Iron/palladium-catalyzed intramolecular hydroamination: An expedient synthesis of pyrrole-annulated coumarin and quinolone derivatives

Article abstract of DOI:10.1055/s-0030-1258311

A highly efficient intramolecular hydroamination reaction of heterocycle-centered aminoalkynes using both substituted and free amines catalyzed by PdCl₂/FeCl₃ catalytic system to form the biologically important pyrrolocoumarin and py

Full text of DOI:10.1055/s-0030-1258311

PAPER
4207
Iron/Palladium-Catalyzed Intramolecular Hydroamination: An Expedient
Synthesis of Pyrrole-Annulated Coumarin and Quinolone Derivatives
S
ynthesis of Pyrro
.
le-Annulated
C
Coumarin and
Q
.
uinolone De
M
r
ivatives ajumdar,* Nirupam De, B. Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B., India
Fax +91(33)925828282; E-mail: kcm_ku@yahoo.co.in
Received 30 August 2010; revised 23 September 2010
cules as these analogues may be interesting and useful to
the medicinal chemists or pharmacologists for further
study.
Abstract: A highly efficient intramolecular hydroamination reac-
tion of heterocycle-centered aminoalkynes using both substituted
and free amines catalyzed by PdCl2/FeCl3 catalytic system to form
the biologically important pyrrolocoumarin and pyrroloquinolone
derivatives is reported. The use of both aliphatic and aromatic sub-
stituted alkynes with different heterocyclic skleton in this strategy
demonstrated the diversity of this method.
OH
HO
Key words: hydroamination, pyrrolocoumarin, pyrroloquinolone,
FeCl3, aminoalkynes
N
HO
HO
OH
OH
O
O
The synthesis of nitrogen containing heterocycles such as
substituted indole derivatives have attracted considerable
attention since this basic motif is present in various natu-
ral products and biologically active substances.1 After ex-
tensive research over the hundred years of the Fisher
indole synthesis, a variety of other well-documented
methods for their synthesis are now available. Among the
various routes employed, the metal-catalyzed intramolec-
ular hydroamination reaction of aminoalkynes2 are the
mostly popular one as it is highly atom economic and can
tolerate a wide range of functionality.
ningalin B
Me
Me
O
O
OH
HO
N
O
Me
HO
O
O
On the other hand coumarins and quinolones are the im-
portant subunits present in a number of natural products
showing broad spectrum biological activity such as anti-
bacterial, antifungal, antiviral, antimicrobial, and sedative
properties.3,4 In particular, the pyrrolocoumarin deriva-
lamellarin D
Figure 1 Natural products containing pyrrolocoumarin nucleus
In general, the intramolecular cyclization reactions in-
tives exhibit photobiological activity5a and antiprolifera- volving a heteroatom-centered nucleophile and the car-
tive effect,5b DNA-binding properties,6 photophysical bon–carbon unsaturated bonds are the most important in
properties,7 anti-inflamatory, and antioxidant activities.8 synthetic heterocyclic chemistry. Among the several met-
These also act as ideal dyes for various modern fluores- als used for such cyclizations, palladium is the most wide-
cent imaging technologies such as FRET.9 Pyrrolocou- ly used and accepted one.1b,15 Recently, a number of
marin derivatives are the important precursors for the methods using gold,16a indium,2c mercury,16b copper,16c
construction of the scaffold of two biologically active zinc,16d iridium,2e rhodium,16e or platinum16f salts proved
marine alkaloids, namely, ningalin B and lamellarin D10 efficient for intramolecular alkyne hydroamination reac-
(Figure 1).Both the alkaloids possess potential bioactivity tions. Among them, there are only few methods that de-
such as cytotoxicity, HIV-1 integrase inhibition, immuno- scribe the cyclization of unprotected amines.16a,17
modulatory activity, multidrug resistance (MDR) reversal Moreover, these cases also necessitate the use of expen-
activity, etc.11 The pyrroloquinolone derivatives are also
sive catalytic system. Only Prim et al. have reported18
important as these can act as phosphodiesterase 5 inhibi- such type of cyclization using FeCl3 in association with
tors,12a show analgesic activity,12b and are important pre- PdCl2. Therefore, in order to explore further scope of this
cursors for the antibiotic martinelline.13 Our continuous methodology we have undertaken a study to synthesize
efforts in synthesizing important heterocycles in a simpli- both protected and unprotected pyrrole-annulated cou-
fied manner14 motivated us to prepare such type of mole- marins and quinolones using FeCl3/PdCl2 catalytic sys-
tem.
