Sulfur ylides: 14.*Synthesis of pyrrolo[2,1-a]phthalazine-2,6-dione derivative from dioxophthalazine-containing sulfur ylide

Article abstract of DOI:10.1007/s11172-007-0364-x

A keto-stabilized sulfur ylide, containing phthalazinedione fragment, was synthesized. During thermolysis, the ylide forms the product of intramolecular cyclization of pyrrolophthalazinedione structure.

Full text of DOI:10.1007/s11172-007-0364-x

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2305—2307, November, 2007
2305
Sulfur ylides
14.* Synthesis of pyrrolo[2,1ꢀa]phthalazineꢀ2,6ꢀdione derivative
from dioxophthalazineꢀcontaining sulfur ylide

F. Z. Galin, I. M. Sakhautdinov, and O. R. Tukhvatullin
Institute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6066, 235 5288. Eꢀmail: galin@anrb.ru
A ketoꢀstabilized sulfur ylide, containing phthalazinedione fragment, was synthesized.
During thermolysis, the ylide forms the product of intramolecular cyclization of pyrroloꢀ
phthalazinedione structure.
Key words: ketoꢀstabilized sulfonium ylide, intramolecular cyclization, phthalazinedione.
It is known2,3 that derivatives of 1,4ꢀphthalazinedione,
viz., 2ꢀaminoꢀ and 5ꢀaminoꢀ1,2,3,4ꢀtetrahydroꢀ1,4ꢀ
phthalazinedione sodium salt (medicine Galavit), show
immunomodulating activity.
Earlier,1,4—6 we discovered a new reaction of intramoꢀ
lecular cyclization of ketoꢀstabilized sulfur ylides, obꢀ
tained from Nꢀphthalylꢀprotected αꢀ and βꢀamino acids,
which opened a convenient way to the construction
of polycyclic compounds with pyrrolizidineꢀ and
indolizidinedione structures. The present work is aimed
* For Part 13 see Ref. 1.
Scheme 1
Reagents and conditions: а. NH2NHBn, 140—150 °C; b. BrCH2COOMe, Et3BnN+Cl–, КОН, THF; c. КОН, МеОН; d. SOCl2,
C6H6, reflux; e. CH2N2, CH2Cl2, 5 °C; f. HBr, CH2Cl2; g. Me2S, CH2Cl2; h. 12.5 M solution of NaOH, K2CO3, CHCl3; i. BzOH,
C6H5Me.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2227—2229, November, 2007.
1066ꢀ5285/07/5611ꢀ2305 © 2007 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Galin et al.
Reaction products 4 and 6 were isolated by column chromatoꢀ
graphy on silica gel (eluent: light petroleum—ethyl acetate, 8 : 2).
2ꢀBenzylꢀ2,3ꢀdihydrophthalazineꢀ1,4ꢀdione (3). A mixture of
finely ground phthalic anhydride (2) (4 g, 27 mmol) and
benzylhydrazine (3.30 g, 27 mmol) was heated for 15 min on an
oil bath at 155—160 °С. After cooling, the solid reaction prodꢀ
uct was dissolved in hot methanol (20 mL), the solution was
filtered and diluted with water (20 mL). The precipitate formed
was filtered off and washed with ether. The yield was 5.98 g
(88%), m.p. 197—199 °С. Found (%): С, 71.47; Н, 4.73;
N, 11.13. С15Н12N2O2. Calculated (%): С, 71.42; Н, 4.79;
N, 11.10. 1H NMR (CDCl3), δ: 1.26 (s, 1 Н, NH); 5.28 (s, 2 H,
CH2); 7.27—7.47 (m, 5 Н, Ph); 7.83—8.47 (m, 4 Н, С6Н4).
Methyl 3ꢀbenzylꢀ1,4ꢀdioxoꢀ1,2,3,4ꢀtetrahydrophthalazinꢀ2ꢀ
ylacetate (4). A mixture of phthalazinedione 3 (1 g, 3.96 mmol),
methyl bromoacetate (1.2 g, 7.92 mmol), ground KOH (0.22 g,
3.96 mmol), and triethylbenzylammonium chloride (14 mg,
0.06 mmol) in THF (10 mL) was subjected to ultrasound treatꢀ
ment (UZDNꢀ2T, operating frequency, 22 kHz) for 40 min.
The reaction mixture was filtered off from the precipitate,
the solvent was evaporated. The target product was isolated by
column chromatography. The yield was 1.03 g (80%), m.p.
93—95 °С. Found (%): С, 66.69; Н, 4.87; N, 8.61. С18Н16N2O4.
