Synthesis of 4-Alkyl-1(2H)-phthalazinones and 4-Alkyl-2, 3-benzoxazin-1-ones via Ring Cleavage of 3-Substituted N-Alkylated-3-hydroxyisoindolin-1-ones

Article abstract of DOI:10.1081/SCC-120030319

N-Alkyl (Me, Et, i-Pr, t-Bu)-substituted phthalimdes 5a-d were easily transformed to 1(2H)-phthalazinones 8d-i and 2,3-benzoxazin-1-ones 9d, f, and j via a one-pot addition-decyclization-cyclocondensation process.

Full text of DOI:10.1081/SCC-120030319

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 7, pp. 1301–1308, 2004
Synthesis of 4-Alkyl-1(2H)-phthalazinones
and 4-Alkyl-2,3-benzoxazin-1-ones via Ring
Cleavage of 3-Substituted N-Alkylated-3-
hydroxyisoindolin-1-ones
Tae Gyu Chun,1 Kyung Soon Kim,2 Sangku Lee,2
Tae-Sook Jeong,2 Hee-Yoon Lee,1 Yong Hae Kim,1
and Woo Song Lee2,
*
1Department of Chemistry and School of Molecular Science,
Korea Advanced Institute of Science and Technology,
Daejeon, Republic of Korea
2Korea Research Institute of Bioscience and Biotechnology,
Yusong, Daejeon, Republic of Korea
ABSTRACT
N-Alkyl (Me, Et, i-Pr, t-Bu)-substituted phthalimdes 5a–d were easily
transformed to 1(2H)-phthalazinones 8d–i and 2,3-benzoxazin-1-ones
9d,f,andjviaaone-pot addition–decyclization–cyclocondensationprocess.
Key Words: Heterocycles; N-alkyl; Hydrazine; Phthalimide.
*
Correspondence: Woo Song Lee, Korea Research Institute of Bioscience and Biotech-
nology, 52 Oun, Yusong, 305-333, Daejeon, Republic of Korea; E-mail: wslee@mail.
kribb.re.kr.
1301
DOI: 10.1081/SCC-120030319
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Chun et al.
3-Substituted-3-hydroxyisoindolins are of considerable important building
blocks for preparation of heterocycles because they behave in many reactions
like ring-chain tautomers of the keto(aldehydo)-amide-hydroxylactam type.[1]
Although numerous construction methods for the synthesis of 4-alkylated-
1(2H)-phthalazin-1-ones have been developed,[2] the closest literature precedent
using 3-substituted-3-hydroxyisoindolins has been independently studied by
[4]
the groups of Ismail,[3] Brzezinski, Kikugawa,[5] and Enders.[6] Ismail and
´
Kikugawa groups reported that the reaction of N-amino (or -N,N-dimethyl-
amino)phthalimide with arenes under Friedel–Crafts reaction conditions gave
2-aroylbenzoic acid hydrazide via an intermediate of 3-hydroxyisoindoline,
which loose water to obtain 4-substituted-1(2H)-phthalazin-1-one. Also, Ismail
et al.[3] described that N-aminophthalimide was reacted with Grignard reagents
(e.g., o-methoxyphenyl-, m-tolyl-, or a-naphthylmagnesium bromides) to give
´
the corresponding 4-arylphthalaz-1-ones in moderate yields. Brzezinski
et al.[4] described that the reaction of N-phenyl-3-pyridyl-3-hydroxyisoindoline
with hydrazine gave 4-pyridyl-1(2H)-phthalazin-1-one. Enders et al.[6] reported
that the reaction of N,N-dimethylaminophthalimide with Grignard reagents
(e.g., methyl- and phenylmagnesium bromides) gave the hydroxy-lactams in
high yields. Recently, we have developed that N-alkyl (Me, Et, i-Pr, t-Bu)-
substituted phthalimides 1 were transformed to multi-substituted pyrazoles 4
via a one-pot addition–decyclization–cyclocondensation process. The key
step involves nucleophilic addition of lithium acetylide onto the N-substituted
phthalimides 1 to give the keto tautomer 3 of alkynyl-3-hydroxyisoindolines 2.
Then, a-acetylenic ketones of type 3 was regioselectively reacted with a variety
of hydrazines to produce the 2,3-pyrazoles 4 (Sch. 1).[7]
Scheme 1.

