Synthetic studies of the phosphatidylinositol 3-kinase inhibitor LY294002 and related analogues

Article abstract of DOI:10.1071/CH03113

Synthetic methodologies have been developed for the direct and high-yielding preparation of the phosphatidyl-inositol 3-kinase inhibitor LY294002. These methods are readily amenable to the efficient generation of analogues, which will facilitate a detailed investigation of this important family of enzymes.

Full text of DOI:10.1071/CH03113

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 1099–1106
Synthetic Studies of the Phosphatidylinositol 3-Kinase Inhibitor
LY294002 and Related Analogues
Belinda AbbottA and Philip ThompsonB,C
A
Department of Medicine, Monash University, Box Hill Hospital, Box Hill 3128, Australia.
B Kinacia Pty Ltd, Clive Ward Centre, Box Hill Hospital, Box Hill 3128, Australia.
C Author to whom correspondence should be addressed (e-mail: phil.thompson@med.monash.edu.au).
Synthetic methodologies have been developed for the direct and high-yielding preparation of the phosphatidyl-
inositol 3-kinase inhibitor LY294002. These methods are readily amenable to the efficient generation of analogues,
which will facilitate a detailed investigation of this important family of enzymes.
Manuscript received: 30 April 2003.
Final version: 18 July 2003.
O
Introduction
ThesyntheticmorpholinochromoneLY294002, 2-morpholin-
4-yl-8-phenyl-4H-chromen-4-one (1) (Diagram 1), together
with the fungal metabolite wortmannin, has been an impor-
tant pharmacological tool used to delineate the critical role
that phosphatidylinositol 3-kinases (PI3-kinases) play in the
regulation of intracellular-signalling pathways.[1] Despite
the extraordinary amount of biological data that has been
generated using LY294002, there has been only a single, lim-
ited structure–activity study[2] since the original report.[3]
Numerous compounds of the morpholinochromone class
have been described by the Upjohn company as antiplatelet
and antiproliferative agents,[4] yet in spite of the potential
connection between these cellular responses and PI3-kinase
inhibition, direct assessment of the PI3-kinase activity of
these compounds has never been described.
O
N
O
(1)
Diagram 1.
methodology was required which would be suitable for
simultaneous synthesis of multiple analogues to be studied in
high-throughput enzyme inhibition screens. Here we report
synthetic methods that are both concise and readily amenable
to the generation of analogue libraries.
Results and Discussion
Determination of the structure–activity relationship of
morpholinochromones is emerging as an important task,
given that more recent evidence suggests that LY294002 is
not as selective against PI3-kinase as first thought. Inhi-
bition of other enzymes in the concentration range that
is effective against PI3-kinase has also now been shown
to occur.[5] Furthermore, LY294002 has demonstrated only
moderate potency and selectivity against individual isoforms
of PI3-kinase.[1] From the recently solved structure of a
LY294002–Class I PI3-kinase p110γ complex, it has been
determined that LY294002 makes contact with catalytic site
residues that are conserved across all the Class I isoforms;[6]
this may explain the lack of isoform selectivity. As a number
of PI3-kinase isoforms have been shown to have distinct roles
within a cell,[7] isoform selective inhibitors are required to
define the roles of each isoform, and to identify the associated
cellular responses.
The great bulk of syntheses that are used to form 2-
aminochromones have come from two synthetic strategies.
In the preparation of a variety of 2-aminochromones, Roma
et al.[8] utilized thiochromone precursor (3) (Scheme 1a).
Vlahos et al. prepared LY294002 in a similar manner.[3]
Unfortunately, the yields are generally quite poor for this
pathway. However, it allows the 2-amino moiety to be altered
at a late stage in the synthesis. Workers at Upjohn devel-
oped a methodology that utilized phosgeniminium chloride
reagents to prepare a wealth of compounds (Scheme 1b).[9]
They also developed an alternate synthetic route in which
2-aminochromones were prepared under condensation/
dehydration conditions that were analogous to classical
flavone syntheses (Scheme 1c).[10] The preparation of 2-
morpholinochromones in this manner is critically dependent
upon the cyclodehydration step of the salicylacetamide (8)
using trifluoromethanesulfonic anhydride or polyphosphoric
ester under neutral conditions. Prior attempts to achieve this
transformation using acid or base catalysis were unsuccessful
In light of this, we felt that further evaluation of mor-
pholinochromone analogues was warranted. In particular,
© CSIRO 2003
10.1071/CH03113
0004-9425/03/111099

1100
B. Abbott and P. Thompson
O
O
O
(a)
(b)
t
(i) KOBu /CS
2
(ii) NaH/MeI
Morpholine
OH
O
SMe
O
N
O
(2)
(3)
(4)
.
NR
O+
(i) BF OEt
2
3
2
Cl
O
O
ꢀ
Cl
ꢁ
(ii) R N
2
Cl
Cl
H O
2
ꢁ
O
NR
OH
B
F
2
O
F
(2)
(5)
(6)
O
N
(c)
O
O
COOMe
Tf O
LDA/THF
2
N
ꢀ
O
OH
O
O
N
O
O
(7)
(4)
OH
(8)
Scheme 1.
O
N
O
O
O
O
COOMe
OH
LDA/THF
(F CSO ) O
2 2
3
N
ꢀ
O
O
N
OH
R
R
O
R
(9a) R ꢂ Ph
(10a) R ꢂ Ph
(1) R ꢂ Ph
(9b) R ꢂ OSO CF
(10b) R ꢂ OSO CF
(11) R ꢂ OSO CF
2
3
2
3
2
3
(CF SO ) NPh
2 2
(9c) R ꢂ OMe
(10c) R ꢂ OMe
(12) R ꢂ OMe
(13) R ꢂ OH
3
AlCl /NaI
3
Scheme 2.
owing to the preferential elimination of the morpholinyl
group.
moiety was varied. In particular, we targeted the trifluoro-
methanesulfonate (11) as a key intermediate. The precursor,
methyl2-hydroxy-3-{[(trifluoromethyl)sulfonyl]oxy}benzo-
ate (9b), was prepared from 2,3-dihydroxybenzoic acid.
Condensation of ester (9b) with the LDA-generated anion
of 4-acetylmorpholine then afforded salicylacetamide (10b),
which underwent cyclodehydration to yield the desired
product (11). In an alternative pathway, 8-methoxy-2-
morpholin-4-yl-4H-chromen-4-one (12) was prepared from
methyl 3-methoxysalicylate (9c) in the same manner, and
was then demethylated with AlCl3/NaI (a competing ring
opening of the morpholinyl group was observed when
this reaction was performed using boron tribromide) to
give the corresponding phenol (13).[11] Formation of the
trifluoromethanesulfonate (11) was then achieved using
N-phenyltrifluoromethanesulfonimide.
The mild conditions required and the excellent yields
obtained for this condensation/dehydration synthetic route
seemed suitable for our own planned studies. Indeed, we
subsequently applied this methodology to the direct and high-
yielding preparation of LY294002 by two alternate methods,
and then to the efficient preparation of an array of LY294002
analogues.
In the most direct synthesis of LY294002, the methyl
ester of the commercially available 3-phenylsalicylic acid
(9a) was condensed with the lithium diisopropylamide
(LDA)-generated anion of 4-acetylmorpholine to yield
salicylacetamide (10a) (Scheme 2). While this intermediate
was contaminated with a small amount of unreacted
4-acetylmorpholine, subsequent cyclodehydration with tri-
fluoromethanesulfonic anhydride produced LY294002 (1) in
goodyield. Compound(1)wasindistinguishablebythin-layer
chromatography, high-performance liquid chromatography,
and 1H NMR spectroscopy to the commercial material
(Calbiochem). This method was well suited to the synthesis
of LY294002 in multigram quantities.
The key trifluoromethanesulfonate intermediate (11) was
then subjected to Suzuki coupling reactions with arylboronic
acids under a variety of conditions to afford LY294002 (1)
and various analogues (14)–(18) in yields ranging from 10
to 70%. The different arylboronic acids used to prepare the
LY294002 analogues are recorded in Table 1.
