Efficient dehydrative C-N bond formation using alcohols and amides in the presence of silica supported perchloric acid as a heterogeneous catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.05.001

Silica supported perchloric acid has been utilized as an efficient heterogeneous recyclable catalyst for N-alkylation of amides (sulfonamides and carboxamides) using alcohols (primary and secondary aliphatic as well as benzylic). The products are formed in high yields within 2-3 h.

Full text of DOI:10.1016/j.tetlet.2011.05.001

Tetrahedron Letters 52 (2011) 3521–3522
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Tetrahedron Letters
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Efficient dehydrative C–N bond formation using alcohols and amides
in the presence of silica supported perchloric acid as a heterogeneous catalyst q
⇑
Biswanath Das , Parigi Raghavendar Reddy, Chithaluri Sudhakar, Maram Lingaiah
Organic Chemistry Division—I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Silica supported perchloric acid has been utilized as an efficient heterogeneous recyclable catalyst for N-
alkylation of amides (sulfonamides and carboxamides) using alcohols (primary and secondary aliphatic
as well as benzylic). The products are formed in high yields within 2–3 h.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 April 2011
Revised 29 April 2011
Accepted 2 May 2011
Available online 5 May 2011
Keywords:
Amide
Alcohol
N-Alkylation
Heterogeneous catalyst
Sulfonamides
N-Alkylation is a fundamental reaction in organic chemistry.
The reaction is highly important in the synthetic methodologies
and in the preparation of pharmaceutical compounds.1 N-Alkyl-
ation of amide with alcohols was carried out earlier using ruthe-
nium catalyst at very high temperature (>180 °C).2,3
Subsequently various Lewis acids have been utilized for this pur-
pose.4–7 However, long reaction time, high temperature, necessity
of the costly reagents, unsatisfactory yields and narrow scope are
the drawbacks in many of the methods involving these catalysts.
Application of Bronsted acids and heterogeneous catalysts for the
preparation of N-alkylated amides is also limited.8,9 Here we report
a convenient method for N-alkylation of amides using a Bronsted
acid under heterogeneous conditions.
the conversion was also good but they were not accepted for envi-
ronmental problem.
N-Alkylation of various amides was subsequently carried out14
using different alcohols in the presence of HClO4ÁSiO2 in 1,4-diox-
ane (Table 2). Both the sulfonamides and carboxamides underwent
the conversion smoothly. Several aliphatic and benzylic alcohols
afforded the desired products efficiently. The benzylic alcohols
contained electron-donating and electron-withdrawing groups.
The conversion was complete within 2–3 h and the products were
formed in high yields (87–98%). The sulfonamides underwent the
conversion more efficiently than the carboxamides. The interesting
point is that from the aliphatic alcohols no olefinic products
(resulting by dehydration) could be detected. The structures of
the products were established from their spectral (IR, 1H and 13C
NMR, and MS) and analytical data.14
In continuation of our work10–12 on the development of useful
synthetic methodologies we have observed that N-alkylation of
amides can efficiently be carried out with alcohols using silica sup-
ported perchloric acid (HClO4ÁSiO2) as a catalyst (Scheme 1).
Initially the reaction of benzhydryl alcohol with p-toluene sul-
fonamide was conducted using various heterogeneous catalysts
in different solvents under reflux for 6 h (Table 1). Considering
the yield of the product silica supported perchloric acid
(HClO4ÁSiO2)13 was found to be the most effective in both 1,4-diox-
ane and THF. The reaction can give the product with equal yield
even after 2 h. However, in the absence of catalyst no product
could be detected. In the chlorinated solvents, CHCl3 and CH2Cl2
The catalyst, HClO4ÁSiO2 works under heterogeneous conditions.
In recent years heterogeneous catalysts have gained much impor-
tance due to eco-economic benefits. The present catalyst can easily
R1
R2
R1
R2
HClO4.SiO2
H2NR3
NH R3
OH
1,4-dioxane
80 0C, 2-3h
87-98%
1
2
3
R1= Ph, Me, n-pr, Bn
R3= SO2Tol (Ts),
COPh,
R2= H, Me, Ph, 4-ClPh,
3-OMe-4-FPh
q
Part 218 in the series ‘Studies on novel synthetic methodologies’.
COMe
⇑
Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
Scheme 1. N-Alkylation of amides with alcohols.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.001

3522
B. Das et al. / Tetrahedron Letters 52 (2011) 3521–3522
Table 1
Acknowledgments
Evaluation of catalytic activity of different catalystsa
Entry
Catalyst
Solvent
Isolated yield (%)
The authors thank the CSIR and UGC, New Delhi for financial
assistance. They are also thankful to NMR, Mass, and IR Divisions
of IICT for spectral recording.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
—
—
1,4-Dioxane
THF
1,4-Dioxane
THF
—
—
19
12
Trace
Trace
34
NaHSO4ÁSiO2
NaHSO4ÁSiO2
NaHSO4ÁSiO2
NaHSO4ÁSiO2
References and notes
CHCl3
CH2Cl2
1,4-Dioxane
THF
1. Shamma, M.; Moniot, J. L. Isoquinoline Alkaloids Research; Plenum press: New
York, 1978.
