Fluorous, Chromatography-Free Mitsunobu Reaction

Article abstract of DOI:10.1021/ol0264511

(Matrix Presented) The reaction of secondary and primary alcohols with highly fluorinated 3,4,5-tris(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluorododecan-1- yloxy)benzoic acid in the presence of Ph₃P and DIAD in THF at room temperature (fluorous Mitsunobu) resulted in a simple, chromatography-free isolation protocol with excellent yields (83-96%).

Full text of DOI:10.1021/ol0264511

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3785-3787
Fluorous, Chromatography-Free
Mitsunobu Reaction
Marcin W. Markowicz and Roman Dembinski*
Department of Chemistry, Oakland UniVersity, 2200 N. Squirrel Rd.,
Rochester, Michigan 48309-4477
dembinsk@oakland.edu
Received July 1, 2002
ABSTRACT
The reaction of secondary and primary alcohols with highly fluorinated 3,4,5-tris(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluorododecan-
1-yloxy)benzoic acid in the presence of Ph3P and DIAD in THF at room temperature (fluorous Mitsunobu) resulted in a simple, chromatography-
free isolation protocol with excellent yields (83−96%).
The term “fluorous” has been introduced as an analogue to
“aqueous” for a highly fluorinated alkane, ether, or tertiary
amine.1 Such compounds are very nonpolar. They commonly
form bilayers with organic solvents at room temperature;
however, many of these combinations become miscible at
elevated temperatures. Many are commercially available.2
Fluorous chemistry develops a “parallel universe” of
organic molecules3 and is designed to facilitate separation
of catalysts or isolation of products. Many applications of
fluorous methodology have been developed over the past
few years focusing mainly on the development of fluorous
catalysts,4 fluorous silica gel,5 or a “tagging” protocol.4a,6
Fluorous compounds are separable or recoverable with
fluorous solvents or fluorous stationary phases.4 Recent
advances include triphase7 and organic liquid/fluorous solid
systems.8
Reactions that furnish easily isolable products are of great
interest in the development of environmentally friendly
technologies. Although the number is increasing, fluorous
analogues of traditional organic reactions remain surprisingly
scarce.6,9-14 The Mitsunobu protocol (Scheme 1), which, as
Scheme 1. Mitsunobu Reaction
(1) Horva´th, I. T. Acc. Chem. Res. 1998, 31, 641-650.
(2) (a) Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. ReV. 1999, 190-
192, 587-605. (b) Betzemeier, B.; Knochel P. Top. Curr. Chem. 1999,
206, 61-78.
(3) Cornils, B.; Herrmann, W. A. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.;
Wiley-VCH: Weinheim, Germany, 1996; Chapter 4.1, pp 1167-1197.
(4) Review literature since 1998: (a) Luo, Z. Y.; Zhang, Q. S.;
Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769. (b) Curran,
D. P. Pure Appl. Chem. 2000, 72, 1649-1653. (c) de Wolf, E.; van Koten,
G.; Deelman, B.-J. Chem. Soc. ReV. 1999, 28, 37-41. (d) Fish, R. H. Chem.
Eur. J. 1999, 5, 1677-1680. (e) Cavazzini, M.; Montanari, F.; Pozzi, G.;
Quici, S. J. Fluorine Chem. 1999, 94, 183-193. (f) Hope, E. G.; Stuart, A.
M. J. Fluorine Chem. 1999, 100, 75-83. (g) Curran, D. P. Angew. Chem.,
Int. Ed. 1998, 37, 1174-1196.
initially formulated, involves the reaction of diethyl azodi-
carboxylate (DEAD, R′ ) Et) with triphenylphosphine,15 has
(5) (a) Curran, D. P. Synlett 2001, 1488-1496. (b) Zhang, Q.; Luo, Z.;
Curran, D. P. J. Org. Chem. 2000, 65, 8866-8873. (c) Curran, D. P.; Luo,
Z. J. Am. Chem. Soc. 1999, 121, 9069-9072.
(6) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997,
62, 2917-2924.
