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Iodotrimethylsilane-Promoted 1,4-Addition of Copper Acetylidesto alpha,beta-Unsaturated Ketones and Aldehydes

Credits: Magnus Eriksson, Tommy Iliefski, Martin Nilsson, and Thomas OlssonDepartment of Organic Chemistry, Chalmers University of Technology, S-412 96 Goteborg, Sweden

Saibalendu sarkar(cy16mscst11022)

Prof. Faiz ahmed khanJ. Org. Chem. 1997, 62, 182-187

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Introduction• Many discussion has been done on the 1,4-conjugate addition of unsaturated aldehydes and

ketones using the organometallic reagents, popularly the organocopper.• Most popular organocopper based reagent is the Gilman reagent, R2CuLi, R2Cu(CN)Li etc.

• But in this type of reagent the ‘R’ group used is the alkyl/aryl/alkenyl and no alkynyl, since the alkynylcopper reagents are far less reactive than other mentioned derivatives.

Modern Methods of Organic Synthesis, William Carruthers and Iain Coldham

O O

R

R2CuLi

THF

Li

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The Scheme• Though Alkynylcopper reagents do not usually gives 1,4-addition products, but it is found that in presence of Iodotrimethylsilane(TMSI) and LiI in Tetrahydrofuran(THF) solvent, Copper acetylides reacts to unsaturated carbonyl that is in s-trans conformer and gives excellent yields.•The reaction is given below:

•Substrate:copper compound:TMSI=1:1:1.5, TMSI is taken in slight excess.•The reaction conditions varies depending on the substrates and usually the reactions of this type are performed below 273K temperatures.•This type of conjugate addition is of great synthetic use since the “C-C” bond making is the central view of an organic chemist.

J. Org. Chem. 1997, 62, 182

O

+ R C C CuTMSI, LiI

THF, -700C

OSiMe3

CC

RTMSI = SiMe3I THF =

O

CyclohexeoneBeta-acetylide enol of TMS

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Substrates, Reagents and Solvents• Substrates: Eligible substrates for this reaction are the ones having s-trans conformation and the examples are given below, s-cis

conformers give poor yield.

• Reagents: Copper acetylides along with Lithium Iodide, RC≡CCu-LiI are used. Usually the “R” group is -C3H7, -Ph, -SiMe3 etc. This reagent is used along with TMSI.

• Solvents: It is observed that the most efficient solvent for particularly this reaction is tetrahydrofuran(THF). Other solvents that can be used are Et2O, CH2Cl2, but the yield is poor with these solvents.

J. Org. Chem. 1997, 62, 182

O

Cyclohexenone Cyclopentenone

O O

OR

Beta-alkoxy alpha-enones

O

H

Alpha,beta-unsat. aldehydes

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Preparation of Copper Acetylides• Treatment of an acetylene with butyllithium followed by copper(I) iodide, gives copper acetylide and lithium

iodide in THF medium.

• When R=-SiMe3, gives acetylides as solutions in THF.

• But when R= -C3H7, -Ph, formed acetylide gives suspension in THF.

• This preparation is carried out at a temperature 243K.

J. Org. Chem. 1997, 62, 182

R C C HBuLi

R C C Li + CuI R C C

BuH

Cu

LiI

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Plausible MechanismThe suggested mechanism is as follows:• Formation of a ᴨ-complex between the Cu and the enone followed by the lewis acid-base interaction

between Oxygen-Silicon. Iodine acts as Bridging ligand between Silicon and Copper.

• Next step is the formation of 6-membered chelate ring as shown in the above mechanism and here Si-O bond is partially formed and Si-I bond is partly broken and the Cu adds to the alpha position and the acetylide adds to the Beta position.

• Solvents like THF acts as lewis base and stabilises the Cu(I) by complexing.• After that “CuIL” eliminates and enol of TMS is formed.

J. Org. Chem. 1997, 62, 185

OSi

I

CuL

R

L = Solvent molecule

O

Cu

R

Si

L

I OSiMe3

R

+ CuIL

Stable chelation

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Evidence in favour of Mechanism• In contrast to alkylcopper reagents, there is often a distinct change when TMSI is added to the alkynyl

reagents; for example, [(trimethylsilyl)ethynyl]-copper(I) goes from a greenish-yellow solution to a lightgreen suspension.

