One-pot synthesis of pyrroles from ketones, hydroxylamine, and 1,2-dibromoethane in the system KOH-DMSO

Article abstract of DOI:10.1134/S1070428014120100

Dibutyl ketone, cyclohexanone, acetophenone, α-tetralone, and methyl 2-thienyl ketone were converted into the corresponding 2,3-substituted pyrroles by reaction with hydroxylamine hydrochloride and 1,2-dibromoethane in the system KOH-DMSO.

Full text of DOI:10.1134/S1070428014120100

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 12, pp. 1775–1778. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.V. Ivanov, V.S. Shcherbakova, A.I. Mikhaleva, B.A. Trofimov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 12, pp. 1794–1797.
One-Pot Synthesis of Pyrroles from Ketones, Hydroxylamine,
and 1,2-Dibromoethane in the System KOH–DMSO
A. V. Ivanov, V. S. Shcherbakova, A. I. Mikhaleva, and B. A. Trofimov
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: boris_trofimov@irioch.irk.ru
Received July 8, 2014
Abstract—Dibutyl ketone, cyclohexanone, acetophenone, α-tetralone, and methyl 2-thienyl ketone were
converted into the corresponding 2,3-substituted pyrroles by reaction with hydroxylamine hydrochloride and
1
,2-dibromoethane in the system KOH–DMSO.
DOI: 10.1134/S1070428014120100
Syntheses of pyrroles continuously attract re-
searchers’ attention. This is determined by permanent
importance of pyrrole compounds which widely occur
in living organisms (hemoglobin, chlorophyll, natural
antibiotics) [1] and are key structural units of modern
medicines (atorvastatin, zomepirac, ketorolac,
tolmetin) [2]; they are also used for the preparation of
semiconductors, electrochromic polymers, biosensors,
and other materials for information technologies [3–8].
New methods are developed for the synthesis of
pyrrole compounds possessing novel properties, and
known procedures for the construction of pyrrole ring
are modified [9–13]. One of the most general synthetic
approaches to pyrrole systems is based on reactions of
ketone oximes with acetylene in superbasic medium
droxylamine hydrochloride in KOH–DMSO using
1,2-dichloroethane as synthetic equivalent of acetylene
[19]. It was reasonable to presume that more reactive
1,2-dibromoethane may also be used in this reaction.
In the present article we discuss the results of the
three-component condensation of various ketones Ia–
Ie with hydroxylamine hydrochloride and 1,2-di-
bromoethane in the system KOH–DMSO (Scheme 1).
The reactions were carried out under the conditions
that ensured the best yield of the target pyrrole com-
pound in the reaction with 1,2-dichloroethane: molar
ratio ketone I–hydroxylamine hydrochloride–1,2-di-
bromoethane–KOH 1:124, temperature 120°C, reac-
tion time 2–3.5 h. In all cases, the expected pyrrole
compounds were obtained, though in fairly low yields
(
4
22–48%, see table). The conversion of ketones I was
0–56%, and unreacted ketones were recovered from
[14]. Some new modifications of this method have
been reported in recent years, in particular the direct
synthesis of pyrroles from ketones, hydroxylamine
hydrochloride, and acetylene in the presence of bases
the reaction mixtures as oximes. The results are given
in table.
[
15–17]. However, the use of gaseous acetylene
The most probable way of formation of pyrroles
involves rearrangement of O-vinyloxime resulting
from dehydrobromination of O-(2-bromoethyl)oxime
involves some limitations related to the risk of ex-
plosion. Therefore, a topical problem is to develop
a procedure utilizing accessible and safe reagents that
are capable of generating acetylene during the syn-
thesis. Attempts to use 1,2-dihaloethanes [18] in the
Trofimov pyrrole synthesis from ketone oximes have
demonstrated some prospects but received no further
development. We have recently reported the first
example of successful synthesis of pharmacologically
promising pyrrole systems (4,5-dihydrobenzo[g]indole
and its N-vinyl derivative) from α-tetralone and hy-
Scheme 1.
(
1) NH OH·HCl, KOH, DMSO
2
7
0°C, 30 min
R2
(2) BrCH CH Br, KOH, DMSO
R1
2
2
1
20°C, 2–4 h
R2
R1
O
N
H
Ia–Ie
IIa–IIe
1
2
For R and R , see table.
1
775