10.1021/ol0264511 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002

been widely used in organic synthesis, in particular for the
inversion of configuration in secondary alcohols (1). Syn-
thetic advances have been summarized in reviews,15,16 and
the general mechanistic features have recently received
additional insight.17 Recent improvements in the isolation
protocol include the use of solid support, such as (diphenyl-
phosphino)polystyrene.18 Furthermore, impurity annihilation
during aqueous acidic (CF3COOH) treatment has simplified
workup procedures.
The “tagging” methodology, conceptually introduced by
Curran and Wipf,6 is based on the introduction of a fluorous
“ponytail” into the product and subsequent exploitation for
separation, followed by “detagging”. We have found this
concept to be well suited for the Mitsunobu reaction,19,20
where separation usually requires column chromatography.
Achieving high fluorous partition significantly improves
separation. For best results, the total fluorine content of
fluorous-compatible molecules should be above 60%.1,5a The
number of perfluoroalkyl groups is also an important factor
controlling the partition coefficient, because appropriate
shielding of the hydrocarbon domain leads to higher fluorous
solubility and higher partition.21 Considering the above, we
have developed a tagging unit from inexpensive gallic acid.
Etherification of gallic acid methyl ester with perfluoroalkyl
iodide F(CF2)8(CH2)4I22 and subsequent base hydrolysis gave
3,4,5-tris(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadeca-
fluorododecan-1-yloxy)benzoic acid (2, Figure 1) with yields
The use of fluorous 2 as the nucleophile in the Mitsunobu
reaction offers two other advantages: (i) fluorous esters 3
are solids and can be easily isolated by simple crystallization,
and (ii) the fluorous part (Nu) can be readily disassociated
from the organic products by saponification with excellent
yield,23 thereby providing facile recycling opportunities.
The reactions of several representative alcohols with
various functional groups and different carbon skeletons were
investigated. All reactions were carried out in the absence
of a fluorous solvent, since THF provided good solubility
for 2. The literature does not provide support for any
advantage of DEAD over DIAD;16a therefore, we choose the
less expensive i-Pr derivative. The results are summarized
in Table 1. Initially, ethanol (entry a) afforded almost
Table 1. Mitsunobu Reaction of Primary and Secondary Alco-
hols 1 with Tris(heptadecafluorododecanyloxy)benzoic Acid 2
Figure 1.
a All reactions were conducted with DIAD (R′ ) i-Pr) in THF. b Reaction
time and stoichiometry were not optimized. Number of equivalents refers
to the Ph3P, 2, and DIAD with respect to 1. c Calculated with regard to 2.
comparable to those reported earlier.23 The three perfluoro-
alkyl ponytails provide appropriate shielding, and a fluorine
content of 60.9% for the ArCOO (Nu, MW ) 1592) unit
exceeds the requirements for good fluorous partition.1,5a
complete reaction and quantitative isolation with respect to
the fluorous tagging group. The THF solution of tris(hepta-
decafluorododecanyloxy)benzoic acid 2 (1.0 equiv) and Ph3P
(1.4 equiv), when treated with an excess of ethanol (1.3
(7) (a) Nakamura, H.; Linclau, B.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 10119-10120. (b) Luo, Z.; Swaleh, S. M.; Theil, F.; Curran, D. P.
Org. Lett. 2002, 4, 2585-2587.
(8) Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc. 2001, 123,
11490-11491.
(17) (a) Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67,
1751-1753. (b) Ahn, C.; DeShong, P. J. Org. Chem. 2002, 67, 1754-
1759. (c) Watanabe, T.; Gridnev, I. D.; Imamoto, T. Chirality 2000, 12,
346-351. (d) Compare also: Crich, D.; Dyker, H.; Harris, R. J. J. Org.
Chem. 1989, 54, 257-259.
(9) Crich, D.; Neelamkavil, S. J. Am. Chem. Soc. 2001, 123, 7449-
7450.
(10) (a) Crich, D.; Barba, G. R. Org. Lett. 2000, 2, 989-991. (b) Crich,
D.; Neelamkavil, S.; Sartillo-Piscil, F. Org. Lett. 2000, 2, 4029-4031.
