Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations

Article abstract of DOI:10.1016/j.tet.2011.06.093

The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-benzo[b]thieno[2,3-c]pyrrolo[2,3-a] indol-11-one via palladium-mediated oxidative cyclisation of benzo[b]thien-2-oyl indole derivatives is also reported.

Full text of DOI:10.1016/j.tet.2011.06.093

Tetrahedron 67 (2011) 6895e6900
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new benzo[b]thieno fused ring systems via transition
metal-mediated cyclisations
a
a
,
b
b
*
Johana M. Mbere , John B. Bremner , Brian W. Skelton , Allan H. White
a
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA 6005, Australia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered
ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-
benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one via palladium-mediated oxidative cyclisation of benzo
Received 8 February 2011
Received in revised form 13 June 2011
Accepted 24 June 2011
[
b]thien-2-oyl indole derivatives is also reported.
Available online 5 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ring closing metathesis
Azonino[3,4-b]benzo[b]thieno[3,2-a]
isoquinolinone
Pyrrolo[2,3-a]indol-11-one
Palladium cyclisation
1
. Introduction
derivative 10 (Scheme 2), with ring II being part of a tetrahy-
droisoquinoline moiety, together with the tightly constrained ana-
logue 13 (Scheme 3), with rings I and II both being five-membered.
The syntheses of 10 and 13 are now reported in this paper.
Compounds based on the benzo[b]thiophene nucleus continue
to attract significant attention in view of the range of biological
activities they display. Recent examples include benzo[b]thiophene
derivatives as anabolic agents for the potential treatment of osteo-
porosis,1 or as anti-inflammatory agents, together with histone
3
Ι
ΙΙ
2
N
3
deacetylase inhibitors, novel antibacterial and antibiotic resistance
S
4
5
inhibitors and antimalarial agents. Ring fused analogues also show
interesting properties as in the recent example of anti-tumour
benzo[b]thienonaphthyridinones derived from benzo[b]thio-
O
1
6
phene-2-carboxamides. As part of a program targeted at potential
antimicrobial (antibacterial and antiplasmodial) agents with novel
structures, we became interested in compounds based on the ge-
neric structure 1 in which was embedded the benzo[b]thiophene-2-
carboxamidic structural motif. Earlier work had established very
Cl
R
R2
N
weak antibacterial activity in compounds of type 2 (R, R
1
, R
2
¼H, F, Br,
S
7
OCH , CH ). In order to modify conformational flexibility and ex-
3 3
O
R
1
plore SAR relationships further, it was planned to incorporate the
amide nitrogen as part of a ring system I or II, or as part of both rings I
and II as shown in the general structure 1. In the context of the latter
design objective, and with a view to potential synthetic accessibility,
we targeted the semi-constrained nine-membered ring (ring I)
2
2. Results and discussion
In the syntheses of both 10 and 13, the overall strategy involved, in
part, a common starting material 3, and completion of ring I in the
penultimate step by a Ru-mediated ring closing metathesis (RCM)
*
Corresponding author. Tel.: þ61 2 4221 4255; fax: þ61 2 4221 4287; e-mail
address: john_bremner@uow.edu.au (J.B. Bremner).
reaction or
a
Pd-promoted oxidative cyclisation reaction,
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.093

6896
J.M. Mbere et al. / Tetrahedron 67 (2011) 6895e6900
respectively. The highly versatile ring closing metathesis procedure
has been applied successfully to nine-membered ring formation but
not, as far as we are aware, with bis-ring fused systems as in 10. The
precursor required for the RCM was the di-allyl substituted benzo[b]
thiophene-isoquinoline 9 and this was conveniently accessed in turn
from commercially available benzo[b]thiophene-2-carboxylic acid
stable than its (E) counterpart. This appears to be due in part to the
steric strain induced on the tertiary carbon adjacent to the amide
nitrogen. In the case of the (E)-isomer there is a larger deviation
from tetrahedral geometry for this carbon than there is in the
corresponding carbon for the Z-isomer. This feature, and the overall
structure of 10, was confirmed by a single crystal X-ray study.
The X-ray structure determination of 10 indicated that one
formula unit (a single molecule), devoid of crystallographic sym-
metry, comprised the asymmetric unit of the structure (Fig.1). The
geometries of the two peripheral benzo[b]thiophene and tetrahy-
droisoquinoline ring systems and the lactam and olefinic compo-
nents were as expected. Torsion angles in the bonds around the
nine-membered ring were as follows (carbon atom numbers
only): 2e3, 3-N(4), N(4)-11, 11e12, 12e13, 13e14, 14e15, 15e16,
2e16: ꢀ52.1(4) ꢀ2.4(3), 107.5(2), ꢀ37.3(3), ꢀ57.6(4), ꢀ5.9(4),
8
(3) (Scheme 1) and 1,2,3,4-tetrahydroisoquinoline (6) (Scheme 2).
Br
a)
9%
c)
4
50%
S
COOH
S
COOR
S
COOR
4a R = H
b R = CH
5a R = CH
3
5b R = H (95%)
3
b)
d)
4
3
(97%)
ꢁ
Scheme 1. (a) (i) CH
3
COOH, CH
3
COONa, (ii) Br
2
, 55 C; (b) (i) MeOH, H
2
SO
4
; (c) (i)
ꢁ
CH
2
]CHCH
2
SnBu
3
, Ph P, PdCl
3
2
, DMF, 90e100 C/sealed tube; (d) (i) 2% LiOH, THF, (ii)
1
M HCl.
