Rapid Fluorous Stille Coupling Reactions Conducted under Microwave Irradiation

Article abstract of DOI:10.1021/jo970362y

Palladium-catalyzed fluorous Stille cross-coupling reactions with organic halides or triflates require only 90-120 s for completion when conducted under microwave irradiation. Comparable thermal reactions require about 1 day. Fourteen different coupling products were synthesized and isolated in good yields after three-phase extraction (FC-84, dichloromethane, water) and chromatography. The examples extend the scope of the fluorous Stille coupling with respect to both the tin and halide/triflate components. Applications in parallel synthesis are suggested.

Full text of DOI:10.1021/jo970362y

J . Org. Chem. 1997, 62, 5583-5587
5583
Ra p id F lu or ou s Stille Cou p lin g Rea ction s Con d u cted u n d er
Micr ow a ve Ir r a d ia tion
†
‡
‡
,‡
Mats Larhed, Masahide Hoshino, Sabine Hadida, Dennis P. Curran,* and
Anders Hallberg*,
†
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University,
Box 574, SE-751 23 Uppsala, Sweden, and Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received February 25, 1997X
Palladium-catalyzed fluorous Stille cross-coupling reactions with organic halides or triflates require
only 90-120 s for completion when conducted under microwave irradiation. Comparable thermal
reactions require about 1 day. Fourteen different coupling products were synthesized and isolated
in good yields after three-phase extraction (FC-84, dichloromethane, water) and chromatography.
The examples extend the scope of the fluorous Stille coupling with respect to both the tin and
halide/triflate components. Applications in parallel synthesis are suggested.
In tr od u ction
have therefore emerged as important reactions in parallel
synthesis and combinatorial chemistry.9 Recently, a
Among the many examples of microwave-assisted
modification of the Stille coupling that relies on fluorous
1
organic reactions that have been disclosed, few are
10ab
tin reactants was introduced.
Readily available tin
transition-metal-catalyzed transformations.2 The dra-
matic acceleration of reactions upon microwave irradia-
tion has been demonstrated in the palladium-catalyzed
3
Heck, Suzuki, and Stille reactions both on solid phase
and in solution.4 Full conversions are achieved in a few
minutes, and high yields of isolated coupling products
are obtained.
The Heck, Suzuki,6,7 and Stille reactions constitute
5
8
robust and general methods for C-C bond formation and
reactants 1 bearing 39 fluorine atoms couple with aryl
halides, aryl triflates, and benzyl bromides to form
products 2 in good yields. The method provides attractive
features for preparative organic synthesis and promising
†
Uppsala University.
University of Pittsburgh.
Abstract published in Advance ACS Abstracts, J uly 1, 1997.
‡
X
(
1) (a) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20,
. (b) Abramovitch, R. A. Org. Prep. Proc. Int. 1991, 23, 683. (c)
Majetich, G.; Hicks, R. J . Microwave Power Electromag. Energy 1995,
0, 27. (d) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665.
e) Caddick, S. Tetrahedron 1995, 51, 10403. For theoretical
1
1
1
options for liquid-phase combinatorial synthesis be-
cause the organic, inorganic, and fluorous (tin-containing)
products can be separated at the end of the reaction by
a simple three-phase extraction with an organic solvent,
3
(
a
background see also: (f) Neas, E. D.; Collins, M. J . In Introduction to
Microwave Sample Preparation; Kingston, H. M., J assie, L. B., Eds.;
American Chemical Society: Washington, DC, 1988; p 7. The technique
has also found use in the preparation of radiopharmaceuticals. See:
g) Stone-Elander, S.; Elander, N. In Chemists’ Views of Imaging
Centers; Emran, A. M., Ed.; Plenum Press: New York, 1995; p 445
10
water, and a fluorocarbon solvent.
