Synthesis of novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives through the application of rongalite: A synergistic combination of [2+2+2]- and [4+2]-cycloaddition reactions

Article abstract of DOI:10.1055/s-2007-965946

An efficient route for the synthesis of several novel 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives has been reported. A synergistic combination of [2+2+2]- and [4+2]-cycloaddition reactions has been used for the synthesis of the des

Full text of DOI:10.1055/s-2007-965946

PAPER
1015
Synthesis of Novel 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid
Derivatives through the Application of Rongalite: A Synergistic Combination
of [2+2+2]- and [4+2]-Cycloaddition Reactions
Synthesis of
N
a
ovel 1, 2,3,
m
4-Tetrahydroisoquin
b
oline-3-carb
a
oxylic
A
cid
s
D
erivativ
i
es varao Kotha,* Shaibal Banerjee
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, 400 076, India
Fax +91(22)5723480; E-mail: srk@chem.iitb.ac.in
Received 5 January 2007; revised 27 January 2007
ethanolamine N-methyltransferase.8 Similarly, the
Abstract: An efficient route for the synthesis of several novel
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives
has been reported. A synergistic combination of [2+2+2]- and
[4+2]-cycloaddition reactions has been used for the synthesis of the
desired targets.
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid unit has
also been incorporated in farnesyl transferase inhibitor 3
and its analogues (Figure 2) as a replacement for phenyl-
alanine.9 Moexipril (2), an ACE inhibitor, contains
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as a core
structural unit (Figure 2).10 In view of the various applica-
tions of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
derivatives, a need remains for new synthetic strategies.
Some of the common methods for the preparation of
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and its
derivatives are: Pictet–Spengler reaction, Bischler–
Napieralski reaction, or by alkylation strategies.11 These
methods, however, employ a preformed benzene ring de-
rivative as a starting material and they provide limited op-
portunities for the introduction of diverse functional
groups in the benzene ring.
Key words: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Ron-
galite, cycloaddition, amino acids, quinones
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (1, Tic;
Figure 1) is a constrained analogue of phenylalanine
(Phe).1 The main advantage of constrained amino acids
and their derivatives is their stability towards enzymatic
degradation.2 Incorporation of constrained amino acid
moieties in a peptide chain can modify the physiological
as well as the binding properties of the resulting peptide.3
In 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the
six-membered heterocyclic ring is formed by incorpora-
tion of a methylene unit between the amino group and the
aromatic ring of phenylalanine. Since the nitrogen atom in
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is pro-
tected, this type of amino acid can play an important role
in the design of peptidomimetics.4 It was found that the in-
sertion of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid in the second position of an opioid receptor exerts
conformational restrictions and results in drastic changes
in its intrinsic activity.5 The tetrahydroisoquinoline unit
has been extensively used in peptide-based drugs and, in
several instances, it appears to play a crucial role in the de-
sign of various lead molecules.6
In view of our interest in developing new methodologies
for 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid–
quinone hybrids12 via a ‘building block approach’,13 we
sought a general and useful approach based on [2+2+2]
cycloaddition14 and Diels–Alder reactions as key steps.15
The strategy based on cycloaddition reactions has a
unique advantage over existing methods as diverse sub-
stituents can be introduced in the aromatic ring by judi-
cious selection of the reacting partners. Although there are
several methods available for the construction of tetrahy-
droisoquinoline units, these strategies cannot easily be ex-
tended to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid derivatives.
Given the synthetic challenge of developing new strate-
gies to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
derivatives, cycloaddition approaches provide a unique
advantage in terms of diversification.16 Unlike other
routes, this approach is well suited to the generation of an-
nulated benzene derivatives and it can also be used to gen-
erate a library of compounds by varying the reacting
partners. The retrosynthetic analysis for 1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic acid based on cycloaddition
reactions is shown in Scheme 1.
