Novel synthesis of heterocycle-annulated azocine derivatives of biological relevance by aromatic aza-claisen rearrangement and intramolecular heck reaction

Article abstract of DOI:10.1055/s-0029-1218630

A synthetic strategy based on the sequential application of an aromatic aza-Claisen rearrangement and an intramolecular Heck reaction sequence as the key steps has been developed for the synthesis of various hitherto unreported coumarin-and quinolone-annulated benzazocine derivatives in excellent yields.

Full text of DOI:10.1055/s-0029-1218630

PAPER
985
Novel Synthesis of Heterocycle-Annulated Azocine Derivatives of Biological
Relevance by Aromatic Aza-Claisen Rearrangement and Intramolecular Heck
Reaction
Synthesis of
Heter
.
ocycle-Annu
C
lated
A
zocine
D
e
.
rivatives Majumdar,* Raj Kumar Nandi, Srikanta Samanta, Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, India
E-mail: kcm_ku@yahoo.co.in
Received 19 November 2009; revised 24 November 2009
new to newer methods for the construction of organic
molecules from simple starting materials has become an
ongoing challenge. In general, the number of methods
available for the synthesis of medium-sized heterocycles
is small. Among various synthetic protocols, the palladi-
um-catalyzed intramolecular Heck reaction has become a
useful technique due to its excellent functional-group tol-
erance and high stereoselectivity. The reaction can be cat-
alyzed by palladium complexes with or without
phosphine ligands (phosphine-assisted vs. phosphine-free
catalysis). A primary role of the phosphine ligands is to
support palladium in its zero oxidation state in the form of
stable PdL4 or PdL3 species. The phosphine-assisted ap-
proach is a classical and well-established method, which
gives excellent results in the majority of cases. Moreover,
although there are many examples of the formation of me-
dium-sized oxa heterocycles,8,9 syntheses of medium-
sized nitrogen heterocycles by use of intramolecular Heck
reactions are rare and thus still a significant synthetic
challenge. It has been reported10 that the palladium-cata-
lyzed cyclization by application of the intramolecular
Heck reaction requires harsh reaction conditions when a
nitrogen-containing compound is used as the starting ma-
terial. Guy et al.11 reported the synthesis of eight-mem-
bered azocines by the intramolecular Heck reaction by the
8-endo-trig mode of cyclization starting from highly acti-
vated precursors, but none from unactivated allylic sub-
strates. It has also been reported12–15 that coumarin and
quinolone moieties are found in a large number of natural
products that possess a broad spectrum of biological activ-
ities such as antifungal, antibacterial, antiviral, and anti-
microbial properties. All these findings prompted us to
investigate the synthesis of biologically interesting cou-
marin- and quinolone-annulated azocines by the applica-
tion of the palladium-mediated intramolecular Heck
reaction.
Abstract: A synthetic strategy based on the sequential application
of an aromatic aza-Claisen rearrangement and an intramolecular
Heck reaction sequence as the key steps has been developed for the
synthesis of various hitherto unreported coumarin- and quinolone-
annulated benzazocine derivatives in excellent yields.
Key words: aza-Claisen rearrangement, Heck reaction, benzazo-
cine, coumarin, quinolone, palladium catalyst
The importance of medium-sized rings in synthetic organ-
ic chemistry is exemplified by their presence as the struc-
tural core moiety in a large number of biologically
important natural products.1 Moreover, these units have
served as target molecules in numerous synthetic studies.2
Medium-sized nitrogen heterocycles, especially eight-
membered azocines, are key intermediates for many natu-
ral products.3,4 For example, nakadomarin A5 (Figure 1)
has a range of potentially useful bioactivities (anticancer,
antifungal, and antibacterial), but limited availability of
natural material has restricted further screening. The poly-
cyclic alkaloid manzamine A (Figure 1),6 isolated from a
sponge, shows cytotoxic activity (IC50 = 0.07 mg/mL)
against the P-388 mouse leukemia cell.
