6.7 Five-membered ring compounds with two or more heteroatoms 6.7.1 Introduction
a N
b z X
a N b
Y
X a N
b z X
a N
b z CH2 a N
b z CH2 a N
b z CH3
z Y-
Azoles reactions involving negatively charged intermediates.
pKa values of some azoles and azoliums.
N H
N S
H
N O
H
O N S N H
H N N H
N N N H
N N N H
N N
N N H
N N H
H
N N H
H
H N N H H
N N N H
H
N N
N N H H
N N H
N N H
H
N O
H O
N H 16.5
14.52 10 9.4 4.8 13.2
7.00 2.53 0.8
5.5
2.5 -0.51 -2.97 -4.7
-2.20
2.2 1.2 -3.0
N N H
R
N N H R
N N H R N
N H R
N N R
H
N N
R H
3
5
5 4
Tautomerism in pyrazoles and imidazoles.
N N O2N
H
N N O2N H
Preference for the 4-nitro structure in 4(5)-nitroimidazole.
6.7.2 Imidazoles
6.7.2.1 Introduction
N N
N N
N N H
H N
N H
N N H
H H+
H-
H+ H- pKa = 14.5 pKa = 7.0
N N H H2N
HO2C H
N O2N N Me
OH
N N OH
Cl
Bu
N N N
N H
N N
Ph Ph
N N
Cl Ph
Ph 1
2
3
4 5
6.7.2.2 Ring Synthesis
R1 O
R2 OH R2 OH
R1
NHCHO OH
R2 O R1 NHCHO
R2 OH NHCHO NHCHO R1
N N R1
R2
H
+ HCONH2 HCONH2
R1 O NH R2
N N R1 R2
H
NH2 N
N R1 R2
H
SH KCNS
H2NCN
N CN OMe Me
N CN NHCH2X Me
N N H2N
Me X
H + H3NCH2XCl NaOEt
(X = CN or CO2Et )
NH MeO
NH CHCl2 N
H OMe MeO OMe
MeO NH2
N N H CHCl2 CHO
HCO2H
N O
R1 O- R2
OMe
O
NTs R3
N H
NHR1 O
N N
O
H2NOC
R2 R1
N H N
R3 R1 R2
1) TFA, H2O 2) HOAc, 100 oC
1) R2NCO, NEt3 2) TFA, H2O
48
45 46
47
TL, 1998, 1477.
H Ar N O
N3
N N
CHO Cl
N POCl3 Ar
DMF
49 50
JOC. 1998, 7136.
Cl N Cl
NC R1 OR2 O
HN NH
S
S
CO2R2 R1
51 52
(NH4)2S
Synthesis, 1998, 1437.
N R1
XMen NAr Ph
N N Ar CH2l2 Ph
Zn / Cu
R1
53, X = S, N 54
TL, 1998, 4785.
N N
N N Boc
Boc
Boc
Boc E 1) sBuLi
2) E+
60 61
TL, 1998, 4255.
6.7.2.3 Reactions N N H
N N+ H
R X O-
N+ N H
R O- X
N N
O+H2 O- R H
N N H
N N
R O + RCOX
- X- H2O
H+ - H+ O H
R N+ N
6
Hydrolysis of N-acylimidazole, 6, and nucleophilic catalysis by imidazole of hydrolysis of RCOX.
N N H Ph
N+R N COPh Ph
N N R Ph
N N COPh Ph
N N
Ph R
BF4 -
RX, NaOMe
(major) (monor) PhCOCl, NaOH
R3O+BF4 -
Na2CO3aq.
