L-proline-catalyzed activation of methyl ketones or active methylene compounds and DMF-DMA for syntheses of (2E)-3-dimethylamino-2- propen-1-ones

Article abstract of DOI:10.1002/ejoc.201200778

A cascade organocatalysis is reported for the nucleophilic and electrophilic dual activation taking place in the reaction of methyl ketones or active methylene compounds with DMF-DMA (N,N-dimethylformamide dimethyl acetal). L-Proline serves as an efficient organocatalyst in the covalent and noncovalent synchronous mode for the ambiphilic activation of various aryl, heteroaryl, and styryl methyl ketones, cyclic ketones, and 1,3-diketones with DMF-DMA to achieve the convenient syntheses of the versatile synthons (2E)-1-aryl/ heteroaryl/styryl-3-(dimethylamino)-2-propen-1-ones, (E)-α- [(dimethylamino)formylidene]cycloalkanones, and (E)-2-(dimethylamino) formylidene-1,3-diketones in high yields under solvent-free conditions.

Full text of DOI:10.1002/ejoc.201200778

FULL PAPER
DOI: 10.1002/ejoc.201200778
L
-Proline-Catalyzed Activation of Methyl Ketones or Active Methylene
Compounds and DMF-DMA for Syntheses of (2E)-3-Dimethylamino-2-
propen-1-ones
Dinesh Kumar,[a] Damodara N. Kommi,[a] Pradeep Chopra,[a] Md Imam Ansari,[a] and
Asit K. Chakraborti*[a]
Keywords: Synthetic methods / Organocatalysis / Hydrogen bonds / Domino reactions / Amino acids
A cascade organocatalysis is reported for the nucleophilic
and electrophilic dual activation taking place in the reaction
of methyl ketones or active methylene compounds with
cyclic ketones, and 1,3-diketones with DMF-DMA to achieve
the convenient syntheses of the versatile synthons (2E)-1-
aryl/heteroaryl/styryl-3-(dimethylamino)-2-propen-1-ones,
(E)-α-[(dimethylamino)formylidene]cycloalkanones, and (E)-
2-(dimethylamino)formylidene-1,3-diketones in high yields
under solvent-free conditions.
DMF-DMA (N,N-dimethylformamide dimethyl acetal).
L-
Proline serves as an efficient organocatalyst in the covalent
and noncovalent synchronous mode for the ambiphilic acti-
vation of various aryl, heteroaryl, and styryl methyl ketones,
(Bredereck’s reagent), or tris(dimethylamino)methane
(TRIS-DMAM, see Scheme 2).[7]
Introduction
Noncovalent synthesis is nature’s strategy to construct
complex molecular architectures for various biological
functions and is the central theme of drug–receptor interac-
tions.[1] The hydrogen bond (HB) is the backbone of non-
covalent synthesis,[2] and the emerging area of organocata-
lysis[3] relies on hydrogen-bonded assemblies of small mole-
cules. Herein, we describe the cooperative formation of the
HB-assisted cascade organocatalyzed reaction for ambi-
philic dual activation during the l-proline-mediated con-
densation of active methylene compounds with N,N-di-
methylformamide dimethyl acetal (DMF-DMA) to give
The various drawbacks associated with reported syn-
thetic protocols, such as the use of an excess amount of
DMF-DMA (1.5–4 equiv.)[7c,7i,7j,7l–7n] and high boiling sol-
vents such as DMF or xylene[6,7i–7k] that are difficult to
recover as well as the requirement of a long reaction time
(7–20 h),[7a–7e,7i,7j] high temperature (110–180 °C),[7f,7i,7j]
and special apparatus such as a microwave oven or reac-
tor,[7g,7h] press the need for convenient and better methodol-
ogy to prepare these versatile synthons. We realized that
there are a limited number of reports on the use of a cata-
lyst that would facilitate the condensation of the carbonyl
substrate with DMF-DMA under milder conditions, for ex-
ample, at lower temperatures and shorter time periods, to
give improved product yields.[8] The recent report[9] on the
use of stoichiometric amounts of the room-temperature
ionic liquid (IL) [bmim][BF4] (bmim = 1-butyl-3-methyl-
imidazolium) at 100 °C for 6 h highlights the possibility of
the general effect of an IL as a medium for the desired
transformation rather than a true representation of the non-
solvent (catalytic) use of ILs.[10] It was anticipated that the
presence of a suitable catalyst would generate the enolate of
the active methylene compound, facilitate the subsequent
nucleophilic displacement of the methoxy group in DMF-
DMA, and accelerate the condensation reaction. In this
context, we recently found that N-methylimidazole (MeIm)
is an effective promoter for the desired transformation.[11]
However, the requirement of a stoichiometric amount of
MeIm underlines the scope of the use of a substoichio-
metric amount of a catalytic agent.
