New efficient synthesis of pyrido[2,3-c]coumarin derivatives by palladium-catalyzed heck cyclization

Article abstract of DOI:10.1055/s-2007-990846

Tetrahydropyrido[2,3-c]coumarin derivatives were synthesized by intramolecular radical cyclization and Heck coupling. This method allowed the synthesis of the backbone of the Santiagonamine alkaloid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990846

PAPER
3647
New Efficient Synthesis of Pyrido[2,3-c]coumarin Derivatives by Palladium-
Catalyzed Heck Cyclization
S
ynthesisof Pyrid
r
o[2,3-
c
]c
i
oumar
s
h
ive
s
na C. Majumdar,* Buddhadeb Chattopadhyay, Abu Taher
Department of Chemistry, University of Kalyani, Kalyani 741 235, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 14 August 2007; revised 28 August 2007
tributyltin hydride. Despite the widespread applicability
of organotin reagents, the problems of toxicity and ex-
pense are frequently highlighted as reasons to avoid these
reagents.8 Sometimes the removal of even traces of an or-
ganotin residue from the product is a critical problem.9
Due to these difficulties, efforts have been directed to find
tin-free methods for the synthesis of desired heterocyclic
compounds. In our present investigation, we have focused
on comparative studies of radical cyclization and the pal-
ladium-catalyzed intramolecular Heck reaction.
Abstract: Tetrahydropyrido[2,3-c]coumarin derivatives were syn-
thesized by intramolecular radical cyclization and Heck coupling.
This method allowed the synthesis of the backbone of the Santi-
agonamine alkaloid.
Key words: organometallic reagents, radical reactions, Heck cou-
pling, intramolecular cyclization, 3-aminocoumarin
As a privileged fragment, the 3-aminocoumarin core is a
ubiquitous subunit in many natural products with remark-
able biological activities. Members of this family have
wide practical applications in medicinal chemistry as an-
tibiotic and antiviral agents.1,2 Novobiocine, for example,
is a 3-aminocoumarin-derived antibiotic, an ATP-com-
petitive inhibitor of the gyrase B subunit blocking the neg-
ative super-coiling of relaxed DNA.1d,2 Lamellarin is
utilized as a selective inhibitor of HIV-1 integrase.1c On
the other hand, the pyrido[2,3-c]coumarin skeleton (A)
constitutes the backbone of santiagonamine (B)
(Figure 1).3
The required precursors 3a–f were synthesized in moder-
ate to good yields by reflux of 3-aminocoumarins 1a–c
with either 2-bromobenzyl bromide (2a) or 2-bromo-5-
methoxybenzyl bromide (2b) in anhydrous methyl ethyl
ketone in the presence of anhydrous potassium carbonate
and a small amount of sodium iodide10 (Scheme 1). 3-
Aminocoumarins 1a–c were prepared from commercially
available substituted a-hydroxybenzaldehydes by a stan-
dard procedure.11 Compounds 3a–f were characterized by
elemental analysis and spectroscopy.
R2
Me2N
N
O
N
O
Br
O
O
Br
R1
NH2
O
Br
OMe
R1
NH
O
A
B
+
Figure 1 The naturally occurring biologically active alkaloid santi-
agonamine (B)
R2
O
O
1a–c
1 = H, Me, OMe
2a,b
R2 = H, OMe
3a–f
R
This alkaloid (B; Figure 1) has been isolated from Berb-
eris darwinii (Berberidaceae) and has shown interesting
wound-healing properties.4 To explore the range of bio-
logical activities of such a compound, we were interested
in synthesizing some known natural analogues. Surpris-
ingly, only a few syntheses of pyrido[2,3-c]coumarin has
been described in the literature.5 Therefore, in continua-
tion of our longstanding interest in coumarin chemistry,6
we became interested in developing an efficient method
for synthesizing pyrido[2,3-c]coumarin derivatives.
Scheme 1 Preparation of the starting materials 3a–f. Reagents and
conditions: K2CO3, NaI, MEK, reflux.
