HBF4·OEt2 as a mild and versatile reagent for the Ritter amidation of olefins: A facile synthesis of secondary amides

Article abstract of DOI:10.1016/j.tetlet.2010.07.032

A variety of alkenes undergo smooth amidation with nitriles in the presence of HBF₄·OEt₂ at room temperature under mild conditions to afford the corresponding secondary amides in good to excellent yields. This is a highly efficient method for the preparation of α-aryl ethyl amides especially from vinyl arenes without any side reactions such as olefin polymerization. The use of readily available and easy to handle reagent HBF₄·OEt₂ makes this method simple, convenient, and practical.

Full text of DOI:10.1016/j.tetlet.2010.07.032

Tetrahedron Letters 51 (2010) 4827–4829
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Tetrahedron Letters
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HBF4ÁOEt2 as a mild and versatile reagent for the Ritter amidation of olefins:
a facile synthesis of secondary amides
*
B. V. Subba Reddy , N. Sivasankar Reddy, Ch. Madan, J. S. Yadav
Division of Organic Chemistry, 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:
A variety of alkenes undergo smooth amidation with nitriles in the presence of HBF4ÁOEt2 at room tem-
Received 22 May 2010
Revised 1 July 2010
Accepted 6 July 2010
Available online 8 July 2010
perature under mild conditions to afford the corresponding secondary amides in good to excellent yields.
This is a highly efficient method for the preparation of a-aryl ethyl amides especially from vinyl arenes
without any side reactions such as olefin polymerization. The use of readily available and easy to handle
reagent HBF4ÁOEt2 makes this method simple, convenient, and practical.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ritter amidation
Alkenes
Nitriles
HBF4ÁOEt2
a-Aryl ethyl amides
The conversion of hydroxyl groups into amides is often known
HBF4ÁOEt2 under neat conditions. The reaction went to completion
in 6 h at room temperature and the corresponding N-(1-phenyl-
ethyl)acetamide 3a was isolated in 85% yield (Scheme 1).
This result encouraged us to extend this process to various al-
kenes and nitriles. Interestingly, various vinyl arenes such as
p-chloro-, p-methyl-, and p-tert-butyl styrenes underwent smooth
coupling with nitriles to give the corresponding N-(1-aryleth-
yl)acetamide derivatives in high yields (Table 1, entries b–g). This
method is also effective for sterically hindered substrates such as,
for example, 2-vinyl naphthalene (Table 1, entry l). Furthermore,
dihydronaphthalene and indene also participated well in this reac-
tion (Table 1, entries k and m). In the case of dihydronaphthalene,
indene, and vinyl arenes, the nitrile attacked the benzylic position
(Table 1, entries a–m). Next, we examined the reaction of cycloalk-
enes with nitriles under similar conditions. For example, the treat-
ment of cyclohexene and cyclopentene with acetonitrile in the
presence of HBF4ÁOEt2 gave 1-acetamidocylohexane and 1-acetam-
idocyclopentane respectively in good yields (Table 1, entries n and
o, Scheme 2).
as the Ritter reaction which is one of the most direct and important
methods for the introduction of an amino functionality onto an or-
ganic molecule.1 Generally, strong acids such as sulfuric acid and
formic acid are known to catalyze this reaction.2 In order to cir-
cumvent serious side reactions in the sulfuric acid approach, sev-
eral modifications and improvements have been made and the
protic acid is often replaced by Lewis acids.3 A variety of Lewis
acids such as AlCl3, FeCl3, SnCl4, and BF3ÁOEt2 have been used for
the selective amidation of benzyl alcohols.4 Subsequently, solid
acid catalysts such as clays, rare earth exchanged HY-zeolite, and
heteropoly acids have also been utilized for the conversion of alco-
hols into amides.5 Although a variety of acid catalysts have been
explored for the amidation of alcohols, only a few catalysts are
known for the amidation of olefins with nitriles.6 Recently, various
modifications of the original Ritter reaction have also been re-
ported for the amidation.7 In particular, haloamidation of olefins,
Betti–Ritter reaction, Mannich–Ritter reaction, and Prins–Ritter
reaction are noteworthy.8 However, to the best of our knowledge,
there have been no reports on the amidation of olefins with nitriles
using HBF4ÁOEt2.
Other nitrile derivatives such as benzonitrile, benzyl cyanide,
and acrylonitrile also underwent smooth addition on styrene to
Following our interest on the use of HBF4ÁOEt2 in organic syn-
thesis,9 we herein report a versatile and mild alternative method
for the synthesis of secondary amides from olefins and nitriles
using a ethereal solution of tetrafluoroboric acid. Initially, we have
attempted the coupling of styrene (1) with acetonitrile (2) using
give the corresponding
a-phenylethyl amide derivatives in high
O
.
N
HBF4 OEt2
CH3CN
+
H
6h, rt
2
3a
1
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Scheme 1. Preparation of N-(1-phenylethyl)acetamide.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.032