However, our preference was to use methods that were
amenable to the synthesis of analogues in which the aryl
Inanextensionofthisstrategy, the2-morpholinochromone
was also transformed into a boronate partner for the Suzuki

Synthetic Studies of Kinase Inhibitor LY294002 and Related Analogues
1101
Table 1. Preparation of LY294002 analogues from trifluoromethanesulfonate (11)
Compound Arylboronic acid
Suzuki coupling conditions
Yield [%]
(1)
Phenylboronic acid
[Pd(OAc)2], K2CO3, BuN+Br− water, 70◦C, 4 h[12]
12
59
47
63
68
37
(14)
(15)
(16)
(17)
(18)
2-(Trifluoromethyl)phenylboronic acid [Pd(PPh3)4], Na2CO3(aq), toluene, 90◦C, 20 h[13]
o-Tolylboronic acid
[Pd(PPh3)4], Na2CO3(aq), toluene, 90◦C, 20 h[13]
[Pd(PPh3)4], Na2CO3(aq), toluene, 90◦C, 20 h[13]
[Pd(OAc)2], K2CO3, CH3CN, 80◦C, 20 h[12]
[Pd(OAc)2], K2CO3, CH3CN, 80◦C, 20 h[12]
2-Chlorophenylboronic acid
4-Fluorophenylboronic acid
4-Phenoxyphenylboronic acid
O
O
O
O
Bis(pinacolato)diboron
2-Bromoanisole
[PdCl (dppf)]
K PO , [PdCl (dppf)]
2
3
4
2
N
O
N
O
N
O
B
O
H CO
3
O
OSO CF
2
3
O
O
(11)
(19)
(20)
Scheme 3.
O
O
R
R
Et
Et
Et
O
Br
Ac O/H SO
AlCl
Br
2
2
2
2
4
3
OH
OH
OH
OH
O
Br
Br
Br
(24a) R = Me
(25a) R = Et
(21)
(22)
(23)
(24b) R = OMe
(25b) R = Me
(25c) R = OMe
LiHMDS,
4-Morpholinecarbonyl
chloride
O
O
O
O
O
R
R
R
C H B(OH)
(F CSO ) O
2 2
N
6
5
2
3
O
N
O
N
OH
Ph
O
Br
O
Br
(28) R = Et
(29) R = Me
(27a) R = Et
(26a) R = Et
(27b) R = Me
(27c) R = OMe
(26b) R = Me
(26c) R = OMe
(30) R = OMe
Scheme 4.
coupling reaction (Scheme 3).Although this requires an addi-
tional reaction step, it expands the breadth of the LY294002
analogues accessible because of the broad range of available
aryl halides that can be utilized. Treatment of the trifluoro-
methanesulfonate (11) with bis(pinacolato)diboron in the
presence of dichloro[1,1ꢀ-bis(diphenylphosphino)ferrocene]
palladium(ii) [PdCl2(dppf)], according to the method of
Ishiyama et al.,[14] afforded the boronate ester (19). Suzuki
couplingoftheboronateester(19)with2-bromoanisoleusing
[PdCl2(dppf)] and potassium phosphate in dioxan[14] yielded
8-(2-methoxyphenyl)-2-morpholin-4-yl-4H-chromen-4-one
(20), albeit in modest yield (13%).
In the course of our work, Heck-type couplings using
8-bromo-2-morpholinochromone were described by Chiosis
et al. as a method of preparing LY294002 analogues.[2] In
that report, the synthesis utilized the thiochromone method
(Scheme 1a) starting from 2-bromophenol. However, in our
hands, yields of the intermediate 3-bromo-2-hydroxyaceto-
phenone, which was obtained by acetylation and ortho-Fries
rearrangement, were very poor as the para-acylation
strongly predominated under all conditions attempted (data
not shown). As an alternative, 3-bromo-2-hydroxyaceto-
phenones, which were blocked at the 5-position were inves-
tigated, and 5-methyl, 5-ethyl, and 5-methoxy substituted
compounds (25a)–(25c) were readily prepared from the
corresponding phenols or acetophenones (Scheme 4).
To access the desired salicylacetamide intermediates,
C-alkylation of the 2-hydroxyacetophenones (25a)–(25c)
was required. Cushman has previously shown excellent
levels of C-alkylation in the synthesis of flavones using
lithiumbis(trimethylsilyl)amidetoformtheenolateanion,[15]
and in our case, condensation of the enolate with mor-
pholinecarbonyl chloride gave good yields of the desired
salicylacetamides (26a)–(26c). These salicylacetamides

1102
B. Abbott and P. Thompson
underwent cyclodehydration with trifluoro-methanesulfonic
anhydride to yield the corresponding 6-substituted-8-bromo-
2-morpholinochromones (27a)–(27c).
As with the trifluoromethanesulfonate, the 6-substituted-
8-bromo-2-morpholinochromones (27a)–(27c) readily
underwent Suzuki coupling, and the 6-ethyl, 6-methyl, and
6-methoxy analogues of LY294002 (compounds (28)–(30),
respectively) were prepared in this manner. For these reac-
tions, the use of [PdCl2(dppf)] and potassium phosphate in
dioxan afforded yields of 30–42%.
It should be noted that whilst a variety of conditions were
employed for the various Suzuki couplings performed in this
study, the chosen reaction conditions, although unoptimized,
did not appear to markedly affect the reaction yield. Interest-
ingly, the use of palladium diacetate and potassium carbonate
in acetonitrile was both effective, and convenient in terms of
catalyst cost and simplicity of workup.
Experimental
Melting points were recorded using a Stuart Scientific SMP3 apparatus
and are uncorrected. Proton and carbon NMR spectra were recorded
on a Bruker Avance DRX400 spectrometer (operating at 400 MHz
for 1H and 100 MHz for 13C) or a Bruker Avance DPX300 spectro-
meter (operating at 300 MHz for 1H and 75 MHz for 13C). All the spec-
tra were recorded in CDCl3 or [D6]DMSO at 30◦C. Low-resolution
electrospray ionization mass spectra (LRESIMS) were performed on a
Waters Micromass ZQ4000 mass spectrometer, which employed a scan
range of 0–1000 m/z and a cone voltage of 20V. High-resolution mass
spectra (HRMS) were recorded on a Bruker BioApex 47e FTMS fit-
ted with an Analytica Electrospray Source. The samples were measured
at a capillary voltage of 75 eV. Reverse-phase high-performance liq-
uid chromatography (RPHPLC) was carried out on a Waters Associates
instrument, whichwascomprisedofaModel600Esystemcontrollerand
a Model 486 detector. Samples were applied according to the method of
Thompson and Hearn,[17] and were eluted through a Phenomonex Luna
C8 column (20 × 4.5 cm i.d.) with detection at 254 nM.
General Methods
Preparation of Salicylacetamides: Method A
Conclusions
As described by Morris et al.,[10] 4-acetylmorpholine (1.6 equiv.) was
added to a solution of lithium diisopropylamide [formed in situ by
treating diisopropylamine (3.2 equiv.) in tetrahydrofuran with 1.6 M n-
butyl lithium (3.2 equiv.)] at 0◦C under nitrogen, and the solution was
stirred at 0◦C for 1 h. The solution at 0◦C was then treated, dropwise,
with the salicylate ester (1 equiv.) in tetrahydrofuran. The reaction was
stirred at room temperature overnight.The mixture was neutralized with
10% aqueous HCl and extracted three times with dichloromethane. The
combined organic fractions were dried (Na2SO4) and the solvent was
removed to yield the crude product.
The synthetic chemistry studies detailed here have identified
concise and adaptable routes for the generation of LY294002
analogues. The methods encompass use of either salicylate
esters or 2-hydroxyacetophenones as precursors to the aryl
trifluoromethanesulfonate, aryl boronate, or aryl halide inter-
mediates required for Suzuki coupling. The development of
these procedures, together with the collection of aryl halides
and arylboronic acids that are commercially available, allows
access to an extensive library of LY294002 analogues. The
nine LY294002 analogues described here are but a small sub-
set of those that should be available by these methodologies.
