Iodine-catalyzed conversion of β-dicarbonyl compounds into β-enaminones within a minute under solvent-free conditions

Article abstract of DOI:10.1080/00397910500290557

Synthesis of β-enaminones from β-dicarbonyl compounds has been achieved in high yields within a minute using primary and aromatic amines and catalytic amounts of iodine under solvent-free conditions at room temperature. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500290557

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Iodine‐Catalyzed Conversion of
β‐Dicarbonyl Compounds into
β‐Enaminones Within a Minute
Under Solvent‐Free Conditions
Siddhartha Gogoi a , Ranjana Bhuyan a & Nabin C.
Barua a
a Natural Products Chemistry Division, Regional
Research Laboratory (CSIR), Jorhat, Assam, India
Published online: 22 Aug 2006.
To cite this article: Siddhartha Gogoi , Ranjana Bhuyan & Nabin C. Barua (2005)
Iodine‐Catalyzed Conversion of β‐Dicarbonyl Compounds into β‐Enaminones Within a
Minute Under Solvent‐Free Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:21, 2811-2818
To link to this article: http://dx.doi.org/10.1080/00397910500290557
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Synthetic Communicationsw, 35: 2811–2818, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500290557
Iodine-Catalyzed Conversion of
b-Dicarbonyl Compounds into
b-Enaminones Within a Minute Under
Solvent-Free Conditions
Siddhartha Gogoi, Ranjana Bhuyan, and Nabin C. Barua
Natural Products Chemistry Division, Regional Research Laboratory
(CSIR), Jorhat, Assam, India
Abstract: Synthesis of b-enaminones from b-dicarbonyl compounds has been
achieved in high yields within a minute using primary and aromatic amines and
catalytic amounts of iodine under solvent-free conditions at room temperature.
Keywords: Amines, b-diketones, b-enaminones, b-ketoesters, iodine
b-Enaminones are versatile intermediates for the synthesis of many bioactive
molecules with a heterocyclic unit. Their basic structural units RNH–C55C–Z
(Z ¼ –COCH3 or –COOC2H5) are responsible for the synthesis of many thera-
peutic agents from both natural and synthetic sources including taxol,[1] anticon-
vulsivant,[1a,2] antiinflammatory,[1a,3] and duocarmycin classes of antitumor
agents[1a,4] as well as quinoline antibacterials[1a,5] and quinoline antimalarials.
In addition, chiral enaminones that can be easily synthesized from optically
active compounds are generally used as ligands for diastereoselective synthesis.
Because of the stability of enaminones under simulated physiological pH con-
ditions and low toxicity,[2,6] the synthesis of b-enaminones is receiving much
attention in recent times. There are several methods reported in the literature
Received in India May 25, 2005
Address correspondence to Nabin C. Barua, Natural Products Chemistry Division,
Regional Research Laboratory (CSIR), Jorhat 785006 Assam, India. Tel.: þ91-2376-
2370121; Fax: þ91-2376-2370011; E-mail: ncbarua2000@yahoo.co.in
2811

2812
S. Gogoi, R. Bhuyan, and N. C. Barua
for the preparation of b-enaminones. Among them, the oldest and most general
method for the preparation of enaminones is the direct condensation of amines
and dicarbonyl compounds under reflux in aromatic solvent with azeotropic
removal of water.[1c,7] Other procedures using Al2O3,[1b] SiO2,[8] montmorillo-
[11]
nite K-10/microwave or ultrasound,[9] NaAuC14,[10] Zn(ClO4)2 6H2O,
.
acetic acid under ultrasound,[12] and CeC13 7H2O[13] have also been reported
.
in the literature. However, most of these procedures suffer from drawbacks
such as reflux temperatures, low yields of the products, the use of expensive
or less easily available reagents, the use of toxic solvents (benzene, toluene,
etc.) and long reaction times. In this context, we felt the need for a mild and
efficient procedure for the preparation of b-enaminones because in many
cases b-enaminones are used as intermediates in organic synthesis.
We observed that when b-dicarbonyl compounds were mixed with
amines and a catalytic amount of iodine under solvent-free conditions, the
corresponding b-enaminones were obtained in excellent yields at room
temperature (Scheme 1).
In recent times, because of its easily availability, low cost, low toxicity, and
environmentally friendly character, iodine is widely used by organic chemists as a
catalyst for various transformations.[14] It is mostly used as a Lewis acid catalyst
for the selective protection of alcohol groups[15] and carbonyl groups,[14e,16] acetyl-
ation reactions,[17] Ferrier reactions,[8] oxidation reactions,[19] allylation reac-
tions,[14d] three-component allylations of imines,[20] and so forth. Herein we
report a very fast iodine-catalyzed conversion of b-dicarbonyl compounds into
b-enaminones under mild and solvent-free conditions at room temperature.
As shown in Table 1, we performed this reaction with both b-ketoesters
and 1,3-diketones. In both the cases, the only isolable products were
b-enaminones. This is probably because of differences in reactivity between
the acetyl carbonyl and the ester carbonyl; the former is more reactive than
the latter. Resonance and conjugation effect also help the formation of
b-enaminones as the sole product. In the case of more nucleophilic amines
(entries 1, 2, 5, 7, 8, and 11), the yields of the corresponding b-enaminones
are higher in our procedure than the reported protocols, and the time
required for completion of the reaction is also much less (1 min. or less). In
the case of very weak amines such as aniline (entries 3 and 9), the reaction
Scheme 1.

