An Easy, General and Practical Method for the Construction of Alkyl Sulfonyl Fluorides

Article abstract of DOI:10.1002/adsc.202000515

A visible light-induced reductive addition of 1°, 2° and 3° alkyl iodides to ethenesulfonyl fluoride, employing Hantzsch ester as a hydrogen source at room temperature was developed. This method featured a wide substrate scope and great functional group compatibility, providing facile and robust process to alkyl sulfonyl fluorides including enzyme inhibitors, natural products and drugs derivatives in up to 99percent yield. Further derivatization of resultant aliphatic sulfonyl fluorides was also achieved through sulfur fluoride exchange (SuFEx) reactions to deliver sulfonates and sulfonamides as privileged motifs for medicinal chemistry. (Figure presented.).

Full text of DOI:10.1002/adsc.202000515

Title: An Easy, General and Practical Method for the Construction of
Alkyl Sulfonyl Fluorides
Authors: Xu Zhang, Wanyin Fang, Lekkala Ravindar, Wenjian Tang,
and Huali Qin
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000515
Link to VoR: https://doi.org/10.1002/adsc.202000515

10.1002/adsc.202000515
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
An Easy, General and Practical Method for the Construction of
Alkyl Sulfonyl Fluorides
Xu Zhang,a,† Wan-Yin Fang,a,† Ravindar Lekkala,a Wenjian Tang,b and Hua-Li Qina*
a
State Key Laboratory of Silicate Materials for Architectures; and School of Chemistry, Chemical Engineering and Life
Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, 430070, P. R. China
Fax: + 86 27 87749300
E-mail: qinhuali@whut.edu.cn
School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University,
b
Hefei, 230032, China
†These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
inhibitors based on the sulfonyl fluoride skeleton to
expand the covalent drug libraries. Aliphatic sulfonyl
fluorides, an attractive part of sulfonyl fluoride
family, have been regarded as privileged “warheads”
along with numerous applications in the development
of enzyme inhibitors in recent decades.[14]
Abstract. A visible light-induced reductive addition of
1o, 2o and 3o alkyl iodides to ethenesulfonyl fluoride,
employing Hantzsch ester as a hydrogen source at room
temperature was developed. This method featured a wide
substrate scope and great functional group compatibility,
providing facile and robust process to alkyl sulfonyl
fluorides including enzyme inhibitors, natural products
and drugs derivatives in up to 99% yields. Further
derivatization of resultant aliphatic sulfonyl fluorides
was also achieved through sulfur fluoride exchange
(SuFEx) reactions to deliver sulfonates and sulfonamides
as privileged motifs for medicinal chemistry.
Figure 1. Biological significance representative aliphatic
sulfonyl fluoride enzyme inhibitors.
Keywords: Radical addition; Ethenesulfonyl fluoride
(ESF); Photocatalysis; Alkyl sulfonyl fluorides; SuFEx
chemistry
Methyl sulfonyl fluoride (MSF),[14a] a selective and
irreversible acetylcholinesterase (AChE) inhibitor,
AM3506[14b] and AM-374,[14c] effective inhibitors of
fatty acid amide hydrolase (FAAH) and lipoprotein
lipase inhibitor (L-28)[14d] were all functionalized
with valuable aliphatic sulfonyl fluorides as core
pharmacophores and exerted excellent activity for
treating the corresponding diseases (Figure 1).
Viewing the significance of aliphatic sulfonyl
fluorides as structurally ubiquitous motifs in chemical
biology and medicinal chemistry, the synthesis of this
class of molecules has been of great interest and
challenge for chemists all the time.
