One-pot synthesis of [4-(tert-butyl)-1H-pyrrol-3-yl](phenyl)methanone from tosylmethyl isocyanide and carbonyl compound

Article abstract of DOI:10.1007/s10593-018-2335-6

[Figure not available: see fulltext.] An efficient one-pot synthetic procedure for [4-(tert-butyl)-1H-pyrrol-3-yl](phenyl)methanone was elaborated using acetophenone and trimethylacetaldehyde in the presence of TosMIC and mild base LiOH·H₂O. Th

Full text of DOI:10.1007/s10593-018-2335-6

DOI 10.1007/s10593-018-2335-6
Chemistry of Heterocyclic Compounds 2018, 54(7), 700–702
One-pot synthesis of [4-(tert-butyl)-1H-pyrrol-3-yl](phenyl)methanone
from tosylmethyl isocyanide and carbonyl compound
1
2,3
Ramandeep Kaur , Kapil Kumar *
1
Department of Pharmaceutical Chemistry, Indo-Soviet Friendship College of Pharmacy (ISFCP),
Moga, Punjab-142001, India; e-mail: rmnkaur30@gmail.com
2
School of Pharmaceutical Sciences, Apeejay Stya University,
Sohna-Palwal Road, Sohna, Gurgaon, Haryana-122103, India;
e-mail: kapil.py@gmail.com
National Institute of Pharmaceutical Education and Research,
Sector-67, S.A.S. Nagar, Mohali, Punjab-160062, India
3
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted March 21, 2018
Accepted June 18, 2018
2
018, 54(7), 700–702
1
. LiOH·H2O, EtOH
rt, 25–40 min
O
O
t-Bu
O
Me
+
t-Bu
H
2. TosMIC
8–65%
R
N
R
H
5
R = H, Me, Hal
An efficient one-pot synthetic procedure for [4-(tert-butyl)-1H-pyrrol-3-yl](phenyl)methanone was elaborated using acetophenone and
2
trimethylacetaldehyde in the presence of TosMIC and mild base LiOH·H O. This method is very economical for the synthesis of pyrrole
derivatives and was successfully utilized with good yields.
Keywords: lithium hydroxide, pyrrole, TosMIC, cycloaddition.
Pyrrole is considered to be a priviledged heterocycle
because of its therapeutic importance including anti-
p-Tosylmethyl isocyanide (TosMIC) (Fig. 1) has atypical
structure and reactivity which had been discussed for more
than four decades. It is considered to be the most versatile
synthon derived from methyl isocyanide exhibiting a
multifaceted chemistry that is of great utility in organic
synthesis.1
TosMIC has been a noteworthy invention since a number of
valuable intermediates like oxazole and oxazoline, imidazole,
1,2,4-triazole, thiazole, ketones, and α-hydroxyaldehydes
can be synthesized from a single synthon. The transfor-
mation includes a dipolar [1,3] cycloaddition reaction
involving base-induced 1,3-dipole formation followed by
reaction with dipolarophile to form a five-membered
heterocycle which can be custom-made to an assortment of
constructive intermediates. Despite the adaptability of this
method to various heterocycles, we found very restricted
literature on the synthesis of pyrrole derivatives. The bases
which are generally used are sodium hydride, potassium
1
2
3
4
bacterial, antifungal, antiviral, anti-inflammatory, and
5
anticancer activities. It is an important structural moiety
found in complex macromolecules comprising porphyrins
of heme, chlorins, bacteriochlorins, chlorophyll, porphyrino-
gens.6 It has also been found to be an important core unit
for many biologically active molecules such as tolmetin,
atorvastatin, chlorfenapyr, premazepam, pyrvinium, roseo-
6–18
–8
8
philin. Therefore, pyrrole cycle is an imperative structural
framework found in a wide range of biologically active
natural products and pharmaceutically active agents.9
Synthesis of various substituted pyrroles always poses a
serious problem due to functional group complexity and
stability issues. Among various methods, few important
strategies are employed for the synthesis of pyrrole deriva-
tives such as: a) condensation reaction of α-aminocarbonyl
,10
compounds with activated ketones (Knorr pyrrole
synthesis);8
,9,11
b) reactions of α-halocarbonyl compounds
with β-keto esters and ammonia (Hantzsch pyrrole
synthesis);12 c) reaction of 1,4-dicarbonyl compounds with
10,13
primary amines (Paal–Knorr synthesis).
Pyrrole chemical
transformations mainly include electrophilic substitution
because of the presence of lone pair of electrons on the
nitrogen and consequent stability of σ-complexes.1
4,15
Figure 1. Structure of p-tosylmethyl isocyanide.
0
009-3122/18/54(7)-0700©2018 Springer Science+Business Media, LLC
700