(11) Betzemeier, B.; Cavazzini, M.; Quici, S.; Knochel, P. Tetrahedron
Lett. 2000, 41, 4343-4346.
(12) (a) Xiang, J.; Toyoshima, S.; Orita, A.; Otera, J. Angew. Chem.,
Int. Ed. 2001, 40, 3670-3672. (b) Hoshino, M.; Degenkolb, P.; Curran, D.
P. J. Org. Chem. 1997, 62, 8341-8349.
(18) (a) Pelletier, J. C.; Kincaid, S. Tetrahedron Lett. 2000, 41, 797-
800. (b) Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2,
2999-3001. For other interesting polystyrene-supported phosphine (not
chromatography-free) protocols see: (c) Charette, A. B.; Janes, M. K.;
Boezio, A. A. J. Org. Chem. 2001, 66, 2178-2180. (d) Tunoori, A. R.;
Dutta, D.; Georg, G. I. Tetrahedron Lett. 1998, 39, 8751-8754.
(19) Fluorous Mitsunobu reaction was recently reported with fluorous
phosphines and diazodicarboxylate and for synthesis of fluorophilic
ethers: (a) Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855-
3864. (b) Dobbs, A. P.; McGregor-Johnson, C. Tetrahedron Lett. 2002,
43, 2807-2810. (c) Ra´bai, J.; Szabo´, D.; Borba´s, E. K.; Ko¨vesi, I.; Ko¨vesdi,
I.; Csa´mpai, A.; Go¨mo¨ry, AÄ .; Pashinnik, V. E.; Shermolovich, Y. G. J.
Fluorine Chem. 2002, 114, 199-207.
(13) (a) Isihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371-1374.
(b) Chen, D.; Qing, F.; Huang, Y. Org. Lett. 2002, 4, 1003-1005.
(14) Moineau, J.; Pozzi, G.; Quici, S.; Sinou, D. Tetrahedron Lett. 1999,
40, 7683-7686.
(15) Mitsunobu, O. Synthesis 1981, 1-28.
(16) (a) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164. (b)
Hughes, D. L. Org. React. 1992, 42, 335-656. (c) Castro, B. Org. React.
1983, 29, 1-162.
3786
Org. Lett., Vol. 4, No. 22, 2002

equiv) and DIAD (R′ ) i-Pr, 1.3 equiv), afforded ester 3a
in 95% yield after 24 h (room temperature) and workup
(Scheme 1). Next, alternative isolation procedures were
investigated for geraniol (1b). This aliphatic alcohol increased
the organic (nonfluorous) domain in ester 3b (fluorous
content 56.0%). The reaction was carried out in a similar
manner for 40 h. The solvent (THF) was evaporated to
dryness, and the remaining solid residue was treated in three
different ways. Supercritical CO2 extraction, which has been
applied in a fluorous protocol,24 gave the 3b/Ph3PO mixture
in a nearly equimolar ratio. Single extraction of the second
portion with a fluorous solvent (perfluorocyclohexane) at
room temperature gave ester 3b (79%), contaminated with
separate. Esters 3a-f, all white solids, were soluble in THF
and CHCl3 and characterized by 1H and 13C NMR spectros-
copy and MS. All gave the correct elemental analyses.
A representative alcohol was also disassociated from the
fluorous part (Nu) in high yield. A 5R-cholestan-3R-ol was
isolated in 94% yield after saponification of the fluorous ester
3f26 (obtained from 5R-cholestan-3â-ol). Then, the tagging
acid 2 was isolated in 78% yield; it was also recycled
efficiently in a separate experiment from the combined 3a-e
in a one-vessel procedure.
In conclusion, we have applied a highly fluorous nucleo-
philic partner in the Mitsunobu reaction, which results in a
simple, chromatography-free separation protocol and excel-
lent yields.