Selective alkylation of 4-phenylimidazole
N N H
N+ N H
H E
N N H
H E
N N
H E H N
N H H
E
N N H
E H N
N H
E H
Electrophilic attack at C-2 and C-5 of imidazole
N N
R
R
N N COPh
H
N N COPh
H
N N H
COPh
7 8
N N Me
Br
N N Me
NC5H10
N N Me
NH2 Me
O2N
N N Me O2N
Cl
N N Me O2N NC N
N Me Me
O2N Br N H
+ NH3
+ NaCN
200oC
75oC
100oC
The nucleophilic displacement in imidazoles 6.7.3 Pyrazoles, triazoles and tetrazoles
6.7.3.1 Introduction
N N Ph
Me Me Ph
N N
N
OH CMe3
Cl
9 10
MeSO4-
N N Ph
Ph
Bu O
O
N N
N
N OH
F
F
N N
11 12
6.7.3.2 Ring synthesis
MeCOCH2COMe + H2NNH2 OH-
R1COCHR2Cl + XCNHNH2
S
MeCOCH2CMe
NNH2 N N
Me
Me H
N N R2 X
R1 H N N
S X
R1 R2
H
H+
Routes to pyrazoles
N N N
Ph Ph
H N
N N Ph Ph
NH2 N
N Ph
Ph O
H
OHN N H
Ph Ph
PhCONHNH2 + PhCSNH2
PhNHNH2 + PhCONHCHO
Routes to 1,2,4-triazoles
NH2NHR1
R OEt
N NHCHO N N
N NHR1 109
110, R1 = H 111, R1 = CO2Et 112, R1 = CO2tBu R
J. Heterocyclic Chem. 1998, 377
SMe SK
NC H2O
N N N H
SH H2N
113
114 H2NNH2
J. Heterocyclic Chem. 1998, 827.
Ph3P+
-O Ph N
N Ph3P+ N
-O
Ph Ph
N N N Ph
Ph
N N N R
Ph NNHPh
NNHPh R
H
R N
H N
NPh NPh
N N N Ph R
NPh + PhN3
Routes to 1,2,3-triazoles
(EtO)2P N3 R1
O
Ph3P O
R2
(EtO)2P R1
N N N R2
O 88
86 87
Synth. Commun. 1998, 1215.
O
Me SnMe Sn
N3 Me
OSiMe3 Me
N N
N N
Ar Sn O
SiMe3
Me Me
N N
N N Ar
H N
N N N R2 R1
N N
N N
R1 R2
NNHR2 N2+
R1
N R2 N3 R1
NNHR2 NH2 R1
N R2 OTf R1 O
R1 N R2 H
+ HONO
Me3SiN3 ArCN H2O
Tf2O NaN3
Routes to tetrazoles
TMSN3 + R1CHO + R2NH2 + CN CO2R3 Me2N
MeOH H3O+
N N N NN R2
R1
CO2R3 rt
120
121 TL, 1998, 2735.
6.7.3.3 Reactions
N N NO2
N N NO2
H
N N H O2N
Rearrangement of 1-nitropyrazole in sulfuric acid
N N Me
CO2Me
Me N N
H Me
CO2Me
CO2Me
Me N Me
N
CH2N2 MeI
N N N SiMe3
N
N N R R
X
+ Me3SiX
N N N Me
N N N Me
Me N
N N Me
Me Me
BF4-
2BF4-
Alkylation of pyrazoles and triazoles
N N
N N Br
Me
N N
N N Me Br
Y
N N
N N Br
Y Me
N N
N N Y
Me Y-
N N
N N Ne
Br N N
N N Me Y
N N
N N Cl
Ph
N N
N N ArO
Ph
N N
N N Ph O
H Y-
+ ArO- H2/Pd
ArH + Y
Br N Me
N N N
Nucleophilic displacement reactions of 5-halotetrazoles
N N N
NHBoc
BuLi
N N N
NBoc
N N N
NHBoc E
TMEDA
E+
101 102 103
JCS P1, 1998, 2301.
