Contrasting behaviour of NBS towards 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides and 4,5-dihydro-1H-indeno[1,2-b]pyridines

Article abstract of DOI:10.1016/j.tet.2013.04.060

Polycyclic 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides and 4,5-dihydro-1H-indeno[1,2-b]pyridines having ester or cyano group at the position 3 of dihydropyridine ring have been synthesised. Reactivity of N-bromosuccinimide (NBS) towards polycyclic

Full text of DOI:10.1016/j.tet.2013.04.060

Tetrahedron 69 (2013) 5550e5557
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Contrasting behaviour of NBS towards 1,4-dihydrobenzothieno
[3,2-b]pyridine 5,5-dioxides and 4,5-dihydro-1H-indeno[1,2-b]
pyridines
Brigita Cekavicus, Brigita Vigante, Martins Rucins, Kintija Birkmane, Marina Petrova,
Sergey Belyakov, Liga Zuka, Aiva Plotniece, Karlis Pajuste, Marina Gosteva,
*
Arkadij Sobolev
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV 1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
Polycyclic 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides and 4,5-dihydro-1H-indeno[1,2-b]pyri-
dines having ester or cyano group at the position 3 of dihydropyridine ring have been synthesised.
Reactivity of N-bromosuccinimide (NBS) towards polycyclic 1,4-dihydropyridine derivatives has been
investigated. It has been found that 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides are easily oxi-
dised with NBS in methanol at rt in high yields, whereas 4,5-dihydro-1H-indeno[1,2-b]pyridines in re-
action with NBS in methanol are brominated at 4a position affording stable 4a-bromo-4a,5-
dihydroindeno[1,2-b]pyridine-3-carboxylates or unstable 3-carbonitriles, which rapidly undergo dehy-
drobromination reaction leading to the corresponding 5H-indeno[1,2-b]pyridine-3-carbonitriles.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 29 January 2013
Received in revised form 28 March 2013
Accepted 15 April 2013
Available online 18 April 2013
Keywords:
Polycyclic 1,4-dihydropyridines
Cyclisation
Bromination
Oxidation
N-Bromosuccinimide
1. Introduction
the positions 3 and 5 of the 1,4-DHP ring condensed and efficiently
delivered plasmid DNA into different cell lines in vitro.11e13
The 1,4-dihydropyridines (1,4-DHPs) possess a wide variety of
biological and pharmacological activities; monocyclic ones represent
the most important group of calcium channel modulating agents and
have been used world-wide for the treatment of cardiovascular
diseases.1 Nifedipine, the first calcium channel antagonist of 1,4-DHP
class, was introduced into clinical medicine about forty years ago.2
Over the years, many monocyclic3 and polycyclic4,5 derivatives of
1,4-DHP were synthesised and have led to numerous antianginal and
antihypertensive preparations.6e8 After the synthesis and de-
velopment of several generations of antihypertensive drugs the in-
terest is growing towards pharmacological activities of 1,4-DHPs that
are not related with their calcium antagonistic properties. Several
derivatives of 4,5-dihydro-1H-indeno[1,2-b]pyridine have been
shown to possess antitumour activities.9 Cytotoxic potencies and
apoptosis inducing properties of tetracyclic 5-aminopyrazolone-
derived indenopyridine compounds were also described recently.10
Our research group has reported that several types of cationic am-
phiphiles comprising 1,4-DHP cycle with long alkyl ester chains at
Oxidation of 1,4-DHPs to the corresponding pyridine derivatives
is the most typical property of these heterocycles, which also
constitutes the principal metabolitic pathway in biological sys-
tems.14 It has been reported that metabolites of calcium antago-
nistic 1,4-DHPs do not possess significant calcium channel blocking
activity.15,16 Oxidised polycyclic pyridine derivatives recently re-
ceived much attention for their more pronounced biological ac-
tivities than their corresponding dihydropyridine derivatives.
Indenopyridines have exhibited cognition enhancer properties,17
they have also found to be active for the treatment of hyper-
lipoproteinaemia and atherosclerosis.18,19 Indenopyridines possess
adenosine A2A receptor binding and phosphodiesterase inhibiting
activity for the treatment of neurodegenerative disorders and in-
flammation related diseases.20,21
Bromination of methyl groups at the positions 2 and 6 of 1,4-
DHPs is one of the most important steps in the synthesis of novel
group of 1,4-DHPsdcationic amphiphilic 1,4-DHPs derivatives as
potential candidates for the development of new gene delivery
systems.22 NBS is widely-used as brominating agent for many
classes of organic compounds. It was reported by our research
group that Hantzsch type N-unsubstituted and N-substituted 4-
alkyl or 4-aryl-2,6-dimethyl-1,4-DHP-3,5-dicarboxylates were
* Corresponding author. Tel.: þ371 67014928; fax: þ371 67550338; e-mail ad-
dress: arkady@osi.lv (A. Sobolev).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.060

B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
5551
brominated with NBS in methanol at rt forming the corresponding
2,6-bis(bromomethyl)-1,4-DHP derivatives.23,24 It is necessary to
emphasise that the unambiguous formation of 2,6-
bis(bromomethyl) derivatives was observed not only in the case
of bis(ethyl) 4-aryl-2,6-dimethyl-1,4-DHP-3,5-dicarboxylates, but
also when ethyl ester is exchanged for an alternative ester with
a long alkyl chain, which include decyl, dodecyl, tetradecyl and
hexadecyl.11,22,24 Oxidation of Hantzsch type 4-aryl-2,6-dimethyl-
1,4-DHP-3,5-dicarboxylates to the corresponding pyridines with
1 equiv of NBS in methanol at rt in 5 min in good yields was re-
ported by Nagrajan et al. recently.25 Unlike the results obtained by
group of Nagrajan25 our laboratory has proven in numerous articles
that with this method only 2-bromomethyl- or/and 2,6-
bis(bromomethyl)-4-aryl-1,4-DHP derivatives can be obtained
without any evidence of formation of oxidised 4-arylpyridine-3,5-
dicarboxylates.22e24,26
On the other hand, NBS in methanol acts as an efficient oxidising
agent for conversion of cationic 1,4-dihydropyridine to the corre-
sponding cationic pyridine. Recently, our research group has re-
ported chemical and electrochemical oxidation of 1,10-{[3,5-
bis(ethoxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]
dimethylene}-bispyridinium dibromide, where the best results
were achieved when NBS was used as oxidising agent.26
indandione and aldehydes in the presence of oxygen led to novel
tetracyclic 5-aminopyrazolone derived indenopyridines.10 Pre-
viously it was reported that 4-aryl-2-methyl-1,4-dihydrobenzo-
thieno[3,2-b]pyridine 5,5-dioxides were oxidised to the corre-
sponding pyridine derivatives with a 15-fold molar excess of NaNO2
in AcOH at 100 ꢀC or electrochemically affording the corresponding
pyridines.28,39
Several good review articles cover the scope and limitations of
methods of preparation and reactions of 1,4-DHPs.35,40e43
In this paper, we describe different behaviour of NBS towards
polycyclic 1,4-DHPsd1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-
dioxides and 4,5-dihydro-1H-indeno[1,2-b]pyridines.
2. Results and discussion
Initially, the main purpose of our studies was the bromination of
the methyl group at the position 2 of 1,4-dihydrobenzothieno[3,2-
b]pyridines 5aee and 4,5-dihydro-1H-indeno[1,2-b]pyridines 7aee
with a view towards the synthesis of novel monocationic amphi-
philic fused 1,4-DHP derivatives (Table 1, Scheme 1 and Table 2).
However, instead of predicted bromination of methyl group at the
position 2 of dihydropyridine ring with NBS, in the case of 4-aryl-2-
methyl-1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 5aee
oxidation of 1,4-dihydropyridine ring resulting in formation of the
corresponding benzothieno[3,2-b]pyridines 6aee was observed;
on the other hand, in the case of 4,5-dihydro-1H-indeno[1,2-b]
pyridines 7aee bromination at the position 4a leading to 4a-bromo
derivatives 8aee was observed.
