Cyanuric chloride catalysed rapid conversion of β-ketoesters into β-enaminoesters under mild and solvent-free conditions

Article abstract of DOI:10.1007/BF03245892

Cyanuric chloride is shown to be an extremely efficient catalyst for the synthesis of β-enaminoesters from β-ketoesters under solvent-free conditions by grinding in a mortar with pestle at 25 °C. A short reaction time, an inexpensive and easily available catalyst, mild reaction conditions and excellent yields of the products are attractive features of this methodology.

Full text of DOI:10.1007/BF03245892

J. Iran. Chem. Soc., Vol. 8, No. 3, September 2011, pp. 616-621.
JOURIrNaAnLiaOnF THE
Chemical Society
Cyanuric Chloride Catalysed Rapid Conversion of β-Ketoesters
into β-Enaminoesters under Mild and Solvent-Free Conditions
V.T. Kamble*, N.S. Joshi and S.T. Atkore
Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand
Teerth Marathwada University, Nanded-431606, Maharashtra, India
(Received 27 July 2009, Accepted 29 October 2009)
Cyanuric chloride is shown to be an extremely efficient catalyst for the synthesis of β-enaminoesters from β-ketoesters under
solvent-free conditions by grinding in a mortar with pestle at 25 °C. A short reaction time, an inexpensive and easily available
catalyst, mild reaction conditions and excellent yields of the products are attractive features of this methodology.
Keywords: Amines, β-Enaminoesters, β-Ketoesters, Cyanuric chloride
INTRODUCTION
of the reported methods. Recently Zr(ClO4)2.6H2O has been
reported to convert β-ketoesters into β-enaminoesters within 3-
30 h. However, this methodology required MgSO4 (30 mol%)
as an additive to obtain the best results [12]. Consequently,
there is a scope for the development of general, mild and
efficient methodology for the synthesis of β-enaminoesters.
Organic chemists continue to explore novel synthetic
methods involving new reagents and catalysts to carry
chemical transformations. One of these novel synthetic
methods is to carry out reactions on the surface of solids or
solid supported reagents. Organic reactions were found to
occur efficiently and selectively in solid state [13]. Since solid
surfaces have properties different than that of the solution or
gas phase, totally new chemistry may occur. Even in the
absence of new chemistry, a surface reaction may be more
desirable than a solution counterpart, because the reaction is
more convenient to run, or a high yield of product is attained.
Solid state synthetic organic chemistry has some advantages
such as (i) easy isolation of products (ii) high yields of
products and suppression of by-product formation (iii)
improved selectivity of catalyst. For these reasons, solid state
synthetic organic chemistry is a rapidly growing field of study.
β-Enamino acid derivatives, particularly β-enaminoesters
are important and versatile building blocks in organic
synthesis [1] for example in the synthesis of biologically
active compounds such as β-amino acids [2a], γ-aminols (3-
hydroxy amines) [2b], alkaloids [3], peptides [4] and
heterocycles [5]. In particular, cyclic β-enamino esters have
been used for the synthesis of many natural products such as
pyrrolizidines, indolizidines, quinolizidines and other
alkaloids [1c-d].
Various methods have been reported for the preparation of
β-enaminoesters, including addition of an ester or amide
enolate to a nitrile [6], tosyl imines [7] and imidoyl halides [8]
and via addition of enamines [9], or ketimines [10] to
activated carboxylic acid derivatives. These compounds can
also be successfully obtained by direct condensation of β-
ketoesters with amines [11]. However, long reaction times,
low chemical yields, drastic reaction conditions and a lack of
general applicability are the limitations associated with most
*Corresponding author. E-mail: vtkd@rediffmail.com

Kamble et al.
