Sulfonamide formation from sodium sulfinates and amines or ammonia under metal-free conditions at ambient temperature

Article abstract of DOI:10.1039/c4gc02236j

A novel, practical and highly efficient method for the construction of a variety of sulfonamides mediated by I₂ was demonstrated. The reaction proceeds readily at room temperature using a variety of sodium sulfinates and amines or ammonia in water in a metal-, base-, ligand-, or additive-free protocol. Primary, secondary and tertiary sulfonamides were obtained in good to excellent yields with a broad range of functional group tolerability. This journal is

Full text of DOI:10.1039/c4gc02236j

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Sulfonamides Formation from Sodium Sulfinates and
Amines or Ammonia under Metal-Free Conditions at
Ambient Temperature
Cite this: DOI: 10.1039/x0xx00000x
Kai Yang,a Miaolin Ke,b Yuanguang Linb and Qiuling Song*,a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
time, poor functional group tolerability and transition metal usage
which might cause pollution in the final product and so on.
Therefore development of a general, practical and efficient method
for the construction of sulfonamides under mild conditions is still a
challenge and highly desirable.
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novel, practical and highly efficient method for the
construction of a variety of sulfonamides mediated by I2 was
demonstrated. The reaction proceeds readily at room
temperature using a variety of sodium sulfinates and amines or
ammonia in water in a metal-, base-, ligand-, or additive-free
protocol. Primary, secondary and tertiary sulfonamides were
obtained in good to excellent yields with a broad range of
functional group tolerability.
OMe O
Celecoxib
Glibenclamide
O
S
O
N
N
O
O
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N
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Dofetillide
Sulfonamides are a common structural motif in biologically
active compounds and pharmaceutical interesting molecules, owing
to their well-known anticonvulsant, antibacterial, anticancer,
antitumor, anti-inflammatory and HIV protease inhibitory activities
Figure 1. Drugs with sulfonamide structure motif
Herein, we report
a
transition-metal-free sulfonamides
formation between sodium sulfinates and amines mediated by I2 at
(Figure 1).[1-7] In addition, sulfonamides are a good type amino room temperature. There are several obvious advances of the present
protection group due to their easily removal property.[8,9] method: 1) Cheap and readily available I2 emerges as an efficient
Consequently, many endeavors have been made towards the catalyst and oxidant as well, instead of a transition-metal catalyst,
which is usually quite expensive and is required to be completely
construction of sulfonamides. Traditional method for the formation
of sulfonamides stems from sulfonyl chloride and amino removed from products, particularly during the process of drug
compounds,[10,11] later on transition metal catalyzed alternative synthesis; 2) The reaction shows broad substrate scopes and
method was developed between primary sulfomides and aryl generality: various sodium sulfinates, including aromatic,
halides[12-17] or arylboronic acids.[18] Very recently, Jiang and co-
heteroaromatic or aliphatic ones and numerous amines, such as
workers developed an efficient method to build up sulfonamides aromatic, heteroaromatic or aliphatic, natural occurred amino ester,
between sodium sulfinates and amines via a copper-catalyzed or even aqueous ammomia, are well tolerable under the standard
aerobic oxidative conditions.[19] Kim et. al. reported a mild copper conditions and the desired sulfonamide compounds were obtained at
room temperature in open air smoothly within 3 h. Therefore we
catalyzed Chan-Lam type coupling by using sulfonyl azide and
boronic acids at room temperature.[20] Although great progress has have reasons to believe that pharmaceutical molecules and bioactive
been achieved on the synthesis of sulfonamides, there are still many compounds could be manipulated by this strategy; 3) The I2/EtOH or
drawbacks existing in the current methods, such as hazardous water system is low cost, easily handled and mild with high
efficiency and safety.
starting materials (mutagenic sulfonyl chlorides or precautious-
handling organic azides), harsh reaction conditions, long reaction
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DOI: 10.1039/C4GC02236J
In our previous research, we found that I2 could functionalize as
a surrogate for CuI in the process of acylation of benzothiazoles with
acetophenones.[21] This reaction inspired us, since sulfonamide could
be formed under a copper-catalyzed aerobic oxidative conditions
between sodium sulfinates and amines, we propose that I2 should
replace copper salt, yet just play the same role to the reaction
between sodium sulfinates and amines, thus making the reaction take
place under transition-metal free conditions.
Scheme 1. Overview of the synthetic approach for sulfonamides.
