Spiro pyrimidines

A study of the 1,3-dipolar cycloaddition of pyrazines, pyrimidines and l//-pyrimidinthiones with nitrilimines (80), generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides (79), was carried out. Reaction of pyrimidine-2( l//)-thiones (81) and -4(l//)-thiones with nitrilimines in benzene at reflux gave spiro[pyrimidine-2(l//), 2 (3 f/)-[ 1,3,4]thiadiazoles... 

Scheme 4.47 Synthesis and recyclization of 4 -methyl-3, 4-dihydro-l/f,r//-spiro [pyrimidine-5,2-quinoxaline]-2,4,6(3//)-trione...

The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture. They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture. Like the HEPT and TIBO derivatives, the 2, 5 -bis-0-(tert-butyldimethylsilyl)-3 -spiro-5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)-pyrimidine (TS AO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture. Subsequently, they were found to act as specific inhibitors of HIV-1 RT. 

Figure 9 2, 5 -Bis-0-(ferf-butyldimethylsilyl)-3 -spiro-5"-(4"-amino-1",2"-oxa-thiole-2",2"-dioxide)pyrimidine (TSAO) derivatives TSAO-T, TSAO-m3T, and TSAO-e3T.

Balzarini J, Perez-Perez M-J, San-Felix A, Schols D, Perno C-F, Vandamme A-M, Camarasa M-J, De Clercq E. 2, 5 -Bis-0-(tert-Butyldimethylsilyl)-3 -spiro- 5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)pyrimidine (TSAO) nucleoside analogues highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc Natl Acad Sci USA 1992 89 4392-4396. 

Table 4 13C NMR chemical shifts of ring carbon atoms of some spiro(cycloalkane-1,2 -[1,2,4]triazolo[1,5-c]pyrimidine carbonitriles measured in DMSO-d6 solutions...

A blue OLED with a very low turn-on voltage of 2.7 V and a luminance of 500 cd/m2 at 5 V with structure ITO/Spiro-TAD/Spiro-PBD/Al Mg has been reported. The robust and morphologically stable spirobifluorene-cored pyrimidine oligoaryl blue emitter... 

Ring closure at the uracil 6-position also occurred with brominated aromatic derivatives 444 linked to the 6-position, to give benzopyrano[4,3-rf pyrimidine-2,4-dione spiro derivatives 445 <2004S1864>. 

The unexpected 8-hydroxymethylhexahydropyrido[2,3-, pyrimidine-6-spiro-l -cyclohexane-2, 4,6 -triones 520 were obtained from microwave-assisted cyclocondensation of equimolar amounts of 6-aminopyrimidin-4-ones 460 and dime-done with a large excess of formaldehyde (37% in water) in the presence of EtsN as a catalyst <2006TL27>. The reaction proceeded via an initial formation of the 2 1 dimedone/formaldehyde adduct 521 that gave intermediate 522 and 523 which could undergo cyclocondensation with excess formaldehyde to give 520 (Equation 42) <2006TL27>. 

Spiro and Plescia (72JHC951) reported that by fusing 3(5)-amino-5(3)-phenylpyrazole (28) with ethyl benzoylacetate (32) at 160°C for 2 hr (55G1160), compound 29 was isolated in addition to pyrazolo[l,5-o]pyrimidine 30,... 

Spiro and Fabra (72MII) reinvestigated the reaction of semicarbazide with benzoylacetonitrile. The authors showed that the product that melted at 170°C, previously reported to be 5-phenylpyrazole-l-carboxamide (52G373), is 3-phenyl-3-ketopropionitrilesemicarbazone. The other product (m.p. 278°C), for which no structure was proposed, is 7-amino-2,5-diphenylpyrazolo[ 1,5-a]pyrimidine (85). 

Diazopyrrole 196 with diethyl acetylenedicarboxylate gives the spiro compound 197. Rearrangement of 197 gives the pyrazolo[l,5-c]pyrimidine 198 (74LA1550). 

Evidence for the formation of Meisenheimer-type adducts from a purine system has been obtained by Liotta in two cases.43 The addition of t-BuO to 6-(2-hydroxyethoxy)-9-methoxymethyIpurine in t-BuOH, as monitored by H-NMR spectroscopy, causes an upfield shift of both pyrimidine and imidazole ring protons and the conversion of two absorptions of the methylene protons of the CH2CH2OH group to a broad absorption of the dioxolane ring, in agreement with the formation of the spiro adduct 19. Similarly, adduct 20 was formed from 6-methoxy-9-methoxymethylpurine by slow reaction with MeCT in 7-BuOH. 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

In the reaction of 2-(hexahydropyrimidin-2-ylidene)cycloalkanone 247 and alkyl propiolate for 20-40 hours, after addition and cis-trans isomerization, the spiro intermediates 248 suffered ring cleavage by the attack of a molecule of alcohol to give alkyl 6-oxo-1,2,3,4-tetrahydro-6//-pyrido[ 1,2-a]pyrimidine-9-alkanoates 249 (Scheme 19) (87CB1803, 87TL1527). 

Tu and co-workers [189] described a series of new 3-pyrimidin-5-ylpropanamides 140, spiro[5.5] undecane-1,5,9-triones 141 and pyrimidin-5-ylpropanoic acids 142... 

Dimethyl-3-hydroxy-5-methoxy-3,4-dihydro- E14a/2, 450 (a-Hal — keton + 4-SH — 5-NH2—pyrimidin) l-Thia-3,4-diaza-spiro 4.5 dec-2-en ... 

Recently, the 6-chloro atom has been nucleophilically exchanged by 2-arylamino-methylfuran and -thiophene. The formyl group then transformed into an oxime and nitriloxide function. Via intramolecular 1,5-dipolar cycloaddition, a complex spiro-linked pyrido[2,3-[Pg.192]

---