Domino Reaction for the Synthesis of Highly Functionalized Triazatricyclo[6.2.2.01,6]dodecane

Article abstract of DOI:10.1080/00397911.2014.987352

A simple and highly efficient protocol has been developed for the synthesis of triazatricyclo[6.2.2.0^1,6]dodecane-9,12-dione (TATCD) derivatives. Use of metal hydroxide catalyst in the presence of protic solvent plays a key role in these reaction transformations. Mechanistic studies specify that the proposed mechanism proceeds only via aldol reaction, condensation, cyclization, and dehydration to form the desired product. This current protocol provides several advantages such as use of a readily available precursor, consumption of less energy, short reaction time, moderate to good yields, and convenient workup. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.987352

This article was downloaded by: [University of Wisconsin-Milwaukee]
On: 30 January 2015, At: 06:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Domino Reaction for the
Synthesis of Highly Functionalized
1,6
Triazatricyclo[6.2.2.0 ]dodecane
a
a
Gunasekar Ramachandran & Kulathu Iyer Sathiyanarayanan
a
Chemistry Division, School of Advanced Sciences, VIT University,
Vellore, India
Accepted author version posted online: 01 Dec 2014.Published
online: 14 Jan 2015.
Click for updates
To cite this article: Gunasekar Ramachandran & Kulathu Iyer Sathiyanarayanan (2015) Domino
1,6
Reaction for the Synthesis of Highly Functionalized Triazatricyclo[6.2.2.0 ]dodecane, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
45:6, 760-767, DOI: 10.1080/00397911.2014.987352
To link to this article: http://dx.doi.org/10.1080/00397911.2014.987352
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“
Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

1
Synthetic Communications , 45: 760–767, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2014.987352
DOMINO REACTION FOR THE SYNTHESIS OF HIGHLY
1
,6
FUNCTIONALIZED TRIAZATRICYCLO[6.2.2.0
DODECANE
]
Gunasekar Ramachandran and Kulathu Iyer Sathiyanarayanan
Chemistry Division, School of Advanced Sciences, VIT University,
Vellore, India
GRAPHICAL ABSTRACT
Abstract A simple and highly efficient protocol has been developed for the synthesis
1,6
of triazatricyclo[6.2.2.0 ]dodecane-9,12-dione (TATCD) derivatives. Use of metal
hydroxide catalyst in the presence of protic solvent plays a key role in these reaction
transformations. Mechanistic studies specify that the proposed mechanism proceeds only
via aldol reaction, condensation, cyclization, and dehydration to form the desired
product. This current protocol provides several advantages such as use of a readily
available precursor, consumption of less energy, short reaction time, moderate to good
yields, and convenient workup.
1
,6
Keywords Aldol condensation; cyclization; Domino reaction; triazatricyclo[6.2.2.0
]
dodecane-9,12-dione
Received September 10, 2014.
Address correspondence to Kulathu Iyer Sathiyanarayanan, Chemistry Division, School of
Advanced Sciences, VIT University, Vellore 632 014, India. E-mail: sathiya_kuna@hotmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
7
60

DOMINO REACTION FOR TRIAZATRICYCLODODECANE
761
INTRODUCTION
It is well known that six-membered nitrogen-containing heterocycles are of
great pharmacological and biological interest. In particular, lactam motifs possess
numerous bioactive molecules implanted in several biological compounds as
[
1,2]
subunit structures.
Our long-term goal is to develop cost-effective and environ-
mentally benign synthetic routes to pharmaceutically and industrially useful
heterocyclic scaffolds. We have successfully synthesized many such scaffolds using
[
3]
domino reactions. Numerous research groups have exploited the uniqueness of
the domino reaction as a powerful tool to explore various therapeutic scaffolds,
[
4,5]
and this is the most challenging objective in synthetic chemistry.
The domino
reaction has emerged as an effective and a significant method for environmentally
[
6]
benign synthesis.
This is because of its good yields, convergence, facile
execution, and ability to generate diverse sets of compounds using commercially
[
7]
available starting materials in a single process. In the past few decades, combi-
natorial synthesis has gained significant attention and it has produced substantial
interest in the domino reaction, in which several reactions offer promise in the gen-
eration of C=C and C=X bonds in organic chemistry. They serve as useful tools in
[
8]
building fascinating and novel drug-like scaffolds. Synthesis of fused cyclic
amide rings has been the most challenging objective in synthetic organic chemistry
for the past few decades because such derivatives are considerably important scaf-
folds for synthesis and drug design as they can directly serve in pharmaceutical
[
9]
research.
RESULTS AND DISCUSSION
1
,6
We report the synthesis of highly functionalized triazatricyclo[6.2.2.0
]
dodecane-9,12-dione (TATCD) starting from N-benzylpiperidone (NBP), cyanoa-
cetamide, and aryl aldehydes using sodium hydroxide as catalyst in methanol via
a domino reaction (aldol reaction/condensation/cyclization and dehydration).
This reaction offers several advantages such as use of low-cost simple precursors,
reduced reaction time, less energy, good yield, and easy workup. Initially, we
carried out this reaction using similar conditions, as previously reported, to obtain
[
10]
TATCD fluorophore,
but unexpectedly, we got a nonfluorescent compound of
highly functionalized lactam derivatives. To investigate further, we focused on the
mechanism to study the path in which the reaction proceeded and observed that
the mechanism followed aldol reaction/condensation/cyclization followed by
dehydration to give the desired product. This reaction was more fascinating
because it provided access to TATCD possessing two quaternary amino function-
alities among four stereogenic centers (Fig. 1). Such an observation is rare, inter-
[
10,11]
esting, and quite exciting in organic chemistry.
Finally, we carried out two
reactions, one between int1 and int2 (Scheme 1), and the other between int3 and
int4 (Scheme 2).
In our initial study, we investigated the optimal condition to evaluate the
efficiency of the catalyst for this reaction under various conditions. To optimize
the reaction conditions, several metal hydroxides were screened in this reaction.
When the reaction was performed in the absence of base catalyst, the reaction
did not proceed further, but when the reaction was performed using any of the