99.2(3), ꢀ34.7(4), 8.2(5), while those in the fused NC
5
ring were:
N(4)-5, 5e6, 6-6A, 6Ae10A, 10A-11, N(4)-11: ꢀ67.5(2), 46.3(3),
ꢀ15.3(3), ꢀ0.2(3), ꢀ15.8(3), 50.2(2); O(3), 2e3-N(4)-5,
a)
0%
b)
1
3e12e11e10a and S-2e3-O(3) were ꢀ4.4(3), 177.3(2), ꢀ159.4(2),
NH
N
NH
8
60%
ꢁ
ꢀ
ꢀ
40.2(3) . The C(13)eC(14) double bond length was 1.319(4) A. The
6
7
dihedral angle between the peripheral C
8
S and C
6
planes was
ꢁ
7
5
8.70(8) and between those and the C.C:C.C plane 80.3(1) and
ꢁ
4.0(1) . The X-ray derived structure closely matched the local AM1
8
minimum structure for the (Z)-isomer (Supplementary data).
c)
7%
5
d)
8%
N
7
S
S
N
O
O
9
1
0
Scheme 2. (a) (i) NBS, DCM, 5 h, (ii) distillation; (b) 7 (i) Zn powder, THF, (ii) CH
CHCH Br, 2 days rt; (c) (i) 5b, DCC, HOBt, DMF; (d) (i) Grubbs’ first generation catalyst
polymer supported), DCM, 12 h reflux.
2
]
2
(
Regiospecific electrophilic bromination of 3 gave the known 3-
bromo derivative 4a in moderate yield, and after protection of the
carboxylic acid as the methyl ester 4b, a Stille coupling with allyl
tributylstannane gave 5a. Alkaline hydrolysis followed by acidifi-
cation then afforded the allylated acid 5b (Scheme 1) required for
coupling with the amine 8 (Scheme 2).
Fig. 1. Molecular projection of 10; 50% probability amplitude displacement ellipsoids
are shown for the non-hydrogen atoms and hydrogen atoms have arbitrary radii of
ꢀ
0
.1 A. Non-systematic numbering is used.
In the synthesis of the other more conformationally constrained
12
target molecule 13, Pd-mediated oxidative cyclisation of the
amide precursors 12a and 12b was investigated (Scheme 3). In this
approach the amide 12a, which was readily accessed from the
carboxylic acid 3 via its acid chloride 11a and indole, was heated
In a separate reaction stream, the 1-allyl-tetrahydroisoquinoline
9
could be obtained in good yield in a two step process involving
9
a
oxidation of 6 to the dihydroisoquinoline 7 on reaction with NBS,
10
followed by an organozinc-mediated nucleophilic addition of the
9
b
X
allyl group at C1 to give 8 in moderate yield (Scheme 2). This
amine 8 was then smoothly converted to the amide 9 on reaction
with the carboxylic acid 5b in the presence of dicyclohex-
ylcarbodiimide and HOBt. With the di-allyl substituted amide 9 in
hand, successful ring closing metathesis using Grubbs’ first gener-
ation Ru catalyst (with the polymer bound or the homogeneous
catalyst) then realised the target fused nine-membered ring de-
rivative 10 in good yield. Both the polymer supported Grubbs’ first
generation catalyst and the homogeneous version gave similar
yields but ease of work-up was an advantage with the former cat-
alyst. The structure of 10, which is the first representative of a new
X
a)
6
2-67%
S
COCl
S
COOH
3 X = H
a X = Br
11a X = H
11b X = Br
4
b)
20-71%
X
N
c)
1
13
N
heterocyclic ring system, was secured on the basis of the H and
C
1
14-23%
NMR and MS data. From the H NMR it appeared that only one
diastereomer was present with the coupling constant for the vicinal
alkenyl protons suggesting the (Z)-configuration for the nine-
membered ring olefinic bond. Preliminary computational studies
using AM1 minimisation1 suggested that the (Z) arrangement of
S
S
O
O
13
12a X = H
2b X = Br
1
1
2 2
Scheme 3. (a) (i) SOCl , pyridine, toluene; (b) (i) NaH, DMF, (ii) indole; (c) (i) Pd(OAc) ,
glacial HOAc, heat.
ꢀ
1
the olefinic double bond in the ring was about 5 kcal mol more

J.M. Mbere et al. / Tetrahedron 67 (2011) 6895e6900
6897
with palladium(II) acetate in glacial acetic acid. It was anticipated
that oxidative cyclisation should proceed to complete the five-
membered fused ring and indeed this was the case with the
fused lactam 13 being obtained although in low yield (14%). Some
improvement in the yield of 13 was realised (23%) when the bromo
analogue 12b (obtained from 4a via 11b and indole) was heated in
acetic acid with palladium(II) acetate. Yields in this cyclisation re-
action were presumably compromised by competitive palladation
at the C5 position in the cyclised product 13 thus providing scope
ratios. Column chromatography was performed with the indicated
solvents freshly distilled over molecular sieves (4 A). Where in-
ꢀ
dicated, preparative plate chromatography for separating smaller
quantities of isolates was performed using pre-made silica plates
with aluminium backing (0.2 mm thickness) supplied by Merck.
Visualization of the separated bands on preparative TLC plates was
done using short and long-wavelength UV light.
2 4
Organic solvent extracts were dried over anhydrous Na SO and
solvents were removed in vacuo by a B u€ chi rotary evaporator. Pe-
13
ꢁ
for other reaction pathways.
troleum spirit (pet. spirit) refers to the boiling point range 40e60 C.
