One-pot fluorosulfurylation of Grignard reagents using sulfuryl fluoride

Article abstract of DOI:10.1039/c9cc08487h

Herein, we report a new method for the one-pot syntheses of sulfonyl fluorides. Addition of an alkyl, aryl, or heteroaryl Grignard to a solution of sulfuryl fluoride at ambient temperature affords the desired sulfonyl fluorides in 18-78% yield. Furthermore, this method is applicable for in situ sequential reactions, whereby the Grignard reagent can be converted to the corresponding diarylsulfone, sulfonate ester, or sulfonamide in a one-pot process.

Full text of DOI:10.1039/c9cc08487h

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One-pot fluorosulfurylation of Grignard reagents
using sulfuryl fluoride†
Cite this: Chem. Commun., 2019,
55, 14753
a
a
Cayo Lee,
Nicholas D. Ball *b and Glenn M. Sammis
*
Received 30th October 2019,
Accepted 15th November 2019
DOI: 10.1039/c9cc08487h
rsc.li/chemcomm
Herein, we report a new method for the one-pot syntheses of numerous functional groups, precluding their use in late-stage
sulfonyl fluorides. Addition of an alkyl, aryl, or heteroaryl Grignard functionalization. Furthermore, there are operational challenges
to a solution of sulfuryl fluoride at ambient temperature affords the with these methods as the sulfonyl chlorides are reactive, and are
desired sulfonyl fluorides in 18–78% yield. Furthermore, this thus susceptible to rapid, undesired processes including: hydro-
method is applicable for in situ sequential reactions, whereby the lysis, elimination of chloride in the presence of base, or nucleo-
Grignard reagent can be converted to the corresponding diarylsul- philic addition to the chlorine atom.1,10 To address these issues,
fone, sulfonate ester, or sulfonamide in a one-pot process.
several groups have developed strategies that circumvent the
formation of sulfonyl chlorides in sulfonyl fluoride synthesis.29–32
Sulfur(VI) fluorides are an important class of biomedical compounds For example, the Ball and Willis groups have recently demonstrated
and synthetic precursors.1,2 Compared to other S(VI) halides,
the strong S–F bond in sulfur(VI) fluoride infers unique
chemical properties, including hydrolytic stability,3–5 resistance
to reduction,6,7 and chemoselective reactivity at the sulfur
center.1,8,9 As a result, the installation of the SO2F group in
organic molecules allows for a diversity of reactivity and
applications.10 Sulfonyl fluorides –RSO2F– are of particular
interest due to studies demonstrating their use as protease
inhibitors11 and pharmaceuticals.12,13 Furthermore, the advent
of sulfur-fluoride exchange (SuFEx) chemistry has led to numerous
applications, ranging from 18F radiolabeling agents,14 fluorinating
agents,12 chemical probes for bioconjugation,15,16 and synthetic
precursors for other sulfur(VI) compounds,17 including sulfones,18
sulfonate esters,19 and sulfonamides.19–22
The utility of sulfonyl fluorides has necessitated new,
efficient methods for their synthesis. Sulfonyl fluorides are
traditionally synthesized using either a Halex reaction from
the corresponding sulfonyl chloride (Scheme 1A),1,23 or oxidative
chlorination of thiols followed by a Halex reaction (Scheme 1B).24,25
These methods require the isolation or in situ formation of a
sulfonyl chloride, necessitating the use of aryl diazonium salts,26
strong acids, or oxidants.27,28 These reagents are incompatible with
a Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, British Columbia V6T 1Z1, Canada. E-mail: gsammis@chem.ubc.ca
b Department of Chemistry, Pomona College, 645 North College Avenue, Claremont,
California 91711, USA. E-mail: nicholas.ball@pomona.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Strategies for the syntheses of sulfonyl fluorides.
c9cc08487h
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the one-pot conversion of aryl halides, or vinyl triflates, to aryl quenching the remaining Grignard at the end of the reaction
sulfonyl fluorides using 1,4-diazabicyclo[2.2.2]octane bis(sulfur (Table 1, entry 1).41 While decreasing the reaction temperature
dioxide) (DABSO) and electrophilic fluorine reagents (Scheme 1C led to no observed diaryl sulfone (3a), the rate of formation of
and D).19,33,34 Kim and coworkers also recently demonstrated the desired product also decreased with a concomitant increase
that sulfonyl fluorides can be accessed from aryne intermediates in the amount of fluorobenzene 4a (Table 1, entry 2). Increasing
(Scheme 1E).35 While obviating the need to generate sulfonyl the reaction temperature to 40 1C to drive the reaction forward
chlorides, certain challenges remain, such as extended reaction only afforded the desired product (2a) in 30% yield (Table 1,
times, limited substrate scope, and the use of expensive sulfo- entry 3), with an increase in the amount of the diarylsulfone (3a).
nylation agents.
