Specific example of the mannich reaction in the series of 5-acetyl-6-aminoacenaphthene and its derivatives

Article abstract of DOI:10.1134/S107042800707010X

Reactions of 5-acetyl-6-aminoacenaphthene and 5-acetyl-6- acetylaminoacenaphthene with aromatic aldehydes under conditions of base and acid catalysis gave derivatives of a new peri-fused heterocyclic system, 2,3,7,8-tetrahydroacenaphtho[5,6-bc]azepin-4(1H

Full text of DOI:10.1134/S107042800707010X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 7, pp. 998–1001. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © A.N. Antonov, R.V. Tyurin, L.G. Minyaeva, V.V. Mezheritskii, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43,
No. 7, pp. 1005–1008.
Specific Example of the Mannich Reaction in the Series
of 5-Acetyl-6-aminoacenaphthene and Its Derivatives
A. N. Antonov, R. V. Tyurin, L. G. Minyaeva, and V. V. Mezheritskii
Institute of Physical and Organic Chemistry, Rostov State University,
pr. Stachki 194/2, Rostov-on-Don, 344090, Russia
e-mail: mezher@ipoc.rsu.ru
Received September 4, 2006
Abstract—Reactions of 5-acetyl-6-aminoacenaphthene and 5-acetyl-6-acetylaminoacenaphthene with aromatic
aldehydes under conditions of base and acid catalysis gave derivatives of a new peri-fused heterocyclic system,
2,3,7,8-tetrahydroacenaphtho[5,6-bc]azepin-4(1H)-ones.
DOI: 10.1134/S107042800707010X
peri-Aminoacetylacenaphthene I and its N-acetyl
derivative Ib were reported for the first time in 1966
[1]. These compounds attract interest as potential pre-
cursors of peri-fused nitrogen-containing heterocycles;
however, their ability to undergo heterocyclization was
not studied until present. peri-Amino ketones of the
naphthalene series could not be isolated because of
their fast intramolecular heterocyclization leading to
benzo[cd]indoles [2]. The presence of an ethylene
bridge connecting peri positions of the naphthalene
core at the side opposite to the peri-aminocarbonyl
moiety changes the molecular geometry so strongly
that closure of five-membered heteroring becomes
difficult. Therefore, derivatives of 5-amino-6-acylace-
naphthene are sufficiently stable to exist as individual
substances.
hand, these findings do not rule out the possibility for
participation of three other intermediates A–C. Thus
N-acetylazepinone IIe was obtained in the reaction of
p-methoxybenzaldehyde with N-acetylaminoacenaph-
thene Ib despite the latter could not give rise to Schiff
base like III. Azepinones IId–IIf can also be prepared
from ketone Ib and aromatic aldehydes in triethyl
orthoformate in the presence of perchloric acid.
Taking into account the character of final products
II and probably one of the mechanisms shown in
Scheme 1 (I → C → II), the examined transformations
may be regarded as a specific example of the Mannich
reaction. The classical Mannich reaction is a three-
component condensation of an aldehyde with amine
and carbanion generated from methyl (methylene)
ketone by the action of a base [3]. In our case, the
difference is that the hydroxyalkylamino and carbanion
moieties formed during the process are fixed at the
peri positions of a rigid aromatic framework (structure
C). Presumably, just this factor is responsible for the
reaction direction involving closure of seven-mem-
bered heteroring.