O S Tol N
N NMe O
O
N
N NMe O
Me O HO
P(OMe)3
115
116
117 TL, 1998, 1405.
6.7.3.4 Ring cleavage
N N
N N R1 R2
N N N R2
R3
R1
NR1 R2
R3
N2 N3 R2 NR1
Ring-chain tautomerism in tetrazoles and in 1,2,3-triazoles
N N N R
H2N
Ph
N N N R
N Ph
H H
N2 H2N N
R
Ph
N2 N NH
Ph H
R
The Dimroth rearrangement N
N
N N Ph Ph
N N
Ph
N N
Ph H 28 hv
-N2
Photolysis of 1,5-disubstituted tetrazoles
N N N R1 R3
R2
R2
R3 NR1
R2
R3
NR1 N
N N R3 R2
R1
30
Pr oduc t s
NR1 R2
R3
Decomposition of 1,2,3-triazole
N N
N N N2+
H
N N
N N N2
Cl- C + 3N3
Decomposition of tetrazole-5-diazonium chloride
N N Me
Me
N N Me
Me
32 33
hv
Photochemical rearrangement of 1,3-dimethylpyrazole
N N
N N Li
Me
MeNCN + N2 Li
34
Cleavage of 5-litho-1-methyltetrazole
CO2Me
N N
CO2Me CO2Me
N Me N
Me
Me Me Me
Me
hv pent ane
145oC CH2N2
CH2N2
Formation and decomposition of 4,5-dihydro-3H-pyrazoles 6.7.3.5 Azoles as ortho-directing groups for metallation
N N
Me N N
Me
Li
N N Me
CO2H
N N
N N
CPh3
N N
N N
CPh3
Li
N N
N N
CPh3
B(OH)2 BuLi,
-70oC
1. CO2 2. H3O+
BuLi
<-20oC
1. B(OPri)3 2. NH4Cl
Azoles as substituents for directed lithiation 6.7.4 Benzodiazoles and benzotriazoles
N N MeO
H
S N
O
Me Me OMe
N N
Me N
N Me
H O
35 36
N N N
OH
N N N
Cl
N N N
X (X = OR, NR2, CN, N3, etc.)
SOCl2 X-
N N N
N
N H
N Pyrrole, AlCl3
1-Alkyl-substituted benzotriazoles as reagents
N R
R N
N N
Me N
N N
R
J 8.65
J 6.79 7.33
37 38 7.8339
NH2
NH2
NHCOR
NH2
N N H + RCOX R
40 Synthesis of benzimidazoles from benzene-1,2-diamine
N N N
NH2 N
N N
NH2
N N N
N N
N N
N Pb(OAc)4
Pb(OAc)4
+ 2N2
+ N2 CN
CN
Oxidative fragmentation of 1- and 2-aminobenzotriazole N
N
N N
Y
X X
Y
N H X Y
heat or hv
The Graebe-Ullmann carbazole synthesis 6.7.5 Oxazoles and thiazoles and their benzo derivatives 6.7.5.1 Introduction
S O
O
H N
O
N O
OH O H
41 OH
O O
N H
OH
O OMe
N O
O N
N O OMe
O OMe Me
O
42
N
S N
N Me
HOCH2CH2
NH2
Me H
N
S S
N HO
CO2H H
43 44
6.7.5.2 Ring synthesis
EtO2CCHMeNH2
4-MeC6H4COCH2NH2
HCO2COMe P2O5
HCO2H P2S5
O O N EtO
Me H
H
O O N
H H Ar
N Ar S
N EtO O
Me
Oxazole and thiazole synthesis
N S Ph Ph
N R2 O
R1 PhCOCH2Br + PhCSNH2
R1COCHXR2 + HCONH2
S
NH2Br- O
Ph
Ph
O
NH2X- O
R2 R1
Synthesis of thiazoles and oxazoles from α-haloketones
S R1 N
H
CO2Et
N2 EtO2C CHO
R1 SMe
N CO2Et
R2 Cl O
R2 OEt S
N O EtO2C
R2 R1
N S R1 R2
EtO2C
N
O R
EtO2C + RCN Rh(II) cat.
