An expeditious protocol for sesquiterpene-cored functionalized arenes from S-(-)-citronellal

Article abstract of DOI:10.1016/j.tetlet.2009.02.117

An expeditious straightforward synthesis of sesquiterpene-cored arenes functionalized with electron-withdrawing or electron-donating substituents is described and illustrated by Michael addition of S-(-)-citronellal on functionalized 2H-pyran-2-one in a s

Full text of DOI:10.1016/j.tetlet.2009.02.117

Tetrahedron Letters 50 (2009) 2086–2089
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An expeditious protocol for sesquiterpene-cored functionalized arenes
from S-(ꢀ)-citronellal q
*
Atul Goel , Deepti Verma
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious straightforward synthesis of sesquiterpene-cored arenes functionalized with electron-
withdrawing or electron-donating substituents is described and illustrated by Michael addition of S-
(ꢀ)-citronellal on functionalized 2H-pyran-2-one in a single step at room temperature. The reaction
was further generalized by synthesizing isoprenylated 9,10-dihydrophenanthrene-2-carbonitrile using
5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitriles and S-(ꢀ)-citronellal under simi-
lar reaction conditions.
Received 1 January 2009
Revised 12 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Keywords:
Bisabolene
Ó 2009 Elsevier Ltd. All rights reserved.
Sesquiterpene
2H-Pyran-2-ones
Citronellal
Ring transformation approach
The monocyclic aromatic sesquiterpenes of the bisabolene fam-
ily are an important class of natural products exhibiting a wide
range of biological activities.1 These scaffolds often possess a ben-
zylic chiral centre carrying a methyl group at this position.
Amongst several bisabolene sesquiterpenoids, the simplest S-(+)-
curcumene has been isolated from rhizomes of Curcuma aromatica
Salisb, and it is the active constituent of a large number of essential
oils.2 The phenolic sesquiterpene (+)-curcuphenol isolated from a
marine sponge (Epipolasis and Didiscus flavus) showed gastric
H,K-ATPase inhibitory and antitumor and antifungal activities.3,4
Interestingly, its enantiomer, which has been isolated from the
gorgonian coral Pseudopterogorgia rigida, exhibits antibacterial
activity against Staphylococcus aureus.4,5 Recently, natural dimers
of curcuphenols displayed lipoxygenase inhibitory activities.6 An
isomeric xanthorrhizol exhibits antitumor activity, and it is used
as traditional medicine in Indonesia.7,8
During our ongoing drug development programme, we became
interested in uncovering the biological properties of functionally di-
verse curcumene-cored novel aromatic compounds. Although
numerous interesting biological properties of these sesquiterpenoids
have prompted considerable synthetic efforts to the targeted natural
products, there is a surprising lack of flexible and donor–acceptor
functional group tolerable general methods for sesquiterpene-cored
aromatic compounds. Herein, we report an efficient and convenient
route for the synthesis of sesquiterpene-cored functionalized arenes
through a ring transformation reaction of 2H-pyran-2-ones or 5,6-
dihydro-2-oxo-2H-benzo[h]chromene-3-carbonitriles using S-(ꢀ)-
citronellal as a source of carbanion. The advantage of the procedure
lies in the construction of a benzene ring with flexibility of substitu-
ent variations in a single step at room temperature.
