Organocatalyzed Thia-Michael Addition and Sequential Inverse Electron Demanding Diels-Alder Reaction to 3-Vinyl-1,2,4- triazine Platforms

Article abstract of DOI:10.1002/adsc.201700831

This work highlights the use of 3-vinyl-1,2,4-triazines as original thia-Michael acceptors and inverse electron demanding Diels-Alder platforms en route to new 7,8-dihydro-5H-thiopyrano[4,3-b]pyridines. The required but rather unstable propargylthiol nucleophiles were successfully generated in-situ upon an innovative DBU-catalyzed methanolysis event of the corresponding propargyl thioacetate derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201700831

Title: Organocatalyzed Thia-Michael Addition and Sequential Inverse
Electron Demanding Diels−Alder Reaction to 3‑Vinyl-1,2,4-
triazine Platforms
Authors: Clément Berthonneau, Floris Buttard, Marie-Aude Hiebel,
Franck Suzenet, and jean-François Brière
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700831
Link to VoR: http://dx.doi.org/10.1002/adsc.201700831

10.1002/adsc.201700831
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalyzed Thia-Michael Addition and Sequential Inverse
Electron Demanding Diels−Alder Reaction to 3-Vinyl-1,2,4-
triazine Platforms
Clément Berthonneau,a Floris Buttard,b Marie-Aude Hiebel,b Franck Suzenetb* and
Jean-François Brièrea*
a
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.
Fax: (+33)-2-3145-2962; phone: (+33)-2-3552-2464; e-mail: jean-francois.briere@insa-rouen.fr
Université d’Orléans, CNRS, ICOA, UMR 7311, 45067 Orléans, France.
b
Fax: (+33)-2-3841-7281; phone: (+33)-2-3849-4580; e-mail: franck.suzenet@univ-orleans.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
of research, organocatalytic processes only appeared
Abstract. This work highlights the use of 3-vinyl-1,2,4-
triazines as original thia-Michael acceptors and inverse to be surfacing in recent years.[6]
electron demanding Diels-Alder platforms en route to new
7,8-dihydro-5H-thiopyrano[4,3-b]pyridines. The required
but rather unstable propargylthiol nucleophiles were
successfully generated in-situ upon an innovative DBU-
catalyzed methanolysis event of the corresponding
propargyl thioacetate derivatives.
Keywords: triazine; organic catalysis; conjugate addition;
propargylthiol; Diels-Alder reaction
Pyridines are privileged scaffolds in medicinal
chemistry ubiquitously represented in pharmaceutical
ingredients.[1] Among the myriad synthetic
approaches towards this valuable heterocycle,[2] the
domino inverse-electron-demand-hetero-Diels–Alder
(ihDA)/retro-Diels–Alder (rDA) reaction between
1,2,4-triazine platforms and 2C-dienophiles such as
alkynes has furnished synthetically useful pathways
to pyridines displaying various substitution patterns
(Scheme 1a).[3] The intramolecular strategies have
also flourished and overcome the lack of reactivity of
alkyne partners meanwhile addressing the
regioselectivity issues towards the construction of
fused
non-aromatic/heteroaromatic
fused
bicycles.[3],[4] However, these cyclization approaches
necessitate the pre-installation of a tether flanked by
the dienophile. On the other hand, vinyl N-
heterocycles, whose alkene-substituted pyridines are
the most representative platforms, emerged as
original and useful Michael-acceptors allowing an
alternative way to provide substituted azaarenes.[5]
Their unique reactivity markedly depends on the
capability of the electron-poor azaarene moiety to
stabilize the developing anionic charge subsequent to
the 1,4-addition reaction.[5] Nonetheless, in this field
Scheme 1. Context of the methodology.
In quest to merge the best of these two worlds, we
recently introduced 3-vinyl-1,2,4-triazine derivatives
1 as a versatile platform able to undergo both a 1,4-
conjugated addition reaction and the subsequent
intramolecular ihDA/rDA reaction (Scheme 1b).[7]
This novel strategy was initially proven by a Michael
reaction of acetylacetone (C-C bond formation) to 3-
vinyl-1,2,4-triazines 1 having a unsubstituted vinyl
1
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10.1002/adsc.201700831
Advanced Synthesis & Catalysis
pendant. However, the conjugated addition process
required a large amount of triethylamine as a base.
Then, the acetyl motif allowed an enamine-based
domino ihDA/rDA-elimination sequence to give
[2,3]-fused pyridines.[3],[7],[8] On this background, we
undertook to probe the reactivity profile of (1) more
substituted vinyl-triazines 1 as (2) unprecedented
hetero-Michael acceptors for C-S bond formation
upon (3) organocatalytic conditions (Scheme 1c).
