A novel one-pot synthesis of unsymmetrical acyclic imides

Article abstract of DOI:10.1055/s-2007-970781

A new and convenient method was found for the one-pot synthesis of symmetrical and unsymmetrical linear imides by reaction of aliphatic and aromatic nitriles with acyclic carboxylic anhydrides in the presence of silica sulfuric acid as an active and recyclable reagent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970781

812
LETTER
A Novel One-Pot Synthesis of Unsymmetrical Acyclic Imides
Synthesis of
U
n
o
symmetrical
h
Acyclic Imi
r
des eh Habibi,a Peyman Salehi,*b Mohammad Ali Zolfigol,c Maryam Yousefia
a
Department of Chemistry, Shahid Beheshti University, Evin, Tehran 19839-63113, Iran
b
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, PO Box 19835-389, Evin,
Tehran, Iran
Fax +98(21)22431783; E-mail: p-salehi@sbu.ac.ir
c
Department of Chemistry, Faculty of Science, Bu-Ali Sina University, Hamadan 65174, Iran
Received 21 April 2006
Silica sulfuric acid is a versatile and stable acidic catalyst
which has been used successfully for several organic
transformations.17
Abstract: A new and convenient method was found for the one-pot
synthesis of symmetrical and unsymmetrical linear imides by
reaction of aliphatic and aromatic nitriles with acyclic carboxylic
anhydrides in the presence of silica sulfuric acid as an active and
recyclable reagent.
The amidation of alcohols with nitriles in the presence of
an acidic catalyst is known as the Ritter reaction.18 By a
careful investigation of this reaction, we have simulated
this method for the one-pot synthesis of a wide variety of
linear imides in fair to good yields by the use of acid
anhydrides instead of alcohols. The reaction of nitriles
with aliphatic anhydrides proceeded smoothly within 6–8
hours in the presence of silica sulfuric acid (Scheme 1).19
Key words: unsymmetrical acyclic imide, silica sulfuric acid,
Ritter reaction, nitrile
The imide group is an interesting functionality due to its
wide presence in the natural products and pharmacologi-
cally active compounds. Mixed acyclic imide functional-
ity is shared by a growing class of natural products with
diverse activity such as immunosuppressants,1 cytotoxic
anticancer agents,2 antibiotics,3 and antifeedants.4
O
.
O
O
O
silica sulfuric acid
RCN
+
R
N
R'
R'
O
R'
H
Unlike cyclic imides, where much is known about their
synthesis and reactivity,5 only few methods have been
reported for the construction of acyclic imides.
Scheme 1
The results are summarized in Table 1. As shown, ex-
Available methods for synthesis of unsymmetrical acyclic cellent yields were obtained in the reactions of aliphatic
imides suffer from low yields, high temperature or nitriles (entries 1–9). In the case of aryl nitriles, the corre-
scrambling of the grouping to give symmetrical imides.6
sponding amides were also produced as side products,
therefore the yields decreased in these cases (entries 10–
16). We decided to conduct the same reaction with other
typical Lewis acids such as AlCl3, FeCl3, ZnCl2, NaHSO4,
etc. but unsatisfactory results were obtained.
Classically, imides are prepared by the reaction of amides
with acyl chlorides, anhydrides and carboxylic esters or
acids.7 However, these methods are not as straightforward
as they seem at the first glance and several side reactions
such as elimination to nitriles, formation of triacyl amides, The recyclability of the catalyst was also studied in the
or acyl group scrambling can occur. The best yields were reaction of acetonitrile and acetic anhydride. After each
reported for the acid-catalyzed reaction of anhydrides reaction, the reagent was recovered and reused in a new
with amides.6a
run. Some decrease in the activity of silica sulfuric acid
was observed, although the reagent was still active after
five cycles (Table 2).
Other procedures for the synthesis of acyclic imides
involve aminocarbonylation of aryl bromides,8 reaction of
azalactone with oxygen and palladium,9 ruthenium tetrox- In conclusion, silica sulfuric acid is efficiently used as a
ide oxidation of N-acylated alkyl amines,10 and reaction of recyclable reagent for the one-pot synthesis of acyclic
pentafluorophenyl (PFP) esters with deprotonated imides by the use of available starting materials. To the
amides.11
best of our knowledge, this is one of the simplest pro-
cedures for preparation of a wide variety of imides as a
valuable class of organic compounds with diverse
pharmacological activities.
