Domino Aza-Michael-ih-Diels-Alder Reaction to Various 3-Vinyl-1,2,4-triazines: Access to Polysubstituted Tetrahydro-1,6-naphthyridines

Article abstract of DOI:10.1021/acs.orglett.7b02132

A straightforward domino aza-Michael-inverse-electron-demand-hetero-Diels-Alder/retro-Diels-Alder reaction between primary and secondary propargylamine derivatives and 3-vinyl-1,2,4-triazines is developed highlighting not only the uniqueness of this dual-

Full text of DOI:10.1021/acs.orglett.7b02132

Letter
pubs.acs.org/OrgLett
Domino Aza-Michael-ih-Diels−Alder Reaction to Various 3‑Vinyl-
1,2,4-triazines: Access to Polysubstituted Tetrahydro-1,6-
naphthyridines
Jabrane Jouha,†,‡,∥ Floris Buttard,†,∥ Magali Lorion,† Clement Berthonneau,§ Mostafa Khouili,‡
́
Marie-Aude Hiebel,† Gerald Guillaumet,† Jean-Franco
̧
is Briere,*,§ and Franck Suzenet*,†
́
̀
†Universite
́
d’Orlea
́
ns, CNRS, ICOA, UMR 7311, 45067 Orlea
́
ns, France
‡Laboratoire de Chimie Organique et Analytique, Universite
23000 Beni-Mellal, Morocco
́
Sultan Moulay Slimane - Faculte des Sciences et Techniques, BP 523,
́
§Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
S
* Supporting Information
ABSTRACT: A straightforward domino aza-Michael-inverse-
electron-demand-hetero-Diels−Alder/retro-Diels−Alder reac-
tion between primary and secondary propargylamine deriva-
tives and 3-vinyl-1,2,4-triazines is developed highlighting not
only the uniqueness of this dual-heterocyclic platform but also
a novel and unprecedented path to polysubstituted tetrahydro-
1,6-naphthyridine scaffolds.
Scheme 1. Previous Results and Project Plan
ncreasing molecular complexity to extend the exploration
Iof chemical space is a major goal for pharmaceutical
industries. After a recognized decline of success in the clinic
over the last two decades, recent studies have underlined the
importance of architectures possessing saturated bonds.1 The
combination of heteroaromatic and saturated N-heterocycles
aims to address this current issue,2 leading to significant
novelty in drug discovery programs.3a In that context, pyridine
scaffolds associated with saturated cycles have displayed
promising biological activities.3 However, while several paths
to polyfunctionalized tetrahydroquinolines and tetrahydroiso-
quinolines have been developed,4 the formation of the
valuable tetrahydronaphthyridines in various regioisomeric
forms is still tedious and remains a prevalent synthetic
challenge.5 The fascinating and original reactivity of 1,2,4-
triazines, which belong to a versatile group of azines, partially
addressed this limitation.6 They can indeed act as electron-
deficient 4π-components able to undergo an inverse-electron-
demand hetero-Diels−Alder (ihDA)/retro-Diels−Alder (rDA)
sequence.7 This powerful strategy enabled a straightforward
access to diversely substituted pyridines,8 among which some
tetrahydro-1,5- and 1,8-naphthyridines bearing only limited
substitution patterns were elaborated via an intramolecular
ihDA/rDA sequence (Scheme 1, a).9 These previous studies
rely on either the well-established SNAr reactivity of the 1,2,4-
triazine ring to introduce the dienophile part or a late
construction of the aza-arene moiety.
heterocyclic platform is prompted to behave as a Michael
acceptor prior to the ihDA/rDA sequence.10 This dual
reactivity remains nevertheless underexploited and limited to
the sole use of acetylacetone as nucleophile on unsubstituted
vinyltriazine as Michael acceptors (Scheme 1, b).10b We are
pleased to describe herein some breakthroughs toward
unprecedented aza-Michael reaction on substituted vinyl-
triazines. Accordingly, propargylamine derivatives were found
However, the 1,6-isomers remain inaccessible through this
useful approach mainly due to the lack of synthetic
approaches to construct the required precursors. Recently,
3-vinyl-1,2,4-triazines aroused our interest since this original
Received: July 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to be well suited to carry out a domino heteroconjugated
addition-ihDA/rDA reaction on various 3-vinyl-1,2,4-triazines
allowing the straightforward and original formation of
variously functionalized tetrahydro-1,6-naphthyridines
(Scheme 1, c).
