Synthetic modification of the 2-oxypropionic acid moiety in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469), and consequent antitumor effects. Part 4

Article abstract of DOI:10.1016/j.bmc.2005.04.011

The criteria for the activity of 2-{4-[(7-chloro-2-quinoxalinyl)oxy] phenoxy}propionic acid (XK469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy} propionic acid (SH80) against transplanted tumors in mice established in previous studies, require a (7-halo-2

Full text of DOI:10.1016/j.bmc.2005.04.011

Bioorganic & Medicinal Chemistry 13 (2005) 3910–3920
Synthetic modification of the 2-oxypropionic acid moiety
in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic
acid (XK469), and consequent antitumor effects. Part 4
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 21 February 2005; revised 6 April 2005; accepted 6 April 2005
Available online 28 April 2005
Abstract—The criteria for the activity of 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) and 2-{4-[(7-bromo-
2-quinolinyl)oxy]phenoxy}propionic acid (SH80) against transplanted tumors in mice established in previous studies, require a (7-
halo-2-quinoxalinoxy)- or a (7-halo-2-quinolinoxyl)-residue, respectively, bridged via a 1,4-OC6H4O-linker to C2 of propionic acid.
The present work demonstrates that substitution of fluorine at the 3-position of the 1,4-OC6H4O-linker of XK469 leads to a 10-fold
reduction in activity, whereas the corresponding 2-fluoro analog proved to be 100-fold less active than XK469. Moreover, the latter
tolerated substitution of but a single, additional methyl group to the 2-position of the propionic acid moiety, that is, the isobutyric
acid analog, without loss of significant in vivo activity. Indeed, an intact 2-oxypropionic acid moiety is a prerequisite for maximum
antitumor activity of 1a.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
very probably similar for both) have been proposed
for 1a.5a–i In the absence of a validated target, our en-
deavor continued to pursue the elaboration of a phar-
macophoric pattern for these structures to gain a
perception of the binding pocket of the receptor, which,
as suggested by Strader,6 may be inferred from the per-
spective of the ligand.
Compounds 1a and 2a, (R+)-2-{4-[(7-chloro-2-quinox-
alinyl)oxy]phenoxy}propionic acid (XK469), and (R+)-
2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid
(SH80), respectively (Fig. 1), are two of the most highly
and broadly active antitumor agents to have been devel-
oped in our laboratories.1–4 The mechanism(s) of action
of these agents remain to be established, though several,
disparate pathways of anticancer action (which are
Our previous studies7–9 clearly established that location
of a halogen substituent in the benzene (ring-A) of either
Figure 1.
Keywords: XK469; SH80; Analogs; Antitumor.
*
Corresponding author. Tel.: +1 313 833 0715x2522; fax: +1 313 831 7518; e-mail: horwitz@kci.wayne.edu
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.04.011

S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
3911
1a or 2a, at other than the 7-position, markedly altered
both the in vitro and in vivo activities of corresponding
analogs. Thus, the 3-, 5-, 6-, and 8-regioisomers of 1a, as
well as the 6-chloro analog of 2a, were all essentially
inactive. In contrast, all of the 7-halogen derivatives
(Fig. 1, 1a–d) proved to be active compounds, with rel-
ative antitumor activities of Cl ꢀ F ꢀ Br > I. Analogs of
2a, bearing either a 7-halogen or a 7-methoxy substitu-
ent (Fig. 1, 2a–e), showed levels of antitumor activities
in mice (Br > Cl > CH3O > F ꢀ I), comparable to or
greater than those manifested by the corresponding quin-
oxaline derivatives, 1a–e. Specifically, the order of
(3) resulted in a loss of antitumor activity, whereas the
corresponding 2-hydroxyisobutyric acid analog (4) man-
ifested reduced in vitro antitumor activity relative to 1a
(Tables 1 and 2). However, short chain alkyl esters of 1a,
as well as both the unsubstituted and the mono N-
alkylamide derivatives of 1a show only minor decreases
in activity, relative to the parent structures.7
In summary, the criteria established, to date, for the
antitumor activity of 1 and 2 include either a (7-halo-
2-quinoxalinoxy)- or a (7-halo-2-quinolinoxyl)-residue,
bridged via a 1,4-OC6H4O-linker to C2 of propionic
acid. Herein, we describe the antitumor effects in mice
consequent to further modification of the 2-(4-oxyphen-
oxy)propionic acid of 1a.
activity of the 7-halogen substituent in
1
is
Cl ꢀ F ꢀ Br > I, whereas in 2, Br > Cl > F > I. More-
over, the R-enantiomers of both 1a and 2a were the
more active of the respective antipodes.
The 5-, 6-, 7-, and 8-chloroquinazoline analogs of 1, and
as well the 6- and 7-chloro-[1,2,4]-benzotriazine analogs,
were all inactive. Changes in the hydroquinone (1,4)
linkage in 1a to either a resorcinol (1,3), or a catechol
(1,2) derivative produced inactive structures, as did
replacement of either the 1- or 4-oxygen atoms compris-
ing the hydroquinone bridge by sulfur or nitrogen.
2. Results and discussion
2.1. Synthesis
Our endeavor turned first to modifications of the linker
of 1a with syntheses of both 2-{4-[(7-chloro-2-quinoxalin-
yl)oxy]-2- and 3-fluoro-phenoxy}propionic acids (Scheme
1, 10a and 10b, respectively). Preparations of the inter-
mediates, methyl 2-(4-amino-2-fluoro- and 3-fluoro-
phenoxy)propionates (6a and 6b), proceeded from the
Our preliminary in vitro data indicated7 that replace-
ment of the lactic acid moiety in 1a by glycolic acid
Table 1. In vitro cytotoxicity of selected racemic analogues of (R,S)-XK469 (1a) against leukemic cells, solid tumor cells, and normal cells in the disk-
diffusion-soft-agar-colony-formation-assaya,b
Compound number lg/disk Mouse leukemia
Mouse tumors
Human tumors
Normal cells
L1210
Panc 03 Colon 38 Mam 17/Adr Colon H116 Colon H15/MDR Fibroblasts
1a
3c
270
225
465
305
535
500
480
530
470
510
0–600
0–50
>800
>850
150–400
0–90
500–600
0
40
800–900 500–600
0–60
0–30
0–100
80
4c
13
0–400
100–190
0–450
0–100
0–380
200–450
0–200
0–450
0–200
0
0–500
80
19b
22
>900
0–250
700–800
300–400
400
0–250
0–100
450
0–500
0–150
0–600
0
200–500
500–800
26b
28b
30b
32b
200–380
0–600
0–600
0–250
500–900
600–900 500–600
550–650
100–200
0–100
200–400
0–250
0–250
a For a detailed description of the testing methodologies, see Refs. 7–9.
b Zone units recorded: 200 units = 6.5 mm.
c First prepared and evaluated as a potential herbicide by DuPont Pharmaceutical Company.
