Epoxymethylation of 2-Acyl-Substituted NH Heterocycles and Transformations of the Epoxymethylation Products

Article abstract of DOI:10.1134/S1070428020100012

Abstract: A new procedure has been proposed for the synthesis of previously unknown pyrrolo- and indolo-1,4-epoxy[1,4]oxazepines by epoxymethylation of 2-benzoyl-1H-pyrrole and 2-benzoyl-1H-indoles with epichlorohydrin. Some transformations of the epoxyme

Full text of DOI:10.1134/S1070428020100012

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 10, pp. 1677–1684. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 10, pp. 1485–1494.
Epoxymethylation of 2-Acyl-Substituted NH Heterocycles
and Transformations of the Epoxymethylation Products
A. O. Kharanekoa,*, T. M. Pekhterevaa, and O. I. Kharanekoa
a Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
Donetsk, 83114 Ukraine
*e-mail: antonhar08@rambler.ru
Received July 13, 2020; revised July 26, 2020; accepted July 28, 2020
Abstract—A new procedure has been proposed for the synthesis of previously unknown pyrrolo- and indolo-
1,4-epoxy[1,4]oxazepines by epoxymethylation of 2-benzoyl-1H-pyrrole and 2-benzoyl-1H-indoles with
epichlorohydrin. Some transformations of the epoxymethylation products have been studied.
Keywords: epoxymethylation, 1-phenyl-4,5-dihydro-1H,3H-1,4-epoxy[1,4]oxazepino[4,3-a]benzimidazole,
7,8,9-trimethyl-1-phenyl-4,5-dihydro-1H,3H-1,4-epoxypyrrolo[2,1-c][1,4]oxazepine, phenyl[3,4,5-trimethyl-1-
(oxiran-2-ylmethyl)-1H-pyrrol-2-yl]methanone, 11-methyl-1-phenyl-4,5-dihydro-1H,3H-1,4-epoxy[1,4]oxa-
zepino[4,3-a]indole, 6-methyl-9-(oxiran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one, 9-[2-hydroxy-3-
(piperidin-1-yl)propyl]-2,3,4,9-tetrahydro-1H-carbazol-1-one
DOI: 10.1134/S1070428020100012
1-Phenyl-4,5-dihydro-1H,3H-1,4-epoxy[1,4]ox-
azepino[4,3-a]benzimidazole (2) is known as the drug
oxapadol [1] exhibiting diuretic, sedative, antiulcer,
analgesic, anti-inflammatory, cardiac, and analeptic
properties. It was synthesized [1] in 50% yield by reac-
tion of 2-benzoyl-1H-benzimidazole (1) sodium salt
with an equimolar amount of epichlorohydrin
[2-(chloromethyl)oxirane] in anhydrous ethanol
(Scheme 1). It can be anticipated that epoxymethylation
of 2-acyl-substituted NH-heterocycles such as pyrrole
and indole will produce structurally related compounds
of pharmacological interest.
methylation of 2-benzoyl-3,4,5-trimethyl-1H-pyrrole
(3) according to the same procedure led to the forma-
tion of two products (Scheme 2), 7,8,9-trimethyl-1-
phenyl-4,5-dihydro-1H,3H-1,4-epoxypyrrolo[2,1-c]-
[1,4]oxazepine (4) and phenyl[3,4,5-trimethyl-1-
(oxiran-2-ylmethyl)-1H-pyrrol-2-yl]methanone (5).
Compounds 4 and 5 had very similar 1H NMR spec-
tra with the difference that the aromatic proton signals
of 4 resonated as two multiplets at δ 7.33–7.40 (3H)
and 7.55–7.62 ppm (2H) and the OCH signal was
located at δ 4.95–5.02 ppm (m), whereas the OCH
signal of 5 was observed at δ 3.61–3.7 ppm (m). The
13C NMR spectrum of 4 lacked carbonyl carbon signal
(δC 186.1 ppm in the spectrum of 5), but there was
a signal at δC 103.9 ppm which was assigned to the
acetal carbon atom (C1).
The present work was aimed at improving the
procedure for the synthesis of oxapadol (2) and utilize
it in the preparation of epoxy-1,4-oxazepines fused to
pyrrole and indole. Benzimidazole 1 was found to react
with 10 equiv of epichlorohydrin in the presence of
2 equiv of potassium hydroxide and a catalytic amount
of 18-crown-6 at 40°C (1 h) to give 63% of 2. Epoxy-
Scheme 3 shows the results of epoxymethylation of
three substituted indoles 6a–6c. The reaction of
(3-methyl-1H-indol-2-yl)(phenyl)methanone (6a) with
Scheme 1.
Ph
O
Ph
O
Ph
O
N
N
N
N
N
O
+
+
Cl
N
H
O
O
1
2
2a
1677

KHARANEKO et al.
1678
Scheme 2.
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
O
Ph
O
Ph
O
O
+
+
Cl
N
H
N
N
O
O
3
4
5
Scheme 3.
