An integrated flow and microwave approach to a broad spectrum protein kinase inhibitor

Article abstract of DOI:10.1039/c5ra09426g

The protein kinase inhibitor CTx-0152960 (6, 2-((5-chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), and the piperazinyl analogue, CTx-0294885 (7, 2-((5-chloro-2-((4-piperazin-1-ylphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), were prepared using a hybrid flow and microwave approach. The use of flow chemistry approaches avoided the need for Boc-protection of piperidine in the key S_NAr coupling with 1-fluoro-4-nitrobenzene. Microwave coupling of 4-morphilinoaniline 8 and 4-(piperazine-1-yl)aniline 9 with 2-(2,5-dichloropyrimidine-4-ylamino)-N-methylbenzamide 10, proved to be the most efficacious route to the target analogues 6 and 7. This hybrid methodology reduced the number of synthetic steps, gave enhanced overall yields and increased atom economy through step reduction and minimal requirement for chromatographic purification, relative to the original batch synthesis approach.

Full text of DOI:10.1039/c5ra09426g

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Journal Name
RSCPublishing
ARTICLE
An integrated flow and microwave approach to a
broad spectrum protein kinase inhibitor
Cite this: DOI: 10.1039/x0xx00000x
Cecilia Russell,a Andrew J. S. Lin,a Peter Hains,b Michela I. Simone,a Phillip J.
Robinsonb and Adam McCluskeya*
Received 00th January 2012,
Accepted 00th January 2012
The
morpholinophenyl)amino)pyrimidinꢀ4ꢀyl)amino)ꢀ
analogue, CTxꢀ0294885 2ꢀ((5ꢀchloroꢀ2ꢀ((4ꢀpiperazinꢀ1ꢀyl)phenyl)amino)pyrimidinꢀ4ꢀ
yl)amino)ꢀ ꢀmethylbenzamide), were prepared using a hybrid flow and microwave approach.
protein
kinase
inhibitor,
CTxꢀ0152960
(
6
,
2ꢀ((5ꢀchloroꢀ2ꢀ((4ꢀ
N
ꢀmethylbenzamide), and the piperazinyl
DOI: 10.1039/x0xx00000x
(7,
N
www.rsc.org/
The use of flow chemistry approaches avoided the need for Bocꢀprotection of piperidine in the
key SNAr coupling with 1ꢀfluoroꢀ4ꢀnitrobenzene. Microwave coupling of 4ꢀmorphilinoaniline
8
and
4ꢀ(piperazineꢀ1ꢀyl)aniline
9
with
2ꢀ(2,5ꢀdichloropyrimidineꢀ4ꢀylamino)ꢀ
Nꢀ
methylbenzamide 10, proved to be the most efficacious route to the target analogues
6
and 7.
This hybrid methodology reduced the number of synthetic steps, gave enhanced overall yields
increased atom economy through step reduction and minimal requirement for chromatographic
purification, relative to the original batch synthesis approach.
Figure 1. Chemical structures of selected clinically used PKI-based drugs:
Imatinib (
Introduction
1
), Gefitinib (
2
), Vemurafenib (
3
), Ruxolitinib (
4
) and the chemical
structure of the protein kinases inhibitor, staurosporine (
clinical approval or initial literature report.
5) and their year of
Protein kinase inhibitors (PKIs) are currently one of the most
important classes of anticancer drugs. Globally there continues
to be a major drive towards the development of more selective
and potent PKIꢀbased drugs for the treatment of an expanding
range of diseases.1ꢀ5 Imatinib was the first clinically approved
PKI in 2001, with 14ꢀPKI based drugs approved for the
While there are a number of selective inhibitors, the
chemical biology of protein kinases has benefited greatly from
the discovery and subsequent use of the broad spectrum
inhibitor staurosporine (
staurosporine, are of particular importance as chemical
proteomics Recently 2ꢀ(5ꢀchloroꢀ2ꢀ(4ꢀ
tools.8ꢀ16
morpholinophenylamino)ꢀpyrimidinꢀ4ꢀylamino)ꢀ
methylbenzamide, CTxꢀ0152960 ( ), was reported as a new
5
).7 Broad spectrum PKIs such as
treatment of cancer over the next decade, e.g. Gefitinib (2,
2002), Vemurafenib (
1).6
3, 2011) and Ruxolitinib (4 2011) (Figure
Nꢀ
6
member of the broad spectrum PKI family and developed as a
Sepharoseꢀsupported kinase capture reagent in the identification
of 235 protein kinases from a digest of human breast
adenocarcinoma, MDAꢀMBꢀ231, cells (Figure 2,
0294885).17,18
7, CTxꢀ
Figure 2. 2-(5-Chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N-
methylbenzamide and 2-(5-chloro-2-(4-(piperazine-1-
yl)phenylamino)pyrimidin-4-ylamino)-N-methylbenzamide ( ).