Table 2. Evaluation of selected analogues of XK-469 (1a) against solid tumors of micea
Compound number SC tumor No. of
injections
Total dose Drug deaths % Body wt. loss T/C (%) Log10 tumor Cures Activity
(mg/kg)
at Nadir
cell kill
rating
1a
1a
Colon 38
Panc 03
Panc 03
Panc 03
Panc 03
Panc 03
Panc 03
Panc 03
9
473
300
480
330
565
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
À1.7
À15.0
À7.4
À9.4
+4.2
0
4
3.9
3.3
2.2
0.8
1.5
0.74
0.0
0.4
2/5
1/5
0/5
0/5
0/5
0/5
0/5
0/5
++++
++++
+++
+
5
4
8 (IV)
5 (IV)
8 (PO)b
8 (IV/PO)c 477
15
18
10a
10b
19b
28b
30b
14
30
++
+
À7.5
À0.0
À0.0
11 (IV)
9 (IV)
615
555
>100
94
À
À
a For a detailed description of testing methodologies, see Refs. 7–9.
b The indicated dose (60–84 mg/kg/day) was administered as an insoluble suspension by the oral (PO) route. Lower doses were soluble, but 50 mg/kg
IV produced pronounced gait disturbances, hyperactivity, and acute agitation. These symptoms resolved within 10 min of IV injection.
c The analog was injected IV on days 3–9. The route was changed on day 10 (8th day of treatment) to PO due to tail vein damage.

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S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
Scheme 1. Reagents: (a) CH3CHBrCO2CH3/K2CO3/acetone; (b) H2/Pd–C/CH3OH; (c) (i) NaNO2/aqueous H2SO4; (ii) aqueous Cu(NO3)2/Cu2O; (d)
K2CO3/CH3CN; (e) (i) aqueous NaOH/THF; (ii) aqueous HCl.
corresponding 4-nitrophenols (5a and 5b), as described
by Rogers.10 Conversion of 6a and 6b to the phenol
derivatives, 7a and 7b, was achieved according to the
methodology reported by Cohen et al.11 Reaction of
7a and 7b with 2,7-dichloroquinoxoline (8),7 followed
by saponification of the corresponding esters, 9a and
9b, provided 10a and 10b, respectively.
methyl 3,3,3-trifluoro-2-diazopropionate (11)12 in tolu-
ene, readily reacted13 with 4-(7-chloro-2-quinoxalinyl-
oxy)phenol (12) to afford 13, though in rather low
(21%) yield. However, repeated, attempts to effect the
selective saponification of the latter led, instead, to
wholesale degradation of the molecule.
The synthesis of 1-{4-[(7-chloro-2-quinoxalinyl)-oxy]-
phenoxy}cyclopropanecarboxylic acid (19b), an analog
of 4, required the preparation of intermediate, 3-(4-
benzyloxyphenoxy)-butyrolactone (16). The latter was
obtained via the alkylation of 4-benzyloxyphenol (14)
with a-bromo-c-butyrolactone (15), which was readily
Efforts then shifted to analogs of the propionic acid moi-
ety in 1a with the preparation, initially, of methyl 2-{4-
[(7-chloro-2-quinoxalinyl)oxy]phenoxy}-3,3,3-trifluoro-
propionate (Scheme 2, 13). The carbenoid-intermediate
generated from a rhodium-catalyzed-decomposition of
Scheme 2. Reagents: (a) Rh2(OAc)4/PhCH3; (b) KF–Celite/CH3CN; (c) I2/CH3OH; (d) p-toluenesulfonyl chloride, Et3N/CH2Cl2; (e) NaH/DME; (f)
H2/Pd–C/CH3OH; (g) K2CO3/CH3CN; (h) (i) aqueous NaOH/THF; (ii) aqueous HCl; (i) H2/Pd–C/AcOEt.

S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
3913
effected in the presence of KF-coated Celite.14 Trans-
esterification of 16 with methanol in the presence of io-
dine, followed by p-tosylation yielded methyl 2-(4-
(25b). Etherification of the latter with 8, followed by
saponification of intermediate 26a, afforded 26b.
benzyloxyphenoxy)-4-p-toluenesulfonylbutyrate
(17).
Reduction of 25a with aluminum–nickel alloy in aque-
ous alkali16 gave 3-(4-hydroxyphenyl)-2-methylprop-
ionic acid (27a), which on successive esterification with
MeOH, O-alkylation with 8, followed by saponification,
yielded the methylene isostere of 1a, that is, 3-{4-[(7-
chloro-2-quinoxalinyl)oxy]phenyl}-2-methylpropionic
acid (28b).
Cyclization of 17 on treatment with NaH in DME, as
described by Chan,15 and catalytic (H2/Pd–C) debenzyl-
ation of the latter yielded methyl 1-(4-hydroxyphen-
oxy)cyclopropanecarboxylate (18). Etherification of 18
with 8, followed by saponification of 19a, afforded 19b.
The route to 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phen-
oxy}-4-hydroxybutyric acid (22), a hydroxyethyl analog
of 1a, proceeded with the debenzylation (H2/Pd–C)
of 16 to give 3-(4-hydroxyphenoxy)butyrolactone (20).
Reaction of the latter with 8 provided 3-{4-[(7-chloro-
2-quinoxalinyl)oxy]phenoxy}butyrolactone (21), which
was then converted, on alkaline hydrolysis, to 22.
2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenyl}propionic acid
(30b) was obtained by conversion of commercially avail-
able 2-(4-hydroxyphenyl)propionic acid (29a) to the
corresponding methyl ester (29b), followed by successive
O-alkylation of the latter with 8, and hydrolysis of the
intermediate (30a) to 30b.
Preparation of 3-{4-[(7-chloro-2-quinoxalinyl)oxy]-
phenyl}-2-methyl-2-propenoic acid (Scheme 3, 26b)
was initiated with 3-(4-hydroxyphenyl)-2-methyl-2-
propenoic acid (25a), which was obtained by a Knove-
naegel condensation reaction, according to that utilized
by Papa16,17 et al. for the synthesis of the corresponding
3,5-diiodo derivative. Thus, condensation of 4-hydroxy-
benzaldehyde (23) and propionic anhydride (24), in the
presence of sodium propionate, yielded 25a, which
was, then, converted to the corresponding methyl ester
Lastly,
4-{4-[(7-chloro-2-quinoxalinyl)oxy]phenyl}-
butyric acid (32b) was prepared by etherification of
methyl 4-(4-hydroxyphenyl)butyrate (31c),18 with 8,
followed by saponification of 32a.
2.2. Cytotoxic activity
All analogs of 1 were initially evaluated in our in vitro
disk diffusion soft agar colony formation assay, as pre-
viously described,7–9 to determine cytotoxicity against
Scheme 3. Reagents: (a) EtCO2Na; (b) CH3OH/H2SO4; (c) K2CO3/CH3CN; (d) (i) aqueous NaOH/THF; (ii) aqueous HCl; (e) (i) Al–Ni/aqueous
NaOH; (ii) aqueous HCl; (f) HBr.

3914
S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
mouse leukemia (L1210) cells, Pancreatic Ductal Carci-
noma (Panc) 03, Colon 38, and/or multi-drug resistant,
Mammary-16/C/Adriamycin-resistant solid tumor cells,
human colon cell lines H116 and H15 (multi-drug resis-
tant), in addition to normal-like fibroblast cells. In vivo
studies were carried out, as previously described,7–9 with
only those analogs that manifested significant in vitro
cytotoxicity, using Panc 03 tumor, transplanted into
BDF1-mice. Tumor-selection was based on the observa-
tion that Panc 03 affords responses comparable to that
of Colon 38 in the evaluation of 1a (see Table 2).
were recorded on instruments in the Department of
Chemistry, Wayne State University. Flash column chro-
matography was carried out with silica gel 200–400
˚
mesh, 60 A (Aldrich), and the crude product was intro-
duced on to the column as a CHCl3 solution. Thin-layer
chromatography was performed on Whatman PE SIL
G/UV (250 lm) plates. Compounds were visualized by
use of 254 or 366 nm light and I2 vapor. Elemental anal-
yses were performed by M-H-W Laboratories, Phoenix,
AZ and are within 0.3% of the calculated values.