EXPERIMENTAL
3H), 4.06 (q, J = 6.9 Hz, 2H), 4.49 (s, 1H), 7.10 (d, J = 7.1 Hz,
2H), 7.35 (d, J = 7.0 Hz, 2H), 9.10 (br, s, 1H); Mass: m/z: 235
The 1H NMR spectra were recorded in CDCl3 at 300 MHz
using TMS as internal standard. IR spectra were recorded
using KBr pellets for solids and neat for liquid samples.
Column chromatography was performed using silica gel (100-
200 Mesh). Chemical shifts are given in ppm with respect to
internal TMS and J values are quoted in Hz.
(M+).
1
3g. IR: ν = 1110, 1325, 1575, 1607, 3020 cm-1; H NMR:
δ = 1.22 (t, J = 7.0 Hz, 3H), 1.89 (s, 3H), 4.10 (q, J = 7.0 Hz,
2H), 4.51 (s, 1H), 7.21 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 7.0 Hz,
2H), 9.10 (br, s, 1H); Mass: m/z: 239 (M+).
1
3h. IR: ν = 1125, 1330, 1570, 1625, 3010 cm-1; H NMR:
δ = 1.25 (t, J = 7.0 Hz, 3H), 1.92 (s, 3H), 4.12 (q, J = 7.0 Hz,
2H), 4.55 (s, 1H), 7.21-7.55 (m, 4H), 9.15 (br, s, 1H); Mass:
m/z: 239 (M+).
General Procedure
The amine (1.5 mmol), β-ketoester (1 mmol) and a
cyanuric chloride (2 mol%) were ground together in a mortar
with a pestle for the specified time. After completion of the
reaction (TLC), water was added and the product was
extracted with diethyl ether. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel
100-120 mesh, petroleum ether:ethyl acetate = 9:1).
1
3i. IR: ν = 1120, 1350, 1595, 1609, 2995 cm-1; H NMR:
δ = 1.25 (t, J = 7.1 Hz, 3H), 1.90 (s, 3H), 4.50 (s, 1H), 4.10 (q,
J = 7.2 Hz, 2H), 7.22 (d, J = 7.1 Hz, 2H), 7.24 (d, J = 7.0 Hz,
2H), 8.75 (br, s, 1H); Mass: m/z: 250 (M+).
1
3j. IR: ν = 1150, 1745, 3315, cm-1; H NMR: 1.25 (t, J =
7.1 Hz, 3H), 2.52 (m, 4H), 3.15 (t, J = 7.3 Hz, 2H), 4.01 (q,
J = 6.6 Hz, 2H), 6.90-7.15 (m, 5H), 11.05 (br, s, 1H); Mass:
m/z: 231 (M+).
1
Spectroscopic Data of Compounds
3k. IR: ν = 1115, 1645, 3295 cm-1; H NMR: 1.98 (t, J =
3a. IR: ν = 1115, 1370, 1609, 1654, 3320 cm-1; H NMR:
7.0 Hz, 3H), 4.03 (q, 2H), 4.50 (s, 1H), 6.90-7.65 (m, 10H),
1
δ = 1.21 (d, J = 6.5 Hz, 6H), 1.24 (t, J = 7.0 Hz, 3H), 1.94 (s,
3H), 3.6 (m, 1H), 4.08 (q, J = 7.0 Hz, 2H), 4.39 (s, 1H), 8.49
(br, s, 1H); Mass: m/z: 171 (M+).
11.02 (br, s, 1H); Mass: m/z: 255 (M+).
1
3l. IR: ν = 1152, 1740, 3310, cm-1; H NMR: 0.94 (t, J =
7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.30 (m, 2H), 1.52 (m,
2H), 1.82 (m, 2H), 2.50 (m, 4H), 3.20 (t, J = 7.3 Hz, 2H), 3.94
(q, J = 6.6 Hz, 2H), 11.24 (br, s, 1H), Mass: m/z (%) = 211
(M+).
3b. IR: ν = 1249, 1577, 1606, 3312 cm-1; H NMR: δ =
1
1.18 (t, J = 6.9 Hz, 3H), 1.27 (m, 10H), 1.35 (m, 1H), 1.95 (s,
3H), 4.02 (q, J = 6.9 Hz, 2H), 4.91 (s, 1H), 11.0 (br, s, 1H);
Mass: m/z: 211 (M+).
