Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions

Article abstract of DOI:10.1039/C8OB02899K

Phenols are extremely valuable building blocks in the areas of pharmaceuticals, natural products, materials and catalysts. In order to carry out modifications on phenols, the phenolic oxygen is routinely protected to prevent unwanted side reactions. Presently many of the protecting groups available can require harsh conditions, specialist equipment, expensive or air/moisture-sensitive reagents to install and remove. Here we introduce the use of the tetrafluoropyridyl (TFP) group as a general protecting group for phenols. TFP can be installed in one step with no sensitivity to water or air, and it is stable under a range of commonly employed reaction conditions including acid and base. The TFP protecting group is readily cleaved under mild conditions with quantitative conversion to the parent phenol, observed in many cases in less than 1 hour.

Full text of DOI:10.1039/C8OB02899K

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Tetrafluoropyridyl (TFP): a general phenol
protecting group readily cleaved under mild
Cite this: DOI: 10.1039/c8ob02899k
conditions†
William D. G. Brittain * and Steven L. Cobb
*
Phenols are extremely valuable building blocks in the areas of pharmaceuticals, natural products, materials
and catalysts. In order to carry out modifications on phenols, the phenolic oxygen is routinely protected
to prevent unwanted side reactions. Presently many of the protecting groups available can require harsh
conditions, specialist equipment, expensive or air/moisture-sensitive reagents to install and remove. Here
we introduce the use of the tetrafluoropyridyl (TFP) group as a general protecting group for phenols. TFP
can be installed in one step with no sensitivity to water or air, and it is stable under a range of commonly
employed reaction conditions including acid and base. The TFP protecting group is readily cleaved under
mild conditions with quantitative conversion to the parent phenol, observed in many cases in less
than 1 hour.
Received 20th November 2018,
Accepted 6th December 2018
DOI: 10.1039/c8ob02899k
rsc.li/obc
Introduction
Phenols are a ubiquitous aromatic motif present in a wide
range of chemical entities. Natural products (e.g., flavonoids,
cannabinoids and rotenoids),1 pharmaceuticals (e.g., antisep-
tics and disinfectants),2 catalysts3 and materials4 all contain
phenols in their structures. Therefore, the need for effective
phenol protecting groups is of importance to synthetic che-
mists. Common phenol protecting group strategies employed
in synthetic organic chemistry include the use of methyl (Me)
or benzyl (Bn) ethers and methoxymethyl acetals (MOM), all of
which can require harsh conditions to remove (Scheme 1).5
Other protecting groups, such as mesylates (Ms) and silyl
groups (e.g., TBS), can require low temperatures6 and phase-
transfer catalysts7 to be removed and installation of a methyl
ether is often achieved using toxic reagents such as dimethyl
sulfate. In addition, many silyl ethers are often found to be
unstable in the presence of acids.8 In many sub-classes of
organic chemistry, phenol protection still presents significant
problems. For example, in peptide synthesis the protection of
tyrosine is important due to the potential for acylation or alkyl-
ation of the phenolic oxygen or the aromatic ring.9 Current
protecting group strategies for tyrosine can require harsh de-
protection conditions (e.g., Bn/Z requires HF or hydrogenation,
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
E-mail: william.d.brittain@durham.ac.uk, s.l.cobb@durham.ac.uk
†Electronic supplementary information (ESI) available. CCDC 1856218–1856219.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ob02899k
Scheme 1 Previous work, currently available protecting groups for
phenols including their installation and deprotection conditions. This
work, the use of a tetrafluoropyridine moiety as an easily installable and
removable phenol protecting group.
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tBu requires 50% TFA : DCM)10 and the limited number which
can be removed under milder conditions are often sensitive to
acid (e.g. Trt).11
Results and discussion
To begin our studies, we wished to develop conditions for clea-
As highlighted, current phenol protecting groups are often vage of a TFP ether using the model compound 2a. Exposing
less than ideal in certain circumstances, and thus there is a m-cresol to PFP in the presence of potassium carbonate in
need to develop new strategies to meet these challenges.
