AgOTf catalyzed direct amination of benzyl alcohols with sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2007.09.087

AgOTf catalyzed direct amination of primary alcohols with sulfonamides is described. This effective catalyst requires no preactivation of the hydroxy group of alcohols and the reaction is environmentally benign with water as a by-product. Various primary alcohols on amination with sulfonamides gave the corresponding products in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2007.09.087

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Tetrahedron Letters 48 (2007) 8174–8177
AgOTf catalyzed direct amination of benzyl alcohols
with sulfonamides
B. Sreedhar,* P. Surendra Reddy, M. Amarnath Reddy, B. Neelima and R. Arundhathi
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 August 2007; revised 6 September 2007; accepted 13 September 2007
Available online 18 September 2007
Abstract—AgOTf catalyzed direct amination of primary alcohols with sulfonamides is described. This effective catalyst requires no
preactivation of the hydroxy group of alcohols and the reaction is environmentally benign with water as a by-product. Various pri-
mary alcohols on amination with sulfonamides gave the corresponding products in moderate to good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Catalytic amination reactions have received significant
interest. Substituted amines are of considerable impor-
tance in the pharmaceutical, agrochemical and fine
chemical industries.1,2 Numerous biologically active
molecules such as alkaloids, amino acids and nucleo-
tides contain the amine group.
tion of only water as the by-product.7 Prim and co-
workers have reported the Lewis acid catalyzed direct
amination of benzhydryl alcohols.8 Very recently, bis-
muth-catalyzed direct substitution of the hydroxy
groups of allylic and propargylic alcohols with sulfon-
amides, carbamates and carboxamides was reported.9
However, the development of more active catalysts
and an environmentally attractive and simple procedure
for direct amination of primary alcohols is highly
desirable.
Nucleophilic substitution of the hydroxy group in alco-
hols by amines generally requires preactivation of the
alcohols by transformation into good leaving groups
such as halides, carboxylates and carbonates. Palla-
dium- and copper-catalyzed aminations of aryl halides,
hydroamination and hydroaminomethylation of alkenes
and alkynes are well-known methods.3–5 However, these
methods have drawbacks in terms of atom economy,
since they generate large amounts of solid waste and
also require a stoichiometric amount of base. Recently,
ruthenium-catalyzed amination of alcohols has been
reported.6 This domino reaction sequence involves
in situ dehydrogenation of the alcohol to give the corres-
ponding carbonyl compound, which on subsequent
imination followed by reduction with the initially pro-
duced hydrogen (Scheme 1) leads to the formation of
the N-alkylated amine.
We report here an efficient method for the direct amina-
tion of benzyl alcohols with sulfonamides using silver
triflate as catalyst, using no other additives (Scheme
2). The advantages of this type of amination are the
ready availability of alcohols and high atom efficiency
with the formation of water as the only by-product.
Moreover, as opposed to typical reductive aminations,
it is possible to run these reactions in the absence of
additional hydrogen.
Initially, we examined the influence of different solvents
using p-chlorobenzyl alcohol and p-toluenesulfonamide
as model substrates in the presence of 5 mol % AgOTf
as catalyst at 100 ꢁC. The results are summarized in
Table 1. It was observed that on using 1 equiv of alcohol
and amine, mono- and disubstituted products (3aa and
4aa) were obtained in a ratio of 3:1 using toluene as
the solvent in 60% yield (Table 1, entry 1). Reaction in
DMF, DMSO or 1,4-dioxane resulted in lower yields
(Table 1, entries 2–4), and there was no reaction in ace-
tonitrile (Table 1, entry 5). In nitromethane, the prod-
ucts were obtained in a ratio of 3:2 in 72% yield
Direct amination of alcohols with amines would involve
no stoichiometric hydroxy group activators and would
be an environmentally benign method, with the forma-
Keywords: Direct amination; Benzyl alcohol; Sulfonamides; Silver
triflate.
*
Corresponding author. Tel.: +91 40 27193510; fax: +91 40
27160921; e-mail: sreedharb@iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.087

