Regioselective synthesis of heterocyclic scaffold by aryl radical cyclization

Article abstract of DOI:10.1002/jhet.5570450414

(Chemical Equation Presented) Regioselective synthesis of a number of coumarin-annulated pentacyclic heterocycles have been achieved by tri-n-butyltin hydride-mediated aryl radical cyclization. The products are formed as a mixture of cis- and trans- forms which were successfully separated by careful silica gel flash chromatography.

Full text of DOI:10.1002/jhet.5570450414

Jul-Aug 2008
1039
Regioselective Synthesis of Heterocyclic Scaffold
by Aryl Radical Cyclization
K. C. Majumdar* and N. Kundu
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
E-mail: kcm_ku@yahoo.co.in
Received Date May 23, 2007
R1
R1
H
H
R1
Br
O
O
O
O
O
O
Me
N
Me
N
Me
N
R
R
R
H
O
H
O
+
O
5a-e
4a-e
3a-e
Regioselective synthesis of a number of coumarin-annulated pentacyclic heterocycles have
been achieved by tri-n-butyltin hydride-mediated aryl radical cyclization. The products are
formed as a mixture of cis- and trans- forms which were successfully separated by careful silica
gel flash chromatography.
J. Heterocyclic Chem., 45, 1039 (2008).
radical cyclization [9], we directed our attention to cyclize
4-arylaminomethylpyrano[3,2-c][1]benzopyran-5(2H)-
ones 3 under radical initiated conditions.
INTRODUCTION
Organotin-mediated intramolecular free radical
cyclization reactions have gained dramatic prominence in
the synthesis of carbo- and heterocyclic ring structures
[1-6]. The mild reaction conditions with these reagents
and normally high levels of chemo-, regio- and often
stereocontrol coupled with functional group tolerance
allow radical reactions to serve as a powerful method for
carbon-carbon bond formations. Contrary to predictions
based on thermodynamic criteria, cyclization of 5-hexenyl
systems, generally gives cyclopentyl methyl radical via a
prominent 5-exo mode of closure [4,5] and not the more
stable cyclohexyl radical via 6-endo cyclization, a feature
that has been rationalized [7] in terms of stereoelectronic
control of the reaction. Nevertheless, for stabilized
radicals the regiochemistry of ring closure of 5-hexenyl
radical is reversed [8]. In continuation of our studies,
directed towards the synthesis of heterocycles using
We initiated our investigation by examining the
cyclization of 3a-e. These were readily prepared in 85-
90% yields by the reaction of 4-chloromethylpyrano-
[3,2-c][1]benzopyran-5(2H)-ones 1 with various o-bromo-
anilines 2a-e in refluxing acetone in the presence of
anhydrous potassium carbonate and catalytic amount of
sodium iodide. The amines 3a-e were treated with
nBu3SnH-AIBN to induce radical cyclization. Compound
3a was heated in degassed toluene at 80°C under nitrogen
n
with Bu3SnH and catalytic amount of AIBN to give a
mixture of trans-fused 4a and cis-fused 5a cyclized
products via 6-endo cyclization (Scheme 1). Compound 1
was prepared by following the literature procedure [10] i.e.
by alkylation of 4-hydroxy coumarin with 1,4-dichloro-
butyne followed by Claisen rearrangement.
Br
R1
O
O
O
NHR
Me
N
R
Me
Cl
Br
R1
(i)
+
2, 3, 4, 5
R
R1
O
O
H
a
b
c
d
e
H
Me
Et
Me
Et
Me
Me
Me
H
O
R1
2a-e
3a-e
R1
H
1
(ii)
H
O
O
O
O
Me
N
Me
N
Isolated product ratio:
4a:5a = 45:30
4b:5b = 50:33
4c:5c = 45:35
4d:5d = 40:35
4e:5e = 42:37
R
R
H
O
+
H
O
4a-e
5a-e
Scheme 1. Reagents and Condition: (i) Acetone, K2CO3, NaI, reflux, 4 h.
(ii) Bu3SnH, toluene, 80oC, 1 h.

1040
K. C. Majumdar and N. Kundu
Vol 45
RESULTS AND DISCUSSION
(HOMCOR/COSY) spectrum of the compound 4a
showed that -OCH2 protons at ꢀ 5.26 and ꢀ 4.25 correlate
with each other and -NCH2 protons at ꢀ 4.52 and ꢀ 3.27
correlate with each other. The 13C chemical shift of the
compound 4a was assigned by DEPT experiment.
Distortionless Enhancement by Polarization Transfer
(DEPT) showed 13 protonated carbons; two –CH3, nine
>CH- and two >CH2. Carbon resonances were established
by direct correlation with proton resonances by
Heteronuclear correlation (HETCOR) experiment (normal
one bond C-H coupling). Methyl proton (ArCH3 and
NCH3) resonance at ꢀ 2.43 and ꢀ 3.03 were related to
carbon resonance at ꢀ 20.95 and ꢀ 38.98 respectively.
Methylene proton (OCH2) resonances at ꢀ 4.25 and ꢀ 5.26
were related to carbon resonance at ꢀ 69.01 and
methylene proton (NCH2) resonances at ꢀ 3.27 and ꢀ 4.52
were related to carbon resonance at ꢀ 54.06. Methine
proton resonance (CHrjCH2N and CHrjCH2O) at ꢀ 2.90
and ꢀ 3.15 were related to carbon resonance at ꢀ 32.99
and ꢀ 36.63 respectively. The mass spectrum of the
compound showed molecular ion peak at m/z 333 (M+).