The compound 13, with the three contiguous five-membered
rings, also represents a new condensed heterocyclic ring system.
An AM1 local minimum-derived molecular model (results not
shown) confirmed that, as expected, 13 was highly planar, and,
The carboxylic acid (3) and the 1,2,3,4-tetrahydroisoquinoline (6)
were obtained from Aldrich and were used as received.
4.2. Activation of zinc powder and syntheses
consistent with the extensive
this compound is a deep orange-red colour. In the H NMR spec-
trum the signal for the indolic H5 proton was assigned to a singlet
p-electron delocalisation possible,
1
Zinc powder (4.0 g, 62.6 mmol) was suspended in 0.1 M HCl
(15 mL) and stirred at room temperature for 1 min. The mixture
was then vacuum filtered and the solid washed successively with
distilled water (20 mL), ethanol (20 mL) and finally diethyl ether
(25 mL). The zinc powder was then dried under vacuum and stored
in a vacuum desiccator over silica gel.
13
at
d 6.57, while a signal at d 162.9 in the C NMR was consistent
with the presence of the lactam.
Studies on the antimicrobial activity of 10 and some other lac-
tams will be reported separately.
3
. Conclusions
4.2.1. 3-Bromobenzo[b]thiophene-2-carboxylic acid (4a). Bromine
(2.48 g, 31.4 mmol) was added dropwise to a solution of the car-
Compact syntheses of two new condensed benzo[b]thiophene-
boxylic acid 3 (1.0 g, 5.61 mmol), and anhydrous sodium acetate
fused heterocyclic ring skeletons containing a central lactam moi-
ety as part of a nine- or five-membered ring were achieved. The
lactam nitrogen was part of a reduced isoquinoline or an indole ring
system. Both synthetic routes used the same benzo[b]thiophene-2-
carboxylic acid as one of the starting materials and a common
strategy of penultimate lactam ring formation via Ru- or Pd-
mediated cyclisations through CeC bond formation. The routes
described should be amenable to further generalisation to
substituted derivatives and analogues of these polycyclic systems of
potential chemical and biological interest.
(1.0 g, 12.1 mmol) in glacial acetic acid (35 mL). The reaction mix-
ture was stirred at 55 C under a reflux condenser in a nitrogen
ꢁ
atmosphere over 24 h. The mixture was poured into ice water and
the resulting precipitate filtered under reduced pressure and then
washed with distilled water (3ꢂ25 mL) followed by cold ethanol
(25 mL) to afford a colourless solid. The product was then oven-
dried for 10 min and recrystallised from hot acetone to afford 4a
ꢁ
14
(0.70 g, 49%) as colourless needles. Mp 280e283 C (lit. mp
ꢁ
1
278e279 C). H NMR (CD
AreH5 and H6), 7.99e8.05 (m, 2H, ArH4 and H7); C NMR:
C3), 122.8 (C7), 125.5 (C5), 125.8 (C6), 128.3 (C2), 138.7 (C3a), 139.4
3 3
COCD , 300 MHz): d 7.58e7.67 (m, 2H,
13
d
115.2
(
þ
þ1 79
81
4
4
. Experimental
(C7) and 161.9 (C]O). MS (CI ), m/z 257, 259 [MH
,
Br, Br].
.1. General
4.2.2. Methyl 3-bromobenzo[b]thiophene-2-carboxylate (4b). The
acid4a (1.0 g, 3.89 mmol) was converted to its methyl esterderivative
4b by heating it at reflux in methanol (15 mL) and a catalytic amount
The melting point (mp) determinations were recorded on
15
a Reichert melting point apparatus and are reported uncorrected.
Unless otherwise stated, proton NMR spectra were acquired on
a Varian Unity 300 NMR spectrometer running at 299.5 MHz at
of concentrated sulfuricacidovernight. Compound 4b was obtained
þ
þ
ꢃ
79
81
as a white solid (0.9 g, 90%). MS (EI ), m/z 270, 272 [M
,
Br, Br].
2
98 K. Chemical shifts are quoted in
d
values in parts per million
4.2.3. Methyl 3-allylbenzo[b]thiophene-2-carboxylate (5a). A glass
high-pressure tube was flushed with nitrogen and a mixture of
palladium(II) chloride (0.1 g, 0.85 mmol) and triphenylphosphine
(0.23 g, 0.87 mmol) added, and to this mixture was then added the
methyl ester 4b (0.5 g, 1.85 mmol) in anhydrous DMF (15 mL) and
stirring continued. Allyl tributylstannane (0.6 mL) was then injec-
ted into the reaction mixture and the tube sealed. The mixture was
heated at 90 C with stirring for 2 h, and then at 100 C for 36 h. The
reaction mixture was then cooled to room temperature and the
solvent evaporated under reduced pressure to give a yellow oil. The
oil was then purified via column chromatography (10% ethyl ace-
shift relative to TMS. Coupling constants (J) are reported in hertz,
with signal multiplicity designated as singlet (s), doublet (d),
doublet of doublets (dd), triplet (t), quartet (q), quintet (qn), sextet
13
(
sx), multiplet (m) and broad (b). Unless otherwise stated, C NMR
spectra were acquired on a Varian Unity 300 NMR spectrometer
running at 74.99 MHz at 298 K. Completely proton decoupled
spectra were recorded. Low-resolution chemical ionization (iso-
ꢁ
ꢁ
þ
butane, CI ) mass spectroscopy (LRMS) was obtained on a Shi-
madzu CC-17A gas chromatograph equipped with a QP-5000 mass
spectrometer and CI-50 chemical ionization controller. The direct
probe insertion method was used to acquire data. High-resolution
mass spectra (HRMS) (methane CI and EI ) were determined on
a VG Autospec spectrometer using PFK (Perfluorokerosene) as the
reference. UV spectra (solvent corrected) were recorded on Shi-
madzu 2401-PC-UVevis spectrophotometer. IR spectra were
recorded on neat solids using a Thermo Avatar 360 FTIR instrument.
