Reaction of α-chloro-β-oxobutanal with indole derivatives

Article abstract of DOI:10.1134/S1070427210120165

The reactions of 2-methylindole and 2-methylindol-3-yldiphenylphosphine with α-chloro-β-oxobutanal was studied.

Full text of DOI:10.1134/S1070427210120165

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2010, Vol. 83, No. 12, pp. 2158–2162. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © M.A. Allakhverdiev, A.A. Niyazova, A.B. Askerov, V.M. Farzaliev, 2010, published in Zhurnal Prikladnoi Khimii, 2010, Vol. 83,
No. 12, pp. 2031–2035.
ORGANIC SYNTHESIS AND INDUSTRIAL
ORGANIC CHEMISTRY
Reaction of α-Chloro-β-oxobutanal with Indole Derivatives
M. A. Allakhverdieva, A. A. Niyazovab, A. B. Askerovb, and V. M. Farzalieva
a Kuliev Institute of Chemistry of Additives, National Academy of Sciences of Azerbaijan, Baku, Azerbaijan
b Sumgait State University, Sumgait, Azerbaijan
Received June 29, 2009
Abstract—The reactions of 2-methylindole and 2-methylindol-3-yldiphenylphosphine with α-chloro-β-
oxobutanal was studied.
DOI: 10.1134/S1070427210120165
α-Chloro-β-oxobutanal was prepared by the proce-
dure described in [5]. The reaction of 2-methylindole
with α-chloro-β-oxobutanal was performed in aceto-
nitrile or ethanol (with addition of catalytic amounts of
pyridine) at the boiling point of the solvent. Aceto-
nitrile is preferable as solvent because of high yield of
product 1 (85%). The structure, composition, and
purity of the compound synthesized were proved by
spectral data and elemental analysis:
Indole and its derivatives are structural fragments
of various alkaloids [1].
Proceeding with studies on synthesis of indolyl-
substituted carbonyl compounds [2–4], we examined
the reactions of 2-methylindole and 3-methylindol-2-
yldiphenylphosphine with α-chloro-β-oxobutanal and
cyclization of the resulting unsaturated ketones.
CH3
C
CH CHO
Cl
O
+
CH3
C
O
C
CH OH
N
H
CH3
Cl
O
H3C
Cl
C
C(O)CH3
C
AlCl3
CH
N
C
N
H
H2
H
I
II
N
CH2
CH
C
H3C
C
O
III
2158

REACTION OF α-CHLORO-β-OXOBUTANAL
2159
Table 1. Physicochemical and spectral characteristics of the compounds synthesized
Found, %
Calculated, %
Comp. Yield,
no.
Tm, °С
Formula
1H NMR spectrum, δ, ppm (acetone-d6) IR spectrum, ν, cm–1
%
N
P
–
Cl
I
85 180–181 5.86
6.00
15.68 C13H12NOCl 2.6 s (3Н, СН3СО); 3.9 d (2Н, СН2); 7.00 d 1580–1620 (С=С);
15.20
–
(2Н, С5Н+С6Н); 7.6 d (2Н, С4Н+С7Н); 1720 (С=О); 3240
8.00 t (1Н, СН=); 8.8 br.s (1Н, NH) (NH amide)
II
77 234–236 7.59
7.11
–
C13H11NO
2.5 s (3Н, СН3О); 3.6 d (2Н, СН2); 6.9 d 1620 (С=С); 1715
(2Н, С5Н+С6Н); 7.55 d (2Н, С4Н+С7Н); (С=О); 3260 (NH
7.78 t (1Н, СН=); 8.6 br.s (1Н, NH)
amide)
IV
68
Oil
3.29 7.64 8.33 C25H21NOPCl 2.4 s (3Н, СН3); 3.8 d (2Н, СН2); 6.8 d (2Н, 1715 (С=О); 1580–
3.35 7.43 8.50
С5Н+С6Н); 7.3 d (2Н, С4Н+С7Н); 7.5–7.75 1600 (С=О); 3280
m (1Н, Ph); 7.9 t (1Н, СH=); 9.00 br.s (1Н, (NH amide)
NH)
V
59 149–150 3.86 8.22
3.67 8.14
–
C25H20NOP 2.45 s (3Н, СН3); 3.8 d (2Н, СН2); 6.85 d 1690 (С=С); 1580–
(2Н, С5Н+С6Н); 7.3 d (2Н, С4Н+С7Н); 1620 (С=С indol)
7.5–7.8 m (1Н, Ph); 8.2 d (1Н, СН=)
The IR spectrum of product I contains absorption
bands confirming its structure: νС=Сarom (1580–1620 cm–1 ),
νС=О (1720 cm–1), νNH (3240 cm–1), νC–Cl (660–
690 cm–1).
dissolves, and the reaction is complete in 5–6 h with a
high yield of heterocycle II.
The resulting heterocyclic compound is a high-
melting crystalline substance stable in storage.
1
The Н NMR spectrum also confirms the structure
The IR spectrum of the cyclization product contains
a band at 3260 cm–1, confirming that the NH proton is
not involved in cyclization, i.e., that the reaction
occurs at the С3 atom (Table 1).
of I. The СН2 protons give a doublet at 3.9 ppm; the
NH proton, a broadened singlet at 8.8 ppm; and the
methine proton, a triplet at 8.00 ppm.
1
In the H spectrum of heterocycle II, the СН=C
Despite activation of the halogen atom at the α-
carbon atom by the carbonyl group, in most cases it is
replaced difficultly. However, in product I in the Z
configuration the Cl atom is sterically close to the C3H
proton of the indole ring. Therefore, an intramolecular
attack of the C3 position of the indole ring by the α-C
atom of the aldehyde can be expected, as it is observed
for compounds with labile halogen. At the same time,
the hydrogen atom bonded to the N atom is also labile,
and therefore the attack of the C2 atom by the nitrogen
atom cannot be ruled out.
proton gives a triplet at 7.78 ppm, in contrast to linear
product I giving the corresponding the signal at 8.00
ppm. The СН2 signal is observed at 3.95 ppm, which
confirms the formation of compound II in the reaction.
The formation of heterocycle II was also confirmed
by mass spectrometry: The molecular ion with m/z 197
corresponds to the empirical formula C13H11NO.
Then, with the aim to perform cyclization at the
indole nitrogen atom, we studied the reaction of 2-
methylindol-3-yldiphenylphosphine with α-chloro-β-
oxobutanal. The reaction was performed in refluxing
dioxane with addition of catalytic amounts of
piperidine. The final cyclization product V is formed
in a two-step process. The first step is formation of
stable product IV, which was isolated pure. The
reaction was accompanied by darkening of the reaction
To determine the possible pathway of cyclization of
I, it was heat-treated in dioxane in the presence of
catalytic amounts of a Lewis acid (AlCl3). We found
that, under the action of AlCl3, compound I underwent
cyclization into II at the С3 position and not at the N
atom. In the process, the starting compound I gradually
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 12 2010

