Synthesis of chromeno[3,4-b ]quinolines: Electrophilic aromatic substitution under heck conditions

Article abstract of DOI:10.1055/s-0030-1258344

The palladium-mediated intramolecular coupling reaction of 2-[(3-substituted-phenoxy)methyl]quinolines for preparing chromeno[3,4-b] quinolines was explored. The results of the cyclizations gave convincing evidence for an electrophilic aromatic substituti

Full text of DOI:10.1055/s-0030-1258344

PAPER
229
Synthesis of Chromeno[3,4-b]quinolines: Electrophilic Aromatic Substitution
under Heck Conditions
Electrophilic
A
rom
n
atic Substitu
d
tion under
H
r
eck Con
e
ditions w L. C. Morris, Yvette A. Jackson*
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies
Fax +1(876)9771835; E-mail: yvette.jackson@uwimona.edu.jm
Received 15 September 2010; revised 1 November 2010
R2
Abstract: The palladium-mediated intramolecular coupling reac-
tion of 2-[(3-substituted-phenoxy)methyl]quinolines for preparing
chromeno[3,4-b]quinolines was explored. The results of the cy-
clizations gave convincing evidence for an electrophilic aromatic
substitution mechanism under standard Heck conditions.
Cl
N
R1
O
1
Key words: palladium catalysis, Heck reaction, electrophilic aro-
matic substitution, chromenoquinoline, aryl–heteroaryl coupling
Cl
N
R1
Br
O
R2
Chromenoquinolines have been implicated in a wide
range of biological activity including mimicry of anti-
inflammatory agents such as cortisone and cortisol,1 as
well as inhibition of estrogens by binding to estrogen re-
ceptor beta (ERb) sites.2 Known to be mild carcinogens,3
these compounds are also highly potent progestins4 as
well as inhibitors of passive cutaneous anaphylaxis.5
2
R
R
1 = H, OMe
2 = H, Me, OMe, NO2, CHO
Cl
MeO
Br
O
Reports of the synthesis of chromenoquinolines, particu-
larly chromeno[3,4-b]quinolines, in the literature are
sparse. We recently reported the first palladium-mediated
N
3
preparation of
a
6H-chromeno[3,4-b]quinoline
1
(R1 = OMe, R2 = H) (Figure 1).6 During our efforts to
synthesize heterocycles of type 1 (R1 = OMe, R2 = H), it
was found that when compound 2 (R1 = OMe, R2 = H)
was treated under standard Heck conditions the expected
product was isolated in fair yields (45–58%) when carried
out under both thermal and microwave conditions. When
compound 3 was treated similarly, however, none of the
desired product was isolated; the starting material was re-
covered unchanged. This led us to attempt elucidation of
the mechanism of cyclization of these compounds.
Figure 1
OH
O
OH
5 (87%)
Pd(PPh3)4
Br
+
t-BuOK, DMA
95 °C, 2 d
O
4
There have been conflicting suggestions in the literature
as to how aryl–aryl as well as aryl–heteroaryl coupling re-
actions proceed when they are mediated by palladium.7
Rawal et al.8 reported the palladium-catalyzed intramo-
lecular coupling of phenols with aryl halides to prepare 1-
hydroxy-6H-benzo[c]chromene (5) (Scheme 1). It was
found that when the phenoxy ring of compound 4 pos-
sessed a hydroxy group, under the basic conditions of the
reaction, the phenoxide rendered the aryl ring more nu-
cleophilic and, thus, more reactive in the coupling reac-
tion. The 3-hydroxy derivative 6 was also isolated.
HO
O
6 (2–5%)
Scheme 1
In 2003 Buchwald and Hennessey9 suggested three con-
ceivable mechanisms, viz. (1) electrophilic substitution,
(2) a Heck-type carbopalladation, and (3) C–H activation,
for the formation of substituted oxindoles from a-chloro-
acetanilides.