Due to diverse biological activities9 associated with this scaffold,
numerous approaches have been adapted;10 however, enantioselec-
tive methods remain sparse in the literature.11 The synthetic meth-
ods include Grignard reaction of p-tolylmagnesium bromide with 6-
methyl-3,5-heptadien-2-one;11a enzymatic resolution of racemic
intermediates;11b the Mitsunobu reaction of synthetic equivalent
of chiral 2-cyclopentenol followed by a concurrent retro-Diels–Al-
der reaction and Claisen rearrangement;11c baker’s yeast reduction
approach;11d,e sparteine-mediated lateral metallation-substitution
reaction,11f from enantiomerically pure benzothiazine precursor
via a stereoselective, intramolecular Michael addition reaction;11g
highly stereoselective addition of aryllithium reagent to chiral a,b-
unsaturated oxazolines;11h asymmetric hydrogen-esterification
reaction11i and 1,4-conjugate addition of chiral citronellal to vinyl
ketones followed by an intramolecular aldol condensation.11j
The newer approaches for the synthesis of bisabolene skeleton
involve asymmetric hydrovinylation followed by Suzuki–Miyaura
reaction,12 the asymmetric conjugate addition using a enantiome-
rically pure sulfoxide as the chiral auxiliary,13 chemoenzymatic
route via lipase-catalyzed kinetic resolution process,14 solvolysis
of (4,5-anti)-4-aryl-5-tosyloxy-(2E)-hexenoate in water-saturated
MeNO2 based on 1,2-aryl migration via phenonium ion.15
q
CDRI Communication No. 7364.
*
Corresponding author at present address: Institut für Organische Chemie,
Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. Tel.: +49 931
8885393; fax: +49 931 8884755.
E-mail addresses: agoel13@yahoo.com, goela@chemie.uni-wuerzburg.de (A.
Goel).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.117

A. Goel, D. Verma / Tetrahedron Letters 50 (2009) 2086–2089
2087
The chemistry of 2H-pyran-2-one derivatives is very interest-
Ar
Ar
ing, which finds diverse synthetic applications as a diene compo-
nent in Diels–Alder reactions.16 During our recent studies on 2H-
pyran-2-ones, we developed new methodologies for the synthesis
of arenes,17 pyridines,18 pyridones19 and polyarylbenzenes20
through nucleophile-induced ring transformation reactions. The
unique feature of 2H-pyran-2-ones 1 is the presence of three elec-
trophilic centres: C2, C4 and C6, in which the latter is highly sus-
ceptible to nucleophilic attack due to the extended conjugation
and the presence of the electron-withdrawing substituent at posi-
tion 3 of the pyranone ring. The precursors 2H-pyran-2-ones 1
were conveniently prepared in high yields by the reaction of
methyl 2-cyano-3,3-dimethylsulfanylacrylate with substituted
acetophenones under alkaline conditions, followed by reaction
with secondary amines.17
The synthesis of terpenylarenes 3a–f was achieved by stirring a
mixture of corresponding 2H-pyran-2-ones 1, S-citronellal 2 and
powdered KOH in DMF for 4–6 h at room temperature (Scheme
1). After usual work-up,21 the crude product obtained was purified
on silica gel column using 0.1% EtOAc in hexane as eluent.
A plausible mechanism for the formation of 3 involves Michael
addition of conjugate base of S-(ꢀ)-citronellal at position C6 of lac-
tone 1, followed by intramolecular cyclization involving the car-
bonyl functionality of 2 and C3 of the pyranone ring, and then
elimination of carbon dioxide, followed by dehydration.
OHC
O
KOH
DMF
rt
+
H3CS
H3CO2C
O
H3CS
COOCH3
4
2
5
5
a
b
c
d
e
f
Ar
Yield (%)
C6H5
57
61
59
57
62
50
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
3,4-(CH2O2)C6H3
Scheme 2. Synthesis of terpenylarenes 5a–f.
sibly follow the pathway that is same as that described in Scheme
1.