Offsetting the advantages of the fluorous Stille reaction
are some detractions. The long reaction times required
(
(about 1 day at 80 °C) are a significant drawback for
and references therein.
rapid parallel synthesis applications. More generally, all
fluorous methods10 need to come to grips with the low
solubilities of fluorous compounds in many types of
(
2) For examples of microwave-assisted transition-metal-catalyzed
reactions: (a) Ad a´ mek, F.; H a´ jek, M. Tetrahedron Lett. 1992, 33, 2039.
b) Bose, A. K.; Banik, B. K.; Barakat, K. J .; Manhas, M. S. Synlett
993, 575. (c) Gordon, E. M.; Gaba, D. C.; J ebber, K. A.; Zacharias, D.
(
1
organic solvents, and several strategies have already
M. Organometallics 1993, 12, 5020. (d) Leskovsek, S.; Smidovnik, A.;
Koloini, T. J . Org. Chem. 1994, 59, 7433. (e) J iang, Y.-L.; Hu, Y.-Q.;
Feng, S.-Q.; Wu, J .-S.; Wu, Z.-W.; Yuan, Y.-C.; Liu, J .-M.; Hao, Q.-S.;
Li, D.-P. Synth. Commun. 1996, 26, 161. (f) Kabza, K. G.; Gestwicki,
J . E.; McGrath, J . L.; Petrassi, H. M. J . Org. Chem. 1996, 61, 9599.
been proposed.1
0c,e
The microwave heating technique
offers potential solutions to these problems, and we
(
3) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996,
(9) (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555. (b)
Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996,
52, 4527. (c) Balkenhohl, F.; von dem Bussche-H u¨ nnefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2289.
(10) (a) Curran, D. P.; Hoshino, M. J . Org. Chem. 1996, 61, 6480.
(b) Curran, D. P.; Hoshino, M. Submitted for publication. (c) Studer,
A.; Hadida, S.; Feritto, R.; Kim, S.-Y.; J eger, P.; Wipf, P.; Curran, D.
P. Science 1997, 275, 823. (d) Horv a´ th, I. T.; R a´ bai, J . Science 1994,
266, 72. (e) Curran, D. P.; Hadida, S. J . Am. Chem. Soc. 1996, 118,
2531. (f) Curran, D. P. Chemtracts-Org. Chem. 1996, 9, 75.
(11) Recent publications in the field of liquid-phase combinatorial
chemistry: (a) Han, H.; J anda, K. D. J . Am. Chem. Soc. 1996, 118,
2539. (b) Cheng, S.; Comer, D. D.; Williams, J . P.; Myers, P. L.; Boger,
D. L. J . Am. Chem. Soc. 1996, 118, 2567. (c) Park, W. K. C.; Auer, M.;
J aksche, H.; Wong, C.-H. J . Am. Chem. Soc. 1996, 118, 10150. (d)
Hogan, L. C. Nature 1996, 384, Suppl. 7, Nov 17. (e) Pinilla, C.; Appel,
J .; Dooley, C.; Blondelle, S.; Eichler, J .; Dorner, B.; Ostresh, J .;
Houghten, R. A. In Combinatorial Peptide and Non-Peptide Libraries;
J ung, G., Ed.; VCH: Weinheim, 1996; p 139.
3
7, 8219.
(
(
4) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582.
5) For recent reviews on the Heck reaction see: (a) de Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b) Cabri,
W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (c) J effery, T. Advances
in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI Press Inc:
Greenwich, 1996; Vol. 5, p 153.
(
6) For reviews on the Suzuki reaction see: (a) Martin, A. R.; Yang,
Y. Acta Chem. Scand. 1993, 47, 221. (b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457.
(
conventional heating were recently reported: Kang, S.-K.; Lee, H.-
W.; J ang, S.-B.; Ho, P.-S. J . Org. Chem. 1996, 61, 4720.
7) Very fast Suzuki coupling reactions with iodonium salts under
(
8) For reviews on the Stille reaction see: (a) Stille, J . K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508. (b) Michell, T. N. Synthesis 1992,
03. (c) Ritter, K. Synthesis 1993, 735. (d) Farina, V.; Roth, G. P. In
8
Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI
Press Inc: Greenwich, 1996; Vol. 5, p 1.
