Solvent-mediated one-pot synthesis of cyclic N-Substituted imides

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Solvent-mediated One-pot Synthesis of
Cyclic N-Substituted Imides
Sambhaji V. Patil a , Keshao A. Mahale a , Kirankumar S. Gosavi a ,
Ganesh B. Deshmukh a & Nilesh S. Patil a
a Organic Chemistry Research Centre, K.T.H.M. College , Nashik ,
422 002 , Maharashtra , India
Published online: 24 Jun 2013.
To cite this article: Sambhaji V. Patil , Keshao A. Mahale , Kirankumar S. Gosavi , Ganesh B.
Deshmukh & Nilesh S. Patil (2013) Solvent-mediated One-pot Synthesis of Cyclic N-Substituted Imides,
Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 45:4,
314-320, DOI: 10.1080/00304948.2013.798569
To link to this article: http://dx.doi.org/10.1080/00304948.2013.798569
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Organic Preparations and Procedures International, 45:314–320, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.798569
OPPI BRIEF
Solvent-mediated One-pot Synthesis of Cyclic
N-Substituted Imides
Sambhaji V. Patil, Keshao A. Mahale, Kirankumar S. Gosavi,
Ganesh B. Deshmukh, and Nilesh S. Patil
Organic Chemistry Research Centre, K.T.H.M. College, Nashik-422 002.
Maharashtra, India.
The development of general, efficient synthetic methods for versatile organic compounds
from readily available reagents is one of the challenges in organic synthesis. N-Substituted
cyclic imides have found numerous applications in biology,1–6 pharmacology,7 syn-
thetic chemistry,8–19 polymer chemistry,20,21 and material science.22,23 Several herbicides,24
pesticides,24 and antifungal1 agents and a host of bioactive natural products have also been
synthesized by elaboration of N-aryl maleimides.16–19 Evaluation of the available methods
for the synthesis of N-substituted cyclic imides indicates that generally the amines are first
reacted with the desired cyclic anhydride and the resulting amic acids are then cyclized to
the corresponding imides using reagents such as Ac2O/NaOAc,25 Et3N/Ac2O,26 dimethyl
sulfate/Na2CO3/tetrabutylammonium bromide,27 cyanuric chloride/Et3N,28 [Bmim] [PF6],
140◦C29 among others.30–35 However, some of these procedures i) lack generality and scal-
ability, ii) use harsh reaction conditions, and hazardous, non-green reagents, iii) involve
tedious work-up and expensive reagents, iv) give low yield and sometimes result in con-
comitant addition of HCl to the maleimide.34 We now report our results to overcome these
shortcomings and have examined the formation of amic acids and their cyclization to the
corresponding imides using acetic acid/sulfuric acid in a one-pot synthesis.
In our initial experiments, acetic acid was used as solvent to generate the amic acids
from aniline and the cyclic anhydrides. In the second step, the isolated amic acids were
cyclized to corresponding imides by replacing acetic anhydride with acetic acid in presence
of sulfuric acid. Although the yields were excellent in both the steps, we were able to
simplify this procedure further into one-pot synthesis thus eliminating the need for the
isolation of the intermediate amic acids in equally good yields (Scheme 1).
The amine was treated in acetic acid with the cyclic anhydride at 25 to 45◦C for
10 minutes followed by treatment with sulfuric acid at 60◦C for 30 to 45 minutes. The
Received December 26, 2012.
Address correspondence to Sambhaji V. Patil, Organic Chemistry Research Centre, K.T.H.M.
College, Nashik-422 002. Maharashtra, India. E-mail: sambhajipatil@yahoo.com
314

One-pot Synthesis of Cyclic N-Substituted Imides
315
Scheme 1
applicability of the general procedure was established with both aliphatic and aromatic
amines and maleic anhydride, succinic anhydride, phtahlic anhydride and glutaric anhydride
(Table 1). This simple method reported here has several advantages, in particular, its use
of simple reagents, easy work-up, short reaction time, excellent yields and versatility;
this procedure may be scaled up easily. While the reaction of glutaric anhydride with
aliphatic amines proceeds in the expected fashion to give the cyclic imides, aromatic amines
invariably gave the corresponding acetanilide but not the expected cyclic imide. The poorer
nucleophilicity of aromatic amines compared to aliphatic amines may cause this variation
as indicated by the exclusive formation of aliphatic glutarimides when glutaric anhydride
was treated under these conditions with a mixture of aliphatic and aromatic amines.
