Key words
sulfonamides - palladium catalysis - sulfinates - amines - aryl halides
Some of the features that contribute to sulfonamide groups finding wide application
in pharmaceuticals and agrochemicals include their chemical and metabolic stability,
three-dimensional structure, polarity, and connectivity. These properties have resulted
in sulfonamide-containing molecules being developed as treatments for a broad range
of indications (Figure [1]).[1] Aryl and heteroaryl sulfonamides are prominent amongst these molecules and are usually
prepared from the combination of an aryl (or heteroaryl) sulfonyl chloride and an
amine.[2] This is an effective and reliable process, although it does have limitations. For
example, certain heteroaryl sulfonyl chlorides are unstable, and ready access to the
desired sulfonyl chloride is also needed.
Figure 1 Bioactive sulfonamides
Sulfonyl chlorides are most often prepared from the electrophilic sulfonylation of
an arene, using either [HSO3]+ or [ClSO2]+ synthons as the electrophile.[3] Again, these are well-established reactions, but the products accessible can be
limited by the inherent characteristics of aromatic electrophilic substitution reactions,
in that only certain substrates are sufficiently reactive to undergo the reactions,
and only certain substitution patterns are straightforward to achieve. An alternative
approach relies on the preparation of an aryl thiol, followed by exhaustive oxidation
of the thiol to the corresponding sulfonyl chloride.[4] This approach avoids the limitations imposed by aromatic electrophilic substitution
reactivity, but instead involves the preparation of a potentially odorous thiol and
the use of strong oxidizing conditions, which can often limit functional-group compatibility.
A conceptually different approach involves transforming a pre-activated, nucleophilic
arene into a sulfinate, and then directly converting the sulfinate into the desired
sulfonamide. Such an approach would avoid both electrophilic aromatic substitution
chemistry, and the need to prepare thiol intermediates. By careful choice of the type
of nucleophilic arenes used, it should be possible to employ readily available substrates
such as Grignard reagents, potentially allowing access to different areas of chemical
space to those achievable using sulfonyl chloride chemistry.[5]
[6]
Scheme 1 DABSO-based sulfonamide and sulfone syntheses
We have recently shown that a variety of metal sulfinates can be readily obtained
from the combination of a preformed organometallic reagent and the sulfur dioxide
surrogate (DABCO)(SO2)2,[7] DABSO (Scheme [1, a]).[8] Organolithium, organozinc, and Grignard reagents could all be successfully used.
The metal sulfinates could then be treated with an aqueous solution of an amine and
sodium hypochlorite (bleach) to provide the corresponding sulfonamide.[9] The method is straightforward to perform and was used to prepare a broad range of
sulfonamides, and was also adapted to an array format. However, the need to use a
preformed organometallic reagent does impose limitations on compatible functional
groups, with base-sensitive and highly electrophilic functionalities not being suitable.
To address the limitations imposed by the use of preformed organometallics, we have
also explored methods starting from benign substrates such as aryl halides and then
catalytically generating reactive organometallic intermediates for reaction with SO2-surrogates.[10]
[11] In this context, we have shown that it is possible to access a wide range of aryl
ammonium sulfinates from the combination of aryl iodides and DABSO using palladium(0)
catalysis (Scheme [1, b]).[12] We were able to demonstrate that the ammonium sulfinate intermediates could be converted
into a range of derivatives, mostly sulfone based, but including a single sulfonamide
example. The sulfonamide was obtained by treatment of the ammonium sulfinate with
sulfuryl chloride, followed by addition of an amine. The need to employ sulfuryl chloride,
a notoriously sensitive reagent that requires frequent purification, represents a
significant limitation to this method. Shavnya and Mascitti have described related
chemistry,[13] in which catalytically generated sodium sulfinates are converted into sulfonamides
by treatment with NBS and an amine.[14] In these cases the sulfonamides were obtained in only moderate (37–65%) yields.
Given our convenient and high-yielding sulfonamide synthesis starting from preformed
organometallics, and our success in producing ammonium sulfinates from aryl iodides
using palladium catalysis, we were attracted to the merger of the two methods, to
deliver a general sulfonamide synthesis that uses aryl halides as substrates (Scheme
[1, c]). This Letter documents the successful realization of this goal.
The main issue in merging the two DABSO-based methods was reconciling the different
solvents used in the two transformations; the palladium-catalyzed ammonium sulfinate
formation was performed in isopropanol,[11] while the Grignard addition to DABSO had employed THF as solvent,[8] before addition of an aqueous amine/hypochlorite solution. Using the coupling of
4-iodotoluene, DABSO and morpholine as a test reaction we evaluated different solvent
combinations (Scheme [2]). Pleasingly, the simplest experimental conditions proved effective, as performing
the initial catalytic sulfinate formation in isopropanol and then adding an aqueous
solution of morpholine and sodium hypochlorite directly to this allowed the target
sulfonamide 3a to be isolated in 90% yield. Experiments that removed the isopropanol after the first
step, and then added a second solvent with the amine, were uniformly less successful.
For example, using only water for the second step resulted in <5% of the sulfonamide,
while employing CH2Cl2 delivered the sulfonamide in 73% yield.
Scheme 2 Solvent evaluation for the formation of sulfonamide 3a
We next explored the variation that was possible for the aryl iodide substrate, using
morpholine as the constant amine component (Table [1]). A variety of neutral and electron-donating substituents performed well, with ortho, meta, and para substitution all possible (entries 1–5). The successful inclusion of the para-SMe derivative is notable (entry 5), as the preparation of products featuring S functionality at differing oxidation levels can be challenging using traditional
methods.
