Reductive Cleavage of Secondary Sulfonamides: Converting Terminal Functional Groups into Versatile Synthetic Handles

Article abstract of DOI:10.1021/jacs.9b10985

Sulfonamides are pervasive in pharmaceuticals and agrochemicals, yet they are typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild and general method to reductively cleave the N-S bonds of sulfonamides to generate sulfinates and amines, components which can further react in situ to access a variety of other medicinally relevant functional groups. The utility of this platform is highlighted by the selective manipulation of several complex bioactive molecules.

Full text of DOI:10.1021/jacs.9b10985

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Communication
Reductive Cleavage of Secondary Sulfonamides: Converting
Terminal Functional Groups into Versatile Synthetic Handles
Patrick S. Fier, Suhong Kim, and Kevin M. Maloney
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10985 • Publication Date (Web): 06 Nov 2019
Downloaded from pubs.acs.org on November 6, 2019
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Reductive Cleavage of Secondary Sulfonamides: Converting
Terminal Functional Groups into Versatile Synthetic Handles
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Patrick S. Fier,* Suhong Kim, and Kevin M. Maloney*
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Supporting Information Placeholder
A. Representative Synthesis of a Complex Sulfonamide
F
ABSTRACT: Sulfonamides are pervasive in pharmaceuticals and
agrochemicals, yet are typically considered as terminal functional
O
O
O O
groups rather than synthetic handles. To enable the general late-
stage functionalization of secondary sulfonamides, we have
developed a mild and general method to reductively cleave the N-
S bonds of sulfonamides to generate sulfinates and amines,
components which can further react in-situ to access a variety of
other medicinally relevant functional groups. The utility of this
platform is highlighted by the selective manipulation of several
complex bioactive molecules.
EtO2C
S
EtO2C
S
Cl
N
F
H
N
N
F
O
O
6 steps
15% yield
NH
O
O
NH
S
N
F
N
H
N
N
N
H
N
ArNH defined early in synthetic sequence
The ability to selectively modify single sites of complex
molecules is a powerful and efficient tool in drug discovery, as
single-point modifications can have profound impacts on biological
and physicochemical properties.1 Given that sulfonamides and
related bioisosteres are prevalent in medicines across all
therapeutic areas,2 the development of methods for their selective
manipulation could accelerate drug discovery. Yet, beyond simple
C-N bond forming reactions, secondary sulfonamides have been
treated as terminal functional groups as there are no other methods
for their late-stage modification.3
B. Novel Transformations of Interest to Drug Discovery (this work)
R'
SO
CO
2 to
Change identity of
group
Conversion of
O
O
S
R''
NH
R'
R
P(III)
R
N
O
H
O
R'
R
S
NH
O
O
S
R'
NH
O
P(V)
R
S
R'
R
O
O
NH
R
Change identity of group
Deletion of
Sulfonamides are ubiquitous in drug design, in part because they
are metabolically stable4 and easy to prepare from sulfonyl
chlorides and amines.5 However, given that sulfonyl chlorides are
highly reactive and not stable within typical complex molecules,
sulfonamides are often formed early in a synthetic sequence and
carried through with the sulfonamide moiety fixed. For example,
the synthesis of a sulfonamide-containing drug candidate (Figure
1A) relied on a 6-step sequence following the installation of the
aniline group.6 While such a sequence could be satisfactory to
prepare a single target, it is not practical for typical structure-
activity relationship studies in drug discovery. In addition, early
installation of sulfonamides could restrict the types of functional
groups present on the substituents of the sulfonamide, as the
downstream chemistry could present incompatibilities. Thus, a
general platform that enables late-stage functionalization of
complex secondary sulfonamides under mild reaction conditions in
a single reaction vessel would be particularly powerful in drug
discovery programs (Fig. 1B).7
Unknown transformations for late-stage functionalization
Figure 1. Secondary Sulfonamides in Drug-Like Molecules
As part of a program to realize sulfonamides as points of
diversification, we recently reported a general platform for the
conversion of primary sulfonamides to a variety of other bioactive
motifs through the in-situ generation of sulfinates (Figure 2A).8,9
While this method has already been adopted for late-stage
functionalization, the reaction mechanism limits this chemistry to
the diversification of primary sulfonamides. As primary and
secondary sulfonamides are equally common across
pharmaceuticals,2 we sought to develop a method that could enable
a similar reductive cleavage of the N-S bonds in secondary
sulfonamides. However, secondary sulfonamides present
additional challenges, most notably that across existing secondary
sulfonamide-containing drugs there is a similar number of
compounds in which the amine-containing piece is complex
(Figure 2B)10 and compounds in which the sulfonyl piece is
complex (Figure 2C).11 Thus, we aimed to develop a method that
enables the functionalization of either component of a secondary
sulfonamide under mild conditions while tolerating functionality
commonly found in drug-like molecules.