The more sophisticated methods involve the treatment of
amides with reagents such as dimethyl acetals of
amides,12 N,N-bis(trimethylsilyl)formamide,13 a,a,a-tri-
chloromethyl carbonyl compounds,14 diketene,15 or vinyl
esters.16
References and Notes
(1) Koehn, F. E.; Longley, R. E.; Reed, J. K. J. Nat. Prod. 1992,
55, 613.
(2) Pettit, G. R.; Kamano, Y.; Dufresne, C.; Cerny, R. L.;
Herald, C. L.; Schmidt, J. M. J. Org. Chem. 1989, 54, 6005.
SYNLETT 2007, No. 5, pp 0812–0814
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970781; Art ID: D11706ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
3.
2
0
0
7

LETTER
Synthesis of Unsymmetrical Acyclic Imides
813
(9) Bates, R. B.; Fletcher, F. A.; Janda, K. D.; Miller, W. A. J.
Org. Chem. 1984, 49, 3038.
(10) Tanaka, K. I.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull.
1987, 35, 364.
(11) Andrus, M. B.; Li, W.; Keyes, R. F. Tetrahedron Lett. 1998,
39, 5465.
Table 1 Products from Reaction of Nitriles and Anhydrides
Entry
1
R
R¢
Time (h) Yield (%)a,b
Me
Me
5.9
6.1
5.8
5.9
6.3
7.1
6.9
7.3
7.1
6.1
6.3
6.2
7.6
7.6
5.8
5.6
96
92
97
93
97
87
83
89
35
58
64
61
48
43
67
64
2
Me
n-Bu
Me
(12) Lin, Y. I.; Lang, S. A. Jr. Synthesis 1980, 119.
(13) Kantlehner, W.; Fischer, P.; Kugel, W.; Moehring, E.;
Bredereck, H. Justus Liebigs Ann. Chem. 1978, 512.
(14) Atanasov, I.; Petrov, I.; Ognyanova, V.; Mollov, N. Synth.
Commun. 1990, 20, 2083.
(15) Yamamoto, Y.; Onishi, S.; Azuma, Y. Synthesis 1981, 122.
(16) Seiller, B.; Heins, D.; Bruneau, C.; Dixneuf, P. H.
Tetrahedron 1995, 51, 10901.
(17) (a) Zolfigol, M. A. Tetrahedron 2001, 57, 9509. (b) Salehi,
P.; Dabiri, M.; Zolfigol, M. A.; Bodaghifard, M. A.
Tetrahedron Lett. 2003, 44, 2889. (c) Zolfigol, M. A.;
Shirini, F.; Ghorbani Choghamarani, A.; Mohammadpoor
Baltork, I. Green Chem. 2002, 4, 562. (d) Salehi, P.; Dabiri,
M.; Zolfigol, M. A.; Bodaghi Fard, M. A. J. Braz. Chem.
Soc. 2004, 15, 773. (e) Salehi, P.; Dabiri, M.; Zolfigol, M.
A.; Bodaghi Fard, M. A. Heterocycles 2003, 60, 2435.
(f) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M.
Tetrahedron Lett. 2005, 46, 7051. (g) Salehi, P.; Zolfigol,
M. A.; Shirini, F.; Baghbanzadeh, M. Curr. Org. Chem.
2006, 10, 2171.
3
Et
4
Me
n-Pr
n-Pr
Me
5
i-Pr
6
ClCH2
ClCH2
ClCH2
Ph
7
n-Pr
n-Bu
Me
8
9
10
11
12
13
14
15
16
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-NO2C6H4CH2
4-NO2C6H4CH2
3-ClC6H4
3-ClC6H4
Me
n-Pr
n-Bu
Me
(18) (a) Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949, 71,
4128. (b) Salehi, P.; Khodaei, M. M.; Keyvan, A. Synth.
Commun. 2001, 31, 1947; and other references cited therein.
(19) General Procedure for Liquid Nitriles
n-Pr
Me
A mixture of 50 mmol of nitrile, silica sulfuric acid (0.18 g,
equal to 1.36 mmol H+) and 1 mmol of carboxylic anhydride
was heated in a 25 mL round-bottomed flask at 60–70 °C.
The reactions were completed within 6–8 h as monitored by
TLC (eluent, EtOAc–PE, 1:1). The mixture was filtered and
solvent was evaporated under reduced pressure. A solution
of NaHCO3 in H2O (1%, 10 mL) was added and the mixture
was extracted with Et2O (3 × 25 mL). The organic layer was
separated and dried over Na2SO4. When necessary, the crude
product was purified by preparative TLC on silica gel.
