Reactions of 2-methylindole with morpholinals of substituted salicylaldehydes

Article abstract of DOI:10.1023/A:1023923226389

Fusion of 2-methylindole with morphinals of substituted salicylaldehydes (in a ratio of 1:1) afforded 3-[(2-hydroxyaryl)morpholinomethyl] -2-methylindoles as normal products of the Mannich reaction. In some cases, the reactions with an excess of 2-methyli

Full text of DOI:10.1023/A:1023923226389

700
Russian Chemical Bulletin, International Edition, Vol. 52, No. 3, pp. 700—704, March, 2003
Reactions of 2ꢀmethylindole
with morpholinals of substituted salicylaldehydes
a
b
L. Yu. Ukhin,a L. V. Belousova, and V. N. Khrustalev
ꢀ
aInstitute of Physical and Organic Chemistry, Rostov State University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863 2) 28 5667. Eꢀmail: may@ipoc.rsu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991, Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: vkh@xrlab.ineos.ac.ru
Fusion of 2ꢀmethylindole with morphinals of substituted salicylaldehydes (in a ratio of 1 : 1)
afforded 3ꢀ[(2ꢀhydroxyaryl)morpholinomethyl]ꢀ2ꢀmethylindoles as normal products of the
Mannich reaction. In some cases, the reactions with an excess of 2ꢀmethylindole resulted in
unusual condensation accompanied by the replacement of the OH group by the morpholino
group to form bis(2ꢀmethylindolꢀ3ꢀyl)(2ꢀmorpholinoaryl)methanes.
Key words: 2ꢀmethylindole, morpholinals of substituted salicylaldehydes, 3ꢀ[(2ꢀhydrꢀ
oxyaryl)morpholinomethyl]ꢀ2ꢀmethylindoles,
aryl)methanes.
bis(2ꢀmethylindolꢀ3ꢀyl)(2ꢀmorpholinoꢀ
Earlier,1 we have reported the synthesis of substituted
proceeds in phenols capable of undergoing the phenolꢀ
quinoid tautomerism.
Mannich bases from aminals of aromatic aldehydes and
2,6ꢀdiꢀtertꢀbutylphenol. The reactions of morpholinals of
substituted salicylaldehydes 1 with 2ꢀmethylindole perꢀ
formed under the same conditions afforded not only the
expected Mannich bases 2 but also, in some cases, unꢀ
usual condensation products 3, whose yields increased
with an excess of 2ꢀmethylindole (Scheme 1).
The condensation resulted in the replacement of the
hydroxy group by the morpholino group. It is known2 that
the replacement of the OH groups by amino groups readily
Aminals, azomethines, and Mannich bases prepared
from salicylaldehyde and its derivatives are characterized
by the presence of intramolecular hydrogen bonds, which
facilitate the proton transfer from the O atom to the
N atom.3 The complete proton transfer to the nitrogen
atom in the aminals under consideration and elimination
of the amine should give rise to оꢀquinomethides. Such
reversible processes can occur in solutions, which has
been confirmed by spectroscopic studies.4,5
Scheme 1
a: R1 = H, R2 = NO2
b: R1 = H, R2 = Cl
c: R1 = R2 = Cl
d: R1 = R2 = Br
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 670—674, March, 2003.
1066ꢀ5285/03/5203ꢀ700 $25.00 © 2003 Plenum Publishing Corporation

Reactions of morpholinals of salicylaldehydes
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
701
Scheme 2
The assumed sequence of the reactions yielding the
final product 3 is shown in Scheme 2. Dissociation of the
Mannich base 2 afforded quinomethide 4. The Cꢀnucleoꢀ
phile present in the equilibrium system can add to comꢀ
pound 4.
mations (the torsion angles are in the ranges of
56.0(4)—61.8(4) and 53.3(4)—61.4(4)°, respectively). The
N(2) and N(3) atoms have pyramidal configurations (the
sums of the bond angles at the N(2) and N(3) atoms are
331.0 and 338.0°, respectively, Table 2). The angle beꢀ
tween the planes of the nitro group and the benzene ring
is 17.4°. The remaining geometric parameters of molecule
1a have standard values.7
The structures of compounds 2a—d and 3c,d were
established based on the data from elemental analysis and
1
IR and H NMR spectroscopy. The structure of aminal
1a synthesized earlier6 was confirmed by Xꢀray diffraction
In the crystal, the molecules are linked through van
der Waals interactions, other short intermolecular conꢀ
tacts being absent (Fig. 2).
analysis.
