An isocyanide-based multicomponent reaction: New route for synthesis of isoxazolinedione derivatives

Article abstract of DOI:10.1002/jhet.719

An efficient and novel multicomponent reaction for synthesis of new isoxazolinedione has been described. This protocol involves reaction of two molecules of isocyanide, aliphatic oxime, alkylidene substituted Meldrum's acid, and water (moisture). Elementa

Full text of DOI:10.1002/jhet.719

Month 2013
An Isocyanide-Based Multicomponent Reaction: New Route for
Synthesis of Isoxazolinedione Derivatives
*
Azizollah Habibi, Fahimeh Vafadarnejad and Marjan Akbari Armand
Faculty of Applied Chemistry, Tarbiat Moallem University, No. 49, P. Code 15719-14911
Mofateh Avenue, Tehran, Iran
*
E-mail: habibi@tmu.ac.ir
Received July 17, 2010
DOI 10.1002/jhet.719
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and novel multicomponent reaction for synthesis of new isoxazolinedione has been
described. This protocol involves reaction of two molecules of isocyanide, aliphatic oxime, alkylidene
substituted Meldrum's acid, and water (moisture). Elemental analyses, IR, 1H NMR, and 13C NMR spectro-
scopic data of products are consistent with the structure defined by X-ray diffraction analysis.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
derivatives were used in Diels–Alder reactions, conjugate
addition, cyclization, and so on [8–10].
Multicomponent reactions (MCRs) have an important
role for the efficient and simple synthesis of wide variety
of different compounds. The diversity, efficiency, and
rapid access to small and highly functionalized organic
molecules makes this approach of central current interest
in the construction of combinatorial libraries and optimiza-
tion in drug discovery process. These reactions have one-
pot procedure and ready operation, facile execution,
generally high yield, and convergence virtue.
Among MCRs, isocyanides-based MCRs are important
tools for the rapid and ready synthesis of a wide variety of
interested organic molecules. On the basis of isocyanides
chemistry, several synthesis of drug-like and heterocyclic
compounds needed in medicinal chemistry were reported
and extensive researches are being made [1–3].
RESULTS AND DISCUSSION
To expand our current work on investigation, three-com-
ponent reaction of isocyanide and alkylidene Meldrum's
acid in the presence of RXH moieties [11,12], here we
wish to report the result of reaction between isocyanide
1, alkylidene Meldrum's acid 2, and Ketoxime 3 (Scheme
1). So, one-pot MCR of alkyl isocyanide 1, alkylidene
Meldrum's acid 2 in the presence of ketoxime 3 occurred
in CH2Cl2 as solvent and at room temperature. After 48 h
the reaction was completed with moderate yield and crude
products were purified with column chromatography using
hexane/ethyl acetate as eluent.
Because of the great rule of Meldrum's acid derivatives in
organic synthesis, we are interested to investigate MCR using
isocyanide, alkylidene Meldrum's acid, and RXH moieties.
Meldrum's acid has several features that make it a magic mol-
ecule. It has high acidity [4], susceptible to nucleophilic attack
at C4 and C6 and electrophilic attack at C5, undergoing ring
opening reactions, and it is applied as an alternative for acyclic
malonic esters. In addition, a lot of Meldrum's acid derivatives
have been used as intermediate compounds in organic synthe-
sis. Several reports have been published in which acyl
Meldrum's is used for preparation of 1,3-dicarbonyl com-
pounds [5]; mono- and di-alkyl and aryl substituted of
Meldrum's at C5 is used for synthesis of different malonic ester
derivatives [6]; 5,5-dibromo Meldrum's acid is applied for
mild α-brominating of aldehyde and ketones [7]. Also, other
This reaction was performed according to our previous
study. It is expected this reaction occurred in a 1:1:1 man-
ner, but on the base of first spectroscopic data; we found
that this reaction occurred in different approach. Initial
1H NMR spectroscopy study of the product appeared that
absorption pattern with a 1:1:1 product is not compatible.