SYNTHESIS 2010, No. 24, pp 4207–4212
Advanced online publication: 21.10.2010
DOI: 10.1055/s-0030-1258311; Art ID: Z21810SS
x
x.
x
x
.
2
0
1
0
The requisite precursors 3a–i were prepared in good
yields by the Sonogashira coupling of the corresponding
© Georg Thieme Verlag Stuttgart · New York

4208
K. C. Majumdar et al.
PAPER
R2
Br
NHR1
(i)
NHR1
NHR1
(ii)
O
X
R2
O
X
O
X
2
1
3a–i
X = O, NMe, NEt
1 = H, Me, Et
X = O, NMe, NEt
R1 = H, Me, Et
R
Scheme 1 Reagents and conditions: (i) NBS (1.2 equiv), MeCN, r.t., 1 h; (ii) Pd(PPh3)2Cl2 (0.05 equiv), CuI (0.05 equiv) DMF, Et3N,
80 °C, 1.5–3 h.
bromo compounds 2, which in turn were prepared by NBS fective. To investigate the role of FeCl3 from the mecha-
bromination of the corresponding 6-aminocoumarin and nistic viewpoint other oxidants such as benzoquinone and
6-aminoquinolone moiety using MeCN as solvent at room IBX were used in stoichiometric ratio in combination with
temperature (Scheme 1).
PdCl2. In these cases (entries 11, 12), the cyclized product
was obtained, but in much lower yields. From this result it
is evident that an oxidant is necessary for this hydroami-
nation reaction to occur and that may facilitate the in situ
reoxidation of Pd(0) to Pd(II) in the catalytic cycle.
We selected compound 3a as a model substrate to study
the cyclization reaction under a variety of reaction condi-
tions like varying the catalyst composition, the solvent
system etc. The results of the investigation are summa-
rized in Table 1. The results show that both PdCl2 and All the other precursors 3b–i were then subjected to the
FeCl3 are required for this hydroamination reaction irre- optimized reaction conditions to give the corresponding
spective of the solvent used. First, 10 mol% PdCl2 with 10 cyclized products 4b–i in 87–98% yields. The results are
mol% FeCl3 catalyst composition (entry 1) in 1,2-di- summarized in Table 2.
choloroethane (DCE) as solvent was used. At refluxing
condition (85 °C) the cyclized product 4a was obtained in
It is important to note that an electron-withdrawing sub-
stituent is usually required for the cyclization of acetylen-
88% yield and the reaction was completed just in 3 hours
ic amines to increase the nucleophilicity of the amine
(monitored by TLC).
nitrogen. Moreover, there are few methods that describe
Similar result was also obtained when the catalyst compo- the cyclizaion of unprotected acetylenic amines using ex-
sition was varied by reducing PdCl2 (1 mol%) and FeCl3 pensive catalysts or high catalyst loading. Here, we have
(5 mol%) and the reaction time to 2.5 hours (entry 6). achieved hydroamination of the unprotected, unactivated
Among various solvents used, DCE was found to be the amines or the acetylenic amines with an electron-donating
suitable one. We also used other Pd(II) sources like group in excellent yields to form the pyrrolocoumarin and
Pd(PPh3)2Cl2, Pd(OAc)2, but these were found to be inef- pyrroloquinolone derivatives.
