The synthesis of new dibenzothiophen amino acid and cyclophane derivatives

Article abstract of DOI:10.1071/CH00029

Some novel dibenzothiophen amino acid and cyclophane derivatives have been produced as a result of synthetic studies on the development of dibenzothiophen-based antibacterial compounds. Allylation through a Stille reaction has produced 2-allyl-8-bromodibenzothiophen (3a) and 2,8-diallyldibenzothiophen (3b). Under different conditions, the Stille reaction also produced 2-bromo-8-(prop-1-enyl)dibenzothiophen (4a) and 2,8-di(prop-1-enyl)dibenzothiophen (4b) via double bond isomerization. Olefin metathesis with (3b) and methyl N-acetylallylglycinate (5) produced two homodimers, the novel [4](5,11)[4](18,24)dibenzothiophenophane-2,15-diene (6), as a mixture of geometrical isomers, and dimethyl (E)- and (Z)-(R,S)-2,7-diacetamidooct-4-enedioate (8), and the two cross-metathesis products methyl (E)- and (Z)-(R,S)-2-acetamido-6-(8-allyldibenzothien-2-yl)hex-4-enoate (7a) and dimethyl (E)- and (Z)-(R,S)-6,6′-(dibenzothiophen-2,8-diyl)bis(2-acetamidohex-4-enoate) (7b). Palladium-catalysed hydrogenation of the homodimer (6) and the cross-metathesis products (7a,b) yielded the corresponding reduced compounds (9) and (10a,b), respectively. CSIRO 2000.

Full text of DOI:10.1071/CH00029

C S I R O P U B L I S H I N G
Australian Journal
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Volume 53, 2000
© CSIRO 2000
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Aust. J. Chem., 2000, 53, 535–540
The Synthesis of New Dibenzothiophen
Amino Acid and Cyclophane Derivatives
John B. Bremner,A Paul A. Keller,A Stephen G. Pyne,A
Alan D. Robertson,B Brian W. Skelton,C Allan H. WhiteC and
Helen M. WitchardA
A Department of Chemistry, University of Wollongong, Wollongong, N.S.W. 2522.
B AMRAD Operations Pty Ltd, Burnley, Vic. 3121. New address: Baker Medical
Research Institute, P.O. Box 6492, St Kilda Road Central, Vic. 8008.
C Department of Chemistry, University of Western Australia, Nedlands, W.A. 6097.
Some novel dibenzothiophen amino acid and cyclophane derivatives have been produced as a result of synthetic
studies on the development of dibenzothiophen-based antibacterial compounds. Allylation through a Stille reaction
has produced 2-allyl-8-bromodibenzothiophen (3a) and 2,8-diallyldibenzothiophen (3b). Under different condi-
tions, the Stille reaction also produced 2-bromo-8-(prop-1-enyl)dibenzothiophen (4a) and 2,8-di(prop-1-
enyl)dibenzothiophen (4b) via double bond isomerization. Olefin metathesis with (3b) and methyl
N-acetylallylglycinate (5) produced two homodimers, the novel [4](5,11)[4](18,24)dibenzothiophenophane-2,15-
diene (6), as a mixture of geometrical isomers, and dimethyl (E)- and (Z)-(R,S)-2,7-diacetamidooct-4-enedioate (8),
and the two cross-metathesis products methyl (E)- and (Z)-(R,S)-2-acetamido-6-(8-allyldibenzothien-2-yl)hex-4-
enoate (7a) and dimethyl (E)- and (Z)-(R,S)-6,6´-(dibenzothiophen-2,8-diyl)bis(2-acetamidohex-4-enoate) (7b).
Palladium-catalysed hydrogenation of the homodimer (6) and the cross-metathesis products (7a,b) yielded the cor-
responding reduced compounds (9) and (10a,b), respectively.
Keywords. Dibenzothiophen; amino acid derivatives; cyclophanes; Stille reaction; olefin metathesis.
Introduction
bromination of dibenzothiophen (1) by modification of a lit-
erature procedure.9 Recrystallization of the reaction product
from dichloromethane/petroleum spirit afforded (2) as
colourless needles in 44% yield, which represents a 20%
improvement over that previously reported (Scheme 1).
The allylation of (2) was attempted under Stille coupling
conditions using dioxan or dimethylformamide as the
solvent10 (Scheme 1), and results from these reactions are
summarized in Table 1. In dioxan, 1 mole equiv. of the allyl-
tributyltin reagent gave mostly starting material in a 5 h reac-
The development of new antibacterial agents is of partic-
ular interest in view of the fact that resistant bacterial strains
are continually emerging.1–4 In recent years, the reduced effi-
cacy of current therapeutic agents, such as vancomycin, has
raised serious concern, as many of these bacterial strains also
carry resistance to a number of antibiotics.5–8 There is thus a
pressing need for the identification of new agents.
As part of a project investigating potential new antibacte-
rial agents, model synthetic studies directed towards novel
dibenzothiophen amino acid derivatives were carried out.
Our synthetic strategy involved olefin cross-metathesis reac-
tions of allylated dibenzothiophens and methyl N-acetyl-
allylglycinate. However, as an initial target, 2-allyl-
8-bromodibenzothiophen was required as a differentially
substituted building block for these targets. Additionally,
during this process, a series of dibenzothiophen-based cyclo-
phanes were generated which represent a new type of hetero-
cyclic cyclophane.
