1-Bromoethene-1-sulfonyl fluoride (BESF) is another good connective hub for SuFEx click chemistry

Article abstract of DOI:10.1039/c8cc03400a

We demonstrate 1,2-dibromoethane-1-sulfonyl fluoride (DESF) as a bench-stable and readily accessible precursor to the robust SuFEx connector, 1-bromoethene-1-sulfonyl fluoride (BESF). The in situ generation of BESF from DESF opens up several new reaction

Full text of DOI:10.1039/c8cc03400a

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1-Bromoethene-1-sulfonyl fluoride (BESF) is
another good connective hub for SuFEx click
Cite this:DOI: 10.1039/c8cc03400a
chemistry†
Received 26th April 2018,
Accepted 18th May 2018
Christopher J. Smedley,
Marie-Claire Giel, Andrew Molino,
Andrew S. Barrow,
David J. D. Wilson and John E. Moses*
DOI: 10.1039/c8cc03400a
rsc.li/chemcomm
We demonstrate 1,2-dibromoethane-1-sulfonyl fluoride (DESF) as a fluorosulfate, iminosulfur oxydifluoride and alkyl sulfonyl
bench-stable and readily accessible precursor to the robust SuFEx fluoride molecular connections, respectively. The resulting
connector, 1-bromoethene-1-sulfonyl fluoride (BESF). The in situ S–F functionality is primed for undergoing SuFEx chemistry, and
generation of BESF from DESF opens up several new reaction creating new linkages that more often than not, arise through S–F
profiles, including application in the syntheses of unprecedented exchange with aryl silyl ethers and/or with amine nucleophiles to
3-substituted isoxazole-5-sulfonyl fluorides, 1-substituted-1H- give the corresponding S–O and S–N bonds, respectively.9
1,2,3-triazole-4-sulfonyl fluorides, 2-amino-1-bromoethane-1-sulfonyl
In addition to S–F exchange, ESF can form additional
fluorides and 4-bromo-b-sultams in good to excellent yields. These connections through carbon-based linkages—reacting with
new modules comprise a pendant sulfonyl fluoride handle, which amines, alcohols and carbon nucleophiles by conjugate addition,1
further undergoes facile and selective SuFEx reactions with a selection and also through cycloaddition pathways as a diene and/or
of aryl silyl ethers to generate stable and useful sulfonate connections. dipolarophile.8,10
In an effort to expand the range of available SuFEx hubs that
Sulfur–Fluoride Exchange (SuFEx) is a new generation click enable the formation of new and SuFEx-able functional cores,
reaction, and a powerful technology for creating molecular we identified 1-bromoethane-1-sulfonyl fluoride (BESF) as an
connections with absolute reliability under metal free attractive prospect.11 In principle, BESF offers the same reac-
conditions.1 SuFEx builds upon the fundamental principles of tion pathways as ESF, but with the additional benefit of an
click chemistry,2 by engaging near perfect reactivity to create embedded functional bromo-group, which creates further
stable covalent linkages between discrete modular units. SuFEx opportunities for reactivity. With this in mind, we envisaged a
exploits the ‘alien-like’ nature of S–F bonds (e.g. sulfonyl 1,3-dipolar cycloaddition/dehydrobromination sequence would
fluorides, fluorosulfates etc.), which are characterised by both lead directly to pharmaceutically relevant sulfonyl fluoride func-
their remarkable kinetic stability and their robust reactivity tionalised 5-membered aromatic heterocycles, including isoxazoles
under special activating conditions.1 The incredible efficiency and triazoles.11 In this regard, the BESF would formally serve as a
and reliability of SuFEx has already been realised in several surrogate for the as yet unreported acetylenesulfonyl fluoride ASF
applications, including in synthetic chemistry,1,3 chemical in 1,3-dipolar cycloaddition chemistry (Fig. 1).
biology,4 polymers5 and post-polymerisation modification.6
Herein we report the development and application of
SuFEx brings a new dimension to the click chemistry toolbox 1-bromoethane-1-sulfonyl fluoride (BESF) as a new connector
by allowing the creation of connections through discrete hubs. for SuFEx click chemistry. Conveniently generated in situ by
These so-called ‘SuFEx-able plugins’, which to-date include the dehydrobromination of the bench-stable 1,2-dibromoethane-1-
connective gases sulfuryl fluoride (SO2F2)1 and thionyl tetra- sulfonyl fluoride (DESF), the versatility of this new SuFEx hub is
fluoride (OQSF4),7 along with the carbon-based linker, ethene- showcased through the syntheses of 5-sulfonyl fluoride isoxazoles,
sulfonyl fluoride (ESF),1,8 serve as junctions for creating 4-sulfonyl fluoride triazoles, amine nucleophile 1,4-addition
products and 4-bromo-b-sultam products with excellent efficiency.
On a selection of these examples, we further demonstrate their
function as SuFEx linkers through reactions with a range of aryl
silyl ethers.