acetonitrile led to clean installation of the TFP ether and com-
1
To address this need, we envisaged that one reaction class pound 2a in 97% yield (Scheme 3). We utilised H NMR spec-
which could be exploited to develop a general phenol protect- troscopy to develop cleavage conditions due to its ease of use
ing group was SNAr (nucleophilic aromatic substitution).12 In and utility in high-throughput applications. Exposing the
the literature, phenols have been shown to react in SNAr reac- model compound 2a to the potassium halides KI, KBr and KCl
tions with a range of electron deficient aryl halides.13 Within in a mixture of acetonitrile-d3 and D2O (D2O was required to
these reported reactions, SNAr processes between phenols and solubilise the inorganic salts) led to no reaction (Table 1,
perfluoroaromatics/perfluoroheteroaromatics
have
been entries 1–3). A trace amount of the desired phenol 1a was
observed to be facile and rapid. For example, pentafluoropyri- observed with KF (Table 1, entry 4). Addition of a crown ether
dine (PFP) has been observed to undergo rapid SNAr with did not improve the conversion of the reaction (Table 1,
phenolic compounds.14 In addition, our own group has entries 5 and 6). Switching to NaI also did not furnish the
reported the use of PFP as a tagging reagent in peptide desired species (Table 1, entry 7). Finally, upon the addition of
chemistry. We observed that PFP could undergo SNAr reactions a thiol, clean and rapid deprotection was observed, and con-
with peptides containing nucleophilic side-chains, including version to 1a was observed to be 78% after 1 h at 50 °C
tyrosine.15 We have also developed a range of unnatural amino (Table 1, entry 8). In the absence of the crown ether the reac-
acids using the same chemistry.16
tion still proceeded, albeit with a decreased rate, with 61%
The reaction between PFP and phenols is highly regio- conversion observed after 1 h (Table 1, entry 9). Decreasing the
selective, with the 4-position of the pyridine ring being the
most susceptible to substitution.17 Simply mixing a 1 : 1 ratio
of phenol and PFP in the presence of base will give the tetra-
fluoropyridyl (TFP) bi-aryl ether at room temperature with no
sensitivity to water or air.18
Previous studies by Vlasov et al.19 and Aksenov et al.20 have
shown that the addition of potassium fluoride (KF) to a reac-
tion between a phenol and PFP leads to a complex mixture of
products. They rationalised this observation by proposing that
Scheme 3 Installation of the tetrafluoropyridyl (TFP) moiety through an
SNAr reaction.
the fluoride ion can cleave the pyridine ether bond, thus
regenerating a perfluoroheteroaromatic species which can
undergo further SNAr reactions to give a complex mixture of
Table 1 Deprotection condition screening
products (Scheme 2).
This led us to postulate that if it were possible to intercept
the regenerated PFP after exposure to KF, then the tetrafluoro-
pyridyl (TFP) group could act as a readily-cleavable protecting
group for phenols. Herein, we explore this idea in detail and
demonstrate that TFP ethers can be installed across a wide
range of phenolic compounds and cleaved under mild con-
ditions utilising a combination of fluoride salts and methyl
thioglycolate.
Entry Conditions
Time/h Conversiona/%
1
2
3
4
5
6
7
8
KI (2 equiv.)
KBr (2 equiv.)
KCl (2 equiv.)
KF (2 equiv.)
KI (2 equiv.), 18-C-6 (3 equiv.)
KF (2 equiv.), 18-C-6 (3 equiv.)
NaI (2 equiv.), 18-C-6 (3 equiv.)
KF (2 equiv.), 18-C-6 (3 equiv.),
methyl thioglycolate (10 equiv.)
KF (2 equiv.), methyl thioglycolate
(10 equiv.)
24
24
24
24
24
24
24
1
—
—
—
<1
<1
1
<1
78
9
1
1
61
57
10
KF (1 equiv.), 18-C-6 (1 equiv.),
methyl thioglycolate (2 equiv.)
Methyl thioglycolate (10 equiv.)
Methyl thioglycolate (10 equiv.).
K2CO3 (2 equiv.)
11
12
24
24
<1
90
Scheme 2 Previous study by Vlasov et al.; proposed mechanism for the
reaction of pentafluoropyridine (PFP) with pentafluorophenol in the
presence of potassium fluoride.
a Conversion was determined by 1H NMR analysis of the reaction mixture
(see ESI). All reactions were carried out in a water bath set to 50 °C.
