Hydroxylamine pyrimidines

Appropriate pyrido[2,3-d]pyrimidin-5-ones with formyl groups in the 6-position have been oxiized to piromidic (68) and pipemidic (69) acids, or to intermediates for these, using moist silver oxide, chromium trioxide (potassium dichromate), potassium permanganate or, alternatively, sodium chlorite/hydroxylamine-O-sulfonic acid. 6-Acetyl groups have been similarly oxidized using sodium hypobromite in aqueous dioxane, whilst 2-acetyl groups give dimethylaminomethylene derivatives en route to 2-pyrazolylpyrido[2,3-d]pyrimidines. 

The reaction of flavylium salts (403a) with hydroxylamine in pyridine gave 2,5-dihy-droisoxazoles (404) in an analogous manner (75T2884). Pyrimidines have also been converted into isoxazoles, and the reaction of the pyrimidines (405) with hydroxylamine hydrochloride gave the isoxazoles (338). 

Only one cyclic hydroxamic acid which contains the pyrido[2,3-d]-pyrimidine ring system has been reported.This is 2-methyl-3-hydroxypyrido[2,3-d]pyrimidin-4(3i/)-one (21) which was prepared by the action of acetic anhydride on 2-aminonieotinhydroxamic acid (20) or from ethyl 2-aeetamidonicotinate (22) and hydroxylamine. In view of the known antibacterial activity of certain cyclic hydroxamic acids further work on these compounds would be of interest. 

Phenylpyrido[4,3-d]pyrimidin-o(677)-ones (145) have been prepared from 7-phenylpyrano[4,3-d]pyrimidin-5(6/7)-ones (144) by treatment with ammonia, hydroxylamine, or hydrazine at room temperature. The utility of the route lies in the rapid preparation of 4-methyl-2-phenylpyrimidine-5-carboxylic acid (143) from cheap... 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

Reaction of 3-formyM/7-pyrido[ 1,2- ]pyrimidin-l-ones with hydroxylamine O-sulfonic acid at 5 °C, then 50 °C yielded 3-nitriles <2003T4113>. Treatment of 2-hydroxy-3-(dimethylamono)methyF4//-pyrido[l,2- ]pyrimidin-4-one with Mel, then with KCN gave the 3-cyanomethyl derivative <2004MI215>. A condensation product was obtained from 5-amino-l-ethyl-6-hydroxy-l,3-dihydrobenzimidazol-2-one and 3-lbrmyl-2-hydroxyA//-pyndo[ 1,2- ]pynmidin-l-one <2002W002/38549>. l-(2-Aminopyrimidin-4-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-ones were prepared from l-(2-methylthiopyrimidin l-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-one by treatment with MCPBA, and then with aralkylamines <2005W005/070932>. 

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

The 1,2,4-oxadiazole dioxolanes 144 react with hydroxylamine and hydrazines to form the 5-pyrazole- and isoxazole-substituted 1,2,4-oxadiazoles 146 via the dioxolane ring-opened intermediates 145 (Scheme 17). Reaction of compounds 144 with amidine or guanidine salts allows access to pyrimidine substituted analogues 147, via intermediate 145 (X = C(NH)R1), albeit in lower yield <1996JHC1943, 1998JHC161>. 

Reaction of (benzothicpino[5,4-, a process that also allows access to l,2,4-oxadiazol-5-yl-dihydronaphthalenes 254 when the benzoquinazolinylamidines 253 are used as starting materials <1999JCM92>. 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

The new metabolite from Red Sea marine invertebrates, Asmarine B (169), presents a hydroxylamine functional group (equation 50). When treated with acetic anhydride at room temperature the Asmarine B (169) underwent an unexpected [3,3]-sigmatropic rearrangement to give 170. After 1,6-addition of methanol and concomitant loss of acetic acid 170 produced the pyrimidine 171. ... 

Pyrimidines can be formed in reactions involving multiple bond formations, and the reactions of this subgroup have a long history <1994HC(52)1>. A recent example is the synthesis of a 6-substituted uracil derivative 740 (Scheme 9), where an a,/3-unsaturated ester 737, A,0-bis(trimethylsilyl)hydroxylamine, phenyl chloroformate, and ammonia supplied the four components of C(4)-C(5)-C(6), N-1, C-2, and N-3, respectively <2000TL4307> ... 

Unexpected products also arose from the reactions of 40 with excess (6-14 equivalents) hydroxylamine hydrochloride <99JHC787>. Unless R was very small (i.e., H or Me), this reaction provided the pyrimidine-opened 42 exclusively the oxime products 41 could not be isolated. With small substituents (i.e, R = H or Me), the normal oximes 41 were the sole product. 

