Chemodivergent, One-Pot, Multi-Component Synthesis of Pyrroles and Tetrahydropyridines under Solvent- and Catalyst-Free Conditions Using the Grinding Method

Article abstract of DOI:10.1021/acscombsci.5b00154

A highly efficient, chemoselective synthesis of a library of polysubstituted pyrroles and tetrahydropyridines has been achieved through the one-pot, multicomponent reactions of ethyl (E)-3-(aryl/alkyl amino) acrylates, 2,2-dihydroxy-1-arylethan-1-ones, and malononitrile under solvent- and catalyst-free grinding conditions. The selective formation of pyrrole or tetrahydropyridines relied on substitution of the N-aryl of ethyl (E)-3-(4-arylamino) acrylates. These reactions presumably occurred via a domino Knoevenagel condensation and Michael addition followed by an intramolecular cyclization sequence of reactions in a single transformation.

Full text of DOI:10.1021/acscombsci.5b00154

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Article
Chemodivergent One-pot Multi-Component Synthesis of Pyrroles and
Tetrahydropyridines under Solvent free, Catalyst free and Grinding method
Isaivani Dhinakaran, Padmini Vediappen, and Nattamai Bhuvanesh
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00154 • Publication Date (Web): 14 Mar 2016
Downloaded from http://pubs.acs.org on March 15, 2016
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Chemodivergent One-pot Multi-Component Synthesis of Pyrroles and
Tetrahydropyridines under Solvent free, Catalyst free and Grinding
method
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Isaivani Dhinakarana, Vediappen Padminia*, and Nattamai Bhuvaneshb
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a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Maduraiꢀ625 021, Tamil Nadu, India.
bDepartment of Chemistry, Texas A&M University, College Station, USA, TX 77842
Abstract
A highly efficient, chemoselective synthesis of a library of polysubstituted pyrroles
and tetrahydropyridines has been achieved through the oneꢀpot, multiꢀcomponent reactions of
ethyl (E)ꢀ3ꢀ(aryl/alkyl amino) acrylates, 2,2ꢀdihydroxyꢀ1ꢀarylethanꢀ1ꢀones and malononitrile
under solvent and catalyst free grinding conditions. The selective formation of pyrrole or
tetrahydropyridines relied on the substitution in the Nꢀaryl of ethyl (E)ꢀ3ꢀ(4ꢀarylamino)
acrylates. These reactions presumably occurred via a domino Knoevenagel condensation,
Michael addition followed by intramolecular cyclization sequence of reactions in a single
transformation.
Key words
Grinding, chemoselective, multi-component, tetrahydropyridines, solvent-free, catalyst-free
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Introduction
Multicomponent reactions (MCRs) are versatile protocols employed for the synthesis
of a variety of complex heterocycles and natural products.1ꢀ3 These reactions involve the
formation of multiple bonds in a single transformation in a oneꢀpot process without the
isolation of intermediates.4ꢀ8 Consequently, MCRs have been significantly used for the
synthesis of wide range of heterocyclic compounds. 9
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Nitrogen containing heterocycles are wide spread in nature10 and play a significant
role in chemical biology. Among these, pyrroles and pyridines are associated with unique
biological activities.11ꢀ13 For instance, arecoline, a naturally occurring tetrahydropyridine
derivative exhibits stimulating effect as muscarinic acetylcholine receptor (Figure 1).14 In
addition several synthetic tetrahydropyridines have been shown to display important
biological activities. On the other hand 2,3,5ꢀtrisubstituted pyrroles have also been studied to
exhibit significant biological activities.15,16 The tetrahydropyridines and pyrroles may be
synthesised via a number of classical methods which also include the treatment of allylic
alcohols with potassium bis(trimethylsilyl)amide,17ꢀ21 intermolecular amido carbonylation of
carbomates22 and intramolecular condensations of aldehydes with enamides. Several methods
such as transition metal catalysed cycloadditions, coupling of enamides with alkynes23 and
oxidative cyclization of Nꢀallyamines are available for the syntheses of polysubstituted
pyrroles.24ꢀ27 However most of these methods have drawbacks such as the use of expensive
reagents or catalysts, lower yields and poor selectivity. In the present work, we have
developed an efficient domino protocol for the synthesis of polysubstituted pyrroles 4 and
tetrahydropyridines 5 from the oneꢀpot threeꢀcomponent domino reactions of 2,2ꢀdihydroxyꢀ
1ꢀarylethanꢀ1ꢀones 1, malononitrile 2 and ethyl (E)ꢀ3ꢀ(4ꢀarylamino) acrylates 3 under catalyst
and solvent free conditions under grinding method (Scheme 1).
