Synthesis of naphtho[2,3-b]-and naphtho[1,2-b]-fused thieno[2,3-d][1] benzoxepins and thieno[2,3-d][1]-benzothiepins

Article abstract of DOI:10.3987/COM-10-12014

Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, naphtho[2,3-b]thieno[2,3-d][1]benzothiepins (Ia), naphtho[1,2-b]thieno[2,3-d][1]benzothiepins (IIa), naphtho[2,3-b]thieno-[2,3-d] [1]benzoxepins (Ib, c) and naphth

Full text of DOI:10.3987/COM-10-12014

HETEROCYCLES, Vol. 81, No. 10, 2010
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HETEROCYCLES, Vol. 81, No. 10, 2010, pp. 2269 - 2290. © The Japan Institute of Heterocyclic Chemistry
Received, 9th July, 2010, Accepted, 26th August, 2010, Published online, 26th August, 2010
DOI: 10.3987/COM-10-12014
SYNTHESIS OF NAPHTHO[2,3-b]- AND NAPHTHO[1,2-b]-FUSED
THIENO[2,3-d][1]BENZOXEPINS
AND
THIENO[2,3-d][1]-
BENZOTHIEPINS
Ivana Ozimec Landek,* Dijana Pešić, Rudolf Trojko, 1 Maja Devčić
Bogdanović,2 Mladen Merćep,3 and Milan Mesić
GlaxoSmithKline Research Centre Zagreb Limited, Prilaz baruna Filipovića 29,
10000 Zagreb, Croatia
Abstract – Synthesis of four novel classes of structurally related fused
hetero-pentacyclic compounds, naphtho[2,3-b]thieno[2,3-d][1]benzothiepins (Ia),
naphtho[1,2-b]thieno[2,3-d][1]benzothiepins
(IIa),
naphtho[2,3-b]thieno-
[2,3-d][1]benzoxepins (Ib,c) and naphtho[1,2-b]thieno[2,3-d][1]benzoxepins
(IIb,c), is described. The key intermediates were the tetracyclic ketones,
benzo[b]-naphtho[f]-fused thiepinones 1a,b and oxepinones 1c-f, formed by
intramolecular cyclization of the corresponding 2-naphthalenylthio- (2a,b) and
2-naphthalenyloxy-substituted (2c-f) phenylacetic acid derivatives. Reaction of
ketones 1a-f with Vilsmeier reagent provided -chlorovinyl aldehydes 10a-f that
readily cyclized with ethyl 2-mercaptoacetate to form thieno[2,3-d]-fused
derivatives of benzo-naphtho-thiepins 11a,b and benzo-naphtho-oxepins 11c-f.
Reduction of ester group of 11a-f afforded final hydroxymethyl derivatives 12a-f.
INTRODUCTION
As a part of our research program on various heterocyclic dibenzo[e,h]azulenes as prospective
anti-inflammatory drugs, we recently reported on the synthesis, properties, structure determination and
preliminary biological results of dibenzoxepino[4,5]- and dibenzothiepino[4,5]-fused five-membered
heterocycles: furan,1 pyrrole,2 thiophene3 and imidazole.4 Preliminary data revealed potential of these
* Author to whom correspondence should be addressed. (E-mail: ivana.o.ozimec-landek@gsk.com)
1
Present address: PLIVA Research and Development Limited, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia
2
Present address: Palinovečka 47, 10000 Zagreb, Croatia
3
Present address: Children’s Hospital Srebrnjak, Srebrnjak 100, 10000 Zagreb, Croatia

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HETEROCYCLES, Vol. 81, No. 10, 2010
polycyclic compounds to act as anti-inflammatory agents. In order to study importance of the additional
benzo- or cyclohexano-ring condensed to dibenzo[b,f]thieno[2,3-d]oxepin or
dibenzo[b,f]thieno[2,3-d]thiepin scaffold for anti-inflammatory activity, we have directed our syntheses
to novel polycondensed benzothiepin and benzoxepin analogs with [1,2]- or [2,3]-fused naphthalene
moiety and [2,3]-fused thiophene ring (I, II, Figure 1). Herein we report the synthesis and structural
characterization of the target hetero-pentacyclic derivatives of benzothiepins Ia and IIa and benzoxepins
Ib,c and IIb,c as well as intermediates for the preparation thereof.
9
8
7
14
13
X
6
12
X
5
5
11
14
4
6
10
1
S
3
7
S
9
2
8
R
R
R = CO2Et, CH2OH
R = CO2Et, CH2OH
I
II
X
X
10
11
1
S
Ia
Ib
Ic
12
2
13
IIa
S
3
4
1
10
11
O
O
12
2
3
O
IIb
IIc
13
10
4
1
11
12
2
3
O
13
4
Figure 1. Synthesized final compounds and numbering according to IUPAC
RESULTS AND DISCUSSION
In the synthesis of dibenzo[b,f]thieno[2,3-d]oxepins and dibenzo[b,f]thieno[2,3-d]thiepins with an
additional condensed benzo- or cyclohexano-ring an analogy of the procedure employed for the parent
dibenzo[b,f]thieno[2,3-d]oxepins and dibenzo[b,f]thieno[2,3-d]thiepins was used.5-7 Starting α- and
β-naphthalenols and naphthalenethiols as well as α- and β-tetrahydronaphthalenols enabled synthesis of a
series of structurally related final compounds, which were along with their precursors thoroughly
spectroscopically characterized. Furthermore, distinctions in reactivity and/or properties of oxygen versus
sulfur analogs were noticed and will be discussed when appropriate.
Tetracyclic ketones 1, possessing an active methylene group and subject to further transformation into
intermediate functionalized for thiophene annulation, were obtained by cyclo-dehydration of 2-substituted
derivatives of phenylacetic acids 2. Depending on the starting (thio)naphthol, acids 2 can be prepared
following one of three available routes: C-1 homologation (route A), thioamide route (route B) or direct
condensation (route C) (Scheme 1).

HETEROCYCLES, Vol. 81, No. 10, 2010
2271
A (C-1 homologization)
I
HX
+
CO2H
X = O, S
X
X
B (thioamide route)
Cl
O
HO
+
CO2H
O
C (direct)
1
2
Cl
HO
X = O, S
X = O, S
+
CO2H
Scheme 1. Retro-synthetic sequence to tetracyclic ketones 1
As the main synthetic method emerged route A, by which naphthalenylthio-derivatives (2a-b) and
1-naphthalenyloxy-derivatives (2c-d) of phenylacetic acid were prepared. This method comprises
introducing cyanide ion into 2-substituted benzoic acid derivative, following published methods for
synthesis
of
analogous
tricyclic
ketones,
11H-dibenzo[b,f]oxepin-10-one
and
11H-dibenzo[b,f]thiepin-10-one.8-19 Although
a
similar route towards the formation of
naphthalenylthio-derivatives (a and b) including ketones 1a-b was previously reported,20,21 poor
spectroscopic or structural analysis had been performed, for some compounds only by melting point and IR
spectrum.
Route A proceeds as depicted in Scheme 2. When dealing with sulfur analogs, the synthesis starts with
copper catalyzed Ullmann type reaction of thionaphthol and 2-iodobenzoic acid in aqueous potassium
hydroxide affording products in high yields (86% for 1-naphthalenyl (3a) and 98% for 2-naphthalenyl (3b)
derivative). On the other hand, Ullmann type coupling for oxygen analogs requires harsher conditions,
potassium carbonate in nitrobenzene or xylene at 140 °C with copper catalysis, and results with lower
yields (49% for 1-naphthalenyl (3c) and 77% for 5,6,7,8-tetrahydro-1-naphthalenyl (3d) derivative).
2-Substituted benzoic acid derivatives 3a-d were subsequently reduced with lithium aluminum hydride in
ether to corresponding alcohols 4a-d (55-95%) and then brominated to facilitate substitution with cyanide.
Bromination instead of chlorination is a main modification of the published procedure.8,10-17,19-21
Comparing with chlorination procedure, bromination appeared more feasible due to shorter reaction time,
complete consumption of reactant, more pure products and introducing a better leaving group for
nucleophilic displacement. Sulfur analogs 4a-b were brominated by refluxing in 47% hydrobromic acid in
almost quantitative yield (99% for 5a and 96% for 5b), while oxygen analogs 4c-d were subjected to milder
conditions with phosphorus tribromide in dichloromethane at 0 °C thus providing bromides 5c-d with
excellent yields (81% for 5c and 92% for 5d). Substitution of bromides 5a-d by reaction with sodium
cyanide in refluxing 96% ethanol afforded nitriles 6a-d. However, partial solvolysis with ethanol occurred
giving as a by-product ethyl ether of the corresponding 2-substituted benzyl alcohols, lowering the yields

