A facile one-pot synthesis of 1-aryl-2-(dimethylaminomethyl)prop-2-en- 1-ones from aryl methyl ketones

Article abstract of DOI:10.1055/s-1998-2056

A generally applicable synthesis of 1-aryl-2-(dimethylaminomethyl)prop- 2-en-1-ones 2 involving reaction of aromatic methyl ketones 1 with paraformaldehyde and dimethylamine in dimethylformamide is described. The majority of experiments were conducted wit

Full text of DOI:10.1055/s-1998-2056

May 1998
SYNTHESIS
715
A Facile One-Pot Synthesis of 1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones from
Aryl Methyl Ketones
Ulrich Girreser, Dieter Heber,* Martin Schütt
Department of Pharmaceutical Chemistry, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
Fax +49(431)8801352; E-mail: dheber@pharmazie.uni-kiel.de
Received 26 September 1997; revised 1 December 1997
Abstract: A generally applicable synthesis of 1-aryl-2-(dimethyl-
aminomethyl)prop-2-en-1-ones 2 involving reaction of aromatic
methyl ketones 1 with paraformaldehyde and dimethylamine in
dimethylformamide is described. The majority of experiments
were conducted with these reagents, but the process can also be
performed using dimethyl(methylene)ammonium chloride.
Key words: 1-arylprop-2-en-1-ones, Mannich Reaction, Eschen-
moser’s salt, aminomethylation, deamination
1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones with
the general structure 2 have gained remarkable attention
in medicinal chemistry as antimicrotubular agents,1, 2 and
anticonvulsants;3 they show antileukemic activity,4–6
while inhibition of the epidermal growth factor (EGF) ty-
Method A: (CH2O)n (3 equiv), Me2NH2Cl (2 equiv); Method B:
CH2=NMe2Cl
rosine kinase by benzyloxy-substituted 2 has been shown
only recently.7 Even antifungal activity2,8 has been re-
Scheme
ported.
Despite their extensive use for in vitro and in vivo studies,
the synthesis of 2 is hampered by either low yields or the
formation of mixtures consisting of the normal Mannich
product 3 and the propenone 2. The synthetic conditions
which allow the synthesis of Mannich bases, starting from
suitable substrates, amines, and aldehydes, have been re-
viewed recently by Tramontini,9 paying particular atten-
tion to the possibility of linking together, through a
methylene bridge, various substrate and amine moieties.
Usually, the normal Mannich product 3 is obtained by em-
ploying ethanol as the solvent and refluxing the aryl me-
thyl ketone with paraformaldehyde and the corresponding
ammonium salt for prolonged time. There are only a few
cases in which more than one aminomethyl group is intro-
duced into the same substrate,10–12 thus producing a meth-
ylene-bis-derivative, which in turn may undergo
deamination11, 13, 14 with formation of an aminomethylat-
ed prop-2-en-1-one derivative. The free bases of 2d and
2e have been synthesized by treating the hydrochlorides
of the corresponding bis-Mannich bases 4 with Sorensen
phosphate buffer, pH 7.4, in a purity of ca. 95% as shown
by HPLC.5 Indeed, the bis-Mannich products 4 can and
have been investigated as prodrugs for the propenones 2.6
For the synthesis of the propenones 2, the aryl methyl ke-
tones 1 are reacted with paraformaldehyde and the appro-
priate amine; the use of glacial acetic acid, mixtures of
dioxane and glacial acetic acid, or even hydrochloric acid
as solvent has been reported.2, 7, 15–19
Even when refluxing 1e for prolonged periods in ethanol
with dimethylamine and formaldehyde no aminomethy-
lated products were formed. Dimmock and co-workers
obtained the Mannich base of this ketone in a yield of only
30% using 1,2-dimethoxyethane as a solvent.5 Thus, we
considered forcing this reaction by employing dipolar
aprotic solvents which are occasionally used in Mannich
reactions. For example, Werner reported on the Mannich
reaction of 2-hydroxyacetophenone in dimethylform-
amide to form 3-(dimethylaminomethyl)chromanone by
introduction of two aminomethyl groups followed by
cleavage of dimethylamine and subsequent ring closure.20
When the reaction was carried out in dimethylformamide,
the normal Mannich product 3 was formed only in traces
and the aminomethylated propenone derivatives 2a–f
were isolated in moderate yields of 40–50%. A reasonable
reaction mechanism involves attack of the methyl ketone
by two molecules of the Mannich reagent to give 4 fol-
lowed by elimination of dimethylamine to produce the
propenone derivative.
These experimental results prompted us to investigate the
general applicability of dimethylformamide as a solvent
for the Mannich reaction of aromatic methyl ketones to
give 1-aryl-2-(dimethylaminomethyl)prop-2-en-1-ones.
To the best of our knowledge the preparation of these
compounds simply by heating the aromatic methyl ke-
tone, paraformaldehyde, and dimethylamine in dimethyl-
formamide has not been evaluated in the literature. This
solvent has the major advantage that the reaction would be
suitable for acid-labile aryl methyl ketones21 as well. Fur-
thermore, the procedure presented here is much easier to
In the course of our attempts to synthesize 4-aryl-1,8-
naphthyridines via cyclization of 2-(3-hydroxy-3-phenyl-
propylamino)pyridines we failed to aminomethylate 3,4-
dichloroacetophenone (1e) under standard conditions.

