Photoredox-mediated mono- And difluorination of remote unactivated methylene C(sp3)-H bonds of N-alkyl sulfonamides

Article abstract of DOI:10.1021/acs.orglett.1c01020

A photoredox-mediated δ-C(sp3)-H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.

Full text of DOI:10.1021/acs.orglett.1c01020

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Letter
Photoredox-Mediated Mono- and Difluorination of Remote
Unactivated Methylene C(sp3)−H Bonds of N‑Alkyl Sulfonamides
Zhiqiang Deng, Zhenxiang Zhao, Gang He, and Gong Chen*
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ABSTRACT: A photoredox-mediated δ-C(sp3)−H fluorination of
sulfonyl-protected primary alkylamines with Selectfluor is developed.
The reaction can proceed in excellent monofluorination selectivity
for amine substrates without α substituent. For α-substituted
substrates, a slightly modified reaction conditions with two rounds
of operation gives the δ,δ-difluorination products in good yield.
Mechanistic studies suggest SET oxidation of sulfonamide group
directly generates the key sulfonamide N radical intermediate, which
triggers a 1,5-HAT process to form the δ alkyl radical.
Scheme 1. Radical-Mediated Remote C−H Fluorination of
Aliphatic Amines via 1,5-HAT
adical-mediated alkyl C−H functionalization reactions
Rhave been widely used to incorporate fluorine atom or
fluorine-containing moieties into various organic molecules.1−3
Among the different types of radical reactions, the intra-
molecularly directed approach via an 1,5-hydrogen atom
transfer (1,5-HAT) process of heteroatom-centered radical
intermediates has proven to be a reliable strategy to selectively
functionalize the unactivated alkyl C−H bond at a remote
position.4 While the strategy has long been used to install
chlorine, bromine, and iodine as in the classic Hofmann−
Loffler−Freytag (HLF) reaction and other heteroatoms and
carbon moieties, the corresponding fluorination reaction is
relatively underdeveloped.5−8 In 2016, Cook first demon-
strated that presynthesized N-fluorocarboxamide precursors
can undergo efficient C−H fluorination at the δ position via an
amidyl radical intermediate under the catalysis of Fe(OTf)2.7a
Later, the groups of Lectka,8a Liu,8b Leonori,8c and Yu8d
reported ketone, O, or iminyl radical intermediates can also
direct the δ C−H fluorination via 1,5-HAT with suitable
fluorination reagents. Very recently, the group of Bafaluy and
Muniz reported that sulfonamides can undergo remote C−H
̃
fluorination via an in situ generated N-iodosulfonamide
intermediate.8e Herein, we report a new photoredox-mediated
method for δ-C(sp3)−H fluorination of sulfonyl protected
primary alkyl amines with Selectfluor reagent (Scheme 1C).
The reaction can proceed in good to excellent monofluorina-
tion selectivity for amine substrates without an α substituent.
For α-substituted substrates, a slightly modified condition with
two rounds of operation gave δ,δ-difluorination products in
good yield and with high selectivity.
Received: March 24, 2021
Published: April 21, 2021
We previously reported a photoredox-mediated method for
δ-C(sp3)−H heteroarylation of sulfonyl-protected primary
alkyl amines with N-heteroarenes using benziodoxole acetate
oxidant.9,10 It was found that the sulfonamide group can be
https://doi.org/10.1021/acs.orglett.1c01020
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3631−3635
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Letter
directly oxidized by single electron transfer (SET) to generate
an N-radical, which triggers the subsequent 1,5-HAT and
Minisci-type arylation.9,11 Encouraged by these results, we
wondered whether a similar alkyl radical via 1,5-HAT can be
trapped by suitable fluorination reagents to give the
fluorination product. As shown in Table 1, we were pleased
70% isolated yield (entry 1). The mono- and difluorination
products are difficult to separate by silica gel chromatography.
