SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides

Article abstract of DOI:10.1021/acs.orglett.0c01397

A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

Full text of DOI:10.1021/acs.orglett.0c01397

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Letter
SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access
Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides
Subham Mahapatra,§ Cristian P. Woroch,§ Todd W. Butler, Sabrina N. Carneiro, Sabrina C. Kwan,
Samuel R. Khasnavis, Junha Gu, Jason K. Dutra, Beth C. Vetelino, Justin Bellenger,
Christopher W. am Ende,* and Nicholas D. Ball*
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ABSTRACT: A method to activate sulfamoyl fluorides, fluoro-
sulfates, and sulfonyl fluorides with calcium triflimide and DABCO
for SuFEx with amines is described. The reaction was applied to a
diverse set of sulfamides, sulfamates, and sulfonamides at room
temperature under mild conditions. Additionally, we highlight this
transformation to parallel medicinal chemistry to generate a broad
array of nitrogen-based S(VI) compounds.
nterest in sulfur(VI) fluorides has grown immensely since
ISharpless and co-workers introduced the concept of sulfur−
fluoride exchange (SuFEx) chemistry in 2014.1,2 For example,
SuFEx has been applied extensively in chemical biology and
medicinal chemistry with application toward protein labeling,
protease inhibition, and drug target discovery.3 In polymer
chemistry, sulfur(VI) fluorides have been employed to
generate novel polysulfates and polysulfonates, materials that
have unique properties with promising applications.1,4,5
Furthermore, advancements in fluorosulfurylation chemistry
and the development of new reagents to install the −SO2F
group have spurred additional exploration into these functional
groups.6−12 However, employment of sulfur(VI) fluorides as
synthetic precursors toward nitrogen-based sulfonylated
compounds is underdeveloped.1,13−18
Nitrogenous sulfur(VI) compounds are well represented
among small molecule drugs. For example, sulfonamides make
up 25% of all sulfur-based FDA approved drugs, with
therapeutic applications for multiple indications (Figure 1A).19
Sulfamides and sulfamates are also valuable motifs; however,
they are comparatively underexplored, despite their presence in
a multitude of biologically active compounds.20 The most
common approach to nitrogen-based sulfur(VI) compounds
relies on the isolation or in situ generation of sulfur(VI)
chlorides, such as sulfonyl chlorides (−SO2Cl), chlorosulfates
(−OSO2Cl), and sulfamoyl chlorides (−NSO2Cl).1,21
Although widely used, there are several challenges with their
application. While some sulfonyl chlorides are commercially
available, the synthesis of sulfonyl chlorides with more complex
architectures can be challenging due to the harsh synthetic
conditions required to access these compounds and their
inherent instability.21b Moreover, in the presence of
nucleophiles, S(VI) chlorides can undergo competing addition
to the chlorine or sulfur atom, dehydrochlorination, and
hydrolysis (Figure 1B).1,21−23
In contrast, the corresponding S(VI) fluorides have
remarkable hydrolytic, redox, and thermal stability, rendering
them attractive alternatives to S(VI) chlorides.21 Despite
innovation in their synthesis, there are still barriers to the
broader application of S(VI) fluorides in organic chemistry. A
key challenge is the reduced reactivity at the sulfur center
compared to other S(VI) halides.1 Furthermore, the canonical
S(VI) fluoridessulfonyl fluorides (−SO2F), fluorosulfates
(−OSO2F), and sulfamoyl fluorides (−NSO2F)have con-
siderably different reactivity at the sulfur center due to the
reduced electrophilicity of the sulfur atom as the C−S bond is
replaced with more resonance-donating atoms. Notably,
disubstituted sulfamoyl fluorides require forcing conditions to
undergo sulfur-fluoride exchange,24 limiting a common
method toward their application in SuFEx chemistry.25
Received: April 22, 2020
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(Table 1, entry 1); however, sulfamoyl fluoride 1 was not fully
consumed in the reaction, and additional heating at 60 °C for
48 h did not further improve the conversion. Increasing the
temperature and equivalents of Ca(NTf2)2 improved the yield,
although the reactions still did not fully consume sulfamoyl
fluoride 1 (entries 2 and 3). We identified that increasing the
concentration to 1 M had a marked effect, affording a 96%
yield of sulfamide 3, with full consumption of starting material
(1) in only 2 h (entry 4).
