Isocyanide-based four-component synthesis of 1,3-indandionylamidinium betaines

Article abstract of DOI:10.1016/j.tet.2012.03.039

An efficient approach for the synthesis of novel 1,3-indandionylamidinium betaines via four-component reaction of 1,3-indandione, aldehydes, amines, and isocyanides, without assistance of any catalyst and under mild reaction conditions has been reported.

Full text of DOI:10.1016/j.tet.2012.03.039

Tetrahedron 68 (2012) 3868e3874
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Isocyanide-based four-component synthesis of 1,3-indandionylamidinium
betaines
*
Roya Akbarzadeh, Tayebeh Amanpour, Hamid Reza Khavasi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the synthesis of novel 1,3-indandionylamidinium betaines via four-component
reaction of 1,3-indandione, aldehydes, amines, and isocyanides, without assistance of any catalyst and
under mild reaction conditions has been reported. The structures of these compounds were confirmed by
IR, mass spectroscopic, 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 6 December 2011
Received in revised form 19 February 2012
Accepted 12 March 2012
Available online 17 March 2012
Keywords:
Indandione
Isocyanide
1,3-Betaine
Amidinium
1. Introduction
nitric oxide synthase inhibitors,18 and tyrosine kinase inhibitors.19
Amidine derivatives also possess antimicrobial activity.20 They are
Multi-component reactions (MCRs) are of increasing impor-
tance in organic synthesis, because the strategies of MCR offer
significant advantages over conventional linear-type syntheses.1e3
The atom-economy, convergent character, operational simplicity,
structural diversity, and complexity of the resultant products are
the major advantages associated with multi-component reactions.
Isocyanide-based multi-component reactions (IMCRs) are particu-
larly interesting as they are more versatile and diverse than other
MCRs.4,5 The great potential of isocyanides for the development of
multi-component reactions lies on the diversity of available bond
forming processes, functional group tolerance, and the high levels
of chemo-, regio-, and stereoselectivity often observed. Thus MCRs
involving isocyanides have emerged as valuable tools for the
preparation of structurally diverse chemical libraries.6e8
1,3-Indanedione has proved to be a versatile starting material
for the synthesis of potentially important compounds. 1,3-
Indanedione and its derivatives have been employed in the syn-
thesis of drugs,9 in forensic chemistry for fingerprint detection,10 in
dyes and pigments,11 and in semi- and photosemiconductors.12
Furthermore, 1,3-indandione derivatives were demonstrated to be
valuable precursors for strong electron acceptors.l3,14 Similarly, the
amidine group is present in many compounds acting on a wide
range of biological targets. It is an important pharmacophore in
serine protease inhibitors,15,16 fibrinogen receptor antagonists,15e17
also versatile synthetic intermediates that have been used for the
further synthesis of heterocyclic compounds and as ligands for
metal complexation.21,22
Despite continuous research for the development of new
isocyanide-based multi-component reactions for the synthesis of
various potentially important compounds,6e8 to the best of our
knowledge, no one has yet reported the synthesis of amidinium
betaines via a multi-component strategy. Recently, the pseudo
three-component synthesis of alkyl or arylamidine-acid zwitter-
ionic compounds by the reaction of isocyanides and carboxylic
acids was described by Shaabani and co-workers.23
As part of our program aimed at developing new isocyanide-based
multi-component reactions,24e26 herein, we describe, for the first
time, an efficient synthetic approach to 1,3-indandionylamidinium
betaines by an isocyanide-based four-component reaction.
2. Results and discussion
The one-pot four-component condensation reactions of 1,3-
indandione 1, aldehydes 2, amines 3, and isocyanides 4 proceeded
spontaneously at room temperature in Et2O and were complete after
24 h to afford the corresponding 1,3-indandionylamidinium betaines
5 in good yields via the formation of three new bonds (two CeC and
one CeN bonds) (Scheme 1). All the products were characterized by
IR, mass, 1H and 13C NMR spectra, and elemental analysis.
