Synthesis of new 10,11-dihydrodibenzo[a,d]cycloheptene S-thiocarbamate derivatives via a benzylic Newman-Kwart rearrangement

Article abstract of DOI:10.1016/j.tetlet.2014.05.088

New S-thiocarbamates possessing a 10,11-dihydro-5H-dibenzo[a,d]cycloheptene moiety were obtained unexpectedly in the process of preparing new O-thiocarbamates starting from 5-dibenzosuberol (10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ol) and aroyl-isothi

Full text of DOI:10.1016/j.tetlet.2014.05.088

Accepted Manuscript
Synthesis of new 10,11-dihydrodibenzo[a,d]cycloheptene S-thiocarbamate de-
rivatives via a benzylic Newman-Kwart rearrangement
Miron Teodor Căproiu, Florea Dumitrascu, Sergiu Shova, Ileana Cornelia
Chirită, Alexandru Vasile Missir, Dana-Mihaela Cioroianu
PII:
S0040-4039(14)00909-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.088
TETL 44679
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 March 2014
9 May 2014
22 May 2014
Please cite this article as: Căproiu, M.T., Dumitrascu, F., Shova, S., Chirită, I.C., Missir, A.V., Cioroianu, D-M.,
Synthesis of new 10,11-dihydrodibenzo[a,d]cycloheptene S-thiocarbamate derivatives via a benzylic Newman-
Kwart rearrangement, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.088
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Graphical Abstract
Synthesis of new 10,11-dihydrodibenzo[a,d]cycloheptene
S-thiocarbamate derivatives via a benzylic Newman-Kwart
rearrangement
Miron Teodor Căproiu, Florea Dumitrascu, Sergiu Shova,
Ileana Cornelia Chirită, Alexandru Vasile Missir,
Dana-Mihaela Cioroianu
O
Ar
N
C S
S
O
OH
ArCONH
O
S
Newman-Kwart
Rearrangement
ArCONH

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of new 10,11-dihydrodibenzo[a,d]cycloheptene S-thiocarbamate derivatives
via a benzylic Newman-Kwart rearrangement
Miron Teodor Căproiu a∗, Florea Dumitrascua∗, Sergiu Shovab, Ileana Cornelia Chirităc, Alexandru Vasile
Missirc, Dana-Mihaela Cioroianu c
a “C.D. Nenitzescu” Organic Chemistry Center of Romanian Academy, Splaiul Independenței 202B, Bucharest, Romania
b“Petru Poni” Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41A, 700487 Iasi, Romania
cDepartment of Pharmaceutical Chemistry, “Carol Davila” Faculty of Pharmacy, University of Medicine and Pharmacy, Traian Vuia 6, Bucharest, Romania
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New S-thiocarbamates possessing a 10,11-dihydro-5H-dibenzo[a,d]cycloheptene moiety were
obtained unexpectedly in the process of preparing new O-thionocarbamates starting from 5-
dibenzosuberol (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol) and aroyl-isothiocyanates.
These compounds were obtained via a benzylic Newman-Kwart rearrangement mechanism. The
structures of the new thiocarbamates were confirmed by elemental analysis, IR and NMR
spectroscopy and by X-ray crystallography.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
10,11-dihydro-5H-dibenzo[a,d]cycloheptene
O-thionocarbamates
S-thiocarbamates
Newman-Kwart rearrangement
The 10,11-dihydrodibenzo[a,d]cycloheptene scaffold can be
considered a privileged structure1 as it is found in marketed drugs
such as triptyline, amitriptyline, nortriptyline, cyproheptadine
and cyclobenzaprine, which are included in the class of tricyclic
antidepressants (TCAs),2,3 but possess a wide range of other
medicinal applications.4,5
NR2
O
NR2
S
X
X
S
O
1
2
In attempts to prepare new bioactive molecules we decided to
synthesize some new O-thionocarbamate derivatives having a
10,11-dihydro-5H-dibenzo[a,d]cycloheptene structure.
Scheme 1
To our surprise, instead of the expected O-aryl
thionocarbamates we obtained the corresponding S-
thiocarbamates, which suggests the formation of these new
compounds through a Newman-Kwart type rearrangement.6 The
Newman-Kwart rearrangement and its key features as a synthetic
tool for obtaining complex organic molecules has been
reviewed.7,8
is a thione-thiol rearrangement characteristic of thiocarbamate
derivatives with an oxygen atom attached to an aryl radical (the
oxygen atom is linked to an sp2 carbon atom).8,12
Allylic13 and benzylic14,15 Newman-Kwart rearrangements are
interesting and rarely encountered in the literature.
Usually, the Newmann-Kwart rearrangement converts O-aryl-
thionocarbamates 1 into their S-aryl isomers 2 (Scheme 1) at
temperatures between 150 and 350 ºC.6-9 The same
rearrangement can also be carried out at a lower temperature and
using a palladium catalyst,10 or under microwave irradiation at
different temperatures.11 The Newman-Kwart rearrangement
Herein we present the synthesis and structural characterization
of new S-thiocarbamate derivatives of 10,11-dihydro-5H-
dibenzo[a,d]cycloheptene by the in situ benzylic Newman-Kwart
rearrangement of the corresponding O-aryl thionocarbamates.
This reaction could provide an easily accessible synthetic route to
dibenzo[a,d]cycloheptadiene derivatives, all the starting materials
being commercially available.
———
∗ Corresponding authors; e-mails: mtc@cco.ro (M. T. Caproiu), fdumitra@yahoo.com (F. Dumitrascu)

