'On-water' one-pot pseudo four-component domino protocol for the synthesis of novel benzo[a]cyclooctenes

Article abstract of DOI:10.1016/j.tetlet.2013.06.139

An environmentally benign 'on-water' pseudo four-component, domino protocol for the synthesis of novel benzo[a]cyclooctenes is reported. The reaction presumably occurs via a domino Knoevenagel condensation-Michael addition-Thorpe-Ziegler cyclization-tautomerization-elimination sequence of reactions.

Full text of DOI:10.1016/j.tetlet.2013.06.139

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
‘On-water’ one-pot pseudo four-component domino protocol
for the synthesis of novel benzo[a]cyclooctenes
⇑
Seeni Maharani, Raju Ranjith Kumar
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally benign ‘on-water’ pseudo four-component, domino protocol for the synthesis of
novel benzo[a]cyclooctenes is reported. The reaction presumably occurs via a domino Knoevenagel con-
densation–Michael addition–Thorpe–Ziegler cyclization–tautomerization–elimination sequence of
reactions.
Received 1 May 2013
Revised 26 June 2013
Accepted 27 June 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
On-water
Domino
Malononitrile
Benzo[a]cyclooctene
Thorpe–Ziegler cyclization
The principle of green chemistry is focused towards the devel-
opment of new methods for chemical reactions that are resource
and energy efficient, practically simple and environmentally safe.
The one-pot, multi-component domino reactions comprise one as-
pect of such methodologies wherein several bond forming trans-
OH
OH
O
1
2
, (-)-Parvifoline
, (+)-Isoparvif olinone
formations occur in
a single process under same reaction
conditions, without further addition of any reagent or catalyst.1
These reactions offer a facile access to novel heterocycles and nat-
ural products from simple precursors often with exquisite stereo-
chemical control.2
Figure 1. Structure of parvifoline.
Furthermore, benzocyclooctene forms the core of (À)-parvifo-
line 1 and (+)-isoparvifolinone 2 (Fig. 1),14 the only examples of
naturally occurring compounds that contain a benzocyclooctene
unit.
Another aspect is the usage of water as a sustainable reaction
medium instead of toxic volatile organic solvents.3 It is pertinent
to note that the ‘on-water’ organic reactions have received much
attention of the synthetic chemists in recent years.4 It has been re-
ported that considerable rate acceleration is often observed in
reactions performed under these conditions when compared to
those in organic solvents.5 In spite of their significance, the ‘on-
water’ organic syntheses have gained little attention in the field
of one-pot multi-component domino reactions.4,6
In this context, we herein report a facile ‘on-water’ one-pot,
pseudo four-component domino protocol for the expedient syn-
thesis of novel benzo[a]cyclooctene-1,3-dicarbonitriles 4. Inciden-
tally, several natural products such as spartidienedione,7 salsolene
ketone,8 asteriscanolide,9 dumortenol,10 roseadione,11 and paclit-
axel,12 etc. comprise the cyclooctanoid skeleton, which are well
known for their wide range of biological activities.13
Initially, to identify the optimum base–solvent pair, a represen-
tative reaction of cyclooctanone 3, 4-chlorobenzaldehyde and
2 equiv of malononitrile affording 2-amino-4-(4-chlorophenyl)-
5,6,7,8,9,10-hexahydrobenzo[a]cyclooctene-1,3-dicarbonitrile 4c
was investigated (Table 1). To begin with, the reaction was carried
out in refluxing ethanol in the presence of different bases. In order
to justify the significance of base in this domino process, the reac-
tion was first performed in the absence of base wherein the reac-
tion failed to occur even at prolonged reaction time (Table 1,
entry 1). In the presence of potassium carbonate or sodium ethox-
ide the reaction occurred and gave 28% and 35% isolated yield of 4c
after 5 h respectively (Table 1, entries 2 and 3). Then this test reac-
tion was carried out in the presence of lithium ethoxide (Table 1,
entry 4) which led to a significant increase in the yield of 4c
(75%) in 3 h. Further increase in the reaction time had no notice-
able change in the isolated yield. The reaction was then performed
⇑
Corresponding author. Tel.: +91 9655591445.
