Annulation of eight-to ten-membered oxaza rings to the benzo[b]thiophene system by intramolecular nucleophilic displacement

Article abstract of DOI:10.1071/CH14055

Concise synthetic routes to 2H-benzo[b]thieno[3,2-b][1,5]oxazocin-6(3H)- one, and the new benzo[b]thieno[3,2-b][1,5]oxazonin-7(2H)-one and 2H-benzo[b]thieno[3,2-b][1,5]oxazecin-8(3H)-one systems, have been developed based on intramolecular nucleophilic displacement in the key ring forming step.

Full text of DOI:10.1071/CH14055

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1217–1221
Full Paper
http://dx.doi.org/10.1071/CH14055
Annulation of Eight- to Ten-Membered Oxaza Rings
to the Benzo[b]thiophene System by Intramolecular
Nucleophilic Displacement
A C
,
A B
,
John B. Bremner
and Zemin Wu
A
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
Current address: Avipep Pty Ltd, 343 Royal Parade, Parkville, Vic. 3052, Australia.
B
C
Corresponding author. Email: john_bremner@uow.edu.au
Concise synthetic routes to 2H-benzo[b]thieno[3,2-b][1,5]oxazocin-6(3H)-one, and the new benzo[b]thieno[3,2-b][1,5]
oxazonin-7(2H)-one and 2H-benzo[b]thieno[3,2-b][1,5]oxazecin-8(3H)-one systems, have been developed based on
intramolecular nucleophilic displacement in the key ring forming step.
Manuscript received: 5 February 2014.
Manuscript accepted: 28 March 2014.
Published online: 22 April 2014.
Introduction
Results and Discussion
Although much progress has been made in the synthesis of N,
O-containing fused medium ring systems, many opportunities
for new systems remain.[1] Such compounds are of inherent
chemical interest and are also of significance as novel scaf-
folds for pharmaceutical development,[2–4] particularly eight-
membered systems.[5–9]
As part of some structure–pharmacological activity studies
on benzo[b]thiophene-based potentiators of the action of sero-
tonin, we required systems in which amide functionality at the
2-position of the benzo[b]thiophene was incorporated in a semi-
flexible ring system, while retaining an electronegative group
at the 3-position. Fused medium-sized [1,5]-oxaza systems 1
(Scheme 1) were thus considered as synthetic targets.
N-Substituted 3-hydroxy derivatives of the fused eight-
membered ring system 1a are known (although not the parent
lactam 1a itself), and were made by lactamisation in the final
medium ring forming step.[10] Lactam formation also featured
in approaches to the recently described 10-methoxy and
10-benzyloxy derivatives of 1a which had some inhibitory
activity against protein kinase D, an enzyme involved in
several important cellular processes.[11] The fused nine- and
ten-membered ring systems 1b and 1c respectively have not
been described previously, although representatives with iso-
meric [1,4]- and [1,5]-oxaza fused skeletons have been
reported.[12] It is of interest to note that the fused seven-
membered ring analogue 1 (n ¼ 1) and bio-active derivatives
(cell adhesion and HIV inhibitors) have been reported and
were accessed by lactamisation at the final step.[13,14]
The essential precursors for the ultimate cyclisation reaction
were the bromo amides 7a–c, which could be accessed by the
alcohols 6b, 6e, and 6f in a series of steps from the readily
available acid chloride 2, prepared in turn from the reaction of
cinnamic acid with thionyl chloride in the presence of pyri-
dine[15] (Scheme 1). Substitution of the 3-chloro group in
acid chlorides of type 2 is readily achieved by a nucleophilic
addition–elimination sequence.[16] Thus reaction of 2 with
sodium methoxide gave the 3-methoxy substituted methyl ester
3,[17] from which the corresponding acid 4[17] could be obtained
by standard alkaline hydrolysis. Amide derivatisation was then
achieved by dicyclohexylcarbodiimide-mediated reaction of
methyl b-alinate 5 (Y ¼ COOCH3, n ¼ 2) with the acid 4 in the
case of 6a, and with the commercially available acetal 5 (Y ¼
CH(OCH2CH3)2, n ¼ 3) or the alcohol 5 (Y ¼ CH2OH, n ¼ 4), to
afford 6c and 6f respectively. These transformations proceeded
in good yield and structural assignments followed from the
spectroscopic data and methods of preparation.
