A general route to unsubstituted N-aryl and heteroarylaminobenzenesulfonamides

Article abstract of DOI:10.1016/j.tetlet.2011.02.034

Starting from suitably protected 3- and 4-aminobenzenesulfonamides, a practical two-step strategy for the synthesis of unsubstituted N-aryl and heteroarylaminobenzenesulfonamides was devised. Strong bases are tolerated during the N-arylation step. Overall moderate to excellent yields are reported.

Full text of DOI:10.1016/j.tetlet.2011.02.034

Tetrahedron Letters 52 (2011) 1882–1887
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A general route to unsubstituted N-aryl and
heteroarylaminobenzenesulfonamides
Franck Lach a, , Marie-Jeanne Pasquet a, Mylène Chabanne b
⇑
a AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France
b Université de Nantes, UMR 6230 CEISAM CNRS, 2, rue de la Houssinnière, 44322 NANTES Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from suitably protected 3- and 4-aminobenzenesulfonamides, a practical two-step strategy for
the synthesis of unsubstituted N-aryl and heteroarylaminobenzenesulfonamides was devised. Strong
bases are tolerated during the N-arylation step. Overall moderate to excellent yields are reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 January 2011
Revised 3 February 2011
Accepted 7 February 2011
Available online 12 February 2011
Keywords:
Buchwald–Hartwig coupling
Sulfonamide
Paramethoxybenzyl
Protecting group
There are an abundant number of molecules that contain the
sulfonamide moiety. Chiral auxiliaries,1 peptidomimetics,2 modi-
fied oligonucleotides,3 amines synthons,4 and therapeutics5–7 illus-
trate the diverse application for the sulfonamide group. Their
ability to serve as amide surrogates and also as zinc-chelators, with
unique physical properties, has made them ideal functional groups
for the development of pharmaceutical and agricultural agents.
More specifically, unsubstituted N-aryl and heteroarylaminoben-
zenesulfonamide compounds with 3- or 4-aminobenzesulfona-
mide (sulfanilamide) motifs have found extensive applications in
oncology, CNS, diabetes, and cardiovascular disease areas but also
as analgesic and anti-inflammatory compounds8–22 (Fig. 1). In par-
ticular, a whole class of carbonic anhydride inhibitors belongs to
the sulfonamide family.23,24
Inconsistency in the outcome of approaches A and B and lack
of a general process applicable to both aryl and heteroaryl series
independent of the electronic nature of the ring systems
prompted us to consider a strategy based on a direct Buchwald–
Hartwig coupling (following route A) with a suitably protected
sulfonamide. We were confident that this alternative would favor-
ably compete with previous routes while affording higher solubil-
ity of the sulfonamide moiety in organic solvents and preventing
the likely competitive side-reaction of the more acidic sulfon-
amide NH2 group for the C–N bond formation. Although many
methods exist for the manipulation of sulfonamide functional
group, there is a general dearth of protecting groups for this func-
tionality.37 In principle, the benzyl group could serve as a useful
protecting group for primary sulfonamides. However, N,N-diben-
zylsulfonamide dealkylation requires either high pressure hydrog-
enolysis that can be quite problematic,38,39 harsh acidic conditions
leading to variable recovery,11,40 or toxic chromium(III) salts in
the presence of periodic acid.41 Sulfonamides protected as acetim-
idates have also been reported,42,43 but these groups will probably
not survive the basic coupling conditions. Eventually, derivatisa-
tion as dimethylaminoformamidine10,44–49 or N,N-bis-p-meth-
oxybenzylsulfonamide seemed more appropriate to our case.
Although very little is known in the literature about primary sul-
fonamides protection using a bis-PMB strategy,50,51 this option
was retained based on the ease in both the protection and re-
moval steps. Thus, key synthons 7 and 8 were prepared in high
yield by first alkylation of the corresponding 3- and 4-nitroben-
zenesulfonamides 5 and 6 using PMBCl, followed by the nitro-
function reduction step. Conveniently, none of the stages required
any purification (Scheme 2).
Standard protocols to access unsubstituted N-heteroarylamino-
benzenesulfonamides from
1 or 2 include transition metal
catalyzed C–N bond formation, direct H+-catalyzed SNAr or nucle-
ophilic substitution under weakly basic conditions (Scheme 1,
Approach A). These methods mostly refer to activated heterocyclic
partners with a chlorine/idodine atom at C-2 position (e.g., pyrim-
idines,25–28 pyridines,29,30 oxazoles,31 pyrazines14,32) or C-4 (e.g.,
quinolines,33 phtalazines34) and moderate to good yields have been
reported. Alternatively, unsubstituted N-aryl and heteroarylamino-
benzenesulfonamides can be delivered in a variable yield by ‘re-
verse’ Buchwald–Hartwig13,20,22,35,36 or Ullmann-type coupling12
(Scheme 1, Approach B), using commercially available halides 3
and 4 with corresponding anilines or aminoheterocycles.
⇑
Corresponding author. Tel.: +33 3 26 91 5912; fax: +33 3 26 61 6842.
E-mail address: franck.lach@astrazeneca.com (F. Lach).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.034