For the cis-isomer 5a (Fig II), in the 1H NMR
spectroscopy, one proton doublet of a doublet centered at
ꢀ 4.54 (J = 11.5, 4.5 Hz) and a one proton triplet centered
at ꢀ 4.15 (J = 11.5 Hz) were assigned to equatorial and
axial protons of -OCH2 respectively. Another one proton
doublet of a doublet centered at ꢀ 3.74 (J = 11.2, 4.0 Hz)
and a one proton triplet centered at ꢀ 3.08 (J = 11.2 Hz)
were assigned to equatorial and axial protons of -NCH2
respectively. The ring juncture (rj) protons appear as one
proton ddd each at ꢀ 3.31 (J = 11.5, 5.3, 4.5 Hz) and ꢀ
3.42 (J = 11.5, 5.3, 4.0 Hz) due to CHrjCH2O and
CHrjCH2N respectively.
Determination of relative stereochemistry. The
streochemical assignments of the trans- and cis-fused
cyclized products are based on 1H NMR, 13C NMR,
DEPT, COSY, HETCOR and decoupling experiments.
Construction of a Dreiding model revealed a structure for
the trans- and cis- isomer as shown by Fig. I and Fig. II
respectively.
Hrj
Ha
He
O
N
He
Me
Ha
Hrj
Figure I
Figure II
Figure I and Figure II represent the part structure of the trans-fused and
cis-fused cyclized product respectively depicted by Dreiding model. Ha,
He and Hrj denote the axial, equatorial and ring juncture hydrogen
respectively.
For the trans-isomer 4a (Fig. I), in the 1H NMR
spectroscopy, one proton doublet of a doublet centered at
ꢀ 5.26 (dd, J = 10.8, 3.7 Hz) and a one proton triplet
centered at ꢀ 4.25 (J = 10.8 Hz) were assigned to
equatorial and axial protons of -OCH2 respectively.
Another one proton doublet of a doublet centered at ꢀ
4.52 (J = 11.1, 5.2 Hz) and a one proton triplet centered at
ꢀ 3.27 (J = 11.1 Hz) were assigned to equatorial and axial
protons of -NCH2 respectively. The ring juncture (rj)
protons appear as one proton ddd each at ꢀ 2.90 (J = 11.2,
11.1, 5.2 Hz) and ꢀ 3.15 (J = 11.2, 10.8, 3.7 Hz) due to
CHrjCH2N and CHrjCH2O respectively.
That the cis-isomer was also formed was confirmed on
the basis of decoupling experiment. With irradiation at ꢀ
4.54 (-OCHe), the multiplicity of OCHa resonance at ꢀ
4.15 collapsed from a triplet to a doublet (J = 11.5 Hz)
and the ring juncture proton resonance of CHrjCH2O at ꢀ
3.31 collapsed from ddd to a doublet of doublet (J = 11.5,
5.3 Hz). The remaining resonances remain unchanged.
With irradiation at ꢀ 4.15 (-OCHa), the multiplicity of
OCHe resonance at ꢀ 4.54 simplified from doublet of
doublet to a doublet (J = 4.5 Hz) and the ring juncture
proton resonance of CHrjCH2O at ꢀ 3.31 simplified from
ddd to a doublet of doublet (J = 5.3, 4.5 Hz). The
remaining resonances remain unchanged. The low
coupling constant value (J = 5.3 Hz) due to the coupling
of the two ring juncture protons clearly indicated that a
cis-isomer was also formed via 6-endo-aryl radical
cyclization.
That the trans-isomer was formed was confirmed on the
basis of decoupling experiment. With irradiation at ꢀ 5.26
(-OCHe), the multiplicity of OCHa resonance at ꢀ 4.25
was simplified from a triplet to a doublet (J = 10.9 Hz)
and the ring juncture proton resonance of CHrjCH2O at ꢀ
3.15 was simplified from ddd to a triplet (J = 11.3 Hz).
The remaining resonances remain unchanged. With
irradiation at ꢀ 4.25 (-OCHa), the multiplicity of OCHe
resonance at ꢀ 5.26 was transformed from a doublet of
doublet to a doublet (J = 3.7 Hz) and the ring juncture
proton resonance of CHrjCH2O at ꢀ 3.15 was transformed
from ddd to a doublet of doublet (J = 11.2, 3.7 Hz). The
remaining resonances remain unchanged. The high
coupling constant value (J = 11.2 Hz) due to the coupling
of the two ring juncture protons clearly indicated that a
trans-isomer was formed via 6-endo-aryl radical
cyclization.