Accordingly, we envisaged the use of propargylthiol
derivatives 2 as a dual entities not only allowing a
thia-Michael reaction to give product 5 but affording
also the opportunity to lead to the subsequent
intramolecular ihDA/rDA reaction (Scheme 1c).[9]
Additionally, this sequence would provide a novel
approach and versatile construction of 7,8-dihydro-
5H-thiopyrano[4,3-b]pyridines 6, whose very few
general synthetic approaches are reported despite the
biological relevance of this scaffold.[10] We are
pleased to report herewith the first sequential domino
thia-Michael-ihDA/rDA reaction to 3-vinyl-1,2,4-
triazine derivatives 1, meanwhile affording an
organocatalytic strategy to manipulate unstable
propargylthiol 2.
Due to the known volatility and instability of the
propargylthiol 2a (R5 = H, Scheme 1c), Moyano and
Pericàs proposed the use of propargyl thioacetate
derivative 3a as stable masked-thiol which was
liberated in-situ as lithium thiolate species upon
treatment by LiAlH4.[11],[12] We postulated that a
tertiary-amine as a Brønsted base would promote the
deacetylation reaction of 3a along with the
nucleophilic addition of methanol to provide a
catalytic amount of the corresponding ammonium
propargylthiolate 4 en route to the thia-Michael
product 5 (Scheme 1c). At the onset of this
hypothesis (Table 1), it was shown that no reaction
took place between vinyl-triazine 1a and acetyl
derivative 3a (1.5 equivalent) in the presence of
methanol but without any base (entry 1). To our
delight, a screening of organic bases in MeCN
(entries 2-4, 20 mol%) revealed that strong guanidine
amine bases furnished the expected thia-Michael
product 5a with promising 32-43% of conversion
(entries 3-4). The amidine DBU turned to be the
optimal organocatalyst giving rise to complete (>
99%) and clean transformation of vinyl-triazine 1a
into product 5a in 3 hours as long as methanol
additive is used (entries 5-6). A rapid survey of
solvents (entries 7-9) revealed that methanol afforded
a slightly faster process allowing a conversion of
99% in 1 hour whereas 70% was obtained in
acetonitrile (entries 5 and 7). However, this outcome
was also counterbalanced by the apparent
decomposition (precipitation events) of the acetyl
compound 3a used in excess in methanol likely
though the rapid concentration of the unstable
propargylthiol 2a and derivatives in the reaction
medium. Then, we made use of the stable benzylthiol
7 as a model S-nucleophile to probe the thia-Michael
reaction into the formation of 8 (Table 1, entries 10-
14). It was demonstrated that a base is crucial for the
success of the conjugated addition reaction and DBU
is a superior organocatalyst than iPr2EtN in toluene
(entries 10-12), although their efficiency was
comparable in acetonitrile (entries 13-14). Eventually,
the use of sodium methanolate as a base led only to
the oxa-Michael product 9 highlighting the usefulness
of the soft DBU/MeOH strategy (entry 15).
Table 1. Optimization of the thia-Michael reaction.[a]
Entry Base
Solvent/
Additive
Product
3a
or 7 (%)[b],[c]
1
2
-
MeCN/MeOH
MeCN/MeOH
5a, 0
5a, 0
3a
3a
DABCO
or
DMAP
or
iPr2EtN
MTBD
TMG
DBU
DBU
DBU
DBU
DBU
DBU
iPr2EtN toluene/-
-
DBU
iPr2EtN MeCN/-
3
4
5
6
7
8
9
10
11
12
13
14
15
MeCN/MeOH
MeCN/MeOH
MeCN/MeOH
MeCN/-
5a, 43
5a, 32
5a, >99 (70)
5a, traces
5a, >99 (>99)
5a, 35
5a, 95
8, >99
8, 6
8, 0
8, 93
3a
3a
3a
3a
3a
3a
3a
7
7
7
7
7
MeOH/-
THF/MeOH
PhCl/MeOH
toluene/-
toluene/-
MeCN/-
8, >99
9, 83
MeONa MeCN/MeOH
3a
[a] Reaction conditions: 1a (0.1 mmol), base (20 mol%),
solvent (1 ml, 0.1M) at rt either in the presence of acetyl
propargylthiol 3a (1.5 equiv.) and MeOH (10 equiv.) for 3
h or BnSH 7 (1 equiv.) for 12 h. [b] Conversion with
1
regard to 1a determined by H NMR of the crude product.
[c] In bracket outcome after 1 hour. TMG: N,N,N’,N’-
tetramethylguanidine,
MTBD:
7-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene.
diazabicyclo[2.2.2]octane.