The elucidation of the product structures are discussed here for
5a as a representative example. The mass spectrum of 5a shows the
* Corresponding author. Fax: þ98 21 22431661; e-mail address: a_bazgir@
sbu.ac.ir (A. Bazgir).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.039

R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
3869
recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13
and 75.47 MHz, respectively. 1H and 13C NMR spectra were obtained
on solutions in DMSO-d6. IR spectra were recorded using a BOMEM
MB-Series. Mass spectra were recorded on a FINNIGAN-MAT 8430
mass spectrometer operating at an ionization potential of 70 eV.
Elemental analyses were performed using a Heracus CHN-O-Rapid
analyzer. The chemicals used in this work were obtained from Fluka
and Merck and were used without purification.
Scheme 1. Synthesis of 1,3-indandionylamidinium betaines 5.
4.2. General procedure for the synthesis of 5
expected molecular-ion peak at m/z 410. The IR spectrum of 5a ex-
hibits one broad absorption band due to carbonyl groups at
1623 cmꢀ1, and a broad absorption band for the NH groups is ob-
served at 3191 cmꢀ1. The 1H NMR spectrum of 5a consists of a singlet
signal for the t-Bu (dH 1.53 ppm) and one singlet for the methine
group (dH 5.01 ppm). Two broad resonances (dH 9.87 and 12.53 ppm)
are observed for the two NH groups. The aromatic hydrogen atoms
give rise to characteristic signals in the aromatic region of the
spectrum. The 1H-decoupled 13C NMR spectrum of 5a showed 17
distinct signals, in agreement with the proposed structure.
To study the generality of the method, a library of fifteen
substituted 1,3-indandionylamidinium betaines 5aen were selec-
tively synthesized in good yields (Table 1). All compounds are
stable solids whose structures were established by IR, Mass, 1H, and
13C NMR spectroscopy and elemental analysis. The structure of 5e
was confirmed by a single-crystal X-ray analysis27 (Fig. 1).
To the best of our knowledge, this new isocyanide-based four-
component strategy provides the first example of an efficient
synthesis of indandionylamidinium betaines, is simple, and con-
venient, and would be applicable for the synthesis of different types
of indandionylamidinium betaines. In addition, as the starting
materials are readily accessible, a modular approach to the syn-
thesis of indandionylamidinium betaines is possible. The work-up
procedure of these reactions involves simply a filtration and crys-
tallization from CHCl3/hexane.
Mechanistically, the formation of amidinium betaines 5 can be
rationalized by initial formation of 2-arylideneindenedione 6
through a Knoevenagel condensation reaction of 1 and 2. Then, the
intermediate 7 is produced by Michael-type addition reaction of 4
to 6, followed by nucleophilic attack of 3 on the nitrilium moiety to
produce intermediate 8. Finally, H-shift produces the amidinium
betaines 5 (Scheme 2).
Ferrocene derivatives have attracted special attention in recent
years.28 Due to the importance of ferrocenyl compounds, we used
ferrocenecarboxaldehyde 9 within the developed process. This
made it possible to synthesize new ferrocenyl amidinium betaines
10 (Scheme 3).
A mixture of 1,3-indandione (1 mmol), aldehyde (1 mmol),
amine (1 mmol), and isocyanide (1 mmol) in Et2O (5 mL) was
stirred at room temperature for 24 h. After completion of the re-
action, as indicated by TLC, the reaction mixture was filtered and
the precipitate recrystallized from CHCl3/hexane (1:3) to afford the
pure product 5.
4.2.1. 2-(2-(tert-Butylamino)-1-phenyl-2-(phenylimino)ethyl)-1,3-
dioxo-2,3-dihydro-1H-inden-2-ide (5a). Yield (0.32 g, 78%) as a yel-
low solid, mp 194e196 ꢁC; [found: C, 78.91; H, 6.31; N, 6.74.
C27H26N2O2 requires C, 79.00; H, 6.38; N, 6.82]; nmax(KBr) 3191,
1623, 1590 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.53 (9H, s, t-Bu), 5.01
(1H, s, CH), 7.04e7.48 (14H, m, AreH), 9.87 (1H, br s, NeH), 12.53
(1H, br s, NeH); dC (75 MHz, DMSO-d6) 27.9, 41.8, 53.6, 101.1, 118.0,
126.8, 127.1, 128.4, 129.0, 129.2, 130.3, 136.2, 139.5, 140.7, 143.2,
166.3, 189.1; MS, m/z: 410 (Mþ).
