Directed Metalation

12 Directed Metalation D. W. S L O C U M and D. I. S U G A R M A N

Downloaded by IMPERIAL COLL LONDON on June 7, 2014 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch012

Southern Illinois University, Carbondale, Ill. 62901

The

directed metalation

reaction—lithiation

with n-butyl-

lithium of a position ortho to a substituent on an aromatic ring—is

described. Aromatic systems in which the reaction

has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation

is provided. Also of

interest is the assessment of the relative directing abilities of directing substituents and

comments and

observations

on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed tion and

lithia-

the synthesis of heterocycles.

T t has been known for 40 years that alkyllithium compounds will react with specifically substituted aromatic compounds to effect metalation — t h a t is, replace an aromatic proton with a metal ion. More recently the orientation in a variety of such metalations has been worked out resulting in the identification of substituents that have been demonstrated to direct metalation to an aromatic proton adjacent to said substituents. This, then, is the reaction that is now

called "the directed metalation

reaction." Since many of these substituents contain a directing nitrogen atom, it is appropriate that this process be reviewed here. Within the past decade, many additional directing substituents have been discovered so that the number of synthetic derivatives available through this method is large. One of the great advantages of this reaction is its extremely high specificity. Assuming that synthesis of a specific ortho-disubstituted benzene compound were feasible via electrophilic substitution, difficulty in separating the ortho from the para- and even meta-substitution product

might be

anticipated. Use

of the directed

metalation reaction in this instance, assuming the same compound could be

synthesized by

the two

methods, would yield pure ortho isomer

uncontaminated by all else save starting material. In addition there are 222 In Polyamine-Chelated Alkali Metal Compounds; Langer, A.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

12.

SLOCUM

AND

223

Directed Metalation

SUGARMAN

m a n y groups t h a t c a n n o t be s i m p l y i n t r o d u c e d i n t o a n a r o m a t i c system b y e l e c t r o p h i l i c s u b s t i t u t i o n that c a n be r e a d i l y i n t r o d u c e d b y d i r e c t e d metalation.

T h u s e l e c t r o p h i l i c s u b s t i t u t i o n a n d d i r e c t e d m e t a l a t i o n of

substituted

aromatic

compounds

appear

to

complement

one

another

nicely. Aromatic Systems in Which Directed Metalations Have Been Effected T h e great a b i l i t y of n - b u t y l l i t h i u m or n - b u t y l l i t h i u m - T M E D A


p l e x to effect m e t a l a t i o n of a r o m a t i c c o m p o u n d s

com-

( 1 ) suggests that most

a r o m a t i c systems s h o u l d also u n d e r g o the d i r e c t e d m e t a l a t i o n r e a c t i o n p r o v i d e d a p p r o p r i a t e d i r e c t i n g groups are present. O n e e x c e p t i o n to this has b e e n the [2.2] p a r a c y c l o p h a n e system w h e r e no e v i d e n c e of m e t a l a t i o n b y either n - b u t y l l i t h i u m or its T M E D A c o m p l e x u n d e r a v a r i e t y of c o n d i t i o n s has b e e n seen

(2).

T o our k n o w l e d g e ,

no other

aromatic

system resists m e t a l a t i o n . T h u s the n u m b e r of systems i n w h i c h d i r e c t e d m e t a l a t i o n m i g h t be u s e f u l is p o t e n t i a l l y l a r g e a l t h o u g h o n l y f o u r h a v e been s y s t e m a t i c a l l y s t u d i e d . T h a t o n l y a s m a l l n u m b e r of s u c h systems h a v e b e e n e x p l o r e d u p to this t i m e is not to say that o n l y a f e w

such

systems exist; r a t h e r it is a n i n d i c a t i o n that f u r t h e r s t u d y is r e q u i r e d . Benzene.

T h e earliest w o r k i n d i r e c t e d m e t a l a t i o n was d o n e o n the

b e n z e n e system i n the e a r l y 1930's ( 3 ) .

T h a t the b e n z e n e r i n g w a s the

most p r o m i s i n g system for the e x p l o i t a t i o n of this r e a c t i o n appears l o g i c a l since i t w a s b y f a r the most e x a m i n e d a r o m a t i c system at t h a t time. o n l y h a v e the largest n u m b e r of d i r e c t i n g substituents b e e n

Not

successfully

d e m o n s t r a t e d for this system, b u t i n a l l p r o b a b i l i t y the d e m a n d for a c o n v e n i e n t route to a specific p o l y s u b s t i t u t e d a r o m a t i c c o m p o u n d

will

be h i g h e s t for this system. I n a l l cases e x a m i n e d , d i r e c t e d m e t a l a t i o n of a m o n o s u b s t i t u t e d b e n z e n e has y i e l d e d almost e x c l u s i v e l y ortho m e t a l a t i o n , w i t h o n l y o r t h o - d i s u b s t i t u t e d p r o d u c t s o b t a i n e d ( R e a c t i o n 1 ).

With

I)

m o r e t h a n one substituent o n the r i n g the s i t u a t i o n becomes m o r e c o m p l e x b u t not too m u c h m o r e so; i n most cases, s i m p l e rules p r e d i c t the p o s i t i o n of m e t a l a t i o n (see

below).

M o n o s u b s t i t u t e d benzenes t h a t u n d e r g o the d i r e c t e d m e t a l a t i o n r e a c t i o n are s u m m a r i z e d i n T a b l e I.

I n e v e r y case a v a r i e t y of

ortho-

d i s u b s t i t u t e d p r o d u c t s h a v e b e e n p r e p a r e d ; these w o u l d b e tedious or i m p o s s i b l e to p r e p a r e b y other routes.

In Polyamine-Chelated Alkali Metal Compounds; Langer, A.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

224

POLY AMINE-CHELATED

Table I. Directing Substituent (R) in Equation 1 —CH N(CH ) —CH CH N(CH ) —CHOHCH N(CH ) —CH,OH —CH NHCH —CH NHPh —OCH —CONHCH —SO,N(CH ) —S0 NHCH —CF —N(CH ) —F 2

3

2

2

2

3

2

3

2

3

2

3


3

3

2

2

3

3

3

a 6

2

COMPOUNDS

Solvent

Substrate

Electrophile Ph CO Ph CO ClSi(CH ) CH I PhCHO Ph CO C0 Ph CO Ph CO Ph CO C0 Ph CO C0 2

2

M E T A L

Directed Metalation of Monosubstituted

2

2

ALKALI

2

3

3

2

2

2

2 2

2

2

2

ether/hexane ether/hexane ether/hexane ether/hexane hexane hexane ether/hexane THF/hexane THF/hexane THF/hexane ether hexane THF

2.0 1.2 2.5 2.6 2.5 ° 1.5 « 1.0 2.5 1.2 2.5 1.5 1.0 1.0

Reaction proceeded to give mostly styrene via elimination. Also gave 8% of meta acid as product.

Ferrocene

(Ruthenocene).

The

directed metalation reaction

has

p r o v e d to be of great s y n t h e t i c v a l u e i n the p r e p a r a t i o n of 1,2-disubstit u t e d ferrocenes.

F r o m a n o r g a n i c chemist's p o i n t of v i e w , ferrocene c a n

b e c o n s i d e r e d to h a v e p r o p e r t i e s s i m i l a r to

five-membered

c y c l e s — g r e a t s e n s i t i v i t y to a c i d a n d o x i d i z i n g c o n d i t i o n s .

ring

hetero-

M a n y electro

p h i l i c reactions cannot b e r u n o n ferrocene, a n d m e t a l a t i o n has thus c o m e to b e the p r e f e r r e d process for p r e p a r i n g m a n y m o n o s u b s t i t u t e d cenes (4, 5 ) .

I n a d d i t i o n , e l e c t r o p h i l i c s u b s t i t u t i o n of

ferro

monosubstituted

ferrocenes c o n t a i n i n g c o n v e n t i o n a l a c t i v a t i n g substituents gives m i x t u r e s of 1,2-, 1,3-, a n d Ι,Γ-disubstituted ferrocenes;

electrophilic substitution

of m o n o s u b s t i t u t e d ferrocenes c o n t a i n i n g c o n v e n t i o n a l d e a c t i v a t i n g s u b stituents y i e l d s o n l y Ι,Γ-disubstituted ferrocenes

(7).

