A facile three-component [3+2]-cycloaddition/annulation domino protocol for the regio- and diastereoselective synthesis of novel penta- and hexacyclic cage systems, involving the generation of two heterocyclic rings and five contiguous stereocenters

Article abstract of DOI:10.1016/j.tet.2011.02.058

An expedient, three-component, [3+2]-cycloaddition/annulation domino protocol for the synthesis of a series of cage penta- and hexacyclic compounds in good to excellent yields is described. The ring systems thus generated contain as structural elements bridged, fused and spiro rings and were obtained with complete selectivity through the creation of two C-C and two C-N bonds, which led to the generation of two azaheterocyclic rings, four carbon and one nitrogen adjacent stereocentres, three of which are quaternary.

Full text of DOI:10.1016/j.tet.2011.02.058

Tetrahedron 67 (2011) 3132e3139
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile three-component [3þ2]-cycloaddition/annulation domino protocol for
the regio- and diastereoselective synthesis of novel penta- and hexacyclic cage
systems, involving the generation of two heterocyclic rings and five contiguous
stereocenters
,
b
,
c,
d
Raju Suresh Kumar a, Hasnah Osman a , Subbu Perumal , J. Carlos Menendez , Mohamed Ashraf Ali ,
*
*
*
ꢀ
Rusli Ismail d, Tan Soo Choon d
a School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
b Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
c
ꢀ
ꢀ
Departamento de Química Organica y Farmaceutica, Universidad Complutense, 28040 Madrid, Spain
d Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 January 2011
Received in revised form 16 February 2011
Accepted 21 February 2011
Available online 26 February 2011
An expedient, three-component, [3þ2]-cycloaddition/annulation domino protocol for the synthesis of
a series of cage penta- and hexacyclic compounds in good to excellent yields is described. The ring
systems thus generated contain as structural elements bridged, fused and spiro rings and were obtained
with complete selectivity through the creation of two CeC and two CeN bonds, which led to the gen-
eration of two azaheterocyclic rings, four carbon and one nitrogen adjacent stereocentres, three of which
are quaternary.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Cage compounds
Multicomponent reactions
Domino reactions
Dipolar cycloadditions
Spiro compounds
1. Introduction
friendliness arising from minimization of waste, time, energy and
cost. Because they provide expeditious and elegant access to li-
Cage compounds, whose defining structural feature is the
presence of a closed cavity, often behave as artificial receptors and
are one of the key structures in the development of supramolecular
chemistry. Because of these properties, the development of bio-
active cage compounds is of considerable current interest.1 Their
preparation has traditionally required multi-step sequences, and
for this reason there is a great interest in the development of
simple, efficient, step-economic routes to cage frameworks. We
describe in this paper a reaction illustrating the use of a three-
component domino protocol to build structurally complex het-
erocyclic cage compounds in a single synthetic operation and with
complete regio- and stereocontrol.
braries of molecules of high levels of complexity and diversity, they
play a key role in combinatorial4 and diversity-oriented synthesis.5
In particular, three-component reactions involving [3þ2]-cycload-
dition of azomethine ylides to olefinic dipolarophiles6,7 constitute
a facile approach to the construction of five-membered heterocyclic
rings of biological importance. Among them, pyrrolidines are par-
ticularly important because of their occurrence in a large number of
natural products8 and the remarkable biological properties of many
of them.9 Regarding the dipolarophile components, we initially
chose piperidine-based frameworks, again because of the biological
importance of heterocycles with piperidine substructures10 and
also because of their role as useful synthons for the construction of
naturally occurring alkaloids.11 In this context, we have recently
Multicomponent reactions (MCRs)2 constitute an efficient and
powerful tool for the construction of novel organic structures due
to their valuable features of convergence, economy,3 and eco-
explored the reaction between 1-substituted
dene)-cyclic ketones and azomethine ylides derived from cyclic
a,a
0-bis(arylmethyli-
ketones and a
-amino acids12 together with the antitubercular ac-
tivity of the resulting products,13 and report here its adaptation to
the creation of cage structures via a one-pot, three-component
protocol. As shown in Fig. 1, our strategy involves the combination
* Corresponding authors. E-mail addresses: ohasnah@usm.my (H. Osman),
ꢀ
subbu.perum@gmail.com (S. Perumal), josecm@farm.ucm.es (J.C. Menendez).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.058

R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
3133
and the products (4 or 6, respectively) were purified by crystallization.
The results obtained for both methods are summarized in Table 1, and
clearly show that microwave irradiation led to an enhancement in the
yield of the product (81e96%) over the conventional thermal method
(72e88%), although in the case 6f both the conventional and the mi-
crowave-assisted reactions gave complex mixtures from which no
identifiable compound could be isolated. This can be attributed to the
presence of an o-methoxyphenol unit, which would render the com-
pound very sensitive to air oxidation. As shown in Table 1, the domino
reaction works well regardless of the position and electronic or steric
properties of the substituents at the aromatic rings of compounds 1.
The structures of products 4 and 6 were elucidated using ele-
mental analysis, IR, 1H, 13C and 2D NMR spectroscopic data, as il-
lustrated below for 4a. The 1H NMR spectrum of 4a has a singlet at
2.26 ppm for the NeCH3 hydrogens of the pyrrolidine ring, which
show HMBC with a methylenic carbon, ascribable to 12-CH2 (Fig. 2).
From the C,H-COSY correlation of 12-CH2, the triplet at 3.81 ppm
(J¼10.4 Hz) and the multiplet at 3.93e3.98 ppm were assigned to
the 12-CH2 hydrogens. The multiplicity of H-13 and its H,H-COSY
correlation with 12-CH2 hydrogens enabled the assignment of the
former to the doublet of doublets at 4.86 ppm (J¼10.0 and 5.2 Hz).
The assignment of the doublet at 2.70 ppm (J¼12.8 Hz) and the
multiplet at 3.93e3.98 ppm to 18-CH2 and that of the doublet at
3.43 ppm (J¼16.4 Hz) and a doublet of doublets at 3.74 ppm (J¼16.8,
2.4 Hz) to 17-CH2 were done similarly on straightforward consid-
erations. The arylmethylidene hydrogen, H-19 appears as a singlet
at 7.11 ppm and the aromatic hydrogens appeared as doublets and
multiplets at 6.78e7.68 ppm. The C]O of ninhydrin occurred at
201.5 ppm. These signal assignments are consistent with the
HMBCs and H,H-COSY correlations depicted in Fig. 1. The fact that
the H-13 benzylic hydrogen appears as a doublet of doublets at
4.86 ppm (J¼10.0 and 5.6 Hz) clearly establishes the regiochemistry
of the cycloaddition, as for the other possible regioisomer 9 that
might have arisen from the cycloaddition, it should give a singlet.
These findings were confirmed by X-ray crystallographic studies of
4a, 4e, 6a and 6c (Fig. 3 and Supplementary data),17 which also
reveal a retention of the stereochemistry of the benzylidene func-
tion of the dipolarophile 1 in the newly generated pyrrolidine ring
during the cycloaddition reaction.
Fig. 1. Our strategy for the synthesis of heterocyclic cage compounds.
of a dipole generation-1,3-cycloaddition sequence with the gener-
ation of a hemiaminal bond in order to allow the creation of the
bond that closes the cage. To this end, the starting a,a
0-bis(aryl-
methylidene) ketone must have an unsubstituted nitrogen atom
and the ketone involved in the generation of the dipole must
contain a 1,2-dicarbonyl moiety.
