Heterocycles with a bridgehead nitrogen atom. 16. Assembly of a peri-fused system from an angular tricycle by recyclization of an oxazole ring into pyrrole one

Article abstract of DOI:10.1007/s11172-005-0248-x

An unusual example of the recyclization of the tricyclic 6,7,8,9-tetrahydrooxazolo[3,2-a]quinolinium system into the 8,9-dihydro-7H- pyrrolo[3,2,1-ij]quinoline system was discovered. The reaction is a topological modification of the known conversion of oxazolo[3,2-a]pyridinium salts into indolizines. The structural feature of this transformation is a change of the annelation type in the tricycle from the angular one to peri-fusion of three rings.

Full text of DOI:10.1007/s11172-005-0248-x

Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 259—261, January, 2005
259
Heterocycles with a bridgehead nitrogen atom.
16.* Assembly of a periꢀfused system from an angular tricycle
by recyclization of an oxazole ring into pyrrole one
ꢀ
E. V. Babaev, A. A. Tsisevich, D. V. Al´bov, V. B. Rybakov, and L. A. Aslanov
Department of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: babaev@org.chem.msu.su
An unusual example of the recyclization of the tricyclic 6,7,8,9ꢀtetrahydrooxazoꢀ
lo[3,2ꢀa]quinolinium system into the 8,9ꢀdihydroꢀ7Hꢀpyrrolo[3,2,1ꢀij]quinoline system was
discovered. The reaction is a topological modification of the known conversion of oxazoꢀ
lo[3,2ꢀa]pyridinium salts into indolizines. The structural feature of this transformation is a
change of the annelation type in the tricycle from the angular one to periꢀfusion of three rings.
Key words: recyclization, oxazole, pyrrole, indolizine, annelation, periꢀfused rings, Xꢀray
diffraction analysis.
Earlier,2,3 we discovered a new family of recyclization
reactions of the oxazole ring into the pyrrole one, through
which fused oxazolo[3,2ꢀa]pyridinium salts 1 were conꢀ
verted to 5ꢀsubstituted indolizines 2 virtually inaccessible
in any other ways (Scheme 1).
additional ring A instead of the methyl group (as in salts 1
and 3) (Scheme 2). In this case, the ring A originally
fused only with the pyridine ring of salt 4 would become
additionally fused with a newly formed pyrrole ring to
give system 5. Therefore, the overall structural reconꢀ
struction of tricycles 4→5 would be an example of an
extremely rare mode of transformation of an angular strucꢀ
ture (three rings with two fused sides) into a periꢀfused
system (three rings are all fused in pairs).
Scheme 1
Scheme 2
Most likely, the conversion proceeds4 through the forꢀ
mation of pyridinium intermediate 3, in which cycloꢀ
condensation of a new pyrrole ring involves the αꢀmethyl
group of the salt 3.
An interesting topological modification of this transꢀ
formation could be conversion of tricyclic systems 4 conꢀ
taining a methylene fragment (as in cation 4) as part of an
We experimentally performed this unusual topoꢀ
logical transformation with 6,7,8,9ꢀtetrahydrooxazoꢀ
lo[3,2ꢀa]quinolinium salt 6 as a tricyclic system of the
type 4 (Scheme 3).
Tricycle 6 was synthesized in three steps starting from
available tetrahydroquinolone 7. To construct the oxazole
* For Part 15, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 253—255, January, 2005.
1066ꢀ5285/05/5401ꢀ0259 © 2005 Springer Science+Business Media, Inc.