Results and Discussion
Preparation of Allylated Dibenzothiophens
2,8-Dibromodibenzothiophen (2), the key precursor for
the allylated dibenzothiophens, was prepared from the
Manuscript received 25 February 2000
© CSIRO 2000
10.1071/CH00029
0004-9425/00/070535

536
J. B. Bremner et al.
Table 1. A comparison of the yields of 2-allyl-8-bromodibenzo-
thiophen (3a) and 2,8-diallyldibenzothiophen (3b) as products of
the Stille reaction under different conditions
Reaction
solvent
Temp. Time Mole equiv. Product Product
(h) allyltributyltin
(3a)
(3b)A
Dioxan
Dioxan
Dioxan
reflux
reflux
reflux
48
6
1.0
2.5
2.5
30%B
36%A
—
—
21%
65%
15
Dimethyl-
formamide
110°C
48
2.2
—
55%
A Yield after column chromatography. B Percentage product from 1H
n.m.r. analysis.
tion; however, a 48 h reaction resulted in a 30 : 70 ratio of
(3a) to starting material (n.m.r. analysis). When 2.5 equiv. of
allyltributyltin in dioxan were used, 2-allyl-8-bromodiben-
zothiophen (3a) was found to be the major product (36%),
along with a 21% yield of (3b) after a 6 h reaction; a 15 h
reaction produced (3b) as the major product (65%).
Changing the solvent to dimethylformamide produced (3b)
as the sole product (n.m.r. analysis); however, the isolated
yield of 55% is probably lower than the actual yield due to
the need for extensive chromatography to remove the non-
polar product from excess tributyltin by-products.
In an attempt to produce the initial target compound (3a)
selectively, the Stille reaction was carried out in dimethyl-
formamide at 110°C using 1 mole equiv. of allyltributyltin.
After a 24 h reaction period, 1H n.m.r. analysis indicated the
presence of (3a), starting material (2) and a third product.
Purification of the reaction mixture on silica gel gave an
inseparable (1.6 : 1) mixture of (3a) and the allylic rear-
rangement product, 2-bromo-8-(prop-1-enyl)dibenzothio-
phen (4a) (Scheme 2).
and racemic methyl N-acetylallylglycinate (5) was studied.12
Treatment of a mixture of (3b) and (5) (4 mole equiv.) with
the Grubbs’ ruthenium catalyst, Cl2(PCy3)2–Ru=CHPh (Cy =
cyclohexyl),13 in refluxing dichloromethane for 36 h gave the
two cross-metathesis products, the amino ester (7a) (13%)
and the bis amino ester (7b) (41%) (Scheme 3). These
racemic compounds were obtained as mixtures of (E) and (Z)
isomers. Two homodimers were also isolated, the novel
cyclophane,
[4](5,11)[4](18,24)dibenzothiophenophane-
2,15-diene (6) (6%), and the bis amino ester (8) (6%) [other
reactions have produced (8) in up to 26% yield].
N.m.r. analysis of (6) indicated a mixture of three isomers
in a ratio of 6 : 4.3 : 1. When this metathesis reaction was
repeated with (3b) only, the cyclophane (6) was isolated in
26% yield as a 9 : 1 :0.1 mixture of isomers. The major
isomer of (6) was isolated through recrystallization from
benzene. Unfortunately, NOESY experiments on this pure
isomer were inconclusive with respect to the geometry of the
alkene groups. Furthermore, molecular modelling studies
using SPARTAN (semiempirical, AM1) suggested little differ-
ence in the heats of formation between the possible
(E),(E)/(E),(Z)/(Z),(Z) isomers of (6).
Longer reaction times (66 h) produced solely rearranged11
vinylic products. Separation of the rearranged products
revealed a 21% yield of the monovinylic compound (4a) and
a 25% yield of the divinylic compound (4b). These com-
pounds not only have distinctive n.m.r. spectra, but, being
colourless solids, are physically different to their allyl coun-
terparts (3a,b) which are colourless oils.
The major isomer was shown to be the (E),(E)-isomer
by a single-crystal X-ray study (Fig. 1); a second con-
former of the (E),(E)-isomer of (6) was present in the crys-
talline state (Fig. 2). The two distinct conformers found in
the crystal of (6) were in a ratio of 1 : 2 (Figs 1 and 2,
respectively), the conformer in Fig. 1 being disposed about
a crystallographic inversion centre. In the conformer
shown in Fig. 2, one of the bridging CH=CH moieties was
disordered over two orientations.
Preparation of Dibenzothiophen Amino Acid and
Cyclophane Derivatives via Olefin Metathesis
With the aim of preparing the dibenzothiophen amino acid
derivatives (7a,b), the olefin cross-metathesis reaction of (3b)
The second product [the major product from cross-
metathesis reaction of (3b) with (5)] could not be isolated
pure, but 13C n.m.r. analysis of the isomer mixture indicated

New Dibenzothiophen Derivatives
537
Fig. 1. Projections of the centrosymmetric molecule of (6) as deter-
mined by the X-ray study: projections ‘normal’ to and through the
central ring plane are shown. The constituent of the asymmetric unit is
labelled (carbon atoms by number only); 50% thermal ellipsoids are
shown for the non-hydrogen atoms, hydrogen atoms having arbitrary
radii of 0.1 Å.