1
776
IVANOV et al.
Synthesis of pyrroles from ketones, hydroxylamine, and 1,2-dibromoethane in the system KOH–DMSO
Oxime–pyrrole ratio in the
a
Ketone
Pyrrole
Reaction time, h
Yield, %
crude product (GLC)
Pr
Me
Me
2
2
.0
.0
73:27
47
48
41
O
Bu
N
H
Ia
IIa
IIb
O
72:28
65:35
N
H
Ib
O
Me
Ph
N
3.0
H
Ic
IIc
O
3
2
.5
.5
74:26
82:18
23
22
N
H
Id
Ie
IId
IIe
O
S
N
S
Me
H
a
Calculated on the reacted ketone.
which is the product of nucleophilic substitution of one
bromine atom in 1,2-dibromoethane by oximate ion
ethane indicates that, unlike analogous reaction with
1,2-dichloroethane [19], the oximate ion is inferior to
hydroxide ion as nucleophile toward 1,2-dibromo-
ethane; therefore, the latter may be consumed for the
formation of vinyl bromide, 2-bromoethanol, ethylene
glycol, and acetylene.
In fact, ethylene glycol was detected in the reaction
mixtures by chromatography, and the reactions were
always accompanied by evolution of some amount of
gaseous products which decolorized an aqueous
(
Scheme 2). The rearrangement of O-vinyloxime
follows a conventional scheme [20] implying proto-
tropic tautomerization into N,O-divinylhydroxylamine
which undergoes 3,3-sigmatropic shift leading to
imino aldehyde. The subsequent intramolecular cy-
clization of the latter is accompanied by aromatization
via elimination of water molecule, yielding the final
pyrrole (Scheme 3).
The low conversion (40–56%) of ketones (ketone
oximes) in the presence of 2 equiv of 1,2-dibromo-
solution of KMnO . The effect of the substituents in
the initial ketones on the yield (see table) is consistent
4
Scheme 2.
R2
O
R1
R1
C
R2
NH
2
OH·HCl, KOH, DMSO
KCl, –H O
R2
2
H
4
Br
2
, KOH, DMSO R1
Br
–
–KBr, –H O
2
2
O
NOH
N
R2
R2
R1
KOH, DMSO
KBr, –H O
KOH, DMSO
CH2
–
2
R1
N
N
O
H
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 12 2014

