The regiospecific synthesis of N-oxidized and N-quaternized polycyclic polyazines and synthesis of unsymmetrical quaterp...

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Title:
The regiospecific synthesis of N-oxidized and N-quaternized polycyclic polyazines and synthesis of unsymmetrical quaterpyridines using palladium-catalyzed cross-coupling
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xii, 152 leaves : ill. ; 29 cm.
Language:
English
Creator:
Cruskie, Michael P., 1968-
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Subjects / Keywords:
Chemistry thesis, Ph. D   ( lcsh )
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Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1995.
Bibliography:
Includes bibliographical references (leaves 143-151).
Statement of Responsibility:
by Michael P. Cruskie, Jr.
General Note:
Typescript.
General Note:
Vita.

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University of Florida
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All applicable rights reserved by the source institution and holding location.
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Full Text











iE REGIOSPECIFIC SYNTHESIS OF N-OXIDIZED AND N-QUATERNIZED
POLYCYCLIC POLYAZINES AND SYNTHESIS OF UNSYMMETRICAL
QUATERPYRIDINES USING PALLADIUM-CATALYZED CROSS-COUPLING


MICHAEL


A DI
OF THE


CRUSKIE


SSERTATION PRESENTED TO THE GRADUATE SCHOOL
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
fPl TMF R flTTM FflfIRr 'PUP fPV flvn ri






























This


work


dedicated


parents,


Michael


Patricia


Cruskie,


whom


respect,


admire


and


love


dearly.


This


dedication


extends


sister,


brother,


grandparents,


aunts,


uncles,


cousins,


godchildren


and


dog.














ACKNOWLEDGMENTS


The author is truly indebted to Dr.


John A.


Zoltewicz for


his guidance,

of this work.


patience and encouragement throughout the course

It has been a pleasure to be associated with Dr.


Zoltewicz.


Appreciation


also


extended


Otto


Phanstiel,


Wayne


Barth


and


members


supervisory


committee


, Dr.


W.R. Dolbier,


J.M. Boncella,


K. Wagener


and Dr.


. Meyer.


Special


thanks


are


Carlton


Dill


kindness


and friendship over the past


three


years.


friendship


and


assistance


certain


graduate


assistants,


and


especially


Paul


Whitley,


will


long


remembered.


A debt of gratitude is owed to Stephen J.


love


Cruskie for his


and devotion.


Melissa G.


Glantz deserves particular thanks for her


dedication


understanding;


has


definitely


been


appreciated and will


forgotten.


Financial support from the Chemistry Department, Division


Sponsored


Research


and


Taiho


Pharmaceutical


gratefully


acknowledged.














TABLE


OF CONTENTS


page


ACKNOWLEDGMENTS


LIST

LIST


OF TABLES

OF FIGURES


viii


ABSTRACT

INTRODUCTION


DIRECT PREPARATION OF N-QUATERNIZED AND N-OXIDIZED
POLYCYCLIC POLYAZINES BY PALLADIUM-CATALYZED CROSS-
COUPLING. AN UNEQUIVOCAL ISOMER SYNTHESIS .


Introduction
Results and
Conclusions


SCUSS


A GENERAL METHOD OF SYNTHESIS FOR REGIOSPECIFICALLY
OXIDIZED OR N-QUATERNIZED POLYCYCLIC POLYAZINES BY
PALLADIUM-CATALYZED CROSS-COUPLING OF N-OXIDIZED
QUATERNIZED HETARYL STANNANES . .


Introduction .
Results and Disc
N-Oxidation


l355


and


N-Methylation


of Hetaryl


Cross
Cross


Stannanes
-Coupling
-Coupling


S
N


Stannane as th
Cross-Coupling of N
Hetaryl Halide
Conclusions . .


N-METHYLATION AND
NITROGEN ATOM OF
Tr'/n nr^\r tWi V7 -rn~r-i


tannyl
-Methy
e Limi
-Methy
as th


N-OXIDATION OF THE
A 2,3'-BIPYRIDINE.


N-Oxides .
lated Stannanes
ting Reagent .
lated Stannanes
e Limiting Reag


LES
TWO


with


wi
ent


th


REACTIVE
GENERAL METHODS









Pd-catal


N-Methy
Addition
Di
Deprote
N-Oxida
Palladi
Ox
Palladi'
Ox
Unsucce
Pr'
Conclusions


yzed


lat
n o
qua
cti
tio
um-
ide
um-
ide
ssf
epa


Cross-Co


on
the
erni
n


Cataly
4-10
Cataly
4-8
ul Pal
re 4-6


Prote
zation


uplin'

acting


Group


Coupling


ladiu]


* .
oupling

m-Cataly


to
to

toz

zed


Sand
and


* Prepare
Prepar

Prepar


upling


a a a a a a a S a a a a S S a


REVISED
TOXIC
WORM.


STRUCTURE AND
QUATERPYRIDINE


CONVERGENT SYNTHES
ISOLATED FROM THE


IS OF THE NEURO-
HOPLONEMERTINE S


a a a S a a a a a a a a a a a a a a a S


EA
46


Introduct
Results a
Synt


ion
nd
hes
Qu
hes
tal


. .
ion
,2'
idi
eme
ure


: 3',2" :4",3"'
ne (5-1)
rtelline (5-3) .
for Nemertelline


THE CORRECT STRUCTURE OF THE OXIDIZED DIMER FORMED FROM
2,2'-BIPYRIDINE IN THE PRESENCE OF LITHIUM DIISOPROPYL-
AMIDE IS 2,2':3',2" '':6'',2'''-QUATERPYRIDINE. .


Introducti
Results an
Indep


Proof


Discu
ndent
,2' :4'


ssion
Synthe
,2'':6


a a a a a a a a a a a a a


of
' '-Quaterpyridine


f the Structure of 6-2,
aterpyridine Formed in
A *


the
the
the


Presence


Mechanism


Coupling


with


LDA


STRATEGIES
QUATERPYR
REACTION
Intro'
Resul


FOR T
DINES


ion
.nd
A-B
Qu
A-B
Qu


fa. a---. a--


SYNTHESIS OF UNSYMMETRICAL
SING PALLADIUM-CATALYZED CROSS-COUPLING
S a a a a a a a a a a a a a a a S a


scussion . .
-D Geometry of 2,2'
erpyridine (7-5)
-A Geometry of 3,3'
erpyridine (7-8) .


.
:4''


* .
,41"


- I


* a a
,3t"I.
* a a
,3"' I-
* a .


5-3


L








General


Procedure


N-Oxidation


Hetaryl


Stannanes


General


He


Cross-Co
General
Qu


Procedu:


t

u]
P
a


General P
N-Q


aryl
Lim
plin
roce
tern
the
roce
uate
Hal


re for the Cro
tannyl N-Oxide
ing Reagent .
of an N-Oxide
re for the Cro
ed Hetaryl Sta
limiting Reagen
re for the Cro
ized Stannanes


Limiting


s-Coupling of
with Stannane as

ith Excess Stannan
s-Coupling of
nanes with Stannan

s-Coupling of
with the Hetaryl


the
94
e 102

e as


Reagent


REFERENCE


LIST


BIOGRAPHICAL


SKETCH














LIST


OF TABLES


Table


pa 2.


Conditions
Stannylated


sence


and


Results


Hetaryl


N-O


of the
xides


Cro
with


of Pd(PPh3)4


ss-


Coupling


Hetaryl


Halides


S. 30


Results


Stannanes
Catalysts


the
and
Under


or Stannane


Cross-Cc
Hetaryl


)upling o0
Halides


Conditions


(B).


Quaternized


with


Molar


Various


Excess


Halide


S S S S S S S 531


Chemical


Shifts


ppm


of 5-1


and


5-3


CDCl3


Possible


to Form


Ways


of Joining


Unsymmetrical


QPYs


Together T
f the type


2'-BPYs


A-B


-C-A


8-1.


Fractional


Therma
Atoms


Par


Coordinates
meters (A2)


of 5-3


and
for


Equivalent
the Carbon


Isotropic


and


Nitrogen


Bond


Lengths


and


Angles


Carbon


and


Nitrogen


Atoms


5-3.


t















LIST


OF FIGURES


Figure


page


Catalytic


cycle


of Pd-catalyzed cross-couplings


1-2.


Generalized Stille coupling reaction


S 3


1-3.

1-4.


Mechanism of oxidative

Transmetalation of Pd


addition

cross-coupling


1-5.


Generalized Suzuki


coupling reaction


. 8


2-1.

2-2.

2-3.


Generalized Suzuki-type coupling


Generalized Stille-type


Couplings


reaction


coupling reaction


with 3,5-dicloropyridine-N-oxide


2-4.


Couplings with 3-bromoquinoline-N-oxide


2-5.


Couplings
iodide


with


3-bromo-l1-methylquinolinium


S S S S S S S S S S


3-1.


Generalized cross-coupling with N-functionalized


hetaryl


halide


S~~~ ~ ~ S S S


3-1.


Generalized cross-coupling with N-functionali


hetaryl


stannane


4-1.


Synthetic


scheme


for pathways


utilized


4-2.

5-1.


Coupling


of 2-halo-hetaryl-N-oxides


Retrosynthetic analysis


quaterpyridine 5-1


5-2.


Retrosynthetic


analysis


for quaterpyridine


5-1


5-3.


Synthetic


scheme


for quaterpyridine


5-1


Ct,,. nI Al-


e(,A


e I In c k A i" : A A 5\ A M A








5-6.


5-7.

5-8.


Retrosynthetic


Palladium


ORTEP
with


analysis


coupling


crystal


quaterpyridine


nemertelline


structure


probability


5-3


5-3


nemertelline


ellipsoids


5-3


. . *57


5-9.


Proton


NMR


spectrum


MHz


of nemerte


lline


(5-3


in CDC13


C C C S C C S S C S C C 559


5-10


. Proton


NMR


spectrum


MHz)


of nemerte


lline


(5-3)


CD30D


S S C S C C S C C C S S C60


COSY


nemertelline


(5-3)


CDCl3


. Proton


NMR


spectrum


(300


MHz)


of 5-1


in CDC13


5-13.


COSY


at 300


5-1


CDCI3


. . 64


Synthetic


scheme


quaterpyridine


6-1


. 69


Proton


NMR


spectrum


of quaterpyridine


6-1


CDCI3


S S C S S C C71


6-3.


COSY
CDCl3


spectrum


quaterpyridine


6-1


Proton


NMR


spectrum


quaterpyridine


6-2


CDC13.


COSY


spectrum


quaterpyridine


6-2


CDC13


6-6.


NOE


difference


spectrum


quaterpyridine


6-2


CDC13


irradiating


H5'"


ppm


6-7.


Partial


proton


NMR


spectrum


upfi


eld


portion


of
6-2


6-6,
in


the
CDC13


dihydro


cursor


puaterpyridine


6-8.


Proposed mechani
2,2'-bipyridine


LDA


reaction


with


7-1.

7-2.


Synthetic

Synthetic


scheme

scheme


quaterpyridine

quaterpyridine


7-1

7-2


63















Abstract


of Dissertation


:he University
Requirements f


Presented


Florida


Degree


Graduate


in Partial


of Doctor


School


Fulfillment


of Philosophy


REGIOSPECIFIC


POLYCYCLIC


SYNTHESIS


POLYAZINES


AND


OF N-OXIDIZED


SYNTHESIS


AND


N-QUATERNIZED


OF UNSYMMETRICAL


QUATERPYRIDINES


USING


PALLADIUM-CATALYZED


CROSS-COUPLING


Michael


December,


. Cruskie


1995


Chairperson:


Major


John


Department


Zoltewicz


: Chemistry


Palladium-catalyzed


cross-coupling


reactions


between


hetarylborane


stannane


N-oxidized


N-quaternized


hetaryl

in term


halides


provide


polyazines


location


of unequivocal structure

N-functionalized group.


Examples


of several


ring


systems


are


given


to illustrate


scope


and


limitations


of the


new


synthetic


method.


