Six-Membered Ring Systems with two or more heteroatoms

7.5. General aspects of the chemistry of diazines, triazines and tetrazines Table 7.5.1. pKa values (aqueous solution, 20oC) of some citations derived from diazines
H+ N N H+ -6.6 OH N N H+ 2.83 N H+ 2.15 N N OH N H+ 1.66

N N N + H 2.24 N H+ 1.23 NH2 N N N H+ 3.54 NH2 N H+ 5.69

N N H+ 0.51 NH+ N H+ -7.1

NH+ N H+ -6.3

H2N

N N

H OH OH2

N N 1

NH O H

H OH

NH2 NCHO

further reactions

H3N

N N N

H2N

H N N 2 N

Figure 7.5.2. Examples of nucleophilic addition to 1,3,5-triazines and 1,2,4-triazines Table 7.5.2. Relative rates of nucleophilic displacement of chloride by 4-nitrophenoxide (4-NO2PhOH, MeOH, 50oC)
Cl Cl N N N
14

N N
14

Cl

1.2 x 10

1.9 x 10 Cl

4.1 x 1014 Cl N N

N N Cl N

6.3 x 1016

1.1 x 10

15

1.2 x 1013

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

166

Cl N N Y-

Cl NN

Cl N N-

Y N N

Figure 7.5.3. Nucleophilic displacement in 4-chloropyrimidine.

Ph N* N * Cl NH2Ph N* H H2N N* Cl H Ph N* NH HN * Cl N H N* * NH KNH2, NH3 N

Ph N* * NH2

Ph

Figure 7.5.4. Substitution by the SN(ANRORC) mechanism. (ANARORC = Addition of Nucleophile, Ring Opening and Ring Closure) 7.6. Pyrimidines and purines 7.6.1. Introduction
O R N H NH O N H 4 NH2 N O R2 R3 O O NR1 N H 5 O

3a: R = H 3b: R = Me 3c: R = F

OMe Cl NH2 MeO OMe NH2 Et 6 NH2 NH2 7 H2N N+ O8 NH2 N

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

167

NH2 NH+ N H
NH2 N N 10 N N H HN H2N N

NH2+ NH N H 9
X N HN O N H 12 O H N O N H

N H 11a: X = O 11b: X = S

O Me O N N Me 13

Me N HN N

N S N N 14 N H N Me N

NO2 S N N 15 N H

O HN H2N N N N H HN 11a H2N

H N N

7.6.2. Synthesis of pyrimidines

Me (a) Me N H N S Me N H Me O NH2 S Me O Me O + H2N NH2 S

O (b) H2N N H O Me (c) O N N NN Ph O Me NH O

O NH C N H N 2 O N Ph H2N OEt O N C

O OEt + H2N

NH2 O

O Me O OEt OEt + H2N

NH2 Ph

Figure 7.6.5. Analysis of routes to pyrimidines.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

168

O HC CO2H + H2NCONH2 H3PO4 80 C

o

O OH NH 61% N H NH2 O

HN

NH2 O CN NH2 N H O

OHCCH2CN + H2NCONH2

H2O 100 C
o

N 30-50% N H O

Figure. 7.6.6. Routes to uracil and cytosine.

O EtO Me O ArCHO EtO Me O O Ar (H2N)2CO Et Me N H O Ar NH O

Figure. 7.6.7. The classical Biginelli dihydropyrimidine synthesis.

O PhN Me

HCONH2, 200oC HN O

HCONH2 53%

N N

N N R1 R2 O

MeC CNEt2

Me Et2N Me NN N R3CN -TfOH R R

1

-HCN 97%

N N R3

Et2N

Tf2O

R R

+
2

+
2

R3CN R
3

R1 R2 N

OTf

Figure 7.6.8. Some other routes to pyrimidines. 7.6.3. Synthesis of purines

R1 R1 N R2 N N N H R3 (b) R2 N (a) R
2

NH2 + N NH2

X Y R1

R3

NH2 X

HN

N N H

R3

Figure 7.6.9. Analysis of two routes to purines.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

169

O HN H2N N NH2 NH2 HCO2H heat HN H2N

O NHCHO HN N NH2 H2N

O N N N H

Figure 7.6.10. The Traube synthesis of guanine.

NH2 N O HN O N H NH2 NH2 H2NCONH2 heat HN O N H NH2 Ac2O heat NHCOMe N NH2 O NHCONH2 NH2 HN O N H N Me N N H O H N O N H H N S N NHMe O N N Me

HN O N

NH2 NHMe

CS2, pyridine heat

HN O

NHCS2-

Figure 7.6.11. Examples of purine synthesis from pyrimidines.