4.2.2. 2-(2-(Cyclohexylimino)-1-phenyl-2-(phenylamino)ethyl)-1,3-
dioxo-2,3-dihydro-1H-inden-2-ide (5b). Yield (0.32 g, 74%) as a yel-
low solid, mp 252e254 ꢁC; [found: C, 79.68; H, 6.38; N, 6.51.
C29H28N2O2 requires C, 79.79; H, 6.46; N, 6.42]; nmax(KBr) 3224, 1657,
1618 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.35e2.02 (10H, m, 5CH2 of
cyclohexyl), 3.84 (1H, br s, CHeN), 5.09 (1H, s, CH), 7.12e7.49 (14H, m,
AreH),10.64(1H, brs,NeH),12.60(1H, brs,NeH);dC (75MHz, DMSO-
d6) 24.1, 25.1, 31.4, 31.6, 51.0,101.3,118.0,127.0,127.1,127.6,128.8,128.9,
129.9, 130.3, 136.4, 139.6, 140.9, 166.3, 189.2; MS, m/z: 436 (Mþ).
4.2.3. 2-(2-(Cyclohexylamino)-1-(4-nitrophenyl)-2-(phenylimino)
ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (5c). Yield (0.34 g,
71%) as a yellow solid, mp 180e182 ꢁC; [found: C, 72.21; H, 5.71; N,
8.80. C29H27N3O4 requires C, 72.33; H, 5.65; N, 8.73]; nmax(KBr)
3231, 1640, 1591 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.34e1.57 (10H, m,
5CH2 of cyclohexyl), 3.87 (1H, br s, CHeN), 5.10 (1H, s, CH),
6.96e7.47 (13H, m, AreH), 10.83 (1H, br s, NeH), 12.50 (1H, br s,
NeH); dC (75 MHz, DMSO-d6) 24.1, 25.0, 31.1, 31.5, 51.6, 111.9, 123.8,
127.7, 128.1, 128.6, 129.1, 129.7, 130.1, 130.5, 132.5, 139.5, 149.8, 172.7,
189.1; MS, m/z: 481 (Mþ).
3. Conclusion
4.2.4. 2-(2-(2,6-Dimethylphenylamino)-1-phenyl-2-(phenylimino)
ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (5d). Yield (0.31 g,
68%) as a yellow solid, mp 165e167 ꢁC; [found: C, 81.06; H, 5.65; N,
6.01. C31H26N2O2 requires C, 81.20; H, 5.72; N, 6.11]; nmax(KBr) 3199,
In conclusion, we have described for the first time a new and
successful strategy for the convenient synthesis of 1,3-
indandionylamidinium betaines via an isocyanide-based four-com-
ponent reaction. The method offers several advantages including
operational simplicity, good yields, and easy work-up procedures.
Moreover, the reaction is performed under neutral conditions by
simple mixing of the starting materials. It is worth noting that two
CeC and one CeN bonds were formed with concomitant creation of
amidinium betaines in this one-pot, four-component process.
1721, 1645 cmꢀ1
; dH (300 MHz, DMSO-d6) 0.85 (6H, s, 2CH3), 3.88
(1H, s, CH), 6.71e7.58 (17H, m, AreH), 10.03 (1H, br s, NeH), 12.43
(1H, br s, NeH); MS, m/z: 458 (Mþ). (Due to very low solubility of the
product 5d, we cannot report the 13C NMR data for this product).
