A one-pot access to pyridine/benzo fused cyclododecanes via multi-component tandem reactions

Article abstract of DOI:10.1016/j.tet.2018.07.020

A facile syntheses of novel poly-substituted pyridine/benzo fused cyclododecane hybrid heterocycles have been achieved through one-pot multi-component tandem strategy employing cyclododecanone, aromatic aldehydes and malononitrile.

Full text of DOI:10.1016/j.tet.2018.07.020

Accepted Manuscript
A one-pot access to pyridine/benzo fused cyclododecanes via multi-component
tandem reactions
Sundaravel Vivek Kumar, Mani Anusha Rani, Abdulrahman I. Almansour, Raju
Suresh Kumar, S. Athimoolam, Raju Ranjith Kumar
PII:
S0040-4020(18)30841-X
10.1016/j.tet.2018.07.020
TET 29680
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 April 2018
Revised Date: 14 June 2018
Accepted Date: 9 July 2018
Please cite this article as: Vivek Kumar S, Rani MA, Almansour AI, Suresh Kumar R, Athimoolam S,
Ranjith Kumar R, A one-pot access to pyridine/benzo fused cyclododecanes via multi-component
tandem reactions, Tetrahedron (2018), doi: 10.1016/j.tet.2018.07.020.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A one-pot access to pyridine/benzo fused
cyclododecanes via multi-component tandem
reactions
Leave this area blank for abstract info.
Sundaravel Vivek Kumar, Mani Anusha Rani, Abdulrahman I. Almansour, Raju Suresh Kumar, S. Athimoolam
and Raju Ranjith Kumar

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A one-pot access to pyridine/benzo fused cyclododecanes via multi-component
tandem reactions
Sundaravel Vivek Kumar,a,b Mani Anusha Rani,a,c Abdulrahman I. Almansour,d Raju Suresh Kumar,d S.
Athimoolame and Raju Ranjith Kumar*,a
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
bDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
cDepartment of Chemistry, Lady Doak College, Madurai 625002, Madurai, Tamil Nadu, India
dDepartment of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
eDepartment of Physics, University College of Engineering, Anna University Constituent College, Nagercoil 629 004, Tamil Nadu, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile syntheses of novel poly-substituted pyridine/benzo fused cyclododecane hybrid
heterocycles have been achieved through one-pot multi-component tandem strategy employing
cyclododecanone, aromatic aldehydes and malononitrile.
Available online
2017 Elsevier Ltd. All rights reserved
.
Keywords:
Tandem reaction
Cyclododecanone
Michael addition
Thorpe-Ziegler cyclization
Cyclododeca[b]pyridine
Decahydrobenzo[12]annulene
1. Introduction
Incidentally the macrocycle fused heterocycles like
muscopyridine15 (Figure 1) and Lignoxan®16 are being used in
perfume industries. In spite of the significance, studies on the
syntheses of heterocycle/benzo fused cyclododecanones have
received less attention. For example, the Diels-Alder reaction of
Recent years have witnessed an upsurge of interest in the
syntheses of heterocycles with biological or materials
applications employing eco-friendly protocols such as multi-
component tandem reactions (MTR). MTR’s possess several
advantages like one-pot process, evade the isolation and
purification of intermediates, and shorten the reaction time, cost
effective, synthetic efficiency and selectivity.1 These advantages
make MTR’s as greener protocols.2
1,2,3-triazines/5-nitropyrimidine
and
enamines
of
cyclododecanone,17 condensation of 3-aminoacrolein and
cyclododecanone in the presence of mixture of triethylamine and
piperidinium acetate and via a three step reaction starting from
cyclododecanone.18 Similarly, only few reports are available for
synthesis of benzo fused cyclododecanes which include
benzoannelation of 2-(hydroxymethylene)-cyclododecanone19
and β-phenol annulation of cyclododecanone.20 Moreover the
above routes have one or more disadvantages like multi-step
sequence, low yield and limited diversity.
On the other hand, heterocycle/benzo fused cycloalkanes have
gained immense interest owing to their unique structural features
and existence in biologically active natural and unnatural
compounds.3 It is pertinent to note that the ring size of the fused
cycloalkanes play crucial role in the nature of biological
activities.4 The macrocycle fused heterocycles such as
rosphellin,5 ingenanes6 and eryngiolide A7 are naturally occurring
biologically active compounds. In particular, the cyclododecane
fused derivatives have been reported as fungicides,8 herbicides,9
and possess antimalarial10 and antiviral11 activities apart from
inhibiting jak kinase12 and cytochrom P45013 (Figure 1). The
cyclododecanone has been employed as key starting material for
the synthesis of the above compounds as well as muscone, (S)-
muscolides, (R)-12-methyltridecanolide and hydroxyambran.14
Ar
CN
N
X
X= N, C-CN
Present work
NH2
N
Cytochrom P450
Inhibitors
Muscopyridine
_____
Figure 1. Macrocycle fused pyridines and the present work
* Corresponding author. Tel.: 0091-9655591445;
E-mail address: raju.ranjithkumar@gmail.com

2
Tetrahedron
In this context, herein we report a facile one-pot green
example (vide ESI). In the cases of 4d, the structure was further
ACCEPTED MANUSCRIPT
protocol for the synthesis of pyridine/benzo fused
cyclododecanes via multi-component tandem reactions. This
work stems from our continuous effort to synthesize novel
heterocycle/benzo fused cycloalkanes employing multi-
component tandem/domino reactions.21 The synthesis of 2-
aminopyridine-3-carbonitrile derivatives through the four-
component reaction of cyclic/acyclic active methylene ketones,
malonitrile, aldehydes and ammonium acetate is well
documented in the literature and offers an efficient platform for
achieving these biologically relevant heterocycles.22
confirmed from single crystal X-ray studies (Figure 2).23
Table 1. Optimization of reaction conditions for synthesizing
4b
Yield (%)a
Entry
Solvent
Time
4b
5b
1
EtOH
8h
8h
5h
4h
4h
6h
3h
3h
3h
4h
29
19
2
MeOH
i-PrOH
CH3CN
THF
27
25
14
-
3
2. Results and Discussion
4
32
-
Our studies commenced with
a pilot experiment of
5
47
-
cyclododecanone 1, p-chlorobenzaldehyde 2b and malononitrile
3 in the presence of ammonium acetate (1.3 equiv.) under reflux
in ethanol for 5h which led to the formation of 2-amino-4-(4-
chlorophenyl)-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca-
[b]pyridine-3-carbonitrile 4b, 2-amino-4-(4-chlorophenyl)-5,6,7,
8,9,10,11,12,13,14-decahydrobenzo[12]annulene-1,3,3(4H)-
tricarbonitrile 5b and the intermediate 2-(4-chlorobenzylidene)-
malononitrile 6a in 29, 19 and 10 % yields, respectively (Scheme
1). The structure of 4b and 5b was confirmed from NMR
analyses.
6
Toluene
AcOH
DCE
85
-
7
26
-
8
12
-
9
1,3-dioxane
-
trace
56
-
10
-
aIsolated yield
Table 2. Synthesis of cyclododeca[b]pyridines 4
Yield
(%)a
Entry Comp Ar
R
mp (oC)
1
4a
4b
4c
4d
4e
4f
4-FC6H4
CN
CN
86
85
83
84
79
84
81
80
82
84
81
85
76
70
64
139–140
120–122
160–161
169–170
190–191
210–211
192–193
122–123
231–233
151–153
98–99
2
4-ClC6H4
4-BrC6H4
C6H5
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
3
4
5
4-MeC6H4
4-iPrC6H4
4-tBuC6H4
4-MeOC6H4
3-FC6H4
Scheme 1. Attempted synthesis of cyclododeca[b]pyridine-3-
carbonitrile 4b
6
7
4g
4h
4i
8
Gratified, by this preliminary result, we started to optimize the
ideal reaction condition for the synthesis of 4b and 5b
exclusively. The above model reaction was initially performed in
solvents such as EtOH, MeOH, i-PrOH, THF, toluene, acetic
acid, DCE, 1,3-dioxane and solvent free conditions (Table 1).
Among these solvents, undoubtedly toluene emerged as the best
choice affording exclusively the cyclododeca[b]pyridine-3-
carbonitrile 4b in 85% yield after 6h of reflux (Table 1, entry 6).
9
10
11
12
13
14
15
4j
3-BrC6H4
3-NO2C6H4
3-Cl,4,5-(MeO)2C6H2
4-ClC6H4
C6H5
4k
4l
186–187
145-146
123-124
137-138
4m
4n
4o
CO2Et
CO2Et
CO2Et
Having established the ideal reaction condition, we explored
the substrate scope of the reaction with various aromatic
aldehydes to create library. From the data in Table 2, it is obvious
that under the optimized conditions this multi-component tandem
reaction works well with all the substrates and the presence of
electron withdrawing or donating substituents in the aromatic
aldehydes posed little effect on the yield of the
cyclododeca[b]pyridine-3-carbonitriles 4a–l (79–86%, Table 2).
The structure of all these compounds 4 was elucidated with the
help of NMR spectroscopy as detailed for 4b as representative
4-MeC6H4
aYield of isolated product
Further, we extended the scope of this reaction to ethyl
cycanoacetate 3b and dimethyl malonate 3c. Under our optimized
reaction condition, 3b afforded the cyclododeca[b]pyridines 4m-
o in 64-76% yields. However, the reaction was not successful in
the case of dimethyl malonate 3c wherein only the intermediate
viz. dimethyl 2-(arylidene)malonates were obtained.