COOH
NH
1
Figure 1
Recently, Lipkowski and co-workers have reported that
6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid (6HTc) can simulate tyrosine conformation in an opi-
oid ligand receptor complex.7 The tetrahydroisoquinoline
unit is also a critical component of inhibitors of phenyl-
In view of our earlier experience in generating o-xylylene
intermediates under mild reaction conditions, we envis-
aged that a novel sultine building block 7 would be useful
for the synthesis of 1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic acid based amino acid derivatives.17 We preferred
sultine 7 as a latent diene intermediate over the other pos-
SYNTHESIS 2007, No. 7, pp 1015–1020
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965946; Art ID: Z00407SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7

1016
S. Kotha, S. Banerjee
PAPER
MeO
MeO
CO2H
O
SMe
OH
Ph
O
N
H2N
HS
N
N
H
NH
O
2
N
H
CO2Et
O
O
3
moexipril
farnesyl transeferase inhibitor
O
O
O
O
H
H
N
N
R
N
N
H
H
N
O
O
O
O
R = OtBu, OH
4
macrocyclic pentapeptide
Figure 2 Biologically relevant compounds containing the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety
sible precursors such as benzocyclobutene derivatives be- um bromide in anhydrous N,N-dimethylformamide to
cause sultine derivatives can be transformed into a highly give the sultine derivative 7 as a mixture of diastereomers.
reactive o-xylylene intermediate 6 under milder condi- Since the stereochemistry of the sultine is of no conse-
tions by chelotropic elimination of sulfur dioxide.18 The quence in the generation of the o-xylylene intermediate 6,
transient diene 6 thus generated under thermal conditions it was not necessary to separate the isomers. Moreover,
is well suited to the Diels–Alder strategy. Herein, we re- TLC behavior indicated that the mixtures of isomers
port the realization of the proposed strategy (Scheme 1) would be inseparable by column chromatography. Having
for the preparation of various 1,2,3,4-tetrahydroisoquino- the sultine derivative in hand, its Diels–Alder chemistry
line-3-carboxylic acid based amino acid derivatives.
with various quinone-based dienophiles was undertaken.
The sultine derivative was heated at 85–90 °C in the pres-
ence of excess dienophiles 12–16 to give the Diels–Alder
adducts. The Diels–Alder adducts were slightly contami-
nated with the aromatized product and therefore no at-
tempts were made to isolate the Diels–Alder adducts.
Aromatization of the Diels–Alder adducts was achieved
using activated manganese dioxide to furnish the 1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid derivatives 17–
21 (Table 1).
The required diol building block 8 was prepared by fol-
lowing literature procedure starting from the alkyne build-
ing block 11, which in turn can be obtained from
benzophenone imine.19 The diol 8 was treated with phos-
phorus tribromide in anhydrous chloroform to generate
the corresponding dibromo derivative 9 in 83% yield. The
formation of 9 was confirmed by the disappearance of
protons attached to the hydroxy group at d = 3.76 and the
appearance of the CH2Br protons at d = 4.58 in the high-
field 1H NMR spectrum. Next, the dibromo derivative was The aromatized products 17–21 were characterized based
treated with Rongalite (sodium hydroxymethanesulfinate, on their spectral data, such as H and 13C NMR and
1
CH3NaO3S·2 H2O) in the presence of tetrabutylammoni- HRMS. The mild reaction conditions employed and the
O
CO2Et
CO2Et
NTs
O
CO2Et
NTs
S
NTs
O
O
5
7
6
CO2Et
NTs
CO2Et
NTs
X
X
TsHN
CO2Et
11
10
8 X = OH
9 X = Br
Scheme 1 Retrosynthetic analysis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives
Synthesis 2007, No. 7, 1015–1020 © Thieme Stuttgart · New York

PAPER
Novel 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid Derivatives
1017
CO2Et
CO2Et
(Ph3P)3RhCl
HC
C
CH2Br
HO
HO
NTs
but-2-yne-1,4-diol
NTs
(96%)
K2CO3, MeCN
TsHN
CO2Et
8
(53%)
10
11
PBr3, CHCl3
r.t.
O
CO2Et
NTs
(69%)
CO2Et
NTs
O
S
Rongalite, TBAB
DMF
Br
Br
+
O
7
O
(83%)
9
1. toluene, ∆
2. MnO2, dioxane
O
CO2Et
Ts
N
O
5
Scheme 2 Synthetic approach to highly functionalized 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives
atom economy process involved make this route attractive We have developed a short and an efficient route for the
for the preparation of several previously inaccessible un- synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
usual amino acid derivatives embodying the 1,2,3,4-tet- acid–quinone hybrids. We found that a combination of
rahydroisoquinoline-3-carboxylic acid moiety.