The oxidation of monocyclic Hantzsch 1,4-DHP remains an im-
portant research issue. Usually for oxidation of 1,4-DHPs strong
oxidants in large excess are employed giving reaction products in
moderate yields and forming side products. A large number of in-
organic reagents, such as manganese dioxide, potassium perman-
Table 1
Synthesis of 4-aryl-2-methyl-1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 5aee from 2-arylidenebenzo[b]thiophen-3(2H)one 1,1-dioxides 3aec and 3-
aminocrotonates 4aed and their oxidation to 4-aryl-2-methylbenzothieno[3,2-b]pyridine 5,5-dioxides 6aee with NBS in methanol at rt
Entry
3
R1
R2
R3
4
R4
5 (Yield, %)
6 (Yield, %)
1
2
3
4
5
3c
3c
3a
3b
3a
OMe
OMe
H
H
H
OMe
OMe
Cl
Br
Cl
OMe
OMe
H
H
H
4a
4b
4c
4c
4d
COOEt
COO(CH2)2CN
CN
CN
COOMe
5a (74)
5b (77)
5c (82)
5d (73)
5e (52)28
6a (86)
6b (89)
6c (81)
6d (87)
6e (95)
ganate,27 nitric acid and in situ generated nitric oxide,28 chromium
derivatives,29 sodium chlorite,30 and organic reagents like DDQ31
and chloranil32 have been applied for oxidation of monocyclic
1,4-DHPs. A number of 1,4-DHPs have been also oxidised electro-
chemically.33,34 The ability of 1,4-DHP ring to undergo oxidation is
dependent on a combination of steric and electronic effects of the
substituents.35
Oxidation of polycyclic 1,4-dihydropyridines, unlike the corre-
sponding Hantzsch type dihydropyridine derivatives, is much less
investigated. Polycyclic 4,5-dihydro-1H-indeno[1,2-b]pyridines
were oxidised to the corresponding pyridines with strong oxidants,
such as in situ generated nitric oxide in large excess36 or chromium
(VI) oxide,37 as well as by irradiation with UV-light.38 Oxidative
cyclisation of 5-amino-1,2-dihydropyrazol-3-one with 1,3-
Scheme 1. Synthesis of 2-(3,4,5-trimethoxybenzylidene)benzo[b]thiophen-3(2H)one
1,1-dioxide (3c) from 3,4,5-trimethoxybenzaldehyde (1) and benzo[b]thiophen-3(2H)
one 1,1-dioxide (2) in acetic acid at the presence of piperidine.

5552
B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
Table 2
Reactions of 4-aryl-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carboxylates 7aec and 3-carbonitriles 7d,e with NBS in methanol at rt
Entry
7
R1
R2
R3
R4
Bromination (Yield, %)
Dehydrobromination (Yield, %)
Debromination (Yield, %)
1
2
3
4
5
7a
7b
7c
7d
7e
COOMe
COOEt
COO(CH2)2CN
CN
H
Me
H
8a (70)
8b (82)
8c (79)
8d (91)a
8e (95)a
d
7a (92)
7b (87)
7c (85)
d
OMe
OMe
H
OMe
OMe
Me
OMe
OMe
H
d
d
9d (81)
9e (79)
CN
OMe
OMe
OMe
d
a
Unstable.
4-Aryl substituted 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-
dioxides 5aed containing an ethyl ester, cyanoethyl ester or cy-
ano group at the position 3 were obtained via a modified Hantzsch
type cyclisation from 2-arylidenebenzo[b]thiophen-3(2H)one 1,1-
dioxides 3aec and 3-aminocrotonates 4aed refluxing in AcOH in
the presence of catalytic amount of piperidine in 73e82% yields.
The starting 2-arylidenebenzothiophene derivatives 3a,b and 4-(4-
chlorophenyl)-3-methoxycarbonyl-2-methyl-1,4-dihydrobenzothi
eno[3,2-b]pyridine 5,5-dioxide (5e) were prepared according to
a procedure elaborated by our research group,28 and the synthesis
of unpublished 2-arylidenebenzothiophene derivative 3c was per-
formed in 70% yield (Scheme 1). For conclusive assessment of the
structure of compounds 5 the X-ray crystallographic analysis of the
crystals of 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide 5b
was undertaken.
to rt, and the mixture was stirred for 1 h (Table 2, entries 1e3). The
reaction mixtures changed their colour from red to yellow within
a few minutes. All reactions proceeded in a similar fashion affording
4a-bromo derivatives 8aec in 70e82% yields after crystallisation
(Table 2, entries 1e3). Suitable crystals for X-ray crystallographic
analysis of methyl ester derivative 8a were obtained by slow crys-
tallisation from methanol. X-ray analysis of the crystals of methyl
ester derivative 8a was undertaken (Fig. 1). The six-membered pyr-
idine cycle in the condensed system is characterised by the envelope
conformation. In the crystal structure between bromine atom and
carbonyl oxygen of the ester group there is a strong halogen bonding
ꢀ
ꢀ
with length of 3.339(3) A (angle C12eBr27/O16 is 165.6(2) ).
The oxidation reactions of 1,4-dihydrobenzothieno[3,2-b]pyri-
dine 5,5-dioxides 5aee were carried out in methanol at rt for 3 h with
good to excellent yields of pyridines 6aee, the results are summar-
ised in Table 1. The molar ratio of NBS to the 4-aryl-2-methyl-1,4-
dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide was 1:1, which is
significant advantage comparing to the previous methodology,28
where structurally related compounds were oxidised under strong
reaction conditions, such as 15-fold molar excess of NaNO2 in AcOH
in moderate yields. No other reaction products were isolated from
oxidation reactions of 1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-
dioxides 5aee. LC-MS data of the reaction mixtures showed the
presence of molecular ion peaks, perhaps matching brominated de-
rivatives of 1,4-dihydropyridine structures in trace amounts.
4,5-Dihydro-1H-indeno[1,2-b]pyridine-3-carboxylates
7aec
and 3-carbonitriles 7d,e were obtained according to the earlier
reported methods.28,37,44,45 Syntheses of compounds 7a46 and
7d,e47 were already reported in the literature.
Fig. 1. ORTEP molecular structure of the compound 8a.
4,5-Dihydro-1H-indeno[1,2-b]pyridines 7aee were subjected to
reactions with NBS in methanol at 10 ꢀC (Table 2). Unlike reactions
of 1,4-dihydrobenzothieno derivatives 5aee shown in Table 1, 4,5-
dihydro-1H-indeno[1,2-b]pyridines 7aee readily undergo bromi-
nation with NBS in methanol, yielding the corresponding 4a-bromo
derivatives 8aee with no evidence of formation of the corre-
sponding 2-bromomethyl derivatives. This completely differs from
bromination of Hantzsch type 4-aryl-2,6-dimethyl-1,4-DHP-3,5-
dicarboxylates with NBS where the corresponding 2,6-
bis(bromomethyl)-1,4-DHP derivatives were obtained.
The bromination reactions of 4,5-dihydro-1H-indeno[1,2-b]
pyridine-3-carbonitriles 7d,e were performed in a similar manner
as was described for carboxylates 7aec, but after the addition of
NBS, the reaction mixtures were stirred only for 10 min, resulting in
formation of desired products 8d,e in 91e95% yields. The afforded
brominated products 8d,e were rather unstable and rapidly
decomposed upon isolation and standing in the solid state, which
precluded their complete structural characterisation. The struc-
tures of unstable intermediates 8d,e were assigned by their 1H NMR
spectra. Complete dehydrobromination was performed by crystal-
lisation of unstable intermediates 8d,e from methanol, which
proceeded to afford the appropriate 4-aryl-2-methyl-5-oxo-indeno
[1,2-b]pyridine-3-carbonitriles 9d,e.
4,5-Dihydro-1H-indeno[1,2-b]pyridine-3-carboxylates
7aec
were brominated with NBS at the molar ratio 1:1 in methanol under
an inert atmosphere. The reaction temperature was maintained at
about 10 ꢀC within the first 5 min, after which it was allowed to come

B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
5553
In contrast to the unstable carbonitriles 8d,e, which undergo
spontaneous dehydrobromination, carboxylates 8aec were found
to be rather stable. Nevertheless, carboxylates 8aec in debromi-
nation reactions with sodium hydroxide in wet acetone formed the
corresponding anions of compounds 7aec, which after neutrali-
sation with dilute hydrochloric acid led to the starting derivatives
7aec.
We have proposed a plausible mechanism based mainly on lit-
erature analysis. Mechanistically, both reactions may be attributed
to the formation in situ of hypobromous acid by NBS in methanol
(Scheme 2). For both 7aee and 5aee the first step involves the
addition of hypobromite to the double bond, which can proceed via
radical or electrophilic mechanisms. The addition of halogens in
protic solvents (hypohalites) to the 5,6-double bond of the pyrim-
idine cycle and subsequent dehydrobromination is well known
reaction.48 The similar addition of hypobromite (NBS in methanol
and dibenzoylperoxide as additive) to the double bond was ob-
served in the case of 6-oxo-1,4,5,6-tetrahydropyridines,49 and the
addition of methylhypobromite to 2-pyridone50 was also reported.
The addition of bromine to the double bond of the 1,4-
dihydropyridine-3,5-dicarboxylates has not been reported in
literature.
Fig. 2. ORTEP molecular structure of the compound 5b.
The contrasting behaviour of NBS towards 4,5-dihydro-1H-
indeno[1,2-b]pyridines 7aee could be because the tricyclic system
is less sterically bulky than benzothieno system.
