Journal of the American Chemical Society
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aFor experimental details, see the Supporting Information. Reaction
conditions: (a) standard deamination conditions; (b) piperidine, I2; (c)
15NH4OH, I2; (d) 2-chloro-5-trifluoromethylpyridine; (e) Xantphos/Pd,
PhI; (f) XPhos/Pd, PhOTf.
(3) For selected modern methods to prepare sulfonamides, see: (a)
Caddick, S.; Wilden, J. D.; Judd, D. B.; Direct Synthesis of Sulfonamides
and Activated Sulfonate Esters from Sulfonic Acids J. Am. Chem. Soc.
2004, 126, 1024. (b) DeBergh, J. R.; Niljianskul, N.; Buchwald, S. L.;
1
2
3
4
5
6
7
8
9
Synthesis
of
Aryl
Sulfonamides
via
Palladium-Catalyzed
The sulfinates generated in situ, as soft, anionic nucleophiles,
can react with various alkyl electrophiles beyond methyl iodide,
as well as electron deficient aryl halides in SNAr reactions
(Scheme 4).9,10c Furthermore, the crude sulfinate salts can engage
in cross-couplings with aryl electrophiles to provide aryl
sulfones.10d Finally, the sulfinates can act as aryl nucleophiles,
analogous to arylboronic acids, in cross-coupling reactions to
form biaryl compounds through loss of SO2.12 The latter reaction
is particularly intriguing, as primary sulfonamides can now be
thought of as precursors to aryl nucleophiles for cross-coupling.
Overall, this diverse set of reactions showcases the remarkable
breadth and utility of the deamination/sulfinate functionalization
strategy reported here.
Chlorosulfonylation of Arylboronic Acids J. Am. Chem. Soc. 2013, 135,
10638. (c) Shavnya, A.; Coffey, S. B.; Smith, A. C.; Mascitti, V.;
Palladium-Catalyzed Sulfination of Aryl and Heteroaryl Halides: Direct
Access to Sulfones and Sulfonamides Org. Lett. 2013, 15, 6226. (d)
Johnson, M. W.; Bagley, S. W.; Mankad, N. P.; Bergman, R. G.; Mascitti,
V.; Toste, F. D.; Application of Fundamental Organometallic Chemistry to
the Development of a Gold‐Catalyzed Synthesis of Sulfinate Derivatives
Angew. Chem., Int. Ed. 2014, 53, 4404. (e) Tsai, A. S.; Curto, J. M.;
Rocke, B. N.; Dechert-Schmitt, A.-M. R.; Ingle, G. K.; Mascitti, V.; One-
Step Synthesis of Sulfonamides from N-Tosylhydrazones Org. Lett. 2016,
18, 508. (f) Deeming, A. S.; Russell, C. J.; Willis, M. C.;
Palladium(II)‐Catalyzed Synthesis of Sulfinates from Boronic Acids and
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60
DABSO:
A Redox‐Neutral, Phosphine‐Free Transformation Angew.
Chem., Int. Ed. 2016, 55, 747. (g) Chen, Y.; Murray, P. R. D.; Davies, A.
T.; Willis, M. C.; Direct Copper-Catalyzed Three-Component Synthesis of
Sulfonamides J. Am. Chem. Soc. 2018, 140, 8781.
(4) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S.
W.; The medicinal chemist's toolbox for late stage functionalization of
drug-like molecules Chem. Soc. Rev. 2016, 45, 546.
(5) (a) Modha, S. G.; Mehta, V. P.; Van der Eycken, E. V.; Transition
metal-catalyzed C–C bond formation via C–S bond cleavage: an overview
Chem. Soc. Rev. 2013, 42, 5042. (b) Aziz, J.; Messaoudi, S.; Alami, M.;
Hamze, A.; Sulfinate derivatives: dual and versatile partners in organic
synthesis Org. Biomol. Chem. 2014, 12, 9743. (c) Smith, J. M.; Dixon, J.
A.; deGruyter, J. N.; Baran, P. S.; Alkyl Sulfinates: Radical Precursors
Enabling
10.1021/acs.jmedchem.8b01303.
(6) (a) Nolan, S. P. N-Heterocyclic Carbenes; Wiley-VCH, 2014. (b)
Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T.;
Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes Chem.
Rev. 2015, 115, 9307.
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Scheidt, K. A.; Conversion of α,β-Unsaturated Aldehydes into Saturated
Esters: An Umpolung Reaction Catalyzed by Nucleophilic Carbenes Org.
Lett. 2005, 7, 905. (d) Reynolds, N. T.; Rovis, T.; Enantioselective
Protonation of Catalytically Generated Chiral Enolates as an Approach to
the Synthesis of α-Chloroesters J. Am. Chem. Soc. 2005, 127, 16406. (e)
Sohn, S. S.; Bode, J. W.; Catalytic Generation of Activated Carboxylates
from Enals:ꢀ A Product-Determining Role for the Base Org. Lett. 2005, 7,
3873. (f) Chen, D.-D.; Hou, X.-L.; Dai, L.-X.; Unexpected Transfer of
Tosyl Group of ArCH═NTs-Catalyzed by N-Heterocyclic Carbene J. Org.
Chem. 2008, 73, 5578. (g) DiRocco, D. A.; Oberg, K. M.; Rovis, T.;
Isolable Analogues of the Breslow Intermediate Derived from Chiral
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Xu, J.; Yang, S.; Song, B.-A.; Chi, Y. R.; Enantioselective Sulfonation of
In conclusion, we have developed a general, reliable, and user-
friendly approach to the late-stage functionalization of
sulfonamides. These reactions occur with exceptional scope in
regards to the steric and electronic properties of the sulfonamide,
as well as the functionality contained within the molecule. The
methods outlined here have been exemplified on several complex
drug and drug-like sulfonamides and have been used to prepare
novel derivatives that would otherwise require lengthy, de novo
syntheses. Moreover, the value of this approach will continue to
grow with the development of new methods for sulfinate
functionalization. Having already witnessed a rapid uptake of this
chemistry amongst our colleagues across drug discovery and
development, we are confident that the work described here will
have an immediate and tangible impact across synthetic
chemistry, as primary sulfonamides can now be applied as
versatile synthetic handles.
Drug
Discovery
J.
Med.
Chem.
DOI:
ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data for new
compounds. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Authors
*E-mail: patrick.fier@merck.com
*E-mail: kevin_maloney@merck.com
ACKNOWLEDGMENTS
We would like to thank L. C. Campeau, Neil Strotman, and
Tamas Benkovics (all employees of Merck) for helpful feedback
on our manuscript.
Enones
with
Sulfonyl
Imines
by
Cooperative
N‐Heterocyclic‐Carbene/Thiourea/Tertiary‐Amine Multicatalysis Angew.
Chem. Int. Ed. 2013, 52, 12354.
(8) Menon, R. S.; Biju, A. T.; Nair, V.; Recent advances in N-
heterocyclic carbene (NHC)-catalysed benzoin reactions Beilstein J. Org.
Chem. 2016, 12, 444.
(9) The nucleophilicity of sulfinate ions have been quantified, see:
Baidya, M.; Kobayashi, S.; Mayr, H.; Nucleophilicity and Nucleofugality
of Phenylsulfinate (PhSO2 ): A Key to Understanding its Ambident
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