R3
H
N
R2
R1
R4
H
H
N
HO
N
H
N
O
N
R6
H
N
N
R5
(–)-nakadomarin A
manzamine A
Figure 1 Nakadomarin A and manzamine A and a biologically im-
portant azocine backbone
The requisite precursors 3a–c for our present syntheses
were prepared in good to excellent yields by the aromatic
aza-Claisen rearrangement of N-allylcoumarins and N-al-
lylquinolones 2a–c in the presence of the boron trifluo-
ride–diethyl ether complex as catalyst in xylene at 130 °C
in a sealed tube (Scheme 1). These coumarins and quino-
lones 2a–c were, in turn, prepared by the reaction of dif-
ferent N-alkylcoumarins and -quinolones 1a–c with allyl
bromide in anhydrous methyl ethyl ketone in the presence
of potassium carbonate and sodium iodide (Scheme 1).
In addition, medium-sized heterocycles fused to aryl rings
are found in many drugs and preclinical leads. Despite
their biological activity, azocine-fused systems are not
sufficiently investigated, perhaps due to the lack of satis-
factory synthetic procedures.7 Recently, the search for
SYNTHESIS 2010, No. 6, pp 0985–0990
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x
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x
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Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1218630; Art ID: Z24709SS
© Georg Thieme Verlag Stuttgart · New York

986
K. C. Majumdar et al.
PAPER
double-bond isomerization. The optimization of the reac-
tion conditions was carried out with substrate 5a and is
summarized in Table 1.
NHR
i
NR
NHR
ii
O
X
O
X
2a–c
O
X
3a–c
1a, X = O, R = Et
1b, X = O, R = Me
1c, X = NMe, R = Me
Table 1 Optimization of the Reaction Conditions for the Intramo-
lecular Heck Reaction Giving 6aa
Scheme 1 Reagents and conditions: (i) AllBr, MEK, K2CO3, NaI,
reflux, 9 h; (ii) BF3·OEt2 (2 equiv), xylene, 130 °C, 6 h.
Entry Catalyst
Solventb
DMA
DMA
DMF
Base
Ligand Yieldc,d (%)
1
2
3
4e
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
K2CO3
KOAc
KOAc
KOAc
K2CO3
Ag2CO3
KOAc
NaOAc
Et3N
–
20
25
65
79
26
30
35
48
n.r.
n.r.
The required Heck precursors 5a,b for our present study
were synthesized in 76–80% yields by refluxing 5-allyl-6-
(ethylamino)coumarin 3a with benzyl bromides 4a,b in
anhydrous methyl ethyl ketone for about 14 hours in the
presence of anhydrous potassium carbonate and a small
amount of sodium iodide (Finkelstein conditions)
(Scheme 2).16
–
–
DMF
DMF
Ph3P
–
DMF
–
DMF
Ph3P
Ph3P
–
Br
Br
Br
NHR1
Pd(OAc)2
Pd(OAc)2
PdCl2
DMF
N
R1
i
+
R2
THF
O
X
O
X
R2
4a, R1 = H
5a, X = O, R1 = Et, R2 = H
3a–c
10
dioxane
KOAc
–
4b, R1 = OMe
5b, X = O, R1 = Et, R2 = OMe
5c, X = O, R1 = Me, R2 = H
a Reagents and conditions: TBAB (1.2 equiv), 90 °C.
b DMA = N,N-dimethylacetamide.
c Isolated yield.
5d, X = O, R1= Me, R2 = OMe
5e, X = NMe, R1 = Me, R2 = H
5f, X = NMe, R1 = Me, R2 = OMe
d n.r. = no reaction.
Scheme 2 Reagents and conditions: (i) K2CO3, MEK, NaI, reflux,
14 h.
e Optimized reaction conditions.
From Table 1, it can be seen that the use of a ligand in-
creases the reaction yield. Among the different bases
used, potassium acetate has the largest effect on the reac-
tion yield. Potassium carbonate and silver(I) carbonate
show nearly similar effects. The reaction did not occur un-
der the reaction conditions described in Table 1, entries 9
and 10. Among the various solvents, N,N-dimethylform-
amide is the best choice. The optimized reaction condi-
tions therefore consist of the use of palladium(II) acetate
(10 mol%), tetrabutylammonium bromide (1.2 equiv), po-
tassium acetate (2.5 equiv), triphenylphosphine (20
mol%), and N,N-dimethylformamide at 90 °C. Other sub-
strates 5b–f were similarly treated under the optimized re-
action conditions to afford the corresponding Heck
cyclized products 6b–f in 75–78% yields. The results are
summarized in Table 2.
