Aromatization of (Z) and (E)-α-atlantones isolated from Cedrus atlantica essential oil followed by condensation with thiosemicarbazide: Synthesis of new thiadiazolines derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.11.103

Aromatization, using Pd/C (10%) of (Z) and (E)-α-atlantones isolated from Cedrus atlantica essential oil, followed by condensation with thiosemicarbazide gave novel 1,3,4-thiadiazolic derivatives by the introduction of new functional groups on the terpeni

Full text of DOI:10.1016/j.tetlet.2015.11.103

Accepted Manuscript
Aromatization of (Z) and (E)-α-Atlantones Isolated from Cedrus atlantica Es-
sential Oil followed by Condensation with Thiosemicarbazide: Synthesis of new
Thiadiazolines Derivatives
Noureddine Mazoir, Mohamed Dakir, Mohamed Tebbaa, Mohamed Loughzail,
Ahmed Benharref
PII:
S0040-4039(15)30411-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.103
TETL 47043
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 May 2015
27 October 2015
30 November 2015
Please cite this article as: Mazoir, N., Dakir, M., Tebbaa, M., Loughzail, M., Benharref, A., Aromatization of (Z)
and (E)-α-Atlantones Isolated from Cedrus atlantica Essential Oil followed by Condensation with
Thiosemicarbazide: Synthesis of new Thiadiazolines Derivatives, Tetrahedron Letters (2015), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2015.11.103
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Leave this area blank for abstract info.
Aromatization of (Z) and (E)-α-Atlantones Isolated
From Cedrus atlantica Essential Oil followed by Condensation with Thiosemicarbazide:
Synthesis of new Thiadiazolines Derivatives
a,b,
Noureddine Mazoir *, Mohamed Dakir , Mohamed Tebbaa , Mohamed Loughzail , Ahmed Benharref
a,c
a
a
a

1
Tetrahedron Letters
journal homepage: www.els evier.com
Aromatization of (Z) and (E)-α-Atlantones Isolated from Cedrus atlantica Essential
Oil followed by Condensation with Thiosemicarbazide: Synthesis of new
Thiadiazolines Derivatives
a,b,
Noureddine Mazoir *, Mohamed Dakir , Mohamed Tebbaa , Mohamed Loughzail , Ahmed Benharref
a,c
a
a
a
a
Laboratoire de Chimie Biomoléculaire, Substances Naturelles et Réactivité (URAC 16), Université Cadi Ayyad, Faculté des Sciences Semlalia, Marrakech, B.P.
390, 40000, Maroc.
Département de Chimie, Faculté des Sciences, Université Chouaib Dokkali, El Jadida, B.P. 20, 24000, Maroc
2
b
c
Département de Chimie, Faculté des Sciences Ain Chock, Université Hassan II, Casablanca, B.P. 5366, Maroc
ARTICLE INFO
ABSTRACT
Article history:
Received
Aromatization, using Pd/C (10%) of (Z) and (E)-α-atlantones isolated from Cedrus atlantica
essential oil, followed by condensation with thiosemicarbazide gave novel 1,3,4-thiadiazolic
derivatives by the introduction of new functional groups on the terpenic skeletons. After
aromatization and thiosemicarbazide condensation, all products were obtained with good yield
to give thiadiazolic compounds bearing new spiro carbons.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Cedrus atlantica essential oil
Atlantones
Aromatization
Thiosemicarbazones
Spiro-heterocyclic compounds
Thiadiazolines
NH
2
The synthesis of novel heterocyclic derivatives and the
investigation of their chemical and biological behaviour have
gained importance in recent decades. During recent years there
has been intense investigation of different classes of thiadiazolic
compounds, many of which possess interesting biological
R2
S
S
R2
O
+
2
H N
N
H
NH
2
NH
R1
N
1
R
Ac
2
O/
1
Ac
activities.
Pyridine
2
N
S
R
N
(
±)
2
In particular, thiosemicarbazones and their derivatives have
1
R
NHAc
been evaluated for their inhibitor activity against Trypanosoma
rhodesiense. Following these studies, a considerable number of
3
Scheme 1. General pathway for the synthesis of thiadiazoline
15
derivatives.
derivatives showed interesting pharmacological activities, such
as antibacterial, antiviral, phytotoxic and antiparasitic. Others
4
5
6
7
8
have been reported as having antineoplastic and antimalarial
In this work, we have focused on the oxygenated fraction of
cedrus atlantica essential oil containing (Z) and (E)-α- atlantones
1 and 2 which were isolated by chromatography on silica gel
column impregnated with silver nitrate (10%) and a mixture of
9
activities. In addition, thiosemicarbazone compounds have
1
0
showed selective inhibition of the herpes simplex virus as we1ll
as an effect against human immunodeficiency virus (HIV).
1
Thiadiazolic compounds are also associated with diverse
biological activities and the 1,3,4-thiadiazole nucleus, which
incorporate a toxiphoric -N=C-S- linkage, possesses fungicidal,
hexane/ethyl acetate (99/1) as eluent.
In the present
1
2
contribution, we present an efficient method to obtain new spiro
19
1
3
14
15
insecticidal, antimicrobial, and bactericidal properties.
carbons. Treatment with thiosemicarbazide,
after the
2
0
21
aromatization reaction of the two atlantones (Figure 1),
followed by the addition of acetic anhydride in the presence of
pyridine yielded new 1,3,4-thiadiazolines: 7a, 7b, 8a and 8b, in
good yield. The structures of the obtained products were
When acetylating the corresponding thiosemicarbazones, a
1
6
simple method for preparing thiadiazolines, by cyclization of
ketones (Scheme 1) has been reported.
1
13
established by H, C NMR spectroscopy and confirmed by
single-crystal X-ray diffraction.
Extending our previous work, for the synthesis of new
compounds from natural products, especially from the
1
constituents of Cedrus atlantica which is an essential oil
7
primarily made up of bicyclic sesquiterpenic hydrocarbons (75%)
8
and oxygenated compounds (25%).
1

