Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

Article abstract of DOI:10.1039/c8sc01221k

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug pK_a, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp³)-H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent N-fluorobenzenesulfonimide. We also report heterobenzylic trifluoromethylthiolation and ¹⁸F-fluorination, providing a suite of reactions for late-stage C(sp³)-H functionalization of drug leads and radiotracer discovery.

Full text of DOI:10.1039/c8sc01221k

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Direct heterobenzylic fluorination, difluorination
and trifluoromethylthiolation with
Cite this: DOI: 10.1039/c8sc01221k
dibenzenesulfonamide derivatives†
ad
Michael Meanwell,a Bharani Shashank Adluri,a Zheliang Yuan,ab Josiah Newton,
d
Philippe Prevost,a Matthew B. Nodwell,a Chadron M. Friesen,
Paul Schaffer,b
c
a
*
Rainer E. Martin
and Robert Britton
Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique
opportunities to modulate drug pKa, influence potency and membrane permeability, and attenuate
metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made,
direct C(sp3)–H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both
mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on
transient sulfonylation by the electrophilic fluorinating agent N-fluorobenzenesulfonimide. We also
report heterobenzylic trifluoromethylthiolation and 18F-fluorination, providing a suite of reactions for
late-stage C(sp3)–H functionalization of drug leads and radiotracer discovery.
Received 15th March 2018
Accepted 25th May 2018
DOI: 10.1039/c8sc01221k
rsc.li/chemical-science
as a carbonyl or alkoxy group mimic.2c Considering that roughly
60% of FDA approved drugs include a nitrogen-containing
heterocycle,7 the development of synthetic strategies that
Introduction
In recent years considerable effort has been directed towards
the development of new methods to selectively uorinate
C(sp2)–H or C(sp3)–H bonds in structurally complex molecules.1
These efforts have been stimulated by the profound effect that
uorination can have on biological activity2 and strategic
advantages manifest by late-stage C–H functionalization in
medicinal and agrochemistry.3 For example, uorination can
signicantly impact potency, selectivity, lipophilicity and
membrane permeability of drug leads,2b and modulate the pKa
of proximal heterocycles (e.g., 1,4 2 5 and 3,6 Fig. 1). The char-
acteristically strong C–F bond is also routinely exploited in
medicinal chemistry as a replacement for C–H bonds and, in
particular, a means to block oxidative metabolism (e.g., 3).2
Furthermore, uorinated alkyl groups can serve as bioisosteres
for more polar or less stable functionalities, and the replace-
ment of a hydroxyl group with a uorine atom is a common
tactic.2 Likewise, the CF2H group (H-bond donor) is a lipophilic
bioisostere for alcohols or thiols and the CF2R group can serve
aDepartment of Chemistry, Simon Fraser University, Burnaby, British Columbia, V5A
1S6, Canada. E-mail: rbritton@sfu.ca
bLife Science Division, TRIUMF, Vancouver, BC, V6T 2A3, Canada
cMedicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche
Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070
Basel, Switzerland
dDepartment of Chemistry, Trinity Western University, Langley, British Columbia, V2Y
1Y1, Canada
† Electronic supplementary information (ESI) available: Experimental procedures,
purication and characterization data for all new compounds. See DOI:
10.1039/c8sc01221k
Fig. 1 Heterobenzylic fluorides in drug discovery and strategies for
their synthesis.