Chemistry of Heterocyclic Compounds 2018, 54(7), 700–702
Scheme 1
tert-butoxide, etc. Despite ensuring reasonable yield these
bases typically necessitate anhydrous conditions and inert
atmosphere. Thus there has been stern requirement to
develop conditions which can be apposite for environment
Table 1. Reaction time and yields
of (aryl)[4-(tert-butyl)-1H-pyrrol-3-yl]methanones 2a–e
Compound
R
Total reaction time, min
Yield, %
1
9
as well as industrial scale-up.
Based on our interest on heterocyclic chemistry and
2a
2b
H
Me
Br
Cl
F
35
40
30
27
25
62
58
65
64
64
2
0–22
development of synthetic methodologies,
to develop an efficient approach for the synthesis of
,4-disubstituted pyrroles. Previously, we synthesized
pyrrole derivatives using TosMIC and aromatic
our aim was
2
c
2
d
3
2
e
20f
aldehydes or aliphatic aldehydes containing α-hydro-
gen.2 It has been established that LiOH·H
1b
O in ethanol
Synthesis of [4-(tert-butyl)-1H-pyrrol-3-yl](aryl)metha-
nones 2a–e (General method). A mixture of trimethyl-
acetaldehyde (86 mg, 1.0 mmol), acetophenone 1a–e
2
can work as efficient base for the synthesis of chalcone
which is formed as the intermediate in this reaction. Since it
was not essential to use sturdy base for deprotonation of
TosMIC that was apparent from synthesis of imidazole,
oxazole, and triazole derivatives, we thought of using
(1.0 mmol), and LiOH·H O (4 mg, 0.1 mmol) in EtOH
2
(3 ml) was stirred at room temperature. The progress of the
reaction was monitored by TLC. After completion of the
LiOH·H
2
O for the [2+3] cycloaddition reaction involving
reaction, LiOH·H O (46 mg, 1.1 mmol) and TosMIC
2
TosMIC and α,β-unsaturated compound in which
potassium carbonate has been generally used. Therefore,
we made an attempt to carry out one-pot synthesis by
stirring a mixture of acetophenones 1a–e, trimethylacet-
(215 mg, 1.1 mmol) were added. Initially, chalcone
dissolved and shortly thereafter pyrrole derivative was
formed. Reaction was monitored by TLC. Once reaction
got completed, water (10 ml) was added and the product
was extracted with EtOAc (2×10 ml). Organic layer was
aldehyde, LiOH·H O in ethanol at room temperature. This
2
led to the formation of chalcone A which further reacted
with TosMIC. The reaction was carefully monitored using
TLC. It was observed that initially chalcone tended to
dissolve and soon after that pyrrole derivatives were
formed. The precipitates formed were filtered and washed
with water. Analysis of the precipitated solids revealed that
dried using Na
2
SO and evaporated under reduced pressure.
4
The product was isolated from the crude mixture by
column chromatography on silica gel (60–120 mesh) using
EtOAc–hexane mixture as eluent. Pyrrole derivatives 2a–e
were obtained in a form of white solids, yields are given in
Table 1.
(
aryl)[4-(tert-butyl)-1H-pyrrol-3-yl]methanones 2a–e have
[4-(tert-Butyl)-1H-pyrrol-3-yl](phenyl)methanone (2a).
1
been formed (Scheme 1).
Mp 186–188°C. H NMR spectrum, δ, ppm: 8.42 (1H,
Various substituted acetophenones were tested to
generalize the scope of reaction and affordable yields were
obtained in all the cases (Table 1). The reaction rates were
faster and good yields were obtained with acetophenones
containing electron-deficient aromatic cycles in compa-
rison to electron-rich cycles which took more reaction time
and gave moderate yields.
br. s, NH); 7.76–7.74 (2H, m, H Ph); 7.52–7.39 (3H, m,
H Ph); 7.02–7.01 (1H, s, H pyrrole); 6.67–6.66 (1H, s,
13
H pyrrole); 1.57 (9H, s, C(CH ) ). C NMR spectrum,
3
3
δ, ppm: 192.5; 141.8; 136.5; 131.1; 129.6; 129.3; 127.9;
+
122.4; 116.2; 31.6; 30.6. Found, m/z: 250.1208 [M+Na] .
C H17NNaO. Calculated, m/z: 250.1208.
15
[4-(tert-Butyl)-1H-pyrrol-3-yl](4-methylphenyl)metha-
1
Thus, the above strategy afforded (aryl)[4-(tert-butyl)-
none (2b). Mp 164–166°C. H NMR spectrum, δ, ppm:
8.42 (1H, br. s, NH); 7.68–7.66 (2H, m, H Ar); 7.26–7.20
(2H, m, H Ar); 7.00–6.99 (1H, m, H pyrrole); 6.65–6.64
1
H-pyrrol-3-yl]methanones with reasonably good yields in
a one-pot reaction using lithium hydroxide as a base and
inexpensive reagent p-tosylmethyl isocyanide.
(1H, m, H pyrrole); 2.41 (3H, s, CH
3
); 1.42 (9H, s, C(CH
C NMR spectrum, δ, ppm: 192.5; 141.6; 139.0; 136.3;
29.5; 129.1; 128.6; 122.4; 116.1; 31.6; 30.7; 21.5. Found, m/z:
3
) ).
3
13
Experimental
1
1H and 13C NMR spectra were registered on a Bruker
264.1368 [M+Na] . C16H19NNaO. Calculated, m/z: 264.1364.
+
spectrometer (400 and 100 MHz, respectively) in CDCl
3
,
(4-Bromophenyl)[4-(tert-butyl)-1H-pyrrol-3-yl]metha-
1
internal standard TMS. High-resolution mass spectra were
registered on a Oracle spectrometer, using electrospray
ionization. Melting points were determined on a Mettler
Toledo apparatus. Column chromatography was performed
on silica gel (60–120 mesh) using EtOAc–hexane mixture
none (2c). Mp 162–164°C. H NMR spectrum, δ, ppm:
8.48 (1H, br. s, NH); 7.63–7.54 (4H, m, H Ar); 6.98 (1H, s,
H pyrrole); 6.66 (1H, s, H pyrrole); 1.41 (9H, s, C(CH ) ).
3
3
13
C NMR spectrum, δ, ppm: 191.2; 140.6; 136.6; 131.1;
130.8; 129.6; 125.8; 122.1; 116.4; 31.6; 30.5. Found, m/z:
+
(
3:7) as eluent. TLC was performed on Merk TLC plates,
328.0316 [M+Na] . C15
328.0313.
H16BrNNaO. Calculated, m/z:
eluent EtOAc–hexane, 1:10, visualization by UV light.
7
01