Aliphatic sulfonyl fluorides were conventionally
prepared from their sulfonyl chloride precursors via
F-Cl exchange reactions using KF or KHF2 as the
fluorine anion source (Scheme 1a).[1] However, the
synthesis of staring material aliphatic sulfonyl
chlorides from halides, thiols and sultones usually
require multi-steps to achieve, and the sulfonyl
chlorides themselves are also sensitive to moisture
and nucleophiles, which has limited their availability
and storage. Although some specific aliphatic
sulfonyl fluorides are accessible from Michael
addition and other conjugated additions to ESF
Sulfur fluoride exchange (SuFEx) chemistry, another
embodiment of click chemistry, introduced by the
Sharpless group in 2014[1] has gained significant
attention in drug discovery,[2] protein target labeling,[3]
bioconjugation,[4] surface chemistry,[5] and polymer
chemistry.[6] The sulfonyl fluoride moiety as an
irreplaceable hub of SuFEx chemistry family is
considerably desirable for applications in various
fields based on the unique stability-reactivity pattern
of S-F bond.[1,7]
On the other hand, covalent drugs have exerted
ubiquitous and extensive utilization in curing various
illnesses.[8-12] And the applications of sulfonyl
fluorides for the discovery of new covalent inhibitors,
have been extensively investigated in biological and
medicinal chemistry since the revival work led by
Sharpless and coworkers,[1] in which sulfonyl
fluorides exhibited prominent activities as covalent
warheads for binding with amino acid residues.[13]
These merits significantly promote the possibility of
designing and preparing new covalent protein
1
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10.1002/adsc.202000515
Advanced Synthesis & Catalysis
derivatives,[7,15] while simple and mild methods for
generation common aliphatic chain-containing
analogues are very limited (Scheme 1b). Due to the
inherent limitations mentioned above of the existing
methods for construction of aliphatic sulfonyl
fluorides, the developments of convenient, versatile
and starting material-abundant protocols for the
preparation aliphatic sulfonyl fluorides are in urgent
demand and of great significance.
Interestingly, the desired product 3a was obtained in
high yield (90%) when 10 mol% Mn2(CO)10 was
employed as photocatalyst (entry 3). Switching
irradiation source from 30W blue light to 5W blue
light resulted in a cleaner reaction, albeit a slightly
lower yield was obtained (entry 4 compared to entry
3). To our delight, increasing the catalyst loading to
15 mol% significantly promoted the efficiency of the
desired transformation, providing the corresponding
aliphatic sulfonyl fluoride 3a in quantitative yield
(99%, entry 5). However, a lower yield (65%) of 3a
was produced from the reaction with 1.0 equiv of
ESF 2 (entry 6). It is worth noting that the final
product 3a was furnished in 97% yield when the
reaction was performed with 1.2 equiv of ESF 2
(entry 7). Further optimization revealed that
decreasing the amount of Hantzsch Ester (HE) from
1.5 equiv to 1.2 equiv or 1.0 equiv led to obvious
decreasing yields of desired product 3a from 99% to
84%, and 79% (entries 5, 8 and 9) respectively. Not
surprisingly, no product was obtained without the aid
of photocatalyst (entry 10 and 12). When the reaction
was conducted in the dark, the corresponding product
3a was formed at a reduced yield of 78% (entry 11),
indicating that the light was beneficial to activate the
Mn2(CO)10 for accelerating the catalytic cycle process.
As a result, the reaction conditions of Table 1, entry
7, were selected as the standard conditions for further
examination of substrate scope and functional group
tolerance.
Scheme 1. Background and synopsis
Recently, photocatalysis has emerged as
powerful tool in synthetic chemistry.[16] The Liao
group reported visible-light-mediated
a
Table 1. Optimization of the reaction conditions.
a
decarboxylative fluorosulfonylethylation for the
construction of aliphatic sulfonyl fluorides from the
corresponding alkyl carboxylic acids,[17] in which
NHPI-redox-active esters were required for activation
of the carboxylic acids (Scheme 1c). Mn2(CO)10 as a
classical and inexpensive photocatalyst has been
widely applied in synthetic organic chemistry and
pharmaceutical industry since 1980s.[18] Recently,
this photocatalyst has exerted prodigious catalytic
activity in visible-light mediated additions of alkyl
iodides to electron withdrawing olefins[18f] (Scheme
1d). Herein, we report a pre-activation free, simple
and practical protocol for quick assembly of aliphatic
sulfonyl fluorides employing abundant and
inexpensive alkyl halides through a radical-mediated
reductive addition,[19] in which all type readily
accessible feed stocks of 1o, 2o and 3o alkyl iodides
(Scheme 1e) are smoothly transformed into their
corresponding aliphatic sulfonyl fluorides at room
temperature in high yields.
