Tris(2-(perfluorohexyl)ethyl)tin hydride: A new fluorous reagent for use in traditional organic synthesis and liquid phase combinatorial synthesis

Full text of DOI:10.1021/ja953287m

J. Am. Chem. Soc. 1996, 118, 2531-2532
2531
Tris(2-(perfluorohexyl)ethyl)tin Hydride: A New
Fluorous Reagent for Use in Traditional Organic
Synthesis and Liquid Phase Combinatorial
Synthesis
phenyltrichlorotin provided 1. Brominolysis of the phenyl-
tin bond and reduction of the resulting tin bromide 2 with lithium
aluminum hydride in ether provided the new tin hydride 3. This
was isolated in 65% overall yield as a clear liquid after
purification by vacuum distillation.
Attempts to reduce a typical organic substrate, 1-bromoada-
Dennis P. Curran* and Sabine Hadida
2
mantane, under fluorous conditions like those used by Zhu,
under biphasic conditions like those used by Horv a´ th and R a´ bai,3
or in normal organic solvents like benzene were not very
successful. Apparently, the partition coefficients for the
Department of Chemistry, UniVersity of Pittsburgh
Pittsburgh, PennsylVania, 15260
1
0
reactants are such that the phase separation prevents a radical
chain from propagating with bromoadamantane. In contrast,
treatment of perfluorodecyl iodide with 1.2 equiv of tin hydride
3 and 10% AIBN in refluxing PFMC provided the corresponding
reduced compound 4 in 72% yield (eq 2). This success
ReceiVed September 26, 1995
The simplest methods to purify the products of organic
reactions involve phase separations. Four phases are commonly
used in standard laboratory separation methods: gas, solid,
organic liquid, and aqueous. It has long been known that low-
boiling perfluorinated fluids are immiscible in both water and
many organic solvents at ambient laboratory temperatures, yet
this property has rarely been exploited in organic synthesis. Zhu
1
(2)
2
has recently described transesterification reactions of esters in
a fluorinated solvent. In these reactions, both the ester and
alcohol products are separated from each other and from the
solvent by phase separation techniques. In a further reaching
report,3 Horv a´ th and R a´ bai introduced a catalyst generated from
,4
5
a partially fluorinated phosphine [(C6F13CH2CH2)3P] and
Rh(CO)2acac, showed that the catalyst functioned in a typical
hydroformylation reaction in a biphasic mixture of toluene and
perfluoromethylcyclohexane (PFMC), separated the catalyst
from the products by simple phase separation, and reused the
recovered catalyst solution for another hydroformylation. These
early successes suggest that the “fluorous” phase provided by
low-boiling fluorocarbon solvents could become an important
new synthetic tool as fluorous reagents become available.
In this communication, we introduce a prototypical example
of a fluorous reagent, tris(2-(perfluorohexyl)ethyl)tin hydride
suggested that a homogeneous medium was important. Al-
though homogeneous organic/fluorous solvent mixtures are
known, we decided instead to try a “mixed” (part hydrocarbon
1
and part fluorocarbon) solvent. BTF was selected because of
1
1
its favorable properties and low cost.
Indeed, adamantyl
bromide was cleanly reduced over 3 h with 1.2 equiv of 3 in
refluxing BTF (stoichiometric procedure). After evaporation
of the BTF and liquid-liquid extraction (PFMC-CH2Cl2) to
separate the tin products, adamantane was isolated in 90% yield
(as determined by GC integration). Under the stoichiometric
procedure, reagent 3 reduces a number of other functional groups
besides halides, as shown in Figure 1.
[
3, (C6F13CH2CH2)3SnH].6 This behaves like normal tin hydride
reagent in radical reductions, yet it has significant practical (and
7
possibly also ecological) advantages over tributyltin hydride,
8
tris(trimethylsilyl)silicon hydride, and related reagents. We also
introduce the use of a partially fluorinated solvent, benzotri-
fluoride (BTF, C6H5CF3, (trifluoromethyl)toluene), to provide
a homogeneous reaction medium. Finally, we suggest that
fluorous reagents will provide simple new reactions and
separation options for the burgeoning field of combinatorial
synthesis.
