Difluorination of α-(bromomethyl)styrenes: Via I(I)/I(III) catalysis: Facile access to electrophilic linchpins for drug discovery

Article abstract of DOI:10.1039/d1sc01132d

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor and simple amine·HF complexes. Modulating Br?nsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters. This journal is

Full text of DOI:10.1039/d1sc01132d

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Difluorination of a-(bromomethyl)styrenes via I(I)/
I(III) catalysis: facile access to electrophilic
linchpins for drug discovery†
Cite this: Chem. Sci., 2021, 12, 6148
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Joel Hafliger, Keith Livingstone, Constantin G. Daniliuc and Ryan Gilmour
¨
Simple a-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building
blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective
organocatalyst when combined with Selectfluor® and simple amine$HF complexes. Modulating
Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing
a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method
facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis.
Preliminary validation of an enantioselective process is disclosed to access a-phenyl-b-difluoro-g-
bromo/chloro esters.
Received 25th February 2021
Accepted 25th March 2021
DOI: 10.1039/d1sc01132d
rsc.li/chemical-science
Structural editing with uorine enables geometric and elec- rst C–F bond forming process (III) with regeneration of the
tronic variation to be explored in functional small molecules catalyst. A subsequent phenonium ion rearrangement12/uori-
whilst mitigating steric drawbacks.1 This expansive approach to nation sequence (III and IV) would furnish the geminal
manipulate structure–function interplay continues to manifest diuoromethylene group and liberate the desired electrophilic
itself in bio-organic and medicinal chemistry.2 Of the plenum of building block.
uorinated motifs commonly employed, the geminal diuoro-
methylene group3 has a venerable history.4 This is grounded in
the structural as well as electronic ramications of CH2 / CF2
substitution, as is evident from a comparison of propane and
2,2-diuoropropane (Fig. 1, upper). Salient features include
localized charge inversion (C–Hd+ to C–FdÀ) and a widening of
the internal angle from 112ꢀ to 115.4ꢀ.5 Consequently, geminal
diuoromethylene groups feature prominently in the drug
discovery repertoire6 to mitigate oxidation and modulate phys-
icochemical parameters. Catalysis-based routes to generate
electrophilic linchpins that contain the geminal diuoro-
methylene unit have thus been intensively pursued, particularly
in the realm of main group catalysis.7–9 Motivated by the
potential of this motif in contemporary medicinal chemistry, it
was envisaged that an I(I)/I(III) catalysis platform could be
leveraged to convert simple a-(bromomethyl)styrenes to gem-
diuorinated linchpins: the primary C(sp3)–Br motif would
facilitate downstream synthetic manipulations (Fig. 1, lower).
To that end, p-TolI would function as a catalyst to generate p-
TolIF2 in situ in the presence of an external oxidant10 and an
amine$HF complex. Alkene activation (I) with subsequent bro-
monium ion formation (II)11 would provide a pre-text for the
¨
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster,
¨
Corrensstraße 36, 48149 Munster, Germany. E-mail: ryan.gilmour@uni-muenster.de
Fig.
1 The geminal difluoromethylene group: bioisosterism, and
† Electronic supplementary information (ESI) available. CCDC 2055892. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc01132d
catalysis-based access from a-(bromomethyl)styrenes via I(I)/I(III)
catalysis.