The recent des[c6r]iption of a complex of LY294002 and
PI3-kinase p110γ demonstrates the likely basis for the
lack of selectivity displayed by LY294002. The amino acid
residues of the enzyme with which LY294002 is proximal are
absolutely conserved across the four Class I isoforms, and
LY294002 is expected to have an analogous interaction with
all four isozymes. The molecular basis of the interaction that
LY294002 undertakes with the less homologous enzymes is
not yet understood. Modification of LY294002 in the manner
described here may have a marked impact on enzyme and
isoform selectivity. The inclusion of additional substituents
may impose further constraints on the interaction, and lead to
one isozyme or enzyme being favoured over the others.These
constraints might be based on (a) steric factors, for example
by the introduction of the bulky phenoxyphenyl substituent;
(b) conformational influences, such as substitution in the
ortho-position; or (c) rely on additional points of interaction
through functional substituents. The distinction between
PI3-kinase inhibition and cAMP phosphodiesterase activity
reported for these compounds will also be important as these
two cellular-signalling enzymes have a number of overlap-
ping pathways.[16] The methodology presented here, coupled
with recent advances in screening techniques, has provided
a means to perform these investigations. The compounds
described here will be studied in activity assays of PI3-kinase
isoforms, related kinases, and cAMP phosphodiesterase
isoforms. The results will be reported in due course.
Preparation of Salicylacetamides: Method B
To a solution of the 2-hydroxyacetophenone (1 equiv.) in tetrahydrofuran
at −78◦C under nitrogen was added lithium bis(trimethylsilyl)amide (3
equiv.). The reaction was allowed to warm to 0◦C, at which tempera-
ture it was maintained for 1 h. The reaction mixture was then cooled
to −78◦C again and 4-morpholinecarbonyl chloride (1.1 equiv.) was
added. The mixture was stirred at room temperature overnight, poured
over ice, acidified to pH 3 with 1 M HCl, and extracted three times with
dichloromethane. The combined extracts were dried (Na2SO4) and the
solvent was removed under vacuum to afford the crude product.
Preparation of Morpholinochromones: Method C
As described by Morris et al.,[10] trifluoromethanesulfonic anhy-
dride (2–3 equiv.) was added to a solution of salicylacetamide in
dichloromethane (0.2 M). After stirring at room temperature overnight,
the solvent was evaporated, and the residue was treated with methanol
(10 mL) and stirred at room temperature for 4 h. The solvent was once
again evaporated, and the residue was diluted with half-saturated sodium
hydrogen carbonate (NaHCO3) solution and extracted three times with
dichloromethane. The combined organic fractions were washed with
saturated sodium chloride (NaCl), dried (Na2SO4), and the solvent was
removed to yield the crude product.
Suzuki Coupling: Method D
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate
(1 equiv.), phenylboronic acid (2 equiv.), potassium carbonate (4 equiv.),
and butylammonium bromide (2 equiv.) were combined. Degassed water
was added, and nitrogen was bubbled through the mixture while palla-
dium diacetate (4 mol-%) was quickly added. The mixture was then
heated at 70◦C for 4 h under nitrogen. Upon cooling to room temper-
ature, the mixture was extracted three times with ethyl acetate, dried
(Na2SO4), and the solvent was removed under vacuum to give the crude
product.

Synthetic Studies of Kinase Inhibitor LY294002 and Related Analogues
1103
Suzuki Coupling: Method E
(lit.[19] mp 80–82◦C). δH (400 MHz; CDCl3; Me4Si) 10.88 (1 H, s, OH),
7.33 (1 H, d, J 8.0, ArH), 7.08 (1 H, d, J 7.6, ArH), 6.77 (1 H, t, J 8.0,
Nitrogen was bubbled through a mixture of 2-morpholin-4-yl-4-oxo-
4H-chromen-8-yl trifluoromethanesulfonate(1equiv.), lithium chloride
(3 equiv.), 2 M aqueous sodium carbonate (2.5 equiv.), and toluene.
Tetrakis(triphenylphosphine)palladium(0) (5 mol-%) was then added to
the mixture. The required arylboronic acid (1.1 equiv.) was dissolved
in ethanol (1 mL) and injected into the reaction flask. The mixture was
stirred at 90◦C under nitrogen overnight, and was then cooled, filtered,
and the solid was washed with chloroform. The organic filtrate was
washed with water, dried (Na2SO4), and concentrated under vacuum
to give the crude compound. The crude product was purified by chro-
matography using ethyl acetate as eluent to afford the desired product.
•
ArH), 3.92 (3 H, s, COCH3). Mass spectrum (ESI) m/z 169 [M + H]+
.
To an ice-cold solution of methyl 2,3-dihydroxybenzoate (4.9 g,
29.1 mmol) in dichloromethane (125 mL) under nitrogen was added
pyridine (4.7 mL, 58.3 mmol) and 4-(dimethylamino)pyridine (0.356 g,
2.91 mmol).Trifluoromethanesulfonic anhydride (5.39 mL, 32.0 mmol)
was then added, dropwise by syringe, and the mixture was allowed
to stir at room temperature for 48 h. The solution was washed with
1 M HCl (2 × 100 mL), dried (Na2SO4), and concentrated under vac-
uum. The crude product was recrystallized from ethyl acetate to give
•
(9b) as white crystals (6.58 g, 76%), mp 93–94◦C (Found: [M + H]+
,
301.1435. C9H7F3O6S requires [M + H]+•, 300.9993). δH (400 MHz;
CDCl3; Me4Si) 11.20 (1 H, s, OH), 7.83 (1 H, d, J 8.0, ArH), 7.41 (1 H,
Suzuki coupling: Method F
d, J 8.0, ArH), 6.91 (1 H, dd, J 8.0 and 8.0, ArH), 3.99 (3 H, s, COCH3).
•
Mass spectrum (ESI) m/z 301 [M + H]+
.
Nitrogen was bubbled through a solution of potassium carbonate
(2.5 equiv.) and 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoro-
methanesulfonate (1 equiv.) in acetonitrile (50 mL/g). The requisite
arylboronic acid (1.2 equiv.) and palladium diacetate (10 mol-%) were
then added. After heating overnight at 80◦C, the mixture was cooled,
filtered, and the solid was washed with acetonitrile (10 mL). The com-
bined washings were evaporated under vacuum to give a crude product;
this was purified by chromatography using ethyl acetate as eluent to
afford the desired product.
Methyl 2-Hydroxy-3-methoxybenzoate (9c)
To a solution of 2-hydroxy-3-methoxybenzoic acid (5.0 g, 29.7 mmol)
in methanol (250 mL) was added concentrated sulfuric acid (5.0 g,
51.0 mmol).The resultant mixture was refluxed for 48 h, cooled, and the
methanol was removed under vacuum. Upon addition of water (200 mL)
a precipitate formed, which was filtered and dried under vacuum to yield
a white crystalline product (9c) (5.15 g, 95%), mp 64–66◦C (lit.[20] mp
61–63◦C). δH (300 MHz; CDCl3; Me4Si) 10.99 (1 H, s, OH), 7.41 (1 H,
d, J 8.4, ArH), 7.02 (1 H, d, J 7.8, ArH), 6.80 (1 H, dd, J 8.1 and 8.1,
Suzuki Coupling: Method G
To a solution of 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-4H-chromen-4-one (1 equiv.) in dioxan (60 mL g−1) was
added potassium phosphate (3 equiv.), dichloro[1,1ꢀ-bis(diphenylphos-
phino)ferrocene]palladium(ii) (3 mol-%), and the required aryl halide
(1 equiv.).The mixture was heated at 80◦C under nitrogen for 48 h.After
being cooled to room temperature, the reaction mixture was filtered and
the solid was washed with dioxan. The filtrate was concentrated under
vacuum to yield the crude product, which was purified by RPHPLC.
ArH), 3.93 (3 H, s, COCH3), 3.88 (3 H, s, OCH3). Mass spectrum (ESI)
•
m/z 183 [M + H]+
.
