Ortho metalation directed by α-amino alkoxides. An improved synthesis of ortho-substituted aryl ketones

Tetrahedron Letters,Vol.24,No.49,pp Printed in Great Britain

ORTHO METALATION

Department

oo40-4039/83 $3.00 + .oO 01983 Pergamon Press Ltd.

5465-5468,1983

DIRECTED BY o-AMINO ALKOXIDES. AN IMPROVED OF ORTHO-SUBSTITUTED ARYL KETONES Daniel L. Comins* and Biochemistry,

of Chemistry

and Jack D. Brown Utah State University,

SYNTHESIS

Logan,

Utah 84322

Summary: Ortho-substituted aryl ketones are prepared from N-[2-(dimethylamino)ethy]-Nmethylbenzamides via ortho lithiation of intermediate a-amino alkoxides, formed in situ by addition of RLi. An ortho lithiation of N-[2-(dimethylamino)ethyl]-N-methylbenzamide is also described. Tertiary

a-amino

to a tertiary

alkoxides,

arylcarboxamide,

subsituted

aryl

thiophenesl

and furans2

reported

using

this

This

by ortho

method

works

due to their ease of method

with

(1) directly

dimethylamino)

in situ by the addition

can be ortho-lithiated

ketones.lm3

chlorobenzamide followed

formed

and reaction

group

are only

moderate.3

systems,

a more powerful

To

with

is not a strong

make

this

method

ortho directing

They

converted

aryl ketones

director,

general

alkoxide

However,

for a variety

group

in our

alkoxides.4-6

were

director

formed

in

have

been

a novel one-pot

situ

in benzene. and vigorous

ortho

For

example,

via

ortho

the

studying

It

increased when

was by

the

alkylation

alkoxides.5 addition

of

The cl-(N-methylpiperazino) metalation

1ithiation.S

be dramatically

alkoxide.8

we

a-(N-methylpiperazino)benzyl

methylpiperazide

could

laboratories

We have reported

ortho-lithiated

to effect

the a-(N,Nyields

of -2

of benzenoid

2

Recently

ortho

of RLi

is needed;

-1

alkoxides

of have

N,N-dimethyl-P-

2 via addition

and the isolated

and useful

ortho-

a-metalation

and co-workers3

an electrophile.

ortho

a-amino

Gschwend

reagent

to provide

for the directed

systems.

into ortho-substituted

lithiation

alkoxide

and alkylated

well

deprotonation.

benzenoid

of an organolithium

conditions

subsequently varying

the

alkoxide

amine

N,N,N'-trimethylethylenediamine

5465

to

group proved

benzene,

reflux)

a-amino

aldehydes

intermediate

aldehydes

discovered

of

of aromatic The

aryl

(3 n-BuLi,

chemistry

lithium

was

of used

N-

to be a weak were

that the metalation

component

via

o-amino

needed rate

the a-amino as the

amine

5466

component, as shown

benzaldehyde below.

TMEDA-like

could be ortho-metalated-silylated

The metalation

assisted

rate

increase

at low temperature

is undoubtedly

in high yield

due to an intramolecular

metalation.6

THF

We have synthesis table.

82% (one-pot)

applied

the

diamine

of ortho-substituted The yields

are high

concept

to the Gronowitz-Gschwend

aryl ketones

as shown

and the method

below.

is clearly

procedure

The results

superior

for the

are given

to the original

in the version

Li I

1. E

+

4 q

2. 3 c-BuLi

q

2. H30+ 4

3 using

N, N-dimethylbenzamides.

(methylthio)acetophenone temperature

to preventbenzyne

chlorobenzamide desired

gave

is most

8), where

evident

ortho

3-chloroacetophenone

(entry

lithiation

(80%) and only

hydrolyzed

ortho

lithiation

The

group

main

results.

is its resistance

with

6N HCl(reflux)

should compliment

This of course

of

the

to hydrolysis.g

(inverse Fund, administered

acid

and work

Me1

Aknowledgements.

support

by the American

(cl%)

analogous

initially amide

of the

attack by

as an ortho

new ortho-directing

toward

by Beak

metalation

the amino

This

does

to the ortho

introduced

(a). lo

is in progress

amide 5 is easily group

that goal.

, 5

of this work Chemical

nucleophilic

In contrast,

addition)15 Financial

N,N-dimethyl-3-

a trace

at -78°C (THF) addition

is directly

methodology

N,N-diethyl

to g-toluic

Beak's methodology,

undergo

with -see-BuLi/TMEDA

a powerful

disadvantage

of 3-chloro-2must occur at low

9).

however,

of N,N-diethylbenzamides,

Brown.8

directing

as demonstrated,

synthesis

Under the same conditions,

formation.7

product

in the

lithiation-alkylation

N-[2-(dimethylamino)ethyll-N-methylbenzamides reagents

not occur and

and

mainly

ortho-substituted

The lithium

This

(entry

55%

by the donors

Society,

!? 81% of the Petroleum

is gratefully

acknowledged.