With the procedure for the n ¼ 2 series further terminal
functional group manipulation by hydride reduction of 6a to
the primary alcohol 6b was necessary, while in the n ¼ 3 series,
the acetal intermediate 6c was hydrolysed to the aldehyde 6d
and then reduced to the required alcohol precursor 6e. In the case
of 6a an uncommon reduction of the ester functionality with
sodium borohydride was involved leaving the amide group
intact. There is some precedent for such reductions (see, for
example, Saeed and Ashraf[18] and Boechat et al.[19]) and in this
case there may be some increased susceptibility of the ester
carbonyl group to hydride attack as a result of intramolecular
H-bonding of the amide N–H group. Reaction of the alcohols 6b,
6e, and 6f with boron tribromide resulted in O-demethylation
with a concomitant primary alcohol to bromide transformation
to give the respective bromides 7a–c in good yields.
Our new ring construction approach to the systems of
type 1a–c involved an alternative and versatile O–CH2 bond
formation by nucleophilic displacement at saturated carbon
in the final cyclisation step. The results of this work are
presented in this paper.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

1218
J. B. Bremner and Z. Wu
OCH3
Cl
Y
n
OCH3
COX
H2N
NaOCH3
(
5
)
H
N
4;
Y
COCl
(
)
n
S
S
S
DCC
O
6
2
3
X ꢁ OCH3
X ꢁ OH
HOꢀ/H2O
n
Y
4
COOCH3
2
2
3
3
6a
6b
6c
6d
NaBH4
CH2OH
CH(OCH2CH3)2
HCl
CHO
NaBH4
CH2OH
3
4
6e
6f
CH2OH
6b; 6e; 6f
BBr3
OH
(
)
n
NH
O
NaH/THF
H
N
Br
(
)
n
S
S
O
O
1
7
n
n
7a
7b
7c
2
1a
1b
1c
2
3
4
3
4
Scheme 1. Synthesis of the fused medium ring derivatives 1a–c.
The key intramolecular nucleophilic displacement reaction
to realise the fused medium ring derivatives 1a–c then pro-
ceeded smoothly on treatment of 7a–c in each case with
sodium hydride in THF to generate the active 3-oxide nucleo-
phile followed by bromide ion loss. Structural confirmation
of the annulated eight- to ten-membered ring products rested
Conclusion
A concise and efficient route based on O–CH2 bond formation in
the final ring forming step allowed smooth access to benzo[b]
thiophene-fused [1,5]-N,O containing medium ring systems.
Extension of this methodology to prepare a range of hetero-
aromatic and aromatic ring fused, medium-sized oxaza hetero-
cyclic systems should be feasible.
on high resolution mass spectroscopic data and the 1H and 13
C
NMR spectra. In the 13C NMR spectra the presence of the
lactam carbonyl group was consistent with signals in the region
of d161–163. Stereochemically stable rotational isomers in the
medium ring products are possible by analogy with the related
bioisosteric naphthalene-ring fused oxaza systems,[7–9] and
some tentative evidence was seen for these in 1a–c on the basis
of the NMR spectra.
Experimental
Methods and Materials
All melting points (uncorrected) were determined on a Reichert
hot stage apparatus. Infrared spectra were recorded on a Bio Rad
Fourier Transform Infrared Spectrometer FTS-7 as mulls in
Nujol unless otherwise stated and the absorption bands are
described as strong (s), medium (m), or weak (w).