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4-Alkyl-1(2H)-phthalazinones and 4-Alkyl-2,3-benzoxazin-1-ones
1303
On the basis of viewpoints, these synthetic methods are found to be
applicable for the synthesis of 4-alkyl-1(2H)-phthalazin-1-ones and 4-alkyl-
2,3-benzoxazin-1-ones. Here, we describe a facial construction method of
1(2H)-phthalazinones and 2,3-benzoxazin-1-ones via a one-pot addition–
decyclization–cyclocondensation process.
Starting materials 5a–d were prepared by a sequential reaction. phthalic
anhydride and phthalimide were converted to N-alkylated phthalimides
5a–d by the Gabriel reaction[8] with azeotropic removal of the water
formed. Subsequently, we investigated a one-pot addition–decyclization–
cyclocondensation process. These results are summarized in Sch. 2. The
typical procedures are as follow; compounds 5a–d was treated with benzyl-
magnesium bromide in THF to give the crude N-alkyl (Me, Et, i-Pr, t-Bu)-3-
benzyl-3-hydroxyisoindoline intermediates 6a–d. After disappearing of
starting materials 5a–d, the reactions were quenched by addition of H2O
and evaporated to afford the residues, which were dissolved in EtOH and
then hydrazine monohydrate was treated to obtain the same 4-benzyl-
1(2H)-phthalazin-1-one 8d in 80% (R1 ¼ Me), 75% (R1 ¼ Et), 82%
(R1 ¼ i-Pr), and 85% (R1 ¼ t-Bu) yields, respectively. In the case of 5d
N-substituted with tert-butyl group, a one to one ratio of the ring-chain tau-
tomers of the hydroxylactam 6d and the ketoamide 7d were determined by
1
the H NMR analysis. Similar reaction of 5d with various organometallic
agents gave the mixture of hydroxylactams 6e–i and keto tautomers 7e–i,
which were cyclized with hydrazine monohydrate to give 8e–i in good
yields, respectively (Sch. 2).
Scheme 2. Reagents and conditions: (a) R2MgBr, THF, 08C, 5 min. (b) NH2NH2,
EtOH, reflux, 12–36 hr. (c) NH2OH, EtOH, reflux, 30–48 hr.

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Chun et al.
On the other hand, treatment of 5d with benzyl-, isopropyl- and biphenyl-
magnesium bromides gave the mixture of 3-hydroxylactams 6d, 6f, and 6j
and keto tautomers 7d, 7f, and 7j, which were cyclized with hydroxylamine
hydrochloride to afford the desired 4-benzyl-, isopropyl- and biphenyl-2,3-
benzoxazin-1-ones 9d, 9f, and9j in 78%, 74%, and 74% yields, respectively
(Sch. 2). Also, 4-isopropyl-2,3-benzoxazin-1-one 9f was treated with hydra-
zine monohydrate in EtOH to give the 4-isopropyl-1(2H)-phthalazin-1-one
8f in good yield, which was identical with 8f that was obtained by the reaction
of a mixture of intermediates of 6d and 7d with hydrazine monohydrate.
The structures of these 4-alkylated-1(2H)-phthalazin-1-ones 8d–i were
determined by their characteristic spectroscopic data; namely, 8d–i show a
strong band in a range of 1650–1670 cm21 due to attributed to the carbonyl of
amide moiety. Especially, 8d was identical with authentic spectrum and showed
IR absorption at 1660 cm21 (nC¼O) (lit. 1660 cm21), 2904– 3163 cm21 (nNH, OH
)
(lit. 2900–3180 cm21), and m.p. 199–2008C (lit. 2018C).
4-Alkylated-2,3-benzoxazin-1-ones (9d, 9f, and 9j) also show a strong band
in a range of 1722–1744cm21 due to attributed to the carbonyl of ester moiety.
In conclusion, we found that 3-substituted-3-hydroxyisoindolins were
easily converted to 4-alkylated-1(2H)-phthalazin-1-ones 8d–i and 4-alkylated-
2,3-benzoxazin-1-ones 9d, 9f, and 9j via a one-pot addition–decyclization–
cyclocondensation process.
Melting points were determined with a Thomas–Hoover capillary appar-
atus and are uncorrected. Magnetic resonance spectra were obtained on Bruker
AVANCE 300 and 400 spectrometers with chemical shift values reported in d
units (part per million) relative to an internal standard (tetramethylsilane).
Infrared spectral data were obtained on a EQUINOX55 spectrometer.
Elemental analyses were performed with a Perkin Elmer 240C.
4-Benzyl-2H-phthalazin-1-one (8a): Typical Procedure
To a solution of benzylmagnesium bromide, which was prepared by
treatment of benzyl bromide (3.24 mL, 4.65 mmol) with magnesium flakes
(113.04 mg, 4.65 mmol) in tetrahydrofuran (10 mL), was added a solution of
5a (500 mg, 3.10 mmol) in tetrahydrofuran (10 mL) at 08C. After 5 min, the
reaction mixture was quenched by addition of water (5 mL) and evaporated
to give the residue, which was dissolved in ethanol (10 mL) and then a solution
of hydrazine monohydrate (465.56 mL, 9.3 mmol, 80% in water) was added at
rt. After being refluxed for 36 hr, the reaction mixture was cooled to rt and
evaporated under reduced pressure to give the residue, which was extracted
with ethyl acetate. The combined organic layer was washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated to give the crude

