Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl Fluorides

Article abstract of DOI:10.1021/acs.orglett.8b01520

A method using calcium triflimide [Ca(NTf₂)₂] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts a wide array of sterically and electronically diverse sulfonyl fluorides and amines into the corresponding sulfonamides in good yield.

Full text of DOI:10.1021/acs.orglett.8b01520

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl
Fluorides
†
‡
†,§
‡
‡
Paramita Mukherjee, Cristian P. Woroch, Leah Cleary, Mark Rusznak, Ryan W. Franzese,
Matthew R. Reese, Joseph W. Tucker, John M. Humphrey, Sarah M. Etuk, Sabrina C. Kwan,
Christopher W. am Ende,* and Nicholas D. Ball*
†
†
†
‡
‡
,†
,‡
†
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
‡
Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, California 91711, United States
*
S Supporting Information
ABSTRACT: A method using calcium triflimide [Ca(NTf ) ] as a Lewis acid to
2
2
activate sulfonyl fluorides toward nucleophilic addition with amines is described.
The reaction converts a wide array of sterically and electronically diverse sulfonyl
fluorides and amines into the corresponding sulfonamides in good yield.
he sulfonamide structural class is prevalent within the
pharmaceutical and agrochemical industries. In 2016,
T
sulfonamides represented 15% of the top 100 most prescribed
drugs, with therapeutic applications against cardiovascular,
1
infectious, and neurological diseases. In the agrochemical
industry, the sulfonamide motif appears in a variety of
pesticides, including asulam, orzalin, fomesafen, halosafen, and
2
sulfentrazone. To date, the most common methods to
synthesize sulfonamides require the oxidation of sulfides or
nucleophilic addition to sulfonyl chlorides. However, these
approaches have several limitations. Sulfide oxidation employs
the use of strong oxidants that are incompatible with many
3
functional groups, precluding late-stage functionalization, and
the high reactivity of sulfonyl chlorides can result in poor
selectivity in the presence of competing nucleophiles,
detrimental reduction of S(VI) to S(IV), as well as instability
3
c
during storage. Therefore, developing alternative methods to
generate a diverse array of sulfonamides that employ more
stable reactants would benefit pharmaceutical and agro-
chemical syntheses (Figure 1). In addition, highlighting the
value of the sulfonyl fluoride (SF) as a useful and stable
functional group provides support for the development and
storage of a more diverse collection of these reagents.
Figure 1. (a) Current methods toward converting sulfonyl fluorides
1
0
In recent years, sulfonyl fluorides have gained renewed
to sulfonamides, (b) proposed modes of Lewis acid activation
sulfonyl fluoride for nucleophilic addition of amines, and (c) our
method using Ca(NTf ) in tert-amyl alcohol.
interest as alternatives to sulfonyl chlorides due to their
4
2
2
inherent stability and chemoselective reactivity at sulfur. The
sulfur−fluorine (S−F) bond in SO F is approximately 40 kcal
2
2
−1
Similarly, sulfonyl fluorides have gained importance as
mol stronger than the sulfur−chlorine (S−Cl) bond in
4
,9
5
alternative precursors to generate sulfonamides. However,
the increased stability of sulfonyl fluorides comes with the
duality of reduced reactivity. Existing methods for synthesizing
sulfonamides from sulfonyl fluorides typically involve using a
SO Cl . An analogous comparison to aryl sulfonyl halides
2
2
suggests that this added bond strength leads to thermody-
6
namic stability and resistance to both reduction and
7
hydrolysis. For the sulfonyl fluorides, a fortuitous balance
between hydrolytic stability and reactivity has enabled their
wide application as reactive electrophiles in chemical biology
to modify specific amino acids in proteins.
