N-methylation and N-oxidation of the less reactive nitrogen atom of a 2,3′-bipyridine. Two general methods for polyazines

Tetrahedron Vol. 51, No. 11, pp. 3103-3114, 1995 Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0040-4020/95 $9.50+0.00

Pergamon

0040-4020(95)00074-7

N-Methylation and N-Oxidation of the Less Reactive Nitrogen Atom of a 2,3'-Bipyridine. Two General Methods for Polyazines 1 John A.

Zoltewicz*

and M i c h a e l

P. Cruskie,

Jr.

D e p a r t m e n t of Chemistry, U n i v e r s i t y of F l o r i d a Gainesville, F l o r i d a 32611-2046

Key words Selective

N-functionalization;

2,3'-bipyridine;

Pd c r o s s - c o u p l i n g

A b s t r a c t : 5 - C a r b a m o y l - 2 , 3 ' - b i p y r i d i n e model c o m p o u n d was Nm e t h y l a t e d or N - o x i d i z e d at the less r e a c t i v e 2 - p y r i d y l ring the first time. Two d i f f e r e n t schemes were developed.

Directing polyazine

or

challenge.

a a

reaction

polycyclic

Especially

is s t e r i c a l l y

atoms

geometry, hindered

the

one

(BPY)

an

markedly

atom much

old

electronically

is a p r o t o t y p i c a l

demonstrate nitrogen

is

annular

nitrogen

and

of

the

less

atom

continuing

is the case where the d e s i r e d

and/or

and t h e r e f o r e

selected

polyazine

difficult

hindered

2,3'-Bipyridine nitrogen

to

for

of

a

synthetic

reaction

site

deactivated.

p o l y a z i n e w h e r e the two annular

different

reactivities

2-pyridyl

ring

nucleophilic

than

being that

due

to

their

more

sterically

of the

3'-pyridyl

ring. We

have

devised

functionalization substrate. atom

of

two one

different annular

When it is d e s i r a b l e

in the

2-pyridyl

ring

methods

nitrogen

to

atom

to f u n c t i o n a l i z e

of the BPY

our

removable

2-(p-nitrophenyl)ethyl

the

reactive

more

nitrogen the

methyl

(NPE)

final

group

protecting

in a similar

is

product.

A

group,

sequence

atom,

by

simpler

approach

readily

iDedicated to P r o f e s s o r of his retirement.

sequence

the

base

removed Scheme

for

as

employs

a

model

nitrogen a three-

on preformed BPY. A is first

bonded

less

reactive

2-pyridyl

or N - o x i d a t i o n

p-nitrostyrene the

N-oxide

by the action

of KI

to

give

employs

W. J e f f o r d

on the

an

in h e a t e d

i.

Charles

3103

as

BPY

group

by N - q u a t e r n i z a t i o n

removed

of steps,

approach

protecting

nitrogen

atom then is f u n c t i o n a l i z e d

protecting

desired

3'-pyridyl

regiocontrolled

a

the less r e a c t i v e

first

step p r o t e c t i o n - f u n c t i o n a l i z a t i o n - d e p r o t e c t i o n

achieve using

occasion

to

and the NDMF

3104

J.A. ZOLTEWlCZ andM. P. CRUSKIE,JR

Scheme la

~

CONH2 i

~CONH2 -eN~

1 ~ ~ or

ii, iii

1

CONH2

+ R~

2, R1 = CH3

4, R1 - (CH2)2C6H4NO2 P

iv, or v, vi or

x or ~ viii,

X

~1/CONH2

~

~

+

t

X

X

i o

R1

R1

3, R1 = R2 = CH3 5, R1 - (CH2)2C6H4NO2 p R2 = CH3

6, R2 - CH3, X = CONH2 8, R2 - O', X - CONH2 10, R2 - O-, X = H

7, R1 = (CH2)2CsH4NO2 P X - CONH 2 9, R1 = CH3, X - CONH2 11, R1 " CH3, X - H

aReagents:(i) Pd(Ph3)4,3-Et2B-pyddine,THF,(ii) Mel, EtOAc,(iii) Br(CH2)2C6H4NO2,(iv)Mel, DMF,(v) Mel,sulfolans(~i) MeOTs,sulfola~, (~(i)NaOAc,MeCNfor5, (~iii)MCPBA, sulfol~ for 7; peroxide,1FA for 9, (ix)MCPBA,CHCI3for 11, (x) NaOAc,MeCNfor7, (xi) KI, DMFfor 9 and 11.

In the second method the desired nitrogen atom is functionalized first and then the two pyridine rings are cross-coupled together to generate the BPY using a palladium catalyst, halogenated pyridine,

a pyridyl borane

and an N-functionalized

Scheme 2.

Scheme 2 i,/0/x

~BEt2 +

Ha

~

8, 10

Pd(PPh3)4 Na2CO3

I O X = CONH2 X=H

Our model

substrate

carbamoyl-2,3'-bipyridine

selected to (i). Not

illustrate these

only

two methods

is the 2-pyridyl

ring

is 5-

sterically

N-Methylation of a 2,3'-bipyridine

d e a c t i v a t e d for n u c l e o p h i l i c s ubs t a n t i a l

additional

so d e a c t i v a t e d differ

widely

reactions but also the c a r b a m o y l

electronic

that we were

markedly

from

applicable

used

in

to other

The r e g i o c o n t r o l l e d

8 were

the

ion. I The

new

The

new r e a c t i o n

first

group presents

2-pyridyl

successful

conditions

are

ring

in 1 is

conditions

which

synthesis

likely

to

of

l-

be

more

nitrogen

atom

substrates.