R2
R2
R2
10
R3
R3
R3
R1
11
R1
O
R1
O
1
O
+
+
6
Cl
O
N
H
N
N
O
7
4
O
6a–6c
7a, 7b
8a–8c
R1 = Ph, R2 = Me, R3 = H (a); R1 = Ph, R2 = CH2C(O)OEt, R3 = H (b); R1R2 = (CH2)3, R3 = Me (c).
epichlorohydrin gave 11-methyl-1-phenyl-4,5-dihydro-
1H,3H-1,4-epoxy[1,4]oxazepino[4,3-a]indole (7a)
which was isolated as colorless crystals in 49% yield.
The residue obtained after isolation of 7a was a yellow
non-crystallizable resin containing [3-methyl-1-
(oxiran-2-ylmethyl)-1H-indol-2-yl](phenyl)methanone
(8a) which was not isolated in pure form. The structure
of 7a was confirmed by two-dimensional homonuclear
COSY and NOESY experiments. The COSY spectrum
of 7a showed cross-peaks with similar intensities
between the C4H proton and protons of the C3H2 and
C5H2 groups, as well as cross-peaks between the ortho
protons and meta and para protons of the phenyl ring
and between 7-H, 8-H, 9-H, and 10-H (indole frag-
ment). The NOESY spectrum of 7a showed cross-peaks
C5H2/C7H, C4H/C3H2, C4H/C5H2, and 11-CH3/1-C6H5.
the cyclization of glycidyl phenyl ether with acetyl-
acetone.
The yields of oxazepines 2, 7a, and 7b were almost
equal to those of glycidyl derivatives 2a, 8a, and 8b,
which suggests equal probabilities of the attack of
alkoxide ion on the carbonyl and C–Cl carbon atoms.
Exceptions were carbazolone 6c and pyrrole 3. The
yield of epoxyoxazepine 4 from pyrrole 3 was quite
low, which may be rationalized by weak polarization of
the C=O bond in 4 and hence reduced probability of
nucleophilic attack on the carbonyl carbon atom. In the
1H NMR spectrum of 3, the ortho protons of the
benzoyl group resonated as a doublet at δ 7.56 ppm
located near the meta- and para-proton signals,
whereas the signal of the ortho protons of the benzoyl
group of benzimidazole 1 and indoles 6a and 6b
appeared as a doublet in the region δ 8.0–8.2 ppm.
These findings cannot be regarded as an unambiguous
proof that benzoyl rather than phenyl substituent is
present in molecule 3. On the other hand, the 13C NMR
spectrum 3 contained a signal at δC 185.9 ppm, which
unambiguously corresponds to carbonyl carbon atom.
These data also confirm weak polarization of the
carbonyl group in 3.
Ethyl 2-(2-benzoyl-1H-indol-3-yl)acetate (6b)
reacted with epichlorohydrin to give ethyl 2-(1-phenyl-
4,5-dihydro-1H,3H-1,4-epoxy[1,4]oxazepino[4,3-a]-
indol-11-yl)acetate (7b) and ethyl 2-[2-benzoyl-1-
(oxiran-2-ylmethyl)-1H-indol-3-yl]acetate (8b) at
a ratio of ~1:1 with an overall yield of 82%. The
epoxymethylation of 6-methyl-2,3,4,9-tetrahydro-1H-
carbazol-1-one (6c) afforded 6-methyl-9-(oxyran-2-yl-
methyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (8c) as
the only product (yield 86%). In this case, no expected
1,4-epoxy[1,4]oxazepine derivative was obtained,
presumably because of rigid structure of the carbonyl-
containing fragment.
The overall yields of oxazepines and oxiranes in the
above epoxymethylation reactions were fairly high but
not quantitative. This may be related to side reaction of
the oxirane with the azolate anion present in the reac-
tion mixture, which leads to the formation of dimeric
product according to Scheme 5.
Scheme 4 shows a plausible mechanism of the
epoxymethylation of compounds 1, 3, 6a, 6b, and 6c.
A similar mechanism was proposed previously [2] for
Getautis et al. [3] studied epoxymethylation of
salicylaldehyde with excess epichlorohydrin in the
presence of benzyl(triethyl)ammonium chloride
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

EPOXYMETHYLATION OF 2-ACYL-SUBSTITUTED NH HETEROCYCLES
1679
Scheme 4.
O
Me
Me
Me
Me
Me
Me
R
O
R
O
O
Cl
X
X
N
X
N
–H+
N
H
a
R
O–
b
Cl
Me
Me
R
X
N
Me
Me
R
X
N
O–
O
O
–Cl–
O
Cl
Me
Me
O
X
N
R
O
–Cl–
(BTEAC). It was found that the reaction was complete
in 10 min with quantitative yield. When the reaction
mixture was further heated for 60 h, the glycidyl
derivative was quantitatively converted to 3,4-dihydro-
2H,6H-3,6-epoxy-1,5-benzodioxocine. In this reaction,
an interesting role is played by BTEAC as catalyst. We
believe that the benzodioxocine derivative is formed
according to the mechanism outlined in Scheme 6.
