Application of organolithium and related reagents in synthesis; Part 26.1 Synthetic strategies based on directed ortho-metalation: Synthesis of 4-methyl-2H-phthalazin-1-ones

Article abstract of DOI:10.1055/s-2001-18056

The synthesis of 3-hydroxy-3-methylisoindolin-1-ones 10, masked ortho-acetylated derivatives of anilides, via metalation (BuLi) of the benzanilides 1 and subsequent reaction of the generated bis-lithiated anilides 2 with acetylating agents such as acetic anhydride or ethyl acetate were studied. The 3-hydroxy-3-methylisoindolin-1-ones 10 thus obtained are very sensitive towards dehydration process, which caused their conversion into enamides 11. Conversion of 3-hydroxy-3-methylisoindolin-1-ones 10 or enamides 11 into the corresponding 4-methyl-2H-phthalazin-1-ones 13 by treatment with hydrazine, as a way of regioseletive transformation of the benzoic acids, is also described.

Full text of DOI:10.1055/s-2001-18056

PAPER
2085
Application of Organolithium and Related Reagents in Synthesis; Part 26.1
Synthetic Strategies Based on Directed ortho- Metalation:
Synthesis of 4-Methyl-2H-phthalazin-1-ones
Synthesis
aof 4-Methy
n
l-2
H
-phthalazin-1-
E
ones psztajn,* Zbigniew Malinowski, Jacek Z. BrzeziÒki, Monika Karzatka
Department of Organic Chemistry, University of £ódü, Narutowicza 68, 90-136 £ódü, Poland
E-mail: epsztajn@krysia.uni.lodz.pl
Received 5 July 2001; revised 28 August 2001
Abstract: The synthesis of 3-hydroxy-3-methylisoindolin-1-ones
10, masked ortho-acetylated derivatives of anilides, via metalation
(BuLi) of the benzanilides 1 and subsequent reaction of the gener-
ated bis-lithiated anilides 2 with acetylating agents such as acetic
anhydride or ethyl acetate were studied. The 3-hydroxy-3-methyl-
isoindolin-1-ones 10 thus obtained are very sensitive towards dehy-
dration process, which caused their conversion into enamides 11.
Conversion of 3-hydroxy-3-methylisoindolin-1-ones 10 or enam-
ides 11 into the corresponding 4-methyl-2H-phthalazin-1-ones 13
by treatment with hydrazine, as a way of regioselctive transforma-
tion of the benzoic acids, is also described.
Key words: lithiation, acylations, isoindolinones, phthalazinones
The observed antiallergic2 and antidiabetic3 activity of 4-
alkyl-2H-phthalazin-1-ones derivatives of type A has pro-
moted
a
widespread interest in their synthesis.
In particular, our attention was focused on obtaining a
general synthetic methodology for 4-methyl-2H-
phthalazin-1-ones C as useful starting materials for A
(Scheme 1).
The available methods reported for the preparation of
phthalazin-1-ones generally require reaction of ortho-car-
bonylated carboxylic acids4–7 or their amides8–10 with hy-
drazine. Therefore, the current interest is centred on
discovering a regiospecific synthetic methodology for the
ortho-acetylated aromatic carboxylic acids or their deriv-
atives, as starting materials for phthalazin-1-ones C.
Available methods for the preparation of ortho-acetylated
aromatic carboxylic acids generally require one of the fol-
lowing techniques. The most common approach involves
the Friedel–Crafts reaction, which is usually effected un-
der harsh conditions and does not often proceed with
a desired positional specificity.11 Alternatively, the de-
sired compounds are synthesised via acetylation of aro-
matic or heteroaromatic zinc, manganese, magnesium, or
tin derivatives predominantly by acid chlorides applying
the palladium cross-coupling process.12–20 These systems
may be also prepared by the reaction of appropriate halo-
genated aromatics with (ethoxyvinyl)tributyltin deriva-
tives in the presence of palladium catalyst.21–23 The most
attractive route so far reported to ortho-acetylated aromat-
ic carboxylic acids is a directed ortho-lithiation of 2-(4-
Scheme 1
methoxy-3-methylphenyl)-4,4-dimethyl-4,5-dihydroox-
azole24 at the position 6 of benzene ring and reaction with
acetic anhydride or N-allylbenzamide25 followed by treat-
ment with N-methoxy-N-methylacetamide. However, the
examples described relate only to specific instances. In a
series of recent studies we have reported9,10,26–28 that the
secondary carboxamides moiety namely N-phenylamides
(anilides) provide an excellent possibility for the re-
giospecific ortho-lithiation and subsequent electrophilic
substitution of the aromatic ring, including benzoylation.