N-methylation

to give 6 and the r e g i o c o n t r o l l e d of 1 to p r e p a r e

deactivation.

forced to devise

those

methyl-2,3'-bipyridinium

3105

achieved

of 1 at the

N-oxidation by the

2-pyridyl

of the 2 - p y r i d y l

first

n i t r o g e n atom

route.

U s i n g the second synthetic a p p r o a c h N - o x i d e 8 also was p r e p a r e d but the cross-coupling

route

failed to provide

N-methylated

6.

RESULTS AND DISCUSSION Pd-Catalyzed Cross-Coupling. Suzuki 2-5

cross-coupling

carbamoylpyridine aqueous

route 6 but

the

benzeneboronic

acid

information to

about learn

The

5-methyl

and

the

toward demethylation.

ester

The c o n d i t i o n s the

limited

thermal

the

of

thermal

the

two

and

been

(92%)

tosylate

selected of

dequaternization. form of BPY

Our

by

not

and a

an

similar

couple

with

1

was

examined

of

atoms

the

and,

obtain as

diquaternized

took p l a c e

iodide

to

seen salt

r e a d i l y to p r o v i d e

in 80% y i e l d with MeI and

(MeOTs).

for the 2,

by a

2-chloro-5-

made

did

nitrogen

instability

The first N - m e t h y l a t i o n

solubility

diquaternized

has

of

2, l ' - m e t h y l - 5 - c a r b a m o y l - 2 , 3 ' - b i p y r i d i n i u m 99% yield with methyl

prepared

of Pd(dppb)Cl2. ~

di-N-methylation

reactivity

about

readily

2-chloro-3-carbamoylpyridine

in the p r e s e n c e

Mono-

1 was

diethyl-3-pyridylborane

tetrakis(triphenylphosphine)palladium(0)

buffer.

isomeric

N-Methylation. below,

with

carbonate

Bipyridine

of

second N - m e t h y l a t i o n

its

diminished

conditions

itself,

MeI

used

were

reactivity for

the

in a c e t o n i t r i l e

dictated

and

preparation

heated

by

subsequent of the

at i00 °C in a

sealed tube, ~ were u n s a t i s f a c t o r y . $ulfolane °C gave DMF

(3),

and

s o l u b i l i z e d m o n o c a t i o n 2 and h e a t i n g with excess MeOTs at ii0

l,l'-dimethyl-5-carbamoyl-2,3'-bipyridinium

MeI

was

unsatisfactory

diquaternized

(3)

decomposition

product

products were

because

along

isolated

with

a

mixture

ion of

(84%). mono

(2)

tetramethylammonium

protecting

monocation

4.

group

to N-I'

was

and

solvent

in low yields.

Addition of the Protecting Group and Diquaternization. The a d d i t i o n NPE

Heated

achieved

easily

in

90%

yield

to

of the provide

3106

J.A. ZOLTEWICZand M. P. CRUSKIE, JR

Again,

the

second

methylation

step

was

a challenge.

The

solvent

of

choice p r o v e d to be sulfolane b e c a u s e of its g o o d solvent p r o p e r t i e s and its inertness

to

the

methylating

agent.

However,

the

yield

of

desired

d i q u a t e r n i z e d 5 was only 15% using MeI b e c a u s e d e p r o t e c t i o n of the starting material by iodide ion f o l l o w e d by m e t h y l a t i o n to form d i m e t h y l a t e d d i c a t i o n 3 was a c o m p e t i n g process. Reverse phase column c h r o m o t o g r a p h y 8 p r o v e d useful in the s e p a r a t i o n of materials. The yield of 5 i m p r o v e d to 85% with MeOTs. No d e q u a t e r n i z a t i o n now was evident with the weakly n u c l e o p h i l i c t o s y l a t e counterion. A t t e m p t s to attach other groups to N-I of 4 were u n s u c c e s s f u l . ethyl t o s y l a t e nor b r o m o a c e t o n i t r i l e nor benzyl bromide,

Neither

the latter in the

presence of silver salts, 9 could be made to react, p r o v i d i n g further evidence of the m a r k e d l y low r e a c t i v i t y of this atom. An attempt was made to b o n d a 2 - c y a n o e t h y l group to the N-I' atom of 1 with the e x p e c t a t i o n that it would be easier to remove by the action of base in the d e p r o t e c t i o n

step. 1°'n However,

the 2 - c y a n o e t h y l

bromide

alkylating

agent only gave rise to low yields of the d e s i r e d N - q u a t e r n i z e d product.

Deprotection.

Selection of conditions for the successful

removal of the N-

p r o t e c t i n g group r e q u i r e d several trials. The 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i n e base used in our e a r l i e r study ~ was u n s a t i s f a c t o r y b e c a u s e of the d i f f i c u l t y encountered

in

removing

it

as

its

tosylate

salt

from

the

desired

ionic

product 6, l - m e t h y l - 5 - c a r b a m o y l - 2 , 3 ' - b i p y r i d i n i u m ion. Dry sodium acetate in refluxing

acetonitrile

regenerate

the

unsubstituted

m o n o m e t h y l a t e d product

N-Oxidation.

brought

about the e l i m i n a t i o n 3'-pyridyl

ring

of 4 - n i t r o s t y r e n e

and

the

formation

to of

6 (55%).

(Nitrophenyl)ethylated material

using 3 - c h l o r o p e r b e n z o i c

acid 12 in sulfolane

4 was easily (57%)

N - o x i d i z e d to 7

and the p r o t e c t i n g group

was removed using sodium acetate in a c e t o n i t r i l e to y i e l d 5 - c a r b a m o y l - 2 , 3 ' bipyridine-l-oxide 8

(62%).

In view of the easy d e a l k y l a t i o n of 3 by iodide ion, another route was explored, now using the N - m e t h y l substituent on N-I'

as a p r o t e c t i n g group.