[2+2+2]- and [4+2]-cycloaddition reactions is extremely
Table 1 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid Derivatives Prepared by Diels–Alder Reaction/Aromatizationa
Entry
Dienophile
Aromatized product
Yieldb (%)
O
O
CO2Et
NTs
1
12
13
14
17
18
19
71
O
O
O
O
Me
CO2Et
NTs
Me
2
3
72
77
Me
Me
O
O
O
O
CO2Et
NTs
O
O
O
O
CO2Et
NTs
4
5
15
16
20
21
82
70
O
O
CO2Me
MeO2C
CO2Et
NTs
MeO2C
CO2Me
a Diels–Alder reaction was carried out in toluene at reflux.
b Isolated overall yield after Diels–Alder and aromatization step.
Synthesis 2007, No. 7, 1015–1020 © Thieme Stuttgart · New York

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S. Kotha, S. Banerjee
PAPER
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.41 (s, 3 H, Ar–CH3), 3.18 (d, J = 4.2 Hz, 2 H,
CHCH2), 3.51 (1/2 ABq, J = 15.3 Hz, 1 H), 3.93–3.99 (m, 2 H,
OCH2CH3), 4.28 (1/2 ABq, J = 15.3 Hz, 1 H), 4.50 (1/2 ABq,
J = 15.9 Hz, 1 H), 4.70 (1/2 ABq, J = 15.6 Hz, 1 H), 4.89 (1/2 ABq,
J = 13.8 Hz, 1 H), 5.01 (t, J = 3.2 Hz, 1 H, CHCH2), 5.21 (1/2 ABq,
J = 13.8 Hz, 1 H), 6.93 (d, J = 8.1 Hz, 2 H, ArH), 7.29 (d, J = 8.1
Hz, 2 H, ArH), 7.71 (s, 1 H, ArH), 7.73 (s, 1 H, ArH).
useful for the generation of polycyclic molecules in an ef-
ficient and atom-economic manner. Since enantiomerical-
ly pure building blocks related to 11 are commercially
available, the methodology can easily be adopted for the
preparation of optically active 1,2,3,4-tetrahydroisoquin-
oline-3-carboxylic acid derivatives. We anticipate that the
introduction of a variety of quinone moieties in 1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid will have im-
pact in medicinal chemistry and also for the design of new
peptidomimetics.
HRMS (Q-TOF): m/z [M + H]+ calcd for C21H24NO6S2: 450.1045;
found: 450.1054.
Ethyl 7,10-Dioxo-2-tosyl-1,2,3,4,7,10-hexahydronaphtho[2,3-
g]isoquinoline-3-carboxylate (17); Typical Procedure
All reactions were monitored by TLC carried out on glass plates
coated with silica gel GF 254 (containing 13% calcium sulfate as a
binder, Acme). Visualization of the spots on TLC plates was
achieved either by exposure to I2 vapor or UV light. Flash chroma-
tography was performed using silica gel (100–200 mesh, Acme).
Petroleum ether (PE) has bp 60–80 °C. All the commercial grade re-
agents were used without further purification. IR spectra were re-
corded on a Nicolet Impact 400 FT-IR spectrometer in KBr, CHCl3,
or CCl4. 1H NMR (300 and 400 MHz) and 13C NMR (75 and 100.6
MHz) spectra were determined at r.t. on a Varian VXR 300 or AX
400 mercury plus in CDCl3 soln with TMS as internal reference
(1H). HRMS were determined on Micromass Q-Tof spectrometer.
1,4-Benzoquinone (12, 6 mg, 0.06 mmol) was added to a soln of the
sultine 7 (14 mg, 0.03 mmol) in anhyd toluene (5 mL) and the mix-
ture was heated at 90 °C for 12 h). The soln was concentrated under
reduced pressure. The crude mixture was dissolved in anhyd di-
oxane (7 mL) and then treated with activated MnO2 (180 mg, 2.07
mmol). The mixture was then allowed to stir at reflux for 30 h and
then filtered through a Celite pad. The residue was washed with di-
oxane (3 × 5 mL) and the solvent was removed from the washings
under reduced pressure to give a crude product that was purified by
column chromatography (silica gel, EtOAc–PE, 3:7) to afford 17 as
a yellow crystalline solid; yield: 11 mg (71%); mp 170–172 °C
(dec.); Rf = 0.35 (silica gel, EtOAc–PE, 3:7).