4.2.5. 2-(1-(4-Bromophenyl)-2-(cyclohexylamino)-2-(phenylimino)
ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (5e). Yield (0.37 g,
73%) as a yellow solid, mp 178e180 ꢁC; [found: C, 67.65; H, 5.33; N,
5.30. C29H27BrN2O2 requires C, 67.58; H, 5.28; N, 5.43]; nmax(KBr)
4. Experimental
4.1. General
3236, 1721, 1645 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.08e1.72 (10H, m,
5CH2 of cyclohexyl), 3.84 (1H, br s, CHeN), 5.03 (1H, s, CH),
7.06e7.47 (13H, m, AreH), 10.70 (1H, br s, NeH), 12.53 (1H, br s,
NeH); dC (75 MHz, DMSO-d6) 24.1, 25.1, 31.3, 31.6, 50.9, 101.0, 118.4,
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. 1H and 13C NMR spectra were

3870
R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
Table 1
Synthesis of tetrazoles 5
R1
R2
R3
Product
Yield (%)
78
C6H5
C6H5
tert-Butyl
5a
C6H5
C6H5
Cyclohexyl
74
5b
4-NO2eC6H4
C6H5
Cyclohexyl
71
5c
C6H5
C6H5
2,6-Dimethylphenyl
68
73
69
5d
4-BreC6H4
C6H5
Cyclohexyl
5e
C6H5
4-MeOeC6H4
Cyclohexyl
5f

R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
3871
Table 1 (continued )
R1
R2
R3
Product
Yield (%)
4-CleC6H4
C6H5
Cyclohexyl
76
5g
C6H5
4-MeeC6H4
Cyclohexyl
79
5h
3-CleC6H4
C6H5
Cyclohexyl
69
78
69
5i
4-MeeC6H4
C6H5
Cyclohexyl
5j
4-MeOeC6H4
C6H5
Cyclohexyl
5k
3-MeOeC6H4
C6H5
tert-Butyl
73
5l
(continued on next page)

3872
R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
Table 1 (continued )
R1
R2
R3
Product
Yield (%)
4-FeC6H4
4-CleC6H4
tert-Butyl
64
5m
C6H5
4-CleC6H4
1,1,3,3-Tetramethyl-buty
68
5n
120.3, 123.6, 127.7, 128.9, 129.2, 130.0, 131.8, 136.3, 139.4, 140.3,
NeH); dC (75 MHz, DMSO-d6) 24.2, 25.3, 31.5, 31.8, 50.5, 101.5, 117.5,
117.9, 126.8, 127.4, 128.9, 129.8, 130.0, 130.2, 131.5, 139.6, 140.4,
164.7, 189.2; MS, m/z: 470 (Mþ).
165.8, 189.1; MS, m/z: 516 (Mþ), 514 (Mþ).
4.2.6. 2-(2-(Cyclohexylamino)-2-(4-methoxyphenylimino)-1-
phenylethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide
(5f). Yield
4.2.8. 2-(2-(Cyclohexylamino)-1-phenyl-2-(p-tolylimino)ethyl)-1,3-
dioxo-2,3-dihydro-1H-inden-2-ide (5h). Yield (0.35 g, 79%) as a yel-
low solid, mp 234e236 ꢁC; [found: C, 79.88; H, 6.79; N, 6.12.
C30H30N2O2 requires C, 79.97; H, 6.71; N, 6.22]; nmax(KBr) 3231,
(0.32 g, 69%) as a yellow solid, mp 163e165 ꢁC; [found: C, 77.33; H,
6.56; N, 5.93. C30H30N2O3 requires C, 77.23; H, 6.48; N, 6.00];
nmax(KBr) 3225, 1644, 1640 cmꢀ1
; dH (300 MHz, DMSO-d6)
1.31e1.73 (10H, m, 5CH2 of cyclohexyl), 3.62 (1H, br s, CHeN), 3.79
(3H, s, MeO), 5.03 (1H, s, CH), 7.00e7.49 (13H, m, AreH), 10.47 (1H,
br s, NeH), 12.48 (1H, br s, NeH). dC (75 MHz, DMSO-d6) 24.1, 25.1,
31.3, 31.5, 50.8, 55.8, 101.4, 114.9, 118.0, 126.9, 127.1, 128.7, 128.9,
129.0, 130.3, 139.5, 140.9, 159.3, 166.6, 189.1; MS, m/z: 465 (Mþ).