Figure 1 Selected drugs comprising tetrahydropyridine and pyrrole core
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Scheme 1 Synthesis of pyrroles 4 and tetrahydropyridines 5
Results and discussion
Initially, to optimize the reaction conditions a representative reaction of 2,2ꢀ
dihydroxyꢀ1ꢀphenylethanꢀ1ꢀone 1{1}, malononitrile 2{1} and ethyl (E)ꢀ3ꢀ((4ꢀbromophenyl)
amino) acrylate 3{3} that presumably affords the pyrrole 4{1,3} was performed under various
conditions (Table 1).
Table 1 Optimization of the reaction conditions
Entry Solvent Temperature (°C) Time
Yield of 4{1,1,3} (%)b
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2
3
4
5
6
7
8
EtOH
EtOH
MeOH Reflux
MeOH RT
MeOH RT
MeCN
THF
CHCl3
Reflux
RT
30 min
2 h
2 h
30 min
2 h
4 h
6 h
6 h
6 h
6 h
80
50
65
62
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60
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Reflux
Reflux
RT
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CH2Cl2 RT
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H2O
Reflux
Grinding
Grinding
ꢀa
10 min
20 min
30 min
ꢀa
ꢀa
Grinding
aSolvent free condition Isolated yield
b
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To begin with, the above reactants were refluxed in ethanol and monitored by TLC
intermittently. After 30 min of continuous reflux the reaction attained completion as evident
from the TLC analysis. Then the reaction mixture was treated with cold ethanol (3 mL) and
the resultant precipitate was filtered and dried to obtain 4{1,3} in 80% yield (Table 1, entry 1)
as shown by the ESI mass and NMR studies (Figureꢀ2) disclosed the formation of pyrrole
4{1,3}.
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Figure 2 1H and 13C chemical shifts and HMB correlations of 4{1,3}
In contrast the above reaction took 2 h for 50 % completion at room temperature
(Table 1, entryꢀ2). Further exploration on the reaction conditions with a view to increase the
yield of 4{1,3} was done by employing solvents such as MeOH, MeCN, THF, CHCl3,
CH2Cl2 and water under RT as well as reflux. From Table 1 it is evident that refluxing the
reactants in ethanol was the optimum condition (Entry 1). However, inspired by solventꢀfree
reactions, we investigated the reaction under the solventꢀfree grinding method. To our
surprise the reaction afforded 4{1,3} in 85% yield after 10 min (Table 1, entry 11). We found
that the solventꢀfree grinding method gave superior yields in less time when compared to
other conditions (Table 1).
Having optimized the reaction conditions, we then explored its applicability for
library production employing various aryl 2,2ꢀdihydroxyꢀ1ꢀarylethanꢀ1ꢀones 1{1-5} and ethyl
(E)ꢀ3ꢀ(arylamino)acrylates 3{1-11} (Figure 3 and Scheme 2). The reaction occurred well in
all these cases affording good yields of the product (Table 2). Moreover, with the available
variations we noted an interesting trend in the reaction with respect to the substitutions in the
Nꢀphenyl ring of enamine 3. In general, the Nꢀphenyl, Nꢀheterocycle and the presence of
electron withdrawing substituent in the Nꢀphenyl ring in 3 afforded the expected pyrroles 4
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(Table 2, Entries 1–7), whereas the enamines 3 with electron donating substituents led to the
unprecedented formation of tetrahydropyridines 5 under similar reaction conditions (Table 2,
Entries 8–19). The formation of 5 was ascertained from the NMR spectroscopy. As a
representative case, in the 1H NMR of 5{3,7} the characteristic Hꢀ4 and Hꢀ3 protons appeared
as doublets at 5.21 and 4.39 ppm (J =7.2, 6.9 Hz), respectively. This revealed the selective
formation of tetrahydropyridines 5 and precluded the formation of pyrrole 4 (Figure 4). The
structure of all the pyrroles 4 and the tetrahydropyridines 5 was elucidated with the help of
NMR spectroscopy.
