Regioselective synthesis of a potent Src kinase inhibitor: 4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-morpholin-4-ylethoxy) benzo[g]quinoline-3-carbonitrile

Article abstract of DOI:10.1055/s-2003-40872

The regioselective synthesis of compound 3, a potent Src kinase inhibitor is described. A key step in this synthesis is the regioselective thermal rearrangement of a substituted benzocyclobutene to provide a 2,3,6,7-tetrasubstituted naphthalene. An effici

Full text of DOI:10.1055/s-2003-40872

1712
PAPER
Regioselective Synthesis of a Potent Src Kinase Inhibitor: 4-(2,4-Dichloro-5-
methoxyphenylamino)-7-methoxy-8-(2-morpholin-4-ylethoxy)benzo[g]quino-
line-3-carbonitrile
Src
K
inase Inhibito
a
r: Substitu
n
te
d
Benzo[g]quinol
M
ine-3-carbonitrile . Berger,* Gary Birnberg, Frenel DeMorin, Minu Dutia, Dennis Powell, Yanong D. Wang
Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA
Fax +1(845)6025561; E-mail: bergerd@wyeth.com
Received 28 April 2003
to synthesize the analogously substituted benzo[g]quino-
Abstract: The regioselective synthesis of compound 3, a potent Src
kinase inhibitor is described. A key step in this synthesis is the
regioselective thermal rearrangement of a substituted benzocy-
clobutene to provide a 2,3,6,7-tetrasubstituted naphthalene. An ef-
line-3-carbonitrile 3. However, the chemistry utilized to
synthesize 2 was not suitable for the synthesis of 3, as this
would provide products possessing a mixture of C-7 and
ficient route to the uniquely substituted benzocyclobutene is C-8 substituents. Since any non-regioselective synthesis
reported.
would generate a mixture of products requiring purifica-
tion by chromatographic separation,6 a synthetic strategy
Key words: drugs, regioselectivity, rearrangements, heterocycles,
ring closure
was devised to unambiguously provide compound 3 as a
single regioisomer.
Scheme 1 outlines the retrosynthetic analysis of the ap-
proach for compound 3. The 2,3,6,7-tetrasubstituted
naphthalene A (P = protecting group, E = alkyl group)
was the key intermediate from which existing methodolo-
gy could be utilized to construct the target compound.7
The regioselective synthesis of this intermediate was
therefore our major challenge, as existing literature proce-
dures would have provided the 2,3,6,7-tetrasubstituted
naphthalene precursor A as a regioisomeric mixture.8a–c
Protein tyrosine kinases catalyze the phosphorylation of a
tyrosine residue on a substrate protein, a process resulting
in cell growth and differentiation. Src is a cytoplasmic
non-receptor kinase that participates in signaling path-
ways controlling proliferation, migration and angiogene-
sis.1 Thus, a small molecule Src kinase inhibitor may
prove useful for therapeutic intervention in cancer2a,b as
well as other disease states affected by this signaling path-
way.3a–c We had identified a series of substituted 4-anili-
no-6,7-dialkoxy-3-quinolinecarbonitriles to be very
potent Src kinase inhibitors (e.g. compound 1,
Figure 1).4a–c Further exploration of this series lead to the
discovery of 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-
carbonitriles such as 2 (Figure 1), which was a more po-
tent Src kinase inhibitor than the corresponding 3-quino-
linecarbonitrile.5 Since the C-7 water-solubilizing group
provided enhanced cellular activity, and improved the
physical properties of compounds such as 1, our goal was
It had been reported that 3-amino-6,7-dimethoxynaphtha-
lene-2-carboxylic acid tert-butyl ester (A: wherein
P = Me, E = tert-butyl) was synthesized via the thermal
rearrangement of a substituted benzocyclobutene.9 This
approach provided a route to the regioselective synthesis
of key intermediate A, which could therefore be obtained
from the thermal rearrangement of uniquely substituted
benzocyclobutene B (R = alkyl or substituted aryl). Our
strategy was to construct intermediate B via a benzyne-
Cl
Cl
OMe
Cl
HN
HN
N
OMe
O
O
CN
O
O
CN
1
2
N
N
O
Cl
Cl
HN
N
OMe
O
O
CN
O
N
3
Figure 1
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1712,1716,ftx,en;C02303SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Src Kinase Inhibitor: Substituted Benzo[g]quinoline-3-carbonitrile
1713
Cl
Cl
HN
OMe
O
CO2E
NH2
O
O
CN
O
PO
N
A
3
N
O
O
O
CO2E
NH2
SR
NH2
CN
C
PO
Br
PO
PO
B
SR
CO2E
Scheme 1
mediated annulation of C,10 followed by installation of the quence from 5-bromovanillin. As part of our effort to
appropriate SR leaving group, and addition of an alkyl ac- maximize the efficiency of this synthesis, a three-step re-
etate anion to the nitrile group. We describe herein our op- action sequence was devised to provide compound 7.
timized reaction sequence to provide target compound 3.
