Chapter 6.2 (2005) Six-membered ring systems: diazines and benzo derivatives (2005)

353

Chapter 6.2 (2005) (2005)

Six-membered ring systems: systems" diazines and benzo derivatives (2005) Michael P. Groziak California State University East Bay, Bay, Hayward, CA, USA USA [email protected] michael.groziak @csueastbay.edu

6.2.1 INTRODUCTION INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, cinnoline, phthalazine, quinazoline, phenazine once again played a central role in phthalazine, quinazoline, quinoxaline, quinoxaline, and phenazine many investigations. investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, computational, spectroscopic, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. whenever

6.2.2 REVIEWS R E V I E W S AND AND GENERAL G E N E R A L STUDIES STUDIES 6.2.2

One review covered the functionalizations functionalizations and synthetic applications of pyridazin-3(2H)pyrimido[4,5-c]pyridazine-5,7(6H,8H)ones <05JHC353>, <05JHC353>, while another on the reactions of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones with nitrogen nucleophiles nucleophiles highlighted their ability to undergo nucleophilic nucleophilic <05JHC375>. The synthesis and heterocyclizations heterocyclizations of 3-alkynylsubstitution of hydrogen <05JHC375>. 4,5-c ]pyridazine-5,7 (6H,8H)-diones and their lumazine analogs was 6,8-dimethylpyrimido[ 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones compounds containing containing functionalized compounds reviewed <05JHC413>, <05JHC413>, as was the synthesis of functionalized pyridazine rings <05JHC361>. <05JHC361>. In the medicinal arena, pyrazolo[4,3-e]l,2,4-triazolo[1,5-c]pyrazolo[4,3-e]l,2,4-triazolo[I,5-c]pyrimidines as A 33 adenosine receptors ligands were covered in a review <05MIl319>, <05MI1319>, as were biologically active pyridazinoquinoxalines pyridazinoquinoxalines <05JHC387>. <05JHC387>. Finally, the history of the discovery of the diarylpyrimidine anti-HIV drug Rilpivirine {R278474, {R278474, 4-[[4-[[4-[(1£)-24-[[4-[[4-[(1E)-2cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile} } was covered <05JMCI90l>. <05JMC1901>. Homoheteraryl coupling mediated by Pd(OAc), Pd(OAc) 2 was used to form the aryl-aryl bonds in new diazines <05JHCI423>. <05JHC1423>. The pyrazine alkaloids botryllazine A and B from Botryllus compounds (la-c) (la-e) were prepared by a regioselective metalation/crossleachi and related compounds metalationlcrosscoupling approach starting from chloropyrazine chloropyrazine <05JOC2616>. <05JOC2616>. The pyridine ring of the

354

M.P. M.P. Groziak

pyridin-2-yldiazines 2-4 was used as an artha-directing ortho-directing group for metalation <05T9637>. The regioselectivity observed was similar to that found for 'H 2H incorporation (percentages ~ shown next to ring positions) after generating the anions with 3-4 eq. LTMP in THF at -78 T for 15 min. The 35Cl 35C1 NQR and IH 'H NMR relaxation times in a 1:2 hydrogen-bonded (chloranilic acid)-(l,3-diazine) acid)-(1,3-diazine) complex 5 were measured, giving an indication of partial Htransfer to the diazines <05BCJl241>. <05BCJ1241>. Aryl substituted diazines 6 and 7 were obtained by Bu3Sn-substituted Stille cross-coupling of Bu 3Sn-substituted precursors, themselves prepared via nucleophilic Bu3SnLi <05T2897>. The metalationffunctionalization substitution of halodiazines with Bu3SnLi metalation/functionalization of 2bromopyrazine, 2,4-dibromopyrimidine, and 3-bromo-6-phenylpyridazine was reported, together with an improved preparation of these halodiazine starting materials <05JHC509>. The ring metalation of cinnoline, quinazoline, and quinazolinone sulfoxides was found to be effective, but curiously that of a quinoxaline sulfoxide was not <05T8924>. 21%

b, RI=H, R2 = 4"HOC6H4CO; c, R1 = 4-HOCsH4CO, R2=H

HO

14

19%

N 81%

N

16%

100%

2

N

11 o

3

o

4

OH

Cl

N

(N)~ N ,

o

o-.,,,.

