Domino Bischler–Napieralski – Michael Reaction and Oxidation – New Route to Coumarin-Pyrrole-Isoquinoline Fused Pentacycles

Article abstract of DOI:10.1002/ejoc.201801244

Lamellarin scaffold is synthesized by a metal free convergent route involving domino Bischler–Napieralski reaction – Michael reaction – oxidation sequence. Six lamellarin analogues were synthesised having substituent on aryl as well as coumarin ring A.

Full text of DOI:10.1002/ejoc.201801244

A Journal of
Accepted Article
Title: Domino Bischler-Napieralski - Michael reaction and oxidation, a
new route to Coumarin-Pyrrole-Isoquinoline fused pentacycles
Authors: Ketan S. Mandrekar, Hari K. Kadam, and Santosh Gajanan
Tilve
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801244
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European Journal of Organic Chemistry
10.1002/ejoc.201801244
FULL PAPER
Domino Bischler-Napieralski - Michael reaction and oxidation, a new route to
Coumarin-Pyrrole-Isoquinoline fused pentacycles
[
a]
[a]$
and Santosh G. Tilve*[a]
Ketan S. Mandrekar , Hari K. Kadam
Abstract: Lamellarin scaffold is synthesized by a metal free convergent route involving domino Bischler-Napieralski reaction –
Michael reaction – oxidation sequence. Six lamellarin analogues were synthesised having substituent on aryl as well as coumarin
ring A.
Introduction
Coumarin–pyrrole-isoquinoline fused pentacyclic systems
are of considerable interest to the synthetic organic chemist
1
and medicinal chemist. Lamellarins constitute a major part
2
of this class of compounds. Most of these contains the
same pentacyclic isoquinolinopyrrole-2-lactone core only
differing with substituents present on each ring (Figure 1).
Early 1980’s period has seen extensive research about the
3
isolations of marine natural products. Most of the lamellarins
were isolated during this period, and till date, more than 70
different lamellarins and related naturally occurring pyrrole-
derived alkaloids have been reported particularly from
marine sources with few instances of terrestrial sources.4
Figure1. Natural Lamellarins
The lamellarins and related pyrrole-derived alkaloids have
shown a diverse range of bioactivities, such as cytotoxicity
antitumor activity, reversal of multidrug resistance (MDR),
HIV-1 integrase inhibition, antibiotic activity, human aldose
reductase (h-ALR2) inhibition, cell division inhibition,
The Bischler-Napieralski reaction of the amide 4 could
provide the enamine 3. The amide 4 was to be obtained by a
Perkin reaction of the acid 5 with salicylaldehyde.
5
immunomodulation, antioxidant activity,
deterrence.
and feeding
The wide range of activities makes these compounds a
particularly important subject for research and have also
provoked
a
great deal of interest regarding their
synthesis.Various groups over the globe have accomplished
6
syntheses of lamellarins using diverse chemistry. Several
reviews about their isolations, syntheses, and biological
2
,7
properties are available in the literature. We herein report
a convergent route for the synthesis of lamellarin scaffold
using domino Bischler-Napieralski reaction
reaction - oxidation sequence.
-
Michael
Scheme 1 shows our retrosynthetic approach to the
lamellarin scaffold. The pentacyclic skeleton of 1 could be
obtained from oxidation of its corresponding dihydro
intermediate 2 which in turn can form after intramolecular
Michael reaction of enamine 3.
Scheme1. Retrosynthetic analysis for lamellarin scaffold
Results and Discussion
[
a] Ketan S. Mandrekar, Prof. Santosh G. Tilve
*
Department of Chemistry, Goa University, Taleigao Plateau, Goa-
403206, India. Tel: +91-832-6519384
Email: stilve@unigoa.ac.in, https://www.unigoa.ac.in/faculty/santosh-g-
tilve.html.
The required starting amide-acid 5a was prepared in a
straightforward
manner.
Commercially
available
homoveratryl amine on alkylation with ethyl bromoacetate
followed by treatment with homoveratric acid under
EDC/HOBt conditions provided amide ester 6a (Scheme 2).
The amide-ester 6a was then selectively and efficiently
Dr. Hari K. Kadam
$Present address: Department of Chemistry, St. Xavier’s College,
Mapusa, Goa - 403507, India.
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European Journal of Organic Chemistry
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10.1002/ejoc.201801244
hydrolyzed in the presence of Cs
2
CO
3
to obtain the
succeed to give the product in high quantity (Table 1, entry
3,4,6).
corresponding amide-acid 5a in 81% yield. Other bases like
CO were inefficient whereas LiOH resulted in the amide
K
2
3
Table 1: Optimisation of reaction conditions.
as well as ester hydrolysis. The product was obtained in
analytically pure form by mere acid-base treatment using 1N
HCl, thus avoiding the time consuming and uneconomic
column purification. The amide-acid 5a was then subjected
to Perkin reaction with salicylaldehyde in refluxing acetic
anhydride using triethyl amine as a base to get the amide-
coumarin 4a in 40% yield. Use of piperidine did not improve
the yield. So we thought of using hitherto unreported P
as an alternative to acetic anhydride for the coumarin ring
synthesis. The rational to choose P 10 was because it is a
4 10
O
4
O
well-known reagent for the preparation of anhydrides as well
as for the Bischler-Napieralski reaction which was the next
reaction in the planned synthesis. After optimizing the
4
reaction conditions, P O10 at 80 °C gave amide-coumarin 4a
in 76% yield. Use of T3P also gave similar yield after a
8
longer duration of time. Further to get the enamine
intermediate 3a via a Bischler-Napieralski reaction, the
reaction was heated at 110 °C overnight (Table 1, entry 1).
