Deoxyfluorination of alcohols with aryl fluorosulfonates

Article abstract of DOI:10.1039/d1cc02617h

Aryl fluorosulfonates are developed as a deoxyfluorinating reagent in the transformation of primary and secondary alcohols into the corresponding alkyl fluorides. These reagents feature easy availability, low-cost, high stability and high efficiency. Diverse functionalities including aldehyde, ketone, ester, halogen, nitro, alkene, and alkyne are well tolerated under mild reaction conditions.

Full text of DOI:10.1039/d1cc02617h

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Deoxyfluorination of alcohols with aryl
fluorosulfonates†
Cite this: DOI: 10.1039/d1cc02617h
b
Xiu Wang, ‡a Min Zhou,‡a Qinghe Liu,‡a Chuanfa Ni,a Zhongbo Fei,§b Wei Li
a
Received 18th May 2021,
Accepted 2nd July 2021
and Jinbo Hu
*
DOI: 10.1039/d1cc02617h
rsc.li/chemcomm
Aryl fluorosulfonates are developed as a deoxyfluorinating reagent in SulfoxFluor13 were distinguished by their good balance
the transformation of primary and secondary alcohols into the corres- between high reactivity and great stability. However, they still
ponding alkyl fluorides. These reagents feature easy availability, low- suffered from safety concerns,14 unsatisfactory results with
cost, high stability and high efficiency. Diverse functionalities including benzylic alcohols, multistep synthesis, and/or the poor fluorine
aldehyde, ketone, ester, halogen, nitro, alkene, and alkyne are well atom economy (especially the PBSF reagent). Therefore, readily
tolerated under mild reaction conditions.
available, bench-stable, easy-to-handle and inexpensive fluor-
inating reagents are still highly desired.
The introduction of a fluorine atom confers unique chemical,
Aryl fluorosulfonates could be easily synthesized from the
physical and biological properties on organic molecules, and reaction of phenols and sulfuryl fluoride (SO2F2) in high yields
has become a standard routine to discover new candidates of under mild reaction conditions.15 They are conventionally used
materials and pharmaceuticals.1 In terms of aliphatic carbon– as aryl electrophile alternatives to aryl triflates and well docu-
fluorine-bond formation, the deoxyfluorination of alcohols is mented in various transformations (Scheme 1b).16–22 The
recognized as a straightforward and efficient approach, due OSO2F unit could not only function as a good leaving group,
to the abundant and readily available alcohol-containing but a stable sulfate connector applied in click chemistry
precursors.2 Conventional fluorinating reagents for deoxyfluor- (Scheme 1b).23 To date, the use of aryl fluorosulfonates as
ination of alcohols include DAST,3 Deoxo-Fluor,4 XtalFluor,5
and Fluolead,6 which are limited by their thermally instability,
high cost, and/or poor functional-group tolerance. Subse-
quently, representative a-fluorinated alkylamines such as
PhenoFluor,7 AlkylFluor,8 and carbon-based CpFluor9 were
developed, which improved the substrate scope and selectivity
to a large extent. Besides, a sulfur-based reagent is another
indispensable category in deoxyfluorination of alcohols, espe-
cially for the analogs of sulfonyl fluoride (Scheme 1a). Only one
example was described that uses gaseous sulfuryl fluoride
(SO2F2) as a fluorination reagent.10 PBSF,11 PyFluor,12 and
a Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032,
China. E-mail: jinbohu@sioc.ac.cn
b Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co., Ltd,
Changshu, Jiangsu 215537, P. R. China
† Electronic supplementary information (ESI) available: More detailed results of
deoxyfluorination of alcohols, spectroscopic data and copies of 1H, 13C and 19F
NMR spectra. CCDC 2084521. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d1cc02617h
‡ These authors contributed equally to this work.
Scheme 1 Deoxyfluorination of alcohols and applications of aryl fluoro-
§ Current address: Suli Pharmaceutical Technology Jiangyin Co., Ltd., Pudong
sulfonates.
