A new approach to the synthesis of 1,2,3,5-tetrasubstituted pyrroles

Article abstract of DOI:10.1002/hc.20265

2-Propargyl-1,3-dicarbonyl derivatives, namely the corresponding cumulenes and diethoxyphosphoryloxy containing substances in the reactions with primary amines, are converted into the corresponding 1,2,3,5-tetrasubstituted pyrroles.

Full text of DOI:10.1002/hc.20265

Heteroatom Chemistry
Volume 18, Number 3, 2007
A
New Approach to the Synthesis of
1
,2,3,5-Tetrasubstituted Pyrroles
1 1 1
2
S. A. Vizer, E. H. Dedeshko, K. B. Yerzhanov, and V. M. Dembitsky
1
Bekturov Institute of Chemical Sciences MES Kazakhstan, 106 Sh. Walikhanov Street,
Almaty 050010, Kazakhstan
2
Department of Organic Chemistry, Hebrew University of Jerusalem, P.O. Box 39231,
Jerusalem 91391, Israel
Received 26 January 2006; revised 23 March 2006
rolecarboxylates from ethyl bromopyruvate and
aminoacetic thioamides via a cyclocondensation re-
action [4]. Brandsma et al. described highly efficient
one-pot synthesis of the 1,2,3,5-tetrasubstituted
pyrroles starting from the alkyl isothiocyanates
and the 2-alkynyl amines or the 2-alkynyl ethers
ABSTRACT: 2-Propargyl-1,3-dicarbonyl deriva-
tives, namely the corresponding cumulenes and
diethoxyphosphoryloxy containing substances in the
reactions with primary amines, are converted into
the corresponding 1,2,3,5-tetrasubstituted pyrroles.
ꢀ
C
2007 Wiley Periodicals, Inc.
8:220–225, 2007; Published online in Wiley InterScience
www.interscience.wiley.com). DOI 10.1002/hc.20265
Heteroatom Chem
[5]. The 1,2,3,5-tetrasubstituted pyrroles can also
1
(
be synthesized in good yields in a one-pot,
three-step, four-component process by a coupling-
isomerization-Stetter reaction-Paal-Knorr sequence
of an electron-poor (hetero)aryl halide, a termi-
nal propargyl alcohol, an aldehyde, and a primary
amine [6]. Arcadi et al. described a synthesis of
the chiral 1,2,3,5-substituted pyrrole derivatives via
gold catalyzed amination/annulation reactions of the
INTRODUCTION
Pyrroles are very important compounds as they oc-
cur in a large number of the natural products and dis-
play a variety of biological activities [1]. The pyrrole
alkaloids of the prodigiosin family make up an un-
usual group in the chemistry of the natural prod-
ucts [2a]; prodigiosin and its derivatives showed
high cytotoxic and/or anticancer activity [2b–e]. The
tetrasubstituted pyrrole derivatives displayed an-
tiproliferative activity against human promyelocytic
leukemia cell line HL60 [3a], antiviral [3b], and anti-
inflammatory activities [3c].
2
-propynyl-1,3-dicarbonyl compounds [7]. The 2-
(2-bromoallyl)-1,3-dicarbonyl compounds were con-
verted into the ꢀ-enamino, ꢀ-hydrazino esters and
ketones, followed by a base-promoted cyclization,
leading to the formation of the corresponding
1
,2,3,5-tetrasubstituted pyrroles [8].
In our previous work on the pyrrole chemistry
[9], we have described a synthesis of the substituted
pyrroles and dipyrroles in high yields using a new
synthetic method under the mild conditions in the
Glaser coupling reaction.
During the last two decades, a few publications
on the synthesis of 1,2,3,5-tetrasubstituted pyrrole
derivatives have been reported. Thus, Mansour and
Sauve synthesized the 1,2,3,5-tetrasubstituted pyr-
RESULTS AND DISCUSSION
Correspondence to: V. M. Dembitsky; e-mail: dvalery@cc.huji.
We had earlier shown that in the Glaser reaction, the
ꢁ-propargyl-substituted ꢀ-dicarbonyl compounds 1
ac.il.
ꢀ
c 2007 Wiley Periodicals, Inc.
