The conversion of alcohols to halides using a filterable phosphine source

Article abstract of DOI:10.1016/S0040-4039(01)00220-9

The conversion of primary and secondary alcohols to chlorides and bromides using 1,2-bis(diphenylphosphino)ethane (diphos) is described. Use of this reagent in lieu of the typical triphenylphosphine-carbontetrahalide complex provides a facile means of purifying the desired halide from the phosphine-oxide byproduct.

Full text of DOI:10.1016/S0040-4039(01)00220-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2459–2460
The conversion of alcohols to halides using a filterable phosphine
source
Michael P. Pollastri,* John F. Sagal and George Chang
Pfizer Global Research and Development, Groton Laboratories, Department of Medicinal Chemistry, MS 8220-3161,
Eastern Point Road, Groton, CT 06475, USA
Received 29 December 2000; revised 2 February 2001; accepted 6 February 2001
Abstract—The conversion of primary and secondary alcohols to chlorides and bromides using 1,2-bis(diphenylphosphino)ethane
(
diphos) is described. Use of this reagent in lieu of the typical triphenylphosphine–carbontetrahalide complex provides a facile
means of purifying the desired halide from the phosphine–oxide byproduct. © 2001 Elsevier Science Ltd. All rights reserved.
The conversion of alcohols to halides is a well-studied
transformation. In particular, use of the triphenylphos-
native phosphine source whose oxide byproduct can be
readily removed would also be an attractive option.
During our exploration for alternative phosphines,
O’Neil et al. reported the use 1,2-bis(diphenylphos-
1
phine–carbontetrahalide complex has become a widely
2
used method. One of the drawbacks to this phosphine
reagent is the stoichiometric phosphine oxide
byproduct, which can sometimes prove difficult to
purify from product. One solution is the use of poly-
phino)ethane (diphos) as
a
replacement for
triphenylphosphine in the Staudinger and Mitsunobu
4
reactions. With methylene chloride as the solvent, the
3
mer-supported triphenyl phosphine. Likewise, an alter-
resulting phosphine oxide was readily removed by
filtration. However, under the same conditions, our
desired conversion of alcohol to halide did not result in
the precipitation of the oxide byproduct.
Table 1. Relative solubility of diphos–O as determined by
2
LC/MS
Ph
P
Solvent
Rel. solubility
Ph Ph
Ph
P
O
Ph
P
O
P
CH Cl2
1
2
Ph Ph
Ph
DCE
THF
Ph–CH3
CCl4
0.30
0.05
0.01
0.01
Diphos
Diphos-O2
Since removal of diphos–O by filtration is critical to
this concept, we sought a solvent system that would
2
Table 2. Summary of experimental conditions
Diphos (equiv.) Chloride source
Solvent
concentration)
Conversiona (%) Comment
(
1
2
3
4
5
0.5
0.5
0.5
1
C Cl (1 equiv.)
None
CH Cl (0.32 M)
CCl4 (0.32 M)
Toluene (0.32 M)
Toluene (0.32 M)
\95
45
80
\95
\95
Minimal precipitate
Significant precipitate
Filtration removed 90% of phosphine oxide byproduct
Gummy residue due to mixture of mono and dioxide
Filtration removed 75% of phosphine oxide byproduct
2
6
2
2
C Cl (1.7 equiv.)
2
6
C Cl (1.7 equiv.)
2
6
0.6
C Cl (1.03 equiv.) THF (0.32 M)
2 6
a
Conversion is based on GC analysis of reaction.
Keywords: diphos; alcohol; phosphines; phosphine oxides.
*
Corresponding author. Tel.: (860) 715-5618; fax: (860) 715-4706; e-mail: pollastrimp@groton.pfizer.com
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00220-9

2
460
M. P. Pollastri et al. / Tetrahedron Letters 42 (2001) 2459–2460
Table 3. Substrate versatility. Yields shown are isolated, with the exception of the entries denoted with *, which were
determined using GC/MS
provide the lowest solubility of the oxidized byproduct
while still promoting the desired conversion. We under-
took a relative solubility study by integrating LC/MS
chromatograms, and several solvents which resulted in
hexachloroethane (3.68 mmol, 1 equiv.) was dissolved
in 11 mL THF and 0.73 g diphos (1.84 mmol, 0.5
equiv.) was added. The reaction was allowed to stir at
room temperature for 3 hours, at which time the sus-
pension was filtered through Celite, the filtrate evapo-
rated, and the resulting residue was purified by hexane
elution through a short pad of silica gel. Evaporation
provided 3-chloro-1-phenylbutane in 64% yield. As
low solubility of diphos–O were identified (Table 1).
2
The utility of these solvents for the alcohol–halide
conversion was then evaluated.
The results shown in Table 2 indicate that diphos can
readily facilitate the desired conversion. Using methyl-
ene chloride as the solvent, >95% conversion was
achieved. However, the desired precipitation of the
shown in entry 5 (Table 2) 75% of the diphos–O was
removed by filtration, and the remaining oxide was
retained on the silica gel.
2
diphos–O was not observed (entry 1). Using the signifi-
We have described an alternative method for conver-
sion of alcohols to halides using diphos, which is con-
verted to a readily-filtered dioxide byproduct. The
reaction provides a good alternative to the standard
triphenylphosphine–carbontetrahalide conversion, as
well as to the polymer supported phosphine reagents.
2
cantly less polar CCl resulted in precipitation of the
4
byproduct but conversion was poor (entry 2). Near
quantitative removal of diphos–O2 by filtration was
achieved when using toluene as the solvent (entry 3).
However, alcohol–halide conversion was incomplete
despite addition of excess hexachloroethane. Higher
conversion can be achieved using a higher concentra-
tion of diphos. Unfortunately, the resulting residue was
not readily removed by filtration (entry 4). The balance
of high conversion and readily filterable byproduct was
achieved when using THF as the solvent (entry 5).
References
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VCH: New York, 1989; pp. 353–360.
2. Appel, R. Angew Chem., Int. Ed. Engl. 1975, 14, 801.
Table 3 lists the various alcohol substrates which were
examined for transformation to the corresponding chlo-
rides and bromides. In a representative reaction, 0.5 g
3. Harrison, C. R.; Hodge, P.; Hunt, B. J.; Khoshdel, E.;
Richardson, G. J. Org. Chem. 1983, 48, 3721.
4. O’Neil, I. A.; Thompson, S.; Murray, C. L.; Kalindjian, S.
B. Tetrahedron Lett. 1998, 39, 7787.
4-phenyl-2-butanol (3.68 mmol, 1 equiv.) and 0.87 g
.
.