3
After establishing selective method to prepare
ACCEPTED MANUSCRIPT
cyclododeca[b]pyridine-3-carbonitriles 4, we turned towards
synthesizing benzo[12]annulene-1,3,3(4H)-tricarbonitrile 5b
exclusively (Scheme 1). Accordingly we performed a model
reaction of 1, 2b and two equiv. of 3 in solvents like EtOH,
MeOH and CH3CN and in solvent-free condition in the presence
of bases such as NH4OAc, KOAc and piperidine (Table 3).
Albeit two equiv. of 3 was used, the reaction afforded mixture of
4b and 5b in the presence of ammonium acetate in ethanol (Table
3, entry 1). When the reaction was carried out in ethanol or
methanol in the presence of piperidine 5b was obtained in
moderate yields (Table 3, entries 2 and 3). To our surprise we
isolated the aromatized product 12b in 47–83% yield when the
model reaction was performed in refluxing acetonitrile or EtOH
in the presence of piperidine or KOAc (Table 3, entries 4–6).
Similarly, the reaction under solvent-free condition with
piperidine or KOAc as base gave 12b in 72 or 65 % yields,
respectively. To our delight, 5b was obtained exclusively when
the reaction was performed at room temperature for 3h. Hence
the reaction in acetonitrile in the presence of piperidine under
reflux emerged as the good choice for synthesis of 12b, whereas
the same reaction under room temperature was found to be
optimal for synthesizing 5b.
Figure 2. ORTEP diagram of 4d
The tentative mechanism for the formation of cyclododeca[b]-
pyridine-3-carbonitriles 4 can be rationalized through a tandem
sequence as depicted in Scheme 2. Initially the base mediated
Knoevenagel condensation of
2
and
3
affords 2-
arylidenemalononitrile 6, which upon Michael addition with 1
forms the intermediate 7. The nucleophilic addition of ammonia
to the carbonyl of 7 forms 8, which undergoes tautomerization to
yield 9. The intermediate 9 undergoes intramolecular N-
cyclization involving the primary amino group and the imine
carbon to afford 10 followed by oxidative aromatization by
molecular oxygen as the sole oxidant to form the
cyclododeca[b]pyridine-3-carbonitriles 4.
Table 3. Optimization of reaction conditions for synthesizing
5b and 12b
Yield (%)a
Entry
Solvent
Base (50 mol%)
Time
4b
5b
47
12b
1
2
3
4
5
6
7
8
9b
EtOH
EtOH
MeOH
NH4OAc
Piperidine
Piperidine
4h
4h
4h
4h
4h
5h
4h
4h
3h
12
-
-
-
-
-
-
-
-
-
55
-
45
-
CH3CN Piperidine
-
83
47
64
72
65
-
EtOH
KOAc
trace
CH3CN
KOAc
-
-
-
-
Piperidine
KOAc
-
CH3CN Piperidine
70
aIsolated yield; bReaction carried out in room temperature
Scheme 2. Plausible mechanism for the formation of
cyclododeca[b]pyridine-3-carbonitriles 4
With the optimized conditions in hand, we subsequently
explored the substrate scope using various aromatic aldehydes,
cyclododecanone and malanonitrile in the presence of piperidine

4
Tetrahedron
under reflux or room temperature. The syntheses of a library of
annulene-1,3-dicarbonitriles 12 is given in Scheme 3. Initially 2
ACCEPTED MANUSCRIPT
benzo[12]annulene-1,3,3(4H)-tricarbonitrile
5
and benzo[12]
and one equiv. of 3 undergoes Knoevenagel reaction to form the
annulene-1,3-dicarbonitrile 12 have been achieved (Tables 4 and
5). The structure of the product 5 was unequivocally determined
by NMR and in the case of 5b single crystal X-ray diffraction
analysis was performed (Figure 3).23
intermediate 6. Simultaneously the Knoevenagel reaction of 1
with the second equiv. of 3 affords 13. The base promoted
Michael addition of 6 and 13 leads to the formation of 14, which
undergoes intramolecular cyclization to afford 15. The
subsequent tautomerization of 15 affords the product 5. Presence
of base and reflux temperature, prompts the benzo[12]annulene-
1,3,3(4H)-tricarbonitrile 5 to undergo further elimination to form
the aromatized product 12.
Table 4. Synthesis of benzo[12]annulene-1,3,3(4H)-
tricarbonitriles 5
Entry
Comp
5a
Ar
Yield (%)a
mp (oC)
220–221
229–230
194–195
218–219
190–191
202–203
201–202
196–197
1
2
3
4
5
6
7
8
4-FC6H4
4-ClC6H4
C6H5
67
70
73
75
70
73
68
74
5b
5c
5d
4-MeC6H4
4-iPrC6H4
4-tBuC6H4
4-MeOC6H4
3-FC6H4
5e
5f
Figure 3. ORTEP diagrams of 5b
5g
5h
O
aYield of isolated product
ArCHO
Table 5. Synthesis of benzo[12]annulene-1,3-dicarbonitriles
12
2
1
piperidine
Knoevenagel
NC
CN
NC
CN
3
3
NC
N
CN
NC
NC
CN
N
Ar
Michael
Ar
CN
6
Entry
Comp
12a
12b
12c
12d
12e
12f
Ar
Yield (%)a
mp (oC)
161–162
198–190
202–203
191–193
170–171
205–206
187–188
194–196
177–178
115–116
208–210
179–181
14
NC
13
1
4-FC6H4
85
83
86
72
79
81
84
80
83
82
85
77
NH2
NH
2
4-ClC6H4
4-BrC6H4
C6H5
CN
CN
NC
3
CN
Ar
CN
Ar
4
piperidine
H
5
4-MeC6H4
4-iPrC6H4
4-tBuC6H4
4-MeOC6H4
3-FC6H4
intramolecular
cyclization
6
5
7
12g
12h
12i
15
8
NH2
9
NC
CN
Ar
Newly formed
bonds
10
11
12
12j
3-BrC6H4
3-NO2C6H4
3-Cl,4,5-(MeO)2C6H2
Elimination
12k
piperidine
reflux
12l
aIsolated yield
12
The plausible mechanism for the formation of
benzo[12]annulene-1,3,3(4H)-tricarbonitriles 5 and benzo[12]
Scheme 3. Plausible mechanism for the formation of 5 and 12

