Base-Catalyzed Tandem Cyclization: Diastereoselective Access to the 3,4-Dihydroisoquinolin-2(1 H)-one Core

Article abstract of DOI:10.1055/s-0037-1610999

A novel, one-pot reaction for the synthesis of 3,4-dihydroisoquinolin-2(1 H)-one derivatives is developed via a base-mediated three-component reaction of ninhydrin, aniline and acetylenic esters. This diastereoselective reaction takes place in methanol at 70A °C under transition-metal-free conditions, and direct construction of the C-N and C-C bonds is readily achieved via tandem cyclization. These cyclic frameworks are resourceful small molecular keys to many natural products.

Full text of DOI:10.1055/s-0037-1610999

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
Synthesis
P. K. Shirsat et al.
Paper
Base-Catalyzed Tandem Cyclization: Diastereoselective Access to
the 3,4-Dihydroisoquinolin-2(1H)-one Core
Prashishkumar K. Shirsata,b
Navnath B. Khomanea,b
Sneha H. Meshrama,b
Balasubramanian Sridharc
Harshadas M. Meshram*b
Ravindra M. Kumbhare*d
O
MeO2C OH
OH
O
O
NH2
E
E
E
E
CO2Me
CO2Me
Metal
∅
O +
+
N
HO
N
MeOH
O
(±)
E = CO2Me, CO2Et
18 Examples
Yield up to 83%
a
Academy of Scientific and Innovative Research (AcSIR), Gha-
ziabad, Uttar Pradesh 201002, India
Medicinal Chemistry and Biotechnology Division, CSIR-Indian
Institute of Chemical Technology, Tarnaka, Hyderabad
Potential intermediate
b
•
•
Tandem cyclization
Formation of C–N and C–C bonds
• Versatile methanolysis reaction
• One-pot synthesis
500007, India
hmmeshram@yahoo.com
Centre for X-ray Crystallography, CSIR-Indian Institute of
Chemical Technology, Tarnaka, Hyderabad 500007, India
Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
kumbhare@iict.res.in
c
d
Received: 01.08.2018
Accepted after revision: 05.09.2018
Published online: 14.11.2018
As a part of our research interest in pharmaceutically
important heterocyclic frameworks, we recently developed
a multicomponent methanolysis reaction for the synthesis
of N-heterocyclic compounds via tandem cyclizations. In
continuation of the same research program, we herein re-
port a base-mediated tandem reaction for the synthesis of
the 3,4-dihydroisoquinolin-2(1H)-one unit starting from
ninhydrin, aniline and acetylenic esters.
DOI: 10.1055/s-0037-1610999; Art ID: ss-2018-n0551-op
10
Abstract A novel, one-pot reaction for the synthesis of 3,4-dihydroiso-
quinolin-2(1H)-one derivatives is developed via a base-mediated three-
component reaction of ninhydrin, aniline and acetylenic esters. This di-
astereoselective reaction takes place in methanol at 70 °C under transi-
tion-metal-free conditions, and direct construction of the C–N and C–C
bonds is readily achieved via tandem cyclization. These cyclic frame-
works are resourceful small molecular keys to many natural products.
Over the past few decades, the tandem cyclization reac-
tion has become a very attractive and powerful tool for the
construction of N-heterocyclic compounds.11
Key words ninhydrin, anilines, 3,4-dihydroisoquinolin-2(1H)-ones,
methanolysis, tandem cyclization
OH
O
O
MeO
HO
Me
Me
HO
OH
OH
H
N
There has recently been a considerable increase in the
HN
O
O
OMe
H
O
development of new reactions for the formation of cyclic
amides and related N-heterocyclic alkaloids because of
their potential synthetic applications and pharmaceutical
value. The 3,4-dihydroisoquinolin-2(1H)-one unit is an im-
portant and pivotal N-heterocyclic building block that is
O
NH
O
thalifoline
thalflavine
OH
Me2NOC
OMe
pancratistin
O
O
MeO
HO
N
1
found in many naturally occurring compounds and biolog-
N
O
N
OMe
2
3
ically active frameworks. Examples include thalifoline,
OMe
4
5
6
pancratistin, thalflavine, a steroidomimetic drug and a H
3
a steroidomimetic drug
a H3 receptor antagonist
7
receptor antagonist (Figure 1). Moreover, compounds bear-
ing such units are well known for their antidepressant, anti-
hypertensive, antiulcer and analgesic activities. These me-
dicinally important compounds are also employed for HIV-1
integrase inhibition, schizophrenia, anxiety and cancer che-
Figure 1 Biologically active compounds containing a dihydroisoquino-
lin-2(1H)-one skeleton
We began our investigations of the tandem cyclization
by optimizing the conditions for the reaction of ninhydrin
(1) and aniline (2a) with dimethyl acetylenedicarboxylate
(DMAD) (3a). The cyclization was initially attempted in
MeOH in the presence of K CO at 70 °C (Table 1, entry 1),
8
motherapy.
Due to the wide spectrum of pharmacological activity
of these heterocyclic alkaloids, a simplified synthesis of the
3
,4-dihydroisoquinolin-2(1H)-one unit would offer signifi-
2
3
9
cant value.
and to our delight, the N-aryl-substituted dihydroisoquino-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
Synthesis
P. K. Shirsat et al.
Paper
lin-2(1H)-one 4a was furnished in 25% yield. We next inves-
tigated several bases and the details are summarized in Ta-
ble 1. Remarkably, the yield of 4a increased to 81% when
Table 1 Screening of the Reaction Conditionsa
MeO2C OH
O
CO2Me
CO2Me
the reaction was carried out in the presence of Et N (entry
MeOH, Et3N
NH2
3
O
+
+
CO Me
N
2
2). The reaction also worked with bases such as DBU, DAB-
Ph
70 °C, 8 h
Ph
CO2Me
CO, K CO , Na CO , NaHCO , pyridine, NaOH and KOH, but
O
2
3
2
3
3
O
the yields of the desired product 4a were much lower in all
cases (entries 3–9).
1
2a
3a
(
± ±)4a
Entry
Additive
Base (mol%)
K2CO3
Yield (%)b
Unfortunately, the reaction failed to give the desired
product 4a in the presence of ethanol and n-propanol (Ta-
ble 1, entries 10 and 11). This may be attributed to the low-
er nucleophilic character of these longer chain alcohols. The
tandem cyclization also failed in the presence of water (en-
try 12). Moreover, the desired product 4a was not obtained
when the reaction was carried with highly steric hindered
alcohols such as isopropanol and tert-butanol. These obser-
vations clearly indicated that only methanol was suitable
for this one-pot synthetic operation. Lowering the reaction
temperature also resulted in poorer yields of 4a. With the
aim of improving the process further, we investigated the
effects of various aprotic solvents (e.g., DMF, THF and CH-
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
25
81
56
50
48
35
43
49
38
–
3
Et N
DBU
DABCO
Na
2 3
CO
NaHCO
3
pyridine
NaOH
KOH
1
0
1
Et
Et
Et
3
3
3
N
N
N
1
n-PrOH
–
Cl ) with methanol as a reactant. However, no positive ef-
3
fect on the yield was detected, the product yields being low-
er than that previously achieved with methanol alone (Sup-
porting Information, Table 1, entries 13–21). Notably, it was
also found that the desired product 4a was not obtained in
EtOH in combination with MeOH (Supporting Information,
Table 1, entry 22).
After optimizing the reaction conditions, we next ex-
plored the substrate scope of the anilines 2 (Scheme 1). It is
noteworthy that the electronic properties of the substitu-
ent on the aromatic ring were shown to have little influence
on the efficiency of this reaction. Anilines bearing electron-
neutral (H), electron-donating (4-Me, 3,4-Me, 3,5-Me) and
12
H
2
O
–
a
Reaction conditions: 1 (1 mmol, 1.0 equiv), 2 (1 mmol, 1.0 equiv), 3 (1
mmol, 1.0 equiv), base (1.0 equiv), additive (5 mL), 70 °C, 8 h.