4.1. General method of the preparation of esters
The absence of in vitro activity in the glycolic acid ana-
log (3) of 1 (see above) is confirmed by the data shown in
Table 1. By contrast, substitution of a methyl group at
the 2-position of the propionic acid moiety of 1a, that
is, the (isobutyric acid) analog 4, showed good in vitro
activity, albeit with higher dose requirements. More-
over, 4 showed significant in vivo activity (2.2 log kill)
without toxicity at an IV total dose of 480 mg/kg (Table
2). However, at individual (IV) doses of 60 mg/kg race-
mic 4 showed a reversible slowing of nerve conduction
velocity, manifested by uncoordinated hind leg move-
ments. This phenomenon was noted previously8 in the
evaluation of much higher doses of racemic and/or
(S)-analogs of 1a and 2a.
A mixture of 8, the phenol, anhydrous K2CO3, and
CH3CN was refluxed until the reaction was complete.
The hot mixture was filtered, the residue was washed
with warm acetone, and the filtrate was evaporated to
dryness. The crude residue was purified by flash column
chromatography, followed by crystallization.
4.2. General procedure for the hydrolysis of esters
To a solution of the ester dissolved in tetrahydrofuran
(THF), was added, in portions, 0.1 M NaOH and the
mixture was stirred overnight at room temperature.
The reaction mixture was concentrated, filtered to re-
move insoluble material, and then cooled and adjusted
to pH 3–4 with 0.25 M HCl. The solid that deposited
on further cooling was collected, washed with ice-water,
dried, and crystallized.
The cyclopropyl derivative (19b), which was minimally
active against Panc 03 (log kill 0.74), also produced
the slowing of nerve conduction velocity at lower indi-
vidual doses than those noted in the treatment of 1a
and 2a. In addition, 19b, as apparent in Table 2, was
inferior to 4 in terms of tumor efficacy. Both 28b and
30b yielded sufficiently interesting in vitro data to war-
rant in vivo evaluation. However, neither analog was ac-
tive against Panc 03, even with the injection of elevated,
total doses of each (Table 2).
4.3. Methyl 2-(2-fluoro-4-nitrophenoxy)propionate10
1
Mp 54–57 ꢁC; H NMR (400 MHz, CDCl3) d 8.01 (d,
J = 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 6.92 (t,
J = 8.0 Hz, 1H), 4.92 (q, J = 6.8 Hz, 1H), 3.78 (s, 3H),
1.71 (d, J = 6.4 Hz, 3H).
4.4. Methyl 2-(4-amino-2-fluorophenoxy)propionate10
(6a)
3. Conclusion
The present biological findings clearly indicate that an
intact 2-oxypropionic acid moiety is a sine qua non to
maximize the antitumor activity of 1a, and presumably
2a as well.
1H NMR (400 MHz, CDCl3) d 6.81 (t, J = 8.8 Hz, 1H),
6.42 (dd, J = 12.0, 2.4 Hz, 1H), 6.34–6.29 (m, 1H), 4.59
(q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.58 (br s, 2H), 1.57 (d,
J = 7.6 Hz, 3H).
4.5. Methyl 2-(2-fluoro-4-hydroxyphenoxy)propionate10,11
(7a)
4. Experimental
All commercially available solvents and reagents were
used without further purification. Melting points were
determined on a Thomas–Hoover melting point appara-
tus and are uncorrected. Infrared spectra were measured
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 instru-
ment in the Department of Chemistry, Wayne State
University, Detroit, MI. Chemical shifts are reported
in parts per million downfield from tetramethylsilane
(TMS). The splitting pattern abbreviations are as fol-
lows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quin-
tet; br, broad; m, unresolved multiplet. Mass spectra
To a solution of 6a (1.06 g, 4.97 mmol) in 1 M H2SO4
(17.5 mL) at 0 ꢁC, NaNO2 (0.36 g, 5.2 mmol) in dis-
solved in water (5 mL) was added dropwise and the
solution stirred for an additional 0.25 h. A solution of
Cu(NO3)2Æ2.5H2O (23.26 g, 100 mmol) in water
(175 mL) was added followed by Cu2O (0.81 g,
5.5 mmol) and the mixture stirred vigorously for 0.5 h.
AcOEt (50 mL) was added and the insoluble material fil-
tered off. The layers were separated and the aqueous
layer extracted with AcOEt (50 mL). The combined ex-
tracts were washed with saturated NaCl (10 mL), dried
with anhydrous MgSO4 and concentrated to give a
brown liquid. This was purified by chromatography
(4:1 hexanes–AcOEt) to give a dark yellow liquid

S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
3915
1
(0.85 g 80% yield). H NMR (400 MHz, CDCl3) d 6.81
376 (M+, 38), 317 (24), 290 (17), 262 (39), 219 (9), 205
(14), 163 (33), 136 (17), 129 (12), 100 (12), 97 (13), 95
(16), 91 (22), 81 (45), 73 (26), 69 (100), 67 (22), 60
(22), 57 (31), 55 (46), 45 (15); Anal. (C18H14N2ClFO4)
C, H, N.
(t, J = 9.2 Hz, 1H), 6.59 (dd, J = 12.4, 2.4 Hz, 1H),
6.49–6.43 (m, 1H), 6.14 (br s, 1H), 4.65 (q, J = 6.8 Hz,
1H), 3.76 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H).
4.6. Methyl 2-(3-fluoro-4-nitrophenoxy)propionate
4.10. 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]-2-fluorophen-
oxy}propionic acid (10a)
Using the procedure for the preparation of esters (Sec-
tion 4.1): 5b (5.15 g, 32.5 mmol), methyl 2-bromopropio-
nate (4.02 mL, 6.02 g, 35.7 mmol), anhydrous K2CO3
(5.61 g, 40.6 mmol), and acetone (75 mL) gave a light
Ester 9a (1.17 g, 3.11 mmol), THF (50 mL), and 0.1 M
NaOH (62 mL, 6.2 mmol) gave 10a (0.83 g, 73% yield),
after recrystallization from EtOH–heptane, as white
1
yellow liquid (7.67 g, 97% yield): H NMR (400 MHz,
1
CDCl3) d 8.08 (t, J = 8.8 Hz, 1H), 6.74–6.67 (m, 2H),
4.83 (q, J = 6.8 Hz, 1H), 3.79 (s, 3H), 1.67 (d,
J = 7.2 Hz, 3H).
crystals: mp 152–153 ꢁC; H NMR (400 MHz, DMSO-
d6) d 13.20 (br s, 1H), 8.84 (s, 1H), 8.05 (d, J = 9.2 Hz,
1H), 7.83 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.0, 1.6 Hz,
1H), 7.37 (dd, J = 11.6, 2.8 Hz, 1H), 7.05–6.85 (m,
2H), 4.94 (q, J = 6.8 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) d 173.3, 158.0, 152.0
(d, J = 244 Hz), 146.1 (d, J = 10 Hz), 143.9 (d,
J = 10 Hz), 140.8, 140.5, 138.4, 135.8, 131.0, 128.9,
126.8, 118.1 (d, J = 3 Hz), 116.2, 111.5 (d, J = 20 Hz),
73.3, 18.9; 19F NMR (376 MHz, DMSO-d6) d 55.02
(m); IR (KBr) 3430 (OH), 1710 (C@O) cmÀ1. MS
(EI) m/z (%) 362 (M+, 100), 317 (17), 303 (5), 290 (72),
262 (78), 237 (9), 233 (6), 163 (82), 136 (45), 128 (22),
100 (28), 83 (13), 73 (11), 69 (12), 57 (16), 55 (18), 43
(22), 41 (11); HRMS (EI) m/z 362.0465 (M+, calcd for
C17H12N2ClFO4 362.0470). Anal. (C17H12N2ClFO4) C,
H, N.
