A simple synthesis of enaminones from reaction between isocyanides and cyclic 1,3-dicarbonyl compounds

Article abstract of DOI:10.3184/030823408X314482

Polarised olfinic systems are synthesised from the reaction between alkyl or aryl isocyanides and cyclic 1, 3-dicarbonyl compounds such as thiobarbituric acid, 5,5-dimethylcyclohexane-1,3-dione and cyclopentane-1,3-dione in good yield.

Full text of DOI:10.3184/030823408X314482

198 RESEARCH PAPER
APRIL, 198–200
JOURNAL OF CHEMICAL RESEARCH 2008
A simple synthesis of enaminones from reaction between isocyanides
and cyclic 1,3-dicarbonyl compounds
Malek Taher Maghsoodlou*, Nourallah Hazeri, Sayyed Mostafa Habibi-Khorassani,
Vahideh Solimani, Ghasem Marandi and Zahra Razmjoo
Department of Chemistry, The University of Sistan and Balouchestan, PO Box 98135-674, Zahedan, Iran
Polarised olfinic systems are synthesised from the reaction between alkyl or aryl isocyanides and cyclic 1,
3-dicarbonyl compounds such as thiobarbituric acid, 5,5-dimethylcyclohexane-1,3-dione and cyclopentane-1,3-
dione in good yield.
Keywords: enaminones, isocyanides, pyrimidinones, 1,3-dicarbonyl compounds, pull–push olefins
The most usual reactivity observed in isocyanides is reaction
of the functional group with acidic reactants.1-4 A general
feature of isocyanide reactions is the formation of α,α-addition
reaction products: i.e. two new bonds are formed to the terminal
isocyanide carbon atom.5-11 Typical examples are the reaction of
isocyanide with protonic acids.1,2 We report here that CH-acids
such as cyclopentane-1,3-dione, 5,5-dimethylcyclohexane-
1,3-dione (dimedone) and thiobarbituric acid react with
alkyl or aryl isocyanides 1 producing 1:1 adducts. This
two-component reaction produces the enaminones 3a–g.
Enaminones are a group of organic compounds containing the
conjugated system N–C=C-C=O formed between a primary
amine and 1,3-dicarbonyl compound. It may act as a pro-drug,
releasing a primary amine that may be an actual drug,12-14 via
proton-catalysed hydrolysis. Enaminones15 have recently been
recognised by several co-workers as compounds of interesting
pharmacological activities.16,17 Enaminones are of interest as
synthetic intermediates for the preparation of a large number of
heterocyclic compounds such as aziridines and pyrroles.18,29
Previous reports of the preparation of enaminones analogous
to those reported here have involved fusing the CH acid
analogue with formanilide or its derivatives,30,31 and the three-
component condensation of dimethylbarbituric acid, trimethyl
orthoformate, and aniline.32 In this work, we reported a facile
synthesis for enaminones.
Results and discussion
Synthesis compounds may be formulated as having
been derived from initial α,α-addition of CH-acids to the
isocyanide and subsequent proton transfer reaction to produce
the polarised olefinic systems 3a–g. The reactions proceed in
fairly high yields.
All the products 3 are stable crystalline solids whose
structures are fully supported by elemental analyses and
1
IR, H, 13C NMR and mass spectral data. The mass spectra
of these 1:1 adduct displayed molecular ion peaks at the
appropriate m/z values.
The 1H NMR spectrum of 2-(benzylaminomethylene)-
3,3-dimethylcyclohexane-1,3-dione 3a exhibited three sharp
singlets, readily recognisable as arising from the CMe2 (δ 1.06)
and two CH2 (δ 2.34 and 2.37) protons, along with a multiplet
(δ 7.23–7.48) for the aromatic protons. HN–CH2 moiety
3
showed an AX2 spin system (δNH 11.36, δCH2 4.57 J = 6.1)
and HC–NH moiety showed an AX spin system (δCH 8.25,
3
δNH 11.38 J = 13.4). The 13C NMR spectrum showed 13
distinct resonances consistent with the structure 3a. Partial
assignments of these resonances are given in the experimental
section. The structural assignments of compounds 3a–g
made on the basis of their H and 13C NMR spectra which
1
are supported by their IR spectra. Of special interest are the
strong carbonyl absorption bands at 1705–1662 cm-1 for all
R'
R'
R'
R'
O
O
toluene
80 °C
O
H
O
+
R
C
O
O
N
1
H
H
O
O
2
N
R
H
RN
3
R
C
N
H
4
R'
R
Yield (%)
3
a
benzyl
-CH2-C(Me)2-CH2-
95
90
b
c
d
e
f
tert-butyl
cyclohexyl
cyclohexyl
cyclohexyl
tert-butyl
-CH2-C(Me)2-CH2-
-CH2-C(Me)2-CH2-
-CH2-CH2-
92
95
75
80
85
-NH-CS- NH-
-NH-CS- NH-
-NH-CS- NH-
g
2,6-dimethylphenyl
Scheme 1
* Correspondent. E-mail: mt_maghsoodlou@yahoo.com
PAPER: 08/5147