Although somewhat more severe conditions were required to
form the eight- and ten-membered fused lactams compared with
the nine-membered congener, yields were still good. In all cases,
delocalisation of the negative charge on the 3-oxide through the
2,3-benzo[b]thiophene bond to the amide carbonyl group would
presumably weaken the C¼N resonance contribution to the
amide and allow for rotation to the cisoid amide form. Suitable
positioning of the CH2–Br moiety would thus be realised for a
subsequent favourable exo-tet intramolecular nucleophilic dis-
placement process. In no case was evidence seen for competing
macro ring formation (16-, 18-, and 20-membered rings)
through dimerisation, nor for any smaller ring products which
could result from amide anion formation; the preferential
formation of the oxide anion would be expected based on the
likely greater acidity of the 3-OH group. An analogous ring
formation strategy, but involving chloride ion displacement
by a phenoxide ion, was employed to access the benz-fused
eight-membered ring derivative, 8-chloro-4,5-dihydro-2H-1,5-
benzoxazocin-6(3H)-one.[20]
1H and 13C NMR spectra were determined at 399.9 and
100.1 MHz, respectively, with a Varian Unity-400 spectro-
meter. All the spectra were measured in CDC13 unless other-
wise stated. Mass spectra were obtained using Vacuum General
12–12, Vacuum General Quattro and MAT-44 spectrometers by
the direct insertion technique with an electron beam energy of
70 eV and a source temperature of 2008C. The peak intensities,
in parentheses, are expressed as the percentage abundance.
High resolution mass spectra were run by Dr X. Song of the
School of Chemistry, University of Sydney, or Dr N. Davies,
Central Science Laboratory, University of Tasmania. Elemental
microanalyses of samples were performed by the Queensland
Microanalytical Service, Department of Chemistry, University
of Queensland. Analytical TLC was performed on Merck silica
gel F254 silica on aluminium sheets. Column chromatography
was performed under medium pressure using Merck silica gel
unless otherwise indicated. All solvent ratios are v/v.

Annulation to Benzothiophenes
1219
All extracts were dried over anhydrous sodium sulfate
before being evaporated under reduced pressure. THF was
freshly distilled from sodium wire in the presence of benzophe-
none under nitrogen. Other commercial chemicals and reagents
were used as received.
(100 %, [M þ Na]þ), 294 (10, [M þ H]þ). m/z (HRMS, EIþ)
Calc. for C14H15NO4S: 293.0722. Found 293.0728.
N-(30-Hydroxypropyl)-3-methoxy-benzo[b]
thiophene-2-carboxamide (6b)
An excess of sodium borohydride (20 mg, 0.8 mmol) was
added to a solution of the methyl ester 6a (140 mg, 0.48 mmol)
in ethanol (5 mL) and the mixture was stirred overnight.
A saturated ammonium chloride solution was added and the
aqueous mixture was extracted with ethyl acetate (3 ꢀ 10 mL).
The extract was washed with brine (10 mL), dried, and evapo-
rated to afford a crude product, which was chromatographed
(60 % ethyl acetate/hexane) to yield the alcohol 6b (125 mg,
98 %) as colourless crystals, mp 64–668C. nmax (film)/cmꢁ1
3379 (br s, OH, NH), 3060 (w), 2878 (w). 1626 (s, C¼O), 1542
(s). dH 7.84–7.80 (m, 3H), 7.46–7.41 (m, 2H), 4.13 (s, 3H), 3.74
(t, J 5.6, 2H), 3.67 (dt, J1 6.4, J2 6.0, 2H), 1.85–1.82 (m, 2H).
dC 162.8, 150.7, 137.8, 132.3, 126.7, 124.4, 123.5, 122.9, 122.0,
61.9, 59.5, 36.5, 32.1. m/z (ESIþ) 266 (100, [M þ H]þ). m/z
(HRMS, EIþ) Calc. for C13H15NO3S: 265.0773. Found
265.0776.
Synthesis
3-Chloro-benzo[b]thiophene-2-carbonyl Chloride (2)
Thionyl chloride (11.1 mL, 90 mmol) was added to a solution
of (E)-cinnamic acid (4.5 g, 30 mmol) in toluene (50 mL) con-
taining pyridine (0.5 mL, 3 mmol). After addition, the mixture
was heated at reflux for 60 h. The reaction mixture was filtered
and the filtrate was concentrated under vacuum. The residue was
chromatographed on a short column (2 % ethyl acetate/hexane)
to give a crude product, which was recrystallised from CH2Cl2 to
afford the acid chloride 2 (4.5 g, 64 %) as yellow needles, mp
114–1168C (lit.[15] mp 114–1168C).