2
20

New Approach to the Synthesis of 1,2,3,5-Tetrasubstituted Pyrroles 221
The pyrroles 7–12 have been isolated by column
chromatography on silica gel. Some degradation
and resinification observed in this process lead to de-
crease in their yields. It has to store the pyrroles 7–
12 at a reduced temperature and in an inert atmo-
sphere because they will quickly resinificate at the
room temperature. The data of an elemental analy-
1
sis (Table 1), the IR (Table 2), H NMR (Table 3), and
1
3
C NMR (Table 4) spectra corroborate a composi-
tion and a structure of the pyrroles 7–12. The inten-
−
1
sive bands at 1360–1448 cm characteristic for the
valency oscillations of a pyrrole ring, the bands at
1
−
1
524–1656 m from a O C C C N conjugate sys-
tem for the 3-acetylsubstituted pyrroles 7–9 and at
−
1
SCHEME 1
1
520–1728 cm for the 3-carboethoxy pyrroles 10–
2 are in the IR spectra. There are the characteristic
1
bands for the functional groups of the N-substituents
in the spectra also (Table 2).
and 2 gave polyfunctional-substituted cumulenes 3
and 4 in a pyridine–methanol solution in the pres-
ence of cupric chloride [9], and with the diethylphos-
phoric acid chloride the same 1 and 2 gave enolphos-
phates 5 and 6 [10] (Scheme 1).
Now we have found that the N-substituted 2,5-
dimethyl-3-acetyl (ethoxy carbonyl) pyrroles 7–12
are formed in a good yield by refluxing of the cumu-
lenes 3 and 4 with primary amines (benzylamine,
1
In the pyrroles 7–9 H NMR spectra, three sin-
glets are presented from three methyl groups at 2.01–
1
2
.54 ppm (Table 3). In the pyrroles 10–12 H NMR
spectra, two singlets are appeared from two methyl
groups directly bounded with a pyrrole ring at 2.09–
2
.50 ppm and the resonance signals from the ethoxyl
radical: a quartet at 4.1–4.2 ppm and a triplet at 1.2–
.3 ppm. A singlet at 6.1–6.3 ppm from one proton
1
2-vinyloxyethylamine, homoveratrylamine) in ben-
gave the proof of one hydrogen atom present in a
pyrrole’s ring. The characteristic signals for the N-
zene or in methylene chloride in the presence of
˚
the 4 A molecular sieves (Scheme 2). The N-ben-
1
substituents are also observed in the H NMR spectra
zylpyrroles 7 and 10 were also obtained by refluxing
of the cumulenes 3 and 4 with the benzylamine in
a benzene medium in an apparatus equipped with a
Dean–Stark trap under an argon atmosphere.
of pyrroles 7–12 (Table 3).
13
In the C NMR spectra of the pyrroles 7–12,
the four signals are appeared in a characteristic area
1
07–136 ppm (Table 4). In the monoresonance spec-
tra, it looks as three singlets and one doublet signals.
The presence of three methyl groups is corroborated
by three quadruplets at 11.5, 12.0, and 28.5 ppm in
the monoresonance spectra.
The formation of the dipyrrole 13 was reg-
istrated only in the reactions of cumulene 3
with 2-vinyloxyethylamine at room temperature in
5
% yield, as it was shown by a chromatomass-
spectrometry method (the mass spectrum of dipyr-
+
role 13, m/z: M 412(1), 343(1), 222(1), 221(1),
2
1
1
1
1
7
4
20(1), 219(1), 208(3), 207(20), 206(8), 193(6),
92(40), 179(9), 178(11), 165(5), 164(20), 163(4),
62(2), 152(3), 151(8), 150(7), 149(20), 138(4),
37(12), 136(16), 135(5), 134(6), 122(21), 121(28),
20(20), 108(20), 107(10), 95(9), 94(10), 93(9), 80(5),
9(8), 77(12), 70(22), 57(10), 56(30), 55(13), 45(30),
4(38), 43(100), 42(50), 41(30), 40(15), 39(15)).
We found that the diethoxyphosphoryloxy
derivatives of the ꢀ-dicarbonyl compounds, namely
the 2-acetyl-1-methylpent-1-en-4-ynyldiethyl ester
of the phosphoric acid 5 and the ethyl-2-[1-
(diethoxyphosphoryloxy)ethyledene]pent-4-ynoate
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

2
22 Vizer et al.
TABLE 1 Physical, Chemical Characteristics and Analytical Data for Pyrroles 7–12
Found, Calculated (%)
Molecular
Yield (%)
a
f
◦
Ab
Bb
Formula
C
H
N
R
M.p. ( C) (Solvent)
7
8
9
1
1
1
C15H17NO
C12H17NO2
C18H23NO3
C16H19NO2
C13H19NO3
C19H25NO4
79.10, 79.26
69.74, 69.54
71.66, 71.73
74.58, 74.68
66.07, 65.80
69.02, 68.86
7.60, 7.54
8.31, 8.27
7.57, 7.69
7.25, 7.44
8.20, 8.07
7.72, 7.60
–
–
–
0.8
0.6
0.5
0.6
0.7
0.6
–
89
73
50
75
35
75
70
65
69
74
82
61
63–65 (hexane)
–
0
1
2
5.51, 5.44
5.98, 5.90
–
41–42 (hexane)
–
–
a
Silufol, Ph-H:Me
2
CO = 5:1.
b
A: yields of pyrroles obtained from cumulenes; B: yields of pyrroles obtained from enolphosphates.