Subsequently, substrate 3a was subjected to radical cy-
clization in the presence of tri-n-butyltin hydride and 2,2¢-
azobis(isobutyronitrile) as radical initiator in anhydrous
degassed benzene under a nitrogen atmosphere for ten
hours (Scheme 2). TLC monitoring of the reaction did not
show any appreciable change. However, when the reac-
tion time was increased to 24 hours, the substrate was
slowly converted into product 4a in very low yield. To
find the optimum conditions, we attempted using a high-
boiling solvent, such as toluene. The reaction in refluxing
toluene resulted in the desired radical cyclization occur-
ring, affording new coumarin derivative 4a in 27% yield
(Scheme 2). Other substrates 3b–f were also subjected to
Recently, radical cyclization7 has become a useful tool for
the construction of C–C bonds in synthetic organic chem-
istry. The most useful mediator of radical cyclization is
SYNTHESIS 2007, No. 23, pp 3647–3652
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990846; Art ID: Z20107SS
© Georg Thieme Verlag Stuttgart · New York

3648
K. C. Majumdar et al.
PAPER
R2
dimethylformamide for ten hours gave the cyclized prod-
uct 4a in 88% yield (Table 1, entry 1). The optimum con-
ditions for the palladium-catalyzed cyclization was found
through a series of experiments in which sequential
changes were made to the catalyst, the base, and the sol-
vent used for the reaction (Table 1).
R2
Br
R1
NH
O
R1
NH
Recently, Kuroda and Suzuki12 found that the best cy-
clization results were obtained when palladium(II) acetate
and sodium hydrogen carbonate were used with tetrabutyl-
ammonium chloride as additive. Under the conditions we
used (KOAc as base, TBAB as additive), 3a gave cyclized
product 4a in 86% yield (Table 1, entry 1). When the cat-
alyst was changed to dichlorobis(phosphine)palladium(II)
or palladium(II) chloride, the yield reduced dramatically
(Table 1, entries 2, 3, 5, 6, and 8). There was also poor re-
covery of the starting material in these cases. When the
base was changed to triethylamine, the cyclization prod-
uct 4a formed in good yield (Table 1, entry 7), with com-
plete consumption of the starting material. The other
substrates 3b–f were also treated under these optimized
conditions to afford the cyclized products, and the results
are summarized in Table 2.
O
O
O
3a–f
4a–f
Scheme 2 General strategy for the radical cyclization of compounds
3a–f. Reagents and conditions: n-Bu3SnH, AIBN, toluene, reflux.
Table 1 Palladium-Catalyzed Cyclization of 3a to 4aa
Br
NH
NH
O
O
O
O
3a
4a
Entry Solvent Catalyst
Base
Temp
(°C)
Yield
(%)
Tetrahydropyrido[2,3-c]coumarin 4c has been oxidized
with 10 mol% palladium on carbon in dichloromethane to
afford the corresponding pyrido[2,3-c]coumarin 5 in 97%
yield (Scheme 3). The other tetrahydropyrido derivatives
are also expected to be aromatized similarly to afford the
corresponding pyrido derivatives.
1
2
3
4
5
6
7
8
DMF
DMF
DMF
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Et3N
140
140
140
80
88
7
<5
<5
<5
0
MeCN Pd(OAc)2
MeCN Pd(PPh3)2Cl2
MeCN PdCl2
80
80
DMF
DMF
Pd(OAc)2
PdCl2
140
140
76
14
MeO
NH
O
MeO
N
O
Et3N
O
O
a Reagents and conditions: cat. (10 mol%), base (2.75 equiv), TBAB
(1.2 equiv), under N2, heat, 10 h.
4c
5
97%
Scheme 3 Synthesis of pyrido[2,3-c]coumarin 5. Reagents and con-
ditions: 10% Pd/C, CH2Cl2, r.t., 4 h.
this reaction, giving products 4b–f in 20–25% yield
(Scheme 2). The structures of compounds 4a–f were elu-
cidated from their elemental analyses and spectroscopic
data.
The mechanistic rationalization for the formation of prod-
ucts 4a–f by intramolecular Heck reaction is outlined in
Scheme 4. First, the ‘s-palladium complex’ 6 may be
formed by oxidative addition of compound 3. Although it
is highly unlikely that the C-4 position of the coumarin
moiety would behave as a nucleophilic center, the reac-
tion proceeds at the C-4 position of the coumarin moiety,
and, finally, after b-hydride elimination, the cyclized
products 4a–f form.