Noticable with an additional signal, it can be concluded
that the two residual structures of isocyanides in the
product molecule is present, but still two more hydrogen
signals is seen. To understand the structure of our products,
we decided to study X-ray structure of the product. It is nota-
ble that when the reaction was performed in the presence of
2–3 drops of water, the reaction did not had any progress.
The structure of compound 4a was elucidated by an X-
ray diffraction analysis [13]. Molecular structure of
© 2013 HeteroCorporation

A. Habibi, F. Vafadarnejad, and M. A. Armand
Vol 000
Scheme 1
compound 4a is shown in Figure 1. Clearly, we can see the
isoxazole ring where three cyclohexyl and cyclopentyl
have normal shape and aligned perpendicular with respect
to the isoxazole core.
undertakes intramolecular ring closure via a “5-exo trig”
that leads to form intermediate 8; after that, addition of
one molecule of water (moisture) leads to form new amide
group and finally obtains isoxazolinedione derivatives 4.
In conclusion, our one-pot and novel protocol as a MCR
(two molecule of) isocyanide, alkylidene Meldrum's acid,
aliphatic ketoxime, and water provides a simple entry into
the synthesis of new derivatives of isoxazolinedione.
1
The IR, H NMR, and 13C NMR data of the products
have similar signal and bands. This information undoubt-
edly indicates the formation of isoxazolinedione deriva-
tives (4a–4f). Also, elemental analyses data are consistent
with this result.
General procedure for synthesis of products and selected
spectroscopic data are mentioned in the experimental. The
IR spectrum of 4a shows NH band at 3326 cm−1 and four
bands for carbonyl stretching at 1806, 1721, 1643, and
1625 cm−1. Molecular ion in mass spectrum appeared at
501. The 1H NMR spectrum of 4a exhibited a complex sig-
nal (δ = 1.29–2.79 ppm) for the cyclohexyl and cyclopentyl
protons along with two signals (δ = 3.03 and 3.75 ppm) be-
cause of the three methine protons. Two signals (appeared at
δ = 5.32 and 7.62 ppm) belong to NH protons. The proton-
decoupled 13C NMR spectrum of 4a exhibited 28 distinct
resonances in agreement with the isoxazoline derivative
structure. The spectral data of 4b–4f were similar to 4a
except for differences in the proton and carbon resonances
of the substituents.
EXPERIMENTAL
Melting points were measured on Electrothermal 9100 appara-
tus. Elemental analyses for C and H were performed using a
Heraeus CHN-S-O-rapid analyzer. IR spectra were measured on
1
a shimadzu IR-460 spectrometer. H and 13C NMR spectra were
recorded at 300.1 and 75.47 MHz, respectively, on a bruker
According to our knowledge on the chemistry of
isocyanides [1–3], a plausible mechanism of the five
molecules reaction between isocyanides 1, alkylidene
Meldrum's acid 2, ketoxime 3, and water is introduced in
Scheme 2. The first step of mechanism involves the [4+1]
cycloaddition reaction of the electron-deficient heterodiene
moiety of alkylidene Meldrum's acid with the isocyanide,
producing an iminolactone intermediate 5. Nucleophilic
attack of oxime on the carbonyl of lactone followed ring
opening, losing acetone and hydrogen transfer leads to
intermediate 6. Nucleophilic attack of second molecule of
isocyanide, produces intermediate 7. This intermediate
Figure 1. Molecular structure of 1 (ORTEP‐III plot).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

An Isocyanide-Based Multicomponent Reaction: New Route for Synthesis of
Isoxazolinedione Derivatives
Month 2013
Scheme 2
3
DRX-300 Avance instrument with CDCl3 and C3D6O as solvent
and tetramethylsilane (TMS) as internal standard. Meldrum's acid
and isocyanides were obtained from fluka (Buches, Switzerland)
and used without further purification. Alkylidene Meldrum's acids
were prepared according to reported procedures [6,8,10]. Oximes
were obtained according to a classic procedure.