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4-Alkyl-1(2H)-phthalazinones and 4-Alkyl-2,3-benzoxazin-1-ones
1305
product, which was purified by column chromatography on silica gel
(EtOAc : hexane ¼ 1 : 2) to give the pure 8a (587.5 mg, 80%) as colorless
prisms (CH2Cl2/hexane), m.p. 199–2008C (lit. m.p. 2018C); IR (KBr):
1
3163, 3012, 2904, 1660, 1493, 1343 cm21; H NMR (300 MHz, CDCl3): d
4.34 (s, 2H), 7.20–7.31 (m, 5H), 7.69–7.75 (m, 3H), 8.46 (dd, 1H, J ¼ 2.7
and 0.8 Hz), 10.97 (br s, 1H); 13C NMR (75 MHz, CDCl3): d 38.9, 125.4,
126.8, 127.0, 128.3, 128.5, 128.7, 129.8, 131.3, 133.4, 137.6, 146.4, 160.6.
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found C, 76.47;
H, 5.30; N, 11.69.
According to the typical procedure, treatment of 5b–d with benzylmag-
nesium bromide, water, and hydrazine monohydrate gave the pure 8a in 75%
(5b: R1 ¼ Et, R2 ¼ Bn, 36 hr), 82% (5c: R1 ¼ i-Pr, R2 ¼ Bn, 36 hr) and 85%
(5d: R1 ¼ t-Bu, R2 ¼ Bn, 34 hr) yields, respectively.
4-Ethyl-2H-phthalazin-1-one (8e). Compound 8e was obtained accord-
ingly, starting from 5d (300 mg, 1.48 mmol). The crude product was purified
by column chromatography on silica gel (EtOAc : hexane ¼ 1 : 2) to give
the pure 8e (141.70 mg, 55%) as colorless prisms (CH2Cl2/hexane), m.p.
1
156–1578C; IR (KBr) 3170, 3015, 2975, 1670, 1348, 1152 cm21; H NMR
(400 MHz, CDCl3): d 1.34 (t, 3H, J ¼ 7.4), 2.97 (q, 2H, J ¼ 7.4), 7.72–
7.82 (m, 3H), 8.47 (d, 1H, J ¼ 7.9), 11.15 (brs, 1H); 13C NMR (100 MHz,
CDCl3): d 11.9, 25.3, 124.5, 127.0, 128.0, 129.8, 131.1, 133.3, 148.5, 160.8.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found C, 69.12;
H, 5.97; N, 16.25.
4-Isopropyl-2H-phthalazin-1-one (8f). Compound 8f was obtained
accordingly, starting from 5d (300 mg, 1.48 mmol). The crude product was
purified by column chromatography on silica gel (EtOAc : hexane ¼ 1 : 2) to
give the pure 8f (317.13 mg, 78%) as colorless prisms (CH2Cl2/hexane),
1
m.p. 155–1568C; IR (KBr): 3168, 3068, 2964, 1650, 1474, 1362 cm21; H
NMR (300 MHz, CDCl3): d 1.33 (d, 6H, J ¼ 6.8), 3.47 (m, 1H), 7.69–7.87
(m, 3H), 8.49 (dd, 1H, J ¼ 1.5 and 0.8), 11.69 (brs, 1H); 13C NMR
(75 MHz, CDCl3): d 21.2, 29.5, 124.2, 127.1, 128.1, 129.4, 130.9, 133.2,
151.5, 160.8. Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88.
Found C, 70.38; H, 6.27; N, 14.72.
The reaction of 9f with hydrazine monohydrate. To a solution of 9f
(500 mg, 2.65 mmol) in EtOH (25 mL) was added hydrazine monohydrate
(321.35 mL, 5.3 mmol, 80% in water) at rt. After being refluxed for 10 hr,
the reaction mixture was cooled to rt and evaporated to give residue, which
was purified by column chromatography on silica gel (EtOAc : hexane ¼ 1 : 2)
to give the pure 8f (408.72 mg, 82%).
4-n-Butyl-2H-phthalazin-1-one (8g). Compound 8g was obtained
accordingly, starting from 5d (300 mg, 1.48 mmol). The crude product was
purified by column chromatography on silica gel (EtOAc : hexane ¼ 1 : 2) to