E-mail address: raju.ranjithkumar@gmail.com (R. Ranjith Kumar).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.139
Please cite this article in press as: Maharani, S.; Ranjith Kumar, R. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.06.139

2
S. Maharani, R. Ranjith Kumar / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
in the presence of bases such as DBU, piperidine, morpholine and
Optimization of reaction conditions
triethylamine (Table 1, entries 5–8). However, these bases could
not promote the reaction efficiently even at prolonged reaction
time and consequently low yields were observed (<32%). From
these results, lithium ethoxide emerged as the ideal choice of base
for these domino reactions. With the optimum base for the reac-
tion in hand, investigation pertaining to the choice of an appropri-
ate solvent was performed. The above reaction was carried out in
solvents such as methanol, acetonitrile, DMF and water (Table 1,
entries 9–12). From the data in Table 1, water was found to be
the ideal solvent for this domino reaction which afforded 80% yield
of 4c in lesser time (2 h) when compared to other solvents. Further,
when water is used as solvent, the product is precipitated in the
reaction vessel and hence no column chromatographic purification
is necessary. After completion of the reaction the product is filtered
and washed with water and ethanol to obtain pure 4c. The effi-
ciency of the reaction was then tested by reducing the equivalent
of lithium ethoxide to 0.50 and 0.25, which did not result in a sub-
stantial decrease in the yield (Table 1, entries 13 and 14). This reac-
tion was then performed in the presence of lithium hydroxide as it
is expected that in refluxing water lithium ethoxide would result in
lithium hydroxide and ethanol. The reaction afforded 79% yield of
4c (Table 1, entry 15) however, the product had to be isolated
through conventional work-up and column chromatography.
The optimal base–solvent pair viz. lithium ethoxide–water thus
established was then employed to the synthesis of a library of no-
vel 2-amino-4-(aryl)-5,6,7,8,9,10-hexahydrobenzo[a]cyclo-octene-
1,3-dicarbonitriles 4a–t through the one-pot pseudo four-compo-
nent reactions of cyclooctanone 3, aromatic aldehydes and 2 equiv
Entry
Condition
Yield of 4ca (%)
1
2
3
4
5
6
7
8
No base, EtOH, reflux, 5 h
0b
K2CO3 (1.0), EtOH, reflux, 5 h
NaOEt (1.0), EtOH, reflux, 5 h
LiOEt (1.0), EtOH, reflux, 3 h
DBU (1.0), EtOH, reflux, 3 h
Piperidine (1.0), EtOH, reflux, 3 h
Morpholine (1.0), EtOH, reflux, 3 h
Et3N, EtOH, reflux, 3 h
LiOEt (1.0), MeOH, reflux, 3 h
LiOEt (1.0), CH3CN, reflux, 3 h
LiOEt (1.0), DMF, reflux, 3 h
LiOEt (1.0), H2O, reflux, 2 h
LiOEt (0.5), H2O, reflux, 2 h
LiOEt (0.25), H2O, reflux, 3 h
LiOH (1.0), H2O, reflux, 2 h
28
35
75
26
30
30
32
64
0b
9
10
11
12
13
14
15
0b
80
79
65
79c
a
b
c
Yield of isolated product.
Reaction failed to occur.
Yield after column chromatographic purification.
CN
O
10
10a
4a
9
1
NH2
CN
8
7
LiOEt, 0.5 eq
2
2
ArCHO
H2O
CN
3
CN
4
Ar
ref lux, 2h
6
5
4a-t
3
Scheme 1. Synthesis of benzo[a]cyclooctenes 4a–t.