The intramolecular Heck reactions were performed in an-
hydrous N,N-dimethylformamide in the presence of po-
tassium acetate as a base, tetrabutylammonium bromide
as a promoter, triphenylphosphine as ligand, and palladi-
um(II) acetate as catalyst under a nitrogen atmosphere at
90 °C for about six hours. All the reactions afforded the
eight-membered heterocyclic compounds 6a–f fused with
aryl ring, coumarin, and quinolone moieties (Scheme 3).
Br
NEt
NEt
NEt
i
+
O
O
O
O
O
O
5a
8a
6a
observed
not observed
The exclusive formation of heterocycle-annulated azocine
derivatives 6a–f via the 8-exo mode of cyclization is quite
unusual. Beletskaya and Cheprakov reported18 that endo
Heck cyclization can occur when the Heck precursor pos-
sesses a Michael-type olefinic fragment such as a highly
activated double bond.
Scheme 3 Reagents and conditions: (i) Pd(OAc)2 (10 mol%), Ph3P
(20 mol%), KOAc (2.5 equiv), TBAB (1.2 equiv), DMF, 90 °C, 6 h.
In the intramolecular Heck reaction, ring closure can oc-
cur by two possible modes, namely the exo-trig and the
endo-trig mode. Of these two possible modes, an exo
mode is usually favored for the formation of small- to
medium-size (5–8) rings,17 because the endo mode is ster-
ically very demanding; the endo mode requires that the
olefinic system moves into the loop of the substrate, gen-
erating an energetically favorable substituted alkene prod-
uct. In our present work we have obtained only the
endocyclic product 6a via 8-exo cyclization followed by
Here the exclusive formation of the endocyclic products
6a–f may be rationalized to occur via two possible path-
ways, such as proceeding by the 8-exo mode of cycliza-
tion followed by double-bond isomerization and,
alternatively, a double-bond isomerization prior to the
Heck reaction leading to the subsequent 8-endo Heck cy-
clization (Scheme 4). It is worthwhile noting that in the
Synthesis 2010, No. 6, 985–990 © Thieme Stuttgart · New York

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Synthesis of Heterocycle-Annulated Azocine Derivatives
987
Table 2 Synthesis of Endocyclic Heck Products
Entry
Starting material
Product
Time (h)
Yielda (%)
Et
N
1
5a
6a
6b
6c
6d
6
79
77
76
78
NEt
Br
O
O
O
O
OMe
Et
N
2
3
4
5b
6.5
Br
NEt
O
O
O
O
MeO
Me
N
5c
7
NMe
Br
O
O
O
O
OMe
Me
N
5d
7
Br
NMe
O
O
O
O
MeO
Me
N
5
6
5e
6e
6f
7.5
6.5
75
78
NMe
Br
O
N
Me
O
N
Me
OMe
Me
N
5f
NMe
Br
O
N
Me
O
N
MeO
Me
a Isolated yield.
case of the formation of dibenzoazocine derivatives19 this
double-bond isomerization did not occur at all. There the
reaction was achieved under ligand-free conditions,
whereas in the present instance the yield of the reaction is
affected by the absence of the triphenylphosphine ligand.
The newly formed double bond is more substituted in
products 6 than in intermediates 7.
Br
H
NEt
NEt
8-exo-trig
O
O
O
O
7a
5a
double bond
isomerization after
Heck reaction
double bond
migration before
Heck reaction
Br
To summarize, we have developed a protocol which is
simple, straightforward, and interesting. A synthetic route
for the construction of heterocycle-annulated azocines
from unactivated allylic substrates by the intramolecular
Heck reaction has been developed.