2. Results and discussion
The three-component [3þ2]-cycloaddition between the N-
unsubstituted 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridi-
nones 1,14 sarcosine (2) and ninhydrin afforded derivatives of the
hitherto unreported pentacyclic diazapentacyclo[12.3.1.02,10.03,8.010,14
]
octadeca-3(8),4,6-triene-9,15-dione system (compounds 4), while
similar reactions employing acenaphthoquinone 5 as the -dicarbonyl
a
component gave diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]henicosa-1
(20),12,14,16,18-pentaen-6-ones 6, both in good to excellent yields and
isolated as the sole reaction products (Scheme 1). The reactions were
initially performed by heating an equimolar mixture of the starting
materials under reflux in methanol and were subsequently in-
vestigated also under microwave irradiation in a focused microwave
synthesizer, as this technique has evolved as a valuable alternative to
conventional heating for the introduction of energy into reactions and
has clear benefits in many chemical transformations,15 including cy-
cloadditions,16 in terms of rate accelerations and yield enhancements.
As in the case of the thermal reactions, an equimolar mixture of the
starting materials 1e3 or 1, 2, 5 in methanol was subjected to micro-
wave irradiation for 6e8 min until completion of the reaction (TLC)
A mechanism proposed to rationalize the formation of the novel
cage heterocycles is summarized in Scheme 2 for the case of the
diazapentacycle 4. The reaction of ninhydrin and sarcosine affords
the azomethine ylide 7, which adds to one of the C]C bonds of the
bisdipolarophile 1 to form the corresponding cycloadduct 8. The
final annulation involves the reaction of the amino function with
the neighbouring carbonyl group, resulting in the formation of
a hemiaminal, that is, presumably stabilized by intramolecular
hydrogen bonding. The remarkable product selectivity observed in
this reaction depends on two factors, the first of which is the
complete selectivity of the starting
a-dicarbonyl compound to-
O
O
O
H
wards sarcosine rather than the potentially competitive piperidine
system, which is probably due to steric reasons. The second is the
complete regioselectivity of the 1,3-dipolar cycloaddition, which
can be viewed as the result of a preferential attack of the nucleo-
philic carbon of the azomethine ylide to the end of the enone
fragment of the starting material 1 to give 8 instead of the alter-
native cycloaddition product 9. While this is the expected regio-
chemical outcome of the reaction,7d,18 the complete selectivity is
somewhat unusual and can be explained by steric factors and also
by the fact that, during the cycloaddition, a secondary orbital in-
teraction between the nitrogen lone pair with the carbonyl function
occurs, lowering the energy of activation for the cycloaddition and
increasing the regioselectivity in favour of 8. In a similar fashion,
the reaction of the azomethine ylide generated in situ from the
reaction of acenapthenequinone and sarcosine with compounds 2
also took place with complete regio- and product selectivity
Ar
Ar
O
O
N
O
N
OH
Ar
Ar
3
CH3
N
H
4
1
+
O
H
H
N
Ar
O
O
CO2H
Ar
H3C
2
N
N
CH3
OH
6
5
Scheme 1. Three-component synthesis of heterocyclic cage compounds 4 and 6.

3134
R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
Table 1
Comparison of the reaction times and yields for the thermal and microwave-assisted three-component domino reactions
Entry
Compound
Ar
Conventional conditions (MeOH, reflux, 60 min)
Microwave conditions (100 ꢀC, 100 W)
4
6
4
6
Yield, %
Yield, %
Time, min
Yield, %
94
Time, min
Yield, %
96
1
2
a
86
85
88
86
6
5
5
5
b
92
94
Cl
Br
F
3
4
5
c
82
83
80
81
82
84
5
5
7
93
90
92
6
6
8
92
90
93
d
e
NO2
6
f
72
0
8
81
d
0
HO
OCH3
7
g
h
i
86
80
87
84
85
83
86
82
5
6
6
5
95
92
96
95
6
8
5
6
94
90
91
90
H3C
8
H3CO
9
Cl
Br
10
j
11
k
85
87
5
94
6
92
F
synthesis of novel cage diazapenta- and hexacyclic ring systems
through a 1,3-dipole generationecycloadditioneannulation se-
quence. The overall process involves the generation of two CeC and
two CeN bonds and the creation of two new five-membered rings
and five contiguous stereocentres, three of which are quaternary.
Further studies on the synthetic applications of this methodology
are currently in progress in our laboratories.
O
O
H19
H19
H
H
H
H
H
H
H
15
15
16
16
3
13
1H 18
13
H
1H 18
O14
O14
H 17
H 17
7
12
N
N
12
10 11
H
11
N
10
H
H 9
H 9
N
7
8
8
2
2
6
CH3
6
CH3
3
OH
OH
5
4
5
4
H
H
4. Experimental section
4.1. General
Fig. 2. HMBC correlations in compound 4a (arbitrary numbering).
affording the hexacyclic ring system 6. It is also pertinent to note
that all the above reactions proceed with complete stereo-
selectivity, affording exclusively one stereoisomer despite of the
presence of five stereocenters (this includes the tertiary nitrogen
atom, which is stereogenic because it cannot undergo inversion).
Melting points were taken using open capillary tubes and are
uncorrected. A CEM microwave synthesizer (Model: Discover-S
908860) operating at 180/240 V and 50/60 Hz with consumption of
1100 W with microwave power maximum level of 300 W and
microwave frequency of 2455 MHz was employed for the irradia-
tion done in this work. 1H, 13C and two-dimensional NMR spectra
were recorded on a Bruker 400 and 300 MHz instruments in CDCl3
using TMS as internal standard. Standard Bruker software was used
3. Conclusions
In conclusion, we describe an expedient, three-component
regio-, stereo- and product-selective domino protocol for the
throughout. Chemical shifts are given in parts per million (
and the coupling constants are given in Hertz. IR spectra were
d-scale)

R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
3135
4.2. Synthesis of compounds 4 and 6. General procedures
Conventional heating method. A mixture of 3,5-bis[(E)-arylme-
thylidene]tetrahydro-4(1H)-pyridinone (1, 0.364 mmol), sarcosine
(2, 0.364 mmol) and ninhydrin/acenaphthenequinone (3/5,
0.364 mmol) was dissolved in methanol (5 mL) and heated under
reflux for 1 h. After completion of the reaction as evident from
TLC, the mixture was poured into water (50 mL). The pre-
cipitated solid was filtered and washed with water to give the
products 4 or 6, which were purified by recrystallisation from
ethyl acetate.
Microwave irradiation method. A mixture of 3,5-bis[(E)-arylme-
thylidene]tetrahydro-4(1H)-pyridinones (1, 0.364 mmol), sarcosine
(2, 0.364 mmol) and ninhydrin/acenaphthenequinone (3/5,
0.364 mmol) was dissolved in methanol (1 mL) and irradiated for
6e8 min in a CEM microwave synthesizer (100 ꢀC, 100 W). After
completion of the reaction as evident from TLC, the mixture was
poured into water. The precipitated solid was filtered and washed
with water to afford the products 4 or 6, which were purified by
recrystallisation from ethyl acetate.