CH), 3.73 (m, 1H, CH), 5.56 (d, 1H, J = 8.1, NH), 7.59 (d, 1H,
3J = 8.1, NH). 13C NMR (75.47 MHZ, CD6CO) δ ppm 23.8,
24.4, 24.9, 25.3, 25.3, 25.7, 26.0, 29.7, 32.6, 32.7, 32.8, 32.9,
35.6, 35.8, 47.5, 49.3, 50.0, 76.0, 165.0, 167.8, 169.7, 174.7. MS
(ESI): m/z (%) = 461 (11, M+), 336 (71), 268 (31), 114 (55), 111
(51), 98 (100), 83 (46), 67 (52), 55 (81), 41 (56). Anal.calcd. for
C25H39N3O5 (461.59): C, 65.05; H, 8.52; N, 9.10% found: C,
64.95; H, 8.68; N, 9.05%.
General procedure for the synthesis of 4a-4f. Exemplified for
N1-cyclohexyl-1-[4-{1-[(cyclohexylamino)carbonyl]cyclo-
pentyl}-3,5-dihydro-2(3H)-isoxazolyl]-1-cyclohexanecarbox-
N1-Cyclohexyl-2-[2-[2-(cyclohexylamino)-1,1-dimethyl-2-
oxoethyl]-3,5-dioxodihydro-4(3H)-isoxazolyl]-2-methylpropana-
mide (4c). White powder; mp 189–191°C; yield: 51%. IR (KBr)
υ cm−1 3393, 3337 (NH), 1812, 1783, 1704, 1640 (C O), 1530 (NH
bending). H NMR (300.1 MHz, CD6CO) δ ppm 1.15–1.90 (m,
20H, 10 CH2), 1.46, 1.61, 1.64 and 1.72 (4s, 12H, 4 CH3), 2.87
amide (4a).
To a magnetically stirred solution of 2 mmol
(0.42 gr) of cyclopentylidene Meldrum's acid and 2 mmol
(0.226 gr) of cyclohexanone oxime in 10 mL of CH2Cl2, added
dropwise solution of 4 mmol (0.484 mL) cyclohexyl isocyanide
in CH2Cl2 during 10 min. The reaction mixture was allowed to
stir for 48 h at room temperature. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel (Merck 230-240 mesh) column chromatography using
hexane–ethyl acetate 4:1 mixture as eluent. The solvent was
removed and the product was obtained as follows:
1
3
(s, 1H, CH), 3.73 (m, 1H, CH), 5.44 (d, 1H, J = 7.8, NH), 7.38
(d, 1H, J = 7.8, NH). 13C NMR (75.47 MHZ, CD6CO) δ ppm
3
24.7, 24.8, 24.9, 25.3, 25.4, 25.7, 26.0, 32.6, 32.7, 32.9, 47.5,
49.1, 49.3, 50.0, 66.3, 165.3, 167.8, 170.6, 174.6. MS (ESI): m/z
(%) = 435 (56, M+), 309 (27), 236 (100), 225 (10), 83 (80), 55
(74). Anal.calcd. for C23H37N3O5 (435.56): C, 63.42; H, 8.56; N,
9.65% found: C, 63.31; H, 8.62; N, 9.59%.
N1-Cyclohexyl-1-[4-{1-[(cyclohexylamino)carbonyl]cyclopen-
tyl}-3,5-dioxodihydro-2(3H)-isoxazolyl]-1-cyclohexanecarboxa-
N1-Cyclohexyl-1-[4-{1-[(cyclohexylamino)carbonyl]cyclopen-
tyl}-3,5-dioxodihydro-2(3H)-isoxazolyl]-1-cyclopentanecarboxa-
mide (4d). White powder; mp 169–171°C; yield: 56%. IR (KBr)
υ cm−1 3327 (N H), 1809, 1720, 1645, 1630 (C O), 1539 (N H
mide (4a).