Iodide 2 was first c o n v e r t e d to the t o s y l a t e at room t e m p e r a t u r e with MeOTs to g e n e r a t e oxidizing

volatile

the

trifluoroacetic

iodide

in an anion

counterion

acid 13 to

(9). Deprotection, DMF,

MeI

and

exchange then

reaction

N-oxidized

in order (86%)

in

to avoid peroxy-

5-carbamoyl-l'-methyl-2,3'-bipyridinium-l-oxide

this time r e m o v i n g the methyl

group u s i n g KI in heated

gave the more s t e r i c a l l y h i n d e r e d mono N - o x i d e 8

(55%).

On the parent BPY lacking the carbamoyl substituent,

the same sequence

of N-I' p r o t e c t i o n with a methyl group f o l l o w e d by N - o x i d a t i o n gave ii which

N-Methylation of a 2,3'-bipyridine

then was d e p r o t e c t e d oxidation

of

thermally

unprotected

BPY

with KI has

3107

in hot DMF to a f f o r d

been

reported

along

with

i0

(40%). N-

spectroscopic

properties. 14,~

Palladium-Catalyzed i0

(68%)

Coupling to Prepare N-Oxide 10. A more direct route to

employed

palladium-catalyzed

c r o s s - c o u p l i n g 2-~

of

diethyl-3-

p y r i d y l b o r a n e and 2 - b r o m o p y r i d i n e - l - o x i d e in aqueous carbonate. A l t h o u g h the 2-bromopyridine-l-oxide reaction

with

reaction

was

can

hydroxide not

undergo

ion

to

important.

A

a

give

facile a

nucleophilic

pyridone, IG this

2-bromopyridine-l-oxide

substitution

potential

has

been

side-

made

to

ability

to

couple w i t h a t h i e n y l b o r o n i c acid under similar conditions. ~7

Unsuccessful

Palladium-Catalyzed

cross-couple

Coupling

diethyl-3-pyridylborane

to

Prepare

with

6.

Our

N-methylated

pyridinium,

q u i n o l i n i u m and i s o q u i n o l i n i u m halides having the h a l o g e n atom located beta to the annular n i t r o g e n atom ~8 e n c o u r a g e d us to attempt the p r e p a r a t i o n

of

6 by such a route using a q u a t e r n i z e d substrate having the h a l o g e n atom at an alpha position. Unfortunately,

all attempts failed. Thus, c o u p l i n g of the

3-pyridylborane

and 2 - b r o m o - l - m e t h y l p y r i d i n i u m

carbonate

bicarbonate

or

palladium(0)

buffers

and

ion was u n s u c c e s s f u l

using

tetrakis(triphenylphosphine)-

or Pd(dppe)~Cl 2 (dppe is 1 , 2 - ( d i p h e n y l p h o s p h i n o ) e t h a n e ) .

CONCLUSIONS The

two

compared,

methods

each

for

the

ultimately

preparation

starting

of

with

carbamoyl

the

N-oxide

3-pyridylborane

8 may and

be

a

2-

halopyridine. The t w o - s t e p p a l l a d i u m coupling route first m a k i n g the N-oxide and then c o u p l i n g the two reactants

is shorter

and gives

8 in 63% overall

yield. The four-step sequence where the 2 , 3 - b i p y r i d i n e is p r e p a r e d first by palladium overall for

the

coupling,

protected,

N-oxidized

and

then

deprotected

yield of 29% for the route using the NPE p r o t e c t i n g methyl

protection

scheme.

Although

unsubstituted

gives

an

group and 43%

N-oxide

i0

was

s y n t h e s i z e d by the two routes the starting points are not the same for both approaches to allow a m e a n i n g f u l comparison. The overall y i e l d for the fourstep route to the N - m e t h y l a t e d carbamoyl 6 was 39%. Our

two

methods

would

seem

to

be

useful

variety of s e l e c t i v e l y N - d e r i v a t i z e d polyazines.

for

the

preparation

of

a

3108

J.A. ZOLTEWICZand M. P. CRUSK1E,JR

EXPERIMENTAL Reverse Kieselgel

phase

60 was

octadecylated

used

for

silica

column

gel

was

purchased

5-Carbamoyl-2,3'-bipyridine (i). D i e t h y l - 3 - p y r i d y l b o r a n e 6-chloronicotinamide

1.04

palladium(0)

(0.591 mmol)

stirring

0.683 g

for

degassed

5

min,

reaction

mixture To

The o r g a n i c

The

give

a precipitate

acid

1.02

(DMSO-d~)

washes

g

carbonate

d, J = 8 Hz),

to

0

50 mL

was

(1.61

°C

7.60

(IH, N,

the

catalyst

was

added

and m a d e

dd,

C,

in

EtOAc

overnight. yield,

mp

9.07

(IH,

Hz),

8.22

gave

crystals

Trituration >250 d,

sodium

J=

65.24;

Calcd.

3.54;

N,

t,

(CD~OD)

8.92

after

4.50;

d,

8 Hz),

C,

(IH,

8.15

42.25;

s),

J = 6 Hz),

H,

(IH, 3.55;

at

d,

9.13

12.32.

8.07

(IH,

1 and excess temperature crystals

(IH, (IH,

d,

dd,

J = 8 Hz),

N,

J = 1.5 and

room

yellow

8.42

H ~ NMR

20.93.

Compound

pale

to

for CIIHgONs. I/4H20: N,

stirring

yielded

6 9.47

(IH,

J = 6 and

for C12HI20N~I:

2

(IH, dd,

to

water

2 and 8 Hz),

Calcd.

H,

carbonate from

°C d e c o m p . ) .

