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The Reaction of Organocuprateswith Bridgehead EnonesGeorge A. Kraus a & Pang Yi aa Department of Chemistry , Iowa State University , Ames,IA, 50011Published online: 06 Dec 2006.

To cite this article: George A. Kraus & Pang Yi (1988) The Reaction of Organocuprateswith Bridgehead Enones, Synthetic Communications: An International Journalfor Rapid Communication of Synthetic Organic Chemistry, 18:5, 473-480, DOI:10.1080/00397918808060739

To link to this article: http://dx.doi.org/10.1080/00397918808060739

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SYNTHETIC COMMUNICATIONS, 1 8 ( 5 ) , 473-480 (1988)

THE REACTION OF ORGANOCUPRATES WITH BRIDGEHEAD ENONES

George A. Kraus* and Pang Yi

Department o f Chemistry, Iowa State University, Ames, IA 50011

ABSTRACT. lithium 2,6-ditert-butyl-4-methylphenoxide in ether affords good to excellent yields of ketones. The alkyl or alkenyl group is introduced via a conjugate addition to an in situ derived bridgehead enone.

The reaction of bromoketones with organocuprates and

Until recently, reaction at a bridgehead carbon to produce a

e quaternary stereogenic center was not a synthetically viab

reaction. As a result of much basic research in this area

methods for generating bridgehead intermediates now permit

introduction of many types of functional groups. Ketones,

amines and aryl groups may be added by way o f bridgehead

the

esters,

carbocation intermediates.'

way of bridgehead enones.'

for the direct introduction of simple alkyl groups.

Additional rings may be annulated by

However, no general procedure exists

The addition of an alkyl group such as a methyl group or a

butyl group failed in some instances because the organometallic

reagent (e.9. , Me'CuLi) did not react with the bridgehead

halide.

halide when 1-bromoadamantane was treated with Me2CuLi .3

A case in point was the complete recovery o f starting

The

473

Copyright 0 1988 by Marcel Dekker, Inc

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474 KRAUS AND YI

reaction of some bridgehead tosylates with Grignard reagents at

elevated temperatures affords good yields o f the corresponding

1-alkyl bicyclooctanes and bicy~lononanes.~

reaction is limited by the narrow array of compatible functional

groups. Bridgehead bromides also react with trimethyl

al~minum.~

regard to both the halide and the organoaluminum reagent.

o f a study of the synthetic potential of bridgehead enones, we

have examined the reactions of organometallic reagents with in

situ derived bridgehead enones and report that good to excellent

yields o f conjugate addition products can be obtained with readily

available cuprate reagents.

However, this

The scope o f this interesting reaction is limited with

A s part

The bromoketones examined in this study were ketones 1 and

2. The preparation of compounds 1 and 2 has already been

described.6 While the corresponding bridgehead enones have been

generated using triethylamine in CH2C12 at O"C, only low yields

FH3

:8 OLi

1 X = H , R = B r 4 2 X = SPh, R = Br 3 X = H , R = C H 3

were obtained when triethylamine was added to a solution o f 1 and

lithium dimethylcuprate in ether at 0°C. Other soluble bases such

as potassium tert-butoxide and lithium 2,6-ditert-butyl-4-

methylphenoxide (4) ' gave much better yields. Surprisingly, the

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REACTION OF ORGANOCUPRATES WITH BRIDGEHEAD ENONES 475

Table 1

Entry RM (eq.) base X % yield Compound

Me2CuLi (2)

Me2CuLi (2)

Bu2CuLi (2)

Bu2CuLi (2)

Ph2CuLi (2 )

Ph2CuLi (1)

CH2=CHMgBr*Cu I (2.5)

MepCuLi (2.4)

CH2=CHMgBr-CuI (2.5)

tBuOK

-

tBuOK

-

4

-

tBuOK

4

4

H

H

H

H

H

H

H

SPh

SPh

ao 3

41

69 10

-

47 11

26

60 12

81 13

60 14

reaction o f 1 with two equivalents o f lithium dimethylcuprate

without added base also produced a good yield o f 3.

Our results are listed in Table 1. It i s clear that a

The variety o f groups can be introduced by this technique.

addition o f a vinyl group is particularly notable, in that this

versatile connective group can not be introduced by the bridgehead

carbocation methodology.

significant in that many classes of natural products such as the

The addition o f a methyl group is

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476 KRAUS AND YI

clovenes (5)8 and the beyeranes (6)' have a methyl group attached

to a bridgehead position.

5 6

In practice, 4 became the base of choice. It was always

freshly prepared as a solution in THF.

ether was a more effective solvent than THF. Lithium

diorganocuprates afforded better yields than their heterocuprate

analogs.

cuprous iodide was also effective and was used when the Grignard

reagent was more readily available than the organolithium

compound.

For the reaction, diethyl

The stoichiometric complex of a Grignard reagent wtih

Organocopper reagents (RCu) did not react.

The result with lithium dimethylcuprate without added base

prompted us to question our original assumption that an enone

intermediate was necessary.

of 1 with sodium borohydride.

ether solution at 0°C with lithium dimethylcuprate afforded a

compound in which a methyl group had been introduced." After

considerable analysis, the structure was assigned as alcohol 8, a

Compound 7a was prepared by reduction

The reaction of bromoalcohol 7a in

7a: R = H

7b: R = THP

OR

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REACTION OF ORGANOCUPRATES WITH BRIDGEHEAD ENONES 477

1:l mixture of diastereomers. This structure is supported by two

doublets around 1.2 ppm in the proton NMR and also by IR and mass

spectroscopy. Alcohol 8 was oxidized to ketone 9 with PCC. It

was produced as shown below. This type of fragmentation has

8

9

literature precedent."

was synthesized. When it was treated with lithium dimethyl-

cuprate, only unreacted halide was recovered, demonstrating the

need for a bridgehead enone intermediate.