1654, 1606 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.26e1.67 (10H, m, 5CH2
of cyclohexyl), 1.83 (3H, s, Me), 3.62 (1H, br s, CHeN), 5.04 (1H, s,
CH), 6.76e7.20 (13H, m, AreH),10.28 (1H, br s, NeH),11.83 (1H, br s,
4.2.7. 2-(1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-(phenylimino)
ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (5g). Yield (0.35 g,
76%) as a yellow solid, mp 188e190 ꢁC; [found: C, 73.86; H, 5.82; N,
5.95. C29H27ClN2O2 requires C, 73.95; H, 5.78; N, 5.95]; nmax(KBr)
3448, 1644, 1590 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.22e1.78 (10H, m,
5CH2 of cyclohexyl), 3.61 (1H, br s, CHeN), 5.02 (1H, s, CH),
6.86e7.42 (13H, m, AreH), 10.43 (1H, br s, NeH), 11.87 (1H, br s,
Scheme 2. Proposed mechanism.
Scheme 3. Synthesis of ferrocenyl amidinium betaines 10.
Fig. 1. X-ray crystal structure of 5e.

R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
3873
NeH); dC (75 MHz, DMSO-d6) 20.9, 24.4, 25.5, 31.7, 31.9, 49.4, 102.9,
117.5, 118.0, 124.9, 126.1, 127.2, 128.3, 129.8, 131.7, 140.2, 142.8, 143.5,
164.1, 189.3; MS, m/z: 450 (Mþ).
br s, NeH), 11.78 (1H, br s, NeH). dC (75 MHz, DMSO-d6) 28.4, 29.0,
31.3, 31.5, 35.6, 42.2, 54.7, 101.3, 123.4, 124.2, 127.7, 127.9, 128.3,
128.8, 130.9, 133.1, 133.2, 139.6, 140.2, 168.8, 189.0; MS, m/z: 501
(Mþ).
4.2.9. 2-(1-(3-Chlorophenyl)-2-(cyclohexylamino)-2-(phenylimino)
ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (5i). Yield (0.32 g,
69%) as a yellow solid, mp 228e230 ꢁC; [found: C, 73.83; H, 5.67; N,
6.04. C29H27ClN2O2 requires C, 73.95; H, 5.78; N, 5.95]; nmax(KBr)
4.2.15. 2-(2-(Cyclohexylamino)-1-ferrocenyl-2-(phenylimino)ethyl)-
1,3-dioxo-2,3-dihydro-1H-inden-2-ide (10a). Yield (0.39 g, 74%) as
a purple solid, mp 163e165 ꢁC; [found: C, 72.69; H, 5.85; N, 5.25.
C33H32FeN2O2 requires C, 72.80; H, 5.92; N, 5.15]; nmax(KBr) 3495,
3222, 1641, 1584 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.27e1.67 (10H, m,
5CH2 of cyclohexyl), 3.67 (1H, br s, CHeN), 5.05 (1H, s, CH),
6.85e7.35 (13H, m, AreH), 10.23 (1H, br s, NeH), 11.07 (1H, br s,
NeH); dC (75 MHz, DMSO-d6) 24.3, 25.4, 31.6, 31.9, 50.0, 101.8, 117.9,
125.8, 125.9, 126.6, 126.9, 129.5, 129.7, 130.1, 130.5, 133.2, 139.7,
142.0, 144.5, 163.1, 189.3; MS, m/z: 471 (Mþ).
1656, 1624 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.26e1.81 (10H, m, 5CH2
of cyclohexyl), 3.77e4.24 (10H, m, CHfer and CHeN), 5.02 (1H, s,
CH), 7.17e7.88 (9H, m, AreH), 10.47 (1H, br s, NeH), 11.94 (1H, br s,
NeH); MS, m/z: 544 (Mþ). (Due to very low solubility of the product
10a, we cannot report the 13C NMR data for this product).
4.2.10. 2-(2-(Cyclohexylamino)-2-(phenylimino)-1-p-tolylethyl)-1,3-
dioxo-2,3-dihydro-1H-inden-2-ide (5j). Yield (0.35 g, 78%) as an
orange solid, mp 156e158 ꢁC; [found: C, 79.91; H, 6.67; N, 6.15.
