Convenient catalytic free radical reductions of alkyl halides using an organotin reagent on non-cross-linked polystyrene support

Article abstract of DOI:10.1021/ol990945p

(matrix presented) A highly efficient and catalytic organotin reagent on soluble support has been developed for free radical reactions. The non-cross-linked polystyrene copolymer support allows solubility in most organic solvents such as CHCl₃, benzene, THF, dimethylacetamide (DMA), DMF, and EtOAc; however, the tin reagent can be readily obtained as a white powder from cold methanol. A variety of alkyl halides (1°, 2°, 3°, aryl) underwent radical reductions in good isolated yields (60-93%) using only 0.01-0.2 equiv of the polymer catalyst.

Full text of DOI:10.1021/ol990945p

ORGANIC
LETTERS
1
999
Vol. 1, No. 8
275-1277
Convenient Catalytic Free Radical
Reductions of Alkyl Halides Using an
Organotin Reagent on Non-Cross-Linked
Polystyrene Support
1
Eric J. Enholm* and James P. Schulte II
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
enholm@chem.ufl.edu
Received August 13, 1999
ABSTRACT
A highly efficient and catalytic organotin reagent on soluble support has been developed for free radical reactions. The non-cross-linked
polystyrene copolymer support allows solubility in most organic solvents such as CHCl , benzene, THF, dimethylacetamide (DMA), DMF, and
3
EtOAc; however, the tin reagent can be readily obtained as a white powder from cold methanol. A variety of alkyl halides (1°, 2°, 3°, aryl)
underwent radical reductions in good isolated yields (60−93%) using only 0.01−0.2 equiv of the polymer catalyst.
3
The reduction of alkyl halides with tributyltin hydride is one
of the most common and highly successful free radical
transformations in organic synthesis. Removal of excess tin
compounds persistently remain in solution. Recently, a few
reports have focused on preparing tin reagents on solid resin
support, where the tin reagents can be removed by a
1
4
reagents, byproducts, and impurities has been a tenacious
problem with these reactions, even on a small laboratory
mechanical separation such as filtration. Unfortunately, most
of these reactions require manyfold excesses of tin reagents
on resin support and up to 3-4 equiv of AIBN inititator,
normally used catalytically, to go to completion. These resins
are insoluble polymer supports, requiring long reaction times
(often >12 h), because a two-phase reaction is involved.5
It had occurred to us that a soluble support for free radical
reactions would have several advantages (vide infra). Reac-
tions using linear copolymers of poly(ethylene glycol) and
polystyrene have recently been investigated, particularly in
2
scale. Moreover, tributyltin hydride has been avoided in the
manufacturing industry and in the synthesis of medicinal
agents and pharmaceuticals, due to the environmental and
2a
physiological toxicity of organotin compounds.
One way to avoid these difficulties is with catalytic tin
hydride radical reactions, using only very small sub-
stoichiometric amounts of tin hydride. Significant efforts
have been advanced in this area; however, some organotin
(
3) (a) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554. (b)
(
1) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303. (c) Hays, D. S.;
Fu, G. C. J. Org. Chem. 1996, 61, 4.
Carbon Bonds; Pergamon Press: New York, 1986. (b) Ramaiah, M.
Tetrahedron 1987, 43, 3541. (c) Curran, D. P. Synthesis 1988, 417, 489.
d) Hart, D. J. Science 1984, 223, 883. (e) Motherwell, W. B.; Crich, D.
Free Radical Chain Reactions in Organic Synthesis; Academic Press: New
York, 1992.
(4) (a) Miller, B. L.; Hershberger, J. W. J. Polym. Sci. 1987, 25, 219.
(b) Gerik, M.; Jurdens, F.; Kuhn, H.; Neumann, W. P.; Peterseim, M. J.
Org. Chem. 1991, 56, 5971. (c) Dumartin, G.; Ruel, G.; Kharboutli, J.;
Delmond, B.; Connil, M.-F.; Jousseaume, B.; Pereyre, M. Synlett 1994,
952. (d) Chemin, A.; Deleuze, H.; Malliard, B. Eur Polym. J. 1998, 1395.
(e) Dumartin, G.; Pourcel, M.; Delmond, B.; Donard, O.; Pereyre, M.
Tetrahedron Lett. 1998, 4663.
(
(2) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200. (b) Farina, V.
J. Org. Chem. 1991, 56, 4985. (c) Curran, D. P.; Chang, C. T. J. Org.
Chem. 1989, 54, 3140. (d) Berg, S. M.; Roberts, S. M. Synthesis 1979,
4
71.
(5) Narita, M. Bull. Chem. Soc. Jpn. 1978, 51, 1477.
1
0.1021/ol990945p CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/21/1999

