Direct and convenient conversion of alcohols to fluorides

Article abstract of DOI:10.1021/ol049672a

Directly mixing primary, secondary, and tertiary alcohols with nC ₄F₉SO₂F-NR₃(HF)₃-NR ₃ in THF or MeCN results in convenient conversion to the corresponding fluorides in high yields. The readily available reagents are easy to handle, and the mild, almost neutral reaction conditions allow for excellent functional group compatibility. A NR₃(HF)₃/NR₃ ratio of ≤ 1:2 gives the highest reactivity.

Full text of DOI:10.1021/ol049672a

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1465-1468
Direct and Convenient Conversion of
Alcohols to Fluorides
Jingjun Yin,* Devin S. Zarkowsky, David W. Thomas, Matthew M. Zhao, and
Mark A. Huffman
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
jingjun_yin@merck.com
Received February 24, 2004
ABSTRACT
Directly mixing primary, secondary, and tertiary alcohols with nC4F9SO2F−NR3(HF)3−NR3 in THF or MeCN results in convenient conversion to
the corresponding fluorides in high yields. The readily available reagents are easy to handle, and the mild, almost neutral reaction conditions
allow for excellent functional group compatibility. A NR3(HF)3/NR3 ratio of e1:2 gives the highest reactivity.
A carbon-fluorine bond is presented in numerous bioactive
compounds due to its resistance to metabolism with minimal
steric interference and other unique effects on a compound’s
biological activity.1 In the extensively studied area of
fluorination,2 direct conversion of an alcohol to the corre-
sponding fluoride has been one of the most effective
approaches. Many reagents have been developed for this
transformation, including SF4,3 SeF4,4 pyridinium poly-
(hydrogen fluoride) (Olah’s reagent) and its analogues,2b,5
fluoroalkyl amino reagents (FAR),6 ammonium and phos-
phonium perfluorocyclobutane ylides,7 2,2-difluoro-1,3-di-
methylimidazolidine (DFI),8 IF5/NEt3(HF)3,9 and perfluoro-
1-butanesulfonyl fluoride-DBU.10 However, these reagents
have seen limited application due to one or more of the
following reasons: being limited in scope, dangerous and
difficult to handle, not readily available, unstable, or low-
yielding or requiring harsh conditions. On the other hand,
DAST (diethylaminosulfur trifluoride)11,12 and its thermally
more stable analogues such as Deoxo-Fluor [bis(2-methoxy-
ethyl)aminosulfur trifluoride]13 have been widely used for
fluorinating alcohols due to their general reactivity,2a,14,15 but
they are expensive, corrosive, and problematic in a few
functionalized systems.16,17 Most of the above reagents
operate under acidic conditions, generating deadly HF. Here
we report a safer and convenient method for direct conversion
of alcohols to fluorides using readily available reagents under
mild and almost neutral conditions.
(1) Welch, J. T. Tetrahedron 1987, 43, 3123.
We envisioned an approach by a mechanism similar to
that in fluorination with DAST or any dialkylaminosulfur
(2) (a) Spargo, P. L. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon: New York, 1995; Vol. 2, p 1. (b) Yoneda, N. Tetrahedron 1991,
47, 5329.
(8) Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T. Chem. Commun.
2002, 1618.
(3) Wang, C. L. J. Org. React. 1985, 34, 319.
(4) Olah, G. A.; Nojima, M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96,
925.
(5) (a) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes,
I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872. (b) Busci, I.; To¨ro¨k, B.; Marco,
A. I.; Rasul, G.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem. Soc. 2002,
124, 7728 and references therein.
(9) Yoneda, N.; Fukuhara, T. Chem. Lett. 2001, 222.
(10) (a) Bennua-Skalmowski, B.; Vorbru¨ggen, H. Tetrahedron Lett. 1995,
36, 2611. (b) Savu, P. M.; Snustad, D. PCT Int. Appl. WO 0031003, 2000.
(11) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(12) For a review and a survey of all the suitable substrates, see: (a)
Hudlicky, M. Org. React. 1988, 35, 513.
(6) For examples: (a) Yarovenko, N. N.; Raksha, M. A. J. Gen. Chem.