S0022-3263(97)00362-9 CCC: $14.00 © 1997 American Chemical Society

5
584 J . Org. Chem., Vol. 62, No. 16, 1997
Larhed et al.
decided to undertake a study of microwave-promoted
fluorous Stille coupling reactions to evaluate the ef-
fectiveness of microwave irradiation on a prototypical
fluorous reaction.
oxidative addition under the heating conditions em-
1
7a
ployed. In common with both the normal Stille coupling
1
0a,b
and the thermal version of the fluorous Stille coupling,
we observed that coupling with the pyridyltin compound
d resulted in an unsatisfactory mixture of products. But
1
Resu lts a n d Discu ssion
this problem was circumvented by substitution of LiCl
for CuO,17 which delivered the coupled pyridyl compound
A series of fluorinated aryltin, heteroaryltin, and
allyltin reactants 1a -e (1.2 equiv) were reacted with a
variety of organic halides and triflates (0.20 mmol, 1.0
2
1
m with high selectivity and in good isolated yield (Table
, entry 15).
The thermal fluorous Stille coupling provided signifi-
1
0b
equiv) in the presence of lithium chloride (3.0 equiv)
and a catalytic amount of bis(triphenylphosphine)palla-
cant amounts (5-10%) of symmetrical biaryl side
10a,b
products.
We were therefore surprised to find that
1
2
dium(II) chloride (0.02 equiv) in DMF, a microwave-
only a very minor amount of symmetrical biaryls were
formed in the microwave-promoted reactions with aryl
halides or aryl triflates (<3%, estimated by GC-MS). The
reactions with electron-rich aryl halides (Table 1, entries
active solvent.13 The reactions were performed under an
1
4
atmosphere of nitrogen in sealed Pyrex vessels, and a
commercially available single mode cavity producing
continuous irradiation was used.15 All reactions were
completed in less than 2 min with microwave dielectric
heating and a microwave power of 50-70 W.
1
, 2, and 6) were exceptions to this generalization,
producing up to 10-15% of biphenyl as a side product.
A control experiment where tri-p-tolylphosphine and
palladium acetate were substituted for bis(triphenylphos-
phine)palladium(II)chloride strongly suggested that the
biphenyl (in Table 1, entries 1, 2, and 6), to a large extent,
was not derived from homocoupling of the tin reactants.
Instead, the major formation of biphenyl, under micro-
The preparative results are summarized in Table 1.
All reactions provided fair to good yields of isolated
products after workup by three-phase extraction (per-
1
6
fluoroheptanes (FC-84), dichloromethane, water) and
subsequent chromatography (Table 1, entries 1-16). The
three-phase extraction procedure was also applied prior
to GC-MS injections (for monitoring of the reactions) to
ensure removal of tin compounds, which are deleterious
for the GC columns. The results in Table 1 illustrate that
not only aryl halides, aryl triflates, and 3-chlorobenzyl
bromide but also vinyl triflates (Table 1, entries 10 and
1
2) are suitable coupling partners. Furthermore, we
learned that the previously unreported fluorous allyl tin
reactant 1e reacts smoothly to give the desired product
2
n with no traces of the conjugated isomer (Table 1, entry
1
6).
A low chemoselectivity was encountered with 4-bro-
moiodobenzene (Table 1, entry 5). This reaction produced
the doubly coupled product 2d in 39% yield along with a
considerable amount of 4-bromobiphenyl (15%). Appar-
ently, there is only a small preference for the aryl-iodide
bond, compared to the aryl-bromide bond, to undergo
wave conditions (Table 1), presumably arises from cou-
pling between the tin reactant and the oxidative addition
(
12) Bis(triphenylphosphine)palladium(II) chloride acts as a pre-
catalyst and is rapidly reduced to active Pd(0) species under typical
Stille conditions. Baker, S. R.; Roth, G. P.; Sapino, C. Synth. Commun.
complex PhPd(PArPh
2 3
)(PPh )X formed after aryl migra-
1
8
1
990, 20, 2185. See also ref 8d.
13) Polar solvents absorb microwave energy efficently. The rate of
tion from ArPd(PPh ) X.