The Homonuclear correlation or HOMCOR (COSY)
spectrum of the compound 5a showed that -OCH2 protons
at ꢀ 4.15 and ꢀ 4.54 correlate with each other and -NCH2
protons at ꢀ 3.08 and ꢀ 3.74 correlate with each other. The
The structure of the trans-isomer was further confirmed
by the following experiments. Homonuclear correlation

Jul-Aug 2008
Regioselective Synthesis of Heterocyclic Scaffold byAryl Radical Cyclization
1041
13C chemical shift of the compound 5a was assigned by
DEPT experiment. DEPT showed 13 protonated carbons;
two –CH3, nine >CH- and two >CH2. Carbon resonances
were established by direct correlation with proton
resonance by Heteronuclear correlation (HETCOR)
experiment (normal one bond C-H coupling). Methyl
proton (ArCH3 and NCH3) resonance at ꢀ 2.42 and ꢀ 2.97
were related to carbon resonance at ꢀ 20.95 and ꢀ 39.01
respectively. Methylene proton (OCH2) resonances at ꢀ
4.15 and ꢀ 4.54 were related to carbon resonance at ꢀ
69.39 and methylene proton (NCH2) resonances at ꢀ
3.08 and ꢀ 3.74 were related to carbon resonance at ꢀ
51.05. Methine proton resonance (CHrjCH2N and
CHrjCH2O) at ꢀ 3.42 and ꢀ 3.31 were related to carbon
resonance at ꢀ 28.38 and ꢀ 33.83 respectively. The
mass spectrum of the compound showed molecular ion
peak at m/z 333 (M+). All these experiments confirmed
the stereochemistry of the ring juncture to be cis. To
test the generality of the reaction, compounds 3b-e
were similarly treated to afford a mixture of trans-
fused 4b-e and cis-fused 5b-e cyclized products
(Scheme 1).
5-ones was carried out. But in certain cases, reduced
diastereoselectivity was observed and the diastereomeric
mixture could not be separated [13]. In a recent
publication [14] we have considered the reaction of
different substituted o-bromo phenols with the same
starting material 4-chloromethylpyrano[3,2-c][1]benzo-
pyran-5(2H)-one. However, it has been reported [14]
previously, that all efforts to separate the mixture of
compounds formed after radical cyclization reaction
failed miserably. In the present work, we were successful
to separate the diastereomeric mixture, obtained after
radical cyclization, by flash column chromatography.
It has already been established [15] that high levels of
diastereoselectivity (>50:1) could be obtained when the
concentration of the reactant is reduced from 0.1 to 0.01
M. These observations have been attributed to the
reversibility of the cyclization and decreased
availability of the nBu3SnH. However, cyclization of 3a-
e even in very dilute condition always yielded a
diastereomeric mixture having similar yields as
obtained in using normal concentration. In conclusion,
we have successfully extended the Bu3SnH mediated
R1
R1
Br
R1
.
O
O
.
O
O
O
Me
N
N
Me
Me
5-exo
N
R
R
R
O
H
O
O
O
3a-e
7a-e
6a-e
R1
Neophyl
rearrangement
R1
R1
6-endo
.
O
O
O
O
O
Me
N
.
Me
N
R
-
Me
N
H
.
R
H
O
R
.
H
+
O
O
O
9a-e
4a-e, 5a-e
8a-e
Scheme 2
The formation of six-membered heterocyclic ring 4a-e
and 5a-e from the substrates 3a-e may be explained by the
initial formation of the aryl radical 6a-e followed by a
6-endo ring closure to give a tertiary radical 9a-e which
may then accept a hydrogen radical to afford the final
products 4a-e and 5a-e. In an alternative route, the aryl
radical 6a-e may undergo a 5-exo ring closure to generate
a spiroheterocyclic radical [11] 7a-e which may be
converted to the tertiary radical 9a-e via radical 8a-e by a
neophyl rearrangement [12] (Scheme 2).
radical cyclizations. All the starting materials gave
regioselectively a mixture of both cis-fused and trans-
fused reduced six-membered heterocyclic ring by
nBu3SnH mediated cyclization.
The methodology
described here is mild, regioselective but not stero-
selective and is attractive because of its simplicity. The
scope of the proposed method is that we could obtain in
considerable yields both the cis-fused and trans-fused
cyclized products in a single reaction step which could
be successfully separated. However, the limitation of
this methodology is that we could in no way obtain a
single isomer even by varying the concentration of
Bu3SnH in the radical cyclization step.
In an earlier report [13], good to excellent diastereo-
selectivity was observed when radical cyclization of 4-(2ꢀ-
bromophenoxymethyl)-7-methylthiopyrano-[3,2-c]pyran-

1042
K. C. Majumdar and N. Kundu
Vol 45
3e: Yield: 88%; White solid; mp 160-162°C; UV (EtOH):
1
EXPERIMENTAL
ꢁmax = 306, 285, 272, 212 nm; IR (KBr): ꢀmax = 1703 cm-1; H
NMR (400 MHz, CDCl3): ꢂH = 1.17 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.39 (s, 3H, ArCH3), 2.52 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 4.39 (s, 2H, CH2NH), 4.96-4.97 (m, 2H, OCH2),
5.61-5.62 (m, 1H, =CH), 6.85-6.86 (m, 1H, ArH), 7.03-7.05 (m,
1H, ArH), 7.19-7.21 (m, 1H, ArH), 7.27-7.28 (m, 1H, ArH),
7.34-7.37 (m, 1H, ArH), 7.54 (s, 1H, ArH); MS: m/z = 425, 427
(M+). Anal. Calcd. for C22H20BrNO3: C, 61.98; H, 4.73; N, 3.29
%. Found: C, 62.05; H, 4.56; N, 3.44 %.
General procedure for the preparation of 4a-e and 5a-e.
Tributyltin hydride (1.1 mmol) was added to a stirred solution of
(3a-e, 1 mmol) and azobisisobutyronitrile (0.5 mmol) in dry
degassed toluene (5 mL) under nitrogen. The mixture was
heated under reflux for 1 h and concentrated. The residue was
dissolved in ether (10 mL) and stirred with a 10% aq. potassium
fluoride solution (10 mL) for 45 min. The white precipitate was
filtered and the aqueous phase extracted with ether (10 mL). The
combined ether extract was washed with brine and dried over
anhyd. Na2SO4. The residual mass, after the removal of solvent,
was subjected to column chromatography using 10% ethyl
acetate-petroleum ether as eluant to give a mixture of cyclized
products 4a-e and 5a-e. The mixture of compounds was then
subjected to flash column chromatography using 10% ethyl
acetate-petroleum ether as eluant whence we obtained the trans-
fused isomers 4a-e in 40-50% yields and cis-fused isomers 5a-e
in 30-37% yields.
