Page 766 - Advanced Organic Chemistry Part B - Reactions & Synthesis

742 Alkyl substituents on boron in 9-BBN derivatives can be coupled with either
vinyl or aryl halides through Pd catalysts. 224b This is an especially interesting reaction
CHAPTER 8 because of its ability to effect coupling of saturated alkyl groups. Palladium-catalyzed
Reactions Involving couplings of alkyl groups by most other methods often fail because of the tendency
Transition Metals
for -elimination

Ar X Pd Ar R
or + RBBN or
R′CH CHX NaOMe R′CH CHR

One catalyst that has been found amenable to alkyl systems is CH P t-Bu or the
3
2
corresponding phosphonium salt. 228 A range of substituted alkyl bromides were coupled
with arylboronic acids.
5 mol % Pd(OAc) 2
) Br + (HO) B Y Z(CH )
Z(CH 2 n 2 2 n Y
10 mol % CH P(t-Bu) 2
3
Z = CH CO , PhCH O, Y = CH O, 65 – 90%
3
3
2
2
TBDMSO, N C, CH 3 S, CF 3
2-dioxolanyl n = 5,6, 10
Suzuki couplings have been used in the synthesis of complex molecules. For
example, coupling of two large fragments of the epothilone A structure was accom-
plished in this way. 229
S
S
Pd(dppf)Cl 2
CH 3 O CCH 3 Cs CO 3 CH 3 O CCH 3
2
2
2
CH 3 DMF, H O, 25°C CH 3
2
+ OTHP PhCH O OTHP
2
PhCH O
2
I 9BBN OTBDMS OTBDMS
CH CH 3
CH CH 3 3 60%
3
A portion of the side chain of calyculin was prepared by a tandem reaction sequence that
combined an alkenylzinc reagent with 2-bromoethenylboronate, followed by Suzuki
coupling with a vinyl iodide in the same pot. 230
ZnCl I P(OC 2 H 5 ) 2
H 2 C Br
+ Pd(PPh) 3 B(Oi Pr) 2 CH 3 P(OC 2 H 5 ) 2
H 2 C O H 2 C
B(Oi Pr) 2
OC 2 H 5 CH 3
Ag 2 O, H 2 O O
OC 2 H 5 OC 2 H 5
64%
There are also several examples of the use of Suzuki reactions in scale-up synthesis
of drug candidates. In the synthesis of CI-1034, an endothelin antagonist, a triflate,
228
J. H. Kirchoff, M. R. Netherton, I. D. Hills, and G. C. Fu, J. Am. Chem. Soc., 124, 13662 (2002).
229 B. Zhu and J. S. Panek, Org. Lett., 2, 2575 (2000); see also A. Balog, D. Meng, T. Kamenecka,
P. Bertinato, D.-S. Su, E. J. Sorensen, and S. J. Danishefsky, Angew. Chem. Int. Ed. Engl., 35,
2801 (1996).
230
A. B. Smith, III, G. K. Friestad, J. Barbosa, E. Bertounesque, J. J.-W. Duan, K. G. Hull, M. Iwashima,
Y. Qui, P. G. Spoors, and B. A. Salvatore, J. Am. Chem. Soc., 121, 10478 (1999).