Fig. 2. Projections of the second independent molecule of (6): pro-
that this compound had the (E),(Z) stereochemistry. The 13
C
jections ‘normal’ to and through the central ring plane are shown.
n.m.r. spectrum of this compound was consistent with the
lack of symmetry of the (E),(Z)-isomer and showed pairs of
resonances at 130.8/129.6 (alkene), 128.1/127.8 (Ar CH),
122.7/122.6 (Ar CH), 120.7/120.6 (Ar CH) and 38.7/33.5
(CH2). The third component from these metathesis reactions,
therefore, was the symmetric (Z),(Z)-isomer.
(Scheme 4). The structural symmetry of (9) was clearly
evident in the 1H and 13C n.m.r. spectra, with further confir-
mation of this structure provided by mass spectrometry.
Similarly, hydrogenation of (7a) produced racemic methyl
2-acetamido-6-(8-propyldibenzothien-2-yl)hexanoate (10a)
in 43% yield, while (7b) was reduced to the two diastereoiso-
mers of dimethyl 6,6´-(dibenzothiophen-2,8-diyl)bis(2-
acetamidohexanoate) (10b) in 75% yield (Scheme 5).
In order to simplify the n.m.r. spectra of the mixture of
isomers of (6), the mixture was hydrogenated to give
[4.4](2,8)dibenzothiophenophane (9) in 83% yield

538
J. B. Bremner et al.
and 2,8-diallyldibenzothiophen (3b) (16 mg, 0.061 mmol, 21%) as
colourless oils.
A method for preparing the dibenzothiophen mono and
bis amino ester derivatives (7a,b) and (10a,b) has been
developed by using the olefin cross-metathesis reaction.
During these studies, a novel dibenzothiophenophane (6)
was also isolated and characterized. Furthermore, these
methods potentially can be extended to the synthesis of other
heterocyclic amino acid and cyclophane derivatives, and the
synthesis of optically active amino acid derivatives by
employing enantiomerically pure (5).
(3a): (Found: M+ , 301.9762. C15H11 79BrS requires M+ , 301.9765).
Mass spectrum m/z (c.i.) 305/303 (100%) [MH+], 225 (52%)
[MH+ –Br]. 1H n.m.r. 8.23, d, J 2 Hz, H9; 7.88, d, J 2 Hz, H1; 7.73,
d, J 8 Hz, H4; 7.66, d, J 8 Hz, H6; 7.50, dd, J 8, 2 Hz, H 7; 7.30, dd, J
8, 2 Hz, H3; 6.03, ddt, J 17, 10, 7 Hz, CH2CH=CH2; 5.14, d, J 15 Hz,
1H, CH2CH=CH2; 5.13, d, J 11 Hz, 1H, CH2CH=CH2; 3.54, d, J 7 Hz,
CH2CH=CH2. 13C n.m.r. 138.4; 137.7; 137.2, CH2CH=CH2; 136.8;
134.7; 130.2; 129.4, Ar CH; 128.4, Ar CH; 124.4, Ar CH; 124.1, Ar CH;
122.7, Ar CH; 121.5, Ar CH; 118.2; 116.2, CH2CH=CH2; 40.1,
CH2CH=CH2.
(3b): (Found: M+ , 265.1044. C18H16S + H requires M+ , 265.1051).
Mass spectrum m/z (c.i.) 265 (100%) [MH+]. 1H n.m.r. 7.95, d, J 2 Hz,
H1 and H9; 7.75, d, J 8 Hz, H4 and H6; 7.28, dd, J 8, 2 Hz, H3 and
H7; 6.06, ddt, J 17, 11, 7 Hz, 2H, CH2CH=CH2; 5.14, d, J 17 Hz, 2H,
CH2CH=CH2; 5.12, d, J 11 Hz, 2H, CH2CH=CH2; 3.56, d, J 7 Hz, 4H,
CH2CH=CH2. 13C n.m.r. 137.6, CH2CH=CH2; 136.3; 135.7; 127.6,
Ar CH; 122.7, Ar CH; 121.4, Ar CH; 116.0, CH2CH=CH2; 40.2,
CH2CH=CH2.
Experimental
General
Melting point (m.p.) determinations were carried out on a
Gallenkamp melting point apparatus. Chemical ionization (c.i.) and
electron impact (e.i.) mass spectra were obtained on a Shimadzu QP-
5000 mass spectrometer by a direct insertion technique with an elec-
tron beam energy of 70 eV. Electrospray (e.s.) mass spectra were
obtained on a VG Quattro spectrometer, and high-resolution mass
spectra were determined on a VG Autospec spectrometer. The m/z
values are stated with their peak intensity as a percentage in paren-
theses. Proton and carbon nuclear magnetic resonance (n.m.r.)
spectra were determined with a Varian Unity 300 MHz spectrometer,
or with a Varian Unity 400 MHz spectrometer where specified.
Spectra were recorded in (D)chloroform (CDCl3) using chloroform
as the internal standard, unless otherwise specified. Chemical shifts
( ) in ppm were measured relative to the internal standard. Where
samples exhibited several isomers, the chemical shifts for the major
form are given since the major and minor isomers could not be sep-
arated, and overlapping peaks made it difficult to specify all the
chemical shifts for the minor isomer(s). All column chromatography
was performed under gravity on Merck Kieselgel 60 (230–400
mesh). Chromatography solvent mixtures were measured by volume.