To minimize the amount of diarylsulfone (3a) formation, the
We hypothesized that we may be able to access sulfonyl addition protocol was reversed so that the Grignard reagent was
fluorides in a one-pot process through the addition of Grignard slowly added to a THF solution of sulfuryl fluoride (Table 1,
reagents to sulfuryl fluoride (SO2F2). To the best of our knowl- entry 4). This change in the addition order had the desired
edge, there are no examples of the syntheses of sulfonyl fluorides effect, and led to an increase in the amount of sulfonyl fluoride
using Grignard reagents and sulfuryl fluoride. Manufactured by 2a relative to diarylsulfone 3a. The yield was further improved
36,37
Dow and used for over 50 years as a fumigant, SO2F2
has by increasing the size of the reaction vessel, which increases the
been successfully employed to synthesize stable fluorosulfates surface area of the gas/liquid interface (entry 5). Increasing the
(ROSO2F) and sulfamoyl fluorides (NR2SO2F).1,36–38 Further- amount of sulfuryl fluoride improved the reaction yield, regard-
more, the gas can readily be generated ex situ in the desired less of the size of the reaction vessel (entries 6 and 7). Further
amount through the addition of trifluoroacetic acid (TFA) to increasing the amount of sulfuryl fluoride beyond 6.1 equi-
1,1-sulfonyldiimidazole (SDI) and potassium fluoride (KF).36 valents had minimal impact on the reaction (entry 8), so we
Additionally, Grignard reagents are commercially accessible or chose 4.6 equivalents for further investigations (entry 7).
readily prepared from the corresponding halides. Therefore, the
With optimized conditions in hand, we next examined the
direct installation of sulfonyl fluorides from the corresponding scope of this new reaction with substituted phenylmagnesium
Grignards39 without the need for transition metal catalysts, bromide reagents (Table 2). Substrates with para-F or Cl sub-
oxidants, low temperatures, or specialized sulfonylation/fluori- stitution led to 78% and 59% yields of the sulfonyl fluorides 2a
nation reagents33 would represent a considerable advance in and 2b, respectively. However, electron poor bis(trifluoromethyl)
sulfur-fluoride exchange chemistry.
derivative 1c was not an effective substrate for our new method,
Investigations into the direct fluorosulfurylation of Grignard affording 2c in only 18% isolated yield, with the corresponding
reagents began by bubbling ex situ generated sulfuryl fluoride40 sulfone as the major product. Phenyl magnesium bromide, and
through a solution of para-fluorophenyl magnesium bromide alkyl-substituted phenyl derivatives were successfully fluorosul-
(1a) in THF (Table 1). In under five minutes, sulfonyl fluoride furylated to give 2d–2h in good isolated yields regardless of the
2a was obtained in modest yield along with diaryl sulfone (3a) steric congestion close to the nucleophilic center. Substrates
and fluorobenzene 4a, the majority of which likely results from with stronger electron-donating substituents were also effective
in this fluorosulfurylation reaction, affording the desired products
2i–2k in 64–70% isolated yields. Biphenyl derivative 2l and naphthyl
Table 1 Optimization of the reaction conditionsa
substrate 2m were converted to the corresponding sulfonyl fluorides
in 64% and 67% yield, respectively. While methylsulfonyl fluoride
(2n) was only formed in moderate yield, less volatile octylsulfonyl
fluoride (2o) was isolated in 64% isolated yield.
Investigations next turned to the preparation of heteroaryl
sulfonyl fluoride derivatives, with a focus on thiophene and
Yieldb (%)
c
benzothiophene derivatives as they are important classes of
synthetic intermediates42,43 and PET imaging precursors14
(Table 3). Unsubstituted thiophene derivative 5a was an effec-
tive substrate for the reaction, affording fluorosulfurylated
product 6a in 59% isolated yield. Methyl-substituted thiophene
Grignard reagents 5b and 5c were also viable, although the yield
decreased when the methyl group was adjacent to the nucleo-
philic center (6c). Further increasing the sterics from a methyl
group (6c) to an octyl group (6d) led to a decrease in the yield
from 48% to 32%. Chloride-substitution was also tolerated,
affording 6e in 48% yield. Benzothiophene derivative 5f was
Solvent/reaction
vessel (v/v; mL)
SO2F2
(equiv.)