Our aim was to extend the scope of this general procedure
to the synthesis of new 4-methyl-2H-phthalazin-1-ones C
and we report here the results obtained starting with a se-
ries of N-phenylbenzoic acid amides (benzanilides) 1. The
route described provides an efficient and general synthetic
sequence for the transformation of benzoic acids B into 4-
methyl-2H-phthalazin-1-ones C in a two-step protocol
starting from benzoic acid anilides 1.
For this purpose, it appeared necessary to undertake stud-
ies which are concerned with the reaction of bis-(N- and
C-ortho-lithiated) anilides with acetylating agents. To this
Synthesis 2001, No. 14, 26 10 2001. Article Identifier:
1437-210X,E;2001,0,14,2085,2090,ftx,en;E04501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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J. Epsztajn et al.
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end, bis-(N- and C-ortho-lithiated) anilides 2 were effi- nyl signal, but it exhibited peaks at d = 94.5, 50.4, 24.2
ciently generated upon the treatment of anilides 1 with and 94.0, 50.3, 24.2, which are appropriate for compounds
2.1 mol equivalents of butyllithium in THF9,10,26–28 9a and 9b, respectively. The peaks of the 13C NMR spec-
(Scheme 2).
trum at d ª 90 are characteristic for a carbon atom at 3 of
the 3-hydroxyisoindolin-1-ones.10,32 The peaks at d ª 50
and ª 25 are carbon atom resonances, which are assigned
to methoxy and methyl groups. The formation of methoxy
derivatives 9 is most probably due to the instability of ad-
ducts 3, which undergo elimination of lithium acetate and
lead to the corresponding 5 D 6 keto-lactol type tautomer-
ic mixture (Scheme 2). Then the lactol-lithium salts 6 re-
acted with acetic anhydride (excess) to give O-acetylated
derivatives 8, which in the presence of the lithium meth-
oxide (methanol quench) produced 3-methoxy-3-methyl-
isoindolin-1-ones 9.
Since the initial report of Nahm and Weinreb29 on the use
of N-methoxy-N-methylamides as carbonyl equivalents,
this acetylating agent has gained tremendous popularity.30
Hence, at first the bis-lithiated anilides 2 were subjected
to reaction with N-methoxy-N-methylacetamide. Unex-
pectedly, instead of an effective ortho-C-acetylation of
the anilides a complex mixture was obtained, in which the
desired product was present but in a low yield, as was de-
termined by 1H NMR spectroscopy.
It has been suggested31 that the addition of acetic anhy-
dride to Grignard reagents at low temperature results in
the formation of appropriate acetylated derivatives.
On the other hand, if water was used for quenching in the
reaction of the bis-lithiated anilides 2 with acetic anhy-
dride, the corresponding acetylated derivatives 8 formed
upon hydrolytic workup were converted spontaneously
into 3-hydroxy-3-methylisoindolin-1-ones 10, as the sta-
ble tautomeric form of ortho-acetylated anilides. The
products were accompanied by their dehydrated deriva-
Therefore, acetic anhydride was reacted with bis-lithiated
anilides 2 which gave new products. However, the com-
pounds formed appeared to be different from the expected
bis-acetylated species 7 or 8 (Figure). The 13C NMR spec-
tra of the products from 2a and 2b lacked a ketonic carbo-
1
tives 11, as determined by H NMR spectroscopy of the
crude materials. This elimination is probably due to the
acidic quenching conditions. It was observed that the ratio
of compounds 10:11 depended upon the position and na-
ture of substituents at the aromatic ring. In the case of the
anilide 1d the sole product appeared to be enamide 11b.
Therefore, it can be concluded that the formed isoindolin-
1-ones 10 appeared to be very sensitive towards even
weak acids, which is responsible for their conversion into
enamides 11. For example, attempted crystallization of
isoindolin-1-one 10c from ethyl acetate caused elimina-
tion of water and gave enamide 11a.