4.2.1. 2-Hydroxy-11-methyl-13-phenyl-16-[(E)-phenyl-methylidene]-
1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]octadeca-3(8),4,6-triene-
9,15-dione (4a). Pale yellow crystals; (0.158 g, 94%); mp
159e160 ꢀC; IR (KBr) nmax 3333, 1708, 1680, 1601 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): dH 2.26 (s, 3H, NeCH3), 2.70 (d, J¼12.8 Hz, 1H, H-
18ax), 3.43 (d, J¼16.8 Hz, 1H, H-17ax), 3.74 (dd, J¼16.8, 2.4 Hz, 1H,
H-17eq), 3.81 (t, J¼10.4 Hz, 1H, H-12), 3.93e3.98 (m, 2H, H-12 and
H-18eq), 4.86 (dd, J¼10.0, 5.2 Hz, 1H, H-13), 6.79 (d, J¼6.4 Hz, 2H,
aromatic), 7.11 (s, 1H, H-19), 7.14e7.34 (m, 7H, aromatic), 7.40e7.45
(m, 3H, aromatic), 7.52 (d, J¼7.6 Hz, 1H, aromatic), 7.67 (d, J¼7.6 Hz,
1H, aromatic). 13C NMR (100 MHz, CDCl3): dC 38.2, 41.2, 53.5, 59.7,
64.1, 75.0, 91.8, 97.2, 123.2, 125.6, 127.3, 128.4, 128.5, 128.9, 129.4,
130.1, 130.6, 133.9, 134.6, 135.9, 136.4, 138.2, 139.7, 149.3, 195.9,
201.5. Anal. Calcd for C30H26N2O3: C, 77.90; H, 5.67; N, 6.06. Found:
C, 78.07; H, 5.33; N, 6.07.
Fig. 3. ORTEP plost for compounds 4a (top) and 6c (bottom).
O
Ar
4.2.2. 13-(2-Chlorophenyl)-16-[(E)-(2-chlorophenyl)-methylidene]-
2-hydroxy-11-methyl-1,11-diaza-pentacyclo[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4b). Pale yellow crystals;
(0.142 g, 92%); mp 112e113 ꢀC; IR (KBr) nmax 3389, 1706, 1678,
N
1
H
O
Ar
Ar
H
O
Ar
CH2
CH3
N
H
O
1601 cmꢂ1 1H NMR (400 MHz, CDCl3): dH 2.22 (s, 3H, NeCH3),
;
2 + 3
N
4
- CO2
N
2.80 (d, J¼12.8 Hz, 1H, H-18ax), 3.10 (d, J¼17.6 Hz, 1H, H-17ax),
3.63e3.75 (m, 3H, H-17eq, H-18eq, H-12), 4.06e4.13 (m, 1H, H-12),
5.01e5.03 (m, 1H, H-13), 6.48 (d, J¼7.6 Hz, 1H, aromatic),
6.97e7.01 (m, 1H, aromatic), 7.10e7.38 (m, 6H, aromatic), 7.44 (s,
1H, H-19), 7.47e7.51 (m, 1H, aromatic), 7.62e7.71 (m, 3H, aro-
matic). 13C NMR (100 MHz, CDCl3): dC 36.9, 37.2, 53.0, 59.4, 65.9,
74.0, 90.8, 96.9, 124.0, 125.2, 126.4, 127.5, 128.6, 129.0, 129.9, 130.0,
130.3, 130.4, 130.6, 132.7, 134.6, 134.7, 135.1, 136.1, 136.2, 139.2,
148.8, 193.7, 201.7. Anal. Calcd for C30H24Cl2N2O3: C, 67.80; H, 4.55;
N, 5.27. Found: C, 67.98; H, 4.27; N, 5.19.
O
CH3
O
7
8
O
Ar
H
O
Ar
CH2
O
N
N
CH3
H
N
CH3
O
O
9
4.2.3. 13-(2-Bromophenyl)-16-[(E)-(2-bromophenyl)-methylidene]-
2-hydroxy-11-methyl-1,11-diaza-pentacyclo[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4c). Pale yellow crystals; (0.134 g,
93%); mp 141e142 ꢀC; IR (KBr) nmax 3380, 1712, 1603 cmꢂ1; 1H NMR
(400 MHz, CDCl3): dH 2.21 (s, 3H, NeCH3), 2.81 (d, J¼12.8 Hz, 1H, H-
18ax), 3.08 (dt, J¼17.6, 1.6 Hz, 1H, H-17ax), 3.63e3.68 (m, 2H, H-12
and H-18eq), 3.74 (dd, J¼17.6, 3.2 Hz, 1H, H-17eq), 4.07e4.12 (m, 1H,
H-12), 4.97 (dd, J¼8.4, 1.6 Hz, 1H, H-13), 6.45e6.47 (m, 1H, aro-
matic), 7.04e7.15 (m, 3H, H-19 and aromatic), 7.28e7.57 (m, 7H,
aromatic), 7.63e7.75 (m, 2H, aromatic). 13C NMR (100 MHz, CDCl3):
dC 37.1, 39.5, 53.0, 59.4, 66.5, 74.1, 90.9, 97.0, 124.2, 125.1, 125.2,
125.3, 127.0, 128.1, 128.9, 129.2, 130.0, 130.5, 130.6, 133.2, 133.8,
134.3, 134.4, 136.1, 136.2, 138.3, 141.2, 148.9, 193.5, 201.6. Anal. Calcd
Scheme 2. A mechanistic proposal to explain the formation of compounds 4 through
a domino sequence.
recorded on a PerkineElmer system 2000 FT IR instrument (KBr).
Single crystal X-ray data set for 4a, 4e, 6a and 6c was collected on
Bruker APEXII DUO CCD area detector diffractometer with Mo K
a
ꢁ
(l
¼0.71073 A) radiation. Scan range was 2.8ꢀꢁ
q
ꢁ35.8ꢀ (4a),
2.3ꢀꢁ
q
ꢁ32.6ꢀ (4e), 2.6ꢀꢁ
q
ꢁ29.9ꢀ (6a), 3.3ꢀꢁ
q
ꢁ35.1ꢀ (6c). Ele-
mental analyses were performed on a Perkin Elmer 2400 Series II
Elemental CHNS analyser. Column chromatography was performed
on silica gel (230e400 mesh) using petroleum ethereethyl acetate
as eluent.

3136
R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
for C30H24Br2N2O3: C, 58.09; H, 3.90; N, 4.52. Found: C, 57.82; H,
3.65; N, 4.34.
13), 6.73 (d, J¼8.0 Hz, 2H, aromatic), 6.99 (d, J¼8.0 Hz, 2H, aro-
matic), 7.12e7.15 (m, 3H, H-19 and aromatic), 7.21e7.24 (m, 1H,
aromatic), 7.34 (d, J¼7.6 Hz, 2H, aromatic), 7.45e7.49 (m, 1H, aro-
matic), 7.53 (d, J¼8.0 Hz, 1H, aromatic), 7.71 (d, J¼7.6 Hz, 1H, aro-
matic). 13C NMR (100 MHz, CDCl3): dC 21.4, 21.8, 38.3, 41.1, 53.6,
59.4, 64.0, 74.7, 91.9, 97.2, 123.3, 125.6, 128.5, 129.3, 129.6, 130.4,
130.6, 131.8, 132.6, 136.0, 136.3, 136.4, 136.9, 138.5, 139.9, 149.3,
195.9, 201.5. Anal. Calcd for C32H30N2O3: C, 78.34; H, 6.16; N, 5.71.
