One-pot synthesis of 3-substituted isoquinolin-1-(2H)-ones and fused isoquinolin-1-(2H)-ones by SRN1 reactions in DMSO

Article abstract of DOI:10.1002/ejoc.200600244

3-Substituted isoquinolin-1-(2H)-ones and fused isoquinolin-1-(2H)-ones have been obtained by the photostimulated S_RN1 reactions of 2-iodobenzamide with the enolates of aromatic (acetophenone, 1-(benzo[d][1,3]dioxol-5-yl)ethanone, 1- and 2-naph

Full text of DOI:10.1002/ejoc.200600244

FULL PAPER
DOI: 10.1002/ejoc.200600244
One-Pot Synthesis of 3-Substituted Isoquinolin-1-(2H)-ones and Fused
Isoquinolin-1-(2H)-ones by S 1 Reactions in DMSO
RN
[a]
[a]
[a]
Javier F. Guastavino, Silvia M. Barolo, and Roberto A. Rossi*
Keywords: Fused-ring systems / Radicals / Nucleophilic substitution / Electron transfer / SRN1 reaction
3
1
-Substituted isoquinolin-1-(2H)-ones and fused isoquinolin-
-(2H)-ones have been obtained by the photostimulated
pyridine), aliphatic (1-adamantyl methyl ketone), and cyclic
ketones (1- and 2-indanone, α- and β-tetralone, and 1-benzo-
suberone) in DMSO.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
S
RN1 reactions of 2-iodobenzamide with the enolates of aro-
matic (acetophenone, 1-(benzo[d][1,3]dioxol-5-yl)ethanone,
- and 2-naphthyl methyl ketones, and 2-, 3-, and 4-acetyl-
1
quinolinone],[ the transformation of isocoumarins by pri-
11]
Introduction
[
12]
mary amines,
double metalation of an N-propenyl-2-
Derivatives of isoquinolin-1-(2H)-one compose an im-
portant class of heterocyclic compounds from both the syn-
thetic and biological points of view. It is well known that
their structures are incorporated in several alkaloids and
other pharmacologically important compounds such as
methyl benzamide to give a cyclocondensation reaction
[13]
with DMF,
SNAr reactions from 2-chlorobenzonitriles
with β-keto esters followed by cyclization in acid condi-
[14]
[2]
tions,
and intramolecular Diels–Alder reactions. Re-
cently, the synthesis of isoquinolinones has been improved
[
1]
[2]
[3]
thalifoline, dorianine, narciclasine, pancratistatin, and
[2,15]
by using transition-metal catalysts.
[
4]
lycoricidine.
Substituted isoquinolinones exhibiting antidepressant,
Although many synthetic approaches toward isoquinol-
inone ring systems have already been reported, we describe
herein an efficient synthesis of 3-substituted isoquinolin-1-
[
5]
[
6]
[7]
[5]
anti-inflammatory,
anti-ulcer,
analgesic,
hypolipid-
emic, and antihypertensive[9] characteristics have also
been described. In addition, it has been shown that some
compounds of this family act on the central nervous system
or behave as inhibitors of lipoxygenase, poly (ADP-ribose)-
polymerase, and cholesterol biosynthesis among others. Iso-
quinolinones are also employed for the treatment of stom-
ach tumors and diseases of human brain cells.[
[8]
(2H)-ones and fused isoquinolin-1-(2H)-ones in one step by
the SRN1 mechanism.
The SRN1 mechanism is a chain process whose key steps
are presented in Scheme 1. This mechanism is an important
route to achieve the formation of a new C–C bond by the
[16]
reaction of aromatic substrates with carbanions.
2]
Considering their chemical stability, substituted isoquin-
olin-1-(2H)-ones are often used as building blocks in or-
ganic synthesis, as useful intermediates in the synthesis of
indenoisoquinolines, protoberberines, and dibenzoquinoliz-
[
10]
ines, and are also of interest in medicinal chemistry.
There are several procedures to obtain isoquinolinones.
The Bischler–Napieralski and Pictet–Spengler[2] reactions
are classic methods for the synthesis of isoquinolinones.
The synthetic methods employed in the synthesis of these
heterocycles involve the use of homophthalic anhydride [e.g.
the base–promoted condensation reactions with 2-(bro-
momethyl)benzonitrile to the synthesis of indolo(3,2-c)iso-
Scheme 1.