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provide access to heterobenzylic uorides is of particular
interest and much success has been realized in tri-
uoromethylation of heterocycles.8 However, introduction of
heterobenzylic monouoroalkyl or diuoroalkyl groups
remains largely reliant on cross coupling reactions9 or deoxy-
uorination of heterobenzylic alcohols10 and carbonyls,11
processes that require prior functionalization. As a notable
exception, Baran has reported innate C(sp2)–H functionaliza-
Results and discussion
Mono- and diuorination of 4-ethylpyridine and 4-
alkylquinolines
While examining the scope of the pyridylic uorination reac-
tion depicted in Fig. 1 (11 / 12),21 we found that at elevated
temperatures (>65 ꢀC) small amounts of the corresponding
diuoroalkyl derivatives were formed and could be identied
by a characteristic resonances at d ꢁ ꢂ95 ppm in 19F NMR
spectra recorded on crude reaction mixtures. These observa-
tions prompted us to investigate the pyridylic diuorination
reaction as a complimentary process. As summarized in Table
1, heating a solution of 4-ethylpyridine in MeCN with an excess
of NFSI afforded exclusively the monouorinated adduct 15 at
60 ꢀC (entry 1). Increasing the reaction temperature above
80 ꢀC (in a microwave) provided a complex mixture of products
that included the corresponding acetamide derived from
displacement of uoride by solvent (MeCN).17d However, when
tion of heterocycles as a means to add each of the CHF2,12a
12c
CH2F12b and CF2CH3
groups (e.g., 5–7) by employing the
corresponding zinc sulnate salts in Minisci-like radical
addition processes. Likewise, the introduction of diuoro-
acetates 8,13 diuoroacetamides 9 14 and diuorophosphonates
10 15 has been accomplished via transition metal catalysis or
radical processes.16 Unfortunately, despite considerable
advances in C(sp3)–H benzylic mono- and diuorination,17
heterobenzylic C(sp3)–H uorination10,18 or diuorination are
largely unexplored owing to fundamental incompatibilities
between common uorine transfer reagents19 (e.g., N-uo-
robenzenesulfonimide (NFSI)) and nucleophilic heterocycles.20
Towards this goal, Van Humbeck has very recently described
the uorination of several alkylheterocycles induced by single
electron transfer to Selectuor.18e Previously, we reported the
serendipitous nding that 2- and 4-alkylpyridines (e.g., 11)
undergo pyridylic uorination by reaction with the electro-
philic uorination agent NFSI, a process that involves the
transient formation of a sulfonylpyridinium intermediate.21
Here, we demonstrate that activation by transient sulfonylation
is general for a range of alkylheterocycles and can be extended
to heterobenzylic diuorination and triuoromethylthiolation.
Collectively, these convenient processes provide a platform for
late-stage functionalization of drug leads and enable direct 18F-
uorination of alkylheterocycles for the purpose of radiotracer
synthesis for positron emission tomography (PET) imaging.
ꢀ
the reaction was repeated at 75 C with a further increase in
equivalents of NFSI, a ꢁ1 : 1 mixture of the mono- and
diuorinated ethylpyridines 15 and 16 were produced in good
yield (74%, entry 2) and were readily separable by ash column
chromatography. Notably, for diuorination, sequential acti-
vation by sulfonylation consumes 2 equivalents of NFSI and
a further 2 equivalents are required for uorination. The
additional excess of NFSI is required to offset its slow
decomposition over the course of the reaction (48 h). Several
alternative solvents were evaluated and a modest increase in
yield was realized in EtOAc (entry 3). The uorination of 4-
ethylquinoline (17) was also examined and we were pleased to
nd that heterobenzylic uorination of this alkylquinoline
provided the monouoroethyl product 18 in good yield (entry
4). However, despite considerable effort, this substrate proved
reluctant to undergo diuorination. Under more forcing
ꢀ
conditions (e.g., >90 C, microwave) decomposition occurred,
Table 1 Mono- and difluorination of ethylpyridine (14) and alkyl quinolines 17 and 20
Entry
Hetero aromatic
Solvent (conc. (M))
NFSI (equiv.)
Temp (ꢀC)
Producta (ratio)
% Yieldb
1
2
3
4
5
6
7
8
14
14
14
17
17
20
20
20
MeCN (0.1)c
MeCN (0.5)d
EtOAc (0.5)d
MeCN (0.1)c
EtOAc (0.5)d
MeCN (0.1)c
MeCN (0.3)d
MeCN (0.5)d
3
60
75
75
65
75
65
75
75
15 : 16 (>20 : 1)
15 : 16 (1 : 1)
15 : 16 (2 : 3)
18 : 19 (>20 : 1)
18 : 19 (10 : 1)
21 : 22 (1 : 3)
21 : 22 (1 : 8)
21 : 22 (1 : 10)
87
74
82
71
81
30
61
74
10
10
3
10
3
4
5
a
b
Ratio of mono- and diuorinated products determined by analysis of crude 1H and 19F NMR spectra. Combined isolated yield of mono- and
diuorinated products. 1.1 equiv. of Li2CO3. d 5 equiv. of Li2CO3.
c
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and aer 36 h at 75 ꢀC with a large excess of NFSI only ꢁ7% of
the diuoroethyl quinoline 19 was produced (entry 5).
