Fe(II)-catalyzed N-alkylation of sulfonamides with benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.02.056

The FeCl₂/K₂CO₃ catalyst system was developed successfully for the N-alkylation of sulfonamides with benzylic alcohols via borrowing hydrogen method. XPS analysis suggested a possible catalyst cycle between Fe(II) and Fe(0). Under the optimized condition, the scope of the protocol was demonstrated in 21 different alkylation reactions. High yields, in general >90%, are achieved in most cases.

Full text of DOI:10.1016/j.tetlet.2010.02.056

Tetrahedron Letters 51 (2010) 2048–2051
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Tetrahedron Letters
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Fe(II)-catalyzed N-alkylation of sulfonamides with benzylic alcohols
a
a,
Xinjiang Cui a,b, Feng Shi a, , Yan Zhang , Youquan Deng
*
*
a Centre for Green Chemistry and Catalysis, Lanzhou Institute of Chemical Physics, CAS, Lanzhou 730000, China
b Graduate School of Chinese Academy and Science, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The FeCl2/K2CO3 catalyst system was developed successfully for the N-alkylation of sulfonamides with
benzylic alcohols via borrowing hydrogen method. XPS analysis suggested a possible catalyst cycle
between Fe(II) and Fe(0). Under the optimized condition, the scope of the protocol was demonstrated
in 21 different alkylation reactions. High yields, in general >90%, are achieved in most cases.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 January 2010
Revised 9 February 2010
Accepted 10 February 2010
Available online 13 February 2010
Keywords:
Sulfonamide
Alkylation
Alcohol
Iron
The N-alkylated sulfonamide is an important class of com-
pounds in agrochemical and pharmaceutical chemistry.1 At the
same time, sulfonamide could also be used as protecting groups
for amine due to the removable sulfonyl group on the nitrogen.
Thus, the N-alkylated sulfonamides could also be led to the forma-
tion of primary amines.2 Typically, the classical methods for the
synthesis of N-alkylated sulfonamides are performed by the reac-
tion of sulfonyl halide and amine, sulfonamide and alky halide or
reductive amination of aldehyde, Scheme 1.3
reported that iron could be a good catalyst for the reduction of ke-
tone and amide with additional hydrogen source and elegant re-
sults were obtained.8 To the best of our knowledge, there is no
report about iron-catalyzed sulfonamide alkylation with alcohol
through hydrogen-borrowing method.
Herein, we report the Fe(II)Cl2-catalyzed coupling reaction of
sulfonamide and benzylic alcohol via hydrogen-borrowing meth-
od, Scheme 2. It was worth noting that a possible cycle between
Fe(II) and Fe(0) was observed.
However, all the methods mentioned above suffer from the for-
mation of unexpected byproducts or the application of sensitive
substrates. The use of alcohol as alkylation reagent for N-alkylation
of sulfonamide is an attractive method because it doesn’t generate
harmful byproducts and alcohol is readily available.4 Some of these
reactions have been reported using homogeneous or heteroge-
neous transition metal catalysts via the so-called borrowing hydro-
gen methods.5 Recently, we have reported a copper-catalyzed
N-alkylation of sulfonamides, but the operation of the reaction un-
der air makes the system relatively complicated.6 N-Alkylation of
sulfonamide and carboxamide have also been realized successfully
via a carbocation mechanism using secondary benzylic and allylic
alcohols as N-alkylation reagents catalyzed by FeCl3, MoCl5 or
Bi(OTf)3.7 However, the utilization of Lewis acid causes the diffi-
culty in reaction controlling and product purification. The develop-
ment of iron catalyzed sulfonamide alkylation method with
alcohol through borrowing hydrogen mechanism should be a good
choice to solve the above-mentioned problem. Recently, it was
In our initial study, the reaction of p-toluene sulfonamide and
benzyl alcohol was chosen as the model reaction to explore the
catalyst system, Table 1. Generally, the reaction was carried out
at 135 °C for 12 h in the presence of a suitable amount of iron salt
and 20 mol % base.9
By varying different iron salts, that is, FeCl2, FeCl3Á6H2O,
Fe3(CO)12, and Fe(acac)3, we found that FeCl2 exhibited the highest
catalytic activity, Table 1, entries 1–4. The conversion could reach
to 90% by simply increasing the FeCl2 loading to 5 mol %, entry 5.
O
O
O
O
R' NH2
+
+
HX
S
R'
R'
+
+
S
S
R
N
R
X
H
O
O
O
O
[R]
H2O
S
R' CHO
R
NH2
R
N
H
O
O
O
O
+
+
S
R'
R'-X
X=halides
S
HX
R
N
R
NH2
* Corresponding authors. Tel.: +86 931 4968142; fax: +86 931 8277088 (F.S.).
E-mail addresses: fshi@licp.cas.cn, fshi@lzb.ac.cn (F. Shi), ydeng@licp.cas.cn
(Y. Deng).
H
Scheme 1. Typical protocols for sulfonamide N-alkylation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.056