4.7. Methyl 2-(4-amino-3-fluorophenoxy)propionate (6b)
Using the same procedure9 as for 6a: 5b (1.22 g,
5.02 mmol), 5% Pd–C (0.06 g), and CH3OH (25 mL)
gave a brown liquid (1.07 g, 100% yield): 1H NMR
(400 MHz, CDCl3) d 6.73 (dd, J = 10.0, 8.0 Hz, 1H),
6.63 (dd, J = 12.0, 2.4 Hz, 1H), 6.55–6.50 (m, 1H),
4.63 (q, J = 6.8 Hz, 1H), 3.86 (br s, 2H), 3.75 (s, 3H),
1.58 (d, J = 7.6 Hz, 3H).
4.8. Methyl 2-(3-fluoro-4-hydroxyphenoxy)propionate
(7b)
Using the same procedure11 as for 7a: 6b (1.07 g,
5.02 mmol) in 1 M H2SO4 (17.5 mL), was converted into
the diazonium salt with NaNO2 (0.36 g, 5.2 mmol) in
water (5 mL). Followed by its decomposition with
Cu2O (0.81 g, 5.5 mmol) and Cu(NO3)2Æ2.5H2O
(23.26 g, 100 mmol) in water (175 mL). This gave an or-
ange-yellow liquid (0.45 g 42% yield) after purification
by chromatography (4:1 hexanes–AcOEt): 1H NMR
(300 MHz, CDCl3) d 6.87 (dd, J = 10.2, 8.7 Hz, 1H),
6.67 (dd, J = 11.7, 2.7 Hz, 1H), 6.58–6.51 (m, 1H),
5.07 (br s, 1H), 4.65 (q, J = 6.9 Hz, 1H), 3.76 (s, 3H),
1.58 (d, J = 6.9 Hz, 3H).
4.11. Methyl 2-{4-[(7-chloro-2-quinoxalinyl)oxy]-3-fluo-
rophenoxy}propionate (9b)
Quinoxaline 8 (0.38 g, 1.9 mmol), 7b (0.45 g, 2.1 mmol),
anhydrous K2CO3 (0.36 g, 2.6 mmol), and CH3CN
(10 mL) were refluxed for 4 h. This was purified by chro-
matography (5:1 hexanes–AcOEt) to give a white solid.
It was recrystallized from AcOEt–heptane to give 9b
(0.39 g, 54% yield) as white crystals: mp 120–122 ꢁC;
1H NMR (400 MHz, CDCl3) d 8.70 (s, 1H), 7.98 (d,
J = 8.8 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.54 (dd,
J = 8.8, 2.4 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 6.78 (dd,
J = 11.2, 3.2 Hz, 1H), 6.73–6.69 (m, 1H), 4.76 (q,
J = 6.4 Hz, 1H), 3.81 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 172.4, 157.0, 156.2 (d,
J = 9 Hz), 154.9 (d, J = 249 Hz), 140.7, 138.8, 138.4,
136.6, 134.0 (d, J = 13 Hz), 130.3, 128.7, 127.0, 124.3
(d, J = 2 Hz), 110.8 (d, J = 3 Hz), 104.8 (d, J = 22 Hz),
73.4, 52.8, 18.8; 19F NMR (376 MHz, CDCl3) d 59.89
(m); IR (KBr) 1740 (C@O) cmÀ1. MS (EI) m/z (%)
376 (M+, 100), 317 (82), 289 (18), 273 (14), 262 (53),
163 (55), 136 (28), 128 (14), 124 (5), 100 (18), 87 (6),
82 (7), 75 (6), 73 (5), 59 (19), 55 (8). Anal.
(C18H14N2ClFO4) C, H, N.
4.9. Methyl 2-{4-[(7-chloro-2-quinoxalinyl)oxy]-2-fluoro-
phenoxy}propionate (9a)
2,7-Dichloroquinoxaline (8) (0.72 g, 3.6 mmol), 7a
(0.85 g, 4.0 mmol), anhydrous K2CO3 (0.69 g,
5.0 mmol), and CH3CN (20 mL) were refluxed for 4 h.
This was purified by chromatography (4:1 hexanes–
AcOEt) to give a white solid. It was recrystallized from
EtOH to give 9a (1.21 g, 89% yield) as white crystals: mp
109–111 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.63 (s, 1H),
7.96 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.54
(dd, J = 8.8, 2.4 Hz, 1H), 7.10 (dd, J = 11.2, 2.4 Hz,
1H), 6.97 (dd, J = 8.8, 8.0 Hz, 1H), 6.96 (dd, J = 9.2,
2.8 Hz, 1H), 4.79 (q, J = 6.4 Hz, 1H), 3.79 (s, 3H),
1.68 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.12. 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]-3-fluorophen-
oxy}propionic acid (10b)
d
172.3, 157.3, 153.2 (d, J = 248 Hz), 146.9 (d,
J = 9 Hz), 143.5 (d, J = 10 Hz), 140.6, 139.4, 138.4,
136.6, 130.3, 128.7, 127.0, 118.0 (d, J = 2 Hz), 117.3
(d, J = 4 Hz), 111.2 (d, J = 22 Hz), 75.2, 52.7, 18.8; 19F
Ester 9b (0.42 g, 1.1 mmol), THF (10 mL), and 0.1 M
NaOH (22 mL, 2.2 mmol) give 10b (0.30 g, 74% yield),
after recrystallization from EtOH–water, as white crys-
tals: mp 215–217 ꢁC; H NMR (400 MHz, DMSO-d6)
d 13.17 (br s, 1H), 8.94 (s, 1H), 8.07 (d, J = 8.8 Hz,
1
NMR (376 MHz, CDCl3)
d
52.30 (dd, J = 11.3,
8.3 Hz); IR (KBr) 1735 (C@O) cmÀ1; MS (EI) m/z (%)

3916
S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
1H), 7.81 (d, J = 2.8 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz,
1H), 7.39 (t, J = 8.8 Hz, 1H), 7.02 (dd, J = 12.0,
3.2 Hz, 1H), 6.80 (br dd, J = 9.2, 2.0 Hz, 1H), 4.93 (q,
J = 6.8 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H); 13C NMR
6.88 (m, 2H), 5.02 (s, 2H), 4.84 (t, J = 8.0 Hz, 1H),
4.54–4.47 (m, 1H), 4.36–4.29 (m, 1H), 2.72–2.62 (m,
1H), 2.50–2.39 (m, 2H).
(100 MHz, DMSO-d6)
d 173.4, 157.3, 156.8 (d,
4.16. Methyl 2-(4-benzyloxyphenoxy)-4-hydroxybutyrate
J = 10 Hz), 154.7 (d, J = 246 Hz), 140.4, 140.1, 138.5,
136.0, 133.3 (d, J = 13 Hz), 131.0, 129.0, 126.7, 125.0,
111.6, 104.6 (d, J = 22 Hz), 72.7, 18.8; 19F NMR
(376 MHz, DMSO-d6) d 57.02 (m); IR (KBr) 3410
(OH), 1705 (C@O) cmÀ1; MS (EI) m/z (%) 362 (M+,
29), 323 (54), 317 (7), 303 (7), 290 (11), 278 (8), 262
(25), 250 (49), 236 (8), 163 (22), 142 (100), 140 (7), 136
(12), 128 (10), 115 (17), 105 (14), 83 (10), 77 (11), 69
(14), 57 (16), 55 (16); HRMS (EI) m/z 362.0469 (M+,
Lactone 16 (2.60 g, 9.14 mmol), I2 (0.05 g), and CH3OH
(50 mL) were refluxed overnight. After the mixture was
concentrated, water (25 mL) was added followed by
Na2SO3 to remove the I2. The mixture was extracted
with AcOEt (2 · 25 mL) and the extracts washed with
saturated NaCl (10 mL), dried with anhydrous MgSO4,
and concentrated to a small volume and recrystallized
from AcOEt–hexanes (2·) to give unreacted lactone 16
(0.55 g). The combined filtrates were purified by chro-
matography (2:1 hexanes–AcOEt) to give an addition
(0.27 g) of unreacted lactone 16 and the product
(1.92 g, 66% yield) as a colorless liquid, which solidified:
calcd
for
(C17H12N2ClFO4) C, H, N.
