Palladium-catalyzed intramolecular biaryl coupling: A highly efficient avenue for benzannulated pyranoquinolines and julolidine derivatives

Article abstract of DOI:10.1055/s-0028-1083363

A new efficient route to the synthesis of benzannulated pyranoquinolines has been accomplished via palladium-catalyzed intramolecular aryl-aryl cross-coupling reactions. The coupling reactions proceeded smoothly under ligand-free conditions with the catal

Full text of DOI:10.1055/s-0028-1083363

PAPER
793
Palladium-Catalyzed Intramolecular Biaryl Coupling: A Highly Efficient
Avenue for Benzannulated Pyranoquinolines and Julolidine Derivatives
P
alladium-Catalyz
.
e
d
Intramole
C
cular Biaryl
C
ou
.
pling Majumdar,* Abu Taher, Pradip Debnath
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 6 October 2008; revised 19 November 2008
OMe
N
Abstract: A new efficient route to the synthesis of benzannulated
pyranoquinolines has been accomplished via palladium-catalyzed
intramolecular aryl–aryl cross-coupling reactions. The coupling re-
actions proceeded smoothly under ligand-free conditions with the
catalytic system Pd(OAc)2/Cs2CO3/TBAB in high yields. Halogen-
reduced product was not obtained in optimum reaction conditions.
Regioselective synthesis of 5,6-dihydro-4H,8H-pyrido[3,2,1-
de]phenanthridine is also described. In the latter case, a pronounced
effect of base (Ag2CO3) has been observed on the efficiency of the
conversion.
OH
O
N
O
OH
geibalansine (I)
helietidine (II)
OMe
N
O
OH
Key words: biaryl coupling, Heck reaction, intramolecular cycliza-
tion, palladium catalyst, pyranoquinolines, dihydropyridophenan-
thridine
O
O
N
O
Me
dutadrupine (III)
ribalinine (IV)
The importance of quinoline and its annulated derivatives
is well recognized by synthetic and biological chemists.1
Compounds possessing this ring system have wide appli-
cations in medicinal chemistry;2 being used as antimalar-
ial, anti-inflammatory, antiasthmatic, antibacterial,
Figure 1 Examples of natural products containing the pyranoquino-
line core structure
densed heteroaromatic compounds using biaryl-coupling
reactions with the palladium reagent under ligand-free
conditions.9
antihypertensive, and tyrosine kinase inhibiting agents.3
Alkaloids containing the pyranoquinoline core constitute
a significant group of the quinoline alkaloids and these
classes of compounds have been shown to exhibit a range
of biological activities.4 Some examples of natural prod-
ucts containing the pyranoquinoline core structure include
geibalansine (I), helietidine (II), dutadrupine (III), and
ribalinine (IV) (Figure 1).4,5 Therefore, considerable ef-
forts have been made towards the preparation and synthet-
ic manipulation of this class of compounds.6 As a result, a
number of compounds have been obtained with diverse
biological activities. However, the corresponding benzan-
nulated analogues of pyranoquinolines have remained un-
explored for their biological activities, which may be due
to the lack of general synthetic route for these classes of
heteroaromatics from easily accessible precursors.
Although a number of protocols have been developed for
the coupling of biaryl moieties, many of them have limit-
ed applicability in organic synthesis due to the harshness
or functional group intolerance10 and high11 (even stoichi-
ometric)12 catalyst loading under optimized conditions.
Use of phosphine ligand may become problematic in the
separation process.13 Overcoming these hurdles will nec-
essarily require the discovery and development of novel
catalytic systems. It has been reported that phenolates
have been shown to exhibit enhanced reactivity in in-
tramolecular arylation reactions.14–16 However, the palla-
dium-catalyzed biaryl-coupling reactions of ethers such
as 2-bromobenzyl phenyl ether that lack a phenolate acti-
vating group proceeded poorly and gave lower yield of the
product.14,17 Rawal et al. reported14 that in the absence of
a phenolate activating group on the nucleophilic arene,
less than 10% of the coupled product was obtained after
prolonged reaction. Recently, Fagnou and co-workers18
also attempted the same type of cyclization reaction, using
Pd(OAc)2 as catalyst and 2-(diphenylphosphino)-2¢-(N,N-
dimethylamino)biphenyl as ligand, for this cyclization.
They obtained a significant amount of dehalogenated
product in the absence of the ligand. Therefore, the above
mentioned observations have prompted us to undertake a
study of the Heck type of reaction on the biaryl ethers as
starting materials, with a view to synthesize the con-
densed heteroaromatic compounds of biological interest.
