Chiral lithio formamidines. Are they configurationally stable?

00404039/91 $3 00 + 0 Perganlon Press plc

Teaahedron Letters, Vo1.32, No 40, Pp 5505-5508.1991 Printed tn Great Brttain

CHIRAL

LITHIO

FORMAMlDlNE!k

ARE

THEY

CONFIGURATIONALLY

STABLE?

A. I. Meyers*, Joseph Guiles, Joseph S. Warmus and Michael A. Gonzalez Department of Chemistry, Colorado State University, Fort Collms, Colorado 80523 U S A.

Summary: Metalation and alkylation of an optically active l-methyl isoqumoline In the presence of an achrral formamidine leads to completely racemic material.

Ever since Letsinger

and Traynham 1 showed that octyllithium

prepared from S-(+)-2-

iodooctane and butyllithium at -70°C lost 80% of its optical activity when quenched with Con, there has been considerable interest in the configuration stability of carbanions.2 The earliest report of a configurationally stable organolithium came from Walborskya who showed clearly that certain cyclopropyllithiums retained 95% of their absolute configuration. Thus, cyclopropyl, vinyl, and aheteroatom carbanions of lithium were eventually all shown to exhrbit considerable stability toward Inversion.4 Studies to substantiate this behavior have come mainly from NMR experiments and it generally agreed that configurational

IS

stability will be considerable if either strain and/or chelation

effects are involved. The use of lithiated chiral formamidines has been adequately demonstrated to afford chiral asubstituted amines (Scheme 1) in high enantiomeric

purity. 5 However, the exact nature of this

process, accompanied by a high degree of stereoselectivity,

IS still an open question.

We have,

along with others,6 assumed with good reason, that the highly selective alkylations are due to the CLi bond in the formamidine 1 possessing considerable covalency (Scheme 1). If the C-U bond in 1 is Indeed strong enough to inhibit inversion of the carbamon, and if the adjacent nitrogen and oxygen ligands are provrding stabilizing influences, then one can ask the question:

Scheme

Is the lrthro

1

R

(R = H, Alkyl) (R’=H.MeO)

1 (R = Alkyl, H)

5505

R = Alkyl, E = H; 95% de

5506

derivative

1 (R = alkyl) able to maintarn

auxrlrary is replaced chelatron) methyl

its absolute

confrguratron

if the stereogenrc

carbon ? In other words, all the factors

by a symmetric

will remain the same except we will replace the isopropyl

groups.

With these

conditions

in place,

the alkylatron

will

selectivity 3 We felt this would be a meaningful

drastereofacial

(I e

center rn the

, ring conformatlon

group and hydrogen

with two

step (E+) still provrde the high

test7 of configurational

stabilrty and

shed some light on the nature of the C-Li bond a Scheme

2

NZHIZ(no rac’mn)

W-4 _

-

[alo 107”

methyl

iodide.

chrral

auxrlrarys

benchmark HOAc)

This reaction which

gave

configurational

stability

4, m 7680%

salsolidme

had

methylrsoqumoline Metalatron 100°C

while

hydrazrnolysis

2.

yield.

IS

in

chloride

IS

furnished

the

from 2-methyl the optically

1 ,l -disubstrtuted

(hydrazme-EtOHof 3O-carbons,5

the

pair could be evaluated

In

2-ammopropanol5

by simple

actrve 1-methyl formamidrne enriched

to the level of 94%

hydrazrnolysis

To assure that no

of 4 returned

the

I-

In Its specrfrc rotation

generated

Introduced

as the

pure by vrrtue of 11s specrfic

center in the molecule

3 to 4,

group

with

for 2 was to act as the

deprotonatton

now a single enantromer,

transforming

s-BULI

using the tbutoxy

or carbon-lithium

derived

1440

of the lrthrated formamrdrne

of the choral auxiliary

now allows

the only stereogenic

was

in detail

This produced

3 with less than 1% vanation of 4 at -78°C with

alkylatron

was 94% optically

3”-carbanion

The latter

4,[a],

Removal

formamrdines

in hot toluene

occurred

benzyl

MeO

The 94% de obsewed

3, 9 which

the achiral auxilrary

ee and the methyl group at C-l racemization

76%

2 through de.

In Scheme

of the resulting

of drmethylamine

rsoquinoline

NH

“H

been studied

2 rn 94-97%

use of methoxy

this regard, we reinstated exchange

has already

reactions

gave the alkalotd Since

CH,

this study by first preparing

for further

rotation

0

3, [a]0 -63” (94%)

(94% de)

We initiated

w

/

Me0 2,

M&3

Me0

the red anion solution Alkylatron

isoquinoline

gave

of 6 which was kept at -

7, ([a]~

8 possessing

[n]~

2.8”)

1.4“.

whtch

af?er

Based on

5507

R R

w

0

BnCl

Me

Me0 4, R = MeO, [alo 144’ (1 2, THF) 5, R = H, [ab 147” (6, THF)

-1oo”-

NI LI N

MeO

Me0 Ph

Y

G,(R=Meo) Q,(R=H)

10 (
t)Me 8. A = H (4% ee)

1 1 (92% D), 6% ee

specrfic rotations (THF), the optical punty went from 94% in 3 to 4% in 8 (based upon [alp 25 0’ (1.6, THF) for 8 at 86% ee).s Further confirmation of the low enantromeric purity of 8 was obtained by chiral HPLC analysis (Chiracel OJ, 3:l hexane-i-PrCH, 1 mUmin) which gave an integrated peak ratio of 49.8:48.6. Thus 8 was indeed close to being racemic and this indicated that even at -lOO’C, the C-LI bond is too weakly associated to prevent any inversion.