In order to verify the hypothesis, aniline (1a) and sodium
benzenesulfinate (2a) were chosen as the substrates in the model
reaction (Table 1). To our delight, the desired product 3aa was
formed in 60% yield (Table 1, entry 4) with 1 equivalent of I2 in
CH3CN just at room temperature in an open flask! This reaction
condition was much milder than the copper-catalyzed one. Further
oxidant screening revealed that I2 was the superior oxidant to NBS,
NCS, NIS, K2S2O8, DDQ and DTBP (Table 1, entries 1-4, 6-8) , also
better than catalytic amount of I2 with one equivalent of TBHP (70%
in water) (Table 1, entry 5). Solvent effect was also investigated
(Table 1, entries 8-14), and both water and EtOH showed optimal
influence on the reaction and afforded desired products in 73% and
75% yields respectively (Table 1, entries 9 and 14), indicating this
reaction was environmentally benign. Gratifying, shortening the
reaction time from 18 hours to 3 hours did not reduce the efficiency
of the reaction, and 76% of desired product was obtained
correspondingly (Table 1, entry 15). Yet the decreasing on the
amount of I2 to 0.2 equivalents did cause the decreasing on the yield
of desired product from 76% to 23% (Table 1, entries 16 and 17).
Notably, catalytic amount of I2 (20 mol%) with TBHP (70% in
water) did not bring satisfactory yield, only 19% of desired product
was obtained after 18 hours reaction. Based on the above results,
EtOH was the optimal solvent for this reaction and water could be an
alternative one for this transformation. It is well known, both EtOH
and water are environmentally benign solvents and there are many
advantages with EtOH and water as solvent over other organic ones.
The property makes the whole process quite green and sustainable.
Together with mild reaction conditions, the process might be used in
late-stage manipulation of complex molecules.
With the optimized reaction conditions in hand, the substrate
scope of amines were explored firstly (Table 2). As listed in Table 2,
both aromatic amines, such as aniline derivatives and aliphatic
amines worked well under the mild reaction conditions. The
electronic property of the substituents on the aromatic rings of
anilines had some effect on yields, with electron-deficient
substitutions usually giving lower yields of the sulfonamides in
comparison to electron-rich substitutions (Table 2, 3ba-3ja), perhaps
due to a result of lower nucleophilic property of the electron-
deficient ones. Secondary aniline, such as N-methylaniline also
reacted well with sodium benzenesulfinate and gave the
corresponding sulfonamide 3ka, albeit with slightly lower yield. All
aliphatic amines showed good reactivity on this novel
transformation. Notably, both terminal alkyne and alkene
functionalities were tolerable in this reaction (Table 2, 3ra and 3sa)
and provide the feasibility for further structural manipulation.
Interestingly, a bis-sulfonamide 3ta was obtained in 66% yield with
a diamine as substrate. A special aromatic secondary amine,
benzoimidazoles, which reacted with a variety of sulfonamide, was
also applicable in the standard reaction condition to give the desired
products in moderate to good yields (Table 2, 3ua-3ud, 3va).
Remarkably, the natural occurred amino esters, which are bioactive
molecules, were also proven to be compatible with this reaction and
generated the corresponding products in reasonable yields (Table 2,
3wa-3xa), which showed our methods potential application in late
stage modification of complex molecule synthesis.
Table 2. I2 mediated synthesis of sulfonamides from amines 1
and sodium sulfinates (2).[a]
Table 1. Condition Screening.
2 | J. Name., 2012, 00, 1-3
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Table 3. I2 mediated synthesis of sulfonamides from morpholine
(1q) and sodium sulfinates 2.
Intrigued by the above results, we further applied the same
conditions to ammonia in water. Delightfully, primary
benzenesulfonamide was obtained in 75% yield when sodium
benzenesulfinate was interacted with aqueous ammonia under the
standard conditions (Table 4, 4a). Without optimization, numerous
primary sulfonamides were found to be formed through various
sodium sulfinates with ammonia in water in moderate to good yields
under the standard conditions (Table 4)，with the similar substrate
scope as the examples list in Table 3.
The scope of sodium sulfinates was investigated by reacting
with morpholine (1q) under the standard conditions (Table 3). Both
electron-rich and electron-deficient substituents on the aromatic ring
of sodium benzenesulfinates were tolerant under the novel
transformation (Table 3, 3qb-3ql), yet the latter ones usually showed
lower efficiencies than the former ones in term of the isolated yields,
which might be explained by the electron-inductive effect. Different
position of substituents on the aromatic ring of sodium
benzenesulfinates do have effect on the efficiency of the reaction,
with the ortho position having lower yield compared with the meta
and the para position, which might be explained by the steric
hindrance of the ortho position. In Table 3, these phenomena were
clearly shown by compounds 3qj, 3qk and 3ql. 2-Naphthyl sodium
sulfinate was also a good reactant for this reaction (Table 3, 3qm).
Intriguingly, quinolinyl group was survived in the standard
conditions and gave the corresponding product 3qn in 60% yield.