Found: C, 78.50; H, 6.03; N, 5.58.
4.2.4. 13-(2-Fluorophenyl)-16-[(E)-(2-fluorophenyl)-methylidene]-2-
hydroxy-11-methyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]octa-
deca-3(8),4,6-triene-9,15-dione (4d). Pale Yellow solid; (0.144 g,
90%); mp 131e132 ꢀC; IR (KBr) nmax 3384, 1718, 1676, 1600 cmꢂ1; 1H
NMR (400 MHz, CDCl3): dH 2.23 (s, 3H, NeCH3), 2.84 (d, J¼12.6 Hz,
1H, H-18ax), 3.19 (d, J¼17.6 Hz, 1H, H-17ax), 3.63e3.68 (m, 2H, H-12
and H-17eq), 3.86e3.89 (m, 1H, H-12), 3.96 (dd, J¼12.6 Hz, 1H, H-
18eq), 4.95 (dd, J¼8.8, 4.8 Hz, 1H, H-13), 6.56e6.59 (m, 1H, aro-
matic), 6.86e6.92 (m, 2H, aromatic), 7.00e7.05 (m, 2H, aromatic),
7.09e7.18 (m, 3H, H-19 and aromatic), 7.23e7.27 (m, 2H, aromatic),
7.40e7.44 (m, 1H, aromatic), 7.58e7.64 (m, 2H, aromatic). 13C NMR
(100 MHz, CDCl3): dC 35.6, 37.8, 53.4 (JCF¼4.0 Hz), 59.7, 63.6, 74.8,
91.2, 97.1, 115.8 (2JCF¼21.7 Hz), 116.3 (2JCF¼22.3 Hz), 122.3
(2JCF¼13.9 Hz), 123.4, 123.8 (4JCF¼3.4 Hz), 124.7 (4JCF¼3.2 Hz), 125.5,
126.8 (2JCF¼14.5 Hz), 129.1 (3JCF¼8.3 Hz), 130.5, 130.6, 131.2, 131.3
(3JCF¼8.3 Hz), 135.7, 136.0, 136.4, 149.0, 160.6 (1JCF¼250.2 Hz), 161.4
(1JCF¼244.8 Hz),194.7, 201.7. Anal. Calcd for C30H24F2N2O3: C, 72.28;
H, 4.85; N, 5.62. Found: C, 72.51; H, 4.67; N, 5.71.
4.2.8. 2-Hydroxy-13-(4-methoxyphenyl)-16-[(E)-(4-methox-
yphenyl)-methylidene]-11-methyl-1,11-diaza-pentacyclo
[12.3.1.02,10.03,8.010,14]-octadeca-3(8),4,6-triene-9,15-dione
(4h). Yellow solid; (0.142 g, 92%); mp 153e154 ꢀC; IR (KBr) nmax
3195, 1712, 1678, 1595 cmꢂ1; 1H NMR (400 MHz, CDCl3): dH 2.26 (s,
3H, NeCH3), 2.73 (d, J¼12.4 Hz, 1H, H-18ax), 3.43 (d, J¼17.6 Hz, 1H,
H-17ax), 3.72e3.77 (m, 1H, H-17eq), 3.77 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 3.82e3.98 (m, 3H, H-12 and H-18eq), 4.83 (dd, J¼10.0, 6.0 Hz,
1H, H-13), 6.71 (d, J¼8.8 Hz, 2H, aromatic), 6.81e6.86 (m, 4H, ar-
omatic), 7.09 (s, 1H, H-19), 7.19e7.23 (m, 1H, aromatic), 7.35 (d,
J¼8.4 Hz, 2H, aromatic), 7.45e7.51 (m, 2H, aromatic), 7.71 (d,
J¼7.6 Hz, 1H, aromatic). 13C NMR (100 MHz, CDCl3): dC 38.4, 40.8,
53.6, 55.7, 59.3, 64.0, 74.6, 91.9, 97.3, 114.0, 114.2, 123.2, 125.6, 127.3,
129.6, 130.6, 131.2, 131.4, 132.4, 136.0, 136.3, 138.2, 149.3, 158.8,
160.7, 195.9, 201.4. Anal. Calcd for C32H30N2O5: C, 73.55; H, 5.79; N,
5.36. Found: C, 73.27; H, 5.94; N, 5.47.
4.2.5. 2-Hydroxy-11-methyl-13-(3-nitrophenyl)-16-[(E)-(3-nitro-
phenyl)-methylidene]-1,11-diazapentacyclo-[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4e). Pale yellow solid; (0.140 g,
92%); mp 188e189 ꢀC; IR (KBr) nmax 3391, 1702, 1603 cmꢂ1; 1H NMR
(400 MHz, CDCl3): dH 2.30 (s, 3H, NeCH3), 2.72 (d, J¼12.4 Hz, 1H, H-
18ax), 3.42 (d, J¼18.0 Hz, 1H, H-17ax), 3.76 (dd, J¼18.0, 2.8 Hz, 1H,
H-17eq), 3.89 (t, J¼10.4 Hz, 1H, H-12), 3.95e3.99 (m, 2H, H-12 and
H-18eq), 4.96 (dd, J¼10.0, 5.6 Hz, 1H, H-13), 7.10 (d, J¼8.4 Hz, 2H,
aromatic), 7.25e7.28 (m, 1H, aromatic), 7.38e7.42 (m, 1H, aro-
matic), 7.46e7.57 (m, 3H, H-19 and aromatic), 7.60 (d, J¼8.0 Hz, 1H,
aromatic), 7.69 (d, J¼7.6 Hz, 1H, aromatic), 7.81 (d, J¼8.0 Hz, 1H,
aromatic), 8.06e8.14 (m, 2H, aromatic), 8.29e8.31 (m, 1H, aro-
matic). 13C NMR (100 MHz, CDCl3): dC 38.2, 41.1, 53.2, 59.5, 63.6,
74.9, 91.7, 97.3, 122.7, 123.0, 123.3, 123.9, 124.1, 125.8, 129.6, 130.0,
130.9, 135.0, 135.2, 135.3, 135.9, 136.3, 136.4, 136.6, 141.6, 148.2,
148.9, 149.1, 195.2, 201.3. Anal. Calcd for C30H24N4O7: C, 65.21; H,
4.38; N, 10.14. Found: C, 65.05; H, 4.34; N, 9.96.
4.2.9. 13-(4-Chlorophenyl)-16-[(E)-(4-chlorophenyl)-methylidene]-
2-hydroxy-11-methyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4i). Pale yellow solid; (0.148 g,
96%); mp 188e189 ꢀC; IR (KBr) nmax 3367, 1715, 1689, 1598 cmꢂ1; 1H
NMR (400 MHz, CDCl3): dH 2.26 (s, 3H, NeCH3), 2.70 (d, J¼12.8 Hz,
1H, H-18ax), 3.39 (d, J¼17.2 Hz, 1H, H-17ax), 3.73 (dd, J¼17.2, 2.4 Hz,
1H, H-17eq), 3.80 (t, J¼10.4 Hz, 1H, H-12), 3.88e3.95 (m, 2H, H-12
and H-18eq), 4.82 (dd, J¼10.0, 5.6 Hz, 1H, H-13), 6.73 (d, J¼8.4 Hz,
2H, aromatic), 7.03 (s, 1H, H-19), 7.15 (d, J¼8.4 Hz, 2H, aromatic),
7.23e7.30 (m, 3H, aromatic), 7.37 (d, J¼8.4 Hz, 2H, aromatic),
7.47e7.53 (m, 2H, aromatic), 7.69 (d, J¼7.6 Hz, 1H, aromatic). 13C
NMR (100 MHz, CDCl3): dC 38.3, 40.8, 53.5, 59.5, 63.8, 74.7, 91.7, 97.2,
123.2, 125.7, 128.8, 129.1, 129.9, 130.8, 131.4, 132.8, 133.1, 134.2,
135.6, 136.3, 136.9, 138.0, 149.1, 195.7, 201.4. Anal. Calcd for
C30H24Cl2N2O3: C, 67.80; H, 4.55; N, 5.27. Found: C, 68.04; H, 4.69;
N, 5.38.
