Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones

Article abstract of DOI:10.3762/bjoc.10.44

The cyclocondensation of enones with aminoacetonitrile furnishes 3,4-dihydro-2H-pyrrole-2-carbonitriles which can be readily converted to 2,4-disubstituted pyrroles by microwave-induced dehydrocyanation. Alternatively, oxidation of the intermediates produ

Full text of DOI:10.3762/bjoc.10.44

Simple two-step synthesis of 2,4-disubstituted
pyrroles and 3,5-disubstituted pyrrole-2-
carbonitriles from enones
Murat Kucukdisli1, Dorota Ferenc1, Marcel Heinz2, Christine Wiebe2
and Till Opatz*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 466–470.
1Institute of Organic Chemistry, Johannes Gutenberg University of
Mainz, Duesbergweg 10–14, 55128 Mainz, Germany and
2Department of Chemistry, University of Hamburg,
doi:10.3762/bjoc.10.44
Received: 30 October 2013
Accepted: 30 January 2014
Published: 24 February 2014
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Email:
Till Opatz* - opatz@uni-mainz.de
Associate Editor: P. R. Hanson
* Corresponding author
© 2014 Kucukdisli et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
α-aminonitriles; cyclization; heterocycles; microwave-assisted
synthesis; pyrroles
Abstract
The cyclocondensation of enones with aminoacetonitrile furnishes 3,4-dihydro-2H-pyrrole-2-carbonitriles which can be readily
converted to 2,4-disubstituted pyrroles by microwave-induced dehydrocyanation. Alternatively, oxidation of the intermediates
produces 3,5-disubstituted pyrrole-2-carbonitriles.
Introduction
Heterocycles are the largest class of organic compounds [1]. α-(Alkylideneamino)nitriles can be used as versatile and readily
Among them, pyrroles have a distinguished position in the accessible pronucleophiles, e.g. for the construction of γ-amino
chemistry of living organisms due to their close biogenetic acids [32], pyrrolidines [33], as well as pyrroles [34,35]. If an
connection to the porphyrins, the chlorins, and the corrins. additional conjugated double bond is present, the anions of
Furthermore, they are regarded as privileged structures by syn- α-(alkylideneamino)nitriles 3 can undergo an electrocyclic ring
thetic chemists because of widespread applications in medic- closure to furnish 3,4-dihydro-2H-pyrrole-2-carbonitriles 6 after
inal chemistry [2,3] and materials science [4]. Not surprisingly, reprotonation [36]. If the products are devoid of an additional
numerous synthetic methods [5-27] are still being developed for substituent in 2-position, the cyclocondensation can be simply
this compound class although many classical methods such as effected by refluxing a mixture of the enone 1 and aminoaceto-
Hantzsch [28], Knorr [29], Paal–Knorr [30], and Barton–Zard nitrile hydrochloride (2) in pyridine. The base-induced dehydro-
[31] have already found their way into the textbooks of organic cyanation of compounds 6 does not produce appreciable yields
chemistry.
of pyrroles 7 since the abstraction of the most acidic proton
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Beilstein J. Org. Chem. 2014, 10, 466–470.
leads to a stable anion reluctant to undergo α-elimination of acidic conditions. Several strong and weak acids were screened
cyanide. Instead, the anions 8 can be added in vinylogous at temperatures ranging from 0–150 °C. The formation of
fashion to α,β-unsaturated carbonyls producing intermediates, pyrrole 7a was observed in acetic acid under microwave heating
the exhaustive reduction of which leads to highly substituted but many byproducts were formed under these conditions,
pyrrolizidines 9 (Scheme 1).
presumably due to oligo- and polymerization of the product.
Gratifyingly, yield and purity of pyrrole 7a increased when 6a
was heated with microwaves to 250 °C under air cooling of the
Results and Discussion
In view of the lacking reactivity of compounds 6 towards base- reaction vessel without any additive under solvent-free condi-
induced dehydrocyanation to the 2,4-disubstituted pyrroles 7, tions. The results of the application of these conditions to
the reaction was attempted on substrate 6a (R1 = R2 = Ph) under cyanopyrrolines 6a–j are summarized in Table 1.
Scheme 1: Synthesis and conversion of 3,4-dihydro-2H-pyrrole-2-carbonitriles 6.
Table 1: Microwave-assisted synthesis of 2,4-disubstituted pyrroles 7a–i.
Entry
R1
R2
Yield of 6 (%)
Yield of 7 (%)
Product
1
2
3
4
5
6
7
8
9
10
Ph
Ph
64a
90a
49a
90a
82
81
7a
7b
7c
7d
7e
7f
Ph
2-Naph
Me
83
Ph
43
3-NO2-C6H4
2,3-Cl2C6H3
2-Br-C6H4
4-CN-C6H4
4-MeO-C6H4
2-Cl-C6H4
3,5-(CH3)2C6H3
4-Cl-C6H4
Ph
n.r.
66
2-Naph
Ph
77a
66b
53a
77a
54
28
32
7g
7h
7i
4-F-C6H4
4-F-C6H4
Ph
61
38
not tested
–
aSee [36].bWhen repeated under identical conditions, a higher yield was obtained than reported in [36] (53%).
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Beilstein J. Org. Chem. 2014, 10, 466–470.
