Novel isocyanide-based one-pot multicomponent syntheses of tetrahydrobenzo[ b][1,4]oxazepine and malonamide derivatives

Article abstract of DOI:10.1021/cc100032d

In this work, a novel one-pot multicomponent reaction of 2-aminophenols, Meldrum's acid, and isocyanides leads to the synthesis of tetrahydrobenzo[b][1, 4]oxazepine or malonamide derivatives using 1 or 2 equiv of 2-aminophenols, respectively, in good to excellent yields at ambient temperature.

Full text of DOI:10.1021/cc100032d

630
J. Comb. Chem. 2010, 12, 630–632
Novel Isocyanide-Based One-Pot Multicomponent Syntheses of
Tetrahydrobenzo[b][1,4]oxazepine and Malonamide Derivatives
Ahmad Shaabani,* Hamid Mofakham, Ali Maleki, and Fatemeh Hajishaabanha
Department of Chemistry, Shahid Beheshti UniVersity, G. C., P.O. Box 19396-4716, Tehran, Iran
ReceiVed October 25, 2009
In this work, a novel one-pot multicomponent reaction of 2-aminophenols, Meldrum’s acid, and isocyanides
leads to the synthesis of tetrahydrobenzo[b][1,4]oxazepine or malonamide derivatives using 1 or 2 equiv of
2-aminophenols, respectively, in good to excellent yields at ambient temperature.
Multicomponent reactions (MCRs) especially isocyanide-
clohexyl-2-methyl-2-(7-methyl-2,4-dioxo-2,3,4,5-tetrahydro-
benzo[b][1,4]oxazepin-3-yl)propanamide 4a in 87% yield.
In the same manner, various 2-aminophenols and isocyanides
were coupled with Meldrum’s acid in a one-pot operation
at room temperature in CH2Cl2 to give the corresponding
tetrahydrobenzo[b][1,4]oxazepine derivatives 4a-e in good
to excellent yields.
This method does not require any catalyst for the promo-
tion of the reaction, and undesired side product was not
observed. The results shown in Table 1 clearly indicate the
scope and generality of the reaction with respect to various
starting materials. The reaction proceeds under mild condi-
tions and is compatible with some functional groups. Two
substituents in the products can be varied independently of
each other.
As shown in Scheme 1, using 2 equiv of 2-aminophenols
3 in the reaction with isocyanide 1 and Meldrum’s acid 2,
malonamide derivatives 5a-f were produced via a novel one-
pot pseudo five-component reaction under the same reaction
conditions in CH2Cl2 at room temperature.
The results shown in Table 2 clearly indicate the efficient
scope and limitations of this reaction. Also, similar to the
previous reaction, this method does not require any catalyst
for the promotion of the reaction, and no undesired side
product was observed.
based MCRs (IMCRs) are fast and selective methods for the
synthesis of large libraries of organic molecules by simply
varying each component through a chain of consecutive
elementary transformations.1
Benzoxazepine derivatives are important scaffolds in
medicinal chemistry with various biological activities,2 and
attractive compounds of growing pharmaceutical interest as
documented by many publications. Among compounds
containing this fragment are a non-nucleoside HIV-1 reverse
transcriptase inhibitor,3 a histamine receptor agonist4 and
calcium antagonists,5 as well as antidepressants6 and anal-
gesics.7 The benzo[b][1,4]oxazepine derivatives demonstrate
various forms of bioactivity such as antidepressive and
anxiolytic activity,8 treating of bronchial asthma and allergic
bronchitis,9 antiserotoninergic and antihistaminic effects,10
and tetrahydrobenzo[b][1,4]oxazepines are progesterone
receptor agonists,11 and anticancer activity against breast
cancer cells.12
Malonamide derivatives are of great interest in various
respects because of their interesting applications in diverse
fields.13 Malonamide derivatives have some important ap-
plications such as excellent ionophores for the construction
of alkali and alkaline-earth cations-selective electrodes,14
effective liquid-liquid extractants for the separation of
actinide ions from acid media,15 as an alternative to car-
bamoylmethylphosphine oxide (CMPO) systems in the
nuclear waste management process, as bidentate chelates
especially for uranium(VI) and plutonium(IV) ions,16 as
monomers in the nylons’ family and as components in
peptidomimetic substances.17
Table 1. Synthesis of Tetrahydrobenzo[b][1,4]oxazepine
Derivatives 4a-e
entry
R1
R2
product
yielda (%)
1
2
3
4
5
cyclohexyl
cyclohexyl
tert-butyl
tert-butyl
H
4-Cl
H
4-CH3
H
4a
4b
4c
4d
4e
87
80
80
80
75
In view of our current studies on IMCRs,18 and a full
account of the our previous results,18g herein, we describe
the synthesis of tetrahydrobenzo[b][1,4]oxazepines 4a-e and
malonamide derivatives 5a-f via a condensation reaction
between an isocyanide 1, Meldrum’s acid 2, and 1 or 2 equiv
of 2-aminophenol 3, in good to excellent yields at ambient
temperature (Scheme 1).