5
3. Conclusions
4.2.1. 2-Amino-4-(4-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4a)
ACCEPTED MANUSCRIPT
In summary, we have developed multi-component tandem
protocol for the selective synthesis of structurally intriguing
multi-substituted pyridine or benzo fused cyclododecane
derivatives in good yields starting from cyclododecanone,
White solid; Yield: 86%, mp: 139–140 ºC; IR νmax: 3465,
3304, 3162, 2918, 2209, 1634, 1554, 1508, 1445, 1222 cm–1; H
1
NMR: (300 MHz, CDCl3) δH 1.24–1.29 (m, 6H) , 1.42–1.52 (m,
4H), 1.67–1.73 (m, 4H), 1.84–1.86 (m, 2H), 2.39–2.48 (m, 2H),
2.74 (t, J = 7.5 Hz, 2H), 5.04 (s, 2H), 7.13–7.28 (m, 4H); 13C
NMR: (75 MHz, CDCl3) δC 22.8, 23.2, 26.2, 26.3, 26.4, 26.9,
27.3, 27.7, 28.7, 33.0, 90.4, 115.7 (2JC,F = 21.6 Hz), 116.4, 124.8,
aromatic
aldehydes
and
malononitrile.
The
cyclododeca[b]pyridine-3-carbonitriles/carboxylates
obtained through four-component tandem Knoevenagel
condensation–Michael addition–nucleophilic addition–N-
cyclization–oxidative aromatization sequence of reactions
involving the formation of two C–N and two C–C bonds in a
single transformation. The benzo[12]annulene-1,3,3(4H)-
tricarbonitriles and benzo[12]annulene-1,3-dicarbonitriles were
were
130.0 (3JC,F = 8.1 Hz), 133.10, 133.15, 153.9, 157.0, 162.8 (1JC,F
=
246.7 Hz), 165.5; ESI-MS: m/z. Calcd: 351.21; Found: 352.22
[M+1]+; Anal. calcd for C22H26FN3: C, 75.18; H, 7.46; N, 11.96;
Found: C, 75.10; H, 7.41; N, 11.89
obtained as
a result of pseudo four-component tandem
Knoevenagel condensations–Michael addition–intramolecular
cyclization–tautomerization/elimination sequence of reactions
with the formation of four C–C bonds in a single transformation.
4.2.2.
2-Amino-4-(4-chlorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4b)
White solid; Yield: 85%, mp: 120–122 ºC; IR νmax: 3395,
3320, 3174, 2926, 2851, 2214, 1646, 1552, 1506, 1221 cm–1; H
1
4. Experimental section
NMR: (300 MHz, CDCl3) δH 1.23–1.86 (m, 16H), 2.41 (t, J = 7.0
Hz, 2H), 2.73 (t, J = 8.4 Hz, 2H), 5.06 (s, 2H), 7.19 (d, J = 8.4
Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H); 13C NMR: (75 MHz, CDCl3)
δC 22.9, 23.2, 26.2, 26.3, 26.4, 27.0, 27.3, 27.7, 28.8, 33.1, 90.2,
116.4, 124.7, 128.9, 129.6, 134.8, 135.6, 153.7, 157.0, 165.6;
ESI-MS: m/z. Calcd: 367.18; found: 368.26 [M+1]+; Anal. calcd
for C22H26ClN3 : C, 71.82; H, 7.12; N, 11.42; Found: C, 71.86; H,
7.07; N, 11.48.
4.1 General information
Melting point of the products was measured on Sigma melting
point apparatus, Sl. No. 71281, watts-250, volts-230 AC. Open
capillary tubes were used for the measurements and are
uncorrected. The 1H,13C, DEPT, H,H-COSY, C,H-COSY and
HMBC spectra were recorded on Bruker (Avance) 300/600 MHz
NMR instrument using TMS as internal standard and CDCl3
and/or DMSO-d6 as a solvents. Standard Bruker software was
used throughout the spectral analysis. Chemical shifts are given
in parts per million (δ-scale) and the coupling constants are given
in Hertz. Electro Spray Ionization Mass Spectrometry (ESI-MS)
analyses were recorded in LCQ Fleet, Thermo Fisher Instrument
in negative or positive ion mode. The collision voltage and
ionization voltage were -70 V and -4.5 kV, respectively, using
nitrogen as atomization and desolvation gas. The desolvation
temperature was set at 300 ºC. The scan range of mass spectrum
was 50–1100 m/z. The relative amount of each component was
determined from the LC-MS chromatogram, using the area
normalization method. Q-Tof ESI-MS instrument (model HAB
273) was used for recording HRMS data. Infrared spectra were
recorded on Shimadzu FT-IR-8400S instrument using neat
samples. Elemental analyses were performed on a Perkin Elmer
2400 Series II Elemental CHNS analyzer. Silica gel-G plates
(Merck) were used for TLC analysis with a mixture of petroleum
ether (60–80 ºC) and ethyl acetate as the eluent. All the
chemicals were purchased from Sigma-Aldrich, Alfa-Aesar or
Merck and used without further purification. The single crystal
X-ray data set was collected on Bruker AXS KAPPA APEX-2
diffractometer equipped with graphite monochromator. The
structure was solved by direct methods and refined by full-matrix
least squares calculations using SHELXL-2014.
4.2.3.
2-Amino-4-(4-bromophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4c)
White solid; Yield: 83%, mp: 160–161 ºC; IR νmax: 3461,
3308, 3173, 2920, 2860, 2210, 1632, 1550, 1443, 1010 cm–1; H
1
NMR: (300 MHz, CDCl3) δH 1.23–1.51 (m, 14H) , 1.71–1.86 (m,
2H), 2.41 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 5.08 (s,
2H), 7.13 (t, J = 9.0 Hz, 2H), 7.61 (t, J = 9.0 Hz, 2H); 13C NMR:
(75 MHz, CDCl3) δC 23.1, 23.5, 26.6, 26.7, 26.9, 27.4, 27.8, 28.2,
29.2, 33.4, 90.4, 116.9, 123.4, 124.9, 130.2, 132.3, 136.5, 154.2,
157.5, 166.0; HRMS (ESI) calcd for [C22H26BrN3+H]+ 412.1388,
found 412.1389; Anal. calcd for C22H26BrN3 : C, 64.08; H, 6.36;
N, 10.19; Found: C, 63.99; H, 6.30; N, 10.15.
4.2.4.
2-Amino-4-phenyl-5,6,7,8,9,10,11,12,13,14-decahydro-
cyclododeca[b]pyridine-3-carbonitrile (4d)
White solid; Yield: 84%, mp: 169–170 ºC; IR νmax: 3426, 3319,
3239, 3105, 2921, 2850, 2200, 1634, 1553, 1464 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.24–1.52 (m, 14H), 1.88 (m, 2H), 2.44 (t,
J = 7.6 Hz, 2H), 2.74 (t, J = 7.9 Hz, 2H), 5.04 (s, 2H), 7.23–7.26
(m, 2H), 7.45–7.49 (m, 3H) ; 13C NMR: (75 MHz, CDCl3) δC
22.8, 23.2, 26.3, 26.4, 26.6, 27.1, 27.5, 27.9, 28.8, 33.1, 90.5,
116.7, 124.8, 128.1, 128.6, 128.7, 137.3, 155.2, 157.0, 165.3;
Anal. calcd for C22H27N3 : C, 79.24; H, 8.16; N, 12.60; Found: C,
79.30; H, 7.8.24; N, 12.51.
4.2.5. 2-Amino-4-(p-tolyl)-5,6,7,8,9,10,11,12,13,14-decahydro-
cyclododeca[b]pyridine-3-carbonitrile (4e)
4.2 General procedure for the synthesis of 2-amino-4-phenyl-
5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[b]pyridine-
3-carbonitriles/carboxylates 4
White solid; Yield: 82%, mp: 190–191 ºC; IR νmax: 3447,
3310, 3174, 2945, 2921, 2851, 2206, 1633, 1553, 1513, 1468 cm–
1; 1H NMR: (300 MHz, CDCl3) δH 1.24–1.29 (m, 4H), 1.42–1.87
(m, 13H), 2.41–2.47 (m, 4H), 2.74 (t, J = 7.5 Hz, 2H), 5.01 (s,
2H), 7.13 (d, J = 9.0 Hz, 2H), 7.25–7.26 (m, 2H); 13C NMR: (75
MHz, CDCl3) δC 21.8, 23.1, 23.5, 26.6, 26.7, 26.9, 27.4, 27.8,
28.2, 29.2, 33.4, 91.0, 117.3, 125.3, 128.4, 129.6, 134.6, 138.8,
155.7, 157.3, 165.5; HRMS (ESI) calcd for [C23H29N3+H]+
348.2440, found 348.2450; Anal. calcd for C23H29N3 : C, 79.50;
H, 8.41; N, 12.09; Found: C, 79.53; H, 8.36; N, 12.01.
A mixture of cyclododecanone (1, 1 mmol), aromatic
aldehydes (2, 1 mmol), malononitrile/ethyl cyanoacetate (3, 1
mmol) and ammonium acetate (1.3 equiv.) in toluene (5 mL) was
refluxed for 6-7h and the reaction progress was monitored by
TLC analysis. After completion of the reaction the solvent was
removed under vacuum. The crude product was purified by
column chromatography using 4:1 (v/v) petroleum ether-ethyl
acetate mixture to obtain pure 4.

