Gem -Dibromomethylarenes as aldehyde surrogates in the pictet-spengler synthesis of tetrahydroisoquinolines and isoindoloisoquinolones

Article abstract of DOI:10.1055/s-0030-1258137

A new variant of the Pictet-Spengler reaction has been developed using gem-dibromomethylarenes as aldehyde surrogates to afford a variety of tetrahydroisoquinoline and isoindoloisoquinolone ring systems in good yields. These systems comprise important motifs in naturally occurring bioactive substances.

Full text of DOI:10.1055/s-0030-1258137

PAPER
2949
gem-Dibromomethylarenes as Aldehyde Surrogates in the Pictet–Spengler
Synthesis of Tetrahydroisoquinolines and Isoindoloisoquinolones
T
etrahydroisoquin
a
olines and
I
g
soindoloisoq
a
uinolones raja Chowdappa,a,b Bailur Sheena Sherigara,b John Kallikat Augustine,*a Kummara Areppa,a
Ashis Baran Mandala
a
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore - 560 099, India
Fax +91(80)28083150; E-mail: john.kallikat@syngeneintl.com
Department of P.G. Studies and Research in Industrial Chemistry, Kuvempu University, Shankaraghatta, Shimoga - 577 451, India
b
Received 19 April 2010; revised 27 April 2010
Our initial intention was to explore the feasibility of uti-
Abstract: A new variant of the Pictet–Spengler reaction has been
lizing gem-dibromomethylarenes as aldehyde surrogates
developed using gem-dibromomethylarenes as aldehyde surrogates
for the synthesis of tetrahydroisoquinolines. Thus, com-
to afford a variety of tetrahydroisoquinoline and isoindoloisoqui-
mercially available benzalbromide was treated with 3,4-
dimethoxyphenethylamine under the Pictet–Spengler re-
action conditions in the presence of trifluoroacetic acid
(TFA) in dichloromethane. To our excitement, the tet-
rahydroisoquinoline 2a was formed in 41% yield after
eight hours reaction time at room temperature (Table 1,
entry 1).
nolone ring systems in good yields. These systems comprise impor-
tant motifs in naturally occurring bioactive substances.
Key words: Pictet–Spengler reaction, gem-dibromomethylarenes,
tetrahydroisoquinolines, isoindoloisoquinolinones, microwave irra-
diation
Isoquinoline alkaloids constitute a large family of natural
products that exhibit a broad range of biological activi-
ties.1 Among the members of this class of compounds, tet-
rahydroisoquinoline derivatives comprise a major group.
Many of them display important biological activities, and
possess for example, anti-inflammatory, anti-microbial,
anti-leukemic and anti-tumor properties,2 which has pro-
moted the development of a number of synthetic method-
ologies for the construction of the tetrahydroisoquinoline
nucleus.3 The Pictet–Spengler4 reaction is an extensively
used method for the synthesis of both indole and isoquin-
oline alkaloids. In general, it is a two-step process that in-
volves acid-catalyzed condensation of an aliphatic amine
attached to a sufficiently reactive aromatic nucleus with
aldehydes. The reaction is traditionally carried out in a
protic solvent with an acid catalyst.5
Br
Br
Me
O
Me
O
R1
+
HN
N
R2
R3
R2
R3
R1
Br
Br
Me
O
Me
O
Me
O
O
R1
+
NH2
N
R2
R2
O
R1
Scheme 1
Although the Pictet–Spengler reaction has been widely
recognized, substitution of the aldehyde component with
an alternative functional group has not attracted much at-
tention. Consequently, the development of a simple and
stable substitute for these aromatic aldehydes would ex-
tend the scope of the Pictet–Spengler reaction in organic
synthesis. Recently, we have reported the use of gem-di-
bromomethylarenes as aldehyde equivalents in the
Knoevenagel–Doebner reaction for the preparation of cin-
namic acids6 and cinnamic esters.7 In this paper, we report
a new and efficient method for the Pictet–Spengler reac-
tion that involves a gem-dibromomethylarene (as an alter-
nate for aldehyde) and a 2-arylethylamine, and provides
access to 1-aryl tetrahydroisoquinolines and isoindoloiso-
quinolones (Scheme 1).
The reaction was further optimized by screening various
acids, solvents and temperature (Table 1). Although prod-
uct formation was observed with trichloroacetic acid
(TCA) and methanesulfonic acid (MsOH), use of neat
TFA was found to be most advantageous for the complete
conversion of 1a into 3a (Table 1, entry 7). Furthermore,
performing the reaction under MW irradiation at 90 °C
considerably reduced the reaction time in addition to pro-
viding a good yield of 3a (Table 1, entry 11).
