Fluorous solvent as a new phase-screen medium between reagents and reactants in the bromination and chlorination of alcohols

Article abstract of DOI:10.1021/ol034060w

(Matrix presented) A perfluorohexane layer regulates the rate of reagent transport in the bromination and chlorination of alcohols. A fluorous triphasic U-tube method is effective for lighter reagents; the thionyl chloride layer (yellow) vanishes, and the chlorides are obtained from the right top organic layer in the chlorination of alcohols.

Full text of DOI:10.1021/ol034060w

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1167-1169
Fluorous Solvent as a New
Phase-Screen Medium between
Reagents and Reactants in the
Bromination and Chlorination of
Alcohols
,†
Hiroyuki Nakamura,* Taikou Usui,† Hirokazu Kuroda,† Ilhyong Ryu,‡
Hiroshi Matsubara,‡ Shinji Yasuda,‡ and Dennis P. Curran§
Department of Chemistry, Faculty of Science, Gakushuin UniVersity,
Mejiro, Tokyo 171-8588, Japan, Department of Chemistry, Faculty of Arts and
Sciences, Osaka Prefecture UniVersity, Sakai, Osaka 599-8531, Japan, and
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
hiroyuki.nakamura@gakushuin.ac.jp
Received January 13, 2003
ABSTRACT
A perfluorohexane layer regulates the rate of reagent transport in the bromination and chlorination of alcohols. A fluorous triphasic U-tube
method is effective for lighter reagents; the thionyl chloride layer (yellow) vanishes, and the chlorides are obtained from the right top organic
layer in the chlorination of alcohols.
Since fluorous biphasic reactions were introduced to organic
synthesis,1 much attention has been paid to the strategic new
option of a fluorous technique for conducting organic
reactions and for separating the reaction mixtures.2 Fluorous
biphasic reactions are based upon an interaction among
fluorous solvents and fluorous compounds such as catalysts,
reagents, and reactants; unfluorinated products are usually
extracted from a fluorous phase into an organic phase, and
fluorinated compounds are recovered from a fluorous phase
at the end of reactions.3,4 As another use for the fluorous
technique, we recently found that a fluorous solvent acts as
a phase-screen medium in the bromination of alkenes and
in the demethylation of aromatic methyl ethers for regulation
of the rate of reagent addition.5 This is important for
controlling heat evolution in exothermic reactions, especially
(3) (a) Cavazzini, M.; Montanari, F.; Pozzi, G.; Quici, S. J. Fluorine
Chem. 1999, 94, 183. (b) Fish, R. H. Chem. Eur. J. 1999, 5, 1677. (c) de
Wolf, E.; van Koten, G.; Deelman, B. J. Chem. Soc. ReV. 1999, 28, 37. (d)
Dinh, L. V.; Gladysz, J. Tetrahedron Lett. 1999, 40, 8995. (e) Nakamura,
Y.; Takeuchi, S.; Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 2000, 41, 57.
(f) Alvey, L. J.; Meier, R.; Soos, T.; Bernatis, P.; Gladysz, J. A. Eur. J.
Org. Chem. 2000, 1975. (g) Rocaboy, C.; Bauer, W.; Gladysz, J. A. Eur.
J. Org. Chem. 2000, 2621. (h) Barrett, A. N.; Braddock, D. C.; Catterick,
D.; Chadwick, D.; Henschke, J. P.; McKinnell, R. M. Synlett 2000, 847.
(4) (a) Curran, D. P. J. Am. Chem. Soc. 1996, 118, 2531. (b) Curran, D.
P.; Hoshino, M. J. Org. Chem. 1996, 61, 6480. (c) Studer, A.; Hadida, S.;
Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997,
275, 823. (d) Hadida, S.; Super, M. S.; Beckman, E. J.; Curran, D. P. J.
Am. Chem. Soc. 1997, 119, 7406. (e) Curran, D. P.; Hadida, S.; Kim, S.-
Y.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 6607. (f) Linclau, B.; Sing, A.
