Regioselective reduction of 3-substituted N -acylpyrazinium salts toward the synthesis of 1,2-dihydropyrazines

Article abstract of DOI:10.1021/jo202498r

The regioselective reduction of 3-substituted N-acylpyrazinium salts with n-Bu₃SnH has been developed for the synthesis of 3-substituted 1,2-dihydropyrazines in yields of 56-94%. Substitution of the pyrazinium salts with electron-donating group

Full text of DOI:10.1021/jo202498r

Note
pubs.acs.org/joc
Regioselective Reduction of 3-Substituted N-Acylpyrazinium Salts
toward the Synthesis of 1,2-Dihydropyrazines
Alfred L. Williams,*,†,‡ Valentine R. St. Hilaire,‡ and Tina Lee§
‡
†Department of Pharmaceutical Sciences and Biomanufacturing Research Institute and Technology Enterprise, North Carolina
Central University, Durham, North Carolina 27707, United States
§Campbell University College of Pharmacy and Health Sciences, Buies Creek, North Carolina 27506, United States
S
* Supporting Information
ABSTRACT: The regioselective reduction of 3-substituted N-acylpyrazinium salts with
n-Bu3SnH has been developed for the synthesis of 3-substituted 1,2-dihydropyrazines in
yields of 56−94%. Substitution of the pyrazinium salts with electron-donating groups
favors the formation of the 1,2-isomers as a result of their better stability over the 1,6-
isomers. Under mild acidic conditions, 3-methoxy substituted 1,2-dihydropyrazine was
easily hydrolyzed in excellent yield to Δ5-2-oxopiperazine.
he reduction of pyrazinium salts is a useful approach for
synthesizing piperazines.1 This scaffold is classified as a
completed after 40 min, the isolated crude product was
analyzed by 1H NMR to determine the regiochemical outcome
of the reaction. Our NMR analysis of the crude reaction
mixture showed that the reduction produced 1-phenoxycar-
bonyl-3-methoxy-1,2-dihydropyrazine (3a) as the sole re-
gioisomer.11 This result was based on the NMR spectrum
showing a rotameric singlet peak at 4.42 and 4.29 ppm for the
methylene protons at C2 of 3a and a pair of rotameric doublet
peaks at 6.61, 6.56 ppm and 6.10, 6.06 ppm for the two vinyl
protons at C5 and C6 of 3a, respectively. Peaks corresponding
to the formation of 1,6-dihydropyrazine 4a were not observed.
With the identification of the regioisomer now confirmed,
purification of the crude material gave 3a in a good yield of 90%
(Table 1, entry 1).
Excited by our initial results, we went on to explore the
regioselective reduction of other 3-substituted pyrazinium salts.
We discovered that when substituted with a tert-butoxy,
benzyloxy, or phenoxy group, the reactions were completed
within 30 min to 3 h, and only the 1,2-dihydropyrazine
regioisomer was isolated in good to excellent yields ranging
from 78% to 94% (Table 1, entries 2−5). Substitution with a
thio or amino group also gave 1,2-dihydroprazines as the only
product but in lower yields (Table 1, entries 6−8). When the
reduction was carried out with a 3-chloro substituted
pyrazinium salt, Δ5-2-oxopiperazine (5) was isolated instead
of 1,2-dihydroprazine (3i) (Table 1, entry 9). It was suggested
that the formation of 5 came from hydrolyzing the imidoyl
chloride functionality of 3i to an amide group during the
aqueous workup of the reaction. Finally, when subjecting
methyl, phenyl, and cyano substituted pyrazines to our reaction
conditions, no desired products were obtained (Table 1, entry
10−12). The methyl substituted pyrazine produced only an
unidentifiable solid, while substitution with both phenyl and
cyano groups gave no reaction.
