Efficient organocatalytic dual activation strategy for preparing the versatile synthons (2 E)-1-(Het)aryl/styryl-3-(dimethylamino)prop-2-en-1-ones and -(E)-[(dimethylamino)methylene]cycloalkanones

Article abstract of DOI:10.1055/s-0030-1260048

A novel organocatalytic dual activation strategy is reported for an efficient synthesis of the versatile synthons (2E)-1-aryl/heteroaryl/styryl-3- (dimethylamino)prop-2-en-1-ones and -(E)-[(dimethylamino)methylene] cycloalkanones. 2-Guanidinoacetic acid (10 mol%) serves as an ambifunctional organocatalyst for the reaction of various aryl/heteroaryl/styryl methyl ketones and cyclic ketones having an -methylene moiety with N,N-dimethylformamide dimethyl acetal at 100 C for 1-3 hours under solvent-free conditions to afford the corresponding (2E)-3-(dimethylamino)prop-2-en-1-ones in 72-95% yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260048

1930
PAPER
Efficient Organocatalytic Dual Activation Strategy for Preparing the Versatile
Synthons (2E)-1-(Het)Aryl/styryl-3-(dimethylamino)prop-2-en-1-ones and
a-(E)-[(Dimethylamino)methylene]cycloalkanones
1
-Aryl/heteroa
a
ryl/styryl-3
c
-(dimethyl
h
i
nones Bindal, Dinesh Kumar, Damodara N. Kommi, Sonam Bhatiya, Asit K. Chakraborti*
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160062, India
Fax +91(172)2214692; E-mail: akchakraborti@niper.ac.in
Received 30 March 2011
formamide dimethyl acetal in anhydrous N,N-
Abstract: A novel organocatalytic dual activation strategy is re-
ported for an efficient synthesis of the versatile synthons (2E)-1-
aryl/heteroaryl/styryl-3-(dimethylamino)prop-2-en-1-ones and a-
(E)-[(dimethylamino)methylene]cycloalkanones. 2-Guanidinoace-
dimethylformamide11 (reflux, 12–14 h), and (vii)
Bredereck’s reagent in anhydrous anisole (reflux, 4.5 h).12
These methodologies suffer from disadvantages such as
tic acid (10 mol%) serves as an ambifunctional organocatalyst for the use of excess N,N-dimethylformamide dimethyl ace-
tal,6,11,13 long reaction times,4–8,11 the use of high-boiling
the reaction of various aryl/heteroaryl/styryl methyl ketones and cy-
solvents that are difficult to recover,11,12 high tempera-
clic ketones having an a-methylene moiety with N,N-dimethyl-
formamide dimethyl acetal at 100 °C for 1–3 hours under solvent-
tures,9,11 the requirement for special apparatus,10 and mod-
free conditions to afford the corresponding (2E)-3-(dimethylami-
erate yields. Thus, the development of a convenient and
no)prop-2-en-1-ones in 72–95% yields.
improved methodology for the synthesis of these versatile
Key words: 2-guanidinoacetic acid, organocatalyst, dual activa-
synthons is necessary. A recent effort towards this direc-
tion, 3-(dimethylamino)propenones, aryl methyl ketone, N,N-di-
tive involves performing the condensation reaction at 100
methylformamide dimethyl acetal
°C for six hours in the presence of stoichiometric amounts
of the ionic liquid [bmim][BF4].14 Although ionic liquids
are used as catalysts for various organic reaction15 the use
Enaminones of type 2 are versatile synthons for the con-
of stoichiometric quantities of [bmim][BF4] for the de-
struction of diverse heterocycles,1 the generation of new
sired reaction14 raises the possibility of a general effect of
chemical entities as potential therapeutic agents,2 and the
the ionic liquid as a medium. We reasoned that use of a
synthesis of drugs, such as antileukemic agent imatanib.3
suitable catalytic species that would generate the enolate
The common strategy for their preparation involves the
of the carbonyl substrate and at the same time activate
reaction of the corresponding carbonyl compounds hav-
N,N-dimethylformamide dimethyl acetal for ease of nu-
ing an a-methylene moiety with N,N-dimethylformamide
cleophilic displacement of the OMe group would promote
dimethyl acetal (DMF-DMA) (Scheme 1).