However, this gave a complex mixture. Hence, the amide-
coumarin 4a was reacted with POCl
3
in refluxing toluene
(
Table 1, entry 2). Interestingly, spectroscopic analysis of the
reaction product obtained after basic work-up and
chromatographic separation revealed the structure to be
lamellarin scaffold 1a. The spectral details were consistent
Entry
Reaction Conditions
1a (%Yield)
6
k,9
with the data available in the literature.
In this reaction, a
o
1
2
3
4
5
6
P
4
O
10, 110 C, 12 h
Complex Mixture
33%
domino Bischler-Napieralski reaction - Michael reaction -
oxidation sequence took place directly giving the final
product 1a in 32% yield. The reaction in refluxing 1,2-DCE
gave a complex mixture (Table 1, entry 5). Attempts to
improve the yield using different solvents, temperature and
POCl
10/POCl
TfOH, DCM, 0 C – r.t., 12 h
3
, Toluene, reflux, 12 h
P
4
O
3
, Xylene, reflux, 12 h
20%
o
Complex Mixture
Complex Mixture
Complex Mixture
POCl3, 1,2-DCE, reflux, 11h
Eatons’s reagent
4 3
reagents like P O10/POCl , TfOH and Eaton’s reagent did not
Scheme 2. Convergent route for lamellarin scaffolds.
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European Journal of Organic Chemistry
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10.1002/ejoc.201801244
Method A: Homoveratryl amine (3.62 g, 20 mmol) was dissolved in
dry THF ( 20 mL), and to it ethyl bromoacetate (1.67 g, 10 mmol)
was added and stirred at r.t. for 12 h. Resulting heterogeneous
mixture (secondary amine-ester and HBr salt of homoveratryl amine)
filtered through a Whatman filter paper. The filtrate evaporated to
get the secondary amine in 88 % (2.35 g) yield, which was as such
used for next reaction.
3
Though the yield of lamellarin scaffold using POCl in refluxing
toluene was 32% only, it involved three steps in the reaction viz.
Bischler-Napieralski reaction, Michael reaction, and oxidation.
Hence, this protocol was further extended to prepare more
derivatives with a different substituent on the lamellarin scaffold
(
scheme 2). However, this method failed to deliver lamellarin G
trimethyl ether 1f in our hands even after numerous attempts.
We could get the intermediate coumarin but the tandem
Bischler-Napieralski reaction – Michael reaction – oxidation
sequence gave a complex mixture. The failure of this reaction
may be due to the instability of lamellarin G trimethyl ether under
the reaction conditions.
Method B: Homoveratryl amine (2.71 g, 15 mmol) and Et
2
1
3
N (2.9 mL,
0 mmol) were mixed in DMSO (10 mL). Ethyl bromoacetate (2.50 g,
5 mmol) was added and stirred at r.t. for 12 h. Water was added
(50 mL), and the product extracted in Et O (3 X 20 mL). The organic
2
layer was washed with water, brine and dried over Na
solvent removed under vacuum, and the product obtained in 76 %
3.04 g) yield was as such used for the next reaction.
2 4
SO . The
(
Secondary amine prepared above (2.67 g, 10 mmol), substituted
phenyl acetic acid (12 mmol), HOBT ( 13 mmol) and DMAP (0.05 g)
were dissolved in dry CH Cl (20 mL) and cooled to 0 °C. EDC (3.10
2 2
g, 15 mmol) was added and stirred at 0 °C - r.t. for 24 h. The
suspension was cooled to 0 °C and filtered. The filtrate was
evaporated to dryness. Fresh CH
solution was cooled to 0 °C and filtered again. The evaporation,
addition of CH Cl , cooling, and filtering was repeated thrice. The
organic layer was washed with water, brine and dried over Na SO
The solvent removed under vacuum, and the crude product purified
by flash chromatography (CH Cl ) to give pure product 6.
2 2
Cl (20 mL) was added, and the
2
2
2
4
.
2
2
Ethyl 2-(N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-
acetamido)acetate 6a: Viscous oil. IR (neat): max 2936, 2835, 1746,
-
1 1
1
643, 1589, 1261 cm . H NMR (400 MHz, CDCl
3
): δ 1.19 (t, J = 7.2
Hz, 3 H), 2.61 [2.71] (t, J = 7.2 Hz, 2 H), 3.43 (s, 3 H), 3.46 [3.52] (m,
2
6
H), 3.77-3.79 (m, 12 H), 3.97 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H),
.53-6.57 (m, 1 H), 6.61-6.63 (m, 1 H), 6.65-6.69 (m, 1 H), 6.71-6.74
13
Scheme 3. A plausible mechanism for the tandem process
(m, 3 H) ppm. C NMR (100 MHz, CDCl
33.41] (CH ), 39.88 [40.66] (CH ), 47.92 [49.94] (CH
CH ), 55.73 (CH ), 55.80 (CH ), 55.83 (CH ), 55.87 (CH
61.59] (CH ), 111.15 (CH), 111.36 (CH), 111.81 (CH), 111.86 (CH),
3
): δ 14.12 (CH
), 51.23 [50.63]
), 61.10
3
), 34.55
[
(
[
2
2
2
2
3
3
3
3
A plausible mechanism for this tandem sequence involving
Bischler-Napieralski reaction – Michael reaction – oxidation is
depicted in scheme 3.
