Mg- and Zn-Mediated Synthesis of Heterocycles in Solution and on the Solid Phase

Episode von Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 01/06 von Ludwig-Maximilians-Universität München · 24. September 2000

This work has focussed on the preparation of functionalized heterocyclic organometallics. In

the first part, functionalized zinc derivatives were used due to their high functional group

tolerance. Thus various thymine derivatives have been prepared both in solution and on the

solid phase.

Alternatively, a new route to functionalized heterocyclic Grignard reagents was developed

using a low-temperature halogen-magnesium exchange. Ester, amide and nitrile functions are

tolerated and the resulting organomagnesium derivatives could be reacted with various

electrophiles.

Finally, we have attempted to perform low-temperature cross-coupling reactions using these

functionalized Grignard reagents.

5.1- Synthesis of thymine derivatives

Zincated thymine derivative 2 was prepared by zinc insertion from the corresponding bromide

4, readily available in four steps from uracil. Negishi cross-coupling reactions were then

performed using zinc reagent 2 and various aryl iodides.

N

N

O

O

Bn

Bn

4

Br HN

N

H

O

O

N

N

O

O

Bn

Bn

2

ZnBr

Ar - I

Pd(dba)2 (2.5 mol %)

N

N

O

O

tfp (5 mol %)

THF, 25 °C, 12 h

Bn

Bn

Ar

3a-j: 62-95 %

THF, 0 °C

Zn*

Scheme 67. Preparation of thymine derivatives 3a-j using a Negishi cross-coupling reaction.

Resin-attached aryl iodides were also suitable substrates and solid phase synthesis of thymine

derivatives could be performed with high HPLC-purities (89-93 %).

X

O I

N

N

O

O

Bn

Bn

X = O, NH

R

8 (10 equiv)

N

N

O

O

Pd(dba)2 (5 mol %)

tfp (10 mol %)

THF, 25 °C, 48 h

Bn

Bn

R = CO2H, CONH2

ZnBr

2) TFA

1)

89-93 % HPLC purity

Scheme 68. Solid phase synthesis of thymine derivatives.

5.2- Synthesis of functionalized heterocyclic derivatives using a low

temperature halogen-magnesium exchange

• Synthesis of pyridine derivatives

Functionalized pyridinyl Grignard reagents were prepared using a low temperature iodinemagnesium

exchange and trapped with electrophiles. Functional groups such as ester, amide

or nitrile functions are tolerated in this process.

N

I

FG 1) i-PrMgBr

-40 °C

2) E+ N

E

FG

50-92 %

FG = Br, CONR2, CN, CO2R etc.

Scheme 69. Preparation of functionalised pyridines using a low temperature iodine-magnesium

exchange.

The bromine-magnesium exchange is less general than the iodine magnesium-exchange and

electron withdrawing groups are often necessary to accelerate the exchange reaction.

However, 2-bromo and 3-bromopyridine were suitable substrates due to the π deficient

character of these heterocycles.

N

Br

1) i-PrMgBr

THF, rt, 6 h

2) E+ N

E

72-75 %

Scheme 70. Preparation of pyridine derivatives using a bromine-magnesium exchange.

• Synthesis of thiazole and thiophene derivatives

A low temperature bromine-magnesium exchange was then used in the synthesis of

functionalized thiazole and thiophene derivatives.

N S

Br

OEt

O Br

1) i-PrMgBr

THF, -78 °C

N S

Br

OEt

O E 2) E+

S Br Br

CO2Et

1) i-PrMgBr

-40 °C, 0.5 h

2)

S Br

CO2Et

1) i-PrMgBr

-40 °C, 0.5 h

2) E+ S E E

CO2Et

S Br

Br

EtO2C

1) i-PrMgBr

-40 °C, 0.5 h

2) E+ S E

Br

EtO2C

58-81 %

68-88 %

74 % 62-71 % Br

CuCN cat.

Scheme 71. Preparation of thiazole and thiophene derivatives using a bromine-magnesium exchange.

• Synthesis of dihydrobenzofurans and tetrahydrobenzazepines

An access to dihydrobenzofurans, benzolactams and tetrahydrobenzazepines was developed

using arylmagnesium reagents bearing an o-chloromethyl group.

Cl

MgBr

CO2Et

Br

83 %

CuCN 2 LiCl cat. .

Cl

CO2Et

RNH2

reflux, 24 h

K2CO3, THF N

CO2Et

R

Cl

I

1) i-PrMgBr (1.0 equiv)

THF -10 °C, 1.5 h

2) RCHO, -10 °C, 1 h

then reflux, 12 h

O

R

55-94 %

54-75 %

X = H, CO2Me

NPh

X

1) i-PrMgBr (1.0 equiv)

THF -10 °C, 1.5 h

2) PhN=C=O

O

X = H, 96 %

X = CO2Me, 75 %

Scheme 72. Preparation of dihydrobenzofurans and tetrahydrobenzazepines using a low temperature

iodine-magnesium exchange.

• Low-temperature halogen-magnesium exchange on the solid phase

The low-temperature halogen-magnesium exchange could also be performed on the solid

phase using an excess of i-PrMgBr and was applied to the synthesis of various thiophene

derivatives.

2) E+

1) i-PrMgBr (10 equiv)

THF, -40 °C

3) TFA

S

E

O

HO

S

O

O Br

83-99 % HPLC-purity

Scheme 73. Solid phase synthesis of thiophene derivatives using a low temperature brominemagnesium

exchange.

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