Equation 1 summarizes the best of several methods that we
have investigated to prepare 3.9 Preparation of the Grignard
reagent from 2-perfluorohexyl-1-iodoethane and quenching with
1
2
A catalytic procedure was also developed by using 10%
tin hydride 3 and 1.3 equiv of NaCNBH in a 1/1 mixture of
3
BTF and tert-butyl alcohol at reflux. After 3 h, the reduction
of 1-bromoadamantane was complete. After evaporation, the
products were isolated by partitioning between three liquid
phases: water removes the inorganic salts, methylene chloride
extracts the adamantane (isolated in 92% yield), and perfluo-
1
romethylcyclohexane takes the tin products. Analyses by H
1
9
NMR and F NMR (estimated detection limit 1-2%) failed to
detect any fluorinated products in the residue from the methylene
chloride phase, and likewise no adamantane was detected in
the fluorous extract. The residue from the fluorous extract was
reused 5 times to reduce bromoadamantane by this catalytic
procedure with no decrease in yield. In separate experiments,
successful reductions of 1-bromoadamantane were observed with
as little as 1% of the tin reagent 2. A control experiment showed
(1)
(
1) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Ellis
Horwood: Chichester, UK, 1992.
(
(
(
2) Zhu, D.-W. Synthesis 1993, 953.
(10) Simple extractions provide crude estimates of partition coefficients.
Tin hydride 3 (1.0 g) was partitioned between PFMC (10 mL) and an organic
solvent (10 mL) by shaking for 5 min in a separatory funnel. Evaporation
of the organic layer provided the following weights: benzene, 22 mg;
MeOH, 30 mg; CH2Cl2, 47 mg; EtOAc, 104 mg; CHCl3, 141 mg.
(11) BTF: bp 102 °C, d ≈ 1.2, 1 kg ) $40 (information taken from the
1995 Aldrich catalog). This has occasionally been used as a solvent, though
we are not aware of applications in organic synthesis. Raner, K. D.; Lusztyk,
J.; Ingold, K. U. J. Am. Chem. Soc. 1989, 111, 3652. Surya Prakash, G. K.
In Synthetic Fluorine Chemistry; Olah, G. A., Chambers, R. D., Surya
Prakash, G. K., Eds.; Wiley: New York, 1992; pp 227-57 (see uncited
reaction on p 256).
3) Horv a´ th, I. T.; R a´ bai, J. Science 1994, 266, 72.
4) Highlights of the chemistry in refs 3 and 4: (a) Gladysz, J. A. Science
1
1
994, 266, 55. (b) Bergbreiter, D. E. Chemtracts: Org. Chem. 1995, 8,
08.
(
5) The “ethylene spacer” serves to insulate the phosphorous from the
powerful inductive effect of the perfluoroalkyl group.
6) The indicated name is only for convenience. The approved name of
(
3
is tris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)tin hydride.
(
(
(
7) Neumann, W. P. Synthesis 1987, 665.
8) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
9) Compounds 1-3 are new, but a number of compounds related to 1
and 2 are known, see: De Clercq, L.; Willem, R.; Gielen, M.; Atassi, G.
Bull. Chem. Soc. Belg. 1984, 93, 1089.
(12) Designed after the procedure in the following: Stork, G.; Sher, P.
M. J. Am. Chem. Soc. 1986, 108, 303.
0
002-7863/96/1518-2531$12.00/0 © 1996 American Chemical Society

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532 J. Am. Chem. Soc., Vol. 118, No. 10, 1996
Communications to the Editor
Figure 2.
To illustrate the possibilities, we simulated a “fluorous/
organic” step in a liquid phase combinatorial synthesis by
18
conducting a series of radical additions in parallel. The results,
which double as a traditional study of scope and limitations,
are shown in Figure 2. Three halides were crossed with three
alkenes (used in excess), and reactions were conducted simul-
taneously under the catalytic procedure. Products were “puri-
fied” only by three-phase liquid-liquid extraction (conducted
in the original reaction vial) and evaporation. Yields were then
determined by recording NMR spectra in the presence of an
internal standard. The crude products were quite pure (no
identifiable starting materials or side products as assayed by
capillary GC) and could hypothetically be used directly in the
next step of a sequence. Automation of the extractions would
make more parallel reactions possible.
Figure 1.
that 1-bromoadamantane was not reduced by NaCNBH3 alone
under these conditions over 24 h.
Synthetic chemists have long lauded the ionic and radical
reactivity profile of tributyltin hydride, but bemoaned its
separation and toxicity problems.13 Although more detailed
studies are needed, the early results suggest that 3 retains the
laudable reactivity profile of tributyltin hydride. Yet it can be
separated from organic products by liquid-liquid extraction.