the reaction effectively. To implement such dual activa-
tion strategy16 we chose 4-methoxyacetophenone (1f) as
O
R1
MeO
MeO
the model substrate and treated it with N,N-dimethylform-
amide dimethyl acetal under various conditions in the
presence of 2-guanidinoacetic acid (glycocyamine) as the
guanidine moiety could serve as a base to generate enolate
of 1f while at the same time the carboxylic acid group
would activate N,N-dimethylformamide dimethyl acetal
through protonation at one of the OMe groups for nucleo-
philic displacement by the enolate of 1f (Scheme 2); the
results are summarized in Table 1.
O
NMe2
R1
+
NMe2
R2
R2
1
2
Scheme 1 Synthetic strategy for enaminones of the type 2
The various methodologies reported for the synthesis
of the enaminones of type 2 are the reaction of the car-
bonyl substrates 1 with (i) N,N-dimethylformamide di-
methyl acetal,4,5 tert-butoxybis(dimethylamino)methane
(Bredereck’s reagent),5 or tris(dimethylamino)methane
(neat, 110 °C, 12 h),5 (ii) N,N-dimethylformamide diethyl
acetal (reflux, 20 h),6 (iii) N,N-dimethylformamide di-
methyl acetal in anhydrous toluene7 or xylene8 (reflux, 8–
12 h), (iv) N,N-dimethylformamide dimethyl acetal under
fusion at 180 °C,9 (v) N,N-dimethylformamide dimethyl
NH
OH
O
O
H2N
N
H
O
NMe2
DMF-DMA
MeO
MeO
1f
2f
Scheme 2 Reaction of 4-methoxyacetophenone (1f) with N,N-di-
acetal under microwave heating,10 (vi) N,N-dimethyl- methylformamide dimethyl acetal in the presence of 2-guanidinoace-
tic acid
SYNTHESIS 2011, No. 12, pp 1930–1935
Advanced online publication: 17.05.2011
DOI: 10.1055/s-0030-1260048; Art ID: C01711SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
The desired product 3-(dimethylamino)-1-(4-methoxy-
phenyl)prop-2-en-1-one (2f) was obtained in 88% yield
when the reaction was performed in the presence of 2-

PAPER
1-Aryl/heteroaryl/styryl-3-(dimethylamino)prop-2-en-1-ones
1931
guanidinoacetic acid (10 mol%) at 100 °C for three hours 3). Decreasing the reaction temperature (entries 7–9) and
(entry 4). The poor yield (25%) obtained in the absence of time (entries 12–14) also resulted in inferior yields. No
any catalyst (entry 1) demonstrated the catalytic assis- distinct beneficial effect of using a temperature higher
tance provided by 2-guanidinoacetic acid. The product than the optimal value (i.e., 100 °C) (entries 10 and 11) or
yield did not improve significantly when using larger increased reaction time (entries 15 and 16) was observed.
amounts (15 mol%) of 2-guanidinoacetic acid (entry 5), The use of solvents (nonpolar, weakly polar, aprotic polar,
and it decreased when lower amounts of 2-guanidinoace- and protic polar) in general exhibited a detrimental effect
tic acid amounts were used (2.5–5 mol%) (entries 2 and (entries 17–26).