NEt
NEt
8-endo-trig
O
O
O
O
6a
Melting points of samples were determined in open capillaries and
are uncorrected. IR spectra of samples prepared as KBr discs (or
neat for liquid samples) were obtained on a Perkin-Elmer 120-000A
apparatus. NMR spectra of solns in CDCl3 were determined on a
Scheme 4 Probable mechanistic path of the Heck reaction
Synthesis 2010, No. 6, 985–990 © Thieme Stuttgart · New York

988
K. C. Majumdar et al.
PAPER
Bruker Ultrashield-400 spectrometer (TMS was used as an internal
standard). HRMS was carried out on a Qtof Micro YA263 instru-
ment. Silica gel (60–120 mesh) was used for chromatographic sep-
arations and silica gel G (E-Merck, India) was used for TLC. PE
refers to the fraction with bp 60–80 °C.
CH=CHaHb), 5.82–5.91 (m, 1 H, HC=CH2), 6.36 (d, J = 9.9 Hz, 1
H, C3-H of coumarin), 6.96 (d, J = 2.8 Hz, 1 H, ArH), 7.21 (d,
J = 8.9 Hz, 2 H, ArH), 7.37 (d, J = 8.7 Hz, 1 H, ArH), 7.46 (d, J = 9
Hz, 1 H, ArH), 7.84 (d, J = 9.8 Hz, 1 H, C4-H of coumarin).
MS (EI, 70 eV): m/z = 427 [M+], 429 [M + 2]+.
Anal. Calcd for C22H22BrNO3: C, 61.69; H, 5.18; N, 3.27. Found: C,
61.95; H, 5.32; N, 3.26.
6-[Allyl(ethyl)amino]coumarin (2a); Typical Procedure
A mixture of 1a (2.0 g, 10.6 mmol), allyl bromide (1.34 mL, 15.8
mmol), and anhyd K2CO3 (4 g, 28.9 mmol) in anhyd MEK (50 mL)
in the presence of NaI was refluxed for 9 h. After cooling, the reac-
tion mixture was filtered and the solvent was removed in vacuo. The
residual mass was extracted with EtOAc (3 × 10 mL), washed with
H2O (10 mL) and brine (10 mL), and dried (Na2SO4). Removal of
the EtOAc gave a crude product which was chromatographed (silica
gel, EtOAc–PE, 15:85); this gave 2a. Compounds 2b,c were pre-
pared similarly.
Compound 5c
Yield: 78%; solid; mp 101–102 °C.
IR (KBr): 2947, 1718, 1567 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.59 (s, 3 H, NCH3), 3.75 (t,
J = 3.2 Hz, 2 H, CH2), 4.06 (s, 2 H, NCH2), 4.70 (dd, J = 1.2 Hz, 1
H, J = 17.2 Hz, =CHaCHb), 4.97 (dd, J = 1.6 Hz, 1 H, J = 10.4
Hz, =CHaCHb), 5.82–5.92 (m, 1 H, HC=CH2), 6.32 (d, J = 10 Hz, 1
H, C3-H of coumarin), 7.02–7.07 (m, 1 H, ArH), 7.16–7.21 (m, 2 H,
ArH), 7.36 (d, J = 7.6 Hz, 1 H, ArH), 7.41 (d, J = 8.8 Hz, 1 H, ArH),
7.47 (d, J = 8 Hz, 1 H, ArH), 7.78 (d, J = 9.6 Hz, 1 H, C4-H of cou-
marin).
5-Allyl-6-(ethylamino)coumarin (3a); Typical Procedure
A mixture of compound 2a (1.2 g, 5.2 mmol) and BF3·OEt2 (1.31
mL, 10.5 mmol) in xylene (4 mL) was heated in a sealed tube at
130 °C for 6 h. After cooling, the reaction mixture was neutralized
with sat. aq NaHCO3. Then it was extracted with EtOAc (3 × 10
mL), washed with H2O (10 mL) and brine (5 mL), and dried
(Na2SO4). Removal of EtOAc afforded a crude mass, which was pu-
rified by column chromatography (silica gel, EtOAc–PE, 20:80);
this gave 3a. Compounds 3b,c were prepared similarly.