Scheme 5.
O–
OH
R
O
R
O
H2O
N
N
+
–OH–
N
O
N
O
N
N
R
R
O
O
R
R
O
Scheme 6.
–O
O
O
O
O
O
Cl
O
Cl
H
H
H
–H+
OH
O
Cl
Cl
O
OH
O–
BTEA+
BTEA+
O
BTEAC
O–
BTEAC
–BTEAC
–BTEAC
Cl
Cl
Cl
Cl
O
O
O
H
OH
Cl
O
O
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

KHARANEKO et al.
1680
Scheme 7.
Me
Me
Me
Ph
O
BTEAC
MeCN/H2O
BTEAC
MeCN/H2O
5
N
4
HO
HO
9
Scheme 8.
Me
Ph
H2O/H3PO4
N
O
7a
HO
OH
10
Me
Me
Me
O
N
N NH
N
N
OH
Me
Me
Me
12
H2O/H3PO4
O
N
8c
Me
HO
OH
O
NH
N
11
N
OH
13
We tried to obtain oxazepine 4 from oxirane 5 in
a similar way. When oxirane 5 was heated in aceto-
nitrile in the presence of BTEAC for 10 h, we isolated
[1-(2,3-dihydroxypropyl)-3,4,5-trimethyl-1H-pyrrol-2-
yl](phenyl)methanone (9) (Scheme 7); i.e., the reaction
involved common hydrolysis of the oxirane ring with
water remaining in acetonitrile after standard purifica-
tion. In an attempt to synthesize pyrrole 9 via addition
of water to oxirane 5 in the presence of H3PO4 as
catalyst, the reaction was accompanied by deben-
zoylation of 5.
of epoxy-1,4-oxazepine derivatives fused to both benz-
imidazole and pyrrole or indole fragments. Exceptions
are derivatives of carbazolone.
The other reaction products, N-glycidyl derivatives,
are equally interesting. Oxiranes are known to react
with water, phenols, primary and secondary amines,
alcohols, and NH-heterocycles. Biological screening of
such compounds revealed their CNS activity [4].
Scheme 8 shows some reactions of compounds 7a and
8c involving the oxirane ring.
By heating oxirane 8c with 3,5-dimethyl-1H-pyr-
azole or piperidine in 2-ethoxyethanol (Strukov reac-
tion) we obtained 9-[3-(3,5-dimethyl-1H-pyrazol-1-
Thus, epoxymethylation of 2-acyl-saubstituted NH-
heterocycles provides a convenient method of synthesis
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

EPOXYMETHYLATION OF 2-ACYL-SUBSTITUTED NH HETEROCYCLES
1681
Scheme 9.
NHNH2
NHNH2
O
O
O
NH
N
H+/H2O
N2H4·H2O
H+
Ph
O
Ph
O
7b
–H2O
N
O
N
N
Ph
HO
HO
OH
OH
14
15
16
yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-1H-carbazol-
1-one (12) and 9-[2-hydroxy-3-(piperidin-1-yl)propyl]-
2,3,4,9-tetrahydro-1H-carbazol-1-one (13). Acid hy-
drolysis of 8c in dioxane in the presence of phosphoric
acid gave 9-(2,3-dihydropropyl)-2,3,4,9-tetrahydro-
1H-carbazol-1-one (11) as a result of opening of the
oxirane ring. [1-(2,3-Dihydropropyl)-3-methyl-1H-in-
dol-2-yl](phenyl)methanone (10) was synthesized in
a similar way from compound 7a. Thus, oxazepine 7a
can be regarded as a latent form of oxirane 8a. How-
ever, oxazepines 2, 4, 7a, and 7b failed to react with
phenols, primary and secondary amines, alcohols, and
NH-heterocycles, in contrast to oxiranes 2a, 5, and 8a–
8c. The reaction of oxazepine 7b with hydrazine
hydrate under reflux involved the ester group rather
than oxazepine ring, and the product was 2-(1-phenyl-
4,5-dihydro-1H,3H-1,4-epoxy[1,4]oxazepino[4,3-a]-
indol-11-yl)acetoxyhydrazide (14) (Scheme 9). It
should be noted that no reaction occurred when com-
pound 7b was heated with excess hydrazine hydrate in
methanol.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
a Bruker Avance II spectrometer at 400 and 100 MHz,
respectively, using DMSO-d6 as solvent and tetra-
methylsilane as internal standard. The melting points
were measured on a Boetius hot stage and are un-
corrected.
Oxazepines 2, 4, 7a, and 7b (general procedure).
A mixture of 25 mmol of benzoyl derivative 1, 3, 6a,
6b, or 6c, 250 mmol of epichlorohydrin, 2.8 g of
potassium carbonate, 50 mmol of potassium hydroxide,
and 5 mol % of 18-crown-6 was vigorously stirred at
40°C for 2 (with compound 1), 6 (3), or 4 h (6a–6c).