The role of 2-guanidinoacetic acid is anticipated as that of
an ambiphilic dual activating agent due to the ability of
Table 1 2-Guanidinoacetic Acid Catalyzed Reaction of 4-Meth-
oxyacetophenone (1f) with N,N-Dimethylformamide Dimethyl Ace-
the guanidine moiety to act as a base to generate the eno-
late (nucleophilic activation)17 of 1f and simultaneous ac-
tivation of one of the methoxy groups of N,N-
dimethylformamide dimethyl acetal (electrophilic activa-
tion) through the carboxylic acidic site. The requirement
of the acid–base dual character of 2-guanidinoacetic acid
in affording the desirable yields of 2f could be demon-
strated by selecting other organocatalysts that either con-
tain only an acidic moiety (Table 2, entries 1–13) or the
basic moiety (entries 14 and 15). The inferior yields ob-
tained with these organocatalysts clearly indicate the im-
plication of the dual functional character of 2-guani-
dinoacetic acid. The improved yield obtained in using
equimolar (10 mol% each) amounts of pyridine and acetic
acid compared (entry 18) to those obtained with acetic
acid or pyridine alone further justifies the implication of
the dual activation strategy. The use of pyridine-2-, -3-, or
-4-carboxylic acids also afforded improved yields (entries
19–21). These further demonstrate the requirement/impli-
cation of nucleophile–electrophile dual activation. The
improved dual activation ability of pyridine-3-carboxylic
acid compared to the 2- or 4-regioisomers is due to the fact
that the pyridine nitrogen in the later compounds is less
basic as the electron lone pair of the pyridyl nitrogen is in
conjugation with the carboxy carbonyl group.
tal under Different Conditionsa
Entry
Catalystb
(mol%)
Solvent
Tempc
(°C)
Time
(h)
Yieldd
(%)
1
2
none
2.5
5
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
toluene
EtOH
MeCN
100
100
100
100
100
100
r.t.
3
3
3
3
3
3
3
3
3
3
3
0.5
1
2
4
5
3
3
3
3
3
3
3
3
3
3
25
35
55
88
88
90
0
3
4
10
15
20
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
6
7
8
50
0
9
80
30
89
90
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
120
140
100
100
100
100
100
100
reflux
reflux
35
60
80
81
20
30
10
20
45
15
0
The essential requirement of the bifunctional character of
the organocatalyst can be further substantiated by inferior
yields obtained using other guanidine derivatives
(Table 3) wherein the guanidine moiety remains in the
protonated/salt form and hence is not available to generate
the enolate of 1f.
To establish the generality, various aryl/heteroaryl/styryl
methyl ketones and cyclic ketones/1,3-diketones 1 having
an a-methylene moiety were treated with N,N-dimethyl-
formamide dimethyl acetal in the presence of 2-guanidi-
noacetic acid (10 mol%) at 100 °C (oil bath) for 0.5–3
hours (Table 4). The desired enaminones 2 were obtained
in 72–95% yields. The reactions were monitored by TLC.
However, the progress of the reaction could also be mon-
itored visually. The enaminone 2 formation was indicated
by the development of yellowish- to reddish-brown color
of the reaction mixture. In some cases, the appearance of
a solid precipitate confirmed the completion of the reac-
tion (TLC, GCMS). In most of the cases, a solid mass was
obtained after removal of the volatile components (e.g.
unreacted DMF-DMA, liberated MeOH etc.) under rotary
evaporation of the reaction mixture. Purification was
achieved by passing the crude product through a column
1,4-dioxane reflux
THF
reflux
100
DMF
CHCl3
CH2Cl2
DCE
reflux
reflux
reflux
100
0
0
H2O
0
a Reaction conditions: 1f (0.375 g, 2.5 mmol), DMF-DMA (0.35 g,
3.0 mmol, 1.2 equiv), 2-guanidinoacetic acid.
b Amount of 2-guanidinoacetic acid used with respect to the substrate.
c Oil bath temperature.
d Yield of 2f obtained after purification.
Synthesis 2011, No. 12, 1930–1935 © Thieme Stuttgart · New York

1932
S. Bindal et al.
PAPER
Table 2 Reaction of 4-Methoxyacetophenone (1f) with N,N-Di-
methylformamide Dimethyl Acetal in the Presence of Various
Organocatalystsa
Table 3 Reaction of 1f with N,N-Dimethylformamide Dimethyl
Acetal in the Presence of Different Guanidine Derivativesa
Entry
Catalyst
Yieldb (%)
Entry
1
Catalyst
Yieldb (%)
25
1
2
3
4
2-guanidinoacetic acid
guanidine acetate
guanidine thiocyanate
guanidine hydrochloride
88
54
57
49
AcOH
2
NCCH2CO2H
27
3
TFA
45
4
Cl3CCO2H
25
a Reaction conditions: 1f (0.375 g, 2.5 mmol), DMF-DMA (0.35 g,
3.0 mmol, 1.2 equiv), guanidine derivative (10 mol%), 100 °C (oil
bath), 3 h.