MS (EI, 70 eV): m/z = 383 [M+], 385 [M + 2]+.
Anal. Calcd for C20H18BrNO2: C, 62.51; H, 4.72; N, 3.65. Found: C,
62.48; H, 4.74; N, 3.44.
Compound 5d
Yield: 76%; liquid.
IR (neat): 2939, 1732, 1559 cm–1.
5-Allyl-6-[(2-bromobenzyl)(ethyl)amino]coumarin (5a); Typi-
cal Procedure
1H NMR (CDCl3, 300 MHz): d = 2.66 (s, 3 H, NCH3), 3.77 (s, 3 H,
OCH3), 3.82 (t, J = 2.7 Hz, 2 H, CH2), 4.08 (s, 2 H, NCH2), 4.78 (dd,
J = 0.9 Hz, 1 H, J = 17.1 Hz, =CHaCHb), 5.05 (dd, J = 0.9 Hz, 1 H,
J = 10.2 Hz, =CHaCHb), 5.90–6.03 (m, 1 H, HC=CH2), 6.39 (d,
J = 9.6 Hz, 1 H, C3-H of coumarin), 6.69 (dd, J = 2.7 Hz, 1 H,
J = 8.7 Hz, ArH), 7.06 (d, J = 2.7 Hz, 1 H, ArH), 7.21 (d, J = 7.2
Hz, 1 H, ArH), 7.42 (d, J = 8.7 Hz, 1 H, ArH), 7.48 (d, J = 8.7 Hz,
1 H, ArH), 7.86 (d, J = 9.6 Hz, 1 H, C4-H of coumarin).
A mixture of 3a (0.40 g, 1.7 mmol), 2-bromobenzyl bromide (4a;
0.52 g, 2.1 mmol), and anhyd K2CO3 (2.0 g) in anhyd MEK (50 mL)
in the presence of NaI was refluxed for 14 h. The reaction mixture
was cooled and filtered and the solvent was removed. The residual
mass was extracted with CH2Cl2 (3 × 10 ml), washed with H2O (10
mL) and brine (5 mL), and dried (Na2SO4). Removal of the CH2Cl2
gave a crude product, which was purified by chromatography (silica
gel, EtOAc–PE, 15:85); this gave 5a. Other substrates 5b–f were
prepared similarly.
MS (EI, 70 eV): m/z = 413 [M+], 415 [M + 2]+.
Anal. Calcd for C21H20BrNO3: C, 60.88; H, 4.87; N, 3.38. Found: C,
60.64; H, 4.90; N, 3.35.
Compound 5a
Yield: 80%; gummy liquid.
IR (neat): 2929, 1732, 1567 cm–1.
Compound 5e
Yield: 77%; solid; mp 73–74 °C.
IR (KBr): 2939, 1655, 1567 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.62 (s, 3 H, NCH3), 3.66 (s, 3 H,
NCH3), 3.84 (t, J = 2.8 Hz, 2 H, CH2), 4.10 (s, 2 H, NCH2), 4.70 (dd,
J = 1.2 Hz, 1 H, J = 17.2 Hz, =CHaCHb), 4.95 (dd, J = 1.2 Hz, 1 H,
J = 10.4 Hz, =CHaCHb), 5.86–5.94 (m, 1 H, HC=CH2), 6.62 (d,
J = 10 Hz, 1 H, C3-H of quinolone), 7.04 (t, J = 7.2 Hz, 1 H, ArH),
7.23 (d, J = 9.2 Hz, 2 H, ArH), 7.42 (d, J = 7.2 Hz, 1 H, ArH), 7.47
(dd, J = 3.6 Hz, 2 H, J = 8.8 Hz, ArH), 7.78 (d, J = 10 Hz, 1 H, C4-
H of quinolone).