Organic solvent extracts were dried with anhydrous magnesium
sulfate, and the solvent removed under reduced pressure with a Büchi
rotary evaporator. Solvents were purified and dried by standard tech-
niques. All compounds were judged to be of greater than 95% purity
Method B. Following the above procedure for the preparation of
(3a) and allowing the reaction to continue for a total of 15 h, 2,8-dial-
lyldibenzothiophen (3b) (50 mg, 0.19 mmol, 65%) was obtained as a
colourless oil after purification on silica gel (petroleum spirit as eluent).
Method C. A dry, glass tube containing a suspension of 2,8-dibro-
modibenzothiophen (2) (300 mg, 0.88 mmol), palladium chloride
(8 mg, 0.044 mmol), triphenylphosphine (46 mg, 0.17 mmol) and allyl-
tributyltin (0.60 ml, 1.93 mmol) in dry dimethylformamide (5 ml) was
flushed with argon before sealing. The reaction mixture was heated at
110°C for 48 h. The dimethylformamide was evaporated in vacuum and
the crude product was dissolved in CH2Cl2, then washed twice with
water, dried and evaporated. The crude product was chromatographed
on a gravity silica gel column twice (40 cm by 1.5 cm, petroleum spirit)
to produce 2,8-diallyldibenzothiophen (3b) (128 mg, 0.48 mmol, 55%)
as a colourless oil. Spectral data for (3b) were as described above.
2-Bromo-8-(prop-1-enyl)dibenzothiophen (4a) and 2,8-Di(prop-
1-enyl)dibenzothiophen (4b)
1
based upon H n.m.r. and t.l.c. analysis except for compound (7a)
A dry, glass tube containing a suspension of 2,8-dibromodibenzo-
thiophen (2) (200 mg, 0.58 mmol), palladium chloride (5 mg, 0.029
mmol), triphenylphosphine (31 mg, 0.12 mmol) and allyltributyltin
(0.18 ml, 0.58 mmol) in dry dimethylformamide (5 ml) was flushed
with argon before sealing. The reaction mixture was heated at 110°C for
66 h. The dimethylformamide was evaporated in vacuum and the crude
product was dissolved in CH2Cl2, then washed twice with water, dried
and evaporated. The crude product was chromatographed on a gravity
silica gel column (42 cm by 1.5 cm, petroleum spirit) to produce 2-
bromo-8-(prop-1-enyl)dibenzothiophen (4a) (37 mg, 0.12 mmol, 21%)
as colourless needles. Further elution with petroleum spirit gave 2,8-
di(prop-1-enyl)dibenzothiophen (4b) (38 mg, 0.14 mmol, 25%) as
colourless needles.
(see below for details). Starting materials and reagents were pur-
chased from Sigma–Aldrich Pty Ltd and were used as received.
Petroleum spirit refers to the 40–60°C b.p. range material.
2,8-Dibromodibenzothiophen (2)
To a suspension of dibenzothiophen (1) (4 g, 21.7 mmol) in glacial
acetic acid (80 ml) was added a solution of bromine (2.46 ml, 47.7
mmol) dissolved in glacial acetic acid (20 ml) over a period of 15 min.
The mixture was stirred for 2 h and then refluxed for 12 h under nitro-
gen. After the reaction mixture had been allowed to cool to room tem-
perature, the solid product was filtered off, washed with cold water and
air-dried. Recrystallization from CH2Cl2/petroleum spirit produced 2,8-
dibromodibenzothiophen (2) (3.3 g, 9.6 mmol, 44%) as colourless
needles, m.p. 220–222°C (lit.9 226–228°C). Mass spectrum m/z (e.i.)
344/342 (99%)/340 [M+], 263/261 (19%) [M+–Br], 182 (100%)
[M+–2Br]. 1H n.m.r. 8.22, d, J 2 Hz, H 1 and H9; 7.70, d, J 8 Hz, H4
and H 6; 7.57, dd, J 8, 2 Hz, H 3 and H 7. 13C n.m.r. 138.6; 136.2;
130.3, Ar CH; 124.7, Ar CH; 124.2, Ar CH; 118.6.
(4a) had m.p. 104–106°C (Found: M+ , 301.9783. C15H1179BrS
requires M+ , 301.9765). Mass spectrum m/z (c.i.) 305/303 (55%)
[MH+], 275 (30%) [MH+ –CH2=CH2], 225 (100%) [MH+ –Br], 197
(33%). 1H n.m.r. 8.22, d, J 2 Hz, H1; 7.96, d, J 1 Hz, H9; 7.71, d, J
8 Hz, H6; 7.65, d, J 8 Hz, H 4; 7.52, dd, J 8, 2 Hz, H3; 7.46, dd, J 8,
1 Hz, H7; 6.52, d, J 16 Hz, CH=CHCH3; 6.34, dq, J 16, 7 Hz,
CH=CHCH3; 1.93, dd, J 7, 2 Hz, CH=CHCH3. 13C n.m.r. 138.5;
138.2; 137.3; 134.9; 134.7; 130.6, CH=CHCH3; 129.5, Ar CH; 126.1,
CH=CHCH3; 125.3, Ar CH; 124.5, Ar CH; 124.1, Ar CH; 122.7, Ar
CH; 118.9, Ar CH; 118.3; 18.6, CH=CHCH3.
