Iron-Catalyzed Fluoroalkylation of Arylborates with Sulfone Reagents: Beyond the Limitation of Reduction Potential

Article abstract of DOI:10.1002/anie.202102597

The iron-catalyzed alkyl–aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron-catalyzed radical difluoroalkylation of arylborates with N-heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N-heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single-electron-transfer process, which enables both fluoroalkyl N-heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N-heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents.

Full text of DOI:10.1002/anie.202102597

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How to cite:
International Edition: doi.org/10.1002/anie.202102597
German Edition: doi.org/10.1002/ange.202102597
Synthetic Methods
Iron-Catalyzed Fluoroalkylation of Arylborates with Sulfone
Reagents: Beyond the Limitation of Reduction Potential
Zhiqiang Wei, Wenjun Miao, Chuanfa Ni,* and Jinbo Hu*
Abstract: The iron-catalyzed alkyl–aryl coupling reaction
between sulfones and arylboron compounds has remained
a challenge. We report the first iron-catalyzed radical di-
fluoroalkylation of arylborates with N-heteroaryl sulfones. The
coordination between the iron catalyst and the nitrogen atom of
N-heteroaryl sulfones was identified to be important in over-
coming the reduction potential limitation of sulfones in the
intermolecular single-electron-transfer process, which enables
both fluoroalkyl N-heteroaryl sulfones (with relatively high
reduction potentials) and nonfluorinated alkyl N-heteroaryl
sulfones (with low reduction potentials) to serve as powerful
alkylation reagents.
reported the first example of using fluoroalkyl sulfones as
fluoroalkyl radical precursors for efficient fluoroalkylation.[7]
In 2018, we reported an iron-catalyzed radical difluorome-
thylation of diarylzincs using difluoromethyl 2-pyridyl sul-
fone.[8] Almost at the same time, the Baran group reported
nickel-catalyzed fluoroalkylation of aryl zinc chlorides using
1-phenyl-1H-tetrazol-5-yl sulfones as fluoroalkyl radical pre-
cursors.[9] Nevertheless, the SET reduction of sulfones via
metal coordination has never been revealed.
Difluoroalkylated compounds are widely used in the
development of agrochemicals, pharmaceuticals, and other
biologically important molecules,[10] and transition metal-
catalyzed aromatic difluoroalkylation reactions have been
emerging.[7–9,11–14] However, although arylboron compounds
have been widely used in organic synthesis, metal- catalyzed
difluoroalkylation of arylboron compounds has remained
a challenging task.[8,9,15] With these considerations in mind, we
aimed at developing an iron-catalyzed cross coupling between
arylboron compounds and difluoroalkyl sulfones to address
the synthetic challenge and to probe the role of metal
coordination in the SETreduction of sulfones. We envisioned
that if we enable an N-Fe coordination by using a difluoroalkyl
N-heteroaryl sulfone (Scheme 1a), an intramolecular SET
Single electron transfer (SET) reduction is a powerful
approach to generate organic radical intermediates from
various neutral organic substrates that are capable of accept-
ing electrons, and has been extensively used in modern
organic synthesis.[1] To facilitate the SET reduction of
challenging systems, common strategies include modifying
the electronic properties of the substrates or the reductants
and taking advantage of ligand effect to modify the redox
potential of the metal catalyst.[2] In addition, proton-coupled
electron transfer (PCET) catalysis is also operative to
promote the SET reduction of substrates that are otherwise
difficult to reduce, and recently has been developed into
a general mode of substrate activation.[3] However, the SET
reduction of challenging substrates through their activation
by coordination with metal catalyst has been little explored in
organic synthesis,[4] despite the fact that a linkage between the
oxidant and reductant reactants by a bridging ligand can
accelerate the electron transfer reactions.[5]
Fluoroalkyl sulfones, a class of stable and easily accessible
organofluorine compounds, have been widely used in selec-
tive fluoroalkylation of organic molecules.[6] In 2016, we
[*] Z. Wei, Dr. W. Miao, Dr. C. Ni, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai 200032 (China)
E-mail: nichuanfa@sioc.ac.cn
jinbohu@sioc.ac.cn
Z. Wei, Prof. Dr. J. Hu
School of Physical Science and Technology
ShanghaiTech University
100 Haike Road, Shanghai 201210 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102597.
Scheme 1. Proposed single electron reduction of sulfones and proof-of-
concept experiments.