Since radical cyclization gave products 4a–f in very poor
yields, we turned our attention to the intramolecular Heck
reaction. The intramolecular Heck reaction of 3a in the
presence of 10 mol% palladium(II) acetate as catalyst, po-
tassium acetate (0.83 mmol) as base, and tetrabutylammo-
nium bromide (0.36 mmol) as additive in N,N-
Pd
Br Pd
N
..
Et3N
N
N
Pd(0)
H
4
3
O
O
O
O
O
O
Pd(0)
6
7
8
Scheme 4
Synthesis 2007, No. 23, 3647–3652 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2,3-c]coumarin Derivatives
3649
Table 2 Comparison of Radical and Heck Reactions of Compounds 3a–f
Yield (%)
Entry
Starting material
Product
Radical
27
Heck
88
Br
1
NH
O
NH
O
O
O
4a
3a
OMe
OMe
2
3
4
5
21
20
22
25
81
77
86
82
Br
O
NH
O
NH
O
O
4b
3b
Br
MeO
NH
O
MeO
NH
O
O
O
4c
3c
OMe
OMe
Br
O
MeO
NH
O
MeO
NH
O
O
4d
3d
Br
Me
NH
Me
NH
O
O
O
O
4e
3e
OMe
OMe
6
21
80
Br
O
Me
NH
O
Me
NH
O
O
4f
3f
In conclusion, we have developed a new, efficient proto- yielding catalytic system for the synthesis of the fused
col for the synthesis of tetrahydropyrido[2,3-c]coumarin heterocycles with a dihydroquinoline moiety. The mecha-
derivatives, which are part of the structure of the Santiago nistic pathway of this reaction by palladium catalysis is
amine alkaloid. We have also shown that the palladi- quite unusual and uncertain. The intramolecular Heck
um(II) acetate/potassium acetate/tetrabutylammonium coupling was found to be an excellent and straightforward
bromide combination is a mild, fast, and efficient high- approach compared to intramolecular radical cyclization.
Synthesis 2007, No. 23, 3647–3652 © Thieme Stuttgart · New York

3650
K. C. Majumdar et al.
PAPER
Melting points were determined in open capillaries and are uncor-
rected. IR spectra of samples prepared as KBr discs were recorded
on a Perkin-Elmer 120-000A apparatus, and NMR spectra of solu-
tions in CDCl3 with TMS as internal standard were determined at
the Bose Institute, Indian Institute of Chemical Biology and the
Chembiotek Research International Pvt. Ltd., Calcutta. Silica gel
(60–120 mesh) was used for chromatographic separation. Silica gel-
G [E-Mark (India)] was used for TLC. Where PE is specified, it re-
fers to petroleum ether (bp 60–80 °C).
H, ArH), 6.78 (dd, J = 8.89, 2.9 Hz, 1 H, ArH), 6.88 (d, J = 3.0 Hz,
1 H, ArH), 7.18 (d, J = 9.0 Hz, 1 H, ArH), 7.47 (d, J = 8.8 Hz, 1 H,
ArH).
MS: m/z = 389 [M+], 391 [M + 2].
Anal. Calcd for C18H16BrNO4: C, 55.40; H, 4.13; N, 3.59. Found: C,
55.56; H, 3.98; N, 3.47.
Compound 3e
Yield: 66%; solid; mp 131–133 °C.
IR (KBr): 1710, 3394 cm–1.
3-(Benzylamino)coumarins 3a–h; General Procedure
A mixture of one of 3-aminocoumarins 1a–c (3.11 mmol), one of 2-
bromobenzyl bromides 2a,b (3.73 mmol), and anhyd K2CO3 (2.0 g)
in anhyd MEK (75 mL) in the presence of NaI (~10 mg, cat.) was
refluxed for 30–35 h. After cooling, the mixture was filtered and the
solvent was removed. The residual mass was extracted with CH2Cl2
(50 mL), washed with H2O (3 × 30 mL) followed by brine–H2O
(1:2; 3 × 30 mL), and dried (Na2SO4). Removal of CH2Cl2 gave a
crude product, which was purified by chromatography (silica gel,
EtOAc–hexane, 1:9).