JOURNAL OF CHEMICAL RESEARCH 2008 199
3414 (N–H), 1617 and 1697 (C=O), 1476(C=C). 1H NMR (300.1
compounds and a fairly broad NH peak at about 3440 cm-1
for amino groups (see experimental).
MHz, CDCl3): δH 1.27–2.02 (10 H, m, 5 CH2), 2.23 (4 H, s, 2 CH2);
3
3.33 (1 H, m, CHN); 7.80 (1 H, d, J = 14.3 Hz, HC–NH), 10.35 (1
We have not established the mechanism of the reaction
between isocyanides and 1,3-dicarbonyl compound, however,
a possible explanation is illustrated in Scheme 1. On the
basis of the well established chemistry of isocyanides,1-4 it
is reasonable to assume that compound 3 results from initial
protonation of the isocyanide carbon atom by the CH-acid.
The positively charged ion is then attacked by the enolate
anion of the CH-acid to produce the α,α-addition product 4.
Such addition product tautomerises under reaction conditions
to produce the enaminone 3 (see Scheme 1).
H, br, NH). 13C NMR (75.5 MHz, CDCl3): δC 24.23, 24.82, 33.15,
33.17, 33.18 (5 CH2), 33.70 (2 CH2), 58.74 (CHNH), 107.41(CO–
C–CO), 152.63 (CH–N), 202.29 and 205.89 (2 C=O). MS (m/z, %):
208 (M+ + 1, 13), 207 (M+, 100), 192 (14), 178 (12), 164 (16). Anal.
Calcd for C12H17NO2 (207.13): C, 69.54; H, 8.27; N, 6.76. Found: C,
69.67; H, 8.32; N, 6.82.
2-(Cyclohexylaminomethylene)thiobarbituric acid (3e): Light
orange powder, yield (75%), m.p. 317–319°C, IR (KBr) (υmax, cm-1):
3418 (N–H), 3217 (2N–H), 1703 and 1648 (C=O), 1598 (C=C) and
1120 (C=S). 1H NMR (300.1 MHz, CDCl3): δH 1.20–2.20 (10 H,
3
m, 5 CH2), 3.50 (1 H, m, CH–NH), 8.22 (1 H, d, J = 14.9 Hz,
In summary, the reaction between alkyl or aryl isocyanides
and 1,3-dicarbonyl compounds provides a simple one-
pot entry into the synthesis of poly functional enaminone
derivatives of potential synthetic interest.
HC–NH), 8.77 (2 H, br, NH), 10.31 (1 H, br, NH). MS (m/z, %): 253
(M+, 90), 210 (30), 157 (16), 111 (14), 97 (69), 55 (100). Anal. Calcd
for C11H15N3O2S (253.10): C, 52.15; H, 5.97; N, 16.59. Found: C,
52.24; H, 6.03; N, 16.57.
2-(tert-Butylaminomethylene)thiobarbituric acid (3f): Yelow
powder, yield (80%), decomposed 238–240°C, IR (KBr) (υmax, cm-1):
3419 (N–H), 3109 (2 N–H), 1675 and 1682 (C=O), 1625(C=C) and
1150 (C=S). 1H NMR (300.1 MHz, CDCl3): δH 1.50 (9 H, s, CMe3),
Experimental
Thiobarbituric acid, dimedone and cyclopentane-1,3-dione, tert-
butyl, cyclohexyl, benzyl and 2,6-dimethylphenyl isocyanides were
purchased from Merck and Fluka, respectively, and used without
further purification. Melting points were taken on an Electrothermal
9100 apparatus and IR spectra of all compounds were run on a
2
8.25 (1 H, d, J = 15.1 Hz, HC–NH), 8.85 (2 H, br, NH), 10.60
(1 H, br, NH). MS (m/z, %): 227 (M+, 3), 144 (100), 116 (48), 84
(9), 69 (47), 59 (54), 44 (16). Anal. Calcd for C9H13N3O2S (227.07):
C, 47.56; H, 5.77; N, 18.49. Found: C, 47.65; H, 5.68; N, 18.58.
2-(2,6-dimethyphenylaminomethylene)thiobarbituric acid (3g):
Pale white powder, yield (85%), decomposed 157–159°C, IR (KBr)
(υmax, cm-1): 3421 (N–H), 3108 (2 N–H), 1669 and 1680 (C=O),
1625 (C=C) and 1150 (C=S). 1H NMR (300.1 MHz, CDCl3): δH 2.29