The second step of this reaction is the elimination of water. For
benzothieno derivatives this step is followed by dehydrobromina-
tion forming the corresponding pyridine derivatives 6aee. In the
case of 4,5-dihydro-1H-indeno[1,2-b]pyridines after elimination of
water 4a-bromo-4a,5-dihydroindeno[1,2-b]pyridine-3-carboxyla-
tes 8aec are formed. It has appeared that the substituents at the
position 3 of 4-aryl-4a-bromo-2-methyl-5-oxo-4a,5-dihydroindeno
[1,2-b]pyridines 8aee have crucial influence on their stability. 4a-
Bromo-4a,5-dihydroindeno[1,2-b]pyridine-3-carboxylates
8aec
are stable while 3-carbonitriles 8d,e rapidly decompose to the cor-
responding 5H-indeno[1,2-b]pyridine-3-carbonitriles 9d,e with the
loss of HBr.
According to the literature data28,51 about structural effects on
NeH acidity of 1,4-DHPs, 1,4-dihydrobenzothieno[3,2-b]pyridine
5,5-dioxides 5 and 5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridines 7
are stronger NeH acids than Hantzsch type 2,6-dimethyl-1,4-DHP-
3,5-dicarboxylates. The experimentally determined values of pKa
for fused 1,4-DHPs were w1551 in DMSO and w12.528 in 50% EtOH;
on the other hand, for Hantzsch type 1,4-DHPs in DMSO pKa values
were w20.51 As a result of the higher acidity of NeH bond of fused
derivatives 5aee and 7aee, they undergo deprotonation more
easily than monocyclic 1,4-DHPs.
Scheme 2. Plausible mechanism of reactions of NBS with 1,4-dihydrobenzothieno[3,2-
b]pyridine 5,5-dioxides 5aee or 4,5-dihydro-1H-indeno[1,2-b]pyridines 7aee.
3. Conclusion
The reaction of polycyclic 1,4-DHPs 5aee and 7aee with NBS is
dependent on a combination of steric and electronic effects. Based
on X-ray diffraction analysis, the behaviour of NBS towards 1,4-
dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 5aee could be
explained by steric effects caused by this molecule. Fig. 2 illustrates
a view of the molecule of 5b, showing the thermal ellipsoids and
the atom-numbering scheme followed in the text. The length of
In conclusion, the oxidation of dihydropyridine ring of polycyclic
1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 5aee under
mild conditions has been achieved. Bromination of 4,5-dihydro-1H-
indeno[1,2-b]pyridines 7aee leading to the corresponding 4a-
bromo derivatives 8aee was disclosed. NBS in methanol acts as an
efficient oxidising agent for the conversion of polycyclic 1,4-
dihydrobenzothieno[3,2-b]pyridine 5,5-dioxides 5aee to the cor-
responding benzothieno[3,2-b]pyridine 5,5-dioxides 6aee in good
yields; on the other hand, it efficiently brominates at the 4a posi-
tion 4,5-dihydro-1H-indeno[1,2-b]pyridines 7aee giving 4a-bromo
derivatives 8aee. These results contrast with the fact that NBS
under the same reaction conditions brominates 2,6-dimethyl
groups of Hantzsch type 1,4-DHP-3,5-dicarboxylates. High acidity
of NeH bond as well as combination of steric and electronic effects
of benzothieno and indeno system and steric and electronic effects
of the substituents of the dihydropyridine ring are the most prob-
able reasons for the different behaviour of NBS towards these sys-
tems, comparing to monocyclic DHPs. It has been found that the
ꢀ
C12eC13 bond is equal to 1.334(3) A and corresponds to an almost
isolated carbonecarbon double bond. However, addition reactions
can be encumbered due to steric hindrances: the C12 position is
surrounded by atoms of O34, O35, C22 and H4; distances O34/C22
ꢀ
ꢀ
(3.225(3) A) and O35/H4 (3.11 A) are slightly greater than the sum
of the van der Waals radii. Methyl group is not sterically hindered
and therefore can be involved in substitution reactions. In the
crystal structure there are intermolecular hydrogen bonds of
NH/O type between NeH group and oxygen atom of O30 with the
ꢀ
ꢀ
ꢀ
length 2.983(2) A (H1/O30¼2.11 A, N1eH1/O30¼155 ). Due to
these hydrogen bonds, the crystal forms chains along the mono-
clinic axis.

5554
B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
substituents at the position 3 of 4a-bromo-4a,5-dihydroindeno[1,2-
b]pyridines 8aee have crucial influence on their stability, thus the
compounds 8d,e bearing strong electron withdrawing substituent
at the position 3, such as carbonitrile, rapidly undergo spontaneous
debromination leading to oxidised derivatives 9d,e, while the car-
boxylates 8aec are found to be rather stable compounds.
(3c) (0.360 g, 1.00 mmol) and ethyl 3-aminocrotonate (4a)
(0.155 g, 1.20 mmol) in acetic acid (15 mL) were refluxed for 1 h.
After cooling a yellow precipitate was filtered off and crystallised
from a mixture of acetic acid and ethanol giving 5a (0.349 g, 74%) as
yellow crystals, mp 252e254 ꢀC, Rf¼0.38 (60% EtOAc/hexane). 1H
NMR (CDCl3)
d
: 1.15 (t, J¼7.0 Hz, 3H), 2.49 (s, 3H), 3.79 (s, 3H), 3.82
(s, 6H), 4.07 (q, J¼7.0 Hz,1H), 4.09 (q, J¼7.0 Hz,1H), 5.20 (s, 1H), 6.21
(br s, 1H), 6.56 (s, 2H), 7.36 (dd, J¼7.5, 1.1 Hz, 1H), 7.53 (ddd, J¼7.5,
7.5, 1.1 Hz, 1H), 7.57 (ddd, J¼7.5, 7.5, 1.1 Hz, 1H), 7.71 (dd, J¼7.5,
4. Experimental
4.1. General
1.1 Hz, 1H). 13C NMR (CDCl3)
d: 14.1, 19.9, 37.4, 56.1, 60.2, 60.8, 105.2,
105.2, 113.5, 118.5, 121.3, 126.2, 130.7, 132.6, 134.2, 137.2, 138.7, 139.7,
All reagents were purchased from Acros, Aldrich, Alfa Aesar or
Merck and used without further purification. TLC was performed on
Silica gel 60 F254 Aluminium sheets 20ꢁ20 cm (Merck). The purities
of compounds were determined by HPLC on a Waters Alliance 2695
system and Waters 2489 UVevis detector equipped with Alltima
143.4, 153.1, 166.7. IR (film) n
: 1506, 1579, 1701, 3360 cmꢂ1. MS
(þESI) m/z (relative intensity) 472 ([MþH]þ, 10). Anal. Calcd for
C24H25NO7S: C 61.13; H 5.34; N 2.97; found: C 61.01; H 5.25; N 2.91.
4.3.2. 3-(2-Cyanoethoxycarbonyl)-2-methyl-4-(3,4,5-trimethoxyphe-
nyl)-1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide (5b). This
compound was prepared via the same method used for compound
5a. Beginning with 2-(3,4,5-trimethoxybenzylidene)benzo[b]thio-
phen-3(2H)one 1,1-dioxide (3c) (0.360 g, 1.00 mmol) and 2-
cyanoethyl 3-aminocrotonate (4b) (0.460 g, 3.00 mmol) in acetic
acid (15 mL), 5b (0.383 g, 77%) was obtained as yellow crystals, mp
C18 column (5
mm, 4.6ꢁ150 mm, Grace) using a gradient elution
with acetonitrile/phosphoric acid (0.1%) in water, at a flow rate of
1 mL/min. Peak areas were determined electronically with a Waters
Empower 2 chromatography data system. 1H NMR spectra were
recorded on a Varian Mercury BB (400 MHz) spectrometer. 13C NMR
spectra were recorded on a Varian-Mercury BB (100.56 MHz)
spectrometer. The chemical shifts of the atoms are reported in parts
per million (ppm) relative to the residual signals of the solvent:
220e222 ꢀC, Rf¼0.27 (80% EtOAc/hexane). 1H NMR (DMSO-d6)
d:
2.44 (s, 3H), 2.79e2.85 (m, 2H), 3.59 (s, 3H), 3.70 (s, 6H), 4.16e4.22
(m, 2H), 4.97 (s,1H), 6.50 (s, 2H), 7.63 (ddd, J¼7.7, 7.7,1.1 Hz,1H), 7.75
(ddd, J¼7.7, 7.7, 1.1 Hz,1H), 7.80 (dd, J¼7.7, 1.1 Hz,1H), 8.04 (dd, J¼7.7,
CDCl3 (
d
: 7.26) or DMSO-d6 (
d
: 2.50) for 1H NMR spectra and CDCl3
(d
: 77.2) or DMSO-d6 (d
: 39.5) for 13C NMR. Multiplicities are ab-
breviated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet; br, broad. The coupling constants are expressed in Hertz.
