Fused pyrazino[2,3-b]indolizine and indolizino[2,3-b]quinoxaline derivatives; synthesis, structures, and properties

Article abstract of DOI:10.1016/j.tet.2011.09.133

The synthesis of six new compounds incorporating either a pyrazino[2,3-b]indolizine or indolizino[2,3-b]quinoxaline core are reported in good yield (58-87%). The intermediates for the key cyclization reaction for one set of compounds (5a-c), with a sterically demanding 3,5-dimethylpyrazole group in the 5-position of the core, were found to be mono-substituted. These intermediates could be isolated and cyclized by heating under acid-catalyzed conditions. To further demonstrate the versatility of the chemistry, compounds 6a-c were synthesized in 58-68% yields. Compounds 5a-c are non-planar in solution and the solid-state, while 6a-c have close to planar conformations, pointing to weak hydrogen bonds between the acidic C-Hs and the adjacent azine nitrogen atoms. The cytotoxicity of the six newly synthesized and three previously prepared compounds was assessed against a human glioblastoma multiforme cell line.

Full text of DOI:10.1016/j.tet.2011.09.133

Tetrahedron 67 (2011) 9368e9375
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Fused pyrazino[2,3-b]indolizine and indolizino[2,3-b]quinoxaline derivatives;
synthesis, structures, and properties
Witold M. Bloch a, Stephanie M. Derwent-Smith a, Fatiah Issa b, Jonathan C. Morris c, Louis M. Rendina b,
,
Christopher J. Sumby a
*
a School of Chemistry & Physics, The University of Adelaide, Adelaide, SA 5005, Australia
b School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
c School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Received in revised form 8 September 2011
Accepted 26 September 2011
Available online 5 October 2011
The synthesis of six new compounds incorporating either a pyrazino[2,3-b]indolizine or indolizino[2,3-b]
quinoxaline core are reported in good yield (58e87%). The intermediates for the key cyclization reaction
for one set of compounds (5aec), with a sterically demanding 3,5-dimethylpyrazole group in the 5-
position of the core, were found to be mono-substituted. These intermediates could be isolated and
cyclized by heating under acid-catalyzed conditions. To further demonstrate the versatility of the
chemistry, compounds 6aec were synthesized in 58e68% yields. Compounds 5aec are non-planar in
solution and the solid-state, while 6aec have close to planar conformations, pointing to weak hydrogen
bonds between the acidic CeHs and the adjacent azine nitrogen atoms. The cytotoxicity of the six newly
synthesized and three previously prepared compounds was assessed against a human glioblastoma
multiforme cell line.
Keywords:
Fused heterocycles
Synthesis
Organic dyes
X-ray crystallography
Biological activity
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Compounds 1aec are electrochemically active and display several
distinct absorption features through the visible range; derivatives
There is considerable interest in ruthenium(II) polypyridine
complexes,1e7 which have been investigated in the context of water
splitting8,9 and as sensitizers for dye-sensitized solar cells.10e15
These investigations are particularly relevant as the planet’s en-
ergy demands are an area of significant societal and scientific
concern.16,17 In exploring complexes for such applications, the
stereochemical, electrochemical, and photophysical properties of
ruthenium(II) polypyridine complexes are of particular in-
terest.3,5,7,18,19 These can be tailored by altering the nature of the
ligands coordinated to the metal center.2,7,20e26 These changes to
the archetypal chelating biheterocyclic ligand structure have led to
new complexes displaying modified electrochemical and photo-
physical properties, and in turn new candidates for the noted
applications.
1b and 1c give intensely purple colored solutions, while 1a gives
a red solution consistent with its shorter wavelength absorption in
the visible range.27 The complexes of the type [RuL(bpy)2]2þ and
[RuL(dmb)2]2þ (where bpy¼2,20-bipyridine; dmb¼4,40-dimethyl-
2,20-bipyridine; L¼1aec) also show a number of characteristic re-
dox potentials, and those complexes containing 1b and 1c are black
dyes.
Other fused heterocyclic compounds with related cores (such as
2 and 3) have also been studied due to their unique structures,
synthetic challenges, and potentially interesting biological prop-
erties (Fig. 1, (b)).28e30 For example, variolin B is a natural product
isolated from the Antarctic sponge Kirkpatrickia varialosai by the
group of Blunt and Munro.31 Variolin B contains the pyrido
[30,20:4,5]pyrrolo[1,2-c]pyrimidine skeleton 4.30 Synthetic ap-
proaches developed by one of us32,33 allows the convergent syn-
thesis of variolin B, while alternative linear synthetic pathways
have been reported.34e39 The chemistry and biological properties of
variolin B and related derivatives have been reviewed.30
We have an interest in a group of planar, highly conjugated
heterocyclic compounds (Fig. 1, (a)), 5-(2-pyridyl)pyrazino[2,3-b]
indolizine (1a), 5-(2-pyridyl)indolizino[2,3-b]quinoxaline (1b), and
8,9-dimethyl-5-(2-pyridyl)indolizino[2,3-b]quinoxaline (1c), that
are effective chelating ligands for transition metal ions.27
As part of our ongoing work on heterocyclic compounds as li-
gands,26 we noted the structural similarities between the core of
the variolins and compounds 1aec. This provoked us to study the
biological properties of these fused heterocyclic compounds and to
explore the synthesis of other derivatives. Herein we report the
* Corresponding author. Tel.: þ61 8 8303 7406; fax: þ61 8 8303 4358; e-mail
address: christopher.sumby@adelaide.edu.au (C.J. Sumby).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.133

W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
9369
first set of targets was the compounds bearing an electron-rich 3,5-
dimethyl-1H-pyrazol-1-yl substituent in the 5-position of the core
5aec. The first target, compound 5a, was ultimately synthesized in
two steps from 2-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyridine
(7)40 and 8a. Typically, 2 equivalents of the anion of the active
methylene compound are used in these reactions because it is
possible for two routes, via the mono- or di-substituted com-
pounds, to be occurring in competition in the cyclization step to
yield the final product (Scheme 1). However, in the case of com-
pound 5a, the normal conditions did not yield the expected final
cyclized product but rather the mono-substituted intermediate 9a
as the major product in 75% yield (Scheme 1).
(a)
N
1a
1b
1c
R
R
N
N
R = H
R = Me
N
(b)
CN
CN
N
N
N
N
NC
NC
N
N
After the isolation of 9a, we endeavored to find conditions to
effect its cyclization to 5a. Previously,27 we had demonstrated that
disubstituted intermediates could be cyclized under reflux condi-
tions with trifluoroacetic acid (TFA) as a catalyst. In the case of 9a,
however, the conversion was found to be slow, and a 1H NMR
spectrum of the reaction mixture revealed only 80% conversion
after 4 days. Hence, 9a was heated in a microwave reactor, with TFA
and acetonitrile as a solvent, at 140 ꢀC for 90 min. The 1H NMR
spectrum of the reaction mixture revealed >99% conversion to
product 5a. The slow conversion of the mono-substituted com-
pound 9a can be attributed to the steric hindrance about the 3,5-
dimethylpyrazolyl ring, which hinders cyclization and/or further
substitution by a second equivalent of 7. An X-ray crystal structure
of 5a shows a possible origin of this steric hindrance, whereby the
methyl substituents on the pyrazole ring impede access to the
adjacent position (C2) by incoming nucleophiles (Fig. 2).