762
G. RAMACHANDRAN AND K. I. SATHIYANARAYANAN
1
,6
Figure 1. Structure of 2-benzylidene-4-benzyl-7-phenyl-4,10,11-triazatricyclo[6.2.2.0 ]dodecane-9,12-
dione.
Scheme 1. Synthesis of tricyclic dilactam (4a) via int1 and int2.
Scheme 2. Synthesis of tricyclic dilactam (4a) via int3, int4, and int5.
metal hydroxides, the reaction proceeded to form highly functionalized TATCD.
When sodium hydroxide was used as catalyst, we noted that the reaction provided
remarkable yield. We carried out the reaction with 0.25 mol% and increased this up
to 2 mol% of catalyst to examine further the catalyst efficiency and the required
molar percentage of the catalyst to generate excellent yield. When 0.5 mol% of
NaOH was used as catalyst, a good yield was observed, whereas it did not further
improve the yield significantly when the quantities of catalyst were increased, and
thus we used 0.5 mol% of NaOH as catalyst in this reaction.

DOMINO REACTION FOR TRIAZATRICYCLODODECANE
763
The solvent was the major factor that influenced the formation of the product
and also affected the product yield. Hence, we carried out this reaction with a variety
of solvents such as polar protic, aprotic, and nonpolar solvents using 0.5 mol% of
NaOH as the catalyst (Table 1, entries 8 and 10–16) to investigate the best solvent
suitable for this reaction. We obtained good yields with polar protic solvents such
as ethanol, methanol, and isopropyl alcohol (IPA) but the product was not obtained
in the absence of solvent, with polar aprotic solvents such as acetonitrile and dichlor-
omethane (DCM), and with nonpolar solvents such as hexane and benzene. Thus,
the optimal solvent for these reaction transformations was methanol. The appropri-
ate optimal condition for these reaction transformations was 0.5 mol% of sodium
hydroxide as catalyst and methanol as solvent. We also investigated the scope and
the limitation of these reactions. To evaluate the generality of this reaction in other
systems, the reaction was carried out using a diverse range of aromatic aldehydes
under the same conditions. Thus we used both electron-donating group (EDG)
and electron-withdrawing group (EWG) of aryl aldehyde substrate for the formation
of diverse TATCD derivatives. We obtained TATCD molecule in moderate to good
a
Table 1. Screening of catalyst and solvent effect for the synthesis of TATCD
b
Entry
Catalyst (mol%)
Solvent (mL)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
None
LiOH (1)
LiOH (0.5)
KOH (1)
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
None
CH CN
3
DCM
Ethanol
IPA
Benzene
Hexane
—
21
—
39
28
71
70
70
58
51
—
—
53
48
—
—
KOH (0.5)
NaOH (2)
NaOH (1)
NaOH (0.5)
NaOH (0.25)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
NaOH (0.5)
1
1
1
1
1
1
1
a
Reaction conditions: N-benzyl-4-piperidone (10 mmol), benzaldehyde (20 mmol), and
cyanoacetamide (20 mmol) at room temperature (30 °C).
b
Isolated yield.