(6)
7
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DOI: 10.1039/C5RA09426G
Given the importance of the PKI families of compounds furnish a mixture of monoꢀ and diꢀ adduct in keeping with our
they have attracted considerable attention from the synthetic earlier efforts to monoꢀprotect piperazine (ESI†).
community, more recently in the application of flow chemistry
Flow hydrogenation of 14’s nitro moiety was effected
approaches.19,20 As part of an onꢀgoing program we were cleanly as a 0.05 M MeOH solution using 10%ꢀPd/C at 50 °C
interested in gaining access to these probes and the parent and 50 bar H2 at 1 mL.minꢀ1 to give quantitative conversion to
inhibitor compound to conduct competition based kinomics aniline
experiments.8,12,21 The synthesis of was detailed by CatCart®).22,25,34,35 This sequence, commencing with
and
Zhang,17,18 but as we desired access to both compounds we morpholine 11 gave the corresponding morpholino analogues
viewed this as an opportunity to investigate the introduction of 13 and in excellent yields (76 and 87%, respectively) and
9
(Scheme 1; ThalesNano HꢀCubePro®; 70 mm
6
7
8
potential efficiencies in the synthesis of both compounds via a purity (>98%) (ESI†).
combination of flow and microwave chemistry approaches.22ꢀ29
Results and discussion
On examination of
10 as key intermediates (Figure 2). Access to piperazine
6
and
7
, we identified fragments
8
/
9
9
and
, on
Scheme 1. Reagents and Conditions: (i) Vapourtec R2+ 80 ºC, 4M 11 or 12 in
DMF, 2M 1-fluoro-4-nitrobenzene in DMF, 8 bar, 5 mL.min-1; (ii) ThalesNano H-
CubePro®, 0.05 M 13 or 14 in MeOH, 10% Pd-C CatCart® (70 mm), 50 bar, 50 °C,
1.0 mL.min-1.
coupling to 10, would facilitate direct conjugation to a solid
support such as Sepharose,17 while the use of morpholine
8
would allow access to
required protocols.
6. We thus set about developing the
Synthesis of the pyrimidine fragment 10, commenced with
the treatment of isatoic anhydride 15 with 40% (w/w) aq.
MeNH2 at 0.5 mL.minꢀ1 at 0 °C (Syrris FRXꢀ100) to give,
Nꢀ
methylamidoaniline 16 in 79% yield (Scheme 3). The yield
was identical to that obtained in the corresponding batch
process. Access to pyrimidine 10 was effected by an SNAr
coupling with 2,3,5ꢀtrichloropyrimidine at 100 ºC and 0.25
mL.minꢀ1 (Vapourtec R2+). Pyrimidine 10 was isolated by
simple filtration in 71% yield and >95% purity after
concentration of the reaction stream, whereas the batch
approach required longer reaction times (ESI†).17
Figure 2. Identification of two key fragments for the synthesis of
anilines and , and the pyrimidine 10
6 and 7, the
8
9
.
Our initial investigations centred on the use of monoꢀboc
piperazine. While commercially available, we were also
interested in accessing an approach applicable across a myriad
of diamine substrates. Despite the apparent simplicity of the
synthesis, current batch approaches to monoꢀboc piperazine via
Boc2O and tertꢀbutyl azido formate, typically afford a 4:1 ratio
of monoꢀ and diꢀ Boc piperazine.30,31 This was further
confounded by the explosive nature of tertꢀbutyl azido
Scheme 2. Reagents and conditions. (i) Syrris FRX-100: 40% w/w aq. MeNH2, 0.5
ꢀ 19 °C, 19 h; (ii) Vapourtec R2+: 2,3,,5-trichloropyrimidine, iPr2NEt,
mL.min-1, 0
iPrOH, 4 bar, 100 °C.