The indolizino[2,3-b]quinoxaline compounds 5b and 5c were
able to be synthesized successfully by the reaction of 7 with either
8b or 8c, in good yields of 89% and 73%, respectively. For both
compounds, spontaneous cyclization of the respective intermediate
compound to the product was observed during the course of the
reaction. In both cases, a small portion of the reaction mixture was
quenched at room temperature and analyzed by 1H NMR spec-
troscopy. In the reaction of compound 7 with 8b, the 1H NMR
spectrum revealed cyclized product 5b as the major species, along
with starting material 7, and aromatic signals corresponding to very
small quantities of the intermediates. However, in the case of the
reaction of 7 with 8c, the 1H NMR spectrum revealed cyclized
product 5c as the minor species, with other peaks in the aromatic
region corresponding to the proposed intermediates.
3
2
N
NH2
OH
N
N
N
N
N
N
N
N
N
H2N
4
variolin B
(c)
N
N
N
R
R
N
R
N
N
N
N
R
N
6a
6b
6c
5a
5b
5c
R = H
R = Me
R = H
R = Me
Fig. 1. (a) The structures of previously synthesized pyrazino[2,3-b]indolizine or in-
dolizino[2,3-b]quinoxalines, 1aec; (b) 14-cyanobenzo[a]indolizino[2,3-b]quinoxaline,
2; pyrazino[2,3-b]indolizine-2,3,10-tricarbonitrile, 3; variolin B, and the pyrido
[30,20:4,5]pyrrolo[1,2-c]pyrimidine core of the variolins, 4; and, (c) the structures of the
new pyrazino[2,3-b]indolizine or indolizino[2,3-b]quinoxaline compounds prepared in
this work (5ae6c).
synthesis of six new compounds containing a pyrazino[2,3-b]
indolizine or indolizino[2,3-b]quinoxaline core (Fig. 1, (c)) and, for
the first time, a comprehensive study into the intermediates in-
volved in the synthesis. Three of the new compounds, 5-(3,5-
dimethyl-1H-pyrazol-1-yl)pyrazino[2,3-b]indolizine (5a), 5-(3,5-
dimethyl-1H-pyrazol-1-yl)indolizino[2,3-b]quinoxaline (5b), and
5-(3,5-dimethyl-1H-pyrazol-1-yl)-8,9-dimethylindolizino[2,3-b]
quinoxaline (5c), have a 3,5-dimethylpyrazole substituent appen-
ded to the 5-position of the core, while the second set 5-(pyrazin-2-
yl)-pyrrolo[1,2-a:4,5-b]dipyrazine (6a), 5-(pyrazin-2-yl)-pyrazino
[1,2-a]pyrrolo[2,3-b]quinoxaline (6b), and 8,9-dimethyl-5-(pyr-
2.2. Investigations of the intermediates 9aec
To obtain a better understanding of the nature of the in-
termediates present prior to heating, the reaction between 8c and 7
was carried out in a 1:1 ratio, and the mixture was quenched at
ꢁ78 ꢀC after 30 min. The major compound in the reaction mixture
was identified as the mono-substituted intermediate 9c, which was
isolated and characterized by X-ray crystallography (Fig. 3). Once
again, the molecular structure confirms the presence of steric
hindrance in 9c, although it should be noted that the 3,5-
dimethylpyrazole substituent can be directed away from the chlo-
rine atom by rotation about the newly formed carbonecarbon
bond. The 1H NMR spectrum of 9c is identical to the major in-
termediate species observed in the 1H NMR spectrum of the re-
action performed by using 1:2 equiv of compounds 8c and 7. Upon
heating the solid 9c above its melting point, a color change from
colorless to purple was observed, indicating cyclization to product
5c. In comparison to the pyrazine analogue 9a, the mono-
substituted quinoxaline compounds require less thermal energy
to undergo the intermolecular cyclization reaction, and this can
occur without the need of acid catalysis. Since the two sets of
compounds (9a and 9b/9c) possess the same degree of steric hin-
drance, the greater reactivity of compound 9b/9c may be attributed
azin-2-yl)-pyrazino[1,2-a]pyrrolo[2,3-b]quinoxaline
(6c),
in-
corporate a pyrazine ring at this position. In addition to our
synthetic studies, for the first time we evaluated the in vitro bi-
ological properties of 1aec and the six new derivatives 5ae6c.
2. Results and discussion
2.1. Synthesis of 5aec
In previous work, we identified a one-pot synthesis that gives
access to indolizino[2,3-b]quinoxaline or pyrazino[2,3-b]indolizine
fused heterocycles 1aec.27 To further develop this chemistry, we
turned our attention to expanding the scope of this reaction. The

9370
W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
N
N
i
iii
N
N
R
R
N
N
N
N
N
N
N
N
N
R
R
N
N
Cl
Cl
N
N
Cl
Cl
Cl
7
Cl
2 equiv.
9b
R = H
R = Me 9c
9a 75%
8b
R = H
8a
R = Me 8c
Δ
ii
- Cl
7
- Cl
4'
4'
N
N
N
N
N
4
N
N
N
7
7
8
8
R
R
N
N
4
N
R
R
Δ
9
N
3
N
N
3
2
- 7
N
1
10
R = H
2
N
1
N
5a 77%
5b 89%
R = Me 5c 73%
N
Scheme 1. (i) n-BuLi, THF, ꢁ78 ꢀC, rt, 9a; (ii) TFA, CH3CN, 5a; (iii) n-BuLi, THF, ꢁ78 ꢀC, 5b or 5c, rt to reflux.
Fig. 3. (a) A perspective view of the solid-state molecular structure of 9c. Thermal
ellipsoids are shown at the 50% probability level. (b) A space-filling representation
alludes to the possibility that the pyrazole ring hinders the approach of nucleophiles to
C2 of 9c.
Fig. 2. (a) A perspective view of the X-ray molecular structure of compound 9a
showing the possible origin of the steric hindrance. Thermal ellipsoids are shown at
the 50% probability level. (b) A space-filling representation of the structure.
orange and purple solutions, respectively, upon dissolution in
dichloromethane, which is indicative of the conjugated indolizino
[2,3-b]quinoxaline core.
to greater resonance stabilization of the reaction intermediates
provided by the quinoxaline ring with respect to the pyrazine ring
during cyclization.