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A. Late-Stage Functionalization of Primary Sulfonamides (ref 8a)
and tris(dimethylamino)phosphine in THF at ambient temperature
1
2
3
4
5
6
7
8
over 15-30 minutes to form N-sulfonyl phenylglycine ester
interemediates. Although the phosphine reagent is moderately air
and moisture sensitive, we carried out all reactions on the benchtop
without any special precautions. For cleavage of the adducts, an
exhaustive screen of bases revealed that reactions with t-butyl
tetramethylguanidine (BTMG, Barton’s base)15 resulted in clean
fragmentation and concomitant generation of the desired sulfinate
and imine products, both of which can be re-functionalized in-situ.
The net transformation in this cleavage process is a two-electron
reduction of the N-S bond driven by the oxidation of P(III) to P(V).
The ethyl benzoylformate in these reactions acts as a redox shuttle,
initially undergoing reduction followed by base-mediated
oxidation.
O
S
O
S
O
S
O
S
E+
R
NH2
R
N
R
E
Ph
O
O
R
O-
O
O
N
PhC
H
+
E: alkyl, aryl, OR,
NR2, X, etc.
H
Ph
-SO2
R
R'
B. Secondary Sulfonamides with Complex Amino Group
tBu
Ph
F
9
F
N
F3C
H
N
HO
O
S
N
10
11
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Pr
O
S
S
O
F
O
O
N
N
H
O
NH2
A. Initial Attempts to Access N-Alkyl Intermediates
N
Dabrafenib
Tipranavir
X
O
O
S
R'
N
C. Secondary Sulfonamides with Complex Sulfonyl Components
O
S
O
S
R'
NH
R'
NH
R
R''
EWG
H
EWG
R
R''B(OH)2
R
H
N
O
EWG
O
N
H
O
O
O
S
O
R''
N
Me
N
N
N
N
S
O
NH
tBu
H
H
O
B. Development of Chemoselective Alkylation and N-S Cleavage
O
Sumatriptan
Fedratinib
O
THF, rt, 30 min,
then BTMG
R'
N
O
S
N
R'
NH
Ph
CO2Et
R
S
R
+
+
CO2Et
H
O
D. Concept for Secondary Sulfonamide Functionalization
O
P(NMe2)3
Ph
(Me2N)3PO
O
O
S
:BTMG
P+(NMe2)3
R'
in-situ
functionalization
O
S
R'
NH
R
S
O
-
R
N
via:
Ph
R
O-
R'
N
sulfinate
amine
of
or
EWG
O
O
O
R'
N
CO2Et
H
+
R
S
EWG
Base-mediated elimination
:B
CO2Et
O-
- Chemoselectivity controlled by acidity of N-H
- Mild Conditions for all steps
Ph
Chemoselective alkylation
of sulfonamide
- Applicable towards late-stage diversification
Figure 2. Late-Stage Functionalization of Sulfonamides:
Inspiration and Strategy
Figure 3. The development of a general platform for N-alkylation
and base-mediated N-S cleavage
In designing a method for the late-stage functionalization of
secondary sulfonamides, we envisioned a reaction that would
selectively functionalize secondary sulfonamides to generate an
intermediate containing an acidic C-H bond adjacent to nitrogen.
