Sulfur ylides 15. Intramolecular cyclization of new keto-stabilized sulfur bis-ylide

Article abstract of DOI:10.1007/s11172-007-0394-4

New sulfur bis-ylide was obtained from 3-amino-3-phenylpropionic acid and pyromellitic dianhydride. Its intramolecular cyclization proceeds regioselectively, leading to 3,4,11,12-tetrahydro-2H,6H-indolizino[2,1-f] pyrido[2,1-a]isoindole derivative in 66% yield. Phosphorus bis-ylide of similar structure gives a cyclization product in 10% yield.

Full text of DOI:10.1007/s11172-007-0394-4

Russian Chemical Bulletin, International Edition, Vol. 56, No. 12, pp. 2479—2481, December, 2007
2479
Sulfur ylides
15.* Intramolecular cyclization of new ketoꢀstabilized
sulfur bisꢀylide

F. Z. Galin, I. M. Sakhautdinov, I. G. Khalikov, S. N. Lakeev, I. O. Maidanova, and A. A. Fatykhov
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 2641. Eꢀmail: galin@anrb.ru, irina_m@anrb.ru
New sulfur bisꢀylide was obtained from 3ꢀaminoꢀ3ꢀphenylpropionic acid and pyromellitic
dianhydride. Its intramolecular cyclization proceeds regioselectively, leading to 3,4,11,12ꢀ
tetrahydroꢀ2Н,6Hꢀindolizino[2,1ꢀf]pyrido[2,1ꢀа]isoindole derivative in 66% yield. Phosphoꢀ
rus bisꢀylide of similar structure gives a cyclization product in 10% yield.
Key words: 3ꢀaminoꢀ3ꢀphenylpropionic acid, pyromellitic dianhydride, sulfur ylides, phosꢀ
phorus ylides, heterocyclization, 2Н,6Hꢀindolizino[2,1ꢀf]pyrido[2,1ꢀа]isoindoles, pyrroꢀ
lo[3,4ꢀf]isoindoleꢀ1,3,5,7ꢀtetraones.
In continuation of the research on intramolecular cyꢀ
clization of ketoꢀstabilized sulfonium ylides, viz., derivaꢀ
tives of Nꢀprotected αꢀ and βꢀamino acids,1—9 in the
present study the synthesis of sulfur bisꢀylide 1a was acꢀ
complished (Scheme 1), starting from the condensation
product of 3ꢀaminoꢀ3ꢀphenylpropionic acid (βꢀphenylꢀ
βꢀalanine) 2 and pyromellitic dianhydride (3).
Pyromellitic dianhydride (3) and 3ꢀaminoꢀ3ꢀphenylꢀ
propionic acid (2), taken in the ratio 1 : 2, upon heating in
nitrobenzene (155—160 °С) gave diacid 4, which was then
converted into the polymeric anhydride upon treatment
with methyl chloroformate in the presence of equimolar
amount of Nꢀmethylmorpholine. The anhydride, without
isolation from the reaction mixture, was treated with a
solution of CH2N2 in СH2Cl2 to afford didiazo diketone 5
in 76% yield. The reaction of didiazo diketone 5 with
aqueous HBr afforded dibromo diketone 6, which reacted
with Me2S to form disulfonium salt 7a. The deprotonaꢀ
tion of salt 7а with sodium hydride led to sulfur bisꢀ
ylide 1a.
two protons, which would have been characteristic of the
transoid junction) serves as the evidence of the cisoid
junction. In the 13С NMR spectrum, signals of the correꢀ
sponding carbon atoms resonate at δC 122.71 and 125.87.
Signals of two thiomethyl group are also informative:
in the 1Н NMR spectrum, there is a singlet of six protons
at δН 2.45, as well as a signal of two carbon atoms at δC
17.76 of the 13С NMR spectrum. Mutual orientation of
the phenyl groups at C(4) and C(10) atoms of the pentaꢀ
cyclic framework was not established by NMR. Neverꢀ
theless, formation of the individual isomer, when racemic
βꢀphenylꢀβꢀalanine was used in the synthesis, is noteworꢀ
thy.
It is known that phosphorus ylides readily react with
carbonyl group to form a double bond (the Wittig reacꢀ
tion). A comparison of the reactivity of sulfur ylide 1а and
phosphorus ylide 1b under the intramolecular cyclization
conditions showed that the latter gives a complicated mixꢀ
ture of products, from which the polycyclic product 8b
was isolated in 10% yield. Phosphorus ylide 1b was
synthesized from dibromo diketone 6 upon treatment with
PPh3 and by subsequent deprotonation of phosphonium
salt 7b with a mixture of NaOH and K2CO3.