Diffraction data for 5b and 8a were collected at 173 K on a Bruker-
Nonius KappaCCD diffractometer with a low temperature device
Oxford Cryostream Plus, using Mo radiation. Mass spectral data
were determined on a Waters Alliance 2695 Separation module
connected to a Micromass 3100 mass detector (Waters) operating
in the ESI positive or negative ion mode on a Xbridge C18 column
1.1 Hz, 1H), 9.86 (br s, 1H). 13C NMR (DMSO-d6)
d: 17.8, 19.2, 36.8,
56.2, 59.2, 60.3, 102.5, 105.2, 111.7, 119.2, 121.1, 122.0, 126.7, 131.4,
133.7, 136.8, 137.0, 138.5, 141.1, 147.5, 153.2, 166.4. IR (film) n: 1506,
1597,1662,1700, 2252, 3336 cmꢂ1. MS (þESI) m/z (relative intensity)
497 ([MþH]þ, 35). Anal. Calcd for C25H24N2O7S: C 60.47; H 4.87; N
5.64; found: C 60.09; H 4.81; N 5.44.
4.3.3. Crystal data for compound 5b. X-ray analysis: the crystal
structure of 5b was solved by direct methods52 and refined by full-
matrix least squares.53 All nonhydrogen atoms were refined in
anisotropical approximation; all H-atoms were refined by riding
(5
m
m, 2.1 mmꢁ50 mm; Waters) using a gradient elution with
acetonitrile/formic acid (0.1%) in water, at a flow rate of 0.6 mL/min.
Infrared spectra were recorded with a FTIR spectrometer Prestige-
21 (Shimadzu). Melting points were determined on an OptiMelt
(SRS Stanford Research Systems) equipment. Elemental analyses
were determined on an Elemental Combustion System ECS 4010
(Costech Instruments) or on an EA 1106 (Carlo Erba Instruments).
model. Crystal data for 5b: monoclinic; a¼10.9360(4),
3
ꢀ
ꢀ
ꢀ
b¼14.9717(5), c¼14.2315(6) A,
b
¼90.913(1) ; V¼2329.8(2) A , Z¼4,
m
¼0.19 mmꢂ1; space group is P21/n. A total of 9971 reflection in-
tensities were collected up to 2qmax¼60ꢀ; for structure refinement
3472 independent reflections with I>3s(I) were used. The final R-
4.2. 2-(3,4,5-Trimethoxybenzylidene)benzo[b]thiophen-3(2H)
one 1,1-dioxide (3c)
factor is 0.054. For further details, see crystallographic data for 5b
deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Number CCDC 863711. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK.
To a solution of 3,4,5-trimethoxybenzaldehyde (1) (0.392 g,
2.00 mmol) in acetic acid (10 mL) piperidine (10% mol equiv) and
benzo[b]thiophen-3(2H)one 1,1-dioxide (2) (0.364 g, 2.00 mmol)
were added. The reaction mixture was stirred under reflux for
30 min. After cooling the precipitate was filtered off and crystallised
from a mixture of acetic acid and methanol giving 3c (0.505 g, 70%)
as yellow crystals, Rf¼0.58 (50% EtOAc/hexane), mp 203e205 ꢀC. 1H
4.3.4. 4-(4-Chlorophenyl)-3-cyano-2-methyl-1,4-dihydrobenzothieno
[3,2-b]pyridine 5,5-dioxide (5c). This compound was prepared via
the same method used for compound 5a. Beginning with 2-(4-
chlorobenzylidene)benzo[b]thiophen-3(2H)one 1,1-dioxide (3a)
(0.305 g, 1.00 mmol) and 3-aminocrotononitrile (4c) (0.246 g,
3.00 mmol) in acetic acid (15 mL), 5c (0.303 g, 82%) was obtained as
yellow crystals, mp 291e293 ꢀC, Rf¼0.36 (60% EtOAc/hexane). 1H
NMR (CDCl3)
d
: 3.95 (s, 6H), 3.99 (s, 3H), 7.43 (s, 2H), 7.83 (dd, J¼7.7,
7.7 Hz, 1H), 7.91 (s, 1H), 7.92 (dd, J¼7.7, 7.7 Hz, 1H), 8.03 (d, J¼7.7 Hz,
1H), 8.10 (d, J¼7.7 Hz, 1H). 13C NMR (CDCl3)
d: 56.4, 61.2, 111.2, 121.4,
124.8, 125.5, 129.5, 132.4, 134.2, 136.5, 143.5, 144.2, 145.4, 153.3,
NMR (CDCl3) d: 2.16 (s, 3H), 4.77 (s, 1H), 7.22e7.26 (m, 4H), 7.46
178.8. IR (film)
n
: 1506, 1578, 1702 cmꢂ1. MS (þESI) m/z (relative
(ddd, J¼7.7, 7.7, 1.5 Hz, 1H), 7.50 (ddd, J¼7.7, 7.7, 1.5 Hz, 1H), 7.59 (dd,
intensity) 361 ([MþH]þ, 100). Anal. Calcd for C18H16O6S: C 59.99; H
J¼7.5, 1.5 Hz,1H), 7.78 (dd, J¼7.5,1.5 Hz,1H), 9.44 (br s, 1H). 13C NMR
4.48; found: C 59.64; H 4.56.
(CDCl3) d: 19.4, 37.7, 86.7,109.7,118.7,120.8,121.2,126.6,128.9,129.4,
130.7, 132.7, 133.8, 136.3, 138.4, 140.1, 147.1. IR (Nujol) n: 1515, 1657,
4.3. Synthesis of 4-aryl-2-methyl-1,4-dihydrobenzothieno
[3,2-b]pyridine 5,5-dioxides 5aed
2200, 3291 cmꢂ1. MS (þESI) m/z (relative intensity) 369 ([MþH]þ,
100). Anal. Calcd for C19H13ClN2O2S: C 61.87; H 3.55; N 7.59; found:
C 61.64; H 3.40; N 7.56.
4.3.1. 3-Ethoxycarbonyl-2-methyl-4-(3,4,5-trimethoxyphenyl)-1,4-
dihydrobenzothieno[3,2-b]pyridine
5,5-dioxide
(5a). 2-(3,4,5-
4.3.5. 4-(4-Bromophenyl)-3-cyano-2-methyl-1,4-dihydrobenzothieno
Trimethoxybenzylidene)benzo[b]thiophen-3(2H)one 1,1-dioxide
[3,2-b]pyridine 5,5-dioxide (5d). This compound was prepared via

B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
5555
the same method used for compound 5a. Beginning with 2-(4-
bromobenzylidene)benzo[b]thiophen-3(2H)one 1,1-dioxide (3b)
(0.349 g, 1.00 mmol) and 3-aminocrotonitrile (4c) (0.246 g,
3.00 mmol) in acetic acid (15 mL), 5d (0.302 g, 73%) was obtained as
yellow crystals, mp 285e287 ꢀC, Rf¼0.31 (70% EtOAc/hexane). 1H
1H), 8.27 (d, J¼7.7 Hz,1H).13C NMR (CDCl3)
d
: 24.8,109.6,115.3,121.9,
123.7, 128.8,129.1, 129.5,130.5,130.6,133.6,134.4,137.8,140.3,149.7,
152.8, 168.5. IR (film)
n
: 1549, 1596, 2226 cmꢂ1. MS (þESI) m/z (rel-
ative intensity) 367 ([MþH]þ, 30). Anal. Calcd for C19H11ClN2O2S: C
62.21; H 3.02; N 7.64; found: C 61.88; H 2.91; N 7.53.
NMR (DMSO-d6)
d
: 2.20 (s, 3H), 4.87 (s, 1H), 7.32 (d, J¼7.9 Hz, 2H),
7.55 (d, J¼7.9 Hz, 2H), 7.66 (ddd, J¼7.7, 7.7, 0.9 Hz, 1H), 7.77 (ddd,
J¼7.7, 7.7, 0.9 Hz, 1H), 7.83 (dd, J¼7.7, 0.9 Hz, 1H), 8.01 (dd, J¼7.7,
4.4.4. 4-(4-Bromophenyl)-3-cyano-2-methylbenzothieno[3,2-b]pyri-
dine 5,5-dioxide (6d). This compound was prepared via the same
method used for compound 6a. Beginning with 4-(4-
bromophenyl)-3-cyano-2-methyl-1,4-dihydrobenzothieno[3,2-b]
pyridine 5,5-dioxide (5d) (82.7 mg, 0.200 mmol) and NBS (35.6 mg,
0.200 mmol) in methanol (3 mL), 6d (71.3 mg, 87%) was obtained as
white crystals, mp 237e238 ꢀC, Rf¼0.69 (50% EtOAc/hexane). 1H
0.9 Hz, 1H), 10.24 (br s, 1H). 13C NMR (DMSO-d6)
d: 18.6, 37.2, 85.8,
108.7, 119.2, 121.2, 121.5, 122.2, 126.3, 130.8, 131.8, 132.0, 133.9, 136.6,
138.3, 142.2, 148.4. IR (Nujol) n
: 1513, 1659, 2200, 3296 cmꢂ1. MS
(þESI) m/z (relative intensity) 413 (79Br) ([MþH]þ, 88). Anal. Calcd
for C19H13BrN2O2S: C 55.22; H 3.17; N 6.78; found: C 54.86; H 3.00;
N 6.60.
