N-Butylammonium carboxylates/Tf2O: Ionic liquid based systems for the synthesis of unsymmetrical imides via a Ritter-type reaction

Article abstract of DOI:10.1016/j.tetlet.2012.03.121

We have developed a new method for the preparation of unsymmetrical imides using liquid carboxylate salts via a Ritter-type process. The reactions were carried out with nitriles and n-butylammonium carboxylates as ionic liquids in the presence of triflic anhydride (Tf₂O) as the promoter. Mild reaction conditions, simplicity of the procedure, and proton-free conditions are the main advantages of this procedure.

Full text of DOI:10.1016/j.tetlet.2012.03.121

Tetrahedron Letters 53 (2012) 2881–2884
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Tetrahedron Letters
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n-Butylammonium carboxylates/Tf2O: ionic liquid based systems for the
synthesis of unsymmetrical imides via a Ritter-type reaction
Mohammad Mehdi Khodaei a, , Ehsan Nazari b
⇑
a Department of Organic Chemistry and Nanoscience & Nanotechnology Research Center (NNRC), Razi University, Kermanshah 67149, Iran
b Office of Education, Masjed Soleyman County, Khuzestan Province, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a new method for the preparation of unsymmetrical imides using liquid carboxylate
salts via a Ritter-type process. The reactions were carried out with nitriles and n-butylammonium car-
boxylates as ionic liquids in the presence of triflic anhydride (Tf2O) as the promoter. Mild reaction con-
ditions, simplicity of the procedure, and proton-free conditions are the main advantages of this
procedure.
Received 10 February 2012
Revised 17 March 2012
Accepted 29 March 2012
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
n-Butylammonium carboxylates
Triflic anhydride
Ritter reaction
Nitriles
Imides
The imide moiety represents an important substructure associ-
ated with natural products, such as fumaramidmycin,1a,b coniothy-
riomycin,1c and SB-253514.1d In addition, the imide group can act
as a useful directing group in Michael addition and alkylation reac-
tions.2,3 Classically, imides are prepared by the reaction of amides
with acyl chlorides, anhydrides, and carboxylic esters or acids.4 In
addition, other reported methods include the reaction of azlac-
tones with O2 and Pd/C,5 aminocarbonylation of aryl bromides,6
reaction of pentafluorophenyl (PFP) esters with deprotonated
amides,7 couplings of amides with thioesters using FeCl2/NBS,8
amidation of an aldehyde with CuBr/NBS,9 and oxidation of N-
alkylamides.10
Most of the above reported methods have one or more of the
following drawbacks: high temperature, long reaction time, use
of a solvent or two phase systems, toxic reagents, corrosive and
hazardous oxidants, tedious work-up, and side reactions such as
elimination to nitriles, formation of triacyl amides, or acyl group
transfer.
acylating reagents (acid anhydrides) are easily available. However,
the preparation of imides through Ritter-type reactions13 has not
been investigated extensively, and there is still considerable inter-
est in developing this type of reaction.
Trifluoromethanesulfonic anhydride (triflic anhydride, Tf2O) is
commercially available and known for its utility for the conversion
of an OH group into an OTf leaving group in organic transforma-
tions.14 Although triflic anhydride is expensive, it has been widely
used as a powerful promoter in different organic reactions.15,16
We were attracted toward the use of ionic liquids (ILs) in view
of their benefits in organic transformations for sustainable devel-
opment such as environmental compatibility, reusability, greater
selectivity, operational simplicity, noncorrosiveness, and ease of
isolation.17 A survey of the literature indicated that there was no
report on the synthesis of imides utilizing ionic liquids. Herein,
we report liquid n-butylammonium carboxylates18 as new nitrile
acylating reagents for the synthesis of a range of imides through
a Ritter-type route in the presence of triflic anhydride as the
promoter.
The structures of the three n-butylammonium carboxylates uti-
lized in this research are shown in Figure 1. Firstly, as a model sys-
tem, the reaction of n-butylammonium acetate (1) (1 mmol) with
4-chlorobenzyl cyanide (1 mmol) was investigated in the presence
of triflic anhydride (1 mmol) at 60 °C (Scheme 1). After 1 h, the cor-
responding imide was obtained in 83% yield, and a small amount of
amide was also formed as a by-product (7%). When acetic acid was
used instead of 1, several by-products were produced in parallel
with the formation of imide. This observation may be due to the
presence of trifluoromethanesulfonic acid generated by the
The amidation of nitriles with alcohols in the presence of acid is
known as the Ritter reaction.11 Recently, Habibi et al.12 extended
this method and reported the synthesis of linear imides by reaction
of nitriles with acid anhydrides in the presence of silica sulfuric
acid. We believe that the extension of the Ritter reaction can be
considered as an efficient procedure for the synthesis of imides be-
cause harsh reaction conditions are not required, and nitriles and
⇑
Corresponding author.
E-mail address: mmkhoda@razi.ac.ir (M.M. Khodaei).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.121