Our recent observation that the reaction of bis-lithiated
anilides 2 reacted with aromatic carboxylic acids
esters10,26–28 readily to give the 3-aryl-3-hydroxy-2-phe-
nylizoindolin-1-ones inspired us to test ethyl acetate as an
acetylating agent. The treatment of bis-lithiated species 2
with the ethyl acetate afforded the corresponding acetylat-
ed derivatives, which spontaneously cyclized to the 3-hy-
droxy-3-methylisoindolin-1-ones 10.
In the experiments, in which for the initial lithiation a 5–
10% excess of butyllithium was used, the formed 3-hy-
droxy-3-methylisoindolin-1-ones 10 were accompanied
by phthalides 12 (ª5%) resulting from the addition of the
lithiating agent to compound 5. This suggests that in both
cases adducts 3 as well as 4 are unstable and eliminate
lithium acetate or the lithium ethoxide, leading to the
5 D 6 keto-lactol tautomeric mixture, respectively. In or-
der to prevent the formation of phthalides 12, an excess of
anilides 1 in the lithiation process appeared to be crucial.
Finally, in order to achieve the synthesis of 4-me-
thylphthalazin-1-ones 13, the reaction of 3-hydroxyisoin-
dolin-1-ones with the hydrazine hydrate was undertaken.
Thus, when the isoindolin-1-ones 10 were treated with hy-
Scheme 2 Reagents and conditions: i: a. BuLi, hexanes–THF, –78
°C, 0.5 h; b. 0 °C, 0.5 h; ii: Ac2O, –78 °C; iii: EtOAc, –78 °C
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Synthesis of 4-Methyl-2H-phthalazin-1-ones
2087
conversion of 2,3-dihydrooxazolate[2,3-a]isoindole into
the phthalazinones.33 Indeed reaction of enamides 11 with
hydrazine in boiling acetic acid furnished the desired
phthalazin-1-ones 13.
The described methodology for the ortho-acetylation of
secondary benzamides 1 shows a considerable versatility
for the regiospecific synthesis of 3-hydroxy-3-methyl-
isoindolin-1-ones 10 as masked ortho-acetylated aromatic
carboxanilides. This, coupled with an effective conver-
sion of 3-hydroxy-3-methylisoindolin-1-ones 10 or their
corresponding enamides 11 into the corresponding 4-me-
thyl-2H-phthalazin-1-ones should allow access to a wide
variety of 2H-phthalazin-1-ones derivatives.
Melting points were determined using a Boetius hot stage apparatus
1
and are uncorrected. H NMR spectra were recorded at 200 MHz
and 13C NMR spectra at 50 MHz on a Varian Gemini 200 BB spec-
trometer with TMS used as an internal reference. A Zeiss-Jena
Specord 71-IR spectrometer was used for the IR spectra. The ana-
lytical TLC tests were carried out on Merck silica gel plates (Kisel-
gel 60 F254, layer thickness 0.2 mm) and the spots were visualised
using UV lamp. Column chromatography purifications were per-
formed on Merck silica gel (Silica gel 60 (0.063–0.100 mm) using
25g of silica gel per 1g of the purified material. BuLi, solution in
hexanes (Aldrich) was titrated each time before use. Hydrazine
monohydrate (98%) (Aldrich) was used without further purifica-
tion. EtOAc (POCh, Poland) and Ac2O (POCh, Poland) were dis-
tilled before use. Anilides 1 are known compounds and were
prepared by a standard method.
Bis-lithiated Anilides; General Procedures for Methods A and
B
To a stirred solution of 1 (0.02 mol) in THF (90 mL) at –78 °C under
argon was added dropwise a solution of BuLi in hexanes (Method
A, 0.042 mol), (Method B, 0.036 mol). The mixture was held at –
78 °C for 0.5 h, then the temperature was allowed to rise to 0 °C and
was kept at this temperature for 0.5 h. This solution of lithiated spe-
cies was used for reactions at –78 °C with acetylating agents (Ac2O
or EtOAc).