Yield of isolated product.
b
ates 3, see compound 7a Scheme 3). β-N-Substituted enam-
ino esters 5 containing electron-neutral (H), electron-do-
nating (4-Me) or weak electron-withdrawing (4-Br) substit-
uents on the benzene ring reacted smoothly to give the
corresponding dihydroindeno[1,2-b]pyrrole derivatives 6a–
c in excellent yields (Scheme 2). Notably, this reaction stops
with the formation of products 6, perhaps due to the elec-
tron-donating effect of the methyl group present at the α-
position of the β-N-substituted enamino esters 5.
To understand the reaction mechanism we carried out
series of control experiments (Scheme 3). Initially we em-
ployed the model substrates 2a and 3a in methanol, which
reacted to afford compound 7a in 72% yield (eq a). Next,
compound 7a was treated with ninhydrin (1) at room tem-
perature for 5 hours to afford the dihydroindeno[1,2-b]pyr-
electron-withdrawing (OCF , 4-F, 4-Br, 4-I and 3-F) groups
3
were transformed smoothly into the corresponding prod-
ucts 4a–i in good to excellent yields. Further, diethyl acetyl-
enedicarboxylate also reacted with the same anilines to
give the corresponding products 4j–r in excellent yields
(68–81%). The relative stereochemistry of bromide deriva-
tive 4c was determined by means of single-crystal X-ray
diffraction studies. White crystals of 4c were grown by
slow diffusion of hexane over a saturated methanol solu-
tion. The compound crystallized in the monoclinic crystal
system and P2 /c space group (Figure 2). The relative con-
1
figuration, pertinent bond lengths, bond angle data and the
atom numbering scheme are given in the Supporting Infor-
mation.
MeO2C OH
CO2Me
CO2Me
N
In order to investigate the scope and limitations of the
N-aryl-substituted isoquinolones, we extended our work by
employing β-N-substituted enamino esters as the sub-
strates instead of dimethyl 2-(phenylamino)maleates13 (i.e.,
the intermediates formed from anilines 2 and dicarboxyl-
O
Br
(
± ±)4c
12
Figure 2 The relative stereochemistry of 4c based on X-ray crystallog-
raphy (CCDC 1588852)
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
Synthesis
P. K. Shirsat et al.
Paper
O
NH2
E
MeO C OH
2
MeOH, Et3N
reflux, 8 h
E
E
O
+
+
N
E
X
O
O
X
1
2
3
(± ±)4
X = H, F, Br, I, Me
E = CO2Me
E
MeO2C OH
MeO2C OH
MeO2C
OH
E
E
E
E
E
N
N
N
O
O
O
F
Br
4c (81%±
4a (80%±
4b (73%±
MeO2C OH
MeO2C OH
MeO2C OH
E
E
E
E
E
E
N
F
N
N
O
O
O
I
Me
4d (74%±
4e (82%±
4f (73%±
MeO2C OH
MeO2C OH
MeO2C
OH
E
E
E
E
E
E
N
Me
N
Me
N
O
O
O
Me
OCF3
Me
4g (76%±
4h (75%±
4i (78%±
E = CO2Et
MeO2C
OH
MeO2C OH
MeO2C
OH
E
E
E
E
E
E
N
N
N
O
O
O
Br
F
4j (80%±
4k (68%±
4l (81%±
MeO2C OH
MeO C OH
MeO2C
OH
2
E
E
E
E
E
E
N
N
N
F
O
O
O
I
Me
4
o (74%±
4
m (68%±
4n (74%±
OH
MeO2C OH
MeO C OH
MeO2C
2
E
E
E
E
E
E
N
Me
Me
N
N
Me
O
O
O
OCF3
Me
4r (80%±
4p (75%±
4q (75%±
Scheme 1 Synthesis of dihydroisoquinolin-2(1H)-ones 4a–r; E = CO Me or CO Et
2
2
role 6d in 81% yield (eq b).14 Notably, under the standard re-
action conditions, the isolated product 6d gave the desired
dihydroisoquinolin-2(1H)-one 4a in 80% yield (eq d).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
Synthesis
P. K. Shirsat et al.
Paper
CO2Me
O
electron donating effect of the methyl substituent at posi-
tion C-3 in 5a (eq e), indicating that the ester group present
at C-2 in 7a participated in the cyclization reaction (eq d).
On the basis of the preliminary mechanistic experi-
ments and previous literature, a plausible mechanism is
proposed (Scheme 4). Firstly, aniline (2a) and dimethyl
acetylenedicarboxylate (3a) underwent an addition reac-
tion to give dimethyl 2-(phenylamino)maleate (7a), which
subsequently reacted with ninhydrin (1) to form intermedi-
ate A. Intermediate A then undergoes intramolecular cy-
OH
CO2Me
Me
O
HN
Me
MeOH, Et3N
reflux, 8 h
HO
N
O
O
X
1
5
6
X
X = H, Me, Br
O
O
O
OH
OH
15
OH
clization to give tricyclic intermediate B, subsequent pina-
CO2Me
Me
CO2Me
Me
CO2Me
col–pinacolone-type rearrangement of which gives inter-
mediate C. Finally, product 4a is obtained with excellent
diastereoselectivity via a methanolysis reaction (intramo-
lecular cyclization). The dihydroisoquinolin-2(1H)-ones
N
HO
N
Me
HO
N
HO
Me
4b–o are obtained in an analogous manner.
Br
6
c (88%±
6a (88%±
6b (90%±
MeOH
Ph NH
MeO2C
CO2Me
Ph NH2
+
MeO2C
CO2Me
Scheme 2 Synthesis of dihydroindeno[1,2-b]pyrroles 6a–c
2
h
3a
7
a
2a
O
O
O
OH
OH
CO2Me
2
CO Me
a
CO2Me
OMe
O
Ph NH
MeO2C
CO2Me
O
MeOH
CO2Me
Ph NH2
a
O
HN
Ph
HO
N
2
h
O
CO2Me
Ph
7a (72%±
2a
3a
1
A
B
O
OH
CO2Me
2
Ph NH
CO2Me
CH2Cl2
5 h, r.t.
b
c
O
1
2
HO
2
CO Me
OH
3
HO
N
MeO2C
CO Me
CO Me
2
CO2Me
CO2Me
MeOH
Ph
7a
6
d (81%±
N
O
N
OMe
Ph
Ph
O
5dd
HO
O
MeOH
OH
C
CO2Me
CO2Me
MeO2C OH
(± ±)4a
7
0 °C, 8 h
CO2Me
NEt3
Scheme 4 A plausible reaction mechanism
HO
N
CO2Me
d
3
h
N
Ph
Ph
6
d
4a (80%±
O
± ±
In conclusion, we have achieved a base-mediated multi-
component heterocyclic reaction for the synthesis of N-
aryl-substituted dihydroisoquinolin-2(1H)-one derivatives.
This protocol involves the formation of one C–C and one C–
N bond in a one-pot synthetic operation under transition-
metal-free conditions. The straightforward reaction condi-
tions and easily accessible starting materials make this pro-
tocol convenient and attractive. Further, extension of this
N-heterocyclic methodology to the synthesis of natural
products is underway in our laboratory.