F. Lach et al. / Tetrahedron Letters 52 (2011) 1882–1887
1883
HO
H
H
N
N
N
N
SO2NH2
N
N
N
CO2Et
N
SO2NH2
S
SO2NH2
SO2NH2
N
HN
N
S
N
H
N
mGluR5a receptor antagonist
(CNS disorders )
Src inhibitor
(oncology/
CDK inhibitor
(oncology)
FBPase inhibitor
(diabetes)
N
cardiovascular)
NO2
N
Cl
Cl
SO2NH2
H2N
N
N
H2N
HN
N
N
NH
N
N
NH
O
F
N
N
H
N
HN
F
CF3
SO2NH2
CO2H
SO2NH2
SO2NH2
SO2NH2
CDK inhibitor
(oncology)
CK2 inhibitor
(oncology)
carbonic anhydrase inhibitor
(antitumor agent)
analgesic agent
anti-inflammatory
agent
Figure 1. Biologically active unsubstituted N-aryl and heteroarylaminobenzenesulfonamides compounds with the 3-aminobenzesulfonamide and sulfanilamide framework.
NH2
NH2
NH-HetAr
NHAr/HetAr
Approach A
HetArX
Conditions
[X= Cl, I]
SNar or Buchwald-Hartwig
coupling
SO2N(PMB)2
SO2NH2
SO2NH2
SO2NH2
9-23a-b
7-8
1: 3-aminobenzenesulfonamide
2: sulfanilamide
Scheme 3. Synthesis of various unsubstituted N-aryl and heteroarylaminobenzene
sulfonamides compounds using our protecting group strategy.
X
NHAr/HetAr
SO2NH2
Approach B
[X= Br, I]
Ar-NH2 or HetArNH2
cess required a simple aqueous workup after N-arylation, followed
by a solvent switch from dioxane to dichloromethane. Final com-
pounds were isolated after adsorption and purification by flash sil-
ica gel chromatography.
"reverse" Buchwald-Hartwig
or Ullmann-type coupling
SO2NH2
3: 3-bromobenzenesulfonamide
4: 4-iodobenzenesulfonamide
Our protocol readily applies to the aryl series and accommo-
dates both electron withdrawing and electron donating substitu-
ents (entries 1–10). Encouragingly, both activated (entries 11–14,
21–25) and unactivated heterocyclic halides (entries 15–20, 26–
32) were efficiently coupled under applied conditions. In the
course of this study, the bidendate chelating ligand Xantphos in
combination with the weak base Cs2CO3 was generally used
because it limits diarylation, increases reductive elimination rate,
and prevents catalyst deactivation by the co-ordination of
pyridine-containing substrates.54 Still, the problematic direct
amination of 3-bromothiophene55 was conducted using the
third-generation monodendate ligand PtBu3 in the presence of
NaOtBu to deliver compounds 27ab in acceptable yield (entries
30 and 31). Following the same trend, poorly reactive substrates,
such as 12, 19, and 28 were easily coupled using the sterically
demanding biaryl monophosphine ligand XPhos (entries 6, 17
and 32), which favors LPd and LPd(Ar)amido intermediates facili-
tating the oxidative addition and reductive elimination steps of
the catalytic cycle. In addition, XPhos in combination with strong
bases (NaOtBu, LiHMDS) was found to promote the chemoselective
N-arylation of the aniline NH2 group (substrate 8) over a primary
amide (entry 10) or a 2-aminopyridine motif (entry 17).
Scheme 1. Synthetic paths to unsubtituted N-aryl and heteroarylaminobenzene-
sulfonamides compounds with 3-aminobenzesulfonamide and 4-aminobenzesulf-
onamide framework.
NO2
NH2
(i-ii)
SO2NH2
SO2N(PMB)2
5: 3-nitrobenzenesulfonamide
6: 4-nitrobenzenesulfonamide
7: 3-amino-N,N-bisPMB-benzenesulfonamide
8: 4-amino-N,N-bisPMB-benzenesulfonamide
Scheme 2. Synthesis of key synthons 7 and 8. Reagents and conditions: (i) PMB-Cl,
K2CO3, NaI, 2-butanone, 80 °C, 16 h, 95%; (ii) H2, PtO2, ethanol, 1 atm, 60 min, quant.
The first step positively compares in terms of yield and cost
with the alternative treatment of commercially available 3- or
4-nitrobenzenesulfonyl chlorides with quite expensive N,N-bis-p-
methoxybenzylamine.52 Key anilines 7 and 8 were reacted next
with a wide range of aryl/heteroaryl halides substrates under
Buchwald conditions (Scheme 3) to deliver after PMB cleavage
the expected compounds 9a–b to 28a–b with moderate to
excellent yield (32–96%, Table 1).53 The optimized telescoped pro-
Eventually, as a proof of concept, we embarked on a direct com-
parison of our process with standard routes A–B. On the one hand,
unsubstituted sulfonamides 1 or 2 were randomly N-arylated
under microwave-heating Buchwald conditions using aryl/hetero-