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086,
Australia. E-mail: j.moses@latrobe.edu.au
† Electronic supplementary information (ESI) available. CCDC 1839108. For ESI
DESF was prepared in an excellent yield of 87% directly from
ESF, following a modified version of Vessiere’s protocol.12
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc03400a
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Fig. 1 (A) SuFEx connectors; (B) the in situ of SuFEx connector BESF.
While BESF may itself be prepared and isolated, we found the
material to be unstable under ambient conditions.13
We have previously reported the successful development of
1,3-dipolar cycloaddition chemistry using reactive intermedi-
ates that are generated and consumed in situ, and elected to
investigate this strategy with BESF.14 In principle, a controlled
dehydrobromination of DESF would generate the corres-
ponding BESF, which upon cycloaddition with
a given
1,3-dipole (e.g. nitrile oxide or azide), would be thermodynamically
driven to undergo a second dehydrobromination to give the
corresponding 5-membered aromatic heterocycle (Fig. 1B).
This approach proved successful—a model study using
DESF and the nitrile oxide precursor (R = 4-methoxybenzene)
in the presence of triethylamine, realised the 3-substituted
isoxazole-5-sulfonyl fluoride 4c. In this particular instance,
both the BESF dipolarophile and the reactive nitrile oxide
1,3-dipole were prepared in situ.15 Optimisation of the reaction
Scheme 1 Synthesis of 5-sulfonyl fluoride substituted isoxazoles. a Isolated
yields, reactions performed on a 1.00 mmol scale of N-hydroxyimidoyl chloride;
b reaction performed on
a 5.38 mmol scale of N-hydroxyimidoyl
chloride; c reaction performed on a 0.30 mmol scale of N-hydroxyimidoyl
chloride; d 2.4 eq. DESF and 6.4 eq. of Et3N added.
conditions revealed the following protocol (Table S1, ESI†): performed at the MP2/def2-TZVPP//M06-2X/def2-TZVP16 level of
[3.2 equivalents of triethylamine, 1.2 equivalents of DESF stirring theory was used to help rationalise the regiochemical outcome of
for 5 min at 0 1C in THF, followed by the addition of 1.0 equivalent the transformation (Fig. 2). The modelling reveals the initial step
of N-hydroxyimidoyl chloride (nitrile oxide precursor), stirring at to form BESF from DESF is endergonic by 38.2 kJ molÀ1, whereas
0 1C to room temperature for 1 h], which resulted in the regio- a second dehydrobromination to give the ASF is significantly
selective syntheses of twenty 3-substituted isoxazole-5-sulfonyl unfavoured at 129.9 kJ molÀ1. Both the 3,5- and 3,4-substituted
fluorides in good to excellent yields (Scheme 1).
isoxazole products are favourable by 132.8 and 136.2 kJ molÀ1
,
The reaction performed well with a number of aryl substituted respectively. While the thermodynamic product is calculated to
N-hydroxyimidoyl chlorides (4a–q) to give the electron-neutral (4a, arise from a 3,4-substituted intermediate, the reaction kinetics
4b and 4i), electron-rich (4c–h) and electron deficient (4j–q) were found to be product determining with the transition state
analogues, and could equally be applied to an N-hydroxyimidoyl (TS1) for cycloaddition found to be significantly higher by
chloride bearing an alkyne (4f). Access to di-substituted products 43.7 kJ molÀ1 for the 3,4-isoxazole. The significant difference in
such as 4p was possible with this method—so too was the use barrier height is consistent with the experimental observation and
of non-phenyl derived N-hydroxyimidoyl chlorides, allowing the exclusive formation of the 3,5-isoxazole product.
syntheses of a thiophene derivative (4r) and two styryl based
analogues in good yields (4s and 4t).
The difference in reactivity can be rationalised by steric
effects, with TS1 for the 3,4-isoxazole product producing a
The regiochemistry of the cycloaddition products was deter- steric clash between the –SO2F and –Ph groups, which is absent
mined by extensive NMR analyses and was corroborated by single for 3,5-isoxazole. The subsequent aromatising dehydrobromi-
crystal X-ray crystallography (4t, Scheme 1). Molecular modelling nation step, for both regioisomeric intermediates (12 and 13)
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Scheme 2 Synthesis of 4-sulfonyl fluoride substituted triazoles. a Isolated
yields, reactions performed on a 0.25 mmol scale of azide; Heated at 90 1C
for 6 h.
We next explored the reactivity of the in situ generated BESF
connector as a 1,4-Michael acceptor. Beginning with secondary
amines, the 1,4-amino adducts (7a–f) were obtained in excellent
yields (Scheme 3). When primary amines were employed, the
corresponding 4-bromo-b-sultams were isolated—heating the
reaction to 50 1C followed by the addition of potassium
carbonate (1 equivalent) 30 minutes after the amine addition,
led to the full conversion to the 4-bromo-b-sultams 8a–c.
With several new sulfonyl fluoride functionalities in-hand,
obtained through both cycloaddition and 1,4-addition pathways
Fig. 2 Calculated free energy profile (DG, kJ molÀ1) of 3,5- and 3,4-
isoxazole formation reactions at the MP2/def2-TZVPP(SMD,THF)//M06-
2X/def2-TZVP level of theory.
was predicted to be a strong driving force for the formation of
the isoxazole core. Mulliken charges provide further support for
the 1,2-cycloaddition preference; the terminal carbon in BESF has
a more negative charge (À0.23 e) and therefore favours attack from
the oxygen anion (À0.40 e) in the nitrile oxide to the sulfonyl
fluoride-bonded carbon rather than the terminal carbon.