We next explored the amine nucleophile and found that
decreasing the equivalents (2 equiv → 1.05 equiv of amine 2,
entry 5) required the addition of a base to drive the reaction to
completion (e.g., DIPEA or DABCO, entries 6 and 7). With
DIPEA, the yield varied depending on the bottle of tert-
amylOH employed. We surmised that this could be a result of
varying amounts of water present in the solvent. Indeed, the
addition of 5% water (by volume) significantly decreased the
yield from 95% to 54% (entry 6). Notably, when DABCO was
employed, the inclusion of 5% water in the reaction had a
minimal effect, yielding 88% yield of the desired sulfamide 3
(entry 7). This result led us to hypothesize that DABCO may
have an expanded role, beyond acting solely as a base in the
reaction, and led us to investigate additional reaction
parameters.1,26,27
Toward this end, we explored the effect of various bases,
solvents, and Lewis acids on the transformation (see the
Supporting Information (SI) for details). DABCO proved
exceptional as compared to other bases explored. With
DABCO, we no longer observed a preference for an alcoholic
solvent, the requirement for high concentration was less
pronounced, and the reaction proceeded at room temperature
when using THF as a solvent (entry 8). Evaluating a selected
set of Lewis acids further established Ca(NTf2)2 as particularly
effective across a variety of substrates (vide infra). In our
screen we found that 0.55 equiv of Ca(NTf2)2, and calcium
triflate Ca(OTf)2 could generate sulfamide 3 in good yields,
although in both cases the reactions required higher temper-
atures and were not as general across different amine
substrates. Lower equivalents of Ca(NTf2)2 resulted in
significantly reduced yield of 3 precluding catalysis (see the
SI for details). Further decreasing the equivalents of Ca-
(NTf2)2 led to incomplete conversion to 3. It is noteworthy
that in the absence of calcium the reaction does not proceed
(entry 9).
Figure 1. (A) Biologically active nitrogenous S(VI) compounds; (B)
S(VI) chloride-based approach to synthesize sulfonamides, sulfa-
mates, and sulfamides; (C) our room-temperature method using
Ca(NTf2)2 and DABCO to synthesize sulfamides, sulfamates, and
sulfonamides from S(VI) fluorides.
We recently reported a Ca(NTf2)2-mediated activation of
sulfonyl fluorides to generate sulfonamides13 and envisioned a
similar Lewis acid approach could be employed to activate less
reactive sulfamoyl fluorides and fluorosulfates to access
sulfamides and sulfamates, respectively. To date, a unified
approach to enable SuFEx chemistry across a broader array of
S(VI) fluorides does not exist, limiting their adoption as
synthetic precursors. Herein, we report a high-yielding, unified
method to access sulfamides, sulfamates, and sulfonamides
through the room-temperature activation of sulfamoyl
fluorides, fluorosulfates, and sulfonyl fluorides with calcium
triflimide and DABCO (Figure 1C).
Applying our previously reported method utilizing excess
amine in tert-amylOH generated sulfamide 3 in 70% yield
a
Table 1. Optimization Studies
entry
amine 2 (equiv)
Ca(NTf2)2 (equiv)
base (equiv)
solvent (conc, M)
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
1.05
1.05
1.05
1.05
1.05
1
1
t-amylOH (0.2)
t-amylOH (0.2)
t-amylOH (0.2)
t-amylOH (1.0)
t-amylOH (1.0)
t-amylOH (1.0)
t-amylOH (1.0)
THF (0.5)
60
90
100
90
90
90
90
rt
24
24
24
2
2
2
2
24
24
70
89
92
96
52
95 (54)
96 (88)
93
NR
1.1
1.1
1.1
1.1
1.1
1.1
0
b
DIPEA (1.5)
DABCO (1.5)
DABCO (1.5)
DABCO (1.5)
b
c
THF (0.5)
rt
a
b
c
Reaction scale: sulfamoyl fluoride 1 (0.35 mmol, 1.0 equiv). Reaction was performed in the presence of 5% water by volume. No reaction.