CI

5

N "

~~~/)

l

~N

N

N

66

"

~-..J v

7

~...J v

DERIVATIVES 6.2.3 PYRIDAZINES PYRIDAZINES AND AND BENZO BENZO DERIVATIVES

X-ray crystallography continued to expand our knowledge of the solid state structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethylpyridazines. The crystal structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethyl7,7a-dihydro-6aH-cyclopropa[d][1,2,3]triazolo[4,3-b]pyridazine <05AX(E)o2142>, 7,7a-dihydro-6aH-cYclopropa[d] [1,2,3]triazolo[4,3-b]pyridazine <05AX(E)02 I42>, 3,6-bis(4-methoxybenzyloxy)pyridazine <05AX(E)02486>, <05AX(E)o2486>, and ethyl 3-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-I ,6-dihydro-I-pyridazineacetate fluoromethyl)phenyl]- 1,6-dihydro1-pyridazineacetate <05AX(E)0 <05AX(E)o 1561> 1561> were determined. N I2 and Ag N I2 metallacycles with a para-cyclophane In the organometallics field, neutral Cu Cu4NI2 Ag4N~2 4 4 framework were prepared by treating Cu(I) and AgO) Ag(I) pyrazolates with pyridazine, and three of these were solved crystallographically <05CCI619>. <05CC1619>. Finally, [pyridazin-3(2H)-one-6-yl]ferrocenes 8 were prepared and characterized by a wide variety of methods, including IR, 1D and 2D NMR, and X-ray <05JOM802>. Q =-(CH2)n-, (E)-CH=CH-,

(N) 8

355

Six-membered ring ring systems: diazines and benzo derivatives (2005) (2005)

6.2.3.1 Syntheses

Condensation approaches to the synthesis of pyridazines were once again popular. A microwave-assisted cyclocondensation reaction involving -diketones and hydrazine in the presence of DDQ produced 3,4,6-trisubstituted pyridazines <05SL2743>. New tricyclic pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones were prepared from 2,3-dihydropyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones thiopyrano[2,3-b]pyridin-4(4H)-ones via condensation with glyoxylic acid followed by thiopyrano[2,3-b]pyridin-4(4H)-ones <05AP126>. hydrazines. Their binding affinity at the benzodiazepine receptor was studied <05API26>. Hydrazonoyl halides were used to access many heterocycles, including pyrazolo[3,4-d]pyridazines <05JHC527, 05SC249>, pyrrolo[l,2-b]pyridazines pyrrolo[1,2-b]pyridazines were among the many heterocycles accessed using -(cyanomethyl)benzylidene-malononitrile as a starting material <05SC2251>, and methyl 3,3,3-trifluoropyruvate was used in a two-step synthesis of 4trifluoromethyl-(2H)-pyridazin-3-ones <05SLl907>. <05SL1907>. Pyridazino[3,4-a]carbazoles Pyridazino[3,4-a]carbazoles 9 were trifluoromethyl-(2H)-pyridazin-3-ones obtained by the reaction of substituted 2-benzylidene-I,2,3,4-tetrahydrocarbazol-I-ones 2-benzylidene-l,2,3,4-tetrahydrocarbazol-l-ones and thiocarbohydrazide or thiosemicarbazide <05CCC223>.

N H

(H2NNH)2C=S KOH, KOH, EtOH EtOH-

0 o

9 N'N~

pyridazino[4,5-b]A new tetraazaheterocyclic system was accessed when substituted pyridazino[4,5-b][l,8]naphthyridin-6(7H)-ones [1,8]naphthyridin-6(7H)-ones like 10 were prepared from 1,8-naphthyridine-3-carboxylates <05H(65)329>. A regioselective synthesis of pyridazines 11 was developed from the cycloaddition of phosphorylated I,2-diaza-1 ,3-butadienes with olefins. Cycloadduct 1,2-diaza-l,3-butadienes formation occurs via an endo transition state with styrene, cyclopentadiene, and dihydrofuran, but via an exo one with norbornadiene <05EJOI142>. <05EJO1142>. The regioselective cycloaddition of tetrazines and alkynylboronic esters gave highly substituted pyridazine boronic esters 12 <05AG(I)3889>. Pyridazine derivatives 13a-c 13a-e were formed via Diels-Alder reaction of di(benzoyl)acetylene and 1,1 ,2,2-tetra(cyano)ethylene <05CJC57>, and 1,1,2,2-tetra(cyano)ethylene pyridazino[4',3'A,5]thieno[3,2-d]-1,2,3-triazines were prepared along a heterocyclization pyridazino[4',3':4,5]thieno[3,2-d]-l,2,3-triazines route <05PS591>.

Ph Ph

Ph Ph

c~ NC~"': "': C02 Et ..-:

..-:

EtO

R1

R1

~

NH

1..-:..-: N

N

N

..-: N

Me

10 10

Br Br

4

C

CO2Et / ~+N'~N ~

NC:CcX",: NH

Br Br - - EtO

N~ N~/---~.N

EtO

N

O 0

R1 " N

B(OR)2 R1 12

Me O=PPh2

PhOC PhOC

CO2Et = ~N'N . ~ ""0 _ "2 O=lSPh2 11

~ == +

COPh N=N N=N COPh ~- A Ar---~\ + r y /)-AAr r Ar-C=N-N=C-Ar PhMe PhMe Ar-C=N-N=C-Ar H H A PhOC COPh COPh PhOC H H '" 13a-c, R = Me, OMe, CI

Some unusual pyridazine syntheses were reported. A dye-sensitized photooxygenation reaction of ribofuranosyl furans gave a new entry to pyridazine C-nucleosides 14

356

M.P. Groziak M.P. Groziak

<05JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion NH,NH 22 reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH easily produced 3-(2-oxo2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c ]pyridazine-5,7-diones 3-(2-oxo-2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenylphosphonium salts <05HAC56>. Me Me 1.102

R

O R(f

~

O

";OR Me

ii

2. Et2S

N

-9 RO

3. NH2NH2~

RO"

;OR Me

CO2Me

14 CO2Me N.~N

?N

A

0

C02Me

~ o0 / ~ h-

If \

o

+

~

o

o0 / / h-

_

If \

CN Ph3p ~ [~CN

o

N'N N-N--~ 0 H H 16

I

~

CN CN

If \

o

+ +

N. N-r 0 N'N

e)=! / ~ J 17(39%) 17 (39%)

16

15

M Me

N..., I N.'NN~--~-.O.~',.Me 0 Me 18a, X X == NH NH (13%) (13%) 18a, b, X=O X = O (19%) (19%) b,

6.2.3.2 Reactions

Removal of the MOM group from 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones 19 with HCI HC1 gave, with certain alkynyl substituents, 5-(2-chloroalkenyl)pyridazin-3(2H)-ones like 20a-d <05T4785>. 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione was transformed into thieno[2,3-c]pyridazines and pyrimido[4',5':4,5]thieno[2,3-c]pyridazines pyrimido[4',5':4,5]thieno[2,3-c]pyridazines <05PS413>. thieno[2,3-c]pyridazines Alkyl/aryl pyridinazinyl ethers were prepared from the corresponding halopyridazinones <05JHC639>.

O o

O

M~

.c, N

= Ph

R

H~~ N ~

c, 91

N~R Ph Ph

20a, R = H, 20a, b, b, R R =CH = CH2OH, 2 0H, c, R R == CH(OH)Me, CH(OH)Me, c, d, d, R R == CH CH2CI 2CI

19

6.2.3.3 Applications Applications

Pyridazines continued to playa play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-

Six-membered Six-membered ring systems: diazines and benzo derivatives (2005)

357 3S7

pyridazin-3-one and related compounds were prepared as aldose reductase inhibitors . Pyrazolo[l',S':1,6]pyrimido[4,S-d]pyridazin-4(3H)-ones <05JMC6326>. Pyrazolo[l',5': 1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones were examined as PDEs5 inhibitors , <05BMCL2381>, pyrazolo[3,4-c]pyridazines as cyclin-dependent kinase (CDK2) inhibitors , <05JMC6843>, pyrazolo[3,4-d]pyridazines as antibacterials and <05EJM401>, and polyfunctionally substituted pyridazines and their fused antifungals , <05HEC89> and certain pyrrolopyridazine cycloadducts <05H(65)1871> were all derivatives prepared as antimicrobials. Some pyridazines were developed as inhibitors of p38 MAP kinase , <05BMCL2409>, others as acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors , <05JHC395>, and still others as GABA-a GABA-t~ receptor ligands . 05JMC7089>. Finally, certain 3(2H)pyridazinones were prepared as fungicides and herbicides . <05JHC427>.

6.2.4 PYRIMIDINES DERIVATIVES PYRIMIDINES AND AND BENZO BENZO DERIVATIVES

We have learned more about the physicochemical properties of pyrimidines through some IS substituted pyrimidines detailed investigations. For example, the electronic structures of 15 like 21a-d were studied by computational methods , <05EJO522>, and mono- and multinuclear Mn(H), Mn(II), Co(lI), Co(II), and Cu(H) Cu(II) complexes of bisazo-dianils containing a pyrimidine moiety were synthesized and examined by a variety of spectroscopic methods (IR, electronic <05JCC683>. The intramolecular stacked conformation of pyrazolo[3,4-d]absorption, ESR) . pyrimidines tethered by a trimethylene linker was documented in solution by 'H NMR and in the solid state by X-ray , <05JMS179>, and complexes between the tautomers of the RNA pyrimidine bases and L-leucine were characterized by ab initio computational methods <05TC31>. Tautomerism in N-methyl regioisomers of uracil, S-fluorouracil, 5-fluorouracil, and thymine . <05TC201>. 4,S,6,7-Tetrahydro-2-methyl-2,4-diphenyl4,5,6,7-Tetrahydro-2-methyl-2,4-diphenylwas also examined this way . 4,7a,12b-triazadibenzo[e,g]azulene-1,3,8-triones 4,7a,12b-triazadibenzo[e,g]azulene-l,3,8-triones 22 were prepared as members of a Aspergillus alkaloids pyrimidine-annulated pyrrolobenzodiazepine ring system related to Aspergillus <05EJO1781>, and their prototropic tautomerism was studied by 'H NMR . <05H(65)625>. , The 4,9-methanoundecafulvene-related [S-( 4,9-methanocycloundeca-2',4',6',8',1 O'-pentaenyl[5-(4,9-methanocycloundeca-2',4',6',8',10'-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones] 23 were prepared, and their physical properties were idene)pyrimidine-2,4,6(l,3,5H)-triones] examined by UV-Vis, cyclic voltammetry, and NMR. The rotational barrier about the 12.55 kcalomol-', <05T7384>. In a kcalomor', by a VT-NMR study . exocyclic C=C was determined to be 12.SS 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H),3,SH)similar fashion, a set of S-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1 triones 24 was prepared by reaction of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid followed by chloranil-mediated oxidation, and these too were extensively characterized by NMR, UV-Vis, cyclic voltammetry, MO computations, and X-ray crystallography <05T8616>. . R R33

R4~R2

N.. N

NyN

R11 R 21a, 21a, R R11 == H, H, C=CH, C-CH, NH NH2, NMe2; 2, NMe2; b, R2 =H, Me, 2= Me, CI, CI, OH, OMe, OMe, NMe2; NMe2; c, r R33 == H, H, C",CH, C-CH, Me, Me, iPr; iPr; OMe d, R44 = H, Me, CI, OMe

O

c(-p

O~-Phh OMe~~ph'O Me

Ph 0

22 22

358

M.P. Groziak M.P. Groziak

ct:r I

-....o:

~

....-::

O

00

N

o0

R R

0,H 0

H

O~r/)=00 + +

ct:::r<; "'::

Ac~O, 120 ~ lh O O

