Synthesis of a Class of Fused δ-Sultone Heterocycles via DBU-Catalyzed Direct Annulative SuFEx Click of Ethenesulfonyl Fluorides and Pyrazolones or 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1002/adsc.201700887

(E)-2-(hetero)arylethenesulfonyl fluorides and (E,E)-1,3-dienylsulfonyl fluorides are bis-electrophiles and rare members of the sulfonyl fluoride family with limited information being known of their reactivity and synthetic utility. The direct annulation reaction of these 2-substituted ethenesulfonyl fluorides with medicinally important enolizable pyrazolones and 1,3-dicarbonyl compounds utilizing catalytic DBU in DCM under mild conditions leads to over 50 structurally diverse δ-sultone fused heterocycles with a pyrazolone ring or a cyclic enone, respectively, in good to excellent yield. The double bond at the 1-position adjacent to the sulfonyl fluoride group in 1,3-dienylsulfonyl fluoride is the chemoselective site of reactivity but is less reactive than the double bond of arylethenesulfonyl fluoride. High turnover and robustness of construction for these fused heterocycles, including the novel fused pyrazolone δ-sultone heterocycle series, may make compounds like these attractive to drug discovery, development and material science. (Figure presented.).

Full text of DOI:10.1002/adsc.201700887

Title: Synthesis of a Class of Fused δ-Sultone Heterocycles via DBU-
Catalyzed Direct Annulative SuFEx Click of Ethenesulfonyl
Fluorides and Pyrazolones or 1,3-Dicarbonyl Compounds
Authors: Xing Chen, Gao-Feng Zha, Grant Bare, Jing Leng, Shi-Meng
Wang, and Huali Qin
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700887
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of a Class of Fused δ-Sultone Heterocycles via DBU-
Catalyzed Direct Annulative SuFEx Click of Ethenesulfonyl
Fluorides and Pyrazolones or 1,3-Dicarbonyl Compounds
Xing Chen,a,† Gao-Feng Zha,a,† Grant A. L. Bare,b,† Jing Leng,a Shi-Meng Wang,a and
Hua-Li Qin*,a
a
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road,
Wuhan, Hubei Province, 430070, P. R. China
Fax: +86 27 87749300; e-mail: qinhuali@whut.edu.cn
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
b
†
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######.((Please
delete if not appropriate))
Abstract. (E)-2-(hetero)arylethenesulfonyl fluorides and
(E,E)-1,3-dienylsulfonyl fluorides are bis-electrophiles and
rare members of the sulfonyl fluoride family with limited
information being known of their reactivity and synthetic
utility. The direct annulation reaction of these 2-substituted
ethenesulfonyl fluorides with medicinally important
enolizable pyrazolones and 1,3-dicarbonyl compounds
utilizing catalytic DBU in DCM under mild conditions
leads to over 50 structurally diverse δ-sultone fused
heterocycles with a pyrazolone ring or a cyclic enone,
respectively, in good to excellent yield. The double bond at
the 1-position adjacent to the sulfonyl fluoride group in 1,3-
dienylsulfonyl fluoride is the chemoselective site of
reactivity but is less reactive than the double bond of
arylethenesulfonyl fluoride. High turnover and robustness
of construction for these fused heterocycles, including the
novel fused pyrazolone δ-sultone heterocycle series, may
make compounds like these attractive to drug discovery,
development and material science.
Keywords: DBU; Ethenesulfonyl fluorides; Fused δ-
sultone; Pyrazolones
Sulfonyl fluorides are an essential sulfur-containing
functional group that serve utilities in a broad range
of chemical disciplines. For example, in industrial
chemistry, DOW AgroSciences-produced Vikane®
(sulfuryl fluoride) is used as a fumigant gas,[1] in
chemical biology, sulfonyl fluorides comprise
warheads in irreversible probes and inhibitors of
proteins,[2] and in organic chemistry they are
identified as connectors for SuFEx-based click
chemistry.[3] Although Truce and Hoerger reported
over one half-century ago the first synthesis of 2-
phenylethenesulfonyl fluoride from the action of
Figure 1. Reactions of substituted ethenesulfonyl fluorides.