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3 H, CH3), 4.44 (d, J = 6.0
Hz, 2 H, ArH), 5.38 (t, J = 6.0 Hz, 1 H, NH), 6.20 (s, 1 H, C4-H of
coumarin), 6.67 (dd, J = 5.9, 2.9 Hz, 1 H, ArH), 7.11–7.18 (m, 4 H,
ArH), 7.34 (d, J = 8.8 Hz, 1 H, ArH), 7.48 (d, J = 8.8 Hz, 1 H, ArH).
MS: m/z = 343 [M+], 345 [M + 2].
Anal. Calcd for C17H14BrNO2: C, 59.32; H, 4.10; N, 4.07. Found: C,
59.13; H, 4.11; N, 3.99.
Compound 3f
Yield: 68%; solid; mp 143–145 °C.
IR (KBr): 1713, 3391 cm–1.
Compound 3a
Yield: 71%; solid; mp 138–140 °C.
IR (KBr): 1710, 3395 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.26 (s, 3 H, CH3), 3.78 (s, 3 H,
OCH3), 4.43 (d, J = 6.0 Hz, 2 H, N-CH2), 5.41 (t, J = 6.0 Hz, 1 H,
NH), 6.23 (s, 1 H, C4-H of coumarin), 6.65 (dd, J = 7.0, 3.0 Hz, 2
H, ArH), 6.80 (dd, J = 8.7, 2.9 Hz, 1 H, ArH), 6.90 (d, J = 3.0 Hz, 1
H, ArH), 7.13 (d, J = 8.9 Hz, 1 H, ArH), 7.46 (d, J = 8.7 Hz, 1 H,
ArH).
1H NMR (400 MHz, CDCl3): d = 4.46 (d, J = 6.0 Hz, 2 H, N-CH2),
5.22 (t, J = 6.0 Hz, 1 H, NH), 6.26 (s, 1 H, C4-H of coumarin), 7.15–
7.23 (m, 3 H, ArH), 7.27–7.40 (m, 4 H, ArH), 7.60 (d, J = 8.0 Hz, 1
H, ArH).
MS: m/z = 329 [M+], 331 [M + 2].
MS: m/z = 373 [M+], 375 [M + 2].
Anal. Calcd for C16H12BrNO2: C, 58.20; H, 3.66; N, 4.24. Found: C,
58. 29; H, 3.71; N, 4.33.
Anal. Calcd for C18H16BrNO3: C, 57.77; H, 4.31; N, 3.74. Found: C,
57.89; H, 4.49; N, 3.84.
Compound 3b
Yield: 69%; solid; mp 156–158 °C.
IR (KBr): 1704, 3392 cm–1.
Pyrido[2,3-c]coumarin 4a by Radical Cyclization of 3-(Benzyl-
amino)coumarin 3a; Typical Procedure
n-Bu3SnH (0.89 mL, 0.33 mmol) was added slowly in one portion
to a magnetically stirred suspension of 3a (100 mg, 0.30 mmol) and
AIBN (24.9 mg, 0.15 mmol) in anhyd degassed toluene (8 mL) un-
der a N2 atmosphere. The mixture was heated at 110 °C for 10–15
h. Then the solvent was removed under reduced pressure. The liquid
mass thus obtained was dissolved in CH2Cl2 (5 mL) and stirred with
10% aq KF (8 mL) for 2–3 h. The white precipitate was separated
by filtration and the aqueous phase was extracted with CH2Cl2
(3 × 15 mL). The combined extract was washed with brine (3 × 30
mL) and dried (Na2SO4). CH2Cl2 was removed by distillation and
the residual mass was subjected to column chromatography (silica
gel, EtOAc–hexane, 1:9); this gave product 4a. Other substrates
3b–f were subjected to the same reaction conditions to afford the
corresponding products 4b–f in 20–27% yield.
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 4.41 (d,
J = 6.0 Hz, 2 H, N-CH2), 5.41 (t, J = 6.0 Hz, 1 H, NH), 6.22 (s, 1 H,
C4-H of coumarin), 6.70–6.74 (m, 3 H, ArH), 6.78 (d, J = 8.9 Hz, 1
H, ArH), 6.87 (d, J = 3.0 Hz, 1 H, ArH), 7.18 (d, J = 8.9 Hz, 1 H,
ArH), 7.47 (d, J = 8.8 Hz, 1 H, ArH).