1
The H NMR spectrum of compound 3d differs from
the spectrum of compound 3c in that it has not only the
major signals for the methylene protons of the morpholine
fragment (triplets at δ 2.93 and 3.74) but also contains
minor signals with identical spinꢀspin coupling constants
(triplets at δ 3.26 and 3.66) (Table 1). This fact is most
probably accounted for by the presence of a minor conꢀ
former (∼15%) in a solution of 3d.
Experimental
The IR spectra were measured on a Specord IRꢀ75 instruꢀ
1
ment in Nujol mulls. The H NMR spectra were recorded on a
Varian UNITYꢀ300 spectrometer.
Synthesis of compound 1a has been described earlier.6 Comꢀ
pounds 1b—d were prepared according to a modified method.2
(5ꢀChloroꢀ2ꢀhydroxyphenyl)dimorpholinomethane (1b).
5ꢀChlorosalicylaldehyde (6 g, 38 mmol) was dissolved in PriOH
(15 mL) with heating and morpholine (7 mL, 80 mmol) was
added. The reaction mixture was heated to boiling and then
cooled to ∼20 °C, after which light petroleum (10 mL) was
added, a crystal seed of the aminal was introduced, and the
reaction mixture was triturated with a rod on cooling in ice. The
precipitate that formed was filtered off, washed with light petroꢀ
leum, dried, and used in the syntheses without additional purifiꢀ
cation. After recrystallization from PriOH, the yield of 1b was
8 g (66%), colorless crystals, m.p. 110—115 °C. Found (%):
C, 57.23; H, 7.18; N, 8.56; Cl, 11.64. C15H21ClN2O3. Calcuꢀ
lated (%): C, 57.60; H, 6.77; N, 8.96; Cl, 11.33.
1
The H NMR spectrum of compound 2d, unlike that
of compound 2c, also has additional signals for the methꢀ
ylene protons of the morpholine fragment (δ 3.21 and
3.97), although their intensities are much lower than those
in the spectrum of 3d.
Xꢀray diffraction study of compound 1a 6 (Fig. 1) reꢀ
vealed the presence of a strong O(1)—H(10)…...N(2) inꢀ
tramolecular hydrogen bond (O…...…N, 2.601(3) Å;
H...…N; 1.686(3) Å; O—H...…N angle, 155(2)°). As a
result, the valent bonds of the N(2) atom are somewhat
longer than the corresponding bonds of the N(3) atom
(Table 2). The morpholine rings adopt chair conforꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
Ukhin et al.
Table 1. Spectroscopic parameters of compounds 2a—d and 3c,d
Comꢀ
pound
IR, ν/cm–1
(Nujol mulls)
1H NMR
(CDCl3, δ, J/Hz)
2a
2b
3380, 3326, 3300 (OH, NH);
1714 (w); 1614, 1548, 1514,
2.48 (s+t, 7 H, CH3+CH2N); 3.65 (t, 4 H, CH2O, J = 4.5); 5.12 (s, 1 H, CH);
6.84 (d, 1 H, C(3´)H, J = 9.0); 6.80—7.00 (m, 2 H, C(5)H+C(6)H);
1487 (arom.), 1580, 1341 (NO2) 7.20 (d, 1 H, C(4)H, J = 7.8); 7.56 (d, 1 H, C(7)H, J = 7.7); 7.88 (dd, 1 H,
C(4´)H, 3J = 9.0, 4J = 2.85); 8.22 (d, 1 H, C(6´)H, J = 2.85); 10.86 (s, 1 H, OH);
12.58 (s, 1 H, NH).