NMR (CDCl3)
d
: 2.97 (s, 3H), 7.61 (d, J¼8.5 Hz, 2H), 7.72 (ddd, J¼7.7,
7.7, 1.2 Hz, 1H), 7.75 (d, J¼8.5 Hz, 2H), 7.78 (ddd, J¼7.7, 7.7, 1.2 Hz,
4.4. Synthesis of 2-methyl-4-arylbenzothieno[3,2-b]pyridine
5,5-dioxides 6aee
1H), 7.85 (dd, J¼7.7, 1.2 Hz, 1H), 8.27 (dd, J¼7.7, 1.2 Hz, 1H). 13C NMR
(CDCl3) d: 24.8, 109.6, 115.2, 121.9, 123.7, 126.3, 128.8, 129.5, 130.6,
130.6, 132.5, 133.6, 134.4, 140.2, 149.7, 152.8, 168.5. IR (Nujol) n:
4.4.1. 3-Ethoxycarbonyl-2-methyl-4-(3,4,5-trimethoxyphenyl)benzo-
thieno[3,2-b]pyridine 5,5-dioxide (6a). To a stirred solution of 3-
ethoxycarbonyl-2-methyl-4-(3,4,5-trimethoxyphenyl)-1,4-
1547, 1588, 2225 cmꢂ1. MS (þESI) m/z (relative intensity) 411 (79Br)
([MþH]þ, 100). Anal. Calcd for C19H11BrN2O2S: C 55.49; H 2.70; N
6.81; found: C 55.27; H 2.69; N 6.68.
dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide (5a) (0.283 g,
0.600 mmol) in methanol (30 mL) NBS (0.107 g, 0.600 mmol) was
added in few portions after which the reaction mixture was stirred
at rt for 3 h. The reaction mixture was diluted with water (10 mL)
and the precipitated product was filtered off. The precipitate was
crystallised from a mixture of acetic acid and methanol and dried in
vacuo to give 6a (0.243 g, 86%) as pale-yellow crystals, mp
4.4.5. 4-(4-Chlorophenyl)-3-methoxycarbonyl-2-methylbenzothieno
[3,2-b]pyridine 5,5-dioxide (6e). This compound was prepared via
the same method used for compound 6a. Beginning with 4-(4-
chlorophenyl)-3-methoxycarbonyl-2-methyl-1,4-
dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide28 (5e) (80.4 mg,
0.200 mmol) and NBS (35.6 mg, 0.200 mmol) in methanol (3 mL),
6e (76.0 mg, 95%) was obtained as white crystals, mp 229e230 ꢀC,
193e195 ꢀC, Rf¼0.73 (60% EtOAc/hexane). 1H NMR (DMSO-d6)
d:
0.93 (t, J¼7.2 Hz, 3H), 2.63 (s, 3H), 3.69 (s, 3H), 3.75 (s, 6H), 4.10 (q,
J¼7.2 Hz, 2H), 6.79 (s, 2H), 7.78 (ddd, J¼7.6, 7.6, 1.0 Hz, 1H), 7.85
(ddd, J¼7.6, 7.6, 1.0 Hz, 1H), 8.00 (dd, J¼7.6, 1.0 Hz, 1H), 8.18 (dd,
Rf¼0.78 (60% EtOAc/hexane). 1H NMR (CDCl3)
d: 2.73 (s, 3H), 3.64 (s,
3H), 7.50 (dd, J¼7.6, 1.1 Hz, 1H), 7.49e7.52 (m, 4H), 7.65 (ddd, J¼7.6,
7.6, 1.1 Hz, 1H), 7.73 (ddd, J¼7.6, 7.6, 1.1 Hz, 1H), 8.23 (d, J¼7.6, 1.1 Hz,
J¼7.6, 1.0 Hz, 1H). 13C NMR (DMSO-d6)
d
: 14.1, 18.6, 56.2, 56.6, 60.9,
1H). 13C NMR (CDCl3)
d: 23.5, 52.7, 121.7, 122.9, 128.7, 129.0, 129.8,
104.5, 119.9, 125.6, 128.4, 128.6, 128.8, 132.3, 134.3, 137.3, 137.7,
129.9, 130.7, 131.3, 132.5, 134.2, 136.3, 140.2, 144.4, 150.9, 161.8,
139.7, 147.2, 151.3, 157.2, 166.0, 167.9. IR (Nujol)
n
: 1541, 1568, 1580,
167.2. IR (film)
n
: 1544, 1589, 1729 cmꢂ1. MS (þESI) m/z (relative
1737 cmꢂ1. MS (þESI) m/z (relative intensity) 470 ([MþH]þ, 100).
Anal. Calcd for C24H23NO7S: C 61.40; H 4.94; N 2.98; found: C 61.12;
H 4.96; N 2.93.
intensity) 400 ([MþH]þ, 100). Anal. Calcd for C20H14ClNO4S: C
60.08; H 3.53; N 3.50; found: C 59.73; H 3.56; N 3.47.
4.5. Synthesis of 2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-
b]pyridine-3-carboxylates 7b,c
4.4.2. 3-(2-Cyanoethoxycarbonyl)-2-methyl-4-(3,4,5-trimethoxyp-
henyl)-benzothieno[3,2-b]pyridine 5,5-dioxide (6b). This compound
was prepared via the same method used for compound 6a. Begin-
ning with 3-(2-cyanoethoxycarbonyl)-2-methyl-4-(3,4,5-trime-
thoxyphenyl)-1,4-dihydrobenzothieno[3,2-b]pyridine 5,5-dioxide
(5b) (99.3 mg, 0.200 mmol) and NBS (35.6 mg, 0.200 mmol) in
methanol (3 mL), 6b (88.0 mg, 89%) was obtained as white crystals,
4.5.1. Ethyl 2-methyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-4,5-
dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate
(7b). 2-(3,4,5-
Trimethoxybenzylidene)-indan-1,3-dione (0.324 g, 1.00 mmol),
ethyl acetoacetate (0.164 mL, 1.30 mmol) and ammonium acetate
(0.231 g, 3.00 mmol) in acetic acid (2 mL) were refluxed for 30 min.
After cooling the dark red precipitate was filtered off and crystal-
lised from acetic acid giving 7b (0.336 g, 77%) as red crystals,
mp 230e231 ꢀC, Rf¼0.65 (80% EtOAc/hexane). 1H NMR (CDCl3)
d:
2.36 (t, J¼6.1 Hz, 2H), 2.76 (s, 3H), 3.90 (s, 6H), 3.94 (s, 3H), 4.23 (t,
J¼6.1 Hz, 2H), 6.86 (s, 2H), 7.68 (ddd, J¼7.8, 7.8, 0.9 Hz, 1H), 7.75
(ddd, J¼7.8, 7.8, 0.9 Hz, 1H), 7.83 (dd, J¼7.8, 0.9 Hz, 1H), 8.25 (dd,
Rf¼0.33 (50% EtOAc/hexane), mp 198 ꢀC. 1H NMR (CDCl3)
d: 1.14 (t,
J¼7.0 Hz, 3H), 2.48 (s, 3H), 3.77 (s, 3H), 3.79 (s, 6H), 4.09 (q, J¼7.0 Hz,
2H), 4.99 (s, 1H), 6.57 (s, 2H), 7.09e7.13 (m, 1H), 7.20 (br s, 1H),
J¼7.8, 0.9 Hz, 1H). 13C NMR (CDCl3)
d: 17.6, 23.5, 56.3, 59.8, 61.0,
106.1, 116.1, 121.5, 123.0, 127.6, 128.6, 128.7, 131.2, 132.6, 134.2, 139.2,
7.24e7.26 (m, 2H), 7.33e7.36 (m, 1H). 13C NMR (CDCl3)
d: 14.1, 19.6,
140.2, 145.9, 151.3, 153.4, 161.9, 166.9. IR (Nujol)
n
: 1507, 1540, 1559,
37.5, 56.1, 60.1, 60.7, 105.1, 107.9, 110.3, 117.1, 121.4, 130.1, 131.3, 133.9,
136.0, 136.5, 141.6, 143.3, 152.9, 167.4, 192.3. MS (þESI) m/z (relative
intensity) 436 ([MþH]þ, 100). Anal. Calcd for C25H25NO6: C 68.95; H
5.79; N 3.22; found: C 68.78; H 5.80; N 3.15.
1653, 1740, 2350 cmꢂ1. MS (þESI) m/z (relative intensity) 495
([MþH]þ, 100). Anal. Calcd for C25H22N2O7S: C 60.72; H 4.48; N
5.66; found: C 60.47; H 4.51; N 5.63.
4.4.3. 4-(4-Chlorophenyl)-3-cyano-2-methylbenzothieno[3,2-b]pyri-
dine 5,5-dioxide (6c). This compound was prepared via the same
method used for compound 6a. Beginning with 4-(4-chlorophenyl)-
4.5.2. 2-Cyanoethyl 2-methyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-4,5-
dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate (7c). This com-
pound was prepared via the same method used for compound 7b.