Table 1 Optimization of the Reaction Conditionsa
Entry
1
Catalyst (mol%)
PdCl2 (10)
PdCl2 (5)
Oxidant (mol%)
FeCl3 (10)
FeCl3 (5)
–
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
EtOH
MeCN
DCE
DCE
DCE
DCE
Temp (°C)
Time (h)
Yield (%)b
88
85
85
85
85
85
85
85
85
85
85
85
85
3
2
2.5
9
90
3
PdCl2 (10)
–
trace
nr
4
FeCl3 (10)
FeCl3 (2)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
BQ (1 equiv)
IBX (1 equiv)
9
5
PdCl2 (1)
8
76
6
PdCl2 (1)
2.5
6
93
7
PdCl2 (1)
25
8
PdCl2 (1)
6
17
9
Pd(PPh3)2Cl2 (5)
Pd(OAc)2 (5)
PdCl2 (5)
8
trace
crm
44
10
11
12
3
4
PdCl2 (5)
6
33
a Optimization was done using 3a as the model substrate.
b Isolated yield, nr = no reaction, crm = nonisolatable complicated reaction mixture; BQ = benzoquinone.
Synthesis 2010, No. 24, 4207–4212 © Thieme Stuttgart · New York

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Synthesis of Pyrrole-Annulated Coumarin and Quinolone Derivatives
4209
Table 2 Summarized Results of the Hydroamination Reaction under Optimized Conditions
Entry
1
Substrate
Product
Time (h)
2.5
Yield (%)
93
O
n-Bu
Ph
n-Bu
Ph
3a
4a
O
O
O
NH
O
O
O
O
NH2
O
2
3
4
3b
3c
3d
O
4b
4c
4d
2.5
2
87
98
96
NH
NH2
O
O
Ph
Ph
O
O
O
O
NMe
NHMe
Ph
Ph
2
NEt
NHEt
OMe
OMe
O
O
5
3e
4e
2
96
O
O
O
NEt
NEt
O
NHEt
NHEt
n-Bu
n-Bu
6
7
3f
4f
3
4
93
89
MeN
MeN
O
Ph
Ph
Ph
3g
MeN
4g
O
NH
NH
MeN
NH2
O
Ph
Ph
8
9
3h
3i
4h
4i
2
91
96
EtN
O
O
EtN
NH2
O
Ph
2.5
MeN
NEt
MeN
NHEt
Ph
Ph
NH
10
5
6
2
95
O
NH2
O
O
O
The scope of the reaction was further examined by chang- synthesis of two naturally occurring potential marine al-
ing the substituents in the terminal alkynes. It was ob- kaloid analogues, namely ningalin B and lamellarin D.
served that both aromatic and aliphatic substituents are
The mechanistic aspect of this hydroamination is outlined
equally effective. The generalization of this method was
in Scheme 3. It is assumed that initially the Pd(II) species
then verified using another coumarin derivative 5. In this
coordinates with the alkyne thus activating the C≡C
case the product is pyrrolocoumarin derivative 6 obtained
bond.19 The cyclization occurs by the nucleophilic attack
of the amine nitrogen atom20 to the resulting electron de-
in 95% yield (Scheme 2), which is the precursor for the
Synthesis 2010, No. 24, 4207–4212 © Thieme Stuttgart · New York

4210
K. C. Majumdar et al.
PAPER
Ph
DPX-300, Bruker DPX-400, Bruker DPX-500 spectrometers in
CDCl3/DMSO (chemical shift in d) with TMS as internal standard.
CHN was recorded on 2400 series II CHN analyzer PerkinElmer.
Silica gel [(60–120 mesh) 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.
Compounds 3b–d, 3g, 4b–d, 4g were reported earlier,14c com-
pounds 5 and 6 were also reported in the literature,10 and their spec-
troscopic data are in accordance with the reported values.
Ph
NH
NH2
(i)
O
O
O
6
O
5
Scheme 2 Reagents and conditions: (i) PdCl2 (1 mol%), FeCl3 (5
mol%), DCE, 85 °C, 2 h, 95%.