Under optimized conditions, the substrate scope of the
Pictet–Spengler reaction was then studied. The gem-di-
bromomethylarenes, which were synthesized using
known protocols,8 were subsequently reacted with 2-aryl-
ethylamines under the standard reaction conditions
(Table 1, entry 7). As summarized in Table 2, most of the
gem-dibromides efficiently participated in the reaction to
provide the respective tetrahydroisoquinolines in moder-
ate to good yields. Surprisingly, a gem-dibromide bearing
SYNTHESIS 2010, No. 17, pp 2949–2956
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258137; Art ID: Z09910SS
© Georg Thieme Verlag Stuttgart · New York

2950
N. Chowdappa et al.
PAPER
a nitro group on the ring (1j) did not participate in the re- successful (Table 2, entry 10). Likewise, the reaction did
action under the standard reaction conditions. Attempts to not tolerate boronate functionality (Table 2, entry 8).
promote the reaction under MW irradiation were also un-
Table 1 Screening for Optimal Conditions
MeO
MeO
MeO
MeO
benzal bromide (1a)
NH2
acid
NH
2a
3a
Entry
Acida
Solvent
CH2Cl2
CH2Cl2
DCE
Temp (°C)
Time (h)
Yield, 3a (%)
1
2
TFA
25
55
75
50
75
100
80
80
80
90
90
8
41
52
23
27
0
TFA
8
3
TCA
3
4
MsOH
AcOH
CH2Cl2
DCE
6
5
5
b
6
H2SO4
TFAb
neat
5
0
7
neat
5
87
0
8
TsOH
TfOH
MsOHb
TFA
DCE
5
9
DCE
3
26
38
84
10
11c
neat
3
neat
0.5
a 2.5 equiv were used.
b 10.0 equiv were used.
c Reaction was carried out under MW irradiation.
Table 2 Synthesis of Tetrahydroisoquinolines and Dihydroisoindoloisoquinolinones from gem-Dibromomethylarenes and 2-Arylethyl-
amines
Entry
gem-Dibromidea
Amine
Time (h)
Product
Yield (%)b
MeO
Br
Br
MeO
NH
MeO
1
5
87 (84)c
NH2
MeO
2a
1a
3a
MeO
NH
Br
MeO
Br
Br
2
2a
2a
5
82
F
Br
1b
F
3b
MeO
Br
Br
NH
MeOOC
MeO
Br
3
6
68
Br
1c
COOMe
3c
Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York

PAPER
Tetrahydroisoquinolines and Isoindoloisoquinolones
2951
Table 2 Synthesis of Tetrahydroisoquinolines and Dihydroisoindoloisoquinolinones from gem-Dibromomethylarenes and 2-Arylethyl-
amines (continued)
Entry
gem-Dibromidea
Amine
Time (h)
Product
Yield (%)b
MeO
Br
Br
NH
MeO
Br
Br
4
2a
6
74
MeOOC
1d
COOMe
NH
3d
MeO
Br
MeO
5
2a
5
68
Br
MeOOC
1e
COOMe
NH
3e
MeO
OMe Br
MeO
Br
OMe
MeO
OMe
6
7
8
2a
2a
2a
7
5
5
65
83
73
MeOOC
1f
COOMe
N
3f
MeO
Br
Br
COOMe
O
MeO
Cl
Cl
1g
3g
MeO
Br
NH
MeO
O
Br
B
O
S
1h
S
3h
MeO
COOMe
Br
NH
MeO
9
2a
2a
6
7
69
Br
COOMe
O
O
Br
1i
Br
3i
MeO
Br
NH
MeO
10
0 (0)c
Br
NO2
NO2
MeO
MeO
1j
3j
Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York

2952
N. Chowdappa et al.
PAPER
Table 2 Synthesis of Tetrahydroisoquinolines and Dihydroisoindoloisoquinolinones from gem-Dibromomethylarenes and 2-Arylethyl-
amines (continued)
Entry
gem-Dibromidea
Amine
Time (h)
Product
Yield (%)b
MeO
Br
Br
NH
MeO
11
2a
5
82
COOMe
COOMe
S
S
1k
3k
MeO
Br
Br
N
O
MeO
12
13
2a
4
4
85
78
COOMe
1l
3l
MeO
NH
S
MeO
Br
Br
MeOOC
S
NH2
2b
1m
COOMe
3m
MeO
Br
Br
N
O
14
15
2b
4
6
81
83
COOMe
Cl
Cl
1g
3n
MeO
Br
Br
MeO
N
MeO
Me
HN
Me
COOMe
MeO
COOMe
S
2c
S
1k
3o
MeO
Br
N
Br
MeO
Me
F
Br
16
2c
5
89
F
1n
Br
3p
a gem-Dibromides were prepared following a literature protocol.8
b Isolated yields.
c Yields in parentheses refer to reactions carried out under MW irradiation.