In summary, we have demonstrated an efficient one-pot synthesis of a series of N-
substituted cyclic imides using table-top reagents and believe this general method will find
applications by their further functionalization to useful molecules.
Experimental Section
Melting points were determined on Gallenkamp apparatus Mod. MFB 595 using capillaries
and are uncorrected. 1H NMR spectra were recorded in CDCl3 (δ) on VarianXL-300 Spec-
trometer (300 MHZ), using tetramethylsilane as an internal standard. Infrared spectra were

316
Patil et al.
Table 1
Physical Constants for N-Substituted Cyclic Imides (3–6)
mp. ◦C (lit.)
R
3
4
5
6
a
b
c
d
e
f
g
h
i
C6H5
90 (89)33
155 (156)33
144
154 (154.8)29
92
172
163 (163.1)29
108
146
152
170
208 (209.9)29
150
206 (208–209)29
—
—
—
—
—
—
—
—
—
—
—
—
4-MeOC6H4
4-MeC6H4
2-MeC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-Cl,6-MeC6H3 62
4-Br,5-ClC6H3 158
3-O2NC6H4
4-O2NC6H4
2-O2NC6H4
155 (157)27
149 (150)33
70
156
—
—
—
—
—
—
—
—
260
—
126
115 (115.3)29
88
j
k
l
131 (132)28
142 (169)27
167 (169)33
m C6H4CH2
68 (69.5–70.5)33 102
118 (118–119)29 Colorless oil
(102–104)33
(Colorless
oil)33
n
o
n-C4H9
Colorless oil
(Colorless
oil)33
Colorless oil
(Colorless
oil)29
Colorless oil
80
Colorless oil
(Colorless
oil)33
HOCH2CH2
62
Colorless oil
Colorless oil
Table 2
Combustion Analysis of New Compounds
Calculated %
Found %
Imide
Molecular Formula
C
H
N
C
H
N
3d
3e
3g
3h
3i
3o
4b
4d
4e
4g
4h
4i
C11H9NO2
70.58
47.65
57.85
59.61
41.92
51.06
64.38
69.83
47.65
57.30
59.07
41.63
4.85
2.40
2.91
3.64
1.76
5.00
5.40
5.86
2.40
3.85
4.51
2.45
7.48
5.56
6.75
6.32
4.89
9.93
6.83
7.40
5.56
6.68
6.26
4.85
70.58
47.95
57.70
59.30
42.10
51.24
64.20
69.98
47.55
57.08
59.16
41.80
4.99
2.28
3.10
3.80
1.60
5.28
5.55
5.98
2.49
4.11
4.36
2.24
7.68
5.76
6.68
6.40
4.90
9.82
6.73
7.65
5.68
6.98
6.56
4.65
C10H6BrNO2
C10H6ClNO2
C11H8ClNO2
C10H5BrClNO2
C6H7NO3
C11H11NO3
C11H11NO2
C10H8BrNO2
C10H8ClNO2
C11H10ClNO2
C10H7BrClNO2
(Continued on next page)

One-pot Synthesis of Cyclic N-Substituted Imides
317
Table 2
Combustion Analysis of New Compounds (Continued)
Calculated %
Found %
H
Imide
Molecular Formula
C
H
N
C
N
4j
4l
C10H8N2O4
C10H8N2O4
C6H9NO3
C15H11NO3
C14H8N2O4
C12H13NO2
C10H9NO3
C7H11NO3
54.55
54.55
50.35
71.14
62.69
70.92
62.82
53.59
3.66
3.66
6.34
4.38
3.01
6.45
4.74
7.05
12.72
12.72
9.79
5.53
10.44
6.89
54.43
54.65
50.47
70.98
62.35
71.03
62.51
53.75
3.49
3.60
6.67
4.61
3.12
6.25
4.62
6.95
12.74
12.61
10.06
5.81
10.60
6.95
4o
5b
5k
5n
5o
6o
7.33
8.91
7.01
8.88
Table 3
Spectral Data of New Compounds
Imide
IR (cm−1
)
1H NMR (CDCl3, δ, ppm)
MS (M+ +1)
3d
2958, 1703, 1589,
1151, 833, 686
2.19 (3H, s, CH3), 6.84 (2H, s, 2 X =
CH), 7.27 (1H, d, J = 9.6, ArH),
7.30–7.35 (3H, m, ArH)
—
3e
1716, 1587, 1143,
825, 684
6.85 (2H, s, 2 X = CH) 7.25 (2H, d, J = 252.4,254.3
8.7 Hz, ArH), 7.58 (2H, d, J = 8.7 Hz,
ArH)
3g
3h
1709, 1586, 819, 685 6.86 (2H, s, 2 X = CH), 7.26–7.43 (4H,
208.2
m, ArH).