Over the past decade, palladium-catalyzed cyclization re-
action has proven to be an extremely powerful and useful
tool for the construction of carbon–carbon, as well as car-
bon–heteroatom bonds.7 In particular, intramolecular bi-
aryl coupling reactions involving a palladium reagent is of
considerable interest due to its significant utility in the
synthesis of many condensed heteroaromatic com-
pounds.8 Recently, we reported the synthesis of con-
SYNTHESIS 2009, No. 5, pp 0793–0800
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083363; Art ID: Z22508SS
© Georg Thieme Verlag Stuttgart · New York

794
K. C. Majumdar et al.
PAPER
Furthermore, this coupling reaction provides a new meth- Table 1 Palladium-Catalyzed Cyclization of 3a to 4aa
odology to construct the pyranoquinoline skeleton present
in numerous natural alkaloids.4,5
N
N
Preparation of the cyclization precursors 3a–f for the
present investigations was carried out by the alkylation of
different hydroxyquinolines with either 2-bromobenzyl
bromide (2a) or 2-bromo-5-methoxybenzyl bromide (2b).
For example, compounds 3a,b were prepared by classical
alkylation procedure according to which 8-hydroxyquino-
line (1a) was dissolved in anhydrous acetone and to this
2-bromobenzyl bromide (2a) or 2-bromo-5-methoxyben-
zyl bromide (2b) and anhydrous K2CO3 were added, and
the reaction mixture was refluxed for 6 hours to afford
3a,b in 88 and 84% yield, respectively (Scheme 1). In a
similar manner, other precursors 3c–f were also prepared
in 78–87% yields from 5-hydroxy-2,4-dimethylquinoline
and 7-hydroxy-2,4-dimethylquinoline.
O
O
3a
4a
Br
Entry Catalystb
Basec
Additived Solvent Yield (%)e
1
2
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TBAB
TBAB
TBACl
TBACl
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
35
3
Pd(OAc)2
PdCl2
46
4
25
5
Pd(OAc)2
Pd(OAc)2
15f
NRg
NR
60
6
–
7
Pd(PPh3)2Cl2 Cs2CO3
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
Br
R
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KOAc
Ag2CO3
K2CO3
Et3N
Br
(i)
N
+
9
28
N
O
R
OH
10
11
12
13
14
15
16
17
NR
NR
Br
1a
2a,b
3a R = H (88%)
3b R = OMe (84%)
Cs2CO3
Cs2CO3
KOAc
KOAc
Ag2CO3
Cs2CO3
DMSO 70
Scheme 1
Reagents and conditions: (i) anhyd acetone, anhyd
MeCN
MeCN
NR
NR
K2CO3, reflux, 6 h.
When the coupling reaction was carried out with precur-
sor 3a in the presence of 5 mol% of Pd(OAc)2 as a cata-
lyst, Cs2CO3 as a base, and tetrabutylammonium bromide
(TBAB) as an additive in anhydrous DMF as a solvent at
95 °C for two hours under nitrogen, the pyranoquinoline
derivative 4a was obtained in 90% yield. The optimum
conditions for the cyclization were found through a series
of experiments where various changes were made to the
catalyst, base, additive, and solvent used in the reaction
(Table 1). We found that the catalyst, base, additive, and
solvent have a profound effect on the reaction yield. The
use of PdCl2, which is mostly used in the Heck type of re-
action provides only 35% yield of the cyclized product 4a
(Table 1, entry 2). The additive tetrabutylammonium
chloride (TBACl) was also found to be effective in this
case, but the yield of the product was reduced to 46 and
25% using Pd(OAc)2 and PdCl2 as catalyst, respectively
(entries 3 and 4). Here, it is pertinent to note that the addi-
tive plays an important role in the cyclization. Without
any additive such as TBAB or TBACl, the reactions be-
came extremely slow and gave a significant amount of de-
halogenated product (entry 5); but with the catalytic
system Pd(OAc)2/Cs2CO3/Ph3P, the reaction did not occur
(entry 6). The catalytic system Pd(PPh3)2Cl2/Cs2CO3/
TBAB was also inactive towards the cyclization (entry 7).
DMSO 55
DMSO 35
dioxane NR
a All reactions were carried out at 95 °C for 2 h.
b Pd(OAc)2 and PdCl2 catalyst were used in 5 mol% and 10 mol%,
respectively.
c Amount of base used in the reaction = 1.5 equiv.
d Amount of additive used in the reaction = 1.5 equiv.
e Isolated yields; NR = no reaction.
f An amount of 55% of debrominated product was obtained.
g Amount of Ph3P as ligand used in the reaction = 20 mol%.
be highly effective with the catalyst Pd(OAc)2 (entries 1,
3, and 12) and excellent yield of the product was obtained
in DMF (entry 1). Other inorganic bases such as K2CO3,
Ag2CO3, and organic base like Et3N were explored. The
use of Ag2CO3 was found to be effective (entries 9 and
16); however, with K2CO3 and Et3N reaction did not occur
at all (entries 10 and 11).