General Procedure for Solid Nitriles
In a round-bottomed flask the solid nitrile (1 mmol), car-
boxylic anhydride (1 mmol) and silica sulfuric acid (0.18 g,
equal to 1.36 mmol H+) were mixed thoroughly. The flask
was heated at 40–50 °C with concomitant stirring. After
completion of the reaction confirmed by TLC (eluent:
EtOAc–PE, 1:9), EtOAc (15 mL) was added and filtered.
The filtrate was concentrated and purified by preparative
TLC.
n-Pr
a All products were fully characterized by their IR, 1H NMR,
13C NMR and MS spectral data.20
b Yield of pure isolated product.
Table 2 Recyclability of Silica Sulfuric Acid in the Reaction of
Acetonitrile and Acetic Anhydride
Run
1
Time (h)
5.9
Yield (%)
96
93
89
80
75
2
6.2
3
6.5
4
7.2
5
8.0
(20) Spectroscopic Data for Entries 1–16
N-Acetylacetamide (entry 1): white solid, mp 73–74 °C. 1H
NMR (300 MHz, CDCl3): d = 2.07 (s, 6 H), 8.72 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.91, 171.96. IR (KBr):
3410, 3265, 3215, 1732 cm–1. MS (EI): m/z (rel. intensity) =
101 (10) [M+], 72 (35), 58 (100).
(3) Nakamura, H.; Iitaka, Y.; Sakakibara, H.; Umezawa, H. J.
Antibiot. 1974, 27, 894.
(4) Nagle, D. G.; Paul, V. J.; Roberts, M. A. Tetrahedron Lett.
1996, 37, 6263.
(5) Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Chem. Rev.
1970, 70, 439.
(6) (a) Davidson, D.; Skovronek, H. J. Am. Chem. Soc. 1958, 80,
376. (b) Zil’berman, E. N. Russ. Chem. Rev. 1960, 29, 331.
(c) Durrell, W. S.; Young, J. A.; Dresdner, R. D. J. Org.
Chem. 1963, 28, 831. (d) Bowser, J. R.; Williams, P. J.;
Kurz, K. J. Org. Chem. 1983, 48, 4111.
(7) (a) Wheeler, O. H.; Rosado, O. In The Chemistry of Amides;
Zabicky, J., Ed.; J. Wiley and Sons: New York, 1970, 335.
(b) Challis, B. C.; Challis, J. In The Chemistry of Amides;
Zabicky, J., Ed.; J. Wiley and Sons: New York, 1970, 759.
(8) Schnyder, A.; Indolese, A. F. J. Org. Chem. 2002, 67, 594.
N-Pentanoylacetamide (entry 2): white solid, mp 62–64 °C.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H),
1.33–1.45 (m, 2 H), 1.60–1.70 (m, 2 H), 2.38 (s, 3 H), 2.52
(t, J = 7.4 Hz, 2 H), 8.57 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 13.75, 22.17, 25.12, 26.45, 37.03, 172.41,
174.03. IR (KBr): 3260, 3230, 1729 cm–1. MS (EI): m/z (rel.
intensity) = 144 (41) [M+], 114 (25), 101 (58), 59 (82), 43
(100).
N-Acetylpropionamide (entry 3): white solid, mp 85–86 °C.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.4 Hz, 3 H),
2.11 (s, 3 H), 2.32 (q, J = 7.4 Hz, 2 H), 8.25 (br s, 1 H). 13
NMR (75 MHz, CDCl3): d = 8.37, 25.10, 29.69, 30.63,
C
Synlett 2007, No. 5, 812–814 © Thieme Stuttgart · New York

814
Z. Habibi et al.
LETTER
172.20, 174.63. IR (KBr): 3265, 3236, 1727 cm–1. MS (EI):
m/z (rel. intensity) = 115 (50) [M+], 97 (25), 71 (81), 57
(100). Anal. Calcd for C5H9NO2: C, 52.16; H, 7.88; N,
12.17; O, 27.79. Found: C, 52.08; H, 7.79; N, 12.09; O,
27.74.