To further expand the scope of this reaction, interest is cur-
rently focused on synthesizing (S)-4-(6-methylhept-5-en-2-yl)-1-
sec-amino-9,10-dihydrophenanthrene-2-carbonitrile
7
through
To demonstrate the utility of such an approach with functional
group diversity, we undertook the synthesis of terpenylarenes 5a–f
with common electron-withdrawing and electron-donating
groups. The successful reaction was carried out by stirring a mix-
ture of 6-aryl-3-methoxycarbonyl-4-methylsulfanyl-2H-pyran-2-
ones17 4, S-(ꢀ)-citronellal and powdered KOH in DMF at ambient
temperature (Scheme 2). Usual work-up and purification yield
(S)-methyl 2-(6-methylhept-5-en-2-yl)-5-(methylsulfanyl)-biaryl-
4-carboxylates 5a–f in a single step from easily accessible precur-
sors. The transformations of 6-aryl-2H-pyran-2-ones 4 into 5 pos-
ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo
[h]chromene-3-carbonitriles using S-(ꢀ)-citronellal as a source of
carbanion. The easily accessible precursors 5,6-dihydro-2-oxo-4-
sec-amino-2H-benzo[h]chromene-3-carbonitriles
6 used in the
synthesis were prepared in two steps. The first step was the
synthesis of 5,6-dihydro-4-methylsulfanyl-2-oxo-2H-benzo[h]
chromene-3-carbonitriles via the base-catalyzed reaction of
methyl 2-cyano-3,3-dimethylthioacrylate and 1-tetralone in
DMSO. The reaction mixture was poured onto crushed ice with vig-
orous stirring to yield desired product, which on amination with a
O
O
Ar
Ar
6
OHC
O1
KOH/DMF
5
NC
2
+
N
H
O
R
4
O
N
3
CN
R
2
1
O
O
Ar
H
Ar
Ar
-CO2
H2O
NC
N
N
N
OH
O
CN
R
CN
R
R
3
3
a
b
c
d
e
f
Ar
R
H
Yield (%)
C6H5
58
69
64
66
62
50
4-BrC6H4
CH3
H
4-CH3C6H4
2-thienyl
CH3
H
4-CH3OC6H4
1-naphthyl
CH3
Scheme 1. Probable mechanism involved in the synthesis of 3a–f.

2088
A. Goel, D. Verma / Tetrahedron Letters 50 (2009) 2086–2089
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rt
10b
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a
b
c
d
e
f
piperidin-1-yl
H
H
H
H
H
60
61
62
51
63
65
54
55
4-methylpiperidin-1-yl
4-benzylpiperidin-1-yl
4-benzylpiperazin-1-yl
morpholin-4-yl
tetrahydroisoquinolin-2-yl
piperidin-1-yl
H
g
h
OCH3
OCH3
4-methylpiperidin-1-yl
Scheme 3. Synthesis of terpenylarenes 7a–h.
13. Lu, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2005, 16, 1435–
1438.
secondary amine in boiling ethanol afforded 5,6-dihydro-2-oxo-4-
sec-amino-2H-benzo[h]chromene-3-carbonitriles22 6 (Scheme 3).
The topographical feature of the 5,6-dihydro-2-oxo-4-sec-ami-
no-2H-benzo[h]chromene-3-carbonitriles 6 is similar to that of
2H-pyran-2-ones 1, which has three electrophilic centres C2, C4
and C10b in which the latter is highly electrophilic and is prone
to nucleophilic attack due to extended conjugation and the pres-
ence of an electron-withdrawing substituent at position 3 of the
lactone ring. The conjugate base in this reaction is generated
in situ from S-citronellal under alkaline conditions. Thus, a mixture
of benzo[h]chromene 6, S-(ꢀ)-citronellal 2 and powdered KOH in
DMF was stirred for 2–3 h. The progress of the reaction was mon-
itored by TLC, and on completion, the reaction mixture was poured
onto crushed ice with vigorous stirring and was then neutralized
with 10% HCl. The precipitate obtained was filtered, washed with
water and dried. The crude product 7 was purified by neutral alu-
mina column chromatography using 0.2% EtOAc in hexane as the
eluent.23
14. Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S. Tetrahedron: Asymmetry 2007, 18,
2547–2553.
15. Ehara, T.; Tanikawa, S.; Ono, M.; Akita, H. Chem. Pharm. Bull. 2007, 55, 1361–
1364.