Beginning with 2-(3,4,5-trimethoxybenzylidene)-indan-1,3-dione
(0.324 g, 1.00 mmol), 2-cyanoethyl acetoacetate (0.202 g,
1.30 mmol) and ammonium acetate (0.231 g, 3.00 mmol) in acetic
acid (2 mL) 7c (0.323 g, 70%) was obtained as red crystals, Rf¼0.21
3-cyano-2-methyl-1,4-dihydrobenzothieno[3,2-b]pyridine
5,5-
dioxide (5c) (73.8 mg, 0.200 mmol) and NBS (35.6 mg,
0.200 mmol) in methanol (3 mL), 6c (59.5 mg, 81%) was obtained as
white crystals, mp237e238ꢀC, Rf¼0.76 (60% EtOAc/hexane).1HNMR
(CDCl3)
d
: 2.97 (s, 3H), 7.59 (d, J¼8.3 Hz, 2H), 7.69 (d, J¼8.3 Hz, 2H),
(50% EtOAc/hexane), mp 200 ꢀC, 1H NMR (CDCl3)
d: 2.48 (dt,
7.72 (dd, J¼7.7, 7.7 Hz,1H), 7.78(dd,J¼7.7, 7.7Hz,1H), 7.85 (d, J¼7.7Hz,
2J¼17.3 Hz, 3J¼6.9 Hz,1H), 2.53 (s, 3H), 2.56 (dt, 2J¼17.3 Hz, 3J¼6.9 Hz,

5556
B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
1H), 3.76 (s, 3H), 3.82 (s, 6H), 4.22(t, J¼6.9Hz, 2H), 4.97(s,1H), 6.58(s,
2H), 7.11 (dd, J¼7.6,1.1 Hz,1H), 7.21 (br s,1H), 7.24e7.26 (m, 2H), 7.35
compound was prepared via the same method used for compound
7a beginning with 4,5-dihydro-1H-indeno[1,2-b]pyridine 7c (2.30 g,
5.00 mmol). Compound 8c was obtained as a yellow powder (2.13 g,
79%), Rf¼0.43 (50% EtOAc/hexane), mp 178e180 ꢀC. 1H NMR (CDCl3)
(dd, J¼7.6, 1.1 Hz, 1H). 13C NMR (CDCl3)
d: 18.0, 20.1, 37.6, 56.2, 58.3,
60.7, 105.0, 106.1, 110.6, 117.0, 117.2, 121.5, 130.2, 131.5, 133.6, 135.9,
136.5, 141.3, 145.5, 152.3, 153.1, 166.6, 192.1. MS (þESI) m/z (relative
intensity) 461 ([MþH]þ, 100). Anal. Calcd for C26H24N2O6: C 67.82; H
5.25; N 6.08; found: C 67.54; H 5.23; N 5.95.
d: 2.62e2.67 (m, 1H), 2.68e2.72 (m, 1H), 2.76 (s, 3H), 3.62 (s, 6H),
3.67 (s, 3H), 4.36 (t, J¼6.1 Hz, 2H), 4.75 (s, 1H), 6.19 (s, 2H), 7.69 (dd,
J¼7.7, 7.7 Hz, 1H), 7.81 (dd, J¼7.7, 7.7 Hz, 1H), 7.82 (d, J¼7.7 Hz, 1H),
8.12 (d, J¼7.7 Hz, 1H). 13C NMR (CDCl3)
d: 18.0, 20.1, 37.6, 56.1, 58.3,
60.7, 105.0, 106.1, 110.6, 117.0, 117.2, 121.5, 130.2, 131.5, 133.6, 135.9,
4.6. Bromination of 4-aryl-2-methyl-5-oxo-4,5-dihydro-1H-
indeno[1,2-b]pyridine-3-carboxylates 7aec
136.5, 141.3, 145.5, 152.3, 153.1, 166.6, 192.4. IR (Nujol) n: 1560, 1595,
1640, 1713, 1733, 2350 cmꢂ1. MS (þESI) m/z (relative intensity) 540
4.6.1. Methyl 4a-bromo-2-methyl-5-oxo-4-(4-methylphenyl)-4a,5-
dihydroindeno[1,2-b]pyridine-3-carboxylate (8a). A stirred solution
of 4,5-dihydro-1H-indeno[1,2-b]pyridine 7a (1.73 g, 5.00 mmol) in
methanol (10 mL) under an argon atmosphere was cooled to 10 ꢀC
whileNBS(0.908g, 5.10mmol)wasaddedportion-wise. Thereaction
mixture was stirred additionally at rt for 1 h, after which the solvent
was removed under reduced pressure at rt. The residue was tritu-
rated with water and a yellow precipitate was filtered off and crys-
tallised from methanol to give 8a (1.48 g, 70%) as a yellow powder,
(
79Br) ([MþH]þ, 100). Anal. Calcd for C26H23BrN2O6: C 57.90; H 4.30;
N 5.19; found: C 57.82; H 4.15; N 5.10.
4.7. Synthesis of 4-aryl-4a-bromo-2-methyl-5-oxo-4a,5-
dihydroindeno[1,2-b]pyridine-3-carbonitriles 8d,e
4.7.1. 4a-Bromo-2-methyl-5-oxo-4-(4-methylphenyl)-4a,5-dihydro-
indeno[1,2-b]pyridine-3-carbonitrile (8d). To a cooled to 10 ꢀC so-
lution of 4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carbonitrile 7d
(0.312 g, 1.00 mmol) in methanol (10 mL) under an argon atmo-
sphere NBS (178 mg, 1.00 mmol) was added. The reaction mixture
was stirred at rt for additional 10 min after which diluted with
water, filtered off giving 8d (0.356 g, 91%) as a yellow powder,
Rf¼0.73 (50% EtOAc/hexane). 1H NMR spectra were recorded im-
mediately, as the resulting brominated product 8d rapidly
decomposed upon isolation and exposure to air in the solid state,
precluding its complete structural characterisation. 1H NMR (CDCl3)
Rf¼0.77 (50% EtOAc/hexane), mp 132e134 ꢀC.1H NMR (CDCl3)
d: 2.13
(s, 3H), 2.76 (s, 3H), 3.72 (s, 3H), 4.81 (s, 1H), 6.85e6.87 (m, 4H), 7.63
(dd, J¼7.6, 7.6 Hz, 1H), 7.79 (dd, J¼7.6, 7.6 Hz, 1H), 7.80 (d, J¼7.6 Hz,
1H), 8.13 (d, J¼7.6 Hz, 1H). 13C NMR (CDCl3)
d: 21.0, 22.0, 46.6, 50.1,
52.0, 117.0, 124.2, 125.1, 128.1, 129.3, 129.4, 134.2, 137.0, 137.8, 138.5,
141.3, 154.3, 164.6, 167.0, 192.4. IR (Nujol) n: 1565, 1580, 1637, 1713,
1733 cmꢂ1. MS (þESI) m/z (relative intensity) 425 (79Br) ([MþH]þ,
70). Anal. Calcd for C22H18BrNO3: C 62.28; H 4.28; N 3.30; found: C
62.44; H 4.11; N 3.26. The structure of this compound was confirmed
by a single crystal X-ray crystallographic analysis.
d
: 2.17 (s, 3H), 2.64 (d, J¼1.0 Hz, 3H), 4.33 (d, J¼1.0 Hz, 1H), 6.83 (d,
J¼8.3 Hz, 2H), 6.93 (d, J¼8.3 Hz, 2H), 7.69 (ddd, J¼7.6, 7.6, 0.9 Hz,
1H), 7.82 (dd, J¼7.6, 0.9 Hz, 1H), 7.83 (ddd, J¼7.6, 7.6, 0.9 Hz, 1H),
8.14 (dd, J¼7.6, 0.9 Hz, 1H).
4.6.2. Crystal data for compound 8a. Diffraction data of 8a were
collected at ꢂ100 ꢀC on a Bruker-Nonius KappaCCD diffractometer
ꢀ
using graphite monochromated Mo-K
a
radiation (l¼0.71073 A).
