Heterocycles with a bridging nitrogen atom. 19. Development of routes for the synthesis of oxazoloisoquinolinium salts based on phenacylation of α-methyl-1(3)-isoquinolones

Article abstract of DOI:10.1007/s10593-009-0231-9

Alkylation of 3-methyl-1-isoquinolone and 1-methyl-3-isoquinolone with phenacyl bromides proceeds regioselectively with the formation in the first case of only an N-phenacyl derivative and in the second only the O-derivative. The 5-methyl[1,3]oxazolo[3,2-

Full text of DOI:10.1007/s10593-009-0231-9

Chemistry of Heterocyclic Compounds, Vol. 45, No. 1, 2009
HETEROCYCLES WITH A BRIDGING NITROGEN
ATOM. 19.* DEVELOPMENT OF ROUTES FOR THE
SYNTHESIS OF OXAZOLOISOQUINOLINIUM SALTS
BASED ON PHENACYLATION OF α-METHYL-
1(3)-ISOQUINOLONES**
E. V. Babaev1***, A. A. Nevskaya1, I. V. Dlinnykh1, and V. B. Rybakov1
Alkylation of 3-methyl-1-isoquinolone and 1-methyl-3-isoquinolone with phenacyl bromides proceeds
regioselectively with the formation in the first case of only an N-phenacyl derivative and in the second
only the O-derivative. The 5-methyl[1,3]oxazolo[3,2-a]isoquinolinium salt has been synthesized and its
reactions with ammonia, morpholine, and sodium methylate have been investigated.
Keywords: 1-isoquinolone, isoquinol-3-one, bridging oxazoloquinolines, O,N-alkylation.
In reactions of oxazolopyridinium salts 1 with nucleophiles both the six- and five-membered fragments
of the bicycle may be subject to opening, see the review [2]. The recyclization discovered by us of the oxazole
nucleus into a pyrrole in 5-methyloxazolopyridinium salts (1, R = Me) leading to 5-substituted indolizines 2 is
of the greatest interest [2-5].
A
A
A
+
N
+
N
+
N
N
X
N
R
X
R
R
O
O
O
3
4
1
2
_______
* For Communication 18 see [1].
** Dedicated to Academician B. A. Trofimov on his 70th jubilee
*** To whom correspondence should be addressed, e-mail: babaev@org.chem.msu.ru.
1Chemical Faculty, M. V. Lomonosov Moscow State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 110-123, January, 2009. Original
article submitted May 6, 2008.
0009-3122/09/4501-0093©2009 Springer Science+Business Media, Inc.
93

We have attempted to broaden the circle of substrates capable of an analogous conversion using the
tricyclic systems 3 and 4. We previously succeeded in synthesizing oxazolopyridinium salt 3 (R = Me), in which
the annelated ring A is cyclohexane. Such a linear tricycle is readily converted into angular tricyclic indolizines
on reaction with secondary amines [6] or alcoholates [7]. The present work is devoted to the problem of
synthesizing and investigating the possibility of recyclizing tricyclic benzo analogs, linear of type 3 and angular
of type 4 (R = Me, A is benzo) in which the oxazole nucleus is linked with an isoquinoline ring by various
means.
The standard route of building up an oxazole ring on a pyridine at the C–N bond comprises
N-phenacylation of alkaline salts of pyridone 5a [8, 9] or methoxypyridines 5b [2, 10] (according to Bradsher)
with subsequent acid cyclocondensation.
R3
R3
R3
+
R2
R2
OX
O
R2
O
1. H2SO4
2. HClO4
BrCH2COAr
Ar
1
1
1
N
N
O
N
R
R
R
R
5a,b
R
R
Ar
1
5 a X = Na, b X = Me
It is possible to obtain bicyclic salts 1 and their (cyclo)homologs (R = H, Me, RR1 is the cycloalkane
fragment) [2]. A tricyclic oxazoloquinoline was synthesized on using 2-methoxyquinoline [10].
The use of an analogous strategy for the synthesis of oxazoloisoquinolinium salts 3, 4 has been
investigated to a small extent. The sole described example is the synthesis of angular salt 4a on using
1-methoxyisoquinoline (7a) [10]. The homologous salt 4b is unknown, and information on linear tricyclic
system 3 is generally absent from the literature.
