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

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.