On the reactivity of (-)-(R)-carvone and (-)-4aα,7α, 7αβ-nepetalactone: Synthesis of new heterocycles

Article abstract of DOI:10.1002/hlca.201000246

The 1,3-dipolar cycloaddition of 4-chlorobenzonitrile oxide to the unsaturated system of (-)-(R)-carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with NH₂OH to yield a new heterocycle, observed f

Full text of DOI:10.1002/hlca.201000246

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On the Reactivity of (ꢀ)-(R)-Carvone and (ꢀ)-4aa,7a,7ab-Nepetalactone:
Synthesis of New Heterocycles
by Aziz El Mebtoula), Mohamed Rouania), Malika Chammacheb), Houcine Bouididaa), and
Abdelkader Ilidrissi*a)1)
a) Department of Chemistry, Laboratory of Plant Chemistry, Organic and Bio-organic Synthesis,
University Mohammed V Agdal, Faculty of Sciences, Rabat, Morocco
b) Department of Chemistry, Heterocyclic Chemistry Laboratory, University Mohammed V Agdal,
Faculty of Sciences, Rabat, Morocco
(phone: þ 212 0668547336; fax: þ 212 0537775440; e-mail: a.ilidrissi@yahoo.fr)
The 1,3-dipolar cycloaddition of 4-chlorobenzonitrile oxide to the unsaturated system of (ꢀ)-(R)-
carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with
NH2OH to yield a new heterocycle, observed for the first time. On the other hand, the addition of 4-
chlorobenzonitrile oxide to the unsaturated lactone (ꢀ)-4aa,7a,7ab-nepetalactone gave, in a good yield,
also a new heterocycle, again obtained for the first time. The terpenoid (ꢀ)-(R)-carvone and iridoid (ꢀ)-
4aa,7a,7ab-nepetalactone were isolated from Moroccan species Mentha viridis (L.) and Nepeta tuberosa
(L.), respectively. The new heterocycles obtained were identified by combination of chromatographic
and spectroscopic methods.
1. Introduction. – 1,3-Dipolar cycloaddition of nitrile oxides to unsaturated systems
as (ꢀ)-(R)-carvone (I; for antimicrobial action, see [1 – 3]) and (ꢀ)-4aa,7a,7ab-
nepetalactone (II; referred to as therapeutic molecule [4 – 10]) is a convenient method
to prepare isoxazoline derivatives. The reactivity of the dipolarophile in our case is
activated by a ketone function in I and a lactone function in II.
Our review of the literature on (ꢀ)-(R)-carvone revealed that the reactivity of
nitrile oxides is regioselective, strongly dependent on the substituents. In general, all
substituents in the dipolarophile (relative to H) strongly accelerate 1,3-dipolar
cycloadditions [11]. Indeed, Shiue et al. have shown in 1976 that the addition of
1
)
Present address: Abdelkader Ilidrissi, Residence Mesk Ellil, Immeuble 9, N8 3, Hay Ryad 10110,
Rabat, Maroc.
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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acetonitrile oxide at C(8)¼C(9) of dipentene (¼1-methyl-4-(1-methylethenyl)cyclo-
hexene; 1) gave the dihydroisoxazole derivatives 2a and 2b, but no adduct 3
(Scheme 1). The same dipole underwent addition to carvone (4a; enantiomer not
specified) at both C¼C bonds to give a mixture of dihydroisoxazole derivatives 5a and
6a. Benzonitrile oxide, however, gave the analogous carvone derivatives 5b and 5c,
respectively, without contamination of the isomers 6b or 6c [11 – 14].
Scheme 1
We note here that the addition of the benzonitrile oxide was carried out after
oximation of the carvone 4a. It is completely the opposite in our case, since we added
NH2OH · HCl to the 5b equivalent after having synthesized it, using 4-chlorobenzoni-
trile oxide instead of benzonitrile oxide (see Schemes 2 and 3).
In the case of iridoid II, the work encountered in the literature is mostly on organic
synthesis or pharmacological activity [15 – 18]. To our knowledge, no study of 1,3-
dipolar cycloaddition on the molecule II has been described previously.
2. Results. – 2.1. Fomation of Ia. (ꢀ)-(R)-Carvone (I) was isolated from Mentha
viridis (L.), a plant cultivated in Morocco. It was identified by combination of
chromatographic and spectroscopic methods. This compound alone represents 70% of
the essential oil of the plant.
Addition of 4-chlorobenzonitrile oxide to (ꢀ)-(R)-carvone was conducted in
CHCl3 with stirring at 08. The addition has affected only the C(8)¼C(9) bond to give
isoxazoline Ia (Scheme 2).

