Send the link below via email or IMCopy
Present to your audienceStart remote presentation
- Invited audience members will follow you as you navigate and present
- People invited to a presentation do not need a Prezi account
- This link expires 10 minutes after you close the presentation
- A maximum of 30 users can follow your presentation
- Learn more about this feature in our knowledge base article
Do you really want to delete this prezi?
Neither you, nor the coeditors you shared it with will be able to recover it again.
Make your likes visible on Facebook?
You can change this under Settings & Account at any time.
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
1. Li, J.; Castro-Stephens Reaction. In Name Reactions for Homologation; Corey, E.J.; John Wiley & Sons: New Jersey, 2009; Part 1, pp 212-221.
2. Mundy, B.; Ellerd, M.; Favaloro Jr., F. Name Reactions and Reagants in Organic Synthesis; John Wiley & Sons: New Jersey, 2005; pp 31, 136.
3. Organic Chemistry Portal. http://www.namereactions.org/castro-stephens-reaction/ (accessed, Feb 4, 2014).
4. Wang, Z.; Comprehensive Organic Name Reactions and Reagants; John Wiley & Sons: New Jersey,2009; Vol. 1, pp 619-622. For further information see: (a) Walker, W.H. and Rokita, S.E., J. Org. Chem., 2003, 68, 1563. (b) Kang, S-K.; Yoon, S.-K. and Kim, Y.-M., Org. Lett., 2001, 3, 2697.
5. Astruc, D.; The metathesis reactions: from a historical perspective to recent developments. New J. Chem. 2005, 29, 42-56.
6. Li, J.; Cosmeceuticals. Contemporary Drug Synthesis. Wiley-Interscience: Hoboken, NJ, 2004; pp 59-62.
7. King, A. O.; Yasuda, N. (2004), "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals Organometallics in Process Chemistry", Top. Organomet. Chem. 6: 205–245
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