A regioselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-chromene thiadiazole derivatives

Article abstract of DOI:10.1016/j.crci.2013.08.004

A variety of 4′-(4-R-phenyl)-4-(methylthio)-2′-phenyl- 2′H-spiro[chromene-2,5′-[1,2,3]thiadiazole] 5a-d and 5′-(4-R-phenyl)-4-(methylthio)-3′-phenyl-3′H-spiro[chromene-2, 2′-[1,3,4]thiadiazole] 6a-d were synthesized regioselectively through the reaction of 4-(methylthio)-2H-chromene-2-thione 2 with diarylnitrilimines under refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2H-chromene-2- thione 3 with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-(allylthio)-5′-(4-R-phenyl)-3′-phenyl-3′H- spiro[chromene-2,2′-[1,3,4]thiadiazole] 7a-d and 5-(4-R-phenyl)-2′- methyl-3-phenyl-2′,3′-dihydro-3H-spiro[[1,3,4]thiadiazole-2, 4′-thieno[3,2-c]chromene] 9a-d as two unisolable diastereoisomeric forms. The structures of the obtained spiro cycloadduct thiadiazoles have been assigned by means of spectroscopic measurements.

Full text of DOI:10.1016/j.crci.2013.08.004

C. R. Chimie 17 (2014) 171–178
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´
Full paper/Memoire
A regioselective 1,3-dipolar cycloaddition for the synthesis of
novel spiro-chromene thiadiazole derivatives
Imen Zghab a, Belsem Trimeche a, David Touboul b, Hichem Ben Jannet a,
*
a
´
Laboratoire de chimie he´te´rocyclique, produits naturels et re´activite´ (LR11ES39), Equipe Chimie bioorganique et produits naturels, faculte´
des sciences de Monastir, universite´ de Monastir, 5000 Monastir, Tunisia
b Centre de recherche de Gif, Institut de chimie des substances naturelles, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France
A R T I C L E I N F O
A B S T R A C T
variety
A
of
40-(4-R-phenyl)-4-(methylthio)-20-phenyl-20H-spiro[chromene-2,50-
Article history:
[1,2,3]thiadiazole] 5a–d and 50-(4-R-phenyl)-4-(methylthio)-30-phenyl-30H-spiro[chro-
mene-2,20-[1,3,4]thiadiazole] 6a–d were synthesized regioselectively through the
Received 29 March 2013
Accepted after revision 6 August 2013
Available online 7 October 2013
reaction of 4-(methylthio)-2H-chromene-2-thione
2 with diarylnitrilimines under
refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2H-chromene-2-thione 3
with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-
(allylthio)-50-(4-R-phenyl)-30-phenyl-30H-spiro[chromene-2,20-[1,3,4]thiadiazole] 7a–d
and 5-(4-R-phenyl)-20-methyl-3-phenyl-20,30-dihydro-3H-spiro[[1,3,4]thiadiazole-2,40-
thieno[3,2-c]chromene] 9a–d as two unisolable diastereoisomeric forms. The structures
of the obtained spiro cycloadduct thiadiazoles have been assigned by means of
spectroscopic measurements.
Keywords:
1,3-Dipolar cycloaddition
Diarylnitrilimines
Regioselective
Spiro cycloadduct thiadiazoles
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
antihistaminic [12], insecticidal [13], and antithrombotic
activity [14]. The fused chromene-2-thione derivatives
The resistance towards available drugs is rapidly
becoming a major worldwide problem. The need to design
new compounds to deal with this resistance has become
one of the most important areas of research today.
Thiadiazoles have been of great interest as antitumor
compounds for several scores of years [1–3]. Recent
literature shows that 1,3,4-thiadiazole derivatives have
received considerable attention due to their synthesis and
biological importance. They exhibit a wide spectrum of
interesting pharmacological properties, such as antic-
onvulsant [4], antituberculosis [5], analgesic [6], and
leishmanicidal [7] activities, in addition to cytotoxic effects
(on human non-small cell lung cancer A549) [8] as well as
potent and selective PDE7 inhibitors [9]. Moreover,
compounds bearing the 1,2,3-thiadiazole ring system have
been reported to show antifungal [10], antitumor [11],
show various biological properties, including anticoagu-
lant [15], anti-inflammatory and HIV-1[16] activities.
1,3-Dipolar cycloaddition is one of the most useful
reactions for the synthesis of five-membered ring hetero-
cycles [17,18], due to a high degree of site-, regio- and
stereoselectivity. Furthermore, these reactions have
attracted the attention of chemists from the standpoint
of reaction mechanisms. Nitrilimines are known to be
among the active dipoles in 1,3-dipolar reactions, and have
been extensively investigated from the viewpoint of
synthetic utility and of elucidation of the reaction
mechanism of 1,3-dipolar reactions [19,20].
The present work is prompted by the previously well-
established results, describing the regioselective behavior
of aromatic nitrilimines with thione-containing com-
pounds. In this context, we investigated the alkylation of
4-mercapto-2H-chromene-2-thione 1, as this was
expected to provide dipolarophiles 2 and 3 with better
yields and was successfully used as suitable starting
materials for implementing this goal. The cycloaddition of
*
Corresponding author.
E-mail address: hichem.benjannet@yahoo.fr (H.B. Jannet).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.08.004

172
I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
diarylnitrilimines to the C5S double bond compound 2
was strictly regioselective and afforded a mixture of both
regioisomer of new spiro cycloadduct thiadiazoles 5a–d
and 6a–d. In similar reaction conditions, 4-(allylthio)-2H-
spirothiadiazoles skeleton. Indeed, the mass spectra
recorded in ES+ mode are identical and showed for both
compounds the molecular ion peaks [M+H]+ at m/z 448.1.
Moreover, the assignment of regiochemistry to 5c and 6c
chromene-2-thione
3
proceeded with exclusive site
cannot be differentiated by analysis of standard 1H and 13
C
selectivity, via 1,3-dipolar cycloaddition, and afforded
only the major regioisomers of the mixture spiro-
chromene[1,3,4]thiadiazoles 7a–d and 9a–d.
