Anomalous beckmann reaction of 4-aryl-2,7,7-trimethyl-5-oxo-5,6,7,8- tetrahydroquinoline oximes in polyphosphoric acid. 1. New synthesis of 1-ethoxycarbonyl-2,5,5-trimethyl-5,6-dihydro-4H-pyrido[2,3,4-k,l]acridines

Article abstract of DOI:10.1023/B:COHC.0000018341.97883.c0

Transformations of oximes of 4-aryl-2,7,7-trimethyl-5-oxo-5,6,7,8- tetrahydroquinolines in PPA have been studied. It is shown that the reaction, depending on substituent at position 4 of quinoline ring, can occur in three directions: aromatization of the

Full text of DOI:10.1023/B:COHC.0000018341.97883.c0

Chemistry of Heterocyclic Compounds, Vol. 39, No. 12, 2003
ANOMALOUS BECKMANN REACTION OF
4-ARYL-2,7,7-TRIMETHYL-5-OXO-5,6,7,8-
TETRAHYDROQUINOLINE OXIMES IN
POLYPHOSPHORIC ACID. 1. NEW SYNTHESIS
OF 1-ETHOXYCARBONYL-2,5,5-TRIMETHYL-
k,l
5,6-DIHYDRO-4H-PYRIDO[2,3,4- ]ACRIDINES
S. V. Tolkunov, A.I. Khyzhan, and V. I. Dulenko
Transformations of oximes of 4-aryl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines in PPA have
been studied. It is shown that the reaction, depending on substituent at position 4 of quinoline ring, can
occur in three directions: aromatization of the saturated ring (Semmler–Wolff aromatization),
formation of azepinones – normal products of Beckmann rearrangement, and formation of
pyridoacridines.
Keywords: 4-aryl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines, 1-ethoxycarbonyl-2,5,5-trimethyl-
5,6-dihydro-4H-pyrido[2,3,4,-k,l]acridines, Semmler–Wolff aromatization, Beckmann rearrangement.
The synthesis of azepinones using the Beckmann and Schmidt reaction from heterocyclic compounds
containing a dimedone fragment is commonly used for obtaining biologically active compounds [1-6]. However,
the Beckmann reaction often proceeds anomalously [7]. We have recently reported the rearrangement of
3,3,6-trimethyl-1-oxo-1,2,3,4-tetrahydrobenzofuro[2,3-c]quinolines and 3,3,6-trimethyl-1-oxo-1,2,3,4-tetra-
hydrobenzoindolo[2,3-c]quinolines in polyphosphoric acid (PPA) [8] involves not a classical Beckmann
rearrangement but rather a migration of methyl groups with Semmler–Wolff aromatization of the unsaturated
ring [9]. Similar transformations have been described for oximes of 3-alkyl-4-oxo-1-phenyl-4,5,6,7-
tetrahydroindazoles and 5-oxo-5,6,7,8-tetrahydrocinnolines [7, 10]. In the present study, we attempted to
understand the Beckmann reaction and Semmler–Wolff aromatization for 4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydroquinolines.
The reaction was carried out by heating the corresponding oximes with a 10-fold excess of PPA at
100°C for 1 h. Under these conditions, 3-ethoxycarbonyl-2,4,7,7-tetramethyl-5-oxo-5,6,7,8-tetrahydroquinoline
oxime (1) and 3,3-dimethyl-1-oxo-1,2,3,4,5,6,7,8-octahydroacridine oxime (2) were found to undergo Semmler–
Wolff aromatization. The possible formation of isomeric products 3 or 4 and 5 or 6 is related to a different
direction of migration of the methyl groups. In order to prove the structure of the products formed, we carried
out the reductive deamination of 1-amino-2,3-dimethyl-5,6,7,8-tetrahydroacridine (5) to 2,3-dimethyl-5,6,7,8-
tetrahydroacridine (6).
__________________________________________________________________________________________
L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of
Ukraine, 340114 Donetsk, Ukraine; e-mail: tolkunov@uvika.dn.ua. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1849-1854, December, 2003. Original article submitted August 28,
2001; revision submitted January 31, 2002.
0009-3122/03/3912-1627$25.00©2003 Plenum Publishing Corporation
1627