DABCO:
DMAP:
1,4-
4-
dimethylaminopyridine. DBU: diazabicyclo[5.4.0]undec-7-
ene.
An NMR investigation revealed that Hünig base
(iPr2EtN) was unable to achieve the deacetylation
reaction of 3a in the presence of methanol (see ESI).
Contrariwise, 20 mol% of DBU allowed the rapid
methanolysis reaction leading to the formation of
20% of methyl acetate A (1H NMR ratio 3a/A =
80/20) after one hour (Figure 1). Interestingly, the
2
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10.1002/adsc.201700831
Advanced Synthesis & Catalysis
disappearance of 3a continued slowly afterwards.
However, the obtained products, among which the
expected thiolate 4, were not identified by NMR
likely due to instability issue.
excess of propargyl thiol derivatives 2a-3a elicited
side reactions leading to complex mixtures beside the
cycloaddition pathway. Pleasingly, by means of an
acidic washing of the reaction mixture followed by a
solvent exchange, the resulted crude product 5a
underwent a smooth cyclization process to yield the
expected fused-pyridine 6a in 78% yield (entry 2).
These results (74-76%) were secured with similar
yields on two mmol scale irrespective to the use of
MW irradiation heating or conductively heating
(entry 2). Importantly, these reaction conditions
displayed less than 5% of the retro-thia-Michael
product 1a. It was found that neither lower
temperature (175 °C, entry 3) nor other solvents
(entries 4-7) surpassed the reaction in chlorobenzene
at 200 °C for 1 hour.
Table 2. Optimization of the cycloaddition reaction.[a]
Figure 1. 1H NMR (CD3CN) monitoring of the
deacetylation event of propargyl thioacetate 3a furnishing
methyl acetate A. (a) 3a (0.15 mmol), in CD3CN (1 mL), rt.
(b) 3a (0.15 mmol), DBU (0.02 mmol) and MeOH (1
mmol), rt, 1 h (3a/A: 80/20). (c) After 3 h (3a/A: 60/40).
(d) After 14 h (3a/A: 42/58).
Entry T (°C)
Solvent
PhCl
PhCl
PhCl
PhCF3
Ethylene glycol
NMP
PhNO2
Product 6a (%)[b]
1
2
3
4
5
6
7
200
200
175
200
200
200
200
27[c]
78 (74) [d] (76) [e]
Most notably, by means of CD3OD in the presence
of propargyl thiobenzoate 3b, preventing the parasitic
hydrogen-deuterium exchanges with acidic protons of
3a (see ESI), the corresponding deuterated-product
5b was obtained with 78% yield and 86% D
incorporation (Scheme 2). This testifies that: (1) the
protonation event mainly takes place at the α-position
of the triazine following a thia-Michael-protonation
sequence and (2) MeOH is the proton source, likely
via the formation of thiolate-DBUH+ ion-pair 4 by
methanolysis (Scheme 1c). Accordingly, one can
assume that the strong basicity of DBU is well-
balanced to allow both the deacylation event of
propargyl thioacetate derivatives 3 and the 1,4-
nucleophilic addition reaction without retarding the
subsequent protonation event; a prerequisite to
regenerate the DBU organocatalyst.
56
74
42
45
59
[a] Reaction conditions: carried out on the crude product
5a (0.1 mmol) obtained after acidic-extraction and
evaporation of the reaction media, diluted in 2 mL of
solvent upon microwave irradiation. [b] NMR yield
determined by an internal standard over two-steps. [c] On
the crude product 5a after evaporation but without work-up.
[d] Reaction carried out in a conductively heated
Monowave 50 reactor. [e] 76% of isolated yield when
carried out on 2 mmol scale.
Mindful of having a convenient protocol in hands,
we carried out a filtration of the crude reaction
mixture through a weak acid cation exchange resin
(Amberlite IRC86) in order to remove the DBU base
(Table 3, conditions A). Then, the intramolecular
ihDA/rDA reaction was achieved upon MW
irradiation after a solvent exchange. Accordingly, we
were pleased to observe the formation of the fused-
pyridine 6a in 77% isolated yield over two-steps from
the corresponding vinyl-triazine 1a. This protocol
was successfully applied to various 5-substituted
vinyl-triazines to synthesize the corresponding
pyridines having a para- (6b-56% and 6c-85%),
meta- (6d-64%) and even diortho-substituted phenyl
ring (6e-70%) with overall yields ranging from 56 to
70%. A heteroaryl connected to the triazine ring was
also tolerated as demonstrated with the elaboration of
thienyl 6f (70%) and pyridine 6g (64%) derivatives.
Next, the formation of 2,3-dimethyl fused-pyridine
6h was achieved with 39% isolated yield.