While performing studies on purposeful synthesis
of peri-fused heterocyclic compounds of the naphtha-
lene and acenaphthene series, we have found that aro-
matic aldehydes react with peri-aminoacetylacenaph-
thene I in alkaline medium to give acenaphtho[5,6-bc]-
azepinones II. The reaction can follow four alternative
pathways involving intermediate formation of β-hy-
droxy ketones A, chalcones B, amino alcohols C, or
Schiff bases III (Scheme 1). In the reactions of amino
ketone Ia with aldehydes, apart from azepinones IIa–
IIc, we isolated small amounts of the corresponding
Schiff bases III; therefore, the latter could mediate
the transformation of compounds I into II. In fact,
azepinones II are formed under analogous conditions
from specially prepared Schiff bases III. On the other
1
According to the H NMR data, methylene protons
neighboring to the asymmetric center in the azepine
ring are magnetically nonequivalent, and they resonate
as two one-proton doublets of doublets. The CHAr
proton gives a one-proton doublet of doublets at 4.7
(IIa–IIc) or 6.4 ppm (IId–IIf). The observed large
difference in the chemical shifts of that proton between
azepinones IIa–IIc and their N-acetyl derivatives IId–
998

SPECIFIC EXAMPLE OF THE MANNICH REACTION
999
Scheme 1.
HO
Ar
Ar
R
O
R
O
NH
NH
NaOH
–H2O
A
B
–H2O
Ar
N
R
O
NHR COMe
ArCHO
HC(OEt)3–HClO4
R = Ac
Ia, Ib
IIa–IIf
–H2O
Ar
Ar
OH
COMe
R
N
N
COMe
NaOH
–H2O (R = H)
C
IIIa–IIIc
I, R = H (a), Ac (b); II, R = H, Ar = Ph (a), 4-MeOC6H4 (b), 3,4-(MeO)2C6H3 (c); R = Ac, Ar = Ph (d), 4-MeOC6H4 (e),
3,4-(MeO)2C6H3 (f); III, Ar = Ph (a), 4-MeOC6H4 (b), 3,4-(MeO)2C6H3 (c).
IIf may be rationalized in terms of electron-with-
drawing effect of the acetyl group on the nitrogen
atom.
Unlike colorless N-acetyl derivatives IId–IIf, NH-
azepinones IIa–IIc are yellow–orange both in solution
and in crystal; this may be the result of the presence of
small amounts of their open-chain tautomers, chal-
cones B, for the nitrogen atom in IIa–IIc is sufficiently
basic to abstract proton from the methylene group.
The steric structure of heterocyclic compounds II
was determined using homo- and heteronuclear cor-
relation techniques (COSY, HETCOR). On the basis of
1
13
these data we also assigned signals in the H and C
NMR spectra. Analysis of cross couplings in the
COSY spectra showed that, among the 2α-H, 3α-H,
and 3β-H protons constituting a strongly coupled spin
system, only the former (2α-H, δ 6.45 ppm) is charac-
terized by a clearly defined spin–spin coupling with
protons in the aromatic substituent (δ 7.25 ppm; see
figure). The structure of the synthesized compounds
was also confirmed by the IR and mass spectra and
elemental analyses.
EXPERIMENTAL
The IR spectra were measured from samples dis-
persed in mineral oil on a Specord IR-71 spectrometer.
The NMR spectra were recorded on a Varian Unity-300
spectrometer in CDCl3 using HMDS as internal refer-
ence. The mass spectra (70 eV) were run on a Kratos
instrument with direct sample admission into the ion
source (accelerating voltage 1.75 kV).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

ANTONOV et al.
1000
COMe), 3.45 br.s (4H, CH2CH2), 3.98 s (3H, OMe),
6.4
4.11 s (3H, OMe), 6.95–6.98 d (1H, Harom), 7.29–
7.36 m (5H, Harom), 7.7 s (1H, Harom), 8.6 s (1H, N=CH).
Found, %: C 76.84; H 5.88; N 3.93. C23H21NO3. Cal-
culated, %: C 76.88; H 5.85; N 3.90.
6.6
6.8
7.0
7.2
2-(4-Methoxyphenyl)-2,3,7,8-tetrahydroace-
naphtho[5,6-bc]azepin-4(1H)-one (IIb). Amino
ketone Ia, 0.162 g (0.77 mmol), was dispersed in 1 ml
of ethanol, and 0.104 ml (0.77 mmol) of p-methoxy-
benzaldehyde and 0.4 ml of 30% aqueous sodium
hydroxide were added to the suspension. The mixture
was heated to 50–60°C, kept for 2 h at room tempera-
ture, and cooled, and the precipitate was filtered off.