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435
Scheme 2
2.1.1. Reaction of Ia with NH2OH · HCl. We have studied the chemical behavior of
isoxazoline derivative Ia towards NH2OH · HCl. The reaction mixture was stirred at
room temperature in EtOH/NaOH. Thereby, derivative Ib was formed as major
compound, accompanied by traces of oxime Ic (Scheme 3). The formation of Ib
indicates the binucleophilic character of H2NꢀOH, as we have already reported in [19].
Scheme 3
2.2. Formation of III. The essential oil obtained by steam distillation contains 80%
of iridoid II. We isolated II from the oil by filtration after having induced its
crystallization. The spectroscopic data agreed well with those in the literature [4 – 7].
To synthesize new molecules starting from II for pharmacodynamic applications, or
having some interesting olfactory properties, we have added 4-chlorobenzonitrile oxide
to 4aa,7a,7ab-nepetalactone II. The reaction took place in the presence of Javel water
with stirring at 08 for 48 h. We obtained a new compound, III, with heterocyclic
structure III (Scheme 4).
Scheme 4

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Helvetica Chimica Acta – Vol. 94 (2011)
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This work was supported by grants from the Unite associee au CNRST ꢀURAC 23ꢁ.
Experimental Part
1. Preparation of Ia. In a 200-ml Erlenmeyer flask, equipped with a Br2 funnel, were introduced 1.00 g
of (ꢀ)-(R)-carvone (6.66 mmol) and 1.03 g of 4-chlorobenzaldehyde oxime in CHCl3 (30 ml). The soln.
was stirred at 08 for 4 h, while 25 ml of Javel water (NaOCl) were added dropwise. The mixture was
stirred at r.t. for 48 h (the progress of the reaction was followed by TLC). The aq. phase was washed with
CH2Cl2 (50 ml), and the combined org. phases were dried (Na2SO4) and evaporated to dryness. The oily
residue was taken up with Et2O (25 ml). A white solid appeared, which was isolated by filtration.
(5R)-5-[3-(4-Chlorophenyl)-4,5-dihydro-5-methyl-1,2-oxazol-5-yl]-2-methylcyclohex-2-en-1-one
(Ia). Yield 70%. M.p. 1668. IR: 1660, 1620. 1H-NMR (200 MHz, CDCl3): 1.82 (s, Me(12)); 1.53 (s,
Me(13)); 2.32 – 2.83 (m, HꢀC(6), CH2(7)); 3.09, 3.20 (AB, J ¼ 16, CH2(4)); 6.76 – 6.84 (m, HꢀC(10)); 7.41
(d, J ¼ 9, HꢀC(3’), HꢀC(5’)); 7.63 (d, J ¼ 9, HꢀC(2’), HꢀC(6’)). 13C-NMR (50 MHz, CDCl3): 16.06
(C(13)); 23.39 (C(12)); 27.52 (C(4)); 40.01 (C(6)); 44.21 (C(7)); 44.28 (C(11)); 88.82 (C(5)); 128.10
(C(3’), C(5’)); 128.45 (C(4’)); 129.43 (C(2’), C(6’)); 135.95 (C(1’)); 136.41 (C(9)); 144.72 (C(10)); 155.28
(C(3)); 199.12 (C(8)).
2. Preparation of Ib and Ic. In a 200-ml Erlenmeyer flask were introduced 3.00 mmol of Ia (ca. 0.93 g),
3.6 mmol of NH2OH · HCl (ca. 0.38 g), 3.60 mmol of NaOH (ca. 0.15 g), and EtOH (50 ml). The mixture
