Simple synthesis of 4-substituted 1(2H)-isoquinolinones via electrophilic trapping of lithiated mono- and dianion precursors

Article abstract of DOI:10.1080/00397910701575343

Synthetic routes have been developed to access 4-substituted 1(2H)-isoquinolinones from readily available precursors. This is achieved via electrophilic trapping of di- and monolithium anions derived from alkyllithium exchange of 4-bromo-1(2H)-isoquinolinones and corresponding 4-bromo-1- methoxyisoquinolines, respectively. Products derived from the latter are then hydrolyzed to the target 4-substituted 1(2H)-isoquinolinones. The methodology has potential application to access 4-substituted 1(2H)-isoquinolinones with additional substituents in either ring. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701575343

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Simple Synthesis of 4‐Substituted
1(2H)‐Isoquinolinones via Electrophilic
Trapping of Lithiated Mono‐ and Dianion
Precursors
Anthony D. Sercel a , Joseph P. Sanchez a & H. D. Hollis Showalter a
a Chemistry Department, Pfizer Global Research and Development, Michigan
Laboratories, Ann Arbor, Michigan, USA
Version of record first published: 10 Dec 2007.
To cite this article: Anthony D. Sercel , Joseph P. Sanchez & H. D. Hollis Showalter (2007): Simple Synthesis
of 4‐Substituted 1(2H)‐Isoquinolinones via Electrophilic Trapping of Lithiated Mono‐ and Dianion Precursors,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:23, 4199-4208
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Synthetic Communicationsw, 37: 4199–4208, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575343
Simple Synthesis of 4-Substituted
1(2H)-Isoquinolinones via Electrophilic
Trapping of Lithiated Mono- and Dianion
Precursors
Anthony D. Sercel, Joseph P. Sanchez, and
H. D. Hollis Showalter
Chemistry Department, Pfizer Global Research and Development,
Michigan Laboratories, Ann Arbor, Michigan, USA
Abstract: Synthetic routes have been developed to access 4-substituted 1(2H)-isoqui-
nolinones from readily available precursors. This is achieved via electrophilic trapping
of di- and monolithium anions derived from alkyllithium exchange of 4-bromo-1(2H)-
isoquinolinones and corresponding 4-bromo-1-methoxyisoquinolines, respectively.
Products derived from the latter are then hydrolyzed to the target 4-substituted
1(2H)-isoquinolinones. The methodology has potential application to access 4-substi-
tuted 1(2H)-isoquinolinones with additional substituents in either ring.
Keywords: alkyllithium–halogen exchange, poly(ADP-ribose)polymerase inhibitors,
4-substituted 1(2H)-isoquinolinones
INTRODUCTION
As part of a program directed toward the synthesis of 1(2H)-isoquinolinones
as inhibitors of the nuclear DNA-binding protein poly(ADP-ribose)polym-
erase-1 (PARP-1),[1] structure–activity studies showed that potency was
increased by selected monosubstitution on the 4- or 5-position of the ring
system and markedly enhanced by 4,5-disubstitution, whereas alkyl
Received in the USA May 9, 2007
Address correspondence to H. D. Hollis Showalter, College of Pharmacy,
University of Michigan, Ann Arbor, MI 48109-1065, USA. E-mail: showalh@
umich.edu
4199

4200
A. D. Sercel, J. P. Sanchez, and H. D. H. Showalter
substitution on the N-2 position abolished activity.[2] In this article, we outline
short, convenient routes to synthesize 2-unsubstituted-1(2H)-isoquinolinones
bearing two of the favorable substitution patterns.
Because of the commercial availability of certain 2-unsubstituted-1(2H)-
isoquinolinones and the ease of synthesis of various A-ring analogs,[3] we
were interested in utilizing these as precursors for selective functionalization
of the 4-position. Recent reviews[4] and earlier studies[5] revealed that direct
nitration, Friedel–Crafts type acylation, and Vilsmeier–Haack formylation
of 1(2H)-isoquinolinone (isocarbostyril) either does not occur or does so inef-
ficiently, although direct bromination takes places essentially quantitatively.