1
Ph3PO (<7% as established by H NMR). The best results
(83%, entry b) were achieved when the crude reaction
mixture was crystallized from 1:1 CHCl3/MeOH, which may
be classified in the organic liquid/fluorous solid category.8
Finally, representative racemic (entries c-e) and optically
active (entry f) secondary alcohols were examined. Isolation
by simple crystallization in an analogous way gave analyti-
cally pure esters 3c-f with excellent yields (92-96%).25 The
somewhat lower yield of geranyl ester 3b (83%) was
attributed to poor separation due to the relatively low melting
point, rather than to contribution of the increased organic
component. The more organic-rich cholestanyl ester 3f
(49.4% fluorous content) was isolated in 94% yield. We have
noted that an excess of nucleophile 2 relative to alcohol 1
resulted in isolation of a 2/3 mixture, which was difficult to
Acknowledgment. We thank the Oakland University,
Research Excellence Fund program in biotechnology for
support of this research, Prof. J. A. Gladysz for helpful
discussions, and Prof. L. Schweitzer for scCO2 extraction.
Supporting Information Available: Synthetic procedures
1
and H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0264511
(25) Representative Experimental Procedure. A round-bottom flask
was charged with 2 (0.478 g, 0.300 mmol), THF (10 mL), and triphenyl-
phosphine (0.211 g, 0.804 mmol). The mixture was stirred under a nitrogen
atmosphere at room temperature. 3-Butyn-2-ol (10% solution in THF
(v/v), 0.30 mL, 0.38 mmol) was added to the reaction mixture, followed
by DIAD (0.15 mL, 0.76 mmol). The reaction mixture was stirred for 40
h. The solvent was evaporated by rotary evaporation and the residue
recrystallized from 1:1 v/v CHCl3/MeOH. A white solid of 3d was isolated
by filtration and dried over P2O5 under an oil pump vacuum (0.458 g, 0.278
mmol, 93%).
(26) A round-bottom flask was charged with 3f (0.500 g, 0.255 mmol),
1:1 v/v THF/methanol (30 mL), and KOH (10 M, 0.6 mL). The mixture
was refluxed for 1.5 h, cooled, and acidified with diluted HCl. The solvent
was removed by rotary evaporation (water pump). The solid residue was
extracted with CH2Cl2 and filtered on a silica gel pad. The solvent was
removed by rotary evaporation to give 5R-cholestan-3R-ol as a white solid
(0.093 g, 0.24 mmol, 94%). The silica gel pad with remaining solid was
washed with THF. The solvent was removed by rotary evaporation and
crystallized from 1:1 v/v CHCl3/MeOH. Filtration gave 2 (0.317 g, 0.199
mmol, 78%).
(20) During the course of this work, a lipase-catalyzed separation
combined with fluorous tagging was reported: Hungerhoff, B.; Sonnen-
schein, H.; Theil, F. J. Org. Chem. 2002, 67, 1781-1785.
(21) Herrera, V.; de Rege, P. J. F.; Horva´th, I. T.; Le Husebo, T.; Hughes,
R. P. Inorg. Chem. Commun. 1998, 1, 197-199.
(22) (a) Vincent, J.-M.; Rabion, A.; Yachandra, V. K.; Fish, R. H. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2346-2349. (b) Johansson, G.; Percec, V.;
Ungar, G.; Smith, K. Chem. Mater. 1997, 9, 164-175.
(23) Johansson, G.; Percec, V.; Ungar, G.; Zhou, J. P. Macromolecules
1996, 29, 646-660.
(24) (a) Leitner, W. Acc. Chem. Res. 2002, 35, 746-756. (b) Wells, S.
L.; DeSimone, J. Angew. Chem., Int. Ed. 2001, 40, 518-527. (c) Jessop,
P. G.; Ikariya, T.; Noyori, R. Chem. ReV. 1999, 99, 475-494. Representative
communications: (d) Komoto, I.; Kobayashi, S. Org. Lett. 2002, 7, 1115-
1118. (e) Carter, C. A. G.; Baker, R. T.; Nolan, S. P.; Tumas, W. Chem.
Commun. 2000, 347-348.
Org. Lett., Vol. 4, No. 22, 2002
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