K.; Curran, D. P. J. Org. Chem. 1999, 64, 2835. (g) Curran, D. P.; Luo, Z.
J. Am. Chem. Soc. 1999, 121, 9069. (h) Luo, Z.; Zhang, Q.; Oderaotoshi,
Y.; Curran, D. P. Science 2001, 291, 1766.
† Gakushuin University.
‡ Osaka Prefecture University.
§ University of Pittsburgh.
(1) (a) Horva´th, I. T.; Ra´bai, J. Science 1994, 266, 72. (b) Horva´th, I. T.
Acc. Chem. Res. 1998, 31, 641.
(2) (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175. (b) Cornils,
B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2057. (c) Kitazume, T. J. Fluorine
Chem. 2000, 105, 265. (d) Furin, G. G. Russ. Chem. ReV. 2000, 69, 491.
(5) (a) Ryu, I.; Matsubara, H.; Yasuda, S.; Nakamura, H.; Curran, D. P.
J. Am. Chem. Soc. 2002, 124, 12946. (b) Matsubara, H.; Yasuda, S.; Ryu,
I. Synlett 2003, 247.
10.1021/ol034060w CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/19/2003

on a large scale. The concept of this Phase-Vanishing (PV)
reaction is based upon the density of three layers: organic
(top), fluorous (middle), and organic and inorganic (bottom).
There is passive transport of heavier reagents (d > 1.67)
from the bottom layer to the top layer (d < 1.67) through
the fluorous layer (C6F14; d ) 1.67).
We applied this method to the bromination of alcohols
and found that thionyl bromide (d ) 2.68) and phosphorus
tribromide (d ) 2.85) are effective for the PV bromination
(Scheme 1). Furthermore, we have now succeeded in the
a test tube, and thionyl bromide (1.5 mmol) was introduced
slowly using a glass pipet. The heavier thionyl bromide sank
to the bottom, forming two layers. The slow addition of
benzyl alcohol 1a (0.5 mmol) dissolved in toluene (2 mL)
formed a triphasic system. The reaction progress in the upper
toluene layer was monitored by GC or TLC analysis. Benzyl
alcohol 1a was consumed for 14 h, and the toluene layer
was decanted, washed with water, dried over anhydrous
MgSO4, and then concentrated. Purification by short column
chromatography on silica gel with hexane gave benzyl
bromide 2a in 97% yield (entry 1 in Table 1). Alcohols 1d-f
Scheme 1. Concept of the Phase-Vanishing Method for
Heavier Reagents
Table 1. Phase-Vanishing Bromination of Alcohols 1 with
SOBr2 and PBr3
a
b
SOBr2
PBr3
entry alcohol bromide
time
14 h
6 h
7 h
24 h
6 h
22 h
yield (%)c time yield (%)c
1
2
3
4
5
6
7
1a
1c
1d
1e
1f
2a
2c
2d
2e
2f
97
50
99
98
99
96
68
12 h
24 h
12 h
15 h
13 h
12 h
24 h
89
84
81
80
96
87d
34
1g
1h
2g
2h
extension of the original PV method not only to heavier
reagents but also to lighter reagents by introducing the
triphasic U-tube system, as shown in Scheme 2.6 A U-tube
3 days
a Amount of reagents used in the bromination with thionyl bromide is
as follows: alcohol 1 (0.5 mmol), SOBr2 (1.5 mmol), FC-72 (1 mL), toluene
(2 mL). b Amount of reagents used in the bromination with phosphorus
tribromide is as follows: alcohol 1 (2.0 mmol), PBr3 (1.0 mmol), FC-72 (3
mL), toluene (3 mL). The PBr3 layer vanished within 2 h. c Isolated yields
based on 1. d Conditions: 1g (0.66 mmol), PBr3 (0.4 mmol), FC-72 (3 mL),
1,2-dichloroethane (3 mL) instead of toluene.