C30H30N2O2 requires C, 79.97; H, 6.71; N, 6.22]; nmax(KBr) 3212,
4.2.16. 2-(2-(tert-Butylamino)-1-ferrocenyl-2-(phenylimino)ethyl)-
1,3-dioxo-2,3-dihydro-1H-inden-2-ide (10b). Yield (0.39 g, 76%) as
a yellow solid, mp 176e178 ꢁC; [found: C, 71.73; H, 5.77; N, 5.35.
C31H30FeN2O2 requires C, 71.82; H, 5.83; N, 5.40]; nmax(KBr) 3254,
1643, 1623 cmꢀ1
;
dH (300 MHz, DMSO-d6) 1.23e1.68 (10H, m, 5CH2
1650, 1616 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.64 (9H, s, t-Bu),
of cyclohexyl), 1.87 (3H, s, CH3), 3.67 (1H, br s, CHeN), 5.04 (1H, s,
CH), 7.01e7.36 (13H, m, AreH),10.03 (1H, br s, NeH),10.90 (1H, br s,
NeH); dC (75 MHz, DMSO-d6) 20.9, 24.3, 25.5, 31.7, 32.0, 49.9, 102.7,
117.6, 125.8, 127.1, 129.1, 129.4, 129.9, 135.4, 139.1, 140.0, 142.6, 162.8,
164.1, 189.3; MS, m/z: 450 (Mþ).
3.47e4.23 (9H, m, CHfer), 5.16 (1H, s, CH), 7.13e7.85 (9H, m, AreH),
10.93 (1H, br s, NeH), 12.08 (1H, br s, NeH); MS, m/z: 518 (Mþ).
(Due to very low solubility of the product 10b, we cannot report the
13C NMR data for this product).
4.2.17. 2-(1-Ferrocenyl-2-(phenylimino)-2-(2,4,4-trimethylpentan-
2-ylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (10c). Yield
(0.4 g, 70%) as a yellow solid, mp 179e181 ꢁC; [found: C, 73.03; H,
6.56; N, 4.80. C35H38FeN2O2 requires C, 73.17; H, 6.67; N, 4.88];
4.2.11. 2-(2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-(phenyl-
imino)ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide
(5k). Yield
(0.32 g, 69%) as a yellow solid, mp 174e176 ꢁC; [found: C, 77.13; H,
6.55; N, 5.91. C30H30N2O3 requires C, 77.23; H, 6.48; N, 6.00];
nmax(KBr) 3242, 1623, 1588 cmꢀ1
; dH (300 MHz, DMSO-d6) 0.82 (9H,
nmax(KBr) 3237, 1646, 1618 cmꢀ1
;
dH (300 MHz, DMSO-d6)
s, 3CH3), 1.39 (3H, s, CH3), 1.46 (3H, s, CH3), 1.63 (2H, ABq, J 11.9 Hz,
CH2), 3.89e4.21 (9H, m, CHfer), 5.01 (1H, s, CH), 7.17e7.68 (9H, m,
AreH), 9.56 (1H, br s, NeH), 11.84 (1H, br s, NeH); dC (75 MHz,
DMSO-d6) 29.0, 31.2, 31.6, 36.4, 39.1, 49.6, 56.8, 67.1, 67.4, 67.7, 69.0,
89.6, 100.0, 117.9, 128.9, 129.0, 129.9, 130.1, 136.5, 166.9, 189.4; MS,
m/z: 574 (Mþ).
1.07e1.91 (10H, m, 5CH2 of cyclohexyl), 3.67 (1H, br s, CHeN),
3.79 (3H, s, MeO), 5.01 (1H, s, CH), 6.79e7.46 (13H, m, AreH),
10.55 (1H, br s, NeH), 12.59 (1H, br s, NeH); dC (75 MHz, DMSO-
d6) 24.1, 25.1, 31.6, 35.9, 51.4, 55.4, 101.6, 114.3, 117.9, 127.7, 128.1,
128.7, 129.9, 130.2, 132.9, 139.6, 158.4, 166.6, 167.0, 189.1; MS, m/z:
466 (Mþ).