3 2
(
The high heating rate associated with microwave
irradiation has been postulated to be useful for control
rise of temperature is controlled by the dielectric loss, specific heat
capacity and emissivity of the reaction mixture, as well as the geometry
and volume of the sample, and the strength of the applied microwave
field. Stone-Elander, S.; Elander, N. Appl. Radiat. Isot. 1991, 42, 885.
See also ref 1a.
1d,19
of product formation.
We presume that the higher
Stille product/homocoupled biaryl ratio20 observed under
microwave irradiation originates from a predominance
of Stille coupling as compared to the competing homo-
coupling at high temperatures.
(14) The Pyrex tube permits the use of higher-boiling solvents than
those that may be used with a Teflon vessel. Baghurst, D. R.; Mingos,
D. M. P. J . Chem. Soc., Dalton Trans. 1992, 1151.
(15) The use of a single mode microwave cavity (focused microwaves)
allows the sample to be exposed to a well-defined microwave field (to
avoid local heating effects) during the entire reaction. This is essential
for high reproducibility and makes it possible to optimize both the
reaction times and the intensities. Carrillo-Munoz, J .-R.; Bouvet, D.;
Guib e´ -J ampel, E.; Loupy, A.; Petit, A. J . Org. Chem. 1996, 61, 7746
and references therein. See also ref 1g.
Macroscopic dielectric loss heating effects associated
with the solvent (DMF) are likely to be responsible for
the startling acceleration of reaction rates, and contribu-
tions from specific molecular absorption effects should
1,21
be less significant.
Since the reaction tubes are made
(16) FC-84 is a commercially available (3M) nontoxic, nonflammable
perfluorinated liquid with a typical boiling point of 80 °C and an
average molecular weight of 388 g/mol. It consists mostly of isomers
of perfluoroheptane.
(18) For recent articles concerning exchange of metal- and phos-
phine-bound organic moieties in the oxidative addition complex see:
(a) Kong, K.-C.; Cheng, C.-H. J . Am. Chem. Soc. 1991, 113, 6313. (b)
Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J . Org. Chem. 1995,
60, 12. (c) Morita, D. K.; Stille, J . K.; Norton, J . R. J . Am. Chem. Soc.
1995, 117, 8576 and references cited therein.
(19) Stuerga, D.; Gonon, K.; Lallemant, M. Tetrahedron 1993, 49,
6229.
(20) It has been reported that stannane homocoupling does not
proceed when careful precautions are taken to exclude atmospheric
oxygen. Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J . Org.
Chem. 1993, 58, 5434.
(17) (a) Gronowitz, S.; Bj o¨ rk, P.; Malm, J .; H o¨ rnfeldt, A.-B. J .
Organomet. Chem. 1993, 460, 127. For additional examples of beneficial
effects of copper additives on the Stille coupling reaction see: (b)
Liebeskind, L. S.; Fengl, R. W. J . Org. Chem. 1990, 55, 5359. (c)
J ohnson, C. R.; Adams, J . P.; Braun, M. P.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 919. (d) Farina, V.; Kapadia, S.; Krishnan,
B.; Wang, C.; Liebeskind, L. S. J . Org. Chem. 1994, 59, 5905. (e)
Hodgson, D. M.; Witherington, J .; Moloney, B. A.; Richards, I. C.;
Brayer, J .-L. Synlett 1995, 32. (f) Gibbs, R. A.; Krishnan, U.; Dolence,
J . M.; Poulter, C. D. J . Org. Chem. 1995, 60, 7821.

Rapid Fluorous Stille Coupling Reactions
J . Org. Chem., Vol. 62, No. 16, 1997 5585
Ta ble 1. F a st Stille Cou p lin gs w ith F lu or ou s Tin Rea cta n ts u n d er Micr ow a ve Ir r a d ia tion a
a
Reactions were conducted under continuous microwave irradiation (2450 MHz) in sealed Pyrex tubes under an atmosphere of nitrogen.
