Regioselective addition of Grignard reagents to N-acylpyrazinium salts: Synthesis of substituted 1,2-dihydropyrazines and Δ5-2-oxopiperazines

Article abstract of DOI:10.3762/bjoc.15.8

The regioselective addition of Grignard reagents to mono- and disubstituted N-acylpyrazinium salts affording substituted 1,2-dihy-dropyrazines in modest to excellent yields (45–100%) is described. Under acidic conditions, these 1,2-dihydropyrazines can be converted to substituted Δ⁵-2-oxopiperazines providing a simple and efficient approach towards their preparation.

Full text of DOI:10.3762/bjoc.15.8

Regioselective addition of Grignard reagents to
N-acylpyrazinium salts: synthesis of substituted
1,2-dihydropyrazines and Δ5-2-oxopiperazines
Valentine R. St. Hilaire1, William E. Hopkins1, Yenteeo S. Miller1,
Srinivasa R. Dandepally1 and Alfred L. Williams*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 72–78.
1Biomanufacturing Research Institute and Technology Enterprise
(BRITE), North Carolina Central University, Durham, North Carolina
27707, United States and 2Department of Pharmaceutical Sciences,
North Carolina Central University, Durham, North Carolina 27707,
United States
doi:10.3762/bjoc.15.8
Received: 22 September 2018
Accepted: 10 December 2018
Published: 08 January 2019
Email:
Associate Editor: D. Y.-K. Chen
Alfred L. Williams* - awilliams@nccu.edu
© 2019 St. Hilaire et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
N-acylpyrazinium salts; 1,2-dihydropyrazines; Grignard reagents;
Δ5-2-oxopiperazines; regioselective addition
Abstract
The regioselective addition of Grignard reagents to mono- and disubstituted N-acylpyrazinium salts affording substituted 1,2-dihy-
dropyrazines in modest to excellent yields (45–100%) is described. Under acidic conditions, these 1,2-dihydropyrazines can be con-
verted to substituted Δ5-2-oxopiperazines providing a simple and efficient approach towards their preparation.
Introduction
Pyrazine and piperazine ring systems are key structural ele- pyrazines. We recently showed that 3-alkoxy-substituted
ments in a large number of biologically active molecules [1-6]. N-acylpyrazinium salts can be selectively reduced by tributyltin
Compounds containing these scaffolds were shown to behave as hydride to afford 1,2-dihydropyrazines in good to excellent
anticancer agents [2-5], sodium channel blockers [5], and also yields [9]. There have been other reports involving the addition
display antiviral activity [7]. Due to their appearance in an array of TMS-ketene acetals to pyrazinium salts [10-12]. A double
of biologically active small molecules and natural products, nucleophilic addition of bis(trimethylsilyl)ketene acetals to
efficient synthetic routes into this class of privileged structures pyrazines activated with methyl chloroformate was found to
would be very beneficial [7,8]. One approach towards their syn- afford polycyclic γ-lactones in moderate yields [3,10,11]. The
thesis involves the addition of nucleophiles to activated work by Garduño-Alva and co-workers demonstrated that these
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Beilstein J. Org. Chem. 2019, 15, 72–78.
TMS-ketene acetals can be regioselectively added to substi- both 3a and the ester were obtained in yields of 41% and 39%,
tuted N-triflate pyrazinium salts to also generate γ-lactones [12]. respectively (entry 3, Table 1). Changing the solvent to diethyl
ether showed no improvement in the yield of 3a but when THF
Grignard reagents have been used as nucleophiles on a variety was used, an excellent yield of 87% was produced (entries 4
of N-acyl-activated pyridines in the production of natural prod- and 5, Table 1).
ucts and biologically active small molecules [13-20]. To our
surprise, there are no reports on the nucleophilic addition of Based on our previously developed selective tin hydride reduc-
Grignard reagents to N-acylpyrazinium salts. A literature search tion of monosubstituted pyrazinium salts [9], we expected the
showed this organometallic reagent reacting with pyrazine Grignard reagent to add regioselectively to give 1,2-dihydro-
N-oxides towards the one-pot synthesis of N-Boc-protected pyrazine 3a. DFT calculations support the observations that the
N-hydroxy-substituted piperazines in good yields [6]. Methyl- isolated regioisomer we obtained was the result of a thermody-
magnesium iodide was observed adding to 2-cyano-6- namically favored 1,2-addition over a 1,6-addition [9]. It has
morpholinylpyrazine [21]. As a part of our continued explo- also been shown that TMS-ketene acetals add selectively to
ration into the synthetic utility of N-acylpyrazinium salts, herein N-triflate pyrazinium salts [12]. 1H NMR analysis confirmed
we report the regioselective addition of Grignard reagents to this by showing a rotameric pair of singlets at 3.89 and
mono- and disubstituted N-acylpyrazinium salts towards the 3.84 ppm for the methoxy group at C3, a rotameric pair of
synthesis of 1,2-dihydropyrazines and Δ5-2-oxopiperazines.