NMR spectra. For this reason, the only difference in
cyclization between the two compounds occurred at the C-
2 spiro center, as judged by the NOESY experiments, by the
observation of a dipolar interaction between the ethylenic
proton H-3 and aromatic protons fixed at the nitrogen,
which confirms the structure of the cycloadduct 6c.
On the other hand, the 13C NMR, reinforced by HMBC for
derivative 6c, indicates the presence of characteristic
signals based on their chemical shifts, readily assigned the
2. Results and discussion
Our first key intermediate was the 4-(methylthio)-2H-
chromene-2-thione 2, which was obtained in good yield
(70%) by stirring a mixture of 4-mercapto-2H-chromene-
2-thione 1 and (5 equiv) N,N,dimethylformamide dimethyl
acetal (DMFDMA) [21] during 3 h in dry toluene (Scheme
1). The mass spectrum, recorded in ESI–HRMS, showed for
product 2 the molecular ion peak [M+H]+ at m/z 209.0096,
which is consistent with the molecular formula of
new spiro center C-2 and the iminic carbon C-50 at
dC 112.5
and at 138.6 ppm, respectively. Additional supports for our
assignments were provided by a HMBC experiment that
revealed significant correlations between the aromatic
protons H-200,600 with carbons C-50 (138.6 ppm) and C-400
(146,7 ppm). The same spectrum showed the correlation of
the ethylenic proton H-3 with both quaternary carbons C-2
and C-4a at 138.6 ppm and at 118,6 ppm, respectively.
On the other hand, the comparison of the 13C NMR data
of the spiro cycloadduct 5c to those of 6c suggest that this
compound did not have the same regiochemistry, showing
the new generated spirocyclic quaternary carbon C-2 at dC
100.9 ppm and the iminic carbon C-40 at dC 149.0 ppm.
However, the relative deshielding of the iminic carbon (C-
40 dC 149.0 ppm) in cycloadduct 5c, due to the absence of
the sulfur atom, reinforces the proposed structure. The
reaction is thus regioselective.
C
10H9OS2, as well as the 1H NMR spectrum showed a
singlet at 2.56 ppm, corresponding to the methyl group.
Likewise, we have studied the behavior of derivative 1
with an excess of allyl bromide [22] in the presence of
potassium carbonate under refluxing dry CHCl3; the S-
alkylation process took place and gave the 4-(allylthio)-
2H-chromen-2-thione 3 (Scheme 1). Compatible ESI–
HRMS and spectral measurements for this compound
were gained (See Experimental section).
A survey of the literature revealed a lack of information
related to the synthesis of two regioisomer spirothiadia-
zoles via the 1,3-dipolar cycloaddition reaction. Most of the
work that we have found described the condensation of
dipolarophile (C5S) with an equivalent amount of a
diarylnitrilimine as a route to the only spiro cycloadduct
[23–25].
Thus, prompted by these findings, we studied the
condensation of the 4-(methylthio)-2H-chromene-2-
thione 2, under refluxing dry chloroform, with a stoichio-
metric amount of diarylnitrilimines (generated in situ via
triethylamine dehydrohalogenation of the corresponding
hydrazonoyl chlorides 4a–d) [26], completed in 24 h as
shown by TLC, and afforded, in each case, two regioisomer
products (Scheme 2). The structure of the isolated products
were established to be 40-(4-R-phenyl)-4-(methylthio)-20-
phenyl-20H-spiro[chromene-2,50-[1,2,3]thiadiazole] 5a–d
and 50-(4-R-phenyl)-4-(methylthio)-30-phenyl-30H-spiro[-
chromene-2,20-[1,3,4]thiadiazole] 6a–d based on the
spectroscopic measurements (1H, 13C NMR, 2D and ESI–
HRMS).
Analogously, 4-(allylthio)-2H-chromene-2-thione
3
reacted with a series of diarylnitrilimines 4a–d [26] under
the same previously described reaction conditions, and
gave two types of spiroheterocycles, 7a–d and 9a–d. For
example, the two spiroheterocycles 7c and 9c were
obtained in the amount of the product ratio 14:75. Once
again, the spiroheterocycles 7c and 9c were obtained
preferentially. Indeed, the 1,3-dipolar cycloaddition reac-
tion did not afford the corresponding regioisomer
cycloadducts 8c and 10c, which could be formed as
minors; it was difficult to isolate them quantitatively
(Scheme 3).
The structures of cycloadducts 7a–d and 9a–d were
confirmed on the basis of their spectroscopic data (ES–MS,
1H, and 13C NMR). Indeed, the mass spectrum recorded in
ES+ mode showed for both products 7c and 9c molecular
ion peaks [M+H]+ at m/z = 474.1. Furthermore, the struc-
tural assignment of the products 7c and 9c was made on
the basis of 1H and 13C NMR spectral analysis and by
comparison of their spectroscopic data with those reported
The comparison of the spectral data of the cycloadducts
5c and 6c shows that the two compounds have the same
Scheme 1. S-Alkylation of 4-mercapto-2H-chromene-2-thione 1.

I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
173
Scheme 2. Synthesis of spiro-chromene[1,2,3]thiadiazole 5a–d and spiro-chromene[1,3,4]thiadiazole 6a–d.
Scheme 3. Synthesis of spiro-chromene[1,3,4]thiadiazoles 7a–d and 9a–d.

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I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
Scheme 4. Proposed mechanism for the synthesis of 2-methyl-2H-thieno[3,2-c]chromene-4(3H)-thione 13.
for related systems. In particular, 1H NMR analysis clearly
indicated that the cycloadduct 7c maintains the allylic
system. In addition, the 13C NMR spectrum showed two
signals at dC 113.3 and 139.6 ppm, attributable to the
spirocarbon C-2 and to the iminic carbon C-50, respectively.