Reactions of Bis-(ortho-lithiated) Anilides 2 with Acetylating
Reagents Acetic Anhydride (Procedure A) and Ethyl Acetate
(Procedure B)
Procedure A: A solution of the bis-lithiated anilide 2 (Method A) at
–78 °C under argon was treated with a solution of Ac2O (0.066 mol)
in THF (20 mL). After 0.5 h at –78 °C, the reaction mixture was
warmed to r.t. over a 2 h period. To this mixture, MeOH (60 mL) or
H2O (70 mL) was added, the solution was stirred for 0.5 h, and
evaporeted to dryness under reduced pressure. H2O (80 mL) and
CHCl3 (100 mL) were added to the residue and neutralized with sol-
id NaHCO3. The H2O layer was separated and extracted with CHCl3
(3 ¥ 50 mL). The combined extracts were dried (MgSO4) and con-
centrated to dryness, and the residue was subjected to column chro-
matography to give the following compounds: a) 3-methoxy-3-
methyl-1H-isoindolin-1-ones 9 and unreacted anilides 1 (MeOH
quenches); and b) 3-hydroxy-3-methyl-1H-isoindolin-1-ones 10
and 3-methylene-1H-isoindolin-1-ones 11 and unreacted anilides 1
(H2O quenches).
Figure
drazine hydrate in boiling propan-1-ol or acetic acid, the
desired phthalazin-1-ones 13 were obtained.
An alternative route to phthalazin-1-ones may be envis-
aged by the addition of hydrazine to the enamide carbon–
carbon double bond of 3-methylene-2,3-dihydro-1H-
isoindolin-1-ones followed by ring opening and ring clo-
sure to afford phthalazin-1-ones, as was recently suggest-
ed in the mechanistic discussion concerning the
2,3-Dihydro-3-methoxy-3-methyl-2-phenyl-1H-isoindolin-1-
one (9a)
Yield: 40%; eluent: benzene–CHCl3 (6:1); Rf 0.05; mp 167–169 °C
(needles from MeOH–H2O, 1:1).
IR (CHCl3): 1690 cm–1 (C=O).
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J. Epsztajn et al.
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1H NMR (CDCl3): d = 7.91–7.95 (m, 1 H, ArH), 7.41–7.71 (m, 7 H,
ArH), 7.26–7.35 (m, 1 H, ArH), 3.00 (s, 3 H, OCH3), 1.64 (s, 3 H,
CH3).
used according to Method B, the residue appeared to be a mixture
of starting anilides 1, 3-hydroxy-3-methyl-1H-isoindolin-1-ones 10
and trace amounts of 3-methylene-1H-isoindolin-1-ones 11.
13C NMR (CDCl3): d = 166.9 (C=O), 144.3, 135.9, 132.8, 131.7,
2,3-Dihydro-3-hydroxy-3-methyl-2-phenyl-1H-isoindolin-1-one
(10a)
a) Yield: 40% [bis-(ortho-lithiated) anilide was generated according
to Method A]; eluent: benzene–EtOAc, 6:1, Rf 0.1; mp 181–186 °C
(needles from EtOAc).
129.8, 129.0, 126.7, 125.6, 123.9, 121.9, 94.5, 50.4, 24.2.
Anal. Calcd for C16H15NO2: C 75.87; H 5.97; N 5.53. Found: C
75.79; H 5.66; N 5.20.
3-Dihydro 3,5-dimethoxy-3-methyl-2-phenyl-1H-isoindolin-1-
one (9b)
Yield: 37%; eluent: benzene–CHCl3 (6:1); Rf 0.15; mp 146–149 °C
(needles from MeOH–H2O, 1:1).
b) Yield: 42%, [bis-(ortho-lithiated) anilide was was generated ac-
cording to Method B], (eluent: benzene–EtOAc = 6:1, Rf 0.1), mp
181–186 °C (needles from EtOAc.
IR (CHCl3): 1700 cm–1 (C=O).
2,3-Dihydro-3-hydroxy-5-methoxy-3-methyl-2-phenyl-1H-
isoindolin-1-one (10b)
Yield: 36% [bis-(ortho-lithiated) anilide was generated according to
Method A]; eluent: benzene–EtOAc (6:1); Rf 0.06; mp 177–182 °C
(needles from EtOAc).
1H NMR (CDCl3): d = 7.84 (d, 1 H, 7 ArH, J = 8.4 Hz), 7.40–7.57
(m, 4 H, C6H5), 7.24–7.32 (m, 1 H, C6H5), 6.96–7.09 (m, 2 H, ArH),
3.92 (s, 3 H, OCH3), 3.02 (s, 3 H, OCH3), 1.61 (s, 3 H, CH3).
13C NMR (CDCl3) d = 166.8 (C=O), 163.9, 146.8, 136.1, 129.0,
126.4, 125.5, 124.1, 116.2, 106.6, 94.0, 55.8, 50.3, 24.2.
