Pyrimidinones, formation

A convergent synthesis of the potent selective inhibitor of the enzyme phosphodiesterase sildenafil (Viagra) has been based on polymer supported reagents [134], In this synthesis, the HOBt-supported resin 126 has been used for the isolation and preparation of the resin-bound active ester 128, performed by coupling polymer 126 with the benzoic acid sulfonamide derivative 127 by means of PyBrop (Scheme 7.40). Subsequent reaction of active ester 128 with aminopyrazole 129 gave rise to the clean synthesis of amide 130, which has been transformed into sildenafil (131) after a base-promoted pyrimidinone formation. 

SCHEME 13.42 Base-mediated pyrimidine and pyrimidinone formation under thermal and MWI conditions [11, 74, 75]. 

Use of sodium sulfite allows selective replacement of iodine by hydrogen at C4 without affecting the ortho-position in 4-iodo-3-(2-iodophenyl)sydnone <2005SC639>. Acrylate groups attached at the C4 position of 4-arylsydnones reacted with guanidine hydrochloride but the result was replacement of the G4 substituent by hydrogen instead of formation of the planned pyrimidinone products <2003T4103>. 

Rearangement of furoxans leads to the formation of new heterocyclic systems derivatives of triazoles, diazoles, isoxazoles, and pyrimidinones. For example, on the basis of the experimental results using labeled compound 52-15N , the formation of 8-phenyltheophylline 53, the 1,3-dimethylalloxazines (54 n = 0, 1), and l,3,7,9-tetramethyl-l//,9//-pyrimido[5,4-g]-pteridine-2,4,6,8-tetraone 55 in the thermal reaction of the iV-oxide 52 with benzylamine, aniline, or piperidine and the generation of NO or NO-related species in the reaction with iV-acetylcysteamine were reasonably explained by... 

The ring closure of )V-(a-N-heterocyclic)aminomethylenemalonates may lead to the formation of nitrogen bridgehead pyrimidinones when the ring nitrogen is involved in the cyclization. Ring closure may also lead to the formation of condensed pyridines when the ring carbon is involved (Scheme 46). 

For the formation of 5-chloropyrimidines, AT-chlorosuccinimide is normally the reagent of choice, but several other electrophilic chlorine sources including chlorine gas or sulfuryl chloride can be used <1994HC(52)1>. For example, the chlorination of 4-(trifluoromethyl)-2(l//)-pyrimidinone 59 with ferric chloride and sulfuryl chloride in acetic acid gave the 5-chloro derivative 60 in 80% yield <2004EJ03714>. 

Alkoxides are usually more difficult to hydrolyze than halides, although hydrolysis can be rapid in activated systems. Pyrimidinethiones can sometimes be hydrolyzed directly to pyrimidinones, but it is often better to convert the thiones into alkylsulfenyl, alkylsulfmyl, or alkylsulfonyl derivatives before hydrolysis <1994HC(52)1, 1996CHEC-II(6)93>. The formation of 5-hydroxypyrimidines is not normally performed using hydrolytic procedures, although it can be achieved by the oxidation of boronate species in aqueous solution <1996CC2719, 2006TL7363>. 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

The enantiomerically pure substituted 1,2-dihydro-4(3//)-pyrimidinone 11 has been employed as a chiral auxiliary for diastereoselective alkylation reactions2. Thus, acylation, followed by enolate formation and alkylation with reactive halides such as halomethanes. (balomethyl)benzenes, 3-halopropenes and 3-halopropynes, affords the alkylation products with high diastereoselectivity (d.r. 93 7 to 99 1) . 

The irradiation of 2-methyltetrahydropyridopyrimidin-4-one 643 (R = Me) in a mixture of acetic acid and acetonitrile under argon at 25°C afforded betaine 651 (R = Me) in 57% yield (83TL5237 87JOC2455). Upon the formation of betaine 651 after the protonation of the imino nitrogen of the Dewar pyrimidinone 646, ring opening yielded azetidinyl cation... 

Basic catalysis of the reactions of urea with unsaturated ketones, as well as thiourea, can lead to heteroaromatization with the formation of oxidized pyrimidinones instead of their dihydro analogues [77] (Scheme 3.23). 

The mechanism probably involves a transition structure TS. Rotation of the allylic chain in TS and N-2 extrusion leads to a biradicalar complex BC1 with the terminal carbon of the allylic chain (C-l) very distant from N-l. Subsequent reaction coordinate calculations consider that C-l approaches N-l to give a biradicalar complex, BC2, thermodynamically more stable by 19.1 kcalmol-1. The formation of pyrimidinone 290 from BC2 ensues through 1,2-migration of hydrogen and exothermic formation of a new G(l)-N(l) single bond (Scheme 35) <2005TL6757>. 

Under conditions of the Hilbert-Johnson reaction, the 2,4-dialkoxypyrimidines (29) can furnish the following by-products uracil,13 1-alkyluracil,3-7 1,3-dialkyluracil,19 4-alkoxy-2(lIZ)-pyri-midinone,7 and l-alkyl-4-alkoxy-2(lH)-pyrimidinone.7,20 Thus, for example, 5-chloro-, 5-bromo-, and 5-iodouracil were isolated32- 33 as by-products in the Hilbert-Johnson reaction (in acetonitrile at 20°) of the corresponding 5-halo-2,4-dimethoxypyrimidines and 3,5-di-O-p-toluyl-2-deoxy-D-ribofuranosyl chloride. The formation of 1,3-dimethyluracil and 1,3,5-trimethyluracil as by-products has been observed quite recently19 when the reaction of 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride with 2,4-dimethoxypyrimidine and 5-methyl-2,4-dimethoxypyrimidine, respectively, was performed in toluene at 70°. 

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