Fused thia-heterocycles via isothiocyanates. Part I. Facile synthesis of some new 1-benzothiopyran-4-one derivatives

Article abstract of DOI:10.1515/znb-2016-0271

A selected set of new 4H-benzothiopyran-4-one derivatives 6a-h has been prepared by a one-pot reaction involving deprotonated methyl 3-oxo-3(2′,4′,5′-trichlorophenyl)propanoate 5 and the appropriate aryl or alkyl isothiocyanate. 2,4,5-Trichloroacetophenone 4, required for the synthesis of 5, is successfully prepared by Friedel-Craft's acetylation of 1,2,4-trichlorobenzene in 82% yield. The structures of the new compounds 5 and 6a-h are based on microanalytical and spectral (NMR, MS(EI), and HRMS) data.

Full text of DOI:10.1515/znb-2016-0271

Z. Naturforsch. 2017; 72(5)b: 369–375
Lina M. Barhoumi, Mustafa M. El-Abadelah*, Salim S. Sabri and Wolfgang Voelter*
Fused thia-heterocycles via isothiocyanates. Part I.
Facile synthesis of some new 1-benzothiopyran-
4-one derivatives
DOI 10.1515/znb-2016-0271
annulating the thiopyranone entity thereupon [1–3].
Examples include various thiophenols (represented, in
their cyclocondensation with β-keto esters [13–15] or pro-
piolates [16, 9], early favored methods), employment of
thiosalicylic acid [17–20], methyl thiosalicylate [21–23],
β-(2-chloroaroyl) thioacetanilides [24], thioisatins [25],
while related routes utilize potassium O-ethylxanthate
[26] or carbon disulfide [27] as the source of sulfur atom.
During the past decades, isothiocyanates have been
employed as attractive synthons in the construction of
various heterocyclic systems, and the subject has been
reviewed [28]. Herein, we wish to report on the synthe-
sis and properties of some new 1-benzothiopyran-4-ones
Received December 22, 2016; accepted February 15, 2017
Abstract: A selected set of new 4H-benzothiopyran-
4-one derivatives 6a–h has been prepared by a one-pot
reaction involving deprotonated methyl 3-oxo-3(2′,4′,5′-
trichlorophenyl)propanoate 5 and the appropriate aryl
or alkyl isothiocyanate. 2,4,5-Trichloroacetophenone 4,
required for the synthesis of 5, is successfully prepared
by Friedel–Craft’s acetylation of 1,2,4-trichlorobenzene
in 82% yield. The structures of the new compounds 5 and
6a–h are based on microanalytical and spectral (NMR,
MS(EI), and HRMS) data.
Keywords: 1,2,4-trichlorobenzene; 4-oxo-1-benzothi- (6a–g) utilizing aryl/alkyl isothiocyanates (as the source
opyrans; Friedel–Craft’s acylation; isothiocyanates; of the sulfur atom) as depicted in Scheme 1 (vide infra).
methyl 3-oxo-3-(2′,4′,5′-trichlorophenyl)propanoate.
2 Results and discussion
1 Introduction
2.1 Chemistry
The 4-oxo-1-benzothiopyran (thiochromone) ring system
1a [1–3] gains continued interest as a sulfur analog of the
The synthesis of methyl 2-(substituted amino)-6,7-di-
naturally occurring chromone nucleus 1b (Fig. 1) [4, 5].
chloro-4-oxo-4H-1benzothiopyran-3-carboxylates 6a–h
Several derivatives of 1a were reported to possess remark-
is achieved by utilizing 2,4,5-trichloroacetophenone (4)
able biological activities and regain pharmacological
as starting material and constructing the thiopyranone
interest. Notable examples include 2a [6] which showed
nucleus thereupon through two-step conversions as illus-
in vitro inhibitory potency against HIV (ED50ꢀ=ꢀ0.65 μm),
trated in Scheme 1. Compound 4, in turn, is prepared by
2b [7] and related analogs [8] acting as antitumor agents,
Friedel–Craft’s acylation of 1,2,4-trichlorobenzene using
and the anti-inflammatory analgesic agent 3 (Fig. 1) [9].
acetyl chloride and anhydrous aluminum trichloride as
Meanwhile, certain other derivatives act as potential anti-
Lewis acid catalyst. Previously, great difficulty was expe-
malarials [10], photoactive pesticides [11], and selective
rienced in a multistep synthesis of 2,4,5-trichloroace-
inhibitors of the v-abl tyrosine protein kinase [12].
tophenone 4 starting from 1,2,4-trichlorobenzene [29].
General synthetic routes to 1a utilize suitably-
Compound 4 was also prepared from 2-amino-4,5-dichlo-
substituted thiophenol as the sulfur atom source, and
roacetophenone [30, 31].
By analogy to the reported procedure for a related
system [32], direct interaction of the enolate anion of 4
with dimethyl carbonate delivered compound 5; this reac-
tion is type of a classical ‘crossed-Claisen’ condensation,
commonly employed for the synthesis of β-keto esters.
