MicrowaveMicrowaveMicrowave---promoted synthesis in waterpromoted synthesis in waterpromoted synthesis in water

Nicholas E. Leadbeater

nicholas.leadbeater@uconn.edu

Outline of what we do

Synthesis / Methodology / New techniques

Pure organic synthesiseg. Baylis-Hillman Reaction

Organometallic and inorganic chemistryfocused towards organic synthesis

Pure organometallic synthesiseg. Making organometallic polymersand other functional materials

• Growing interest in microwave synthesisMany papers and reviews coming out in 2002, 2003 and now 2004

• Enhanced reaction times and product yieldsMinutes instead of hours

• New avenues for chemistryUsing microwaves, chemists are finding that they can do new chemistry

Microwave-promoted synthesis

Microwave reactions using aryl halides

• Aryl halides are widely used to form new carbon-carbonand carbon-heteroatom bonds

• Also useful in nucleophilic displacement reactions

• I and Br substituted aryl halides are most reactive, howeverCl analogues are cheaper and more readily available

Halogen exchange reactions in aryl halides

DMFCl Br+

µw, x min, y °C

Optimum microwave power = 100 W

Optimum quantity of NiBr2 = 2 equiv.Best solvent = DMFOptimum volume = 0.5 mL

Use of 1 equiv has the effect of lowering product yield considerably

Optimum temperature = 170 °C

Lower temperature means longer reaction timeand lower product yields

Optimum reaction time = 5 min

Shorter times mean starting material remains

44 % isolated yieldNiBr2

Halogen exchange reactions in aryl halides

• Methodology is suitable for a range of halide exchanges

Br

MeO

Br

NiBr2Cl

R

Br

R

NiBr2I

R

Br

R

Cl

Cl

COMe

Cl

OMe

Cl

CHO

44

43

45

41

I

I

COMe

I

OMe

I

NO2

72

70

68

72

NiCl2Br

R

Cl

R

Br

Br

COMe

Br

OMe

94

99

99

NiCl2I

R

Cl

R

I

I

COMe

I

OMe

I

CO2H

92

97

95

94

99

94

yield (%) yield (%) yield (%) yield (%)

Latest developments

Tetrabutylammonium halides can be used as halogen sources

+µw, DMF

ITBAB

O

10 mol % NiBr2 Br

O

72% yield

+µw, DMF

ClTBACl

O

10 mol % NiBr2 Cl

O

50% yield

Cyanation of aryl halides

• Aryl nitriles are valuable intermediates in organic chemistry

Form integral parts of of dyes, herbicides, natural productsand pharmaceuticals

• Many methodologies have been developed over the years

Most direct and versatile method found so far is transition-metalcatalyzed cyanation of aryl halides

Microwave promotion has been used as a tool for the Pd-mediatedcyanation of aryl bromides (J. Org. Chem. 2000, 65, 7984)

Cyanation of aryl halides

• Use of nickel cyanide

We have developed a fast, easy methodology using nickel cyanideas a reagent

R. K. Arvela and N. E. Leadbeater, J. Org. Chem., 2003, 68, 9122

X CNR R

X = Cl, Br, I

Ni(CN)2or

NiBr2 + NaCN

Cyanation of aryl halides

NMPBr CN+

µw, x min, y °C

Optimum microwave power = 100 W

Optimum quantity of Ni(CN)2 = 0.6 equiv.Best solvent = NMPOptimum volume = 1 mL

Use of 0.5 equiv has the effect of lowering product yield considerably

Optimum temperature = 200 °C

Lower temperature means longer reaction timeand lower product yields

Optimum reaction time = 10 min

Shorter times mean starting material remains

99 % isolated yieldNi(CN)2

Cyanation of aryl halides

• Using Ni(CN)2

Conditions suitable for a wide range of substrates

Br NO2

Br

COMe

BrBr

Br Br

MeO

Br

OMe

Br

CO2H

Br

CHO

Br

NH2

99 48 9899

99 86

99

33 6096 95

86

N Br S Br

+BrR

CNR

µw

NMPISOLATED YIELDS (%)Ni(CN)2

Cyanation of aryl halides

• Using NiBr2 and NaCN

Form Ni(CN)2 in-situ

Can effect a tandem halide exchange / cyanation of aryl chlorides

+Br CNµw

NMPNiBr2 + NaCN 93% yield

+ClR

CNR

µw

NMPISOLATED YIELDS (%)NiBr2 + NaCN

Cl CO2H

Cl

COMe

ClCl Cl

OMe

Cl

OH

80 99 9985 78 61 24

N Cl

Water as a solvent for microwave chemistry

• In principle, water is a good solvent for use in synthesis

CheapReadily availableNon-toxic Non-flammableSuitable for scale-upMicrowaves interact well with it

• There are however problems

Solubility of reagents and catalystsUnwanted side reactions

The Suzuki reaction• Suzuki couplings are used on a small and multi-ton scale and

are big business

• Millions of $ / £ / € spent every year on Pd catalysts and rangesof ligands for performing this reaction

• Biaryl units are found in:

Pharmaceuticals

Herbicides

Conducting materials

Liquid crystals

Water as a solvent for the Suzuki reaction

• Water has been used as a solvent with ‘ligandless’palladium catalysts

One of the first examples was with water-soluble aryl iodides(Tetrahedron 1997, 53, 14437)

B(OH)2

R = OH, COOH

+IPdCl2, Na2CO3

H2OR R

Water as a solvent for the Suzuki reaction

• Tetrabutylammonium bromide (TBAB) has been used as anadditive for couplings in water using conventional heating(J. Org. Chem., 1997, 62, 7170)

Acts as a phase-transfer agent to aid substrate solubilityActivates boronic acid to reaction

