Regioselective synthesis of trialkylpyrazines via nickel-catalyzed Negishi cross-coupling of pyrazine triflate

Article abstract of DOI:10.1055/s-0031-1290972

A regioselective synthesis of trialkylpyrazines via nickel-catalyzed cross-coupling reaction of pyrazine triflate is reported. The 5-substituted 2,3-dimethylpyrazine derivatives including trail pheromone components of the ant Eutetramorium mocquerysi have been successfully synthesized in good yields by nickel-catalyzed Negishi cross-coupling reactions of pyrazine triflate mediated by alkyl and arylzinc halides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290972

PAPER
▌1631
paper
Regioselective Synthesis of Trialkylpyrazines via Nickel-Catalyzed Negishi
Cross-Coupling of Pyrazine Triflate
Regioselective Synthesis of Trialkylpyrazines
Arigala Pitchaiah, In Taek Hwang, Jin-Soo Hwang, Hyungrok Kim, Kee-In Lee*
Green Chemistry Division, Korea Research Institute of Chemical Technology, P. O. Box 107, Yusong, Taejon 305-600, Korea
Fax +82(42)8607034; E-Mail: kilee@krict.re.kr
Received: 05.03.2012; Accepted after revision: 28.03.2012
carbon bonds in the synthesis of highly functionalized
Abstract: A regioselective synthesis of trialkylpyrazines via nickel-
aromatic and heterocyclic compounds. The cross-cou-
catalyzed cross-coupling reaction of pyrazine triflate is reported.
pling reaction usually proceeds under mild reaction con-
ditions and the key advantage is the exceptional tolerance
The 5-substituted 2,3-dimethylpyrazine derivatives including trail
pheromone components of the ant Eutetramorium mocquerysi have
been successfully synthesized in good yields by nickel-catalyzed of most functional groups. Thus, a number of functional-
Negishi cross-coupling reactions of pyrazine triflate mediated by al-
kyl and arylzinc halides.
ized pyrazine molecules have been prepared by transition-
metal-catalyzed cross-coupling reaction using halopyr-
azines,4a,8 and also by direct arylation process using pyr-
Key words: trialkylpyrazine, pheromone, Negishi cross-coupling,
pyrazine triflate, organozinc halide
azine N-oxides9 and pyrazines.10 Even though the cross-
coupling reactions work very effectively for the synthesis
of 2,5-dimethylpyrazine analogues,4a,8a,c the synthesis of
Pyrazine molecules are ubiquitously distributed in plants, 5-alkyl-2,3-dimethylpyrazines has not been documented
animals, and microorganisms, and show a wide range of clearly up to date.3a Herein, we wish to report nickel-cat-
biological properties.1 Among them, a large number of tri- alyzed synthesis of 5-alkyl-2,3-dimethylpyrazines from
alkylpyrazines have been identified mostly as flavor com- the corresponding pyrazine triflate with organozinc or
ponents in many food stuffs2 and trail pheromone Grignard reagents.11
components in various species of ants.3 Recent explora-
Halopyrazines are very important starting materials for
tions have revealed that volatiles in the headspace bou-
their ability to undergo nucleophilic substitution and tran-
quets released by marine bacteria are composed of several
sition metal-catalyzed cross-coupling reactions. Most fre-
alkylated and methoxypyrazines as the major compo-
quently, chloropyrazines are prepared by halogenation of
nents.4 It has been suggested that the bacterial volatiles are
pyrazine N-oxides by treating with phosphoryl chloride
possibly involved in cell-to-cell communication with oth-
under refluxing conditions.4a However, 5-chloropyrazine
er organisms in order to influence populations, communi-
has been obtained in very low yield from 2,3-dimethyl-
ties, and ecosystems.5 Due to their interesting structural
pyrazine, since the N-oxide affords two regioisomeric
chlorides, in which chlorination takes place preferentially
features and unique sensory properties, regiocontrolled
synthesis of trialkylpyrazines has elicited much attention.