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process from iron to sulfur could readily occur to give
difluoroalkyl radical species (CCF2R), which reacts with
aryliron (Fen+1Ar) to form RCF2Fen+2Ar. The latter inter-
mediate undergoes reductive elimination to afford product
Ar-CF2R. Herein, we report our results on the first iron-
catalyzed difluoroalkylation of arylborates with N-heteroaryl
sulfones, which is facilitated by an additional coordination of
sulfone to iron.
Initially, we attempted iron-catalyzed difluoromethylation
of arylborates 2d with difluoromethyl phenyl sulfone
(PhSO2CF2H), no desired product was observed and
PhSO2CF2H (1a) remained (Scheme 1b).[16] However, in the
case of isopropyl 2-pyridyl sulfone (1b), the reduction
potential of which (À2.18 V vs. Ag/AgCl) is lower than that
of PhSO2CF2H (À2.05 V vs. Ag/AgCl),[17] the cross coupling
product can be obtained in 32% yield (Scheme 1c). It
indicates that this kind of cross coupling reaction goes
beyond the limit of reduction potential of sulfones, which is
distinctly different from our previously reported one-electron
reduction of sulfones by the photocatalyst.[7] In other words,
under certain conditions, a sulfone with lower reduction
potential can undergo better radical cross coupling reaction
than another sulfone with higher reduction potential does.
Next, we set out to synthesize various difluoromethyl
(hetero)aryl sulfones 1c–1i, and screened their reactivity in
the iron-catalyzed cross-coupling reaction with lithium phe-
nylborate 2a’ (Table 1; for more details, see SI).[18] It should
be noted that in all cases, lithium phenylborate 2a’ is
compatible with difluoromethyl sulfones 1, and there was
no observable consumption of 1 in the absence of FeCl2
catalyst. In general, the yields are more closely related to
the structure of N-heteroaryl moieties, but remarkably, much
less related to the reduction potentials of sulfones 1c–1i. For
instance, the reduction potentials of sulfones 1c (À1.68 V)
and 1i (À1.67 V) are almost the same, but their chemical
behaviors are significantly different (Table 1, entries 1 and 7).
Under the same conditions, the reaction with sulfone 1c gave
15% yield of product 3a’ (with 43% of 1c being recovered;
entry 1), while that with sulfone 1i gave 80% yield of 3a’
(with full consumption of 1i; entry 7).[19] As their reduction
potentials are similar, the reactivity difference between
sulfones 1c and 1i supports our assumption that intermolec-
ular N-Fe coordination (yes for 1i, but no for 1c) can play an
important role in enhancing the intramolecular SETreactivity
between iron and sulfur (as depicted in Scheme 1a).
With the standard reaction conditions in hand (Table 1,
entry 7), we examined the substrate scope of this iron-
catalyzed fluoroalkylation protocol. As shown in Scheme 2,
under the iron catalysis, (fluoro)alkyl 4,6-dimethylpyrimidin-
2-yl sulfones 1i–1o were able to undergo efficient aromatic
difluoromethylation, difluoroalkylation, and even non-fluori-
nated alkylation of lithium arylborates 2, giving the corre-
sponding (fluoro)alkylated products 3. The reactions with
lithium arylborates bearing meta- and para-substituents on
the aryls gave good to excellent yields (3a–3g, 3q and 3r),
whereas reactions with those bearing ortho-substituents on
aryls gave medium yields of the corresponding products (3s).
This reaction was also amenable to polysubstituted or fused
ring-containing arylborates (3e and 3h). Furthermore, lith-
Table 1: Screening the reactivity of various (hetero)aryl sulfones with
different reduction potentials.[a]
=
ium arylborates bearing morpholine (3k), amide (3m), C C
double bond (3o) and OTBS (3g) are all applicable in this
iron-catalyzed reaction. This sulfone-mediated cross coupling
reaction proceeds smoothly with substrates bearing a range of
heterocyclic motifs, including benzpyrole (3l) and carbazole
(3i). More importantly, this iron-catalyzed fluoroalkylation
protocol enabled the difluoromethylation of biologically
relevant compounds such as the estradiol (3n), S-citronellol
(3o), and Vitamin E (3p). Previously, the Genicot group
synthesized 18F-labeled difluoromethyl benzothiazolyl sul-
fone, and used the sulfone reagent in 18F-labeled difluorome-
thylation of aryl-substituted heterocycles.[20] We found that
our iron-catalyzed fluoroalkylation reaction basically com-
pleted in about 1 h, and when the temperature rose to 608C,
the yield did not change significantly. Hence, it is promising
that our method can be expanded to synthesize 18F-labeled
products.