In contrast, a variety of electrophilic substitution reactions occur readily and
in good yield on 2-alkyl congeners.[5,6] This, coupled with a report[7]
wherein 2-methyl-1(2H)-isoquinolinone was converted in one step to
1-chloro-1(2H)-isoquinolinone in reasonable yield (69%), presented a
potential alternative route to our target compounds. Finally, there have been
sparse reports of the introduction of C-4 substitutents from 4-bromo or iodo
precursors via palladium-catalyzed chemistry (Suzuki and Stille
reactions).[8] There are no reports in which such functionalization has been
carried out via simple carbanion chemistry. Thus, we embarked on a study
of the reaction of lithiated species, derived from alkyllithium exchange of
4-bromo-1(2H)-isoquinolinones (and corresponding 4-bromo-1-methoxyiso-
quinolines), with representative common electrophiles.
RESULTS AND DISCUSSION
The routes utilized to generate our targeted 4-substituted 1(2H)-isoquinoli-
nones are shown in Scheme 1.
Initial studies to develop our chemistry were carried out on isocarbostyril
(1a). Reaction of this with pyridinium bromide perbromide cleanly gave the
4-bromo adduct (2a)[2,5,9] in 80% yield. The generation of the lithiated
dianion of 2a was evaluated under a number of conditions. Initially, we
encountered difficulties in generating a clean dianion at 2788C in THF (as
determined by quenching experiments) when utilizing 2.2 eq of n-butyl-
lithium. This suggested that the rate of metal–halogen exchange was competi-
tive with that of lactam proton abstraction, leading to self-quenching. Thus,
we carried out a stepwise addition of first 1 equivalent of methyllithium to
selectively deprotonate the lactam, followed by two equivalents of n-buty-
lithium for metal–halogen exchange. Trapping the resultant dilithiated
species with representative common electrophiles followed by standard
workup provided the 4-substituted products in good to excellent isolated
yields (Table 1; compounds 5–8). It was important in this and subsequent
studies that the THF utilized in all anion chemistry be scrupulously dry.
An attempt was then made to extend the dianion methodology to
an A-ring substituted 1(2H)-isoquinolinone. Thus, 4-bromo-5-methyl-1

4-Substituted 1(2H)-Isoquinolinones
4201
Scheme 1.
(2H)-isoquinolinone (2b), synthesized from 1b[3] as described previously, was
treated under a variety of lithiation conditions (methyllithium and then
n-butyl- or t-butyllithium) followed by treatment with DMF or iodomethane.
This resulted in substantial amounts of quenched anion after workup (i.e.,
Br exchanges for H in 2b). To address this problem, we decided to utilize a
workaround strategy by masking the lactam function as a lactim so that less
challenging monolithiation could be achieved. Accordingly, conversion of
2b to the 1-methoxy ether 4b was carried out in a standard two-step process
in 68% yield. Treatment of 4b with n-butyllithium resulted in clean
Table 1. Products of electrophilic trapping of lithiated mono- and di-anions
Starting
material
Electrophile
Product
E
Yield (%)
2a
2a
2a
2a
4a
4b
4b
4b
DMF
CO2
CH3I
5
6
CHO
CO2H
CH3
82
52
73
56
66
86
79
35
7
(CH3S)2
PhN(CH3)CHO
DMF
8
SCH3
CHO
CHO
CH3
9
10
11
12
CH3I
(CH3S)2
SCH3

4202
A. D. Sercel, J. P. Sanchez, and H. D. H. Showalter
lithium–halogen exchange to give the mono anion. Reaction of this was
carried out with representative electrophiles to provide products in moderate
to excellent isolated yields (compounds 10–12 in Table 1). This methodology
was also applied to a single example of a 5-unsubstituted lactim (compound 9,
Table 1). Aqueous HBr hydrolysis of representative lactims (compounds 9–11
of Table 1) provided target 4-substituted 1(2H)-isoquinolinones (5, 13, 14,
respectively, of Scheme 1) in 52–88% yields.
