Palladium-catalyzed cyclization/carbonylation as a direct route to 4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones

Article abstract of DOI:10.1002/ejoc.200800747

An efficient synthetic protocol for the preparation of 4-[(methoxycarbonyl) methyl]-3,4-dihydroisoquinolin-1-ones from N-allylamides of 2-iodobenzoic acids has been performed under 100 atm of carbon monoxide. Pyridine ring formation occurs through an intramolecular Pd-catalyzed carbon-carbon bond formation, followed by an alkoxycarbonylation process. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800747

FULL PAPER
DOI: 10.1002/ejoc.200800747
Palladium-Catalyzed Cyclization/Carbonylation as a Direct Route to
4-[(Methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones
G. Attilio Ardizzoia,[a] Egle M. Beccalli,[b] Elena Borsini,[a] Stefano Brenna,[a]
Gianluigi Broggini,*[a] and Micol Rigamonti[a]
Keywords: Carbonylations / Cyclizations / Palladium / Nitrogen heterocycles
An efficient synthetic protocol for the preparation of
4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolin-1-ones
from N-allylamides of 2-iodobenzoic acids has been per-
formed under 100 atm of carbon monoxide. Pyridine ring for-
mation occurs through an intramolecular Pd-catalyzed car-
bon–carbon bond formation, followed by an alkoxycarbon-
ylation process.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tion of N-allyl-2-iodobenzylamines, followed by a 1,3-di-
polar cycloaddition.[6]
Introduction
The Pd-catalyzed carbonylation of unsaturated sub-
strates represents an attractive methodology for the entry
into functionalized heterocyclic compounds.[1] These reac-
tions can take place with carbon monoxide incorporation
into the cycle by a cyclocarbonylation process[2] or with a
cyclization/carbonylation process with formation of rings
having an exocylic carbonyl group.[3]
We herein report a synthetic procedure to attain 4-
[(methoxycarbonyl)methyl]-substituted isoquinolin-1-ones
by an intramolecular Heck-type cyclization of aryl iodides
bearing a carbon–carbon double bond, carried out in the
presence of carbon monoxide.
In this field, despite not being as extensively studied as
other Pd-catalyzed carbon–carbon bond-forming reactions,
carbonylative cyclizations with vinyl or aryl halides bearing
an ethylenic functionality were proven to be useful pro-
cesses for the preparation of (hetero)aromatic carboxylic
acid derivatives (Figure 1).[4]
Results and Discussion
As starting materials suitable to build the isoquinolinic
skeleton, we envisioned the N-allylamides of the 2-iodoben-
zoic acids 3, easily available from the 2-iodobenzoyl chlo-
ride (1) and the N-alkyl-N-allylamines 2a–d (Scheme 1).
Figure 1. General Pd-catalyzed carbonylative cyclization process.
Among the nitrogen-containing heterocycles, isoquinol-
ines represent one of the most attractive products, due to
their presence in a wide range of compounds endowed with
biological and pharmacological properties.[5]
Recently, we reported a protocol for the preparation of
4-spiroannulated isoquinoline derivatives in which the key
step consisted of an intramolecular, Pd-catalyzed cycliza-
Scheme 1. Synthetic approach to access 4-[(methoxycarbonyl)-
methyl]-3,4-dihydroisoquinolin-1-ones.
[a] Dipartimento di Scienze Chimiche e Ambientali, Università
dell’Insubria,
Via Valleggio 11, 22100 Como, Italy
Fax: +39-031-2386449
E-mail: gianluigi.broggini@uninsubria.it
[b] Istituto di Chimica Organica “A. Marchesini”, Facoltà di Far-
macia, Università di Milano,
In order to test the feasibility of the carbonylative cycli-
zation of amides 3, we investigated the intramolecular reac-
tion of N,N-diallylamide 3a in the presence of Et3N
Via Venezian 21, 20133 Milano, Italy
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4-[(Methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones
(2 equiv.), MeOH (4 equiv.) and catalytic amounts of amides 3b–d, starting with 2-iodobenzoyl chloride and the
PdCl2(PPh3)2. The reaction was performed in MeCN at commercially available N-alkyl- and N-aryl-N-allylamines.
80 °C under carbon monoxide (50 atm). Under these condi- The isoquinoline products 4b–d were obtained in 55–61%
tions, the desired 3,4-dihydroisoquinolinone product was yield.
obtained in 32% yield, along with the competitive acyclic
We next examined the cyclization of N-allylamides 9 by
methoxycarbonyl product 5 and product 6, deriving from starting from differently substituted benzoic acids 8a–c. The
the shift of the C–C double bond of the initially formed reactions occurred analogously to those of amides 3 giving
1
Heck product 7. The latter was detected in the H NMR rise to 4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinol-
spectrum of the crude mixture but could not be isolated in inones 10 (Table 2).
pure form. On substrate 3a, we screened different combina-
The mechanism of the process can be rationalized as de-
tions of three parameters (catalyst, solvent and pressure) picted in Scheme 2. The oxidative addition of the carbon–
with the aim to optimize the reaction and prevent the acy- iodine bond of aryl iodides 3 to Pd0, generated in situ from
clic product of alkoxycarboxylation of the iodine-substi-
tuted aromatic carbon atom.
From the conditions collected in Table 1, some features
should be pointed out. First, the carbonylative cyclization
was significantly accomplished only in the presence of cata-
lytic systems with phosphane ligands. In fact, PdCl2-
(PPh3)2, PdCl2(PTol3)2, PdCl2(PCy3)2 and Pd(PPh3)4 gave
similar results, even though better results were achieved
with PdCl2(PPh3)2. The reaction required the use of polar
aprotic solvents, among which MeCN was the most suit-
able. The addition of a co-solvent, such as toluene, DMF,
THF or DMSO did not improve the yields. With MeOH as
solvent, only unreacted starting material was recovered.
The temperature was also important, and was optimal at
80 °C. By working at higher temperatures the yields de-
creased due to an increase in the amount of degradation
products (Entry 5, Table 1). Finally, the conversion of the
amide 3 took place in better yields by increasing the pres-
sure to 100 atm. Having optimized the parameters, we con-
firmed the general effectiveness of the conditions of Entry 4
Scheme 2. Plausible mechanism for the carbonylative catalytic cy-
(Table 1) for the alkoxycarbonylation process on N-allyl- cle.
Table 1. Optimization of the carbonylative cyclization conditions.
Entry
Catalyst
MeOH [equiv.]