N-Butyrylpropionamide (entry 4): white solid, mp 109–110
°C. 1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.4 Hz, 3
H), 1.17 (t, J = 7.4 Hz, 3 H), 1.65–1.73 (m, 2 H), 2.58 (t,
J = 7.2 Hz, 2 H), 2.66 (q, J = 7.1 Hz, 2 H), 8.84 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 8.35, 13.62, 17.86, 30.76,
39.27, 174.18, 175.21. IR (KBr): 3260, 3227, 1731 cm–1. MS
(EI): m/z (rel. intensity) = 144 (12) [M+], 115 (25), 87 (28),
74 (80), 57 (100).
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.9; O,
18.06. Found: C, 67.62; H, 5.83; N, 8.00; O, 18.54.
N-Butyryl-4-methylbenzamide (entry 11): white solid, mp
87–88 °C. 1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.3
Hz, 3 H), 1.73–1.82 (m, 2 H), 2.44 (s, 3 H), 7.31 (d, J = 8.0
Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 8.64 (br s, 1 H). 13C NMR
(75 MHz, CDCl3): d = 13.74, 17.59, 21.59, 39.42, 127.69,
129.65, 130.00, 144.05, 165.37, 176.24. IR (KBr): 3270,
2950, 2935, 1710 cm–1. MS (EI): m/z (rel. intensity) =
205(32) [M+], 136 (20), 119 (100), 91 (33). Anal. Calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82; O, 15.59. Found: C,
69.95; H, 7.01; N, 6.79; O, 15.52.
N-Pentanoyl-4-methylbenzamide (entry 12): white solid, mp
101–102 °C. 1H NMR (300 MHz, CDCl3): d = 0.97 (t,
J = 7.3 Hz, 3 H), 1.38–1.48 (m, 2 H), 1.66–1.76 (m, 2 H),
2.44 (s, 3 H), 3.02 (t, J = 7.5 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2
H), 7.79 (d, J = 8.2 Hz, 2 H), 8.53 (br s, 1 H). 13C NMR (75
MHz, CDCl3): d = 13.89, 21.59, 22.32, 26.27, 37.30, 127.73,
129.65, 130.04, 144.04, 165.40, 176.46. IR (KBr): 3280,
2920, 2924, 1699 cm–1. MS (EI): m/z (rel. intensity) = 219
(34) [M+], 136 (20), 119 (100), 91 (50).
N-Butyrylisobutyramide (entry 5): white solid, mp 108–109
°C. 1H NMR (300 MHz, CDCl3): d = 0.72 (t, J = 7.4 Hz, 3
H), 0.95 (d, J = 6.9 Hz, 6 H), 1.37–1.48 (m, 2 H), 2.45 (t,
J = 7.4 Hz, 2 H), 2.49–2.56 (m, 1 H), 7.90 (br s, 1 H). 13
C
NMR (75 MHz, CDCl3): d = 13.63, 17.72, 18.80, 35.86,
39.32, 175.64, 177.57. IR (KBr): 3260, 3234, 1727 cm–1. MS
(EI): m/z (rel. intensity) = 157 (40) [M+], 88 (62), 71(100),
43 (81).
N-Acetyl-2-chloroacetamide (entry 6): white solid, mp 114–
115 °C. 1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 4.28
(s, 2 H), 8.67 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d =
24.91, 43.66, 166.83, 171.31. IR (KBr): 3260, 3245, 1740
cm–1. MS (EI): m/z (rel. intensity) = 137 (11) [M + 2], 135
(34) [M+], 93 (20), 43(100).
N-Butyryl-2-chloroacetamide (entry 7): white solid, mp
111–112 °C. 1H NMR (300 MHz, CDCl3): d = 1.00 (t,
J = 7.4 Hz, 3 H), 1.70 (m, 2 H), 2.64 (t, J = 7.3 Hz, 2 H), 4.35
(s, 2 H), 8.51 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d =
13.54, 17.67, 39.05, 44.11, 167.30, 173.75. IR (KBr): 3255,
3242, 1740 cm–1. MS (EI): m/z (rel. intensity) = 165 (5) [M
+ 2], 163 (16) [M+], 135 (77), 114 (35), 71 (100), 43 (80).
N-Pentanoyl-2-chloroacetamide (entry 8): white solid, mp
104–105 °C. 1H NMR (300 MHz, CDCl3): d = 0.95 (t,
J = 7.3 Hz, 3 H), 1.34–1.46 (m, 2 H), 1.61–1.71 (m, 2 H),
N-Acetyl-4-nitrobenzamide (entry 13): white solid, mp
118 °C. 1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H), 4.07
(s, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 8.1 (br s, 1 H), 8.23 (d,
J = 8.6 Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 25.08,
41.06, 124.00, 130.57, 140.63, 147.33, 170.66, 171.98. IR
(KBr): 3435, 3250, 2990, 1732 cm–1. MS (EI): m/z (rel.
intensity) = 222 (11) [M+], 163 (88), 137 (30), 43 (100).