When tested in vitro in an assay utilizing PARP prepared from calf
thymus,[10] the 4- and 4,5-substituted 1(2H)-isoquinolinones reported in
this article were found to be potent inhibitors of the enzyme with
IC50 ¼ 0.02–0.31 mM.
In conclusion, we have developed simple routes to 4-substituted 1(2H)-
isoquinolinones from readily available precursors. Yields ranged from
modest to excellent for the electrophilic trapping of mono- and dilithium car-
banions. Yields have not been optimized except for representative examples
from both routes that were developed to a modest scale. The methodology
has potential application to access 4-substituted 1(2H)-isoquinolinones with
additional substituents in either ring.
EXPERIMENTAL
Melting points were taken on a Thomas-Hoover Unimelt capillary melting-
point apparatus and are uncorrected. NMR spectra were obtained on a
Bruker AM-250 spectrometer (1H) and a Varian Unity 400 spectrometer
(1H, 13C). Chemical shifts are reported as d (ppm) values downfield from
internal TMS. The following abbreviations are used to describe peak
patterns when appropriate: br ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet.
Combustion analyses were determined on a CEC 440 elemental analyzer or
by Robertson Microlit Laboratories, Inc., Madison, N.J. Column chromato-
graphy was carried out in the flash mode utilizing Merck 230–400-mesh
SiO2. Analytical thin-layer chromatography (TLC) was carried out on
Merck (Kiesegel 60F-254) silica-gel plates with detection by UV light. All
reaction solvents were reagent grade or distilled in glass. THF utilized in
lithiation reactions was freshly distilled over lithium aluminium hydride
(LAH). Following normal workup procedures, organic extracts were dried
over anhydrous MgSO4 or Na2SO4 prior to concentration. All lithiation
reactions were run under a positive pressure of dry N2.
General Procedure
4-Bromo-1(2H)-isoquinolinone (2a)
A stirred mixture of 50 g (334 mmol) of isocarbostyril (1a) in 1 L of dichlor-
omethane at 258C was treated with 121. 4 g (342 mmol) of 90% pyridinium

4-Substituted 1(2H)-Isoquinolinones
4203
bromide perbromide. After ca. 20 min, a suspension began to form, and after
3 h, TLC (SiO2; 6:5 EtOAc–cyclohexane) showed complete reaction. The
suspension was filtered, and the solids were washed with CH2Cl2. The
filtrate was diluted carefully with 5% aqueous NaHCO3 saturated with
Na2SO3, which caused immediate precipitation of additional solids. The
solids were filtered off, combined with the others, and recrystallized from
DMF to provide 61.2 g (80%) of analytically pure 2a, mp 247–2498C
(lit.[2] 245–2508C; lit.[5] 247–2488C; lit.[9] 248–2498C), in two crops. The
1H NMR was the same as previously reported.[5]
4-Bromo-5-methyl-1(2H)-isoquinolinone (2b)
Reaction was performed on 20 g (126 mmol) of 5-methyl-1(2H)-isoquinoli-
none (1b)[3] and 60 g (169 mmol) of 90% pyridinium bromide perbromide
overnight followed by workup as described previously to give 17.8 g (59%)
1
of 2b, mp 207–2098C, in two crops. H NMR (DMSO-d6, 400 MHz): d
11.59 (br s, 1H, D2O exchangeable), 8.21 (dd, J ¼ 8 Hz, 1 Hz, 1H), 7.61
(dd, J ¼ 8 Hz, 1 Hz, 1H), 7.48 (s, 1H), 7.45 (t, J ¼ 7.6 Hz, 1H), 2.89
(s, 3H). Anal. calcd. for C10H8BrNO: C, 50.45; H, 3.39; N, 5.88. Found: C,
50.60; H, 3.43; N, 5.93.