2. Watanbe, Y.; Ohta, T.; Tsuji, Y. Bull. Chem. Soc. Jpn. 1983, 56, 2647.
3. Jenner, G. J. Mol. Catal. 1989, 55, 241.
4. Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68,
9340.
5. Sreedhar, B.; Reddy, P. S.; Reddy, M. A.; Neelima, B.; Arundhathi, R. Tetrahedron
Lett. 2007, 48, 8174.
6. Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J.-M.; Prim, D. Adv. Synth.
Catal. 2006, 348, 2063.
7. Fujita, K.-I.; Komatsubara, A.; Yamaguchi, R. Tetrahedron 2009, 65, 3624.
8. Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Org. Chem.
2007, 72, 6006.
9. Wang, G.-W.; Shen, Y.-B.; Wu, X.-L. Eur. J. Org. Chem. 2008, 4367.
10. Das, B.; Shinde, D. B.; Kanth, B. S.; Satyalakshmi, G. Synthesis 2010, 2823.
11. Das, B.; Reddy, C.; Kumar, D. N.; Krishnaiah, M.; Narender, R. Synlett 2010, 391.
12. Das, B.; Srinivas, Y.; Sudhakar, C.; Damodar, K.; Reddy, P. R. Chem. Lett. 2010, 39,
246.
b
BDMSÁSiO2
BDMSÁSiO2
BDMSÁSiO2
BDMSÁSiO2
22
CHCl3
Trace
Trace
51
35
27
26
98
94
76
CH2Cl2
1,4-Dioxane
THF
c
PMAÁSiO2
PMAÁSiO2
PMAÁSiO2
PMAÁSiO2
HClO4ÁSiO2
HClO4ÁSiO2
HClO4ÁSiO2
HClO4ÁSiO2
CHCl3
CH2Cl2
1,4-Dioxane
THF
CHCl3
CH2Cl2
73
a
Reaction conditions: benzhydryl alcohol (1.0 mmol), p-toluene sulfonamide
(1.2 mmol) in solvent (2 ml), catalyst (50 mg) at 80 °C.
b
Silica supported bromodimethylsulfonium bromide.
Silica supported phosphomolybdic acid.
c
13. Chakraborti, A. K.; Gulhane, R. Chem. Commun. 2003, 1896.
14. General experimental procedure for N-alkylation of amides: To a mixture of an
alcohol (1.0 mmol) and an amide (1.2 mmol) in 1,4-dioxane (2 ml) HClO4ÁSiO2
(50 mg) was added. The mixture was stirred at 80 °C and the reaction was
monitored by TLC. After completion the mixture was filtered to recover the
catalyst and the residue was washed with EtOAc (3 Â 5 ml). The combined
organic portion was subjected to column chromatography (silica gel, hexane–
EtOAc) to obtain a pure N-alkylated amide.
Table 2
N-Alkylation of amides with alcohols in the presence of HClO4ÁSiO2 in 1,4-dioxanea
Entry R1
R2
R3
Product Time Yield
(h)
(%)b
The recovered catalyst was dried and reused. With the fresh catalyst the yield
of the product of the reaction of benzhydryl alcohol and p-toluene sulfonamide
was 98% in 2 h following the above experimental procedure while the yields of
the product of the reaction with the reused catalyst were 97%, 96%, and 94%,
respectively, for the subsequent three consecutive cycles.
The spectral (IR, 1H and 13C NMR and MS) and analytical data of some
representative compounds are given below.
a
b
c
d
e
f
g
h
i
C6H5
C6H5
C6H5
C6H5
4-Cl-C6H4
3-OMe-4-F-C6H3
3-OMe-4-F-C6H3
CH3
CH3
H
Ts
3a
2.0
98
93
91
95
92
94
90
87
89
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
n-
COC6H5 3b
COCH3
Ts
2.25
2.50
2.25
2.50
2.25
3.0
3c
3d
3e
COCH3
N-Benzhydrylbenzamide (3b): IR: 3314, 1645, 1518, 1447, 1271 cmÀ1 1H
;
COC6H5 3f
Ts 3g
COC6H5 3h
NMR(CDCl3, 200 MHz): d 7.80 (2H, d, J = 8.0 Hz), 7.53–7.21 (14H, m), 6.41 (1H,
d, J = 7.0 Hz); 13C NMR (CDCl3, 50 MHz): 167.8, 142.9, 133.2, 130.9, 129.1,
127.6, 127.3, 58.8; ESI-MS: m/z 288 [M+H]+. Anal. Calcd for C20H17NO: C, 83.62;
H, 5.92; N, 4.87. Found: C, 83.68; H, 5.98; N, 4.93.