The targeted 4-oxo-1-benzothiopyrans 6a–h were finally
obtained by interaction of the appropriate isothiocyanate
with deprotonated 5 in anhydrous DMF and consequent
*Corresponding authors: Mustafa M. El-Abadelah, Chemistry
Department, Faculty of Science, The University of Jordan,
Amman 11942, Jordan, e-mail: mustelab@ju.edu.jo; and
Wolfgang Voelter, Interfakultäres Institut für Biochemie, Universität
Tübingen, Hoppe-Seyler Straße 4, 72076 Tübingen, Germany,
e-mail: wolfgang.voelter@uni-tuebingen.de
Lina M. Barhoumi and Salim S. Sabri: Chemistry Department,
Faculty of Science, The University of Jordan, Amman 11942, Jordan
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢁꢁꢁꢂ
370ꢀ
ꢀL.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanates
OMe
O
O
O
X
R
R
S
Ar
S
2a (Ar = C6H5, R = OAc)
1a (X = S)
1b (X = O)
3
N
2b (Ar =
; R = H)
Fig. 1:ꢁExamples of bioactive 1-benzothiopyran-4-ones (2, 3).
H
2
O
O
1
Cl
Cl
Cl
Cl
3
OMe
Cl
Cl
(enol)
(i)
O
O
O
1
O
4
6'
3'
5
Cl
Cl
Cl
Cl
Cl
Cl
CO2Me
R
3
2
6
7
5'
4'
3
Me
OMe
1'
2
(ii)
(iii)
2'
(iv)
Cl
Cl
S
1
N
8
H
4
5
6a−h
(i) AlCl3, MeCOCl / 125 oC, 3 h
(ii) (MeO)2C=O, NaH / 84−86 oC, 2 h
(iii) NaH, DMF / 5−10 oC
(iv) R-N=C=S / 145−150 oC, 16−20 h
Entry
R
a
f
b
c
d
e
1'
4'
1'
1'
1'
1'
4'
4'
4'
4'
Cl
CH3
OCH3
F
Entry
R
g
h
3'
10'
9'
8'
5'
1'
2'
1'
4'
5'
1'
8'a
4'a
4'
4'
8'
7'
6'
Scheme 1:ꢁSynthetic route for compounds 6a–h.
intracyclization of the resulting intermediate adduct at the intermediate adduct occurred via nucleophilic addition
refluxing temperature (Scheme 2). Herein, treatment of 5 of the anionic sulfur at the benzenoid C-2, followed by
with sodium hydride in dry DMF led to the formation of the subsequent displacement of the chloride anion through
enolate anion. The latter ‘carbanion’ adds to the central sp nucleophilic addition–elimination (SNAE) mechanism
carbon of the isothiocyanate reactant. Cyclization of the (Scheme 2). Moderate to low yields of highly pure 6a–h
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢂꢁꢁꢁ
L.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanatesꢀ
ꢀ371
O
O
Cl
Cl
CO2Me
Cl
Cl
CO2Me
DMF
NaH, r. t.
S
C
NR
Cl
Cl
O
O
Cl
Cl
CO2Me
H
Cl
Cl
CO2Me
NHR
NR
S
S
Cl
Cl
O
S
O
S
CO2Me
Cl
Cl
H
Cl
CO2Me
NHR
NR
Cl
Scheme 2:ꢁA plausible mecahanism for the formation of compounds 6a–h.
O
O
O
R'
R'
R
R
R'
R
− MeS
NaH
C6H6
Ar
N
C
S
/
MeS
NHAr
8
S
SMe
MeS
S
NHAr
MeS
SMe
7a−c
9a−c
compounds 7 / 9: a (R = R' = H); b (R = H, R' = Me); c (R = R' = Me)
compounds 8: Ar = C6H5; 4-MeC6H4, 4-ClC6H4
Scheme 3:ꢁA reported synthesis [33] of some 4H-thiopyran-4-ones utilizing aryl isothiocyanates.
were obtained in DMF, whereas the reaction did neither 2D (correlation spectroscopy, heteronuclear multiple-
proceed in THF nor in 1,4-dioxane, and no attempt was quantum coherence, heteronuclear multiple-bond correla-
made to optimize the yield. In this context, it should be tion) experiments showed correlations that helped in the
noted that a closely related approach to the construction 1H and 13C signal assignments to the different carbons and
of the monocyclic 4H-thiopyran-4-one ring system, exem- their attached and/or neighboring hydrogen atoms.
plified by its derivatives 9a–c, has once been reported uti-
lizing the reaction of aryl isothiocyanates 8 with ketene
dithioacetals 7a–c as illustrated in Scheme 3 [33].