5
PhCH2CO2H
55
b Yield of 2f obtained after purification.
6
2-naphthylCH2CO2H
PhOCH2CO2H
4-ClC6H4CH2CO2H
PhSCH2CO2H
3,4,5-(MeO)3C6H2CH2CO2H
Ph2CHCO2H
30
7
50
action took place in a shorter time period compared to that
for acetophenone. The shorter reaction time required for
such substrates could be due to the ease of generation of
the corresponding enolate because of lower pKa values of
the corresponding acetophenone derivatives.18
8
25
9
60
10
11
12
13
14
15
16
17
18
19
20
21
55
38
Table 4 2-Guanidinoacetic Acid Catalyzed Synthesis of 3-(Di-
methylamino)prop-2-enones 2a
3,4-(MeO)2C6H3CH2CO2H
4-HOC6H4CH2CO2H
pyridine
40
Entry
Substrate
Time (h) Product Yieldb,c (%)
37
O
35
Et3N
30
R2
R1
urea
40
1
2
3
4
5
6
7
8
9
R1 = R2 = H
1.5
2
1
1
1.5
3
0.5
0.5
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
89
90
85
86
88
90
93
80
R1 = H; R2 = Me
R1 = H; R2 = F
thiourea
35
R1 = H; R2 = Cl
R1 = H; R2 = I
pyridine–AcOH
pyridine-2-carboxylic acid
pyridine-3-carboxylic acid
pyridine-4-carboxylic acid
56
42
R1 = H; R2 = OMe
R1 = H; R2 = NO2
R1 = H; R2 = CF3
R1 = R2 = OMe
51
44
a Reaction conditions: 1f (0.375 g, 2.5 mmol), DMF-DMA (0.35 g,
3.0 mmol, 1.2 equiv), organocatalyst (10 mol%), 100 °C (oil bath), 3
h.
R1
R2
b Yield of 2f obtained after purification.
10
11
R1 = Ac, R2 = H
R1 = H, R2 = Ac
3
3
2j
2k
85
90
of silica gel (EtOAc–hexane). In some cases the crude sol-
id residue on trituration (Et2O or EtOAc–hexane) afforded
the pure (spectral data) enaminone 2.
R
Very good to excellent yields were obtained from sub-
strates 1b–i bearing various substituents (e.g., Me, OMe,
CF3, NO2, F, Cl, I) in the aryl moiety. However, no prod-
uct formation took place in case of 4-hydroxyacetophe-
none and 4-aminoacetophenone probably due to
competitive deprotonation of the hydroxy or amino group,
respectively, by 2-guanidinoacetic acid. The reaction was
influenced by the electronic effect of the substituent at-
tached to the aromatic ring of the aryl methyl ketones.
Substrates with an alkoxy group required a longer time
period. Perhaps the electron-donating or -releasing effect
of the alkoxy substituent did not permit the abstraction of
the a-hydrogen atom of the methyl ketone efficiently. For
substrates bearing an electron-withdrawing group, the re-
N
12
13
14
R = 2-Ac
R = 3-Ac
R = 4-Ac
1
1.5
1
2l
2m
2n
89 (56)d
91 (72)d
95 (51)d
R
X
O
15
16
17
18
19
X = NH, R = H
X = NMe, R = H
X = O, R = H
X = O, R = Me
X = S, R = H
2
2
1.5
1.5
1.5
2o
2p
2q
2r
2s
87 (38)d
72 (12)d
92
92
90
Synthesis 2011, No. 12, 1930–1935 © Thieme Stuttgart · New York

PAPER
1-Aryl/heteroaryl/styryl-3-(dimethylamino)prop-2-en-1-ones
1933
Table 4 2-Guanidinoacetic Acid Catalyzed Synthesis of 3-(Di-
methylamino)prop-2-enones 2a (continued)
alytic effect as the nitrogen atom at position 4 of the pyra-
zine moiety serves as a base to abstract the hydrogen atom
from the COMe group and generates the corresponding
enolate for condensation with N,N-dimethylformamide
dimethyl acetal. The inferior result obtained with 2-
acetyl-1-methyl-1H-pyrrole (1p) is indicative of the im-
portance of the influence of the acidity of the COMe hy-
drogen atoms on the rate of enaminone formation. In case
of the pyrrole derivatives the nitrogen atom does not ex-
hibit an appreciable basic property as its lone pair elec-
trons are engaged in establishing the aromatic sextet of the
parent heterocyclic moiety and, hence, in the process in-
creasing the acidic character of the COMe protons. The
methyl group attached to the nitrogen atom in 2-acetyl-1-
methyl-1H-pyrrole (1p) decrease the acidity of the COMe
hydrogen atoms compared to that of 2-acetyl-1H-pyrrole
(1o) and accounts for the lower yields.