IR (neat): 1731 (ester C=O), 1644 cm–1 (ArC=O).
Ethyl 6,7-Bis(bromomethyl)-2-tosyl-1,2,3,4-tetrahydroisoquin-
oline-3-carboxylate (9)
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.38 (s, 3 H, ArCH3), 3.41 (d, J = 4 Hz, 2 H, CHCH2),
3.86–3.98 (m, 2 H, OCH2CH3), 4.72 (1/2 ABq, J = 16 Hz, 1 H), 4.91
(1/2 ABq, J = 16.2 Hz, 1 H), 5.05 (t, J = 4.8 Hz, 1 H, CH2CH), 7.06
(s, 2 H, COCH=CH), 7.29 (d, J = 8 Hz, 2 H, ArH), 7.74–7.77 (m, 4
H, ArH), 8.50 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.0, 21.7, 32.8, 45.0, 54.2,
61.7, 127.3, 127.6, 128.5, 128.6, 129.6, 129.8, 133.7, 133.8, 134.1,
134.7, 135.8, 140.3, 144.0, 170.2, 184.7.
To a stirred soln of the diol 8 (0.30 g, 0.7 mmol) in anhyd CHCl3
(30 mL) was added PBr3 (0.33 mL, 3.5 mmol) at 0 °C and the mix-
ture was stirred at r.t. for 6 h. The mixture was then poured into ice-
cold H2O (40 mL) and extracted with CHCl3 (3 × 50 mL). The com-
bined organic extracts were washed with H2O and brine and dried
(MgSO4). The solvent was concentrated under reduced pressure and
the crude product was purified by column chromatography (silica
gel, EtOAc–PE, 25:75) to afford the dibromide 9 as a colorless sol-
id; yield: 0.32 g (83%); mp 156 °C; Rf = 0.40 (silica gel, EtOAc–
PE, 2:8).
HRMS (Q-TOF): m/z [M + H+] calcd for C27H24NO6S: 490.1324;
found: 490.1325.
IR (neat): 1163, 1738 cm–1 (ester C=O).
UV (CHCl3): lmax (e) = 240 nm (11428).
1H NMR (300 MHz; CDCl3): d = 1.01 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.41 (s, 3 H, ArCH3), 3.16 (d, J = 5.6 Hz, 2 H, CHCH2),
3.91–3.98 (m, 2 H, OCH2CH3), 4.45 (1/2 ABq, J = 15.6 Hz, 1 H),
4.58 (s, 4 H, CH2Br), 4.69 (1/2 ABq, J = 16.2 Hz, 1 H), 4.99 (t,
J = 4.2 Hz, 1 H, CHCH2), 7.05 (s, 1 H, ArH), 7.09 (s, 1 H, ArH),
7.28 (d, J = 8.1 Hz, 2 H, ArH), 7.71 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 13.9, 21.7, 29.71, 29.74, 31.7,
44.1, 53.6, 61.6, 127.5, 128.9, 129.7, 131.6, 132.4, 133.1, 135.2,
135.9, 143.8, 170.1.
Ethyl 8,9-Dimethyl-7,10-dioxo-2-tosyl-1,2,3,4,7,10-hexahydro-
naphtho[2,3-g]isoquinoline-3-carboxylate (18)
According to the typical procedure using 2,3-dimethyl-1,4-benzo-
quinone (13, 6 mg, 0.04 mmol) and sultine 7 (13 mg, 0.03 mmol) at
90 °C for 12 h, followed by aromatization with activated MnO2
(200 mg, 2.29 mmol) at reflux for 30 h; purification by flash column
chromatography (silica gel, EtOAc–PE, 3:7) afforded 18 as a yel-
low crystalline solid; yield: 11 mg (72%); mp 178–180 °C (dec.);
Rf = 0.30 (silica gel, EtOAc–PE, 3:7).
HRMS (Q-TOF): m/z [M + H]+ calcd for C21H24Br2NO4S:
543.9793; found 543.9780.
IR (neat): 1731 (ester C=O), 1654 cm–1 (ArC=O).