2160
ALLAKHVERDIEV et al.
mixture. The brown mother liquor was passed through
silica gel L100/400, and phosphorylated product IV
was isolated from the resulting yellow solution as
viscous oil. Its attempted crystallization failed:
CH3
C
O
CH CHO
Cl
PPh2
CH3
+
C
O
C
CH OHO
N
H
CH3
Cl
PPh2
PPh2
Et3N
N
N
CH2
CH
H
Cl
C
C
H3C
C
O
H3C
O
V
IV
The product was identified as compound IV on the
basis of spectroscopic data. The Н NMR spectrum of
oil according to GOSTs (State Standards) 9.052–75
and 9.085–75 (Table 2). The data we obtained show
that all the compounds exhibit pronounced anti-
microbial effect at a low concentration (0.5–1.0%), are
well soluble in DS-11 oil, and do not stimulate
corrosion. With respect to performance, indolyl-sub-
stituted compounds I, II, IV, and V surpass the
commercial antimicrobial additive, sodium pentachlo-
rophenolate, used as reference. At 0.5% concentrations
of the compounds we prepared, the suppression zone
width was 0.9–1.3 cm for bacteria and 1.2–1.5 cm for
fungi, whereas with sodium pentachlorophenolate at
the same concentration the suppression zone width for
bacteria and fungi was 0.7 cm. Similar pattern was
observed at 1% concentration.
1
IV contains the following signals, ppm: 2.4 s
(СН3СО), 3.8 d (СН2), 6.8 and 7.3 d.d (С5Н + С6Н;
С4Н + С7Н), 7.5–7.75 m (2Ph), 7.9 d (СН=), 9.00 br.s
(NH).
The 31P NMR spectrum is characterized by a signal
at –5.8 ppm. In the IR spectrum, there are absorption
bands at 3238 (νNH assoc.), 1580–1600 (νС=С of
indole), and 1715 cm–1 (νС=О).
With the aim of subsequent heterocyclization, the
isolated oil was dissolved in absolute ethanol, an
equimolar amount of triethylamine was added to bind
HCl, and the reaction mixture was kept first for 1 h at
room temperature and then for 2 h at 60°С.
31
EXPERIMENTAL
The reaction progress was monitored by IR and Р
NMR spectroscopy. The 31Р NMR signal is shifted by
1 ppm (from –5.8 to –6.8 ppm). In the IR spectrum, the
absorption band of the associated NH group at
1
The Н NMR spectra were recorded with a Bruker
DPX-300 spectrometer operating at 300 MHz (solvent
CDCl3). The IR spectra were measured on a Specord-
75-IR spectrometer. The mass spectra were taken with
a Finnigan MAT Incos 50 device with ionization by
electron impact (70 eV). Elemental analysis was
performed with a Hewlett–Packard 185 B CHN
analyzer.
1
3280 cm–1 disappears. In the Н NMR spectrum, the
methine proton signal shifts from 7.9 to 8.2 ppm.
These data also show that the reaction occurs along the
heterocyclization pathway.
The synthesized compounds I, II, IV, and V were
tested as antimicrobial additives to DS-11 lubricating
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 82 No. 12 2010

