous nitrobromination of a sp 3 carbon in an organic compound. In addition, since a stereogenic center is created during the reaction, this protocol can be developed for enantioselective synthesis of pyrimidines with various biological activities in optically pure form which is useful in drug discovery. More studies are underway to expand the scope of this reaction to other reactive electrophilic species or substrates as well as developing a protocol for the synthesis of optically active pyrimidines.

Experimental
Melting points were measured by an Electrothermal type 9200 melting point apparatus. The 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were obtained on a Bruker Advance DRX-300 Fourier transform spectrometer at 25 °C. An Avatar 370 FT-IR Thermo Nicolet spectrometer was employed to record the IR spectra and a Varian Mat CH-7 instrument for scanning mass spectra at 70 eV. Micro analytical data were obtained on a Thermo Finnigan Flash EA 1112 microanalyzer.

General procedure for the preparation of compounds 1a-1i [42]
To a solution of 241 mg of commercially available 5-bromo-2,4-dichloro-6-methylpyrimidine (1 mmol) in acetonitrile, secondary amine (4 mmol) was added at room temperature and refluxed for 3 h. After removal of solvent in vacuo, the residue was washed with water, and recrystallized from ethanol to give the desired products.

General procedure for the preparation of compounds 2a-2i
To a 1:1 stirring mixture of concentrated H 2 SO 4 (2.2 cm 3 ) and fuming HNO 3 (2.2 cm 3 ) at 0 °C in a beaker was added portion-wise pyrimidine derivatives 1a-1i (1 mmol). The mixture was allowed to stir for 30 min. After the completion of reaction monitored by TLC (using n-hexane and ethyl acetate as eluent), the reaction mixture was added dropwise to 180 g crushed ice with vigorous stirring. The yellow precipitate was filtered-off, washed with water, and dried in vacuo to give the desired product. Column chromatography was used where further purification was needed.

Computational details
The structure of 2f and 2f' were optimized at mPW1PW91/6-31G(d) level of theory in the gas phase and characterized by frequency analysis. The magnetic shielding constants were computed using the gauge including atomic orbitals (GIAO) method [47] at the mPW1PW91/6-31G(d) level of theory in the gas phase. The GIAO 13 C chemical shifts were predicted by multi-standard approach (MSTD) [48]. All calculations were carried out with the Gaussian 09 package [49].