The initiation step is the electron transfer (ET) from an
[
a] INFIQC, Departamento de Química Orgánica, Facultad de Ci- electron donor to the substrate to afford the radical anion
encias Químicas, Universidad Nacional de Córdoba, Ciudad
of the substrate [Scheme 1, Equation (1)]. Only a few sys-
Universitaria,
5
000 Córdoba, Argentina
tems are known to react by the SRN1 mechanism in a ther-
mal (or spontaneous) reaction. Most of these systems need
to be initiated by different means. Photoinitiation, chemical
initiation by alkali metals in liquid ammonia, or electro-
Fax: +54-351-4333030
E-mail: rossi@mail.fcq.unc.edu.ar
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3898
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3898–3902

One-Pot Synthesis of Isoquinolin-1-(2H)-ones by SRN1 Reactions
FULL PAPER
chemical initiation at a cathode are the most frequently anion scavenger (Table 1, Experiments 1–3). These results
used techniques. However, other reagents to initiate the re- provide strong experimental evidence that this reaction pro-
2+
[16]
actions, such as Fe , SmI , or Na(Hg) are also known.
ceeds through the SRN1 mechanism.
2
In the propagation steps, the radical anion fragments
into a radical and the anion of the leaving group [Equa-
tion (2)]. The radical reacts with the nucleophile to form Expt. Nucleophile
Table 1. Reactions of 1 with ketone enolates.[a]
% I–[b]
Products[c] (%) % Benzamide
the radical anion of the substitution product [Equation (3)].
The ET from this radical anion to the substrate affords the
substitution product and the radical anion of the substrate,
which propagates the chain reaction [Equation (4)]. Overall,
Equations 2–4 depict a nucleophilic substitution in which
radicals and radical anions are intermediates [Equation (5)].
A particularly useful application of the SRN1 reaction is
the synthesis of heterocycles from aromatic compounds that
have an appropriate substituent ortho- to the leaving
1
2
3
4
5
6
7
8
9
1
1
1
2
2
100
Ͻ2
67
100
90
78
92
88
94
97
86
93
96
90
93
3 (91)
–
3 (68)
5 (87)
–
–
–
–
–
7
–
–
–
20
23
44
–
–
–
[
[
d]
e]
2
4
6a
6b
8a
8b
8c
7a (83)
7b (68)
9a (81)
9b (79)
9c (72)
11 (71)
13a (51)
13b (42)
13c (88)
15a (70)
15b (80)
[f]
0
1
2
10
12a
12b
12c
14a
14b
[
16,17]
group.
Recently, this method has been applied to the
synthesis of a new family of 2H-1,2-benzothiazine 1,1-diox- 13
[
18]
14
ides
and 1-phenyl-1-oxazolino-indane derivatives con-
[19]
15
taining quaternary carbon atoms. In this field, an impor-
tant example is the synthesis of 2-substituted and fused in- [a] Reactions carried out under N
ketone (4 mmol) and tBuOK (4.04 mmol)]. Irradiation time:
80 min. [b] Determined potentiometrically. [c] Isolated yield in
2
in 10 mL of DMSO [1 (1 mmol),
doles by the reaction of 2-iodoaniline with ketone enol-
1
[
20]
ates.
Substituted isoquinolin-1-(2H)-ones have been ob-
parentheses. [d] Reaction in the dark. [e] p-DNB (20 mol-%) was
added. [f] Quantified by GLC.
tained by reaction of o-iodo- or o-bromobenzamides with
enolates of ketones in liquid ammonia under photostimula-
[
21]
tion.
The reaction between substituted o-iodobenzamide and
the enolate derived from the 2-acetyl homoveratric acid so-
dium salt leads to tricyclic isoquinolinones that can be read-
ily converted to either berberine or benzo[c]phenanthridone
ring systems, affording a versatile access to both families
[
22]
of alkaloids. In addition, there is only one report of the
synthesis of 1- and 2-naphthylisoquinoline derivatives,
which consists of the reaction of o-bromobenzamide with
enolates derived from 1- or 2-naphthyl methyl ketones un-
der photostimulation in DMSO. The isoquinolinones were
not isolated but were transformed into isoquinoline deriva-
It should be noted that the intermediate formed by the
SRN1 reaction cyclizes spontaneously by polar intramolecu-
lar reaction to give corresponding product 3 [Equation (7)].
[
23]
tives.
Although isoquinolinones are important compounds,
little effort has been devoted to the synthesis of these com-
pounds by the SRN1 mechanism in DMSO. In the present
study, we undertake the synthesis of 3-substituted isoquin-
A related nucleophile, the enolate of 1-(benzo[d][1,3]di-
olinones with acyclic aromatic and aliphatic ketones, and oxol-6-yl)ethanone (4), gives the ring closure product 5 in
for the first time, we report the synthesis of fused isoquinol- similar yields under irradiation with 1 [Equation (8) and
inones by the photostimulated SRN1 reactions of the enol- Table 1, Experiment 4].
ates of cyclic ketones with o-iodobenzamide under irradia-
tion in DMSO.
Results and Discussion
3-(Naphthalen-1-yl)isoquinolin-1-(2H)-one (7a) is ob-
tained by a photostimulated reaction of 1 with the enolate
of 1-naphthyl methyl ketone (6a) in 83% yield in DMSO.