TABLE 2 IR Data for Pyrroles 7–12, ν (cm 1
−
)
7
8
9
1
1
1
1656 (N C C C O), 1312, 1416, 1472, 1541 (pyrrole), 696, 728 (Ph)
1652 (N C C C O), 1364, 1384, 1420, 1524, 1548, 1576 (pyrrole), 1008, 1200 (C O C)
1652 (N C C C O), 1364, 1384, 1420, 1524, 1548, 1576 (pyrrole), 690, 724 (Ph)
1728 (O C O), 1376, 1400, 1448, 1520, 1560 (pyrrole), 688, 720, 1608 (Ph)
1728 (O C O), 1632 (C C), 1360, 1392, 1448, 1520 (pyrrole)
0
1
2
1728 (O C O), 1376, 1400, 1448, 1526, 1548 (pyrrole), 694, 734, 1600 (Ph)
TABLE 3 1H NMR Data for Pyrroles 7–12, δ (ppm) and J (Hz)
7
8
2.12 (3H, s, Pyr-CH ), 2.39 (3H, s, Pyr-CH ), 2.47 (3H, s, C(O)CH ), 5.02 (2H, s, N CH -Ph); 6.28 (1H, brs,
Pyr-H), 6.82–7.30 (5H, m, Ph)
3
3
3
2
2.22 (3H, s, Pyr-CH ), 2.33 (3H, s, Pyr-CH ), 2.54 (3H, s, C(O)CH ); 3.82 (2H, t, J = 6.0, N CH CH2 O), 4.05
3
3
3
2
(
2H, t, J = 6.0, N CH CH O); 4.00 (1H, dd, J = 2.4, 6.9, CH CH , cis); 4.13 (1H, dd, J = 2.7, 14.1,
2
2
2
CH CH , trans), 6.19 (1H, brs, Pyr-H); 6.36 (1H, dd, J = 6.9, 4.4, O CH CH )
2
2
9
1
1
2.00 (3H, s, Pyr-CH ), 2.34 (3H, s, Pyr-CH ), 2.44 (3H, s, C(O)CH ); 2.82 (2H, t, J = 7.2, N CH CH -Ar), 3.95
3
3
3
2
2
(
2H, t, J = 7.2, N CH CH -Ar), 3.75 (3H, s, OCH ); 3.84 (3H, s, OCH ), 6.16 (1H, brs, Pyr-H), 6.34 (1H, d,
2
2
3
3
J = 2.1, Ar-H), 6.61 (1H, dd, J = 2.1, 8.1, Ar-H); 6.76 (1H, d, J = 8.1, Ar-H)
0
1
1.32 (3H, t, J = 7.2, OCH CH ), 2.09 (3H, s, Pyr-CH ), 2.43 (3H, s, Pyr-CH ); 4.21 (2H, q, J = 7.2,
2
3
3
3
OCH CH ), 4.95 (2H, s, N CH -Ph), 6.33 (1H, brs, Pyr-H); 6.86 (2H, d, J = 6.3, 2Ph-H), 7.22–7.31 (3H, m,
2
3
2
3
Ph-H)
1.30 (3H, t, J = 7.2, OCH CH ), 2.20 (3H, s, Pyr-CH ), 2.53 (3H, s, Pyr-CH ); 3.80 (2H, t, J = 6.0,
2
3
3
3
N CH CH O), 4.04 (2H, t, J = 6.0, N CH CH O); 4.01 (1H, dd, J = 2.4, 6.9, CH CH , cis), 4.13 (1H,
2
2
2
2
2
dd, J = 2.4, 14.4, CH CH , trans); 4.22 (2H, q, J = 7.2, O CH CH ), 6.25 (1H, brs, Pyr-H), 6.36 (1H, dd,
2
2
3
J = 6.9, 14.4, CH CH )
2
12
1.23 (3H, t, J = 7.2, OCH CH ), 1.93 (3H, s, Pyr-CH ), 2.16 (3H, s, Pyr-CH ); 2.77 (2H, t, J = 6.9,
2
3
3
3
N CH CH -Ph), 3.40 (2H, q, J = 6.9, N CH CH -Ph), 387 (3H, s, OCH ); 3.89 (3H, s, OCH ), 4.06 (2H, q,
2
2
2
2
3
3
J = 7.5, OCH CH ), 6.22 (1H, s, Pyr-H), 6.71–6.84 (3H, m, Ar-H)
2
3
6
, gave the same pyrroles 7–12 by refluxing in the
pyrroles 3–12 (Scheme 3). It is worthnoting that the
diethyloxyphosphoryl derivatives 5 and 6 are rather
stable when heated in the aproton solvents in the
presence of a catalytic amount of p-toluenesulfonic
acid and in the absence of the nucleophiles and not
transformed for 20 h.