Thus, 4-benzyloxy-3-methoxybenzyl alcohol 4 was bro-
minated in acetic acid to provide 5 in 86% yield.12 The
substituted benzyl bromide 5 was converted to nitrile 6 by
reaction with the lithium salt of acetonitrile (45%).13
Compound 6 was converted to benzocyclobutene 7 in
65% yield by treatment with NaNH2 in liquid NH3.10
Of key importance to the success of this synthesis was the
choice of protecting group for the C-4 oxygen substituent
of intermediate C. This protecting group would have to be
compatible with the strongly basic conditions of the ben-
zyne-mediated cyclization step, but readily removable in
the presence of the functional groups on intermediate A. Benzocyclobutene 7 was readily converted to 8a in 76%
Since the benzyloxy substituted benzocyclobutene 7 had yield by treatment with NaN(TMS)2 at –78 °C, followed
previously been prepared via benzyne-mediated cycliza- by the rapid addition of dimethyl disulfide. The addition
tion, the benzyl group was the logical choice.11 In this of the magnesium bromide anion of tert-butyl acetate to
work,11 7 (Scheme 2) was prepared by a five-step se- 8a at 0 °C provided 9a in 87% yield.9 The cyclization re-
O
O
O
c
Br
b
OH
a
CN
BnO
Br
BnO
Br
BnO
4
5
6
O
O
O
e
d
SR
SR
CN
BnO
BnO
BnO
NH2
CN
7
9a R = Me
9b R = Ph
8a R = Me
8b R = Ph
CO2tBu
9c R = p-chlorophenyl
8c R = p-chlorophenyl
CO2tBu
NH2
O
O
O
CO2tBu
h
f
O
N
PO
R1
12 R1 = NH2
10 P = Bn
11 P = H
i
g
13 R1 =
N
N
X
O
O
CN
l
j
O
3
N
N
14 X = OH
15 X = Cl
k
Scheme 2 Reagents and conditions: (a) Br2, HOAc, 10 °C to r.t, 2 h (87%); (b) BuLi, MeCN, THF, –78 °C, 1 h (45%); (c) NaNH2 (4 equiv),
NH3, –33 °C, 45 min (65%); (d) (1) Na(TMS)2, THF, –78 °C, 5 min; (2) RSSR, –78 °C to r.t., 1 h (R = Me,76%; R = Ph, 92%; R = p-chloro-
phenyl, 86%); (e) EtMgBr, HNi-Pr2, MeCO2t-Bu, THF, 0 °C, 1 h (R = Me, 87%; R = Ph, 87%; R = p-chlorophenyl, 85%); (f) 1,2-dichloroben-
zene, reflux, 1 h (67%); (g) H2 (40 psi), Pd/C, THF, 24 h (95%); (h) DEAD, diphenyl-2-pyridylphosphine, 2-morpholinoethanol, THF, 1.5 h
(70%); (i) DMF-dimethylacetal, reflux, 1.5 h (used directly in step j); (j) BuLi, MeCN, THF, –78 °C, 1 h (59% from steps i and j); (k) POCl3,
reflux, 1 h (used directly in step l); (l) 2,4-dichloro-5-methoxyaniline, ethoxyethanol, Pd2(dba)3, K3PO4, ligand, DME, reflux, 4 h (56% from
steps k and l).