716
Short Papers
SYNTHESIS
perform than alternative syntheses via silyl enol ether for- only sluggishly.22 Therefore, we also performed the reac-
mation and subsequent Lewis acid catalyzed coupling.11
tion with the commercially available dimethyl(methyl-
ene)ammonium chloride (2 equiv, Method B). The results
are listed in Table 1, and an improvement of the yield is
noticeable. When employing only one equivalent of
Eschenmoser,s salt, the normal Mannich product 3 is
formed in 60–70% yield; the propenone derivative is only
detected as minor product in ca. 10% yield.23
Thus, when the aryl methyl ketone was heated together
with paraformaldehyde (3 equiv) and dimethylammonium
chloride (2 equiv) for 1.5 hours in dimethylformamide
(Method A), the propenones 2 were formed in up to 50%
yield. In order to get rid of the excess dimethylammonium
chloride, the crude product mixture was treated with sodi-
um hydrogen carbonate solution at 0°C and extracted with
dichloromethane. Under these alkaline conditions minor
amounts of the bis-Mannich product 4 probably are
cleaved to 2 as well. After evaporation of the dichlo-
romethane without thermally stressing the free base, and
subsequent acidification, the hydrochlorides 2 are ob-
tained analytically pure by recrystallization from acetone/
ethanol; no fractional crystallization is necessary.
In summary, treatment of an aryl methyl ketone with
paraformaldehyde and dimethylamine in dimethylform-
amide, or in the case of more expensive starting methyl
ketones preferably using Eschenmoser’s salt, offers a very
promising, synthetically very simple to perform, straight-
forward and generally applicable route to 1-aryl-2-(dime-
thylaminomethyl)prop-2-en-1-ones, especially in cases
when glacial acetic acid as solvent is not recommended. It
is likely that this procedure can be extended to include
heteroaromatic methyl ketones as well as substituted pro-
penones and heterocycles with a propenone moiety. The
Preformed iminium salts, the so-called Eschenmoser’s
salts, are known to work successfully even when the usual
reagents do not bring about the Mannich reaction or react
Table 1. Yield of 1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones 2 (Isolated as Hydrochlorides)
2
Substituent
Reaction
Yield (%) of 2
mp (°C)
Conditions
(Solvent, Lit.)
Method A
Method B
58
a
a
a
b
c
d
e
f
H
H
H
4-Me
4-Br
4-OMe
3,4-Cl2
3,4-(OMe3)2
DMF, 125°C, 1.5 h
DMF, 110°C, 3 h
DMF, 100°C, 5 h
DMF, 125°C, 1.5 h
DMF, 125°C, 1.5 h
DMF, 125°C, 1.5 h
DMF, 125°C, 1.5 h
DMF, 125°C, 1.5 h
36
34
33
38
38
44
26
41
158 (156–l58)5
62
66
57
38
56
160
181 (EtOAc)
153 (151–152)5
177
165
Table 2. Selected Spectroscopic Data of 2 Prepareda
Compound
1H NMR d, J (Hz);13C NMR d; MS m/z (%); IR n (cm-1)
2b
1H NMR: 2.44 (s, 3H, CH3), 2.88 [d, 6H, J = 3.6, N(CH3)2], 4.15 (d, 2H, J = 4.3, NCH2), 6.38/7.11 (2 ´ s, 2 ´ 1H,
=CH2), 7.29/7.70 (2 ´ d, 2 ´ 2H, J = 7.6, Harom), 12.45 (br s, 1H, NH);13C NMR: 22.4 (CH3), 43.3 (CH3), 56.4 (CH2),
129.9 (CH), 130.4 (CH), 133.6, 136.9, 138.5 (CH2), 144.9, 195.9; MS: 203 [M+, 5], 202 (10), 186 (71), 145 (15), 119
(24), 91 (30), 84 (9), 65 (21), 58 (100), 42 (34); IR: 2200–2800 (br, s), 1650 (s)
2c
2e
2f
1H NMR: 2.90 [d, 6H, J = 4.8, N(CH3)2], 4.17 (d, 2H, J =5.4, NCH2), 6.37/7.17 (2 ´ s, 2 ´ 1H, =CH2), 7.65 (m, 4H,
Harom), 12.44 (br s, 1H, NH);13C NMR: 43.4 (CH3), 56.2 (CH2), 128.8, 131.7 (CH), 132.5 (CH), 135.1, 136.7, 139.2
(CH2), 195.1; MS: 269/267 [M+, 2], 268/266 (3), 252/250 (18), 185/183 (6), 157/l55 (6), 145 (5), 58 (100), 42 (27);
IR: 2250–2800 (br, s), 1660 (s)
1H NMR: 2.86 [d, 6H, J = 3.4, N(CH3)2], 4.09 (d, 2H, J = 4.0, NCH2), 6.43/7.27 (2 ´ s, 2 ´ 1H, =CH2), 7.59/7.64 (2 ´ d,
2 ´ 2H, J = 8.4, Harom), 7.88 (s, 1H, Harom), 12.93 (br s, 1H, NH);13C NMR: 42.9 (CH3), 55.5 (CH2), 128.7 (CH), 130.7
(CH), 131.2 (CH), 133.3, 135.3, 136.0, 137.8, 139.0 (CH2), 193.2; MS: 257 [M+, 4], 242 (28), 240 (37), 173 (19), 145
(19), 112 (12), 109 (13), 75 (10), 58 (100), 42 (45); IR: 2200–2850 (br, s), 1660 (s)
1H NMR: 2.83 [d, 6H, J = 4.9, N(CH3)2], 3.94/3.96 (2 ´ s, 2 ´ 3H, 2 ´ OCH3), 4.07 (d, 2H, J = 5.5, NCH2), 6.35/7.28
(2 ´ s, 2 ´ 1H, =CH2), 6.92/7.50 (2 ´ d, 2 ´ 1H, J = 8.4, Harom), 7.41 (s, 1H, Harom), 12.48 (br s, 1H, NH);13C NMR:
42.7 (CH3), 55.99 (CH3), 56.04 (CH3), 56.3 (CH2), 110.0 (CH), 111.6 (CH), 125.0 (CH), 128.2, 136.0 (CH2), 136.6,
149.3, 153.8, 194.1; MS: 249 [M+, 20], 248 (13), 233 (16), 232 (100), 175 (15), 165 (12), 151 (9), 112 (7), 58 (69), 42
(23); IR: 2200–2800 (br, s), 1640/1630 (s)
a All new compounds afforded elemental analysis within ± 0.4% for C, H, and N. 1H NMR spectra were recorded at 300 MHz in CDCl3, 13
{1H} NMR spectra at 75 MHz in CDCl3. EI mass spectra were obtained at 70 eV ionization energy. IR spectra were recorded as KBr pellets.
C

