A Simple Protocol for the Stereoselective Construction of Enaminyl Sulfonyl Fluorides

Article abstract of DOI:10.1021/acs.orglett.0c01360

A clickable connective hub 1-bromo-2-triazolethane-1-sulfonyl fluoride BTESF (1) was developed and successfully applied for the fluorosulfonylvinylation of a host of primary and secondary cyclic or acyclic amines including amino acids and pharmaceuticals. Further antimicrobial experiments revealed that vinyl sulfonyl fluoride functionalized norfloxacin (3ak), ciprofloxacin (3am), and lomefloxacin (3an) exhibited 4-fold improved antimicrobial activity against Gram-positive bacteria compared to their parent drugs.

Full text of DOI:10.1021/acs.orglett.0c01360

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Letter
A Simple Protocol for the Stereoselective Construction of Enaminyl
Sulfonyl Fluorides
Jing Leng,§ Wenjian Tang,§ Wan-Yin Fang, Chuang Zhao, and Hua-Li Qin*
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ABSTRACT: A clickable connective hub 1-bromo-2-triazol-
ethane-1-sulfonyl fluoride BTESF (1) was developed and
successfully applied for the fluorosulfonylvinylation of a host of
primary and secondary cyclic or acyclic amines including amino
acids and pharmaceuticals. Further antimicrobial experiments
revealed that vinyl sulfonyl fluoride functionalized norfloxacin
(3ak), ciprofloxacin (3am), and lomefloxacin (3an) exhibited 4-
fold improved antimicrobial activity against Gram-positive bacteria
compared to their parent drugs.
arbon−nitrogen bonds are ubiquitous in biological
electrophilic handles and covalent pharmacophores (vinyl
sulfone and sulfonyl fluoride group), which were successfully
applied as novel scaffolds in the discovery of covalent
inhibitors and fluorogenic probes (Scheme 1). Currently, the
straightforward strategies to access aryl ethenesulfonyl
fluorides are achieved through Pd-catalyzed Heck-type
coupling reactions8,10c,11 and C−H bond activation oriented
fluorosulfonylvinylation (Scheme 2, a).12 2-Aminoethenesul-
fonyl fluorides (N-ESF), another category of ESF derivatives,
exhibiting somewhat structural similarity with 2-arylethene-
sulfonyl fluorides, bearing both a sulfonyl fluoride group and a
enamine functionality, bode extremely well for their future
C
systems, natural products, and materials.1 Among all
types of C−N-containing molecules, enamines have been
particularly recognized as important moieties in natural
products and pharmaceuticals2,3 (Scheme 1) and as valuable
Scheme 1. Representative Compounds Containing
Enamine, Vinyl Sulfone, or Sulfonyl Fluoride Motifs
Scheme 2. Synthesis of Ethenesulfonyl Fluoride Derivatives
synthetic intermediates for chemical transformations.4 One of
the most atom-economic strategies for the construction of
enamines is hydroamination of alkynes.5 However, the further
development of these direct amination reactions has been
severely hampered due to the control of reaction selectivity.5b
In view of the high value and wide application of enamines, the
development of efficient methods for the construction of
enamines is of great importance and highly desirable.
On the other hand, with the prevalence of sulfur fluoride
exchange (SuFEx) click chemistry,6 ethenesulfonyl fluoride
(ESF)7 and its derivatives8 have attracted wide attention due
to their versatile application in medicinal chemistry,9 polymer
syntheses,10 and organic chemistry.8 As a family of ESF
derivatives, 2-arylethenesulfonyl fluorides bear two important
Received: April 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01360
© XXXX American Chemical Society
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a−d
application in the discovery of targeted covalent drugs and the
development of SuFEx chemistry. However, the convenient
synthesis of N-ESF has rarely been accomplished. A cursory
index of the literature indicated that only one report13
involving the synthesis of N-ESF through a manganese dioxide
oxidation of the Michael addition product of ESF with amines
(Scheme 2, b). However, the reported conditions provided
limited examples and give 2-aliphatic amino ethenesulfonyl
fluoride in a low yield (33%) with the promotion of a
transition-metal oxide, which largely restrained the further
application of N-ESF.