This value located the spiro center near the electronegative
nitrogen atom of the thiadiazole ring.
starting from the rearranged compound 13 formed as
explained in Scheme 4 [27,28], we subjected compound 3
under reflux of chloroform in the absence of the
diarylnitrilimines, and we also applied the same conditions
to compound 7c. This allowed us to conclude that
cycloadducts 9a–d could be obtained at the same time
from the reaction of cycloaddition on the rearranged 2-
methyl-2H-thieno[3,2-c]chromene-4(3H)-thione 13 and
from the rearrangement of compounds 7a–d.
Indeed, the 1H NMR spectrum of 9c revealed the two
methyl groups as two doublet signals at dH 1.06 and 1.37,
corresponding to the major (CH3b, J = 6.6 Hz) and minor
(CH3a, J = 6.6 Hz) diasterioisomers, respectively, together
3. Conclusion
with a multiplet signal at
2a,b. In addition, the major diasterioisomer H-3b exhibits
two closely spaced doublet of doublets ( H 2.76 J = 15.6 Hz,
dH 3.81 relative to the proton H-
In this paper, we described the two-step synthesis of an
interesting rigid heterosystem with a strategy that allows
the development of a new series of novel spiro-chromene
thiadiazole derivatives in a fast way through the cycload-
ditions of diarylnitrilimines to the C5S double bond. The
fusion of two biologically relevant systems as they are, the
thiadiazole ring along with the S-alkyl chromene-2-thione
system spirojoined, may make them excellent compounds
for bioactivity trials.
d
J = 6.9 Hz and dH 2.83 J = 16.2 Hz, J = 8.1 Hz), while the
minor diasterioisomer H-3a exhibits two widely spaced
doublet of doublets (dH 2.28 J = 16.5 Hz, J = 3.6 Hz and dH
3.21 J = 16.5 Hz, J = 8.7 Hz). The same spectrum showed
two doublets at dH 7.98 (J = 8.1 Hz, H-200,600) and 8.17
(J = 8.1 Hz, H-300,500) in addition to the multiplet for the
aromatic protons at dH 6.91–7.39 ppm.
The 13C NMR spectrum of 9c was also a good support for
the proposed structure, since it exhibited characteristic
signals at dC 22.5; 23.5, 44.0; 44.3 and 44.4 ppm,
corresponding to the carbons of the methyl groups, to C-
3a,b and C-2a,b of the 2-methyl-2,3-dihydrothiophene
moiety, respectively. Furthermore, the comparison of the
13C NMR data of spirothiadiazole 9c with those of
compound 7c confirmed that compound 9c shows the
same regiochemistry, with the spiro carbon C-4 appearing
at dC 113.8 ppm. Moreover, the regiochemistry was also
confirmed by the NOE observed between the protons
CH3a,b and H-2a,b and the aromatic protons fixed at the
nitrogen.
4. Experimental
Melting points were taken on a Bu¨chi-510 capillary
melting point apparatus. 1H (300 MHz) and 13C (75 MHz)
NMR spectra were recorded with AC-300 Bruker spectro-
meters. HRMS spectra were acquired with an ESI–TOF (LCT
Premier XE, Waters) using the reflectron mode in the
positive ion mode. Leucine–enkephaline peptide was
employed as the LockSpray lockmass. Commercial TLC
plates (Silica gel 60, F254, SDS) were used to monitor the
progress of the reaction. Column chromatography analysis
With the aim of understanding if compounds 9a–d
were obtained starting from compounds 7a–d or directly
was performed with silica gel 60 (particle size 40–63
SDS).
mm,

I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
175
4.1. General procedure for the reaction of the 4-mercapto-
4.3.1. 4-(Methylthio)-20,40-diphenyl-20H-spiro[chromene-
2,50-[1,2,3]thiadiazole] (5a)
2H-chromene-2-thione 1 with DMFDMA
Orange solid, yield 15%, mp 103 8C (CH2Cl2/EP, 2:8). 1H
To a stirred suspension of compound 1 (1 g, 1 mol) in
dry toluene (70 mL), an excess of N, N-dimethylformamide
dimethylacetal (12 mL, 5 equiv.) was added. The mixture
was heated at 100 8C for almost 3 h. After the removal of
the volatile components in vacuo, the purification of the
obtained brownish oily residue on silica gel (ether
petroleum/ethyl acetate as 7:3 v/v) afforded 2 as an
orange powder.
NMR (300 MHz, CDCl3): dH 2.35 (s, 3H, CH3), 5.23 (s, 1H, H-
3), 6.89–7.13 (m, 5H, H-2000,4000,6000,6,8), 7.32–7.63 (m, 7H,
H-300,3000,400,500,5000,5,7), 7.94 (d, 2H, J = 8.1 Hz, H-200,600). 13C
NMR (75 MHz, CDCl3): dC 14.4 (CH3), 101.0 (C-3), 101.0 (C-
2), 116.0 (C-6), 117.6 (C-4000), 122.0 (C-4a), 123.5 (C-
2000,6000), 124.8 (C-8), 126.1 (C-3000,5000), 128.2 (C-200,600),
128.2 (C-300,500), 128.6 (C-5), 129.5 (C-7), 137.2 (C-4), 142.0
(C-100), 146.7 (C-1000), 148.0 (C-400), 149.0 (C-40), 150.0 (C-
8a). ESI–HRMS: m/z [M+H]+ calcd for (C23H19N2OS2)+:
403.0939; found: 403.0937.
4.1.1. 4-(Methylthio)-2H-chromene-2-thione (2)
Orange powder, yield 70%, mp 179 8C (CH2Cl2/EP, 2:8).
1H NMR (300 MHz, CDCl3):
d
H 2.56 (s, 3H, CH3), 7.06 (s, 1H,
4.3.2. 40-(4-Chlorophenyl)-4-(methylthio)-20-phenyl-20H-
spiro[chromene-2,50-[1,2,3]thiadiazole] (5b)
H-3), 7.32 (t, 1H, J = 8.1 Hz, H-6), 7.47 (m, 1H, H-8), 7.59 (t,
1H, J = 8.4 Hz, H-7), 7.79 (d, 1H, J = 8.1 Hz, H-5). 13C NMR
(75 MHz, CDCl3): dC 14.0 (CH3), 117.2 (C-3), 119.3 (C-8),
120.6 (C-7), 123.6 (C-5), 125.2 (C-4a), 132.6 (C-6), 151.5 (C-
8a), 154.3 (C-4), 194.2 (C-2). ESI–HRMS: m/z [M+H]+ calcd
for (C10H9OS2)+: 209.0095; found: 209.0096.