NH2 Me
N
NOH Me
NH2 Me
COOEt
COOEt
Me
Me
COOEt
PPA
PPA
Me
Me
N
N
Me
Me
Me
Me
Me
4
1
3
NH2
NH2
NOH
Me
Me
Me
Me
N
N
N
Me
2
5
Me
6
1
The finding of three aromatic proton singlets in the H NMR spectrum of 7 indicates migration of the
methyl group adjacent to the amino group and formation of products 3 and 5 in the reaction of oximes 1 and 2
with PPA. Otherwise, the 1H NMR spectrum of 7 would have shown an aromatic proton doublet.
Me
HNO2
5
H3PO4
Me
N
7
4-Aryl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline oximes react differently under these
conditions. Thus, 3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydroquinoline oxime (8a)
gives 3-ethoxycarbonyl-2,5,5-trimethyl-5,6-dihydro-4H-pyrido[2,3,4,-k,l]acridine (9a). This transformation
involves attack of the 4-phenyl substituent in starting oxime 8a by the intermediate nitrenium cation. The
1H NMR spectra show signals for the 1,2-disubstituted phenyl fragment. A similar reaction occurs for
4-(3',4'-dimethoxyphenyl)-3-ethoxycarbonyl-2,7,7-trimethyltetrahydroquinoline oxime (8b) with the exception
1
that demethylation with loss of the 4-methoxy group occurs in this latter reaction. The H NMR spectrum of
pyridoacridine 9b lacks the signal for one of the methoxy groups and shows an OH group band at 10.35 ppm.
The introduction of an electron-withdrawing substituent such as a nitro group into the benzene ring
might presumably hinder the electrophilic attack of the 4-phenyl substituent by the nitrenium cation and, thus,
the reaction would proceed through the classical pathway to give an azepinone. However, the formation of
pyridoacridine 9c was also discovered in this case as well.
1
As in the case of 9a and 9b, the H NMR spectra of the products formed provide considerable
1
information. Thus, the pattern of the aromatic protons in the H NMR spectrum of 9c is different from that in
the spectrum of starting oxime 8c. While the 1H NMR spectrum of oxime 8c has signals for a 1,4-disubstituted
1
aromatic system, the H NMR spectrum of the final product 9c has signals for a 1,2,4-trisubstituted system
(Table 1). The transformations of the oximes of 4-(2'-chlorophenyl)- (9d), 4-(4'-methylthiophenyl)- (9e), and
4-(3'-bromophenyl)-5-oxo-5,6,7,8-tetrahydroquinolines (9f) proceed similarly. The structures of reaction
products 9d-f were demonstrated analogously.
1628

R1
R1
R2
R2
HO
R3
R3
N
N
COOEt
COOEt
Me
Me
Me
Me
N
N
Me
Me
9a–f
8a–f
8, 9 a R1 = R2 = R3 = H, 8b R1 = R2 = OMe, R3 = H, 9b R1 = OH, R2 = OMe, R3 = H;
8, 9 c R1 = NO2, R2 = R3 = H, d R1 = R2 = H, R3 = Cl, e R1 = SMe, R2 = R3 = H,
f R1 = R3 = H, R2 = Br
4-(2',5'-Dimethoxyphenyl)-3-ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline oxime
(8g) gives 9-(2',5'-dimethoxyphenyl)-8-ethoxycarbonyl-4,4,7-trimethyl-2,3,4,5-tetrahydropyrido[3,2-b]azepin-2-
one (10). Hence, this reaction involves the classical Beckmann rearrangement.
MeO
HO
MeO
OMe
COOEt
N
OMe
COOEt
O
H
N
Me
Me
Me
Me
N
N
Me
Me
10
8g
The 1H NMR spectrum of 10 shows a band for the HNC=O group at 10.78 ppm.
4-(2',3'-Dimethoxyphenyl)-5-oxo-5,6,7,8-tetrahydroquinoline oxime (8h) undergoes a similar reaction to give
azepinone 11. This reaction course is likely related to the noncoplanarity of the 4-phenyl substituent at C(4) in 8g
and 8h due to steric hindrance created by the 2'-methoxy group. As a result, attack of the phenyl group by the
nitrenium cation becomes impossible.
OMe
OMe
HO
OMe
COOEt
N
OMe
COOEt
O
H
N
Me
Me
Me
Me
N
N
Me
Me
8h
11
Thus, we have shown that the transformation of 2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinoline
oximes in PPA depends on the substituents at C(4) of the tetrahydroquinoline system and may proceed in several
directions involving 1) aromatization of the saturated ring (Semmler–Wolff aromatization), 2) formation of
azepinones, which are the normal products of the Beckmann rearrangement, and 3) attack of the 4-phenyl
substituent by the intermediate nitrenium ion to give pyridoacridines.
1629