N-Oxides


of tributyl


stannylated


pyridine,


quinoline


and


isoquinoline


and


N-methylated


tributylstannylpyridine


quinoline


were


readily


prepared,


many


the


first


time.


presence


catalyst


ese


material


cross-couple


with


various


chloro,


bromo


iodo


hetaryl


halides


give


polycylic


polyazines


having


N-functional


group


placed


~rn -rrnt S *-A rr 1 1 ..


a 1 a e a - - a -


SI *C t... a .n


~1


L


u i








use


of a tosylate


as a counterion


with


quaternized salts


minimized decomposition


stannane.


5-Carbamoyl-2,3'-bipyridine


model


compound


was


methylated and N-oxidized at the less reactive 2-pyridyl ring


for the


first


time.


Two different


schemes


were developed.


quaterpyridine


first


time.


called


nemertelline


proton


was


NMR


synthesized


spectrum


2' :3' :2'' :4 3' '-quaterpyridine


shows


that


natural product isolated from the hoplonemertine


sea


worm.


correct


structure


3,2' :3'


the natural


product has been


,3'''-quaterpyridine.


was


identified

synthesized


using a key palladium-catalyzed cross-coupling step and X-ray


analysis


confirmed


structure


well


providing


conformation in


solid state.


2,2'-Bipyridine


presence


LDA


gives


2' :3'


:6'


,2' '-quaterpyridine resulting from a reaction


position


one


bipyridine


and


the


position


another,


2,2' :4'


:6'


,2'''-quaterpyridine


coming from


the reaction at the 4 and


6 position as originally claimed by


others.


independent


synthesis


2,2' :4'


:6'


quaterpyridine involved palladium-catalyzed cross-coupling of


,6-dichloro-2,4-bipyridine and


(tributylstannyl)pyridine.


The correct


structure


follows


from analysis


the COSY,


NOE


difference and proton NMR spectra.


*1~~~~~~~~~~~~~~ -L -- .-js an .. aa


14'':2''


1211


2'


12''


,2'


~ yl ACI I C.~ rl


~AU~ *








stannane


chlorinated


bipyridine.


pyridyl


N-oxide


synthon


was used


to regioselectively


introduce


the


required a-


chloro


group.














CHAPTER 1
INTRODUCTION


Palladium


extremely


useful


reagent


that


catalyzes a wide variety of known organic reactions.


Palladium


salts


and


complexes


have


been


widely


used


many


organic


reactions


such


double


bond


isomerizations,


molecular


rearrangements,


eliminations,


oxidations,


dimerizations


allylic


and


substitutions


oligomerizations,


carbonylations, cyclopropanations, reductions, and couplings.


Since


there


are


basic


reactions


that


generate


new


carbon-carbon bond, palladium-assisted coupling reactions have


become


an important


tool


organic chemists.


Palladium-assisted coupling reactions proceed by several


closely


related


pathways.


these


pathways,


initial


step


believed


formation


organopalladium


salt.


There


are


four


general


ways


which


these


organopalladium salts


can be


formed.


These are


direct metallation of


a hydrocarbon,


arene,


or a heterocylic


compound


with


Pd(II)


salt;


(ii)


addition


palladium(II)


salt


acetylene,


diene,


alkene;


(iii)










Grignard


reagent


anion


exchange


on palladium(II);


(iv)


oxidative


addition


organic


halide,


triflate,


acetate,


or ether


onto a


palladium(0)


moiety.


formation


the possibility


of the


organopalladium complex now


of manufacturing


coupling products by


allows


one


three


plausible


routes:


disproportionation


form


diorganopalladium intermediate which can reductively eliminate


to give a homocoupled product;

addition complex to an alkene,


(ii) addition of the oxidative

diene, or acetylene followed by


reductive elimination


or the


elimination


of palladium halide


or hydride to produce the coupled products;


(iii)


formation


of a diorganopalladium species by transmetalation


organometallic reagent,


to produce


of another


which can again reductively eliminate


a cross-coupled product.


palladium-catalyzed


cross-couplings,


more


specifically


Stille2


and


Suzuki3


coupling


reactions,


catalytic


process


consists


oxidative


addition,


transmetalation,


and reductive elimination


(Figure


1-1) .


Stille coupling reaction utilizes a palladium catalyst and is


defined


cross-coupling


between


organic


electrophiles


typically an organic halide or triflate)


and organostannanes


Figure


1-2)


2 The organic halide or triflate participates


oxidative


addition


and


organostannane


takes


part


4-hanCrlC 4- neA .4- a


..(~1~ Fr~~r *i n -a-- -I










stability


organostannanes


and


boranes,


usually


mild


reaction


conditions,


compatibility


this


chemistry


with


virtually


functional


group,


have


made


Stille


Suzuki


couplings


quite


popular


among


synthetic


chemists.


fact,


survey


applications


trans


ition


metal-mediated


cross


-coupling


reactions


the


year


1992


shows


that


Stille


and Suzuki


reactions


account


over


cross-


couplings


Figure 1-1


R-PdL


oxid. addn.


PdLn


R'SnR"3

trans metallation

XSnR"3


R-PdLn-R"3


red. elim.


Figure 1-2 Generalized Stille coupling reaction








4

Several fundamental questions arise when considering the


transformations which occur during any organic reaction:


What


rate determining


step? What


the exact mechanism of


this


step?


it possible


facilitate


this


step?


What


are


the side reactions involved with this process?


Is it possible


to suppress such side reactions? These types of questions have


substantial


amount


research


toward


fully


understanding


scope


and


limitations


three-step


process


palladium-catalyzed


cross-couplings.


During


catalytic process,


considerable electronic demands are made on


palladium


catalyst.


Oxidative


addition


requires


electron rich metal


that


oxidation


will


favored5'6


, but


transmetalation


requires


an electron deficient


palladium


the nucleophile to attack the metal center.


reagents and conditions used,


Depending on the


the exact mechanism may vary and


either


oxidative


addition


transmetalation


can


rate


determining.


To better understand the catalytic process,


each


step must


be considered individually.


It has become generally accepted that oxidative addition


organic


halides


or triflates


to Pd(0)


complexes


proceeds


through


unsaturated


14-electron


Pd(0)


intermediate.


Ligand


dissociation


leads


open


coordination


sites


palladium


which


can


now


allow


halide


triflate


, e- 4 t 1 1. nnrnA ..a4-- d- M.1. fla IA ALr I1r


a). j.. -


8-10


I










Meisenheimer


intermediate


(Figure


1-3)


9-11


Meisenheimer


intermediate


influenced by C-halogen bond strength,


while


transition


state


preceding


intermediate


mainly


influenced


by the electrophilicity


carbon atom being


attacked.


relative


rate


which


organic


halides


triflates


oxidatively


add


palladium


generally


order


OTf,


suggesting


that


transition


state


succeeding


the


Meisenheimer


intermediate


rate


determining


in oxidative


addition.


Figure 1-3


PdL2 + Ar-X

X-I,Br,CI


Ar--X

PdL2


PdXL2


S


Meisenheimer intermediate


oddative addition complex


Depending on the type of ligands used with the catalyst,


irreversible


formation


the oxidative addition


complex


can


very


often


lead


stable


material.


13-15


Recent


studies


have


suggested


that


type


ligands


used


with


palladium


can


play


very


important


role


catalytic


process.


Among


such


developments


discovery


large


ligand


__










triphenylarsine


tri (2-furyl)phosphine


instead


typical


triphenylphosphine.


Triphenylarsine


and


tri (2-


furyl)phosphine do not coordinate to palladium as strongly as


triphenylphosphine which allows


ligand dissociation more


readily.


Ligand dissociation


oxidative


addition


can


complex


lead to


well


faster


open


formation


coordination


sites


on the oxidative addition


complex


for transmetalation.


While the mechanism for oxidative addition is reasonably


well understood,


16 some evidence suggests that


transmetalation


rate


determining


most


cross-couplings.


17,18


Unfortunately,


little


known


about


mechanism


this


step although some indirect information has come from studies


on transmetalation at


platinum(II)


19-24


Stille


and Suzuki


coupling


reactions


use


different


reagents


transmetalation and therefore,


will be


addressed separately.


Figure 1-4


-..RP
L--- Pd --X


Pd R
,1 I
X


.lR
L Pd--RI
L









7

the nucleophile is the organostannane and the leaving group is


halide


triflate.


Therefore,


reaction


might


expected to proceed


through a


classical


associative process25


which


the nucleophile


approaches


the plane


complex


perpendicularly.


intermediate


result,


formed which


unstable


then releases t


pentacoordinated

he leaving group


(Figure


1-4)


Recently,


work


Farina


shown


that


with


olefinic


stannanes,


ligand


dissociation


formation


palladium-stannane


x-complex


are


steps


transmetalation.


An important development in facilitating transmetalation


Stille coupling


reactions


involves


use


cocatalytic


copper


iodide,


along


with


palladium.26-29


Farina


have


shown


that


with


triphenylphosphine


and


palladium(0),


cocatalytic copper


iodide can


give


a >100-fold rate


increase


over


typical


Stille


reaction.


Though


there


widespread


use


copper


iodide


coupling


reactions,


extact


functions


in the


reaction are not


completely understood.


plausible


role


that


copper


involved


stannyl/copper


transmetalation,


thus


producing


organocopper


oxidative


moiety


addition


which


complex


could


more


then


transmetalate


readily


than


onto


stannane


-- a


- .


a -I -


1 fl rL I C- -L __-- '-- -u :A A


II S


.


~L L L L










When


using


arylstannane,


one


major


side


reactions


homocoupling


arylstannane


give


biaryl


Mechanistically,


reaction


may


initiated


oxidative


addition


of palladium


into


carbon-stannyl


bond


arylstannane.


Oxidation


of the


aryl-palladium-stannyl


species


involves


and


seems


have


radical


component;


this


presumably


complex


step


may


followed


transmetalation


with


a second


arylstannane


and


then


reductive


elimination


give


biaryl


In certain


cases,


removing


with


many


freeze-thaw


cycles


under


vacuum


suppressed


homocoupling


some


degree


Suzuki


coupling


uses


an organoborane


or boronic


acid


instead


an organostannane


transmetalation.


reaction










requirement


in order to give an intermediate


"ate"


complex of


the boron reagent


on addition


of hydroxide


ion.


this


"ate" complex that tranfers an organic ligand to the oxidative


addition


complex


transmetallation


1,3,13,32,33


Though


aqueous

procedure


alkaline


this


conditions


type


have


become


reaction,


there


somewhat

are ex


standard


amples


coupling reactions


with


organoboranes


or boronic acids


under


alternate


conditions.


31,34,35


A classical problem in heterocyclic chemistry deals with

the question of how to control and thereby direct N-oxidation


N-quaternization


atom of


single,


a polycyclic polyazine.


preform


palladium-catalyzed


polycyclic


selected


annular


solution


polyazine


cross-coupling


and


this


with


then


nitrogen


problem


use


selectively


functionalize the desired annular nitrogen atom.


the reactivity of the nitrogen atom,


directly

pathway.


Depending on


it may be functionalized


protection/functionalization/deprotection


The protection/functionalization/deprotection pathway


will be discussed further


A potential


chapter


way to eliminate the protection/deprotection


steps


would


functionalize


the


desired


nitrogen


atom


prior


linking


rings


together.


Using


palladium-


catalyzed cross-coupling chemistry,


either the hetaryl halide


a - t I I A


arInn Ii 1 fl l | I rnnn__^'r na n j t "i


ri l r r


r


I I 1


.,,,,,, I


iv










nitrogen atom is N-functionlized.


The scope and limitations of


these


processes


will


discussed in


chapters


and 3.


development


palladium-catalyzed


cross-coupling


reactions has exploded in recent years and now allows for easy


construction


polyhetarenes


that


would


otherwise


difficult


construct.


For


example,


there


are


theoretically possible


quaterpyridines,


both symmetrical


unsymmetrical,


with only seven of these being reported in the


literature. Five are symmetrical structures of the type A-B-B-


they


are easily prepared by


homocoupling the A-B


portions


under


variety


conditions.


36-40


Both


two


reported


unsymmetrical


quaterpyridines


were


originally


assigned


incorrectly.


They


include


natural


product


nemertelline,


which was first isolated in 1976 from the phylum of the marine


worms


called nemertines,


and


product


from


reaction


LDA


with


2,2'-bipyridine.


