Table 2 DBU-catalysed hydroalkoxylation and hydroamination
product in 30% yield after chromatography. This concise strategy
compares favourably with previously reported multistep-syntheses
11
of this biologically relevant compound.
Given the wide scope of the alkene hydroalkoxylation processes
summarised in Table 2, the possibility of developing a novel
dihydroalkoxylation reaction of alkynones was intriguing, not least
because the products of such reactions would be synthetically
useful mono-protected 1,3-dicarbonyl compounds. Treatment of
terminal alkyne 23 with ethylene glycol in the presence of 5 mol%
1
2
DMAP gave smooth conversion to acetal 24, which was isolated
in high yield after chromatography (Scheme 3). To our knowledge
this is the first example of a nucleophile-promoted dihydroalk-
13
oxylation reaction to be reported.
In summary, it has been found that tertiary nucleophilic amines
such as DBU and DMAP catalyse the efficient hydroalkoxylation
of activated alkenes under mild conditions. The reaction scope
with respect to both the olefin and the alcohol is comparable to
previously reported phosphine-catalysed reactions, while the air-
a
Substrate Pronucleophile Mol% DBU Product Time/h Yield (%)
3
3
3
4
5
6
7
7
7
8
9
a
MeOH
PrOH
5
5
5
5
5
10
5
5
5
10
5
10
11
12
13
14
15
16
17
18
19
20
24
70
24
72
18
93
3
62
86
76
77
79
60
95
69
i
b
Pyrrole
MeOH
MeOH
MeOH
MeOH
EtOH
14
stability, commercial availability, ease of removal and low cost of
DBU make it an attractive alternative to phosphine-based systems.
Preliminary efforts to expand the synthetic potential of these
processes have led to the discovery of efficient analogous catalytic
hydroamination (involving pyrrole) and alkynone dihydroalkoxy-
lation reactions. It thus seems likely that considerable potential
exists for further scope expansion with respect to both the
pronucleophilic and electrophilic components. Investigations along
these lines are in progress in our laboratory.
c
c
c
3
i
PrOH
MeOH
MeOH
8.5 97
93
47
49
93
c
b
Refers to isolated yield unless otherwise indicated. Conditions:
pyrrole (1.0 mmol), acrylonitrile (1.3 mmol), DBU (0.05 mmol), rt,
H NMR spectroscopy using
anisole as an internal standard.
c
air atmosphere. Determined by
1
We would like to thank Dr. John O’Brien for NMR spectra and
the Irish Research Council for Science Engineering and
Technology (IRCSET) for financial support.
Julie E. Murtagh, S e´ amus H. McCooey and Stephen J. Connon*
Department of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
E-mail: connons@tcd.ie; Fax: +353 1 6712826
Notes and references
Scheme 2 One-pot synthesis of danaidone.
{
Representative procedure (Table 2): To a solution of the Michael
acceptor (1.8 mmol) in alcohol (500 mL) in a 1 mL reaction vessel was
added DBU (0.09 mmol) via a syringe. After stirring for the time indicated
in Table 2 the solution was diluted with ether (30 mL) and washed with sat.
The putative hydroalkoxylation mechanism (Scheme 1) sug-
gested that pronucleophiles of suitable acidity other than alcohols
could also participate in this type of addition reaction. This was
verified via the observation of a novel and efficient nucleophile-
4 4
NH Cl (2 6 15 mL). The organic extracts were dried (MgSO ) and the
solvent removed to afford the spectroscopically pure adduct. The products
can be further purified by column chromatography, although this is
necessary only in cases involving recalcitrant substrates such as 6 and 8.
catalysed N-cyanoethylation of pyrrole (pK 5 16.5) to give 12 in
a
{
One-pot synthesis of danaidone (21): DBU (33 mL, 0.22 mmol) was
added to a magnetically stirred solution of 3-methylpyrrole (89 mg,
.10 mmol) in acrylonitrile (290 mL, 4.40 mmol) via a syringe. The reaction
good yield (Table 2).
To demonstrate the potential synthetic utility of these catalytic
processes we have utilised a DBU-catalysed cyanoethylation
reaction as a key step in a novel, one-pot synthesis of the
1
vessel was fitted with a stopper and the resulting solution stirred at rt until
complete conversion of 3-methylpyrrole was achieved (72 h). Excess
acrylonitrile was removed in vacuo and both anhydrous ether (2.0 mL) and
10
Monarch butterfly pheromone danaidone (21) (Scheme 2).{
Addition of 3-methylpyrrole to acrylonitrile catalysed by DBU
gave intermediate 22 (Scheme 2), which underwent subsequent
2
anhydrous ZnCl (75 mg, 0.55 mmol) were added. Dry HCl gas was passed
through the resulting mixture with precipitation of a yellow solid. The
vessel was fitted with a stopper and allowed to stand for 12 h at rt, after
which time the ether was decanted and a solution of the iminohydrochlor-
electrophilic cyclisation in the presence of added HCl–ZnCl . The
2
ide salt in H
0 uC for 1 h. After allowing the reaction vessel to cool, the mixture was
extracted with CH Cl (3 6 20 mL), the organic layers were separated,
dried (MgSO ) and the solvent removed in vacuo to give a brown oil,
which was purified by column chromatography (gradient: 1 : 1 CH Cl
hexane to 2 : 1 CH Cl : EtOAc) to give 21 (44 mg, 30%). Mp (66–68 uC,
lit. 68–70 uC); H NMR (CDCl , 400 MHz) d 2.34 (s, 3H), 3.07 (t, 2H,
J 5 6.2 Hz), 4.23 (t, 2H, J 5 6.3 Hz), 6.32 (d, 1H, J 5 1.3 Hz), 6.89 (d, 1H,
2 2 3
O (2 mL) was basified to pH 8–9 (Na CO ) and stirred at
resultant iminohydrochloride was hydrolysed to give the natural
8
2
2
4
2
2
:
2
2
11c
1
3
13
3
J 5 1.3 Hz); C NMR (CDCl , 100 MHz) d 189.0, 129.2, 122.0, 121.2,
116.9, 41.3, 39.1, 10.6.
Scheme 3 DMAP-promoted one-pot alkynone dihydroalkoxylation.
2
28 | Chem. Commun., 2005, 227–229
This journal is ß The Royal Society of Chemistry 2005
Murtagh, Julie E.