OMe
O
O
O
or
Ar
N+
N
NH
N
O
R
R
R
R
Ar
3a,b
8a,b
9a,b
R
R
R
or
N
N
OMe
NH
O
Ar
N+
O
O
Ar
O
6a,b
7a,b
4a,b
R
3, 4, 6−9 a R = H, b R = Me
For the synthesis of salts 3b, 4b by such a scheme it is evidently necessary to effect a regioselective
N-phenacylation of methylisoquinolones 8b and 6b (or their alkaline salts) or of the corresponding α-methyl-
α'-methoxy derivatives 9b, 7b. There are data in the literature on the N-alkylation of 1(3)-methoxyisoquinolines
7a, 9a and the simplest 1(3)-isoquinolones 6a, 8a, however information on analogous reactions of their
homologs 6b-9b is extremely scanty.
It is known that the alkaline salts of 1-isoquinolone 6a may be subject to selective N-alkylation by
various alkylating agents [11-13], including phenacyl bromide [14]. The N-phenacylation of 1-methoxy-
94

isoquinoline 7a in low yield (~8%) has been described [10]. Examples of the N-alkylation of the homologous
isoquinolone 6b or the methoxy derivative are unknown, although an unusual intramolecular N-alkylation,
accompanying O-demethylation, for the structurally analogous 1-methoxy-3-(ω-bromopropyl)isoquinoline has
been described [15].
Ar
1. EtONa
2. MeI
O
OMe
O
O
1. EtONa
BrCH COAr
BrCH2COAr
Ar
O
N
N
NH
N
2.
2
O
Me
Me
Me
Me
8b
11
10
9b
Ar = p-BrC6H4
There are few examples of N-alkylation among derivatives of 3-isoquinolone 8a and also of 3-methoxy-
isoquinoline 9a. Strangely, alkylation reactions of the simplest 3-isoquinolones 8a,b, were not studied in detail
(because it is possible that such N-alkyl derivatives are obtained more conveniently by recyclization of
benzopyrones), although examples of O-acylation [16] (and also of O-silylation and O-tosylation) of compounds
8a,b are described in the literature. 3-Ethoxyisoquinoline (with additional substituents in the benzene ring)
successfully undergo N-alkylation [17]. It is interesting that on methylation of the sodium salt of 3-oxopapaverine
(a derivative of 1-benzyl-3-isoquinolone), in which the nitrogen atom is sterically hindered, a mixture was obtained
of the products of N- and O-alkylation (43:10) with a clear preference for the N-isomer [18]. There is mention of a
regioselective N-methylation of a 1,4-disubstituted 3-isoquinolone in [19].
TABLE 1. Crystallographic Characteristics, Details of the X-ray
Diffraction Experiment, and Stuctural Refinement for Compounds 10, 13,
and 14
Compound
10
13
14
Empirical formula
М
C18H14BrNO2
356.21
C19H13ClN2O2
336.76
C21H15Cl2N3O5
460.26
System
Triclinic
P-1
Triclinic
P-1
Triclinic
P-1
Space group
а, Å
b, Å
c, Å
α, deg
β, deg
γ, deg
8.285(4)
4.6601(18)
11.786(3)
14.764(5)
82.91(2)
81.09(4)
83.51(3)
7.5329(10)
9.6985(14)
14.521(4)
98.165(16)
101.181(17)
95.752(11)
8. 11.559(3)
11.559(3)
83.015(18)
86.40(3)
69.59(3)
V, Å3
752.7(5)
2
791.3(4)
2
1021.2(4)
2
Z
ρcalc, mg/m3
1.572
1.413
1.497
Absorption coefficient, mm-1
Crystal dimensions, mm
Range of angles θ, deg
Range of indexes
3.775
2.252
3.215
0.2 × 0.2 × 0.2
3.85–74.91
-10≤h≤10,
-10≤k≤10,
0≤l≤14
0.2 × 0.2 × 0.2
3.04–74.73
-5≤h≤5,
-14≤k≤14,
0≤l≤18
3261
0.2 × 0.2 × 0.2
3.15–73.97
-9≤h≤9,
-12≤k≤11,
0≤l≤17
4163
Size of experiment
Number
3161
independent reflections
parameters refined
GOOF
2995
3261
3987
200
218
282
1.009
0.899
0.820
R-factor [I>2σ(I)], R1/wR2
R-factor from all data R1/wR2
∆ρmax/∆ρmin, e/ Å3
0.0379/0.0916
0.0408/0.0936
0.268/-0.481
0.0436/0.1012
0.0473/0.1020
0.235/-0.201
0.0635/0.0857
0.2569/0.1494
0.262/-0.251
95

Study of the Phenacylation of Derivatives of 1-Methyl-3-isoquinolones 8b, 9b and Attempts to
Synthesize the Linear System 3b. We discovered that heating equimolar amounts of the sodium derivative of
1-methyl-3-isoquinolone 8b and p-bromophenacyl bromide in DMF leads to the formation of a single product of
O-alkylation 10, the structure of which was established unequivocally by X-ray structural analysis (Fig. 1,
Tables 2 and 3).