(
O
MeOH, Et3N
70 °C, 8 h
OH
Ph NH
CO2Me
CO2Me
Me
1
e
3
2
Me
HO
N
Ph
6a (88%±
5a
Scheme 3 Mechanistic insights
However, the isolated product 6d, in the absence of tri-
ethylamine under the optimized reaction conditions, un-
derwent no changes, which indicated that the reaction is
base-mediated and that 6d would be the probable interme-
diate derived from 7a (eqs c and d). Further, as expected,
treating the model substrate 1 with 5a under the standard
reaction conditions did not lead to the formation of dihy-
droisoquinolin-2(1H)-one 4a, probably due to the weak-
All solvents and reagents were purchased from commercial sources,
unless otherwise noted. Commercial reagents were used as supplied
or purified by standard techniques wherever necessary. Column chro-
matography was performed using Merck 200–300 mesh silica gel
with the appropriate solvent system (determined by TLC analysis us-
ing I stain and UV light to visualize the reaction components). Melt-
2
ing points were determined on a WRS-1B digital melting point in-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
Synthesis
P. K. Shirsat et al.
Paper
1
strument. IR spectra were recorded on a Thermo Nicolet Nexus 670
FTIR spectrophotometer (KBr) and are reported in cm–1. NMR spectra
were recorded in CDCl3 on an Agilent 400, 500, and 125 MHz spec-
trometers at r.t., and resonances are reported relative to TMS. NMR
data are reported as follows: chemical shift, multiplicity (standard
abbreviations), coupling constant in hertz (Hz), integration. Chemical
H NMR (400 MHz, CDCl ): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.69 (d, J = 7.7
3
Hz, 1 H), 7.61–7.46 (m, 4 H), 7.31 (s, 1 H), 7.12 (s, 1 H), 5.25 (s, 1 H),
3.79 (s, 3 H), 3.66 (s, 3 H), 3.58 (d, J = 17.1 Hz, 1 H), 3.28 (s, 3 H), 2.93
(d, J = 17.1 Hz, 1 H).
13
C NMR (125 MHz, CDCl ): δ = 172.9, 169.9, 169.2, 164.8, 137.2,
3
1
7
36.6, 133.1, 132.9, 132.4, 131.9, 129.5, 128.7, 128.4, 124.2, 122.8,
8.2, 70.5, 53.7, 52.1, 36.8.
13
shifts for C NMR spectra are recorded in ppm from TMS using the
central peak of CDCl (77.0 ppm) as the internal standard. HRMS data
3
HRMS (ESI): m/z [M + H]+ calcd for C22H21BrNO : 506.037; found:
5
8
were recorded on an Orbitrap MS analyzer using ESI ionization with
06.043.
100000 (FWHM) maximum resolution.
Dimethyl4-Hydroxy-2-(4-iodophenyl)-3-(2-methoxy-2-oxoethyl)-
-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4d)
Compounds 4a–r; General Procedure
1
A mixture of ninhydrin (1) (1 mmol, 1.0 equiv), aniline 2 (1 mmol, 1.0
equiv) and dialkyl acetylenedicarboxylate 3 (1 mmol, 1.0 equiv) in
MeOH (5 mL) was heated at 70 °C in a round-bottom flask for 8 h (TLC
monitoring). After completion of the reaction, MeOH was removed
using a rotary evaporator. The residue was purified by column chro-
matography with hexane/EtOAc (9:1) to afford the pure product 4 as a
white solid.
Yield: 409 mg (74%); white solid; mp 175–177 °C; R = 1.8 (hex-
f
ane/EtOAc, 7:3).
IR (KBr): 3391, 2953, 1737, 1665, 1372, 1241, 1200 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.80–7.67 (m, 3
3
H), 7.58 (t, J = 8.3 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.18 (s, 1 H), 6.98 (s,
1
3
H), 5.25 (s, 1 H), 3.79 (s, 3 H), 3.66 (s, 3 H), 3.58 (d, J = 17.1 Hz, 1 H),
.29 (s, 3 H), 2.92 (d, J = 17.1 Hz, 1 H).
Dimethyl 4-Hydroxy-3-(2-methoxy-2-oxoethyl)-1-oxo-2-phenyl-
13
C NMR (100 MHz, CDCl ): δ = 173.0, 169.9, 169.2, 164.9, 138.4,
3
1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4a)
138.0, 137.3, 137.2, 133.3, 132.9, 132.6, 128.7, 128.4, 124.3, 94.6, 78.2,
Yield: 341 mg (80%); white solid; mp 203–205 °C; R = 1.8 (hex-
70.5, 53.8, 52.1, 37.1.
f
ane/EtOAc, 7:3).
IR (KBr): 3478, 3017, 2958, 1735, 1656, 1372, 1242, 1203 cm–1
HRMS (ESI): m/z [M + H]+ calcd for C22H21INO : 554.023; found:
454.030.
8
.
1
H NMR (500 MHz, CDCl ): δ = 8.08 (d, J = 6.6 Hz, 1 H), 7.69 (d, J = 7.7
3
Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.45–7.34 (m,
Dimethyl 4-Hydroxy-3-(2-methoxy-2-oxoethyl)-1-oxo-2-(p-tolyl)-
4
3
H), 7.17 (d, J = 6.7 Hz, 1 H), 5.33 (s, 1 H), 3.81 (s, 3 H), 3.66 (s, 3 H),
.58 (d, J = 17.1 Hz, 1 H), 3.23 (s, 3 H), 2.94 (d, J = 17.1 Hz, 1 H).
1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4e)
Yield: 361 mg (82%); white solid; mp 175–177 °C; R = 1.6 (hex-
f
13
C NMR (75 MHz, CDCl ): δ = 173.2, 170.1, 169.3, 165.1, 137.5, 137.4,
ane/EtOAc, 7:3).
3
1
5
32.6, 131.1, 130.6, 129.4, 129.1, 128.8, 128.7, 128.4, 124.1, 78.3, 70.5,
3.7, 51.9, 37.2.
IR (KBr): 3464, 3005, 2951, 1737, 1665, 1374, 1242, 1194 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 8.08 (dd, J = 7.7, 1.0 Hz, 1 H), 7.68 (dd,
3
HRMS (ESI): m/z [M + H]+ calcd for C22H22NO : 428.126; found:
8
J = 7.7, 0.7 Hz, 1 H), 7.56 (td, J = 7.6, 1.3 Hz, 1 H), 7.48 (td, J = 7.6, 1.2
Hz, 1 H), 7.27 (s, 1 H), 7.20 (d, J = 7.5 Hz, 2 H), 7.04 (d, J = 7.4 Hz, 1 H),
428.132.
5.35 (s, 1 H), 3.80 (s, 3 H), 3.65 (s, 3 H), 3.53 (d, J = 15.8 Hz, 1 H), 3.24
Dimethyl 2-(4-Fluorophenyl)-4-hydroxy-3-(2-methoxy-2-oxoeth-
yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4b)
(s, 3 H), 2.93 (d, J = 17.1 Hz, 1 H), 2.37 (s, 3 H).
13
C NMR (125 MHz, CDCl ): δ = 173.3, 170.1, 169.4, 165.2, 138.6,
3
Yield: 324 mg (73%); white solid; mp 184–186 °C; R = 1.7 (hex-
ane/EtOAc, 7:3).
137.4, 134.8, 132.6, 130.7, 130.3, 129.5, 129.3, 129.1, 128.4, 124.1,
78.3, 70.6, 53.7, 51.9, 37.2, 21.2.
f
IR (KBr): 3421, 3077, 2957, 1744, 1659, 1378, 1238, cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C23H24NO : 442.142.; found:
8
1
442.149.
H NMR (500 MHz, CDCl ): δ = 8.07 (dd, J = 7.7, 1.1 Hz, 1 H), 7.69 (dd,
3
J = 7.7, 0.8 Hz, 1 H), 7.58 (td, J = 7.6, 1.3 Hz, 1 H), 7.49 (td, J = 7.6, 1.2
Hz, 1 H), 7.42 (s, 1 H), 7.21 (s, 1 H), 7.15–7.03 (m, 2 H), 5.28 (s, 1 H),
Dimethyl 2-(3-Fluorophenyl)-4-hydroxy-3-(2-methoxy-2-oxoeth-
yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4f)
3.80 (s, 3 H), 3.66 (s, 3 H), 3.60 (d, J = 17.2 Hz, 1 H), 3.28 (s, 3 H), 2.94
(
1
d, J = 17.2 Hz, 1 H).