Melting points were determined in an open capillary and are
uncorrected. IR spectra were recorded on a Perkin-Elmer L 120-
000A spectrometer (ꢀmax in cm-1) using samples as neat liquids
and solid samples were recorded on KBr disks. UV absorption
spectra were recorded in EtOH on a Shimadzu UV-2401PC
1
spectrophotometer (ꢁmax in nm). H NMR (400 MHz, 500 MHz)
and 13C NMR (125 MHz) spectra were recorded on a Bruker
DPX-400 and Bruker DPX-500 spectrometer in CDCl3
(chemical shift in ꢂ) with TMS as internal standard. Silica gel
[(60-120 mesh), Spectrochem, India] was used for
chromatographic separation. Silica gel G [E-Merck (India)] was
used for TLC. Petroleum ether refers to the fraction boiling
between 60° and 80°C.
General procedure for the preparation of 3a-e. A mixture
of 1 (5 mmol), 2-bromoanilines (2a-e, 5 mmol) and anhydrous
potassium carbonate (5 g) was heated under reflux in dry
acetone (125 mL) for 4 h. The reaction mixture was cooled,
filtered and concentrated. The residual mass was extracted with
CH2Cl2 (3 ꢃ 50 mL), washed with 10% Na2CO3 solution (2 ꢃ 25
mL), brine (3 ꢃ 50 mL) and dried (Na2SO4). The residual mass
after the removal of solvent was subjected to column
chromatography on silica gel using 5% ethylacetate-petroleum
ether as eluant to give compounds 3a-e, which were
recrystallized from CHCl3-petroleum ether.
3a: Yield: 92%; White solid; mp 180-182°C; UV (EtOH):
1
ꢁmax = 349, 284, 214 nm; IR (KBr): ꢀmax = 1715 cm-1; H NMR
4a: Yield: 45%; White solid; mp 248-250°C; UV (EtOH):
1
ꢁmax = 310, 281, 265, 211 nm; IR (KBr): ꢀmax = 1706 cm-1; H
(400 MHz, CDCl3): ꢂH = 2.39 (s, 3H, ArCH3), 2.75 (s, 3H,
NCH3), 4.24 (s, 2H, CH2NCH3), 4.97-4.99 (m, 2H, OCH2), 5.94-
5.96 (m, 1H, =CH), 6.85-6.89 (m, 1H, ArH), 7.15 -7.18 (m, 2H,
ArH), 7.20-7.22 (m, 1H, ArH), 7.30-7.33 (m, 1H, ArH), 7.51-
7.54 (m, 2H, ArH); MS: m/z = 411, 413 (M+). Anal. Calcd. for
C21H18BrNO3: C, 61.18; H, 4.40; N, 3.40 %. Found: C, 61.12; H,
4.61; N, 3.31 %.
NMR (500 MHz, CDCl3): ꢂH = 2.43 (s, 3H, ArCH3), 2.90 (ddd,
1H, J = 11.2, 11.1, 5.2 Hz, CHCH2NCH3), 3.03 (s, 3H, NCH3),
3.15 (ddd, 1H, J = 11.2, 10.8, 3.7 Hz, CHCH2O), 3.27 (t, 1H, J =
11.1 Hz, NCHa), 4.25 (t, 1H, J = 10.8 Hz, OCHa), 4.52 (dd, 1H,
J = 11.1, 5.2 Hz, NCHe), 5.26 (dd, 1H, J = 10.8, 3.7 Hz, OCHe),
6.73-6.76 (m, 2H, ArH), 6.93-6.94 (m, 1H, ArH), 7.21-7.23 (m,
2H, ArH), 7.34-7.35 (m, 1H, ArH), 7.63 (s, 1H, ArH); 13C NMR
(CDCl3, 125 MHz): ꢂC = 20.95 (ArCH3), 32.99 (CHCH2NCH3),
36.63 (CHCH2O), 38.98 (NCH3), 54.06 (NCH2), 69.01 (OCH2),
101.01 (ArC), 115.09 (ArC), 116.24 (ArCH), 122.53 (ArCH),
122.72 (ArCH), 128.48 (ArCH), 129.95 (ArCH), 130.01 (ArC),
132.96 (ArC), 133.04 (ArCH), 133.92 (ArCH), 134.20 (ArC),
150.75 (ArC), 161.95 (ArC), 162.50 (CO); MS: m/z = 333 (M+).
Anal. Calcd. for C21H19NO3: C, 75.66; H, 5.74; N, 4.20 %.
Found: C, 75.68; H, 5.83; N, 4.13 %.
