Heterocyclization using phase transfer catalysis: A simple and convenient synthesis of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles

Article abstract of DOI:10.1081/SCC-100104038

A simple and convenient synthesis of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles has been studied with and without phase transfer conditions. The best results were obtained using 18-crown-6 under solid-liquid phase transfer conditions in a

Full text of DOI:10.1081/SCC-100104038

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HETEROCYCLIZATION USING
PHASE TRANSFER CATALYSIS:
A SIMPLE AND CONVENIENT
SYNTHESIS OF 2-AMINO-1-
ARYL-5-OXO-4,5-DIHYDRO-1H-
PYRROLE-3-CARBONITRILES
Chaitanya G. Dave a & Vaishali A. Parikh a
a Organic Syntheses Laboratory , M.G. Science
Institue , Navrangpura, Ahmedabad, 380 009,
India
Published online: 09 Nov 2006.
To cite this article: Chaitanya G. Dave & Vaishali A. Parikh (2001)
HETEROCYCLIZATION USING PHASE TRANSFER CATALYSIS: A SIMPLE AND CONVENIENT
SYNTHESIS OF 2-AMINO-1-ARYL-5-OXO-4,5-DIHYDRO-1H-PYRROLE-3-CARBONITRILES,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:9, 1301-1306, DOI: 10.1081/SCC-100104038
To link to this article: http://dx.doi.org/10.1081/SCC-100104038
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SYNTHETIC COMMUNICATIONS, 31(9), 1301–1306 (2001)
HETEROCYCLIZATION USING PHASE
TRANSFER CATALYSIS: A SIMPLE
AND CONVENIENT SYNTHESIS OF
2-AMINO-1-ARYL-5-OXO-4,5-DIHYDRO-
1H-PYRROLE-3-CARBONITRILES
Chaitanya G. Dave* and Vaishali A. Parikh
Organic Syntheses Laboratory, M.G. Science Institue,
Navrangpura, Ahmedabad-380 009, India
ABSTRACT
A simple and convenient synthesis of 2-amino-1-aryl-5-oxo-
4,5-dihydro-1H-pyrrole-3-carbonitriles has been studied with
and without phase transfer conditions. The best results were
obtained using 18-crown-6 under solid-liquid phase transfer
conditions in acetonitrile.
o-Aminonitriles are important building blocks for the construction of
a variety of fused heterocycles.1 Schafer and Gewald2 have reported the
synthesis of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles
in varying yields of 33–75%. Phase transfer catalysis (PTC) has many
advantages over conventional homogeneous methodologies.3–5 The use of
PTC in the reactions involving heterocyclic compounds are extremely
* Corresponding author.
1301
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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DAVE AND PARIKH
diverse,6–8 heterocyclizations under PT conditions have a great scope9 as
little attention is attributed to such reactions.
In continuation of our interest in the use of PTC in heterocycles,10 we
report a simple and cleaner method for the synthesis of 2-amino-1-aryl-5-
oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles via heterocyclization under
solid-liquid PT conditions with good yields. A comparison with phase trans-
fer catalysts such as tetrabutylammonium bromide (TBAB), tetrabutylam-
monium hydrogen sulfate (TBHSO4), triethylbenzylammonium chloride
(TEBA) under liquid-liquid PTC, and 18-crown-6 using solid-liquid PTC
and without phase transfer catalyst has been undertaken.
The reactions between N-aryl-2-chloroacetamids (1) and malononitrile
(2) where carried out without PTC and with PTC at room temperature
under liquid-liquid and solid-liquid phase transfer conditions to get 2-
amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles. (3). The reac-
tions employing quaternary ammonium salts (TBAB, TBHSO4, TEBA) as
catalysts were performed in methylene chloride, whereas acetonitrile was
used as a solvent for 18-crown-6. TBAB and TEBA are not the catalyst
of choice for this particular heterocyclization, whereas the use of TBHSO4
in equimolar ratio with the reactants yielded compounds 3 in 50–63%
yields.11,12 The best results were obtained for 3 with 68–83% yields when
the reactions were performed in acetonitrile using 18-crown-6 as catalyst
and powdered KOH as a base at room temperature.13 In the conventional
method,2 when a mixture of N-aryl-2-chloroacetamides (1), malononitrile
(2), and potassium carbonate was refluxed in ethanol, the target 2-amino-1-
aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles3 were not obtained gener-
ally in good yields. Further, this conventional method is not as clean as PTC
methodology, which is evident from the melting point range reported (Tab. 1).
Looking to the mechanistic aspect of this process, the initial C-alkyla-
tion of active methylene group of malononitrile (2) should have taken place
with 1, followed by the heterocyclization step, which is supposed to proceed
via an intramolecular nucleophilic addition of -NH-Ar onto the nitrile
group to give an imine that could yield an enamine and also aromatic
system for the formation of o-aminonitrile system. A comparison of
the results obtained without and with PT catalysis using TBHSO4 and
18-crown-6 has been depicted in Table 1.

