Nucleophilic fluorination of triflates by tetrabutylammonium bifluoride

Article abstract of DOI:10.1021/jo8015659

(Chemical Equation Presented) Careful examination of nucleophilicity, basicity, and leaving group ability led us to discover the nucleophilic fluorination of triflates by weakly basic tetrabutylammonium bifluoride, which provides excellent yields with minimal formation of elimination-derived side products. Primary hydroxyl groups as well as secondary hydroxyl groups in acyclic chains or in five-membered rings are excellent substrates, whereas benzylic and aldol-type secondary hydroxyl groups give poor yields as a result of the instability of their triflates.

Full text of DOI:10.1021/jo8015659

crown ether or cryptand,4 tetraalkylammonium fluoride,5 and
its analogs.6 Although tetraalkylammonium fluoride and its
analogs became very popular reagents, they still suffered from
low stability and difficult control of the quality of the reagent.7
These problems were improved significantly by the recent
discovery by DiMagno et al. of “truly anhydrous TBAF”
generated in situ from the nucleophilic aromatic substitution
reaction of hexafluorobenzene with tetrabutylammonium cya-
nide.8 As an alternative, a new medium for this reaction was
studied by Chi et al., who reported that alkali metal fluorides
in ionic liquids,9 t-BuOH,10 or combinations thereof11 are
excellent for nucleophilic fluorination. As illustrated, most
investigations on nucleophilic fluorination were directed toward
the development of more reactive fluoride ion sources, which
is occasionally complicated by the formation of undesired
elimination side products due to fluoride’s strongly basic
character. In this regard, considering the immensely enhanced
leaving group ability of triflates (ca. 10,000 times faster than
tosylate toward solvolysis)12 compared to halides, mesylates,
or tosylates, we investigated the reaction profile of triflates with
fluoride ion species that are less nucleophilic than tetrabuty-
lammonium fluoride (TBAF) to determine whether they are
reactive enough to give both good conversion and selectivity
for displacement over elimination.13
In the course of the process development of LC15-0133 (1,
Scheme 1),14 a potent DPP-IV inhibitor, we had to devise a
viable large-scale synthesis of a key intermediate, 4-fluoro-
proline derivative 2a.15 Earlier in the development, it was
prepared by the reaction of 3-hydroxyl-proline 3a with DAST
(Table 1, entry 1). However, its high cost and exothermic
character, particularly during quenching of excess reagent,
rendered its use impractical for a large-scale operation. As
alternatives to DAST, we tested various methods such as CsF
in t-BuOH10 (entries 3 and 4), acetone (entry 5), and acetonitrile
in the presence of polymer-supported ionic liquids16 (entry 2)
with either 4-triflyl- or 4-mesyl-prolines (3a and b). In most of
Nucleophilic Fluorination of Triflates by
Tetrabutylammonium Bifluoride
Kyu-Young Kim, Bong Chan Kim, Hee Bong Lee,* and
Hyunik Shin*
Chemical DeVelopment DiVision, LG Life Sciences, Ltd.,
R&D Park, 104-1 Moonji-dong, Yusung-gu,
Daejeon 305-380, Korea
hbonglee@lgls.com; hisin@lgls.com
ReceiVed July 18, 2008
Careful examination of nucleophilicity, basicity, and leaving
group ability led us to discover the nucleophilic fluorination
of triflates by weakly basic tetrabutylammonium bifluoride,
which provides excellent yields with minimal formation of
elimination-derived side products. Primary hydroxyl groups
as well as secondary hydroxyl groups in acyclic chains or
in five-membered rings are excellent substrates, whereas
benzylic and aldol-type secondary hydroxyl groups give poor
yields as a result of the instability of their triflates.
Although organofluorine compounds are rarely found in
nature,1 the frequency of incorporation of fluorine into phar-
maceuticals is increasing at an explosive rate.2 As the most
electronegative element, the inclusion of fluorine into a molecule
commonly alters its metabolic stability, the basicity of basic
groups when embedded within proximity, and occasionally its
affinity toward a target protein. It also induces delicate changes
in conformational behavior,3 which can result in dramatic
changes in physicochemical properties.
