LETTER
Solvent-Free Enamine Synthesis
2201
Ph
Table 1 Reaction of Dialkylacetylendicarboxylates or (1a,b) Alkyl-
propiolates (1c,d) with Aminesa
Ph
HN
CO2Me
HN
CO2Me
CO2Me
CO2Me
aniline
+
Yield (%)b Ratio
solvent-free
40 °C, 5 min
Entry
Alkyne
Amine
MeO2C
E/Zc
CO2Me
(E)-2a
(Z)-2a
1a
2a
2b
2c
2d
2e
2f
1a
aniline
91
87
88
89
82
84
94
92
93
89
85
81
83
96
92
87
97:3
Scheme 2 Reaction of 1a (5 mmol) and aniline (5 mmol) in a flask
under solvent-free conditions (40 °C, 5 min)
p-toluidine
o-toluidine
m-anisidine
piperidine
morpholine
diisopropylamine
aniline
98:2
96:4
tion time without noticeable formation of side products,
and in case of secondary alkyl amines the resulting enam-
ines were stereoisomerically pure as well.
97:3
>99:<1
>99:<1
>99:<1
97:3
Supporting Information for this article is available online at
experimental details and NMR characterization data.
2g
2h
2i
1b
1c
Acknowledgment
p-toluidine
aniline
97:3
This work was funded by the German Federal Environmental Foun-
dation (DBU; grant No. 27281-31). Authors would like to thank
B. Ondruschka (ITUC) for interesting discussions and ongoing co-
operation.
2j
7:93
2k
2l
p-toluidine
piperidine
morpholine
diisopropylamine
aniline
8:92
>99:<1
>99:<1
>99:<1
7:93
2m
2n
2o
2p
References
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1d
p-toluidine
7:93
a Reactions conditions: alkyne (1 mmol), amine (1 mmol), SiO2 (5 g),
13.3 Hz, 5 min, 45-mL ZrO2 milling beaker, 6 × 15 mm ZrO2 milling
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b Isolated yields.
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Figure 1 1H NMR spectrum of extracted crude product of 2j (bot-
tom); zoom-in of vinylic proton region (top)
ing a ball mill the reaction was chemoselective and result-
ed in a E/Z ratio of 97:3 (Table 1).
In conclusion, a new solvent-free protocol for the addition
of amines to dialkylacetylendicarboxylates or alkylpropi-
olates using a planetary ball mill has been developed.
Yields were nearly quantitative within five minutes reac-
Synlett 2011, No. 15, 2200–2202 © Thieme Stuttgart · New York