The newly synthesized compounds 6a–h were char-
2.2 Mass spectra
1
13
acterized by elemental analysis, IR, MS, H and C NMR The major fragment ions are shown in Scheme 4. The
spectral data. These data, detailed in the experimental principle fragmentation pathway is initiated by loss of
+.
section, are consistent with the suggested structures. Thus, MeOH from [M] to give fragment ion [A], [M–32] as base
the mass spectra display the correct molecular peaks for peak in most cases. The latter ion [A] suffered loss of
which the measured high resolution (HRMS) data are in CO to produce ion [B], [M–60], or loss of R-NC to deliver
good agreement with the evaluated values. Dept. and ion [C] (m/zꢀ=ꢀ244) which in turn eliminates [:C=C=O]
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢁꢁꢁꢂ
ꢀL.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanates
372ꢀ
O
O
O
O
Cl
Cl
CO2Me
NHR
Cl
− MeOH
Cl
Cl
C
- RNC
C
O
S
S
NR
Cl
S
[M]
[A]
− CO
[C]
m / z = 244
−
C
C
O
O
C
O
Cl
Cl
Cl
Cl
Cl
C
S
NR
S
S
Cl
[D]
m / z = 204
[F]
m / z = 176
[B]
RN
C
C
C
O
[E]
Scheme 4:ꢁPrinciple fragmentation pathways of compounds 6a–h under electron impact (EI).
to form ion [D] (m/zꢀ=ꢀ204). Further fragmentation of dimethyl carbonate, and sodium hydride (60% dispersion
ion [B] generated either ion [E], [RN=C=C=C=O], or ion in mineral oil) were purchased from Acros (Geel, Belgium).
[F] (m/zꢀ=ꢀ176). Except for compound 6e, which incor- Dimethyl formamide (DMF) was dried over anhydrous
porates three chlorine atoms, the molecular ion region calcium chloride for 24 h, distilled under reduced pres-
+
+
showed the corresponding isotopic cluster ([M] , [Mꢀ+ꢀ2] , sure (53°C/20 mmHg), and stored over molecular sieves
+
[Mꢀ+ꢀ4] ) with the relative intensity ratios of 9:6:1 which (4 Å grade) before use. Melting points (uncorrected) were
confirms the presence of two chlorine atoms for the rest measured on a Gallenkamp electrothermal melting tem-
1
compounds.
perature apparatus (London, UK). H, 13C, and 2D NMR
spectra were recorded on a Bruker-DPX 300 MHz spec-
trometer (Karlsruhe, Germany), using CDCl3 as solvent
and TMS as internal reference. Mass spectra (EI) and high
resolution data (HRMS) were obtained using a Finnigan
MAT TSQ-70 spectrometer (IL, USA) at 70 eV; ion source
temperatureꢀ=ꢀ200°C. IR spectra were determined as KBr
disks on a Nicolet Impact – 400 FT-IR spectrophotometer
(Waltham, MA, USA). Elemental analysis was performed
at the Microanalytical Lab. of Al-Najah National Univer-
sity, West Bank, Palestine.
3 Conclusion
The present work demonstrates successful application
of aryl and alkyl isothiocyanates as sulfur atom source
in one-pot synthesis of 2-(aryl/alkylamino)-1-benzothi-
opyran-4-one derivatives 6a–h utilizing deprotonated
3-oxo-3-(2,4,5-trichlorophenyl)propanoates 5. This new
route utilizes readily available isothiocyanates together
with accessible suitably substituted β-(o-haloaryl)-β-
keto esters and is of promising wide scope and versatility
toward synthesis of diverse thiochromone dervatives.
4.1 2,4,5-Trichloroacetophenone (4)
To a stirred mixture of 1,2,4-trichlorobenzene (18.2 g,
100 mmol) and anhydrous aluminum trichloride (33.4 g,
250 mmol), acetyl chloride (11.8 g, 150 mmol) was drop-
wise added at room temperature. The reaction mixture
4 Experimental section
The aryl and alkyl isothiocyanates used in this study, was gradually heated to 120–125°C (oil bath) and main-
were purchased from Sigma Aldrich (St. Louis, MO, USA). tained at this temperature for 3 h. The resulting viscous
1,2,4-Trichlorobenzene, anhydrous aluminum trichloride, mixture was cautiously poured onto ice-water (125 mL),
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢂꢁꢁꢁ
L.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanatesꢀ
ꢀ373
and the aqueous mixture was extracted with dichlo- The resulting mixture was gradually heated and main-
romethane (3ꢀ×ꢀ70 mL). The combined organic extracts tained at 145–150°C for 16–20 h. The reaction mixture
were dried (MgSO4), evaporated, and the residue was was then neutralized with aqueous acetic acid (5 mL),
distilled under reduced pressure to give a colorless liquid and extracted with chloroform (3ꢀ×ꢀ25 mL). The com-
which solidified upon standing at room temperature. bined organic extracts were dried (MgSO4) and con-
Yield: 15.6 g (82%); m. p. 43–45°C, b. p. 135°C/6 mmHg (lit. centrated to give a viscous product. This crude product
[29]: m. p. 47°C; lit. [30]: m. p. 44–46°C; lit. [31]: 45.5–46°C, was purified by preparative TLC chromatography on
b. p. 114–116°C/2 mmHg).