4-Bromo-1-chloroisoquinoline (3a)
Fresh Vilsmeier’s reagent was prepared as follows: A 08C solution of 47 mL
(604 mmol) of DMF in 350 mL of 1,2-dichloroethane was treated dropwise
over 1 h with 52.7 mL (604 mmol) of oxalyl chloride. The viscous suspension
was stirred at 258C for 10 min, and then 61.2 g (273 mmol) of 4-bromo-
1(2H)-isoquinolinone (2a) was added to the reagent as a solid. The suspension
was heated at 808C for 1 h, cooled, and diluted with CH2Cl2. The solution was
washed with H2O, dried, and concentrated to afford 65.4 g (99%) of a pale
yellow solid, mp 95–988C. A small sample was crystallized from isopropyl
1
ether to give an analytical sample of 3a, mp 97–988C. The H NMR was
identical to that previously reported.[11] Anal. calcd. for C9H5NBrCl: C,
44.58; H, 2.08; N, 5.78; Br, 32.95; Cl, 14.62. Found: C, 44.54; H, 1.72; N,
5.64; Br, 32.74; Cl, 14.53.
4-Bromo-1-chloro-5-methyl-isoquinoline (3b)
Reaction of 38.7 g (163 mmol) of 4-bromo-5-methyl-1(2H)-isoquinolinone
(2b) with Vilsmeier’s reagent for 3 h followed by workup as described pre-
viously gave 32.2 g (77%) of 3b, mp 128–1318C, following trituration from
1:1 diethyl ether–petroleum ether. The product was used directly in the
next step.

4204
A. D. Sercel, J. P. Sanchez, and H. D. H. Showalter
4-Bromo-1-methoxyisoquinoline (4a)
A mixture of 65.4 g (270 mmol) of 4-bromo-1-chloroisoquinoline (3a),
27.75 g (488 mmol) of 95% NaOMe, and 550 mL of anhydrous MeOH was
stirred at reflux for 16 h at which time TLC (three elutions with 10:1
ether–hexanes) showed no starting material. The suspension was concentrated
to a residue that was diluted with H2O and extracted with CHCl3. The
combined organic extracts were dried and concentrated to a viscous oil that
solidified upon standing. Crystallization from EtOH afforded 59 g (92%) of
1
4a, mp 53–558C, in four crops. The H NMR spectrum was identical to
that previously reported.[12] Anal. calcd. for C10H8NOBr: C, 50.45; H, 3.39;
N, 5.88; Br, 33.56. Found: C, 50.43; H, 3.30; N, 5.70; Br, 33.54.
4-Bromo-1-methoxy-5-methylisoquinoline (4b)
Reaction of 46.5 g (181 mmol) of 4-bromo-1-chloro-5-methylisoquinoline
(3b) with 2.5 equiv. of NaOMe for 3 h followed by workup as described
previosly gave a viscous oil that slowly crystallized. Filtration of the solids
followed by washing with cold isopropyl ether gave 40.4 g (88%) of 4b, mp
1
55–588C. H NMR (CDCl3, 250 MHz): d 8.28–8.13 (m, 2H), 7.58–7.38
(m, 2H), 4.09 (s, 3H), 3.05 (s, 3H). Anal. calcd. for C11H10NOBr: C, 52.41;
H, 4.00; N, 5.56; Br, 31.70. Found: C, 52.80; H, 4.06; N, 5.68; Br, 31.76.