Having established the reaction conditions, a wide range of
3-vinyl-1,2,4-triazines and propargylamines were examined as
displayed in Schemes 2 and 3. The scope is a salient aspect of
Scheme 2. Modification of the Pyridine Part
In order to achieve the optimized conditions, the aza-
Michael addition was first examined. 5-Phenyl-3-vinyl-1,2,4-
triazine 1a was selected as the model substrate, and the
reaction was performed with propargylamine 2a in various
solvents (Table 1). First, methanol was used, and the need for
Table 1. Optimization for the Aza-Michael Reaction and
the One-Pot Procedure
a
entry temp (°C) time (h)
solvent
MeOH
yield (%) 1a/3aa/4aa
b
1
2
3
4
5
6
rt
rt
24
24
0/81 /0
c
THF
100/0/0
f
f
f
f
b
180
180
180
180
3.5
MeOH
THF
0/0/59 (53)
3.5
3.5
3.5
12/0/18
d
THF
-/0/52
e
b
THF/MeOH
0/0/47, (45)
a
b
c
NMR yield with Bn2O as internal standard. Isolated yield. Same
d
e
issue for PhCl and toluene. Result obtained starting from 3aa. A
mixture of THF/MeOH (1/1) was used. Microwave irradiations were
f
used.
an excess of amine was rapidly identified since the completion
of the reaction was observed with only 3 equiv of
propargylamine (entry 1, see the Supporting Information for
details). We were pleased to isolate 3aa in 81% yield,
validating 3-vinyl-1,2,4-triazines as efficient Michael acceptors
toward primary amines. Other polar and nonpolar aprotic
solvents such as THF, toluene, or chlorobenzene, generally
preferred for the anticipated ihDA/rDA sequence, were
inappropriate and underlined the crucial need of the protic
solvent for the success of the reaction (entry 2, see the SI).
To initiate an ihDA/rDA reaction with the best solvent in
hand for the aza-Michael step, 5-phenyl-3-vinyl-1,2,4-triazine
1a and propargylamine 2a were heated under microwave
(MW) irradiation in methanol. After 3.5 h at 180 °C, 4aa was
obtained in excellent overall 53% yield, highlighting 3-vinyl-
1,2,4-triazine as a competent platform for the aza-Michael
addition followed by the domino ihDA/rDA reaction (entry
3). Next, in order to attain the temperature required for the
ihDA/rDA sequence without facing a critical pressure issue, a
more appropriate solvent was used, such as THF (entry 4).
However, even at high temperature, the aza-Michael addition
remained delicate. This limitation in the absence of protic
solvent was confirmed when the aza-Michael adduct 3aa was
directly used as the starting material in THF (entry 5). In this
case, 4aa was formed in 52% yield. Fortunately, an additional
amount of methanol in THF enabled us to overcome this lack
of reactivity, and the desired product was successfully isolated
in 45% yield after column chromatography under reasonable
pressure conditions (entry 6). Further attempts to diminish
the reaction time or the temperature showed no improvement
(see SI).
a
Reaction performed on a 2 mmol scale.
this methodology since various original polyfunctionalized
tetrahydro-1,6-naphthyridines were obtained in good yields
over this three-step cascade reaction.
First, 5-aryl-3-vinyltriazines were successfully used, giving
access to the corresponding 2-aryl-tetrahydro-1,6-naphthyr-
Scheme 3. Modification on the Piperidine Part
a
The propargylamine 2k was used as the HCl salt, and K2CO3 (3
equiv) was added to the solution for the one-pot procedure.
B
DOI: 10.1021/acs.orglett.7b02132
Org. Lett. XXXX, XXX, XXX−XXX

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
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02132.