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7 Hz, 3 H, NCH2CH3),
3.01 (q, J = 7 Hz, 2 H, NCH2CH3), 3.79 (t, J = 2.6 Hz, 2 H, CH2),
4.13 (s, 2 H, NCH2), 4.73 (d, J = 17.1 Hz, 1 H, CH=CHaHb)), 4.98
(d, J = 10.5 Hz, 1 H, CH=CHaHb), 5.77–5.87 (m, 1 H, HC=CH2),
6.35 (d, J = 9.8 Hz, 1 H, C3-H of coumarin), 7.06 (t, J = 7.5 Hz, 1
H, ArH), 7.18–7.22 (m, 2 H, ArH), 7.32 (d, J = 7.5 Hz, 1 H, ArH),
7.48 (t, J = 9.8 Hz, 2 H, ArH), 7.83 (d, J = 9.8 Hz, 1 H, C4-H of cou-
marin).
13C NMR (100 MHz, CDCl3): d = 12.3, 30.5, 49.1, 59.1, 115.6,
115.8, 116.0, 118.58, 124.4, 127.2, 127.6, 128.5, 130.3, 132.8,
134.9, 136.6, 137.7, 141.6, 145.7, 151.6, 160.8.
MS (EI, 70 eV): m/z = 396 [M+], 398 [M + 2]+.
ESI-HRMS: m/z calcd: 398.0750 [M + H]+, 400.0732 [M + H + 2]+;
found: 398.0781 [M + H]+, 400.0703 [M + H + 2]+.
Anal. Calcd for C21H21BrN2O: C, 63.48; H, 5.33; N, 7.05. Found: C,
63.53; H, 5.56; N, 6.87.
Anal. Calcd for C21H20BrNO2: C, 63.33; H, 5.06; N, 3.52. Found: C,
63.54; H, 5.18; N, 3.45.
Compound 5f
Yield: 76%; gummy liquid.
IR (neat): 2924, 1649, 1569 cm–1.
Compound 5b
Yield: 77%; gummy liquid.
1H NMR (400 MHz, CDCl3): d = 2.65 (s, 3 H, NCH3), 3.72 (s, 3 H,
NCH3), 3.77 (s, 3 H, OCH3), 3.84 (t, J = 2.7 Hz, 2 H, CH2), 4.10 (s,
2 H, NCH2), 4.78 (d, J = 16.8 Hz, 1 H, =CHaHb), 5.03 (d, J = 10.2
Hz, 1 H, =CHaHb), 5.93–6.05 (m, 1 H, CH=CH2), 6.69 (d, J = 9.9
Hz, 1 H, C3-H of quinolone), 7.10 (d, J = 2.4 Hz, 1 H, ArH), 7.30
IR (neat): 2932, 1732, 1568 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H,
NCH2CH3), 3.00 (q, J = 7.1 Hz, 2 H, NCH2CH3), 3.71 (s, 3 H,
OCH3), 3.81 (d, J = 5.2 Hz, 2 H, CH2), 4.08 (s, 2 H, NCH2), 4.74 (d,
J = 17.5 Hz, 1 H, CH=CHaHb)), 5.00 (d, J = 9.9 Hz, 1 H,
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Synthesis of Heterocycle-Annulated Azocine Derivatives
989
(d, J = 9.9 Hz, 2 H, ArH), 7.42 (d, J = 8.4 Hz, 1 H, ArH), 7.54 (d,
J = 9.0 Hz, 1 H, ArH), 7.85 (d, J = 9.9 Hz, 1 H, C4-H of quinolone).
MS (EI, 70 eV): m/z = 426 [M+], 428 [M + 2]+.
13C NMR (100 MHz, CDCl3): d = 24.5, 44.8, 60.3, 115.5, 116.1,
117.6, 123.5, 125.8, 126.2, 127.6, 127.8, 128.4, 130.1, 134.9, 141.3,
142.8, 143.5, 145.6, 148.9, 161.0.
MS (EI, 70 eV): m/z = 303 [M+]
Anal. Calcd for C22H23BrN2O2: C, 61.83; H, 5.42; N, 6.56. Found:
C, 61.90; H, 5.36; N, 6.44.
Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C,
79.06; H, 5.64; N, 4.46.
