A highly efficient conversion of primary or secondary alcohols into fluorides with n-perfluorobutanesulfonyl fluoride-tetrabutylammonium triphenyldifluorosilicate

Article abstract of DOI:10.1055/s-0028-1087931

Direct fluorination of primary and secondary alcohols by a combination of perfluoro-1-butanesulfonyl fluoride (PBSF) and tetrabutylammonium triphenyldifluorosilicate (TBAT) under mild conditions provides the corresponding fluorides in high yields. With th

Full text of DOI:10.1055/s-0028-1087931

LETTER
779
A Highly Efficient Conversion of Primary or Secondary Alcohols into
Fluorides with n-Perfluorobutanesulfonyl Fluoride–Tetrabutylammonium
Triphenyldifluorosilicate
C
onversion of
Prim
u
ary or Sec
o
e
ndary
A
lco
q
F
lu
i
orides ng Zhao,*a Weiping Zhuang,a Dongsheng Fang,a Xiaowen Xue,*b Jingming Zhoua
a
Fujian Institute of Microbiology, Fuzhou 350007, P. R. of China
E-mail: fim@pub3.fz.fj.cn
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. of China
Fax +86(25)3273714; E-mail: xwenxue@cpu.edu.cn
b
Received 3 September 2008
ondary alcohols, the formed configuration-inverted fluo-
rides are contaminated with the stereoisomers with
retention of configuration. Here we report an efficient
method to convert primary or secondary alcohols into
Abstract: Direct fluorination of primary and secondary alcohols by
a combination of perfluoro-1-butanesulfonyl fluoride (PBSF) and
tetrabutylammonium triphenyldifluorosilicate (TBAT) under mild
conditions provides the corresponding fluorides in high yields. With
this combination, elimination side reactions could be significantly their corresponding fluorides in high yields by a combina-
suppressed and chiral secondary alcohols were less prone to epimer-
ization at the reaction center.
tion of PBSF with TBAT under mild conditions. This ap-
proach overcomes the shortcomings of PBSF and TBAT,
Key words: fluorination, elimination, stereoselectivity, PBSF,
TBAT
without losing their benefits.
Considering the intermediate perfluoro-1-butanesulfonate
ester1,2 (n-C4F9SO3) is a much better leaving group than
OTs or OMs during the fluorination of alcohols by PBSF,
we envisioned a new strategy for fluorinating alcohols,
which is similar to the fluorination of tosylates or mesy-
lates by TBAT (Scheme 1). The alcohol 1 could be first
activated by PBSF via the intermediate 2, which is then
nucleophilically attacked in situ by TBAT to provide cor-
responding fluoride.
Organofluorine compounds play a significant role in our
lives. Many efficient drugs, such as Norfloxacin, Levo-
floxacin and Clofarabine, possess a C–F bond in their
chemical structures. However, the preparation of organo-
fluorine compounds remains challenging since fluorine is
so reactive that it is not easy to handle. Recently, n-perfluo-
robutanesulfonyl fluoride (PBSF)–base combinations,
2
The chiral secondary alcohol (2S,4R)-methyl 4-hydroxy-
1-(4-methylphenylsulfonyl)pyrrolidine-2-carboxylate (4)
was chosen to verify our postulate (Scheme 2). In addition
to the configuration-inverted product (2S,4S)-3a, fluori-
nation of 4 also provided configuration-retention product
(2S,4R)-3a, and elimination products 5 and 6.4 As expect-
ed, it was found that elimination reactions could be
strongly inhibited after the introduction of PBSF–TBAT
(Table 1, entries 1 and 3). Inspired by our primary suc-
cess, we attempted to optimize reaction conditions by
varying the ratios of TBAT, solvents, and bases (Table 1).