Received: May 14, 2018
7c,d,8
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
strong base/nucleophile, a vast excess of the amine
component, and/or extended periods of heating (Figure
Calcium triflimide was selected for further examination of
solvent effects due to its improved organic solubility and
reduced cost vs barium triflimide. The reaction could be run
in water, although a reduction in yield was observed, and the
solubility of the starting materials was generally poor (Table
2, entry 2). Alcoholic solvents afforded the desired
1
0
1
a). Additionally, sulfonamide formation is highly dependent
on the electronic nature of the sulfonyl fluoride and the
amine. Herein, we report a mild, calcium triflimide
Ca(NTf ) ] mediated activation of sulfonyl fluorides toward
7
c
[
2
2
sulfonamide formation in tert-amyl alcohol (t-amylOH, Figure
b,c). This method was demonstrated on a wide variety of
a
1
Table 2. Solvent Optimization
aromatic, heteroaromatic, and alkyl sulfonamides and, to our
knowledge, is the first example of a single set of reaction
conditions to convert a myriad of sulfonyl fluorides and
amines to sulfonamides.
The supposition that Lewis acid (LA) catalysis may
facilitate nucleophilic displacement of fluoride under mild
entry
solvent
yield (%)
11,12
conditions guided our initial approach to this project.
This
1
2
3
4
5
6
7
8
9
t-amylOH
88
63
40
71
87
42
13
51
could potentially occur via formation of Lewis acid/base
H O
2
adducts either with the sulfonyl oxygens or the fluorine atom
MeOH
i-PrOH
t-BuOH
MeCN
DMF
8
a,13,14
(Figure 1b).
In turn, these adducts would increase the
susceptibility of the sulfur atom toward nucleophilic addition.
A screen of Lewis acids and solvents with benzenesulfonyl
fluoride and aniline identified a promising lead: barium
triflimide [Ba(NTf ) ] in t-amylOH, (Table 1, entry 2). Upon
2
2
toluene
HFIP
b
9
a
Table 1. Lewis Acid Optimization
a
Reaction conditions: PhSO F (1 equiv), aniline (2 equiv), Ca(NTf )
2 2
2
(
1 equiv), solvent (0.20 M), 60 °C, 24 h. Isolated yields are averages of
b
two independent trials. Ca(NTf2)2 showed minimal solubility in
HFIP. Isolated yield is reported for one trial.
sulfonamide as well, with sterically congested alcohols
providing higher conversion to sulfonamide (Table 2, entries
3−5). Switching to polar aprotic solvents such as MeCN and
DMF (Table 2, entries 6 and 7), the conversion dropped
significantly, while a nonpolar solvent such as toluene
produced moderate yields of the sulfonamide (Table 2,
entry 8). Reports in the literature suggest using hexafluor-
oisopropanol (HFIP) as a solvent or NBu PF as an additive
entry
Lewis acid
yield (%)
1
2
3
4
5
6
7
8
9
Ca(NTf2)2
Ba(NTf2)2
Mg(NTf2)2
LiNTf2
88
80
38
9
b
AgNTf2
N/R
KNTf2
<2
4
6
1
2a,15
b
CaF2
N/R
could improve the activation of Ca(NTf2)2.
However,
Ca(OTf)2
La(OTf) ·xH O
4
30
2
Ca(NTf ) showed minimal solubility in HFIP, and only 9%
2 2
sulfonamide product 3 was isolated (Table 2, entry 9).
3
2
10
11
12
LiCl
Additionally, the NBu PF /Ca(NTf ) combination also
4
6
2 2
HNTf2
none
3
resulted in considerably decreased yields of 3 (see the
Supporting Information (SI)). Overall, t-amylOH and t-BuOH
provided the highest yields with t-amylOH emerging as the
solvent of choice due to convenience of use and environ-
b
N/R
a
Reaction conditions: PhSO F (1 equiv), aniline (2 equiv), Lewis acid
1 equiv), t-amylOH (0.32 M), 60 °C, 24 h. N/R denotes no
reaction.
2
b
(
16
mental factors.