boiling aqueous potassium fluoride on the
corresponding sulfonyl chloride precursor, this class
1
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
of sulfonyl fluoride remains the least studied,
although several methods have been developed for
the accessibility of nearly 100 structurally diverse
(E)-2-(hetero)arylethenesulfonyl fluorides. [4-9]
of intriguing substrates attracted us to functionalized
pyrazoles, which represent the core motif of
numerous biologically active molecules and have
been widely used in pharmaceuticals, agrochemicals,
and in other functional materials.[14] Many pyrazole
derivatives have been successfully developed as
drugs or drug candidates for the treatment of a variety
of diseases (Figure 2).[15] Among various types of py-
The attractiveness of arylethenesulfonyl fluoride as
a useful synthetic intermediate in organic chemistry
lies in their unusual simultaneous incorporation of
two chemoselective electrophilic sites: a Michael
acceptor olefinic site and a latent S−F bond that may
be activated toward substitution via DBU catalysis
and the presence of aryl silyl ethers (Figure 1).[7]
Thus, the vinyl sulfonyl fluoride group is preloaded
for initial Michael addition and subsequent
intramolecular cyclizations at the sulfur center. The
synthesis of fused 1,2,4-thiadiazine 1,1-dioxides from
the reaction of ESF and heterocyclic amines in good
yield by Krutag and Hyatt in 1979 provides the oldest
example.[10] ESF holds one of the highest positions on
the Michael acceptor reactivity scale although β-
substitution modulates its potential to undergo attack
by a significant magnitude.[7,11] Ungureanu et al. in
2015 showed one of the best to date examples of
arylethenesulfonyl fluoride reactivity in the synthesis
of δ-sultones through N-heterocyclic carbene (NHC)
catalysis of trimethylsilylated 1,3-dicarbonyl
compounds and arylethenesulfonyl fluorides.[5a] The
trimethylsilyl group serves necessary dual roles in
this case by preloading the enol while becoming
available to scavenge the fluoride leaving group. The
sultones, in turn are oxidized sulfur analogues of
lactones first reported by Erdmann in 1888, and
considerable advances have been made in their
synthesis and application.[12] Only a few other
reactions of arylethenesulfonyl fluorides are known
such as the participation of electon-deficient 2-p-
nitrophenylethenesulfonyl fluoride as a dienophile in
a Diels−Alder[4] reaction with cyclopentadiene and in
a Friedal−Crafts[7] like reaction with p-xylene and
stoichiometric aluminum trichloride.
Figure 2. Representative drugs containing pyrazole
moities.
razoles, enolizable pyrazolones have been
particularly recognized as outstanding scaffolds for
the discovery and development of new drugs,
therefore, the development of efficient methods for
the synthesis of novel pyrazolone heterocycles is of
great significance.[16] Herein, we report a DBU-
catalyzed
direct
annulation
of
(E)-2-
(hetero)arylethenesulfonyl fluorides and (E,E)-1,3-
dienylsulfonyl fluorides with pyrazolones (or 1,3-
dicarbonyl compounds) for the synthesis of a class of
novel δ-sultone fused pyrazolones (or δ-sultones
fused cyclic enones). These reactions proceed under
mild conditions of DBU catalysis and NaHCO3 in
DCM at room temperature with good to excellent
yield without the need for preformed silylated enols.
It has been reported that the δ-sultones fused cyclic
enones are accessible through a N-heterocyclic
carbene
(NHC)
catalyzed
reaction
of
trimethylsilylated 1,3-dicarbonyl compounds and
arylethenesulfonyl fluorides[5a] or via a stoichiometric
amount of triethylamine promoted procedure.[11] DBU,
an abundant and inexpensive unique base has been
widely used as nucleophilic catalyst for activation of
a variety of nucleophiles.[17] It will be of great
advantage if the δ-sultones fused heterocycles can be
directly furnished through the reaction of
arylethenesulfonyl fluorides and carbonyl compounds
with catalytic amount of DBU. Accordingly, the
reaction of (E)-2-phenylethenesulfonyl fluoride 1a
and enolizable pyrazolone 2a in the presence of
nitrogenous catalyst and stoichiometric NaHCO3 to
form fused δ-sultone heterocycle 3a was initially
investigated (Table 1). Extensive screening of
catalyst (entries 1−4), catalytic loading (entries 2,
5−8), stoichiometric equivalents (entries 9−11), and
solvent (entries 12−15) revealed that equimolar
amounts of both pyrazolone and NaHCO3 and 5
mol% DBU in DCM at room temperature for 24 h
were required to afford the optimized isolated yield
of 94% of 3a (entry 15). Next, we turned our
attention to the evaluation of functional group tolera-
We were inspired together by elucidating the
reactivity of the ethenesulfonyl fluoride family and
by a long withstanding problem in the field of
medicinal chemistry. Large data cluster analysis
going back four decades in drug discovery and
manufacturing points to an invariable bias toward
certain reaction types, particularly amide bond
formation, Suzuki−Miyaura coupling, and SNAr N-
arylation.[13] Heterocyclic synthesis on the other hand
is comparatively underutilized[13c-d] or has observed a
dramatic decrease in use in this context.[13b]
Consequently, developing efficient methods that
include a high degree of functional group tolerance,
robustness, and easy availability of diverse starting
materials for the synthesis of difficult to access or
otherwise novel heterocyclic scaffolds is an attractive
goal to overcome constraints on chemical space. We
hypothesized that Michael reaction between an
enolizable
substrate
and
a
2-substituted
ethenesulfonyl fluoride using weak base while
leaving the S−F bond intact followed by DBU
activation of fluoride and cyclization could be
achieved synthetically in one reaction flask. A survey
2
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
Table 1. Screening of reaction conditions of annulative δ-
approximating an orthogonal conformation (Table 2).