Pale yellow solid, yield 16%, mp 115 8C (CH2Cl2/EP, 2:8).
1H NMR (300 MHz, CDCl3):
dH 2.35 (s, 3H, CH3), 5.23 (s, 1H,
H-3), 6.89–7.13 (m, 5H, H-2000,4000,600,6,8), 7.32–7.63 (m, 6H,
H-2000,3000,5000,5,600,7), 7.94 (d, 2H, J = 8.1 Hz, H-300,500). 13C
NMR (75 MHz, CDCl3):dC 14.4 (CH3), 101.8 (C-3), 101.8 (C-
20)0,0 116.0 (C-6), 117.6 (C-4000), 120.0 (C-4a), 123.5 (C-
4.2. Reaction of compound 1 with allylic halide
2
,300,500,6000), 124.8 (C-8), 126.1 (C-3000,5000), 128.2 (C-
200,600), 128.6 (C-5), 130.0 (C-7), 137.2 (C-4), 142.0 (C-100),
147.0 (C-1000), 148.0 (C-400), 149.0 (C-40), 150.0 (C-8a). ESI–
HRMS: m/z [M+H]+ calcd for (C23H18N2OS2Cl)+: 437.0549;
found: 437.0553.
An excess of allyl bromide was added to a solution of
compound 1 (0.5 g, 0.25 mmol) and 0.11 mmol of anhy-
drous potassium carbonate in dry CHCl3 (30 mL). The
mixture was refluxed for 24 h. The residue obtained after
removing the solvent in vacuo was chromatographed on
silica gel, employing ether petroleum/dichloromethane;
1:1, as an eluent. Crystallization from (CH2Cl2/EP, 2:8)
gives orange cottony 3.
4.3.3. 4-(Methylthio)-40-(4-nitrophenyl)-20-phenyl-20H-
spiro[chromene-2,50-[1,2,3]thiadiazole] (5c)
Orange solid, yield 18%, mp 144 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3): dH 2.39 (s, 3H, CH3), 5.57 (s, 1H, H-
30)0,0 6.95 (m, 1H, H-6), 7.09–7.20 (m, 6H, H-
4.2.1. 4-(Allylthio)-2H-chromene-2-thione (3)
2
,3000,4000,5000,6000,8), 7.35 (m, 1H, H-7), 7.81 (m, 3H, H-
Orange cottony, yield 64%, mp 131 8C (CH2Cl2/EP, 2:8).
200,5,600), 8.27 (d, 2H, J = 8.1 Hz, H-300,500). 13C NMR (75 MHz,
CDCl3): C 13.9 (CH3), 100.9 (C-3), 100.9 (C-2), 116.0 (C-6),
1H NMR (300 MHz, CDCl3):
d
H 3.75 (d, 2H, J = 7.5 Hz, CH2),
d
5.37 (dd, 1H, J = 12.0 Hz, J = 1.2 Hz, –CH5CH2(a)), 5.48 (dd,
1H, J = 16.8 Hz, J = 1.2 Hz,–CH5CH2(b)), 5.95 (m, 1H,–CH2–
CH5), 7.12 (s, 1H, H-3), 7.33 (m, 1H, H-6), 7.46 (dd, 1H,
J = 8.4 Hz, J = 1.2 Hz, H-8), 7.60 (m, 1H, H-7), 7.76 (dd, 1H,
J = 8.1 Hz, J = 1.5 Hz, H-5). 13C NMR (75 MHz, CDCl3): dC
34.1 (CH2), 117.5 (C-3), 119.8 (C-4a), 120.7 (C-8), 121.8 (–
CH5CH2), 124.0 (C-6), 125.5 (C-5), 130.3 (–CH2–CH5),
132.9 (C-7), 150.1 (C-4), 154.9 (C-8a), 194.4 (C-2). ESI–
HRMS: m/z [M+H]+ calcd for (C12H11OS2)+: 235.0251;
found: 235.0242.
117.6 (C-4000), 122.0 (C-4a), 123.5 (C-2000,300,500,6000), 124.8
(C-8), 126.1 (C-3000,5000), 128.2 (C-200,600), 128.6 (C-5), 130.0
(C-7), 137.2 (C-4), 142.0 (C-100), 147.0 (C-1000), 148.0 (C-400),
149.0 (C-40), 150.0 (C-8a). ESI–HRMS: m/z [M+H]+ calcd for
(C23H18N3O3S2)+: 448.0790; found: 448.0794.
4.3.4. 4-(Methylthio)-20-phenyl-40-(p-tolyl)-20H-
spiro[chromene-2,50-[1,2,3]thiadiazole] (5d)
Yellow solid, yield 20%, mp 166 8C (CH2Cl2/EP, 2:8). 1
H
NMR (300 MHz, CDCl3): dH 2.35 (s, 3H, CH3), 2.80 (s, 3H,
CH3–Ph), 5.23 (s, 1H, H-3), 6.89–7.13 (m, 5H, H-
2000,4000,6000,6,8), 7.32–7.63 (m, 6H, H-300,3000,500,5000,5,7),
7.94 (d, 2H, J = 8.1 Hz, H-200,600). 13C NMR (75 MHz, CDCl3):
4.3. Synthesis of compounds 5a–d and 6a–d (general
procedure)
d
C 14.4 (CH3), 21.3 (CH3–Ph), 100.8 (C-3), 100.8 (C-2), 116.0
A
mixture of
2
(1 mmol) and the appropriate
(C-6), 117.6 (C-4000), 122.0 (C-4a), 124.8 (C-8), 126.1 (C-
3000,5000), 128.2 (C-2000,300,500,6000), 128.2 (C-200,600), 128.6 (C-
5), 130.0 (C-7), 137.2 (C-4), 142.0 (C-100), 147.0 (C-1000),
148.0 (C-400), 149.0 (C-40), 150.0 (C-8a). ESI–HRMS: m/z
[M+H]+ calcd for (C24H21N2OS2)+: 417.1017; found:
417.1022.
hydrazonoyl chloride 4a–d (1 mmol) in anhydrous CHCl3
(20 mL) containing triethylamine (1 mmol) was boiled
under reflux for 24 h. The formed triethylamine hydro-
chloride was separated by filtration and the clear
reaction mixture was evaporated till dryness under
reduced pressure. After completion of the reaction, the
resulting crude brownish oil was chromatographed on
silica gel and eluted with (ether petroleum/dichloro-
methane; 1:1). This allowed the separation of com-
pounds 5a–d and 6a–d.
