Synthesis of Arenesulfonyl Fluorides via Sulfuryl Fluoride Incorporation from Arynes

Article abstract of DOI:10.1021/acs.orglett.8b03610

Transition-metal-free multicomponent reactions involving aryne precursors, secondary amines, and sulfuryl fluoride are reported herein. Zwitterionic intermediates formed from the reaction of arynes with amine nucleophiles can capture SO₂F₂ under mild conditions, offering a novel and practical protocol for the synthesis of 2-dialkyl-, 2-alkylaryl-, or 2-diarylamino-substituted arenesulfonyl fluoride derivatives in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.8b03610

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Arenesulfonyl Fluorides via Sulfuryl Fluoride
Incorporation from Arynes
Jungmin Kwon and B. Moon Kim*
Department of Chemistry, College of Natural Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
*
S Supporting Information
ABSTRACT: Transition-metal-free multicomponent reac-
tions involving aryne precursors, secondary amines, and
sulfuryl fluoride are reported herein. Zwitterionic intermedi-
ates formed from the reaction of arynes with amine
nucleophiles can capture SO2F2 under mild conditions,
offering a novel and practical protocol for the synthesis of 2-dialkyl-, 2-alkylaryl-, or 2-diarylamino-substituted arenesulfonyl
fluoride derivatives in good to excellent yields.
romatic amines are abundant in biologically active
molecules. Among numerous aromatic amines, o-amino-
Scheme 1. Synthetic Routes to Arenesulfonyl Fluorides
1
A
arenesulfonyl derivatives exhibit a wide range of pharmaco-
2
3
4
logical activities like antitumor, antiviral, antihypertensive,
5
6
2
diuretic, antipsychotic, and anti-inflammatory properties.
Therefore, much research effort has been focused on the
development of efficient synthetic methods for 2-amino-
7
substituted arenesulfonyl derivatives.
Sulfonyl fluorides have received significant attention due to
8
their unique utility in the fields of chemistry and chemical
9
biology. In comparison to other aryl sulfonyl halides, aryl
sulfonyl fluorides possess considerable stability toward
1
0
11
reduction and hydrolysis, often resulting in increased
12
chemoselectivity. These characteristics make them privileged
motifs in novel drug discovery efforts. Recently, considerable
9
research effort has been focused on new applications of
1
8
13
arenesulfonyl fluorides, such as F-radiolabeling, deoxy-
1
4
15
16
fluorination, click reaction, and sulfonamide preparation.
However, despite the importance of sulfonyl fluorides, direct
8
synthetic approaches toward them have been limited. Sulfonyl
(
MCRs) of arynes afforded diverse 1,2-disubstituted benzene
20
compounds are often used as starting materials for sulfonyl
fluorides, as found in the reactions of potassium bifluoride with
sulfonyl chlorides and Selectfluor with sulfonyl hydrazides
derivatives under transition-metal-free conditions. Typically,
nucleophiles add to arynes generating zwitterion intermediates,
which are readily trapped by electrophiles. Sharpless et al.
reported an extremely useful employment of sulfuryl fluoride
(SO F ) for efficient construction of aryl fluorosulfates from
phenol derivatives, while N-disubstituted sulfamoyl fluorides
form secondary alkylamines in the presence of a base. We
envisioned that SO2F can be captured by the reactive
zwitterions generated from the reaction of arynes, producing
sulfonyl fluorides. We report herein a new SO F incorporation
reaction via MCRs using arynes and nucleophiles including
secondary amines.
1
2,17
(Scheme 1, a).
Recently, Willis et al. reported a Pd-
catalyzed one-pot synthesis of arenesulfonyl fluorides from aryl
18
bromides (Scheme 1, b). This process involves transition-
metal-catalyzed sulfonylation of aryl bromides using 1,4-
diazabicyclo[2.2.2]octane−bis(sulfur dioxide), followed by
treatment of the sulfinate with a fluorine source, e.g., N-
fluorobenzenesulfonimide (NFSI). The tolerance of this two-
step reaction to diverse functional groups is noteworthy;
nevertheless, an alternative transition-metal-free synthetic
protocol is more desirable. We herein report the development
of an efficient protocol to obtain arenesulfonyl fluorides
without using transition-metal-based reagents (Scheme 1, c).
Arynes have been recognized as valuable intermediates and
have been utilized in several interesting synthetic trans-
2 2
12
2
2
2
First, we investigated various known nucleophiles for the
three-component reaction of arynes in the presence of sulfuryl
Received: November 12, 2018
1
9
formations.