T
privileged structure and is present in a number of biologically
active compounds.2 The partial reduction of pyrazinium salts to
generate dihydropyrazines,3 on the other hand, has not received
as much attention compared to reports on the reduction of
pyridinium salts to synthesize dihydropyridines.4 While it has
been shown that 3-substituted pyridinium salts are selectively
reduced to generate 1,2-dihydropyridines,5 studies examining
the regioselective reduction of 3-substituted pyrazinium salts to
produce 1,2-dihydropyrazines are limited.6 A report by Hirano
and Tada mentioned observing the regioselective reduction of
3-cyano-5-(3,4-dimethoxyphenyl)-L-methylpyrazinium fluoro-
sulfonate to give the dihydropyrazine 3-cyano-5-(3,4-dimethox-
yphenyl)-L-methyl-l,6-dihydropyrazine using sodium borohy-
dride or Hantzsch ester, but the authors did not provide any
explanation for their observed selectivity.6b This lack of
information on the regioselective outcome of reducing
substituted activated pyrazines provides a good opportunity
to explore whether this reduction mimics what was observed
with substituted pyridinium salts. Also, because dihydropyr-
azines have been shown to behave as a NPY antagonist and
possess DNA strand-breaking abilities,7 new approaches toward
their synthesis would be quite valuable. As part of our research
program exploring the synthetic utility of pyrazinium salts, we
wish to report our findings on the regoiselective reduction of 3-
substituted N-acylpyrazinium salts.
We began our research effort by first examining the
regiochemical outcome of reducing a pyrazinium salt
substituted with a methoxy group. To carry out the reduction,
we used tributyltin hydride as the reducing agent due to its
reported use for reducing N-acylisoquinolinium salts to
dihydroisoquinolines.8,9 Starting with commercially available
2-methoxypyrazine (1a) in DCM, tributyltin hydride was added
at 0 °C. Phenyl chloroformate was then added to generate the
N-acyl 3-methoxypyrazinium salt, which was then readily
reduced by the tributyltin hydride.10 When the reaction was
Received: December 19, 2011
Published: March 9, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. Reduction of 3-Substituted N-Acylpyrazinium Salts
a
yield (%)
entry
compound
R
time (min)
temp (°C)
3a−l
4a−l
5
1
1a
1b
1c
1d
1e
1f
OMe
40
0
90
94
81
91
78
65
62
56
0
0
0
0
0
0
0
0
0
0
b
c
0
2
O-t-Bu
OBn
35
0
0
0
0
0
0
0
0
46
b
3
50
0
4
OPh
30
0
5
OPh-p-NO2
SCH2CH3
SPh-p-Me
morpholinyl
Cl
3 h
5
rt
0
6
7
1g
1h
1i
10
0
8
15
0
9
18 h
30
0
10
11
12
1j
Me
0−rt
rt
rt
b
1k
1l
Ph
24 h
14 h
c
c
CN
d
d
d
a
b
c
d
Isolated yields. An unidentifiable solid product was isolated. No reaction. Target molecule was not obtained, and 18% of the starting material
was recovered.
Table 2. Acylation Effects on Regioselective Reduction
a
entry
R
time (min)
temp (°C)
product
yield (%)
1
2
3
4
5
OMe
35
45
5
0
0
0
0
0
7a
7b
7c
7d
7e
91
85
OBn
b
Me
74
Ph
60
15
89
93
cyclohexyl
a
b
Isolated yields. Compound 7c sublimes under high vacuum.
We next carried out the reduction with other acylating
reagents and sulfonyl chlorides to determine their effect on the
reactions regioselectivity. We observed that the use of methyl
and benzyl chloroformates (Table 2, entry 1 and 2) along with
acid chlorides (Table 2, entry 3−5) gave only the 1,2-
dihydropyazine isomer in good yield. Unfortunately, when we
tried to use mesyl or tosyl chloride, no reaction occurred, even
after allowing the reaction to stir at rt for 24 h.
From our reaction results, we can see that N-acylpyrazinium
salts substituted with electron-donating groups exclusively gave
N-acyl-1,2-dihydroprazines as the only regioisomer. This
outcome is similar to what was observed by Sundberg et al.
when they reduced 3-substituted pyridinium salts with a variety
of reducing agents.5b They proposed that the electronic nature
of the different substituents at the 3-position influences the
regiochemical outcome and that the observed regioselectivity
was due to the stability of the dihydropyridine products.5b To
study this potential effect on the reduction of 3-substituted
pyrazinium salts, we calculated the energy difference between
1,2- and 1,6-dihydropyrazines using DFT calculations at the
B3LYP/6-31G* level.12 As the data in Table 3 shows, the 1,2-
dihydropyrazine having electron-donating groups are more
stable than their 1,6-adducts. This stability is due to the 1,2-
isomer having the donating substituents lone pair of electrons
in conjugation with the π-system of the dihydropyrazine ring
while the 1,6-isomer lone pair of electrons are in cross-
conjugation with the π-system.5b This stabilizing effect was
calculated to be highest when the dihydropyrazines are
substituted with a thioethyl or morpholinyl group (Table 3,
entries 6 and 8) and lowest for a p-toluenethiol group (Table 3,
entry 7). It is interesting to note that although the stabilizing
effect is highest for the thioethyl and morpholinyl group, the
relative yields of reducing N-acylpyrazinium salts containing
these two substituents are lower (Table 1). This decrease in
yield is apparently due to an increase in the number of
unidentifiable side products during the reaction when these two
groups are present. These results support the fact that the
regioselectivity, during the reduction of the 3-substituted N-
acylpyrazinium salts with tributyltin hydride reduction, depends
on the stability of the products.