2
1
1
4
20.65 (2X CH), 120.74 (CH), 127.22 (Cq), 130.54 (Cq), 147.80 (Cq),
49.00 (2X Cq), 169.22 (Cq), 171.77 (Cq) ppm. LCMS (m/z): [M+H]
46. HRMS (m/z): calculated for C24
+
+
H31NO
7
Na [M+Na] 468.1998;
found 468.1998.
Conclusions
Ethyl
2-(N-(3,4-dimethoxyphenethyl)-2-(4-
methoxyphenyl)acetamido)acetate 6b: Viscous oil. IR (neat): max
-
1
1
In conclusion, lamellarin scaffold is synthesized by a metal-
free convergent route involving Perkin type reaction and tandem
Bischler-Napieralski reaction – Michael reaction – oxidation
sequence. Six derivatives of lamellarins were efficiently
prepared with different substituents on aryl as well as coumarin
ring in good overall yields. The method fails to provide
lamellarins with two methoxy groups on the A ring.
2936, 2835, 1746, 1643, 1589, 1261 cm . H NMR (400 MHz,
CDCl ): δ 1.28 (t, J=7.2 Hz, 3 H), 2.69 [2.79] (t, J = 7.2 Hz, 2 H),
.51 (s, 2 H), 3.57 [3.60] (m, 1 H), 3.78 (s, 3 H), 3.86 (s, 6 H), 4.04 (s,
3
3
1
6
H), 4.16-4.22 (m, 2 H), 6.60-6.63 (m, 1 H), 6.79 (d, J = 8.0 Hz, 1 H),
.84-6.87 (m, 3 H), 7.12 (d, J = 8.8 Hz, 2 H) ppm. C NMR (100
13
3 3 2
MHz, CDCl ): δ 14.16 (CH ), 34.66 [33.46] (CH ), 39.47 [40.16]
(CH ), 48.05 [49.09] (CH ), 51.30 [50.66] (CH ), 55.92 (CH ), 55.94
2
2
2
3
3 2
(CH ), 61.17 [61.64] (CH ), 111.94 (CH), 114.07 (2X CH), 120.76
(CH), 126.77 (Cq), 129.74 (2X CH), 130.54 (Cq), 131.48 (CH),
1
47.88 (Cq), 149.08 (Cq), 158.46 (Cq), 169.33 (Cq), 171.86 (Cq)
+
ppm. LCMS (m/z): + [M+H] 416. HRMS (m/z): calculated for
Experimental Section
C H29NO Na [M+Na] 438.1893; found 438.1894.
23 6
Ethyl 2-(N-(3,4-dimethoxyphenethyl)-2-phenylacetamido)acetate
c: Viscous oil. IR (neat): max 2936, 2835, 1746, 1640, 1589, 1260
General: Commercial reagents were purchased from Sigma–Aldrich
and used without further purification. Solvents were distilled before
use. Reactions were monitored by thin-layer chromatography (TLC
Silica gel 60 F254 purchased from Merck). Flash chromatography
was performed on CombiFlash companion instrument with silica gel
6
-
1
1
cm . H NMR (400 MHz, CDCl
3
): δ 1.25 (t, J= 7.6 Hz , 3H), 2.64
[
2.80] (t, J= 7.2 Hz , 2H), 3.52-3.61 (m, 2H), 3.63 (s, 2H), 3.79 (s,
1
H), 3.43 (s, 6H), 4.04 (s, 1H), 4.13 (m, 2H), 6.58- 6.80 (m, 3H),
13
1
13
7.20-7.24 (m, 3H), 7.25- 7.32 (m, 2H) ppm. C NMR (100 MHz,
(230–400 mesh). H NMR (400 MHz) and C NMR (100 MHz) were
CDCl
4
6
3
): δ 14.15 (CH
8.05 [49.85] (CH ), 51.35 [50.68] (CH
1.65 [61.63] (CH
3
), 34.60 [33.44] (CH
2
), 40.37 [41.06] (CH
), 55.86 (CH
2
),
),
recorded with a Bruker Avance 400 MHz instrument using CDCl as
3
2
), 51.34 (CH
3
3
solvent and TMS as an internal standard. HRMS were recorded with
MicroMass ESQTOF instrument and LCMS on Agilent Technology
instrument. IR spectra were recorded with a Shimadzu FTIR
instrument. Melting points are recorded with a Thiele apparatus and
are uncorrected.
2
2
), 111.54 (CH), 112.02 (CH), 120.71 (CH), 126.84
(CH), 128.67 (2XCH), 128.82 (2XCH), 130.53 (Cq), 131.50 (Cq),
1
34.84 (Cq), 147.97 (Cq), 149.17 (C q), 169.32 (Cq), 171.53 (Cq)
+
ppm. MS (m/z): calculated for C22
5
H27NO H [M+H] 386.1967 ; found
386.1978.
General procedure for preparation of amide ester (6a-c)
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European Journal of Organic Chemistry
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FULL PAPER
General procedure for hydrolysis of ester (6a-c) to acid (5a-c):
A mixture of amide-esters 6 (5 mmol), Cs
mL) in EtOH (10 mL) was stirred at r.t. for 12 h. The reaction mixture
then dried under vacuum, and to it, aqueous sat. Na CO (20 mL)
was added. The basic aqueous layer was washed with Et O (2 X 15
mL) and acidified with 1N HCl. The product was extracted in CH Cl
2 X 20 mL), dried over Na SO and concentrated under vacuum to
give analytically pure product 5.
2
CO
3
(7 mmol) and H
2
O (2
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-(7-
methoxy-2-oxo-2H-chromen-3-yl)acetamide 4b: Light brown oil.