2
Tetrahedron Letters
The new 10,11-dihydrodibenzo[a,d]cycloheptene S-
thiocarbamate derivatives were synthesized using
ppm, which indicated the presence of a carbonyl group instead of
8
a
a C=S group.15 All the other carbon atoms appeared in the
expected ranges.
condensation reaction between alcohol 6 (5-dibenzosuberol), and
the corresponding aroylisothiocyanates 5, in anhydrous acetone.
The aroylisothiocyanates 5 were generated in anhydrous acetone
by the reaction between the corresponding aromatic acid
chlorides 3 and ammonium thiocyanate 4 (Scheme 2), and were
used further without isolation. Three new thiocarbamate
derivatives were obtained in yields of 72-76%. The new light
yellow crystalline compounds were crystallized from
isopropanol.
The IR spectra show evidence of a C-S single bond.17 This bond
is highlighted by the medium intensity stretching band at ~900
cm-1. The stretching bands of the two carbonyl groups are in the
range 1619-1630 cm-1 and 1696-1706 cm-1.
The Newman-Kwart rearrangement is a type of reaction in
which the aryl group of O-aryl thionocarbamates migrates from
the oxygen atom to the sulfur atom, forming S-aryl
thiocarbamates.6-8 The three new S-thiocarbamate compounds
NH4SCN
Ar COCl +
Ar-COSCN
3
4
5
with
a 10,11-dihydro-5H-dibenzo[a,d]cycloheptene structure
O
were obtained unexpectedly via a benzylic Newman-Kwart
rearrangement from the O-isomer (-O-CS-NH-CO-Ar) to the S-
isomer (-S-CO-NH-CO-Ar), under the reaction conditions. The
difference between the usual Newman-Kwart rearrangement and
the rearrangement described herein is that the oxygen or sulfur
atom are linked to an sp3 hybridized carbon atom (the carbon
atom located at position 5 of the dibenzo[a,d]cycloheptane ring)
and the nitrogen atom is linked to an acyl radical (-CO-Ar).
Ar
N=C=S
acetone
O
S
OH
S
O
NHCOAr
NHCOAr
8a-c
5a-c
7a-c
6
a: Ar=C6H5; b: Ar=2-BrC6H4; c: Ar=4-BrC6H4
Scheme 2
Our particular case implies that, for the first time, acyl-
isothiocyanates can be used for obtaining S-thiocarbamates via a
benzylic Newman-Kwart rearrangement.
The structures of the new compounds 8a-c and their key NMR
features are presented in Table 1.
11
10
9
1
The structure of the new compounds was unequivocally
elucidated by X-ray diffraction analysis of the representative
compound 8a (Figure 1).18 The bond lengths and angles are
summarized in Table 2 (and Table 1S in the Supporting
Information).
8
2
3
5
7
6
4
H
S
R
CONHCO
Table 1: Characteristic spectral NMR data of 8a-c
NMR-
N-H
H-5
C-5
C=O
Product
R
H
solvent δ (ppm) δ (ppm) δ (ppm)
δ (ppm)
8a
11.79 6.08
51.11
53.33
168.31
166.45
165.15
DMSO-d6
CDCl3
9.00
6.19
169.76
8b
8c
DMSO-d6 11.92 6.03
CDCl3 8.86 6.13
52.07
53.48
167.23
168.80
166.76
165.29
2-Br
DMSO-d6 11.85 6.07
CDCl3 9.27 6.17
52.04
53.72
168.24
170.19
165.65
164.89
4-Br
The structures of compounds 8a-c were deduced on the basis
of elemental analysis, NMR spectroscopy,16 and confirmed for a
representative compound (8a) by X-ray analysis.
The characteristic features in the 1H-NMR spectra of
compounds 8a-c are the presence of NH protons which appear in
the range 8.86-9.27 ppm in CDCl3 and 11.79-11.92 ppm in
DMSO-d6. The chemical shifts of the benzylic protons are in the
range 6.13-6.19 ppm. It is noteworthy that in all cases the four
methylenic protons at positions 10 and 11 appear as A2B2
systems.
The most specific characteristic of the 13C-NMR spectra is the
value of the chemical shift of the benzylic carbon (C-5), which is
strongly shielded (ca. 53 ppm) in comparison with 5-
dibenzosuberol (ca. 72 ppm). This is strong evidence that the C-5
atom is attached to a sulfur atom rather than an oxygen atom. The
two carbon atoms in the carbonyl groups are the most deshielded
atoms. Their chemical shift values are in the range 164.9-170.2
Figure 1. X-ray molecular structure of compound 8a with
thermal ellipsoids at 40% probability level. Only the major
component of the disordered cycloheptane is shown.
Table 2: Selected bond lengths (Å) for 8a
S1-C1
S1-C9
O2-C2
O1-C1
N1-C2
N1-C1
C2-C3
1.759(4)
1.857(4)
1.209(4)
1.228(4)
1.385(5)
1.377(5)
1.485(5)
C3-C8
C18-C19
C18-C17
C20-C19
C20-C21
C22-C21
C8-C7
1.388(5)
1.382(5)
1.519(1)
1.383(6)
1.373(5)
1.374(5)
1.385(6)