The ability to use reagent 3 in catalytic amounts and to
repeatedly reuse the fluorous residue suggests that large scale
applications of 3 or a suitable relative might be practical because
it is not necessary to synthesize or to dispose of large quantities
of tin. We envision that a family of related tin reagents will in
the future provide similar practical benefits for other important
organotin reactions.14 In preliminary experiments, we have
successfully conducted ionic reductions with tin hydride 3 and
Stille couplings with phenyltin 1.15
We also envision that reagents like this fluorous tin hydride
will have important applications in combinatorial synthesis.
Most current combinatorial synthetic strategies place the
substrate on the solid phase so that it can be separated from
other compounds in the reaction mixture by the phase separation
technique of filtration. However, there are a number of synthetic
advantages to combinatorial strategies that place the substrate
Combinatorial synthesis with substrates in the organic liquid
phase can already be conducted without chromatography if all
the other reagents are volatile, water soluble, or on a solid phase.
As more and more fluorous reagents become available, the
19
possibilities for liquid phase combinatorial synthesis in a
20
spatially separated mode will expand. Like filtration, the phase
separation techniques of extraction and evaporation also allow
ready separation of components, so excesses of reagents can
be used. The pairing of organic substrates with fluorous
reagents is expected to be especially important since a full range
of traditional (including anhydrous) reactions can in principle
be conducted under homogeneous liquid phase conditions, yet
the products and reagents can still be separated by extraction.
In short, the detractions to synthesis posed by phase separation
1
6
20
can be divorced from its advantages in purification.
in the organic liquid phase, especially for syntheses of relatively
small libraries (say tens to hundreds of compounds).17 Fluorous
Acknowledgment. We thank the National Science Foundation for
funding this work. S.H. thanks the Ministerio de Educacion y Ciencia
of Spain for a postdoctoral fellowship.
reagents will provide new options for these types of syntheses
because the reagents (fluorous) and the substrates (organic
soluble) can be separated by the phase separation technique of
extraction.
Supporting Information Available: Contains complete details on
the preparation and characterization of 1-3, representative stoichio-
metric and catalytic experimental procedures, and copies of GC
chromatograms and NMR spectra assessing the purity of adamantane
and the nine products of eq 2 (14 pages). This material is contained
in many libraries on microfiche, immediately follows this article in
the microfilm version of the journal, can be ordered from the ACS,
and can be downloaded from the Internet; see any current masthead
page for ordering information and Internet access instructions.
(13) Other alternatives to tributyltin hydride are as follows: Polymeric
hydrides: (a) Neumann, W. P.; Peterseim, M. React. Polym. 1993, 20, 189.
Acid soluble tin hydrides: (b) Clive, D. L. J.; Yang, W. J. Org. Chem.
1
995, 60, 2607. (c) Vedejs, E.; Duncan, S. M.; Haight, A. R. J. Org. Chem.
993, 58, 3046. Water soluble tin hydrides: (d) Light, J.; Brelsow, R.
1
Tetrahedron Lett. 1990, 31, 2957. (e) Rai, R.; Collum, D. B. Tetrahedron
Lett. 1994, 35, 6221.
(14) Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic Synthesis;
Butterworths: London, 1986.
JA953287M
(
15) Hadida, S.; Hoshino, M. Unpublished results.
(
16) Reviews: (a) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki,
(18) All the products are known compounds. Giese, B. Angew. Chem.
1983, 95, 771.
(19) The reagents may also find use in the liquid phase synthesis of
mixtures. See: Carell, T.; Wintner, E. A.; Sutherland, A. J.; Rebek, J., Jr.;
Dunayevskiy, Y. M.; Vouros, P. Chem. Biol. 1995, 2, 171.
(20) For a discussion of the possibilities for liquid phase combinatorial
synthesis, see: Curran, D. P. Chemtracts: Org. Chem., in press.
R. J.; Steele, J. Tetrahedron 1995, 51, 8135. (b) Liskamp, R. M. J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 633. (c) Gallop, M. A.; Barrett, R. W.;
Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37,
1
233, 1385.
17) Such syntheses have been christened “mutiplex syntheses”. Mitscher,
L. A. Chemtracts: Org. Chem. 1995, 8, 19.
(