of malononitrile (Scheme 1).15
benzo[a]cyclooctene-1,3-dicarbonitriles
A
total of twenty novel
were synthesized in
Table 2
4
Yield and melting point of 4a–t
good yields (70–81%, Table 2). The structures of all benzo[a]cyclo-
octene-1,3-dicarbonitriles 4a–t are in complete agreement with
elemental analysis, 1H, 13C and 2D NMR spectroscopic data.16 The
structure of 4 elucidated from NMR spectroscopic data was further
confirmed by a single crystal X-ray crystallographic study. The OR-
TEP diagrams of 4c and 4k are shown in Figure 2.17
This transformation probably occurs via a domino mechanism
as shown in Scheme 2. Initially, the Knoevenagel condensation of
aromatic aldehyde with one mole of malononitrile affords
2-(arylmethylene)malononitrile 5 whereas the condensation of
second mole of malononitrile with cyclooctanone affords 2-cyclo-
octylidenemalononitrile 6. Intermediate 6 presumably undergoes
Michael addition with 5 furnishing 7, which upon Thorpe–Ziegler
Entry
Compd
Ar
Yield (%)
mp (°C)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-MeOC6H4
4-iPrC6H4
3-O2NC6H4
3-BrC6H4
70
72
79
73
78
77
80
74
73
71
75
76
76
70
73
79
78
81
77
73
190–192
180–183
195–196
191–193
186–189
192–194
192–193
182–185
190–191
175–177
196–198
183–185
188–190
212–213
213–215
183–185
186–188
204–207
201–203
188–191
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
2-FC6H4
2-ClC6H4
2-MeC6H4
2-MeOC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
2,5-(OMe)2C6H3
3,5-(OMe)2C6H3
3,4,5-(OMe)3C6H2
1-Naphthyl
2-Thienyl
4m
4n
4o
4p
4q
4r
4s
4t
cyclization
yields
2-imino-4-aryl-4,4a,5,6,7,8,9,10-octa-
hydrobenzo[8]annulene-1,3,3(2H)-tricarbonitrile 8. This imine 8
then undergoes tautomerization to afford amine 9 followed by
elimination to give the product 2-amino-4-(aryl)-5,6,7,8,9,10-
hexahydrobenzo[a]cyclooctene-1,3-dicarbonitriles 4.
Figure 2. ORTEP diagrams of 4c17a and 4k.17b
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S. Maharani, R. Ranjith Kumar / Tetrahedron Letters xxx (2013) xxx–xxx
3
O
NC
NC
LiOEt
NC
CN
Ar
H
Knoevenagal
Ar
-H2O
5
O
NC
NC
LiOEt
NC
CN
Knoevenagal
-H2O
6
3
NH
N
C
NC
NC
NC
CN
CN
CN
CN
CN
CN
Thorpe-Ziegler
cyclization
Michael
addition
CN
Ar
Ar
H
5
Ar
8
7
6
CN
Ar
CN
NH2
CN
NH2
CN
Tautomerization
Elimination
CN
H
Ar
4
9
Scheme 2. Plausible mechanism for the formation of 4.
4. (a) Gawande, M. B.; Bonifacio, V. D. B.; Laque, R.; Branco, P. S.; Varma, R. S.
Chem. Soc. Rev. 2013, 42, 5522–5551; (b) Butler, R. N.; Coyne, A. G. Chem. Rev.
2010, 110, 6302–6337; (c) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725–
748.
5. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275–3279.
6. (a) Prasanna, P.; Perumal, S.; Menendez, J. C. Green Chem. 2013, 15, 1292–1299;
(b) Dandia, A.; Laxkar, A. K.; Singh, R. Tetrahedron Lett. 2012, 53, 3012–3017; (c)
Beare, K. D.; McErlean, C. S. P. Tetrahedron Lett. 2013, 54, 1056–1058.
7. Norte, M.; Cataldo, F.; Sanchez, A.; Gonzalez, A.-G.; Rivera, P.; Castillo, M.
Tetrahedron Lett. 1993, 34, 5143–5146.
In conclusion, the present work reports an environmentally be-
nign ‘on-water’ one-pot, pseudo four-component domino protocol
for an efficient synthesis of twenty novel benzo[a]cyclooctene-1,3-
dicarbonitriles via Knoevenagel condensation–Michael addition–
intramolecular Thorpe–Ziegler cyclization–tautomerization–elimi-
nation sequence of reactions. The reaction results in the formation
of four new C–C bonds in a single operation. The significant advan-
tages of this methodology include usage of water as reaction med-
ium, readily available reagents and simple work-up. No column
chromatographic purification is required as the product is obtained
in a pure form just by filtration.
8. Weyerstahl, P.; Schneider, S.; Marschall, H.; Rustaiyan, A. Liebigs Ann. Chem.
1993, 111–116.
9. San Feliciano, A.; Barrero, A. F.; Medarde, M.; del Corral, J. M. M.; Aramburu, A.
Tetrahedron Lett. 1985, 26, 2369–2372.