Compounds 6a–f by Heck Reaction; General Procedure
A mixture of 5a (150 mg, 0.37 mmol), TBAB (145.9 mg, 0.45
mmol), fused KOAc (92.3 mg, 0.94 mmol), and Ph3P (19.7 mg, 20
mol%) was taken up in anhyd DMF (10 mL), and N2 was bubbled
through the mixture. Pd(OAc)2 (8.4 mg, 10 mol%) was added and
the reaction mixture was stirred at 90 °C for 6 h. The reaction mix-
ture was cooled, H2O (20 mL) was added, and the mixture was ex-
tracted with EtOAc (3 × 20 mL). The EtOAc extract was washed
with H2O (4 × 10 mL) and brine (10 mL) and dried (Na2SO4). The
solvent was distilled off to furnish a viscous mass, which was puri-
fied by column chromatography (silica gel, EtOAc–PE, 15:85) to
afford 6a. The other substrates 5b–f were similarly treated to give
the corresponding products 6b–f.
Compound 6d
Yield: 78%; solid; mp 135–136 °C.
IR (KBr): 2924, 2854, 1729 cm–1.
1H NMR (CDCl3, 300 MHz): d = 2.24 (s, 3 H, CH3), 3.03 (s, 3 H,
NCH3), 3.73 (s, 3 H, OCH3), 4.33 (s, 2 H, NCH2), 6.30 (d, J = 9.9
Hz, 1 H, C3-H of coumarin), 6.45 (s, 1 H, =CH), 6.72–6.77 (m, 2 H,
ArH), 6.99–7.06 (m, 3 H, ArH), 7.82 (d, J = 9.6 Hz, 1 H, C4-H of
coumarin).
13C NMR (100 MHz, CDCl3): d = 24.7, 44.9, 55.2, 60.4, 113.3,
115.3, 115.5, 116.1, 117.6, 123.1, 126.5, 126.9, 128.5, 135.2, 136.4,
141.3, 143.0, 145.6, 149.0, 158.7, 161.0.
MS (EI, 70 eV): m/z = 333 [M+]
Compound 6a
Anal. Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C,
75.59; H, 5.78; N, 4.09.
Yield: 79%; solid; mp 119–120 °C.
IR (KBr): 2924, 2850, 1726, 1567 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 (t, J = 7.0 Hz, 3 H,
NCH2CH3), 2.24 (s, 3 H, CH3), 3.34 (q, J = 7.1 Hz, 2 H, NCH2CH3),
4.33 (s, 2 H, NCH2), 6.28 (d, J = 9.8 Hz, 1 H, C3-H of coumarin),
6.44 (s, 1 H, =CH), 6.95 (d, J = 9.1 Hz, 1 H, ArH), 7.04 (d, J = 9.1
Hz, 1 H, ArH), 7.09–7.18 (m, 4 H, ArH), 7.79 (d, J = 9.7 Hz, 1 H,
C4-H of coumarin).
13C NMR (100 MHz, CDCl3): d = 13.1, 24.5, 51.6, 56.7, 115.3,
116.1, 117.6, 123.4, 125.7, 127.5, 127.6, 128.9, 129.6, 130.2, 135.1,
141.3, 142.8, 143.1, 144.6, 149.3, 161.1.
Compound 6e
Yield: 75%; gummy liquid.
IR (neat): 2924, 2853, 1649 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H, CH3), 3.04 (s, 3 H,
NCH3), 3.60 (s, 3 H, NCH3), 4.35 (s, 2 H, NCH2), 6.57 (s, 1
H, =CH), 6.61 (d, J = 9.6 Hz, 1 H, C3-H of quinolone), 7.07 (d,
J = 8.8 Hz, 1 H, ArH), 7.11–7.16 (m, 2 H, ArH), 7.23 (d, J = 6.8 Hz,
1 H, ArH), 7.46–7.49 (m, 1 H, ArH), 7.64–7.69 (m, 1 H, ArH), 7.80
(d, J = 10 Hz, 1 H, C4-H of quinolone).
13C NMR (100 MHz, CDCl3): d = 24.6, 29.4, 44.9, 60.5, 114.0,
119.7, 120.8, 124.5, 125.9, 126.2, 127.3, 127.6, 128.4, 129.3, 130.0,
135.1, 135.9, 142.6, 143.0, 143.9, 161.7.