Entry
Substrate
Time (h) Product Yieldb,c (%)
N
S
20
1.5
1.5
1
2t
93
O
21
22
23
2u
2v
2w
89
S
O
O
91 (75)d
N
N
O
O
O
We realized that the influence of the electronic effect on
the substrate aryl/heteroaryl methyl ketones 1 resulting in
differential reaction time may be used as handle for selec-
tive enaminone formation during competitive environ-
ments. Thus, we designed intermolecular competition
studies involving (a) two aryl methyl ketones with varying
electronic factors and (b) an aryl methyl ketone and a het-
eroaryl methyl ketone. To represent typical examples of
aryl methyl ketone with usual electronic factor we consid-
ered acetophenone (1a) whereas 4-methoxyacetophenone
(1f) and 4-nitroacetophenone (1g) were chosen as repre-
sentatives of electron-rich and electron-deficient aryl
methyl ketones, respectively. When equimolar (2.5 mmol
each) amounts of acetophenone (1a) and 4-methoxyace-
tophenone (1f) were treated with N,N-dimethylformamide
dimethyl acetal (3 mmol, 1.2 equiv) in the presence of 2-
guanidinoacetic acid (0.25 mmol, 10 mol%) (100 °C oil
bath, 1.5 h) the isolated product ratio of enaminones 2a/2f
was found to be 60:40 (GCMS), from which the individu-
al pure enaminones 2a and 2f were obtained in 52 and
28% yields, respectively, after column chromatographic
purification (Table 5). On the other hand performing the
reaction under the same conditions with acetophenone
(1a) and 4-nitroacetophenone (1g) afforded a ratio of
enaminones 2a/2g 14:86 (GCMS) and the pure compo-
nents 2a and 2g were obtained in 6 and 74% yields, re-
spectively, after column chromatographic purification.
Similarly intermolecular completion studies were per-
formed between aryl methyl ketones, acetophenone (1a),
and heteroaryl methyl ketones, 2-acetylpyridine (1l), 2-
acetyl-1H-pyrrole (1o), and 2-acetyl-1-methyl-1H-pyr-
role (1p) to obtain the corresponding pairs of enaminones
with 2a/2l 30:70, 2a/2o 85:15, and 2a/2p 90:10 selectivi-
ties (GCMS) reflecting the relative time taken for the in-
dividual heteroaryl methyl ketones compared to that of
acetophenone. From the respective product mixtures the
individual enaminones were obtained in 28 and 56%, 72
and 8%, and 86 and 5% yields, respectively, after purifi-
cation.
1.5
85
O
R1
R2
24
25
R1 = R2 = H
1.5
1.5
2x
2y
91
83
R1 = R2 = OMe
O
26
27
1.5
1.5
2z
87
90
O
2aa
a Reaction conditions: ketone 1 (2.5 mmol), DMF-DMA (3.0 mmol,
1.2 equiv), 2-guanidinoacetic acid (10 mol%), 100 °C (oil bath).
b The yield of the corresponding enaminone obtained after purifica-
tion.
c The products were characterized by IR, NMR, and MS.
d Yield from the reaction performed under similar conditions in the
absence of 2-guanidinoacetic acid.