Table 1. Synthesis of b-enamino esters and b-enamino ketones from amines and dicarbonyl compounds under solvent-free conditions
Reaction time
(min)
Entry
1
Substrates
Amines
Productsa
Yieldsb (%) [ref.]
92[22]
C6H11NH2
1
2
3
4
5
CH3(CH2)4CH2NH2
PhNH2
0.5
3
94[13]
79[22]
90[22]
98[22]
CH3NH2
1
PhCH2NH2
0.30
6
7
NH2(CH2)2NH2
C6H11NH2
1
95[21]
0.4
97[12]
(continued)

Table 1. Continued
Reaction time
(min)
Entry
8
Substrates
Amines
Productsa
Yieldsb (%) [ref.]
CH3(CH2)4CH2NH2
0.5
2.5
95[12]
9
PhNH2
81[12]
10
11
CH3NH2
1
92[22]
PhCH2NH2
0.30
99[12]
12
NH2(CH2)2NH2
1
97[21]
aAll the products were characterized by H NMR, IR, mass, and CHN analysis.[12,13,21,22]
bYields are of pure isolated products.
1

Conversion of b-Dicarbonyl Compounds
2815
Scheme 2.
took somewhat longer time (2–3 min) and gave comparatively better yields
than the reported methods. When we performed this reaction with symmetrical
diamines (entries 6 and 12), the corresponding dimerized products were
obtained in high yield (95% and 97%). In all these cases, the chemoselectivity
was very good, that is, only Z-b-enaminones were formed predominantly as
confirmed by 1H NMR spectra of the crude products.
We also observed that this reaction proceeds with unsymmetrical b-ketoesters
and 1,3-diketones with equal ease. However, in the case of aryl-b-ketoesters
(Scheme 2), the reactions were somewhat slow but the yields were good
(85–95%). In the case of phenylacetylacetone, the yields were good to excellent
(92–98%) (Scheme 3). In these cases, the regiochemistry was controlled by the
more reactive carbonyl groups, which underwent preferential attack on the amine.
As for the mechanism of this reaction, we believe that the enol or enolate
form of A reacts with iodine and drives the reaction toward formation of the
iodinated product B. The lone pair on nitrogen of the amine then undergoes
nucleophilic addition to the more active carbonyl to give species C. The IQ
ion present in the reaction mixture then picks up iodine with concomitant
dehydration driven by more stabilized product with liberation of iodine to
give the desired product as shown in Scheme 4.
In conclusion, we have demonstrated a very mild and efficient method for
the conversion of b-ketoesters and b-diketones to b-enaminones in
the presence of amines using a catalytic amount of iodine at room temperature
within a minute under solvent-free conditions. The yields of the products are
quite good in comparison to other methods reported in the literature. Because
iodine is a less expensive, easily available, and environmentally friendly
catalyst, this method may find wide acceptance among organic chemists.
Scheme 3.

2816
S. Gogoi, R. Bhuyan, and N. C. Barua
Scheme 4.
EXPERIMENTAL
NMR spectra were recorded in Bruker DPX-300 NMR machine in deuterio-
chloroform and chemical shift values were recorded in d relative to TMS as
the internal standard. IR spectra were recorded on Perkin-Elmer 1640 FT-
IR spectrometer on chloroform. Mass spectra were recorded in a Brucker
Daltonic Data Analysis 2.0 spectrometer. All reagents were of commercial
quality from freshly opened containers and were purchased from Aldrich
Chemical Company and used without further purification.
General Procedure for the Formation of Enaminones
Iodine (20 mol%) was added to a mixture of ethyl acetoacetate or acetylacetone
(1.5 mmol) and amine (1.5 mmol) [but in the case of aniline and ethylene
diamine (entries 3, 6, 9 and 12), iodine was first added to the substrates, the
mixture was cooled to 58C, and then amine was added dropwise]. When iodine
was added, heat evolved (exothermic reaction). Then, the reaction mixture was
cooled under tap water. During this period, the reaction completed, which was
indicated by TLC. Then, the reaction mixture was diluted with CH2Cl2 and
washed with water. The extract was dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by preparative TLC on silica gel using
n-hexane/EtO Ac (1 : 1), which gave the pure b-enaminones (79–99%).
Spectral Data of Selected Compounds
(3Z)-4-(Cyclohexylamino)-3-penten-2-one (entry 1): IR (thin film, CHCl3):
1606, 1577 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 1.27–1.86 (m, 10H),