District, Shanghai, 201318, P. R. China.
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halogenating agents has not been reported.23b Herein, we
The performance of 2b with primary alcohols under the
reported the novel application of ArOSO2F in deoxyfluorination optimized reaction conditions was evaluated as shown in
of alcohols, which constitutes a practical method for the Table 2. Pharmaceutically important heterocycles such as
synthesis of alkyl fluorides, due to their easy availability, low phthalimide (3a), benzofuran (3b), and benzodioxine (3c) could
cost, and high stability towards air and moisture (Scheme 1c). proceed smoothly, affording the corresponding fluoroalkanes
Initially, N-hydroxyethyl phthalimide (3a) and aryl fluorosul- 4a–4c in 66–86% yields; whereas pyridine and benzoquinone-
fonate bearing a nitro group (2a) were chosen as the model containing compounds provided 4d and 4s in 33% and 40%
reaction substrates. Various reaction parameters including yields, respectively. Notably, 20 mmol scale synthesis of 4a was
solvent (Table S1, ESI†), amount of aryl fluorosulfonate (2a) tested with 76% (2.9 g) isolated yield, which demonstrated the
and base (Table S2, ESI†) were systematically evaluated. As a practicability and effectiveness of this methodology, as well as
result, 73% yield of the desired product 4a was obtained with its value and prospects in industry. Unhindered benzylic alco-
1 equivalent of 3a and 1.2 equivalent of 2a activated by hols bearing methyl, iodo, nitro and cyano groups regardless of
1.5 equivalent of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) in the steric effect delivered fluorinated products 4e–4h and 4t in
toluene at room temperature for 20 h (Table 1, entry 1). Other good yields, which showed the advantages of our method over
organic bases such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5, PyFluor.12 Fused aromatic rings such as naphthyl (3i), pyrene
7-triazabicyclo[4.4.0]dec-5-ene (TBD), and 1,1,3,3-tetramethylgua- (3j) or long alkyl chain (3k) containing primary alcohols could
nidine (TMG) were also tested, and all of them were proved to be also be fluorinated in this transformation. The present protocol
less efficient in the present transformation (entries 2–4). The effect was highlighted by various functionalities including alkene (4l),
of the electronic nature of aryl fluorosulfonates on the fluorinating alkynes (4m–4o), ketone (4p, 4q), and ester (4r), which proved
ability of aryl fluorosulfonate was further studied, and electron- that 2b is a practical alternative to other fluorinating reagents.
deficient functional groups incorporated into phenyl sulfurofluo-
Deoxyfluorination of secondary alcohols was also accom-
ridate including nitro (2a), mesyl (2b), and triflyl (2c) displayed plished with the assistance of tris(dimethylamino)sulfonium
moderate to good yields. In particular, 4a was obtained with 80% difluorotrimethylsilicate (TASF) under the optimized reaction
yield when 4-(methylsulfonyl)phenyl sulfurofluoridate (2b) was used conditions (Table 3). Acyclic secondary alcohols were reliable
(entry 5). In contrast, electron-neutral 2d and electron-rich 2f showed for the generation of fluorinated products 6a–6e. Good selec-
poor reactivity, along with target product 4a in 16% and 12% yields, tivity was demonstrated by the substrates with ketone (5f) or
respectively (entries 7 and 8). Hetero-atom-containing aryl fluorosul-
fonates (2f) also led to inferior results (entry 9). On the other hand,
the yield of 4a was further increased to 88% when 2-tert-butyl-1,1,3,
3-tetramethylguanidine (BTMG) was used instead of DBU under the
identical reaction conditions (entry 10).