A l l this reveals

t h e i n a c c e s s i b i l i t y , for the most p a r t , of h o m o a n n u l a r l y d i s u b s t i t u t e d ferrocenes b y a route i n v o l v i n g e l e c t r o p h i l i c s u b s t i t u t i o n . I n a n u m b e r of instances d i r e c t e d m e t a l a t i o n has p r o v i d e d c l e a n , concise routes

to

specific 1,2-disubstituted ferrocenes ( R e a c t i o n 2 ) that w e r e either difficult

(2)

to p r e p a r e or inaccessible b y c o n v e n t i o n a l e l e c t r o p h i l i c methods.

Syn

thesis of s u b s t i t u t e d ferrocenes b y m e t a l a t i o n of ferrocene itself or b y the d i r e c t e d m e t a l a t i o n of c e r t a i n s u b s t i t u t e d ferrocenes has b e e n r e v i e w e d («).


12.

SLOCUM

AND

Benzenes with

tt-Butyllithium


Metalation Period, hrs

Temp, C°

18.00 11.00 21.00 18.00 1.50 4.00 21.00 0.25 0.25 0.25 6.00 2.00 7.00 c

225

Directed Metalation

SUGARMAN

%

Reference

Yield

6 66 2 2 56 66 33 46 53 52 67 68 12

84

25 25 25 25 25 25 35 65 0 0 35 68 -50

61 45 64 86 65 81 82 82 48 55 60

6

T M E D A required.

S e v e r a l d i r e c t i n g groups k n o w n to b e g o o d directors i n the b e n z e n e system h a v e b e e n f o u n d to p r o v i d e d i r e c t e d m e t a l a t i o n i n the

ferrocene

system; others, h o w e v e r , are u n i q u e to t h e ferrocene system.

Table II

s u m m a r i z e s the d i r e c t i n g substituents a v a i l a b l e for ferrocene.

O f these,

—CH N(CH ) , —CH CH N(CH ) , —CONHR, —CPh OH, —OCH , a n d — S 0 N ( C H ) are k n o w n directors i n benzene, b u t — C H O R , 2

3

2

2

2

3

2

3

2

2

3

2

2

— C I , and

are u n i q u e to ferrocene.

The — C H N ( C H ) 2

3

2

s i d e - c h a i n has also b e e n

f o u n d to effect d i r e c t e d m e t a l a t i o n i n r u t h e n o c e n e

(9).

A c o m p l i c a t i o n t h a t does not e x t e n d to other a r o m a t i c s exists i n ferrocene

T h i s is h e t e r o a n n u l a r d i m e t a l a t i o n , w h i c h

gives

p r o d u c t s t h a t often c o n t a m i n a t e the d e s i r e d 2 - m e t a l a t i o n p r o d u c t .

metalation.

This

phenomenon

w a s i n v e s t i g a t e d i n one i n s t a n c e a n d f r o m m e t a l a t i o n of

d i m e t h y l a m i n o m e t h y l f e r r o c e n e w i t h excess n - b u t y l l i t h i u m , the l , 2 , l ' - t r i substituted product shown i n Reaction 3 was isolated (10).

Considerable

amounts of a l , 2 , l ' - t r i s u b s t i t u t e d ferrocene p r o d u c t c o u l d also b e i s o l a t e d

Fe

Fe

Fe

(3)


226

P O LYA M I N E - C H E L A T E D

Table II. Directing Substituent R in Equation 2 —CH N(CH ) —CH CH N(CH ) —2-pyridyl —CPh OH —CH OCH —OCH —CI 2

3

2

3

Ph CO Ph CO Ph CO C0 Ph CO (CH 0)x CH I Ph CO 2 2

2

2

2

2

2

2

3

2

3

—S0 N(CH )


2

3

H.

C

H

3

2

COMPOUNDS

Substituents that Direct Solvent

2.5 1.5 25.5 2.5 1.6 1.6 2.0 1.2

ether/hexane ether/hexane ether/hexane ether ether/hexane ether/hexane ether/hexane ether/hexane

2

'

ClSi(CH )

3

2.5

ether/hexane

ClSi(CH )

3

1.16

ether/hexane

3

—CH(CH )N(CH ) 3

a

M E T A L

C 4H9L1/ Substrate

Electrophile

2

2

ALKALI

3

3

2

Isolated as — C H 0 - C H 2

3

from the metalation a n d condensation

of dimethylaminoethylferrocene

I t seems q u i t e p o s s i b l e that most, i f n o t a l l , t h e m o n o s u b s t i t u t e d

(11).

ferrocenes that u n d e r g o d i r e c t e d m e t a l a t i o n m a y p r o v i d e 2 , l - d i m e t a l a ,

tion under certain conditions. Naphthalene.

A l t h o u g h n o t as m u c h w o r k has b e e n p e r f o r m e d o n

the n a p h t h a l e n e system as o n t h e t h i o p h e n e system (see t h e next s e c t i o n ) , results i n these systems thus f a r are s t i l l i n t e r e s t i n g . P e r h a p s t h e m o s t u n u s u a l aspect of t h e m e t a l a t i o n of 1-substituted n a p h t h a l e n e s is that m e t a l a t i o n takes p l a c e at either t h e 2- or t h e 8-position. T o some extent the r a t i o of m e t a l a t i o n at t h e 2 - p o s i t i o n c a n b e c o n t r o l l e d b y j u d i c i o u s exercise of r e a c t i o n c o n d i t i o n s a n d m e t a l a t i n g reagent.

A m i x t u r e of 8-

a n d 2 - m e t a l a t e d i n t e r m e d i a t e s has b e e n p o s t u l a t e d ( R e a c t i o n 4 ) .

Those

g r o u p s at t h e 1-position t h a t h a v e b e e n d e m o n s t r a t e d t o p r o v i d e p a t t e r n of m e t a l a t i o n i n n a p h t h a l e n e a r e — F ( 1 2 ) , — O C H —CH N(CH ) 2

3

2

(15).

naphthalene compound

3

2 - F l u o r o n a p h t h a l e n e is t h e o n l y e x a m i n e d , a n d i t has b e e n

l i t h i a t i o n at b o t h t h e 3- a n d t h e 1-position

this

(13,14), a n d 2-substituted

f o u n d to

undergo

(16).

(4) U n L 4

9

Thiophene. R e c e n t w o r k i n t h e a u t h o r s ' laboratories has d e m o n s t r a t e d that the directed metalation concept works w e l l i n substituted thiophenes once a c e r t a i n l i m i t a t i o n is r e a l i z e d — n a m e l y , t h a t t h e 2,5-positions

of

t h i o p h e n e are m u c h m o r e r e a c t i v e t o w a r d m e t a l a t i o n t h a n are t h e 3,4-


12.

SLOCUM

AND

SUGARMAN

227

Directed Metalation


Metalation in the Ferrocene Series Metalation Period, hrs

Temp, °C

1 2 6 36 2.5 3 3.5 6

25 25

45

Reference

Yield

25 25 25 25

71 68 51 72 32.5 60° 72 17

10 11 69 70 26 71 71 72

25

57

37

57.7

40

— 25

1

positions.

%

T h i s gives significance to the fact t h a t a n u m b e r of 3-substi-

t u t e d t h i o p h e n e s are m e t a l a t e d i n the 2-position w i t h little or no p r o d u c t s f r o m 5 - m e t a l a t i o n b e i n g d e t e c t e d ( R e a c t i o n 5 ). A s u m m a r y of the groups that p r o v i d e s u c h d i r e c t e d m e t a l a t i o n i n thiophenes is g i v e n i n T a b l e I I I .

(5)

S i n c e t h i o p h e n e itself is r e a d i l y m e t a l a t e d i n the 2-position, a 3-position substituent's c a u s i n g m e t a l a t i o n to take p l a c e at the 2 - p o s i t i o n suggests that the r e a d y m e t a l a t i o n at a p o s i t i o n adjacent to s u l f u r is f u r t h e r a i d e d b y the d i r e c t i n g 3-substituent. It has also b e e n f o u n d i n a f e w instances that w h e n a b l o c k i n g g r o u p is p l a c e d i n the 5-position of t h i o p h e n e , a directing

substituent i n the 2-position

3-position ( 1 7 ) .

will

direct

m e t a l a t i o n to

the

A n e x a m p l e of this is s h o w n i n R e a c t i o n 6.