X. Cui et al. / Tetrahedron Letters 51 (2010) 2048–2051
2049
O
O
O O
S
O O
S
S
R2
NH2
[Fe(II)]
[Base]
[Fe(0)]
[Base]
R1
N
R2
R1
OH
R1
N
R2
R1
O
H
Scheme 2. Iron-catalyzed sulfonamide alkylation with alcohol.
Table 1
The N-alkylation of p-toluene sulfonamide with benzyl alcohola
Table 2
The coupling reaction of sulfonamides and benzyl alcohola
Entry
Catalyst
mol %
Base/20 mol %
T (h)
Con.b (%)
Entry RSO2NH2
Products
Yieldb (%)
1
2
3
4
5
6
7
8
9
FeCl2
1
1
1
1
5
5
5
5
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KO-t-Bu
K3PO4
Cs2CO3
K2CO3
12
12
12
12
12
12
12
12
20
40
10
19
25
90
0
20
10
100
O O
S
O O
S
FeCl3Á6H2O
Fe3(CO)12
Fe(acac)3
FeCl2
FeCl2
FeCl2
1
98
96
NH2
N
H
O
O
O
O
S
S
2
3
N
NH2
H
FeCl2
FeCl2
O
S
O
O O
S
a
2.0 mmol (428 mg) p-toluene sulfonamide, 10 mmol (1.08 g) benzyl alcohol, Ar.
Determined by GC–MS, no other byproduct produced from sulfonamide was
observed.
b
N
NH2
93
H
Br
Br
O O
S
O O
S
The usage of other bases such as KO-t-Bu, K3PO4, and Cs2CO3
doesn’t work better, entries 6–8. There is no observable product
if using KO-t-Bu as the catalyst. 100% conversion and selectivity
could be achieved if prolonging the reaction time to 20 h, entry 9.
In order to explore why FeCl2 exhibited higher catalytic activity,
the reaction system was measured by XPS before and after reac-
tion, Figure 1. The binding energy determined by XPS provides use-
ful information on the oxidation states of different elements.10 For
the fresh sample, the typical bind energy number, that is, 711.6 eV
for Fe(II) could be clearly observed. Interestingly, a strong peak at
707.3 eV for Fe(0) could be observed after reaction and there is
no evidence for the formation of Fe(III). Therefore, the possible ac-
tive catalyst species for this coupling reaction is Fe(II) and Fe(0).
The transfer hydrogenative process might be realized through the
cycle between Fe(II) and Fe(0). At the same time, there is no obser-
vable copper element by XPS analysis. So the activity should be
originated from iron but not copper pollution although it was
reported that copper is the real catalyst in some examples.11 For
the XPS analysis of reaction mixture using FeCl3 as catalyst (not
shown here), only Fe(III) could be detected. Thus, both Fe(III) and
Fe(II) can promote the reaction but Fe(II) is more active due to
the cycle between Fe(II) and Fe(0).
4
5
95
95
92
N
NH2
H
O O
S
O O
S
NH2
N
H
O O
O O
S
S
6c
NH2
N
H
N
N
O O
S
O O
S
S
S
NH2
N
7c
90
89
Cl
Cl
Cl
Cl
H
Cl
Cl
O O
S
O O
S
S
S
8c
N
NH2
H
a
Conditions: 1.0 mmol sulfonamides, 5 mmol benzyl alcohols, 5 mol % FeCl2,
20 mol % K2CO3, 20 h, 135 °C, Ar.
b
Isolated yield.
40 mol % base.
c
710.6
713.8
711.6
before use
715.4
after use
707.3
720
715
710
705
700 720
715
710
705
700
Binding Energy (eV)
Binding Energy (eV)
Figure 1. The XPS spectra of the catalyst before and after use.