2952, 1712, 1639,
1587, 1155, 833,
684
2.17 (3H, s, CH3), 6.88 (2H, s),
7.22–7.36 (3H, m, ArH)
222.5
3i
1718, 1662, 1591,
1151, 827, 696
6.87 (2H, s, 2 X = CH), 7.25–7.29 (2H,
m, ArH), 7.47 (1H, dd, J = 2.1 &
8.7 Hz, ArH)
288.2
142.1
—
3o
4b
4d
4e
3450, 2898, 2883
1757, 1724,
2.02 (1H, s, OH), 3.80 (2H, t, J =
5.2 Hz., CH2), 4.24 (2H, t, J = 5.2 Hz,
CH2), 6.74 (2H, s, 2 X = CH)
2.88(4H, s, 2 X CH2), 3.82 (3H, s,
OCH3), 6.97 (2H, d, J = 8.7 Hz, ArH),
7.19 (2H, d, J = 8.7 Hz, ArH)
2.15 (3H, s, CH3), 2.92 (4H, s, 2 X CH2),
7.08 (1H, d, J = 7.2 Hz, ArH),
7.26–7.35 (3H, m, ArH)
2953, 1710, 1603.
830, 685
1703, 1494, 1190,
767, 661
190.6
256.5
1700, 1486, 1188,
824, 672
2.90 (4H, s, 2 X CH2), 7.20 (2H, d, J =
8.7 Hz, ArH), 7.61 (2H, d, J = 8.7 Hz,
ArH)
(Continued on next page)

318
Patil et al.
Table 3
Spectral Data of New Compounds (Continued)
Imide
IR (cm−1
)
1H NMR (CDCl3, δ, ppm)
MS (M+ +1)
4g
1708, 1583, 1186,
819, 690
2.92 (4H, s, 2 X CH2), 7.37–7.45 (4H, m,
ArH)
210.4
4h
4i
2995, 1708, 1465,
1180, 777, 676
1704, 1178, 829, 661 2.89 (4H, s, 2 X CH2), 7.18–7.28 (2H, m,
2.17 (3H, s, CH3), 2.95 (4H, s, 2 X CH2),
7.21–7.38 (3H, m, ArH)
224.1
289.1
ArH), 7.40 (1H, dd, J = 1.8 & 8.4 Hz,
ArH)
4j
4l
1710, 1529, 1377,
1353, 817, 682
1728, 1716, 1525,
1386, 1357, 1176,
707
2.95 (4H, s, 2 X CH2), 7.63–8.26 (4H, m,
ArH)
221.2
2.93 (4H, t, 2 X CH2), 7.30 (1H, d, J =
8 Hz, ArH), 7.50 (1H,dd, J = 7.8
&8.1 Hz, ArH), 7.75 (1H, dd, J = 8.1
& 7.8 Hz, ArH), 8.15 (1H, d, J = 8 Hz,
ArH).