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HETEROCYCLES, Vol. 81, No. 10, 2010
(66-86%). Formation of analogous by-product was already reported for similar compounds.13
Homologation procedure ended with hydrolysis of nitriles 6a-d in alkaline medium. Nitriles a, b and d
were converted smoothly to corresponding phenylacetic acids 2 (71-88%), while hydrolysis of analog c
stopped at intermediary amide to the extent of 40-50% even after prolonged reaction time. The same issue
was already noticed for similar compound.22 Nevertheless, unreacted amide was easily separable during
work-up.
CO2H
HX
X
I
a X=S, 1-naphthalenyl
X
i
ii-v
b X=S, 2-naphthalenyl
c X=O, 1-naphthalenyl
d X=O, 5,6,7,8-tetrahydro-1-naphthalenyl
+
CO2H
X = O, S
Y
X = O, S
Y=OH, 4a-d
Y=Br, 5a-d
3a-d
Y=CN, 6a-d
Y=CO2H, 2a-d
Scheme 2. Route A for synthesis of 2-substituted derivatives of phenylacetic acids 2a-d. Reagents and
conditions: i, X=S: Cu, KOH/H2O, reflux, 8 h; X=O: K2CO3, Cu, nitrobenzene or xylene, 140 °C, 1 h; ii,
LiAlH4, diethyl ether, r.t., 4 h; iii, X=S: 47% HBr, reflux, 2 h; X=O: PBr3, CH2Cl2, 0 °C, 30 min; iv, NaCN,
96% EtOH, reflux, 4 h; v, KOH/H2O, EtOH, reflux, 15 h, then conc. HCl
In order to shorten multistep reaction path for preparation of phenylacetic acids 2, three-step synthesis
(route B) was employed which includes conversion of 2-substituted acetophenone to a thioamide with the
same number of C-atoms (Scheme 3), according to the previously described procedure for analogous
tricyclic compounds.8,23 Starting 2-chloroacetophenone and 2-naphthol were coupled in an Ullmann type
reaction in the presence of copper(I) catalyst and potassium carbonate in isoamyl alcohol to yield
2-substituted acetophenone 7 (78%). Subjecting compound 7 to sulfur in boiling morpholine gave
thioamide 8,24 that was hydrolyzed in acidic conditions to the expected 2-substituted phenylacetic acid 2e
(52% from 7).
O
Cl
O
HO
K2CO3, CuCl
O
+
isoamyl alcohol
7
O
O
AcOH / H2SO4
H2O
S
O
HN
CO2H
S
N
O
2e
8
Scheme 3. Thioamide route (route B) for synthesis of 2-substituted phenylacetic acid 2e
An attempt to perform analogous reaction with 1-naphthol was encountered with side-reactions and

HETEROCYCLES, Vol. 81, No. 10, 2010
2273
difficulties during isolation and resulted in formation of only minor amount of the corresponding acid 2c.
Substantial reduction of the yield due to formation of the α-oxo by-product was previously described for
similar compounds.25 Hence the method B, although attractive due to reduced number of reaction steps,
proved less effective for the synthesis of 2-naphthalenyl phenylacetic acids.
Condensation of 2-chlorophenylacetic acid with a suitable naphthol (route C) represents the shortest and the
most effective method for synthesis of 2-substituted phenylacetic acids 2. Variation of Ullmann type
reaction between 2-halophenylacetic acid (halo is chloro, bromo or iodo) and (substituted) phenol [cf. refs
26-28], as employed in route C, is scarcely applied due to low reactivity of aryl halides, particularly aryl
chlorides, under the common reaction conditions used for nucleophilic aromatic substitution, unless they
are activated by the presence of electron withdrawing substituents. Dry heating of 5,6,7,8-tetrahydro-2-
naphthalenol and 2-chlorophenylacetic acid with potassium carbonate and copper(I) catalyst at 160 °C
affords the expected acid 2f in a high yield (89%) (Scheme 4). Addition of xylene enables azeotropic
distillation of water, shifting the equilibrium to the right and enhancing the yield. Analogous reactions in
preparation of 2c and 2d failed, or yielded minor quantity of the expected product. Acid 2f can be
efficiently prepared by C-1 homologation too. Therefore, the one-step route C is the optimized procedure
for synthesis of 2f.
O
HO
Cl
K2CO3, CuCl
+
CO2H
160 °C
CO2H
2f
Scheme 4. Synthesis of the acid 2f by direct condensation (route C)
Spectroscopic and analytical data for compounds 2a-f, 3a-d, 4a-d, 5a-d and 6a-d can be found in Tables 1
and 2.
Acids 2a-f were cyclized to corresponding tetracyclic ketones 1a-f in a high yield using an excess of
polyphosphoric acid (PPA) at 110 °C (Scheme 5).
2
3
1
13
12
4
X
11
10
X
PPA
X
5
110 °C
S
a
b
c
d
e
f
6
9
7
8
CO2H
O
S
1a,c,d
2a,c,d
O
O
O
O
7
6
4
5
8
X
3
X
PPA
9
2
110 °C
10
11
12
1
13
CO2H
O
2b,e,f
1b,e,f
Scheme 5. Synthesis of ketones 1 by cyclodehydration of acids 2 and numbering of the two isomers
according to IUPAC

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HETEROCYCLES, Vol. 81, No. 10, 2010
Cyclization of compounds 2b,e,f, derived from 2-naphthalenols, can proceed either via electrophilic attack
of acyl group on the α-position to obtain ketones 9 or via attack on the β-position to give isomeric ketones 1,
Scheme 6.
X
-attack
O

X
9
isomerization

6
O
-attack
X
OH
2
11
O
1
Scheme 6. Alternatives for intramolecular acylation of acids 2 derived from 2-naphthalenyl precursors
In the present case, isolated main products of cyclodehydration of acids 2b,e,f are linearly condensed
1
ketones with 2,3-disubstituted naphthalene moiety as represented by structure 1, which is proved by H
NMR spectra possessing singlets for C-6 and C-11 protons in aromatic region of the compounds 1b,e,f.
Previously described synthesis of 1b also brings evidence for formation of the linearly condensed isomer.21
Moreover, confirmation of linear structure was obtained by single X-ray crystallographic analysis of the
selected representative 12f that was derived from ketone 1f (see below). ORTEP diagram, molecular
packing and unit cell of 12f are depicted in Figure 2 with crystal data shown in Table 3. Crystallographic
analysis also revealed angular arrangement of benzene versus tetrahydronaphathalene moiety in the
so-called butterfly shape32,33 due to non-planar conformation of the central oxepine ring.
Figure 2. Molecular and crystal structure of compound 12f