PTC IN HETEROCYCLES
1303

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DAVE AND PARIKH
In conclusion, we have described a simple and convenient synthesis
of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles, which are
important building blocks for the construction of various fused heterocycles.
A comparison of conventional method, liquid-liquid PTC, and solid-liquid
PTC suggests that the solid-liquid PT conditions using 18-crown-6 is the
method of choice with better yields.
EXPERIMENTAL
Synthesis of 2-Amino-1-aryl-5-oxo-4,5-dihydro-1H-
pyrrole-3-carbonitriles (3)
Typical Procedure 1 (Liquid-Liquid PT Condition)
To the stirred mixture of dichloromethane (15 mL), KOH solution
(5 mL, 50% w/v), and TBHSO4 (3.39 g, 0.01 mol) was added malononitrile
(2, 0.792 g, 0.01 mol) at room temperature. To this was added N-aryl-2-
chloroacetamides14 (1, 0.01 mol) portionwise. The reaction mixture was stir-
red further at room temperature for 2.5–3.5 h (TLC). The organic phase was
separated, washed with water, acetic acid (10% v/v), and again with water.
The solvent was distilled under reduced pressure and cooled to 5ꢀ–10ꢀC,
the solid thus obtained was filtered and crystallized from a mixture of
acetonitrile and ethanol (6:4).
Typical Procedure 2 (Solid-Liquid PT Condition)
To the stirred mixture of acetonitrile (15 mL), KOH (0.700 g,
0.012 mol), and 18-crown-6 (0.120 g, 10 mol%) was added malononitrile
(0.330 g, 0.005 mol) and stirred for 10 m. To this was added N-aryl-2-chlor-
oacetamides14 (1, 0.005 mol) portionwise. The reaction mixture was further
stirred at room temperature for 30–40 min (TLC). The solvent was distilled
under reduced pressure and the reaction mixture was poured onto crushed
ice (20 g), neutralized with acetic acid (50% v/v) and kept at room tempera-
ture for 3 h. The products thus obtained were crystallized from the mixture
of acetonitrile and alcohol (6:4). The selected spectroscopic data of
compounds 3 are given.
2-amino-5-oxo-1-(4-methylphenyl)-4,5-dihydro-1H-pyrrole-3-
carbonitrile (3b)
M.p. 258ꢀ–260ꢀC (lit.2 230ꢀ–240ꢀC); IR (KBr) cmꢁ1: 3428and 3298
(NH2), 2210 (CN), 1714 (C ¼ O); 1H NMR (300 MHz, CDCl3þDMSOd6) ꢀ:

PTC IN HETEROCYCLES
1305
2.31 (s, 3H, CH3), 3.25 (s, 2H, CH2), 6.72 (s, 2H, NH2), 7.10–7.74 (m, 4H,
Ar-H).
2-amino-5-oxo-1-(4-bromophenyl)-4,5-dihydro-1H-pyrrole-3-
carbonitrile (3e)
M.p. 221ꢀ–223ꢀC; IR (KBr) cmꢁ1: 3431 and 3277 (NH2), 2207 (CN),
1
1720 (C ¼ O); H NMR (300 MHz, CDCl3þDMSOd6) ꢀ: 3.35(s, 2H, CH2),
6.37 (s, 2H, NH2), 7.16–7.75 (m, 4H, Ar-H).
2-amino-5-oxo-1-(4-fluorophenyl)-4,5-dihydro-1H-pyrrole-3-
carbonitrile (3f)
M.p. 230ꢀ–232ꢀC; IR (KBr) cmꢁ1: 3378and 3268(NH 2), 2200 (CN),
1713 (C ¼ O); 1H NMR (300 MHz, CDCl3þDMSOd6) ꢀ: 3.36 (s, 2H, CH2),
6.26 (s, 2H, NH2), 7.12–7.71 (m, 4H, Ar-H). MS (70 eV) m/z (%): 277 (79.9,
Mþ), 249 (22.1), 197 (38.4), 170 (100), 278 (49.9, Mþ1).
2-amio-5-oxo-1-(4-iodophenyl)-4,5-dihydro-1H-pyrrole-3-
carbonitrile (3g)
M.p. 215ꢀ–217ꢀC; IR (KBr) cmꢁ1: 3380 and 3298 (NH2), 2205(CN),
1715(C ¼ 0); 1H NMR (300 MHz, CDCl3þ DMSOd6) ꢀ : 3.32 (s, 2H, CH2),
6.28(s, 2H, CH ), 7.13–7.72 (m, 4H, Ar-H).
2
2-amino-5-oxo-1-(3-chloro-4-fluorophenyl)-4,5-dihydro-1H-
pyrrole-3-carbonitrile (3h)
Mp. 225–27ꢀC I(KBr)cm: 3410 and 3332(NH2), 2211 (CN), 1720
(C ¼ O); 1H NMR (300 MHz, CDCl3þDMSOd6) ꢀ: 3.34 (s, 2H, CH2),
6.60 (s, 2H, NH2), 7.20–7.42 (m, 3H, Ar-H).
ACKNOWLEDGMENTS
1
We thank RSIC, Chandigadh, India, for H NMR and mass spectra
and Dishman Pharmaceuticals and Chemicals, Ahmedabad, India, for the
gift of Phase Transfer Catalysts.

1306
DAVE AND PARIKH
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Received in the UK May 30, 2000