With fragments 8/9 and 10 in hand, we next examined the
coupling to access
6 and 7. All flow chemistry approaches
failed to afford a satisfactory outcome with considerable
reagent degradation observed at the temperatures and residence
times required to effect an acceptable level of coupling.
formate.32
Despite considerable optimisation, the flow
selective monoꢀboc protection was unsuccessful, and in keeping
with a recent report by Jong and Bradley, our optimal outcome
was a 88:12 ratio.33 Despite this, we were able to carry the diꢀ
bocꢀpiperazine through all subsequent synthetic steps with no
major complications (ESI†).
However, microwave assisted coupling of
9 and 10 provided 7
in a 47% yield, as a mixture of benzamide rotamers.36 An
identical microwave assisted coupling of
51% yield (Scheme 3).
8 and 10 gave 6 in
Reꢀevaluation of our flow strategy saw omission of the
protecting group step and investigation of the direct SNAr
coupling of piperazine 12 with 1ꢀfluoroꢀ4ꢀnitrobenzene.
Optimisation of the flow SNAr coupling of 12 with 1ꢀfluoroꢀ4ꢀ
nitrobenzene at 80 ºC and 5 mL.minꢀ1 (Vapourtec R2+), using 5
equivalents of 12 gave exclusively 1ꢀ(4ꢀnitrophenyl)piperazine
14 in a 95% yield (Scheme 1). The equivalent batch approaches
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA09426G
4-(4-Nitrophenyl)morpholine (13)
A stream of morpholine (11) (0.436 g, 5.0 mmol) in DMF
(100 mL) and another stream of 4ꢀfluoronitrobenzene (0.352 g,
2.5 mmol) in DMF (100 mL) was passed through a Vapourtec
R2+ reaction system at 0.5 mL.minꢀ1. The instrument was fitted
with two 10 mL PFA coils, maintained at 120 °C and 8 bar of
pressure. The resulting product stream was taken up in DCM
(200 mL) and washed with water (2 × 100 mL) and saturated
NaCl (1 × 100 mL). The organic layer was then dried (MgSO4)
and concentrated in vacuo to give a yellow solid (0.396 g, 76%
yield).
1H NMR (CDCl3, 400 MHz): δ 8.13 (2H, d,
6.82 (2H, d, = 9.3 Hz), 3.61 (4H, m), 3.42 (4H, m), 1.49 (9H,
J = 9.3 Hz),
Scheme 3. Reagents and conditions. (i) n-BuOH, 4M HCl in dioxane (cat), 150 °C,
W 20 minutes
J
ꢀ
s); 13C NMR (CDCl3, 101 MHz): δ 154.6, 154.6, 138.8, 126.0
(2C), 112.9 (2C), 80.4, 46.9 (2C), 43.9ꢀ42.1 (bs, 2C), 28.4 (3C);
Mass spectrum (ESI, +ve) 308 m/z [(M + H)+, 20%], 252
(100), 208 (7), 146 (7), 100 (13); FTIR νmax (cmꢀ1): 3007, 2970,
2865, 167, 1585, 1485, 1417, 1367, 1318, 1238, 1162, 1112,
1040, 1081, 1001, 919, 830, 774, 754, 714, 691, 666, 640, 538,
500.
Conclusions
The synthesis of 13 and 14 were readily accomplished
through flow SNAr reaction either morpholine 11 or piperazine
12 with 1ꢀflouroꢀ4ꢀnitrobenzene, the subsequent aryl nitro
functionality of 13 and 14 were reduced to the corresponding
anilines
8 and 9, via flow hydrogenation. No protection of the
1-(4-Nitrophenyl)piperazine (14)
piperazine moiety was required under these conditions. This
allowed a reduction in the number of chemical steps, and thus
an increase in atom economy overall. The coupling of 8/9 with
10 under flow conditions failed, but was smoothly affected
under microwave irradiation.
A stream of piperazine (12, 1.05 g, 12.1 mmol), in DMF (50
mL) solution and another stream of 4ꢀfluoronitrobenzene (0.375
g, 2.65 mmol) in DMF (25 mL) was passed through a
Vapourtec R2+ reaction system at 0.5 mL.minꢀ1. The
instrument was fitted with two 10 mL PFA coils, maintained at
100 °C and 8 bar of pressure. The resulting product stream was
diluted with water (50 mL), extracted with DCM (3 × 20 mL),
washed with water (3 × 40 mL) and brine (1× 40 mL), dried
(MgSO4), filtered and then concentrated under reduced pressure
to give a yellow solid (0.521 g, yield 95%), m.p. 118ꢀ122 °C.