HETEROCYCLES, Vol. 81, No. 10, 2010
2277
Table 3. Crystal data for compound 12f
Molecular formula
Molecular weight
Crystal system
C21H18O2S
334.41
Monoclinic
P 21
Space group
Unit cell dimensions
a = 11.188(1) Å
b = 5.022(1) Å
c = 14.967(1) Å
829.02(2) Å3
2
α = 90.00 °
β = 99.657(1) °
γ = 90.00 °
Unit cell volume
No. of molecules in the unit cell
Calculated density
1.34 g/cm3
In view of the greater reactivity of the naphthalene α-position in electrophilic substitutions, including
Friedel-Crafts acylations, as compared with that of the β-position, we had to consider formation of the
angular structure 9 that, however, is not compatible with the above given results (for analogies see refs
34-38). The preference for cyclization at 3-position can be explained either by spatial orientation of the
carbonyl group vis-à-vis the naphthalene nuclei that sterically hinders formation of 1,2-disubstituted
moiety,21,35 or more likely, by the kinetically controlled formation of compounds 9 that under
thermodynamically controlled conditions, e.g. in PPA at elevated temperatures, isomerise to more stable,
less sterically hindered products 1.36,37
Compounds 1a,c,d, derived from corresponding 1-(thio)naphthols and containing 1,2-disubstituted
1
naphthalene moiety, possess in the aromatic region of H NMR spectrum two characteristic doublets for
C-5 and C-6 protons (see numbering in Scheme 5.), that are mutually coupled with J (ortho) = 8-9 Hz. In
addition, notable feature in 1H NMR spectra of 1a and 1c is the multiplet of the peri-naphthalene C-1 proton,
separated from the signals of other aromatic protons and markedly shifted for approximately 1.0 ppm
toward higher values of ppm with δ = 8.8-8.9 ppm. At position C-1 of analogous tetralin derivative 1d a
down-field shift of methylene protons for 0.25 ppm as compared to precursors is also noticeable. The
rationale for this is probably associated with the vicinity of sulfur or oxygen atom respectively, that with
nonbonding electron pairs deshield C-1 protons. This same phenomenon was observed also for subsequent
1
compounds from a, c and d series (see below). H NMR spectra of all ketones 1a-f show significant
deshielding of proton at position C-11 in linear and position C-6 in angular isomers due to the diamagnetic
anisotropy of the nearby carbonyl group, as already reported for similar compounds.36,37,39 Thus, signal of
this proton is shifted down-field for 0.2-0.9 ppm depending on particular derivative, with linear compounds
displaying the greatest signal shift.
To enable annulation of thiophene ring in the succeeding step, tetracyclic ketones 1a-f were reacted with in
situ formed Vilsmeier reagent to give β-chlorovinyl aldeydes 10a-f (Scheme 7). A markedly lower

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HETEROCYCLES, Vol. 81, No. 10, 2010
reactivity for thiepin derivatives comparing to oxepin analogs was noticed in chloroformylation reaction.
Oxepin derivatives react quantitatively, with yields after work-up > 87%, while the reaction of thiepin
analogs stops before completion, affording 42% of 10a and 60% of 10b after separation from unreacted
ketones 1a and 1b, respectively. Dependency of the reactivity in Vilsmeier reaction on the heteroatom in
the central seven-membered ring was already reported for similar ketones.6
Singlet of the aldehyde proton of compounds 10a-f appears in the 1H NMR spectra in the range of 10.5-10.8
ppm. Chloro atom exerts smaller deshielding effect on the closest aromatic proton comparing to carbonyl
group in corresponding starting ketones. Nevertheless, the signal of the proton in the vicinity of chloro atom
shows the highest δ value, except for compounds 10a and 10c where again C-1 proton suffers from the
strongest deshielding effect of the nearby sulfur or oxygen atom, respectively (δ = 8.9 ppm for 10a and δ =
8.65 ppm for 10c).
To obtain compounds with fused thiophene ring, reaction of β-chlorovinyl aldeydes 10a-f with ethyl
2-mercaptoacetate in the presence of triethylamine and pyridine was used. The thiophene ring was formed
according to the well established process.40-43 Cyclocondensation afforded series of novel, fused
hetero-pentacyclic
compounds:
naphtho[1,2-b]thieno[2,3-d][1]benzothiepin
11a,
naphtho[2,3-b]thieno[2,3-d][1]benzothiepin 11b, naphtho[1,2-b]thieno[2,3-d][1]benzoxepins 11c,d and
naphtho[2,3-b]thieno[2,3-d][1]benzoxepins 11e,f, substituted with ethyloxycarbonyl at thiophene
2-position. Reaction proceeds with total conversion providing after purification crystalline products in very
good yields (60-86%), Scheme 7.
X
X
S
[1,2] fused
[2,3] fused
[1,2] fused
[1,2] fused
[2,3] fused
[2,3] fused
a
b
c
d
X
X
POCl3, DMF
HSCH2CO2Et
NEt3, pyridine
S
trichloroethene
S
O
O
O
O
O
Cl
OHC
R
1a-f
10a-f
R = CO2Et, 11a-f
R = CH2OH, 12a-f
LiAlH4
diethyl ether / THF
e
f
Scheme 7. Final steps in the synthesis of naphtho[2,3-b]- and naphtho[1,2-b]-fused
thieno[2,3-d][1]benzoxepins and thieno[2,3-d][1]benzothiepins
1
In the aromatic region of H NMR spectra singlet of the thiophene proton is distinguished at δ
approximately 8.0-8.2 ppm. For compounds 11a and 11c with [1,2]-fused naphthalene moiety deshielded
peri-naphthalene proton in the vicinity of the heteroatom from the seven-membered ring repeatedly shows
the signal with the greatest shift (δ = 9.2 ppm for 11a and δ = 8.7 ppm for 11c).
Guided by the designed structures of potentially biologically active target molecules,44 ester group of 11a-f
was subjected to reduction. The reaction was performed with lithium aluminum hydride in ether and/or

HETEROCYCLES, Vol. 81, No. 10, 2010
2279
THF to obtain crystalline alcohols 12a-f in excellent yields after purification (73-98%).
Singlet of the thiophene proton is shifted toward lower values of ppm for approximately 0.7-0.8 ppm
comparing to proton from preceding carboxyl-substituted thiophene ring, with δ about 7.3-7.4 ppm.
Continually, doublet of deshielded peri-naphthalene proton next to thiepin or oxepin heteroatom in
compounds 12a and 12c is considerably shifted down-field (δ = 8.9 ppm and δ = 8.7 ppm respectively).
The most salient features of the IR, 1H NMR, 13C NMR and MS spectra for compounds 1a-f, 10a-f, 11a-f
and 12a-f are summarized in Experimental.
EXPERIMENTAL
Chemistry – general methods. Commercial reagents were used as received without additional
purification. All used chemicals and solvents were p.a. purity. Melting points were determined using
Büchi Melting Point B-545 apparatus and are uncorrected. IR spectra were recorded on Nicolet Magna IR
760 FT IR-spectrophotometer as a KBr pastille or as a film. NMR spectra were recorded at room
temperature on Bruker Avance DPX 300 spectrometer at 300 MHz. Deuterated chloroform (CDCl3) or
deuterated dimethyl sulfoxide (DMSO-d6) were used as solvent and tetramethylsilane (TMS) as internal
standard. Mass spectra were acquired using ES (Electrospray) ionization at Platform LCZ (Micromass,
UK) and LCQ Deca (Finnigan, US) instruments, and using chemical ionization (CI) at GC-MS system
Varian Chrompack Saturn 2000. Purity of the compounds was estimated by HPLC-MS system Waters
2690 + Micromass Quattro Micro, by HPLC-UV system Waters 2690 + Waters 996 Photodiode Array
Detector or by the above mentioned GC-MS system. Microanalyses were performed using Perkin-Elmer
2400 C H N S analyzer. Thin layer chromatography (TLC) was performed on aluminum plates Merck
Silica gel 60 F254 with UV light detection at 254 nm and/or 365 nm. Proportions of solvents used for TLC
are by volume. Column chromatography was performed on silica gel 60 (Merck, 0.063-0.200 nm). X-Ray
diffraction data were collected on a Bruker Nonius FR591 diffractometer using CuK(α) radiation.
Spectroscopic and analytical data for compounds 2a-f, 3a-d, 4a-d, 5a-d and 6a-d are given in Tables 1
and 2.
General procedure for preparation of 2-(naphthalenylthio)benzoic acids 3a,b. To an aqueous solution
of KOH (11.70 g, 0.21 mol in 110 mL) heated to 50 °C, naphthalenethiol (62.4 mmol) was added. The
reaction mixture was stirred at this temperature for additional 10 min, then 2-iodobenzoic acid (15.48 g,
62.4 mmol) and Cu powder (1.0 g, 15.7 mmol) were added. The mixture was refluxed under stirring for 8 h.
Cu was removed by filtering off while the mixture was still hot. Filtrate was cooled to rt and acidified with
conc. HCl to pH approximately 2. The colorless precipitate of the product (3a,b) was filtered off, washed a
few times with water and dried.