Both


structures


have


been


corrected


independent


synthesis


involving


strategies


developed


this


document;


they


are


based


palladium(0)-


catalyzed


cross-coupling chemistry.














CHAPTER


DIRECT PREPARATION OF N-QUATERNIZED


AND


N-OXIDIZED


POLYCYCLIC POLYAZINES BY PALLADIUM-CATALYZED CROSS-COUPLING-


-AN UNEQUIVOCAL


ISOMER SYNTHESIS


Introduction


The

catalyzed


number


cross-coupli


recently rej

no reactions


ported


used


transition


prepare


metal-


polyaryl


and


polyhetaryl


compounds


grown


explosively,


palladium


being the metal of choice.


3,43-46 But the number of preparations


N-oxides


this


means


using


preformed


N-oxides


coupling reaction has been


very


limited.47-50 For example,


ability


2-bromopyridine


N-oxide


undergo


coupling


without


competing


nucleophilic


substitution


replace


bromine


atom


been


demonstrated47


and


control


over


location of the N-oxide group within a pyrazine ring by using


preformed


chloropyrazine-N-oxide


cross-coupling


reaction


been


reported.48-50


preparation


quaternized


polyhetaryls


such


coupling


reactions


using


quaternized


starting


materials


seems


have


been


exploited at


all.


will


employ


two


types


coupling


reactions


preparation


N-oxidized


N-quaternized


polycyclic










N-quaternized hetaryl


halide along with a


palladium reagent,


now


something


standard


procedure


known


Suzuki


reaction


(Figure


2-1)


3,44,51


The use of an alkaline medium for such coupling reactions


seems


necessary


requirement


order


give


intermediate "ate" complex of the boron reagent on addition of

hydroxide ion.31 This "ate" complex then transfers its aromatic


ligand


palladium


oxidative


addition


product


halide


prior


product


formation


final


reductive


elimination step.1'3'32,33 Pyridylboronic acids have been made to


cross-couple


a nonaqueous


solvent


such


DMF


containing


triethylamine


presence


palladium


catalyst.


Boranes couple with triflates in a suspension of Na3PO4


in dry


- -


,..,, I! ~ rl!..l..4


- *


J~ n.. *I L cl *I L










Both


known


nucleophilic


N-oxidatic

activate


and


especially


enormously


substitution


N-quaternization


halogenated


displacing


hetarene


halogen


atom52'53


and


this


knowledge may


have


prevented


others


from attempting


coupling


reactions


now


report.


For


example,


methoxydechlorination


2-chloro-


and


4-chloropyridine


oxides is some 1012 times faster than that of chlorobenzene and


same


reaction


2-chloro-


and


4-chloro-l-


methylpyridinium


about


1021


and


ia's


times


faster,


respectively, than substitution of chlorobenzene.


under alkaline condition,


52,53 Moreover,


N-quaternized hetarenes may degrade


ring cleavage reactions.


54 While nucleophilic


substitution


SNAr mechanism


largely


insensitive


the


identity


of the halogen nucleofuge,


cross-coupling rates decrease


order


atom and the


> Br > Cl.


reaction


Clearly then,


conditions,


choice


especially pH,


of a halogen


expected


to be


quite


important


success


cross-coupling


reaction


of hydrolytically


labile substrates.










In certain


cases,


the coupling of N-functionalized halo-


heteroaromatic


compounds


stannylhetarenes


under


non-


aqueous conditions was examined.


Known


as the Stille coupling


reaction,


util


izes


stannane


instead


borane


occurs under non-aqueous conditions such


as dry THF,


dioxane,


or DMF


(Figure 2-2).


Results


and Discussion


The compounds we selected to be prepared were designed to

illustrate the power of our approach and to establish some of


its scope and limitations.


Consider our synthesis of


5-chloro-


3,3'-bipyridine-1-oxide


(2-1)


from


3,5-dichlorpyridine-l-


oxide55 and diethyl-3-pyridylborane


(Figure 2-3).


The position


oxide


ligand


with


respect


chlorine


atom


unequivocal


because


the


N-oxide


group


was


present


chlorinated


ring


start.


contrast,


attempts


oxidize 5-chloro-3,3'-bipyridine following a similar coupling


reaction

expected


prepare


to provide


the

the


unoxidized


1-oxide


material


the major


would

product.


not be

Mixed


mono


N-oxides


are


likely


because


electron-withdrawing


chlorine


atom would have


caused N-oxidation


take


place


the more reactive unsubstituted ring to give the isomeric


nv, a -~ a' A--- -- -A k


4-~ 1~? ~ u --a -- .3.


nv; rl h


rl 1


-^ <"


mq































direct


preparation


symmetrical


3,3' :5'3'-


terpyridine


(2-2)


having the center ring N-oxidized as


2-2


by direct N-oxidation is an even greater challenge because all


three pyridyl rings are expected to have similar reactiviti


synthesis


2-2


is both


trivial


and unequivocal


that


the same 3,5-dichloropyridine-1-oxide55 used to prepare 2-1 was


employed


synthesize


2-2


now


equivalents


diethyl (3-pyridyl) borane


were


present


along with a


carbonate


buffer


(Figure 2-3).


Surprisingly,


the nonoxidized form of


2-2


was prepared from 3,5-dibromopyridine


1936 by


a palladium


CaC03


that


coupling


substantially


reaction


under


predates


heterogeneous


recent


synthesis


conditions5"


using


completed palladium metal.


-n ,- 'I -


4 .


-Ih At


5, ,It1) n*W *rI UA it n a i-1 '1 nf *~ fl llIt1 Ufrf










Here


the N-oxide unit


located on a nitrogen atom highly


sterically


hindered


peri


position60


2-3


would


have been formed only


as a minor product on N-oxidation of the


preformed pyridylquinoline.


To further extend this


approach,


was


shown


that


Stille-type conditions


will


afford


coupled


products


well.


DMF,


2-3


coupled


(tributylstannyl)pyridine


give


3- (2-pyridyl)quinoline-1-


oxide


(2-5)


yield


Figure


2-4) .


substrate


even


more


activated


nucleophilic


substitution and ring cleavage by hydroxide ion is found in 3-


iodo-l-methylpyridinium ion.


1-Methyl-3, 3'-bipyridinium ion'


was


formed


from


3-iodopyridine


and


diethyl (3-


pyridyl)borane.


quaternizations


While


alternate


3,3'-bipyridine


yield


syntheses


1-methyl-3,3'-


S -


* _


- -A.


fl, rrr~ I rflr n r fi n in nmn n n r. Cr n Wi Ur fl fllf 'mn. In *7ll U ra Jr 3~ nf nf l


*


r u








17
quaternized substrates very highly activated for nucleophilic


substitution and ring


cleavage may


be employed


cross-


coupling


under


aqueous


alkaline


conditions.


This


approach


would


useful,


example,


prepare


unsymmetrically


carbon


substituted derivatives


of 1-methyl-3,3'-bipyridinium


ion of known and controlled structure


in the


case


of 2-1.


The f<

couple with


failure


4-chloro-1-methylpyridinium


diethyl(3-pyridyl)borane even


iodide


under weakly


basic


conditions promoted us to try Stille-type conditions.


The move


3-(tributylstannyl)pyridine


and


dry


DMF


allowed


formation of


the coupled product,


1-methyl-3'


,4-bipyridinium


iodide


(2-9),


yield.


similar


reactivity


between the two annular nitrogens,


selective quaternization of


preformed 3,4-bipyridine,


undoubtably,


would have resulted in


a mixture.

The reactivity of halogenated N-methylquinolinium and N-


methylisoquinolium


salts


also


were


examined.


These


bicyclic


materials


are


still


more


activated


than


the


pyridinium


ions


for nucleophilic substitution62


and for pseudo-base


formation


addition


of hydroxide


ion,


often


accompanied by


ring


cleavage.


54,63


Several


attempt


were


necessary


find


proper


alkaline


buffer


minimize


side-reactions.


Borate,


phosphate


and bicarbonate buffers


were


examined


order


fltaa r. I ,. p s C l ir *r -. -a a*


in rrar


^ ^













reaction


mixture


consisting


diethyl (3-pyridyl)borane


3-bromo-l1-methylquinolinium


ion64


and


palladium


catalyst.


This


is a useful preparation because quaternization


of preformed


3- (3-pyridyl) quinoline


is not


expected to


yield


2-7


directly,


owing


considerable


steric


hindrance


peri position.


60 Replacing the aqueous solvent by anhydrous DMF


did


lead


increase


yield


product.


Bicarbonate


been


used


palladium


induced


coupling


reactions of thiopheneboronic51 and pyridylboronic acids,


65 for


example.


Employing


4-bromo-2-methylisoquinolinium


ion66


benzeneboronic


acid


was


possible


prepare


phenylated isoquinolinium ion with borate base. Unfortunately,


attempts


make


4-pyridylated


isoquinolinium


(2-8)


using


borate,


unsuccessful


phosphate


degradation


bicarbonate


the


buffers


heterocyclic


were

cation


when the reaction was run with two phases,


the alkaline layer


containing


isoquinolinium


ion.


However,


the


addition


some methanol


to make


the mixture homogeneous


allowed


2-8


be isolated in


43% yield in the presence of


a borate buffer.


A slight


improvement


in the


yield of


2-8


(51%)


was


seen


when


4-bromo-2-methylisoquinolinium


iodide


was


coupled


with


(tributylstannyl)pyridine using a palladium(0) catalyst in dry


- 4- .


-~


-r a


.a. -


I A L. *T IL a. ar I 5 t L L l r & .-.-aa-


1


*^-J






























Having


demonstrated


that


weakly


basic


buffers


are


sufficient to induce cross-coupling,


a perdeuterated substrate


was


examined


order


learn


whether


possible


employ


isotopically


labelled


reagent


coupling


process.


deuterium


isotopes


equivalent


positions


3, 5-dichloropyridine-l-oxide-2, 4, 6-d3


are


known


to be


removed


easily


with


dilute


alkali68


and


their presence


therefore


Partially


serves as


deuteriated


a sensitive


product


test


2-10


reaction


was


conditions.


prepared


presence


bicarbonate


from


essentially


completely


labelled


(95%)


dichloride.


No deuterium was found at position


D at position


and the original


amount


Unequal


labelling of the 2 and 6 positions of 2-10 indicates that some
AC CI\ k. Aa -- __- --~ --










coupling


conditions


are


mild


enough


allow


selected


sites


retain


their


hydrogen


label.


Conclusions


Palladium-catalyzed


cross-coupling


may


used


successfully


prepare


N-oxidized


and


N-quaternized


polycyclic polyazines


unequivocal


structure


under


aqueous


conditions


(Suzuki-type conditions). An isotopically


labelled


substrate


may


employed


reactant


when


the


buffer


selected judiciously so that a hydrogen isotope at carbon will


retained.


seems


likely


that


other


types


functionalized compounds


such as


N-amines


can be prepared by


our method.

It is also possible to prepare N-functionalized polcyclic
l t^1 m na t d nh n f l 11 anrI n- ^ 1 tr4 r-vee-r/rnin nl ir rr nrhlar In n ..








21

conditions with 3-(tributylstannyl)pyridine. While Suzuki-type


conditions did not yield any


coupled product with


4-chloro-l-


methylpyridinium


iodide


and


diethyl (3-pyridyl) borane,


some


product


was


obtained


with


Stille-type


conditions.


However,


Suzuki-type


conditions


gave


a better


yield


over


Stille-type


conditions


in the coupling


3-bromoquinoline-N-oxide.


synthesis


isomers


having


bond


position of N-quaternized materials is still more challenging


to the enhanced ease


of nucleophilic


substitution


of the


halogenated precursors.















CHAPTER 3


A GENERAL METHOD OF


SYNTHESIS


FOR REGIOSPECIFICALLY N-


OXIDIZED OR N-QUATERNIZED


POLYCYCLIC POLYAZINES


PALLADIUM-CATALYZED CROSS-COUPLING OF N-OXIDIZED


OR N-


QUATERNIZED


HETARYL


S TANNANE S


Introduction


A classical problem in heterocyclic chemistry deal


with


the question of how to control and thereby direct N-oxidation


N-quaternization


single,


selected


annular


nitrogen


atom of


a polyazine


or polycyclic polyazine.