2
3
IR (neat): 
max
3020, 2932, 1708, 1664, 1604, 1518, 1460, 1258,
-
1
1
2
1151 cm . H NMR (400 MHz, CDCl ): δ 2.28-2.94 (m, 2 H), 3.36-
3
2
2
3.55 (m, 2 H), 3.68-3.69 (m, 2 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 3.82 (s,
3 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 6.60-6.64 (m, 3 H), 6.69-6.75 (m, 3
(
2
4
13
H), 6.78-6.84 (m, 4 H) ppm. C NMR (100 MHz, CDCl ): δ 33.55
3
(
2 2 2 3 3
CH ), 42.67 (CH ), 47.43 (CH ), 55.49 (CH ), 55.75 (CH ), 55.77
2-(N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acet-
3 3 3
(CH ), 55.80 (CH ), 55.88 (CH ), 100.62 (CH), 108.65 (CH), 109.19
amido)acetic acid 5a: Light brown oil. IR (neat): max 3205, 3017,
(CH), 111.13 (Cq), 111.18 (Cq), 111.19 (Cq), 111.29 (CH), 111.67
(CH), 112.05 (Cq), 112.08 (Cq), 112.14 (Cq), 112.22 (CH), 119.87
(Cq), 120.95 (CH), 128.69 (CH), 133.85 (CH), 142.22 (CH), 147.81
-
1
1
2
935, 1732, 1662, 1608, 1514, 1458, 1261, 1155 cm . H NMR
CDCl , 400MHz): δ 2.60 [2.70] (t, J = 6.8 Hz, 2H), 3.42 (s, 2H), 3.48
m, 2H), 3.75 – 3.78 (m, 12H), 4.00 (s, 2H), 5.77 (br s, 1H), 6.52 –
(
(
3
(Cq), 148.85 (Cq), 149.24 (Cq), 161.26 (Cq), 169.33 (Cq) ppm.
13
+
6
.73 (m, 6H) ppm. C NMR (100 MHz, CDCl
), 39.85 [40.65] (CH ), 48.42 [50.00] (CH ), 51.60 [50.32] (CH
5.85 (CH ), 55.88 (CH ), 55.91 (CH ), 55.94 (CH ), 111.24 (CH),
11.48 (CH), 111.76 (CH), 111.97 (CH), 120.76 (2X CH), 126.82
3
): δ 34.50 [34.41]
LCMS (m/z): 534 [M+H] . HRMS (m/z): calculated for C30
8
H31NO Na
+
(
CH
2
2
2
2
),
[M+Na] 556.1947; found 556.1948.
5
1
3
3
3
3
N-(3,4-Dimethoxyphenethyl)-N-(7-methoxy-2-oxo-2H-chromen-3-
yl)-2-(4-methoxyphenyl)acetamide 4c: Light brown oil. IR (neat):
(
1
Cq), 130.27 (Cq), 147.94 (2X Cq), 149.12 (2X Cq), 172.56 (Cq),
+
-1 1
7
72.84 (Cq) ppm. HRMS (m/z): calculated for C22H27NO Na [M+Na]
max 3026, 2938, 1706, 1665, 1602, 1516, 1456, 1254, 1148 cm . H
440.1685; found 440.1681.
NMR (400 MHz, CDCl ): δ 2.72-2.88 (m, 2 H), 3.31-3.36 (m, 2 H),
3
3
.45-3.48 (m, 1 H), 3.69 (s, 3 H), 3.71 (s, 3 H), 3.75 (s, 3 H), 3.83 (s,
2
-(N-(3,4-Dimethoxyphenethyl)-2-(4-methoxyphenyl)acet-
3 H), 4.17-4.21 (m, 1 H), 6.58-6.69 (m, 6 H), 6.76-6.81 (m, 2 H), 6.91
13
amido)acetic acid 5b: Colourless oil. IR (neat): max 3200, 3007,
(d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8 Hz, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ 33.68 (CH ), 40.92 (CH ), 49.47 (CH ), 55.26 (CH ), 55.85
(CH ), 55.89 (CH ), 55.95 (CH ), 100.69 (CH), 111.15 (CH), 111.70
(Cq), 112.15 (CH) 113.31 (Cq), 113.92 (Cq), 120.948 (2X CH),
125.36 (Cq), 127.03 (Cq), 129.17(CH), 129.98 (CH) 131.28 (Cq),
142.01 (2X CH), 147.52 (CH), 148.91 (Cq), 155.46 (CH), 158.46
(Cq), 159.26 (Cq) 163.40 (Cq), 171.47 (Cq) ppm. LCMS (m/z): 504
-
1 1
2
935, 1731, 1666, 1606, 1518, 1462, 1263, 1151 cm . H NMR (400
MHz, CDCl ): δ 2.66 [2.77] (t, J = 7.2 Hz, 2 H), 3.50 (s, 2 H), 3.54-
.54 [3.59] (m, 2 H), 3.74 (s, 3 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 4.07 (s,
H), 6.59-6.66 (m, 2 H), 6.78 (s, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 7.07
3
2
2
2
3
3
3
3
3
3
2
13
(
d, J = 8.4 Hz, 2 H), 8.48 (br s, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ 34.47 [33.55] (CH ), 39.28 [40.03] (CH ), 48.37 [49.89]
), 51.59 [50.31] (CH ), 55.24 (CH ), 55.92 (CH ), 55.94 (CH ),
11.50 (CH), 111.98 (CH), 114.12 (2X CH), 120.78 (CH), 126.36
3
2
2
+
+
(CH
2
2
3
3
3
[M+H] . HRMS (m/z): calculated for
526.1842; found 526.1842.