8.63

(IH, dd,

hot m e t h a n o l

H ~ NMR

J = 8 Hz),

(IH,

Anal.

°C).

with

of

of 2M

with

5-Carbamoyl-l'-methyl-2,3'-bipyridinium Iodide (2a). MeI

layer

basic

J = 6 a n d 8 Hz) . A n a l Found:

under

i0 mL p o r t i o n s

(IH, d, J = 1.5 Hz),

of

aqueous

with

(mp 2 2 7 - 2 2 9

mL

removed

the

recrystallized

solid

13

for 6 h. The

twice

and

8.36

was

and

THF. A f t e r

in

at r e f l u x

and

of a w h i t e

20.63.

dissolved

of E t O A c

J = 2 a n d 8 Hz),

4.70;

g)

was s t i r r e d

collected

9.15

0.809 g (5.5 mmol),

w e r e a d d e d to 25 mL of d e g a s s e d

combined

(IH, s),

(IH, dd,

H,

were which

Aldrich.

and t e t r a k i s ( t r i p h e n y l p h o s p h i n e ) -

layer was e x t r a c t e d

(92% yield)

6 9.25

8.5

64.86:

cooled

filtrate,

HCI.

C,

potassium

was

the

was removed.

6 Hz),

(6.63 mmol),

w a t e r was a d d e d a n d the s o l u t i o n

nitrogen.

afford

g

from

chromotography.

J = 2 Hz), J = 6 and

4.52

Found:

(80%

(CHs,

8

s) .

C, 42.01;

H,

12.61.

5-Carbamoyl-l'-methyl-2,3"-bipyridiniumTosylate (2b). C o m p o u n d 1 a n d e x c e s s MeOTs

in

CHsCN

Filtration crystals 9.20

crystals

(99% yield,

(2H,

(IH, bd, 9 Hz),

gave

m),

9.03

J= 9 Hz), 7.08

C19HIgO4NsS:

of

of the hot s o l u t i o n

(2H,

C,

mp 1 8 5 - 1 9 2 (IH,

8.23 d,

59.20;

d,

9 Hz) H,

4.97;

after

stirring

°C, d e c o m p . ) .

J =

(IH,

2

a n d t h e n two w a s h e s

6 Hz),

dd,

H I NMR

8.46

(IH,

J= 6 and 9 Hz),

4.44

(3H,

N,

10.90.

s),

5-Carbamoyl-l,l'-dimethyl-2,3'-bipyridinium dissolved overnight.

in d r y The

DMF

tube

with was

excess

cooled

MeI and

were

H,

(IH, s),

9 Hz), 7.45

s) . Anal.

Diiodide

solids

6 9.71

(IH, bs),

58.85;

to

overnight.

CHsCN gave b e i g e

J = 2 and

(3H,

and heated the

dd,

C,

reflux

(DMSO-d6)

7.75

2.26

Found:

at

w i t h hot

4.90;

Calcd. N,

( 3 a ) . Salt

95 °C in

The

for

10.80.

2

a sealed

collected.

8.33

(2H, d,

was tube

solids

N-Methylationof

were triturated were

from

needle-like

crystals

orange (IH,

s),

8 Hz), 4.38

w i t h hot m e t h a n o l

recrystallized

9.20

8.43

(IH,

(IH,

d,

dd,

(CH3, s). Anal.

Found:

C,

31.59;

H,

to g i v e

water

and

orange

J = 8.3 Hz),

Calcd.

9.13

8 Hz),

(IH,

8.36

was

stirred

added

at

ii0

sulfolane °C.

(D20),

~ 9.60

d, J = 6 Hz), d,

C, 31.73;

The

Ditosylate

(i0 mL)

solution

was

(3H, m), (CH3, N,

8 9.65

(IH, d, J = 8 Hz), 7.42

s),

7.13.

(DMS0-d~),

(4H,

d,

2.26

(6H,

Found:

C,

s).

Anal. H,

The

(IH,

8.85

J = 8 Hz),

55.24;

mmol)

of 1.52 g

of NaI

allowed

9.36

(4H,

Calcd.

was

(IH,

d, J = 8 Hz),

7.08

4.98;

product

s),

(IH,

concentrated

(6.61 mmol)

and the

and the f i l t r a t e

was c o n c e n t r a t e d mL

added. was

The

still

suspension hot

yellow

solids

yellow

solid

(IH,

d,

(IH,

dd,

Hz),

8.20

C,

the were

47.85;

J = 2 and (2H, Ph, Anal. H,

was

(IH,

(IH,

s),

4.42 C,

stirred

N,

d,

8.26

7.58

Calcd.

3.60;

(IH,

8 Hz), d),

with

J = 5

s),

54.99;

H,

Iodide The

removed.

The i n s o l u b l e

to

this

hot

4.24 5.29;

for C19HITO3N4I:

5.0 C,

(2H,

47.91;

i

8.22

were

(6.5 the

and

to

(IH,

filtrate

(IH,

dd,

H,

3.53;

N,

was

resultant

(IH,

J = 7.0

t, J = 7 Hz),

was

suspension

3.1

8 9.8

was

This was mmol)

the

yield

d,

A (20

removed

iodide.

of

While

(DMSO-d~), 9.02

(4).

and 3 g

suspension

The

solids

off

1,4-dioxane

J = 8 Hz),

d),

g

filtered

°C) . H I N M R

(H, d,

1.3

overnight.

was

J = 2 Hz),

(2H, Ph,

d,

mp

8.37-8.27

(CH3,

bromide

at reflux. were

at r e f l u x

mp >200

9.20

and

material

triturated

and

(84% yield,

9.21

to y i e l d p - n i t r o p h e n e t h y l

heated

insoluble

and

product

6.99.