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General procedure for preparation of 2-(naphthalenyloxy)benzoic acids 3c,d. A mixture of naphthol
(30.2 mmol), 2-iodobenzoic acid (7.5 g, 30.2 mmol), K2CO3 (6.27 g, 45.4 mmol) and Cu powder (0.15 g,
2.36 mmol) in nitrobenzene (10 mL) or xylene (10 mL) was heated with stirring at 140 °C for about 1 h.
After the completion of the reaction water (100 mL) and EtOAc (50 mL) were added and the organic
layer was separated. The aqueous layer was boiled with decolorizing charcoal for 5 min and then acidified
with conc. HCl to pH approximately 2. The product precipitate (3c,d) was filtered off or extracted with
EtOAc. Analytical sample was purified by recrystallization from the appropriate solvent or by column
chromatography.
General procedure for preparation of [2-(naphthalenylthio)phenyl]methanols 4a,b and
[2-(naphthalenyloxy)phenyl]methanols 4c,d. To a suspension of LiAlH4 (4.40 g, 0.116 mol) in Et2O
(100 mL) acid 3a-d was added in small portions with vigorous stirring (60.6 mmol). After 4 h of stirring
at rt the excess of LiAlH4 was decomposed by adding ether and water. The inorganic precipitate was
filtered off and washed few times with Et2O. The filtrate was dried (Na2SO4) and evaporated under
reduced pressure to give a crude product (4a-d) which was purified by recrystallization from the
appropriate solvent or by column chromatography.
General procedure for preparation of {[2-(bromomethyl)phenyl]thio}naphthalenes 5a,b. A mixture
of alcohol 4a,b (36.9 mmol) and 47% HBr (30 mL) was heated with stirring at reflux temperature for 2 h.
After the completion of the reaction the mixture was cooled, cautiously poured into water (50 mL) and
extracted with Et2O (250 mL). The combined organic extracts were washed with sat. aq. NaHCO3, dried
(Na2SO4) and solvent evaporated under reduced pressure to give a crude product (5a,b) that was
sufficiently pure for the next step reaction. Analytical sample was purified by column chromatography.
General procedure for preparation of {[2-(bromomethyl)phenyl]oxy}naphthalenes 5c,d. To a
dichloromethane solution of alcohol 4c,d (8.0 mmol in 30 mL) cooled to 0 °C, PBr3 (290 μL, 3.05 mmol)
was added dropwise and the mixture was stirred at this temperature for about 30 min (TLC control,
hexane/EtOAc 2:1). Then the mixture was poured into cool water (100 mL), the organic layer was
separated and the aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic extracts
were washed with sat. aq. NaHCO3, dried (Na2SO4) and solvent evaporated under reduced pressure. The
crude products (5c,d) were used in the next step without purification, but analytical sample was purified by
column chromatography.
General procedure for preparation of [2-(naphthalenylthio)phenyl]acetonitriles 6a,b and
[2-(naphthalenyloxy)phenyl]acetonitriles 6c,d. A mixture of bromide 5a-d (36.4 mmol) and NaCN

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2281
(2.24 g, 45.7 mmol) in 96% EtOH (50 mL) was refluxed for approximately 4 h. After the completion of
the reaction EtOH was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (100
mL) and water (60 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2
(250 ml). The combined organic extracts were washed with water (70 mL), dried (Na2SO4) and solvent
evaporated under reduced pressure. The crude product (6a-d) was purified by column chromatography.
1-[2-(2-Naphthalenyloxy)phenyl]ethanone45 (7). A mixture of 2-naphthalenol (5.0 g, 34.7 mmol),
2-chloracetophenone (4.0 g, 25.9 mmol), K2CO3 (5.36 g, 38.8 mmol) and CuCl (0.10 g) in isoamyl
alcohol (3 mL) was refluxed overnight. The reaction mixture was then cooled and filtered and the
precipitate was washed few times with EtOAc. Filtrate was washed with 10% aq. NaOH and water, dried
(Na2SO4) and solvent evaporated under reduced pressure. The residue was distilled under high vacuum to
give a pure product 7 in the form of a yellow liquid, 5.30 g (78%), bp 205 °C (10 mm Hg). IR (film)
ν/cm-1: 3058, 1681 (C=O), 1633, 1599, 1575, 1511, 1478, 1463, 1447, 1359, 1286, 1248, 1222, 1161,
1122. 1H NMR (CDCl3) δ/ppm: 2.68 (s, 3H, CH3), 6.97 (dd, J = 8.3 Hz, 0.9 Hz, 1H, arom.), 7.10-7.33 (m,
3H, arom.), 7.40-7.50 (m, 3H, arom.), 7.69-7.72 (m, 1H, arom.), 7.82-7.91 (m, 3H, arom.). MS (CI) m/z:
263 (MH+, 100%). Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C, 82.63; H, 5.55.
4-{2-[2-(2-Naphthalenyloxy)phenyl]ethanethioyl}morpholine (8). A mixture of compound 7 (5.25 g,
20.0 mmol), morpholine (2.41 g, 27.7 mmol) and sulfur (1.0 g, 31.2 mmol) was refluxed for about 2.5 h
during which the reaction solution became dark red. The reaction mixture was purified by column
chromatography (eluent hexane/EtOAc 1:1) to obtain the pure product 8 as yellow viscous substance,
4.24 g (58%). IR (film) ν/cm-1: 3055, 2966, 2921, 2856; 1652, 1632, 1597, 1582, 1509, 1487, 1453, 1275,
1
1249, 1226, 1160, 1112, 1030. H NMR (CDCl3) δ/ppm: 3.43-3.46 (m, 2H, CH2), 3.67-3.73 (m, 4H,
2CH2), 4.32-4.35 (m, 4H, 2CH2), 6.96 (dd, J = 8.0 Hz, 1.1 Hz, 1H, arom.), 7.14-7.28 (m, 3H, arom.),
7.38-7.53 (m, 3H, arom.), 7.59-7.67 (m, 2H, arom.), 7.75-7.89 (m, 2H, arom.). 13C NMR (CDCl3) δ/ppm:
43.6 (CH2), 50.1, 50.7, 66.2, 66.4 (CH2, morph.), 112.8, 119.0, 119.6, 124.6, 124.8, 126.8, 127.0, 127.8,
128.7, 129.7, 130.2 (CH), 127.6, 130.1, 134.2, 153.2, 154.9 (C), 200.3 (C=S). MS (ES+) m/z: 386
([M+Na]+, 100%); 364 (MH+, 20%). Anal. Calcd for C22H21NO2S: C, 72.70; H, 5.82; N, 3.85; S, 8.82.
Found: C, 72.35; H, 5.49; N, 4.00; S, 8.52.
General procedure for preparation of 2-substituted phenylacetic acids 2a-d. A mixture of nitrile 6a-d
(25.8 mmol) and KOH (3.76 g, 67.0 mmol) in EtOH (40 mL) and water (10 mL) was stirred under reflux for
approximately 15 h. Then EtOH was evaporated under reduced pressure. The residue was diluted with
water (80 mL) and the aqueous solution was washed with CH2Cl2 (40 mL). The aqueous layer was acidified