With the 1,2-dihydropyrazines in hand, we envisioned that
the embedded imino ether functionality of these compounds
could be easily hydrolyzed to generate Δ5-2-oxopiperazines.
This hydrolysis was based on observed compound 3i being
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The Journal of Organic Chemistry
Note
better solubility that 1 M HCl (aq) in MeOH has over aqueous
1 M HCl in DCM when hydrolyzing 3a.
Table 3. Energy Difference Between 1,2- and 1,6-
Dihydropyrazines
a
In conclusion, we have demonstrated that 3-substituted N-
acylpyrazinium salts are regioselectively reduced by tributyltin
hydride. When the substituents on these compounds are
electron-donating, the 1,2-dihydropyrazine isomer is the only
product produced. The observed selectivity appears to be
controlled by the stability difference between the resulting
possible 1,2- and 1,6-dihydropyrazine products. This reaction
can be carried out with a variety of other acylating reagents
giving only the 1,2-isomer. Under acidic conditions, the 3-
substituted 1,2-dihydropyrazines are easily converted to Δ5-2-
oxopiperazines. Investigation into the synthetic utility of this
reaction is currently underway and will be reported in due
course.
ΔE
ratio
entry isomer
R
E (kcal/mol)
(kcal/mol)
4.95
(3:4)
1
2
3
4
5
6
7
8
9
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
OMe
−501782.29
−501777.34
−575794.58
−575790.52
−646769.63
−646764.86
−622102.22
−622095.76
−750408.16
−750404.67
−729128.31
−729118.69
−849439.81
−849437.51
−609766.16
−609753.12
−718318.23
−718313.69
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
Ot-Bu
4.05
4.77
6.45
3.48
9.62
2.30
13.04
4.55
OBn
OPh
OPh-p-NO2
SCH2CH3
SPh-p-Me
morpholinyl
Cl
4f
EXPERIMENTAL SECTION
3g
4g
3h
4h
3i
■
All solvents and reagents were obtained from commercial sources and
used without further purification unless otherwise stated.14 Toluene
and THF were dried using a solvent purification system. Anhydrous
dichloromethane and all acylating agents were pretreated with K2CO3
́
and 4 Å molecular sieves. All reactions were performed in oven-dried
4i
glassware (either in round-bottom flasks or 25 mL vials fitted with
rubber septa) under an atmosphere of nitrogen, and the reaction
progress was monitored by thin-layer chromatography, GC/MS (EI)
and/or LC/MS (ESI-APCI). Analytical thin-layer chromatography was
performed on precoated 250 μm layer thickness silica gel 60 F254 plates
and precoated 170−220 μm layer thickness neutral aluminum oxide Si
60 F254 plates. Visualization was by ultraviolet light and/or by staining
with phosphomolybdic acid (PMA). Purifications were carried out on
flash silica gel columns (230−400 mesh) with EtOAc/hexanes
mixtures as the eluent that was basified with 0.5−1.5% triethylamine.
Melting points were measured on a capillary melting point apparatus
and are uncorrected. Proton nuclear magnetic resonance (1H NMR)
spectra and carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a 500 MHz spectrometer. Chemical shifts (δ) for
protons are reported in parts per million (ppm) downfield from
tetramethylsilane and are referenced to it (TMS 0.0 ppm). Coupling
constants (J) are reported in hertz. Multiplicities are reported using
the following abbreviations: br = broad; s = singlet; d = doublet; t =
triplet; q = quartet; m = multiplet. Chemical shifts (δ) for carbon are
reported in parts per million (ppm) downfield from tetramethylsilane
and are referenced to residual solvent peaks (CDCl3 77.0 ppm).
a
Total energies were obtained by DFT calculations at the B3LYP/6-
31G* level.
converted to compound 5 during the aqueous workup. The Δ5-
2-oxopiperazines structure can be used as a building block for
the synthesis of a number of small molecules and natural
products.13
When we treated 1-phenoxycarbonyl-3-benzyloxy-1,2-dihy-
dropyrazine (3a) with aqueous 1 M HCl, phenyl 2-oxo-1,3-
dihydropyrazine-4-carboxylate (5) was formed very rapidly and
in an excellent yield of 94% (Scheme 1). The success of our
Scheme 1. Hydrolysis of 1-Phenoxycarbonyl-3-methoxy-1,2
Dihydropyrazine (3a)
1
Rotameric ratios of all compounds were determined by H NMR.
