PURINES

6 7
1 N 5 N
8
2 N 4 N
H
3 9
H
N N N N
N N HN N
N N N N N N N
H N
H
9H purine 7H purine 1H purine 3H purine

two 6 elctron aromatic ring

ReactionwithelectrophilesatNProtonation
N N
N H N N N N
N H+ N N N N

N N N N N N N N N N
H H H H H
N
pKa 2.5 major protonated form
 ReactionwithelectrophilesatNAlkylation
Me Me
N N MeI N N N N

N N N N N N
H
Me Me
NH2 NH

N N RX N N
major prod.
N N Selectivity depends on substituents
N H - H+ N
H andconditions
R

Base
NH2 NH2 NH2 NH2 R

N N N RX N N
N N N
N N N N N N N N
R
O major
Cl Cl isomer
N N H+ N N RX
n.r.
N N N N
H
O Base

complete Cl Cl Cl Cl R
selectivity N N N RX N N
N N N
N N N N N N N N
R
 N7/N9:Stericalfactors(Large6subst)
Termodyn.control(reversiblereact.)
X Time N9 / N7
X Base X X COMe Cl 1h 4.3 : 1
N N COMe N N
N N Cl 24h 19 : 1
H2N N N N N
H H2N N H2N N Cl 24h 200 : 1
COMe
X
OMe 1h 1:1
R
X X
N
R OMe 14 days Still mixt.
N N H2 O N
N RX N
Y N N
Y N N Y N N
O
O
OR
OR RO
RO
OR Electrophilescancer
OR
X

X X N N
R
N N
N N Y N N N9 / N7
N O /
Y N N Y N
H
NH OR
RO
R N OR
N
NH-R' RX
N N
N N
R=H R
N N NH2 R NH R
MeOHN
R R=OMe R N RX N
N N
N N
N N N N
N N R
R
 ReactionwithelectrophilesatNAcylation/Sulfonation Cl
Cl KOH
N N
Acylationproductsgenerallyunstable N ClSO2 Ph
SulfonationStableprod.,selectiveN9 N
H2 O / acetone N N
N N O S O
H 64%
Ph
ReactionwithelectrophilesatNoxidation
NH2 X X
O N N N
N ROOH N ROOH N

N Y N N Y N N
N X=NH 2
R R X="OH", Y=NH R
Y=H 2
X=CN, Y=H O
O O
O
O
O N
mCPBA N
N N N N

N N N N N N
R R R
NH2 NH2 NHOMe
O MeO
N N Me2 NH, HI N
N MeI N N

N N N N Heat N N
R R R

NH2 NH2
MeO N MeO N
N N
H
N N N N
Me2N Me2N H
R R
ReactionwithelectrophilesatC

Electron rich
N pyrole like N
N Pyridine like
N N
N H
H

+ More benzene like

N
+ +
N
ReactionwithelectrophilesatC EfilArsubst,generallynotworking
Mechanism?
NH2 NH2 Br
Br2 Br
N Br2 N H
N N NaOAc N N N
Br Br
N N N Br N -HBr
N N N
R R R R
R
Cl Cl

N
N NXS N
N
X Radical mech.?
N N N N
R R
Reactivity towards Nu
Cl Reactionwithnucleophiles
N N N
N N N
Cl
N N N Cl N N
N
Me Me Me

Most probably react. on

Cl
Cl
N N N N N N
Cl N N N N
N N N Cl
N N Cl N
H H H N N N N
Nu
H
N N
N H+ N
Cl Cl activated for Nu attack
N N N N
Me Me Nu
 R R-Met Cl Cl

N N cat. Pd N Nu N N
N
Cl Cl Nu
N N N N N N
R R R
Nu.Ar.Subst:ReactivityF>Cl>Br>I
Otherleavinggroups

N
Cl N Nu
N N Nu N N
N Me3N N N
N N
N N N N N N
R R R N N
R
from DABCO
N N
N N
NH2 Me2N NMe2 N Nu
N TMS-Cl, pyridine N Nu N N
N N