29 7
C H29NO Na [M+Na]
1
(Cq), 129.80 (2X CH), 130.32 (Cq), 147.90 (Cq), 149.09 (Cq),
1
58.51 (Cq), 172.52 (Cq), 173.03 (Cq) ppm. HRMS (m/z): calculated
N-(3,4-dimethoxyphenethyl)-N-(2-oxo-2H-chromen-3-yl)-2-
phenylacetamide 4d: Light brown oil. IR (neat): max 3024, 2930,
+
6
for C21H25NO Na [M+Na] 410.1580; found 410.1578.
-
1 1
1
708, 1662, 1600, 1509, 1459, 1255, 1147 cm . H NMR (400 MHz,
2
5
1
2
3
-(N-(3,4-dimethoxyphenethyl)-2-phenylacetamido)acetic
c: Colourless oil. IR (neat): max 3219, 3010, 2939, 1725, 1672,
3
611, 1520, 1459, 1269, 1149 cm . H NMR (400 MHz, CDCl ): δ
.65 [2.79] (t, J= 6.8 Hz , 2H), 3.54 (s, 2H), 3.63 (s, 1H), 3.77 (s, 1H),
.83 (s, 3H), 3.85 (s, 3H), 4,07 (s, 2H), 6.59-6.66 (m, 2H), 6.79 (d,
acid
CDCl ): δ 2.73-2.85 (m,2H), 3.33-3.36 (m, 2H), 3.51-3.55 (m, 1H),
3
3.67 (s, 3H), 3.71 (s 3H), 4.21 (m, 1H), 6.55-6.61 (m, 2H), 6.67 (s,
1H), 6.96 (s, 1H), 7.11 (s, 3H), 7.19-7.26 (m, 3H), 7.46-7.50 (m, 1H)
-
1
1
13
ppm. C NMR (100 MHz, CDCl
3 2 2
): δ 33.71 (CH ), 41.91 (CH ), 49.47
(CH ), 55.85 (CH ), 55.89 (CH ), 111.23 (CH), 112.19 (CH), 116.67
2
3
3
13
J= 8 Hz, 1H), 7.15-7.32 (m, 5H) ppm. C NMR (100 MHz, CDCl
4.52 [33.41] (CH ), 40.24 [41.02] (CH ), 48.58 [49.89] (CH ), 51.74
50.31] (CH ), 55.93 (CH ), 55.97 (CH ), 111.50 (CH), 111.95 (CH),
20. 73 (CH), 126.99 (CH), 128.66 (2XCH), 128.80 (2XCH), 129.398
3
): δ
(Cq), 118.25 (CH), 120.98 (Cq), 125.01 (Cq), 126.90 (2X CH),
128.27 (Cq), 128.56 (Cq), 128.66 (CH), 128.92 (CH), 131.12 (CH),
132.47 (CH), 134.87 (Cq), 141.89 (2XCH), 147.58 (CH), 148.94 (Cq),
3
[
1
2
2
2
2
3
3
153.08 (CH), 158.92
C H25NO H [M+H] 444.1811 HRMS (m/z): 444.1819.
27 5
(
Cq), 170.97 (Cq) ppm. LCMS (m/z):
+
(Cq), 134.374 (Cq), 147.96 (Cq), 149.13 (Cq), 172.70 (Cq), 173.00
+
5
(Cq) ppm. MS (m/z): calculated for C20H23NO H [M+H] 358.1654;
+
found 358.1666. [M+Na] : 526.1842; found 526.1844.
N-(3,4-dimethoxyphenethyl)-N-(6-methoxy-2-oxo-2H-chromen-3-
yl)-2-phenylacetamide 4e: Light brown oil. IR (neat): max 3024,
-
1 1
General procedure for Perkin reaction: A mixture of amide-acids 5
2930, 1708, 1662, 1600, 1509, 1459, 1255, 1147 cm . H NMR (400
(
2 mmol), salicylaldehyde (4 mmol) and P
neat at 80 °C for 2 h. To the reaction flask ice cold water (30 mL)
was added and then extracted with CH Cl (4 X 10 mL). The organic
layer was dried over Na SO and concentrated under vacuum and
4
O
10 (3 eq) were heated
MHz, CDCl ): δ 2.83-2.94 (m, 2H), 3.45- 3.49 (m, 2H), 3.61-3.65 (m,
1H), 3.77 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.29 (broad singlet, 1H),
3
2
2
6.60 (s, 1H), 6.65-6.71 (m, 4H), 7.07 (s, 2H), 7.12-7.15 (m, 1H), 7.22
13
2
4
(m, 3H), 7.27-7.29 (m, 2H) ppm. C NMR (100 MHz, CDCl ): δ
3
directly purified by flash column chromatography using Ethyl
Acetate: Hexane (60:40) to afford the pure product 4.
33.73 (CH ),41.92 (CH ), 49.50 (CH ), 55.86 (2XCH ), 55.90 (CH ),
2
2
2
3
3
110.02 (CH), 111.26 (CH), 112.25 (CH), 117.74 (2XCH), 118.66
CH), 120.17 (Cq), 120.97 (CH), 126.88 (CH), 128.56 (2XCH),
(
N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-(2-oxo-
128.94 (2XCH), 131.22 (Cq), 134.91 (Cq), 141.65 (Cq), 147.55 (Cq),
2
H-chromen-3-yl)-acetamide 4a: Light brown oil. IR (neat): max
147.64 (Cq), 149.02 (Cq), 156.41 (Cq), 158.92 (Cq), 170.90 (Cq)
-
1
1
+
3
017, 2935, 1710, 1662, 1608, 1514, 1458, 1261, 1155 cm .