Solvent
Pressure [atm] / T [°C]
R
Yield [%]
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PTol3)2
PdCl2(Pcyclohexyl3)2
Pd(PPh3)4
Pd sponge + PPh3
Pd black
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
4
4
4
4
4
40
–
4
4
4
4
4
4
4
MeCN
DMF
50 / 80
50 / 80
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
32
15
26
59
51
13
–
55
52
43
–
40
36
34
4
6
64
–
6
5
8
–
13
21
–
–
–
–
–
–
–
–
–
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50 / 100
100 / 80
100 / 120
100 / 80
100 / 80
100 / 80
100 / 80
100 / 80
110 / 80
110 / 80
100 / 80
100 / 80
100 / 80
allyl
allyl
allyl
5
8
–
–
–
cyclohexyl
cyclopentyl
phenyl
58
55
61
4
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Table 2. Synthesis of substituted 4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones (under the conditions of Entry 4 of Table 1).
PdCl2L2, resulted in the corresponding PdII complex inter- and high temperatures were determinant factors in optimiz-
mediates A. The following intramolecular carbopalladation ing the production of the desired 4-[(methoxycarbonyl)-
gave the (σ-alkyl)Pd complexes B. The carbon monoxide methyl]-3,4-dihydroisoquinolinones.
activation yielded a complex with a carbonyl ligand (C),
and the insertion of CO into the Pd–C bond, occurring
faster than β-elimination, formed the (acyl)Pd complexes Experimental Section
D. The nucleophilic displacement by MeOH finally led to
General: Melting points were determined by the capillary method
products 4, with the simultaneous regeneration of the cata-
with a Büchi B-540 apparatus and are uncorrected. NMR spectra
lytically active Pd0 species.
were recorded with an AVANCE 400 Bruker spectrometer at
1
400 MHz for H NMR and 100 MHz for 13C NMR spectroscopy.
Chemical shifts are given as δ values in ppm relative to the residual
solvent peaks (CHCl3) as the internal reference. 13C NMR spectra
are H-decoupled, and the determination of the multiplicities was
achieved by the APT pulse sequence. IR spectra were measured
with a Jasco FT/IR 5300 spectrometer. Mass spectra were deter-
mined with a VG-7070 EQ-HF instrument. Elemental analyses
Conclusions
1
We have developed a new protocol for the direct synthe-
sis of dihydroisoquinolinones bearing a (methoxycarbonyl)-
methyl group in position 4 by means of a Pd-catalyzed car-
bonylative cyclization. We found that a high CO pressure were executed with a Perkin–Elmer CHN Analyzer Series II 2400.
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Eur. J. Org. Chem. 2008, 5590–5596

4-[(Methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones
Thin-layer chromatographic separations were performed with
Merck silica gel 60-F254 (precoated). Preparative separations were
performed by flash chromatography with Merck silica gel (0.035–
0.070 mm). High-pressure experiments were conducted with a
100 mL PARR stainless steel autoclave reactor equipped with an
Ashcroft Duralife (3000 psi) pressure gauge and a PARR 4842 tem-
perature controller.
7.6, 7.4 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, minor conformer): δ = 24.6 (t), 30.2 (t), 49.0
(t), 57.0 (d), 93.2 (s), 117.0 (t), 127.7 (d), 128.3 (d), 130.3 (d), 135.3
(d), 139.2 (d), 143.4 (s), 171.4 (s) ppm. MS: m/z = 355 [M]+.
C15H18INO (355.21): calcd. C 50.72, H 5.11, N 3.94; found C
50.95, H 4.93, N 3.81.
N-Allyl-N-phenyl-2-iodobenzamide (3d): Yield 924 mg (67%); pale
General Procedure for the Synthesis of N-Alkyl-N-allyl-2-iodobenz-
amides 3: A solution of N-alkyl-N-allylamine (3.8 mmol) in dry
CH2Cl2 (6 mL) was added dropwise into a solution of 2-iodoben-
zoyl chloride (1.0 g, 3.8 mmol) and Et3N (0.63 mL, 4.5 mmol) in
dry CH2Cl2 (6 mL). After stirring overnight, the mixture was
washed with HCl (1 , 30 mL) and aqueous NaHCO3 (5%,
30 mL). The organic phase was dried with Na2SO4, and the solvent
was evaporated. The products were obtained pure enough for char-
acterization.
yellow oil. IR (nujol): ν = 1655 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 4.53 (d, J = 6.0 Hz, 2 H), 5.18 (d, J = 10.6 Hz, 1 H), 5.22 (d,
J = 19.0 Hz, 1 H), 6.03 (ddt, J = 19.0, 10.6, 6.0 Hz, 1 H), 6.79 (dd,
J = 7.8, 7.3 Hz, 1 H), 6.99–7.19 (m, 6 H), 7.28–7.48 (m, 1 H), 7.62
(d, J = 7.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.7
(t), 94.2 (s), 118.8 (t), 127.7 (d), 127.8 (d), 128.4 (d), 128.9 (d), 129.3
(d), 130.1 (d), 133.1 (d), 139.5 (d), 142.2 (s), 142.6 (s), 170.1 (s)
ppm. MS: m/z = 363 [M]+. C16H14INO (363.19): calcd. C 52.91, H
3.89, N 3.86; found C 53.06, H 4.71, N 3.99.
N,N-Diallyl-2-iodobenzamide (3a): Yield 1.106 g (89%); pale yellow General Procedure for the Synthesis of N-Alkyl-N-allyl-2-iodoaryl-
1
oil. IR (nujol): ν = 1672 cm–1. H NMR (400 MHz, CDCl ): δ =
amides 9. Procedure A: DCC (824 mg, 4 mmol), N-alkyl-N-allyl-
amine (3.33 mmol) and DMAP (6 mg, 0.05 mmol) were added to
a solution of 2-iodobenzoic acid 8a–c (4 mmol) in dry CH2Cl2
(30 mL), cooled to 0 °C. The mixture was stirred at room tempera-
ture for 48 h and then filtered through Celite. The solvent was evap-
orated, and the crude mixture was purified by silica gel column
chromatography with light petroleum/AcOEt (7:3) as the eluent.