This intermediate would then react under basic conditions to
liberate a sulfinate anion while at the same time generating an imine
(Figure 2D). Such a reaction manifold would enable subsequent
functionalization of the sulfinate using well-established chemistry,
or functionalization of the amine after imine cleavage.
With conditions in hand for the chemoselective N-S cleavage of
secondary sulfonamides, we carried out an initial survey of the
scope with respect to the electronic properties of the sulfonamide.
Four sulfonamide substrates comprising the combinations of alkyl
and aryl groups on S and N were subjected to the standard reaction
conditions and the conversion was analyzed on an HPLC
instrument (Scheme 1). Across the four sulfonamides, high
conversion to the sulfinate and imine were observed. The imines
generated in the reaction were stable to HPLC analysis, and the free
amine could be revealed in quantitative yield within minutes
through the addition of aqueous hydroxylamine to the crude
reaction mixture.
Initially, we investigated reactions for the chemo-selective
alkylation of secondary sulfonamides with alkyl halides containing
electron-withdrawing groups that would promote the subsequent
elimination step. However, the use of such alkyl halides resulted in
complex mixtures when we tried to apply this approach to complex,
drug-like molecules (Figure 3A). Next, approaches based on the
Petasis reaction were explored as a chemoselective entry to access
N-sulfonyl phenylglycine ester intermediates.12 While the Petasis
reaction worked on simple substrates, the reaction was not general
enough for a broadly useful platform in late-stage functionalization.
Finally, we investigated reactions that would be chemoselective
based on the acidity of the N-H bond of secondary sulfonamides.
We found that Mitsunobu reactions of secondary sulfonamides
with ethyl mandelate proceeded smoothly to form N-sulfonyl
phenylglycine ester intermediates.13 Unfortunately, the subsequent
elimination was complicated due to the byproducts of the
Mitsunobu Reaction. Therefore, to simplify the C-N bond forming
step and avoid the hydrazine byproducts of the Mitsunobu reaction,
the activated phosphonium intermediate was generated from ethyl
benzoylformate and tris(dimethylamino)phosphine (Figure 3B).14
Scheme 1. Initial survey of scope for N-S cleavage with
simple secondary sulfonamides
R'
N
O
S
O
i) PhC(O)CO2Et, P(NMe2)3
rt, 30 min
R'
NH
+
R
S
R
CO2Et
O-
O
1
ii) BTMG, 65 °C, 4 h
Ph
2
3
O
S
O
S
O
S
O
S
Ph
NH
alkyl
NH
Ph
NH
alkyl
NH
Ph
Ph
alkyl
alkyl
O
O
O
O
1a 99%
,
1b 95%
,
1c 98%
,
1d 95%
,
aPercent conversion of 1 to 2 + 3 based on HPLC area percent at
210 nm for reactions carried out on 1.0 mmol scale. Alkyl =
CH2CH2Ph. For experimental details, see the Supporting
Information.
Having validated the methodology on simple substrates, we then
applied this N-S cleavage concept towards late-stage
diversification. First, we carried out reactions on drug-like
We found that secondary sulfonamides react rapidly and
chemoselectively with the combination of ethyl benzoylformate
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compounds containing secondary sulfonamides in which the
sulfinate species generated in-situ from the reductive cleavage
process react with exogenous electrophiles to form a variety of
S(VI) functional groups, such as sulfones, as shown in Scheme 3.
The mild conditions are highlighted by the site-selective
modification of sulfonamides in the presence of free amines,
secondary amides, cyano groups, halides, and diverse heterocyclic
functional groups.