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number of equivalents of reagents also led to clean de- (Table 2, entries 4 and 5). Across all the other conditions
protection but at a decreased rate (Table 1, entry 10). This tested, the TFP ether was observed to be stable.
result demonstrated that if rapid deprotection is not required,
significantly fewer equivalents of reagents can be employed other nucleophiles in a basic environment. It has been pre-
during deprotection.
viously reported17 that PFP can react sequentially with mul-
Next we tested the TFP protecting group in the presence of
We also tested the thiol on its own, but only a trace conver- tiple nucleophiles and we wished to confirm that the fluoro-
sion to the phenol 1a was observed after 24 h (Table 1, entry pyridine group could still be cleaved even if additional fluorine
11). Finally, we decided to try adding base and thiol to the TFP substitutions did occur. Exposing 2a to forcing reaction con-
ether; this also led to deprotection with the reaction reaching ditions of 2.1 equivalents of piperidine, and 2.1 equivalents of
90% conversion after 24 h (Table 1, entry 12). Due to the rapid potassium carbonate in refluxing acetonitrile for 24 h resulted
nature of deprotection, we decided to continue the study using in recovery of compound 3 (Scheme 4).
the conditions from Table 1, entry 8, but it should be noted
Exposure of 3 to the developed deprotection conditions
that deprotection will occur (but at a slower rate) with fewer showed conversion to the free phenol, but the rate of conver-
equivalents of KF, 18-C-6 and methyl thioglycolate or by the sion was slower than that for 2a (Scheme 4). This reaction
application of methyl thioglycolate in the presence of potass- demonstrated that it was still possible to cleave the fluoropyri-
ium carbonate.
dine group even if it has undergone unwanted SNAr reactions.
In order to probe the utility of the protecting group, we syn-
With the selected deprotection conditions in hand, we then
progressed to study the stability of the bi-aryl tetrafluoropyri- thesised a range of TFP bi-aryl ethers in good to excellent
dine moiety. 2a was dissolved in chloroform-d (non-polar), yields (70–99%) (Fig. 1, 2a–2n). The only substrate tested
methanol-d4 (polar, protic) or acetonitrile-d3 (polar, aprotic) which was not compatible with TFP-ether formation was di-
and exposed to a range of common synthetic reagents at room tert-butyl 2f presumably due to its steric bulk. All of the TFP
temperature for 24 h (see ESI† for details). Under all of the bi-aryl ethers prepared were susceptible to the selected de-
conditions tested, compound 2a was seen to be stable in protection conditions with complete quantitative conversion
chloroform-d (Table 2, entries 1–11). Notably, both acid and to the phenol, observed in some cases in less than 1 h (2g, 2l,
base were tolerated (Table 2, entries 1 and 5). In methanol-d4 2n see ESI, pages S-107/S-112/S-114†).
the TFP ether was seen to be unstable in the presence of base
It should also be noted that di-ortho-substituted TFP bi-aryl
(Table 2, entries 3, 4 and 12). It has previously been reported ethers took longer to deprotect than mono substituted vari-
that perfluoroaromatic ethers are unstable in the presence of ents. For example, di-methyl 2d had only reached 18% conver-
methoxide and thus it was not surprising that the TFP-ether sion to its parent phenol after 1 h. Presumably, this is due to
was also unstable under such conditions.21 In acetonitrile-d3 the increased steric bulk surrounding the aryl-ether bond.
the TFP ether was unstable in the presence of strong base
We were able to demonstrate the flexibility of the TFP group
in protecting a range of phenols (Fig. 1). The TFP moiety was
also installed and cleanly removed from hydroxypyridine,
showing quantitative conversion after 1 h (Fig. 1, 2q). Tyrosine
was another phenolic species we wished to test, due to its
utility in peptide chemistry, and as part of our ongoing
research program into the synthesis of new amino acids.22 The
TFP group was installed to give ether 2o in 75% yield, and
Table 2 TFP stability screening
Stability
(CDCl3)
Stability
(MeOD)
Stability
(CD3CN)
Entry
Conditionsa
1
2
3
4
5
6
7
8
0.1 mL TFA
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
—
Stable
Stable
Unstable
Unstable
—
Stable
Stable
Stable
Stable
Stable
Stable
Unstable
Stable
—
0.1 mL 12 M HCl
20 mg K2CO3
20 mg tBuOK
20 mg NaH
Stable
Unstable
Unstable
Stable
Stable
Stable
Stable
Stable
Stable
—
0.1 mL TEAb
0.1 mL DIPEA
0.1 mL SOCl2
20 mg NaBH4
20 mg I2
9
10
11
12
20 mg DCC
20 mg NaOH
a All reactions were carried out in 0.7 mL of solvent with 10 mg of the
tetrafluoropyridyl ether 2a. b 1H NMR resonances were seen to shift in
the presence of TEA. Upon concentration under reduced pressure and
resuspension in chloroform-d, the resonances were observed to shift
back to their original positions.