One example of the generation of this system has appeared, in which the treatment of a pyrrolo[2,3-i/]pyrimidine 128 with hydroxylamine gives the m -fused nucleoside analogue 129 <2003W003/061385>. 

A similar effect occurs in the reaction of some pyrimidine nucleoside derivatives with hydroxylamine. Studies of the mechanism of this reaction with uridine derivatives340 shows that the initial point for nucleophilic attack is at C-6, and the resultant 5,6-dihydro-6-(hydroxy-amino)uridine derivative (86) is an intermediate in the conversion of the uridine derivative into the ribosylurea derivative 87 and 2-isoxazolin-5-one (88), as shown in Scheme 8. 

One of the powerful chemical mutagens inducing point mutations is hydroxylamine, NH2OH, and its N- and O-methyl derivatives.125-133 These react with the pyrimidine bases, and their reaction with cytosine (or cytidine) leads to the formation of several modified cytosines (or cytidines), among which are lV4-hydroxycytosine (21, 22, R = R = H), and A4-methoxycytosine (21, 22, R = H, R = Me) and the... 

Reactions of nucleophiles. A number of nucleophilic reagents add reversibly at the 6 position of pyrimidines. Thus, bisulfite adds to uridine (Eq. 5-10).528 Hydroxylamine (HONH2) adds in a similar fashion to give a compound with -HNOH in the 6 positions.528 Sodium borohydride (NaBH4), which can be viewed as a donor of a hydride ion (H ), reduces uridine to the 5,6-dihydro derivative. This presumably occurs by attack of the hydride ion at position 6 in a manner analogous to the reaction of bisulfite in Eq. 5-10. 

Mesoionic pyrido[2,l- >][1,3]oxazines (54) afforded 4-oxo-4//-pyrido[l,2-a]pyrimidin-l-iumolates (55) and 4//-quinolizin-4-one (56) with phenyl iso(thio)cyanates [78LA1655 79CB1585 82ZN(B)222] and dimethyl acetylenedicarboxylate (79CB1585), respectively. Reaction of 2-cyano-3-methyl-lH,6//-pyridol[l,2-a][3,l]benzoxazine-l,6-dione with ammonium acetate and hydroxylamine, hydrazines, primary aliphatic or aromatic amines, and (thio)ureas gave 5-unsubstituted and 5-substituted 2-cyano-3-methyl-l//,6H-pyrido[l,2-a]quinazoline-l,6-diones (93CCC1953). 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

Two closely related reports of pyrazole generation by condensation of substituted hydrazines with enamino carbonyl compounds have appeared. In situ formation of an enaminoketone, by treatment of a diketone with dimethylformamide dimethyl acetal, was followed by tandem Michael addition-elimination/cyclodehydration under aqueous conditions in sealed microwave vessels (Scheme 3.12)17. Isoxazoles and pyrimidines were also prepared by replacing the substituted hydrazine with hydroxylamine or amidines, respectively (see Chapter 5, Section 5.3.2). The overall process may be regarded as another example of a multi-component coupling. In a similar fashion, enamino propenoates were condensed with substituted hydrazines to afford substituted pyrazoles (see Chapter 5, Section 5.3.2) (Scheme 3.12)18. 

The thiazine dithiones also react with hydrazine, hydroxylamine, semi-carbazide, and thiosemicarbazide. Hydrazine gives 3-aminopyrimidine-2,4-dithiones (214) (Scheme 87) [80JCR(S)148]. Thiosemicarbazide reacts in the same way as diamines to give [l,2,4]triazolo[l,5-a]pyrimidines (215) (Scheme 88). 

The treatment of 6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-lH,3H-pyr-ido[l, 2-c]pyrimidine-1,3-dione with 0-(2,4-dinitrophenyl)hydroxylamine in the presence of K2C03 in a mixture of THF and DMF at 80 °C for 2 h gave 2-amino derivative in 88% yield (09TL785). 

Dihydropyridines containing at position 3 a carbonyl group similar to oc,(3-unsaturated ketones can be involved in cyclocondensation reactions with 1,2-binucleophiles. Dihydropyridine 376 treated with hydroxylamine yields isoxazoline derivatives 377 [363, 382, 383, 384, 385, 386] (Scheme 3.122). Dihydro-l,2,4-triazolo[l,5- ]pyrimidine 378 reacts with hydrazine and hydroxylamine in the same manner, giving the condensation products 379 [387]. 

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