C17H12N2ClFO4
362.0470);
Anal.
4.13. Methyl 3,3,3-trifluoro-2-diazopropionate (11)
1
mp 39–41 ꢁC; H NMR (400 MHz, CDCl3) d 7.43–7.30
(m, 5H), 6.92–6.82 (m, 4H), 5.01 (s, 2H), 4.79 (t,
J = 6.0 Hz, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.76 (s, 3H),
2.18 (q, J = 6.0 Hz, 2H).
By using the reported procedure12 but using methyl
3,3,3-trifluoro-2-oxypropionate instead of the ethyl var-
iant, this was prepared as a yellow liquid (55% yield): bp
1
45 ꢁC (50 mmHg); H NMR (400 MHz, CDCl3) d 3.85
(s, 3H); 13C NMR (100 MHz, CDCl3) d 161.5, 122.8
(q, J = 268 Hz), 52.9.
4.17. Methyl 2-(4-benzyloxyphenoxy)-4-p-toluene-
sulfonylbutyrate (17)
4.14. Methyl 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phen-
oxy}-3,3,3-trifluoropropionate (13)
To a solution of methyl 2-(4-benzyloxyphenoxy)-4-
hydroxybutyrate (1.47 g, 4.65 mmol) and Et3N
(0.82 mL, 0.60 g, 5.8 mmol) in CH2Cl2 (10 mL) at
0 ꢁC, p-toluenesulfonyl chloride (0.90 g, 4.7 mmol) was
added and the mixture stirred overnight at room tem-
perature. Water (10 mL) was added and the mixture ex-
tracted with AcOEt (2 · 50 mL) and the extracts washed
with saturated NaCl (10 mL), dried with anhydrous
MgSO4, and concentrated to give 17 as a brown-yellow
To a mixture of 12 (0.31 g, 1.1 mmol), Rh2(OAc)4
(5.0 mg, 0.011 mmol), and toluene (50 mL), 11 (0.21 g,
1.2 mmol) dissolved in toluene (5 mL) was added drop-
wise and the mixture was stirred at room temperature
for 0.5 h and at 50 ꢁC for 1 h. Pure material was ob-
tained, after chromatography (4:1 hexanes–AcOEt) to
give a light yellow solid, which was recrystallized from
EtOH to give 13 (0.10 g, 21% yield) as off white crystals:
1
liquid (2.00 g, 91% yield): H NMR (400 MHz, CDCl3)
d 7.74–7.70 (m, 2H), 7.44–7.30 (m, 5H), 7.23 (d,
J = 8.0 Hz, 2H), 6.87–6.82 (m, 2H), 6.72–6.68 (m, 2H),
5.01 (s, 2H), 4.61 (dd, J = 8.8, 4.4 Hz, 1H), 4.24 (dd,
J = 7.6, 4.0 Hz, 2H), 3.72 (s, 3H), 2.39 (s, 3H), 2.35–
2.26 (m, 1H), 2.24–2.15 (m, 1H).
1
mp 123–125 ꢁC; H NMR (400 MHz, CDCl3) d 8.65 (s,
1H), 7.97 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H),
7.54 (dd, J = 8.8, 2.4 Hz, 1H), 7.25–7.20 (m, 2H),
7.08–7.01 (m, 2H), 5.01 (q, J = 6.4 Hz, 1H), 3.91 (s,
3H); 13C NMR (100 MHz, CDCl3) d 164.7, 157.6,
154.4, 148.2, 140.6, 139.5, 138.3, 136.6, 130.3, 128.6,
127.0, 123.1, 121.8 (q, J = 281 Hz), 117.2, 76.5 (q,
J = 33 Hz), 53.9; 19F NMR (376 MHz, CDCl3) d
4.18. Methyl 1-(4-benzyloxyphenoxy)cyclopropane-
carboxylate
À74.24 (d, J = 6.0 Hz); IR (KBr) 1755 (C@O) cmÀ1
;
NaH (60%, 0.42 g, 10.5 mmol) was added to 17 (2.00 g,
4.2 mmol) in DME (25 mL) and the mixture stirred at
room temperature for 2 days. It was filtered and the so-
lid washed with AcOEt. The solid was dissolved in water
and acidified to pH 3 to give 2-(4-benzyloxyphenoxy)-4-
hydroxybutyric acid, which can be recycled to 17 via the
ester. To the filtrate, water (10 mL) was added and the
layers separated. The aqueous layer was extracted with
AcOEt (25 mL) and the combined organic liquids
washed with saturated NaCl (10 mL), dried with anhy-
drous MgSO4, and concentrated to give a light yellow
liquid. This was purified by chromatography (4:1
hexanes–AcOEt) to give the product (0.56 g, 45% yield)
as a colorless liquid, which solidified, mp 67–69 ꢁC and
MS (EI) m/z (%) 412 (M+, 100), 384 (9), 272 (7), 255
(12), 243 (69), 208 (6), 192 (5), 163 (28), 136 (15), 109
(6), 100 (7), 81 (5), 69 (10), 45 (34); Anal.
(C18H12N2ClF3O4) C, H, N.
4.15. 3-(4-Benzyloxyphenoxy)butyrolactone (16)
Phenol 14 (2.02 g, 10.0 mmol), 15 (2.40 mL, 4.28 g,
25.0 mmol), 50% KF–Celite (6.0 g), and CH3CN
(25 mL) were refluxed overnight. After isolating using
the standard method used for the esters, it was purified
by filtering through silica gel with AcOEt. The filtrate
was concentrated to a small volume and recrystallized
from AcOEt–hexanes to give 16 (2.70 g, 95% yield) as
white crystals: mp 113–115 ꢁC; 1H NMR (400 MHz,
CDCl3) d 7.44–7.30 (m, 5H), 7.00–6.95 (m, 2H), 6.95–
1
unreacted 17; H NMR (400 MHz, CDCl3) d 7.44–7.30
(m, 5H), 6.91–6.82 (m, 4H), 5.01 (s, 2H), 3.73 (s, 3H),
1.61–1.55 (m, 2H), 1.32–1.28 (m, 2H).

S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
3917
4.19. Methyl 1-(4-hydroxyphenoxy)cyclopropanecarb-
oxylate (18)
catalyst was removed, and the filtrate concentrated and
purified by chromatography (1:1 hexanes–AcOEt) to
give 20 (0.39 g, 100% yield) as a colorless liquid that
solidified: mp 96–97 ꢁC; H NMR (400 MHz, CDCl3)
d 6.96–6.91 (m, 2H), 6.79–6.74 (m, 2H), 4.82 (t,
J = 7.6 Hz, 1H), 5.01 (s, 2H), 4.54–4.48 (m, 1H), 4.37–
4.30 (m, 1H), 2.72–2.63 (m, 1H), 2.51–2.40 (m, 1H).
