Allylation of uracil

We have studied the direct allylation of uracil 190, thymine 191, and 6-methyluracil 192 (Scheme 43) under Pd(0) catalysis and forcing conditions (93T1457). The results are summarized in Table V. Uracil and thymine... 

Sinou and co-workers also studied the allylation of uracil 190 and thymine 191, but in an aqueous solvent (water/acetonitrile in a ratio 17/2) and in the presence of trisodium triphenylphosphine trisulfonate (tppts, 199) as water-soluble phosphine. Their results are summarized in Table VI. Cinna-myl acetate was used with one equivalent of diazabicycloundecene (DBU) as a base instead of mixed carbonate. Under these conditions, good regiose-lectivities at N-l (to 193 and 185) were observed, as well as lack of diallyla-tion products for uracil and thymine, even with an excess of cinnamyl acetate. It seems that the nonformation of diallylated products is related to the precipitation of the N-l isomers 193 and 185 in the aqueous medium (94TL7085). 

A dramatic enhancement of selectivity has been noted for the allylation of uracils and thiouracils. In DMSO or dioxane the reaction in the presence of Pd(OAc)2-Ph3P gave a mixture of substitution products at N-1 and N-3, while the reactions in aqueous MeCN catalyzed by TPPTS complex of palladium gave selectively 1-Al-allyluracils and S-allylthiouracils (Scheme 64). ... 

Sigismondi, S. Sinou, D. Perez, M. Morenomanas, M. Pleixats, R. Villarroya, M. (1995) Palladium(0)-catalyzed allylation of uracils and 2-thiouracils. Drastic effect of an aqueous reaction medium on the regioselectivity. Tetrahedron Lett., 35,7085-8. 

A series of pyrido[2,3-rf pyrimidine-2,4-diones bearing substituents at C-5 and/or C-6 were synthesized using palladium-catalyzed coupling of uracil derivative 417 with vinyl substrates or allyl ethers to give the regioisomeric mixtures of 418/419 and 420/421, respectively. The ratio of the isomeric structures was dependent on the substituent R. In the case of the reaction with -butyl vinyl ether, only the product 419 was obtained. However, the reactions with acrylonitrile, ethyl acrylate, 2-trifluoromethylstyrene, and 3-nitrostyrene afforded only 418. Also, reaction with allyl phenyl ether gave only 420. The key intermediate 417 was prepared by the reaction of 6-amino-l-methyluracil with DMF-DMA (DMA = dimethylacetamide), followed by N-benzylation with benzyl chloride and vinyl iodination with iV-iodosuccinimide (NIS) (Scheme 15) <2001BML611>. 

Pd/tppts-catalysed allylations of aromatic amines (Equation 13) and phenols49,534 or uracils and 2-thiouracils.535... 

In Section III.B.2, the difficulties inherent in the use of insoluble unmodified heterocycles were described, together with some methods of overcoming this difficulty reported by Benneche and Undheim. This problem is also encountered in the field of uracils. Thus, the same authors reported the Pd(0)-catalyzed allylation of the bis-(O-trimethylsilyl) derivative of thymine (181) which gives directly the mono- and the bis-JV-allylated products 182 and 183 (Scheme 41). The same reaction with rac-160 affords rac-184, with overall retention of configuration (92ACS761). 

Although the palladium-catalyzed reaction of uracils with cinnamyl acetate in DMSO gave a complex mixture of all N-allylation products, performing the reaction in an aqueous acetonitrile (9 1) medium allowed the highly regio-selective formation of 1-cinnamyl uracils in reasonable yields [Eq. 12)]... 

Although the first aim of the use of a water-soluble palladium catalyst in allylic alkylation in a two-phase system was the recycling of the catalyst, this methodology finds quite interesting applications in the deprotection of peptides as well as in the selective alkylation of uracils and thiouracils. More recently, the effective use of supported aqueous-phase catalysis as well as asymmetric alkylation in water in the presence of surfactants or amphiphilic resin-supported phosphines open new applications and developments for the future. 

Allyltrialkylsilanes can serve as allyl transfer agents for carbon-centered radicals under tin-free reaction conditions. An early example, published by Saito in 1985, involves the allylation of the uracil derivative 111 under photolytic conditions with allyltrimethylsilane 112 (Scheme 24) [65]. No comment was made regarding the mechanism of this process, but it is presumably radical in nature. In 1994, Hirao... 