Table 2 Deoxyfluorination of primary alcoholsab
Table 1 Optimization of the reaction conditionsa
Entry
2
Base
4ab (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2c
2d
2e
2f
DBU
DBN
TBD
TMG
DBU
DBU
DBU
DBU
DBU
BTMG
73
9
34
28
80
55
16
12
34
88 (86)
10
2b
a
a
Reaction conditions: 3a (0.5 mmol), 2 (1.2 equiv.), base (1.5 equiv.),
Reaction conditions: 3 (0.5 mmol), 2b (0.6 mmol), BTMG (0.75 mmol),
toluene (5 mL), r.t., 20 h. Determined by 19F NMR analysis of the toluene (5 mL), r.t., 20 h. Isolated yields. Isolated yield in a 20 mmol
b
b
c
crude mixture, using fluorobenzene as an internal standard. An isolated scale reaction. d 19F NMR yield using fluorobenzene as an internal
yield is given in parentheses.
standard.
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Table 3 Deoxyfluorination of secondary alcoholsab
process was essentially completed within 2 h, and the yields of 3g
reached a maximum within 10 h (Fig. S1 and S2, ESI†). Subse-
quently, differential scanning calorimetry (DSC) analysis showed
that no exothermic decomposition was observed in the range of
0–330 1C (Scheme S1, ESI†). In addition, thermo gravimetric
analysis (TGA) pointed out that 2b was hardly decomposed below
127 1C (Scheme S2, ESI†). Both DSC and TGA data proved that 2b
is a safe and stable deoxyfluorinating reagent with considerable
thermal stability. Furthermore, 2b could be stored in a glass vial
on the benchtop and handled under an air atmosphere. Notably, a
gram-scale synthesis of 2b could be easily achieved via the
reaction of commercially available phenol and sulfuryl fluoride
(SO2F2), an inexpensive commodity chemical which is widely used
as an insecticide. Given the above, 2b is distinguished by high
reactivity and selectivity, great stability, simple operation and low-
cost.
In summary, we discovered the fluorinating ability of
4-(methylsulfonyl)phenyl sulfurofluoridate in deoxyfluorina-
tion of alcohols for the first time. A wide range of primary
and secondary alcohols were efficiently fluorinated with
4-(methylsulfonyl)phenyl sulfurofluoridate, especially benzylic,
aldehyde or ketone-substituted alcohols. The merits of high
reactivity and selectivity, great stability, low-cost and mild
reaction conditions made the 4-(methylsulfonyl)phenyl sulfur-
ofluoridate a promising deoxyfluorinating reagent.
This work was supported by the National Key Research and
Development Program of China (2016YFB0101200), the
National Natural Science Foundation of China (21632009), the
Key Program of the Chinese Academy of Sciences (KGZD-EW-
T08), the Key Research Program of Frontier Sciences of CAS
(QYZDJ-SSW-SLH049) and the Fellowship of Postdoctoral
Science Foundation of China (2020M671273).
a
Reaction conditions: 5 (0.5 mmol), 2b (1.0 mmol), BTMG (0.75 mmol),
b
TASF (0.5 mmol), toluene (5 mL), r.t., 20 h. Isolated yields.
c
The abbreviation e.s. refers to enantiospecifity, e.s. = (ee of 6)/
(ee of 5) Â 100%.
aldehyde (5g) groups, which are prone to form geminal
difluorides.24 Other heterocyclic secondary alcohols were inves-
tigated and transformed into the desired products 6h–6j with
moderate to good yields. Deoxyfluorination of chiral secondary
alcohol (5k) gave inverted product 6k with 69% yield and 99.6%
enantiospecificity.
A set of control experiments were conducted to illustrate the
high selectivity of 2b (Scheme 2). Based on the research of
Sanford and co-workers, aryl fluorosulfonates could be directly
reacted with tetramethylammonium fluoride (Me4NF) to give
out aryl fluorides.22 Thus, deoxyfluorination of 2b was tried
with their standard reaction conditions, and fluorinated pro-
duct 7 was obtained in 69% isolated yield. Unexpectedly, only
the deoxyfluorination of alcohol 3i occurred in the presence of
3i, 2b, and an external fluorine source (NMe4F), and similar
yields of 4i were obtained under Sanford’s or the present
conditions.
Conflicts of interest
There are no conflicts to declare.
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