The inorganic precipitate was filtered off and washed
with 10 mL of epichlorohydrin, and epichlorohydrin
was removed from the filtrate under reduced pressure
(first, using a water-jet pump and then under high
vacuum) to leave a crude product.
1-Phenyl-4,5-dihydro-1H,3H-1,4-epoxy[1,4]-
oxazepino[4,3-a]benzimidazole (2). The crude prod-
uct was recrystallized from propan-2-ol. Yield 63%,
Compound 14 in acidic aqueous medium was
presumed to undergo oxazepine ring opening to give
indole 15. The latter can be regarded as a 1,5-dicarbonyl
compound which, by analogy with the data of [5],
could be converted to diazepinone derivative,
10-(2,3-dihydroxypropyl)-1-phenyl-5,10-dihydro[1,2]-
diazepino[4,5-b]indol-4(3H)-one (16). However, from
the reaction mixture we isolated a yellow non-crystal-
1
colorless crystals, mp 149–150°C. H NMR spectrum,
δ, ppm: 4.12 d.d (1H, CH2O, J = 8.0, 1.6 Hz), 4.28 t
(1H, CH2O, J = 6.4 Hz), 4.33 d (1H, CH2N, J =
12.0 Hz), 4.53 d.d (1H, CH2N, J = 12.0, 3.2 Hz), 5.33–
5.41 m (1H, CH), 7.20 t (1H, Harom, J = 7.2 Hz), 7.27 t
(1H, Harom, J = 7.2 Hz), 7.41–7.51 m (4H, Harom),
7.55 d (1H, Harom, J = 8.0 Hz), 7.71–7.81 m (2H,
1
lizable resin whose H NMR spectrum did not corre-
H
arom). 13C NMR spectrum, δC, ppm: 47.5 (CH2), 67.9
spond to structure 16. Presumably, it was a dimerization
product.
(CH2), 71.7 (CH), 103.4, 109.6 (CH), 119.6 (CH),
121.7 (CH), 122.6 (CH), 126.9 (2C, CH), 127.3
(2C, CH), 128.8 (CH), 133.8, 134.6, 141.7, 150.1.
Found, %: C 73.36; H 5.10; N 10.05; O 11.49.
C17H14N2O2. Calculated, %: C 73.37; H 5.07; N 10.07;
O 11.50. M 278.31.
Thus, the epoxymethylation reaction considered in
this work is an important tool for the synthesis of not
only epoxy-1,4-oxazepine derivatives but also N-glyci-
dyl-substituted nitrogen heterocycles which can be
used as starting materials in the synthesis of potentially
biologically active compounds.
7,8,9-Trimethyl-1-phenyl-4,5-dihydro-1H,3H-
1,4-epoxypyrrolo[2,1-c][1,4]oxazepine (4). The crude
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

KHARANEKO et al.
1682
product was mixed with 70 mL of heptane, the solution
was heated to the boiling point, 6 g of silica gel was
added, and the mixture was refluxed for 10 min with
stirring and transferred while hot to a Soxhlet extractor.
After 30-min extraction, the solvent was removed by
half, the flask was cooled to room temperature, and the
precipitate was filtered off and washed with heptane.
Yield 10%, colorless crystals, mp 131–132°C.
1H NMR spectrum, δ, ppm: 1.04 s (3H, CH3), 1.76 s
(3H, CH3), 2.07 s (3H, CH3), 3.78 d (1H, CH2, J =
12.0 Hz), 3.87 d.d (1H, CH2, J = 7.6, 1.2 Hz), 4.04–
4.16 m (2H, CH2), 4.94–5.03 m (1H, CH), 7.31–7.41 m
(3H, Harom), 7.55–7.65 m (2H, Harom). 13C NMR spec-
trum, δC, ppm: 8.7 (CH3), 8.8 (CH3), 8.9 (CH3), 47.2
(CH2), 66.7 (CH2), 71.1 (CH), 103.9, 111.7, 112.6,
122.1, 126.3 (CH), 128.2 (2C, CH), 128.6 (2C, CH),
129.3, 137.6. Found, %: C 75.79; H 7.15; N 5.18;
O 11.88. C17H19NO2. Calculated, %: C 75.81; H 7.11;
N 5.20; O 11.88. M 269.35.
(1H, Harom, J = 7.6 Hz), 7.28 d (1H, Harom, J = 8.4 Hz),
7.36 d (1H, J = 7.6 Hz), 7.40–7.48 m (3H, Harom),
7.63–7.71 m (2H, Harom). 13C NMR spectrum, δC, ppm:
8.1 (CH3), 47.0 (CH2), 67.3 (CH2), 71.4 (CH), 103.9,
105.0, 108.5 (CH), 118.6 (CH), 118.8 (CH), 121.8
(CH), 127.7 (4C, CH), 128.0, 128.7 (CH), 132.2,
134.8, 137.0. Found, %: C 78.30; H 5.92; N 4.80;
O 10.98. C19H17NO2. Calculated, %: C 78.33; H 5.88;
N 4.81; O 10.98. M 291.35.