6-Amino-5-hex-1-ynyl-2H-chromen-2-one (3a); Typical Proce-
dure
ficient triple bond forming the organopalladium15c species
II. It may be assumed that a 5-endo-dig cyclization path-
way is maintained during cyclization as 4-exo-dig path-
way is energetically unfavorable.21 The reductive
elimination afforded the cyclized products 4a–i and 6.
The active Pd(II) species is regenerated by the oxidation
of Pd(0) by FeCl3.18 The reaction was performed in open
air flask. It may be concluded that the reoxidation of
Fe(II) to Fe(III) may occur by aerial oxidation, which may
account for the use of catalytic amount of FeCl3.
A mixture of 6-amino-5-bromocoumarin (2; R1 = H, X = O; 300 mg,
1.25 mmol) and hex-1-yne (0.18 mL, 1.50 mmol) in DMF–Et3N
(3:2, 5 mL) was degassed with N2. [Pd(PPh3)2Cl2] (42.2 mg, 0.06
mmol) and CuI (11.4 mg, 0.06 mmol) were then added to the well-
stirred solution. The mixture was heated with stirring at 100 °C for
3 h. The reaction mixture was allowed to cool and CHCl3 (20 mL)
was added. After filtration of the mixture over Celite, the filtrate
was washed with H2O (10 mL) followed by brine (10 mL) and dried
(Na2SO4). The solvent was removed to give a crude mass, which
was purified by column chromatography over silica gel using
EtOAc–PE (15:85) to afford compound 3a as a yellow solid; yield:
215 mg (72%); mp 126–128 °C.
In conclusion, we have demonstrated the development of
intramolecular hydroamination strategy in synthesizing
the biologically active pyrrolocoumarin and pyrroloqui-
nolone derivatives. The methodology is straightforward
and mild using less expensive catalytic system in low cat-
alyst-loading resulting in high yield of the products in the
cyclization of both substituted and unprotected amines.
IR (KBr): 1705, 3353, 3466 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.98 (t, J = 7.2 Hz, 3 H, CH3),
1.53 (m, 2 H, CH2), 1.50 (t, J = 7.2 Hz, 2 H, CH2), 2.57 (t, J = 7.2
Hz, 2 H, CH2), 4.23 (s, 2 H, NH2), 6.42 (d, J = 9.6 Hz, 1 H, C3-H of
coumarin), 6.87 (d, J = 8.8 Hz, 1 H, ArH), 7.10 (d, J = 8.8 Hz, 1 H,
ArH), 8.04 (d, J = 9.6 Hz, 1 H, C4-H of coumarin).
13C NMR (100 MHz, CDCl3): d= 13.6, 19.5, 22.2, 30.9, 73.4,102.4,
105.1, 116.7, 116.9, 118.3, 119.7, 142.1, 144.8, 147.0, 161.1.
All the chemicals were procured from either Sigma Aldrich Chem-
icals Pvt. Ltd. or Spectrochem, India. Melting points were deter-
mined in open capillaries and are uncorrected. IR spectra were
recorded on a PerkinElmer L 120-000A spectrometer (cm–1) on KBr
MS (EI): m/z = 241 [M]+.
Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C,
74.49; H, 6.43; N, 5.97.
1
disks. H NMR and 13C NMR spectra were recorded on Bruker
Cl–
[O] air
FeCl2
R2
FeCl3
[Pdo]
R1HN
PdCl2
R2
substrate
NR1
product
Cl–
R2
PdCl2
R1HN
R2
PdCl(H)
NR1
I
Cl–
II
Scheme 3 Probabale mechanistic pathway for the hydroamination reaction
Synthesis 2010, No. 24, 4207–4212 © Thieme Stuttgart · New York

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Synthesis of Pyrrole-Annulated Coumarin and Quinolone Derivatives
4211
3e
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.6 Hz, 3 H, CH3),
1.43 (m, 2 H, CH2), 1.75 (m, 2 H, CH2), 2.83 (t, J = 7.6 Hz, 2 H,
CH2), 6.44 (d, J = 9.6 Hz, 1 H, C3-H of coumarin), 6.49 (s, 1 H, CH)
7.10 (d, J = 8.8 Hz, 1 H, ArH), 7.44 (d, J = 8.8 Hz, 1 H, ArH), 8.09
(d, J = 9.6 Hz, 1 H, C4-H of coumarin), 8.25 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 13.9, 22.4, 28.1, 31.3, 97.6, 110.0,
110.2, 114.4, 114.5, 125.3, 131.8, 141.2, 142.9, 149.9, 162.2.