TABLE 1. 1H NMR Spectra of Products
Chemical shifts, δ, ppm (SSCC, J, Hz)
Com-
pound
2-СН3
(7-СН3)
(3Н, s)
СООС2Н5
Н arom.
Other protons
(3Н, t, 2Н, q)
—
—
7.78 (1Н, s, 9-Н)
1.00 (6Н, s, 3-, 3-СН3);
1.78 (2Н, m, 6-СН2);
1.86 (2Н, m, 7-СН2);
2.62 (2Н, s, 2-СН2);
2.74 (4Н, m, 5-, 8-СН2);
2.90 (2Н, s, 4-СН2);
10.73 (1Н, s, NOН)
2.14 (3Н, s, 6-СН3);
2.85 (3Н, s, 4-СН3);
5.20 (2Н, s, NH2)
2
2.44
(2.35)
1.34 (J = 7.0),
4.40 (J = 7.0)
7.06 (1Н, s, 8-Н)
8.17 (1Н, s, 9-Н)
3
5
2.11
—
1.83 (4Н, m, 6-, 7-СН2);
2.32 (3Н, s, 3-СН3);
2.89 (4Н, m, 5-, 8-СН2);
5.20 (2Н, s, NH2);
6.95 (1Н, s, 4-Н)
2.31
2.64
—
7.55 (1Н, s, 1-Н);
7.60 (1Н, s, 4-Н);
7.80 (1Н, s, 9-Н)
1.83 (4Н, m, 6-, 7-СН2);
7
2.46 (3Н, s, 3-СН3);
2.89 (4Н, m, 5- and 8-СН2)
1.36 (J = 7.1),
4.59 (J = 7.1)
7.69 (1Н, t, 10-Н);
7.87 (1Н, t, 9-Н);
8.06 (1Н, d, J = 8.1,
8-Н); 8.15 (1Н, d,
J = 8.1, 11-Н)
1.06 (6Н, s, 5-, 5-СН3);
3.09 (2Н, s, 6-СН2);
3.11 (2Н, s, 4-СН2)
9a
2.58
2.69
2.85
1.36 (J = 7.1),
4.59 (J = 7.1)
7.35 (1Н, s, 11-Н);
1.04 (6Н, s, 5-, 5-СН3);
3.02 (2Н, s, 6-СН2);
3.06 (2Н, s, 4-СН2);
3.86 (3Н, s, ОСН3);
10.36 (1Н, s, 9-ОН)
9b
9c
9d
7.45 (1Н, s, 8-Н)
1.39 (J = 7.1),
4.63 (J = 7.1)
8.32 (1Н, d, J = 9,2
11-Н,); 8.48 (1Н,
dd, J1 = 9.2, J2 = 2.56,
10-Н); 8.73 (1Н, d,
J = 2.56, 8-Н)
1.10 (6Н, s, 5-, 5-СН3);
3.18 (4Н, s, 4- and 6-СН2)
1.04 (J = 7.1),
4.18 (J = 7.1)
7.66 (1Н, dd,
1.04 (6Н, s, 5-, 5-СН3);
3.06 (2Н, s, 6-СН2);
3.12 (2Н, s, 4-СН2)
J1 = 7.66, J2 = 1.36,
10-Н,); 7.78 (1Н, t,
9-Н); 7.96 (1Н, dd,
J1 = 8.02, J2 = 1.36,
8-Н)
2.60
1.35 (J = 7.1),
4.54 (J = 7.1)
7.56 (1Н, dd,
1.04 (6Н, s, 5-, 5-СН3);
2.63 (3Н, s, 9-SСН3);
3.04 (2Н, s, 6-СН2);
3.08 (2Н, s, 4-СН2)
9e
J1 = 8.80, J2 = 1.96,
10-Н); 7.77 (1Н, d,
J = 1.96, 8-Н);
7.97 (1Н, d, J = 8.80,
11-Н)
2.63
1.41 (J = 7.1),
4.54 (J = 7.1)
7.97 (2Н, s, 8-Н
and 9-Н); 8.21 (1Н,
s, 11-Н)
6.57 (1Н, d, J = 2.8
6-Н); 6.84 (1Н, dd,
J1 = 11, J2 = 2,8,
4-Н); 6.90 (1Н, d,
J = 11, 3-Н)
6.60 (1Н, t, 5'-Н);
6.97 (1Н, d, 4'-Н,
J = 11); 7.00 (1Н, d,
6'-Н, J = 11)
1.04 (6Н, s, 5-, 5-СН3);
3.05 (2Н, s, 6-СН2);
3.10 (2Н, s, 4-СН2)
0.92 (3Н, s, 4-СН3); 1.07 (3Н, s,
4-СН3); 2.42 (2Н, s, 3-СН2);
2.52 (2Н, s, 5-СН2); 3.53 (3Н, s,
ОСН3); 3.67 (3Н, s, ОСН3);
10.78 (1Н, s, NHCO)
9f
(2.69)
0.92 (J = 7.1),
3.95 (J = 7.1)
10
(2.42)
0.88 (J = 7.1),
3.92 (J = 7.1)
0.91 (3Н, s, 4-СН3); 1.07 (3Н, s,
4-СН3); 2.53 (2Н, d, 5-СН2,
J = 3.64); 2.73 (2Н, d, 3-СН2,
J = 3.64); 3.46 (3Н, s, ОСН3);
3.79 (3Н, s, ОСН3);
11
10.78 (1Н, s, NHCO)
1630