The feasibility of the proposed reaction sequence
was evaluated by employing 4-(2-iodoethyl)-1,1'-
biphenyl 1a as the model substrate for the
photocatalyst screening (Table 1; see Supporting
Information for details). The reaction of 1a with ESF
2 under the irradiation of a 30W blue LED bulb in the
presence of 1.5 equiv Hantzsch Ester (HE) catalyzed
by 10 mol% Ir(ppy)3 furnished the corresponding
product 3a in 8% yield (entry 1), while no product
was generated with Ru(bpy)3Cl2 (entry 2).
Photocatalyst
(X mol%)
Blue
LED
Yield
Entry
HE (Y eq.)
(3a, %)[a]
1
2
Ir(ppy)3 (10)
Ru(bpy)3Cl2 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (15)
Mn2(CO)10(15)
Mn2(CO)10 (15)
Mn2(CO)10 (15)
Mn2(CO)10 (15)
/
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1
30 w
30 w
30 w
5 w
5 w
5 w
5 w
5 w
5 w
5 w
/
8
n.d.
90
85
99
65
97
84
79
0
3
4
5
6[b]
7[c]
8
9
10
11[d]
12[d]
1.5
1.5
1.5
Mn2(CO)10 (15)
/
78
0
/
[a]Reaction conditions: 4-(2-iodoethyl)-1,1'-biphenyl
1a, 0.2 mmol, 61.6 mg), ESF (
(
2
, 0.4 mmol),
2
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10.1002/adsc.202000515
Advanced Synthesis & Catalysis
photocatalyst (X mol%), Hantzsch Ester, regular
undried DMSO (0.1 M) and reacted at argon
atmosphere under the irradiation of blue LED bulb for
24 h. The yield was determined by HPLC using pure
(Table 3, 1t-1v). Eventually, the desired of 3t-3v
were synthesized in excellent yields (84-99%) using
this
developed
method.
Furthermore,
fluorosulfonylethylations of natural products were
also achieved through transformation of their 2o and
3o alkyl iodides 1w-1z providing their corresponding
sulfonyl fluoride derivatives 3w-3z in high yields
(64%-82%). Noteworthily, the transformations of
drug molecules derived 1o alkyl iodine skeleton (1aa-
1ac) were also accomplished to afford their sulfonyl
fluoride derivatives 3aa-3ac in good to excellent
yields (Table 3, 61%-96%).
3a as the external standard (tR,3a = 6.990 min, λmax,
=
3a
252.3 nm, CH3OH/H2O = 80 : 20 (v / v)). [b]1.0 eq. of
ESF. [c]1.2 eq. of ESF. [d]In the dark.
Table 2. Scope of the reductive addition of alkyl iodides to
ethenesulfonyl fluoride (ESF). [a]
Table 3. Synthesis of potentially biological active alkyl
sulfonyl fluorides.[a]
[a]Reaction conditions: Isolated yield. Alkyl iodide (
0.5 mmol), ESF ( , 0.6 mmol), Mn2(CO)10 (15 mol%),
1,
2
Hantzsch Ester (0.75 mmol, 190 mg), DMSO (0.1 M,
5.0 mL) and reacted under argon atmosphere under the
irradiation of 5W blue LED bulb for 24 h.