benzene with primary amines in the presence of
the 4 A molecular sieves and the catalytic amounts
˚
of the p-toluenesulfonic acid. Probably, a reaction
may proceed through the following stages: a proton
of a catalyst and an amine attack the phosphoryl
derivative 5 (or 6), and an amine substitutes a di-
ethoxyphosphoryloxy group giving the intermediate
enamine A. Simultaneously, a proton—a catalyst of
a process—is regenerated. The enamine A through
the imine B passes in the enamine C, which by
an intramolecular attack of a nitrogen atom on
a carbon–carbon triple bond is cyclized into the
The reactions of 3-acetylhex-5-yn-2-one 1 and
ethyl-2-acetylpent-4-ynoate 2 with the same primary
amines in the similar conditions (namely under re-
˚
fluxing in benzene at 8 h in the presence of the 4 A
molecular sieves and p-toluenesulfonic acid) give
only the mixtures of imines 14–19, enamines 20–
25, and pyrroles 7–12 having a very small content of
Heteroatom Chemistry DOI 10.1002/hc

New Approach to the Synthesis of 1,2,3,5-Tetrasubstituted Pyrroles 223
SCHEME 3
SCHEME 4
the pyrroles 7–12 as it was established by an anal-
ysis for the spectral data of the reaction mixtures
physical characteristics were similar to those de-
scribed in the literature [11]. The IR spectra were
recorded on a Specord M-80 spectrometer for the
(Scheme 4).
1
13
solutions in CCl
4
. The H and C NMR spectra were
measured on a Mercury-300 spectrometer (300 MHz
CONCLUSION
1
13
for H, 75.457 MHz for C), using HMDS as an
internal standard. The mass spectra were measured
on an HP 5972 instrument under the standard con-
ditions (EI, 70 eV). A reaction course and a purity of
the compounds were monitored by TLC on Silufol
UV-254 plates in a benzene:acetone (5:1 or 10:1)
It has been established that tetrasubstituted cumu-
lenes 3 and 4 gave 1,2,3,5-tetrasubstituted pyrroles
7
–12 in good and high yields in the reactions with
primary amines. This process is accompanied by the
splitting off a central double bond for a cumulene’s
system. It has been found that the same pyrroles
mixture using Chromatoscop instrument or I
visualization.
2
for
7
–12 can be obtained in the mild conditions in high
yields in the reactions of enolphosphates 5 and 6 with
primary amines.
General Procedures for the Synthesis of
1,2,3,5-Tetrasubstituted Pyrroles
EXPERIMENTAL
Synthesis from Cumulenes. A mixture of 3
The 2-propargyl-1,3-dicarbonyl compounds 1 and
or 4 (0.001 mol), fresh distilled primary amine
(0.002 mol), and the 4 A molecular sieves (1 g) in
˚
2
were synthesized by a routine method and their
Heteroatom Chemistry DOI 10.1002/hc