3-Substituted Isoquinolin-1-(2H)-ones
The photostimulated reaction of o-iodobenzamide (1) In the photostimulated reaction of 1 with 2-naphthyl methyl
with the enolate of acetophenone (2) affords the 3-phenyl- ketone (6b), 3-(naphthalen-2-yl)isoquinolin-1-(2H)-one (7b)
isoquinolin-1-(2H)-one (3) in 91% yield [Equation (6)]. This is obtained in 68% yield together with the reduced product
reaction does not occur in the dark and is partially in- benzamide in 7% yield [Equation (9) and Table 1, Experi-
hibited by p-dinitrobenzene (p-DNB), a known radical ments 5 and 6].
Eur. J. Org. Chem. 2006, 3898–3902
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3899

J. F. Guastavino, S. M. Barolo, R. A. Rossi
FULL PAPER
6
H-Indeno[2,1-c]isoquinolin-5-(7H)-one (15a) is ob-
tained by a photostimulated reaction of 1 with the enolate
of 2-indanone (14a) in 70% yield. Under the same condi-
tions, the reaction of 1 with the enolate of β-tetralone (14b)
furnishes 80% of 15b [Equation (13) and Table 1, Experi-
ments 14 and 15]. The reduction product benzamide was
not observed in these reactions.
Excellent yields of 3-pyridyl-substituted isoquinolinones
are obtained when heteroaromatic ketone enolates are em-
ployed as nucleophiles. Thus, the enolates of 2-, 3-, and 4-
acetylpyridines (8a–c) react with 1 under photostimulation
in DMSO to afford the 3-pyridinyl-isoquinolin-1-(2H)-ones
(9a–c) in 72–81% yield [Equation (10) and Table 1, Experi-
ments 7–9].
Conclusions
The photostimulated reactions of several acyclic enolates
of aromatic (acetophenone, 1-(benzo[d][1,3]dioxol-5-yl)eth-
anone, 1- and 2-naphthyl methyl ketones, and 2-, 3-, and 4-
acetylpyridine), aliphatic (1-adamantyl methyl ketone), and
cyclic ketones (1- and 2-indanone, α- and β-tetralone, and
The lipophilic adamantyl moiety has been used to im-
prove the pharmacological activities of certain compounds,
and hence, we considered the possibility of obtaining the 3-
adamantyl-substituted isoquinolinone. In the photostimu-
lated reaction of the enolate of 1-adamantyl methyl ketone
with 1, 3-(adamantan-1-yl)isoquinolin-1-(2H)-one (11) was
obtained in high yield [Equation (11) and Table 1, Experi-
ment 10].
1-benzosuberone) with substrate 1 in DMSO afford 3-sub-
stituted isoquinolinones and fused isoquinolinones in very
good yields (42–91%) by the SRN1 mechanism.
Considering the availability and simplicity of the starting
materials and the readiness and mild conditions of the pro-
cedure, we have demonstrated that this methodology be-
comes a general technique for the synthesis of isoquinolin-
1-(2H)-ones.
Experimental Section
General Methods and Materials
Methods: H NMR (200 MHz) and 13C NMR (50 MHz) spectra
1
3 6
were obtained in CDCl or [D ]DMSO as solvents. The purifica-
tion of the products was performed by column chromatography on
silica gel. Irradiation was conducted in a photochemical reactor
equipped with two 400-W Hg lamps emitting maximally at 350 nm
Fused Isoquinolin-1-(2H)-ones
6
H-Indeno[1,2-c]isoquinolin-5-(11H)-one (13a) and (air- and water-refrigerated). Potentiometric titration of iodide ions
+
1
1,12-dihydrobenzo[c]phenanthridin-6-(5H)-one (13b) are was performed with a pH meter using a Ag/Ag electrode. Melting
points were performed with an Electrothermal 9100 instrument.
obtained by photostimulated reactions of 1 with the enol-
ates of 1-indanone (12a) and α-tetralone (12b), respectively, Materials: tBuOK was commercially available and used as received.
[
Equation (12) and Table 1, Experiments 11 and 12]. The DMSO was distilled under vacuum and stored under molecular
reduction product benzamide was formed together with the sieves (4 Å). Acetophenone, 1- and 2-naphthyl methyl ketones, 1-
(
benzo[d][1,3]dioxol-5-yl)ethanone, 1-adamantyl methyl ketone, 2-,
target fused isoquinolinones. On the other hand, the enolate
of 1-benzosuberone (12c) reacts with 1 to give the tetra-
cyclic isoquinolinone 13c in 88% yield, uncontaminated
with benzamide [Equation (12) and Table 1, Experiment
3
1
-, and 4-acetypyridine, α- and β-tetralone, 1- and 2-indanone, and
-benzosuberone were commercially available and distilled under
reduced pressure. o-Iodobenzamide (1) was prepared from 2-iodo-
benzoic acid according to the literature procedure.[
24]
1
3].