260
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Babaev et al.
Scheme 3
C(11)
C(10)
C(8)
C(12)
C(1)
C(2)
C(15)
C(19)
C(13)
C(9)
N(4)
C(16)
C(17)
C(7)
C(6)
C(14)
C(3)
Cl(1)
C(18)
C(5)
N(20)
C(21)
C(22)
C(25)
C(24)
C(23)
Fig. 1. Structure 10a (from Xꢀray diffraction data). The selected
bond lengths in the tricycle are:
Bond
d/Å
Bond
d/Å
C(1)—C(2)
C(1)—C(9)
C(1)—C(12)
C(2)—C(3)
C(2)—C(14)
C(3)—N(4)
N(4)—C(9)
N(4)—C(5)
C(1)—C(6)
1.455 (3)
1.357 (3)
1.526 (3)
1.386 (3)
1.455 (3)
1.360 (2)
1.410 (3)
1.378 (3)
1.352 (3)
C(5)—N(20)
C(6)—C(7)
C(7)—C(8)
C(7)—C(13)
C(8)—C(9)
C(1)—C(10)
1.408 (3)
1.449 (3)
1.345 (3)
1.510 (3)
1.406 (3)
1.519 (3)
C(10)—C(11) 1.521 (3)
C(11)—C(12) 1.532 (3)
1
rings. The H NMR spectra of heterocycles 10 and 11
contain no signals for one of the methylene units (as
distinct from salts 6), while the lowꢀfield singlet for the
oxazole ring is replaced by a singlet for the pyrrole ring at
δ 7.2—7.4. The structure of the tricycle obtained was unꢀ
ambiguously proved by Xꢀray diffraction analysis for comꢀ
pound 10a (Fig. 1); the structure will be extensively disꢀ
cussed elsewhere*.
The discovered transformation opens up a new stratꢀ
egy of the synthesis of the pyrrolo[3,2,1ꢀij]quinoline sysꢀ
tem. Compounds of this class first obtained in the 1980s7,8
attracted attention as agonists of dopamine receptors.9
Note that amino or alkoxy derivatives of this system have
been unknown hitherto. Our subsequent studies will be
devoted to the effects of the substituent nature in the
pyridine ring and the size of the saturated fragment in
system 6 on the recyclization in question.
8—11: Ar = pꢀCl—Ph (a), pꢀNO2—Ph (b)
10: X = CH2 (a), O (b)
ring of system 6, selective Nꢀphenacylation in the pyridone
fragment of compound 7 was required. Using Bradsher´s
known methodology,5 which employs a protective methyl
group to prevent Oꢀphenacylation, we obtained 2ꢀmethoxy
derivative 8. Reactions of the latter with halogen ketones
yielded, via simultaneous Nꢀphenacylation and Oꢀdeꢀ
methylation, the desired intermediate products 9a,b. Their
cyclodehydration into tricycles 6a,b was carried out by
successive treatment with sulfuric and perchloric acids.
The 1H NMR spectra of perchlorates 6 contain no signals
for two methylene protons; instead, a lowꢀfield aromatic
singlet for the oxazole ring appears at δ 9.4—9.6. Earlier,
compounds 6a, 8, and 9a were synthesized and characterꢀ
ized by Xꢀray diffraction data.6
Experimental
In reactions with secondary amines or sodium
methoxide, the obtained representatives of the angular
tricyclic system 6 smoothly underwent recyclization to
give amino or methoxy derivatives of 8,9ꢀdihydroꢀ7Hꢀ
pyrrolo[3,2,1ꢀij]quinolines 10 and 11 with the periꢀfused
1
H NMR spectra were recorded on a Bruker AC 400 instruꢀ
ment. The syntheses and Xꢀray diffraction analysis of compounds
* The material is being prepared for publication.