In particular, multicomponent reactions
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
1
fluoride (Table 1). Several nucleophiles like isocyanides,
fluoride (3e) in 70% yield, apparently from the hydrolysis of
the resultant iminium ion after the desired three-component
reaction. When triphenylphosphine (2f) was used as a
nucleophile, (2-(fluorosulfonyl)phenyl)triphenylphosphonium
triflate (3f) was furnished in 75% yield. Unfortunately, for N-
heterocyclic nucleophiles like quinoline and isoquinoline, no
product was formed. Since the reaction with N-isopropylani-
line proceeded effectively, we have investigated various amine
derivatives for the generation of diversely substituted o-
aminoarenesulfonyl fluorides, which can be used for the
synthesis of important drug intermediates.
2
2
23
24
25
amines, imines, N-heterocycles, and phosphines have
a
Table 1. MCRs Involving Arynes, Nucleophiles, and SO2F2
We proceeded to further optimize the reaction conditions
for the three-component reactions using N-isopropylaniline
(
2a) as a representative nucleophile. We chose compound 1a
as the aryne precursor and carried out reactions at −10 °C
under 1 atm SO F atmosphere, following Yoshida’s and Biju’s
CO capture procedure. The results are collected in Table 2.
2
2
22
2
a
Table 2. Reaction Optimization
F− source
(equiv)
3a
b
4a
b
entry
additive (equiv)
solvent
(%)
(%)
1
2
3
4
5
6
7
8
CsF (4.5)
KF (4.5)
TBAF (4.5)
TBAT (4.5)
CsF (4.5)
KF (4.5)
KF (4.5)
KF (4.5)
KF (4.5)
KF (4.5)
KF (4.5)
KF (3.0)
KF (3.0)
KF (3.0)
CH CN
0
0
0
0
3
0
0
3
THF
THF
THF
29
24
39
38
3
26
21
29
53
18
35
11
18-crown-6 (4.5) CH CN
3
18-crown-6 (4.5) CH CN
7
3
3
18-crown-6 (4.5) MTBE
18-crown-6 (4.5) DME
18-crown-6 (4.5) THF
18-crown-6 (4.5) THF
18-crown-6 (4.5) THF
18-crown-6 (3.0) THF
18-crown-6 (3.0) THF
18-crown-6 (3.0) THF
66
78
68
36
82
60
0
9
c
1
0
d
a
11
12
Reaction conditions: 1a, nucleophile, KF, 18-crown-6, and THF
b
under SO F atmosphere (1 atm). Not detected.
2
2
e
1
1
3
4
f
previously been used for MCRs with arynes. We screened
various nucleophiles using 2-(trimethylsilyl)phenyl triflate (1a)
as a model substrate, following the procedure reported for each
nucleophile. When N-isopropylaniline (2a) was added to 1a in
THF at room temperature in 1 atm SO2F2 atmosphere,
sulfonyl fluoride derivative 3a was obtained in 53% yield. To
see if the reaction works with a primary amine nucleophile, a
reaction with either methylamine (2b) or tert-butylamine (2c)
was investigated. The reaction using methylamine (2b) did not
afford the desired three-component product because of further
reaction with another aryne. Even though 2-(trimethylsilyl)-
phenyl triflate (1a) disappeared completely, the reaction
afforded 2-(methyl(phenyl)amino)benzenesulfonyl fluoride
a
Reaction conditions: 1a (1.5 equiv), 2a (1.0 equiv, 0.25 mmol) and
solvent (2.5 mL) at −10 °C under SO F atmosphere (1 atm) for 24
2
2
b
h. Determined by GC analysis with dodecane as an internal standard.
c
d
Reaction was performed at 0 °C. Reaction was performed at 25 °C.
1a (1.0 equiv, 0.25 mmol), 2a (1.5 equiv). Fluorosulfuryl
e
f
imidazolium salt (1.0 equiv) was used instead of SO F under Ar
atmosphere (1 atm).
2
2
First, examination of diverse fluoride sources revealed that the
reactivity highly depends upon the fluoride source. No product
was obtained from the reactions using KF or CsF (entries 1
and 2). When tetrabutylammonium fluoride (TBAF) or
tetrabutylammonium difluorotriphenylsilicate (TBAT) was
used as the fluoride source, the protonated product, N-
isopropyl-N-phenylaniline (4a), was obtained as the only
product (entries 3 and 4). However, the desired three-
component reaction product 3a was formed in a small amount
when 18-crown-6 was used as an additive along with KF or
CsF in acetonitrile (entries 5 and 6, respectively). Still, the
protonated product 4a was formed in a significant amount.