Methyl 3-Methoxy-benzo[b]thiophene-2-carboxylate (3)
Methanol (0.9 mL, 22.2 mmol) was added dropwise to a sus-
pension of sodium hydride (860 mg, 60 % content, 21.5 mmol)
in THF (15 mL) at room temperature under nitrogen. After
stirring for 1 h, a solution of the acid chloride 2 (1.7 g, 7.4 mmol)
in THF (15 mL) was added dropwise. The reaction mixture was
heated at reflux overnight and then allowed to cool to room
temperature before being quenched with a saturated NH4Cl
solution. The mixture was extracted with ethyl acetate
(3 ꢀ 30 mL). The combined extracts were washed with brine
(20 mL) and dried. Removal of the solvent afforded the ester 3
(1.46 g, 89 %) as colourless crystals, mp 110–1128C (lit.[17] mp
64.5–65.58C). nmax /cmꢁ1 1718 (s, C¼O), 1593 (m). dH 8.08
(m, 1H), 7.92 (m, 1H), 7.60 (m, 2H), 4.10 (s, 3H), 3.9 (s, 3H). m/z
(EIþ) 222 (100 %, Mþ . ), 207 (10), 191 (60), 176 (45).
N-(30-Bromopropyl)-3-hydroxy-benzo[b]
thiophene-2-carboxamide (7a)
An excess of boron tribromide (0.25 mL) was added drop-
wise to a solution of the alcohol 6b (100 mg, 0.38 mmol) in
CH2Cl2 (5 mL) at ꢁ788C under nitrogen. The dry-ice bath was
then removed and the reaction mixture stirred overnight. The
reaction was quenched with water and the reaction mixture
extracted with CH2Cl2 (3 ꢀ 15 mL). The combined extracts
were washed with brine (10 mL), dried, and evaporated.
Column chromatography of the residue (60 % ethyl acetate/
hexane) afforded the bromo derivative 7a (80 mg, 69 %) as a
white powder, mp 135–1368C. nmax /cmꢁ1 3349 (w, NH), 1611
(m, C¼O). dH 7.94 (d, J 8.0, 1H), 7.71 (d, J 8.0, 1H), 7.48 (dt, J1
1.2, J2 8.0, 1H), 7.42 (dt, J1 1.2, J2 8.0, 1H), 5.78 (br s, 1H), 3.63
(dt, J1 6.4, J2 6.4, 2H, NHCH2), 3.50 (t, J 6.4, 2H), 2.21 (quint., J
6.4, 2H). dC 167.1, 158.9, 136.2, 131.2, 128.5, 124.7, 123.0,
122.9, 102.1, 38.2, 32.1, 30.7. m/z (EIþ) 315, 313 (10 %, Mþꢂ),
297, 295 (5). m/z (HRMS, EIþ) Calc. for C12H1279BrNO2S:
312.9772. Found 312.9771.
3-Methoxy-benzo[b]thiophene-2-carboxylic Acid (4)
A mixture of the ester 3 (1 g, 4.5 mmol) and sodium hydro-
xide (1 M, 5 mL) in methanol (25 mL) was stirred overnight. The
solvent was removed and the residue dissolved in water (5 mL)
and neutralised with hydrochloric acid (1 M) to give a pre-
cipitate. Filtration under vacuum afforded the acid 4 (0.9 g,
97 %) as colourless crystals, mp 2508C (dec.) (lit.[17] mp
176–1778C). nmax /cmꢁ1 1686 (m, C¼O). dH 8.08 (m, 1H),
7.92 (m, 1H), 7.60 (m, 2H), 4.10 (s, 3H). m/z (EIþ) 208 (97 %,
4,5-Dihydro-2H-benzo[b]thieno[3,2-b][1,5]
oxazocin-6(3H)-one 1a
M
þꢂ), 164 (15), 149 (40).
Sodium hydride (10 mg, 0.4 mmol) was added to a solution of
the bromide 7a (30 mg, 0.1 mmol) in THF (10 mL) under nitro-
gen. After stirring for 2 h, no reaction was observed by TLC
analysis (20 % ethyl acetate/hexane). The reaction mixture was
then heated at reflux for 2 h and quenched with water. The
mixture was extracted with ethyl acetate (3 ꢀ 15 mL) and the
combined extracts were washed with brine (10 mL) and dried.