Procedure B: A solution of 2-iodobenzoic acid 8a,c (1 mmol) in
˜
3
3.72 (s, 2 H), 3.77–3.83 (m, 1 H), 4.54–4.60 (m, 1 H), 5.12 (dd, J
= 17.1, 1.4 Hz, 1 H), 5.20 (dd, J = 10.1, 1.4 Hz, 1 H), 5.28 (dd, J
= 10.1, 1.3 Hz, 1 H), 5.33 (dd, J = 17.1, 1.3 Hz, 1 H), 5.69 (ddt, J
= 17.1, 10.1, 5.7 Hz, 1 H), 5.96 (ddt, J = 17.1, 10.1, 6.2 Hz, 1 H),
7.09 (ddd, J = 7.8, 7.6, 1.7 Hz 1 H), 7.22 (dd, J = 7.6, 1.7 Hz, 1
H), 7.38 (ddd, J = 8.0, 7.8, 1.1 Hz, 1 H), 7.84 (dd, J = 8.0, 1.1 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 46.8 (t), 50.7 (t), 93.0
(s), 118.5 (t), 118.8 (t), 127.4 (d), 128.6 (d), 130.6 (d), 132.8 (d), SOCl2 (2 mL) was refluxed for 4 h. The solvent was removed under
133.0 (d), 139.5 (d), 142.6 (s), 170.8 (s) ppm. MS: m/z = 327 [M]+.
C13H14INO (327.16): calcd. C 47.73, H 4.31, N 4.28; found C
47.82, H 4.19, N 4.45.
reduced pressure, and the crude product was dissolved in CH2Cl2
(10 mL). After cooling the mixture to 0 °C, N-alkyl-N-allylamine
(1.5 mmol) and Et3N (0.20 mL, 1.5 mmol) were added dropwise.
The mixture was stirred at room temperature for 48 h and then
washed with HCl (1 , 20 mL) and with aqueous NaHCO3 (5%,
20 mL). The organic phase was dried with Na2SO4, and the solvent
was removed under reduced pressure. The products were obtained
pure enough for characterization.
N-Allyl-N-cyclohexyl-2-iodobenzamide (3b): Yield 1.024 g (73%);
yellow oil. IR (nujol): ν = 1658 cm–1. 1H NMR (400 MHz, CDCl ,
˜
3
mixture of two conformers in a 1:1 ratio): δ = 0.81–2.10 (m, 20 H),
3.14–3.24 (m, 1 H), 3.59–3.83 (m, 2 H), 3.99 and 4.23 (AB part of
ABX system, J = 15.4, 5.1 Hz, 2 H), 4.45–4.51 (m, 1 H), 4.91 (d,
J = 17.1 Hz, 1 H), 5.01 (d, J = 10.3 Hz, 1 H), 5.28 (d, J = 10.3 Hz, N,N-Diallyl-6-fluoro-2-iodobenzamide (9aa): Procedure A; yield
1 H), 5.34 (d, J = 17.1 Hz, 1 H), 5.69 (ddt, J = 17.1, 10.3, 5.1 Hz, 1.0 g (87%); colourless oil. IR (nujol): ν = 1682 cm–1. 1H NMR
˜
1 H), 6.06 (ddt, J = 17.1, 10.3, 5.1 Hz, 1 H), 7.04–7.11 (m, 2 H), (400 MHz, CDCl3): δ = 3.73 (d, J = 6.1 Hz, 2 H), 3.98 and 4.42
7.18–7.21 (m, 2 H), 7.33–7.41 (m, 2 H), 7.81 (d, J = 8.0 Hz, 1 H), (AB part of ABX system, J = 15.0, 6.0 Hz, 2 H), 5.12 (d, J =
7.86 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, mix-
ture of two conformers in a 1:1 ratio): δ = 25.5 (t), 26.0 (t), 26.1
17.1 Hz, 1 H), 5.18 (d, J = 10.2 Hz, 1 H), 5.27 (d, J = 10.2 Hz, 1
H), 5.27 (d, J = 17.4 Hz, 1 H), 5.73 (ddt, J = 17.1, 10.2, 6.1 Hz, 1
(t), 26.4 (t), 32.2 (t), 32.4 (t), 44.4 (t), 48.3 (t), 54.8 (d), 59.7 (d), H), 5.92 (ddt, J = 17.4, 10.2, 6.0 Hz, 1 H), 7.06–7.11 (m, 2 H), 7.62
92.9 (s), 93.3 (s), 116.8 (t), 117.2 (t), 126.8 (d), 127.9 (d), 128.3 (d),
128.6 (d), 130.2 (d), 130.4 (d), 135.5 (d), 135.7 (d), 139.3 (d) 139.7
(d), 143.4 (s), 143.5 (s), 170.8 (s), 171.2 (s) ppm. MS: m/z = 369
[M]+. C16H20INO (369.24): calcd. C 52.05, H 5.46, N 3.79l; found
C 52.26, H 5.31, N 3.64.
(d, J = 7.1 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 46.8
(t), 51.0 (t), 93.9 (s), 116.0 (d), 116.2 (d), 118.7 (t), 119.3 (t), 131.0
(d, JC,F = 21.4 Hz), 131.8 (dd, JC,F = 8.1 Hz), 132.7 (dd, JC,F
=
28.2 Hz), 135.4 (d), 158.3 (d, JC,F = 249.9 Hz), 166.2 (s) ppm. MS:
m/z = 345 [M]+. C13H13FINO (345.15): calcd. C 45.24, H 3.80, N
4.06; found C 44.99, H 3.92, N 3.79.