Nishioka and co-workers10 proposed analogous mecha-
nisms for intramolecular aryl–aryl couplings. These are
depicted in Scheme 2. While examining the palladium-
assisted biaryl coupling involved in the preparation of
phenanthridin-6(5H)-ones 8 from benzanilide precursors
7 (Scheme 3) formation of the biaryl bond was believed to
SYNTHESIS 2011, No. 2, pp 0229–0234
Advanced online publication: 26.11.2010
DOI: 10.1055/s-0030-1258344; Art ID: M06210SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

230
A. L. C. Morris, Y. A. Jackson
PAPER
– HX
H
+
Pd
Pd
X–
electrophilic
substitution
reductive
elimination
– HPdX
carbopalladation
Heck-type
H
Pd
X
Pd
C–H
activation
reductive
elimination
– HX
Pd
Pd
X
H
s-bond metathesis
Scheme 2
have proceeded through a C–H activation process. They thridinones in only 37–45% yield. When the rings bore
postulated that the substituents would have no effect on electron-donating groups yields increased to 67–92%.
the outcome of the reaction other than that due to steric
factors.
Many coupling reactions mediated by palladium have
been referred to in the literature as ‘Heck reactions’.
Later, during their synthesis of phenanthridinone deriva- When the coupling partners are two aryl (or heteroaryl)
tives 12 via a palladium-mediated coupling process, Kan rings a different nomenclature may be required. The
et al.11 found that the synthesis, which involved an aryl– Heck-type reaction should usually proceed via cis addi-
aryl coupling, depended on the electronic properties of the tion and syn b-elimination. Thus, a route via carbopallada-
ring (Scheme 3). The reaction proceeded through a domi- tion would be less likely, although there has been
no process with associated C–C and C–N bond-forming suggestion of an alternative mechanism involving anti
reactions, via intermediate 13. Those compounds with elimination or isomerization followed by syn elimina-
electron-withdrawing substituents proceeded in poor tion.12
yields. In fact, those bearing a nitro group failed to give
In our efforts to elucidate the mechanism of the intramo-
any of the desired products, while those bearing the weak-
lecular coupling of 2-substituted 4-chloroquinolines, we
ly deactivating halogens gave the corresponding phenan-
prepared a series of ethers of type 2 from bromides 14
R
Pd(OAc)2 (0.1 equiv)
PPh3 (0.2 equiv)
I
+
N
N
N
K2CO3 (2 equiv)
DMF, 50 °C to reflux
78–100%
R
Me
R
Me
Me
O
O
O
7 R = OMe, CO2Me
8
9
O
R1
R2
Bn
O
N
R1
R2
Bn
Ph2P
OMe
Pd(OAc)2, ligand 11
N
H
Cs2CO3, 1,4-dioxane
100 °C, 24 h
0–92%
R3
Br
R3
R1
R3
R2
11
10
12
O
R
1 = H, Cl, OMe, NO2
R2 = H, Me, OMe
3 = H, Me, NO2
R1
R2
R
N
Pd
Bn
R3
13
Scheme 3
Synthesis 2011, No. 2, 229–234 © Thieme Stuttgart · New York

PAPER
Electrophilic Aromatic Substitution under Heck Conditions
231
R2
Cl
Cl
N
Cl
R1
R1
Br
R1
Br
Pd(OAc)2, Ph3P
Br
O
R2
O
K2CO3, MeCN
reflux
N
1
N
2
14
Scheme 4 Intramolecular palladium-mediated coupling of 2-substituted quinolines 2
with a view to preparing chromeno[3,4-b]quinoline 1 ductive elimination of palladium thus furnishes the ob-
(Scheme 4) according to a protocol previously reported.6 served tetracycle 1a.
The cyclizations were carried out under standard Heck
When the phenoxy ring possesses an electron-withdraw-
conditions: palladium(II) acetate, triphenylphosphine, po-
ing group, such as a formyl or nitro group, its nucleophilic
tassium carbonate, acetonitrile, reflux under an atmo-
ability is significantly reduced. In our case, no reaction
sphere of nitrogen. The results of the attempted
occurred. It is likely that the reduced electron density of
cyclizations are presented in Table 1 and show that elec-
the aromatic ring imparted by the presence of these groups
tronic factors dominate the course of the reaction under
does not allow for the formation of intermediate 16, and
hence, none of the tetracycle. It should also be noted that
the prevailing conditions.
