Organic Letters
Letter
idines bearing substituents in the meta- (4ba, 44%), di-ortho-
(4ca and 4da, 60% and 62%, respectively), and para- (4ea
and 4fa, 37% and 35% respectively) positions of the phenyl
ring (Scheme 2). Our method can also be extended to
heteroaryl substituents since 2-pyridyl and 2-thienyl were well
tolerated (4ga and 4ha). In this series, 3-vinyl-1,2,4-triazine
(R1 = H, R2 = H) and 5-methyl-3-vinyl-1,2,4-triazine (R1 =
Me, R2 = H) were not evaluated due to their challenging
synthesis. Next, the 2,3-dimethyl and 2,3-diphenyl derivatives
4ia and 4ja were obtained in 49% and 67% isolated yield,
respectively. Then the modification of the propargylamine
part was examined. Various 3-arylpropargylamines were
submitted to our experimental conditions, and the desired
4-aryl-tetrahydro-1,6-naphthyridines were isolated with overall
yields ranging from 35 to 67% (4ab-aj). Overall, the reaction
tolerates different electron-donating (Me, OMe) and electron-
withdrawing groups (NO2, CN) in the ortho, di-ortho, meta,
and para positions of the phenyl ring. On the C4 position,
our cascade reaction exhibits very little steric effect (4ah−aj).
Recently, it has been reported that increasing the number
of sp3-hybridized carbons as well as stereogenic carbon
contribute to decrease the toxicity.1c Therefore, we turned our
attention on introducing substituents on the piperidine part of
the tetrahydro-1,6-naphthyridines (Scheme 3). First, Csp3- and
N-substituted propargylamines were successfully used as 4ak−
am and 4kk were efficiently synthesized allowing access to
C5- and N-functionalized tetrahydro-1,6-naphthyridines.
Next, the more challenging 3-vinyl-1,2,4-triazines 1k−m
substituted in the α or β positions of the alkenyl moiety were
examined. Interestingly, reaction with a methyl or a
hydroxymethyl group in the β-position gave the expected
products 4ka and 4la in 62% and 57% yield, respectively,
regardless of steric hindrance.
propargylamines allowing afterward a straightforward and
unique access to diversely substituted tetrahydro-1,6-naph-
thyridines thanks to a subsequent ihDA/rDA process.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Experimental details and characterization data for all
new compounds, table of optimization for the synthesis
of 3ma, and a complete list of compounds synthesized
AUTHOR INFORMATION
Corresponding Authors
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ORCID
Author Contributions
∥J.J. and F.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was partially supported by Labex SynOrg (ANR-
11-LABX-0029), Labex IRON (ANR-11-LABX-0018-01),
University of Orleans, region Centre, INSA Rouen, Rouen
University, CNRS, EFRD, and region Haute-Normandie.
Nonetheless, with 5-phenyl-3-(prop-1-en-2-yl)-1,2,4-triazine
1m, the desired bicyclic product 4ma was not isolated under
our original experimental conditions. A slight loss of planarity
(and conjugation) between the alkenyl and the triazine parts
for steric reasons could explain this lack of reactivity.
Therefore, an optimization was carried out on this substrate
this limitation, the reaction was performed in the presence of
BF3·Et2O (6 equiv) in refluxing THF with a larger excess of
2a (5 equiv). Under these conditions, 3ma was isolated in
62% yield and directly engaged in the ihDA/rDA sequence
(Scheme 4).
REFERENCES
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Scheme 4. Synthesis of 4ma
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After irradiation, 4ma was successfully obtained in 75%
yield, allowing the efficient introduction of a wide range of
functional groups in each position of the tetrahydro-1,6-
naphthyridine ring.
In summary, we report herein a novel three-step domino
transformation exploiting the versatile reactivity of 3-vinyl-
1,2,4-triazines. This α,β-unsaturated 4π deficient scaffold
demonstrated a high synthetic usefulness being at first an
efficient aza-Michael acceptor toward primary and secondary
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C
Org. Lett. XXXX, XXX, XXX−XXX