10. Toyota, M.; Bardon, A.; Kamiya, N.; Takaoka, S.; Asakawa, Y. Chem. Pharm. Bull.
1997, 45, 2119–2121.
11. Adesomoju, A. A.; Okogun, J. I.; Cava, M. P.; Carroll, P. J. Phytochemistry 1983, 22,
2535–2536.
12. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J. Am. Chem. Soc.
1971, 93, 2325–2327.
13. Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881–930.
14. (a) Zuniga, A. C.; Cantu, F.; Maldonado, L. A. J. Org. Chem. 1998, 63, 2918–2921;
(b) Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 535–
537.
Acknowledgments
R.R.K. thanks the University Grants Commission, New Delhi for
funds through Major Research Project F. No. 42-242/2013 (SR) and
Department of Science and Technology, New Delhi for funds under
(i) DST-SERC Fast Track scheme No. SR/FT/CS-073/2009 and (ii)
IRHPA program for the high resolution NMR facility in the Depart-
ment. S.M. thanks the University Grants Commission, New Delhi
for the fellowship under UGC-BSR meritorious scheme.
15. General procedure for the synthesis of 2-amino-4-(aryl)-5,6,7,8,9,10-
hexahydrobenzo[a]cyclooctene-1,3-dicarbonitriles
4:
A
mixture
of
cyclooctanone (3, 1 mmol), aromatic aldehyde (1 mmol) and malononitrile
(2 mmol) was taken in water (10 mL) to which lithium ethoxide (0.5 equiv)
was added. The reaction was heated under reflux at 100 °C for 2 h. After
completion of the reaction, the free flowing solid that separated on water was
filtered, washed with ethanol (3 mL) and dried over vacuum to afford 4 as
white or pale yellow solid. 2-Amino-4-(4-chlorophenyl)-5,6,7,8,9,10-
hexahydrobenzo[a]cyclooctene-1,3-dicarbonitrile (4c). Obtained as white
solid; yield: 79%, mp: 195–196 °C; 1H NMR: (300 MHz, CDCl3) dH 1.25–1.45
(m, 6H, 6,7,8-CH2), 1.79–1.90 (m, 2H, 9-CH2), 2.45–2.52 (m, 2H, 5-CH2), 3.00–
3.05 (m, 2H, 10-CH2), 5.05 (s, 2H, NH2), 7.16 (d, J = 8.5 Hz, 2H, Ar–H), 7.45 (d,
J = 8.5 Hz, 2H, Ar–H); 13C NMR: (75 MHz, CDCl3) dC 25.8, 25.9, 27.7, 30.3, 31.0,
31.7, 96.9, 97.4, 115.4, 115.6, 129.0, 129.7, 130.1, 134.9, 136.2, 148.4, 149.9,
151.8. Anal. Calcd for C20H18ClN3: C, 71.53; H, 5.40; N, 12.51%. Found: C, 71.41;
H, 5.50; N, 12.42%.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.
139.
References and notes
1. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Tietze, L. F.; Lieb, M. E. Curr.
Opin. Chem. Biol. 1998, 2, 363–371; (c) Tietze, L. F.; Brasche, G.; Gericke, K.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006;
(d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131–163; (e) Tietze,
L. F. Chem. Ind. 1995, 12, 453–457; (f) de Graaff, C.; Ruijter, E.; Orru, R. V. A.
Chem. Soc. Rev. 2012, 41, 3969–4009.
16. The NMR structural elucidation for the representative example 4c is provided
in the Supplementary data.
17. (a) Swamy, V. R.; Srinivasan, N.; Ranjith Kumar, R.; Krishnakumar, R. V. Acta
Cryst. 2012, E68, 2692; (b) Crystallographic data (excluding structure factors)
for compound 4k has been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number CCDC 931925. Copy 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].
2. (a) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304–322; (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983.
3. (a)Organic Reactions in Water: Principles, Strategies and Applications; Lindstrom,
U. M., Ed.; Wiley-Blackwell: Germany, 2008; (b) Li, C.-J.; Chan, T.-H. In
Comprehensive Organic Reactions in Aqueous Media, 2nd ed.; John Wiley & Sons:
New Jersey, 2007; (c) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68–82; (d)
Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772.
Please cite this article in press as: Maharani, S.; Ranjith Kumar, R. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.06.139