N N N N N N
R R R
DeprotonationatN

N N N N N N N N N
N

N N - H+ N N N N N N N N
H

pKa 8.9

N N

N N
H H
pKa 14.2 pKa 12.3
DeprotonationatC/Cmetallation

D D D
N N D2O N N N N
N N
H H
N N N N - H+ N N N N
H
H H H
c.f. H-2 in imidazoles
D+

D
N N N
N
D D
N N - D+ N N
H
OMe Me OMe Me H

N N CD3 OD N N
H D
R N R N
N N N N
R' Me R' Me
Heteromines

X X X
+
N LDA or BuLi N
N "E " N N
N
H Li E
Y N N Y N N Y N N
R R R
X, Y: NH 2, "OH" ; Excess base
 I Li E

N
N n-BuLi N
N "E+ " N
N

N - 130 o C N - 130 oC N
N N N
THP THP THP
- 78 o C

N
N "E+ " N
N
Li LiE
N - 130 oC N
N N
THP
O

I ZnI Ar
N N N
N Riecke Zn N ArX, cat. Pd N
N N N N
N N
R R R

Org.Lett,2003,4289
 JOC1997,6833

Cl
N
N

Bu3Sn N N
R
11

Cl Cl Cl
1) LDA
N N 2) BrCN N N
N N
Br + Br
N N N N N
Br N
R R R
Nolse et al., Synth Commun 1998, 4303
 Oxypurines
Oxoforms O O O
H H
N N N N HN N
HN HN N HN
O O
N N N O N N O N N
O N N N H H
H H H H H
Hypoxanthine Xanthine Uric acid

Alkylation,acylationetc O
O R N
N N-alkylation
N N
R'-X N N
O N N R
N R
HN Base
N N
R Me3 SiCl, RSO 2 Cl,
O (RCO) 2 O OSiMe3 OSO 2R OCOR
N N N N
N N N N O-Silylation
N O-Sulfonation
N N N N N N
N O-Acylation
R R R R

Ph Ph Ph Ph
Ph
Base N N
N
N
N N N
N N N N
HN PhCH2 X
N O N N O N N N O N N
O N N O N O N
H Ph
26% 37% 9% X% Ph
Ph Ph Ph
not detected
Isolated yields
ReplacementofOwithotherheteroatoms

X I

N N HI N
POX 3 N
O
Base N N X=Cl N N
HN N R R
X=Cl, Br
N N
(Me3 Si)2NH
R
OSiMe3 NHR
P4 S 10
S N N NH2 R N
N
HN N
N N N N
N R R
N
R
Aminopurines
NH2 O
N N N N
HN
Aminoform N NH2
N N H2N N N N N
H H H
Adenine Guanine
Alkylation,acylationetc
NH

N N
NH2 RX
N N
N H
N R
RCOX R
N N
H NHCOR NHCH2R N NH2
N N LAH N NaB(CN)H3 N N RCHO N
N N
N N
N N N N H+ N N
H H H H

Diazotationetc. X X
N N
N HBF 4 N
X NaNO2
N2 N N F N N
N
N R R

H2N N N
R RONO
X CCl4 X
X
CHBr 3
N N N N N
N or
N N N CH 2 I2 X N N
N N
N R R R
RO
CarbonylcondensationsSynthesisofPurines NH2
N
"C+"
a N NH2
StrategyATraubesynth.etc
N N
NH2 CH(OEt) 3 / HCONH 2
N N b O
H+ N N N
H H2N N
N NH2 N N
H "C+"
Ac2 O H2N N
H
N N
Me
N N
H
Cl Cl Cl
NH2 NH2 N
N NH2 R N N