precoated silica gel plates employing chloroform-petro-
leum ether (5:1 v/v) as the developing solvent. The title
compound was further purified by recrystallization from
4.2 Methyl 3-oxo-3-(2′,4′,5′-trichlorophenyl) chloroform–methanol.
propanoate (5)
Compound 5 was prepared from 2,4,5-trichloroacetophe-
4.3.1 Methyl 6,7-dichloro-4-oxo-2-(N-phenylamino)-4H-
none (4) by a similar procedure as reported in [32] for the
synthesis of related β-keto ester from its 3-acetyl-2,5-di-
chlorothiophene: sodium hydride (2.8 g, 60% dispersion
in oil; 70 mmol) was portionwise added to a cold solution
(5–10°C) of 4 (6.2 g, 34 mmol) in anhydrous dimethyl car-
bonate (100 mL). The mixture was heated at 84–86°C for
2 h and poured onto ice-cold water (250 mL) containing
acetic acid (5 mL). The resulting mixture was extracted
with diethyl ether (3ꢀ×ꢀ70 mL); the combined organic
extracts were dried (MgSO4), and the solvent was evapo-
rated. The residual product was recrystallized from pet.
ether (40–60°C) giving the title compound 5 as color-
less crystals. Yield: 8.1 g (84%); m. p. 71–72°C. – IR (KBr):
νmaxꢀ=ꢀ1660, 1626 cm−1. – HRMS (EI): m/zꢀ=ꢀ279.94581 (calcd.
1benzothiopyran-3-carboxylate (6a)
Yield: 32%; m. p. 121–122°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, CDCl3):
δꢀ=ꢀ3.97 (s, 3H, CO2CH3), 7.35 (s, 1H, 8-H), 7.36 (m, 2H, 2′-
H/6′-H), 7.42 (m, 1H, 4′-H), 7.50 (m, 2H, 3′-H/5′-H), 8.49
(s, 1H, 5-H), 11.75 (s, 1H, N-H, exchangeable with D2O)
ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3): δꢀ=ꢀ52.4 (CO2CH3), 100.4
(C-3), 125.2 (C-2′/C-6′), 127.0 (C-8), 127.1 (C-4′), 129.0 (C-6),
129.5 (C-3′/C-5′), 130.0 (C-5), 130.9 (C-7), 132.4 (C-4a),
136.2 (C-8a), 137.3 (C-1′), 166.0 (C-2), 170.2 (CO2Me), 175.9
(C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3421, 3055, 3013, 2953, 1636,
1626 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ378.98416 (calcd. 378.98367
+
+
for C17H11Cl2NO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ379 (7) [M] , 347
(100), 319 (9), 244 (4), 204 (17), 143 (19), 176 (13), 77 (72)
+
1
279.94608 for C10H7Cl3O3, [M] ). – H NMR (300 MHz,
CDCl3): δꢀ=ꢀ3.75 (s, 1.5 H, enol OCH3), 3.78 (s, 1.5 H, keto
OCH3), 4.04 (s, 1H, keto 2-H2), 5.63 (s, 0.5 H, enol 2-H), 7.55
(br s, 1H, keto-enol 3′-H), 7.71 (s, 0.5 H, enol 6′-H), 7.75
+
[R] .ꢀꢀ−ꢀꢀC17H11Cl2NO3S (380.25): calcd. C 53.70, H 2.92, N 3.68;
found C 53.56, H 2.88, N 3.75.
13
(s, 0.5 H, keto 6′-H), 12.20 (s, 0.5 H, enol OH). – C NMR
(75 MHz, CDCl3): δꢀ=ꢀ48.6 (keto CH2-2), 51.8 (enol OCH3), 4.3.2 Methyl 6,7-dichloro-2-[N-(4-methylphenyl)amino]-
52.6 (keto OCH3), 93.7 (enol CH-2), 131.3, 131.6 (CH-3′, keto-
enol), 132.1, 132.3 (CH-6′, keto-enol), 130.4, 130.8, 131.5,
4-oxo-4H-1-benzothiopyran-3-carboxylate (6b)
132.2, 132.8, 134.8, 136.6, 136.9 (keto-enol pairs of the Yield: 35%; m. p. 146–147°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, CDCl3):
quaternary carbons: C-1′, C-2′, C-4′, C-5′), 167.0 (enol C-1), δꢀ=ꢀ2.43 (s, 3H, 4′-CH3), 3.96 (s, 3H, CO2CH3), 7.22 (d,
167.7 (keto C-1), 172.7 (enol HO–C-3), 192.1 (keto O=C-3). – Jꢀ=ꢀ8.3 Hz, 2H, 2′-H/6′-H), 7.30 (d, Jꢀ=ꢀ8.3 Hz, 2H, 3′-H/5′-
C10H7O3Cl3 (281.52): calcd. C 42.66, H 2.51, Cl 37.78; found C H), 7.32 (s, 1H, 8-H), 8.48 (s, 1H, 5-H), 11.65 (s, 1H, N-H,
42.43, H 2.48, Cl 37.52.