In addition to difluoromethyl (CF2H) group, other
difluoroalkyl groups are also useful for biologically important
molecules. For instance, difluoroethyl (CF2CH3) moiety has
been recognized as a bioisostere of the methoxy group.[21]
Hence, we synthesized difluoroethyl 4,6-dimethylpyrimidin-
2-yl (1i; for details, see SI) and successfully applied it in
aromatic 1,1-difluoroethylation (3aa–3ai). Similarly, we also
prepared other functionalized 1,1-difluoroalkyl 4,6-dimethyl-
pyrimidin-2-yl sulfones (for details, see SI), and was pleased
Entry
1
E (V vs. Ag/AgCl)[b]
Yield
[%][c]
Conversion of 1
[%][c]
1
2
3
4
5
6
7
1c
1d
1e
1 f
1g
1h
1i
À1.68
À1.48
À1.73
À1.57
À1.80
À1.27
À1.67
15
37
52
71
54
51
80
57
>99
70
>99
75
>99
>99
[a] Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2a’ (0.85 mmol,
1.7 equiv), FeCl2 (0.15 equiv), TMEDA (0.7 equiv), MgBr2 (0.4 equiv),
THF (10.0 mL). [b] E refers to the reduction potential using Ag/AgCl as
reference. [c] Determined by 19F NMR spectroscopy using trifluorome-
thoxybenzene as an internal standard.
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Scheme 2. Iron-catalyzed alkylation of lithium arylborates with 4,6-dimethylpyrimidin-2-yl sulfones.[a] [a] Unless otherwise mentioned, the yields
refer to isolated yields, and the reaction conditions are: 1i (0.5 mmol, 1.0 equiv), 2 (0.85 mmol, 1.7 equiv), and THF (10.0 mL). [b] Determined by
19F NMR spectroscopy using trifluoromethoxybenzene as an internal standard. [c] Reaction time was 3 h. [d] 1j–1n (0.3 mmol, 1.0 equiv), 2
(0.6 mmol, 2.0 equiv), THF (6.0 mL). [e] The reaction was stirred at 408C for 4 h. [f] 20 mol% of FeCl2 and 0.9 equiv of TMEDA were used.
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Table 2: Competition experiments with 1i and 1p.[a]
to find that these sulfone reagents were able to undergo
efficient aromatic 1,1-difluoroalkylations (3aj–3ap). To our
surprise and joy, we found that this iron-catalyzed, and 4,6-
dimethylpyrimidin-2-yl sulfone-enabled method was also able
to install nonfluorinated alkyl groups onto aromatic rings
(3aq–3as), which features the broad applicability of this new
synthetic method.
Entry Conditions
1
E (V vs. Ag/AgCl) Conversion of 1 [%][b]
To gain mechanistic insights into this reaction, we carried
out several experiments to probe the N-Fe coordination
between the iron catalyst and 4,6-dimethylpyrimidin-2-yl
reagents. Firstly, NMR study was conducted on difluoro-
methyl 4,6-dimethylpyrimidin-2-yl sulfone (1i) in the pres-
ence of FeCl2. One equivalent of 1i was added into the pre-
generated 1:1 complex of TMEDA and FeCl2 in dichloro-
methane. After removal of the volatile in vacuo and washing
with hexane, the residue was purified by dissolving in CDCl3,
filtering to remove solid impurities, and removing CDCl3 in
vacuo to give a white solid. Its CDCl3 solution is very sensitive
towards air, leading to the ready formation of a brown solid
and free 1i. Fortunately, it can be characterized by NMR
1i
À1.67
60
57
15
16
1
2
508C, 2 h
1p À1.90
1i
À1.67
1p À1.90
rt, 10 h
[a] Reaction conditions: 1i (0.5 mmol, 1.0 equiv), 1p (0.5 mmol,
1.0 equiv), 2a’ (1.0 mmol, 2.0 equiv), THF (10.0 mL). [b] Determined by
19F NMR spectroscopy using trifluoromethoxybenzene as an internal
standard.
Thirdly, sterically hindered difluoromethyl 4,6-di-tert-
butylpyrimidin-2-yl sulfone (1q, À1.89 V vs. Ag/AgCl) was
designed as a prober and its reduction by iron species was
investigated (Scheme 3a). The reduction of less sterically
demanding 4,6-dimethylpyrimidin-2-yl sulfone that is of
similar reduction potential (1p, À1.90 V vs. Ag/AgCl) was
performed separately under the same conditions
(Scheme 3b). The observed much lower conversion rate of
sulfone 1q than that of 1p suggests that the steric hindrance
can inhibit the reduction of sulfone by blocking the N-Fe
interaction.
