Selective Late-Stage Sulfonyl Chloride Formation from Sulfonamides Enabled by Pyry-BF4

Article abstract of DOI:10.1002/anie.201910895

Reported here is a simple and practical functionalization of primary sulfonamides, by means of a pyrylium salt (Pyry-BF₄), with nucleophiles. This simple reagent activates the poorly nucleophilic NH₂ group in a sulfonamide, enabling the formation of one of the best electrophiles in organic synthesis: a sulfonyl chloride. Because of the variety of primary sulfonamides in pharmaceutical contexts, special attention has been focused on the direct conversion of densely functionalized primary sulfonamides by a late-stage formation of the corresponding sulfonyl chloride. A variety of nucleophiles could be engaged in this transformation, thus permitting the synthesis of complex sulfonamides, sulfonates, sulfides, sulfonyl fluorides, and sulfonic acids. The mild reaction conditions and the high selectivity of Pyry-BF₄ towards NH₂ groups permit the formation of sulfonyl chlorides in a late-stage fashion, tolerating a preponderance of sensitive functionalities.

Full text of DOI:10.1002/anie.201910895

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Accepted Article
Title: Selective Late-Stage Sulfonyl Chloride Formation from
Sulfonamides Enabled by Pyry-BF4
Authors: Alejandro Gómez-Palomino and Josep Cornella
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10.1002/anie.201910895
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Selective Late-Stage Sulfonyl Chloride Formation from
Sulfonamides Enabled by Pyry-BF4
Alejandro Gómez-Palomino[a] and Josep Cornella[a]*
Abstract: Here we report a simple and practical functionalization of
primary sulfonamides by means of a pyrylium salt (Pyry-BF4) with
nucleophiles. This simple reagent is capable of activating the poorly
nucleophilic NH2 group in a sulfonamide thus enabling the formation
of one of the best electrophiles in organic synthesis: a sulfonyl
chloride. Due to the great variety of primary sulfonamides in
pharmaceutical contexts, special attention has been placed for the
direct conversion of densely functionalized primary sulfonamides
through a late-stage formation of the corresponding sulfonyl chloride.
A variety of nucleophiles could be engaged in this transformation
thus permitting the synthesis of complex sulfonamides, sulfonates,
sulfides, sulfonyl fluorides or sulfonic acids, as highlighted with the
>45 examples provided. The mild reaction conditions and the high
selectivity of Pyry-BF4 towards NH2 groups permit the formation of
sulfonyl chlorides in a late-stage fashion, tolerating a preponderance
of sensitive functionalities.
use when more complex targets are required. As a result, the
powerful reactivity of sulfonyl chlorides has only been harvested
in earlier stages of medicinal chemistry campaigns, resulting in
virtually inexistent methods for late-stage functionalization
contexts.
Since the seminal report of the antibacterial activity of
sulfonamides from the collaborative effort by Domagk, Mietzsch
and Klarer in 1932 at I. G. Farbenindustrie,[1] sulfonamide-based
drugs represented a turning point in the history of medicine and
became of capital importance for the treatment of a great variety
of diseases.[2] With Prontosil as the flagship compound, the
sulfonamide linkage is still an ever-present motif in a large
variety of biologically relevant compounds (Figure 1).[3] For this
reason, intense efforts have been placed to develop efficient
strategies for their synthesis and a plethora of methods have
appeared in the literature.[4] However, a closer analysis of these
precedents reveals that primary sulfonamide moiety has always
been conceived as an endgame point, rather than a modifiable
handle for derivatization. Based on the importance of sulfur-
containing motifs for drug discovery and their large presence in
many medicinal chemistry libraries,[2] we envisaged that primary
sulfonamides could be repurposed as powerful coupling partners
in drug discovery if methods to convert the NH2 into other
functionalities would exist. Indeed, the traditional and most
common strategy for the formation of complex sulfonamides has
Figure 1. The sulfonamide bond in medicinally relevant compounds
Recently, our group has started a program to selectively
activate amino groups by means of pyrylium salts.[9] In this line,
we have reported on the synthesis of a simple and practical
reagent (Pyry-BF4, 1) and its high reactivity towards NH2 groups
in heteroaromatic amines thus priming them for SNAr reaction to
forge a plethora of new C‒Heteroatom bonds (Figure 2B).
Based on this precedent, we envisaged that this simple reagent
could engage with primary sulfonamides in a similar fashion and
hence, prime the amino group for nucleophilic substitution.