Pd(OAc)2, Na2CO3, TBAB

H2OB(OH)2+Br

R R

Generally, activated aryl bromides used

Water as a solvent for the Suzuki reaction

• Microwaves have been used for Suzuki couplings

Using water / organic solvent mixtures (J. Org. Chem., 1996, 61, 9582)

Using water soluble aryl iodides (J. Org. Chem., 1999, 64, 3885)

B(OH)2

R = COOMe or PEG-based polymer support

+IR

Rxn time = 2 - 5 minRPd(OAc)2, Na2CO3

H2O or PEG

µw

B(OH)2+IPd(PPh3)4, µw

EtOH, DMF, H2O

Rxn time with microwave = 3.6 minProduct yield = 55%

Rxn time conventionally = 6 hProduct yield = 88%

Water as a solvent for the Suzuki reaction

• We wanted to couple the advantages of microwaves andTBAB

Can we form biaryls rapidly in neat water and activate aryl iodides,bromide and chlorides?

B(OH)2

X = Cl, Br, I

+XR R

µw

Pd(OAc)2, Na2CO3TBAB, H2O

N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973

Water as a solvent for the Suzuki reaction

• Conditions suitable for a wide range of substrates

Br NO2

Br

COMe

Br

Br Br Br

Br

OMe

Br

CHO

Br

CO2Me

Br

OH

I Cl

Cl Cl

OMe

Br

COOH

I

OH

I

COOH

84 92 6879 91 73

91 86 8391 8790

80 89 87 45 62 50

MeO Br

B(OH)2+XR R

µw

Pd(OAc)2, Na2CO3TBAB, H2O

ISOLATED YIELDS (%)

Using water as a solvent in other reactions

• Sonogashira coupling reactions

Like the Suzuki reaction, the Sonogashira coupling finds used in arange of applications

Usually a catalyst mixture of a Pd complex and CuI is used

X = Cl, Br, I

+Catalyst

BaseX R H R

Sonogashira coupling reactions

• We have developed a rapid, copper-free methodology

PdCl2(PPh3)2, baseTBAB, H2O

Br +µw, x min, y °C

Optimum microwave power = 60 W

Optimum catalyst loading = 4 mol %

Optimum quantity of TBAB = 1 equiv.

Optimum volume of water = 2 mL

Best base = piperidine

Temperature = 140-150 °C

Reaction time = 5 min or shorter

99 % isolated yield

H

Sonogashira coupling reactions

• Reaction times are very fast with a range of substratesReaction needs only 20 sec microwave irradiation

Conventional heating can be used with reactions taking 5 min

Good yields of product are obtained with aryl bromides

Aryl iodides give slightly lower yields (like Suzuki couplings)

OMeO

Br

99%

99%

99%

BrBr

Br

94%

92%

93%

61%

-

62%

90%

88%

77%

µw, 60W, 5 min then 5 min cool

µw, 60W, 20 sec then 5 min cool

oil bath, 140°C, 5 min then 5 min cool

Sonogashira coupling reactions

• Not the first methodology using water but the fastest, most versatile and easiest

• Not the first copper free methodology

PPh2O N

H

O

PdCl

Heterocycles 2003, 59, 71

Tetrahedron Lett., 1997, 38, 7843

P

SO3

SO3O3Sn

J. Org. Chem., 1995, 60, 6829

Tetrahedron Lett., 1998, 39, 525

-

--

PdN

C6H4-p-Cl

OH

ClCl2

NNBu+ PF6

-

Tetrahedron Lett., 2002, 43, 9365 Org. Lett., 2002, 4, 1691

New Suzuki-type couplings

• Whilst probing the microwave-promoted coupling protocol we have found that it is possible to perform Suzuki-typecouplings

without the need for addition of atransition-metal catalyst

No catalyst added Suzuki couplings

B(OH)2+XR R

µw

Na2CO3TBAB, H2O

N. E. Leadbeater and M. Marco, Angew. Chem. Int. Ed., 2003, 42, 1407

Latest developments

Vinylboronic acids can be used in the no added catalyst protocol

+Brµw, H2OB(OH)2

R R

+Brµw, H2O

B(OH)2

R

Latest developments

Vinylboronic acids can be used in the no catalyst added protocol

+µw, H2OB(OH)2

R

Br

R

Scaling in the Initiator

Synthesis of losartan• Anti-hypertensive drug also known as ‘Cozaar’

Nonpeptide angiotensin II receptor antagonist

A number of syntheses have been patented and published(eg: J. Med. Chem. 1994, 37, 542; J. Org. Chem., 1994, 59, 6391)

NNH

NN

NN

Cl

OH

Synthesis of losartan• Develop a rapid synthesis with scope for diversity

Bring together several microwave steps

NNH

NN

NN

Cl

OH

NNH

NN

NN

Cl

OH

NN

Cl

OH

B(OH)2N

NHN

NBr

NNH

NN

Br

NN

Cl

OH

B(OH)2

NN

Cl

OH

HBr

B(OH)2

Br CNNaN3

Br CNBr ICuCN

Br II INiBr2

NaN3

CuCN

Synthesis of losartan• Putting the synthesis together

(HO)2B

Br

NN

Cl OH

H B(OH)2

NN

Cl

OH

1

BrI µw

CuCN, TBAB,H2O

BrCN µw

NaN3, ZnBr2,H2O

Br

NNH

NN

µw, 1N

NHN

N

NN

Cl

OH

Losartan

DMA

Pd(OAc)2TBAB, Na2CO3, H2O

Acknowledgements

I acknowledge the hard work and dedication of the students who have been involved in the work presented here:Riina ArvelaEmilie JoliboisMaria Marco Sharon PillsworthErik ShanahanBonnie TominackVicki Willams

I thank Hoffmann La Roche, EvotecOAI and CEM Microwave Technology for financial support of our work