In comparison ESF, whose reactivity as a Michael
acceptor has been measured recently as 4.5 orders of
magnitude larger than 1a,[11] when used in the
reaction with pyrazolone 2a forms approximate
amounts the cyclized δ-sultone product 8a (46%) and
the bis-Michael adduct 8b (41%) (Scheme 1). This
observation provides important mechanistic insight
that presumably in this case 1) Michael addition
proceeds before substitution at sulfur and 2) that the
rate of the second intermolecular Michael addition of
ESF is competitive with the rate of intramolecular
cyclization at the S−F bond.
sultonation.a
NaHCO3
(equiv)
Yield b
Entry
Solvent
Base (mol%)
Ratio (1a: 2a)
(3a, %)
88 (82)
1
2
DCM
DCM
Et3N (20)
DBU (20)
1 : 2
1 : 2
2
2
2
97
96
DCM
DCM
DABCO (20)
Na2CO3 (20)
DBU (1)
DBU (5)
DBU (10)
DBU (50)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
3
Table 2. Annulative δ-sultonation of pyrazolones with
(hetero)arylethenesulfonyl fluorides.a
2
2
2
2
2
1
/
9
11
4
DCM
5
DCM
97
6
DCM
94
7
DCM
43
8
DCM
98
9
DCM
17
10
11
12
13
14
15c
a)
DCM
1
1
1
1
1
95
CH3CN
Acetone
DMSO
DCM
65
45
75
97 (94)
Reaction conditions: (E)-2-phenylethene-1-sulfonyl
fluoride (1a, 0.1 mmol ), 3-methyl-1-phenyl-2-pyrazolin-5-
one（2a）, base, NaHCO3, solvent (1 mL) were added in
a reaction tube (20 mL) and reacted at the corresponding
b)
condition for 24 h at room temperature. The yield was
determined by HPLC using 3a as the external standard (tR
= 4.4 min, λmax = 247.6 nm, methanol/water = 80 : 20 (v /
v)). Isolated yield is reported in parenthesis. c) 0.4 M.
nce and scope for the reaction of substituted
(hetero)arylethenesulfonyl
fluorides
1
and
pyrazolones under the optimized reaction
2
conditions (Table 2). Yields were found to typically
be excellent (>85%) for a wide range of electron-
withdrawing and electron-donating groups in the
para- or meta- positions of both the ethenesulfonyl
fluorides (3a−p; 3t−u) or the pyrazolones (3af−ak).
Yields suffered somewhat for ortho- substitution on
either substrate, possibly attributed to sterics (3q−s;
3ae). Heteroarylethenesulfonyl fluorides with
nitrogen, oxygen, and sulfur in the ring were well
tolerated (3x−ad). Notably, an x-ray crystallographic
structure of fused heterocycle 3a showed the phenyl
of the pyrazolone to be close to coplanar with the
pyrazolone/δ-sultone ring system while the phenyl
stemming from the ethenesulfonyl fluoride to be
a)
Reaction conditions: 2-(hetero)arylethenesulfonyl
fluoride (1, 1.0 mmol), pyrazolone (2, 1.0 mmol), DBU (5
mol%), NaHCO3 (1.0 mmol, 1.0 equiv), DCM (2.0 mL),
reaction for 24 h at room temperature. b) 60 mol% DBU
was used. c) 6.0 equiv 2a and 2.0 equiv NaHCO3 were used.
d) 20 mol% DBU was used.
Scheme 1. Reaction of ESF and pyrazolone 2a.