Yield: 70%; yellow solid; mp 107–109 °C.
IR (KBr): 1713, 2187, 3407 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H, CH3),
3.29 (q, J = 7.2 Hz, 2 H, CH2), 3.86 (s, 3 H, OCH3), 4.58 (s, 1 H,
NH), 6.44 (d, J = 9.6 Hz, 1 H, C3-H of coumarin), 6.82 (d, J = 9.2
Hz, 1 H, ArH), 6.93 (d, J = 8.8 Hz, 2 H, ArH), 7.19 (d, J = 9.2 Hz,
1 H, ArH), 7.50 (d, J = 8.8 Hz, 2 H, ArH), 8.12 (d, J = 9.6 Hz, 1 H,
C4-H of coumarin).
HRMS (TOF, ES+): m/z [M + Na]+ calcd for C15H15NO2 + Na:
264.1000; found: 264.1000.
Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N, 4.39. Found: C,
75.41; H, 5.20; N, 4.49.
4e
Yield: 96%; off-white solid; mp 120–122 °C.
3f
IR (KBr): 1709 cm–1.
Yield 68%; yellow solid; mp 106–108 °C.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H, CH3),
3.89 (s, 3 H, OCH3), 4.22 (q, J = 7.2 Hz, 2 H, CH2), 6.45 (d, J = 9.6
Hz, 1 H, C3-H of coumarin), 6.69 (s, 1 H), 7.03 (d, J = 8.8 Hz, 2 H,
ArH), 7.20 (d, J = 8.8 Hz, 1 H, ArH), 7.43 (d, J = 8.8 Hz, 2 H,
ArH), 7.52 (d, J = 8.8 Hz, 1 H, ArH), 8.13 (d, J = 9.6 Hz, 1 H, C4-
H of coumarin).
13C NMR (100 MHz, CDCl3): d = 15.6, 39.1, 55.4, 99.3, 110.5,
113.8, 114.2, 114.5, 114.7, 124.6, 130.6, 131.8, 133.0, 140.9, 143.3,
150.0, 159.9, 162.0.
IR (KBr): 1646, 3401 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 3 H, CH3),
1.32 (t, J = 7.2 Hz, 3 H, CH3), 1.52 (m, 2 H, CH2), 1.68 (m, 2 H,
CH2), 2.60 (t, J = 7.6 Hz, 2 H, CH2), 3.26 (q, J = 7.2 Hz, 2 H,
NCH2), 3.68 (s, 3 H, NCH3), 4.48 (s, 1 H, NH), 6.71 (d, J = 9.6 Hz,
1 H, C3-H of quinolone), 6.90 (d, J = 9.2 Hz, 1 H, ArH), 7.21 (d,
J = 9.2 Hz, 1 H, ArH), 8.07 (d, J = 9.6 Hz, 1 H, C4-H of quinolone).
Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C,
76.71; H, 8.01; N, 9.67.
MS (EI): m/z = 319 [M]+.
Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N, 4.39. Found: C,
75.33; H, 5.17; N, 4.45.
3h
Yield: 65%; yellow solid; mp 121–123 °C.
IR (KBr): 1719, 3337, 3438 cm–1.
4f
Yield: 93%; yellow solid; mp 99–101 °C.