Me3O+BF4-
Methods of synthesis of oxazole- and thiazole-4-carboxylic esters 6.7.5.3 Chemical properties
N X R2 R3
R1
N S Me
HOCH2CH2
R
N S Me
HOCH2CH2
R
45 46
N
O CHO
N
O Li OLi
NC
OSiMe3
Me2NCHO Me3SiCl NC
Reversible ring opening of 2-oxazolyllithium
N O Cl Ph
Ph
N
O NHPh Ph
Ph + PhNH2 145oC
N S Br
N S NO2
N S SPh
N S Me
N S Me
NH2 N
S OMe + PhSH 50oC
+ MeO-
+ NaNH2 150oC
Nucleophilic substitution in oxazoles and thiazoles
N O Me
EtO N
CO2Et EtO2C OEt
Me O
N CH2OH
OH
Me HOCH2
N
OH
Me CO2Et EtO2C
N
OEt
Me CO2Et EtO2C
O
CO2Et EtO2C
H
H+ 110oC
LiAlH4
Synthesis of pyridoxol by Diels-Alder addition N
O N
CN CH2 CHCN O
N CN TEA, 80oC
MeO2CC CCO2Me
N
OEt CO2Me MeO2C
O N
Et O O
20oC
O
MeO2C CO2Me
OEt
+ HCN
N O
O
Me
Me Me N
Me O
O
Me O
O Me
+ HCN 136oC
Oxazoles as dienes
N O R1 R3
R2
O O N O R2
R3 R1 O
N O O R2
R3
R1
N R3
R1 R2
O
O O
1O2
The addition of singlet oxygen to oxazoles
N N Ph Me
O N
Me Ph
N O Me Ph
N CHO Me
Ph
N O Ph Me
O N
Ph Me
Photorearrangement of 4-methyl-2-phenyloxazole
N
O R
Y X
O
X Y
O O
N CR N
O R
X Y
O heat
The Cornforth rearrangement ( X = H, Cl, NR2; Y = Cl, OR, O-)
N O Me Me
R1
N O Me
Me R2
R1
N
S R
N
S R
Me
N S
Me
R R2
R1 OEt
O
R H
O TfO-
MeOSO2CF3 NaBH4
H+, EtOH 1. BuLi
2. R2I
4,5-Dihydrooxazoles and thiazoles as protecting groups.
6.7.6 Isoxazoles, isothiazoles, and their benzo derivatives 6.7.6.1 Introduction
O N O-
H3NCH2 N O N
O- H
H
O N H3N O-
O N H
Cl H3N
-O2C H
49 50 51
52
N
X X
N
53 54
6.7.6.2 Ring synthesis
C CHOEt EtO2C
PhOC O N
EtO2C
Ph + NH2OH
O N Ph
+ NH2OH PhC CCHO
O N R3
R2 R1
HO N
R2 R1
N R2
-O R1
2 BuLi 1. R3CO2Me 2. conc. H2SO4 Isoxazoles by cyclization reactions
HC CCHO H2NNSO3K+ HC CCH NSSO3K+ A route to isothiazole
S H2N
NH Me
I S H2N
NH Me
S N H2N
Me I2
CN CN HO2C
Na+S-
Me S Cl
CN C
N S N
NH2 NC
NH3 Me NH2Cl
O N Ph HO2C
Me S N
Me
HO2C Ph Ph
NH2 HO2C
Me O
H2/Ni 1. P2S5
2 chloranil
Isothiazole synthesis by formation of the N-S bond.
X R
N
OH N
O R
base ( X = Cl, Br, NO2)
NO2 R
O O
N reducing R
agent
O2N
N S O2N R
R O SBr
NH3
N S CH2NH2
SH
I2
Routes to benzisoxazoles and benzisothiazoles
N N2 R
O O
N R
+ N2
2,1-Benzisoxazoles from 2-azidozryl ketones
6.7.6.3 Chemical properties
O N R1 R2
R3 R3 NH2
R1 R2
O
R3
R2 R1
O metal-ammonia
reduction
O N R1
R2
R1 CN R2 O-
O N
Ph Ph
PhC CO- + PhCN
Cleavage of isoxazoles
O N
O N Me
Me
O
NH2
H2N O Me Me
O N
H2N Me Me
H2/Ni Et3N
Reductive cleavage of isoxazoles in corrin synthesis.
O N R2 H
R1 R3
:B
R2 R3
O-
NR1
R3 R2
O
C NR1
O N
H
R
C O
NR N
R :B O
Anionic cleavage of isoxazolium
N Y X
O U
V
W N WV
U O X
Y
Rearrangement of isoxazoles and related heterocycles
O N Me
N
H NHPh
S N
N S Me
NHPh O
57 58
6.7.7 Oxadiazoles, thiadizoles and related systems 6.7.7.1 Introduction
N N
X N X N
N X N N
X N
1,2,3- 1,2,4- 1,2,5- 1,3,4-
Isomeric oxadiazoles and thiadiazoles
N O N R1
R2
N N
S N R
N N S N MeO2C
O
Ar R
R1 R2 O
N2
59 60 61 62
N S N
N OCH2CHOHCH2NHCMe3 O
N N
MeCON S SO2NH2 H
N S N EtO
CCl3
N S N N2
+
Ph
63 64 65 66
6.7.7.2 Ring synthesis
O O N H2N
R2
R1 N
O N R1 R2
heat
N O N R1 R2
R1 R2
HON NOH
heat
N R1
R2CH2 N H OEt O
N S N R1
R2 SOCl2
NH2Cl-
H2N R N
S N Cl
R Cl3CSCl
R
H2N NH2 O
N S N
R OH
S2Cl2
Some general methods for preparing oxadiazoles and thiadiazoles.