B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 8174–8177
8175
Catalyst, Ts-NH2
Preactivation
Base
Ph
X
(a)
Salt waste
Salt waste
Ts
Catalyst, Ts-NH2
Direct substitution
Ph
OH
Ph
N
H
(c)
H2O
(b)
Ts
N
O
Ts-NH2
Ph
H
Ph
H
Dehydrogenation
Condensation
Hydrogenation
Scheme 1. Substitution of benzyl alcohol by (a) preactivation, (b) catalytic hydrogen transfer and (c) direct catalytic substitution.
5 mol% AgOTf
H
R
nitromethane, 100 ºC
N
R
Ts
OH
N
Ts
+
- H2O
3
2
1
Scheme 2.
Table 1. Optimization of the conditions for the reaction of 1a with 2aa
Ts
OH
0.05 mol% AgOTf
solvent, 100 oC
N
H
N
+ H2N Ts
+
Ts
Cl
Cl
Cl
Cl
1a
2a
3aa
4aa
Entry
1b (equiv)
2a (equiv)
Solvent
Product 3/4 ratio
Yieldb,c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1.5
2
1
Toluene
DMF
DMSO
1,4-Dioxane
Acetonitrile
Nitromethane
Nitromethane
Nitromethane
Nitromethane
3/1
1/1
3/1
3/1
No reaction
3/2
6/1
19/1
1/9
60
15
30
45
72
81
90
95
a Reaction conditions as exemplified in the typical experimental procedure.10
b Isolated yield.
c Products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.11
(Table 1, entry 6). Variation of the alcohol and amine
ratio changed the yields as well as selectivities of the
products formed. The reaction with 1.5 or 2 equiv of
amine resulted in monosubstituted product in high
yields, whereas the presence of 2 equiv of alcohol affor-
ded the disubstituted product in good yield. Various
other Lewis acids were screened for the reaction under
the optimized conditions. As can be seen from Table
2, Cu(OTf)2, Sc(OTf)3 and Bi(OTf)3 gave the corre-
sponding products in 92, 90 and 90% yields, whereas
La(OTf)3 and Ce(OTf)4 gave the products in only mod-
erate yields (entries 4 and 5). Zn(OTf)2 and Ag(0) affor-
ded the desired products in poor yields (entries 6 and 7)
and there was no reaction with CuCl2 and Ag(NO)3 (en-
tries 8 and 9). Among the several catalysts screened,
AgOTf was the catalyst of choice and, as can be seen,
the nature of the counterion also plays a significant role
in the amination reaction.
Under the optimized reaction conditions (2 equiv of
amine and nitromethane as solvent), various primary
Table 2. Screening of catalysts for the reaction of 1a with 2aa
Entry
Catalyst
Product 3aa/4aa
Yield (%)b
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Sc(OTf)3
Bi(OTf)3
Ce(OTf)4
La(OTf)3
Zn(OTf)2
Ag(0) powder
CuCl2
9/1
6/1
19/1
9/1
9/1
3/2
3/2
—
92
90
90
65
75
45
30
0
AgNO3
—
0
a Reaction conditions as exemplified in the typical experimental
procedure.10
b Isolated yield.

8176
B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 8174–8177
Table 3. Amination of benzyl alcohols with various sulfonamidesa
Entry
1
Benzyl alcohol (1)
Sulfonamide (2)
Productb (3)
Yieldc (%)
90
O
OH
N
Ts
H2N
S
H
Cl
O
Cl
1a
2a
N
H
Ts
OH
2
2a
74
OH
Cl
N
H
Ts
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
80
85
64
72
0
Cl
OH
N
H
Ts
F
F
OH
N
Ts
H
H3C
H3C
OH
N
H
Ts
Ts
F3C
F3C
OH
N
H
O2N
O2N
OH
N
H
Ts
45
85
O
N
SO2-Ph
H
1a
1a
H2N
S
O
Cl
O
N Ms
H
10
11
90
82
H2N
S
CH3
Cl
Cl
O
N
H
SO2
O
S
1a
H2N
O
O
N
Ts
Ts
12
13
1a
1a
64
52
HN
S
Ph
Cl
Cl
Ph
O
O
S
N
HN
O
a Reaction conditions as exemplified in the typical experimental procedure.10
b Isolated yield.
c All products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.11
alcohols were subjected to amination with different sul-
fonamides and the results are given in Table 3. The reac-
tion of electronically and structurally diverse benzyl
alcohols such as o-chloro, p-fluoro, p-methyl and p-tri-
fluoromethyl benzyl alcohols with 2a gave the desired
products in good yields (entries 1–6), whereas the pres-
ence of a strong electron-withdrawing substituent (p-
nitrobenzyl) gave no product (entry 7). 2-Naphthyl
methanol on reaction with 2a gave the product in low
yield (entry 8). Reaction of 1a with benzenesulfonamide,
methanesulfonamide and triisopropylbenzenesulfon-
amide gave the corresponding products in high yields