3c. IR: ν = 1492, 1599, 1655, 2926, 3264 cm-1; H NMR:
RESULTS AND DISCUSSION
1
δ = 1.26 (t, J = 7.1 Hz, 3H), 1.96 (s, 3H), 3.70 (q, J = 7.1 Hz,
2H), 4.67 (s, 1H), 6.85-7.21 (m, 5H), 10.33 (br, s, 1H); Mass:
m/z: 205 (M+).
Over the last few years, there has been a considerable
growth in interest in the use of cyanuric chloride or its
derivatives in organic synthesis [14]. In this communication,
we wish to report cyanuric chloride as a highly efficient
catalyst for the synthesis of β-enaminoesters under solvent-
free and mild conditions (Scheme 1).
Initially, a systematic study was carried out for the
evaluation of cyanuric chloride as a promoter for the reaction
of aniline and ethylacetoacetate under various conditions
(Table 1). Reaction between ethyl acetoacetate and aniline, in
the absence of a catalyst produced only a trace amount of
product after 20 h (entry 1) and inferior results were obtained
in the presence of solvents (Table 1, entries 2-5). Next we
3d. IR: ν = 1150, 1720, 3300 cm-1; H NMR: δ = 1.28 (t,
1
J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.94 (q, J = 7.2 Hz, 2H), 4.41 (d,
J = 6.6 Hz, 2H), 5.14 (s, 1H), 7.30-7.42 (m, 5H), 11.63 (t, J =
6.6 Hz, 1H); Mass: m/z: 219 (M+).
3e. IR: ν = 1135, 1320, 1480, 1580, 1615, 2950, 3210 cm-1;
1H NMR: δ = 1.25 (t, J = 7.2 Hz, 3H), 1.91 (s, 3H), 2.36 (s,
3H), 4.08 (q, J = 7.2 Hz, 2H), 4.50 (s, 1H), 7.20 (d, J = 7.0 Hz,
2H), 7.25 (d, J = 7.0 Hz, 2H), 8.95 (br, s, 1H); Mass: m/z: 219
(M+).
3f. IR: ν = 1105, 1321, 1470, 1585, 1605, 3045 cm-1;
1H NMR: δ = 1.24 (t, J = 6.9 Hz, 3H), 1.90 (s, 3H), 3.75 (s,
617

Cyanuric Chloride Catalysed Rapid Conversion of β-Ketoesters
Cl
N
N
3
R
H
H
N
Cl
N
Cl
(2mol %)
O
O
N
O
+
3
R
1
R
1
R
OR2
OR2
grinding, r.t.
H
R1 = alkyl, aryl
R3 = alkyl, aryl, benzyl R2 = Et, Me
Scheme 1
O
O
O
p
MeOC6H5NH
Me
cynuric chloride (2 mol%)
grinding r.t., 10 min.
Me
OtBu
p
MeOC6H5NH2
OtBu
+
98%
Scheme 2
Table 1. Reaction between Aniline and Ethyl
there was no improvement in the yield or decrease in reaction
time (entries 10-11). With less than 2 mol% of cyanuric
chloride, the reaction was incomplete and resulted in a low
yield of the product (50-85%) even after grinding the reaction
mixture for 1 h.
Acetoacetates under Various Conditions
Entry Solvent
Catalyst
Time
Yield
(%)
(mol%) min/[h]
The results presented in Table 2 showed that the
methodology is successful for primary, benzylic and aromatic
amines. β-Ketoesters such as methyl and ethyl acetoacetates
were efficiently transformed into the corresponding β-
enaminoesters. Excellent yields and short reaction times are
noteworthy advantages of the present method over the
reported ones. More important is the requirement only 2 mol%
of cyanuric chloride for all the examples selected for the
present study. It was reported [12] that this reaction suffers
from steric hindrance in the case of β-ketoesters carrying a
substituent different from hydrogen in the α-position, or with a
bulky amine, therefore requiring long reaction times and
drastic reaction conditions.