materials

1,4-dioxane

(90% yield,

J = 8 Hz),

J = 7 Hz).

of

8.54.

mmol)

s),

for C27H2907N3S2.H20:

N,

was

insoluble

dissolved

25

N,

the

8.65

d, J = 8 Hz),

a n d 20 mL of E t O A c was added.

in

J =

collected

solid

of 2 - ( 4 - n i t r o p h e n y l ) e t h y l

in 20 m L of a c e t o n e

to cool

d,

(CH3, s),

(0.887 and

5-Carbamoyl-l'-(2-(4-nitrophenyl)ethyl)-2,3'-bipyridinium mixture

(IH,

4.6

of 9.35

(3b). Salt 2 (0.519

cooled

w i t h M e O H a n d E t O A c to give an o f f - w h i t e

H ~ NMR

s),

H, 3.28;

MeOTs

with

9.05

EtOAc/Et20.

with

recrystallized >200 °C).

8.94

which

(25%)

(IH,

J = 8 Hz),

precipitated

Hz),

i:i

yield

8.48.

to d i s t i l l e d

overnight

to

(IH,

5-Carbamoyl-l,l'-dimethyl-2,3"-bipyridinium mmol)

crystals

alcohol

for C13HI60N312.1/2H20: N,

3109

needle-like

isopropyl

(mp >250 °C). H I N M R

J = 6 and

3.18;

a 2,3'-bipyridine

g

of

a

s),

9.22

Hz),

8.43

J = 7 and

8

3.43

(2H, t,

11.76.

Found:

11.77.

5-Carbamoyl-l-methyl-l'-(2-(4-nitrophenyl)ethyl)-2,3'-bipyridiniumDiiodide (5a). A s o l u t i o n MeI

(16 mmol)

of 200 mg

in a s e a l e d

(0.42 mmol) tube

was

was c o o l e d to 0 °C a n d t h e n p r e c i p i t a t e d the oily b r o w n

s o l i d was d i s s o l v e d

of 4 in 3 mL of s u l f o l a n e

heated

at

120 °C o v e r n i g h t .

w i t h 8 mL of EtOAc.

in m e t h a n o l ,

concentrated

After

a n d 1 mL of The m i x t u r e filtration

a n d c o a t e d onto

3110

J.A. ZOLTEWlCZand M. P. CRUSKIE,JR

200 m g of o c t a d e c y l

functionalized

silica

to the t o p of a r e v e r s e p h a s e

silica

of the

oil

was

water

gave

an

recrystallized

from

crystals

(15% yield,

s),

(IH,

9.22

8.65

(IH,

NH),

8.18

s,

(2H, 3.45

N,

methanol

8.39

(IH,

d, Ph),

7.54

(2H,

9.06:

9.03

and

EtOAc

t,

C,

38.78;

w i t h HzO. 8 R e m o v a l

standing.

The

afford

65 (IH,

s),

8.90

(IH,

d, J = 7 Hz),

8 Hz),

8.30

(IH,

mg

solid

6 9.63

d, J = 8 Hz),

Anal. H,

added

to

d, Ph),

J = 7 Hz).

Found:

on

was t h e n

(DMSO-d6).

J = 6 and

(2H,

and eluted

crystallized

(IH,

dd,

This m a t e r i a l

gel c o l u m n

which

mp >200 °C) . H I N M R

d, J = 6 Hz),

s, NH),

CH3),

3.26;

orange

gel.

d),

4.98

(2H,

t,

Calcd.

for

C20H2003N412:

3.50;

N,

of

yellow

9.48

8.27

J = 7 Hz),

(IH,

(IH,

4.19

C,

s,

(3H,

38.85;

H,

8.99.

5 - C a r b a m o y 1 - 1 - m e t h y l - 1 ' - (2- (4-nit rophenyl ) ethyl ) -2,3' - b i p y r i d i n i u m Ditosylate (5b). A m i x t u r e of 500 mg (1.05 mmol) of 4, i0 ml of s u l f o l a n e , and

1.0

g

(5.4 mmol)

was c o o l e d collected a white (IH, Hz),

8.65

Hz),

8.27

of OTs),

4.89;

(IH,

(IH,

d,

s,

(IH, 7.08

N,

3 times

(85% yield,

9.22

(2H, t, CH2), H,

was

heated

to 0 °C a n d t h e n p r e c i p i t a t e d and w a s h e d

solid

s),

of M e O T s

8.39

s, NH),

2.22

8.18

(6H,

9.03

(IH, (2H,

dd,

C,

d, Ph), 4.98

58.20;

of the

(1.7 mmol)

of s o d i u m

was

to

cooled

concentrated EtOAc.

to a b r o w n

The H20 was

material

eluted

with

of E t O A c

was

H20.

then

Anal.

(55% yield,

mp

(2H,

NH),

8.18

Ph),

7.10

material

34.53;

oil

m),

J =

(2H,

d,

Ph),

3.15;

80 mL

silica of

water

4.22

Ph),

7.50

(3H,

(6) . A

for

48 h.

collected.

s,

N-CH3),

(4H,

9

d, Ph

and

The

3.45

of

0.14

g

suspension

filtrate

and then

phase

a yellow

silica

was

oil.

s),

J = 5 and 2.29

(3H,

9.00

8 Hz),

C, 34.80;

H,

3.16;

N,

and

of

30 mL

brown

solid

(IH,

d,

J =

8.22

(IH,

s,

7.45

(2H,

d,

s CH 3 of

salt on the a d d i t i o n

with

column

Addition

325 m g of a l i g h t

(IH,

mixed

to a powder.

gel

(IH,

(3H,

J =

s, CH3),

The

d J = 8 Hz),

dd,

d,

suspension

(DMSO-d6) . ~ 9.62 8.28

9.48 J = 7

for C34H34N409S2: C, 57.76;

of m e t h a n o l

gave

(IH,

s), d,

(IH,

s, NH), 7.70

(IH, (IH,

gel a n d c o n c e n t r a t e d

yielding

for CI2HI3CI2N309:

i0.00.