6
n
the laboratories of Janda. The application of these polymers
3 4
for use with Bu SnCl (2a) with NaBH , which would allow
3a
to free radical reactions, however, has currently not been
reduced to practice. These studies will show that an organotin
reagent can be mounted on soluble support and react in
catalytic amounts with alkyl halides in a free radical reaction.
for catalytic use of the tin reagent in these studies. Because
polystyrene readily precipitates from the ethanol solvent used
in this method, DMA, which allows the polymer to remain
in solution, was substituted. Of initial concern in this regard
was the limited solubility of the sodium borohydride under
these conditions.
These reactions appear to rival solution phase catalytic
n
reactions with Bu
3
SnH, both in short reaction times (typi-
cally <2 h) and similar sub-stoichiometric amounts of tin
The polymer was constructed as shown in Scheme 2. To
obtain a large amount of reactive sites and reduce the amount
reagents.3
We have recently started a program of liquid phase organic
chemistry (LPOC) using non-cross-linked polystyrene sup-
7
ported reactions and reagents. This soluble polymer support
Scheme 2
differs markedly from the standard 2-3% divinylbenzene
cross-linked resin polymers currently used in solid phase
organic chemistry (SPOC).3 The use of non-cross-linked
polystyrene allows for the complete organic solubility
,4
3 2 2
(EtOAc, benzene, CHCl , CH Cl , and THF) of each product
in the synthesis and in subsequent free radical reactions of
the stannane reagent.6 Because a single phase is utilized
with non-cross-linked polystyrene, the reactions have rates
up to 100 times faster than those of standard cross-linked
solid-phase methods.5
,7
Unlike classic cross-linked resins, these reactions can be
1
conveniently monitored by standard H NMR spectroscopy
without cleavage from polymer support.6 Intermediate
product steps used to prepare a stannane reagent and tin
halide byproducts obtained after the radical reaction are
virtually quantitatively obtained as white crystalline-like
,7
of polymer used in each reaction, styrene and p-chloro-
methylstyrene were reacted in a 2:1 ratio to prepare the non-
5
solids filtered from cold methanol.6,7 Also, commercial resins
cross-linked copolymer 7 in 94% yield. Confirmation of the
presence and content of the CH
2
Cl functionality was cor-
roborated by direct proton H NMR integration in CDCl
giving an active content value (ACV) of 2.77 mmol/g of
chloride 7. Subsequent formation of allyl ether 8 by S
displacement (74%) and photochemical hydrostannylation
using HClSnBu gave the desired tin chloride 2b in 93%
are often found to have a very low percentage of reactive
sites available (Wang resin ) 1.0-1.5 mmol/g of resin;
Merrifield resin ) 1.0-1.5 mmol/g of resin). This means
that for a prep-scale reaction to occur, a significant amount
of resin would be needed.
1
3
,
N
2
2
Scheme 1 shows the reaction we wished to investigate
involving the simple catalytic reduction of an alkyl halide 1
9
yield with an active content value of 2.62 mmol/g. It is worth
noting that all of these intermediates are precipitated white
powders. The crystalline-like nature of non-cross-linked
polymers allows for convenient handling of potentially toxic
tin reagents.
Scheme 1
It can be seen from Table 1 that the reductions of alkyl
halides with 2b were highly successful. Yields ranging from
6
0% to 93% were obtained from isolated products. Typically,
the alkyl halide was dissolved in DMA and heated to 80 °C
with 0.1 equiv of 2b and 1.5 equiv of NaBH . After stirring
4
for 2.5 h and then cooling, the reaction solution could be
directly applied to a flash column to isolate the pure product
without tin impurities. Except for the special cases, such as
some aromatic halides discussed below, most reactions were
complete in 2.5 h.
Products of tertiary halides such as adamantane (10) could
be isolated in 60% yield (GC yield ) 99%) in 2 h. Primary
alkyl halides in entries 2 and 3 reacted quickly, requiring
only 0.5-1 h. To test the catalyst’s limitations, some
reactions had only 0.01 equiv of polymer 2b present (entries
4-6 and 9) and some reactions took longer; for example,
8
with polystyrene-supported tin chloride reagent 2b. Corey
and Suggs originally developed the solution phase procedure
(
6) For a review, see: Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97,
89. See also: Chen, S.; Janda, K. D. Tetrahedron Lett. 1998, 39, 3943.
7) Enholm, E. J.; Gallagher, M.; Moran, K. M.; Lombardi, J. S.; Schulte,
J. P., II. Org. Lett. 1999, 1, 689.
8) For a “fluorous” approach to this problem, see: Curran, D. P.; Hadida,
S.; Kim, S.-Y.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 6607.
4
(
(
(9) Gerigk, U.; Gerlach, M.; Neumann, W. P.; Vieler, R.; Weintritt, V.
Synthesis 1990, 448.
1276
Org. Lett., Vol. 1, No. 8, 1999