HRMS data was recorded on an LC-TOF. Elemental analyses were
carried out on an elemental analyzer.
Procedures for the Synthesis of 2-Substituted Pyrazines 1e
and 1g. 2-(p-Nitrophenoxy)pyrazine (1e). 2-Chloropyrazine
(1.0 g, 8.73 mmol), p-nitrophenol (1.8 g, 12.94 mmol), and
sodium hydride (0.7 g, 17.50 mmol) in 8 mL of DMF (anhyd)
were heated to 120 °C under nitrogen for 20 h. The reaction
mixture was quenched into 10 g of ice, extracted into diethyl
ether (2 × 15 mL), washed with 3 M NaOH, dried over sodium
sulfate, and then concentrated in vacuo. The crude material was
purified by flash silica gel column chromatography (0−50%
EtOAc/hexanes) to afford 1e (0.616 g, 33%) as a white
hydrolysis of 3a prompted us to develop a one-pot approach
toward synthesizing 5 (Scheme 2). As described above, we first
generated 1,2-dihydropyrazine (3a) from 2-methoxypyrazine
(1a) in DCM. Next, aqueous 1 M HCl was added at 0 °C, and
the reaction was monitored by TLC. After 2 h, the hydrolysis of
3a was completed to give 5 in a good yield of 84%. While
examining other hydrolyzing conditions, we found that we
could greatly shorten the reaction time to 5 min and increase
the yield to 92% when 1 M HCl (aq) in MeOH was used. We
attribute this improvement in yield and reaction time to the
1
crystalline solid: mp 105−106 °C; H NMR (CDCl3, 500
MHz) δ 8.54 (s, 1H), 8.39 (s, 1H), 8.31 (d, J = 9.0 Hz, 2H),
Scheme 2. One-Pot Synthesis of Phenyl 2-oxo-1,3-dihydropyrazine-4-carboxylate (5)
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Note
8.15 (s, 1H), 7.34 (d, J = 9.0 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ 158.9, 158.2, 144.7, 141.0, 140.0, 136.4, 125.6, 121.4;
HRMS (ESI) m/z calcd for C10H8N3O3 [M + H]+ 218.0562,
found 218.0560.
1-Phenoxycarbonyl-3-phenoxy-1,2-dihydropyrazine (3d).
91% yield; white crystalline solid (64:36 mixture of rotamers); mp
1
128−129 °C; H NMR (CDCl3, 500 MHz) δ 7.45−7.35 (m, 4H),
7.29−7.12 (m, 6H), 6.63 and 6.59 (two doublets due to rotamers, J =
5.0 and 5.5 Hz, 1H), 6.01 and 5.98 (two doublets due to rotamers, J =
5.5 and 5.0 Hz, 1H), 4.66 and 4.52 (two singlets due to rotamers, 2H);
13C NMR (CDCl3, 125 MHz) δ 158.6, 158.1, 151.8, 151.3, 150.7,
2-(p-Tolylsulfanyl)pyrazine (1g). p-Tolylthiol (1.20 g, 9.66
mmol) was added to a slurry of sodium hydride (0.7 g, 17.50
mmol) in 5 mL of dimethoxyethane, and the mixture heated to 45−50
°C under nitrogen. A solution of 2-chloropyrazine (1.0 g, 8.73 mmol)
in 3 mL of dimethoxyethane was then added over 10 min, and heating
was continued for 5 h. The reaction mixture was quenched into 10 g of
ice, extracted into diethyl ether (2 × 15 mL), dried over sodium
sulfate, and then concentrated in vacuo. The crude material was
purified by flash silica gel column chromatography (0−15% EtOAc/
hexanes) to afford 1g (1.71 g, 97%) as a white crystalline solid: mp
150.6, 129.5, 129.5, 126.0, 125.9, 121.7, 121.5, 121.4, 118.0, 117.9,
113.5, 113.1, 42.9, 42.1; HRMS (ESI) m/z calcd for C17H15N2O3 [M +
H]+ 295.1077, found 295.1077.