8.30

was

600 mg of

up in 20 mL of H20 a n d 20 mL of

a reverse

to its p e r c h l o r a t e

Calcd N,

(IH,

8 Hz),

was c o n v e r t e d Anal.

H I NMR

taken

8.90

of a c e t o n i t r i l e ,

was

solid

8.07.

at r e f l u x

with

top

of the

8.65

d,

H,

on

N,

The

solution

to g i v e

4.19

Diperchlorate

NaOTs

was

d,

Calcd.

5.01;

heated

to s o l i d i f y

>200 °C).

(IH,

acid-EtOAc. C,

placed

(2H,

30 mL

insoluble

diluted

7.54

The

~ 9.63

9 Hz),

(2H, t, CH~),

H,

functionalized

the

8 Hz),

was

(DMSO-d~).

of 5b,

oil w h i c h

Removal

caused

8.85

acetate

0 °C a n d the

500 m g of o c t a d e c y l This

tosylate

of E t O A c

J = 7 and

s, CH 3 of OTs).

Found:

(1.4 mmol)

i0 mL of EtOAc.

(IH, d, J = 9 Hz),

5-Carbamoyl-l-methyl-2,3"-bipyridinium 1.0 g

with

20 m L p o r t i o n s

d, Ph of OTs),

7.93.

115 °C o v e r n i g h t .

mp >220 °C). H I N M R

J = 7 Hz),

NH),

(4H,

with

at

OTs).

This

of p e r c h l o r i c 10.14:

Found:

N-Methylation of a 2,3'-bipyridine

3111

5-Carbamoyl-1 ' - (2- (4-nitrophenyl) ethyl) -2,3' -bipyridinium-l-oxide (7). The i o d i d e a suspension MeOTs

(200

nitrogen which (763

salt was first

of

4

mg,

(500

1.07

suspended

rag, 4.42

20 mL

retool) . The

s),

7.95

(3H,

Ph OTs), for

8.22

(IH,

m),

7.57

4.96

of

dd,

HI N M R

C,

58.20;

H,

under

solid

50%

was

a

(540 mg,

room

under

6 9.72 8.19

Ph),

(IH,

(3H,

7.44(2H,

10.44.

9.08

for

320 mg

C,

8.84

Ph a n d NH), 7.08

(2H, d,

(3H, s, CHs) . Anal.

Found:

3

ether.

7,

(2H, m),

J = 9 Hz,

d, Ph OTs),

(2H, m, CH2), 2.28 N,

to g i v e

s),

d,

acid

temperature

vacuum

of

1.04 mmol)

m-chloroperbenzoic

at

To

added

stream

w i t h 50 mL of I:i E t O A c : d i e t h y l

8 Hz),

4.51;

salt as follows.

acetonitrile

stirred

stirred

and d r i e d

J = 8 Hz,

(2H, m, CH2) , 3.50

C26H~4N40~S:

was

and

(DMSO-dG):

J = 5 and

of

was a w h i t e

was

filtered

(2H, d,

50 mL

sulfolane

reaction

was

(mp >220 °C, 57 % yield). (IH,

in

suspension

was p r e c i p i t a t e d

precipitate

to the t o s y l a t e

mmol)

The p r e c i p i t a t e

in

days and the p r o d u c t The w h i t e

converted

1.04

mmol) . The

for two days.

was

mg,

Tosylate

58.24;

Calcd.

H,

4.51;

N,

To

50

of

10.38.

5-Carbamoyl-2,3'-bipyridine-l-oxide acetonitrile mg,

1.19

solids gel give (IH,

were

and

added

removed

added

to

d,

dd,

19.53.

and

J = 5 and C,

the

0.596

was

dd,

(IH,

9 Hz).

Anal.

H,

4.22;

dry

sodium

for

24 h.

concentrated

eluted

with

70%

5 Hz),

8.52

EtOAc

9 Hz),

7.61

(IH,

Calcd.

for

C11HgNsO2:

Tosylate mmol)

(320

mg) . The

additional mixture with

(bd,

solution

diluted

isopropyl

IH), 2H,

C,

was

with

alcohol

mp >200 °C).

8.38

to

7.48

(d, 2H,

55.22;

H,

4.59;

of

give

iH N M R

Calcd.

(750

1.95

overnight

water

after

at

and

IH,

9 Hz),

filtration

6 and

g of 30%

silica MeOH

to

8.27

J =

(IH,

9 Hz), H,

dt, 7.48

4.22;

N,

7.11

urea-H202

temperature

after

mg

(s, IH),

(d, 2H,

(9): To t r i f l u o r o -

the

product 700

9 Hz),

for C19HIgNsOsS.0.5H20: N,

s),

and

room

the

(DMSO-d6) : ~ 9.60

(dd,

8.03 9 Hz),

C, 55.60;

first

was of

2 h. The

a yellow

IH,

4.42

an

precipitated

9.07 (d,

complex with

solid

(m, 2H),

8.85

9 Hz),

7.95

(s,

H, 4.91;

3H),

2.26

N, 10.24.

10.47.