Considering the importance of both the mono- and diuor-
omethyl groups as bioisosteres,2c we also investigated the
uorination of 4-methyl quinoline (20) and were surprised to
nd that diuorination predominated even at low conversion,
suggesting that here the second uorination event is a more
facile process (entry 6). Increasing the equivalents of NFSI
and reaction temperature (entry 7) as well as concentration
(entry 8) ultimately provided the diuoromethyl quinoline 22
in excellent yield while further increases in reaction temper-
ature, time or equivalents of NFSI failed to promote tri-
uorination on this or any other substrate. In both the mono-
and diuorination of alkylquinolines 17 and 20, phenyl-
sulfonyl uoride was observed as a by-product, suggesting
that these reactions rely on activation of quinoline through
transient sulfonylation by NFSI.21 It is notable that this
approach to heterobenzylic uorination is complimentary to
the Minisci-like radical reactions described by Baran, which
favour triuoromethylation at C7 or diuoromethylation at
C2 of quinolines.12
Scope of heterobenzylic mono- and diuorination
Encouraged by the susceptibility of 4-alkylquinolines 17 and 20
to undergo mono- or diuorination, we explored the scope of
these reactions with a broader range of heterocycles including
pyridines, isoquinolines, pyrimidines, quinazolines and
purines. As summarized in Fig. 2, by simply modifying the
equivalents of reagent and temperature, in several cases mono-
or diuorination could be effected selectively. For example,
both mono- and diuoroalkyl pyridines, quinazolines and
purines could be produced in good yield following this
straightforward procedure (e.g., 23/42, 30/44, 31/43 and 32/45).
As noted above, alkylquinolines were reluctant to diuorinate
but were monouorinated in excellent yield providing 24 and
25. Conversely, a series of methylquinolines were transformed
directly into the corresponding diuoromethylquinolines 33–39
in good yield. In addition to the obvious compatibility with
azaheterocycles, substituted aromatics (e.g., 36–41), esters (e.g.,
25) and amides (e.g., 24) were well tolerated. It is notable that
both 2,4-dimethylquinoline and 2,4,6-trimethylpyridine failed
to undergo uorination (<5% yield) using our standard reaction
conditions. Here, we postulate that steric hindrance from the
adjacent alkyl group(s) impedes sulfonylation of the heterocycle
by NFSI and thus prevents uorination. In several cases,
complete separation of mono- and diuorinated products by
ash column chromatography proved challenging. Thus, while
puried product could be isolated this way, yields for these
reactions were determined by analysis of NMR spectroscopic
data using an internal standard.21
Sulfonyl transfer promotes heterobenzylic triuoromethyl-
thiolation
Considering that sulfonyl transfer from NFSI is a key feature
of this process (e.g., 48, Fig. 3),21 we examined a small
Fig.
2 Mono- and difluorination of pyridines, quinolines, iso-
quinolines, quinazolines, pyrimidines and purines. aYield deter- Fig. 3 Trifluoromethylthiolation and chlorination of purine and qui-
mined by analysis of NMR spectroscopic data using an internal nazolines. aConditions: N(SCF3)SI (2.4 equiv.), Li2CO3 (1.1 equiv.),
standard; breaction at 125 ꢀC in a microwave reactor; caccompanied MeCN, 75 ꢀC, 48 h; bN(SCF3)SI (2.4 equiv.), Li2CO3 (1.1 equiv.), MeCN,
by 25% of the difluorinated quinazoline 44; dreaction at 25 ꢀC; 125 ꢀC (microwave), 50 min; cyield determined by analysis of NMR
eaccompanied by ꢁ40% of a monofluorinated product; f10 equiv. of spectroscopic data using an internal standard; dN(Cl)SI (1.2 equiv.),
NFSI in EtOAc.