• This indicates the formation of a complex between the organocopper compound and TMSI.

• On adding 2-cyclohexenone to RC≡CCu-LiI-TMSI preparations, at 195K , we sometimes observe a coclour change to yellow.

• This proves the formation of a ᴨ-complex of substrate with the copper acetylide and supports the mechanism.

• Moreover, after hydrolysis the product is isolated which confirms the predicted path.J. Org. Chem., Vol. 62, No. 1, 1997 185

Me3Si Cu + TMSI Light Green

O

THF, -780CYellow

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How to isolate TMS Enol ether?• When the reaction is complete, dry Et3N is added at low temperature (ca. 3 mol equiv

versus TMSI) instead of NH4Cl.

• The reaction mixture is stirred at room temperature for 1 h and then diluted with Et2O or pentane.

• The organic layer is washed once with saturated NaHCO3 and once with brine and dried over Na2SO4.

• Evaporation of the solvent gives the crude product, generally as a slightly brown-yellow oil.

J. Org. Chem., Vol. 62, No. 1, 1997 185SAIBALENDU SARKAR

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Why enol of TMS?

• Though both Si- and Li- are likely to make a bond with oxygen, but preferentially the O-Si bond is formed instead of O-Li.

• The reason is simply the high bond energy of O-Si (798kJ/mol) compared to O-Li (341kJ/mol), thus O-Si bond formation releases more energy than O-Li bond formation.

labs.chem.ucsb.edu/zakairan/armen/11---bonddissociationenergy

RR

O OSiMe3 Li

WHY THIS? WHY NOT THIS?

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ResultsScheme 1

REACTION OF CYCLOALKENONES (SUBSTITUTED) :

J. Org. Chem., Vol. 62, No. 1, 1997 183

(CH2)n

1)RC Cu.LiI TMSI-300C, 30 min., THF

2)Et3N

O

(CH2)n

OTMS

CC

R

H30+

(CH2)n CC

R

O

1.n=12.n=0

R=C3H7R=SiMe3

89%78%

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Results Scheme 2

REACTION OF CHROMONE :

J. Org. Chem., Vol. 62, No. 1, 1997 183

O

O

1)RC CCu-LiI,TMSI

-300C, 70min, THF2)NH4Cl then HCl O

O

RR=SiMe3 98%R=t-Bu 90%

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ResultsScheme 3This scheme is a suitable pathway for preparing beta-acetylide substituted enones which can further react.

REACTION OF ACYCLIC ENONES (SUBSTITUTED) :

J. Org. Chem., Vol. 62, No. 1, 1997 183

OMe

O

1)RC CCu-LiI,TMSI

-400C, 4Hr., THF

OTMS

MeO

R

H3O+

O

R

R=Ph 88% trans:cis=96:4R=SiMe3 78% trans:cis=97:3

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ResultsTable 1. Conjugate Addition of RC≡CCu(LiI)-TMSI to 2-Cyclohexenone (1), 2-Cyclopentenone (2), 2-Methyl-2-

cyclopentenone (3).

J.Org. Chem., Vol. 62, No. 1, 1997, 183

Entry Enone R Solvent Temp(K),Time Yield(%)

1 1 C3H7 THF 243,30 min 89

2 1 C3H7 Et2O 243,30 min 32

3 1 C3H7 CH2CL2 243,30 min 33

4 2 C3H7 THF 243,30 min 68

5 2 Ph THF 243,1 h 75

6 3 C3H7 THF 223,4 h 45

7 3 BnO(CH2)3 THF 223,4 h 54

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ResultsTable 2. The Influence of Different Additives. Conjugate Addition of RC≡CCu(LiI)-X in THF to 2-

Cyclohexenone (1), 2-Cyclopentenone (2).

J.Org. Chem., Vol. 62, No. 1, 1997, 184

Entry Enone R X Temp(K),Time Yields(%)

1 1 C3H7 TMSI 243,30 min 89

2 1 C3H7 TMSBr 243,30 min <2

3 1 C3H7 TMSCl 243,30 min 0

4 2 Ph TMSI 243,1 h 75

5 2 Ph BF3 233,2 h 0

6 2 C3H7 TMSOTf 243,30 min 25

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Discussion about the Results

• The highest amount of yield is obatined only using TMSI. This is because of the better polarisability of Iodine which helps in forming the ᴨ-complex.