Furthermore, if the C-l methyl in 6

was attached to a trigonal carbon (or mainly so) the rotation of the N-C=N-morety in the formamidrne would lead to enantiomers,

which would also explain the racemic-like nature of 8.

Not totally

satisfied with this behavior, we performed two additional experiments to assess configurational stability.

The isoquinoline 5 (99+% ee), prepared as described above and from earlier studies,10

was metalated with n-BuLi and then alkylated wrth 1-chloro-3-iodopropane followed by Since the latter was prepared11 in 75% ee hydrazinolysis to the pyrroloquinoline 10 [a]D =0-l’. usmg a chiral auxiliary, we were able to assess the level of survival of the carbanion, which was obviously very poor. The lrthiated isoquinoline 9 was also treated with DMSO-de to give 92% D incorporation (NMR) at -1OO’C but, once again removal of the achiral formamidine showed [a]b -4.2” (2, THF) which amounts to -6% optical purity. 1s The residual optical actrvity is no doubt due to unmetalated 5 (-8%) and once agam convinced us that there was little configurational

stability in

these lithiated formamrdines, due to poor levels of covalent character In the C-U bond.12 Acknowledgement: support of this work.

The authors are grateful to the National Science Foundation for financial

5508

References 1.

Letsmger,

2.

For leading references New

J. G. J. Amer. Chem. Sot. 1950, 72, 7642

R L.; Traynham,

York, 1965.

M.; Grutzner,

see (a) Cram, D. J. Fundamentals

(b) Lambert,

J B Stereochem

J. B. Stereodynamics

of Carbamon

Chemistry

1971, 6, 19 &) Peoples,

in Molecular

Systems,

Academic

P R , Tramor, T

R H , Ed , Pergamon

Shanna,

New York, 1979, 131 3 4

Walborsky,

H. M , Impastato,

Walborsky,

H M., Banks, R. B. Bull. Sot. Chim. Se/g. 1980, 649

(a) Grutzner,

F J., Young, A E. J. Am. Chem

Chem. Sot. 1986, 108, 59, 83.

(d) Tanlkaga,

(e) Shll, W C , Sreekumar,

R.; Murashlma, C. J. Am

Am. Chem. Sot. 1988, 770, 6249. (h) Rondon, Chandra 5

Left, previous 6

T J Chem. Sot

Chem

Perk/n Trans

Sot. 1980, 702, 1201

(f)

R J , Godfrey, A J

(g) Lmderman,

N. G , Houk, K N , Beak, P , Zajdel, W. J ,

P. V R. J. Org. Chem. 1981, 46, 4108

Sekhan, J.: Schleyer,

Meyers, A. I ; Gonzalez,

D ;

(b) Seebach,

(c)Mullen, K , Lex, J , Hoell, D J Am

G J.; Kimura, J J. Org. Chem. 1985, 50, 4655.

McGarvey,

1964, 86, 3283; see also

P. R J. Am. Chem. Sot. 1980, 102, 4709

J B., Peoples,

Helnzer, J.; Oth, J He/v. Chum Acta 1985, 68, 1848

7 1989, 2142

Sot

M. A.; Struzka, V , Akahane,

paper and reference

Rein, K., Golcoechea-Pappas,

A.; Gurles, J , Warmus, J S Tetrahedron

1 cited.

M.; Anklekar,

T. V.; Hart, G C.; Smith, G. A., Gawley,

R. E J

Am. Chem. Sot. 1989, 7 17, 2211. 7.

Tests for configuratlonal non-racemic

stablllty

electrophlles

1991, 195) and earlier a.

A considerable

references

body of evidence

(see ref 4a, 4b, 4c) and therefore prudent to proceed

using a clever

have been described

with caution

9

Meyers, A. I.; Boes, M.; Dickman,

10

(S)-1 -methyl-l

senes recently

of reactlons

Prepared assessed

has been gathered possesses

University, 12.

A recent processes

via t-leucine

derived

and

Comm.

to show that carbon In C-LI is pyramldal,

considerable

covalent

However,

character

in assummg that allC-LI bonds are as described

It

IS

above

D. A. Organic Syntheses 1988, 67, 63

,2,3,4-tetrahydrolsoqumolme

by chiral

racemlc

(JCS-Chem.

cited

was prepared

>97% ee as described

-71 3” (0.6, THF); Meyers, A I.; Dickman, D. A.; Boes, M. Tetrahedron 11

mvolvmg

by Hoffman

auxiliary,

HPLC to be 74-76%

[cr]~ 9.0” (0.8, EtOH), ee

earlier,

[Cc]0

1987, 43, 5095 (a]436

1 I.43 which

Gurles, J. Ph D. Dissertation,

Colorado

was State

1991. report

by Gawley,

accompany

et al.; Tetrahedron

Lett. 1991, 32, 1941,

the polar process and result In non-selective

SET process was observed

(Received in USA 12 June 1991)

when using alkyl halides as electrophlles

indicates

alkylatrons

that SET

However,

no