221.2.
4o
5b
3445, 2960, 1774,
1735, 1701
2.06 (1H, s, OH), 2.73 (4H, s, 2 X CH2),
3.78 (2H, t, J = 5.2 Hz., CH2), 4.24
(2H, t, J = 5.2 Hz., CH2)
144.2
254.4
2989, 2945, 1772,
1739, 1716, 885,
715
3.84 (3H, s, OCH3), 7.1 (2H, d, J =
9.3Hz., ArH), 7.34 (2H, d, J = 9.3Hz.,
ArH), 7.78 (2H, dd, J = 3 & 8.7 Hz.,
ArH), 7.94 (2H, dd, J = 3 & 8.7 Hz.,
ArH)
5k
5n
1782, 1751, 1731,
1521, 1346, 838
7.79 (2H, d, J = 9 Hz., ArH), 7.86 (2H,
dd, J = 3.3 & 8.7Hz, ArH), 8.02 (2H,
dd, J = 3.3 & 8.7Hz., ArH), 8.39 (2H,
dJ = 9 Hz., ArH)
269.0
204.0
3024, 2960, 2937,
1772, 1710,
0.91 (3H, t, J = 7.2Hz., CH3), 1.35 (2H,
m, CH2), 1.65 (2H, m, CH2), 3.69 (2H,
t, J = 7.2 Hz., CH2), 7.70 (2H, dd, J =
1.8 & 8.7 Hz., ArH), 7.83 (2H, dd, J =
1.8 & 8.7Hz., ArH)
5o
6o
3465, 2981, 2954,
1776, 1731, 1706,
2.03 (1H, s, OH), 3.97 (2H, t, J =
10.5Hz., CH2), 4.32 (2H, t, J =
10.5Hz., CH2), 7.76 (2H, dd, J =
1.5&10.8Hz., ArH),7.86 (2H, dd, J =
1.5 & 10.8Hz., ArH)
1.98 (2H, m, CH2), 2.10 (1H, s, OH),
2.46(4H, t, J = 5.8Hz., 2 X CH2),
4.07(2H, t, J = 6Hz., CH2), 4.22 (2H, t,
J = 6Hz., CH2)
192.1
—
3288, 3024, 2925,
1708

One-pot Synthesis of Cyclic N-Substituted Imides
319
acquired on Shimadzu FTIR-408 instrument. Bruker Daltonics instrument, ESI/Q/TOF
(HMRS), Micro TOTQ mass spectrometer with an ionization potential of 70 eV was used
for mass analysis. The combustion analysis for all new compounds was found to be within
the range of 0.3.
Synthesis of N-Substituted Cyclic Imides (3–6). General Procedure
To a vigorously stirred (stir bar) solution of the amine (1, 0.04 mole) in acetic acid (30 ml),
the anhydride (2a–d, 0.044 mole) was added in one lot. The reaction mixture was stirred
further for 10 minutes at room temperature in case of 2a and 2d and at 45◦C in case of
2b and 2c. The clear solution turned into slurry due to separation of the amic acid. To this
stirred slurry, concentrated sulfuric acid (9.20 g, 0.0938 mole) was added in one lot. Due
to the exothermic reaction, temperature increased by 10 to 15◦C and the suspension turned
into a clear solution. The temperature of reaction mixture was then maintained at 60◦C for
30–45 minutes. The cooled reaction mixture was poured onto crushed ice (100 g). The solid
separated was collected, washed with aqueous sodium bicarbonate and then with water,
and recrystallized from aqueous ethanol. The products were purified by chromatography
on silica gel column using chloroform as eluent to prepare analytical samples. (Table 1).
Acknowledgment
Authorities of Maratha Vidya Prasarak Samaj, Nashik and K. T. H. M. College are thanked
for their support in providing infrastructural facilities. UGC New Delhi is thanked for
financial support [F.2-2/2011(SAP-II)]. Dr. V. Balasubramaniyan is thanked for fruitful
discussion and encouragement.
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