MS: m/z = 359 [M+], 361 [M + 2].
Anal. Calcd for C17H14BrNO3: C, 56.69; H, 3.92; N, 3.89. Found: C,
56.83; H, 4.04; N, 3.82.
Compound 3c
Yield: 66%; solid; mp 129–131 °C.
IR (KBr): 1711, 3392 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 4.45 (d,
J = 6.0 Hz, 2 H, N-CH2), 5.39 (t, J = 6.0 Hz, 1 H, NH), 6.20 (s, 1 H,
C4-H of coumarin), 6.70 (d, J = 3.0 Hz, 1 H, ArH), 6.78 (dd, J = 9.0,
2.9 Hz, 1 H, ArH), 7.16–7.19 (m, 4 H, ArH), 7.55 (d, J = 9.0 Hz, 1
H, ArH).
Pyrido[2,3-c]coumarin 4a by Heck Reaction of 3-(Benzylami-
no)coumarins 3a; Typical Procedure
A mixture of 3a (100 mg, 0.33 mmol), TBAB (116 mg, 0.36 mmol),
and anhyd KOAc (80 mg, 0.83 mmol) was dissolved in anhyd DMF
(10 mL) under a N2 atmosphere. Pd(OAc)2 (6.7 mg, 10 mol%) was
added, and the mixture was stirred on an oil bath at 100 °C for ap-
proximately 10 h. The mixture was cooled, and H2O (3 mL) was
added. The mixture was extracted with EtOAc (3 × 10 mL) and
washed with H2O (2 × 10 mL), followed by brine (15 mL). The or-
ganic layer was dried (Na2SO4); evaporation of EtOAc furnished a
crude mass, which was purified by column chromatography (silica
gel, EtOAc–hexane, 1:9); this afforded 4a. Other substrates 3b–f
were subjected to the same reaction conditions to afford the corre-
sponding products 4b–f.
MS: m/z = 359 [M+], 361 [M + 2].
Anal. Calcd for C17H14BrNO3: C, 56.69; H, 3.92; N, 3.89. Found: C,
56.61; H, 4.00; N, 3.92.
Compound 3d
Yield: 70%; solid; mp 166–168 °C.
IR (KBr): 1704, 3376 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.73 (s, 3 H, OCH3), 3.78 (s, 3 H,
OCH3), 4.40 (d, J = 6.0 Hz, 2 H, N-CH2), 5.41 (t, J = 6.0 Hz, 1 H,
NH), 6.19 (s, 1 H, C4-H of coumarin), 6.71 (dd, J = 6.9, 3.0 Hz, 2
Synthesis 2007, No. 23, 3647–3652 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2,3-c]coumarin Derivatives
Compound 4f
3651
Compound 4a
Yield: 88%; solid; mp 162–164 °C.
Yield: 80%; solid; mp 163–165 °C.
IR (KBr): 1691, 3385 cm–1.
IR (KBr): 1696, 3392 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.37 (s, 2 H, N-CH2), 5.02 (s, 1 H,
NH), 7.23–7.36 (m, 3 H, ArH), 7.29–7.39 (m, 3 H, ArH), 7.90 (q,
J = 4.8 Hz, 1 H, ArH), 8.06 (dd, J = 7.6, 1.7 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 40.8, 112.4, 113.7, 114.4, 119.2,
119.4, 120.5, 121.5, 121.7, 122.5, 124.3, 124.4, 125.9, 128.5, 143.9,
153.9.
1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.76 (s, 3 H,
OCH3), 4.41 (s, 2 H, N-CH2), 5.03 (s, 1 H, NH), 6.73 (d, J = 2.7 Hz,
1 H, ArH), 6.81 (dd, J = 8.6, 2.7 Hz, 1 H, ArH), 6.88 (dd, J = 7.5,
2.4 Hz, 1 H, ArH), 7.21 (d, J = 8.6 Hz, 1 H, ArH), 7.29 (d, J = 8.5
Hz, 1 H, ArH), 7.56 (d, J = 2.7 Hz, 1 H, ArH).
MS: m/z = 293 [M+].
HRMS: m/z calcd for C16H11NO2: 249.0790; found: 249.0796.
Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C,
73.88; H, 5.11; N, 4.68.