2882
M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 2881–2884
O
O
In order to study the generality of this procedure, other types of
NH3
nitriles were reacted with ILs 1, 2, and 3 according to the reaction
conditions shown in Scheme 1, and the results are presented in Ta-
ble 1. The reaction of 4-chlorobenzyl cyanide with ILs 2 and 3 affor-
ded the desired products in good yields (Table 1, entries 2 and 3).
In comparison with IL 1, the results of the reactions of 2 and 3 did
not show any noticeable differences with respect to yield and reac-
tion time. The reactions of benzyl cyanide were investigated under
similar reaction conditions, and a remarkable decrease in yield was
observed (Table 1, entries 4 and 5). In these reactions, Friedel–
Crafts acylation19 on the aromatic ring occurred as a competitive
side reaction. When benzyl cyanides with electron-donor groups
such as an o-methoxy group and p-methyl group were used, no
imides were produced since the aromatic rings were activated.
However, the reaction of 4-nitrobenzyl cyanide with ILs 1 and 2
in the presence of triflic anhydride afforded the desired products
in 46% and 45% yields, respectively (Table 1, entries 6 and 7). In
these cases, the electron-withdrawing NO2 group decreased the
nucleophilicity of the nitrogen of the CN group, and therefore these
reactions did not go to completion.
NH3
O
O
1
2
O
NH3
O
3
Figure 1. n-Butylammonium carboxylates.
O
O
CN
N
H
O
Tf2O (1 mmol)
NH3
+
O
60 °C, neat, 1 h
Cl
Cl
1 mmol
1 mmol
The reactions of several other aryl nitriles were investigated un-
der the present reaction conditions. As shown in Table 1, benzoni-
trile produced the corresponding imide in 81% yield (Table 1, entry
8). The introduction of halides such as Cl and Br also afforded the
corresponding imides (Table 1, entries 10 and 11). Finally, the
Scheme 1. Model reaction.
reaction of acetic acid and triflic anhydride. It seems that the use of
n-butylammonium acetate (1) creates proton-free conditions.
Table 1
Synthesis of imides using ILs 1–3 and various nitriles in the presence of triflic anhydride
O
O
Tf2O
CN
IL
+
R
R
N
H
R'
Entry
1
Nitrile
IL
Product
Yielda (%)Ref.
O
O
N
H
1
2
3
8320
Cl
Cl
Cl
CN
O
O
O
O
N
H
2
3
85
85
Cl
N
H
O
O
O
O
N
H
4
5
1
2
425
448
CN
N
H