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.02 Hz, 3 H,
OCH2CH3), 2.23 (s, 6 H, 2 CH3), 2.38 (s, 3 H, Ar-CH3), 3.39 (d,
J = 5.04 Hz, 2 H, CHCH2), 3.86–3.97 (m, 2 H, OCH2CH3), 4.69
(1/2 ABq, J = 16.2 Hz, 1 H), 4.91 (1/2 ABq, J = 15.9 Hz, 1 H), 5.04
(t, J = 4 Hz, 1 H, CHCH2), 7.24–7.26 (m, 2 H, ArH), 7.73–7.77 (m,
4 H, ArH), 8.50 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 13.4, 14.1, 21.7, 32.8, 45.1,
54.3, 61.7, 127.1, 127.6, 128.0, 128.1, 128.9, 129.4, 129.8, 133.6,
133.7, 133.8, 134.2, 135.9, 144.0, 145.33, 145.34, 170.3, 184.54,
184.55.
Sultine 7
To a suspension of Rongalite (0.30 g, 1.94 mmol) in DMF (15 mL)
was added dibromo 9 (0.08 g, 0.15 mmol) and TBAB (0.03 g, 0.09
mmol) at 0 °C, and the resulting suspension was stirred at 0 °C for
3 h and then at r.t. for 4 h. The mixture was quenched with H2O (10
mL) and extracted with CHCl3 (3 × 50 mL). The combined organic
extracts were dried (MgSO4) and concentrated under reduced pres-
sure. The crude product thus obtained was purified by column chro-
matography (silica gel, EtOAc–PE, 3:7) to afford compound 7 as a
colorless liquid; yield: 46 mg (69%); Rf = 0.30 (silica gel, EtOAc–
PE, 3:7).
HRMS (Q-TOF): m/z [M + H]+ calcd for C29H28NO6S: 518.1637;
found: 518.1629.
IR (neat): 1738 (ester C=O), 1454, 1347, 1162 cm–1.
UV (CHCl3): lmax (e) = 240 nm (11270).
Synthesis 2007, No. 7, 1015–1020 © Thieme Stuttgart · New York

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Novel 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid Derivatives
1019
Ethyl 7,12-Dioxo-2-tosyl-1,2,3,4,7,12-hexahydroanthra[2,3-
g]isoquinoline-3-carboxylate (19)
Hz, 1 H, CH2CH), 7.26 (d, J = 6.4 Hz, 2 H, ArH), 7.47 (d, J = 6.8
Hz, 2 H, ArH), 7.60 (s, 1 H, ArH), 7.65 (s, 1 H, ArH), 8.13 (s, 2 H,
ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.0, 21.6, 32.8, 45.1, 52.9,
54.4, 61.6, 125.7, 127.6, 128.0, 128.6, 129.7, 129.8, 132.3, 132.9,
133.6, 143.9, 168.2, 170.4.
According to the typical procedure using 1,4-naphthoquinone (14,
7 mg, 0.04 mmol) and sultine 7 (14 mg, 0.03 mmol) at 90 °C for 24
h, followed by aromatization with activated MnO2 (250 mg, 2.87
mmol) at reflux for 30 h; purification by flash column chromatog-
raphy (silica gel, EtOAc–PE, 3:7) afforded 19 as a yellow crystal-
line solid; yield: 13 mg (77%); mp 205–207 °C (dec.); Rf = 0.35
(silica gel, EtOAc–PE, 4:6).
HRMS (Q-TOF): m/z [M + H]+ calcd for C27H28NO8S: 526.1536;
found: 526.1536.
IR (neat): 1730 (ester C=O), 1648 cm–1 (ArC=O).
UV (CHCl3): lmax (e) = 240 nm (11043).
1H NMR (300 MHz, CDCl3): d = 1.00 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 2.38 (s, 3 H, Ar-CH3), 3.42 (d, J = 3.6 Hz, 2 H,
CH2CH), 3.88–3.99 (m, 2 H, OCH2CH3), 4.72 (1/2 ABq, J = 16 Hz,
1 H), 4.94 (1/2 ABq, J = 16 Hz, 1 H), 5.05 (t, J = 5 Hz, 1 H, CH2CH),
7.26–7.29 (m, 2 H, ArH), 7.75–7.84 (m, 6 H, ArH), 8.37–8.40 (m,
2 H, ArH), 8.74 (s, 2 H, ArH).
Acknowledgement
We thank the CSIR, New Delhi for the financial support and SAIF-
Mumbai for providing spectral facilities. S.B. thanks the UGC, New
Delhi for the award of research fellowship.