We have devised a simple and direct


solution to this old


challenge.


use


recently


developed


and


now


highly


popular


palladium-catalyzed


cross-coupling


reaction


hetaryl


synthesize


halide


hetaryl


a polyazine.


unlike


organometallic


the approaches


compound


of others,


we N-oxidize or N-quaternize the desired annular nitrogen atom


prior to


linking the rings together.


Thus,


the regiochemistry


final


product


assured and unequivocal.


our


original


application


this


approach,


hetaryl halide was functionalized either by N-oxidation or N-


methylation and then coupled to a hetarylborane


in a Suzuki-


type


reaction)


hetarylstannane


Stille-type


ra3 nt- 4 n


* I


C)~~~~~~r V e1n n.a -


e: nLII* F~


'1,1


A 1 L Ir All*l*


6.


ft *


L,~L


f v


I














Figure 3-1


Pd(0)


R= CH3, O-
X= CI, Br, I


M= BEt2, SnBu3


Suzuki-type


reaction


generally


requires


aqueous


alkali


generate


reactive


hydroxide


adduct


borane or boronic acid,


an "ate"


complex.3,30o,7071 Under aqueous


conditions,


the N-oxidized or N-quaternized hetaryl halide is


highly


activated


nucleophilic


substitution,


hydroxydehalogenation,


52,72


as well


as other undesirable


side-


reactions


such


hydrolytic


ring


cleavage.


54 However,


nonaqueous conditions31'34 and more recently fluoride ion under

aqueous and nonaqueous conditions35 also have been found to be


useful.


Boronic acid esters may be made to cross-couple under


nonaqueous


conditions


presence


both


palladium


and


thallium(I)


catalysts.


overcome


this


problem


would


use


1- aC ... r n fl -r nr ar -r fl AJ n n a a. ar a 2 2 a a a I~ l e










halides but not


with N-oxidized hetaryl


halides.


Others


have


taken this approach and coupled a stannane with a halogenated


N-oxide.


49,50


Another approach might make use of


a hetaryl halide that


N-oxidized


N-quaternized


and


thereby


minimize


possibility


side


reactions.


Suzuki-type


reaction,


the hetaryl borane or boronic acid now would be functionalized


at the annular nitrogen atom.


Unfortunately,


the necessary N-


functionalized hetaryl boranes


and boronic acids


are


largely


unknown


materials,


with


good


reason.


For


example,


methylation


3-pyridyl


borane


been


achieved


spite of repeated attempts44'74', because this borane exists


solution


a cyclic


tetramer


which


the


nitrogen


atom


one


molecule


Thus,


lone


coordinated


electron


boron


pair


atom


nitrogen


second.


atom


unavailable


for nucleophilic


reaction.


N-methylation


a 3-


pyridyl


borane


was


achieved


only


when


borane


first


was


converted to an


"at e"


complex with cyanide ion to destroy the


oligomer.


Unfortunately,


cyanide


retained


betaine


final


product.


Other


hetaryl


boranes


are


known


have high melting points and so they too are expected to exist


in solution as


N-quaternization.


coordinated aggregates


Moreover,


which


"at e"


therefore


complex


resist


formed


-4- r~ kAarr-r'na fl t'%l


A rr


C c,:,ll,,.lt,,,,,A


CA ~











substitution


a boronic acid in


place


a borane


also has its


severe


limitations.


The successful N-methylation


of 3-pyridylboronic acid has only been reported recently;


method requires the use of


an alkylating agent


with a leaving


group


that


non-nucleophilic


such


sulfonate


ion.


reactive


anion


such


iodide


from methyl


iodide


alkylating


agent


causes


decomposition


product.


In view of such limitations,


we now employ a variation of


Stille


reaction.


2,78 We


use


a hetarylstannane


place


the borane


and N-oxidize or N-quaternize


this


organometallic


compound instead of the halide,


method.


a so-called "reverse polarity"


The palladium cross-coupling step is carried out in a


q


- -


flflfl nfn ~ r~~ E~ na *~ *.n r* Sr *T1 r I a Ir AS~~l U --A


fit Y ~lY~a


r


,,~,, L


~'''~~~'


1










While


many


hetaryl


stannane


precursors


are


known


substances,


50o79-86 their


N-oxides


and N-methyl


derivatives


are


largely unknown


compounds.


Several


are prepared and reported


here


for


the


first


time


Stannylated


(alkoxycarbonyl)pyridinium ions


have been


generated but


only


reactive


intermediates.


scope and some


limitations


the new method


are


illustrated by the


following preparations.


In many


cases


examples


were


selected


show


how


easy


prepare


functionalized derivatives


that


otherwise


would be difficult


tedious


prepare


and


purify


standard


oxidation


quaternization


reactions


preformed


polycyclic


azine


free base.


Three


different


stannylated


heterocyclic


rings


were


successfully


cross-coupled.


With


pyridine,


quinoline and


isoquinoline


substrates


functionalized


annular


nitrogen


atom


located


stannylated


site


arrangement


while


with


respect


geometry


another


pyridine.


Special problems were encountered when attempting to


N-methylate


2-stannylated


pyridine


provide


geometry;


coupling was not


attempted.


The diverse group of five halogenated compounds included


3-bromoquinoline,


4-bromoisoquinoline,


5-bromopyrimidine,


i nnnr7 ri no


Innr


9 1r) n -r'H ar ~ant: r n


LI ~~~r I N-


4-n4- ~1


h~h (r n,


JJ


J










Results


and Discussion


N-Oxidation


. ..11111- I l-ll l1" IIIIIII II-III-IIIIIII


3- (Tributylstannyl) -pyridine"


and


-quinoline79


and


(tributylstannyl


isoquinoline


were


N-oxidized


with


chloroperbenzoic acid in chloroform to give the corresponding


pyridyl


3-1


(88%),


quinolyl


3-2


(88%),


and


isoquinolyl


3-3


(80%)


N-oxides.


Only


4- (trimethylstannyl) 08'89


and


(triphenylstannyl)


pyridines


have been N-oxidized.


N-Methylation


3- (tributylstannyl)pyridine


quinoline


went


smoothly to give


respective N-quaternized


3-stannylpyridine


3-4


100%


iodide


and b


tosylate)


3-quinoline


3-5


(92% iodide)


. Similarly,


the corresponding 4-


stannylpyridine


3-6


iodide


and


tosylate)


was


readily


prepared.


N-methylation


3- (trimethylstannyl)


pyridine


with


been


reported


patents.


flnnunrc4 a nn nfa 4-H 4l ,-r1 na na.,n4-a,. 4C an at -A 4- 4--. *


and N-Methv la+inn


flf HPt ~rV]


St~nn~nP~


:


I





























marked


contrast,


N-methylation


(tributylstannyl)pyridine


(CH2C12,


7 C)


could only be achieved


with


methyl


triflate


give


labile


product


which


was


unstable


at room temperature,


giving rise to the destannylated


N-methylpyridinium ion on


standing.


The material was,


however,


stable when kept below 0 C but pure product was not isolated.


triflate


salt


immediately


destannylated in DMSO to


yield


N-methylpyridinium


ion.


Attempts


quaternization


using


either


methyl


iodide


methyl


tosylate


proved


unsuccessful


pyridinium


Cross-coupling


ylide


was


generated


attempted.


destannylation


doubt


and


stability


this


intermediate


accounts


the


facile


decomposition.


91-93










with


4-bromoisoquinoline


give


N-oxide


3-8,


Table


Whereas the alternate synthesis of


3-7


might well be achieved


N-oxidation at


less


sterically


hindered nitrogen


atom


of the known preformed


(3-pyridyl)quinoline free base67 this


likely


the


case


with


4-(3-


pyridyl)isoquinoline where both nitrogen atoms are expected to


have


very


similar


reactivities,


making


preparation


isolation of 3-8 quite difficult by such a route


Moreover,


both


cases


N-oxidization


preformed coupled bihetarene


likely


result


mixture


mono-


and


di-N-oxidized


products.


Cross-coupling


pyridine


N-oxide


3-1


with


bromopyrimidine in THF gave pyrimidine N-oxide 3-9. Similarly,


quinoline


N-oxide


3-2


4-isoquinoline


N-oxide


3-3


coupling with 5-bromopyrimidine in toluene afforded pyrimidine


N-oxides 3-10 and 3-11,


respectively,


Table I. Again,


in these


three examples the efficient preparation of the final products


3-9,


3-10


and


3-11


from


preformed


polyazine


free


bases


such


known"9


precursor


3-9


unlikely


due


to both


steric


and electronic


factors


which favor the


formation


mixture


served as


isomers.


limiting


these


reagent


experiments


and


the


yields


stannane


cross-


coupled products


were moderate


(43-66%).


fl ~~' -% a. n 4-. '- 4- Lb & Lb fl 1 a. -a- aI..a- --. .t


tlrr rr nnC r.rr nL











yield


coupled


product


3-12


was


essentially


quantitative


Table


Tabl


Condition


Result


of the


Cross-


Coupling


Stannylated


Hetaryl


N-Oxide


with


Hetaryl


Halides


Presence


of Pd(PPh3)4


Stannane


Halide"


Solvent/
time (h)


Product


Yield


3-1 3Br DMF/(24) 3-7 66
3-1 4Br THF/20) 3-8 43
3-1 5Br THF/(12) 3-9 64
3-2 5Br toluene/ 3-10 51
(18)
3-3 5Br toluene/ 3-11 58
(10)____________
3-1 2C1 THF/(36) 3-12 98b


*3Br


3-bromoquinoline,


5-bromopyrimidine


4-bromoi


soquinoline,


2-chloropyrazine.


limiting


reagent


stannane


this


one


case


halide


Cross


-Couplinn


of N


-Methylated


Stannanes


with


Stannane


as the


Limiting


Reaqent


Cross


-coupling


N-methylated


hetaryl


stannanes


proved


to be


more


a challenge


than


coupling


N-oxides


the


~____










N-Methyl-3-tributylstannylquinolinium


iodide


3-5


was


coupled


to 3-iodopyridine


in the


presence


of Pd(PPh3)4


to give


3-13


(15%),


Table


yield


seems


to be


result


using


iodide


as a counter


. We


have


observed


that


such


quaterni


zed stannanes are easily destannylated by


halide


ions.


Table


Stannanes
Conditions


Result


and


Hetaryl


Molar


Cros


Halides


Excess


s-Coupling


with


Halide


of N-Quaterni


Catalya
Excess


Under


Stannane


I. U


Stannane


Halide"


Catalys
(Method


Solvent/


time


Product


Yield


3-5 3I Pd (PPh3)4 THF/(18) 3-13 15
(A)
3-4C 5Br Pd(PPh3)4 toluene/ 3-14 55
(A) (12)
3-4C 2C1 Pd(PPh3)4 toluene/ 3-15a 29
(A) (16)
3-4C NaBPh4 Pd (dppe) THF/(10) 3-16 64
Cl2 (A)
3-4b 3Br Pd(PPh3)4 toluene/ 3-17a 54
(A) (10)
3-6b 3Br Pd(PPh3) THF/(24) 3-18 54
________(A)
3- 6b 5Br Pd(PPh3)4 toluene/ 3-19 74
(A) (30)
3-6b 3I Pd (PPh3)4 DMF/(12) 3-20 64
(A)
3-4b 3Br Pd(dppe) toluene/ 3-17b 87
Cl2 (B) (20)
3-4b 2C1 Pd(dppe) toluene/ 3-15b 87
Cl2 (B) (30)










Initially,


attempting


overcome


competing


destannylation


counter


ion


was


changed


from


iodide


to the


less nucleophilic tetraphenylborate


Cross-coupling in the


presence


of Pd(PPh3)


occurred


between


N-quaternized


pyridine


3-4c


and


5-bromopyrimidine


yield


3-14


moderate


yield


(55%),


Table


II. Compound


3-4c


was


also found


to couple


to 2-


chlororpyrazine


to give


3-15a


yield


(29%)


was


discovered


that


essential


use


a Pd(0)


catalyst


with


tetraphenylborate


counter


order


minimize


competing


presence


phenylation


Pd (dppe


this


Cl2,


anion.


