D. Tejdor, G. Mꢀndez-Abt, and F. Garcꢁa-Tellado
studied. Both aliphatic and aromatic substituents were toler-
ant in the terminal position of the triple bond (R1; entries 1–
6). It is remarkable that unsubstituted derivative 1b gave
the poorest yield even under forced conditions (entry 2).
This result could be pointing out to the necessity of some
conformational control in this kind of processes (a substitu-
ent-biased conformational control) or/and a certain degree
of substitution at the terminal double bond. Propargylic de-
rivatives 1g and 1h featuring a substituent at the O terminus
of the enol function reacted with 4a to give the correspond-
ing pentasubstituted 1,2-dihydripyrines 6ga and 6ha, al-
though in low yields and under vigorous conditions (300 W,
1508C, 3 h) (entries 7 and 8).[14] This fact reflects the difficul-
ty for ketimine formation under these conditions and its di-
minished reactivity for the 6p-aza-electrocyclization reac-
tion. Substitution at the sp3-propargylic position (R2) was
found to be dependent on the nature of substituent R1.
Whereas R2 could be hydrogen, aliphatic, or aromatic for
terminal alkynes (R1 =H; entries 1–4) and aromatic for in-
ternal alkynes (R1 =Ph or cHex; entries 5 and 6), the combi-
nation of R2 =Alk, and an internal alkyne [i.e., 7a and 7b,
Eq. (2)] did not afford 1,2-dihydropyridines. Instead, mix-
tures of compounds 8 and 9 were systematically obtained.
Importantly, the same mixtures were obtained when these
reactions were performed in the absence of the amine.
These results seem to point out to a new reaction pathway
involving different thermally-driven rearrangements of the
2,4-dienal 3 intermediate. The study and synthetic utility of
this interesting transformation are in progress in our lab.
Scheme 4. Domino synthesis of substituted alkyl 3-pyridinecarboxylates
(10) from propargyl enol ethers 1 and methoxyamine hydrochloride.
dine by means of an elimination reaction. Methoxyamine
has proved to be an excellent amine derivative for this kind
of transformation.[4b] Accordingly, the microwave irradiation
of an ethanolic mixture of propargyl enol ether 1a (1 mmol)
.
and MeONH2 HCl (1.1 mmol) in the presence of NaOAc
(50 mol%) yielded the methyl 2-phenyl-4-pyridinecarboxy-
late (10a) in a convenient 54% yield (4% of transesterifica-
tion product; Scheme 4). A similar result was obtained with
propargylic derivative 1e (52% as a ꢀ3:1 mixture of methyl
and ethyl esters). Derivative 1j featuring an ethyl ester
group at the enol position afforded, under the same condi-
tions, the expected pyridine 10j in 55% yield. To the best of
our knowledge, this is the first example of a metal-free
domino synthesis of nicotinic acid derivatives from proparg-
yl enol ethers and amines involving this spectacular cascade
of chemical processes. Although these preliminary results
constitute an excellent proof of concept, more experimental
work needs to be developed to increase the efficiency of this
pyridine synthesis.[16]
In summary, we have reported our preliminary results on
the metal-free domino synthesis of substituted alkyl 1,2-di-
hydropyridine-3-carboxylates from propargyl enol ethers
and primary amines by means of an unprecedented [3,3]
propargyl Claisen rearrangement/isomerization/amine con-
densation/6p-aza-electrocyclization cascade reaction net-
work. 1,2-Dihydropyridines 6 are obtained with remarkable
high efficiency, good level of diversity (four possible diversi-
ty points), and bearing a convenient chemical handle for
complexity-diversity generation (carboxylic ester at C3-posi-
tion). This methodology has been extended to the synthesis
of substituted nicotinic acid derivatives 10.
With regard to the vinyl functionality tolerance, propargyl
enol ether 1i bearing a SO2Tol as the electron-withdrawing
group afforded the corresponding 1,2-dihydropyridine 6ia in
very good yield (80%) (entry 9).
Finally, the domino reaction with enantiopure propargyl
derivative (R)-1a (prepared from enantiopure (R)-1-phenyl-
prop-2-yn-1-ol and methyl propiolate) and p-anisidine (4a)
afforded the expected product 6aa in racemic form (Table 1,
entry 17). Observe that the chiral information present in the
starting propargyl enol ether is completely lost in the rear-
rangement-isomerization process previous to the ketimine
formation.
As a logical extension of this methodology, we attempted
its application to the domino synthesis of pyridines 10, fea-
turing a biologically and chemically relevant nicotinic acid
motive (Scheme 4).[15] Evidently, implementation of this
methodology required an additional step to convert the 1,2-
dihydropyridine intermediate into the corresponding pyri-
Experimental Section
Representative procedure for the microwave-assisted synthesis of 1,2-di-
hydropyridines 6: A solution of propargyl vinyl ether 1a (1.0 mmol) and
p-anisidine (4a) (1.1 mmol) in toluene (5 mL) was placed in a micro-
wave-special closed vial and the solution was irradiated for 30 min in a
single-mode microwave oven (150 W, 1208C). The reaction mixture was
dried over anhydrous sodium sulfate and filtrated using dichloromethane
as solvent. After removing the solvent at reduced pressure the products
were purified by flash column chromatography (silica gel, n-hexane/
EtOAc 80:20) to yield 6aa (100% yield).1H NMR (400 MHz, CDCl3,
430
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 428 – 431
Tejedor, David