4.2.6. 2-Hydroxy-13-(4-hydroxy-3-methoxyphenyl)-16-[(E)-(4-hy-
droxy-3-methoxyphenyl)methylidene]-11-methyl-1,11-diazapentacyclo
[12.3.1.02,10.03,8.010,14]octadeca-3(8),4,6-triene-9,15-dione
(4f). Colourless crystals; (0.123 g, 81%); mp 164e165 ꢀC; IR (KBr)
nmax 3382, 1718, 1679, 1601 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH
4.2.10. 13-(4-Bromophenyl)-16-[(E)-(4-bromophenyl)-methylidene]-
2-hydroxy-11-methyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4j). Pale yellow crystals; (0.135 g,
95%); mp 184e185 ꢀC; IR (KBr) nmax 3392, 1710,1679, 1600 cmꢂ1; 1H
NMR (400 MHz, CDCl3): dH 2.26 (s, 3H, NeCH3), 2.70 (d, J¼12.8 Hz,
1H, H-18ax), 3.39 (d, J¼17.6 Hz, 1H, H-17ax), 3.72 (dd, J¼17.6, 2.4 Hz,
1H, H-17eq), 3.80 (t, J¼10.4 Hz, 1H, H-12), 3.87e3.95 (m, 2H, H-12
and H-18eq), 4.81 (dd, J¼10.0, 5.6 Hz, 1H, H-13), 6.66 (d, J¼8.4 Hz,
2H, aromatic), 7.02 (s, 1H, H-19), 7.24e7.32 (m, 5H, aromatic), 7.44
(d, J¼8.4 Hz, 2H, aromatic), 7.48e7.53 (m, 2H, aromatic), 7.69 (d,
J¼8.0 Hz, 1H, aromatic). 13C NMR (100 MHz, CDCl3): dC 38.2, 40.9,
53.4, 59.5, 63.8, 74.7, 91.7, 97.3, 123.2, 123.9, 125.7, 130.3, 130.8,
131.5, 131.8, 132.0, 132.1, 132.3, 133.8, 134.3, 135.8, 136.2, 136.9,
149.2, 195.6, 201.3. Anal. Calcd for C30H24Br2N2O3: C, 58.09; H, 3.90;
N, 4.52. Found: C, 57.90; H, 3.78; N, 4.64.
2.27 (s, 3H, NeCH3), 2.77 (d, J¼15.2 Hz, 1H, H-18ax), 3.42e3.50
(m, 1H, H-17ax), 3.74e0.79 (m, 2H, H-17eq and H-12), 3.08 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 3.93e4.04 (m, 2H, H-12 and H-18eq),
4.81 (dd, J¼10.2, 6.0 Hz, 1H, H-13), 6.41e6.47 (m, 2H, aromatic),
6.72e6.75 (m, 1H, aromatic), 6.95 (s, 1H, H-19), 7.22e7.27 (m, 1H,
aromatic), 7.51e7.53 (m, 2H, aromatic), 7.87e7.92 (m, 2H, aro-
matic), 8.00e8.04 (m, 2H, aromatic). 13C NMR (100 MHz, CDCl3):
dC 38.4, 40.6, 41.2, 41.4, 54.5, 59.7, 70.1, 74.5, 91.7, 97.5, 111.8, 111.9,
113.1, 114.7, 120.5, 124.8, 125.7, 127.1, 130.6, 131.0, 131.2, 136.3,
136.7, 138.7, 140.3, 144.9, 146.4, 146.8, 147.4, 149.2. 195.8, 201.2.
Anal. Calcd for C32H30N2O7: C, 69.30; H, 5.45; N, 5.05. Found: C,
69.52; H, 5.23; N, 4.94.
4.2.7. 2-Hydroxy-11-methyl-13-(4-methylphenyl)-16-[(E)-(4-meth-
ylphenyl)-methylidene]-1,11-diazapentacyclo-[12.3.1.02,10.03,8.010,14
]
octadeca-3(8),4,6-triene-9,15-dione (4g). Pale yellow crystals;
(0.152 g, 95%); mp 195e196 ꢀC; IR (KBr) nmax 3380, 1708, 1679,
1598 cmꢂ1; 1H NMR (400 MHz, CDCl3): dH 2.27 (s, 3H, NeCH3), 2.29
(s, 3H, CH3), 2.33 (s, 3H, CH3), 2.73 (d, J¼12.8 Hz, 1H, H-18ax), 3.46
(d, J¼17.6 Hz, 1H, H-17ax), 3.75e3.81 (m, 2H, H-17eq, H-12),
3.93e4.04 (m, 2H, H-12 and H-18eq), 4.85 (dd, J¼10.0, 5.6 Hz, 1H, H-
4.2.11. 13-(4-Fluorophenyl)-16-[(E)-(4-fluorophenyl)-methylidene]-
2-hydroxy-11-methyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]oc-
tadeca-3(8),4,6-triene-9,15-dione (4k). Pale yellow crystals;
(0.150 g, 94%); mp 189e190 ꢀC; IR (KBr) nmax 3363, 1720, 1668,
1605 cmꢂ1; 1H NMR (300 MHz, CDCl3): dH 2.26 (s, 3H, NeCH3), 2.71
(d, J¼12.6 Hz, 1H, H-18ax), 3.39 (d, J¼17.4 Hz, 1H, H-17ax), 3.71e3.84

R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
3137
(m, 2H, H-17eq and H-12), 3.93e3.98 (m, 2H, H-12 and H-18eq), 4.84
(dd, J¼10.2, 5.7 Hz, 1H, H-13), 5.64 (br s, 1H, OH), 6.80e6.91 (m, 4H,
aromatic), 6.97e7.05 (m, 3H, H-19 and aromatic), 7.20e7.25 (m, 1H,
aromatic), 7.38e7.53 (m, 4H, aromatic), 7.69 (d, J¼7.5 Hz, 1H, aro-
matic). 13C NMR (100 MHz, CDCl3): dC 38.2, 40.7, 53.5, 59.5, 64.1,
74.8, 91.8, 97.2, 115.6 (2JCF¼21.5 Hz), 115.7 (2JCF¼21.1 Hz), 123.2,
125.6, 130.0 (3JCF¼7.8 Hz), 130.6, 130.7, 132.2 (2JCF¼8.5 Hz), 133.6,
135.2 (4JCF¼3.3 Hz), 136.1, 136.4, 137.0, 149.2, 162.2 (1JCF¼244.0 Hz),
163.3 (1JCF¼249.8 Hz), 195.8, 201.4. Anal. Calcd for C30H24F2N2O3: C,
72.28; H, 4.85; N, 5.62. Found: C, 72.64; H, 4.57; N, 5.64.