The solvent was evaporated to furnish a crude product, which
was subjected to column chromatography (methanol/ethyl ace-
tate/hexane, 10 : 80 : 100) to give the cyclised compound 1a
(15 mg, 68 %) as a yellow powder, mp 196–1978C. nmax /cmꢁ1
1626 (s, C¼O). dH 7.98–7.94 (m, 1H), 7.62–7.59 (m, 1H), 7.42
(dt, J1 1.2, J2 8.0, 1H), 7.28 (dt, J1 1.2, J2 8.0, 1H), 4.49–4.40
(m, 2H), 3.60–3.56 (m, 2H), 2.22–2.16 (m, 2H). dC 178.5, 162.8,
140.6, 134.7, 129.6, 124.2, 123.5, 123.3, 90.0, 66.3, 37.5,
21.2. m/z (EIþ) 233 (55, Mþꢂ). m/z (HRMS; EIþ) Calc. for
C12Hl1NO2S: 233.0511. Found 233.0479. Anal. Calc. for
N-(3-Methoxy-benzo[b]thien-2-oyl)-b-alanine
Methyl Ester (6a)
A solution of b-alanine methyl ester (5, Y ¼ COOCH3, n ¼ 2;
150 mg, 1.4 mmol) in DMF (10 mL) was added to a solution of
the acid 4 (208 mg, 1 mmol), 1,3-dicyclohexylcarbodiimide
(206 mg, 1 mmol), and 1-hydroxybenzotriazole (150 mg,
1.1 mmol) in DMF (10 mL). The reaction mixture was stirred
overnight. The solvent was removed under vacuum and the
residue was column chromatographed (20 % and then 40 %
ethyl acetate/hexane) to give the ester 6a (230 mg, 79 %) as
colourless crystals, mp 61–628C. nmax (film)/cmꢁ1 3387
(m, NH), 1732 (s, COOCH3), 1641 (s, ArCONH), 1535 (s).
dH 8.10 (br s, 1H), 7.82–7.80 (m, 2H), 7.43–7.39 (m, 2H), 4.10
(s, 3H), 3.75 (dt, J 6.0, 6.8, 2H), 3.72 (s, 3H), 2.68 (t, J 6.0, 2H).
dC 172.9, 161.6, 150.5, 137.8, 132.4, 126.6, 124.3, 123.6,
123.5, 122.0, 61.9, 51.7, 48.8, 34.8. m/z (ESIþ) 316

1220
J. B. Bremner and Z. Wu
C12H11NO2SꢃH2O: C 57.36, H 5.21, N 5.57. Found: C 57.59,
grey powder, mp 87–888C. nmax /cmꢁ1 3354 (w, NH), 1626
(m, C¼O), 1586 (s). dH 7.94 (dd, J1 0.8, J2 8.0, 1H), 7.72 (dd, J1
0.8, J2 8.0, 1H), 7.49 (dt, J1 1.2, J2 8.0, 1H), 7.42 (dt, J1 1.2, J2
8.0, 1H), 5.60 (br s, 1H), 3.5 (dt, J1 7.2, J2 6.8, 2H), 3.47 (t, J 6.4,
2H), 1.99–1.95 (m, 2H), 1.85–1.81 (m, 2H). dC 166.9, 158.9,
136.1, 131.2, 128.5, 124.7, 122.9, 122.8, 102.5, 38.6, 33.1, 29.8,
28.3. m/z (EIþ) 327, 329 (15 %, Mþꢂ). m/z (HRMS, EIþ)
326.9926. C13H1479BrNO2S requires 326.9929.
H 4.66, N 5.67 %.