6
Tetrahedron
4.2.6. 2-Amino-4-(4-isopropylphenyl)-5,6,7,8,9,10,11,12,13,14-
131.1, 131.9, 139.2, 153.3, 157.0, 165.8; HRMS (ESI) calcd for
ACCEPTED MANUSCRIPT
decahydrocyclododeca[b]pyridine-3-carbonitrile (4f)
[C22H26BrN3+H]+ 412.1388, found 412.1395; Anal. calcd for
C22H26BrN3 : C, 64.08; H, 6.36; N, 10.19; Found: C, 63.99; H,
6.40; N, 10.13.
White solid; Yield: 84%, mp: 210–211 ºC; IR νmax: 3322, 3186,
2925, 2214, 1650, 1556, 1273 cm–1; 1H NMR: (300 MHz, CDCl3)
δH 1.26–1.88 (m, 22H) , 2.44 (t, J = 7.3 Hz, 2H), 2.74 (t, J = 8.1
Hz, 2H), 2.96 (sep, J = 6.8 Hz, 1H), 5.14 (s, 2H), 7.15 (d, J = 8.1
Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H); 13C NMR: (75 MHz, CDCl3)
δC 22.8, 23.2, 24.0, 26.4, 26.5, 26.7, 27.1, 27.5, 27.9, 28.9, 32.9,
33.4, 90.8, 116.8, 124.9, 126.6, 128.1, 134.5, 149.2, 155.6, 157.2,
165.0; HRMS (ESI) calcd for [C25H33N3+H]+ 376.2753, found
376.2759; Anal. calcd for C25H33N3 : C, 79.95; H, 8.86; N, 11.19;
Found: C, 80.05; H, 8.91; N, 11.25.
4.2.11.
2-Amino-4-(3-nitrophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4k)
White solid; Yield: 81%, mp: 98–99 ºC; IR νmax: 3475, 3298,
3085, 2918, 2847, 2208, 1639, 1557, 1473, 1429, 1270, 1050 cm–
1; 1H NMR: (300 MHz, CDCl3) δH 1.22–1.88 (m, 16H), 2.41(t, J
= 7.3 Hz, 2H), 2.72–2.79 (m, 2H), 5.18 (s, 2H), 7.61–7.64 (m,
1H), 7.70 (t, J = 7.8 Hz, 1H), 8.16–8.17 (m, 1H), 8.32–8.36 (m,
1H); 13C NMR: (75 MHz, CDCl3) δC 22.7, 23.1, 26.2, 26.4, 26.9,
27.4, 27.8, 28.8, 33.1, 89.7, 116.2, 123.4, 123.8, 124.4, 130.0,
134.5, 138.8, 148.2, 152.2, 166.3; HRMS (ESI) calcd for
[C22H26N4O2+H]+ 379.2134, found 379.2147; Anal. calcd for
C22H26N4O2 : C, 69.82; H, 6.92; N, 14.80; Found: C, 69.88; H,
6.90; N, 14.71.
4.2.7. 2-Amino-4-(4-(tert-butyl)phenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4g)
White solid; Yield: 81%, mp: 192–193 ºC; IR νmax: 3426, 3325,
3236, 3113, 2924, 2853, 2201, 1638, 1556, 1458 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.15–1.51 (m, 23H) , 1.88 (m, 2H), 2.44 (t,
J = 7.5 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 5.06 (s, 2H), 7.16 (d, J
= 9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H); 13C NMR: (75 MHz,
CDCl3) δC 23.1, 23.6, 26.6, 27.4, 27.8, 28.1, 29.3, 31.7, 33.3,
35.1, 91.0, 117.1, 125.3, 125.7, 128.2, 134.5, 151.8, 155.8, 157.4,
165.5; ESI-MS: m/z. Calcd: 389.28; Found: 390.33 [M+1]+;
Anal. calcd for C26H35N3 : C, 80.16; H, 9.06; N, 10.79; Found: C,
80.18; H, 9.14; N, 10.83.
4.2.12. 2-Amino-4-(3-chloro-4,5-dimethoxyphenyl)-5,6,7,8,9,10,
11,12,13,14-decahydrocyclododeca[b]pyridine-3-carbonitrile
(4l)
White solid; Yield: 85%, mp: 186–187 ºC; IR νm1ax: 3478, 3370,
2931, 2846, 2215, 1624, 1553, 1492, 1049 cm–1; H NMR: (300
MHz, CDCl3) δH 1.25–1.51 (m, 12H) , 1.66–1.69 (m, 2H), 1.84–
1.87 (m, 2H), 2.44 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H),
3.87 (s, 3H), 3.94 (s, 3H), 5.04 (s, 2H), 6.69 (s, 1H), 6.87 (s, 1H);
13C NMR: (75 MHz, CDCl3) δC 23.0, 23.4, 26.4, 26.7, 27.2, 27.5,
27.9, 29.2, 33.2, 56.5, 61.0, 90.3, 111.6, 116.5, 121.9, 124.9,
128.7, 133.4, 145.9, 153.5, 153.9, 157.1, 165.8; ESI-MS: m/z.
Calcd: 427.20; Found: 428.20 [M+1]+; Anal. calcd for
C24H30ClN3O2: C, 67.36; H, 7.07; N, 9.82; Found: C, 67.40; H,
7.15; N, 8.96.
4.2.8.
2-Amino-4-(4-methoxyphenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4h)
White solid; Yield: 80%, mp: 122–123 ºC; IR νmax: 3423, 3364,
3322, 3220, 2924, 2846, 2212, 1607, 1553, 1243 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.24–1.28 (m, 2H), 1.42–1.52 (m, 10H),
1.69–1.87 (m, 4H), 2.46 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz,