Synthesis 2003, No. 11, 1712–1716 © Thieme Stuttgart · New York

1714
D. M. Berger et al.
PAPER
action of 9a was carried out in refluxing 1,2-dichloroben- activity of 3, and a number of analogs, will be described
zene which was carefully de-gassed with N2 prior to elsewhere.19
heating.9 However, a modest yield (32%) of 10 was ob-
Mps are uncorrected. These were determined in open capillary
tubes using a Meltemp mpt apparatus. H NMR spectra were re-
1
tained, along with 22% of C-4 methylsulfide substituted
product (derived from air oxidation of the initial cyclized corded on a NT-300 WB NMR spectrometer. 13C NMR were re-
intermediate9). Since elimination of the methylsulfide
corded on a Bruker DRX 400 MHz spectrometer. Chemical shifts
( ) are in parts per million referenced to Me4Si. Electrospray (ES)
substituent was incomplete, we set out to install a more la-
mass spectra were recorded in positive mode on a Micromass Plat-
form spectrometer. Chemical ionization (CI) mass spectra were de-
termined by atmospheric pressure chemical ionization (APCI) using
bile leaving group, such as thiophenyl, or a thiophenyl
group with electron-withdrawing substituents. Com-
pounds 8b and 9b were prepared by the same methods de-
scribed for the preparation of 8a and 9a. The cyclization
of 9b gave improved results as compared to 9a, providing
10 in 52–69% yields. The major naphthalene by-product
identified in these reactions possessed a C-2 carboxylic
acid (7–9%), presumably due to the thermal cleavage of
the tert-butyl ester group of 10. Additionally, C-4 thiophe-
nyl substituted product (ca. 5%) was isolated. A cleaner
reaction was achieved with 9c, possessing the more labile
p-chlorophenyl sulfide leaving group. Purification of the
crude product was readily achieved by trituration with di-
ethyl ether to provide 10 in good yield (typically 67–
73%). Since the best yields were obtained under very di-
lute conditions ( 0.6 g/100 mL), it was necessary to mod-
ify the reaction conditions for large-scale reactions. This
was achieved by adding 9c slowly to a heated solution of
1,2-dichlorobenzene to maintain a higher dilution of the
starting material throughout the reaction period. In this
way, multigram quantities of the 2,3,6,7-tetrasubstituted
naphthalene 10 were readily prepared.
H2O–MeCN–HCO2H (1:1:0.0025) as a carrier solvent system on
the same spectrometer. Flash chromatography was performed using
Baker 40 M silica gel. Unless otherwise mentioned, reactions were
carried out under nitrogen.
5-(Benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene
(5)
4-Benzyloxy-3-methoxybenzyl alcohol (4) (4.8 g, 19.65 mmol) was
dissolved in HOAc (30 mL) and cooled to 10 °C in a H2O–ice bath.
A solution of Br2 (1.25 mL, 24.39 mmol) in HOAc (10 mL) was
added dropwise to the reaction mixture while stirring. The reaction
was allowed to warm to r.t. and was stirred for 2 h. The reaction was
diluted with H2O and the resulting precipitate collected by filtration.
The precipitate was washed with H2O and purified by flash chroma-
tography (silica gel; hexanes–EtOAc, 93:7) to provide 5.
Yield: 6.61 g (87%); white solid; mp 103–105 °C (Lit 110 °C).
The analytical data were consistent with the data given in the liter-
ature.20
3-(4-Benzyloxy-2-bromo-5-methoxyphenyl)propionitrile (6)
To a solution of BuLi (20.3 mL of a 1.6 M solution in hexane, 32.38
mmol) in anhyd THF (20 mL) was added a solution of MeCN (1.8
mL, 32.38 mmol) in THF (15 mL). The reaction mixture was stirred
at –78 °C for 1 h. A solution of 5 (0.7 g, 1.8 mmol) in anhyd THF
(30 mL) was added in one portion and stirring was continued for 1
h at –78 °C. The reaction was quenched by the addition of H2O (25
mL), and the mixture was allowed to warm to r.t. To this was added
EtOAc (50 mL). An insoluble by-product was removed by filtra-
Debenzylation of 10 cleanly provided 11 (95%) when hy-
drogenated at 40 psi in a Parr shaker in the presence of Pd/
C. The coupling reaction of 11 with 4-(2-hydroxyeth-
yl)morpholine was carried out under Mitsunobu reaction
conditions14 to provide 12 in 70% yield. Compound 12
was converted to the amidine 13 in refluxing DMF dime- tion. Following separation of the layers, the organic layer was dried
(MgSO4). After reducing in vacuo, the crude product was purified
by flash chromatography (silica gel; hexanes–EtOAc, 95:5 to
87:13) to provide 6.