N-(30-Methoxy-benzo[b]thien-20-oy1)-4-
aminobutanal (6d)
A mixture of the acid 4 (208 mg, 1 mmol), 1,3-dicyclohexyl-
carbodiimide (206 mg, 1 mmol), 1-hydroxybenzotriazole
(150 mg, 1.1 mmol), and 4-aminobutanal diethyl acetal 5
(Y ¼ CH(OCH2CH3)2, n ¼ 3; 0.3 mL, 1.74 mmol) in THF
(15 mL) was stirred overnight. The reaction was quenched with
water and the aqueous mixture extracted with ethyl acetate
(3 ꢀ 15 mL). The combined extracts were washed with brine
and dried. Removal of the solvent gave a residue, which was
chromatographed (20 % ethyl acetate/hexane) to give the par-
tially characterised acetal intermediate 6c (300 mg, 85 %) as
colourless crystals, mp 110–1118C. nmax /cmꢁ1 3387 (m, NH),
3065 (w), 1648 (s), 1534. dH 7.80–7.78 (m, 2H), 7.54 (br s, 1H),
7.43–7.40 (m, 2H), 4.53 (t, J 4.8 Hz, 1H), 4.10 (s, 3H), 3.65
(q, J 7.2, 4H), 3.55–3.48 (m, 4H), 1.74–1.72 (m, 2H), 1.21
(t, J 7.2, 6H). m/z (EI) 322 (,1 %, [M – CH2CH3]þ), 305 (3), 259
(20), 224 (30), 191(100), 176 (60). m/z (HRMS, EIþ) 351.1489.
C18H25NO4S requires 351.1504. The acetal 6c (70 mg,
0.2 mmol) in acetone (10 mL) was then treated with a few drops
of 1 M hydrochloric acid at room temperature and stirred
overnight. The solvent was removed and the residue was
chromatographed (40 % ethyl acetate/hexane) to give the alde-
hyde 6d (55 mg, 100 %) as an oil. nmax /cmꢁ1 3387 (s, NH),
3060 (w), 1725 (s, CHO), 1641 (s, ArCONH), 1527 (s). dH 9.80
(t, J 0.8, 1H), 7.82–7.80 (m, 2H), 7.60 (br s, 1H), 7.43–7.40
(m, 2H), 4.10 (s, 3H), 3.50 (dt, J1 7.2, J2 6.8, 2H), 2.60 (t, J 6.8,
2H), 2.02 (t, J 6.8, 2H), 1.98 (t, J 6.8, 2H). dC 201.6, 162.1, 150.4,
137.9, 132.4, 126.7, 124.5, 123.7, 122.1, 108.3, 61.97, 41.4,
38.9, 29.7. m/z (EI) 277 (8, Mþꢂ), 249 (5), 191 (100). m/z
(HRMS, EIþ) 277.0769. C14H15NO3S requires 277.0773.
3,4,5,6-Tetrahydro-benzo[b]thieno[3,2-b][1,5]
oxazonin-7(2H)-one (1b)
Sodium hydride (10 mg, 0.4 mmol) was added to a solution of
the bromide 7b (40 mg, 0.12 mmol) in THF (20 mL) under
nitrogen. After stirring overnight, water was added to stop
the reaction. The reaction mixture was extracted with ethyl
acetate (3 ꢀ 15 mL). The extracts were washed with brine
(10 mL) and dried. The solvent was evaporated to furnish, after
column chromatography (15 % ethyl acetate/hexane) of the
residue, the cyclised compound 1b (28 mg, 70 %) as colourless
crystals, mp 95–968C. nmax /cmꢁ1 1621 (w, C¼O), 1565 (s). dH
7.99–7.96 (m, 1H), 7.75–7.73 (m, 1H), 7.48 (dt, J1 1.2, J2 8.0,
1H), 7.41 (dt, J1 1.2, J2 8.0, 1H), 3.84–3.80 (m, 4H), 2.01–1.98
(m, 4H). dC 166.6, 160.9, 137.9, 130.8, 128.1, 124.3, 122.8,
122.4, 101.6, 76.6, 47.0 (C3,4,5). m/z (EIþ) 247 (Mþꢂ, 69). m/z
(HRMS, EIþ) 247.0670. C13H13NO2S requires 247.0667. Anal.
Calc. for C13H13NO2S: C 63.14, H 5.30, N 5.66. Found: C 63.55,
H 5.80, N 5.19 %.