Among the many methods used for the introduction of
fluorine, nucleophilic substitution reactions of aliphatic halides
or sulfonates by fluoride ion is the most commonly used due to
its high functional group tolerance compared with other methods.
As a classical method, alkali metal fluoride was frequently used
as a nucleophilic partner toward halides or sulfonates, although
usually at high temperatures to overcome limited solubility and
lower reactivity. Later, a more reactive “naked fluoride”
generated by the action of PTC led to the development of KF-
(4) Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250. (b) Gokel,
G. W. In Crown Ethers and Cryptands; Royal Society of Chemistry: Cambridge,
1991.
(5) Landini, D.; Montanari, F.; Rolla, F. Synthesis 1974, 428. (b) Cox, D. P.;
Terpinsky, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3216.
(6) Pilcher, A. S.; Ammon, H. L.; Deshong, P. J. Am. Chem. Soc. 1995,
117, 5166.
(7) Albanese, D.; Landini, D.; Penso, M. J. Org. Chem. 1998, 63, 9587.
(8) (a) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050. (b)
Sun, H.; DiMagno, S. G. Chem. Commun. 2007, 528.
(9) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124, 10278.
(10) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee,
S. J.; Kim, J. S.; Ryu, J. S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006,
128, 16394.
(11) Shinde, S. S.; Lee, B. S.; Chi, D. Y. Org. Lett. 2008, 10, 733.
(12) Crossland, R. K.; Wells, W. E.; Shiner, V. J., Jr. J. Am. Chem. Soc.
1971, 93, 4217.
(13) Schwesinger, R.; Link, R.; Wenzl, P.; Kossek, S. Chem. Eur. J. 2006,
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(14) Kim, B. C.; Kim, K.-Y.; Lee, H. B.; Shin, H. Org. Process Res. DeV.
(1) O′Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T. G.; Murphy,
C. D. Nature 2002, 416, 279.
(2) (a) Bo¨lm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller,
K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (b) Thayer, A. M.
Chem. Eng. News 2006, 84, 15.
(3) Shoulders, M. D.; Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2006,
128, 8112. (b) Nicolleti, M.; O′Hagan, D.; Slawin, A. M. Z. J. Am. Chem. Soc.
2005, 127, 482. (c) Hunter, L.; O′Hagan, D.; Slawin, A. M. Z. J. Am. Chem.
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1169. (b) Giardina, G.; Dondio, G.; Grugni, M. Synlett 1995, 55. (c) Ishi, A.;
Kuriyama, K.; Sudu, K.; Ootsuda, T.; Yasumoto, M.; Inomiya, N.; Ueda, K.;
Tsuruta, H. Chem. Abstr. 2005, 144, 88557; JP 2006008534, 2006. (d) Chiba,
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8106 J. Org. Chem. 2008, 73, 8106–8108
10.1021/jo8015659 CCC: $40.75 2008 American Chemical Society
Published on Web 09/23/2008

TABLE 2. Substrate Scope of Nucleophilic Fluorination of
Triflates 6a-n
SCHEME 1. Synthesis of LC15-0133
TABLE 1. Synthesis of 2a from 3a-c using Various Reagents
yield (%)
entry starting material
reagents and conditions
2a
4
1
2
3
4
5
6
7
8
9
3a
3b
3b
3c
3c
3c
3c
3c
3c
DAST (1.8 equiv)/0 °C to rt
CsF, PSIL, CH3CN, 100 °C, 3.5 h 54
CsF, t-BuOH, 100 °C, 7 h
CsF, t-BuOH, rt, 1.5 h
CsF, acetone, rt, 1.5 h
84
3
38
26
15
39
28
3
64
69
50
54
85
60
TBAF, THF, rt, 2 h
n-Bu4NHF2, CH2Cl2, rt, 2 h
n-Bu4NH2F3, CH2Cl2, rt, 2 h
HF·pyridine, CH2Cl2, rt
3
decomposed
these instances, 15-40% of elimination product 4 was formed
as a major side product. Since the leaving group ability of triflate
is enhanced significantly over mesylate, tosylate, or halide,12
we speculated that a less nucleophilic fluoride ion having
reduced basicity would be effective enough for this conversion
and would lead to minimal formation of the elimination side
product. Therefore, we tested the reaction of triflate 3c
systematically with tetrabutylammonium fluoride (TBAF), bi-
fluoride (TBABF),17 dihydrogen-trifluoride (TBADTF),18 and
hydrogen fluoride pyridine complex,19 which are less nucleo-
philic and less basic in sequence. As summarized in Table 1,
reaction of an in situ formed solution of triflate 3c in dichlo-
romethane with TBABF provided the best result (entry 7), with
only 3% of the elimination product being formed compared to
28% using TBAF (entry 6). Less basic dihydrogen trifluoride
also showed the same level of elimination product formation
as observed with bifluoride; however, a significant amount of
unidentified side product was also formed. With the least basic