1
2
3
4
5
6
7
8
nitrogen component is complex. The standard conditions were
applied to sulfonamides containing ketone, ester, triflate, halide,
indole N-H, unprotected aminopyrimidine, secondary amide, and
various heterocyclic functional groups. In all cases, the reductive
cleavage process was chemoselective for reactions at secondary
sulfonamides due to the acidity of the N-H bonds. Despite the broad
generality, it should be noted that the acidity-controlled alkylation
did present issues with substrates containing acidic functionality,
namely carboxylic acids and electron-poor phenols. The imine
generated in the reductive process was readily cleaved with
aqueous hydroxylamine and the amine could be functionalized in-
situ. As shown in Scheme 2, this sequence allows for the facile
interconversion of sulfonamides and the transformation of
sulfonamides to amides.
Scheme 3. Late-Stage Modification of Secondary
Sulfonamides Containing Complex Sulfonyl Fragments
i) PhC(O)CO2Et, P(NMe2)3
rt, 30 min
9
O
S
O
1
O
S
O
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ii) BTMG, 65°C, 2 h
NH
R'
E
R
R
iii) E+, rt, 1 h
Scheme 2. Late-Stage Modification of Secondary
Sulfonamides Containing Complex Nitrogen Fragments
O
O
F
S
F
S
N
N
F
F
N
N
H
H
i) PhC(O)CO2Et, P(NMe2)3
N
N
rt, 30 min
ii) BTMG, 65°C, 2 h
N
N
O
F
F
R
S
O
1
E
NH
R'
NH
R'
F
F
F
F
iii) NH2OH (aq), rt, 30 min
iv) E+, rt, 1 h
O
O
4
4i, 72%
Me
N
H
Me
O
S
O
Cl
Cl
H
O
O
Me
H2N
N
H2N
N
N
Me
S
S
Br
S
O
Br
O
NH
NH
N
Cl
4j
N
Cl
S
O
O
F
F
, 79%
F
F
H
NH
S
O
NH
O
N
O
Pr
Me
S
CF3
O
4e
Pr
, 84%
S
CF3
S
O
O
O
N
N
N
N
N
O
O
O
O
O
O
4k
, 55%
S
S
F3C
NH
F3C
NH
O
O
OMe
N
O
S
O
O
S
O
S
S
O
O
S
N
Me
H
N
N
N
N
MeO
Cl
Cl
O
H
H
b
O
O
4l
, 71% (77%)
Cl
Cl
4f
, 75%
F
O
O
F
S
F
S
O
HN
O
HN
HN
S
N
N
N
S
O
F
O
N
N
N
N
N
O
O
O
N
O
N
OMe
OMe
4m
, 38%
O
O
aIsolated yields shown for reactions carried out with 0.5 mmol of
sulfonamide substrate. For experimental details, see the Supporting
Information.bYield in parentheses is for a separate reaction in
which step iii was not carried out, and the sulfinic acid intermediate
was isolated in pure form.
4g
, 61%
Cl
Cl
F
tBu
S
tBu
S
F
F
N
N
H
H
N
Lastly, we demonstrated the application of this method towards
metabolite and labeled compound synthesis, both integral facets of
drug discovery and development.16 In the synthesis of metabolites
or labeled compounds, the direct use of the drug molecule is
generally preferred, as it is usually available and avoids long
synthetic sequences. As depicted in Scheme 4, the complex N-
methylsulfonamide was subjected to the reductive N-S cleavage,
followed by treatment of the crude sulfinate mixture with either
NH4OH and iodine to preapre the des-methylated metabolite, or
CD3NH3Cl and iodine to prepare the CD3-labeled compound. The
labeled compound was prepared in a one-pot process on 3-gram
scale and led to net conversion of the CH3 group to a CD3 group.
Notably, the methylamino group cleaved in the first step remained
N
Ph
S
F
O
O
O
N
N
N
NH2
NH2
4h
, 66%
N
aIsolated yields shown for reactions carried out with 0.5 mmol of
sulfonamide substrate. For experimental details, see the Supporting
Information.
Similar to the modification of the nitrogen component of
secondary sulfonamides, this methodology was successfully
applied to the late-stage functionalization of several secondary
sulfonamides containing complex sulfonyl pieces. The resultant
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sequestered as an imine and did not interfere in the reactions to
reform sulfonamides.
