Heck reaction pyrimidines

Some interesting fused 1,2,3-triazole ring systems have been reported. A series of 5-piperidyl-substituted 7-hydroxy-3f/-l,2,3-triazolo[4,5-d]pyrimidines 143 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide <06CHE246>. 4-Alkylidene-5,6-dihydro-4//-pyrrolo-[l,2-c][l,2,3]triazoles 144 were prepared from alkylidenecyclopropanes via diiodogenation/Cu(I)-catalyzed 1,3-dipolar cycloaddition/intra-molecular Heck reaction sequence <06SL1446>. 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-27/-benzotriazol-4-one 145 were prepared from A-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine and... 

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>. 

Representative reactions of pyrrolo[2,3-d]pyrimidine triflate 3436 using four major types of palladium-catalyzed carbon-carbon bond-forming reactions are illustrated in Eq. 6. Thus, methoxycarbonylation of 34 was performed using the standard protocol of Ortar and co-workers37a and afforded ester 35 in good yield. The Heck reaction with an electron-deficient alkene, represented by ethyl acrylate, provided 36 in respectable yield.37b The copper (I)-promoted coupling with A-trifluoro-... 

The Heck reaction of 2- or 4(6)-halopyrimidines was less straightforward. Initial attempts with the Heck reaction of 4-iodopyrimidines without a substituent at the 5-position were plagued by homocoupling, giving rise to bis-pyrimidine 224 as the major product [109]. Yamanaka and colleagues later discovered that the homocoupling could be eliminated if the reaction was carried out in the absence [110-112]. The same... 

Several examples of the palladium-assisted Heck reaction with 6-bromopyrido[2,3- /]-pyrimidines 29 are known, the reaction conditions being refluxing of the bromo compound with the alkene in the presence of palladium(Il) acetate, copper(I) iodide, triethylamine, and tri(2-tolyl)phosphane in acetonitrile. 

Several variations on a Friedlander reaction strategy were investigated for the construction of palbociclib, one of which is shown in Scheme 9. In this approach, pyrimidine 28 was treated with cyclopentylamine, which provided aminopyridine 29. Heck reaction with n-butyl vinyl ether provided 30, which was hydrolyzed with aqueous trifluoroacetic acid to give the ketone 31. Palladium-catalyzed amination, with aminopyridine 22, then provided the key ketone intermediate 32. The Friedlander annulation was then evaluated using a variety of acetoacetate and diketene analogs. 

The synthesis of chloropyrimidine 21 is shown in Scheme 13. The synthesis starts with an SnAt reaction between cyclopentylamine and pyrimidine 28, which provides bromopyrimidine 29. This reaction provides approximately 9 1 selectivity for the desired product versus the regioisomer formed by displacement of the other chlorine. The subsequent Heck reaction required significant screening and optimization, but the established conditions provide for efficient Heck reaction with crotonic acid. Subsequent treatment with acetic anhydride provides the cyclized product 45, which can be treated... 

The first asymmetric synthesis of (20 S)-camptothecin using catalytic asymmetric induction was achieved by Fang et al. in 1994 [74], They carried out a catalytic enantioselective synthesis of Comins s intermediate (23) in order to avoid the use of the expensive chiral auxiliary, 8-phenylmenthol, or similar compound. Intramolecular Heck reaction of pyridine derivative (26) gave the cyclic olefins (27) and (28) in a ratio 1 8. The allylic ether (27) can be isomerized to (28) upon treatment with Wilkinson s catalyst [75], Asymmetric Sharpless dihydroxylation of (28) proceeded successfully when 2,5-diphenyl-4,6-bis(9-0-dihydroquinidyl)pyrimidine [(DHQD)2-PYR] was used as the chiral catalyst [76], and subsequent oxidation gave (29) in 94% ee. Treatment of (29) with acid gave the target molecule (23, Scheme 2.5), which was converted to (20S)-camptothecin in 2 steps using the Comins s procedure [73]. 

A positive effect of water was observed in Heck reactions of 2,3-dihydrofuranes (e.g., glycals) with iodo- and bromoderivatives of pyrimidines and other nitrogen-containing heterocycles (Scheme 31). In several cases the reactions that could not be achieved using a standard method (in anhydrous DMF with EtsN and NaOAc as base) took place in aqueous ethanol (1 1, v/v) with NaHCOj-EtsN mixture in the presence of BU4NCI with suppression of double bond migration. ... 

In contrast, the carbonylative Heck reaction, representing a variant of the palladium based multicomponent olefination reactions, has only been described to a hmited extent. Nevertheless, the resulting a,/ -unsaturated ketones serve as very important building blocks, as demonstrated by the many applications of the Michael addition, and constimte an attractive entry point to the assembly of heterocyclic compounds including pyridines, pyrimidines and pyrazoles etc [97, 98]. 

Next, tosylated hydroxypyrimidines were tested in the regioselective Heck reaction using NVA and n-butyl vinyl ether in order to investigate the influence of the heteroaromatic core system on the catalytic outcome (Scheme 5.3). Similar yields of the vinylated pyrimidines compared to the pyridine equivalents were achieved indicating a robust catalytic system. Even a double Heck reaction could be accomplished yielding 56 in 36 % corresponding to an average of 60 % yield of each vinylation. 

A study of the a-arylation of diazine mono iV-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very substantial improvement in yield <06AG(I)7781>. 

Reddy and collaborators reported a new one-pot, three-component procedure toward the synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/aryl) phenyl] pyrimidine libraries starting with the Michael addition of enaminone 64 with 3-bromobenzimidamide hydrochloride (65) (Scheme 28) (13S75). This was followed by a cyclization, an isomerization, a dehydration, and a subsequent Sonogashira reaction with terminal alkynes or a Suzuki reaction with arylboronic acids or a Heck coupling reaction with alkenes. 

Many years ago, one of the authors (AJB) had the pleasure of conducting his first arylation reaction - which was a Heck-Mizoroki reaction between an activated pyrimidine and methyl acrylate - and he was struck by the simplicity and efficacy of the coupling process. Thus, a keen interest in these reactions was awakened, and this has been manifested in the recent research activities conducted in this group. 

Tin Reagents. The presence of a 3-methyl group in the 2-chloroquinoline 202 has a beneficial effect on reaction rates and efficiency in Stille-type alkenylations with terminal stannyl alkenes (Scheme 77). This was attributed to steric acceleration in the reductive elimination of Pd(0) from a Pd(II) complex. The purine 6-position is highly electrophilic. A chloro substituent is readily replaced under Stille conditions using tri(n-butyl)vinylstannane. The 6-vinylpurine product 203 from the coupling is reacted further in situ in Heck couphngs. These reactions proceed readily because of the electron-withdrawing effect from the ir-deficient pyrimidine moiety of the heterocycle.t ... 

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