When the intramolecular coupling was carried out with none of this intermediate or its precursor 15 was ever iso-
compounds 2a–f the reactions proceeded as expected in lated.
reasonable yields. Compounds 2g and 2h, which pos-
Compound 3 was prepared from 6-methoxy-2-methyl-
sessed strongly deactivating substituents, a formyl and a
nitro group, respectively, on the phenoxy ring, did not
give any product of cyclization after heating at reflux for
12 hours. From these reaction mixtures only starting ma-
1H-quinolin-4-one (17)6 as shown in Scheme 6. Heating a
mixture of compound 17 and phosphorus pentachloride in
the presence of pyridine-derived bases at reflux for two
hours furnished 4-chloroquinoline 18 in 84% yield. Sub-
sequent bromination in the presence of light afforded
compound 19 in only 40% yield. Substitution of bromide
19 with 2-bromophenol provided ether 3 in 81% yield.
terial was recovered. The cyclizations are believed to pro-
ceed as shown in Scheme 5, similar to the mechanism
proposed by Rawal.8
Compound 2a, for example, oxidatively adds to palladi- When compound 3 was treated in similar manner to com-
um(0) resulting in s-arylpalladium intermediate 15. Al- pounds 2a–h, there was no reaction. With the bromine
though the phenyl ring is not as electron-rich as a now on the phenoxy ring, following oxidative addition to
phenolate anion the oxygen atom is able to render the ben- palladium, formation of the tetracycle 1d requires nucleo-
zene ring sufficiently nucleophilic to displace bromide philic attack of palladium by a quinoline ring. The re-
from 15. Abstraction of a proton by the base results in re- duced electron density of this ring compared to, for
aromatization and formation of palladium species 16. Re- example, benzene, prevents formation of intermediate 16
and, hence, no cyclized product is formed.
Table 1 Results of Cyclization of 3-Bromo-4-chloro-2-[(3-substituted phenoxy)methyl]quinoline 5 to Tetracycle 6
R2
Cl
Cl
R1
Br
R1
Pd(OAc)2, Ph3P
O
R2
K2CO3, MeCN
reflux
O
N
2
N
1
Substrate
R1
R2
Time (h)
Product
1a
Yield (%)
2a
2b
2c
2d
2e
2f
H
H
9
8
51
40
58
586
49
52
–
H
Me
OMe
H
1b
H
6
1c
OMe
OMe
OMe
OMe
OMe
8
1d
Me
OMe
CHO
NO2
8
1e
6
1f
2g
2h
12
12
–
Synthesis 2011, No. 2, 229–234 © Thieme Stuttgart · New York

232
A. L. C. Morris, Y. A. Jackson
PAPER
Cl
N
Br
Cl
O
Pd(0)
2a
O
N
1a
Br
Cl
N
Pd(II)
O
Cl
N
Pd(II)
15
O
16
base
HBr
Scheme 5 Proposed mechanism for the formation of tetracycle 1a from 2a
Cl
O
Cl
MeO
MeO
MeO
NBS, CCl4
PCl5, DMAP
hν, 4 h, 40%
2,6-lutidine, DMAP
reflux, 2 h, 84%
Br
N
N
H
N
17
18
19
2-BrC6H4OH,
K2CO3, acetone,
reflux, 2 h, 81%
Cl
Cl
MeO
MeO
Br
O
O
N
N
1d
3
Scheme 6 Synthesis of compound 3 and its attempted cyclization
silica gel. All palladium-mediated reactions were performed under
N2 atmosphere. Pd(OAc)2 was used as purchased from Aldrich.
In summary, the cyclization of 2-[(3-substituted phen-
oxy)methyl]quinolines to chromeno[3,4-b]quinolines
under typical Heck conditions has been investigated.
When subjected to these conditions the substrates demon-
strate the role of electronic factors on the palladium-
assisted reaction. Electron-donating groups increased the
rate of the reaction, while electron-withdrawing groups
retarded the cyclization. These findings give compelling
evidence for an electrophilic aromatic substitution mech-
anism for the intramolecular direct aryl–aryl coupling me-
diated by palladium.
2-(Bromomethyl)-4-chloro-6-methoxyquinoline (19)
Chloroquinoline 18 (200 mg, 0.96 mmol) was dissolved in CCl4 (5
mL) and irradiated with a 150-W tungsten bulb. NBS (206 mg, 1.2
mmol) was added in small portions over 10 min. The mixture was
then heated at reflux for 4 h while being irradiated. The mixture was
then filtered and the filtrate concentrated, diluted with CH2Cl2 (15
mL), and washed with 30% NaHSO3 soln (3 × 10 mL). The organic
layer was dried (Na2SO4), concentrated, and recrystallized to give
bromide 19 (110 mg, 40%) as orange plates; mp 78–80 °C (ace-
tone).