1,1,3,3-tetramethylbutyl
a Isolated yield.
Table 2. Synthesis of Malonamide Derivatives 5a-f
entry
R1
R2
product
yielda (%)
1
2
3
4
5
6
cyclohexyl
1,1,3,3-tetramethylbutyl
2,6-dimethylphenyl
2,6-dimethylphenyl
4-methylphenylsulfonyl
4-methylphenylsulfonyl
4-CH3
4-CH3
H
4-CH3
H
5a
5b
5c
5d
5e
5f
87
80
84
82
80
78
In a pilot experiment, the treatment of cyclohexyl isocya-
nide, Meldrum’s acid, and 2-aminophenol afforded N-cy-
4-CH3
* To whom correspondence should be addressed. E-mail: a-shaabani@
cc.sbu.ac.ir.
a Isolated yield.
10.1021/cc100032d  2010 American Chemical Society
Published on Web 07/27/2010

Syntheses of Tetrahydrobenzo[b][1,4]oxazepine
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 631
Scheme 1. Synthesis of Tetrahydrobenzo[b][1,4]oxazepines 4a-e and Malonamide Derivatives 5a-f
Scheme 2. Possible Mechanism for the Formation of Products 4a-e and 5a-f
The suggested mechanism for the formation of products
4a-e and 5a-f is shown in Scheme 2. It is conceivable that,
the initial event is the formation of intermediate 7 or 11 from
condensation between a Meldrum’s acid 2 and one or two
molecules of 2-aminophenol 3 and releasing a molecule of
acetone, respectively.19 Intermediate 7 or 11 undergoes a
Knoevenagel condensation reaction with acetone to produce
intermediate 8 or 12, respectively.20 On the basis of the well-
established chemistry of reaction of isocyanides with electron
deficient R,ꢀ-unsaturated carbonyl compounds,21 intermedi-
ate 9 or 13 was produced by nucleophilic attack of an
isocyanide 1 to intermediate 8 or 12, followed by nucleo-
philic attack of an H2O molecule on the activated nitrilium
moiety to produce compound 10 or 14. Finally, tautomer-
ization of compound 10 or 14 leads to the formation of
products 4a-e or 5a-f.
ization potential of 70 eV. IR spectra were recorded on a
Shimadzu IR-470 spectrometer. The 1H and 13C NMR
Spectra were recorded on a Bruker DRX-300 Avance
spectrometer 300.13 and 75.47 MHz. NMR spectrum were
obtained on solution in DMSO-d6 using TMS as internal
standard. The chemicals used in this work were purchased
from the Merck and Fluka Chemical Companies.
General Procedure for the Preparation of Tetrahydro-
benzo[b][1,4]oxazepines 4a-f. A mixture of an isocyanide
(1 mmol), Meldrum’s acid (1 mmol), and a 2-aminophenol
(1 mmol) in 3 mL of CH2Cl2 was stirred for 12 h at room
temperature. After completion of reaction, as indicated by
thin-layer chromatography (TLC; ethyl acetate/n-hexane,
1/1), the reaction mixture was filtered, and the solid
precipitate washed with n-hexane (5 mL). Further purification
was followed by crystallization from ethanol to give pure
crystalline products 4a-f.
Conclusions
In summary, we have developed a mild and straightfor-
ward procedure for the synthesis of a new class of substituted
malonamide and tetrahydrobenzo[b][1,4]oxazepine deriva-
tives from a novel IMCR between isocyanides, Meldrum’s
acid, and 2-aminophenols in CH2Cl2 in good to excellent
yields at room temperature. In this reaction, for the first time,
some potentially excellent ionophores have been reported
that can be applied for the construction of alkali and alkaline-
earth cations-selective electrodes that can be applied in
medicinal chemistry. In other words, this reaction can be
regarded as an efficient approach for the synthesis of
malonamide derivatives as effective liquid-liquid extractants
and tetrahydrobenzo[b][1,4]oxazepine derivatives as effective
pharmaceutical compounds with various biological activities.