was stirred for 12 h. After removal of EtOH under reduced pressure, the aq. residue was extracted with
CH2Cl2 (30 ml). The org. phase was washed with H2O (50 ml), dried (Na2SO4), and concentrated to
dryness. Chromatographic and spectroscopic methods evidenced the formation of the major compound Ib
with ca. 10% of oxime Ic.
Data of 3-[3-(4-Chlorophenyl)-4,5-dihydro-5-methyl-1,2-oxazol-5-yl]-8-methyl-6-oxa-7-azabicy-
1
clo[3.2.1]octan-5-ol (Ib). Yield 60%. M.p. 2088. IR: 3230, 3150. H-NMR (200 MHz, CDCl3): 1.23 (s,
Me(13)); 1.25 (d, J ¼ 8, Me(12)); 1.43 – 2.09 (m, HꢀC(6), CH2(7), CH2(11)); 1.83 (m, HꢀC(9)); 3.20 (m,
HꢀC(10)); 3.47 (m, NH); 3.68, 3.79 (AB, J ¼ 16, CH2(4)); 5.92 (m, OH); 7.34 (d, J ¼ 9, HꢀC(3’),
HꢀC(5’)); 7.54 (d, J ¼ 9, HꢀC(2’), HꢀC(6’)). 13C-NMR (50 MHz, CDCl3): 17.57 (C(6)); 18.32 (C(7));
22.88 (C(12)); 23.76 (C(13)); 26.27 (C(4)); 41.69 (C(9)); 43.97 (C(11)); 58.33 (C(10)); 89.22 (C(5));
127.70 (C(2’), C(6’)); 128.38 (C(3’), C(5’)); 129.36 (C(8)); 132.30 (C(4’)); 135.85 (C(1’)); 156.24 (C(3)).
3. Preparation of III. In a 200-ml Erlenmeyer flask, equipped with a Br2 funnel, were introduced
1.00 g of iridoid II (6.024 mmol) and 0.94 g of 4-chlorobenzaldehyde oxime in CHCl3 (30 ml). According
to the same procedure as for Ia, the reaction gave compound III in pure form.
Data of (4aS,7S,7aS)-5,6,7,7a-Tetrahydro-4,7-dimethylcyclopenta[c]pyran-1(4aH)-one (II). M.p. 37 –
398. [a]2D0 ¼ ꢀ24.2 (c ¼ 6.2, CHCl3). IR (KBr): 1765, 1662, 1140. H-NMR (300 MHz, CDCl3): 1.10 (d,
1
J ¼ 8, Me(9)); 1.71 (s, Me(8)); 2.20 – 2.51 (m, CH2(5), CH2(6), HꢀC(7)); 2.36 – 2.43 (m, HꢀC(7a),
HꢀC(4a)); 6.23 (s, HꢀC(3)). 13C-NMR (50 MHz, CDCl3): 14.26 (C(8)); 17.66 (C(9)); 26.12 (C(5)); 29.99
(C(6)); 32.02 (C(7)); 37.33 (C(4a)); 49.11 (C(7a)); 120.44 (C(4)); 135.88 (C(3)); 170.21 (C(1)). MS: 166
(24, Mþ), 138 (26), 123 (50), 95 (80), 81 (100).
Data of 3-(4-Chlorophenyl)-5a,6,7,8,8a,8b-hexahydro-6,8b-dimethylcyclopenta[4,5]pyrano[2,3-
d][1,2]oxazol-5(3aH)-one (III). Yield 87%. M.p. 153 – 1548. IR (KBr): 1757, 1494, 1376, 1015, 837.
1H-NMR (300 MHz, CDCl3): 1.00 (d, J ¼ 8, Me(10)); 1.55 (s, Me(9)); 1.92 – 2.22 (m, HꢀC(5a), HꢀC(6),
CH2(7), CH2(8), HꢀC(8a)); 5.56 (s, HꢀC(3a)); 7.35 (d, J ¼ 10, HꢀC(2’), HꢀC(6’)); 7.75 (d, J ¼ 10,
HꢀC(3’), HꢀC(5’)). 13C-NMR (50 MHz, CDCl3): 16.42 (C(9)); 21.64 (C(10)); 23.54 (C(7)); 31.53 (C(8));
32.14 (C(6)); 42.93 (C(8a)); 44.79 (C(5a)); 85.45 (C(3a)); 89.10 (C(8b)); 126.19 (C(4’)); 128.24 (C(3’),
C(5’)); 129.22 (C(2’), C(6’)); 136.64 (C(1’)); 154.34 (C(3)); 170.26 (C(5)). MS: 320 (90, [M þ H]þ).
REFERENCES
[1] S. Pattnaik, V. R. Subramanyam, M. Bapaji, C. R. Kole, Microbios 1997, 89, 39.
[2] S. Lee, R. Tsao, C. Peterson, J. R. Coats, J. Econ. Entomol. 1997, 90, 883.

