Multifaceted ion exchange resin-supported hydrogen fluoride: A path to flow hydrofluorination

Article abstract of DOI:10.1039/c8gc03166e

A solid anhydrous hydrogen fluoride equivalent was prepared by mixing HF gas with an inexpensive anion exchange resin (A26-HF, HF content 30% wt/wt). This reagent is capable of hydrofluorinating alkenes, of ring-opening aziridines to give fluoroamines, and of yielding fluorotetrahydropyrans through a fluoro-Prins reaction, all with high selectivity under mild conditions. Our ion exchange resin supported HF reagent could be easily packed into a plastic column and used in flow fluorinations.

Full text of DOI:10.1039/c8gc03166e

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Multifaceted ion exchange resin-supported
hydrogen fluoride: a path to flow
hydrofluorination†
Cite this: DOI: 10.1039/c8gc03166e
Received 9th October 2018,
Zhichao Lu, a Bhvandip S. Bajwa,b Okoromoba E. Otome,a
Accepted 24th December 2018
c
Gerald B. Hammond *a and Bo Xu
*
DOI: 10.1039/c8gc03166e
rsc.li/greenchem
A solid anhydrous hydrogen fluoride equivalent was prepared by liquid solutions such as Olah’s reagent (pyridine·9HF),11 tri-
mixing HF gas with an inexpensive anion exchange resin (A26-HF, ethylamine/HF (Et3N·3HF),13 or DMPU·12HF.14 However, these
HF content 30% wt/wt). This reagent is capable of hydrofluorinat- stabilizers reduce the acidity of the resulting HF solution and
ing alkenes, of ring-opening aziridines to give fluoroamines, and of decrease its reactivity, especially in reactions that need strong
yielding fluorotetrahydropyrans through a fluoro-Prins reaction, all acid media. Moreover, after the reaction is completed, the
with high selectivity under mild conditions. Our ion exchange resin excess of HF needs to be neutralized, and pyridine, triethyl-
supported HF reagent could be easily packed into a plastic column amine or DMPU need to be separated during the reaction
and used in flow fluorinations.
work-up.
Fluorinations, like most organic reactions, are typically con-
ducted in conventional batch reactors. In contrast to batch
reactors, continuous flow and microreactor methodologies
offer advantages in automation, control of the reaction con-
ditions, heat and mass transfer, safety profile, and scalability.
To the best of our knowledge, hydrofluorinations in a continu-
ous flow reactor using HF have not been reported.15–17
Preparing a solid equivalent of anhydrous HF would enable
flow hydrofluorination but, only two attempts to prepare a
polymer-supported HF reagent have been reported, the most
recent one over 25 years ago. Zupan and co-workers reported a
copolymer of styrene and 4-vinylpyridine that complexed with
HF.18–20 Olah and co-workers prepared a polymeric hydrogen
fluoride reagent using poly-4-vinylpyridium as a support.21–23
Both polymer-supported HF reagents have met with limited
success. In addition to the high expense of the polymers used
in both methods, the pyridine presence reduces the acidity of
both polymeric HF reagents, curtailing their effectiveness. We
have recently reported that HF formed a stable and easily
handled complex with KHSO4 – an ionic hydrogen bond accep-
tor. Its effectiveness as a fluorinating agent was demonstrated
Introduction
Fluorine’s proven worth in enhancing the pharmacokinetic
and physicochemical properties of active pharmaceutical
ingredients, such as improved metabolic stability and
enhanced membrane permeation,1 has spurred the explosive
growth of synthetic strategies for the selective incorporation of
fluorine in organic molecules.2–8 Many fluorinating agents
have been developed over the years with the goal of solving
this fundamental problem, with varying degrees of success.
The fluorinating agents reported are, for the most part, expen-
sive or non-atom economical, they require complex reaction
conditions or have a narrow range of synthetic applications.9,10
Arguably hydrogen fluoride is the most atom-economical
nucleophilic fluorination agent, but it is also corrosive, highly
toxic and a reactive gas at ambient conditions.11,12 Amines
(pyridine, triethylamine) or
(DMPU), have been used to stabilize gaseous HF, forming
a hydrogen bond acceptor
−
in the hydrofluorination of alkenes.24 If we could affix HSO4
to an inexpensive ion exchange resin the bisulfate anion would
not only stabilize HF through hydrogen bonding but it would
also increase the acidity of the resulting ion exchange resin-
supported HF complex. This complex could be used in batch
hydrofluorination—with the added advantage of a simplified
reaction workup (only filtration or decantation are needed)—
or in continuous flow hydrofluorination. We are now pleased
to report that a solid anhydrous hydrogen fluoride equivalent
aDepartment of Chemistry, University of Louisville, Louisville, Kentucky 40292, USA.
