Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5

Article abstract of DOI:10.1016/j.bmc.2005.11.036

Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To this end, a synthesis has been achieved of (R,S)-2-[(8-chlorobenzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a), a highly rigidified, polycyclic analog of 2-{4-[(7-chloro-2-quinoxalinyl) oxy]phenoxy}propionic acid (2a, XK469). Efforts to effect the same synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro (9a), and 8-bromo-2-hydroxybenzofurano[2,3-b]quinoline (9b), generated by halogen-exchange, via an aromatic S_RN1(A_RN1) reaction of precursor, 8b, with pyridine hydrochloride. The presumption that conformational restriction of 1b-12a might enhance the antitumor potency of the latter has not been sustained. In fact, 12a proved to be significantly less active than 1b. However, it is apparent that virtually all of the spatial and steric properties of 12a, necessary for improved activity, including the disposition of the 2-oxypropionic acid side chain remain to be identified.

Full text of DOI:10.1016/j.bmc.2005.11.036

Bioorganic & Medicinal Chemistry 14 (2006) 2462–2467
Synthesis and biological evaluation of conformationally constrained
analogs of the antitumor agents XK469 and SH80. Part 5
Stuart T. Hazeldine, Lisa Polin, Juiwanna Kushner, Kathryn White,
Thomas H. Corbett and Jerome P. Horwitz*
Department of Internal Medicine, Division of Hematology and Oncology, Wayne State University School of Medicine,
Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
Received 23 September 2005; revised 14 November 2005; accepted 14 November 2005
Available online 5 December 2005
Abstract—Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To
this end, a synthesis has been achieved of (R,S)-2-[(8-chlorobenzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a), a highly
rigidified, polycyclic analog of 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (2a, XK469). Efforts to effect the same
synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro (9a), and 8-bromo-2-hydroxybenzofur-
ano[2,3-b]quinoline (9b), generated by halogen-exchange, via an aromatic SRN1(ARN1) reaction of precursor, 8b, with pyridine
hydrochloride. The presumption that conformational restriction of 1b–12a might enhance the antitumor potency of the latter
has not been sustained. In fact, 12a proved to be significantly less active than 1b. However, it is apparent that virtually all of the
spatial and steric properties of 12a, necessary for improved activity, including the disposition of the 2-oxypropionic acid side chain
remain to be identified.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
OCH CH3 CO2H
Our recent studies have shown 2-{4-[(7-bromo-2-quinoli-
nyl)oxy]phenoxy}propionic acid (Fig. 1, 1a, SH80) to be a
X
N
O
highly and broadly active antitumor agent.1–3 However,
the mechanism of action of this agent, as is the case
with the closely related 2-{4-[(7-chloro-2-quinoxali-
nyl)oxy]phenoxy}propionic acid (2a, XK469), remains
unknown, though several disparate mechanisms of anti-
cancer action have been proposed for the latter.4a–i
1a. X = Br
b. X = Cl
c. X = F
d. X = CH3O
N
OCH CH3 CO2H
Lacking knowledge of a molecular target, we turned to
the classical pharmacophore approach, which is exem-
plified5 in an elegant study leading to the discovery of
the novel cholesterol-lowering agent, ꢀezetimibeꢁ. In the
latter effort, even the existence of the target itself was un-
known at the inception of the research. However, as the
discovery process continued, the nature of the target was
inferred from a consistent pattern of structure–activity
relationships (SARs).
X
N
O
2a. X = Cl
b. X = Br
c. X = F
d. X = I
e. X = CH3O
Figure 1.
The 7-halogen derivatives of 11 manifest the following
order of antitumor activity in mice: (a) Br > (b)
Cl > (c) F, whereas in 26 (a) Cl ꢀ (b) Br ꢀ (c) F > (d)
I. Interestingly, the activities of the former are greater
Keywords: XK469; SH80; Analogs; Conformational restriction;
Antitumor.