Entry
Temp. (1C)
2a
3a
4a
1d
2d
3d
4e
5e
6e
7e
8e
23
0
3/4
3/4
3/4
3/4
3/20
3/20
3/20
3/20
3.1
3.1
3.1
3.1
3.1
4.6
4.6
6.1
45
25
30
53
59
66
78
77
10
0
15
8
6
2
35
75
40
31
29
30
10
11
40
23
23
23
23
23
6
6
a
b
Reaction conditions: 1a (1 equiv.) on 0.29 mmol scale. The yields
were determined by 19F NMR using trifluorotoluene as the internal
c
standard. SO2F2 gas was generated ex situ from the addition of TFA to
SDI/KF; equivalents of SO2F2 was adjusted by increasing the equivalents an effective substrate, providing 6f in 50% isolated yield. As
d
of SDI, KF and TFA in a 1 : 2.7 : 7.5 molar ratio. SO2F2 was bubbled
Grignard 5g (X = Br) is challenging to synthesize under standard
e
into a THF solution of the Grignard reagent for 30 min. The Grignard
reagent was added into a 0.1 M SO2F2 solution in THF and stirred
for 1 h.
conditions, it was prepared under the conditions described by
Knochel.44 Treatment of this Grignard (5, X = ClÁLiCl) under our
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a
Table 2 Substrate scope for the fluorosulfurylation of Grignard reagents
with SO2F2
Table 3 Fluorosulfurylation of heteroaryl Grignard reagents with SO2F2
a
a
Reaction conditions: 5 (X = Br, 1 equiv.), SO2F2 (4.6 equiv.), THF
(0.1 M) at 23 1C for 1 hour. All reactions were run on 0.6 mmol scale.
Isolated yields for the one-pot reaction are reported, with 19F NMR
yields using trifluorotoluene as the internal standard provided in
parentheses. With the exception of the 1 mmol scale reaction, all
b
reported yields represent the average of two independent trials. Reac-
tion conditions: 1 (X = ClÁLiCl, 1 equiv.), SO2F2 (4.6 equiv.), THF (0.1 M)
at 23 1C for 1 hour.
a
Reaction conditions: 1 (X = Br or Cl, 1 equiv.), SO2F2 (4.6 equiv.), THF
(0.1 M) at 23 1C for 1 hour. All reactions were run on 0.6 mmol scale.
Isolated yields for the one-pot reaction are reported, with 19F NMR
yields using trifluorotoluene as the internal standard provided in
parentheses. With the exception of the 1 mmol scale reaction, all
reported yields represent the average of two independent trials.
standard reaction conditions afforded the pyridine sulfonyl
fluoride (6g) in 44% isolated yield. A similarly prepared Grignard
was also successfully utilized in the preparation of thiazole
sulfonyl fluoride 6h on both 0.6 and 1 mmol scale (Table 3).
A distinct advantage of this new method over previously
developed fluorosulfurylation reactions is that the generated
sulfonyl fluoride has the potential to directly be used in situ for
sequential reactions (Scheme 2). To explore this possibility, we
first examined the one-pot synthesis of asymmetric diaryl
sulfone 7a. Grignard 1a was first converted to arylsulfonyl
fluoride 2a under our standard reaction conditions, followed
by addition of phenyl magnesium bromide. Gratifyingly, this
one pot process afforded diarylsulfone 7a in 75% isolated yield,
which suggests a high reaction efficiency for the second addi-
tion step. Similarly, 2a could either be converted to the corres-
ponding sulfonate ester (8a)45 or to the sulfonamide (9a),46
both in high isolated yields.
Scheme 2 One-pot generation of S(VI) compounds from sulfonyl fluor-
ides. All reactions were run on 0.6 mmol scale. Isolated yields for the one-
pot reaction are reported, with 19F NMR yields using trifluorotoluene as the
internal standard provided in parentheses. All reported yields represent the
average of two independent trials. a Reaction conditions: 1a (1 equiv.),
SO2F2 (4.6 equiv.), THF (0.1 M) at 23 1C for 1 hour. b Reaction conditions:
PhMgBr (1 equiv.), 23 1C for 2 hours. c Reaction conditions: PhOSiMe3
(1 equiv.), TBAF (1 equiv.), 23 1C for 1 hour. d Reaction conditions: imidazole
(2 equiv.), DBU (3 equiv.), 23 1C for 20 hours.
We have developed a new one-pot, ambient temperature the nucleophilic center. Some electron poor phenyl derivatives were
fluorosulfurylation reaction using Grignard reagents and ex situ also successful, but strongly electron-withdrawing substituted phenyl
generated sulfuryl fluoride. The desired aryl and alkyl sulfonyl derivatives were not efficient substrates for this transformation.
fluorides are formed in high yields for neutral and electron rich A similar trend in substituent effects was also observed with
phenyl derivatives, regardless of the steric environment near thiophene derivatives; however, the fluorosulfurylation of thiophene
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The authors would like to thank the University of British
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