N Cl N NH N N
R R
Cl Cl Cl Cl Cl
N2Ar N Ar Zn/H+ NH2 N
N N N N N N
Y N Cl Y N NH Y N NH Y N NH Y N N
R R R R

HNO3 CH(OEt) 3
H2 SO4 NO2 H2 /cat. NH2 HN N
HN HN HN H+
NH2 NH2 NH2 O N N
O N O N O N H
cytosin
 NH2
Carbonylcondensations N
"C+"
StrategyB a N NH2
N
N
O b O
O O N N
H2N CH(OEt) 3 H H2N N
HN N (RCO) 2 O N HN N
+
H+ "C "
H2N H2N N
R N N N N N H
R R R
(EtO)2 CO Ph-N=C=S
O O
N HN N
HN

O N N S N N N
H H R NH2
R
N N
HCONH2 N
H2N N N
N
Cycloadditions R R

CO2Et HO2C N CO2Et CO2Et

N N N Diels Alder EtO2C H N
N
H2N N N
EtO2C N CO2Et N N
- CO 2 EtO2C N N
R EtO2C H2N N - EtO2 CCN R
R
 BioactivePurines
NH2 O
DNA/RNAbases
N N HN N

N N H2N N N
H H
Adenine Guanine

Anticancer/antiviraldrugs
SH S O
N N HN N
HN N
N N N N
H H H2N N N
HN
6-MP O
HO N N
NH2
N O Acyclovir N
N H2N N
HN N
F N N HO
N N
HO
O HO
O
OH
Abacavir
HO
ddI
Fludarabine
 Adenosinogadenosinreseptorligander
NH2
N O CH3
N
H3C N
N O
N N
O N N
HO N N
O CH3
Coffein H2N N N

HO OH Ph
Sel.A2Aantag.
AKBPhDlecture,august05 Parkinston/Alsheimer?

CytokininsPlantgrowthhormones

Ph

HN

N N

N N
H
 Naturalproducts
OMe Me

N N Heteromines
H
R N
IsolatedfromHeterostemmabrownii
N N
R' Me TreatmentoftumorsinTaiwanesefolk
Heteromines medicine

Agelasinesfrom Asmarines
marinesponges formarinesponges
(Agelasspp)
H
H

HO N
NH2
N N
N N
Cl N N
N N
Me Asmarine A
AgelasineD
Reversine

O
HN
N
N N

N N N
H H

http://www.scripps.edu/news/press/122203.html

Elcompuestosintticoreversinainducedediferenciacin,queeselprocesoclaveenla
regeneracin epimrfica en la naturaleza cuando un miembro perdido, por ejemplo,
crecedenuevoensuformaoriginal.
 HETEROCYCLESMORETHAN2HETEROATOMSINONE
RING
5memberedrings
Triazolesandtetrazoles N N N N N
N N
N N N
X=O, S H H H

N N N N N N
N N N N N
X X X X X
unstable X=O Only X=S

6memberedringsTriazinesandtetrazines

N N N N
N N N N N N N N N
N N N N N N
N N N N N N N
unknown
5memberedrings
Triazolesandtetrazoles(pentazoleshighlyunstable)
Moreacidiclessbasiccomptodiazoles

N
H
pKa (base): ca 0 (NB aromaticity)
N
pKa (Acid): 17.5
N
N N
H H
pKa (base): 7.1 pKa (base): 2.5
pKa (Acid): 14.2 pKa (Acid): ca 12

N N N NH N N
N NH
N N N N
H H
pKa (base): 2.2 pKa (base): 1.2
pKa (Acid): 10.3 N N N N pKa (Acid): 9.4
N NH
N N
H
pKa (base): ?
pKa (Acid): 4.9 BioisostereCO2H
 1,2,3Triazole
N N
N NH
React.atN N N
H
More aromatic
(calculations)
N N pKa (base): 1.2 - Also difficult to alkylate neutral cond
N NH pKa (Acid): 9.4
N N
H
Base

N N N N
N
N N NH N SiMe3
N N N
N N H N

RX RCOX
R-X
N N
N SiMe3 N SiMe3
N N N N
N + N R R COR
N N
- Me3Si+ - Me3Si+
R
N N
N N N
N N
N COR
R N COR
React.atC 1,2,3Triazole
Br
N N Br
Br2 N Br2 N
N N
N N N R N R
N + Fe-cat.
R R N
less reactive
O2N
N N N
N
HNO3 / H2SO4
N NO2 N
N N N

+ N2
Li N
R

r.t.