Ethyl 2-(1-phenyl-4,5-dihydro-1H,3H-1,4-epoxy-
[1,4]oxazepino[4,3-a]indol-11-yl)acetate (7b). The
crude product was treated with 100 mL of heptane, the
mixture was heated to the boiling point with stirring,
and 6 g of silica gel was added. The mixture was
refluxed with stirring for 10 min and transferred while
hot to a Soxhlet extractor. After 3-h extraction, the
solvent was completely removed. The residue (a mix-
ture of 7b and 8b; overall yield 82%) was treated with
30 mL of methanol, the mixture was heated to the
boiling point and left to stand for crystallization, and
the precipitate was filtered off and washed with
methanol. Yield 43%, colorless crystals, mp 141–
Phenyl[3,4,5-trimethyl-1-(oxiran-2-ylmethyl)-
1H-pyrrol-2-yl]methanone (5). After extraction of 4,
the Soxhlet thimble content was dried from heptane
and extracted with methanol. The solvent was removed
almost completely, and the residue was left overnight.
A small amount of cold (0°C) methanol was added to
the solidified material, and the precipitate was quickly
filtered off and washed with a small amount of cold
methanol. Yield 52%, brownish crystals, mp 115–
1
142°C. H NMR spectrum, δ, ppm: 1.15 t (3H, CH3,
J = 6.8 Hz), 2.67 d (1H, CH2C=O, J = 17.2 Hz), 2.98 d
(1H, CH2C=O, J = 17.2 Hz), 3.86–3.95 m (2H, CH2O),
4.09 d.d (1H, CH2N, J = 7.6, 1.2 Hz), 4.18–4.30 m
(2H, CH2), 4.42 d.d (1H, CH2N, J = 11.6, 3.2 Hz),
5.21–5.28 m (1H, CH), 7.02 t (1H, Harom, J = 8.0 Hz),
7.19 t (1H, Harom, J = 7.2 Hz), 7.34 d (2H, Harom, J =
8.0 Hz), 7.39–7.49 m (3H, Harom), 7.56–7.73 m (2H,
Harom). 13C NMR spectrum, δC, ppm: 13.9 (CH3), 28.6
(CH2), 47.1 (CH2), 59.4 (CH2), 67.5 (CH2), 71.4 (CH),
102.6, 103.5, 108.8 (CH), 118.8 (CH), 119.2 (CH),
122.0 (CH), 127.5, 127.7 (2C, CH), 128.8 (CH), 133.8,
134.8, 136.4, 169.9 (C=O). Found, %: C 72.70; H 5.84;
N 3.84; O 17.62. C22H21NO4. Calculated, %: C 72.71;
H 5.82; N 3.85; O 17.62 M 363.42.
1
117°C. H NMR spectrum, δ, ppm: 1.56 s (3H, CH3),
1.89 s (3H, CH3), 2.26 s (3H, CH3), 3.29–3.37 m (2H,
CH2O), 3.61–3.70 m (1H, CH), 4.05 d.d (1H, CH2N,
J = 14.4, 8.4 Hz), 4.29 d.d (1H, CH2N, J = 14.4,
3.6 Hz), 7.43 t (2H, Harom, J = 7.2 Hz), 7.51 t (1H,
Harom, J = 7.2 Hz), 7.60 d (2H, Harom, J = 7.2 Hz).
13C NMR spectrum, δC, ppm: 9.0 (CH3), 10.3 (CH3),
12.0 (CH3), 47.5 (CH2), 69.8 (CH2), 72.0 (CH), 115.5,
127.0, 127.6, 127.8 (2C, CH), 128.6 (2C, CH), 130.8
(CH), 135.0, 141.3, 186.1 (C=O). Found, %: C 75.78;
H 7.14; N 5.18; O 11.90. C17H19NO2. Calculated, %:
C 75.81; H 7.11; N 5.20; O 11.88. M 269.35.
Ethyl 2-[2-benzoyl-1-(oxiran-2-ylmethyl)-1H-in-
dol-3-yl]acetat (8b). The mother liquor obtained after
separation of 7b was evaporated, and the residue was
left to stand for several days in an open vessel. The
resinous material gradually crystallized. The product
contained ~20% of 7b, and we failed to find an ap-
propriate solvent to purify compound 8b from 7b. The
NMR spectra of 8b were obtained by subtracting
signals of 7b from the spectrum of their mixture.