IR: 1618, 1561, 1488 cm–1.
1H NMR: d = 3.98 (s, 3 H, OCH3), 4.65 (s, 2 H, CH2Br), 7.42 (m, 2
H, H5, H7), 7.64 (s, 1 H, H3), 7.98 (d, J = 9.8 Hz, 1 H, H8).
13C NMR: d = 33.8, 55.8, 101.7, 101.8, 120.1, 121.5, 123.7, 126.8,
141.7, 144.3, 159.2.
Melting points were determined in capillary tubes on a Thomas
Hoover Melting Point apparatus and are uncorrected. IR spectra
were recorded neat on a Bruker Vector 22 FTIR spectrophotometer
1
and H and 13C NMR spectra in CDCl3 on a Bruker Avance 200
MHz or 500 MHz spectrometer; TMS was used as an internal stan-
dard (d = 0.0). Microanalyses were carried out at MEDAC Ltd.,
Chobham, Surrey, UK. Column chromatography was carried out on
Anal. Calcd for C11H9BrClNO: C, 46.11; H, 3.17; N, 4.89. Found:
C, 46.04; H, 3.31; N, 4.64.
Synthesis 2011, No. 2, 229–234 © Thieme Stuttgart · New York

PAPER
Electrophilic Aromatic Substitution under Heck Conditions
IR: 3001, 2050, 1489, 1229 cm–1.
233
2-[(2-Bromophenoxy)methyl]-4-chloro-6-methoxyquinoline (3)
To a stirred suspension of 2-bromophenol (86 mg, 0.50 mmol) and
K2CO3 (250 mg, 1.81 mmol) in acetone (5 mL) was added a soln of
2-(bromomethyl)-4-chloro-6-methoxyquinoline (19, 0.131 g, 0.45
mmol) in acetone (5 mL). The mixture was heated at reflux for 2 h
and filtered; the filtrate was concentrated, diluted with EtOAc (20
mL), and washed with 1.5 M NaOH (3 × 10 mL). The organic layer
was dried (Na2SO4) and then concentrated to give the crude product
which was recrystallized to give compound 3 (138 mg, 81%) as
light-brown needles; mp 133–135 °C (MeOH).
1H NMR: d = 3.79 (s, 3 H, OCH3), 5.46 (s, 2 H, CH2), 6.55 (ddd,
J = 8.2, 2.3, 0.8 Hz, 1 H, H2¢), 6.67 (m, 2 H, H6¢, H4¢), 7.20 (t,
J = 8.6 Hz, 1 H, H5¢), 7.66 (dd, J = 7.2, 1.4 Hz, 1 H, H6), 7.78 (dd,
J = 7.2, 1.5 Hz, 1 H, H7), 8.13 (dd, J = 8.6, 1.0 Hz, 1 H, H5), 8.23
(dd, J = 8.2, 1.0 Hz, 1 H, H8).
13C NMR: d = 55.3, 72.1, 101.6, 107.1, 107.1, 118.4, 124.6, 126.9,
128.8, 129.9, 130.0, 130.7, 143.2, 146.4, 154.6, 159.9, 160.8.
Anal. Calcd for C17H13BrClNO2: C, 53.92; H, 3.46; N, 3.70. Found:
C, 53.63; H, 3.44; N, 3.74.
IR: 2996, 2040, 1477, 1453 cm–1.
1H NMR: d = 3.98 (s, 3 H, OCH3), 5.37 (s, 2 H, CH2O), 6.88 (ddd,
J = 8.2, 1.7, 0.5 Hz, 1 H, H4¢), 6.99 (dd, J = 8.2, 1.0 Hz, 1 H, H6¢),
7.25 (ddd, J = 8.1, 2.0, 0.5 Hz, 1 H, H5¢), 7.42 (dd, J = 8.8, 2.5 Hz,
1 H, H7), 7.45 (s, 1 H, H5), 7.60 (dd, J = 7.9, 1.7 Hz, 1 H, H3¢), 7.89
(s, 1 H, H3), 7.96 (dd, J = 9.7, 0.7 Hz, 1 H, H8).