thyl acetal. Subsequent treatment of compound 13 with
the lithium anion of MeCN afforded the cyclized interme-
diate 14 in 59% yield from 12.7 The reaction of 14 with re-
Yield: 2.0 g (45%); white solid; mp 52–53 °C.
fluxing POCl3 generated the 4-chloro intermediate 15,
1H NMR (DMSO-d6, 300 MHz): = 7.39 (m, 5 H), 7.33 (s,1 H),
7.08 (s, 1 H), 5.09 (s, 2 H), 3.77 (s, 3 H), 2.92 (t, J = 5.5 Hz, 2 H),
2.78 (t, J = 5.1 Hz, 2 H).
which was used in the subsequent step without purifica-
tion. Addition of 2,4-dichloro-5-methoxyaniline15 to 15
under standard conditions7 (ethoxyethanol, pyridine·HCl,
120 °C, 90 min) provided modest yields of 3 (40–45% 13C NMR (DMSO-d6, 100 MHz): = 148.52, 147.34, 136.56,
129.88, 128.33, 127.86, 127.76, 119.67, 116.95, 114.09, 113.02,
70.06, 55.72, 30.35, 17.03.
overall from 14). An improved yield of 3 was obtained us-
ing Pd2(dba)3, 2-(dicyclohexylphosphino)-2 -(N,N-dime-
thylamino)-1,1 -biphenyl16 and K3PO4 in refluxing DME
MS (CI): m/z = 346.2, 348.2 (M + 1).
(56% overall from 14).17
Anal. Calcd for C17H16BrNO2: C, 58.98; H, 4.66; N, 4.05. Found: C,
58.77; H, 4.71; N, 3.89.
In summary, target compound 3 was prepared as a single
regioisomer via a 12-step reaction sequence from a com-
mercially available starting material. Methodology was
4-Benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbo-
nitrile (7)
elucidated for the regioselective construction of 2,3,6,7-
tetrasubstituted naphthalenes bearing four different sub-
stituents. With this synthesis, we prepared multigram
quantities of 3, which allowed us to carry out extensive
testing of this compound as an Src kinase inhibitor. As
was anticipated, this compound proved to be significantly
more potent than l. A preliminary report of the activity of
3 has been presented.18 A more detailed discussion of the
A suspension of NaNH2 was prepared from liquid NH3 (100 mL),
Na (0.52 g, 22.8 mmol) and a catalytic amount of ferric nitrate. To
this was added 6 (2 g, 5.7 mmol) in portions and the reaction was
stirred at –33 °C for 45 min. The reaction was then cooled down to
–78 °C and quenched with aq NH4Cl. The liquid NH3 was allowed
to evaporate and the resulting solid residue was washed with H2O.
Purification by flash chromatography (silica gel; hexanes–EtOAc,
4:1) provided 7.
Yield: 1.0 g (65%); white solid; mp 85–87 °C (Lit: 90–92 °C).
Synthesis 2003, No. 11, 1712–1716 © Thieme Stuttgart · New York

PAPER
Src Kinase Inhibitor: Substituted Benzo[g]quinoline-3-carbonitrile
1715
The analytical data were consistent with the data given in the liter-
ature.11
1H NMR (DMSO-d6, 300 MHz): = 8.18 (s, 1 H), 7.4 (m, 5 H), 7.18
(s, 1 H), 7.01 (s, 1 H), 6.85 (s, 1 H), 6.21 (s, 2 H), 5.17 (s, 2 H), 3.74
(s, 3 H), 1.58 (s, 9 H).
4-Benzyloxy-7-(4-chlorophenylsulfanyl)-3-methoxybicyclo-
[4.2.0]octa-1,3,5-triene-7-carbonitrile (8c)
13C NMR (DMSO-d6, 100 MHz): = 166.93, 150.74, 146.71,
145.95, 136.64, 133.51, 130.50, 128.35, 127.92, 127.86, 120.10,
112.66, 108.29, 107.43, 104.57, 80.32, 69.53, 55.28, 27.89.
To a solution of 7 (1.0 g, 3.70 mmol) in anhyd THF (10 mL) at
–78 °C was added sodium NaN(TMS)2 (5.65 mL of a 1 M solution
in THF, 5.60 mmol) over a period of 4 min, followed by the addition
of 4,4 -dichlorodiphenyl disulfide in one portion. The mixture was
stirred at –78 °C for 15 min and then at r.t. for 1 h. The reaction was
quenched with H2O (20 mL), and EtOAc (20 mL) was subsequently
added. Following separation of the layers, the aq layer was extract-
ed twice more with EtOAc. The organic layers were combined and
dried (Na2SO4). After reducing in vacuo, the crude material was pu-
rified by flash chromatography (silica gel; hexanes–EtOAc, 4:1) to
give 8c.