3b: Yield: 95%; White solid; mp 157-159°C; UV (EtOH): ꢁmax
1
= 316, 284, 214 nm; IR (KBr): ꢀmax = 1707 cm-1; H NMR (400
MHz, CDCl3): ꢂH = 2.25 (s, 3H, ArCH3), 2.38 (s, 3H, ArCH3 of
coumarin ring), 2.72 (s, 3H, NCH3), 4.02 (s, 2H, CH2NCH3), 4.96-
4.98 (m, 2H, OCH2), 5.92-5.93 (m, 1H, =CH), 7.01-7.02 (m, 1H,
ArH), 7.04-7.06 (m, 1H, ArH), 7.15-7.17 (m, 1H, ArH), 7.30-7.32
(m, 1H, ArH), 7.35-7.36 (m, 1H, ArH), 7.54 (s, 1H, ArH); MS:
m/z = 425, 427 (M+). Anal. Calcd. for C22H20BrNO3: C, 61.98; H,
4.73; N, 3.29 %. Found: C, 61.82; H, 4.59; N, 3.23 %.
5a: Yield: 30%; White solid; mp 188-190°C; UV (EtOH):
3c: Yield: 90%; White solid; mp 130-132°C; UV (EtOH):
1
1
ꢁmax = 315, 280, 263, 220 nm; IR (KBr): ꢀmax = 1703 cm-1; H
ꢁmax = 329, 285, 213 nm; IR (KBr): ꢀmax = 1709 cm-1; H NMR
NMR (500 MHz, CDCl3): ꢂH = 2.42 (s, 3H, ArCH3), 2.97 (s,
3H, NCH3), 3.08 (t, 1H, J = 11.5 Hz, NCHa), 3.31 (ddd, 1H, J
= 11.5, 5.3, 4.5 Hz, CHCH2O), 3.42 (ddd, 1H, J = 11.5, 5.3,
4.0 Hz, CHCH2NCH3), 3.74 (dd, 1H, J = 11.5, 4.0 Hz, NCHe),
4.15 (t, 1H, J = 11.5 Hz, OCHa), 4.54 (dd, 1H, J = 11.5, 4.5
Hz, OCHe), 6.75-6.76 (m, 2H, ArH), 7.14-7.15 (m, 1H, ArH),
7.19-7.24 (m, 2H, ArH), 7.33-7.35 (m, 1H, ArH), 7.59 (s, 1H,
ArH); 13C NMR (CDCl3, 125 MHz): ꢂC = 20.95 (ArCH3),
28.38 (CHCH2NCH3), 33.83 (CHCH2O), 39.01 (NCH3), 51.05
(NCH2), 69.39 (OCH2), 101.06 (ArC), 115.05 (ArC), 116.42
(ArCH), 122.36 (ArCH), 122.54 (ArCH), 128.76 (ArCH),
129.84 (ArCH), 130.01 (ArC), 132.96 (ArC), 133.04 (ArCH),
133.92 (ArCH), 134.20 (ArC), 150.75 (ArC), 161.95 (ArC),
162.50 (CO); MS: m/z = 333 (M+). Anal. Calcd. for C21H19O3:
C, 75.66; H, 5.74; N, 4.20 %. Found: C, 75.89; H, 5.90; N,
4.07 %.
(400 MHz, CDCl3): ꢂH = 1.18 (t, 3H, J = 7.5 Hz, ArCH2CH3),
2.38 (s, 3H, ArCH3), 2.55 (q, 2H, J = 7.5 Hz, ArCH2CH3), 2.72
(s, 3H, NCH3), 4.21 (s, 2H, CH2NCH3), 4.97-4.99 (m, 2H,
OCH2), 5.94-5.96 (m, 1H, =CH), 7.02-7.05 (m, 1H, ArH), 7.07-
7.09 (m, 1H, ArH), 7.15-7.17 (m, 1H, ArH), 7.30-7.32 (m, 1H,
ArH), 7.37-7.38 (m, 1H, ArH), 7.54 (s, 1H, ArH); MS: m/z =
439, 441 (M+). Anal. Calcd. for C23H22BrNO3: C, 62.74; H, 5.04;
N, 3.18 %. Found: C, 62.90; H, 4.93; N, 3.11 %.
3d: Yield: 85%; White solid; mp 120-122°C; UV (EtOH): ꢁmax
1
= 313, 305, 284, 211 nm; IR (KBr): ꢀmax = 1703 cm-1; H NMR
(400 MHz, CDCl3): ꢂH = 2.19 (s, 3H, ArCH3), 2.38 (s, 3H, ArCH3
of coumarin ring), 4.41 (s, 2H, CH2NH), 4.95-4.96 (m, 2H,
OCH2), 5.56-5.58 (m, 1H, =CH), 6.91-6.93 (m, 1H, ArH), 7.17-
7.23 (m, 2H, ArH), 7.32-7.35 (m, 2H, ArH), 7.53 (s, 1H, ArH);
MS: m/z = 411, 413 (M+). Anal. Calcd. for C21H18BrNO3: C,
61.18; H, 4.40; N, 3.40 %. Found: C, 60.94; H, 4.49; N, 3.45 %.

Jul-Aug 2008
Regioselective Synthesis of Heterocyclic Scaffold byAryl Radical Cyclization
1043
4b: Yield: 50%; White solid; mp 223-225°C; UV (EtOH):
C21H19NO3: C, 75.66; H, 5.74; N, 4.20 %. Found: C, 75.41; H,
5.88; N, 4.25 %.