V e r y f e w examples of d i r e c t e d m e t a l a t i o n i n f u r a n or p y r r o l e d e r i v a tives h a v e b e e n r e p o r t e d . 3 - B r o m o t h i o p h e n e has b e e n s h o w n to u n d e r g o m e t a l a t i o n i n the 2-position w i t h l i t h i u m d i i s o p r o p y l a m i d e

(18).

(6)


228

POLYAMINE-CHELATED

ALKALI

Table III. ireding Substituent R in Equation 5 —OCH —OC(CH ) —SCH —CN —Br —CH N(CH ) -CH OCH —CONHCH 3

3

2

2

3

2

2

2

2

3


3

Bond Types

C0 C0 C0 C0 C0 HCON(CH ) HCON(CH ) Ph CO 2

3

(Functional

2

Groups)

3

2

3

2

1.0 0.98 0.995 1.06 0.906 1.2

—

2.11

that can be

COMPOUNDS

Directed Metalation of

C4H9IA/ Substrate

Electrophile 2

3

M E T A L

Solvent ether

— —

ether ether ether/hexane

—

ether/hexane Introduced

at the Metalation Site O n e aspect of the d i r e c t e d m e t a l a t i o n r e a c t i o n that makes i t s u c h a p o w e r f u l s y n t h e t i c t o o l is the large n u m b e r of d e r i v a t i v e s that c a n b e p r e p a r e d at the site of l i t h i a t i o n .

T h e h i g h c o n c e n t r a t i o n of

negative

charge o n the c a r b o n a t o m b o n d e d to t h e l i t h i u m a t o m makes the f o r m e r h i g h l y n u c l e o p h i l i c , l i k e a G r i g n a r d reagent a n d a b o u t as versatile.

A

v a r i e t y of d e r i v a t i v e s h a v e b e e n p r e p a r e d , a n d there are p r o b a b l y

a

significant n u m b e r yet to c o m e . R e p r e s e n t a t i v e routes to most types of d e r i v a t i v e s are r e c o r d e d here w i t h recent l e a d i n g references. h a v e b e e n w o r k e d out w i t h N - c h e l a t e d i n t e r m e d i a t e s .

M o s t routes

The following

s y m b o l is u s e d to designate a g e n e r a l i z e d a r o m a t i c 2 - l i t h i o i n t e r m e d i a t e :

Carbon-Carbon Bonds.

S y n t h e t i c m e t h o d s i n v o l v i n g the f o r m a t i o n

of c a r b o n - c a r b o n b o n d s are a l w a y s of great interest. P r i m a r y , secondary, or t e r t i a r y alcohols c a n b e p r e p a r e d b y the r e a c t i o n of the l i t h i o i n t e r m e d i a t e w i t h the a p p r o p r i a t e a l d e h y d e or ketone ( R e a c t i o n s 7 - 9 )


(6,

12.

SLOCUM

AND

SUGARMAN

229

Directed Metalation

3-Substituted Thiophenes with w-Butyllithium Metalation Period, hrs

Temp. °C


0.5 0.5 0.5 1.0 3.0 — — — 19).

35 34 35 -70 25 — — —

E t h y l e n e oxide

or other epoxides

% Yield

Reference

86 62 70 68 36 75 72 23

78 74 75 76 77 17 17 25

c a n also be

^ - s u b s t i t u t e d e t h y l a l c o h o l d e r i v a t i v e s ( R e a c t i o n 10)

u s e d to

prepare

(6).

K e t o n e s m a y b e p r e p a r e d b y the r e a c t i o n of the l i t h i o i n t e r m e d i a t e w i t h a n i t r i l e ( R e a c t i o n 11) (6).

N i t r i l e s possessing n o a l p h a h y d r o g e n s

w o r k best i n this r e a c t i o n . F o r m y l d e r i v a t i v e s of aromatics m a y b e s y n t h e s i z e d b y t r e a t i n g the l i t h i a t e d species w i t h d i m e t h y l f o r m a m i d e ( R e a c t i o n 12)

(19).

C a r b o x y l i c acids are r e a d i l y a v a i l a b l e b y c a r b o n a t i o n of

s u c h l i t h i o i n t e r m e d i a t e s (14,16).

T r e a t m e n t of these l i t h i o i n t e r m e d i a t e s

w i t h a r y l or a l k y l isocyanates y i e l d s a m i d e s ( R e a c t i o n 13)

(10).

T h e lithium atom may be replaced w i t h a m e t h y l group b y treating the m e t a l a t e d species w i t h m e t h y l i o d i d e o r d i m e t h y l s u l f a t e 14) (20).

(Reaction

I n this case the d i r e c t i n g g r o u p cannot be a n a m i n e since t h e

a m i n e site is also a l k y l a t e d i n the process, c o m p l i c a t i n g i s o l a t i o n

(21).

O t h e r a l k y l groups c a n n o t be i n t r o d u c e d this w a y because of the p r e d i l e c t i o n of a l k y l h a l i d e s for e l i m i n a t i o n i n t h e presence of strong base. R a t h e r , the routes to e t h y l , i s o p r o p y l , a n d other a l k y l d e r i v a t i v e s i n v o l v e r e d u c t i o n of the c o r r e s p o n d i n g a l c o h o l ( R e a c t i o n 15)

(22).


230

POLYAMINE-CHELATED

Carbon-Halogen Bonds.

ALKALI

METAL

COMPOUNDS

C a r b o n - h a l o g e n b o n d s m a y be

prepared

d i r e c t l y via the l i t h i o i n t e r m e d i a t e or a s e c o n d i n t e r m e d i a t e p r e p a r e d Downloaded by IMPERIAL COLL LONDON on June 7, 2014 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch012

f r o m the l i t h i o i n t e r m e d i a t e . F o r e x a m p l e , r e a c t i o n of with

2-lithiodimethylaminomethylferrocene

( R e a c t i o n 16)

(23).

hexachloroethane

gave the c h l o r o

derivative

H o w e v e r , p r e p a r a t i o n of other h a l o g e n d e r i v a t i v e s

via l i t h i o intermediates has not b e e n successful. A better a n d m o r e v e r satile m e t h o d

for p r e p a r i n g the c h l o r o , b r o m o ,

and iodo

derivatives

i n v o l v e s i s o l a t i n g a b o r o n i c a c i d i n t e r m e d i a t e as i n R e a c t i o n 17

(24).

(16)

Carbon-Nitrogen

and

Carbon-Oxygen

Bonds.

Carbon-nitrogen

b o n d s m a y b e f o r m e d b y t r e a t i n g the l i t h i o i n t e r m e d i a t e w i t h either m e t h o x y l a m i n e or e t h y l n i t r a t e ( R e a c t i o n s 18 a n d 19) (25).

T h e s e reac-

tions a p p a r e n t l y i n v o l v e a d i s p l a c e m e n t o n n i t r o g e n a n d result i n the p r e p a r a t i o n of the a m i n o a n d n i t r o d e r i v a t i v e , r e s p e c t i v e l y . oxygen

b o n d s m a y b e p r e p a r e d via a b o r o n i c

r e a c t i o n w i t h c u p r o u s acetate ( R e a c t i o n 2 0 )

Carbon-

acid intermediate and

(71), a reaction completely

analogous to the synthesis of h a l o g e n d e r i v a t i v e s d e s c r i b e d i n R e a c t i o n 17. Other Carbon-Heteroatom Bonds. C a r b o n - m e r c u r y b o n d s are r e a d i l y f o r m e d b y t r e a t i n g the m e t a l a t e d species w i t h m e r c u r i c c h l o r i d e tion 21)

(27).

T h e r e s u l t i n g c h l o r o m e r c u r y d e r i v a t i v e i n one case is a

u s e f u l i n t e r m e d i a t e i n the p r e p a r a t i o n of ferrocene

(Reac-

2-iododimethylaminomethyl-

(27).


12.

SLOCUM

AND

Carbon-silicon bonds

231

Directed Metalation

SUGARMAN

can be formed

b y t r e a t i n g the l i t h i o i n t e r -

m e d i a t e w i t h h a l o g e n - c o n t a i n i n g silanes ( R e a c t i o n 2 2 )

(28).


phosphorus bonds can be prepared similarly (Reaction 23)

Relative Directing W h e n more

Abilities

of

Carbon-

(29).