Anal. Calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62. Found: C,
77. 21; H, 4.41; N, 5.73.
Pyrido[2,3-c]coumarin 5; Typical Procedure
To a magnetically well-stirred soln of 4c (100 mg) in CH2Cl2, 10%
Pd/C (3.0 mg) was added. The mixture was stirred for 4 h. It was
then filtered and concentrated under reduced pressure. The crude
mass obtained was chromatographed (silica gel, EtOAc–hexane,
15:85); this gave oxidized product 5.
Compound 4b
Yield: 81%; solid; mp 172–174 °C.
IR (KBr): 1696, 3392 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3 H, OCH3), 4.33 (s, 2 H,
N-CH2), 4.93 (s, 1 H, NH), 6.78 (d, J = 2.6 Hz, 1 H, ArH), 6.91 (dd,
J = 8.6, 2.7 Hz, 1 H, ArH), 7.29–7.38 (m, 3 H, ArH), 7.84 (d, J = 8.7
Hz, 1 H, ArH), 8.02 (dd, J = 7.6, 1.6 Hz, 1 H, ArH).
Yield: 97%; solid; mp 210–212 °C.
IR (KBr): 1727 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.93 (s, 3 H, OCH3), 7.17 (dd,
J = 6.3 Hz, 1 H, ArH), 7.46 (d, J = 9.0 Hz, 1 H, ArH), 7.91 (t,
J = 7.5 Hz, 1 H, ArH), 7.99 (dd, J = 10.6, 3.0 Hz, 2 H, ArH), 8.21
(d, J = 7.9 Hz, 1 H, ArH), 8.92 (d, J = 8.5 Hz, 1 H, ArH), 9.41 (s, 1
H, N = CH).
MS: m/z = 279 [M+].
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C,
73.01; H, 4.53; N, 4.89.
Compound 4c
Yield: 77%; solid; mp 157–159 °C.
MS: m/z = 277 [M+].
Anal. Calcd for C17H11NO3: C, 73.64; H, 4.00; N, 5.05. Found: C,
73.61; H, 4.08; N, 4.99.
IR (KBr): 1699, 3389 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 4.37 (s, 2 H,
N-CH2), 5.02 (s, 1 H, NH), 7.20 (d, J = 8.4 Hz, 1 H, ArH), 7.49 (d,
J = 8.8 Hz, 1 H, ArH), 8.00 (d, J = 8.0 Hz, 1 H, ArH), 8.09 (m, 1 H,
ArH), 8.32 (m, 1 H, ArH), 8.99 (d, J = 8.4 Hz, 1 H, ArH), 9.6 (s, 1
H, ArH).
Acknowledgment
We thank the CSIR (New Delhi) for financial assistance, and two of
us (B.C. and A.T.) are grateful to the CSIR (New Delhi) for fel-
lowships.
MS: m/z = 279 [M+].
Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C,
73.22; H, 4.66; N, 5.13.
References
Compound 4d
Yield: 86%; solid; mp 183–185 °C.
IR (KBr): 1698, 3388 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 4.36 (s, 2 H, N-CH2), 5.29 (s, 1 H, NH), 6.70 (d, J = 2.8 Hz,
1 H, ArH), 6.75 (dd, J = 9.0, 2.8 Hz, 1 H, ArH), 6.78 (dd, J = 9.0,
2.4 Hz, 1 H), 6.83 (dd, J = 8.3, 2.3 Hz, 1 H, ArH), 6.93 (d, J = 7.5
Hz, 1 H), 7.17 (d, J = 9.0 Hz, 1 H, ArH).
(1) (a) Santana, L.; Uriarte, E.; Gonzalez-Diaz, H.; Zagotto, G.;
Soto-Otero, R.; Mendez-Alvarez, E. J. Med. Chem. 2006,
49, 1149. (b) Rivkin, A.; Adams, B. Tetrahedron Lett. 2006,
47, 2395. (c) Yamaguchi, T.; Fukuda, T.; Ishibashi, F.;
Iwao, M. Tetrahedron Lett. 2006, 47, 3755; and references
cited therein. (d) Burlison, J. A.; Neckers, L.; Smith, A. B.;
Maxwell, A.; Blagg, B. S. J. J. Am. Chem. Soc. 2006, 128,
15529.