It is noteworthy that benzal bromides bearing carboxylate to give good yields of N-substituted tetrahydroisoquino-
functionality at the ortho position on the six-membered lines (Table 2, entries 15 and 16).
ring easily cyclized to isoindoloisoquinolones as sole
products in one-pot (Table 2, entries 7, 12 and 14), in a re-
gem-Dibromomethylarenes are known to produce alde-
hydes under acidic conditions.10 As the formation of alde-
action that would lead to easy access to isoquinoline alka-
hyde was not observed at any stage of the reaction, we
loids such as Nuevamine.9 Conversely, such
a
contemplated the formation of an iminium ion in situ,
which would perform the aromatic substitution leading to
the ring-closed heterocycle (Scheme 2). It can be conclud-
phenomenon was not exhibited by five-membered gem-
dibromides (Table 2, entries 9 and 11). Furthermore, the
reaction worked well on N-substituted b-arylethylamines
Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York

PAPER
Tetrahydroisoquinolines and Isoindoloisoquinolones
2953
Methyl 4-Dibromomethyl-1-naphthoate (1e)6
Yield: 71%.
Br
Br
MeO
MeO
Methyl 3,5-Dimethoxy-4-(dibromomethyl)benzoate (1f)
Yield: 68%; white solid; mp 163 °C.
HN
Br
+
NH2
– HBr
IR (liquid film): 1716, 1412, 1232, 1096, 762, 629 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.87 (s, 3 H), 3.93 (br, 6 H),
7.22 (br, 2 H), 7.34 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.7, 52.1, 55.7, 55.8, 104.7 (2C),
121.0, 131.9, 156.3 (2C), 166.2.
MeO
MeO
H+
– HBr
NH
NH
Anal. Calcd for C11H12Br2O4: C, 35.90; H, 3.29. Found: C, 35.98;
H, 3.36.
Methyl 2-Chloro-6-(dibromomethyl)benzoate (1g)
Yield: 76%; colorless liquid.
Scheme 2
IR (liquid film): 1724, 1443, 1268, 1104, 651, 515 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.94 (s, 3 H), 7.15 (s, 1 H),
7.57–7.65 (m, 2 H), 7.93 (dd, J = 7.7, 1.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 38.4, 53.8, 129.1, 129.4,
129.5, 131.1, 132.5, 140.7, 165.4.
ed that formation of this iminium species is the key step in
the cyclization.
In summary, a new variation of the Pictet–Spengler reac-
tion, wherein gem-dibromomethyl aromatics are em- Anal. Calcd for C9H7Br2ClO2: C, 31.57; H, 2.06. Found: C, 31.66;
H, 2.12.
ployed as aldehyde surrogates for the efficient synthesis
of 1-substituted tetrahydroisoquinolines and isoindoloiso-
quinolones, is demonstrated. This procedure appears to be
useful in terms of synthetic competency because benzal
bromides serve as convenient precursors for the construc-
tion of tetrahydroisoquinoline derivatives, which can be
further elaborated for the synthesis of natural products
containing the tetrahydroisoquinoline framework.
5-(Dibromomethyl)-1-benzothiophene-2-boronic Acid Pinacol
Ester (1h)6
Yield: 73%.
Methyl 5-Bromo-2-dibromomethylfuran-3-carboxylate (1i)6
Yield: 70%.
1-(Dibromomethyl)-4-methoxy-2-nitrobenzene (1j)6
Yield: 82%.
1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz,
respectively, with a Bruker spectrometer. Elemental analyses were
performed with a Thermo Finnigan FLASH EA 1112 CHN analyz-
er. Melting points were recorded (uncorrected) with a Büchi Melt-
ing Point B-545 instrument. Infrared spectra were recorded with a
Thermo Scientific Nicolet 6700 FT-IR spectrometer. Coupling con-
stants are reported wherever necessary in hertz (Hz). Microwave re-
actions were performed with a Biotage Microwave Synthesizer.
Methyl 3-Dibromomethylthiophene-2-carboxylate (1k)11
Yield: 77%.
Methyl 2-Dibromomethylbenzoate (1l)
Yield: 82%; white solid; mp 55 °C.
IR (KBr): 1707, 1532, 1455, 1261, 1093, 647 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.87 (s, 3 H), 7.50 (t,
J = 10.2 Hz, 1 H), 7.71–7.79 (m, 2 H), 7.85 (s, 1 H), 8.08 (d,
J = 10.6 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 38.8, 52.7, 125.2, 129.5, 129.9,
131.0, 133.0, 141.7, 166.1.
gem-Dibromomethyl Aromatics 1b–n; General Procedure
All gem-dibromomethyl aromatics except 1a were prepared and pu-
rified by chromatography in accordance to a reported protocol.8
2-Bromo-4-(dibromomethyl)-1-fluorobenzene (1b)
Yield: 71%; colorless liquid.
