A practical microwave method for the synthesis of fluoromethy 4-methylbenzenesulfonate in tert-amyl alcohol

Article abstract of DOI:10.1016/j.tetlet.2018.03.039

Fluorine substitution is an established tool in medicinal chemistry to favourably alter the molecular properties of a lead compound of interest. However, gaps still exist in the library of synthetic methods for accessing certain fluorine-substituted motifs. One such area is the fluoromethyl group, particularly when required in a fluoroalkylating capacity. The cold fluorination of methylene ditosylate is under evaluated in the literature, often proceeding with low yields or harsh conditions. This report describes a novel microwave method for the rapid nucleophilic fluorination of methylene ditosylate using inexpensive reagents in good isolated yield (65%).

Full text of DOI:10.1016/j.tetlet.2018.03.039

Accepted Manuscript
A practical microwave method for the synthesis of fluoromethy 4-methylben-
zenesulfonate in tert-amyl alcohol
Kayleigh L. Brocklesby, Jennifer S. Waby, Chris Cawthorne, Graham Smith
PII:
S0040-4039(18)30353-8
https://doi.org/10.1016/j.tetlet.2018.03.039
TETL 49808
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 January 2018
12 March 2018
15 March 2018
Please cite this article as: Brocklesby, K.L., Waby, J.S., Cawthorne, C., Smith, G., A practical microwave method
for the synthesis of fluoromethy 4-methylbenzenesulfonate in tert-amyl alcohol, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.03.039
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A practical microwave method for the synthesis of fluoromethy 4-
methylbenzenesulfonate in tert-amyl alcohol
Kayleigh L. Brocklesby1,2, Jennifer S. Waby3, Chris Cawthorne4 and Graham Smith2*
1Hull-York Medical School, University of York, Heslington, York YO10 5DD; 2Division of Radiotherapy
3
and Imaging, Institute of Cancer Research, London, SW7 3RP, UK;
Faculty of Life Sciences,
Richmond Building Room H15, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK; 4PET
Research Centre, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
* Email: graham.smith@icr.ac.uk; Tel +44 (0)2087224482
Graphical abstract:
Abstract:
Fluorine substitution is an established tool in medicinal chemistry to favourably alter
the molecular properties of a lead compound of interest. However, gaps still exist in
the library of synthetic methods for accessing certain fluorine-substituted motifs. One
such area is the fluoromethyl group, particularly when required in a fluoroalkylating
capacity. The cold fluorination of methylene ditosylate is under evaluated in the
literature, often proceeding with low yields or harsh conditions. This report describes
a novel microwave method for the rapid nucleophilic fluorination of methylene
ditosylate using inexpensive reagents in good isolated yield (65%).
Keywords: PET, fluorination, microwave, fluoromethyl tosylate, tert-amyl alcohol

Introduction
The use of fluorine in medicinal chemistry and agrochemicals has grown rapidly in
recent years, culminating in approximately one third of the top selling drugs in the
world containing at least one fluorine atom.1 This design trend is a result of the
unique properties of fluorine such as high electronegativity, high carbon-fluorine
bond strength and small steric size, which enable fluorine to impart substantial
changes in molecular properties such as lipophilicity/bioavailability and metabolic
stability at minimal steric cost.2-3 A further avenue of interest for fluorine is nuclear
medicine, specifically Positron Emission Tomography (PET), where incorporation of
cyclotron-produced fluorine-18 into radiopharmaceuticals is of widespread interest.4
For PET applications the stable isotope analogue is also required to enable accurate
confirmation of product identity by radio-chromatographic methods.
Fluoromethylation is an underexplored strategy in both medicinal chemistry and
nuclear medicine, partly as a result of the complex synthetic methodology required to
access the necessary structures. The alkylating fragment [18F]fluoromethyl 4-
methylbenzenesulfonate (“[18F]fluoromethyl tosylate”) is well-established in
radiochemistry for the automated, GMP-compatible radiosynthesis of
[18F]fluoromethyl choline.5-6 Consequently, it would be advantageous to access both
the radiochemistry precursor and the stable isotope standard via the same
fluoromethylation pathway to minimise synthetic effort. Fluoromethyl bromide and
fluoromethyl iodide have been used in this capacity but are either a volatile
greenhouse gas (FCH2Br) or are not commercially available and are troublesome to
synthesise (FCH2I). Fluoromethyl tosylate is not volatile but current methods to
access this reagent are typically low-yielding or use expensive reagents such as
phase-transfer agents (Kryptofix K222 or 18-crown-6).7-8 Herein, we report a method
for rapid access to stable isotope fluoromethyl tosylate from inexpensive reagents to
complement radiochemical methods to access [18F]fluoromethyl tosylate.
Scheme 1: Fluorination of methylene ditosylate
A survey of the literature was carried out to identify conditions for the conversion of
methylene distosyate 1 to fluoromethyl tosylate 2, with minimal formation of the by-
product tosyl fluoride 3 (Scheme 1). Our efforts to replicate previously reported
conditions and also independently identify suitable reaction parameters are
summarised in Table 1. When the fluorination was attempted in the presence of
acetonitrile and using caesium fluoride (Entry 2) this reaction gave an inadequate 5%
conversion. Conversion to the by-product p-tosyl fluoride 3 was identified by 1H NMR
1
(see ESI for the H-NMR spectrum of 3). The use of microwave heating to effect
fluoride displacement of a sulfonate by Qu and co-workers provided a rationale for