I

-....0:

~....-::

o0

0

,~,

NR R N

R

23

O

N, R

+

'~--' ~-~' ' ~ "'~~

,

+) ~ ~

H

N

,~-~

)=0 -- [ :,

N N,

-~ ~ )=0o -oo

ctJ{0 ,H

H

N

>

-)=0 /

N /)--N, , O 0 R

R R

N

- ' )=0 )~=O N, R

24a, X = O 0

b, X= X = NMe NMe b,

There was again a large number of X-ray crystallographic determinations of pyrimidine1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one (25) <05AX(E)0594>, <05AX(E)o594>, 2,3based structures. 1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline <05AX(E)02746>, bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline <05AX(E)o2746>, 2,4,6-tris(pyrimidin-2-yl2,4,6-tris(pyrimidin-2-ylsulfanyl)-l,3,5-triazine <05AX(E)o1133>, 4-(2-naphthyl)pyrimidine <05AX(E)02256>, <05AX(E)o2256>, and sulfanyl)I,3,5-triazine <05AX(E)0 II33>, 4-(2-naphthyl)pyrimidine 2-chloro-4-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine 1821> were among the 2-chloro-4-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine <05AX(E)0 <05AX(E)o1821> simpler ones. Others were 3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno[3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one [3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one <05AX(E)02663>, <05AX(E)o2663>, 10"-(4-chlorobenzylidene)10"-(4-chlorobenzylidene)5"-(4-chlorophenyl)-4'-(2,4-dichlorophenyl)5 "-( 4-c hl orophe n y 1)-4'-(2,4-di c hl orophe n y 1)- 1I'-methyl-2,3,2",3",7",8",9", '-meth y 1-2,3,2 ",3 ",7 ", 8 ",9", 10"-octahydro10"-oc tah y dro- IH, 1H, 5"H,6"Hindole-3-spiro-2'-pyrrolidine-3'-spiro-2"-cyclohepteno[ ,2-a ]pyrimi5"H, 6"H-indole3- spiro- 2'-pyrrolidine- 3'- spiro- 2"-cyclohepteno [ 1,2-d]thiazolo[3 1,2-d] thiazolo [3,2-a] pyrimidine-2,3"-dione <05AX(E)0 1411>, 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]<05AX(E)ol411>, 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]pyrimidin-4(3H)-one <05AX(E)02649>, pyrimidin-4(3H)-one <05AX(E)o2649>, and 10"-(4-methoxybenzylidene)-5",4'-bis(410"-(4-methoxybenzylidene)-5",4'-bis(4methoxyphenyl)-1l'-methyl-2,3,2",3",7",8",9",l '-methyl-2,3,2",3",7",8",9", 1O"-octahydromethoxyphenyl)0"-octahydro- IH,5"H 1H,5"H and 6"H-indole-3-spiro6"H-indole-3-spiro2'-pyrrolidine-3'-spiro-2"-cyclohepteno[ 2'-pyrrolidine- 3'- spiro- 2"-cyclohepteno [ 1,2-d]thiazolo[3,2-a]pyrimidine-2,3"-dione 1,2-d] thiazolo [3,2- a] pyrimidine- 2,3"- dione <05AX(E)02086>. ,2,3]triazolo[5', 1':6,1]<05AX(E)o2086>. Still others were 3-methyl-6,8-di(2-pyridyl)-[1 3-methyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',l':6,1]I,3,4,4a,5,6,7,8a-octahydro- 2Hpyrido[2,3-d]pyrimidine <05ARK71 >, 4-(o-methoxypheny1)pyrido[2,3-d]pyrimidine 4-(o-methoxyphenyl)- 1,3,4,4a,5,6,7,8a-octahydro-2Hpyrano[2,3-d]pyrimidine-2-thione 1228>, 4-(E)2-[3-(3- [(E)- 2-(4-cyanopheny1)pyrano[2,3-d]pyrimidine-2-thione <05AX(E)0 <05AX(E)o1228>, 4-(E)-2-[3-(3-[(E)-2-(4-cyanophenyl)I-diazenyl]hexahydro-l-pyrimidinylmethyl)hexahydro-I-pyrimidinyl]-I-diazenylbenzonitrile 1-diazenyl]hexahydro- 1-pyrimidinylmethyl)hexahydro- 1-pyrimidinyl]- 1-diazenylbenzonitrile <05MI297>, ,3,7-triphenyl-2,3,5,6,7,7a-hexahydro-lH-pyrrolo<05MI297>, 4,7-bis(4-methoxyphenyl)-1 4,7-bis(4-methoxyphenyl)- 1,3,7-triphenyl-2,3,5,6,7,7a-hexahydro1H-pyrrolo[2,3-d]pyrimidine-2,5,6-trione [2,3-d]pyrimidine-2,5,6-trione (26) <05AX(E)0635>, <05AX(E)o635>, and the related 4-p-tolylI,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one (27) <05AX(E)0 I049>. 1,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one <05AX(E)o 1049>.

/~_N

.X-'-N--

N\ ~ " ' S ~ " 25 25

O

'S"

~176

O~O ?" OMe Ph, I

iX

N

~:::o-..

INN MeO/tt-..~ ph~ N-..~Nph MeO ~ Ph" I( 'Ph

o0

26

~

Oy~ O.~N HN

HNo~ o

:::0-..

Me

Me

I

27

27

,5-a]pyrimidine-3In addition to these, 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile <05AX(E)02506>, <05AX(E)o2506>, 7"-benzyl-9"-benzylidene-4'-[4-(dimethylamino)phenyl]-1 7"-benzyl-9"-benzylidene-4'-[4-(dimethylamino)phenyl]-l'-'methyl-5"-phenyl-2",3",6",7",8",9"-hexahydro-lH-indole-3(2H)-spiro-2'-pyrrolidine-3'-spiromethyl- 5 "-phen yl- 2 ",3 ",6", 7", 8 ",9"-he xah y dro- 1H- indo 1e- 3 (2H)- spiro- 2 '-p yrroli dine- 3 '- spiro2"-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2"-dione I830>, ethyl 3-cyano-72"-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2"-dione <05AX(E)0 <05AX(E)o1830>, methylpyrazolo[I,5-a]pyrimidine-6-carboxylate methylpyrazolo[ 1,5-a]pyrimidine-6-carboxylate <05AX(E)01459>, <05AX(E)o 1459>, methyl 2-[2-(5,7,2,4-triazolo[ 11,5-a]pyrimidin-2-ylsulfanylmethyl)phenyl]-3-methoxyacrylate ,5-a]pyrimidin-2-ylsulfanylmethyI)pheny1]-3-methoxyacrylate dimethy1-1 dimethyl- 1,2,4-triazolo[ 3-[(3-{ (E)-2-[4-(methoxycarbonyl)phenyl]-I<05AX(E)01992>, <05AX(E)o1992>, and methyl 4-«E)-2-{ 4-((E)-2-{3-[(3-{(E)-2-[4-(methoxycarbonyl)phenyl]-l-

359

Six-membered ring ring systems: systems: diazines diazines and benzo derivatives derivatives (2005) (2005)

diazenyl }-5,5-dimethylhexahydro-I-pyrimidinyl)methyl]-5,5-dimethylhexahydro-I-py}-5,5-dimethylhexahydro- 1-pyrimidinyl)methyl]-5,5-dimethylhexahydro- 1-pyrimidinyl }-l-diazenyl)benzoate }-1-diazenyl)benzoate <05MI307> were also analyzed by X-ray crystallography. The isostructural compounds 5-methyl-2-(4-methylphenyl)- (28), 2-(4-chlorophenyl)-5methyl-, and 2-(4-bromophenyl)-5-methyl-7,S-dihydro-6H2-(4-bromophenyl)-5-methyl-7,8-dihydro-6H- cyclopenta[g]pyrazolo[1,5-a]pyrimidines displayed chains linked by a single CH...1t(arene) CHooo~(arene) H bond, but the 5-methyl-2-ptolyl- derivative was found linked by a single CH"'NH CHoo~ bond into chains, which themselves were linked into sheets by a 1t-1t ~-~ stacking interaction <05AX(C)o452>. 7-Hydroxy-3methoxy-4-methyl-5,6,7,S-tetrahydropyrido[1,2-c]pyrimidin-l(9H)-one 29 was shown to methoxy-4-methyl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidin-l(9H)-one have a planar pyrimidine ring involved in three CH...1t CHo~ interactions interactions <05AX(C)o15S>. <05AX(C)o158>. 5-(4Methoxybenzoyl)-4-(4-methoxyphenyl)-I-( 1-(4-methoxyphenyl)-ethylideneamino) Methoxybenzoyl)-4-(4-methoxyphenyl)1-(1-(4-methoxyphenyl)-ethylideneamino) <05AX(E)o622> and 5-(4-methoxybenzoyl)-1-(4-methoxybenzylideneamino)-4-(45-(4-methoxybenzoyl)- 1-(4-methoxybenzylideneamino)-4-(4methoxyphenyl)- <05AX(E)o637> pyrimidin-2(1H)-one (30a and b, respectively) were each solved crystallographically. OMe OMe

o Me

- .;: N,,,: Me --Q-(X . _ ~ . ~~

Me

-~

'

t5N"Me ~ ~ W~N //

}--N

it{

HO HO~ •• ~

MeO MeO

Me

28 28

0 o

OMe }-OMe

-~_ -N

~--~_OM e

~---{N-~~OMe

29 29

OR~ R

'No

R=H H 30a, R = Me; b, R

In the organometallic field, a complicated nonanuclear Ni(II) complex containing the 7,S7,8dihydro-l,2,4-triazolo[4,3-a]pyrimidin-7-one anion 31 as a ligand was characterized by Xdihydro-1,2,4-triazolo[4,3-a]pyrimidin-7-one ray <05EJI2779>, <05EJl2779>, as were bis(pyrimidine-2-thiolato)bis(triphenylphosphine)ruthenium(II) bis(pyrimidine-2-thiolato)bis(tripheny1phosphine)ruthenium(II) 32 cis, cis, trans:N, N; P,P; S,S-[bis(triphenylphosphine)] [bis(pyrimidine-2<05AX(E)m714>, trans:N,N;P,P;S,S-[bis(triphenylphosphine)][bis(pyrimidine-2<05JCC429>, and catena-poly[[[(acetonitrilethiolato)]ruthenium(II) catena-poly[[[(acetonitrile- N)silver(I)]- 2N1:N 11 tetrafluoroborate] 165S>. In bis(pyrimidin-2-ylsulfanyl)methanebis(pyrimidin-2-ylsulfanyl)methane-2NI:N1] tetrafluoroborate] 33 <05AX(E)m <05AX(E)m1658>. the biological-medicinal field, pyrimidines solved crystallographically included 3-bromo-1(2-deoxy- -D-erythro-pentofuranosyl)-lH-pyrazolo[3,4-d]pyrimidine-4,6-diamine -D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 34, a DNA stabilizing nucleoside <05AX(C)o67>, the herbicide isopropyl 2-(5,7-dimethyl-l,2,4duplex stabilizing isopropyI2-(5,7-dimethyl-l,2,4triazolo[ 1,5-a ]pyrimidin-2-yloxy)benzoate <05AX(E)o2079>, and 2-methyl-7-oxo-5,6,7,Striazolo[1,5-a]pyrimidin-2-yloxy)benzoate 2-methyl-7-oxo-5,6,7,8tetrahydropyrimido-[4,5-d]pyrimidin-3-ium chloride 35, from the thermal decomposition of the HCI HC1 salt of nimustine {1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3{ 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3nitrosourea, 36}, an antitumor DNA cross-linker for treating malignant glioma <05AX(E)o544>.

_ 0"-%./N"',/~N,

O~yN'N ~N-.5

31 31

Ph3P\/PPh3 3 P\!Ph 3 Ph

N:) AI

S~'-" Ru····'''''8 .........S 8 - Ru

N~CN 32

N

C

y

/ON

-

(8 8

N",+ Ag

t

CH 3CN

33 33

nBF nBF44-

n

360

M.P. Groziak

Br\

Cl CI

'NH2 I

"---( N:)-; Me_--~N.__y .k /;) ~ Me-{ H, + NH2

a-- -N-~- NH2

Me...~N I.~ N...~---.0 H

0 H 34

CII- N C

35 35

)

0

< ,9 < N-N N-N'

HN-{ H'N-fk00

36, 36, nimustine nimustine

6.2.4.1 6.2.4.1 Syntheses

Cyclization routes to pyrimidines continued to be a rather popular approach for preparing H-I ,2,3-triazolo[4,5-d]pyrimidin-7-ones like 37 were prethese heterocycles. 3,6-Dihydro-7 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones pared via cyclization of guanidine intermediates <05CLl022>, <05CL1022>, and 3-substituted 4-oxo3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic 3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid esters were prepared along a heterocyclization route <05PS95>. A new route to pyrido[4,3-d]pyrimidines like 39 relied upon an intramolecular cyclization of 4-amino-5-(tert-butyliminomethyl)-2(methylthio)-6-(phenylethynyl)pyrimidine 38 <05CHE268>, <05CHE268>, and a regioselective, radical cyclization-based synthesis of pyrimidine-annulated spiro-heterocyclic compounds was photo-induced oxidative cyclization reaction, areno[b]reported <05SCI96l>. <05SC1961>. Using a photo-induced perchIorates and tetrafluoroborates 41 were pyrimido[5,4-e ]pyran-2,4(1 ,3H)-dionylium perchlorates pyrimido[5,4-e]pyran-2,4(1,3H)-dionylium prepared from alkylidenated barbituric acids 40, and were characterized by NMR, UV-Vis, 19>. and X-ray <05T49 <05T4919>. o