Scheme 2. Triphasic U-Tube System for Light Reagents
containing aromatic substituents also underwent the bromi-
nation under the same conditions, giving the corresponding
bromides 2d-f in 96-99% yields (entries 3-5), although
the reaction of cinnamyl alcohol 1c gave 2c in 50% yield
(entry 2). The reaction of 1-adamantanol 1g proceeded very
smoothly to afford 2g in 96% yield (entry 6); however,
cholesterol 1h needed a longer reaction time (3 days) to give
2h in 68% yield (entry 7). We also examined the bromination
of alcohols using phosphorus tribromide as shown in Table
1. The reaction proceeded, and the bromides were obtained
in 81-96% yields under the PV reaction conditions except
for 1h (34% yield).
Next, we examined a chlorination of alcohols8 with thionyl
chloride as a lighter reagent using the triphasic U-tube system
(Scheme 2). A toluene solution of benzyl alcohol 1a was
added to FC-72 held on the U-tube from one side (“the
reactant layer”), and thionyl chloride was floated on the other
side. The reaction progress in the reactant layer was
holds a lower fluorous phase that serves as a phase-screen
to separate the upper reagent and organic phases (d < 1.67).
The substrate added in the organic phase reacts with the
reagent regularly transported through the fluorous phase to
afford a product, and the reagent phase vanishes as it is
consumed. In this paper, we report the chlorination of
alcohols using thionyl chloride (d ) 1.63) and phosphorus
trichloride (d ) 1.57) as a lighter reagent as well as the
bromination of alcohols using thionyl bromide and phos-
phorus tribromide as a heavier reagent.
(6) (a) Nakamura, H.; Linclau, B.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 10119. (b) Luo, Z.; Swaleh, S. M.; Theil, F.; Curran, D. P. J. Org.
Chem. 2002, 4, 2582.
(7) For the established procedures of bromination of alcohols using SOBr2
and PBr3, see: (a) Organic Syntheses; Gilman, H., Ed.; Wiley: New York,
1941; Collect. Vol. I, p 36. (b) Organic Syntheses; Blatt, A. H., Ed.;
Wiley: New York, 1943; Collect. Vol. II, p 358.
(8) For the established procedures of chlorination of alcohols using SOCl2
and PCl3, see: (a) Organic Syntheses; Rabjohn, N., Ed.; Wiley: New York,
1963; Collect. Vol. IV, p 110. (b) Organic Syntheses; Blatt, A. H., Ed.;
Wiley: New York, 1943; Collect. Vol. II, p 136.
We first examined the bromination of alcohols7 using the
PV method. FC-72 (perfluorohexane, 2 mL) was placed in
1168
Org. Lett., Vol. 5, No. 8, 2003

monitored by GC or TLC analysis. The possibility of the
transport of toluene or 1a from the reactant layer to the
reagent layer through the fluorous layer was considered;
however, the thionyl chloride layer vanished within 3 h and
benzyl bromide 3a was obtained from the toluene reactant
layer in 95% yield (entry 1 in Table 2). 4-Methoxybenzyl
Scheme 3. Parallel Chlorination Using The Triphasic Multislit
Apparatus
Table 2. Triphasic U-Tube Chlorination of Alcohols 1 with
10
a
SOCl2 and PCl3
SOCl2
yield (%)b
PCl3
yield (%)b
entry alcohol chloride
time
4 h
time
12 h
1c
2c
3
4
5
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
95
98
94
98
93
80
83
94
62
86
52
36
70
58
30
28
12 h
12 h
27 h
21 h
25 h
27 h
50 h
6 h
12 h
20 h
13 h
13 h
apparatus as the phase-screen layer. Each toluene solution
of 1e, 1f, and 1g was added to FC-72 from each slit (P1-
P3), and thionyl chloride was floated on the slit R. The figure
at the right of Scheme 3 depicts the concept of the parallel
synthesis using the multislit system. Thionyl chloride was
transported through the FC-72 layer into the reactant layer
of each slit (P1-P3). After 24 h, the chlorination reactions
of alcohols in each slit were complete and the corresponding
chlorides 3e, 3f, and 3g were obtained in 70, 80, and 75%
yields, respectively, without any contamination of products.