our investigation in this area.9 Previous reports have described radiolabelling via the
nucleophilic fluorination of methylene distosylate in polar aprotic solvents.7-8
Application of these conditions to a bulk scale with greatly increased stoichiometry of
the fluoride source compared to the radiolabelling reaction (Entries 4 and 5) and
more polar aprotic solvents yielded a 20% conversion to tosyl fluoride 3 again, with
an inadequate conversion to 2. A potential alternative strategy for fluoride
displacement of an alkyl sulfonate leaving group is the use of a tertiary alcohol
solvent.10-11 Gratifyingly, application of the reaction conditions reported by Kim and
co-workers (Entry 7) yielded a 100% conversion to the fluoromethyl tosylate 2. It is
thought that the partial positive charge of the polar protic solvent aids the fluoride ion
by increasing its nucleophilicity through weakening of the ionic cesium-fluorine bond
and enhancing the leaving group ability of the tosylate group through hydrogen
bonding.11
Table 1: Preliminary evaluation of reaction conditions for the synthesis of fluoromethyl tosyate 2a
Conversion (%)b
MF/Catalyst
(eq.)
Temp
(°C)
Time
(h)
Entry Solvent
Ref
1
2
3
This
work
This
1c
MeCN
TBAF
110
0.5
100
-
-
2c
3
MeCN
MeCN
DMF
CsF
110
110
120
0.5
1
95
85
75
5
15
5
-
-
work
8
KF/K222 (1.4)
CsF
This
work
This
4
24
20
5
DMSO
CsF
TBAF
CsF
CsF
120
110
80
24
0.5
6
100
100
-
-
-
-
-
-
-
work
9
6c
7d
8d
THF
t-amyl
alcohol
t-BuOH
10
100
43
10
80
6
57
a Unless otherwise stated, all reactions were carried out using 0.06 mmol of 1, 0.12 mmol of CsF, in 1 mL of the
specified solvent
b Conversion determined by 1H NMR
c Microwave irradiation
d 3 equivalents of CsF were used
Upon identifying conditions suitable for the synthesis of fluoromethyl tosylate,
attempted optimisation of the reaction as a prerequisite for larger-scale synthesis
was investigated. Therefore, the effect of temperature, reaction time and excess of
cesium fluoride on the conversion of 1 to fluoromethyl tosylate 2 or tosyl fluoride 3
was studied. Figure 1 clearly demonstrates the use of one equivalent of caesium
fluoride is less than satisfactory, never achieving above a 16% conversion. Although
two equivalents of caesium fluoride is sufficient to achieve an average of 87%
conversion after 6 hours, with no traceable starting material 1, five equivalents
achieves full conversion after one hour (see ESI, Table S1 for the full table).
Conditions were further optimised by studying the effect of temperature and reaction
duration (Table 2)

Figure 1: Equivalent dependant conversion to 2 over time. N=3. Reported as average with the error bars
indicating standard deviation. ^ No standard deviation calculated for these bars
Table 2: Microwave synthesis of 2a
Conversion(%)b
Entry
Temp. (ºC)
Time (min)
1
-
45
-
2
3
5
-
1
2
3
80
80
90
30
15
15
95
55
95
5
a Reactions conducted in 1mL of t-amyl alcohol, using 0.06 mmol of 1 and 0.3 of CsF (n=3)
b conversion determined by 1H NMR
Probing this nucleophilic fluorination on a larger scale afforded unexpected
problems, notably a low isolated yield of 37%. Table 3 summarises different work-up
conditions that were attempted in order to improve the isolated yield. As highlighted
by Entry 8, the optimal work-up conditions were removal of the residual t-amyl
alcohol followed by trituration of the resultant solid with diethyl ether and
concentration of the filtrate to furnish fluoromethyl tosylate in 65% isolated yield.