Fig. 1. Numbering of atoms and spatial structure of compound 10. Ellipsoids of thermal
vibrations are given with a probability of 50%. The numbering of atoms does not
correspond to IUPAC nomenclature.
TABLE 2. Bond Lengths (d) in Structure 10
Bond
d, Å
Bond
C(8)–C(9)
d, Å
Br(17)–C(17)
N(1)–C(10)
N(1)–C(2)
C(2)–C(3)
C(2)–O(2)
O(2)–C(12)
C(3)–C(4)
C(4)–C(9)
C(4)–C(5)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
1.886(2)
1.323(2)
1.357(2)
1.360(3)
1.363(2)
1.411(3)
1.399(3)
1.426(2)
1.433(3)
1.343(4)
1.394(4)
1.373(4)
1.413(3)
1.416(3)
1.500(2)
1.505(3)
1.211(3)
1.482(3)
1.391(3)
1.396(3)
1.398(3)
1.372(3)
1.371(3)
1.391(3)
C(9)–C(10)
C(10)–C(11)
C(12)–C(13)
C(13)–O(13)
C(13)–C(14)
C(14)–C(19)
C(14)–C(15)
C(15)–C(16)
C(16)–C(17)
C(17)–C(18)
C(18)–C(19)
Attempts at selective N-phenacylation according to Bradsher of the 3-methoxy derivative 9b proved to
be unsuccessful. The initial compounds were recovered from the reaction mixture even after boiling for many
hours in acetonitrile or heating in DMF.
Selective O-alkylation of isoquinolone 8b may be explained not only by the steric effect of the two
substituents in the positions α to the nitrogen atom. It is extremely probable that the formation of the N-isomer
11 may be hindered further by a thermodynamic factor linked with the quinonoid type of structure of the whole
class of N-alkyl-3-isoquinolones.
Theoretically isoquinoline 10 might serve as the precursor of the desired tricycle 3b. (An example of a
similar process is known, the synthesis of the thioanalog of system 3 by the acid cyclization of
3-(phenacylthio)isoquinoline [20]). Meanwhile, all attempts to close the oxazolium ring in O-phenacyl
derivative 10 by the action of conc. H2SO4 or oleum proved to be unsuccessful and led only to salts of the initial
isoquinoline 10.
96

TABLE 3. Valence Angles (ω) in Structure 10
Angle
ω, deg
Angle
ω, deg
C(10)–N(1)–C(2)
N(1)–C(2)–C(3)
N(1)–C(2)–O(2)
C(3)–C(2)–O(2)
C(2)–O(2)–C(12)
C(2)–C(3)–C(4)
C(3)–C(4)–C(9)
C(3)–C(4)–C(5)
C(9)–C(4)–C(5)
C(6)–C(5)–C(4)
C(5)–C(6)–C(7)
C(8)–C(7)–C(6)
C(7)–C(8)–C(9)
C(8)–C(9)–C(10)
C(8)–C(9)–C(4)
C(10)–C(9)–C(4)
N(1)–C(10)–C(9)
118.21(18)
124.68(17)
117.78(18)
117.53(15)
119.42(14)
118.10(16)
118.75(18)
122.21(17)
119.02(18)
119.6(2)
N(1)–C(10)–C(11)
C(9)–C(10)–C(11)
O(2)–C(12)–C(13)
O(13)–C(13)–C(14)
O(13)–C(13)–C(12)
C(14)–C(13)–C(12)
C(19)–C(14)–C(15)
C(19)–C(14)–C(13)
C(15)–C(14)–C(13)
C(14)–C(15)–C(16)
C(17)–C(16)–C(15)
C(18)–C(17)–C(16)
C(18)–C(17)–Br(17)
C(16)–C(17)–Br(17)
C(17)–C(18)–C(19)
C(14)–C(19)–C(18)
115.64(19)
121.83(18)
112.92(17)
121.84(17)
120.94(19)
117.22(16)
119.03(18)
118.94(17)
122.03(16)
119.70(17)
119.98(18)
121.10(19)
119.44(15)
119.44(16)
119.46(17)
120.71(18)
122.3(3)
119.7(2)
121.0(2)
123.95(17)
118.3(2)
117.70(17)
122.52(16)
Synthesis of the Angular System 4b by Phenacylation of the 3-Methyl-1-isoquinolone Derivative
6b. The most available* representative of the 3-methyl-1-isoquinolone series is the 4-cyano derivative 12, which
was synthesized from accessible reactants in three steps according to the known methods. We carried out
alkylation of it with p-chlorophenacyl bromide under conditions analogous to the phenacylation of compound
Fig. 2. Numbering of atoms and spatial structure of compound 13. Ellipsoids of thermal
vibrations are given with a probability of 50%. The numbering of atoms does not
correspond to IUPAC nomenclature.