To find out whether in case of the nitrogen-containing het-
eroaryl methyl ketones the reactions are self-catalyzed,
the reactions of 2- (1l), 3- (1m), and 4-acetylpyridine (1n),
2-acetyl-1H-pyrrole (1o), 2-acetyl-1-methyl-1H-pyrrole
(1p), and 2-acetylpyrazine (1v) were carried out in the ab-
sence of 2-guanidinoacetic acid; the corresponding enam-
inones were formed in 56, 72, 51, 38, 12, and 75% yields,
respectively. Thus, the pyridine moiety of 3-acetylpyri-
dine (1m) serves as the base catalyst while in case of the
2- (1l) and 4-acetylpyridine (1n) the 2-guanidinoacetic
acid exhibits a distinct catalytic effect as in these cases the
pyridine nitrogen is in conjugation with the acetyl group
and cannot serve as effectively as a base. The much im-
proved yields obtained with 2-acetylpyrazine (1v) in the
absence of 2-guanidinoacetic acid was due to the self-cat-
Synthesis 2011, No. 12, 1930–1935 © Thieme Stuttgart · New York

1934
S. Bindal et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 181.41, 161.93, 153.78, 133.13,
Table 5 Selectivity in Enaminone Formation during Intermolecular
Competition between Methyl Ketones with Varying Electronic Re-
quirements
129.43, 113.28, 91.72, 55.33, 47.12, 36.52.
MS (APCI): m/z = 206.4 (M + 1).
O
O
The remaining reactions were performed following this typical pro-
cedure and the physical data (mp, IR, NMR, and MS) of all known
compounds were identical with those reported in the literature.
Me
Ph
Ph
N
1a
2a
Me
MeO
MeO
Me
Me
2.5 mmol
100 °C
1.5 h
+
+
O
N
Intermolecular Competition Studies; Typical Procedures
Aryl Methyl Ketones with Varying Electronic Factor;
Acetophenone (1a) vs 4-Nitroacetophenone (1g)
O
3 mmol
Me
Ar
Ar
N
To a magnetically stirred mixture of acetophenone (1a, 300 mg, 2.5
mmol), 4-nitroacetophenone (1g, 412 mg, 2.5 mmol), and DMF-
DMA (357 mg, 0.39 mL, 3 mmol, 1.2 equiv), 2-guanidinoacetic
acid (29 mg, 0.25 mmol, 10 mol% of one of the substrates) was add-
ed and the mixture was heated at 100 °C (oil bath) for 1.5 h. The
crude mixture on being subjected to GCMS analysis was found to
contain 3-(dimethylamino)-1-phenylprop-2-en-1-one (2a) and 3-
(dimethylamino)-1-(4-nitrophenyl)prop-2-en-1-one (2g) in a ratio
of 14:86 and afforded the respective enaminones in 26 mg (6%) and
407 mg (74%) yields, respectively, after purification by flash col-
umn chromatography (silica gel 230–400 mesh, hexane–EtOAc).
1f,g,l,o,p
2f,g,l,o,p
Me
2.5 mmol
60:40 (52%; 28%)
Entry Ar
Ratioa
Yieldb (%)
2a/2f,g,l,o,p 2a
2f,g,l,o,p
1
2
3
4
5
4-MeOC6H4 2f
4-O2NC6H4 2g
2-pyridyl 2l
60:40
14:86
30:70
85:15
52
6
28
74
56
8
24
72
86
Heteroaryl Methyl Ketones; Acetophenone (1a) vs 2-Acetyl-1H-
pyrrole (1o)
1H-pyrrol-2-yl 2o
To a magnetically stirred mixture of acetophenone (1a, 300 mg, 2.5
mmol), 2-acetyl-1H-pyrrole (1o, 272 mg, 2.5 mmol), and DMF-
DMA (357 mg, 0.39 mL, 3 mmol, 1.2 equiv), 2-guanidinoacetic
acid (29 mg, 0.25 mmol, 10 mol% of one of the substrates) was add-
ed and the mixture was heated at 100 °C (oil bath) for 1.5 h. The
crude mixture on being subjected to GCMS analysis was found to
contain 3-(dimethylamino)-1-phenylprop-2-en-1-one (2a) and 3-
(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (2o) in a ratio
1-methyl-1H-pyrrol-2-yl 2p 90:10
5
a By GCMS.
b After column chromatography.
