THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 68

N N N

HexLi (1.3 equiv) ZnCl2, THF

-90 to 0°C

206

THF/pentane, -95°C

MeO MeO MeO

Br Li ZnCl

203 A B Pd(PPh 3 ) 4

(0.8 mol%)

DMF

By products

N N N

Br

Pd(Br)Ln

MeO MeO MeO

207 208

0-22°C
79%

N
O

C 6 H 13

N

N
O

N
O

202 C

N N

N
O

N

209

SCHEME 2.49 Large-scale synthesis of PDE472 202 : intermediates of the Negishi coupling.

on the unreacted bromoaryl derivative (Scheme 2.49).

As a consequence, a slight excess of hexyllithium (1.3 equiv) was necessary to
complete the lithiation step.
While the aryllithium species

203 to afford by-product 209

was not very stable for prolonged stirring
(120min) and at temperatures higher than

A

95 C, the organozinc species

B

was

slowly formed at those temperatures. This problemwas partially solved by adding at

95 C and then leaving the mixture to warm up to 0 C. With all these adjustments, it
was also possible to minimize the formation of by-product 208 . Hence, arylbromide
203

B

could be ortho -lithiated by hexyllithium, transmetalated by zinc, and coupled
with the arylpalladium complex . Moreover, it could also be involved in other

cross-coupling reactions with various arylzinc intermediate of type

C

B to afford

untreatable mixtures of polyaromatic by-products.
However, slow reaction rates and low yields were obtained for the sequential
addition of the palladium catalyst followed by the arylbromide derivative

,
probably because of the easy complexation of Pd(0) with 4-(4-methoxyphenyl)
pyridine moiety. This problem was solved by first forming in situ the arylpalladium
complex and then adding it to the solution containing organozinc species. All these
adjustments allowed to (1) increase the yield from 38% to 79%, (2) decrease the
quantity of palladium used from 8 mol% in laboratory-scale experiments to 0.8 mol%
in pilot scale, and (3) produce 4.5 kg of PDE472

206

202 , containing less than 0.5 ppm of

palladium after purification.

2.3.3. Reverse Transcriptase Inhibitor MIV-150
A stereospecific Negishi cross-coupling was applied for the large-scale (168 g)
preparation of a nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150
210

[102] (Figure 2.18).
Thus, fluoroketal

was coupled to enantiomerically pure iodocyclopropyl
ester ( þ )- 212 in a Pd(II)-mediated reaction to afford 214 in excellent yield (85%)

211