_______
* Synthesis of the simplest isoquinolone 6b by hydrolysis of nitrile 12 in sulfuric acid is described in [21]. We
discovered however, that a significant amount of sulfonation byproduct is formed in this reaction, consequently
compound 12 was used in later experiments.
97

TABLE 4. Bond Lengths (d) in Structure 13
Bond
C(1)–O(1)
d, Å
Bond
C(7)–C(8)
d, Å
1.2294(18)
1.414(2)
1.439(2)
1.389(2)
1.4614(18)
1.368(2)
1.493(2)
1.432(2)
1.444(2)
1.142(2)
1.375(2)
1.416(2)
1.371(3)
1.403(3)
1.403(3)
1.363(3)
1.410(2)
1.509(2)
1.2243(18)
1.4837(19)
1.382(2)
1.401(2)
1.373(2)
1.386(3)
1.345(3)
1.7321(16)
1.386(2)
C(1)–N(2)
C(1)–C(10)
N(2)–C(3)
N(2)–C(11)
C(3)–C(4)
C(3)–C(31)
C(4)–C(41)
C(4)–C(5)
C(41)–N(41)
C(5)–C(10)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
C(8)–C(9)
C(9)–C(10)
C(11)–C(12)
C(12)–O(12)
C(12)–C(13)
C(13)–C(14)
C(13)–C(18)
C(14)–C(15)
C(15)–C(16)
C(16)–C(17)
C(16)–Cl(16)
C(17)–C(18)
TABLE 5. Valence Angles (ω) in Structure 13
Angle
ω, deg
Angle
ω, deg
O(1)–C(1)–N(2)
O(1)–C(1)–C(10)
N(2)–C(1)–C(10)
C(3)–N(2)–C(1)
C(3)–N(2)–C(11)
C(1)–N(2)–C(11)
C(4)–C(3)–N(2)
C(4)–C(3)–C(31)
N(2)–C(3)–C(31)
C(3)–C(4)–C(41)
C(3)–C(4)–C(5)
C(41)–C(4)–C(5)
N(41)–C(41)–C(4)
C(10)–C(5)–C(6)
C(10)–C(5)–C(4)
C(6)–C(5)–C(4)
C(7)–C(6)–C(5)
C(6)–C(7)–C(8)
C(9)–C(8)–C(7)
117.51(14)
125.58(15)
116.91(13)
123.16(12)
121.59(13)
115.19(13)
118.29(14)
123.46(15)
118.17(13)
118.26(15)
121.74(14)
119.99(14)
175.1(2)
C(8)–C(9)–C(10)
118.47(17)
121.05(14)
120.90(14)
118.05(14)
113.16(12)
122.01(14)
120.47(13)
117.52(12)
119.16(14)
119.00(13)
121.83(14)
121.15(16)
118.71(16)
121.12(15)
119.49(14)
119.28(14)
120.88(16)
118.81(15)
C(5)–C(10)–C(9)
C(5)–C(10)–C(1)
C(9)–C(10)–C(1)
N(2)–C(11)–C(12)
O(12)–C(12)–C(13)
O(12)–C(12)–C(11)
C(13)–C(12)–C(11)
C(14)–C(13)–C(18)
C(14)–C(13)–C(12)
C(18)–C(13)–C(12)
C(15)–C(14)–C(13)
C(14)–C(15)–C(16)
C(17)–C(16)–C(15)
C(17)–C(16)–Cl(16)
C(15)–C(16)–Cl(16)
C(16)–C(17)–C(18)
C(17)–C(18)–C(13)
118.90(15)
118.88(13)
122.22(15)
120.75(17)
118.74(16)
122.08(17)
8b. The N-alkyl derivative 13 was isolated in 25% yield as the sole reaction product. A combination of 1H NMR
and IR spectroscopy was carried out to establish the direction of alkylation. Structural investigation of a
monocrystal of compound 13 by X-ray structural analysis (Fig. 2, Tables 4 and 5) finally confirmed these
conclusions.