Yield: 324 mg (73%); white solid; mp 194–196 °C; R = 1.8 (hex-
ane/EtOAc, 7:3).
f
3
C NMR (125 MHz, CDCl ): δ = 173.2, 170.0, 169.2, 165.2, 163.6
3
3
1
1
61.1, 133.2 (d, J = 8.6 Hz), 132.6, 129.5, 128.8, 128.4, 124.2, 116.1,
15.8 (d, J = 22.5 Hz), 115.6, 78.2, 70.5, 53.7, 52.1, 37.1.
IR (KBr): 3309, 2952, 1743, 1654, 1384, 1226, 1004 cm–1
C–F
.
2
C–F
1
H NMR (500 MHz, CDCl ): δ = 8.07 (dd, J = 7.7, 1.1 Hz, 1 H), 7.70 (dd,
3
HRMS (ESI): m/z [M + H]+ calcd for C22H21FNO : 446.117; found:
4
8
J = 7.7, 0.7 Hz, 1 H), 7.59 (td, J = 7.6, 1.3 Hz, 1 H), 7.49 (td, J = 7.6, 1.2
Hz, 1 H), 7.39 (s, 1 H), 7.27–7.13 (m, 1 H), 7.13–7.07 (m,1 H), 7.02 (s, 1
H), 5.31 (s, 1 H), 3.81 (s, 3 H), 3.67 (s, 3 H), 3.59 (d, J = 17.0 Hz, 1 H),
3.30 (s, 3 H), 2.92 (s, 1 H).
46.122.
Dimethyl 2-(4-Bromophenyl)-4-hydroxy-3-(2-methoxy-2-oxoeth-
yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4c)
13
1
C NMR (125 MHz, CDCl ): δ = 172.9, 169.2, 169.2, 164.9, 162 (d, J
3
C–F
3
2
Yield: 409 mg (81%); white solid; mp 198–200 °C; R = 1.4 (hex-
ane/EtOAc, 7:3).
= 248 Hz), 139 (d, J = 9.5 Hz), 130 (d, J = 47.0 Hz), 128.6, 128.3,
127.1, 126.8 (d, J = 47.8 Hz), 124.3, 118.3, 118.2, 116, 115.8, 78.2,
f
C–F C–F
2
C–F
IR (KBr): 3454, 3000, 2951, 1767, 1677, 1369, 1238, 1227 cm–1
.
70.5, 53.8, 53.7. 52.1. 37.
HRMS (ESI): m/z [M + H]+ calcd for C22H21FNO : 446.117; found:
8
446.122.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
Synthesis
P. K. Shirsat et al.
Paper
1
Dimethyl 2-(3,4-Dimethylphenyl)-4-hydroxy-3-(2-methoxy-2-ox-
oethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate
H NMR (400 MHz, CDCl ): δ = 8.08 (d, J = 7.6 Hz, 1 H), 7.70 (d, J = 7.7
3
Hz, 1 H), 7.57 (t, J = 8.2 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.45–7.33 (m,
4 H), 7.18 (d, J = 7.2 Hz, 1 H), 5.43 (s, 1 H), 4.19–4.07 (m, 2 H), 3.81 (s,
(4g)
3
1
H), 3.76–3.68 (m, 1 H), 3.60–3.53 (m, 2 H), 2.94 (d, J = 17.3 Hz, 1 H),
.00–0.97 (m, 6 H).
Yield: 345 mg (76%); white solid; mp 184–186 °C; R = 1.6 (hex-
ane/EtOAc, 7:3).
f
13
IR (KBr): 3515, 2999, 2953, 1743, 1669, 1368, 1231, 1194, 1169 cm–1
.
C NMR (125 MHz, CDCl ): δ = 172.8, 169.6, 169.2, 165.2, 137.5,
3
1
6
32.5, 131.2, 130.7, 129.4, 129.1, 128.8, 128.6, 128.1, 124.2, 78.4, 70.2,
3.1, 61.1, 53.6, 37.2, 13.7, 13.4.
1
H NMR (400 MHz, CDCl ): δ = 8.10 (d, J = 7.5 Hz, 1 H), 7.69 (d, J = 7.5
3
Hz, 1 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.22–7.08 (m,
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO : 456.158; found:
2 H), 6.89 (d, J = 9.3 Hz, 1 H), 5.42 (d, J = 14.5 Hz, 1 H), 3.82 (s, 3 H),
3.67 (s, 3 H), 3.53 (d, J = 17.1 Hz, 1 H), 3.26 (d, J = 7.6 Hz, 3 H), 2.96–
2.90 (m, 1 H), 2.27 (d, J = 10.5 Hz, 6 H).
8
456.163.
1
3
3-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(4-fluorophenyl)-4-
hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate
C NMR (100 MHz, CDCl ): δ = 173.2, 170.2, 169.4, 165.1, 137.3,
3
1
7
34.9, 132.5, 130.3, 129.9, 128.3, 127.89, 127.82, 124.0, 78.3, 70.6,
0.5, 53.6, 51.8, 51.7, 37.3, 20.1, 19.9, 19.5, 19.4.
(4k)
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO : 456.158; found:
Yield: 321 mg (68%); white solid; mp 194–196 °C; R
ane/EtOAc, 7:3).
IR (KBr): 3356, 2990, 2938, 1748, 1651, 1385, 1235, 1181 cm–1
f
= 2.2 (hex-
8
456.163.
.
1
Dimethyl 2-(3,5-Dimethylphenyl)-4-hydroxy-3-(2-methoxy-2-ox-
oethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate
H NMR (400 MHz, CDCl ): δ = 8.07 (dd, J = 7.6, 1.2 Hz, 1 H), 7.70 (dd,
3
J = 7.7, 0.9 Hz, 1 H), 7.58 (td, J = 7.6, 1.4 Hz, 1 H), 7.48 (td, J = 7.5, 1.2
(4h)
Hz, 1 H), 7.43 (s, 1 H), 7.22 (s, 1 H), 7.15–7.01 (m, 2 H), 5.33 (s, 1 H),
4
.18–4.06 (m, 2 H), 3.79 (s, 3 H), 3.77–3.70 (m, 1 H), 3.63 (d, J = 17.2
Yield: 341 mg (75%); white solid; mp 202–104 °C; R = 1.5 (hex-
ane/EtOAc, 7:3).
f
Hz, 2 H), 2.95 (d, J = 17.3 Hz, 1 H), 1.04–0.94 (m, 6 H).
13
IR (KBr): 3455, 2995, 2951, 1743, 1656, 1374, 1229, 1196, 1166 cm–1
.
C NMR (125 MHz, CDCl ): δ = 172.8, 169.6, 169.1, 165.3, 162.4 (d,
3
1JC–F = 246.8 Hz), 137.5, 133.4, 133.3 (d, JC–F = 8.2 Hz), 131.5, 129.4,
3
1
H NMR (500 MHz, CDCl ): δ = 8.10–8.05 (m, 1 H), 7.68 (dd, J = 7.7, 0.8
3
2
129.1, 128.2, 124.3, 115.9 (d, JC–F = 22.6 Hz), 78.2, 70.3, 63.2, 61.2,
Hz, 1 H), 7.56 (td, J = 7.6, 1.4 Hz, 1 H), 7.48 (td, J = 7.6, 1.2 Hz, 1 H), 6.97
53.6, 37.1, 13.7, 13.4.
(d, J = 17.7 Hz, 2 H), 6.73 (s, 1 H), 5.42 (s, 1 H), 3.81 (s, 3 H), 3.65 (s, 3
HRMS (ESI): m/z [M + H]+ calcd for C24H25FNO : 474.148; found:
H), 3.51 (d, J = 17.1 Hz, 1 H), 3.28 (s, 3 H), 2.90 (d, J = 17.0 Hz, 1 H),
8
474.153.
