Loading presentation...

Present Remotely

Send the link below via email or IM


Present to your audience

Start 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.



No description

on 8 May 2014

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of Castro-Stephens


a. general
b. specific


Stereochemical control

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
-nitrogen atoms
General Definition
Specific mechanism of classical castro-stephens
General Mechanism of alkynylative couplings
Overview of general mechanism
oxidative addition:
- Pd reacts w/ aryl or vinyl halide

- Cu acetylide reacts w/ Pd intermediate

reductive elimination:
- 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
Castro-Stephens Today
limited usage

mostly in pharmaceutical synthesis/compounds used in drug synthesis

related to other reactions:
- Sonogashira
- Heck
- Cadiot-Chodkiewicz
The end
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

Stereochemical control
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
-cuprous iodide/halide

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

2) transmettallation

3) reductive elimination
Epothilone B
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
intramolecular Castro-Stephens

anti-cancer studies agent

R.S Coleman work w/ 12 member diene/ triene lactones
- seen in Oximidine I and II
Rofecoxib (Vioxx)
step 1
component in anti-inflammatory medication Rofecoxib, or Vioxx.

(1) (2) (3)
(1) (2) (3)
(1) Aryl/Vinyl halide
(2) Copper Acetylide
(3) Disubstituted Alkyne
Rofecoxib (Vioxx)
step 2
diarylacetylene reacted to create Rofecoxib
p-iodophenyl sulfone reacts w/ copper (I) phenyl acetylene
product = diarylacetylene
Epothilone B
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
Full transcript