CN
CN
CN
Me
Me
Me
1. H2SO4
2. HClO4
1. EtONa
+
–
ClO4
N
NH
2. BrCH2COAr
N
O
O
O
O
Ar
Ar
12
13
14
Ar = p-ClC6H4
98

Cyclization of the obtained N-phenacyl-1-isoquinolone 13 was effected by the action of conc. H2SO4,
the reaction product was isolated as the perchlorate.
We discovered that cyclization did not take place with a brief (15 min) action of acid, however it was
fully complete after 1 day. Under these conditions hydrolysis of the cyano group did not occur and the
perchlorate of the tricyclic oxazoloisoquinoline 14 was formed in 72% yield. The results of X-ray structural
analysis of a monocrystal of this compound obtained from solution in acetonitrile are given in Fig. 3 and Tables
6 and 7.
Reaction of Salt 14 with Nucleophiles. The reaction of perchlorate 14 with morpholine proceeded
completely in 15 min. After treating the reaction mixture with water a compound was isolated which had the
structure of N-phenacyl-1-isoquinolone 13 according to spectral data. The interaction of salt 14 with a
methanolic solution of sodium methylate led to the same compound 13.
1. morpholine
or MeONa
X
X
O
14
13
+
N
N
N
2. H2O
NC
NC
NC
Me
Ar
Me
O
X
Ar
Ar
17
15
16
13−17 Ar = p-ClC6H4, X = OMe, morpholine
Fig. 3. Numbering of atoms and spatial structure of compound 14. Ellipsoids of thermal
vibrations are given with a probability of 50%. The numbering of atoms does not
correspond to IUPAC nomenclature.
In both cases no formation of the benzoindolizine structure 17 was observed. Since the isoquinoline
fragment remains unchanged, the observed conversion is evidently linked with attack of nucleophile at the
oxazole ring, for example, at position 2. The resulting opening form 15 subsequent treatment with water
99

converts into N-phenacylisoquinolone 13. Clevage of the C(2)–O bond under the action of sodium methylate
was observed by us previously for oxazolopyridinium salt 1 (R = H) [22]. An analogous direction of opening the
azole ring was also observed for the reaction of a thiazoloisoquinolinium salt (isostructure of salt 14) with a
secondary amine [20].
Interaction of salt 14 with ammonia in anhydrous medium leads to the formation of a new compound,
imidazoisoquinoline 18.
TABLE 6. Bond Lengths (d) in Structure 14
Bond
C(1)–O(1)
d, Å
Bond
C(9)–C(10)
d, Å
1.341(9)
1.353(9)
1.371(10)
1.381(8)
1.382(9)
1.389(9)
1.384(10)
1.513(9)
1.422(10)
1.454(9)
1.119(10)
1.412(9)
1.413(9)
1.388(10)
1.404(10)
1.361(10)
1.414(9)
1.381(10)
1.390(9)
1.422(10)
1.332(9)
1.403(10)
1.374(10)
1.389(10)
1.722(9)
1.366(10)
1.444(5)
1.464(5)
1.498(5)
1.561(5)
1.446(12)
1.158(12)
C(1)–N(2)
C(1)–C(10)
O(1)–C(12)
N(2)–C(11)
N(2)–C(3)
C(3)–C(4)
C(3)–C(31)
C(4)–C(41)
C(4)–C(5)
C(41)–N(41)
C(5)–C(6)
C(5)–C(10)
C(6)–C(7)
C(7)–C(8)
C(8)–C(9)
C(13)–C(14)
C(13)–C(18)
C(13)–C(12)
C(11)–C(12)
C(14)–C(15)
C(15)–C(16)
C(16)–C(17)
C(16)–Cl(16)
C(17)–C(18)
Cl(1)–O(14)
Cl(1)–O(11)
Cl(1)–O(12)
Cl(1)–O(13)
C(51)–C(52)
C(52)–N(53)
TABLE 7. Valence Angles (ω) in Structure 14
Angle
ω, deg
Angle
ω, deg
O(1)–C(1)–N(2)
O(1)–C(1)–C(10)
N(2)–C(1)–C(10)
C(1)–O(1)–C(12)
C(1)–N(2)–C(11)
C(1)–N(2)–C(3)
C(11)–N(2)–C(3)
C(4)–C(3)–N(2)
C(4)–C(3)–C(31)
N(2)–C(3)–C(31)
C(3)–C(4)–C(41)
C(3)–C(4)–C(5)
C(41)–C(4)–C(5)
N(41)–C(41)–C(4)
C(6)–C(5)–C(10)
C(6)–C(5)–C(4)
C(10)–C(5)–C(4)
C(7)–C(6)–C(5)
C(6)–C(7)–C(8)
C(9)–C(8)–C(7)
C(8)–C(9)–C(10)
C(1)–C(10)–C(9)
C(1)–C(10)–C(5)
107.7(8)
126.9(8)
125.4(9)
108.2(6)
108.5(7)
120.3(8)
131.0(7)
118.5(7)
125.5(8)
116.0(7)
119.5(8)