IR (KBr): 1643 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3.32 (q, J = 7.2 Hz, 2 H, NCH2), 4.60 (s, 2 H, NH), 6.76 (d, J = 9.6
Hz, 1 H, C3-H of quinolone), 6.96 (d, J = 9.2 Hz, 1 H, ArH), 7.28
(m, 1 H, ArH), 7.41 (m, 3 H, ArH), 7.59 (m, 2 H, ArH), 8.16 (d,
J = 9.6 Hz, 1 H, C4-H of quinolone).
1H NMR (400 MHz, CDCl3): d = 1.0 (t, J = 7.2 Hz, 3 H, CH3), 1.38
(t, J = 7.2 Hz, 3 H, CH3), 1.50 (m, 2 H, CH2), 1.74–1.82 (m, 2 H,
CH2), 2.78 (t, J = 7.6 Hz, 2 H, CH2), 3.81 (s, 3 H, NCH3), 4.19 (q,
J = 7.2 Hz, 2 H, NCH2), 6.56 (s, 1 H, CH), 6.76 (d, J = 9.6 Hz, 1 H,
C3-H of quinolone), 7.17 (d, J = 9.2 Hz, 1 H, ArH), 7.49 (d, J = 9.2
Hz, 1 H, ArH), 8.10 (d, J = 9.6 Hz, 1 H, C4-H of quinolone).
Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
78.97; H, 5.43; N, 9.81.
3i
13C NMR (100 MHz, CDCl3): d = 13.9, 15.6, 22.6, 26.5, 30.1, 30.8,
37.9, 96.7, 107.5, 112.5, 119.8, 125.3, 131.2, 134.9, 135.4, 142.5,
162.5.
Yield: 64%; yellow solid; mp 192–193 °C.
IR (KBr): 1682, 3381 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H, CH3),
3.01 (s, 3 H, NCH3), 3.69 (q, J = 7.1 Hz, 2 H, NCH2), 4.69 (s, 1 H,
NH), 6.76 (d, J = 9.5 Hz, 1 H, C3-H of quinolone), 6.91 (d, J = 8.9
Hz, 1 H, ArH), 7.31 (d, J = 8.6 Hz, 1 H, ArH), 7.38–7.40 (m, 3 H,
ArH), 7.58–7.59 (m, 2 H, ArH), 8.14 (d, J = 9.5 Hz, 1 H, C4-H of
quinolone).
MS (EI): m/z = 282 [M]+.
Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C,
76.67; H, 8.02; N, 9.71.
4h
Yield: 91%; yellow solid; mp 261–263 °C.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.13; H, 5.98; N, 9.49.
IR (KBr): 1639, 3222 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H, CH3),
4.48 (q, J = 7.2 Hz, 2 H, NCH2), 6.81 (d, J = 9.6 Hz, 1 H, C3-H of
quinolone), 7.13 (s, 1 H, CH), 7.28 (d, J = 8.8 Hz, 1 H, ArH), 7.37
(t, J = 7.2 Hz, 1 H, ArH), 7.48 (t, J = 8.0 Hz, 2 H, ArH), 7.62 (d,
J = 8.8 Hz, 1 H, ArH), 7.72 (d, J = 7.6 Hz, 2 H, ArH), 8.17 (d,
J = 9.6 Hz, 1 H, C4-H of quinolone), 8.76 (s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 12.9, 36.8, 97.1, 109.0, 112.0,
115.3, 119.3, 124.9, 125.8, 127.6, 128.9, 131.8, 131.9, 133.7, 135.6,
130.8, 160.5.
Compounds 4a–i and 6; 2-Butylpyrano[3,2-e]indol-7(3H)-one
(4a); Typical Procedure
Compound 3a (200 mg, 0.828 mmol) was dissolved in 1,2-dichlo-
roethane (6 mL) in a 10 mL round-bottomed flask fitted with a re-
flux condenser. PdCl2 (1.5 mg, 0.0084 mmol) and FeCl3 (11 mg,
0.0406 mmol) were added to the flask, and then the reaction mixture
was heated with stirring at 85 °C for 3 h. The mixture was cooled to
r.t., and CHCl3 (10 mL) and H2O (10 mL) were added. The organic
layer was collected, washed with H2O (10 mL) and brine (10 mL),
and dried (Na2SO4). The solvent was evaporated under reduced
pressure to furnish a crude mass, which was purified by column
chromatography over silica gel using EtOAc–PE (20:80) as eluent
to give compound 4a as yellow solid; yield: 186 mg (93%); mp
157–159 °C.