and 2.33 (6 H, s, 2 CH3-C); 7.10–7.23 (3 H, m, C6H3), 8.11 (1 H, d,
Shimadzu IR-470 spectrometer. The H and 13C NMR spectra were
1
measured with a Bruker DRX-300 AVANCE instrument with CDCl3
as solvent at 300.1 and 75.5 MHz, respectively. Elemental analyses
for C, H and N using a Heraeus CHN–O–Rapid analyser. Mass
spectra were recorded on a Shimadzu GC/MS QP 1100 EX mass
spectrometer operating at an ionisation potential of 70 eV.
2J = 14.25 Hz, CHN), 8.44 (2 H, br, NH), 10.43 (1 H, br, NH). 13
C
NMR (75.5 MHz, CDCl3): δC 17.88 and 18.10 (6 H, 2 s, ArMe2),
82.31 (CO–C–CO), 126.56, 127.47, 128.62, 131.9 and 134.67 (5
C, C6H3), 158.35 (CH–NH), 161.69 (C–NH and C=S), 174.76 and
179.77 (2 C=O). MS (m/z, %): 275 (M+, 1), 144 (100), 116 (61), 84
(8), 69 (58), 59 (73), 44 (20). Anal. Calcd for C13H13N3O2S (275.07):
C, 56.71; H, 4.76; N, 15.26. Found: C, 56.78; H, 4.58; N, 15.33.
General procedure (exemplified by 3a)
To a magnetically stirred solution of 5,5-dimethylcyclohexane-1,3-
dione (1 mmol) in toluene 10 ml was added, dropwise a solution of
benzyl isocyanide (1 mmol) in toluene 3 ml at –5°C over 10 min.
The reaction mixture then kept for 48 hours at 80°C. The solvent was
removed under reduced pressure and the solid residue was washed
with cold diethyl ether (2 × 5 ml).
The authors gratefully acknowledge financial support
from the Research Council of the University of Sistan and
Balouchestan.
2-(Benzylaminomethylene)-5,5-dimethylcyclohexane-1,3-dione
(3a): Light brown powder; yield (95%), m.p. 118–120°C, IR (KBr)
1
(υmax, cm-1): 3407 (N–H), 1665 (C=O) and 1583 (C=C). H NMR
(300.1 MHz, CDCl3): δH 1.05 (6 H, s, 2 CH3), 2.34, 2.37 (4 H, 2 s,
3
2 CH2), 4.57 (2 H, d, J = 6.1 Hz, CH2), 7.23–7.48 (5 H, m, C6H5),
Received 10 March 2008; accepted 17 April 2008
Paper 08/5147 doi: 10.3184/030823408X314482
8.25 (1 H, d, 3J = 13.4 Hz, CH–NH), 11.36 (1 H, br, NH). 13C NMR
(75.5 MHz, CDCl3): δC 27.53 (2 CH3), 30.15 (CMe2), 50.04 and
50.37 (2 CH2), 53.16 (CH2NH), 106.67 (CO–C–CO), 126.53 (2 CH),
127.48 (CH), 128.11 (2 CH), 134.27 (Cipso), 157.31(N–CH), 195.34
and 198.31 (2 C=O). MS (m/z, %): 258 (M+ + 1, 20), 257 (M+, 100),
242 (8), 240 (13), 214 (3), 173 (20), 166 (27), 91 (88), 55 (14). Anal.
Calcd for C16H19NO2 (257.14): C, 74.68; H, 7.44; N, 5.44. Found: C,
74.81; H, 7.45; N, 5.60.
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1
2
3
4
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2-(tert-Butylaminomethylene)-5,5-dimethylcyclohexane-1,3-dione
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1
(υmax, cm-1): 3415 (N–H), 1663 (C=O) and 1467 (C=C). H NMR
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MHz, CDCl3): δC 24.26, 24.93 and 28.23 (3 CH2 of cyclohexyl),
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18), 249 (M+, 100), 234 (13), 220 (8), 194 (7), 97 (79), 55 (73). Anal.
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72.32; H, 9.28; N, 5.69.
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200 JOURNAL OF CHEMICAL RESEARCH 2008
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