3380, 3313, 3287 sh (OH,
2.47 (s, 3 H, CH3), 2.56 (m, 4 Н, CH2N); 3.74 (m, 4 H, CH2O);
NH), 1607, 1581, 1554 (arom.), 5.03 (s, 1 H, CH); 6.78 (d, 1 H, C(3´)H, J = 8.7); 6.85 (d, 1 H, C(6´)H, J = 2.6);
1107 (C—O—C)
7.04 (dd, 1 H, C(4´)H, 3J = 8.7, 4J = 2.6); 7.11 (m, 2 H, C(5)H+C(6)H);
7.27 (d, 1 H, C(4)H, J = 7.9); 7.57 (d, 1 H, C(7)H, J = 7.9); 8.00 (s, 1 H, NH);
12.77 (s, 1 H, OH)
2c
2d
3313 (OH, NH), 1594, 1561,
1547 (arom.), 1114 (C—O—C)
2.44 (s, 3 H, CH3); 2.60 (m, 4 Н, CH2N); 3.80 (m, 4 H, CH2O);
5.10 (s, 1 H, CH); 6.77 (d, 1 H, C(6´)H, J = 2.4); 7.00—7.15 (m, 2 H,
C(5)H+C(6)H); 7.20 (d, 1 H, C(4´)H, J = 2.4); 7.28 (d, 1 H, C(4)H, J = 7.9);
7.49 (d, 1 H, C(7)H, J = 7.9); 8.00 (s, 1 H, NH); 14.00 (s, 1 H, OH)
2.46 (s, 3 H, CH3); 2.59 (m, 4 Н, CH2N); 3.75 (m, 4 H, CH2O);
5.08 (s, 1 H, CH); 6.95 (d, 1 H, C(6´)H, J = 1.5); 7.00—7.16 (m, 2 H,
C(5)H+C(6)H); 7.28 (d, 1 H, C(4)H, J = 8.0); 7.49 (two d, 1 H each, C(7)H+С(4´)H);
8.03 (s, 1 H, NH); 14.15 (s, 1 H, OH)
3319 (OH, NH); 1594, 1567,
1554 (arom.), 1114 (C—O—C)
3с
3d
3447, 3393 (NH), 1634, 1621,
1581, 1557 (arom.), 1114
(C—O—C)
3447, 3400 (NH); 1641, 1621,
1574, 1560 (arom.);
2.07 (s, 6 H, CH3); 2.83 (t, 4 Н, CH2N, J = 4.7); 3.65 (t, 4 H, CH2O, J = 4.7);
6.07 (s, 1 H, CH); 6.85—7.25 (m, 10 H, CHarom); 7.80 (s, 2 H, NH)
2.06 (s, 6 H, CH3); 2.93 (t, 3.4 Н, CH2N, J = 4.7); 3.26 (t, 0.6 H, CH2N, J = 4.7);
3.66 (t, 0.6 H, CH2O, J = 4.7); 3.74 (t, 3.4 H, CH2O, J = 4.7);
1114 (C—O—C)
6.05 (s, 1 H, CH); 6.85—7.10 (m, 6 H, CHarom); 7.11 (d, 1 H, C(6´)H, J = 2.3);
7.25 (d, 2 H, C(7)H, J = 8.0); 7.53 (d, 1 H, C(4´)H, J = 2.3); 7.81 (s, 2 H, NH)
C(14)
O(5)
C(15)
C(13)
N(3)
O(3)
C(12)
C(7)
N(1)
C(5)
C(11)
C(6)
N(2)
O(2)
C(4)
C(3)
C(10)
O(4)
C(8)
C(1)
C(2)
C(9)
O(1)
Fig. 1. Molecular structure of compound 1a with 30% probability ellipsoids; a hydrogen bond is indicated by a dashed line.