764
G. RAMACHANDRAN AND K. I. SATHIYANARAYANAN
a
Table 2. Domino reactions for the synthesis of synthesis of TATCD
b
Entry
ArCHO
Product
Yield (%)
1
2
3
4
5
6
7
8
9
H
4a
4b
4c
4d
4e
4f
4 g
4 h
4i
70
72
60
68
66
58
62
71
70
61
2-F
3-F
4-F
2-Me
3-Me
4-Me
2-Cl
4-Cl
1
0
1-Napthaldehyde
4j
a
Reaction conditions: N-benzyl-4-piperidone (10 mmol), benzaldehydes (20 mmol), and
cyanoacetamide (20 mmol) at room temperature (30 °C).
b
Isolated yield.
yield using either EWG or EDG of aryl aldehyde substrate. The results obtained are
summarized in Table 2. Initially, we tried this reaction with other cyclic ketone to
synthesize various TATCD moities. Unexpectedly, we obtained dimeric tetracyclic
[10]
dilactam fluorophores (DTDF). Extensive studies of those DTDF were discussed
[10]
in our previous report. Initially, we expected that the synthesized TATCD would
be a fluorophore motif, but it did not show any fluorescence properties. Hence, we
focused on the mechanism of the path in which the reaction proceeded to form
TATCD. There are two mechanisms possible for the formation of TATCD (4). One
possible mechanism is the formation of aldol product in the first step, the second step
is the formation of malonamide from the condensation of cyanoacetamide, and the final
step is the cyclization of these two intermediates to give the desired product. Another
possible mechanism is the formation of two different intermediates of Knoevenagel
condensation, which in turn rearrange C=C bond followed by [4 þ 2] cycloaddition,
subsequently undergoing intramolecular Michael-type addition followed by the attack
of aryl aldehyde via aldol condensation to give the desired product.
Thus, to investigate the exact mechanism, we carried out several reactions
under optimal conditions. Initially we carried out a few reactions to synthesize aldol
product between 1 and 2a (int1) and condensation between two molecules of 3 (int2).
Similarly, we formed two different Knoevenagel products between 1 and 3 (int3) and
2
a and 3 (int4) under the same conditions.

DOMINO REACTION FOR TRIAZATRICYCLODODECANE
765
Finally, we carried out two reactions, one between int1 and int2; the other
between int3 and int4. In the first reaction, we successfully got the expected product
(
4a), whereas in the second reaction we did not get the expected intermediate (int5),
which could further react with benzaldehyde to give the product 4a. Thus, from these
mechanistic studies, we infer that the mechanism proceeds only via aldol reaction,
condensation, followed by cyclization and dehydration to form the desired product
(
Scheme 3). However, the mechanism for the formation of tetracyclic dilactam
[10]
fluorophore discussed in the previous report
proceeded in another way. Thus,
from Scheme 3, it is very clear that the first step involves double aldol reaction
between 1 and 2 equivalents of 2a. The second step is the condensation between
two molecules of cyanoacetamide, and finally this condensed intermediate reacts
with aldol product obtained in the first step, leading to cyclization and dehydration
to yield the final product.
Scheme 3. Most feasible mechanism for the formation of product (4).