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HETEROCYCLES, Vol. 81, No. 10, 2010
with conc. HCl to pH approximately 2 and thus separated product was filtered off or extracted with EtOAc
(370 mL). The crude product (2a-d) was used in the next step without purification. Analytical sample was
purified by recrystallization or column chromatography.
[2-(2-Naphthalenyloxy)phenyl]acetic acid (2e). A mixture of compound 8 (4.15 g, 11.4 mmol), acetic
acid (6.1 mL) and 50% H2SO4 (1.2 mL) was stirred under reflux for about 8 h. Then the reaction mixture
was poured into water (30 mL) and extracted with CH2Cl2 (350 mL). The combined dichloromethane
extracts were washed with 10% aq. NaOH. Alkaline aqueous phase was acidified with conc. HCl to pH
approximately 2. The separated product was extracted with CH2Cl2 (350 mL), the combined organic
extracts dried (Na2SO4) and boiled with decolorizing charcoal for 5 min. Solvent was removed under
reduced pressure to obtain 2e as colorless crystals.
[2-(5,6,7,8-Tetrahydro-2-naphthalenyloxy)phenyl]acetic acid (2f). A mixture of 2-chlorophenylacetic
acid (11.51 g, 67.5 mmol) and K2CO3 (17.40 g, 0.126 mol) was heated with stirring to 80 °C, then
5,6,7,8-tetrahydro-2-naphthalenol (10.0 g, 67.5 mmol) and CuCl (700 mg) were added. Temperature was
elevated to 160 °C and during warming-up the mixture temporarily solidified and stirring was disabled.
Afterwards the mixture was heated with stirring at 160 °C for about 2.5 h with TLC monitoring
(CH2Cl2/MeOH 95:5). The mixture was cooled; water (100 mL) and EtOAc (100 mL) were added. The
layers were agitated. The organic layer was discarded and the aqueous phase was washed once more with
EtOAc (30 mL), boiled with decolorizing charcoal for 5 min and acidified with conc. HCl to pH
approximately 2. The precipitate was filtered off, washed with water and dried to obtain 2f as pale brown
crystals. Analytical sample was prepared by recrystallization from EtOH.
General procedure for preparation of tetracyclic ketones 1a-f. To a reaction flask containing PPA (50
g) heated to 90 °C, acid 2a-f (25 mmol) was portion-wise added and mixed in. The mixture was vigorously
stirred at 110 °C for about 2 h, whereby it became dark. Reaction course was monitored by TLC
(hexane/EtOAc 3:1). The mixture was poured into ice-water (500 mL) and then extracted with CH2Cl2
(3100 mL). The combined organic extracts were washed with 10% aq. NaOH and water, boiled with
decolorizing charcoal for 10 min, dried (Na2SO4) and solvent evaporated under reduced pressure to obtain
products 1a-f. Analytical samples were prepared by column chromatography purification or by vacuum
distillation.
Benzo[b]naphtho[2,1-f]thiepin-7(8H)-one20 (1a). This compound was obtained starting from 2a, light
yellow solid, 88%. IR (film) ν/cm-1: 3056, 1666 (C=O), 1594, 1471, 1444, 1312, 1270. 1H NMR (CDCl3)
δ/ppm: 4.51 (s, 2H, CH2), 7.21 (dt, J = 7.5 Hz, 1.5 Hz, 1H, arom.), 7.41 (dt, J = 7.5 Hz, 1.3 Hz, 1H,

HETEROCYCLES, Vol. 81, No. 10, 2010
2283
arom.), 7.49-7.52 (m, 1H, arom.), 7.60-7.74 (m, 4H, arom.), 7.82-7.85 (m, 1H, arom.), 8.22 (d, J = 8.8 Hz,
1H, arom. 6-H), 8.86-8.90 (m, 1H, arom. 1-H). MS (CI) m/z: 277 (MH+, 100%).
Benzo[b]naphtho[2,3-f]thiepin-12(13H)-one21 (1b). This compound was obtained starting from 2b, light
yellow solid, 97%. IR (KBr) ν/cm-1: 3045, 1677 (C=O), 1620, 1574, 1468, 1428, 1316, 1250, 1217, 1142,
1134, 1075. 1H NMR (CDCl3) δ/ppm: 4.55 (s, 2H, CH2), 7.21 (dt, J = 7.5 Hz, 1,4 Hz, 1H, arom.), 7.36 (dt,
J = 7.5 Hz, 1.3 Hz, 1H, arom.), 7.44-7.50 (m, 2H, arom.), 7.53-7.59 (m, 1H, arom.), 7.70 (dd, J = 7.5 Hz,
1.0 Hz, 1H, arom.), 7.78 (d, J = 8.3 Hz, 1H, arom.), 7.91 (d, J = 8.1 Hz, 1H, arom.), 8.11 (s, 1H, arom.
6-H), 8.78 (s, 1H, arom. 11-H). MS (CI) m/z: 277 (MH+, 100%).
Benzo[b]naphtho[2,1-f]oxepin-7(8H)-one (1c). This compound was obtained starting from 2c, purified
by column chromatography (eluent hexane/EtOAc 2:1), yellow viscous oil, 84%. IR (film) ν/cm-1: 3061,
1674 (C=O), 1625, 1598, 1567, 1487, 1457, 1427, 1398, 1371, 1345, 1277, 1232, 1181, 1147, 1113, 1078,
1
1025. H NMR (CDCl3) δ/ppm: 4.20 (s, 2H, CH2), 7.19-7.41 (m, 4H, arom.), 7.57 (d, J = 8.7 Hz, 1H,
arom. 5-H), 7.62-7.68 (m, 2H, arom.), 7.80-7.84 (m, 1H, arom.), 8.04 (d, J = 8.7 Hz, 1H, arom. 6-H),
13
8.74-8.78 (m, 1H, arom. 1-H). C NMR (CDCl3) δ/ppm: 48.5 (CH2); 120.2, 123.4, 124.1, 125.0, 126.5,
126.9, 127.7, 128.3, 129.3, 129.8 (CH); 121.5, 127.2, 131.9, 137.2, 157.2, 158.0 (C); 190.6 (C=O). MS
(CI) m/z: 261 (MH+, 100%). Anal. Calcd for C18H12O2: C, 83.06; H, 4.65. Found: C, 83.45; H, 4.70.
1,2,3,4-Tetrahydrobenzo[b]naphtho[2,1-f]oxepin-7(8H)-one (1d). This compound was obtained starting
from 2d, purified by column chromatography (eluent hexane/EtOAc 3:1), pale yellow solid, 90%. IR
(KBr) ν/cm-1: 2934, 1678 (C=O), 1601, 1563, 1488, 1456, 1414, 1332, 1319, 1283, 1260, 1231, 1181,
1
1112, 1069. H NMR (DMSO-d6) δ/ppm: 1.70-1.80 (m, 2H, tetralin), 1.80-1.89 (m, 2H, tetralinski),
2.76-2.81 (m, 2H, tetralin), 3.02-3.06 (m, 2H, tetralin), 4.08 (s, 2H, CH2C=O), 6.99 (d, J = 8.1 Hz, 1H,
arom. 5-H), 7.22-7.34 (m, 2H, arom.), 7.37-7.44 (m, 2H, arom.), 7.66 (d, J = 8.1 Hz, 1H, arom. 6-H). MS
(CI) m/z: 265 (MH+, 100%). Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.55; H, 5.85.
Benzo[b]naphtho[2,3-f]oxepin-12(13H)-one (1e). This compound was obtained starting from 2e, distilled
under high vacuum, yellow solid, 69%, bp 195 ° C (10 mm Hg). IR (film) ν/cm-1: 3058, 1682 (C=O),
1
1628, 1586, 1487, 1444, 1338, 1237, 1144, 1127. H NMR (DMSO-d6) δ/ppm: 4.26 (s, 2H, CH2),
7.26-7.30 (m, 1H, arom.), 7.36-7.56 (m, 4H, arom.), 7.63-7.67 (m, 1H, arom.), 7.99 (d, 1H, arom.), 8.00
(s, 1H, arom. 6-H), 8.12 (d, J = 8.2 Hz, 1H, arom.), 8.64 (s, 1H, arom. 11-H). MS (CI) m/z: 261 (MH+,
100%). Anal. Calcd for C18H12O2: C, 83.06; H, 4.65. Found: C, 83.01; H, 4.44.
7,8,9,10-Tetrahydrobenzo[b]naphtho[2,3-f]oxepin-12(13H)-one (1f). This compound was obtained
starting from 2f, distilled under high vacuum, light yellow solid, 44%, bp 180 °C (10 mm Hg). IR (KBr)
1
ν/cm-1: 2931, 1680 (C=O), 1612, 1586, 1480, 1456, 1416, 1316, 1275, 1231, 1177, 1129. H NMR
(DMSO-d6) δ/ppm: 1.70-1.73 (m, 4H, 2×CH2 tetralin), 2.68-2.74 (bm, 2H, tetralin), 2.76-2.82 (bm, 2H,
tetralin), 4.08 (s, 2H, CH2CO), 7.18 (s, 1H, arom. 6-H), 7.21-7.33 (m, 3H, arom.), 7.40-7.43 (m, 1H,