(2E)-3-(dimethylamino)-2-propen-1-ones.
These
com-
pounds are useful starting materials for preparing various
heterocyclic scaffolds,[4] new chemical entities for new thera-
peutic indications,[5] and the antileukemic drug imatanib[6]
(see Scheme 1).
The (2E)-3-(dimethylamino)-2-propen-1-ones, repre-
sented by the general structural formula A, are obtained
by the condensation of active methylene compounds
with DMF-DMA, DMF-DEA (N,N-dimethylformamide
diethyl acetal), tert-butoxybis(dimethylamino)methane
[a] National Institute of Pharmaceutical Education and Research
(NIPER),
Sector 67, S. A. S. Nagar, Punjab 160062, India
Fax: +91-221-4692
E-mail: akchakraborti@niper.ac.in
Homepage: http://www.niper.ac.in/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200778.
Eur. J. Org. Chem. 2012, 6407–6413
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Kumar, D. N. Kommi, P. Chopra, M. I. Ansari, A. K. Chakraborti
FULL PAPER
Scheme 1. (2E)-3-(Dimethylamino)-2-propen-1-ones as a versatile synthon for heterocyclic scaffolds.
Table 1. Reaction of 4-methoxyacetophenone (1i) with DMF-
DMA in the presence of various organocatalysts to form 2i.[a]
Entry
Catalyst
% Yield[b]
1
2
3
4
5
6
7
8
9
no catalyst
l-proline
l-prolinamide
l-proline methyl ester
N-methyl-l-proline
l-pyroglutamic acid
pyrrolidine
20
82
Scheme 2. Synthesis of (2E)-3-(dimethylamino)-2-propen-1-ones.
52 (77)[c]
32
25
32
25
32
Results and Discussion
glycine
phenylalanine
31
10
11
acetic acid
pyrrolidine + acetic acid
28
45
We reasoned that using an organocatalyst that does not
involve a proton exchange with the active methylene com-
pound, but instead forms a covalent bond to generate the
enolate equivalent, might feasibly be regenerated after the
enolate equivalent undergoes a reaction with the electro-
phile (DMF-DMA). Such a strategy is observed during en-
amine-mediated reactions where the secondary amine pyr-
rolidine is used as the enamine-forming agent.[12] The pres-
[a] 4-Methoxyacetophenone (1i, 0.375 g, 2.5 mmol) was treated
with DMF-DMA (0.35 g, 3.0 mmol, 1.2 equiv.) in the presence of
different organocatalysts (10 mol-%) at 100 °C for 3 h. [b] Yield of
2i after chromatographic purification. [c] Yield of 2i after 5 h.
The desired product (2E)-3-(dimethylamino)-1-(4-meth-
ence of an additional structural feature in the enamine- oxyphenyl)-2-propen-1-one (2i) was obtained in 82% yield,
forming agent that could simultaneously activate the acetal upon performing the reaction in the presence of l-proline
moiety of DMF-DMA would offer the dual benefit of nu- (10 mol-%) at 100 °C for 3 h (complete consumption of 1i,
cleophilic and electrophilic activation. The proline moiety TLC; see Table 1, Entry 2). The poor yield (20%) obtained
offers this framework of dual activation, and it has been in the absence of any catalyst (see Table 1, Entry 1) demon-
demonstrated that proline-catalyzed aldol reactions proceed strated the catalytic assistance provided by l-proline. Other
through an enamine intermediate.[13] To implement a dual organocatalysts having the pyrrolidine framework but de-
activation strategy,[14] we chose 4-methoxyacetophenone void of the carboxylic acid moiety or the NH hydrogen
(1i) as the model substrate and treated it with DMF-DMA atom either afforded inferior yields or did not exhibit any
under various conditions in the presence of various organo- significant catalytic activity (see Table 1, Entries 3–7).
catalysts bearing the pyrrolidine moiety. The results are
summarized in Table 1.
