Stille coupling pyrimidines

In the more prolific aspect of the Stille couplings involving a pyrimidine fragment, pyrimidinyl halides or triflates have been coupled with a variety of stannanes. When there is only one reactive halide on the pyrimidine ring, the reaction outcome is straightforward with no regiochemical concern. The simpler stannanes are vinyl stannanes [35-37]. More complicated variants include stannylquinones [38] and l-(trialkylsilyloxy)vinyltin [39] as illustrated by the synthesis of 66. 

Copper(I) salts sometimes have a dual role in the Stille coupling. In the reaction of 3-methyltio-l,2,4-triazine and 2-tributylstannylthiophene (6.33.), for example, besides facilitating the transmetalation copper(I) is also crucial to activate the methyltio group to undergo oxidative addition46 The established Stille coupling conditions also worked well with other substrates, such as 2-methyltio-pyrimidine or 2-methyltio-benzthiazole.47... 

Figure 10.12 ORTEP drawings of Fc-pyrimidines obtained by Stille coupling having the Fc directly attached to the nucleobase. Left Fc-deoxyuridine Right Fc-deoxycytidi ne. Reproduced by permission from Ref. 91 of The Royal Society of Chemistry.

In a similar manner, Stille coupling of 2-tributylstannylthiazole and 5-bromopyrimidine 90 afforded 5-(2 -thiazolyl)-2,4-bis(trimethylsilyl)pyrimidine (91), which was hydrolyzed with acid to the corresponding uracil 92 [46]. 

Recent advances in functionalization of 2-chloropyridine via C(6) lithiation followed by tributylstannation has provided access to 6-tributylstannyl-2-chloropyridine 158, which in turn can be coupled to halopyrimidines under standard Stille conditions [74]. Subsequent refinement of this procedure has provided a one-pot protocol for the lithia-tion/electrophilic stannation/Stille coupling to provide heteroaryl substituted pyrimidines, wherein the tributylstannane intermediate is not isolated [75]. 

Di-t-butoxy-pyrimidines are used as protected forms of uracil 5-boronic acids and 5-halides for Suzuki and Stille couplings, respectively, but suffer from the problem that an intermediate in their preparation (2,4-dichloro-5-bromopyrimidine) is highly allergenic. Unprotected 5-iodouracil will couple in some cases, but the Stille coupling of the 5-bromo-2,4-bis(trimethylsilyloxy) derivative is more consistently successful. ... 

The similar situation was observed with fluoro-iodo diazines. Fluoro-iodo pyrimidine 354 (see Scheme 59) was subjected to Stille coupling followed by intramolecular cyclization into targeted azacarboline 438 [212] (Scheme 79). 

Later the different iodo/fluoro activity was used in nicotinic acetylcholine receptor (nAChR) PET ligand 447. On the early step of the synthesis starting from 2-fluoro-5-iodopyrunidine 444 the corresponding tiialkyltin heteroaromatic intermediate 445 was obtained based on stanno-Stille coupling in 90 % yield. Further the fluorinated stannate was entered in reaction with iodopyridine 446 leading to cross-coupled pyridine-pyrimidine in 50 % yield. The final step of the synthesis was Boc-deprotection by TEA affording 447 [235] (Scheme 81). 

Another useful Stille coupling was performed based on tributyl(l-ethoxyvinyl) stannane 463 which allowed to obtain additional function in pyrimidine ring. The reaction of stannane 463 with 158 in presence of bis(triphenylphosphine) PdCl2 in DMF leads to corresponding 4-vinyl ether 464 in 84 % yield. The amino group was introduced at position 2 upon treatment with aqueous concentrated ammonia in ethanol under heating with microwaves, and bromination of the resulting vinyl ether 465 to a-bromo-ketone 466 was accomplished with N-bromosuccinimide in aqueous... 

The traditional Stille-type cross coupling of stannane 88 with bromopyrimidine 89 was reported by Fort and co-workers to provide pyrimidine 90 in 80% yield <00OL803>. This illustrates a novel route to heterocyclic chlorobiaryls. 

In addition, some Stille adducts have been further manipulated to form condensed heteroaromatic ring systems. The coupling of 4-acetylamino-5-bromopyrimidine 69 and ( )-1-ethoxy-2-(tributylstannyl)ethene resulted in ( )-4-acetylamino-5-(2-ethoxyethenyl)pyrimidine 70, which then cyclized under acidic conditions to furnish pyrrolo[2,3-d]pyrimidine 71. Pyrrolo[3,2-d]pyrimidines were also synthesized in a similar fashion by using 5-acetylamino-4-bromopyrimidine [40]. 

Although much less common than with fully conjugated pyrimidines, cross-coupling reactions can still be performed with dihydropyrimidines, and thus the Heck reaction of the dihydropyrimidinone 518 with 4-iodoanisole 517 gave the product 519 where the double bond had migrated to the more stable 1,2-position <1996OS201>. 

Even though orotidine has been implicated in the complex set of reactions leading to pyrimidine formation, the role of orotic acid per se must still be evaluated. On the one hand, it is possible that it is a normal intermediate which condenses with ribose to yield orotidine during pyrimidine synthesis. In contrast, an aliphatic acid, such as amino-fumaric i or ureidosuccinic, could conceivably couple with ribose and subsequently yield orotidine directly without the existence or participa-... 

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