Organocatalytic synthesis of amides from nitriles via the Ritter reaction

Article abstract of DOI:10.1016/j.tetlet.2011.08.121

A simple, inexpensive, environmentally friendly, and efficient route for the synthesis of a wide variety of amides in high yields via the Ritter reaction of alcohols with nitriles has been demonstrated. Pentafluorophenyl ammonium triflate (PFPAT) is used as an organocatalyst and is air-stable, cost-effective, easy to handle, and easily removed from the reaction mixtures.

Full text of DOI:10.1016/j.tetlet.2011.08.121

Tetrahedron Letters 52 (2011) 5943–5946
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic synthesis of amides from nitriles via the Ritter reaction
Samad Khaksar a, , Eskandar Fattahi a, Esmail Fattahi b
⇑
a Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
b Department of Biology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2011
Revised 25 July 2011
Accepted 22 August 2011
Available online 7 September 2011
A simple, inexpensive, environmentally friendly, and efficient route for the synthesis of a wide variety of
amides in high yields via the Ritter reaction of alcohols with nitriles has been demonstrated. Pentafluor-
ophenyl ammonium triflate (PFPAT) is used as an organocatalyst and is air-stable, cost-effective, easy to
handle, and easily removed from the reaction mixtures.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pentafluorophenyl ammonium triflate
Organocatalyst
Alcohols
Nitrile
The N-tert-butyl amide group is found in many natural and syn-
thetic biologically active materials, and its derivatives are applied in
various pharmaceutical and biochemical fields.1,2 The simple and
straightforward procedure reported by Ritter in 1948 involves con-
densation of alcohols, suitably substituted alkenes, or tertiary ha-
lides, with nitriles in the presence of a stoichiometric amount of a
strong acid, typically H2SO4, and often together with a highly ioniz-
ing solvent, such as AcOH, forming amides upon hydrolysis.3,4 The
main disadvantage of the classical Ritter procedure is the use of an
excess amount of corrosive sulfuric acid, which has limited its appli-
cability to compounds containing functional groups stable to acid.
The classical Ritter reaction requires several modifications to over-
come its limitations. Some of the modified methods are as follows:
Nafion-H as a solid catalyst,5,6 Nafion-H along with microwave irra-
diation,7 formic acid under reflux,8 HBF4ÁEt2O,9 2,4-dinitrobenzene-
sulfonic acid,10 HClO4-functionalized silica-coated nanoparticles,11
liquid HF,12 TMS–CN/H2SO4 as a reagent for the synthesis of forma-
mides,13 t-BuOAc instead of t-BuOH as a carbocation precursor,14
Tf2O/ROH as an in situ source of ROTf,15 metal complexes,16 Bi(OTf)3
and other metallic triflates,17 I2,18 ionic liquids,19 and a nitrosonium
salt to effect the Ritter reaction of halides with nitriles.20 However,
these methods suffer from the disadvantages, such as high cost, poor
availability or toxicity of the reagents, and extended reaction times.
Additionally the main drawback of almost all the existing methods is
that the catalysts decompose during the aqueous work-up and their
recovery is often impossible. Reymond and co-workers21 found that
FeCl3 catalyzed the Ritter reaction of nitriles with benzylic alcohols
as well as the Ritter reaction of nitriles with t-BuOAc producing,
respectively, benzylic amides and t-butyl-protected primary
amides. However, realizing the fact that metal-free organocatalysis
has drawn considerable interest from chemists, and that metal-free
homogeneous catalysis is advantageous for designing suitable drugs
devoid of any metal content, it would be desirable to develop this
reaction using metal-free Lewis acid catalysts.22 Organocatalysts
have gained importance due to the economic and environmental
considerations.23 These catalysts are generally less expensive,
highly reactive, eco-friendly, easy to handle, reduce reaction times,
impart greater selectivity, and can be applied under less demanding
reaction conditions, such as rigorously anhydrous or anaerobic con-
ditions. Pentafluorophenylammonium triflate (PFPAT)24 has re-
ceived considerable attention as an inexpensive and readily
available catalyst for various organic transformations due to its
moderate Lewis acidity, stability to air, and water tolerance. In this
regard and in connection with our previous work,25 herein, we re-
port the Ritter reaction of various nitriles with alcohols 1–5 and
tert-butyl acetate using PFPAT as an efficient organocatalyst
(Scheme 1).
Initially, in order to investigate the catalytic activity of PFPAT in
the Ritter reaction, we examined its efficiency in a model reaction
between benzonitrile (2.0 equiv) and tert-butanol (2.2 equiv) un-
der neat conditions at 90 °C to give the corresponding N-substi-
tuted amide in 90% yield (Table 1, entry 3). After some efforts, a
O
PFPAT (10 mol%)
+
R
R-OH
R'
N
R'
N
H
solvent-free, 90 °C
⇑
Corresponding author. Fax: +98 121 2517087.
E-mail address: S.khaksar@iauamol.ac.ir (S. Khaksar).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.121

