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PURINES - kap 24
N
N NH
N
9H purine
N
N N
HN
7H purine
two 6π elctron aromatic ring
HN
N N
N N
NH
N
N
1H purine 3H purine
Reaction with electrophiles at N - Protonation
N
N NH
N
pKa 2.5
H+ N
N NH
NH
major protonated form
N
N NH
NN
N NH
N N
N NH
N
N
N N
N
N NH
N1
2
34
56 7
8
9
Reaction with electrophiles at N - Alkylation
N
N NH
N N
N N
NMeI
Me
Me
N
N N
N
Me
Me
Selectivity depends on substituents and conditions
N
N NH
N RX
NH2
- H+
N
N NH
N
NH
R
Base
N
N N
N
NH2
N
N N
N
NH2
RX N
N N
N
NH2
N
N N
N
NH2
major prod.
R
R
majorisomer
N
N NH
N RX
Cl
N
N N
N
Cl
N
N N
N
Cl
RX N
N N
N
Cl
N
N N
N
Cl
R
R
≈ n.r.
O
H+N
N N
N
Cl
O
completeselectivity
Base
N7/N9: - Sterical factors (Large 6-subst) Termodyn. control (reversible react.)
N
N NH
N
X
H2N
Base
COMe N
N N
N
X
H2NCOMe
N
N N
N
X
H2N
COMe
X Time N9 / N7
Cl 1h 4.3 : 1
Cl 24h 19 : 1
Cl 24h 200 : 1
OMe 1h 1 : 1
OMe 14 days Still mixt.
N
N N
N
X
YO
RO OR
OR
RXN
N N
N
X
YO
RO OR
OR
R
N
N N
N
X
Y
R
H2O N
N N
N
X
Y
R
Electrophiles - cancer
N
N NH
N
X
Y
N
N N
N
X
YO
RO OR
OR
N9 / N7α / β
N
N N
N
NH2 RRX
N
N N
N
NH R
R
N
N N
N
NH-R'
R
R=H
N
N N
N
NH
R
RX
R
R=OMeN
N N
N
MeOHN
R
R
Reaction with electrophiles at N - Acylation / Sulfonation
Acylation products generally unstableSulfonation - Stable prod., selective N9
N
N NH
N
Cl KOHClSO2Ph
H2O / acetone64%
N
N N
N
Cl
S OO
Ph
Reaction with electrophiles at N - oxidation
N
N N
N
X
RY
ROOHROOH
X=NH2Y=H
N
N N
N
NH2
R
ON
N N
N
X
RY
OX="OH", Y=NH2X=CN, Y=H
N
N N
N
R
O
O
N
N N
N
R
N
N N
N
R
O
mCPBA OO
N
N N
N
NH2
R
OMeI N
N N
N
NH2
R
MeOMe2NH, HI
Heat
N
N N
N
NHOMe
R
N
N N
N
NH2
R
MeO
H
Me2N
N
NH
N
N
NH2
R
MeO
Me2N
Reaction with electrophiles at C
N
N NH
N
N
Nδ+ δ+
δ+ More benzene like
NH
NElectron richpyrole like
Pyridine like
Reaction with electrophiles at C E-fil Ar subst, generally not working
N
N N
N
NH2
R
Br2NaOAc N
N N
N
NH2
R
Br
Mechanism?
N
N
R
Br2
N
N
R
Br
Br N
N
R
BrH
Br -HBr
N
N N
N
Cl
R
NXS N
N N
N
Cl
R
X Radical mech.?