Experimental details and characterization data for all
new compounds, table of optimization for the synthesis
of 3ma, and a complete list of compounds synthesized
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean-francois.briere@insa-rouen.fr.
*E-mail: franck.suzenet@univ-orleans.fr.
ORCID
Franck Suzenet: 0000-0003-1394-1603
Author Contributions
∥J.J. and F.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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
(see the Supporting Information for details). To overcome
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
■
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009,
52, 6752−6756. (b) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko,
M. A. J. Med. Chem. 2011, 54, 6405−6416. (c) Lovering, F.
MedChemComm 2013, 4, 515−519. (d) Schneider, P.; Schneider, G.
Angew. Chem., Int. Ed. 2017, 56, 7971−7974.
(2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257−10274.
(3) (a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med.
Chem. 2014, 57, 5845−5859. (b) Palmer, A. M.; Grobbel, B.; Brehm,
C.; Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Holst, H. C.; Simon,
W. A. Bioorg. Med. Chem. 2007, 15, 7647−7660. (c) Catozzi, N.;
Edwards, M. G.; Raw, S. A.; Wasnaire, P.; Taylor, R. J. K. J. Org.
Chem. 2009, 74, 8343−8354. (d) Basarab, G. S.; Galullo, V.;
DeGrace, N.; Hauck, S.; Joubran, C.; Wesolowski, S. S. Org. Lett.
2014, 16, 6456−6459. (e) Glinkerman, C. M.; Boger, D. L. J. Am.
Chem. Soc. 2016, 138, 12408−12413. (f) Murray, C. W.; Rees, D. C.
Angew. Chem., Int. Ed. 2016, 55, 488−492.
Scheme 4. Synthesis of 4ma
(4) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−
1730. (b) Bracca, A. B. J.; Kaufman, T. S. Tetrahedron 2004, 60,
10575−10610. (c) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C.
Chem. Rev. 2011, 111, 7157−7259. (d) Fochi, M.; Caruana, L.;
Bernardi, L. Synthesis 2014, 46, 135−157. (e) Kotha, S.; Deodhar,
D.; Khedkar, P. Org. Biomol. Chem. 2014, 12, 9054−9091.
(f) Munoz, G. D.; Dudley, G. B. Org. Prep. Proced. Int. 2015, 47,
179−206. (g) Bello Forero, J. S.; Jones, J., Jr.; da Silva, F. M. Curr.
Org. Synth. 2016, 13, 157−175. (h) Singh, I. P.; Shah, P. Expert
Opin. Ther. Pat. 2017, 27, 17−36.
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
(5) (a) Wijtmans, M.; Pratt, D. A.; Valgimigli, L.; DiLabio, G. A.;
Pedulli, G. F.; Porter, N. A. Angew. Chem., Int. Ed. 2003, 42, 4370−
4373. (b) Nam, T.-g.; Rector, C. L.; Kim, H.-y.; Sonnen, A. F. P.;
Meyer, R.; Nau, W. M.; Atkinson, J.; Rintoul, J.; Pratt, D. A.; Porter,
C
DOI: 10.1021/acs.orglett.7b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
N. A. J. Am. Chem. Soc. 2007, 129, 10211−10219. (c) Zhou, Y.;
Porco, J. A., Jr.; Snyder, J. K. Org. Lett. 2007, 9, 393−396.
(d) Mailyan, A. K.; Peregudov, A. S.; Dixneuf, P. H.; Bruneau, C.;
Osipov, S. N. J. Org. Chem. 2012, 77, 8518−8526. (e) Johnson, R. J.;
O’Mahony, D. J. R.; Edwards, W. T.; Duncton, M. A. J. Org. Biomol.
Chem. 2013, 11, 1358−1366. (f) Sirakanyan, S. N.; Spinelli, D.;
Geronikaki, A.; Hovakimyan, A. A.; Noravyan, A. S. Tetrahedron
2014, 70, 8648−8656. (g) Xiong, B.; Li, Y.; Lv, W.; Tan, Z.; Jiang,
H.; Zhang, M. Org. Lett. 2015, 17, 4054−4057. (h) Wu, Y.; Chen,
Y.-Q.; Liu, T.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138,
14554−14557. (i) Jackl, M. K.; Kreituss, I.; Bode, J. W. Org. Lett.