Acknowledgements
4.2.12. 2-(2-(tert-Butylamino)-1-(3-methoxyphenyl)-2-(phenyl-
imino)ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide
(5l). Yield
(0.32 g, 73%) as an orange solid, mp 196e198 ꢁC; [found: C, 76.21; H,
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
6.34; N, 6.25. C28H28N2O3 requires C, 76.34; H, 6.41; N, 6.36];
nmax(KBr) 3223, 1657, 1613 cmꢀ1
; dH (300 MHz, DMSO-d6) 1.52 (9H,
s, t-Bu), 3.64 (3H, s, MeO), 4.97 (1H, s, CH), 6.54e7.49 (13H, m,
AreH), 9.86 (1H, br s, NeH), 12.56 (1H, br s, NeH). dC (75 MHz,
DMSO-d6) 27.9, 41.8, 53.6, 55.3, 101.1, 112.1, 112.8, 118.0, 119.1, 128.4,
129.2, 129.9, 130.1, 130.3, 136.2, 139.5, 142.2, 159.5, 166.1, 189.1; MS,
m/z: 440 (Mþ).
References and notes
ꢀ
1. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005.
ꢀ
2. Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602e1634.
3. Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957e4980.
€
4. Domling, A. Chem. Rev. 2006, 106, 17e89.
€
4.2.13. 2-(2-(tert-Butylamino)-2-(4-chlorophenylimino)-1-(4-
fluorophenyl)ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide
(5m). Yield (0.29 g, 64%) as a cream solid, mp 218e220 ꢁC; [found:
C, 69.91; H, 5.13; N, 6.16. C27H24ClFN2O2 requires C, 70.05; H, 5.23;
5. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210.
6. Shaabani, A.; Maleki, A.; Rezayan, A. H.; Sarvary, A. Mol. Divers. 2011, 15, 41e68.
7. Sadjadi, S.; Heravim, M. M. Tetrahedron 2011, 67, 2707e2752.
8. Ivachtchenko, A. V.; Ivanenkov, Y. A.; Kysil, V. M.; Krasavin, M. Y.; Ilyin, A. P.
Russ. Chem. Rev. (Engl. Transl.) 2010, 79, 787e817.
N, 6.05]; nmax(KBr) 3251, 1683, 1654 cmꢀ1
; dH (300 MHz, DMSO-d6)
9. Leblois, D.; Piessard, S.; Le Baut, G.; Kumar, P.; Brion, J. D.; Sparfel, L.; Sanchez,
R. Y.; Juge, M.; Petit, J. Y.; Welin, L. Eur. J. Med. Chem. 1987, 22, 229e288.
10. Hansen, D. B.; Joulie, M. M. Chem. Soc. Rev. 2005, 34, 408e417.
11. Bello, K.; Cheng, L.; Griffiths, J. J. Chem. Soc., Perkin Trans. 2 1987, 815e818.
12. Bryce, M. R.; Davies, S. R.; Hasan, M.; Ashwell, G. J.; Szablewski, M.; Drew, M. G.;
Short, R.; Hursthouse, M. B. J. Chem. Soc, Perkin Trans. 2 1989, 1285e1292.
13. Khodorkovsky, V.; Ellern, A.; Neilands, O. Tetrahedron Lett. 1994, 35, 2955e2958.
14. Khodorkovsky, V.; Ellern, A.; Shapiro, L.; Neilands, O. Tetrahedron Lett. 1999, 40,
4851e4854.
15. Rewinkel, J. B. M.; Adang, A. E. P. Curr. Pharm. Des. 1999, 5, 1043e1075.
16. Scarborough, R. M.; Gretler, D. D. J. Med. Chem. 2000, 43, 3453e3473.
17. Sielecki, T. M.; Liu, J.; Mousa, S. A.; Racanelli, A. L.; Hausner, E. A.; Wexler, R. R.;
Olson, R. E. Bioorg. Med. Chem. Lett. 2001, 11, 2201e2204.
1.23 (9H, s, t-Bu), 5.30 (1H, s, CH), 7.00e7.92 (12H, m, AreH), 10.12
(1H, br s, NeH), 12.66 (1H, br s, NeH); dC (75 MHz, DMSO-d6) 32.3,
42.1, 53.8, 103.5, 120.6, 120.9, 125.0, 126.3, 129.3, 133.2, 134.6, 137.2,
139.0, 142.1, 145.6, 171.7, 197.3; MS, m/z: 462 (Mþ).