O H2NCO H2N N N H HCO2H heat H2NCO OHCN H N N H heat HN N N N H NH2 N N N H Me N N N H O H2NCO H2N N N R Cl H2NCS H2N N N R PhH2CS NCOPh H2NCS PhH2CS PhCON N H N N R HN H2N N EtO2CN C NCH2Ph H2NCO PhH2CN H EtO2CN N H N N R HN H2N N S N N R N N R

NC H2N

N N H

MeC

N+H2Cl-

H2NCO NH Me N H

SCH2Ph pyridine, heat

Figure 7.6.12. Examples of purine synthesis from imidazoles.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

170

7.6.4 Reactions of pyrimidines

HCN + NH3 NH 3 HCN H2NCH(CN)2 2 NH3 H2N H2N NH H2N H2N N N H H2NHC NH N N NH2 N N H NH2 NH2 H2NHC NH

Figure 7.6.13. A route to adenine from hydrogen cyanide.

O R NH N H O Ac2O NH N Ac 17 O

O R

Figure 7.6.14. Acetylation of uracil and thymine. Table 7.6.3. Electrophile substitution of uracil Electrophile NO2 Br+ Cl+ F+ SO2Cl+ CH2=NMe2+ CH2Cl+ CH2OH+
+

Reagents and conditions HNO (d. 1.5), 75 C Br2, H2O, 100oC NCS, AcOH, 50oC F2, AcOH, 10oC ClSO3H, 40-100oC (CH2O)n, Me2NH, 78oC (CH2O)n, HCl, 80oC CH2O aq., rt
3 o

Yield (%) 80 90 52 92 76 57 -

O NH N H O Br2, H2O Br HO

O NH N H O Br

O NH N H O

Figure 7.6.15. Bromination of uracil.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

171

Cl N N Cl KCN, Me2NCHO SO2Me OMe N N H O NH3, MeOH 100 C

o

OMe NaOMe, MeOH 20oC N N Cl

N N

N N NH2 N N H O CN

100 C

Figure 7.6.16. Examples of nucleophilic displacement.

MeO Cl N N Cl LiNPr 2
i

CHO OH OMe MeO MeO OMe N Cl N Cl

Cl Li N N Cl

MeO

7
N N Cl N Cl + MeO ZnBr Pd(0)cat. 65% MeO N Cl

Figure 7.6.17. Substitution of pyrimidines by directed lithiation and by palladium(0) coupling.

OH N Ph N H X N NH N+ H 22 N+ Me H2N N Me N

21

23

24

N N R 25 NH

H2O HO N R

N NH

(slow) O HN R

N NH N

N NHR

26

Figure 7.6.18. The Dimroth rearrangement.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

172

O NH HO N H O

27

O HN O

O MeMe NH HN O

O Me Me NH

N N H H H H 28 O Me H H N

N N H H H H 29 O Me H H N

HN O

O NH

HN O

O NH

N H H MeO 30

N H H Me O 31

7.6.5 Reactions of purines

I N + N N - +NBu4 PhO2C PhO2C OTf CH2Cl2, rt H2N PhO2C N N N N

I N H2N

PhO2C Cl N Ac N N TMS N + N TMS AcO O O-iPr Ac N H O-iPr TMSOTf, -30oC N N

Cl N N O-iPr O-iPr O

Figure 7.6.19 Examples of selective alkylation at N-9 and N-7

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

173

Cl N Cl N N N H NH3, MeOH 100oC Cl N

NH2 N N N H

Cl N Cl N N Cl N R Cl NaOH(aq) N

Cl

H N O N R

Figure 7.6.20 Examples of selective displacement of chloride.

NH2 R N
+

NH2 N NaOH 100oC RN H O N H N H Cl N N

NH2 N N N H

N H

Figure 7.6.21 Dimroth rearrangement of an alkylated adenine. 7.6.6 Pyrimidines and purines in nucleic acids
H N O H N O (b) H N N H O N sugar N Me sugar

HN O O base N N N sugar

O P OH O base O O O O P OH N N N sugar N

H H N H

(a)

(c)

Figure 7.6.22 (a) Two of the repeating units in the primary structure of DNA; (b) adenine-thymine pairing; (c) guanine-cytosine pairing. 7.7 Other diazines, triazines and tetrazines 7.7.1. Introduction

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

174

OH O N H 35 N Et Me

CH2CHMe2

N N O 37

N O OH 36

S P(OEt)2

NH2 N H2N N 38 N NH2 EtHN N

Cl N N 39 NHEt Ar1HN N

Cl N N 40 NHAr2

7.7.2. Methods of ring synthesis

R2 R1 O O + N2H4 R1 N N

(a)

R2 R1 N N

R2

Ar (b) HO O O + N2H4 O N H N

Ar

Figure 7.6.23 Routes to the pyridazine ring system.

R1 R
2

NH2 + O

O H2N

R2 R1

R1 R2

N N

R2 R1

R1 air R2

N N

R2 R1

R1 R
2

O + O

H2N H2N

R3 R
3

R1 R
2

N N

R3 R
3

air,OH

R1 R2

N N

R3 R3

Figure 7.6.24 General routes to pyrazines

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

175

Ar

Ar Ar N3 140 C
o

Ar Ar N

Ar

N N

R1 R
1

O + O

H2N H2N N

R2 base

R1 R1

N N N

R2

Figure 7.6.25. Routes to 1,2,3- and 1,2,4-triazines.