(Engl. Transl.) 1959, 29, 2125. (b) Takaoka, A.; Iwakiri, H.; Ishikawa, N.
Bull. Chem. Soc. Jpn. 1979, 52, 3377. (c) Dmowski, W.; Kamin´ski, M. J.
Fluorine Chem. 1983, 23, 219. (d) Petrov, V. A.; Swearingen, S.; Hong,
W.; Petersen, W. C. J. Fluorine Chem. 2001, 109, 25.
(7) (a) Pasenok, S. V.; de Roos, M. E.; Appel, W. K. Tetrahedron 1996,
52, 2977.
(13) (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215. (b) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F.
M.; Cheng, H. J. Org. Chem. 1999, 64, 7048.
(14) For a recent review, see: Singh, R. P.; Shreeve, J. M. Synthesis
2002, 17, 2561.
(15) DAST and analogues have compared favorably with most other
fluorinating reagents. See ref 12.
10.1021/ol049672a CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

the best solvent to carry out both triflate formation and
fluorination in one pot.
Scheme 1
NEt3(HF)3 (7)22 was found to be the most reactive fluoride
source.23 In addition, it is anhydrous, soluble in organic
solvents, and inexpensive. Although NEt3(HF)2, prepared
from NEt3(HF)3/NEt3 in a 2:1 ratio, had been found to be
better than a 1:0 or 1:2 ratio,24 we found that NEt3HF, from
a 1:2 ratio of NEt3(HF)3/NEt3, was most reactive in various
solvents for this substrate. Therefore, a practical, one-pot
synthesis of 6 could be achieved in 73% yield by treating
the in situ-formed triflate solution in MeCN, 5a, with
NEt3(HF)3/NEt3 (1:2) at 50 °C.
Encouraged by the initial success, we attempted a simpler
procedure by adding the triflic anhydride into the mixture
of alcohol, base, and the fluorinating reagents, but a
significant amount of starting material was recovered,
indicating the incompatibility between Tf2O and NEt3(HF)3/
NEt3.25 The result also suggests the requirement of complete
triflate formation before fluorination, which makes the two-
step procedure discontinuous and problematic if the triflate
is unstable.26
Perfluoro-1-butanesulfonyl fluoride (PBSF) was then used
to activate alcohols due to its compatibility with NEt3(HF)3.
To study the extent of elimination as a major side reaction,
4-phenyl-2-butanol (8) was used to optimize the reaction
conditions (Table 1).
trifluoride (Scheme 1).11,12 The alcohol is activated by DAST
via the intermediate 2a,18 which is then attacked in situ by
fluoride to form the carbon-fluorine bond in 3 with 1 equiv
of HF as the byproduct. To achieve the same results without
using an expensive F3SNR12 reagent or generating free HF,
one could form a similar sulfonate leaving group as in 2b
followed by in situ fluorination with a compatible fluorinating
reagent under near-neutral conditions.
Fluorination of 2-hydroxy-1,3,5-tri-O-benzoyl-R-D-ribo-
furanose (4) and its analogues has attracted much interest
for the synthesis of many biologically active compounds. It
has been achieved in one step by using DAST19 or in two
steps by fluorinating the isolated sulfonates 5a-c (Scheme
2).16b,20 To establish an appropriate sulfonate leaving group
Table 1. Optimization of Conditions with PBSFa
Scheme 2a
7
NEt3
PBSF
conversion 9b
entry (equiv) (equiv) (equiv) solvent
(%)
(%) 9/10c
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.0
6.0
6.0
6.0
6.0
4.0
3.0
2.0
4.5
3.3
3.3f
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.3e
1.3e
MeCN
CH2Cl2
toluene
THF
THF
THF
THF
THFd
CH2Cl2
CH2Cl2
tolueneg
100
98
94
98
94
84
57
99
97
96
92
75 3.5
81 5.3
79 7.5
82 6.8
79 6.6
70 6.3
47 5.8
82 6.4
72 3.2
69 3.1
61 6.4
a One-pot procedure: Pyr, Tf2O, MeCN, rt; then NEt3(HF)3-
NEt3, 50 °C, 18 h, 73% yield.