In conclusion, on the basis of the condensation prodꢀ
uct of βꢀphenylꢀβꢀalanine (2) and pyromellitic dianhyꢀ
dride (3), the new ketoꢀstabilized sulfur bisꢀylide 1a was
synthesized, which upon heating in the presence of
equimolar amount of benzoic acid gives the product of
intramolecular cyclization 8a in 66% yield. The reacꢀ
tion proceeds regioꢀ and stereospecifically to form the subꢀ
stituted 3,4,10,11ꢀtetrahydroꢀ2Н,6Hꢀindolizino[2,1ꢀf]ꢀ
pyrido[2,1ꢀа]isoindole 8a.
The heating of ylide 1а in boiling toluene in the preꢀ
sence of equimolar amount of benzoic acid gives the prodꢀ
uct of intramolecular cyclization 8a in 66% yield. The
reaction proceeds regiospecifically to form the isomer with
the cisoid mutual junction of the dihydropyridinone rings
at the pyrroloisoindole tricycle.
The structure of product 8а was confirmed by spectral
characteristics. The presence of two signals of Н(7) and
Н(14) protons of the aromatic ring at δН 8.31 and 9.45 of
1
the Н NMR spectrum (rather than of one signal of the
* For Part 14, see Ref. 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2394—2396, December, 2007.
1066ꢀ5285/07/5612ꢀ2479 © 2007 Springer Science+Business Media, Inc.

2480
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 12, December, 2007
Galin et al.
Scheme 1
O
O
O
O
O
Ph
Ph
O
Ph
a
b
2
+
O
O
HO
N
N
OH
HOOC
NH2
2
O
O
O
O
3
4
O
O
O
O
O
Ph
Ph
O
O
Ph
Ph
O
d (for 7a) or
e (for 7b)
R
N
R
RCH2
Br–
N
CH2R
N
N
Br–
O
O
O
O
7a,b
5: R = CHN2
6: R = CH2Br
c
O
O
7
O
O
O
Ph
Ph
O
Ph
Ph
N
N
10
4
f (for 1a, 7a) or
g (for 1b, 7b)
h
–
–
N
N
O
R CH
CH R
14
1
13
R
R
O
O
O
8a,b
1a,b
R = +SMe2 (1a, 7a), SMe (8a); +PPh3 (1b, 7b), H (8b)
Reagents and conditions: а. PhNO2, 155—160 °С; b. ClCOOMe, then, СН2N2, THF, 0 °С; c. HBr, CH2Cl2, 20 °С; d. Me2S, Me2CO;
e. PPh3, Me2CO; f. NaH, THF; g. NaOH, K2CO3, CHCl3; h. PhCO2H, PhCH3.
276—278 °С. Found (%): С, 65.62; Н, 3.9; N, 5.45; C28H20N2O8.
Calculated (%): С, 65.62; Н, 3.93; N, 5.47. IR, ν/cm–1: 1686,
1750, 3548.
Experimental
IR spectra were recorded on a URꢀ20 and Specord Mꢀ80
spectrometers (in Nujol), 1Н and 13С NMR spectra were reꢀ
corded on a Bruker AMꢀ300 (300 and 75 MHz, respectively) for
solutions in CDCl3 (except for the spectrum of 8b), Me4Si was
used as the internal standard. The reaction course was moniꢀ
tored by TLC on Silufol UVꢀ254 plates with visualization of
substances in the UV light, iodine vapors, and by spraying of the
plates with ninhydrin solution or with anisaldehyde solution
with subsequent heating at 100—120 °С. Acetone, CCl4, and
nitrobenzene were distilled over P2O5, Nꢀmethylmorpholine,
over КОН. Toluene, THF, and light petroleum were refluxed
and distilled over sodium metal, СН2Cl2 was distilled, Me2S was
dried over molecular sieves 4 Å. Hydrobromic acid was used as
the 48% aq. solution (pure for analysis grade), NaH, as the 60—
65% dispersion in oil (Fluka). Pyromellitic dianhydride 3 (pure
grade), racemic 3ꢀaminoꢀ3ꢀphenylpropionic acid (βꢀphenylꢀβꢀ
alanine, pure grade), PPh3 (pure grade), methyl chloroformate
(pure for analysis grade), and benzoic acid (pure grade) were
used without additional purification.
