Exploitation of dual character of CN moiety in the synthesis of uniquely decorated 3 H-pyrroles: A rare observation

Article abstract of DOI:10.1021/ol402950a

This is the first report of an innovative, one-pot, organocatalyzed, multicomponent synthesis of 3H-pyrroles from ketones, thiols, and malononitrile in ecofriendly solvent water. The approach to 3H-pyrroles presented herein offers, for the first time, an unprecedented coupling which leads to the construction of the nitrogen containing ring without starting from any amine moiety. In this context, cyanide-based multicomponent reactions involving the dual nature of the CN moiety has blossomed in an unprecedented way.

Full text of DOI:10.1021/ol402950a

ORGANIC
LETTERS
2
013
Vol. 15, No. 22
622–5625
Exploitation of Dual Character of CN
Moiety in the Synthesis of Uniquely
Decorated 3H‑Pyrroles: A Rare
Observation
5
Paramita Das, Suman Ray, and Chhanda Mukhopadhyay*
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India
cmukhop@yahoo.co.in
Received August 2, 2013
ABSTRACT
This is the first report of an innovative, one-pot, organocatalyzed, multicomponent synthesis of 3H-pyrroles from ketones, thiols, and
malononitrile in ecofriendly solvent water. The approach to 3H-pyrroles presented herein offers, for the first time, an unprecedented coupling
which leads to the construction of the nitrogen containing ring without starting from any amine moiety. In this context, cyanide-based
multicomponent reactions involving the dual nature of the CN moiety has blossomed in an unprecedented way.
5
ꢀ7
3H-pyrrole is a little known ring system with a poten-
tially rich chemistry in terms of rearrangement, addition,
using nitrile ylides; etc.
However, the reaction con-
ditions are often inconvenient and the starting materials
are not easily accessible. Therefore, an alternative way
would be to assemble structures directly from several
readily available and easily diversified building blocks in
a one-pot multicomponent fashion and preferably using
organocatalysis.
1
and cycloaddition reactions. Some 3H compounds showed
antimicrobial activity against Gram-positive bacteria, and
2
some have antitumor activity. Unlike other pyrrole com-
pounds, relatively little attention is paid in the synthesis of
3H-pyrroles presumably because of difficulties associated
with the synthesis of these compounds. Only a few novel
unconventional routes are reported for their synthesis which
We thus wish to disclose the one-pot, organocatalyzed
synthesis of 3H-pyrrole from ketones, a sulfur nucleophile,
and malononitrile in an environmentally benevolent sol-
vent (Scheme 1).
3
involve reaction of electrophiles with 1H-pyrroles; cycliza-
4
tion of open-chain compounds; 1,3 dipolar cycloadditions
(
1) (a) Katritzky, A. R.; Lagowski, J. M. The Principles of Hetero-
cyclic Chemistry; Academic Press: New York, 1968. (b) Sammes, M. P.;
Katritzky, A. R. Adv. Heterocycl. Chem. 1982, 32, 233. (c) Trofimov,
B. A.; Mikhaleva, A. I. Heterocycles 1994, 37, 1193.
Scheme 1. Synthesis of 3H-Pyrrole (4)
(2) (a) Cirrincione, G.; Almerico, A. M.; Dattolo, G.; Aiello, E.;
Grimaudo, S.; Diana, P.; Misuraca, F. Farmaco 1992, 47, 1555. (b)
Cirrincione, G.; Almerico, A. M.; Grimaudo, S.; Diana, P.; Misuraca,
F.; Barraja, P.; Misuraca, F. Farmaco 1996, 51, 49.
(3) Wong, J. L.; Ritchie, M. H. J. Chem. Soc., Chem. Commun. 1970,
1
4
42.
(
4) (a) Leblanc, R.; Corre, E.; Foucaud, A. Tetrahedron 1972, 28,
039. (b) Svilarich-Soenen, M.; Foucaud, A. Tetrahedron 1972, 28, 5149.
(
5) Firestone, R. A. Tetrahedron 1977, 33, 3009.
Inthispresent synthesis, cyanide-basedmulticomponent
ꢀ
(6) McEwen, W. E.; Yee, T. T.; Liao, T. K.; Wolf, A. P. J. Org. Chem.
1
967, 32, 1947.
reactions (CMCRs) involving the dual nature of the CN
(both as a carbon center nucleophile and an electrophile)
moiety blossomed in an unprecedented way, thanks to the
(
7) (a) McEwen, W. E.; Berkebile, D. H.; Liao, T. K.; Lin, Y. S.
J. Org. Chem. 1971, 36, 1459. (b) Xu, X.; Zhang, Y. J. Chem. Soc., Perkin
Trans. 1 2001, 2836.
1
0.1021/ol402950a r 2013 American Chemical Society
Published on Web 10/29/2013