*
Corresponding author. Tel.: +1 313 833 0715x2522; fax: +1 313 831
7518; e-mail: horwitz@kci.wayne.edu
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.11.036

S. T. Hazeldine et al. / Bioorg. Med. Chem. 14 (2006) 2462–2467
2463
than, or at least comparable, to those of the correspond-
ing quinoxaline analogs (Fig. 1: 2a–e). It is also note-
worthy that the 7-methoxy analogs of both 1 and 2
exhibit levels of antitumor activity comparable to those
of the corresponding halogen derivatives.
proceeded from the 4-halo-2-nitrotoluenes, 3a and 3b.
The latter were converted to the enamines, 4a and b, on
treatment with N,N-dimethylformamide dimethyl acetal.
Periodate oxidation of the enamines to the corresponding
4-halo-2-nitrobenzaldehydes, 5a and 5b, was effected
according to procedures described by both Coe8a and
Caron et al.8b Reduction of 5a and 5b to amino deriva-
The criteria for maximum antitumor activity of both 1
and 2 also include linkage of the 7-halo(methoxy)-2-
quinolinyl, or -2-quinoxalinyl-moiety, via a 1,4-hydro-
quinone bridge, to the 2-carbon atom of an intact
(R)-propionic acid moiety.
9
tives, 6a and 6b, was readily achieved with FeSO4 and
NH3 in aqueous CH3OH. Friedla¨nder reactions,10 be-
tween (available) 2,5-dimethoxyphenylacetic acid (7)
and 6a and 6b, each in acetic anhydride, containing trieth-
ylamine, and in accord with the modified conditions of Bu
et al.11 provided the 7-halo-3-(2,5-dimethoxyphenyl)-2-
quinolinols 8a and 8b. Fusion of a mixture of 8a and anhy-
drous pyridine hydrochloride,11 followed by a period of
reflux for ca. 1.5 h, provided 8-chloro-2-hydroxybenzof-
uro[2,3-b]quinoline (9a) in 98% yield. By contrast, the
same reaction with 8b led to an equimolar mixture of
the chloro- and bromo-derivatives, 9a and 9b, as deter-
mined from 1H NMR, 13C NMR, and mass spectra.
Conformational restriction of bioactive molecules af-
fords an opportunity of gaining valuable insights in to
both topographical and chemical features of small mol-
ecule-binding sites. Such restriction also offers the possi-
bility of generating structures of increased potency,
which may result from a set of more favorable, hydro-
gen bonding, and hydrophobic interactions with the
putative receptor, together with a reduction in the entro-
pic penalty of the precursory flexible structure.7
The partial exchange of the 7-bromo substituent by chlo-
rine, in the process of cyclization of 8b in refluxing pyri-
dine hydrochloride leading to 9a, may be attributed to
the occurrence of an SRN1 reaction. Indeed, a radical
chain mechanism of aromatic nucleophilic substitution
by halogen, first recorded by Bunnett,12 is now well estab-
lished. The observed order of reactivity of the nucleofuge
in these transformations is ArI > ArBr > ArCl > ArF,
with the nucleophile, invariably, occupying the position
vacated by the leaving group. Of additional relevance is
the fact that aromatic SRN1 (ARN1) reactions occur as
well with halogen-substituted heterocyclic structures,
including pyridines, quinolines, and aromatic polynucle-
ar systems.
These considerations prompted efforts to introduce
restrictions in the mobility of the 2-oxyphenoxypropion-
ic acid moiety of 1a and 1b by conversion of the latter to
a series of polycyclic derivatives.
2. Results and discussion
2.1. Synthesis
Our approach to the highly rigidified polycyclic analogs
of 1a and 1b, 8-chloro- and 8-bromo-3-hydroxybenzo-
furo[2,3-b]quinolines (Scheme 1, 9a and 9b, respectively),
CHO
CHO
CH3
NO2
NH(CH3)2
c
b
a
X
NH2
X
X
NO2
X
NO2
4a, b
6a, b
3a. X = Cl
b. X = Br
5a, b
OH
OCH3
5'
3
OCH3
CO2H
d
6a, b
+
1
8
2'
O
e
X
X
N
H3CO
OCH3
X
N
O
9a, b
7
H
OH
8a, b
OCH(CH3)CO2R
O
N
f
10a
O
Cl
N
11a. R = CH3
12a. R = H
g, h
Scheme 1. Reagents and conditions: (a) (CH3)2N(OCH3)2/DMF/120 °C, 18 h; (b) NaIO4/THF-H2O/rt, 2 h; (c) FeSO4/NH3/CH3OH–H2O/80 °C, 1 h;
(d) Ac2O/Et3N/100 °C, 4 days; (e) pyridineÆHCl/reflux, 1.5 h; (f) CH3CHBrCO2CH3/K2CO3/CH3CN/reflux, 18 h; (g) NaOH/THF–H2O/rt, 18 h;
(h) aqueous HCl.