2.3. Synthesis of 6aec
In summary, the three compounds 5a, 5b, and 5c were isolated
as red (5a) and purple (5b, and 5c) solids, and gave intense red-
The synthesis of compounds 6aec required the identification of
a reliable procedure to prepare di-2-pyrazinylmethane (10). A

W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
9371
potential precursor, di-2-pyrazinylketone (11), is known41 and
could be synthesized from 2-iodopyrazine (12) using n-BuLi in
a lithiumehalogen exchange protocol.42 In order to avoid the un-
wanted nucleophilic substitution of 2-iodopyrazine with the butyl
anion, we attempted the preparation of ketone 11 by metalation of
12 using commercially-available i-PrMgCl or n-BuMgCl43 (Scheme
2) and reacting the newly-formed Grignard reagent with methyl
ester 13. With i-PrMgCl only trace amounts of the desired ketone 11
what we propose occurs in solution for 1aec and 6aec where the
heterocyclic ring in the 5-position of the core is close to planar and
involved in two H-bonding interactions.
A single crystal of compound 5b, suitable for X-ray crystallog-
raphy, was obtained by slow evaporation of a dichloromethane/
diethyl ether solution of 5b. Compound 5b crystallizes in the
monoclinic space group P21/c with one complete molecule in the
asymmetric unit (Fig. 4). As observed for other closely related
O
N
N
I
N
N
N
N
iii
N
N
N
N
N
ii
i
O
Cl
N
10
N
N
N
11
from : 53%
from 14: 25%
O
12
14
11 27%
N
15
13
Scheme 2. (i) n-BuMgCl, THF, 0 ꢀC; (ii) ethylene glycol, KOH, NH2NH2$H2O; (iii) LDA, THF, ꢁ78 ꢀC.
were obtained, while performing the reaction with n-BuMgCl gave
the ketone in 27% yield, with a major portion of the Grignard ma-
terial isolated as 2-butylpyrazine. A WolffeKishner reduction on 11
gave diarylmethane 10 in 53% isolated yield.
An alternative route to 10 involving a one-step reaction, which
proceeds via a lithiation of 2-methylpyrazine was also investigated.
Based on the synthesis of di-2-pyridylmethane,44 metalation of 2-
methylpyrazine (14) by using LDA,45 and its subsequent reaction
with 2-chloropyrazine (15), gave 10 directly in 25% yield. The iso-
lated yield of 25% is an improvement on the synthesis of 10 by
means of the ketone method (ca. 14% overall).
Deprotonation of 10 and subsequent reaction with either 8a, 8b
or 8c gave three new compounds (Scheme 3) possessing either an
pyrrolo[1,2-a:4,5-b]dipyrazine (6a) or pyrazino[1,2-a]pyrrolo[2,3-
b]quinoxaline (6b and 6c) core, respectively. The propensity of
n-BuLi to act as a nucleophile in the presence of pyrazine de-
rivatives46 led us to first examine the use of LDA as the base. LDA
has been widely used on pyrazine derivatives,45,47,48 however, the
isolated yields of 6b and 6c using LDA were 35% and 36%, re-
spectively. In contrast, when n-BuLi was used as the base, the
compounds 6a, 6b, and 6c were isolated in much improved yields
of 58%, 67%, and 69%, respectively. Like compounds 5aec, these
heterocycles were isolated as red and purple solids that gave in-
tense orange and purple solutions upon dissolution in chloroform.
compounds,27 the core of 5b is planar. The conformation of the 3,5-
dimethylpyrazolyl ring in the solid-state is in agreement with that
observed in solution by 1H NMR spectroscopy. The twisted con-
formation, where the torsion angle is 58.4ꢀ, can be attributed to
a steric hindrance between the 50-methyl group of the 3,5-
dimethylpyrazolyl ring and H4.
For the compounds 6a, 6b, and 6c, it was expected that the
pyrazine ring in the 5-position would be close to planar with re-
spect to the core, as the position of the H4 atom in the 1H NMR
spectrum was relatively downfield due to deshielding by the ad-
jacent nitrogen atom. A single crystal X-ray structure confirmed
this conformation to be present in the solid-state of 6a (Fig. 5) and
6b (Fig. 6). In the structure of 6a the torsion angle for the pendent
pyrazine ring is 17.6ꢀ, while in the structure of 6b the torsion angle
is 5.6ꢀ. These conformations are consistent with an H-bonding in-
teraction between the acidic CeHs (H4 and H30) and the adjacent
nitrogen atoms in both structures.
2.5. Biological activity
Due to the promising biological activity of the variolin family of
compounds,30 we assessed the biological activity of selected com-
pounds against the T98G (human glioblastoma multiforme) cell
line. Variolin B has an IC50 of 0.716 mM against the P388 murine
5'
5'
N
N
6'
6'
3'
3'
N
N
7
R 8
N
N
N
N
N
N
N
N
i
i
7
8
4
4
9
8b 8c
or
8a
N
R
N
N
N
10
1
1
0
2
1
2
2 equiv.
6b
R = H
58%
6a
58%
R = Me 6c 69%
Scheme 3. (i) n-BuLi, THF, ꢁ78 ꢀC, rt to reflux.
2.4. Solution and solid-state structures
leukemia cell line,30 and both variolin B and deoxyvariolin B have
been observed to affect cell-cycle progression. The cytotoxicity of
our compounds was assessed using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay49 and cell via-
bility was determined by measuring the absorbance of the purple
formazan solution at 600 nm using a microplate reader. The results
are shown below in Table 1, with no determination being possible
for compound 5c, which was found to be poorly soluble in the cell
culture medium.
The structures and purity of compounds 5aec and 6aec were
confirmed by 2D NMR spectroscopy, mass spectrometry, and ele-
mental analysis. In the 1H NMR spectrum of compounds 5a, 5b and
5c, H4 appears significantly upfield relative to 1aec.27 Therefore, it
was deduced that the 3,5-dimethylpyrazolyl ring in the 5-position
is in a significantly twisted conformation, with the
pyrazolyl ring shielding the H4 atom. This differs significantly from
p-system of the

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W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
Fig. 6. (a) A perspective view of the molecular structure of 6b showing the planar core,
with thermal ellipsoids at the 50% probability level. (b) A view of 6b perpendicular to
the core showing the near planar conformation of the pyrazine ring.
Table 1
In vitro cytotoxicity of compounds 1aec, 5a, 5b, and 6aec in an MTT cytotoxicity
assay using the human glioblastoma multiforme (T98G) cell line
Fig. 4. (a) A perspective view of the molecular structure of 5b showing the planar
indolizino[2,3-b]quinoxaline core with thermal ellipsoids at the 50% probability level.
(b) A view of 5b perpendicular to the core showing the out-of-plane twist of the
pyrazole ring.
Compound
1a
2a
3a
5a
5b
5c
6a
6b
6c
Average (
SEa
m
M) 88.8 66.7 72.7 324.0 62.1 NDc 33.8 46.0 36.4
8.5
5
6.2
5
4.9
5
34.6
4
6.7 NDc
3
5.8
3
6.5
5
1.6
4
Nb
a
SE¼standard error.
b
c
N¼number of cytotoxicity assays run.
ND¼not determined due to solubility limitations.
isolable mono-substituted intermediates 9a and 9c under forcing
conditions. The intermediate 9b cyclizes upon warming to room
temperature and it was not isolated from the reaction mixture. The
synthesis of 6aec required the preparation of di-2-
pyrazinylmethane (7), which after some investigation, was ac-
complished in 25% isolated yield. Thereafter, the synthesis of 6aec
proceeded in a facile manner to generate the three new compounds
in good yields (58e68%).