Reaction with nucleophiles
N
N N
N
Me
Cl
Reactivity towards Nu
N
N N
N
Me
Cl
N
N N
N
MeCl
N
N NH
NCl
N
N NH
N
Cl
N
N NH
N
Cl
Most probably react. on
N
N N
NCl
N
N N
N
Cl
Nu
N
N N
N
Me
ClH+
N
N N
N
Me
Cl
H
Nu
activated for Nu attack
N
N N
N
R
Cl
Cl
Nu N
N N
N
R
Nu
ClR-Metcat. PdN
N N
N
R
Cl
R
Nu.Ar.Subst: Reactivity F>Cl>Br>I
Other leaving groups
N
N N
N
R
Cl
Me3N N
N N
N
R
N
Nu N
N N
N
R
Nu
N
N N
N
R
N
N
from DABCO
N
N N
N
R
NH2
N N
NMe2Me2N
TMS-Cl, pyridineN
N N
N
R
N
NN
Nu N
N N
N
R
Nu
N
N NH
N
- H+
N
N N
N N
N N
N N
N N
N N
N N
N
pKa 8.9
Deprotonation at N
N
NH
pKa 14.2
NH
N
pKa 12.3
Deprotonation at C / C-metallation
N
N N
N
OMe
N
Me
Me
HR
R'
CD3OD N
N N
N
OMe
N
Me
Me
DR
R'Heteromines
N
N N
N
X
YR
HLDA or BuLi N
N N
N
X
YR
Li"E+"
N
N N
N
X
YR
E
X, Y: NH2, "OH" ; Excess base
N
N NH
NH
D2O N
N N
NH
H
D
- H+
N
N N
N
H
D
c.f. H-2 in imidazoles
N
N N
N
H
D
D+
N
N N
ND
H
D
- D+
N
N NH
ND
N
N N
N
I
THP
n-BuLi
- 130 oCN
N N
N
Li
THP
"E+"
- 130 oCN
N N
N
E
THP
- 78 oC
N
N N
NLi
O
"E+"
- 130 oCN
N N
N
THP
Li
N
N N
N
I
R
Riecke Zn N
N N
N
ZnI
R
ArX, cat. Pd N
N N
N
Ar
R
Org. Lett, 2003, 4289
N
N N
N
Cl
RBu3Sn
11
JOC 1997, 6833
N
N N
N
Cl
R
1) LDA2) BrCN N
N N
N
Cl
R
Br + N
N N
N
Cl
R
Br
Br
Nolsøe et al., Synth Commun 1998, 4303
Oxy purines-Oxo forms
HN
N NH
N
O
HN
N NH
N
O
Hypoxanthine
N
N NH
HN
OHN
NH
NH
N
O
Xanthine
O
HN
NH
NH
HN
O
Uric acid
O
O
Alkylation, acylation etc
HN
N N
N
O
Base
R
N
N N
N
O
R
R'-X
N
N N
N
O
R
RN-alkylation
N
N N
N
O
R
Me3SiCl, RSO2Cl, (RCO)2O
N
N N
N
OSiMe3
R
N
N N
N
OSO2R
R
N
N N
N
OCOR
R
O-SilylationO-SulfonationO-Acylation
HN
N NH
N
O
BasePhCH2X N
N N
N
O
Ph
Ph
N
N N
N
O
Ph
Ph
N
N N
N
O
Ph Ph
N
N N
N
O
Ph
Ph
N
N N
N
O
Ph Ph
not detected26% 37% 9% X%
Isolated yields
Replacement of O with other hetero atoms
HN
N N
N
O
R
POX3Base
N
N N
N
X
RX=Cl, Br
HI
X=ClN
N N
N
I
R
N
N N
N
OSiMe3
R
(Me3Si)2NH
NH2R N
N N
N
NHR
R
HN
N N
N
S
R
P4S10
Amino purines
N
N NH
N
NH2
Adenine
HN
N NH
N
O
H2N
Guanine
N
N NH
NNH2Amino form
Diazotation etc.
