The 2-(trimethylsilyl)ethoxymethoxy (OSEM) directed ortho metalation group. New regiospecific synthetic routes to substituted benzenes and pyridines

The 2-(trimethylsilyl)ethoxymethoxy (OSEM) directed ortho metalation group. New regiospecific synthetic routes to substituted benzenes and pyridines

Temhednm Lettm. Vo131. No.30. p~42674270.1990 Rintcd in Great Britain 00404039/90 s3.00 + .oo PcrB-hplc THE 2-(lRIMBTHYLSILYL)ETHO XYMJZTHOXY (OSRM...

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Temhednm Lettm. Vo131. No.30. p~42674270.1990 Rintcd in Great Britain

00404039/90 s3.00 + .oo PcrB-hplc

THE 2-(lRIMBTHYLSILYL)ETHO

XYMJZTHOXY (OSRM) DIRRCIRD

GROUP. NBW RBGIOSPECIPIC

-C

ORTHO METAL&DON

ROUTES To SUBSTIlVFED

BRNZBNBSANDPYRIDINRS

Saumitra Sengupta and Victor S&&us* Guelph-Waterloo

Cemre for Graduate Work in Chemistry

University of Waterloo, Waterloo, Ontario

Abstractr

Regiospecific metalation

of OSEM aryl(2)

diversely substituted aromatic (3, Table), 4pyridyl(6),

The horizons development polysubstituted

of the directed

of new directed

and 3pyridyl

groups

aromatics devoid of regioisomeric

N2L 3Gl

(5) systems allows the preparation

and, significantly, 2pyridyl(7,9)

ortho metalation

metalation

CANADA

reaction1

(DMGs)2

continue

and

complications.

the

derivatives.

to broaden

increasing

of

owing to the

need

Among oxygen-based

to construct

DMGs (Q3 the

originalla but still widely useful4 OMe group, has been superseded in recent years by the versatile 0MOM5 and OCONEt21ds1e6 functionalityg

and the less developed

OTHP1~’

groups.

Promising

results using OP(O)NR2

as a DMG has been reported recently while attempts to use the OMEM group9 has failed

owing to predominaut

side reactions.

Deprotection

of all these systems to phenols normally

effected by moderately strong acidic or basic conditions. and its ease of preparation

and deprotection

The resemblance

has been

of OSEM to the OMOM group

under virtually neutral conditions (fluoride ion)l” prompted a

systematic investigation of the OSEM moiety.ll

In this Letter, we report that OSEM serves as an excellent

oxygen-based DMG both for aryl and for pyridyl systems and thereby provides new and general synthetic protocols for the construction

of polysubstituted

aromatic derivatives.

DMG (Directed Metalation Group) = OMe, OMOM, OCONEt,, OTHP, OP(O)(NMe,), \

4267

4268

Exploratory studies withp-tolyl was achieved using n-B&

OSEM derivative 212 showed that optimum conditions for lithiation

in Et20 at room temperature

suspension of the ortho-lithiated

(2 - 2.5 h).

Treatment

of the resulting white

species with a wide range of electrophiles provided, after standard workup,

substituted products 3 (Table). Yields are generally very good, except in cases of enolixable (entries 3,4).

In the case of 2,4-dimethylphenyl

2), metalation

under the above conditions

electrophiles

OSEM (prepared in 90% yield by Me1 quench of lithiated

occurred exclusively at the alternate

ortho site (entry 8).13

Naphthyl OSEM systems may also be smoothly metalated leading to regiospecific (entry 9) or regiorandom (entry 10) results.

To verify the viability of the method for the synthesis of orfho substituted

number of compounds 3 were treated with TBAF under standard conditions”

phenols, a

to afford the deprotected

products 4 in high yield. OSEM

OSEM

OH E

E

1. n-BuLi / Et20 / RT Me

TBAF / THF / HMPA (2 equiv)

2. EC

40’ / 2-3 h

Me 3

2 SEM =

( > 90% ) Me 4

\ho-TMS

, COPh

E OSEM

TMS OSEM

1. t-BuLi/EtzO/-76’C

pq

1. t-BuLi/Et20/-780C

w 2. E+

2. PhCHO 6

5

7

Ph TBAFITHFIRT

The OSEM DMG is similarly effective in heteroaromatic conversion of the 3-pyridyl derivative 514 into 4-substituted competitive nucleophilic metalation trisubstituted

It was demonstrated

products 6 using t-BuLi conditions

by the to avoid

attack on the pyridine ring. Moreover, the 4-TMS derivative 6a underwent further

at the 2-position

under the same conditions;

pyridine 7 (82%).

known C-4 metalation

metalation.llb

benxaldehyde

The facile, yet selective desilylation

of 3-pyridyl 0-carbamateslS

for the regiospecific construction

subsequent

of 7 to 9 (90%), coupled with the

allows consideration

of either 2-, 4-, and, in principle,

quench, afforded the

of the silicon protection tactice 16

higher substituted

pyridines.

This

4269

Table.

Entry

Synthesis

SEM-Ether

of

orfho-Substituted

Aryl-OSEM

Electrophile

Derivatives

Yield%a

Product

OSEM

OSEM

76

1

=“O Me

MO

80

PhcHo

CHO

52

0

57

PhCONMe

70

>

0

MO OSEM

6

_Bfb

76 Ma OSEM

7

55

(TMW2 OSEM

OSEM

Ma

MI

a

p4AeOCGH4CH0

OH C6H,-p-OMe

70

Ma OSEM

OSEM

9

TMSCI

Mel

TMS

a7

aoc

a: Isolated yields; b: in prkence of CuBr.DMS (10%); c: 1:1 mixture (by NMR) of l-Me and S-Me isomers.

