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