B
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a
Scheme 1. Scope of Sulfamide, Sulfamate, and Sulfonamide Formation
a
b
S(VI) fluoride (1.0 equiv), amine (1.05 equiv), Ca(NTf2)2 (1.1 equiv), DABCO (1.5 equiv) in THF (0.5 M) at rt for time indicated. No
c
d
reaction in the absence of Ca(NTf2)2 2.0 equiv of 7 N NH3 in MeOH was used as the amine source. The corresponding amine salt of morpholine
was used, along with 3.0 equiv of DABCO. Reaction was conducted on a 1.2 mmol scale in fluorosulfate for 24 h at room temperature. Amine (2.0
equiv), Ca(NTf2)2 (1.0 equiv), t-amylOH (0.2 M), 60 °C; see ref 13. 2 M solution of NH3 in iPrOH was used. 1.1 equiv of TMG was used.
e
f
g
h
We next investigated the generality of the sulfamide
preparation by exploring a diverse set of amine nucleophiles
with sulfamoyl fluoride 1 (Scheme 1A). Primary and secondary
amines, as well as weaker amine nucleophiles such as aniline,
methylimidazole and tetramethyl guanidine, readily underwent
SuFEx to produce sulfamides (3−7). Ammonia was also a
competent nucleophile, generating sulfamide 8 with a free
amino group. In addition, amine salts (i.e., HCl, TFA, and
MsOH) of morpholine were tolerated, giving sulfamide 9,
albeit with a reduction in yield compared to the free base. To
further evaluate the versatility of the reaction, we paired a
diverse array of sulfamoyl fluorides with various amines
(Scheme 1B, 10−18). The reaction was compatible with a
broad range of functional groups (e.g., primary amide, halides,
alkyne, etc.) and acid sensitive functionality (e.g., Boc and
acetal protecting groups), as well as multiple heterocyclic
motifs.
Fluorosulfates pose additional challenges, as multiple
reaction pathways can be envisioned upon reaction with
amine nucleophiles (Figure 2).3b Indeed, 4-cyanophenyl
fluorosulfate in the presence of DABCO and amine 2
(excluding Ca(NTf2)2) resulted in significant side-product
formation, including products outlined in Figure 2 (see the SI
for details). Remarkably, inclusion of Ca(NTf2)2 into the
C
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Scheme 2. PMC of S(VI) Fluorides with Amines
Figure 2. Possible modes of fluorosulfate reactivity with amines.
reaction mixture completely rescued the transformation,
affording sulfamate 19 in 98% yield. A structurally diverse
set of sulfamates were synthesized with secondary amines and
phenolic fluorosulfates in excellent yield (Scheme 1C, 19−29).
Notably, the reaction was run on a 1.2 mmol scale with the
synthesis of estrone-derived sulfamate 29 in near-quantitative
yield. Utilizing a primary amine with the electron-poor 4-
benzoylphenyl fluorosulfate resulted in elimination of the
phenol (see the SI for details);24 however, on a more electron-
rich substrate (i.e., 4-methoxyfluorosulfate) the desired
product 28 could be isolated with only a minor amount of
side product formation.
Our previous work demonstrated the conversion of sulfonyl
fluorides to sulfonamides using Ca(NTf2)2 with various
amines; however, the reaction required elevated temperature
(60 °C) and long reaction time (24 h). Applying the new
Ca(NTf2)2/DABCO combination had an exceptional effect:
phenylsulfonyl fluoride undergoes the SuFEx reaction to form
sulfonamide 30 in 94% yield in less than 30 min at room
temperature (Scheme 1D). Encouraged by these results, we
revisited a series of amine nucleophiles and sulfonyl fluorides
for comparison. In all cases, comparable or improved yields
were obtained, along with a dramatic increase in reaction rate,
at a lower reaction temperature (i.e., sulfonamides 30−33).