Research

5467

Table Synthesis

of Ortho-Substituted Aryl Ketones From Tertiary Benzamides ____________________~~~~~~~-----------------------------~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~_~__

Entry

Amide

Reaction Productb Yieldc mp,"C E Conditionsa (lit. mp) % _______________________~~_~_~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~_~_~~_~__________________ 1

N,N-dimethyl benzamide

1) 1.5 MeLi, PhH, 0", 2) 3 n-BuLi, RT, 5h

l/2 h

Me1

g-methylacetophenone

2

j,X=H

1) 1.5 MeLi, PhH, 0", 2) 3 fl-BuLi, RT, 5h

l/2 h

Me1

g-methylacetophenone

33d

w-m

[i8)d

2,4-DNP 160-162 (161-162)11

3

&X=H

1) 1.1 n-BuLi, PhH, 0", l/2 h 2) 3 I-BuLi, RT, 24h

Me1

c-methylvalerophenone

4

J,X=H

1) 1.1 n-BuLi, PhH, 0", l/2 h 2) 3 n-BuLi, RT, 24h

MeSSMe

o-(methylthio)-77 valerophenone

Me1

o-methylbenzophenone

o-(methylthio)-85 chloroacetophenone

5

&X=H

1) 1.5 PhLi, PhH, O", 2) 3 fl-BuLi, RT, 12h

6

3, X = p-Cl

1) 1.5 MeLi, THF -2O", 3/4 h 2) 3 fi-BuLi, -20b, 4h

MeSSMe

l/2 h

55

2,4-DNP 75-77 (76-78)'l

2,4-DNP 130-132,

85

62-6 3 (62)

7

3, x = p-Cl

1) 1.5 MeLI, THF, -2O", 3/4 h 2) 3 n-BuLi, -2O", 4h

Me1

o-methyl-e87 chloroacetophenone

oxime 68-6 73 (69)

8

3, X = m-Cl

1) 1.5 MeLi, THF, -78', 3/4 h 2) 3 fi-BuLi, -78", 7h

MeSSMe

o-(methylthio)-63 fi-chloroacetophenone

2,4-DNP 107-108,

1 2

MeSSMe

o-(methylthio)ld ij-chloroacetophenone

-_-

___

9 N,N-dimethyl-mchlorobenzamiae

-78", 3/4 h

10 N,N-dimethyl-emethoxybenzamide

1) 1.5 MeLi, PhH, RT, 4h 2) 3 E-BuLi, THF, -2O", 24h,

Me1

o-methyl-e2d methoxyacetophenone

11

1) 1.5 MeLi, PhH, RT, 4h 2) 3 E-BuLi, THF, -2O", 24h

Me1

o-methyl-e83 methoxyacetophenone

1, X =p-OMe

b

b

semicarbazone

---______________-__~~~~~~~~~~-----~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~_~~__~_ aReactions were performed on a 3-mmol scale. THF was added to the reaction mixtures in benzene prior to cooling to -42°C and adding the electrophile (6 equiv). The workup consisted of pouring the reaction mixture into stirred cold 10% aqueous HCl followed by extraction with ether.

5468

bAll products gave the expected IR and 'H NMR spectra. New products, from entries 4 and 8, gave satisfactory analytical data. 'Yields are for isolated, pure, material obtained from preparative layer chromatography (silica gel, acetone-hexanes). dGC yield. References and Notes. 1.

U. Michael and S. Gronowitz, Acta. Chem.Scand.,_,22 1353 (1968); V. P. Litvinov, Ya. L. Gol'dfarb, V. V. Zelentosovm.anova, and N. N. Pewtukhova, Khim. Geterotsikl. Soedin., 486 (1975); V. P. Litvinov, T. V. Schchedningskaya, P. A. Konstantinov, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin., 492 (1975).

2.

S. Gronowitz, _-*-, Ark. Kemi

3.

L. Barsky, H. W. Gschwend, J. McKenna, and H. R. Rodriquez, J. Org. Chem., 41, 3651 (1976).

4.

D. L. Comins, and W. Dernell, Tetrahedron &., 4213 (1981). Brown, Tetrahedron &,

5.

D. L. Comins,

6.

D. L. Comins and J. D. Brown, J.Drg. Chem., in press. This paper was presented in part at a recent ACS meeting. D. L.Comins, J. D. Brown, and N. B. Mantlo, ORGN, 117, 185th National Meeting of the American Chemical Society, Seattle, Washington, March 20-25, 1983.

7.

H. Gilman and R. D. Gorsich, J. Am. Chem.&., 23 2091(1982). Rieker, Tetrahedron m., _,

8.

P. Beak and R. A. Brown, J. Orq. Chem., 42, 1823 (1977).

9.

For a review on directed lithiation of aromatic tertiary amides, see P. Beak and V. Snieckus, __-.)-) Act. Chem. Res 15 306 (1982).

32 283 (1970).

1085 (1981); D. L. Comins and J. D.

J. D. Brown, and N. B. Mantlo, Tetrahedron w.,

3979 (1982).

7B, 2217 (1956); A. I. Meyers and W.

10. Hydrolysis of N,N-diethyl-g-methylbenzamidedid not occur under these conditions. 11. B. Cazes and S. Julia, Tetrahedron, 35, 2655 (1979). 54 12. P. R. Austin and J. R. Johnson, J. Am. Chem. Sot., _, 13. J. Claus, J * Prak- Chem -s_s2

647 (1932).

43 (1892).

46 14. C. R. Noller and R. Adams, J. Am. Chem. Sot., _,

1889 (1924).

15. The amino amide was added to -set-BuLi/TMEDA in THF at -78°C. (Received

in USA 9 September

1983)