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To validate this conceptual framework, a short process of
reaction optimization (1a / 2a) was conducted to assess the
inuence of solvent, amine$HF ratio (Brønsted acidity)13 and
catalyst loading (Table 1). Initial reactions were performed with
p-TolI (20 mol%), Selectuor® (1.5 equiv.) as an oxidant, and
CHCl3 as the reaction medium. Variation of the amine : HF
ratio was conducted to explore the inuence of Brønsted acidity
on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was
observed enabling the product 2a to be generated in >95%
NMR-yield. Although reducing the catalyst loading to 10 and
5 mol% (entries 5 and 6, respectively) led to high levels of effi-
ciency (79% yield with 5 mol%), the remainder of the study was
performed with 20 mol% p-TolI. Notably, catalytic vicinal
diuorination was not observed at any point during this opti-
mization, in contrast with previous studies from our labo-
ratory.9d,i
A solvent screen revealed the importance of
chlorinated solvents (entries 7 and 8): in contrast, performing
the reaction in ethyl triuoroacetate (ETFA) and acetonitrile
resulted in a reduction in yield (9 and 10). Finally, a control
reaction in the absence of p-TolI conrmed that an I(I)/I(III)
manifold was operational (entry 11). An expanded optimization
table is provided in the ESI.†
To explore the scope of this geminal diuorination, a series of
a-(bromomethyl)styrenes were exposed to the standard reaction
conditions (Fig. 2). Gratifyingly, product 2a could be isolated in
80% yield aer column chromatography on silica gel. The
parent a-(bromomethyl)styrene was smoothly converted to
species 2b, as were the p-halogenated systems that furnished 2c
and 2d (71 and 79%, respectively). The regioisomeric bromides
2e and 2f (70 and 62%, respectively) were also prepared for
completeness to furnish a series of linchpins that can be
functionalized at both termini by displacement and cross-
Fig. 2 Exploring the scope of the geminal difluorinative rearrange-
ment of a-(bromomethyl)styrenes via I(I)/I(III) catalysis. Isolated yields
after column chromatography on silica gel are reported. X-ray crystal
structure of compound 2n (CCDC 2055892†). Thermal ellipsoids
shown at 50% probability.
Table 1 Reaction optimizationa
coupling protocols (2a, 2e and 2f). Modifying the amine : HF
ratio to 1 : 4.5 provided conditions to generate the tBu derivative
2g in 68% yield.14 Electron decient aryl derivatives were well
tolerated as is demonstrated by the formation of compounds
2h–2k (up to 91%). Disubstitution patterns (2l, 81%), sulfon-
amides (2m, 75%) and phthalimides (2n, 80%) were also
compatible with the standard catalysis conditions. Gratifyingly,
compound 2n was crystalline and it was possible to unequivo-
cally establish the structure by X-ray crystallography (Fig. 2,
lower).15 The C9–C8–C7 angle was measured to be 112.6ꢀ (cf.
115.4ꢀ for 2,2-diuoropropane).5 Intriguingly, the C(sp3)–Br
bond eclipses the two C–F bonds rather than adopting
a conformation in which dipole minimization is satised (F1–
C8–C9–Br dihedral angle is 56.3ꢀ).
Catalyst loading
[mol%]
Entry
Solvent
Amine/HF
Yieldb [%]
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
DCE
ETFA
MeCN
CHCl3
1 : 4.5
1 : 6.0
1 : 7.5
1 : 9.23
1 : 6.0
1 : 6.0
1 : 6.0
1 : 6.0
1 : 6.0
1 : 6.0
1 : 6.0
20
20
20
20
10
5
20
20
20
20
0
72
>95
94
87
87
79
>95
93
84
50
<5
9
10
11
a
Standard reaction conditions: 1a (0.2 mmol), Selectuor® (1.5 equiv.),
amine : HF source (0.5 mL), solvent (0.5 mL), p-TolI, 24 h, rt.
Cognizant of the inuence of Brønsted acidity on the regio-
selectivity of I(I)/I(III) catalyzed alkene diuorination,9d the
inuence of the amine : HF ratio on the uorination of
Determined by 19F NMR using a,a,a-triuorotoluene as internal
b
standard.
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electronically non-equivalent divinylbenzene derivatives was
explored (Fig. 3, top). Initially, compound 3 bearing an a-(tri-
uoromethyl)styrene motif was exposed to the standard catal-
ysis conditions with a 1 : 4.5 amine : HF ratio. Exclusive,
chemoselective formation of 4 was observed in 79% yield.