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S. T. Hazeldine et al. / Bioorg. Med. Chem. 14 (2006) 2462–2467
A model of 9a, as depicted in Figure 2, clearly indicates
a structure with planar core geometry. Were ring closure
to involve, instead, the distal 50-methoxy substituent of
8a, the reaction would lead to the non-planar pyran
structure (Fig. 2, 10a). Clearly, the latter would be ener-
getically much less favorable due to a large increase in
steric strain in the formation of bonds that would be
forced to assume abnormal angles in order to accommo-
date closure to the non-planar pyran ring of 12a.
[Pancreatic Adenocarcinoma 03 (Panc 03), Colon ade-
nocarcinoma 38 (Colon 38), and/or multi-drug-resistant
mammary-17/adriamycin-resistant and human colon
H15/MDR], in addition to normal-like fibroblast cells.
As (R,S)-12a manifested sufficient in vitro cytotoxicity
(see Table 1), in vivo studies were then conducted, as
previously described.1,13–19 Tumor selection was based
on our prior biological observations and findings that
2a and the 7-bromoquinoline derivative (1a) both exhib-
ited broad antitumor efficacy against several mouse tu-
mor models,13–17 including mammary adenocarcinoma
16/C, a metastatic, mouse tumor model18,19 (see Table
2). Although a higher IV total dose was administered,
the restricted conformation of 1b, that is, 12a, proved
to be inactive (63.5% T/C, 0.6 log kill; Table 2). Thus,
it is clear that the conformational restriction of 1b to
12a generated a product of dramatically reduced antitu-
mor efficacy and potency.
A 500 MHz NMR spectrum of the putative product
(9a), wherein aromatic ring proton #5 (Fig. 2) was irra-
diated concurrently at its exact frequency, produced
uncoupling of all aromatic protons, as would be
predicted by a Nuclear Overhauser Effect for the planar
structure. Etherification of 9a with (R,S)-methyl 2-
bromopropionate, followed by saponification of the
intermediate ester (11a), yielded (R,S)-2-[(8-chloro-
benzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a).
2.2. Cytotoxic activity
3. Conclusion
All analogs were initially evaluated in our in vitro disk
diffusion soft agar colony formation assay, as previously
described,1–3 to determine cytotoxicity against mouse
leukemia (L1210) cells, mouse and human solid tumors
Our presumption that conformational restriction of 1b
to 12a would enhance the antitumor potency of the lat-
ter has not been sustained. Indeed, to the contrary, 12a
proved to be significantly less active than 1b.
OH
3
H5
N
1
8
O
Cl
9a
OH
Cl
N
O
10a
Figure 2.
Table 1. In vitro cytotoxicity of selected racemic analogs of XK469 against leukemic cells, solid tumor cells, and normal cells in the disk-diffusion-
soft-agar-colony formation-assaya
Compound
lg/disk
Mouse leukemia
L1210
Mouse tumors
Panc 03
Human tumors
colon H15/MDR
Normal cells
fibroblasts
Colon 38
>800
Mam 17/Adr
(R,S)-1b
(R,S)-2a
(R,S)-12a
480
270
480
0–700
0–600
0–500
>900
600–800
>850
500–600
0–400
0–500
0–500
0–700
500–600
0–350
500–600
a Zone units recorded: 200 U = 6.5 mm.