IR (KBr): 1680 (C=O), 2800–3600 cm–1 (O–H).
1H NMR (DMSO-d6): d = 7.65 (d, 1 H, 7 ArH, J = 8.3 Hz), 7.41–
7.55 (m, 4 H, C6H5), 7.28–7.37 (m, 1 H, C6H5), 7.25 (d, 1 H, 4 ArH,
J = 2.2 Hz), 7.09 (dd, 1 H, 6 ArH, J = 8.4, 2.3 Hz), 6.78 (s, 1 H,
OH), 3.89 (s, 3 H, OCH3), 1.52 (s, 3 H, CH3).
Anal. Cald for C17H17NO3: C 72.07; H 6.05; N 4.94. Found: C
71.96; H 5.90; N 4.78.
2,3-Dihydro-3-hydroxy-3-methyl-2-phenyl-1H-isoindolin-1-one
13C NMR (DMSO-d6): d = 165.1 (C=O), 163.1, 151.3, 136.1, 128.5,
(10a)
Yield: 36%; eluent: benzene–EtOAc (6:1); Rf 0.1; mp 181–186 °C
(needles from EtOAc).
IR (KBr): 1675 (C=O), 2800–3600 cm–1 (O–H).
127.3, 126.5, 124.3, 122.3, 115.6, 106.8, 89.0, 55.7, 24.8.
Anal. Calcd for C16H15NO3: C 71.36; H 5.61; N 5.20. Found: C
71.39; H 5.63; N 5.27.
1H NMR (DMSO-d6): d = 7.69–7.77 (m, 3 H, ArH), 7.42–7.63 (m,
4 H, C6H5), 7.31–7.40 (m, 1 H, C6H5), 6.80 (s, 1 H, OH), 1.53 (s, 3
H, CH3).
13C NMR (DMSO-d6): d = 165.6 (C=O), 149.2, 136.2, 133.0, 130.0,
129.5, 128.9, 127.9, 127.1, 123.0, 122.7, 89.8, 25.1.
2,3-Dihydro-3-hydroxy-7-methoxy-3-methyl-2-phenyl-1H-
isoindolin-1-one (10c)
Yield: 30% [bis-(ortho-lithiated) anilide was generated according to
Method A]; eluent: benzene–CHCl3 (6:1); Rf 0.1); mp 137–141 °C
(white powder).
Anal. Calcd for C15H13NO2: C 75.30; H 5.48; N 5.85. Found: C
75.12; H 5.48; N 5.91.
IR (CHCl3): 1710 (C=O), 2400–3700 cm–1 (O–H).
1H NMR (DMSO-d6): d = 7.59–7.68 (m, 1 H, 5 ArH), 7.38–7.50 (m,
4 H, C6H5), 7.28–7.36 (m, 1 H, C6H5), 7.23 (d, 1 H, 6 ArH, J = 7.3
Hz), 7.12 (d, 1 H, 4 ArH, J = 8.3 Hz), 6.64 (s, 1 H, OH), 3.88 (s, 3
H, OCH3), 1.46 (s, 3 H, CH3).
5-Chloro-2,3-dihydro-3-methylene-2-phenyl-1H-isoindolin-1-
one (11b)
Yield: 40%; mp 167.5–170 °C (needles from EtOAc).
13C NMR (DMSO-d6): d = 163.9 (C=O), 156.6, 151.5, 136.2,
IR (CHCl3): 1701 cm–1 (C=O).
134.4, 128.5, 127.7, 126.5, 116.5, 113.9, 112.0, 88.1, 55.6, 24.9.
1H NMR (DMSO-d6): d = 8.30 (d, 1 H, 4 ArH, J = 1.5 Hz), 7.85 (d,
1 H, 7 ArH, J = 8.3 Hz), 7.70 (dd, 1 H, 6 ArH, J = 8.1, 1.8 Hz),
7.38–7.62 (m, 5 H, C6H5), 5.67 (d, 1 H, CH2, J = 2.2 Hz), 4.78 (dd,
1 H, CH2, J = 2.2 Hz).
13C NMR (DMSO-d6): d = 164.5 (C=O), 141.1, 137.6, 133.9, 130.1,
129.2, 128.1, 128.0, 126.7, 124.6, 121.2, 92.8.
Attempted crystallization of 10c from EtOAC led to elimination of
H2O from the material and gave 11a.