2-Allyl-8-bromodibenzothiophen (3a) and 2,8-
Diallyldibenzothiophen (3b)
Method A. To a suspension of 2,8-dibromodibenzothiophen (2)
(100 mg, 0.29 mmol), palladium chloride (3 mg, 0.015 mmol) and
triphenylphosphine (15 mg, 0.058 mmol) in dry dioxan (5 ml) was
added allyltributyltin (0.23 ml, 0.73 mmol) under nitrogen, and the
reaction mixture was refluxed for 6 h. The dioxan solvent was evapo-
rated and the crude product was dissolved in CH2Cl2, then washed with
water, dried and evaporated. The crude product was chromatographed
on a gravity silica gel column (44 cm by 1.5 cm, petroleum spirit) to
afford 2-allyl-8-bromodibenzothiophen (3a) (32 mg, 0.11 mmol, 36%)
(4b) had m.p. 100–102°C (Found: M+ , 264.0956. C18H16S requires
M+ , 264.0973). Mass spectrum m/z (c.i.) 265 (100%) [MH+], 237
(18%) [MH+ –CH2=CH2]. 1H n.m.r. 8.04, d, J 1 Hz, H1 and H9; 7.71,
d, J 8 Hz, H4 and H6; 7.44, dd, J 8, 2 Hz, H3 and H7; 6.55, dd, J 16,
2 Hz, CH=CHCH3; 6.35, dq, J 16, 6 Hz, CH=CHCH3; 1.93, dd, J 6,
2
Hz, CH=CHCH3. 13C n.m.r.
138.2; 135.8; 134.6; 130.9,
CH=CHCH3; 125.6, CH=CHCH3; 124.7, Ar CH; 122.7, Ar CH; 118.8,
Ar CH; 18.5, CH=CHCH3.

New Dibenzothiophen Derivatives
539
Methyl (RS)-Allylglycinate Hydrochloride
136.7; 135.8; 131.0, alkene CH; 128.1, Ar CH; 122.6, Ar CH; 121.0,
Ar CH; 38.4, alkane CH2.
A solution of dry methanol (6 ml) was cooled to 0°C under a nitro-
gen atmosphere and thionyl chloride (1.27 ml, 17.4 mmol) was added
dropwise. Racemic allylglycine (1.0 g, 8.69 mmol) was added and the
reaction mixture was stirred at room temperature for 12 h. The methanol
solvent was evaporated and the product was purified by redissolving in
methanol and evaporating several times. The yellow oil was dried in
vacuum and solidified at –20°C to afford methyl (RS)-allylglycinate
hydrochloride (1.46 g, 8.85 mmol, 100%) as a pale yellow solid, m.p.
174–176°C (Found: M+ , 130.0865. C6H11NO2 + H requires M+ ,
Methyl (E)- and (Z)-(R,S)-2-Acetamido-6-(8-allyldibenzothien-2-
yl)hex-4-enoate (7a)
From the reaction that produced (6) (method A), the ester (7a)
(40 mg, 0.098 mmol, 13%) was obtained as a yellow oil, after the
elution of (6). 1H n.m.r. analysis of (7a) showed a mixture of (E)- and
(Z)-isomers of (7a) plus what appeared to be their allylic rearranged
products (about 10–15%) (Found: MH+ , 408.1625. C24H25NO3S + H
requires MH+ , 408.1633). Mass spectrum m/z (c.i.) 408 (100%) [MH+],
132 (55%). 1H n.m.r. 8.08–7.68, m, 4H, ArH; 7.43–7.18, m, 2H, ArH;
6.14, m, NH; 5.90–5.35, m, 3H, alkene CH; 5.18–5.00, m,
CH2CH=CH2; 4.65, m, CHN; 3.71, s, OCH3; 3.60–3.38, m,
CH2CH=CH2; 2.90–2.38, m, CH2CH=CH; 1.98, s, COCH3. 13C n.m.r.
172.4, COOCH3; 169.7, COCH3; 137.5, alkene CH; 137.0; 136.4;
135.7; 134.2, alkene CH; 130.8, alkene CH; 127.6, Ar CH; 127.4, Ar
CH; 122.8, Ar CH; 122.7, Ar CH; 121.4, Ar CH; 121.3, Ar CH; 116.0,
CH2=CH; 52.4, OCH3; 52.0, CHN; 40.2, ArCH2CH=CH2; 38.9,
COCH3; 35.3, ArCH2CH=CH; 33.3, CH2CH=CH.
130.0868). Mass spectrum m/z (c.i.) 130 (100%) [MH+]. H n.m.r.
1
8.66, br s, NH; 5.81, br s, CHN; 5.26, d, J 16 Hz, 1H, CH2CH=CH2;
5.19, d, J 8 Hz, 1H, CH2CH=CH2; 4.25, br s, CH2CH=CH2; 3.76, s,
OCH3; 2.81, br s, CH2CH=CH2. 13C n.m.r. 169.1, COOCH3; 130.5,
CH2CH=CH2; 121.5, CH2CH=CH2; 54.9, OCH3; 53.8, CHN; 34.9,
CH2CH=CH2.