13C NMR: d = 55.7, 71.4, 101.8, 112.3, 113.6, 119.5, 121.3, 122.5,
123.6, 128.6, 130.8, 133.5, 137.0, 142.1, 144.3, 154.6, 158.8.
3-Bromo-4-chloro-6-methoxy-2-[(3-methylphenoxy)meth-
yl]quinoline (2e)
Brown plates; yield: 89%; mp 105–107 °C (EtOH).
IR: 2990, 2047, 1477, 1225 cm–1.
1H NMR: d = 2.34 (s, 3 H, CH3), 3.98 (s, 3 H, OCH3), 5.42 (s, 2 H,
CH2), 6.80 (d, J = 7.2 Hz, 1 H, H4¢), 6.88 (m, 2 H, H2¢, H6¢), 7.18
(t, J = 7.6 Hz, 1 H, H5¢), 7.40 (m, 2 H, H5, H7), 8.00 (dt, J = 9.7, 1.3
Hz, 1 H, H8).
13C NMR: d = 21.6, 55.8, 72.1, 102.3, 111.9, 116.0, 119.1, 122.1,
123.4, 129.2, 131.6, 133.9, 135.3, 135.9, 139.5, 151.9, 158.7, 159.6.
Anal. Calcd for C17H13BrClNO2: C, 53.92; H, 3.46; N, 3.70. Found:
C, 54.17; H, 3.88; N, 3.51.
2-[(3-Substituted phenoxy)methyl]quinolines 2; General Proce-
dure
Anal. Calcd for C18H15BrClNO2: C, 55.06; H, 3.85; N, 3.57. Found:
C, 55.05; H, 3.80; N, 3.52.
A mixture of the appropriate 3-substituted phenol (1.2 equiv) and
K2CO3 (5 equiv) was dissolved in acetone and the mixture stirred at
r.t. for 15 min. (Bromomethyl)quinoline 14 was then added as a soln
in acetone and the mixture heated at reflux for 2–3 h. The mixture
was then filtered to remove inorganic material, concentrated, dilut-
ed with CH2Cl2 (20 mL) and washed with 2 M NaOH (2 × 5 mL).
The organic layer was dried (Na2SO4) and concentrated to give 2.
3-Bromo-4-chloro-6-methoxy-2-[(3-methoxyphenoxy)meth-
yl]quinoline (2f)
Peach-colored needles; yield: 91%; mp 118–119 °C (EtOH).
IR: 2990, 2051, 1470, 1222 cm–1.
1H NMR: d = 3.79 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 5.43 (s, 2
H, CH2), 6.54 (dd, J = 8.3, 2.5 Hz, 1 H, H2¢), 6.70 (m, 2 H, H4¢,
H6¢), 7.19 (t, J = 8.6 Hz, 1 H, H5¢), 7.40 (m, 2 H, H5¢, H7), 8.00 (dd,
J = 8.6, 0.7 Hz, 1 H, H8).
13C NMR: d = 54.0, 54.8, 71.6, 100.4, 101.6, 106.1, 118.4, 122.9,
124.6, 127.5, 128.2, 129.2, 130.9, 140.0, 141.6, 151.3, 159.4, 160.4.
3-Bromo-4-chloro-6-methoxy-2-(phenoxymethyl)quinoline (2d)6
is consistent with literature data.
3-Bromo-4-chloro-2-(phenoxymethyl)quinoline (2a)
Off-white needles, yield: 85%; mp 67–69 °C (EtOH).
IR: 3000, 2049, 1489, 1228 cm–1.
Anal. Calcd for C18H15BrClNO3: C, 52.90; H, 3.70; N, 3.43. Found:
C, 53.09; H, 3.74; N, 3.42.
1H NMR: d = 5.48 (s, 2 H, CH2O), 6.99 (tt, J = 6.6, 0.7 Hz, 1 H,
H4¢), 7.08 (dd, J = 8.8, 0.6 Hz, 2 H, H2¢, H6¢), 7.31 (m, 2 H, H3¢,
H5¢), 7.67 (ddd, J = 8.1, 6.4, 0.5 Hz, 1 H, H6), 7.79 (ddd, J = 8.1,
6.6, 1.5 Hz, 1 H, H7), 8.13 (ddd, J = 8.2, 1.2, 0.5 Hz, 1 H, H5), 8.24
(ddd, J = 8.1, 1.6, 0.5 Hz, 1 H, H8).