N-Allyl-N-cyclopentyl-2-iodobenzamide (3c): Yield 1.107 g (82%) as
a mixture of two conformers in a 2:1 ratio; yellow oil. IR (nujol):
˜
N-Allyl-6-fluoro-2-iodo-N-methylbenzamide (9ae): Procedure B;
1
ν = 1667 cm–1. 1H NMR (400 MHz, CDCl3 major conformer): δ
yield 252 mg (79%); colourless oil. IR (nujol): ν = 1677 cm–1. H
˜
= 1.37–1.51 (m, 2 H), 1.54–1.82 (m, 5 H), 1.88–1.99 (m, 1 H), 3.73–
3.86 (m, 1 H), 3.94 and 4.21 (AB part of ABX system, J = 15.6,
5.8 Hz, 2 H), 5.21 (d, J = 10.3 Hz, 1 H), 5.36 (d, J = 17.3 Hz, 1
H), 6.10 (ddt, J = 17.3, 10.3, 5.8 Hz, 1 H), 7.08 (dd, J = 7.9, 7.4 Hz,
1 H), 7.21 (d, J = 7.5 Hz, 1 H), 7.39 (dd, J = 7.5, 7.4 Hz, 1 H),
7.85 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, major
conformer): δ = 24.1 (t), 30.2 (t), 44.4 (t), 60.9 (d), 92.9 (s), 116.4
(t), 127.0 (d), 128.6 (d), 130.3 (d), 135.2 (d), 139.6 (d), 143.6 (s),
NMR (400 MHz, CDCl3, mixture of two conformers in a 1:1 ra-
tio): δ = 2.83 (s, 3 H), 3.12 (s, 3 H), 3.73 and 3.78 (AB part of ABX
system, J = 18.4, 6.3 Hz, 2 H), 4.16 and 4.30 (AB part of ABX
system, J = 14.5, 5.7 Hz, 2 H), 5.19 (d, J = 11.8 Hz, 1 H), 5.23 (d,
J = 10.3 Hz, 1 H), 5.30 (d, J = 10.2 Hz, 1 H), 5.36 (d, J = 17.2 Hz,
1 H), 5.76 (ddt, J = 17.2, 10.2, 5.7 Hz, 1 H), 5.92 (ddt, J = 11.8,
10.3, 6.3 Hz, 1 H), 7.04–7.16 (m, 4 H), 7.62–7.66 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 32.6 (q), 35.6 (q), 49.8 (t), 54.0
(t), 93.2 (s), 93.6 (s), 116.0 (d), 116.2 (d), 118.5 (t), 119.3 (t), 129.6
1
170.8 (s) ppm. H NMR (400 MHz, CDCl3, minor conformer): δ
= 1.37–1.51 (m, 2 H), 1.54–1.82 (m, 5 H), 2.05–2.15 (m, 1 H), 3.63–
(d, JC,F = 22.8 Hz), 131.0 (d, JC,F = 21.4 Hz), 131.3 (dd, JC,F =
3.72 (m, 2 H), 4.72–4.84 (m, 1 H), 5.01 (d, J = 17.1 Hz, 1 H), 5.08 8.2 Hz), 131.7 (dd, JC,F = 7.8 Hz), 132.2 (dd, JC,F = 28.5 Hz), 132.6
(d, J = 10.3 Hz, 1 H), 5.69 (ddt, J = 17.1, 10.3, 5.9 Hz, 1 H), 7.05 (dd, JC,F = 27.7 Hz), 132.8 (d), 133.3 (d), 158.3 (d, JC,F
(dd, J = 7.8, 7.4 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.35 (dd, J = 249.9 Hz), 163.8 (d, JC,F = 242.1 Hz), 166.0 (s), 166.2 (s) ppm. MS:
=
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G. Broggini et al.
FULL PAPER
m/z = 319 [M]+. C11H11FINO (319.11): calcd. C 41.40, H 3.47, N
4.39; found C 41.65, H 3.23, N 4.45.
J = 7.5 Hz, 1 H), 5.24 (d, J = 15.6 Hz, 1 H), 5.62 (ddt, J = 15.6,
7.5, 6.2 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 7.09 (dd, J = 8.2,
1.8 Hz, 1 H), 7.13–7.45 (m, 5 H), 7.68 (d, J = 1.8 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 52.8 (t), 94.4 (s), 118.9 (t), 127.4
(d), 128.0 (d), 128.3 (d), 129.4 (d), 129.5 (d), 132.8 (d), 134.9 (s),
139.0 (d), 141.2 (s), 142.0 (s), 169.3 (s) ppm. MS: m/z = 397 [M]+.
C16H13ClINO (397.64): calcd. C 48.33, H 3.30, N 3.52; found C
48.42, H 3.19, N 3.68.
N,N-Diallyl-2-iodo-3-methylbenzamide (9ba): Procedure A; yield
977 mg (86%); pale yellow oil. IR (nujol): ν = 1686 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.68 (d, J = 4.9 Hz, 2 H),
3.77 and 4.56 (AB part of ABX system, J = 14.8, 5.0 Hz, 2 H),
5.09 (d, J = 17.1 Hz, 1 H), 5.15 (d, J = 10.2 Hz, 1 H), 5.25 (d, J =
10.2 Hz, 1 H) 5.30 (d, J = 16.2 Hz, 1 H), 5.66 (ddt, J = 17.2, 10.2,
4.9 Hz, 1 H), 5.95 (ddt, J = 16.2, 10.2, 5.0 Hz, 1 H), 6.96 (d, J =
7.1 Hz, 1 H), 7.19–7.28 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 29.3 (q), 46.7 (t), 50.7 (t), 99.8 (s), 118.5 (t), 118.8 (t),
124.6 (d), 128.7 (d), 130.0 (d), 132.9 (d), 133.1 (d), 143.0 (s), 143.7
(s), 171.5 (s) ppm. MS: m/z = 341 [M]+. C14H16INO (341.19): calcd.
C 49.28, H 4.73, N 4.11; found C 49.07, H 4.84, N 4.26.
4-Chloro-N-ethyl-2-iodo-N-(2-methylallyl)benzamide (9cf): Pro-
cedure A; yield 1.078 g (89%) as a mixture of two conformer in
a 1.5:1 ratio; colourless oil. IR (nujol): ν = 1651 cm–1. 1H NMR
˜
(400 MHz, CDCl3, major conformer): δ = 1.28 (t, J = 7.1 Hz, 3
H), 1.60 (s, 3 H), 3.04–3.16 (m, 2 H), 3.57–3.67 (m, 2 H), 4.90 (d,
J = 22.8 Hz, 2 H), 7.15 (d, J = 8.2 Hz, 1 H), 7.35 (dd, J = 8.2,
1.9 Hz, 1 H), 7.83 (d, J = 1.9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, major conformer): δ = 12.3 (q), 20.5 (q), 39.7 (t), 49.2 (t),
60.8 (s), 93.4 (s), 113.4 (t), 128.3 (d), 128.9 (d), 139.2 (d), 140.8
(s), 141.1 (s), 170.2 (s) ppm. 1H NMR (400 MHz, CDCl3, minor
conformer): δ = 1.06 (t, J = 7.1 Hz, 3 H), 1.86 (s, 3 H), 3.95–4.07
(m, 3 H), 4.38–4.44 (m, 1 H), 5.01 (d, J = 11.4 Hz, 2 H), 7.15 (d,
J = 8.2 Hz, 1 H), 7.39 (dd, J = 8.2, 1.9 Hz, 1 H), 7.87 (d, J =
1.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, minor conformer):
δ = 13.7 (q), 21.1 (q), 42.6 (t), 54.1 (t), 59.8 (s), 93.1 (s), 114.0 (t),
128.4 (d), 129.0 (d), 138.9 (d), 140.4 (s), 141.8 (s), 170.0 (s) ppm.