Methyl (RS)-N-Acetylallylglycinate (5)
To a solution of methyl (RS)-allylglycinate hydrochloride (1.46 g,
8.85 mmol) in dry pyridine (8 ml) was added acetic anhydride (2.50 ml,
26.5 mmol) under a nitrogen atmosphere, and the reaction mixture was
allowed to stir for 24 h at 25–30°C. The pyridine solvent was evapo-
rated and the product was dissolved in ethyl acetate, then washed with
water, dried and evaporated. The crude brown oily product was chro-
matographed on a gravity silica gel column (30% ethyl acetate in
hexane) to afford methyl (RS)-N-acetylallylglycinate (5) (998 mg, 5.84
mmol, 66%) as a pale yellow, hygroscopic solid. The spectral data for
(5) matched closely with those reported in the literature for (5) prepared
by a different method.14 Mass spectrum m/z (c.i.) 172 (100%) [MH+].
1H n.m.r. 6.48, br s, NH; 5.58, m, CH2CH=CH2; 5.00, d, J 16 Hz, 1H,
CH2CH=CH2; 4.99, d, J 11 Hz, 1H, CH2CH=CH2; 4.54, m, CHN; 3.62,
s, OCH3; 2.41, m, CH2CH=CH2; 1.90, s, COCH3. 13C n.m.r. 172.3,
COOCH3; 169.6, COCH3; 132.1, CH2CH=CH2; 119.2, CH2CH=CH2;
52.4, OCH3; 51.6, CHN; 36.5, COCH3; 23.1, CH2CH=CH2.
Dimethyl (E)- and (Z)-(R,S)-6,6´-(Dibenzothiophen-2,8-diyl)bis(2-
acetamidohex-4-enoate) (7b)
From the reaction that produced (6) (method A), the diester (7b) (170
mg, 0.31 mmol, 41%) was obtained as a yellow oil, after the elution of
(7a). Mass spectrum m/z (c.i.) 551 (15%) [MH+], 132 (100%). 1H n.m.r.
8.01–7.91, m, 2H, ArH; 7.72, d, J 8 Hz, H 4 and H 6; 7.26–7.20, m,
2H, ArH; 6.28, m, 2H, NH; 5.90–5.35, m, 4H, CH=CHCH2; 4.71, m,
2H, CHN; 3.67, s, 6H, OCH3; 3.51, m, 4H, CH=CHCH2; 2.89–2.40, m,
4H, ArCH2; 1.94, s, 6H, COCH3. 13C n.m.r. 172.5, COOCH3; 169.8,
COCH3; 137.6; 136.7; 136.5; 135.7; 133.9, alkene CH; 132.4, alkene
CH; 127.6, Ar CH; 127.3, Ar CH; 125.3, alkene CH; 123.9, alkene CH;
122.8, Ar CH; 122.7, Ar CH; 121.2, Ar CH; 52.4, OCH3; 52.0, CHN;
39.0, COCH3; 35.4, ArCH2; 33.3, CH2CH=CH.
Dimethyl (E)- and (Z)-(R,S)-2,7-Acetamidooct-4-enedioate (8)
[4](5,11)[4](18,24)Dibenzothiophenophane-2,15-diene (6)
From the reaction that produced (6) (method A), dimethyl 2,7-diac-
etamidooct-4-enedioate (8) (30 mg, 0.096 mmol, 6%) was obtained as
a yellow solid, after the elution of (7b). Mass spectrum m/z (c.i.) 315
(78%) [MH+], 174 (33%), 89 (100%). 1H n.m.r. 6.38, d, J 8 Hz, 2H,
NH; 5.37, m, CH2CH=CH; 4.68, m, 2H, CHN; 3.73, s, 6H, OCH3; 2.42,
m, 4H, CH2CH=CH; 2.07, s, 6H, COCH3. 13C n.m.r. 172.3, COOCH3;
170.5, COCH3; 128.7, CH2CH=CH; 52.5, OCH3; 51.7, CHN; 35.7,
COCH3; 23.0, CH2CH=CH.
Method A. To a solution of 2,8-diallyldibenzothiophen (3b) (200
mg, 0.76 mmol) and methyl (RS)-N-acetylallylglycinate (5) (520 mg,
3.04 mmol) in dry CH2Cl2 (4 ml) was added Grubbs’ ruthenium cata-
lyst13 (31 mg, 0.038 mmol) dissolved in dry CH2Cl2 (1 ml) under a
nitrogen atmosphere. The reaction mixture was boiled under reflux for
36 h, allowed to cool and evaporated. The crude product was chro-
matographed on a gravity silica gel column (20% CH2Cl2 in petroleum
spirit with gradient elution up to 50% ethyl acetate in petroleum spirit)
to afford (E),(E)–(E),(Z)–(Z),(Z)-[4](5,11)[4](18,24)dibenzothiopheno-
phane-2,15-diene (6) (10 mg, 0.021 mmol, 6%) as colourless crystals.
Mass spectrum m/z (c.i.) 473 (100%) [MH+]. 1H n.m.r. [400 MHz,
(D6)benzene], 8.10, d, J 1.6 Hz, H12, H13, H25 and H 26; 7.57, d, J
8.0 Hz, H 7, H 9, H 20 and H 22; 7.08, dd, J 8.0, 1.6 Hz, H 6, H 10, H 19
and H 23; 5.62, m, H 2, H 3, H 15 and H 16; 3.40, d, J 4.4 Hz, 1, 4, 14,
17-CH2. 13C n.m.r. (in part) 137.2; 137.0; 130.8, alkene CH; 129.6,
alkene CH; 128.1, Ar CH; 127.8, Ar CH; 122.7, Ar CH; 122.6, Ar CH;
120.7, Ar CH; 120.6, Ar CH; 38.7, alkane CH2; 33.5, alkane CH2.