Table 1 Scope of the Aryl Iodide Component in One-Pot Sulfonamide Formationa
 
|
|
Entry
|
Arene
|
Yield (%)
|
|
1
|
|
90
|
|
2
|
|
78
|
|
3
|
|
64
|
|
4
|
|
78
|
|
5
|
|
86
|
|
6
|
|
57
|
|
7
|
|
79
|
|
8
|
|
50
|
|
9
|
|
71
|
|
10
|
|
82
|
|
11
|
|
75
|
|
12
|
|
60b
|
|
13
|
|
77
|
|
14
|
|
79
|
a Reaction conditions: Pd(OAc)2 (5 mol%), PAd2Bu (7.5 mol%), DABSO (0.6 equiv), Et3N (3.0 equiv), i-PrOH (0.2 M), 75 °C, 16 h, then morpholine (3 equiv), NaOCl (10.3% aq solution, 2
equiv), r.t., 90 min.
b NCS (2 equiv) used in place of NaOCl.
A para-hydroxyl substituent was successfully incorporated into the sulfonamide product,
providing a good illustration of a substrate that would likely be incompatible with
the Grignard-based method (entry 6). Electron-withdrawing substituents, including
halides, were also efficient substrates, providing sulfonamides in good yields (entries
7–12). Amongst these examples are several substrates that are potentially susceptible
to nucleophilic addition from preformed organometallics (ester, nitrile, ketone; entries
10–12). It should be noted that NCS was employed as the oxidant with the ketone example,
as hypochlorite delivered only a poor yielding reaction. A simple heterocycle (entry
13) and a 1-naphthyl (entry 14) example are also shown to work well.
Variation of the amine component is shown in Scheme [3]. Primary amines generally performed well (4a–d); notable amongst this group are several that feature potentially sensitive functionality,
including an acetal (4b), a trisubstituted alkene (4c), and a pyridyl group (4d). Cyclopropane and cyclobutane-substituted amines delivered the targeted sulfonamides,
although in slightly reduced yields (4e,f). Aniline derivatives could also be successfully employed as substrates (4g,h). Finally, amino acid derivatives could be employed, allowing the corresponding sulfonamides
to be isolated in reasonable yields (4i,j). The reactions to prepare sulfonamides 4d and 4j were both performed on a 4.23 mmol scale (1.0 g of aryl iodide), demonstrating that
synthetically useful scales are not problematic.
In conclusion, we have shown that a variety of aryl sulfonamides can be prepared from
aryl iodides, the SO2 surrogate DABSO, and amines. The aryl iodide substrates first undergo conversion
to an ammonium sulfinate intermediate using a palladium(0)-catalyzed sulfination.
Addition of an aqueous solution of the amine and sodium hypochlorite then provides
the desired sulfonamides. The reactions are straightforward to perform, tolerate a
variety of acidic and electrophilic functional groups on the arene, as well as encompassing
the use of both primary and secondary amines, anilines, and amino acid derivatives.
Scheme 3 Scope of the amine component in one-pot sulfonamide formation. Reagents and conditions: Pd(OAc)2 (5 mol%), PAd2Bu (7.5 mol%), DABSO (0.6 equiv), Et3N (3.0 equiv), i-PrOH (0.2 M), 75 °C, 16 h, then amine (3 equiv), NaOCl (10.3% aq solution, 2 equiv),
0 °C to r.t., 45 min to 3.5 h. a The reaction was performed on 4.23 mmol scale (1.0 g) of starting aryl iodide. b Additional amine (3.0 equiv) and NaOCl (2.0 equiv) added after 2 h. c The solvent from first step was removed and replaced by water. The ee of the methyl
ester derivative was confirmed by chiral HPLC to be >99%.
General Procedure for the Formation of Sulfonamides Using Morpholine, Exemplified
by the Preparation of 4-Tosylmorpholine 3a
An oven-dried glass reaction tube was charged with the relevant aryl iodide (4-iodotoluene)
(87 mg, 0.40 mmol, 1 equiv), DABSO (58 mg, 0.24 mmol), Pd(OAc)2 (5.0 mg, 20.0 μmol, 5 mol%), and CataCXium A (11.0 mg, 31.6 μmol, 7.5 mol%), sealed
with a rubber septum and flushed with nitrogen. Under positive pressure of nitrogen,
Et3N (168 μL, 1.20 mmol, 3 equiv), and anhydrous 2-PrOH (1.5 mL) were added sequentially
through the septum. The reaction mixture was then immersed in a preheated oil bath
at 75 °C for 16 h. The formation of the ammonium sulfinate and the disappearance of
the aryl iodide are easily followed by HPLC. After cooling to r.t., the relevant amine
(morpholine) (104 μL, 1.20 mmol, 3 equiv) and previously titrated 10.31% w/w aq NaOCl
(0.47 mL, 0.80 mmol, 2 equiv) were added sequentially through the septum and stirred
at r.t. for 90 min until consumption of the sulfinate was observed by HPLC. Upon completion,
the reaction mixture was filtered through Celite and the filter washed with acetone
until disappearance of the brown color. The organic solution was then concentrated
and the residue purified by flash chromatography with silica gel under standard eluent
mixtures [typically EtOAc in PE (40–60 °C bp PE)]. The products were dried under high
vacuum and analyzed by NMR and IR spectroscopy and MS.