TABLE 2. Physicochemical Characteristics of 3, 5, 7-11
Found, %
——————
Com-
pound
Empirical
formula
Yield,
%
Calculated, %
mp, °С*
Rf*2
Hal
(S)
C
H
N
С16Н20N2О2
С15Н18N2
70.81
70.59
7.23
7.35
10.52
10.29
—
—
—
—
—
—
77-78
230-231
124-125
187
0.47
0.3
—
48.4
48
3
79.91
7.74
12.20
5
79.65
8.02
12.39
С15Н17N
85.10
85.30
8.10
8.06
6.57
6.64
43
7
С21Н24 N2O3
С23 Н28 N2O5
С21Н23 N3O5
С21Н23ClN2O3
С22Н26 N2O3S
С21Н23BrN2O3
С23 Н28N2O5
С23Н28N2O5
С21Н22N2О2
С22Н24N2О4
С21Н21N3О4
С21Н21ClN2О2
С21Н24N2О2S
С21Н21BrN2 О2
С23Н28N2О5
С23Н28N2О5
71.84
7.00
7.72
75
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
10
11
71.59
6.86
7.95
67.00
66.97
6.81
6.84
7.00
6.78
214
80.4
48.1
70.3
94
63.20
5.93
10.30
222
63.48
5.83
10.58
65.43
65.20
6.15
5.99
7.12
7.24
9.32
9.18
210
66.56
6.37
7.20
(8.31)
207
66.33
6.53
7.04
(8.04)
58.62
58.47
5.15
5.34
6.69
6.50
18.30
18.56
210-211
235
31
67.10
6.87
6.90
—
—
—
—
—
78
66.97
6.84
6.78
67.00
66.97
6.85
6.84
7.00
6.78
215
80.4
20.8
26
75.70
6.41
8.52
111-112
166
0.65
0.52
0.73
0.75
0.55
0.22
0.45
0.71
75.45
6.59
8.38
69.80
69.47
6.10
6.32
7.20
7.39
66.23
5.31
11.00
196
67
66.49
5.54
11.08
68.1
5.44
5.70
7.81
7.60
9.42
9.63
104
25
68.39
69.60
6.44
7.52
(8.60)
94
22
69.47
6.36
7.39
(8.42)
61.25
61.02
5.14
5.12
6.89
6.78
19.48
19.33
204
35.7
46
66.72
6.71
6.78
—
227
66.99
6.84
6.80
66.75
66.99
6.64
6.84
6.79
6.80
—
205
44
_______
*Crystallization solvents: ethanol for 3 and 5, acetone–water for 9a,
benzene–hexane for 9b, acetone for 9c, and acetone–hexane for 7, 9d-f, 10,
11.
*2 Eluent: 5:10:1 chloroform–benzene–ethanol for 3 and 9c, 10:1 benzene–
2-propanol for 5, 9a,e,f, 8:1:2 benzene–2-propanol–ethyl acetate for 9b, and
4:1 ethyl acetate–benzene for 9d, 10, 11.
EXPERIMENTAL
1
The H NMR spectra were taken on a Varian VXR-300 spectrometer at 300 MHz and a Gemini-200
spectrometer at 200 MHz in DMSO-d6 with TMS as the internal standard. The purity of the products was
monitored by thin-layer chromatography on Silufol UV-254 plates with detection by UV light or iodine.
Oximes 1, 2, and 8a-f were obtained by the well-known method from the corresponding 4-aryl-3-
ethoxycarbonyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroquinolines [11-13]. The configuration of the oximes
was not determined.
1631

General Method for the Preparation of Products 3, 5, 9a-f, 10, and 11. A mixture of PPA (10 g) and
oxime (1 g) was heated for 1 h at 100°C. The reaction mixture was poured into water (100 ml) and neutralized
by adding aqueous ammonia. The precipitate formed was filtered off or extracted with chloroform. The products
were purified by chromatography on silica gel.
2,3-Dimethyl-5,6,7,8-tetrahydroacridine (7). A solution of NaNO2 (0.60 g, 0.01 mol) in water (5 ml)
was added to a solution of 1-amino-2,3-dimethyl-5,6,7,8-tetrahydroacridine (5) (2.26 g, 0.01 mol) in
hypophosphoric acid (20 ml) at 5°C. The mixture was maintained at room temperature for 5 h and then heated at
60°C for 1 h, cooled, neutralized by adding ammonia, and filtered to give 0.9 g of compound 7. The product was
crystallized from acetone–hexane.
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1632