Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles

Article abstract of DOI:10.1021/acs.orglett.9b00681

The reaction of 6-chloro-1-methylpyrazin-2(1H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1H)-ones. This regioselective three-component reaction represe

Full text of DOI:10.1021/acs.orglett.9b00681

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Functionalized Pyrazin-2(1H)‑ones via Tele-Nucleophilic
Substitution of Hydrogen Involving Grignard Reactants and
Electrophiles
Pieter Mampuys,†,⊥ Timofey D. Moseev,‡,⊥ Mikhail V. Varaksin,‡,§ Johan De Houwer,†
Christophe M. L. Vande Velde,∥ Oleg N. Chupakhin,‡,§ Valery N. Charushin,*,‡,§
and Bert U. W. Maes*,†
†Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
‡Ural Federal University, Mira St. 19, 620002 Ekaterinburg, Russia
§Institute of Organic Synthesis, S. Kovalevskaya St. 22, 620990 Ekaterinburg, Russia
∥Faculty of Applied Engineering, Advanced Reactor Technology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp,
Belgium
S
* Supporting Information
ABSTRACT: The reaction of 6-chloro-1-methylpyrazin-
2(1H)-one with Grignard reactants followed by quenching
with different electrophiles gave access to a variety of 3,6-
difunctionalized 1-methylpyrazin-2(1H)-ones. This regiose-
lective three-component reaction represents the first example
of a tele-nucleophilic substitution of hydrogen (SNH) in which
the anionic σH adduct is quenched by electrophiles (other
than a proton) before elimination takes place. Quenching the
reaction with iodine (I2) or bromine (Br2) provides an
alternative reaction pathway, yielding a 3-functionalized 6-
chloro-1-methylpyrazin-2(1H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1H)-one, respectively. The halogens present offer
opportunities for further selective transformations.
ur research group previously reported the cine-nucleo-
philic substitution of hydrogen (SNH)1 on 2-substituted 5-
chloropyridazin-3(2H)-ones via a sequential one-pot three-
component reaction involving Grignard reactants and electro-
philes other than a proton (Scheme 1a).2 Intrigued by this
a suitable substrate could be obtained. In this communication,
we disclose tele-functionalization of 6-chloro-1-methylpyrazin-
2-(1H)-one (1) via a one-pot three-component reaction with
Grignard reactants (2) and electrophiles (3) (Scheme 1b).
The pyrazin-2(1H)-one core constitutes an important class of
biologically active compounds as it occurs in a variety of natural
products, drugs, and (agro)chemicals (Scheme 2).3 However, so
far, only limited synthetic methods to perform C-functionaliza-
tion of the pyrazin-2(1H)-one core have been reported.4
O
Scheme 1. Double Functionalization via Nucleophilic
Substitution of Hydrogen (SNH), Cine versus Tele
Scheme 2. Selected Examples of Biologically Active Pyrazin-
2(1H)-ones
H
protocol and the potential of such SN methodology to easily
give access to polysubstituted heteroaromatic systems by
introducing two substituents in one reaction step, we looked
into the extension of this challenging methodology. In particular,
H
the hitherto unknown double functionalization via tele-SN
caught our attention.1 We envisioned that by exchanging the
Received: February 22, 2019
C5−Cl and N1 in 2-substituted 5-chloropyridazin-3(2H)-ones,
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Model Reaction and Optimization Data
b
entry
1
2a (equiv)
3a (equiv)
T1 (°C)
t1 (min)
T2 (°C)
t2 (h)
yield of 5a (%)
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.3
1.1
1.1
1.1
1.1
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.1
1.3
1.3
1.3
−78
−78
−20
0
0
0
0
0
0
0
15
15
15
15
10
5
5
5
5
5
−78
rt
rt
rt
rt
rt
rt
rt
rt
rt
0.25
2
2
2
2
2
2
2
2
0
c
d
d
2
3
70
81
75
73
c
4
5
6
7
8
9
d
81 (84)
75
60
70
6
72
54
e
10
2
2
2
11
12
0
rt
5
5
0
rt
a
Reaction conditions: 6-chloro-1-methylpyrazin-2(1H)-one (1, 1.0 mmol), PhMgBr (2a, 1.1 equiv), THF (2 mL, dry), argon, T1, t1. Then 4-
b
c
bromobenzaldehyde (3a, 1.3 equiv), T2, t2. 1H NMR yield using 1,3,5-trimethoxybenzene as internal standard. 3a is added at 0 °C before the
mixture is stirred at rt for 2 h. Isolated yield. 2-MeTHF (2 mL, dry) as solvent.