120.2(8)
120.3(8)
176.1(10)
120.0(7)
120.3(9)
119.7(8)
118.7(9)
119.9(9)
123.0(8)
117.8(8)
123.4(8)
115.9(7)
C(9)–C(10)–C(5)
120.6(8)
117.2(8)
121.0(8)
121.6(8)
107.1(7)
108.4(7)
134.5(8)
117.1(7)
121.8(8)
118.7(8)
120.4(8)
119.9(7)
119.5(7)
119.4(8)
122.3(8)
113.7(4)
110.8(3)
111.3(4)
109.0(3)
105.7(3)
105.8(3)
179.1(14)
C(14)–C(13)–C(18)
C(14)–C(13)–C(12)
C(18)–C(13)–C(12)
C(12)–C(11)–N(2)
C(11)–C(12)–O(1)
C(11)–C(12)–C(13)
O(1)–C(12)–C(13)
C(13)–C(14)–C(15)
C(16)–C(15)–C(14)
C(15)–C(16)–C(17)
C(15)–C(16)–Cl(16)
C(17)–C(16)–Cl(16)
C(18)–C(17)–C(16)
C(17)–C(18)–C(13)
O(14)–Cl(1)–O(11)
O(14)–Cl(1)–O(12)
O(11)–Cl(1)–O(12)
O(14)–Cl(1)–O(13)
O(11)–Cl(1)–O(13)
O(12)–Cl(1)–O(13)
N(53)–C(52)–C(51)
100

In this case the mechanism of recyclization probably includes attack of an ammonia molecule at the
bridging position of the oxazoloisoquinolinium cation, the opening of the ring, and its subsequent closing onto
the incoming amino group.
CN
CN
CN
Me
Ar
Me
Ar
Me
NH3
14
+
N
N
N
H2N
N
O
NH
O
2 Ar
18
Ar = p-ClC6H4
The result obtained in the reaction with ammonia does not exclude the alternative explanation of the
conversaion of salt 14 under the action of morpholine and alcoholate. The unstable ylid 16, which readily
undergoes subsequent hydrolysis, may serve in the intermediate opening of the tricycle under the action of
secondary amine or alcoholate. The closing of the pyrrole ring in ylid 16 (analogous to the recyclization of salt
1) expected by us should lead to the tricyclic indolizine 17. Possibly such recyclization did not occur due to the
low aromaticity of indolizine 17, which has a clear quinonoid structure.
In this way attempts to generalize the strategy of recyclization of the oxazole nucleus into a pyrrole
(1 →2) by transfer from the oxazolopyridinium system 1 to its benzenologs 3b, 4b (containing an isoquinoline
fragment in the tricycle) encounter two inherent difficulties. The angular tricyclic cation 4b was synthesized,
however it proved not to have the capacity of recyclization into linear tricyclic indolizines 17. The linear
tricyclic cation 3b generally was not obtained (in the standard strategy for the synthesis of salt 1), since the
isomeric O-alkyl derivative 10 is formed in place of the key intermediate 11. It is interesting that in both cases
the key factor distinguishing the isoquinoline system from the pyridine may be the instability of derivatives 11,
17, having a quinonoid motif in the isoquinoline fragment.
EXPERIMENTAL
1
The IR spectra were recorded on a UR 20 instrument in nujol. The H and 13C NMR spectra were
recorded on a Bruker AC 400 instrument (400 and 90 MHz) in DMSO-d6, internal standard was TMS. The mass
spectra were obtained on a Finnigan MAT Incos 50 spectrometer with direct insertion of sample into the ion
source, ionization energy was 70 eV.
X-Ray Structural Investigation of Compounds 10, 13, and 14. The experimental intensities of the
diffraction patterns were obtained on a CAD4 diffractometer [23] (CuKα radiation, λ = 1.5418 Å, graphite
monochromator, ω-scanning). The parameters of the unit cells were determined and refined according to 25
reflections in the angle intervals θ 34.97-36.74o, 30.03-31.91o, and 25.05-26.60o. An absorption correction was
introduced for compound 10 in accordance with North–Phillips–Mathews [24]. For compounds 13 and 14 no
absorption correction was introduced, since they have low absorption coefficients and small linear dimensions.