1
A mixture of methyl 1-(4-benzyloxyphenoxy)cyclopro-
panecarboxylate (0.68 g, 2.3 mmol), 10% Pd–C
(0.04 g), concentrated HCl (one drop), and CH3OH
(50 mL) were shaken under 50 psi of H2 in a Parr shaker
for 6 h. The catalyst was removed, and the filtrate con-
centrated, and purified by chromatography (2:1 hex-
anes–AcOEt) to give 18 (0.45 g, 96% yield) as a
colorless liquid that solidified: mp 95–100 ꢁC; 1H
NMR (400 MHz, CDCl3) d 6.82–6.70 (m, 4H), 4.85 (s,
1H), 3.73 (s, 3H), 1.61–1.57 (m, 2H), 1.32–1.28 (m, 2H).
4.23. 3-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}but-
yrolactone (21)
Quinoxaline 8 (0.42 g, 2.2 mmol), 20 (0.39 g, 2.0 mmol),
anhydrous K2CO3 (0.35 g, 2.5 mmol), and CH3CN
(10 mL) were refluxed for 4 h. This was purified by chro-
matography (1:1 hexanes–AcOEt) to give an off white
solid. It was recrystallized from AcOEt–heptane to give
21 (0.59 g, 83% yield) as off white crystals. Mp 179–
181 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.64 (s, 1H),
7.96 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.53
(dd, J = 8.8, 2.4 Hz, 1H), 7.23–7.17 (m, 2H), 7.15–7.09
(m, 2H), 4.97 (t, J = 7.6 Hz, 1H), 4.58–4.51 (m, 1H),
4.41–4.34 (m, 1H), 2.80–2.70 (m, 1H), 2.57–2.46 (m,
1H); 13C NMR (100 MHz, CDCl3) d 173.7, 157.8,
155.1, 147.3, 140.7, 139.5, 138.3, 136.5, 130.3, 128.5,
127.0, 122.8, 117.2, 73.3, 65.6, 30.1; IR (KBr) 1775
(C@O) cmÀ1; MS (EI) m/z (%) 356 (M+, 100), 298 (3),
271 (14), 243 (72), 208 (4), 163 (31), 136 (13), 110 (4),
100 (6), 81 (5), 69 (9); Anal. (C18H13N2ClO4) C, H, N.
4.20. Methyl 1-{4-[(7-chloro-2-quinoxalinyl)oxy]phen-
oxy}cyclopropanecarboxylate (19a)
Quinoxaline 8 (0.42 g, 2.2 mmol), 18 (0.45 g, 2.2 mmol),
anhydrous K2CO3 (0.38 g, 2.8 mmol), and CH3CN
(10 mL) were refluxed for 6 h. This was purified by chro-
matography (4:1 hexanes–AcOEt) to give a colorless li-
quid that solidified. It was recrystallized from EtOH to
give 19a (0.54 g, 68% yield) as white crystals: mp 105–
106 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.61 (s, 1H),
7.93 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.50
(dd, J = 8.8, 2.4 Hz, 1H), 7.19–7.13 (m, 2H), 7.00–6.94
(m, 2H), 3.75 (s, 3H), 1.66–1.61 (m, 2H), 1.38–1.33
(m, 2H); 13C NMR (100 MHz, CDCl3) d 172.8, 157.8,
155.0, 146.7, 140.7, 139.6, 138.2, 136.4, 130.2, 128.4,
127.0, 122.5, 116.3, 58.6, 52.9, 17.8; IR (KBr) 1720
cmÀ1 (C@O); MS (EI) m/z (%) 370 (M+, 100), 311
(84), 283 (43), 269 (38), 255 (17), 243 (55), 228 (11),
208 (7), 192 (8), 163 (73), 136 (39), 131 (12), 124 (5),
110 (5), 100 (21), 75 (9), 63 (9), 59 (21), 55 (10), 50 (8);
Anal. (C19H15N2ClO4) C, H, N.
4.24. 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}-4-
hydroxybutyric acid (22)
Ester 21 (0.54 g, 1.5 mmol), THF (25 mL), and 0.1 M
NaOH (30 mL, 3.0 mmol) gave 22 (0.52 g, 91% yield),
as an off white solid; mp 167–168 ꢁC; 1H NMR
(400 MHz, DMSO-d6) d 13.04 (br s, 1H), 8.83 (s, 1H),
8.05 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.68
(dd, J = 8.4, 2.0 Hz, 1H), 7.27–7.21 (m, 2H), 6.98–6.92
(m, 2H), 4.79 (dd, J = 8.8, 4.0 Hz, 1H), 4.69 (br s,
1H), 3.59 (br t, J = 6.0 Hz, 2H), 2.08–1.92 (m, 2H);
13C NMR (100 MHz, DMSO-d6) d 173.6, 158.3, 156.1,
146.5, 140.8, 140.6, 138.2, 135.7, 130.9, 128.6, 126.7,
123.2, 116.4, 73.6, 57.2, 36.3; IR (KBr) 3420 (OH),
3170 (OH), 1715 (C@O) cmÀ1; MS (EI negative ion)
m/z (%) 747 (2MÀH, 6), 373 (MÀH, 100), 322 (2), 271
(69), 249 (2), 111 (7), 101 (39), 98 (4), 80 (3), 69 (15).
Anal. (C18H15N2ClO5) C, H, N.
4.21. 1-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}cyclo-
propanecarboxylic acid (19b)
Ester 19a (0.51 g, 1.4 mmol), THF (25 mL), and 0.1 M
NaOH (28 mL, 2.8 mmol) gave 19b (0.45 g, 92% yield),
after recrystallization from EtOH–water, as off white
1
crystals: mp 225–227 ꢁC; H NMR (400 MHz, DMSO-
d6) d 13.02 (br s, 1H), 8.83 (s, 1H), 8.04 (d, J = 9.2 Hz,
1H), 7.80 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz,
1H), 7.27–7.22 (m, 2H), 7.01–6.95 (m, 2H), 1.55–1.50
(m, 2H), 1.29–1.25 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) d 173.5, 158.3, 155.4, 146.6, 140.9, 140.6,
138.2, 135.7, 130.9, 128.6, 126.7, 123.1, 116.6, 58.2,
16.9; IR (KBr) 3410 (OH), 1695 (C@O) cmÀ1; MS
(EI) m/z (%) 356 (M+, 100), 311 (48), 283 (18), 269
(15), 256 (48), 243 (53), 241 (16), 228 (9), 215 (5), 208
(6), 192 (6), 163 (70), 136 (41), 131 (7), 124 (5), 109
(9), 105 (10), 100 (22), 81 (5), 77 (7), 75 (9), 65 (7), 63
(9), 55 (7), 50 (8), 45 (6); HRMS (EI) m/z 356.0570
(C18H13N2ClO4: 356.0570); Anal. (C18H13N2ClO4) C,
H, N.
4.25. 3-(4-Hydroxyphenyl)-2-methyl-2-propenoic acid
(25a)16
Mp 207–208 ꢁC; 1H NMR (400 MHz, DMSO-d6) d
12.25 (br s, 1H), 9.81 (br s, 1H), 7.48 (s, 1H), 7.34–
7.29 (m, 2H), 6.82–6.77 (m, 2H), 2.00 (s, 3H).
4.26. Methyl 3-(4-hydroxyphenyl)-2-methyl-2-propenoate
(25b)
4.22. 3-(4-Hydroxyphenoxy)butyrolactone (20)
Acid 25a (0.89 g, 5.0 mmol), concentrated H2SO4
(0.1 mL), and CH3OH (10 mL) were refluxed overnight.