Column chromatography was performed using silica gel 60
230e400 mesh, Merck). Reactions were monitored with thin layer
chromatography (0.25 mm aluminium backed silica gel plates)
using analytical grade solvents and R values were determined us-
ing these plates. Chromatographic solvent mixtures refer to volume
tate/pet. spirit) to give 5a (0.21 g, 50%) as a yellow oil. R
f
0.7 (10%
þ
þ
1
ethyl acetate/pet. spirit). H NMR (CDCl
3
, 300 MHz):
d
3.91 (s, 3H,
0
0
CH
3
), 4.15 (d, J¼4.2 Hz, 2H, H1 ), 5.04e5.13 (m, 2H, H3 ), 5.97e6.06
0
(m, 1H, H2 ), 7.46 (m, 2H, ArHeH5 and H6), 7.85 (m, 2H, ArHeH4
and H7). C NMR:
1
3
0
0
d
31.6 (C1 ), 52.4 (CH
3
), 116.2 (C3 ), 122.9 (C7),
0
124.1 (C4), 124.7 (C5), 124.8 (C6), 127.4 (C2), 135.4 (C2 ), 140.9 (C3b),
þ
þ1
142.7 (C3a) and 163.6 (C]O). MS (CI ) m/z 233 [MH ]; HRMS (CI)
found: 232.0555 (1.0 ppm), required: 232.0558 for C13 S.
(
12 2
H O
f
4.2.4. 3-Allylbenzo[b]thiophene-2-carboxylic acid (5b). A mixture of
5a (0.17 g, 0.73 mmol) and 2% aqueous LiOH (10 mL) in

6898
J.M. Mbere et al. / Tetrahedron 67 (2011) 6895e6900
tetrahydrofuran (15 mL) was heated at reflux for 3 h. The reaction
mixture was then cooled to room temperature and the solvent was
concentrated under reduced pressure. The residue was then acidified
The precipitated dicyclohexylurea was removed by vacuum filtra-
tion. The solvent was then evaporated under reduced pressure to
give an oily residue, which was then taken up in ethyl acetate
(20 mL) and filtered to remove further dicyclohexylurea. The fil-
trate was then washed with distilled water (40 mL), dried and the
solvent evaporated to give a yellow oil. The oil was further purified
ꢁ
with 1 M HCl at 5e10 C (ice bath). The precipitate was vacuum fil-
tered, washed with distilled water (20 mL) and then dried under
1
vacuum to give 5b (0.14 g, 93%) as a colourless solid. H NMR
0
(
CD
3
COCD
3
, 300 MHz):
d
4.13 (d, J¼4.2 Hz, 2H, H1 ), 4.97; 5.14 (m, 2H,
via column chromatography (20% ethyl acetate/pet. spirit) to give 9
0
0
1
H3 ), 5.96; 6.05 (m, 1H, H2 ), 7.52 (m, 2H, ArHeH5 and H6), 7.97 (dd,
(0.10 g, 55%) as a clear oil. R
NMR (CDCl , 300 MHz):
f
0.6 (20% ethyl acetate/pet. spirit). H
13
0
0
0
00
J¼3.45, 5.26 Hz, 2H, ArHeH4andH7). CNMR:
d
31.6(C1 ),116.2(C3 ),
3
d
2.70; 2.95 (m, 2H, H1 allyl THIQ; tetra-
hydroisoquinoline), 3.50; 3.66 (m, 2H, H4 ), 3.66e3.88 (m, H3 and
0
0
1
1
22.9 (C7), 124.1 (C4), 124.7 (C5), 124.8 (C6), 127.4 (C2), 135.4 (C2 ),
þ
þ1
00
00
40.9 (C3b), 142.7 (C3a) and 163.6 (C]O). MS (CI ) m/z 219 [MH ].
H1 allyl BTP; benzo[b]thiophene), 4.85e5.18 (m, 5H, 2ꢂ H3 (CH
2
)
0
00
and H1 ), 5.91e6.02 (m, 2H, 2ꢂ H2 ), 7.11e7.36 (m, 4H, ArH THIQ),
4.2.5. 3,4-Dihydroisoquinoline (7). The tetrahydroisoquinoline 6
7.42 (m, 2H, ArHeH5 and H6), 7.79 (m, 2H, ArHeH4 and H7).
13
0
00
00
(
3.0 g, 22.6 mmol) was dissolved in DCM (50 mL) under nitrogen.