4.3.5. 4-(Methylthio)-30,50-diphenyl-30H-spiro[chromene-
2,20-[1,3,4]thiadiazole] (6a)
Orange solid, yield 78.5%, mp 177 8C (CH2Cl2/EP, 2:8).
1H NMR (300 MHz, CDCl3):
dH 2.39 (s, 3H, CH3), 5.76 (s, 1H,

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I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
H-3), 6.99 (d, 1H, J = 8.1 Hz, H-6), 7.10 (m, 2H, H-5000,8), 7.32
(m, 3H, H-3000,6000,7), 7.41 (m, 2H, H-2000,7000), 7.56 (m, 4H, H-
300,400,500,5), 7.73 (m, 2H, H-200,600). 13C NMR (75 MHz,
was added at room temperature to 1 equiv of triethyla-
mine. The reaction medium was heated to 75 8C and kept
under reflux for 24 h (TLC). The inorganic salts were
filtered off; the filtrate was evaporated in vacuo. Chroma-
tography of the brownish oily residue on silica gel eluting
with (ether petroleum/dichloromethane; 1:1) allowed the
separation of compounds 7a–d and 9a–d.
CDCl3): dC 14.0 (CH3), 112.6 (C-3), 112.6 (C-2), 117.9 (C-6),
118.8 (C-2000,7000), 119.8 (C-4a), 122.6; 122.7 (C-8, 5000),
123.9 (C-5), 126.5 (C-300,500), 128.6 (C-200,600), 128.7 (C-
3000,6000), 129.5 (C-7), 130.8 (C-100), 131.3 (C-400), 137.1 (C-4),
142.1 (C-50), 142.2 (C-1000), 149.7 (C-8a). ESI–HRMS: m/z
[M+H]+ calcd for (C23H19N2OS2)+: 403.0939; found:
403.0949.
4.4.1. 4-(Allylthio)-30,50-diphenyl-30H-spiro[chromene-2,20-
[1,3,4]thiadiazole] (7a)
Orange powder, yield 12%, mp 160 8C (CH2Cl2/EP, 2:8).
4.3.6. 50-(4-Chlorophenyl)-4-(methylthio)-30-phenyl-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (6b)
1H NMR (300 MHz, CDCl3):
dH 3.53 (m, 2H, CH2), 5.14 (dd,
1H, J = 10.0 Hz, J = 1.2 Hz, –CH5CH2(a)), 5.21 (dd, 1H,
J = 16.8 Hz, J = 1.2 Hz, –CH5CH2(b)), 5.86 (m, 1H, –CH2–
CH5), 5.97 (s, 1H, H-3), 6.99 (m, 1H, H-6), 7.11 (m, 2H, H-
4000,8), 7.28–7.35 (m, 6H, H-2000,3000,5000,5,6000,7), 7.54 (m, 3H,
H-300,400,500), 7.63 (m, 2H, H-200,600). 13C NMR (75 MHz,
Pale yellow solid, yield 80.5%, mp 192 8C (CH2Cl2/EP,
2:8). 1H NMR (300 MHz, CDCl3):
dH 2.38 (s, 3H, CH3), 5.73
(s, 1H, H-3), 6.98 (d, 1H, J = 8.1 Hz, H-6), 7.10 (m, 2H, H-
5000,8), 7.33 (m, 3H, H-3000,6000,7), 7.38 (d, 2H, J = 8.1 Hz, H-
200,600), 7.54 (m, 3H, H-2000,5,7000), 7.61 (d, 2H, J = 8.1 Hz, H-
CDCl3): dC 33.8 (CH2), 114.0 (C-2), 116.1 (C-3), 117.5 (C-8),
300,500). 13C NMR (75 MHz, CDCl3):
d
C 14.0 (CH3), 112.3 (C-
118.5 (C-2000,6000), 118.5 (–CH5CH2), 119.4 (C-4a), 122.3 (C-
4000), 122.4 (C-6), 124.0 (C-5), 127.1 (C-300,500), 128.2 (C-
3000,5000), 128.3 (C-200,600), 129.4 (C-400), 130.3 (–CH2–CH5),
131.7 (C-7), 134.0 (C-100), 134.8 (C-4), 140.5 (C-50), 141.3
(C-1000), 149.3 (C-8a). ESI–HRMS: m/z [M+H]+ calcd for
(C25H21N2OS2)+: 429.1095; found: 429.1105.
3), 113.0 (C-2), 117.9 (C-6), 118.8 (C-8,5000), 119.7 (C-4a),
122.7 (C-2000,7000), 123.0 (C-5), 127.6 (C-300,500), 128.7 (C-
200,600), 128.8 (C-3000,6000), 129.9 (C-100), 130.1 (C-7), 135.3 (C-
400), 137.4 (C-4), 141.0 (C-50), 141.9 (C-1000), 149.5 (C-8a).
ESI–HRMS: m/z [M+H]+ calcd for (C23H18N2OS2Cl)+:
437.0549; found: 437.0538.