(4-Morpholinyl)-3-[3ꢀ-(2ꢀ-hydroxybiphenyl)]-
3-oxopropanamide (10a)
Methyl 3-phenylsalicylate (1.48 g, 6.46 mmol) was reacted according
to Method A to yield an oil. This was purified by chromatography
using 0–10% methanol in dichloromethane as eluent to afford a yel-
low oil (10a) (2.2 g), which was contaminated by a small amount of
4-acetylmorpholine. δH (300 MHz; CDCl3; Me4Si) 7.86 (1 H, d, J 8.1,
ArH), 7.58–7.35 (6 H, complex m, ArH), 7.01 (1 H, dd, J 7.8 and 7.8,
Suzuki Coupling: Method H
To 8-bromo-6-substituted-2-morpholin-4-yl-4H-chromen-4-one under
nitrogen was added potassium phosphate (3–6 equiv.), phenylboronic
acid(1.1–2equiv.), dichloro[1,1ꢀ-bis(diphenylphosphino)ferrocene]pal-
ladium(ii) (0.03–0.07 equiv.), and dioxan (20 mL mmol−1).The mixture
was refluxed at 85◦C for 48 h, cooled to room temperature, and filtered.
The solvent was removed under vacuum and the residue was purified by
RPHPLC.
ArH), 4.17 (2 H, s, CH2), 3.54–3.43 (8 H, complex m, CH2). Mass
•
spectrum (ESI) m/z 326 [M + H]+
.
2-Hydroxy-3-(3-morpholin-4-yl-3-oxopropanoyl)phenyl
Trifluoromethanesulfonate (10b)
Treatmentofmethyl2-hydroxy-3-{[(trifluoromethyl)sulfonyl]oxy}ben-
zoate (3.62 g, 3.43 mmol) according to Method A yielded the crude
product as a yellow oil (5.94 g). This was purified by chromatogra-
phy using ethyl acetate as eluent to obtain the desired product (10b)
(3.58 g, 75%) as a solid, mp 138–140◦C (Found: [M + H]+•, 398.0514.
C14H14F3NO7S requires [M + H]+•, 398.0521) [(10b) was contami-
nated by a small amount of 4-acetylmorpholine]. δH (400 MHz; CDCl3;
Me4Si) 7.89 (1 H, d, J 7.6, ArH), 7.44 (1 H, d, J 8.0, ArH), 6.96 (1 H,
Syntheses
Methyl 3-Phenylsalicylate (9a)
To a stirred suspension of 3-phenylsalicylic acid (3.36 g, 15 mmol) in
dry methanol (50 mL) was added, dropwise over 10 min, concentrated
sulfuric acid (4.38 g, 43 mmol). The mixture was heated at 80◦C for
70 h and the cooled solution was evaporated under vacuum to near dry-
ness. The residue was treated with water (60 mL) and extracted with
dichloromethane.The combined organic fractions were washed with sat-
urated aqueous NaHCO3 (2 × 30 mL) and water (30 mL), and then dried
(Na2SO4). Removal of the solvent afforded a pale-yellow oil (2.65 g,
74%), which crystallized upon standing, The crude product was recrys-
tallized from methanol to give compound (9a), mp 41–42◦C (lit.[18] mp
54–56◦C). δH (300 MHz; CDCl3; Me4Si) 11.34 (1 H, s, OH), 7.88 (1 H,
d, J 7.8, ArH), 7.62–7.36 (6 H, complex m, ArH), 6.98 (1 H, dd, J 8.0
and 8.0, ArH), 3.99 (3 H, s, COCH3).
dd, J 8.0 and 8.0, ArH), 4.10 (2 H, s, CH2), 3.71–3.42 (8 H, complex m,
•
CH2). Mass spectrum (ESI) m/z 398 [M + H]+
.
1-(2-Hydroxy-3-methoxyphenyl)-3-morpholin-4-yl-3-oxopropan-
1-one (10c)
Treatmentofmethyl2-hydroxy-3-methoxybenzoate(4.50 g, 24.7 mmol)
according to MethodA afforded a tan solid (10c) (5.22 g, 86%), mp 140–
•
142◦C (Found: [M + H]+•, 280.1179. C14H17NO5 requires [M + H]+
,
280.1185). δH (300 MHz; CDCl3; Me4Si) 7.39 (1 H, d, J 7.5,ArH), 7.06
(1 H, d, J 6.9, ArH), 6.85 (1 H, dd, J 8.3 and 8.3, ArH), 4.11 (2 H, s,
CH2), 3.88 (3 H, s, OCH3), 3.68–3.44 (8 H, complex m, CH2). Mass
Methyl 2-Hydroxy-3-{[(trifluoromethyl)sulfonyl]oxy}benzoate (9b)
•
spectrum (ESI) m/z 280 [M + H]+
.
To a solution of 2,3-dihydroxybenzoic acid (4.0 g, 26.0 mmol) in
methanol (200 mL) was added concentrated sulfuric acid (4.0 g). The
reaction was stirred at reflux overnight then cooled, and the solvent was
removed under vacuum. A precipitate was obtained upon the addition of
water (300 mL); this was filtered and dried under vacuum to give methyl
2,3-dihydroxybenzoate (3.81 g, 87%) as a mauve solid, mp 79–80◦C
2-Morpholin-4-yl-8-phenyl-4H-chromen-4-one (1)
(4-Morpholinyl)-3-[3ꢀ-(2ꢀ-hydroxybiphenyl)]-3-oxopropanamide(2.1 g,
6.46 mmol) was treated with trifluoromethanesulfonic anhydride
(2.31 mL, 13.3 mmol) according to Method C to give a brown solid. The

1104
B. Abbott and P. Thompson
product was recrystallized from ethyl acetate as colourless crystals (1)
(0.895 g, 44%), mp184◦C(lit.[3] mp185–187◦C).Theproductco-eluted
on TLC with an authentic sample of LY294002 (Calbiochem) (Found:
[M + H]+•, 308.1286. C19H17NO3 requires [M + H]+•, 308.1281). δH
(400 MHz; CDCl3; Me4Si) 8.16 (1 H, dd, J 8.0 and 1.6,ArH), 7.54 (1 H,
dd, J 7.6 and 1.2,ArH), 7.49–7.39 (6 H, m,ArH), 5.50 (1 H, s, CH), 3.71
(4 H, t, J 4.8, CH2CH2), 3.33 (4 H, t, J 4.8, CH2CH2). δC (100 MHz;
CDCl3; Me4Si) 177.2, 162.6, 150.6, 136.4, 133.5, 130.4, 129.4, 128.4,
of the crude product by chromatography using ethyl acetate as eluent
gave the desired compound (11) (2.32 g, 32%); this was identical to the
material prepared by Method A.
2-Morpholin-4-yl-8-phenyl-4H-chromen-4-one (1):
Alternative Method
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate
(0.199 g, 0.525 mmol) was reacted with phenylboronic acid (70.5 mg,
0.578 mmol) according to Method D to give a dark-orange oil. The
crude product was purified by chromatography using 0–5% methanol
in dichloromethane as eluent to afford the desired product (1) (0.179 g,
12%); this was identical to the material described above.
128.0, 125.1, 124.8, 123.4, 87.1, 65.9, 44.8. Mass spectrum (ESI) m/z
•
308 [M + H]+
.
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl
Trifluoromethanesulfonate (11)
2-Hydroxy-3-(3-morpholin-4-yl-3-oxopropanoyl)phenyltrifluorometh-
anesulfonate (0.823 g, 2.07 mmol) was treated with trifluoromethane-
sulfonic anhydride (1.25 mL, 7.46 mmol) according to Method C to
yield the desired compound (11) after recrystallization from ethyl
acetate (0.469 g, 60%), mp 174–175◦C (Found: [M + H]+•, 380.0404.