in 2b as well as a reactive fluoride source, we decided to
first develop a practical one-pot synthesis of 6 from com-
mercially available 4. After numerous experiments, we found
that triflate, as in 5a, was the best leaving group21 and MeCN
10
11
1.8 equiv of DBU,
1.8 equiv of PBSF
1.2 equiv of Deoxo-Fluor CH2Cl2
(16) (a) Konas, D. W.; Coward, J. K. J. Org. Chem. 2001, 66, 8831. (b)
Tann, C. H.; Brodfuehrer, P. R.; Brundidge, S. P.; Sapino, C., Jr.; Howell,
H. G. J. Org. Chem. 1985, 50, 3644. (c) Tewson, T. J.; Welch, M. J. J.
Org. Chem. 1978, 43, 1090.
(17) In those cases (ref 16), the fluorination could be realized via isolated
triflate/imidazolylsulfonate.
h
12
91
72 5.4
a Reaction conditions: 1.0 mmol 8, NEt3(HF)3 (7), NEt3, PBSF, solvent
(3 mL/mmol), rt, 15-20h. b Estimated LC yield. c Uncorrected LC area
ratio. d Conditions: 1 mL/mmol. e Tf2O was used instead; triflate formation
at -78 to 0 °C; fluorination at 0 °C to room temperature. f iPr2NEt was
used as the base; iPr2NEt(HF)3 was used instead of 7. g Conditions: 1 mL/
mmol, 0 °C, DBU added last. h Conditions: 0.5 mL/mmol, -78 °C to room
temperature.
(18) For an isolation of the intermediate, see: Sutherland, A.; Vederas,
J. C. Chem. Commun. 1999, 1739.
(19) Scha¨rer, O. D.; Verdine, G. L. J. Am. Chem. Soc. 1995, 117, 10781.
(20) (a) Chou, T. S.; Becke, L. M.; O’Toole, J. C.; Carr, A.; Parker, B.
E. Tetrahedron Lett. 1996, 37, 17. (b) Alauddin, M. M.; Conti, P. S.;
Mathew, T.; Fissekis, J. D.; Prakash, G. K. S.; Watanabe, K. A. J. Fluorine
Chem. 2000, 106, 87. (c) Rubira, M.-J.; Jimeno, M.-L.; Balzarini, J.;
Camarasa, M.-J.; Pe´rez-Pe´rez, M.-J. Tetrahedron 1998, 54, 8223. (d) Ma,
T.; Pai, S. B.; Zhu, Y. L.; Lin, J. S.; Shanmuganathan, K.; Du. J.; Wang,
C.; Kim, H.; Newton, M. G.; Cheng, Y. C.; Chu, C. K. J. Med. Chem.
1996, 39, 2835. (e) Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose,
N.; Izawa, K. Tetrahedron Lett. 2001, 42, 2321.
The fluorination of 8 proceeded smoothly to give 9 with
PBSF activation in the presence of NEt3(HF)3/NEt3 in various
solvents with a mixture of olefinic isomers 10 as major
byproducts. MeCN gave the fastest reaction but with a low
1466
Org. Lett., Vol. 6, No. 9, 2004

product/elimination selectivity of 3.5 (entry 1). Toluene gave
the highest selectivity of 7.5 (entry 3), but the reaction was
slow as a bilayer mixture. THF was chosen as a good
compromise to give a fast reaction and good selectivity (entry
4). Once again, a lower ratio of NEt3(HF)3/NEt3 at e1:2 gave
a faster reaction as well as a better product/elimination ratio
(entries 4-7). Less reagents could be used at a higher
concentration with slightly more elimination (entry 8).
Use of triflic anhydride resulted in higher amounts of
elimination with NEt3 or Hu¨nig’s base as the base (entries 9
and 10). The combination of PBSF-DBU in toluene10b
resulted in slightly more elimination and a significantly less
clean reaction with only 61% of the fluorinated product
formed (entry 11). Deoxo-Fluor gave a slower reaction with
slightly more elimination under the literature conditions13
(entry 12).
a
Table 2. Fluorination with PBSF-NEt3(HF)3-NEt3
Under the optimized conditions (entry 4), all the reagents
could be mixed together with the alcohol in any order for
fluorination without the need to preform the sulfonate
intermediate.27 Therefore, PBSF-NEt3(HF)3-NEt3 functions
as a reagent combination that fluorinates alcohols operation-
ally similar to DAST and Deoxo-Fluor.