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HETEROCYCLES, Vol. 81, No. 10, 2010
arom.), 7.61 (s, 1H, arom. 11-H). MS (CI) m/z: 265 (MH+, 100%). Anal. Calcd for C18H16O2: C, 81.79; H,
6.10. Found: C, 81.50; H, 5.99.
General procedure for preparation of β-chlorovinylaldehydes 10a-f. To N,N-dimethylformamide (6.30
mL, 81 mmol) in trichloroethene (5 mL) previously cooled to –5 °C, POCl3 (5.0 mL, 54.0 mmol) was added
dropwise with continuous stirring while maintaining the reaction temperature below 18 °C. The mixture
was stirred at rt for 30 min, whereupon the solution of ketone 1a-f (18.0 mmol) in trichloroethene (10.0 mL)
was added stepwise. The resulting mixture was refluxed for 8 h when by TLC checking (CH2Cl2) the
reaction progress wasn’t further noticeable. The reaction mixture was cooled and 30% aq. NaOAc (20 mL)
was added very slowly dropwise. When exothermic reaction was finished the layers were separated and the
aqueous phase was extracted with CH2Cl2 (350 mL). The combined organic extracts were boiled with
decolorizing charcoal for 5 min, dried (Na2SO4) and solvent removed under reduced pressure. The crude
product was purified by column chromatography. Analytical samples were obtained by recrystallization
from EtOAc/hexane.
7-Chlorobenzo[b]naphtho[2,1-f]thiepin-8-carbaldehyde (10a). This compound was obtained starting
from 1a, separated from unreacted 1a by column chromatography (eluent CH2Cl2), pale yellow solid,
1
42%. H NMR (CDCl3) δ/ppm: 7.23-7.84 (m, 8H, arom.), 8.21-8.23 (m, 1H, arom.), 8.87-8.91 (m, 1H,
arom. 1-H), 10.79 (s, 1H, CHO). MS (CI) m/z: 323, 325 (MH+, 100%, 37%). Anal. Calcd for
C19H11ClOS: C, 70.69; H, 3.43; S, 9.93. Found: C, 70.32; H, 3.40; S, 10.17.
12-Chlorobenzo[b]naphtho[2,3-f]thiepin-13-carbaldehyde (10b). This compound was obtained starting
from 1b, separated from unreacted 1b by column chromatography (eluent CH2Cl2), pale yellow solid,
1
60%. H NMR (CDCl3) δ/ppm: 7.27-7.37 (m, 3H, arom.), 7.50-7.57 (m, 2H, arom.), 7.61-7.64 (m, 1H,
arom.), 7.77-7.80 (m, 1H, arom.), 7.85-7.88 (m, 1H, arom.), 8.07 (s, 1H, arom. 6-H), 8.32 (s, 1H, arom.
11-H), 10.73 (s, 1H, CHO). MS (CI) m/z: 323, 325 (MH+, 100%, 37%). Anal. Calcd for C19H11ClOS: C,
70.69; H, 3.43; S, 9.93. Found: C, 71.02; H, 3.55; S, 10.20.
7-Chlorobenzo[b]naphtho[2,1-f]oxepin-8-carbaldehyde (10c). This compound was obtained starting
from 1c, light yellow solid, 97%. IR (KBr) ν/cm-1: 3062, 2926; 2761, 1682 (C=O), 1626, 1595, 1583,
1
1557, 1487, 1444, 1386, 1371, 1343, 1309, 1260, 1201, 1152, 1124, 1088, 1064. H NMR (CDCl3)
δ/ppm: 7.18-7.23 (m, 1H, arom.), 7.33-7.41 (m, 2H, arom.), 7.55-7.58 (m, 1H, arom.), 7.60-7.72 (m, 3H,
arom.), 7.79-7.87 (m, 2H, arom.), 8.64-8.67 (m, 1H, arom. 1-H), 10.73 (s, 1H, CHO). MS (CI) m/z: 307,
309 (MH+, 100%, 39%). Anal. Calcd for C19H11ClO2: C, 74.40; H, 3.61. Found: C, 74.61; H, 3.26.
7-Chloro-1,2,3,4-tetrahydrobenzo[b]naphtho[2,1-f]oxepin-8-carbaldehyde (10d). This compound was
obtained starting from 1d, yellowish solid, 87%. IR (KBr) ν/cm-1: 2934; 1681 (C=O), 1601, 1565, 1486,
1
1441, 1416, 1318, 1202, 1125. H NMR (DMSO-d6) δ/ppm: 1.65-1.87 (bm, 4H, tetralin), 2.74-2.79 (m,

HETEROCYCLES, Vol. 81, No. 10, 2010
2285
2H, tetralin), 3.00-3.05 (bm, 2H, tetralin), 7.11 (d, J = 8.2 Hz, 1H, arom. 5-H), 7.22-7.28 (m, 1H, arom.),
7.40-7.46 (m, 3H, arom.), 7.56 (d, J = 8.2 Hz, 1H, arom. 6-H), 10.51 (s, 1H, CHO). MS (CI) m/z: 311,
313 (MH+, 100%, 37%). Anal. Calcd for C19H15ClO2: C, 73.43; H, 4.86. Found: C, 73.74; H, 5.09.
12-Chlorobenzo[b]naphtho[2,3-f]oxepin-13-carbaldehyde (10e). This compound was obtained starting
from 1e, yellowish solid, 90%. IR (KBr) ν/cm-1: 3057, 2927; 2754, 1681 (C=O), 1598, 1487, 1443, 1310,
1
1239, 1209. H NMR (CDCl3) δ/ppm: 7.19-7.58 (m, 6H, arom.), 7.68 (s, 1H, arom. 6-H), 7.81-7.94 (m,
2H, arom.), 8.38 (s, 1H, arom. 11-H), 10.73 (s, 1H, CHO). MS (CI) m/z: 307, 309 (MH+, 100%, 39%).
Anal. Calcd for C19H11ClO2: C, 74.40; H, 3.61. Found: C, 74.74; H, 3.88.
12-Chloro-7,8,9,10-tetrahydrobenzo[b]naphtho[2,3-f]oxepin-13-carbaldehyde (10f). This compound was
obtained starting from 1f, yellowish solid, 96%. IR (KBr) ν/cm-1: 2933, 2858, 1683 (C=O), 1608, 1552,
1
1483, 1443, 1411, 1308, 1286, 1248, 1205, 1124, 1062. H NMR (DMSO-d6) δ/ppm: 1.67-1.71 (m, 4H,
2×CH2 tetralin), 2.71-2.79 (bm, 4H, 2×CH2 tetralin), 7.13 (s, 1H, arom. 6-H), 7.21-7.26 (m, 1H, arom.),
13
7.33-7.37 (m, 1H, arom.), 7.41-7.47 (m, 2H, arom.), 7.51 (s, 1H, arom. 11-H), 10.51 (s, 1H, CHO). C
NMR (DMSO-d6) δ/ppm: 21.9, 22.2, 28.0, 28.7 (tetralin CH2); 120.66, 120.73, 124.7, 129.6, 130.75,
130.80 (CH); 124.8, 126.2, 132.6, 134.5, 144.2, 145.8, 157.0, 159.0 (C); 190.5 (CHO). MS (CI) m/z: 311,
313 (MH+, 100%, 35%). Anal. Calcd for C19H15ClO2: C, 73.43; H, 4.86. Found: C, 73.41; H, 5.02.
General procedure for preparation of pentacyclic esters 11a-f. To the solution of chloroaldehyde
10a-f (6.20 mmol) in pyridine (15 mL) ethyl 2-mercaptoacetate (0.76 g, 4.6 mmol) and Et3N (2 mL) were
added. The reaction mixture was stirred at 70 °C for 1 h and then at reflux temperature for additional 2 h.
Solvent was removed under reduced pressure till dryness and the residue was partitioned between water
and ethyl acetate. The aqueous phase was extracted with ethyl acetate (225 mL). The combined organic
extracts were washed with dil. HCl (5%) and water, boiled with decolorizing charcoal for 5 min, dried
(Na2SO4) and solvent evaporated. Thus obtained crude product 11a-f was purified by recrystallization or
column chromatography.
Ethyl naphtho[1,2-b]thieno[2,3-d][1]benzothiepin-8-carboxylate (11a). This compound was obtained
starting from 10a, purified by column chromatography (eluent hexane/EtOAc 3:1), yellowish solid, 75%.
1H NMR (CDCl3) δ/ppm: 1.33 (t, J = 7.1 Hz, 3H, CH3), 4.20 (q, J = 7.1 Hz, 2H, CH2), 7.09-8.06 (m, 9H,
arom.), 8.36-8.40 (m, 1H, arom.); 9.18-9.22 (m, 1H, arom. 1-H). MS (CI) m/z: 389 (MH+, 100%). Anal.
Calcd for C23H16O2S2: C, 71.11; H, 4.15; S, 16.51. Found: C, 71.60; H, 4.49; S, 16.58.
Ethyl naphtho[2,3-b]thieno[2,3-d][1]benzothiepin-2-carboxylate (11b). This compound was obtained
starting from 10b, purified by column chromatography (eluent hexane/EtOAc 3:1), light yellow solid,
80%. 1H NMR (CDCl3) δ/ppm: 1.43 (t, J = 7.1 Hz, 3H, CH3), 4.43 (q, J = 7.1 Hz, 2H, CH2), 7.30-7.41 (m,
2H, arom.), 7.49-7.56 (m, 3H, arom.), 7.71 (dd, J = 7.5 Hz, 1.5 Hz, 1H, arom.), 7.78-7.85 (m, 2H, arom.),