): δ 2.75-2.85 (m, 2 H), 3.35-3.50 (m, 2 H),
.59 (s, 2 H), 3.69 (s, 3 H), 3.72 (s, 6 H), 3.74 (s, 3 H), 6.49 (buried
m, 2 H), 6.56-6.63 (m, 4 H), 6.69 (buried m, 1 H), 7.14 (d, J = 7.2 Hz,
H
ppm. LCMS (m/z): C28
H
27NO
6
H [M+H] 474.1917 HRMS (m/z):
NMR (400 MHz, CDCl
3
474.1927.
3
N-(6,7-dimethoxy-2-oxo-2H-chromen-3-yl)-N-(3,4-
1
8
H), 7.21 (t, J = 8.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.50 (t, J =
dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide
4f:
13
.0 Hz, 1 H) ppm. C NMR & DEPT (100 MHz, CDCl
3
): δ 33.69
), 55.83 (CH ), 55.86
), 111.15 (CH), 111.19 (CH), 112.02 (CH), 112.16
Light brown oil. IR (neat):  3028, 2926, 1707 1665, 1611, 1509,
max
-
1
1
(
(
(
CH
CH
2
), 41.58 (CH
), 55.88 (CH
2
), 49.45 (CH
2
), 55.65 (CH
3
3
1461, 1257, 1149 cm . H NMR (400 MHz, CDCl ): δ 2.74-2.91 (m,
3
3
3
2H), 3.30- 3.42 (m, 2H), 3.49-3.53 (m, 1H), 3.65 (s, 3H), 3.71 (s, 3H),
3.76 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 4.16-4.23 (m,
1H), 6.48-6.53 (m, 3H), 6.57-6.61 (m, 2H), 6.63-6.65 (m, 3H), 6.80 (s,
CH), 116.68 (CH), 118.30 (Cq), 120.95 (2X CH), 124.99 (CH),
1
1
1
27.28 (Cq), 128.17 (CH), 128.43 (Cq), 131.10 (Cq), 132.41 (CH),
41.74 (CH), 147.59 (Cq), 147.90 (Cq), 148.93 (Cq), 153.07 (Cq),
58.84 (Cq), 171.13 (Cq) ppm. HRMS (m/z): calculated for
13
1H) ppm. C NMR (100 MHz, CDCl ): δ 33.69 (CH ), 41.55 (CH ),
3
2
2
2 3 3 3 3
49.52 (CH ), 55.72 (CH ), 55.86 (CH ), 55.88 (CH ), 55.91 (CH ),
56.38 (CH ), 56.55 (CH ), 99.73 (CH), 107.82 (CH), 110.68 (Cq),
3 3
+
C
29
H
29NO
7
Na [M+Na] 526.1842; found 526.1844.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801244
FULL PAPER
1
1
1
1
11.14 (CH), 111.20 (CH), 112.13 (CH), 112.22 (CH), 120.98 (CH),
21.03 (CH), 125.66 (Cq), 127.60 (Cq), 131.33 (Cq), 142.17 (CH),
46.82 (CH), 147.59 (Cq), 147.88 (Cq), 148.92 (Cq), 148.98 (Cq),
147.36 (Cq), 148.85 (Cq), 152.56 (Cq), 155.48 (Cq), 159.14 (Cq),
+
159.48 (Cq) ppm. MS (m/z): calculated for C29
H
25NO
6
[M] 483.1682;
found 483.1685.
49.28 (Cq), 153.43 (Cq), 159.30 (Cq), 171.28 (Cq) ppm. LCMS
+
(m/z): C28
H27NO
6
H [M+H] 563.2155 HRMS (m/z): 563.2158.
Lamellarin 1d: Brown solid; m.p: 239-241 °C. IR (KBr): max 3019,
-1 1
3
1701, 1523, 1480, 1321, 1214 cm . H NMR (400 MHz, CDCl ): δ
N-(3,4-dimethoxyphenethyl)-N-(7-isopropoxy-2-oxo-2H-
chromen-3-yl)-2-(4-methoxyphenyl)acetamide 4g: Light brown oil.
3.041 (t, J= 6.8 Hz , 2H), 3.206 (s, 3H), 3.816 (s, 3H), 4.745 (t, J =
7.2 Hz , 2H), 6.418 (s, 1H), 6.684 (s, 1H), 6.880 (m, 1H), 7.083 (m,
13
IR (neat): max 3028, 2941, 1711, 1663, 1596, 1516, 1455, 1259,
1H), 7.298 (m, 1H), 7.431 (m, 5H) ppm. C NMR (100 MHz, CDCl
δ 28.72 (CH ), 42.51 (CH ), 55.02 (CH ), 55.92 (CH ), 108.70 (CH),
110.92 (CH), 114.63 (Cq), 116.09 (Cq), 117.16 (CH), 118.30 (Cq),
3
):
1142 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.33 (s, 3H),
2
2
3
3
2.70-2.90 (m, 2 H), 3.32-3.37 (m, 2 H), 3.44-3.48 (m, 1 H), 3.69 (s, 3
H), 3.71 (s, 3 H), 3.75 (s, 3 H), 4.15-4.53 (m, 1H), 4.54-4.59 (m, 1 H), 119.93 (CH), 123.31 (2XCH), 123.72 (Cq), 126.60 (CH), 127.28 (Cq),
6.57-6.62 (m, 3 H), 6.64-6.70 (m 3H), 6.74-6.6.79 (m, 2 H), 6.91 (d,
128.16 (2XCH), 129.49 (2XCH), 131.12 (Cq), 135.72 (Cq), 136.01
J = 8.4 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ 21.77 (CH3), 33.67 (CH2), 40.86 (CH2), 49.45 (CH2),
(Cq), 147.43 (Cq), 148.92 (Cq), 151.28 (Cq), 155.31 (Cq) ppm. MS
+
4
(m/z): calculated for C27H21NO H [M+H] 424.1549; found 424.1558.
