Sequential Michael Addition and Enamine-Promoted Inverse Electron Demanding Diels-Alder Reaction upon 3-Vinyl-1,2,4-triazine Platforms

Article abstract of DOI:10.1021/acs.orglett.5b01487

An original one-pot Michael addition-ihDA/rDA sequence was achieved from 3-vinyl-1,2,4-triazine platforms used as unprecedented Michael acceptors. This sequence provides a novel access to functionalized [2,3]-fused pyridine derivatives via a unique enamin

Full text of DOI:10.1021/acs.orglett.5b01487

Letter
pubs.acs.org/OrgLett
Sequential Michael Addition and Enamine-Promoted Inverse
Electron Demanding Diels−Alder Reaction upon 3‑Vinyl-1,2,4-
triazine Platforms
Magali Lorion,† Gerald Guillaumet,† Jean-Francois Briere,*,‡ and Franck Suzenet*,†
̧
̀
́
†Universite
́ ́ ́
d’Orleans, CNRS, ICOA, UMR 7311, 45067 Orleans, France
‡Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen, INSA Rouen; CNRS, IRCOF, 1 rue Tesnier
̀
e, 76821 Mont Saint
Aignan cedex, France
S
* Supporting Information
ABSTRACT: An original one-pot Michael addition-ihDA/
rDA sequence was achieved from 3-vinyl-1,2,4-triazine plat-
forms used as unprecedented Michael acceptors. This
sequence provides a novel access to functionalized [2,3]-
fused pyridine derivatives via a unique enamine promoted
intramolecular ihDA reaction of 1,2,4-triazine intermediates.
1,2,4-Triazine derivatives 1 belong to an important class of
heterocycles encompassing applications in medicine and
agrochemistry, but there are also useful building blocks in
organic synthesis (Scheme 1).1 As depicted in Scheme 1a, these
context, Boger and colleagues developed a robust strategy using
enamine reactants as electron-rich dienophiles2,3 involved in
the domino ihDA/rDA reactions as depicted in Scheme 1b
(transient intermediate 6).4,5 This approach both fulfills the
stereoelectronic requirement of the ihDA reaction of 6 and
secures the final rearomatization event while eliminating the
secondary amine group. For instance, [3,4]-fused pyridines 7
were accessible from the corresponding cyclopentanone
(Scheme 1b).3−5 Nevertheless, the regioselectivity of this
intermolecular sequence depends on the substitution pattern of
the triazine derivative 5. Although preformed enamines are
usually employed, the one-pot procedure starting from the
corresponding amine and ketone was also successful in certain
cases.2c,6 To the best of our knowledge, however, the
intramolecular version of this powerful enamine-promoted
domino ihDA/rDA reaction remains elusive despite the
opportunity to elicit novel annulation processes.
Scheme 1. Chemistry of 1,2,4-Triazines and Project Plans
At the onset of the following research program, we desired to
capitalize on the accessibility of vinyl-triazine derivatives 4
through an SNAr reaction between readily available 3-sulfonyl-
triazines 2 and vinyl Grignard nucleophiles (Scheme 1a). Then,
we reasoned that a Michael addition reaction of ketones 8 to
vinyl-triazine derivatives 4 would furnish suitable ketone-
triazine precursors, en route to intramolecular domino ihDA/
rDA reactions via transient enamine intermediate 9 (Scheme
1c). We believe this approach would afford salient features.
First of all, the regioselectivity control through trans-annular
constraints would lead eventually to a complementary
accessibility to [2,3]-fused pyridines 107 (versus [3,4]-
homologues 7 with the intermolecular version). Next, although
the 1,4-conjugated addition reaction to alkene-substituted
heterocyles has recently emerged as an innovative synthetic
π-electron-deficient triazines 1, flanked by a suitable leaving
group, undergo aromatic nucleophilic substitution (SNAr)
reactions to give functionalized products 3 (Scheme 1a).