5-Carbamoyl-2,3'-bipyridine-l-oxide 0.847 mmol)

mg,

of the urea-H~O 2 c o m p l e x i0 mL

8.25

9 Hz),

2

stirred

(s, NH),

(s, 3H, NCH~) . Anal. Found:

added

i00 mg a d d i t i o n

was

(86% yield, (s,

was

(I00

insoluble

19.55.

acetic

(i0 mL)

20

61.39;

5-Carbamoyl-l'-methyl-2,3'-bipyridinium-l-oxide acid

acetate The

and

d,

C,

mL

(DMSO-d6) : ~ 8.96

(IH,

J =

N,

onto

mp >220°C) . H I N M R

J = 2,

d,

and

at r e f l u x

was

(62% yield,

(IH,

mmol)

stirred

which

7.71

61.23;

was

filtrate

solid

8.60

9 Hz),

Found:

(320 mg,

a column

J = 2 Hz), 2 and

7

solution

90 mg of a w h i t e

J = 2, (IH,

was

mmol) . The

(8) by NPE Deprotection.

(8) by

Demethylation.

dissolved in 20 mL of DMF was added KI

To

9

(340

mg,

(280 mg, 1.68 mmol).

The

3112

J.A. ZOLTEWlCZand M. P. CRUSKE, JR

mixture

was

heated

and dissolved filtrate

at

120 °C for

in 40 m L

was

36 h a n d t h e n

of MeOH.

concentrated

The

concentrated

insoluble

material

o n t o 50 g of s i l i c a g e l

same

as t h e

solid.

(55% yield,

m p >220°C).

removed

oil

and the

a n d a d d e d t o t h e t o p of a

s i l i c a gel c o l u m n w h i c h t h e n w a s e l u t e d w i t h 80% E t O A c i00 m g of a w h i t e

to a b r o w n

was

a n d 20% M e O H to y i e l d

The IH N M R

(DMSO-d6)

was the

above.

l'-Methyl-2,3"-bipyridinium-l-oxide Tosylate (11). To 20 m L o f CH2CI 2 added 2,3'-bipyridine solution

was

concentrated

(500 mg,

stirred

at

to yield

3.20 mmol)

room

and MeOTs

temperature

I.i0 g r a m s

(600 mg,

for

(3.20 mmol)

24

h.

was a d d e d t o 30 m L of C H C I 3 a n d 50% of m - c h l o r o p e r b e n z o i c mmol).

The solution

washed

once

with

concentrated for t h e 8.50 and

was 30

mL

(IH, d,

step.

J = 5 Hz),

7.60

NCH3) , 2 . 2 5

of

at r o o m t e m p e r a t u r e

water.

to 800 m g of y e l l o w

deprotection

8 Hz),

stirred

(3H,

oil;

H I NMR

8.24

(2H, m),

The

(2H,

J = 5 and Ph),

The C H C I 3 was separated

s),

9.05

7.85

(2H,

oil w h i c h

and

was used directly

(IH,

8 Hz),

7.05

was

(2.21 g, 12.8

was

this crude material

d,

yellow

acid

layer

The

solvent

for 48 h.

(DMSO-d6) : ~ 9.58

(IH, dd,

7.48

aqueous

3.22 m m o l ) .

The

of a s l i g h t l y

was

d,

(IH,

Ph),

(2H, dd,

4.40

m),

J = 8

(3H,

s,

s, CH3) •

2,3'-Bipyridine-l-oxide (10) by Deprotection: Crude 11 (300 mg, 0 . 8 4 0 mmol) was

dissolved

reaction

in

was heated

and dissolved was

i0

mL

DMF

and

onto

The

insoluble

I0 g of

then was eluted

of a w h i t e

(mp 1 3 5 - 1 3 7

J = 2 Hz), 8.27 dd,

(IH,

8.63 dt,

4.63;

N,

(IH,

dd, 2 and

9 Hz),

7.44

16.27:

Found

C,

gel

with

mg,

and

9 Hz), (2H,

70.03;

5 Hz),

7.73

m). H,

1.68

4.69;

removed

added

to

and

8.37

The s o l u t i o n

(930 mg)

was stirred

300 m g urea-H202 a f t e r

were dissolved overnight

(IH,

for

with

combined, with

dried,

silica

(86% yield,

gel mp

and and

3 times

concentrated 80%

124-128

EtOAc/20%

°C).

H I NMR

dd,

of

a silica

to yield

J = 2 and 8 Hz),

CIoH~N20:

C,

60 m g

(IH,

gave

(DMSO-d6)

d,

6 Hz),

7.52

(IH,

69.75:

5 . 7 5 mmol)

H,

The reaction

850

mg

~ 8.80

The

Column of (d,

an IH,

of

was diluted

layer was separated

liquid.

and

acid.

with the addition

50 m L of E t O A c .

to a c l e a r MeOH

top

(800 mg,

two hours.

aqueous

extracted

oil

filtrate

in i0 m L of t r i f l u o r o a c e t i c

The organic

was

to a brown

16.29.

w i t h 50 m L of H20 a n d 50 m L of E t O A c . layer

the

at r o o m t e m p e r a t u r e

e a c h of t h e f i r s t

The

( D M S O - d 6) 6 8 . 9 5

6-Chloronicotinamide-l-oxide: 6 - C h l o r o n i c o t i n a m i d e urea-H~O 2 complex

added.

and the

J = 2 and

Calcd. N,

was

10% M e O H

H I NMR

(IH, dd,

Anal.

mmol)

concentrated was

90% E t O A c

°C, 40% y i e l d ) .

J = 2 and

J = 2,

J = 5 and

(280

material

silica

gel c o l u m n w h i c h solid

KI

at 120 °C for 24 h a n d t h e n

in MeOH.

concentrated

of

and the

extracts

were

chromotography off-white J = 2 Hz),

solid 8.24

N-Methylation of a 2,3'-bipyridine

(s,

IH),

7.88

Hz) . A n a l . C,

40.50;

(d,

Calcd. H,

IH,

J =

9 Hz),

f o r CsH5N~O2CI

2.91;

N,

7.82

(s,

1H),

.1/3 HzO: C,

3113

7.70

40.35:

H,

(dd,

IH,

3.20;

N,

J = 2 and 16.69:

15.24.