N
N N
N
X
RH2N
NaNO2
N
N N
N
X
RN2
HBF4 N
N N
N
X
RF
RONO
N
N N
N
X
RN
NRO
N
N N
N
X
R
CCl4CHBr3or CH2I2
N
N N
N
X
RX
N
N NH
N
NH2 RXN
N NH
N
NH
RRCOX
N
N NH
N
NHCOR
LAH N
N NH
N
NHCH2R
N
N NH
N
NH2
RCHON
N NH
N
N
R
H+
NaB(CN)H3
Alkylation, acylation etc
Synthesis of Purines
Carbonyl condensations
Strategy A - Traube synth. etcN
N NH
N
N
N
NH2
NH2
"C+"
N
NH
H2N
H2N
O
"C+"
a
bN
N
NH2
NH2
CH(OEt)3 / HCONH2
H+ N
N NH
N
Ac2O
N
N NH
NMe
N
N
NH2
Cl
Cl
NH2R N
N
NH2
NH
Cl
R
N
N N
N
Cl
R
N
N Cl
Cl
N
N N
N
Cl
RY
N2Ar N
N NH
Cl
Y
NN
Ar Zn/H+N
N NH
Cl
Y
NH2N
N NH
Cl
Y
R R R
Y
HN
N NH
N
O
CH(OEt)3
H+HN
N NH2
NH2
O
H2/cat.HN
N NH2
NO2
O
HNO3H2SO4HN
N NH2Ocytosin
Carbonyl condensations
Strategy BN
N NH
N
N
N
NH2
NH2
"C+"
N
NH
H2N
H2N
O
"C+"
a
b
N
NH2N
R
H2NO
CH(OEt)3
H+ HN
N N
N
O
R
(RCO)2OHN
N N
N
O
RR
Ph-N=C=S
HN
NH
N
N
O
RS
(EtO)2CO
HN
NH
N
N
O
RO
N
NH2N
R
N
N N
N
NH2
R
N
HCONH2
Cycloadditions
N
N
HO2C
H2N
R
N
N
N
CO2Et
CO2EtEtO2C
Diels AlderN
N
N
N
N
R
H
H2N- CO2
CO2Et
EtO2C
EtO2C
- EtO2CCN
N
N N
N
R
CO2Et
EtO2C
Bioactive Purines
DNA / RNA bases
N
N NH
N
NH2
Adenine
HN
N NH
N
O
Guanine
H2N
Anticancer / antiviral drugs
N
N NH
N
SH
6-MP
HN
N NH
N
S
N
N N
N
NH2
F
OHO
HO
OH
Fludarabine
HN
N N
N
O
H2NO
HO
AcyclovirHN
N N
N
O
OHO
ddI
N
N N
N
HN
H2N
HO
Abacavir
Adenosin og adenosinreseptorligander
N
N N
N
NH2
OHO
OHHO
N
N N
N
O
O
CH3
CH3
H3C
Coffein
AKB PhD-lecture, august 05
N
N N
N
H2N
Ph
O
Cytokinins - Plant growth hormones
N
N NH
N
HN
Ph
Sel. A2A antag.Parkinston /Alsheimer?
Natural products
N
N N
N
OMe
N
Me
Me
HR
R'Heteromines
N
N N
N
NH2
Me
H
Cl
Agelasine D
Agelasines from marine sponges(Agelas spp)
Asmarinesfor marine sponges
Heteromines
•Isolated from Heterostemma brownii
•Treatment of tumors in Taiwanese folk medicine
N
N N
N
NHO
H
Asmarine A
Reversine
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
N
N NH
N
HN
NH
N
O
http://www.scripps.edu/news/press/122203.html
Heterocycles cont. more than 2 heteroatoms in one ring kap 26
5-membered ringsTriazoles and tetrazoles
N
NH
N
NN
NH
NN
NH
N
N
XN
X=O, S
unstable X=O
N
XN
NN
XN
XN
NN
XN
Only X=S
6-membered ringsTriazines and tetrazines
NN
N
NN
NN
N
N N
NN
N N
NN
N N
NN
NN
NN
NN
unknown
5-membered ringsTriazoles and tetrazoles (pentazoles highly unstable)
More acidic - less basic comp to diazoles
N
NH
NNN
NH
N
NNH
pKa (base): 1.2pKa (Acid): 9.4
NHN
N
pKa (base): 2.2pKa (Acid): 10.3
NN
NH
N
NN
NNH
pKa (base): ?pKa (Acid): 4.9
NH
pKa (base): ca 0 (NB aromaticity)pKa (Acid): 17.5
N
NH
pKa (base): 7.1pKa (Acid): 14.2
NH
N
pKa (base): 2.5pKa (Acid): ca 12
Bioisostere - CO2H
N
NH
N
N
NNH
pKa (base): 1.2 - Also difficult to alkylate neutral condpKa (Acid): 9.4
Base
N
NN
N
NN
R-X
N
NN
N
NN+
R
R
React. at N
1,2,3-Triazole
N
NH
N
N
NNH
More aromatic(calculations)
N
NH
NN
NNH
N
NN
R
N
NN SiMe3
RX RCOX
N
NN SiMe3
R
- Me3Si+
N
NN
COR
N
NN SiMe3
COR
- Me3Si+
N
NN COR
1,2,3-TriazoleReact. at C
N
NN
R
Br2N
NN
R
Br
N
NN R
Br2
+ Fe-cat.less reactive
N
NN R
Br
N
NN HNO3 / H2SO4
N
NN
O2NN
NN NO2
N
NN
R
n-BuLi
< -20 oC
N
NN
R
Li
MeI
< -20 oC
N
NN
R
Me
ZnX2< -20 oC
N
NN
R
IZn
Negishi, higher temp
Sn-comp. less stable
r.t.