Furthermore, these heterocyclic platforms 5 are capable of
undergoing domino inverse-electron-demand hetero-Diels−
Alder (ihDA)/retro-Diels−Alder (rDA) reactions with various
2C dienophiles that allow for a straightforward access to
substituted pyridine derivatives 7 (Scheme 1b), which are
ubiquitous derivatives in pharmaceutical ingredients.2 In this
Received: May 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
strategy,8 the application to vinyl-triazine derivatives 4 remains
almost unknown.9 A reactivity investigation must then be
undertaken. We are pleased to report here the achievement of
the first Michael addition-ihDA/rDA sequence to furnish [2,3]-
fused pyridine derivatives 10 in a one-pot synthesis.
With keto-triazine 12 in hand, we attempted the synthesis of
[2,3]-fused pyridine 10a upon the influence of secondary
amines (R2NH) (Table 2). In order to develop a user-friendly
Table 2. Optimization of the ihDA/rDA Sequence
As a model Michael process, we studied the 1,4-addition
reaction of acetylacetone 8 to 5-phenyl-3-vinyl-1,2,4-triazine 4a
in the presence of amine bases (Table 1). A rapid survey of
Table 1. Michael Addition Reaction to 3-Vinyl-1,2,4-
a
Triazine 4a
coacid
(equiv)
yield
a
b
entry
solvent
base (mol %)
product
yield (%)
entry
R2NH (equiv)
toluene (M) product
(%)
1
2
3
4
5
toluene
MeOH
MeOH
MeOH
tBuOH
Et3N (20)
Et3N (20)
DIPEA (20)
Et3N (50)
Et3N (50)
−
−
30(39)
1
2
3
4
5
6
7
8
pyrrolidine (3)
pyrrolidine (3)
pyrrolidine (3)
pyrrolidine (3)
pyrrolidine (3)
pyrrolidine (1)
pyrrolidine (1)
pyrrolidine (3)
−
0.1
0.1
0.2
0.5
1.0
0.5
0.5
0.5
15
60
22
28
c
11
11
12
11
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (1)
10a
10a
10a
10a
10a
10a
10a
38
d
b
82
62
16
56
27
39
55
a
Reaction conditions: 3-vinyl-1,2,4-triazine 4a (1 equiv), base (20−50
mol %), acetylacetone 8 (2 equiv), solvent (0.2 M), reflux, 12 h.
Isolated yield after column chromatography. After 24 h. No
b
c
d
PhCOOH
(3)
reaction took place at room temperature.
9
pyrrolidine (3)
pyrrolidine (3)
PivOH (3)
APTS (3)
AcOH (3)
0.5
0.5
0.5
10a
10a
10a
54
43
45
10
11
2-Mepyrrolidine
(3)
reaction conditions revealed that the use of methanol versus
toluene both favored the 1,4-addition process and addressed
the solubility issue of starting material 4a (entries 1−2). Protic
assistance seems to increase the electrophilic character of the
Michael acceptor through a hydrogen bond activation. In the
presence of 20 mol % of triethylamine in refluxing methanol for
12 or 24 h, the corresponding diacetyl-adduct 11 was obtained
albeit in moderate 30−39% yields (entry 2). The use of a
cd
,
12
13
14
proline (3)
AcOH (3)
AcOH (3)
AcOH (3)
0.5
0.5
10a
10a
10a
28
22
34
prolinol (3)
pyrrolidine (3)
MeOH
(0.5)
e
a
b
Isolated yield after column chromatography. 35% yield without
c
d
molecular sieves. Toluene/DMF (2:1), at 125 °C. No product
formation without acetic acid additive. MeOH was used instead of
toluene, and MS (3 Å) was used.