13C NMR: d = 72.1, 115.1, 118.4, 121.4, 124.5, 126.9, 128.7, 129.5,
130.0, 130.6, 142.7, 154.6, 156.7, 158.6.
3-[(3-Bromo-4-chloro-6-methoxyquinolin-2-yl)methoxy]benz-
aldehyde (2g)
Cream-colored prisms; yield: 73%; mp 147–149 °C (EtOH).
IR: 2999, 2780, 2044, 1692 cm–1.
1H NMR: d = 4.00 (s, 3 H, OCH3), 5.51 (s, 2 H, CH2), 7.34 (dd,
J = 7.9, 1.3 Hz, 1 H, H6), 7.47 (m, 4 H, H4, H5, H5¢, H7¢), 7.59 (br
s, 1 H, H2), 8.00 (d, J = 9.1 Hz, 1 H, H8¢), 9.99 (s, 1 H, CHO).
Anal. Calcd for C16H11BrClNO: C, 55.12; H, 3.18; N, 4.02. Found:
C, 55.58; H, 2.97; N, 4.22.
13C NMR: d = 55.8, 72.2, 102.3, 113.8, 119.0, 120.0, 122.3, 123.7,
123.8, 128.3, 130.2, 131.6, 137.8, 142.5, 151.1, 159.2, 159.8, 192.1.
3-Bromo-4-chloro-2-[(3-methylphenoxy)methyl]quinoline (2b)
Cream-colored prisms; yield: 92%; mp 111–113 °C (EtOH).
IR: 2991, 2044, 1480, 1222 cm–1.
Anal. Calcd for C18H13BrClNO3: C, 53.16; H, 3.22; N, 3.44. Found:
C, 53.03; H, 3.25; N, 3.13.
1H NMR: d = 2.34 (s, 3 H, CH3), 5.46 (s, 2 H, -OCH2-), 6.79–6.91
(m, 3 H, H2¢, H4¢, H6¢), 7.19 (t, J = 7.8 Hz, 1 H, H5¢), 7.67 (ddd,
J = 8.4, 7.0, 1.5 Hz, 1 H, H6), 7.79 (ddd, J = 8.4, 7.0, 1.5 Hz, 1 H,
H7), 8.14 (ddd, J = 8.4, 1.4, 0.5 Hz, 1 H, H5), 8.23 (ddd, J = 8.4,
1.5, 0.5 Hz, 1 H, H8).
13C NMR: d = 21.5, 72.1, 111.9, 116.0, 118.4, 122.2, 124.5, 126.9,
128.7, 129.2, 130.0, 130.6, 139.5, 142.9, 146.4, 158.7, 163.1.
3-Bromo-4-chloro-6-methoxy-2-[(3-nitrophenoxy)methyl]quin-
oline (2h)
Pale-yellow prisms; yield: 83%; mp 177–179 °C (EtOH).
IR: 3001, 2041, 1531, 1343 cm–1.
1H NMR: d = 3.99 (s, 3 H, OCH3), 5.55 (s, 2 H, CH2), 7.41 (m, 2 H,
H2¢, H6¢), 7.70 (dd, J = 8.1, 7.8 Hz, 1 H, H5¢), 7.83 (m, 2 H, H5,
H7), 8.11 (d, J = 8.3 Hz, 1 H, H8), 8.25 (d, J = 8.0 Hz, 1 H, H4¢).
13C NMR: d = 55.8, 72.4, 102.3, 109.7, 116.3, 118.1, 122.0, 123.7,
124.6, 128.9, 130.0, 131.5, 146.3, 149.2, 150.6, 153.4, 159.9, 160.0.
Anal. Calcd for C17H13BrClNO: C, 56.30; H, 3.61; N, 3.86. Found:
C, 56.04; H, 3.56; N, 3.68.
3-Bromo-4-chloro-2-[(3-methoxyphenoxy)methyl]quinoline
(2c)
Anal. Calcd for C17H12BrClN2O4: C, 48.20; H, 2.86; N, 6.61.
Found: C, 48.56; H, 2.85; N, 6.84.