M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 2881–2884
2883
Table 1 (continued)
Entry
Nitrile
IL
Product
Yielda (%)Ref.
O
O
O
N
H
6
7
1
4612
CN
NO2
O
N
H
NO2
2
4512
NO2
O
O
O
O
8
9
1
2
819
839
N
H
CN
N
H
CN
CN
O
O
O
889
918
N
H
10
11
1
2
Cl
Cl
O
N
H
Br
Br
O
O
O
12
13
1
2
9312
9212
N
H
CN
O
N
H
a
Isolated yield.
placed by a nucleophile. Subsequent replacement of triflate with
nitrile produces intermediate 5 which was hydrolyzed by dilute
NaHCO3 solution to yield the corresponding imide.
In conclusion, the present procedure involving mild reaction
conditions, the use of inexpensive ionic liquids, and the avoidance
of volatile organic and toxic solvents, is very simple and conve-
nient.21 Other advantages of this procedure are proton-free condi-
tions and relatively short reaction times.
R
N
O
S
O
O
S
O
F3C
O
CF3
O
O
O
S
O
R'
NH3
O
R'
F3C
OH
O
RT to 60 °C
0 °C to RT
4
O
Acknowledgment
CF3
S
O
O
O
OH/H2O
O
O
O
We thank the Razi University for generous financial support of
this work.
R'
N
R
R'
N
H
R
R'
N
R
5
References and notes
Scheme 2. A proposed reaction mechanism.
1. (a) Maruyama, H. B.; Suhara, Y.; Suzuki-Watanabe, J.; Maeshima, Y.; Shimizu,
N.; Ogura-Hamada, M.; Fujimoto, H.; Takano, K. J. Antibiot. 1975, 28, 636–647;
(b) Suhara, Y.; Maruyama, H. B.; Kotoh, Y.; Miyasaka, Y.; Yokose, K.; Shirai, H.;
Takano, K.; Quitt, P.; Lanz, P. J. Antibiot. 1975, 28, 648–655; (c) Krohn, K.;
Franke, C.; Jones, P. G.; Aust, H. J.; Draeger, S.; Shultz, B. Liebigs Ann. Chem. 1992,
789–798; (d) Pinto, I. L.; Boyd, H. F.; Hickey, D. M. B. Bioorg. Med. Chem. Lett.
2000, 10, 2015–2017.
2. (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204–11205; (b)
Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706–
707; (c) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem.
Soc. 2003, 125, 11796–11797.
3. (a) Kim, S. K.; Lim, C. J.; Song, C.; Chung, W. J. Am. Chem. Soc. 2002, 124, 14306–
14307; (b) Flitsch, W.; Hohenhorst, M. Liebigs Ann. Chem. 1990, 397–399.
4. (a) Wheeler, O. H.; Rosado, O. In The Chemistry of Amides; Zabicky, J., Ed.; John
Wiley and Sons: New York, 1970; p 335; (b) Challis, B. C.; Challis, J. In The
Chemistry of Amides; Zabicky, J., Ed.; John Wiley and Sons: New York, 1970; p
759.
reaction of acetonitrile as a representative alkyl nitrile was inves-
tigated with ILs 1 and 2, and excellent yields of the corresponding
imides were observed (Table 1, entries 12 and 13).
It should be noted that in all cases, except for acetonitrile, a
small amount of the corresponding amide by-product was gener-
ated. Also, the attempted synthesis of ILs containing aromatic car-
boxylate anions was not successful because the solid state of the
corresponding carboxylic acids prevented formation of the desired
ILs.
A proposed reaction mechanism is outlined in Scheme 2. Nucle-
ophilic attack of the carboxylate on triflic anhydride leads to mixed
anhydride 4 in which the triflate leaving group is ready to be re-