[a]Reaction conditions: Isolated yield. Corresponding
alkyl iodide (1, 0.5 mmol ), ESF (2, 0.6 mmol),
Mn2(CO)10 (15 mol%), Hantzsch Ester (0.75 mmol,
190 mg), DMSO (0.1 M, 5.0 mL) and reacted under
argon atmosphere under the irradiation of 5W blue
LED bulb for 24 h. [b]ESF (2, 2.0 eq.), Mn2(CO)10 (20
mol%).
With the established reaction conditions in hand,
we next evaluated the reaction scope with a broad
range of 1o, 2o and 3o alkyl iodides (Table 2). Under
the optimal photoredox conditions, 1o alkyl iodides
containing aryl(hetero) groups (1a-1c), alicyclic ring
(1d), acyclic long chains (1e-1g), chloride substituent
(1h), alkyne moiety (1i), benzyl carbamate moiety
(1j), ester group (1k), and also 1, 4-diiodobutane (1l)
were all reacted smoothly and moderate to
quantitative yields (54%-99%) were achieved. And
notably, benzyl iodide (1m) was also converted
smoothly to the desired product in 60% yield. The 2o
alkyl iodides with different alicyclic ring members
(1n and 1o) and aromatic rings (1p and 1q) were
tolerated well and furnished the corresponding
products in excellent yields (93%-99%). Iodoethyl
adamantane (1r) was also successfully converted to
the corresponding product in 79% yield. In cases of
3o alkyl iodide (1s), moderate yield (66%) was
obtained under identical reaction conditions. Notably,
instead of their alkyl iodide counterpart 1, either
alkyl bromides or alkyl chlorides were not compatible
under current condition to proceed the radical
additions with ESF for the generation of their
corresponding alkyl sulfonyl fluoride 3a.
In order to disclose the practicality of this well-
established method, a series of 4.0-mmol scale
reactions were performed under optimal reaction
conditions. Remarkably, as shown in Scheme 2, all
the gram-scale reactions performed efficiently
transforming the corresponding 1o, 2o and 3o alkyl
iodides (1c, 1o, 1p, 1t, 1u, 1x) into their
corresponding aliphatic sulfonyl fluorides (3c, 3o, 3p,
3t, 3u, 3x) in good to excellent yields (60%-94%).
Interestingly, gram-scale synthesis of fatty acid amide
hydrolase (FAAH) inhibitors (3t and 3u) and natural
compound derivative (3x) were also achieved from
the corresponding alkyl iodides in high yields (85%-
91%).
To demonstrate the high efficiency of this
developed visible-light-induced reductive addition,
further examination was conducted for the
construction of established bioactive sulfonyl fluoride
molecules from their corresponding 1o alkyl iodides
Scheme 2. Gram-scale experiments.
3
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10.1002/adsc.202000515
Advanced Synthesis & Catalysis
Subsequently, we
further
evaluated
the
diversification of resultant hexadecane-1-sulfonyl
fluoride 3t through SuFEx reactions (Scheme 3).
Corresponding sulfonamide 4 was furnished in 71%
yield from the compound 3t upon reacting with
morpholine in the presence of triethylamine in
o
acetonitrile at 80 C. SuFEx reaction of 3t with
phenol in the presence of Cs2CO3 in acetonitrile at
room temperature afforded the desired alkyl sulfonate
5 in excellent yield (93%), whereas alkyl sulfonates
6a and 6b were obtained in 75% and 78% yields
respectively by the SuFEx reactions of 3t with
methanol and isopropanol at 37 oC.
Scheme 4. A plausible mechanism of the radical mediated
alkyl sulfonylation
In conclusion, a simple, general and practical
method for the assembly of highly valuable aliphatic
sulfonyl fluorides was achieved using readily
available alkyl iodides through visible light-induced
reductive additions to ESF. This methodology
featured with mild conditions, inexpensive and
abundant starting materials, wide scope and excellent
functional group compatibility with a broad range of
1o, 2o and 3o alkyl iodides. The iodides derived from
natural products and drugs were also smoothly
transformed to their corresponding aliphatic sulfonyl
fluorides. Further derivatization of hexadecane-1-
sulfonyl fluoride AM-374 (3t) was also accomplished
through SuFEx click reactions with diverse
nucleophiles in good to excellent yields (71-93%).