After the mixture was concentrated, water (25 mL) was
added followed by NaHCO3 until pH 8. The mixture
was extracted with AcOEt (2 · 25 mL) and the extracts
A mixture of 16 (0.56 g, 2.0 mmol), 10% Pd–C (0.02 g),
concentrated HCl (one drop), and AcOEt (25 mL) were
shaken under 50 psi of H2 in a Parr shaker for 6 h. The

3918
S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
washed with saturated NaCl (10 mL), dried with anhy-
drous MgSO4, and purified by filtering through silica
gel to give 25b (0.91 g, 95% yield) as a pale yellow solid
after concentrating: mp 100–102 ꢁC; 1H NMR
(400 MHz, CDCl3) d 7.63 (s, 1H), 7.35–7.30 (m, 2H),
6.89–6.84 (m, 2H), 5.25 (s, 1H), 3.81 (s, 3H), 2.12 (d,
J = 1.6 Hz, 1H).
CDCl3) d 7.03–6.98 (m, 2H), 6.75–6.60 (m, 2H), 5.12
(s, 1H), 3.64 (s, 3H), 2.93 (dd, J = 13.2, 7.2 Hz, 1H),
2.74–2.65 (m, 2H), 2.61 (dd, J = 13.8, 7.2 Hz, 1H),
1.14 (d, J = 7.2 Hz, 3H).
4.31. Methyl 3-{4-[(7-chloro-2-quinoxalinyl)oxy]phenyl}-
2-methylpropionate (28a)
4.27. Methyl 3-{4-[(7-chloro-2-quinoxalinyl)oxy]phenyl}-
2-methylacrylate (26a)
Quinoxaline
8
(0.40 g, 2.0 mmol), 27a (0.41 g,
2.1 mmol), anhydrous K2CO3 (0.36 g, 2.6 mmol), and
CH3CN (10 mL) were refluxed together for 4 h. This
was purified by chromatography (4:1 hexanes–AcOEt)
to give a colorless liquid. It was recrystallized from hex-
anes to give 28a (0.65 g, 92% yield) as off white crystals.
Quinoxaline
8
(0.20 g, 1.0 mmol), 25b (0.20 g,
1.0 mmol), anhydrous K2CO3 (0.18 g, 1.3 mmol), and
CH3CN (5 mL) were refluxed together for 4 h. This
was purified by chromatography (4:1 hexanes–AcOEt)
to give a white solid. It was recrystallized from hexanes
to give 26a (0.30 g, 86% yield) as white crystals. Mp 120–
122 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.68 (s, 1H), 7.98
(d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.71 (s,
1H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H), 7.52–7.47 (m, 2H),
7.33–7.29 (m, 2H), 3.84 (s, 3H), 2.17 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 169.3, 157.4, 152.5, 140.7,
139.6, 138.4, 138.2, 136.6, 133.5, 131.3, 130.3, 128.7,
128.6, 127.0, 121.6, 52.4, 14.4; IR (KBr) 1720 (C@O)
cmÀ1; MS (EI) m/z (%) 354 (M+, 100), 326 (8), 323
(13), 295 (15), 266 (21), 163 (8), 136 (10), 131 (5), 115
(17), 100 (5); Anal. (C19H15N2ClO3) C, H, N.
1
Mp 69–70 ꢁC; H NMR (400 MHz, CDCl3) d 8.65 (s,
1H), 7.96 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H),
7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.27–7.22 (m, 2H),
7.19–7.15 (m, 2H), 3.67 (s, 3H), 3.07 (dd, J = 12.4,
6.0 Hz, 1H), 2.82–2.69 (m, 2H), 1.21 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 176.7, 157.7,
151.1, 140.8, 139.6, 138.3, 137.0, 136.5, 130.4, 130.2,
128.5, 127.0, 121.5, 51.9, 41.7, 39.3, 17.1; IR (KBr)
1730 (C@O) cmÀ1; MS (EI) m/z (%) 356 (M+, 65), 341
(10), 325 (6), 297 (100), 269 (94), 241 (95), 205 (5), 163
(20), 136 (19), 115 (7), 107 (22), 100 (12), 91 (9), 77
(11), 69 (7), 51 (5); Anal. (C19H17N2ClO3) C, H, N.
4.32. 3-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenyl}-2-meth-
ylpropionic acid (28b)
4.28. 3-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenyl}-2-meth-
ylacrylic acid (26b)
Ester 28a (0.65 g, 1.8 mmol), THF (35 mL), and 0.1 M
NaOH (36 mL, 3.6 mmol) gave 28b (0.55 g, 89% yield),
after recrystallization from EtOH–water to give off
white crystals: mp 155–157 ꢁC; 1H NMR (400 MHz,
DMSO-d6) d 12.19 (br s, 1H), 8.83 (s, 1H), 8.05 (d,
J = 8.8 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.69 (dd,
J = 8.8, 2.4 Hz, 1H), 7.31–7.26 (m, 2H), 7.25–7.20 (m,
2H), 2.93 (dd, J = 16.0, 10.8 Hz, 1H), 2.70–2.61 (m,
2H), 1.07 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) d 177.5, 158.0, 151.2, 140.9, 140.6, 138.3,
137.7, 135.7, 131.0, 130.8, 128.7, 126.7, 121.9, 41.3,
Ester 26a (0.26 g, 0.73 mmol), THF (15 mL), and 0.1 M
NaOH (15 mL, 1.5 mmol) gave 26b (0.19 g, 76% yield),
after recrystallization from AcOEt–heptane to give off
white crystals: mp 206–208 ꢁC; 1H NMR (400 MHz,
DMSO-d6) d 12.45 (br s, 1H), 8.88 (s, 1H), 8.07 (d,
J = 8.0 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.70 (dd,
J = 8.8, 2.4 Hz, 1H), 7.62 (s, 1H), 7.62–7.56 (m, 2H),
7.42–7.37 (m, 2H), 2.06 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) d 170.1, 157.8, 152.7, 140.9, 140.5, 138.4,
137.2, 135.8, 133.7, 131.9, 131.0, 129.6, 128.9, 126.7,
122.3, 14.7; IR (KBr) 3430 (OH), 1655 (C@O) cmÀ1
;
39.0, 17.5; IR (KBr) 3420 (OH), 1720 (C@O) cmÀ1
;
MS (EI) m/z (%) 340 (M+, 100), 312 (31), 296 (27),
267 (17), 241 (7), 163 (16), 136 (21), 131 (6), 115 (21),
103 (6), 100 (13), 77 (9), 63 (5), 51 (5); HRMS (EI) m/z
340.0618 (C18H13N2ClO3: 340.0615); Anal. (C18H13-
N2ClO3) C, H, N.
MS (EI) m/z (%) 342 (M+, 73), 327 (8), 307 (6), 297
(54), 269 (100), 241 (95), 163 (16), 136 (17), 107 (23),
100 (10), 91 (6), 89 (5), 77 (9); HRMS (EI) m/z
342.0771 (C18H15N2ClO3:
(C18H15N2ClO3) C, H, N.
342.0771);
Anal.
4.29. 3-(4-Hydroxyphenyl)-2-methylpropionic acid
(22a)16
4.33. Methyl 2-(4-hydroxyphenyl)propionic acid (29b)
Acid 29a (0.85 g, 5.0 mmol), concentrated H2SO4
(0.1 mL), and CH3OH (10 mL) were refluxed overnight.