such as PBSF–DBU1 and PBSF–NR3 (HF)3–NR3 have
been employed to replace DAST or SF4 to fluorinate alco-
hols under mild conditions. Their ready availability, ease
of handling, low cost, and stability make them very desir-
able in industrial-scale synthesis, but the yields are not
perfect due to the accompanying eliminations, which also
make the separation difficult. On the other hand, tetra-
butylammonium triphenyldifluorosilicate (TBAT), devel-
oped by DeShong and co-workers, has shown great
promise as a potent fluorinating reagent because of its
easy availability, low basicity, and nonhygroscopic stabil-
ity.3 While having a lot of advantages, TBAT also pre-
sents some limitations. The alcohols must be converted
into their tosylates or mesylates first before the fluorina-
tion. Moreover, the excessive equivalents of TBAT (4–6
equiv) required for reasonable reaction rates also limit its
applications to some extent. Especially for the chiral sec-
Bases are believed critical to this fluorination reaction. It
has been well documented that the higher basicity of
amines is responsible for the higher percentage of elimi-
nation product,6 and amines can cause the decomposition
of PBSF, which would account for the use of excess PB-
SF.7 At the beginning DBU was investigated, but disap-
F
OSO2C4F9-n
OH
R1
R2
R1
R2
R1
R2
n-C4F9SO2F
TBAT
or F– from step 1
H
H
base
H
1
2
3
Scheme 1
SYNLETT 2009, No. 5, pp 0779–0782
x
x.
x
x.
2
0
0
9
Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087931; Art ID: W13608ST
© Georg Thieme Verlag Stuttgart · New York

780
X. Zhao et al.
LETTER
F
HO
F
N
CO2Me
N
CO2Me
CO2Me
CO2Me
N
CO2Me
N
N
Ts
Ts
Ts
4
Ts
Ts
5
(2S,4S)-3a
(2S,4R)-3a
6
Scheme 2
pointedly, ratios of F/E (ratio of fluorination product to Based on our research, we found that temperature has a
elimination products) were improved slightly from 2.6 to small influence on the fluorination reactions. The ratio of
4.1 (entry 2, 6). Later we switched to Et3N and the more F/E increased slightly (entry 5) when temperature
bulky i-Pr2NEt. Using triethylamine as a base and gradual dropped from 25 °C to 0 °C, and meanwhile no obvious
addition of TBAT, ratios of F/E sharply increased in tolu- variations for the dr value and conversion could be ob-
ene, THF, or CH2Cl2, (entries 3–5, 7, 8, 11, 14). Further- served.
more, with i-Pr2NEt, the reactions were accomplished at
As TBAT is very sensitive to acids8 and PBSF may inter-
much better ratios of F/E (entries 9, 10, 12, 13, 15). Con-
act with the amines, the order of reagent addition should
sequently, it would not be difficult to draw a conclusion
be taken into careful consideration. The addition order
that more bulky amines would be more efficient to sup-
was determined as follows: 4, TBAT, base, and solvent fi-
nally followed by PBSF.
press elimination since their steric hindrance makes them
more difficult to abstract a proton from intermediate 2.
Our results supported our initial envisage: enhancement
Among the solvents tested, toluene gave a better balance
of fluorine anion resource by TBAT could strongly sup-
between F/E ratios and the reaction conversion (e.g., F/E
press elimination side reactions, which may prove that
TBAT, as a fluoride anion resource, could react with 2
more easily to give fluoride 3 under mild conditions.
selectivity of 17.7 and 100% conversion; entry 10). THF
gave the highest F/E selectivity of 20.8 (entry 13) but the
worst conversion of 76.8% (entry 12). We speculated that
This reagent combination was then extended to a wide
a limited solubility of TBAT in toluene might account for
range of alcohols, primary, secondary, or tertiary under
optimized condition (0.8 equiv TBAT, i-Pr2NEt in toluene
the lower ratio of F/E than that in THF, since TBAT was
completely dissolved in THF.