A convenient preparation of 2 -0-methylguanosine involves the interaction of N -isobutyiyl-5 -0-dimethoxytritylguanosine with trimethylsilyldiazomethane, followed by deprotection.279 Allylation of uridine and cytidine at 0-2 can be achieved with some regioselectivity by use of either allyl ethyl carbonate and a Pd° catalyst, in which case protection of A3- of the uracil unit was necessary,280 or by allylation of a stannylene derivative.28i Alkylation of UMP also has some selectivity towards 0-2. 282... 

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

The pyrimidone ring system is not fully aromatic, since such compounds exist as amides, rather than hydroxypyrimidines, and the rr-system does not extend fully around the ring. In the case of the uracils, the 5,6-double bond possesses allylic character, and various relatively stable adducts can be obtained, for example, with bromine or chlorine water [210, 486—488]. Catalytic reduction across the 5,6-double bond is also readily accomplished [441, 489—491]. 

Uracil-type compounds are insoluble in common organic solvents. Radicals R4 in 168 have been used to permit a more facile allylation or rearrangement to 167, as shown in Scheme 37). Further transformation into the amide functional group permits preparation of 169, and finally 170 (93ACS72). 

Nemoto, Yamamoto, and Cai[30a] later modified the preparation of their water-soluble carborane to include the attachment of a tumor seeking uracil moiety (Scheme 5.8). Key transformations allowing the synthesis of this unique dendritic carborane (33) included construction of masked uracil allyl carbonate 34 and its subsequent connection to the benzyl protected o-carborane cascade 35, the intermediate precursor to tetraol 30, via palladium bis(dibenzylideneacetone) [Pd(dba)2] and l,2-bis(diphenylphosphino)ethane (dppe) mediation. 

Bicyclic A(0-Mti-homonucleoside analogues such as 591 were synthesized through 1,3-dipolar cycloaddition of an enantiopure 3-hydroxy-l-pyrroline A -oxide and protected allyl alcohol and subsequent introduction of thymine by a Mitsunobu reaction <2003T5231>. Furthermore, isoxazole, isoxazoline, and isoxazolidine analogues of (7-nucleo-sides such as 592-594 were synthesized by 1,3-dipolar cycloaddition of nitrile oxides and nitrones derived from uracil-5-carbaldehydes with suitable dipolarophiles <2003T4733, 2006T1494>. 

Reductive coupling of RCHO and allylic alcohols A synthesis of tunicaminyl-uracil (5) involves a novel coupling of an aldehyde with an allylic alcohol, effected with dichlorodimethylsilane. Thus treatment of the alcohol 1 and the aldehyde 2 with bcnzenesclcnol and (CH,)2SiCI2 (excess) in pyridine at 23° provides the product 3 in 92% yield as a mixture of cpimers (1 1). Radical cyclization of 3 in acetonitrile with BuiSnll and (C2Hi)B, followed by siloxanc hydrolysis provides the protected... 

Catalytic deuteration of carbon-carbon multiple bonds is thus preferably restricted to small uncomplicated molecules or, as in the formation of [D2]-dihydrouracil from uracil,24 to such as contain a limited number of C-H bonds. Good results can also always be obtained when the substance to be reduced does not contain hydrogen in the allyl position, e.g., withJ1-3-keto steroids,25 and in partial reduction of carbon-carbon triple bonds. Khan20 gives the following description of the last-mentioned reaction ... 

Due to the much lower rate of allylic H-abstraction by the H-atom as compared to the OH radical, this process is generally of small importance (cf. Table 7). In so far as the base is methylated at carbon, the pattern of site preference exhibited by the H atom is influenced by the position of the methyl group in ways different from the OH radical (Table 1). It may be the effect of hyperconjugation that appears to enhance the relative attraction for the hydrogen atom to become attached, cf. the pronounced preference for addition at C(5) in 6-methyluracil, and the reversal of the preference in thymine, as compared to uracil. 

The synthesis of the 5-allyl and 5-n-propyl derivatives used organopallad-ium intermediates. The uracil derivative 299 first was treated with mercuric acetate, then was condensed with allyl chloride in the presence of Li2PdCl4 to give the 5-allyl derivatives 300 whose reduction gave 301. Treatment of... 

---