C14H12F3NO6S requires [M + H]+•, 380.0415). δH (400 MHz; CDCl3;
Me4Si) 8.17 (1 H, d, J 8.0, ArH), 7.48 (1 H, d, J 8.0, ArH), 7.38
(1 H, dd, J 8.0 and 8.0, ArH), 5.52 (1 H, s, CH), 3.84 (4 H, t, J 4.9,
2-Morpholin-4-yl-8-[2-(trifluoromethyl)phenyl]-4H-chromen-
4-one(14)
Treatment of the trifluoromethanesulfonate (11) with 2-(trifluoro-
methyl)phenylboronic acid (55.1 mg, 0.29 mmol) according to Method
E yielded the title compound (14) (58.3 mg, 59%), mp 172–173◦C
(Found: [M + H]+•, 376.1157. C20H16F3NO3 requires [M + H]+
,
•
376.1160). δH (300 MHz; CDCl3; Me4Si) 8.20 (1 H, dd, J 7.8 and 1.8,
ArH), 7.80 (1 H, d, J 7.8, ArH), 7.65–7.53 (2 H, complex m, ArH),
7.47–7.35 (3 H, complex m, ArH), 5.45 (1 H, s, CH), 3.61 (4 H, t, J
5.0, CH2CH2), 3.09 (4 H, t, J 5.0, CH2CH2). δC (100 MHz; CDCl3;
Me4Si) 177.0, 162.2, 151.0, 134.9, 133.3, 132.1, 131.5, 128.5, 127.7,
CH2CH2), 3.57 (4 H, t, J 5.0, CH2CH2). Mass spectrum (ESI) m/z
•
380 [M + H]+
.
8-Methoxy-2-morpholin-4-yl-4H-chromen-4-one (12)
126.2, 125.8, 124.1, 122.9, 87.0, 65.8, 44.5, 29.7 (one signal obscured
•
or overlapping). m/z (ESI) 376 [M + H]+
.
1-(2-Hydroxy-3-methoxyphenyl)-3-morpholin-4-yl-3-oxopropan-1-one
(3.96 g, 14.2 mmol) was treated with trifluoromethanesulfonic anhy-
dride(8.58 mL, 51.0 mmol)acccordingtoMethodCtoyieldan off-white
solid (12) (2.84 g, 77%) after recrystallization from ethyl acetate,
mp 145–147◦C (Found: [M + H]+•, 262.1079. C14H15NO4 requires
[M + H]+•, 262.1079). δH (300 MHz;CDCl3;Me4Si)7.69(1 H, d, J 8.1,
ArH), 7.24 (1 H, dd, J 8.1 and 8.1, ArH), 7.07 (1 H, d, J 6.9, ArH), 5.49
8-(2-Methylphenyl)-2-morpholin-4-yl-4H-chromen-4-one (15)
Treatment of the trifluoromethanesulfonate (11) with o-tolylboronic
acid (39.4 mg, 0.290 mmol) according to Method E yielded the title com-
pound (15) (39.7 mg, 47%) (Found: [M + H]+•, 322.1432. C20H19NO3
requires [M + H]+•, 322.1443). δH (400 MHz; CDCl3; Me4Si) 8.15
(1 H, m, ArH), 7.45–7.37 (2 H, complex m, ArH), 7.29–7.20 (4 H, com-
plex m, ArH), 5.46 (1 H, s, CH), 3.64 (4 H, m, CH2CH2)•, 3.14 (4 H, m,
(1 H, s, CH), 3.93 (3 H, s, OCH3), 3.83 (4 H, t, J 5.0, CH2CH2), 3.53
•
(4 H, m, J 4.8, CH2CH2). Mass spectrum (ESI) m/z 262 [M + H]+
8-Hydroxy-2-morpholin-4-yl-4H-chromen-4-one (13)
.
CH2CH2), 2.11 (3 H, s, CH3). m/z (ESI) 322 [M + H]+
.
To stirred aluminium chloride (1.53 g, 11.5 mmol) was carefully
added, over 30 min, sodium iodide (1.76 g, 11.5 mmol) in aceto-
nitrile (15.3 mL). 8-Methoxy-2-morpholin-4-yl-4H-chromen-4-one
(1.0 g, 3.83 mmol) was then added and the mixture was heated at
reflux overnight. Once cool, 1 M HCl (10 mL) was added and the mix-
ture was heated for a further 2 h, after which time the mixture was
cooled again and the two layers were allowed to separate. The organic
layer was collected, dried (Na2SO4), and concentrated under vacuum.
The residue was purified by chromatography using 0–5% methanol
in dichloromethane as eluent to give a crude orange solid (0.711 g).
This was dissolved in 1 M sodium hydroxide (20 mL) and extracted
into ethyl acetate in order to remove any starting material. HCl (1 M)
was added to the aqueous phase until a solid precipitated at around
pH 5. The precipitate was filtered and dried under vacuum to yield
8-(2-Chlorophenyl)-2-morpholin-4-yl-4H-chromen-4-one (16)
Treatment of the trifluoromethanesulfonate (11) with 2-chlorophenyl-
boronic acid (45.4 mg, 0.290 mmol) according to Method E yielded
the title compound (16) (56.7 mg, 63%), mp 178–179◦C (Found:
[M + H]+•, 342.0892. C19H16ClNO3 requires [M + H]+•, 342.0897).
δH (400 MHz; CDCl3; Me4Si) 8.20 (1 H, br m, ArH), 7.48–7.35 (6 H,
complex m, ArH), 5.48 (1 H, s, CH), 3.67 (4 H, br m, CH2CH2), 3.23
(4 H, br m, CH2CH2). δC (75 MHz; CDCl3; Me4Si) 177.1, 162.2, 150.7,
135.4, 133.7, 133.5, 131.7, 129.6, 129.4, 127.8,• 126.9, 125.7, 124.5,
123.0, 86.9, 65.9, 44.5. m/z (ESI) 342 [M + H]+
.
8-(4-Fluorophenyl)-2-morpholin-4-yl-4H-chromen-4-one (17)
Treatment of the trifluoromethanesulfonate (11) with 4-fluorophenyl-
boronic acid (88.5 mg, 0.632 mmol) according to Method F yielded
the title compound (17) (116.3 mg, 68%), mp 120–121◦C (Found:
[M + H]+•, 326.1192. C19H16FNO3 requires [M + H]+•, 326.1192).
δH (300 MHz; CDCl3; Me4Si) 8.18 (1 H, dd, J 7.8 and 1.8, ArH). 7.55–
7.46 (3 H, complex m, ArH), 7.40 (1 H, dd, J 7.8 and 7.8, ArH), 7.16
(2 H, dd, J 8.7 and 8.7, ArH), 5.52 (1 H, s, CH), 3.74 (4 H, t, J 5.0,
CH2CH2), 3.33 (4 H, t, J 5.0, CH2CH2). δC (100 MHz; CDCl3; Me4Si)
an off-white solid (13) (0.616 g, 65%), mp 304–305◦C (lit.[21] mp
•
300◦C)(Found:[M + H]+•, 248.0923. C13H13NO4 requires[M + H]+
,
248.0923). δH (400 MHz; [D6]DMSO; Me4Si) 10.14 (1 H, s, OH), 7.31
(1 H, br m, ArH), 7.11 (2 H, br m, ArH), 5.45 (1 H, s, CH), 3.69 (4 H,
br m, CH2CH2), 3.49 (4 H, br m, CH2CH2). Mass spectrum (ESI) m/z
•
247 [M + H]+
.
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl Trifluoromethanesulfonate
(11): Alternative Method
177.1, 163.8, 162.6, 150.6, 133.4, 132.4, 131.1, 131.0, 129.4, 125.3,
•
124.8, 123.5, 115.5, 115.3, 87.2, 65.9, 44.8. m/z (ESI) 326 [M + H]+
8-[4-Phenoxyphenyl]-2-morpholin-4-yl-4H-chromen-4-one (18)
.
To a suspension of 8-hydroxy-2-morpholin-4-yl-4H-chromen-4-one
(2.70 g, 10.9 mmol) in acetonitrile (250 mL) were added N-phenyl
triflimide (10.7 g, 29.9 mmol) and diisopropylethylamine (5.2 mL,
29.9 mmol). The resultant mixture was stirred for 48 h and was then
filtered. The filtrate was evaporated under vacuum and the residue was
dissolved in dichloromethane (60 mL). The solution was washed suc-
cessively with 0.5 M HCl (30 mL), water (30 mL), and 10% aqueous
NaHCO3 (30 mL), and was then dried (Na2SO4). Evaporation of the
solvent under vacuum afforded the crude material (9.37 g). Purification
Treatment of the trifluoromethanesulfonate (11) with 4-phenoxyphenyl-
boronic acid according to Method F yielded the title compound
(18) (77.9 mg, 37%), mp 194–195◦C (Found: [M + H]+•, 400.1540.