Recently, Fier and Maloney reported an elegant method to
convert primary sulfonamides into the corresponding sulfinate
salt under N-heterocyclic carbene catalysis (Figure 2C, left).[10]
This work permits the late-stage modification of complex primary
sulfonamides in a practical and straightforward manner. Despite
the tremendous power of this transformation, the subsequent
modification of the sulfinate is restricted to the use of
electrophiles, which could potentially be a hurdle when complex
amines or alcohols are the desired coupling moiety. Therefore,
we envisaged that a complementary strategy based on an
umpolung reactivity, where the sulfonamide becomes the
electrophile and reacts selectively with a nucleophile would be
highly versatile and desirable. Herein we report on the ability of
Pyry-BF4 in combination with simple and cheap MgCl2 towards
the activation of poorly nucleophilic primary sulfonamides and
the subsequent formation of the corresponding sulfonyl chloride
(Figure 2C, right). The mild conditions and the high
chemoselectivity permit the formation of sulfonyl chlorides in
densely functionalized molecules which contain a wide variety of
been the reaction between
a sulfonyl chloride and the
corresponding amine.[5] Since many years, sulfonyl chlorides
have become extremely powerful electrophiles, permitting a
great variety of nucleophiles to be engaged in fast and selective
couplings.[6] Although alternative methodologies have been
reported,[7] the synthesis of sulfonyl chlorides has been largely
dominated by the conversion of sulfonic acids through
dehydration by the use of highly oxidizing and unselective
reagents namely POCl3, SO2Cl2 and derivatives thereof (Figure
2A).[8] Yet, the low chemoselectivity and the low functional group
compatibility of these reagents have restricted its widespread
sensible functionalities. With this method,
a plethora of
nucleophiles including drug and agrochemicals could efficiently
be coupled in a late-stage functionalization fashion, thus and
expanding the palette of opportunities for drug discovery.
[a]
A. Gómez-Palomino and J. Cornella
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
Mülheim an der Ruhr, 45470, Germany.
E-mail: cornella@kofo.mpg.de (J.C.)
Supporting information for this article is given via a link at the end of
the document.
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sulfonamides. In this case, smooth conversion to the
corresponding acid or sulfonyl chloride was obtained
independently of the sterics and electronics on the alkyl groups
(13-18). In an attempt to trap the intermediate of the
condensation, tert-butylsulfonamide was reacted with 1 in the
absence of MgCl2 in CD3OD. Indeed, a 65% of sulfonate product
19 was obtained after 3 h of reaction thus highlighting the ability
of mildly nucleophilic oxygenated compounds to outcompete
sulfonic acid formation. Although the use of a primary alcohol as
solvent affords the corresponding sulfonate, attempts to reduce
the amount of ROH in solution resulted in almost exclusive
formation of sulfonic acid.[11]
Figure 2. (A) Synthetic approaches to sulfonyl chlorides; (B) Prior work on the
application of Pyry-BF4 in SNAr with aminoheterocycles; (C) State-of-the-art of
primary sulfonamide modification: electrophiles versus nucleophiles as
coupling partners.
To explore the reactivity of 1 with primary sulfonamides,
tosylsulfonamide (2) was chosen as a model substrate (Table
1A). An initial reaction between 1 and 2 in BuOH revealed the
Table 1. (A) Initial discovery. (B) Scope of the conversion of primary
sulfonamides to sulfonyl chlorides, sulfonic acids and sulfonates. Reaction
conditions: sulfonamide (1.00 equiv.), Pyry-BF4 (1.10 – 1.30 equiv.), with or
without MgCl2 (2.05 equiv.) in tBuOH at 60 °C for 3 h. a Reaction carried out in
CD3OD without MgCl2.
t
formation of the corresponding sulfonic acid (3) in quantitative
yields (Table 1A). We envisaged that such interesting hydration
could proceed through an initial condensation of 1 and the
amino group of 2, with concomitant formation of one molecule of
H2O. The activated sulfonyl group is hence reactive enough to
permit the attack of H2O to finally deliver the sulfonic acid. At this
point, we speculated that the presence of a mildly nucleophilic
chloride source could engage with the sulfonyl intermediate and
override the formation of the sulfonic acid. Indeed, if the
deaminative reaction is performed in the presence of MgCl2,
quantitative yields of p-toluensulfonyl chloride (4) were obtained
(Table 1A). The simplicity of the reaction setup is exemplified by
carrying the reaction without any precautions for air-exclusion or
water sensitivity. Having a practical protocol in hand, we
explored the effect of the electronics and sterics on the
sulfonamide moiety both in the hydration reaction and in the
formation of sulfonyl chlorides. As shown in Table 1, ortho-,
meta- or para-substitution did not affect the reactivity and
delivered the sulfonyl chloride and the acid in almost quantitative
yields in all cases (5-12, Table 1B). The presence of
electrondeficient groups in the aryl ring of the sulfonamide,
afforded lower yields both of sulfonic acid and sulfonyl chloride
(5 and 6), suggesting that the lone pair of the NH2 group in these
cases is even less nucleophilic and condensation with 1 is
slower. We next turned our attention to the use of simple alkyl
The use of simple reagents and mild conditions to form
sulfonyl chlorides led us to hypothesize that a wide variety of
functional groups could potentially be tolerated. In this sense, we
speculated that this protocol could serve as an excellent tool for
providing sulfonyl chlorides in late-stage functionalization
contexts were functional group compatibility is essential. To this
end, we explored a variety of complex drug-like derivatives
bearing primary sulfonamides in their structure (Table 2).