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Chun et al.
give the pure 8g (239.30 mg, 80%,) as colorless prisms (CH2Cl2/hexane), m.p.
1
1528C; IR (KBr) 3164, 3008, 2952, 1650, 1358 cm21; H NMR (300 MHz,
CDCl3): d 0.96 (t, 3H, J ¼ 7.3), 1.45 (m, 2H), 1.74 (m, 2H), 2.93 (t, 2H,
J ¼ 7.5), 7.77 (m, 3H), 8.47 (d, 1H, J ¼ 7.7), 10.80 (brs, 1H); 13C NMR
(75 MHz, CDCl3): d 13.9, 22.6, 30.0, 31.8, 124.7, 127.0, 128.1, 130.0,
131.2, 133.3, 147.9, 160.6. Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98;
N, 13.85. Found C, 71.50; H, 6.81; N, 13.62.
4-n-Pentyl-2H-phthalazin-1-one (8h). Compound 8h was obtained
accordingly, starting from 5d (300 mg, 1.48 mmol). The crude product was
purified by column chromatography on silica gel (EtOAc : chexane ¼ 1 : 2)
to give the pure 8h (172.73 mg, 54%) as colorless prisms (CH2Cl2/hexane),
1
m.p. 129–1308C; IR (KBr) 3163, 3012, 2937, 1652, 1598 cm21; H NMR
(300 MHz, CDCl3): d 0.9 (t, 3H, J ¼ 7.0), 1.36–1.76 (m, 6H), 2.91 (t, 2H,
J ¼ 7.7), 7.72–7.83 (m, 3H), 8.46 (dd, 1H, J ¼ 2.1 and 0.8), 10.04 (brs,
1H); 13C NMR (75 MHz, CDCl3): d 14.0, 22.5, 27.6, 31.7, 32.1, 124.7,
127.0, 128.1, 129.9, 131.2, 133.4, 148.0, 160.6. Anal. Calcd for
C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found C, 71.98; H, 7.52; N, 12.72.
4-Phenethyl-2H-phthalazin-1-one (8i). Compound 8i was obtained
under refluxing condition, starting from 5d (300 mg, 1.48 mmol). The crude
product was purified by column chromatography on silica gel
(EtOAc : hexane ¼ 1 : 2) to give the pure 8i (281.32 mg, 76%) as colorless
prisms (CH2Cl2/hexane), m.p. 146–1478C; IR (KBr) 3180, 3053, 1651,
1
1452, 1354 cm21; H NMR (300 MHz, CDCl3): d 3.10 (m, 2H), 3.25 (dt,
2H, J ¼ 1.5 and 7.4), 7.20–7.30 (m, 6H), 7.80 (m, 3H), 8.49 (dd, 1H,
J ¼ 1.0 and 8.6), 10.99 (brs, 1H); 13C NMR (75 MHz, CDCl3): d 33.6, 33.8,
124.4, 126.2, 127.1, 128.0, 128.4, 128.5, 129.8, 131.3, 133.4, 141.1, 146.7,
160.6. Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found C,
76.95; H, 5.82; N, 11.30.
4-Benzyl-2,3-benzoxazin-1-one (9d): Typical Procedure
To a solution of benzylmagnesium bromide, which was prepared by treat-
ment of benzyl bromide (3.24 mL, 4.65 mmol) with magnesium flakes
(113.04 mg, 4.65 mmol) in tetrahydrofuran (10 mL), was added a solution of
5d (629.58 mg, 3.10 mmol) in tetrahydrofuran (10 mL) at 08C. After 5 min,
the reaction mixture was quenched by addition of water (10 mL) and added
the solution of hydroxylamine hydrochloride (646.26 mg, 9.3 mmol) in 10 mL
of ethanol was refluxed for 48 hr. After cooling to rt, the reaction mixture was
evaporated under reduced pressure to give the residue, which was extracted
with ethyl acetate. The combined organic layer was washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated to give the crude