Reactions of morpholinals of salicylaldehydes
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
703
Table 2. Bond lengths (d) and bond angles (ω) in compound 1a
Bond
d/Å
Bond
d/Å
Angle
ω/deg
Angle
ω/deg
O(1)—C(1)
O(2)—N(1)
O(3)—N(1)
O(4)—C(9)
O(4)—C(10) 1.422(4)
O(5)—C(13) 1.420(4)
O(5)—C(14) 1.421(4)
N(1)—C(4)
N(2)—C(11) 1.472(4)
N(2)—C(7)
N(2)—C(8)
N(3)—C(7)
1.349(4)
1.237(3)
1.228(3)
1.418(4)
N(3)—C(12) 1.465(4)
C(9)—O(4)—C(10) 108.3(3)
C(13)—O(5)—C(14) 109.0(3)
C(5)—C(4)—N(1)
C(3)—C(4)—N(1)
C(4)—C(5)—C(6)
C(5)—C(6)—C(1)
C(5)—C(6)—C(7)
C(1)—C(6)—C(7)
N(3)—C(7)—N(2)
N(3)—C(7)—C(6)
N(2)—C(7)—C(6)
N(2)—C(8)—C(9)
O(4)—C(9)—C(8)
O(4)—C(10)—C(11) 112.4(3)
N(2)—C(11)—C(10) 109.5(3)
N(3)—C(12)—C(13) 109.6(3)
O(5)—C(13)—C(12) 110.9(3)
O(5)—C(14)—C(15) 111.9(3)
N(3)—C(15)—C(14) 110.4(3)
118.5(3)
119.5(3)
120.3(3)
118.0(3)
120.2(3)
121.6(3)
110.6(2)
113.6(2)
109.1(2)
109.6(3)
110.7(3)
C(1)—C(2)
C(1)—C(6)
C(2)—C(3)
C(3)—C(4)
C(4)—C(5)
C(5)—C(6)
C(6)—C(7)
C(8)—C(9)
1.392(4)
1.414(4)
1.372(4)
1.384(4)
1.380(4)
1.383(4)
1.528(4)
1.504(4)
O(3)—N(1)—O(2)
O(3)—N(1)—C(4)
O(2)—N(1)—C(4)
123.5(3)
118.9(3)
117.7(3)
C(11)—N(2)—C(7) 113.6(2)
C(11)—N(2)—C(8) 108.0(2)
1.460(4)
C(7)—N(2)—C(8)
109.4(2)
C(7)—N(3)—C(15) 112.1(2)
C(7)—N(3)—C(12) 115.2(2)
C(15)—N(3)—C(12) 110.7(2)
1.478(3)
1.485(4)
1.463(4)
C(10)—C(11) 1.513(4)
C(12)—C(13) 1.504(5)
C(14)—C(15) 1.500(4)
O(1)—C(1)—C(2)
O(1)—C(1)—C(6)
C(2)—C(1)—C(6)
C(3)—C(2)—C(1)
C(2)—C(3)—C(4)
C(5)—C(4)—C(3)
118.3(3)
121.5(3)
120.2(3)
121.0(3)
118.2(3)
122.0(3)
N(3)—C(15) 1.463(4)
Compounds 1c,d were prepared analogously.
H, 4.28; N, 6.13; Br, 37.07. C15H20Br2N2O3. Calculated (%):
C, 41.31; H, 4.62; N, 6.42; Br, 36.64.
(3,5ꢀDichloroꢀ2ꢀhydroxyphenyl)dimorpholinomethane (1c),
the yield was 85%, m.p. 140—145 °C. Found (%): C, 51.46;
H, 6.21; N, 7.92; Cl, 20.68. C15H20Cl2N2O3. Calculated (%):
C, 51.88; H, 5.81; N, 8.07; Cl, 20.42.
(3,5ꢀDibromoꢀ2ꢀhydroxyphenyl)dimorpholinomethane (1d),
the yield was 80%, m.p. 135—140 °C. Found (%): C, 40.92;
3ꢀ[(2ꢀHydroxyꢀ5ꢀnitrophenyl)morpholinomethyl]ꢀ2ꢀmethylꢀ
indole (2a). A mixture of morpholinal 1a 6 (3.2 g, 10 mmol) and
2ꢀmethylindole (1.4 g, 11 mmol) was ground in a mortar, fused
at 140 °C, and cooled to ∼20 °C. Then CH3CN (10 mL) was
added and the mixture was triturated with a rod on cooling in
a
0
c
Fig. 2. Crystal packing of molecules 1a along the y axis; the hydrogen bonds are shown by dashed lines.

