6480
J . Org. Chem. 1996, 61, 6480-6481
compounds of the general structure ArSn(CH2CH2C6F13)3
participate in representative Stille couplings to make
biaryls and diarylmethanes, and that all the advantages
of the fluorous strategy are exhibited. These are the first
transformations with fluorous reactants,6 and they il-
lustrate new options for the emerging field of liquid-phase
combinatorial synthesis.7
Stille Cou p lin gs w ith F lu or ou s Tin
Rea cta n ts: Attr a ctive F ea tu r es for
P r ep a r a tive Or ga n ic Syn th esis a n d
Liqu id -P h a se Com bin a tor ia l Syn th esis
Dennis P. Curran* and Masahide Hoshino
We have already described the preparation of fluorous
tin reactant 2a , which is an intermediate in our prepara-
tion of the fluorous tin hydride.2a The supporting infor-
mation provides an improved procedure for the synthesis
of 2a by Grignard reaction of perfluorohexylethyl mag-
nesium iodide (1) with phenyltrichlorotin (eq 2). This
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received J uly 10, 1996
Horva´th and Raba´i recently introduced the concept of
“fluorous biphasic reactions” by synthesizing a fluorous
phosphine ligand [P(CH2CH2C6F13)3] and showing that
a rhodium complex of this ligand catalyzed hydrofor-
mylation reactions in a biphasic mixture of toluene and
a liquid perfluoroalkane.1 Simple separation of the two
liquid phases sufficed to provide the organic products and
the fluorous catalyst, which could be reused. We ex-
tended this concept by making a fluorous tin hydride
reagent [(C6F13CH2CH2)3SnH] and conducting reactions
in a homogeneous medium (usually benzotrifluoride,
C6H5CF3) followed by separation by two- or three-phase
liquid-liquid extractions.2 The tin compound from the
fluorous liquid phase was recovered and recycled in very
high yield. The fluorous strategy retains the attractive
features of the organotin hydride reagent but mitigates
its liabitites (toxicity, separation, disposal).
We selected the Stille reaction to probe the potential
of the fluorous tin strategy for solving these problems in
a different reaction class. The Stille reaction3 is an
important member of a family of transition metal-
catalyzed cross-coupling reactions that is regularly used
in modern organic synthesis, and it has recently been
extended to solid phase combinatorial synthesis.4 The
characteristic feature of the Stille reaction is that one of
the coupling partners is a trialkylorganotin compound
(eq 1). The Stille reaction is popular because the tin
(2)
procedure has been used to prepare over 50 g of 2a .
Brominolysis of 2a as previously described2a provided the
tin bromide 3, which served as the precursor for prepar-
ing the 4-methoxyphenyl (2b), 2-furyl (2c), and 2-pyridyl
(2d ) fluorous tin reactants by standard reactions with
either aryllithium or Grignard reagents.
Stille reactions were conducted under the standard set
of conditions shown in eq 3. These conditions were
selected on the basis of a number of trial experiments
with phenyl tin reactant 1a . These experiments showed
(1)
(3)
reactants are relatively air and moisture stable, can be
easily synthesized and purified, and tolerate a wide
variety of both protected and unprotected functional
groups. The alkyl on tin substituents are almost always
methyl or butyl groups:5 trimethyltin byproducts are easy
to remove but toxic while tributyltin byproducts are less
toxic but difficult to remove. Herein, we report that
that lithium chloride was a beneficial additive for cou-
plings with both triflates and halides. Equal parts of
DMF/THF and DMF/C6H5CF3 both provided homoge-
neous mixtures (as judged by the naked eye) and reason-
able reaction rates (<22 h) at 80 °C. The DMF/THF
mixture (1/1) was selected for the standard experiments.
A mixture of 1.2 equiv of tin reagent (2a -d ), 1 equiv
of halide or triflate (4a -e, 0.2 mmol), 2 mol % PdCl2-
(PPh3)2, and 3 equiv of LiCl in 1/1 DMF/THF (1 mL) was
heated at 80 °C. Reactions were conducted in individual
vessels in groups of five (one tin reagent with all five
(1) (a) Horva´th, I. T.; Raba´i, J . Science 1994, 266, 72. (b) Horva´th,
I. T.; Raba´i, J ., U.S. Patent no. 5,463,082, 1995. (c) Hughes, R. P.;
Trujillo, H. A. Organometallics 1996, 15, 286. (d) DiMagno, S. G.;
Dussault, P. H.; Schultz, J . A. J . Am. Chem. Soc. 1996, 118, 5312.
(2) (a) Curran, D. P.; Hadida, S. J . Am. Chem. Soc. 1996, 118, 2531.
(b) Curran, D. P. Chemtracts-Org. Chem. 1996, 9, 75.
(3) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Mitchell, T. N. Synthesis 1992, 803. (c) Farina, V.; Roth, G. P. In
Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI:
Greenwich, 1995; Vol. 5.
(6) For the purposes of combinatorial synthesis, a “reactant” provides
a variable piece to the product library.
(4) (a) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613. (b)
Forman, F. W.; Sucholeiki, I. J . Org. Chem. 1995, 60, 523. (c) Plunkett,
M. J .; Ellman, J . A. J . Am. Chem. Soc. 1995, 117, 3306.
(5) Important exceptions. (a) Vedejs, E.; Haight, A. R.; Moss, W. O.
J . Am. Chem. Soc. 1992, 114, 6556. (b) Brown, J . M.; Pearson, M.;
J astrzebski, J . T. B. H.; van Koten, G. J . Chem. Soc., Chem. Commun.
1992, 1440.
(7) (a) Carell, T.; Wintner, E. A.; Sutherland, A. J .; Rebek, J ., J r.;
Dunayevskiy, Y. M.; Vouros, P. Chem. Biol. 1995, 2, 171. (b) Han, H.;
Wolfe, M. M.; Brenner, S. D.; J anda, K. D. Proc. Natl. Acad. Sci. U.S.A.
1995, 92, 6419. (c) Han, H.; J anda, K. D. J . Am. Chem. Soc. 1996,
118, 2539. (d) Cheng, S.; Comer, D. D.; Williams, J . P.; Myers, P. L.;
Boger, D. L. J . Am. Chem. Soc. 1996, 118, 2567. (e) Boger, D. L.; Tarby,
C. M.; Myers, P. L.; Caporale, L. H. J . Am. Chem. Soc. 1996, 118, 2109.
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