4.4.2. 4-(Allylthio)-50-(4-chlorophenyl)-30-phenyl-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (7b)
4.3.7. 4-(Methylthio)-50-(4-nitrophenyl)-30-phenyl-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (6c)
Brown solid, yield 21%, mp 106 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3): dH 3.53 (m, 2H, CH2), 5.14 (dd,
1H, J = 9.0 Hz, J = 0.9 Hz, –CH = CH2(a)), 5.21 (dd, 1H,
J = 16.8 Hz, J = 0.9 Hz, –CH = CH2(b)), 5.86 (m, 1H, –CH2–
CH5), 5.97 (s, 1H, H-3), 6.99 (d, 1H, J = 8.1 Hz, H-6), 7.11
(m, 2H, H-4000,8), 7.28–7.37 (m, 5H, H-2000,3000,5000,6000,7),
7.54 (d, 2H, J = 7.8 Hz, H-300, 500), 7.63 (m, 3H, H-200,5,600).
13C NMR (75 MHz, CDCl3): dC 33.8 (CH2), 112.2 (C-2),
116.1 (C-3), 117.5 (C-8), 118.5 (C-2000,6000), 118.5 (–
CH5CH2), 119.4 (C-4a), 122.3 (C-4000), 122.4 (C-6), 124.0
(C-5), 127.1 (C-300,500), 128.2 (C-3000,5000), 128.3 (C-200,600),
129.4 (C-100), 130.3 (–CH2–CH5), 131.4 (C-7), 134.4 (C-
400), 134.8 (C-4), 140.5 (C-50), 141.3 (C-1000), 149.3 (C-8a).
ESI–HRMS: m/z [M+H]+ calcd for (C25H20N2OS2Cl)+:
463.0706; found: 463.0692.
Orange solid, yield 92%, mp 208 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3): dH 2.29 (s, 3H, CH3), 6.87 (s, 1H, H-
3), 6.90 (d, 1H, J = 8.1 Hz, H-6), 7.03 (m, 2H, H-5000,8), 7.22
(m, 1H, H-7), 7.24 (m, 2H, H-3000,6000), 7.46 (m, 3H, H-
2000,5,7000), 7.73 (d, 2H, J = 8.1 Hz, H-200, 600), 8.16 (d, 2H,
J = 8.1 Hz, H-300, 500). 13C NMR (75 MHz, CDCl3): dC 13.0
(CH3), 110.8 (C-3), 112.5 (C-2), 116.8 (C-6), 118.1 (C-
2000,7000), 118.6 (C-4a), 122.4; 122.6 (C-8, 5000), 122.9 (C-
300,500), 122.9 (C-5), 125.8 (C-200,600), 127.7 (C-3000,6000), 130.0
(C-7), 136.5 (C-100), 136.8 (C-4), 138.6 (C-50), 140.4 (C-1000),
146.7 (C-400), 148.1 (C-8a). ESI–HRMS: m/z [M+H]+ calcd for
(C23H18N3O3S2)+: 448.0790; found: 448.0789.
4.3.8. 4-(Methylthio)-30-phenyl-50-(p-tolyl)-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (6d)
Yellow solid, yield 85%, mp 170 8C (CH2Cl2/EP, 2:8). 1
H
4.4.3. 4-(Allylthio)-50-(4-nitrophenyl)-30-phenyl-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (7c)
NMR (300 MHz, CDCl3): dH 2.38 (s, 3H, CH3), 2.80 (s, 3H,
CH3–Ph), 5.73 (s, 1H, H-3), 6.98 (d, 1H, J = 8.1 Hz, H-6), 7.10
Red solid, yield 14%, mp 109 8C (CH2Cl2/EP, 2:8). 1H
(m,
2H,
H-5000,8),
7.33–7.54
(m,
8H,
H-
NMR (300 MHz, CDCl3): dH 3.42 (m, 2H, CH2), 5.03 (dd, 1H,
2000,300,3000,500,5,6000,7,7000), 7.61 (d, 2H, J = 8.1 Hz, H-200,600).
13C NMR (75 MHz, CDCl3): dC 14.0 (CH3), 21.3 (CH3–Ph),
112.3 (C-3), 113.0 (C-2), 117.9 (C-6), 118.8 (C-8,5000), 119.7
(C-40a0), 122.7 (C-2000,7000), 123.0 (C-5), 127.6 (C-300,500), 127.6
(C-2 ,600), 128.8 (C-3000,6000), 129.9 (C-100),130.1 (C-7), 135.3
(C-400),137.4 (C-4), 141.0 (C-50), 141.9 (C-1000), 149.5 (C-8a).
ESI–HRMS: m/z [M+H]+ calcd for (C24H21N2OS2)+:
417.1017; found: 417.1022.
J = 10.2 Hz, J = 1.2 Hz,–CH5CH2(a)), 5.12 (dd, 1H,
J = 16.8 Hz, J = 1.2 Hz,–CH5CH2(b)), 5.71 (m, 1H,–CH2–
CH5), 5.79 (s, 1H, H-3), 6.88 (m, 1H, H-6), 7.02 (m, 2H,
H-4000,8), 7.22 (m, 1H, H-7), 7.24 (m, 2H, H-3000,5000), 7.41 (m,
2H, H-2000,6000), 7.51 (dd, 1H, J = 8.1 Hz, J = 1.5 Hz, H-5), 7.71
(d, 2H, J = 8.1 Hz, H-200,600), 8.14 (d, 2H, J = 8.1 Hz, H-300,500).
13C NMR (75 MHz, CDCl3):
dC 34.3 (CH2), 113.3 (C-2), 115.8
(C-3), 117.9 (C-8), 119.3 (–CH5CH2), 119.7 (C-2000,6000),
120.3 (C-4a), 123.0 (C-4000), 123.6 (C-6), 123.9 (C-200,600),
124.5 (C-5), 126.8 (C-300,500), 128.8 (C-3000,5000), 131.0 (C-7),
131.8 (–CH2–CH5), 135.5 (C-100), 137.5 (C-4), 139.6 (C-50),
141.4 (C-1000), 147.8 (C-400), 149.4 (C-8a). ESI–HRMS: m/z
[M+H]+ calcd for (C25H20N3O3S2)+: 474.0946; found:
474.0936.