MS (ES): m/z = 379.9 (M + 1).
Anal. Calcd for C23H25NO4·0.7 H2O: C, 70.50; H, 6.08; N, 3.57.
Found: C, 70.45; H, 6.24; N, 3.40.
3-Amino-6-hydroxy-7-methoxynaphthalene-2-carboxylic Acid
tert-Butyl Ester (11)
A solution of 10 (4.7 g, 12.39 mmol) was dissolved in DMF (40
mL). To this was added MeOH (100 mL) and 10% Pd/C (2.0 g). The
reaction mixture was hydrogenated on a Parr shaker at 40 psi for 20
h. The catalyst was removed by filtration through a pad of Celite,
and the filltrate was concentrated in vacuo. To complete the reac-
tion, the resulting residue was again hydrogenated as described
above for 4 h. After removal of the catalyst through Celite, the sol-
vent was evaporated. The resulting residue was dissolved in CH2Cl2
and passed through a plug of magnesol, eluting with CH2Cl2 and
EtOAc. The filtrate was reduced in vacuo to provide 11.
Yield: 1.3 g (86%); off-white solid; mp 114–115 °C.
1H NMR (DMSO-d6, 300 MHz): = 7.62–7.54 (m, 4 H), 7.41 (m,
4 H), 7.36 (m, 1 H), 6.97 (s,1 H), 6.83 (s, 1 H), 5.08 (dd, J = 9.1,
10.5 Hz, 2 H), 3.98 (d, J = 10.5 Hz, 1 H), 3.78 (s, 3 H), 3.60 (d,
J = 10.5 Hz, 1 H).
13C NMR (DMSO-d6, 100 MHz): = 152.80, 149.20, 136.69,
135.87, 134.92, 132.48, 131.05, 129.55, 129.39, 128.32, 127.81,
127.65, 118.91, 108.30, 107.14, 70.15, 55.94, 45.48, 43.71.
Yield: 3.40 g (95%); yellow solid; mp 262–263 °C.
1H NMR (DMSO-d6, 300 MHz): = 9.61 (br s, 1 H), 8.15 (s, 1 H),
7.13 (s, 1 H), 6.74 (d, J = 2.7 Hz, 2 H), 6.12 (s, 2 H), 3.82 (s, 3 H),
1.58 (s, 9 H).
13C NMR (DMSO-d6, 100 MHz): = 166.99, 149.87, 146.42,
145.71, 133.97, 130.65, 119.94, 112.11, 10.47, 107.27, 106.17,
80.17, 55.25, 27.90.
MS (CI) : m/z = 408.1, 410.2 (M + 1).
Anal. Calcd for C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43. Found:
C, 67.99; H, 4.63; N, 3.33.
3-Amino-3-[4-benzyloxy-7-(4-chlorophenylsulfanyl)-3-meth-
oxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]acrylic Acid tert-Butyl
Ester (9c)
MS (ES): m/z = 289.9 (M + 1).
To a stirred solution of EtMgBr (3.26 mL of a 3 M solution in Et2O,
9.8 mmol) in anhyd THF (10 mL) at 0 °C under N2 was added di-
isopropylamine (2.75 mL, 19.6 mmol). The mixture was stirred at
0 °C for 1 h. tert-Butyl acetate (0.5 mL, 3.6 mmol) and a solution of
8c (1.0 g, 2.45 mmol) in anhyd THF (10 mL) were added succes-
sively, and the resulting mixture was stirred for 1 h. The reaction
was quenched with aq NH4Cl and the product mixture was extracted
with EtOAc. The EtOAc extract was washed with brine, dried
(Na2SO4) and passed through a plug of silica gel (EtOAc) to give 9c.
Anal. Calcd for C16H19NO4·0.1 EtOAc: C, 66.06; H, 6.69; N, 4.70.
Found: C, 66.30; H, 6.96; N, 4.30.