Table 1 Optimization of the Reaction Conditions by Mixing of PBSFa,b with TBAT5
Entry
1
TBAT (equiv) Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Temp (°C)
Time (h)c
24
F/Ed
2.4
Conversion (%) dr (%)
0
Et3N
25
25
25
25
0
99.7
100
100
99.7
92.3
99.1
95.8
97.4
98.9
2
0
DBU
24
2.6
3
0.4
0.6
0.6
0.6
0.8
1.2
0.8
1.2
1.2
0.8
1.2
0.8
0.8
Et3N
24
4.5
4
Et3N
24
8.0
5
Et3N
24
8.8
98.1
99.4
99.7
98.3
98.9
6
DBU
25
25
25
25
25
0
24
4.1
100
7
Et3N
24
9.1
97.7
98.5
98.2
8
Et3N
24
12
9
i-Pr2NEt
i-Pr2NEt
Et3N
24
13.5
17.7
14.5
20.6
20.8
7.2
10
11
12
13
14
15
24
100
100
72
86.5
76.8
80.2
96.7
99.0
98.2
97.7
98.6
98.9
i-Pr2NEt
i-Pr2NEt
Et3N
THF
25
25
25
25
72
THF
72
CH2Cl2
CH2Cl2
24
i-Pr2NEt
24
9.7
100
a Conditions: 2.2 equiv of PBSF and 2.5 equiv of base were used.
b The reaction mixture was cooled down to 0 °C when PBSF was added.
c Reaction time.
d F/E: ratio of fluorination product (2S,4S)-3a to elimination products (5 and 6).
Synlett 2009, No. 5, 779–782 © Thieme Stuttgart · New York

LETTER
Conversion of Primary or Secondary Alcohols into Fluorides
781
Table 2 Fluorination of Various Alcohols Using Optimized Conditions
Entry
1
Alcohol
Product
Time (h) Yield (%)
PhCO2(CH2)9OH
OMe
1b
1c
PhCO2(CH2)9F
OMe
3b
3c
24
94
2
24
92
F
OH
O
O
MeO
MeO
3
4
1d
1e
3d
3e
24
24
91
79
OH
F
O
O
OH
F
TrO
S
TrO
S
OH
F
5
1f
3f
24
86
S
S
S
S
OH
F
S
S
6
7
1g
1h
3g
3h
24
72
84
72
N
N
MeO2C
MeO2C
HO
F
CO2Me
CO2Me
N
N
Tr
OH
Tr
F
8
9
1i
1j
3i
3j
24
24
88
91
CH COPh
CH COPh
Ph
Ph
Ph
Ph
OH
F
CH CO2Bn
CH CO2Bn
at 25 °C for 24 h, Table 2).9 Primary alcohols generally more sensitive to the steric inhibitor than PBSF–NR3
gave corresponding fluorides in excellent yields (86– (HF)3–NR3.
94%, entries 1–3, 5). The only exception (79% of yield)
In summary, we have developed a highly efficient method
was the fluorination of 4-triphenylmethoxybutan-1-ol, an
for conversion of primary and secondary alcohols, espe-
alcohol with a trityl group (entry 4). The b-hydroxyl
cially those with less steric hindrance, into their fluorides
group of double bond, which is prone to elimination,
by combining PBSF with TBAT, by which elimination
could also be successfully converted to the corresponding
side reactions could be significantly suppressed and chiral
fluoride in good yield (entry 5). However, 4,4-bis-(3-me-
secondary alcohols were less prone to epimerization. The
thyl-2-thienyl)-3-buten-1,4-diol only gave a cyclization
reactions could be performed in different solvents under
product, instead of the desired fluoride, as a major prod-
mild conditions, best in toluene with i-Pr2NEt as a base, to
uct.10 For secondary alcohols, the yields (72–91%) of their
give fluorides in good to excellent yields. Various func-
fluorides decreased somewhat as compared to the primary
tional groups could be tolerated. The fluorinating reagents
alcohols (entries 6–9). Interestingly, the tertiary amine
PBSF and TBAT are readily available, inexpensive, non-
group exhibited no impact on fluorination (entry 6). Pos-
corrosive, stable upon exposure to air or moisture, and
sibly due to the steric factor of the bulky N-trityl protec-
easy to handle.