In conclusion, a novel ambifunctional organocatalytic
procedure has been developed for a convenient synthesis
of acyclic enaminones from the condensation of aryl/het- of 85:15 and afforded the respective enaminones in 315 mg (72%)
and 33 mg (8%) yields, respectively, after purification by flash col-
umn chromatography (silica gel 230–400 mesh, hexane–EtOAc).
eroaryl/styryl methyl ketones and cyclic ketones having
a-methylene group promoted by 2-guanidinoacetic acid
under neat conditions in high yields and short reaction
times.
Acknowledgment
The authors D.K. and D.N.K. thank CSIR, New Delhi, India for
award of RA and SRF, respectively.
1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded on
a Bruker Avance DPX 400 MHz NMR spectrometer in CDCl3 using
TMS as an internal standard. IR spectra were recorded either as KBr
References
pellets (for solids) or neat (for liquids) on a Nicolet Impact 410
FTIR spectrophotometer. Mass spectra were recorded on a GCMS-
QP 5000 (Shimadzu) [for EI], and Finnigan MAT-LTQ [for APCI]
mass spectrometers. The reactions were monitored by TLC
(Merck®, Silica gel 60 F254). Evaporation of solvents was per-
formed at reduced pressure, using a Büchi rotary evaporator.
(1) (a) For review see: Elassar, A.-Z. A.; El-Khair, A. A.
Tetrahedron 2003, 59, 8463. (b) Svete, J. Monatsh. Chem.
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Golič, L.; Golobič, A.; Meden, A.; Stanovnik, B.; Svete, J.
Synthesis 2005, 2969. (d) Svete, J. J. Heterocycl Chem.
2005, 42, 361. (e) Valla, A.; Valla, B.; Cartier, D.; Guillou,
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Potier, P. Eur. J. Med. Chem. 2006, 41, 142.
(2) (a) Chakraborti, A. K.; Sarin, S.; Rudrawar, S. V.; Kumar,
R.; Chankeshwara, S. V.; Dastidar, S.; Ray, A. IN 566/DEL/
2006, 2006. (b) Chakraborti, A. K.; Sarin, S.; Rudrawar, S.
V.; Kumar, R.; Chankeshwara, S. V.; Dastidar, S.; Ray, A.
IN 565/DEL/2006, 2006.
3-(Dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (2f);
Typical Procedure
To a magnetically stirred mixture of 4-methoxyacetophenone (1f,
375 mg, 2.5 mmol) and DMF-DMA (357 mg, 0.39 mL, 3 mmol, 1.2
equiv) at 100 °C (oil bath) was added 2-guanidinoacetic acid (29
mg, 0.25 mmol, 10 mol%). After completion of the reaction (3 h,
TLC) the mixture was subjected to rotary vacuum evaporation to re-
move the volatile components (excess of DMF-DMA and the liber-
ated MeOH) and the crude product was purified by column
chromatography (EtOAc–hexane) to afford 2f (451 mg, 88%) as a
reddish-brown viscous liquid that became solid on standing; mp 90–
92 °C.
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IR (KBr): 2906, 1639, 1544, 1433, 1358, 1305, 1244, 1172, 1116,
1056, 1026, 899, 774 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.97 (br s, 6 H), 3.84 (s, 3 H), 5.70
(d, J = 12.3 Hz, 1 H), 6.88–6.92 (m, 2 H), 7.77 (d, J = 12.3 Hz, 1 H),
7.88–7.92 (m, 2 H).
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Synthesis 2011, No. 12, 1930–1935 © Thieme Stuttgart · New York

PAPER
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Synthesis 2011, No. 12, 1930–1935 © Thieme Stuttgart · New York