Novel N-dealkylation of N-alkyl sulfonamides and N,N-dialkyl sulfonamides with periodic acid catalyzed by chromium(III) acetate hydroxide

Article abstract of DOI:10.1055/s-2004-830851

Chromium(III) acetate hydroxide has been found to be an efficient catalyst for N-dealkylation of N-alkyl sulfonamides and N,N-dialkyl sulfonamides to furnish sulfonamides in good to excellent yields with periodic acid in acetonitrile at room temperature.

Full text of DOI:10.1055/s-2004-830851

LETTER
1901
Novel N-Dealkylation of N-Alkyl Sulfonamides and N,N-Dialkyl Sulfonamides
with Periodic Acid Catalyzed by Chromium(III) Acetate Hydroxide
N
-Dealkylation
i
of
N
-A
a
lkyl Sulfon
n
amides and
N
g
,
N
-Dialkyl Sulfon
X
amides u,a Suhong Zhang,b Mark L. Trudell*b
a
St Charles Pharmaceuticals, Inc., P.O. Box 850815, New Orleans, Louisiana 70185, USA
b
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA
Fax +1(504)2806860; E-mail: mtrudell@uno.edu.
Received 19 March 2004
and H5IO6 resulted in shorter reaction times. The N-ethyl
and N-propyl benzenesulfonamides were readily dealkyl-
ated with Cr3(OAc)7(OH)2 [2.5 mol% of Cr(III)] at r.t.
(entries 4 and 6). To achieve dealkylation of the N-isopro-
pyl benzenesulfonamide on the same time scale either 5
mol% of Cr(III) (entry 10) or 8 equivalents of H5IO6
(entry 13) were required. In either case, the yield of the
benzenesulfonamide (93%) was unaffected. However,
when the substrate was N-isopropyl benzenesulfonamide
the reaction afforded benzenesulfonamide in higher yield
and purity than the other N-alkyl benzenesulfonamides.
Abstract: Chromium(III) acetate hydroxide has been found to be
an efficient catalyst for N-dealkylation of N-alkyl sulfonamides and
N,N-dialkyl sulfonamides to furnish sulfonamides in good to excel-
lent yields with periodic acid in acetonitrile at room temperature.
Key words: N-dealkylation, N-alkyl sulfonamide, N,N-dialkyl
sulfonamide, periodic acid, chromium(III) acetate hydroxide
The sulfonamide functionality has achieved great utility
in organic synthesis as a strong directing group in ortho-
metalation reactions.1,2 However, the methods for further
transformation of N-alkyl and N,N-dialkyl sulfonamides
are limited in scope. Several examples of sonochemical
dealkylation of N-alkyl sulfonamides have been reported,
the scope of this procedure is limited and furnished only
moderate yields of the corresponding sulfonamides.3 Ad-
ditional methods exist for the conversion of tertiary sul-
fonamides (N-SEM and N-PMB) into secondary
sulfonamides4 and secondary sulfonamides (N-t-Bu) into
primary sulfonamides,5 however, a method for the dealky-
lation of either N-alkyl sulfonamides or N,N-dialkyl sul-
fonamides that contain typical alkyl groups (e.g. Et and i-
Pr) used in ortho-metalation reactions is still not avail-
able. Moreover, the oxidation of N-alkyl amides has been
used for the transformation of alkylamines into carboxylic
acids or ketones,6 but the similar oxidation of N-alkyl
sulfonamides has only been achieved with N-benzyl-
sulfonamides.7 Herein, we report an unprecedented N-
dealkylation of N-alkyl sulfonamides and N,N-dialkyl
sulfonamides via a chromium(III)-catalyzed oxidation
with periodic acid to afford primary sulfonamides using a
one-pot procedure.
Demethylation required a longer reaction time and higher
catalyst loading (entries 1 and 2).