55.25 (CH3), 55.84 (CH3), 55.88 (CH3), 70.97 (CH), 101.97 (CH),
111.14 (CH), 111.34 (Cq), 112.14 (CH) 113.90 (CH), 114.42 (CH),
120.94 (2X CH), 125.06 (Cq), 127.06 (Cq), 129.20(CH), 129.99 (CH)
131.29 (Cq), 142.08 (2X CH), 147.50 (CH), 148.89 (Cq), 155.12
.
Lamellarin 1e: Brown solid; m.p.; 229-232°C IR (KBr): max 3015,
1712, 1515, 1469, 1329, 1215 cm . H NMR (400 MHz, CDCl ): δ
3.045 (t, J = 6.4 Hz , 2H), 3.213 (s, 3H), 3.349 (s, 3H), 3.820 (s, 3H),
-
1
1
3
(CH), 158.44 (Cq), 159.37 (Cq) 161.86 (Cq), 171.48 (Cq) ppm.
4.748 (t, J = 7.2 Hz, 2H), 6.492 (s, 1H), 6.537 (d, 1H), 6.689 (s, 1H),
LCMS (m/z): 504 [M+H]+. HRMS (m/z): calculated for
C31H34NO7Na [M+H]+ 532.2335; found 532.2322.
6.752 (m, 1H), 7.205 (s, 1H), 7.420 (s, 1H), 7.453 (m, 3H), 7.488 (m,
13
1H) ppm. C NMR (100 MHz, CDCl ): δ 28.68 (CH ), 41.47 (CH ),
3
2
2
3 3
53.99 (CH ), 54.90 (CH ), 104.70 (CH), 107.65 (2XCH), 109.92 (Cq),
1
13.79 (CH), 114.10 (Cq), 114.90 (2XCq), 116.98 (2XCH), 117.53
General procedure for POCl
coumarins 4 (1 mmol), freshly distilled POCl
10 mL) was refluxed at 120 °C for 12 h. The reaction mixture was
cautiously poured over ice, basified with Na CO and extracted in
CH Cl (3 X 30 mL). The crude product was purified by flash column
3
cyclisation: A solution of amide-
(CH), 118.916 (CH), 125.545 (Cq), 127.17 (2XCH), 128.37 (2XCq),
130.22 (Cq), 134.72 (Cq), 144.60 (Cq), 146.43 (Cq), 147.90 (Cq),
154.40 (Cq) ppm. MS (m/z): calculated for C H NO H [M+H]
3
(3 mL) and, toluene
+
(
28
23
5
2
3
454.1654; found 454.1669.
2
2
chromatography using CH
product 1.
2
Cl
2
: MeOH (100:1) to afford the pure
Lamellarin 1g: Yellow solid; m.p.; 242-246. IR (KBr): max 3019,
1707, 1531, 1478, 1338, 1244 cm-1. 1H NMR (400 MHz, CDCl3):
δ1.25(s, 3H), 1.27 (s, 3H), 3.04 (t, J = 6.8 Hz, 2H), 3.27 (s, 3H), 3.82
(s, 3H), 3.84 (s, 3H), 4.41-4.50 (septet, 1H), 4.72 (d, J= 6.8 Hz, 2H),
6.48-6.50 (m, 2H), 6.68 (s, 1H), 6.81 (s, 1H), 7.00 (m, 3H), 7.34 (d, J
= 8.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.91 (CH3),
28.75 (CH2), 42.39 (CH2), 55.10 (CH3), 55.46 (CH3), 55.92 (CH3),
70.29 (CH), 103.38 (CH), 108.69 (CH), 110.91 (CH), 111.36 (Cq),
112.87 (CH), 113.39 (Cq), 114.84 (2X CH), 114.96 (Cq), 120.15 (Cq),
123.99 (CH), 126.63 (Cq), 127.64 (Cq), 128.20 (Cq), 132.25 (2X CH),
136.24 (Cq), 147.36 (Cq), 148.33 (Cq), 152.58 (Cq), 155.55 (Cq),
157.48 (Cq), 159.46 (Cq) ppm. MS (m/z): calculated for C31H30NO6
[M+H]+ 512.2073; found 512.2077.
Lamellarin 1a: Brown solid; m.p.: 242-244 °C [lit.: m.p.: 244-
6k
-1 1
2
45 °C] IR (KBr): max 3025, 1700, 1525, 1480, 1430, 1345 cm . H
NMR (400 MHz, CDCl ): δ 3.05 (t, J = 6.8 Hz, 2 H), 3.29 (s, 3 H),
.78 (s, 3 H), 3.82 (s, 3 H), 3.91 (s, 3 H), 4.72-4.77 (m, 2 H), 6.57 (s,
H), 6.68 (s, 1 H), 6.93-6.95 (m, 2 H), 7.00 (s, 2 H), 7.16 (d, J = 8.0
3
3
1
13
Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H) ppm.