704
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 3, March, 2003
Ukhin et al.
ice. The precipitate that formed was filtered off, washed with
cold MeCN and EtOH, and dried. Compound 2a was obtained
in a yield of 2.74 g (75%) as colorless crystals with m.p.
220—225 °C (decomp.) (from MeNO2). Found (%): C, 65.19;
H, 5.84; N, 11.63. C20H21N3O4. Calculated (%): C, 65.38;
H, 5.76; N, 11.44.
3ꢀ[(5ꢀChloroꢀ2ꢀhydroxyphenyl)morpholinomethyl]ꢀ2ꢀmethylꢀ
indole (2b). A mixture of morpholinal 1b (1.25 g, 4 mmol) and
2ꢀmethylindole (0.7 g, 5 mmol) was ground in a mortar, fused at
150 °C, and cooled to ∼20 °C. Then MeOH (20 mL) was added.
The reaction mixture was triturated with a rod on refluxing and
cooled in ice. The precipitate that formed was filtered off, washed
with MeOH and hexane, and dried. The yield of the crude
product was 0.62 g. The product was recrystallized from MeNO2
and washed on a filter with MeOH and hexane. Compound 2b
was obtained in a yield of 0.45 g (31.7%) as colorless crystals
with m.p. 207—211 °C. Found (%): C, 67.15; H, 6.21; N, 7.79;
Cl, 10.13. C20H21ClN2O2. Calculated (%): C, 67.32; H, 5.93;
N, 7.85; Cl, 9.93.
3ꢀ[(5ꢀDichloroꢀ2ꢀhydroxyphenyl)morpholinomethyl]ꢀ2ꢀ
methylindole (2c). A mixture of morpholinal 1c (0.5 g, 1.3 mmol)
and 2ꢀmethylindole (0.2 g, 1.5 mmol) was fused at 135 °C and
cooled to ∼20 °C. Then MeOH (2.5 mL) was added and the
reaction mixture was triturated with a rod on refluxing. Crystalꢀ
lization started from the boiling solution. The reaction mixture
was cooled in ice. The precipitate that formed was filtered off,
washed with cold MeOH and light petroleum, and dried. The
yield was 0.24 g (43%), m.p. 203—206 °C (from MeNO2). Found
(%): C, 60.98; H, 5.36; N, 7.23; Cl, 17.87. C20H20Cl2N2O2.
Calculated (%): C, 61.39; H, 5.15; N, 7.16; Cl, 18.12.
Xꢀray diffraction study of morpholinal 1a. The crystals of 1a
(C15H21N3O5, M = 323.35) are monoclinic, space group Р21/n,
at 293 К: a = 10.652(2), b = 10.598(2), c = 13.658(3) Å,
β = 95.70(3)°, V = 1534.2(5) Å, Z = 4, dcalc = 1.400 mg cm–3
,
F(000) = 688, µ = 0.106 mm–1. The unit cell parameters and
intensities of 2741 reflections were measured on an automated
fourꢀcircle Siemens Р3/РC diffractometer (293 K, λꢀMoꢀKα
radiation, graphite monochromator, θ/2θ scan technique,
θ
= 25°). The structure was solved by direct methods and
max
refined by the fullꢀmatrix leastꢀsquares method with anisotropic
thermal parameters for nonhydrogen atoms. The hydrogen atꢀ
oms were located from difference Fourier syntheses and refined
isotropically. The final reliability factors were as follows:
R1 = 0.0553 for 1456 independent reflections with I > 2σ(I ) and
wR2 = 0.1039 for all 2589 independent reflections. All calculaꢀ
tions were carried out with the use of the SHELXTL PLUS
program package (Version 5.10).8
The tables of the atomic coordinates, bond lengths, bond
angles, torsion angles, and anisotropic thermal parameters for
compound 1a were deposited with the Cambridge Structural
Database.