3-Amino-7-methoxy-6-(2-morpholin-4-ylethoxy)naphthalene-
2-carboxylic Acid tert-Butyl Ester (12)
To a solution of 11 (0.72 g, 2.49 mmol) in THF (7.5 mL) was added
4-(2-hydroxyethyl)morpholine (0.46 mL, 3.74 mmol), followed by
the addition of diphenyl-2-pyridylphosphine (1.34 g, 4.98 mmol)
and DEAD (0.6 mL, 3.87 mmol). The resulting mixture was stirred
at r. t. for 1.5 h, quenched with H2O, diluted with EtOAc and the two
layers were separated. The organic layer was extracted with aq HCl
(0.2 N). After neutralizing the aqueous layer with sat. aq NaHCO3,
it was extracted with EtOAc. The EtOAc extract was dried
(Na2SO4), filtered and evaporated to yield a brown oil. The oil was
purified by flash chromatography (silica gel; EtOAc–hexane, 85:15
to 100:0) to give 12.
Yield: 1.194 g (85%); white solid; mp 112–115 °C.
1H NMR (DMSO-d6, 300 MHz): = 7.60–7.29 (m, 9 H), 6.81 (s, 1
H), 6.72 (s, 1 H), 5.08 (dd, J = 9.1, 11.8 Hz, 2 H), 4.15 (s, 1 H), 3.73
(s, 3 H), 3.48 (d, J = 10.7 Hz, 1 H), 3.30 (d, J = 10.6 Hz, 1 H), 1.36
(s, 9 H).
13C NMR (DMSO-d6, 100 MHz): = 168.84, 161.41, 151.58,
148.16, 136.95, 136.21, 136.07, 133.82, 132.55, 130.88, 128.64,
128.25, 127.69, 127.62, 108.89, 108.10, 84.56, 77.54, 70.21, 60.07,
55.84, 44.87, 28.11.
Yield: 0.70 g (70%); orange solid; mp 125–127 °C.
1H NMR (CDCl3, 300 MHz): = 8.24 (s, 1 H), 7.00 (s, 1 H), 6.81
(d, J = 2.34 Hz, 2 H), 5.47 (br s, 2 H), 4.26 (t, J = 4.5 Hz, 2 H), 3.92
(s, 3 H), 3.75 (t, J = 3.5 Hz, 4 H), 2.93 (t, J = 4.5 Hz, 2 H), 2.65 (br
s, 4 H), 1.63 (s, 9 H).
13C NMR (DMSO-d6, 100 MHz): = 166.94, 150.92, 146.62,
145.91, 133.62, 130.46, 120.05, 112.57, 108.29, 107.37, 104.15,
80.29, 66.09, 65.79, 56.77, 55.29, 53.60, 27.88.
MS (ES): m/z = 523.9, 525.9 (M + 1).
Anal. Calcd for C29H30ClNO4S: C, 66.46; H, 5.77; N, 2.67. Found:
C, 66.31; H, 5.91; N, 2.61.
3-Amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic
Acid tert-Butyl Ester (10)
MS (ES): m/z = 403.3 (M + 1).
N2 was bubbled through a solution of 1,2-dichlorobenzene (150
mL) for 1 h and the reaction was heated to 179 °C. A solution of 9c
(3.0 g, 5.72 mmol) was added dropwise over a period of 30 min. Af-
ter heating for a further 1 h, the reaction was cooled and reduced in
vacuo. The residue was triturated with Et2O, collected by filtration
and washed with Et2O to give 10.
Anal. Calcd for C22H30N2O5: C, 65.65; H, 7.51; N, 6.96. Found: C,
65.65; H, 7.30; N, 6.98.
4-Hydroxy-7-methoxy-8-(2-morpholin-4-ylethoxy)benzo[g]-
quinoline-3-carbonitrile (14)
A mixture of 12 (0.69 g, 1.70 mmol) and DMF dimethyl acetal (2.4
mL) in toluene (7.0 mL) was heated under reflux for 1.5 h. The sol-
Yield: 1.46 g (67%); yellow solid; mp 179–180 °C.
Synthesis 2003, No. 11, 1712–1716 © Thieme Stuttgart · New York

1716
D. M. Berger et al.
PAPER
vent was evaporated and the residue was dried under high vacuum
to yield 13 as a light purple foam. This material was used immedi-
ately in the next step.
Acknowledgment
We thank members of the discovery analytical chemistry group for
spectral data and elemental analyses.
To THF (15 mL) at –78 °C was added BuLi (2.6 mL of a 1.6 M so-
lution in hexane, 1.63 mmol) and the mixture was stirred for 5 min.