on the methyl group over the ring.12 Our attention was
Unsymmetrical alkylpyrazines were frequently produced turned to a facile synthesis of 5-hydroxypyrazine as an al-
from pyrazines by the treatment of alkyllithium or ternative.13,14 Although the condensation 1,2-dicarbonyls
Grignard reagents, while the outcomes were over- with α-amino acid amides was commonly employed for
whelmed with the disadvantages such as incomplete con- the synthesis of 5-hydroxy-2,3-dimethylpyrazine (3), this
version and formation of isomers, which may cause route also suffered from low yields.14 Therefore, fine-
troublesome purification of the product.2a,3a,6 To over- tuning of the reaction conditions was necessary in order to
come the regioselectivity problem, much effort has been improve the yield.
expended on multistep synthetic sequences. Thus, the re-
giocontrolled synthesis of trialkylpyrazines has been con-
When glycinamide hydrochloride (2) was used without
pretreatment with alkali, the yield was considerably lower
ducted based upon thermal electrocyclization of 1-
as previously described. Surprisingly, when glycinamide
hydroxy-1,4-diazahexatrienes, pyrolysis of 2-norbornyl-
was regenerated from its hydrochloride by addition of
3,5-dimethylpyrazines, zirconium-mediated reactions of
aqueous sodium hydroxide in methanol prior to mixing
alkylpyrazines and alkynes, and cyclocondensation of 2-
with butane-1,2-dione (1), the yield was greatly improved
aminoketones with 2-nitroketones using an electron-
as 81%. A similar phenomenon was previously observed
transfer reagent, respectively.7
in the selective formation of 5-hydroxypyrazines.15 The
Transition-metal-catalyzed cross-coupling reaction is one reason is unclear; however, it is interesting to note that the
of the most powerful tools for constructing new carbon– readily available nitrogen dominate the formation of the
products at very initial conditions in terms of selectivity
and reactivity. Some efforts on the chlorination of 3 (e.g.,
SYNTHESIS 2012, 44, 1631–1636
Advanced online publication: 08.05.2012
DOI: 10.1055/s-0031-1290972; Art ID: SS-2012-F0234-OP
© Georg Thieme Verlag Stuttgart · New York
POCl3, POCl3/PCl5, POCl3–pyridine, SOCl2/benzotri-
azole) were unsuccessful, in turn triflation was readily
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1632
A. Pitchaiah et al.
PAPER
achieved by the treatment of trifluoromethanesulfonic an-
Table 1 Nickel-Catalyzed Cross-Coupling Reactions of 4 with Or-
hydride in the presence of pyridine as shown in Scheme 1. ganometallic Reagentsa
RM (3 equiv)
N
NiCl2(dppp) (5 mol%)
THF, r.t., 12 h
ClH3N
H2N
O
O
N
aq 15 N NaOH
MeOH, –30 °C
4
+
N
R
O
N
OH
5
1
2
3 (81%)
Yield (%)b
38
Entry RM
Product 5
N
Tf2O, pyridine
CHCl3, –78 °C
N
N
N
OTf
Me2Zn
1
2
4 (80%)
Scheme 1 Synthesis of pyrazine triflate (4)
5a
N
The triflate 4 was readily cross-coupled with different
types of organometallics by the catalysis of [1,3-bis(di-
phenylphosphino)propane]dichloronickel(II) [NiCl2(dppp)]
and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4]
to afford 5-subsituted 2,3-dimethylpyrazines and the re-
sults are summarized in Tables 1 and 2. All reactions were
carried out using 3 equivalents of organometallic reagents
in the presence of 5 mol% of the catalyst in tetrahydrofu-
ran where the employed reagents were all available from
commercial suppliers. The Negishi cross-coupling reac-
tion of 4 was first investigated using primary and second-
ary dialkylzinc (R2Zn) with NiCl2(dppp) as catalyst. The
reactions with dialkylzincs proceeded efficiently leading
to the formation of the desired 5-alkylpyrazines, however
the yield was moderate (Table 1, entries 1–3). When al-
kylzinc halide (RZnX) was used instead, the result
showed an increased yield of the corresponding trialkyl-
pyrazines (entries 4–9). All synthesized trialkylpyrazines
5a–f were volatile under reduced pressure, and thus ob-
tained from chromatographic fractions by slow evapora-
tion in a stream of nitrogen. Even though the use of tert-
butylzinc bromide was unsuccessful, the primary and sec-
ondary alkylzinc halides consistently gave superior re-
sults. On the other hand, when Grignard reagents were
used in place of zinc, the reactions were incomplete and
the yields decreased considerably (entries 10 and 11).