4-Substituted 1(2H)-Isoquinolinones via Lithiated Dianions
(General Procedure)
1,2-Dihydro-1-oxo-4-isoquinolinecarboxaldehyde (5)
A 08C suspension of 15 g (67 mmol) of 4-bromo-1(2H)-isoquinolinone (2a) in
600 mL of THF was charged with 54 mL (75.6 mmol, 1.13 equiv) of MeLi
(1.4 M in diethyl ether). The resultant solution was stirred for 10 min, cooled
to 2788C, and treated with 85.5 mL (136.8 mmol, 2 equiv) of n-BuLi (1.6 M
in hexanes). After stirring for 30 min, the solution was treated with 15 mL
(194 mmol, 2.9 equiv) of DMF. The solution was maintained at 278 08C for
1 h and then quenched with sat. aqueous NH4Cl. The mixture was slowly
warmed to 258C, diluted with H2O, and extracted with CH2Cl2 (3ꢀ). The
combined extracts were washed with H2O, dried, and concentrated to a solid
that was crystallized from EtOH to provide 9.55 g (82%) of 5, mp 235–
1
2388C (lit.[13] 222–2238C. H NMR (DMSO-d6, 400 MHz): d 12.25 (br s,
1H, D2O exchangeable), 9.78 (s, 1H), 8.97 (d, J ¼ 8.2 Hz, 1H), 8.27
(d, J ¼ 8.0 Hz, 1H), 8.17 (s, 1H), 7.85 (t, J ¼ 7.7 Hz, 1H), 7.62
(t, J ¼ 8.1 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz): d 190.3, 162.2, 147.4,
134.1, 133.8, 128.0, 127.5, 125.1, 124.6, 114.1. Anal. calcd. for C10H7NO2:
C, 69.36; H, 4.07; N, 8.09. Found: C, 69.22; H, 4.00; N, 8.00.

4-Substituted 1(2H)-Isoquinolinones
4205
1,2-Dihydro-1-oxo-4-isoquinolinecarboxylic acid (6)
Reaction of the dianion formed from 223 mg (1 mmol) of 2a as discussed
previously was followed by trapping with excess dry CO2. Following the
NH4Cl quench and dilution with H2O, the aqueous layer was extracted with
CHCl3 to remove organic impurities and then acidified to pH 2 with aqueous
HCl. The formed precipitate was collected by filtration, washed with H2O,
and dried to leave 146 mg (73%) of 6, mp . 2508C (lit.[14] 296–2978C dec).
1H NMR (DMSO-d6, 250 MHz): d 12.68 (br s, 1H, D2O exchangeable),
d 11.85 (br s, 1H, D2O exchangeable), 8.83 (d, J ¼ 8.3 Hz, 1H), 8.23
(d, J ¼ 7.8 Hz, 1H), 8.04 (s, 1H), 7.76 (t, J ¼ 7.5 Hz, 1H), 7.52
.
(t, J ¼ 7.5 Hz, 1H). Anal. calcd. for C10H7NO3 0.6H2O: C, 60.06; H, 4.13;
N, 7.00. Found: C, 59.66; H, 3.76; N, 7.25.
4-Methyl-1(2H)-isoquinolinone (7)
Following the general procedure, reaction of 223 mg (1 mmol) of 2a with 3
equiv. of CH3I provided 84 mg (52%) of 7, mp 170–1728C, following crystal-
lization from EtOAc–hexanes. The 1H NMR was identical to that previously
reported.[15] Anal. calcd. for C10H9NO 0.1 H2O: C, 74.61; H, 5.76; N, 8.70.
.
Found: C, 74.68; H, 5.53; N, 8.74.
4-(Methylthio)-1(2H)-isoquinolinone (8)
Following the general procedure, reaction of 223 mg (1 mmol) of 2a provided
1
107 mg (56%) of 8, mp 170–1728C, following trituration from 2-PrOH. H
NMR (CDCl3, 250 MHz): d 11.45 (br s, 1H, D2O exchangeable), 8.42
(d, J ¼ 8.0 Hz, 1H), 8.12 (d, J ¼ 8.0 Hz, 1H), 7.85–7.73 (m, 1H),
7.61–7.48 (m, 1H), 7.46 (s, 1H), 2.33 (s, 1H). Anal. calcd. for C10H9NOS:
C, 62.80; H, 4.74; N, 7.32. Found: C, 63.06; H, 4.61; N, 6.93.