To this was added MeCN (0.36 mL, 6.8 mmol) dropwise, followed
by stirring for 1 h. Then a solution of 13 in THF (5 mL) was added
dropwise over a period of 15 min. The mixture was stirred at –78 °C
for 1 h, then at r.t. for 1 h. After cooling again to –78 °C, the reaction
was quenched with MeCO2H (0.5 mL), then warmed to r.t. and
stirred for 1 h. The resulting solid was collected by filtration,
washed with EtOAc and dried in vacuo. Purification was carried out
by flash chromatography (silica gel; CH2Cl2–MeOH, 95:5 to 89:11)
to give 14.
References
(1) Boschelli, D. H.; Boschelli, F. Drugs Future 2000, 25, 717.
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M.; Cheresh, D. A. Nat. Med. 2001, 7, 222.
(4) (a) Boschelli, D. H.; Wang, D. Y.; Ye, F.; Wu, B.; Zhang, N.;
Dutia, M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber, J.
M.; Boschelli, F. J. Med. Chem. 2001, 44, 822. (b) Wang,
D. Y.; Miller, K.; Boschelli, D. H.; Ye, F.; Wu, B.; Floyd, M.
B.; Powell, D. W.; Wissner, A.; Weber, J. M.; Boschelli, F.
Bioorg. Med. Chem. Lett. 2000, 10, 2477. (c) Boschelli, D.
H.; Ye, F.; Wang, D. Y.; Dutia, M.; Johnson, S.; Wu, B.;
Miller, K.; Powell, D. W.; Arndt, K.; Discafani, C.; Etienne,
C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J. M.; Boschelli,
F. J. Med. Chem. 2001, 44, 3965.
(5) Zhang, N.; Wu, B.; Wissner, A.; Powell, D. W.; Rabindran,
S. K.; Kohler, C.; Boschelli, F. Bioorg. Med. Chem. Lett.
2002, 12, 423.
(6) Berger, D. M.; Dutia, M.; Demorin, F. F.; Boschelli, D. H.;
Powell, D. W.; Tsou, H.-R.; Wissner, A.; Zhang, N.; Ye, F.;
Wu, B. US 2001051620, 2001; Chem. Abstr. 2001, 136,
37618.
(7) Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B.;
Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.; Mamuya,
N.; Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou, H. R.;
Upeslacis, E.; Wang, Y. F.; Wu, B.; Ye, F.; Zhang, N. J.
Med. Chem. 2000, 43, 3244.
(8) (a) McOmie, J. F. W.; Perry, D. H. Synthesis 1973, 416.
(b) Kienzle, F. Helv. Chim. Acta. 1980, 63, 2364.
(c) Anderson, N. G.; Maddaford, S. P.; Keay, B. A. J. Org.
Chem. 1996, 61, 2885.
Yield: 0.38 g (59%); yellow solid; mp 275 °C (decomp).
1H NMR (DMSO-d6–TFA-d1, 300 MHz): = 8.74 (s, 1 H), 8.69 (s,
1 H), 8.00 (s, 1 H), 7.65 (s, 1 H), 7.59 (s, 1 H), 4.59 (t, J = 3.3 Hz, 2
H), 4.1 (d, J = 9.2 Hz, 2 H), 3.97 (s, 3 H), 3.75 (m, 4 H), 3.66 (d,
J = 9.3 Hz, 2 H), 3.34 (t, J = 7.0 Hz, 2 H).
13C NMR (DMSO-d6, 100 MHz): = 175.11, 151.12, 149. 89,
146.87, 134.69, 131.98, 126.64, 123.37, 122.30, 117.33, 114.01,
106.88, 105.74, 90.30, 66.14, 66.10, 56.66, 55.58, 53.58.
MS (ES): m/z = 380.2 (M + 1).
Anal. Calcd for C21H21N3O4·2.5 H2O: C, 60.71; H, 6.07; N, 10.12.
Found: C, 60.93; H, 6.11; N, 9.76.
4-Chloro-7-methoxy-8-(2-morpholin-4-ylethoxy)benzo[g]quin-
oline-3-carbonitrile (15)
A mixture of 14 (2.32 g, 6.11 mmol) in POCl3 (35 mL) was heated
under reflux for 1 h, then cooled to r.t. Excess POCl3 was evaporat-
ed to yield a residue, to which toluene was added and the resulting
solution was reduced in vacuo. Toluene was added and evaporated
twice more. The resulting residue was cooled in an ice bath, neutral-
ized with cold aq NaHCO3 and stirred. The solid was collected by
filtration, washed with cold H2O and dried in vacuo to yield 1.99 g
of 15 as a yellow solid. This was used without further purification
in the next step.