766
G. RAMACHANDRAN AND K. I. SATHIYANARAYANAN
CONCLUSION
Herein, for the first time, we report the synthesis of a new series of multifunctio-
nalized TATCD derivatives via a domino reaction using NaOH as catalyst. A wide
range of easily available chemicals, namely N-benzyl-4-piperidone, aryl aldehyde,
and cyanoacetamide, were employed as substrates. The synthesized TATCD deriva-
tives afford enormous flexibility for additional structural alterations and the synthe-
sized TATCD derivatives are indeed lactam analogs, which are directly useful in
medicinal and pharmaceutical chemistry.
EXPERIMENTAL
A dry 100-mL Erlenmeyer flask was charged with N-benzyl-4-piperidone
(10 mmol), aromatic aldehydes (20 mmol), cyanoacetamide (20 mmol), sodium
hydroxide (0.5 mol%), and methanol (15 mL). The reaction mixture was stirred at
room temperature for 30–60 min. The reaction was monitored by thin-layer chroma-
tography (TLC), and after the completion of reaction, the mixture was neutralized
using 0.1 N HCl and extracted with DCM (3 × 20 mL). The crude reaction mixture
was purified by column chromatography on silica gel using ethyl acetate/hexane as
the eluents. Light creamy powder; yield 70%; mp > 300 °C; R 0.67 (60% ethyl
f
ꢀ
1
1
acetate/hexane); FTIR (KBr) n: 3541, 3309, 3045, 2870, 1687 cm
;
H NMR
(
(
400 MHz, DMSO-d ): 1.63 (s, CH , 2H), 1.92 (s, CH, 1H), 1.99 (s, CH, 1H), 2.41
6
2
t, CH , 1H), 2.76 (q, CH , 1H), 3.94 (s, CH, 1H), 4.04 (s, CH , 2H), 6.05 (s,
2
2
2
1
3
vinylic-H, 1H), 6.98–7.49 (ArH, 15H), 9.43 (s, amide NH, 2H) ppm; C NMR
100 MHz, DMSO-d ): 26.36, 28.90, 49.68, 58.39, 70.91, 126.48, 127.68, 128.04,
(
6
1
28.95, 129.08, 129.66, 131.50, 133.35, 137.32 169.60, 169.73 ppm. HRMS: calculated
þ
for C H N O ([M] ) 449.2103; found 449.2102.
2
9
27
3
2
ACKNOWLEDGMENT
The Department of Science and Technology/Funding for Infrastructure in
Science and Technology (DST-FIST) NMR facility at VIT University is greatly
acknowledged.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1
. (a) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 1, 36; (b) Moody, C.M.; Young, D.W.
Tetrahedron Lett. 1994, 35, 7277; (c) Rigo, B.; Fasseur, D.; Cherepy, N.; Couturier, D.
Tetrahedron Lett. 1989, 30, 7057; (d) Poli, G.; Baffoni, S. C.; Giambastiani, G.;
Renginato, G. Tetrahedron 1998, 54, 10403.
2
. (a) Gouliaev, A. H.; Senning, A. Brain Res. Rev. 1994, 19, 180; (b) Cory, E. J.; Zhang, F.
Org. Lett. 2000, 2, 4257; (c) Aslanian, R.; Lee, G.; Iyer, R.V.; Shih, N.; Piwinski, J. J.;
Draper, R. W.; McPhail, A. T. Tetrahedron: Asymmetry 2000, 11, 3867; (d) Paraskar,
J.S.; Sudalai, A. Tetrahedron 2006, 62, 4907.

DOMINO REACTION FOR TRIAZATRICYCLODODECANE
767
3
. (a) Ramachandran, G.; Karthikeyan, N. S.; Sathiyanarayanan, K.; Girdharan, P. Org.
Biomol. Chem. 2012, 10, 5343–5346; (b) Karthikeyan, N. S.; Ramachandran, G.; Rathore,
R. S.; Sathiyanarayanan, K. Asian J. Org. Chem. 2012, 1, 173–179.
4
5
6
7
. (a) Zhou, H.; Liu, A.; Li, X.; Ma, X.; Feng, W.; Zhang, W.; Yan, B. J. Comb. Chem. 2008,
10, 303; (b) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647.
. Dolle, R. E.; Bourdonnec, B. L.; Goodman, A. J.; Morales, G.A.; Salvino, J.M.; Zhang, W.
J. Comb. Chem. 2007, 9, 855.
. (a) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (b) Ulaczyk-Lesanko,
A.; Hall, D. G. Curr. Opin. Chem. Biol. 2005, 9, 266.
. (a) Wender, P. A.; Handy, S. L.; Wright, D. L. Chem. Ind. London 1997, 765; (b) Domling,
A.; Ugi, I. Angew. Chem. 2000, 112, 3300; Angew. Chem. Int. Ed. 2000, 39, 3168; (c)
Sunderhaus, J. C.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223.
. (a) Lieby-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 49, 17176;
8
(
b) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 3702; (c) Zhang, M.; Jiang, H.;
Liu, H.; Zhu, Q. Org. Lett. 2007, 21, 4111; (d) Yamamoto, Y.; Ishii, J.; Nishiyama, H.;
Itoh, K. J. Am. Chem. Soc. 2004, 12, 3712; (e) Dondoni, A.; Massi, A.; Minghini, E.;
Sabbtini, S.; Bertolasi, V. J. Org. Chem. 2003, 16, 6172.
9
. (a) Paquette, L. A. J. Org. Chem. 1964, 29, 3447; (b) Davies, L. B.; Leci, O. A.; Sammes,
P. G.; Watt, R. A. J. Chem. Soc., Perkin Trans. 1 1978, 11, 1293; (c) Jiang, B.; Li, C.;
Shi, F.; Tu, S.; Kaur, P.; Wever, W. J. Org. Chem. 2010, 75, 2962.
10. Ramachandran, G.; Raman, A.; Easwaramoorthi, S.; Rathore, R. S.; Sathiyanarayanan,
K. RSC Adv. 2014, 4, 29276.
11. Jiang, B. S.; Kaur, T. P.; Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660.