2884
M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 2881–2884
5. Bates, R. B.; Fletcher, F. A.; Janda, K. D.; Miller, W. A. J. Org. Chem. 1984, 49, 3038.
6. Schnyder, A.; Indolese, A. F. J. Org. Chem. 2002, 67, 594–597.
Soc. 2008, 130, 18–19; (h) Aridos, G.; Laali, K. K. J. Org. Chem. 2011, 76, 8088–
8094.
7. Andrus, M. B.; Li, W.; Keyes, R. F. Tetrahedron Lett. 1998, 39, 5465–5468.
8. Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2009, 351, 246–
252.
17. Wasserscheid, P.; Welton, T. Ionic Liquid in Synthesis; Wiley-VCH: Weinheim,
2004.
18. Preparation of n-butylammonium carboxylates: 1 mmol of liquid carboxylic acid
was added to 1 mmol of n-butylamine at 0 °C, and the mixture was stirred for
10 min at room temperature to give the desired ionic liquid.
19. Khodaei, M. M.; Alizadeh, A.; Nazari, E. Tetrahedron Lett. 2007, 48, 4199–4202.
20. Knittel, D. Monatsh. Chem. 1988, 119, 379–388.
21. General Procedure for the synthesis of imides: 1 mmol of Tf2O (0.16 mL) was
added to 1 mmol of ionic liquid at 0 °C, and the mixture was stirred for 5 min at
room temperature. Then, 1 mmol of the nitrile was added and the mixture was
heated at 60 °C. After 1 h, NaHCO3 (2%, 5 mL) was added and the mixture was
extracted with EtOAc (2 Â 5 mL). The organic layer was dried over Na2SO4 and
evaporated. The crude product was purified by column chromatography using
EtOAc/n-hexane (2:8) as eluent to afford the desired imide. Spectral and
analytical data for new compounds:
9. Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2008, 14, 10722.
10. For selected examples of the oxidation of N-alkylamides, see: (a) Xu, L.; Zhang,
S.; Trudell, M. L. Chem. Commun. 2004, 1668–1669; (b) Nicolaou, K. C.;
Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44, 5992–5997; (c) Bjorsvik, H. R.;
Fontana, F.; Liguori, L.; Minisci, F. Chem. Commun. 2001, 523–524; (d) Minisci,
F.; Punta, F. C.; Recupero, F.; Fontana, F.; Pedulli, G. F. J. Org. Chem. 2002, 67,
2671–2676; (e) Sueda, T.; Kajishima, D.; Goto, S. J. Org. Chem. 2003, 68, 3307–
3310; (f) Gledhill, A. P.; McCall, C. J.; Threadgill, M. D. J. Org. Chem. 1986, 51,
3196–3201; (g) Jin, Z.; Xu, B.; Hammond, G. B. Tetrahedron Lett. 2011, 52, 1956–
1959; (h) Sperry, J. Synthesis 2011, 3569–3580.
11. Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949, 71, 4128–4129.
12. Habibi, Z.; Salehi, P.; Zolfigol, M. A.; Yousefi, M. Synlett 2007, 812–814.
13. (a) Mohammadpoor-Baltork, I.; Tangestaninejad, S.; Moghadam, M.; Mirkhani,
V.; Nasr-Esfahani, M. J. Iran. Chem. Soc. 2011, 8, 401–410; (b) Nasr-Esfahani, M.;
Montazerozohori, M.; Filvan, N. J. Serb. Chem. Soc. 2011, 76, 1–12.
14. Effenberger, F. Angew. Chem. 1980, 92, 147–232.
(Table 1, entry 2): White solid; Mp 142–143 °C. IR (KBr): 1732, 3172,
3265 cmÀ1 1H NMR (200 MHz, CDCl3): d 0.90 (t, J = 3.4 Hz, 3H), 1.57–1.72
.
(m, 2H), 2.57 (t, J = 7.4 Hz, 2H), 3.89 (s, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.31 (d,
J = 8.4 Hz, 2H), 8.71 (br s, 1H). 13C NMR (50 MHz, DMSO-d6): 13.5, 17.4, 42.3,
128.1, 131.4, 131.5, 133.8, 171.4, 173.8. Anal. Calcd for C12H14ClNO2: C, 60.13;
H, 5.89; N, 5.84. Found: C, 60.07; H, 5.92; N, 5.77.
15. Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000, 56,
3077–3119.
16. For selected examples of the use of triflic anhydride in organic reactions, see:
(a) Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277–2280; (b) Chain, W. J.; Myers,
A. G. Org. Lett. 2007, 9, 355–357; (c) Lévesque, F.; Bélanger, G. Org. Lett. 2008,
10, 4939–4942; (d) Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789–9799; (e)
Carret, S.; Deprés, J. P. Tetrahedron Lett. 2008, 49, 5642–5644; (f) Wei, P.; Kerns,
R. J. J. Org. Chem. 2005, 70, 4195–4198; (g) Barbe, G.; Charette, A. B. J. Am. Chem.
(Table 1, entry 3): White solid; Mp 121–122 °C. IR (KBr): 1684, 1732, 3151,
3201 cmÀ1 1H NMR (200 MHz, CDCl3): d 0.95 (d, J = 6.6, 6H), 2.06–2.19 (m, 1H),
.
2.46 (d, J = 7.0 Hz, 2H), 3.91 (s, 2H), 7.20 (d, J = 8.4 Hz, 2H), (7.30, J = 8.4 Hz, 2H),
9.37 (br s, 1H). 13C NMR (50 MHz, CDCl3): 22.4, 25.2, 43.2, 46.3, 128.8, 130.9,
132.0, 133.3, 172.1, 174.3. Anal. Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N,
5.52. Found: C, 61.47; H, 6.43; N, 5.49.