"i"NN~~N/~j Ph

H2:~N

N PI~

>-=N MeS

37

NHEt

0 Me'N ~ ~ "

r."

<~)

_

CHCl3

38

AC20 ,II O "J 60%HCLO4 M e . N ~ . 9 I'~, hv,

-

r .

HBF O 42% ----4, ,', or____L._ O"~N "O ,, aerootc,r.t. Me 40 "-- I

~j

H2N

Ag.o

N

,

Me

F--N~ Ph

~-=N MeS 39 r."

"O" Y

I'~,

,',

, 41 ~'-~.-'~ |!

CIO 4(BF4)

2-Amino-5-methyl-7 H-I ,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones in a sequence beginning 2-Amino-5-methyl-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones <05JHCl105>. A with the condensation of 2-bromo-5-amino-I,3,4-thiadiazole 2-bromo-5-amino-l,3,4-thiadiazole and diketene <05JHC1105>. three-component condensation route to 5-aryl-5,8-dihydroazolo[ I ,5-a]pyrimidine-75-aryl-5,8-dihydroazolo[1,5-a]pyrimidine-7carboxylic acids was developed, and the solvent effect on regioisomer production was studied <05S2597>. A condensation approach to pyrrolylthieno[2,3-d]pyrimidines and thieno[2,3-d][4,5-d]dipyrimidines was described <05PS633>, as was the preparation of pyrimidines by condensation of N-substituted lactams and Viehe's salt (dichloromethylenedimethylammonium chloride) <05TLlI77>. <05TL1177>. Carbonylative alkynylation followed by cyclocondensation constituted a new four-component pyrimidine synthesis of 42 (variolin B) and 43 (variolin D), tricyclics related to the meridianins 44 <05AG(I)695l>, <05AG(I)6951>, and condensation of

diazines and benzo derivatives (2005) Six-membered ring ring systems: diazines

361

6-[(dimethylamino)methylene]aminouracil 6-[(dimethylamino)methylene]aminouracil with aryl isocyanates and isothiocyanates gave Me,NH from the initial adduct <05TL1433>. The pyrimido[4,5-d]pyrimidines upon loss of Me2NH diketo 2-(2-oxocyclohexylcarbonyl)benzoic acid ester was condensed with NH2NH NH,NH,2 to give <05PS 163>. an indazole, which was subsequently transformed into a fused pyrimidine <05PSI63>. H2N"

N OH

.CO2Me

H2N" N N/~

~

N

~

?=N

R 4 R4

H2N H 2N

42, variolin variolin B 42,

variolin D 43, variolin

meridianins 44, meridianins R R1-R H/OH/Br 1-R 44 = H/OH/Br

The use of microwave acceleration in pyrimidine syntheses continued to grow. For example, a microwave assisted synthesis of pyrimidines from ketones and formamide in the presence of HMDS was reported <05TL7889>, as was one which generated pyrazolo[l,5-a]pyrazolo[1,5-a]pyrimidines from enaminones and 5-amino-1H-pyrazoles 5-amino-lH-pyrazoles <05JHC925>. A microwavet~,~-unsaturated esters generated carbocyclic assisted Michael addition of pyrimidines to a,~-unsaturated nucleoside analogs <05S419>, and a microwave-assisted one-pot synthesis of 2-amino-6,7disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one from 2,6-diaminopyrimidin-4-one, aldehydes, and acyclic 1,3-dicarbonyl compounds was found to proceed in very good yields in the absence of a catalyst <05ARK76>. Microwaves accelerated the synthesis of imidazo- and pyrimidopyrido[4',3':4,5]thieno[2,3-d]pyrimidines from a thienopyridinecarboxylate and pyridothienopyrimidine <05ZN(B)221>, and an improvement in the microwave-assisted synthesis of 1,2,4-triazolo[4,5-a]pyrimidin-5-ones 1,2,4-triazolo[4,5-a]pyrimidin-5-ones was noted when a paste-like medium was employed <05S2833>. The use of microwave acceleration in combination with solid-phase approaches was used as well. Tetrahydropyrimidinones were obtained via microwave assisted, solid-phase intramolecular cyclization <05TL5747>, and a microwave-assisted solid support synthesis of dihydropyrido[2,3-d]pyrimidines was also described <05TL1345>. Resin-bound amidines were condensed with -dicarbonyl <05JCO517>. compounds to give 2-alkyl/aryl-pyrimidines and related 3H-pyrimidin-4-ones <05JC0517>. Solid-phase approaches to pyrimidines were used both to generate libraries of compounds and simply for convenience. A combinatorial library of 3,5,6-trisubstituted pyrrolo[3,2-d]pyrimidines (9-deazapurines) was generated by a solid-phase synthetic approach <05JC0977>, <05JCO977>, and the solid phase preparation of pyrido[2,3-d]pyrimidin-7-ones was described <05TL8749>. Solid-phase approaches to trisubstituted IH-pyrido[2,3-d]pyrimidin1H-pyrido[2,3-d]pyrimidin<05JCO589>, 4-ones <05JCO96>, <05JC096>, 3-substituted pyrrolo[3,2-d]pyrimidine-6-carboxylates <05JC0589>, and 3H-imidazo[1 ,2-a ]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[ I ,2-a]pyrimidin-23H-imidazo[1,2-a]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidin-2ones, and 3,4,6,7,8,9-hexahydro-1H-pyrimido[ 1,2-a][ 1,3]diazepin-2-ones were developed 3,4,6,7,8,9-hexahydro-lH-pyrimido[1,2-a][1,3]diazepin-2-ones <05TL5289>. A solid-phase synthesis of N-(pyrimidin-2-yl)amino acid amides relied upon <05ARK172>, and a traceless nucleophilic aromatic substitution using 2-fluoropyrimidine <05ARKl72>, solid-phase sulfone linker approach was used to prepare 3,4-dihydropyrimidin-2-ones <05JC0721>. <05JCO721>. Solid-phase approaches were not solely used to generate libraries, however. A pyrazolo[1,5-a]pyrimidines were prepared via large number of 7-trifluoromethyl-substituted pyrazolo[I,5-a]pyrimidines parallel solution-phase synthesis <05JC0236>. <05JCO236>.

362

M.P. Groziak M.P. Groziak

Efficiency in pyrimidine synthesis was sometimes achieved by the use of metal-catalyzed reactions. 4-Substituted and bicyclic pyrimidines were prepared via a Pd-catalyzed reaction of -Me and -methylene ketones with formamide. Among the products obtained, S,65,6dihydrobenzo[h]quinazoline and 4-naphth-2-ylpyrimidine were characterized by X-ray dihydrobenzo[h]quinazoline methods . <05H(65)2593>. 6-[(Phosphonomethoxy)alkynyl- and alkyl]pyrimidines 45 and 46 Pd-C/CuUPPh 3-catalyzed were prepared via Sonogashira coupling , <05CCC247>, and the Pd-C/CuI/PPh3-catalyzed Sonogashira coupling of 3-iodopyrazolo[I,S-a]pyrimidines 3-iodopyrazolo[1,5-a]pyrimidines with propargylic and homopropargylic reagents followed by catalytic hydrogenation gave -functionalized 3-(3I,S-a ]pyrimidines . OH (NH2)

OH (NH2)

3..

N,~N~ H2N

-q 45

n = 1,2

H2N 46 . ~ O v

POaH2

OvPO3H 2

Often, simply conducting several steps in a one-pot fashion or using more than two components in a reaction was found to generate pyrimidines efficiently. A one-pot preparation of pyrimidines relied on the condensation of a,~-unsaturated ~,~-unsaturated imines and amidines or guanidines , <05TL1663>, and another of 2-arylimidazo[I,2-a]pyrimidines 2-arylimidazo[1,2-a]pyrimidines from ketones, [hydroxy(tosyloxy)iodo]benzene, and 2-aminopyrimidine was found to be accelerated by the use of an ionic liquid as solvent . <05SC1741>. A one-pot synthesis of substituted 1,2,3,4-tetrahydropyrimidines 1,2,3,4-tetrahydropyrimidines from N,S-acetals, formaldehyde, and diamines was <05JHC975>, as was a one-pot, three-component, KF/alumina-catalyzed synthesis reported , of pyrido[2,3-djpyrimidines 1921>. A one-step synthesis of 2-amino-7-chlorothiazolopyrido[2,3-d]pyrimidines . 2-amino-7-chlorothiazolo[S,4-djpyrimidines [5,4-d]pyrimidines 48 from 4,6-dichloro-S-aminopyrimidine 4,6-dichloro-5-aminopyrimidine (47) gave a ready entry to 2,7diaminothiazolo[S,4-djpyrimidines 49 , and -dicarbonyl compounds were diaminothiazolo[5,4-d]pyrimidines <05JOC10194>, found to add regioselectively to 2-ethoxymethyleneaminonitriles 2-ethoxymethyleneaminonitfiles in a one-pot, [S+l]-annula[5+ 1]-annulation synthesis of quinazolines and fused pyrimidines . A one-pot synthesis of 3,4dihydropyrimidin-2-(lH)-ones dihydropyfimidin-2-(1H)-ones developed using Bi(lI!) Bi(III) nitrate as catalyst represents an improvement over the classical Biginelli reaction conditions . <05ARK74>. A three-component, base-mediated reaction of 2-alkyl-4,S-dichloropyridazin-3(2H)-ones 2-alkyl-4,5-dichloropyridazin-3(2H)-ones 50 with p-cyanophenol and 2-mercaptopyrimidine (51) gave 2,4,S-trisubstituted-pyridazin-3(2H)-ones 2,4,5-tfisubstituted-pyfidazin-3(2H)-ones like 52a-d, together with S-cyano-S-(pyrimidin-2-yl)-2,7-dialkyl-SH-dipyridazino[ 4,S-b:4,S-e]5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyfidazino[4,5-b:4,5-e]4H-thiopyran-I,6-diones 4H-thiopyran-l,6-diones . <05T5389>. Finally, tri- and tetrasubstituted pyrimidines like 53 were prepared by a four-component coupling reaction involving a silane, two aryl nitriles, nitfiles, and an acetal . <05OL4705>. CI

CI

N~NH2 II

/.

"N

47 47

CI CI

base

\ N//~ S 48

NHR2

H+ or base MW, 150 ~

S 49

363

Six-membered ring systems: systems: diazines diazines and and benzo benzo derivatives derivatives (2005) Six-membered

CI

OH

C C ' ~ Nl .n N O N,N

°

¢

+ +

+

R so 50

SH

Yy

N~N

base

V

CH 3CN CH3CN

° N'~

O

I

51 Sl

CN CN

52a, 52a, X X= =CI, CI, Y Y= =SAr; SAr; b, b, X X= =SAr, SAr, Y Y= =OAr; OAr; rc, XX ==OAr, OAr, Y Y= =SAr; SAr; d, d, X X= =YY ==SAr SAr

base= Xx ~ Nn .N

+ L~ N + N

R

R)C~' I 1 OR4

R1CH2SiMe33 ++ BuLi SuLi R1CH2SiMe

R2CN R2CN

R h RI'"

R3CN R3CN

R2

NH 2

~2

I

1l

N

.

(R 4O)4C (R40)4C

R3

RI~N

R2

N

53 R3