1
ꢀmax = 312, 285, 213 nm; IR (KBr): ꢀmax = 1718 cm-1; H NMR
(500 MHz, CDCl3): ꢁH = 2.26 (s, 3H, ArCH3), 2.42 (s, 3H,
ArCH3 of coumarin ring), 2.84 (ddd, 1H, J = 11.2, 11.1, 5.2 Hz,
CHCH2NCH3), 2.96 (s, 3H, NCH3), 3.06 (ddd, 1H, J = 11.2,
10.8, 3.7 Hz, CHCH2O), 3.16 (t, 1H, J = 11.1 Hz, NCHa), 4.22
(t, 1H, J = 10.8 Hz, OCHa), 4.44 (dd, 1H, J = 11.1, 5.2 Hz,
NCHe), 5.23 (dd, 1H, J = 10.8, 3.7 Hz, OCHe), 6.56 (d, 1H, J =
8.2 Hz, ArH), 6.70 (s, 1H, ArH), 7.00 (d, 1H, J = 8.2 Hz, ArH),
7.20 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.33 (d, 1H, J = 8.3
Hz, ArH of coumarin), 7.64 (s, 1H, ArH of coumarin); MS: m/z
= 347 (M+). Anal. Calcd. for C22H21NO3: C, 76.06; H, 6.09; N,
4.03 %. Found: C, 76.31; H, 5.98; N, 3.94 %.
5d: Yield: 35%; White solid; mp 168-170°C; UV (EtOH):
ꢀmax = 365, 353, 285, 272, 215 nm; IR (KBr): ꢀmax = 1708cm-1;
1H NMR (500 MHz, CDCl3): ꢁH = 2.29 (s, 3H, ArCH3), 2.41 (s,
3H, ArCH3 of coumarin ring), 3.10 (t, 1H, J = 11.2 Hz, NCHa),
3.28-3.31 (m, 1H, CHCH2O), 3.44-3.47 (m, 1H, CHCH2NH),
4.01 (dd, 1H, J = 11.2, 3.4 Hz, NCHe), 4.14 (t, 1H, J = 11.5 Hz,
OCHa), 4.59 (dd, 1H, J = 11.5, 3.3 Hz, OCHe), 6.92-6.93 (m,
1H, ArH), 7.00-7.03 (m, 2H, ArH), 7.20 (d, 1H, J = 8.3 Hz, ArH
of coumarin), 7.33 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.57
(s, 1H, ArH of coumarin); 13C NMR (CDCl3, 125 MHz): ꢁC =
20.60 (ArCH3), 20.96 (ArCH3 of coumarin), 28.63 (CHCH2NH),
33.14 (CHCH2O), 42.42 (CH2NH), 69.01 (OCH2), 100.91 (ArC),
114.96 (ArC), 116.41 (ArCH), 117.65 (ArC), 117.85 (ArC),
122.38 (ArCH), 129.42 (ArCH), 130.46 (ArCH), 133.04
(ArCH), 133.25 (ArCH), 133.73 (ArC), 133.95 (ArC),
150.75(ArC), 161.15 (ArC), 162.72 (CO); MS: m/z = 333 (M+).
Anal. Calcd. for C21H19NO3: C, 75.66; H, 5.74; N, 4.20 %.
Found: C, 75.40; H, 5.59; N, 4.32 %.
4e: Yield: 42%; White solid; mp 220-222°C; UV (EtOH):
ꢀmax = 366, 354, 311, 285, 212 nm; IR (KBr): ꢀmax = 1702 cm-1;
1H NMR (500 MHz, CDCl3): ꢁH = 1.20 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.42 (s, 3H, ArCH3), 2.54 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 2.86 (ddd, 1H, J = 11.2, 11.1, 5.2 Hz, CHCH2NH),
3.06 (dt, 1H, J = 11.1, 1.5 Hz, NCHa), 3.15 (ddd, 1H, J = 11.2,
10.8, 3.7 Hz, CHCH2O), 4.01(br s, 1H, NH), 4.21(t, 1H, J = 10.8
Hz, OCHa), 4.75 (ddd, 1H, J = 11.1, 5.2, 4.2 Hz, NCHe), 5.25
(dd, 1H, J = 10.8, 3.7 Hz, OCHe), 6.52 (d, 1H, J = 8.2 Hz, ArH),
6.77 (s, 1H, ArH), 6.92 (d, 1H, J = 8.2 Hz, ArH), 7.20 (d, 1H, J
= 8.3 Hz, ArH of coumarin), 7.34 (d, 1H, J = 8.3 Hz, ArH of
coumarin), 7.62 (s, 1H, ArH of coumarin); 1H NMR (500 MHz,
CDCl3, D2O exchange): ꢁH = 1.20 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.42 (s, 3H, ArCH3), 2.54 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 2.86 (ddd, 1H, J = 11.2, 11.1, 5.2 Hz, CHCH2NH),
3.06 (t, 1H, J = 11.1 Hz, NCHa), 3.15 (ddd, 1H, J = 11.2, 10.8,
3.7 Hz, CHCH2O), 4.21(t, 1H, J = 10.8 Hz, OCHa), 4.75 (dd,
1H, J = 11.1, 5.2 Hz, NCHe), 5.25 (dd, 1H, J = 10.8, 3.7 Hz,
OCHe), 6.52 (d, 1H, J = 8.2 Hz, ArH), 6.77 (s, 1H, ArH), 6.92
(d, 1H, J = 8.2 Hz, ArH), 7.20 (d, 1H, J = 8.3 Hz, ArH of
coumarin), 7.34 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.62 (s,
1H, ArH of coumarin); 13C NMR (CDCl3, 125 MHz): ꢁC = 16.14
(ArCH2CH3), 20.97 (ArCH3), 28.14 (ArCH2CH3), 32.75
(CHCH2NH), 37.25 (CHCH2O) 44.96 (NCH2), 69.53 (OCH2),
101.87 (ArC), 113.82 (ArCH), 115.19 (ArC), 116.20 (ArCH),
118.32 (ArC), 122.54 (ArCH), 123.06 (ArCH), 127.55 (ArCH),
132.13 (ArC), 132.93 (ArCH), 133.57 (ArC), 141.96 (ArC),
150.84 (ArC), 161.49 (ArC), 162.01 (CO); MS: m/z = 347 (M+).