2,6ꢀBis(4ꢀdiazoꢀ3ꢀoxoꢀ1ꢀphenylbutꢀ1ꢀyl)pyrrolo[3,4ꢀf]ꢀ
isoindoleꢀ1,3,5,7(2Н,6Н)ꢀtetraone (5). Methyl chloroformate
(1 mL, 12.9 mmol) was added to a suspension of diacid 4 (5.1 g,
10 mmol) in anhydrous THF and then, Nꢀmethylmorpholine
(1.8 mL, 12.9 mmol) was added dropwise at 0 °С. This was
stirred for 30 min and the precipitate of Nꢀmethylmorpholine
hydrochloride formed was quickly filtered off. Then, a solution
of СH2N2 (obtained from 87 mmol of Nꢀnitrozomethylurea) in
CH2Cl2 (20 mL) was added dropwise at 0 °С to a solution of the
polymeric anhydride obtained. The product was isolated by colꢀ
umn chromatography (eluent, light petroleum—ethyl acetate,
2 : 1). The yield was 4.26 g (76%), m.p. 94—97 °С. Found (%):
С, 64.26; Н, 3.9; N, 14.96. C30H20N6O6. Calculated (%):
С, 64.28; Н, 3.6; N, 14.99. IR, ν/cm–1: 1698, 1740, 2120.
1H NMR, δ: 3.05—3.55 (m, 4 Н, СН2); 4.32 (s, 2 Н, СНN2);
5.85—5.98 (m, 2 Н, СН—N); 7.22—7.58 (m, 10 Н, Ph); 8.19 (s,
2 Н, С6Н2). 13С NMR, δ: 47.95, 50.98, 51.72, 118.56, 127.70,
128.57, 129.13, 137.04, 138.28, 166.17, 199.69.
2,6ꢀBis(4ꢀbromoꢀ3ꢀoxoꢀ1ꢀphenylbutꢀ1ꢀyl)pyrrolo[3,4ꢀf]ꢀ
isoindoleꢀ1,3,5,7(2Н,6Н)ꢀtetraone (6). Hydrobromic acid (2 mL
of 48% aq. solution) was added to a stirred solution of didiazo
diketone 5 (0.56 g, 1 mmol) in CH2Cl2 (20 mL) at ~20 °C. After
the evolution of gas was over, the solution was stirred for anothꢀ
er 1 h. Organic layer was separated, washed with 5% Na2CO3
(aq.), and dried with MgSO4. The solvent was evaporated and
the product was isolated by column chromatography (eluent,
2,6ꢀBis(3ꢀhydroxyꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀyl)pyrrolo[3,4ꢀf]ꢀ
isoindoleꢀ1,3,5,7(2Н,6Н)ꢀtetraone (4). A solution of pyromelꢀ
litic dianhydride 3 (2 g, 10 mmol) and ( )ꢀβꢀphenylꢀβꢀalanine 2
(3.3 g, 20 mmol) in nitrobenzene (100 mL) was vigorously stirred
for 1 h at 155—165 °С. Then, the reaction mixture was cooled to
~20 °С, diacid 4 formed was filtered off, washed with light
petroleum, and dried in air. The yield was 5.1 g (95%), m.p.

Cyclization of sulfur bisꢀylide
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 12, December, 2007 2481
light petroleum—ethyl acetate, 4 : 1). The yield was 0.6 g (90%),
m.p. 108—110 °С. Found (%): С, 54.04; Н, 3.39; Br, 23.97;
N, 4.4. C30H22Br2N2O6. Calculated (%): С, 54.08; Н, 3.33;
was filtered, the organic layer was separated and dried with
K2CO3. The solvent was evaporated, ylide 1b was used in the
subsequent reaction without additional purification. The yield
was 5.5 g (96%), m.p. 210—212 °С. Found (%): C, 77.13;
H, 5.09; N, 2.58; P, 5.77. C66H50N2O6P2. Calculated (%):
1
Br, 23.98; N, 4.2. IR, ν/cm–1: 1696, 1745. H NMR, δ: 3.51,
3.92 (both s, 4 Н each, СН2); 5.83—5.88 (m, 2 Н, СН);
7.22—7.74 (m, 10 Н, Ph); 8.18 (s,
2
Н, С6Н2).
C, 77.03; H, 4.90; N, 2.72; P, 6.02. IR, ν/cm–1: 1550, 1708, 1732.