Anal. Calcd for C10H10N2O4: C, 54.05; H, 4.54; N, 12.61; O,
28.80. Found: C, 54.02; H, 4.50; N, 12.55; O, 28.77.
N-Butyryl-4-nitrobenzamide (entry 14): white solid, mp
122 °C. 1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.4 Hz,
3 H), 1.64–1.74 (m, 2 H), 2.50 (t, J = 7.3 Hz, 2 H), 4.16 (s, 2
H) 7.47 (d, J = 8.8 Hz, 2 H), 8.09 (br s, 1 H), 8.22 (d, J = 8.8
Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 13.56, 17.80,
39.30, 43.51, 123.74, 130.60, 140.87, 147.27, 171.25,
174.20. IR (KBr): 3205, 3000, 1729 cm–1. MS (EI): m/z (rel.
intensity) = 250 (10) [M+], 180 (30), 163 (50), 133 (25), 88
(50), 71 (100), 43 (75).
N-Acetyl-3-chlorobenzamide (entry 15): white solid, mp
105–107 °C. 1H NMR (300 MHz, CDCl3): d = 2.63 (s, 3 H),
7.45–7.49 (m, 3 H), 7.88 (s, 1 H), 8.71 (br s, 1 H). 13C NMR
(75 MHz, CDCl3): d = 25.65, 125.75, 128.24, 130.23,
133.24, 134.41, 135.27, 164.63, 173.81. IR (KBr): 3418,
3196, 1718 cm–1. MS (EI): m/z (rel. intensity) = 199 (8) [M
+ 2], 197 (16) [M+], 168 (18), 139 (100), 111 (25), 75 (20),
71 (100), 43 (50).
2.66 (t, J = 7.4 Hz, 2 H), 4.33 (s, 2 H), 8.53 (br s, 1 H). 13
NMR (75 MHz, CDCl3): d = 13.76, 22.15, 26.22, 36.99,
C
44.01, 166.97, 173.76. IR (KBr): 3260, 3235, 1739 cm–1. MS
(EI): m/z (rel. intensity) = 179 (3) [M + 2], 177 (10) [M+],
135 (30), 107(33), 85 (100), 57 (88). Anal. Calcd for
C7H12ClNO2: C, 47.33; H, 6.81; Cl, 19.96; N, 7.89; O, 18.01.
Found: C, 47.03; H, 6.77; N, 7.81; O, 17.95.
N-Acetylbenzamide (entry 9): white solid, mp 112–114 °C.
1H NMR (300 MHz, CDCl3): d = 2.39 (s, 3 H), 7.21–7.63 (m,
5 H), 8.44 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d = 25.47,
127.58, 129.08, 132.72, 133.30, 165.53, 173.15. IR (KBr):
3295, 1722 cm–1. MS (EI): m/z (rel. intensity) = 163 (10)
[M+], 105 (100), 77 (78).
N-Acetyl-4-methylbenzamide (entry 10): white solid, mp
103–104 °C. 1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H),
2.63 (s, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 8.2 Hz,
2 H), 8.59 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d = 21.59,
25.65, 127.93, 129.58, 129.80, 144.08, 165.84, 174.10. IR
(KBr): 3395, 3285, 1709 cm–1. MS (EI): m/z (rel. inten-
sity) = 177 (25) [M+], 162 (30), 119 (100), 91 (80), 65 (52).
N-Butyryl-3-chlorobenzamide (entry 16): white solid, mp
97–100 °C. 1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.4
Hz, 3 H), 1.73–1.80 (m, 2 H), 2.98 (t, J = 7.4 Hz, 2 H), 7.44–
7.73 (m, 3 H), 7.87 (s, 1 H), 8.54 (br s, 1 H). 13C NMR (75
MHz, CDCl3): d = 13.71, 17.46, 39.58, 125.87, 128.22,
129.78, 130.16, 133.13, 133.50, 134.59, 135.20, 164.55,
176.88. IR (KBr): 3420, 3185, 2920, 1710 cm–1. MS (EI):
m/z (rel. intensity) = 227 (2) [M + 2], 225 (7) [M+], 196 (30),
156 (75), 139 (100), 111 (75), 75 (50), 43 (88).
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