2016, 18, 1713−1715.
(6) (a) Ratz, R.; Schroeder, H. J. Org. Chem. 1958, 23, 1931−1934.
̈
(b) Paudler, W. W.; Barton, J. M. J. Org. Chem. 1966, 31, 1720−
1722. (c) Saraswathi, T. V.; Srinivasan, V. R. Tetrahedron Lett. 1971,
12, 2315−2316. (d) Lukin, A.; Vedekhina, T.; Tovpeko, D.; Zhurilo,
N.; Krasavin, M. RSC Adv. 2016, 6, 57956−57959. (e) Tang, D.;
Wang, J.; Wu, P.; Guo, X.; Li, J.-H.; Yang, S.; Chen, B.-H. RSC Adv.
2016, 6, 12514−12518. (f) Crespin, L.; Biancalana, L.; Morack, T.;
Blakemore, D. C.; Ley, S. V. Org. Lett. 2017, 19, 1084−1087.
(7) (a) Neunhoeffer, H. Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3,
Chapter 2.19, pp 385−456. (b) Boger, D. L. Chem. Rev. 1986, 86,
781−793. (c) Neunhoeffer, H. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 6, Chapter 6.11, pp 507−573;.
(d) Lindsley, C. W.; Layton, M. E. Sci. Synth. 2004, 17, 357−447.
(e) Charushin, V.; Rusinov, V.; Chupakhin, O. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: Oxford, 2008; Vol. 9, Chapter 9.02, pp 95−196.
(f) Foster, R. A.; Willis, M. C. Chem. Soc. Rev. 2013, 42, 63−76.
(8) (a) Taylor, E. C.; Macor, J. E. Tetrahedron Lett. 1986, 27,
2107−2110. (b) Taylor, E. C.; Macor, J. E.; French, L. G. J. Org.
Chem. 1991, 56, 1807−1812. (c) Raw, S. A.; Taylor, R. J. K. Chem.
́
Commun. 2004, 508−509. (d) Fernandez Sainz, Y.; Raw, S. A.;
Taylor, R. J. K. J. Org. Chem. 2005, 70, 10086−10095. (e) Shi, B.;
Lewis, W.; Campbell, I. B.; Moody, C. J. Org. Lett. 2009, 11, 3686−
3688.
(9) (a) Neipp, C. E.; Ranslow, P. B.; Wan, Z.; Snyder, J. K.
Tetrahedron Lett. 1997, 38, 7499−7502. (b) Rickborn, B. The
Retro−Diels−Alder Reaction Part II. Dienophiles with One or More
Heteroatom. In Organic Reactions; John Wiley & Sons, 1998; Vol. 53,
pp 224−287. (c) Butler, R.; Leblanc, C.; McKeown, S. C.; Charlton,
S. J. Ip receptor agonist heterocyclic compounds. WO2014125413A1,
Aug 21, 2014; Chem. Abstr. 2014, 161, 389970. (d) Haenel, F.; John,
R.; Seitz, G. Arch. Pharm. 1992, 325, 349−352. (e) Seitz, G.; Richter,
J. Chem.-Ztg. 1989, 113, 252−254. (f) John, R.; Seitz, G. Arch.
Pharm. 1989, 322, 561−564.
(10) (a) Badarau, E.; Bugno, R.; Suzenet, F.; Bojarski, A. J.; Finaru,
A.-L.; Guillaumet, G. Bioorg. Med. Chem. 2010, 18, 1958−1967.
(b) Lorion, M.; Guillaumet, G.; Brier
2015, 17, 3154−3157.
̀
e, J.-F.; Suzenet, F. Org. Lett.
D
DOI: 10.1021/acs.orglett.7b02132
Org. Lett. XXXX, XXX, XXX−XXX