Substituents

than one directing group

is present i n a n a r o m a t i c

m o l e c u l e i t is i m p o r t a n t to k n o w w h i c h d i r e c t i n g g r o u p w i l l exert the p r i n c i p a l effect—that

is, w h i c h is the stronger d i r e c t o r .

Competitive

m e t a l a t i o n of n i n e of the o r t h o - d i r e c t i n g substituents for t h e ring

has

recently

been

examined

in

our

laboratories.

—CH N(CH ) , —CH CH N(CH ) , —CONHR, —OCH , 2

3

2

2

2

3

2

3

2

3

2

2

are:

—N(CH ) ,

3

— C F , — F , — S 0 N ( C H ) , and — S 0 N H C H .

benzene

These

3

2

Ratings were based on

3

t h e c o m p e t i t i v e l i t h i a t i o n of the a p p r o p r i a t e p a r a - d i s u b s t i t u t e d benzenes. D a t a are n o w a v a i l a b l e for t h e c o m p e t i t i v e m e t a l a t i o n of the m e t h o x y g r o u p vs. the eight other d i r e c t i n g groups that — C H N ( C H ) 2 , 2

3

—CONHR,

(30).

T h e s e results d i c t a t e

— S O > N ( C H ) , and L

3

—S0 NHCH

2

2

: i

are stronger directors t h a n — O C H , a n d — C H C H N ( C H ) , — N ( C H ) , 3

— F , and — C F

3

2

2

3

2

3

2

are w e a k e r directors ( R e a c t i o n s 24 a n d 25 ). F r o m some

additional data now

a v a i l a b l e , i t is a p p a r e n t t h a t — C O N H C H

stronger d i r e c t o r t h a n — C H N ( C H ) 2

3

2

(31).

3

is a

I t is also l i k e l y t h a t the


232

POLYAMINE -CHEL ATED

sulfonamides

are the strongest

ALKALI METAL

COMPOUNDS

directors k n o w n so that a r a n k i n g of

—S0 NHCH ,

—S0 N(CH )

>

—CH CH N(CH ) , — N(CH ) , — F , —CF

2

3

—OCH

3

>

2

2

3

2

>

2

3

—CONHCH 2

3

3

>

—CH N(CH ) 2

2

3

3

2

m i g h t be


i n f e r r e d for the b e n z e n e system, at least.

I n a l l cases w h e r e

a meta-disubstituted benzene containing

o r t h o - d i r e c t i n g groups has b e e n e x a m i n e d , m e t a l a t i o n has t a k e n

two place

ortho to e a c h of the d i r e c t i n g g r o u p s — t h a t is, the 2-position of a 1,3disubstituted benzene (Reaction 26)

(30, 32).

F o r ortho-disubstituted

benzenes w h e r e b o t h groups w e r e ortho directors, the stronger d i r e c t i n g g r o u p (as d e t e r m i n e d a b o v e ) was f o u n d to c o n t r o l the m e t a l a t i o n site. M o d i f i c a t i o n of the m e t a l a t i o n p a t t e r n b y steric effects of some of the m o r e b u l k y substituents w a s not r e a l i z e d . A n extreme e x a m p l e of this has n o w b e e n e x a m i n e d .

o - t e r i - B u t y l a n i s o l e has b e e n m e t a l a t e d w i t h

n - b u t y l l i t h i u m ( R e a c t i o n 27)

(33).

A s a n t i c i p a t e d , the y i e l d of m e t a l a -

t i o n p r o d u c t w a s significantly d i m i n i s h e d c o m p a r e d w i t h t h e m e t a l a t i o n of anisole. H o w e v e r , even the 5 % y i e l d of p r o d u c t r e a l i z e d was that f r o m m e t a l a t i o n ortho to the m e t h o x y g r o u p — t h a t is, the site of m e t a l a t i o n h a d not c h a n g e d . TMEDA product

complex previously

M e t a l a t i o n of this c o m p o u n d brought a 3 0 % described

with n-butyllithium-

y i e l d of the same ortho m e t a l a t i o n

(Reaction

27).

Thus

the

steric

effect

o r i g i n a l l y n o t e d c o u l d be o v e r c o m e b y a stronger m e t a l a t i n g reagent. E x t e n s i o n of this s t u d y of the efficiency of d i r e c t i n g groups to other a r o m a t i c systems s h o u l d p r o v i d e f u r t h e r i n s i g h t i n t o the r e l i a b i l i t y of the a b o v e r a n k i n g .

The Directing

Mechanism

I n a l l d i r e c t e d metalations s t u d i e d , t h e l i t h i u m a t o m is d i r e c t e d to a p r o t o n adjacent to the d i r e c t i n g substituent. N o single e x p l a n a t i o n c a n b e p r o p o s e d n o w to a c c o u n t for a l l the k n o w n examples of the d i r e c t e d m e t a l a t i o n r e a c t i o n . R a t h e r , a c o m b i n a t i o n of v a r y i n g degrees of a


12.

SLOCUM

233

Directed Metalation

AND SUGARMAN

(26)

(27)


c o o r d i n a t i o n m e c h a n i s m c o u p l e d w i t h a n i n d u c t i v e effect seems most appropriate. A g o o d e x a m p l e of the i n t e r v e n t i o n of a c o o r d i n a t i o n m e c h a n i s m is that i n the ortho m e t a l a t i o n of d i m e t h y l b e n z y l a m i n e (6).

T h e methylene

g r o u p essentially insulates t h e r i n g f r o m any i n d u c t i v e influence of the n i t r o g e n atom.

T h e fact t h a t this m o l e c u l e

c a n be

ortho

strongly indicates that some other effect is o p e r a t i n g .

metalated

S u c h a n effect

involves the c o o r d i n a t e d l i t h i o i n t e r m e d i a t e d e p i c t e d i n R e a c t i o n 28.

A

c o o r d i n a t i o n m e c h a n i s m w o u l d also seem to be the most l i k e l y d i r e c t i v e effect w i t h — C H C H N ( C H ) , — C O N H R , a n d — C H N H R side chains. 2

2

3

2

2

A most i n t r i g u i n g d e m o n s t r a t i o n of the c o o r d i n a t i n g effect of n i t r o g e n i n d i m e t h y l b e n z y l a m i n e is p r o v i d e d b y a s t u d y of r i n g vs. s i d e - c h a i n m e t a l a t i o n w i t h a l k y l sodio reagents (34).

T h e benzylamine was initially

m e t a l a t e d at the ortho p o s i t i o n , b u t after 20 hours, r e a r r a n g e m e n t to the m o r e stable a l p h a p o s i t i o n was c o m p l e t e ( R e a c t i o n 2 9 ) . rearrangement

could be

reversed b y

M o r e o v e r , the

adding lithium bromide

s o l u t i o n c o n t a i n i n g the a l p h a - m e t a l a t e d species ( R e a c t i o n 3 0 ) .

to

the

These

results c a n be i n t e r p r e t e d to signify that the a l p h a - m e t a l a t e d species w a s


234

POL Y AMINE-CHELATED

ALKALI

METAL

COMPOUNDS

(30)

m o r e c a r b a n i o n i c i n t h e case of t h e sodio d e r i v a t i v e . H e n c e , i t w a s m o r e c o n d u c i v e to resonance s t a b i l i z a t i o n at the b e n z y l p o s i t i o n , a n d t h e ortho p o s i t i o n m e t a l a t i o n site is greatly s t a b i l i z e d b y c o o r d i n a t i o n i n t h e case of t h e l i t h i o i n t e r m e d i a t e . T h e r m o d y n a m i c a n d k i n e t i c roles h a v e b e e n


r e v e r s e d i n these t w o instances. N o m e t a o r p a r a p r o d u c t w a s detected i n either sequence. Substituents s u c h as — S 0 N R , — C F , 2

—N(CH ) 3

2

2

3

— C l , — F ,—OCH , 3

and

s i g n i f i c a n t l y p o l a r i z e t h e a r o m a t i c r i n g a n d m i g h t b e s a i d to

operate b y some c o m b i n a t i o n of i n d u c t i v e a n d field effects. the s u l f o n a m i d e s a n d — C F

Certainly

possess significant field effect c o n t r i b u t i o n

3

w h i l e t h e r e m a i n i n g f o u r s u b s t i t u e n t s — e a c h w i t h a n electronegative a t o m b o n d to t h e r i n g — m u s t h a v e significant i n d u c t i v e c o n t r i b u t i o n .