d
e
a
Scheme 3. Tele-SNH on 6-Chloro-1-methylpyrazin-2(1H)-one (1) Involving PhMgBr (2a) and Electrophiles (3)
a
Reaction conditions: 6-chloropyrazin-2(1H)-one (1a, 1.0 mmol), PhMgBr (2a, 1.0 M in THF, 1.1 equiv), THF (2 mL, dry), argon, 0 °C, 5 min.
Then electrophile (3, 1.3 equiv), rt, 2 h. Isolated yield.
B
DOI: 10.1021/acs.orglett.9b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Tele-SNH on 6-Chloro-1-methylpyrazin-2(1H)-one (1) Involving Grignard Reactants (2) and 4-Bromobenzaldehyde
a
(3a)
a
Reaction conditions: 6-chloropyrazin-2(1H)-one (1, 1.0 mmol), commercial Grignard reactant (2, 1.1 equiv), THF (2 mL, dry), argon, 0 °C, 5
b
min. Then 4-bromobenzaldehyde (3a, 1.3 equiv), rt, 2 h. Isolated yield. In situ formation of Grignard reactant from the corresponding (hetero)aryl
bromide and Mg turnings.
Therefore, readily available 6-chloro-1-methylpyrazin-2(1H)-
one (1) was selected to develop tele-SN with Grignard
reactants (2) and electrophiles (3).
resonance and inductive stabilization effects of the σH adduct
explain why weak electrophiles such as DMF (3m) and PhSSPh
(3u) cannot be used in our process. However, replacing
disulfides by the more electrophilic thiosulfonates 3s and 3t
delivered 5s and 5t in good yield.5
H
PhMgBr (2a) and 4-bromobenzaldehyde (3a) were selected
as model nucleophile and electrophile, respectively. The
intended tele-functionalization was successfully achieved when
6-chloro-1-methylpyrazin-2(1H)-one (1) was treated with 2a at
−78 °C, quenched with 3a at 0 °C, and subsequently stirred for
2 h at room temperature (Table 1, entries 1 and 2). Interestingly,
using 1.1 equiv of the Grignard reactant 2a at 0 °C and a reaction
time of 5 min before the anionic σH adduct 4 was quenched with
1.3 equiv of the electrophile 3a delivered 6-[(4-bromophenyl)-
hydroxymethyl]-1-methyl-3-phenyl-pyrazin-2(1H)-one (5a) in
84% isolated yield (entry 6). Altering the ratio between 1, 2a,
and 3a led to a diminished yield of 5a (entries 6−9). A lower
yield of 5a was also obtained with 2-MeTHF as solvent (entry
10). A reaction temperature of 0 °C turned out to be important
for the stability and reactivity of the anionic σH adduct 4 (entries
11 and 12). The structure of 5a was also unambiguously
established by a single-crystal X-ray measurement (Table 1,
top).
In addition to PhMgBr (2a), other organomagnesium
reactants were also tested with 1 and 3a as coupling partners
(Scheme 4). (Hetero)aromatic organomagnesium reactants
(2b−2d) successfully resulted in the corresponding 3,6-
difunctionalized 1-methylpyrazin-2(1H)-ones (6b−6d) in
moderate yield. We were pleased to observe that allylic
organomagnesium reactants, such as allyl- (2e) and butenyl-
magnesium chloride (2f), resulted in similar yields for 6e and 6f.
However, aliphatic butylmagnesium chloride (2g) and
octylmagnesium chloride (2h) resulted in lower yields for 6g
and 6h. We reasoned that the generated σH adduct is less stable
in those cases due to the enhanced nucleophilicity of aliphatic
Grignard reactants. Unfortunately, dropwise addition of the
nucleophile, lowering of the initial temperature, or shortening of
the quenching time of the σH adduct did not significantly
improve the yield.