Thus, it was found that alkylzinc halides participated
more efficiently in the nickel-catalyzed Negishi cross-
coupling with pyrazine triflate.
Et2Zn
45
63
N
5b
N
N
3
Zn
5c
5a
4
5
MeZnBr
EtZnBr
61
71
5b
6
5c
72
ZnBr
N
ZnBr
7
74
N
5d
N
N
8
9
74
81
ZnBr
5e
N
ZnBr
N
5f
10
11
EtMgBr
5b
38
35
Whereas we evaluated the same strategy using the palla-
dium catalyst, a dramatic difference was observed in the
cases of secondary alkylzinc bromides. The Negishi
cross-coupling with isopropylzinc bromide under the
palladium catalyst resulted in a chromatographically sep-
arable mixture of 5-isopropylpyrazine 5c and 5-propyl-
pyrazine 5d in 18 and 38% yield, respectively (Table 2,
entry 2). The coupling with sec-butylzinc also resulted in
accompanying alkyl group isomerization from secondary
to primary, in which 5-butylpyrazine (5f) was predomi-
nant (entry 3).
5c
MgCl
a All reactions were performed with pyrazine triflate 4 (1 mmol), or-
ganometallic (RM, 3 mmol), NiCl2(dppp) (5 mol%) in THF (3 mL).
b Isolated yield.
metals, it is of great value to develop such site-selective
cross-coupling reactions. Currently, palladium and nickel
complexes are known to catalyze isomerization of sec-
ondary alkyl regents to primary ones through a β-hydride
elimination/hydrometallation sequence (path b),16 which
thus compete with desired reductive elimination process
(path a), as illustrated in Scheme 2. It is interesting to note
that nickel-catalyzed Negishi cross-coupling reactions
In turn, considering the number of observations of alkyl
group isomerization in metal-catalyzed cross-coupling re-
actions of alkenyl and aryl halides with secondary alkyl-
Synthesis 2012, 44, 1631–1636
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Synthesis of Trialkylpyrazines
1633
with secondary alkylzinc halides bearing β-hydrogen pro- aration of trisubstituted pyrazines via organozinc mediat-
duced the corresponding 5-alkylpyrazines as the sole ed cross-coupling under the nickel-catalyst, and also
products in good yields, without any isomerization of the achieved a significant improvement for the synthesis of 5-
alkyl groups (entries 6 and 8, Table 1).
hyroxypyrazine from the condensation of glycinamide
with butane-1,2-dione. This provides a ready access to re-
giocontrolled synthesis of trialkylpyrazines, which show
interesting sensory properties in nature.
Table 2 Palladium-Catalyzed Cross-Coupling Reactions of 4 with
Alkylzinc Bromidesa
RZnBr (3 equiv)
Pd(PPh3)4 (5 mol%)
Table 3 Nickel-Catalyzed Cross-Coupling Reactions of 4 with
4
5
Alkyl- and Arylzinc Bromidesa
THF, r.t., 12 h
RZnBr (3 equiv)
Yield (%)b
46
NiCl2(dppp) (5 mol%)
Entry
1
RZnX
Product 5
4
5
THF, r.t., 12 h
5d
ZnBr
RZnBrb
Yield (%)c
78
Entry
Product (5)
56c
43d
2
3
5c + 5d
5e + 5f
ZnBr
N
N
ZnBr
1
2
ZnBr
a All reactions were performed with pyrazine triflate 4 (1 mmol),
RZnBr (3 mmol), Pd(PPh3)4 (5 mol%) in THF (3 mL).
b Isolated yield.
5g
N
ZnBr
c Combined yield of 5c (18%) and 5d (38%).
d Combined yield of 5e (15%) and 5f (28%).