Based on these results, the reactivity of N-a-CH bonds in
this dealkylation reaction decreased in the order of: sec-
ondary>tertiary>primary. This order is different than the
order of reactivity of chromium mediated oxidation of al-
kane CH bonds: tertiary>secondary>primary. In addition,
the reactivity of N-a-C-H bonds is highly influenced by
the group attached to the b-position relative to the nitro-
gen atom. N-Benzyl benzenesulfonamide (entry 18) ex-
hibited the greatest reactivity toward this oxidation (86%
yield of N-a-CH bond oxidation products) by requiring
the lowest catalyst loading (1 mol%) for complete con-
sumption of the starting material. Alternatively, no reac-
tion was observed for the dealkylation of N-2,2,2-
trifluoroethyl benzenesulfonamide (entry 5). Dealkylation
of N-tert-butyl benzenesulfonamide did not proceed well
at room temperature either with (entry 15) or without (en-
try 16) catalyst. Presumably, the lack of an N-a-C-H bond
prevents the catalytic oxidation. Therefore, it is envisaged
that this dealkylation reaction proceeds via the oxidation
of the C-H bonds a to the nitrogen atom of the sulfon-
amide moiety.
Initially, the oxidative dealkylation of N-alkyl benzene-
sulfonamides with periodic acid catalyzed by chromi-
um(III) acetate hydroxide [Cr3(OAc)7(OH)2] was
examined (Table 1). The reactions were conveniently per-
formed by stirring a solution of N-alkyl benzenesulfona-
mide, H5IO6 and Cr3(OAc)7(OH)2 in acetonitrile at room
temperature. N-Alkyl benzenesulfonamides with primary
alkyl as well as secondary alkyl chains were easily
dealkylated to yield benzenesulfonamide in good to excel-
lent yields. Generally, higher loading of Cr3(OAc)7(OH)2
The formation of N-acyl- or N-aroyl-sulfonamides is a
competitive reaction pathway in the dealkylation of N-
alkyl sulfonamides bearing a methylene group. Dealkyla-
tion of N-benzyl benzenesulfonamide (entry 17 and 18)
afforded benzenesulfonamide as the minor product and N-
benzoyl benzenesulfonamide was obtained as the major
product. However, the selectivity can be partially con-
trolled by increasing the loading of H5IO6 and reducing
the catalyst loading (entry 18). Dealkylation of N-methyl
benzenesulfonamide afforded only a trace of N-formyl
benzenesulfonamide with either high (10 mol%) or low
SYNLETT 2004, No. 11, pp 1901–1904
0
6
.0
9
.2
0
0
4
Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-830851; Art ID: S02704ST
© Georg Thieme Verlag Stuttgart · New York

1902
L. Xu et al.
LETTER
Table 1 Dealkylation of N-Alkyl Benzenesulfonamide
tophenone in 80% yield. This suggests that this dealkyla-
tion reaction might be used for the transformation of
secondary alkyl amines into ketones.6
Cr3(OAc)7(OH)2
O
O
R
H
H5IO6
S NH2
O
S N
O
From the above study it was determined that N-isopropyl
benzenesulfonamide could be dealkylated cleanly to
benzenesulfonamide with Cr3(OAc)7(OH)2 [Cr(III) 5
mol%] in high yield with reasonable reaction times. This
dealkylation reaction should therefore extend the utility of
the N-isopropyl sulfonamide group both in its use as a pro-
tective group and as a directing group in metalation reac-
tions. To this end, the dealkylation of a variety substituted
N-isopropyl sulfonamides was examined. As summarized
in Table 2, N-isopropyl sulfonamides with various elec-
tron-donating groups or electron-withdrawing groups on
the aryl ring were readily dealkylated. The 1-naphthyl de-
rivative (entry 11) was dealkylated without significant
competing oxidation of the naphthyl ring system. In addi-
tion, the N-isopropyl benzylsulfonamide (entry 17) was
dealkylated in high yields without competing benzylic
oxidation. Moreover, the N-isopropyl octylsulfonamide
(entry 18) was dealkylated cleanly to afford the octylsul-
fonamide in 96% yield. These results demonstrate the
mildness and specificity of the H5IO6–Cr3(OAc)7(OH)2
system for a-C-H activation of the N-alkyl group of the
sulfonamide.
CH3CN, r.t.