MS (EI): m/z = 288 [M]+.
Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
78.95; H, 5.71; N, 9.79.
4i
Yield: 96%; yellow solid; mp 243–245 °C.
IR (KBr): 1694, 3234 cm–1.
Synthesis 2010, No. 24, 4207–4212 © Thieme Stuttgart · New York

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K. C. Majumdar et al.
PAPER
(7) Quanten, E.; Adriaens, P.; Schryver, F. C.; Roelandts, R.;
IR (KBr): 1681 cm–1.
Degreef, H. Photochem. Photobiol. 1986, 43, 485.
(8) Kontogiorgis, C.; Litinas, K. E.; Makri, A.; Nicolaides, D.
N.; Vronteli, A.; Litina, D. J. H.; Pontiki, E.; Siohou, A.
J. Enzyme Inhib. Med. Chem. 2008, 23, 43.
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 6.9 Hz, 3 H, CH3),
3.79 (s, 3 H, NCH3), 3.83 (q, J = 6.9 Hz, 2 H, NCH2), 6.81 (d,
J = 9.5 Hz, 1 H, C3-H of quinolone), 6.84 (s, 1 H, =CH), 7.27 (d,
J = 9.0 Hz, 1 H, ArH), 7.45 (d, J = 7.2 Hz, 1 H, ArH), 7.48–7.58 (m,
5 H, ArH), 8.15 (d, J = 9.5 Hz, 1 H, C4-H of quinolone).
13C NMR (100 MHz, CDCl3): d = 15.7, 30.1, 39.1, 99.9, 108.8,
112.9, 113.5, 120.2, 125.4, 128.4, 128.7, 129.3, 132.2, 132.5, 135.3,
142.6, 162.6, 162.5.
(9) Chen, L.; Hu, T.-S.; Yao, Z.-J. Eur. J. Org. Chem. 2008, 36,
6175.
(10) Chen, L.; Xu, M. H. Adv. Synth. Catal. 2009, 351, 2005.
(11) (a) Ridley, C. P.; Reddy, M. V. R.; Rocha, G.; Bushman, F.
D.; Faulknera, D. J. Bioorg. Med. Chem. 2002, 10, 3285.
(b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. H. Chem. Rev.
2008, 108, 264. (c) Yamaguchi, T.; Fukuda, T.; Ishibashi,
F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755. (d) Tardy,
C.; Facompre, M.; Laine, W.; Baldeyrou, B.; Garcia-
Gravalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jimenez,
J. A.; Manzanares, I.; Cuevasb, C.; Bailly, C. Bioorg. Med.
Chem. 2004, 12, 1697.
MS (EI): m/z = 302 [M]+.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.59; H, 6.19; N, 9.09.
Acknowledgment
We thank the CSIR (New Delhi) for financial assistance. N.D. is
grateful to the UGC (New Delhi) for a fellowship. We also thank the
DST (New Delhi) for providing FT-IR, NMR spectrometers, and
CHN analyzer under its FIST program.
(12) (a) Jiang, W.; Alford, V. C.; Qiu, Y.; Bhattacharjee, S.; John,
T. M.; Johnson, D. H.; Kraft, P. J.; Lundeen, S. G.; Sui, Z.
Bioorg. Med. Chem. 2004, 12, 1505. (b) Yamashkin, S. A.;
Yudin, L. G.; Kost, A. N. Chem. Heterocycl. Compd. (Engl.
Transl.) 1983, 19, 401.
(13) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287.
(14) (a) Majumdar, K. C.; Mondal, S.; De, N. Synlett 2008, 2851.
(b) Majumdar, K. C.; Mondal, S.; De, N. Synthesis 2009,
2385. (c) Majumdar, K. C.; Chattopadhyay, B.; Samanta, S.