Method B. To a solution of 2,8-diallyldibenzothiophen (3b) (336
mg, 1.27 mmol) in dry CH2Cl2 (4 ml) was added Grubbs’ruthenium cat-
alyst (52 mg, 0.064 mmol) dissolved in dry CH2Cl2 (2 ml) under a nitro-
gen atmosphere. The reaction mixture was boiled under reflux for 24 h,
allowed to cool and evaporated. The crude product was chro-
matographed on a gravity silica gel column (10% CH2Cl2 in petroleum
spirit with gradient elution up to 20% CH2Cl2 in petroleum spirit) to
afford (E),(E)–(E),(Z)–(Z),(Z)-[4](5,11)[4](18,24)dibenzothiopheno-
phane-2,15-diene (6) (77 mg, 0.16 mmol, 26%) as colourless crystals.
Recrystallization from benzene produced the (E),(E)-isomer as
rhombic, colourless plates, m.p. 225°C (dec.) (Found: MH+ , 473.1375.
C32H24S2 + H requires MH+ , 473.1391). Mass spectrum m/z (c.i.) 473
(60%) [MH+], 237 (15%). 1H n.m.r. [400 MHz, (D6)benzene] 8.11, d,
J 1.6 Hz, H 12, H13, H 25 and H 26; 7.52, d, J 8.0 Hz, H 7, H9, H20
and H 22; 6.99, dd, J 8.0, 1.6 Hz, H6, H 10, H 19 and H 23; 5.61, m, H 2,
H3, H 15 and H 16; 3.40, d, J 4.0 Hz, 1,4,14,17-CH2. 13C n.m.r. 137.6;
[4.4](2,8)Dibenzothiophenophane (9)
A suspension of the dibenzothiophenophane-2,15-diene (6) (10 mg,
0.021 mmol) and 10% palladium on activated carbon (4 mg, 0.0019
mmol) in ethyl acetate (20 ml) was stirred at room temperature under a
hydrogen atmosphere for 72 h. The reaction mixture was filtered
through Celite and evaporated to afford [4.4](2,8)dibenzothiopheno-
phane (9) (8.4 mg, 0.018 mmol, 83%) as a pale brown solid, m.p. 210°C
(dec.) (Found: MH+ , 477.1702. C32H28S2 + H requires MH+ ,
477.1711). Mass spectrum m/z (c.i.) 477 (70%) [MH+]. 1H n.m.r. 7.99,
br s, Wh/2 4 Hz, H 1, H1´, H9 and H 9´; 7.70, d, J 8 Hz, H4, H4´, H6
and H6´; 7.25, m, H 3, H3´, H 7 and H7´; 2.87, m, 8H, ArCH2; 1.79, m,
8H, ArCH2CH2. 13C n.m.r. 138.5; 137.1; 135.4; 127.7, Ar CH; 122.7,
Ar CH; 120.8, Ar CH; 34.9, Ar CH2; 29.4, ArCH2CH2.
Methyl (R,S)-2-Acetamido-6-(8-propyldibenzothien-2-
yl)hexanoate (10a)
A suspension of the methyl hex-4-enoate (7a) (60 mg, 0.15 mmol)
and 10% palladium on activated carbon (31 mg, 0.015 mmol) in
methanol (20 ml) was stirred at room temperature under a hydrogen
atmosphere for 24 h. The reaction mixture was filtered through Celite
and evaporated to afford the methyl hexanoate (10a) (26 mg, 0.063
mmol, 43%) as a yellow oil (Found: MH+ , 412.1933. C24H29NO3S + H
requires MH+ , 412.1946). Mass spectrum m/z (c.i.) 412 (100%) [MH+].
1H n.m.r. 7.93 and 7.90, 2 br s, Wh/2 4 Hz, H1 and H 9; 7.71, d, J 8 Hz,

540
J. B. Bremner et al.
H4 and H 6; 7.24, m, H3 and H7; 5.94, d, J 8 Hz, NH; 4.62, dt, J 8, 5
Hz, CHN; 3.69, s, OCH3; 2.75, m, 4H, ArCH2; 1.97, s, COCH3; 1.71
and 1.35, 2m, 8H, CH2; 0.97, t, J 7 Hz, CH3. 13C n.m.r. 173.1,
COOCH3; 169.7, COCH3; 139.0; 138.3; 137.2; 137.1; 135.7; 135.5;
127.6, Ar CH; 127.3, Ar CH; 122.6, Ar CH; 122.5, Ar CH; 121.2, Ar
CH; 121.1, Ar CH; 52.3, OCH3; 52.0, CHN; 38.1, COCH3; 35.6, 32.4,
31.2, 25.0, 24.6, 23.2, 6×CH2; 13.8, CH3.
Crystal data for compound (E),(E)-(6). C32H24S2, M 472.7.
–
Triclinic, space group P1, (C1i , No. 2), a 11.880(2), b 12.101(2), c
14.442(2) Å, 112.494(2), 93.562(2), 107.436(2)°, V 1793 Å3.