Further scope was exemplified by varying the electronics on
the sulfonyl fluoride, amine, and highlighting the use of both
ammonia and tetramethyl guanidine nucleophiles (34−37). In
addition, to probe the mechanism of this reaction, we
conducted NMR (1H and 19F) and LCMS studies and propose
a SuFEx mechanism that first involves Ca/DABCO activation
of the S(VI) fluoride to form an activated N-sulfonyl-DABCO
salt, that in the presence of an amine undergoes product
formation (see the SI for details).27
Parallel medicinal chemistry (PMC) is frequently used in
drug discovery to rapidly expand SAR and optimize lead
compound properties. PMC-enabled chemistry should be
tolerant of a wide range of functional groups and have
relatively simple reaction setup and purification. This is to
facilitate the use of a plate-based (e.g., 96-well or greater)
format, automated liquid handling equipment, and HPLC
purification of final products, with the goal of generating
numerous compounds in a more efficient manner than in
singleton or batch format. To explore the utility of our
Ca(NTf2)2/DABCO reaction conditions in PMC, we selected
three S(VI) fluoride templates (sulfonyl fluoride 38,
fluorosulfate 39, and sulfamoyl fluoride 1) and a diverse set
of amine monomers (Scheme 2; see the SI for the full set of
amines). Our protocol successfully translated to PMC format,
generating >100 unique nitrogen-based S(VI) compounds with
high overall success rate and purity across three classes of
nitrogen-based S(VI) compounds (i.e., sulfonamide 40/44,
sulfamate 27/31, and sulfamides 35/44 compounds). These
results highlight the application of this robust transformation
to a diverse set of functional groups and heterocycles.
In conclusion, we have developed a unified Ca(NTf2)2/
DABCO-mediated method that activates S(VI) fluorides, with
considerably different reactivity, toward SuFEx with amines.
The reaction proceeds at room temperature, a diverse array of
sulfamides, sulfamates, and sulfonamides can be readily
prepared, and application to parallel medicinal chemistry is
exemplified. We anticipate the introduction of this Ca(NTf2)2/
DABCO SuFEx method will further solidify S(VI) fluorides as
privileged S(VI) synthons in synthetic chemistry.28
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01397.
General methods, LC−MS traces, procedures, NMR
spectra (PDF)
Pure lab results (XLSX)
D
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AUTHOR INFORMATION
REFERENCES
■
■
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Corresponding Authors
Nicholas D. Ball − Department of Chemistry, Pomona College,
Claremont, California 91711, United States; orcid.org/
0000-0002-6816-1113; Email: nicholas.ball@pomona.edu
Christopher W. am Ende − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
orcid.org/0000-0001-8832-9641;
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Authors
Subham Mahapatra − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States
Cristian P. Woroch − Department of Chemistry, Pomona
College, Claremont, California 91711, United States
Todd W. Butler − Pfizer Worldwide Research and Development,
Groton, Connecticut 06340, United States
Sabrina N. Carneiro − Department of Chemistry, Pomona
College, Claremont, California 91711, United States
Sabrina C. Kwan − Department of Chemistry, Pomona College,
Claremont, California 91711, United States
Samuel R. Khasnavis − Department of Chemistry, Pomona
College, Claremont, California 91711, United States
Junha Gu − Department of Chemistry, Pomona College,
Claremont, California 91711, United States
Jason K. Dutra − Pfizer Worldwide Research and Development,
Groton, Connecticut 06340, United States
Beth C. Vetelino − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States
Justin Bellenger − Pfizer Worldwide Research and Development,
Groton, Connecticut 06340, United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01397
(9) Zhou, H.; Mukherjee, P.; Liu, R.; Evrard, E.; Wang, D.;
Humphrey, J. M.; Butler, T. W.; Hoth, L. R.; Sperry, J. B.; Sakata, S.
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Author Contributions
This work was performed in collaboration between the Ball
laboratory at Pomona College and Pfizer, Inc.
(10) Laudadio, G.; de A Bartolomeu, A.; Verwijlen, L. M. H. M.;
̈
Cao, Y.; de Oliveira, K. T.; Noel, T. Sulfonyl Fluoride Synthesis
Author Contributions
§S.M. and C.W.P are co-first authors.
Funding
through Electrochemical Oxidative Coupling of Thiols and Potassium
Fluoride. J. Am. Chem. Soc. 2019, 141, 11832−11836.
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Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.;
Sharpless, K. B.; Dong, J. A New Portal to SuFEx Click Chemistry: A
■
N.D.B. thanks Pomona College for start-up funds and Prof.
Daniel O’Leary for sharing laboratory resources. C.P.W., J.G.,
S.N.C., S.C.K., and S.R.K. thank the Pomona SURF program
and the Pomona College Department of Chemistry for their
funding. S.N.C. thanks the Linares Fellowship program. C.P.W.
and N.D.B. thank the ACS Scholars Program. C.P.W., N.D.B.,
and C.W.A. thank the Beckman Scholars Program. Addition-
ally, we thank current and former Pfizer employees
Christopher Helal, John Humphrey, and Patrick Mullins for
helpful discussions.
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