1H NMR spectrum, δ, ppm: 1.12 t (3H, CH3, J =
6.8 Hz), 2.30 t (1H, CH2O, J = 2.4 Hz), 2.65 t (1H,
CH2O, J = 4.0), 3.22–3.29 m (1H, CH), 3.47 s (2H,
CH2), 3.95 q (2H, CH2, J = 6.8 Hz), 4.38 d.d (1H,
CH2N, J = 15.2, 4.8 Hz), 4.77 d.d (1H, CH2N, J =
11-Methyl-1-phenyl-4,5-dihydro-1H,3H-1,4-
epoxy[1,4]oxazepino[4,3-a]indole (7a). The crude
product was treated with 10 mL of propan-2-ol, the
mixture was heated to the boiling point and left over-
night, and the crystalline solid was filtered off and
washed with propan-2-ol. Yield 49%, colorless crystals,
1
mp 150–151°C. H NMR spectrum, δ, ppm: 1.42 s
(3H, CH3), 4.03 d.d (1H, CH2O, J = 7.6, 1.6 Hz),
4.19 d (1H, CH2N, J = 11.6 Hz), 4.23 d (1H, CH2O, J =
6.8 Hz), 4.37 d.d (1H, CH2N, J = 11.6, 3.6 Hz), 5.19–
5.23 m (1H, CH), 7.00 t (1H, Harom, J = 7.2 Hz), 7.15 t
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EPOXYMETHYLATION OF 2-ACYL-SUBSTITUTED NH HETEROCYCLES
1683
15.6, 2.8 Hz), 7.14 t (1H, Harom, J = 7.6 Hz), 7.35 t (1H,
Harom, J = 7.6 Hz), 7.51 t (2H, Harom, J = 7.6 Hz), 7.55–
7.66 m (3H, Harom), 7.78 d (2H, Harom, J = 8.0 Hz).
13C NMR spectrum, δC, ppm: 13.8 (CH3), 30.5 (CH2),
44.4 (CH2), 44.9 (CH2), 50.7 (CH), 60.0 (CH2), 110.8
(CH), 113.8, 120.2 (CH), 124.9 (CH), 126.3 (CH),
127.7, 127.3 (2C, CH), 128.4, 129.1 (2C, CH), 132.6
(CH), 138.0, 138.9, 169.6 (C=O), 188.9 (C=O).
(1.01 mmol) of compound 7a, 10 mL of water, and
2 mL of 85% H3PO4 was refluxed for 4 h with stirring.
The mixture was cooled to room temperature and
neutralized to pH ~7 with aqueous ammonia. The
aqueous phase was separated by decanting from the
yellow viscous oil, and the oil was washed with water
and dried at 110°C. Yield 0.30 g (94%), yellow viscous
1
oily material. H NMR spectrum, δ, ppm: 2.02 s (3H,
CH3), 3.27–3.36 m (2H, CH2O), 3.65–3.75 m (1H,
CH), 4.32 d.d (1H, CH2N, J = 14.8, 8.0 Hz), 4.48 d.d
(1H, CH2N, J = 14.4, 3.6 Hz), 7.10 t (1H, Harom, J =
7.2 Hz), 7.31 t (1H, Harom, J = 7.2 Hz), 7.48–7.59 m
(4H, Harom), 7.62 t (1H, Harom, J = 7.2 Hz), 7.83 d (2H,
Harom, J = 7.6 Hz). 13C NMR spectrum, δC, ppm: 10.6
(CH3), 46.4 (CH2), 63.6 (CH2), 70.9 (CH), 110.9 (CH),
116.5, 119.3 (CH), 119.9 (CH), 124.4 (CH), 127.0,
128.2 (2C, CH), 129.4 (2C, CH), 132.3 (CH), 133.8,
139.5, 189.7 (C=O). Found, %: C 73.81; H 6.21;
N 4.50; O 15.48. C19H19NO3. Calculated, %: C 73.77;
H 6.19; N 4.53; O 15.51. M 309.37.
6-Methyl-9-(oxiran-2-ylmethyl)-2,3,4,9-tetra-
hydro-1H-carbazol-1-one (8c). The crude product
was treated with 10 mL of methanol, the mixture was
heated to the boiling point with stirring and left
overnight, and the crystalline solid was filtered off and
washed with methanol. Yield 86%, colorless needles,
1
mp 77–78°C. H NMR spectrum, δ, ppm: 2.18 quint
(2H, CH2, J = 6.4 Hz), 2.43 s (3H, CH3), 2.51–2.60 m
(3H, CH2), 2.68 t (1H, CH2, J = 6.0 Hz), 2.96 t (2H,
CH2, J = 6.0 Hz), 3.16–3.24 m (1H, CH), 4.42 d.d (1H,
CH2N, J = 14.8, 5.2 Hz), 4.88 d.d (1H, CH2N, J = 14.8,
3.6 Hz), 7.16 d.d (1H, Harom, J = 8.4, 1.2 Hz), 7.36 d
(1H, Harom, J = 8.4 Hz), 7.38 s (1H, Harom). 13C NMR
spectrum, δC, ppm: 21.0 (CH3), 21.2 (CH2), 24.2
(CH2), 39.2 (CH2), 44.5 (CH2), 45.7 (CH2), 50.7 (CH),
110.7 (CH), 120.0 (CH), 1214.5, 128.2 (CH), 128.3,
128.7, 129.3, 137.8, 190 (C=O). Found, %: C 75.30;
H 6.73; N 5.52; O 12.45. C16H17NO2. Calculated, %:
C 75.27; H 6.71; N 5.49; O 12.53 M 255.32.