4,10ꢀDiphenylꢀ3,4,8,10,11ꢀtetrahydroꢀ2H,6Hꢀindoliziꢀ
no[2,1ꢀf]pyrido[2,1ꢀa]isoindoleꢀ2,6,8,12ꢀtetraone (8b). Benzoꢀ
ic acid (5 mg, 0.04 mmol) was added to a solution of phosphorus
bisꢀylide 1b (0.2 g, 0.2 mmol) in anhydrous toluene (20 mL) and
the mixture was refluxed for 6 h. The solvent was evaporated,
the product was isolated by column chromatography (eluent,
light petroleum—ethyl acetate, 2 : 1). The yield was 0.009 g
(10%). Found (%): C, 76.20; Н, 4.19; N, 5.86. C30H20N2O4.
Calculated (%): C, 76.26; Н, 4.27; N, 5.93. IR, ν/cm–1: 1118,
1708, 1732. 1H NMR ((CD3)2CO), δ: 3.09 (d, 2 Н, СН2,
J = –15.6 Hz); 3.25 (dd, 2 Н, СН2, J = –15.6 Hz, J = 6.6 Hz);
5.92 (d, 2 H, CHPh, J = 6.6 Hz); 6.25 (s, 2 H, CH=C);
7.23—7.38 (m, 10 H, Ph); 8.12, 8.42 (both s, 1 H each, C6H2).
13С NMR, δ: 42.14, 52.16, 103.57, 120.56, 126.13, 128.55,
129.16, 131.21, 133.03, 138.47, 163.67, 166.68, 169.31, 192.20.
13С NMR, δ: 33.78, 40.98, 50.94, 118.44, 127.59, 128.52, 128.93,
129.22, 136.78, 165.94, 198.81.
2,6ꢀBis(4ꢀdimethylsulfonioꢀ3ꢀoxoꢀ1ꢀphenylbutꢀ1ꢀyl)ꢀ
pyrrolo[3,4ꢀf]isoindoleꢀ1,3,5,7(2H,6H)ꢀtetraone dibromide (7а).
Dimethyl sulfide (0.192 g, 6 mmol) was added to a stirred soluꢀ
tion of dibromo diketone 6 (0.67 g, 1 mmol) in anhydrous aceꢀ
tone (10 mL) and the mixture was kept for ~14 h. The precipiꢀ
tate formed was filtered off and washed with acetone. The yield
was 0.54 g (68%), m.p. 214—218 °С. Found (%): С, 52.08;
Н, 4.25; Br, 20.16; N, 3.43; S, 8.11. C34H34Br2N2O6S2. Calcuꢀ
lated (%): С, 51.65; Н, 4.33; Br, 20.21; N, 3.54; S, 8.11. IR,
ν/cm–1: 1686, 1750, 1764.
4
2,6ꢀBis[4ꢀ(dimethylꢀλ ꢀsulfanylidene)ꢀ3ꢀoxoꢀ1ꢀphenylbutꢀ1ꢀyl]ꢀ
pyrrolo[3,4ꢀf]isoindoleꢀ1,3,5,7(2Н,6Н)ꢀtetraone (1а). Sodium
hydride (0.053 g, 2.2 mmol) was added in one portion to a
stirred suspension of bisꢀsulfonium salt 7а (2.37 g, 3 mmol) in
anhydrous THF (10 mL) at ~20 °C under argon atmosphere.
The reaction mixture was stirred for 30 min, then, filtered, and
dried with K2CO3. The solvent was evaporated, ylide 1а was
used in the subsequent reaction without additional purification.
The yield was 1.2 g (63%). Found (%): С, 64.56; Н, 5.15; N, 4.46;
S, 10.32. C34H32N2O6S2. Calculated (%): С, 64.95; Н, 5.13;
N, 4.46; S, 10.2. IR, ν/cm–1: 1560, 1686, 1750.
References
1. F. Z. Galin, I. M. Sakhautdinov, and O. R. Tukhvatullin, Izv.
Akad. Nauk, Ser. Khim., 2007, 2227 [Russ. Chem. Bull., Int.
Ed., 2007, 56, 2305].
2. F. Z. Galin, S. N. Lakeev, I. Z. Mullagalin, and I. O. Maidꢀ
anova, Khim. Geterotsikl. Soedin., 2004, 1813 [Chem. Heteroꢀ
cycl. Compd., 2004 (Engl. Transl.)].
3. I. M. Sakhautdinov, S. N. Lakeev, I. G. Khalikov, M. F.
Abdullin, and F. Z. Galin, Bashkir. Khim. Zh. [Bashkir Chem.
J.], 2004, 32 (in Russian).
4. I. Z. Mullagalin, S. N. Lakeev, I. O. Maidanova, M. F. Abꢀ
dullin, and F. Z. Galin, in Selected Methods for the Synthesis
and Modification of Heterocycles, Ed. V. G. Kartsev, IBS Press,
Moscow, 2002, Vol. 1, 527.