4.2.14. 2-(2-(4-Chlorophenylimino)-1-phenyl-2-(2,4,4-
trimethylpentan-2-ylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-inden-
2-ide (5n). Yield (0.34 g, 68%) as a cream solid, mp 204e206 ꢁC;
[found: C, 74.23; H, 6.59; N, 5.51. C31H33ClN2O2 requires C, 74.31; H,
6.64; N, 5.59]; nmax(KBr) 3247, 1662, 1605. dH (300 MHz, DMSO-d6)
0.69 (9H, s, 3CH3), 1.01 (3H, s, CH3), 1.04 (3H, s, CH3), 1.37 (2H, ABq, J
6.3 Hz, CH2), 5.28 (1H, s, CH), 7.13e8.29 (13H, m, AreH), 10.21 (1H,
18. Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee, S.; Garvey, E. P.; Salter, M.; Dufry,
C.; Burnette, T. C.; Furtine, E. S. J. Med. Chem. 1998, 41, 2858e2871.
19. Nakamura, H.; Sasaki, Y.; Uno, M.; Yoshikawa, T.; Asano, T.; Ban, H. S.; Fukazawa,
H.; Shibuya, M.; Uehara, Y. Bioorg. Med. Chem. Lett. 2006, 16, 5127e5131.

3874
R. Akbarzadeh et al. / Tetrahedron 68 (2012) 3868e3874
3
V¼2557.55(19) A , Z¼4, Dcalcd¼1.339 g cmꢀ3
, m(MoKa
)¼1.635 mmꢀ1, crystal di-
ꢁ
20. Stephens, C. E.; Tanious, E.; Kim, S.; Wilson, D. W.; Schell, W. A.; Perfect, J. R.;
Franzblau, S. G.; Boykin, D. W. J. Med. Chem. 2001, 44, 1741e1748.
21. Boyd, G. V. In; Patai, S., Rappoport, Z., Eds. The Chemistry of Amidines and
Imidates; Wiley: New York, NY, 1991; Vol. 2; (Chapter 8).
22. Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038e2039.
23. Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Keshipour, S.; Khavasi, H. R. Tetrahe-
dron Lett. 2010, 51, 4091e4094.
mension of 0.30ꢂ0.07ꢂ0.05 mm. The structure was solved by using SHELXS. The
structure refinement and data reduction was carried out with SHELXL of the X-
Step32 suite of programs.29 The non-hydrogen atoms were refined anisotropi-
cally by full matrix least-squares on F2 values to final R1¼0.1182, wR2¼0.2226 and
S¼1.170 with 315 parameters using 6914 independent reflection ( range¼1.
q
92e29.30ꢁ). Hydrogen atoms were located from expected geometry and were
not refined. Crystallographic data for 5e have been deposited with the Cam-
bridge Crystallographic Data Centre. Copies of the data can be obtained, free of
charge, on application toThe Director, CCDC 855656, Union Road, Cambridge CB2
1EZ, UK. Fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
24. Akbarzadeh, R.; Mirzaei, P.; Bazgir, A. J. Organomet. Chem. 2010, 695,
2320e2324.
25. Akbarzadeh, R.; Amanpour, T.; Mirzaei, P.; Bazgir, A. J. Organomet. Chem. 2011,
696, 3421e3424.
26. Akbarzadeh, R.; Amanpour, T.; Mirzaei, P.; Bazgir, A. Helv. Chim. Acta 2011, 94,
1527e1532.
28. Torres, J. C.; Pilli, R. A.; Vargas, M. D.; Violante, F. A.; Garden, S. J.; Pinto, A. C.
Tetrahedron 2002, 58, 4487e4492 and references cited therein.
27. X-ray data for 5e: C29H27Br1N2O2, M¼515.43 g/mol, monoclinic system, space
29. X-STEP32 Version 1.07b, X-ray Structure Evaluation Package; Stoe
Darmstadt, Germany, 2000.
& Cie:
¼107.491(4)ꢁ,
ꢁ
group P21/c, a¼11.1140(5), b¼18.7276(7), c¼12.8834(6) A,
b