GCMS analysis of the crude reaction material revealed greater
than 95% of the desired compound.
Our hybrid flow and microwave assisted route provided
rapid and scalable access to CTxꢀ0152960 (
0294885 ( ) in a five step process in overall yields of 19 and
25%, requiring essentially filtration through a short silica gel
6) and CTxꢀ
7
plug with minimal chromatographic requirement.
This
compares favourably against the initial synthesis of
yield, with multiple chromatographic requirements.17
7
in 6.5%
1H NMR (600 MHz, DMSOꢀd6) δ 8.04 (1H, d,
7.00 (2H, d,
= 8.1 Hz), 3.37 (4H, s),. 13C NMR (101 MHz,
J = 8.4 Hz),
A
CKNOWLEDGEMENTS
J
Financial support was received from the Australian
DMSOꢀd6) δ 155.1, 136.6, 125.7, 112.4, 47.3, 45.1. Mass
spectrum (ESI, +ve) 179 m/z [(M + H)+, 100%] FTIR νmax
(cmꢀ1): 3334, 2948, 2838, 1580, 1480, 1309, 1244, 1100, 834,
753, 696, 665, 599.
Research Council (ARCDP 14101565), the Australian Cancer
Research Foundation and the Ramaciotti Foundation.
Experimental
All reagents were purchased from SigmaꢀAldrich, Matrix
Scientific or Lancaster Synthesis and were used without
purification. With the exception of THF (anhydrous > 99%)
obtained from SigmaꢀAldrich, all solvents were reꢀdistilled
from glass prior to use.
1H and 13C NMR spectra were recorded on a Brüker
Avance™ AMX 400 MHz spectrometer at 400 and 101 MHz,
4-Morphilinoaniline (8)
A solution of 4ꢀ(4ꢀnitrophenyl)morpholine (13) (0.475 g, 2.28
mmol) and DMSO (3 mL) in methanol (100 mL) was pumped
through a ThalesNano HꢀCube® fitted with a 70 mm 10% Pd/C
CatCart® at 1 mL.minꢀ1. The resulting product stream was
concentrated under reduced pressure to afford a yellow oil that
was then diluted with DCM (30 mL), washed with water (3
×
respectively. Chemical shifts (
million (ppm) measured relative to the internal standards, and
coupling constants ( ) are expressed in Hertz (Hz). Mass
spectra were recorded on a Shimadzu LCMS 2010 EV using a
mobile phase of 1:1 acetonitrile:H2O with 0.1% formic acid.
δ) are reported in parts per
30mL), saturated NaCl (30 mL), dried (Mg2SO4), filtered and
then concentrated under reduced pressure to afford a tan solid
(0.350 g, 87% yield). This material was identical, in all
aspects, with an authentic sample and commercially available
from Sigma Aldrich.17,18
J
HPLC analysis was recorded using a Shimadzu 20A with
Grace econosphere C18 5µ 150 x 4.6 mm column, and GCMS
analysis was carried out using a Shimadzu QP 2010 GCMS.
4-(Piperazin-1-yl)aniline (9)
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DOI: 10.1039/C5RA09426G
A solution of 1ꢀ(4ꢀnitrophenyl)piperazine 14 (0.219 g, 1.06 22%], 297 (24), 157 (100); FTIR νmax (cmꢀ1): (cmꢀ1) 3376,
mmol) in methanol (100 mL) was passed through a ThalesNano 2846, 1645, 1585, 1531, 1463, 1416, 1333, 1260, 1191, 1159,
HꢀCube Pro® using 30 mm 10% PdꢀC CatCart® catalyst at 1 1106, 1037, 925, 831, 794, 681, 657, 546, 526, 410.
mL.minꢀ1 at 50 °C and 50 bar of pressure. The resulting reactant
2-((5-Chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-
yl)amino)-N-methylbenzamide (6) – CTx0-0152960
stream was concentrated under reduced pressure to afford a
white solid (0.187 g, 99%) that darkened and decomposed over
time on standing at room temperature. This material was
To a quartz walled Smith tube was charged with 2ꢀ(2,5ꢀ
ꢀmethylbenzamide 10 (476
mg, 1.60 mmol), 4ꢀmorphoaniline ( ) (0.158 g, 0.76 mmol) and
ꢀbutanol (4 mL). The ensuing slurry was crimp capped
deemed pure by 1H NMR spectroscopy and used in the dichloropyrimidinꢀ4ꢀylamino)ꢀ
N
(
)
subsequent step without further purification.