Photostimulated Reaction of Acetophenone Enolate (2) with o-Iodo-
benzamide (1) in DMSO: The following procedure is representative
of all these reactions. They were carried out in a 20-mL three-neck
round-bottomed flask equipped with a nitrogen inlet and magnetic
stirrer at room temperature. To dry and deoxygenated DMSO
(
10 mL) under nitrogen was added tBuOK (0.453 g, 4.04 mmol)
and acetophenone (0.468 mL, 4.00 mmol). After 15 min, 1 (0.247 g,
mmol) was added, and the reaction mixture was irradiated for
1
3900
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3898–3902

One-Pot Synthesis of Isoquinolin-1-(2H)-ones by SRN1 Reactions
80 min. The reaction was quenched with excess ammonium nitrate
and water. The precipitate formed was removed by filtration and
dried under vacuum to give 3 as light-colored crystals. The filtrate
was extracted with dichloromethane, and the organic extract was
FULL PAPER
(br. d, J = 4.4 Hz, 1 H, CH), 8.26–8.17 (m, 2 H, CH), 8.02–7.93
(m, 1 H, CH), 7.81–7.72 (m, 2 H, CH), 7.59–7.45 (m, 3 H, CH)
1
1
3
6
ppm. C NMR (50 MHz, [D ]DMSO): δ = 161.37, 149.05, 148.92,
137.65, 137.49, 136.39, 132.77, 127.25, 126.76, 126.00, 124.23,
120.16, 103.69 ppm. MS: m/z (%) = 223 (16), 222 (100), 194 (17),
193 (14), 118 (21), 90 (14), 89 (21), 78 (11), 63 (10), 51 (13), 43
4
washed with water and dried with anhydrous MgSO , and benz-
amide was purified and quantified by column chromatography on
silica gel. The concentration of iodide ions in the aqueous solution
was determined potentiometrically.
(11). HRMS: (EI) calcd. for C14
10 2
H N O 222.0793; found 222.0801.
3
-(Pyridin-3-yl)isoquinolin-1-(2H)-one (9b): Compound 9b (176 mg,
Isolation and Identification of Products
79%) was purified by column chromatography on silica gel eluting
with an n-hexane/acetone gradient (75:25Ǟ0:100) and recrys-
3-Phenylisoquinolin-1-(2H)-one (3): Compound 3 (201 mg, 91%)
tallized from acetone/water as light yellow crystals. M.p. 234–
was obtained according to the general procedure and recrystallized
from acetone as white needles. M.p. 199–200 °C (lit m.p. 205 °C).
1
2
35 °C. H NMR (200 MHz, [D
6
]DMSO): δ = 11.66 (br. s, 1 H,
[25]
NH), 8.99 (d, J = 2.6 Hz, 1 H, CH), 8.64 (dd, J = 4.8, 1.5 Hz, 1
H, CH), 8.25–8.16 (m, 2 H, CH), 7.73–7.72 (m, 2 H, CH), 7.55–
1
H NMR (200 MHz, [D
d, J = 8.0 Hz, 1 H, CH), 7.82–7.70 (m, 4 H, CH), 7.55–7.44 (m,
H, CH), 6.91 (s, 1 H, CH) ppm. 13C NMR (50 MHz, [D
]-
DMSO): δ = 162.69, 140.00, 137.87, 133.83, 132.53, 129.16, 128.70,
26.60, 126.31, 124.82, 103.15 ppm. MS: m/z (%) = 222 (15), 221
100), 194 (8), 165 (16), 143 (9), 89 (16), 82 (9), 77 (8), 63 (9).
6
]DMSO): δ = 11.49 (br. s , 1 H, NH), 8.21
(
4
1
3
7
.49 (m, 2 H, CH), 7.00 (s, 1 H, CH) ppm. C NMR (50 MHz,
]DMSO): δ = 162.64, 149.89, 147.57, 137.60, 137.33, 134.20,
32.64, 129.70, 126.74, 126.60, 125.07, 123.50, 104.12 ppm. MS:
6
[D
6
1
1
(
m/z (%) = 223 (15), 222 (100), 221 (13), 194 (10), 193 (12), 139 (9),
18 (21), 90 (13), 89 (22), 63 (14), 51 (12), 43 (16). HRMS: (EI)
calcd. for C14 O 222.0793; found 222.0795.
1
3
-(Benzo[d][1,3]dioxol-6-yl)isoquinolin-1-(2H)-one (5):[26] Com-
10 2
H N
pound 5 (230 mg, 87%) was obtained according to the general pro-
3
-(Pyridin-4-yl)isoquinolin-1-(2H)-one (9c): Compound 9c (160 mg,
cedure and recrystallized from methanol as white needles. M.p.
72%) was obtained according to the general procedure as light-
1
2
51–252 °C. H NMR (200 MHz, [D
6
]DMSO): δ = 11.36 (br. s, 1
colored crystals and recrystallized from acetone as white crystals.