13C NMR (100.6 MHz, CDCl3): d = 14.1, 21.7, 32.9, 45.1, 54.2,
61.7, 127.1, 127.63, 127.68, 129.1, 129.2, 129.5, 129.8, 129.9,
134.02, 134.07, 134.1, 134.4, 134.60, 134.64, 135.8, 144.0, 170.3,
183.0.
HRMS (Q-TOF): m/z [M + H]+ calcd for C31H26NO6S: 540.1481;
found: 540.1461.
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N.; Andahazy, M. L.; Carboni, J. M.; Gullo-Brown, J. L.;
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Ethyl 7,14-Dioxo-2-tosyl-1,2,3,4,7,14-hexahydrotetraceno[2,3-
g]isoquinoline-3-carboxylate (20)
According to the typical procedure using 1,4-anthraquinone 15 (11
mg, 0.05 mmol) and sultine 7 (11 mg, 0.02 mmol) at 90 °C for 20 h,
followed by aromatization with activated MnO2 (200 mg, 2.29
mmol) at reflux for 28 h; purification by flash column chromatog-
raphy (silica gel, EtOAc–PE, 3:7) afforded 20 as a yellow crystal-
line solid; yield: 12 mg (82%); mp 262 °C (dec.); Rf = 0.30 (silica
gel, EtOAc–PE, 4:6).
IR (neat): 1731 (ester C=O), 1658 cm–1 (Ar C=O).
1H NMR (300 MHz, CDCl3): d = 1.02 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 2.38 (s, 3 H, ArCH3), 3.43 (d, J = 6.4 Hz, 2 H, CHCH2),
3.87–3.99 (m, 2 H, OCH2CH3), 4.73 (1/2 ABq, J = 16 Hz, 1 H), 4.95
(1/2 ABq, J = 16 Hz, 1 H), 5.05 (dd, J = 5.4, 4.2 Hz, 1 H), 7.26–7.28
(m, 2 H, ArH), 7.71–7.86 (m, 6 H, ArH), 8.12–8.14 (m, 2 H, ArH),
8.83 (s, 2 H, ArH), 8.93 (s, 1 H, ArH), 8.94 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.0, 21.7, 32.9, 45.1, 54.3,
61.7, 127.1, 127.6, 129.3, 129.4, 129.7, 129.8, 129.9, 130.3, 130.7,
130.8, 134.0, 134.1, 134.2, 134.7, 135.4, 135.9, 143.9, 170.3, 182.9.
MS (MALDI-TOF): m/z [M + H]+ calcd for C35H27NO6S: 590.16;
found: 590.32.
UV (CHCl3): lmax (e) = 308 nm (22410).
3-Ethyl 7,8-Dimethyl 2-Tosyl-1,2,3,4-tetrahydrobenzo[g]iso-
quinoline-3,7,8-tricarboxylate (21)
According to the typical procedure using dimethyl acetylenedicar-
boxylate (16, 7 mg, 0.05 mmol) and sultine 7 (12 mg, 0.03 mmol)
at 90 °C for 24 h, followed by aromatization with activated MnO2
(200 mg, 2.29 mmol) at reflux for 30 h; purification by flash column
chromatography (silica gel, EtOAc–PE, 3:7) afforded 21 as a semi-
solid; yield: 10 mg (70%); Rf = 0.30 (silica gel, PE–EtOAc, 3:7).
IR (neat): 1729 cm–1 (ester C=O).
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.37 (s, 3 H, Ar-CH3), 3.72 (d, J = 4.4 Hz, 2 H,
CHCH2), 3.89–3.96 (m, 8 H, 2 COOCH3, OCH2CH3), 4.69 (1/2
ABq, J = 16 Hz, 1 H), 4.95 (1/2 ABq, J = 16 Hz, 1 H), 5.00 (t, J = 4.4
(10) (a) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J.
Chem. Rev. 2006, 106, 2734. (b) O’Reilly, N. J.; Derwin,
W. S.; Lin, H. C. Synthesis 1990, 550.
Synthesis 2007, No. 7, 1015–1020 © Thieme Stuttgart · New York

1020
S. Kotha, S. Banerjee
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