The HFIP/H2O ratio had a significant impact to the mono- vs
difluorination selectivity. Changing the ratio of HFIP/H2O
from 4.6:1 to 1:1 gave comparable yield of 2 but dramatically
reduced monoselectivity (entry 3). Replacing HFIP with
trifluoroethanol (TFE) gave lower yield (entry 4). Use of other
organic solvents such as CH3CN and acetone caused
significantly lower reactivity (entries 5 and 6). The substituent
on the phenyl ring of the arylsulfonamide protecting group
(PG) had a significant impact to the reactivity. For example,
replacing the 4-methoxy group (PG1) with a 4-methyl group
(PG3) gave 21% of the fluorination product. Use of
trifluoromethyl sulfonamide (PG8), trifluoromethylacetamide
(PG9), and benzamide (PG10) gave no desired product.
Table 1. Reaction Optimization of δ C−H Fluorination of
N-Protected Pentylamine
−
Selectfluor I (BF4 ) served as the best fluorination reagent
a
(entries 7−12). Photocatalyst and visible light irradiation were
critical (entries 13−16). The addition of (2,2,6,6-tetramethyl-
piperidin-1-yl)oxyl or oxidanyl (TEMPO) reagent abolished
the reaction (entry 18).
change from the standard conditions (equiv of yield of 2 (2m/2d)
entry
reagents)
(%)
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
No change
76 [70 ] (>20:1)
HFIP/H2O (4.6:1 → 5.5:1)
HFIP/H2O (4.6:1 → 1:1)
HFIP is replaced with TFE
HFIP is replaced with CH3CN
HFIP is replaced with acetone
2 equiv of Selectfluor I (BF4−) is used
3 equiv of Selectfluor I (BF4−) is used
Selectfluor I (OTf−) is used
Selectfluor II (BF4−) is used
Selectfluor II (OTf−) is used
Selectfluor is replaced with NFSI
0.5 mol % of Ru(bpy)3Cl2 is used
1.5 mol % of Ru(bpy)3Cl2 is used
without Ru(bpy)3Cl2
70 (>20:1)
67 (2.5:1)
50 (11.8:1)
25 (19:1)
22 (>20:1)
69 (>20:1)
80 (>20:1)
70 (>20:1)
75 (19.7:1)
43 (>20:1)
ND
64 (>20:1)
66 (>20:1)
ND
ND
41 (>20:1)
ND
The scope of amines was then examined under the
optimized conditions A and B with different ratios of HFIP
and H2O solvents (Scheme 2). Primary amines with both
linear and cyclic alkyl scaffolds can work. Most linear alkyl
amines proceeded with excellent δ regioselectivity (δ: other
isomers >20:1) (e.g., 4−7) under conditions A using a 4.6:1
mixture of HFIP and H2O. Notably, the reaction of hexylamine
3 gave a moderate regioselectivity. Besides the δ methylene C−
H bonds, fluorination at the more inert δ methyl group can
also work albeit in lower yield. Conditions B using 1:1 mixture
of HFIP and H2O gave slightly higher yield (see 8).
Fluorination of the δ tertiary C−H of 9 proceeded in moderate
yield along with the formation of 20% of cyclized pyrrolidine
byproduct. In comparison to 1, substrate bearing a α-methyl
substitunt showed higher reactivity and gave significantly more
difluorination product 10d under conditions A. A 1.1:1 ratio of
mono- vs difluorination product was obtained under
conditions B. Similarly, 16 bearing an α-substituent was
significantly more reactive than 14. Fluorination of δ
methylene C−H bonds of cyclic scaffolds proceeded in varied
yield and selectivity. For example, the reactions of cyclooctyl-
amine and cyclododecylamine gave 12 and 13 in 60% and 50%
yield, respectively. Small amounts of difluorination products of
cyclooctylamine at both the δ and δ′ positions were obtained
and can be readily separated from the monofluorination
product by silica gel column chromatography. δ-Methyl
fluorination of α-amino acid substrates gave the corresponding
fluorinated product in low to moderate yield under conditions
B (17−19).