The organic halide or organic triflate (0.20 mmol, 1.0 equiv) was reacted with the tin reactants (1.2 equiv) in the presence of PdCl2(PPh3)2
0.02 equiv) and LiCl (3.0 equiv) in DMF (1.0 mL). After cooling, a small sample was partitioned between FC-84, dichloromethane, and
(
b
water, and the organic phase was analyzed by GC-MS. The microwave power and the irradiation time were selected to allow >95%
c
d
conversion in all cases. Based on the organic halide or organic triflate. >95% purity by GC-MS. 15% 4-bromobiphenyl was also isolated.
e
CuO (1.0 equiv) was added instead of LiCl.
of Pyrex, conductivity heat losses are small22 and the
irradiation energy, with very high energy density, is
absorbed by the reaction mixture directly, an effect that
within a short time leads to a “pressure cooker effect” in
the sealed tubes. Wall effects are largely eliminated, and
the whole of the reaction medium is heated simulta-
neously without local heating effects.1
d,21e
This methodol-
(
21) For recent investigations into nonthermal “microwave effects”,
ogy provides a rapid and convenient way of synthesizing
compounds that are thermally stable but are the final
products of kinetically slow reactions.14
see: (a) J ahngen, E. G. E.; Lentz, R. R.; Pesheck, P. S.; Sackett, P. H.
J . Org. Chem. 1990, 55, 3406. (b) Pollington, S. D.; Bond, G.; Moyes,
R. B.; Whan, D. A.; Candlin, J . P.; J ennings, J . R. J . Org. Chem. 1991,
5
6, 1313. (c) Laurent, R.; Laporterie, A.; Dubac, J .; Berlan, J .; Lefeuvre,
S.; Audhuy, M. J . Org. Chem. 1992, 57, 7099. (d) Mingos, D. M. P.
Res. Chem. Intermed. 1994, 20, 85. (e) Bagnell, L.; Cablewski, T.;
Strauss, C. R.; Trainor, R. W. J . Org. Chem. 1996, 61, 7355. See also
ref 2d.
(22) Pyrex is almost transparent to microwave energy and is a poor
conductor of heat. Stone-Elander, S. A.; Elander, N.; Thorell, J .-O.;
Solås, G.; Svennebrink, J . J . Labelled Cmpds. Radiopharm. 1994, 10,
949. See also ref 1f.

5
586 J . Org. Chem., Vol. 62, No. 16, 1997
Larhed et al.
Con clu sion s
[2-(perfluorohexyl)ethyl](4′-methoxyphenyl)tin (1b ), tris[2-
(perfluorohexyl)ethyl](2′-furyl)tin (1c), and tris[2-(perfluoro-
The microwave variant of the fluorous Stille reaction
hexyl)ethyl](2′-pyridyl)tin (1d ) were prepared as described
previously.1
0a,b,e
Structure and purity of isolated coupling
is an expedient procedure that couples the facile workup
and separation features associated with the fluorous
Stille reactants and the rapid reaction time associated
with microwave methods. An unexpected benefit of the
microwave method is the reduced amount homocoupled
byproduct that is formed in many reactions. Additional
work will be needed to ascertain if the application of
microwave radiation provides a mild and general method
to promote reactions between organic and fluorous reac-
tion components. But even at this early stage, it appears
as if the combination of these two techniques holds
significant potential for parallel synthesis applications
to make combinatorial libraries in the solution phase
because time and effort are minimized at both the
reaction and the separation stages.
1
products were determined by H NMR and GC-MS (>95%
purity). Products 2g,30 2i, 2j, 2k , 2l, 2m , and 2n
31
32
33
34
35
36,37
have been synthesized and fully characterized before. Com-
pounds 2a ,b,d ,e,f,h are commercially available, and the
structures were determined by comparison with an authentic
sample (2d ,f,h ) or by comparison of their spectroscopic data
37,38
with the reported values (2a ,b,e).
The biaryl 2c was
previously reported but not characterized.39
Ca u tion ! Th e m icr owa ve-a ssisted r ea ction s d escr ibed
in th is pa per sh ou ld n ot be r epea ted in closed vessels
u n less a n a ppr opr ia te septu m is u sed a s a pr essu r e r elief
4
0
d evice sin ce th is cou ld r esu lt in a n explosion .