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4-Alkyl-1(2H)-phthalazinones and 4-Alkyl-2,3-benzoxazin-1-ones
1307
product. Purification by flash column chromatography on silica gel
(EtOAc : hexane ¼ 1 : 1) gave the pure 9d (573.26 mg, 78%) as colorless
prisms (CH2Cl2/hexane), m.p. 128–1298C; IR (KBr) 3035, 2923, 1744,
1
1452, 1281 cm21; H NMR (400 MHz, CDCl3): d 4.28 (s, 2H), 7.23–7.32
(m, 5H), 7.61 (m, 1H), 7.76 (m, 2H), 8.36 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 37.0, 123.0, 125.8, 126.8, 127.4, 128.4, 128.9, 129.0, 133.5,
135.3, 135.6, 154.7, 163.6. Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67;
N, 5.90. Found C, 76.12; H, 4.85; N, 5.68.
4-Isopropyl-2,3-benzoxazin-1-one (9f). Compound 9f was obtained
under refluxing condition, starting from 5d (300 mg, 1.48 mmol). The crude
product was purified by column chromatography on silica gel
(EtOAc : hexane ¼ 1 : 2) to give the pure 9f (207.08 mg, 74%) as colorless
prisms (CH2Cl2/hexane), m.p. 79–808C; IR (KBr) 2975, 1722, 1595, 1456,
1
1289, 1062 cm21; H NMR (400 MHz, CDCl3): d 1.40 (d, 6H, J ¼ 6.8),
3.42 (m, 1H), 7.76 (dd, 1H, J ¼ 0.5 and 7.8), 7.82 (dd, 1H, J ¼ 1.1 and
7.7), 7.90 (dd, 1H, J ¼ 1.4 and 7.6), 8.38 (dd, 1H, J ¼ 0.9 and 7.7); 13C
NMR (100 MHz, CDCl3): d 20.7, 29.9, 122.8, 124.5, 126.5, 129.0, 133.2,
135.3, 159.2, 163.7. Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N,
7.40. Found C, 69.61; H, 5.99; N, 7.19.
4-Biphenyl-2,3-benzoxazin-1-one (9j). Compound 9j was obtained under
refluxing condition, starting from 5d (300mg, 1.48mmol). The crude product
was purified by column chromatography on silica gel (EtOAc: hexane ¼ 1 : 2)
to give the pure 9j (327.56mg, 74%) as colorless prisms (CH2Cl2/hexane), m.p.
1
142–1438C; IR (KBr) 1738, 1488,1285 cm21; H NMR (400MHz, CDCl3):
d 4.3 (s, 2H), 7.31–7.80 (m, 12H), 8.36 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 36.6, 122.9, 125.8, 126.8, 126.9, 127.1, 127.3, 127.4, 127.7,
127.78, 128.8, 133.6, 134.6, 135.4, 140.3, 154.7, 163.6. Anal. Calcd for
C20H13NO2: C, 80.25; H, 4.38; N, 4.68. Found C, 80.37; H, 4.40; N, 4.75.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation Grant (KRF-
2000-015-DP0281).
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Chun et al.
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Received in Japan August 18, 2003

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