J . Org. Chem. 1999, 64, 4539-4541
4539
Ta ble 1. Micr ow a ve P r om oted Stille-Cou p lin gs w ith
F -21 Com p ou n d 2a a
High -Sp eed , High ly F lu or ou s Or ga n ic
Rea ction s
Kristofer Olofsson,† Sun-Young Kim,‡ Mats Larhed,†
Dennis P. Curran,*,‡ and Anders Hallberg*,†
Department of Organic Pharmaceutical Chemistry, BMC,
Uppsala University, Box 574, SE-75123 Uppsala, Sweden,
and Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received December 28, 1998
The rapidly growing field of combinatorial chemistry
has precipitated the development of new techniques
aimed at improving the efficiency of performing chemical
reactions and separations in both the solid- and liquid-
phase.1 Solid-phase chemistry has a great advantage at
the separation stage because the product is easily sepa-
rated by filtration. But the same heterogeneity that is
useful in separation can sometimes be a liability in the
reaction stage.
Recently introduced fluorous synthesis techniques2
capitalize on the immiscibility of fluorous (highly fluori-
nated) phases with organic solvents and water at room
temperature. Fluorous molecules or molecules equipped
with fluorous tags will seek the fluorous phase in a
separation stage but can under heating in a reaction
stage often be dissolved in organic solvents and combined
with organic reactants. Thus, fluorous techniques are a
means of integrating synthetic and purification strategy
in combinatorial chemistry.2a-c Fluorous and solid-phase
techniques can often speed the separation process to the
point where the reaction times limit sample throughput
in a combinatorial or parallel synthesis. Convenient
methods to promote rapid reactions then become impor-
tant. The new microwave technique provides such a
method. The efficiency of microwave flash-heating chem-
istry in dramatically accelerating reactions rates has
recently been proven in several different fields of syn-
thetic organic chemistry,3 among them solid-phase, liquid-
phase, and fluorous palladium-catalyzed reactions.4
Early work in fluorous chemistry employed CH2-
CH2C6F13 tags (shortened F-13),2,5 which had sufficient
a
b
For experimental details, see Experimental Section. Con-
tinuous irradiation at 2450 MHz. c >95% by GC/MS. Pd(OAc)2
and P(m-PhSO3Na)3 instead of Pd(PPh3)2Cl2 as precatalyst.
d
fluorine content to drive a number of trialkyltin and
phosphine reagents and catalysts into a fluorinated phase
in a convenient liquid-liquid extraction. However, the
degree of fluorination is critical for achieving a high
partitioning of the tagged compounds into the fluorous
phase,6 and the F-13 tag proved to be too small with
respect to liquid-liquid extraction for some compounds.
The CH2CH2C10F21 (F-21) tag was introduced to enable
an increased partitioning into the fluorous phase, and
this was used with success in fluorous Ugi (Flugi) and
fluorous Biginelli (Fluginelli) reactions, provided hybrid
fluorous/organic solvents were used.5 However, initial
attempts to use the highly fluorous F-21 tin compounds
in Stille and radical reactions were largely unsuccessful.7
Very sluggish reactions and poor yields were encountered
in organic solvents with traditional thermal heating
techniques.7
We now report that flash-heating by microwave ir-
radiation promotes rapid reactions of highly fluorous tin
compounds. The usefulness of the microwave technique
is exemplified by a series of Stille- and radical-mediated
reactions as shown below.
Stille-couplings with organohalides 1a -d and PhSn-
(CH2CH2C10F21)3 (2a ) under standard conditions (DMF,
Pd(PPh3)2Cl2, LiCl) were all finished within 6 min of
single-mode microwave irradiation at 50 W (Table 1). In
a typical run with iodobenzene 1a and 2a (entry 1),
† Uppsala University.
‡ University of Pittsburgh.
(1) (a) Felder, E. R.; Poppinger, D. In Approaches in Advanced Drug
Research; Testa, B., Meyer, U. A., Eds.; Academic Press: San Diego,
1997; Vol. 30, pp 111-199. (b) Gravert, D. J .; J anda, K. D. Chem. Rev.
1997, 97, 489-509. (c) Borman, S. Chem. Eng. News 1998, 76, (14),
47-67.
(2) (a) Studer, A.; Hadida, S.; Ferrito, R.; Kim, S.-Y.; J eger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826. (b) Studer, A.; Curran,
D. P. Tetrahedron 1997, 53, 6681-6696. (c) Curran, D. P. Angew.
Chem., Int. Ed. 1998, 37, 1175-1196. (d) Horva´th, I. T. Acc. Chem.
Res. 1998, 31, 641-650.
(3) (a) Majetich, G.; Wheless, K. In Microwave-Enhanced Chemistry;
Kingston, H. M.; Haswell, S. J ., Eds; American Chemical Society:
Washington, DC, 1997; pp 455-505. (b) For the first example of a
microwave-heated tin hydride mediated radical reaction, see: Bose,
A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.; Bari, S. S.;
Newaz, S. N.; Banik, B. K.; Chaudhary, A. G.; Barakat, K. J . J . Org.
Chem. 1991, 56, 6968-6970.
(4) (a) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett.
1996, 37, 8219-8222. (b) Larhed, M.; Hallberg, A. J . Org. Chem. 1996,
61, 9582-9584. (c) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D.
P.; Hallberg, A. J . Org. Chem. 1997, 62, 5583-5587. (d) Olofsson, K.;
Larhed, M.; Hallberg, A. J . Org. Chem. 1998, 63, 5076-5079. (e)
Villemin, D. Presented at the International Conference on Microwave
Chemistry, Prague, September 1998; paper PL 5.
(5) Studer, A.; J eger, P.; Wipf, P.; Curran, D. P. J . Org. Chem. 1997,
62, 2917-2924.
(6) The concentration of fluorous tin compounds enables a very
convenient collection of the toxic tin compounds from the reaction
mixture. Other methods for removing tin substrates: Crich, D.; Sun
S. J . Org. Chem. 1996, 61, 7200-7201.
(7) Attempts to reduce adamantyl bromide with the F-21 tin hydride
under standard stoichiometric conditions for F-13 reagents were
irreproducible. In most cases, the starting materials were recovered,
but in one experiment small amounts of adamantane were formed.
Stille-couplings with the F-21 phenyl tin reagent gave biphenyl in much
slower rates and lower yields than the F-13 reagents. Hadida, S. and
Kim, S.-Y. Unpublished results, University of Pittsburgh.
10.1021/jo982511y CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/19/1999