singlets at 5.89 and 5.58 ppm for the proton at C2 and a
rotameric pair of doublets at 6.17, 6.15 ppm and 6.68, 6.63 ppm
for the two vinyl protons at C5 and C6, respectively. This result
Results and Discussion
Our journey began by first reacting 2-methoxypyrazine with is in agreement with our observation that nucleophiles favored
phenyl chloroformate to generate the N-acylpyrazinium salt 2 1,2-addition over a 1,6-addition [9]. A formation of 1,6-di-
using DCM as the solvent. Next, phenylmagnesium bromide in hydropyrazine was not observed.
THF was added at −41 °C. After stirring for 60 min, dihydro-
pyrazine 3a was isolated in a yield of 40% (entry 1, Table 1). With THF identified as the optimal solvent to use, we sought to
This initial low yield prompted us to switch the Grignard sol- expand the scope of the Grignard addition to various mono- and
vent from THF to DCM. Using modified reaction conditions disubstituted N-acylpyrazinium salts (Figure 1). Phenyl chloro-
from Andersson and co-wokers [22], phenylmagnesium bro- formate was the acylating reagent of choice for this study due to
mide in DCM was added to 2 at −41 °C and after 35 min, di- benzyl or methyl chloroformates producing products in very
hydropyrazine 3a was only isolated in a 32% yield (entry 2, poor yields. A variety of alkyl Grignard reagents were shown to
Table 1). The lower yields appear to be caused by the Grignard add regioselectively to methoxy-substituted salts to give the
attacking the carbonyl of the N-acyl salt 2 causing the forma- dihydropyrazines in yields ranging from 48% to 73% (Figure 1,
tion of phenyl benzoate. When toluene was used as the solvent, compounds 3b–g). Aryl Grignard reagents containing an elec-
Table 1: Phenyl Grignard addition to methoxy-substituted N-acylpyrazinium salts.
entrya
solvent
time (min)
yield 3a (%)b
1
2c
3
DCM
DCM
60
35
40
60
30
40
32
toluene
diethyl ether
THF
41d
15
4
5
87e
aGrignard reagent in THF. bIsolated yields. cGrignard reagent added as solution in DCM. dPhCO2Ph (39%) was also isolated. eTrace amounts of the
ester byproduct PhCO2Ph was isolated.
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Figure 1: Regioselective addition of Grignard reagents to mono- and disubstituted pyrazinium salts (yields refer to isolated yields).
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Beilstein J. Org. Chem. 2019, 15, 72–78.
tron-withdrawing and donating group proceeded to give the moderate to good yields of 45–88% (Figure 1, compounds 8,
desired substituted products in moderate yields (Figure 1, com- 9a,b) while the presence of an electron-withdrawing ester group
pounds 3h–j). The examination of the Grignard addition to generated 13 in a yield of 49%.
benzyloxy- or p-methoxybenzyloxy (PMB)-substituted
pyrazinium salts, resulted in obtaining dihydropyrazines in With the substituted 1,2-dihydropyrazines in hand, we next
yields that were comparable to the methoxy salts (Figure 1, wanted to demonstrate their usefulness for synthesizing substi-
compounds 4a,b and 5).
tuted Δ5-2-oxopiperazines. Processes into this structural motif
would be very useful due to their presence in a variety of bio-
We next subjected disubstituted N-acylpyrazinium salts to this logically active small molecules and natural products [23-30].
reaction. Based on our results from the monosubstituted sub- We previously reported that 3-methoxy-1,2-dihydropyrazines
strates, a 1,2-addition of the Grignard was expected to occur. can be easily converted to Δ5-2-oxopiperazines using
When an aryl group was present on the ring, trisubstituted dihy- 1 M HCl(aq) in methanol [9]. When we applied these acidic
dropyrazines in good yields ranging from 78–100% were pro- conditions on the phenyl-substituted 3-methoxy-1,2-dihydro-
duced (Figure 1, compounds 6, 7a,b and 12). An alkyl substitu- pyrazine 3a, only a 5% yield of Δ5-2-oxopiperazine 14a was
tion with either an ethyl or benzyl group on the pyrazinium salts obtained (Table 2, entry 1). This low yield appears to be due to
gave an 81% yield for both 10 and 11 (Figure 1). Reacting a the presence of a ring-opened side product [31]. The yields of
Grignard with pyrazinium salts disubstituted with electron-do- the Δ5-2-oxopiperazines were improved to 61% and 92%, re-
nating alkoxy groups gave us the desired dihydropyrazine in spectively, when the reaction was repeated on phenyl-substi-
Table 2: Conversion of dihydropyrazine to Δ5-2-oxopiperazines under acidic conditions.