We then applied this new reagent combination to a variety
of alcohols (Table 2).28
Secondary alcohols were fluorinated in high yields (entries
1-3), and a primary tosylate could be tolerated (entry 3).
Secondary benzylic alcohols also gave good yields (entries
4 and 5).29 The protected arabinofuranose and glucopyranose
precursors to 12e and 12f were readily fluorinated, giving
an R/â anomer ratio of 1:2.4 and 3.5:1, respectively (entries
6 and 7). Interestingly, the same reactions with Deoxo-Fluor
gave reversed selectivity of 1.8:1 and 1:2.3 for 12e and 12f,
respectively. The tertiary alcohol fluorinated to produce 12g
required forcing conditions at 95 °C (entry 8).30
a Reaction conditions: 1.0 mmol of ROH, 2 equiv of PBSF, 2 equiv of
NEt3(HF)3, 6 equiv of of NEt3, THF (1-4 mL/mmol ROH). b Parenthetical
numbers are LC yields. c MeCN as the solvent. d DCE as the solvent.
e Conditions: 3 equiv of PBSF, 3 equiv of NEt3(HF)3, 9 equiv of NEt3,
sealed Schlenk tube.
Unfortunately, fluorination of primary and activated ben-
zylic alcohols gave significant amounts of impurities, likely
from the displacement of the activated hydroxy group by
triethylamine.31 To overcome this problem, the bulkier
Hu¨nig’s base32 and its trishydrofluoride were used instead.
This Hu¨nig’s base variant gave excellent results on these
alcohols (Table 3).
Primary alcohols typically gave very clean reactions in
excellent yields (entries 1-5).33 It is noteworthy that the
aldehyde group in 12k was tolerated with this method,
although the reaction using Deoxo-Fluor resulted in a mixture
of products.34 Other functional groups such as esters (entries
5 and 6) and a ketone (entry 7) are also well tolerated. The
fluorination of benzhydrol and 9-hydroxyfluorene with
DAST gave only 40-48% of fluorides with a significant
amount of dimeric ether (13-44%);35 we faced the same
problem with MeCN as the solvent. Switching the solvent
(21) Formation of an imidazolylsulfonate 5b (also the precursor to 5c)
would produce a chloride that would act as a nucleophile. Other sulfonates
such as mesylate and tosylate are not active enough.
(22) For a review of this commercially available reagent, see: McClinton,
M. A. Aldrichimica Acta 1995, 28, 31.
(23) Tetrabutylammonium fluoride (TBAF) is wet as a solid or solution.
Metal fluorides such as KF and CsF need to be used in highly toxic solvents
such as formamide and N-methylformamide and often give significant
hydrolysis. See: (a) Fritz-Langhals, E. Tetrahedron: Asymmetry 1994, 5,
981. (b) Fritz-Langhals, E. Tetrahedron Lett. 1994, 35, 1851. (c) Ref 20b.
Many modified metal fluoride reagents have been reported, but most are
less efficient than TBAF: (d) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am.
Chem. Soc. 2002, 124, 10278 and references therein.
(24) (a) Giudicelli, M. B.; Picq, D.; Veyron, B. Tetrahedron Lett. 1990,
31, 6527. (b) Ref 20a.
(25) FSO2CF3 might be formed as a gas.
(26) One-pot conversion of few ethanols with a 2-electron-withdrawing
group to fluorides using methane- or benzene-sulfonyl fluoride and KF in
<60% yields has been reported: Pattison, F. L. M.; Millington, J. E. Can.
J. Chem. 1956, 34, 757.
(27) We only observed the sulfonate intermediate by LC or GC in very
few cases.