For


(dppe


example,


(diphenylpho


sphino)


ethane)


(10%)


3-4c


of the


and


5-bromopyrimidine


expected product


3-14


gave


with


only


main


small


product


amount


being


3-phenylpyridinium


3-1669


(62%).


tetraphenylborate


known


phenylating


agent


accordance


with


this,


compound


3-4c


presence


Pd (dppe) Cl2


one


equivalent


NaBPh4


gave


3-16


yield,


Table


Tosylate


was


found


most


useful


counterion


because


was


inert


N-Quaternized pyridyl


stannanes


3-4b and


3-6b


with


this


anion


were


coupled


to 3-bromoquinoline


to give


known


3-17"6


and


3-18,


respectively.


Note


that


3-13


and


3-17


are


isomers,


site


specific


N-methylation


having


been


achieved


each


case.


addition,


stannane


3-6b


was


coupled


1%- ...n .- -4 1 2 a -a I --- -J- j -~- -fl -


a- -- -


-Inn


- -J


r rr


-1


m


In










coupling


route


providing


3-20.


This


salt


known


accelerate


cross-coupling


stannanes


acting


phosphine


alternate


trap,


thereby


synthesis


facilitating


these


compounds


transmetallation.


might


28 An


be possible


selective quaternization of the coupled free base such


as the


known


neutral


precursor58


3-18


diquaternization


likely to be an important


competing process especially in the


case


precursor97


3-20


where


steric


and


electronic


differences


between


nitrogen


atoms


are


minimal.


some instances it


was prudent to convert the tosylate coupled


product


a tetraphenylborate


or perchlorate


salt


easy


isolation.


Cross-coupling


of N-Methvlated Stannanes


with Hetarvi Halide


the Limiting


Reagent


above


cross-coupling


reactions


with


oxidized and N-quaternized stannanes,


the major side reaction


homocoupling


diquaternized material.


stannane


Attempts


give


suppress


di-N-oxidized


homocoupling by


degassing


system


remove


dissolved


oxygen


found by


others4'30


did


improve


yields


greatly


diminishing


amount of homocoupled side-product.


It has been suggested that


Pd(II)


and


Pd(0)


responsible


homocoupling.98


4-4- ~ ~ ~ ~ ~ ~ ~ ~ ,,., aI, aa- .--- t. .


with Hetarvl


Halide


~ICC nm~rC Fl










acetonitrile


wash


recovered


desired


soluble


product


leaving the insoluble dication.


The di-N-oxidized homocoupled


product was removed easily on standard column chromatography.


When


hetaryl


stannane


now


halide


was


served


present


molar


limiting


reagent


excess


equivalents),


yields


desired


cross-coupling


product


improved significantly,


Table II.


For example,


cross-coupling


pyridyl


stannane


3-4b


with


3-bromoquinoline


chlororpyrazine in the presence


of Pd(dppe)C12 gave compounds


3-17b


(87%)


and


3-15b


(87%),


respectively,


Table


contrast,


3-bromoquinoline


and


2-chlororpyrazine


under


our


previous conditions using the stannane as the limiting reagent


gave


these products


only


and 29%


yield,


respectively.


In addition,


N-methylated pyridines 3-4b and 3-6b were coupled


4-bromoquinoline


compound 3-21"6 and


under


3-22,


similar


respectively


condition

fy. Thus,


give


yields of


known

cross-


coupled


increase,


products


ranging


under


conditions


from


87%,


excess


Table


stannane


Again,


impurity was the homocoupled material.



Conclusions


Hetaryl


stannanes


N-functionalized


form


- 2 a - -ii --'A- 2 A-t





L


_ _- -


--










stannanes,


contrast


with


boranes,


are


the


reagents


choice


cross-coupling


organometallic


component


reaction


which


N-functionalized.


When


quaternized


hetaryl


stannane


is employed,


advisable


select


an inert


ylate


as the


counteranion


of the


salt.


examples


shown


here


reveal


the


power


new


synthetic


method


whereby


annular


nitrogen


atom


functionalized


structure


prior


N-oxide


cross-coupling.


or N-quaternized


this


coupled


way


product


both


obvious


assured.


Clearly,


our


approach


may


applied


rings


of other


size


and


construction


the


introduction


other


substituents


onto


an annular


nitrogen


atom.


scope


seems


be wide


and the method


useful.


coupled products


themselves


may


serve


starting


materials.


N-functional


groups


provide


a special


chemistry


that


directs


new


substituents


their


activated


ring


and


thereby


allow


further


controlled


elaboration.


99-103















N-METHYLATION AND


ATOM OF


CHAPTER


N-OXIDATION OF THE LESS REACTIVE NITROGEN


A 2,3'-BIPYRIDINE--TWO GENERAL METHODS
POLYAZINES


Introduction


FOR


Directing


atom


reaction


of a polyazine


one


a polycyclic


selected


annular


polyazine


nitrogen


old


and


continuing


synthetic


challenge.


Espec


ally


difficult


case


where


desired


reaction


site


sterically


hindered


and/or electronically


deactivated.


2,3'-Bipyridine is a prototypical polyazine where the two


annular


nitrogen


atoms


demonstrate


markedly


different


reactivities


to their geometry,


the nitrogen


atom


of the


2-pyridyl


ring


being more


sterically


hindered


and


therefore


much less nucleophilic than


that


of the


3'-pyridyl


ring.


have


devised


two


different


methods


achieve


regiocontrolled functionalization of one annular nitrogen atom


using


2, 3'-bipyridine


model


substrate.


When


desirable to functionalize the less reactive nitrogen atom in


the 2-pyridyl


ring


the 2,3'-bipyridine


our


first


approach


employs a three-step protection-functionalization-deprotection


sequence


preformed


2,3'-bipyridine.


removable










2-pyridyl


nitrogen


atom


then


functionalized


quaternization


N-oxidation


and


protecting


group


removed


base


p-nitrostyrene


give


the


desired


final


product.


simpler


approach


N-oxide


employs


methyl


protecting


group,


readily


removed


the


action


of KI


in heat


ed DMF


in a similar


sequence


steps


(Figure


Figure 4-1a


ONH2
I


CONH2


ONH2


4-2 R1 -CH3
44, R1 (CH2)2C6H4N02 p

VIII, O or
ix ,X


ONH2


x


SRI -R2 CH3
,R (CH2)2C6H4N02 p
R2- CH3


,R2-CH3, XCONH2
, R2-O, XCONH2
, R2-0, X-H


4-7, R1 (CH2)2CgH4N02 p
X -CONH2
4-9, R1 -CH3, X-CONH2
4-11, Ri-CH3, X-H


aReeuts: () Pd(Ph3)4. 3-Et2B-pyridine, HF, (ii) Mel,. EtOAc, (iii)
Br(CH2)2C6H4N02. iv) Mel, DMF, (%$ Mel. sulfane (v)
MeOTs, suodane, (i) NOAc, MeCN lor 4-5. (iii) MCPBA.
sulolane br :Z; peroxide. TFA for 4. (ix) MCPBA, CHa3 or
411, (x) NaOAc, MeCN or Z (xi) KI. DMF fo 4-9 nd 4-11.










catalyst,


pyridyl


borane


and


N-oxidized


halogenated


pyridine


(Figure


4-2).


model


substrate


selected


illustrate


these


methods is 5-carbamoyl-2,3'-bipyridine


(4-1) .


Not only is the


2-pyridyl


ring


sterically


deactivated


nucleophilic


reactions


also


carbamoyl


group


presents


substantial


additional electronic deactivation.


The 2-pyridyl ring in 4-1


so deactivated


that


we were


forced


to devise new


reaction


conditions which differ markedly from those used in the

successful synthesis of 1-methyl-2,3'-bipyridinium ion.


first

104 The


new


conditions


are


likely


more


widely


applicable


other


substrates.


The regiocontrolled N-methylation of 4-1 at the 2-pyridyl
n; -rnn an 4nv -. nA C.. ~. -'I-at








39

Using the second synthetic approach N-oxide 4-8 also was


prepared


cross-coupling


route


failed


provide


methylated 4-6.


Results and Discussion


Pd-Catalvzed Cross-Couplinc


Bipyridine


4-1


was


readily


prepared


(92%)


Suzuki3'4344'4'6 cross-coupling of diethyl (3-pyridyl) borane and


chloro-5-carbamoylpyridine with tetrakis-


(triphenylphosphine)


palladium(0)


and


aqueous


carbonate


buffer.


5-methyl


ester


been made by


similar


route67


isomeric


chloro-3-carbamoylpyridine did not couple with benzeneboronic


acid in


presence of Pd(dppb)Cl2.


N-Methvlation


Mono- and di-N-methylation of 4-1


was examined to obtain


information


about


reactivity


nitrogen


atoms


and,


as seen below,


to learn about the thermal


instability of


diquaternized


salt


toward


demethylation.


first


methylation


took


place


readily


provide


4-2,


l'-methyl-5-


carbamoyl-2,3'-bipyridinium iodide


yield with Mel


yield


with methyl


tosylate


(MeOTs).


'Ill. -2,, K,~, -- -,,~~ ----------------------2 -.- -- -








40

conditions used for the preparation of the diquaternized form


of BPY

sealed


itself,


tube,


Mel

were


acetonitrile


unsatisfactory.


heated


Sulfolane


solubilized


monocation


4-2


and heating


with


excess


MeOTs


gave


(4-3),


1,1'-dimethyl-5-carbamoyl-2,3'-bipyridinium ion


(84%)


Heated


was


unsatisfactory


because


mixture


mono


(4-2)


and


diquaternized


(4-3)


products


along


with


tetramethylammonium


solvent


decomposition


product


were


isolated in


Addition of


low yields.



the Protecting Group and Diquaternization


addition


NPE


protecting


group


N-I'


was


achieved easily


yield to provide monocation


4-4.


Again,


solvent


second methylation step was


of choice proved to


a challenge.


sulfolane because


The

good


solvent properties and its inertness to the methylating agent.


However,


yield of


desired diquaternized


4-5


was


only


using


because


deprotection


the


starting


material


iodide


followed


methylation


form


dimethylated


dication


4-3


was


competing


process.


Reverse


phase


column


chromotography'05 proved useful in the separation of materials.


yield


4-5


improved


with


MeOTs.


dequaternization now was evident with the weakly nucleophilic


- I -


I










benzyl bromide,


the latter in the presence of


silver salt


could


made


react,


providing


further


evidence


markedly


low reactivity


of this


atom.


An attempt


was made


to bond a


2-cyanoethyl


group


to the


N-'


atom of 3-1


with the expectation that


would be easier


to remove by the action of base in the deprotection step.


107,108


However,


the 2-cyanoethyl bromide alkylating


agent


only


gave


rise


low yields


of the desired N-quaternized product.


Deprotection


Selection of conditions for the successful removal of the


N-protecting


group


required


several


trials.


2,2,6,6-


tetramethylpiperidine


base


used


our


earlier


study'04


was


unsatisfactory


because


difficulty


encountered


removing


tosylate


salt


from


desired


ionic


product


4-6,


1-methyl-5-carbamoyl-2,3'-bipyridinium ion.


sodium


acetate


refluxing


acetonitrile


brought


about


elimination of 4-nitrostyrene to regenerate the unsubstituted


3'-pyridyl


ring


and the monomethylated product


4-6


55%)


N-Oxidation


(Nitrophenyl) ethylated material 4-4 was easily N-oxidized


to 4-7


using


3-chloroperbenzoic acid'9


sulfolane


(57%)


LL L -I










view


easy


dealkylation


4-3


iodide


ion,


another route was explored,


now using the N-methyl substituent


on N-l'


as a protecting group.


Iodide


4-2


was


first


converted


tosylate


volatile Mel


room


an anion


temperature


exchange


with


MeOTs


reaction in


generate


order to


avoid


oxidiz


ing the


iodide counterion and


then N-oxidized


peroxytrifluoroacetic


acid'09


5-carbamoyl-1'-methyl-2


bipyridinium-l-oxide


(4-9)


Deprotection,


this


time


removing


methyl


group


using


heated


DMF,


gave


more


sterically


hindered mono


N-oxide


4-8


(55%).


parent


bipyridine


lacking


carbamoyl


substituent,


same


sequence


N-I'


protection


with


methyl


group followed by N-oxidation gave 4-11


which then was


deprotected thermally with KI in hot DMF to afford 4-10


(40%).