To determine the best operative conditions for the cataly-
sis by l-proline, the reactions of 1i with DMF-DMA were
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l-Proline-Catalyzed Activation of Methyl Ketones and DMF-DMA
performed under different conditions such as varying the Table 3. l-Proline-catalyzed reaction in various solvents of 1i with
DMF-DMA to form 2i.[a]
amounts of organocatalyst, the reaction temperature, and
% Yield[b]
the reaction time (see Table 2). The optimal amount of the
organocatalyst l-proline was 10 mol-%, as no significant in-
crease in the product yield was observed by using larger
quantities (15–20 mol-%). However, the yield decreased
when l-proline was used in smaller amounts (1–5 mol-%).
The optimal reaction temperature was 80 °C, with no fur-
ther increase in product yield by increasing the reaction
temperature to 120 °C. However, the reaction did not pro-
ceed upon reducing the reaction temperature to room temp.
or 50 °C.
Entry
Solvent
Temp [°C]
1
2
3
4
5
6
7
8
9
neat
toluene
1,4-dioxane
THF
80
80
80
82
20
0
30
0
reflux[c]
reflux[c]
reflux[c]
80
DCE
CHCl3
MeCN
DMF
EtOH
H2O
0
30
35
10
0
80
80
80
80
10
11
H2O
0[d]
[a] 1i (0.375 g, 2.5 mmol) was treated with DMF-DMA (0.35 g,
3.0 mmol, 1.2 equiv.) in the presence of l-proline (10 mol-%) in dif-
ferent solvents at 80 °C for 3 h. [b] Yield of 2i after chromato-
graphic purification. [c] The bath temperature was 80 °C. [d] The
reaction was performed in using l-prolinamide as the organocata-
lyst.
Table 2. l-Proline-catalyzed reaction of 1i with DMF-DMA to
form 2i under different conditions.[a]
Entry l-Proline [mol-%][b] Temp [°C] Time [h] % Yield[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1.0
2.5
5
100
100
100
100
100
100
room temp.
50
3
3
3
3
3
3
3
3
3
3
3
0.5
1
2
3
4
5
3
25
30
50
82
82
82
trace
12
82
82
82
trace
25
55
82
82
82
20
10
15
20
10
10
10
10
10
10
10
10
10
10
10
0
molecule, initially generated during the enamine formation,
leads to enaminone 2. This sequence of events demonstrates
the role of proline in the ambiphilic dual (i.e., nucleophilic
and electrophilic) activation through
a cooperatively
80
formed hydrogen-bond-assisted cascade catalysis.
100
120
80
80
80
80
80
80
80
[a] 1i (0.375 g, 2.5 mmol) was treated with DMF-DMA (0.35 g,
3.0 mmol, 1.2 equiv.) in the presence of l-proline under various
conditions. [b] Amount of catalyst used with respect to 1i. [c] Yield
of 2i after chromatographic purification.
Next, the condensation of 1i with DMF-DMA was car-
ried out in various solvents (nonpolar, weakly polar, polar
aprotic, and polar protic) to determine its effect on the reac-
tion. In general, using a solvent was detrimental to the reac-
tion, as no significant catalytic activity was exhibited by l-
proline or prolinamide (see Table 3).
The catalytic role of l-proline is depicted in Scheme 3.
Nucleophilic activation of the carbonyl group of ketone 1
takes place by a condensation with the pyrrolidine moiety
of l-proline through the cooperatively formed hydrogen-
bonded intermediates Ia and Ic to give enamine I (nucleo-
philic activation).[15] The carboxylic acid hydrogen atom of
I, in turn, forms a hydrogen bond with one of the methoxy
groups of DMF-DMA, which increases the potential (elec-
trophilic activation) for its removal through a nucleophilic
attack by the α-carbon atom in the enamine I moiety of
intermediate II to generate imminium intermediate III. The
carboxylate anion in III then abstracts one of the α-hydro-
gen atoms of the imminium moiety through hydrogen-
Scheme 3. The catalytic role of l-proline during the reaction of aryl
methyl ketones with DMF-DMA to form an enaminone.