Conversion of b-Dicarbonyl Compounds
2817
1.95 (s, 3 H), 1.98 (s, 3H), 3.34–3.38 (m, 1H), 4.91 (s, 1H), 11.00 (br, s, 1H).
13C NMR (75 MHz, CDCl3) d (ppm): 18.25, 24.07, 24.99, 28.34, 33.46, 51.13,
94.59, 161.56, 193.91. MS (ESI): m/z 204 [M+ + Na]. Anal calcd. for
C11H19NO: C, 72.79; H, 10.47; N, 7.68. Found: C, 72.88; H, 10.56; N, 7.73.
(3Z)-4-(Methylamino)-3-penten-2-one (entry 4): IR (thin film, CHCl3):
1610, 1572 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 10.64 (br s, 1H, NH),
4.91 (s, 1H), 2.86 (d, 3H, J ¼ 5.4 Hz), 1.94 (s, 3H), 1.83 (s, 3H). 13C NMR
(75 MHz, CDCl3) d (ppm): 194.4, 164.0, 94.7, 29.4, 28.4, 18.5 MS (ESI):
m/z 136 (M+ + Na). Anal calcd. for C6H11NO: C, 63.62; H, 9.75; N, 12.32.
Found: C, 63.69; H, 9.80; N, 12.38.
(3Z)-4-(Benzylamino)-3-penten-2-one (entry 5): IR (thin film, CHCl3):
1607, 1572 cm21. 1H NMR (300 MHz, CDCl3) d (ppm): 11.15 (br s, 1H, NH),
7.22–7.34 (m, 5H, C6H5), 5.04 (s, 1H), 4.41 (d, J ¼ 6.5 Hz, 2H) 2.01 (s, 3H),
1.89 (s, 3H) 13C NMR (75 MHz, CDCl3) d (ppm): 195.3, 162.8, 137.7, 128.6,
127.2, 126.5, 95.7, 46.5, 28.7, 18.7. Anal calcd. for C12H15NO: C, 76.09; H,
8.01; N, 7.32. Found: C, 76.16; H, 7.99; N, 7.40.
Ethyl (2Z)-3-(cyclohexylamino) but-2-enoate (entry 7): IR (thin film,
1
CHCl3): 1658, 1605 cm21. H NMR (300 MHz, CDCl3) d (ppm): 1.24 (t,
3H, J ¼ 7.1 Hz), 1.25–1.88 (m, 10H), 1.93 (s, 3H), 3.29–3.33 (m, 1H),
4.07 (q, 2H, J ¼ 7.1 Hz), 4.38 (s, 1H), 8.64 (br, s, 1H). 13C NMR (75 MHz,
CDCl3) d (ppm): 14.73, 19.21, 24.71, 25.47, 34.56, 51.41, 58.23, 60.36,
81.78, 160.79, 170.63. MS (ESI): m/z 234 [M+ + Na]. Anal calcd. for
C12H21NO2: C, 68.13; H, 9.91; N, 6.59. Found: C, 68.21; H, 10.02; N, 6.63.
Ethyl (2Z)-3-(Methylamino)-2-butenoate (entry 10): IR (thin flim,
1
CHCl3): 1651, 1610 cm21. H NMR (300MHz, CDCl3) d (ppm): 8.42 (br s,
1H, NH), 4.41 (s, 1H), 4.01 (q, 2H, J ¼ 7.0 Hz), 2.85 (d, 3H, J ¼ 5.5), 18.2
(s, 3H), 1.21 (t, 3H, J ¼ 7.0 Hz) 13C NMR (75 MHz, CDCl3) d (ppm): 170.4,
162.5, 81.7, 58.21, 29.4, 19.0, 14.5. MS (ESI): m/z 166 (M+ + Na). Anal calcd.
for C7H13NO2: C, 58.67; H, 9.11; N, 9.69. Found: C, 58.72; H, 9.15; N, 9.78.
Ethyl (2Z)-3-(benzylamino) but-2-enoate (entry 11): IR (thin film,
CHCl3): 1655, 1605 cm21 1H NMR (300 MHz, CDCl3) d (ppm): 1.25
.
(t, 3H, J ¼ 7.1 Hz), 1.90 (s, 3H), 4.10 (q, 2H, J ¼ 7.1 Hz), 1.90 (s, 3H),
4.10 (q, 2H, J ¼ 7.1 Hz), 4.42 (d, 2H, J ¼ 6.4 Hz), 4.55 (s, 1H), 7.22–7.40
(m, 5H), 8.95 (br s, 1H, NH) 13C NMR (75 MHz, CDCl3) d (ppm): 14.7,
19.5, 24.1, 46.8, 58.5, 83.2, 126.8, 127.4, 128.8, 138.8, 161.0, 170.6. MS
(ESI): m/z 242 (M+ + Na) Anal calcd. for C13H17NO2: C, 71.16; H, 7.89;
N, 6.31. Found: C, 71.21; H, 7.81; N, 6.39.
ACKNOWLEDGMENT
The authors gratefully acknowledge the Director, Regional Research
Laboratory (CSIR), Jorhat, Assam, India, for providing facilities for this
work. S. G. and R. B. thank the CSIR, New Delhi, India, for the financial
assistance.

2818
S. Gogoi, R. Bhuyan, and N. C. Barua
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