C25H21NO4 requires [M + H]+•, 400.1549). δH (300 MHz; CDCl3;
Me4Si) 8.16 (1 H, dd, J 3.9 and 1.8, ArH), 7.51 (1 H, dd, J 3.8
and 1.7, ArH), 7.45–7.41 (2 H, complex m, ArH), 7.39–7.33 (3 H,
complex m, ArH), 7.16–7.11 (1 H, complex m, ArH), 7.10–7.03

Synthetic Studies of Kinase Inhibitor LY294002 and Related Analogues
1105
(4 H, complex m, ArH), 5.59 (1 H, s, CH), 3.71 (4 H, t, J 5.0,
CH2CH2), 3.34 (4 H, t, J 5.0, CH2CH2). δC (100 MHz; CDCl3;
Me4Si) 177.2, 162.6, 157.4, 156.9, 150.7, 133.4, 131.2, 130.9, 129.9,
1-(3-Bromo-5-ethyl-2-hydroxyphenyl)ethenone (25a)
To a stirred suspension of 2-bromo-4-ethylphenyl acetate (5.0 g,
20.5 mmol) was carefully added aluminium chloride (5 g). The resul-
tant mixture was then heated at 125◦C under a drying tube overnight.
Upon cooling, the mixture was dissolved in dichloromethane and poured
onto ice. The organic layer was removed, and the aqueous layer was
extracted with dichloromethane. The combined organic extracts were
dried (Na2SO4), and the solvent was removed under vacuum to give a
crude brown material (4.30 g). The crude product was purified by chro-
matography using 99 : 1 petroleum spirit/ethyl acetate as eluent to give
the pure product (25a) (1.75 g, 35%) as an oil. δH (400 MHz; CDCl3;
Me4Si) 12.76 (1 H, s, OH), 7.60 (1 H, d, J 2.1, ArH), 7.50 (1 H, d, J 2.1,
129.8, 125.0, 124.8, 123.8, 123.4, 119.1, 118.6, 87.2, 66.0, 44.9.
•
m/z (ESI) 400 [M + H]+
.
2-Morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
4H-chromen-4-one (19)
Nitrogen was bubbled through a stirred suspension of potassium
acetate (217.0 mg, 2.215 mmol), bis(pinacolato)diboron (206.2 mg,
0.812 mmol), dichloro[1,1ꢀ-bis(diphenylphosphino)ferrocene]palladi-
um(ii) (36.2 mg, 0.044 mmol), and dioxan (10 mL). 2-Morpholin-
4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate (280.0 mg,
0.738 mmol) in dioxan (10 mL) was injected into the reaction; this was
then heated at 75◦C overnight. The mixture was cooled to room tempera
ture and diluted with toluene, and was then washed twice with brine.
The solution was dried (Na2SO4), filtered, and concentrated under vac-
uum to give a brown oil (316.3 mg). The crude product was purified
by chromatography using 95 : 5 dichloromethane/methanol as eluent to
afford the pure product (19) (182.7 mg, 69%), mp 165–166◦C (Found:
[M + H]+•, 358.1833. C19H24BNO5 requires [M + H]+•, 358.1826).
δH (300 MHz; CDCl3; Me4Si) 8.26 (1 H, d, J 7.8, ArH), 7.98 (1 H, d,
J 7.2, ArH), 7.31 (1 H, t, J 7.5, ArH), 5.58 (1 H, s, CH), 3.80 (4 H, t, J
4.7, CH2CH2), 3.67•(4 H, t, J 4.7, CH2CH2), 1.34 (12 H, s, CH3). m/z
ArH), 2.65 (3 H, s, OCH3), 2.61 (2 H, q, J 7.6, CH2CH3), 1.24 (3 H, t,
•
J 7.6, CH2CH3). m/z (ESI) 243 [M + H]+
.
1-(3-Bromo-2-hydroxy-5-methylphenyl)ethenone (25b)
To a solution of 2ꢀ-hydroxy-5ꢀ-methylacetophenone (5.0 g, 0.033 mol)
in chloroform (25 mL) at 0◦C under nitrogen was slowly added bromine
(1.74 mL, 0.034 mol). After 3 h at 0◦C, the reaction was allowed to
warm to room temperature and was then treated with water (25 mL).The
organic phase was washed with water, brine, 10% aqueous NaHCO3,
and brine again (50 mL of each), and was then dried (Na2SO4). The
solvent was removed under vacuum and the residue was purified by
chromatography using 99 : 1 petroleum spirit/ethyl acetate as eluent to
give the product (25b) (5.622 g, 74%), mp 86–87◦C (lit.[22] mp 88–
(ESI) 358 [M + H]+
.
89◦C) (Found: [M + H]+•, 228.9859. C9H9BrO2 requires [M + H]+
,
•
228.9864). δH (400 MHz; CDCl3; Me4Si) 12.74 (1 H, s, OH), 7.56 (1 H,
8-(2-Methoxyphenyl)-2-morpholin-4-yl-4H-chromen-4-one (20)
s, ArH), 7.49 (1 H, s, ArH), 2.64 (3 H, s, OCH3), 2.32 (3 H, s, CH3).
•
m/z (ESI) 229 [M + H]+
.
Asolutionof2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)-4H-chromen-4-one (100.0 mg, 0.280 mmol) in dioxan (6 mL)
was treated with 2-bromoanisole (34.9 µL, 0.280 mmol) according
1-(3-Bromo-2-hydroxy-5-methoxyphenyl)ethenone (25c)
to Method G to yield a white solid (20) (12.6 mg, 13%), mp
Toasolutionof 2-hydroxy-5-methoxyacetophenone(3.42 g, 20.6 mmol)
in acetic acid (15.6 mL) was added sodium acetate (1.87 g, 22.8 mmol).
The reaction mixture was then cooled to 0◦C and a solution of bromine
(1.0 mL, 19.6 mmol) in acetic acid (6.24 mL) was added dropwise by
pipette. The resultant mixture was stirred for 48 h. Further portions of
bromine (0.5 mL, 9.8 mmol) and sodium acetate (0.935 g, 11.4 mmol)
were added, and stirring was continued overnight. The reaction was
poured onto ice, and the resultant precipitate was filtered and dried
under vacuum to give the desired product (25c) (4.88 g, 97%), mp 76–
78◦C (lit.[23] mp 76–76.5◦C). δH (300 MHz; CDCl3; Me4Si) 7.38 (1 H,
s, ArH), 7.19 (1 H, s, ArH•), 3.80 (3 H, s, OCH3), 2.64 (3 H, s, COCH3).
•
133–134◦C (Found: [M + H]+
, 338.1386. C20H19NO4 requires
[M + H]+•, 338.1392). δH (300 MHz; CDCl3; Me4Si) 8.17 (1 H, d,
J 7.8, ArH), 7.65 (1 H, d, J 8.1, ArH), 7.51 (1 H, dd, J 7.7 and
7.7, ArH), 7.44 (1 H, dd, J 8.0 and 8.0, ArH), 7.27 (1 H, m, ArH),
7.08 (1 H, dd, J 7.4 and 7.4, ArH), 7.01 (1 H, d, J 8.1, ArH),
6.84 (1 H, s, CH), 3.75 (3 H, s, OCH3), 3.73 (4 H, t, J 5.1,
CH2CH2), 3.47 (4 H, t, J 4.8, CH2CH2). δC (100 MHz; CDCl3; Me4Si)
175.9, 162.8, 156.6, 150.7, 135.5, 131.3, 130.3, 127.5, 125.6, 124.7,
124.3, 12•0.9, 119.4, 110.9, 86.2, 65.9, 55.6, 45.0. m/z (ESI) 338
[M + H]+
.
m/z (ESI) 245 [M + H]+
.