H, NH), 8.18 (d, J = 8.0 Hz, 1 H, CH), 7.74–7.64 (m, 2 H, CH),
1
M.p. 265–266 °C. H NMR (200 MHz, [D
s, 1 H, NH), 8.69 (dd, J = 4.5, 1.8 Hz, 2 H, CH), 8.24 (dd, J = 8.0,
.7 Hz, 1 H, CH), 7.82 (dd, J = 4.5, 1.8 Hz, 2 H, CH), 7.76 (dd, J
4.5, 0.7 Hz, 2 H, CH), 7.61–7.49 (m, 1 H, CH), 7.18 (d, J =
6
]DMSO): δ = 11.64 (br.
7
1
.50–7.30 (m, 3 H, CH), 7.03 (d, J = 8.0 Hz, 1 H, CH), 6.85 (br. s,
H, CH), 6.10 (s, 2 H, CH ]-
2
) ppm. 13C NMR (50 MHz, [D
6
0
=
DMSO): δ = 162.66, 148.16, 147.70, 139.67, 137.98, 132.53, 127.84,
126.58, 126.49, 126.06, 124.58, 120.81, 108.44, 106.95, 102.48,
101.48 ppm. MS: m/z (%) = 266 (17), 265 (100), 264 (9), 206 (6),
178 (11), 152 (11), 151 (9), 132 (13), 89 (18), 76 (21), 63 (16).
13
0
1
1
6
.7 Hz, 1 H, CH) ppm. C NMR (50 MHz, [D ]DMSO): δ =
62.56, 150.13, 140.70, 137.27, 137.19, 132.77, 127.30, 127.14,
26.68, 125.60, 120.65, 105.01 ppm. MS: m/z (%) = 223 (16), 222
HRMS: (EI) calcd. for C16
-(Naphthalen-1-yl)isoquinolin-1-(2H)-one (7a):[27] Compound 7a
225 mg, 83%) was obtained according to the general procedure
and recrystallized from acetone as white needles. M.p. 222–224 °C.
3
H11NO 265.0739; found 265.0748.
(
100), 221 (13), 194 (12), 193 (14), 139 (8), 90 (10), 89 (21), 78 (8),
3
(
63 (14), 51 (11), 43 (12). HRMS: (EI) calcd. for C H N O
14 10
2
222.0793; found 222.0795.
-(Adamantan-1-yl)isoquinolin-1-(2H)-one (11): Compound 11
198 mg, 71%) was purified by column chromatography on silica
gel eluting with petroleum ether/diethyl ether gradient
90:10Ǟ50:50) and recrystallized from dichloromethane/diethyl
3
(
1
H NMR (200 MHz, [D
d, J = 8.0 Hz, 1 H, CH), 8.08–7.90 (m, 3 H, CH), 7.79–7.49 (m,
H, CH), 6.66 (s, 1 H, CH) ppm. 13C NMR (50 MHz, [D
]-
DMSO): δ = 162.23, 139.51, 137.76, 133.15, 132.80, 132.48, 130.91,
6
]DMSO): δ = 11.62 (br. s, 1 H, NH), 8.27
(
7
a
6
(
1
ether as white needles. M.p. 271–273 °C. H NMR (200 MHz,
CDCl ): δ = 10.19 (br. s, 1 H, NH), 8.36 (d, J = 8.0 Hz, 1 H, CH),
.62 (ddd, J = 8.0, 6.8, 1.4 Hz, 1 H, CH), 7.52–7.49 (m, 1 H, CH),
.42 (ddd, J = 8.0, 6.8, 1.4 Hz, 1 H, CH), 6.32 (d, J = 1.4 Hz, 1 H,
), 1.83 (t, J
): δ = 164.22,
1
1
29.27, 128.30, 127.36, 126.79, 126.63, 126.44, 126.36, 126.17,
25.28, 125.07, 124.98, 105.98 ppm. MS: m/z (%) = 272 (17), 271
3
7
7
(
(
100), 270 (99), 269 (14), 252 (15), 241 (14), 240 (10), 127 (15), 126
14), 121 (27), 107 (14), 106 (11), 89 (10). HRMS: (EI) calcd. for
CH), 2.16 (m, 3 H, CH), 2.02 (d, J = 2.9 Hz, 6 H, CH
2
C
19
H
13NO 271.0997; found 271.1002.
-(Naphthalen-2-yl)isoquinolin-1-(2H)-one (7b): Compound 7b
184 mg, 68%) was purified by column chromatography on silica
gel eluting with dichloromethane/diethyl ether gradient
100:0Ǟ0:100) and recrystallized from acetone as white needles.
13
=
2 3
2.9 Hz, 6 H, CH ) ppm. C NMR (50 MHz, CDCl
1
4
2
49.55, 138.80, 132.57, 127.34, 126.37, 126.02, 124.78, 100.90,
0.77, 36.70, 36.30, 28.54 ppm. MS: m/z (%) = 280 (21), 279 (100),
78 (11), 222 (18), 91 (7), 89 (12), 79 (6), 77 (8), 41 (13). HRMS:
3
(
a
(
EI) calcd. for C19H21NO 279.1623; found 279.1632.