The mixture was isolated as in 25b to give 29b (0.89 g,
99% yield) as a brown liquid: 1H NMR (400 MHz,
CDCl3) d 7.18–7.12 (m, 2H), 6.80–6.74 (m, 2H), 5.40
(br s, 1H), 3.67 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 1.47
(d, J = 7.2 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) d 12.05 (br s, 1H), 9.17
(br s, 1H), 6.96–6.91 (m, 2H), 6.65–6.60 (m, 2H), 2.74
(dd, J = 12.4, 6.0 Hz, 1H), 2.53–2.40 (m, 2H), 0.97 (d,
J = 6.8 Hz, 3H).
4.30. Methyl 3-(4-hydroxyphenyl)-2-methylpropionate
(27b)
4.34. Methyl 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phen-
yl}propionate (30a)
Acid 27a (0.68 g, 3.8 mmol), concentrated H2SO4
(0.1 mL), and CH3OH (10 mL) were refluxed overnight.
The mixture was isolated as in 25b to give 27b (0.72 g,
99% yield) as a brown liquid: 1H NMR (400 MHz,
Quinoxaline
2.2 mmol), anhydrous K2CO3 (0.38 g, 2.7 mmol), and
8
(0.40 g, 2.0 mmol), 29b (0.40 g,

S. T. Hazeldine et al. / Bioorg. Med. Chem. 13 (2005) 3910–3920
3919
CH3CN (10 mL) were refluxed together for 4 h. This
was purified by chromatography (4:1 hexanes–AcOEt)
to give a colorless liquid that solidified. It was recrystal-
lized from hexanes to give 30a (0.65 g, 96% yield) as off
white crystals. Mp 107–108 ꢁC; 1H NMR (400 MHz,
CDCl3) d 8.66 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.76
(d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.8, 2.4 Hz, 1H),
7.41–7.36 (m, 2H), 7.25–7.20 (m, 2H), 3.79 (q,
J = 7.2 Hz, 1H), 3.70 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 175.1, 157.6, 151.7,
140.7, 139.6, 138.3, 138.0, 136.5, 130.3, 129.0,
128.6, 127.0, 121.7, 52.4, 18.9; IR (KBr) 1730 (C@O)
cmÀ1; MS (EI) m/z (%) 342 (M+, 54), 283 (100), 255
(36), 163 (6), 136 (8), 121 (5), 103 (6), 100 (5), 91 (5),
77 (7), 69 (8), 57 (7), 55 (5); Anal. (C18H15N2ClO3) C,
H, N.
to give 32a (0.32 g, 89% yield) as white crystals. Mp 96–
97 ꢁC; H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 7.96
1
(d, J = 9.2 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.53 (dd,
J = 8.8, 2.4 Hz, 1H), 7.28–7.24 (m, 2H), 7.19–7.15 (m,
2H), 3.69 (s, 3H), 2.70 (t, J = 8.0 Hz, 2H), 2.38 (t,
J = 7.6 Hz, 2H), 2.01 (quintet, J = 7.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 174.1, 157.8, 150.8, 140.8,
139.6, 139.0, 138.3, 136.4, 130.2, 129.9, 128.5, 127.0,
121.5, 51.8, 34.8, 33.6, 26.7; IR (KBr) 1730 (C@O)
cmÀ1; MS (EI) m/z (%) 356 (M+, 28), 325 (12), 283
(100), 269 (7), 254 (23), 241 (20), 163 (10), 136 (10),
107 (10), 100 (6), 91 (6), 77 (6), 74 (5), 69 (8), 57 (7),
55 (6); Anal. (C19H17N2ClO3) C, H, N.
4.39. 4-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenyl}butyric
acid (32b)
4.35. 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenyl}prop-
ionic acid (30b)
Ester 32a (0.29 g, 0.81 mmol), THF (15 mL), and 0.1 M
NaOH (16 mL, 1.6 mmol) gave 32b (0.25 g, 89% yield),
after recrystallization from EtOH–water to give white
crystals: mp 132–134 ꢁC; H NMR (400 MHz, DMSO-
1
Ester 30a (0.65 g, 1.9 mmol), THF (25 mL), and 0.1 M
NaOH (38 mL, 3.8 mmol) gave 30b (0.57 g, 92% yield),
after recrystallization from EtOH–water to give off
white crystals: mp 170–172 ꢁC; 1H NMR (400 MHz,
DMSO-d6) d 12.40 (br s, 1H), 8.85 (s, 1H), 8.06 (d,
J = 8.8 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.69 (dd,
J = 8.8, 2.4 Hz, 1H), 7.41–7.36 (m, 2H), 7.31–7.26 (m,
2H), 3.74 (q, J = 7.2 Hz, 1H), 1.39 (d, J = 7.2 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) d 176.0, 157.9, 151.7,
140.9, 140.5, 139.1, 138.3, 135.8, 130.9, 129.5, 128.7,
126.7, 122.1, 44.8, 19.2; IR (KBr) 3430 (OH), 1685
(C@O) cmÀ1; MS (EI) m/z (%) 328 (M+, 95), 283
(100), 255 (75), 163 (12), 142 (7), 138 (5), 136 (16), 121
(9), 103 (9), 100 (10), 91 (9), 83 (6), 77 (13), 71 (5), 69
(8), 57 (10), 55 (8); HRMS (EI) m/z 328.0618
(C17H13N2ClO3: 328.0615); Anal. (C17H13N2ClO3) C,
H, N.
d6) d 12.08 (br s, 1H), 8.83 (s, 1H), 8.04 (d, J = 9.2 Hz,
1H), 7.76 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.8, 2.4 Hz,
1H), 7.30–7.26 (m, 2H), 7.24–7.20 (m, 2H), 2.62 (t,
J = 7.6 Hz, 2H), 2.25 (t, J = 7.6 Hz, 2H), 1.82 (quintet,
J = 7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) d
175.0, 158.1, 151.0, 140.9, 140.6, 139.7, 138.3, 135.7,
131.0, 130.3, 128.7, 126.7, 122.0, 34.5, 33.8, 27.0; IR
(KBr) 3420 (OH), 1690 (C@O) cmÀ1; MS (EI) m/z (%)
342 (M+, 30), 283 (100), 269 (12), 254 (24), 241 (39),
163 (13), 136 (14), 107 (14), 100 (9), 91 (7), 77 (9), 69
(6), 60 (6), 57 (7), 55 (7); HRMS (EI) m/z 342.0771
(C18H15N2ClO3: 342.0771); Anal. (C18H15N2ClO3) C,
H, N.
Acknowledgments
4.36. 4-(4-Hydroxyphenyl)butyric acid (31b)18
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.
1H NMR (400 MHz, DMSO-d6) d 11.99 (br s, 1H), 9.13
(br s, 1H), 6.96–6.91 (m, 2H), 6.67–6.62 (m, 2H), 2.44 (t,
J = 7.2 Hz, 2H), 2.16 (t, J = 7.6 Hz, 2H), 1.71 (qu,
J = 7.2 Hz, 2H).
4.37. Methyl 4-(4-hydroxyphenyl)butyrate (31c)
Acid 31b (0.90 g, 5.0 mmol), concentrated H2SO4
(0.1 mL), and CH3OH (10 mL) were refluxed overnight.
The mixture was isolated as in 25b to give 31c (0.94 g,
97% yield) as a brown liquid: 1H NMR (400 MHz,
CDCl3) 7.06–7.00 (m, 2H), 6.78–6.72 (m, 2H), 4.98 (s,
1H), 3.67 (s, 3H), 2.57 (t, J = 7.2 Hz, 2H), 2.32 (t,
J = 7.2 Hz, 2H), 1.91 (qu, J = 7.2 Hz, 2H).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2005.04.011.
References and notes
4.38. Methyl 4-{4-[(7-chloro-2-quinoxalinyl)oxy]phen-
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