2,3-Dihydro-7-methoxy-3-methylene-2-phenyl-1H-isoindolin-
1-one (11a)
Yield: 24% [bis-(ortho-lithiated) anilide was generated according to
Method A]; eluent: benzene–EtOAc (6:1); Rf 0.6; mp 106–110 °C
(powder from THF).
Anal. Calcd for C15H10ClNO: C 70.46; H 3.94; Cl 13.86; N 5.48.
Found: C 70.33; H 3.69; Cl 13.85; N 5.56.
IR (CHCl3): 1710 (C=O), 1635 cm–1 (C=C).
Procedure B: A solution of the bis-lithiated anilide 2 was cannulated
into a stirred solution of EtOAc (5g, 0.066 mol) in THF (15 mL) at
–78 °C under argon. After 0.5 h at –78 °C, the reaction mixture was
warmed to r.t. over 2 h. MeOH (60 mL) was added and the stirring
was continued for 0.5 h. The mixture was then evaporated to dry-
ness under reduced pressure. To the resulting residue, H2O (60 mL)
and CHCl3 (100 mL) were added and neutralized with the conc.
HCl. The H2O layer was separated and extracted with CHCl3 (3 ¥
50 mL). The combined organic extracts were dried (MgSO4 ) and
concentrated to dryness. Purification was achieved by column chro-
matography. In the case of the bis-lithiated anilides 2 (Method A),
the residue appeared to be a mixture of similar amounts of starting
anilides 1, 3hydroxy-3-methyl-1H-isoindolin-1-ones 10, and 3-bu-
tyl-3-methylphthalides 12 and trace amounts of 3-methylene-1H-
1H NMR (DMSO-d6): d = 7.35–7.70 (m, 7 H, ArH, C6H5), 7.21 (d,
1 H, ArH, J = 8.1 Hz), 5.43 (d, 1 H, CH2, J = 1.9 Hz), 4.63 (d, 1 H,
CH2, J = 1.9 Hz), 3.91 (s, 3 H, OCH3).
13C NMR (DMSO-d6): d = 164.0 (C=O), 156.6, 142.1, 138.1, 134.4,
129.2, 128.7, 128.1, 127.8, 114.7, 112.7, 112.5, 90.2, 55.7.
Anal. Calcd for C16H13NO2: C 76.48; H 5.21; N 5.57. Found: C
76.09; H 4.97; N 5.34.
5-Chloro-2,3-dihydro-3-hydroxy-3-methyl-2-phenyl-1H-
isoindolin-1-one (10d)
Yield 36% [bis-(ortho-lithiated) anilide was generated according to
Method A]; mp 160.5–164 °C (plates from EtOH–H2O, 1:2).
1
isoindolin-1-ones 11, which were identified by H NMR of the
crude materials. On the other hand, when bis-lithiated anilide 2 was
IR (KBr): 1679 (C=O), 3000–3500 cm–1 (O–H).
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Synthesis of 4-Methyl-2H-phthalazin-1-ones
2089
1H NMR (DMSO-d6): d = 7.86 (d, 1 H, 4 ArH, J = 2.2 Hz), 7.78 (d,
1 H, 7 ArH, J = 8.1 Hz), 7.65 (dd, 1 H, 6 ArH, J = 8.1, 2.2 Hz),
7.33–7.52 (m, 5 H, C6H5), 6.94 (s, 1 H, OH), 1.54 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 164.1 (C=O), 150.4, 137.2, 135.4, 129.3,
128.6, 128.4, 127.3, 126.8, 124.4, 122.4, 89.0, 24.3.
4-Methyl-2H-phthalazin-1-ones 13; General Procedure
A mixture of 3-hydroxy-3-methylisoindolin-1-ones 10 (0.0021
mol) (Method A) or 3methylene-isoindolin-1-ones 11 (0.0021 mol)
(Method B) and hydrazine monohydrate (1.6 mL) in propan-1-ol
(10 mL) or AcOH (10 mL) was heated under reflux until TLC anal-
ysis (EtOAc) indicated the absence of starting material 10 or 11. Af-
ter the reaction was complete all the volatile materials were
removed under reduced pressure. When propan-1-ol was used as the
solvent and H2O (5 mL) was added to the residue and neutralized
with glacial AcOH. The separated product was collected by filtra-
tion and purified by recrystallization.