(
1
6H-Indeno[1,2-c]isoquinolin-5-(11H)-one (13a):[11] Compound 13a
(118 mg, 51%) was obtained according to the general procedure
M.p. 238–239 °C. H NMR (200 MHz, [D
6
]DMSO): δ = 11.60
(br.s, 1 H, NH), 8.43 (br. s, 1 H, CH), 8.24 (d, J = 8.0 Hz, 1 H,
CH), 8.06–7.90 (m, 4 H, CH), 7.76–7.70 (m, 2 H, CH), 7.61–7.47 and recrystallized from DMF as light yellow crystals. M.p. 376–
13
1
(
m, 3 H, CH), 7.1 (s, 1 H, CH) ppm. C NMR (50 MHz, [D
6
]- 378 °C. H NMR (200 MHz, [D ]DMSO): δ = 12.30 (br. s, 1 H,
6
DMSO): δ = 162.72, 139.75, 137.89, 132.99, 132.69, 132.61, 130.97,
NH), 8.26 (d, J = 8.0 Hz, 1 H, CH), 8.03–7.99 (m, 1 H, CH), 7.76–
7.75 (m, 2 H, CH), 7.64–7.60 (m, 1 H, CH), 7.51–7.31 (m, 3 H,
CH), 3.91 (s, 2 H, CH ) ppm. C NMR (50 MHz, [D ]DMSO): δ
2 6
1
1
28.41, 128.27, 127.49, 126.90, 126.71, 126.63, 126.44, 125.82,
24.93, 124.15, 103.67 ppm. MS: m/z (%) = 272 (21), 271 (100), 215
1
3
(
18), 143 (11), 127 (11), 120 (10), 115 (11), 108 (10), 107 (12).
= 162.69, 143.04, 139.43, 136.79, 135.66, 132.69, 127.82, 126.93,
126.76, 125.66, 124.80, 123.26, 119.43, 115.74, 32.78 ppm. MS:
m/z (%) = 234 (17), 233 (100), 232 (51), 204 (23), 203 (14), 102 (15),
HRMS: (EI) calcd. for C19 13NO 271.0997; found 271.0996.
H
3
-(Pyridin-2-yl)isoquinolin-1-(2H)-one (9a): Compound 9a (91%)
8
8 (13), 76 (11). Compound 13a exhibits spectral and analytical
was quantified by GLC, purified by column chromatography on
silica gel eluting with an n-hexane/dichloromethane gradient
[11]
data in accordance with that in ref.
(100:0Ǟ0:100) and recrystallized from n-hexane/dichloromethane
11,12-Dihydrobenzo[c]phenanthridin-6-(5H)-one (13b):[29] Com-
pound 13b (104 mg, 42%) was obtained according to the general
[28]
as light yellow crystals. M.p. 140–142 °C (lit m.p.
136–137 °C).
1
H NMR (200 MHz, [D
6
]DMSO): δ = 10.74 (br. s, 1 H, NH), 8.70 procedure as light-colored crystals and recrystallized from acetone
Eur. J. Org. Chem. 2006, 3898–3902
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3901

J. F. Guastavino, S. M. Barolo, R. A. Rossi
FULL PAPER
as white crystals. M.p. 273–275 °C. 1H NMR (200 MHz, [D
]-
6
DMSO): δ = 11.37 (br. s, 1 H, NH), 8.31–8.26 (m, 1 H, CH), 7.95–
[1] M. S. Chern, W. R. Li, Tetrahedron Lett. 2004, 45, 8323–8326.
[2] V. A. Glushkov, Y. V. Shklyaev, Chem. Heterocycl. Compd.
7
7
.86 (m, 2 H, CH), 7.76 (ddd, J = 8.0, 6.8, 1.5 Hz, 1 H, CH), 7.55–
.47 (m, 1 H, CH), 7.33–7.28 (m, 3 H, CH), 2.91 (s, 4 H, CH
2
001, 37, 663–687.
[3] D. Gonzalez, T. Martinot, T. Hudlickly, Tetrahedron Lett.
999, 40, 3077–3080.
4] R. C. Thompson, J. Kallmerten, J. Org. Chem. 1990, 55, 6076–
078.
2
)
13
ppm. C NMR (50 MHz, [D
6
]DMSO): δ = 161.99, 137.06, 136.87,
1
132.88, 132.64, 128.65, 128.49, 127.79, 127.14, 126.66, 126.17,
[
[
1
2
1
25.42, 123.02, 110.19, 27.53, 20.90 ppm. MS: m/z (%) = 248 (18),
47 (100), 246 (63), 232 (20), 228 (31), 217 (14), 115 (9), 114 (14),
09 (12). Compound 13b exhibits spectral and analytical data in
6
5] S. Senda, O. Ohtani, E. Katho, H. Miyake, K. Fujiwara, Ger.