Tr is(3,3,4,4,5,5,6,6,7,7,8,8,8-t r id eca flu or ooct yl)a llyl-
tin (Tr is[2-(p er flu or oh exyl)eth yl]a llyltin ) (1e). Allylmag-
nesium bromide (1.0 mL, 1.0 mmol) 1 M in diethyl ether was
added to a solution of tris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluo-
rooctyl)tin bromide (1.0 g, 0.80 mmol) in diethyl ether (10 mL).
The mixture was heated at reflux for 2 h with stirring. To
the reaction cooled at 0 °C were added a saturated solution of
amonium chloride (8 mL) and diethyl ether (5 mL). The two
phases were separated, and the aqueous phase was extracted
twice with diethyl ether (2 × 10 mL). The combined ether
Exp er im en ta l Section
P r oced u r es. Reactions were performed in a MicroWell 10
2
2
single-mode microwave cavity producing continuous irradia-
tion (2450 MHz) from Labwell AB, SE-753 19 Uppsala,
Sweden. The reactions were performed under nitrogen in
heavy-walled Pyrex tubes (8 mL, l ) 150 mm) sealed with a
silicon septum. In the event of overpressurization, this septum
was distorted. Silicone septa (110.623-18) and screwcaps with
aperture (110.627-18) were purchased from KEBO Lab AB,
SE-163 94 Spånga, Sweden. The reaction volume occupied not
more than 1/5th of the total volume of the tube, thereby
allowing head space for pressure buildup during the microwave
treatment. To ensure a satisfactory antenna function of the
reaction liquid, the height of the liquid column was >2.5 cm.
All couplings were conducted in the absence of stirring. After
irradiation, small samples were removed and partitioned
between FC-84, dichloromethane, and water, and the dichlo-
extracts were dried over MgSO
4
, evaporated, and purified by
column chromathography on neutral alumina (hexanes), yield-
ing 1e as a colorless oil (770 mg, 80%): MS m/ z (relative
+
1
intensity, 70 eV) 1201 (M , 12), 1161 (100), 855 (25); H NMR
CDCl ) δ 5.95 (m, 1H), 5.0-4.8 (m, 2H), 2.30 (m, 6H), 1.95 (d,
J ) 9 Hz, J ( Sn-H) ) 66 Hz, 2H), 1.20 (t, J ) 8.3 Hz,
(
3
2
119
2
119
119
J ( Sn-H) ) 59 Hz, 6H); Sn NMR (CF
ppm; IR (thin film) 2884, 2872, 1627, 1442, 1351, 1317, 1236,
204, 1144, 1119, 1063, 843, 699 cm
3 6 5 6 6
C H /C D ) -9.76
-1
1
.
Gen er a l P r oced u r e for Cou p lin g Rea ction s (Ta ble 1).
In a screw-capped Pyrex tube were placed tris[2-(perfluoro-
hexyl)ethyl]organotin (0.24 mmol), organic halide or organic
triflate (0.20 mmol), bis(triphenylphosphine)palladium(II) chlo-
ride (0.004 mmol, 2.8 mg), lithium chloride (0.60 mmol, 25.4
mg), and DMF (1.0 mL). The tube was capped, and the
suspension was purged with nitrogen. The contents of the tube
were mixed with a whirlimixer and thereafter rapidly heated
by the application of microwave power (see Table 1 for details
concerning reaction times and microwave power). The micro-
wave power was adjusted to give full conversion in less than
1
romethane phase was analyzed by GC-MS. H NMR spectra
of the coupling products were measured at 270 MHz in CDCl
Sn NMR spectra, chemical shifts are
relative to tetramethyltin. Mass spectra were determined at
0 eV (EI). IR spectra were recorded on a FTIR spectrometer.
Column chromatography was performed on silica using Kie-
selgel S (0.032-0.063 mm, Riedel-de Haen). Elemental analy-
ses were carried out by Mikro Kemi AB, Uppsala, Sweden.