Anal. Calcd. for C22H21NO3: C, 76.06; H, 6.09; N, 4.03 %.
Found: C, 75.84; H, 6.15; N, 4.00 %.
5b: Yield: 33%; White solid; mp 156-158°C; UV (EtOH):
1
ꢀmax = 364, 244, 209 nm; IR (KBr): ꢀmax = 1708 cm-1; H NMR
(500 MHz, CDCl3): ꢁH = 2.26 (s, 3H, ArCH3), 2.42 (s, 3H,
ArCH3 of coumarin ring), 2.91 (s, 3H, NCH3), 2.99 (t, 1H, J =
11.2 Hz, NCHa), 3.25 (ddd, 1H, J = 11.5, 5.3, 3.3 Hz, CHCH2O),
3.39 (ddd, 1H, J = 11.2, 5.3, 3.4 Hz, CHCH2NCH3), 3.69 (dd,
1H, J = 11.2, 3.4 Hz, NCHe), 4.14 (t, 1H, J = 11.5 Hz, OCHa),
4.53 (dd, 1H, J = 11.5, 3.3 Hz, OCHe), 6.61 (d, 1H, J = 8.2 Hz,
ArH), 6.93 (s, 1H, ArH), 7.00 (d, 1H, J = 8.2 Hz, ArH), 7.22 (d,
1H, J = 8.3 Hz, ArH of coumarin), 7.33 (d, 1H, J = 8.3 Hz, ArH
of coumarin), 7.58 (s, 1H, ArH of coumarin); MS: m/z = 347
(M+). Anal. Calcd. for C22H21NO3: C, 76.06; H, 6.09; N, 4.03 %.
Found: C, 75.97; H, 5.96; N, 4.23 %.
4c: Yield: 45%; White solid; mp 270-272°C; UV (EtOH):
1
ꢀmax = 306, 283, 259, 208 nm; IR (KBr): ꢀmax = 1708 cm-1; H
NMR (500 MHz, CDCl3): ꢁH = 1.22 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.43 (s, 3H, ArCH3), 2.58 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 2.90 (ddd, 1H,
J = 11.2, 11.1, 5.2 Hz,
CHCH2NCH3), 3.00 (s, 3H, NCH3), 3.11 (ddd, 1H, J = 11.2,
10.8, 3.7 Hz, CHCH2O), 3.20 (t, 1H, J = 11.1 Hz, NCHa), 4.25
(t, 1H, J = 10.8 Hz, OCHa), 4.47 (dd, 1H, J = 11.1, 5.2 Hz,
NCHe), 5.24 (dd, 1H, J = 10.8, 3.7 Hz, OCHe), 6.70 (d, 1H, J =
8.2 Hz, ArH), 6.76 (s, 1H, ArH), 7.07 (d, 1H, J = 8.2 Hz, ArH),
7.21 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.34 (d, 1H, J = 8.3
Hz, ArH of coumarin), 7.63 (s, 1H, ArH of coumarin); MS: m/z
= 361(M+). Anal. Calcd. for C23H23NO3: C, 76.43; H, 6.41; N,
3.88 %. Found: C, 76.67; H, 6.35; N, 3.75 %.
5c: Yield: 35%; White solid; mp 165-167°C; UV (EtOH):
1
ꢀmax = 312, 284, 260, 218 nm; IR (KBr): ꢀmax = 1704 cm-1; H
NMR (500 MHz, CDCl3): ꢁH = 1.23 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.42 (s, 3H, ArCH3), 2.58 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 2.95 (s, 3H, NCH3), 3.05 (t, 1H, J = 11.2 Hz,
NCHa), 3.28 (m, 1H, CHCH2O), 3.41 (m, 1H, CHCH2NCH3),
3.71 (dd, 1H, J = 11.2, 3.4 Hz, NCHe), 4.15 (t, 1H, J = 11.5 Hz,
OCHa), 4.55 (dd, 1H, J = 11.5, 3.3 Hz, OCHe), 6.73 (d, 1H, J =
8.2 Hz, ArH), 7.05 (s, 1H, ArH), 7.17 (d, 1H, J = 8.2 Hz, ArH),
7.22 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.34 (d, 1H, J = 8.3
Hz, ArH of coumarin), 7.58 (s, 1H, ArH of coumarin); MS: m/z
= 361 (M+). Anal. Calcd. for C23H23NO3: C, 76.43; H, 6.41; N,
3.88 %. Found: C, 76.61; H, 6.48; N, 3.78 %.