3.0
3.0
Ts
3i
C3H7
CH3
C6H5-
CH2
N-(1-(4-fluoro-3-methoxyphenyl) ethyl) acetamide (3e): IR: 3311, 1645, 1518,
j
k
H
H
Ts
Ts
3j
3k
3.0
3.0
87
89
1447, 1271 cmÀ1 1H NMR(CDCl3, 200 MHz): d ppm 7.08–6.81 (4H, m), 4.38
;
(1H, m), 3.88 (3H, m), 2.51 (3H, s), 1.40 (3H, d, J = 7.0 Hz); 13C NMR (CDCl3,
50 MHz): d 167.3, 150.2 (d, J = 280 Hz), 149.2, 140.8, 135.6, 126.4, 123.5, 122.2,
116.4 (d, J = 10.0 Hz), 112.1, 63.2, 46.0, 26.4, 24.2; ESI-MS: m/z 212 [M+H]+.
Anal. Calcd for C11H14FNO2: C, 62.55; H, 6.63; N, 6.63. Found: C, 62.59; H, 6.58;
N, 6.68.
a
The structures of the products were established from their spectral (IR, 1H, 13C
NMR and MS) and analytical data.
b
Isolated yield after purification.
N-(1-(4-fluoro-3-methoxyphenyl)ethyl) benzamide (3f): IR: 3448, 1678, 1613,
1517, 1434, 1276 cmÀ1 1H NMR (CDCl3, 200 MHz): d 8.06 (1H, br s), 7.72–7.64
;
(4H, m), 7.01–6.92 (4H, m), 4.23 (1H, m), 3.88 (3H, s), 3.41 (3H, d, J = 7.0 Hz);
13C NMR (CDCl3, 50 MHz): d 161.0, 152.8 (d, J = 280.0 Hz), 150.8, 136.2, 125.5,
121.9, 115.9 (d, J = 10.0 Hz), 113.8 (d, J = 10.0 Hz), 113.2, 112.1, 77.8, 55.8, 24.0;
ESI-MS: m/z 274 [M+H]. Anal. Calcd for C16H16FNO2: C, 70.32; H, 5.86; N, 5.12.
Found: C, 70.27; H, 5.91; N, 5.16.
be prepared from the readily available ingredients, HClO4 and silica
gel.13 It can conveniently be handled and also be removed from the
reaction mixture. The catalyst was recovered, dried, and reused
consecutively thrice with only slight variation in the yields of the
products.
In conclusion, we have applied a Bronsted acid-based heteroge-
neous catalyst for dehydrative C–N bond formation using alcohols
and amides. Both the sulfonamides and carboxamides and various
alcohols including primary and secondary aliphatic as well as ben-
zylic alcohols have been successfully utilized for the N-alkylation
reaction. The method is simple, less costly, and comparatively
rapid.
N-Butyl-4-methylbenzenesulfonamide (3i): IR: 3281, 1598, 1423, 1320 cmÀ1 1H
;
NMR (CDCl3, 200 MHz): d ppm 7.74 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz),
2.89 (2H, q, J = 7.0 Hz), 2.42 (3H, s), 1.48–1.38 (2H, m), 1.32–1.21 (2H, m), 0.82
(3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 50 MHz): d 143.3, 137.0, 129.8, 136.9, 42.8,
31.2, 21.1, 19.5, 13.2; ESI-MS: m/z 228 [M+H]+. Anal. Calcd for C11H17NO2S: C,
58.14; H, 7.48; N, 6.16. Found: C, 58.19; H, 7.42; N, 6.21.
4-Methyl-N-phenethyl benzenesulfonamide (3k): IR: 3281, 1598, 1422,
1323 cmÀ1 1H NMR (CDCl3, 200 MHz): d 7.70 (2H, d, J = 8.0 Hz), 7.28–7.09
;
(5H, m), 7.02 (2H, d, J = 8.0 Hz), 3.12 (2H, q, J = 7.0 Hz), 2.71 (2H, t, J = 7.0 Hz),
2.40 (3H, s); 13C NMR (CDCl3, 50 MHz): d 143.2, 137.8, 137.0, 130.0, 129.1,
127.9, 127.7, 44.2, 35.6, 21.2; ESI-MS: m/z 276 [M+H]+. Anal. Calcd for
C
15H17NO2S: C, 65.45; H, 6.18; N, 5.09. Found: C, 65.51; H, 6.24; N, 5.03.