B. Sreedhar et al. / Tetrahedron Letters 48 (2007) 8174–8177
8177
C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O.;
Tillack, A.; Trauthwein, H. Synlett 2002, 1579–1594.
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1999, 99, 3329–3366.
(entries 9–11) and the reaction of 1a with N-substituted
p-toluenesulfonamides gave the desired products in
moderate yields (entries 12 and 13).
In conclusion, we have developed an efficient procedure
to obtain benzylic amines from the corresponding pri-
mary alcohols and sulfonamides in the presence of silver
triflate as catalyst. The methodology is straightforward
and environmentally benign with the formation of water
as the only by-product.
6. (a) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M.
Tetrahedron Lett. 2006, 47, 8881–8885; (b) Hollmann, D.;
Tillack, A.; Michalilk, D.; Jackstell, R.; Beller, M. Chem.
Asian J. 2007, 2, 403–410.
Acknowledgement
7. (a) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto,
S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002,
124, 968–977; (b) Kinoshita, H.; Shinokubo, H.; Oshima,
K. Org. Lett. 2004, 6, 4085–4088; (c) Kimura, M.;
Futamata, M.; Shibata, K.; Tamaru, Y. Chem. Commun.
2003, 234–235; (d) Kayaki, Y.; Koda, T.; Ikariya, T. J.
Org. Chem. 2004, 69, 2595–2597.
P.S.R. and B.N. thank the Council of Scientific and
Industrial Research, New Delhi, for the award of Senior
Research Fellowships.
Supplementary data
8. Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J. M.;
Prim, D. Adv. Synth. Catal. 2006, 348, 2063–2067.
9. Qin, H.; Yoaagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2007, 46, 409–413, and references
cited therein.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.09.087.
10. Typical experimental procedure: A mixture of benzyl
alcohol (1 mmol), sulfonamide (2.0 mmol) and silver
triflate (5 mol %) in nitromethane (5 mL) was stirred at
100 ꢁC for 8 h (Table 1). After completion of the reaction
as indicated by TLC, the reaction mixture was diluted with
water and extracted with ethyl acetate (2 · 10 mL). The
combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by column
chromatography on silica gel to afford the pure product.
11. Spectroscopic data for representative examples: N-(4-chlo-
robenzyl)-4-methylbenzenesulfonamide (3aa): IR (KBr): m
References and notes
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Science 1991, 254, 1471–1477.
2. (a) Lawrence, S. A. In Amines: Synthesis, Properties and
Applications; Cambridge University: Cambridge, 2004; (b)
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Interscience: New York, 2002; Vol. 1, p 1051; (c) Salva-
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S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth.
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4. For hydroamination reviews see: (a) Hultzsch, K. C.;
Gribkov, D. V.; Hampel, F. J. Organomet. Chem. 2005,
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3053, 2924, 1596, 1344, 1185, 837 cmÀ1
.
1H NMR
(300 MHz, CDCl3): d (ppm) 2.44 (s, 3H), 4.07 (d, 2H,
J = 6.8 Hz), 4.81 (t, 1H, J = 6.8 Hz), 7.11 (d, 2H,
J = 8.3 Hz), 7.20–7.28 (m, 4H), 7.70 (d, 2H, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d (ppm) 21.49, 46.43, 127.08,
128.66, 129.16, 129.67, 133.56, 134.85, 136.64, 143.67. LC
MS (m/z): 295.9 (M)+, 318.0 (M+Na)+. N,N-Bis-(4-
chlorobenzyl)-4-methylbenzenesulfonamide (4aa): IR
(KBr): m 3246, 2921, 1600, 1460, 1293, 1167, 812 cmÀ1
.
1H NMR (300 MHz, CDCl3): d (ppm) 2.47 (s, 3H), 4.23 (s,
4H), 6.842–7.07 (m, 8H), 7.31 (d, 2H J = 8.0 Hz), 7.72 (d,
2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d (ppm)
21.54, 47.26, 127.18, 127.91, 128.64, 129.70, 132.19,
133.4, 136.29, 143.54. LC MS (m/z): 420.1 (M)+, 443.0
(M+Na)+. Please see Supplementary data for spectral
data of all other compounds.