Yield 76%, orange–red powder, mp 109–110°C. IR
1
spectrum, ν, cm–1: 3420 (NH), 1700 (C=O). H NMR
spectrum, δ, ppm: 3.16 d.d (1H, 3-H, J1 = 16.7, J2 =
2.34 Hz), 3.38 m (4H, 7-H, 8-H), 3.56 d.d (1H, 3-H,
J1 = 16.7, J2 = 11.15 Hz), 3.84 s (3H, OMe), 4.36 br.s
(1H, NH), 4.7–4.76 d (1H, 2-H, J1 = 11.1, J2 = 2.3 Hz),
6.8 d (1H, 10-H, J = 7.4 Hz), 6.93 d (2H, C6H4, J =
8.6 Hz), 7.15 d (1H, 6-H, J = 7.32 Hz), 7.34 d (1H,
5-H, J = 7.34 Hz), 7.35 (2H, C6H4, J = 8.6 Hz), 8.15 d
(1H, 9-H, J = 7.4 Hz). Found, %: C 80.21; H 5.83;
N 4.28. C22H19NO2. Calculated, %: C 80.24; H 5.78;
N 4.26.
7.2
7.0
6.8
6.6
6.4
F2, δ, ppm
1
Fragment of the two-dimensional (COSY) H NMR spec-
trum of compound IIb.
1-[6-(4-Methoxybenzylideneamino)acenaphthen-
5-yl]ethanone (IIIb). Amino ketone I, 0.478 g
(2.27 mmol), was dissolved on heating in 1 ml of etha-
nol, 0.31 ml (2.27 mmol) of p-methoxybenzaldehyde
was added, the mixture was heated for 3–4 min under
reflux and cooled, and the precipitate was filtered off.
Yield 0.608 g (82%), yellow powder, mp 109–110°C
(from EtOH). IR spectrum, ν, cm–1: 1607, 1620 (C=N);
Compounds IIa and IIc were synthesized in
a similar way.
2-Phenyl-2,3,7,8-tetrahydroacenaphtho[5,6-bc]-
azepin-4(1H)-one (IIa). Yield 79%, yellow powder,
mp 176–177°C. IR spectrum, ν, cm–1: 3314 (NH),
1
1
1687 (C=O). H NMR spectrum, δ, ppm: 2.5 s (3H,
1680 (C=O). H NMR spectrum, δ, ppm: 3.2 d.d (1H,
COMe), 3.4 br.s (4H, CH2CH2), 3.9 s (3H, OMe), 6.9–
7.9 (8H, Harom), 8.5 s (1H, N=CH). Found, %: C 80.20;
H 5.81; N 4.27. C22H19NO2. Calculated, %: C 80.24;
H 5.76; N 4.26.
3-H, J1 = 16.75, J2 = 2.3 Hz), 3.42 m (4H, 7-H, 8-H),
3.6 d.d (1H, 3-H, J1 = 16.5, J2 = 11.24 Hz), 4.45 br.s
(1H, NH), 4.8 d.d (1H, 2-H, J1 = 11.1, J2 = 2.4 Hz),
6.84 d (1H, 10-H, J = 7.4 Hz), 7.2 d (1H, 6-H, J =
7.4 Hz), 7.42–7.5 m (6H, Harom), 8.2 d (1H, 9-H, J =
7.4 Hz). Found, %: C 84.30; H 5.64; N 4.70.
C21H17NO. Calculated, %: C 84.28; H 5.69; N 4.68.
Compounds IIIa and IIIc were synthesized in
a similar way.
1-(6-Benzylideneaminoacenaphthen-5-yl)-
ethanone (IIIa). Yield 83%, yellow powder, mp 133–
134°C (from EtOH). IR spectrum: ν(C=O) 1673 cm–1.