Some

c o o r d i n a t i o n m a y also c o n t r i b u t e to t r a n s i t i o n states i n v o l v i n g — C l , — F , —OCH , 3

a n d — N ( C H ) , but d r a w i n g coordinate 3

2

structures s u c h as

that f o r t h e 2 - l i t h i a t i o n of d i m e t h y l b e n z y l a m i n e ( R e a c t i o n 2 8 ) for these substituents i n v o l v e s p o s t u l a t i o n of a f o u r - m e m b e r e d r i n g . T h i s c a n b e

Li

(Coordinating

A

butyls

have been

omitted from bottom and back

0(C H ) 2

5

f Q 2

ces

for

clarity.)


12.

SLOCUM

AND

SUGARMAN

235

Directed Metalation

a v o i d e d w h e n the t e t r a m e r i c structure of n - b u t y l l i t h i u m (30) because a p s e u d o

five-membered

is i n v o k e d ,

r i n g c a n t h e n be d r a w n ( R e a c t i o n 31 ).

T h e i n t e r p l a y of i n d u c t i v e effect a n d c o o r d i n a t i o n is b r o u g h t out i n the c o m p e t i t i v e m e t a l a t i o n of p-fluoroanisole a n d p - d i m e t h y l a m i n o a n i sole. I n e a c h case the m e t h o x y g r o u p controls the site of m e t a l a t i o n C o o r d i n a t i o n effects f a l l i n the o r d e r — N ( C H ) 3

>

2

—OCH

3

(30).

> —F,

w h i l e the i n d u c t i v e o r d e r w o u l d b e just the reverse of this. S i n c e n e i t h e r o r d e r w a s o b s e r v e d , a c o m b i n a t i o n of effects is p r e s u m e d to b e o p e r a t i n g .


Asymmetric Directed

Lithiation

T h e r e s o l u t i o n of r a c e m i c m i x t u r e s is c e r t a i n l y the most w i d e l y u s e d m e t h o d of p r e p a r i n g o p t i c a l l y a c t i v e c o m p o u n d s .

A n alternate m e t h o d

of p r e p a r i n g c e r t a i n o p t i c a l l y active c o m p o u n d s ,

usually quicker and

often

P o s s i b l y the

m o r e p r a c t i c a l , is a s y m m e t r i c i n d u c t i o n .

newest

e x a m p l e of s u c h i n d u c t i o n is a s y m m e t r i c l i t h i a t i o n . T h e p r i n c i p l e of a s y m m e t r i c l i t h i a t i o n i n v o l v e s b o t h the fact that f o r m a t i o n of d i a s t e r e o m e r i c i n t e r m e d i a t e s s h o u l d i n v o l v e different energies of a c t i v a t i o n , a n d the i d e a that, i n d i r e c t e d l i t h i a t i o n s , a l i t h i u m a t o m is c o o r d i n a t e d w i t h n i t r o g e n or some other h e t e r o a t o m

(see

above).

W h e n the c o o r d i n a t i n g n i t r o g e n a t o m resides i n a c h i r a l e n v i r o n m e n t , one of the t w o possible diastereomeric l i t h i o i n t e r m e d i a t e s is e n e r g e t i c a l l y f a v o r e d for steric or other reasons.

T h u s one of the t w o possible i n t e r -

mediates s h o u l d be f o r m e d p r e f e r e n t i a l l y , w i t h the r e s u l t i n g c o n d e n s a t i o n p r o d u c t s reflecting the stereoselectivity of the l i t h i a t i o n . O n e of the earliest descriptions of a n a s y m m e t r i c l i t h i a t i n g reagent was r e p o r t e d b y N o z a k i a n d c o - w o r k e r s i n 1968 ( 3 5 ) .

( — )-Sparteine

w a s u s e d to c o o r d i n a t e n - b u t y l l i t h i u m , a n d this c o m p l e x stereoselectively a d d e d to several c a r b o n y l c o m p o u n d s

(Reaction 32).

Moreover,

the

S k a t t e b o l - M o o r e m e t h o d ( w h i c h consists of d e h a l o g e n a t i n g g e r a - d i h a l o cyclopropanes

w i t h a n a l k y l l i t h i u m c o m p l e x ) b y N o z a k i to synthesize

aliènes gave o p t i c a l l y a c t i v e p r o d u c t s w h e n the n - b u t y l l i t h i u m / ( — ) -sparteine c o m p l e x was u s e d

(36).

O n c e i t w a s d e m o n s t r a t e d t h a t i t adds stereoselectively, the n - b u t y l l i t h i u m / ( — ) -sparteine c o m p l e x w a s u s e d to p r e p a r e a series of o p t i c a l l y a c t i v e ferrocenes (36).

T r e a t m e n t of i s o p r o p y l ferrocene w i t h a 2.5-molar

excess of the l i t h i a t i n g c o m p l e x f o l l o w e d b y r e a c t i o n w i t h a n e l e c t r o p h i l e

Ph-

CHOH

(32)

^4 9 H

6%

optical yield


236

POLYAMINE-CHELATED

+

Enantiomer

ALKALI

M E T A L

COMPOUNDS

r Enantiomer R= - S i ( C H ) 3

-

C0 CH 2

3

3

-C0 H


2

(S)(R)

(S)

(S)(S)

(R)(R)

(R)

(R)(S)

I Electrophile


12.

SLOCUM

237

Directed Metalation

A N D SUGARMAN

y i e l d e d 3 , l ' - d i s u b s t i t u t e d i s o p r o p y l ferrocenes i n 3 % o p t i c a l y i e l d ( R e a c t i o n 33 ). W e t e r m this a n a s y m m e t r i c m e t a l a t i o n p r o c e d u r e . Carrying

t h e c o n c e p t o f a s y m m e t r i c l i t h i a t i o n o n e step

further,

N o z a k i a n d co-workers incorporated the asymmetry-inducing complexing reagent w i t h t h e m e t a l a t e d m o l e c u l e ( ferrocene ) itself ( 37, 38 ). 1-Ferrocenylmethyl-2-methylpiperidine was resolved a n d treated w i t h n - b u t y l l i t h i u m to give a m i x t u r e of d i a s t e r e o m e r i c l i t h i o intermediates b y d i r e c t e d metalation (Reaction 3 4 ) . A n optical yield of 9 3 % was initially claimed for this r e a c t i o n , b u t subsequent w o r k b y U g i a n d c o - w o r k e r s

(39) re


s u l t e d i n t h e suggestion that o n l y a 6 7 % o p t i c a l y i e l d w a s o b t a i n e d . F u r t h e r syntheses i n v o l v i n g a s y m m e t r i c l i t h i a t i o n h a v e b e e n r e p o r t e d b y U g i (40). O p t i c a l l y active 1 - f e r r o c e n y l e t h y l d i m e t h y l a m i n e w a s u s e d to o b t a i n stereoselective syntheses i n 9 6 % o p t i c a l y i e l d ( R e a c t i o n 3 5 ) . K n o w l e d g e o f the configuration o f the s t a r t i n g a m i n e a l l o w e d t h e absolute c o n f i g u r a t i o n o f t h e p r i n c i p a l l i t h i o i n t e r m e d i a t e t o b e i n f e r r e d as t h e ( R ) ( R ) diastereomer.

A d d i t i o n a l s u p p o r t for this assignment has b e e n

p u b l i s h e d (41). A v e r y i n t e r e s t i n g c o m p o u n d m a y b e p r e p a r e d via this m e t h o d a n d u s e d i n t h e stereoselective

syntheses of peptides.

asymmetrically induced four-component

U g i has f o u n d that

syntheses

will form

optically

active p e p t i d e s ( R e a c t i o n 3 6 ) (42, 43). C o m p o u n d s o f the t y p e R * — N H , 2

m u s t , to b e u s e f u l i n this synthesis, m e e t these c r i t e r i a : 1) C o n d e n s a t i o n o f t h e a m i n e w i t h t h e other components, i f neces sary via t h e Schiff base o f t h e a m i n e a n d a l d e h y d e , s h o u l d take p l a c e rapidly and i n high yield. 2 ) A s a c o m p o n e n t o f t h e c o n d e n s a t i o n , t h e a m i n e m u s t also possess the effect o f a n a s y m m e t r i c a l l y i n d u c i n g steric m a t r i x a n d p r o v i d e f o r a h i g h l y steroselective synthesis o f t h e n e w l y f o r m e d a m i n o a c i d u n i t i n t h e d e s i r e d configuration. R, I -NH-CH-COgH

2

-r

NH I*

R

hi

R I CHO

?