ONE-POT SYNTHESIS OF PYRROLES
1777
Scheme 3.
R2
O
R2
R2
R2
R1
O
R1
R1
HN
[3,3]
CH2
CH2
R2
H
R1
N
NH
R2
N
O
OH
R1
R1
N
N
H
with the assumption that the key step in the described
reaction is nucleophilic substitution of bromine in
chloride was stirred for 30 min at room temperature,
a solution of 1.65 g (0.012 mol) of nonan-5-one in
5 mL of DMSO was added, the mixture was stirred for
1
,2-dibromoethane by oximate ion. The best yields of
pyrroles were obtained in the reactions with dibutyl
ketone (Ia) and cyclohexanone (Ib) which should give
rise to more nucleophilic oximate ions due to higher
electron-donor power of the substituents on the car-
bonyl carbon atoms. Unlike our previous data on reac-
tions of ketone oximes with dihaloethanes in super-
basic systems [21–23], no ethylene glycol oxime ethers
were detected.
Despite fairly low yields of the target pyrroles, the
use of 1,2-dibromoethane as synthetic equivalent of
acetylene in one-pot syntheses of pyrroles from
ketones and hydroxylamine hydrochloride may be
appropriate, taking into account the high selectivity for
30 min at 70°C, 1.95 g (0.03 mol) of KOH·0.5H O
2
was added, the mixture was heated to 120°C, and
a solution of 1,2-dibromoethane in DMSO was added
dropwise. The addition was terminated when traces of
N-vinylpyrrole appeared in the mixture (GLC). The
mixture was cooled, neutralized with aqueous ammo-
nium chloride, and extracted with diethyl ether (3×
3
0 mL). The extract was dried over potassium carbon-
ate and evaporated, and the residue was analyzed by
GLC. The chromatogram typically contained only two
peaks belonging to unreacted oxime and final pyrrole
(
see table). Separation by column chromatography on
silica gel using chloroform as eluent gave 1.1 g of
nonan-5-one oxime and 0.38 g (47%) of pyrrole IIa.
1
H-pyrroles. For instance, a considerable amount of
1
Orange oily substance, bp 89–91°C (1–2 mm). H NMR
N-vinylpyrrole was formed in the reaction of α-tetra-
lone (Id) with 1,2-dichloroethane [19]. Furthermore, it
should be emphasized that in the present work the
reactions were carried out under the conditions optim-
ized for the pyrrole synthesis from 1,2-dichloroethane.
Obviously, the syntheses with more reactive 1,2-di-
bromoethane require additional optimization.
spectrum, δ, ppm: 1.2 m (6H, CH ), 1.6 m (2H, CH ),
3
2
1
2
8
1
.8 m (4H, CH ), 2.7 m (2H, CH ), 2.8 m (2H, CH ),
2 2 2
.9 m (4H, CH ), 6.3 s (1H, 4-H), 6.9 s (1H, 5-H),
2
13
.0 br.s (1H, NH). C NMR spectrum, δ , ppm:
C
3.9 (CH ), 15.4 (CH ), 21.0 (CH ), 22.0 (CH ), 23.5
3
3
2
2
4
5
(CH ), 25.0 (CH ), 28.8 (CH ), 107.9 (C ), 117.6 (C ),
2 2 2
3
2
119.4 (C ), 128.9 (C ). Found, %: C 80.03; H 11.66;
N 8.54. Calculated, %: C 79.94; H 11.59; N 8.47.
EXPERIMENTAL
Compounds IIb–IIe were synthesized in a similar
This study was performed with the use of the equip-
ment of the Baikal Joint Analytical Center, Siberian
Branch, Russian Academy of Sciences. The H and C
NMR spectra were recorded on a Bruker DPX 400
spectrometer at 400.13 and 100.61 Hz, respectively,
way.
4,5,6,7-Tetrahydro-1H-indole (IIb). Yield 0.3 g
(48%), pink crystals, mp 51−52°C; 0.77 g of cyclohex-
anone oxime was recovered. H NMR spectrum, δ,
1
13
1
ppm: 1.6 m (2H, 5-H), 1.7 m (2H, 6-H), 2.4 t (2H, 4-H,
3
3
from solutions in CDCl using hexamethyldisiloxane
J4,5 = 6.0 Hz), 2.5 t (2H, 7-H, J = 6.0 Hz), 6.0 s
3
6,7
as internal reference. GLC analyses were obtained on
an Agilent 6890N chromatograph. The elemental com-
positions were determined on a Thermo Finnigan 1112
elemental analyzer. All initial reagents and solvents
were commercial products.
(1H, 3-H), 6.6 s (1H, 2-H), 7.6 br.s (1H, NH).
1
3
C NMR spectrum, δ , ppm: 23.9, 23.4, 22.9, 22.6
C
4
6
5
7
3
2
3a
(C , C , C , C ); 107.4 (C ), 115.6 (C ), 116.8 (C ),
126.9 (C ). Found, %: C 79.01; H 9.21; N 11.47. Cal-
culated, %: C 79.29; H 9.15; N 11.56.
7
a
2
-Butyl-3-propyl-1H-pyrrole (IIa). A mixture of
2-Phenyl-1H-pyrrole (IIc). Yield 0.39 g (41%),
pink crystals, mp 126−128°C; 0.72 g of acetophenone
oxime was recovered. H NMR spectrum, δ, ppm: 6.3 s
1
0 mL of DMSO, 0.78 g (0.012 mol) of KOH·0.5H O,
and 0.84 g (0.012 mol) of hydroxylamine hydro-
2
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 12 2014