S. T. Hazeldine et al. / Bioorg. Med. Chem. 14 (2006) 2462–2467
2465
Table 2. Intravenous treatment of mammary adenocarcinoma 16/C with selected analogsa
Compound
No. of iv
injections
Total dose
(mg/kg)
Drug deaths
% Body wt loss
at Nadir
T/C (%)
Log10 tumor
cell killb
Curesc
Activity
rating
(R,S)-1b
(R,S)-12a
6
9
300
698.8
0/5
0/5
ꢂ13.1
ꢂ3.5
0
63.5
3.0
0.6
1/5
0/5
++++
ꢂ
A T/C = 0% means no tumor growth (high antitumor activity).
A T/C = 100% means no antitumor activity, that is, the treated and control tumors grew equally.
a These agents were soluble in aqueous formulation (0.5% NaHCO3 + PBS; pH 7.4) and injected intravenously (iv) beginning one day after tumor
implantation; early stage disease for the rapidly growing Mam 16/C (1.0–1.2 day doubling). Two or three dosages were tested, with the highest
nontoxic dosage shown. Treatment was stopped when toxicity or significant weight loss occurred, or the drug supply was exhausted. A dose-
escalation schedule13 was administered for 12a.
b The log10 kill values were based on tumors that grew (cures were excluded from the calculation).
c All cured mice were re-implanted with 30 mg fragments of Mam 16/C after day 150. These rechallenged mice grew tumor to 1500 mg in the expected
fashion, with the expected Td, indicating that immunologic factors were not involved in the original cures.
On one hand, the disparity in molecular weights
(ꢁ2.0 amu) between 1b and 12a is negligible, and each
presents an identical number of hydrogen bond accep-
tors (5), and donors (1), though a comparison of physi-
cal parameters, such as logP and logD, remains to be
determined.
4.1. 7-Chloro-3-(2,5-dimethoxyphenyl)-2-quinolinol (8a)
A mixture of 6a8 (1.80 g, 11.6 mmol), 7 (4.55 g,
23.2 mmol), Et3N (6 mL), and Ac2O (60 mL) was heated
at 100 °C for 4 days. After cooling, it was concentrated
to give a yellow-brown solid to which water (100 mL)
and AcOEt (750 mL) were added. The mixture was heat-
ed until the solid dissolved and NaHCO3 added until pH
8. The layers were separated and the AcOEt layer was
washed several times with dilute NaHCO3 (25 mL) and
the combined NaHCO3 layers were extracted with
AcOEt (100 mL). Unreacted 2,5-dimethoxyphenylacetic
acid was recovered from the combined NaHCO3 layers
on acidification with concentrated HCl to pH 3. The
combined AcOEt layers were washed with saturated
NaCl (25 mL), dried with anhydrous MgSO4, and
recrystallized from AcOEt–CHCl3 to give 8a as pale yel-
low crystals (1.38 g, 38% yield). Mp 253–254 °C; 1H
NMR (400 MHz, DMSO-d6) d 11.91 (br s, 1H), 7.85
(s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.6 Hz,
1H), 7.20 (dd, J = 8.4, 1.6 Hz, 1H), 6.98 (d, J = 9.2 Hz,
1H), 6.90 (dd, J = 9.2, 3.2 Hz, 1H), 6.86 (d, J = 3.2 Hz,
1H), 3.70 (s, 3H), 3.65 (s, 3H).
It is plausible that the activities of 1b and 12a may be
attributed to intrinsic differences in such critical phar-
macological properties as absorption, distribution,
metabolism and excretion (ADME). A comparison of
the latter properties along with a comparison of logP
and logD, both of which were beyond the scope of the
present investigation, is currently the subject of an on-
going investigation. The latter also includes a quantita-
tive structure–activity relationship (CoMFA) study, that
is, currently, in progress.