exchangeable with D2O) ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3):
δꢀ=ꢀ21.3 (4′-CH3), 52.4 (OCH3), 100.1 (C-3), 126.4 (C-8), 127.0
(C-2′/C-6′), 129.1 (C-6), 129.4 (C-7), 130.5 (C-3′/C-5′), 130.9
(C-5), 132.3 (C-4a), 133.5 (C-4′), 136.0 (C-8a), 139.2 (C-1′),
166.4 (C-2), 170.2 (CO2Me), 175.9 (C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr):
4.3 General prodedure for the preparation
of 1-benzothiopyran-4-ones 6a–h
νmaxꢀ=ꢀ3422, 3064, 2996, 2951, 1643, 1630 cm−1.ꢀꢀ−ꢀꢀHRMS (EI):
+
Sodium hydride (2.8 g, 60% dispersion oil; 70 mmol) m/z – 392.99856 (calcd. 392.99932 for C18H13Cl2NO3S, [M] ).
+
was portionwise added to a stirred solution of 5 (6.2 g, – EIMS: m/z (%)ꢀ=ꢀ393 (14) [M] , 361 (100), 333 (17), 244
+
34 mmol) in anhydrous DMF (50 mL) during 30 min. A (7), 204 (13), 157 (61), 176 (4), 91 (48) [R] .ꢀꢀ−ꢀꢀC18H13Cl2NO3S
solution of appropriate isothiosynate (10 mmol) in dry (394.28): calcd. C 54.83, H 3.32, N 3.55; found C 54.64, H
DMF (3 mL) was then added to the reaction mixture. 3.25, N 3.51.
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢁꢁꢁꢂ
ꢀL.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanates
374ꢀ
4.3.3 Methyl 6,7-dichloro-2-[N-(4-methoxyphenyl)amino]-
4-oxo-4H-1-benzothiopyran-3-carboxylate (6c)
1634 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ412.94413 (calcd. 412.94470
+ +
for C17H10Cl3NO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ415 (21) [M] ,
381 (100), 253 (11), 244 (7), 204 (45), 177 (64), 176 (10), 111
Yield: 21%; m. p. 201–202°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, (12) [R] . – C17H10Cl3NO3S (414.69): calcd. C 49.24, H 2.43, N
CDCl3): δꢀ=ꢀ3.88 (s, 3H, 4′-OCH3), 3.97 (s, 3H, CO2CH3), 3.38; found C 49.06, H 2.39, N 3.35.
7.00 (d, Jꢀ=ꢀ8.8 Hz, 2H, 3′-H/5′-H), 7.25 (d, Jꢀ=ꢀ8.8 Hz, 2H,
+
2′-H/6′-H), 7.33 (s, 1H, 8-H), 8.49 (s, 1H, 5-H), 11.56 (s, 1H,
N-H, exchangeable with D2O) ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, 4.3.6 Methyl 6,7-dichloro-2-[N-(1′-naphthyl)amino]-4-
CDCl3): δꢀ=ꢀ52.3 (CO2CH3), 55.6 (4′-OCH3), 100.0 (C-3),
115.1 (C-3′/C-5′), 126.5 (C-8), 128.8 (C-2′/C-6′), 129.0 (C-6),
oxo-4H-1-benzothiopyran-3-carboxylate (6f)
129.2 (C-1′), 130.6 (C-7), 130.9 (C-5), 132.3 (C-4a), 136.0 Yield: 22%; m. p. 330°C (decomp.).ꢀꢀ−ꢀꢀ1H NMR (300 MHz,
(C-8a), 160.0 (C-4′), 167.1 (C-2), 170.3 (CO2Me), 175.9 (C-4) CDCl3): δꢀ=ꢀ4.03 (s, 3H, CO2CH3), 7.21 (s, 1H, 8-H), 7.60 (m,
ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3420, 3014, 2994, 2843, 1668, 4H, 2′-Hꢀ+ꢀ4′-Hꢀ+ꢀ6′-Hꢀ+ꢀ8′-H), 7.97 (m, 3H, 3′-Hꢀ+ꢀ5′-Hꢀ+ꢀ
1619 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ408.99414 (calcd. 408.99432 7′-H), 8.50 (s, 1H, 5-H), 12.04 (s, 1H, N-H, exchangeable with
+
+
for C18H13Cl2NO4S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ409 (20) [M] , D2O) ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3): δꢀ=ꢀ52.5 (CO2CH3),
377 (100), 349 (11), 244 (5), 204 (7), 173 (78), 176 (10), 107 (2) 100.3 (C-3), 122.0 (C-2′), 125.4 (C-4′), 126.0 (C-3′), 126.4 (C-8),
+
[R] . – C18H13Cl2NO4S (410.28): calcd. C 52.70, H 3.19, N 3.41; 127.2 (C-6′), 127.8 (C-7′), 128.7 (C-8′), 129.2 (C-6), 129.9 (C-5′),
found C 52.58, H 3.12, N 3.32.