Anal. Calcd for C15H12ClNO2: C 65.82; H 4.42; Cl 12.95; N 5.12.
Found: C 65.46; H 4.72; Cl 12.86; N 5.40.
7-Chloro-2,3-dihydro-3-hydroxy-3-methyl-2-phenyl-1H-
isoindolin-1-one (10e)
Yield: 39% [bis-(ortho-lithiated) anilide was generated according to
Method A); mp 121–124.5 °C (white powder).
6-Chloro-4-methyl-2H-phthalazin-1-one (13c) (One-Pot
Procedure)
IR (KBr): 1688 (C=O), 3200–3500 cm–1 (O–H).
The crude material from the reaction of metalated 4-chlorobenzanil-
ide 1d, with EtOAc (Procedure B) [bis-(ortho-lithiated) anilide was
generated according to Method A] was treated with hydrazine
monohydrate (9.5 mL) in AcOH (47 mL) and refluxed until TLC
analysis (EtOH) of the reaction mixture indicated the absence of
starting material 1d. All volatile materials were removed under re-
duced pressure and the crude material was washed with the EtOAc
(3 ¥ 15 mL) in order to remove some starting anilide 1d. The sepa-
rated product was collected by filtration and purified by recrystalli-
zation.
1H NMR (DMSO-d6): d = 7.62–7.74 (m, 2 H, ArH), 7.32–7.64 (m,
6 H, ArH), 6.80 (s, 1 H, OH), 1.52 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 163.2 (C=O), 151.9, 135.8, 134.3, 130.8,
129.6, 128.9, 128.2, 127.4, 126.0, 121.5, 88.3, 24.8.
Anal. Calcd for C15H12ClNO2: C 65.82; H 4.42; Cl 12.95; N 5.12.
Found: C 65.79; H 4.57; Cl 12.60; N 5.08.
3-Butyl-3-methylphthalide (12a)
Yield: 27% [bis-(ortho-lithiated) anilide was generated according to
Method A]; eluent: benzene; Rf 0.16; bp 131–133 °C/9 mmHg
(Kugelrohr) (pale-yellow oil).
IR (film): 1760 cm–1 (C=O).
4-Methyl-2H-phthalazin-1-one (13a)
Method A, solvent: propan-1-ol; time: 120 h; yield: 75%; mp 227–
231 °C (needles from propan-1-ol).
1H NMR (CDCl3): d = 7.87 (d, 1 H, 7 ArH, J = 7.4 Hz), 7.64–7.72
(m, 1 H, ArH), 7.47–7.57 (m, 1 H, ArH), 7.39 (d, 1 H, 4 ArH, J = 7.4
Hz), 1.76–2.14 (m, 2 H, CH2), 1.65 (s, 3 H, CH3), 1.12–1.38 (m, 3
H, CH2), 0.78–1.08 (m, 4 H, CH3, CH2).
13C NMR (CDCl3): d = 170.0 (C=O), 153.9, 134.0, 128.8, 125.9,
125.5, 120.8, 87.7., 39.6, 26.0, 25.5, 22.5, 13.8.
IR (CHCl3): 1670 cm–1 (C=O).
1H NMR (CDCl3): d = 10.86 (s, 1 H, NH), 8.46–8.51 (m, 1 H, ArH),
7.75–7.90 (m, 3 H, ArH), 2.61 (s, 3 H, CH3).
13C NMR (CDCl3): d = 160.7 (C=O), 144.7, 133.5, 131.4, 130.4,
127.8, 126.9, 125.0, 18.8.
Anal. Calcd for C9H8N2O: C 67.49; H 5.03; N 17.49. Found: C
67.24; H 4.62; N 17.65.
Anal. Calcd for C13H16O2: C 76.44; H 7.90. Found: C 76.42; H 7.95.
3-Butyl-5-methoxy-3-methylphthalide (12b)
6-Methoxy-4-methyl-2H-phthalazin-1-one (13b)
Method A, solvent: propan-1-ol; time: 135 h; yield: 70%; mp 247–
251 °C (needles from propan-1-ol).
IR (CHCl3): 1660 cm–1 (C=O).
1H NMR (CDCl3): d = 10.28 (s, 1 H, NH), 8.39 (d, 1 H, 8 ArH,
J = 8.8 Hz), 7.33 (dd, 1 H, 7ArH, J = 8.8, 2.4 Hz), 7.09 (d, 1 H, 5
ArH, J = 2.4 Hz), 3.98 (s, 3 H, OCH3), 2.56 (s, 3 H, CH3).