entry
R
H
R1
R2
Ph
acid
time (min)
product
yield (%)a
1
Me
HCl(aq)/MeOH
60
5
14a
14a
14a
14a
2
3
H
H
H
Bn
PMB
Me
Ph
Ph
Ph
HCl(aq)/MeOH
HCl(aq)/MeOH
HCl/dioxane
45
60
30
61
92
93
4b
5b
H
H
Me
Me
Bn
HCl/dioxane
HCl/dioxane
30
45
95
85
14b
14c
6b
2-BrBn
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Beilstein J. Org. Chem. 2019, 15, 72–78.
Table 2: Conversion of dihydropyrazine to Δ5-2-oxopiperazines under acidic conditions. (continued)
7b
8b
H
H
Bn
Ph
Ph
HCl/dioxane
HCl/dioxane
20
10
14a
14a
100
100
PMB
9b
p-MeOPh
Me
Ph
HCl/dioxane
45
73
15a
aIsolated yields. b4 M HCl/dioxane was used.
tuted 1,2-dihydropyrazines containing benzyl and p-methoxy- (Table 2, entries 5 and 6). When we examined the use of an-
benzyl (PMB) ether groups (Table 2, entries 2 and 3). This en- hydrous acidic conditions on 4b and 5, quantitative yields of
hancement in yield can be attributed to the benzyl and PMB Δ5-2-oxopiperazine 14a were obtained (Table 2, entries 7 and
groups’ better sensitivity towards removal under acidic condi- 8). Finally, under these conditions, the trisubstituted dihydro-
tions [32]. With the aqueous acidic conditions not being suit- pyrazine 7a was easily converted to a disubstituted Δ5-2-
able for converting 3-methoxy-1,2-dihydropyrazine 3a, we oxopiperazine 15a in a yield of 73% (Table 2, entry 9).
decided to run this reaction under anhydrous acidic conditions.
After stirring dihydropyrazine 3a in the presence of HCl/ Following the step-wise conversion of 1,2-dihydropyrazines to
dioxane at 0 °C for 30 min, we were pleased to see that Δ5-2- Δ5-2-oxopiperazines, we decided to develop a one-pot ap-
oxopiperazine 14a was obtained in an excellent yield of 93% proach towards their synthesis (Table 3). As described above,
(Table 2, entry 4). Subjecting both benzyl and 2-bromobenzyl- we first synthesized the phenyl-substituted 1,2-dihydropyrazine
substituted dihydropyrazines 3f and 3g to these acidic condi- 4b by adding a phenyl Grignard reagent to benzyloxy-substi-
tions gave 95% and 88% yields of 14b and 14c, respectively tuted N-acylpyrazinium salt in THF at −41 °C. Next,
Table 3: One-pot synthesis of substituted Δ5-2-oxopiperazines.
entry
R
H
product
yield (%)a
1
80
14a
15b
2
Et
80
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Beilstein J. Org. Chem. 2019, 15, 72–78.
Table 3: One-pot synthesis of substituted Δ5-2-oxopiperazines. (continued)
3
Bn
Ph
72
71
15c
15d
4
aIsolated yields.
1 M HCl(aq)/MeOH was added and the reaction was monitored Mount, NC, for their financial support in setting up the BRITE
by TLC. After 1 h, the hydrolysis of 4b was completed to give Institute. HRMS data were obtained at the North Carolina State
14a in a good yield of 80% (Table 3, entry 1). Disubstituted University Department of Chemistry Mass Spectrometry
Δ5-2-oxopiperazines 15b–d can be made similarly with yields Facility.
ranging from 71–80% (Table 3, entries 2–4). This simple ap-
ORCID® iDs
Srinivasa R. Dandepally - https://orcid.org/0000-0002-6943-3029
proach towards Δ5-2-oxopiperazines provides access into com-
pounds that can be reduced into mono- and disubstituted
Alfred L. Williams - https://orcid.org/0000-0001-8998-762X
2-oxopiperazines [33,34]. This structure is a common scaffold
found in natural products and biologically active small mole-
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