Gratifyingly, the pyrazole derivative celecoxib was smoothly
converted to the corresponding sulfonyl chloride in 77% isolated
yield after 3 h at 60 °C (20). A sulfonamide bearing a
trifluoromethyl ketone and an amide in their structure smoothly
reacted to afford 77% of sulfonyl chloride (21). Despite the
presence of a secondary amine, an ester and furan, furosemide
could successfully be modified and high yields of the sulfonyl
chloride were obtained (22). The highly chelating precursor to
glibenclamide (diabetes type-II) also afforded good yields (23). A
sulfonamido-urea derivative bearing an aryl bromide smoothly
reacted under the optimized conditions (76%, 24). Compounds
bearing the medicinally relevant trifluoromethoxy group (OCF3)
were also amenable for sulfonyl chloride formation (25). The
protocol boded well with the presence of unprotected alcohols
as exemplified by the good yields obtained of compound 26
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(83%). Gratifyingly, free carboxylic acids were also compatible
with these reaction conditions, affording 69% of sulfonyl chloride
(27). N-Boc protected anilines also posed no difficulties in
forging the sulfonyl chloride (62%, 28). Oryzalin, a microtubule
disruptor herbicide bearing a tertiary amine, smoothly converted
the sulfamino group into the corresponding sulfonyl chloride
(85%, 29). Alkyl sulfonamides were also amenable to sulfonyl
chloride formation as exemplified by (1S)-10-camphor
sulfonamide, which could successfully be converted into the
corresponding sulfonyl chloride (30). Not surprisingly, when the
sulfonamide compound bears an unprotected amine in their
structure, competition for condensation with 1 occurs, thus
preventing sulfonyl chloride formation (31). This result highlights
one of the main limitations of this protocol. It is important to
mention that the mild conditions of this method for the synthesis
of sulfonyl chlorides from sulfonamides are in stark contrast to
the methods reported utilizing POCl3 and sulfonic acids as
starting materials. As a result, the reactions are plagued with
side reactions resulting in low-selectivities and limited functional
group tolerance. For example, the use of POCl3 in the presence
of simple amides, lactames or ureas leads to Vilsmeyer acyl
chloride derivatives and subsequent side-reactions occur.[12]
sulfonamide bonds, capitalizing on the high reactivity and facile
coupling of sulfonyl chlorides with amines (Table 3). The
biologically active furosemide could be rapidly converted to the
corresponding sulfonyl chloride, and further modified with
complex nucleophiles in a simple one-pot operation (32-35). To
provide medicinally relevant examples, we decided to explore
even more complex nucleophiles as potential coupling partners
in sulfonamide or sulfonate bond formation. To this end, we
turned our attention to biologically active compounds bearing
various functional groups embedded in their structure. In this
sense, furosemide could be coupled with the polycyclic
antidepressant amoxapine in excellent yields (36). Celecoxib
was also successfully coupled with a variety of primary and
secondary amines, affording excellent yields of the
corresponding sulfonamides over two steps (37-42).
Pharmacologically relevant and highly functionalized molecules
such as paroxetine bearing a benzodioxole (86%, 43) or
sitagliptin bearing two Lewis-basic nitrogen atoms (70%, 44)
were both amenable for sulfonamide linkage with celecoxib.
When the glibenclamide precursor was subjected to coupling
with warfarin, an anticoagulant drug, a 67% yield of the sulfonate
linkage was obtained (45). On the other hand, sulfonamide
linkage between the glibenclamide precursor and duloxetine
proceeded in
a 75% yield (46). Other complex primary
sulfonamides were also compatible in the sulfonamide bond
formation via this simple two-step process and through the
parent sulfonyl chloride as exemplified by 47, 48 and 49. It is
important to mention that the yields reported in Table 3 are over
two-steps, starting from the corresponding primary sulfonamide.
As mentioned in Table 1, when the reaction of a primary
sulfonamide and 1 was carried out in the presence of a primary
or secondary alcohol,
a sulfonate linkage was obtained.
Capitalizing on this reactivity, the complex antipsychotic (±)-
sulpiride bearing a tertiary amine reacted similarly and afforded
excellent yields of methyl sulfonate (90%, 50). In a similar
manner, the diuretic and anti-edema hydrochlorothiazide bearing
a cyclic secondary sulfonamide and a secondary amine in their
core posed no difficulties for the obtention of the ethyl sulfonate
when the reaction was carried in EtOH (73%, 51).
