General, mild and efficient synthesis of β-enaminones catalyzed by ceric ammonium nitrate

Article abstract of DOI:10.1055/s-2007-973862

Ceric ammonium nitrate catalyzes the reaction between aromatic or aliphatic primary amines and a variety of β-dicarbonyl compounds, including β-ketoesters, β-ketothioesters and β-diketones. The reaction proceeds smoothly at room temperature in short react

Full text of DOI:10.1055/s-2007-973862

LETTER
881
General, Mild and Efficient Synthesis of b-Enaminones Catalyzed by Ceric
Ammonium Nitrate
C
A
N
-Catalyzed
b
-
e
E
naminone
l
Synthe
l
sis aisamy Sridharan, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
Received 9 January 2007
Lanthanide salts, and particularly their triflates, are con-
sidered as ‘green’ alternatives to traditional Lewis acids,27
since they have low toxicities and are compatible with
aqueous reaction media. Although cerium is the most
common lanthanide, the use of its salts as Lewis acids has
received relatively little attention and most work has fo-
cused on Ce(III) compounds.28 However, Ce(IV) species
have low toxicities and are the only tetravalent lan-
thanides that are stable in water. These qualities make
them particularly attractive as environmentally benign re-
agents and, indeed, they are, to date, the only synthetically
useful Ln(IV) reagents. Although Ce(IV) derivatives are
normally employed as one-electron oxidants, the use of
the commercially available, inexpensive and easily han-
dled cerium(IV) ammonium nitrate (CAN) in C–C bond-
forming reactions has recently attracted much attention,29
although these studies are still in their early stages. As
stated in a recent review on the subject,29d one of the main
goals yet to be achieved in this area is the development of
reactions that allow the use of catalytic amounts of
CAN.30 Within this context, we describe here our work on
the use of cerium(IV) ammonium nitrate as a catalyst for
b-enaminone synthesis.
Abstract: Ceric ammonium nitrate catalyzes the reaction between
aromatic or aliphatic primary amines and a variety of b-dicarbonyl
compounds, including b-ketoesters, b-ketothioesters and b-dike-
tones. The reaction proceeds smoothly at room temperature in short
reaction times and gives b-enaminones in good to excellent yields.
Key words: enaminones, ceric ammonium nitrate, lanthanides,
Lewis acids, b-dicarbonyl compounds
The preparation of enamines from b-dicarbonyl deriva-
tives is an important transformation due to the wide range
of synthetic applications of b-enaminones1 in the prepara-
tion of heterocycles,2 including alkaloids,3 a-4 and b-ami-
no acids,5 peptides,6 b,g-unsaturated ketones,7 g-amino
alcohols,8 azo compounds9 and azacarbasugars,10 among
other synthetically relevant compounds. Existing methods
for the preparation of b-enaminones normally involve the
reaction of b-dicarbonyl compounds with amines in the
presence of catalysts such as protic acids,11 K-10 montmo-
rillonite and other clays,12 silica gel,13 alumina,14 bismuth
trifuoroacetate in water15a or molten TBAB,15b zinc per-
chlorate,16 cerium trichloride,17 indium tribromide,18 tri-
methylsilyl triflate19 or boron trifluoride.20 Occasionally,
these reactions can be performed in the absence of cata-
lysts by use of ionic liquids21a or water21b as the reaction
media, or under ultrasound irradiation,22 but in these cases
the scope of the method is limited by solubility issues. Al-
ternative, less direct procedures include the acylation of
imines via benzotriazole derivatives,23 the ruthenium-cat-
alyzed reaction between anilines and propargyl alco-
hols,24 the addition of ester or amide enolates to a variety
of electrophiles,25 and the transformation of enamino-
esters into enaminoketones by reaction with organolithi-
um reagents.26 In spite of this abundance of methods, they
suffer from a number of limitations such as the use of tox-
ic or expensive catalysts or reaction media, moderate
yields and limited scopes, since many methods do not
work well with aromatic amines, some require the use of
the neat b-dicarbonyl compound as the reaction medium,
and some of them are restricted to b-ketoesters. For this
reason, the development of a general and efficient method
for b-enaminone synthesis that uses a nontoxic and inex-
pensive catalyst is still important.
Table 1 shows the results obtained in the CAN-catalyzed
reaction between b-ketoesters and aromatic amines
(Scheme 1), which were initially chosen as nucleophiles
due to the unsatisfactory results that they give in many of
the published b-enaminone syntheses.31 We first set out to
establish the optimal amount of CAN, finding that the re-
action with a 10% catalyst loading gave a 81% yield after
1.5 hours (entry 1), which was lowered to 76% when the
reaction time was extended to 4 hours (entry 2). However,
the best result (91% yield) corresponded to the use of 5%
catalyst and a reaction time of 1.5 hours (entry 3). The
preference for a 5% catalyst loading was confirmed when
p-toluidine was used as the nucleophile (compare the
yields in entries 4 and 5). Other reactions involving cyclic
b-ketoesters proceeded uneventfully, and gave yields
higher than 90% in all cases (entries 6–11). In the case of
open-chain b-ketoesters, an initial study of the reaction
R2
H
O
O
CAN
N
R3
Ar
R1
R3
ArNH2
+
R1
O
EtOH, r.t.
R2
1
SYNLETT 2007, No. 6, pp 0881–0884
0
3.
0
4.
2
0
0
7
2
3
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973862; Art ID: D01007ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