1884
F. Lach et al. / Tetrahedron Letters 52 (2011) 1882–1887
Table 1
Unsubstituted N-aryl and heteroarylaminobenzenesulfonamides 9–28ab produced via Scheme 3 (with selected comparative examples according to Scheme 1)
Entry
Sulfonamide
Aryl/hetaryl halide
Product
Isolated yield (%)
1
7
65a
Br
N
H
SO2NH2
SO2NH2
9
9a
2
3
8
7
70a (27)e
83a (13)f
N
H
9b
Br
N
H
SO2NH2
10
10a
SO2NH2
4
5
8
8
59a
N
H
10b
SO2NH2
68a
N
H
Br
11
11b
Me2N
Me2N
SO2NH2
6
7
8
7
83b
N
H
Br
12
12b
F
F
45a (11)f
N
SO2NH2
SO2NH2
Br
H
13a
13b
13
F
8
9
8
8
66a
N
H
CF3
CF3
SO2NH2
83a
N
H
Br
14
14b
O
O
SO2NH2
H2N
10
8
94b
H2N
15
N
H
Br
15b
11
12
7
8
71a (17)f
N
Cl
N
N
N
H
SO2NH2
SO2NH2
16
16a
38a
N
H
16b
OMe
N
OMe
13
7
43a
Cl
N
N
H
SO2NH2
17
17a

F. Lach et al. / Tetrahedron Letters 52 (2011) 1882–1887
1885
Table 1 (continued)
Entry
Sulfonamide
Aryl/hetaryl halide
Product
Isolated yield (%)
OMe
SO2NH2
SO2NH2
14
15
8
70a (0)e
N
N
H
17b
Br
H
N
7
50a
N
18
N
N
18a
18b
H
N
16
17
8
8
63a (13)e
SO2NH2
Br
H
N
47c
H2N
N
19
H2N
N
SO2NH2
19b
N
N
60a (18)e
N
18
7
N
Br
N
SO2NH2
SO2NH2
H
20
20a
N
19
20
21
22
8
8
7
8
38a
N
N
H
20b
MeO2C
N
MeO2C
N
SO2NH2
40a
N
N
Br
N
H
21
21b
N
N
N
N
96a (38)e
Cl
N
SO2NH2
SO2NH2
H
22
22a
N
38a
N
N
H
22b
N
SO2NH2
N
N
23
8
80a
N
N
N
Cl
Cl
H
23b
24a
24b
23
24
25
7
8
32a
32a
N
N
N
N
H
SO2NH2
SO2NH2
N
24
N
N
H
Br
H
N
N
N
26
7
80a
25
25a
SO2NH2
(continued on next page)