Gratifyingly, this reaction was applicable to aliphatic sodium
sulfinates as well, and cyclopropyl sodium sulfinate was a good
candidate for this novel metal-free reaction with 81% isolated yield
(Table 3, 3qo).
Primary sulfonamide was a type of very useful building blocks
which could be used as starting materials in the cross coupling
reaction for polysubstituted sulfonamide synthesis as well as key
scaffolds in many bioactive molecules and pharmaceutical
compounds. Additionally, this reaction showed a very wide range of
functional groups tolerability and all primary, secondary and tertiary
sulfonamides could be generated under the standard conditions
smoothly. Therefore this is a universal method for the formation of
sulfonamides in a transition-metal-free, ligand-, base- and additive-
free conditions at ambient temperature.
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DOI: 10.1039/C4GC02236J
Table 4. I2 mediated synthesis of sulfonamides from ammonia in
water and sodium sulfinates 2.
Scheme 3. Control experiment
On the basis of the above results, two tentative reaction
mechanisms for this I2-mediated sulfonamide formation were given
in Scheme 4: in path a, amine might be activated in the presence of
iodine to give N-iodoamine 5, which reacted with sodium
benzenesulfinate to give the sulfonamide with the release of HI; or in
path b, sodium benzenesulfinate reacted firstly with I2 to give
benzenesulfonyl iodide 6 which further react with amine to afford
the desired product sulfonamide.
To our delight, this reaction could be easily scaled up to 10
mmol without dramatically losing the efficiency. As shown below,
morpholine (1a) and sodium benzenesulfinate (2a) were interacted
with each other under the standard conditions to generate desired
product 3qa in 70% yield (1.6 gram) (Scheme 2), which might
suggest a potential application in industry.
Scheme 4. Plausible reaction mechanism for sulfonamide
formation
Conclusions
In summary, a highly efficient, practical, and chemoselective
sulfonamides synthesis have been developed. All types of
sulfonamides, such as primary, secondary and tertiary sulfonamides
could be generated in good to excellent yields. Wide substrate scope
compatibility and mild reaction conditions plus transition-metal-,
base-, ligand- and additive-free features recommends that this
method might be applied for the synthesis of bioactive compounds
and medically important compounds, also could be used in late stage
structural manipulation of complex molecules. This method will
widely expand the utility of sodium sulfinates in organic synthesis.
Scheme 2. Scale up reaction with morpholine (1q) and sodium
benzenesulfinate (2a).
Control experiments were performed in order to understand and
gain insight into the mechanism (Scheme 3). A radical scavenger
BHT (2,6-di-tert-butyl-4-methylphenol) was added to the reaction
system, 65% of desired product 3aa was obtained (Scheme 3, eq. 1),
almost no significant influence on the reaction. Furthermore, no
radical intermediate was trapped by radical inhibitor TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl). These two reactions
suggested that a radical reaction might not be involved in the
reaction. N-iodomorpholine (1q’) and 4-MeObenzene sulfinyl iodide
(2b’) were prepared according to the literature,[22-23] and they were
used as the substrates with 4-MeObenzene sodium sulfinate and
morpholine correspondingly under the standard conditions,
remarkably, the desired product was obtained in 85% and 53%
respectively. These two reactions suggested that 1q’ and 2b’ might
be the key intermediates for this novel and sustainable reactions.
Notes and references
a
Institute of Next Generation Matter Transformation, College of
Chemical Engineering, Huaqiao University.
b
College of Materials Science & Engineering, Huaqiao University, 668
Jimei Blvd, Xiamen, Fujian, 361021, P. R. China.
Electronic Supplementary Information (ESI) available: H NMR and 13C
1
NMR analysis for all products . See DOI: 10.1039/c000000x/
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DOI: 10.1039/C4GC02236J
Sulfonamide Formation from Sodium Sulfinates and Amines or
Ammonia under Metal-Free Conditions at Ambient
Temperature
Kai Yang,a Miaolin Ke,b Yuanguang Linb and Qiuling Song*,a
a Institute of Next Generation Matter Transformation, College of Chemical Engineering,
Huaqiao University
b College of Materials Science & Engineering, Huaqiao University, 668 Jimei Blvd, Xiamen,
Fujian, 361021, P. R. China
fax:86-592-6162990; email: qsong@hqu.edu.cn
Abstract
A practical and highly efficient method for the construction of a variety of sulfonamides
mediated by I2 was demonstrated. The reaction proceeds readily at room temperature using a
variety of sodium sulfinates and amines or ammonia in water in a metal-, base-, ligand-, or
additive-free protocol. Primary, secondary and tertiary sulfonamides were obtained in good to
excellent yields with a broad range of substrates tolerability.