henicosa-1(20),12,14,16,18-pentaen-6-one (6d). Pale yellow crystals;
(0.150 g, 90%); mp 146e147 ꢀC; IR (KBr) nmax 3408,1693,1602 cmꢂ1
;
1H NMR (300 MHz, CDCl3): dH 1.98 (s, 3H, NeCH3), 2.87 (d,
J¼12.8 Hz, 1H, H-21ax), 3.19 (d, J¼17.8 Hz, 1H, H-4ax), 3.64 (dd,
J¼17.8, 2.0 Hz, 1H, H-4eq), 3.75 (t, J¼10.4 Hz, 1H, H-9), 4.01e4.12 (m,
2H, H-9 and H-21eq), 5.10 (dd, J¼10.0, 5.2 Hz, 1H, H-8), 6.18e6.21
(m, 1H, aromatic), 6.40 (s, 1H, H-22), 6.75e6.82 (m, 2H, aromatic),
7.02e7.16 (m, 3H, aromatic), 7.20e7.30 (m, 2H, aromatic), 7.35 (d,
J¼7.2 Hz, 1H, aromatic), 7.51e7.60 (m, 4H, aromatic), 7.73 (d,
J¼8.0 Hz, 1H, aromatic). 13C NMR (75 MHz, CDCl3): dC 35.5, 38.3,
53.3 (JCF¼3.7 Hz), 57.9, 62.9, 73.7, 94.2, 102.7, 115.5 (2JCF¼21.9 Hz),
116.3 (2JCF¼22.7 Hz), 121.2, 122.2 (2JCF¼13.9 Hz), 123.5, 124.6
(4JCF¼3.3 Hz), 126.2, 127.0 (2JCF¼14.2 Hz), 127.8, 128.1, 128.7
(4JCF¼3.3 Hz), 129.0 (3JCF¼8.3 Hz), 130.4, 130.5, 130.8 (3JCF¼8.4 Hz),
131.2, 135.5, 136.1, 137.1, 138.8, 160.2 (1JCF¼250.3 Hz), 161.4
(1JCF¼245.4 Hz), 195.9. Anal. Calcd for C33H26F2N2O2: C, 76.14; H,
5.03; N, 5.38. Found: C, 76.40; H, 5.17; N, 5.21.
4.2.12. 2-Hydroxy-10-methyl-8-phenyl-5-[(E)-phenyl-methylidene]-
3,10-diazahexacyclo-[10.7.1.13,7.02,11. 07,11.016,20]henicosa-1(19),12(20),-
13,15,17-pentaen-6-one (6a). Pale yellow crystals; (0.170 g, 96%);
mp 144e145 ꢀC; IR (KBr) nmax 3445, 1685, 1599 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): dH 2.04 (s, 3H, NeCH3), 2.72 (d, J¼12.4 Hz, 1H,
H-21ax), 3.40 (d, J¼17.6 Hz, 1H, H-4ax), 3.64 (dd, J¼17.6, 2.4 Hz, 1H,
H-4eq), 3.73 (t, J¼10.4 Hz, 1H, H-9), 4.06 (dd, J¼12.8, 2.4 Hz, 1H,
H-21eq), 4.11e4.15 (m, 1H, H-9), 4.97 (dd, J¼10.0, 6.4 Hz, 1H, H-8),
6.33 (s, 1H, H-22), 6.42 (d, J¼8.0 Hz, 2H, aromatic), 7.06e7.11 (m,
3H, aromatic), 7.24e7.28 (m, 2H, aromatic), 7.33e7.36 (m, 3H, ar-
omatic), 7.49e7.57 (m, 5H, aromatic), 7.70 (d, J¼8.4 Hz, 1H, aro-
matic). 13C NMR (100 MHz, CDCl3): dC 38.8, 41.5, 53.5, 57.9, 63.0,
74.0, 94.6, 103.0, 121.4, 123.4, 126.1, 126.2, 127.4, 127.9, 128.1, 128.2,
128.7, 128.8, 128.9, 130.0, 131.3, 133.9, 134.3, 136.3, 136.4, 137.1,
138.9, 139.7, 197.4. Anal. Calcd for C33H28N2O2: C, 81.79; H, 5.82; N,
5.78. Found: C, 81.95; H, 5.91; N, 5.70.
4.2.16. 2-Hydroxy-10-methyl-8-(3-nitrophenyl)-5-[(E)-(3-nitro-
phenyl)-methylidene]-3,10-diaza-hexacyclo[10.7.1.13,7.02,11.07,11.016,20
]
henicosa-1(20),12,14,16,18-pentaen-6-one (6e). Pale yellow solid;
(0.147 g, 93%); mp 202e203 ꢀC; IR (KBr) nmax 3414,1703,1606 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH 2.09 (s, 3H, NeCH3), 2.74 (d,
J¼12.4 Hz, 1H, H-21ax), 3.30 (d, J¼17.2 Hz, 1H, H-4ax), 3.64 (dd,
J¼17.2, 2.4 Hz, 1H, H-4eq), 3.83 (t, J¼10.4 Hz, 1H, H-9), 4.07 (d,
J¼12.4 Hz, 1H, H-21eq), 4.18 (dd, J¼10.8, 6.4 Hz, 1H, H-9), 5.06 (dd,
J¼10.0, 6.4 Hz, 1H, H-8), 6.04 (br s, 1H, OH), 6.21 (s, 1H, aromatic),
6.72 (d, J¼7.6 Hz, 1H, aromatic), 7.13 (s, 1H, H-22), 7.21e7.31 (m, 2H,
aromatic), 7.37 (d, J¼6.8 Hz, 1H, aromatic), 7.49e7.70 (m, 4H, aro-
matic), 7.84 (d, J¼8.4 Hz, 1H, aromatic), 7.88 (d, J¼7.6 Hz, 1H, aro-
matic), 8.00 (d, J¼8.0 Hz, 1H, aromatic), 8.15 (d, J¼8.0 Hz, 1H,
aromatic), 8.39 (s, 1H, aromatic). 13C NMR (100 MHz, CDCl3): dC
38.8, 41.3, 53.4, 58.0, 62.5, 74.3, 94.7, 103.0, 110.0, 121.6, 122.7, 123.3,
123.4, 124.5, 126.2, 126.5, 128.1, 128.4, 129.2, 130.0, 131.3, 133.2,
134.9, 135.6, 135.9, 136.7, 137.0, 138.6, 141.7, 147.9, 148.8, 196.9. Anal.
Calcd for C33H26N4O6: C, 68.98; H, 4.56; N, 9.75. Found: C, 68.84; H,
4.33; N, 9.89.