With favorable conditions in hand, we next focused our
attention on exploring the versatility of the method using
sterically and electronically diverse aromatic and aliphatic
amines as nucleophiles (Scheme 1). When aromatic and
heteroaromatic amines were reacted with benzenesulfonyl
fluoride, in the presence of Ca(NTf ) , sulfonamide formation
a thorough analysis of additional triflimide salts, divalent
second group salts such as Ba(NTf2)2 and Ca(NTf2)2
emerged as superior Lewis acids, affording the sulfonamide
product in higher yields than the monovalent cationic
triflimides (Table 1, entries 1−3 and entries 4−6,
respectively). Solubility of the Lewis acids showed a marked
effect on the extent of reaction. In general, the triflimide salts
were more soluble in the reaction than Lewis acids with other
counteranions (Table 1, entries 7−10). Using the conjugate
2
2
was achieved in good to excellent yield. It is noteworthy that
in the absence of Lewis acid these reactions proceeded with
little to no sulfonamide formation, highlighting the crucial role
Ca(NTf ) plays in activating the sulfonyl fluorides toward
2
2
nucleophilic addition. We generally used two molar
equivalents of the amine component for these reactions but
were pleased to show that when only 1 equiv of aniline was
used in combination with triethylamine sulfonamide 3 was
acid of the triflimide anion, HNTf , in lieu of a Lewis acid
2
resulted in a marginal 3% isolated yield of compound 3
(Table 1, entry 11). We also note that calcium fluoride, a
17
potential byproduct of the reaction, does not affect
sulfonamide formation (Table 1, entry 7). Attempts to reduce
the molar equivalents of Lewis acid and/or amine resulted in
incomplete consumption of the benzenesulfonyl fluoride.
isolated in 71% yield (Scheme 1).
Interestingly, 4-aminophenol reacts with sulfonyl fluoride 1
to form the sulfonamide 7 as the major product. This
preference for sulfonamide formation is opposite to the
B
DOI: 10.1021/acs.orglett.8b01520
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Organic Letters
Letter
Scheme 1. Substrate Scope Reacting Aryl, Heteroaryl, and Aliphatic Amines with PhSO F*
2
*
Reaction conditions: PhSO F (1 equiv), amine (2 equiv), Ca(NTf ) (1 equiv), t-amylOH (0.20 M), 60 °C, 24 h. Isolated yields for Ca(NTf )
2 2
2
2
2
reactions are averages of two independent trials. Reactions without Ca were conducted as a single reaction. Mass balance is unreacted starting
a
b
material. PhSO F (1 equiv), aniline (1 equiv), Ca(NTf ) (1 equiv), Et N (1 equiv), t-amylOH (0.20 M), 60 °C, 24 h. N/R denotes no reaction.
2
2
2
3
c
d
Trace product was detected by LC/MS; however, it could not be isolated. Yield of sulfonamide 14 on 6.2 mmol scale.
observed reactivity in the presence of Cs CO , which instead
provides the corresponding sulfonic ester. Analogues of
the increased electrophilicity of the sulfonyl fluoride resulting
from the electron-withdrawing groups in the aryl ring.
2
3
1
8
7c
compound 10 with variations on the arylsulfonyl were
We next wanted to explore a less nucleophilic amine in
combination with the electron-deficient sulfonyl fluorides to
19
valuable leads in a drug discovery project within Pfizer.
Under our reaction conditions, we obtained compound 10 in
3% yield from benzenesulfonyl fluoride, highlighting the
determine if Ca(NTf ) would be required in those cases.
2 2
Accordingly, 4-cyanobenzenesulfonyl fluoride was reacted with
6
aniline in the presence and absence of Ca(NTf ) in t-amyl
value of our chemistry on a pharmaceutically relevant
template. Additionally, both primary and secondary aliphatic
amines reacted with sulfonyl fluoride 1 to generate their
corresponding sulfonamides (11−14) in good yield, with the
synthesis of compound 14 exemplified on gram scale. Initial
attempts to react phenylsulfonyl fluoride with weakly
nucleophilic anilines containing electron withdrawing groups
at the 4-position (e.g., −SCF and −CF ), using our general
2 2
alcohol at 60 °C and analyzed by LC/MS (see the SI). In the
absence of Ca(NTf ) no sulfonamide formation was detected
2
2
after 24 h. However, in the presence of Ca(NTf ) , the
2
2
reaction was nearly complete after 1 h, affording sulfonamide
6 in 85% yield (Scheme 3 and SI). We observed similar
reactivity with the heteroarylsulfonyl fluorides, as demon-
strated in the synthesis of sulfonamides 27 and 28 (Scheme
2
3
3
3
). Although Ca(NTf ) is not required for reaction between
2 2
procedure, did not result in detectable sulfonamide product.