4-Substituted 1-Methoxyisoquinolinones via Lithiated monoanions
(General Procedure)
1-Methoxy-4-isoquinolinecarboxaldehyde (9)
A 2788C solution of 30 g (126 mmol) of 4-bromo-1-methoxyisoquinoline
(4a) in 230 mL of THF was charged slowly with 86.6 mL (139 mmol, 1.1
equiv) of n-BuLi (1.6 M in hexanes). The resultant yellow suspension was
stirred for 35 min and then treated with 15.7 mL (127 mmol) of N-methylfor-
manilide. After stirring for 30 min at 2788C, the cold mixture was quenched
with 80 mL of H2O. The mixture was concentrated and extracted with CHCl3
(3ꢀ). The combined extracts were washed with H2O, dried, and concentrated
to a yellow oil that solidified on standing. Crystallization from isopropyl ether

4206
A. D. Sercel, J. P. Sanchez, and H. D. H. Showalter
afforded 15.6 g (66%) of 9, mp 83–858C. A small sample was sublimed at
658C/0.01 mm to provide analytical material, mp 87–898C. 1H NMR
(DMSO-d6, 250 MHz): d 10.18 (s, 1H), 9.05 (d, J ¼ 8.4 Hz, 1H), 8.67
(s, 1H), 8.26 (d, J ¼ 8.0 Hz, 1H), 7.94 (dt, J ¼ 7.5 Hz, 1.1 Hz, 1H), 7.74
(t, J ¼ 7.5 Hz, 1H), 4.18 (s, 3H). Anal. calcd. for C11H9NO2: C, 70.58; H,
4.85; N, 7.48. Found: C, 70.50; H, 4.80; N, 7.44.
1-Methoxy-5-methyl-4-isoquinolinecarboxaldehyde (10)
Following the general procedure, 12.6 g (50 mmol) of 4-bromo-1-methoxy-5-
methylisoquinoline (4b) in 250 mL of THF was with treated with 1.2 equiv. of
n-BuLi and then 2.4 equiv. of DMF. After slowly warming to 108C over 1 h,
the mixture was cooled to 2508C and further processed as described pre-
viously to leave an oil that solidified. Crystallization from isopropyl ether
gave 8.7 g (86%) of 10, mp 87–898C. A small sample was sublimed at
608C/0.5 mm to provide analytical material, mp 93–958C. 1H NMR
(CDCl3, 250 MHz): d 10.67 (s, 1H), 8.51 (s, 1H), 8.24 (d, J ¼ 5.0 Hz, 1H),
7.63 (d, J ¼ 6.8 Hz, 1H), 7.52 (t, J ¼ 7.7 Hz, 1H), 4.20 (s, 3H), 2.76
(s, 3H). Anal. calcd. for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C,
71.66; H, 5.48; N, 7.01.
4,5-Dimethyl-1-methoxyisoquinoline (11)
Following the general procedure, the anion derived from 2 g (7.9 mmol) of 4b
was treated with 3 equiv. of CH3I. Further processing as described previously
left a brown oil that was purified by column chromatography eluting with
hexanes–EtOAc (97:3). Concentration of product fractions followed by
molecular distillation afforded 1.18 g (79%) of 11, bp 708C/0.1 mm. 1H
NMR (CDCl3, 250 MHz): d 8.17 (d, J ¼ 8.0 Hz, 1H), 7.75 (s, 1H),
7.53–7.28 (m, 2H), 4.08 (s, 3H), 2.87 (s, 3H), 2.71 (s, 3H). Anal. calcd. for
.
C12H13NO 0.1H2O: C, 76.24; H, 7.04; N, 7.41. Found: C, 76.13; H, 7.03;
N, 7.57.
1-Methoxy-5-methyl-4-(methylthio)isoquinoline (12)
Following the general procedure, the anion derived from 3 g (11.9 mmol) of
4b was treated with 2.5 equiv. of methyl disulfide. Workup and chromato-
graphy as discussed previously gave an oil that solidified on standing. Tritura-
tion in isopropyl ether afforded 921 mg (35%) of 12, mp 39–418C. 1H NMR
(CDCl3, 250 MHz): d 8.19 (d, J ¼ 8.0 Hz, 1H), 8.08 (s, 1H), 7.53–7.35
(m, 2H), 4.10 (s, 3H), 3.09 (s, 3H), 2.44 (s, 3H). Anal. calcd. for
C12H13NOS: C, 65.72; H, 5.97; N, 6.39; S, 14.62. Found: C, 65.59; H, 5.97;
N, 6.38; S, 14.78.