This compound class comprises important starting materials for
the preparation of the BODIPY dyes (4,4-difluoro-4-bora-3a,4a-
diaza-s-indacenes) [37,38] as well as their aza-analogues [39],
the 4,4-difluoro-4-bora-3a,4a,8-triaza-s-indacenes. Various
methods to prepare 2,4-disubstituted pyrroles have been
described in the literature. They can be obtained from enones by
Michael addition of nitromethane, partial reduction and de-
hydrogenation of the resulting pyrroline with selenium or sulfur
in moderate yields (3 steps) [40,41]. Alternatively, a Nef reac-
tion of the nitromethane adducts gives masked 1,4-dicarbonyls
which can be cyclized to compounds 7 in yields of up to 50%
(over 4 steps) [42]. Other methods involve the use of stoichio-
metric zirconocene dichloride [43], the reductive coupling of
alkynes to enones followed by ozonolysis and Paal–Knorr
cyclization [21] or the reaction of vinylazides with aldehydes or
ketones [23]. The most practical approach to a 2,4-disubstituted
pyrrole reported to date is the recently disclosed microwave-
assisted Stetter reaction of chalcone with carbohydrates as
“green” formaldehyde equivalents followed by a microwave-
assisted Paal–Knorr cyclization of the resulting 1,4-dicarbonyl
Table 2: Pyrrole-2-carbonitriles 10a–j.
Entry R1
R2
Product Yield (%)
1
2
3
4
5
6
7
8
9
10
Ph
Ph
10a
10b
10c
10d
10e
10f
94
59
–
Ph
2-Naph
Me
Ph
3-NO2-C6H4
2,3-Cl2-C6H3
2-Br-C6H4
4-CN-C6H4
4-MeO-C6H4
2-Cl-C6H4
4-Cl-C6H4
Ph
65
71
47
70
77
71
54
2-Naph
Ph
10g
10h
10i
4-F-C6H4
4-F-C6H4
3,5-(CH3)2-C6H3 Ph
10j
[44]. Compared to this elegant strategy, our two-step protocol tuted pyrrole-2-carbonitriles by means of a cyclocondensation
provides a higher overall yield of compound 7a and uses less with aminoacetonitrile and a microwave-assisted dehydrocyana-
expensive reagents.
tion or a dehydrogenation with DDQ. These methods provide a
simple an efficient entry into these useful compound classes.
In addition to the thermal elimination of HCN, intermediates 6
can also be aromatized by dehydrogenation. In this case, the Experimental
nitrile group remains in the products and 3,5-disubstituted Typical procedure for the synthesis of cyanopyrrolines 6a–j:
pyrrole-2-carbonitriles 10 are obtained. Tsuge et al. reported the The cyanopyrrolines 6a–j were prepared according to an earlier
oxidation of pyrroline-3-carboxylates with chloranil [45] while publication [36]. As an illustrative example, compound 6e is
pyrrole-2-carboxylates were obtained from the oxidation of prepared as follows: To a solution of (E)-3-(2,3-
pyrroline-2-carboxylate with chloranil [46,47] or DDQ [48]. dichlorophenyl)-1-phenylprop-2-en-1-one (2.20 g, 7.94 mmol,
Different oxidants were screened for the oxidation of cyano- 1e) in pyridine (40 mL) was added aminoacetonitrile hydrochlo-
pyrroline 6a to pyrrole 10a and the results were judged by TLC. ride (1.10 g, 11.76 mmol, 1.48 equiv, 2). The suspension was
While chloranil, MnO2, NBS/DBU, and iodine/DBU in toluene heated to reflux for 15 h. The mixture was cooled down, diluted
or chlorobenzene did not give any conversion, bromotrichloro- with ethyl acetate, washed with saturated aqueous NaHCO3,
methane/DBU and DDQ gave positive results. The latter was and dried over anhydrous Na2SO4. All volatiles were removed
found to be more suitable since the use of bromotrichloro- in vacuo and the crude product was purified by column chroma-
methane/DBU resulted in many side reactions. Table 2 summa- tography (ethyl acetate/cyclohexane 1:7) to obtain cis/trans-6e
rizes the results of the oxidation of 6a–j with DDQ in toluene (2.05 g, 6.50 mmol, 82%) as a yellow oil.
under reflux.
General procedure for the synthesis of 2,4-disubstituted
The reaction worked smoothly with aryl-substituted com- pyrroles 7a–i: A solution of cyanopyrroline 6a–i in
pounds. The only failure was observed in case of compound 6c dichloromethane was transferred into a microwave reaction
which possesses an alkyl substituent (Table 2, entry 3). As vessel. After removing the solvent in vacuo, the vessel was
autoxidation and oxidative dealkylation of 2-alkylpyrroles can flushed with argon and closed with a cap. It was irradiated for
even be effected by exposure to air [49,50], the lability of 10c 30 min (Pmax 180 W, pressure limit 7 bar, temperatures indi-
towards DDQ oxidation is not very surprising.
cated in Supporting Information File 1) in a monomode
microwave apparatus under air cooling. The pressurized vessel
was opened very carefully inside a well-ventilated hood
Conclusion
Two simple two-step procedures have been developed to (caution, hydrogen cyanide!) and the residue was purified by
convert enones to 2,4-disubstiuted pyrroles and 3,5-disubsti- column chromatography.
468

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13C NMR spectra.
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