in some cases. Furthermore, these catalyst systems tend to
be unreactive toward the more readily available and less-
expensive aryl chloride substrates (generally attributed to the
lower rate of oxidative addition to Pd(0)).7
has since seen a number of variations including the use of
17
fluorine-containing diones and the synthesis of bis(phospha-
adamantyl)alkanes from diprimary phosphines.18 While
phosphines incorporating an adamantane motif have been
used previously in organopalladium chemistry (adamantyl-
Recent work has established that certain palladium-
catalyzed coupling reactions of the more demanding electron-
deficient aryl halides can be accomplished efficiently in the
19
di-tert-butylphosphine, for example ), systems such as 1
have the phosphorus entrenched within the adamantane
framework and the inherent steric crowding about the P
atom makes 1 an ideal architecture for further deriviti-
zation to bulky trisubstituted phosphines suitable for use as
ligands.
8
presence of sterically hindered, electron-rich phosphines.
3
The addition of P(tBu) , for example, results in a marked
9
10
11
improvement of the Suzuki, Heck, and Stille couplings
of aryl halides including aryl chlorides. Using bulky,
electron-rich ligands such as PCy
3 3
or P(iPr) allowed for
We have synthetically elaborated 1 to introduce both aryl
and alkyl groups. Arylation of 1 to give 2 or 3, for example,
can be carried out by treating the secondary phosphine with
either bromobenzene or o-bromotoluene in refluxing xylene
in the presence of either di(µ-acetato)bis[o-(di-o-tolylphos-
phino)benzyl] dipalladium(II) or nickel acetate, respectively,
as the catalyst. Purified specimens of 2 or 3 were obtained
by recrystallization of the crude products from 95% ethanol.
Alternatively, alkylation at the phosphorus can be affected
via a phosphinyl radical addition protocol described previ-
palladium-catalyzed amination of various aryl chlorides in
excellent yields.12 While others
13,14
have shown similar
benefits exhibited by bulky alkylphosphines, work to deter-
1
5
mine their exact role and mode of action is ongoing.
Scheme 1. Synthesis of the Phospha-adamantanes
2
0
ously. Using this procedure, 1 was reacted with 1-tetra-
decene in the presence of a radical initiator to afford 4. Unlike
the other phospha-adamantanes, 4 is an oily white solid that
21
oxidizes slowly when exposed to air. Crystal structures for
compounds 1, 2, and 3 appear in Figure 1.
Attention was then turned to the application of the
phospha-adamantanes to palladium-catalyzed cross-coupling
chemistry. While our initial screening revealed that each of
In an effort to develop new, sterically hindered ligands
for use in transition-metal catalysis, a reexamination of the
1,3,5,7-tetramethyl-2,4,8-trioxa-6-phospha-adamantane sys-
2
, 3, and 4 affected Suzuki coupling, our studies focused on
the development of a general, robust methodology involving
phosphine 2. Preliminary studies determined that Pd (dba)
tem (1, Figure 1) has been undertaken. First described by
2
3
was the best palladium source for the reaction and that
optimum conditions were achieved when using Pd(0) and 2
in a 1:1 ratio (although slightly higher ligand loadings were
used for the aryl chlorides). While the reactions proceed with
3 2
various bases (Et N, iPr NEt, etc.) or solvents (THF, di-
oxane), the best results were obtained with either potassium
phosphate or cesium carbonate as the base and toluene as
the solvent.
(
12) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807.
Also see: Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
413.
13) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen,
J. L. J. Org. Chem. 1999, 64, 6797.
14) Shen, W. Terahedron Lett. 1997, 38, 5575. Nishiyama, M.;
2
(
(
Figure 1. Structures of the phospha-adamantanes.
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617. Hammann, B.
C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369.
(
15) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
2905 and references therein.
16) Epstein, M.; Buckler, S. A. J. Am. Chem. Soc. 1961, 83, 3279.
(17) Bekairis, G.; Lork, E.; Offermann, W.; Roschenthaler, G.-V. Chem
Ber. 1997, 130, 1547.
18) Gee, V.; Orpen, A. G.; Phetmung, H.; Pringle, P. G.; Pugh, R. I.
1
16
Epstein and Buckler, the phospha-adamantane 1 is a white
crystalline solid readily prepared via the condensation of PH
with 2,4-pentanedione under acidic conditions. The reaction
(
3
(
Chem. Commun. 1999, 901.
(19) Stambuli, J. P.; Buehl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 9346.
(20) Robertson, A.; Bradaric, C.; Frampton, C. S.; McNulty, J.; Capretta,
A. Tetrahedron Lett. 2001, 42, 2609.
(21) Treatment of 4 with an aqueous solution of HBF4 allowed for the
production of the corresponding, air-stable phosphonium salt. Netherton,
M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(
(
(
7) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047.
8) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
9) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem Soc. 2000, 122, 4020.
Yin, J.; Rainka, M. P.; Zhang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
24, 1162.
1
(
(
10) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10.
11) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411.
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Org. Lett., Vol. 5, No. 6, 2003