Primary processing of the masses of diffraction data was carried with the WinGX set of programs [25]. All the
subsequent calculations were carried out with the SHELX97 set of programs [26]. The crystal structures were
determined by direct methods with subsequent refinement of the positional and thermal parameters in an
anisotropic approximation for all the non-hydrogen atoms. The hydrogen atoms were calculated from geometric
101

considerations and were refined within the framework of the "rider-atom" model. Individual crystallographic
characteristics and experimental parameters, interatomic distances, and valence angles in the investigated
compounds are set out in Tables 1-7. The spatial disposition of atoms in the molecules of compounds 10, 13,
and 14, and their numbering are shown in Figs. 1-3, and were obtained using the ORTEP-3 program [27]. The
crystallographic information on compounds 10, 13, and 14 is deposited in the Cambridge structural data bank
(deposit CCDC Nos. 687065, 687066, and 687067 respectively) [28].
1-Methyl-3-isoquinolone (8b). Ethyl diethoxyacetate (27 ml, 150 mmol) was added to a solution of
sodium hydroxide (6.2 g, 155 mmol) in ethanol. The mixture was boiled for 1 h and the solvent removed in
vacuum. The sodium diethoxyacetate obtained was suspended in anhydrous ether (120 ml), and thionyl chloride
(11 ml, 150 mmol) was added to it in portions with stirring and cooling, maintaining the reaction temperature
below 0oC. After the end of the addition the reaction mixture was boiled for 40 min, then poured into a mixture
of benzene (75 ml), pyridine (45 ml), and α-methylbenzylamine (19 ml, 150 mmol) cooled in an ice bath. The
mixture obtained was once again boiled for 40 min, then cooled to room temperature, and poured into water.
The organic layer was separated and the aqueous layer was additionally extracted with benzene. The combined
organic extracts were washed with 2% hydrochloric acid solution (1 liter), and evaporated in vacuum. Yield of
19
1
N-(1-Phenylethyl)-2,2-diethoxyacetamide was 16 g (42%), nD 1.5016. H NMR spectrum, δ, ppm (J, Hz):
7.72 (1H, d, J = 7.96, NH); 7.18-7.32 (5H, m, C6H5); 4.98 (1H, m, CH); 4.68 (1H, s, CH(OEt)2); 3.58 (4H, m,
CH2CH3); 1.45 (3H, d, J = 7.08, CH3); 1.20 (6H, m, CH2CH3).
N-(1-Phenylethyl)-2,2-diethoxyacetamide without further purification was induced into acid
cyclization by the procedure of [29]. 1-Methyl-3-isoquinolone (8b) was obtained in this way in 64% yield.
3-Methoxy-1-methylisoquinoline (9b). Compound 8b (0.5 g, 3.14 mmol) was boiled for 30 min with a
solution of sodium ethylate (3.14 mmol) in ethanol. The solvent was evaporated in vacuum. Methyl iodide
(0.6 ml, 9.4 mmol) and absolute DMF (10 ml) were added to the obtained dry sodium salt. The mixture was
maintained at 40oC for 16 h, then poured into water, and the mixture extracted with carbon tetrachloride. The
solvent was removed in vacuum, and the residue chromatographed on a column of silica gel (eluent chloroform).
Yield was 0.12 g (22%), Rf 0.6, oil. 1H NMR spectrum, δ, ppm (J, Hz): 8.01 (1H, d, J = 8.85, H-8); 7.68 (1H, d,
J = 7.96, H-5); 7.54 (1H, m, H-6); 7.34 (1H, m, H-7); 6.85 (1H, s, H-4); 3.96 (3H, s, OCH3); 2.87 (3H, s, CH3).
4-Cyano-3-methylisoquinol-1-one (12) was obtained by the procedure of [30].
1-(4-Bromophenyl)-2-[(1-methylisoquinolin-3-yl)oxy]ethanone (10). 1-Methylisoquinol-3-one (2 g,
13 mmol) was boiled for 30 min with a solution of sodium ethylate (13 mmol) in ethanol. The solvent was
removed in vacuum. 4-Bromophenacyl bromide (3.6 g, 13 mmol) and absolute DMF (50 ml) were added to the
obtained sodium salt. The reaction mixture was heated on a water bath for 4 h, then cooled to room temperature,
and poured into water. The reaction product was extracted with chloroform, the extract washed with water, and
evaporated in vacuum. The dry residue was crystallized from ethanol. Yield was 3.6 g (78%). Mp 123-125°C
1
(ethanol). IR spectrum, ν, cm-1: 1700, 1630, 1590. H NMR spectrum, δ, ppm (J, Hz): 8.00 (1H, d, J = 7.96,
H-8); 7.94 (2H, d, J = 8.0, ArH); 7.73 (1H, d, J = 8.84, H-5); 7.69 (2H, d, J = 8.0, ArH); 7.56 (1H, m, H-6); 7.36
(1H, m, H-7); 7.03 (1H, s, H-4); 5.62 (2H, s, CH2); 2.74 (3H, s, CH3). Found, %: C 60.75; H 3.91; N 4.02.