The combination of the alcohols 1a, 1e, and 1g was also
examined under the same conditions, and 3e and 3g were
obtained in 91 and 75% yields, respectively, after 24 h.
Interestingly, 24% of 1a was converted into 3a at this
moment; however, the addition of another equivalent of
thionyl chloride to the slit (R2) and removal of other reactant
layers (P1 and P3) accelerated the chlorination of 1a to give
3a in 99% yield.
We have demonstrated that a fluorous solvent acts as a
phase screen between reagent and reactant phases and
regulates the bromination and the chlorination of alcohols.
The triphasic U-tube system was efficient for regulation of
the lighter reagent transport in the PV reaction. In this system,
it is essential that the rate of the passive transport of
unfluorinated reagents to the reactant layer through fluorous
media should be higher than that of reactant and product
transport from the reactant layer to the reagent layer. The
parallel chlorination of alcohols has been achieved using the
multislit apparatus without any contamination. It is now
possible to conduct reactions with controlled addition rates
of various unfluorinated reagents by the fluorous phase screen
independent of whether the reagent is more or less dense
than the phase screen.
6
7
8
1g
1h
3g
3h
3 days
3 days
a Conditions: 1 (0.3 mmol), PCl3 (1.2 mmol), FC-72 (3 mL), toluene (1
mL). b Isolated yields based on 1. c Addition of HOBt (3 equiv relative to
1) accelerated the reaction progress. Dichloromethane was used instead of
toluene. Without the addition of HOBt, 3a was obtained in 28% yield.9
alcohol 1b was also transformed into the corresponding
chloride 3b in 98% yield (entry 2). In both cases, the addition
of 1-hydroxybenzotriazole (HOBt) into the reactant layer was
effective for obtaining the chlorides in high yields.9 The
reaction of cinnamyl alcohol 1c and 1-naphthyl alcohol 1d
also proceeded smoothly, giving 3c and 3d in 94 and 98%
yields, respectively (entries 3 and 4). Not only primary
alcohols but also secondary and tertiary alcohols such as
diphenylmethanol 1e, 1-phenylpentan-1-ol 1f, 1-adamantanol
1g, and cholesterol 1h underwent the chlorination to afford
the corresponding chlorides 3e-h in 80-94 yields (entries
5-8). As the other lighter chlorination reagent, we chose
phosphorus trichloride and examined the chlorination of
alcohols under the same conditions. The chlorination of
alcohols proceeded, although the yields of the corresponding
chlorides were not necessarily high (28-86% yields in Table
2) in all cases.
It was envisioned that the triphasic U-tube system would
be suitable for a parallel synthesis. We designed the multislit
apparatus with an open bottom, as shown in Scheme 3. The
figure at the left of Scheme 3 depicts the designed multislit
apparatus for the parallel synthesis, and FC-72 to this
(9) Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 1763.
(10) Typical procedure is as follows: a solution of 1 (0.5 mmol) in
toluene (1 mL) was put into one side of the U-tube, in which FC-72 (3
mL) was placed, and SOCl2 (0.15 mL, 2 mmol) was put into the other side
of the U-tube. The SOCl2 layer vanished after 3-5 h. The reaction progress
was monitored by GC or TLC analysis. After the reaction was completed
(between 4 h and 3 days), the toluene layer was decanted and poured into
water. The mixture was extracted with ether, washed with a saturated NaCl
aqueous solution, and concentrated. The residue was purified by column
chromatography on silica gel with hexane (or ether) to give 3.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for compounds
1f, 2f, 2h, and 3f. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034060W
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