Due to steric hindrance, compounds 5aec are non-planar in
solution and the solid-state, while 6aec have close to planar con-
formations, pointing to H-bonding interactions between the acidic
CeH groups (H4 and H30) and the adjacent nitrogen atoms in these
compounds, as confirmed by NMR spectroscopy and X-ray crys-
tallography. The cytotoxicity of these newly synthesized com-
pounds and three previously synthesized compounds was also
assessed. Despite their structural similarity to variolin B, there was
no significant cytotoxic activity observed for any of the compounds,
with 6a, 6b, and 6c being the most active of the series. In future
studies, we will utilize their bidentate chelating motifs to prepare
transition metal complexes, which should have improved aqueous
solubility and cytotoxicity. Our work on the coordination chemistry
of these compounds and investigation into applications in dye-
sensitized solar cells is ongoing and will be reported in due course.
Fig. 5. (a) A perspective view of 6a, with thermal ellipsoids at the 50% probability level.
(b) A view of 6a perpendicular to the core showing the near planar conformation of the
pyrazine ring.
None of the compounds tested exhibited marked cytotoxic ac-
tivity against the T98G cell line, although the pyrrolo[1,2-a:4,5-b]
dipyrazine (6a) and pyrazino[1,2-a]pyrrolo[2,3-b]quinoxaline (6b
and 6c) derived compounds were found to be the most active
compounds. The least active compound, 5a, is the one with the
smallest core aromatic surface area, and consequently might point
to some type of DNA intercalation being important in the cyto-
toxicity of this particular set of compounds.
4. Experimental details
4.1. General experimental
3. Conclusions
Melting points were measured on a Gallenkamp melting point
apparatus and are uncorrected. Elemental analyses were performed
by the Campbell Microanalytical Laboratory at the University of
Otago. Unless otherwise stated, NMR spectra were recorded on
a Varian 600 MHz spectrometer at 23 ꢀC using a 5-mm probe. 1H
The syntheses of six fused heterocyclic compounds 5ae6c have
been accomplished in good yield. Due to steric hindrance caused by
the 3,5-dimethylpyrazole ring, the synthesis of the series of com-
pounds 5aec proceeded via cyclization of the corresponding

W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
9373
NMR spectra recorded in CDCl3 were referenced relative to the
internal standard Me4Si. When required, one-dimensional nuclear
Overhauser effect correlation spectroscopy (1D NOESY), total cor-
relation spectroscopy (TOCSY), rotating frame Overhauser effect
spectroscopy (ROESY), two-dimensional correlation spectroscopy
(2D COSY), 2D NOESY, 2D ROESY, heteronuclear multiple quantum
coherence (HMQC), and heteronuclear multiple bond correlation
(HMBC) experiments were performed using standard pulse se-
quences. Electrospray (ES) mass spectra were recorded using
a Finnigan LCQ mass spectrometer. Infrared spectra were collected
on a PerkineElmer Spectrum 100 using a UATR sampling accessory.
UV/vis absorption spectra were recorded on a Varian Cary 5000 UV/
vis/NIR spectrometer in dichloromethane solutions with concen-
trations of w0.25 mM.
Unless otherwise stated, all chemicals were obtained from
commercial sources and used as received. Tetrahydrofuran was
dried by standard literature procedures and distilled fresh from
sodium/benzophenone, and diisopropylamine was freshly distilled
from potassium hydroxide. 1,4-Dihydro-2,3-quinoxalinedione,50
1,4-dihydro-6,7-dimethyl-2,3-quinoxalinedione,50 2,3-dichloroqu-
inoxaline,51 2,3-dichloro-6,7-dimethylquinoxaline,51 2-((3,5-dime-
thyl-1H-pyrazol-1-yl)methyl)pyridine (7),40 2-iodopyrazine (12),42
and 2-pyrazinecarboxylate methyl ester (13)52 were prepared
according to the methods described in the literature.
organic layer was dried over MgSO4 and the solvent was removed
under reduced pressure.
4.2.3. 2-Chloro-3-[(3,5-dimethyl-1H-pyrazol-1-yl)(pyridin-2-yl)
methyl]pyrazine (9a). 2-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]
pyridine (7) (1.05 g, 5.61 mmol), n-BuLi (2.48 mL, 5.71 mmol) and
2,3-dichloropyrazine (8a) (0.284 mL g, 2.72 mmol) were combined
according to the general procedure. The reaction mixture was
stirred at room temperature for 4 h and then quenched. The sol-
vent was removed under reduced pressure and the dark oil was
left to stand for 24 h, during which time the product crystallized.
The crystals were separated from the oily residue by decanting,
and the remainder of the product was isolated by adding diethyl
ether to the oily mixture and cooling to ꢁ20 ꢀC, which induced
further crystallization of 9a. The crystalline samples were com-
bined and recrystallized from diethyl ether to yield the product as
an off-white crystalline solid (0.62 g, 75%). Mp 147e149 ꢀC; nmax
(neat, cmꢁ1) 1590, 1557, 1439, 1381; 1H NMR (600 MHz/CDCl3):
d
2.18 (s, 3H, CH3), 2.24 (s, 3H, CH3), 5.92 (s, 1H, H40), 7.02 (d, 1H,
J¼7.7 Hz, H300), 7.05 (s, 1H, CH), 7.24 (dd, 1H, J¼4.8, 7.7 Hz, H500),
7.70 (t, 1H, J¼7.7 Hz, H400), 8.31 (d, 1H, J¼2.5 Hz, H5/H6), 8.44 (d,
1H, J¼2.5 Hz, H5/H6), 8.54 (d, 1H, J¼4.8 Hz, H600); 13C NMR
(151 MHz/CDCl3):
d 11.3, 13.7, 65.2, 106.0, 122.8, 123.0, 137.1, 140.6,
141.9, 142.7, 148.8, 148.9, 149.4, 152.3, 157.6; m/z 264.0 (MHþ)
(cyclizes); Found: C 60.1, H 4.7, N 23.5, C15H14ClN5 requires: C 60.1,
H 4.7, N 23.4%.