9-(2,3-Dihydroxypropyl)-2,3,4,9-tetrahydro-1H-
carbazol-1-one (11). A mixture of 1 g (3.9 mmol) of
compound 8c, 5 mL of 1,4-dioxane, 0.2 mL of water,
and 0.2 mL of H3PO4 was refluxed for 2 h. The mixture
was cooled to room temperature, 15 mL of water was
added, and a mobile oily material separated and crys-
tallized on grinding. The precipitate was filtered off
and washed with water. Yield 1 g (94%), colorless floc-
culent crystals, mp 117–118°C. The product required
[1-(2,3-Dihydroxypropyl)-3,4,5-trimethyl-1H-
pyrrol-2-yl](phenyl)methanone (9). A mixture of
150 mg (0.56 mmol) of compound 5 and 100 mg of
BTEAC in 8 mL of undried acetonitrile was refluxed
for 10 h. The solvent was distilled off, the residue was
treated with 5 mL of water, and the oily material
rapidly solidified. The precipitate was filtered off and
washed with water. The product required no further
purification. Yield 0.147 g (92%), fine colorless crys-
tals, mp 113–114°C. 1H NMR spectrum, δ, ppm: 1.55 s
(3H, CH3), 1.89 s (3H, CH3), 2.25 s (3H, CH3), 3.26–
3.34 m (2H, CH2OH), 3.63 sept (1H, CH, J = 4.4 Hz),
4.03 d.d (1H, CH2N, J = 14.0, 8.4 Hz), 4.28 d.d (1H,
CH2N, J = 14.0, 3.6 Hz), 4.37 t (1H, OH, J = 5.6 Hz),
4.73 d (1H, OH, J = 6.0 Hz), 7.43 t (2H, Harom, J =
7.2 Hz), 7.51 t (1H, Harom, J = 7.2 Hz), 7.59 t (2H,
Harom, J = 7.2 Hz). 13C NMR spectrum, δC, ppm: 9.0
(CH3), 10.3 (CH3), 12.0 (CH3), 47.4 (CH2), 63.7 (CH2),
71.7 (CH), 115.5, 126.9, 127.5, 127.8 (2C, CH), 128.6
(2C, CH), 130.8 (CH), 135.0, 141.3, 186.1 (C=O).
Found, %: C 71.01; H 7.42; N 4.82; O 16.75.
C17H21NO3. Calculated, %: C 71.06; H 7.37; N 4.87;
O 16.70. M 287.36.
1
no further purification. H NMR spectrum, δ, ppm:
2.18 quint (2H, CH2, J = 5.6 Hz), 2.42 s (3H, CH3),
2.56 t (2H, CH2, J = 6.0 Hz), 2.96 t (2H, CH2, J =
5.6 Hz), 3.28–3.40 m (2H, CH2O), 3.72–3.83 m (1H,
CH), 4.35 d.d (1H. CH2N, J = 14.0, 6.8 Hz), 4.53 d.d
(1H, CH2N, J = 14.0, 5.2 Hz), 7.14 d (1Harom, J =
8.8 Hz), 7.36 s (1Harom), 7.43 d (1Harom, J = 8.4 Hz).
13C NMR spectrum, δC, ppm: 21.0 (CH3), 21.3 (CH2),
39.4 (CH2), 47.1 (CH2), 63.5 (CH2), 71.4 (CH), 111.2
(CH), 119.7 (CH), 124.3, 127.9 (CH), 128.0, 128.2,
129.7, 138.0, 190.4 (C=O). Found, %: C 70.34; H 7.04;
N 5.09; O 17.53. C16H19NO3. Calculated, %: C 70.31;
H 7.01; N 5.12; O 17.56. M 273.33.
9-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-hydroxy-
propyl]-2,3,4,9-tetrahydro-1H-carbazol-1-one (12)
and 9-(2-hydroxy-3-piperidin-1-ylpropyl)-2,3,4,9-
tetrahydro-1H-carbazol-1-one (13) (general proce-
dure). A mixture of 1 mmol of compound 8c and
1.5 mmol of 3,5-dimethyl-1H-pyrazole or piperidine in
2 mL of 2-ethoxyethanol was refluxed for 6 h. The
mixture was treated with 8 mL of water, an oily mate-
rial separated and was ground until complete crystal-
[1-(2,3-Dihydroxypropyl)-3-methyl-1H-indol-
2-yl](phenyl)methanone (10). A mixture of 0.3 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

KHARANEKO et al.