N-oxidation of unprotected bipyridine has been reported along


with


spectroscopic properties.


56, 110


Palladium-Catalyzed Couplinq to


Prepare N-Oxide


4-10


more


direct


route


4-10


(68%)


employed


palladium-


catalyzed cross-coupling'3',4'4446 of diethyl (3-pyridyl)borane and


2-bromopyridine-1-oxide in aqueous carbonate. Although the


bromopyridine-1-oxide


can


undergo


facile


nucleophilic


substitution reaction with hydroxide ion to give a pyridone,


S* SI


A S S


-k % l fl .L -L -~ a a1 dr -1 a -a -----


. .










Palladium-Catalyzed


Coupling to


Prepare N-Oxide


6-Chloro-nicotinamide


was


N-oxidized


with


urea-Hy20


complex


and


triflouroacetic


acid


give


N-oxide


(86%).


Coupling


with


diethyl(3-pyridyl)borane,


Pd(0)


and


carbonate


gave


4-8


yield


(Figure


4-2).


Unsuccessful


Palladium-Catalyzed


Coupling to


Prepare


Our ability to cross-couple diethyl (3-pyridyl)borane with


N-methylated


pyridinium,


quinolinium


and


isoquinolinium


halides


having


the


halogen


atom


located beta


annular


nitrogen atom79 encouraged us to attempt the preparation of 4-6


such


route


using


quaternized


substrate


having


halogen atom at an alpha position.


Unfortunately,


all attempts


failed.


Thus,


coupling


3-pyridylborane and 2-bromo-1-


methylpyridinium


was


unsuccessful


using


carbonate


bicarbonate

palladium(0)


buffers


and


or Pd(dppe)2C12


tetrakis(triphenylphosphine


(dppe


1,2-(diphenylphosphino)


ethane).


Switching to


3- (tributylstannyl)pyridine


methyl pyridinium under non-aqueous


conditions


and 2-bromo-l-

(Stille-type


conditions)


also


failed


give


coupled


product.


variety


solvents


(THF,


dioxane,


and


DMF)


and


catalysts


(Pd (PPh3) 4,


Pd (dppe) 2C12


Pd2dba3)


were


tried


with












Conclusions


The NPE group is useful


to protect"'


an annular nitrogen


atom of


a preformed polycyclic


azine


where


can be


removed


subsequently as 4-nitrostyrene in the presence of a base such


acetate


regiospecific


lon.


deprotection


preparation


pathway


N-derivatized


allows


compounds


having


substituent s


less


reactive


annular


nitrogen


atom


polyaza compounds. For N-oxides,


an N-methyl substituent is an


attractive


alternate


protecting


group


readily


removable


thermally


induced nucleophilic


substitution


with iodide


ion.


The two methods for the preparation of carbamoyl N-oxide


3-8


may


compared,


each


ultimately


starting


with


pyridylborane


and


2-halopyridine.


two-step


palladium


coupling route first making the N-oxide and then coupling the


reactants


is shorter


and gives


4-8


overall


yield.


four-step


sequence


where


,3-bipyridine


prepared


first


palladium


coupling,


protected,


N-oxidized


and


then


deprotected gives an overall


yield of 29%


for the route using


NPE


protecting


group


and


methyl


protection


scheme. Although unsubstituted N-oxide 4-10 was synthesized by


routes


starting points


are


same


both


- I A


ml~ 'I










methods


would


seem


useful


preparation


variety


selectively


N-derivatized


polyazines.


If the construction of


an inter-ring bond to make


a polycyclic


structure


an option,


then


functionalizing


annular nitrogen atom of an azine prior to palladium-catalyzed


cross-coupling


serves


useful


shorter


second


route


regiospecifically


N-functionalized


polycyclic


polyazines.


However,


while this approach was successful


for the synthesis


of an N-oxide it failed here for an N-quaternized azine having


the halide group located alpha to this nitrogen.


For the later


compounds,


first


method


using


protecting


group


preformed polycyclic polyazines remains the method of choice.














CHAPTER


REVISED


STRUCTURE


AND


CONVERGENT


SYNTHESIS


OF THE


NEUROTOXIC


QUATERPYRIDINE


ISOLATED


FROM


HOPLONEMERTINE


SEA


WORM


Introduction


Neurotoxic


substances


have


been


isolated


from


phylum


marine


worms


hoplonemertine


call


(armed)


nemertines.


worm


contain


Extracts


anabaseine


from


3,4,5,6-


tetrahydro-2,3'-bipyridine),


,3'-bipyridine


and


quate


rpyridine


given


the


name


nemerte


lline


:4''


,3' '-quaterpyridine,


5-1).


proof


structure


of this


first


quaterpyridine


isolated


from


a living


source


rested


1976


entirely


proton


NMR


ctrum,


homonuclear


decoupling


experiments,


and


similarity


proton NMR spectrum to


that


nicotelline


Nicotelline


(5-2),


tripyridyl


tobacco


alkaloid,


also


contains


the


B-C-D


ring


structure


present


5-1,


lacks


ring


proton


NMR


spectrum


nicotelline


strikingly


similar


to the


proton


resonances


assigned


to rings


and


D of the


natural


product


synthesis


this


unsymmetrically


substituted


quaterpyridine


seemed


us to be


readily


poss


ible


given


-~~~~ .1 .


12''


.


~I










and heterocyclic polyaromatic


substrates


from organometallic


halide


precursors.


Suzuki


coupling


boranes


borates3'44"69-71 and Stille coupling of


stannanes2'43'78,84,112,113 now


are


the preferred methods


of joining


such rings.


We now report the first synthesis of 5-1


and its correct


proton


NMR


spectrum.


Spectral


differences


between


this


synthetic


quaterpyridine


and


that


natural


substance


clearly


indicate


that


5-1


the


natural


product.


correct


structure


the


natural


product


nemertelline


3,2'


,IIrr:I'


,3 ''-quaterpyridine (5-3) which is verified by


an independent


synthesis


involving


a key palladium-catalyzed


cross-coupling


step.


isomers


differ


only


1 -, L- ...r_ Lt -t~ _L tL A !! t2A--2--- n











natural


product


nemertelline


(5-3)


unsymmetrical


dimer


of 2


,3'-bipyridine.


Results


and


Discussion


Synthesis


3.2' 3' r. r (S-fl


-3// -Diatprnvri Hi n<=


retrosyntheti


approaches


5-1


are


given


Figures


and


Both


are


predicated


use


palladium-catalyzed


cross


-coupling2'43'70


of organometallic


and


halide


hetarenes


to form


bipyridine


(bpy)


rings.


According


successful


Figure


two


3-pyridyl


ring


of 5-1


are


disconnected


from


central


B-C


rings,


aI a




Figure 5-1: Retrosynthetic Analysis for Quaterpyridine 5-1



Di



Nc +


N 5-4


3'


3.2'


r4"


(5-1


I I I I


r r


i


r I











In Figure


disconnection


made between


the B


rings


give


two


different


bpy


rings


, 3,4'-bpy


containing


the


rings


and


2,3'-bpy


having


A-B


rings.


polarity


of this


disconnection


was


reversed


our


approaches.


route


C-D


rings


contain


organometallic


stannane


A-B


rings


the


chloride.


route


positions


stannyl


and


chloro


groups


are


reversed.


Although


both


routes


Figure


gave


some


desired


quaterpyridine


cross-coupling,


material


was


- -A- ---.--


I q .


.. -S


I 1


I~ .~ _.I -1


J1


J 1










approaches


constructed


individual


palladium-catalyzed


bpy


union


rings


two


were


pyridine


rings.


Retrosynthetic


Figure


5-1:


4-Dichloropyridine,


made


from


4-nitropyridine


N-oxide114


was


coupled


with


diethyl(3-


pyridyl)borane under Suzuki conditions


(Figure 5-3) .


Coupling


took place at


the


and not


4-position


the dichloride


to give 4-chloro-2,3'-bipyridine


(5-6)


(57%).


There is a


clear


preference


coupling


over the


4-position


2,4-dichloride


. But as the 4-chloro bipyridine product formed


large quantities,


starting material


this product


coupling


began


to compete


reaction


yield


with


known


terpyridine


(3,2' :4'3''-terpyridine,


nicotelline97).


coupling reaction


was


readily


followed by


silica


TLC and


was


stopped when


the


terpyridine


started to appear.


The structure of the 4-chlorobipyridine


(5-5)


was easily


established

deshielding


making


effect


assignments


interannular


based


large


nitrogen


atom.


singlet


of H-2


and the doublet


of H-4


3'-pyridyl


ring


this


bipyridine


are


highly


deshielded,


being


9.33


8.34


ppm,


respectively.


Monochloro


5-5


was


selectively N-oxidized


with MCPBA at


the less sterically hindered nitrogen atom to form


5-6.


Using


..











. Use


of POC13


directly


on the


N-oxide


expected


to give


a mixture


two


chlorinated


isomers.


final


Suzuki


coupling


with


slightly


more


than


equivalents


diethyl (3-pyridyl) borane


and


dichloride


5-4


provided


5-1


yield.


Retrosvnthetic


Figure


, Route


: The


C-D


ring


system


was


made


quite


easily


using


chemistry


recently


developed


our


group


provide


regioselectively


N-functionalized


bpy


".4 A -


-r


A _


k t


-


m










good


yield


(75%)


This material


then


was


converted


to 5-8


with


POCIa


and


diisopropyl


amine


followed


conversion


Grignard


reagent


and


transmetalation


with


tributyltin


chloride.


2'-Tributylstannyl


5-9


was


formed


moderate


yield


(34%)


required 3-chloro-2,3'-bipyridine


(5-10)


was


easily


constructed from 2,3-dichloropyridine


(92%)


and the diethyl(3-


pyridyl)borane under Suzuki conditions.


Cross-coupling of the


2,3-dichloropyridine


and


position


was


eas


ily demonstrated from the proton NMR spectrum by making use


large deshielding


effect


annular nitrogen


atom


of the B ring on the 3'-pyridyl A ring.


To verify that


was


possible


cross-couple


sterically


hindered


3-Cl


position


this


bpy,


model


coupling


with


diethyl (3-


pyridyl)borane was


attempted.


The expected new


* 3I,13.'










final


coupling


give


5-1


was


carried


under


typical


Stille


conditions using tetrakis(triphenylphosphine)


palladium(0)


refluxing


toluene.


Unfortunately,


inseparable


mixture


5-1


homocoupled


product


stannane


5-9


could


easily


separated


silica


chromotography.


Retrosynthetic Figure


5-2,


Route


In order to suppress


homocoupling,


the polarities of the bpy rings were reversed.


Two approaches were tried,


only one being successful.


successful


approach


organometallic


group


was


first


added


B-ring


and


then


A-ring


was


joined.


unsuccessful attempts this sequence was reversed.


The A and B-


rings


were


first bonded


together


and attempts


then


were made


unsuccessfully to add an organometallic group to the B-ring of

the bipyridine.


Taking advantage of known


chemistry,115-118


directed ortho


lithiation


of 2-bromopyridine


with LDA at


followed by


transmetalation


with


tributyltin


chloride


gave


2-bromo-3-


tributylstannylpyridine


(5-12)


(57%).


This stannane was easily


coupled


with


diethyl(3-pyridyl)borane


presence


tetrakis (triphenylphosphine) palladium (0


under


usual


aqueous


alkaline


Suzuki


conditions


give


tributylstannyl-2,3'-bipyridine


(5-13).


Significantly,


-























In the alternate route a number of


attempts to metallate


A-B


ring


3-halo-2,3'-bipyridine


were


tried.


attempts


convert


monochloride


metallated


material


failed


to give


a substantial


amount


of the


product.


Thus,


attempted


transmetalation


with


n-BuLi


temperatures

lithiated pr


(-78


:oduct


and

alone


-100


with


yielded


butylated


minimal

addition


amounts

product.


Attempted Grignard formation from the chloride provided mostly


3'-bipyridine


reduction


product.


Tributylstannide


the chloride gave only


10% of the 3-stannane.


Use of the more


reactive


3-bromo-2, 3' -bipyridine


(5-14)


made


from


corresponding 3-amine 5-15


in place of the 3-chloride did not


change


outcome


significantly.