83
82
N
5h
N
R
R
R
CH2CH2R
Pd(Ln)
Pd(0)
N
3
4
H
Pd(Ln)
Pd(Ln)
a
ZnBr
ZnBr
b
5i
N
N
N
N
R
N
N
R
72
85
ZnBr
Scheme 2 Alkyl group isomerization of secondary alkylzinc halides
with Pd(PPh3)4
5j
N
The scope of this protocol for synthesis of structurally di-
versified pyrazine derivatives was demonstrated next. All
alkyl- and arylzinc bromides used were prepared by trans-
metallation of the corresponding Grignard reagents with
activated zinc bromide in tetrahydrofuran,17 and were
used in situ for the coupling reactions. A range of alkyl
and arylzinc halides containing electronically and steri-
cally demanding groups proved to be compatible with this
operation as shown in shown in Table 3. Among them are
trail pheromone components 5g–i, eliciting trail-follow-
ing behavior in various species of ants.3a It was also found
that cycloalkyl, aromatic, and heteroaromatic substrates
were uniformly cross-coupled without any problem.
N
5
6
7
ZnBr
5k
N
MeO
N
73
78
ZnBr
OMe
5l
N
F
N
F
ZnBr
In summary, we have examined the nickel- and palladi-
um-catalyzed cross-coupling reactions of pyrazine triflate
using organozinc and Grignard reagents. It was found that
5-substituted 2,3-dimethylpyrazines was efficiently pre-
pared by nickel-catalyzed Negishi cross-coupling reaction
with alkyl and arylzinc reagents, and the alkyl group
isomerization took place in palladium-catalyzed cross-
coupling reactions with secondary alkylzinc halides.
Thus, we have disclosed a simple procedure for the prep-
5m
N
N
8
62
ZnBr
5n
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1631–1636

1634
A. Pitchaiah et al.
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Table 3 Nickel-Catalyzed Cross-Coupling Reactions of 4 with
sultant reaction mixture was stirred for 2 h at –78 °C and at r.t. for
30 min. The reaction was quenched with ice water (20 mL) and the
organic layer was extracted with CH2Cl2 (2 × 20 mL). The com-
bined organic extracts were washed with brine (2 × 20 mL) and
dried (MgSO4). The solvents were filtered and removed by reduced
pressure resulted residue. The crude residue was purified by flash
silica gel chromatography (Et2O–hexane, 15:85) to give 4 (1.82 g,
80%) as an oil.
1H NMR (300 MHz, CDCl3): δ = 8.28 (s, 1 H), 2.60 (s, 3 H), 2.56
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.6, 151.9, 150.7, 133.1, 118.5
(d, J = 318.6 Hz), 21.7, 21.5.
Alkyl- and Arylzinc Bromidesa (continued)
RZnBr (3 equiv)
NiCl2(dppp) (5 mol%)
4
5
THF, r.t., 12 h
RZnBrb
Yield (%)c
82
Entry
Product (5)
N
N
ZnBr
9
EI-MS: m/z (%) = 256 (M+, 100), 246 (5), 228 (42), 95 (11), 82 (56),
5o
69 (47).
N
EI-HRMS: m/z calcd for C7H7F3N2O3S: 256.0129; found:
256.0123.
N
10
74
S
ZnBr
S
Nickel- and Palladium-Catalyzed Cross-Coupling of 4 with
Organometallics; General Procedure
5p
In
a
flame-dried flask, the triflate
4
(1 mmol) and
a All reactions were performed with pyrazine triflate 4 (1 mmol),
RZnBr (3 mmol), NiCl2(dppp) (5 mol%) in THF (3 mL).
b All alkyl- and arylzinc bromides were prepared by transmetallation
of the corresponding Grignard reagents (1 equiv) with anhyd ZnBr (1
equiv) in THF.