2
24 Vizer et al.
TABLE 4 13C NMR (Monoresonance) Data for Pyrroles 7 12, δ (ppm) and J (Hz)
7
8
11.4 (q, J = 129, Pyr-CH ), 11.8 (q, J = 128, Pyr-CH ), 28.2 (q, J = 125, C(O)CH ); 46.3 (t, J = 138, N CH -Ph),
3
3
3
2
1
08.1 (d, J = 170, Pyr-CH), 119.9 (s, Pyr-C C(O)), 127.5 (s, Pyr-C CH ); 134.8 (s, Pyr-C CH ), 125.2 (d,
3
3
J = 156, Ph), 127.1 (d, J = 161, Ph), 128.6 (d, J = 160, Ph); 136.4 (s, Ph), 194.8 (s, C O)
11.6 (q, J = 129, Pyr-CH ), 12.1 (q, J = 127, Pyr-CH ), 28.3 (q, J = 127, C(O)CH ); 42.2 (t, J = 138,
3
3
3
N CH CH O), 66.1 (t, J = 139, N CH CH O), 87.0 (t, J = 159, OCH CH ); 108.1 (d, J = 170,
2
2
2
2
2
Pyr-C H), 119.9 (s, Pyr-C C(O)), 127.5 (s, Pyr-C CH ), 134.7 (s, Pyr-C CH ); 150.8 (d, J = 183,
3
3
OCH CH ), 195.7 (s, C O)
2
9
11.8 (q, J = 129, Pyr-CH ), 12.1 (q, J = 127, Pyr-CH ), 28.5 (q, J = 127, C(O)CH ); 36.3 (t, J = 125,
3
3
3
N CH CH -Ar), 45.1 (t, J = 142, N CH CH -Ar); 55.8 (qd, q, J = 144, d, J = 10, 2OCH ), 108.1 (d,
2
2
2
2
3
J = 170, Pyr-CH), 119.9 (s, Pyr-C C(O)); 127.4 (s, Pyr-C CH ), 130.2 (s, Pyr-C CH ), 11.3 (d, J = 154,
3
3
Ar-CH), 112.0 (d, J = 154, Ar-CH); 120.8 (d, J = 154, Ar-CH), 134.6 (s, Ar-C C ), 148.0 (s, Ar-C O), 149.0 (s,
Ar-C O), 194.9 (s, C O)
1
1
1
0a
10.9 (q, J = 105, Pyr-CH ), 11.7 (q, J = 106, Pyr-CH ), 14.2 (q, J = 107, OCH CH ); 46.4 (t, J = 103, OCH Ph),
3
3
2
3
2
5
1
1
8.8 (t, J = 115, OCH CH ), 107.4 (d, J = 121, Pyr-C H); 110.8 (s, Pyr-C C(O)), 125.2 (d, J = 104, 2C-Ph),
2
3
27.0 (d, J = 103, Ph), 127.9 (s, Pyr-C CH ); 128.5 (d, J = 104, 2C-Ph), 135.1 (s, Pyr-C CH ), 136.7 (s, Ph),
3
3
65.3 (brs, O C O)
1
11.4 (q, J = 129, Pyr-CH ), 12.3 (q, J = 127, Pyr-CH ), 14.5 (q, J = 126, OCH CH ); 42.6 (t, J = 137,
3
3
2
3
N CH CH O), 59.1 (t, J = 147, OCH CH ), 66.5 (t, J = 141, N CH CH O); 87.2 (t, J = 157, OCH CH ),
2
2
2
3
2
2
2
1
07.7 (d, J = 173, Pyr-CH), 111.1 (s, Pyr-C(O)), 127.8 (s, Pyr-C CH ); 135.4 (s, Pyr-C CH ), 151.2 (d,
3
3
J = 183, OCH CH ), 165.6 (s, O C O)
2
2
14.0 (q, J = 129, Pyr-CH ), 14.1 (q, J = 127, Pyr-CH ), 16.7 (q, J = 134, OCH CH ); 36.8 (t, J = 125,
3
3
2
3
N CH CH -Ar), 44.9 (t, J = 142, N CH CH -Ar); 55.6 (qd, q, J = 144, d, J = 10, 2OCH ), 58.5 (t, J = 147,
2
2
2
2
3
OCH CH ), 110.4 (d, J = 172, Pyr-CH); 112.5 (d, J = 154, Ar), 119.5 (s, Pyr-C C(O)), 121.2 (d, J = 154, Ar),
2
3
1
30.7 (s, Pyr-C CH ); 131.2 (s, Pyr-C CH ), 134.7 (s, Ar), 147.6 (s, Ar), 148.8 (s, Ar), 161.7 (s, O C O)
3 3
aSpectrum was recorded under partial quench of the resonance with protons.
benzene or methylene chloride (10–20 mL) was re-
fluxed 1–6 h till a full conversion of 3 or 4 was gained
according the thin-layer chromatography data. Then
a reaction mixture was cooled to room temperature,
and acetic acid was added up to a neutral reaction.
The molecular sieves were filtered off and the solu-
tion was concentrated. The pyrroles 7–12 were pu-
rified by column chromatography on silica gel with
an elution by benzene and then by benzene–acetone
in different ratios (20:1, 10:1, 5:1, 2:1, 1:1).
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Synthesis from Enolphosphates. A mixture of 5
or 6 (0.0012 mol), fresh distilled primary amine
(
toluenesulfonic acid (0.01 g) in 15 mL benzene was
refluxed 1–3 h till a full conversion of an amine
was gained according the thin-layer chromatography
data. Then the reaction mixture was cooled to room
temperature. The molecular sieves were filtered off
and the solution was concentrated. The pyrroles
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˚
0.001 mol), the 4 A molecular sieves (3 g), and p-
2
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–12 were purified by column chromatography on
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4
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