May 1998
SYNTHESIS
717
(4) Lestavel-Delattre, S.; Martin-Nizard, F.; Clavey, V.; Testard,
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resulting Mannich compounds are not only interesting tar-
gets themselves, but are also valuable building blocks,
characterized by three different electrophilic reaction cen-
ters which can be attacked by ambifunctional nucleophilic
reagents to form either aroyl- or dimethylaminomethyl-
substituted heterocyclic compounds.23
1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones 2; General
Procedure:
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Kawamura, Y. J. Med. Chem. 1987, 30, 1497.
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Method A: To a solution of 1 (20 mmol) in DMF (20 mL) was added
paraformaldehyde (68 mmol) and Me2NH2Cl (44 mmol), and the
mixture was stirred at 120–130°C for 1.5 h, and then concentrated in
vacuo. After addition of acetone (30 mL) to the residue, the resulting
suspension was triturated at 0°C for 15 min, followed by filtration and
washing of the crude product with acetone and Et2O. In some cases
only traces of the monomethylated ketone were detected in this crude
product. Purification of the Mannich salt 2 was performed by dissolv-
ing the crude product in water (50 mL) and adding NaHCO3 until the
solution was pH 8. The aqueous solution was extracted with CH2Cl2
(6 ´ 10 mL) and the organic layer was dried (anhyd Na2SO4). After
evaporation of the solvent in vacuo (bath temperature 25–30°C), con-
cd HCl (20 mmol) and a small amount of EtOH (10–20 mL) were
added and the solvent again evaporated in vacuo. The remaining solid
was recrystallized from acetone and a small amount of EtOH; in the
case of 2c EtOAc was employed for recrystallization. The crystals
were dried over P2O5 at 40–50°C/0.1 Torr for 1 to 2 h.
Method B: The reactions were performed as described above, starting
from the aryl methyl ketone 1 (10 mmol) and dimethyl(methyl-
ene)ammonium chloride (Fluka) (20 mmol) in DMF (10 mL). Work-
up, isolation and purification of 2 was performed identically to the
procedure given above.
(17) Back, W. Arch. Pharm. (Weinheim, Ger.) 1971, 304, 27.
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gew. Chem. 1971, 83, 355; Angew. Chem., Int. Ed. Engl. 1971,
10, 330.
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(23) Girreser, U.; Heber, D.; Schütt, M. unpublished results.
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