2H), 3.86 (s, 3H), 5.01 (s, 2H), 6.99 (d, J = 9.0 Hz, 2H), 7.18 (d,
J = 9.0 Hz, 2H); 13C NMR: (75 MHz, CDCl3) δC 22.9, 23.2, 26.3,
26.4, 26.5, 27.0, 27.4, 27.8, 28.7, 33.1, 55.2, 90.8, 114.0, 116.8,
125.1, 126.9, 129.4, 154.9, 157.0, 159.7, 165.1; ESI-MS: m/z.
Calcd: 363.23; found: 364.26 [M+1]+; Anal. calcd for
C23H29N3O: C, 76.00; H, 8.04; N, 11.56; Found: C, 75.94; H,
8.11; N, 11.51.
4.2.13. Ethyl 2-amino-4-(4-chlorophenyl)-5,6,7,8,9,10,11,12,
13,14-decahydrocyclododeca[b]pyridine-3-carboxylate (4m)
White solid; Yield: 76%, mp: 145–146 ºC; IR νm1ax: 3421, 3261,
2924, 2847, 1672, 1611, 1489, 1474, 1085 cm–1; H NMR: (600
MHz, CDCl3) δH 0.75 (t, J = 7.1 Hz, 3H), 1.19–1.25 (m, 5H),
1.40–1.45 (m, 6H), 1.50–1.55 (m, 2H), 1.70 (m, 1H), 1.85–1.89
(m, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 8.2 Hz, 2H), 3.84
(q, J = 7.1 Hz, 2H), 5.76 (s, 2H), 7.06–7.08 (m, 2H), (7.33–7.34
(m, 2H); 13C NMR: (151 MHz, CDCl3) δC 13.4, 22.7, 23.2, 26.7,
26.8, 26.9, 27.4, 27.8, 28.1, 29.0, 33.1, 60.6, 106.7, 124.6, 127.9,
129.8, 133.0, 139.1, 151.3, 156.2, 164.0, 168.4; HRMS (ESI):
m/z. Calcd for [C24H31ClN2O2+H]+: 415.2152, found 415.2185;
Anal. calcd for C24H31ClN2O2: C, 69.47; H, 7.53; N, 6.75; Found:
C, 69.55; H, 7.50; N, 6.80.
4.2.9.
2-Amino-4-(3-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4i)
White solid; Yield: 82%, mp: 231–233ºC; IR νmax: 3456, 3391,
3311, 3154, 2920, 2850, 2217, 1644, 1557, 1445 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.25–1.51 (m, 14H),1.87 (m, 2H), 2.43 (t,
J = 7.3 Hz, 2H), 2.74 (t, J = 7.9 Hz, 2H), 5.06 (s, 2H), 6.97 (d, J
= 9.0 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.15 (td, J = 8.5, 2.3 Hz,
1H), 7.45 (dd, J = 13.8, 7.9 Hz, 1H); 13C NMR: (75 MHz,
CDCl3) δC 26.6, 26.7, 26.9, 27.3, 27.8, 28.1, 29.2, 33.4, 90.4,
115.7, 116.1 (2JC,F = 20.7 Hz), 116.8, 124.5 (4JC,F = 2.9 Hz),
124.9, 130.8 (3JC,F = 8.3 Hz), 139.5 (3JC,F = 7.6 Hz), 153.9, 157.3,
162.9 (1JC,F = 246.6 Hz), 166.0; HRMS (ESI) calcd for
[C22H26FN3+H]+ 352.2189, found 352.2189; Anal. calcd for
C22H26FN3 : C, 75.18; H, 7.46; N, 11.96; Found: C, 75.25; H,
7.41; N, 11.88.
4.2.14.
Ethyl
2-amino-4-phenyl-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carboxylate (4n)
White solid; Yield: 70%, mp: 123–124 ºC; IR νmax: 3496, 3303,
2928, 2864, 1670, 1625, 1552, 1494, 1276, 1088 cm–1; 1H NMR:
(600 MHz, CDCl3) δH 0.66 (t, J = 7.1 Hz, 3H), 1.16–1.19 (m,
2H), 1.22–1.25 (m, 2H), 1.38–1.45 (m, 6H), 1.49–1.54 (m, 4H),
1.85–1.88 (m, 2H), 2.34 (t, J = 7.8 Hz, 2H), 2.71 (t, J = 8.2 Hz,
2H), 3.78 (q, J = 7.1 Hz, 2H), 5.69 (s, 2H), 7.11–7.12 (m, 2H),
7.30–7.34 (m, 3H); 13C NMR: (151 MHz, CDCl3) δC 13.3, 22.7,
23.2, 26.7, 26.8, 26.9, 27.4, 27.7, 28.1, 29.0, 33.1, 60.4, 107.3,
124.7, 127.0, 127.6, 128.3, 140.5, 152.5, 155.9, 163.5, 168.8;
HRMS (ESI): m/z. Calcd for [C24H32N2O2+H]+: 381.2537, found
381.2501 [M+1]+; Anal. calcd for C24H32N2O2: C, 75.75; H, 8.48;
N, 7.36; Found: C, 75.81; H, 8.55; N, 7.34.
4.2.10.
2-Amino-4-(3-bromophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carbonitrile (4j)
White solid; Yield: 84%, mp: 151–153 ºC; IR νm1ax: 3393, 3324,
3158, 2923, 2850, 2216, 1655, 1548, 1467 cm–1; H NMR: (300
MHz, CDCl3) δH 1.26–1.87 (m, 16H) , 2.42 (t, J = 7.5 Hz, 2H),
2.69–2.78 (m, 2H), 5.06 (s, 2H), 7.20 (d, J = 7.8 Hz, 1H), 7.36 (d,
J = 7.8 Hz, 1H), 7.40–7.41 (m, 1H), 7.59 (d, J = 8.1 Hz, 1H); 13C
NMR: (75 MHz, CDCl3) δC 22.8, 23.2, 26.3, 26.4, 26.6, 27.0,
27.5, 27.8, 28.9, 33.1, 90.1, 116.5, 122.7, 124.7, 127.0, 130.3,
4.2.15.
Ethyl
2-amino-4-(p-tolyl)-5,6,7,8,9,10,11,12,13,14-
decahydrocyclododeca[b]pyridine-3-carboxylate (4o)