Interestingly, it was demonstrated that this sequence
Scheme 2. Deuteration experiment.
Thereafter, we undertook the investigation of the
intramolecular ihDA/rDA reaction on the crude
propargyl product 5a (obtained after evaporation) due
to the sensitivity of this compound to oxidation upon
purification through column chromatography (Table
2).[13] However, after heating under microwave (MW)
irradiation at 200 °C in chlorobenzene for 1 hour a
low 27% NMR yield was measured (entry 1). It
turned out that either the presence of DBU or the
3
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10.1002/adsc.201700831
Advanced Synthesis & Catalysis
could be extended to substituted alkynes 3c-d (R5 =
Me, Ph) which furnished the crude thia-Michael
intermediates 5i-j with more than 98% of conversion.
However, the corresponding cyclized-products 6i-j
displaying substituents at the 2 and 4 positions were
obtained with modest 23-28% yields. These last
examples might result from the more challenging
cycloaddition events due to steric hindrance issues.
78% yield. These conditions were also successfully
achieved to yield β-pentyl 6l (7968% yields) and α-
methyl 6m (8369% yields) pyridine derivatives. The
fact that the thia-Michael reaction was never
completed (86-95% of conversion into adduct 5k-m)
may be explained by an equilibrated process upon
thermodynamic control. Indeed, the cycloaddition
reaction into products 6k-m also gave rise to the
formation of 9-17% of vinyl-triazine 1i-k upon MW
irradiation.
Table 3. A thia-Michael-ihDA/rDA sequence.[a]
In summary, we have demonstrated that 3-vinyl-
1,2,4-triazines are useful platforms for the synthesis
of
7,8-dihydro-5H-thiopyrano[4,3-b]pyridine
derivatives via an original sequence based on a thia-
Michael reaction and the subsequent ihDA/rDA-
process. This successful outcome was based on the
innovative use of propargyl thioacetates, as
convenient sources of rather unstable propargylthiol
nucleophiles thanks to the organocatalytic DBU-
based methanolysis event; a process that might find
further application in synthesis.
Experimental Section
General Procedure
To a solution of 3-vinyl-1,2,4-triazine 1a-h (0.3 mmol, 1
equiv.), the appropriate thioacetate 3a, 3c or 3d (0.33
mmol, 1.1 equiv.) and methanol (3.0 mmol, 10 equiv.) in
acetonitrile (3 mL) was added DBU (9 μL, 0,06 mmol, 20
mol%). The resulting solution was stirred for 3 hours at
room temperature and filtered through a AMBERLITE
IRC86-H form column. Resin was rinced with methanol
and the filtrate was evaporated under reduced pressure.
Chlorobenzene (6 mL) was added and the resulting
mixture was placed in a microwave vial (30 mL). The vial
was sealed and the solution was heated at 200 °C for 1-3
hours under microwave irradiation. After cooling down to
room temperature, the reaction mixture was concentrated
under reduced pressure. The crude product was purified by
flash column chromatography on silica gel to yield the
desired 7,8-dihydro-5H-thiopyranopyridine 6a-j.
[a] Isolated yields after silica gel column chromatography.
Acknowledgements
This work has been partially supported by INSA Rouen, Rouen
University, Orléans University, CNRS, EFRD and Labex SynOrg
(ANR-11-LABX-0029), région Normandie (CRUNCh network)
and région Centre-Val de Loire.
We subsequently tackled the thia-Michael addition
reaction to triazines 1 flanked by α- or β-
functionalized alkene pendants (Table 3, conditions
B). Unfortunately, only traces of the Michael product
5k was observed by mixing the vinyl-triazine 1i (R4 =
Me) and propargyl thioacetate 3a in MeCN in the
presence of methanol (conditions A). The 1,4-
nucleophilic addition reaction appears to be highly
sensitive to steric hindrance at the β-position of the
vinyl-pendant of triazine 1. To our delight, by adding
dropwise the thioacetate partner 3a in methanol, in
order to prevent a rapid decomposition of the
corresponding thiol intermediate 2a in this solvent
(vide supra), we succeeded in the formation of thia-
Michael adduct 5k with 77% isolated yield after a
flash column chromatography purification (see SI for
more details). Next, the intramolecular ihDA/rDA
reaction into fused-pyridine 6k was carried out in
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Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Organocatalyzed Thia-Michael Addition and
Sequential Inverse Electron Demanding
Diels−Alder Reaction to 3‑ Vinyl-1,2,4-triazine
Platforms
Adv. Synth. Catal. Year, Volume, Page – Page
Clément Berthonneau,a Floris Buttard,b Marie-
Aude Hiebel,b Franck Suzenetb* and Jean-François
Brièrea*
6
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