130.6 (C-7), 130.9 (C-5), 132.2 (C-8′a), 132.3 (C-4a), 134.6
(C-1′), 134.7 (C-4′a), 136.0 (C-8a), 167.6 (C-2), 170.4 (CO2Me),
176.0 (C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3404, 3081, 2926, 2860,
1653, 1634 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ428.99894 (calcd.
4.3.4 Methyl 6,7-dichloro-2-[N-(4-fluorophenyl)amino]-
4-oxo-4H-1-benzothiopyran-3-carboxylate (6d)
+
428.99932 for C21H13Cl2NO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ429
+
(25) [M] , 397 (100), 369 (11), 244 (3), 204 (6), 193 (82), 176
Yield: 22%; m. p. 173–174°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, CDCl3):
δꢀ=ꢀ3.96 (s, 3H, CO2CH3), 7.18 (dd, JH−Hꢀ=ꢀ8.7 Hz, 2JH−Fꢀ=ꢀ7.4 Hz,
+
(3), 127 (15) [R] .ꢀꢀ−ꢀꢀC21H13Cl2NO3S (430.31): calcd. C 58.62, H
3.05, N 3.26; found C 58.38, H 2.98, N 3.17.
3
2H, 3′-H/5′-H), 7.33 (dd, JH−Hꢀ=ꢀ8.7 Hz, JH−Fꢀ=ꢀ2.8 Hz, 2H, 2′-
H/6′-H), 7.35 (s, 1H, 8-H), 8.47 (s, 1H, 5-H), 11.64 (s, 1H, N-H,
exchangeable with D2O) ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3):
4.3.7 Methyl 2-[N-(cyclohexyl)amino]-6,7-dichloro-4-
oxo-4H-1-benzothiopyran-3-carboxylate (6g)
2
δꢀ=ꢀ52.4 (OCH3), 100.5 (C-3), 117.1 (d, JC−Fꢀ=ꢀ22.2 Hz, C-3′/C-
3
5′), 126.5 (C-8), 128.8 (C-6), 129.5 (d, JC−Fꢀ=ꢀ8.8 Hz, C-2′/C-
6′), 130.5 (C-7), 130.9 (C-5), 132.2 (d, 4JC−Fꢀ=ꢀ3.2 Hz, C-1′), 132.6
(C-4a), 136.2 (C-8a), 162.6 (d, 1JC−Fꢀ=ꢀ250 Hz, C-4′), 166.3 (C-2),
170.2 (CO2Me), 175.8 (C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3413, 3065,
2995, 2952, 1646, 1627 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ396.97402
Yield: 23%; m. p. 110–112°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, CDCl3):
δꢀ=ꢀ1.43–2.07 (m, 10H, 2′-H2ꢀ+ꢀ3′-H2ꢀ+ꢀ4′-H2ꢀ+ꢀ5′-H2ꢀ+ꢀ6′-H2),
3.64 (m, 1H, 1′-H), 3.91 (s, 3H, CO2CH3), 7.46 (s, 1H, 8-H),
8.49 (s, 1H ,5-H), 10.67 (d, Jꢀ=ꢀ8 Hz, 1H, N-H, exchangeable
with D2O) ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3): δꢀ=ꢀ24.2 (C′-3/
C-5′), 25.2 (C-4′), 32.5 (C-2′/C-6′), 52.1 (CO2CH3), 53.9 (C-1′),
98.3 (C-3), 126.2 (C-8), 128.3 (C-6), 130.9 (C-5), 131.1 (C-7),
132.4 (C-4a), 135.9 (C-8a), 164.3 (C-2), 170.5 (CO2Me), 175.5
(C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3413, 3089, 2928, 2862, 1636,
1619 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ385.03014 (calcd. 385.03062
+
(calcd. 396.97425 for C17H10Cl2FNO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z
+
(%)ꢀ=ꢀ397 (31) [M] , 365 (100), 337 (19), 244 (7), 204 (47), 161
+
(95), 176 (14), 95 (3) [R] .ꢀꢀ−ꢀꢀC17H10Cl2FNO3S (398.24): calcd.
C 51.27, H 2.53, N 3.52; found C 51.03, H 2.44, N 3.41.