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H.; Afarinkia, K.; Dai, H. Org. Synth. 1995, 73, 231–239; (c) Afarinkia, K.;
Bearpark, M. J.; Ndibwami, A. J. Org. Chem. 2005, 70, 1122–1133. and references
cited therein.
17. (a) Goel, A.; Verma, D.; Dixit, M.; Raghunandan, R.; Maulik, P. R. J. Org. Chem.
2006, 71, 804–807; (b) Singh, F. V.; Kumar, V.; Kumar, B.; Goel, A. Tetrahedron
2007, 63, 10971–10978; (c) Singh, F. V.; Kumar, V.; Goel, A. Synlett 2007, 2086–
2090; (d) Kumar, A.; Singh, F. V.; Goel, A. Tetrahedron Lett. 2007, 48, 7283–
7286; (e) Dixit, M.; Raghunandan, R.; Kumar, B.; Maulik, P. R.; Goel, A.
Tetrahedron 2007, 63, 1610–1616; (f) Kumar, A.; Singh, F. V.; Goel, A.
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18. (a) Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J. J. Org. Chem. 2003, 68, 2983–
2985; (b) Goel, A.; Singh, F. V.; Sharon, A.; Maulik, P. R. Synlett 2005, 623–626.
19. Goel, A.; Singh, F. V.; Verma, D. Synlett 2005, 2027–2030.
20. (a) Goel, A.; Singh, F. V.; Dixit, M.; Verma, D.; Raghunandan, R.; Maulik, P. R.
Asian Chem. J. 2007, 2, 239–247; (b) Goel, A.; Singh, F. V.; Kumar, V.; Reichert,
M.; Gulder, T. A. M.; Bringmann, G. J. Org. Chem. 2007, 72, 7765–7768; (c) Goel,
A.; Dixit, M.; Chaurasia, S.; Kumar, A.; Raghunandan, R.; Maulik, P. R.; Anand, R.
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Tetrahedron Lett. 2009, 50, 680–683.
In summary, we have demonstrated highly convenient and
functional group tolerable one-step ring transformation approach
for the synthesis of several sesquiterpene-cored aromatic com-
pounds of synthetic and biological importance. This stereoselective
protocol offers easy access to various terpenylarenes with the flex-
ibility of introducing the electron-donor or electron-acceptor sub-
stituents that are essentially required in drug development
perspectives.
21. General procedure for the synthesis of 3a–f and 5a–f: A mixture of 6-aryl-2H-
pyran-2-ones (1a–f and 4a–f) (1 mmol), (S)-(ꢀ)-citronellal (1.2 mmol) and
powdered KOH (1.5 mmol) in DMF was stirred at room temperature for 4–6 h.
After completion of the reaction, excess DMF was removed under reduced
pressure and was poured onto crushed ice with vigorous stirring. The solution
was neutralized with 10% HCl, and the resulting precipitate was filtered,
washed with water, dried and purified through silica column chromatography
using 0.1% ethyl acetate in hexane as the eluent. (3a): Viscous oil; ½a D25
ꢁ
+40.0 (c
0.1, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.11 (d, J = 6.84 Hz, 3H, CH3), 1.43–
1.60 (m, 10H, 2CH2 and 2CH3), 1.69–1.80 (m, 6H, 3CH2), 2.71–2.83 (m, 1H, CH),
3.14 (t, J = 5.34 Hz, 4H, 2CH2), 4.83–4.88 (m, 1H, CH), 6.78 (s, 1H, ArH), 7.19–
7.23 (m, 2H, ArH), 7.35–7.44 (m, 3H, ArH), 7.48 (s, 1H, ArH); 13C NMR (CDCl3,
75 MHz): d 16.28, 21.08, 22.81, 24.31, 24.61, 24.88, 32.13, 37.01, 51.94, 103.98,
117.68, 118.82, 122.77, 126.13, 126.86, 127.55, 130.30, 130.63, 137.34, 139.58,
145.97, 152.60; IR (Neat) 2220 cmꢀ1 (CN); MS (ESI) m/z 373 (M++1); HRMS (EI)
Acknowledgements
A.G. is thankful to Professor G. Bringmann for his kind support,
Alexander von Humboldt Foundation for AvH fellowship and to
DST, New Delhi, for Ramanna Fellowship. D.V. is grateful to CSIR,
New Delhi, for senior research fellowship. Sophisticated Analytical
Instrument Facility, CDRI, Lucknow, from which spectroscopic data
were obtained, is gratefully acknowledged.
