TMSI promoted 1,4-addition of Copper acetylides to unsaturated aldehydes and ketones.This ppt is totally based on a paper published in Journal of American Chemical Society. The ppt is more about the analysis of the paper
1,4- Addition of copper acetylides to unsaturated ketones
1. Iodotrimethylsilane-Promoted 1,4-Addition of Copper Acetylides
to alpha,beta-Unsaturated Ketones and Aldehydes
Credits: Magnus Eriksson, Tommy Iliefski, Martin Nilsson, and Thomas Olsson
Department of Organic Chemistry, Chalmers University of Technology, S-412 96 Goteborg, Sweden
Saibalendu sarkar
(cy16mscst11022)
Prof. Faizahmedkhan
J. Org. Chem. 1997, 62, 182-187
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2. 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
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3. 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
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4. 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.
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5. 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
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6. Plausible Mechanism
The 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
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7. 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
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8. 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.
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9. 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
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11. Results
Scheme 2
REACTION OF CHROMONE :
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12. Results
Scheme 3
This scheme is a suitable pathway for preparing beta-acetylide substituted enones which can further react.
REACTION OF ACYCLIC ENONES (SUBSTITUTED) :
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13. Results
Table 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
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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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14. Results
Table 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
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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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15. 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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16. Enones which are sterically hindered are less reactive
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17. Consequence of reaction with hindered Enone
The Solvolysis of TMSI occurs when a hindered enone is used.
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18. 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
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19. Isolation and Confirmation of product
Obtained as colourless oil after flash
chromatography:
• 1
H NMR Data:
δ 2.82-2.92 (m, 1H), 1.42-2.58 (m, 12H), 0.90 (t,
J ) 7.0, 3H)
• 13
C 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
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20. 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
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21. 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.
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