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Transcript of Castro-Stephens
Requirements and limitations
C.E. Castro and R.D. Stephens
1963 Univeristy of California Riverside
Studied metal-promoted reductions of alkynes / heterocyclic formation from substituted biaryl acetylenes
Certain precursors from reacting aryl iodides and copper acetylides in pyridine.
Coupled biaryl acetylenes cyclizing with
Specific mechanism of classical castro-stephens
General Mechanism of alkynylative couplings
Overview of general mechanism
- Pd reacts w/ aryl or vinyl halide
- Cu acetylide reacts w/ Pd intermediate
- organo Pd reacts to give disubstituted alkyne + Pd catalyst
Overview of specific mechanism
Cu acetylide reacts with halide, forms Cuprate
Cuprate undergoes structural changes
product formed via coupling of carbon ligands + by-product
Additional mechanism information
Cu and Pd cross coupling similar
Cu acetylide mechanisms uncertain:
- fluidity/ complexity of Cu
Cu has 4 stable oxidation states:
- allows diff transition structures
mostly in pharmaceutical synthesis/compounds used in drug synthesis
related to other reactions:
Requirements and Limitations
Oxygen must be excluded:
- avoid homocoupling of alkynes
Creating Cu acetylide sensative to oxygen = time consuming:
- rinsing/ flitering
- 24 + hours
Cu acetylides = highly explosive
Poor coupling of Cu acetylides w/:
- electron withdrawing groups
- epoxides, quinone groups
Advantages and advancements
proceeds best under partial heterogenous conditions
pKa of acetylinc proton doesn't exert infl. on reaction outcome
removal of pre-generated, oxygen sensative acetylide
1993 Miura research:
- catalytic version
- didn't require pre-formed acetylide
Requirements and Limitations
narrow range of coupling partners:
- simple, robust molecules
- able to withstand Cu salt solutions for long periods
narrow range of solvents:
- DMF/ pyridines at high temps = successful
- Cu acetylides = insoluble polymeric species
no regio/ stereroselectivity complications
potential olefin scrambling:
- use of vinyl halides w/ defined geometry
- rare cases w/ olefin isomerization
olefin scrambling = alkene fragments migrate through regeneration/ scission of C=C.
Requires stoichiometric copper
Generates copper(I) salt as by-product
pre-generated copper acteylides:
- CuCl + terminal acetylene + ammonia
vinyl/ aryl reactivities:
- vinyl = I > Br > Cl
- alkyl = I > Br > Cl >> F
more reactive halide = more reactive cross coupling
1) oxidative addition
3) reductive elimination
prevent cancer cells from dividing:
- interfere w/ tubulin
J.D. White used modified Castro-Stephens instead of Witting:
- avoid basic conditions
Oximidine i and II
Oximidine I and II
anti-cancer studies agent
R.S Coleman work w/ 12 member diene/ triene lactones
- seen in Oximidine I and II
component in anti-inflammatory medication Rofecoxib, or Vioxx.
(1) (2) (3)
(1) (2) (3)
(1) Aryl/Vinyl halide
(2) Copper Acetylide
(3) Disubstituted Alkyne
diarylacetylene reacted to create Rofecoxib
p-iodophenyl sulfone reacts w/ copper (I) phenyl acetylene
product = diarylacetylene
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8. Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.; McDonald, I. A.; A Practical and Efficient Synthesis of the Selective Neuronal Acetylcholine-Gated Ion Channel Agonist (S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y). J. Org. Chem. 1998, 63, 1109–1118.
9. Li, J.; Anti-inflammatory Cyclooxygenase-2 Selective Inhibiters. Contemporary Drug Synthesis. Wiley-Interscience: Hoboken, NJ, 2004; pp 16-18
10. Eisch, J.J.; Hordis, C.K., J. Am. Chem. Soc. 1971, 93, 2971-2981
11. New Scientist Health. http://www.newscientist.com/article/dn6918-up-to-140000-heart-attacks-linked-to-vioxx.html#.UzDBV_ldXfd. (March 2014).
12. László, K.; Czakó, B.; Strategic applications of named reactions in organic synthesis: background and detailed mechanisms. Elsevier Academic: Burlington, MA, 2005; pp 78-79
13. Schneider, C.M.; Khownium, K.; Li, W.; Spletstoser, J.T.; Haack, T.; Georg, G.I. Synthesis of Oximidine II Via a Cu-Mediated Reductive Ene-Yne Macrocyclization. Angew Chem Int Ed Engl.2011, 50, 7855-7857.
14. Ojima, I.; Vite, G.D.; Altmann, K.H.; Anticancer Agents: Frontiers in Cancer Chemotherapy. Am. Chem. Soc. 2001
15. Agency for Toxic Substances and Disease Registry 1996. "Polycyclic Aromatic Hydrocarbons (PAHs)" (April 2014)
16. Fetzer, J. C.; The Chemistry and Analysis of the Large Polycyclic Aromatic Hydrocarbons. Polycyclic Aromatic Compounds . Wiley: New York, 2000; pp 143.
17. Meijere, A. D.; Additional Reductive Coupling Reactions for the synthesis of PAHs. Carbon Rich Compounds I. Berlin:Springer, 1998; pp 62-63
by Stephanie Perko