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HETEROCYCLES, Vol. 81, No. 10, 2010
8.01 (s, 1H, thioph.), 8.04 (s, 1H, arom. 9-H), 8.17 (s, 1H, arom. 14-H). MS (CI) m/z: 389 (MH+, 100%).
Anal. Calcd for C23H16O2S2: C, 71.11; H, 4.15; S, 16.51. Found: C, 71.45; H, 4.01; S, 16.40.
Ethyl naphtho[1,2-b]thieno[2,3-d][1]benzoxepin-8-carboxylate (11c). This compound was obtained
starting from 10c, purified by column chromatography (eluent hexane/EtOAc 2:1), yellowish crystals,
86%. IR (KBr) ν/cm-1: 3056, 2980; 1714 (C=O), 1598, 1546, 1494, 1477, 1456, 1436, 1393, 1366, 1293,
1277, 1244, 1198, 1152, 1128, 1082, 1017. 1H NMR (CDCl3) δ/ppm: 1.43 (t, J = 7.1 Hz, 3H, CH3), 4.42
(q, J = 7.1 Hz, 2H, CH2), 7.21-7.26 (m, 1H, arom.), 7.35-7.41 (m, 1H, arom.), 7.48-7.59 (m, 4H, arom.),
7.63-7.73 (m, 2H, arom.), 7.85 (d, J = 8.0 Hz, 1H, arom.), 8.09 (s, 1H, thioph.), 8.65-8.69 (m, 1H, arom.
1-H). MS (ES+) m/z: 395 ([M+Na]+, 100%). Anal. Calcd for C23H16O3S: C, 74.17; H, 4.33; S, 8.61.
Found: C, 74.54; H, 4.04; S, 8.52.
Ethyl 1,2,3,4-tetrahydronaphtho[1,2-b]thieno[2,3-d][1]benzoxepin-8-carboxylate (11d). This compound
was obtained starting from 10d, purified by column chromatography (eluent hexane/EtOAc 2:1),
yellowish crystals, 83%. IR (KBr) ν/cm-1: 2934, 1705 (C=O), 1604, 1543, 1493, 1459, 1432, 1381, 1324,
1
1277, 1249, 1197, 1129, 1082, 1071. H NMR (DMSO-d6) δ/ppm: 1.34 (t, J = 7.1 Hz, 3H, CH3),
1.68-1.88 (bm, 4H, tetralin), 2.72-2.76 (m, 2H, tetralin), 3.02-3.07 (m, 2H, tetralin), 4.35 (q, J = 7.1 Hz,
2H, ester CH2), 7.02 (d, J = 8.0 Hz, 1H, arom. 5-H), 7.27-7.32 (m, 1H, arom.), 7.31 (d, J = 8.0 Hz, 1H,
arom. 6-H), 7.42-7.44 (m, 2H, arom.), 7.72 (d, J = 7.7 Hz, 1H, arom.), 8.14 (s, 1H, thioph.). MS (CI) m/z:
377 (MH+, 100%). Anal. Calcd for C23H20O3S: C, 73.38; H, 5.35; S, 8.52. Found: C, 73.70; H, 5.49; S,
8.90.
Ethyl naphtho[2,3-b]thieno[2,3-d][1]benzoxepin-2-carboxylate (11e). This compound was obtained
starting from 10e, purified by column chromatography (eluent hexane/EtOAc 2:1), then crystallized from
hexane, colorless crystals, 60%. IR (KBr) ν/cm-1: 1714 (C=O), 1547, 1494, 1478, 1443, 1383, 1262, 1206,
1
1132, 1085, 1023. H NMR (DMSO-d6) δ/ppm: 1.37 (t, J = 7.1 Hz, 3H, CH3), 4.38 (q, J = 7.1 Hz, 2H,
CH2), 7.30-7.35 (m, 1H, arom.), 7.44-7.60 (m, 4H, arom.), 7.75-7.79 (m, 1H, arom.), 7.93-7.96 (m, 1H,
arom.), 7.99 (s, 1H, arom. 9-H), 8.02-8.05 (m, 1H, arom.), 8.22 (s, 1H, thioph.), 8.27 (s, 1H, arom. 14-H).
MS (ES+) m/z: 395 ([M+Na]+, 100%). Anal. Calcd for C23H16O3S: C, 74.17; H, 4.33; S, 8.61. Found: C,
74.41; H, 3.98; S, 8.80.
Ethyl 10,11,12,13-tetrahydronaphtho[2,3-b]thieno[2,3-d][1]benzoxepin-2-carboxylate (11f). This
compound was obtained starting from 10f, crystallized from EtOAc, pale yellow crystals, 80%. IR (KBr)
ν/cm-1: 2925, 1705 (C=O), 1613, 1543, 1492, 1468, 1437, 1384, 1245, 1197, 1174, 1127, 1079. 1H NMR
(DMSO-d6) δ/ppm: 1.34 (t, J = 7.1 Hz, 3H, CH3), 1.70 (bs, 4H, 2×CH2 tetralin), 2.69-2.75 (bm, 4H,
2×CH2 tetralin), 4.35 (q, J = 7.1 Hz, 2H, ester CH2), 7.14 (s, 1H, arom. 9-H), 7.24 (s, 1H, arom. 14-H),
7.25-7.31 (m, 1H, arom.), 7.35-7.46 (m, 2H, arom.), 7.68 (d, J = 7.5 Hz, 1H, arom.), 8.12 (d, J = 0.7 Hz,
13
1H, thioph.). C NMR (DMSO-d6) δ/ppm: 14.3 (CH3); 22.3, 22.5, 28.1, 28.7 (tetralin CH2); 61.4 (ester