4.2.13. 8-(2-Chlorophenyl)-5-[(E)-(2-chlorophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diaza-hexacyclo[10.7.1.13,7.02,11.07,11.016,20
]
henicosa-1(20),12,14,16,18-pentaen-6-one (6b). Pale yellow solid;
(0.150 g, 94%); mp 194e195 ꢀC; IR (KBr) nmax 3402,1699,1610 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH 1.94 (s, 3H, NeCH3), 2.82 (d,
J¼12.4 Hz, 1H, H-21ax), 3.13 (d, J¼17.6 Hz, 1H, H-4ax), 3.66 (dd,
J¼17.6, 2.4 Hz, 1H, H-4eq), 3.83e3.94 (m, 3H, H-9 and H-21eq), 5.21
(dd, J¼8.4, 3.2 Hz, 1H, H-8), 5.85 (br s, 1H, OH), 6.03 (d, J¼7.6 Hz, 1H,
aromatic), 6.79 (s, 1H, H-22), 6.90e6.94 (m, 1H, aromatic),
7.02e7.06 (m, 1H, aromatic), 7.30 (d, J¼8.0 Hz, 1H, aromatic),
7.21e7.25 (m, 1H, aromatic), 7.34e7.47 (m, 4H, aromatic), 7.54e7.60
(m, 2H, aromatic), 7.70 (d, J¼8.0 Hz, 1H, aromatic), 7.77 (d, J¼8.4 Hz,
2H, aromatic). 13C NMR (100 MHz, CDCl3): dC 37.3, 37.7, 52.4, 57.5,
65.2, 72.6, 94.1, 102.5, 121.1, 124.0, 126.3, 126.4, 127.5, 128.2, 128.4,
128.6, 129.1, 129.6, 129.7, 129.9, 130.4, 131.4, 133.0, 133.8, 134.3,
134.4, 134.7, 136.0, 137.1, 138.8, 139.2, 194.9. Anal. Calcd for
C33H26Cl2N2O2: C, 71.61; H, 4.73; N, 5.06. Found: C, 71.84; H, 4.56; N,
5.21.
4.2.17. 2-Hydroxy-10-methyl-8-(4-methylphenyl)-5-[(E)-(4-methyl-
phenyl)-methylidene]-3,10-diazahexacyclo-[10.7.1.13,7.02,11.07,11.016,20
]
henicosa-1(20),12,14,16,18-pentaen-6-one (6g). Pale yellow crystals;
(0.158 g, 94%); mp 130e131 ꢀC; IR (KBr) nmax 3415, 1683, 1604 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH 2.02 (s, 3H, NeCH3), 2.22 (s, 3H, CH3),
2.32 (s, 3H, CH3), 2.72 (d, J¼12.4 Hz, 1H, H-21ax), 3.40 (d, J¼17.2 Hz,
1H, H-4ax), 3.61e3.70 (m, 2H, H-9 and H-4eq), 4.04e4.11 (m, 2H, H-9
and H-21eq), 4.93 (dd, J¼10.4, 6.8 Hz, 1H, H-8), 6.36 (d, 2H, H-aro-
matic), 6.87 (d, J¼8.0 Hz, 2H, aromatic), 7.13 (d, J¼8.0 Hz, 2H, aro-
matic), 7.22e7.33 (m, 2H, aromatic), 7.38 (d, J¼7.6 Hz, 2H, aromatic),
7.49e7.54 (m, 2H, aromatic), 7.57 (d, J¼6.8 Hz, 1H, aromatic), 7.66
(d, J¼8.4 Hz, 1H, aromatic). 13C NMR (100 MHz, CDCl3): dC 21.5, 21.7,
38.9, 41.4, 53.5, 57.7, 62.9, 73.8, 94.7, 103.1, 121.4, 123.4, 126.0, 126.2,
127.9, 128.0, 128.6, 129.0, 129.5, 130.2, 131.3, 131,6. 132.9, 136.4,
136.5, 136.9, 137.1, 139.0, 197.3. Anal. Calcd for C35H32N2O2: C, 82.00;
H, 6.29; N, 5.46. Found: C, 82.29; H, 6.17; N, 5.67.
4.2.14. 8-(2-Bromophenyl)-5-[(E)-(2-bromophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]he-
nicosa-1(20),12,14,16,18-pentaen-6-one (6c). Pale yellow crystals;
(0.135 g, 92%); mp 186e187 ꢀC; IR (KBr) nmax 3405, 1708, 1613 cmꢂ1
;
1H NMR (300 MHz, CDCl3): dH 1.93 (s, 3H, NeCH3), 2.84 (d,
J¼12.6 Hz, 1H, H-21ax), 3.12 (d, J¼18.0 Hz, 1H, H-4ax), 3.64 (dd,
J¼18.0, 2.7 Hz, 1H, H-4eq), 3.78e3.94 (m, 3H, H-9 and H-21eq), 5.16
(dd, J¼8.4, 3.3 Hz, 1H, H-8), 5.84 (br s, 1H, OH), 5.93e5.96 (m, 1H,
aromatic), 6.80 (s, 1H, H-22), 6.93e6.98 (m, 2H, aromatic), 7.11e7.17
(m, 1H, aromatic), 7.31e7.61 (m, 7H, aromatic), 7.73 (d, J¼8.1 Hz, 1H,
aromatic), 7.78 (d, J¼8.1 Hz, 2H, aromatic). 13C NMR (100 MHz,
CDCl3): dC 37.6, 40.1, 52.0, 57.2, 65.5, 72.4, 94.1, 102.5, 121.1, 124.1,
124.2, 125.4, 126.5, 126.6, 126.9, 128.1, 128.3, 128.4, 128.9, 129.3,
129.5, 130.0, 131.4, 133.0, 133.8, 133.9, 135.0, 135.9, 136.2, 137.1,
138.9, 141.0, 194.6. Anal. Calcd for C33H26Br2N2O2: C, 61.70; H, 4.08;
N, 4.36. Found: C, 61.53; H, 4.30; N, 4.21.
4.2.18. 2-Hydroxy-8-(4-methoxyphenyl)-5-[(E)-(4-methoxy-phenyl)
methylidene]-10-methyl-3,10-diazahexacyclo-[10.7.1.13,7.02,11.07,11.016,20
]
henicosa-1(20),12,14,16,18-pentaen-6-one (6h). Yellow solid; (0.146 g,
90%); mp 158e159 ꢀC; IR (KBr) nmax 3412, 1686, 1605 cmꢂ1; 1H NMR
(400 MHz, CDCl3): dH 2.01 (s, 3H, NeCH3), 2.73 (d, J¼12.4 Hz, 1H, H-
21ax), 3.39 (d, J¼17.6 Hz,1H, H-4ax), 3.63e3.68 (m,1H, H-4eq), 3.69 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 3.79e3.82 (m, 1H, H-9), 4.03e4.12 (m,
2H, H-9 and H-21eq), 4.92 (dd, J¼10.4, 6.8 Hz, 1H, H-8), 6.33 (s, 1H, H-
22), 6.47 (d, J¼8.8 Hz, 2H, aromatic), 6.60 (d, J¼8.8 Hz, 2H, aromatic),
6.86 (d, J¼8.8 Hz, 2H, aromatic), 7.26e7.32 (m, 2H, aromatic), 7.40 (d,
J¼8.8 Hz, 2H, aromatic), 7.47e7.53 (m, 2H, aromatic), 7.58 (d, J¼6.8 Hz,
4.2.15. 8-(2-Fluorophenyl)-5-[(E)-(2-fluorophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diaza-hexacyclo[10.7.1.13,7.02,11.07,11.016,20
]

3138
R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
1H, aromatic), 7.65 (d, J¼8.0 Hz, 1H, aromatic). 13C NMR (100 MHz,
CDCl3): dC 38.9, 41.1, 53.5, 55.5, 55.6, 57.5, 62.8, 73.7, 94.6, 103.1, 113.7,
114.2, 121.3, 123.4, 125.9, 126.1, 127.1, 127.8, 128.0, 129.7, 131.2, 131.4,
131.5, 132.1, 136.2, 136.4, 137.1, 139.0, 158.8, 160.1, 197.2. Anal. Calcd for
C35H32N2O4: C, 77.18; H, 5.92; N, 5.14. Found: C, 77.56; H, 6.07; N, 5.21.