4.7.2. 4a-Bromo-2-methyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-4a,5-
dihydroindeno[1,2-b]pyridine-3-carbonitrile (8e). This compound
was prepared via the same method used for compound 8d begin-
ning with 4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carbonitrile 7e
(0.388 g, 1.00 mmol). Compound 8e (0.444 g, 95%) was obtained as
yellow powder, Rf¼0.57 (50% EtOAc/hexane). 1H NMR spectra were
recorded immediately, as the resulting brominated product 8e
rapidly decomposed upon isolation and exposure to air in the solid
state, precluding its complete structural characterisation. 1H NMR
The crystal structure was solved by heavy atom method and refined
by full-matrix least squares using complex of programs maXus.53
All nonhydrogen atoms were refined in anisotropical approxima-
tion, all H-atoms were refined by riding model. Crystal data for 8a:
ꢀ
monoclinic; ꢀ a¼9.8031(3), b¼17.0930(5), c¼11.2627(4) A,
3
ꢀ
b
¼99.917(1) ; V¼1859.0(1) A , Z¼4,
m
¼2.23 mmꢂ1; space group is
P21/n. A total of 4236 reflection intensities were collected up to
2
qmax¼55ꢀ; for structure refinement 2826 independent reflections
with I>3
s
(I) were used. The final R-factor is 0.041. For further de-
(CDCl3)
d
: 2.65 (d, J¼0.9 Hz, 3H), 3.64 (s, 6H), 3.72 (s, 3H), 4.28 (d,
tails, see crystallographic data for 8a deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publication Num-
ber CCDC 915341. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
J¼0.9 Hz,1H), 6.15 (s, 2H), 7.74 (ddd, J¼7.8, 7.8,1.1 Hz,1H), 7.86 (ddd,
J¼7.8, 7.8, 1.1 Hz, 1H), 7.87 (d, J¼7.8 Hz, 1H); 8.15 (dd, J¼7.8, 1.1 Hz,
1H).
4.8. Synthesis of 4-aryl-2-methyl-5-oxo-5H-indeno[1,2-b]pyr-
4.6.3. Ethyl 4a-bromo-2-methyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-
4a,5-dihydroindeno[1,2-b]pyridine-3-carboxylate (8b). This com-
pound was prepared via the same method used for compound 7a
beginning with 4,5-dihydro-1H-indeno[1,2-b]pyridine 7b (2.18 g,
5.00 mmol). Compound 8b (2.11 g, 82%) was obtained as a yellow
powder, Rf¼0.59 (50% EtOAc/hexane), mp 200e202 ꢀC. 1H NMR
idine-3-carbonitriles 9d,e
4.8.1. 2-Methyl-5-oxo-4-(4-methylphenyl)-5H-indeno[1,2-b]pyri-
dine-3-carbonitrile (9d). To a cooled to 10 ꢀC solution of 4,5-
dihydro-1H-indeno[1,2-b]pyridine-3-carbonitrile 7d (0.312 g,
1.00 mmol) in methanol (10 mL) under an argon atmosphere NBS
(178 mg, 1.00 mmol) was added. The reaction mixture was stirred
for additional 10 min at rt after which a bright yellow precipitate
was filtered off, dissolved in methanol under reflux for 10 min. The
solution was cooled and yellow precipitate was filtered off to give
compound 9d as a pale yellow powder (0.251 g, 81%), Rf¼0.70 (50%
(CDCl3)
d
: 1.28 (t, J¼7.1 Hz, 3H), 2.75 (s, 3H), 3.61 (s, 6H), 3.68 (s, 3H),
4.21 (q, J¼7.1 Hz, 2H), 4.77 (s, 1H), 6.19 (s, 2H), 7.67 (dd, J¼7.7, 7.7 Hz,
1H), 7.81 (dd, J¼7.7, 7.7 Hz, 1H), 7.82 (d, J¼7.7 Hz, 1H), 8.15 (d,
J¼7.7 Hz, 1H). 13C NMR (CDCl3)
d: 14.2, 21.9, 47.2, 49.8, 55.9, 60.3,
61.0, 106.0, 117.0, 124.0, 125.2, 128.3, 134.4, 136.3, 137.5, 138.6, 141.3,
152.9, 154.0, 164.9, 166.5, 192.4. IR (Nujol)
n
: 1558, 1597, 1637, 1713,
EtOAc/hexane), mp 245 ꢀC. 1H NMR (DMSO-d6)
d: 2.41 (s, 3H), 2.81
1733 cmꢂ1. MS (þESI) m/z (relative intensity) 515 (79Br) ([MþH]þ,
100). Anal. Calcd for C25H24BrNO6: C 58.38; H 4.70; N 2.72; found: C
58.38; H 4.60; N 2.61.
(s, 3H), 7.33 (d, J¼8.5 Hz, 2H), 7.43 (d, J¼8.5 Hz, 2H), 7.60 (ddd, J¼7.4,
7.4, 1.4 Hz, 1H), 7.66 (dd, J¼7.4, 1.4 Hz, 1H), 7.75 (ddd, J¼7.4, 7.4,
1.4 Hz, 1H), 7.92 (dd, J¼7.4, 1.4 Hz, 1H). 13C NMR (DMSO-d6)
d: 21.4,
25.0, 30.0, 109.1, 116.9, 122.2, 122.3, 124.4, 129.0, 129.2, 129.7, 133.2,
4.6.4. 2-Cyanoethyl 4a-bromo-2-methyl-5-oxo-4-(3,4,5-trimethoxy-
phenyl)-4a,5-dihydroindeno[1,2-b]pyridine-3-carboxylate (8c). This
135.6, 136.2, 140.3, 141.4, 151.7, 166.9, 168.1, 189.1. IR (Nujol) n: 1588,
1617, 1741, 2404 cmꢂ1. MS (þESI) m/z (relative intensity) 311

B. Cekavicus et al. / Tetrahedron 69 (2013) 5550e5557
5557
([MþH]þ, 100). Anal. Calcd for C21H14N2O: C 81.27; H 4.55; N 9.03;
9. Bisenieks, E. A.; Uldrikis, J. R.; Dubur, G. J.; Tirzit, G. D.; Dauvarte, A. Z.; Zi-
dermane, A. A.; Ivanov, E. V.; Ponomareva, T. V. SU 1050261, 1995.
10. Manpadi, M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K. M.; Wong, Y.-S. C.; Anderson,
L. A.; Ortega, A. J.; Van Slambrouck, S.; Steelant, W. F. A.; Rogelj, S.; Tongwa, P.;
Antipin, M.Y.;Magedov, I. V.;Kornienko, A. Org. Biomol.Chem. 2007, 5, 3865e3872.
11. Hyvonen, Z.; Plotniece, A.; Reine, I.; Chekavichus, B.; Duburs, G.; Urtti, A. Bio-
chim. Biophys. Acta 2000, 1509, 451e466.
found: C 80.95; H 4.51; N 9.01.
4.8.2. 2-Methyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-5H-indeno[1,2-b]
pyridine-3-carbonitrile (9e). This compound was prepared via the
same method used for compound 9d beginning with 4,5-dihydro-
1H-indeno[1,2-b]pyridine-3-carbonitrile 7e (0.388 g, 1.00 mmol).
Compound 9e was obtained as a pale yellow powder (0.305 g, 79%),
12. Hyvonen, Z.; Ruponen, M.; Ronkko, S.; Suhonen, P.; Urtti, A. Eur. J. Pharm. Sci.
2002, 15, 449e460.
13. Hyvonen, Z.; Ronkko, S.; Toppinen, M. R.; Jaaskelainen, I.; Plotniece, A.; Urtti, A.
J. Controlled Release 2004, 99, 177e190.
14. Kill, R. J.; Widdowson, D. A. In Bioorganic Chemistry; van Tamelen, E. E., Ed.;
Academic: New York, NY, 1978; pp 239e275.
15. Lorimer, A. R.; Smedsrud, T.; Walker, P.; Tyler, H. M. J. Hum. Hypertens. 1989, 3,
191e196.
Rf¼0.51 (50% EtOAc/hexane), mp 240 ꢀC. 1H NMR (DMSO-d6)
d: 2.92
(s, 3H), 3.91 (s, 6H), 3.96 (s, 3H), 7.00 (s, 2H), 7.52 (ddd, J¼7.5, 7.5,
0.8 Hz, 1H), 7.66 (dd, J¼7.5, 0.8 Hz, 1H), 7.71 (ddd, J¼7.5, 7.5, 0.8 Hz,
1H), 7.96 (dd, J¼7.5, 0.8 Hz, 1H). 13C NMR (DMSO-d6)
d: 25.0, 56.6,
16. Glasser, S. P.; Chrysant, S. G.; Graves, J.; Rofman, B.; Koehn, D. K. Am. J. Hyper-
tens. 1989, 3, 154e157.
60.6, 107.8, 109.1, 117.1, 122.2, 122.4, 124.5, 127.2, 133.2, 135.7, 136.2,
17. Eearl, R. A.; Myers, M. J.; Nickolson, V. J. US 5173489 (A), 1992.
18. Brandes, A.; Loegers, M.; Schmidt, G.; Angerbauer, R.; Schmeck, C.; Bremm, K.
D.; Bischoff, H.; Schmidt, D.; Schuhmacher, J. EP 0825185 (A1), 1998.
19. Brandes, A.; Loegers, M.; Schmidt, G.; Angerbauer, R.; Schmeck, C.; Bremm, K.
D.; Bischoff, H.; Schmidt, D.; Schuhmacher, J. US 6063788 (A), 2000.
20. Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest, K. T.; Tang, Y.; Jackson,
P. F. US 2004082578 (A1), 2004.
139.3, 141.3, 150.8, 152.8, 166.8, 168.0,188.9. IR (Nujol) n: 1508, 1548,
1587, 1715, 2222 cmꢂ1. MS (þESI) m/z (relative intensity) 387
([MþH]þ, 100). Anal. Calcd for C23H18N2O4: C 71.49; H 4.70; N 7.25;
found: C 71.15; H 4.63; N 7.27.
4.9. Debromination of 4-aryl-4a-bromo-2-methyl-5-oxo-4a,5-
dihydroindeno[1,2-b]pyridine-3-carboxylates 8aec
21. Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest, K. T.; Tang, Y.; Jackson,
P. F. WO 03088963 (A1), 2003.
22. Pajuste, K.; Plotniece, A.; Kore, K.; Intenberga, L.; Cekavicus, B.; Kaldre, D.;
Duburs, G.; Sobolev, A. Cent. Eur. J. Chem. 2011, 9, 143e148.
23. Skrastinsh, I. P.; Kastron, V. V.; Chekavichus, B. S.; Sausinsh, A. E.; Zolotoyabko,
R. M.; Dubur, G. Y. Khim. Geterotsikl. Soedin. 1991, 1230e1235 (Chem. Heterocycl.
Comp. (Engl. Ed.) 1991, 27, 989e994).
4.9.1. Debromination of compound 8a. To a solution of 8a (0.424 g,
1.00 mmol) in a mixture of acetone (2 mL) and water (0.1 mL),
crushed sodium hydroxide (80.0 mg, 2.00 mmol) was added at rt.
The reaction mixture was stirred for 2 min, after which it was
acidified with diluted hydrochloric acid to pH 4.0e5.0. The pre-
cipitated red coloured product was filtered off, yielding 4,5-dihy-
dro-1H-indeno[1,2-b]pyridine 7a (0.317 g, 92%) as red crystals. The
compound 7a was already described in the literature.46
24. Petrova, M.; Muhamadejev, R.; Vigante, B.; Cekavicus, B.; Plotniece, A.; Duburs,
G.; Liepinsh, E. Molecules 2011, 16, 8041e8052.
25. Nagarajan, R.; Anthonyraj, J. C. A.; Muralidharan, D.; Saikumar, C.; Perumal, P. T.
Indian J. Chem., Sect. B 2006, 45, 826e828.
26. Plotniece, A.; Pajuste, K.; Kaldre, D.; Cekavicus, B.; Vigante, B.; Turovska, B.;
Belyakov, S.; Sobolev, A.; Duburs, G. Tetrahedron 2009, 65, 8344e8349.
27. Vanden Eynde, J. J.; D’Orazio, R.; Haverbeke, Y. V. Tetrahedron 1994, 50,
2479e2484.
28. Dubure, R. R.; Vigante, B. A.; Ozols, Y. Y.; Dubur, G. Y.; Rozentale, G. I. Khim.
Geterotsikl. Soedin. 1986, 1563e1567 (Chem. Heterocycl. Comp. (Engl. Ed.) 1986,
22, 1267e1271).
29. Vanden Eynde, J. J.; Mayence, A.; Maquestiau, A. Tetrahedron 1992, 48, 463e468.
30. Liao, X.; Lin, W.; Lu, J.; Wang, C. Tetrahedron Lett. 2010, 51, 3859e3861.
31. Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Haverbeke, Y. V. Tetrahedron 1995,
51, 6511e6516.
4.9.2. Debromination of compound 8b. This compound was pre-
pared via the same method described at Section 4.9.1, but begin-
ning with 8b (0.514 g, 1.00 mmol). Compound 7b was obtained as
red crystals (0.379 g, 87%). The 1H NMR and mass spectral data of 7b
were identical with those described in Section 4.7.1.
32. Makarova, N. V.; Plotniece, A.; Tirzitis, G.; Turovskii, I.; Dubur, G. Khim. Geterotsikl.
Soedin. 1997, 202e211 (Chem. Heterocycl. Comp. (Engl. Ed.) 1997, 33, 175e183).
33. Turovska, B.; Stradins, J.; Turovskis, I.; Plotniece, A.; Shmidlers, A.; Duburs, G.
Khim. Geterotsikl. Soedin. 2004, 880e886 (Chem. Heterocycl. Comp. (Engl. Ed.)
2004, 40, 753e758).
4.9.3. Debromination of compound 8c. This compound was pre-
pared via the same method described at Section 4.9.1, but begin-
ning with 8c (0.539 g, 1.00 mmol). Compound 7c was obtained as
red crystals (0.392 g, 85%). The 1H NMR and mass spectral data of 7c
were identical with those described in Section 4.7.2.
ꢁ~
34. Nunez-Vergara, L. J.; Salazar, R.; Camargo, C.; Carbajo, J.; Conde, B.; Navarrete-
Encina, P. A.; Squella, J. A. Bioorg. Med. Chem. 2007, 15, 4318e4326.
35. Kuthan, J.; Kurfurst, A. Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 191e261.
36. Vigante, B.; Tirzitis, G.; Tirzite, D.; Cekavicus, B.; Uldrikis, J.; Sobolev, A.; Duburs,
G. Khim. Geterotsikl. Soedin. 2007, 280e288 (Chem. Heterocycl. Comp. (Engl. Ed.)
2007, 43, 225e232).
Acknowledgements
37. Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134e2139.
38. Rose, U. J. Heterocycl. Chem. 1990, 27, 237e242.
39. Dubure, R. R.; Vitolina, R. O.; Ozols, J. J.; Duburs, G. J.; Kimenis, A. A.; Zarins, G.
V. SU 1018396 (A1), 1986.
This research work was supported by European Regional De-
velopment Fund (ERDF) project No. 2010/2DP/2.1.1.1.0/10/APIA/
VIAA/072 and Grant of Latvian Council of Science No. 09.1566.
Authors are indebted to professor Gunars Duburs for his helpful
suggestions during the course of investigation.
40. Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1e42.
41. Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269e289.
42. Sausins, A.; Duburs, G. Khim. Geterotsikl. Soedin. 1992, 435e467 (Chem. Heter-
ocycl. Comp. (Engl. Ed.) 1992, 28, 363e391).
43. Sausins, A.; Duburs, G. Khim. Geterotsikl. Soedin. 1993, 579e612 (Chem. Heter-
ocycl. Comp. (Engl. Ed.) 1993, 29, 489e520).
44. Chatterjea, J. N.; Shaw, S. C.; Singh, S. N. J. Indian Chem. Soc. 1978, 55, 149e153.
45. Vigante, B. A.; Ozols, Y. Y.; Dubur, G. J. Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1980,
707e716.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.060.
46. Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50,
7096e7098.
47. Hassanein, A. A. Synth. Commun. 2000, 3883e3896.
48. Sedova, V. F.; Gatilov, Y. V.; Shkurko, O. P. Russ. J. Org. Chem. 2005, 41, 417e422.
49. Kalme, Z.; Shmidlers, A.; Celmins, J.; Liepinsh, E.; Krauze, A.; Duburs, G. Khim.
Geterotsikl. Soedin. 2007, 786e788 (Chem. Heterocycl. Comp. (Engl. Ed.) 2007, 43,
662e664).
References and notes
1. Edraki, N.; Mehdipour, A. R.; Khoshneviszadeh, M.; Miri, R. Drug Discovery Today
2009, 14, 1058e1066.
50. Shone, R. L. Tetrahedron Lett. 1979, 20, 2185e2188.
2. Vater, W.; Kroneberg, G.; Hoffmeister, F.; Saller, H.; Meng, K.; Oberdorf, A.; Puls,
W.; Schlossmann, K.; Stoepel, K. Arzneim. Forsch. 1972, 22, 1e14.
3. Goldmann, S.; Stoltefuss, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1559e1578.
4. Safak, C.; Simsek, R. Mini-Rev. Med. Chem. 2006, 6, 747e755.
5. Bulbul, B.; Ozturk, G. S.; Vural, M.; Simsek, R.; Sarioglu, Y.; Linden, A.; Ulgen, M.;
Safak, C. Eur. J. Med. Chem. 2009, 44, 2052e2058.
6. Murdoch, D.; Heelk, R. C. Drugs 1991, 41, 478e505.
7. Rozner, E.; Eggers, A.; Rosenbaum, D. Curr. Hypertens. Rep. 2009, 11, 246e252.
8. de Portu, S.; Mantovani, L. G. J. Med. Econ. 2009, 12, 60e68.
51. Vigante, B. A.; Terekhova, M. I.; Ozols, Y. Y.; Petrov, E. S.; Dubur, G. Y. Khim.
Geterotsikl. Soedin. 1989, 1228e1231 (Chem. Heterocycl. Comp. (Engl. Ed.) 1989,
25, 1028e1031).
52. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Gua-
gliardi, A.; Moliterni, A. G. G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115e119.
53. Mackay, S.; Dong, W.; Edwards, C.; Henderson, A.; Gilmore, C. J.; Stewart, N.;
Shankland, K.; Donald, A. maXus, Integrated Crystallography Software; Bruker-
Nonius and University of Glasgow: 2003.