2

-r

R I CN-CH-CO" 3

-f

ι

ft

2

- N H - C H - C O - N - C H - C O - N H - C H - C O I* *

(36)

R| R R-J I* I* I* * - N H - C H - C O - NH — C H — C O — N H — C H — C O — l - R — X 2

Denotes

optically active


238

POLYAMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

3) T h e residual R * must be readily cleaved from the intermediate polymer under m i l d conditions—for example, i n cold formic or trifluoroacetic a c i d — p r e f e r a b l y i n s u c h a w a y that t h e a m i n e c a n b e regenerated. T h e o n l y c o m p o u n d s m e e t i n g a l l these c r i t e r i a w e r e f e r r o c e n e c o m p o u n d s p r e p a r e d b y U g i via t h e a s y m m e t r i c d i r e c t e d m e t a l a t i o n m e t h o d , s h o w n i n R e a c t i o n 35. G o l d b e r g a n d B a i l e y (44) h a v e u s e d t h e a s y m m e t r i c - d i r e c t e d m e t a l a t i o n p r o c e d u r e as a route to c o m p o u n d s d e m o n s t r a t i n g ( f o r t h e first t i m e ) p s e u d o a s y m m e t r y i n ferrocenes.

A pseudoasymmetric

1,2-disubsti-

t u t e d ferrocene w a s p r e p a r e d b y procedures s u c h as those i l l u s t r a t e d i n Downloaded by IMPERIAL COLL LONDON on June 7, 2014 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch012

F i g u r e 1. Me

Bu Li

H00CCH - Men-H o

Men-H

Men-H

Men-H J ^Men-H

M e n - H means (-)-carbomenthoxy derivative Figure 1.

Preparation of a pseudoasymmetric 1,2-disubstituted ferrocene


12.

SLOCUM

N(CH ) 3

239

Directed Metalation

A N D SUGARMAN

Ν (CH ) 3

2

2

I. n - C H L i 4

9

2. P h C O R

R=

(37)

H.Ph

CH.

0 200° R


A

Ph

phthalan

O u r c o n c l u s i o n is that t h e a s y m m e t r i c l i t h i a t i o n p r o c e d u r e a n d t h e a s y m m e t r i c d i r e c t e d m e t a l a t i o n r e a c t i o n a r e o f great p o t e n t i a l v a l u e f o r s y n t h e s i z i n g a v a r i e t y of c h i r a l c o m p o u n d s as w e l l as b e i n g elegant a n d p r o f o u n d exercises i n stereochemistry. Heterocyclic

Synthesis v i a Directed

Metalation

O n e of the most u s e f u l synthetic a p p l i c a t i o n s of t h e d i r e c t e d m e t a l a t i o n reactions is i n p r e p a r i n g h e t e r o c y c l i c systems. O f the a v a i l a b l e d i r e c t i n g groups, those i n v o l v i n g N - c h e l a t e d i n t e r m e d i a t e s have b e e n b y far t h e most u s e f u l . I n several instances t h e route p r o v i d e d b y ortho l i t h i a t i o n constitutes t h e o n l y a v a i l a b l e m e t h o d f o r p r e p a r i n g c e r t a i n heterocycles. I n other cases s u c h syntheses, a l t h o u g h n o t t h e o n l y routes a v a i l a b l e , represent a c o n s i d e r a b l e i m p r o v e m e n t over m o r e c o n v e n t i o n a l m e t h o d s , e s p e c i a l l y c o n s i d e r i n g t h e n u m b e r of steps i n t h e o v e r a l l synthesis a n d yields.

F u r t h e r m o r e m a n y of t h e h e t e r o c y c l i c c o m p o u n d s

p r o d u c e d via

d i r e c t e d m e t a l a t i o n procedures are of extreme interest i n that they a r e n a t u r a l p r o d u c t s or d e r i v a t i v e s thereof. I n i t i a l l y u s e d to p r o v e t h e 1,2-disposition o f t h e c o n d e n s a t i o n p r o d ucts of t h e respective compounds

lithio intermediates, cyclization to

rapidly developed

heterocyclic

i n t o a r e l a t i v e l y v a l u a b l e synthetic tool.

T h e b u l k o f t h e i n i t i a l w o r k i n this area w a s p e r f o r m e d b y H a u s e r a n d c o - w o r k e r s ; later, significant c o n t r i b u t i o n s ( e s p e c i a l l y i n n a t u r a l p r o d u c t heterocycle synthesis ) w e r e m a d e i n I n d i a b y N a r a s i m h a n a n d associates. O n e of the first uses of d i r e c t e d m e t a l a t i o n as a route to heterocycles w a s the synthesis of p h t h a l a n s ( 2 , 3 - b e n z o - l , 4 - d i h y d r o f u r a n s ) m a l l y i n d u c e d c y c l i z a t i o n of t h e m e t h i o d i d e s

b y the ther

of ortho-substituted d i -

methylbenzylamines (Reaction 37) ( 4 5 ) . T h e amine was lithiated i n the ortho p o s i t i o n b y n - b u t y l l i t h i u m a n d c o n d e n s e d w i t h b e n z a l d e h y d e a n d benzophenone.

T h e corresponding

alcohols

obtained

upon

w o r k - u p w e r e c o n v e r t e d t o t h e i r respective m e t h i o d i d e s .

aqueous

Heating the

m e t h i o d i d e s to 200 ° C f o r o n e h o u r u n d e r n i t r o g e n gave t h e p h t h a l a n s


240

POLYAMINE-CHELATED

ALKALI

M E T A L

CONHCH3

CONHCH;

COMPOUNDS

0

|.n-C H Li 4

9

2. P h C 0 2

(38)

NCH, /

3


Ph Ph

A phthalimidine

s h o w n i n R e a c t i o n 37. A q u i t e analogous p r o c e d u r e w i t h d i m e t h y l a m i n o m e t h y l f e r r o c e n e as t h e s t a r t i n g m a t e r i a l gave t h e ferrocene a n a l o g of t h e phthalan derived from the benzophenone

condensation ( 1 0 ) .

D i s c o v e r y that t h e N - s u b s t i t u t e d c a r b o x a m i d e

group could

direct

metalation(46) l e d to t h e e v e n t u a l establishment o f s y n t h e t i c routes t o a n u m b e r o f heterocycles, i n c l u d i n g s u b s t i t u t e d lactones, p h t h a l i m i d i n e s , a n d isocarbostyrils (47).

C y c l i z a t i o n o f t h e p r o d u c t s o f c o n d e n s a t i o n of

the l i t h i o i n t e r m e d i a t e s of N - m e t h y l b e n z a m i d e y i e l d e d heterocycles ( R e a c t i o n 3 8 ) (48).

the m e t h y l g r o u p w a s l i t h i a t e d , gave s i x - m e m b e r e d ( R e a c t i o n 3 9 ) (49).

five-membered

o-Methyl-N-methylbenzamide, i n which ring

heterocycles

T h e m e c h a n i s m of t h e c y c l i z a t i o n step i n t h e latter

p r o c e d u r e has b e e n dealt w i t h i n some d e p t h i n t h e l i t e r a t u r e ( 5 0 ) ; a n i n d e p e n d e n t r e i n v e s t i g a t i o n , h o w e v e r , has cast d o u b t o n t h e v a l i d i t y o f t h e d i h y d r o i s o c a r b o s t y r i l structures p r o p o s e d

(51).

S u l f o n a m i d e s as o r t h o - d i r e c t i n g substituents f o r m e t a l a t i n g a r o m a t i c systems o p e n e d (sultones)

t h e d o o r to synthetic routes t o c y c l i c sulfonic

a n d amides ( s u l t a m s ) .

esters

T h e first step i n this p r o c e d u r e f o r

p r e p a r i n g sultams i n v o l v e d t h e 2 - m e t a l a t i o n of 2V-alkylbenzenesulfonamides ( 5 2 ) a n d c o n d e n s a t i o n w i t h a v a r i e t y o f ketones.

T h e tertiary alco-

C O N H C H ,0

1

(39) 0

An

isocarbostyril


12.