General Procedure for the Preparation of Malona-
mides 5a-f. A mixture of an isocyanide (1 mmol), Mel-
drum’s acid (1 mmol), and a 2-aminophenol (2 mmol) in 3
mL of CH2Cl2 was stirred for 12 h at room temperature.
After completion of reaction, as indicated by TLC (ethyl
acetate/n-hexane, 1/1), the reaction mixture was filtered, and
the solid precipitate washed with n-hexane (5 mL). Further
purification was followed by crystallization from ethanol to
give pure crystalline products 5a-f.
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti
University.
Experimental Section
Supporting Information Available. Experimental pro-
1
cedures, Mass, IR, H NMR, and 13C NMR spectra for
Melting points were measured on an Electrothermal 9200
apparatus. Mass spectra were recorded on a Shimadzu
GCMS-QP1100EX mass spectrometer operating at an ion-
compounds 4a-e and 5a-f. This material is available free
of charge via the Internet at http://pubs.acs.org.

632 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Shaabani et al.
(12) D´ıaz-Gavila´n, M.; Rodr´ıtimeguez-Serrano, F.; Go´mez-Vidal,
References and Notes
´
J. A.; Marchal, J. A.; Ara´nega, A.; Gallo, M. A.; Espinosa,
(1) (a) Zhu, J.; Bienayme´, H., Eds.; Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (b) Do¨mling, A. Chem. ReV.
2006, 106, 17–89.
(2) (a) DeSarro, G.; Chimirri, A.; DeSarro, A.; Gitto, R.; Grasso,
S.; Zappala, M. Eur. J. Med. Chem. 1995, 30, 925–929. (b)
MiKi, T.; Kori, M.; Mabuchi, H.; Tozawa, R.; Nishimotos,
T.; Sugiyama, Y.; Teshima, K.; Yukimasa, H. J. Med. Chem.
2002, 45, 4571–4580. (c) Bihel, F.; Kraus, J.-L. Org. Biomol.
Chem. 2003, 1, 793–799.
(3) (a) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.; Grozinger,
K.; Skoog, M.; Wu, J. C.; Shih, C.-K.; Eckner, K.; Hattox,
S.; Adams, J.; Rosenthal, A. S.; Faanes, R.; Eckner, R. J.;
Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411–1413.
(b) Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.;
Pal, K.; Behnke, M. L.; Kapadia, S. R.; McNeil, D. W.; Wu,
J. C.; Chow, G. C.; Adams, J. J. Med. Chem. 1992, 35, 1887–
1897. (c) Xing, X. L.; Wu, J. L.; Luo, J. L.; Dai, W. Synlett
2006, 2099–2103.
(4) Smits, R. A.; Lim, H. D.; Stegink, B.; Bakker, R. A.; de Esch,
I. J. P.; Leurs, R. J. Med. Chem. 2006, 49, 4512–4516.
(5) Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.;
Quilliam, M. A.; Walter, J. A.; Howlett, S. E. Drug Des.
DiscoVery 1995, 12, 337–358.
A.; Campos, J. M. Tetrahedron 2004, 60, 11547–11557.
(13) (a) Ibrahim, Y. A.; Elwahy, H. M. Synthesis 1993, 503–508.
(b) Ibrahim, Y. A.; Behbehani, H.; Ibrahim, M. R. Tetrahedron
Lett. 2002, 43, 4207–4210. (c) Shoukry, A. F.; Shuaib, N. M.;
Ibrahim, Y. A.; Malhas, R. N. Talanta 2004, 64, 949–954.
(d) Kannan, Sh.; Ferguson, G. Inorg. Chem. 1997, 36, 1724–
1725.
(14) (a) Gadzekpo, P. Y.; Hungerford, J. M.; Kadry, A. M.;
Ibrahim, Y. A.; Christian, G. D. Anal. Chem. 1985, 57, 493–
495. (b) Kimura, K.; Kumami, K.; Kitazawa, S.; Shono, T.
J. Chem. Soc., Chem. Commun. 1984, 442–443.
(15) (a) Cullerdiev, C.; Musikas, C.; Hoel, P. In New Separation
Technique for RadioactiVe Waste and Other Specific Applica-
tions; Cecille, L., Cesarci, M., Pietrelli, L., Eds.; Elsevier
Applied Science: Oxford, 1991; p 41. (b) Musikas, C. Inorg.
Chim. Acta 1987, 140, 197–206.
(16) (a) Bowen, S. M.; Duesler, E. N.; Paine, R. T. Inorg. Chem.