Yield: 32%; [bis-(ortho-lithiated) anilide was generated according
to Method A]; eluent: benzene; Rf 0.05; bp 210–228 °C/0.6 mmHg
(Kugelrohr) (pale-yellow oil).
IR (film): 1755 cm–1 (C=O).
1H NMR (CDCl3): d = 7.77 (d, 1 H, 7 ArH, J = 8.6 Hz), 7.00 (dd, 1
H, 6 ArH, J = 8.5, 2.2 Hz), 6.78 (d, 1 H, 4 ArH, J = 2.0 Hz), 3.92 (s,
3 H, OCH3), 1.74–2.10 (m, 2 H, CH2), 1.62 (s, 3 H, CH3), 1.16–1.40
(m, 3 H, CH2), 0.79–1.02 (m, 4 H, CH3, CH2).
13C NMR (CDCl3): d = 163.5 (C=O), 160.3, 144.1, 132.4, 129.1,
121.4, 119.6, 107.0, 55.7, 18.9.
13C NMR (CDCl3): d = 169.9 (C=O), 164.7, 156.7, 127.2, 118.3,
115.8, 105.2, 86.9, 55.8, 39.6, 26.1, 25.5, 22.6, 13.9.
Anal. Calcd for C10 H10N2O2: C 63.15; H 5.30; N 14.73. Found: C
62.95; H 4.95; N 14.80.
Anal. Calcd for C14H18O3: C 71.77; H 7.74. Found: C 72.02; H 8.06.
6-Chloro-4-methyl-2H-phthalazin-1-one (13c)
Method A, solvent: AcOH; time: 22 h; yield: 40%; mp 293.5–
297 °C (plates from AcOH–H2O, 1:1).
3-Butyl-7-methoxy-3-methylphthalide (12c)
Yield: 9% [bis-(ortho-lithiated) anilide was generated according to
Method A]; eluent: benzene; Rf 0.3; bp 190–198 °C/0.8 mmHg
(Kugelrohr) (pale-yellow oil).
IR (thin film): 1760 cm–1 (C=O).
1H NMR (CDCl3): d = 7.60 (dd, 1 H, 5 ArH, J = 8.3 Hz), 6.87–6.93
(m, 2 H, 4, 6 ArH), 3.99 (s, 3 H, OCH3), 1.70–2.10 (m, 2 H, CH2),
1.60 (s, 3 H, CH3), 1.15–1.35 (m, 3 H, CH2), 0.78–1.05 (m, 4 H,
CH3, CH2).
Method B, solvent: AcOH; time: 60 h; yield: 30%.
One-pot procedure, time: 45 h; yield: 35%.
IR (CHCl3): 1657 cm–1 (C=O).
1H NMR (DMSO-d6): d = 12.61 (s, 1 H, NH), 8.27 (d, 1 H, 8 ArH,
J = 8.6 Hz), 8.04 (d, 1 H, 5 ArH, J = 1.8 Hz), 7.93 (dd, 1 H, 7 ArH,
J = 8.6, 1.8 Hz), 2.52 (s, 3 H, CH3).
13C NMR (CDCl3): d = 168.1 (C=O), 158.4, 156.8, 136.2, 113.4,
112.5, 110.3, 86.3, 55.9, 39.6, 26.2, 25.5, 22.6, 13.9.
13C NMR (DMSO-d6): d = 158.7 (C=O), 142.5, 138.3, 131.6, 131.2,
128.1, 126.0, 125.1, 18.4 (CH3–C).
Anal. Calcd for C14H18O3: C 71.77; H 7.74. Found: C 71.84; H 7.85.
Anal. Calcd for C9H7ClN2O: C 55.54; H 3.63; Cl 18.22; N 14.39.
Found: C 55.20; H 3.67; Cl 18.07; N 14.15.
Synthesis 2001, No. 14, 2085–2090 ISSN 0039-7881 © Thieme Stuttgart · New York

2090
J. Epsztajn et al.
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Acknowledgment
We gratefully acknowledge the support by Grant-in-Aid for Scien-
tific Research from the State Committee for Scientific Research
(KBN) and from the University of £ódü.
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Synthesis 2001, No. 14, 2085–2090 ISSN 0039-7881 © Thieme Stuttgart · New York