Simple alteration of the amine : HF ratio to 1 : 7.5 furnished the
tetrauorinated product 5 bearing both the geminal and vicinal
diuoromethylene16 groups (55% yield. 20% of the geminal–
geminal product was also isolated. See ESI†). Relocating the
electron-withdrawing group (a-CF3 / b-CO2Me) and repeating
the reaction with 1 : 4.5 amine : HF generated the geminal CF2
species 7 in analogy to compound 4. However, increasing the
amine : HF ratio to 1 : 6.0 led exclusively to double geminal
diuorination (8, 55%).
Similarly, bidirectional geminal diuorination of the
divinylbenzene derivatives 9 and 11 was efficient, enabling the
synthesis of 10 (46%) and 12 (70%), respectively. This enables
Fig. 4 Selected modification of building blocks 2a and 2h. Conditions:
(a) NaN3, DMF, 110 ꢀC, 16 h. (b) Pd(OH)2/C (10 mol%), EtOH, 1 M HCl, rt,
24 h; (c) CDI, Et3N, THF, 60 ꢀC, 16 h; (d) malonyl chloride, DCM, 0 ꢀC,
2 h.
facile access to bis-electrophilic uorinated linchpins for
application in materials chemistry.
Preliminary validation of an enantioselective variant8d was
achieved using the trisubstituted alkene 13. To that end, a series
of C2-symmetric resorcinol-based catalysts were explored (see
Fig. 3, inset). This enabled the generation of product 15 in up to
18 : 82 e.r. and 71% isolated yield. It is interesting to note that
this catalysis system was also compatible with the chlorinated
substrate E-14. A comparison of geometric isomers revealed
a matched-mismatched scenario: whilst E-14 was efficiently
converted to 16 (75%, 14 : 86 e.r.), Z-14 was recalcitrant to
rearrangement (<20%).
To demonstrate the synthetic utility of the products, che-
moselective functionalization of linchpin 2a was performed to
generate 17 (57%) and 18 (87%), respectively (Fig. 4). Finally,
this method was leveraged to generate an API for amyotrophic
lateral sclerosis. Whereas the reported synthesis17 requires the
exposure of a-bromoketone 19 to neat DAST over 7 days,18
compound 2h can be generated using this protocol over a more
practical timeframe (24 h) on a 4 mmol scale. This key building
block was then processed, via the amine hydrochloride salt 20,
to API 21.
Conclusions
Fig.
3 Exploring the synthetic versatility of this platform. (Top)
Leveraging Brønsted acidity to achieve chemoselective fluorination.
(Centre) Bidirectional functionalization. (Bottom) Preliminary valida-
tion of an enantioselective variant.
In conclusion, an I(I)/I(III) catalysis manifold that facilitates the
diuorinative rearrangement of a-(bromomethyl)styrenes is
6150 | Chem. Sci., 2021, 12, 6148–6152
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disclosed. In addition to generating electrophiles with a single
geminal diuoro motif, bidirectional processes are presented
together with simultaneous geminal and vicinal diuorination.
Preliminary validation of an enantioselective reaction is
demonstrated, to enable the generation of versatile a-phenyl-b-
diuoro-g-bromo/chloro esters. Finally, the transformation has
been leveraged to enable the synthesis of an amyotrophic lateral
sclerosis drug: this provides an operationally simple alternative
to common deoxyuorinating reagents when preparing gem-
diuoro linchpins for contemporary medicinal chemistry.
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Author contributions
All authors have given approval to the nal version of the
manuscript.
Conflicts of interest
There are no conicts to declare.
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This article replaces the version published on 31st March 2021.
The title contained a typesetting error. The oxidation state
change in the title was incorrect and should read I(I)/I(III).
¨
Acknowledgements
¨
N. Erdeljac, K. Bussmann, A. Scholer, F. K. Hansen and
We acknowledge generous nancial support from the WWU
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¨
Munster and the European Commission (ERC Consolidator
Grant, 818949 RECON).
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6152 | Chem. Sci., 2021, 12, 6148–6152
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