Scheme 4. Substrates Scope of N-ESF
Learning from the previous design of SuFEx reagents14 and
the difficult dehydrobromination of the Michael addition
products of 1-Br-ESF with amines,14a we considered that
synthesizing a new sulfonyl fluoride reagent bearing a C−C
single bond and two leaving groups to react with nitrogen
nucleophiles by substitution or elimination process will act as
an effective method for achieving N-ESF products (Scheme 2,
c).15
However, due to the properties of amine as both a
nucleophile and a base, as well as the different reactivity of
the two leaving groups, the sequence of substitution and
elimination reaction on the new reagent and the preference for
substitution on the primary carbon or secondary carbon were
difficult to determine, which could result in the formation of a
series of unexpected byproducts I−IX (Scheme 3). In theory,
Scheme 3. Reactivity of the New SuFEx Reagent
a
Reaction conditions: 1 (0.5 mmol, 167 mg), 2 (2.0 equiv, 1.0
b
mmol), 1, 4-dioxane (5 mL), rt, 3−12 h. Corresponding 2·HCl or 2·
HBr was used, Et3N (1 mmol, 101 mg). 5.0 mmol scale. More Et3N
(1 mmol, 101 mg) was added.
c
d
triazole and bromide both can act as leaving groups,16 and the
triazole group was less reactive than bromide when it was
connected with saturated carbon.17 Therefore, we anticipated
that with the promotion of base (amines) intermediate I could
be generated initially followed by sequential Michael addition
and elimination to provide the desired N-ESF.
further diversification. Alkyl- or aryl-protected piperazines 2o,
2q, and 2r reacted smoothly with 1 to afford the corresponding
products 3o, 3q, and 3r in satisfactory yields. The analogue of
chlorcyclizine 2s was also shown to have good compatibility.
Bicycle substrates 2u−2w generated their desired products
3u−3w in good to excellent yields. Benzyl- and alkyl-
substituted amines 2y−2ac were smoothly converted to the
target N-ESF products in moderate to good yields.
Remarkably, primary amine substrate 2ad was also compatible
under these conditions, providing vinylated 3ad in 89% yield.
Considering that amino acids are one of the most important
moieties in the life sciences and pharmaceutical industries, the
generality of the newly developed protocol was also evaluated
in the derivatization of amino acids. Ethyl L-phenylalaninate
2ae and methyl L-prolinate 2af yielded their corresponding N-
ESF 3ae and 3af in 75% and 90% yields, respectively.
Meaningfully, this protocol was also successfully applied to
late-stage functionalization of drugs 2ag−2aj. The derivatives
of desloratadine 3ag, troxipide 3ah, betahistine 3ai, and
sertraline 3aj were smoothly achieved in good yields (54−
97%). Notably, anilines, sulfonamides, and amides were not
compatible under these conditions for generating their
After screening a variety of reaction conditions (for more
details, see the SI), we found the best conditions for
construction of N-ESF, and the functional group compatibility
was subsequently investigated with a section of amines 2
(Scheme 4). Cyclic amines 2a−2d were well transformed into
their corresponding N-ESF 3a−3d with high efficiency.
Hydroxy 2e, bromide 2f, ester 2g, benzyl 2i, or piperidine 2j
groups on the para position of piperidine were all tolerated in
this process. Acetal-protected piperidine 2h was also trans-
formed into fluorosulfonylvinylated product 3h with 89% yield.
Strong electron-withdrawing groups on the ring 2k generated
corresponding product 3k in relatively lower yield, which could
be attributed to the reduced nucleophilicity of amine.
Thiomorpholine 2l and morpholine 2m with an extra
heteroatom on the piperidine ring were also compatible,
furnishing the corresponding products 3l and 3m in 71% and
86% yields, respectively. It was worth noting that only one of
the amino groups on piperazines 2n and 2p was
fluorosulfonylvinylated, leaving the other amino group for
B
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corresponding N-ESF products, which could be attributed to
the low nucleophilicity of their nitrogen atoms.
Next, post modifications of N-ESF were conducted as shown
in Scheme 5. α,β-Unsaturated compounds and sulfonyl
yl)ethene-1-sulfonyl fluoride I (for more details, see the SI)
was used, the corresponding 3b and triazole 6 were obtained in
96% and 95% yields, respectively (Scheme 6, c), which
indicated vinyl triazole I was a key intermediate during the
formation of N-ESF.