4.2. Synthesis
4.2.4. 5-(3,5-Dimethyl-1H-pyrazol-1-yl)pyrazino[2,3-b]indolizine
(5a). 2-Chloro-3-((3,5-dimethyl-1H-pyrazol-1-yl)(pyridin-2-yl)
methyl)pyrazine (0.132 g, 0.440 mmol) was dissolved in acetoni-
trile (9 mL) and TFA (0.5 mL) in a sealed vessel and reacted in a CEM
Discover S microwave reactor at 145 ꢀC for 1.5 h with stirring. The
microwave settings were 150 W, with a maximum pressure of
250 psi. During the course of the reaction the pressure was stable at
around 50 psi. The resulting dark red mixture was neutralized with
saturated aqueous NaHCO3 solution and extracted with dichloro-
methane (4ꢂ15 mL). The solvent was dried over MgSO4 and re-
moved under reduced pressure. The red solid obtained was
recrystallized from diethyl ether to yield 5a as a bright red fluffy
solid (0.09 g, 77%) mp: 134e136 ꢀC; nmax (neat, cmꢁ1) 2914, 1633,
4.2.1. Di-2-pyrazinylmethane (10). A solution of 2-methylpyrazine
(2.31 mL, 25.2 mmol) in THF (50 mL) was added dropwise to
freshly prepared LDA (26.0 mmol) in THF (15 mL) at ꢁ78 ꢀC under
an atmosphere of argon. The resulting dark red solution was stirred
for 1 h at ꢁ78 ꢀC, then cooled to ꢁ95 ꢀC. 2-Chloropyrazine (1.00 mL,
11.4 mmol) in THF (50 mL) was cooled to ꢁ78 ꢀC and transferred via
cannula to the solution of the anion. Once the addition was com-
plete the dark mixture was stirred at ꢁ95 ꢀC for 5 min, then the
cooling was removed and the reaction vessel was allowed to warm
to room temperature, during which a color change to deep purple
was observed. After stirring for 15 min, water (50 mL) was added
and the mixture was stirred for a period of 2 h during which a color
change to dark brown was observed. The mixture was concentrated
under reduced pressure, and repeatedly extracted with dichloro-
methane (5ꢂ50 mL) until the extracts were almost colorless. The
organic extracts were combined and dried over MgSO4 and the
solvent was evaporated under reduced pressure. The dark residue
was twice extracted by adding hexane to the residue and refluxing
for a period of 1.5 h. The extracts were combined and evaporated
under reduced pressure, yielding a yellow crystalline solid, which
was sublimed under reduced pressure at 110e120 ꢀC (bath tem-
perature) to afford 10 as a pale yellow crystalline solid. (0.49 g,
25%), mp: 61e63 ꢀC; nmax (neat, cmꢁ1) 3010, 1579, 1520, 1479, 1405;
1578, 1558, 1487; 1H NMR (600 MHz/CDCl3)
d 2.22 (s, 3H, Me), 2.34
(s, 3H, Me), 6.08 (s, 1H, H40), 6.77 (t, 1H, J¼6.8 Hz, H2), 7.22 (dd, 1H,
J¼6.8, 9.3 Hz, H3), 7.52 (d, 1H, J¼9.3 Hz, H4), 8.37 (d, 1H, J¼2.4 Hz,
H8), 8.75 (d, 1H, J¼2.4 Hz, H7),
d
8.82 (d, 1H, J¼6.8 Hz, H1); 13C NMR
(151 MHz/CDCl3):
d 11.5, 13.8, 103.4, 105.7, 110.4, 116.9, 123.8, 127.5,
132.8, 134.3, 134.8, 135.5, 142.5, 143.2, 149.9; m/z 264.1 (MHþ);
Found: C 68.6, H 4.9, N 26.8, C15H13N5 requires: C 68.4, H 5.0, N
26.6%; lmax/nm: 452 (
/Mꢁ1 cmꢁ1 4010).
3
4.2.5. 5-(3,5-Dimethyl-1H-pyrazol-1-yl)indolizino[3,2-b]quinoxaline
(5b). 2-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]pyridine (7)
1H NMR (300 MHz/CDCl3):
d
8.64 (d, 2H, H3), 8.52 (dd, 2H, J¼2.5 Hz,
(0.459 g, 2.45 mmol), n-BuLi (1.11 mL, 2.50 mmol), and 2,3-
dichloroquinoxaline (8b) (0.238 g, 1.20 mmol) were combined
and reacted as described in the general procedure. The crude re-
action mixture was subject to a standard work-up with dichloro-
methane. The crude solid obtained was suspended in cold hexane,
isolated under reduced pressure, and thoroughly washed with cold
hexane (4ꢂ25 mL), to afford the product 5b as a purple solid
(0.33 g, 89%). Mp: 214e216 ꢀC; nmax (neat, cmꢁ1) 2917, 1636, 1589,
H5), 8.47 (d, 2H, J¼2.5 Hz, H6), 4.39 (s, 2H, CH2); 13C NMR
(75.4 MHz/CDCl3):
d 41.8, 143.1, 144.43, 145.2, 154.0; Found: C 62.8,
H 4.9, N 32.3, C9H8N4 requires: C 62.8, H 4.7, N 32.5%.
4.2.2. General procedure for the synthesis of 5aec and 6aec. n-BuLi
(1.05 equiv) was added dropwise to a solution of the diarylmethane
(1 equiv) in dry THF at ꢁ78 ꢀC under an argon atmosphere. The
solution was stirred for 0.5 h, followed by the dropwise addition of
the electrophile (0.49 equiv) in THF. The reaction mixture was
slowly allowed to warm to room temperature overnight, followed
by heating at reflux (16 h). The reaction mixture was quenched
with H2O (2 mL) and the solvent was removed under reduced
pressure. The residue was taken up into chloroform or dichloro-
methane (3ꢂ50 mL) and washed with water (3ꢂ50 mL). The
1540, 1518, 1485; 1H NMR (600 MHz/CDCl3):
d 2.28 (s, 3H, Me), 2.38
(s, 3H, Me), 6.13 (s, 1H, H40), 6.71 (t, 1H, J¼6.8 Hz, H2), 7.28 (dd, 1H,
J¼9.2, 6.8 Hz, H3), 7.49 (d, 1H, J¼9.2 Hz, H4), 7.71e7.81 (m, 2H, H7/
H10), 8.27 (d, 1H, J¼8.2 Hz, H8/H9), 8.31 (d, 1H, J¼8.2 Hz, H8/H9),
8.94 (d, 1H, J¼6.8 Hz, H1); 13C NMR (151 MHz/CDCl3):
d 11.6, 13.7,
101.9, 105.8, 109.5, 116.8, 125.2, 127.1, 128.6, 128.7, 128.9, 130.4,
134.6, 136.0, 137.1, 140.8, 142.8, 143.3, 149.9; m/z: 314.3 (MHþ);

9374
W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
Found: C 68.8, H 4.8, N 21.5, C19H15N5$H2O requires: 68.85, 5.2,
21.1%; lmax/nm: 527 (
/Mꢁ1 cmꢁ1 4620).