ESI-HRMS: m/z calcd: 318.1489 [M + H]+; found: 318.1484 [M +
H]+.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C,
79.30; H, 6.09; N, 4.36.
MS (EI, 70 eV): m/z = 316 [M+]
Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C,
79.86; H, 6.34; N, 8.90.
Compound 6b
Yield: 77%; gummy liquid.
IR (neat): 2923, 2852, 1726 cm–1.
Compound 6f
Yield: 78%; gummy liquid.
IR (neat): 2931, 2851, 1654 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.39 (t, J = 7.5 Hz, 3 H,
NCH2CH3), 2.23 (s, 3 H, CH3), 3.33 (q, J = 6.9 Hz, 2 H, NCH2CH3),
3.74 (s, 3 H, OCH3), 4.31 (s, 2 H, NCH2), 6.29 (d, J = 9.6 Hz, 1 H,
C3-H of coumarin), 6.42 (s, 1 H, =CH), 6.73 (d, J = 6.3 Hz, 1 H,
ArH), 6.79 (s, 1 H, ArH), 6.96–7.08 (m, 3 H, ArH), 7.82 (d, J = 9.6
Hz, 1 H, C4-H of coumarin).
13C NMR (100 MHz, CDCl3): d = 12.9, 24.7, 51.8, 55.2, 56.9,
113.3, 115.3, 116.1, 117.6, 123.0, 126.8, 128.0, 129.1, 129.9, 135.2,
136.6, 141.3, 142.6, 144.5, 149.4, 158.7, 161.1.
1H NMR (CDCl3, 300 MHz): d = 2. 26 (s, 3 H, CH3), 3.03 (s, 3 H,
NCH3), 3.60 (s, 3 H, NCH3), 3.72 (s, 3 H, OCH3), 4.32 (s, 2 H,
NCH2), 6.54 (s, 1 H, =CH), 6.61 (d, J = 9.9 Hz, 1 H, C3-H of qui-
nolone), 6.71 (d, J = 8.1 Hz, 1 H, ArH), 6.77 (s, 1 H, ArH), 7.06 (t,
J = 9 Hz, 2 H, ArH), 7.16 (d, J = 9.3 Hz, 1 H, ArH), 7.81 (d, J = 9.6
Hz, 1 H, C4-H of quinolone).
13C NMR (100 MHz, CDCl3): d = 24.3, 29.2, 44.6, 55.2, 61.6,
114.0, 119.7, 120.6, 123.9, 125.9, 126.4, 127.0, 127.6, 128.6, 129.4,
130.0, 134.9, 136.3, 141.7, 143.9, 157.8, 161.7.
MS (EI, 70 eV): m/z = 347 [M+]
Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
75.91; H, 6.13; N, 3.99.
MS (EI, 70 eV): m/z = 346 [M+]
Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.24; H, 6.42; N, 8.05.
Compound 6c
Yield: 76%; gummy liquid.
IR (neat): 2925, 2854, 1742 cm–1.
1H NMR (CDCl3, 500 MHz): d = 2.27 (s, 3 H, CH3), 3.04 (s, 3 H, Acknowledgment
NCH3), 4.36 (s, 2 H, NCH2), 6.29 (d, J = 9.8 Hz, 1 H, C3-H of cou-
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. Three of us (R.K.N., S.S., and B.C.) are grateful
to the CSIR (New Delhi) for research fellowships.
marin), 6.49 (s, 1 H, =CH), 6.98–7.04 (m, 2 H, ArH), 7.12–7.19 (m,
2 H, ArH), 7.23 (d, J = 8.5 Hz, 1 H, ArH), 7.35 (d, J = 9.1 Hz, 1 H,
ArH), 7.81 (d, J = 9.8 Hz, 1 H, C4-H of coumarin).
Synthesis 2010, No. 6, 985–990 © Thieme Stuttgart · New York

990
K. C. Majumdar et al.
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Synthesis 2010, No. 6, 985–990 © Thieme Stuttgart · New York