2.32 (d, J = 15.8 Hz, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 173.2, 170.2, 169.4, 165.1, 138.8,
3
3
-Ethyl 4-Methyl 2-(4-Bromophenyl)-3-(2-ethoxy-2-oxoethyl)-4-
1
7
38.4, 137.3, 137.1, 132.6, 130.4, 129.3, 129.1, 128.3, 128.1, 124.1,
8.3, 70.5, 53.6, 51.9, 37.3, 21.4, 21.3.
hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate
4l)
(
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO : 456.158; found:
8
Yield: 431 mg (81%); white solid; mp 176–178 °C; R = 2.1 (hex-
ane/EtOAc, 7:3).
f
456.163.
IR (KBr): 3448, 2981, 2950, 1739, 1669, 1372, 1228, 1180 cm–1
.
Dimethyl 4-Hydroxy-3-(2-methoxy-2-oxoethyl)-1-oxo-2-[4-(tri-
fluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-3,4-dicar-
boxylate (4i)
1
H NMR (400 MHz, CDCl ): δ = 8.07 (d, J = 7.5 Hz, 1 H), 7.70 (d, J = 7.6
3
Hz, 1 H), 7.61–7.47 (m, 4 H), 7.31 (s, 1 H), 7.13 (s, 1 H), 5.35 (s, 1 H),
4
.18–4.08 (m, 2 H), 3.79 (s, 3 H), 3.77–3.73 (m, 1 H), 3.67–3.56 (m, 2
Yield: 398 mg (78%); white solid; mp 160–162 °C; R = 0.4 (hex-
ane/EtOAc, 6:4).
f
H), 2.94 (d, J = 17.3 Hz, 1 H), 1.05–0.95 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 172.7, 169.6, 169.1, 165.0, 137.4,
IR (KBr): 3444, 3008, 2956, 2854, 1750, 1732, 1668, 1374, 1254, 1200
3
–1
136.6, 133.2, 132.8, 132.3, 129.4, 129.1, 128.3, 124.3, 122.8, 78.2, 70.2,
3.3, 61.4, 53.7, 37.1, 13.8, 13.5.
HRMS (ESI): m/z [M + H]+ calcd for C24H25BrNO : 534.068.; found:
cm
.
6
1
H NMR (500 MHz, CDCl ): δ = 8.07 (dd, J = 7.7, 1.1 Hz, 1 H), 7.70 (dd,
3
J = 7.7, 0.8 Hz, 1 H), 7.59 (td, J = 7.6, 1.3 Hz, 1 H), 7.49 (td, J = 7.6, 1.2
Hz, 2 H), 7.28 (s, 2 H), 7.26 (s, 1 H), 5.23 (s, 1 H), 3.80 (s, 3 H), 3.67 (s, 3
H), 3.62 (d, J = 17.2 Hz, 1 H), 3.24 (s, 3 H), 2.95 (d, J = 17.2 Hz, 1 H).
8
5
34.074.
1
3
3-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-4-hydroxy-2-(4-io-
dophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxyl-
ate (4m)
C NMR (100 MHz, CDCl ): δ = 173.1, 169.2, 165.1, 149.0, 137.2,
3
1
1
36.0, 133.1, 133.9, 133.2, 132.9, 132.3, 129.5, 128.6, 128.4, 124.3,
21.4, 78.2, 70.4, 53.8, 51.9, 36.9.
+
Yield: 374 mg (68%); white solid; mp 178–180 °C; R = 1.8 (hex-
f
ane/EtOAc, 7:3).
HRMS (ESI): m/z [M + Na] calcd for C23H20F NO Na: 534.109; found:
3
9
534.115.
IR (KBr): 3494, 2980, 2939, 1741, 1672, 1369, 1237, 1185 cm–1
.
1
3-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-4-hydroxy-1-oxo-2-
H NMR (400 MHz, CDCl ): δ = 8.07 (d, J = 7.4 Hz, 1 H), 7.73 (dd, J =
3
phenyl-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4j)
27.0, 7.5 Hz, 3 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.19
(
2
2
H).
d, J = 6.9 Hz, 1 H), 6.99 (d, J = 7.0 Hz, 1 H), 5.35 (s, 1 H), 4.18–4.07 (m,
H), 3.79 (s, 3 H), 3.77–3.71 (m, 1 H), 3.61 (dd, J = 17.7, 7.4 Hz, 2 H),
.94 (d, J = 17.3 Hz, 1 H), 1.03 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.1 Hz, 3
Yield: 364 mg (80%); white solid; mp 219–221 °C; R = 2.2 (hex-
ane/EtOAc, 7:3).
f
IR (KBr): 3358, 3085, 2980, 2940, 1746, 1649, 1381, 1235 cm–1
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
Synthesis
P. K. Shirsat et al.
Paper
1
3
C NMR (125 MHz, CDCl ): δ = 172.6, 169.5, 169.1, 165.0, 138.4,
3-Ethyl 4-Methyl 2-(3,5-Dimethylphenyl)-3-(2-ethoxy-2-oxoeth-
yl)-4-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarbox-
ylate (4q)
3
1
6
38.0, 137.5, 133.4, 132.7, 129.4, 129.0, 128.2, 124.3, 94.6, 78.2, 70.2,
3.3, 61.4, 53.7, 37.1, 13.9, 13.5.
HRMS (ESI): m/z [M + H]+ calcd for C24H25INO : 582.054; found:
Yield: 362 mg (75%); white solid; mp 185–187 °C; R = 0.4 (hex-
f
8
582.060.
ane/EtOAc, 6:4).
IR (KBr): 3425, 2984, 2939, 1743, 1655, 1385, 1238, 1173, 1027 cm–1
.
3
-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-4-hydroxy-1-oxo-2-(p-
1
H NMR (400 MHz, CDCl ): δ = 8.07 (dd, J = 7.6, 1.2 Hz, 1 H), 7.69 (dd,
3
tolyl)-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate (4n)
J = 7.7, 0.9 Hz, 1 H), 7.56 (td, J = 7.6, 1.4 Hz, 1 H), 7.47 (td, J = 7.5, 1.2
Hz, 1 H), 6.99 (d, J = 7.0 Hz, 2 H), 6.74 (s, 1 H), 5.51 (s, 1 H), 4.13 (q, J =
7.1 Hz, 2 H), 3.80 (s, 3 H), 3.77–3.58 (m, 2 H), 3.53 (d, J = 17.1 Hz, 1 H),
2.92 (d, J = 17.1 Hz, 1 H), 2.31 (d, J = 20.4 Hz, 6 H), 0.99 (td, J = 7.1, 0.7
Hz, 6 H).
Yield: 347 mg (74%); white solid; mp 189–191 °C; R = 1.7 (hex-
ane/EtOAc, 7:3).
IR (KBr): 3371, 2982, 2949, 1741, 1672, 1373, 1232, 1178 cm–1
f
.
1
H NMR (500 MHz, CDCl ): δ = 8.07 (d, J = 7.5 Hz, 1 H), 7.69 (d, J = 7.6
3
13
C NMR (100 MHz, CDCl ): δ = 172.8, 169.7, 169.2, 165.1, 138.7,
Hz, 1 H), 7.56 (t, J = 7.1 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.29 (d, J = 7.6
Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 7.16 (d, J = 7.7 Hz, 1 H), 7.05 (d, J = 7.4
Hz, 1 H), 5.43 (s, 1 H), 4.17–4.06 (m, 2 H), 3.79 (s, 3 H), 3.76–3.68 (m, 1
H), 3.64–3.53 (m, 2 H), 2.94 (d, J = 17.2 Hz, 1 H), 2.36 (s, 3 H), 0.97 (q,
J = 7.1 Hz, 6 H).
3
1
6
38.3, 137.6, 137.2, 132.4, 130.3, 129.4, 129.2, 128.3, 128.2, 78.4, 70.2,
3.1, 61.0, 53.6, 37.3, 21.4, 21.2, 13.7, 13.5.