Ma ter ia ls. Organo halides, lithium chloride, copper(II)
oxide, tri-p-tolylphosphine, DMF, and allylmagnesium bromide
3
1
19
solution. In the
7
2
.0 min. After the reaction mixture was cooled to room
temperature, toluene (2 mL) was added, and most of the DMF
was azeotropically evaporated under reduced pressure at 50-
(
1 M in diethyl ether) were purchased from commercial
suppliers and were used directly as received. Bis(tri-
phenylphosphine)palladium(II)chloride was obtained from
Acros and used without further purification. FC-84 was
obtained from 3M. The aryl triflates were synthesized from
the corresponding phenols using an excess of triflic anhydride
and 2,4,6-trimethylpyridine, essentially following a literature
(
29) Stang, P. J .; Treptow, W. Synthesis 1980, 283.
(30) (a) Blackwell, J .; Hickinbottom, W. J . J . Chem. Soc. 1961, 1405.
(
b) Ebert, G. W.; Pfennig, D. R.; Suchan, S. D.; Donovan, T. A., J r.;
Aouad, E.; Tehrani, S. S.; Gunnersen, J . N.; Dong, L. J . Org. Chem.
1995, 60, 2361.
(31) Lourak, M.; Vanderesse, R.; Fort, Y.; Caub e` re, P. J . Org. Chem.
1989, 54, 4844.
(32) (a) Bergman, F.; Szmuszkiowics, J .; Fawaz, G. J . Am. Chem.
Soc. 1947, 69, 1773. (b) Schneider, M. R.; Schiller, C. D. Arch. Pharm.
2
3
24
procedure.
-formylphenyl trifluoromethanesulfonate, and methyl 4-[[(tri-
4-Acetylphenyl trifluoromethanesulfonate,
2
5
3
2
6
fluoromethyl)sulfonyl]oxy]benzoate are known compounds.
The vinyl triflates 1-cyclohexenyl trifluoromethanesulfonate27
and 6-methoxy-3,4-dihydro-1-naphthyl trifluoromethane-
sulfonate were prepared according to the method described
by Stang. Tris[2-(perfluorohexyl)ethyl]phenyltin (1a ), tris-
(
Weinheim) 1990, 323, 17.
(33) (a) Khan, M. A.: Uberti, S. M. L. Rev. Latinoamer. Quim. 1983,
14, 79. (b) Young, R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, C. R.;
Griffiths, R.; J ones, M.; Rana, K. K.; Saunders, D.; Smith, I. R.; Sore,
N. E.; Wilks, T. J . J . Med. Chem. 1988, 31, 656.
2
8
2
9
(34) (a) Fisera, L.; Kov a´ c, J .; Lucky, M.; Sur a´ , J . Chem. Zvesti 1974,
2
8, 386. (b) Fisera, L.; Kov a´ c, J .; Komanov a´ , E.; Lesko, J . Tetrahedron
(
23) Sa a´ , J . M.; Dopico, M.; Martorell, G.; Garc ´ı a-Raso, A. J . Org.
Chem. 1990, 55, 991.
24) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109,
478.
1974, 30, 4123.
(35) (a) Butterworth, E. C.; Heilbron, I. M.; Hey, D. H. J . Chem.
Soc. 1940, 355. (b) Cohen, T.; Deets, G. L. J . Org. Chem. 1972, 37, 55.
(36) Hiyama, T.; Yamamoto, H.; Nishio, K.; Kitatani, K.; Nozaki,
H. Bull. Chem. Soc. J pn. 1979, 52, 3632.
(37) Atlas of Spectral Data and Physical Constants for Organic
Compounds; Grasselli, J . G., Ed.; CRC Press: Cleveland, OH, 1973.
(38) Pouchert, C. J .; Campbell, J . R. The Aldrich Library of NMR
Spectra; Aldrich Chemical Co.: Milwaukee, 1974.
(39) Meyer, G.; Rollin, Y.; Perichon, J . J . Organomet. Chem. 1987,
333, 263.
(
5
1
1
(
25) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
557.
(
26) (a) Hansen, R. L. U. S. Patent 3, 346, 612, 1967; Chem. Abstr.
968, 68, P21698c. (b) Percec, V.; Bae, J .-Y.; Zhao, M.; Hill, D. H. J .