We selected 1-(5-(trifluoromethyl)-2-pyridinyl)piperazine
an electron-deficient sulfonyl fluoride and a highly nucleo-
philic amine, for all other combinations of sulfonyl fluorides
and amines that we explored, Ca(NTf2)2 activation to
generate sulfonamides in high yield has been demonstrated
to be essential.
We wanted to show the complementarity of this method
and the stability of the sulfonyl fluoride toward traditional
sulfonamide synthesis from sulfonyl chlorides. Therefore, we
subjected piperazine 29 to a sequential Boc deprotection,
sulfonamidation with benzenesulfonyl chloride. The reactivity
of the sulfonyl fluoride was then unveiled for reaction with 3-
aminopyridine via the action of Ca(NTf2)2 to afford
(15) as the nucleophilic amine to assess the versatility of
the method with various sulfonyl fluorides. Toward this end,
we successfully synthesized an array of sulfonamides using
aryl- and heteroarylsulfonyl fluorides (Scheme 2). Addition-
ally, alkylsulfonyl fluorides provided the desired sulfonamides
(24 and 25) under identical reaction conditions. Interestingly,
while Ca(NTf ) was required for reactivity of electron-rich
2
2
arylsulfonyl fluorides, reactions of electron-deficient sulfonyl
fluorides with amine 15 proceeded in the absence of any
Lewis acid (see 21−23, Scheme 2). This is presumably due to
C
DOI: 10.1021/acs.orglett.8b01520
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Organic Letters
Letter
Scheme 2. Substrate Scope Reacting Aryl- and Alkylsulfonyl
Fluorides with Amine 15*
Scheme 3. Comparing the Reactivity of Electron-Deficient
Sulfonyl Fluorides with Amines 2 and 15*
*
Reaction conditions: RSO F (1 equiv), amine, 15 or 2 (2 equiv),
2
Ca(NTf ) (1 equiv), t-amylOH (0.20 M), 60 °C, 24 h. Isolated yields
2
2
for Ca(NTf ) reactions are averages of independent trials. Reactions
2
2
a
without Ca weere conducted as a single reaction. N/R denotes no
reaction. Trace product was detected by LC/MS; however, it could
b
not be isolated.
Scheme 4. Sulfonyl Fluoride as a Latent Electrophile
*
Reaction conditions: RSO F (1 equiv), 1-(5-trifluoromethyl)-2-
2
pyrdinyl piperazine, 18 (2 equiv), Ca(NTf ) (1 equiv), t-amylOH
2
2
(
0.20 M), 60 °C, 24 h. Isolated yields for Ca(NTf ) reactions are
2 2
averages of two independent trials. Reactions without Ca where
conducted as a single reaction. N/R denotes no reaction.
a
compound 31 in high yield (Scheme 4). Notably, sulfonyl
fluoride 30 withstood the Boc-deprotection under acidic
conditions, and the first sulfonamidation in the presence of
triethylamine proceeded without detectable self-condensation.
The synthesis of compound 31 demonstrates how synthetic
strategies can exploit the robust nature of sulfonyl fluorides
and then unlock the latent reactivity using calcium triflimide.
In conclusion, we have developed a method that employs
calcium triflimide activation of aryl- and alkylsulfonyl fluorides
to synthesize sulfonamides. This method can be used to
couple a wide array of sterically and electronically diverse
sulfonyl fluorides and amines to produce sulfonamides in
good to excellent yields. Preliminary results suggest that
divalent cations and the triflimide anion are essential for
efficient conversion, with future studies focusing on
developing a better understanding of the reaction mechanism.
With the contribution of this new method, we envision that
the sulfonyl fluorides will emerge as the preferred sulfonyl
halide for a myriad of sulfonylation reactions.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01520.
Experimental methods and NMR spectra (PDF)
Accession Codes
CCDC 1842164−1842166 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nicholas.ball@pomona.edu.
*E-mail: christopher.amEnde@pfizer.com.
D
DOI: 10.1021/acs.orglett.8b01520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(b) Bebernitz, G. R.; Aicher, T. D.; Stanton, J. L.; Gao, J.; Shetty, S.