NR
Li+ N2
Benzo-1,2,3-Triazole
NN
N
R
usefull synthetic intermediates
NN
N
R R'
Stabilized anion
NN
N
R R'
Stabilized cation
NN
N
R R'
Good leaving groupR''
Nu
1,2,4-TriazoleReact. at N
NN
NH
HN
NN
lone pair - lone pair interact.
RCOClRXBase
N
NN
R
N
NN
COR
Me3O+ BF4- N
NN
COR
MeHydrol. N
NN
Me
React. at C
NN
NH
Br2, BaseN
N
NH
Br
BrN
N
NH
Cl2, BaseN
N
N
Cl
NN
NH
Cl
heat
N
NN
R
n-BuLiN
NN
R
Li
Rel. stable
N
NN
R
H2N Diazotation etc
N
N N
N
R
NH2
N N
NMe2Me2N
TMS-Cl, pyridineN
N N
N
R
N
NN
Nu N
N N
N
R
Nu
TetrazoleNN
NH
N
NN
NNH
pKa (base): ?pKa (Acid): 4.9
Bioisostere - CO2H
NN
NH
N
NN
NNH
R R
BaseR'-X
NN
NN
NN
NN
R R
R
R+
R / SelectivityCa same selectivity in acylations
NN
NN
RSnBu3
NN
NN
RSnBu3
R'
R'-X
NN
NN
R
R
Small diff. stab. taut.
React. at N
React. at CNN
NN
R
NN
NN
X
R
X2 etcMe2NH, HCl, CH2O"Mannich"
NN
NN
R
N
NN
NN
X
R
Nu NN
NN
Nu
R
Also coupling react.
NN
NN
R
BuLi
- 65 oC
NN
NN
R
Li
NN
NN
R
E
> - 50 oC
N
NR
Li+ N2
NN
NN
H
H2N
NN
NN
H
N2
-H+
NN
NNNN
3 N2 + C
Explosive
Oxadiazoles and thiadiazoles
N
XN
X=O, S
unstable X=O
N
XN
NN
XN
XN
NN
XN
Only X=S
(thiatriazole)
NN
O
R
O
SydnonesMesoionic
Aromaticity (NMR shifts, bond lenghts)
NS
NS
NN
SN
ON
- No acidic NH-Generally low basicity(cf triazoles)-Some examles N-quart.-Few ex. Introd of E-fils on C-Prone to Nu attack
N
SN
NN
S
Reactiv. towards Nu (piperidine)
Cl Cl
N
SN
Cl
Ring opening (esp. O-cont. rings)
NO
N
Most aromaticoxadiazole
aq.NaOH, r.t.
t 1/2 = 4.3 min
H NN
ONa
C-lithiation easy, but often low stab of lithiated prod
NN
N
NN
NN
N
N N
NN
N N
NN
N N
NN
NN
NN
NN
unknown
6-membered ringsTriazines and tetrazines
Highly activated for Nu attackNo simple react with electrophiles
N
NN
NNH3 (l)
R
N
NN
HN
R
H
NH2[ox] N
NN
N
R
NH2
NaNH2 in react with pyridine and diazines
N
N
N
NuNu
NH
+ N2
Diels Alder react. Leading to azines with fewer N(see synth of pyridines, diazines)
N
NN
N SMe
MeS
MeLiH+ HN
NN
N SMe
Me
Nu attack on N
X
NN
N
R
SMe RONa(or amine) X
NN
N
R
OR