4-Substituted 1(2H)-Isoquinolinones
4207
Hydrolysis of 4-Substituted 1-Methoxyisoquinolines (General
Procedure)
1,2-Dihydro-5-methyl-1-oxo-4-isoquinolinecarboxaldehyde (13)
A suspension of 23.85 g (118.5 mmol) of 1-methoxy-5-methyl-4-isoquinoli-
necarboxaldehyde (10) and 150 mL of 20% HBr was stirred at 258C
overnight, and then poured into 780 mL of cold H2O. After stirring for 3 h,
the solids were collected and then washed successively with H2O, MeOH,
and diethyl ether. Crystallization from MeOH afforded 12.6 g (55%) of 13,
1
mp 231–2338C. H NMR (DMSO-d6, 250 MHz): d 12.13 (br s, 1H, D2O
exchangeable), 9.98 (s, 1H), 8.14 (d, J ¼ 7.7 Hz, 1H), 8.00 (s, 1H), 7.66
(d, J ¼ 7.3 Hz, 1H), 7.51 (t, J ¼ 7.5 Hz, 1H), 2.54 (s, 3H). Anal. calcd. for
.
C11H9NO2 0.3 H2O: C, 68.60; H, 5.02; N, 7.27. Found: C, 68.56; H, 4.66;
N, 7.27.
4,5-Dimethyl-1(2H)-isoquinolinone (14)
Reaction of 5.6 g (30 mmol) of 4,5-dimethyl-1-methoxy-4,5-isoquinoline (11)
with 40 mL of 48% HBr for 6 h at 808C followed by workup as described pre-
viously and crystallization from EtOH gave 2.7 g (52%) of 14, mp
1
237–2398C. H NMR (CDCl3 þ DMSO-d6, 250 MHz): d 10.88 (br s, 1H,
D2O exchangeable), 8.36 (d, J ¼ 7.8 Hz, 1H), 7.45 (d, J ¼ 7.0 Hz, 1H),
7.42–7.31 (m, 1H), 6.84 (s, 1H), 2.79 (s, 3H), 2.50 (s, 3H). Anal. calcd. for
C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.58; H, 6.63; N, 7.87.
1,2-Dihydro-1-oxo-4-isoquinolinecarboxaldehyde (5)
Reaction of 5 g (26.7 mmol) of 1-methoxy-4-isoquinolinecarboxaldehyde (9)
and 50 mL of 48% HBr for 16 h at 258C followed by workup as described pre-
viously provided solids that were boiled in 100 mL of H2O for 4 h. The solids
were collected and dried to leave 4.1 g (88%) of 5, identical to that reported
previously.
REFERENCES
1. (a) Recent reviews on PARP-1 inhibitors: (a) Peukert, S.; Schwahn, U. New inhibi-
tors of poly(ADP-ribose) polymerase (PARP). Expert Opin. Therapeu. Pat. 2004,
14, 1531–1551; (b) Woon, E. C. Y.; Threadgill, M. D. Poly(ADP-ribose)polymer-
ase inhibition—where now? Curr. Med. Chem. 2005, 12, 2373–2392.
2. Suto, M. J.; Turner, W. R.; Werbel, L. M. Preparation of substituted dihydroisoqui-
nolinones and related compounds as radiation therapy potentiators and chemother-
apeutic agents. Eur. Pat. Appl. 355750, 1990, Chem. Abstr. 113, 132025.
3. Showalter, H. D. H.; Sercel, A. D.; Stier, M. A.; Turner, W. A. Synthesis of 3,4-
dihydro-1(2H)-isoquinolinones. J. Heterocycl. Chem. 2001, 38, 961–964.