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Figure 3 Diversity of reactants
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Scheme 2 Synthesis of pyrroles 4 and tetrahydropyridines 5
Table-2 Yield of pyrrole 4 and tetrahydropyridine 5
Entry Comp
R1
R2
Yield (%)a
82
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1
C6H5
C6H5
4{1,1}
4{1,2}
4{1,3}
4{1,4}
4{1,5}
4{3,1}
4{4,1}
5{1,6}
5{1,7}
5{1,8}
5{1,9}
5{1,10}
5{2,9}
5{2,11}
5{3,6}
5{3,7}
5{3,8}
5{4,6}
5{5,11}
4{1,12}
4{2,12}
4{3,12}
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C6H5
C6H5
C6H5
C6H5
4ꢀOMeC6H5
4ꢀMeC6H4
C6H5
C6H5
C6H5
4ꢀClC6H4
4ꢀBrC6H4
4ꢀFC6H4
2ꢀPyridyl
C6H5
80
84
78
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70
75
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C6H5
4ꢀC2H5C6H4
4ꢀiPrC6H4
4ꢀC5H11C6H4
4ꢀOMeC6H4
3ꢀMeC6H4
4ꢀOMeC6H4
4ꢀMeC6H4
4ꢀC2H5C6H4
4ꢀiPrC6H4
4ꢀC5H11C6H4
4ꢀC2H5C6H4
4ꢀMeC6H4
ꢀCH2ꢀC6H5
ꢀCH2ꢀC6H5
ꢀCH2ꢀC6H5
C6H5
C6H5
4ꢀClC6H4
4ꢀClC6H4
4ꢀOMeC6H4
4ꢀOMeC6H4
4ꢀOMeC6H4
4ꢀMeC6H4
4ꢀBrC6H4
C6H5
75
72
79
75
4ꢀClC6H4
4ꢀOMeC6H5
80
aIsolated yields after filtration
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Figure 4 HMB correlations and 1H and 13C NMR chemical shifts of 5{3,6}
A plausible mechanism for the formation of 5 is depicted in Scheme 3. Initially, the
Knoevenagel condensation of 2,2ꢀdihydroxyꢀ1ꢀarylethanꢀ1ꢀone 1 and malononitrile 2
furnishes 2ꢀ(2ꢀoxoꢀ2ꢀarylethylidene)malononitrile A. Further, the Michael addition of A with
enamine 3 affords intermediate C. The subsequent intramolecular Nꢀcyclization of C may
presumably involve the secondary amine group and the carbonyl or the nitrile functions via
path A or B, respectively as shown in Scheme 3. Interestingly, in the cases of Nꢀphenyl, Nꢀ
heterocycle and the presence of electron withdrawing substituent in the Nꢀphenyl ring in C,
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cyclization involving the secondary amine group and the carbonyl is favoured and proceeds
through path A leading to the formation of intermediate D, which then undergoes cyclization
to afford E. The bicyclic intermediate E further undergoes ring opening via intermediate F to
afford the polysubstituted pyrroles 4.27 On the other hand, the presence of electron donating
substituents in the Nꢀphenyl ring of the intermediate C favours the cyclization involving the
secondary amine group and the nitrile function to afford the tetrahydropyridine 5 via path B.
These tetrahydropyridine 5 were reluctant towards tautomerization to afford the
dihydropyridine isomer 6. Furthermore, it is to be noted that albeit the formation of two
contiguous stereocentres, the reaction afforded a single diastereomer of the product 5. The
above two factors were evident from the NMR studies.