N n-BuLi N MeI N
N N N
N < -20 oC Li N < -20 oC Me N
R R R

< -20 oC ZnX2

N Negishi,
N higher temp
IZn N
Sn-comp. less stable R
 Benzo1,2,3Triazole

N
N
N
R

usefull synthetic intermediates

N N N
N N N
N N N Nu
R R' R R' R R'
R''
Stabilized anion Stabilized cation Good leaving group
BAMBERGERSntesisdeBenzotriazina
Apartirdehidrazonadelcidopirvicoysalesdearildiazonio

BISCHLERSntesisdeBenzotriazina
React.atN 1,2,4Triazole
N HN lone pair - lone
N N pair interact.
N N
H
RX RCOCl
Base
Me Me
N N Me3O+ BF4- N Hydrol. N
N N N N
N N N N
R COR COR

React.atC
Br
N Br2, Base N N Cl2, Base N N
N
heat
N N N N
N Br N N N Cl N
H H H H
Cl

N N
N
N n-BuLi N
N Li N N Diazotation etc
H2N N
R R
R
Rel. stable
 N N
N N
NH2 Me2N NMe2 N Nu

N N TMS-Cl, pyridine N Nu N N
N

N N N N N N
R R R
 Smalldiff.stab.taut. Tetrazole
N N N N

N
N
N
NH BioisostereCO2H
H
pKa (base): ?
pKa (Acid): 4.9 N N R'-X N N
N SnBu3 N SnBu3
R N R N
React.atN R'
N N N N
N NH
R N R N
H

Base
R'-X N N
N
R N
N N N N R
+
N N R
R N R N
R

R / Selectivity
Ca same selectivity in acylations
React.atC
N N N N
N N Me2NH, HCl, CH2O X2 etc
N N N N
N "Mannich" N X N
R R R

N N
N N Nu N N N
N N Also coupling react. H2N N
X N Nu N H
R R

N N BuLi N N N N
N N N N N
N - 65 oC Li N E N N
R R R N2 N
H Explosive
> - 50 oC
-H+

N
N N
+ N2 N
Li N N N N
R

3 N2 + C
 Oxadiazolesandthiadiazoles
X=O, S
N N N N N N
N N N N N
X X X X X
unstable X=O Only X=S
(thiatriazole)

R NoacidicNH
N Generallylowbasicity
N (cftriazoles)
O O
SomeexamlesNquart.
Sydnones Fewex.IntrodofEfilsonC
Mesoionic PronetoNuattack

Aromaticity(NMRshifts,bondlenghts)

N N
N N N N
S S S O
 Reactiv. towards Nu (piperidine) Ringopening(esp.Ocont.rings)

Cl
N N N N Most aromatic
Cl N Cl
N oxadiazole
S S S aq.NaOH,
H r.t. N
N
N N
t 1/2 = 4.3 min ONa
O

Clithiationeasy,butoftenlowstaboflithiatedprod
 6memberedrings
Triazinesandtetrazines

N N N N
N N N N N N N N N
N N N N N N
N N N N N N N
unknown

HighlyactivatedforNuattack
Nosimplereactwithelectrophiles

H H
N N
N NH3 (l) N NH2 [ox] N NH2
N
N N
R N R N N
R N

NaNH2 in react with pyridine and diazines

 N SMe RONa N
X OR
(or amine) X
N
R N N
R N

N SMe
N MeLi N SMe
N H+ HN
MeS N N
N Me
Nu attack on N
Nu
Nu
N
N + N2
N
NH

DielsAlderreact.LeadingtoazineswithfewerN
(seesynthofpyridines,diazines)