_
1
2
3
4
5
6
7
8
neat
CH2Cl2
THF
CH3CN
CHCl3
neat
neat
neat
neat
neat
[20]
45
60
45
45
[1]
[1]
[1]
10
10
10
15
65
70
60
65
50
65
85
98
98
2.0
2.0
2.0
2.0
0.5
1.0
1.5
2
9
10
11
2.5
3.5
neat
98
However the present methodology (Scheme 2 and Scheme
3) was found much superior in terms of reaction times
compared to the reported method [12] (48 h and 26 h). High
yields of products were obtained even in the case of cyclic and
aromatic β-ketoesters (Table 2, entries, j, k and l). We also
assessed our methodology with a β-diketone (Scheme 4).
The condensation of pentane-2,4-dione with aniline
proceeded smoothly in an almost quantitative yield in 10 min
optimized the quantity of cyanuric chloride at room
temperature under solvent-free conditions for this reaction
(Table 1, entries 6-11) and it was observed that with just 2
mol% of cyanuric chloride, the reaction was complete in 10
min and an almost quantitative yield of the corresponding β-
enaminoester (98%) was obtained (entry 9). It is important to
note that when the amount of cyanuric chloride was increased,
618

Kamble et al.
Table 2. Cyanuric Chloride Catalyzed Synthesis of β-Enaminoesters from β-Ketoesters and
Amines
Yielda,b
Time
β-Ketoester
Product
NH
Entry
a
Amine
(min)
(%)
R=Me/Et
O
H3C
H3C
O
H3C
H3C
O
O
CH
CH NH2
10
10
98
97
R=Et
OR
OR
R=Me
OR
OR
O
O
NH2
NH
b
c
10
10
98
97
R=Et
R=Me
H
N Ph
O
O
O
Ph NH2
10
10
98
98
R=Et
R=Me
OR
OR
OR
PhH2C NH
O
O
O
Ph
NH2
15
15
96
97
d
e
R=Et
R=Me
OR
H3C
NH
NH
O
O
O
O
O
O
O
45
50
91
94
H3C
NH2
R=Et
R=Me
OR
OR
OR
OR
MeO
O
MeO
Cl
NH2
NH2
60
60
90
91
f
R=Et
R=Me
Cl
Cl
NH
NH
O
30
30
90
91
g
R=Et
R=Me
OR
OR
OR
OR
OR
O
O
O
O
O
NH2
NH2
40
35
89
88
h
i
R=Et
R=Me
Cl
O2N
O2N
NH
O
45
50
80
81
R=Et
R=Me
OR
O
HN Ph
O
O
OEt
OEt
PhNH2
PhNH2
10
90
j
O
O
HNPh
O
OEt
10
10
96
98
k
l
OEt
O
O
nBu.HN
O
n
BuNH2
OEt
OEt
aYields of pure isolated products. bProducts were characterized by IR, 1H NMR and Mass
spectroscopy.
CH2Ph
NH
O
O
O
cyanuric chloride (2 mol%)
grinding, r.t., 60 min.
OtBu
NH2
OtBu
Ph
+
87%
Scheme 3
619

Cyanuric Chloride Catalysed Rapid Conversion of β-Ketoesters
H
Ph
O
O
N
O
cyanuric chloride (2 mol%)
grinding, r.t., 10 min.
PhNH2
+
98%
Scheme 4
whereas the reported method [12] took a longer reaction time
(4 h) for the same conversion.
Michael, A.S. Parsons, Tetrahedron 55 (1999) 10915.
L.G. Beholz, P. Benovsky, D.L. Ward, N.S. Barta, J.R.
Stille, J. Org. Chem. 62 (1997) 1033.