A comparison was made to appraise the efficiency of the
catalyst at reducing 2-bromofluorene (22) to fluorene (23).
Using 0.2 equiv of the polymer catalyst and 2.5 equiv of
Table 1. Catalytic Reduction of Alkyl Halides by a
Non-Cross-Linked Polymer Supported Tin Chloride
4
NaBH , GC and TLC analysis showed that the reaction went
to completion in 24 h. Under the exact same conditions,
without use of catalyst 2b, only 30% conversion to product
13
occurred after the same amount of time. In all reactions, C
1
NMR and H NMR analysis indicated no contamination by
tin byproducts. This method was also found to be very
convenient for the regioselective reaction of p-bromoben-
zylbromide (24) in entry 9 (86% yield). When just 0.01 equiv
of the tin polymer catalyst was used, p-bromotoluene (25)
was obtained in 1 h.
Tin chloride reagent 2b was investigated for residual tin
4
e
pollution in a typical free radical reaction. Dodecyl iodide
13) and aromatic bromide 26 were each reacted with 2b,
(
and reduction products dodecane (14) and biphenyl (27) were
obtained, respectively, by flash column chromatography.
Compounds 14 and 27 were each dissolved in nitric acid
and tested for ppm tin using ICP-MS. We obtained 5.4 ((
0
2
.1) ppm and 11.1 (( 0.1) ppm for the reactions of 14 and
7, respectively. A test sample of unreacted precipitated 2b
was also dissolved in nitric acid and ICP MS which gave
40 (( 10) ppm. We conclude from these studies that the
5
catalytic tin byproducts from the reactions are readily reduced
to extremely minute levels using our simple procedure.
In summary, the new and highly effective catalyst 2b was
designed for free radical reduction of alkyl halides in high
yields without substantial byproducts. Non-cross-linked
polystyrene supported the tin chloride catalyst as a white
solid which was soluble in organic solvents.
Acknowledgment. We gratefully acknowledge support
by the National Science Foundation (Grant CHE-9708139)
for this work. We also thank B. W. Smith, E. E. Austin, and
the NSF Engineering Research Center for Particle Science
and Technology at the University of Florida for the ICP-
MS results.
a
GC yield. b GC shows the reaction complete in 0.5 h when 0.1 equiv
c
of catalyst is used. Nonisolated yield by GC, 74% conversion with 26%
starting material remaining. Under identical conditions without 2b, the
d
reaction was 30% complete after 24 h.
Supporting Information Available: General procedure
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
15 needed 6.5 h. Increasing the catalyst to 0.1 equiv afforded
total conversion in 0.5 h, by GC analysis.
OL990945P
Org. Lett., Vol. 1, No. 8, 1999
1277