4. Experimental
All commercially available solvents and reagents were
used without further purification. Melting points were
determined with a Thomas-Hoover melting point appa-
ratus and are uncorrected. Infrared spectra were mea-
sured on a Perkin-Elmer 1330 spectrometer in KBr
pellets. Nuclear magnetic resonance (1H and 13C
NMR) spectra were recorded at room temperature,
and referenced to a residual solvent signal, on a Varian
Mercury 400 or 500 instrument in the Department of
Chemistry, Wayne State University, Detroit, MI. Chem-
ical shifts are reported in parts per million downfield
from tetramethylsilane (TMS). The splitting pattern
abbreviations are as follows: s, singlet; d, doublet; t, trip-
let; q, quartet; b, broad; m, unresolved multiplet. Mass
spectra were recorded on instruments in the Department
of Chemistry, Wayne State University. Flash column
chromatography was carried out with silica gel 200–
4.2. 7-Bromo-3-(2,5-dimethoxyphenyl)-2-quinolinol (8b)
A mixture of 6b8 (2.46 g, 12.3 mmol), 7 (4.83 g,
24.5 mmol), Et3N (6 mL), and Ac2O (60 mL) was heated
at 100 °C for 4 days. It was isolated as in Section 4.1 to
give 8b as off-white crystals (2.45 g, 55%). Mp 252–
1
253 °C; H NMR (400 MHz, DMSO-d6) d 11.87 (br s,
1H), 7.85 (s, 1H), 7.61 (d, J = 8.0 Hz, lH),7.47(d,
J = 1.6 Hz, 1H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H), 6.98 (d,
J = 9.2 Hz, 1H), 6.90 (dd, J = 9.2, 3.2 Hz, 1H), 6.85 (d,
J = 3.2 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 3H).
4.3. 8-Chloro-2-hydroxybenzofuro[2,3-b]quinoline (9a)
˚
400 mesh, 60 A (Aldrich), and the crude product was
A mixture of 8a (1.37 g, 4.39 mmol), anhydrous pyridine
hydrochloride (14 g) was heated at gentle reflux for 1.5 h
until all the solid had dissolved. After cooling, water was
added and after the solid had broken up it was filtered,
washed with water, and dried to give 9a as a yellow-
brown solid (1.15 g, 98%). A sample was recrystallized
from CH3OH to give tan crystals. Mp 312–314 °C
introduced onto the column as a CHCl3 solution.
Thin-layer chromatography was performed on What-
man PE SIL G/UV (250 lm) plates. Compounds were
visualized by use of 254 or 366 nm light and I2 vapor.
Elemental analyses were performed by M-H-W Labora-
tories, Phoenix, AZ, and are within 0.3% of the calcu-
lated values.
1
(dec); H NMR (400 MHz, DMSO-d6) d 9.66 (s, 1H),

2466
S. T. Hazeldine et al. / Bioorg. Med. Chem. 14 (2006) 2462–2467
9.04 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.01 (d,
J = 1.6 Hz, 1H), 7.58 (dd, J = 8.8, 2.0 Hz, 1H), 7.54–
7.50 (m, 2H), 7.03 (dd, J = 8.8, 2.4 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) d 163.6, 154.8, 149.3, 146.2,
134.8, 130.9, 130.5, 127.0, 126.1, 124.8, 122.7, 118.6,
118.3, 112.8, 108.2. IR (KBr) 3160 (OH) cmꢂ1. ESI-
MS m/z 270 (M+l)+.
filtered. The filtrate was cooled and acidified to pH 3–
4 with 0.25 M HCl. After recooling, it was filtered and
washed with ice water to give a light yellow solid. This
was then recrystallized from EtOH to give 12a as light
tan crystals (0.38 g, 96% yield). Mp 261–262 °C; 1H
NMR (400 MHz, DMSO-d6) d 13.06 (br s, 1H), 9.06
(s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 2.4 Hz,
1H), 7.72 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H),
7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (dd, J = 8.8,
3.2 Hz, 1H), 4.95 (q, J = 6.4 Hz, 1H), 1.56 (d,
J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) d
173.7, 163.5, 154.8, 150.3, 146.2, 134.9, 130.9, 130.7,
127.0, 126.2, 124.8, 122.6, 118.6, 118.3, 113.0, 108.0,
4.4. Mixture of 8-chloro-(8-bromo-)2-hydroxybenzof-
uro[2,3-b]quinoline (9a and 9b)
A mixture of 8b (1.01 g, 2.80 mmol), anhydrous pyridine
hydrochloride (10 g) was heated at gentle reflux for 1.5 h
until all the solid had dissolved. It was isolated as in Sec-
tion 4.3 to give a yellow-brown solid (0.83 g). This was
determined to be an equal mix of the 8-bromo 9b and
8-chloro 9a isomers as determined by NMR and MS.