NiCl2(dppp)/Pd(PPh3)4 (5 mol%) was dissolved in THF (3 mL) at
r.t. under argon atmosphere. To this solution was added the corre-
sponding organometallic reagent (3 equiv) and the mixture was
stirred for 12 h at r.t. The reaction mixture was concentrated and to
this residue 5% aq NaHCO3 (5 mL) was added via a syringe. The
precipitate was filtered off and the mixture was extracted with Et2O
(2 × 10 mL). The combined organic layers were dried (MgSO4), and
concentrated under a gentle stream of N2 or evaporated under re-
duced pressure (bath temp below 20 °C). The residue was subjected
to column chromatography on silica gel (hexane–Et2O, 8:2) and the
solvent was evaporated to dryness under a gentle stream of N2 to af-
ford the desired product as an oil (Tables 1 and 2).
c Isolated yield.
All of the chemicals used in this work were of analytical grade pur-
chased from commercial suppliers and used without further purifi-
cation. The reactions were monitored by TLC with Merck silica gel
60 F254 TLC glass plates and the products were purified by flash
chromatography on Merck silica gel 60 (particles size 0.040–0.063
mm) using a glass column. Melting points were measured on a
Clarkson IA9200 Electrothermal Melting Point apparatus and are
2,3,5-Trimethylpyrazine (5a)6a,7a (Table 1, entry 4)
Yield: 74.5 mg (61%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H), 2.51 (s, 3 H), 2.50
(s, 3 H), 2.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.3, 150.4, 149.1, 140.8, 22.1,
21.6, 21.1.
EI-MS: m/z (%) = 122 (M+, 100), 111 (22), 97 (29), 69 (47), 57 (83).
uncorrected. H and 13C NMR spectra were recorded at 300 MHz
1
and 75 MHz, respectively, on a Jeol Eclipse FT 300 MHz Spectrom-
eter in CDCl3 as solvent using TMS as internal standard and chem-
ical shifts are expressed as δ ppm. Mass spectra were detected by
electron impact (EI) and obtained on an Agilent 1100 Series VLL
or Jeol MStation JMS 700 mass spectrometer.
5-Ethyl-2,3-dimethylpyrazine (5b)6a,7a (Table 1, entry 5)
Yield: 96.7 mg (71%); yellow oil.
5-Hydroxy-2,3-dimethylpyrazine (3)
To a suspension of glycinamide hydrochloride (2; 1.12 g, 10.1
mmol) in MeOH (20 mL) at –30 to –40 °C was added a solution of
aq 15 N NaOH (17 mL, 25.5 mmol) and then the mixture allowed
to regenerate glycinamide from its hydrochloride for 10 min. A so-
lution of 1 (1.03 g, 12 mmol) in MeOH (10 mL) was added to this
mixture dropwise and the reaction mixture was maintained at
–30 °C for additional 0.5 h and at r.t. for 3 h. The precipitated salts
were filtered off and the filtrate was dried (MgSO4), and concentrat-
ed to give a residue. The residue was purified by column chroma-
tography on silica gel (CH2Cl2–MeOH, 15:1) to give 1.02 g (81%)
of 3 as a solid; mp 198–200 °C (Lit.14a mp 199–200 °C; Lit.14b mp
201–202 °C).
1H NMR (300 MHz, CDCl3): δ = 13.8 (1 H, s), 8.03 (1 H, s), 2.34
(3 H, s), 2.31 (3 H, s).
13C NMR (75 MHz, CDCl3): δ = 158.4, 143.7, 133.7, 131.6, 18.6,
16.4.
EI-MS: m/z (%) = 124 (M+, 78), 111 (4), 99 (2), 95 (100), 81 (36),
69 (12), 54 (23).
1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H), 2.75 (q, J = 7.4 Hz,
2 H), 2.51 (s, 3 H), 2.50 (s, 3 H), 1.29 (t, J = 7.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.1, 151.4, 149.4, 139.9, 28.3,
22.1, 21.7, 14.0.
EI-MS: m/z (%) = 136 (M+, 18), 121 (20), 111 (27), 97 (39), 85 (44),
71 (63), 57 (87).
EI-HRMS: m/z calcd for C8H12N2: 136.1000; found: 136.1002.