e
sterically more hindered Hunig base (entry 3), in order to
̈
prevent any parasitic addition events to the alkene pendant, did
not improve the reaction efficiency. Eventually, we were
delighted to observe that an increased amount of triethylamine
(50 mol %) led to a complete transformation of triazine 4a into
the corresponding monoacetyl product 12 with a good 82%
yield (entry 4). In line with previous observations by Canac and
Lubineau under different conditions,10 we believe that the
formation of this unexpected compound 12 results from the
initial tandem 1,4-conjugated addition−protonation reaction of
acetylacetone 8 to the alkene pendant of 4a followed by a retro-
Claisen condensation onto intermediate 11. The acetyl
elimination is likely triggered by nucleophilic attack of
nonencumbered methanol, since no product 12 formation
occurred in tert-butanol (diketone 11 was isolated instead,
entry 5). Considering the much lower yield of compound 11
observed in tert-butanol, it is assumed that the deacetylation
event drives the reaction to completion by interrupting the
otherwise thermodynamically controlled 1,4-addition of
acetylacetone 8. In connection with the following study (vide
infra), we also investigated an enamine-promoted process.
Unfortunately, preliminary investigations in the presence of
secondary amines such as pyrrolidine, with either the
acetylacetone 8 or the acetone as nucleophiles, led to a mixture
of products revealing the competitive 1,4-addition reaction of
the amines to 4a.
protocol, we tackled the challenging in situ formation of
enamine reagent 13 in the presence of molecular sieves
following Boger’s protocol.6 Nonetheless, one has to take into
account the requisite preferential reaction of the kinetic-
enamine 13, versus the thermodynamic one, in order to achieve
the unprecedented intramolecular domino ihDA-rDA sequence
(14 to 15). The subsequent amine eliminative-rearomatization
reaction would then lead to pyridine 10a. Making use of
pyrrolidine (3 equiv) in refluxing toluene, we observed a
complete transformation of ketone 12 (entry 1, Table 2) into
dihydropyridine 15 with a 60% yield without providing the
expected pyridine 10a. Accordingly, the intramolecular domino
ihDA/rDA reaction upon in situ enamine 13 formation was
established but the elimination of the secondary amine did not
occur. Carrying out the reaction under more drastic conditions
(up to 200 °C), by means of microwave heating, led to the
recovery of starting material.5c This issue is indeed a known
bottleneck of the ihDA-rDA sequence and depends on the
topology of the intermediate compounds. In the literature, the
elimination step was successfully achieved by means of diamine
assistance,5 performing oxidative eliminations,4e or making use
of coacids.3−5 As diamine assistance was unsuccessful in our
case, we assumed that the coacid strategy would suit our system
best by facilitating the amine R2N-elimination upon the
B
DOI: 10.1021/acs.orglett.5b01487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
protonation event. We were very pleased to discover that a
mixture of pyrrolidine and an excess of acetic acid introduced at
the start of the reaction allowed the formation of pyridine 10a
albeit in a low 22% isolated yield (entry 2, Table 2). Worthy of
note, this one-pot sequence completes the literature precedents,
whereby the acid treatment is usually applied sequentially after
completion of the cycloaddition step. Working in a more
concentrated solution (entries 3−5, Table 2) improved the
yields up to 62% at 0.5 M (entry 4, Table 2). The optimum was
exceeded at 1 M concentration (56% yield, entry 5, Table 2)
which led to some decomposition as evidenced by the 1H NMR
analysis of the crude reaction mixture. Attempts to decrease the
amount of coacid or pyrrolidine gave lower yields (entries 6−7,
Table 2). The examination of various additives showed that
other carboxylic acids such as benzoic acid (55% yield, entry 8,
Table 2) or the sterically hindered pivaloic acid (54% yield,
entry 9, Table 2) did not improve the process. More acidic
APTS appears more disadvantageous for the success of the
reaction (43% yield, entry 10, Table 2). The use of α-
substituted secondary amine promoters was detrimental to the
process efficiency (22−45% yield, entries 11−13, Table 2).11
Subsequently, we envisaged a tandem Michael-ihDA/rDA
sequence, having in mind that the first 1,4-conjugated addition
step was favored in the presence of a protic solvent (see Table
1). Unfortunately, it turned out that the domino ihDA/rDA
reaction occurred with only a 34% yield in methanol (entry 14,
Table 2). Nonetheless, as described in Scheme 2, we carried out
corresponding product 10a with an improved 60% overall
yield from the corresponding vinyl-triazine 4a. With this user-
friendly protocol in hand, the scope of the one-pot Michael-
ihDA/rDA process was explored for various 3-vinyl-1,2,4-
triazine derivatives 4 (Scheme 2). This multistep sequence was
performed from the vinylic starting materials 4b−d and 4f to
provide novel fused-pyridines flanked at C6 by either
substituted aryl rings (10b−10c), heterocyclic pyridine, or
thiophene moieties (10d, 10f) with reasonably good overall
isolated yields ranging from 32% to 64%. The electron deficient
3-vinyl-1,2,4-triazine derivative 4e, having a pendant 5-
pNO2C6H5, was nicely transformed into the corresponding
pyridine derivative 10e with 49% isolated yield. However, the
pyridine analogue 10e′ featuring a 5-pNH2C6H5 ring was also
formed, as an unexpected product, with 22% isolated yield.