REACTION OF α-CHLORO-β-OXOBUTANAL
Table 2. Antimicrobial activity of compounds in DS-11 oil
2161
Diameter the microorganism growth suppression zone, mm
Concentration,
Compound
%
mixture of bacteria
meat–peptone agar)
mixture of fungi
(must–agar medium)
0.5
1.0
0.9
2.0
1.2
2.5
N
H
CH2CH
CCl
COCH3
I
0.5
1.0
0.8
1.9
1.0
2.2
COCH3
N
C
H
H2
II
0.5
1.0
1.2
2.6
1.3
2.8
PPh2
N
H
CH2CH
CCl
COCH3
IV
0.5
1.0
1.3
2.8
1.5
2.9
PPh2
N
H3CCO
V
Sodium pentachlorophenolate (reference)
0.5
1.0
0.7
1.3
0.7
1.4
3-Chloro-5-(indol-2-yl)pent-3-en-2-one (I). A mix-
ture of 2.62 g (0.02 mol) of 2-methylindole and 2.41 g
(0.02 mol) of α-chloro-β-oxobutanal with addition of
1.0 g of pyridine was refluxed in 60 ml of acetonitrile
for 8 h. After removing the solvent from the filtrate at
reduced pressure, a dark brown oil was obtained. It
was dissolved in 20 ml of a 1 : 1 ether–hexane mixture,
and the solution was left overnight in a refrigerator.
The crystals of 1 were filtered off and vacuum-dried.
Yield 3.97 g (85%).
mixture (2 : 1) was added to the residue. The pre-
cipitated crystals were filtered off and dried. Yield
3.03 g (77%).
3-Chloro-5-(3-diphenylphosphinoindol-2-yl)pent-
3-en-2-one (IV). A mixture of 6.3 g (0.02 mol) of 3-
methylindol-2-yldiphenylphosphine and 2.41 g (0.02 mol)
of α-chloro-β-oxobutanal with addition of 0.3 g of
piperidine was refluxed in dioxane for 4 h. The result-
ing brown mother liquor was passed two times through
silica gel. By evaporation of the resulting yellow
solution, we obtained phosphorylated product IV in the
form of viscous oil. Yield 5.68 g (68%).
1-Acetylcyclopent-1-eno[4,5-b]indole (II). 4.67 g
(0.02 mol) of I was dissolved in 30 ml of dioxane, a
catalytic amount of AlCl3 was added, and the mixture
was refluxed for 6 h. Then the solvent was removed at
reduced pressure, and 15 ml of an ether–MeCN
1-Acetylcyclopent-1-eno[5,4-a]-3-diphenylphos-
phinoindole (V). A solution of 4.18 g (0.01 mol) of
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2162
ALLAKHVERDIEV et al.
4 in 100 ml of absolute ethanol and 1.01 g (0.01 mol)
of Еt3N, cooled to 0°С, was stirred for 2 h. Then the
mixture was kept for 1 h at room temperature and for
2 h at 50–60°С. The triethylamine hydrochloride pre-
cipitate was filtered off, the solvent was removed, and
the product was purified by reprecipitation from ethanol
solution into anhydrous hexane. Yield 2.25 g (59%).
(3) The compounds synthesized exhibit high
antimicrobial activity.
REFERENCES
1. Indoles, Houlihan, W.J., Ed., New York: Wiley–
Interscience, 1979, parts 1–3.
2. Magerramov, A.M., Niyazova, A.A., Askerov, A.B., et al.,
Vestn. Bak. Univ., 2006, no. 3, pp. 5–17.
CONCLUSIONS
3. Mamedov, A.F., Farzaliev, V.M., Ismiev, A.I., et al.,
(1) The reactions of 2-methylindole and (2-me-
thylindol-3-yl)diphenylphosphine with α-chloro-β-oxo-
butanal were carried out.
Zh. Khim. Probl., 2003, no. 2, pp. 73–78.
4. Magerramov, A.M., Aliev, S.G., Askerov, A.B., et al.,
Vestn. Bak. Univ., 2007, no. 4, pp. 42–47.
5. Guseinov, F.I. and Moskva, V.V., Zh. Org. Khim., 1994,
(2) Cyclization of the reaction products at both the
С3 atom and indole nitrogen atom was performed.
vol. 30, no. 3, pp. 360–365.
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