• THF as a solvent is most useful in the reaction and gives upto 98% yield. Other solvents like Et2O, CH2CL2 can be used but inefficient.

• s-trans enones are far more reactive than s-cis ones.

• Possibly the reason is the difficulty in the formation of chelate complex.

• It is believed that THF is used to co-ordinate with the Li+ ion, while the Iodide ion from LiI helps copper in complexation and makes coordination of TMSI to Carbonyl Oxygen easier.

J. Org. Chem., Vol. 62, No. 1, 1997 183

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OCu

SiI Chelate complex formation forbidden

s-cis conformation

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Enones which are sterically hindered are less reactive

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O

RC CCu-LiI-TMSI

-500C,4 hSlow

Me3SiO

R

45%

Crowded centre for complexation Poor Yield

Reaction of 2-methyl-2-cyclopentenone

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Consequence of reaction with hindered Enone

The Solvolysis of TMSI occurs when a hindered enone is used.

J. Org. Chem., Vol. 62, No. 1, 1997 183

OSiMe3 i

O+

SiMe3

I-

OSiMe3

I

1-Iodo-4[(trimethylsilyl)oxy]butane

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Why Only Copper Acetylide?• Other organoetallics can be used in place of Copper acetylides, e.g. Organoaluminium, Organoborane.• But the results are not what is expected. Instead aluminium acetylides gives 1,2-addition for s-trans conformer and

1,4-addition to only s-cis conformers.

AlEt2

I. Siletanylmethylithium, an ambiphilic Siletane, By Mariya V. Kozytska

Et2Al C C R (Alkynyldiethylalanes)

O

s-cis

Et2Al C C RO

CCR

1,4-Addition

O

Et2Al C C R

O

AlEt2

CCR

1,2-Addition

s-trans

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Isolation and Confirmation of product

Obtained as colourless oil after flash chromatography:

• 1H NMR Data:δ 2.82-2.92 (m, 1H), 1.42-2.58 (m, 12H), 0.90 (t, J )

7.0, 3H)• 13C NMR Data:δ209.7, 82.8, 81.4,47.6, 41.3, 31.3, 30.3, 24.0, 22.4,

20.7, 13.5• IR Data(neat):2254 (C≡C), 1715 (C=O) cm-1• HRMS Data:Calculated for C11H160 and exact mass found to be

164.120 amu.

The compound is : 3-(1-Pentynyl)cyclohexanone

J. Org. Chem., Vol. 62, No. 1, 1997 186

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O

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Synthetic Application• The synthetic application of the reaction of the preparation of Hormothamnione, which is used as an

exceptionally potent cytotoxin to cancer cells and appears to be a selective inhibitor of RNA synthesis.

• This scheme is so special because of the use of Green Chemistry in the second step of reduction.

Tetrahedron Letters.Volume 27, Issue 18, 1986, Pages 1979–1982

H3CO

H3CO

OR

OCH3

O

O

CH3

OCH3

1)R1C CCu-LiI,TMSI

-780C,THF2)H3O+

H3CO

H3CO

OR

OCH3

O

O

CH3

R11,4-addition of copper acetylide

H3CO

H3CO

OR

OCH3

O

O

CH3

R1

HORMOTHAMNIONE

*R=H,COCH3

*R1=

OR

OR

Na2S.9H20 (Green Water)THF,1400C,10hr

Green Chemistry

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References

• Kim, S.; Park, J. H.; Jon, S. Y. Bull. Korean Chem. Soc. 1995, 16, 783.• Eriksson, M.; Hjelmencrantz, A.; Nilsson, M.; Olsson, T. Tetrahedron

1995, 51, 12631• Nilsson, K.; Ullenius, C. Tetrahedron 1994, 50, 13173.• Chuit, C.; Foulon, J. P.; Normant, J. F. Tetrahedron, 1980, 36, 2305. • Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron

1989, 45, 349.• Vellekoop, A. S.; Smith, R. A. J. J. Am. Chem. Soc. 1994, 116, 2902.• House, H. O.; Wilkins, J. M. J. Org. Chem. 1978, 43, 2443.• Berlan, J.; Battioni, J. P.; Koosha, K. Bull. Soc. Chim. Fr. 1979,• 183.SAIBALENDU SARKAR

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THANK YOU VERY MUCH

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