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Modern Drug Research. In Molecular Modification in Drug Design;
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G. A.; LaVoie, E. J. Bioisosterism: A Rational Approach in Drug Design.
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1
2
3
Scheme 4. Late-Stage Metabolite Synthesis and Isotopic
Labeling through N-S Cleavage and Reconstitution
4
5
6
7
8
9
2. (a) Lesch, J. E. The First Miracle Drugs: How the Sulfa Drugs
Transformed Medicine; Oxford University Press, 2006. (b) Li, J. J.; Corey,
E. J. Drug Discovery. Practices, Processes, and Perspectives; Wiley, 2013.
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Analysis of the Elemental Composition of U.S. FDA Approved Drug
Architectures. J. Med. Chem. 2014, 57, 9764. (d) Ilardi, E. A.; Vitaku, E.;
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Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery.
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of US FDAApproved Drugs Containing Sulfur Atoms Top. Curr. Chem.
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3. (a) Wuts, P. G. M Protection for the Amino Group. In Greene’s
Protective Groups in Organic Synthesis, 5th ed.; John Wiley & Sons:
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5. For modern alternaive 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.
O
F
S
P(NMe2)3
CO2Et
O
O
O
O
N
F
N
H
F
Ph
N
N
F
N
H
N
N
F3C
N
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
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CH3
N
F3C
O
Ph
CO2Et
NH
CH3
O
O
S
-O
F
F
N
N
H
N
NH
3, I2
N
F3C
Metabolite Synthesis
, 77% isolated yield
O
S
NH2
5i
O
Synthesis
of
Aryl
Sulfonamides
via
PalladiumCatalyzed
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
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Bagley, S. W.; Mankad, N. P.; Bergman, R. G.; Mascitti, V.; Toste, F. D.
Application of Fundamental Organometallic Chemistry to the Development
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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 DABSO: A Redox-Neutral,
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F
S
N
F
N
H
N
D3C NH Cl
, I2
3
N
F3C
Labeled Compound Synthesis
6i, 3 gram scale
O
NH
CD3
O
73% isolated yield
>99% isotopic purity
aIsolated yields shown. For experimental details, see the
Supporting Information
In summary, we have developed a general platform for the late-
stage functionalization of secondary sulfonamides as part of our
program on upgrading sulfonamides from terminal functional
groups to synthetic handles. The exceptional functional group
tolerance, use of simple reagents in air, and the ability to carry out
unprecedented transformations on prevalent sulfonamide
functional groups makes this a powerful tool for complex molecule
functionalization.
6. Patents WO2012/101239, US2013/85144, WO2014/16434
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The medicinal chemist’s toolbox for late stage functionalization of drug-
like molecules. Chem. Soc. Rev. 2016, 45, 546−576.
8. a) Fier, P. S.; Maloney, K. M. NHC-Catalyzed Deamination of
Primary Sulfonamides: A Platform for Late-Stage Functionalization. J. Am.
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published: Gomez-Palomino, A.; Cornella, J. Selective Late-Stage Sulfonyl
Chloride Formation from Sulfonamides Enabled by Pyry-BF4 Angew.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: patrick.fier@merck.com
*E-mail: kevin_maloney@merck.com
ACKNOWLEDGMENT
We would like to thank our colleagues L. C. Campeau, Neil
Strotman, Ben Sherry, and J. J. Yin for their helpful feedback. S.K.
would like to thank the Merck internship program.
REFERENCES
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Journal of the American Chemical Society
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Insert Table of Contents artwork here
Change identity of R' group
Conversion of SO2 to CO
O
O
S
R''
NH
R'
R
P(III)
R
N
O
H
O
R'
NH
R
S
O
O
S
R'
NH
O
P(V)
R
S
R'
R
O
O
Deletion of NH
Change identity of R group
Unknown transformations for late-stage functionalization
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