4.4. Preparation of compounds 7a–d and 9a–d (general
procedure)
A mixture of 2 (1 mmol) and the appropriate hydrazo-
noyl chloride 4a–d (1 mmol) in anhydrous CHCl3 (20 mL)

I. Zghab et al. / C. R. Chimie 17 (2014) 171–178
177
4.4.4. 4-(Allylthio)-30-phenyl-50-(p-tolyl)-30H-
spiro[chromene-2,20-[1,3,4]thiadiazole] (7d)
1.37 (d, 3H, J = 6.6 Hz, CH3b), 2.28 (dd, 1H, J = 16.5 Hz,
J = 3.6 Hz, H-3a), 2.76 (dd, 1H, J = 15.6 Hz, J = 6.9 Hz, H-3b),
2.83 (dd, 1H, J = 16.2 Hz, J = 8.1 Hz, H-3b), 3.21 (dd, 1H,
J = 16.5 Hz, J = 8.7 Hz, H-3a), 3.81 (m, 2H, H-2a,b), 6.91 (m,
1H, H-6), 7.03 (m, 1H, H-9), 7.06 (m, 2H, H-2000,6000), 7.18 (m,
1H, H-7), 7.24 (m, 2H, H-3000,5000), 7.39 (m, 2H, H-4000,8), 7.98
(d, 2H, J = 8.1 Hz, H-200,600), 8.17 (d, 2H, J = 8.1 Hz, H-300,500).
Yellow solid, yield 19%, mp 140 8C (CH2Cl2/EP, 2:8). 1
H
NMR (300 MHz, CDCl3): dH 3.42 (m, 2H, CH2), 5.03 (dd, 1H,
J = 9.0 Hz, J = 0.9 Hz,–CH5CH2(a)), 5.12 (dd, 1H, J = 16.8 Hz,
J = 0.9 Hz,–CH5CH2(b)), 5.71 (m, 1H,–CH2–CH5), 5.79 (s,
1H, H-3), 6.88 (m, 1H, H-6), 7.02 (m, 2H, H-4000,8), 7.20–7.51
(m, 8H, H-2000,300,3000,5,500,5000,6000,7), 7.63 (d, 2H, J = 8.1 Hz, H-
13C NMR (75 MHz, CDCl3):
dC 22.5 (CH3a), 23.5 (CH3b), 44.0
200,600). 13C NMR (75 MHz, CDCl3):
d
C 21.3 (CH3), 34.3 (CH2),
(C-3a), 44.3 (C-3b), 44.4 (C-2), 113.8 (C-4), 116.9 (C-6),
117.9 (C-4000), 118.4 (C-2000,6000), 119.7 (C-3a), 120.2 (C-9a),
122.9 (C-8), 123.9 (C-300,500), 125.3; 125.4 (C-9), 126.8 (C-
200,600), 128.9; 129.0 (C-3000,5000), 130.7 (C-7), 137.5; 137.6
(C-100), 138.6; 138.7 (C-9b), 139.2; 139.3 (C-50), 141.2;
141.4 (C-1000), 147.8 (C-400), 149.8 (C-5a). ESI–HRMS: m/z
[M+H]+ calcd for (C25H20N3O3S2)+: 474.0946; found:
474.0934.
114.0 (C-2), 115.8 (C-3), 117.9 (C-8), 119.3 (–CH5CH2),
119.7 (C-2000,6000), 120.3 (C-4a), 123.0 (C-4000), 123.6 (C-6),
124.5 (C-5), 126.8 (C-300,500), 126.8 (C-200,600), 128.8 (C-
3000,5000), 131.0 (C-7), 131.8 (–CH2–CH5), 135.5 (C-100),
137.5 (C-4), 137.7 (C-400), 139.6 (C-50), 141.4 (C-1000), 149.4
(C-8a). ESI–HRMS: m/z [M+H]+ calcd for (C26H23N2OS2)+:
443.1207; found: 443.1211.
4.4.5. 20-Methyl-3,5-diphenyl-20,30-dihydro-3H-
4.4.8. 20-Methyl-3-phenyl-5-(p-tolyl)-20,30-dihydro-3H-
spiro[[1,3,4]thiadiazole-2,40-thieno[3,2-c]chromene] (9d)
spiro[[1,3,4]thiadiazole-2,40-thieno[3,2,c]chromene] (9a)
Red crystals, yield 89%, mp 190 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3): dH 1.09 (d, 3H, J = 6.6 Hz, CH3a),
1.36 (d, 3H, J = 6.6 Hz, CH3b), 2.31 (dd, 1H, J = 16.5 Hz,
J = 3.0 Hz, H-3a), 2.76 (dd, 1H, J = 16.2 Hz, J = 6.6 Hz, H-3b),
2.83 (dd, 1H, J = 16.5 Hz, J = 8.1 Hz, H-3b), 3.24 (dd, 1H,
J = 16.5 Hz, J = 8.7 Hz, H-3a), 3.80 (m, 2H, H-2a,b), 6.82–7.21
(m, 4H, H-4000,6,7,8), 7.25–7.30 (m, 5H, H-2000,3000,5000,6000,9),
7.38–7.41 (m, 3H, H-300,400,500), 7.51 (m, 2H, H-200,600). 13C
Yellow solid, yield 70%, mp 156 8C (CH2Cl2/EP, 2:8). 1
H
NMR (300 MHz, CDCl3): dH 1.07 (d, 3H, J = 6.6 Hz, CH3a),
1.36 (d, 3H, J = 6.6 Hz, CH3b), 2.34 (s, 3H, CH3), 2.31 (dd, 1H,
J = 16.5 Hz, J = 3.6 Hz, H-3a), 2.71 (dd, 1H, J = 15.6 Hz,
J = 6.9 Hz, H-3b), 2.84 (dd, 1H, J = 16.2 Hz, J = 8.1 Hz, H-
3b), 3.21 (dd, 1H, J = 16.5 Hz, J = 8.7 Hz, H-3a), 3.80 (m, 2H,
H-2a,b), 6.88 (m, 1H, H-6), 7.01 (m, 1H, H-9), 7.06 (m, 2H,
H-2000,6000), 7.14 (m, 1H, H-7), 7.18 (m, 2H, H-3000,5000), 7.39
(m, 2H, H-4000,8), 7.30 (d, 2H, J = 8.1 Hz, H-300,500), 7.85 (d,
NMR (75 MHz, CDCl3): dC 22.9 (CH3a), 23.5 (CH3b), 42.9 (C-
3a), 43.0 (C-3b), 44.4 (C-2), 114.4 (C-4), 116.9 (C-6), 117.5
(C-4000), 117.9 (C-2000,6000), 122.0 (C-3a), 122.2 (C-9a), 122.7
(C-8), 125.1 (C-9), 126.4 (C-300,500), 128.6 (C-3000,5000), 128.6
(C-200,600), 129.0 (C-400), 129.6 (C-100), 130.4 (C-7), 137.9;
138.1 (C-9b), 140.5; 140.7 (C-50), 141.8; 142.0 (C-1000),
150.2 (C-5a). ESI–HRMS: m/z [M+H]+ calcd for
(C25H21N2OS2)+: 429.1095; found: 429.1104.