4208
A. D. Sercel, J. P. Sanchez, and H. D. H. Showalter
4. Recent reviews: (a) Alvarez, M.; Joule, J. A. Product class 6: Isoquinolinones. Sci.
Synth. 2005, 15, 839–906; (b) Glushkov, V. A.; Shklyaev, Y. V. Synthesis of
1(2H)-isoquinolones. Chem. Heterocycl. Compd. 2001, 37, 663–687.
5. Muchowski, J. M.; Horning, D. E.; Lacasse, G. Isocarbostyrils: I. electrophilic
substitution reactions. Can. J. Chem. 1971, 49, 2785–2796.
6. Muchowski, J. M.; Horning, D. E.; Lacasse, G. Isocarbostyrils, II: conversion of
2-methyl-4-acyl-5-nitroisocarbostyrils to 2-substituted indole-4-carboxylic acids.
Can. J. Chem. 1971, 49, 2797–2802.
7. Nuvole, A.; Pinna, G. A. Synthesis of 1-amino-4-chloroisoquinoline: a new
approach to 1-aminoisoquinoline. J. Heterocycl. Chem. 1978, 15, 1513–1514.
8. (a) Fujio, M.; Satoh, H.; Matsumoto, T.; Futamura, T. Preparation of 4-piperidinyl-1-
isoquinolinone derivatives as polyadenosine diphosphoribose polymerase inhibitors
for treatment of cerebral infarction. PCT Intl. Appl. WO 2005/113540, 2005; Chem.
Abstr. 144, 22822; (b) Asano, J.; Shiga, F.; Takano, Y.; Ishiyama, J. 4-Aryl-5-hydro-
xyisoquinolinones, their preparation, and poly(ADP-ribose) polymerase inhibitors
containing them. Jpn. Pat. Appl. 2004/043458, 2004; Chem. Abstr. 140, 157492.
9. Robison, M. M.; Robison, B. L. Reaction of 1-chloroisoquinoline with peracetic
acid. J. Org. Chem. 1958, 23, 1071–1072.
10. Shizuta, Y.; Ito, S.; Nakata, K.; Hayaishi, O. Poly(ADP-ribose) synthetase from
calf thymus. Methods Enzymol. 1980, 66, 159–165.
11. Bender, S. L.; Bhumralkar, D.; Collins, M. R.; Cripps, S. J.; Deal, J. G.;
Nambu, M. D.; Palmer, C. L.; Peng, Z.; Varney, M. D.; Jia, L. Synthesis of hetero-
arylbenzamides and analogs used for inhibiting protein kinases. PCT Int. Appl.
WO 2001/053274, 2001; Chem. Abstr. 135, 137516.
12. Lee, W.-C.; Sun, L.; Shan, F.; Chuaqui, C.; Cornebise, M.; Pontz, T. W.;
Carter, M.; Singh, J.; Boriack-Sjodin, P. A.; Ling, L.; Petter, R. C. Preparation
of 2-pyrazolylpyridine derivatives as TGFb receptor inhibitors. PCT Int. Appl.
WO 2004/072033, 2004; Chem. Abstr. 141, 225504.
13. Bold, G.; Manley, P. W. Preparation of isoquinolinamines inhibiting angiogenesis
and/or VEGF receptor tyrosine kinase. PCT Int. Appl. WO 2001/058899, 2001;
Chem. Abstr. 135, 180710.
14. Kimura, M.; Waki, I.; Deguchi, Y.; Amemiya, K.; Maeda, T. 1(2H)-Isoquinolones
as potential antiallergic agents. Chem. Pharm. Bull. 1983, 31, 1277–1282.
15. Wang, X. A.; Sun, L.-Q.; Sit, S.-Y.; Sin, N.; Scola, P. M.; Hewawasam, P.;
Good, A. C.; Chen, Y.; Campbell, J. A. Preparation of peptides as hepatitis C
virus inhibitors. PCT Int. Appl. WO 2003/099274, 2003; Chem. Abstr. 140,
16975.