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-mor-
pholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile (3)
(9) Kobayashi, K.; Kanno, C.; Seko, S.; Suginome, H. J. Chem.
Soc., Perkin Trans. 1. 1992, 3111.
(10) Kametani, T.; Ogasawara, K.; Takahashi, T. Tetrahedron
1973, 29, 73.
(11) Kametani, T.; Takemura, M.; Ogasawara, K.; Fukumoto, K.
J. Heterocycl. Chem. 1974, 11, 179.
(12) Dai-Ho, G.; Mariano, P. S. J. Org. Chem. 1987, 52, 704.
(13) Taber, D. F.; Kong, S. J. Org. Chem. 1997, 62, 8575.
(14) Mitsunobu, O. Synthesis 1981, 1.
To a mixture of Pd2(dba)3 (354 mg, 0.387 mmol), K3PO4 (1.23 g,
5.80 mmol) and 2-(dicyclohexylphosphino)-2 -(N,N-dimethylami-
no)-1,1 -biphenyl16 (471 mg, 1.20 mmol) in DME (20 mL) were
added 15 (1.54 g, 3.87 mmol) and 2, 4-dichloro-5-methoxyaniline15
(0.896 g, 4.64 mmol). The resulting mixture was heated at reflux for
4 h, cooled to r.t. and diluted with sat. aq NaHCO3 (300 mL). The
precipitated solids were collected by filtration, washed with H2O
thoroughly and purified by flash chromatography (silica gel;
CH2Cl2–MeOH, 99:1 to 97:3) to give 3.
(15) Theodoridis, G.; Hotzman, F. W.; Scherer, L. W.; Smith, B.
A.; Tymonko, J. M.; Wyle, M. J. Pestic. Sci. 1990, 30, 259.
(16) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722.
(17) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q.
J. Am. Chem. Soc. 1999, 121, 6090.
Yield: 1.45 g (56% from 14); off-white solid; 231–234 °C.
1H NMR (DMSO-d6 + TFA-d1, 300 MHz): = 9.35 (s, 1 H), 9.24 (s
1 H), 8.42 (s, 1 H), 7.91 (s, 1 H), 7.82 (s 1 H), 7.61 (s, 1 H), 7.48 (s,
1 H), 4.66 (m, 2 H), 4.07 (s, 3 H), 4.04-3.97 (m, 2 H), 3.90 (s, 3 H),
3.83–3.63 (m, 6 H), 3.34 (m, 2 H).
(18) Boschelli, F.; Weber, J. M.; Lucas, J.; Etienne, C.; Arndt, K.;
Gibbons, J.; Boschelli, D. H.; Dutia, M.; Powell, D.; Wu, B.;
Yaczko, D.; Ye, F. 93rd Annual Meeting of the American
Association of Cancer Research; San Francisco: CA, 2002,
Abstract 4206.
(19) Berger, D.; Dutia, M.; Birnberg, G.; DeMorin, F.; Powell,
D.; Wang, Y. D.; Boschelli, D. H.; Ye, F.; Golas, J. M.;
Boschelli, F. J. Med. Chem., manuscript in preparation.
(20) Fukuyama, Y.; Yaso, H.; Mori, T.; Takahashi, H.; Minami,
H.; Kodama, M. Heterocycles 2001, 54, 259.
13C NMR (DMSO-d6 –TFA-d1, 100 MHz): = 158.84, 158.48,
158.11, 157.75, 153.89, 151.01, 150.82, 149.21, 133.83, 132.31,
129.69, 128.32, 122.65, 117.07, 116.68, 114.95, 114.16, 106.67,
106.31, 82.94, 63.53, 63.29, 56.75, 55.92, 54.77, 52.03.
MS (ES) m/z = 553.3, 555.3 (M + 1).
Anal. Calcd for C28H26Cl2N4O4·2.0 H2O: C, 57.05; H, 5.13; N, 9.50.
Found: C, 56.88; H, 4.96; N, 9.10.
Synthesis 2003, No. 11, 1712–1716 © Thieme Stuttgart · New York