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Scheme 3 Plausible mechanism for formation of tetrahydropyridines and pyrroles
With the above interesting results in hand we then studied the outcome of the above
domino reaction in the presence of ethyl (E)ꢀ3ꢀ(benzylamino)acrylate 3{12} with a view to
investigate the selectivity involved in the reaction. However, the reaction afforded the
expected pyrrole 4 as a sole product under similar conditions (Scheme 2 and Table 2, Entries
20–22). The structure of these pyrroles was elucidated with NMR spectroscopy and in one
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representative case viz. 4{1,12}, the structure was further confirmed from the single crystal
Xꢀray studies (Figure 5).
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Figure 5 ORTEP diagram of 4{1,12} (CCDC No.1428613)
It is to be noted that the fourꢀcomponent reactions of 2,2ꢀdihydroxyꢀ1ꢀphenylethanꢀ1ꢀ
one 1, malononitrile 2, diethyl acetylene carboxylate 7 and aromatic amines 8 have been
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reported by the Feng et al. This reaction in ethanol under reflux for 30 min led to the
formation of pyrroles 9 up to 80% yields. We investigated this reaction under our optimized
conditions with a view to study the selectivity involved, viz., whether the reaction affords
pyrrole or tetrahydropyridine. Accordingly a mixture of 2,2ꢀdihydroxyꢀ1ꢀphenylethanꢀ1ꢀone
1, malononitrile 2, diethyl acetylene carboxylate 7, aromatic amines 8 was ground well for 10
min (Scheme 4). The reaction afforded pyrroles 9a-c as the sole products in up to 85% yield
Substrate scope of these reaction conditions were explored with aromatic amines comprising
electron withdrawing or electron releasing substituents. However, in all these cases the
reaction afforded pyrrole 9 as the sole product.
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Scheme 4 Synthesis of fully substituted pyrroles 9a-c
Conclusions
In conclusion, we have developed a facile method for synthesis of a library of
polysubstituted pyrroles and tetrahydropyridines chemoselectively in excellent yields via a
oneꢀpot, multiꢀcomponent domino reactions of ethyl (E)ꢀ3ꢀ(4ꢀarylamino) acrylates, 2,2ꢀ
dihydroxyꢀ1ꢀarylethanꢀ1ꢀones and malononitrile under solvent and catalystꢀfree conditions
under grinding. The chemoselectivity depended on the substitution in the Nꢀphenyl ring of
ethyl (E)ꢀ3ꢀ(4ꢀarylamino) acrylates.
Experimental Procedures
General procedure for synthesis of 4 and 5
A mixture of 2,2ꢀdihydroxyꢀ1ꢀarylethanꢀ1ꢀone 1 (1 mmol), malononitrile 2 (1 mmol)
and ethyl (E)ꢀ3ꢀ(4ꢀarylamino)acrylate 3 (1 mmol) was taken in a mortar and ground
continuously for 10 min. The reaction was monitored by TLC until completion. The syrupy
formed was washed with cold ethanol and filtered through the filtration flask to afford the
pure product.
Ethyl
4ꢀ(2ꢀaminoꢀ1ꢀcyanoꢀ2ꢀoxoethyl)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate 4{1,3}
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White solid, yield: 84% (394mg), mp: 190–193 °C H NMR (300 MHz, CDCl3) δ 7.60 (s,
1H), 7.42 (d, J = 8.2 Hz, 2H), 7.38 – 7.31 (m, 3H), 7.24 – 7.18 (m, 2H), 6.95 (d, J = 8.2 Hz,
13
2H), 5.61 (s, 2H), 4.94 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); C NMR
8
9
(75 MHz, CDCl3) δ 166.21, 163.54, 137.13, 134.89, 131.84, 130.35, 128.52, 128.28, 128.12,
126.71, 121.12, 116.32, 113.99, 112.57, 59.95, 35.70, 13.87 ppm; LCꢀMS. calcd. m/z 451.05
found 452.25 (M+H)+. Anal. Calcd. For C22H18BrN3O3 calcd. C, 58.42; H, 4.01; N, 9.29,
found C, 58.43; H, 4.03; N, 9.28%.