C NMR:
d
29.8 (C4 ), 31.7 (C1 , allyl BTP), 41.5 (C1 , allyl THIQ), 41.8
(C3 ), 52.2 (C1 ), 116.6 (C3 , THIQ), 118.1 (C3 , BTP), 122.7 (C7), 123.3
(C4), 124.7 (C6), 125.5 (C5), 127.0 (C5 ), 135.0 (C2 , THIQ), 135.4 (C2),
136.6 (C2 , BTP) and 164.7 (C]O). MS (CI ), 374 [MH ]; 332
0
0
00
00
To this stirred solution, N-bromosuccinimide (4.41 g, 24.8 mmol)
was gradually added over 20 min. The mixture was stirred at room
temperature for 1.5 h. Sodium hydroxide solution (15 mL, 30%) was
added and stirring was continued for 1 h. Distilled water (20 mL)
was added to the mixture, and stirred for a further 15 min. The two
phases were separated and the aqueous phase washed with DCM
0
0
0
þ
þ1
þ
(C21
H
18NOS ).
4.2.8. 5,8,16,17-Tetrahydroazonino[3,4-b]benzo[b] thieno[3,2-a] iso-
quinolin-14(4bH)-one (10). Dry DCM (10 mL) was added to a mix-
ture of 9, (0.1 g, 0.26 mmol) and polymer supported Grubbs’ first
generation catalyst (0.15 g) under nitrogen and the mixture heated
at reflux for 12 h. The reaction mixture was then cooled to room
temperature and then filtered to recover the catalyst. The filtrate
was evaporated under reduced pressure to afford a clear oil, which
solidified rapidly. The crude product was further purified via col-
umn chromatography (30% ethyl acetate/pet. spirit) to give a col-
ourless solid, which was recrystallised from ethanol to give 10
(0.07 g, 78%) as a highly crystalline solid. Note: A similar reaction
was also attempted using the homogeneous Grubbs’ first genera-
tion catalyst to give 10 (0.18 g, 75%) as a crystalline solid after
chromatography and re-crystallisation from ethanol. Mp
(
(
1
20 mL). The combined organic phases were washed with water
25 mL) and extracted with 2 M hydrochloric acid (2ꢂ30 mL,
5 mL). Combined aqueous extracts were washed with DCM
(
25 mL) and basified to pH 11 with concentrated aqueous ammonia
solution, to afford a yellow oil, which was back extracted with DCM
20 mL, 2ꢂ15 mL), dried and the solvent evaporated under reduced
pressure. The yellow oil was distilled under reduced pressure on
(
16
a Kugelrohr distillation apparatus and the imine 7 collected at
ꢁ
1
40 C between 50 and 70 mbar as a colourless oil (2.32 g, 79%),
1
which turned pale yellow on standing. H NMR (CDCl
3
, 300 MHz):
d
2.71 (t, J¼7.8 Hz, 2H, H4), 3.74 (t, J¼6.6 Hz, 2H, H3), 7.12 (d,
J¼7.5 Hz, 1H, H8), 7.21e7.34 (m, 3H, H5, H6 and H7) and 8.31 (s, 1H,
13
H1). C NMR:
d
25.2 (C4), 47.5 (C3), 127.2 (C7), 127.3 (C5), 128.6
þ
ꢁ
ꢀ1
(
[
C8), 131.2 (C6), 136.4 (C8a) and 160.4 (C1). MS (CI ), m/z 132
MH ].
233e235 C. R
f
0.4 (30% ethyl acetate/pet. spirit).
nmax 1600 cm .
þ1
1
H NMR (CDCl
3
, 300 MHz): 2.73e2.86 (m, 4H, H5 and H16),
d
3
.64e3.88 (m, 2H, H17); 4.10 (q, J¼13.8 Hz, 2H, H8), 5.02 (t,
4.2.6. 1-Allyl-1,2,3,4-tetrahydroisoquinoline
(8). Allyl
bromide
J¼6.6 Hz, 1H, H15a), 5.99 (q, J¼3.3 Hz, 1H, H7), 6.17 (q, J¼10.3 Hz,
(
1.83 g, 15.3 mmol) was added to a stirred suspension of activated
1H, H6), 6.92e7.16 (m, 4H, ArHeH1eH4), 7.46 (m, 2H, ArHeH5 and
13
zinc powder (1.00 g, 15.4 mmol) in dry tetrahydrofuran (20 mL)
H6), 7.82 (dd, J¼3.45, 5.3 Hz, 2H, ArHeH4 and H7). C NMR:
d 27.9
ꢁ
under nitrogen. The mixture was cooled to 0 C then 7 (2.00 g,
(C8), 28.2 (C17), 36.2 (C5) 36.7 (C16), 59.0 (4b), 122.8 (C9 and C12),
125.8e127.1 (C1eC3, C10 and C11), 129.4 (C7), 130.2 (C6), 133.2
(C13a), 138.0 (C4a), 138.9 (C17a), 140.0 (C8a) and 164.3 (C]O). MS
15.0 mmol) in dry tetrahydrofuran (30 mL) was added slowly and
stirring maintained for 2 days. Saturated sodium bicarbonate so-
lution (25 mL) was then added and the mixture stirred for 15 min
before being filtered through Celite. The organic solvent was re-
moved under reduced pressure and the resulting aqueous mixture
extracted with DCM (1ꢂ25 mL, 1ꢂ10 mL). The combined organic
extracts were extracted with 2 M hydrochloric acid (2ꢂ25 mL).
Combined aqueous portions were washed with DCM (25 mL), ba-
sified with concentrated aqueous ammonia solution to pH 11 on an
ice bath, and then back extracted with DCM (2ꢂ25 mL, 1ꢂ15 mL).
The combined organic extract was dried, and solvent evaporated
under reduced pressure to afford the 1-allylated tetrahy-
þ
þ1
(CI ), 346 [MH ]; HRMS (CI) found: 345.1183 (1.3 ppm), required:
345.1187 for C22 19NOS [M].