C18H14BrNO2. Calculated, %: C 60.69; H 3.96; N 3.93. X-ray structural analysis see Fig. 1, monocrystal was
grown from acetonitrile.
2-[2-(4-Chlorophenyl)-2-oxoethyl]-4-cyano-3-methyl-1-isoquinolone (13) was obtained analogously
to compound 10 from 4-cyano-3-methyl-1-isoquinolone (12) (1 g, 5 mmol) and p-chlorophenacyl bromide
(1.3 g, 5 mmol). Reaction time was 5 h. Yield was 0.63 g (32%). Mp 247-249oC (ethanol). IR spectrum, ν, cm-1:
2260, 1680 (1660 sh), 1600. 1H NMR spectrum, δ, ppm (J, Hz): 8.24 (1H, d, J = 7.96, H-8); 8.14 (2H, d,
J = 7.96, ArH); 7.86 (1H, m, H-7); 7.78 (1H, d, J = 7.96, H-5); 7.56-7.61 (3H, m, H-6, ArH); 5.77 (2H, s, CH2);
2.63 (3H, s, CH3). Found, %: C 67.64; H 3.78; N 8.34. C19H13ClN2O2. Calculated, %: C 67.76; H 3.89; N 8.32.
X-ray structural analysis see Fig 2, monocrystal was grown from acetonitrile.
102

2-(4-Chlorophenyl)-6-cyano-5-methyl[1,3]oxazolo[2,3-a]isoquinolin-4-ium Perchlorate (14). Conc.
H2SO4 (20 ml) was added to compound 13 (0.5 g, 1.5 mmol) and the mixture left overnight. The reaction
mixture was poured into water, and an insoluble contaminant was filtered off. Perchloric acid (70%; 3 ml) was
added to the filtrate. The resulting solid was filtered off, dried in vacuum, and crystallized from acetonitrile.
Yield was 0.68 g (72%). Mp 298-299oC (acetonitrile. 1H NMR spectrum, δ, ppm (J, Hz): 9.79 (1H, s, H-3); 9.00
(1H, d, J = 7.96, H-10); 8.36 (2H, m, H-7,8); 8.25 (2H, d, J = 7.96, ArH); 8.21 (1H, m, H-9); 7.71 (2H, d,
J = 7.96, ArH); 3.20 (3H, s, CH3). Found, %: C 54.60; H 3.16; N 8.99. C21H15Cl2N3O5. Calculated, %: C 54.80;
H 3.28; N 8.99. X-ray structural analysis see Fig. 3 (solvate with acetonitrile), monocrystal grown from
acetonitrile.
2-(4-Chlorophenyl)-5-methylimidazo[2,1-a]isoquinoline-6-carbonitrile (18). A current of dry
ammonia was passed through a suspension of oxazoloisoquinolinium perchlorate 14 (60 mg, 0.13 mmol) in
acetonitrile (3 ml) for 2 h. The suspension rapidly passed into solution, and then a white precipitate formed. The
mixture was allowed to stand for 5 days without access to air. The solvent was removed in vacuum, the solid
residue extracted with chloroform, and the extract evaporated. Yield was 20 mg (40%). Mp 222-225oC. 1H NMR
spectrum, δ, ppm (J, Hz): 8.58 (1H, d, J = 7.05, H-10); 8.29 (1H, s, H-3); 8.10 (2H, d, J = 7.58, ArH); 7.90 (1H,
m, H-8); 7.80 (2H, m, H-9,7); 7.54 (2H, d, J = 7.58. ArH); 2.93 (3H, s, CH3). Mass spectrum, m/z (Irel, %):
317/319 [M]+ (100/35), 282 (6), 153 (8), 140 (32), 126 (12), 113 (16), 101 (13), 87 (14), 75 (40). Found, %:
C 1.64; H 3.65; N 13.44. C19H12ClN3. Calculated, %: C 71.81; H 3.81; N 13.22.
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