9
1H NMR (600 MHz, CDCl ) δ 6.83 – 6.78 (m, 2H), 6.68 – then
n
3
6.63 (m, 2H), 3.01 (tdd,
J
= 7.8, 4.0, 1.1 Hz, 8H) ; 13C NMR and heated in the microwave (Biotage) at 150 °C for 20 min.
(151 MHz, CDCl3) δ 145.26, 140.25, 118.78, 116.34, 52.42, After cooling to 18 °C, the ensuing reaction mixture was
46.46; Mass spectrum (ESI, +ve) 178 m/z [(M + H)+, 100%], concentrated under reduced vacuum to afford a light greenishꢀ
279 (33), 222 (22); FTIR νmax (cmꢀ1): 3301, 1644, 1633, 1519, brown solid. Subjection of this material to flash
1085.
chromatography
methanol/dichloromethane gradient elution) and concentration
of the relevant fractions (Rf 0.4 in 1:20
(silica,
0:1
ꢁ
1:9
v/v
2-Amino-N-methylbenzamide (16)
=
v/v
To a flask containing isatoic anhydride (15) (1.86 g, methanol/dichloromethane) gave the title compound (0.169 g,
11.4 mmol), at 0 °C, methylamine (10 mL, 144.0 mmol of 40% 51%) as an offꢀwhite coloured solid (slow decomposition from
w/v
aqueous solution) at a rate of 0.25 mL.minꢀ1 using a Syrris 180 °C).
FRXꢀ100. The mixture was warm room temperature and stirred
overnight, diluted with ethyl acetate (100 mL). The aqueous 9.75ꢀ9.74 (m, 2H), 8.16 (1H, s), 7.75ꢀ7.74 (3H, m), 7.13 (1H, t,
layer was extracted with ethyl acetate (3 × 100 mL), and the J = 6 Hz), 6.89 (2H, d, = 8.9 Hz), 6.89 (2H, d, = 6.9 Hz),
= 6
1H NMR (d6ꢀDMSO, 400 MHz): 11.59 (1H, s), 9.22 (1H, s),
J
J
combined organic extracts were washed with water (200 mL), 3.75 – 3.74 (4H, m), 3.06 – 3.04 (4H, m), 2.81 (3H, d,
J
brine (2 × 200 mL), dried (MgSO4) and then concentrated Hz); 13C NMR (d6ꢀDMSO 151 MHz) δ 170.3, 158.5, 155.6,
under reduce pressure to afford the title compound (1.35 g, 153.8, 147.7, 139.2, 133.0, 131.3, 127.4, 122.3, 121.9 (2C),
79%), as an offꢀwhite solid.
1H NMR (CDCl3, 400 MHz): δ 7.29 (1H, dd, J = 9.3, 1.5 Mass spectrum (ESI, +ve) 460 [(M+Na)+, 15%], 462 (8), 438
Hz), 7.19 (1H, ddd, = 8.6, 7.1, 1.5 Hz), 6.67 (1H, ddd,
= 8.1, [(M), 65], 256 (54), 178 (100); FTIR νmax (cmꢀ1) 3374, 2923,
= 8.6, 7.2, 1.5 Hz), 6.10 (1H, bs), 5.49 2854, 1682, 1601, 1562, 1515, 1448, 1416, 1228, 1161, 1081,
= 4.9 Hz); 13C NMR (CDCl3, 101 1048, 1024, 1001, 824, 759, 593, 531.
121.9, 121.5, 116.7 (2C), 104.9, 50.5 (2C), 45.1 (2C), 25.4;
J
J
0.9 Hz), 6.65 (1H, ddd,
(2H, bs), 2.96 (3H, d,
J
J
MHz): δ 170.0, 148.6, 132.2, 127.1, 117.3, 116.6, 116.3, 26.5;
Mass spectrum (EI+) m/z 150 (M); FTIR νmax (cmꢀ1): 3478, 2-((5-Chloro-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-
3424, 3304, 2939, 1616, 1585, 1535, 1488, 1447, 1407, 1305, yl)amino)-N-methylbenzamide (7) – CTx-0294885
1259, 1171, 1158, 1037, 1007, 938, 859, 813, 679, 658, 561,
530, 496, 431.