6.7.7.3 Chemical properties
N S N Cl
Ph
N S N Cl
Y
Ph
N S N Y
Ph N
S N- Cl
Y
Ph
Y- -Cl-
Nucleophilic displacement of chloride in 5-chloro-3-phenyl-1,2,4-thiadiazole N
N
PhCO S Cl N
S N
Cl N N
Ph O SO2Me
N O N Cl
Me
67 68 69 70
N S N H3C
CH3
N S N LiCH2
CH3
N S N HO2CCH2
CH3 BuLi
N S N
CH2PPh3Cl-
S N N
CHPPh3 NaOH aq
Acidity of α-hydrogen atoms
ArCN + NCO MeS-
N O N H
R
N O N HO- H
NCCH NO-
N O N
H Ph
Et HO-
EtN C
Ph NO
N N
S Ph
EtO- H PhCN -SCN
N S N Ar
HO- H
ArC CS- N2 +
Examples of anionic cleavage
N N
Me O Me
N N Me N
R
Me N N
Me H
NHR Me O
+ H2O RNH2
Ring opening of 2,5-dimethyl-1,3,4-xoadiazole and recyclization
N O N
Ph N
NHAr
Ph N
N N N
Ph H
Ph
Ar O
76 An example of ring interconversion.
N O N R2 R1
-O
R2 NO R1
ON N
O N O- R2 R1
R1C N O- + R2C N O-
Thermal reactions of 1,2,5-oxadiazole 2-oxides
N S N R1
R2
N Se N R1
R2
R1 R2 S
C R1 R2
S
R1C CR2 + N2 + Se heat
heat
Thermolysis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles
6.7.8 Betaines and mesoionic compounds Betaine: dipolar structure
Mesoionic compounds: cannot satisfactorily be represented by a single covalent or dipolar structure.
N N N R
R
Me
O-
N N N R
R
Me
O- a.
N N Me R R
R O-
N N R R
R O-
Me b.
N N N
-O
Me
Me
N N N
-O
Me
Me
N N N O
Me
Me
N N Me MeSO2N
Me Me
Me
N N Me MeSO2N
Me Me
Me
N N Me MeSO2N
Me Me
Me c.
d.
Betains and mesoionic azoles 6.7.8.1 N-Oxides and N-imides
NO2 NCHO Me
NHOH NCHO Me
N+ N
O-
Me
N N
O
CO2Me Me
N N
Me
CHCO2Me CHO NaBH4/Pd
HC CCO2Me
Formation and dipolar cycloaddition of 1-methylbenzimidazole 3-oxide
N S
N S
NH2
N S
NCO2Et
N S
N CO2Et
CO2Me
CO2Me
Me
SO2ONH2 Me
Me
-OSO2Ar
79 79
ClCO2Et, K2CO3
MeO2CC CCO2Me
N-Amination of thiazole and generation of thiazolium N-imide
N N
O OH
PH O
N N
O O Ph
Me O
O
O N
Ph N O
(MeCO)2O heat
Formation of N-phenylsynone
Examples of 1,3-dipolar addition of mesoionic heterocycles
N
O O
Me Ph
Ar
ON Me
Ar Ph
MeO2C MeO2C
O (E)- MeO2CCH CHCO2Me , 80oC
Mesoi oni c c ompound Di pol ar phi l e Pr oduc t
O
N O
Ph Me
Ph
N Ph
Ph
Me HC CH , 120-130oC
N
S O
Ph Ph
MeO2CC CCO2Me , 80oC
N O
Ph CO2Me MeO2C
Ph
, 140oC O
N
N O
PhCH2N
N N Ph
CH2Ph PhCH CH2
N N
N O
Me
Me EtO2CN NCO2Et N N N
N
Me
EtO2C O
EtO2C ,140oC Me
N O O
Ph
N O O
Ph H
O
MeO2C CO2Me
Ph
+ HNCO
Tautomerization of 2-phenyloxazol-4-one