White prisms; yield: 89% mp 91–93 °C (EtOH).
Synthesis 2011, No. 2, 229–234 © Thieme Stuttgart · New York

234
A. L. C. Morris, Y. A. Jackson
PAPER
Substituted 12-Chloro-6H-chromeno[3,4-b]quinolines 1; Gen-
eral Procedure
IR: 2999, 2925, 1629, 1479 cm–1.
1H NMR: d = 2.40 (s, 3 H, CH3), 3.99 (s, 3 H, OCH3), 5.18 (s, 2 H,
CH2), 6.99 (m, 2 H, H2, H4), 7.36 (dd, J = 9.0, 2.5 Hz, 1 H, H9),
7.59 (d, J = 2.9 Hz, 1 H, H11), 7.91 (dd, J = 9.0, 0.4 Hz, 1 H, H8),
8.46 (dd, J = 8.0, 0.3 Hz, 1 H, H1).
13C NMR: d = 21.6, 55.6, 72.0, 102.8, 107.1, 113.5, 118.0, 120.5,
120.7, 122.0, 130.7, 132.9 137.7, 138.3, 139.5, 140.5, 156.7, 158.9.
A mixture of the appropriate quinoline 2, (Pd(OAc)2 (0.2 equiv),
Ph3P (0.4 equiv), and K2CO3 (20 equiv) in MeCN (6 mL) was
stirred under a steady stream of N2 at reflux until no starting mate-
rial remained. The mixture was filtered and the filtrate concentrated.
Without further purification the mixture was then subjected to flash
chromatography (CH2Cl2–hexanes, 9:1) to give 1.
12-Chloro-10-methoxy-6H-chromeno[3,4-b]quinoline (1d)6 is con-
sistent with literature data.
Anal. Calcd for C18H14ClNO2: C, 69.35; H, 4.53; N, 4.49. Found: C,
68.35; H, 3.82; N, 4.46.
12-Chloro-3,10-dimethoxy-6H-chromeno[3,4-b]quinoline (1f)
Pale-brown needles; yield: 52%; mp 157–159 °C (EtOH).
IR: 3002, 2923, 1620, 1485 cm–1.
12-Chloro-6H-chromeno[3,4-b]quinoline (1a)
Pale-yellow liquid; yield: 51%.
IR: 2924, 1618, 1489 cm–1.
1H NMR: d = 3.87 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 5.19 (s, 2
H, CH2), 6.68 (dd, J = 2.6, 0.4 Hz, 1 H, H4), 6.75 (dd, J = 9.1, 2.9
Hz, 1 H, H2), 7.36 (dd, J = 9.1, 2.8 Hz, 1 H, H9), 7.58 (dd, J = 2.8,
0.4 Hz, 1 H, H11), 7.91 (d, J = 9.2 Hz, 1 H, H8), 8.52 (d, J = 8.8,
0.5 Hz, 1 H, H1).
13C NMR: d = 55.5, 55.7, 72.1, 105.8, 108.1, 113.5, 118.0, 120.5,
120.7, 122.0, 125.6, 130.7, 137.7, 138.7, 139.0, 156.4, 158.6, 159.0.
1H NMR: d = 5.20 (s, 2 H, CH2O), 7.15 (dd, J = 8.2, 0.5 Hz, 1 H,
H9), 7.18 (dt, J = 7.8, 0.7 Hz, 1 H, H11), 7.38 (m, 2 H, H2, H3), 7.60
(d, J = 8.2 Hz, 1 H, H9), 7.78 (ddd, J = 8.2, 8.4, 1.5 Hz, 1 H, H10),
7.93 (d, J = 8.2 Hz, 1 H, H8), 8.58 (dd, J = 8.2, 0.5 Hz, 1 H, H1).
13C NMR: d = 72.1, 115.1, 118.4, 121.4, 124.2, 124.5, 125.7, 125.8,
126.9, 128.7, 129.5, 130.0, 130.6, 137.0, 146.4, 158.6.
Anal. Calcd for C16H10ClNO: C, 71.78; H, 3.77; N, 5.23. Found: C,
71.51; H, 3.40; N, 5.39.
Anal. Calcd for C18H14ClNO3: C, 65.96; H, 4.31; N, 4.27. Found: C,
65.82; H, 4.71; N, 3.94.