hydrogen fluoride pyridine complex, only decomposition of 3c
was observed. We also prepared trans-(4R)-fluoroproline (2b)
from cis-(4S)-hydroxyproline, and comparison of 1H NMR
spectra of 2a and 2b (see Supporting Information) unambigu-
ously revealed complete inversion of the hydroxyl group, thus
suggesting an SN2 mechanism in operation. Considering the easy
preparation of triflates and ready availability of TBABF from
either commercial sources or the simple reaction of potassium
bifluoride and tetrabutylammonium hydrogensulfate,20 the es-
a Most of the reactions were completed in 1-2
h at ambient
temperature. b Completed in 30 h at 40 °C. c Completed in 50 h at 40
°C. d Yield using mesylate at 40 °C in 24 h. e At the stage of triflate
formation, significant elimination product was formed.
tablished conditions are highly cost-effective as well as opera-
tion-friendly compared to the DAST method.
Since there is no detailed investigation on the fluorination of
triflates with TBABF, which is a well-balanced partner to form
minimal levels of elimination products, we tested a diverse set
of triflates under the established conditions with a head-to-head
(17) (a) Bosch, P.; Camps, F.; Chamorro, E.; Gasol, V.; Guerrero, A.
Tetrahedron Lett. 1987, 28, 4733. (b) Moughamir, K.; Atmani, A.; Mestdagh,
H.; Rolando, C.; Francesch, C. Tetrahedron Lett. 1998, 39, 7305.
(18) Landini, D.; Penso, M. Tetrahedron Lett. 1990, 31, 7209.
(19) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 779 and 780.
(20) Landini, D.; Molinari, H.; Penso, M.; Rampildi, A. Synthesis 1988, 953.
J. Org. Chem. Vol. 73, No. 20, 2008 8107

2.95 mmol, 1.2 equiv) in CH2Cl2 (10 mL) was added dropwise
Tf2O (0.69 mL, 2.71 mmol, 1.1 equiv) at -10 to -5 °C. The
resulting mixture was stirred for 30 min and washed with 1 N HCl
solution. The separated organic layer was dried (MgSO4) and
filtered. To the filtrate was added TBABF (831 mg, 2.95 mmol,
1.2 equiv). The resulting mixture was stirred at room temperature
until the starting triflate was completely consumed. Volatiles were
removed in vacuo, and the residue was diluted with n-hexane with
stirring. After 30 min, stirring was stopped to result in a two-phase
mixture of a n-hexane layer and a viscous TBABF-related substance
layer. Simple decantation of the n-hexane layer and concentration
provided the product, or if necessary, the residue was purified by
column chromatography.
comparison using DAST (Table 2). Primary alcohols provided
excellent yields of ca. 90%, in most cases in less than 1 h (entries
1-4), with much better functional group tolerance than with
DAST (entries 3 and 4). For secondary acyclic hydroxyl groups,
various amounts of elimination products were observed, ranging
between 7% and 17% (entries 5-10). However, in most cases,
the yields were better than those using DAST. Secondary
hydroxyl groups positioned R to an ester or lactone moiety, as
well as an unfunctionalized secondary alcohol, were converted
to their fluorides in excellent yields (entries 5-8). However,
an aldol-type secondary alcohol was contaminated with an
increased level of elimination product (entry 10). It is noteworthy
that a simple concentration and dilution of the residue with
n-hexane at the end of the reaction led to a two-phase mixture
of n-hexane and viscous TBABF-containing layers. Decantation
of the n-hexane layer followed by concentration provided the
pure product, which makes this reaction highly practical (entries
1-7). With benzylic alcohol, its triflate was very unstable, with
significant decomposition being observed at the stage of triflate
formation. Attempted direct mixing of the alcohol, triflic
anhydride, pyridine, and TBABF completely failed to give
recovery of the starting material. Use of the corresponding
mesylate instead of triflate 6i still provided only 16% of 7i at
40 °C after 24 h (entry 9). Secondary hydroxyl groups in five-
membered ring systems were converted to the corresponding
fluorides with comparable yields using DAST (entries 11 and
12). However, hydroxyl groups in six-membered rings showed
increased levels of elimination side products (entries 13 and
14), presumably due to the preferred antiperiplanar alignment
of a trans-ꢀ-hydrogen to the triflate group when compared to
the five-membered ring system.