Entry
R
Cr(III)a
(mol%)
H5IO6
(equiv) (h)
Time
Yield
(%)b
1
2
Me
10
5
8
8
14
20
6
89
Me
89
3
Et
10
2.5
10
2.5
10
10
10
5
6
76
4
Et
6
16
16
16
9
82
5
CH2CF3
n-Pr
i-Pr
6
0c
6
6
82
7
4
93
8
i-Pr
4
16
6
10d
93
9
i-Pr
8
10
11
12
13
14
15
16
17
18
19
i-Pr
4
16
10
9
93
i-Pr
5
6
93
i-Pr
5
8
93
The ease at which N-ethyl benzenesulfonamide was
dealkylated with the Cr3(OAc)7(OH)2–H5IO6 system sug-
gested that N,N-dialkyl benzenesulfonamides with prima-
ry alkyl groups could be converted into the corresponding
unsubstituted sulfonamides (Table 3). The N,N-dialkyl
benzenesulfonamides with ethyl or propyl groups were
readily dealkylated (Table 3, entry 5 and 7). For N,N-di-
alkyl benzenesulfonamide containing one or two methyl
groups afforded N-formyl N-alkyl benzenesulfonamides
(Table 3, entries 1, 3 and 4). For N,N-dimethyl benzene-
sulfonamide the major product that was obtained was N-
formyl-N-methyl benzenesulfonamide (45%, Table 3, en-
try 1). Unsymmetrical N,N-dialkyl derivatives could be
dealkylated to furnish benzenesulfonamide so long at
least one n-alkyl group (Et or n-Pr) was present. For N-
ethyl-N-methyl and N-methyl-N-propyl benzenesulfona-
mides formation of N-methyl benzenesulfonamide was
observed as an intermediate indicating that the more reac-
tive n-alkyl chain was cleaved prior to the methyl group.
Various N,N-diethyl sulfonamides with either electron-
donating groups (entries 8 and 9) or electron-withdrawing
groups (entries 10 and 11) on the aryl ring were readily
i-Pr
2.5
10
10
0
8
15
24
18
18
8
93
Cyclo-Pr
t-Bu
t-Bu
Bn
10
6
88
10e
10
6
10
1
4
28 (5)f
40g
82h
Bn
6
18
18
CHPhMe
5
8
a Cr3(OAc)7(OH)2 is 24% Cr(III).
b Isolated yield.
c Starting material recovered (95%).
d Reaction performed in the presence of Ac2O (10 equiv); starting
material recovered (80%).
e Starting material recovered (82%).
f H5IO6 (3 equiv), CrO3 (10 mol%), r.t., 30 min; PhSO2NHCOPh
(88%) was obtained.
g PhSO2NHCOPh (46%) was also obtained.
h Acetophenone was also obtained (80%).
(5 mol%) catalyst loading probably because the N- dealkylated to the corresponding unsubstituted sulfon-
formyl benzenesulfonamide is easily hydrolyzed by amides in good yields. It is noteworthy that N,N-di-n-pro-
pyl-ortho-trimethylsilylbenzenesulfonamide
(Table 3,
periodic acid.
entry 13) was readily converted into the corresponding
primary sulfonamide in 75% yield. This example demon-
strates the potential utility of the reaction when coupled
with ortho-metalation reactions as well as its tolerance of
acid-sensitive functional groups (SiMe3). The dealkyla-
tion of N,N-dialkyl sulfonamides will certainly serve to
enhance the utility of this functional group in organic
synthesis.
It was also found that H2O played an important role in this
dealkylation reaction. The dealkylation of N-isopropyl-
benzenesulfonamide under anhydrous conditions (10
equiv Ac2O, entry 8) afforded benzenesulfonamide in
only 10% yield and most of the starting material was re-
covered (80%). Finally, the dealkylation of N-a-methyl
benzyl benzenesulfonamide (entry 19) not only furnished
benzenesulfonamide in 82% yield but also provides ace-
Synlett 2004, No. 11, 1901–1904 © Thieme Stuttgart · New York

LETTER
N-Dealkylation of N-Alkyl Sulfonamides and N,N-Dialkyl Sulfonamides
1903
Table 2 Dealkyation of N-Isopropyl Sulfonamides
Table 3 Dealkylation of N,N-Dialkyl Sulfonamides
H5IO6 (6 equiv)
H5IO6 (10 equiv)
Cr3(OAc)7(OH)2
[5 mol% Cr(III)]
Cr3(OAc)7(OH)2
[2.5 mol% Cr(III)]
R1 S NH2
O
O
O
R2
O
R S NH2
R1 S N
R S N
O
CH3CN, r.t.