12-Chloro-3-methyl-6H-chromeno[3,4-b]quinoline (1b)
Brown prisms; yield: 40%; mp 229–231 °C (EtOH).
IR: 2938, 1629, 1480 cm–1.
References
(1) Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.;
Luly, J. R.; Wilcox, D.; Stashko, M.; Lin, C.-W.; Miner, J.;
Tyree, C.; Nakane, M.; Jacobson, P.; Lane, B. C. J. Med.
Chem. 2001, 44, 2879.
(2) Vu, A. T.; Campbell, A. N.; Harris, H. A.; Unwalla, A. J.;
Manas, E. S.; Mewshaw, R. E. Bioorg. Med. Chem. Lett.
2007, 17, 4053.
1H NMR: d = 2.36 (s, 3 H, CH3), 5.19 (s, 2 H, CH2), 6.67 (d, J = 2.7
Hz, 1 H, H4), 6.95 (dd, J = 9.0, 2.7 Hz, 1 H, H2), 7.70 (m, 2 H, H9,
H10), 8.02 (ddd, J = 8.4, 1.8, 0.9 Hz, 1 H, H11), 8.35 (ddd, J = 8.6,
1.6, 0.8 Hz, 1 H, H8), 8.52 (d, J = 8.8 Hz, 1 H, H).
13C NMR: d = 21.5, 72.3, 116.6, 120.6, 120.8, 124.5, 125.6, 127.9,
128.2, 129.8, 130.4, 132.1, 136.9, 138.3, 140.3, 144.2, 158.4.
(3) Bistochi, G. A.; De Me, G.; Ricci, A.; Croisy, A.;
Anal. Calcd for C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C,
72.55; H, 4.02; N, 4.63.
Jacquignon, P. Heterocycles 1978, 9, 247.
(4) Zhi, L.; Tegley, C. M.; Pio, B.; Edwards, J. P.; Motamedi,
M.; Jones, T. K.; Marschke, K. B.; Mais, D. E.; Risek, B.;
Shrader, W. T. J. Med. Chem. 2003, 46, 4104.
(5) Nohara, A.; Ishigura, T.; Kuyoshi, U. J. Med. Chem. 1985,
28, 559.
12-Chloro-3-methoxy-6H-chromeno[3,4-b]quinoline (1c)
Pale-yellow prisms; yield: 58%; mp 102–104 °C (MeOH).
IR: 2931, 1620, 1479 cm–1.
1H NMR: d = 3.87 (s, 3 H, OCH3), 5.23 (s, 2 H, CH2), 6.69 (d,
J = 2.7 Hz, 1 H, H4), 6.76 (dd, J = 9.0, 2.7 Hz, 1 H, H2), 7.70 (m, 2
H, H9, H10), 8.02 (ddd, J = 8.4, 1.8, 0.9 Hz, 1 H, H11), 8.35 (ddd,
J = 8.6, 1.6, 0.8 Hz, 1 H, H8), 8.53 (d, J = 8.8 Hz, 1 H, H1).
13C NMR: d = 55.5, 71.6, 108.9, 119.8, 124.6, 126.9, 127.6, 127.7,
128.2, 129.0, 129.7, 130.0, 135.1, 141.6, 146.9, 158.2, 161.6.
(6) Morris, A. L. C.; Jackson, Y. A. Heterocycles 2010, 81, 371.
(7) (a) Wiegand, S.; Schäfer, H. J. Tetrahedron 1995, 51, 5341.
(b) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.
(8) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem.
1997, 62, 2.
(9) Hennessey, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 12084.
Anal. Calcd for C17H12ClNO2: C, 68.58; H, 4.06; N, 4.70. Found: C,
68.35; H, 3.82; N, 4.46.
(10) Nishioka, H.; Nagura, C.; Abe, H.; Takeuchi, Y.; Harayama,
T. Heterocycles 2006, 70, 549.
(11) Furuta, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.; Yanaka,
12-Chloro-10-methoxy-3-methyl-6H-chromeno[3,4-b]quino-
line (1e)
Off-white prisms; yield: 49%; mp 176–178 °C (EtOH).
K.; Kan, T. Org. Lett. 2007, 9, 183.
(12) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301.
Synthesis 2011, No. 2, 229–234 © Thieme Stuttgart · New York