1-Phenoxycarbonyl-3-(p-nitrophenol)-1,2-dihydropyrazine
(3e). 78% yield; white crystalline solid (62:38 mixture of rotamers);
mp 157−158 °C; 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J = 9.0 Hz,
2H), 7.52−7.33 (m, 4 H), 7.33−723. (m, 1H), 7.23−7.08 (m, 2H),
6.70 and 6.45 (two doublets due to rotamers, J = 5.0 Hz, J = 5.0 Hz
1H,), 5.99 and 5.96 (two doublets due to rotamers, J = 5.5 Hz, J = 5.0
Hz, 1H), 4.70 and 4.56 (two singlets due to rotamers, 2H); 13C NMR
(CDCl3, 125 MHz) δ 157.2, 156.6, 151.3, 151.2, 150.6, 145.2, 129.4,
126.1, 125.3, 122.6, 122.6, 121.4, 117.1, 117.0, 114.6, 114.2, 42.8, 41.9;
HRMS (ESI) m/z calcd for C17H14N3O5 [M + H]+ 340.0928, found
340.0932.
1-Phenoxycarbonyl-3-thioethyl-1,2-dihydropyrazine (3f).
65% yield; clear light-yellow oil (64:36 mixture of rotamers); 1H
NMR (CDCl3, 500 MHz) δ 7.38 (t, J = 7.5 Hz, 2H), 7.24 (t, 7.5 Hz, J
= 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.64 and 6.59 (two doublets
due to rotamers, J = 5.5 Hz, 1H), 6.43 and 6.38 (two doublets due to
rotamers, J = 5.5 Hz, 1H), 4.35 and 4.23 (two singlets due to rotamers,
2H), 3.01−3.11 (m, 2H), 1.30−1.39 (m, 3H); 13C NMR (CDCl3, 125
MHz) δ 158.7, 157.8, 151.5, 151.2, 150.7, 150.5, 129.5, 126.0, 125.9,
122.0, 121.5, 121.4, 114.4, 113.8, 45.7, 44.8, 23.9, 23.8, 14.0; HRMS
(ESI) m/z calcd for C13H15N2O2S [M + H]+ 263.0849, found
263.0854.
1-Phenoxycarbonyl-3-thiotolyl-1,2-dihydropyrazine (3g).
62% yield; light-yellow semisolid (67:43 mixture of rotamers); 1H
NMR (CDCl3, 500 MHz) δ 7.44 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0
Hz, J = 7.5 Hz, 3H), 7.27−7.15 (m, 3H), 7.12 (d, d, J = 8.0 Hz, 2H),
6.63 and 6.58 (two doublets J = 5.5 Hz, J = 5 Hz, 1H), 6.38 and 6.33
(two doublets J = 5.0 Hz, 1H), 4.37 and 4.23 (two singlets due to
rotamers, 2H), 2.37 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.2,
158.0, 151.3, 150.7, 140.2, 135.2, 135.2, 135.0, 130.7, 130.3, 129.5,
126.0, 123.6, 123.4, 122.4, 121.9, 121.4, 114.8, 114.1, 44.9, 43.9, 29.7,
21.4; HRMS (ESI) m/z calcd for C18H17N2O2S [M + H]+ 325.1005,
found 325.1001.
1
30−32 °C; HNMR CDCl3 (500 MHz) δ 8.32 (s, 1H), 8.21 (s, 1H),
8.17 (s, 1H), 7.50 (d, J = 8 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 2.40 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 159.2, 143.8, 142.6, 140.1,
139.9, 135.2, 130.7, 125.2, 21.4. HRMS (ESI) m/z calcd for
C11H11N2S [M + H]+ 203.0637, found 203.0637.