Dc(Z = 3) 1.313 g cm–3; F(000) 744. Mo 2.4 cm–1; specimen: 0.55 by
0.30 by 0.12 mm; ‘T’min, max 0.78, 0.96.
Acknowledgments
We thank AMRAD Operations Pty Ltd for their financial
support and encouragement. The support of the
Biomolecular Research Centre, University of Wollongong,
is also gratefully acknowledged.
Dimethyl (R,S)-6,6´-(Dibenzothiophen-2,8-diyl)bis(2-
acetamidohexanoate) (10b)
A suspension of the bishex-4-enoate (7b) (100 mg, 0.18 mmol) and
10% palladium on activated carbon (39 mg, 0.018 mmol) in methanol
(20 ml) was stirred at room temperature in a hydrogen atmosphere for
48 h. The reaction mixture was filtered through Celite and evaporated
to afford the bisdihexanoate (10b) (76 mg, 0.14 mmol, 75%) as a yellow
oil (Found: MH+ , 555.2517. C30H38N2O6S + H requires MH+ ,
555.2529). Mass spectrum m/z (e.s.) 555 (4%) [MH+]. 1H n.m.r. 7.91,
br s, Wh/2 6 Hz, H 1 and H 9; 7.70, d, J 8 Hz, H 4 and H 6; 7.22, m, H 3
and H 7; 6.08, d, J 8 Hz, 2H, NH; 4.60, m, 2H, CHN; 3.67, s, 6H, OCH3;
2.75, t, J 7 Hz, 4H, ArCH2; 1.96, s, 6H, COCH3; 1.71 and 1.36, 2m,
12H, CH2. 13C n.m.r. 173.1, COOCH3; 169.9, COCH3; 138.4; 137.2;
135.5; 127.4, Ar CH; 122.5, Ar CH; 121.1, Ar CH; 52.3, OCH3; 52.0,
CHN; 35.5, COCH3; 32.2, 31.1, 24.6, 23.1, 4×CH2.
References
1
Handwerger, S., Raucher, B., Altarac, D., Monka, J., Marchione, S.,
Singh, K. V., Murray, B. E., Wolff, J., and Walters, B., Clin. Infect.
Dis., 1993, 16, 750.
2
Kjerulf, A., Pallesen, L., and Westh, H., APMIS, 1996, 104, 475.
3
Coque, T. M., Tomayko, J. F., Ricke, S. C., Okhyusen, P. C., and
Murray, B. E., Antimicrob. Agents Chemother., 1996, 40, 2605.
4
Hook, V., Chem. Br., 1997, 33, 34.
5
Handwerger, S., Perlman, D. C., Altarac, D., and McAuliffe, V.,
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6
Clark, N. C., Cooksey, R. C., Hill, B. C., Swenson, J. M., and
Tenover, F., Antimicrob. Agents Chemother., 1993, 37, 2311.
Structure Determination*
7
Pegues, D. A., Pegues, C. F., Hibberd, P. L., Ford, D. S., and Hooper,
Asphere of diffraction data was measured at c. 153 K using a Bruker
D. C., J. Clin. Microbiol., 1997, 35, 1565.
8
AXS CCD area-detector instrument, 20875 reflections merging to 8704
Chu, D. T. W., Annu. Rep. Med. Chem., 1998, 141.
9
(Rint = 0.032) after ‘empirical’ absorption correction (2
= 58°;
monochromatic Mo K radiation, = 0.71073 Å; proprietarmyaxsoftware
SMART, SAINT), 5423 with F > 4 (F) being considered ‘observed’ and
used in the full-matrix least-squares refinement with anisotropic
Neumoyer, C. R., and Amstutz, E. D., J. Am. Chem. Soc., 1947, 69,
1920.
10
Cummins, C. H., Tetrahedron Lett., 1994, 35, 857.
11
Yamamoto, A., in ‘Organotransition Metal Chemistry’ pp. 372–374
thermal parameter forms for S, C, and refining (x, y, z, Uiso)H for the
(John Wiley: New York 1986).
12
non-disordered component of the structure (Fig. 1), these latter being
constrained at estimated values for those associated with the disordered
C(n142,2´), n = 2,3, of molecule 2 (Fig. 2), and associated and adjacent
hydrogen atoms; site occupancies of these components were set at 0.5
after trial refinement. Conventional residuals R and Rw (statistical
weights) on |F| at convergence were 0.051 and 0.054. Neutral atom
complex scattering factors were employed, computation using the Xtal
3.6 program system.15
For a recent related study see Biagini, S. C. G., Gibson, S. E., and
Keen, S. P., J. Chem. Soc., Perkin Trans. 1, 1998, 2485.
13
Brümmer, O., Rückert, A., and Blechert, S., Chem. Eur. J., 1997, 3,
441.
14
Turner, N. J., and Whitesides, G. M., J. Am. Chem. Soc., 1989, 111,
624.
15
Hall, S. R., du Boulay, D. J., and Olthof-Hazekamp, R., ‘The Xtal
3.6 System’, University of Western Australia, 1999.
* The crystal structure data for (E),(E)-(6) have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 127651. Tables of coordinates, anisotropic displacement parameters, bond lengths and bond angles are available (until 31 December 2005)
from the Australian Journal of Chemistry, P.O. Box 1139, Collingwood, Vic. 3066.