882
V. Sridharan et al.
LETTER
Table 1 CAN-Catalyzed Synthesis of Enaminones Derived from Aromatic Amines
Entry
1
Product
3a
3a
3a
3b
3b
3c
Ar
R1
R2
R3
CAN (mol%) Time (h)
Yield (%)
81
76
91
88
79
93
99
99
99
98
99
83
87
66
89
73
83
71
74
98
99
93
88
93
98
76
68
99
99
99
7
Ph
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)3
(CH2)3
(CH2)3
(CH2)3
(CH2)3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
t-BuO
t-BuS
t-BuS
t-BuS
Me
10
10
5
1.5
4
2
Ph
3
Ph
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
Ph
5
5
10
5
6
7
3d
3e
5
8
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
Ph
5
9
3f
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3g
3h
3i
5
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
H
H
5
3i
Ph
5
3i
Ph
10
5
1.5
1.5
3
3j
4-MeOC6H4
4-FC6H4
3-MeC6H4
3,5-Me2C6H4
Ph
3k
3l
5
5
1.5
3
3m
3n
3o
3p
3q
3r
5
5
2
Ph
5
2
4-MeOC6H4
4-ClC6H4
Ph
5
1.5
1.5
1
5
5
3s
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Ph
Me
5
1
3t
Me
5
1
3u
3u
3v
3w
3x
3e
Me
5
2
Me
5
4
Ph
5
1
Ph
Ph
5
1
4-MeC6H4
Ph
Ph
5
1
(CH2)3
OEt
0
1.5
between aniline and ethyl acetoacetate (entries 12–14) We next examined the reaction between aromatic amines
confirmed the preference for a 5% catalyst loading (com- and other types of b-dicarbonyl compounds. In the case of
pare the yields in entries 13 and 14). Other reactions with b-ketothioesters the yields were excellent, irrespectively
ethyl acetoacetate (entries 15–18) and tert-butyl aceto- of the presence of electron-releasing or electron-with-
acetate (entry 19) gave yields between 71% and 89%.
drawing substituents in the aniline derivative (entries 20–
22). Several experiments involving b-diketones were also
carried out (entries 23–30), normally in excellent yields.
Synlett 2007, No. 6, 881–884 © Thieme Stuttgart · New York