Interestingly, this reduction reaction can be avoided by
performing the reaction under an air atmosphere. This
reductive phenomenon is not fully understood yet but shows
that the transformation of functional groups is allowed.
Although the synthesis of more sterically hindered products
with either a 2,6-dimethylphenyl moiety 10g or a 5,6-
diphenylpyridine ring 10h was practically possible, it occurred
with modest 6−9% overall yields. Analysis of the crudes (12g,
12h) showed that the Michael addition proceeded completely
and that the ihDA is disfavored, probably due to steric
repulsion in the formation of intermediate 14 featuring a 3D
topology.
In summary, we report here for the first time a one-pot
sequential domino Michael-ihDA/rDA reaction using 3-vinyl-
1,2,4-triazine as an unprecedented Michael acceptor. This
sequence provides a novel access to functionalized [2,3]-fused
pyridine derivatives via a unique intramolecular ihDA reaction
of 1,2,4-triazines promoted by enamine intermediates. The
extension of this novel one-pot annulation process to other
substrates is currently under investigation.
Scheme 2. Scope and Limitations of the One-Pot Michael-
ihDA/rDA Sequence
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01487.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: franck.suzenet@univ-orleans.fr.
*E-mail: jean-francois.briere@insa-rouen.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been partially supported by Labex SynOrg
(ANR-11-LABX-0029), University of Orleans, reg
INSA Rouen, Rouen University, CNRS, EFRD and region
Haute-Normandie.
́
ion Centre,
this novel strategy in a one-pot sequential fashion, namely by
performing the Michael reaction (4a to 12) with 50 mol % of
triethylamine in refluxing methanol followed by a solvent
evaporation under reduced pressure. Then, the domino ihDA/
rDA reaction was achieved by the subsequent addition of
pyrrolidine, acetic acid, and molecular sieves in toluene.
Gratifyingly, this multistep sequence finally led to the
REFERENCES
■
(1) Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 6, p 507. (b) Lindsley, C. W.; Layton, M. E. In Science of
Synthesis; Weinreb, S. M., Eds.; Thieme: Stuttgart, 2003; Vol. 17, p
C
DOI: 10.1021/acs.orglett.5b01487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
357. (c) Kumar, R.; Sirohi, T. S.; Singh, H.; Yadav, R.; Roy, R. K.;
Chaudharyand, A.; Pandeya, S. N. Mini Rev. Med. Chem. 2014, 14, 168.
(2) For reviews on ihDA/rDA reactions, see: (a) Boger, D. L.;
Weinreb, S. N. Hetero Diels−Alder Methodology in Organic Synthesis;
Academic: London, 1987; Chapter 10, p 300. (b) Boger, D. L. Chem.
Rev. 1986, 86, 781. (c) Boger, D. L. Tetrahedron 1983, 39, 2869.