Scheme 4 Exposure of TFP aryl ether 2a to nucleophiles under forcing
conditions followed by deprotection to the parent phenol.
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Fig. 1 Scope of installation (yields shown in red) and subsequent cleavage of TFP aryl ethers (conversion to the phenol shown in blue). (a) Isolated
yield following purification. (b) Conversion to the phenol following 1 h under deprotection conditions, measured by integration of 1H NMR spectra
(see ESI†). (c) TFP ether formation carried out in DMF due to solubility. (d) Reaction time = 96 h. (e) TFP ether formation carried out in a mixture of
MeCN and DMF.
after 1 h under deprotection conditions the reaction had mixture of 2a with LCMS, we observed a species with a mass
reached 75% conversion.
equating to a pentafluoropyridine (PFP) with 2 positions sub-
Modification of 1,1′-bi-2-naphthol (BINOL) through SNAr stituted by methyl thioglycolate (see ESI†). This supports our
with PFP has been previously disclosed by Koltunov et al.23 hypothesis in terms of a mechanism for the deprotection in
BINOL and substituted BINOLs have been utilised extensively in that after the fluoride regenerates the free PFP it is intercepted
asymmetric catalysis.24 Exposing BINOL to 2 equivalents of PFP in situ by the thiol (e.g. 2× methyl thioglycolate) to form a
in the presence of K2CO3 gave the bis-TFP aryl ether 2r in 69% species which is unable to undergo an SNAr reaction with the
yield. This product was susceptible to the cleavage conditions, released phenol.
but the rate of deprotection was observed to be slow, with 96 h
required to reach quantitative conversion back to BINOL.
To further validate the developed conditions we undertook
the deprotection of 2i using non-deuterated solvents on a
To demonstrate the TFP group’s applicability to steroid larger scale. After 2 h, we were able to successfully isolate
chemistry, we synthesised the TFP protected estrone derivative 4-nitrophenol from the reaction mixture in 98% isolated yield
2s in 87% yield. Exposure of the steroid derivative 2s to the de- (see ESI page S-15†).
protection conditions cleanly removed the TFP ether, with
During the synthesis of the TFP aryl ethers (Fig. 1), we
83% conversion to estrone observed after 1 h. It should be observed that may of the examples were highly stable crystal-
noted that other perfluoroaromatics have been previously line solids. Therefore, we were able to obtain crystal structures
employed as protecting groups in steroid synthesis, but these for compounds 2r and 2i (Fig. 1) which confirmed the regio-
required the use of sodium methoxide in DMF to recover the chemistry of the products.25
parent steroids.21
Finally, to further demonstrate the synthetic scope of the
To confirm that the phenol was being successfully liberater- methodology developed we carried out a range of chemical
ated using our developed conditions NMR spiking experiments transformations on our synthesised TFP ethers (Scheme 5).
were undertaken on a selection of the synthesised substrates. The free amine 4 was prepared by exposing the tyrosine TFP
In all cases, spiking the reaction sample with reference com- ether 2o to standard Boc-deprotection conditions. 4 was
pounds clearly demonstrated that the phenols were being suc- allowed to react with Boc-Ala-OH using common amide bond-
cessfully generated (see ESI pages S-123 to S-129†).
forming reagents (e.g. PyBOP) to afford the dipeptide 5 in 94%
We also probed the fate of the methyl thioglycolate using yield (Scheme 5a). No cleavage of the TFP moiety was observed
mass spectrometry. Analysing the deprotection reaction during the process.
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that the TFP group was stable; no cleavage of the ether was
observed under the reaction conditions.