HRMS (ESI): m/z [M + H]+ calcd for C26H30NO : 484.189; found:
484.194.
8
13
C NMR (125 MHz, CDCl ): δ = 172.9, 169.6, 169.2, 165.2, 138.4,
3
1
6
37.5, 134.8, 132.4, 130.3, 129.7, 129.5, 129.2, 128.2, 124.1, 78.4, 70.3,
3.1, 61.1, 53.6, 37.3, 21.2, 13.7, 13.4.
3-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-4-hydroxy-1-oxo-2-[4-
(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-3,4-
dicarboxylate (4r)
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO : 470.173; found:
8
470.178.
Yield: 436 mg (80%); white solid; mp 123–125 °C; R = 0.5 (hex-
f
ane/EtOAc, 6:4).
3-Ethyl 4-Methyl 3-(2-Ethoxy-2-oxoethyl)-2-(3-fluorophenyl)-4-
IR (KBr): 3356, 2987, 2940, 1742, 1653, 1381, 1251, 1182, 1025 cm–1
.
hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarboxylate
4o)
1
H NMR (400 MHz, CDCl ): δ = 8.01 (d, J = 7.7 Hz, 1 H), 7.71 (t, J = 7.3
3
(
Hz, 3 H), 7.60 (td, J = 7.6, 1.2 Hz, 2 H), 7.54–7.40 (m, 2 H), 5.30 (s, 1 H),
4.16–4.10 (m, 2 H), 3.80 (s, 3 H), 3.78–3.73 (m, 1 H), 3.65 (d, J = 17.5
Hz, 1 H), 3.57–3.52 (m, 1 H), 2.96 (d, J = 17.5 Hz, 1 H), 0.99 (t, J = 7.1
Hz, 6 H).
Yield: 350 mg (74%); white solid; mp 183–185 °C; R = 2.2 (hex-
f
ane/EtOAc, 7:3).
IR (KBr): 3378, 2990, 2939, 1747, 1652, 1383, 1234, 1190 cm–1
.
13
1
C NMR (125 MHz, CDCl ): δ = 172.9, 169.5, 169.1, 165.2, 149.0,
H NMR (500 MHz, CDCl ): δ = 8.07 (d, J = 7.7 Hz, 1 H), 7.70 (d, J = 7.7
3
3
1
6
37.5, 133.2, 132.8, 132.3, 129.5, 129.0, 128.2, 124.3, 121.2, 79.2, 70.1,
3.3, 61.2, 53.7, 36.9, 13.5.
Hz, 1 H), 7.58 (td, J = 7.6, 1.2 Hz, 1 H), 7.49 (td, J = 7.6, 0.9 Hz, 1 H),
.39–7.30 (m, 1 H), 7.21 (s, 1 H), 7.10 (td, J = 8.3, 1.8 Hz, 1 H), 7.03 (s, 1
H), 5.42 (s, 1 H), 4.19–4.10 (m, 2 H), 3.80 (s, 3 H), 3.74 (s, 1 H), 3.69–
7
+
HRMS (ESI): m/z [M + Na] calcd for C25H24F NO Na: 562.140; found:
3
9
3.57 (m, 2 H), 2.93 (s, 1 H), 1.00 (t, J = 7.1 Hz, 6 H).
562.146.
1
3
C NMR (100 MHz, CDCl ): δ = 172.6, 169.5, 169.1, 163.7, 162.4 (d,
3
1JC–F = 246.8), 139.0 (d, JC–F = 9.1 Hz), 137.5, 132.8, 129.9 (d, JC–F
3
3
2
=
Compound 6a–c, general procedure
2
0.0 Hz), 129.4, 129.0, 128.2, 126.9 (d, JC–F = 40.0 Hz), 124.3, 118.5,
A mixture of ninhydrine (1) (1.0 equiv), compound 5 (1.0 equiv.) and
triethylamine (1.0 equiv.) were heated in MeOH (5ml) at 70 °C in a
round-bottom flask for 8 h (TLC monitoring). After completion of the
reaction, MeOH was removed using a rotary evaporator. The residue
was purified by column chromatography with hexane/EtOAc (9:1) to
afford the pure product 6 as solid compound.
1
15.8, 78.2, 70.2, 63.3, 61.2, 53.7, 37.1, 13.8, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C24H25FNO : 474.148; found:
8
474.153.
3
-Ethyl 4-Methyl 2-(3,4-Dimethylphenyl)-3-(2-ethoxy-2-oxoeth-
yl)-4-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3,4-dicarbox-
ylate (4p)
Methyl (3aS,8bS)-3a,8b-Dihydroxy-2-methyl-4-oxo-1-phenyl-
1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-3-carboxylate (6a)
Yield: 362 mg (75%); white solid; mp 192–194 °C; R = 1.8 (hex-
f
ane/EtOAc, 7:3).
Yield: 312 mg (88%); white solid; mp 175–177 °C; R = 0.6 (hex-
f
IR (KBr): 3377, 2984, 2940, 1745, 1653, 1392, 1237, 1184 cm–1
.
ane/EtOAc, 7:3).
IR (KBr): 3435, 3286, 2940, 1726, 1645, 1556, 1239, 1173 cm–1
1H NMR (400 MHz, CDCl
): δ = 7.88–7.55 (m, 1 H), 7.49–7.44 (m, 5 H),
.
1
H NMR (500 MHz, CDCl ): δ = 8.07 (d, J = 7.2 Hz, 1 H), 7.68 (d, J = 7.5
3
Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.19–7.09 (m,
3
2
H), 6.89 (d, J = 8.5 Hz, 1 H), 5.47 (d, J = 4.8 Hz, 1 H), 4.16–4.07 (m, 2
7.17–7.15 (m, 2 H), 6.76–6.73 (m, 1 H), 4.93 (s, 1 H), 4.57 (s, 1 H), 3.83
H), 3.80 (d, J = 7.6 Hz, 3 H), 3.75–3.67 (m, 1 H), 3.62–3.51 (m, 2 H),
(s, 3 H), 2.07 (s, 3 H).
2
.93 (t, J = 16.9 Hz, 1 H), 2.25 (t, J = 13.0 Hz, 6 H), 1.02–0.92 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 198.2, 166.4, 160.4, 147.6, 135.9,
3
13
C NMR (100 MHz, CDCl ): δ = 172.9, 169.7, 169.2, 165.2, 137.5,
135.2, 134.9, 130.1, 129.1, 128.5, 124.9, 124.4, 96.1, 94.5, 83.4, 50.9,
50.8, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C20H18NO : 352.110; found:
3
1
5
36.9, 135.0, 131.7, 129.5, 128.2, 127.8, 124.1, 78.4, 70.3, 63.1, 61.0,
3.5, 37.3, 20.0, 19.9, 19.5, 19.4, 13.6, 13.5.
5
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO : 484.189; found:
352.117.
8
484.194.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
Synthesis
P. K. Shirsat et al.
Paper
Methyl (3aS,8bS)-3a,8b-Dihydroxy-2-methyl-4-oxo-1-(p-tolyl)-
,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-3-carboxylate (6b)
Methyl (Z)-3-(p-Tolylamino)but-2-enoate (5b)13b
1
A mixture of methyl acetoacetate (1 mmol), p-toluidine (2b) (1 mmol)
Yield: 329 mg (90%); white solid; mp 160–162 °C; R = 0.5 (hex-
and Yb(OTf) (0.02 mmol) was stirred at ambient temperature for 9 h.
f
3
ane/EtOAc, 7:3).
IR (KBr): 3471, 3408, 2949, 1730, 1559, 1513, 1240, 1197 cm–1
After completion of the reaction, 1 M NaOH (2 mL) was added and the
resulting white precipitate was removed by filtration. The filtrate was
.
extracted with Et O (2 × 2 mL). The organic layers were dried
2
1
H NMR (400 MHz, CDCl ): δ = 7.86 (s, 1 H), 7.49 (d, J = 2.4 Hz, 2 H),
3
(
Na SO ), filtered and concentrated under reduced pressure. The resi-
2 4
7.27–7.21 (m, 2 H), 7.03 (d, J = 7.3 Hz, 2 H), 6.81 (s, 1 H), 4.91 (s, 1 H),
due was subjected to column chromatography to afford the desired
product.