On the basis of the results of mechanism-investigated
experiments, a plausible mechanism of the fluorosulfonylviny-
lation of amines was proposed in Scheme 7. Initially, after β-
a
Scheme 5. SuFEx Reactions of N-ESF with Phenols
Scheme 7. Plausible Mechanism for the Generation of N-
ESF
elimination with the promotion of base, BTESF 1 was
converted into (E)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethene-
1-sulfonyl fluoride I which could be stabilized by the triazole
group.19 Then, Michael addition of amine followed by the
elimination of triazole 6 provided the final thermodynamically
more stable E-configuration of vinyl product 3.
SuFEx click chemistry is a newly developed tool for drug
discovery.9 With this amine fluorosulfonylvinylation procedure
in hand, a panel of known antibacterial drugs were converted
to their fluorosulfonylvinylated products, and their potential
activity in antibacterial fields was further explored. Fluoroqui-
nolones are a large and powerful group of synthetic
antimicrobial compounds whose main action is the inhibition
of bacterial DNA-gyrase within the bacterial cells. These
compounds have been widely used to treat various diseases due
to their high activity against Gram-negative and Gram-positive
bacteria.20 In Scheme 8, seven fluoroquinolone drugs were
a
Reaction conditions: 3 (0.5 mmol), 4 (2.0 equiv, 1.0 mmol), KOH
(2.0 equiv, 1 mmol), CH3CN (5 mL), 50 °C under oil bath, 5−15 h.
fluorides are two classes of well-known warheads for targeted
covalent inhibitors, which could bind to amino acid residues of
proteins undergoing a bond-forming event via Michael
addition or SuFEx reaction.18 Theoretically, N-ESF along
with previously reported 2-arylethenesulfonyl fluorides could
react with oxygen- and nitrogen-containing nucleophiles
effectively.8,12b,c Interestingly, the newly generated N-ESF
were found to be much less reactive as electrophiles compared
with their vinyl sulfonyl fluoride counterparts.13 The SuFEx
reactions of N-ESF with phenols occurred under the
promotion of strong base at elevated temperature, while the
SuFEx reactions with amines were not achieved. After
screening a series of bases and temperatures, we found a
suitable condition for converting N-ESF to their corresponding
sulfonates 5a−5d in good to excellent yields with the
assistance of 2 equiv of KOH at 50 °C.
a
Scheme 8. Modification of Quinolones
As illustrated in Scheme 6, in order to gain more insight into
the mechanism of the formation of N-ESF, some control
Scheme 6. Control Experiments
a
Reaction conditions: 1 (1.2 equiv, 0.6 mmol, 200.4 mg), 2 (0.5
experiments were carried out accordingly. Quantitative yields
of 3b and 4-phenyl-1H-1,2,3-triazole 6 were generated under
the standard reaction conditions (Scheme 6, a). When a similar
starting material 7 without the substitution of bromine atom
was used (Scheme 6, b), only the SuFEx reaction occurred
with 98% yield of sulfamide 8 generated, which revealed that
the triazole group16 was not reactive enough as a leaving group
when it was connected directly with a saturated carbon.17
Interestingly, when pure (E)-2-(4-phenyl-1H-1,2,3-triazol-1-
mmol), Et3N (0.5 mmol, 50.5 mg), DCE (5 mL), rt, 12−18 h.
successfully fluorosulfonylvinylated in the presence of 1.2 equiv
of BTESF 1 and 1.0 equiv of triethylamine, and most of the
substrates were transformed to their desired products 3 in
moderate to good yields.
As shown in Table 1, the fluorosulfonylvinylation did not
alter the antimicrobial spectrum of quinolones. Seven
fluoroquinolone drugs and their vinyl sulfonyl fluoride derived
C
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Table 1. MIC (μM) of Quinolones against Bacteria and
Fungi
ASSOCIATED CONTENT
* Supporting Information
■
a b
,
sı
Gram-positive
Gram-negative
fungus
CA
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01360.