7
White solid; Yield: 64%, mp: 137–138 ºC; IR νmax: 3437, 3051,
4.3.4. 2-Amino-4-(p-tolyl)-5,6,7,8,9,10,11,12,13,14-decahydro
benzo[12]annulene-1,3,3(4H)-tricarbonitrile (5d)
ACCEPTED MANUSCRIPT
2927, 2865, 1680, 1634, 1550, 1277, 1105, 1022 cm–1; 1H NMR:
(600 MHz, CDCl3) δH 0.70 (t, J = 7.1 Hz, 3H), 1.18–1.21 (m,
2H), 1.24–1.27 (m, 2H) 1.41–1.45 (m, 7H), 1.50–1.55 (m, 2H,
overlapped with water peak), 1.85–1.88 (m, 2H), 2.10 (s, 1H),
2.36 (t, J = 8.1 Hz, 2H), 2.39 (s, 3H), 2.72 (t, J = 8.2 Hz, 2H),
3.81 (q, J = 7.1 Hz, 2H), 5.90 (s, 2H), 7.00 (d, J = 7.8 Hz, 2H),
7.14 (d, J = 7.7 Hz, 2H); 13C NMR: (151 MHz, CDCl3) δC 13.3,
21.4, 22.7, 23.1, 26.8, 27.0, 27.5, 27.8, 28.1, 29.0, 32.7, 60.6,
108.0, 124.8, 128.1, 128.3, 136.7, 137.2, 153.0, 155.7, 162.8,
168.7; ESI: Calcd: 395.27; found: 395.26 [M+1]+; Anal. calcd for
C25H34N2O2: C, 75.91; H, 8.92; N, 7.08; Found: C, 75.87; H,
9.01; N, 7.13.
White solid; Yield: 75%, mp: 218–219 ºC; IR νmax: 3438,
3314, 3207, 2930, 2847, 2211, 1651, 1588, 1466 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.39–1.80 (m, 17H), 2.20–2.35 (m, 1H),
2.35 (s, 3H), 2.54–2.59 (m, 1H), 2.69–2.78 (m, 1H), 3.92 (s, 1H),
5.05 (s, 2H), 7.11 (d, J = 6.0 Hz, 2H), 7.16 (d, J = 9.0 Hz, 2H);
13C NMR: (75 MHz, CDCl3) δC 21.3, 22.1, 22.6, 24.2, 24.8, 25.1,
26.1, 26.6, 26.9, 42.5, 50.3, 83.8, 111.6, 112.9, 126.7, 127.7,
128.9, 129.5, 129.9, 139.9, 141.4; HRMS (ESI) calcd for
[C26H30N4–H]– 397.2398, found 397.2395; Anal. calcd for
C26H30N4 : C, 78.35; H, 7.59; N, 14.06; Found: C, 78.43; H, 7.52;
N, 14.10.
4.3. General procedure for the synthesis of 2-amino-4-aryl-
5,6,7,8,9,10,11,12,13,14-decahydrobenzo[12]annulene-
1,3,3(4H)-tricarbonitrile 5
4.3.5. 2-Amino-4-(4-isopropylphenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5e)
White solid; Yield: 70%, mp: 190–191 ºC; IR νmax: 3443,
3320, 3214, 2932, 2864, 2209, 1651, 1589, 1468 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.23 (d, J = 6.9 Hz, 6H), 1.32–1.61 (m,
18H), 2.22–2.28 (m, 1H), 2.55–2.59 (m, 1H), 2.72–2.59 (m, 1H),
2.72–2.91 (m, 1H), 5.02 (s, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.20 (d,
J = 8.1 Hz, 2H); 13C NMR: (75 MHz, CDCl3) δC 22.2, 22.6, 23.8,
23.9, 24.9, 25.1, 26.1, 26.7, 26.9, 27.2, 33.9, 42.5, 50.3, 84.0,
115.6, 112.9, 116.5, 126.8, 127.3, 127.9, 128.9, 129.6, 141.4,
150.7; HRMS (ESI) calcd for [C28H34N4–H]– 425.2711, found
425.2707; Anal. calcd for C28H34N4 : C, 78.83; H, 8.03; N, 13.13;
Found: C, 78.89; H, 8.07; N, 13.04.
A mixture of cyclododecanone (1, 1 mmol), aromatic
aldehydes (2, 1 mmol), malononitrile (3, 2 mmol) and piperidine
(50 mol%) was taken in acetonitrile and stirred in room
temperature for 3h with intermittent monitoring by TLC. After
completion of the reaction the solvent was removed under
vacuum. The crude product was purified by column
chromatography using 4:1 (v/v) petroleum ether-ethyl acetate
mixture to obtain pure 5.
4.3.1.
2-Amino-4-(4-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5a)
4.3.6. 2-Amino-4-(4-(tert-butyl)phenyl)-5,6,7,8,9,10,11,12,13,14-
White solid; Yield: 67%, mp: 220–221 ºC; IR νmax: 3436,
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5f)
1
3317, 3212, 2927, 2858, 2212, 1650, 1588, 1505, 1227 cm–1; H
White solid; Yield: 73%, mp: 202–203 ºC; IR νmax: 3439,
3320, 3211, 2929, 2862, 2211, 1650, 1588 cm–1; 1H NMR: (300
MHz, CDCl3) δH 1.30 (s, 9H), 1.39–1.63 (m, 17H), 2.21–2.28 (m,
1H), 2.57–2.59 (m, 1H), 2.69–2.76 (m, 1H), 3.94 (s, 1H), 5.07 (s,
2H), 7.14 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H); 13C NMR:
(75 MHz, CDCl3) δC 22.1, 22.6, 24.2, 24.9, 25.1, 26.1, 26.7, 26.9,
27.2, 31.3, 34.8, 42.5, 50.1, 83.9, 111.6, 112.9, 126.2, 126.8,
127.5, 128.9, 129.3, 141.4, 152.9; HRMS (ESI) calcd for
[C29H36N4–H]– 439.2867, found 439.2853; Anal. calcd for
C29H36N4 : C, 79.05; H, 8.24; N, 12.72; Found: C, 79.08; H, 8.18;
N, 12.79.
NMR: (300 MHz, CDCl3) δH 1.24–1.82 (m, 17H), 2.22–2.29 (m,
1H), 2.55–2.60 (m, 1H), 2.68–2.75 (m, 1H), 3.94 (s, 1H), 5.16 (s,
2H), 7.03–7.09 (m, 2H), 7.22–7.25 (m, 2H); 13C NMR: (75 MHz,
CDCl3) δC 22.1, 22.6, 24.1, 24.8, 24.5, 25.1, 26.0, 26.6, 26.9,
27.2, 42.4, 49.7, 85.6, 111.4, 112.7, 116.3 (2JC,F = 21.7 Hz),
116.4, 126.3, 126.5 (4JC,F = 3.0 Hz), 129.3, 131. 6 (3JC,F = 8.2 Hz),
141.4, 163.5 (1JC,F = 248.2 Hz); ESI-MS: m/z. Calcd: 402.22;
–
Found: 401.43 [M–1] ; Anal. calcd for C25H27FN4 : C, 74.60; H,
6.76; N, 13.92; Found: C, 74.58; H, 6.84; N, 13.88.
4.3.2.
2-Amino-4-(4-chlorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5b)
4.3.7.
2-Amino-4-(4-methoxyphenyl)-5,6,7,8,9,10,11,12,13,14-
White solid; Yield: 70%, mp: 230–231 ºC; IR νmax: 3445,
3314, 3208, 2931, 2862, 2211, 1651, 1588 cm–1; 1H NMR: (300
MHz, CDCl3) δH 1.24–1.80 (m, 17H), 2.22–2.23 (m, 1H), 2.55–
2.60 (m, 1H), 2.68–2.78 (m, 1H), 3.93 (s, 1H), 5.14 (s, 2H), 7.17
(d, J = 9.0 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H); 13C NMR: (75
MHz, CDCl3) δC 22.1, 22.6, 24.2, 24.8, 24.9, 25.1, 26.1, 26.6,
26.9, 27.3, 42.2, 49.8, 83.6, 111.3, 112.6, 126.0. 129.3, 129.52,
129.55, 131.0, 136.0, 141.4; HRMS (ESI) calcd for [C25H27ClN4–
H]– 417.1851, found 417.1862; Anal. calcd for C25H27ClN4 : C,
71.67; H, 6.50; N, 13.37; Found: C, 71.79; H, 6.54; N, 13.42.
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5g)
White solid; Yield: 68%, mp: 201–202 ºC; IR νmax: 3433,
3313, 3205, 2932, 2863, 2209, 1644, 1586 cm–1; 1H NMR: (300
MHz, CDCl3) δH 1.22–1.82 (m, 17H), 2.19–2.29 (m, 1H), 2.54–
2.58 (m, 1H), 2.68–2.78 (m, 1H), 3.80 (s, 3H), 3.92 (s, 1H), 5.07
(s, 2H), 6.87 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H); 13C
NMR: (75 MHz, CDCl3) δC 22.1, 22.6, 24.9, 25.1, 26.1, 26.7,
26.9, 42.5, 50.0, 55.4, 83.6, 111.6, 112.9, 114.5, 122.4, 126.8,
128.9, 130.9, 141.5, 160.6; HRMS (ESI) calcd for [C26H30N4O–
H]– 413.2347, found 413.2317; Anal. calcd for C26H30N4O : C,
75.33; H, 7.29; N, 13.52; Found: C, 75.28; H, 7.36; N, 13.48.
4.3.3.
2-Amino-4-phenyl-5,6,7,8,9,10,11,12,13,14-decahydro
benzo[12]annulene-1,3,3(4H)-tricarbonitrile (5c)
4.3.8.
2-Amino-4-(3-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
White solid; Yield: 73%, mp: 194–195 ºC; IR νmax: 3427,
3308, 3200, 2928, 2863, 2209, 1647, 1585, 1468 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.39–1.83 (m, 17H), 2.23–2.28 (m, 1H),
2.55–2.56 (m, 1H), 2.69–2.76 (m, 1H), 3.95 (s, 1H), 5.09 (s, 2H),
7.24–2.26 (m, 2H), 7.36–7.38 (m, 3H); 13C NMR: (75 MHz,
CDCl3) δC 22.2, 22.6, 24.3, 24.8, 25.0, 25.1, 26.1, 26.5, 26.9,
27.2, 42.3, 50.6, 84.2, 111.4, 112.8, 126.6, 129.1, 129.5, 129.8,
130.9, 141.2; ESI-MS: m/z. Calcd: 384.23; Found: 383.38 [M–
1]–; Anal. calcd for C25H28N4 : C, 78.09; H, 7.34; N, 14.57
Found: C, 78.04; H, 7.41; N, 14.53.
decahydrobenzo[12]annulene-1,3,3(4H)-tricarbonitrile (5h)
White solid; Yield: 76%, mp: 196–197 ºC; IR νmax: 3382,
1
3328, 2928, 2857, 2206, 1656, 1580, 1485 cm–1; H NMR: (300
MHz, CDCl3) δH 1.39–1.82 (m, 17H), 2.24–2.31 (m, 1H), 2.59–
2.61 (m, 1H), 2.69–2.76 (m, 1H), 3.95 (s, 1H), 5.10 (s, 2H), 6.93
(d, J = 9.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.11 (dd, J = 8.7,
2.1 Hz, 1H), 7.36 (dd, J = 13.9, 7.9 Hz, 1H); 13C NMR: (75 MHz,
CDCl3) δC 22.1, 22.6, 24.2, 24.8, 24.9, 25.1, 26.1, 26.6, 27.0,
27.3, 42.2, 50.0, 83.9, 111.3, 112.6, 116.4 (2JC,F = 22.4 Hz), 117.1