tive group,11 TBAT did not work well as a nucleophilic
source; therefore, compound 3h was obtained in a rela-
tively low yield (72%, entry 7). Fluorination of a-hydroxy
group of esters and ketones, however, succeeded in good
yields (88–91%, entries 8 and 9). Unfortunately, fluorina-
tion of tertiary alcohols such as 1,1-diphenyl-ethanol and
1-benzylcyclohexanol by PBSF–TBAT combination
failed, which further demonstrated that PBSF–TBAT was
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank Science Fund of Fujian Province (2004J078) and
China Pharmaceutical University (211080) for financing this work.
Synlett 2009, No. 5, 779–782 © Thieme Stuttgart · New York

782
X. Zhao et al.
LETTER
665 cm–1. 1H NMR (600 MHz, CDCl3): d = 2.45 (s, 3 H),
2.44 (s, 3 H), 2.66–2.90 (m, 2 H), 3.81 (s, 3 H), 4.10–4.30
(m, 3 H), 5.07–5.16 (m, 2 H), 5.65–5.70 (m, 1 H), 5.86–5.89
(m, 1 H), 6.39 (t, J = 2.0 Hz, 1 H), 7.33–7.36 (m, 4 H), 7.71
(d, J = 8.2 Hz, 2 H), 7.79 (d, J = 8.2 Hz, 2 H). HRMS: m/z
calcd for C13H15NO4S + Na: 304.0619; found: 304.0612.
(6) Takamastu, S.; Katayama, S.; Hirose, N.; De Cock, E.;
Schelkens, G.; Demillequand, M.; Brepoels, J.; Izawa, K.
Nucleosides, Nucleotides Nucleic Acids 2002, 21, 849.
(7) (a) Bennua-Skalmowski, B.; Krolikiewicz, K.; Vorbrüggen,
H. Bull. Soc. Chim. Belg. 1994, 103, 453. (b) Bennua-
Skalmowski, B.; Klar, U.; Vorbrüggen, H. Synthesis 2008,
1175.
References and Notes
(1) (a) Bennua-Skalmowski, B.; Vorbrueggen, H. Tetrahedron
Lett. 1995, 36, 2611. (b) Vorbrüggen, H. Synthesis 2008,
1165.
(2) Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.;
Huffman, M. A. Org. Lett. 2004, 6, 1465.
(3) Picher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166.
(4) These side products were determined by LC-MS or other
means. For details, please see ref. 12.
(5) Typical Procedure
The alcohol 4, TBAT in the amount indicated, base, and
solvent (8 mL/mmol) were added in turn at the temperature
indicated. Then PBSF (2.2 equiv) was introduced and
stirring was continued for the time given. The final reaction
mixture was directly assayed by HPLC or LC-MS, and the
calculation of HPLC data gave conversion, dr value, and
ratio of fluorination product/elimination product in the
mixture. The final reaction mixture was then concentrated
under reduced pressure and purified by flash chromatog-
raphy (eluent: PE to PE–acetone) to give (2S,4S)-3a, and a
mixture of 5 and 6 (not separated).
(8) Handy, C. J.; Lam, Y.-F.; DeShong, P. J. Org. Chem. 2000,
65, 3542.
(9) Typical Procedure for the Synthesis of (2S,4S)-Methyl 1-
[4,4-Bis(3-methyl-2-thienyl)-3-buten-1-yl]-4-fluoropyr-
rolidine-2-carboxylate (3g)
To a mixture of alcohol 1g (1 equiv) and TBAT (0.8 equiv),
i-Pr2NEt (2.5 equiv) and toluene (8 mL per mmol of alcohol)
were added in turns at r.t. The resulting mixture was stirred,
and then PBSF (2.2 equiv) was introduced. The stirring was
continued until TLC revealed complete conversion. The
reaction mixture was concentrated under reduced pressure.