NMR & DEPT (100MHz, CDCl
C
3
): δ 27.67 (CH
2 2
), 41.48 (CH ), 54.17
(
(
(
(
(
(
CH ), 54.90 (CH ), 55.07 (CH ), 107.66 (CH), 109.91 (CH), 110.94
3 3 3
CH), 112.68 (CH), 113.45 (Cq), 114.80 (Cq), 116.12 (CH), 117.28
Cq), 118.97 (Cq), 122.26 (CH), 122.36 (CH), 122.76 (CH), 125.59
Cq), 126.34 (CH), 126.51 (Cq), 126.79 (Cq), 135.10 (Cq), 146.43
Cq), 147.88 (Cq), 147.95 (Cq), 148.77 (Cq), 150.25 (Cq), 154.28
Cq) ppm. HRMS (m/z): calculated for
06.1580; found 506.1580.
+
29 6
C H25NO Na [M+Na]
5
Acknowledgments
Lamellarin 1b: Brown solid; m.p.: 248-250 °C. IR (KBr): max 3021,
-
1
1
1
3
3
3
706, 1531, 1480, 1427, 1250 cm . H NMR (400 MHz, CDCl ): δ
We gratefully acknowledge Department of Science and
Technology (DST) EMR/2016/00091, New Delhi for financial
support. We thank IISc, Bangalore and Syngenta Bioscience,
Goa for HRMS analysis.
.04 (t, J = 6.8 Hz, 2 H), 3.28 (s, 3 H), 3.74 (s, 3 H), 3.77 (s, 3 H),
.82 (s, 3 H), 3.91 (s, 3 H), 4.69-4.74 (m, 2 H), 6.55 (d, J = 8.8 Hz, 1
H), 6.57 (s, 1 H), 6.68 (s, 1 H), 6.83 (s, 1 H), 6.92 (s, 1 H), 6.98 (s, 1
1
3
H), 7.03 (d, J = 8.8 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ
), 55.90 (CH ),
), 101.49 (CH), 108.67 (Cq), 110.93 (CH), 111.41 (Cq),
2
5
1
1
1
1
8.67 (CH
6.07 (2X CH
2
), 42.37 (CH
3
2
), 55.17 (CH
3
), 55.48 (CH
3
3
Keywords: Lamellarin, domino reaction, Pyrrole, Bischler-
Napieralski reaction, Oxidation.
11.44 (CH), 111.94 (CH), 113.30 (Cq), 113.76 (CH), 115.09 (Cq),
20.01 (Cq), 123.32 (CH), 124.07 (CH), 126.62 (Cq), 127.86 (Cq),
28.09 (Cq), 136.18 (Cq), 147.39 (Cq), 148.83 (Cq), 148.91 (Cq),
1
.
K. Tangdenpaisal; R. Worayuthakarn; S. Karnkla; P.
Ploypradith; P. Intachote; S. Sengsai; B. Saimanee; S.
Ruchirawat; M. Chittchang, Chem. Asian J. 2015, 10, 925.
H. Fan; J. Peng; M. T. Hamann; J. F. Hu, Chem. Rev. 2008, 108,
49.74 (Cq), 152.53 (Cq), 155.41 (Cq), 159.16 (Cq) ppm. HRMS
+
(m/z): calculated for
C
30
H27NO
7
Na [M+Na] 536.1685; found
536.1687.
2
.
2
64.
Lamellarin 1c: Brown solid; m.p.: 234-236 °C. IR (KBr): max 3022,
-
1
1
3. (a) T. F. Molinski; D. S. Dalisay; S. L. Lievens; J. P. Saludes,
Nature Reviews Drug Discovery, 2009, 8, 69. (b) J. W. Blunt; B.
R. Copp; R. A. Keyzers; M. H. G. Munro; M. R. Prinsep, Nat.
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Keyzers; M. H. G. Munro; M. R. Prinsep, Nat. Prod. Rep. 2013,
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3
3
3
702, 1528, 1480, 1339, 1244 cm . H NMR (400 MHz, CDCl ): δ
.11 (t, J = 6.8 Hz, 2 H), 3.34 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H),
.90 (s, 3 H), 4.77-4.80 (m, 2 H), 6.57 (s, 1 H), 6.59 (d, J = 8.8 Hz, 1
H), 6.74 (s, 1 H), 6.90 (s, 1 H), 7.07-7.11 (m, 1 H), 7.39 (d, J = 8.8
13
Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3 2
): δ 28.73 (CH ), 42.39
3
0, 237.
(
(
(
CH
2
), 55.10 (CH
3
), 55.46 (CH
3
), 55.50 (CH ), 55.91 (CH ), 101.51
3
3
4
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Cq), 111.63 (Cq), 114.85 (2X CH), 120.10 (Cq), 124.02 (CH),
126.63 (Cq), 127.58 (Cq), 128.13 (Cq), 132.24 (2X CH), 136.29 (Cq),
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201801244
FULL PAPER
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FULL PAPER
Synthetic Methodology
Ketan S. Mandrekar , Hari K. Kadam[a]$,
[a]
and Santosh G. Tilve*[a]
Domino Bischler-Napieralski - Michael
reaction and oxidation, a new route to
Coumarin-Pyrrole-Isoquinoline
pentacycles
fused
The pentacyclic lamellarin core divides into four units, which can be connected through N- alkylation, EDC-coupling, and
domino Bischler-Napieralski – Michael- Oxidation reaction sequences. This concise synthesis of lamellarin scaffolds makes
its oneness among other routes to be highlighted in the big sphere of lamellarin chemistry.
This article is protected by copyright. All rights reserved.