Calculated (%): С, 66.66; Н, 4.97; N, 8.64. IR, ν/cm–1: 1620,
1650, 1760. 1H NMR (CDCl3), δ: 3.91 (s, 3 Н, Me); 4.81, 5.18
(both s, 2 H each, CH2); 7.19—7.37 (m, 5 Н, Ph); 7.71—8.39
(m, 4 Н, С6Н4).
3ꢀBenzylꢀ1,4ꢀdioxoꢀ1,2,3,4ꢀtetrahydrophthalazinꢀ2ꢀylacetic
acid (5). A solution of potassium hydroxide (0.84 g, 15 mmol) in
minimum water was added in one portion to a stirred suspension
of ester 4 (1 g, 3 mmol) in methanol (20 mL) at ~20 °C.
A practically instant dissolution of the ester took place, after
this, the solution was stirred for another 20 min, the solvent was
evaporated, then water (10 mL) was added and the mixture was
extracted with ethyl acetate until the color in the organic layer
disappeared. The aqueous layer was acidified with hydrochloric
acid to рН 1—2, the precipitate of white color that formed was
filtered off and dried in air. The yield was 0.88 g (92%),
m.p. 152—155 °С. Found (%): С, 65.83; Н, 4.51; N, 9.09.
at the synthesis of potentially biologically active comꢀ
pounds with pyrrolophthalazinedione structure with the
use of intramolecular cyclization of dioxophthalazineꢀ
containing sulfur ylides and at the study of their propꢀ
erties.
The synthesis of dioxophthalazineꢀcontaining sulfur
ylide 1 was performed starting from the product of the
fusion of phthalic anhydride (2) with benzylhydrazine in
the ratio 1 : 1 (155—160 °С), i.e., from 2ꢀbenzylꢀ2,3ꢀ
dihydrophthalazineꢀ1,4ꢀdione (3) (Scheme 1). Alkylation
of the latter with methyl bromoacetate under the phase
transfer catalysis conditions and ultrasonic treatment led to
methyl 3ꢀbenzylꢀ1,4ꢀdioxoꢀ1,2,3,4ꢀtetrahydrophthalazinꢀ
2ꢀylacetate (4). The alkaline hydrolysis of compound 4 in
methanol gave rise to 3ꢀbenzylꢀ1,4ꢀdioxoꢀ1,2,3,4ꢀtetraꢀ
hydrophthalazinꢀ2ꢀylacetic acid (5), which upon treatꢀ
ment with thionyl chloride was transformed to the acyl
chloride. The latter without isolation was converted to
diazoketone 6 upon treatment with a solution of CH2N2
in СH2Cl2.
The reaction of compound 6 with aqueous HBr gives
bromoketone 7, which upon treatment with Me2S forms
sulfonium salt 8. The deprotonation of salt 8 with a mixꢀ
ture of saturated aq. potash and 12.5 M aq. sodium hydrꢀ
oxide leads to sulfur ylide 1.
The reflux of sulfur ylide 1 in toluene in the presence
of equimolar amount of benzoic acid gives the product of
intramolecular cyclization 9 in 52% yield. The structure
of pyrrolophthalazinedione 9 obtained was confirmed by
1
spectral methods: in the Н NMR spectrum, a singlet of
three protons of the methylthio group at δ 2.41 is obꢀ
served, in the 13С NMR spectrum, C(11) and C(3) atoms
of the double bond resonate at δ 123.6 and 147.0, respecꢀ
tively. It should be noted that methyl benzoate was also
formed during the reaction, which was identified by GLC.
In conclusion, a method for the synthesis of
pyrrolo[2,1ꢀa]phthalazineꢀ2,6ꢀdione derivative on the
basis of 2ꢀbenzylꢀ2,3ꢀdihydrophthalazineꢀ1,4ꢀdione was
elaborated.
С
17Н14N2O4. Calculated (%): С, 65.80; Н, 4.55; N, 9.03. IR,
ν/cm–1: 1580, 1740, 3140.
3ꢀBenzylꢀ2ꢀ(3ꢀdiazoꢀ2ꢀoxopropyl)ꢀ2,3ꢀdihydrophthalazineꢀ
1,4ꢀdione (6). Thionyl chloride (1.82 mL, 25.14 mmol) was
added to a suspension of acid 5 (2.6 g, 8.38 mmol) in anhydrous
benzene (15 mL) and this was refluxed until evolution of a gas
ceased (~6 h). After evaporation of the solvent and excess of
thionyl chloride, the acyl chloride obtained was used without
additional purification. A solution of the acyl chloride (2.67 g,
8.12 mmol) in СН2Cl2 (10 mL) was added dropwise to a stirred
and cooled to –5 °С solution of diazomethane, obtained from
nitrosomethylurea (3.35 g, 40.6 mmol). The solvent was evapoꢀ
rated the target product was isolated by column chromatography.