1684
lization, and the solid product was filtered off, washed
with water, dried, and recrystallized from methanol.
for 1 h with stirring. The suspension was cooled to
room temperature and diluted with 15 mL of water, and
the precipitate was filtered off, washed with water, and
recrystallized from 7 mL of methanol. Yield 1.7 g
Compound 12. Yield 91%, colorless crystals,
1
mp 139–140°C. H NMR spectrum, δ, ppm: 2.08 s
1
(88%), colorless crystals, mp 118–119°C. H NMR
(3H, CH3), 2.19 t (2H, CH2, J = 6.0 Hz), 2.21 s (3H,
CH3), 2.43 s (3H, CH3), 2.57 t (2H, CH2, J = 5.6 Hz),
2.97 t (2H, CH2, J = 6.0 Hz), 3.84 d.d (1H, CH2NN,
J = 14.0, 4.0 Hz), 3.92 d.d (1H, CH2NN, J = 14.0,
7.6 Hz), 4.08–4.21 m (1H, CH), 4.37 d.d (1H, CH2N,
J = 14.0, 7.2 Hz), 4.59 d.d (1H, CH2N, J = 14.0,
5.6 Hz), 4.96 br.s (1H, OH), 5.68 s (1H, CH), 7.15 d.d
(1H, Harom, J = 8.8, 1.2 Hz), 7.35 d (1H, Harom, J =
8.4 Hz), 7.37 s (1H, Harom). 13C NMR spectrum, δC,
ppm: 10.8 (CH3), 13.2 (CH3), 21.0 (CH3), 21.3 (CH2),
24.3 (CH2), 39.4 (CH2), 48.1 (CH2), 51.7 (CH2), 70.0
(CH), 104.1 (CH), 111.0 (CH), 119.9 (CH), 124.4,
128.1 (CH), 128.2, 128.4, 129.5, 137.9, 139.1, 145.5,
190.4 (C=O). Found, %: C 71.79; H 7.20; N 12.00;
O 9.01. C21H25N3O2. Calculated, %: C 71.77; H 7.17;
N 11.96; O 9.10. M 351.45.
spectrum, δ, ppm: 2.42 d and 2.77 d [1H each,
CH2C(O), J = 16.4 Hz], 4.04–4.15 m (1H, CH2), 4.16–
4.29 m (2H, CH2), 4.34–4.48 m (1H, CH2), 5.15–
5.30 m (1H, CH2), 7.02 t (1H, Harom, J = 7.2 Hz), 7.18 t
(1H, Harom, J = 7.2 Hz), 7.32 d (1H, Harom, J = 8.0 Hz),
7.38 d (1H, Harom, J = 7.6 Hz), 7.40–7.51 m (3H,
H
arom), 7.55–7.83 m (2H, Harom), 8.04 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 28.9 (CH2), 47.0 (CH2),
67.5 (CH2), 71.4 (CH), 103.4, 103.7, 108.7 (CH), 119.1
(2C, CH), 122.0 (CH), 126.6, 127.5, 127.6 (2C, CH),
128.9 (CH), 133.9, 134.9, 136.3, 169.0 (C=O).
Found, %: C 68.72; H 5.51; N 12.06; O 13.71.
C20H19N3O3. Calculated, %: C 68.75; H 5.48;
N 12.03; O 13.74. M 349.39.
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
REFERENCES
Compound 13. Yield 88%, colorless crystals,
mp 109–110°C. 1H NMR spectrum, δ, ppm: 1.40 quint
(2H, CH2, J = 5.2 Hz), 1.53 quint (4H, CH2, J =
5.2 Hz), 2.18 quint (2H, CH2, J = 6.0 Hz), 2.29 d (2H,
CH2, J = 6.0 Hz), 2.35–2.45 m (4H, CH2), 2.42 s (3H,
CH3), 2.55 t (2H, CH2, J = 6.0 Hz), 2.96 t (2H, CH2,
J = 5.6 Hz), 3.86–3.98 m (1H, CH), 4.23 d.d (1H, CH2,
J = 14.0, 7.6 Hz), 4.62 d.d (1H, CH2, J = 14.0, 4.4 Hz),
7.12 d.d (1H, Harom, J = 8.8, 1.2 Hz), 7.35 s (1H, Harom),
7.41 d (1H, Harom, J = 8.8 Hz). 13C NMR spectrum, δC,
ppm: 21.0 (CH3), 21.3 (CH2), 23.9 (CH2), 24.3 (CH2),
25.5 (2C, CH2), 48.9 (CH2), 54.5 (2C, CH2), 62.6
(CH2), 67.5 (CH), 111.3 (CH), 119.7 (CH), 127.7 (CH),
127.8, 128.1, 129.7, 138.2, 190.3 (C=O). Found, %:
C 74.05; H 8.31; N 8.26; O 9.38. C21H28N2O2.
Calculated, %: C 74.08; H 8.29; N 8.23; O 9.40.
M 340.47.
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oxazepino[4,3-a]indol-11-yl)acetohydrazide (14).
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8 mL (160 mmol) of hydrazine hydrate was refluxed
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020