4828
B. V. Subba Reddy et al. / Tetrahedron Letters 51 (2010) 4827–4829
Table 1
Direct synthesis of amides from olefins and nitriles using HBF4ÁOEt2
Entry
a
Olefin (1)
Nitrile (2)
Product (3)a
Time (h)
6.0
Yieldb (%)
85
O
CH3CN
N
H
O
O
N
H
b
CH3CN
7.0
80
Cl
Cl
Cl
Cl
N
H
Ph
c
PhCN
6.5
6.5
82
85
O
d
CH3CN
N
H
O
N
e
CH3CN
7.0
90
H
O
O
Ph
N
f
PhCH2CN
7.5
6.5
89
80
Cl
Cl
H
Cl
Cl
N
H
g
CH3CN
O
O
O
Ph
h
i
PhCH2CN
7.0
6.5
6.0
91
85
81
N
H
PhCN
N
H
Ph
CN
j
N
H
O
HN
k
l
CH3CN
CH3CN
7.0
8.0
85
75
O
N
H
H
N
m
n
CH3CN
CH3CN
CH3CN
8.0
7.5
8.5
70
72
70
O
H
N
O
H
N
o
O
a
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b
H
tions (Table 1, entry g). However, no reaction was observed in
the absence of HBF4ÁOEt2 even after an extended reaction time
(12 h). In all cases, the reactions proceeded rapidly at room tem-
perature under mild conditions and the products were obtained
in good to excellent yields. As shown in Table 1, this method works
well with both terminal as well as internal olefins. In all cases, sec-
ondary amides were obtained exclusively without the formation of
any side products such as fluorinated compounds under the
N
.
HBF4 OEt2
CH3CN
+
O
( )n
7.5-8.5h,rt
( )n
Scheme 2. Preparation of cyclohexyl and cyclopentyl acetamides.
yields (Table 1, entries c, f, h, i and j). Furthermore,
styrene also reacted well with acetonitrile under identical condi-
a-substituted