The coupling


of chloride


5-8


= Cl)


and stannane 5-13


Bu Sn)


again


gave


inseparable


mixture


5-1


homocoupled product,


that


from 5-8.










disconnected


give


A-B


and


bipyridyl


rings


fragments.


organometallic


elected


component


have

and t


A-B


he C-D


fragment


portion


serve


as the


halide


the

. In


reversed


halide


polarity


and


approach


unit


contains


which


A-B


fragment


organometallic


group


ere


risk


that


desired


cross-c


oupling


might


fail.


Such


cross-coupling


sterically


hindered


while


homo


coupling


of the


stannane,


a common


side-reaction


Stille


coupling,


4,98,120-122


hindered


and


therefore


might


dominate


In our


favored approach homocoupling


of the


stannane


more


sterically


hindered


process


than


cross-coupling.


Stille


Couplina to aive


bipyridines


5-13


and


5-5


were


smoothly


cross-coupled


with


Pd(0)


catalyst


heated


--

























Crystal


Structure of Nemertelline


(5-3)


X-ray


analysis


monoclinic


crystals


was


obtained


order


confirm


structure


natural


product


and thereby


aid in the analysis


the NMR spectrum,


Figure


5-8.


molecule


folded


into


nonplanar


approximate


U-shape with,


as expected from the


structures


related polypyridines,


37,39,123,124 the orientation of the annular


nitrogen atoms in adjacent rings adopt an s-trans conformation


with


respect


each


other.


and


rings


are


approximately


parallel


each


other


and


are


skewed


with


respect


the common B ring.


The dihedral


angle between


rings is 440 for the A and B portion,


530 for the B and C rings


-2 30


group.


ring


twisted


away


from the A ring


the opposite direction


from that


the A


and


C rings


The geometry


the A,


B and C


rings


similar


that


1,2-diphenylbenzene.


Figure 5-7



Pd(O) A

Ci B I Toluene
NBN
5-5 5-13

Nemertelline,5-3














C6"'


C5"'


C4'

C3"'



N'flb#


C2"'


C2"


C3"


C6"


IA"


Cs,


Figure


5-8.


ORTEP


crystal


structure of nemertelline


(5-3)


with










final


proof


structure.


early


report


used


as a


solvent.


41 We find little


difference in the spectra using this


solvent or CDCl.


The 300 MHz NMR spectrum of


5-3


in CDCIl with


peak


assignments


shown


in Figure


5-9.


Some


signal


overlap


for three protons does occur


in CDCI3 at


8.6 ppm.


Remarkably,


none


aromatic


protons


overlap


CD3OD


where


the total


shift


scale


only


ppm,


Figure


5-10.


assignments


are


based


COSY


and


NOE


difference


spectra as well as the general


pattern of


chemical shifts and


spin


couplings


observed for polypyridines.


each ring the


signals


usually


follow


and


positional


order


(increasing

deshielding


magnetic

caused


field)


modified


lone


additional


electron


pair


interannular


nitrogen


atom40, 126


as well


as a shielding


effect


of stacked rings127128


case


of the A and C


rings.


COSY


5-3


CDC13


given


Figure


5-11


where


the proton assignment


of the two


important


3-pyridyl rings


emphasized.


Significantly,


one of


these two


rings


a pair


signals


9.01


and


8.19


ppm


which


are


located


much


lower


field


than


those


equivalent


positions


the other


ring


These deshielded protons are easily


identified


as being


nitrogen


atom


their


spin


coupling


pattern.


Moreover,


irradiation


a proton at


9.00 ppm gave


rise


a --h ..2 rr.-----.


a -


f


-n A


m l --





































































3
Ca








f~l'a


~Cs,





C,'__


a 1























































Figure


5-10

















0


9.g* 3.3 3. 3.4 3.3 u.s


71(p"3I


Figure


COSY
-no


300 1
ltno c


MHz for


nemertelline


fn' rra l at-1


-tho


ryrnt nn


(5-3)


,. tJI


. The


the


A rina


upper


and


S


O










and


signals


field


3-pyridyl


ring


must


associ


ated with the D ring,


i.e.,


they are due to protons 2'''


4I'


. Because


they


are


located


across


ring


from


lone


electron


pair


nitrogen


atom


ring


they


experience


deshielding


effect


this


electron


pair


causing them to


shifted to


such


field.


This pair of low field signals was assigned by the early


workers


to 2


and


positions


of the A ring41


and not


the D


ring


have


done.


crucial


error


giving


rise


incorrect


structure


which


the nitrogen


atom of


the C ring


positioned as


in 5-1


and not


5-3.


Proton NMR Spectra of 5-1:


The 300 MHz NMR spectrum of


CDC13


shown


assignments.


Figure


aromatic


5-12


proton


along

signals,


with

only


shift

three


overlap


seriously


before,


peak


assignments


were


made


using


COSY


(Figure


5-13),


NOE


difference,


and


splitting


patterns.


Splitting patterns are essential in identifying the degree and


position


substitution in


each ring.


Comparison of Proton NMR Spectra of 5-1 and 5-3:


Table


shows


chemical


shifts of


5-1


and nemertelline


(5-3)


CDCl3.


Only


ring


protons


have


similar


shifts.


Five


protons


have


shift


differences


least


0.3 ppm.


Three


J~~pas~~aI -'I AI St S .t


I


I # 9


r














tm "_
I


IC~4




































































8.8 8.6 8.4 8.2 8.0


Fl (ppe)


Figure


rIncv


c-I IVn fl


E ~










reason


large


other two protons,


differences


and 5'"


shifts


protons


ring,


less obvious and more subtle.


The major conformation about the


bond


between


and


rings


not


same


both


isomers.


it is not


That shown in 5-1 or 5-1E is correct.


5-3Z,


However,


the conformation found in the solid state.


Rather it is conformation 5-3E that


is present in chloroform.


Hence,


the position of protons 3''


and 5'"


differ with respect


to the shielding region of the A ring.


In 5-1E,


is located


over the aromatic A ring


and is


shielded and in


5-3E,


shielded by the A ring.


Table


5-1.


Chemical


Shifts


in ppm of


5-1


and


5-3


in CDCl3


We believe the incorrect structural assignment in 1976 is

the result of assuming the wrong conformation for the natural


product,


shown then as 5-1Z,


where the B and C rings have the


Cpd A-Ring B-Ring C-Ring D-Ring
5-1 8.57 (H2) 8.57(H2"'')
7.87 (H4) 8.12 (H4') 7.23 (H3"'') 7.61(H4'"')
7.30 (H5) 7.48 (H5') 7.43 (H5'') 7.35(H5"')
8.57 (H6) 8.82 (H6') 8.76 (H6"'') 8.64(H6'"')

5-3 8.63 (H2) 9.01 (H2'''")
7.77 (H4) 7.84 (H4') 7.55 (3'') 8.19(H4"')
7,26 (H5) 7.49 (H5') 7.13 (HS''5) 7.38(H5' ")
8.56 (H6) 8.83 (H6') 8.67 (H6") 8.65(H6"')










nitrogen


reported


atoms


of the


structural


C rings,


assignment.


This


thus


small


giving


error


rise


marred


successful


outcome


otherwise


difficult


structure


determination.















THE CORRECT


2,2'-BIPYRIDINE


CHAPTER


STRUCTURE OF THE OXIDIZED DIMER FORMED


FROM


IN THE PRESENCE OF LITHIUM DIISOPROPYLAMIDE


IS 2,2


':3'


' 6'"


,2'''-QUATERPYRIDINE.


Introduction


Lithium


diisopropylamide


(LDA)


known


react


with


pyridine to give a radical anion which then undergoes coupling


to yield

amounts


4,4' -bipyridine


depending


and


reaction


2,4'-bipyridine


conditions.


varying


Recently,


symmetrical bipyridines have been dimerized in the presence of


LDA to give quaterpyridines.


The mechanism is,


again,


believed


involve


electron


transfer


and the


formation


a reactive


radical


anion


that


gives


rise


quaterpyridine


product


following


coupling


oxidation.


Thus,


LDA


with


3,3'-


bipyridine


gives


3,3' :4'


, 3" -quaterpyridine


coupling


4-position38


and


4,4'-bipyridine


yields


Ir: 4II


4,4'


, 4'''-quaterpyridine


reaction


position.


Recently,


such


oxidative


dimerization


reaction


been


reported for


2,2'-bipyridine


the presence of LDA and


product


said


6-1,


2,2' :4'


:6'


quaterpyridine.


The oxidized dimer was initially claimed to be


14'':3''


12''


12'''-










author


corrected


structure


with


help


X-ray


anal


ysis


now


claimed


6-2,


:6'', 2' '-quaterpyridine.


We have independently prepared authentic 6-1 by a simple


synthesis


utilizing


palladium (0) -catalyzed


cross-coupling


reaction


and have


found


that


proton


NMR


spectrum


our


quaterpyridine unmistakably does not match that of the product


reaction


with LDA.


have


,2'-bipyridir


repeated

ie and h


LDA


rave


induced


obtained


the


coupling

reported


reaction

product


comparable


yield.


proton


NMR


analysis,


show


this


material


corrected


structure


6-2,


2,2' :3'


:6''


,2' '-quaterpyridine,


132 a substance having been


formed by coupling at the


3 and 6 positions


of two bipyridine


rings


and


dihydro precursor of


positions


6-2


also


has been


formerly


claimed.


identified.


Results


and Discussion


Independent


Synthesis


2,2' :4'


,2' '-Quaterpvridine


Un-)


Employing


construction


strategies


recently


unsymmetrical


developed


quaterpyridines,


132,133


a a a S -


3' 2'


12''


,2' 6'


1










quaterpyridine,


was


di-N-oxidized


with


MCPBA


give


6-3


(54%)


N-oxide


synthons


allow


further


functionalization of the bipyridine rings into


2',6-dichloride


6-4.


was


advantageous


first


convert


6-3


into


dipyridone


with acetic


anhydride


and


then


to make dichloride


6-4


with


POC13/DMF


thereby


minimize


formation


isomers.


Direct


conversion


6-3


into


dichloride


6-4


with


POC13/DMF was unsatisfactory because


it yielded a 1:1 mixture


6-4


and 2'


4-dichloride


6-5.


Since both isomers representing chlorination at the 4 and


6 positions of the 2-pyridyl ring were at hand,


identification










palladium-catalyzed


cross-coupling


with


2-(tributylstannyl)


pyridine"9


completed


synthesi


6-1


(57%)


proton


shift


assignments


NMR spectrum


given


6-1


Figure


along

6-2.


with

They


chemical


based


COSY


(Figure


6-3)


and NOE difference


spectra.


Proof


of the


Structure


6-2,


the Quaterpyridine


Formed in


the Presence of LDA


The proton NMR spectrum of


6-2


given in Figure


6-4.


comparison with our spectrum of


6-1


clearly indicates the two


quaterpyridines are not the same material.


They both must have


an unsymmetrical four ring A-B-C-A and not a symmetrical A-B-


B-A structure,


owing to


large number of


signals.


Because


there are just six different ways to join two


2,2'-bipyridines


together to give such an unsymmetrical material,


Table 1,


and


one of these,


entry


is our newly synthesized material


6-1,


there are


just


five


possibilities


for the


product


of the LDA


reaction.


these


five


structures


but


material


question have not


yet been


prepared.


With


both


6-1


6-2


ring


protons


are


easily


assigned by their


similarity to


chemical


shifts


and spin


coupling constants


identification


of 2,2'-bipyridine


structure


itself.


6-2


key to


substitution


- A S a -.-a a jn -


i


L





















Ip


7.4


7.6-


7.8


U.9-


3.8-


I.4


1.6


8.8


9.


9.0 8.8 8.6 1.4 38.8 .h 7.1 ?7. 7.4 7.8


II (pp.)


Figure


6-3.


COSY


spectrum


of quaterpyridine


6-1


CDC13.













CE
U~
S


































































.I., if., *. if if TV,.


Fl (pp.)


Figure


''' T'' r rI r 'r'l'' 1 I'''`I''' 1'










belong


one


these


rings.