thieno[2,3-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones The preparation of 2-substituted thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones isomerization of the corresponding [4,3-c] isomers was reported <05H(65)2683>, and was by isomerization pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, pyrido[3",2":4',5']thieno[3',2':4,5]pyrimidopyrido[3",2":4',5']thieno[3',2':4,5]pyrimidothat of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, [1,6-a]benzimidazoles, polyheterocyc1es <05JHC1069>. 2,32,3[1,6-a]benzimidazoles, and related fused polyheterocycles 54a-c were generated by a sterically stericaUy induced Dihydroimidazo[I,2-a]pyrimidin-5(lH)-ones 54a-e Dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones 1,2-a]pyrimidin- 5(3H)-ones multihetero-retro-ene fragmentation of the 8-alkoxyimidazo[ multihetero-retro-ene 8-alkoxyimidazo[1,2-a]pyrimidin-5(3H)-ones 55a-c initially formed by reacting 2-alkoxyiminoimidazolidines 2-alkoxyiminoimidazolidines and acetylenedicarboxylates 55a-e acetylenedicarboxylates <05T5303>. <05T5303>. 3-Formyl- and 3-cyano coumarin N-functionalized amidines amidines were used as starting materials for the preparation of[1 of [1]benzopyrano[4,3-bj-[4,3-d]pyrimidin-5-ones ]benzopyrano[4,3-b]- and and-[4,3-d]pyrimidin-5-ones <05T4957>, and 6-hydroxy-4H-4-oxo[lj-benzopyran-3-carboxaldehyde like 56 <05T4957>, 6-hydroxy-4H-4-oxo[1]-benzopyran-3-carboxaldehyde was shown to be a versatile starting starting material for the preparation of pyrimidines like 58a,b when condensed with barbituric or thiobarbituric acid (57a or 57b, respectively) <05HAC20>. H H N [~NN~=N'OCH2R' R2 =~ N NCO2R3 /~~-R .- 3 O H

C>=N

R2 or or

~NN~~_R2OCH2R,

N~R2

°O

O

54a-c, 54a-r R R1 1 = = H; R22 = = Me, Me, Ph, Ph, C0 CO2R 2R

55a, R 1 =

o CH3CO2- NH4+

N ~N

H;

r R 1 = H, R2 = Me

o R1

R 2 =

b, R1 = Ph, R2 = H;

PhMe, A PhMe,L'.

N

O

=- R1

0~~

56

o

o )NH

O~N~X o x H H

57a,b, X = = O,S O,S 57a,b,

o

o

° ° [ I x ° ° NAX H

H O W X " , , : NH [

~

H

58a,b, X =a,s = O,S 58a,b,

A tandem aza-Wittiglheterocumulene-mediated aza-Wittig/heterocumulene-mediated annulation route was developed for the ,2,4-triazolo[11,5-a]pyrimidin,5-ajpyrimidinefficient production of 6,7,8,9-tetrahydro-benzothieno[2,3-d]-1 6,7,8,9-tetrahydro-benzothieno[2,3-d]- 1,2,4-triazolo[ 10(3H)-ones <05S160l>, <05S1601>, and an amine amine oxide rearrangement was key to the regioselective IO(3H)-ones preparation of pyrrolo[2,3-d]pyrimidines <05S1164>. <05S1164>. Hexahydro-2-phenacylideneHexahydro-2-phenacylidenepyrimidines gave -lactam fused fused 8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[l,2-ajpy8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[1,2-a]pyrimidine-6-ones when treated with (COC!), (COC1)2 in the presence of NaH Nail <05IJH87>, <05IJH87>, and methyl

364

Groziak M.P. Groziak

N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates underwent base-catalyzed ring closure and rearrangement to 6-substituted 4-methylamino-5-nitrosopyrimidines 4-methylamino-5-nitrosopyrimidines or 9<05TL1841>. Pyrrolo[2,3-djpyrimidine-2,4-diones Pyrrolo[2,3-d]pyrimidine-2,4-diones were prepared from methylpurin-8-ones <05TLl84l>. N-(5-vinyluracil-6-yl)sulfilimines by sunlight-mediated photolysis <05TL555l>, <05TL5551>, and thieno[2,3-d]pyrimidine-6-carboxaldehydes were prepared for the first time by oxidation of thieno[2,3-djpyrimidine-6-carboxaldehydes thieno[2,3-d]pyrimidin-6-ylmethanols with 112 <05CHE800>. thieno[2,3-djpyrimidin-6-ylmethanols <05CHE800>. 2 A general approach to 1,6-dihydro-7H-pyrazolo[4,3-djpyrimidin-7-ones 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-ones from 4-amino-l4-amino-1<05JHC751>, a reaction of alkyl-3-propylpyrazole-5-carboxamides was developed <05JHC75l>, carbodiimides and secondary amines or alcohols was found to give 5-dialkylamino or 5H-l ,2,3-triazolo[4,5-djpyrimidin-7-ones <05S2544>, the new ring systems alkoxy 77H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones ,2-a]pyrimidinone, and indeno[ 1,2-e]indeno[ 1,2-djpyrimidinone, 1,2-e]pyrrolo[ 11,2-a]pyrimidinone, 1,2-d]pyrimidinone, indeno[ indeno[1,2-e]pyrrolo[ indeno[1,2-e]pyrimido[1,2-a]isoindole pyrimido[1,2-a]isoindole were accessed via ring expansion of azetidinone and ring closure of <05ARK416>, and substituted pyrazolo[4,3-djpyrimidin-7pyrazolo[4,3-d]pyrimidin-7amino esters and 1,3-diamines <05ARK416>, <05JHC1085>. Enaminones ones were prepared from pyrazole-5-carboxylic acid precursors <05JHC1085>. were used to access pyrazolo[I,5-a]pyrimidines pyrazolo[1,5-a]pyrimidines <05JHC307>, <05JHC307>, sulfone-containing sulfone-containing ,5-a]pyrimidines were obtained <05JHC609>, and tetrahydropyrazolo[ pyrazolo [11,5-a]pyrimidines <05 JHC609>, 2(1H)quinazolinones and cyclopenta[dj-2(lH)pyrimidinones cyclopenta[d]-2(1H)pyrimidinones were prepared from 2(lH)quinazolinones alkoxyvinyl trifluoromethyl ketones <05SC3055>. <05SC3055>. Triazolino[4,3-a]pyrimidines Triazolino[4,3-a]pyrimidines were among <05PS149>, and new the various heterocycles prepared using hydrazonoyl halides <05PSI49>, naphtho[2,1-b]furo[3,2-djpyrimidines naphtho[2,1-b]furo[3,2-d]pyrimidines were prepared and examined for biological activity <05IJH 189>. <05IJHI89>. As for biologically-related pyrimidines, a chemoenzymatic asymmetric total synthesis of the polycyclic pyrazolo[3,4-djpyrimidine pyrazolo[3,4-d]pyrimidine analogs S9 59 of a phosphodiesterase phosphodiesterase (PDE) inhibitor was reported <05JOC2824>, <05JOC2824>, and the conversion of 2-amino-4,6-dichloro-52-amino-4,6-dichloro-5pyrimidinecarboxaldehyde pyrimidinecarboxaldehyde to methyl 2-amino-4-(methoxy)thieno[2,3-djpyrimidine-62-amino-4-(methoxy)thieno[2,3-d]pyrimidine-6carboxylate for obtaining antifolates was optimized <05JHC1305>. <05JHC1305>. Heptadienes containing containing building blocks for carbocyclic pyrimidine nucleic acid bases were prepared as building oligonucleotide <05SC1003>, l',3'-anhydro- -D-psicooligonucleotide analog synthesis <05SC 1003>, pyrimidine-based pyrimidine-based 1',3'-anhydroand -sorbo-furanosyl nucleosides nucleosides were obtained from 02,3'-anhydroO2,3'-anhydro- -D-fructofuranosyl<05SLl683>, and the total synthesis of of N-malayamycin A and related pyrimidine uracil <05SL1683>, 60a-c achieved <05JOC672l>.The preparation of 1,3nucleosides nucleosides 60a-c was <05JOC6721 >.The preparation dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium dimethylcyclohepta[4,5]pyrrolo[2,3-djpyrimidine-2,4( 1,3H)-dionylium ions like 62, models <05JOC9780>. The dionylium ion 62 can be reduced NAD+/NADH, were reported <05JOC9780>. reduced with for NADTNADH, NaBH 44 to give an NADH-like H- delivery agent (61) effective at reducing ketones to r2 ~ alcohols. o

Ph'N'~ ;

:

H2N"~NH I-I- O Bn

59 59 (and (and enantiomer) enantiomer)

/"~~

R~ ~...O/~ ;OH O R22 == Me; 60a, RR11 == OOMe, Me, R b, R1 R1 = = F, F, RR2 == H; H; b, rC, R 11 ==OMe, R22 == H

O

365

Six-membered ring systems: diazines and benzo derivatives (2005)

Ph Ph

H HH H

oO I I )l

Ph Ph

Me, N N.A ~ A .1(1 Me N M e / 1,Me N

o~ ~ I _ \ Me Me'

'00

61 61

/

R11"p4''R R R22

to

,

Me "Me

~

OH

R1'''k" R2 Ph . MeikI ~

Ph ~

Me

N

Y 0 O/

NaBH4

M~

'(3

62

O'

"Me

6.2.4.2 Reactions reactivity of Cyclization reactions of pyrimidines were studied, for instance, the reactIvIty tetrahydropyrido[ 4,3-b ]pyrimidines with DMAD leading to dihydropyrimidinylethylamines tetrahydropyrido[4,3-b]pyrimidines <05TL1975> and pyrimido[4,5-d]pyrimidines obtained efficiently by hetero Diels-Alder <05TLl975> cycloaddition of methyl 6-methyl-4-phenyl-2-thioxo-1 ,2,3,4-tetrahydropyrimidine-56-methyl-4-phenyl-2-thioxo-l,2,3,4-tetrahydropyrimidine-5carboxylate (64), a Biginelli compound, with N-arylidine-N'-methylformamidines to form 63 and N-arylidine guanidines to form 65. The mechanism of this cycloaddition was probed using semiempirical MO methods <05T4237>. Acetylenic pyrimidines underwent microwave-assisted intramolecular hetero-Diels Alder reactions to form fused bicyclic pyridines <05TL3423>.

HN~-N/EAr S~N.H PhH S~N.-'Ph Ir'Ar S.~NH p hH H . H r ' ' ~ ' '~CO2Me .,Me"N~/'N HN'~~CO2Me H2N ni,i~r./-.~r~A ,. rl,,l~l//....h ~ u ~ ,~CO2Me , Me"l I Me'll Ar Me..N,,,~ N

Me

63

HNyN

64

65

NH2 Nucleophilic addition/substitution addition/substitution reactions of pyrimidines were investigated as well. The selectivity of nucleophilic substitution in 2,4-disulfanyl-substituted 2,4-disulfanyl-substituted thieno[2,3-d]pyrimidin-6thieno[2,3-d]pyrimidin-6carboxylic acids was studied <05JHC84l>, <05JHC841>, as was the SN(ANRORC) S,(ANRORC) reactivity of substituted 5-ethoxycarbonylpyrimidines <05JHC557>. Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with nucleophiles by SNAr S,Ar and Suzuki and Stille cross-couplings was achieved <05TL585l>. <05TL5851>. The regioselectivity of conjugate additions to 3-(pyridin-3-yl or pyrimidin-2-yl)-propenoates and their N-oxides (66) to give 67a,b was studied by a <05EJO3297>, and 4-azido-2combination of theoretical and experimental methods <05EJ03297>, pyrimidinone nucleosides 68 were shown to react with nucleophiles at the modified base's C2 report. position, giving tetrazole nucleosides 69 <05JOCI96l>, <05JOC 1961>, contrary to a previous report.

CO2Et (O,),,,N,~ ~L~J 66 66

CO2Et PESH ? ; ' ~ N R2 NaOet~ (O EtOH ~L,,~IJ 67a, 67a, R R 11 = = H, H, R R 22 = = SPr SPr b, R 11 = SPr, SPr, R22 = H

N--N Jl ,, /~N'~:

N.. .N~N N N" "NI

x'~-~a )-NH NuH NuH

-=

~ (

Nu Nu N~O N%

AcO ACO~

AcO AcO" 68

AcO" Aco"

69 69

366

M.P. Groziak M.P. Groziak

Rearrangements of pyrimidine compounds were also reported. 9H-Cycloalka[I,2-e]9H-Cycloalka[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones were found to undergo intramolecular rearrangement in oxazolo[3,2-a]pyrimidin-7- and -5-ones (70 and 71, refluxing xylene to give cycloalkyl-fused oxazolo[3,2-a]pyrimidin-7respectively) <05T4453>. A regioselective thio-Claisen rearrangement starting from 5-prop<05T10774>, and 2-ynyl/enyl-sulfanyl pyrimidinones generated thienopyrimidinones 72a,b <05Tl0774>, O

Q o

RCH2__~Oi ~

:2 "~RCH,-{_\ 0 RCH,-{_<:Q

C02 Et

+ [~n/CO2Et .~ RCH2 NH2 n = 1,0

~

R2

)n

70

N

iv} n

r~

NJ.--W~~ ~S'Y"'JN" R N N 1.-. R11 R1 pTsCI, Et3N, ~ ~-.....~. NII . , ~ '0 N ~ anhyd. CH2CI2 " ~ "O 73a,b, R R = = H, H, Me Me SR 73a,b, r.t. SR33 72a-b, R3 3 = CH CH2C=CH, CH2CH=CH 2 2C",CH, CH 2CH=CH 2

d

N"J~'N .,Jl Me2N

O 0 n ++ RCH2__~oSL~, ~ N 71 71