2H, J = 8.1 Hz, H-200,600). 13C NMR (75 MHz, CDCl3):
dC 21.3
(CH3), 22.6 (CH3a), 23.6 (CH3b), 43.0 (C-3a), 44.3 (C-3b),
44.4 (C-2), 114.4 (C-4), 116.9 (C-6), 117.0 (C-4000), 117.9 (C-
2000,6000), 120.4 (C-3a), 120.7 (C-9a), 122.7 (C-8), 125.3;
125.4 (C-9), 129.0 (C-300,500), 129.0 (C-200,600), 129.4 (C-
3000,5000), 130.5 (C-7), 135.2; 135.3 (C-100), 137.9; 138.1 (C-
9b), 140.7 (C-400), 140.5;140.7 (C-50), 141.6; 141.8 (C-1000),
150.1 (C-5a). ESI–HRMS: m/z [M+H]+ calcd for
(C26H23N2OS2)+: 443.1207; found: 443.1211.
4.4.6. 5-(4-Chlorophenyl)-20-methyl-3-phenyl-20,30-
dihydro-3H-spiro[[1,3,4]thiadiazole-2,40-thieno[3,2-
c]chromene] (9b)
4.5. Synthesis of compound 13 (general procedure)
Yellow crystals, yield 90%, mp 110 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3):
d
H 1.07 (d, 3H, J = 6.9 Hz, CH3a), 1.36
Compound 3 (1 mmol) was dissolved in anhydrous
CHCl3 (20 mL) and boiled under reflux for 24 h. The solvent
was then removed under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(EP/AcOEt, 8:2) to give compound 13.
(d, 3H, J = 6.9 Hz,CH3b), 2.31(dd, 1H,J = 16.5 Hz, J = 3.0 Hz, H-
3a), 2.72 (dd, 1H, J = 16.2 Hz, J = 6.6 Hz, H-3b), 2.84 (dd, 1H,
J = 16.5 Hz, J = 8.1 Hz, H-3b), 3.21 (dd, 1H, J = 16.5 Hz,
J = 8.7 Hz, H-3a), 3.80 (m, 2H, H-2a,b), 6.88 (m, 1H, H-6),
7.01 (m, 1H, H-9), 7.06 (m, 2H, H-2000,6000), 7.14 (m, 1H, H-7),
7.18 (m, 2H, H-3000,5000), 7.33 (d, 2H, J = 8.1 Hz, H-200,600), 7.42
(m, 2H, H-4000,8), 7.57 (d, 2H, J = 8.1 Hz, H-300,500). 13C NMR
(75 MHz, CDCl3): dC 22.6 (CH3a), 23.6 (CH3b), 43.0 (C-3a),
44.3 (C-3b), 44.4 (C-2), 114.4 (C-4), 116.9 (C-6), 117.0 (C-
4000), 117.9(C-2000,6000), 120.4 (C-3a), 120.7(C-9a), 122.7(C-8),
122.9 (C-100), 125.3; 125.9 (C-9), 127.5 (C-300,500), 128.8 (C-
200,600), 128.9 (C-3000,5000), 130.5 (C-7), 135.2; 135.3 (C-400),
137.9;138.1(C-9b), 140.5; 140.7 (C-50), 141.6;141.8 (C-1000),
150.1 (C-5a). ESI–HRMS: m/z [M+H]+ calcd for
(C25H20N2OS2Cl)+: 463.0706; found: 463.0728.
4.5.1. 2-Methyl-2H-thieno[3,2-c]chromene-4(3H)-thione
(13)
Orange solid, yield 75%, mp 160 8C (EP/AcOEt, 8:2). 1H
NMR (300 MHz, CDCl3): dH 1.45 (s, 3H, CH3), 2.97 (dd, 1H,
J = 16.5 Hz, J = 5.4 Hz, H-3a), 3.42 (dd, 1H, J = 16.5 Hz,
J = 8.7 Hz, H-3b), 4.09 (m, 1H, H-2), 7.15–7.31 (m, 3H, H-
6,8,9), 7.43 (m, 1H, H-7). 13C NMR (75 MHz, CDCl3):
dC 23.0
(CH3), 41.4 (C-3), 45.7 (C-2), 116.7 (C-3a), 116.9 (C-6),
119.3 (C-9a), 124.2 (C-8), 125.8 (C-9), 131.7 (C-7), 157.4 (C-
5a), 160.1 (C-9b), 193.2 (C-4). ES–MS m/z 235 [M+H]+.
4.4.7. 20-Methyl-5-(4-nitrophenyl)-30-phenyl-20,30-dihydro-
3H-spiro[[1,3,4]thiadiazole-2,40-thieno[3,2-c]chromene] (9c)
Red solid, yield 75%, mp 148 8C (CH2Cl2/EP, 2:8). 1H
NMR (300 MHz, CDCl3): dH 1.06 (d, 3H, J = 6.6 Hz, CH3a),
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