811133, 304/PKIMIA/639004 and R.S.K. thanks Universiti Sains
Malaysia for the award of a postdoctoral fellowship.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.058. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
4.2.19. 8-(4-Chlorophenyl)-5-[(E)-(4-chlorophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]he-
nicosa-1(20),12,14,16,18-pentaen-6-one (6i). Pale yellow solid;
(0.145 g, 91%); mp 205e206 ꢀC; IR (KBr) nmax 3380, 1687,1611 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH 2.06 (s, 3H, NeCH3), 2.73 (d,
J¼12.4 Hz, 1H, H-21ax), 3.37 (d, J¼17.6 Hz, 1H, H-4ax), 3.64 (dd,
J¼17.6, 2.8 Hz, 1H, H-4eq), 3.72 (t, J¼9.6 Hz, 1H, H-9), 4.04 (dd,
J¼12.4, 1.6 Hz, 1H, H-21eq), 4.10 (dd, J¼10.8, 6.8 Hz, 1H, H-9), 4.94
(dd, J¼10.0, 6.4 Hz, 1H, H-8), 6.12 (br s, 1H, OH), 6.23 (s, 1H, H-22),
6.36 (d, J¼8.4 Hz, 2H, aromatic), 7.08 (d, J¼8.4 Hz, 2H, aromatic),
7.32e7.35 (m, 4H, aromatic), 7.45 (d, J¼8.8 Hz, 2H, aromatic),
7.54e7.59 (m, 3H, aromatic), 7.72 (d, J¼8.4 Hz, 1H, aromatic). 13C
NMR (100 MHz, CDCl3): dC 38.8, 41.0, 53.5, 57.8, 62.8, 74.0, 94.6,
102.9, 121.5,123.3,126.1,126.3,128.0,128.1,128.5, 129.1,130.0,131.2,
131.3, 132.7, 133.2, 134.3, 134.8, 134.9, 136.1, 137.1, 138.0, 138.8, 197.2.
Anal. Calcd for C33H26Cl2N2O2: C, 71.61; H, 4.73; N, 5.06. Found: C,
71.38; H, 4.92; N, 5.21.
References and notes
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Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210; (b) Orru, R. V.
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1602e1634; (e) Tejedor, D.; Gonzalez-Cruz, D.; Santos-Exposito, A.; Marrero-
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(f) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Wein-
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4.2.20. 8-(4-Bromophenyl)-5-[(E)-(4-bromophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diazahexacyclo[10.7.1.13,7.02,11.07,11.016,20]he-
nicosa-1(20),12,14,16,18-pentaen-6-one (6j). Pale yellow solid;
(0.133 g, 90%); mp 197e198 ꢀC; IR (KBr) nmax 3408,1692,1602 cmꢂ1
;
1H NMR (400 MHz, CDCl3): dH 2.02 (s, 3H, NeCH3), 2.69 (d,
J¼12.8 Hz, 1H, H-21ax), 3.33 (d, J¼17.2 Hz, 1H, H-4ax), 3.59 (dd,
J¼17.2, 2.4 Hz, 1H, H-4eq), 3.70 (t, J¼10.8 Hz, 1H, H-9), 3.97e4.07 (m,
2H, H-9 and H-21eq), 4.89 (dd, J¼10.4, 6.4 Hz, 1H, H-8), 6.20 (s, 1H,
H-22), 6.26 (d, J¼8.4 Hz, 2H, aromatic), 7.20 (d, J¼8.4 Hz, 2H, aro-
matic), 7.28e7.32 (m, 2H, aromatic), 7.36 (d, J¼8.4 Hz, 2H, aro-
matic), 7.45 (d, J¼8.8 Hz, 2H, aromatic), 7.52e7.57 (m, 3H,
aromatic), 7.69 (d, J¼8.4 Hz, 1H, aromatic). 13C NMR (100 MHz,
CDCl3): dC 38.8, 41.1, 53.4, 57.8, 62.7, 73.9, 94.6, 103.0, 121.2, 121.5,
123.2, 123.3, 126.1,126.3,128.0,128.1,130.4,131.2,131.3,131.4,132.0,
133.1, 134.4, 134.9, 136.1, 137.0, 138.5, 138.9, 197.0. Anal. Calcd for
C33H26Br2N2O2: C, 61.70; H, 4.08; N, 4.36. Found: C, 61.84; H, 4.17; N,
4.43.
4. For reviews of the impact of multicomponent reactions in combinatorial
€
chemistry, see: (a) Domling, A. Comb. Chem. High Throughput Screening 1998, 1,
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4.2.21. 8-(4-Fluorophenyl)-5-[(E)-(4-fluorophenyl)-methylidene]-2-
hydroxy-10-methyl-3,10-diaza-hexacyclo[10.7.1.13,7.02,11.07,11.016,20
]
henicosa-1(20),12,14,16,18-pentaen-6-one (6k). Pale yellow solid;
(0.152 g, 92%); mp 186e187 ꢀC; IR (KBr) nmax 3446, 1694,
1600 cmꢂ1; 1H NMR (400 MHz, CDCl3): dH 2.04 (s, 3H, NeCH3), 2.72
(d, J¼12.8 Hz, 1H, H-21ax), 3.36 (d, J¼17.4 Hz, 1H, H-4ax), 3.63 (dd,
J¼17.4, 2.4 Hz, 1H, H-4eq), 3.73 (t, J¼10.4 Hz, 1H, H-9), 4.04 (dd,
J¼12.8, 2.4 Hz, 1H, H-21eq), 4.06e4.11 (m, 1H, H-9), 4.94 (dd, J¼10.4,
6.8 Hz, 1H, H-8), 6.25 (s, 1H, H-22), 6.40e6.43 (m, 2H, aromatic),
6.77e6.81 (m, 2H, aromatic), 7.02e7.06 (m, 2H, aromatic),
7.27e7.33 (m, 2H, aromatic), 7.45e7.58 (m, 5H, aromatic), 7.71 (d,
J¼8.4 Hz, 1H, aromatic). 13C NMR (100 MHz, CDCl3): dC 38.8, 40.9,
53.5, 57.8, 62.9, 74.0, 94.6, 103.0, 115.3 (2JCF¼21.5 Hz), 115.7
(2JCF¼21.0 Hz), 121.4, 123.3, 126.1, 128.0, 130.2 (3JCF¼7.8 Hz), 130.4
(4JCF¼3.1 Hz), 131.2, 131.9 (3JCF¼8.3 Hz), 133.7, 135.0, 135.2
(4JCF¼3.0 Hz), 136.3, 137.1, 138.9, 162.1 (1JCF¼244.0 Hz), 162.7
(1JCF¼248.9 Hz), 197.3. Anal. Calcd for C33H26F2N2O2: C, 76.14; H,
5.03; N, 5.38. Found: C, 76.01; H, 5.19; N, 5.29.
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Acknowledgements
The synthetic chemistry work was funded by Universiti Sains
Malaysia (USM) under University Research grant No. 1001/PKIMIA/

R. Suresh Kumar et al. / Tetrahedron 67 (2011) 3132e3139
3139
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