N-(50-Hydroxypenty1)-3-methoxy-benzo[b]
thiophene-2-carboxamide (6f)
A mixture of the acid 4 (208 mg, 1 mmol), 1,3-dicyclohexyl-
carbodiimide (206 mg, 1 mmol), 1-hydroxybenzotriazole
(150 mg, 1.1 mmol), and 5-aminopentan-l-ol in DMF (10 mL)
was stirred overnight. The solvent was removed under high
vacuum, and the residue was chromatographed (30 % ethyl
acetate/hexane) to afford the alcohol 6f (240 mg, 80 %) as
colourless crystals, mp 68–698C. nmax (film)/cmꢁ1 3463
(m, OH), 3387 (m, NH), 1634 (s, C¼O), 1535 (s). dH 7.83–
7.80 (m, 2H), 7.53 (br s, 1H), 7.42–7.39 (m, 2H), 4.1 (s, 3H),
3.67 (t, J 6.4, 2H), 3.50 (dt, J1 7.2, J2 6.8, 2H), 1.76 (br s, 1H),
1.66–1.68 (m, 4H), 1.52–1.49 (m, 2H). dC 161.8, 150.0, 137.7,
132.4, 126.6, 124.4, 123.6, 121.9, 124.2, 62.5, 61.9, 39.3, 32.3,
29.6, 23.1. m/z (ESIꢁ) 292 (65 %, [M – H]ꢁ); (ESIþ) 316
(100 %, [M þ Na]þ), 294 (22, [M þ H]þ). m/z (HRMS, EIþ)
293.1090. C15H19NO3S requires 293.1086.
N-(40-Hydroxybuty1)-3-methoxy-benzo[b]
thiophene)-2-carboxamide (6e)
An excess of sodium borohydride (20 mg, 0.8 mmol) was
added to a solution of the aldehyde 6d (55 mg, 0.2 mmol) in
ethanol (10 mL) and the mixture was allowed to stir overnight.
The reaction was quenched with a saturated NH4Cl solution and
the mixture extracted with ethyl acetate (3 ꢀ 10 mL). The
combined extracts were washed with brine (10 mL) and dried.
Removal of the solvent gave the alcohol 6e (55 mg, 100 %) as
colourless crystals, mp 139–1408C. nmax (film)/cmꢁ1 3243 (br s,
OH), 1641 (s, C¼O), 1535 (s). dH 7.82 (dd, J1 2, J2 6.8, 2H), 7.59
(br s, 1H), 7.42–7.40 (m, 2H), 4.10 (s, 3H), 3.74 (t, J 6.0, 2H),
3.55 (dt, J1 6.8, J2 6.4, 2H), 1.73–1.70 (m, 4H). dC 162.0, 151.0,
139.1, 132.5, 126.7, 124.5, 124.0, 123.7, 122.0, 62.3, 61.9, 39.0,
30.1, 26.50. m/z (ESIþ) 280 (100 %, [M þ H]þ), 191 (10). m/z
(HRMS, EIþ) 279.0929. C14H17NO3S requires 279.0929.
N-(50-Bromopenty1)-3-hydroxy-benzo[b]
thiophene-2-carboxamide (7c)
An excess of boron tribromide (0.2 mL) was added dropwise
to a solution of the alcohol 6f (100 mg, 0.34 mmol) in CH2Cl2
(10 mL) at ꢁ788C under nitrogen. After addition, the dry ice
bath was removed and the reaction mixture stirred overnight.