MS: m/z = 363 [M]+. C13H15ClINO (363.62): calcd. C 42.94, H
4.16, N 3.85; found C 42.71, H 4.24, N 3.70.
N,N-Diallyl-4-chloro-2-iodobenzamide (9ca): Procedure A; yield
1
975 mg (81%); colourless oil. IR (nujol): ν = 1663 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 3.63–3.75 (m, 3 H), 4.45–4.55 (m, 1 H),
5.07 (d, J = 17.1 Hz, 1 H), 5.18 (d, J = 10.3 Hz, 1 H), 5.23 (d, J =
10.1 Hz, 1 H), 5.28 (d, J = 17.1 Hz, 1 H), 5.58–5.66 (m, 1 H), 5.86–
5.94 (m, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H),
7.79 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 47.0 (t), 50.7
(t), 93.3 (s), 118.6 (t), 119.0 (t), 128.1 (d), 128.9 (d), 132.6 (d), 132.8
(d), 135.4 (s), 139.0 (d), 141.1 (s), 170.0 (s) ppm. MS: m/z = 361
[M]+. C13H13ClINO (361.61): calcd. C 43.18, H 3.62, N 3.87; found
C 43.19, H 3.84, N 3.76.
N-Allyl-4-chloro-N-cyclohexyl-2-iodobenzamide (9cb): Procedure A;
1
yield 739 mg (55%); colourless oil. IR (nujol): ν = 1654 cm–1. H
General Procedure for the Pd-Catalyzed Carbonylative Cyclization:
A mixture of 2-iodobenzamide 3 or 9 (1 mmol), PdCl2(PPh3)2
(35 mg, 0.05 mmol), Et3N (0.28 mL, 2 mmol) and MeOH
(0.16 mL, 4 mmol) in MeCN (20 mL) was placed in an autoclave.
It was first purged 3 times with 20 atm of CO to remove residual air
and then charged with 100 atm of CO. Caution: Carbon monoxide is
highly toxic! The autoclave was heated at 80 °C for 24 h and then
cooled to room temperature. After CO removal, the yellow solution
was diluted with brine (20 mL), extracted with AcOEt (3ϫ20 mL),
and the organic phases were dried with Na2SO4. The solvent was
evaporated. The products were purified by silica gel column
chromatography with light petroleum/AcOEt (9:1) to AcOEt as the
eluent to give 4 or 10.
˜
NMR (400 MHz, CDCl3, mixture of two conformers in a 1:1 ra-
tio): δ = 0.98–2.05 (m, 20 H), 3.10–3.18 (m, 1 H), 3.49–3.81 (m, 2
H), 3.96 and 4.19 (AB part of ABX system, J = 15.4, 5.8 Hz, 2 H),
4.39–4.49 (m, 1 H), 4.92 (d, J = 18.3 Hz, 1 H), 5.03 (d, J = 10.3 Hz,
1 H), 5.16 (d, J = 10.3 Hz, 1 H), 5.32 (d, J = 17.3 Hz, 1 H) 5.61–
5.70 (m, 1 H), 5.97–6.07 (m, 1 H), 7.09 (d, J = 8.2 Hz, 1 H), 7.10
(d, J = 8.2 Hz, 1 H), 7.32 (dd, J = 8.2, 2.0 Hz, 1 H), 7.36 (dd, J =
8.2, 2.0 Hz, 1 H), 7.79 (d, J = 2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.2 (t), 25.5 (t), 25.9
(t), 26.0 (t), 26.1 (t), 30.5 (t), 31.3 (t), 32.2 (t), 32.4 (t), 33.2 (t), 44.5
(t), 48.3 (t), 54.9 (d), 59.8 (d), 93.1 (s), 93.5 (s), 117.0 (t), 117.4 (t),
128.2 (d), 128.6 (d), 128.7 (d), 129.0 (d), 135.0 (s), 135.1 (s), 135.3
(d), 135.5 (d), 138.7 (d), 139.1 (d), 141.2 (s), 142.1 (s), 169.9 (s),
170.4 (s) ppm. MS: m/z = 403 [M]+. C16H19ClINO (403.69): calcd.
C 47.61, H 4.74, N 3.47; found C 47.84, H 4.66, N 3.61.
2-Allyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolin-1-one
(4a): Yield 153 mg (59%); pale yellow oil. IR (nujol): ν = 1663,
˜
1709 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.50 (dd, J = 16.0,
5.5 Hz, 1 H), 2.61 (dd, J = 16.0, 8.6 Hz, 1 H), 3.33–3.39 (m, 1 H),
3.36 (dd, J = 13.7, 3.2 Hz, 1 H), 3.61 (s, 3 H), 3.67 (dd, J = 13.7,
5.2 Hz, 1 H), 4.01 and 4.22 (AB part of ABX system, J = 14.8,
6.3 Hz, 2 H), 5.16 (d, J = 11.1 Hz, 1 H), 5.19 (d, J = 15.7 Hz, 1
H), 5.78 (ddt, J = 15.7, 11.1, 6.3 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1
H), 7.29 (dd, J = 7.5, 7.4 Hz, 1 H), 7.37 (dd, J = 7.7, 7.4 Hz, 1 H),
8.03 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
34.6 (q), 38.1 (t), 49.2 (t), 50.0 (t), 52.1 (d), 118.8 (t), 126.8 (d),
127.9 (d), 128.9 (d), 129.0 (s), 132.4 (d), 133.1 (d), 140.9 (s), 164.0
(s), 172.3 (s) ppm. MS: m/z = 259 [M]+. C15H17NO3 (259.30): calcd.
C 69.48, H 6.61, N 5.40; found C 69.70, H 6.33, N 5.36.
N-Allyl-4-chloro-N-cyclopentyl-2-iodobenzamide (9cc): Procedure
B; yield 335 mg (86%); pale yellow oil. IR (nujol): ν = 1669 cm–1.