[4]
[5]
In conclusion we have developed a novel, mild and highly
efficient protocol for the synthesis of β-enaminoesters under
solvent-free conditions. The use of an inexpensive and easily
available catalyst, experimental simplicity, a simple work-up
procedure, and rapid reaction are the important attractive
features of this method.
a) A.-Z.A. Elassar, A.A. El-Khair, Tetrahedron 59
(2003) 8463; b) C. Agami, L. Dechoux, S. Hebbe,
Tetrahedron Lett. 43 (2002) 2521; c) H.A. Stefani, E.
de Avila, Synth. Commun. 32 (2002) 2041; d) H.M.C.
Ferraz, F.L.C. Pereira, F.S. Leite, M.R.S. Nunes, M.E.
Payret-Arrua, Tetrahedron 55 (1999) 10915; e) A.W.
Trautwein, G. Jung, Tetrahedron Lett. 39 (1998) 8263;
f) A.W. Erian, J. Prakt. Chem. 341 (1999) 147; g) V.
Daley, J. d’Angelo, C. Cave, J. Mahuteau, A. Chiaroni,
C. Riche, Tetrahedron Lett. 40 (1999) 1657; h) J.
d’Angelo, C. Cave, D. Desmaele, A. Gassama, C.
Thominiaux, C. Riche, Heterocycles 47 (1998) 725.
a) S.M. Hannick, Y. Kishi, J. Org. Chem. 48 (1983)
3833; b) A.S.Y. Lee, R.-Y. Cheng, Tetrahedron Lett. 38
(1997) 443; c) T.G.C. Bird, A. Olivier, Bioorg. Med.
Chem. Lett. 6 (1996) 515.
REFERENCES
[1]
S. Danishefsky, S.J. Etheredge, J. Org. Chem. 39
(1974) 3430; b) H. Taguchi, H. Yazawa, J.F. Arnett, Y.
Kishi, Tetrahedron Lett. (1977) 627; c) M.D. Bachi, R.
Breiman, H. Meshulam, J. Org. Chem. 48 (1983) 1439;
d) P. Brunerie, J.P. Celerier, M. Huche, G. Lhommet,
Synthesis (1985) 735; e) N.S. Barta, B. Brode, J.R.
Stille, J. Am. Chem. Soc. 116 (1994) 6201; f) K.
Paulvannan, J. Stille, J. Org. Chem. 59 (1994) 1613.
a) W.D. Lubell, M. Kitamura, R. Noyori, Tetrahedron:
Asymmetry 2 (1991) 543; b) G. Bartoli, C. Cimarelli,
E. Marcantoni, G. Palmieri, M. Petrini, J. Org. Chem.
59 (1994) 5328.
G.R. Cook, L.G. Beholz, J.R. Stille, J. Org. Chem. 59
(1994) 3575; d) C.Y. Hong, Y. Kishi, J. Am. Chem.
Soc. 114 (1992) 7001; e) J. Blot, A. Bardou, C. Bellec,
M.-C. Fargeau-Bellassoued, J.P. Celerier, G. Lhommet,
D. Gardette, J.-C. Gramain, Tetrahedron Lett. 38 (1997)
8511; f) J.P. Michael, C.B. de Koning, D. Gravestock,
G.D. Hosken, A.S. Howard, C.M. Jungmann, R.W.M.
Krause, A.S. Parsons, S.D. Pelly, T.V. Stanbury, Pure
Appl. Chem. 71 (1999) 979; g) A. Hermandez, M.
Marcos, H. Rapoport, J. Org. Chem. 60 (1995) 2683; h)
O. David, J. Blot, C. Bellec, F.-M.-C. Bellassoued, G.
Haviari, J.P.J. Celerier, G. Lhommet, J.-C. Gramain, D.
Gardette, J. Org. Chem. 64 (1999) 3122; i) J.P.