R3
O
H
CH3CN, r.t.
O
O
Entry
1
R1
R2
Me
Me
Me
Me
Et
R3
Time (h) Yield (%)a
R
Time (h)
Yield (%)a
93
Entry
1
Ph
Me
Me
Et
24
6
35b
0c
4-MeO-C6H4
4-t-Bu-C6H4
4-Br-C6H4
12
14
20
14
14
18
18
20
14
12
20
16
16
18
18
16
6
2
94
2
Ph
72d
72d
82
82
82
81
72
76e
75e
82
75
3
93
3
Ph
18
18
14
14
14
16
16
20
24
14
20
4
4-AcNH-C6H4
4-MeCO-C6H4
4-MeSO2-C6H4
4-CF3-C6H4
90b
86
4
Ph
n-Pr
Et
5
5
Ph
6
92
6
Ph
Et
n-Pr
n-Pr
Et
7
94
7
Ph
n-Pr
Et
8
4-NO2-C6H4
93c
93c
92
8
4-t-Bu-C6H4
4-Me-C6H4
4-Br-C6H4
4-NO2-C6H4
Benzyl
9
3-MeO-C6H4
3-MeO2CC6H4
3-NO2-C6H4
9
Et
Et
10
11
12
13
14
15
16
17
18
10
11
12
13
Et
Et
92c
93
Et
Et
2-MeO-4-Cl-C6H3
2-MeO-5-Br-C6H3
2-Me-3-Cl-C6H3
3-NO2-4-Me-C6H3
1-Naphthyl
Et
Et
93
2-(SiMe3)-C6H4 n-Pr
n-Pr
a Isolated yield.
84
b 10 mol% Cr(III); PhSO2NMeCHO (45%) and PhSO2NHMe (5%)
85
were obtained.
c H5IO6 (6 equiv), CrO3 (10 mol%); PhSO2NMeCHO (95%) was
84d
93
obtained.
d 10 mol% Cr(III); PhSO2NR3CHO (12%) and PhSO2NHMe (5%)
Benzyl
were obtained.
e H5IO6 (12 equiv).
Me(CH2)7
7
96
a Isolated yield.
b 10 mol% Cr(III), H5IO6 (10 equiv).
c H5IO6 (8 equiv).
less toxic chromium(III) acetate hydroxide. Other chromi-
um(III) compounds, such as CrBr3, CrCl3, Cr2O3 and
Cr(acac)3 were inferior as catalysts while KMnO4,
Pb(OAc)4, TEMPO,8 RuCl3,9 RuO2,10 FeCl311 afforded no
observable dealkylation products under these reaction
conditions.
d 10 mol% Cr(III), H5IO6 (8 equiv).
Chromium(VI) oxide CrO3 was also found to be an effi-
cient catalyst for N-demethylation and N-deisopropyla-
tion. Shorter reaction times were needed when the same
loading of CrO3 as catalyst. However, CrO3 facilitated the
formation of N-acyl or N-aroyl sulfonamide side products
for dealkylation of N-alkyl and N,N-dialkylsulfonamides
bearing a a-methylene group (Table 3, entries 3, 4 and 6).
