Organic Letters
Letter
The classical synthesis of primary sulfonamides involves the
reaction of activated sulfonyl electrophiles, usually sulfonyl
chlorides, with ammonia, or an ammonia surrogate with a
subsequent deprotection step (Scheme 1a). Although this
(HOSA, Scheme 1c).26 This strategy is limited by the
explosive risk of such reagents.27 Sulfinate salts can also
undergo halogenation followed by the addition of an ammonia
source.28 The low commercial availability of sulfinate salts is an
issue, although new methods have further expanded access to
these compounds, including by C−H activation (via
thianthrenium salts and Pd catalysis)29 and using inexpensive
nickel catalysts with DABSO and boronic acids.30 Useful
oxidative syntheses of primary sulfonamides from thiols have
also been developed,31 notably including a recent paper by Bull
using iodobenzene diacetate and ammonium carbonate as an
ammonia equivalent (Scheme 1d).32 Disadvantages of these
methods include the use of thiols and lack of tolerance of some
functional groups such as amines and thioethers to strong
oxidants. Considering all these factors, a bespoke approach to
primary sulfonamides starting from widely available alkyl and
aryl halides would likely be welcomed by the synthetic
community; the work reported in this Letter describes such an
approach (Scheme 1e).
Scheme 1. Common Methods to Prepare Primary
Sulfonamides: (a) Reaction of Sulfonyl Chlorides with
̈
Ammonia or Ammonia Surrogates; (b) Noel’s
Electrochemical Approach; (c) Reaction of Sulfinates with
+
NH2 Sources; (d) Chemical Oxidation−Amination of
Thiols; (e) Our Alkyl/Aryl Halide Based Approach
Our group has pioneered the use of sulfinylamine33 reagents
(R(O)−NSO) for the preparation of synthetically and
medicinally valuable high oxidation state sulfur compounds.
Using organometallic nucleophiles generally derived from alkyl
and aryl bromides, such as Grignard and organolithium
reagents, we have designed one-pot syntheses of sulfonimida-
mides,34 sulfilimines (precursors to sulfondiimines),35 and
sulfoximines.36 During our investigation into the synthesis of
sulfoximines we developed a new class of sulfinylamines, N-
sulfinyl-O-arylhydroxylamines, containing a cleavable N−O
bond. When reacted with organometallic reagents at −78 °C,
these compounds form highly electrophilic sulfinyl nitrenes;37
these reactive intermediates could then be reacted with a
second carbon nucleophile, or amine, to give sulfoximines or
sulfonimidamides, respectively. Our initial intention at the
outset of this project was to develop a variant of this reaction
which could be performed at noncryogenic temperatures. We
therefore set out to design a reagent with a stronger N−O
bond, reasoning that this would raise the barrier to N−O
cleavage. We decided that replacing the aryl group on oxygen
with an electron-releasing tert-butyl group would be optimal.
The synthesis of this reagent, N-sulfinyl-O-(tert-butyl)-
hydroxylamine (t-BuONSO, 1), was conveniently achieved in
one step using commercially available O-tert-butylhydroxyl-
amine hydrochloride, thionyl chloride, and triethylamine, with
a simple distillation (under reduced pressure) delivering the
pure reagent 1 (Scheme 2a). The reaction was scalable and
could be performed on 200 mmol scale to afford 15 g of t-
BuONSO, as a stable, colorless nonviscous liquid.38
reaction is still widely used where the appropriate sulfonyl
chloride is easily available, it has some notable drawbacks.
Sulfonyl chlorides are moisture-sensitive and are not always
available due to limitations in both functional group tolerance
and available substitution patterns inherent in their synthesis
via harshly acidic and oxidizing chlorosulfonation conditions.22
Furthermore, the handling of gaseous ammonia can be
challenging, while the use of solid or liquid ammonia
surrogates necessarily leads to losses in atom and step
economy. For these reasons, the development of alternative
methods for sulfonamide synthesis in general, and primary
sulfonamide synthesis in particular, has received much
attention in recent years.
Two recent papers have redefined the state of the art of
sulfonamide synthesis. A copper-catalyzed direct synthesis of
sulfonamides23 from the SO2 surrogate DABSO,24 boronic
acids, and amines by our laboratory showed broad scope and
functional group tolerance, but failed when ammonia was used.
When we reacted t-BuONSO 1 with the commercially
available Grignard reagent 4-fluorophenylmagnesium bromide
and morpholine, in sequence at −78 °C, our standard reaction
conditions for the preparation of sulfonimidamides using our
original BiPhONSO reagent, we were frustrated to observe
only 10% of the sulfonimidamide product in the crude reaction
mixture (Scheme 2b). Similar reactions using two organo-
metallic reagents as nucleophiles did not result in appreciable
sulfoximine formation. Curiously, precipitation of a white solid
was observed in both reactions when deuterated chloroform
was added to the crude sample after aqueous workup. The
solid did, however, dissolve in deuterated acetone, and we were
An elegant electrochemical synthesis of sulfonamides using
25
̈
thiols and amines from the Noel group did succeed in using
ammonia (Scheme 1b). However, only one example was
shown on a simple aryl scaffold, and electrochemistry has not
yet been widely adopted in academic synthetic chemistry
laboratories. The use of thiols as starting materials can also be
problematic due to their malodorous nature and tendency to
oxidize in air to form disulfides. Primary sulfonamides may also
be prepared from sulfinate salts by reaction with an
electrophilic nitrogen source such as O-mesitylenesulfonyl-
hydroxylamine (MSH) or hydroxylamine-O-sulfonic acid
1
surprised to find the H NMR spectra matched that of the
primary sulfonamide 2a. Indeed, when the reaction was
performed without the addition of a second nucleophile,
B
Org. Lett. XXXX, XXX, XXX−XXX
Davies, Thomas Q.