H
4.2.9. Benzo[b]thiophene-2-carbonyl chloride (11a). Thionyl chlo-
ride (0.81 mL, 11.1 mmol) was added to a solution of benzo[b]
thiophene-2-carboxylic acid 3 (0.4 g, 2.24 mmol), in pyridine
(0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The
reaction mixture was quenched in ice water and the toluene
evaporated in vacuo. The acid chloride was extracted with distilled
DCM (2ꢂ25 mL, 2ꢂ10 mL) and the combined organic extracts
washed with distilled water (2ꢂ20 mL) and dried. The solvent was
evaporated under reduced pressure to give a brown residue, which
was purified using flash chromatography with DCM as the eluent to
9b
1
droisoquinoline 8 as a pale yellow oil (1.55 g, 59%). H NMR
0
(
CDCl
3
, 300 MHz):
d
2.63; 2.49 (m, 2H, H1 ), 2.69 (qn, J¼1.72 Hz, 2H,
0
H4), 2.93 (qn, J¼4.05 Hz, 2H, H3), 5.15 (m, 2H, H3 ), 5.81 (m, 1H,
0
17
1
H2 ), 4.03 (t, J¼4.5 Hz, 1H, H1), 7.05e7.16 (m, H5, H6, H7 and H8).
3
yield 11a (0.27 g, 61%) as a colourless solid. H NMR (CDCl ,
1
3
0
0
13
C NMR:
d
30.2 (C4), 40.9 (C3), 41.3 (C2 ), 55.3 (C1), 118.1 (C3 ),
300 MHz):
d 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s,1H). C NMR: d 123.1
0
1
26.0 (C7), 126.2 (C5), 129.5 (C5 and C8), 135.6 (C1 ), 135.9 (C8a),
(C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3
þ
þ1
þ
þ1
and 138.9 (C4a). MS (CI ), m/z 174 [MH ].
(C3a), 144.3 (C7) and 161.9 (C]O). MS (CI ), m/z 197, 199 [MH ,
Cl, Cl].
3
5
37
4
.2.7. (1-Allyl-1,2,3,4-tetrahydroisoquinolin-2-yl)(3-allylbenzo[b]
thien-2-yl)methanone (9). The isoquinoline 8 (0.11 g, 0.063 mmol)
was added to a cooled mixture (ice bath) of 5b (0.14 g, 0.61 mmol),
4.2.10. 3-Bromobenzo[b]thiophene-2-carbonyl chloride (11b). In the
same manner as that reported for 11a, reaction of 4a (0.60 g,
1
,3-dicyclohexylcarbodiimide (0.13 g, 0.63 mmol), and 1-
2.33 mmol) yielded 11b (0.43 g, 67%) after chromatography (DCM)
1
hydroxybenzotriazole (0.10 g, 0.74 mmol) in dry DMF (10 mL). The
mixture was stirred at room temperature under nitrogen (24 h).
as a colourless solid. H NMR (CDCl
3
, 300 MHz):
d
7.58e7.67 (m, 2H,
13
ArHeH5 and H6), 7.99e8.05 (m, 2H, ArHeH4 and H7). C NMR:

J.M. Mbere et al. / Tetrahedron 67 (2011) 6895e6900
þ1
6899
d
115.2 (C3), 122.8 (C7), 125.5 (C5), 125.8 (C6), 128.3 (C2), 138.7
[MH ]; HRMS (CI) found: 276.0484 (0.3 ppm), required:
þ
(
[
C3a), 139.4 (C7), and 161.9 (C]O). MS (CI ), m/z 273, 275, 277
276.0483 for C17H10NOS.
þ1
MH , Cl, Br].
4.2.14. 11H-Benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one
(13)
4
.2.11. (Benzo[b]thien-2-yl)(1H-indol-1-yl)methanone
from the bromoamide 12b. In the same manner as that described for
12a above, 12b (0.20 g, 0.75 mmol) was reacted with palladium(II)
acetate in glacial acetic acid to form 13, which was isolated after
chromatography as a deep orange coloured solid (0.05 g, 23%).
(12a). Anhydrous DMF (10 mL) was syringed in to a flask con-
taining sodium hydride (0.082 g, 3.51 mmol) under nitrogen and
the solution cooled to 5 C (ice bath) with stirring. Indole (0.16 g,
ꢁ
1
.36) dissolved in dry DMF (10 mL) was then added and stirring
ꢁ
maintained for 45 min between 0 and 5 C. The reaction mixture
4
.3. Single crystal X-ray structure determination of (10)
was then warmed to room temperature and stirring continued for
ꢁ
a further 45 min after which time the mixture was cooled to ꢀ60 C
A full sphere of CCD/area-detector diffractometer data was
(
liquid nitrogen/chloroform). The acid chloride 11a (0.27 g,
measured (Bruker AXS instrument; monochromatic Mo Ka radia-
tion;
1.37 mmol) dissolved in dry DMF (15 mL) was then added slowly
ꢀ
ꢁ
u
-scans;
l
¼0.7107
3
A; 2
q
max¼58 ; T ca. 150 K) yielding 15,200
and the mixture warmed to room temperature and stirring main-
tained over 12 h. After all the substrate had reacted, the solvent was
concentrated in vacuo to give a brown solid residue. Distilled water
reflections, these merging to 4146 unique (Rint¼0.062) after ‘em-
pirical’/multiscan absorption correction (proprietary software;
m
Mo¼0.21 mm; specimen: 0.11ꢂ0.10ꢂ0.04 mm; ‘T’min/max¼0.90),
(
20 mL) was added to the flask containing the residue and the
2
which were used in the full matrix least squares refinement on F
mixture stirred for 1 h, after which time it was extracted with DCM
18
(neutral atom complex scattering factors; SHELXL program; re-
(
2ꢂ25 mL). The aqueous layer was washed once with DCM (15 mL).