Chemistry of Heterocyclic Compounds 2018, 54(7), 700–702
[
4-(tert-Butyl)-1H-pyrrol-3-yl](4-chlorophenyl)metha-
Bergamini, A.; Crespan, E.; Maga, G.; Di Santo, R.
ChemMedChem 2006, 1, 1379.
1
none (2d). Mp 176–178°C. H NMR spectrum, δ, ppm:
1
2. (a) Hantzsch, A. Ber. 1890, 23, 1474. (b) Feist, F. Ber. 1902,
8
.45 (1H, br. s, NH); 7.70–7.68 (2H, m, H Ar); 7.40–7.38
3
5, 1537. (c) Trautwein, A. W.; Süßmuth, R. D.; Jung, G.
(
(
2H, m, H Ar); 6.99–6.98 (1H, m, H pyrrole); 6.67–6.66
1
3
Bioorg. Med. Chem. Lett. 1998, 8, 2381. (d) Roomi, M. W.;
MacDonald, S. F. Can. J. Chem. 1970, 48, 1689.
1H, m, H pyrrole); 1.41 (9H, s, C(CH ) ). C NMR
3
3
spectrum, δ, ppm: 191.1; 140.1; 137.3; 136.6; 130.6; 129.5;
1
3. (a) Paal, C. Ber. 1885, 18, 367. (b) Knorr, L. Ber. 1885, 18,
1
[
28.2; 122.1; 116.4; 31.6; 30.5. Found, m/z: 284.0815
2
99. (c) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M.
+
M+Na] . C15
H
16ClNNaO. Calculated, m/z: 284.0818.
Eur. J. Org. Chem. 2005, 5277. (d) Rao, H. S. P.; Jothilingam, S.;
Scheeren, H. W. Tetrahedron 2004, 60, 1625.
[
4-(tert-Butyl)-1H-pyrrol-3-yl](4-fluorophenyl)metha-
1
none (2e). Mp 214–216°C. H NMR spectrum, δ, ppm
14. (a) Garabatos-Perera, J. R.; Rotstein, B. H.; Thompson, A.
J. Org. Chem. 2007, 72, 7382. (b) The Chemistry of Pyrroles;
Jones, R. A.; Bean, G. P., Eds.; Academic Press: London,
(
J, Hz): 8.42 (1H, br. s, NH); 7.80–7.76 (2H, m, H Ar);
7
6
.11–7.07 (2H, m, H Ar); 7.00–6.98 (1H, m, H pyrrole);
1
977, p. 525.
.67 (1H, t, J = 2.3, H pyrrole); 1.42 (9H, s, C(CH ) ).
3
3
1
3
15. Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.;
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36.5; 131.7; 129.1; 122.3; 116.3; 115.0; 114.8; 31.6; 30.6.
3
753.
+
Found, m/z: 268.1112 [M+Na] . C15
H16FNNaO. Calcu-
1
6. Van Leusen, A. M.; Hoogenboom, B. E.; Houwing, H. A.
lated, m/z: 268.1114.
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1
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02