Among the several aprotic polar solvents examined, DMF
resulted to give the highest yield. Other solvent such as
DMSO was also found to be effective, but gave lower
yield of the product (entries 12, 15, and 16) whereas no re-
action occurred in MeCN and dioxane (entries 13, 14, and
17). The reaction also did not occur at 80 °C or at lower
temperature. In order to examine the versatility of this in-
tramolecular biaryl coupling reaction, a number of pyra-
noquinoline derivatives 4b–f were synthesized under the
The effect of base on the reaction was also investigated.
The use of KOAc as a base gave 60% and 55% of 4a in
DMF and DMSO, respectively (entries 8 and 15). Re-
placement of the base, KOAc with Cs2CO3 was found to
Synthesis 2009, No. 5, 793–800 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Intramolecular Biaryl Coupling
795
Table 2 Ether Cyclization by Palladium-Catalyzed Heck Type of Reactiona
Entry
1
Starting material
Product
Yield (%)b
OMe
N
3b
4b
95
N
O
O
O
MeO
Br
Br
O
2
3
3c
4c
86
88
N
O
N
N
Br
MeO
O
3d
4d
OMe
N
4
5
3e
4e
4f
78c
84
Br
O
N
O
N
N
OMe
MeO
3f
Br
O
N
O
a All reactions were performed under optimized conditions.
b Isolated yields.
c Angular fused product was obtained in 5% yield.
optimized reaction conditions, Pd(OAc)2/Cs2CO3/TBAB/ use of these conditions in our system gave only 5% yield
DMF. The results are summarized in Table 2.
of the desired cyclized product (Table 3, entry 1). Indeed,
the halogen-reduced product was isolated in 84% yield.
Therefore, a further optimization study was needed. With
Pd(OAc)2 catalyst, variation of bases such as KOAc,
Cs2CO3, K2CO3, and phosphine ligand such as triphe-
nylphosphine, and solvents (DMF, DMSO, MeCN, diox-
ane) used in the reaction had little effect on the outcome
of the reaction. All efforts gave mainly the dehalogenated
product (Table 3). Finally, the best result was achieved af-
ter 8 hours using Ag2CO3 as a base, PdCl2 as a catalyst
along with TBAB as additive and DMSO as a solvent at
120 °C under nitrogen. This provided a 72% yield of the
cyclized product 7, and 10% of the reduced N-benzyltet-
We next examined the palladium-catalyzed intramolecu-
lar aryl–aryl cross coupling of compounds 6a,b. This cou-
pling reaction would provide a new methodology to
construct the 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-
i,j]quinoline skeleton present as a basic structural moiety
in a number of alkaloids such as julolidine alkaloids.19
Some derivatives of the latter show very interesting phar-
macological properties and, as a result, synthesis has been
attempted.20
Treatment of tetrahedroquinoline (5) with sodium hydride
followed by addition of 2-bromobenzyl bromide afforded
the precursor 6a in 87% yield. The related aryl iodide pre-
cursor 6b was also prepared in a similar manner
(Scheme 2).
Br
X
Here, it is important to note that under the above opti-
mized conditions the substrates 6a and 6b did not give any
cyclized product; only halogen-reduced product was ob-
tained. Flippin et al.21 reported that the use of Pd(OAc)2 as
a catalyst and triethylamine as a base, and with the addi-
tion of Ph3P as a ligand, afforded the best result for similar
type of cyclization with indole derivatives. Surprisingly,
N
(i)
+
N
H
2a,c
5
X
X = Br, I
6a X = Br (87%)
6b X = I (90%)
Scheme 2 Reagents and conditions: (i) anhyd THF, NaH, reflux,
4 h.
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796
K. C. Majumdar et al.
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Table 3 Palladium-Catalyzed Cyclization of 6 to 7
N
N
N
+
X
6a X = Br
6b X = I
7
8
Entry
Substrate
Catalyst
(mol%)
Basea
Additiveb
Solvent
Yield (%)
7/8
1
2
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
Pd(OAc)2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
Pd(OAc)2 (10)
Et3N
–
DMF
5:84
Ag2CO3
Ag2CO3
Cs2CO3
Ag2CO3
Cs2CO3
KOAc
TBAB
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
72:10
20:65
56:36
82:0
3c
4
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
5
6
65:25
0:95
7
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
45:45
25:30
15:70
0:90
9
MeCN
dioxane
DMSO
10
11
a Amount of base used in the reaction = 2.5 equiv.
b Amount of additive used in the reaction = 2.0 equiv.
c Amount of Ph3P used as ligand = 20 mol%.
rahydroquinoline 8 (Table 3, entry 2). However, without halides 3 to give a s-arylpalladium intermediate. Electro-
TBAB the yield of the cyclized product was dramatically philic attack on the aromatic ring leads to the biarylpalla-
reduced to 20% at the expense of a significant amount of dium species, which after reductive elimination of
dehalogenated product (Table 3, entry 3). Use of Cs2CO3 palladium affords the cyclized products 4. A plausible cat-
as a base with catalyst PdCl2 gave only 56% of the cy- alytic cycle for the formation of the product 7 from the
clized product (Table 3, entry 4). The positive effect of substrate 6 is outlined in Scheme 3. Abstraction of
Ag2CO3 is presumably due to abstraction of halide from halide22 by silver carbonate leads to cationic intermediate
the arylpalladium complex22 and formation of a cationic
arylpalladium intermediate 10 (Scheme 3).