(d) Raw, S. A.; Taylor, R. J. K. Adv. Heterocycl. Chem. 2010, 100, 76.
(e) Fosterand, R. A. A.; Willis, M. C. Chem. Soc. Rev. 2013, 42, 63.
(f) Knall, A.-C.; Slugovc, C. Chem. Soc. Rev. 2013, 42, 5131.
(3) (a) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.
(b) Boger, D. L. Tetrahedron 1983, 39, 2869. (c) Boger, D. L.; Panek,
J. S. J. Am. Chem. Soc. 1985, 107, 5745 and references cited therein.
(4) For representative examples, see: (a) Kozhevnikov, V. N.;
Kozhevnikov, D. N.; Shabunina, O. V.; Rusinovand, V. L.; Chupakhin,
O. N. Tetrahedron Lett. 2005, 46, 1521. (b) Kozhevnikov, V. N.;
Kozhevnikov, D. N.; Shabunina, O. V.; Rusinovand, V. L.; Chupakhin,
O. N. Tetrahedron Lett. 2005, 46, 1791. (c) Altuna-Urquijo, M.;
Stanforthand, S. P.; Tarbit, B. Tetrahedron Lett. 2005, 46, 6111.
(d) Chenardand, B. L.; Renaud, R. T. J. Org. Chem. 1988, 53, 5175.
(e) Branowska, D. Molecules 2005, 10, 265. (f) Altuna-Urquijo, M.;
Gehre, A.; Stanforth, S. P.; Tarbit, B. Tetrahedron 2009, 65, 975.
(g) Gehre, A.; Stanforth, S. P.; Tarbit, B. Tetrahedron 2009, 65, 1115.
(5) (a) Taylor, R. J. K. J. Org. Chem. 2005, 70, 10086. (b) Rawand, S.
A.; Taylor, R. J. K. Chem. Commun. 2004, 508. (c) Bromley, W. J.;
Gibson, M.; Lang, S.; Raw, S. A.; Whitwoodand, A. C.; Taylor, R. J. K.
Tetrahedron 2007, 63, 6004. (d) Taylorand, E. C.; Macor, J. E. J. Org.
Chem. 1989, 54, 1249.
(6) Boger, D. L.; Panekand, J. S.; Meier, M. M. J. Org. Chem. 1982,
47, 895.
(7) (a) For an alternative domino ihDA/rDA reaction of 1,2,4-
triazines to [2,3]-fused pyridines, see: Branowska, D.; Ostrowski, S.;
Rykowski, A. Chem. Pharm. Bull. 2002, 50, 463. (b) For an alternative
domino ihDA/rDA reaction of 1,2,3-triazines to [2,3]-fused pyridines,
see: Anderson, E. D.; Duerfeldt, A. S.; Zhu, K.; Glinkermanand, C. M.;
Boger, D. L. Org. Lett. 2014, 16, 5084. (c) For an alternative synthesis
to cyclopenta-[2,3]-fused pyridines, see: Borioni, A.; Del Giudice, M.
R.; Mustazza, C.; Gatta, F. J. Heterocycl. Chem. 2000, 37, 799. Kaiser,
S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45, 5194.
(8) For reviews, see: (a) Klumpp, D. A. Synlett 2012, 1590.
(b) Bestand, D.; Lam, H. W. J. Org. Chem. 2014, 79, 831.
(9) Badarau, E.; Bugno, R.; Suzenet, F.; Bojarski, A. J.; Finaru, A. L.;
Guillaumet, G. Bioorg. Med. Chem. 2010, 18, 1958.
(10) Rodrigues, F.; Canacand, Y.; Lubineau, A. Chem. Commun.
2000, 2049.
(11) Xie, H.; Zu, L.; Oueis, H. R.; Li, H.; Wangand, J.; Wang, W. Org.
Lett. 2008, 10, 1923.
D
DOI: 10.1021/acs.orglett.5b01487
Org. Lett. XXXX, XXX, XXX−XXX