8
Tetrahedron
(2JC,F = 20.9 Hz), 125.7, 126.1, 130.9 (3JC,F = 8.1 Hz), 133.4
116.0, 128.4, 128.6, 128.8, 130.1, 149.9, 151.0, 151.3; HRMS
ACCEPTED MANUSCRIPT
(3JC,F = 7.0 Hz), 141.2, 163.0 (1JC,F = 246.6 Hz), 165.5; HRMS
(ESI) calcd for [C25H27FN4–H]– 401.2147, found 401.2121; Anal.
calcd for C25H27FN4 : C, 74.60; H, 6.76; N, 13.92; Found: C,
74.68; H, 6.71; N, 14.01.
(ESI) calcd for [C24H27N3+NH4]+ 375.2543, found 375.2543;
Anal. calcd for C24H27N3 : C, 80.63; H, 7.61; N, 11.75; Found: C,
80.69; H, 7.54; N, 11.80.
4.4.5.
2-Amino-4-(p-tolyl)-5,6,7,8,9,10,11,12,13,14-decahydro
benzo[12]annulene-1,3-dicarbonitrile (12e)
4.4. General procedure for the synthesis of 2-amino-4-phenyl-
5,6,7,8,9,10,11,12,13,14-decahydrobenzo[12]annulene-1,3-
dicarbonitrile 12
White solid; Yield: 79%, mp: 170–171 ºC; IR νmax: 3463,
3352, 3236, 2987, 2924, 2865, 2220, 1634, 1561, 1445 cm–1; 1H
NMR: (300 MHz, CDCl3) δH 0.88–1.85 (m, 16H), 2.42 (m, 5H,
methyl peak overlapped), 2.89 (t, J = 9.0 Hz, 2H), 5.01 (s, 2H),
7.11 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H); 13C NMR: (75
MHz, CDCl3) δC 21.4, 21.5, 22.5, 22.7, 27.4, 27.7, 27.8, 28.3,
28.4, 29.0, 31.2, 97.3, 97.9, 116.0, 116.1, 128.2, 129.3, 130.3,
135.6, 149.8, 151.2; HRMS (ESI) calcd for [C25H29N3+NH4]+
389.2700, found 389.2700; Anal. calcd for C25H29N3 : C, 80.82;
H, 7.87; N, 11.31; Found: C, 80.75; H, 7.92; N, 11.23.
A mixture of cyclododecanone (1, 1 mmol), aromatic
aldehydes (2, 1 mmol), malononitrile (3, 2 mmol) and piperidine
(50 mol%) was refluxed in acetonitrile for 4–5h and the reaction
progress was monitored by TLC. After completion of the reaction
the solvent was removed under vacuum. The crude product was
purified by column chromatography using 4:1 (v/v) petroleum
ether-ethyl acetate mixture to obtain pure 12.
4.4.1.
2-Amino-4-(4-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
4.4.6. 2-Amino-4-(4-isopropylphenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12f)
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12a)
White solid; Yield: 85%, mp: 161–162 ºC; IR νmax: 3470,
White solid; Yield: 81%, mp: 205–206 ºC; IR νmax: 3471,
3350, 3237, 2923, 2865, 2215, 1632, 1556, 1441 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.25–1.83 (m, 22H), 2.41–2.49 (m, 2H),
2.86–3.01 (m, 3H), 5.02 (s, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.30 (d,
J = 8.1 Hz, 2H); 13C NMR: (75 MHz, CDCl3) δC 22.7, 24.0, 27.4,
27.8, 27.9, 28.3, 29.1, 31.3, 34.0, 97.5, 98.0, 116.1, 116.2, 126.7,
128.3, 128.4, 130.5, 135.4, 149.4, 149.9, 151.2; HRMS (ESI)
calcd for [C27H33N3+NH4]+ 417.3013, found 417.3015; Anal.
calcd for C27H33N3 : C, 81.16; H, 8.32; N, 10.52; Found: C,
81.25; H, 8.28; N, 10.46.
1
3363, 3235, 2924, 2866, 2223, 1632, 1563, 1511, 1446 cm–1; H
NMR: (300 MHz, CDCl3) δH 1.25–1.85 (m, 16H), 2.39 (t, J = 7.5
Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 5.04 (s, 2H), 7.14–7.21 (m,
4H); 13C NMR: (75 MHz, CDCl3) δC 22.5, 22.7, 27.3, 27.5, 27.8,
28.11, 28.15, 28.3, 28.6, 31.2, 97.2, 98.0, 115.4, 115.7 (2JC,F
=
21.5 Hz), 115.8, 130.2 (3JC,F = 8.2 Hz), 133. 9 (4JC,F = 3.3 Hz),
149.7, 149.8, 151.4, 162.8 (1JC,F = 247.1 Hz); HRMS (ESI) calcd
for [C24H26FN3+NH4]+ 393.2449, found 393.2451; Anal. calcd for
C24H26FN3 : C, 76.77; H, 6.98; N, 11.19 ; Found: C, 76.83; H,
6.90; N, 11.10.
4.4.7. 2-Amino-4-(4-(tert-butyl)phenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12g)
4.4.2.
2-Amino-4-(4-chlorophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12b)
White solid; Yield: 84%, mp: 187–188 ºC; IR νmax: 3477,
3364, 3232, 2930, 2863, 2213, 1629, 1556, 1440 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.26–1.86 (m, 25H), 2.38–2.41 (m, 2H),
2.90 (t, J = 7.5 Hz, 2H), 5.02 (s, 2H), 7.15 (d, J = 6.0 Hz, 2H),
7.47 (d, J = 9.0 Hz, 2H); 13C NMR: (75 MHz, CDCl3) δC 22.8,
22.9, 27.4, 27.8, 28.0, 29.1, 31.3, 31.5, 34.9, 97.5, 98.0, 115.8,
116.1, 125.5, 128.1, 130.5, 135.1, 149.9, 151.2, 151.8; HRMS
(ESI) calcd for [C28H35N3+NH4]+ 431.3169, found 431.3172;
Anal. calcd for C28H35N3 : C, 81.31; H, 8.53; N, 10.16; Found: C,
81.26; H, 8.55; N, 10.26.
White solid; Yield: 83%, mp: 198–190 ºC; IR νmax: 3465,
3355, 3235, 2987, 2924, 2864, 2848, 2220, 1633, 1561, 1445 cm–
1
1; H NMR: (300 MHz, CDCl3) δH 1.26–1.84 (m, 16H), 2.39 (m,
2H), 2.90 (t, J = 7.5 Hz, 2H), 5.04 (s, 2H), 7.18 (d, J = 6.0 Hz,
2H), 7.46 (d, J = 6.0 Hz, 2H);13C NMR: (75 MHz, CDCl3) δC
22.5, 22.7, 27.4, 27.7, 27.9, 28.2, 28.3, 28.4, 29.0, 31.2, 96.9,
98.4, 115.5, 116.0, 129.1, 129.8, 130.1, 134.9, 136.4, 149.5,
149.9, 151.6; HRMS (ESI) calcd for [C24H26ClN3+NH4]+
409.2154, found 409.2160; Anal. calcd for C24H26ClN3: C, 73.55;
H, 6.69; N, 10.72; Found: C, 73.48; H, 6.74; N, 10.78.
4.4.8.
2-Amino-4-(4-methoxyphenyl)-5,6,7,8,9,10,11,12,13,14-
4.4.3.
2-Amino-4-(4-bromophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12h)
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12c)
White solid; Yield: 80%, mp: 194–196 ºC; IR νmax: 3471,
3352, 3236, 2920, 2846, 2215, 1632, 1560, 1480 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.18–1.76 (m, 16H), 2.35 (m, 2H), 2.82–
2.84 (m, 2H), 3.79 (s, 3H), 4.97 (s, 2H), 6.91 (d, J = 6.0 Hz, 2H),
7.14 (d, J = 9.0 Hz, 2H);13C NMR: (75 MHz, CDCl3) δC 22.5,
22.7, 27.4, 27.7, 27.8, 28.3, 28.9, 31.2, 55.4, 97.5, 97.8, 106.0,
114.1, 115.9, 116.2, 129.6, 130.2, 130.6, 149.9, 151.2, 159.8;
HRMS (ESI) calcd for [C25H29N3O+NH4]+ 405.2649, found
405.2653; Anal. calcd for C25H29N3O: C, 77.48; H, 7.54; N,
10.84; Found: C, 77.44; H, 7.46; N, 10.80.
White solid; Yield: 86%, mp: 202–203 ºC; IR νmax: 3475,
3359, 3233, 2923, 2863, 2213, 1629, 1557, 1440 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.26–1.85 (m, 16H), 2.38 (t, J = 7.5 Hz,
2H), 2.90 (t, J = 7.5 Hz, 2H), 5.04 (s, 2H), 7.12 (d, J = 9.0 Hz,
2H), 7.62 (d, J = 9.0 Hz, 2H); 13C NMR: (75 MHz, CDCl3) δC
22.5, 22.7, 27.4, 27.7, 27.9, 28.2, 28.3, 28.4, 29.0, 31.2, 96.9,
98.5, 115.6, 115.9, 123.2, 130.09, 130.1, 132.0, 136.9, 149.5,
149.9, 151.6; HRMS (ESI) calcd for [C24H26BrN3+NH4]+
453.1648, found 453.1648; Anal. calcd for C24H26BrN3: C, 66.06;
H, 6.01; N, 9.63; Found: C, 66.03; H, 6.09; N, 9.59.
4.4.9.
2-Amino-4-(3-fluorophenyl)-5,6,7,8,9,10,11,12,13,14-
4.4.4.
2-Amino-4-phenyl-5,6,7,8,9,10,11,12,13,14-decahydro
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12i)
benzo[12]annulene-1,3-dicarbonitrile (12d)
White solid; Yield: 83%, mp: 177–178 ºC; IR νmax: 3463,
3333, 3239, 2927, 2860, 2210, 1636, 1581, 1444 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.26–1.85 (m, 16H), 2.40 (t, J = 6.9 Hz,
2H), 2.90 (t, J = 8.5 Hz, 2H), 5.05 (s, 2H), 6.93–6.99 (m, 1H),
7.02 (d, J = 7.6 Hz, 1H), 7.16 (td, J = 8.5, 1.7 Hz, 1H), 7.42–
7.49 (m, 1H); 13C NMR: (75 MHz, CDCl3) δC 21.9, 22.1, 26.8,
White solid; Yield: 72%, mp: 191–193 ºC; IR νmax: 3460,
3344, 3239, 2928, 2862, 2223, 2209, 1635, 1562, 1445 cm–1; H
1
NMR: (300 MHz, CDCl3) δH 1.18–1.78 (m, 16H), 2.33 (t, J = 7.5
Hz, 2H), 2.83 (t, J = 9.0 Hz, 2H), 4.97 (s, 2H), 7.14–7.19 (m,
2H), 7.38–7.43 (m, 3H); 13C NMR: (75 MHz, CDCl3) δC 22.7,
22.8, 27.4, 27.7, 27.9, 28.3, 28.4, 29.0, 31.3, 97.3, 98.2, 115.7,