m/z calcd for C26H32N2 372.2566 found: 372.2595. (5b): Viscous oil; ½a D25
ꢁ
+20.0
(c 0.1, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.15 (d, J = 6.87 Hz, 3H, CH3), 1.46
(s, 3H, CH3), 1.48–1.63 (m, 5H, CH2 and CH3), 1.68–1.79 (m, 2H, CH2), 2.40 (s,
3H, SCH3), 2.71–2.80 (m, 1H, CH), 3.94 (s, 3H, OCH3), 4.85–4.90 (m, 1H, CH),
6.99 (s, 1H, ArH), 7.17–7.21 (m, 2H, ArH), 7.38–7.42 (m, 2H, ArH) 7.95 (s, 1H,
ArH); 13C NMR (CDCl3, 75 MHz): d 14.33, 16.29, 21.09, 24.31, 24.65, 32.37,
36.92, 50.77, 122.75, 124.40, 125.25, 127.09, 127.93, 129.08, 130.40, 132.26,
138.00, 138.27, 139.64, 143.62, 165.54; IR (Neat) 1716 cmꢀ1 (CO); MS (ESI) m/z
403 (M++1); HRMS (ESI) calcd for C23H28ClO2S: 403.14985, found: 403.15051.
22. Gompper, R.; Topfl, W. Chem. Ber. 1962, 95, 2861.
References and notes
23. General procedure for the synthesis of 7a–h: A mixture of 5,6-dihydro-2-oxo-4-
1. (a) Heathcock, C. H.. In The Total Synthesis of Natural Products; ApSimon, J. W.,
sec.amino-2H-benzo[h]chromene-3-carbonitriles
6
(1 mmol) and S-(ꢀ)-
Ed.; Wiley: New York, 1973; Vol. 2, p 197; (b) Heathcock, C. H.; Graham, S. L.;

A. Goel, D. Verma / Tetrahedron Letters 50 (2009) 2086–2089
2089
citronellal 2 (1.2 mmol) in dry DMF using KOH as base (1.5 mmol) was stirred
for 2–3 h. After completion, excess of DMF was removed under reduced
pressure and the reaction mixture was poured onto crushed ice with vigorous
stirring followed by neutralization with 10% HCl. The crude thus obtained was
purified by neutral alumina column chromatography using 0.2% EtOAc in
hexane as the eluent. (7a) Viscous oil; 1H NMR (CDCl3, 300 MHz): d 1.31 (d,
J = 6.78 Hz, 3H, CH3), 1.44 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.58–1.78 (m, 10H,
5CH2), 2.58–2.73 (m, 3H, CH and CH2), 2.90–2.97 (m, 1H, CH), 3.15–3.20 (m,
4H, 2CH2), 3.37–3.45 (m, 1H, CH), 4.90 (t, J = 6.64 Hz, 1H, CH), 7.24–7.32 (m,
3H, ArH), 7.35–7.40 (m, 1H, ArH), 7.44 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz): d
16.24, 21.29, 22.91, 24.18, 24.30, 24.51, 25.55, 28.32, 28.41, 32.55, 38.12, 51.20,
104.95, 118.68, 122.61, 124.51, 125.98, 126.43, 127.20, 130.15, 130.45, 132.55,
136.32, 138.96, 139.31, 148.87; IR (Neat) 2220 cmꢀ1 (CN); MS (ESI) m/z 399
(M++1); HRMS (EI) calcd for C28H34N2: 398.2722, found: 398.2715.