˜
1H NMR (400 MHz, CDCl3, mixture of two conformers in a 1:1
ratio): δ = 1.25–2.10 (m, 16 H), 3.50–3.80 (m, 3 H), 3.93 and 4.19
(AB part of ABX system, J = 15.6, 5.5 Hz, 2 H), 4.71–4.77 (m, 1
H), 5.04 (d, J = 10.4 Hz, 1 H), 5.12 (d, J = 10.1 Hz, 1 H), 5.21 (d,
J = 10.3 Hz, 1 H), 5.32 (d, J = 17.3 Hz, 1 H) 5.64–5.73 (m, 1 H),
6.03–6.13 (m, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.2 Hz,
1 H), 7.33 (dd, J = 8.2, 2.0 Hz, 1 H), 7.39 (dd, J = 8.2, 2.0 Hz, 1
H), 7.81 (d, J = 2.0 Hz, 1 H), 7.86 (d, J = 2.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.1 (t), 24.6 (t), 29.3 (t), 30.3 (t),
30.4 (t), 31.3 (t), 32.2 (t), 32.4 (t), 44.5 (t), 48.9 (t), 57.1 (d), 61.0
(d), 93.1 (s), 93.5 (s), 116.7 (t), 117.2 (t), 127.8 (d), 128.5 (d), 128.7
(d), 129.0 (d), 135.0 (s), 135.1 (s), 135.0 (d), 135.1 (d), 138.7 (d),
139.1 (d), 142.2 (s), 142.1 (s), 169.9 (s), 170.4 (s) ppm. MS: m/z =
389 [M]+. C15H17ClINO (389.66): calcd. C 46.24, H 4.40, N 3.59;
found C 46.31, H 4.28, N 3.42.
N,N-Diallyl-2-(methoxycarbonyl)benzamide (5a): Yield 10 mg (4%);
pale yellow oil. IR (nujol): ν = 1671, 1729 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 3.66 (d, J = 5.8 Hz, 2 H), 3.87 (s, 3 H),
4.10–4.24 (m, 2 H), 5.07 (d, J = 17.1 Hz, 1 H), 5.14 (d, J = 10.2 Hz,
1 H), 5.26 (d, J = 10.3 Hz, 1 H), 5.29 (d, J = 16.0 Hz, 1 H), 5.64
(ddt, J = 16.0, 10.3, 5.8 Hz, 1 H), 5.95 (ddt, J = 17.1, 10.2, 6.2 Hz,
1 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.43 (dd, J = 7.7, 7.6 Hz, 1 H),
7.54 (dd, J = 7.6, 7.5 Hz, 1 H), 8.01 (d, J = 7.7 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 46.8 (t), 50.9 (t), 52.7 (q), 118.3 (t),
N-Allyl-4-chloro-2-iodo-N-phenylbenzamide (9cd): Procedure B;
1
yield 378 mg (95%); colourless oil. IR (nujol): ν = 1681 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 4.53 (d, J = 6.2 Hz, 2 H), 5.21 (d,
5594
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5590–5596

4-[(Methoxycarbonyl)methyl]-3,4-dihydroisoquinolinones
118.5 (t), 127.3 (d), 127.7 (s), 129.1 (d), 131.0 (d), 133.0 (d), 133.2
(t), 122.7 (dd, JC,F = 3.4 Hz), 133.0 (d), 133.6 (dd, JC,F = 9.6 Hz),
143.8 (s), 161.0 (s), 162.6 (d, JC,F = 261.0 Hz), 172.0 (s) ppm. MS:
(d), 133.3 (d), 139.0 (s), 166.5 (s), 171.2 (s) ppm. MS: m/z (%) =
259 [M]+. C15H17NO3 (259.30): calcd. C 69.48, H 6.61, N 5.40; m/z = 277 [M]+. C15H16FNO3 (277.29): calcd. C 64.97, H 5.82, N
found C 69.36, H 6.88, N 5.60.
5.05; found C 64.88, H 5.96, N 5.18.
2-Cyclohexyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolin-1-
8-Fluoro-2-methyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquin-
one (4b): Yield 175 mg (58%); colourless oil. IR (nujol): ν = 1658,
olin-1-one (10ae): Yield 168 mg (67%); pale yellow oil. IR (nujol):
˜
1
1703 cm–1. H NMR (400 MHz, CDCl3): δ = 0.61–1.01 (m, 1 H), ν = 1693, 1711 cm–1. 1H NMR (400 MHz, CDCl ): δ = 2.59 (dd, J
˜
3
1.10–1.55 (m, 5 H), 1.59–1.91 (m, 4 H), 2.52 (dd, J = 16.4, 5.4 Hz,
= 16.1, 5.6 Hz, 1 H), 2.90 (dd, J = 16.1, 8.9 Hz, 1 H), 3.14 (s, 3
1 H), 2.67 (dd, J = 16.4, 9.3 Hz, 1 H), 3.25–3.46 (m, 1 H), 3.51 and H), 3.35–3.43 (m, 2 H), 3.69 (s, 3 H), 3.82 (dd, J = 12.9, 3.8 Hz, 1
3.58 (AB part of ABX system, J = 12.9, 3.3 Hz, 2 H), 3.70 (s, 3 H), 7.02 (dd, J = 8.2, 7.5 Hz, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.36–
H), 4.62–4.75 (m, 1 H), 7.21 (d, J = 7.3 Hz, 1 H), 7.36 (dd, J = 7.41 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.4 (q),
7.5, 7.5 Hz, 1 H), 7.43 (dd, J = 7.3 7.5 Hz, 1 H), 8.10 (d, J = 7.5 Hz, 35.7 (q), 37.7 (t), 51.8 (t), 52.3 (d), 116.8 (dd, JC,F = 22.3 Hz), 117.5
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.9 (t), 26.1 (t), 26.3
(d, JC,F = 5.3 Hz), 133.5 (dd, JC,F = 3.1 Hz), 133.6 (dd, JC,F
=
(t), 30.2 (t), 30.4 (t), 34.7 (q), 37.5 (t), 43.9 (t), 51.3 (d), 51.9 (d), 9.7 Hz), 143.8 (s), 161.2 (s), 162.7 (d, JC,F = 222.9 Hz), 172.2 (s)
126.7 (d), 127.9 (d), 129.6 (d), 130.6 (s), 131.7 (d), 141.0 (s) 163.1
ppm. MS: m/z = 251 [M]+. C13H14FNO3 (251.25): calcd. C 62.14,
(s), 172.0 (s) ppm. MS: m/z = 301 [M]+. C18H23NO3 (301.38): calcd. H 5.62, N 5.57; found C 62.25, H 5.43, N 5.42.
C 71.73, H 7.69, N 4.65; found C 71.52, H 7.97, N 4.86.