Table 2. Late-stage conversion of drug-like compounds bearing primary
sulfonamides into sulfonyl chlorides. Isolated yields. Sulfonamide (1.00 equiv.),
t
a
1 (2.00 equiv.), MgCl2 (2.55 equiv.), BuOH (0.1 M) at 60 °C for 3 – 5 h.
Addiitional 2.00 equiv. of 1 were added after 3 h.
Having established a protocol for synthesizing highly versatile
and electrophilic sulfonyl chlorides from various complex
molecules, selective diversification of these entities is within
reach in
a facile and straightforward fashion. With the
importance of complex sulfonamide linkages in drug
discovery,[2],[3] we initially investigated the possibility of forging
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primary sulfonamides. The reaction capitalizes on the use of a
simple pyryilium reagent (Pyry-BF4, 1) as activating agent and
MgCl2 as the chloride source. The mild conditions and the
tolerance to a wide variety of functional groups permit the
derivatization of complex sulfonamides, whose diversification
would be troublesome with other methods available. This report
also highlights the simplicity of stitching together molecules
through the venerable and “old-school” sulfonamide coupling
without recurring to complicated setups or tedious work-arounds.
The method reported herein intends to provide a platform for
rapid derivatization of libraries of complex primary sulfonamides
which are currently conceived as an unreactive end-point. With
this method, those compounds could be revisited and
repurposed to implement further complexity. We strongly believe
that the combined practicality and robustness of this method will
find direct applications in the chemical community.
Figure 3. (A) Derivatization of complex sulfonamides through the parent
sulfonyl chloride; See Supporting Information for conditions in each particular
case; (B) Formation of the sulfonyl chloride at gram-scale.
Table 3. Scope of the pyrylium-medaited sulfonamide coupling. Conditions for
step 1: Sulfonamide (1.00 equiv.), 1 (2.00 equiv.), MgCl2 (2.55 equiv.), tBuOH
(0.1 M) at 60 °C for 3 – 5 h. Conditions for step 2. Nucleophile (1.5 equiv.),
Et3N (2 equiv.) in MeCN or CH2Cl2. See supporting Information for specific
details. Yields of isolated product. a Yield after step 1 without MgCl2 in MeOH
as solvent. b Yield after step 1 without MgCl2 in EtOH as solvent.
Acknowledgements
Having stablished the facile formation of SO2‒NR2 and SO2‒
OR bonds, we intended to extend the protocol to other desirable
linkages derived from complex primary sulfonamides, namely S‒
P bonds and S‒F bonds. In the former, we capitalized on the
report by Li and Zhang,[13] where sulfonyl chlorides were
Financial support for this work was provided by Max-Planck-
Gesellschaft, Max-Planck-Institut für Kohlenforschung and Fonds
der Chemischen Industrie (VCI). We thank Mr. Niski for help in the
preparation of Pyry-BF4 reagent. We also thank Prof. Dr. A. Fürstner
for discussions and generous support.
engaged in
a
reductive phosphorylation. Indeed, when
benzylated furosemide was subjected to our sulfonyl chloride
synthesis followed by Zhang’s protocol, excellent yields of S‒P
bond formation were obtained (Figure 3A, left, 52, 82% over 2
steps). In a similar way, the conversion of sulfonyl chlorides into
more robust sulfonyl fluorides has recently attracted a lot of
attention for its tremendous properties as click reagents.[14]
When the glibenclamide precursor was subjected to the two-step
operation with potassium hydrogen difluoride,[4d],[15] smooth
conversion to the corresponding sulfonyl fluoride was obtained
(Figure 3A right, 53, 76% over 2 steps). To further illustrate the
robustness of the protocol, we scaled-up our sulfonyl chloride
synthesis using benzyl furosemide as starting material. Without
modification of the original protocol, 1 gram of benzyl furosemide
could successfully be converted to 22 without noticeable erosion
on the yield (Figure 3B, 85%).
Keywords: pyrylium • transulfonamidation • sulfonamides • late-
stage functionalization • heterocycles
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COMMUNICATION
Alejandro Gómez-Palomino and Josep
Cornella*
Selective Late-Stage Sulfonyl
Chloride Formation from
Sulfonamides Enabled by Pyry-BF4
The conversion of primary sulfonamides to sulfonyl chlorides has been achieved capitalizing on the use of Pyry-BF4 as
activating reagent. The mild conditions and high selectivity of the protocol permit the presence of a preponderance of
functional groups and the conversion of porrly nucleophilic and unreactive sulfonamides in late-stage functionalization
contexts.
For internal use, please do not delete. Submitted_Manuscript
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