1
N-Boc-cis-4-Fluoro-L-proline Methyl Ester (2a). H NMR (a
mixture of rotamers, 400 MHz, CDCl3) δ 5.20 (br d, J ) 52.8 Hz,
1H), 4.55 (d, J ) 9.2 Hz, 0.5H), 4.43 (d, J ) 9.2 Hz, 0.5H), 3.75
(s, 3H), 3.56-3.93 (m, 2H), 2.25-2.55 (m, 2H), 1.49 (s, 4H), 1.44
(s, 5H); 13C NMR (125 MHz, CDCl3) δ 171.8, 171.4,. 153.5, 153.2,
1
1
91.9 (d, JCF ) 176.5 Hz), 90.8 (d, JCF ) 176.5 Hz), 79.7, 79.6
2
2
57.2, 56.8, 52.6 (d, JCF ) 23.9 Hz), 52.4 (d, JCF ) 23.9 Hz),
2
2
51.7, 51.6, 36.9 (d, JCF ) 21.5 Hz), 36.1 (d, JCF ) 21.5 Hz),
27.9, 27.7.
1
4-(2-Fluoroethyl)-2-phenyloxazole (7a). H NMR (500 MHz,
CDCl3) δ 7.98 - 7.95 (m. 2H), 7.43 - 7.38 (m, 3H), 4.69 (dt, J )
6.1, 47.1 Hz, 2H), 2.89 (dt, J ) 6.1, 23.2 Hz, 2H), 2.33 (s, 3H);
3
13C NMR δ 159.7, 145.3, 131.8 (d, JCF ) 7.2 Hz), 129.9, 128.8,
127.8, 126.0, 82.5 (d, 1JCF ) 166.9 Hz), 27.6 (d, 2JCF ) 21.5 Hz),
10.2; MS (EI) m/z (relative intensity) 205 (100); HRMS (EI) calcd
for C12H12FNO 205.0903 [M]+, found 205.0905.
Typical Experimental Procedure for the Fluorination by
DAST. To a stirred solution of 5a (500 mg, 2.46 mmol) in CH2Cl2
(20 mL) was added DAST (0.55 mL, 4.43 mmol, 1.8 equiv) at 0
°C, and the resulting mixture was slowly warmed to room
temperature and stirred for 14 h. The reaction was carefully
quenched with saturated NaHCO3 solution and extracted with
CH2Cl2 (10 mL × 2). The combined extracts were washed with
0.5 N HCl solution and dried over MgSO4. After evaporation of
the solvent under reduced pressure, the resulting residue was
chromatographed using silica gel (1:9 EtOAc/n-hexane) to give a
desired fluoride 7a as light yellow oil (409 mg, 81%).
In summary, a careful examination of basicity, nucleophilicity,
and leaving group ability led us to discover that the nucleophilic
fluorination of triflates by weakly basic TBABF is an optimal
combination considering the minimal formation of elimination
products and reasonable reaction rates at ambient temperature.
An examination of a broad group of substrates fully disclosed
the advantages and limitations of this protocol compared to the
DAST method. Further fine-tuning of these parameters will be
pursued in the future.
Acknowledgment. We thank Prof. Jongki Hong of Kyung
Hee University for MS analysis.
Supporting Information Available: All the experimental
procedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Experimental Section
Typical Experimental Procedure for Fluorination by TBABF. To
a stirred mixture of alcohol (2.46 mmol) and pyridine (0.37 mL,
JO8015659
8108 J. Org. Chem. Vol. 73, No. 20, 2008