Heterocycles with bridgehead nitrogen atom
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
261
6a and 9a were described earlier.6 Compound 7 was prepared
according to a known procedure.10
compound 10b was 40%, m.p. 218—220 °C. Found (%):
N, 11.05. C22H23N3O3. Calculated (%): N, 11.13. 1H NMR
(CDCl3), δ: 8.25, 7.73 (both m, 2 H each, ArH); 7.40 (s, 1 H,
H(3)); 5.88 (s, 1 H, H(6)); 3.95, 3.10 (both m, 4 H each, CH2);
3.03, 2.80 (both m, 2 H each, CH2); 2.19 (s, 3 H, CH3); 2.06
(m, 2 H, CH2).
4ꢀMethoxyꢀ6ꢀmethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ8,9ꢀdihydroꢀ7Hꢀ
pyrrolo[3,2,1ꢀij]quinoline (11b). Perchlorate 6b (0.5 mmol) was
added to a solution of MeONa in methanol (prepared from Na
metal (7.4 mmol) and anhydrous MeOH (10 mL)). The reaction
mixture was left for 16 h. The precipitate that formed was filꢀ
tered off and recrystallized from acetonitrile. The yield of comꢀ
pound 11b was 0.10 g (62%), m.p. 183—185 °C. Found (%):
N, 8.50. C19H18N2O3. Calculated (%): N, 8.69. 1H NMR
(CDCl3), δ: 8.23, 7.72 (both m, 2 H each, ArH); 7.48 (s,
1 H, H(3)); 5.56 (s, 1 H, H(6)); 4.02 (s, 3 H, OCH3); 3.02,
2.77 (both m, 2 H each, CH2); 2.19 (s, 3 H, CH3); 2.05
(m, 2 H, CH2).
2ꢀMethoxyꢀ4ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline (8). A mixꢀ
ture of 4ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinolinꢀ2ꢀone (7)
(57 mmol), CH3I (72 mmol), and freshly prepared and well
dried Ag2CO3 (28.5 mmol) in 90 mL of benzene was refluxed for
50 to 60 h in a lightꢀprotected flask. The precipitate was filtered
off, the solvent was removed from the mother liquor, and the
residue was distilled in vacuo while collecting a fraction with
b.p. 147 °C (20 Torr). The yield of compound 8 was 3.8 g (38%),
m.p. 40—41 °C (cf. Ref. 6: m.p. 35—40 °C).
4ꢀMethylꢀ1ꢀ(4ꢀnitrophenacyl)ꢀ5,6,7,8ꢀtetrahydroquinolinꢀ2ꢀ
one (9b). A solution of compound 8 (25 mmol) and 4ꢀnitroꢀ
phenacyl bromide (20 mmol) in 40 mL of MeCN was refluxed
for 40 h. The precipitate was filtered off and recrystallized from
acetonitrile. The yield of compound 9b was 3.56 g (55%), m.p.
194—196 °C. Found (%): N, 5.50. C18H18N2O4. Calculated (%):
1
N, 5.56. H NMR (DMSOꢀd6), δ: 8.33 (m, 4 H, ArH); 6.14 (s,
1 H, H(3)); 5.52 (s, 2 H, NCH2); 2.47 (m, 4 H, CH2); 2.12 (s,
3 H, CH3); 1.74 (m, 4 H, CH2).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ
32823ꢀa).
5ꢀMethylꢀ2ꢀ(4ꢀnitrophenyl)ꢀ6,7,8,9ꢀtetrahydrooxazoꢀ
lo[3,2ꢀa]quinolinium perchlorate (6b). Compound 9b (5 mmol)
was carefully dissolved in 30 mL of conc. H2SO4 and left at
room temperature for 16 h. The mixture was carefully poured
into 300 mL of water and allowed to cool. Then 70% HClO4
(15 mL) was added dropwise. The precipitate was filtered off,
washed with water to a neutral reaction, and dried. The yield of
compound 6b was 1.93 g (95%), m.p. 283—285 °C. Found (%):
N, 6.75. C18H17N2O3•ClO4. Calculated (%): N, 6.85. 1H NMR
(DMSOꢀd6), δ: 9.62 (s, 1 H, H(1)); 8.50, 8.28 (both m, 2 H each,
ArH); 8.23 (s, 1 H, H(4)); 3.13, 2.82 (both m, 2 H each, CH2);
2.60 (s, 3 H, CH3); 1.90, 1.99 (both m, 2 H each, CH2).
Recyclization of salts 6 in the presence of secondary amines
(general procedure). A secondary amine (1 mL, ~20ꢀfold excess)
was added to a solution of perchlorate 6 (0.5 mmol) in 10 mL of
acetonitrile. The mixture was refluxed to give a crimson soluꢀ
tion, which rapidly turned greenish yellow. The resulting soluꢀ
tion was poured into water. The precipitate was filtered off,
dried, and recrystallized from acetonitrile.
1ꢀ(4ꢀChlorophenyl)ꢀ6ꢀmethylꢀ4ꢀpiperidinoꢀ8,9ꢀdihydroꢀ7Hꢀ
pyrrolo[3,2,1ꢀij]quinoline (10a) was obtained from perchlorate
6a and piperidine. The reaction duration was 2 min. The yield of
compound 10a was 98%, m.p. 138—139 °C (yellow prismatic
crystals). Xꢀray diffraction data are shown in Fig. 1. Found (%):
N, 7.61. C23H25ClN2. Calculated (%): N, 7.68. 1H NMR
(DMSOꢀd6), δ: 7.51, 7.33 (both m, 2 H each, ArH); 7.18 (s,
1 H, H(3)); 5.76 (s, 1 H, H(6)); 3.00 (m, 4 H, CH2); 2.95, 2.74
(both m, 2 H each, CH2); 2.15 (s, 3 H, CH3); 2.00 (m, 2 H,
CH2); 1.80, 1.67 (both m, 4 H each, CH2).
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Received October 18, 2004;
in revised form December 10, 2004