2-Bromo-4-ethylphenyl Acetate (23)
1-(3-Bromo-5-ethyl-2-hydroxyphenyl)-3-morpholin-4-yl-3-oxopropan-
1-one (26a)
To a solution of 4-ethylphenol (10.5 g, 85.9 mmol) in chloroform
(50 mL) at 0◦C under nitrogen was slowly added bromine (4.5 mL,
87.8 mmol), and the resultant mixture was then stirred at 0◦C for 3 h.
The mixture was allowed to reach room temperature, at which time water
was added (50 mL).The organic phase was separated, washed with water
(50 mL), brine(50 mL), 10%aqueousNaHCO3 (50 mL), andbrineagain
(50 mL), and was then dried (Na2SO4). The solvent was removed under
vacuum to give the desired 2-bromo-4-ethylphenol (22) (15.9 g, 92%)
as an oil. δH (400 MHz; CDCl3; Me4Si) 7.28 (1 H, s, ArH), 7.04 (1 H,
d, J 8.0, ArH), 6.92 (1 H, d, J 8.0, ArH), 2.56 (2 H, q, J 7.8, CH2CH3),
1.20 (3 H, t, J 7.6, CH2CH3).
1-(3-Bromo-5-ethyl-2-hydroxyphenyl)ethenone (0.5 g, 2.06 mmol) was
treated with lithium bis(trimethylsilyl)amide (6.17 mL, 6.17 mmol)
and 4-morpholinecarbonyl chloride (264 µL, 2.26 mmol), according
to Method B, to afford the desired product (26a) (0.861 g) as an oil,
which was not purified any further (Found: [M + H]+•, 356.0517.
C15H18BrNO4 requires [M + H]+•, 356.0497). δH (400 MHz; CDCl3;
Me4Si) 12.34 (1 H, s, OH), 7.64 (2 H, s, ArH), 4.13 (2 H, s, CH2), 3.52
(4 H, t, J 4.8, CH2CH2), 3.26 (4 H, t, J 4.8, CH2CH2), 2.62 (2 H, q,
•
J 7.6, CH2CH3), 1.24(3 H, t, J 7.6, CH2CH3). m/z(ESI)356[M + H]+
.
To stirred 2-bromo-4-ethylphenol (15.0 g, 74.6 mmol) at room tem-
perature under a drying tube was added acetic anhydride (90 mL)
and concentrated sulfuric acid (3 mL), and stirring was continued
for 48 h. The mixture was then poured onto ice and extracted with
dichloromethane (3 × 50 mL). The organic phase was washed with
saturated aqueous NaHCO3 and then dried (Na2SO4). Removal of the
solvent under vacuum gave an oil, which was dissolved in diethyl ether
(100 mL) and treated with solid NaHCO3. After being stirred for 2 h,
thereactionmixturewasfilteredandthediethyletherwasremovedunder
vacuum to give a pale-yellow oil (23) (14.72 g, 81%). δH (400 MHz;
CDCl3; Me4Si) 7.43 (1 H, s, ArH), 7.14 (1 H, d, J 8.0, ArH), 7.02 (1 H,
1-(3-Bromo-2-hydroxy-5-methylphenyl)-3-morpholin-4-yl-
3-oxopropan-1-one (26b)
1-(3-Bromo-2-hydroxy-5-methylphenyl)ethanone (0.5 g, 2.20 mmol) in
tetrahydrofuran (12 mL) was treated with lithium bis(trimethylsilyl)-
amide (6.55 mL, 6.55 mmol) and 4-morpholinecarbonyl chloride
(280.0 µL, 2.40 mmol) according to Method B. The crude product
was purified by column chromatography using ethyl acetate as eluent
to yield the title compound (26b) (0.395 g, 52%) as an oil (Found:
[M + H]+•, 342.0342. C14H16BrNO4 requires [M + H]+•, 342.0341).
δH (300 MHz; CDCl3; Me4Si) 7.60 (1 H, s, ArH); 7.57 (1 H, s, ArH),
d, J 8.2, ArH), 2.62 (2 H, q, J 7.6, CH2CH3), 2.34 (3 H, s, OCH3), 1.23
4.12 (2 H, s, CH2), 3.72 (4 H, br m, CH2CH2), 3.49 (4 H, t, J 4.8,
•
•
(3 H, t, J 7.6, CH2CH3). m/z (ESI) 243 [M + H]+
.
CH2CH2), 2.31 (3 H, s, CH3). m/z (ESI) 342 [M + H]+
.

1106
B. Abbott and P. Thompson
1-(3-Bromo-2-hydroxy-5-methoxyphenyl)-3-morpholin-4-yl-
3-oxopropan-1-one (26c)
129.3, 128.5, 128.4, 124.5, 120.1, 86.3, 65.9, 45.1, 21.0 (one signal
•
obscured or overlapping). m/z (ESI) 322 [M + H]+
.
A solution of 1-(3-bromo-2-hydroxy-5-methoxyphenyl)ethanone (2.5 g,
10.2 mmol) in tetrahydrofuran (100 mL) was treated with lithium
bis(trimethylsilyl)amide (30.6 mL, 30.6 mmol) and 4-morpholinecar-
bonyl chloride (1.31 mL, 11.2 mmol) according to Method B. The crude
product was purified by column chromatography using ethyl acetate
as eluent to yield the title compound (26c) (2.11 g, 58%) as a solid,
mp 150–152◦C. δH (300 MHz; CDCl3; Me4Si) 7.40 (1 H, s, ArH), 7.38
(1 H, s, ArH), 4.10 (2 H, s, CH2), 3.79•(3 H, s, OCH3), 3.66–3.52 (8 H,
6-Methoxy-2-morpholin-4-yl-8-phenyl-4H-chromen-4-one (30)
8-Bromo-6-methoxy-2-morpholin-4-yl-4H-chromen-4-one
(0.2 g,
0.588 mmol)wastreatedwithphenylboronicacid(78.8 mg, 0.647 mmol)
according to Method H to yield the title compound (30) (77.4 mg, 39%),
mp 110–111◦C (Found: [M + H]+•, 338.1388. C20H19NO4 requires
[M + H]+•, 338.1392). δH (300 MHz;CDCl3;Me4Si)7.57(1 H, s,ArH),
7.48 (5 H, br m, ArH), 7.23 (1 H, s, ArH), 6.35 (1 H, s, ArH), 3.92 (3 H,
s, OCH3), 3.75 (4 H, br m, CH2CH2), 3.46 (4 H, br m, CH2CH2).
δC (100 MHz; CDCl3; Me4Si) 176.3, 162.7, 156.8, 145.1, 135.5,
br m, CH2). m/z (ESI) 358 [M + H]+
.
131.9, 129.3, 128.6, 123.3, 122.3, 122.0, 105.2, 86.4, 65.9, 56.0, 45.0.
8-Bromo-6-ethyl-2-morpholin-4-yl-4H-chromen-4-one (27a)
•
m/z (ESI) 338 [M + H]+
.
1-(3-Bromo-5-ethyl-2-hydroxyphenyl)-3-morpholin-4-yl-3-oxopropan-
1-one (0.861 g, 2.42 mmol) was treated with trifluoromethanesulfonic
anhydride (8.58 mL, 51.0 mmol) according to Method C to afford a tan
solid (0.530 g). The crude product was purified by chromatograhy using
ethyl acetate as the eluent to give the pure product (27a) (383 mg, 47%),
mp 162–164◦C (Found: [M + H]+•, 338.0380. C15H16BrNO3 requires
[M + H]+•, 338.0392). δH (300 MHz; CDCl3; Me4Si) 7.91 (1 H, d,
J 1.8, ArH), 7.60 (1 H, d, J 2.1 Hz, ArH), 5.48 (1 H, s, ArH), 3.84 (4 H,
Acknowledgments
The authors wish to thank the Australian Research Council
for the provision of anAustralian PostgraduateAward to B.A.