1H NMR (400 MHz, DMSO-d6) d 9.66 (s, Br + Cl),
8.90 + 8.89 (s, Br + Cl), 8.07 (d, J = 1.6 Hz, Br), 8.02
(d, J = 8.0 Hz, Cl), 7.95 (d, J = 8.8 Hz, Br), 7.90 (d,
J = 1.6 Hz, Cl), 7.59 (dd, J = 8.8, 1.6 Hz, Br + Cl),
7.51–7.43 (m, Br + Cl), 7.00 (dd, J = 8.8, 2.4 Hz,
Br + Cl). 13C NMR (100 MHz, DMSO-d6) d 163.6
(Br), 163.5 (Cl), 154.7 (Br + Cl), 149.3 (Br + Cl), 146.4
(Br), 146.2 (Cl), 134.8 (Br + Cl), 130.9 (Br + Cl), 130.5
(Br + Cl), 130.2 (Br), 128.6 (Br), 127.0 (Cl), 126.1 (Cl),
125.0 (Br), 124.8 (Cl), 123.5 (Br), 122.7 (Cl), 118.7
(Br), 118.6 (Cl), 118.3 (Br + Cl), 112.8 (Br + Cl), 108.2
(Br + Cl). ESI-MS m/z 313 (79Br, M)+, 314 (79Br,
M+l)+ 316 (81Br, M+1)+, 270 (35Cl, M+1)+, 272 (37Cl,
M+1)+.
73.0, 19.0. IR (KBr) 3440 (OH), 1715 (C@O) cmꢂ1
.
ESI-MS m/z 342 (M+l)+. Anal. (C18H12NO4Cl): C,
63.26; H, 3.54; N, 4.10. Found: C, 63.35; H, 3.55; N,
3.91.
Acknowledgments
The authors are grateful for the support of this research
through grants from the National Institutes of Health
(CA82341), and the Jack and Miriam Schenkman Re-
search Fund. Thanks are also due to the Resource Lab-
oratory of the Chemistry Department, Wayne State
University, Detroit, MI, wherein instrumental analyses
were performed.
Supplementary data
4.5. Methyl 2-[(8-chloro-2-benzofuro[2,3-b]quinoli-
nyl)oxy]propionate (11a)
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2005.11.036.
A mixture of 9a (0.44 g, 1.6 mmol), methyl 2-bromopro-
pionate (0.27 mL, 0.40 g, 2.4 mmol), anhydrous K2CO3
(0.28 g, 2.0 mmol), and CH3CN (15 mL) was refluxed
together overnight. The mixture was filtered hot, washed
with hot CHCl3, and the filtrate was purified by filtering
through silica gel, washing with 2:1 CHCl3–AcOEt.
After concentrating, this mixture was recrystallized from
EtOH to give 11a as tan-yellow crystals (0.51 g, 88%
References and notes
1. Hazeldine, S.; Polin, L.; Kushner, J.; White, K.; Boure-
geois, N. H.; Crantz, B.; Palomino, E.; Corbett, T. H.;
Horwitz, J. P. J. Med. Chem. 2002, 45, 3130–3137.
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T. H.; Biehl, J.; Horwitz, J. P. Bioorg. Med. Chem. 2005,
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1
yield). Mp 186–187 °C; H NMR (400 MHz, CDCl3) d
8.45 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.81 (d,
J = 9.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.41 (dd,
J = 8.8, 1.6 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.09 (dd,
J = 8.8, 2.4 Hz, 1H), 4.84 (q, J = 6.4 Hz, 1H), 3.79 (s,
3H), 1.68 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 172.7, 163.6, 154.4, 151.1, 146.5, 135.7,
129.4, 129.0, 127.6, 126.3, 124.4, 122.6, 118.4, 118.2,
113.0, 107.7, 74.0, 52.7, 18.9. IR (KBr) 1765 (C@O) cm1.
ESI-MS m/z 356 (M+l)+. Anal. (C19H14NO4C1): C,
64.14; H, 3.97; N, 3.94. Found: C, 64.12; H, 3.78; N,
3.77.
3. Hazeldine, S.; Polin, L.; Kushner, J.; White, K.; Corbett,
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