From this preliminary result, we expected that the use of
Pd(II)
o-iodobenzyl derivative 6b as a starting material may de-
crease the yield of the reduction product and improve the
yield of the cyclized product. It was indeed found that
6
Pd(0)
7
treatment of o-iodobenzyl derivative 6b with the catalytic
system PdCl2/Ag2CO3/TBAB in anhyd DMSO at 120 °C
11
9
N
for 10 hours, afforded an improved yield of 7 (82%,
Table 3, entry 5). Other bases such as Cs2CO3 gave 65%
yield of the product (entry 6) whereas KOAc afforded de-
halogenated product only (entry 7). The solvents DMF,
MeCN, and dioxane were also effective with the catalytic
system PdCl2/Ag2CO3, but afforded lower yield of the
product (entry 8–10). However, compound 6b with cata-
lyst Pd(OAc)2/Ag2CO3 gave only reduced product 8
(95%, Table 3, entry 11).
N
X-Pd
– AgX
– base-H
Pd
10
+
N
H
base
Pd
From a mechanistic point of view, the cyclization pro-
ceeds through the oxidative addition of Pd(0) to the aryl
Scheme 3
Synthesis 2009, No. 5, 793–800 © Thieme Stuttgart · New York

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Palladium-Catalyzed Intramolecular Biaryl Coupling
797
8-[(2-Bromo-5-methoxybenzyl)oxy]quinoline (3b)
Eluted from the column with EtOAc–PE (3:17) as a colorless solid
(84%); mp 92–94 °C (CHCl3–hexane).
10 presumably stabilized by the nitrogen atom of the tet-
rahydroquinoline moiety.
It has been observed that the biaryl coupling reactions
proceeded smoothly in our optimized reaction conditions
and give much better yields of the cyclized products as
compared to previous reports10,14,18 under ligand-free con-
ditions. Halogen-reduced product was not obtained at all.
The use of o-iodobenzyl derivative and Ag2CO3 as base
completely inhibit the formation of the undesired reduced
product 8 and dramatically improve the yield of the de-
sired product 7.
IR (KBr): 2921, 1617, 1015 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.66 (s, 3 H), 5.46 (s, 2 H), 6.69
(dd, J = 3.1, 8.7 Hz, 1 H), 6.94 (dd, J = 2.3, 6.6 Hz, 1 H), 7.20 (d,
J = 3.0 Hz, 1 H), 7.35–7.46 (m, 4 H), 8.12 (dd, J = 1.7, 8.3 Hz, 1 H),
8.96 (dd, J = 1.7, 4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.3, 70.1, 110.0, 111.8, 114.0,
115.1, 120.2, 121.6, 126.6, 129.4, 133.0, 135.9, 137.0, 140.2, 149.3,
153.8, 159.2.
MS: m/z = 343, 345 [M+].
In conclusion, we have developed a convenient and high
yielding method for the synthesis of benzannulated pyra-
noquinolines and 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-
i,j]quinoline system, present in many biologically active
alkaloids by palladium-catalyzed intramolecular Heck re-
action under ligand-free conditions. The method is new,
mild and highly effective for the cyclization of biaryl sys-
tem, and afforded the cyclized products in high yields.
The method would be applicable for several other ring
systems and heteroatomic species.
Anal. Calcd for C17H14BrNO2: C, 59.32; H, 4.10, N, 4.07. Found: C,
59.43; H, 4.19, N, 4.12.
5-[(2-Bromobenzyl)oxy]-2,4-Dimethylquinoline (3c)
Eluted from the column with EtOAc–PE (1:9) as a colorless solid
(80%); mp 78–80 °C (CHCl3–hexane).