The residual was mixed with a little bit of silica gel, air-
dried, and finally purified by flash chromatography (SiO2,
300–400 mesh; eluent: PE to PE–acetone) to give 3g as a
yellow oil; [a]D24 –31 (c 0.89, EtOAc). IR (NaCl): n = 3104,
3060, 2952, 2843, 1748, 1733, 1435, 1200, 1174, 715 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.00 (s, 3 H), 2.03 (s, 3 H),
2.19–2.58 (m, 6 H), 2.93 (br s, 1 H), 3.20 (br s, 1 H), 3.33–
3.42 (m, 1 H), 3.73 (s, 3 H), 5.13 (d, J = 59.8 Hz, 1 H), 6.04
(t, J = 6.6 Hz, 1 H), 6.76 (d, J = 3.8 Hz, 1 H), 6.84 (d, J = 3.8
Hz, 1 H), 7.05 (d, J = 3.8 Hz, 1 H), 7.21 (d, J = 3.8 Hz, 1 H).
13C NMR (600 MHz, CDCl3): d = 14.8, 28.7, 37.0, 37.1,
52.0, 53.6, 59.3, 59.4, 64.6, 91.0, 92.2, 122.7, 124.3, 128.7,
129.6, 131.2, 135.4, 139.5, 173.3. HRMS: m/z calcd for
C20H24FNO2S2 + 1): 394.1310; found: 394.1316.
(10) Klar, U.; Neef, G.; Vorbrüggen, H. Tetrahedron Lett. 1996,
37, 7497.
(2S,4S)-Methyl 4-Fluoro-1-(4-methylphenylsulfonyl)-
pyrrolidine-2-carboxylate [(2S,4S)-3a]
White crystals; Rf = 0.44 (PE–acetone, 70:30); mp 100–103
°C; [a]D24 –60 (c 0.94, EtOAc). IR (KBr): n = 3006, 2960,
1759, 1599, 1344, 673 cm–1. 1H NMR (600 MHz, CDCl3):
d = 2.22 (dtd, J = 32.2, 12.3, 5.8 Hz, 1 H), 2.54 (dd, J = 15.2,
1.4 Hz, 1 H), 2.46 (s, 3 H), 3.58–3.68 (m, 2 H), 3.73 (s, 3 H),
4.67 (d, J = 9.4 Hz, 1 H), 5.21 (dd, J = 50.2, 3.2 Hz, 1 H),,
7.35 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 8.2 Hz, 2 H). 13C NMR
(600 MHz, CDCl3): d = 21.6, 37.4, 37.5, 52.6, 54.0, 54.2,
59.2, 91.4, 92.6, 127.6, 129.7, 144.0, 171.5. HRMS: m/z
calcd for C13H16FNO4S + Na: 324.0681; found: 324.0672.
The absolute configuration of the 4-position was determined
by NOE.
Mixture of Two Elimination Products: (2S)-Methyl 1-(4-
Methylphenylsulfonyl)-3,4-dihydropyrrole-2-carbox-
ylate and (2S)-Methyl 1-(4-Methylphenylsulfonyl)-4,5-
dihydropyrrole-2-carboxylate (5 and 6)
White crystals; Rf = 0.28 (PE–acetone, 80:20); mp 190–197
°C. LC-MS: tR = 11.21 min; MS: m/z = 282 [M + 1]+, 304 [M
+ Na]+; tR = 12.39 min; MS: m/z = 282 [M + 1]+, 304 [M +
Na]+. IR (KBr): n = 3100, 2961, 1765, 1598, 1098, 820, 802,
(11) (a) Barlos, K.; Papaioannou, D.; Patrianakou, S.; Tsegenidis,
T. Liebigs Ann. Chem. 1986, 1950. (b) Baldwin, J. E.;
North, M.; Flinn, A.; Moloney, M. G. Tetrahedron 1989, 45,
1453.
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