to construct the 2,5-dihydropyridine skeleton has pre-
vented an in depth investigation on the biological activity
of this isomer of dihydropyridines.
Table 1. Synthesis of 2,5-Dihydropyridine Derivative 9a under
Different Reaction Conditions
All the above-mentioned reasons led us to evaluate new
methods for the synthesis of 2,5-dihydropyridine deriva-
tives. Thus, inspired by the work of S. Cacchi and G.
Fabrizi on the synthesis of pyridines and pyrroles,9 we
hypothesized that the condensation of 2-substituted β-
ketoesters 6 and propargyl amines 7 would provide N-
propargylic β-enaminoester intermediates 8, which in the
presenceof a catalystabletoactivatethe alkynecould react
by a 6-endo-dig cyclization process to form the 2,5-dihy-
dropyridine derivatives 9 in an apparently very simple way
from readily available starting materials (Scheme 1).10 The
excellent work of S. F. Kirsch and co-workers on metal-
catalyzed reactions of propargyl vinyl ethers (related to β-
enaminoester intermediates 8) to get different heterocyclic
compounds should be remarked upon at this point.11
entry
catalyst
temperature (T, °C)
yield (%)a
b
1
2
3
4
5
6
7
8
(pic)AuCl2
rt
40
75
40
40
rt
10
82
b
(pic)AuCl2
(pic)AuCl2
NaAuCl4
b
55
91c
d
(Ph3P)AuCl/AgOTf
PtCl2
À
d
À
e
PtCl4
rt
À
d
TfOH
40
À
a Determined by 1H NMR analysis of the crude reaction mixture by
using p-xylene as internal standard. b (pic)AuCl2 = dichloro(2-pyridine-
c
carboxilato)gold. Reaction performed in the presence of 4 A molecular
˚
˚
sieves. In the absence of 4 A molecular sieves the yield was slightly lower
(85%). d Starting materials were recovered. e We only observed the
formation of the corresponding condensation product 8.
Scheme 1. Proposed Reaction for the Synthesis of 2,5-Dihy-
dropyridine Derivatives
By increasing the temperature to 40 °C the yield of the
reaction also increased to a promising 82% yield after 48 h
of reaction (Table 1, entry 2). Surprisingly, the yield
diminished when the temperature was increased to 75 °C
probably due to the decomposition of the product under
these conditions (Table 1, entry 3). The best result was
obtained by using as catalyst the simpler and cheaper
gold(III) salt NaAuCl4. With this catalyst we observed
the formation of the 2,5-dihydropyridine derivative 9a in
91% yield when the reaction was performed at 40 °C for 48
h (Table 1, entry 4). The cationic gold(I) complex in situ
formed by mixing (Ph3P)AuCl and AgOTf did not pro-
mote the reaction (Table 1, entry 5). We also checked the
possibility of using platinum(II) and platinum(IV) cata-
lysts but we did not observed the formation of the desired
product (Table 1, entries 6,7). Finally, to check if a simple
Brønsted acid could promote the process, we performed an
experiment by using triflic acid (TfOH) as catalyst, but we
did not observe any conversion and we recovered the
starting materials (Table 1, entry 8). Among the different
solvents used, methanol gave the best results.
To check the feasibility of the proposed reaction, the
initial proof-of-concept investigations were performed
with ketoester 6a and propargylamine 7a (Table 1). Con-
sidering the high affinity of gold to alkynes and having in
mind the specific quality of gold(III) salts of accelerating
the condensation between ketones and amines,12 we fo-
cused our attention on this specific kind of catalysts. Thus,
by using 5 mol % of dichloro(2-pyridinecarboxilato)gold
in methanol as solvent at room temperature for 48 h, we
were able to observe the formation of the desired 2,5-
dihydropyridine derivative 9a although in low yield
(Table 1, entry 1).
Under the optimized conditions, 5 mol % of NaAuCl4 as
˚
catalyst in methanol as solvent in the presence of 4 A
molecular sieves at 40 °C, we examined the scope of this
new synthesis of 2,5-dihydropyridine derivatives (Scheme
2). As shown, different substitution on both, the ketoester
and the propargylamine is allowed and the corresponding
2,5-dihydropyridine derivatives are isolated, in general, in
moderate togood yields. The reaction seems toworkbetter
with propargylamines unsubstituted at the triple bond
(R4 = H) or with an aromatic ring at this position. However,
when R4 is an aliphatic chain we observed the lowest yields
(see 9e). We have not observed isomerization of the
obtained 2,5-dihydropyridine derivatives 9 to any of the
other possible isomers 1À4. The structure of compounds 9
(9) (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629. See
also:(b) Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli,
F.; Rossi, E. J. Org. Chem. 2003, 68, 6959.
(10) Note that dihydropyridines 9 could be considered as 2,5-dihy-
dropyridine derivatives or alternatively as 3,6-dihydropyridine-
carboxylates.
(11) (a) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
(b) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (c) Menz, H.;
Kirsch, S. F. Org. Lett. 2006, 8, 4795. (d) Harschneck, T.; Kirsch, S. F. J.
Org. Chem. 2011, 76, 2145.
(12) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv. Synth.
Catal. 2001, 343, 443.
Org. Lett., Vol. 13, No. 16, 2011
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