N "::

l'

an acid-catalyzed O-N-type Smiles rearrangement reaction was noted in 2-pyrimidinyloxy-N<05SL1239>. Ru(II) complexes arylbenzylamines, giving the corresponding phenols <05SLl239>. containing hemilabile 2-(pyridin-2-ylmethylthio)pyrimidine ligands 73a,b were shown to interconvert between N,S- and N-coordinated species <05EJI2423>. In the first example of catalytic C-C coupling involving activation of a C-F bond in the presence of a C-CI C-C1 one, 5-chloro-2,4,6-trifluoropyrimidine (74) reacted with arylboronic acids in the presence of a Ni(II) catalyst to generate 5-chloro-2-fluoro-4,6-diarylpyrimidines 75 <050M4057>. <05OM4057>. A theoretical and experimental investigation of the structure and reactivity of 4-(4-chlorophenyl)pyrimidinium ylides was undertaken <05ARK7>, and the structure, stability, and reactivity of 4-methyl- and 4-(halophenyl)pyrimidinium (4halobenzoyl)methylides (76a-d and 76e-h, respectively) were examined by theoretical and experimental methods <05HCA2747>. The Biginelli 3,4-dihydropyrimidin-2(1H)-one 77 was converted in two steps to a variety of multifunctionalized pyrimidines with general structure 78 <05JOCI957>. <05JOC1957>. In a more biological light, N,N'-bis(3-aminopropyl)-2,7-diamino1,S-naphthyridine 1,8-naphthyridine was found to stabilize a single pyrimidine bulge in dsDNA <05BMC4507>. Finally, separate enantioselective microbial reductions of 6-oxo-S-[4-[4-(26-oxo-8-[4-[4-(2pyrimidinyl)-1-piperazinyl]butyl]-S-azaspiro[4.5]decane-7,9-dione pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 79 generating either of the 2° 2 ~ alcohol epimers (80a,b) was reported <05TA277S>. <05TA2778>.

F N F F. N 10% 10%

F

1'+ II

~'t~

"~CCI V I

F

Ph3P-Ni-PPh3 Ph3P-~i-PPh3

N'~N F

~R

itr

.~

F~ F

F CI 74

THF, THF,CS Cs2CO 3 2C03 PPh 3, PhS(OH)2 PPh3'PhB(OH)2

N Ph

d I"::

N

X Ph

CI 75

NVN

0

~

76a-d, R R = = Me, Me, X = F, CI, CI, Sr, Br, I 76a-d, X= e-h, e-h, R R == 4-CIC 4-CIC6H4, = F, F, CI, CI, Sr, Br, II 6 H4 , X =

367

Six-membered ring ring systems: diazines and benzo derivatives (2005) Six-membered

Ph

Ph

HN.fi...~/CO2Me 2. I.[0] Null,base ,.

0"~ N M%e77H

N~CO2M

~:RIHi ~:R ~N 0 R [H] 0

e

,'~N)3 {-PBr -PF6Nu"~"N %Me78

O

0 ° ° 79, 6-keto Buspirone

°

HO 80a,b

79, 6-keto Buspirone

R =4-(pyrimidin-2-yl)piperazin-1-yi 4-(pyrimidin-2-yl)piperazin-l-yl

R

6.2.4.3 Applications

Some interesting non-medical applications were found for pyrimidines. The combination of Pd(OAc), Pd(OAc) 2 and 2-aminopyrimidine-4,6-diol 81 was discovered to form a stable, efficient catalytic system for the Suzuki-Miyaura cross coupling of arylboronic acids and aryl halides <05SLl897>, <05SL1897>, and it rendered the Sonogashira cross-coupling of aryl halides with terminal alkynes efficient and copper-free <05EJ04256>. <05EJO4256>. New rhodium 1,3-dialkyl-3,4,5,6tetrahydro-2-pyrimidinylidene complexes 82 prepared as aromatic aldehyde arylation catalysts were characterized by multinuclear NMR <05JOM5849>. Supramolecular systems were constructed from complexes of 2,6-disubstituted 1-oxa-4-thia-3,5-diazine l-oxa-4-thia-3,5-diazine 4,4-dioxides with symmetric triazines <05RJ0289>. <05RJO289>. 6-Substituted 2,4-bis(acrylamido)pyrimidines 83 were used as the key pieces in the construction of optically responsive imide receptors 4-amino-l-methyl-5-nitroso-6-oxo-l ,6-dihydropyrimidin-2-yl)-N'<05JOC2729>, and N-( N-(4-amino-l-methyl-5-nitroso-6-oxo-l,6-dihydropyrimidin-2-yl)-N'[bis(2-aminoethyl)]ethylenediamine [bis(2-aminoethyl)]ethylenediamine 84 was synthesized and characterized by multinuclear NMR methods. It's use as an ion receptor was investigated by assessing it's ability to adsorb Zn(H) Zn(II) and Cd(H) Cd(II) out of aqueous solution when anchored to activated carbon <05EJI3093>. 1-dimensional coordination polymers [M(N0 [M(NO3)2(pyrimidine)(H:O)2]= = Mn, Co, ),(pyrimidine)(H,O),]= (M = A set of I-dimensional 3 Ni, or Zn) like 85 was prepared and their phase purity was determined <05EJIl572>. <05EJI1572>. The pressure-sensitive magnetism of guest-tunable weak ferromagnets of the type [Fe{N(CN),},(pyrimidine)](guest) [Fe{N(CN)2}2(pyrimidine)](guest) (guest = - EtOH or pyrimidine) was studied <05CL974>. Metal complexes with the new ditopic ligand 4-[6-(2-pyridyl)-2-pyridyl]-6-(2pyridyl)pyrimidine 86 were shown to self-assemble into 2x2 grid complexes which had - ions. These complexes were characterized by X-ray <05EJI894>. encapsulated NO 3J

RI~~/I

(Br)

+

R2~

HO cat. /~--N~__NH2 ~N

HO

,R R' k//~N ~ N ~ /

81

k~N _

cat. Pd(OAc)2

~'k~---f/ - -

o

n2

N- - /

'R' R'

82

CsCO 3, CH3CN

Me'N@N'O HN'~N | I~NH2 ~I 84

N03- PH 2 ~ \:2+ 2[=\, /~ ~ \.-" N N N-Mn N--Mn 2+-N -N x /.NN U '==J /~/ \ \ 'L3 H20 -OaN H -03N 20

85

[~

~ ~=N Y--N ,---4 f/ ~,k~-/x--~N ~-'~1_.#'

/ o

83 o

,..~ N.-~ N//L..N.~./ ~, '," 7 r H ! H O%/N...~.O

~ ~t--%./N.Bn

86

I

N(CH2CH2NH2)2

As for nucleic acid applications, the syntheses and fluorescent properties of the DNA nucleobase replacements like the 1,2,3-triazolo[4,5-d]pyrimidine 2'-deoxyribofuranosides 87

368

M.P. Groziak M.P.

were reported . <05HCA751>. A 4-(2'-pyridyl)-pyrimidinone deoxyriboside was prepared and was shown to form a self-pair in the presence of Ni(II), stabilizing dsDNA as in 88 . <05CC1342>. Chiral 2-(aminoalkoxy)-substituted 4-(2-thienyl)pyrimidines and 4,6-bis(2thienyl)pyrimidines were prepared as dsDNA intercalators. Their binding constants showed up to a 2.4: 2.4:11 discrimination of the (S)-enantiomers over the (R)-counterparts <05BMCL2720>. Finally, DNA-intercalating annelated pyrrolo-pyrimidines were prepared . from substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles . <05BMC1545>.

oO

g::.."',.Ni2.~

H~~~'N ~.. JL~ HN

N

~N.

:Ni:+

H:~ HO-

87 87

.~J: I

l:Xo0

"~,v

~II

OH OH

0

88 88

oNVV

I

. gN"N .-..

~I[

oNVV

1- and 2-Alkyl-4-aminopyrazolo[3,4-d]pyrimidines were developed as adenosine deaminase inhibitors , I ,S-c]pyrimidin<05JMC5162>, 2-(2-furanyl)-7-phenyl[ 1,2,4]triazolo[ 1,5-c]pyrimidin, antagonists , 05BMCL3675>, 2 pyrazolo[ 4,3-e] 1,2,4-triazolo[ 1,S-c]pyrimidines were prepared as human A 33 adenosine pyrazolo[4,3-e]l,2,4-triazolo[1,5-c]pyrimidines <05JMC152>, 5-phenyl-7-(5-deoxy- -Dand 4-substituted S-phenyl-7-(S-deoxyreceptor antagonists , ribofuranosyl)pyrrolo[2,3-d]pyrimidines (diaryltubercidins) , <05JMC7808>, 6,7-disubstituted ribofuranosyl)pyrrolo[2,3-d]pyrimidines 4-aminopyrido[2,3-d]pyrimidines , <05BMCL2803>, and S-(3-bromophenyl)-7-(6-morpholin5-(3-bromophenyl)-7-(6-morpholin4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine <05BMC3705> were prepared as inhibitors of adenosine kinase. Pyrimidine-based compounds compounds continue to be of interest as antimalarial agents. Among the <05BMC4645> ones synthesized for this bioactivity were 2,4,6-trisubstituted pyrimidines and 4-pyrido-6-aryl-2-substituted aminopyrimidines . <05BMC6226>. Libraries of 2,4,6trisubstituted pyrimidines were prepared and screened for antimalarial activity 05BMCL3130> and also for topoisomerase II activity , <05BMCL47>, while other libraries of 6-aryl-2-substituted pyrimidin-4-ylphenols <05BMCL4923> and trisubstituted pyrimidines <05BMCL5218> were prepared and screened for antimalarial and 5-Substituted pyrimidine nucleosides were examined as antiantitubercular activities. S-Substituted mycobacterial agents , 05BMC6663>, spiro-pyrazolo-3,3'-thiopyrano[2,3-b]spiro-pyrazolo-3,3'-thiopyrano[2,3-b]pyridines were prepared as antifungal and antibacterial agents , <05JHC221>, a set of pyrimidine-based antifungal agents was synthesized , <05AAC2226>, and some unusual [1,2,4]triazolo[I,S-a]pyrimidine-based [1,2,4]triazolo[1,5-a]pyrimidine-based triorganotin(IV) complexes 89 were prepared and characterized by IR and Mossbauer spectroscopy and quantum chemical calculations . <05JOM4773>. These had good antifungal and antibiofilm activities. Bu I/

Bu \

-O-Sn-O~O-Sn-o -- O- S n - ~ , - - O . \ / , ~ ~O--Sn-~--O

I' Bu Bu

1 ~I

HN

1\

Bu N Bu Bu 'N N-.'l' 89

'II

N- and O-Substituted terpenyl pyrimidines <05EJM552> as well as dihydropyrido[2,3-d]pyrimidines <05BMC6678> were prepared as antileishmanial agents. S-Alkynyl5-Alkynyl- and 6<05BMC1239>, alkyl-furo[2,3-d]pyrimidine acyclic nucleosides , acyclic furo- and

369

Six-membered ring ring systems: diazines diazines and benzo derivatives (2005)

pyrrolo[2,3-d]pyrimidine nucleosides <05JMC4690>, and bicyclic furano pyrimidine nucleosides were synthesized as antiviral agents <05AAC1081>. Other bioactivities sought were pyrimidine-5-carboxamides as tyrosine kinase inhibiting anti-allergic agents <05BMC4936>, <05BMC4936>, mono, bi and tricyclic pyrimidines as analgesics and anti-inflammatory agents <05BMC6l58>, <05BMC6158>, and 2,4,6-trisubstituted pyrimidines as pregnancy interceptive agents <05BMC1893>. Substituted pyrimidines containing a thiazolidinedione moiety were investigated as hypoglycemic and hypolipidemic agents <05EJM862>. Pyrimidine heterocycles were examined as receptor site agonists or antagonists. Among 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl these were 2-phenylpyrazolo[ 1,5-a jpyrimidin-3-yl acetamides for the benzodiazepine receptor <05BMC4821>, <05BMC4821>, 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-diones for the a,-adrenoceptor oq-adrenoceptor <05JMC2420>, bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7thiazolino[3,2-c]pyrimidine-5,7diones, prepared by treating 2-methyloxazolines or -thiazolines with chlorocarbonyl or-thiazolines isocyanate, for the hGnRH receptor <05BMCLl407>, <05BMCL1407>, piperidinyl- and 1,2,3,65-HT,a receptor <05BMCL2990>, and tetrahydropyridinyl-pyrimidines selective for the 5-HT,u substituted 3H-pyrimidin-4-ones for the calcium receptor <05BMCL2537>. Pyrimidines were also prepared as enzyme inhibitors. Many of these were kinase inhibitors, including 2anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones pyrido[l1',2': ',2': 1,5]anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones <05BMCLl931> <05BMCL 1931> and pyrido[ pyrazolo[3,4-d]pyrimidines <05BMCL3778> <05BMCL3778> as kinase inhibitors, 4-aminofuro[2,3-d]pyrimidines as tyrosine kinase inhibitors <05BMCL2203>, <05BMCL2203>, pyrazolo[ pyrazolo[1,5-a]pyrimidines 1,5-a jpyrimidines as inhibitors of human cyclin-dependent kinase 2 (CDK2) <05BMCL863>, pyrido[2,3-d]pyrimidin-7-ones as inhibitors of cyclin-dependent kinase 4 (CDK4) <05JMC2371>, and substituted aminobenzimidazole pyrimidines as inhibitors of cyclin-dependent kinase <05BMCLl973>. {4-[2-(3-chlorophenylamino)pyrimidin-4-ylj<05BMCL1973>. A short synthesis of 33-{4-[2-(3-chlorophenylamino)pyrimidin-4-yl]pyridin-2-ylamino}propanol, pyridin-2-ylamino }propanol, a protein kinase C inhibitor, relied on the Negishi crosscoupling reaction of a pyridine zincate and 2,4-dichloropyrimidine (90) to generate the key intermediate 91 <05JOC52l5>. <05JOC5215>.