(20 mL), n-BuLi (0.674 mL,1.28 mmol), and 2,3-dichloroquinoxaline
(8b) (0.123 g, 0.618 mmol) in THF (15 mL) and reacted in the
manner described. After stirring at room temperature, the reaction
mixture was warmed to 50 ꢀC for 1 h and then quenched. The
purple reaction mixture was subjected to the standard work-up
(using CHCl3) and yielded a dark solid, which was isolated by fil-
tration and repeatedly washed with diethyl ether until the wash-
ings were clear. This afforded the title compound as a purple solid
(0.11 g, 58%). Sublimes 280e283 ꢀC; nmax (neat, cmꢁ1) 3074, 1577,
3
4.2.6. 5-(3,5-Dimethyl-1H-pyrazol-1-yl)-8,9-dimethylindolizino[2,3-
b]quinoxaline (5c). 2-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]pyri-
dine (7) (0.647 g, 3.46 mmol), n-BuLi (1.50 mL, 3.50 mmol), and 2,3-
dichloro-6,7-dimethylquinoxaline (8c) (0.383 g, 1.69 mmol) were
combined and reacted in the manner described in the general
procedure. The crude reaction mixture was subjected to a standard
work-up with dichloromethane. The solid obtained was suspended
in cold hexane, isolated by filtration, and thoroughly washed with
cold hexane (4ꢂ25 mL) to afford 5c as a purple solid (0.42 g, 73%).
Mp: 201e203 ꢀC; nmax (neat, cmꢁ1) 2910, 1634, 1587, 1536, 1511,
1546, 1521, 1509, 1466; 1H NMR (600 MHz/CDCl3):
d
7.86 (dd, J¼7.4,
7.8 Hz, 1H, H8/H9), 7.91 (dd, J¼7.4, 7.8 Hz, 1H, H8/H9), 7.95 (d,
J¼4.7 Hz, 1H, H1), 8.29 (d, J¼8.4 Hz, 1H, H7/H10), 8.43 (d, J¼8.4 Hz,
1H, H7/H10), 8.48 (s, 1H, H60), 8.67 (s, 1H, H50), 8.76 (d, J¼4.7 Hz, 1H,
1488; 1H NMR (600 MHz/CDCl3):
d
2.28 (s, 3H, Me0), 2.35 (s, 3H,
H2), 10.48 (s, 1H, H30), 10.50 (s, 1H, H4); 13C NMR (151 MHz/
d
Me0), 2.53 (s, 3H, Me), 2.55 (s, 3H, Me), 6.10 (s, 1H, H40), 6.67 (t, 1H,
J¼6.8 Hz, H2), 7.22 (dd, 1H, J¼9.3, 6.8 Hz, H3), 7.45 (d, 1H, J¼9.3 Hz,
H4), 7.98 (s, 1H, H7/H10), 8.04 (s, 1H, H7/H8), 8.88 (d, 1H, J¼6.8 Hz,
CDCl3): 101.1, 116.8, 127.2, 128.9, 129.0, 129.5, 129.7, 134.6, 135.4,
138.2, 138.5, 141.1, 143.7, 144.0, 144.5, 149.5, 149.6; m/z: 298.9
(MHþ); Found: C 67.9, H 3.4, N 28.4. C17H10N6 requires: C 68.4, H 3.4,
H1); 13C NMR (151 MHz/CDCl3):
d
11.6, 13.8, 20.3, 20.4, 102.1, 105.7,
N 28.2%; lmax/nm: 536, 570 (
/Mꢁ1 cmꢁ1 4760, 4200).
3
109.1,116.7,125.0, 127.4, 127.9, 129.5, 134.2,135.5,136.2,137.8, 139.2,
139.6, 142.4, 142.6, 149.7; m/z: 342.2 (MHþ); Found: C 73.0, H 5.8, N
20.1. C21H19N5$¼H2O requires: C 72.9, H 5.7, N 20.25%; lmax/nm:
4.2.10. 8,9-Dimethyl-5-(pyrazin-2-yl)-pyrazino[1,2-a]pyrrolo[2,3-b]
quinoxaline (6c). Di-2-pyrazinylmethane (10) (0.224 g, 1.30 mmol)
inTHF (20 mL), n-BuLi (0.576 mL,1.32 mmol), and 6,7-dimethyl-2,3-
dichloroquinoxaline (8c) (0.140 g, 0.616 mmol) in THF (15 mL) were
combined and reacted in the manner described. The purple reaction
mixture was worked-up as described in the general procedure,
yielding a dark solid, which was isolated by filtration and repeatedly
washed with diethyl ether until the washings were clear. This
afforded the title compound as a purple solid (0.14 g, 69%). Sublimes
278e280 ꢀC; nmax (neat, cmꢁ1) 2919,1577,1540,1507,1491,1464; 1H
NMR (600 MHz/CDCl3) 2.57 (s, 3H, Me), 2.58 (s, 3H, Me), 7.89 (d, 1H,
J¼4.8 Hz, H1), 7.94 (s, 1H, H7/H10), 8.08 (s, 1H, H7/H10), 8.45 (d, 1H,
J¼2.5 Hz, H60), 8.64 (s, 1H, H50), 8.67 (d, 1H, J¼4.8 Hz, H2), 10.40 (s,
524 (
/Mꢁ1 cmꢁ1 4800).
3
4.2.7. 2-Chloro-3-[(3,5-dimethyl-1H-pyrazol-1-yl)(pyridin-2-yl)
methyl]-6,7-dimethylquinoxaline (9c). 2-[(3,5-Dimethyl-1H-pyr-
azol-1-yl)methyl]pyridine (7) (0.397 g, 2.12 mmol), n-BuLi
(0.962 mL, 2.10 mmol), and 2,3-dichloro-6,7-dimethylquinoxaline
(0.438 g, 1.93 mmol) were combined as described in the general
procedure. The reaction mixture was allowed to stir at ꢁ78 ꢀC for
0.5 h, and then quenched with EtOH (20 mL). The solvent was re-
moved under reduced pressure and the residue was purified by
column chromatography eluting with 9:1 dichloromethane/ethyl
acetate to afford a white solid (0.25 g, 34%). Mp: 176e179 ꢀC; nmax
(neat, cmꢁ1) 1590, 1555, 1474, 1436; 1H NMR (600 MHz/CDCl3):
1H, H30), 10.41 (s, 1H, H4); 13C NMR (151 MHz/CDCl3):
d 20.5, 20.6,
100.9, 116.7, 127.0, 127.4, 128.2, 133.7, 134.9, 137.3, 137.5, 140.0, 140.4,
140.9, 143.1, 143.6, 144.4, 149,4, 149.6; Found: C 66.2, H 4.3, N 24.6.
d
2.15 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.46 (s, 3H,
CH3), 5.93 (s, 1H, H40), 7.13 (d, 1H, J¼7.7 Hz, H300), 7.18 (s, 1H, CH),
7.25 (dd, 1H, J¼4.8, 7.7 Hz, H500), 7.67 (s, 1H, H5/H10), 7.70e7.75 (m,
3H, H400, H5/H10), 8.55 (d, 1H, J¼4.8 Hz, H600); 13C NMR (151 MHz/
C19H14N6$H2O requires:C66.3, H4.3, N24.6; m/z: 327.0 (MHþ);lmax
/
nm: 531, 564 (
/Mꢁ1 cmꢁ1 4680, 3800).
3
CDCl3):
d
11.4, 13.7, 20.1, 20.4, 66.2, 106.1, 122.7, 123.4, 127.0, 128.8,
4.3. Cell line
136.9, 139.4, 140.2, 140.4, 140.6, 141.7, 146.3, 148.5 148.7, 149.9,
157.9; m/z 342.0 (MHþ) (cyclizes); Found: C 66.8, H 5.3, N 18.6.