1
778
IVANOV et al.
(
1H, 4-H), 6.5 s (1H, 3-H), 6.8 s (1H, 2-H), 7.2 m (1H,
6. Hou, S.-S.P. and Yeh, Y.H., Tetrahedron Lett., 2001,
vol. 42, p. 1309.
Ph), 7.3 m (2H, Ph), 7.4 m (2H, Ph), 8.4 br.s (1H, NH).
1
3
3
4
7
8
9
. Silva, C.D. and Walker, D.A., J. Org. Chem., 1998,
vol. 63, p. 6715.
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. Pan, B., Wang, C., Wang, D., Wu, F., and Wan, B.,
C NMR spectrum, δ , ppm: 106.02 (C ), 110.2 (C ),
C
5
o
p
m
1
18.8 (C ), 123.9 (C ), 126.9 (C ), 128.9 (C ), 132.1
2
i
(
C ), 132.7 (C ). Found, %: C 83.93; H 6.40; N 9.80.
Calculated, %: C 83.88; H 6.34; N 9.78.
,5-Dihydro-1H-benzo[g]indole (IId). Yield
.28 g (23%), yellow powder, mp 109–110°C; 0.77 g
4
Chem. Commun., 2013, vol. 49, no. 44, p. 5073.
0. Hu, Y., Wang, C., Wang, D., Wu, F., and Wan, B., Org.
Lett., 2013, vol. 15, p. 3146.
0
1
1
of α-tetralone oxime was recovered. H NMR spec-
trum, δ , ppm: 2.6 t (2H, 5-H, J = 7.8 Hz), 2.9 t (2H,
4
7
NH). C NMR spectrum, δ , ppm: 22.5 (C ), 30.3
(
1
3
C
1
1
1
1
1
1
1. Iida, K., Miura, T., Ando, J., and Saito, S., Org. Lett.,
3
-H, J = 7.7 Hz), 6.1 s (1H, 3-H), 6.8 s (1H, 2-H),
2
013, vol. 15, p. 1436.
.1 m (1H, Harom), 7.3–7.2 m (3H, Harom), 8.2 br.s (1H,
2. Li, B., Wang, N., Liang, Y., Xu, S., and Wang, B., Org.
Lett., 2013, vol. 15, p. 136.
3. Chen, Z., Lu, B., Ding, Z., Gao, K., and Yoshikai, N.,
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Zh. Org. Khim., 1978, vol. 14, p. 1119.
5. Schmidt, E.Yu., Mikhaleva, A.I., and Vasil’tsov, A.M.,
1
3
4
C
5
3
2
3a
9
C ), 110.3 (C ), 121.4 (C ), 122.3 (C ), 123.1 (C ),
24.7 (C ), 125.8 (C ), 127.1 (C ), 127.3 (C ), 128.9
7
5a
8
9b
6
9a
(
C ), 33.7 (C ). Found, %: C 85.22; H 6.66; N 8.35.
Calculated, %: C 85.17; H 6.55; N 8.28.
-(Thiophen-2-yl)-1H-pyrrole (IIe). Yield 0.19 g
22%), white powder, mp 75–76°C; 0.87 g of methyl
2
Arkivoc, 2005, part (vii), p. 11.
(
1
6. Mikhaleva, A.I., Shmidt, E.Yu., Ivanov, A.V., Vasil’-
tsov, A.M., Senotrusova, E.Yu., and Protsuk, N.I., Russ.
J. Org. Chem., 2007, vol. 43, p. 228.
2
-thienyl ketone oxime was recovered. H NMR spec-
trum, δ, ppm: 6.2 s (1H, 3-H), 6.3 s (1H, 4-H), 6.8 s
(
8
(
1H, 2-H), 7.0 m (2H, 4′-H, 5′-H), 7.1 s (1H, 3′-H),
1
3
17. Trofimov, B.A., Ivanov, A.V., Shmidt, E.Yu., and
Mikhaleva, A.I., Chem. Heterocycl. Compd., 2010,
vol. 46, no. 6, p. 762.
.2 br.s (1H, NH). C NMR spectrum, δ , ppm: 106.8
C
3
4
5
3′
5′
C ), 110.2 (C ), 118.5 (C ), 120.9 (C ), 122.7 (C ),
26.7 (C ), 127.6 (C ), 136.3 (C ). Found, %: C 64.51;
2
4′
2′
1
1
8. Trofimov, B.A. and Mikhaleva, A.I., Izv. Akad. Nauk
SSSR, Ser. Khim., 1979, no. 12, p. 2840.
H 4.81; N 9.40; S 21.60. Calculated, %: C 64.40;
H 4.73; N 9.39; S 21.49.
1
9. Ivanov, A.V., Barnakova, V.S., Mikhaleva, A.I., and
Trofimov, B.A., Russ. Chem. Bull., Int. Ed., 2013,
vol. 62, no. 11, p. 2557.
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