Offen. 3031574, 1981 [Chem. Abstr. 1981, 95, 132692].
[29]
accordance with that in ref.
[6] K. Kubo, N. Ito, I. Souzu, Y. Isomura, H. Homma, Ger. Offen.
828528, 1979 [Chem. Abstr. 1979, 90, 168468].
2
5
6
,11,12,13-Tetrahydro-5-aza-benzo[3,4]cyclohepta[1,2-a]naphthalen-
-one (13c): Compound 13c (230 mg, 88%) was obtained according
[
7] S. Senda, O. Ohtani, E. Katho, M. Nagasaka, H. Miyake, K.
Fujiwara, M. Tanaka, Fr. Demande 2502619, 1983 [Chem.
Abstr. 1983, 98, 71955].
to the general procedure and recrystallized from acetone as a white
solid. M.p. 243–245 °C. 1H NMR (200 MHz, [D
]DMSO): δ =
1.39 (br. s, 1 H, NH), 8.30 (dd, J = 8.0, 1.8 Hz, 1 H, CH), 7.93
br. d, J = 8.4 Hz, 1 H, CH), 7.80–7.72 (m, 1 H, CH), 7.54–7.37
m, 5 H, CH), 2.59–2.48 (m, 4 H, overlapped, CH ), 2.25–2.15 (m,
]DMSO): δ = 161.83,
6
[8] M. Hasegava, K. Shirai, K. Matsumoto, Y. Suzuki, I. Takah-
1
asi, US Patent 5441962, 1994 [Chem. Abstr. 1994, 121, 912].
[
9] S. Senda, O. Ohtani, E. Katho, M. Nagasaka, H. Miyake, K.
Fujiwara, M. Tanaka, Ger. Offen. 3211501, 1982 [Chem. Abstr.
1983, 98, 198048].
(
(
2
1
1
2
) ppm. 1 C NMR (50 MHz, [D
3
H, CH
2
6
[
[
10] F. Coelho, D. Veronese, E. C. S. Lopes, R. C. Rossi, Tetrahe-
dron Lett. 2003, 44, 5731–5735.
11] P. G. Jagtap, E. Baloglu, G. Southan, W. Williams, A. Roy, A.
Nivorozhkin, N. Landrau, K. Desisto, A. L. Salzman, C.
Szabó, Org. Lett. 2005, 7, 1753–1756.
40.29, 137.03, 136.66, 134.55, 132.56, 128.89, 128.73, 128.11,
27.25, 126.36, 125.85, 125.47, 122.88, 111.54, 33.37, 31.06, 22.22
ppm. MS: m/z (%) = 262 (20), 261 (100), 260 (16), 246 (36), 233
22), 232 (28), 228 (14), 115 (12), 114 (11), 102 (12). HRMS: (EI)
calcd. for C18 15NO 261.1154; found 261.1148.
(
H
[12] S. Otha, S. Kimoto, Tetrahedron Lett. 1975, 16, 2279–2282.
[
13] L. E. Fisher, J. M. Muchowski, R. D. Clark, J. Org. Chem.
992, 57, 2700–2705.
6
(
H-Indeno[2,1-c]isoquinolin-5-(7H)-one (15a): Compound 15a
163 mg, 70%) was purified by column chromatography on silica
gel eluting with dichloromethane/diethyl ether gradient
100:0Ǟ0:100). White solid. M.p. 316–318 °C. 1H NMR
200 MHz, [D ]DMSO): δ = 12.16 (br. s, 1 H, NH), 8.41–8.32 (m,
H, CH), 8.05 (br. d, J = 7.7 Hz, 1 H, CH), 7.85 (td, J = 7.5,
.1 Hz, 1 H, CH), 7.58–7.51 (m, 2 H, CH), 7.42–7.34 (m, 1 H, CH),
1
[
14] R. J. Snow, T. Butz, A. Hammach, S. Kapadia, T. M. Morwick,
A. S. Prokopowicz, H. Takahashi, J. D. Tan, M. A. Tschantza,
X. Wangb, Tetrahedron Lett. 2002, 43, 7553–7556.
a
(
(
[15] K. Cherry, A. Duchêne, J. Thibonnet, J. L. Parrain, M. Abar-
bri, Synthesis 2005, 2349–2355.
6
2
1
7
[
16] For reviews, see: a) R. A. Rossi, A. B. Pierini, A. B. Peñéñory
in The Chemistry of Functional Groups (Eds.: S. Patai, Z. Rap-
poport), Wiley, Chichester, 1995, Supplement D2, ch. 24, pp.
1
3
.23–7.15 (t, J = 7.3 Hz, 1 H, CH), 3.85 (s, 2 H, CH
]DMSO): δ = 161.77, 146.41, 140.78, 138.38,
34.12, 132.94, 128.11, 126.95, 125.60, 124.90, 124.34, 123.64,
22.61, 119.65, 113.10, 35.40 ppm. MS: m/z (%) = 234 (7), 233
2
) ppm.