C21H20ClN5 requires: C 66.7, H 5.4, N 18.5%.
T98G human glioblastoma multiforme cells were purchased
from the ATCC. The cells were maintained as a monolayer in min-
imum essential medium (MEM), supplemented with 10% fetal bo-
vine serum, penicillin (100 units/mL), streptomycin (100 g/mL), and
4.2.8. 5-(Pyrazin-2-yl)-pyrrolo[1,2-a:4,5-b]pyrazine
(6a). Di-2-
pyrazinylmethane (10) (0.244 g, 1.41 mmol) in THF (20 mL), n-
BuLi (0.740 mL, 1.43 mmol), and 2,3-dichloropyrazine (8a)
(0.0730 mL, 0.698 mmol) in THF (20 mL) were combined and
reacted in the manner described. The reaction mixture was stirred
at room temperature for 16 h then heated at reflux for 20 h. The
reaction mixture was quenched with methanol (2 mL). Upon
cooling to room temperature a red precipitate formed. The solvent
was removed under reduced pressure and the crude product was
isolated as described in the general procedure using CHCl3 as the
extracting solvent. The isolated product was recrystallized from
THF to afford the title compound 6a as an orange solid (0.10 g, 58%).
Mp: 262 ꢀC; nmax (neat, cmꢁ1) 3098, 1576, 1542, 1504, 1482, 1467;
L
-glutamine (2.5 mM), at 37 ꢀC in a humidified 5% CO2 atmosphere.
4.4. Cytotoxicity assays
Cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay.49 Cells were
harvested with trypsin (0.1% v/v), and cell pellets were isolated by
centrifugation. Cells were then re-suspended to single cells sus-
pension, cell numbers counted using a Hemocytometer counter
(Weber) and then seeded at a density of 1ꢂ104 cells/well in 96-well
plates, in 100 mL growth medium and allowed to adhere overnight
at 37 ꢀC. Cells were incubated at 37 ꢀC in a humidified atmosphere
of 5% CO2 in the presence of compounds 1aec, 5a, 5b, and 6aec,
and vehicle (control). Serial dilutions (1:2 and 1:10) of compound
solution in cell medium were added to wells in triplicate. Com-
pounds were tested at a concentration range prescribed by the
limits of compound solubility and that produced a sigmoidal cy-
totoxic response. After 72 h of drug exposure, MTT solution in PBS
1H NMR (300 MHz/CDCl3):
d
7.97 (d, J¼4.8 Hz, 1H, H60), 8.47 (d,
J¼2.4 Hz, 1H, H1), 8.59 (d, J¼2.3 Hz, 1H, H8), 8.65e8.68 (m, 2H, H2/
H50), 9.00 (d, J¼2.3 Hz, 1H, H7), 10.18 (d, J¼1.5 Hz, 1H, H4), 10.45 (d,
J¼1.7 Hz, 1H, H30); 13C NMR (151 MHz/CDCl3): 102.7, 115.9, 128.0,
130.6, 134.3, 136.3, 137.9, 141.4, 143.7, 144.4, 144.6, 149.4, 149.4; m/z
249.2 (MHþ); Found: C 61.9, H 3.4, N 33.3. C13H8N6$¼H2O requires:
C 61.8, H 3.4, N 33.3%; lmax/nm: 464 (
3
/Mꢁ1 cmꢁ1 4200).
(20 mL, 0.25% w/v) was added to each well and the incubation
continued for 4 h. Culture medium and excess MTT solution were
removed and the resulting reduced formazan crystals dissolved by
4.2.9. 5-(Pyrazin-2-yl)-pyrazino[1,2-a]pyrrolo[2,3-b]quinoxaline
(6b). Di-2-pyrazinylmethane (10) (0.220 g, 1.27 mmol) in THF
addition of 150 mL DMSO.

W.M. Bloch et al. / Tetrahedron 67 (2011) 9368e9375
9375
2. Browne, W. R.; Hage, R.; Vos, J. G. Coord. Chem. Rev. 2006, 250, 1653e1668.
Cellviability was determined bymeasuring the absorbance of the
purple formazan solution at 600 nm using a Victor3V microplate
reader (PerkineElmer). All readings were corrected for absorbance
from negative control and wells containing medium alone. The level
of purple intensity was expressed relative to the corresponding
control as percent viability. Corresponding IC50 values for each of the
compounds tested were then determined at the dose required to
induce a 50% decrease in cell viability from sigmoidal dos-
eeresponse curves produced in GraphPad Prism 5 (Version 5.04).
Experiments were repeated at least three times for each compound
and all IC50 values are reported with standard errors.
3. D’Alessandro, D. M.; Keene, F. R. Chem. Rev. 2006, 106, 2270e2298.
4. Kaim, W.; Lahari, G. K. Angew. Chem., Int. Ed. 2007, 46, 1778e1796.
5. Keene, F. R. Coord. Chem. Rev. 1997, 166, 121e159.
6. Medlycott, E. A.; Hanan, G. S. Chem. Soc. Rev. 2005, 34, 133e142.
7. Balzani, V.; Juris, A.; Venturi, M.; Campagna, S.; Serroni, S. Chem. Rev. 1996, 96,
759e833.
8. Walter, M. G.; Warren, E. L.; McKone, J. R.; Boettcher, S. W.; Mi, Q.; Santori, E. A.;
Lewis, N. S. Chem. Rev. 2010, 110, 6446e6473.
9. Chen, X.; Shen, S.; Guo, L.; Mao, S. S. Chem. Rev. 2010, 110, 6503e6570.
10. Clifford, J. N.; Martinez-Ferrero, E.; Viterisi, A.; Palomares, E. Chem. Soc. Rev.
2010, 40, 1635e1646.
11. Hagfeldt, A.; Boschloo, G.; Sun, L. C.; Kloo, L.; Pettersson, H. Chem. Rev. 2010, 110,
6595e6663.
12. Youngblood, W. J.; Lee, S. H. A.; Maeda, K.; Mallouk, T. E. Acc. Chem. Res. 2009,
42, 1966e1973.
13. Gratzel, M. Acc. Chem. Res. 2009, 42, 1788e1798.
4.5. Crystallography
14. O’Regan, B. C.; Durrant, J. R. Acc. Chem. Res. 2009, 42, 1799e1808.
15. Imahori, H.; Umeyama, T.; Ito, S. Acc. Chem. Res. 2009, 42, 1809e1818.
16. Armaroli, N.; Balzani, V. Chem.dAsian J. 2011, 6, 768e784.
17. Eisenberg, R.; Nocera, D. G. Inorg. Chem. 2005, 44, 6799e6801.
18. D’Alessandro, D. M.; Keene, F. R. Chem. Soc. Rev. 2006, 35, 424e440.
19. D’Alessandro, D. M.; Keene, F. R. Chem. Phys. 2006, 324, 8e25.
20. Steel, P. J. Coord. Chem. Rev. 1990, 106, 227e265.
21. Constable, E. C.; Steel, P. J. Coord. Chem. Rev. 1989, 93, 205e223.
22. Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553e3590.