In order to circumvent this reaction, 7b

The use o f cuprates to effect bridgehead alkylation of

bromoketones permits the introduction of several alkyl and alkenyl

groups.

intermediates in synthetic organic chemistry. It also makes

available new pathways by which natural products such as the

clovenes and the beyeranes can be constructed.

This work extends the versatility of bridgehead enone

EXPERIMENTAL SECTION

Unless otherwise noted, materials were obtained from

commercial suppliers and were used without purification.

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475 KRAUS AND YI

Dichlorumethane was distilled from phosphorus pentoxide.

spectra were determined on a Perkin-Elmer model 1320 spectro-

meter.

Varian EM 360 60 MHz instrument and on a Nicolet 300 MHz

instrument.

300 MHz instrument. High resolution mass spectra were determined

on a Kratos mass spectrometer.

Infrared I

Nuclear magnetic resonance spectra were determined on a

Carbon-13 NMR spectra were determined on a Nicolet

Alkylation reactions - General Procedure

To a solution o f enone 1 or 2 (1 eq) and the organometallic

reagent ( 2 eq) in diethyl ether (2 mL/mmol enone) at 0°C was added

4 (2 eq).

quenched with saturated ammonium chloride solution.

was partitioned between methylene chloride and water.

layer was then dried, concentrated and purified by chromatography

on silica gel using hexanes: ethyl acetate.

The solution was stirred at 0°C for 3-6 h and then

The product

The organic

1-Methyl bicyclo [ 3.3.11 nonan-3-one (3 )

NMR (CDC13) 6 : 1.02 ( s , 3 H), 1.15-1.95 (m, 8 H) , 2.10-2.70

(m, 4 H) , 3.08 ( b s , 1 H). I R (film): 1700, 1456, 1228, 1216

cm- . MS: m/e 41, 55, 67, 81, 95, 109, 137, 152. 1

l-Butylbicyclo[3.3.1]nonan-3-one (101

NMR (CDC13) 6: 0.80-1.90 (m, 18 H ) , 2.15-2.70 (m, 4 H). I R

(film): 1700, 1450, 1228 cm-l. MS: 55, 67, 81, 95, 109, 137,

151, 194.

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-~ REACTiON OF ORGANOCUPRATES WITH BRIDGEHEAD ENONES 479

l-Phenylbicyclo[3.3.l]nonan-3-one (11)

NMR (CDC13) 6: 1.30-2.30 (m, 9 H ) , 2.40-2.75 (m, 4 H ) , 7.32

( s , 5 H) . I R (film): 1700, 1595, 1470, 910, 760 cm-'. MS: m/e

55, 67, 91, 157, 171, 214.

1-Ethenylbicyclo[ 3.3.llnonan-3-one (12)

NMR (CDC13) 6: 1.15-1.90 (my 9 H ) , 2.10-2.60 (m, 4 H ) , 4.75-

6.20 ( m y 3 H ) .

MS: m/e 55, 67, 81, 107, 164.

I R (film): 1700, 1630, 1400, 1215, 910 cm-'.

1-Methy 1 -8-pheny l t hi obi cycl o [ 3.3.1 ] nonan-3-one ( 13)

NMR (CDC13) 6: 1.20 (s , 3 H), 1.25-2.14 (m, 7 H ) , 2.20-3.10

(my 5 H) . I R (film): 1700, 1610, 1450, 1221 cm-l. MS: m/e 55,

67, 81, 93, 110, 133, 151, 260.

260.12349; found 260.12336.

HRMS: m/e for C16H200S calcd.

l-Ethenyl-8-phenylthiobicyclo[ 3.3.1joctan-3-one (14)

300 MHz NMR (CDC13) 6: 1.35-1.72 (my 3 H) , 1.78-1.95 (m, 4

H), 2.22-2.52 ( m y 3 H) , 2.85-2.95 (m, 1 H) , 3.00-3.10 (m, 1 H) ,

4.95-5.12 (my 2 H) , 5.82-6.03 (my 1 H), 7.14-7.30 (my 3 H ) , 7.34-

7.45 (m, 2 H). MS: m/e 55, 67, 77, 91, 105, 121, 136, 149, 163,

272. HRMS: m/e for C17HZ00S calcd. 272.12349; found 272.12368.

3-(2-0xopropyl)-methylenecyclohexane (9)

NMR (CDC13) 6: 0.90-2.55 (m, 11 H) , 2.14 (s, 3 H), 4.62 (bs,

2 H). I R (film): 1710, 1645, 1442, 1355, 1152 cm-l. MS: m/e

109, 137, 152.

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KRAUS AND YI 480

ACKNOWLEDGEMENT. We thank the National Institutes o f Health

(grant GM 33604) for financial assistance.

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Org. Chem., 1983, 3, 1654. Kraus, G. A.; Hon, Y.-S. J. Am. Chem. SOC., 1985, 107, 4341.

J. Am. Chem. SOC., 1984, 106, 2105. House, H. 0.; OeTar,

M. B.; VanDerVeer, 0. J. Org. Chem., 1986, 51, 116.

2.

Magnus, P.; Gallagher, T.; Brown, P.; Huffman, J. C.

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R. W.; House, H. 0. J. Am. Chem. SOC., 1969, 91, 4871. 4. Kraus, W.; Graf, H.-0. Synthesis, 1977, 461.

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Kraus, G. A.; Hon, Y . 4 . ; Sy, J.; Raggon, J.

7. Corey, E. J.; Chen, R. H. K. J. Org. Chem., 1973, 3. 4086. 8. Doyle, P.; Ferguson, G.; Hawley, 0. M.; McKillop, T. F. W.;

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