2050
X. Cui et al. / Tetrahedron Letters 51 (2010) 2048–2051
Table 3
O
O
D
D
The coupling reaction of p-toluene sulfonamide and benzyl alcohol derivativesa
5 mol% Fe (II)
20 mol% base
S
OH
N
Yieldb
(%)
+
Entry RCH2OH
Products
135oC Ar 10h
d5
O
O
O
O
OH
OH
S
S
1
2
89
94
N
H
D
O
H
O
2
4
3
5
O
d5
N
H
106
112
D
O
OH
S
H
D O O
D
O O
S
N
3
93
92
F3C
S
H
N
N
CF3
H
H
O
O
d5
OH
OH
S
N
107
113
4
H
Scheme 3. Reaction of benzyl alcohol-d7 with N-benzylidene-p-toluene
sulfonamide.
O O
S
N
5
96
94
95
S
H
S
sulfonamide, 95%isolatedyieldwasalso obtained, entry4. Toourde-
light, if other sulfonamides include naphthalene sulfonamide, thio-
phene sulfonamide and pyridine sulfonamide were applied, the
yields of the desired products were all ꢀ90%, entries 5–8. These
yields were higher than the former reports using iron oxide immobi-
lized nano-ruthenium as catalyst5a and the utilizationof noble metal
was avoided here.
Br
Br
O
O
O
S
6
N
H
OH
O
OH
S
N
H
7
Br
Br
Nice results were also obtained with the alteration of benzyl alco-
hols possess different functional groups, Table 3. Under the devel-
oped system, all substituted groups, that is, Cl, Br, –CH3, –CF3, –
OCH3, –SCH3, –CH(CH3)2, and –CF3, were stable, and excellent results
were achieved. Interestingly, the thiophen-2-ol could also be good
alkylation reagentand 90% isolatedyield was obtainedto thedesired
product. However, this system is still inactive for the coupling reac-
tion of sulfonamide with aliphatic alcohol. Almost no reaction was
observed by applying 1-octanol as starting material.
The mechanism was explored by the reaction of benzyl alcohol-
d7 with p-toluene sulfonamide or N-benzylidene-p-toluene sulfon-
amide. By tracing the reactions with GC–MS, it showed that the
formation of products 2, 3, 4, and 5, Scheme 3, which proved the
transfer hydrogenative mechanism and also the whole process
was reversible. Isotope effect investigation suggested that the
KIE1 was 3.6, which provided strong evidence that the hydrogen
elimination was the rate-determining step.12
Cl
Cl
O
O
O
S
S
8
91
93
92
93
OH
N
H
O
OH
N
H
9
Cl
Cl
F
F
O
O
O
OH
S
S
10
N
H
O
OH
N
H
11
F
F
O
O
S
O
O
S
In conclusion, a new FeCl2/K2CO3 catalyst was developed for the
environmentally benign N-alkylation of sulfonamide with benzylic
alcohol. The underlying C–N bond formation reaction takes place
with high selectivity giving only water as side product. Generally,
isolated yields higher than 90% were achieved. XPS analysis sug-
gested a possible catalyst cycle between Fe(II) and Fe(0).
12
91
90
OH
OH
N
H
S
O O
S
13c
N
H
a
Conditions: 1.0 mmol sulfonamides, 5 mmol benzyl alcohols, 5 mol % FeCl2,
20 mol % K2CO3, 20 h, 135 °C, Ar.
Acknowledgment
b
Isolated yield.
c
40 mol % base.
This work was financially supported by the ‘Hundred Talents
Program’ of the Chinese Academy of Sciences.
With a satisfactory protocol in hand, we began to investigate the
scope of the reaction of benzylic alcohols and sulfonamides, Table 2.
By comparing the N-alkylation reactions of p-toluene sulfonamide
and 4-bromobenzenesulfonamide with benzyl alcohol, it was clear
that electron-rich as well as the electron-poor groups were all
tolerant, entries 1–3. For the aliphatic sulfonamide, that is, methyl
Supplementary data
Supplementary data (procedure for the reaction and 1H NMR re-
sults for the products) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.056.

X. Cui et al. / Tetrahedron Letters 51 (2010) 2048–2051
2051
Tetrahedron Lett. 2008, 49, 858; (d) Reddy, C. R.; Madhavi, P. P.; Reddy, A. S.
Tetrahedron Lett. 2007, 48, 7169.
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p-toluenesulfonamide (171 mg), 5.0 mmol benzyl alcohol (540 mg), 5 mol %
FeCl2 (10 mg) catalyst and 20 mol % K2CO3 (69 mg) were added to the reaction
tube, respectively. Then, the reaction was carried out applying a multi-reactor
(Carousel 12 station, RADLEYS) at 135 °C for 20 h. Then it was cooled to room
temperature. ꢀ20 mL acetone was added to dissolve the reaction mixture and
filtered by Celite. The acetone and benzyl alcohol were removed under vacuum
and a white solid was obtained with 98% isolated yield. 1H NMR (400.1 MHz,
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127.84, 128.64, 129.70, 136.23, 136.79, 143.49; MS (E.I., 70 eV) m/z (rel. int.)
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