2-Allyl-4-[(methoxycarbonyl)methyl]-5-methyl-3,4-dihydroisoquin-
2-Cyclopentyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquinolin- olin-1-one (10ba): Yield 142 mg (52%); colourless oil. IR (nujol): ν
˜
1-one (4c): Yield 158 mg (55%); colourless oil. IR (nujol): ν = 1676,
= 1669, 1723 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.97 (s, 3 H),
1715 cm–1. H NMR (400 MHz, CDCl3): δ = 1.39–1.98 (m, 8 H), 2.03 (dd, J = 16.3, 2.1 Hz, 1 H), 2.49 (dd, J = 16.3, 11.3 Hz, 1 H),
˜
1
2.52 (dd, J = 16.3, 5.0 Hz, 1 H), 2.66 (dd, J = 16.3, 9.4 Hz, 1 H),
3.35–3.48 (m, 2 H), 3.60 (dd, J = 12.9, 4.0 Hz, 1 H), 3.69 (s, 3 H),
4.48–4.60 (m, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.35 (dd, J = 7.5,
7.5 Hz, 1 H), 7.43 (dd, J = 7.4 7.5 Hz, 1 H), 8.09 (d, J = 7.5 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.6 (t), 26.0 (t), 26.5
(t), 29.8 (t), 33.5 (q), 36.8 (t), 43.7 (t), 51.2 (d), 51.8 (d), 126.6 (d),
128.1 (d), 129.4 (d), 130.7 (s), 132.5 (d), 141.6 (s) 163.3 (s), 172.1
(s) ppm. MS: m/z = 287 [M]+. C17H21NO3 (287.35): calcd. C 71.06,
H 7.37, N 4.87; found C 71.23, H 7.21, N 4.65.
3.13 (dd, J = 13.2, 9.2 Hz, 1 H), 3.23–3.28 (m, 2 H), 3.36 (s, 3 H),
3.72 and 4.29 (AB part of ABX system, J = 14.7, 6.5 Hz, 2 H),
5.02 (d, J = 18.3 Hz, 1 H), 5.04 (d, J = 10.1 Hz, 1 H), 5.78 (ddt, J
= 18.3, 10.1, 6.5 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 7.08 (dd, J =
7.6, 7.7 Hz, 1 H), 8.32 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.3 (q), 31.3 (d), 35.1 (t), 48.0 (t), 50.4 (t),
51.4 (q), 118.9 (t), 127.3 (d), 127.9 (d), 128.9 (s), 132.6 (d), 134.2
(s), 134.7 (d), 139.3 (s), 165.8 (s), 171.9 (s) ppm. MS: m/z = 273
[M]+. C16H19NO3 (273.33): calcd. C 70.31, H 7.01, N 5.12; found
C 70.08, H 7.13, N 5.33.
4-[(Methoxycarbonyl)methyl]-2-phenyl-3,4-dihydroisoquinolin-1-one
(4d): Yield 180 mg (61 %); colourless oil. IR (nujol): ν = 1691,
2-Allyl-6-chloro-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquin-
˜
1707 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.76 (dd, J = 16.1,
olin-1-one (10ca): Yield 256 mg (87%); colourless oil. IR (nujol): ν
˜
5.8 Hz, 1 H), 2.90 (dd, J = 16.1, 8.9 Hz, 1 H), 3.52–3.61 (m, 1 H), = 1685, 1704 cm–1. H NMR (400 MHz, CDCl3): δ = 2.52 (dd, J
1
3.69 (s, 3 H), 3.84 and 4.27 (AB part of ABX system, J = 12.6,
= 16.2, 5.5 Hz, 1 H), 2.63 (dd, J = 16.2, 8.5 Hz, 1 H), 3.34–3.38
3.5 Hz, 2 H), 7.18–7.21 (m, 1 H), 7.22–7.33 (m, 2 H), 7.38–7.49 (m, (m, 2 H), 3.65 (s, 3 H), 3.69 (AB system, J = 5.1 Hz, 1 H), 3.95
4 H), 7.59 (dd, J = 7.5, 7.5 Hz, 1 H), 8.19 (d, J = 7.7 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 35.2 (q), 38.2 (t), 52.3 (d),
53.6 (t), 126.0 (d), 126.9 (d), 127.0 (d), 128.2 (d), 129.3 (s), 129.5
(d), 129.6 (d), 132.9 (d), 141.1 (s), 143.3 (s), 163.1 (s), 172.0 (s)
and 4.28 (AB part of ABX system, J = 14.8, 5.9 Hz, 2 H), 5.19 (d,
J = 9.1 Hz, 1 H), 5.21 (d, J = 12.0 Hz, 1 H), 5.77 (ddt, J = 12.0,
9.1, 5.9 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.29 (dd, J = 8.3,
2.0 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (100 MHz,
ppm. MS: m/z = 295 [M]+. C18H17NO3 (295.33): calcd. C 73.20, H CDCl3): δ = 34.4 (q), 37.9 (t), 49.1 (t), 50.0 (t), 52.2 (d), 119.1 (t),
5.80, N 4.74; found C 73.10, H 6.06, N 4.62.
126.9 (d), 127.6 (s), 128.3 (d), 130.7 (d), 132.9 (d), 138.4 (s), 142.6
(s), 163.3 (s), 172.0 (s) ppm. MS: m/z = 293 [M]+. C15H16ClNO3
(293.75): calcd. C 61.33, H 5.49, N 4.77; found C 61.54, H 5.23, N
4.89.
2-Allyl-4-methylisoquinolin-1-one (6a): Yield 26 mg (13%) from the
conditions of Entry 1 of Table 1; colourless oil. IR (nujol): ν =
˜
1680 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H), 4.62 (d,
J = 5.7 Hz, 2 H), 5.20 (d, J = 15.7 Hz, 1 H), 5.27 (d, J = 12.6 Hz, 6-Chloro-2-cyclohexyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroiso-
1 H), 5.78 (ddt, J = 15.7, 12.6, 5.7 Hz, 1 H), 6.86 (s, 1 H), 7.49 (dd,
J = 7.7, 7.8 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.0,
7.8 Hz, 1 H), 8.48 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.8 (q), 50.9 (t), 112.6 (s), 118.2 (t), 123. 4 (d), 126.4
quinolin-1-one (10cb): Yield 238 mg (71%); colourless oil. IR (nu-
1
jol): ν = 1672, 1721 cm–1. H NMR (400 MHz, CDCl ): δ = 0.91–
˜
3
1.83 (m, 10 H), 2.52 (dd, J = 16.5, 5.4 Hz, 1 H), 2.66 (dd, J = 16.5,
9.2 Hz, 1 H), 3.35–3.39 (m, 1 H), 3.53 (AB system, J = 13.0 Hz, 2
(s), 127.0 (d), 128.7 (d), 129.2 (d), 132.4 (d), 133.7 (d), 137.7 (s), H), 3.71 (s, 3 H), 4.58–4.67 (m, 1 H), 7.21 (d, J = 2.0 Hz, 1 H),
162.0 (s) ppm. MS: m/z = 199 [M]+. C13H13NO (199.25): calcd. C
78.36, H 6.58, N 7.03; found C 78.28, H 6.76, N 6.88.