4.3.5 Methyl 2-[N-(4-chlorophenyl)amino]-6,7-dichloro-
4-oxo-4H-1-benzothiopyran-3-carboxylate (6e)
+
+
for C17H17Cl2NO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ385 (20) [M] ,
354 (4), 325 (21), 244 (41), 204 (25), 148 (100), 176 (5), 83
Yield: 30%; m. p. 177–178°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz, CDCl3): (38) [R] .ꢀꢀ−ꢀꢀC17H17Cl2NO3S (386.30): calcd. C 52.86, H 4.44,
δꢀ=ꢀ3.96 (s, 3H, CO2CH3), 7.31 (d, Jꢀ=ꢀ8.6 Hz, 2H, 2′-H/6′-H), N 3.63; found C 52.58, H 4.35, N 3.56.
7.47 (d, Jꢀ=ꢀ8.6 Hz, 2H, 3′-H/5′-H), 7.34 (s, 1H, 8-H), 8.46
+
(s, 1H, 5-H), 11.68 (s, 1H, N-H, exchangeable with D2O)
ppm.ꢀꢀ−ꢀꢀ13C NMR (75 MHz, CDCl3): δꢀ=ꢀ52.4 (OCH3), 100.7 4.3.8 Methyl 2-[N-(1′-adamantyl)amino]-6,7-dichloro-4-
(C-3), 126.5 (C-8), 128.5 (C-2′/C-6′), 128.8 (C-6), 130.2 (C-3′/C-
5′), 130.5 (C-7), 130.9 (C-5), 132.6 (C-4a), 134.7 (C-4′), 134.8
oxo-4H-1-benzothiopyran-3-carboxylate (6h)
(C-1′), 136.3 (C-8a), 165.6 (C-2), 170.1 (CO2Me), 175.7 (C-4) Yield: 24%; m. p. 219–220°C.ꢀꢀ−ꢀꢀ1H NMR (300 MHz,
ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3421, 3054, 2991, 2960, 1644, CDCl3): δꢀ=ꢀ1.62 (br s, 3H, 3′-Hꢀ+ꢀ5′-Hꢀ+ꢀ7′-H), 1.75 (br s, 6H,
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM

ꢂꢁꢁꢁ
L.M. Barhoumi et al.: Fused thia-heterocycles via isothiocyanatesꢀ
ꢀ375
[8] M. H. Holshouser, L. J. Loeffler, I. H. Hall, J. Med. Chem. 1981,
24, 853.
[9] I. Hirao, M. Yamaguchi, M. Terada, K. Hasebe, Bull. Chem. Soc.
Jpn. 1985, 58, 220.
[10] R. K. Razdan, R. J. Bruni, A. C. Mehta, K. K. Weinhardt, Z. B.
Papanastassiou, J. Med. Chem. 1978, 21, 643.
[11] M. L. Borges, O. C. Matos, I. Pais, J. S. de Meb, C. P. Ricardo, A.
Macanita, R. S. Becker, Pestic. Sci. 1995, 44, 155.
[12] J. F. Geissler, J. L. Roesel, T. Meyer, U. P. Trinks, P. Traxler, N. B.
Lydon, Cancer Res. 1992, 52, 4492.
[13] F. Bossert, Justus Liebigs Ann. Chem. 1964, 680, 40.
[14] S. W. Schneller, Adv. Heterocyclic Chem. 1975, 18, 60, and refer-
ences cited therein.
[15] H. Nakazumi, T. Ueyama, T. Kitao, J. Heterocycl. Chem. 1985, 22,
1593.
[16] W. E. Truce, D. L. Goldhamer, J. Am. Chem. Soc. 1959, 81, 5795.
[17] S. Kikionis, V. McKee, J. Markopoulos, O. Igglessi-
Markopoulou, Tetrahedron 2008, 64, 5454.
[18] J. I. Lee, Bull. Korean Chem. Soc. 2009, 30, 710.
[19] J.-C. Jung, J.-C. Kim, O.-S. Park, Synth. Commun. 2000, 30, 1193.
[20] P. Kumar, M. S. Bodas, Tetrahedron 2001, 57, 9755.
[21] P. J. C. Mabe, S. L. Knick, W. G. Shuler, S. S. Carlisle, E. A.
Smith, A. J. Puciaty, T. M. C. McFadden, C. Potter, C. R. Metz, C.
F. Beam, W. T. Pennington, D. G. VanDerveer, C. D. McMillan,
Ind. Eng. Chem. Res. 2015, 54, 7207.
[22] K. L. French, A. J. Angel, A. R. Williams, D. R. Hurst, C. F. Beam,
J. Heterocycl. Chem. 1998, 35, 45, and references cited therein.
[23] A. J. Angel, A. E. Finefrock, K. L. French, D. R. Hurst,
A. R. Willims, M. E. Rampey, S. L. Studer-Martinez, C. F. Beam,
Can. J. Chem. 1999, 77, 94.
[24] L.-R. Wen, J.-H. Sun, M. Li, E.-T. Sun, S.-S. Zhang, J. Org. Chem.
2008, 73, 1852.