Anal. Calcd for C9H8Br2O2: C, 35.10; H, 2.62. Found: C, 35.14; H,
2.69.
IR (liquid film): 1577, 1462, 1409, 1266, 1147, 1028, 810, 715
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.20–7.25 (m, 2 H), 7.69 (dd,
J = 8.8, 5.4 Hz, 1 H), 7.75 (dd, J = 9.5, 3.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 40.8, 114.8, 117.9 (d), 119.5
(d), 135.3 (d), 142.1 (d), 161.6 (d).
Methyl 5-Dibromomethylthiophene-2-carboxylate (1m)11
Yield: 83%; colorless liquid.
4-Bromo-2-(dibromomethyl)-1-fluorobenzene (1n)
Yield: 67%; colorless liquid.
IR (liquid film): 1577, 1462, 1265, 1147, 810, 715, 536 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.21 (dd, J = 8.8, 3.0 Hz, 1 H),
7.24 (s, 1 H), 7.67–7.70 (m, 1 H), 7.74 (dd, J = 9.5, 2.8 Hz, 1 H).
Anal. Calcd for C7H4Br3F: C, 24.24; H, 1.16. Found: C, 24.30; H,
1.19.
Methyl 4-Bromo-3-(dibromomethyl)benzoate (1c)7
Yield: 74%.
13C NMR (100 MHz, DMSO-d6): d = 40.2, 114.8, 117.9 (d), 119.6
(d), 135.5 (d), 142.1 (d), 161.8 (d).
Anal. Calcd for C7H4Br3F: C, 24.24; H, 1.16. Found: C, 24.29; H,
1.21.
Methyl 3-Bromo-4-(dibromomethyl)benzoate (1d)6
Yield: 76%.
Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York

2954
N. Chowdappa et al.
PAPER
1,2,3,4-Tetrahydroisoquinolines 3a–p; Typical Procedure
A mixture of 2-(3,4-dimethoxyphenyl)ethylamine (5 g, 0.0275 mol)
and benzal bromide (1a; 7.57 g, 0.0303 mol) in TFA (21 mL, 0.275
mol) was stirred at 80 °C for 5 h under a nitrogen atmosphere. The
completion of reaction was confirmed by TLC. The reaction mix-
ture was cooled and excess TFA was removed under vacuum. The
residue was neutralized with sat. NaHCO3 and the product was ex-
tracted with CH2Cl2 (2 × 50 mL). The combined organic phase was
washed with H2O (50 mL), brine (50 mL) and dried over Na2SO4.
The solvent was removed under vacuum and the residue was puri-
fied by column chromatography (MeOH–CHCl3, 3%) to afford 6,7-
dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3a; 6.46 g,
87%)12 as a white solid.
13C NMR (100 MHz, DMSO-d6): d = 29.0, 41.5, 52.7, 55.8, 55.9,
59.3, 111.0, 112.6, 128.4, 128.9, 129.2, 129.6, 130.1, 131.7, 133.5,
145.3, 147.2, 147.9, 166.0.
Anal. Calcd for C19H20BrNO4: C, 56.17; H, 4.96; N, 3.45. Found: C,
56.23; H, 5.02; N, 3.37.
LC-MS (MeOH–10 mM NH4OAc; 1.0 mL/min; XBridge C8):
tR = 2.73 min; m/z = 408.0 [M + 2]+.
Methyl 3-Bromo-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
lin-1-yl)benzoate (3d)
Yield: 74%; light-brown liquid.
IR (liquid film): 3335, 2923, 1722, 1512, 1255, 1108, 752 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.63–2.69 (m, 1 H), 2.74–2.92
(m, 3 H), 3.47 (s, 3 H), 3.72 (s, 3 H), 3.84 (s, 3 H), 5.35 (s, 1 H),
6.17 (s, 1 H), 6.72 (s, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.83 (dd,
J = 8.0, 1.6 Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 29.0, 40.6, 52.8, 55.8, 55.8,
59.2, 111.0, 112.5, 124.6, 128.4, 128.4, 128.5, 130.4, 131.7, 133.3,
147.3, 148.0, 149.6, 165.3.
Alternatively, a mixture of 2-(3,4-dimethoxyphenyl)ethylamine
(0.5 g, 0.00275 mol) and 1a (0.757 g, 0.00303 mol) in TFA (5 mL)
was irradiated under MW for 30 min at 90 °C. The reaction mixture
was cooled and excess TFA was removed under vacuum. The resi-
due was neutralized with sat. NaHCO3 and the product was extract-
ed with CH2Cl2 (2 × 10 mL). The combined organic phase was
washed with H2O (20 mL), brine (10 mL) and dried over Na2SO4.
The solvent was removed under vacuum and the residue was puri-
fied by column chromatography (MeOH–CHCl3, 3%) to afford 3a
(0.63 g, 84%) as a white solid.
Anal. Calcd for C19H20BrNO4: C, 56.17; H, 4.96; N, 3.45. Found: C,
56.21; H, 5.04; N, 3.41.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3a)
Yield: 87%; white solid; mp 103 °C.
tR = 2.40 min; m/z = 408.0 [M + 2]+.
IR (KBr): 3249, 2909, 2790, 1510, 1216, 1033, 821 cm–1.
Methyl 4-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl)naphthoate (3e)
Yield: 68%; white solid; mp 56 °C.
IR (KBr): 3335, 2925, 1712, 1511, 1248, 1126, 755 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.75–2.82 (m, 1 H), 3.88–3.92
(m, 3 H), 3.37 (s, 3 H), 3.74 (s, 3 H), 3.91 (s, 3 H), 5.77 (s, 1 H),
6.19 (s, 1 H), 6.77 (s, 1 H), 7.18 (br, 1 H), 7.54–7.63 (m, 2 H), 7.79
(d, J = 7.5 Hz, 1 H), 8.31 (s, 1 H), 8.49 (d, J = 8.5 Hz, 1 H), 8.74 (d,
J = 8.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 24.9, 40.6, 53.0, 53.5, 55.9
(2C), 111.1, 112.0, 123.8, 124.6, 125.9, 126.3, 127.8, 128.4 (2C),
129.0, 129.2, 131.0, 132.0, 138.4, 148.1, 149.1, 167.7.
1H NMR (400 MHz, DMSO-d6): d = 2.59–2.64 (m, 1 H), 2.74–2.85
(m, 2 H), 2.97–3.01 (m, 1 H), 3.45 (s, 3 H), 3.71 (s, 3 H), 4.90 (s,
1 H), 6.16 (s, 1 H), 6.68 (s, 1 H), 7.20–7.24 (m, 3 H), 7.27–7.31 (m,
2 H).
13C NMR (100 MHz, DMSO-d6): d = 28.8, 41.1, 55.4, 55.5, 60.5,
111.3, 112.1, 126.8, 127.7, 127.9, 128.8, 130.3, 145.4, 146.5, 147.3.
Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
75.82; H, 7.14; N, 5.17.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.06 min; m/z = 270.2 [M + H]+.
Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C,
73.21; H, 6.17; N, 3.62.
1-(3-Bromo-4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (3b)
Yield: 82%; white solid; mp 127 °C.
IR (KBr): 3251, 2964, 2807, 1515, 1216, 1036, 828 cm–1.
LC-MS (MeOH–10 mM NH4OAc; 1.0 mL/min; XBridge C8):
tR = 2.84 min; m/z = 378.3 [M + H]+.
1H NMR (400 MHz, DMSO-d6): d = 2.59–2.63 (m, 1 H), 2.74–2.84
(m, 2 H), 2.91–2.94 (m, 1 H), 3.50 (s, 3 H), 3.71 (s, 3 H), 4.93 (s,
1 H), 6.19 (s, 1 H), 6.69 (s, 1 H), 7.20–7.24 (m, 1 H), 7.27–7.31 (m,
1 H), 7.51 (dd, J = 6.9, 2.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 29.0, 41.2, 55.8, 56.0, 59.4,
107.8 (d), 112.1 (d), 116.5 (d), 128.2, 129.7, 130.4 (d), 133.8, 144.2
(d), 147.1, 147.9, 155.9, 159.1.
Methyl 4-(6,7-Dimethoxy-1,2,3,4-tertahydroisoquinolin-1-yl)-
3,5-dimethoxybenzoate (3f)
Yield: 65%; white solid; mp 236 °C.
IR (KBr): 2946, 2521, 1718, 1459, 1238, 1118, 766 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.84–2.88 (m, 1 H), 3.07–3.13
(m, 1 H), 3.37–3.40 (m, 1 H), 3.42 (s, 3 H), 3.45–3.54 (m, 1 H),
3.72 (s, 3 H), 3.79 (br, 6 H), 3.88 (s, 3 H), 5.89 (s, 1 H), 5.96 (s,
1 H), 6.81 (s, 1 H), 7.28 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 28.7, 43.6, 51.7, 52.2, 55.3,
55.5, 56.0 (2C), 105.4 (2C), 109.0, 112.3, 125.0, 127.4, 129.8,
131.1, 146.6, 146.7, 158.0 (2C), 165.9.
Anal. Calcd for C17H17BrFNO2: C, 55.75; H, 4.68; N, 3.82. Found:
C, 55.77; H, 4.76; N, 3.78.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.67 min; m/z = 368.0 [M + 2]+.
Anal. Calcd for C21H25NO6: C, 65.10; H, 6.50; N, 3.62. Found: C,
65.17; H, 6.55; N, 3.54.
Methyl 6-Bromo-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
lin-1-yl)benzoate (3c)
Yield: 68%; white solid; mp 153 °C.
IR (KBr): 3330, 2923, 1722, 1514, 1255, 1107, 753 cm–1.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.59 min; m/z = 388.2 [M + H]+.
1H NMR (400 MHz, DMSO-d6): d = 2.63–2.67 (m, 1 H), 2.82–2.87
(m, 2 H), 2.94–3.00 (m, 1 H), 3.46 (s, 3 H), 3.73 (s, 3 H), 3.77 (s,
3 H), 5.36 (s, 1 H), 6.14 (s, 1 H), 6.74 (s, 1 H), 7.67 (d, J = 2.0 Hz,
1 H), 7.73 (dd, J = 8.3, 2.0 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1 H).
9-Chloro-2,3-dimethoxy[5,12b]dihydro-6H-isoindolo[1,2-a]iso-
quinolin-8-one (3g)
Yield: 83%; white solid; mp 149 °C.
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Tetrahydroisoquinolines and Isoindoloisoquinolones
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IR (KBr): 2927, 1703, 1455, 1224, 1093, 747 cm–1.
2,3-Dimethoxy[5,12b]dihydro-6H-isoindolo[1,2-a]isoquinolin-
8-one (3l)13
Yield: 72%; white solid; mp 61 °C.
IR (KBr): 2919, 1673, 1460, 1222, 1090, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.75–2.81 (m, 1 H), 2.94–3.05 (m,
1 H), 3.38–3.47 (m, 1 H), 3.85 (s, 3 H), 3.93 (s, 3 H), 4.47–4.53 (m,
1 H), 5.63 (s, 1 H), 6.66 (s, 1 H), 7.12 (s, 1 H), 7.47–7.52 (m, 1 H),
7.59–7.64 (m, 1 H), 7.82–7.89 (m, 2 H).
1H NMR (400 MHz, DMSO-d6): d = 2.74–2.78 (m, 2 H), 3.28–3.29
(m, 1 H), 3.70 (s, 3 H), 3.80 (s, 3 H), 4.23–4.28 (m, 1 H), 5.75 (s,
1 H), 6.77 (s, 1 H), 7.26 (s, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.65 (t,
J = 7.8 Hz, 1 H), 8.13 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.3, 37.7, 55.4, 55.8, 57.5,
109.5, 112.3, 123.2, 125.4, 126.4, 127.5, 129.5, 129.7, 133.0, 147.5,
147.9, 147.9, 164.5.
Anal. Calcd for C18H16ClNO3: C, 65.56; H, 4.89; N, 4.25. Found: C,
65.63; H, 4.92; N, 4.18.
13C NMR (75 MHz, CDCl3): d = 29.0, 38.2, 55.9, 56.2, 58.9, 108.6,
111.9, 123.0, 123.9, 125.9, 126.9, 128.4, 131.5, 132.7, 144.6, 147.8,
148.3, 167.9.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 3.67 min; m/z = 330.2 [M + H]+.
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
73.29; H, 5.86; N, 4.69.
1-Benzo[b]thiophen-5-yl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (3h)
Yield: 73%; colorless liquid.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 3.48 min; m/z = 296.2 [M + H]+.
IR (liquid film): 2920, 1727, 1514, 1256, 1111, 782 cm–1.
Methyl 2-(6-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl)thiophene-5-carboxylate (3m)
Yield: 85%; light-yellow solid; mp 99 °C.
IR (KBr): 3260, 2948, 1704, 1460, 1234, 1087, 835 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.66–2.71 (m, 2 H), 2.86–2.97
(m, 2 H), 3.70 (s, 3 H), 3.75 (s, 3 H), 5.24 (s, 1 H), 6.67–6.69 (m,
2 H), 6.91 (d, J = 9.1 Hz, 1 H), 7.02 (d, J = 3.6 Hz, 1 H), 7.63 (d,
J = 3.6 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 2.99–3.05 (m, 1 H), 3.16–3.20
(m, 1 H), 3.22–3.28 (m, 2 H), 3.46 (s, 3 H), 3.77 (s, 3 H), 5.79 (s,
1 H), 6.29 (s, 1 H), 6.89 (s, 1 H), 7.37 (d, J = 8.3 Hz, 1 H), 7.49 (d,
J = 5.4 Hz, 1 H), 7.83 (d, J = 5.4 Hz, 2 H), 8.07 (d, J = 8.3 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 24.9, 40.8, 56.0, 56.4, 58.2,
111.3, 112.0, 123.3, 124.0, 124.6, 125.5, 126.0, 126.3, 129.1, 133.7,
139.8, 140.2, 147.9, 149.0.
Anal. Calcd for C19H19NO2S: C, 70.12; H, 5.88; N, 4.30. Found: C,
70.21; H, 5.97; N, 4.23.
13C NMR (100 MHz, DMSO-d6): d = 29.0, 40.1, 52.0, 54.9, 55.1,
111.9, 113.4, 126.3, 128.6, 129.1, 131.0, 133.2, 136.2, 157.7, 159.3,
162.1.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.64 min; m/z = 326.2 [M + H]+.
Anal. Calcd for C16H17NO3S: C, 63.35; H, 5.65; N, 4.62. Found: C,
63.39; H, 5.72; N, 4.53.
Methyl 5-Bromo-2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
lin-1-yl)furan-3-carboxylate (3i)
Yield: 69%; white solid; mp 126 °C.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.60 min; m/z = 304.2 [M + H]+.
IR (KBr): 2914, 1703, 1513, 1195, 1053, 747 cm–1.
9-Chloro-3-dimethoxy[5,12b]dihydro-6H-isoindolo[1,2-a]iso-
quinolin-8-one (3n)
Yield: 81%; white solid; mp 156 °C.
IR (KBr): 2929, 1687, 1394, 1253, 1033, 761 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.64–2.69 (m, 2 H), 2.88–2.91
(m, 1 H), 3.06–3.09 (m, 1 H), 3.54 (s, 3 H), 3.71 (s, 3 H), 3.80 (s,
3 H), 5.66 (s, 1 H), 6.33 (s, 1 H), 6.71 (s, 1 H), 6.83 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.2, 40.6, 51.0, 51.8, 55.3,
55.5, 110.1, 111.8, 112.3, 115.8, 121.4, 125.5, 127.8, 146.9, 147.7,
162.4, 165.3.
1H NMR (400 MHz, DMSO-d6): d = 2.83–2.87 (m, 2 H), 3.33–3.42
(m, 1 H), 3.70 (s, 3 H), 4.14–4.20 (m, 1 H), 5.76 (s, 1 H), 6.79 (s,
1 H), 6.83 (dd, J = 8.6, 2.7 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.61–
7.66 (m, 2 H), 8.04 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 29.3, 38.0, 55.5, 57.6, 113.1,
114.3, 123.7, 126.5, 127.2, 128.0, 130.0, 130.2, 133.4, 136.4, 148.2,
158.6, 164.8.
Anal. Calcd for C17H18BrNO5: C, 51.53; H, 4.58; N, 3.53. Found: C,
51.55; H, 4.59; N, 3.49.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.53 min; m/z = 398.0 [M + 2]+.
Anal. Calcd for C17H14ClNO2: C, 68.12; H, 4.71; N, 4.67. Found: C,
68.15; H, 4.78; N, 4.59.
Methyl 3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl)thiophene-2-carboxylate (3k)
Yield: 82%; light-yellow liquid.
IR (liquid film): 2925, 1701, 1513, 1245, 1223, 1099, 751 cm–1.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 3.91 min; m/z = 300.2 [M + H]+.
Methyl 3-(6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquino-
lin-1-yl)thiophene-2-carboxylate (3o)
Yield: 83%; light-yellow solid; mp 122 °C.
IR (KBr): 2934, 1707, 1459, 1240, 1087, 756 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.63–2.67 (m, 1 H), 2.74–2.86
(m, 2 H), 2.95–3.00 (m, 1 H), 3.48 (s, 3 H), 3.71 (s, 3 H), 3.83 (s,
3 H), 5.77 (s, 1 H), 6.21 (s, 1 H), 6.70–6.71 (m, 2 H), 7.68 (d,
J = 5.1 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 29.1, 41.4, 52.5, 53.5, 55.8,
55.9, 111.3, 112.6, 127.2, 127.8, 129.6, 131.0, 131.4, 147.1, 147.8,
154.3, 162.8.
1H NMR (400 MHz, DMSO-d6): d = 2.10 (s, 3 H), 2.60–2.70 (m,
1 H), 2.95–3.01 (m, 3 H), 3.43 (s, 3 H), 3.70 (s, 3 H), 3.85 (s, 3 H),
5.30 (s, 1 H), 6.10 (s, 1 H), 6.70 (s, 1 H), 6.84 (d, J = 5.2 Hz, 1 H),
7.71 (d, J = 5.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.4, 43.6, 51.3, 52.1, 55.3,
55.4, 61.4, 110.9, 111.6, 126.2, 127.8, 128.3, 130.0, 131.6, 146.7,
147.3, 152.5, 162.5.