White powder; mp 184–186°C; yield: 58%. IR
(KBr) υ cm−1 3326 (NH), 1806, 1721, 1643, 1625 (C O), 1538
(NH bending). 1H NMR (300.1 MHz, CD6CO) δ ppm 1.29–
2.79 (m, 38H, 19 CH2), 3.03 (s, 1H, CH), 3.75 (m, 1H, CH),
5.32 (d, 1H, 3J = 8.0, NH), 7.62 (d, 1H, 3J = 8.0, NH). 13C
NMR (75.47 MHz, CD6CO) δ ppm 21.8, 22.3, 24.7, 24.8, 25.4,
25.4, 25.6, 25.7, 31.4, 31.8, 32.6, 32.8, 32.8, 32.9, 35.8, 36.7,
47.7, 49.1, 49.3, 57.4, 70.6, 76.6, 77.0, 77.4, 165.6, 168.5,
170.1, 175.6. MS (ESI): m/z (%) = 501 (4, M+), 375 (80), 279
(41), 262 (87) 248 (80), 194 (25), 180 (50), 154 (64), 114 (53),
109 (53), 98 (100), 96 (81), 83 (53), 67 (52), 56 (71), 55 (81),
41 (59). Anal.calcd. for C28H43N3O5(501.66): C, 67.04; H,
8.64; N, 8.38% found: C, 66.90; H, 8.80; N, 8.34%.
1
bending). H NMR (300.1 MHz, CD6CO) δ ppm 1.26–2.60 (m,
36H, 18 CH2), 2.954 (s, 1H, CH), 3.749 (m, 1H, CH), 5.33 (d,
1H, J = 7.8, NH), 7.64 (d, 1H, J = 7.8, NH). 13C NMR (75.47
MHZ, CD6CO) δ ppm 23.8, 24.4, 24.8, 25.4, 25.5, 25.7, 32.6,
32.8, 32.8, 32.9, 35.7, 35.8, 36.6, 47.8, 49.2, 57.7, 76.0, 165.3,
168.5, 169.7, 175.5. MS (ESI): m/z (%) = 487 (10, M+), 362
(73), 347 (44), 154 (24), 128 (45), 114 (31), 98 (100), 83 (58),
55 (36). Anal.calcd. for C27H41N3O5 (487.63): C, 66.50; H,
8.47; N, 8.62% found: C, 66.43; H, 8.54; N, 8.57%.
3
3
N1-Cyclohexyl-1-[4-[2-(cyclohexylamino)-1,1-dimethyl-2-
oxoethyl]-3,5-dioxodihydro-2(3H)-isoxazolyl]-1-cyclohexanecar-
boxamide (4b). White powder; mp 174–176°C; yield: 46%. IR
(KBr) υ cm−1 3369 (NH), 1817, 1730, 1650, 1645 (C O), 1549
N1-Cyclohexyl-1-[4-[2-(cyclohexylamino)1,1-dimethyl-2-
oxoethyl]-3,5-dioxodihydro-2(3H)-isoxazolyl]-1-cyclohexanecar-
boxamide (4e). White powder; mp 150°C; yield: 43%. IR (KBr)
υ cm−1 3343 (N H), 1821, 1746, 1723, 1637 (C O), 1555 (N H
1
1
(NH bending). H NMR (300.1 MHz, CD6CO) δ ppm 1.17–2.31
bending). H NMR (300.1 MHz, CD6CO) δ ppm 1.16–2.67 (m,
(m, 28H, 14 CH2), 1.61 and 1.64 (2s, 6H, 2 CH3), 2.91 (s, 1 H,
30H, 15 CH2), 1.62 and 1.66 (2s, 6H, 2 CH3), 2.99 (s, 1H, CH),
Journal of Heterocyclic Chemistry
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A. Habibi, F. Vafadarnejad, and M. A. Armand
Vol 000
3.73 (m, 1H, CH), 5.55 (d, 1H, 3J = 8.1, NH), 7.57 (d, 1H, 3J = 8.1,
REFERENCES AND NOTES
NH). 13C NMR (75.47 MHZ, CD6CO) δ ppm 21.8, 22.3, 24.7,
24.9, 25.4, 25.8, 26.0, 27.0, 31.5, 32.0, 32.6, 32.8, 32.8, 33.0,
47.3, 49.1, 49.8, 70.7, 165.4, 167.9, 170.1, 174.7 (4C O) ppm.