3
1. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin.
Chem. Biol. 2010, 14, 347.
C4-C3
C4-C5
1.382(5)
1.374(5)
1.530(5)
1.373(6)
1.369(5)
1.392(5)
1.512(5)
1.385(5)
C6-C5
1.378(6)
1.361(6)
1.378(6)
1.405(7)
1.5195(9)
1.5194(9)
1.331(8)
1.348(7)
C6-C7
2. Merkas S.; Litvic, M.; Cepanec, I.; Vinkovic, V. Molecules 2005,
10, 1429.
3. Ramesha, A. R.; Roy, A. K. Synth. Commun. 2001, 31, 2419.
4. Peddi, S.; Roth, B. L.; Glennon, R. A.; Westkaemper, R. B.
Bioorg. Med. Chem. Lett. 2003, 13, 2565.
5. Ilies, M.; Banciu, M. D.; Scozzafava, A.; Ilies, M. A.; Caproiu, M.
T.; Supuran, C. T. Bioorg. Med. Chem. 2003, 11, 2227.
6. Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980.
7. Zonta, C.; De Lucchi, O.; Volpicelli, R.; Cotarca, L. Top. Curr.
Chem. 2007, 275, 131-161.
C10-C9
C10-C11
C10-C15
C23-C18
C23-C9
C23-C22
C11-C12
C15-C14
C15-C16
C17-C16
C13-C14
C13-C12
8. Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008,
661-689.
In the crystal packing, two centrosymmetrically related
molecules are associated into a dimer via H-bonds where N1 acts
as a donor and O1 as an acceptor (Figure 2).
9. Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410.
10. Harvey, J. N.; Jover, J.; Lloyd-Jones, G. C.; Moseley, J. D.;
Murray, P. M.; Renny, J. S. Angew. Chem. Int. Ed. 2009, 48,
7612.
11. Das, J.; Le Cavelier, F.; Rouden, J.; Blanchet, J. Synthesis 2012,
44, 1349.
12. Moseley, J. D.; Lenden, P. Tetrahedron 2007, 63, 4120.
13. Sakamoto, M.; Yoshiaki, M.; Takahashi, M.; Fujita, T.; Watanabe,
S. J. Chem. Soc., Perkin Trans. 1 1995, 373.
14. Alajarin, M.; Marin-Luna, M. Ortin, M. M.; Sanchez-Andrada, P.;
Vidal, A. Tetrahedron, 2009, 65, 2579.
15. Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem.
2012, 124, 1.
16. S-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N-
benzoylcarbamothioate (8a). To an acetone solution of
aroylisothiocyanate 5a (obtained in a previous step) was added 5
mmol of an anhydrous acetone solution of 5-dibenzosuberol. The
reaction mixture was heated under reflux for 3 h and then
evaporated to dryness under vacuum. The final compound 8a was
crystallized from isopropanol (see Supporting Information for 8a-
c). Yield=72%; mp=165-166 oC; Anal. Calcd. for C23H19NO2S: C
73.97%, H 5.13%, N 3.75%, S 8.58%; Found: C 74.12%, H
4.99%, N 3.89%, S 8.33%. FT-IR (solid in ATR, ν cm-1): 3263m;
3058w; 3023w; 2973w; 2914w; 2829w; 1695m; 1620vs; 1456m;
1441m; 1425m; 1251s; 1187s; 1156m; 1102m; 906m; 870w;
848w; 767w; 698m; 671m; 617m. 1H-NMR (CDCl3, 300 MHz δ
ppm, T=298 K): 9.00 (br s, 1H, NH-CS, deuterable); 7.82 (dd, J =
1.4, 7.9 Hz, 2H, Ph); 7.58 (tt, J = 1.4, 7.7 Hz, 1H, Ph); 7.48 (dd, J
= 7.9, 7.7 Hz, 2H, Ph); 7.42 (d, J = 7.2 Hz, 2H, H-1, H-10); 7.22-
7.09 (m, 6H, H-1, H-2, H-3 and H-7, H-8, H-9); 6.19 (s, 1H, H-
5); 3.60 (m, 2H, H-10, H-11, syst. A2B2); 2.98 (m, 2H, H-10, H-