1982, 21, 261–265. (b) Caudle, L. J.; Duesler, E. N.; Paine,
R. T. Inorg. Chem. 1985, 24, 4441–4444. (c) McCabe, D. J.;
Duesler, E. N.; Paine, R. T. Inorg. Chem. 1985, 24, 4626–
4629. (d) Karthikeyan, S.; Paine, R. T.; Ryan, R. R. Inorg.
Chim. Acta 1988, 144, 135–141. (e) Ruikar, P. B.; Nagar,
M. S. Polyhedron 1995, 14, 3125–3132.
(6) Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.;
Shenoy, S. J.; Upadhyaya, P. Eur. J. Med. Chem. Chim. Ther.
1986, 21, 21–26.
(17) Tereshko, V.; Navarro, E.; Puiggali, J.; Subirana, J. A.
Macromolecules 1993, 26, 7024–7028.
(18) (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem.
2007, 72, 6309–6311. (b) Shaabani, A.; Maleki, A.; Mofa-
kham, H.; Moghimi-Rad, J. J. Org. Chem. 2008, 73, 3925–
3927. (c) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi,
H. R. J. Comb. Chem. 2008, 10, 323–326. (d) Shaabani, A.;
Maleki, A.; Mofakham, H. J. Comb. Chem. 2008, 10, 595–
598. (e) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi,
H. R. J. Comb. Chem. 2008, 10, 883–885. (f) Shaabani, A.;
Maleki, A.; Mofakham, H. Mol. DiVersity 2009, 13, 63–67.
(g) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Keshipour,
S.; Ng, S. W. Org. Lett. 2009, 11, 3342–3345.
(19) Shaabani, A.; Teimouri1, M, B,; Bazgir, A.; Bijanzadeh, H. R.
Mol DiVersity 2003, 6, 199–206.
(20) (a) McNab, H. Chem. Soc. ReV. 1978, 7, 345–358. (b) Chen,
C. H.; Reynolds, G. A.; Luss, H. R.; Perlstein, J. H. J. Org.
Chem. 1986, 51, 3282–3289.
(7) (a) Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1968, 11, 1158–
1160. (b) Lawrence, R. A.; Jones, R. L.; Wilson, N. H. Br. J.
Pharmacol. 1992, 105, 271–278. (c) Hallinan, E. A.; Hagen,
T. J.; Husa, R. K.; Tsymbalvo, S.; Rao, S. N.; vanHoeck, J.-
P.; Rafferty, M. F.; Stapelfeld, A.; Savage, M. A.; Reichman,
M. J. Med. Chem. 1993, 36, 3293–3299. (d) Hallinan, E. A.;
Stapelfeld, A.; Savage, M. A.; Reichman, M. Bioorg. Med.
Chem. Lett. 1994, 4, 509–514. (e) Hallinan, E. A.; Hagen,
T. J.; Tsymbalov, S.; Husa, R. K.; Lee, A. C.; Stapelfeld, A.;
Savage, M. A. J. Med. Chem. 1996, 39, 609–613. (f) Hallinan,
E. A.; Hagen, T. J.; Tsymbalov, S.; Stapelfeld, A.; Savage,
M. A. Bioorg. Med. Chem. 2001, 9, 1–6. (g) Wu, J.; Jiang,
Y.; Dai, W. M. Synlett 2009, 1162–1166.
(8) Van der Burg, W. J. Chem. Abstr. 1974, 81, 3986; DE2347727.
(9) Walther, G.; Schneider, C. S.; Weber, K. H.; Fuegner, A.
Chem. Abstr. 1982, 96, 6777; DE3008944.
(10) Sulman, F. G.; Pfeifer, Y.; Superstine, E. Arzneimittelfors-
chung 1981, 31, 109–112.
(11) Dols, P. P. M. A.; Folmer, B. J. B.; Hamersma, H.; Kuil,
C. W.; Lucas, H.; Ollero, L.; Rewinkel, J. B. M.; Hermkens,
P. H. H. Bioorg. Med. Chem. Lett. 2008, 18, 1461–1467.
(21) (a) Huang, X.; Chen, C. C.; Wu, Q. L. Tetrahedron Lett. 1982,
23, 75–76. (b) Yavari, I.; Habibi, A. Synthesis 2004, 989–
991. (c) Shaabani, A.; Yavari, I.; Teimouri, M. B.; Bazgir,
A.; Bijanzadeh, H. R. Tetrahedron 2001, 57, 1375–1378.
CC100032D