S.; Knorr, D. C.; Strohschein, R. J.; Tan, J.; Brand, L. J.; Liu, C.;
Wang, W. H.; Vinluan, C. C.; Kaplan, E. L.; Dragland, C. J.;
DelGrande, D.; Islam, A.; Lozito, R. J.; Liu, X.; Maniara, W. M.;
Mann, W. R. J. Med. Chem. 2000, 43, 2248. (c) Berg, S.; Bergh, M.;
Paramita Mukherjee: 0000-0003-0990-7744
John M. Humphrey: 0000-0001-8753-9479
Christopher W. am Ende: 0000-0001-8832-9641
Nicholas D. Ball: 0000-0002-6816-1113
Present Address
Hellberg, S.; Ho
S.; Weigelt, T.; Ormo
̈
gdin, K.; Lo-Alfredsson, Y.; So
̈
derman, P.; von Berg,
, M.; Xue, Y.; Tucker, J.; Neelissen, J.; Jerning,
̈
E.; Nilsson, Y.; Bhat, R. J. Med. Chem. 2012, 55, 9107. (d) Harris, P.
A.; Cheung, M.; Hunter, R. N.; Brown, M. L.; Veal, J. M.; Nolte, R.
T.; Wang, L.; Liu, W.; Crosby, R. M.; Johnson, J. H.; Epperly, A. H.;
Kumar, R.; Luttrell, D. K.; Stafford, J. A. J. Med. Chem. 2005, 48,
610.
11) For an example of base-catalyzed activation of sulfonyl
fluorides, see: Gembus, V.; Marsais, F.; Levacher, V. Synlett 2008,
008, 1463.
12) For representation of Lewis acid complexation with sulfonyl
compounds, see: (a) Qi, C.; Hasenmaile, F.; Gandon, V.; Lebœuf, D.
ACS Catal. 2018, 8, 1734. (b) Peyronneau, M.; Roques, N.;
Mazieres, S.; Le Roux, C. Synlett 2003, 5, 0631.
(13) Begouin, J.-M.; Niggemann, M. Chem. - Eur. J. 2013, 19, 8030.
14) There is also potential for interaction of the Lewis acid with
the amine nucleophile. For an example of Ca(NTf ) participating in
coordination of sulfonyl oxygens and NH bonds with the assistance
of an alcoholic solvent, see: Lebœuf, D.; Gandon, V. Synthesis 2017,
9, 1500.
15) Lebœuf, D.; Gandon, V. Synthesis 2017, 49, 1500 and
references cited therein.
16) Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013,
§(
L.C.) Ideaya Biosciences, 7000 Shoreline Ct, Suite 305,
South San Francisco, CA 94080.
Author Contributions
1
(
This work was performed in collaboration between the Ball
laboratory at Pomona College and Pfizer.
Notes
2
(
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.D.B. thanks Pomona College for start-up funds. Addition-
ally, acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund for support
(
2
2
(
544180-UNI). S.M.E., R.W.F., S.C.K., M.R., and C.P.W.
thank the Pomona SURF program and the Pomona
Department of Chemistry for their funding. 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. The authors
also thank Mona Shahgholi and Nassem Torian (Caltech) for
the HRMS analyses, Ivan Samardjiev (Pfizer) for X-ray
crystallography, and Patrick Mullins (Pfizer) and Christopher
Helal (Pfizer) for critical review of the manuscript.
4
(
(
15, 3950.
(17) Additional stoichiometry/base combinations were explored;
see the Supporting Information for selected examples.
18) Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D. J. Org.
Chem. 2017, 82, 2294.
19) Chappie, T. A.; Henderson, J. L.; Young, J. M.; Wager, T. T.;
Kormos, B. L.; Patel, N. C.; Sciabola, S.; Tuttle, J. B.; Verhoest, P.
R.; Tucker, J. W. (Pfizer, Inc., USA). Preparation of 6,7,8,9-
tetrahydro-5H-pyrido[2,3-d]azepine compounds as selective dopa-
mine D3 ligands. PCT Int. Appl. WO 2017122116A1 20170720,
(
(
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