LETTER
CAN-Catalyzed b-Enaminone Synthesis
883
The reaction between 4-chloroaniline and 2,4-pentanedi-
one (entries 26 and 27) showed again that long reaction
times are detrimental to yield. The reactions starting from
1-phenyl-1,3-butanedione (entries 28–30) can in principle
give two different enaminones, but they proceeded with
complete regiocontrol and afforded exclusively the prod-
uct with a double bond adjacent to the methyl group, in
quantitative yield in all cases studied. Finally, a control
experiment (entry 31) showed that the reaction between
aniline and ethyl 2-oxocyclopentanecarboxylate proceed-
ed in a very low conversion in the absence of catalyst.
CAN (5 mol%)
solvent, r.t.,
1.5 h
CO2Et
NH2
H
O
N
CO2Et
+
3a
Scheme 3
Table 3 Solvent Effects in the Reaction Between Aniline and Ethyl
2-Oxocyclopentanecarboxylate
Entry
Solvent
H2O
Yield (%)
Finally, in order to extend the scope of this method and to
include also the more favorable cases, some CAN-cata-
lyzed reactions between aliphatic amines and b-dicarbon-
yl compounds were also performed. As shown in
Scheme 2 and Table 2, all b-ketoesters, b-ketothioesters
and b-diketones assayed gave yields normally above 90%
in their reactions with benzylamine and butylamine, the
only exception being the reaction between benzylamine
and ethyl 2-oxocyclopentane-1-carboxylate that proceed-
ed in a slightly lower 80% yield.
1
2
3
4
5
6
7
8
9
88
98
99
92
99
93
81
98
85
MeOH
EtOH
MeCN
1,4-Dioxane
THF
CHCl3
CH2Cl2
Benzene
R3
O
O
H
N
R4
CAN (5 mol%)
EtOH, r.t.
R1
R1NH2
R2
R4
+
R2
O
R3
4
In an effort to clarify whether CAN exerts its role in our
enaminone synthesis through a one-electron oxidative
pathway, we have performed the reaction between ethyl
2-oxocyclohexanecarboxylate and aniline (entry 3 in
Table 1) in the presence of a large amount of a radical
trap, namely 1,1-diphenylethylene. In this experiment we
found no noticeable loss in yield, which indicates that a
radical mechanism is not in operation under our condi-
tions. In this regard, it is relevant to note that some litera-
ture results can be interpreted by assuming that CAN may
behave as a Lewis acid, although this role has not been
systematically studied. The clearest example can be found
in a study about the use of CAN as a catalyst for acetal and
ketal deprotection, where it has been proved by cyclic
voltammetry that cerium remains in the Ce(IV) oxidation
state, strongly suggesting that it acts as a Lewis acid.32
5
3
Scheme 2
Table 2 CAN-Catalyzed Synthesis of Enaminones Derived from
Aliphatic Amines
Entry Product R1
R2
R3
R4
Time Yield
(h)
(%)
1
2
3
4
5
6
3y
Bn
(CH2)3
Me
OEt
2
80
3z
Bn
H
H
H
H
H
OEt
2
91
3aa
3ab
3ac
3ad
Bn
Me
t-BuS
OEt
1
97
n-Bu
n-Bu
Bn
Me
0.5
0.5
1
98a
94a
90
Me
t-BuS
Me
Me
In conclusion, we have shown that CAN is an inexpen-
sive, eco-friendly catalyst that allows the general and effi-
cient construction of b-enaminone derivatives from
primary amines under mild conditions and using an exper-
imentally simple protocol. Furthermore, most reactions
were extremely clean, as shown by the NMR spectra of
the crude reaction mixtures. We expect that the very high
efficiency of our method, coupled with the unusually
broad solvent tolerance of the reaction, will allow the de-
velopment of one-pot multicomponent procedures involv-
ing the in situ generation of b-enaminones, followed by
the addition of further reactants. Work along these lines is
in progress in our laboratory.
a In these cases, 1.5 equiv of amine were used.
As a final check of the flexibility of the CAN-catalyzed
synthesis of b-enaminones, we investigated its scope in
terms of the range solvents that it is able to tolerate. Using
the reaction between aniline and ethyl 2-oxocyclopen-
tane-1-carboxylate as a reference system, we were able to
ascertain that the method proceeds in excellent yields in
nine different solvents, which ranged in polarity from wa-
ter to benzene (Scheme 3, Table 3). We expect that this
unusual broad solvent tolerance of the reaction will facil-
itate its synthetic application, and more specifically the
development of one-pot multicomponent procedures
based on the well-known1 reactivity of enaminones.
Synlett 2007, No. 6, 881–884 © Thieme Stuttgart · New York