For N-benzyl benzenesulfonamide only 5% yield of ben-
zenesulfonamide was obtained and most of the product
was N-benzoylbenzenesulfonamide (88%) when CrO3 (10
mol%) was used as catalyst (Tables 1, 17). It is notewor-
thy that only N-formyl-N-methyl benzenesulfonamide
(92%) was obtained when dealkylation of N,N-dimethyl
benzenesulfonamide was attempted with 10 mol% CrO3
(Table 3, entry 2). This suggests that H5IO6–CrO3 system
might be used for preparation N-benzoylsulfonamides
(e.g. saccharin ring system). In addition, the high toxicity
of CrO3 made it less attractive as a catalyst than the much
The mechanism of this dealkylation reaction is still not
completely clear. However, it appears that a carbinola-
mide-like species 3, is formed as an intermediate via a
chromium oxo or peroxo species mediated oxidation of
the N-a-CH bond of the N-alkyl sulfonamide
(Scheme 1).6,12 It is possible that 3 is formed via a radical
mediated process similar to that observed for the dealkyl-
ation of amides.12 However, radical formation seems un-
likely with this dealkylation system since oxidation of N-
methylcyclopropyl benzamide with H5IO6–CrO3 gave
only the corresponding imide without radical rearrange-
ment products.13
Once formed the carbinolsulfonamide 3 may then be
hydrolyzed to give the unsubstituted sulfonamide 4 and
carbonyl compound 5. If R¢ = H then further oxidation
afforded the corresponding carboxylic acid 6 as the by-
Synlett 2004, No. 11, 1901–1904 © Thieme Stuttgart · New York

1904
L. Xu et al.
LETTER
product. It has been established that chromium oxo vided good to high yields of the sulfonamides and was
species including O=Cr(VI),14 O=Cr(V)15 and O=Cr(VI)16 tolerant of a variety of functional groups.18 Additional
can activate saturated C-H bonds and effect C-H oxida- studies directed toward the elucidation of the mechanism
tions. Recently, a Cr(VI)-catalyzed hydroxylation of satu- and applications of this reaction are under investigation.
rated C-H bonds of alkanes with periodic acid was
reported.17 Although the carbinolsulfonamide intermedi-
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(Table 1, entry 19) supports the proposed mechanism.
Moreover, benzoic acid, derived from the oxidation of the
benzaldehyde by-product, was also obtained (30%) for the
dealkylation of N-benzyl benzenesulfonamide (Table 1,
entry 18). Under these reaction conditions, the N-acyl or
N-aroyl sulfonamide side products were not hydrolyzed
even when the reaction mixture was heated at reflux for
one hour. Though it was not clear what factors controlled
the cleavage regiochemistry, it has been found that replac-
ing chromium(III) acetate hydroxide with CrO3 as catalyst
significantly increased the formation of N-acyl or N-aroyl
sulfonamide side products. Alternatively, reduction of the
catalyst loading facilitated the hydrolysis and gave higher
yields of dealkylation products.
In summary, we have developed the first one-pot proce-
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sulfonamides. The H5IO6–Cr3(OAc)7(OH)2 system pro-
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O
R S N
O
H
R'
H
1
R"
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O
O
Crn+
HIO3
O
H
R S N
O
R'
H
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2
R"
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(18) Typical Procedure for Dealkylation of N-Alkyl-
sulfonamides and N,N-Dialkylsulfonamides with
Periodic Acid–Chromium(III) Acetate Hydroxide: A
mixture of H5IO6 (4.6 g, 20 mmol), chromium(III) acetate
hydroxide [11 mg, 2.5 mol% of Cr(III)] and N,N-dialkyl
sulfonamide (2 mmol) in MeCN (50 mL) was stirred at r.t.
until the reaction was complete (monitored by TLC). The
intermediate monodealkylation products of the
O
O
Crn+
H5IO6
O-insertion
O Cr (n-1)+
O
H
R S N
O
R'
OH
3
R"
hydrolysis
O
O
R S NH2
O
R'
R"
dialkylsulfonamides can be observed by TLC during the
reaction. The reaction mixture was then filtered and the
filtrate was concentrated by rotary evaporation. The residue
was extracted with EtOAc (120 mL), washed, respectively,
with sat. NaHCO3 solution, sat. Na2S2O3 solution, brine and
dried over MgSO4. The solvent was removed by rotary
evaporation and the resultant residue was purified by flash
chromatography eluting with EtOAc–hexanes (1:8) to afford
the pure unsubstituted sulfonamides (1H NMR, mp).
4
5 (R' = H)
[Ox]
6 (R' = OH)
Scheme 1 Possible mechanism for dealkylation of N-alkyl sulfon-
amides
Synlett 2004, No. 11, 1901–1904 © Thieme Stuttgart · New York