Li2CO3 (1.1 equiv.), MeCN, 75 ꢀC, 48 h.
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Heterobenzylic functionalization and 18F-uorination of drug
leads
collection of dibenzenesulfonamide derivatives22 to explore
their potential in the direct heterobenzylic functionalization
of alkylquinazolines and purines. As depicted in Fig. 3, we
found that both triuoromethylthiolation (e.g., 49–51 and 53–
55) and chlorination (e.g., 52) were facile processes. For
example, 2- and 4-alkylquinazolines and 6-ethylpurine
underwent heterobenzylic triuoromethylthiolation using
In an effort to further demonstrate the utility of this suite of
transformations, we explored the monouorination, diuori-
nation and triuoromethylthiolation of quazodine (58),25
a cardiac stimulant. As depicted in Scheme 1, each of these
transformations proceeded smoothly and provided access to
the unique quazodine derivatives 59–61 in good to excellent
yield. To gauge the impact of heterobenzylic functionalization
on relevant physiochemical properties, the pKa, distribution
coefficient (log D) at pH 7.4 and aqueous solubility of each
compound was measured. As summarized in Scheme 1, these
transformations signicantly affected each property and
provide a straightforward means to modulate lipophilicity and
basicity. Likewise, the peracetate 63 of the cytotoxic purine
nucleoside analogue 62 26 could be mono- or diuorinated,
affording the analogues 64 or 65, respectively, in good yield.
Finally, we explored the direct 18F-uorination of the annulated
pyridine 66 to demonstrate the additional utility of this trans-
formation for rapidly generating radiotracers for positron
emission tomography (PET) imaging. We have previously
exploited [18F]NFSI27 in the direct radiouorination of branched
aliphatic amino acids28 and were pleased to nd that simply
heating a solution of the annulated pyridine 66 and [18F]NFSI in
MeCN at 75 ꢀC for 40 min provided the 18F-labelled derivative 67
in good radiochemical conversion (RCC) and yield (RCY). This
streamlined heterobenzylic 18F-uorination does not rely on
prior functionalization or sensitive reagents and thus offers
certain advantages for the rapid generation of radiotracers for
PET imaging.
N-triuoromethylthiodibenzenesulfonimide
(N(SCF3)SI).22
Surprisingly, we observed no competing heteroaryl tri-
uoromethylthiolation22 of quinazolines and purines, and
attempts to effect the equivalent transformation using tri-
uoromethylthiophthalimide, an electrophilic triuoro-
methylthiolation reagent,23 delivered none of the expected
triuoromethylthiolated products. This later result provides
support for a mechanism involving activation by transient
sulfonylation with dibenzenesulfonamide derivatives. Again,
2,4-disubstituted quinazolines failed to provide any tri-
uoromethylthiolated product (e.g., 56 or 57) presumably due
to steric hindrance impeding sulfonylation of the
heterocycle by N(SCF3)SI. Notably, this heterobenzylic tri-
uoromethylthiolation24 reaction offers a unique opportunity
to signicantly alter lipophilicity (Hansch hydrophobicity
parameter p ¼ 1.44)23 and pKa of a drug lead.
Conclusions
In summary, we demonstrate that transient sulfonylation of
a range of nitrogen-containing heterocycles enables direct het-
erobenzylic mono or diuorination using the bench stable
electrophilic uorinating agent NFSI or radiouorination with
[18F]NFSI. Taking advantage of this heterocycle activation
process, both triuoromethylthiolation and chlorination could
also be achieved using the corresponding dibenzenesulfona-
mide derivatives. This collection of late-stage transformations
should enable the rapid tuning of pKa and lipophilicity of
heterocycle-containing drug leads and provides a complimen-
tary means to incorporate pharmaceutically relevant bio-
isosteres (e.g., –CHF2, –CF2R and –CH(SCF3)R) as well as
a method to rapidly generate 18F-labelled imaging agents for
PET imaging.