The importance and necessity of this nucleophilic acti-
bonded intermediate IV. This is followed by the nucleophilic vation through the intermediacy of the enamine and immin-
removal of the OMe group to generate imminium species ium ions is demonstrated by observing that other amino
V, which upon subsequent hydrolytic cleavage by the water acids unable to generate intermediates I–V were ineffective
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D. Kumar, D. N. Kommi, P. Chopra, M. I. Ansari, A. K. Chakraborti
FULL PAPER
in the reaction (see Table 1, Entries 8 and 9). The insignifi- indicated that a general Brønsted acid catalyzed mechanism
cant catalytic potential of HOAc (see Table 1, Entry 10) is not operative. The lack of an appreciable catalytic effect
Table 4. l-Proline-catalyzed synthesis of 3-(dimethylamino)propenones from different methyl ketones and active methylene compounds.[a]
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l-Proline-Catalyzed Activation of Methyl Ketones and DMF-DMA
Table 4. (continued)
[a] The methyl ketone/active methylene compound (2.5 mmol) was treated with DMF-DMA (3.0 mmol, 1.2 equiv.) in the presence of l-
proline (10 mol-%) at 80 °C (oil bath) under neat conditions. [b] Yield of the corresponding enaminone obtained after purification. [c] The
products were characterized by IR, NMR, and MS. [d] The enaminone formation occurred selectively at the methylene group flanked by
the two carbonyl groups. [e] Yield of the corresponding product upon performing the reaction in the absence of l-proline. [f] The product
was identified as 1-(dimethylamino)-5-phenylpent-1-en-3-one.
by pyrrolidine (see Table 1, Entry 7) justifies the critical role ous solvents may not be because of the solubility or the
of the HB-assisted activation of DMF-DMA. On the other effective reaction temperature (that depends on the b.p. of
hand, when a combination of pyrrolidine and acetic acid the solvent). It is possible that the polar character (and
was used (see Table 1, Entry 11), the increase in the product competitive HB formation ability) of such solvents may not
yield (although moderately because of intermolecular par- provide the conducive environment for formation of the hy-
ticipation) justifies the combined and synergistic effects of drogen-bonded assemblies (i.e., the effective catalytic spe-
the pyrrolidine and carboxylic acid moieties of l-proline.
cies), leading to the lack of formation of the desired prod-
The implication of the nucleophilic and electrophilic dual uct. Hence, no appreciable catalytic influence in water and
activation during the progress of the reaction is further EtOH (in which it is soluble) is observed because of the
demonstrated by the insignificant catalytic effects from l- interference in the formation of hydrogen-bonded adducts
proline methyl ester (see Table 1, Entry 4), N-methyl-l-pro- Ia, Ic, II, and IV in protic polar solvents (see Scheme 3).
line (see Table 1, Entry 5), and l-pyroglutamic acid (see
The generality of this organocatalytic protocol was tested
Table 1, Entry 6). In case of l-proline methyl ester, the elec- in the reaction of versatile active methylene compounds
trophilic activation of DMF-DMA is not feasible because with DMF-DMA (see Table 4), affording the desired en-
of the lack of HB formation through the carboxylic acid aminones in 76–80% yields. The reaction worked well with
hydrogen atom, whereas for N-methyl-l-proline and l-pyro- active methylene compounds containing other functional
glutamic, the formation of the enamine and imminium ion groups such as those with a halogen, nitro, alkoxy, methyl,
is not possible. The appreciable catalytic potential of l-pro- or trifluoromethyl group, and so forth. However, no prod-
linamide (see Table 1, Entry 3) is justified by the fact that uct formation took place in case of 4-hydroxyacetophenone
the amide hydrogen atoms are capable of forming a hydro- or 4-aminoacetophenone (see Table 4, Entries 11 and 12).
gen bond with DMF-DMA. However, because of the poor Carbonyl substrates bearing an alkoxy group took longer
HB donor ability of the amide hydrogen atom in compari- reaction times (see Table 4, compare Entries 1, 9, and 10).
son to the carboxylic acid hydrogen atom, the l-prolin- For 1,3-dicarbonyl compounds (see Table 4, Entries 29–31),
amide-catalyzed reaction takes a longer time and affords a the regioselective enaminone formation took place with the
lower yield. The lack of formation of the desired product active methylene group flanked by the two carbonyl groups.
in solvents such as toluene, MeCN, 1,4-dioxane, THF No aqueous workup was necessary to isolate the product.