The yield was 1.5 g (53%), m.p. 79—81 °С. Found (%): С, 64.68;
Н, 4.25; N, 16.73. С18Н14N4O3. Calculated (%): С, 64.66;
Н, 4.22; N, 16.76. IR, ν/cm–1: 1592, 1663, 2120. 1H NMR
(CDCl3), δ: 4.82 (s, 2 H, CH2); 5.28—5.31 (m, 2 H, CH2);
5.56 (s, 1 Н, СН); 7.17—7.49 (m, 5 Н, Ph); 7.73—8.48 (m,
4 Н, С6Н4).
Experimental
IR spectra were recorded on a URꢀ20 and Specord Mꢀ80
spectrometers for suspensions in Nujol. 1Н and 13С NMR specꢀ
tra were recorded on a BrukerꢀAMꢀ300 (300 and 75 MHz, reꢀ
spectively) for solutions in CDCl3, Me4Si was used as the interꢀ
nal standard. The reaction course was monitored by TLC on
Silufol UVꢀ254 plates with visualization of substances in the
UV light, iodine vapors, and by spraying of the plates with ninꢀ
hydrin spray reagent or with anisaldehyde solution with subseꢀ
quent heating at 100—120 °С. Acetone, СН2Cl2, and ethyl acꢀ
etate were distilled over P2O5. Toluene, THF, and light petroꢀ
leum were refluxed and distilled over sodium metal; Me2S was
dried over molecular sieves 4А. Pure for analysis HBr was used
as 48% aq. solution; thionyl chloride (pure for analysis) and
benzoic acid (pure) were used without additional purification.
3ꢀBenzylꢀ2ꢀ(3ꢀbromoꢀ2ꢀoxopropyl)ꢀ2,3ꢀdihydrophthalazineꢀ
1,4ꢀdione (7). A concentrated aq. solution of НBr (2.75 mL) was
added dropwise to a stirred solution of diazoketone 6 (1.1 g,

Pyrrolo[2,1ꢀa]phthalazineꢀ2,6ꢀdione derivative
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2307
3.3 mmol) in CH2Cl2 (10 mL), after this, the mixture was reꢀ
fluxed for 1 h, cooled, and diluted with threeꢀfold volume of
water. The organic layer was separated, washed with soda soluꢀ
tion, and dried with magnesium sulfate. The solvent was evapoꢀ
rated, bromoketone obtained was recrystallized from ether. The
yield was 1.16 g (92%), m.p. 135—136 °С. Found (%): С, 55.85;
Н, 3.88; Br, 20.68; N, 7.27. С18Н15BrN2O3. Calculated (%):
С, 55.83; Н, 3.90; Br, 20.63; N, 7.23. IR, ν/cm–1: 1659, 1762.
1H NMR (CDCl3), δ: 3.84, 5.07, 5.25 (all s, 2 H each, CH2);
7.23—7.45 (m, 5 Н, Ph); 7.78—8.47 (m, 4 Н, С6Н4).
[3ꢀ(3ꢀBenzylꢀ1,4ꢀdioxoꢀ2,3ꢀdihydrophthalazinꢀ2ꢀyl)ꢀ2ꢀoxoꢀ
propyl]dimethylsulfonium bromide (8). A solution of bromoꢀ
ketone 7 (1 g, 2.58 mmol) and dimethyl sulfide (9.2 mL,
7.74 mmol) in CH2Cl2 (10 mL) was stirred for 5 h. The reaction
mixture was kept for ~14 h at ~20 °C. The precipitate formed
was filtered and washed with CH2Cl2. The yield was 0.83 g
(72%), m.p. 126—127 °С. Found (%): С, 53.49; Н, 4.69;
Br, 17.75; N, 6.27; S, 7.11. С20Н21BrN2O3S. Calculated (%):
С, 53.46; Н, 4.71; Br, 17.78; N, 6.23; S, 7.14. IR, ν/cm–1: 1455,
1478, 1674.
Found (%): С, 67.87; Н, 4.82; N, 8.31; S, 9.55. С19Н16N2O2S.
Calculated (%): С, 67.84; Н, 4.79; N, 8.33l; S, 9.53. IR, ν/cm–1
:
1327, 1637, 1691. 1H NMR (CDCl3), δ: 2.41 (s, 3 H, Me);
5.01—5.03, 5.14—5.28 (both m, 2 Н each, CH2): 6.94—7.50 (m,
5 Н, Ph); 7.77—8.46 (m, 4 Н, С6Н4). 13С NMR, δ: 25.7 (MeS);
54.0 (C(9)); 69.1 (CH2Ph); 123.2 (C(5)); 123.6 (C(11)); 127.5
(C(7)); 127.6, 128.4, 128.6 (CHPh); 129.3 (C(7a)); 129.8 (C(6));
130.1 (C(4)); 136.8 (CH2CPh); 147.0 (C(3)); 158.4 (C(3a));
164.5 (С(8); 199.0 (С(10)).