H N N N

2 RCN + 2 H2NNH2 R

NNH2 NH2

H2N

R NNH2

HN R

R R

N N N

Figure 7.6.26. A route to 1,2,4,5-tetrazines. 7.7.3. Chemical properties

N N H O N+ ONH CH2O, MeNH2 Ph O HNO3, HOAc O2N N N H O H Me N N+ O NH Me H N Ph O

O N+ ONH

Figure 7.6.27. Examples of electrophilic substitution.

N KMnO4 N K+ NH2

N N NH2 N

Ph NLi

N N N Li Ph Li N + N Li N Li Ph

air

N N Ph

N N

PhLi

Figure 7.6.28. The reaction of pyrazine with phenyllithium.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

176

Table 7.5 Diels-Alder reactions of 1,2,4,5-tetrazines

R in R N N N N Me (i) CO2Me Me Me CH2Cl2, 25oC MeO2C N H Me CO2Me N R Dienophile, conditions Product

CN Ph (ii) Ph CN 100oC/5 days Ph N N H Ph SMe (ii) SMe PhC CH 166oC/12 h MeS N N CO2Me (iv) CO2Me OEt , dioxane, 25oC MeO2C N N CF3 N (v) CF3 140oC/24 h CF3

Cl Cl

N N N

Cl

Me2NH, Et2O Me2N Cl

N N N

NMe2

Me2NH 195oC

Me2N Me2N

N N N

NMe2

Figure 7.6.29. Sequential displacement of chloride from trichloro-1,2,4-triazine. 7.7. Some fused ring systems 7.7.1 Introduction
N N 5 N3 N 1 48 5 N N 10 49

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

177

O O HN H2N N N N N H 50

CO2H CO2H

O HN O N N N Me Me OH OH OH 51 OMe MeO MeO N H 53 Me NH2 N N NH2 N N Me 52

OH

O N N Me Me MeO MeO

NH2 N N N N O O

54

55

7.7.2 Ring synthesis

R1 R2 (a) N2+

R1 + N N

R1 R2 N N R2

Ph (b) N H N

O Ph

Ph H+ N N Ph

Figure 7.6.30. Routes to cinnolines

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

178

O (a) R1 NHCOR2 NH3, EtOH heat

R1 N N R2

O (b) N O R2 R NH2
1

O O +N H
-

O NHR1 R2 N NR1 R2

Figure 7.6.31. Routes to quinazolines.

R1 R2

(a)

NH2 + NH2

O O

R1 R2

N N

O (b) O R1 + R2 H2NNH2

R1 N N R2

Figure 7.6.32. Routes to quinoxalines and phthalazines. 7.7.3 Chemical properties

OH (a) N N+ H H2O NH N+ H

OH + NH N H

Ar (b) N N ArH CF3CO2H NH N+ H

Figure 7.6.33. Addition reaction of 1-quinazolinium cations.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

179

N N OH 56

N N R CN

COR

57

O POCl3 N H N

Cl R2NH N N

NR2

Figure 7.6.34. Formation and reaction of 4-chlorocinnoline.

Me N N Me Me2NH2+Cl-, CH2O N N

NMe2

Me

Figure 7.6.35. Mannich reaction of 2,4-dimethylquinazoline. 7.8 Oxazines and thiazines 7.8.1 Introduction
N O 58 O 59 N O 60 N

+ N O 61 O + N

N O 62

N S 63

N S 65

H 1 N 10 S

NMe2 N S 66a: R = Cl 66b: R = CF3 R

65

7.8.2 1,3-Oxazines
Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

180

R2 N R3 O+ 67 R1

Me

Me NH O 68 R

Me

Ph Cl Ph O (i) PhCN, SnCl4 (ii) NH3

Ph N Ph O Ph Ph3Cl+ Cl

Ph N O Ph N Ph O + Ph PhC CH SnCl4 Ph

Figure 7.6.36. Routes to 2,4,6-triphenyloxazinium salts.

Ph N Ph N Ph O + Ph Ph PhCH2MgBr N Ph PhH2C O Ph heat NH3 Ph O H2N Ph Ph

Ph N NH2 O Ph Ph

Ph N N Ph

Ph N Ph Ph Ph

Figure 7.6.37. Reactions with nucleophiles.

Ph N Ph O 69 Ph Ph O 70 NPh Ph O 71 Ph NH Ph

Ph

Figure 7.6.38. Ring contraction of the anion 69.

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

181

Me

Me N O CH2R1

Me (i) BuLi (ii) R2X Me O

Me N CHR1R2 H+, H2O

NaBH4

Me

Me NH O CHR1R2

Me

Me

R1R2CHCHO

Figure 7.6.39. Formation of aldehydes by way of tetrahydrooxazines. 7.8.3 Phenothiazines

NMe2 PhHN CF3 S8, I2 150oC H N S CF3 Me2N(CH2)3Cl NaH, 140oC N S
66b

CF3

Figure 7.6.40. A route to triflupromazine.

H N + S 73

N S + 74 Y-

Heterocyclic Chemistry, C. Chen, 2009/3/20 11:51

182