B. V. Subba Reddy et al. / Tetrahedron Letters 51 (2010) 4827–4829
4829
L. R. Tetrahedron Lett. 1989, 30, 581; (c) Barton, D. H. R.; Magnus, P. D.; Young, R.
N. J. Chem. Soc., Chem. Commun. 1973, 331; (d) Barton, D. H. R.; Magnus, P. D.;
Garbarino, J. A.; Young, R. N. J. Chem. Soc., Perkin Trans. 1 1974, 2101; (e) Reddy,
K. L. Tetrahedron Lett. 2003, 44, 1453.
CH
3
..
N
R
H
CH
3
N
R
3. Kacan, M.; McKillop, A. Synth. Commun. 1993, 23, 2185.
4. Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth. Commun. 1994, 24, 601.
5. (a) Kumar, H. M. S.; Reddy, B. V. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S. New J.
Chem. 1999, 23, 955; (b) Sanz, R.; Martínez, A.; Guilarte, V.; Álvarez-Gutiérrez, J.
M.; Rodríguez, F. Eur. J. Org. Chem. 2007, 4642; (c) Yadav, J. S.; Reddy, B. V. S.;
Pandurangam, T.; Reddy, Y. J.; Gupta, M. K. Catal. Commun. 2008, 9, 1297; (d)
Wang, G. W.; Shen, Y. B.; Wu, X. L. Eur. J. Org. Chem. 2008, 4367.
6. (a) Trost, B. M.; Fleming, I.; Martin, F. In Comprehensive Organic Synthesis;
Pergamon press: Oxford, 1991; Vol. 4, p 292; (b) Clarke, T.; Devine, J.; Dicker, D.
W. J. Am. Oil. Chem. Soc. 1964, 41, 78.
..
H O
2
CH
O
CH
CH OH
3
3
3
N
H
R
N
N
R
R
-H
7. Cazorla, C.; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50,
6855.
Scheme 3. A plausible reaction mechanism.
8. (a) Rawal, G. K.; Kumar, A.; Tawar, U.; Vankar, Y. D. Org. Lett. 2007, 9, 5171; (b)
Yeung, Y. Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644; (c) Yadav, J.
S.; Reddy, B. V. S.; Chary, D. N.; Chandrakanth, D. Tetrahedron Lett. 2009, 50,
1136; (d) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Bioorg. Med. Chem. Lett.
2008, 18, 788; (e) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735;
(f) Yadav, J. S.; Reddy, B. V. S.; Aravind, S.; Kumar, G. G. K. S. N.; Madhavi, C.;
Kunwar, A. C. Tetrahedron 2008, 64, 3025; (g) Yadav, J. S.; Reddy, B. V. S.; Kumar,
G. G. K. S. N.; Reddy, G. M. Tetrahedron Lett. 2007, 48, 4903.
present reaction conditions. The scope and generality of this pro-
cess is illustrated with respect to various alkenes and nitriles and
the results are presented in Table 1.10
Mechanistically, we assume that the reaction likely proceeds via
the protonation of alkene by HBF4ÁOEt2. The resulting carbocation
might be trapped by nitrile to give the nitrilium cation which sub-
sequently reacts with water to furnish the desired amide as shown
in Scheme 3.
In summary, we have developed a simple, convenient, and effi-
cient method for the preparation of secondary amides by means of
amidation of olefins with nitriles using HBF4ÁOEt2. This method of-
fers significant advantages including mild conditions, simplicity of
the reagent, and no formation of by-products. This method pro-
vides an easy access to a wide variety of secondary amides.
9. (a) Yadav, J. S.; Reddy, B. V. S.; Anusha, B.; Reddy, U. V. S.; Reddy, V. V. B.
Tetrahedron Lett. 2010, 51, 2872; (b) Yadav, J. S.; Reddy, B. V. S.; Ramesh, K.;
Kumar, G. G. K. S. N.; Grée, R. Tetrahedron Lett. 2010, 51, 1578.
10. Typical procedure: a mixture of styrene (1 mmol), acetonitrile (1 mmol), and
HBF4ÁOEt2 complex (1 mmol) was stirred at 23 °C for the specified amount of
time (Table 1). After completion of the reaction as indicated by TLC, the
reaction mixture was quenched with saturated NaHCO3 solution and extracted
with ethyl acetate (2 Â 10 mL). The combined organic layers were dried over
anhydrous Na2SO4. Removal of the solvent followed by the purification on
silica gel (Merck, 100–200 mesh, ethyl acetate–hexane, 0.5–9.5) gave the pure
N-(1-phenylethyl)acetamide. The products thus obtained were characterized
by IR, NMR, and mass spectroscopy. Spectral data for selected compounds:
compound 3a: N-(1-phenylethyl)acetamide: pale yellow solid, mp 63–65 °C; 1
H
NMR (300 MHz, CDCl3): d 7.29 (m, 5H), 5.84 (br s, 1H), 5.07 (m, 1H), 1.94
Acknowledgment
(s, 3H), 1.49 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 169.2, 143.2, 128.4,
127.1, 126.1, 48.6, 23.1, 21.6; IR (KBr):
m 3265, 1644, 1552, 1447, 1374,
700 cmÀ1; EIMS: m/z: 163 [M]+. Compound 3b: N-(1-(4-chlorophenyl)ethyl)-
acetamide: white solid, mp 89–91 °C; 1H NMR (300 MHz, CDCl3): d 7.15–7.36
(m, 4H), 5.57 (br s, 1H), 5.0–5.16 (m, 1H), 1.96 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 169.1, 141.7, 132.8, 128.6, 127.4, 48.1, 23.2, 21.6;
N.S.R. and Ch.M. thank Director, IICT, for the financial
assistance.
IR (KBr):
m
3293, 1648, 1551, 1369, 828, 738 cmÀ1; EIMS: m/z: 197 [M]+.
References and notes
Compound 3h: (2-phenyl-N-(1-phenylethyl)acetamide: white solid, mp 93–
95 °C; 1H NMR (300 MHz, CDCl3): d 7.10–7.36 (m, 5H), 5.51 (br s, 1H), 5.02–
5.13 (m, 1H), 3.53 (s, 2H), 1.39 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
1. (a) Ritter, J. J.; Minier, P. P. J. Am. Chem. Soc. 1948, 70, 4045; (b) Krimen, L. I.;
Cota, D. J. Org. React. (NY) 1969, 17, 213.
2. (a) Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78; (b) Garcia Martinez, A.;
Martinez Alvarez, R.; Teso Vilar, E.; Garcia Fraile, A.; Hanack, M.; Subramanian,
169.9, 142.9, 129.2, 128.8, 128.4, 127.1, 125.8, 48.6, 43.7, 21.7; IR (KBr): m 3313,
1647, 1532, 1245, 698; EIMS: m/z: 240 [M+H]+.