2
Tetrahedron
of acetic anhydride. This allowed, after chromatography on silica
gel, the synthesis of 1,3,4-thiadiazolines 7(a,b) and 8(a,b) in
good yields (Scheme 4).
Figure 1. Principal carbonyl compounds isolated from oxygenated
fraction of Cedrus atlantica essential oil.
Aromatization of these compounds with 5% Pd/C at 120 °C for
1
2 h led to product 3 in 98% yield as a colorless oil after
purification on silica gel (Scheme 2). Aromatization could be
carried out on a mixture of the two atlantones to give the same
22
products, namely racemic 3 and 4. The newly prepared
compound 3 was characterized from its spectroscopic data
NMR).
Scheme 4. Synthesis of thiadiazolic compounds 7(a,b) and 8(a,b).
(
(
2
a) Ac O, Pyridine, 110 °C, 1 h
The structures of the newly prepared thiadiazolines 7(a,b) and
1 13
(a,b) were fully characterized by H NMR. The C NMR
8
spectra showed new peaks, characteristic for the spiro carbons in
products 7a, 7b, 8a and 8b at 76.8, 76.6, 84.9 and 83.7 ppm
respectively. The relative stereochemistry of the thiadiazolic
derivatives was definitively confirmed by single-crystal X-ray
diffraction (Figure 3 and 4).
(
a)
Scheme 2. Aromatization of compounds 1 and 2.
1
Pd/C (5%),
(
b)
20 °C (12 h), Pd/C (5%), 160 °C (12 h).
23
Figure 3. ORTEP representation of compound 7b.
In order to prepare new heterocyclic derivatives, we were
interested in the reactivity of terpenoid compounds,
semisynthesized from Cedrus atlantica essential oil, using
thiosemicarbazide (TSC) condensation. Thus, treatment of
compounds 3 and 4 with thiosemicarbazide in the presence of
HCl in EtOH, yielded respectively, after heating at reflux for 5h,
products 5 and 6 (Scheme 3).
24
Figure 4. ORTEP representation of compound 8b.
In conclusion, we have described the synthesis of new 1,3,4-
thiadiazolic terpenoid derivatives 7(a,b) and 8(a,b) from natural
Scheme 3. Thiosemicarbazide condensation of compounds 3 and 4.
(
(
Z) and (E)-α-atlantones 1 and 2, which were isolated from
2 2
a) NH CSNHNH , EtOH, HCl.
Cedrus atlantica essential oil. The synthesis of thiadiazolic
compounds could be carried out from their precursors,
thiosemicarbazones (5 and 6), which were prepared by
The compounds 5 and 6 were characterized after condensation
1
13
with thiosemicarbazide from their H and C NMR spectra by
the appearance of new signals.
condensation of carbonyl products
3
and
4
with
thiosemicarbazide (TSC). The thiadiazolines prepared were
characterized by the presence of new spiro carbons and were
analysed by single crystal X-ray diffraction.
In the second step, thiadiazoline derivatives were prepared by
treating thiosemicarbazones 5 and 6 with pyridine in the presence

