Ligand-, Copper-, and Amine-Free Sonogashira Reaction of Aryl Iodides and Bromides with Terminal Alkynes

Claire Coleman Current Lit. July 24 2004

Sameer Urgaonkar and John G. Verkade Department of Chemistry, Gilman Hall, Iowa State University

Pd(OAc)2 or Pd2(dba)3 1 X + R1 R R R No ligand No Copper X = I, Br No Amine

room temperature

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The Sonogashira Coupling

L2PdX2 1 R H + R1 X R R CuI/base (amine)

Overall elimination of HX. Occurs via organocuprates:

amine base CuI + R H R CuI

Sonogashira et al, Tett. Lett 1975, 4467. clairecoleman@wipfgroup 3 Uses of the Sonogashira Coupling

Extensively used in organic synthesis

Liquid Crystalline materials

Conducting Polymers

Natural Product Synthesis

clairecoleman@wipfgroup The Sonogashia Reaction is often the key step in 4 Natural Product Synthesis

phytotoxin

Anti-mitotic

J. Org. Chem, 1997, 62, 1582. clairecoleman@wipfgroup 5

The Catalytic Cycle

R1 H

CuI/NEt3 NEt3.HCl L 1 1 L2PdX2 R Pd R L

R1 R1

L2Pd(0) R X

R PdL2 Sonogashira

R1 R PdL2 X

R1 H NEt3.HCl CuI/NEt3 clairecoleman@wipfgroup 6

The Catalytic Cycle

CuI/NEt3 R1 H Cu R1 Pd(0)

Ar L Pd R1 Ar R1 Ar Pd(0) L Ar X L Pd X reductive elimination oxidative insertion L

clairecoleman@wipfgroup 7 Problem-Side Reaction

In the presence of Cu(I) cocatalyst------Glaser type oxidative dimerisation of the alkyne

2 H

2 CuCl, NH4OH EtOH

2 Cu

NH4OH EtOH

To address this several reports described Copper free Sonogashira Couplings

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Ideally a ligandless, copperless and amine free process would improve Sonogashira couplings by

Cheaper: Avoid the use of expensive and sensitive ligands

Enviromentally Friendly: No disposal of large quantities of amines for industrial purposes

Higher Yields: Avoid Glasier dimerisations

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Coupling of Enol Triflates with Terminal Alkynes under Copper Free conditions

[C6H5)3P]2Pd(OAc)2/DMF

R1 OTf + R2 H R1 R2 NaOAc, 60 oC, 1h

71 % yield C2H5OOC

Using phosphine ligated palladium precursor 2 examples that were copper and amine free

clairecoleman@wipfgroup Cacci et al Synthesis, 1986, 320. 10

Phosphine and Copper Free Sonogashira Coupling

Coupling of a vinyl iodide and terminal alkyne 1 example

n-C5H11 PdCl2(PhCN)2 (CH2)2OH + n-C H (CH2)2OH 5 11 I pyrrolidine, rt, 22 h 57%

But still required amine

clairecoleman@wipfgroup Linstrumelle et al, Tett Lett, 1993, 6403 Copper free, Palladium catalysed Sonogashira reaction of 11 aryl bromides with terminal alkynes at rt.

No CuI as cocatalyst employing Et3N as solvent

C6H5 C(O)CH3 (H3C)3Si Si(CH3)3

0.5 mol-%palladium and 99% 100 % TON 200 TON 200 ligand triethylamine as base 1.5 eqv. Et3N, THF as solvent

C H C(O)CH3 6 5 (H3C)3Si Si(CH3)3

79% 99% Air sensitive and pyrophoric TON 158 TON 198

P(t-Bu)3 C6H5 OCH3 C6H5 F

42% 71% TON 84 Herrmann, Eur. J. Org. Chem., 2000, 3679 TON 142 clairecoleman@wipfgroup 12 Copper free Sonogashira Coupling Of aryl iodides in Ionic Liquids

Extracted products with hexane from catalyst Washed ionic layer with water to remove Ammonium salts Ionic liquid with Pd catalyst could be reused

clairecoleman@wipfgroup Ryu, Org. Lett, 2002, 1691. 13 Copper free Sonogashira Couplings of aryl iodides and activated aryl bromides

Aryl halide Alkyne Product Yield % Using Pd(PPh )Cl OMe 2 2 91 I 0.5 to 4 mol%

CO2Me 93 Piperidine as base

Aryl halide Alkyne Product Yield %

0 OMe C4H9 96 I I

COMe 94 COCl Br 99 Br

NO2 90 CO Me 2 99 Br Me3Si I Leadbeater, Tett Lett, 2003, 8653 clairecoleman@wipfgroup 14

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Copper free Palladium catalyst for reaction with aryl halides

Astruc, Chem Comm, 2003, 1934 clairecoleman@wipfgroup Have to synthesise the ligand, 16 but works with some aryl chlorides

clairecoleman@wipfgroup 17 Coupling of aryl Chlorides and Aryl tsoylates with terminal alkynes using a bulky phosphine ligand under copper and amine free conditions

PCy2 i Pr Pr i

1 Pr i

Buchwald, Angewandte, Int. Ed., 2003, 42, 5993. clairecoleman@wipfgroup 18 Coupling of aryl Chlorides and Aryl tsoylates with terminal alkynes using a bulky phosphine ligand under copper and amine free conditions

PCy2 i Pr Pr i

1 Pr i

89% 79% 93%

93% 88% 93%

94% 77% clairecoleman@wipfgroup84% 19 First report of Sonogashira couplings of aryl tsoylates

ArOTs PRODUCT 73%

62%

78%

clairecoleman@wipfgroup Buchwald, Angewandte, Int. Ed., 2003, 42, 5993. 20 First report of a ligand, copper and amine free Sonogashira coupling at rt

Employing Pd(Oac)2 or Pd2(dba)3 as catalyst

Tetrabutylammonium acetate as the base

For reaction of aryl iodides and bromides with terminal alkynes

Pd(OAc)2 or Pd2(dba)3 1 X + R1 R R R No ligand No Copper X = I, Br No Amine

room temperature

clairecoleman@wipfgroup 21 Initial goal--finding a suitable base

Base Yield % 93, 6h Bu4NOAc Cs2CO3 69

Et3N 5 DBU 8 piperidine 5

Na2CO3 30 DMF was the optimum solvent clairecoleman@wipfgroup 22

Using phenylacetylene

b = 1 mol% Pd(OAc)2 [3 mol%]

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Series of aliphatic Terminal alkynes

Isolated yields (average of two runs). c 1 mol % of Pd(OAc)2 was employed. d Parenthesized yields were obtained with 3 mol % of Pd(OAc)2. e Pd2(dba)3 was used in place of Pd(OAc)2.

clairecoleman@wipfgroup 24 a Isolated yields (average of two runs).

Aryl bromides

Electron rich were sluggish

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The choice of tetrabutylammonium acetate as the base is important

Authors unsure of its role but suggest

It removes the most acidic hydrogen in the alkyne

May facilitate reduction of Pd(Oac)2 to a catalytically active Pd(0) species

Stabilises the oxidative addition adduct ArPd(II)X (12 e- unstable complex)

2- + - [ArPd(II)X3] 2Bu4N (16 e )

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Conclusion

The first Ligand, Copper and Amine free Sonogashira coupling was described

Future benefits Useful for key steps in natural product synthesis Enviromentally useful for industry

clairecoleman@wipfgroup