4.56 (s, 1 H), 3.81 (s, 3 H), 2.44 (s, 3 H), 2.06 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 198.3, 166.5, 160.7, 147.7, 138.5,
3
Yield: 155 mg (76%); yellow liquid; R = 0.5 (pentane/EtOAc/Et N,
f
3
1
2
35.1, 134.9, 133.1, 130.0, 129.7, 125.1, 124.4, 95.7, 94.5, 83.5, 50.8,
1.2, 14.3.
97:2:1).
IR (KBr): 3258, 2946, 1657, 1609, 1227, 1164 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C21H20NO : 365.126; found:
5
1
H NMR (400 MHz, CDCl ): δ = 10.25 (s, 1 H), 7.12 (d, J = 8.1 Hz, 2 H),
365.132.
3
6.98 (d, J = 8.3 Hz, 2 H), 4.67 (s, 1 H), 3.68 (s, 3 H), 2.33 (s, 3 H), 1.95 (s,
3
H).
Methyl (3aS,8bS)-1-(4-Bromophenyl)-3a,8b-dihydroxy-2-methyl-
-oxo-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-3-carboxylate
6c)
4
(
Methyl (Z)-3-[(4-Bromophenyl)amino]but-2-enoate (5c)13b
A mixture of methyl acetoacetate (1 mmol), 4-bromoaniline (2c) (1
Yield: 377 mg (88%); white solid; mp 150–152 °C; R = 0.6 (hex-
ane/EtOAc, 7:3).
f
mmol) and Yb(OTf) (0.02 mmol) was stirred at ambient temperature
3
for 6 h. After completion of the reaction, 1 M NaOH (2 mL) was added
and the resulting white precipitate was removed by filtration. The fil-
IR (KBr): 3410, 2945, 1723, 1666, 1565, 1513, 1242, 1194 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 7.87–7.86 (m, 1 H), 7.59 (d, J = 8.8 Hz, 2
trate was extracted with Et O (2 × 2 mL). The organic layers were
3
2
H), 7.52–7.50 (m, 2 H), 7.06 (d, J = 8.5 Hz, 2 H), 6.80–6.78 (m, 1 H),
dried (Na SO ), filtered and concentrated under reduced pressure. The
2
4
4
.92 (s, 1 H), 4.58 (s, 1 H), 3.82 (s, 3 H), 2.07 (s, 3 H).
residue was subjected to column chromatography to afford the de-
sired product.
13
C NMR (125 MHz, CDCl ): δ = 197.9, 166.2, 159.7, 147.5, 135.4,
3
1
5
35.1, 134.9, 132.4, 131.6, 130.3, 124.7, 124.6, 122.5, 96.8, 94.4, 83.3,
0.9, 14.3.
Yield: 236 mg (88%); colorless liquid; R = 0.6 (hexane/EtOAc, 97:3).
f
IR (KBr): 2924, 2853, 1623, 1267, 1165, 798 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C20H17BrNO : 430.021; found:
5
1
H NMR (400 MHz, CDCl ): δ = 10.25 (s, 1 H), 7.37 (d, J = 8.7 Hz, 2 H),
3
430.027.
6.89 (d, J = 8.6 Hz, 2 H), 4.66 (s, 1 H), 3.61 (s, 3 H), 1.92 (s, 3 H).
Dimethyl 2-(Phenylamino)maleate (7a)13a
Dimethyl 3a,8b-Dihydroxy-4-oxo-1-phenyl-1,3a,4,8b-tetrahy-
droindeno[1,2-b]pyrrole-2,3-dicarboxylate (6d)
A mixture of aniline (2a) (1 mmol), dimethyl acetylenedicarboxylate
(
3a) (1 mmol) and MeOH (3 mL) in a dried round-bottom flask was
A mixture of aniline (2a) (1 mmol, 1.0 equiv), dimethyl acetylenedi-
carboxylate (3a) (1 mmol, 1.0 equiv) and ninhydrin (1) (1 mmol, 1.0
equiv) in CH Cl (5 mL) in a round-bottom flask was stirred for 5 h at
stirred at r.t. for 2 h. After completion of the reaction, the solution was
dried (Na SO ), filtered and concentrated under reduced pressure. The
2
4
2
2
residue was purified by flash chromatography (silica gel, pen-
r.t. until complete conversion of the substrates (TLC analysis). After
completion of the reaction, CH Cl was removed using a rotary evapo-
tane/EtOAc/Et N, 97:2:1).
3
2
2
Yield: 206 mg (72%); yellow viscous liquid; R = 0.6 (hexane/EtOAc,
rator. The residue was purified by column chromatography (hex-
f
9:1).
ane/EtOAc, 9:1) to afford the pure product 6d.
IR (KBr): 3281, 3033, 2952, 1740, 1617, 1597, 1279, 1216 cm–1
.
Yield: 320 mg (81%); white solid; mp 148–150 °C; R = 0.4 (hex-
f
1
ane/EtOAc, 7:3).
H NMR (400 MHz, CDCl ): δ = 9.67 (s, 1 H), 7.28 (t, J = 7.0 Hz, 2 H),
3
IR (KBr): 3460, 3286, 2950, 1728, 1571, 1441, 1221 cm–1
.
7.08 (t, J = 8.4 Hz, 1 H), 6.89 (d, J = 7.7 Hz, 2 H), 5.39 (s, 1 H), 3.73 (s, 3
H), 3.68 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 7.90 (d, J = 8.1 Hz, 1 H), 7.55–7.48 (m, 2
3
H), 7.41 (d, J = 7.1 Hz, 3 H), 7.30 (d, J = 5.3 Hz, 2 H), 6.77 (d, J = 7.3 Hz,
Methyl (Z)-3-(Phenylamino)but-2-enoate (5a)13c
1
H), 4.68 (s, 2 H), 3.79 (s, 3 H), 3.66 (s, 3 H).
A mixture of methyl acetoacetate (2 mmol), aniline (2a) (2 mmol) and
AcOH (0.2 mmol) was stirred at r.t. for 18 h. After completion of the
reaction, EtOH (5 mL) was added and the solution was dried (Na SO ),
13
C NMR (125 MHz, CDCl ): δ = 197.1, 164.2, 161.8, 151.3, 146.9,
3
135.9, 135.7, 135.1, 130.6, 129.2, 128.6, 128.4, 124.9, 124.7, 98.1, 95.6,
2
4
83.3, 53.1, 51.5.
filtered and concentrated under reduced pressure. The residue was
HRMS (ESI): m/z [M + Na]+ calcd for C21H17NO : 418.090; found:
7
purified by flash chromatography (silica gel, pentane/EtOAc/Et N,
3
418.090.
97:2:1).
Yield: 155 mg (82%); yellow liquid; R = 0.25 (pentane/EtOAc/Et N,
f
3
9
5:4:1).
Funding Information
IR (KBr): 3258, 2947, 1657, 1618, 1273, 1164 cm–1
.
1
The authors thank CSIR, New Delhi for financial support as part of the
H NMR (500 MHz, CDCl ): δ = 10.35 (s, 1 H), 7.32 (t, J = 7.9 Hz, 2 H),
.16 (s, 1 H), 7.09 (d, J = 7.5 Hz, 2 H), 4.70 (s, 1 H), 3.71 (s, 3 H), 2.01 (s,
3
XII five-year plan program under the title ACT ().
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
Synthesis
P. K. Shirsat et al.
Paper
Acknowledgment
(8) (a) Billamboz, M.; Bailly, F.; Lion, C.; Touati, N.; Vezin, H.;
Calmels, C.; Andreola, M.; Christ, F.; Debyser, Z.; Cotelle, P.