1886
F. Lach et al. / Tetrahedron Letters 52 (2011) 1882–1887
Table 1 (continued)
Entry
Sulfonamide
Aryl/hetaryl halide
Product
Isolated yield (%)
H
N
N
27
28
8
62a
SO2NH2
25b
Br
H
N
7
86a
N
N
N
SO2NH2
N
N
26a
26
H
N
29
8
7
88a
SO2NH2
26b
N
S
S
27a
SO2NH2
30
31
45d
27
Br
HN
S
27b
8
8
33d (0)e
HN
SO2NH2
SO2NH2
S
N
S
N
32
54b
Cl
N
H
28
28b
a
Method A: (i) 7 or 8 (1 equiv), Ar–Br or HetArX (1 equiv), Cs2CO3 (2 equiv), Pd(OAc)2 (0.02 equiv), Xantphos (0.05 equiv), dioxane, 85 °C, 4 h; (ii) TFA, CH2Cl2, anisole
(3.5 equiv), 25–45 °C.
b
Method B: (i) 8 (1.2 equiv), 12, 15 or 28 (1 equiv), NaOtBu (1.4 equiv), Pd2dba3 (0.04 equiv), XPhos (0.12 equiv), toluene, 100 °C, 16 h; (ii) TFA, CH2Cl2, anisole (3.5 equiv),
25–45 °C.
c
Method C: (i) 8 (1.2 equiv), 19 (1 equiv), LiHMDS (2.8 equiv), Pd2dba3 (0.04 equiv), XPhos (0.12 equiv), dioxane, 85 °C, 16 h; (ii) TFA, CH2Cl2, anisole (3.5 equiv), 25–45 °C.
d
Method D: (i) 7 or 8 (1 equiv), 27 (1.2 equiv), NaOtBu (1.2 equiv), Pd2dba3 (0.02 equiv), PtBu3 (0.04 equiv), toluene, 100 °C; (ii) TFA, CH2Cl2, anisole (3.5 equiv), 25–45 °C.
e
Method E: 1 or 2 (1 equiv), Ar–Br or HetArX (1 equiv), Cs2CO3 (1.2 equiv), Pd(OAc)2 (0.04 equiv), Xantphos (0.08 equiv), DMA, 130–150 °C, 15–30 min, microwave.
Method F: 3 (1 equiv), p-toluidine, p-fluoroaniline or 2-aminopyridine (1 equiv), Cs2CO3 (1.2 equiv), Pd(OAc)2 (0.04 equiv), Xantphos (0.08 equiv), DMA, 150 °C, 15–
f
30 min, microwave.
aryl halides 9 (entry 2), 17 (entry 14), 18 (entry 16), 20 (entry 18),
22 (entry 21), and 27 (entry 31) with overall marked lower yields
than using our protective group strategy. Furthermore, attempts to
prepare final compounds 10a, 13a, and 16a from 3-bromobenzene-
sulfonamide 3 by ‘reverse Buchwald coupling’ under similar micro-
wave-heating conditions, respectively, with p-toluidine (entry 3),
p-fluoroaniline (entry 7) or 2-aminopyridine (entry 11), did not
give satisfactory outcomes (poor yields ranking 11–17%).
In summary, a practical synthesis of unsubstituted N-aryl and
heteroaryl aminobenzenesulfonamides has been validated. In par-
ticular, the sulfonamide protecting group strategy tolerates the use
of strong bases for the N-arylation step, whereas the unsubstituted
sulfonamide group would certainly be deprotonated leading to
unchemoselective C–N bond formation. Besides, our protocol spe-
cially applies to substrates not amenable toward nucleophilic aro-
matic substitution.
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(200 mg, 0.48 mmol), 22 (0.060 mL, 0.48 mmol), diacetoxy-palladium (6 mg,
0.02 mmol), cesium carbonate (316 mg, 0.97 mmol), and Xantphos (28 mg,
0.05 mmol) in degassed dioxane (4.0 mL) was heated at 85 °C in a sealed vessel
under inert atmosphere for 4 h. The resulting mixture was diluted with
dichloromethane and ethanol, extracted with a saturated aqueous solution of
NaHCO3. The organics were dried over MgSO4 and concentrated in vacuo. TFA
(5 mL) and anisole (0.32 mL, 2.9 mmol) were added to a solution of the crude
product in dichloromethane (7 mL). The mixture was stirred at 25–40 °C for
24 h and slowly quenched with a saturated aqueous solution of Na2CO3.
Extractive workup (at pH 8–9) with ethyl acetate and then dichloromethane
afforded a residue which was adsorbed on silica gel and purified by flash
chromatography (2/100 to 5/100 EtOH/DCM + 0.5% NH4OH) to yield 22b
(108 mg, 80%) as a pale yellow solid.1H NMR (500 MHz, DMSO) d 8.56 (NH),
7.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.17 (SO2NH2), 2.49
(s, 3H), 2.36 (s, 3H). ESIMS (m/z): 279.3 (MH+).
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