General Procedure for the Reduction of 3-Substituted N-
Acylpyrazinium Salts To Synthesize 1,2-Dihydropyrazines
(3a−3h). Representative Procedure for the Preparation of
1-Phenoxycarbonyl-3-methoxy-1,2-dihydropyrazine (3a). To a
solution of 2-methoxypyrazine (1a) (112 mg, 1.017 mmol) in
2.5 mL of anhydrous dichloromethane was added tributyltin
hydride (330 μL, 1.208 mmol), and the resulting solution was
stirred under nitrogen at 0 °C. Phenyl chloroformate (190 μL,
1.510 mmol) in 0.5 mL of dichloromethane was added over 15
min, and the reaction was allowed to stir at 0 °C. The reaction
was completed in 40 min, as determined by TLC (neutral
alumina, EtOAc/hexanes (1/19, v/v)), and then quenched with
1.5 mL of aqueous 20% NH4OH/NH4Cl (1/1, w/w). The
solution was extracted with dichloromethane (2 × 15 mL),
dried over Na2SO4, and concentrated in vacuo. Purification of
the crude mixture by flash silica gel column chromatography
(0−15% EtOAc/hexanes) afforded 3a (213.5 mg, 90%) as a
white crystalline solid (65:35 mixture of rotamers): mp 48−49
°C; 1H NMR (CDCl3, 500 MHz) δ 7.37 (t, J = 7.5 Hz, J = 8.5
Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.59
and 6.54 (two doublets due to rotamers, J = 6.0 Hz, J = 5.5 Hz,
1H), 6.08 and 6.03 (two doublets due to rotamers, J = 5.0 Hz, J
= 5.5 Hz, 1H), 4.39 and 4.26 (two singlets due to rotamers,
2H), 3.84 and 3.83 (two singlets due to rotamers, 3H); 13C
NMR (CDCl3, 125 MHz) δ 159.4, 158.9, 151.4, 151.3, 150.8,
150.6, 129.4, 125.9, 125.9, 121.5, 121.4, 118.4, 118.3, 112.8,
112.4, 53.8, 53.7, 42.8, 42.0; HRMS (ESI) m/z calcd for
C12H13N2O3 [M + H]+ 233.0926, found 233.0921.
1-Phenoxycarbonyl-3-morpholinyl-1,2-dihydropyrazine
1
(3h). 56% yield; off-white semisolid (78:22 mixture of rotamers); H
NMR (CDCl3, 500 MHz) δ 7.38 (t, J = 8.0 Hz, 2H), 7.24 (t, J = 7.5
Hz, 2H), 7.13 (d, J = 8 Hz, 2H), 6.45 and 6.40 (two doublets due to
rotamers, J = 5.0 Hz, J = 5.5 Hz, 1H), 6.22 and 6.19 (two doublets due
to rotamers, J = 5.5 Hz, J = 5.0 Hz, 1H), 4.47 and 4.33 (two singlets
due to rotamers, 2H), 3.76 and 3.74 (two triplets due to rotamers, J =
7.0 Hz, J = 7.5 Hz, 4H), 3.52 (t, J = 7.0 Hz, J = 7.5 Hz, 4H); 13C NMR
(CDCl3, 125 MHz) δ 153.0, 152.5, 151.8, 151.4, 150.9, 150.6, 129.8,
129.5, 129.5, 129.4, 126.2, 126.0, 125.8, 121.7, 121.6, 121.5, 124.3,
120.1, 115.4, 109.1, 108.6, 67.4, 66.4, 66.3, 45.4, 44.9, 44.8, 40.7, 39.7;
HRMS (ESI) m/z calcd for C15H18N3O3 [M + H]+ 288.1343, found
288.1341.
1-Phenoxycarbonyl-3-tert-butoxy-1,2-dihydropyrazine (3b).
1
94% yield; clear colorless oil (67:33 mixture of rotamers); H NMR
(CDCl3, 500 MHz) δ 7.37 (t, J = 7.5 Hz, J = 8.0 Hz, 2H), 7.23 (t, J =
8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.53 and 6.47 (two doublets due
to rotamers, J = 5.0 Hz, J = 5.5 Hz, 1H), 6.05 and 6.01 (two doublets
due to rotamers, J = 5.5 Hz, 1H), 4.25 and 4.12 (two singlets due to
rotamers, 2H), 1.55 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 157.40,
156.89, 151.55, 151.37, 150.87, 150.70, 129.57, 129.42, 125.80, 121.54,
121.47, 120.91, 119.15, 111.72, 111.36, 82.01, 43.31, 42.51, 28.13;
HRMS (ESI) m/z calcd for C15H18NaN2O3 [M + Na]+ 297.1215,
found 297.1225.
Phenyl 2-oxo-1,3-dihydropyrazine-4-carboxylate (5). Sub-
jecting 2-chloropyrazine 1i (250 mg, 2.183 mmol) to the above
procedure and purification of the crude mixture by flash silica gel
column chromatography (0−75% EtOAc/hexanes) gave 5 (218.1 mg,
46%) as a white crystalline solid (56:44 mixture of rotamers): mp
1-Phenoxycarbonyl-3-benzyloxy-1,2-dihydropyrazine (3c).