C
NMR (50 MHz, [D
1
1
6
1
395–1485; b) R. A. Rossi, A. B. Pierini, A. N. Santiago, “Aro-
matic Substitution by the SRN1 Reaction” in Organic Reactions
Eds.: L. A. Paquette, R. Bittman), John Wiley & Sons, New
(
(
(
100), 232 (13), 204 (15), 177 (6), 176 (7), 102 (6), 88 (7). HRMS:
EI) calcd. for C16 11NO 233.0841; found 233.0844.
York, 1999, vol. 54, pp. 1–271; c) R. A. Rossi, A. B. Pierini,
H
A. B. Peñéñory, Chem. Rev. 2003, 103, 71–167.
[
17] R. A. Rossi, M. T. Baumgartner, “Synthesis of Heterocycles by
the SRN1 Mechanism” in Targets in Heterocyclic Systems:
Chemistry and Properties (Eds.: O. A. Attanasi, D. Spinelli),
Societa Chimica Italiana, Rome, 1999, vol. 3, pp. 215–243.
7
3
,8-Dihydrobenzo[a]phenanthridin-5-(6H)-one (15b):[29] Compound
(198 mg, 80%) was obtained according to the general procedure
and recrystallized from acetone/water as white needles. M.p. 279–
1
2
80 °C. H NMR (200 MHz, [D
6
]DMSO): δ = 11.65 (br. s, 1 H,
[18] W. J. Layman, T. D. Greenwood, A. L. Downey, J. F. Wolfe, J.
Org. Chem. 2005, 70, 9147–9155.
NH), 8.30 (dd, J = 8.0, 1.5 Hz, 1 H, CH), 8.19 (br. d, J = 8.0 Hz,
[19] M. D. Roydhouse, J. C. Walton, Chem. Commun. 2005, 4453–
4455.
1
H, CH), 7.79–7.70 (m, 2 H, CH), 7.50 (td, J = 7.5, 1.1 Hz, 1 H,
1
3
CH), 7.34–7.14 (m, 3 H, CH), 2.80–2.65 (m, 4 H, CH
2
) ppm.
C
[
20] S. M. Barolo, A. E. Lukach, R. A. Rossi, J. Org. Chem. 2003,
NMR (50 MHz, [D
1
1
6
]DMSO): δ = 161.18, 140.81, 135.98, 135.01,
32.34, 132.02, 127.79, 127.46, 126.25, 125.77, 125.47, 125.31,
23.53, 108.52, 27.50, 26.61 ppm. MS: m/z (%) = 248 (17), 247
68, 2807–2811, and references therein.
[
[
21] R. Beugelmans, M. Bois-Choussy, Synthesis 1981, 729–731.
22] R. Beugelmans, M. Bois-Choussy, Tetrahedron 1992, 48, 8285–
8294.
(100), 246 (29), 232 (12), 228 (15), 218 (10), 217 (10), 203 (7), 202
(
8), 189 (7), 109 (8), 95 (9), 43 (19). Compound 15b exhibits spectral
[23] R. Beugelmans, M. Bois-Choussy, J. Org. Chem. 1991, 56,
[29]
and analytical data in accordance with that in ref.
2518–2522.
[
24] R. A. Moss, S. Chatterjee, W. Boguslawa, J. Org. Chem. 1986,
Supporting Information (see footnote on the first page of this arti-
51, 4303–4307.
1
3
1
cle): C- and H NMR spectroscopic data of compounds 3, 5, 7a,
b, 9a, 9b, 9c, 11, 13a, 13b, 13c, 15a, and 15b.
[25] E. Bisagni, C. Landras, S. Thirot, C. Huel, Tetrahedron 1996,
7
52, 10427–10439.
26] W. J. Cho, M. J. Park, B. H. Chung, C. O. Lee, Bioorg. Med.
Chem. Lett. 1998, 8, 41–46.
[
[
27] Although this compound was synthesized, no product charac-
terization was reported, see: W. J. Cho, S. Y. Min, T. N. Le, T. S.
Kim, Bioorg. Med. Chem. Lett. 2003, 13, 4451–4454.
28] E. M. Brun, S. Gil, M. Parra, Arkivoc 2002, X, 80–89.
29] J. H. Rigby, D. D. Holsworth, K. James, J. Org. Chem. 1989,
Acknowledgments
This work was supported in part by the Agencia Córdoba Ciencia,
the Consejo Nacional de Investigaciones Científicas y Técnicas
[
[
(CONICET), SECYT, Universidad Nacional de Córdoba, and
54, 4019–4020.
FONCYT, Argentina. S.M.B. and J.F.G. gratefully acknowledge re-
ceipt of a fellowship from CONICET and FONCYT, respectively.
Received: March 20, 2006
Published Online: July 11, 2006
3902
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3898–3902