To a quartz walled Smith tube was charged with 2ꢀ(2,5ꢀ
dichloropyrimidinꢀ4ꢀylamino)ꢀ ꢀmethylbenzamide 10
(0.159 g, 0.54 mmol), 4ꢀ(piperazinꢀ1ꢀyl)aniline ( ) (0.103 g,
0.50 mmol), ꢀbutanol (4 mL) and then HCl solution (4 drops
N
(
)
9
2-(2,5-Dichloropyrimidin-4-ylamino)-N-methylbenzamide (10)
n
A stream of 2ꢀaminoꢀNꢀbenzeneamide (16, 0.94 g, 6.25 of a 4M dioxane solution). The ensuing slurry was crimp
mmol), 2,4,5 trichloropyrimidine (1.26 g, 6.88 mmol), iPr2NEt capped and heated in the microwave (Biotage) at 150 °C for 1
(1.21 g, 9.38 mmol) in isopropanol (200 mL) solution was h. After cooling to 18 °C, the ensuing reaction mixture was
passed through a Vapourtec R2+ reaction system at 0.25 concentrated under reduced vacuum to afford a light white
mL.minꢀ1. The instrument was fitted with two 10 mL PFA coils, solid. Subjection of this material to flash chromatography
maintained at 100 °C and 4 bar of pressure. HPLC analysis of (Grace Reveleris® amino column, 0:1
the product stream, from firstꢀpass, revealed 71% product 10 methanol/dichloromethane gradient elution) and concentration
with regard to 2ꢀaminoꢀNꢀbenzeneamide (15). The volume of of the relevant fractions (Rf 0.4 in 1:9 v/v
ꢁ
1:9
v/v
=
the resulting product stream was reduced in half, via methanol/dichloromethane) gave the title compound as an offꢀ
concentration under reduced pressure, to give a white slurry. white coloured solid (0.102 mg, 47%), slow decomposition
Isolation of the product 10 by vacuum filtration afforded a from 159 °C.
creamy white solid (0.54 g, 62%).
1H NMR (d6ꢀDMSO, 400 MHz): δ 12.12 (1H, s), 8.86 (1H, 8.03 (s, 1H), 7.69 – 7.63 (m, 1H), 7.45 – 7.42 (3H, dd,
m), 8.51 (1H, d, = 6 Hz), 8.46 (1H, bs), 7.80 (1H, dd, J = 7.9, 8.2 Hz), 7.12 (1H, t, = 7.3 Hz), 6.97 (2H, d, = 8.9 Hz), 3.13
1.5 Hz), 7.61 (1H, t, = 7.6 Hz), 7.23 (1H, t, = 7.6 Hz), 2.82 (4H, d, = 5.1 Hz), 3.04 (4H, d,
= 4.9 Hz), 2.94 (s, 3H). 13C
(3H, d,
= 4.5 Hz); 13C NMR (CDCl3, 101 MHz): δ 169.2, NMR (151 MHz, d4ꢀMeOD) δ 170.3, 158.5, 155.6, 153.8,
1H NMR (600 MHz, d4ꢀMeOD) δ 8.71 (1H, d,
J
= 8.3 Hz),
J
= 19.3,
J
J
J
J
J
J
J
J
157.1, 156.7, 155.8, 138.6, 132.3, 128.6, 123.8, 121.8, 121.4, 147.7, 139.2, 133.0, 131.3, 127.4, 122.3, 121.9 (2C), 121.9,
115.4, 26.8; Mass spectrum (ESI, +ve) 298 m/z [(M + H)+, 121.5, 116.7 (2C), 104.9, 50.5 (2C), 45.1 (2C), 25.4; Mass
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA09426G
spectrum (ESI, +ve) m/z 459 [(M+Na)+, 19%], 437 [(M), 100],
439 (33), 304 (19), 256 (38), 219 (20), 178 (100), 156 (95);
FTIR νmax (cmꢀ1): 3254, 1622, 1570, 1514, 1423, 1228, 827,
771, 750.
14
15
K. Godl, J. Wissing, A. Kurtenbach, P. Habenberger, S. Blencke, H.
Gutbrod, K. Salassidis, M. SteinꢀGerlach, A. Missio, M. Cotten and
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Notes and references
a Centre for Chemical Biology, Chemistry, School of Environmental and
Life Science, The University of Newcastle, University Drive, Callaghan,
New South Wales 2308, Australia. Tel: +61 (0)249 216486; Fax: +61
(0)249 215472; Eꢀmail: Adam.McCluskey@newcastle.edu.au
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Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
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