91% yield; white crystalline solid (64:36 mixture of rotamers); mp
1
1
76−78 °C; H NMR (CDCl3, 500 MHz) δ 7.43−7.30 (m 7 H), 7.22
170−172 °C; H NMR (CDCl3, 500 MHz) δ 8.02 and 7.88 (two
(t, J = 7.0 Hz, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.61 and 6.56
(two doublets due to rotamers, J = 6.0 Hz, 1H), 6.10 and 6.06 (two
doublets due to rotamers, J = 5.5 Hz, J = 5.0 Hz, 1H), 5.26 (s, 2H),
4.44 and 4.32 (two singlets due to rotamers, 1H); 13C NMR (CDCl3,
125 MHz) δ 158.6, 158.2, 151.4, 151.3, 150.8, 150.6, 135.8, 129.5,
128.6, 128.6, 128.4, 128.3, 128.3, 128.2, 125.9, 121.5, 121.4, 118.4,
118.2, 113.1, 112.6, 68.4, 68.3, 42.9, 42.2. Anal. Calcd for C18H16N2O3:
C, 70.12; H, 5.23; N, 9.09. Found: C, 70.09; H, 5.24; N, 9.16
broad singlets due to rotamers, 1H), 7.39 (t, J = 7.5 Hz, J = 8.0 Hz,
2H), 7.25 (t, J = 6.5 Hz, J = 7.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.51
and 6.47 (two doublets due to rotamers, J = 6.0 Hz, 1H), 5.72 and
5.67 (two triplets due to rotamers, J = 5.0 Hz, J = 5.5 Hz, 1H), 4.51
and 4.38 (two singlets due to rotamers, 2H); 13C NMR (CDCl3, 125
MHz) δ 164.9, 164.5, 151.5, 151.3, 150.7, 150.6, 129.5, 126.0, 121.4,
121.4, 109.1, 108.7, 108.3, 47.6, 46.9. Anal. Calcd for C11H10N2O3: C,
60.55; H, 4.94; N, 12.84. Found: C, 60.64; H, 4.80; N, 12.54.
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The Journal of Organic Chemistry
Note
General Procedure for the Synthesis of N-Acyl-3-Methoxy-
1,2-Dihydropyrazines (7a−7e). Representative Procedure for
the Preparation of 1-Methoxycarbonyl-3-methoxy-1,2-dihy-
dropyrazine 7a. To a solution of 2-methoxypyrazine (1a) (112
mg, 1.017 mmol) in 2.5 mL of anhydrous dichloromethane was
added tributyltin hydride (330 μL, 1.208 mmol), and the
resulting solution was stirred under nitrogen at 0 °C. Methyl
chloroformate (125 μL, 1.569 mmol) in 0.5 mL of dichloro-
methane was added over 5 min, and the reaction was allowed to
stir at 0 °C. The reaction was completed in 45 min, as
determined by TLC (neutral alumina, EtOAc/hexanes (1/19,
v/v)), and then quenched with 1.5 mL of aqueous 20%
NH4OH/NH4Cl (1/1, w/w). The solution was extracted with
dichloromethane (2 × 15 mL), dried over Na2SO4, and
concentrated in vacuo. Purification of the crude mixture by flash
silica gel column chromatography (0−15% EtOAc/hexanes)
afforded 7a (158.1 mg, 91%) as a clear colorless oil (62:38
mixture of rotamers): 1H NMR (CDCl3, 500 MHz) δ 6.50 and
6.37 (two doublets due to rotamers, J = 5.5 Hz, J = 5.0 Hz,
1H), 5.99 and 5.92 (two doublets due to rotamers, J = 5.0 Hz, J
= 5.5 Hz, 1H), 5.22 (s, 2H), 4.19 and 4.17 (two singlets due to
rotamers, 2H), 3.81 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 159.2, 158.7, 153.5, 153.4, 117.4, 117.4, 113.2,
112.6, 53.6, 53.4, 42.3, 41.9; HRMS (ESI) m/z calcd for
C7H10N2O3 [M + H]+ 171.0764, found 171.0766.
Na2SO4, and concentrated in vacuo. Purification of the crude mixture
by flash silica gel column chromatography (0−75% EtOAc/hexanes)
afforded 5 (132.7 mg, 94%) as a white crystalline solid.