[6]
[2]
[3]
[7]
[8]
a) T. Fukuyama, Y.M. Yung, Tetrahedron Lett. 22
(1981) 3760; b) N. Jiang, J. Qu, Z. Wang, J. Org. Lett. 3
(2001) 2989.
a) K. Uneyama, O. Morimoto, F. Yamashita,
Tetrahedron Lett. 30 (1989) 4821; b) S. Fustero, B.
Pina, A. Simon-fuentes, Tetrahedron Lett. 38 (1997)
6771; c) S. Fustero, B. Pina, E. Salavert, A. Navarro,
M.C. Ramirez de Arellano, A. Simon-Fuentes, J. Org.
Chem. 67 (2002) 4667; d) S. Fustero, B. Pina, M.
Garcia de la Torre, A. Navarro, M.C. Ramirez de
Arellano, A. Simon, Org. Lett. 1 (1999) 977.
[9]
a) G. Bartoli, C. Cimarelli, R. Dalpozzo, G. Palmieri,
Tetrahedron 51 (1995) 8613; b) A.R. Katritzky, Y.
Fang, A. Donkor, J. Xu, Synthesis (2000) 2029.
[10] S. Fustero, M. Garcia de la Torre, V. Jofre, R. Perez
Carlon, A. Navarro, A. Simon Fuentes, J. Org. Chem.
63 (1998) 8825.
620

Kamble et al.
[11] a) H.M.C. Ferraz, E.O. Oliveira, M.E. Payret-Arrua,
593; e) H.L. Rayle, L. Fellmeth, Org. Procs. Res. Devp.
3 (1999) 172; f) M. Falorni, G. Giacomelli, A.
Porcheddu, M. Taddei, J. Org. Chem. 64 (1999) 8962;
g) L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett.
3 (2001) 1519; h) R. Samaritani, R. Menicagli,
Tetrahedron 58 (2002) 1381; i) M. Falorni, A.
Porcheddu, M. Taddei, Tetrahedron Lett. 40 (1999)
4395; j) D.C. Forbes, E.J. Barrett, D.J. Lewis, M.C.
Smith, Tetrahedron Lett. 41 (2000) 9943; k) L. De
Luca, G. Giacomelli, A. Porcheddu, J. Org. Chem. 67
(2002) 5152; l) G. Blothy, Tetrahedron Lett. 44 (2003)
1499; m) B. Karimi, H. Hazarkhani, Synthesis 16
(2003) 2547; n) B.P. Bandgar, S.S. Pandit, Tetrahedron
Lett. 43 (2002) 3413; o) B.P. Bandgar, S.S. Pandit,
Tetrahedron Lett. 44 (2003) 2331; p) B.P. Bandgar, S.S.
Pandit, Tetrahedron Lett. 44 (2003) 3855.
C.A. Brandt, J. Org. Chem. 60 (1995) 7357; b) J.A.
Kloek, K.L. Leschinsky, J. Org. Chem. 43 (1978) 1460;
c) V.A. Soloshonok, V. Kukhar, Tetrahedron 52 (1996)
6953; d) N. Leflemme, P. Dallemagne, S. Rault,
Synthesis (2002) 1740; c) S. Calvet, O. David, M.-C.
Vanucci-Bacque Fargeau-Bellassoued, G. Lhommet,
Tetrahedron 59 (2003) 6333.
[12] G. Bartoli, M. Bosco, M. Lacatelli, E. Marcantoni, P.
Melchiorre, L. Sambri, Synlett 2 (2004) 239.
[13] F. Toda, Acc. Chem. Res. 28 (1995) 480.
[14] K. Venkatraman, D.R. Wagle, Tetrahedron Lett. 32
(1979) 3037; b) Z.J. Kaminski, Synthesis (1987) 17; c)
M. Kunishima, J. Morita, C. Kawachi, F. Iwasaki, K.
Terao, S. Tani, Synlett 8 (1999) 1255; d) J.E.
Kaminska, Z.J. Kaminski, J. Gora, Synthesis 4 (1999)
621