in darkness
under air
2.0 equiv of TEMPO is added
Methods for selective double C−H fluorination of
unactivated methylene groups remain scarce.7b,8d,13 We were
pleased to find that reaction of 20 under slightly modified
condition B with 3.5 equiv of Selectfluor I (BF4) and 0.5 mol
% of Ru(bpy)3Cl2 gave 10 in a 1.4:1 ratio of di- and
monofluorination (d/m) (Scheme 3). Furthermore, subjecting
the purified product to the same fluorination treatment gave
10d with excellent selectivity and in good overall yield. As
exemplified by 21d and 23d, the two-round protocol worked
well for α-substituted alkyl amines, forming the otherwise
difficult-to-access products in good yield and with excellent
difluoroselectivity.14
a
Yields were based on 1H NMR analysis of the crude reaction
mixture at a 0.2 mmol scale. The ratio of 2m/2d was measured by 19F
NMR. Isolated yield. ND: not detected.
b
to find that reaction of p-methoxyphenyl (PMP) sulfonyl
pentylamine 1 with 2.5 equiv of Selectfluor I (BF4) and 1.0
mol % of Ru(bpy)3Cl2 photocatalyst under the irradiation of
household compact fluorescent lamp (CFL, 23 W) in the
mixed solvents of hexafluoroisopropanol (HFIP)12 and water
(4.6/1) at 30 °C for 12 h gave the desired monofluorination
product 2m along with a small amount of difluorination 2d in
As shown in eq 1, the p-methoxyphenylsulfonyl group in
product 4 can be cleanly removed by the treatment of SmI2/
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Letter
a
Scheme 2. Scope of Aliphatic Amines
pyrrolidine/H2O in THF at rt.15 Capping of the resulting free
amine with benzoyl chloride gave product 24 in 49% yield over
two steps.
As shown in Scheme 4A, the treatment of N-fluorosulfona-
mide intermediate 25 under our typical photoredox conditions
Scheme 4. Mechanistic Consideration
in the absence of Selectfluor reagent did not form any δ-
fluorination product 2m. Based on this evidence and the
related work by Knowles, Rovis, and our group, the following
mechanism is proposed for this reaction system (Scheme
4B).9,11 Upon photoexcitation, Ru(II) can be oxidized by
Selectfluor or its derived intermediate via SET to form a
Ru(III) species. The sulfonamide substrate 1 can be directly
oxidized by Ru(III) via SET or proton-coupled electron
transfer process to form N-radical 26 and Ru(II).16 Compound
26 undergoes 1,5-HAT to generate C-centered radical 27,
which reacts with F+ species 28 to give the fluorination product
2 and 29.
a
Isolated yield on a 0.2 mmol scale. Unless otherwise specified,
excellent δ regioselectivity (δ: other regioisomers >20:1) was
b
obtained. m/d: mono vs difluorination product at δ position. 0.5%
c
mmol of Ru(bpy)3Cl2 was used. 8% of δ,δ′-difluorination byproduct
d
was also obtained. The two diastereomers can be separated.
e
Difluorination on the same methyl group.
Scheme 3. δ, δ-Difluorination of α-Substituted Aliphatic
Amine
a
In summary, we have developed a radical-mediated δ-
C(sp3)−H fluorination reaction of N-sulfonyl primary alkyl
amines with Selectfluor reagent under photoredox catalysis.
The reaction can proceed in good yield and with excellent
monofluorination selectivity for amine substrates without α
substituent. For α-substituted substrates, δ, δ-difluorination
products can be obtained in good yield and with high
selectivity using a two-round protocol. Mechanistic studies
suggest that photoredox oxidation of a sulfonamide group
directly generates the key sulfonamide N radical intermediate,
which triggers the subsequent 1,5-HAT and radical trapping
with Selectfluor. This reaction offers a useful method to
prepare mono- and difluorinated alkyl amines from simple
precursors.
a
Isolated yield on a 0.2 mmol scale. The ratio of d/m was measured
by 19F-NMR. Yields were based on the initial nonfluorinated amines.
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Details for mechanistic investigation; copies of the H,
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AUTHOR INFORMATION
Corresponding Author
■
Gong Chen − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-5067-
9889; Email: gongchen@nankai.edu.cn
Authors
Zhiqiang Deng − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Zhenxiang Zhao − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Gang He − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-9064-
3418
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01020
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the Natural Science Foundation of China
(21725204), the “111” project (B06005) of MOE China, and
Nankai-Cangzhou Green Chemistry Institute
(NCC2020FH02) for financial support of this work.
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