One-Pot Synthesis of 4-Phenoxycarbonyl-1,2-dihydro-2-
pyrazinone 5. To a solution of 2-methoxypyrazine (1a) (112 mg,
1.017 mmol,) in 2.5 mL of anhydrous dichloromethane was added
tributyltin hydride (330 μL, 1.208 mmol), and the resulting solution
was stirred under nitrogen at 0 °C. Phenyl chloroformate (190 μL,
1.510 mmol) in 0.5 mL of dichloromethane was added over 15 min,
and the reaction was allowed to stir at 0 °C. Formation of 1,2-
dihydropyrazine 3a was completed in 25 min, as determined by TLC
(neutral alumina, EtOAc/hexanes (1/19, v/v)). Next, 1 M HCl in
methanol (1.5 mL, 1.5 mmol) was added at 0 °C. The hydrolysis
reaction was completed in 5 min, as determined by TLC (silica gel,
EtOAc/hexanes (2/3, v/v)). Water (1.0 mL) was added, and the
reaction mixture was extracted with dichloromethane (2 × 10 mL).
The organic layer was washed with saturated sodium bicarbonate (1.0
mL), dried over Na2SO4, and concentrated in vacuo. Purification of the
crude mixture by flash silica gel column chromatography (0−75%
EtOAc/hexanes) afforded 5 (200.9 mg, 91%) as a white crystalline
solid.
ASSOCIATED CONTENT
■
S
* Supporting Information
Total energies and Cartesian coordinates; copies of 1H and 13
C
1-Benzyloxycarbonyl-3-methoxy-1,2-dihydropyrazine (7b).
1
NMR of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
85% yield; clear colorless oil (61:39 mixture of rotamers); H NMR
(CDCl3, 500 MHz) δ 7.41−7.29 (m, 5H), 6.51 and 6.41 (two doublets
due to rotamers, J = 5.0, 1H), 5.99 and 5.91 (two doublets due to
rotamers, J = 5.0 Hz, 1H), 5.21 (s, 2H), 4.20 (s, 2H), 3.80 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 159.2, 158.7, 152.9, 152.7, 135.8, 135.7,
128.6, 128.5, 128.4, 128.3, 128.2, 117.5, 117.4, 113.1, 112.6, 68.0, 53.6,
42.3, 41.9; HRMS (ESI) m/z calcd for C13H14N2O3 [M + H]+
247.1077, found 247.1077.
AUTHOR INFORMATION
Corresponding Author
*E-mail: awilliams@nccu.edu.
■
Notes
1-Acetyl-3-methoxy-1,2-dihydropyrazine (7c). 74% yield;15
white crystalline solid (89:11 mixture of rotamers); mp 51−53 °C; 1H
NMR (CDCl3, 500 MHz) δ 6.77 and 6.23 (two doublets due to
rotamers, J = 5.5 Hz, 1H), 6.06 and 6.00 (two doublets due to
rotamers, J = 6.0 Hz, J = 5.5 Hz, 1H), 4.25 and 4.20 (two singlets due
to rotamers, 2H), 3.83 and 3.82 (two singlets due to rotamers, 3H),
2.17 and 2.13 (two singlets due to rotamers, 3H); 13C NMR (CDCl3,
125 MHz) δ 168.2, 168.0, 160.6, 158.6, 118.7, 118.7, 113.0, 111.9,
53.8, 53.6, 44.0, 40.5, 21.6, 20.9; HRMS (ESI) m/z calcd for
C7H10N2O2 [M + H]+ 155.0815, found 155.0816.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Golden LEAF Foundation,
Rocky Mount, NC, for financial support in setting up the
BRITE Institute. We thank Dr. Li-An Yeh, Director, BRITE, for
the encouragement and support. HRMS data were obtained at
the North Carolina State University Department of Chemistry
Mass Spectrometry Facility.
1-Phenylcarbonyl-3-methoxy-1,2-dihydropyrazine (7d). 89%
1
yield; off-white solid, mp 56−58 °C; H NMR (CDCl3, 500 MHz) δ
REFERENCES
■
7.55−7.28 (m 5H), 6.17 (s, 1H), 5.94 (s, 1H), 4.38 (s, 2H), 3.86 (s,
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128.7, 128.5, 118.3, 114.9, 53.8, 41.6; HRMS (ESI) m/z calcd for
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4102
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