The reaction was quenched with water and the mixture was
extracted with CH2Cl2 (3 ꢀ 10 mL). The combined extracts
were washed with brine (10 mL) and dried. Chromatography
of the residue (15 % ethyl acetate/hexane) yielded the bromide
7c (100 mg, 86 %) as pink crystals, mp 94–958C. nmax /cmꢁ1
3356 (m, NH), 1610 (s, C¼O), 1550 (m). dH 7.93 (dd, J1 0.8, J2
8.0, 1H), 7.71 (dd, J1 0.8, J2 8.0, 1H), 7.48 (dt, J1 1.2, J2 8.0, 1H),
7.40 (dt, J1 1.2, J2 8.0, 1H), 5.60 (br s, 1H), 3.46 (dt, J1 7.2, J2 6.8,
2H), 3.42 (t, J 6.4, 2H), 1.95–1.49 (m, 6H). dC 166.9, 158.7,
136.1, 131.2, 128.4, 124.6, 122.9, 122.8, 102.4, 39.3, 33.5, 32.1,
N-(40-Bromobuty1)-3-hydroxy-benzo[b]
thiophene-2-carboxamide (7b)
Boron tribromide (0.2 mL) was added dropwise to a solution
of the alcohol 6e (100 mg, 0.36 mmol) in CH2Cl2 (10 mL) at
ꢁ788C under nitrogen. The dry ice bath was then removed and
the reaction mixture stirred overnight. The reaction was
quenched with water and the mixture extracted with CH2Cl2
(3 ꢀ 10 mL). The combined extracts were washed with brine
(10 mL) and dried. Chromatography of the residue (10 % ethyl
acetate/hexane) afforded the bromide 7b (105 mg, 90 %) as a

Annulation to Benzothiophenes
1221
28.9, 25.3. m/z (ESIꢁ) 340, 342 (95 %, [M– H]ꢁ), 79, 81 (89).
m/z (HRMS, EIþ) 341.0079. C14H1679BrNO2S requires 341.0085.
[4] B. Roy, R. N. De, S. Hazra, Lett. Org. Chem. 2011, 8, 391. doi:10.2174/
157017811796064502
[5] G. Cirrincione, P. Diana, in Comprehensive Heterocyclic ChemistryIII
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M. Tandon, S. Leimgruber, E. R. Sharlow, J. S. Lazo, Q. J. Wang,
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PHARMACEUTICS3020186
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4,5,6,7-Tetrahydro-2H-benzo[b]thieno[3,2-b]
[1,5]oxazecin-8(3H)-one (1c)
An excess of sodium hydride (10 mg, 0.4 mmol) was added to
a solution of the bromide 7c (68 mg, 0.2 mmol) in THF (20 mL).
After stirring for 1 h, no reaction occurred. The reaction mixture
was heated at reflux for 1 h, and then quenched with water.
The mixture was extracted with ethyl acetate (3 ꢀ 10 mL). The
combined extracts were washed with brine (10 mL) and dried.
The solvent was evaporated and the residue was chromato-
graphed (15 % ethyl acetate/hexane) to give the cyclised
compound 1c (42 mg, 81 %) as pink crystals, mp 69–708C.
nmax /cmꢁ1 1573 (m), 1527 (m). dH 7.98–7.96 (m, 1H), 7.72–
7.70 (m, 1H), 7.47–7.45 (m, 1H), 7.42–7.39 (m, 1H), 3.86–3.83
(m, 4H), 2.08 (br s, 1H), 1.72–1.70 (m, 6H). dC 167.0, 161.8,
137.3, 130.8, 128.4, 124.4, 122.8, 122.1, 101.2, 46.1 (2C), 26.2
(2C), 24.5. m/z (EIþ) 261 (Mþꢂ, 65), 176 (94). m/z (HRMS, EIþ)
M
þꢂ 261.0787. C14H15NO2S requires 261.0824. Anal. Calc. for
C14H15NO2S: C 64.34, H 5.79, N 5.36. Found: C 64.15, H 5.97,
N 5.36 %.
Supplementary Material
NMR and mass spectra are available on the Journal’s website.
Acknowledgements
[15] W. B. Wright, Jr, H. J. Brabander, J. Heterocycl. Chem. 1971, 8, 711.
doi:10.1002/JHET.5570080504
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D. O. Thueson, C. D. Wright, M. C. Conroy, J. Med. Chem. 1992, 35,
958. doi:10.1021/JM00083A023
The authors thank the Australian Research Council for financial support.
They also thank Dr M. Song, University of Sydney, and Dr N. Davies,
University of Tasmania, for the high resolution mass spectra, and
Mr A. Shakoori for help with the manuscript. Assistance for this research
from the University of Wollongong is also gratefully acknowledged,
together with the valued friendship and support of the late Emeritus
Professor Roger Brown.
[17] Y. Matsuki, Y. Adachi, Nippon Kagaku Zasshi 1968, 89, 192 (Chem.
Abstr. 1968, 69, 67165).
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