E-mail: gb.hammond@louisville.edu
bDepartment of Chemistry, California State University, Fresno, California 93740,
USA
cKey Laboratory of Science and Technology of Eco-Textiles, Ministry of Education,
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University,
Shanghai 201620, China. E-mail: bo.xu@dhu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03166e
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Table 1 Reaction condition optimization for hydrofluorination of
alkene
was prepared by mixing HF gas with an inexpensive anion
exchange resin. The resulting ion exchange supported-HF
reagent was used effectively in the hydrofluorination of
alkenes, in the ring opening of aziridines and in the fluoro-
Prins reaction as well as in the continuous flow hydrofluorina-
tion of an alkene.
Results and discussion
We examined several types of commercially available anionic
resins: Amberlyst A21 has a free amine functional group,
whereas Amberlyst A26 and Amberlite IRN78 possess a qua-
ternary ammonium functional group. The preparation pro-
cedure is straightforward: the commercially available ion
exchange resin was treated with a slight excess of aqueous sul-
furic acid to substitute the original anion in the resin with
HSO4− (Scheme 1). The modified ion exchange resin was dried
and complexed with anhydrous hydrogen fluoride to furnish
the ion exchange resin supported HF reagent (for detailed
preparation please see the ESI†). We tested the reactivity of the
ion exchange resin-supported anhydrous hydrogen fluoride
reagent using the hydrofluorination of alkene 1a as our model
reaction. We found that Amberlyst A-26 affixed more hydrogen
fluoride per gram of dry resin and showed higher reactivity in
the hydrofluorination 1a than the other two resin-HF com-
plexes (Table 1, entry 4 vs. entries 1 and 2). To underscore the
importance of the bisulfate in the polymeric HF complex, we
tested another ion exchange resin, Amberlite IR-120 Na+,
bearing an SO3−Na+ functionality. As expected, the resulting
complex showed a lower reactivity than the A26 resin HF
complex because of its weaker acidity (Table 1, entry 3 vs.
entry 4). Solvent optimization indicated that dichloroethane
(DCE) was the best (Table 1, entries 4 and 7–14). Further
optimization demonstrated that 15 equivalents of HF (Table 1,
entries 4–6) and a reaction time of 15 h gave the best results
(Table 1, entry 15).
HF
equiv.
Yielda
(%)
Entry
Resin-HF (wt/wt%)
Solvent
1
2
3
4
5
6
7
8
HSO4− A21 resin-HF (30%)
HSO4− IRN78 resin-HF (28%)
IR-120-Na+ resin-HF (23%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
HSO4− A26 resin-HF (30%)
10
10
10
10
15
5
10
10
10
10
10
10
10
10
15
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
DCM
Dioxane
DMF
DMSO
Et2O
EtOAc
Toluene
DCE
19
23
0
28
58
7
0
22
0
0
0
0
0
9
10
11
12
13
14
15b
51
87
a NMR yield with benzotrifluoride as internal standard. b 15 hours.
Table 2 Hydrofluorination of alkenesa
Having found an optimal reaction protocol in the hydro-
fluorination of alkenes, we explored the substrate scope and
functional group tolerance. As shown in Table 2, disubstituted
and trisubstituted alkenes showed good to excellent yield.
However, monosubstituted alkenes were unreactive. A wide
range of functional groups such as esters (2a, 2g, 2h, 2n, 2p),
a Reaction conditions: 1 (0.2 mmol), A26 resin-HF(15 equiv. HF), DCE
(0.4 mL), room temperature, 15 h. All yields are for the isolated
product.
ethers (2b–2f), nitro (2c), nitrile (2d), aldehyde (2e), ketones
(2f, 2k, 2m), alcohols (2l, 2o) were well tolerated. Acceptable to
very good yields were obtained with different heterocyclic sub-
Scheme 1 Preparation of polymer supported HF reagent.
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Table 3 Ring-opening of aziridines 3a
strates like thiophene (2g), pyridine (2h), indazole (2i) and ben-
zotriazole (2j). It should be noted that longer reaction times
were needed for substrates containing basic moieties (2h, 2i, 2j).
Since alkenes are commonly found in natural products, we
screened an estrone-tethered disubstituted alkene, which furn-
ished a good yield of the product (2k). We found that a natural
product with a secondary alcohol, such as (−)-dihydrocarveol (2l),
gave only a moderate yield of the product whereas nootkatone,
possessing an α,β-unsaturated ketone group (2m), gave a very
good chemical yield. The hydrofluorination of (−)-β-citronellol,
which bears a primary alcohol functionality, gave also a very
good yield of the product 2o. And we found that the cyclo-
propane motif remained intact after the reaction of ethyl
chrysanthemate with HF (2p).
The synthesis of β-fluoroamines via ring-opening of aziri-
dines with HF is, in principle, an ideal preparation method
because of the low cost of reagents, mild reaction conditions
and general accessibility of substrates, but the production of
regioisomers and stereoisomers has muddled the efficiency of
this strategy.25–28 Recently, we reported that DMPU-HF
achieved regio- and stereo-control in the fluorination of aziri-
dines.29 However, the reaction introduces DMPU, which com-
plicates the purification step. Using our modified ion
exchange resin supported HF (resin A26-HF), we achieved
high selectivity and good functional group tolerance and
avoided the introduction of impurities to the reaction mixture
and simplified the workup procedure (only filtration
was needed).
a Reaction conditions: 3 (0.2 mmol), A26 resin-HF (5 equiv. HF),
DCE (0.4 mL), room temperature, 3 h. All yields are for the isolated
product. b Numbers in parenthesis are regioisomeric ratio determined
by 19F NMR. c Starting aziridine are mixture of cis- and trans-isomers.