IR (KBr): 2928, 1615, 1236 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.63 (s, 3 H), 2.80 (s, 3 H), 5.24
(s, 2 H), 6.82 (d, J = 7.5 Hz, 1 H), 6.99 (s, 1 H), 7.19 (t, J = 7.6 Hz,
1 H), 7.31–7.35 (m, 1 H), 7.48–7.53 (m, 2 H), 7.61–7.63 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.6, 24.7, 70.4, 106.0, 119.1,
122.2, 122.9, 123.9, 127.5, 128.6, 129.5, 129.6, 132.8, 135.7, 145.3,
150.0, 156.2, 158.4.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer L 120-000A
spectrometer using samples as neat liquids and solid samples were
recorded as KBr discs. 1H NMR (300 MHz, 400 MHz, 500 MHz)
spectra were recorded on a Bruker-300, Bruker DPX-400 and Bruk-
er DRX-500 spectrometer in CDCl3 (chemical shift in d) with TMS
as internal standard. Silica gel [(60–120, 230–400 mesh), Spectro-
chem, India] was used for chromatographic separation. Silica gel G
[E-Merck (India)] was used for TLC. Petroleum ether (PE) refers to
the fraction boiling between 60–80 °C.
MS: m/z = 341, 343 [M+].
Anal. Calcd for C18H16BrNO: C, 63.17; H, 4.71, N, 4.09. Found: C,
63.38; H, 4.68, N, 4.19.
5-[(2-Bromo-5-methoxybenzyl)oxy]-2,4-dimethylquinoline (3d)
Eluted from the column with EtOAc–PE (1:9) as a colorless solid
(87%); mp 120–122 °C (CHCl3–hexane).
IR (KBr): 2931, 1596, 1238 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.63 (s, 3 H), 2.84 (s, 3 H), 3.76
(s, 3 H), 5.20 (s, 2 H), 6.75 (dd, J = 3.1, 8.7 Hz, 1 H), 6.83 (d, J = 7.7
Hz, 1 H), 7.00 (s, 1 H), 7.10 (d, J = 3.0 Hz, 1 H), 7.48–7.52 (m, 2
H), 7.61 (dd, J = 0.8, 8.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.7, 24.8, 55.3, 70.5, 106.1,
112.8, 114.9, 115.0, 119.1, 122.2, 124.0, 128.7, 133.3, 136.6, 145.3,
149.9, 156.1, 158.5, 159.0.
Compounds 3a–f; General Procedure
A mixture of 8-hydroxyquinoline (1a; 0.20 g, 1.38 mmol), 2-bro-
mobenzyl bromide (2a; 0.410 g, 1.65 mmol) or 2-bromo-5-meth-
oxybenzyl bromide (2b; 0.460 g, 1.65 mmol), anhyd K2CO3 (3 g)
was refluxed in anhyd acetone (75 mL) on a water bath for 6 h. The
reaction mixture was cooled, filtered, and the solvent was removed.
The residual mass was extracted with CH2Cl2 (3 × 30 mL). The
combined CH2Cl2 extracts were washed with H2O (3 × 30 mL) and
dried (Na2SO4). The residual mass after removal of CH2Cl2 was
subjected to column chromatography over silica gel (60–120 mesh)
using PE–EtOAc as eluent to give compounds 3a,b. Similarly other
substrates 3c–f were prepared from 5-hydroxy-2, 4-dimethylquino-
line and 7-hydroxy-2,4-dimethylquinoline.
MS: m/z = 371, 373 [M+].
Anal. Calcd for C19H18BrNO2: C, 61.30; H, 4.87, N, 3.76. Found: C,
61.57; H, 4.95, N, 3.90.
7-[(2-Bromobenzyl)oxy]-2,4-dimethylquinoline (3e)
Eluted from the column with EtOAc–PE (1:9) as a colorless solid
(82%); mp 80–81 °C (CHCl3–hexane).
IR (KBr): 2918, 1618, 1134 cm–1.
8-[(2-Bromobenzyl)oxy]quinoline (3a)
Eluted from the column with EtOAc–PE (3:17) as a colorless solid
(88%); mp 104–106 °C (CHCl3–hexane).
1H NMR (400 MHz, CDCl3): d = 2.62 (s, 3 H), 2.64 (s, 3 H), 5.25
(s, 2 H), 7.01 (s, 1 H), 7.16 (td, J = 1.5, 7.7 Hz, 1 H), 7.24 (d, J = 2.6
Hz, 1 H), 7.30–7.34 (m, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.57 (dd,
J = 1.2, 8.0 Hz, 2 H), 7.85 (d, J = 9.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.4, 24.9, 69.3, 108.4, 118.1,
120.8, 121.6, 122.2, 124.8, 127.3, 128.5, 129.1, 132.5, 135.7, 144.0,
149.1, 158.9, 159.0.
IR (KBr): 2852, 1571, 1107 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.49 (s, 2 H), 6.94 (dd, J = 2.4, 6.5
Hz, 1 H), 7.12–7.62 (m, 7 H), 8.12 (dd, J = 1.8, 8.3 Hz, 1 H), 8.97–
8.98 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 69.8, 109.6, 115.4, 120.7, 121.6,
126.5, 127.5, 128.4, 128.9, 129.4, 132.4, 135.8, 140.2, 149.3, 153.7,
158.68.
MS: m/z = 341, 343 [M+].