Reaction in methyl tert-butyl ether gave a very low yield of
both the desired product 3a (3%) and 4a (3%) (entry 7).
(
3b) as a major product in 10% yield along with other side
products. However, the reaction with tert-butylamine (2c)
furnished 2-(tert-butylamino)benzenesulfonyl fluoride (3c) in
26
7
0% yield. Interestingly, when tert-butyl isocyanide (2d) was
used as a nucleophile, 2-(tert-butylamidocarbonyl)-
benzenesulfonyl fluoride (3d) and 2-cyanobenzenesulfonyl
fluoride (3d′) were obtained in 67% and 20% yields,
respectively. When we treated 1a with N-benzylidenemethyl-
amine (2e), we obtained 2-(N-methylamino)benzenesulfonyl
B
DOI: 10.1021/acs.orglett.8b03610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
However, reaction in dimethoxyethane (DME) yielded 66% of
the desired product 3a and 26% of 4a (entry 8). The reaction
in tetrahydrofuran (THF) improved the yield of the desired
product significantly (entries 9 and 12). The selectivity for the
three-component product, compared with the protonation
product, was also dependent on temperature (entries 9−11).
Warming the reaction to room temperature yielded more of
the protonated product 4a, presumably due to rapid proton
transfer from the ammonium salt intermediate at higher
temperatures (entry 11). Use of 4.5 equiv of KF did not
provide better selectivity for the desired product than that of
Scheme 2. Scope of Secondary Amines
3
.0 equiv KF (entries 9 and 12). Use of excess amine (1.5
equiv) under otherwise the same reaction conditions did not
improve the selectivity or the yield (entry 13). When
fluorosulfuryl imidazolium salt was employed instead of
SO F , which is a more reactive fluorosulfating reagent for
2
2
amines and phenols only a small amount of 4a was formed
,
27
without any desired fluorosulfonyl product (entry 14).
With the optimized reaction conditions in hand, various
secondary amines, such as alkylarylamines, dialkylamines, and
diarylamines, were examined as nucleophiles in the three-
component reactions. Scheme 2 shows that different reaction
temperatures had to be employed to provide high yields of the
desired products, depending on the amine substituents. We
found that the choice of the reaction temperature should be
based on the propensity for proton ransfer of the intermediate
aryl anion. Reactions involving alkylarylamines like N-
isopropyl-, N-ethtyl-, N-allyl-, N-cyclohexyl-, and N-benzylani-
line were conducted at −10 °C and afforded the desired
products in 81, 84, 83, 90, and 70% yields, respectively. N-
Methylaniline and diversely substituted (p-methoxy, m-bromo,
p-acetyl, p-trifluoromethyl, and p-nitro) N-methylanilines
afforded the desired products in 75, 76, 70, 89, 77, and 71%
yields, respectively. Reactions employing dialkylamines were
carried out at 25 °C and furnished the o-dialkylamino-
substituted benzenesulfonyl fluorides in good (74−82%)
yields. The reaction of diisopropylamine in the presence of
sulfuryl fluoride proceeded efficiently, affording the desired
product in 82% yield. Reaction involving diallylamine or N-
isopropylcyclohexylamine also proceeded smoothly with 81
and 80% yields, respectively. Even sterically demanding bis(2-
ethylhexyl)amine participated well in the three-component
reaction to give the desired product in 74% yield. Bis-
a
Reaction conditions for the reactions employing alkylarylamine: 1a
(
1.5 equiv), amine (1.0 equiv), KF (3.0 equiv), 18-crown-6 (3.0
equiv), and THF (2.5 mL) at −10 °C under SO F atmosphere (1
2
2
atm) for 24 h. Reaction conditions for the reactions employing
dialkylamine: 1a (1.0 equiv), amine (1.5 equiv), KF (3.0 equiv), 18-
crown-6 (3.0 equiv), and THF (2.5 mL) at 25 °C under SO2F2
atmosphere (1 atm) for 24 h. Reaction conditions for the reactions
employing diarylamine: 1a (1.5 equiv), amine (1.0 equiv), KF (3.0
equiv), 18-crown-6 (3.0 equiv), and DME (0.5 mL) at −30 °C under
b
SO F atmosphere (1 atm) for 24 h. 77% yield was obtained on a 1
mmol scale reaction.
(
methoxyethyl)amine, benzylisopropylamine, and dibenzyl-
2 2
amine all emerged as good substrates for the coupling
reactions, furnishing 76, 81, and 75% yields, respectively.