The helpful discussion provided by Drs Hishani Prabaharan
and Vijaya Kenche (Kinacia) is gratefully acknowledged. We
also wish to thank Dr JoWeigold and Ms Sally Duck (Monash
University) for the provision of NMR and MS services,
respectively.
t, J 5.0, CH2CH2), 3.57 (4 H, t, J 5.1, CH2CH2), 2.70 (2 H, q, J 7.8,
•
CH2CH3), 1.26 (3 H, t, J 7.7, CH2CH3). m/z (ESI) 338 [M + H]+
8-Bromo-6-methyl-2-morpholin-4-yl-4H-chromen-4-one (27b)
.
1-(3-Bromo-2-hydroxy-5-methylphenyl)-3-morpholin-4-yl-3-oxopropan-
1-one (0.4 g, 1.17 mmol) was treated with trifluoromethanesulfonic
anhydride (0.708 mL, 4.21 mmol) according to Method C to afford a
brown solid (0.272 g). The crude product was purified by chromatogra-
phy using ethyl acetate as eluent to give the pure product (27b) (94.6 mg,
25%), mp 185–186◦C (Found: [M + H]+•, 324.0231. C14H14BrNO3
requires [M + H]+•, 324.0235). δH (300 MHz; CDCl3; Me4Si) 7.88
(1 H, s, ArH), 7.58 (1 H, s, ArH), 5.48 (1 H, s, CH), 3.84 (4 H, t,
References
[1] R. C. Stein, M. D. Waterfield, Mol. Med. Today 2000, 6, 347.
[2] G. Chiosis, N. Rosen, L. Sepp-Lorenzino, Bioorg. Med. Chem.
Lett. 2001, 11, 909.
[3] C. J. Vlahos, W. F. Matter, K. Y. Hui, R. F. Brown, J. Biol.
Chem. 1994, 269, 5241.
[4] R. B. Gammil, T. M. Judge, J. Morris, International Patent
WO 91/19707, 1991.
[5] S. P. Davies, H. Reddy, M. Caivano, P. Cohen, Biochem.
J. 2000, 351, 95.
J 5.1, CH2CH2), 3.56 (4 H, t, J 5.0, CH2CH2), 2.40 (3 H, s, CH3).
•
m/z (ESI) 324 [M + H]+
.
[6] E. H. Walker, M. E. Pacold, O. Perisic, L. Stephens, P.T. Hawkins,
M. P. Wymann, R. L. Williams, Mol. Cell 2000, 6, 909.
[7] C. A. Beeton, E. M. Chance, L. C. Foukas, P. R. Shepherd,
Biochem. J. 2000, 350, 353.
[8] M. Di Braccio, G. Roma, G. Leoncini, M. Poggi, Farmaco
1995, 50, 703.
[9] J. Morris, D. G. Wishka, Y. Fang, J. Org. Chem. 1992, 57, 6502.
[10] J. Morris, D. G. Wishka,Y. Fang, Synth. Commun. 1994, 24, 849.
[11] T. Horie, T. Kobayashi, Y. Kawamura, I. Yoshida, H. Tominaga,
K. Yamashita, Bull. Chem. Soc. Jpn. 1995, 68, 2033.
[12] D. Badone, M. Baroni, R. Cardamone, A. Ielmini, U. Guzzi,
J. Org. Chem. 1997, 62, 7170.
8-Bromo-6-methoxy-2-morpholin-4-yl-4H-chromen-4-one (27c)
1-(3-Bromo-2-hydroxy-5-methoxyphenyl)-3-morpholin-4-yl-3-oxopropan-
1-one (2.11 g, 5.89 mmol) was treated with trifluoromethanesulfonic
anhydride (3.57 mL, 21.2 mmol) according to Method C to give the
desired product (27c) (1.32 g, 66%), which was not purified any further,
mp 188–189◦C (Found: [M + H]+•, 340.0197. C14H14BrNO4 requires
[M + H]+•, 340.0184). δH (300 MHz;CDCl3;Me4Si)7.52(1 H, s,ArH),
7.38 (1 H, s, ArH), 5.56 (1 H, s, CH), 3.87 (3 H, s, OCH3), 3.85 (4 H, •t,
J 4.8, CH2CH2), 3.59(4 H, t, J 4.8, CH2CH2). m/z(ESI)340[M + H]+
6-Ethyl-2-morpholin-4-yl-8-phenyl-4H-chromen-4-one (28)
.
8-Bromo-6-ethyl-2-morpholin-4-yl-4H-chromen-4-one (0.1 g, 0.296
mmol) was treated with phenylboronic acid (43.6 mg, 0.358 mmol)
according to Method H to yield the title compound (28) (41.6 mg, 42%),
mp 115–116◦C (Found: [M + H]+•, 336.1590. C21H21NO3 requires
[M + H]+•, 336.1599). δH (300 MHz; CDCl3; Me4Si) 7.99 (1 H, d,
J 2.1 Hz, ArH), 7.50–7.40 (6 H, m, ArH), 6.54 (1 H, s, CH), 3.75 (4 H,
t, J 4.8, CH2CH2), 3.51 (4 H, t, J 5.0, CH2CH2), 2.79 (2 H, q, J 7.8,
CH2CH3), 1.31 (3 H, t, J 7.7, CH2CH3). δC (75 MHz; CDCl3; Me4Si)
[13] V. Percec, J.-Y. Bae, D. H. Hill, J. Org. Chem. 1995, 60, 1060.
[14] T. Ishiyama, Y. Itoh, T. Kitano, N. Miyaura, Tetrahedron Lett.
1997, 38, 3447.
[15] M. Cushman, D. Nagarathnam, Tetrahedron Lett. 1990, 31, 6497.
[16] C. W. Benjamin, A. H. Lin, J. Morris, D. G. Wishka,
R. R. Gorman, J. Pharmacol. Exp. Ther. 1993, 265, 457.
[17] P. E. Thompson, M. T. Hearn, J. Biochem. Biophys. Methods
1995, 30, 153.
[18] N. N. Vorozhtsov, A. T. Troschenko, Russ. J. Gen. Chem.
1938, 8, 424.
[19] Y. Sawada, T. Yanai, H. Nakagawa, Y. Tsukamoto, S. Yokoi,
M. Yanagi, T. Toya, H. Sugizaki, Y. Kato, H. Shirakura,
T. Watanabe, Y. Yajima, S. Kodama, A. Masui, Pest Manage.
Sci. 2003, 59, 25.
[20] J. E. Bishop, C. M. Mathis, J. M. Gerdes, J. M. Whitney,
A. M. Eaton, R. B. Mailman, J. Med. Chem. 1991, 34, 1612.
[21] R. B. Gammill, T. M. Judge, J. Morris, International Patent
WO 90/06921, 1990.
[22] V. R. Naik, H. B. Naik, Asian J. Chem. 2000, 12, 305.
[23] C. T. Chang, M. F.Young, F. C. Chen, Taiwan Kexue 1962, 16, 29.
176.1, 162.9, 148.6, 142.1, 135.7, 134.7, 130.3, 129.3, 128.5, 128.4,
•
123.3, 120.1, 86.2, 65.8, 45.1, 28.4, 15.4. m/z (ESI) 336 [M + H]+
6-Methyl-2-morpholin-4-yl-8-phenyl-4H-chromen-4-one (29)
.
8-Bromo-6-methyl-2-morpholin-4-yl-4H-chromen-4-one (95.0 mg,
0.293 mmol)wastreatedwithphenylboronicacid(39.3 mg, 0.322 mmol)
according to method H to yield the title compound (29) (28.2 mg, 30%),
mp 148–149◦C (Found: [M + H]+•, 322.1438. C20H19NO3 requires
[M + H]+•, 322.1443). δH (300 MHz;CDCl3;Me4Si)7.96(1 H, s,ArH),
7.49–7.43 (6 H, complex m, ArH), 6.67 (1 H, s, ArH), 3.76 (4 H, t, J
5.0, CH2CH2), 3.53 (4 H, t, J 5.0, CH2CH2), 2.50 (3 H, s, CH3). δC
(100 MHz; CDCl3; Me4Si) 176.1, 162.9, 148.6, 135.7, 135.6, 130.2,