5944
S. Khaksar et al. / Tetrahedron Letters 52 (2011) 5943–5946
Table 1
Ritter reaction of various alcohol and nitriles catalyzed by PFPAT
Entry
Alcohol
Nitrile
Amide
Time (h)
2
Yield (%) Ref
9011
O
O
O
OH
1
MeCN
Me
1
N
H
CN
2
3
4
5
6
1
1
2
3
2
2
3
9211
9019
9518
9511
9218
N
H
PhCN
Ph
N
H
OH
O
O
O
MeCN
N
Me
Ph
2
H
CN
2
2
N
H
PhCN
N
H
OH
O
O
O
H
Me
N
7
8
MeCN
1
1
9518
3
CN
H
H
N
N
3
3
9511
Ph
O
9
PhCN
1
2
9218
OH
10
MeCN
9511
N
H
Me
Ph
4
O
O
CN
11
12
4
4
2
9511
N
H
PhCN
2.5
9211
N
H
OH
O
Me
N
9011
5
13
MeCN
3
H

S. Khaksar et al. / Tetrahedron Letters 52 (2011) 5943–5946
5945
Table 1 (continued)
Entry
Alcohol
Nitrile
Amide
Time (h)
Yield (%) Ref
O
N
CN
14
15
5
3
9511
H
O
N
Ph
5
PhCN
3
9011
H
catalytic amount of PFPAT (10 mol %) was found to be superior for
this functional transformation. We decided to generalize this new
protocol by subjecting it to various substituted alcohols and ni-
triles, and a series of N-substituted amides were prepared in high
yields. The reaction was general and various benzylic amides were
obtained using different nitriles and benzylic alcohols. The reaction
of alcohol 1 with MeCN led to the expected amide in 90% isolated
yield (Table 1, entry 1). Acrylonitrile appeared to be a suitable ni-
trile which reacted with 1 to give the corresponding amide in 92%
yield (Table 1, entry 2). Benzhydrol 3 also reacted quickly with
MeCN, acrylonitrile, and PhCN to produce the corresponding
amides in 95%, 95%, and 92% isolated yields, respectively (Table
1, entries 7–9). This method could be extended to allylic alcohol,
cinammyl alcohol, and a benzyl alcohol. The results of the present
study are summarized in Table 1.
these conditions (Scheme 2, entries 1–4). Although the amount
of catalyst had been optimized to 10 mol %, a lesser amount
(5 mol %) also worked but led to longer reaction times. In addition,
the PFPAT catalyst was easily separated from the reaction mixture
after work-up; washing with NaOH aqueous solution removed
CF3SO3H, followed by distillation under reduced pressure
(C6F5NH2: bp 153 °C at 760 mmHg).
In conclusion, we have developed a simple chemoselective
methodology for a modified Ritter reaction using PFPAT as an
organocatalyst. In contrast to the existing methods using poten-
tially hazardous catalysts/additives, the present method offers
the following advantages: (i) PFPAT is easy to prepare from com-