MS (ESI): m/z (%) = 475 (44, M+), 349 (95), 333 (92), 253 (35),
236 (84), 154 (35), 128 (64), 114 (43), 98 (100), 95 (63), 83 (85),
55 (72), 41 (50). Anal.calcd. for C26H41N3O5 (475.62): C, 65.66;
H, 8.69; N, 8.83% found: C, 65.51; H, 8.81; N, 8.84%.
[1] Ugi, I. Angew Chem Int Ed Engl 1982, 21, 810.
[2] Domling, A.; Ugi I. Angew Chem Int Ed Engl 2000,
39, 3168.
[3] Domling, A. Chem Rev 2006, 106, 17.
[4] (a) McNab, H. Chem Soc Rev 1978, 7, 345; (b) Atlan, V.;
Buron, C.; El Kaïm, L. Synlett 2000, 489.
[5] Oikawa, Y.; Sugano, K.; Yonemitsu, O. J Org Chem 1978, 43,
2087.
N1-(tert-Butyl)-1-[4-{1-[(tert-butylamino)carbonyl]cyclopen-
tyl}-3,5-dioxodihydro-2(3H)-isoxazolyl]-1-cyclohexanecarbox-
amide (4f). White powder; mp 175°C; yield: 38%. IR (KBr) υ
cm−1 3414, 3358 (N H), 1812, 1706, 1675, 1637 (C O), 1534
(N H bending). 1H NMR (300.1 MHz, CD6CO) δ ppm 1.13–
1.74 (m, 18H, 9 CH2), 1.32 and 1.38 (2s, 18H, 2 CMe3), 2.91
(s, 1H, CH), 5.35 (s, 1H, NH), 6.52 (s, 1H, NH). 13C NMR
(75.47 MHZ, CD6CO) δ ppm 23.7, 24.3, 25.2, 25.7, 28.2,
28.5, 28.6, 47.9, 50.2, 51.6, 66.7, 165.2, 167.6, 169.7, 174.2.
MS (ESI): m/z (%) = 449 (15, M+), 351 (30), 279 (26), 236
(50), 128 (42), 98 (100), 83 (61), 81 (25), 55 (52). Anal.calcd.
for C24H39N3O5 (449.58): C, 64.12; H, 8.74; N, 9.35% found:
C, 64.03; H, 8.80; N, 9.29%.
[6] Ivanov, A. S. Chem Soc Rev 2008, 37, 789.
[7] Bloch, R. Synthesis 1978, 140.
[8] Chen, B. C. Heterocycles 1991, 32, 529.
[9] Gaber, A.; McNab, H. Synthesis 2001, 14, 2059.
[10] Gerencser, J.; Dorman, G., Darvas, F. QSAR Comb Sci 2006,
5–6, 439.
[11] Yavari, I.; Habibi, A. Synthesis 2004, 989.
[12] Habibi, A.; Mousavifar, L. Monatsh Chem 2007, 138, 603.
[13] Crystallographic data for the structure in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 733794. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road, Cam-
bridge, CB2 1EZ, UK [Fax: +44
deposit@ccdc.cam.ac.u].
0 1223 336033 (or) e-mail:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet