Microwave-assisted intramolecular cyclization of electron-rich heterocycle derivatives by a palladium-catalyzed coupling reaction

Article abstract of DOI:10.1055/s-2007-990947

Nitrogenated heteropolycyclic systems were obtained by intramolecular palladium-catalyzed coupling reactions promoted by microwave irradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990947

136
PAPER
Microwave-Assisted Intramolecular Cyclization of Electron-Rich Heterocycle
Derivatives by a Palladium-Catalyzed Coupling Reaction
Intramolecular
C
g
yclizationo
l
f
E
lect
e
M
cle Derivatives . Beccalli,*a Gianluigi Broggini,b Michela Martinelli,a Silvia Sottocornolab
a
Istituto di Chimica Organica ‘A. Marchesini’, Facoltà di Farmacia, Università di Milano, via Venezian 21, 20133 Milan, Italy
Fax +39(02)50314476; E-mail: egle.beccalli@unimi.it
b
Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11, 22100 Como, Italy
Received 28 September 2007; revised 9 October 2007
and are useful as novel therapeutic agents to combat the
hepatitis C virus (HCV).6 Thieno[3,2-c]isoquinoline de-
rivatives are useful in the treatment of a variety of inflam-
mations, including, but not limited to, arthritis,
inflammatory bowel disease, Crohn’s disease, and ulcer-
ative colitis.7 These compounds are also effective as anti-
cancer agents.8 Furoisoquinoline derivatives are
considered to be anti-inflammatory and/or anti-arterio-
sclerotic agents. In addition, thieno[3,2-b]pyrrole and fu-
roisoquinoline derivatives (Figure 1) were recently found
to possess glycogen phosphorylase inhibiting activity and
to be useful for the treatment of diabetes.9
Abstract: Nitrogenated heteropolycyclic systems were obtained by
intramolecular palladium-catalyzed coupling reactions promoted
by microwave irradiation.
Key words: palladium catalyst, microwaves, intramolecular cy-
clization, indoles, carbamates
Heteropolycyclic compounds with a nitrogen nucleus
have attracted the attention of researchers, and some strat-
egies for the synthesis of heterocycles based on palladi-
um-catalyzed reactions nicely complement the classical
synthetic approaches.1 The introduction of functionalized
aryl or alkenyl moieties onto heterocyclic compounds is
also an important task in organic synthesis. To this aim,
cross-coupling reactions (Kumada, Negishi, Hiyama,
Stille, Suzuki) are efficient methods, but have several
drawbacks,2 such as low compatibility with a number of
important functional groups and being limited to intermo-
lecular coupling reactions. Palladium-catalyzed coupling
of nucleophilic hetarenes to aryl- and alkenyl halides of-
fers an attractive alternative for the construction of com-
plex polycyclic systems. In addition to its mildness and
functional-group tolerance, this method of carbon–carbon
bond formation offers significant advantages in the syn-
thesis of complex hetarenes through intramolecular cou-
pling.
H
O
N
HOOC
S
N
H
MeO
O
PARS inhibitor
antiviral agent
Figure 1
Starting from furan- or thiophene-2-carboxylic acid
(1a,b) or furan-, thiophene-, or 1-methyl-1H-indole-3-
carboxylic acid (6a–c), the corresponding carbamates
2a,b and 7a–c were prepared via the corresponding non-
isolated carbonyl azides (Scheme 1). The treatment of
carbamates 2 and 7 with 2-iodobenzyl bromide (3a) and
2,3-dibromopropene (3b) gave functionalized substrates
4a,b, 8a–c, and 10a–c (Scheme 1), suitable for intramo-
lecular coupling reactions. The C–C bond formation
through intramolecular coupling was the key step in the
formation of the polycyclic fused systems. The reaction
was performed in dimethylacetamide (DMA) as solvent,
with potassium acetate as base and palladium(II) acetate/
triphenylphosphine as catalyst at 110 °C for 24 hours; this
gave compounds 5a,b, 9a–c, and 11a–c in poor to accept-
able yields (Scheme 1, Table 1). Different mechanistic
pathways can be envisaged for this coupling reaction
(Heck-type mechanism, electrophilic arylation), but elec-
trophilic substitution has been considered the most plausi-
ble hypothesis for this transformation.10
In connection with our previous work on finding synthetic
methods toward heterocondensed nitrogenated ring sys-
tems,3 we decided to investigate the reactivity of carbam-
ates of heterocycles such as furan, thiophene, and indole.
The p-electron-rich heterocycles are suitable substrates
for the electrophilic palladation step because of the favor-
able nucleophilicity of these arenes. Exploiting this strat-
egy, starting from the mentioned substrates, intra-
molecular cyclization gives rise to the following hetero-
polycyclic systems: thieno-, and furo[3,2-b]pyrroles, in-
dolo-, thieno- and furo[3,2-c]isoquinolines, pyrrolo[3,2-
b]indoles, and thieno- and furo[2,3-c]isoquinolines.4
We also noticed from literature data that these types of
skeletons have promising biological properties. Some of
them are considered for the treatment of allergies and
asthma5 and they also show allosteric inhibitory activity
SYNTHESIS 2008, No. 1, pp 0136–0140
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Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-990947; Art ID: Z23107SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Intramolecular Cyclization of Electron-Rich Heterocycle Derivatives
137
Table 1 Comparison of the Yields of Cyclized Products 5a,b, 9a–c,
and 11a–c under Conventional Heating and Microwave Irradiation
I
Br
1) SOCl2
2) aq NaN3, Et2O
NaH,
Product
Yield (%)
3a
NHCO2Et
X
CO2H
3) EtOH, reflux
X
Conventional heatinga Microwave irradiationb
THF, N2
1a: X = O
1b: X = S
2a,b
5a
5b
35
50
70
58
61
71
23
53
80
76
81
65
66
79
33
60
I
Pd(OAc)2, KOAc
9a
PPh3, DMA, 110 °C
N
N
9b
X
X
CO2Et
CO2Et
9c
5a,b
4a,b
11a
11b
11c
R2
R2
CO2H
NHCO2Et
1) SOCl2
2) aq NaN3, Et2O
R1
R1
6a: X = O R1 = R2 = H
3) EtOH, reflux
X
X
a Reagents and conditions: KOAc, Pd(OAc)2, PPh3, DMA, 110 °C, 24
h.
7a–c
6b: X = S
R
1 = R2 = H
Br
6c: X = NMe R1-R2 = -(CH=CH)2-
b Reagents and conditions: KOAc, Pd(OAc)2, PPh3, DMA, 100 °C,
450-W microwave irradiation, 1 h.
Br
3b
I
NaH
In summary, palladium-catalyzed functionalization of
electron-rich heterocycle derivatives was performed in the
intramolecular version; this provided an easy preparation
protocol for fused heteroaromatic compounds. The meth-
od would be applicable for the synthesis of several other
heterocyclic ring systems.
THF, N2
Br
NaH,
CO2Et
3a
THF, N2
CO2Et
R2
R2
N
N
I
Br
10a–c
R1
R1
X
X
8a–c
Melting points were determined on a Büchi B-540 heating appara-
tus and are uncorrected. 1H and 13C NMR spectra were obtained on
an Bruker Avance 400 spectrometer, and chemical shifts are report-
ed relative to TMS. 13C NMR spectra are proton-decoupled, and the
multiplicities were determined by the APT pulse sequence. IR spec-
tra were recorded on a Jasco FT/IR 5300 spectrophotometer.
Pd(OAc)2, KOAc
Pd(OAc)2, KOAc
PPh3, DMA, 110 °C
PPh3, DMA, 110 °C
CO2Et
N
CO2Et
N
R2
R2
Carbamates 2a,b and 7a–c; General Procedure
R1
R1
X
X
A soln of the appropriate acid 1a, 1b, 6a, 6b, or 6c (10 mmol) and
SOCl2 (10 mL) was stirred at 100 °C for 5 h. After evaporation of
the solvent, the residue was taken up with CH2Cl2 (20 mL). A soln
of NaN3 (50 mmol) in H2O (5 mL) and cetyltrimethylammonium
bromide (2.5 mmol) were added. After the mixture had stirred for
18 h at r.t., the organic layer was separated and dried (Na2SO4) and
the solvent was evaporated under reduced pressure. EtOH (10 mL)
was then added and the soln was stirred at 80 °C for 4 h. The solvent
was evaporated under reduced pressure and the residue was purified
by column chromatography (silica gel, CH2Cl2); this gave the cor-
responding products 2a,b or 7a–c.
9a–c
11a–c
Scheme 1
To improve the results, the coupling reactions were per-
formed under microwave irradiation for much shorter re-
action times. Experiments when this methodology is used
may have a different outcome when compared to those
carried out under conventional heating. In Table 1, the
yields for the cyclization reactions carried out under con-
ventional heating are compared with those obtained under
microwave irradiation. Reactions were performed in di-
methylacetamide (DMA) as solvent, with potassium ace-
tate as base and palladium(II) acetate/triphenylphosphine
as catalyst at 100 °C under 450-Watt microwave irradia-
tion for one hour.
Ethyl 2-Furylcarbamate (2a)11
Yield: 70%.
Ethyl 2-Thienylcarbamate (2b)12
Yield: 75%.
Ethyl 3-Furylcarbamate (7a)13
Yield: 65%.
The following comments are applicable to this transfor-
mation: (a) both aryl- and vinyl halides can be used for the
synthesis of a variety of nitrogen-containing heterocycles;
(b) several different heterocyclic systems could be ob-
tained from a common starting material.
Ethyl 3-Thienylcarbamate (7b)14
Yield: 68%.
Synthesis 2008, No. 1, 136–140 © Thieme Stuttgart · New York

138
E. M. Beccalli et al.
PAPER
Ethyl (1-Methyl-1H-indol-3-yl)carbamate (7c)
Yield: 65%; pale yellow oil.
Anal. Calcd for C14H14INO3 (371.18): C, 45.30; H, 3.80; N, 3.77.
Found: C, 45.29; H, 3.71; N, 3.82.
IR (Nujol): 1628, 3273 cm–1.
Ethyl (2-Iodobenzyl)(3-thienyl)carbamate (8b)
Yield: 84%; pale red oil.
IR (Nujol): 1620 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H), 4.27 (q,
J = 7.1 Hz, 2 H), 5.00 (s, 2 H), 6.98 (br s, 1 H), 7.10–7.21 (overlap-
ping, 3 H), 7.24–7.30 (overlapping, 2 H), 7.57 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.9 (q), 54.2 (t), 62.6 (t), 120.1
(s), 122.4 (s), 124.6 (d), 128.0 (d), 128,1 (d), 128,2 (d), 129.0 (d),
133.2 (d), 133.3 (d), 136.9 (s), 156.7 (s).
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.0 Hz, 3 H), 3.75 (s,
3 H), 4.26 (q, J = 7.0 Hz, 2 H), 6.51 (br s, 1 H, absent after deuter-
ation) 7.10 (ddd, J = 1.6, 7.6, 8.2 Hz, 1 H), 7.22–7.39 (overlapping,
3 H), 7.47 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.1 (q), 33.3 (q), 56.8 (t), 110.1
(d), 116.3 (s), 117.7 (s), 118.8 (d), 120.4 (d), 122.1 (d), 124.5 (s),
130.3 (d), 157.0 (s).
Anal. Calcd for C12H14N2O2 (218.26): C, 66.04; H, 6.47; N, 12.84.
Found: C, 66.20; H, 6.31; N, 12.71.
Anal. Calcd for C14H14INO2S (387.24): C, 43.42; H, 3.64; N, 3.62.
Found: C, 43.40; H, 3.61; N, 3.81
Alkylation of Carbamates 2a,b and 7a–c; General Procedure
To a soln of 2a,b or 7a–c (2 mmol) in anhyd THF (15 mL), cooled
to 0 °C, 60% NaH (100 mg, 2.5 mmol) was added in small portions
under N2. The resulting mixture was stirred and allowed to warm to
r.t., and then 3a or 3b (3 mmol) in anhyd THF (5 mL) was added
dropwise. After 4 h the solvent was evaporated and the residue was
diluted with 1 M HCl (10 mL) and extracted with Et2O (2 × 20 mL).
The organic phase was dried (Na2SO4) and evaporated under re-
duced pressure. The residue was purified by column chromatogra-
phy (silica gel, CH2Cl2–Et2O, 5:1); this gave the corresponding
4a,b, 8a–c, or 10a–c.
Ethyl (2-Iodobenzyl)(1-methyl-1H-indol-3-yl)carbamate (8c)
Yield: 65%; brownish oil.
IR (Nujol): 1637 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H), 3.67 (q,
J = 7.1 Hz, 2 H), 4.26 (s, 2 H), 4.97 (s, 3 H), 6.85–6.98 (overlap-
ping, 2 H), 7.15–7.39 (overlapping, 3 H) 7.49–7.54 (overlapping, 2
H), 7.79–7.93 (overlapping, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.1 (q), 33.2 (q), 60.0 (t), 62.5
(t), 100.8 (s), 109.9 (d), 118.9 (d), 120.0 (d), 122.4 (d), 124.7 (s),
125.1 (d), 128.5 (d), 128.7 (d), 129.2 (d), 134.9 (s), 135.7 (s), 139.8
(d), 140.7 (s), 169.8 (s).
Ethyl 2-Furyl(2-iodobenzyl)carbamate (4a)
Yield: 55%; pale yellow oil.
IR (Nujol): 1635 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H), 4.21 (q,
J = 7.1 Hz, 2 H), 4.83 (s, 2 H), 7.16 (br s, 1 H), 7.24–7.33 (overlap-
ping, 5 H), 7.80 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.6 (q), 57.7 (t), 62.8 (t), 93.3
(s), 111.2 (d), 116.1 (s), 128.1 (d), 128.4 (d), 128.5 (d), 129.1 (d),
129.4 (d), 139.6 (d), 147.6 (s), 155.3 (s).
Anal. Calcd for C19H19IN2O2 (434.28): C, 52.55; H, 4.41; N, 6.45.
Found: C, 52.40; H, 4.55; N, 6.48.
Ethyl (2-Bromoprop-2-enyl)(3-furyl)carbamate (10a)
Yield: 46%; brownish oil.
IR (Nujol): 1642 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 4.25 (q,
J = 7.1 Hz, 2 H), 4.44 (s, 2 H), 5.59 (s, 1 H), 5.70 (s, 1 H), 6.45 (br
s, 1 H), 7.30 (s, 1 H), 7.81 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.8 (q), 56.0 (t), 62.8 (t), 117.0
(t), 119.8 (d), 126.0 (d), 128.2 (s), 136.2 (s), 142.1 (d), 158.6 (s).
Anal. Calcd for C14H14INO3 (371.18): C, 45.30; H, 3.80; N, 3.77.
Found: C, 45.40; H, 3.61; N, 3.91.
Ethyl (2-Iodobenzyl)(2-thienyl)carbamate (4b)
Yield: 70%; mp 60–61 °C (Et2O).
IR (Nujol): 1638 cm–1.
Anal. Calcd for C10H12BrNO3 (274.12): C, 43.82; H, 4.41; N, 5.11.
Found: C, 43.80; H, 4,28; N, 5.41.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 4.30 (q,
J = 7.1 Hz, 2 H), 4.98 (s, 2 H), 6.42 (br s, 1 H), 6.77 (dd, J = 5.3, 5.5
Hz, 1 H), 6.93–7.01 (overlapping, 2 H), 7.13 (br s, 1 H), 7.30 (d,
J = 7.4 Hz, 1 H), 7.85 (d, J = 7.8 Hz, 1 H).
Ethyl (2-Bromoprop-2-enyl)(3-thienyl)carbamate (10b)
Yield: 70%; yellow oil.
IR (Nujol): 1628 cm–1.
13C NMR (100 MHz, CDCl3): d = 14.9 (q), 63.3 (t), 69.6 (t), 95.9
(s), 111.7 (d), 113.6 (d), 124.9 (d), 128.7 (d), 128.9 (d), 129.0 (d),
138.7 (s), 139.9 (d), 144.2 (s), 153.3 (s).
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H), 4.25 (q,
J = 7.1 Hz, 2 H), 4.51 (s, 2 H), 5.60 (d, J = 2.1 Hz, 1 H), 5.75 (d,
J = 2.1 Hz, 1 H), 7.12–7.26 (overlapping, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.9 (q), 57.7 (t), 62.9 (t), 117.7
(t), 120.8 (d), 124.7 (d), 126.6 (d), 129.0 (s), 140.0 (s), 155.1 (s).
Anal. Calcd for C14H14INO2S (387.24): C, 43.42; H, 3.64; N, 3.62.
Found: C, 43.40; H, 3.61; N, 3.81.
Anal. Calcd for C10H12BrNO2S (290.18): C, 41.39; H, 4.17; N, 4.83.
Found: C, 41.34; H, 4.31; N, 4.70.
Ethyl 3-Furyl(2-iodobenzyl)carbamate (8a)
Yield: 70%; yellow oil.
IR (Nujol): 1633 cm–1.
Ethyl (2-Bromoprop-2-enyl)(1-methyl-1H-indol-3-yl)carbam-
ate (10c)
Yield: 49%; mp 69–70 °C (i-Pr2O).
IR (Nujol): 1639 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3 H), 3.76 (s,
3 H), 4.28 (q, J = 7.0 Hz, 2 H), 4.60 (s, 2 H), 5.60 (s, 1 H), 5.81 (s,
1 H), 7.12 (s, 1 H), 7.20 (dd, J = 7.2, 7.4 Hz, 1 H), 7.29 (dd, J = 7.2,
7.6 Hz, 1 H), 7.35 (d, J = 7.4 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.0 Hz, 3 H), 4.28 (q,
J = 7.0 Hz, 2 H), 4.84 (s, 2 H), 6.36 (br s, 1 H), 6.97 (dd, J = 7.4, 7.8
Hz, 1 H), 7.11 (br s, 1 H), 7.24–7.32 (overlapping, 2 H), 7.69 (br s,
1 H), 7.86 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.9 (q), 57.6 (t), 62.8 (t), 97.6
(s), 106.1 (s), 127.1 (d), 128.9 (d), 129.3 (d), 132.9 (s), 139.1 (d),
139.9 (d), 140.0 (d), 142.1 (d), 158.3 (s).
Synthesis 2008, No. 1, 136–140 © Thieme Stuttgart · New York

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Intramolecular Cyclization of Electron-Rich Heterocycle Derivatives
139
13C NMR (100 MHz, CDCl3): d = 15.1 (q), 33.2 (q), 58.7 (t), 62.5
(t), 110.0 (d), 117.3 (s), 118.7 (t), 118.9 (d), 120.1 (d), 122.5 (d),
124.5 (s), 125.6 (d), 130.4 (s), 135.8 (s), 157.0 (s).
13C NMR (100 MHz, CDCl3): d = 15.0 (q), 48.3 (t), 62.7 (t), 122.6
(d), 122.7 (d), 122.9 (d), 125,5 (s), 126.1 (d), 127.5 (d), 128.6 (d),
125.9 (s), 136.5 (s), 153.6 (s), 168.1 (s).
Anal. Calcd for C15H17BrN2O2 (337.22): C, 53.43; H, 5.08; N, 8.31.
Found: C, 53.40; H, 5.19; N, 8.45.
Anal. Calcd for C14H13NO2S (259.33): C, 64.84; H, 5.05; N, 5.40.
Found: C, 64.79; H, 5.01; N, 5.52.
Thermal Cyclization of Carbamates 4a,b, 8a–c, and 10a–c;
General Procedure
Ethyl 11-Methyl-5,11-dihydro-6H-indolo[3,2-c]isoquinoline-6-
carboxylate (9c)
Yield: 61%; yellow oil.
IR (Nujol): 1619 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (t, J = 7.0 Hz, 3 H), 4.04 (s,
3 H), 4.30 (q, J = 7.0 Hz, 2 H), 4.95 (s, 2 H), 7.19 (dd, J = 7.3, 7.6
Hz, 1 H), 7.25–7.33 (overlapping, 2 H) 7.37–7.44 (overlapping, 3
H), 7.67–7.71 (overlapping, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.0 (q), 32.6 (q), 49.8 (t), 62.4
(t), 109.8 (d), 120.1 (d), 121.2 (d), 121.4 (s), 122.6 (d), 123.1 (d),
127.1 (d), 127.2 (d), 127.5 (s), 128.2 (d), 128.9 (s), 134.0 (s), 138.0
(s), 140.1 (s), 159.6 (s).
A soln of 4a,b, 8a–c, or 10a–c (1 mmol), Pd(OAc)2 (242 mg, 0.1
mmol), KOAc (196 mg, 2 mmol), and PPh3 (278 mg, 1 mmol) in
DMA (8 mL) was stirred at 100 °C for 24 h. After cooling to r.t., the
mixture was diluted with brine (15 mL) and extracted with Et2O (2
× 20 mL). The organic layer was dried (Na2SO4) and evaporated un-
der reduced pressure. The residue was purified by column chroma-
tography (silica gel, CH2Cl2–Et2O, 1:1); this gave the corresponding
5a,b, 9a–c, or 11a–c.
Ethyl Furo[2,3-c]isoquinoline-4(5H)-carboxylate (5a)
Yield: 45%; brownish oil.
IR (Nujol): 1629 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.0 Hz, 3 H), 4.29 (q,
J = 7.0 Hz, 2 H), 4.99 (s, 2 H), 6.65 (d, J = 2.2 Hz, 1 H), 7.14–7.30
(overlapping, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.9 (q), 50.1 (t), 63.0 (t), 106.7
(d), 107.4 (s), 122.1 (d), 126.2 (d), 126.5 (d), 128.4 (d), 129.7 (s),
132.8 (s), 139.8 (d), 145.7 (s), 167.1 (s).
Anal. Calcd for C19H18N2O2 (306.37): C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.40; H, 5.85; N, 9.28.
Ethyl 6-Methyl-4H-furo[3,2-b]pyrrole-4-carboxylate (11a)
Yield: 71%; pale red oil.
IR (Nujol): 1632 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 2.18 (s,
3 H), 4.41 (q, J = 7.1 Hz, 2 H), 6.65 (br s, 1 H), 7.01 (br s, 1 H), 7.38
(br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 9.2 (q), 14.7 (q), 30.4 (t), 102.4
(d), 109.9 (s), 119.7 (d), 125.9 (d), 149.8 (s), 150.7 (s), 158.4 (s).
Anal. Calcd for C14H13NO3 (243.26): C, 69.12; H, 5.39; N, 5.76.
Found: C, 69.05; H, 5.21; N, 5.81.
Ethyl Thieno[2,3-c]isoquinoline-4(5H)-carboxylate (5b)
Yield: 50%; mp 119–120 °C (cream crystals from Et2O).
IR (Nujol): 1621 cm–1.
Anal. Calcd for C10H11NO3 (193.20): C, 62.17; H, 5.74; N, 7.25.
Found: C, 62.21; H, 5,88; N, 7.31.
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H), 4.31 (q,
J = 7.1 Hz, 2 H), 4.99 (s, 2 H), 6.86 (d, J = 5.6 Hz, 1 H), 7.13–7.38
(overlapping, 4 H), 7.41 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.8 (q), 48.9 (t), 63.1 (t), 117.5
(s), 118.6 (d), 120.5 (d), 122.2 (d), 126.1 (d), 128.4 (d), 128.9 (s),
130.4 (d), 134.9 (s), 138.4 (s), 153.3 (s).
Ethyl 6-Methyl-4H-thieno[3,2-b]pyrrole-4-carboxylate (11b)
Yield: 30%; yellow oil.
IR (Nujol): 1628 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.46 (t, J = 7.1 Hz, 3 H), 2.24 (s,
3 H), 4.46 (q, J = 7.1 Hz, 2 H), 7.19–7.35 (overlapping, 3 H).
13C NMR (100 MHz, CDCl3): d = 11.6 (q), 14.8 (q), 63.5 (t), 115.5
(d), 117.1 (s), 121.4 (d), 125.2 (d), 129.3 (s), 150.5 (s), 168.1 (s).
Anal. Calcd for C14H13NO2S (259.33): C, 64.84; H, 5.05; N, 5.40.
Found: C, 64.80; H, 5.01; N, 5.33.
Anal. Calcd for C10H11NO2S (209.278): C, 57.40; H, 5.30; N, 6.69.
Found: C, 57.34; H, 5.21; N, 6.70.
Ethyl Furo[3,2-c]isoquinoline-4(5H)-carboxylate (9a)
Yield: 70%; yellow oil.
IR (Nujol): 1633 cm–1.
Ethyl 3,4-Dimethylpyrrolo[3,2-b]indole-1(4H)-carboxylate
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.0 Hz, 3 H), 4.28 (q,
J = 7.0 Hz, 2 H), 4.96 (s, 2 H), 6.96 (dd, J = 7.7, 7.8 Hz, 1 H), 7.09–
7.59 (overlapping, 3 H), 7.76 (ddd, J = 1.2, 7.7, 8.0 Hz, 1 H), 7.84
(d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.8 (q), 48.4 (t), 62.4 (t), 107.7
(d), 118.4 (d), 124.6 (s), 126.0 (d), 126.2 (s), 126.8 (d), 128.2 (d),
128.4 (s), 140.3 (s), 141.7 (d), 153.4 (s).
(11c)
Yield: 53%; pale yellow oil.
IR (Nujol): 1631 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (t, J = 7.2 Hz, 3 H), 2.39 (s,
3 H), 3.87 (s, 3 H), 4.57 (q, J = 7.2 Hz, 2 H), 7.14–7.20 (overlap-
ping, 2 H) 7.26 (dd, J = 7.8, 8.0 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H),
8.17 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 10.9 (q), 15.0 (q), 30.9 (q), 63.5
(t), 109.3 (d), 109.5 (s), 116.4 (s), 119.1 (d), 121.6 (d), 129.2 (d),
131.3 (d), 132.8 (s), 141.2 (s), 151.1 (s), 171.5 (s).
Anal. Calcd for C14H13NO3 (243.26): C, 69.12; H, 5.39; N, 5.76.
Found: C, 69.29; H, 5.41; N, 5.83.
Ethyl Thieno[3,2-c]isoquinoline-4(5H)-carboxylate (9b)
Yield: 58%; brownish oil.
IR (Nujol): 1620 cm–1.
Anal. Calcd for C15H16N2O2 (256.31): C, 70.29; H, 6.29; N, 10.93.
Found: C, 70.40; H, 6.19; N, 10.85.
1H NMR (400 MHz, CDCl3): d = 1.37 (t, J = 7.1 Hz, 3 H), 4.30 (q,
J = 7.1 Hz, 2 H), 4.97 (s, 2 H), 7.16–7.24 (overlapping, 4 H), 7.29
(ddd, J = 1.7, 7.4, 8.3 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H).
Cyclization of Carbamates 4a,b, 8a–c, and 10a–c under Micro-
wave Irradiation; General Procedure
A soln of 4a,b, 8a–c, or 10a–c (1 mmol), Pd(OAc)2 (242 mg, 0.1
mmol), KOAc (196 mg, 2 mmol), and PPh3 (278 mg, 1 mmol) in
DMA (8 mL) was stirred at 100 °C under 450-W microwave irradi-
Synthesis 2008, No. 1, 136–140 © Thieme Stuttgart · New York

140
E. M. Beccalli et al.
PAPER
ation for 1 h. After cooling to r.t., the mixture was diluted with brine
(15 mL) and extracted with Et2O (2 × 20 mL). The organic layer was
dried (Na2SO4) and evaporated under reduced pressure. The residue
was purified by column chromatography (silica gel, CH2Cl2–Et2O,
1:1); this gave the corresponding 5a,b, 9a–c, or 11a–c (see Table 1
for yields).
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Acknowledgment
The authors gratefully acknowledge the MUR for financial support.
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Synthesis 2008, No. 1, 136–140 © Thieme Stuttgart · New York