With the optimized reaction conditions in hand (Table 1,
entry 6), the scope of our three-component reaction with respect
to the electrophile 3 was investigated with 6-chloro-1-
methylpyrazin-2(1H)-one (1a) and PhMgBr (2a) as coupling
partners (Scheme 3). Benzaldehydes bearing electron-donating
and electron-withdrawing substituents were generally tolerated
well, and the corresponding 3,6-difunctionalized 1-methylpyr-
azin-2(1H)-ones 5b−5h were obtained in medium to high yield.
Heteroaromatic aldehydes, such as 2-thiophenecarboxaldehyde
(3i) and furfural (3j), also delivered the corresponding products
(5i, 5j) in good yield. Aliphatic aldehydes such as acetaldehyde
(3k) worked smoothly (5k). The lower yield for aliphatic
aldehyde 3l can be explained by steric hindrance. Subsequently,
a variety of aliphatic and aromatic ketones (3n−3q) and methyl
oxo(phenyl)acetate (3r) were also tested under the optimal
reaction conditions and delivered 5n−5r in moderate to good
yield, although they are less electrophilic than aldehydes. The
Interestingly, in a reaction of 1 with 2a as reactant and I2 as
electrophile, 6-chloro-1-methyl-3-phenylpyrazin-2(1H)-one
(7) was obtained in good yield and 6-iodo-1-methyl-3-
phenylpyrazin-2(1H)-one was not isolated (Scheme 5, bottom).
This result can be rationalized in terms of the better leaving
group properties of iodine versus those of chlorine in
intermediate 4w. Mechanistically, this is an oxidative nucleo-
philic substitution of hydrogen.1 With bromine as the electro-
phile, an additional electrophilic substitution on 7 occurred,
delivering 5-bromo-6-chloro-3-phenylpyrazin-2(1H)-one (8)
(Scheme 5, top). This tandem reaction gave 72% overall yield.
The latter reactivity was not observed with I2, even when using a
larger excess.
7 and 8 are very interesting compounds as the C-5 bromine
and C-6 chlorine atoms both allow further selective decoration
of the pyrazin-2(1H)-one via SN(AE) and Pd-catalyzed cross-
coupling reactions.
C
DOI: 10.1021/acs.orglett.9b00681
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Oxidative Tele-SNH on 6-Chloro-1-methylpyrazin-
2(1H)-one (1) with PhMgBr (2a) and Bromine or Iodine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00681.
Experimental procedures, characterization of new com-
pounds, and spectral data (PDF)
Accession Codes
CCDC 1897429 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: valery-charushin-562@yandex.ru.
*E-mail: bert.maes@uantwerpen.be.
ORCID
Scheme 6. Proposed Reaction Mechanism for Tele-SNH on 6-
Chloro-1-methylpyrazin-2(1H)-one (1a)
Pieter Mampuys: 0000-0001-7599-8168
Timofey D. Moseev: 0000-0003-3341-5838
Mikhail V. Varaksin: 0000-0002-7997-3686
Oleg N. Chupakhin: 0000-0002-1672-2476
Bert U. W. Maes: 0000-0003-0431-7606
Author Contributions
⊥P.M. and T.D.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the University of
Antwerp (BOF), the Research Foundation-Flanders (FWO),
the Hercules Foundation, COST action CA15106 (CHAOS,
C−H Activation in Organic Synthesis), and the Russian Science
Foundation (Project No. 18-73-00088). The authors thank Prof.
A proposal for the reaction mechanism is depicted in Scheme
6. The carbonyl of the lactam function of 6-chloro-1-
methylpyrazin-2(1H)-one (1) can coordinate to a Grignard
reactant (2), which favors nucleophilic addition at C-3 of the
pyrazin-2(1H)-one core. The lactam function acts as a directing
group for the nucleophilic addition reaction, which resembles a
directed metalation group (DMG) in the directed ortho
metalations (DoMs) with organometallic species.6,7 The
generated anionic σH adduct B is resonance stabilized and
inductively stabilized by the halogen atom at C-6. This σH
adduct is then quenched by an electrophile (other than a proton;
C) before elimination of hydrochloric acid takes place. In this
manner, 3,6-disubstituted 1-methylpyrazin-2(1H)-ones (5 and
6) are obtained.
̀
Filip Lemiere (University of Antwerp) for HRMS analysis.
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