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos. 00ꢀ03ꢀ32807
and 00ꢀ15ꢀ97359).
References
1. V. N. Komissarov and L. Yu. Ukhin, Zh. Org. Khim., 1989,
25, 2594 [J. Org. Chem. USSR, 1989, 25 (Engl. Transl.)].
2. WeygandꢀHilgetag, OrganischꢀChemische Experimentirkunst,
Johann Ambrosius Barth Verlag, Leipzig, 1964.
3. R. P. Bell, The Proton in Chemistry, Chapman and Hall, 1972,
London.
3ꢀ[(5ꢀDibromoꢀ2ꢀhydroxyphenyl)morpholinomethyl]ꢀ2ꢀ
methylindole (2d) was prepared analogously to compound 2c
(a mixture of morpholinal 1d (1.32 g, 3 mmol) and 2ꢀmethylꢀ
indole (0.45 g, 3 mmol) was fused at 165 °C). The yield
was 0.65
MeNO2). Found (%): C, 49.78; H, 4.52; N, 5.69; Br, 33.58.
20H20Br2N2O2. Calculated (%): C, 50.02; H, 4.20; N, 5.83;
Br, 33.28.
(3,5ꢀDichloroꢀ2ꢀmorpholinophenyl)ꢀbis(2ꢀmethylindolꢀ3ꢀ
yl)methane (3c). A mixture of morpholinal 1c (1.75 g, 5 mmol)
and 2ꢀmethylindole (1.5 g, 12 mmol) was ground in a mortar
and fused at 155 °C. The product was isolated analogously to
compound 2c. The yield was 1.3 g (51%), m.p. 175—185 °C
(from toluene). Found (%): C, 68.73; H, 5.57; N, 8.21; Cl, 14.43.
C29H27Cl2N3O. Calculated (%): C, 69.05; H, 5.39; N, 8.33;
Cl, 14.05.
g (45%), m.p. 214—216 °C (decomp.) (from
4. V. N. Komissarov, V. A. Kharlanov, L. Yu. Ukhin, E. Yu.
Bulgarevich, and V. I. Minkin, Zh. Org. Khim., 1992, 28, 512
[Russ. J. Org. Chem., 1992, 28 (Engl. Transl.)].
C
5. V. N. Komissarov, L. Yu. Ukhin, V. A. Kharlanov, V. A.
Lokshin, E. Yu. Bulgarevich, V. I. Minkin, O. S. Filipenko,
M. A. Novozhilova, S. M. Aldoshin, and L. O. Atovmyan,
Izv. Akad. Nauk, Ser. Khim., 1992, 2389 [Bull. Russ. Acad.
Sci., Div. Chem. Sci., 1992, 41, 1875 (Engl. Transl.)].
6. L. Yu. Ukhin, V. N. Komissarov, S. V. Lindeman, V. N.
Khrustalev, and Yu. T. Struchkov, Izv. Akad. Nauk, Ser.
Khim., 994, 455 [Russ. Chem. Bull., 1994, 43, 413 (Engl.
Transl.)].
(3,5ꢀDibromoꢀ2ꢀmorpholinophenyl)ꢀbisꢀ3ꢀ(2ꢀmethylindolꢀ3ꢀ
yl)methane (3d) was prepared analogously to compound 3c from
morpholinal 1d (5 mmol) and 2ꢀmethylindole (1.5 g, 12 mmol).
The yield was 1.5 g (50%), m.p. 165—172 °C (from toluꢀ
ene). Found (%): C, 58.50; H, 4.83; N, 6.84; Br, 27.19.
C29H27Br2N3O. Calculated (%): C, 58.70; H, 4.59; N, 7.08;
Br, 26.93.
7. Cambridge Crystallographic Database, Release 2002, Camꢀ
bridge.
8. G. M. Sheldrick, SHELXTL, V5.10, Bruker AXS Inc., Madiꢀ
son, WIꢀ53719, USA, 1997.
Received April 23, 2002;
in revised form October 14, 2002