HETEROCYCLES, Vol. 81, No. 10, 2010
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CH2); 121.70, 121.74, 125.9, 128.6, 128,8, 130.2, 133.6 (CH); 123.4, 127.5, 131.4, 134.8, 136.1, 141.0,
143.1, 154.9, 156.7 (C); 161.2 (C=O). MS (CI) m/z: 377 (MH+, 100%). Anal. Calcd for C23H20O3S: C,
73.38; H, 5.35; S, 8.52. Found: C, 73.67; H, 5.24; S, 8.44.
General procedure for preparation of pentacyclic alcohols 12a-f. To the suspension of LiAlH4 (0.17 g,
4.5 mmol) in Et2O (50 mL) and/or THF (30 mL) ester 11a-f (4.50 mmol) was added in small portions.
The mixture was stirred at room temperature for 2 h, when TLC (hexane/EtOAc 3:1) showed total
conversion. The excess of LiAlH4 was decomposed by dropwise addition of water/Et2O 1:1. The
inorganic precipitate was filtered off and washed few times with ether, and filtrate was evaporated under
reduced pressure. Thus obtained crude product 12a-f was purified by recrystallization or column
chromatography.
Naphtho[1,2-b]thieno[2,3-d][1]benzothiepin-8-ylmethanol (12a). This compound was obtained starting
1
from 11a, purified by column chromatography (eluent hexane/EtOAc 1:1), yellowish crystals, 92%. H
NMR (DMSO-d6) δ/ppm: 4.79 (d, J = 5.7 Hz, 2H, CH2), 5.75 (t, J = 5.7 Hz, 1H, OH), 7.37-7.49 (m, 3H,
arom.), 7.60-7.80 (m, 5H, arom.), 7.68 (d, J = 8.5 Hz, 1H, arom. 5-H), 8.00 (d, J = 8.5 Hz, 1H, arom.
6-H), 8.94 (d, J = 8.0 Hz, 1H, arom. 1-H). MS (ES+) m/z: 329 ([M-OH]+, 100%). Anal. Calcd for
C21H14OS2: C, 72.80; H, 4.07; S, 18.51. Found: C, 72.35; H, 4.42; S, 18.62.
Naphtho[2,3-b]thieno[2,3-d][1]benzothiepin-2-ylmethanol (12b). This compound was obtained starting
from 11b, purified by column chromatography (eluent hexane/EtOAc 2:1), pale yellow crystals, 96%. 1H
NMR (CDCl3) δ/ppm: 1.70 (bs, 1H, OH), 4,95 (s, 1H, CH2), 7.26 (s, 1H, thioph.), 7.27-7.38 (m, 2H,
arom.), 7.45-7.51 (m, 3H, arom.), 7.68-7.71 (m, 1H, arom.), 7.78-7.83 (m, 2H, arom.), 7.98 (s, 1H, arom.
9-H), 8.16 (s, 1H, arom. 14-H). 13C NMR (CDCl3) δ/ppm: 60.2 (CH2); 126.6, 126.9, 127.2, 127.8, 128.0,
128.3, 128.7, 128.8, 129.0, 131.9, 133.1 (CH); 133.0, 133.4, 134.4, 135.00, 135.07, 138.9, 139.3, 140.7,
143.0 (C). MS (ES+) m/z: 329 ([M-OH]+, 100%). Anal. Calcd for C21H14OS2: C, 72.80; H, 4.07; S, 18.51.
Found: C, 73.15; H, 4.41; S, 18.71.
Naphtho[1,2-b]thieno[2,3-d][1]benzoxepin-8-ylmethanol (12c). This compound was obtained starting
from 11c, purified by column chromatography (eluent hexane/EtOAc 1.5:1), colorless crystals, 81%. IR
(KBr) ν/cm-1: 3600-3100 (broad, O-H), 3052, 2922, 2852; 1598, 1565, 1495, 1462, 1438, 1362, 1242,
1202, 1150, 1121, 1045, 1015. 1H NMR (CDCl3) δ/ppm: 1.69 (bs, 1H, OH), 4.94 (s, 2H, CH2), 7.18-7.23
(m, 1H, arom.), 7.33 (s, 1H, thioph.), 7.33-7.38 (m, 1H, arom.), 7.48-7.56 (m, 4H, arom.), 7.61-7.67 (m,
2H, arom.), 7.83 (d, J = 7.9 Hz, 1H, arom.), 8.67 (d, J = 8.2 Hz, 1H, arom. 1-H). MS (ES+) m/z: 313
([M-OH]+, 100%). Anal. Calcd for C21H14O2S: C, 76.34; H, 4.27; S, 9.70. Found: C, 76.55; H, 4.49; S,
9.52.
1,2,3,4-Tetrahydronaphtho[1,2-b]thieno[2,3-d][1]benzoxepin-8-ylmethanol (12d). This compound was

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HETEROCYCLES, Vol. 81, No. 10, 2010
obtained starting from 11d, crystallized from hexane/EtOAc 1:1, then filtrate purified by column
chromatography (eluent hexane/EtOAc 2:1), colorless crystals, overall 98%. IR (KBr) ν/cm-1: 3500-3100
(broad, O-H), 2932; 1493, 1459, 1435, 1417, 1372, 1323, 1250, 1219, 1205, 1155, 1126, 1011. 1H NMR
(DMSO-d6) δ/ppm: 1.69-1.84 (dm, 4H, tetralin), 2.71-2.75 (m, 2H, tetralin), 3.02-3.07 (m, 2H, tetralin),
4.70 (d, J = 5.7 Hz, 2H, CH2OH), 5.64 (t, J = 5.7 Hz, 1H, OH), 6.96 (d, J = 7.9 Hz, 1H, arom. 5-H), 7.16
(d, J = 7.9 Hz, 1H, arom. 6-H), 7.23-7.28 (m, 1H, arom.), 7.32 (s, 1H, thioph.), 7.34-7.41 (m, 2H, arom.),
7.54-7.57 (m, 1H, arom.). MS (CI) m/z: 334 (M+, 100%). Anal. Calcd for C21H18O2S: C, 75.42; H, 5.43; S,
9.59. Found: C, 75.75; H, 5.49; S, 9.77.
Naphtho[2,3-b]thieno[2,3-d][1]benzoxepin-2-ylmethanol (12e). This compound was obtained starting
from 11e, purified by crystallization from hexane/EtOAc 1:1, colorless crystals, 73%. IR (KBr) ν/cm-1:
3600-3100 (broad, O-H), 3049, 2922, 2852; 1498, 1487, 1443, 1375, 1338, 1327, 1257, 1235, 1207, 1156,
1129, 1115, 1024. 1H NMR (DMSO-d6) δ/ppm: 4.76 (d, J = 5.7 Hz, 2H, CH2), 5.74 (t, J = 5.7 Hz, 1H, OH),
7.27-7.33 (m, 1H, arom.), 7.41 (s, 1H, thioph.), 7.40-7.55 (m, 4H, arom.), 7.60-7.63 (m, 1H, arom.),
7.90-7.93 (m, 1H, arom.), 7.93 (s, 1H, arom. 9-H), 7.98-8.02 (m, 1H, arom.), 8.05 (s, 1H, arom. 14-H). MS
(ES+) m/z: 313 ([M-OH]+, 100%). Anal. Calcd for C21H14O2S: C, 76.34; H, 4.27; S, 9.70. Found: C, 76.71;
H, 3.98; S, 9.44.
10,11,12,13-Tetrahydronaphtho[2,3-b]thieno[2,3-d][1]benzoxepin-2-ylmethanol (12f). This compound
was obtained starting from 11f, crystallized from EtOAc, light yellow crystals, 90%. IR (KBr) ν/cm-1:
1
3400-3100 (broad, O-H), 2930, 1493, 1438, 1396, 1354, 1255, 1209, 1171, 1113. H NMR (DMSO-d6)
δ/ppm: 1.69 (bs, 4H, 2×CH2 tetralin), 2.68-2.73 (bm, 4H, 2×CH2 tetralin), 4.71 (d, J = 5.7 Hz, 2H, Ar-CH2),
5.65 (t, J = 5.7 Hz, 1H, OH), 7.08 (s, 1H, arom. 9-H), 7.10 (s, 1H, arom. 14-H), 7.22-7.28 (m, 1H, arom.),
13
7.33 (s, 1H, thioph.), 7.33-7.40 (m, 2H, arom.), 7.52-7.56 (m, 1H, arom.). C NMR (DMSO-d6) δ/ppm:
22.2, 22.5, 28.0, 28.4 (tetralin CH2); 58.4 (CH2OH); 121.3, 121.5, 124.43, 125.5, 127.87, 127.93, 129.3
(CH); 124.40, 128.4, 134.1, 134.7, 135.2, 138.9, 146.0, 154.1, 156.3 (C). MS (CI) m/z: 334 (M+, 100%).
Anal. Calcd for C21H18O2S: C, 75.42; H, 5.43; S, 9.59. Found: C, 75.70; H, 5.10; S, 9.28.
ACKNOWLEDGEMENTS
The authors express gratitude to Mr. Josip Kleščić for his assistance in the synthesis, Mr. Željko Osman
for the mass spectroscopy support, Mrs. Biserka Metelko for the NMR spectroscopy and Mrs. Štefica
Flegar for the IR spectra and elemental analysis data.
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