Experimental
General procedure for heterobenzylic monouorination
Scheme
1
Late-stage
mono-
and
difluorination,
tri-
fluoromethylthiolation and 18F-fluorination of heterocycles. aNFSI (1.2
equiv.), Li2CO3 (1.1 equiv.), MeCN, rt, 96 h; bNFSI (3.0 equiv.), Li2CO3 (1.1
equiv.), MeCN, 125 ꢀC (microwave), 50 min; cN(SCF3)SI (2.4 equiv.),
Li2CO3 (1.1 equiv.), MeCN, 75 ꢀC, 48 h; dsolubility measured by lyo-
philisation solubility assay (LYSA) at pH 6.5 in 0.05 M phosphate buffer;
To a solution of substrate in CH3CN (0.1–0.25 M substrate) was
added N-uorobenzenesulfonimide (NFSI) (3.0 equiv.) and
Li2CO3 (1.1 equiv.). The resulting reaction mixture was then
heated to 65 ꢀC and maintained at this temperature for 18–24 h.
The reaction mixture was cooled, diluted with CH2Cl2 and
eNFSI (3.0 equiv.), Li2CO3 (1.1 equiv.), MeCN, 75 ꢀC, 48 h; NFSI (5.0
equiv.), Li2CO3 (5.0 equiv.), MeCN, 75 ꢀC, 48 h.
f
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washed with saturated NaHCO3 solution. The organic layer was
dried (MgSO4), concentrated and the crude reaction product
was puried by column chromatography on silica gel.
J.-D. Hamel, M. Vandamme and J.-F. Paquin, Chem. Rev.,
2015, 115, 9073.
2 (a) N. A. Meanwell, J. Med. Chem., 2018, DOI: 10.1021/
acs.jmedchem.7b01788; (b) E. P. Gillis, K. J. Eastman,
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General procedure for heterobenzylic diuorination
To a solution of substrate in CH3CN (0.25–0.50 M substrate) was
added N-uorobenzenesulfonimide (NFSI) (5.0 equiv.) and
Li2CO3 (5.0 equiv.).ꢀThe resulting reaction mixture was then
either heated to 75 C and maintained at this temperature for
48 h or heated to 125 ꢀC and maintained at this temperature for
1 h in a microwave reactor. The reaction mixture was then
cooled, diluted with CH2Cl2 and washed with saturated
NaHCO3 solution. The organic layer was dried (MgSO4),
concentrated and the crude reaction product was puried by
column chromatography on silica gel.
¨
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7 E. Vitaku, D. J. Smith and J. T. Njardarson, J. Med. Chem.,
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8 For reviews on triuoromethylation of (hetero)aromatics,
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To a solution of substrate in CH3CN (0.25–0.50 M substrate) was
added N-triuoromethylthiobenzenesulfonimide (2.4 equiv.)
and Li2CO3 (1.1 equiv.). The resulting reaction mixture was then
ꢀ
either heated to 75 C and maintained at this temperature for
48 h or heated to 125 ꢀC and maintained at this temperature for
1 h in a microwave reactor. The reaction mixture was cooled,
diluted with CH2Cl2 and washed with saturated NaHCO3 solu-
tion. The organic layer was dried (MgSO4), concentrated and the
crude reaction product was puried by column chromatography
on silica gel.
9 For transition metal catalyzed diuoromethylation, see: (a)
P. S. Fier and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134,
5524; (b) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones,
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11 For example, see: (a) W.-P. Deng, G. Nam, J. Fan and
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by an NSERC Discovery Grants to R. B.,
a MSFHR Career Investigator Award to R. B., a Hoffmann-La
Roche Fellowship (RPF) for M. B. N. an NSERC PGS and a SFU
MYF for M. M. We would like to thank Pascal Hasenfratz, Laura
Martin, Simona Capomolla, Maria Giraldo, Silvio Binkert and
Christelle Jablonski for the preparation of starting materials,
Catherine Karrer for LYSA, Aynur Ekiciler for log D and Bjoern
Wagner for pKa measurements.
12 (a) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter,
D. D. Dixon, M. R. Collins, D. G. Blackmond and
P. S. Baran, J. Am. Chem. Soc., 2011, 134, 1494; (b)
Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder,
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