MS: m/z = 313, 315 [M+].
Anal. Calcd for C18H16BrNO: C, 63.17; H, 4.71, N, 4.09. Found: C,
63.03; H, 4.73, N, 4.14.
Anal. Calcd for C16H12BrNO: C, 61.17; H, 3.85, N, 4.46. Found: C,
61.36; H, 3.91, N, 4.49.
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K. C. Majumdar et al.
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7-[(2-Bromo-5-methoxybenzyl)oxy]-2,4-dimethylquinoline (3f)
Eluted from the column with EtOAc–PE (1:9) as a colorless solid
(78%); mp 99–100 °C (CHCl3–hexane).
IR (KBr): 2919, 1567, 1111 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.62 (s, 3 H), 2.65 (s, 3 H), 3.77
(s, 3 H), 5.21 (s, 2 H), 6.72 (dd, J = 3.0, 8.7 Hz, 1 H), 7.01 (s, 1 H),
7.15 (d, J = 3.0 Hz, 1 H), 7.27 (d, J = 2.6 Hz, 1 H), 7.44–7.47 (m, 2
H), 7.85 (d, J = 9.1 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 2.64 (s, 3 H), 2.85 (s, 3 H), 5.22
(s, 2 H), 7.01 (s, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.4 Hz,
1 H), 7.39 (t, J = 7.5 Hz, 1 H), 7.68–7.74 (m, 2 H), 7.98 (d, J = 8.8
Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.3, 19.8, 63.4, 113.0, 114.1,
117.2, 118.1, 119.2, 119.3, 119.4, 122.4, 123.7, 125.4, 125.5, 140.5,
144.9, 147.2, 153.8.
MS: m/z = 261 [M+].
13C NMR (100 MHz, CDCl3): d = 18.3, 24.9, 55.3, 69.2, 108.5,
112.1, 114.2, 114.4, 118.0, 120.8, 121.6, 124.7, 133.0, 136.7, 143.9,
149.1, 157.8, 158.9, 159.0.
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C,
82.92; H, 5.87; N, 5.42.
8-Methoxy-2,4-dimethyl-6H-isochromeno[4,3-f]quinoline (4d)
Eluted from the column with EtOAc–PE (1:4) as a colorless solid
(88%); mp 100–102 °C (MeCN–MeOH).
IR (KBr): 2920, 1595, 1184 cm–1.
MS: m/z = 371, 373 [M+].
Anal. Calcd for C19H18BrNO2: C, 61.30; H, 4.87, N, 3.76; found: C,
61.49; H, 4.99, N, 3.85.
Heck Reaction of Compound 3a–f; General Procedure
To a mixture of 3a–f (0.318 mmol), Bu4NBr (0.150 g, 0.47 mmol),
and Cs2CO3 (0.153 g, 0.47 mmol) in anhyd degassed DMF (15 mL)
in a screw-cap-sealed tube was added Pd(OAc)2 (3.56 mg, 5 mol%)
under an inert atmosphere and the sealed tube was placed in a pre-
heated oil bath at 95 °C with stirring for 2–5 h. After completion of
the reaction as monitored by TLC, the reaction mixture was cooled
and diluted with H2O (50 mL). This was extracted with EtOAc
(3 × 25 mL). The combined organic extracts were washed with aq 1
N HCl (25 mL), H2O (3 × 20 mL), brine (30 mL), and dried
(Na2SO4). The solvent was removed by distillation and the crude
product was purified by column chromatography over silica gel
(60–120 mesh) using PE–EtOAc mixture as eluent to give com-
pounds 4a–f (Table 2).
1H NMR (400 MHz, CDCl3): d = 2.63 (s, 3 H), 2.85 (s, 3 H), 3.85
(s, 3 H), 5.18 (s, 2 H), 6.74 (d, J = 2.1 Hz, 1 H), 6.94 (dd, J = 2.3,
8.5 Hz, 1 H), 6.99 (s, 1 H), 7.64 (t, J = 8.9 Hz, 2 H), 7.92 (d, J = 8.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.2, 24.7, 55.3, 68.5, 110.0,
113.8, 118.1, 119.0, 122.9, 123.2, 123.5, 123.8, 124.2, 131.9, 133.3,
145.2, 149.2, 158.2, 159.3.
MS: m/z = 291 [M+].
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.40; H, 5.91; N, 4.86.
2,4-Dimethyl-8H-isochromeno[4,3-h]quinoline (4e)
Eluted from the column with EtOAc–PE (3:17) as a colorless solid
(78%); mp 156 °C (MeCN–MeOH).
