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Castro-Stephens

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on 8 May 2014

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Transcript of Castro-Stephens

Overview
History

Mechanism
a. general
b. specific

Characteristics

Stereochemical control

Requirements and limitations

Advantages

Advancements

Applications
Castro-Stephens
Coupling

History
C.E. Castro and R.D. Stephens

1963 Univeristy of California Riverside

Studied metal-promoted reductions of alkynes / heterocyclic formation from substituted biaryl acetylenes
Observations
Certain precursors from reacting aryl iodides and copper acetylides in pyridine.

Coupled biaryl acetylenes cyclizing with
ortho
-oxygen/
ortho
-nitrogen atoms
General Definition
Specific mechanism of classical castro-stephens
General Mechanism of alkynylative couplings
References
Overview of general mechanism
oxidative addition:
- Pd reacts w/ aryl or vinyl halide

transmetallation:
- 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.
Characteristics
Requires stoichiometric copper

Generates copper(I) salt as by-product
-cuprous iodide/halide

pre-generated copper acteylides:
- CuCl + terminal acetylene + ammonia
Characteristics
vinyl/ aryl reactivities:

- vinyl = I > Br > Cl

- alkyl = I > Br > Cl >> F

more reactive halide = more reactive cross coupling
Mechanism
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
Applications
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
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