Pd-Catalyzed Coupling to Prepare 5-Carbamoyl-2,3'-Bipyridine-l-oxide Chloronicotinamide-l-oxide (150 mg,

1.01 m m o l ) ,

0 . 1 7 3 mmol)

(175

and

mg,

1.01

mmol),

THF.

under nitrogen

for 5 m i n a n d t h e n K2CO 3 (280 mg,

was

solution

The

°C a n d t h e b l a c k diluted and

Solids which

heated

at r e f l u x

were

to

a

yellow

collected

and

recrystallized

(73%

yield,

mp>

diethyl-3-pyridyl

The

suspension

borane

2 . 0 3 mmol)

solid

the

with

220

filtrate

The

was

was

95% E t O H

°C) .

The aqueous

which

IH N M R

cooled

a

hot

MeOH.

white

solid

160 m g

was

the

0

was

separated

with to

to g i v e

to

The reaction

layer was

concentrated

(DMSO-d6)

stirred

in i0 m L of w a t e r

triturated

and EtOAc

(200 mg, was

for 24 h a n d t h e n

solid was removed by filtration.

w i t h 30 m L of w a t e r a n d 30 m L E t O A c .

was

solid

was

insoluble

concentrated

(8): 6-

tetrakis(triphenylphosphine)palladium(0)

w e r e a d d e d t o 20 m L of d e g a s s e d

added.

9

Found

of a w h i t e

same

as

that

above.

Pd-Catalyzed Coupling to Prepare 2,3'-Bipyridine-l-oxide (i0): 2Bromopyridine-l-oxide h y d r o c h l o r i d e (500 mg, 2.38 m m o l ) , d i e t h y l - 3 - p y r i d y l borane mg,

(350 mg, 2.38 mmol)

0.260

stirred of

cooled of

were

added

under nitrogen

water

mL

mmol)

was

added.

concentrated

and to

solid material

The

m g of a w h i t e same

as t h a t

i.

Zoltewicz,

mL

was

was

degassed

heated

The

solid which

THE.

The

To t h e

was t r i t u r a t e d layer

°C, 68% y i e l d ) .

for

48

filtrate

layer

was

with was

was

in 15 m L

h

and

was

then

added

separated

20 m L

of M e O H ;

concentrated

The H I N M R

(300

suspension

12.0 mmol)

reflux

aqueous

The m e t h a n o l i c

(mp 1 3 6 - 1 3 7

at

collected.

water.

collected.

of

a n d t h e n K2CO 3 (1.65 g,

solution

mL

a white

solid

30

catalyst

30

was

to

for 5 m i n

to 0 °C a n d t h e EtOAc

and tetrakis(triphenylphosphine)palladium(0)

(DMSO-d6)

30 and the

to 280 was the

above.

REFERENCES J.

A.;

Bloom,

L.

B.;

W.

Kem,

R.

J.

Org.

Chem.

1992,

57,

2392. 2.

Suzuki,

3.

Terashima,

A.

4.

Snieckus,

5.

Undheim,

6.

Ishikura,

7.

Ali,

Acc. M.; V.

K.; M.;

Chem. Res. 1982, M. Adv.

Ishikura,

Chem. Rev. Benneche, Kamada,

N. M.; M c K i l l o p ,

J. T e t r a h e d r o n 1992,

1990,

15,

178.

Heterocycl.

A.;

Terashima, Mitchell,

48, 8117.

1989,

46,

143.

90, 879.

T. H e t e r o c y c l e s M.;

Chem.

M.

1990,

30,

1155.

S y n t h e s i s 1984,

M. B.;

Rebelo,

R. A.;

936. Wallbank,

P.

3114

J.A. ZOLTEWICZand M. P. CRUSKIE,JR

8.

0'Neil,

I. A. Synlett.

9.

Katritzky, A. R.; Rubio, 0.; Szajda, M.; Nowak-Wydra, (S) 1984,

1991,

661.

i0.

Bunting,

ii.

Heo, C. K. M.; Bunting,

12.

Katritzky,

J. W.; Moors, A.

R.

R. G. J. Am. Chem. J. W. J. Org.

Lagowski,

N-Oxides; Academic Press:

J.

M.

New York,

14.

Moran, D. B.; Morton, G. 0.; Albright,

15.

Kireev,

2258.

iii,

57, 3570. of

the

Heterocyclic

C. Tetrahedron 1994,

50,

9505.

J. D. J. Heterocycl.

Chem 1986,

1071. G. V.; Leont'ev,

Sadykov,

Illuminati,

17.

Malm,

G. Adv. Heterocycl.

J.; H~rnfeldt,

Zoltewicz, press,

V. B.; Kurbatov,

Y. V.; 0troshchenko,

A. S. Izv. Akad. Nauk SSSR, Set.

16.

19.

1992,

1971.

0cana, B.; Espada,

18.

M.; Avendano,

1989,

Soc.

Chem.

Chemistry

13.

23,

B. J. Chem. Res.

234.

J. A.;

A.-B.;

Cruskie,

Chem.

Khim.

1964,

1980,

5, 1034.

3, 285.

Gronowitz,

S. H e t e r o c y c l e s 1993,

35, 245.

M.

Dill,

Chem.

P.,Jr.;

C.

D.

J.

Org.

1995,

Yamamoto,

O. S.;

Y.; Yanagi, A. Chem. Pharm. Bull.

(Received in USA 2 December 1994; accepted 19 January 1995)

1982,

30,

1731.

in