Helvetica Chimica Acta – Vol. 94 (2011)
437
[3] J. Wang, M. Froeyen, C. Henrix, C. Andrei, R. Snoeck, E. Lescrinier, E. De Clercq, P. Herdewijn,
Nucleosides, Nucleotides Nucleic Acids 2001, 20, 727.
[4] E. J. Eisenbraun, C. E. Browne, R. L. Irvin-Willis, D. J. McGurk, E. L. Eliel, D. L. Harris, J. Org.
Chem. 1980, 45, 3811.
[5] Y. Takeda, Y. Kiba, T. Masuda, H. Otsuka, M. Tagawa, E. Sezik, E. Yesilada, Chem. Pharm. Bull.
1999, 47, 1433.
[6] F. Murai, M. Tagawa, H. Inouye, T. Ishida, M. Inoue, Chem. Pharm. Bull. 1987, 35, 2533.
[7] X. Xie, S. Uesato, H. Inouye, T. Fujita, F. Murai, M. Tagawa, T. Shingu, Phytochemistry 1988, 27, 469.
´
[8] J. Bellakhdar, ꢂLa pharmacopee marocaine traditionnelleꢃ, Ibis Press, Paris, 1997, pp. 264 – 290.
´
[9] H. Bouidida, K. Alaoui, Y. Cherrah, S. Fkih-Tetouani, A. Ilidrissi, Phytotherapie 2004, 4, 120.
´
[10] H. Bouidida, K. Alaoui, Y. Cherrah, S. Fkih-Tetouani, A. Ilidrissi, Therapie 2006, 61, 447.
[11] C.-Y. Shiue, R. G. Lawler, L. B. Clapp, J. Org. Chem. 1976, 41, 2210.
[12] C.-Y. Shiue, K. P. Park, L. B. Clapp, J. Org. Chem. 1970, 35, 2063.
[13] G. C. Levy, G. L. Nelson, J. Am. Chem. Soc. 1972, 94, 4897.
[14] G. Grundman, P. Grunanger, ꢂNitrile oxidesꢃ, Springer-Verlag, New York, 1971, p. 85.
[15] A. Nangia, G. Prasuna, Tetrahedron 1996, 52, 3435.
[16] P. Callant, P. Storme, E. Van der Eycken, M. Vandewalle, Tetrahedron Lett. 1983, 24, 5797.
[17] S. Aydin, T. Demir, Y. ꢄztꢁrk, K. H. C. Bas¸er, Phytoter. Res. 1999, 13, 20.
[18] S. Aydin, R. Beis, Y. ꢄztꢁrk, K. H. C. Bas¸er, J. Pharm. Pharmacol. 1998, 50, 813.
[19] S. Ghoulami, A. Ilidrissi, S. Fkih-Tetouani, Tetrahedron Lett. 2001, 42, 2107.
Received June 29, 2010