J. Med. Chem. 2011, 54, 1812. (b) Billamboz, M.; Suchaud, V.;
Bailly, F.; Lion, C.; Demeulemeester, J.; Calmels, C.; Andreola,
M.; Christ, F.; Debyser, Z.; Cotelle, P. ACS Med. Chem. 2013, 4,
P.K.S., N.B.K. and S.H.M. thank CSIR-UGC for their fellowship awards.
We are grateful to Dr. Amit B. Pawar (DST-INSPIRE Faculty, CSIRIICT)
for valuable suggestions.
606. (c) Tsou, H.; Otteng, M.; Tran, T.; Floyd, M. B.; Reich, M. Jr.;
Birnberg, G.; Kutterer, K.; Kaloustian, S. A.; Ravi, M.; Nilakantan,
R.; Grillo, M.; McGinnis, J. P.; Rabindran, S. K. J. Med. Chem.
Supporting Information
2
008, 51, 3507. (d) Komoda, M.; Kakuta, H.; Takahashi, H.;
Supporting information for this article is available online at
Fujimoto, Y.; Kadoya, S.; Kato, F.; Hashimoto, Y. Bioorg. Med.
Chem. 2001, 9, 121.
https://doi.org/10.1055/s-0037-1610999.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
(9) (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2
011, 133, 6449. (b) Xia, D.; Li, Y.; Miao, T.; Lia, P.; Wang, L.
References
Chem. Commun. 2016, 52, 11559. (c) Zhou, W.; Ni, S.; Mei, H.;
Han, J.; Pan, Y. Org. Lett. 2015, 17, 2724. (d) Yoon, H.; Petrone, D.
A.; Lautens, M. Org. Lett. 2014, 16, 6420. (e) Bai, P.; Huang, K. L.
Synthesis 2017, 49, 5357. (f) Tazawa, A.; Ando, J.; Ishizawa, K.;
Azumaya, I.; Hikawa, H.; Tanaka, M. RSC Adv. 2018, 8, 6146.
(
1) (a) Pettit, G. R.; Ducki, S.; Eastham, S. A.; Melody, N. J. Nat. Prod.
009, 72, 1279. (b) Jin, Z. Nat. Prod. Rep. 2013, 30, 849.
2
(
2) (a) Cappelli, A.; Pericot Mohr, G.; Giuliani, G.; Galeazzi, S.;
Anzini, M.; Mennuni, L.; Ferrari, F.; Makovec, F.; Kleinrath, E. M.;
Langer, T.; Valoti, M.; Giorgi, G.; Vomero, S. J. Med. Chem. 2006,
(
10) Shirsat, P. K.; Khomane, N. B.; Mali, P. R.; Reddy Maddi, R.;
Nanubolu, J. B.; Meshram, H. M. ChemistrySelect 2017, 2, 11218.
11) (a) Peng, S.; Liu, S.; Zhang, S.; Cao, S.; Sun, J. Org. Lett. 2015, 17,
49, 6451. (b) Khadka, D. B.; Yang, S. H.; Cho, S. H.; Zhao, C.; Cho,
(
W.-J. Tetrahedron 2012, 68, 250. (c) Matsui, T.; Sugiura, T.;
Nakai, H.; Iguchi, S.; Shigeoka, S.; Takada, H.; Odagaki, Y.; Nagao,
Y.; Ushio, Y. J. Med. Chem. 1992, 35, 3307.
5032. (b) Qiu, Y.-F.; Zhu, X.-Y.; Li, Y.-X.; He, Y.-T.; Yang, F.; Wang,
J.; Hua, H.-L.; Zheng, L.; Wang, L.-C.; Liu, X.-Y.; Liang, Y.-M. Org.
Lett. 2015, 17, 3694. (c) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Adv.
Synth. Catal. 2012, 354, 1873. (d) Yi, X.; Xi, C. Org. Lett. 2015, 17,
(3) (a) Thompson, R. C.; Kallmerten, J. J. Org. Chem. 1990, 55, 6076.
(b) Asano, Y.; Kitamura, S.; Ohra, T.; Itoh, F.; Kajino, M.; Tamura,
5836. (e) Li, J.; Huang, R.; Xing, Y.-K.; Qiu, G.; Tao, H.-Y.; Wang,
T.; Kaneko, M.; Ikeda, S.; Igata, H.; Kawamoto, T.; Sogabe, S.;
Matsumoto, S.; Tanaka, T.; Yamaguchi, M.; Kimura, H.;
Fukumoto, S. Bioorg. Med. Chem. 2008, 16, 4699. (c) Snow, R. J.;
Cardozo, M. G.; Morwick, T. M.; Busacca, C. A.; Dong, Y.; Echner,
R. J.; Jakes, S.; Kapadia, S.; Lukas, S.; Moss, N.; Panzenbeck, M.;
Peet, G. W.; Peterson, J. D.; Prokopowicz, A. P.; Sellati, R.;
Tschantz, M. A. J. Med. Chem. 2002, 45, 3394.
C.-J. J. Am. Chem. Soc. 2015, 137, 10124.
(
12) (a) Würtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F.
Angew. Chem. Int. Ed. 2008, 47, 7230. (b) Varala, R.; Nuvula, S.;
Adapa, S. R. Aust. J. Chem. 2006, 59, 921. (c) Jenner, G. Tetrahe-
dron Lett. 1996, 37, 3691.
13) (a) Sagar, A.; Vidaycharan, S.; Shinde, A. H.; Sharada, D. S. Org.
Biomol. Chem. 2016, 14, 4018. (b) Choudhary, G.; Peddinti, R. K.
Green Chem. 2011, 13, 3290. (c) Brandt, C. A.; da Silva, A. C. M. P.;
Pancote, C. G.; Brito, C. L.; da Silveira, M. A. B. Synthesis 2004,
(
(
4) (a) Krane, B. D.; Shamma, M. J. Nat. Prod. 1982, 45. (b) Chern, M.
S.; Li, W. R. Tetrahedron Lett. 2004, 45, 8323. (c) Xiang, Z.; Luo,
T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. Org. Lett.
1
557.
14) Yavari, I.; Seyfi, S.; Nematpour, M.; Hossaini, Z. Helv. Chim. Acta
010, 93, 1413.
2
004, 6, 3155.
5) Umarov, K. S.; Ismailov, Z. F.; Yunusov, S. Y. Chem. Nat. Compd.
973, 6, 452.
6) Leese, M. P.; Jourdan, F. L.; Major, M. R.; Dohle, W.; Thomas, M.
P.; Hamel, E.; Ferrandis, E.; Mahon, M. F.; Newman, S. P.;
Purohit, A.; Potter, B. V. L. ChemMedChem 2014, 9, 798.
(
(
(
(
2
1
15) (a) Sun, M.-Y.; Meng, X.-Y.; Zhao, F.-J.; Dang, Y.-J.; Jiang, F.; Liu,
K.; Wang, C.-S.; Jiang, B.; Tu, S.-J. Eur. J. Org. Chem. 2014, 3690.
(b) Muthusaravanan, S.; Sasikumar, C.; Bala, B. D.; Perumal, S.
Green Chem. 2014, 16, 1297. (c) Yavari, I.; Arab-Salmanabadi, S.;
Aminkhani, A. J. Iran Chem. Soc. 2012, 9, 503. (d) Alizadeh, A.;
Ghanbaripour, R.; Feizabadi, M.; Zhu, L.-G.; Dusek, M. RSC Adv.
(
7) Zhou, D.; Gross, J. L.; Adedoyin, A. B.; Aschmies, S. B.; Brennan,
J.; Bowlby, M.; Di, L.; Kubek, K.; Platt, B. J.; Wang, Z.; Zhang, G.;
Brandon, N.; Comery, T. A.; Robichaud, A. J. J. Med. Chem. 2012,
2015, 5, 80518.
55, 2452.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I