4′-H2ꢀ+ꢀ6′-H2ꢀ+ꢀ10′-H2), 2.20 (br s, 6H, 2′-H2ꢀ+ꢀ8′-H2ꢀ+ꢀ9′-H2),
3.89 (s, 3H, CO2CH3), 7.50 (s, 1H, 8-H), 8.48 (s, 1H, 5-H),
10.65 (s, 1H, N-H, exchangeable with D2O) ppm.ꢀꢀ−ꢀꢀ13C
NMR (75 MHz, CDCl3): δꢀ=ꢀ29.5 (C-″ꢀ+ꢀC-5′ꢀ+ꢀC-7′), 35.9(C-
4′ꢀ+ꢀC-6′ꢀ+ꢀC-10′), 41.6 (C-2′ꢀ+ꢀC-8′ꢀ+ꢀC-9′), 52.1 (CO2CH3), 56.3
(C-1′), 99.2 (C-3), 125.9 (C-8), 128.9 (C-6), 130.8 (C-5), 131.1
(C-7), 132.2 (C-4a), 135.8 (C-8a), 163.5 (C-2), 170.5 (CO2Me),
175.5 (C-4) ppm.ꢀꢀ−ꢀꢀIR (KBr): νmaxꢀ=ꢀ3416, 3098, 2911, 2840,
1651, 1617 cm−1.ꢀꢀ−ꢀꢀHRMS (EI): m/zꢀ=ꢀ437.06161 (calcd.
+
437.06192 for C21H21Cl2NO3S, [M] ).ꢀꢀ−ꢀꢀEIMS: m/z (%)ꢀ=ꢀ437
+
(30) [M] , 405 (3), 377 (1), 244 (1), 204 (3), 201 (1), 176 (1),
+
135 (100) [R] .ꢀꢀ−ꢀꢀC21H21Cl2NO3S (438.38): calcd. C 57.54, H
4.83, N 3.20; found C 57.36, H 4.72, N 3.15.
Acknowledgments: We wish to thank the BMBF (Bonn,
Germany) and the Deanship of Scientific Research at
the University of Jordan (Amman, Jordan) for financial
support.
References
[1] S. W. Schneller, in Advanced Heterocyclic Chemistry, Vol. 18
(Eds.: A. R. Katritzky, A. J. Boulton), Academic Press, New York,
1975, pp. 59–96.
[2] R. Livingstone, in Rodd’s Chemistry of Carbon Compounds,
Vol. IV (Ed.: S. Goffey), 2nd ed., Elsevier, Amsterdam, 1977,
chapter 21.
[3] J. D. Hepworth, B. M. Heron, in Comprehensive Heterocyclic
Chemistry III, Vol. 7 (Eds.: A. R. Katritzky, C. R. Ramsden, E. F.
Scriven, R. K. Taylor), Elsevier, London, 2008, pp. 727–954.
[4] J. D. Hepworth, in Comprehensive Heterocyclic Chemistry, Vol. 3
(Eds.: A. E. Katritzky, C. W. Rees), Pergamon Press, Oxford, 1984,
pp. 737–883.
[5] R. Livingstone, in Rodd’s Chemistry of Carbon Compounds, Vol. IV
(Ed.: S. Goffey), 2nd ed., Elsevier, Amsterdam, 1977, chapter 20.
[6] H.-K. Wang, K. F. Bastow, L. M. Cosentino, K. H. Lee, J. Med.
Chem. 1996, 39, 1975.
[7] K. Watanabe, T. Saito, K. Niimura, Eur. Pat. Appl. EP 758 649
(1997); Chem. Abstr. 1997, 126, 199456b.
[25] T. Inami, T. Kurahashi, S. Matsubara, Org. Lett. 2014, 16, 5660.
[26] P. Boutillier, B. Quiclet-Sire, S. N. Zafar, S. Z. Zard, Tetrahedron:
Asymmetry 2010, 21, 1649.
[27] J. Charris, J. Dominguez, G. Lobo, F. Riggione, Pharm. Pharma-
col. Commun. 1999, 5, 107.
[28] A. K. Mukerjee, R. Ashare, Chem. Rev. 1991, 91, 1.
[29] J. W. Baker, W. T. Tweed, J. Chem. Soc. 1941, 796.
[30] W. P. Trompen, H. O. Huisman, Recueil 1966, 85, 167.
[31] G. G. Yakobson, L. I. Denisova, L. B. Krasnova, Zh. Obshch.
Khim. 1962, 32, 3131; Chem. Abstr. 1963, 58, 11243g.
[32] M. M. El-Abadelah, M. R. Kamal, W. M. Tokan, S. O. Jarrar,
J. Prakt. Chem. 1997, 339, 284.
[33] L. W. Singh, H. Ila, H. Junjappa, Synthesis, 1985, 531.
Brought to you by | University of Florida
Authenticated
Download Date | 5/2/17 10:52 AM