Future studies of the synthetic aliphatic sulfonyl
fluorides in chemical biology and medicinal
chemistry are undergoing in our laboratory.
Scheme 3. Products diversification via SuFEx chemistry.
A plausible mechanism of this reaction was
proposed based on previous literatures[18] and our
investigation as postulated in scheme 4. Initially,
under irradiation of the blue LED, Mn2(CO)10 was
induced to proceed a homolytic cleavage of the Mn-
Mn bond to form [·Mn(CO)5] radical. Subsequent
reaction of [·Mn(CO)5] with alkyl iodide (1) to
generate the nucleophilic alkyl radical A and
Mn(CO)5I. In the flowing step, the radical addition of
Experimental Section
A
to ethenesulfonyl fluoride (2) to furnish
intermediate B, which trapped a hydrogen radical
from the Hantzsch ester to form the diverse alkyl
sulfonyl fluorides (3). Finally the aromatization of
dienyl radical C in presence of Mn(CO)5I to provide
pyridine-HI salt D with concomitant regeneration of
[·Mn(CO)5] to star the next catalytic cycle.
General procedure for synthesis of alkyl sulfonyl
fluorides from alkyl iodides.
Alkyl iodide (1, 0.5 mmol ), ESF (2, 1.2 eq.), Mn2(CO)10
(15 mol%, 30 mg), Hantzsch Ester (0.75 mmol, 190 mg)
and DMSO (0.1 M, 5.0 mL) were added to an oven-dried
reaction tube (30 mL) equipped with a magnetic stirring
bar, and the resulting mixture was stirred under argon
atmosphere under the irradiation of 5W blue LED bulb for
24 h. Once the reaction reached its completion, the mixture
was diluted with water, extracted with ethyl acetate (3×20
mL) and the combined organic layers were further washed
with brine, and dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure and the
residue was further purified by column chromatography on
silica gel via gradient elution with petroleum ether/ethyl
acetate (20:1 to 1:1, v/v) as eluent to afford pure alkyl
sulfonyl fluoride 3.
Acknowledgements
4
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10.1002/adsc.202000515
Advanced Synthesis & Catalysis
We are grateful to the National Natural Science Foundation
Angew. Chem. Int. Ed. 2014, 53, 9466-9470; b) J.
Yatvin, K. Brooks, J. Locklin, Angew. Chem. 2015, 127,
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Brooks, J. Locklin, Chem. Eur. J. 2016, 22, 16348-
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Klivansky, J. Lu, Y. Liu, J. Dong, P. Wu, K. B.
Sharpless, Nat. Chem. 2017, 9, 1083-1088; f) H. Wang,
F. Zhou, G. Ren, Q. Zheng, H. Chen, B. Gao, L.
Klivansky, Y. Liu, B. Wu, Q. Xu, J. Lu, K. B. Sharpless,
P. Wu, Angew. Chem. 2017, 129, 11355-11360; Angew.
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Flynn, J. Niu, Angew. Chem. 2018, 130, 16426-16431;
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Xu, P. Wu, J. Dong, Syntheses and Perspectives,
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of China (Grant No. 21772150), the Wuhan Applied Fundamental
Research Program of Wuhan Science and Technology Bureau
(Grant No. 2017060201010216) and the Fundamental Research
Funds for the Central Universities (Grant No. 2020-YB-013) for
the financial support.
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10.1002/adsc.202000515
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10.1002/adsc.202000515
Advanced Synthesis & Catalysis
COMMUNICATION
An Easy, General and Practical Method for the
Construction of Alkyl Sulfonyl Fluorides
Adv. Synth. Catal. Year, Volume, Page – Page
Xu Zhang,a,† Wan-Yin Fang,a,† Ravindar Lekkala,a
Wenjian Tang,b and Hua-Li Qina*
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