884
V. Sridharan et al.
LETTER
(26) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron Lett.
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(27) Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72,
1373.
Acknowledgment
Financial support from MEC (grant CTQ2006-10930/BQU) and
CAM-UCM (Grupos de Investigación, grant 920234) is gratefully
acknowledged.
(28) Some examples are: (a) CeCl3·nH2O/NaI: Bartoli, G.;
Marcantoni, E.; Sambri, L. Synlett 2003, 2101. (b)
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(29) Some reviews on CAN-promoted synthetic
transformations: (a) Nair, V.; Matthew, J.; Prabhakaran, J.
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(30) Some synthetically useful CAN-catalyzed reactions have
been described very recently. See: (a) Zeng, X.-F.; Ji, S.-J.;
Wang, S. Y. Tetrahedron 2005, 61, 10235. (b) Wang, S. Y.;
Ji, S.-J. Tetrahedron 2006, 62, 1527. (c) Savitha, G.;
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(31) General Experimental Procedure for b-Enaminone
Synthesis
References and Notes
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To a stirred solution of 3 mmol of amine 1 and 3 mmol of b-
dicarbonyl compound 2 in 3 mL of EtOH was added 5 mol%
of CAN. The mixture was stirred at r.t. for the time periods
specified in Tables 1 and 2. After completion of the reaction
the mixture was dissolved in CH2Cl2, washed with H2O,
dried, and evaporated. Analytically pure compounds 3 were
obtained by a rapid column chromatography on Et3N-
pretreated silica gel, eluting with PE–EtOAc mixtures.
Characterization data for two representative, previously
unknown enamines follow.
Ethyl 2-(4-methylphenylamino)cyclohex-1-enecarboxylate
(3b): viscous liquid. IR (neat): 3228.5, 2935.4, 2858.6,
1650.6, 1603.4, 1515.9, 1236.9, 1175.8, 1077.8 cm–1. 1H
NMR (250 MHz, CDCl3): d 1.33 (t, J = 7.1 Hz, 3 H), 1.61–
1.63 (m, 4 H), 2.26–2.40 (m, 7 H), 4.21 (q, J = 7.1 Hz, 2 H),
6.98 (d, J = 8.2 Hz, 2 H), 7.13 (d, J = 8.2 Hz, 2 H), 10.69 (br
s, 1 H). 13C NMR (62.9 MHz, CDCl3, DEPT-135): d = 15.1
(CH3), 21.3 (CH3), 22.7 (CH2), 23.1 (CH2), 24.3 (CH2), 28.5
(CH2), 59.5 (CH2), 92.7 (CH), 125.7 (CH), 129.8 (CH),
134.6 (C), 137.5 (C), 157.5 (C), 171.3 (C). Anal. Calcd for
C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.06; H,
8.32; N, 5.71.
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tert-Butyl 3-(butylamino)but-2-enethioate (3ac): viscous
liquid. IR (neat): 3253.3, 2960.1, 2928.2, 1606.0, 1582.8,
1499.8, 1360.6, 1266.3, 1084.5 cm–1. 1H NMR (250 MHz,
CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.37–1.56 (m, 4 H),
1.50 (s, 9 H), 1.87 (s, 3 H), 3.20 (q, J = 7.3 Hz, 2 H), 4.86 (s,
1 H), 9.34 (br s, 1 H). 13C NMR (62.9 MHz, CDCl3, DEPT-
135): d = 14.2 (CH3), 19.2 (CH3), 20.4 (CH2), 31.0 (CH3),
32.8 (CH2), 43.3 (CH2), 46.8 (C), 94.2 (CH), 160.1 (C),
188.9 (C). Anal. Calcd for C12H23NOS: C, 62.83; H, 10.11;
N, 6.11; S, 13.98. Found: C, 62.76; H, 9.96; N, 5.86; S,
13.74.
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Synlett 2007, No. 6, 881–884 © Thieme Stuttgart · New York