3
Acknowledgments
The authors are grateful to Professor Moha BERRAHO for
crystallographic data.
(17) (a) Auhmani, A.; Kossareva, E.; Eljamili, H.; Reglier, M.; Pierrot, M.;
Benharref, Synthetic Commun. 2002, 32, 707. (b) Dakir, M.; Auhmani,
A.; Ait Itto, My. Y.; Mazoir, N.; Akssira, M.; Pierrot, M.; Benharref, A.
Synthetic Communication 2004, 34, 2001. (c) El Jamili, H.; Auhmani, A.;
Dakir, M.; Lassaba, E.; Benharref, A.; Pierrot.; Chiaroni, A.; Riche, C.
Tetrahedron Letters 2002, 43, 6645. (d) El Haib, A.; Benharref, A.;
Parrès-Maynadié, S.; Manoury, E.; Urrutigoı¨ty, M.; Gouygou, M..
Tetrahedron Asymmetry 2011, 22, 101.
References
(
1) (a) Holla, B. S.; Prasanna, C. S.; Poojary, B.; Rao, K. S.; Shridhara, K.;
Bhat, U. G. Ind. J. Chem. 2004, 43B, 2170. (b) Amir, M.; Shikha, K. Eur.
J. Med. Chem. 2004, 39, 535.
(18)Plattier, M. ; Teisseire, P, Recherches 1972, 167.
(
(
2) Mazoir, N.; Benharref, A., J. Mater. Environ. Sci. 2015, 6, 592.
3) Robert, A. C.; Daniel, L. K.; George, E. C.; John, P. S.; Robert, E. D.
Antibio. Chemother. 1980, 18, 317.
(19) Ourhriss, N.; Giorgi, M.; Mazoir, N.; Benharref, A. Acta Cryst. 2005,
C61, o699.
(20)Hayashi, M.; Kawashita, Y. Letters in Organic Chemistry 2006, 3, 571.
(21)(a) Plattier, M.; Teisseire, P. Recherches 1974, 19, 131. (b) Chalchat, J.
C.; Garry, R. P.; Michet, A.; Benjilali, B.; Essent, J. Oil Res. 1994, 6,
323.
(
(
(
4) Protivinsky, R. Antibio. Chemother. 1971, 17, 101.
5) Weinstein, L.; Whang, T.-W. N. Engl. J. Med. 1973, 289, 725.
6) Mazoir, N.; Benharref, A.; Bailén, M., Reina, M.; González-Coloma, A.
Phytochemistry 2008, 69, 1328.
(22)El Karroumi, J.; El Haib, A.; Manoury, E.; Benharref, A.; Darana, J. C.;
Gouygoua, M.; Urrutigoïty, M. Journal of Molecular Catalysis A:
Chemical 2015, 401, 18.
(
7) (a) Mazoir, N.; Benharref, A.; Bailén, M.; Reina, M.; González-Coloma,
A.; Martínez-Díaz, R. Z. Naturforsch C. 2011, 66c, 360. (b) Klayman, D.
L.; Skovill, J. P.; Bartosevich, J. F.; Griffin, T. S.; Mason, C. G. J. Med.
Chem. 1979, 22 1367.
(23)Mazoir, N.; El Ammari, L.; Bouhmaida, N.; Dahaoui, S.; Benharref, A.;
Berraho, M. Acta Cryst. 2009, E65, o1269.
(
(
(
8) Wilson, H. R.; Revankar, G. R.; Tolman, R. L. J. Med. Chem. 1974, 17,
(24) Loughzail, M.; Mazoir, N.; Maya, C. M.; Berraho, M.; Benharref, A.;
Bouhmaida, N. Acta Cryst. 2009, E65, o-4.
7
60.
9) Giner-Sorolia, A. M.; Mc Cravey, J.; Burchenal, J. H. J. Med. Chem.
973, 16, 984.
1
10) Blumenkopf, T. A.; Harrington, J. A.; Koble, C. S.; Bankston, D. D.;
Morrison, R. W.; Bigham, E. C.; Styles, V. L.; Spector, T. J. Med. Chem.
1
992, 35, 2306.
(
(
(
11) Teitz, Y.; Ronen, D.; Vansover, A.; Stematsky, T.; Riggs, J. L.; Antivir
Res. 1994, 24, 305.
12) Abdou, N. A.; Soliman, I. N.; Sier Abou, A. H.; Bull Facpharm (Cairo
Univ.) 1991, 28, 629.
13) Omar, A.; Mohsen, M. E.; Aboul, W.; Omainma M. J. Heterocycl.
Chem. 1986, 23, 1339.
(
(
(
14) Griffin; A. D.; Sally, K.; EP 119474. Chem Abstr. 1986, 106, 98120.
15) Zhang, Z. Y.; Liu Y.; Yang, S. Y. Pharmaceutica Sinica 1991, 26, 809.
16) Beatriz, N. B.; Albertina, G. M.; Miriam, M. A.; Angel, A. L.; Graciela,
Y. M.; Norma, B. D. Arkivok 2002, X, 14.
Click here to remove instruction text...