Importantly,


their


major


coupling constants of 5 and 9 Hz unequivocally require them to


part


2, 3-disubstituted


ring


and


not,


originally


suggested,


ortho


part


couplings


2, 6-disubstitued


proton


pyridine


position


where

would


both

have


essentially


bipyridine


the


the


same


value.


coupling


"3 Typically,


constant


a pyridine


the


,3-position


smaller


(5 Hz)


than that


for the 3, 4-position


(8 Hz)


134 Thus,


ring


2, 3-disubstituted


and


only


first


three


entries


Table 1


represent


correct possible


structures.


Table 6-1.


Six Possible Ways of Joining Together Two 2,2'-


BPYs to


Form Unsymmetrical


QPYs


the


Type A-B-C-A.


The incorrect assignment of these three signals to a 2,6-


disubstituted


ring


probably


was


crucial


error


original


report.


I










Irradiation


signal


8.28


(H5'")


caused


this


four


proton multiple to reduce to a simple one proton triplet with


coupling


constant,


showing that


this


resonance must


associated


with


proton


at position


ring


(Figure


6-6)


Therefore,


this


ring must be


2,6-disubstituted


as in our C ring of


6-2


and not 2,4-disubstituted


in the B


ring


of 6-1.


Thus,


the correct


structure


LDA reaction


product


must


that


given


6-2,


entry


Table


complete


signal


assignment


found


experimental


section.


The partial proton spectrum of


a crude dihydro precursor


of 6-2 isolated prior to its oxidation is given in Figure 6-7.

The spectrum is consistent with the C ring being either a 1,2-


dihydro-2,6


or a


1,4-dihydro-2, 4


disubstituted pyridine


with


characteristic


coupling


constants


double


and


single bonds


of the


(6 Hz)


as well as allylic coupling


four carbon bound protons have


an eight


(5 Hz)

line c


135 Two


oupling


pattern characteristic of a four spin system while the one at


the highest


field has


lines


consistent


with


an additional


coupling to


the proton


on nitrogen.


suggest


this material


6-6


(Figure


6-8),


having


a nucleophilic


carbon


bonded


position


of the C ring.























































Figure 6-6













position

dihydro


second


intermediate


bipyridine


6-6


following


ring


give


quenching


the

with


observed


proton


source

Carbon


Oxidation

nucleophiles


then

are


gives

known


quaterpyridine


product.


position


,2'-bipyridine


119,136


Supporting


this


suggestion


rich


ionic


chemistry


assoc


iated


with


deprotonation


and


lithiation


LDA


ring


positions


heterocycles.


wide


117, 137


our


variety


attempts


aromatic


find


nitrogen


evidence


proposed 3-lithiated


6-7


quenching the LDA reaction mixture


with


either


CH30D


and


then


examinining


NMR


recovered


unsuccessful


complex


evidence


Curiously,


2,2'-bipyridine


deuterium


position


known


incorporation


the


undergo


were


ruthenium


hydrogen-


deuterium


exchange


but


only


with


CD3OD-CD3ONa-DMSO















CHAPTER


STRATEGIES


QUATERPYRIDINES


FOR


USING


SYNTHESIS


OF UNSYMMETRICAL


PALLADIUM-CATALYZED


CROSS-COUPLING


REACTIONS


Introduction


Unsymmetrical


and


unsubst ituted


quat


erpyridines


type


A-B


-C-D


where


letters


represent


individual


pyridine


rings


are


largely unknown substances


Of the


theoretically


poss


ible


structures,


just


seven


were


reported


prior


start


our


investigations


. Many


contain


the


,2'-bipyridine


unit


because


of the


eres


ting


ability


this


bipyridine


coordinate


various


structures


type


metal


ions


A-B-B-A;


Five


they


are


are


easily


symmetri


prepared


homocoupling


the


A-B


portions


under


variety


conditions.


36-40


the


two


reported


unsymmetrical


quaterpyridines,


both


were


originally


assigned


incorrect


structures


. Both


structures41'


have


been


corrected


either


independent


cross-coupling


synthesis

chemistry c


based


)r X-ray


palladium(0


analysis


-catalyzed


129,132


now


demonstrate


strategy


that


has


considerable


generality


for the


synthesis


unsymmetrical


quaterpyridines


types


A-B-C-D


and


A-B-C-A.


Individual


pyridine


rings










pyridyl


stannane


(Stille


coupling2)


borane


(Suzuki


coupling7")


Of the


different possible arrangements for the


central


bipyridine


rings,


start


with


two


different


model bipyridines


that


compr


ise


the central B-C portion,


one


linked 2,4'


and the other


and show


how to


functionalize


selectively


one


pyridine


ring


time


order


achieve


selective cross-coupling.


Liberal use is made of a pyridine N-


oxide


synthon


and


specific


conversion


into


a-chloro


pyridine


suitable


for the metal-catalyzed cross-coupling.


one


instance


N-oxide


atom


was


introduced


onto


preformed


bipyridine


controlled


N-oxidation


while


another example a


stannylated pyridine N-oxide directly


gave


N-oxidized bipyridine on cross-coupling with a chloropyridine.


Results


and Discussion


The A-B-C-D Geometry


--- ---_ r N -


3"'-Quaterpyridine


(7-5)


known


precursor,


4-chloro-2, 3' -bipyridine-1'-


oxide'32


(5-6)


Figure


7-1,


was


made


from


dichloropyridine


coupling


and


followed


diethyl (3-pyridyl) borane


regioselective


Pd(0)


N-oxidation


sterically


less hindered nitrogen atom.


To this was added the


- S -


2.2' 3'


2' r4'










chloride


7-4.


was


advantageous


carry


this


conversion


two-step


with acetic


rather


than


anhydride


one-step


pyridone


and


sequence,


then


first


converting


making


into


chloride


more


with


sterically


POCl3/DMF.


hindered


With


two-step


position


was


approach


specifically


functionalized.


Direct


conversion


the


N-oxide


with


POC13


was


attempted


because


often


mixture


both


chlorinated


products


produced.










Proof


that


conversion


N-oxide


7-3


more


hindered a-chloride actually took place to give terpyridine


was


easily


demonstrated by


coupling pattern


ring which contained three highly coupled protons and not


just


as would have resulted from the


undesired a'


or y'


chloro


isomers.


Eight


different


proton


signals


7-4


(CDC13)


are


clearly


resolved


making


their


assignment


quite


easy.


Addition of the A-ring by means of


(tributylstannyl)


pyridine"9 with Pd(0)


completed the


synthesis


to give


7-5.


Clearly


in our synthesis the bonding


site of


the A and D


pyridyl


rings


easily


could


have


been


varied


using


isomerically


metallated


pyridine


starting


material.


this


way and by keeping the same bonding pattern of the original B


and C rings a total


of nine quaterpyridines could easily have


been prepared.


The A-B-C-A Geometry


3,3' :2'


,3' -Quaterpvridine


(7-8)


3-Chloro-2, 4'-bipyridine-1'-oxide (7-6)


in Figure 7-2 was


easily


prepared


from


2,3-dichloropyridine


(tributylstannyl)pyridine


N-oxiden13


the


palladium


route


discussed in chapter


We assume that


coupling took place at


2 and not the 3 position as expected from a consideration


-~~~~~~I ft S ft *S--


r4'


. 1


.










a chloro


derivative by


two-step


acetic


anhydride-POCl3


method


give


dichloride


which


then


with


diethyl (3-


pyridyl) borane


and


Pd(O)


gave


the


quaterpyridine


7-8


having


same


two


3-pyridyl


terminal


rings.


Others


have


used


similar


approach


first


making


B-B


portion


followed


coupling


form


A-B-B-A


quaterpyridine


having


methyl


groups


Had


our


assumption


been


wrong


about


site


coupling


first


cross-coupling


step


prepare


7-6


Scheme


final


product


would


have


been


isomeric


quaterpyridine


natural


product,


nemertelline,


that


have


independently


prepared


a convergent


synthesis










Clearly,


chloro N-oxide


7-6


could have been cross-coupled


some


other


pyridine


ring


then


N-oxide


resultant


terpyridine


could


have


been


converted


new


chloride


as we have done.


This new terpyridine,


in turn,


could


have been


cross-coupled


to a different


fourth ring to give a


family


nine


isomeric quaterpyridines


the A-B-C-D


type.


Chemical


shift


assignments


the


quaterpyridines


are


found


the


Experimental


Section


and are


based


on COSY


NOE difference


spectra


samples


CDCl3


Because


there


less


signal


overlap


these


compounds


when


dissolved


CD30D,


useful


to record spectra


with both solvents.


Overview of


Quaterpvridine Preparations


three


isomers


potential


stannyl


pyridine"9


starting


materials


are


known


well


three


corresponding


boranes.


However,


2-pyridyl


borane


never


been


forms


cross-coupled


unusually


reaction


stable


cyclic


with


dimer


because


resembling


dihydroanthracene.


and


4-stannylated


pyridine


oxides


are


easily


prepared


isomer


still


unknown.


large


number


mono


and


dihalogenated


pyridines


are


commercially


available


for the


preparation


of bipyridines by


-


- --










Cross-couplings


dihalopyridines


may


made


selective


choice


halogen


where


reactivity


order


> Br > Cl


and by the


realization


that


the a and


positions are more reactive than a f position when the halides


are the same.

the crucial I


Thus,


considerable control in the preparation of


central bipyridines


is possible.














CHAPTER


EXPERIMENTAL


Diethyl (3-pyridyl) borane,


4-chloropyridine-N-oxide,


amino-2-chloropyridine,


oxychloride,


bromopyridine,


bipyridine, 2,4'-

acetic anhydride,


tributyltin


chloride,


2, 3-dichloropyridine,


57-80% m-chloroperbenzoic acid


-bipyridine,


phosphorus

n-BuLi, 2-


(MCPBA),


1.5 M lithium diisopropylamide,


4-nitrophenethyl bromide,


urea-H202 complex,


methyl


triflate,


methyl


iodide,


methyl


tosylate,


nitropyridine-n-oxide, 6-chloronicotinamide, 4-bromopyridine,


4-chloropyridine,

chloropyrazine,


3-iodopyridine,

3-bromoquinoline,


5-bromopyrimidine,

4-bromoisoquinoline,


tetrakis (triphenylphosphine)


dibenzylideneacetone


palladium(0)


palladium


tris-


dimer,


(diphenylphosphino)ethane


palladiun (II)


dichloride


were


purchased


from


Aldrich


Chemical


Company


AcrOs


Chemical


Company.

pyridine79


3- (Tributylstannyl) pyridine"7


, 4- (tributylstannyl) pyridine79


(tributylstannyl)


, 3- (tributylstannyl


quinoline79


, and


4- (tributylstannyl)isoquinoline79


were


prepared


literature


methods


from


tri-n-butylstannyl










Quaternized


hetaryl


iodides


were


prepared


with


neat


methyl


iodide


unless


indicated


otherwise.


Quaternized


hetaryl


tosylates were prepared in chloroform or ethyl acetate unless


indicated


otherwise.


attempt


was


made


optimize


yields


of the


final


cross-coupled products;


yields


refer


to isolated materials.


Variable amounts of water were found on


repeated combustion analysis of N-oxides;


the amount of water


found


extent


solid


of drying.


seems


Reverse


dependent


phase


method


octadecylated silica


and


was


purchased


from


Aldrich.


Flash


chromatography


made


use


Kieselgel


230-400 mesh


or alumina


80-200 mesh.


Thin


layer


chromatography


used


Whatman


polyester


backed


silica


plates.


1H NMR spectra were recorded on Varian Gemini 300


(300


MHz),


(300


MHz),


Varian


Unity


(500


MHz).


Grignard


reactions


were


initiated


with


dibromoethane.


Solvents


often


were


freshly


distilled


and


degassed


bubbling


through


them


15-30


minutes.


melting points


are uncorrected.


The drying


agent


was either


sodium or magnesium sulfate.


5-Chloro-3,3'-bipvridine-l-oxide (2-1)


A mixture of 3,5-


dichloropyridine-N-oxide55


pyridyl) borane


(400


(0.36


2.44


mmol)


mmol),


and


diethyl(3-


tetrakis-


(triphenylphosphine) palladium (0)


(0.30 mg,


0.25 mmol)


in 20 mL


-. -