SA
MRSA
EC
PA
General methods, synthetic procedures, and character-
ization (PDF)
norfloxacin
3ak
enoxacin
3al
ciprofloxacin
3am
lomefloxacin
3an
gatifloxacin
3ao
balofloxacin
3ap
moxifloxacin
3aq
3.12
1.56
3.12
3.12
1.56
0.39
3.12
0.78
0.39
0.19
0.39
0.39
0.39
0.19
3.12
0.78
3.12
6.25
0.78
0.39
3.12
0.78
0.39
0.19
0.39
0.39
0.19
0.19
0.78
0.39
1.56
3.12
0.19
0.19
0.39
0.78
0.09
0.19
0.19
3.12
0.09
0.78
3.12
6.25
6.25
50.00
0.78
6.25
6.25
50.00
3.12
12.50
25.00
100.00
6.25
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
Accession Codes
CCDC 1941924 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
50.00
>200
b
Hua-Li Qin − State Key Laboratory of Silicate Materials for
Architectures; and School of Chemistry, Chemical Engineering
and Life Sciences, Wuhan University of Technology, Wuhan
430070, P.R. China; orcid.org/0000-0002-6609-0083;
Email: qinhuali@whut.edu.cn
a
MICs representing mean values of at least three replicates. SA:
Staphylococcus aureus, MRSA: methicillin resistant Staphylococcus
aureus, PA: Pseudomonas aeruginosa, EC: Escherichia coli, CA: Candida
albicans.
Authors
Jing Leng − State Key Laboratory of Silicate Materials for
Architectures; and School of Chemistry, Chemical Engineering
and Life Sciences, Wuhan University of Technology, Wuhan
430070, P.R. China
Wenjian Tang − School of Pharmacy, Anhui Medical University,
Hefei 230032, China; orcid.org/0000-0002-2798-6557
Wan-Yin Fang − State Key Laboratory of Silicate Materials for
Architectures; and School of Chemistry, Chemical Engineering
and Life Sciences, Wuhan University of Technology, Wuhan
430070, P.R. China
Chuang Zhao − State Key Laboratory of Silicate Materials for
Architectures; and School of Chemistry, Chemical Engineering
and Life Sciences, Wuhan University of Technology, Wuhan
430070, P.R. China
compounds 3ak−3aq showed a moderate to strong level of
antibacterial activity against Gram-positive and Gram-negative
bacteria but no activity against fungi (MIC values >200 μM).
Among them, compounds 3ak and 3am−3ao exhibited
improved antimicrobial potential against Gram-positive bac-
teria. In particular, compounds 3ak and 3an showed obviously
enhanced antimicrobial activity than norfloxacin and lome-
floxacin against clinical methicillin-resistant Staphylococcus
aureus (MRSA) (MIC = 0.78 μM). The activity of 3am
(MIC = 0.39 μM) and 3an (MIC = 0.78 μM) against S. aureus
(SA) also exhibited 4-fold improvement compared with
ciprofloxacin and lomefloxacin. Quinolone resistance, espe-
cially the second-generation quinolones, has multiple mecha-
nisms and significant clinical impact.21 The vinyl sulfonyl
fluoride functionalized norfloxacin, ciprofloxacin, and lome-
floxacin could improve their anti-Gram-positive bacteria
activity, which may be a novel approach to result in effective
antibacterial therapies to sustainably combat antibacterial
resistance.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01360
Author Contributions
§J.L. and W.T. contributed equally to this work.
Notes
In conclusion, we have developed a new SuFEx reagent 1-
bromo-2-triazolethane-1-sulfonyl fluoride 1 and demonstrated
its practical application in construction of novel enaminyl
sulfonyl fluorides through simple reactions with amines. The
general method for effective installation of vinyl sulfonyl
fluoride onto amines was successfully utilized for late-stage
functionalization of drugs. Antimicrobial experiments of seven
vinyl sulfonyl fluoride functionalized fluoroquinolone drugs
indicated that their antibacterial activities against MRSA and
SA were equal or enhanced compared with their parent drugs.
Notably, the vinyl sulfonyl fluoride functionalized norfloxacin
3ak, ciprofloxacin 3am, and lomefloxacin 3an exhibited 4-fold
improved antimicrobial activity against Gram-positive bacteria.
Further explorations of this method for synthesizing N-ESF
compound libraries for medicinal application are ongoing in
our laboratory.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), the Wuhan applied fundamental
research plan of Wuhan Science and Technology Bureau
(Grant No. 2017060201010216), the 111 Project (Grant No.
B18038), and Wuhan University of Technology for financial
support.
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