versatility of cyanide chemistry. The most exciting feature
ofthiscommunicationisits mechanism, that we postulated
here involving the dual nature of CN moiety.
Scheme 2. Proposed Mechanism
Mechanistically, it is conceivable that the aromatic
ketones first undergo a Knoevenagel condensation reac-
tion with malononitrile which is a very characteristic reac-
8
tion of carbonyl compounds in the presence of a base.
This is evident from the NMR spectrum of the major
0
product [(5), (R = 4 -Cl-C H -)] isolated after 30min. This
6
4
intermediate (5) underwent nucleophilic attack by thiols
on ꢀCN functionality to give the in situ intermediate 6
(
Scheme 2). Intermediate 6 undergoes cheletropic addition
with a cyanide ion to give an amidine species (7) that
tautomerizes to yield an amino-3H-pyrrole (4). A highly
reactive cyanide species was presumed to be formed by the
nucleophilic attackof thiols onmalononitrile by a mechan-
ism drawn in Scheme 2. This proposition was further sup-
ported by the isolation of the byproduct, 2-(phenylthio)-
acetonitrile (8), formed by the nucleophilic attack of PhSH
on malononitrile which furnishes cyanide ions for the
reaction. Thus, malononitrile acts as a nontoxic cyanide
source in this reaction.
Here, despite Knoevenagel condensation being a net
dehydration of the water molecule, the reaction is favored
in an aqueous medium. A plausible explanation is that
Table 1. Optimization of Reaction Conditions for the
Multicomponent Coupling Reactions
a
water aids in better contact between the catalyst (Et N)
3
and the active methylene compounds through hydrogen
8
b,9
bonding.
Thus, realizing environmental concerns, as
well as the vast utility and scope of reactions carried out in
water, we established water to be the preferred solvent.
The reaction between acetophenone (1a), malononitrile
(
2), and thiophenol (3a) was selected for the survey of
amount
of
yield
of
reactions. The yield decreased substantially with stronger
base catalysts instead; significant tarring was ob-
served (Table 1, entries 1 and 2) probably due to the self-
condensation of the carbonyl compounds at high tempera-
catalyst
(mol %)
temp (°C)/
time (h)
4aa
b
(%)
entry
catalyst
NaOH
solvent
8
1
2
3
4
5
6
7
8
9
10
10
ꢀ
2
H O
2
H O
2
H O
2
H O
100, 2
22
47
ꢀ
ture with stronger bases. Importantly, no product was
K
2
CO
3
100, 2
observed when a background reaction was carried out
without any catalyst (Table 1, entry 3). Interestingly, the
basicity of the common organic bases did not assert any
obvious effect on the product yield. However, pyridine and
ꢀ
100, 20
100, 3
20
20
20
20
20
20
20
20
20
20
20
20
20
guanidine
DBU
86
88
89
62
94
91
84
74
79
64
65
41
21
2
H O
100, 3
piperidine
2
H O
2
H O
2
H O
2
H O
100, 3
Et
Et
3
N
N
60, 10
Et N afforded a slightly better yield than DBU, guanidine,
3
3
100, 3
or piperidine presumably due to the lesser extent of poly-
merization of the ketones with weaker bases such as
pyridine and Et N. However pyridine is potentially harm-
pyridine
100, 3
10
Et
Et
3
N
N
toluene
DMSO
DMF
100ꢀ110, 3
120ꢀ130, 3
120ꢀ130, 3
70ꢀ80, 3
70ꢀ80, 3
50ꢀ60, 3
30ꢀ35, 3
3
11
3
8
a
ful to the experimentalist. Therefore, Et N was our
3
12
13
14
3
Et N
obvious choise of catalyst. Again, temperature played a
significant role since there was only a 62% yield at 60 °C
compared to the 94% yield at 100 °C (Table 1, entries 7
and 8). Albeit the reaction was successful in common high
boiling point organic solvents such as toluene, DMSO,
DMF, etc., the isolated yields were comparatively low
3
Et N
ACN
Et
3
Et
3
Et
3
N
N
N
EtOH
MeOH
DCM
1
1
5
6
a
Reaction conditions: Acetophenone (1 mmol), malononitrile (2 mmol),
thiophenol (2 mmol), different catalysts, different solvents, different
b
temperatures, different times. Isolated yields.
(
Table 1, entries 10ꢀ12). The reaction in low boiling point
solvents (DCM, MeOH) afforded poor yields of 4aa
Table 1, entries 15, 16). However comparatively better
(
yields were obtained in EtOH and acetonitrile (Table 1,
entries 13, 14).
(
8) (a) Mukhopadhyay, C.; Ray, S. Tetrahedron 2011, 67, 7936. (b)
Mukhopadhyay, C.; Das, P.; Butcher, R. J. Org. Lett. 2011, 13, 4664.
9) (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999,
033. (b) Mukhopadhyay, C.; Ray, S. Catal. Commun. 2011, 12, 1496.
With the optimized conditions in hand, to delineate this
approach, the scope and generality of this protocol was
next assessed by employing various ketones, thiols, and
(
1
Org. Lett., Vol. 15, No. 22, 2013
5623