3
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
Since 1,3-dienylsulfonyl fluorides 4 possess two
sultone heterocycles (7d, 7e) (Table 4). Furthermore,
1,3-dienylethenesulfonyl fluorides also form fused
cyclic enone δ-sultone heterocycles (7f, 7g)
chemoselectively from a cyclic 1,3-dicarbonyl.
conjugated double bonds with the sulfonyl fluoride
group, they are a scaffold with the propensity to
undergo chemoselective reaction (Table 3). Indeed, in
the presence of 20 mol% DBU catalyst good to
excellent yields (57-99%) for 13 substrates with
pyrazolone 2a were obtained for the δ-sultone
products 5 and not of the hypothetical 8-membered
sultone or 6-membered ether ring products stemming
Table 4. δ-Sultonation of ketones with p-
nitrophenylethenesulfonyl fluoride 1i or diethenesulfonyl
fluorides.a
Table 3. Annulative δ-sultonation of pyrazolones with
dienylsulfonyl fluorides.a
a)
Reaction conditions: 2-(hetero)arylethenesulfonyl
fluoride or diethenesulfonyl fluoride (1 or 4, 1.0 mmol),
ketone (6, 1.0 mmol), DBU (20 mol%), NaHCO3 (1.0
mmol, 1.0 equiv), DCM (2.0 mL), reaction for 24 h at
b)
c)
room temperature. DMSO (2.0 mL) as the solvent. 40
mol% DBU was used and reacted for 96 h.
On the other hand, p-nitrophenylethenesulfonyl
fluoride
1i
and
diethyl
malonate
(or
dibenzoylmethane) under catalytic DBU and
NaHCO3 in DCM afford the Michael adduct 9a
without cyclization which can then be driven to
eliminate sulfonyl fluoride to form enedione 9b (or
10) when DBU approaches one equivalent (Scheme
3). A deuterium labeling experiment is consistent
with 9a undergoing a benzylic hydride shift with
elimination of SO2 and HF. Decomposition and loss
of SO2 was also observed for δ-sultone 7d in the
presence of stoichiometric DBU (Scheme 4).
a)
Reaction conditions: diethenesulfonyl fluoride (4, 1.0
mmol), pyrazolone (2a, 1.0 mmol), DBU (20 mol%),
NaHCO3 (1.0 mmol, 1.0 equiv), DCM (2.0 mL), reaction
for 24 h at room temperature. b) Reaction for 48 h. 30
c)
mol% DBU was used.
from addition at the distal double bond and then
cyclization. This is the first reported reaction as far as
we know of the novel 1,3-dienylsulfonyl fluorides,
which supports their synthetic usefulness.
A
competition experiment between equimolar amounts
of 2-phenylethenesulfonyl fluoride 1a, and 4-phenyl-
1,3-dienylsulfonyl fluoride 4a, for pyrazolone 2a
demonstrated the reactivity to be greater for the
single double bonded sulfonyl fluoride 1a (Scheme 2).
Scheme 2. Competition between ethenesulfonyl fluorides
for annulative δ-sultonation.
The cyclic symmetrical 1,3-dicarbonyl compounds
(6a−c) were found to form fused cyclic enone δ-
sultone heterocycles (7a−c) when reacted with p-
nitrophenylethenesulfonyl fluoride 1i, whereas less
sterically hindered acyclic substrates (6d, 6e) form δ-
Scheme 3. Reaction of arylethenesulfonyl fluoride 1i and
acyclic 1,3-dicarbonyls and
experiment.
a
deuterium labeling
4
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
was stirred at room temperature for 24-96 h with
monitoring by TLC. The crude products were purified by
column chromatography on silica gel to give 7.
CCDC-1538641, 1538640, and 1546566 contains the
supplementary crystallographic data for compounds 3a, 10
and 11, respectively, in this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
Scheme 4. Decomposition experiment of fused cyclic
enone δ-sultone 7d.
Acknowledgements
In conclusion, we have demonstrated here that the
rare 2-(hetero)arylethenesulfonyl fluorides and 1,3-
dienylsulfonyl fluorides, whose wider synthesis and
reactivity has remained elusive until very recently,
are versatile substrates for the synthesis of many
fused δ-sultone-based heterocycles with pyrazolones
or directly from 1,3-dicarbonyl compounds. The
reactions described herein are characterized by
heterocyclic novelty, high functional group tolerance,
operation under mild conditions, and accessibility of
starting materials lending them to high turnover and
product structural diversity. These features may be
advantageous to the search and development of new
molecular-based medicines, which has observed
limitations on chemical space and reaction usage over
time.
This work was supported by Wuhan University of Technology and
the Fundamental Research Funds for the Central Universities
(2016-YB-012 to H.L.Q). We are grateful to professor K. B.
Sharpless (The Scripps Research Institute) for helpful discussion.
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5
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10.1002/adsc.201700887
Advanced Synthesis & Catalysis
UPDATE
Synthesis of a Class of Fused δ-Sultone
Heterocycles via DBU-Catalyzed Direct
Annulative SuFEx Click of Ethenesulfonyl
Fluorides and Pyrazolones or 1,3-Dicarbonyl
Compounds
Adv. Synth. Catal. Year, Volume, Page – Page
Xing Chen,a,† Gao-Feng Zha,a,† Grant A. L. Bare,b,†
Jing Leng,a Shi-Meng Wang,a and Hua-Li Qin*,a
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