IR (KBr): 2919, 1624, 1156 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.68 (s, 3 H), 2.71 (s, 3 H), 5.20
(s, 2 H), 7.03 (s, 1 H), 7.20 (d, J = 7.5 Hz, 1 H), 7.32 (t, J = 7.2 Hz,
1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.61 (s, 1 H), 7.88 (d, J = 7.7 Hz, 1
H), 8.26 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.7, 20.2, 63.5, 109.0, 112.9,
116.5, 117.80, 117.82, 118.0, 119.9, 123.1, 123.5, 124.8, 127.5,
139.1, 144.1, 150.7, 154.4.
6H-Isochromeno[4,3-h]quinoline (4a)
Eluted from the column with EtOAc–PE (1:3) as a colorless solid
(90%); mp 114–116 °C (MeCN–MeOH).
IR (KBr): 2919, 1624, 1556 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.43 (s, 2 H), 7.22 (d, J = 7.4 Hz,
1 H), 7.28–7.43 (m, 3 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.73 (d, J = 7.7
Hz, 1 H), 7.90 (d, J = 8.6 Hz, 1 H) 8.90 (dd, J = 1.4, 8.3 Hz, 1 H),
8.91 (dd, J = 1.5, 4.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 68.9, 120.5, 120.7, 121.3, 121.5,
121.9, 124.6, 128.0, 128.4, 129.0, 129.6, 130.7, 135.7, 139.9, 149.7,
149.8.
HRMS: m/z calcd for C18H16NO: 262.1227 [M + H]; found:
262.1228 [M + H].
HRMS: m/z calcd for C16H12NO: 234.0938 [M + H]; found:
234.0917 [M + H].
10-Methoxy-2,4-dimethyl-8H-isochromeno[4,3-h]quinoline (4f)
Eluted from the column with EtOAc–PE (3:17) as a colorless solid
(84%); mp 110–112 °C (MeCN–MeOH).
8-Methoxy-6H-isochromeno[4,3-h]quinoline (4b)
Eluted from the column with EtOAc–PE (1:3) as a colorless solid
(95%); mp 92–94 °C (MeCN–MeOH).
IR (KBr): 2921, 1463, 1114 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H), 5.40 (s, 2 H), 6.94–
7.06 (m, 3 H), 7.35–7.51 (m, 3 H), 8.27 (d, J = 8.3 Hz, 1 H), 8.51
(d, J = 4.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.0, 69.7, 109.7, 111.5, 113.7,
114.7, 119.9, 121.3, 126.3, 129.1, 132.8, 135.6, 136.7, 140.0, 149.0,
153.5, 158.9.
IR (KBr): 2921, 1606, 1165 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.71 (s, 6 H), 3.86 (s, 3 H), 5.17
(s, 2 H), 6.72 (d, J = 2.5 Hz, 1 H), 6.95 (dd, J = 2.6, 8.6 Hz, 1 H),
7.03 (s, 1 H), 7.67 (s, 1 H), 7.81 (d, J = 8.6 Hz, 1 H), 8.16 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.5, 24.8, 55.2, 68.3, 109.5,
113.4, 114.3, 116.5, 121.2, 122.1, 122.6, 122.7, 124.1, 133.7, 143.8,
148.1, 155.0, 158.5, 159.5.
HRMS: m/z calcd for C19H18NO2: 292.1332 [M + H]; found:
292.1335 [M + H].
HRMS: m/z calcd for C17H14NO2: 264.1016 [M + H]; found:
264.1017 [M + H].
Compounds 6a,b
To a solution of tetrahydroquinoline (5; 133 mg, 1.0 mmol) in an-
hyd degassed THF (10 mL) in a two-necked flask was added NaH
(48.0 mg, 2 mmol) 0–5 °C under N2. After the evolution of H2 had
stopped, 2-bromobenzyl bromide (2a; 250 mg, 1.0 mmol) or 2-io-
dobenzyl bromide (2c; 297 mg, 1.0 mmol) was added and the stir-
ring was continued at r.t for 4 h. The reaction mixture was slowly
poured into a mixture of ice-cold H2O (20 mL) and Et2O (20 mL).
2,4-Dimethyl-6H-isochromeno[4,3-f]quinoline (4c)
Eluted from the column with EtOAc–PE (1:4) as a colorless solid
(86%); mp 112–114 °C (MeCN–MeOH).
IR (KBr): 2925, 1591, 1199 cm–1.
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Palladium-Catalyzed Intramolecular Biaryl Coupling
799
The organic layer was collected and the aqueous layer was extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with brine (20 mL) and dried (Na2SO4). The solvent was removed
by distillation and the crude product was purified by column chro-
matography over silica gel (60–120 mesh) using PE–EtOAc mix-
ture as eluent to give compounds 6a or 6b as colorless oil.
Anal. Calcd for C16H15N: C, 86.84; H, 6.83; N, 6.33. Found: C,
86.90; H, 6.86; N, 6.35.
1-Benzyl-1,2,3,4-tetrahydroquinoline (8)
Prepared from 6b. Eluted from the column with EtOAc–PE (1:49)
as a colorless oil.