a
Scheme 3. Diversity of Uniquely Decorated 3H-Pyrrole
Figure 1. ORTEP representation of 4aa (CCDC 952788).
a
Scheme 4. Synthesis of Unexpected Pyridine (10)
a
Reaction conditions: Knoevenagel product (5) (1 mmol), thiophe-
nol (1 mmol), isocyanide (1 mmol), Et
1
3
N (20 mol %), reflux in water at
00 °C for 3 h.
Figure 2. ORTEP representation of 10a (CCDC 965798).
difficulty of a Knoevenagel condensation reaction with
electron-rich ketones, the reaction occcured successfully
0
0
with 3 ,4 -dimethoxy acetophenone (4caꢀ4cc). In addi-
tion, the use of aliphatic ketones was also examined
(
4da). The modularity of this pyrrole- forming reaction
a
Reaction conditions: Ketones (1 mmol), malononitrile (2 mmol),
N (20 mol %), reflux in water at 100 °C for 3 h.
sequence was further demonstrated by the use of hetero-
aryl ketones (4faꢀ4fe). It is important to mention that, in
addition to methyl ketones, other substituted alkyl ketones
(e.g., ethyl phenyl ketone and 1,2-diphenylethanone) re-
acted smoothly under the present conditions. The low
reactivity of substituted alkyl ketones (4gaꢀ4ha) in this
reaction which is also reflected in the reaction yield may be
due to the steric crowding among the substituents.
thiols (2 mmol), Et
3
malononitrile. An assembly of 25 compounds was synthe-
sized using this protocol (Scheme 3). Aromatic, alicyclic
4bg), and alkyl thiols (4bh) all afforded good to excellent
yields. It was pleasing to find that sterically bulky naphtha-
lene-2-thiol also reacted very efficiently with no side reac-
tions (4af, 4bf). To further expand the scope of the reaction
the use of different ketones was investigated. Despite the
(
The structures of the compounds were confirmed un-
ambiguously from X-ray single crystal analysis of four
5
624
Org. Lett., Vol. 15, No. 22, 2013

unexpected pyridine compound (10) according to Scheme 4.
The structure of 10a was confirmed by X-ray single crystal
analysis (Figure 2).
Scheme 5. Mechanism of Pyridine Formation
It is worth mentioning that the mechanism of this reac-
tion is a special case which depicts the incorporation of only
one carbon atom from isocyanide to pyridine (Scheme 5).
In conclusion, this present approach to 3H-pyrroles de-
picted herein offers for the first time an unprecedented
coupling of ketones, thiols, and malononitrile which leads
to the construction of the nitrogen-containing ring without
starting from any amine moiety. Thus, this newly devel-
oped protocol is a significant proof of the fact that nitrile is
one of the most versatile functional groups, as it can be
readily transformed into various other functional groups
or reactive intermediates. This novel 3H-pyrrole synthesis
describes an entirely new approach involving the dual role
of the CN moiety (as both a carbon center nucleophile and an
electrophile), an area that remains elusive in current organic
research. Moreover it opens a brand new way to build CꢀC,
CꢀS, and CꢀN bonds in a single operation. All of the
cycloadducts were quite stable and easy to handle under
standard conditions. Furthermore, the presence of a cyano
group in the pyrroles makes them useful synthetic inter-
mediates for the preparation of other nitrogen-containing
distinct compounds 4aa, 4ab, 4bb, 4ha. An ORTEP plot of
4aa is given in Figure 1, and plots of the other compounds
are in the Supporting Information.
1
0
heterocycles. It is hoped that this methodology will be
embraced by the synthetic organic community at large.
After the mechanism of 3H-pyrrole formation was
realized, the question remained regarding what would be
the product if instead of using 2 equiv of malononitrile, the
Knoevenagel product of ketone and malononitrile (inter-
mediate 5) is allowed to react with thiophenol and iso-
cyanide compounds under the same reaction conditions.
We could not isolate the corresponding pyrrole. How-
ever instead of the anticipated 3H-pyrrole we generated an
Acknowledgment. P.D. and S.R. thank the CSIR, New
Delhi for their fellowship (SRF).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(
10) Fontaine, P.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 1555.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
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