1H NMR spectrum, δ, ppm: 2.5 s (3H, COMe), 3.4 br.s
(4H, CH2CH2), 7.22–7.24 d (1H, Harom), 7.3–7.36 m
(3H, Harom), 7.48–7.52 m (3H, Harom), 7.9–7.94 m (2H,
2-(3,4-Dimethoxyphenyl)-2,3,7,8-tetrahydroace-
naphtho[5,6-bc]azepin-4(1H)-one (IIIc). Yield 82%,
orange–red powder, mp 154–155°C. IR spectrum, ν,
1
cm–1: 3354 (NH), 1677 (C=O). H NMR spectrum, δ,
ppm: 3.18 d.d (1H, 3-H, J1 = 16.75, J2 = 2.45 Hz),
3.39 d.m (4H, 7-H, 8-H), 3.57 d.d (1H, 3-H, J1 = 16.7,
J2 = 11.1 Hz), 3.85 s (3H, OMe), 3.9 s (3H, OMe),
4.4 br.s (1H, NH), 4.72 d.d (1H, 2-H, J1 = 11.1, J2 =
2.42 Hz), 6.82 d (1H, 10-H, J = 7.36 Hz), 6.86–7.0 m
(3H, C6H3), 7.14 d (1H, 6-H, J = 7.36 Hz), 7.34 d (1H,
5-H, J = 7.36 Hz), 8.14 d (1H, 9-H, J = 7.36 Hz). Mass
spectrum, m/z (Irel, %): 359 (40) [M]+, 208 (90), 195
H
arom), 8.6 s (1H, N=CH). Found, %: C 84.29; H 5.66;
N 4.71. C21H17NO. Calculated, %: C 84.28; H 5.69;
N 4.68.
1-[6-(3,4-Dimethoxybenzylideneamino)acenaph-
then-5-yl]ethanone (IIIc). Yield 56%, yellow powder,
mp 104–105°C (from EtOH). IR spectrum: ν(C=O)
1
1673 cm–1. H NMR spectrum, δ, ppm: 2.5 s (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

SPECIFIC EXAMPLE OF THE MANNICH REACTION
1001
(90), 180 (15), 166 (50), 164 (100), 151 (35), 149 (40),
139 (20), 121 (15), 91 (15), 77 (20), 65 (10), 43 (10).
Found, %: C 76.86; H 5.82; N 3.7. C23H21NO3. Cal-
culated, %: C 76.88; H 5.85; N 3.4.
ture. The precipitate was filtered off. Yield 0.25 g
(62%), mp 172–173°C.
1-Acetyl-2-phenyl-2,3,7,8-tetrahydroacenaphtho-
[5,6-bc]azepin-4(1H)-one (IId). Yield 51%, pale yel-
low powder, mp 144–145°C. IR spectrum, ν, cm–1:
1-Acetyl-2-(4-methoxyphenyl)-2,3,7,8-tetra-
hydroacenaphtho[5,6-bc]azepin-4(1H)-one (IIe).
a. N-Acetylamino ketone Ib, 0.254 g (1 mmol), was
dispersed in 3 ml of triethyl orthoformate, 0.136 ml
(1 mmol) of p-methoxybenzaldehyde was added, and
0.15 ml of 70% perchloric acid was added dropwise.
The mixture was kept for 3 h at room temperature, the
solvent was evaporated, and the dry residue was dis-
solved in chloroform and subjected to chromatography
on aluminum oxide. Yield 49%, pale yellow powder,
mp 172–173°C. IR spectrum, ν, cm–1: 1687 (C=O),
1
1687 (C=O), 1647 (NC=O). H NMR spectrum, δ,
ppm: 1.65 s (3H, NCOMe), 3.1–3.2 d.d (1H, 3-H, J1 =
13.6, J2 = 6.4 Hz), 3.4–3.6 m (5H, 3-H, 7-H, 8-H),
6.48 d.d (1H, 2-H, J1 = 10.1, J2 = 6.5 Hz), 7.18–7.4 m
(8H, Harom), 8.0 d (1H, Harom). Found, %: C 81.13;
H 5.65; N 4.00. C23H19NO2. Calculated, %: C 80.94;
H 5.57; N 4.11.