11, syst. A2B2). 13C-NMR (CDCl3, 75 MHz, δ ppm, T=298 K):
169.76 (CONH); 165.15 (COPh); 140.32 (C-4a, C-5a); 137.75
(C9a, C-11a); 133.37 (Ph); 131.92 (Ph); 130.75 (C-4, C-6); 130.35
(CH); 129.03 (CH); 128.06 (CH); 127.57 (CH); 126.36 (CH);
53.33(C-5); 33.14 (C-10, C-11).
Figure 2. Hydrogen bonding and π-π stacking interactions in the
crystal structure. Symmetry code; (i) 0.5 – x, 0.5 – y. 1- z. H-
bond parameters: N1−H···O1 [N1−H 0.91 Å, H···O1(0.5 - x, 0.5 -
y, 1 - z) 2.03 Å, N1···O1 2.918(4) Å, N1−H···O1 165.3°].
Apart from the H-bonding, significant π-π stacking
interactions are observed in the crystal packing. They occur
between adjacent C3-C8 and C18-C23 aromatic rings with a
centroid-to-centroid distance of 3.915 Å and shift of 1.742 Å.
Thus, each associated H-bond is involved in the stacking
interaction along four directions, such that the crystal structure
can be characterized as a three-dimensional supramolecular
network.
In conclusion, we have synthesized three new S-
thiocarbamates
with
a
10,11-dihydro-5H-
17. Socrates, G., Infrared and Raman Characteristic Group
Frequencies, 3rd edition, Wiley, New York, 2001, 209-228.
18. Crystal data: C23H19NO2S, Mr = 373.45 g mol-1, size 0.5 × 0.1 ×
0.05 mm3, monoclinic, space group C2/c, a = 27.401(4) Å, b =
8.0970(7) Å, c = 17.799(3) Å, β = 108.865(16)°, V = 3736.8(8)
Å3, Z = 8, ρcalcd = 1.328 g cm-3, µ(MoKα) = 0.191 mm-1, F(000) =
1568, 7287 reflections in h(-33/24), k(-6/9), l(-21/21), measured in
the range 3.14 ≤ Θ ≤ 52°, T = 173 K, completeness Θmax=99.98%,
3666 independent reflections, Rint = 0.0489, 246 parameters, 19
dibenzo[a,d]cycloheptene moiety. These new compounds were
obtained following the condensation reaction between 5-
hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and the
corresponding aroylisothiocyanates. The new S-thiocarbamates
are derived via a benzylic Newman-Kwart rearrangement from
the O-isomer into the S-isomer. The structures of these new
derivatives were confirmed by elemental analysis, spectrometric
methods (IR, 1H-NMR, 13C-NMR) and X-ray crystallography.
restraints, R1obs=0.0776, wR2obs = 0.1623, R1all = 0.1332, wR2all
=
0.1881, GoF = 1.035, largest difference peak and hole: 0.92/-0.58
e A-3. CCDC-991426 contains the supplementary crystallographic
data and can be obtained free of charge from the Cambridge
Acknowledgements
This work was partially supported by FEST (“Finantare
Europeana pentru Studii Doctorale”), project number
POSDRU/88/1.5/S/64334 and by the European Regional
Development Fund, Sectoral Operational Programme "Increase
of Economic Competitiveness", Priority Axis 2 (SOP IEC-A2-
O2.1.2-2009-2, ID 570, COD SMIS-CSNR: 12473, Contract
129/2010-POLISILMET).
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data
Supplementary data associated with this article can be found
in the online version at DOI:
References and notes