Org. Chem. 1995, 60, 176.
27) Dueber, T. E.; Stang, P. J .; Pfeifer, W. D.; Summerville, R. H.;
(
Imhoff, M. A.; Schleyer, P. v. R.; Hummel, K.; Bocher, S.; Harding, C.
E.; Hanack, M. Angew. Chem. 1970, 82, 517.
(40) For a discussion of safety precautions in microwave systems
see: Raner, K. D.; Strauss, C. R.; Trainor, R. W.; Thorn, J . S. J . Org.
Chem. 1995, 60, 2456.
(28) (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron 1993, 49,
4
955. (b) Pal, K. Synthesis 1995, 1485.

Rapid Fluorous Stille Coupling Reactions
0 °C. The residue was then partitioned in a three-phase
J . Org. Chem., Vol. 62, No. 16, 1997 5587
7
P r oced u r e for th e Con tr ol Exp er im en t. A mixture of
tris[2-(perfluorohexyl)ethyl]phenyltin (1a ) (0.24 mmol, 297
mg), 4-iodoanisole (0.20 mmol, 46.8 mg), palladium(II) acetate
extraction between water (10 mL, top), dichloromethane (20
mL, middle), and FC-84 (10 mL, bottom). The three layers
were separated, and the dichloromethane layer was washed
three additional times with water (3 × 10 mL) and FC-84 (3
(
0.004 mmol, 0.90 mg), tri-p-tolylphosphine (0.008 mmol, 2.4
mg), lithium chloride (0.60 mmol, 25.4 mg), and DMF (1.0 mL)
was treated with microwaves (2.0 min, 60 W) under nitrogen.
The reaction was repeated twice (to increase the amount of
products). All three reaction mixtures were then cooled,
combined, and purified by three-phase extraction and column
chromatography (silica, isohexane) to afford 81% (89.8 mg) of
×
10 mL) and evaporated under reduced pressure.41 The
resulting crude product was purified by chromatography (silica
4
2
column) to afford pure coupling product (see Table 1, >95%
pure by GC-MS). No attempt was made to recover the
1
0a,b
fluorous tin chloride from the FC-84 phase.
-(Tr iflu or om eth yl)bip h en yl (2c):39 pale red oil, 0.021 g
47%); eluent isohexane: MS m/ z (relative intensity, 70 eV)
2
4
-methoxybiphenyl (based on 4-iodoanisole, expected product,
(
+
1
37,38
2
7
7
22 (M , 100), 201 (30), 183 (8), 152 (10); H NMR (CDCl
.28-7.49 (m, 7H), 7.54 (br t, J ) 7.6 Hz, 1H), 7.73 (br d, J )
.6 Hz, 1H). Anal. Calcd for C13 C, 70.3; H, 4.1.
3
) δ
2a ), 10% (10.4 mg) of 4-methylbiphenyl
(based on 4-io-
doanisole, from aryl interchange in the oxidative addition
complex), and 2% (2.5 mg) biphenyl3
7,38
(based on 1a , from
H
9
F
3
:
Found: C, 70.2; H, 4.3.
stannane homocoupling). This product distribution is in
accordance with yields estimated by GC-MS.
(
41) In most cases small amounts of fluoroalkyl transfer products
were detected (GC-MS) in the dichloromethane layer after the FC-
4/water wash.
42) Eluents; 2a isohexane/diethyl ether (9/1), 2b isohexane/ethyl
acetate (19/1), 2d isohexane, 2e isohexane, 2f pentane/ethyl acetate
9/1), 2g isohexane/diethyl ether (99/1), 2h isohexane, 2i isohexane/
8
(
Ack n ow led gm en t. We thank the Swedish Natural
Science Research Council, the National Institutes of
Health, and the Kao Corporation for financial support.
(
ethyl acetate (7/1), 2j isohexane/ethyl acetate (99/1), 2k isohexane/
ethyl acetate (19/1), 2l isohexane/ethyl acetate (7/1), 2m isohexane/
ethyl acetate (2/1), 2n isohexane.
J O970362Y