N;:>-znl +N~CI J-N Znl

F F

+ N

CI

CI

90 90

N~

Pd[PPh3]4, N Pd[PPh 3]4, THF, reflux, reflux 4 h F F ' 90%

,,,

91

N

Cl

CI

2-Amino-3-nitropyrazolo[l,5-ajpyrimidines 2-Amino-3-nitropyrazolo[1,5-a]pyrimidines were prepared as inhibitors of coxsackievirus B33 replication <05BMCL37>, fused pyrimidines as PDE 77 inhibitors <05BMCLl829>, <05BMCL1829>, and pyrimidinetriones as inhibitors of MMPs <05BMCLl807>. <05BMCL1807>. Methylated 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one nucleoside analogs 92 incorporated into triplex-forming oligonucleotides were shown to selectively bind CG inversions <05CC2555>, and pyrimidine-linked biphenyl anionic RSV fusion inhibitors were found to be less active than <05BMCL427>. their corresponding triazine-linked counterparts <05BMCL427>. R

eo/~--"H

H

370

M.P. Groziak M.P.

anticancer field, 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones In the anticancer <05BMCL4731> and 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones 6-[I-(2,6-difluorophenyl)ethyl]pyrimidinones <05JMC6776> <05JMC6776> were <05BMCL4731> prepared as cytotoxic/antitumor agents, pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides prepared <05BMCLl591> and thieno[2,3-d]pyrimidin-4(1H)-ones thieno[2,3-d]pyrimidin-4(lH)-ones <05BMCL3763> <05BMCL3763> were prepared prepared as <05BMCL1591> tumor cell antiproliferative agents, and 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines <05BMC5475>, trimethylene-bridged 2,4-diaminopyrrolo[2,3-d]pyrimidines <05JHC1127>, <05JHCI127>, 2,4-diamino-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidines <05JHC589>, and pyrrolo[2,3-d]pyrimidines <05JMC7215> were prepared as dihydrofolate reductase (DHFR) inhibitors. 5-Substituted furo[2,3-d]pyrimidines and 6-substituted pyrrolo[2,3-d]pyrimidines <05JMC5329>, 2-amino-4-oxo-5-arylthio-substituted pyrrolo[2,3-d]pyrimidines <05BMCL2225>, and 2-amino-4-oxo-5-substituted benzylthiopyrrolo[2,3-d]pyrimidines <05JHC165> ofthymidylate <05JHC 165> were all synthesized as antifolate inhibitors of thymidylate synthase.

6.2.5 PYRAZINES PYRAZINES AND AND BENZO BENZO DERIVATIVES DERIVATIVES 6.2.5

Our understanding of the physicochemical properties of pyrazines has deepened. The internal rotation and IR spectrum of 2,5-pyrazinedicarboxamide were studied by quantum chemical calculations <05TC73>, and ab initio MO calculations at the MP2/6-31++G(**) MP2/6-31++G(**) level were used to explain the electronic and vibrational properties of complexes of pyrazine and HX linear acids <05JMS2822>. MM and MO calculations were used to investigate the conformational and electronic properties of odor-active pyrazines <05JMS 169>, and NMR, pyrido[1,2-a]pyrazinium IR, X-ray, and DFT methods were used to examine the structures of pyrido[ 1,2-a]pyrazinium bromide <05JMS7>. The amino-imino tautomerism in 2,3-disubstituted pyrazines in both solution and the solid state was investigated by NMR and X-ray methods <05JMS67>. Metal complexes containing a pyrazinecarboxamide ligand were investigated by a variety of spectroscopies <05JCC1241>. Pyrazine-based heterocycles examined by X-ray crystallography included 5, 1O-dihydroxy-5H, lOH-diimidazo[1,2-a: 5,10-dihydroxy-5H, 10H-diimidazo[ 1,2-a: I',2'-d]pyrazine l',2'-d]pyrazine 93 <05AX(C)o361> <05AX(C)o361 > and 7-ethyl-2methy1-4-phenylhexahydropyrazino[ I ,2-a]pyrazin-3-one <05TL51>. Those within an methyl-4-phenylhexahydropyrazino[1,2-a]pyrazin-3-one Ca(II) complex with pyrazine-2,3-dicarboxylate ligands organometallic complex included a Ca(H) <05JCC891>, a Ag(I) complex containing the trans-2-(2-phenylethenyl)pyrazine trans-2-(2-phenylethenyl)pyrazine ligand catena-bis( -pyrazine-2,3-dicarboxylato-N, 0, 0 )zinc(II) <05JCC931 >, <05JMS37>, O,O)zinc(II) <05JCC931>, diaqua(pyrazine-2,3-dicarboxylato-N, 0:0',0 ')calcium(II) <05JCC963>, and 0:0', O')calcium(II) Ni(II) complexes containing pyrazine-2-carboxylate ligands <05JCCI429>. <05JCC1429>. In addition, X-ray crystallography was used to examine the one-dimensional coordination polymer 94 of Cu(II) with 2-pyrazinecarboxylate <05AX(E)m499>, osmium clusters like 95 containing 2,3-bis(2pyridyl)pyrazine as a chelating ligand <05JOM622>, and pyrazine-bridged benzyl dicobaloximes 96a,b, which were also characterized by cyclic voitammetry voltammetry <05JOM3746>.

371

Six-membered ring ring systems: diazines and benzo derivatives (2005)

CH2Ar OH .... O ~

a '1'\;

~ , N

I/OH2 ---N

9

OH

-

"=N

N-Cu

Z r-j OC -;.

93 _

94

b

_ n

N

R

N

./

~ .'" OC-Os-OS(CO)4 OC-Os--Os(CO)4.../

O/No

o ~ 11[,.

N~ c

O--~- HO

~1 k~ ~-/; (~'\;

OH ,,~-...N .--'~'~.~N <~N~.~.. NI~

~N R

OH .... O

R~_~ I ~ ~ / R

~l~ c~ ~

OC "~/s Os

95 (CO)4 (CO)4

R

NI /

O--

~N I

,-,

n

- HO

CH2Ar

96a,b, R = Me, Ph

6.2.5.1 Syntheses

A modified Ugi four-component condensation route was used to prepare substituted 4<05JCO806>. Microwaveoxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxamides <05JCOS06>. 2(1H)-pyrazinones via "click assisted reactions enhanced the synthesis of substituted 2(lH)-pyrazinones chemistry" <05JC0490>, <05JCO490>, and 6,S-diarylimidazo[1,2-a]pyrazines 6,8-diarylimidazo[1,2-a]pyrazines were prepared from 1-(2aryl-2-oxoethyl)-2-aryloylimidazoles using NH4OAc/AcOH NH40Ac/AcOH under microwave conditions <05JHC3l9>. <05JHC319>. A regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines 98 from 2,3-dichloropyrido[2,3-b]pyrazine (97) was reported <05JOC2878>, and a solid-phase synthesis of substituted 2(lH)-pyrazinones 2(1H)-pyrazinones was developed <05JOC2S7S>, for future generation of libraries of these heterocycles <05JC090>. <05JCO90>. Furoxano[3,4-b]pyrazines were prepared by treating 2-alkoxy-3,5-dinitro-6-chloropyrazines with NaN 3J <05JHC691>. Polyfunctional tetrahydropyrido[3,4-b]pyrazines like 99 were prepared in a CsFsN and diamines <05JOCnOS>, <05JOC7208>, while the sequential reaction of one-pot reaction using CsFsN CsFsN CsFsN with sodium phenylsulfinate and a diamine generated polyfunctional tetrahydropyrido[2,3-b]pyrazines like 100 <05JOC9377>. O Me'Nl

r(YNyCI

t.AA N N CI

A

F N.Me FnN'Me

97 97

'-R

MeO MeO"

NN 99 99

N)

NEt2 NEt2 100

Pyrazino[1,2-a]indoles 101 and 102 were prepared by intramolecular cyclization of 2acyl-l-propargylindoles and NH J3 <05JOC40SS>. <05JOC4088>. Pyrrolo[1,2-a]pyrazin-l-ones 103 were obtained from 2-acylpyrroles <05T1077>. Pyrazines doubly activated with MeO,CCI MeO2CC1 in the presence of bis(TMS)ketene acetals generated polycyclic -lactone products <05TL3449>. SeO 2 to give 2,5-dimethylpyrazine-3,6-dicarboxaldehyde, Tetramethylpyrazine reacted with SeO, which in turn reacted with (iPr),NH (iPr)2NH to give 2,5-dimethyl-3,6-bis[(2,6-diisopropylphenyl<05ZN(B)22>. imino)methyl]pyrazine, a chelating ligand for transition metal complexes <05ZN(B)22>_

372

M.P. Groziak M.P. Groziak

Finally, trialkyl-substituted pyrazines 104 were prepared in a regiocontrolled manner from <05OL5529>. nitroketones by reaction with -amino ketones .

~R

~ N N : :,. . I

V--NI\'o

~R'

Q-rO H

f--./

N

"R 'R

/"

Pd(OAc): Pd(OAc)2 NaOAc NaOAc BU4NCI .u4.c,

DMSO DMSO

R1 ~-./N" R /

0 +

R

102

NO2

R2" '-0

\

"----iCHR' CHR'

CH2R'

101

~

H

103

R3 octylviologen I-

Na2S406 K2003

-~

R)[N R 1

R22

r

3

N N

104

6.2.5.2 Reactions Palladium-catalyzed reactions on pyrazines were the subject of quite a few investigations. 3,S-Dichloropyrazinones 3,5-Dichloropyrazinones 105 were shown to undergo regioselective Suzuki and Heck reactions to give 3-substituted 3-substituted products, while the less reactive S-position 5-position could be corresponding S-bromo 5-bromo or -iodo derivatives functionalized only after transhalogenation to the corresponding . <05T3953>. The Suzuki, Sonogashira, Heck, and Buchwald-Hartwig reactions were explored using 7-bromo-2,3-diphenylpyrido[2,3-bJpyrazine 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine as the key starting material . <05S1345>. bi-2(lH)-pyrazinones were obtained by homocoupling homocoupling in a Functionalized, symmetric bi-2(1H)-pyrazinones Suzuki-type reaction involving an in situ generated boronic acid , <05SL777>, while highly substituted bipyrazines like 107 were obtained by a Suzuki cross-coupling approach from 2amino-5-bromopyridazine (106) . <05JOC388>. The Pd-catalyzed heteroannulation amino-S-bromopyridazine heteroannulation of N-(3chloropyrazin-2-yl)methanesulfonamide with alkynes was used to prepare 6,7-disubstituted5H-pyrrolo[2,3-b]pyrazines <05TL 1845>. SH-pyrrolo[2,3-b Jpyrazines . OMe (HO)2B - - ~ B ( O H ) 2