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Ethyl 5ꢀcyanoꢀ1ꢀ(4ꢀethylphenyl)ꢀ6ꢀiminoꢀ4ꢀ(4ꢀmethoxybenzoyl)ꢀ1,4,5,6ꢀtetrahydropyridineꢀ
3ꢀcarboxylate 5{3,6}
1
White solid, yield: 83% (373mg), mp: 125–126 °C H NMR (300 MHz, CDCl3) δ 10.27 (s,
1H), 7.95 (d, J = 9 Hz, 2H), 7.21 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 9 Hz, 2H),
6.86 (d, J = 8.4 Hz, 2H), 5.21 (d, J = 6.3 Hz, 1H), 4.41 (d, J = 7.2 Hz,1H), 4.36 (q, J = 7.4
Hz, 2H), 2.63 (q, 2H), 1.42 (t, J = 7.2 Hz 3H), 1.18 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 192.59, 167.59, 164.45, 145.34, 140.50, 137.35, 131.46, 129.18, 129.04, 126.57,
116.77, 112.68, 112.49, 90.65, 61.01, 55.67, 48.78, 28.21, 26.42, 15.71, 14.54 ppm; LCꢀMS.
calcd. m/z 431.18, found 432.22 (M+H)+. Anal. Calcd. For. C25H25N3O4 calcd. C, 69.59; H,
5.84; N, 9.74, found C, 69.57; H, 5.82; N, 9.75%.
Diethyl 4ꢀ(2ꢀaminoꢀ1ꢀcyanoꢀ2ꢀoxoethyl)ꢀ5ꢀphenylꢀ1ꢀ(pꢀtolyl)ꢀ1Hꢀpyrroleꢀ2,3ꢀdicarboxylate
9a
White solid, yield: 86% (232mg) mp:189–190 °C 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, J =
8.3, 2.7 Hz, 4H), 7.18 – 7.14 (m, 2H), 7.04 (d, J = 7.4 Hz, 4H), 6.77 (s, 1H), 5.67 (s, 2H),
4.89 (s, 1H), 4.37 (dd, J = 14.2, 7.1 Hz, 2H), 4.15 (dd, J = 14.3, 7.1 Hz, 2H), 2.30 (s, 3H),
1.37 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.79,
163.83, 161.53, 138.98, 137.30, 134.08, 131.07, 130.70, 129.46, 129.20, 128.59, 128.15,
127.57, 116.32, 114.24, 111.71, 61.95, 61.30, 36.25, 21.18, 14.12, 13.80 ppm; LCꢀMS. calcd.
m/z 459.18 found, 458.07 (M-H)ꢀ. Anal. Calcd. For C26H25N3O5 calcd. C, 67.96; H, 5.48; N,
9.14, found C, 68.47; H, 5.21; N, 10.42%.
ASSOCIATED CONTENT
Supporting Information
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Experimental details and Spectroscopic characterization of 4aꢀj, 5aꢀl and 9aꢀc and Xꢀray
crystallographic information for compound 4{1,12} are available in supporting information.
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AUTHOR INFORMATION
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Corresponding Author
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Eꢀmail: padimini_tamilenthi@yahoo.co.in Tel:+91-9095169125
Acknowledgement
Prof. S. Muthusubramanian and Dr. R. Ranjith Kumar, Dept. of Organic Chemistry, School
of Chemistry, Madurai Kamaraj University, Maduraiꢀ625021, Tamil Nadu, India, for
valuable scientific discussion.
Funding
V.P. and I.D. thank (i) the University Grants Commission, New Delhi, for providing funds
under (i) Rajiv Gandhi National Research Fellowship F.No.1420 (Sc)/2009 SAꢀIII, (ii) DSTꢀ
IRPHA programme for the high resolution NMR facility and (iii) Department of Chemistry,
Texas A&M University, USA for single crystal Xꢀray diffraction studies.
NOTES
The authors declare no competing financial interest
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ACS Paragon Plus Environment

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ACS Combinatorial Science
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Graphical abstract
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ACS Paragon Plus Environment