Thienopyrimidines

The earboxylie aeid derivative of an isomerie fused thienopyrimidine exhibits mediator release inhibiting activity. The apparently complex thiophene 126 can be obtained in a single step by 

2(l//)-thiones 4c were obtained by heating o-aminocarboxylates 1 with allyl isothiocyanate followed by treatment with sodium hydroxide (89CPB2122). 

2-isocyanothiophene-3-carboxylates, which were converted into ureas Sa by reaction with amines and then cyclized in DMF containing base to the products 3b [89EUP311321, 89MIP1 90JAP(K)225485]. 

Carbamate intermediate 7 derived from aminothiophenes 1 and ethyl chloroformate were converted into 3-substituted thieno[2,3-d]pyrimidine- 

5- dihydrothiophene-3-carboxylate 13. The latter was cyclized in base into 

Reaction of thiophenes 1 with alkyl or aryl isothiocyanates gave the corresponding thiourea derivatives 5b, which were cyclized in base and 

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Thieno[2,3-d]pyrimidine-6-catboxylic acid, 5-amino-synthesis, 4, 1019 Thienopyrimidines, 4, 1017-1022 Thieno[2,3-6]pyrimidines synthesis, 4, 748... 

Synthesis, chemistry, and biological properties of thienopyrimidines 96AHC(65)235, 96AHC(66)193. 

Several useful specialized reviews have appeared during the reporting period of this chapter. The chemistry of thienothiophenes <06AHC(90)125> and thienopyrimidines <06AHC(92)83> has been discussed in detail, whereas accounts of related interest highlight the field of thiaheterohelicenes <06OBC2518> as well as similar fused thiophene systems <06AG(E)8092>. 

In another example of a tandem displacement/annulation sequence, Neidlein and co-workers reported the reaction of ethyl 2-mercaptoacetate with chlorocyanopyrimidine 47 <00S255>. Thienopyrimidine 48 was produced in high yield through this one-pot procedure. 

Topological resonance energy studies of the three isomeric thienopyrimidines show that while all of the ring systems are aromatic, the thieno[3,4-, pyrimidine class of compounds is less aromatic by approximately 20%. Correspondingly this system is believed to be considerably more reactive than its isomers <1997CCA841>. 

Surprisingly, only one example of the synthesis of thieno[3,4-,7 pyrimidines has been described starting from a pyrimidine ring. In CHEC-II(1996) <1996CHEC-II(7)229>, substituted 5-cyanouracils, upon reaction with elemental sulfur, led to the formation of compounds in this class. Now the use of a 5-cyanopyrimidino-2-thione 419 under similar conditions (Equation 156) leads to the thienopyrimidine 420 <1997HC0151>. 

The Thorpe-Ziegler reaction has been employed in the synthesis of thieno[3,4-t4pyritnidines by providing the thiophene 421. Heating this compound under reflux in formic acid leads to a series of thienopyrimidines 422 (Equation 157) <2002IZK854>. 

Other imine-like structures such as 453, when allowed to react with hydrazines at room temperature, produce similar fused thienopyrimidines 454 (Equation 170) <2000JFC(105)83>. 

A heated solution of 458 in dry EtOH containing hydrazine gives 459b <1995JHC69>. The thienopyrimidine-acetonitriles 459c-f were prepared from 458 through an initial reaction with malononitrile to form a thioureido intermediate, followed by treatment with alkyl halides <2001JHC419>. 

If the amide moiety, in lieu of the carboalkoxy group, is used, then a monooxy derivative is obtained. Thus, the simple thiophene 465 is first acylated on the amine using chloroacetyl chloride. Subsequent treatment with piperidine affords intermediate 466. Cyclization in alkali produces the thienopyrimidine 467 (no yield given) (Scheme 38) <1998JME4021>. 

The cyanoacetamidine derivative 475 can be readily cyclized to the thienopyrimidines 476 (Equation 178) <1996T1011>. 

There is one example of annulation of a pyrimidine ring to a saturated thiophene ring. Ketone 477 is condensed with. J-ethylthiourea HBr at room temperature in water over 18 h. The product is the reduced thienopyrimidine 478 (Equation 179) <1994NN1 B5>. 

One example of the synthesis of a thienopyrimidine commencing with a pyrimidine precursor appeared in 2006. Thus, 4-chloro-5-cyano-6-aryl-2-methylthiopyrimidines react with either ethyl (or f-butyl) 2-mercaptoacetate to afford 5-amino-4-aryl-2-methylthiothieno[2,3-,y]pyrimidine-6-carboxylic acids <2006JMC3888>. 

An interesting synthesis of a condensed thienopyrazine resembling the preparation of a condensed thienopyrimidine (Scheme 103) is shown in Scheme 109 (80H(14)651, 81JHC739). Starting with 2-amino-3-cyanothiophene the 2-(l-pyrrolyl)-3-thienylcarboxylic acid (369) could be obtained in two steps, first by condensation with 2,5-dimethoxytetrahydrofuran... 

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