Table 4 Fluoro-Prins reactiona
As shown in the Table 3, hydrofluorination of the mono
alkyl-, aryl-, and benzyl-substituted N-tosylaziridines (3a–3d)
occurred at the most substituted carbon and delivered primary
alkyl amines (4a–4d) in good to excellent yields. The trisubsti-
tuted aziridine 3f was fluorinated at the more substituted
carbon in acceptable yield. When 2-ethyl-3-methyl-1-tosylaziri-
dine was the substrate, an inseparable mixture of regioisomers
and diastereomers was generated (4f). A bicyclic aziridine was
also tested and converted to trans-β-fluoroamine 4g in good
yield and diastereoselectivity. Various N-protecting groups
such as tosyl (4a–4g), benzoyl (4h), and Cbz (carboxybenzyl)
(4i) were well tolerated under the reaction conditions,
affording the corresponding products in excellent yields and
regioselectivity.
a Reaction conditions: 5 (0.2 mmol), 6 (0.2 mmol), A26 resin-HF(10
equiv. HF), DCE (0.4 mL), room temperature, 5 h. All yields are for the
isolated product.
The Prins reaction of a homoallylic alcohol and an aldehyde hydes (7g, 7h) gave good to excellent yields of the corres-
in the presence of an acid is a well-established synthetic meth- ponding products.
odology for the preparation of tetrahydropyrans.30,31 However,
Electron-poor aldehyde substrates (7b–7e) gave higher
there are only few reports on the fluoro-Prins reaction for the yields than electron rich aldehydes (7f). Notably,
di-
a
synthesis of fluorinated tetrahydropyrans.32–35 Moreover, most substituted fluorinated tetrahydropyran could be synthesized
of the reported syntheses of fluorinated tetrahydropyrans with good yield and diastereoselectivity when isoprenol was
suffer from either low yields or, especially, low diastereo- used as substrate (7i). Next, we compared the reactivity of our
selectivity. With our ion exchange resin supported-HF reagent, polymer supported HF reagent with the only commercially
we obtained fluorinated tetrahydropyrans with high diastereo- available polymeric hydrogen fluoride reagent – poly-4-vinyl-
selectivities and in good yields. The high stereoselectivity is pyridium poly(hydrogen fluoride) (PVP-HF) (equations A, B
consistent with previous studies by Rychnovsky et al.,36–38 and C). Our reagent showed much better efficiency in all three
where the cyclization proceeds through a chair transition state reactions. It should be noted that our ion exchange resin is
with a syn addition of nucleophile across the alkene. As illus- much less costly than PVP, making it suitable for larger scale
trated in Table 4, both aromatic (7a–7f) and aliphatic alde- synthesis.
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Fig. 2 Thermostability test of polymer supported HF reagent at room
temperature.
As mentioned above, the use of HF based reagents under flow
conditions has not been reported. Our ionic exchange resin-
supported HF reagent could be easily packed into a plastic
tube or a column suitable for flow reactions (see ESI†). We
used the hydrofluorination of alkene 1a to test the flow con-
ditions at room temperature (Fig. 1). A solution of alkene was
injected into the packed column and the column was flushed
with neat solvent (DCE) at 0.5 mL h−1 flow rate. We used an
HF-scavenger at the bottom of column to prevent excess HF
from enter in the eluent stream and to avoid etching the glass-
ware. The eluent was collected and concentrated to afford the
crude product in 92% NMR yield. This flow reactor could be
used for large scale synthesis. In addition, if desired, the ion
exchange resin could be recycled to complex with more HF
and reused.
Conclusions
In summary, we have developed an inexpensive and stable ion
exchange resin-supported anhydrous hydrogen fluoride
reagent. The reagent showed its effectiveness in three reactions
that required strong acid conditions. This reagent was also
used in a flow reactor with a simplified reaction workup pro-
cedure. Further applications and possible commercialization
are currently being considered in our laboratory.
Conflicts of interest
The thermal stability of the polymeric HF reagent (resin
A26-HF) was also investigated (Fig. 2). We found only a 2 wt%
HF loss when an open vial containing the resin was placed in
a well vented fume hood for 30 h. The stability of this reagent
should facilitate its packing, transportation and storage (see
ESI†).
The authors declare no conflict of interest.
Acknowledgements
We are grateful to the National Institutes of Health for finan-
cial support (R01GM121660). B. Xu is grateful to the National
Science Foundation of China (NSFC-21672035) and the China
Recruitment Program of Global Experts for financial
support. B. S. Bajwa is grateful to the Camille and Henry
Dreyfus Foundation and to the California State University,
Fresno for a summer research scholarship.
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