IR (KBr): 2928, 1629 cm–1.
1-(2-Bromobenzyl)-1,2,3,4-tetrahydroquinoline (6a)
Eluted from the column with EtOAc–PE (1:49) as a gummy mass
(87%).
IR (KBr): 2931, 1622, 1512 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.99–2.05 (m, 2 H), 2.83 (t,
J = 6.3 Hz, 2 H), 3.38 (t, J = 5.6 Hz, 2 H), 4.30 (s, 2 H), 6.27 (d,
J = 7.9 Hz, 1 H), 6.60 (t, J = 6.9 Hz, 1 H), 6.99–7.30 (m, 5 H), 7.89
(d, J = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.3, 28.0, 49.8, 56.1, 110.8,
115.9, 121.8, 122.0, 127.4, 127.5, 128.2, 128.6, 128.9, 136.8, 139.3,
144.9.
1H NMR (400 MHz, CDCl3): d = 1.97–2.03 (m, 2 H), 2.79 (t,
J = 6.2 Hz, 2 H), 3.34 (t, J = 5.7 Hz, 2 H), 4.47 (s, 2 H), 6.48 (d,
J = 8.4 Hz, 1 H), 6.54 (t, J = 7.1 Hz, 1 H), 6.94 (t, J = 7.0 Hz, 2 H),
7.20–7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 22.2, 28.1, 49.7, 55.1, 110.9,
115.8, 122.1, 126.5, 126.6, 127.0, 128.2, 128.4, 128.5, 128.8, 138.7,
145.4.
MS: m/z = 223 [M+].
Anal. Calcd for C16H17N: C, 86.05; H, 7.67; N, 6.27. Found: C,
86.31; H, 7.69; N, 6.36.
MS: m/z = 301, 303 [M+].
Acknowledgment
Anal. Calcd for C16H16BrN: C, 63.59; H, 5.34; N, 4.63; Found: C,
63.76; H, 5.42; N, 4.59.
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. P.D. and A.T are thankful to the CSIR for their
fellowships.
1-(2-Iodobenzyl)-1,2,3,4-tetrahydroquinoline (6b)
Eluted from the column with EtOAc–PE (1:49) as a gummy mass
(90%).
IR (KBr): 2925, 1602, 1505 cm–1.
References
1H NMR (400 MHz, CDCl3): d = 2.02–2.08 (m, 2 H), 2.82 (t,
J = 6.2 Hz, 2 H), 3.38 (t, J = 5.6 Hz, 2 H), 4.31 (s, 2 H), 6.25 (d,
J = 8.0 Hz, 1 H), 6.56 (t, J = 7.3 Hz, 1 H), 6.93–7.27 (m, 5 H), 7.84
(d, J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.3, 28.0, 50.0, 61.2, 97.8, 110.8,
116.0, 122.0, 127.3, 127.4, 128.3, 128.6, 128.9, 139.3, 140.5, 144.9.
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MS: m/z = 349 [M+].
Anal. Calcd for C16H16IN: C, 55.03; H, 4.62; N, 4.01. Found: C,
55.26; H, 4.76; N, 4.08.
Palladium-Catalyzed Cyclization of 6a,b to 7 and 8
The procedure for the preparation of compounds 7 and 8 from 6a
and 6b (0.33 mmol), respectively, are same as the procedure de-
scribed previously for compounds 3a–f, except that the following
reagents were used: PdCl2 (10 mol%) as catalyst, Ag2CO3 (2.5
equiv) as base, TBAB (2 equiv) as additive, and DMSO as solvent
at 120 °C for 10 h.
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5,6-Dihydro-4H,8H-pyrido[3,2,1-de]phenanthridine (7)
Prepared from 6a. Eluted from the column with EtOAc–PE (1:49)
as a gummy mass (82%).
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IR (KBr): 2928, 1611, 1115 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.78–0.88 (m, 2 H), 2.10–2.16 (5
lines, m, 2 H), 3.00 (t, J = 6.2 Hz, 2 H), 4.30 (t, J = 5.9 Hz, 2 H),
7.18 (t, J = 7.6 Hz, 1 H), 7.28 (d, J = 6.6 Hz, 1 H), 7.55–7.59 (m, 1
H), 7.72–7.76 (m, 1 H), 8.12 (d, J = 7.8. Hz, 1 H), 8.26 (d, J = 8.2
Hz, 1 H), 8.5 (dd, J = 0.8, 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.3, 28.0, 49.9, 55.9, 110.6,
115.9, 121.9, 122.7, 127.1, 127.3, 127.5, 128.1, 128.8, 132.6, 136.8,
144.9.
MS: m/z = 221 [M+].
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K. C. Majumdar et al.
PAPER
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Synthesis 2009, No. 5, 793–800 © Thieme Stuttgart · New York