Bn (Ph) (Ph) ~n

N

OMe _N

I

R

N

0

c,1NXc, CI

N

1115 105

Cl

;

N ~

106

Br Pd[PPh3]4, Na2C03 THF, reflux, 24 h 56%

MeO 107

Olefinic pyrazines like 108 were shown to react with C C6H TfOH to give oH66 in the superacid UOH anti-Markovnikov addition products like 109 . <05OL2505>. The orientation observed is presumed to be due to the multiply charged heterocycle adjacent to the olefin. Pyrazine 0oquinodimethanes underwent Diels-Alder condensation with meso-tetraarylporphyrins meso-tetraarylporphyrins to give new 1t-extended n-extended porphyrins . <05TL2189>. A one-pot formation of polycyclic - and lactones like 111 was developed using the reaction of pyridine and pyrazine (110) with bis(trimethylsilyl)ketene acetals. Many of them were characterized by X-ray . <05EJO3724>.

373

diazines and benzo derivatives (2005) Six-membered ring systems: diazines

~N~

N

CF3SO3H= ~ N ~ P h

N

C6H6, 80 ~

N

96%

108

l)

MeO2C Me N L...Me 1" Me2C=C(OSiMe3),. 2 ~ " ~ O

~ iN~ 2. CICO2Me 110

109

"N/-O MeO2C 111

6.2.5.3 Applications Applications 6.2.5.3 The non-medicinal applications reported for pyrazine-based compounds were extremely diverse. By studying substituent effects, the rate-determining step for chemiluminescence in 6-arylimidazo[I,2-a]pyrazin-3(7H)-ones was indicated to be a single electron transfer from 6-arylimidazo[1,2-a]pyrazin-3(7H)-ones 0z2 <05TL7701>. Reaction of the diamide ligands N,N'-bis(2the anion to triplet O pyridylmethyl)pyrazine-2,5-dicarboxamide and N,N'-bis[2-(2-pyridyl)ethyl]pyrazine-2,5dicarboxamide 112 with Cu(BF4)2o4H20 Cu(BF4)204HP gave dinuclear Cu(II) complexes which were <05EJII530>. The Cu(II) Cu(H) complex [Cu characterized by EPR <05EJI1530>. characterized [Cu2(pyrazine-2,5z(pyrazine-2,5dicarboxylato)(l,1O-phenanthroline)4](N0 3) z~o lOHP 113 was examined by X-ray dicarboxylato)(1,10-phenanthroline)4](NO3)2 crystallography, and the magnetic exchange through the pyrazine bridge was studied <05EJI2586>. The colorimetric sensor properties of solvatochromic substituted 2UVNis and SM1phenylimidazo[I,2-a]pyrazin-3(7H)-ones phenylimidazo[1,2-a]pyrazin-3(7H)-ones 114a-e ll4a-e were examined by UV/Vis COSMO computations <05T10073>. <05Tl0073>. Pyrazine itself was found to bind to the cavities formed Mn(H), Fe(II), Fe(H), Ni(II), and Cu(H) in Mn(II), Cu(II) complexes bridged with squarate molecules, forming a supramolecular network. The X-ray crystal structure of a similar Zn(H) Zn(II) complex was determined <05BCJ445>. Two axially chiral quinazoline-equipped phosphinamine ligands, 115a and 2-(2-pyrazinyl)quinazolinap 115b, 2-(2-pyridyl)quinazolinap l15a l15b, were prepared, resolved, and their diastereomeric palladacycles were examined crystallographically ll6a-f were also prepared. A total of 27 volatile <05T9808>. Other related quinazolines like 116a-f pyrazines such as 117-120 were isolated and characterized from the myxobacterium Chondromyces Chondromyces crocatus crocatus and marine bacteria <05EJ04141>. <05EJO4141>.

~

\ ,,--" N

Me-N:'N~O

N n= 1 or2

N

[": .&

112

O N(~

R

R == NMe2' NMe2, 114a-e, R

OMe,H, H, CI, CI, CN CN OMe,

X y ~

~

NyC ] N /ON

I"

PPh 2

115a, 115a,XX==CH; CH;

b,X=N

N~. R NyR

y

[

~

~

~

"

N /ON PPh PPh22

116a-f, 116a-f, R R= = Ph, Ph, Me, Me, Pri Bu!, But, H, H, Bn Bn Pri,

>-{}-\ 117 117

MeO MeO

MeO

\

R-~ 119 119

(i~ 118 118

N N

Me Me

MeiNXSMe Me N SMe 120

374 374

M.P. Groziak Groziak M.P.

In medicinal medicinal applications, applications, [1,2,4jtriazolo[1,5-a]pyrazines [1,2,4]triazolo[1,5-a]pyrazines have have been been examined examined as as In adenosine receptor antagonists <05H(65)2321, 05BMCL4809>, pyrazolo[4,3-ejadenosine A A2,~ receptor antagonists <05H(65)2321, 05BMCL4809>, pyrazolo[4,3-e]2U pyrrolo[I,2-ajpyrazines pyrrolo[1,2-a]pyrazines were were prepared prepared from from l-phenyl-5-(pyrrol-1-yl)-lH-pyrazole-31-phenyl-5-(pyrrol-l-yl)-lH-pyrazole-3carboxylic acid acid azide azide as as antibacterials antibacterials and and antifungals antifungals <05M217>, <05M217>, and and pyrazinones pyrazinones were were carboxylic examined as as inhibitors inhibitors of of the the TFNIIa TF/VIIa complex complex <05BMCL3006> <05BMCL3006> and and as as non-nucleoside non-nucleoside examined reverse transcriptase inhibitors (NNRTIs) (NNRTIs) <05JMC191O>. <05JMC1910>. New thrombin inhibitors were built around around aa pyrazinone core <05EJM782>, pyrazinone monoamides were prepared as as ascaspase-3 ,2,4jtriazolo[4,3-a jpyrazines as ascaspase-3 inhibitors <05BMCLlI73>, <05BMCL1173>, and and 5,6-dihydro[1 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazines as dipeptidyl peptidase IV (DPP-IV) (DPP-IV) inhibitors <05JMCI41>. <05JMC141>. A QSAR study study on 1,2,3,41,2,3,4dipeptidyl tetrahydropyrrolo[ I ,2-a jpyrazine-4-spiro-3'-pyrrolidine-1 ,2',3,5'-tetrone as tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-l,2',3,5'-tetrone as aldose aldose reductase <05BMC1445>, the synthesis <05JMC1886> <05JMC1886> and SAR SAR inhibitors was conducted <05BMC1445>, <05JMC4892> <05JMC4892> of pyrazine-pyridine biheteroaryls as vascular endothelial growth factor (VEGF) receptor-2 inhibitors were reported, and the effect of L-pyrazinylalanine as a <05JMC4025>. Finally, the phenylalanine replacement in a somatostatin was explored <05JMC4025>. <05AAC804> and resistance <05AAC444, <05AAC444, 05AAC221O> 05AAC2210> of Mycobacterium Mycobacterium susceptibility <05AAC804> tuberculosis to pyrazinamide was further investigated. tuberculosis

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376 376 05BMC4821 05BMC482I 05BMC4936 05BMC4936 05BMC5475 05BMC5475 05BMC6158 05BMC6158 05BMC6226 05BMC6226 05BMC6663 05BMC6663 05BMC6678 05BMC6678 05BMCL37 05BMCL37 05BMCL47 05BMCL47 05BMCL427 05BMCL427 05BMCL863 05BMCL863

05BMCLll73

05BMCL1407 05BMCLl407 05BMCL1591 05BMCLl591 05BMCL1807 05BMCLl807

05BMCL1829 05BMCLl829 05BMCL1881 05BMCLl881 05BMCL1931I 05BMCLl93 05BMCL1973 05BMCLl973

05BMCL2203 05BMCL2203 05BMCL2225 05BMCL2225 05BMCL2381 05BMCL238I 05BMCL2409

05BMCL2537 05BMCL2537 05BMCL2720 05BMCL2720 05BMCL2803 05BMCL2803

05BMCL2990 05BMCL2990 05BMCL3006 05BMCL3006

05BMCL3130 05BMCL3130

M.P. Groziak Groziak M.P.

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Six-membered S&-membered ring systems: diazines and benzo derivatives (2005)

05BMCL3670 05BMCL3670 05BMCL3675 05BMCL3675 05BMCL3763 05BMCL3763 05BMCL3778 05BMCL3778 05BMCL4731 05BMClA731 05BMCL4809 05BMCL4809 05BMClA923 05BMCL4923 05BMCL5218 05BMCL5218 05CC1342 05CC1342 05CC1619 05CC1619 05CC2555 05CCC223 05CCC247 05CHE268 05CHE800 05CHE800 05CJC57 05CL974 05CL1022 05CLl022 05EJI894 05EJl894 05EJI1530

05EJI1572 05EJI1572 05EJI2423 05EJI2586 05EJI2586 05EJI2779 05EJl2779 05EJI3093 05EJM40l 05EJM401 05EJM552 05EJM782 05EJM862 05EJ0522 05EJO522 05EJOl142 05EJO 1142

05EJO1781 05EJ01781 05EJO3297 05EJ03297 05EJ03724 05EJO3724 05EJ04141 05EJO4141 05EJ04256 05EJO4256 05H(65)329 05H(65)329 05H(65)625 05H(65)625 05H(65)1871

377

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378 05H(65)2321 05H(65)2321 05H(65)2593 05H(65)2683 05HAC20 05HAC56 05HCA751 05 HCA2747 05HCA2747 05HEC89 05IJH87 05IJH189 05JCC429 05JCC683 05JCC891 05JCC931 05JCC963 05JCC1241 05JCC 1241 05JCC1429

05JCO90 05JC090 05JC096 05JCO96 05JCO236 05JC0236 05JCO490 05JC0490 05JC0517 05JCO517 05JCO589 05JC0589 05JC0721 05JCO721 05JCO806 05JC0806

05JCO977 05JC0977 05JHC165 05JHC221 05JHC307 05JHC319 05JHC353 05JHC361 05JHC375 05JHC387 05JHC395 05JHC413 05JHC427 05JHC509 05JHC527 05JHC557 05JHC589 05JHC609 05JHC639 05JHC691 05JHC751 05JHC841 05JHC925 05JHC975 05JHC1069 05JHCI069 05JHC1085 05JHCI085

M.P. Groziak

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Six-rnernbered Six-membered ring systerns: systems: diazines and benzo derivatives (2005)

05JHCII05 05JHC 1105 05JHCl127 05JHCl223 05JHC1223 05JHCl305 05JHC1305 05JHC1423 05JHC1423 05JMC141 05JMCl41

05JMC152 05JMCl52 05JMCl886 05JMC1886

05JMCl901 05JMC 1901

05JMCl910 05JMC1910

05JMC2371 05JMC2420 05JMC2420 05JMC4025 05JMC4690 05JMC4690 05JMC4892 05JMC4892

05JMC5162 05JMC5162

05JMC5329 05JMC5329 05JMC6004 05JMC6004 05JMC6326 05JMC6326

05JMC6776 05JMC6776 05JMC6843 05JMC6843

05JMC7012 05JMC7012

05JMC7089 05JMC7089

05JMC7215 05JMC7215 05JMC7808 05JMC7808 05JMS7 05JMS37

379

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Mol. Struct. 2005, 743, 7. 754,37. X.-F. Shi, Shi, H.-M. Liu, W.-Q. Zhang, J. Mol. Struct. 2005, 754, 37.

380 05JMS67 05JMS169 05JMS 169 05JMS179 05JMS2822 05JOC388 05JOC1957 05JOC1961 05JOC 1961 05JOC2616 05JOC2729 05JOC2824 05JOC2878 05JOC4088 05JOC5215 05JOC6503 05JOC6721 05JOC6721 05JOC7208 05JOC9377 05JOC9780 05JOC10194 05JOM622 05JOM802 05JOM3746 05JOM4773 05JOM5849 05M217 05MI297 05MI307 05MI1319 050L2505 05OL2505 050L4705 05OL4705 050L5529 05OL5529 050M4057 05OM4057 05PS95

05PS 149 05PS149 05PS163 05PS339 05PS413 05PS591 05PS633 05RJ0289 05RJO289 05S 131 05S131 05S419 05S1083 05S1164 05S 1164

M.P. Groziak

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Six-membered ring systems: diazines and benzo derivatives (2005)

05S1345 05S1601 05S2544 05S2597 05S2833 05SC249 05SCI003 05SC 1003 05SC1741 05SC1921 05SCI921

05SC1961 05SCI961 05SC225I 05SC2251 05SC3055 05SL777 05SLl239 05SL1239 05SL1683 05SLl683 05SLl897 05SL 1897 05SL1907 05SL I907 05SL2743 05TI077 05T1077 05T2897 05T3953 05T4237 05T4453 05T4785 05T4805 05T4919 05T4957 05T5303 05T5389 05T7384 05T8616 05T8924 05T9637 05T9808 05T 10073 05TI0073 05TI0774 05T10774 05TA2778 05TA2778 05TC31 05TC73 05TC201 05TL51

05TL 1177 05TLlI77 05TLl345 05TL 1345 05TLl433 05TL1433 05TL1663 05TLl663 05TL 1841 05TLl841 05TLl845 05TL 1845

381

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