1-Acetyl-2-(3,4-dimethoxyphenyl)-2,3,7,8-tetra-
hydroacenaphtho[5,6-bc]azepin-4(1H)-one (IIf).
Yield 59%, pale yellow powder, mp 184–185°C. IR
spectrum, ν, cm–1: 1687 (C=O), 1647 (NCOMe).
1H NMR spectrum, δ, ppm: 2.7 s (3H, NCOMe),
3.25 d.d (1H, 3-H, J1 = 14.2, J2 = 6.5 Hz), 3.4–3.6 m
(5H, 3-H, 7-H, 8-H), 3.75 s (3H, OMe), 3.8 s (3H,
OMe), 6.43 d.d (1H, 2-H, J1 = 9.3, J2 = 6.5 Hz), 6.66 d
(1H, C6H3, J = 8.3 Hz), 6.8 s (1H, C6H3, J = 1.95 Hz),
6.85 d.d (1H, C6H3, J1 = 8.3, J2 = 1.95 Hz), 7.17 d (1H,
6-H, J = 7.3 Hz), 7.26 d (1H, 5-H, J = 7.3 Hz), 7.4 d
(1H, 10-H, J = 7.25 Hz), 8.0 d (1H, 9-H, J = 7.25 Hz).
Found, %: C 75.02; H 5.75; N 3.27. C25H23NO4. Cal-
culated, %: C 74.81; H 5.74; N 3.49.
1
1647 (NC=O). H NMR spectrum, δ, ppm: 1.6 s (3H,
NCOCH3), 3.2 d.d (1H, 3-H, J = 13.7, 6.5 Hz), 3.4–
3.5 m (5H, 3-H, 7-H, 8-H), 3.7 s (3H, OMe), 6.47 d.d
(1H, 2-H, J = 9.9, 6.6 Hz), 6.74 d (2H, C6H4, J =
8.75 Hz), 7.14 d (1H, 10-H, J = 7.25 Hz), 7.24 d (2H,
C6H4, J = 8.75 Hz), 7.29 d (1H, 9-H, J = 7.25 Hz),
7.68 d (1H, 6-H, J = 7.25 Hz), 7.98 d (1H, 5-H, J =
7.25 Hz). 13C NMR spectrum, δC, ppm: 23.0, 30.0,
31.0, 48.0, 55.0, 56.5, 76.5, 77.0, 77.5, 113.6, 119.6,
119.8, 128.4, 130.2, 131.2, 131.6, 132.4, 132.8, 140.0,
146.0, 152.0, 158.5, 170.5, 200.0. Found, %: C 77.86;
H 5.62; N 3.87. C24H21NO3. Calculated, %: C 77.63;
H 5.66; N 3.77.
REFERENCES
Compounds IId and IIf were synthesized in
a similar way.
1. Dokunikhin, N.S. and Vorozhtsov, G.N., Zh. Org. Khim.,
1966, vol. 2, p. 148.
b. A mixture of 0.3 g (1.2 mmol) of N-acetylamino
ketone Ib, 0.16 ml (1.2 mmol) of p-methoxybenzal-
dehyde, 0.6 ml of 30% aqueous sodium hydroxide, and
2 ml of ethanol was stirred for 3 h at room tempera-
2. Mezheritskii, V.V., Pikus, A.L., Minyaeva, L.G., and
Dorofeenko, G.N., Zh. Org. Khim., 1981, vol. 17, p. 998.
3. Mannich, C. and Krosche, W., Arch. Pharm., 1912,
vol. 250, p. 647.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007