9
27.1, 27.3, 27.6, 27.7, 27.8, 28.5, 30.7, 96.3, 97.9, 114.9, 115.1,
References and notes
ACCEPTED MANUSCRIPT
115.3, 115.4 (2JC,F = 20.6 Hz), 123.8 (4JC,F = 3.0 Hz), 129.4,
129.9, 130.0 (3JC,F = 8.6 Hz), 139.3, 148.7, 149.3, 151.1, 162.0
(1JC,F = 246.5 Hz); HRMS (ESI) calcd for [C24H26FN3+NH4]+
393.2449, found 393.2457; Anal. calcd for C24H26FN3 : C, 76.77;
H, 6.98; N, 11.19 ; Found: C, 76.69; H, 6.93; N, 11.12.
1. (a) Ho, T-L, Tandem Organic Reactions; John Wiley & Sons,
1992; (b) Ugi, I, Dӧmling, A, Hӧrl, W, Endeavour 1994; 18:115;
(c) Zhu, J, Bienaymé, H, Multicomponent Reaction; Wiley-VCH:
Weinheim, 2005; (d) Armstrong, RM, Combs, AP, Tempest, PA,
Brown, SD, Keating, TA, Acc. Chem. Res. 1996; 29:123; (e)
Dçmling, A, Chem. Rev. 2006;106:17; (f) Ruijter, E, Scheffelaar,
R, Orru, RVA, Angew. Chem. Int. Ed. 2011;50:6234; (f) Dçmling,
A, Wang, W, Wang, K, Chem. Rev. 2012;112:3083.
4.4.10.
2-Amino-4-(3-bromophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12j)
2. (a) Anastas, PT, Warner, JC, Green Chemistry, Theory and
Practice; Oxford University Press: Oxford, UK, 2000; p. 135; (b)
Matlack, AS, Introduction to Green Chemistry; Marcel Dekker:
New York, NY, USA, 2001; p. 570.
White solid; Yield: 82%, mp: 115–116 ºC; IR νmax: 3393,
3324, 3156, 2923, 2846, 2215, 1653, 1548, 1468 cm–1; 1H NMR:
(300 MHz, CDCl3) δH 1.26–1.51 (m, 15H), 1.84–1.86 (m, 2H),
2.39–2.44 (m, 1H), 2.69–2.80 (m, 2H), 5.05 (s, 2H), 7.19 (d, J =
7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.58 (d, J =
8.1 Hz, 1H); 13C NMR: (75 MHz, CDCl3) δC 21.7, 23.1, 27.7,
27.9, 28.2, 28.5, 28.6, 28.7, 29.3, 31.6, 94.32, 94.35, 116.0,
116.1, 120.6, 127.4, 130.5, 130.7, 131.6, 132.3, 132.9, 139.8,
151.9, 152.8; HRMS (ESI) calcd for [C24H26BrN3+NH4]+
453.1648, found 453.1645; Anal. calcd for C24H26BrN3: C,
66.06; H, 6.01; N, 9.63; Found: C, 66.02; H, 6.06; N, 9.69.
3. (a) EIgemeie, GEH, Attia, AME, Hussain, BAW, Nucleos Nucleot
Nucl, 1998;17:855; (b) Egea, J, de los Rios, C, Curr. Top. Med.
Chem. 2011;11:2807; (c) Gill, RK, Kaur, R, Kumar, V, Gupta, V,
Singh, G, Bariwal, J, 2016;7:1966; (d) Taylor, EC, Berrier, JV,
Cocuzza, AJ, Kobylecki, R, McCormack, JJ, J. Med. Chem. 1977;
20:1215; (e) Poutiainen, PK, Oravilahti, T, Perakyla, M, Palvimo,
JJ, Ihalainen, JA, Laatikainen, R, Pulkkinen, JT, J. Med. Chem.
2012;55:6316; (f) Yoshizumi,T, Takahashi, H, Miyazoe, H,
Sugimoto, Y, Tsujita, T, Kato, T, Ito, H, Kawamoto, H, Hirayama,
M, Ichikawa, D, Azuma-Kanoh, T, Ozaki, S, Shibata, Y, Tani, T,
Chiba, M, Ishii, Y, Okuda, S, Tadano, K, Fukuroda, T, Okamoto,
O, Ohta, H, J. Med. Chem. 2008;51:4021.
4. (a) Naydenova, E, Pencheva, N, Popova, J, Stoyanov, N,
Lazarova, M, Aleksiev, B, II Farmaco 2002;57:189; (b) Kim, HS,
Nagai, Y, Ono, K, Begum, K, Wataya, Y, Hamada, Y, Tsuchiya,
K, Masuyama, A, Nojima, M, McCullough, KJ, J. Med. Chem.
2001;44:2357; (c) Taylor, EC, Berrier, JV, Cocuzza, AJ,
Kobylecki, R, McCormack, JJ, J. Med. Chem. 1977; 20:1215;
5. (a) Hayakawa, Y, Kawakami, K, Seto, H, Tetrahedron Lett.
1992;33:2701; (b) Boger, DL, Hong, J, J. Am. Chem. Soc.
2001;123:8515.
6. (a) Harmata, M, Elahmad, S, Barnes, CL, Tetrahedron Lett.
1995;36:1397; (b) Harmata, M, Tetrahedron 1997;53:6235.
7. Wang, S-J, Li, Y-X, Bao, L, Han, J-J, Yang, X-L, Li, H-R, Wang,
Y-Q, Li, S-J, Liu, H-W, Org. Lett. 2012;14:3672.
8. Odile C, Fungicides; InTech, 2010; p.497; (b) Zhu, W-J, Wu, P,
Liang, X-M, Dong, Y-H, Zhang, J-J, Yuan, H-Z, Qi, S-H, Meng,
X-Q, Wu, J-P, Chen, F-H, Wang, D-Q, J. Agric. Food Chem.
2008;56:6547; (c) Li, X-H, Yang, X-L, Ling, Y, Fan, Z-J, Liang,
X-M, Wang, D-Q, Chen,F-H, Li, Z-M, J. Agric. Food Chem.
2005;53:2202
4.4.11.
2-Amino-4-(3-nitrophenyl)-5,6,7,8,9,10,11,12,13,14-
decahydrobenzo[12]annulene-1,3-dicarbonitrile (12k)
White solid; Yield: 85%, mp: 208–210 ºC; IR νmax: 3497,
1
3393, 2923, 2211, 1615, 1518, 1445, 1342 cm–1; H NMR: (300
MHz, CDCl3) δH 1.24–1.86 (m, 16H), 2.35–2.38 (m, 2H), 2.91 (t,
J = 8.2 Hz, 2H), 5.10 (s, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.70 (t, J
= 7.9 Hz, 1H), 8.15 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H); 13C NMR:
(75 MHz, CDCl3) δC 22.6, 27.4, 27.6, 27.9, 28.1, 28.3, 28.4, 29.0,
31.3, 96.6, 99.1, 115.3, 115.7, 123.7, 123.9, 130.0, 134.7, 139.5,
147.8, 148.2, 150.0, 152.2; HRMS (ESI) calcd for
[C24H26N4O2+NH4]+ 420.2394, found 420.2394; Anal. calcd for
C24H26N4O2 : C, 71.62; H, 6.51; N, 13.92; Found: C, 71.56; H,
6.43; N, 14.01.
4.4.12. 2-Amino-4-(3-chloro-4,5-dimethoxyphenyl)-5,6,7,8,9,10,
11,12,13,14-decahydrobenzo[12]annulene-1,3-dicarbonitrile
(12l)
9. Zhang, Y, Li, X.-W, Li, X.-H, Wang Y.-Zi , Qi, Z.-Q, Ji, M.-
S, Gu, Z.-M, Wei, S.-H, Chin. Patent CN 102633697 A, 2012.
10. Hamada, Y, Tokuhara, H, Masuyama, A, Nojima, M, Kim, H-S,
Ono, K, Ogura, N, Wataya, Y. J. Med. Chem. 2002;45:1374.
11. Kim, S.H. U.S. Patent, US4814335 A, 1989.
12. Pericle, F, Ross, J. A. U.S. Patent, US9371265 B2, 2016.
13. Schilling, B, Woggon, W.D, Chougnet, A, Granier, T, Frater, G,
Hanhort, A. WO 2008/116339 A2, 2008.
14. (a) Scafato, P, Larocca, A, Rosini, C, Tetrahedron: Asymmetry
2006;17:2511; (b) Shi, Z, Qiang, J, Li, Z, Chin. Sci. Bull. 2001;
46:393; (c) Bollbuck, B, Kraft, P, Tochtermann, W, Tetrahedron
1996;52:4581; (d) Dowd, P, Choi, S-C, Tetrahedron
1992;48:4773; (e) Nowicki, J, Molecules 2000;5:1033; (f) Hafner,
W, Gebauer, H, Markel, E, Regiert, M. U.S. Patent 4 948 780,
1990;
White solid; Yield: 77%, mp: 179–181 ºC; IR νmax: 3431,
1
3354, 3250, 2928, 2212, 1741, 1560, 1453 cm–1; H NMR: (300
MHz, CDCl3) δH 1.30–1.85 (m, 16H), 2.42 (t, J = 6.0 Hz, 2H),
2.89 (t, J = 9.0 Hz, 2H), 3.87 (s, 3H), 3.95 (s, 3H), 5.04 (s, 2H),
6.67 (s, 1H), 6.86 (s, 1H); 13C NMR: (75 MHz, CDCl3) δC 22.3,
22.5, 27.3, 27.6, 27.8, 28.1, 28.1, 28.2, 29.1, 31.1, 56.2, 60.9,
96.8, 98.3, 111.3, 115.4, 115.8, 121.8, 128.5, 130.1, 134.0, 145.6,
149.0, 149.7, 151.5, 153.7; Anal. calcd for C26H30ClN3O2: C,
69.09; H, 6.69; N, 9.30; Found: C, 69.12; H, 6.65; N, 9.36.
Acknowledgments
R.R.K. thanks the Department of Science and Technology,
New Delhi, for funds under IRHPA program for the high
resolution NMR facility and PURSE programme. M.A.R. thanks
the University Grants Commission, New Delhi, for funds through
UGC-BSR meritorious fellowship. The authors acknowledge the
Deanship of Scientific Research at King Saud University for the
Research Grant No. RG-1438-052.
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Supplementary Material
Supplementary data associated with this article can be found in
the online version, at http://

10
Tetrahedron
Adv. 2015;5:105446; (d) Maleki, A, Jafari, AA, Yousefia, S,
Crystallographic Data Center as supplementary publication
ACCEPTED MANUSCRIPT
Eskandarpoura, V, Comptes Rendus Chimie 2015;18:1307; (e)
numbers CCDC 1840402 and 1840401, respectively. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 762911
or e-mail: deposit@ccdc.cam.ac.uk].
Wang, J, Li, Z, Wang, X, Zhou, Y, Guo, C, Heterocycles
2015;91:49.
23. Crystallographic data (excluding structure factors) for compounds
4d and 5b have been deposited with the Cambridge

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Highlights
One-pot multi-component approach to pyridine/benzo fused cyclododecanes
Tandem Knoevenagel–Michael–intramolecular cyclization–air oxidation/elimination steps
Formation of two C–N and two C–C/four C–C bonds in a single transformation
Structure elucidated unambiguously by NMR and single crystal X-ray