(2) (a) Gellert, M.; O’Dea, M. H.; Itoh, T.; Tomizawa, Z. I.
Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474. (b) Levine,
C.; Hiasa, H.; Marians, K. J. Biochim. Biophys. Acta 1998,
1400, 29.
(3) Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo,
V. Tetrahedron Lett. 1984, 25, 3163.
(4) Lewis, W. H.; Stonard, R. J.; Porras-Reyes, B.; Mustoe, T.
A.; Thomas, A. US Patent 5156847, 1992; Chem. Abstr.
1992, 117, 245630t.
(5) (a) Khan, M. A.; Gemal, A. L. J. Heterocycl. Chem. 1977,
14, 1009. (b) Tabakovic, K.; Tabakovic, I.; Trkovnik, M.;
Juric, A.; Trinajstic, N. J. Heterocycl. Chem. 1980, 17, 801.
(c) Sagi, M.; Wada, K.; Konno, S.; Yamaka, H. Heterocycles
1990, 30, 1009.
(6) (a) Majumdar, K. C.; Muhuri, S.; Rahaman, H.; Islam, R.;
Roy, B. Chem. Lett. 2006, 35, 1430. (b) Majumdar, K. C.;
Rahaman, H.; Roy, B. Lett. Org. Chem. 2006, 3, 526.
(c) Majumdar, K. C.; Chattopadhyay, B. Synth. Commun.
MS: m/z = 309 [M+].
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C,
70.03; H, 4.88; N, 4.39.
Compound 4e
Yield: 82%; solid; mp 149–151 °C.
IR (KBr): 1701, 3391 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.27 (s, 3 H, CH3), 4.37 (s, 2 H,
N-CH2), 4.96 (s, 1 H, NH), 7.23–7.34 (m, 3 H, ArH), 7.48–7.52 (m,
2 H, ArH), 7.85 (s, 1 H, ArH), 7.90–7.92 (m, 1 H, ArH).
MS: m/z = 263 [M+].
Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C,
77.41; H, 5.09; N, 5.51.
Synthesis 2007, No. 23, 3647–3652 © Thieme Stuttgart · New York

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K. C. Majumdar et al.
PAPER
(8) For a detailed report on the toxicity of tin reagents, see:
2006, 36, 3125. (d) Majumdar, K. C.; Mukhopadhyay, P. P.;
Basu, P. K. Synth. Commun. 2005, 35, 1291. (e) Majumdar,
K. C.; Chattopadhyay, S. K. Tetrahedron Lett. 2004, 45,
6871. (f) Majumdar, K. C.; Bhattacharyya, T. Tetrahedron
Lett. 2001, 42, 4231.
Occupational Exposure to Organotin Compounds, US
Department of Health Education and Welfare: Washington
D.C., Nov. 1976.
(9) Lee, S.; Robinson, G. Process Development: Fine
Chemicals from Gram to Kilograms; Oxford University
Press: New York, 1995.
(10) (a) Gazith, M.; Noys, R. M. J. Am. Chem. Soc. 1955, 77,
6091. (b) Gardner, I. J.; Noyes, R. M. J. Am. Chem. Soc.
1961, 83, 2409.
(7) (a) Majumder, K. C.; Alam, S. Org. Lett. 2006, 8, 4059.
(b) Curran, D. P. In Comprehensive Organic Synthesis, Vol.
4; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
715–779. (c) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals
in Organic Synthesis; Wiley: Chichester, 1995.
(d) Motherwell, W. B.; Crich, D. Free Radical Chain
Reaction in Organic Synthesis; Academic Press: London,
1992. (e) Radicals in Organic Synthesis; Renaud, P.; Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001. (f) Giese, B.;
Kopping, B.; Goble, T.; Dickhaut, J.; Thoma, G.; Kulicke,
K. J.; Trach, F. Org. React. 1996, 48, 301. (g) Jasperse, C.
P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237.
(11) (a) Dean, F. M.; Robertson, A.; Whalley, W. B. J. Chem.
Soc. 1950, 895. (b) Trivedi, K. N.; Sethna, S. J. Org. Chem.
1960, 25, 1817.
(12) Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915.
Synthesis 2007, No. 23, 3647–3652 © Thieme Stuttgart · New York