Pyridine, 3-bromo metalation

The regioselective functionalization of pyridines using metallation or halogen/metal exchange reactions has been reviewed. There has been a detailed mechanistic study of the ort/io-lithiation of 2-fluoro- and 2,6-difluoro-pyridines by lithium diisopropy-lamide (LDA) in tetrahydrofuran at -78°C where aggregation and aggregate-exchange phenomena are critical.The mono-lithiation of the boron trifluoride adduct of 3-chloro- and 3-bromo-pyridines results in reaction at the 2-position. However, with two equivalents of LDA, the 2,6-dilithiated derivatives may be formed. Subsequent reaction with electrophiles may result in the formation of 2-, 6-, or 2,6-substituted products. " ... 

TIPS groups have been used in different ways to prevent undesired C-2 lithiation of indoles and benzothiophenes. The introduction of a TIPS group onto 4-bromo-l/f-pyrrolo[2,3b]pyridine permitted metalation to occur exclusively at C-4, affording the 4-fluoro product (eq 16). The TIPS group was removed with TEAR Without TIPS, transmetalation at C-2 was observed. 

The rearrangement of 5-bromo-3-methoxy-2-phenylimidazolo[l,2-a] pyridine (70) into the 8-isomer 73 also undoubtedly involves a sequential metalation, transmetalation, and metal-halogen exchange pathway involving intermediates 71-75 and the noncatalytic generation of the 5,8-dibromo derivative 75 (Scheme 20) (83S987). 

Certain structural indications of thromboxane A2 biosynthesis inhibition and hence potential therapeutic utility in arterial thrombosis prompted the synthesis of the pyridine prostanoid 544 (Scheme 165) (83TL3291). Brief metalation of 42 followed by DMF quench afforded aldehyde 541, which upon Homer-Emmons chain extension, reduction, and protection gave 542. Having served as a DMG, the bromo function was subjected to metal-halogen exchange, transmetalation (CuCN), and condensation with an iodo allene to furnish the 3,4-disubstituted pyridine 543. The latter was transformed into two derivatives 544 (with and without double bond), which were shown to be effective inhibitors of thromboxane A2. 

With the aim of developing new analogues of the cyclic AMP phosphodiesterase inhibitor lixazinone (554), the synthesis of agents 553 and 555-557 was undertaken (Scheme 167) (88JMC2136). Thus, all possible 1,2-related N-r-Boc aldehydes 551 were prepared by directed metalation on isomers 549, with the exception of that which required the use of a metal-halogen exchange reaction on the bromo precursor 550 (attempts to metalate 4-TMS-3-N-f-Boc pyridine proved inefficient). As exemplified for one particular isomer, conversion of 551 into 552 by reductive amination... 

Finally, compound (iv) is condensed with either trimethyl(6-methyl-3-pyridyl)tin or the boronate ester by means of Pd(PPh3)4 to afford etoricoxib. The metallated pyridine (vii) is obtained by esterification of 3-hydroxy-2-methylpyridine with triflic anhydride to give the corresponding triflate, which is treated with a tin reagent to yield the target tin intermediate. The boron lithium salt (viii) is prepared by treatment of 5-bromo-2-methylpyridine with butyllithium followed by addition of triisopropyl borate. 

The most convenient preparative scale precursor of 1-alkoxycyclopropyllithium reagents was found to be 1-bromo-l-ethoxycyclopropane 139, prepared in good yields by reaction of 1-ethoxy-1-trimethylsiloxycyclopropane 27) with phosphorus tribromide in the absence of pyridine. Addition of 139 to r-butyllithium (2 equivalents) in ether at —78 °C resulted in immediate and exothermic halogen metal exchange to form the expected 1-ethoxycyclopropyllithium 140, Eq. (43) 74). 

In contrast to the well known metal-halogen exchange of bromo and iodo aromatics, commercially available halopyridines are amenable, for all halogens, to DoM chemistry of considerable synthetic value [9d]. Recent results [9d, 41], have pointed to the additional feature of the halogen dance as a tool for the construction of unusually substituted pyridines. Illustrative are the conversion of 69 into 2,3,4-substituted pyridines 70 and, more interestingly, of 71 into the tetrasubstituted 72 bearing all but one of the theoretically possible halogens (Scheme 24) [42]. 

Alkylation of compound (1) to give l-(2-hydroxyethyl)pyrrolo[2,3-Z>]pyridine was achieved in 71% yield using fairly drastic conditions heating the reactants with aluminum chloride in carbon disulfide at 50°C for 30 min. To carry out alkylation at the 3-position of the pyrrole ring, a regiospecific alkylation was done via metallation of 3-bromopyrrolo[2,3-Z>]pyridine (35), giving the 1,3-dianion <84JHC42i>. In this manner, 3-(2-hydroxyethyl)pyrrolo[2,3-i]pyridine (36) was obtained in 57% yield. Further reaction to the bromo derivative (37) was carried out as outlined in Scheme 7. 

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