Synthesis 2009, 311. (d) Majumdar, K. C.; Chakravorty, S.;
De, N. Tetrahedron Lett. 2008, 49, 3419. (e) Majumdar, K.
C.; Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008,
49, 7213.
(15) (a) Tang, Z.-Y.; Hu, O.-S. Adv. Synth. Catal. 2006, 348,
846. (b) Kaspar, L. T.; Ackermann, L. Tetrahedron 2005,
61, 11311. (c) Yasuhara, A.; Takeda, Y.; Naoyuki, S.;
Sakamoto, T. Chem. Pharm. Bull. 2002, 50, 235.
(16) (a) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9,
627. (b) Kurisaki, T.; Naniwa, T.; Yamamoto, H.; Imagawa,
H.; Nishizawa, M. Tetrahedron Lett. 2007, 48, 1871.
(c) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.;
Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277. (d)Yin, Y.;
Chai, Z.; Ma, W.-Y.; Zhao, G. Synthesis 2008, 4036.
(e) Trost, B. M.; McClory, A. Angew. Chem. Int. Ed. 2007,
46, 2074. (f) Cariou, K.; Ronan, B.; Mignani, S.;
Fensterbank, L.; Malacria, M. Angew. Chem. Int. Ed. 2007,
46, 1881.
References
(1) (a) Glasby, J. S. Encyclopedia of Alkaloids; Plenum Press:
New York, 1975. (b) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873. (c) Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon: Oxford, 2000, Chap. 3.
(d) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.
(2) (a) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004,
610. (b) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007,
9, 627. (c) Sakai, N.; Annaka, K.; Konakahara, T.
Tetrahedron Lett. 2006, 47, 631. (d) Namba, K.; Nakagawa,
Y.; Yamamoto, H.; Imagawa, H.; Nishizawa, M. Synlett
2008, 1719. (e) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree,
R. H. Org. Lett. 2005, 7, 5437.
(3) (a) Hagen, S. E.; Domagala, J. M.; Heifetz, C. L.; Sanchez,
J. P.; Solomon, M. J. Med. Chem. 1990, 33, 849. (b) Raski,
S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723.
(c) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.;
Furukawa, H.; Takahasi, D.; Koshimizu, K.; Ohigash, H.
Biorg. Med. Chem. Lett. 2000, 10, 59. (d) Laborde, E.;
Kiely, J. S.; Culbertson, T. P.; Lesheski, L. E. J. Med. Chem.
1993, 36, 1964.
(4) (a) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71.
(b) Piorung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642.
(c) Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.;
Mackerracher, D.; Malone, J. F. J. Chem. Soc., Perkin Trans.
1 2000, 3397.
(5) (a) Rodighiero, P.; Chilin, A.; Pastorini, G.; Guiotto, A.
J. Heterocycl. Chem. 1987, 24, 1041. (b) Guiotto, A.;
Chilin, A.; Manzini, P.; Dall’Acqua, F.; Bordin, F.;
Rodighiero, P. Farmaco 1995, 50, 479.
(17) Koradin, C.; Dohale, W.; Rodriguez, A. L.; Schmidt, B.;
Knochel, P. Tetrahedron 2003, 59, 1571.
(18) Terrasson, V.; Michaux, J.; Gaucher, A.; Wehbe, J.; Marque,
S.; Prim, D.; Campagne, J.-M. Eur. J. Org. Chem. 2007, 35,
5332.
(19) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.;
Li, J.-H. Org. Lett. 2006, 8, 3017.
(20) Tang, S.; Xie, Y.-X.; Li, J.-H.; Wang, N.-X. Synthesis 2007,
1841.
(21) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(6) Gia, O.; Mobilio, S.; Chilin, A.; Rodghiero, P.; Palumbo, M.
J. Photochem. Photobiol., B. 1988, 2, 435.
Synthesis 2010, No. 24, 4207–4212 © Thieme Stuttgart · New York