(tetrahydrofuran), DMF, DCE (dichloroethylene), and The crude reaction mixture was passed through a flash
CHCl3 could be a result of the insolubility of l-proline. chromatography column, and the desired product was
However, the lack of appreciable product formation in vari- eluted with EtOAc/hexane.
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D. Kumar, D. N. Kommi, P. Chopra, M. I. Ansari, A. K. Chakraborti
FULL PAPER
113.3, 91.7, 55.3, 44.9, 37.1 ppm. MS (APCI): m/z = 206.25 [M +
H]+. HRMS (ESI): calcd. for C12H15NO2Na [M + Na]+ 228.0995;
found 228.0998.
The lack of product formation in case of 4-hydroxy-
acetophenone and 4-aminoacetophenone (see Table 4, En-
tries 11 and 12) could be, because the competitive HB for-
mation of the hydroxy and amino group, respectively, with
the carboxylic hydrogen atom of l-proline interferes with
the HB-assisted activation of DMF-DMA. The retarding
effect exhibited by aryl methyl ketones with an alkoxy sub-
stituent on the aryl moiety (see Table 4, compare Entry 1
with 9 and 10, and Entry 27 with 28) may also be, because
of the competitive HB formation with the carboxylic acid
hydrogen atom in l-proline.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral data for all compounds and scanned spectra.
Acknowledgments
D. K. and D. N. K. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for a Research Associateship and a
Senior Research Fellowship, respectively.
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We have described the use of l-proline as an efficient
organocatalyst for the convenient syntheses of (2E)-3-(di-
methylamino)-2-propen-1-ones. The condensation of aryl,
heteroaryl, and styryl methyl ketones, cyclic ketones, and
1,3-diketones under solvent-free conditions afforded prod-
ucts in high yields and short reaction times. The organocat-
alytic role of l-proline has been envisaged in the synchro-
nous mode of covalent and noncovalent dual activation of
the methyl ketones or active methylene compounds with
DMF-DMA. The reaction represents an organocatalytic
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Typical Experimental Procedure for the Synthesis of 3-(Dimeth-
ylamino)-1-(4-methoxyphenyl)prop-2-en-1-one: Table 4, Entry 9. To
a magnetically stirred mixture of 4-methoxyacetophenone (1i,
0.37 g, 2.5 mmol) and DMF-DMA (0.39 mL, 357 mg, 3 mmol,
1.2 equiv.) at 80 °C (oil bath) was added l-proline (29 mg,
0.25 mmol, 10 mol-%), and the mixture was stirred for 2 h. The
mixture was concentrated in vacuo to remove the volatile compo-
nents (excess amount of DMF-DMA and the liberated methanol),
and the crude product was purified by flash chromatography
(EtOAc/hexane) to afford 3-(dimethylamino)-1-(4-methoxyphenyl)-
prop-2-en-1-one (2i) as reddish brown viscous solid[8] (0.41 g, 80%).
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IR (KBr): ν
= 2930, 1635, 1605, 1432, 1350, 1252, 1210, 1105,
˜
max
1032, 892, 835 cm–1. H NMR (400 MHz, CDCl3): δ = 7.89–7.91
(m, 2 H), 7.79 (d, J = 12.3 Hz, 1 H), 6.89–6.92 (m, 2 H), 5.71 (d,
J = 12.3 Hz, 1 H), 3.84 (s, 3 H), 3.10 (s, 3 H), 2.93 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 187.5, 161.9, 153.8, 133.1, 129.5,
1
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l-Proline-Catalyzed Activation of Methyl Ketones and DMF-DMA
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[14] For dual activation of the nucleophile and electrophile by coor-
dinating an alkali metal hydroxide, see: a) A. Ba-
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[15] Hydrogen bond assisted/mediated nucleophilic activation has
been demonstrated during the demand-based in situ thiolate
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Received: June 11, 2012
Published Online: October 4, 2012
Eur. J. Org. Chem. 2012, 6407–6413
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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