7.32 (dd, J = 8.3, 2.0 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 25.8 (t), 26.0 (t), 30.2 (q), 30.3 (t),
34.3 (d), 37.3 (t), 44.0 (t), 52.3 (d), 126.7 (d), 128.2 (s), 128.3 (d),
130.9 (d), 138.2 (s), 142.3 (s), 162.9 (s), 172.3 (s) ppm. MS: m/z =
335 [M]+. C18H22ClNO3 (335.83): calcd. C 64.38, H 6.60, N 4.17;
found C 64.51, H 6.42, N 4.43.
2-Allyl-8-fluoro-4-[(methoxycarbonyl)methyl]-3,4-dihydroisoquin-
olin-1-one (10aa): Yield 238 mg (86%); colourless oil. IR (nujol): ν
˜
1
= 1678, 1724 cm–1. H NMR (400 MHz, CDCl3): δ = 2.50 (dd, J
= 16.4, 5.7 Hz, 1 H), 2.61 (dd, J = 16.4, 8.8 Hz, 1 H), 3.30–3.38
(m, 2 H), 3.62 (s, 3 H), 3.65 (dd, J = 12.8, 3.6 Hz, 1 H), 3.93 and
4.26 (AB part of ABX system, J = 14.7, 6.5 Hz, 2 H), 5.16 (d, J =
6-Chloro-2-cyclopentyl-4-[(methoxycarbonyl)methyl]-3,4-dihydroiso-
quinolin-1-one (10cc): Yield 219 mg (68%); colourless oil. IR (nu-
9.9 Hz, 1 H), 5.19 (d, J = 15.9 Hz, 1 H), 5.76 (ddt, J = 15.9, 9.9, jol): ν = 1659, 1718 cm–1. H NMR (400 MHz, CDCl ): δ = 1.24–
1
˜
3
6.5 Hz, 1 H), 6.95–7.00 (m, 2 H), 7.30–7.36 (m, 1 H) ppm. 13C 1.95 (m, 8 H), 2.54 (dd, J = 16.6, 5.3 Hz, 1 H), 2.67 (dd, J = 16.6,
NMR (100 MHz, CDCl3): δ = 35.2 (d), 37.6 (t), 48.8 (t), 49.7 (t), 9.1 Hz, 1 H), 3.36–3.45 (m, 2 H), 3.60 (AB system, J = 9.0 Hz, 1
52.1 (q), 116.7 (dd, JC,F = 22.4 Hz), 117.4 (d, JC,F = 5.4 Hz), 119.1
H), 3.72 (s, 3 H), 5.13–5.21 (m, 1 H), 7.22 (d, J = 2.1 Hz, 1 H),
5595
Eur. J. Org. Chem. 2008, 5590–5596
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Broggini et al.
FULL PAPER
7.34 (dd, J = 8.3, 2.1 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.5 (t), 24.6 (t), 28.3 (t), 29.1 (t),
34.4 (q), 37.2 (t), 44.0 (t), 52.3 (d), 54.2 (d), 126.7 (d), 128.1 (s),
128.4 (d), 130.9 (d), 138.3 (s), 142.3 (s), 163.5 (s), 172.3 (s) ppm.
MS: m/z = 321 [M]+. C17H20ClNO3 (321.80): calcd. C 63.45, H
6.26, N 4.35; found C 63.22, H 6.35, N 4.53.
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6-Chloro-4-[(methoxycarbonyl)methyl]-2-phenyl-3,4-dihydroisoquin-
olin-1-one (10cd): Yield 274 mg (83%); colourless oil. IR (nujol): ν
˜
1
= 1672, 1714 cm–1. H NMR (400 MHz, CDCl3): δ = 2.74 (dd, J
= 16.2, 5.8 Hz, 1 H), 2.88 (dd, J = 16.2, 8.7 Hz, 1 H), 3.50–3.58
(m, 1 H), 3.69 (s, 3 H), 3.82 (dd, J = 12.7, 3.2 Hz, 1 H), 4.26 (dd,
J = 12.7, 3.9 Hz, 1 H), 7.06–7.46 (m, 7 H), 8.11 (d, J = 8.4 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.0 (q), 37.9 (t), 52.4
(d), 53.5 (t), 118.6 (s), 125.9 (d), 127.0 (d), 127.1 (d), 127.9 (s), 128.6
(d), 129.6 (d), 131.2 (d), 138.9 (s), 142.8 (s), 163.4 (s), 172.0 (s)
ppm. MS: m/z = 329 [M]+. C18H16ClNO3 (329.78): calcd. C 65.56,
H 4.89, N 4.25; found C 65.44, H 4.96, N 4.41.
6-Chloro-2-ethyl-4-[(methoxycarbonyl)methyl]-4-methyl-3,4-dihy-
droisoquinolin-1-one (10cf): Yield 163 mg (55%); colourless oil. IR
(nujol): ν = 1649, 1723 cm–1. 1H NMR (400 MHz, CDCl ): δ = 1.26
˜
3
(t, J = 7.2 Hz, 3 H), 1.47 (s, 2 H), 2.59 (AB system, J = 14.6 Hz, 2
H), 3.48 (d, J = 12.7 Hz, 1 H), 3.56–3.71 (m, 7 H), 7.27 (d, J =
1.9 Hz, 1 H), 7.34 (dd, J = 8.3, 1.9 Hz, 1 H), 8.07 (d, J = 8.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.9 (q), 22.8 (q),
36.8 (s), 42.5 (t), 42.7 (t), 52.0 (q), 54.9 (t), 124.5 (d), 128.0 (s),
128.8 (d), 130.8 (d), 138.6 (s), 146.6 (s), 163.3 (s), 171.4 (s) ppm.
MS: m/z = 295 [M]+. C15H18ClNO3 (295.76): calcd. C 60.91, H
6.13, N 4.74; found C 61.08, H 5.98, N 4.82.
Acknowledgments
The authors thank the Ministero dell’Università e della Ricerca for
financial support and for a Ph.D. fellowship to M. R. (Progetto
Giovani 2006).
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Received: July 28, 2008
Published Online: October 15, 2008
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