To explore the scope of reactivity of BESF further, we next
investigated the in situ 1,3-dipolar cycloaddition reaction of
BESF with a selection of organic azides. Using slightly modified
reaction conditions [4 equivalents of triethylamine, 3 equivalents
of DESF and 1 equivalent of azide at 90 1C in MeCN for 3 h], a
selection of 1-substituted-1H-1,2,3-triazole-4-sulfonyl fluorides
were obtained (6a–e) in excellent yields (Scheme 2). This is
important since until now, the synthesis of 1,2,3-triazoles bearing
sulfonyl fluorides, which have significant potential in click chemi-
stry applications, remained unprecedented.
The 1,4-regioselectivity of the 1,3-dipolar cycloaddition of
BESF with azides can be explained using a similar rationale
proposed for the analogous reaction with nitrile oxides
(Fig. S1, ESI†). Molecular modelling studies reveal that the
corresponding energy of the transition state for BESF-azide
cycloaddition is significantly higher than that of the analogous
isoxazole, which is reflected experimentally in the higher reac-
tion temperature required (Fig. S3, ESI†).17
Scheme 3 1,4-Michael addition products of secondary amines into BESF
and 4-bromo-b-sultam synthesis with primary amines. a Isolated yields,
reactions performed on a 0.10 mmol scale; b reactions performed on a
1.00 mmol scale; c heated to 50 1C; d HCl salt of amine used, 2.0 eq. of
Et3N added.
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Future Fellowship (FT170100156). NCI, Intersect and La Trobe
University are acknowledged for grants of computing resources.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Scheme 4 SuFEx reactions with isoxazole, triazole and 1,4-addition pro-
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from BESF, we elected to test the SuFEx-ability of these novel
modules. Thus, SuFEx reactions with selected aryl silyl ethers were
performed with chosen BESF derived sulfonyl fluorides to give the
corresponding sulfonate products 16a–h in excellent yields,
thereby demonstrating their effectives as SuFEx-able connective
hubs (Scheme 4).
In summary, we have found applications of 1,2-dibromoethane-
1-sulfonyl fluoride (DESF), as a new and bench stable reagent.
Treatment of DESF with triethylamine results in the in situ gen-
eration of the SuFEx linker 1-bromoethene-1-sulfonyl fluoride
(BESF), which serves as a reactive dipolarophile and Michael
9 Q. Zheng, J. Dong and K. B. Sharpless, J. Org. Chem., 2016, 81,
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10 H. U. Daeniker and J. Druey, Helv. Chim. Acta, 1962, 45, 1972–1981.
acceptor for making covalent connections. The conditions used 11 During the preparation of this manuscript a report describing the
synthesis and isolation of 1-bromoethane-1-sulfonyl fluoride, along with
its application in the synthesis of 5-sulfonylfluoroisoxazoles appeared
online: J. Ling and H.-L. Qin, Chem. Commun., 2018, 54, 4477–4480.
to generate BESF also allow concomitant formation of reactive
nitrile oxide 1,3-dipoles from the corresponding N-hydroxyimidoyl
chlorides, which undergo regiospecific 1,3-dipolar cycloaddition 12 A. Champseix, J. Chanet, A. Etienne, A. Berre, J. C. Lemasson,
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13 The in situ generation and reaction of BESF gave superior yields of
with BESF to form the corresponding 3-substituted isoxazole-5-
sulfonyl fluorides. We also demonstrate that the reactive BESF
the isoxazoles with less equivalents than the analogous reaction
undergoes regioselective 1,3-dipolar cycloaddition reactions with a
number of organic azides to give the corresponding 1-substituted-
1H-1,2,3-triazole-4-sulfonyl fluoride products, which until now
were unprecedented and also reacts with secondary amines to
give the 1,4-addition products, and with primary amines to give
4-bromo-b-sultams.
On these products, we have validated the capability of these
SuFEx-able sulfonyl fluoride handles to react with aryl silyl
ethers to give new sulfonate linkages. Finally, we have provided
a rationale to explain the regiochemistry of the 1,3-dipolar
cycloaddition reactions, which is supported by high level mole-
cular modelling studies.
using isolated BESF (see ref. 11).
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We thank Dr Jason Dutton for performing X-ray crystal-
lography on 4t; Prof. K. Barry Sharpless and Dr Pallavi Sharma
for insightful discussions; La Trobe University (C. J. S., M.-C. G.
and A. M.) for PhD Scholarships. J. E. M thanks the ARC for a
17 The analogous reaction of organic azides with the related 1-bromoethane-
1-sulfonyl chloride has been reported to result in elimination of
sulfur dioxide and HCl: C. S. Rondestvedt and P. K. Chang, J. Am.
Chem. Soc., 1955, 77, 6532–6540.
Chem. Commun.
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