(28) Typical Procedure (Table 2, entry 1): 4-Phenyl-2-butanol (306
mg, 2.0 mmol, 1.0 equiv), PBSF (0.72 mL, 4.0 mmol, 2.0 equiv), NEt3(HF)3
(0.656 mL, 4.0 mmol, 2.0 equiv), and NEt3 (1.67 mL, 12.0 mmol, 6.0 equiv)
were stirred in 6 mL of THF at room temperature for 26 h when LC revealed
>98% conversion (LC assay yield 88%). The mixture was filtered through
a short SiO2 plug, concentrated, and purified by SiO2 column to give 240
mg of 9 (79% isolated yield, 9% loss in distillate during concentration) as
a colorless oil (ref 24a). 19F NMR (377 MHz, CDCl3) δ -174.5.
(29) LC yields are given due to the low boiling points and rather fast
decomposition of the isolated products.
(31) LC-MS data and its water solubility support the proposed assign-
ment. Reaction of primary triflate with pyridine to form water-soluble
pyrdinium salt has been reported: Ambrose, M. G.; Binkley, R. W. J. Org.
Chem. 1983, 48, 674. We also observed a similar product when pyridine
was used.
(32) Use of other bases such as pyridine, 2,6-lutidine, DABCO, DBU,
TMEDA, and so on gave inferior results.
(33) We generally saw slower and incomplete reactions for fluorination
of primary alcohols using Deoxo-Fluor.
(34) Deoxo-Fluor is known to react with aldehydes. See ref 13.
(35) Johnson, A. L. J. Org. Chem. 1982, 47, 5220.
(30) Treating 4 with the reagent combination failed to give 6.
Org. Lett., Vol. 6, No. 9, 2004
1467

In addition to its general reactivity and some unique
selectivities shown above, the new reagent combinations
fluorinate alcohols under almost neutral and thus safer
conditions, because HF is quenched by 1 equiv of base in
situ.36,37 Unlike DAST, Deoxo-Fluor, and Tf2O, which react
violently with water, all reagents are relatively stable upon
exposure to air or moisture.38 Reactions could be readily
carried out in capped vials/flasks without special precaution
to remove air or moisture. All these features should make
the combination of PBSF-NEt3(HF)3-NEt3 and its Hu¨nig’s
base variant valuable additions to the arsenal for direct
fluorination of alcohols.
Table 3. Fluorination with PBSF-iPr2NEt(HF)3-iPr2NEta
In summary, we have developed a novel reagent combina-
tion, PBSF-NEt3(HF)3-NEt3, for direct and convenient
fluorination of alcohols in high yields. The Hu¨nig’s base
variation, PBSF-iPr2NEt(HF)3-iPr2NEt, is preferred with
primary and activated benzylic alcohols. Various functional
groups could be tolerated. A combination of NEt3(HF)3/NEt3
in e1:2 ratio was found to be the most reactive fluorinating
species. All reagents are readily available and easy to handle,
and the reactions are carried out under mild and near-neutral
conditions without generating free HF.
Acknowledgment. We thank Far Research for a generous
gift of iPr2NEt(HF)3.
Supporting Information Available: Experimental pro-
cedures and characterization data for fluorination products
(Tables 2 and 3). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049672A
a Reaction conditions: 1.0 mmol ROH, MeCN (1 mL/mmol ROH).
b MeCN (0.5 mL/mmol ROH). c Parenthetical number is an LC yield. d THF
is the solvent (4 mL/mmol ROH).
(36) In the reaction to give 12k, direct quench of the reaction with water
gave a pH of 6, well above the pKa of HF (3.2 in water).
(37) By contrast, fluorination with DAST or Deoxo-Fluor generates 1
equiv of HF, which also etches glass as we have observed. We have not
seen any etching using the reagent combination. NEt3(HF)3 is also reported
to be noncorrosive to glassware due to its almost neutral pH. See refs 20a
and 22.
(38) PBSF is immiscible with water. After stirring with water for 6 h at
room temperature, it is still effective for fluorination, giving 12k (Table 3,
entry 4).
to THF along with a higher dilution improved the yields of
the desired fluorination to 88 and 65% (entries 8 and 9). A
combination of 2 equiv of PBSF, 2 equiv of iPr2NEt(HF)3,
and 6 equiv of iPr2NEt is generally effective, but lower levels
of reagents could also be used (entries 4, 6, and 7).
1468
Org. Lett., Vol. 6, No. 9, 2004