SLOCUM

AND

241

Directed Metalation

SUGARMAN

hols thus p r o d u c e d w e r e t h e r m a l l y d e h y d r a t e d to f o r m the c o r r e s p o n d i n g sultams ( R e a c t i o n 4 0 )

(52).

F o r the p r e p a r a t i o n of sultones,

N,N-ài-

methylbenzenesulfonamide was likewise 2-metalated (53) a n d condensed w i t h b e n z o p h e n o n e ( R e a c t i o n 41 ). T h i s p r o d u c t undergoes t w o reactions (54).

U p o n treatment w i t h cold, concentrated sulfuric a c i d / m e t h a n o l ,

the t e r t i a r y a l c o h o l w a s c y c l i z e d to the sultone. reagents

gave the m e t h y l ether.

reaction conditions

to

A t — 78 ° C , the same

similar effect—namely

o b t a i n different p r o d u c t s — w a s

changing

observed

with

tertiary alcohols p r o d u c e d b y c o n d e n s a t i o n of c a r b o n y l c o m p o u n d s

with

2 - l i t h i o b e n z a m i d e (48). Downloaded by IMPERIAL COLL LONDON on June 7, 2014 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch012

A

H e a t or w e a k a c i d c o n v e r t e d 2 - d i p h e n y l h y d r o x y -

m e t h y l - N - m e t h y l b e n z a m i d e to the

five-membered

lactone r i n g ( R e a c t i o n

3 8 ) , w h e r e a s t r e a t m e n t w i t h strong a c i d gave the c o r r e s p o n d i n g l a c t a m (Reaction 38).

M i l d a c i d i n the case of a c y c l i c ether i n the ferrocene

series o p e n e d t h e r i n g ( R e a c t i o n 42)

Ph

(55).

Λ.

Fe I

Fe I

H a u s e r et al. ( 56 ) h a v e r e p o r t e d the use of N - m e t h y l a m i n o m e t h y l as a n o r t h o - d i r e c t i n g substituent. T r e a t m e n t w i t h a c i d of the s e c o n d a r y a n d tertiary alcohols p r o d u c e d b y c o n d e n s a t i o n of the 2 - l i t h i o i n t e r m e d i a t e — i n this case w i t h b e n z a l d e h y d e a n d acetophenone,

respectively—produced

isoindolines (Reaction 43). N a r a s i m h a n a n d R a n a d e (57)

h a v e i n c o r p o r a t e d the 2 - m e t a l a t i o n

p r o c e d u r e i n t o t h e p r e p a r a t i o n of i s o q u i n o l i n e . F u r t h e r m o r e t h e i r obser-



242

POLYAMINE-CHELATED

ALKALI

M E T A L COMPOUNDS

v a t i o n t h a t m e t a l a t i o n occurs i n b e t w e e n t w o m e t a - o r i e n t e d ortho d i r e c t i n g groups ( R e a c t i o n 26) a l l o w e d t h e m to synthesize 5 - m e t h o x y i s o q u i n o lines via the d i r e c t e d m e t a l a t i o n process (see b e l o w ) .

B o t h condensation

of 2 - l i t h i o - N , N - d i m e t h y l b e n z y l a m i n e w i t h e t h y l e n e o x i d e f o l l o w e d c y c l i z a t i o n a n d subsequent d e h y d r o g e n a t i o n

(Reaction 44), and

by con-

d e n s a t i o n of 2 - l i t h i o N , ] V - d i m e t h y l - ^ - p h e n e t h y l a m i n e w i t h p a r a f o r m a l d e h y d e f o l l o w e d b y c y c l i z a t i o n a n d subsequent a r o m a t i z a t i o n ( R e a c t i o n 44) yielded isoquinoline. M e t h o x y - a n d ethoxy-substituted quinolines were metalated a n d c o n d e n s e d w i t h a v a r i e t y of electrophiles to y i e l d , after o t h e r steps, a v a r i e t y of n a t u r a l p r o d u c t s a n d d e r i v a t i v e s ( 5 8 ) .

A m o n g the c o n d e n s i n g

agents w e r e e t h y l e n e o x i d e a n d a l l y l b r o m i d e , a n d t h e

Figure 2.

heterocyclic

Synthesis of furoquinolines



12.

SLOCUM

A N D SUGARMAN

Rj = 0CH ; R =H

Dihydropteleine

Rj ' H ; R 2 0 C H

Dihydro"^~ fargarine

3

2

S

3

R|=R2=H Figure 3.

243

Directed Metalation

Dihydrodictamine Synthesis of edulitine, dihydropteleine, dihydro-y-fargarine, and dictamine

natural products

synthesized i n c l u d e d furoquinolines

(Figure 2) and

e d u l i t i n e , d i h y d r o p t e l e i n e , dihydro-γ-ίargarine, a n d d i c t a m i n e ( F i g u r e 3 ) . N a r a s i m h a n a n d B h i d e ( 5 9 ) have also d e v i s e d a n elegant route f o r t r a n s f o r m i n g l a u d a n o s i n e t o t e t r a h y d r o p a l m i t i n e via a d i r e c t e d m e t a l a t i o n procedure

( R e a c t i o n 4 5 ) . T h i s r e a c t i o n sequence is i m p o r t a n t b e c a u s e

there w a s p r e v i o u s l y n o s y n t h e t i c route f o r this t r a n s f o r m a t i o n .


244

POLYAMINE-CHELATED

ALKALI

METAL

COMPOUNDS

N a r a s i m h a n a n d B h i d e (60) also f o u n d that t h e d i m e t h y l a m i n o m e t h y l a n d 2V-methyl c a r b o x a m i d e f u n c t i o n a l groups are stronger ortho directors than the methoxy group.

A p p l y i n g this k n o w l e d g e , t h e y w e r e a b l e t o

synthesize m e t h o x y - s u b s t i t u t e d i s o q u i n o l i n e s a n d i s o c o u m a r i n s .

Among

t h e d e r i v a t i v e s of i s o c o u m a r i n p r e p a r e d w e r e m e l l e i n a n d 8-methoxyisoc o u m a r i n ( F i g u r e 4 ) (61, 62).

R e l a t e d d i r e c t e d metalations h a v e b e e n


p e r f o r m e d o n some p e r h y d r o i n d i a n d e r i v a t i v e s ( R e a c t i o n 4 6 ) (63, 64).

8 - methoxyisocoumarin Figure 4.

Preparation of isocoumarin derivatives mellein and 8-methoxyisocoumarin



12.

SLOCUM

AND

SUGARMAN

245

Directed Metalation

R = CH,,

Y=

49% (47)

3

R=Ph, Y *

22%

I n c r e a s i n g n u m b e r s of researchers are c o n t r i b u t i n g to syntheses u s i n g d i r e c t e d m e t a l a t i o n reactions a l t h o u g h the of this w o r k i n the l i t e r a t u r e is just b e g i n n i n g . (65)

Recently

heterocyclic appearance Lombardino

r e p o r t e d the synthesis of a c o m p l e x h e t e r o c y c l i c system c o n t a i n i n g

carbon, nitrogen, and sulfur (Reaction 47).

S y n t h e t i c routes to

these

c o m p o u n d s are c o m p a r e d — n a m e l y , that via d i r e c t e d m e t a l a t i o n a n d that i n v o l v i n g e l e c t r o p h i l i c s u b s t i t u t i o n . Y i e l d s f r o m the d i r e c t e d m e t a l a t i o n sequence w e r e h i g h e r a n d the n u m b e r of steps l o w e r t h a n those f r o m electrophilic

s u b s t i t u t i o n , thus

demonstrating

the

potential value

of

d i r e c t e d m e t a l a t i o n i n p r e p a r i n g c o m p o u n d s w h o s e synthesis has a l r e a d y b e e n established b y a n alternate route.


246

POLYAMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

Acknowledgment T h e authors a r e g r a t e f u l f o r p r o o f r e a d i n g assistance b y W . A c h e r mann, R. M a r c h a i , a n d R. Fellows. Special acknowledgment

is m a d e t o

M . V a n Ness f o r t y p i n g t h e m a n u s c r i p t a n d to B . S l o c u m f o r p r e p a r i n g the illustrations.