4d: Yield: 40%; White solid; mp 208-210°C; UV (EtOH):
ꢀmax = 371, 354, 284, 272, 212 nm; IR (KBr): ꢀmax = 1705 cm-1;
1H NMR (400 MHz, CDCl3): ꢁH = 2.22 (s, 3H, ArCH3), 2.42 (s,
3H, ArCH3 of coumarin ring), 2.97-2.99 (m, 1H, CHCH2NCH3),
3.20-3.26 (m, 2H, CHCH2O and NCHa), 4.24 (t, 1H, J = 10.8
Hz, OCHa), 4.89 (dd, 1H, J = 11.1, 5.2 Hz, NCHe), 5.23 (dd, 1H,
J = 10.8, 3.7 Hz, OCHe), 6.86-6.87 (m, 1H, ArH), 7.06-7.08 (m,
1H, ArH), 7.18-7.20 (m, 2H, ArH), 7.33-7.35 (m, 1H, ArH),
7.60 (s, 1H, ArH); MS: m/z = 333 (M+). Anal. Calcd. for
5e: Yield: 37%; White solid; mp 130-132°C. UV (EtOH):
ꢀmax = 360, 347, 310, 282, 202 nm; IR (KBr): ꢀmax = 1709 cm-1;
1H NMR (500 MHz, CDCl3): ꢁH = 1.21 (t, 3H, J = 7.5 Hz,
ArCH2CH3), 2.41 (s, 3H, ArCH3), 2.55 (q, 2H, J = 7.5 Hz,
ArCH2CH3), 3.05 (t, 1H, J = 11.2 Hz, NCHa), 3.32-3.30 (m, 2H,
CHCH2O and CHCH2NH), 3.84 (dd, 1H, J = 11.2, 3.4 Hz,
NCHa), 3.96 (br s, 1H, NH), 4.19 (t, 1H, J = 11.5 Hz, OCHa),
4.58 (dd, 1H, J = 11.5, 3.3 Hz, OCHe), 6.53-6.55 (m, 1H, ArH),
6.92-6.94 (m, 2H, ArH), 7.21 (d, 1H, J = 8.3 Hz, ArH of
coumarin), 7.33 (d, 1H, J = 8.3 Hz, ArH of coumarin), 7.58 (s,
1H, ArH of coumarin); 13C NMR (CDCl3, 125 MHz): ꢁC = 15.90
(ArCH2CH3), 20.96 (ArCH3), 27.94 (ArCH2CH3), 29.18

1044
K. C. Majumdar and N. Kundu
Vol 45
Kulicka, K. L.; Trach, F. Org. React. 1996, 48, 301.
(CHCH2NH), 33.48 (CHCH2O), 42.50 (NCH2), 69.44 (OCH2),
101.49 (ArC), 115.16 (ArCH), 116.36 (ArCH), 117.03 (ArC),
117.24 (ArC), 122.32 (ArCH), 127.87 (ArCH), 129.21 (ArCH),
132.83 (ArCH), 133.40 (ArC), 133.62 (ArC), 143.11 (ArC),
150.72 (ArC), 160.95 (ArC), 162.88 (CO); MS: m/z = 347 (M+).
Anal. Calcd. for C22H21NO3: C, 76.06; H, 6.09; N, 4.03 %.
Found: C, 76.14; H, 5.86; N, 4.11 %.
[5] Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions- Concepts, Guidelines and Synthetic Applications;
VCH: Weinheim, Germany, 1996.
[6] Pattenden, G.; Sandeep, H. Contemp. Org. Synth. 1997, 197.
[7] Beckwith, A. L. J. Tetrahedron 1981, 37, 3073 and
references therein.
[8] (a) Della, E. W.; Graney, S. D. Tetrahedron Lett. 2000, 41,
7987. (b) Della, E. W.; Graney, S. D. Org. Lett. 2002, 4, 4065. (c) Cid,
M. M.; Dominguez, D.; Castedo, L.; Va’zquez-Lopez, E. M.
Tetrahedron 1999, 55, 5599. (d) Ishibashi, H.; Kato, I.; Takeda, Y.;
Kogure, M.; Tamura, O. Chem. Commun. 2000, 1527.
[9] (a) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.
Tetrahedron Reports, 2004, 60, 6239. (b) Majumdar, K. C.; Basu, P. K.;
Mukhopadhyay P. P. Tetrahedron Reports, 2005, 61, 10603. (c)
Majumdar, K. C.; Basu, P. K.; Chattopadhyay, S. K Tetrahedron
Reports, 2007, 63, 793.
Acknowledgement. We thank the CSIR (New Delhi) for
financial assistance. One of us (N.K.) is grateful to CSIR for a
Senior Research Fellowship. We also thank Dr. B. C. Maiti
(Chemgen Pharma Int. Pvt. Ltd., Kolkata) for his help in the
spectral interpretation.
REFERNCES
[10] Majumdar, K. C.; Das, D. P.; Khan, A. T. Synth. Commun.
1988, 18 (16 and 17), 2027.
[11] Ishibashi, H.; Kawanami, H.; Nakagawa, H.; Ikeda, M. J.
Chem. Soc., Perkin Trans. I, 1997, 2291.
[12] Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J. Org.
Chem. 1987, 52, 4072.
[13] Majumdar, K. C.; Muhuri, S. Synthesis, 2006, 2725.
[14] Majumdar, K. C.; Jana, M. Synth. Commun. 2007, 37, 1735.
[15] (a) Enholm, E. J.; Prasad, E. J.; Kinter, K. S. J. Am. Chem.
Soc. 1991, 113, 7784. (b) Enholm, E. J.; Kinter, K. S. J. Org. Chem.
1995, 60, 4850.
ꢀ[a] Corresponding author. Department of Chemistry, University of
Kalyani, Kalyani 741235, WB, India. Tel.: +91-33-2582-7521, fax: +91-33-
25828282; e-mail: kcm_ku@yahoo.co.in
[1] Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon: New York, 1986.
[2] Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237.
[3] Motherwell, M. B.; Crich, D. Best Synthetic Methods, Free
Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1991.
[4] Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, L.; Thoma, G.;