5. S. N. Lakeev, I. Z. Mullagalin, F. Z. Galin, I. O. Maidanova,
and M. F. Abdullin, Izv. Akad. Nauk, Ser. Khim., 2002, 2071
[Russ. Chem. Bull., Int. Ed., 2002, 51, 2230].
6. S. N. Lakeev, I. Z. Mullagalin, I. O. Maidanova, F. Z. Galin,
and G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 2002, 177
[Russ. Chem. Bull., Int. Ed., 2002, 51, 189].
7. F. Z. Galin, S. N. Lakeev, L. F. Chertanova, and G. A.
Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1998, 2376 [Russ.
Chem. Bull., 1998, 47, 2304 (Engl. Transl.)].
8. 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.)].
1,13ꢀBis(methylthio)ꢀ4,10ꢀdiphenylꢀ3,4,10,11ꢀtetrahydroꢀ
2Н,6Hꢀindolizino[2,1ꢀf]pyrido[2,1ꢀа]isoindoleꢀ2,6,8,12ꢀtetraꢀ
one (8а). Sulfur bisꢀylide 1а (0.63 g, 1 mmol) was dissolved in
anhydrous toluene (20 mL) under heating, PhCO2H (0.12 g,
1 mmol) was added, and this was refluxed for 30 min. Toluene
was evaporated, the residue was subjected to chromatography
(eluent, acetone—chloroform, 1 : 9). The yield was 0.37 g (66%),
m.p. 84—88 °С. Found (%): С, 68.42; Н, 4.29; N, 4.92; S, 11.3.
C32H24N2O4S2. Calculated (%): С, 68.06; Н, 4.28; N, 4.96;
1
S, 11.36. IR, ν/cm–1: 1686, 1750, 3548. H NMR, δ: 2.98 (s,
6 Н, Me); 3.25 (d, 2 Н, СН2, J = –15.3 Hz); 3.69 (dd, 2 Н,
СН2, J = –15.3 Hz, J = 6.9 Hz); 5.96 (d, 2 Н, СН,
J = 6.9 Hz); 7.22—7.62 (m, 10 Н, Ph); 8.29, 9.45 (both s, 1 Н
each, С6Н2). 13С NMR, δ: 17.77, 42.46, 51.57, 65.74, 122.71,
125.87, 128.5, 128.86, 129.19, 137.88, 148.98, 163.07, 189.49.
2,6ꢀBis(3ꢀoxoꢀ4ꢀtriphenylphosphonioꢀ1ꢀphenylbutꢀ1ꢀyl)ꢀ
pyrrolo[3,4ꢀf]isoindoleꢀ1,3,5,7(2Н,6Н)ꢀtetraone dibromide (7b).
A solution of PPh3 (0.37 g, 1.4 mmol) in acetone (5 mL) was
added to a stirred solution of dibromo diketone 6 (0.47 g,
0.7 mmol) in anhydrous acetone (5 mL) and the mixture was
kept for 12 h. The precipitate formed was filtered off and washed
with acetone. The yield was 0.52 g (63%), m.p. 281—283 °С.
Found (%): C, 66.02; H, 4.08; Br, 13.69; N, 2.35; P, 5.24.
C66H52Br2N2O6P2. Calculated (%): C, 66.11; H, 4.16; Br, 13.74;
N, 2.41; P, 5.33. IR, ν/cm–1: 742, 1440, 1462, 1712, 1743.
9. G. A. Tolstikov, F. Z. Galin, S. N. Lakeev, L. M. Khalilov,
and V. S. Sultanova, Izv. Akad. Nauk SSSR, Ser. Khim., 1990,
612 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1990, 39, 535
(Engl. Transl.)].
5
2,6ꢀBis[3ꢀoxoꢀ1ꢀphenylꢀ4ꢀ(triphenylꢀλ ꢀphosphorꢀ
anylidene)butꢀ1ꢀyl]pyrrolo[3,4ꢀf]isoindoleꢀ1,3,5,7(2Н,6Н)ꢀ
tetraone (1b). A mixture of 12.5 M NaOH (1.4 mL) and saturaꢀ
ted aq. K2CO3 (8 mL) was added in one portion to a stirred
suspension of diphosphonium salt 7b (6.7 g, 5.6 mmol) in CHCl3
(10 mL) at 10 °С and the mixture was stirred at this temperature
for 30 min. The temperature was raised to ~20 °C, the mixture
Received January 12, 2007;
in revised form November 14, 2007