1
spectroscopy in a well-sealed NMR tube. H NMR analysis
showed that there is no TMEDA in the so-obtained white
solid, indicating that 1i could completely exchange with
TMEDA to afford a new iron complex. Moreover, both the
N-heteroaryl-hydrogen (from d 7.31 to d 7.45) and the
methyl-hydrogen (from d 2.64 to d 2.70) of 1i shifted
downfield (Figure 1), which was in accordance with the
deshielding effect caused by the coordination of iron to
nitrogen on the N-heteroaryl ring.
Secondly, competition experiments between 4,6-dimethyl-
pyrimidin-2-yl sulfones 1i and 1p were per formed at
different temperatures (Table 2). As monitored by
19F NMR, the two sulfones of similar structure were con-
sumed at the similar rate, despite the significant difference of
their reduction potentials (1i, À1.67 V vs. Ag/AgCl; 1p,
À1.90 V vs. Ag/AgCl). These results demonstrate the general-
ity of the reduction of 4,6-dimethylpyrimidin-2-yl sulfones by
the in situ formed aryliron species. Furthermore, the ready
reduction of sulfone 1p supports the importance of N-Fe
coordination in facilitating the single electron transfer from
aryliron species to sulfones that are otherwise difficult to
reduce.
Scheme 3. Effect of steric hindrance.
Based on the above-mentioned experimental results and
previous investigations,[8] we propose the following reaction
mechanism (Scheme 4). Initially, catalytically active low-
valent iron species A is formed through the interaction
between FeCl2 and TMEDA in the presence of lithium
arylborate. Then, a highly redox-active iron intermediate C is
generated via N-Fe coordination between a sulfone reagent
(such as 4,6-dimethylpyrimidin-2-yl sulfone) and aryliron
species B. Subsequently, intramolecular single electron trans-
fer (SET) from iron to sulfur (inner sphere electron trans-
fer)[5] readily occurs to produce aryliron species D and an sp3-
carbon radical in very close proximity, the efficient recombi-
nation of which affords the high-valent iron intermediate E.
Finally, TMEDA-promoted reductive elimination leads to the
formation of the desired product and regeneration of the low-
valent iron species A.
Figure 1. 1H NMR study of 1i-FeCl2 complex. a) 1H NMR of 1i;
b) 1H NMR of 1i-FeCl2.
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Scheme 4. Proposed reaction mechanism.
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In summary, we have developed a novel iron-catalyzed
alkylation of arylborates with sulfones. This method can use
both difluoroalkyl and nonfluorinated alkyl N-heteroaryl
sulfones as the sp3-carbon radical sources to construct various
alkylated aromatics. More importantly, we have shown that
the coordination of low-valent iron to the nitrogen atom of N-
heteroaryl sulfones can overcome the reduction potential
limitation in intermolecular electron transfer process, thus
enabling sulfones of low reduction potentials to efficiently
participate in radical cross-coupling. Our work not only
provides a useful protocol for organic synthesis, but it also
gives new insights into single electron transfer chemistry.
Further study in this direction is underway in our laboratory.
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Acknowledgements
This work was supported by the National Key Research and
Development Program of China (2016YFB0101200), the
National Natural Science Foundation of China (21632009),
the Key Programs of the Chinese Academy of Sciences
(KGZD-EW-T08), the Key Research Program of Frontier
Sciences of CAS (QYZDJ-SSW-SLH049), and Shanghai
Science and Technology Program (18JC1410601).
Conflict of interest
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The authors declare no conflict of interest.
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Keywords: arylborates · fluoroalkylation · iron catalysis ·
reduction potential · sulfones
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[16] Reaction conditions: difluoromethyl phenyl sulfone (0.5 mmol,
1.0 equiv), lithium arylborate (1.0 mmol, 2.0 equiv), FeCl2
(0.1 mmol, 0.20 equiv), TMEDA (0.45 mmol, 0.9 equiv), MgBr2
(0.2 mmol, 0.4 equiv), THF (10.0 mL), 508C, 2 h.
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Voltammetry Study” part in the Supporting Information (SI).
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that the lithium arylborate possesses high reactivity in trans-
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Manuscript received: February 20, 2021
Accepted manuscript online: March 24, 2021
Version of record online: && &&, &&&&
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