mercially available pentafluoroaniline and triflic acid, (ii) short
reaction times, (iii) ease of product isolation/purification, (iv) no
side reactions, (v) low costs and simplicity in process and handling,
and (vi) metal-free synthesis avoiding toxic reagents and solvents.
To further expand the scope of this process, we next examined
the reactions between benzonitrile and tert-butyl acetate. As ex-
pected, these substrates underwent smooth, one-pot conversion
to give the corresponding N-substituted amide in an excellent yield
(Scheme 2, entry 3).
Experimental
General experimental procedure for the synthesis of amides
Subsequently, the Ritter reaction of tert-butyl acetate was ex-
tended to various aromatic and aliphatic nitriles and a range of
tert-butyl amides was isolated in good to excellent yields under
Alcohol (2 mmol) and nitrile (2.2 mmol) were mixed with
PFPAT (10 mol %) under neat conditions at 90 °C, until complete
disappearance of the starting alcohol (as monitored by TLC). After
cooling to room temperature, the organic phase was washed with
aqueous 1 M NaOH solution (1 ml). The separated organic phase
was evaporated under reduced pressure to give a crude residue,
which was purified by distillation or by column chromatography
(hexane–EtOAc).
O
O
PFPAT (10 mol%)
H2O, 90 C, 3 h
+
R
N
Me
R
N
H
O
ref
Entry
Nitrile
Product
O
Yield %
General experimental procedure for the synthesis of tert-butyl
amides
9011
9211
Me-CN
1
Me
tert-butyl acetate (2 mmol), nitrile (2.2 mmol), and H2O
(2 mmol) were mixed with PFPAT (10 mol %) and heated to
90 °C, until complete disappearance of the starting nitriles (as
monitored by TLC). After cooling to room temperature, the organ-
ic phase was washed with aqueous 1 M NaOH solution (1 ml). The
separated organic phase was evaporated under reduced pressure
to give a crude residue, which was purified by distillation or by
column chromatography (hexane–EtOAc). The products were
characterized by comparison of their physical and spectral data
with those of authentic samples. Spectroscopic data for selected
examples:
N
H
O
2
CN
Ph-CN
N
H
O
9018
9018
3
4
Ph
N
H
O
(Table 1, entry 3):1H NMR (400 MHz, CDCl3): d = 7.76 (d,
J = 8.03 Hz, 2H), 7.43–7.52 (m, 3H), 5.98 (br s, 1H, NH), 1.51 (s, 9H).
13C NMR (100 MHz, CDCl3): d = 167.3, 136.3, 131.5, 128.9, 127.2,
52.1, 29.3.
Ph-CH2CN
PhH2C
N
H
Scheme 2. Preparation of N-tert-butyl amides using PFPAT.