Unfortunately, reactions involving cyclic amines like piperidine
and pyrrolidine proceeded directly with SO F , instead of with
To investigate the scope of the aryne part, we investigated
substituted aryne precursors for the three-component reactions
(Table 3). Using N-isopropylaniline (2a) as a model
nucleophile, we examined the reactions of various function-
alized arynes. The reaction with 4-methylbenzyne (1b)
proceeded well, affording 5a and 5a′ in a 1.3:1 ratio and
80% yields. While high regioselectivity (10:1) was observed
with 6-methylbenzyne (1c), the yield (46%) was lower than
2
2
the aryne to give N-sulfamoyl fluorides. In the reactions
involving diarylamines, we discovered that THF participated as
a nucleophile, presumably due to its higher nucleophilicity
than the diarylamines. Therefore, the solvent was switched to
2
8
DME. Due to the higher acidities of diarylammonium salts,
their reactions produced more protonated compounds at high
temperatures; therefore, the reactions were conducted at −30
22,29
that of the reaction with 4-methylbenzyne.
Symmetrical
°
C, and somewhat reduced yields were obtained due to the
aryne precursors like dimethoxy (1d) and naphthyl (1e)
derivatives afforded single products in 86 and 80% yields,
respectively. Decreased yield (35%) was obtained with 4-
fluorobenzyne (1f), providing 5e and 5e′ in 4.2:1 ratio.
To probe the reaction mechanism, reactions of 1a with N-
sulfamoyl fluorides were performed under the optimized
conditions in an Ar atmosphere (Scheme 3). As mentioned
above, cyclic secondary alkylamines like pyrrolidine, piperidine,
decreased activity at low temperatures. The reactions were
well-tolerated, however, regardless of the substituents on the
diarylamines, such as electron-donating methoxy and tert-butyl
groups and electron-withdrawing bromo and cyano groups.
Notably, a variety of functional groups, including allyl,
methoxy, bromo, carbonyl, trifluoromethyl, nitro, and cyano
groups, survived the reaction conditions.
C
DOI: 10.1021/acs.orglett.8b03610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of Arynes
Scheme 4. Proposed Mechanism
sulfuryl fluoride in an appropriate position for nucleophilic
capture.
In conclusion, we have developed a novel transition-metal-
free protocol for the direct synthesis of arenesulfonyl fluorides
via incorporation of fluorosulfonyl group to arynes. This
multicomponent reaction works efficiently with 1 atm of
sulfuryl fluoride under mild conditions, producing diversely
substituted 2-aminoarenesulfonyl fluoride derivatives in good
to excellent yields. With a wide range of functional group
compatibility, various secondary amines, including dialkyl-
amines, alkylarylamines, and diarylamines, underwent the
three-component reaction with good selectivity. With this
new sulfuryl fluoride incorporation reaction in hand, diverse
nucleophiles can also be utilized for the direct synthesis of
sulfonyl fluoride derivatives.
a
Reaction conditions: aryne precursor (1.5 equiv), 2a (1.0 equiv, 0.25
mmol), KF (4.5 equiv), 18-crown-6 (4.5 equiv), and THF (2.5 mL)
at −10 °C under SO F atmosphere (1 atm) for 24 h. The
regioisomer ratio was determined by H NMR analysis.
b
2
2
1
ASSOCIATED CONTENT
Supporting Information
Scheme 3. Reactions of Aryne Precursors with N-Sulfamoyl
Fluorides
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03610.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: kimbm@snu.ac.kr.
■
*
ORCID
B. Moon Kim: 0000-0001-6924-268X
Notes
azepane, 1,2,3,4-tetrahydroisoquinoline, and morpholine gave
N-disubstituted sulfamoyl fluorides upon reaction with SO F .
2
2
In the reactions in Scheme 3, the desired product was not
obtained in either case, suggesting the involvement of the
three-component reactions. Based on these results, a plausible
reaction mechanism was proposed (Scheme 4). Nucleophilic
attack of the secondary amine on the aryne, generated in situ
from 1a in the presence of a fluoride source, would lead to the
formation of a zwitterionic intermediate B, which would react
with SO F to provide the desired arenesulfonyl fluoride D or
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Nano Material Development Program for an
NRF grant funded by the Ministry of Education, Science and
Technology, Republic of Korea (NRF-2012M3A7B4049644).
2
2
REFERENCES
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2
D
DOI: 10.1021/acs.orglett.8b03610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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