2
2
2
ꢀ1
2
2
flection weights ð
s
ðF Þ þ ð0:040P Þ þ 1:78PÞ
ðP ¼ ðFo þ 2F Þ=
o
c
The combined organic solvents were then dried and evaporated to
3Þ); 2681 with I>2
s(I) were considered ‘observed’.
give a brown oil, which solidified rapidly. The solid was purified by
Residuals at convergence were R1¼0.060, wR2¼0.14; S¼1.02.
column chromatography (40% ethyl acetate/hexane) to give 12a
ꢀ
ꢀ3
jDrmaxj¼0.41 e A . CCDC798767.
ꢁ
(
0.27 g, 71%) as a brown crystalline solid. Mp 44e47 C. R
f
0.8 (40%
Crystal data: C22
H
19NOS, M
r
¼345.4. Monoclinic, space group
ꢀ
1
1
ethyl acetate/hexane).
n
max 1662 cm
(CO). H NMR (CDCl
3
,
5
P2
1
/n (C2h No. 14 (variant)), a¼13.515(3), b¼8.1116(16),
3
00 MHz):
d
6.71 (d, J¼3.6 Hz, 1H, H3), 7.28 (d, J¼15.6 Hz, 1H, H2),
ꢀ
ꢁ
ꢀ
3
c¼16.273(4) A,
b
¼111.684(3) , V¼1657.7(6) A .
D
c
(Z¼4)¼
0
0
7
.33e7.46 (m, 4H, H5; H6, H5 ; H6 ), 7.74 (d, J¼3.9 Hz, 1H, H4), 7.90
ꢀ3
1
.38
4
g cm
.
0
(
s, 1H, H3 ), 7.93 (dd, J¼3.45, 5.3 Hz, 2H, ArHeH4 and H7), 8.44 (dd,
13
J¼1.2, 2.6 Hz, 1H, H7). C NMR:
d 102.8 (C3), 111.2 (C7), 120.0 (C4),
4
.4. Molecular modelling
0
0
0
120.9 (C6), 121.2 (C3 ), 122.2e125.5 (C5, C6, C4 -C7 ), 125.8 (C2),
þ
þ1
þ
130.4 (C3a) and 138.7 (C7a). MS (CI ), 278 [MH ]; 161 (C
9
H
5
OS ).
The modelling studies were performed using AM111 running on
the computer program Spartan’02 (Wavefunction Inc., 2002).
4.2.12. (3-Bromobenzo[b]thien-2-yl)(1H-indol-1-yl)
methanone
(
12b). In the same manner as that reported for 12a, reaction of the
Acknowledgements
bromo substituted acid chloride 11b (0.60 g, 2.33 mmol) and in-
dole (0.34 g, 2.90 mmol) yielded 12b after chromatography (40%
We gratefully acknowledge support from the Institute for Bio-
molecular Science and the University of Wollongong. We also thank
Dr. D. Perkins for help with the molecular modelling.
ethyl acetate/hexane) as a brown solid (0.20 g, 45%). R
f
0.6 (10%
1
ethyl acetate/hexane). H NMR (CDCl , 300 MHz): d 6.71 (d,
3
J¼3.6 Hz, 1H, H3), 7.26 (d, J¼15.6 Hz, 1H, H2), 7.33e7.44 (m, 4H,
0
0
H5; H6, H5 ; H6 ), 7.74 (d, J¼3.9 Hz, 1H, H4), 7.93 (dd, J¼3.45,
13
5
.26 Hz, 2H, ArHeH4 and H7), 8.44 (dd, J¼1.2, 2.5 Hz, 1H, H7).
C
Supplementary data
NMR:
d 102.6 (C3), 111.3 (C7), 120.0 (C4), 120.9 (C6), 122.2e125.5
0
þ
0
(
C5, C6, C4 -C7 ), 125.8 (C2), 130.2 (C3a), 138.7 (C7a) and 164.3 (C]
The minimum energy conformation model of compound 10.
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2011.06.093.
þ1 79
81
þ
O). MS (CI ), m/z 356, 358 [MH
,
Br, Br], 239,241 [C
9
H
4
BrOS ,
7
9
81
Br, Br].
4
.2.13. 11H-Benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one
(13)
References and notes
from the amide 12a. To a mixture of 12a (0.22 g, 0.79 mmol) and
palladium(II) acetate (0.17 g, 0.75 mmol) was added glacial acetic
acid (70 mL) and the mixture heated to 100 C with continuous
1. Guo, H.-F.; Shao, H.-Y.; Yang, Z.-Y.; Xue, S.-T.; Li, X.; Liu, Z.-Y.; He, X.-B.; Jiang, J.-
D.; Zhang, Y.-Q.; Si, S.-Y.; Li, Z.-R. J. Med. Chem. 2010, 53, 1819.