5946
S. Khaksar et al. / Tetrahedron Letters 52 (2011) 5943–5946
9. Subba Reddy, B. V.; Sivasankar Reddy, N.; Madan, C.; Yadav, J. S. Tetrahedron
(Table 1, entry 6): 1H NMR (500 MHz, CDCl3): d = 7.70–7.72 (m,
Lett. 2010, 51, 4827.
2H), 7.30–7.50 (m, 8H), 6.44 (br s, 1H, NH), 5.30 (t, J = 6.8 Hz, 1H),
1.62 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 167.3, 143.5,
135.2, 131.9, 129.1, 128.8, 127.9, 127.3, 126.7, 49.6, 22.1.
(Table 1, entry 9): 1H NMR (400 MHz, CDCl3): d = 7.86–7.87 (m,
2H), 7.52–7.57 (m, 1H), 7.46–7.50 (m, 2H), 7.38–7.42 (m, 4H),
7.30–7.38 (m, 6H), 6.80 (br s, 1H), 6.50 (d, J = 7.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d = 166.8, 141.9, 134.6, 132.1, 129.1,
129.8, 128.3, 127.9, 127.5, 57.8.
10. Sanz, R.; Martinez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J.
Org. Chem. 2007, 4642.
11. Ma’mani, L.; Heydari, A.; Sheykhan, M. Appl. Catal., A: Gen. 2010, 384, 122.
12. Norell, J. R. J. Org. Chem. 1970, 35, 1611.
13. Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdorf, J. Tetrahedron Lett. 1996, 45,
8129.
14. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207.
15. Martinez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.; Hanack, M.;
Subramanian, I. R. Tetrahedron Lett. 1989, 30, 581.
16. (a) Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78; (b) Barton, D. H. R.; Magnus, P.
D.; Young, R. N. J. Chem. Soc., Chem. Commun. 1973, 331; (c) Mukhopadhyay, M.;
Reddy, M. M.; Maikap, G. G.; Iqbal, J. J. Org. Chem. 1995, 60, 2670.
17. Callens, E.; Burton, A. J.; Barrett, A. G. M. Tetrahedron Lett. 2006, 47, 8699.
18. Theerthagiri, P.; Lalitha, A.; Arunachalam, P. N. Tetrahedron Lett. 2010, 51, 2813.
19. Kalkhambkar, R. G.; Waters, S. N.; Laali, K. K. Tetrahedron Lett. 2011, 52, 867.
20. Olah, G. A.; Balaram Gupta, B. G.; Narang, S. C. Synthesis 1979, 274.
21. Anxionnat, B.; Guérinot, A.; Reymond, S.; Cossy, J. Tetrahedron Lett. 2009, 50,
3470.
22. Prakash, G. K. S.; Panja, C.; Do, C.; Mathew, T.; Olah, G. A. Synlett 2007, 2395.
23. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Connon, S. J. Synlett 2009,
354; (d) Connon, S. J. Chem. Commun. 2008, 2499; (e) Takemoto, Y. Org. Biomol.
Chem. 2005, 3, 4299; (f) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289; (g) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (h) List, B. Chem. Commun.
2006, 819; (i) Marigo, M.; Jrgensen, K. A. Chem. Commun. 2006, 2001; (j)
Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (k)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
Acknowledgment
This research was supported by the Islamic Azad University,
Ayatollah Amoli Branch.
References and notes
1. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045; (b) Denson, F. R.;
Ritter, J. J. J. Am. Chem. Soc. 1949, 71, 4128.
2. Samguigni, J. A.; Levins, R. J. Med. Chem. 1964, 7, 573.
3. (a) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4045; (b) Krimen, L. I.; Cota,
D. J. Org. React. 1969, 17, 213.
4. Brewer, A. R. E. In Name Reactions for Functional Group Transformations; Li, J. J.,
Corey, E. J., Eds.; Wiley: Hoboken, NJ, 2007; p 471.
24. PFPAT is commercially available; TCI Product No- P1626: (a) Funatomi, T.;
Wakasugi, K.; Misaki, T.; Tanabe, Y. Green Chem. 2006, 8, 1022; (b) Iida, A.;
Osada, J.; Nagase, R.; Misaki, T.; Tanabe, Y. Org. Lett. 2007, 9, 1859.
25. Montazeri, N.; Khaksar, S.; Nazari, A.; Alavi, S. S.; Vahdat, S. M.; Tajbakhsh, M. J.
Fluorine Chem. 2011, 132, 450.
5. Olah, G. A.; Yamato, T.; Iyer, P. S.; Trivedi, N. J.; Singh, B. P.; Surya Prakash, G. K.
Mater. Chem. Phys. 1987, 17, 21.
6. Yamato, T.; Hu, J. Y.; Shinoda, N. J. Chem. Res. 2007, 11, 641.
7. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 2661.
8. Gullickson, G. C.; Lewis, D. E. Synthesis 2003, 681.