4210

methodology complements methoqpyridine

and offers advantage in deprotection

devised recently by CominsM

Predictably,

compared to that using ametalated metalation

followed by quench with benxaldehyde led to the side-chain carbinol8

of the 4-picolyl derivative

36h

(82%).

In stumnary, we have shown that OSEM is an excellent DMG with which to pursue directed ortho metalation electrophiles

chemistry in aryl and pyridyl frameworks. is evident.

A reactivity profile amenable

These results, together with the mild, neutral deprotection

to a wide variety of protocol place the

OSEM in a favorable comparative position vi.s a vis other oxygen-based DMGs and suggest new avenues in synthetic aromatic and heteroaromatic

chemistry.18~19

References and Footnotes 1. 2. 3. 4. 5. 6. ;: 9. 10. 11.

$2. 13. :z* 16: 17. 118. 19.

schwend H.W.; Rodri ex, H.R. Org. React. 1979, & 1; (b) Beak, P.; Snieckus, V. Ace. tie:&. 1982 1% 306; (c $ Narasimhan, N.S.; Mail, R.S. Topics Cwr. Chem. 1987, Xj& 63; (d) Snieckus, V. Chem. Rev. in press. Snieckus, V. Bull Sot. Chim. Fr. . Sibi,_M.P.; Sniedkas, V. J. 1937; Iwao, M.; Iihama, T.; Mahalanabis, KK; Pemer, H.; Snieckus, V. ib’ 2 1989, %, 24; Quesnelle, C.; Iihama, T.; Aubert, T.; Perrier, H.; Snieckus, V. in preparation. Phenol itself may be dimetalated albeit under rather special conditions: Posner, G.H.; Canella, KA. J. Am. Chem. Sot. 1985,1M, 2571. Cf. tier al& Screttas, C.G.; Steele, B.R. J. Org. Chem. 1989, j&, 1013; Coll, .G_.;Morey, J.; Costa, A.; Saa, J.M. ibid 1988, % 5345 and refs cited therein; Einhom, J.; Luche, J.L. rbld 1987,52,4124. a) Townsend, CA; Bloom, L.M. Tetrahedron L&t. 1981, 3923; (b) Winkle, M.R.; Ronald, R.C. f . Org. Chem. 1982, 42 2101; (c) For recent use, see, inter uZiu, Harvey, R.G.; Cortez, C.; Ananthanara an, T.P.; Schmolka, S. ibid 1988, Xj, 3936; Kamikawa, T.; Kubo, I. Synthesis 1986,431. Sibi, M.P.; C l!attopadhyay, S.; Dankwardt, J.W.; Snieckus, V. J. Am. Chem. Sot. 1985, m, 6312 and refs cited therein. Buchi, G.; Chu, P.-S. J. 0 . Chem. 1978, a 3717. Date, M.; Kawanishi, K.; ?I ori, T.; Watanabe, M.; Furukawa, S. Chem Pharm. Bull. Jpn 1989, 32, 2884 and refs cited therein. Mayrargue, J.; Essamkaoui, M.; Moskowitx, H. Tetrahedron Lett. 1989,6867. Lipshutz, B.H.; Pegram, J.J. Tetrahedron L.&t. 1980, 3343; Lipshutx, B-H.; Miller, T.A. ibid. 1989, 7149 and refs cited therein. Two solitary cases of OSEM metalation have been reported: a) a 3-methoxyphenyl OSEM derivative Marino, J.P.; Dax, S.L. J. Org. Chem. 1984, @, 3672) and b) a bipyridyl diOSEM system Hasseberg, H.-A; Gerlach, H. Helv. Chim. Acta 1988, a 957). For metalation of N-OSEM ole, indole, and imidaxole see Edwards, M.P.; Doherty, AM.; Ley, S.V.; Organ, H.M. Yrr etrahedrvn, 1986, a, 3723; Muchowski, J.M.; Solas, D.R. I. Org. Chem. 1984, @, 203; Whitten, J.P.; ibid 1986, 5l., 1891; Lipshutx, B.H.; Huff, B.; Hagen, W. Matthews, D.P.; McCarthy, J.R. Tetrahedron L.&t. 1988,34 11. All OSEM derivatives were pre ared from the corresponding phenols under standard conditions (SEMCl/EtN(iPr)2/CHel2/R+!/24 h) (ref. 10). Nonregioselective metala ‘on as a function of conditions has been explored for the o-tolyl OMOM stem (ref. 5b). z epared from 3-pyridinol in 90% yield (NaH/SEMCl/DME/RT). Miah, M.A.J.; Smeckus, V. J. Org. Chem. 1985, a 5436. Mills, R.J.; Taylor, NJ.; Snieckus, V. J. Org. Chem. 1989, $$, 4372. Cormns, D.L.; LaMun on, D.H. Tetrahedron Lett. 1988,773. All new compounds s!Iow analytical and spectral (IH NMR, MS) data consistent with the indicated structures. We gratefully acknowledge NSERC Canada for financial support through Operating and Strategic Grant programs.

(Received in USA 10 May 1990)