Anal. Calcd for C17H19NO4S: C, 61.24; H, 5.74; N, 4.20. Found: C,
61.30; H, 5.82; N, 4.13.
LC-MS (0.1% TFA in H2O–0.1% TFA in MeCN; 2.0 mL/min;
Xbridge C8): tR = 2.65 min; m/z = 334.0 [M + H]+.
Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York

2956
N. Chowdappa et al.
PAPER
(2) (a) Brown, R. T. The Monoterpenoid Indole Alkaloids, In
Anal. Calcd for C18H21NO4S: C, 62.23; H, 6.09; N, 4.03. Found: C,
62.32; H, 6.17; N, 3.96.
Indoles, Part 4; Saxton, J. E., Ed.; Wiley Interscience: New
York, 1983. (b) Iwasa, K.; Moriyasu, M.; Yamori, T.;
Turuo, T.; Lee, D.-U.; Wiegrebe, W. J. Nat. Prod. 2001, 64,
896. (c) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.11 min; m/z = 348.2 [M + H]+.
1-(5-Bromo-2-fluorophenyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (3p)
Yield: 89%; colorless liquid.
IR (liquid film): 2934, 1510, 1252, 1013, 760 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.11 (s, 3 H), 2.44–2.51 (m,
1 H), 2.63–2.68 (m, 1 H), 2.94–3.02 (m, 2 H), 3.45 (s, 3 H), 3.70 (s,
3 H), 4.22 (s, 1 H), 6.08 (s, 1 H), 6.69 (s, 1 H), 7.10–7.13 (m, 1 H),
7.21–7.27 (m, 1 H), 7.32–7.39 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.7, 44.0, 51.4, 55.8, 55.9,
68.8, 111.9 (2C), 117.7 (dd), 126.0, 126.1, 126.8, 129.5, 142.5 (t),
147.2, 147.6 (dd), 147.8, 150.9 (dd).
(3) (a) Bringmann, G.; Ewers, C. L. J.; Walter, R. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M., Ed.;
Pergamon: Oxford, 1991, Chap. 4.2, 733. (b)Chrzanowska,
M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.
(4) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(5) (a) Stuart, K.; Woo-Ming, R. Heterocycles 1975, 3, 223.
(b) Brown, R. T.; Chapple, C. J. Chem. Soc., Chem.
Commun. 1976, 886. (c) Saito, A.; Takayama, M.;
Yamazaki, A.; Numaguchi, J.; Hanzawa, Y. Tetrahedron
2007, 63, 4039. (d) Saha, B.; Sharma, S.; Sawant, D.;
Kundu, B. Tetrahedron Lett. 2007, 48, 1379.
(6) Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa,
N.; Praveen, V. B. J. Org. Chem. 2007, 72, 9854.
(7) Augustine, J. K.; Naik, Y. A.; Poojari, S.; Chowdappa, N.;
Sherigara, B. S.; Areppa, K. Synthesis 2009, 2349.
(8) Mandal, A. B.; Augustine, J. K.; Quattropani, A.; Bombrun,
A. Tetrahedron Lett. 2005, 46, 6033.
Anal. Calcd for C18H19BrFNO2: C, 56.86; H, 5.04; N, 3.68. Found:
C, 56.93; H, 5.11; N, 3.61.
LC-MS (MeOH–0.1% HCO2H; 1.0 mL/min; ATLANTIS dc18):
tR = 2.44 min; m/z = 382.0 [M + 2]+.
(9) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.;
Lebrun, S. Tetrahedron 2004, 60, 6169.
(10) (a) Chung, S. J.; Kim, D. H. Tetrahedron 1995, 51, 12549.
(b) Segesser, J. R.; Calvin, M. J. Am. Chem. Soc. 1942, 64,
825.
Supporting Information for this article is available online at
http://www.thieme-connect.de/ejournals/toc/synthesis.
Acknowledgment
(11) Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa,
N.; Praveen, V. B. Tetrahedron 2008, 64, 688.
(12) Minor, D. L.; Wyrick, S. D.; Charifson, P. S.; Watts, V. J.;
Nichols, D. E.; Mailman, R. B. J. Med. Chem. 1994, 37,
4317.
The authors are grateful to Dr. Goutam Das, COO, Syngene Inter-
national Ltd for his invaluable support.
(13) Alonso, R.; Castedo, L.; Dominguez, D. Tetrahedron Lett.
1985, 26, 2925.
References
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Synthesis 2010, No. 17, 2949–2956 © Thieme Stuttgart · New York