ꢁ
2
. (a) Radwan, M. A. A.; Shehab, M. A.; El-Shenawy, S. M. Monatsh. Chem. 2009,
40, 445; (b) Boschelli, D. H.; Kramer, J. B.; Khatana, S. S.; Sorenson, R. J.;
stirring under nitrogen for 7 h. The reaction mixture was cooled
to room temperature and solvent evaporated under reduced
pressure to give a black residue. The crude residue was dissolved
in DCM (15 mL) and vacuum filtered through Celite to remove
suspended palladium(0) particles. After solvent evaporation, the
impure solid was purified by chromatography (40% ethyl acetate/
hexane) to give 13 (0.03 g, 14%) as a deep orange coloured solid.
The product was further purified by multi-development pre-
parative TLC (20% ethyl acetate/hexane) to give 13 (6.6 mg). Mp
1
Connor, D. T.; Ferin, M. A.; Wright, C. D.; Lesch, M. E.; Imre, K.; Okonkwo, G. C.;
Schrier, D. J.; Conroy, M. C.; Ferguson, E.; Woelle, J.; Saxena, U. J. Med. Chem.
1995, 38, 4597.
3. Witter, D. J.; Belvedere, S.; Chen, L.; Secrist, J. P.; Mosley, R. T.; Miller, T. A. Bioorg.
Med. Chem. 2007, 17, 4562.
4. (a) Thakar, K. M.; Paghdar, D. J.; Chovatia, P. T.; Joshi, H. S. J. Serb. Chem. Soc.
2005, 70, 807; (b) Venturelli, A.; Tondi, D.; Cancian, L.; Morandi, F.; Cannazza,
G.; Segatore, B.; Prati, F.; Amicosante, G.; Shoichet, B. K.; Costi, M. P. J. Med.
Chem. 2007, 50, 5644.
5. Perez-Silanes, S.; Berrade, L.; Garcia-Sanchez, R. N.; Mendoza, A.; Galiano, S.;
Perez-Solorzano, B. M.; Nogal-Ruiz, J. J.; Martinez-Fernandez, A. R.; Aldana, I.;
Monge, A. Molecules 2009, 14, 4120.
ꢁ
ꢀ1
nmax 1714 cm
1
(
2
88e190 C. R
f
0.8 (30% ethyl acetate/hexane).
CO). H NMR (CDCl , 300 MHz): 6.57 (s, 1H, H5), 7.00e7.17 (m,
H, H2 and H3), 7.25e7.55 (m, 3H, H1, H7 and H8), 7.72 (d,
1
3
d
6. Ester, K.; Hranjec, M.; Piantanida, I.; Caleta, I.; Jarak, I.; Pavelic, K.; Kralj, M.;
Karminski-Zamola, G. J. Med. Chem. 2009, 52, 2482.
7. T. Rees, B. Med. Chem. Hons Thesis, University of Wollongong, 1998.
13
J¼3.9 Hz, 1H, H4), 8.06 (m, 2H, H6 and H9). C NMR:
d 102.1 (C5),
8
. (a) Walters, M. A. In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A.,
Eds.; Elsevier Science Ltd: Oxford, 2003; Vol. 15, pp 1e36; (b) Deiters, A.;
Martin, S. F. Chem. Rev. 2004, 104, 2199.
1
11.4 (C1), 119.6 (C2), 121.7 (C3 and C9), 124.7e124.9 (C5a, C7 and
þ
C8), 128.0 (C4a) 135.2 (C12a) and 162.9 (C]O) MS (CI ), m/z 276

6900
J.M. Mbere et al. / Tetrahedron 67 (2011) 6895e6900
9
. (a) Pelletier, J. C.; Cava, M. P. J. Org. Chem. 1987, 52, 616; (b) Seebach, D.; Loh-
mann, J.-J.; Syfrig, M. A.; Yoshifuji, M. Tetrahedron 1983, 39, 1963.
0. Wang, D.-K.; Dai, L.-X.; Hou, X.-L.; Zhang, Y. Tetrahedron Lett. 1996, 37, 4187.
1. Dewar, M. J.; Zoebisch, E. G.; Healey, E. F. J. Am. Chem. Soc. 1985, 107, 3902.
2. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Tetrahedron Organic
Chemistry Series; Elsevier Science Ltd: Oxford, 2000; Vol. 20, pp 2e4 and
3e89.
3. Itahara, T. Heterocycles 1986, 24, 2557.
4. Smirnov-Zamkov, I. V.; Zborovskii, Y. L. Zh. Org. Khim. 1975, 11, 1776; Chem. Abstr.
975, 83, 178685.
15. Queiroz, M.-J. R. P.; Calhelha, R. C.; Vale-Silva, L. A.; Pinto, E.; Nascimento, M. S.-
J. Eur. J. Med. Chem. 2009, 44, 1893.
16. (a) Avramoff, M.; Sprinzak, Y. J. Am. Chem. Soc. 1956, 78, 4090; (b) Scully, F. E., Jr.;
1
1
1
Schlager, J. J. Heterocycles 1982, 19, 653.
17. (a) Snyder, D. A.; Selegue, J. P.; Tice, N. C.; Wallace, C. E.; Blankenbuehler, M. T.;
Parkin, S.; Allen, K. D. E.; Beck, R. T. J. Am. Chem. Soc. 2005, 127, 15010; (b)
Pessoa-Mahana, H.; Johann, K. C.; Nadia, R. H.; Recabarren-Gajardo, G.; Clau-
dio, S. B.; Araya-Maturana, R.; Pessoa-Mahana, C. D. Heterocycles 2008, 75,
1913.
8
1
1
1
18. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.