Table 3: Scale up conditionsa (A: t-amyl alcohol was removed under reduced pressure then extracted with
the stated solvent. B: poured onto water then extracted with the stated solvent. C: solvent added to the
microwave vial then sonicated to break up the reaction mixture then filtered and washed with the solvent.
The filtrate was concentrated under reduced pressure. D: t-amyl alcohol removed under reduced pressure
and the solid was triturated with the stated solvent and the filtrate concentrated under reduced pressure)
Entry
Work Up
Solvent
Yield 2b (%)
37
Yield 3c (%)
1
2
3
4
5
6
7
8d
A
B
C
C
C
D
D
D
EtOAc
Et2O
EtOAc
Et2O
CH2Cl2
EtOAc
CH2Cl2
Et2O
5
36
38
88
40
60
42
65
5
5
2
5
5
5
3
a Reactions conducted using 0.28 mmol of 1 and 1.4 mmol of CsF in 5 mL of t-amyl alcohol.
b Isolated yield
c Determined by 1H NMR
d Reaction conducted with 1.4 mmol of 1, and 7 mmol of CsF in 5mL of t-amyl alcohol.
In summary we have reported conditions for the synthesis of fluoromethyl tosylate on
a bulk scale that are superior to those previously reported. Reaction times of 15
minutes were achieved in the microwave using tert-amyl alcohol, obtaining a best
isolated yield of 65%. These results will facilitate further adoption of this important
functionality in medicinal chemistry and nuclear medicine.
Acknowledgements
The Hull-York Medical School and the University of Hull are thanked for studentship
funding (to KLB). This work was supported by the Cancer Research UK-Cancer
Imaging Centre (C1060/A16464), the Institute of Cancer Research and the
University of Hull. We thank Dr. Amin Mirza, Dr. Maggie Liu, and Meirion Richards
for assistance in analytical chemistry and spectroscopy.
References:
1.
Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H., Chem. Rev. 2014, 114 (4), 2432-2506.
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Chem. Soc. Rev. 2008,
37, 320-330.
2.
3.
4.
O'Hagan, D., Chem. Soc. Rev. 2008, 37 (2), 308-319.
van der Born, D.; Pees, A.; Poot, A. J.; Orru, R. V. A.; Windhorst, A. D.; Vugts,
D. J., Chem. Soc. Rev. 2017, 46 (15), 4709-4773.
5.
6.
Rodnick, M. E.; Brooks, A. F.; Hockley, B. G.; Henderson, B. D.; Scott, P. J.,
Appl. Radiat. Isot. 2013, 78, 26-32.
Witney, T. H.; Alam, I. S.; Turton, D. R.; Smith, G.; Carroll, L.; Brickute, D.;
Twyman, F. J.; Nguyen, Q. D.; Tomasi, G.; Awais, R. O.; Aboagye, E. O.,
Clin. Cancer Res. 2012, 18 (4), 1063-72.
7.
Neal, T. R.; Apana, S.; Berridge, M. S., J. Labelled Compd. Radiopharm.
2005, 48, 557-568.

8.
Smith, G.; Zhao, Y.; Leyton, J.; Shan, B.; Nguyen, Q.-d.; Perumal, M.; Turton,
D.; Årstad, E.; Luthra, S. K.; Robins, E. G.; Aboagye, E. O., Nucl. Med. Biol.
2011, 38 (1), 39-51.
9.
Qu, W.; Kung, M.-P.; Hou, C.; Oya, S.; Kung, H. F., J. Med. Chem. 2007, 50
(14), 3380-3387.
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
(50), 16394-16397.
11.
Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen, J. A.;
Chi, D. Y., J. Org. Chem 2008, 73, 957-962.

Highlights
 Significantly improved yield of fluoromethyl 4-methylbenzenesulfonate
 Reaction carried out using inexpensive reagents and short reaction time
 Methodology demonstrated on a preparative scale.