23. Constable, E. C. Adv. Inorg. Chem. 1989, 34, 1e33.
24. D’Alessandro, D. M.; Keene, F. R.; Steel, P. J.; Sumby, C. J. Aust. J. Chem. 2003, 56,
657e664.
25. Steel, P. J.; Sumby, C. J. Chem. Commun. 2002, 322e323.
26. Sumby, C. J. Coord. Chem. Rev. 2011, 255, 1937e1967.
27. Sumby, C. J. Aust. J. Chem. 2008, 61, 894e904.
Crystals were mounted under paratone-N oil on a plastic loop.
X-ray diffraction data were collected with (i) Mo K
a
radiation
¼0.7107 A) using an Oxford Diffraction X-calibur single crystal
X-ray diffractometer at 150(2) K (structures 9a, 9c, and 6b), or (ii)
ꢀ
(l
ꢀ
synchrotron radiation (
l
¼0.7107 A) at 150(2) K using the Protein
Micro-crystal and Small Molecule X-ray Diffraction beam line (MX2)
at the Australian Synchrotron (structures of 5b, and 6a).53 Data sets
were corrected for absorption using a multi-scan method, and
structures were solved by direct methods using SHELXS-9754 and
refined by full-matrix least squares on F2 by SHELXL-97,55 interfaced
through the program X-Seed.56 In general, all non-hydrogen atoms
were refined anisotropically and hydrogen atoms were included as
invariants at geometrically estimated positions, unless specified
otherwise in additional details below. Figures were produced using
the program POV-Ray,57 interfaced through the program X-Seed.
Publication materials were prepared using the program CIFTAB.58
Details of data collections and structure refinements are given be-
low. CCDC 818294e818298 contain the supplementary crystallo-
graphic data for this structure. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. A summary of the crystallo-
graphic data and structure refinements are given in Table 2.
28. Pratt, E. F.; Keresztesy, J. C., Jr. J. Org. Chem. 1967, 32, 49e53.
29. Volovenko, Y. M.; Dubinina, G. G. Chem. Heterocycl. Compd. 2000, 35,
1089e1093.
30. Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109,
3080e3098.
31. Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G. Tetrahedron
1994, 50, 3987e3992.
32. Anderson, R. J.; Hill, J. B.; Morris, J. C. J. Org. Chem. 2005, 70, 6204e6212.
33. Anderson, R. J.; Morris, J. C. Tetrahedron Lett. 2001, 42, 8697e8699.
34. Molina, P.; Fresneda, P. M.; Delgado, S. J. Org. Chem. 2003, 68, 489e499.
35. Molina, P.; Fresneda, P. M.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2002, 43,
1005e1007.
36. Ahaidar, A.; Fernandez, D.; Danelon, G.; Cuevas, C.; Manzanares, I.; Albericio, F.;
Joule, J. A.; Alvarez, M. J. Org. Chem. 2003, 68, 10020e10029.
37. Ahaidar, A.; Fernandez, D.; Perez, O.; Danelon, G.; Cuevas, C.; Manzanares, I.;
Albericio, F.; Joule, J. A.; Alvarez, M. Tetrahedron Lett. 2003, 44, 6191e6194.
38. Baeza, A.; Mendiola, J.; Burgos, C.; Alvarez-Builla, J.; Vaquero, J. J. Tetrahedron
Lett. 2008, 49, 4073e4077.
Acknowledgements
39. Baeza, A.; Mendiola, J.; Burgos, C.; Alvarez-Builla, J.; Vaquero, J. J. Eur. J. Org.
Chem. 2010, 29, 5607e5618.
C.J.S. thanks the Australian Research Council for an Australian
Post-Doctoral Fellowship (DP0773011) and a Future Fellowship
(FT0991910). L.M.R. wishes to thank the National Breast Cancer
Foundation of Australia and the Australian Research Council for
funding. J.C.M. thanks the Australian Research Council for funding
(DP0770653). The Australian Synchrotron is thanked for funding
travel and access to the MX1 and MX2 beam lines (AS091and
AS092). The views expressed herein are those of the authors and
are not necessarily those of the owner or operator of the Australian
Synchrotron.
40. House, D. A.; Steel, P. J.; Watson, A. A. Aust. J. Chem. 1986, 39, 1525e1536.
41. Wan, C.; Mak, T. C. W. Inorg. Chim. Acta 2008, 361, 1496e1502.
42. Ple, N.; Turck, A.; Heynderickx, A.; Queguiner, G. Tetrahedron 1998, 54,
9701eˇ 9710.
ꢁ
ꢁ
43. Lepretre, A.; Turck, A.; Ple, N.; Knochel, P.; Queguiner, G. Tetrahedron 2000, 56,
265e273.
44. Dyker, G.; Muth, O. Eur. J. Org. Chem. 2004, 4319e4322.
45. Houminer, Y.; Sanders, E. B. J. Heterocycl. Chem. 1980, 17, 647e649.
46. Rizzi, G. P. J. Org. Chem. 1968, 33, 1333e1337.
47. Turck, A. Tetrahedron 2001, 57, 4489e4505.
48. Haroutounian, S. A.; Katzenellenbogen, J. A. Tetrahedron 1995, 51, 1585e1598.
49. Mosmann, T. J. Immunol. Methods 1983, 65, 55e63.
50. Oxtoby, N. S.; Blake, A. J.; Champness, N. R.; Wilson, C. Chem.dEur. J. 2005, 11,
4643e4654.
51. Phillips, M. A. J. Chem. Soc. 1928, 2393e2399.
52. Ligiero, C. B. P.; Visentin, L. C.; Giacomini, R.; Filgueiras, C. A. L.; Miranda, P. C.
Supplementary data
M. L. Tetrahedron Lett. 2009, 50, 4030e4032.
Electronic Supplementary data (ESD) available: 1H and 13C NMR
spectra for all new compounds, crystallographic information files
for 9a, 9c, 5b, 6a, and 6b. The following are the Supplementary data
related to this article: doi:10.1016/j.tet.2011.09.133.
53. McPhillips, T. M.; McPhillips, S. E.; Chiu, H. J.; Cohen, A. E.; Deacon, A. M.; Ellis,
P. J.; Garman, E.; Gonzalez, A.; Sauter, N. K.; Phizackerley, R. P.; Soltis, S. M.;
Kuhn, P. J. Synchrotron Radiat. 2002, 9, 401e406.
54. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467e473.
55. Sheldrick, G. M. SHELXL-97; University of Gottingen: Gottingen, Germany,
€
€
1997.
56. Barbour, L. J. J. Supramol. Chem. 2001, 1, 189e191.
57. Persistence of Vision Raytracer Pty. Ltd, POV-Ray, Williamstown, Australia,
2003e2008.
References and notes
€
€
58. Sheldrick, G. M. CIFTAB; University of Gottingen: Gottingen, Germany, 1997.
1. Vos, J. G.; Kelly, J. M. Dalton Trans. 2006, 4869e4883.