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Mallan, J. M., Bebb, R. L . , Chem. Rev. (1969) 69, 693. Achermann, W., Slocum, D. W., unpublished results. Gilman, H . , Morton, J. W., Org. React. (1954) 8, 258. Plesske, K., Angew. Chem., Internat. Ed., Engl. (1962) 1, 312, 394. Bublitz, D. E . , Rinehart Jr., K. L . , Org. React. (1969) 17, 1. Jones, F. N., Vaulx, R. L., Hauser, C. R., J. Org. Chem. (1963) 28, 3461. Rosenblum, M., "Chemistry of the Iron Group Metallocenes," Wiley, New York, 1965. Slocum, D. W., Engelmann, T. R., Ernst, C., Jennings, C. Α., Jones, W., Koonsvitsky, B. P., Lewis, J., Shenkin, P., J. Chem. Educ. (1969) 46, 144. Hoofer, O., Schlögl, K., J. Organomet. Chem. (1968) 13, 443. Slocum, D. W., Rockett, B. W., Hauser, C. R.,J.Amer. Chem. Soc. (1965) 87, 1241. Slocum, D. W., Jennings, C. Α., Engelmann, T. R., Rockett, B. W., Hauser, C. R., J. Org. Chem. (1971) 36, 377. Gilman, H . , Soddy, T. S., J. Org. Chem. (1957) 22, 1715. Graybill, Β. M., Shirley, D. Α., J. Organomet. Chem. (1968) 31, 443. Shirley, D. Α., Cheng, C. F.,J.Organomet. Chem. (1970) 20„ 251. Gay, R. L . , Hauser, C. R.,J.Amer. Chem. Soc. (1967) 89, 2297. Kinstle, T. H . , Bechner, J. P., J. Organomet. Chem. (1970) 22, 497. Slocum, D. W., Gierer, P. L . , Chem. Comm. (1971) 305. Davies, G. M . , Davies, P. S., Tetrahedron Lett. (1972) 3507. Marr, G., Rockett, B. W., Rushworth, Α., J. Organomet. Chem. (1969) 16, 141. Slocum, D. W., Stonemark, F. S., J. Org. Chem. (1973) 38, 1677. Slocum, D. W., Jones, W. E., Crimmins, T. F., Hauser, C. R., J. Org. Chem. (1969) 34, 1973. Stonemark, F. S., Ph.D. Thesis, Southern Illinois University, 1971. Gay, R. L . , Crimmins, T. F., Hauser, C. R., Chem. Ind. (London) (1966) 1635. Marr, G., Moore, R. E., Rockett, B. W., J. Chem. Soc. C (1968) 24. Gierer, P. L., Ph.D. Thesis, Southern Illinois University, 1972. Slocum, D. W., Koonsvitsky, B. P., Chem. Commun. (1969) 846. Slocum, D. W., Engelmann, T. R., J. Organomet. Chem. (1970) 24, 753. Marr, G., J. Organomet. Chem. (1967) 9, 147. Marr, G., Hunt, T., J. Chem. Soc. C (1969) 1970. Slocum, D. W., Jennings, C. Α., "Abstracts of Papers," 161st National Meeting, ACS, Los Angeles, March 1971 ORGN 186. Sugarman, D. I., Slocum, D. W., unpublished results. Grocock, D. E . , Jones, T. K., Hallas, G., Hepworth, J. D.,J.Chem. Soc. C (1971) 3305. Slocum, D. W., Koonsvitsky, B. P., J. Org. Chem. (1973) 38, 1675. Puterbaugh, W. H . , Hauser, C. R., J. Amer. Chem. Soc. (1963) 85, 2467. Nozaki, H . , Aratani, T., Toraya, T., Tetrahedron Lett. (1968) 4097. Nozaki, H . , Aratani, T., Toraya, T., Noyori, R., Tetrahedron (1971) 905.



12.

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A N D SUGARMAN

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247

37. Aratani, T., Gonda, T., Nozaki, H . , Tetrahedron (1970) 26, 5453. 38. Aratani, T., Gonda, T., Nozaki, H . , Tetrahedron Lett. (1969) 2265. 39. Gokel, G., Hoffmann, P., Kleinamm, H . , Klusacek, H . , Marquarding, D., Ugi, I., Tetrahedron Lett. (1970) 1771. 40. Marquarding, D., Klusacek, H . , Gokel, G., Hoffmann, P., Ugi, I.,J.Amer. Chem. Soc. (1970) 92, 5389. 41. Battelle, L . F., Bau, R., Gokel, G. W., Oyakawa, R. T., Ugi, I. K.,J.Amer. Chem. Soc. (1973) 95, 482. 42. Ugi, I., Rec. Chem. Prog. (1969) 30, 289. 43. Marquarding, D., Klusacek, H . , Gokel, G., Hoffmann, P., Ugi, I., Angew. Chem. Internat. Edit. (1970) 9, 371. 44. Goldberg, S. I., Bailey, W. D., Tetrahedron Lett. (1971) 4087. 45. Vaulx, R. L . , Jones, F. N., Hauser, C. R., J. Org. Chem. (1964) 29, 505. 46. Puterbaugh, W. H . , Hauser, C. R., J. Org. Chem. (1964) 29, 853. 47. Barnish, I. T., Mao, C. L., Gay, R. L., Hauser, C. R., Chem. Comm. (1968) 564. 48. Mao, C. L . , Barnish, I. T., Hauser, C. R., J. Heterocycl. Chem. (1969) 6, 475. 49. Mao, C. L., Barnish, I. T., Hauser, C. R.,J.Heterocycl. Chem. (1969) 6, 83. 50. Mao, C. L., Henoch, F. E . , Hauser, C. R., Chem. Comm. (1968) 1595. 51. Bailey, D. M., DeGrazia, C. G., Tetrahedron Lett. (1970) 633. 52. Watanabe, H . , Gay, R. L., Hauser, C. R., J. Org. Chem. (1968) 33, 900. 53. Watanabe, H . , Schwarz, R. Α., Hauser, C. R., Lewis, J., Slocum, D. W., Can. J. Chem. (1969) 47, 1543. 54. Watanabe, H . , Schwarz, R. A., Hauser, C. R., Chem. Comm. (1968) 287. 55. Slocum, D. W., Silverman, B., Rockett, B. W., Hauser, C. R., J. Org. Chem. (1967) 32, 464. 56. Ludt, R. E . , Hauser, C. R., J. Org. Chem. (1971) 36, 1607. 57. Narasimhan, N. S., Ranade, A. C., Chem. Ind. (London) (1967) 120. 58. Narasimhan, N. S., Paradkar, M. V., Alurkar, R. H . , Tetrahedron (1971) 1351. 59. Narasimhan, N. S., Bhide, Β. H . , Chem. Ind. (London) (1969) 621. 60. Narasimhan, N. S., Bhide, Β. H . , Tetrahedron Lett. (1968) 4159. 61. Narasimhan, N. S., Bhide, Β. H . , Chem. Comm. (1970) 1552. 62. Narasimhan, N. S., Bhide, Β. H . , Tetrahedron (1971) 6171. 63. House, H . O., Hanners, W. E., Racah, E . J.,J.Org. Chem. (1972) 37, 985. 64. House, H . O., Hudson, C B., Racah, E . J., J. Org. Chem. (1972) 37, 989. 65. Lombardino, J. G., J. Org. Chem. (1971) 36, 1843. 66. Slocum, D. W., Engelmann, T. R., Jennings, C. Α., Aust. J. Chem. (1968) 21, 2319. 67. Roberts, J. D., Curtin, D. Y., J. Amer. Chem. Soc. (1946) 68, 1658. 68. Slocum, D. W., Book, G., Jennings, C. Α., Tetrahedron Lett. (1970) 3443. 69. Booth, D. J., Rockett, B. W., J. Chem. Soc. C (1968) 656. 70. Benkeser, R. Α., Fitzgerald, W. P., Melzer, M . S., J. Org. Chem. (1961) 26, 2596. 71. Slocum, D. W., Koonsvitsky, B. P., Ernst, C. R., J. Organometal. Chem. (1972) 38, 125. 72. Slocum, D. W., Achermann, W., Teymouri, E . , unpublished results. 73. Gronowitz, S., Ark. Kemi. (1958) 12, 239. 74. Gronowitz, S., Ark. Kemi. (I960) 16, 363. 75. Gronowitz, S., Ark. Kemi. (1958) 13, 269. 76. Gronowitz, S., Eriksson, B., Ark. Kemi. (1963) 21, 335. 77. Gronowitz, S., Ark. Kemi. (1954) 7, 361. RECEIVED March 13, 1973.


Directed Metalation

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