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program for Fundaꢀ
mental Research "Directed Synthesis of Organic Comꢀ
pounds with Preꢀset Properties and Creation of Funcꢀ
tional Materials on Their Basis") and by the Russian
Federation President Council for Grants (Program for the
State Support of Young Russian Scientists and Leading
Scientific Schools of the RF, Grant NShꢀ4434.2006.3).
[3ꢀ(3ꢀBenzylꢀ1,4ꢀdioxoꢀ2,3ꢀdihydrophthalazinꢀ2ꢀyl)ꢀ2ꢀoxoꢀ
propylidene]dimethylsulfuran (1). A mixture of sodium hydroxide
(0.15 mL of 12.5 M solution) and saturated aq. potash (0.8 mL)
was added in one portion to a stirred (10 °С) suspension of
sulfonium salt 8 (600 mg, 1.33 mmol) in chloroform (15 mL).
The reaction mixture was stirred for 15 min, after the temperaꢀ
ture reached ~20 °C, the precipitate was filtered off. The layers
were separated, the organic layer was dried with К2СО3, the
solvent was evaporated to obtain a crystalline product of dark
orange color. The yield was 439 mg (89%), m.p. 43—44 °С.
Found (%): С, 65.23; Н, 5.45; N, 7.57; S, 8.72. С20Н20N2O3S.
References
1. F. Z. Galin, I. M. Sakhautdinov, S. N. Lakeev, V. A. Egorov,
A. A. Fatykhov, and I. O. Maidanova, Izv. Akad. Nauk, Ser.
Khim., 2005, 2771 [Russ. Chem. Bull., Int. Ed., 2005, 54, 2867].
2. Galavit. Klinicheskoe ispol´zovanie i mekhanizmy deistviya
[Galavit. The Clinical Use and Mechanism of Action], Sb. nauch.
trudov MGMSU, Moscow, 2002, 55 (in Russian).
3. Pat. RF 2113222; Byul. Izobret., 1998, No. 17, 189.
4. F. Z. Galin, I. M. Sakhautdinov, I. G. Khalikov, S. N. Lakeev,
I. O. Maidanova, and A. A. Fatykhov, Izv. Akad. Nauk,
Ser. Khim., 2007, 2394 [Russ. Chem. Bull., Int. Ed., 2007,
56, No. 12].
5. I. Z. Mullagalin, S. N. Lakeev, I. O. Maidanova, M. F.
Abdullin, and F. Z. Galin, in Izbrannye metody sinteza i
modifikatsii geterotsiklov [Selected Methods for the Synthesis
and Modification of Heterocycles], Ed. V. G. Kartsev, IBS Press,
Moscow, 2003, 1, 572 (in Russian).
6. F. Z. Galin, S. N. Lakeev, and G. A. Tolstikov, Izv. Akad.
Nauk, Ser. Khim., 1996, 165 [Russ. Chem. Bull., 1996, 45, 156
(Engl. Transl.)].
Calculated (%): С, 65.20; Н, 5.47; N, 7.60; S, 8.70. IR, ν/cm–1
:
1540, 1590, 1650. 1H NMR (CDCl3), δ: 2.81 (s, 6 H, 2 Me);
3.96 (s, 1 H, CH); 4.68, 5.16—5.28 (both m, 2 Н each, CH2);
7.13—7.49 (m, 5 Н, Ph); 7.66—8.37 (m, 4 Н, С6Н4). 13С NMR,
δ: 28.4 (2 Me); 51.1 (СН); 53.9 (СН2Рh); 69.2 (СН2); 123.2,
127.4, 127.0 (CHPh); 124.5 (C(3a)), 129.0 (C(7a)); 137.0
(СН2CPh); 128.2 (C(7)); 128.7 (C(4)); 131.6 (С(5)); 132.5
(C(6)); 145.0 (C(3)); 158.2 (C(8)); 184.0 (С=О).
5ꢀBenzylꢀ1ꢀ(methylthio)pyrrolo[2,1ꢀа]phthalazineꢀ
2,6(3Н,5Н )ꢀdione (9). Benzoic acid (139 mg, 1.14 mmol) was
added to a solution of sulfur ylide 1 (420 mg, 1.14 mmol) in
anhydrous toluene (10 mL). The reaction mixture was refluxed
for 30 min. Toluene was evaporated, the product was isolated by
column chromatography on SiO2 (eluent: ethyl acetate—hexꢀ
ane, 1 : 3). The yield was 200 mg (52%), m.p. 142—146 °С.
Received April 13, 2007;
in revised form July 27, 2007