Conclusions
In conclusion, we have demonstrated that TFP ethers can be
utilised as general protecting groups for phenolic oxygens. The
TFP ether moiety was installed in up to 99% yield across a
diverse range of substrates. TFP ethers were shown to be stable
to a range of synthetic reaction conditions, and there is no
need to take additional precautions to exclude water or air
during their synthesis or storage. In addition, in many cases
the TFP ethers were highly crystalline solids, and this offers
the opportunity to characterise intermediates in long synthetic
sequences using X-ray crystallography. The TFP group also con-
veniently incorporates a 19F NMR handle, which allows for
additional spectroscopic possibilities during structural ana-
lysis or reaction monitoring. A mixture of KF, 18-C-6 and
methyl thioglycolate led to rapid and clean removal of the TFP
group to liberate the parent phenols, and in some cases de-
protection occurred with quantitative conversion in 1 h at
50 °C. TFP ethers were demonstrated to be compatible with
the reaction conditions required to carry out amide bond for-
mation, palladium cross-coupling, carbonyl reduction and
click chemistry (CuAAC). The ease of installation and de-
protection of the TFP group in combination with its chemical
stability and physical properties make it an attractive option
for phenol protection.
Experimental
General procedure for the synthesis of tetrafluoropyridyl
ethers
To a stirred solution of phenol (1 equiv.) in acetonitrile
(20 mL) was added pentafluoropyridine (1.05 equiv.) and
potassium carbonate (1.05 equiv.). The reaction mixture was
stirred at room temperature for 16 h. After this time the
reaction mixture was concentrated under reduced pressure
and the resulting residue was purified by flash column
chromatography.
Scheme 5 (a) Boc-deprotection of a TFP ether followed by amide for-
mation to garner a dipeptide. (b) Suzuki–Miyaura cross-coupling of an
iodo-TFP aryl ether. (c) CuAAC reaction of a TFP ether. (d) Reduction of
estrone TFP ether 2s.
Using Suzuki–Miyaura cross-coupling conditions, the iodo-
TFP ether 2k reacted effectively with phenylboronic acid to give
compound 2n in 86% yield (Scheme 5b). 2n had previously General procedure for the deprotection of tetrafluoropyridyl
been found to be readily susceptible to the developed de- ethers
protection conditions (Fig. 1). We found that the alkyne-
appended TFP ether 2m could undergo copper-catalysed
azide–alkyne cycloaddition (CuAAC) (click chemistry) to give
triazole 6 in excellent 93% yield (Scheme 5c).
To a stirred solution of TFP ether (1 equiv.) in acetonitrile
(5 mL) and water (0.1 mL) was added potassium fluoride
(2 equiv.), 18-crown-6 (3 equiv.) and methyl thioglycolate
(10 equiv.). The reaction mixture was stirred for 2 h at 50 °C.
After this time the reaction mixture was concentrated under
reduced pressure and the resulting residue purified by flash
column chromatography.
Exposure of 6 to the developed deprotection conditions
afforded the phenolic triazole 1b with quantitative conversion
observed by 1H NMR spectroscopy (see ESI page S-120†). We
carried out a borohydride-mediated reduction of the TFP-
estrone derivative 2s (Scheme 5d). The reaction between 2s
and sodium borohydride proceeded smoothly to give the sec-
ondary alcohol 7 in 90% yield. We deliberately allowed the
Conflicts of interest
reaction to stir for an extended period of 24 h to make sure There are no conflicts to declare.
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Acknowledgements
SLC and WDGB would like to acknowledge the Biotechnology
and Biological Sciences Research Council [BB/P003656/1] and
Durham University’s Medical Research Council Confidence in 14 G. Sandford, in Encyclopedia of Reagents for Organic
Concept scheme for financial support [MC-PC-17157]. Dr Juan Synthesis, 2005, DOI: 10.1002/047084289X.rn00518.
A. Aguilar and Catherine Heffernan are thanked for NMR spec- 15 (a) D. Gimenez, C. A. Mooney, A. Dose, G. Sandford,
troscopy support. Dr Dmitry S. Yufit is thanked for help in the
collection of X-ray crystal data and solving of the reported
crystal structures. Dr Brette Chapin and Dr Matthew Kitching
are thanked for helpful comments and suggestions during the
preparation of the manuscript.
C. R. Coxon and S. L. Cobb, Org. Biomol. Chem., 2017, 15,
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G. Sandford, S. L. Cobb and C. R. Coxon, Org. Biomol.
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17 G. Sandford, R. Slater, D. S. Yufit, J. A. K. Howard and
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as supplementary publication CCDC 1856218–1856219.†
Org. Biomol. Chem.
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