5-Isopropyl-2,3-dimethylpyrazine (5c) (Table 1, entry 6)
Yield: 108.1 mg (72%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H), 3.02 (sept, J = 7.3
Hz, 1 H), 2.51 (s, 3 H), 2.49 (s, 3 H), 1.30 (d, J = 7.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 158.7, 151.2, 149.4, 138.8, 33.7,
22.4, 22.2, 21.7.
EI-MS: m/z (%) = 150 (M+, 3), 149 (100), 145 (12), 140 (18), 132
(22), 123 (29).
EI-HRMS: m/z calcd for C9H14N2: 150.1157; found: 150.1159.
2,3-Dimethyl-5-trifluoromethanesulfonyloxypyrazine (4)
To a solution of 3 (1.24 g, 10 mmol) in CHCl3 (45 mL) at –78 °C
was added Tf2O (2.52 mL, 15 mmol) and pyridine (1.83 mL, 15.5
mmol) successively via a syringe under argon atmosphere. The re-
2,3-Dimethyl-5-propylpyrazine (5d)3c (Table 1, entry 7)
Yield: 111.2 mg (74%); yellow oil.
Synthesis 2012, 44, 1631–1636
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regioselective Synthesis of Trialkylpyrazines
1635
1H NMR (300 MHz, CDCl3): δ = 8.14 (s, 1 H), 2.72 (t, J = 7.4 Hz,
2 H), 2.51 (s, 3 H), 2.50 (s, 3 H), 1.74 (sext, J = 7.5 Hz, 2 H), 0.97
(t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.9, 151.5, 149.3, 140.5, 37.2,
23.2, 22.2, 21.7, 13.9.
5-Isobutyl-2,3-dimethylpyrazine (5g)3a
Yield: 128.1 mg (78%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.10 (s, 1 H), 2.58 (d, J = 7.3 Hz,
2 H), 2.51 (s, 3 H), 2.50 (s, 3 H), 2.14–1.98 (m, 1 H), 0.93 (d, J =
6.3 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 153.0, 151.4, 149.2, 141.0, 44.1,
28.9, 22.3, 22.0, 21.5.
EI-MS: m/z (%) = 150 (M+, 18), 121 (20), 111 (27), 97 (39), 85 (44),
71 (63), 57 (87).
EI-MS: m/z (%) = 164 (M+, 23), 156 (4), 149 (100), 136 (62), 122
(22), 113 (6), 109 (16).
EI-HRMS: m/z calcd for C8H12N2: 150.1157; found: 150.1156.
5-(sec-Butyl)-2,3-dimethylpyrazine (5e) (Table 1, entry 8)
Yield: 121.5 mg (74%); yellow oil.
EI-HRMS: m/z calcd for C10H16N2: 164.1313; found: 164.1313.
1H NMR (300 MHz, CDCl3): δ = 8.12 (s, 1 H), 2.75 (q, J = 7.2 Hz,
1 H), 2.51 (s, 3 H), 2.50 (s, 3 H), 1.80–1.57 (m, 2 H), 1.27 (d, J =
7.0 Hz, 3 H), 0.84 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 157.9, 151.4, 149.3, 139.6, 40.9,
29.7, 22.2, 21.7, 20.2, 12.1.
5-Isopentyl-2,3-Dimethylpyrazine (5i)3a
Yield: 146.2 mg (82%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.14 (s, 1 H), 2.72 (t, J = 7.3 Hz,
2 H), 2.51 (s, 3 H), 2.50 (s, 3 H), 1.68–1.52 (m, 3 H), 0.95 (d, J =
6.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 154.3, 151.4, 149.2, 140.4, 38.9,
33.2, 28.0, 22.5, 22.1 21.6.
EI-MS: m/z (%) = 164 (M+, 23), 156 (4), 149 (100), 136 (62), 122
(22), 113 (6), 109 (16).
EI-MS: m/z (%) = 178 (M+, 6), 149 (41), 122 (100), 97 (36), 83 (40),
69 (55), 57 (55).
EI-HRMS: m/z calcd for C10H16N2: 164.1313; found: 164.1312.
5-Butyl-2,3-dimethylpyrazine (5f) (Table 1, entry 9)
Yield: 133.0 mg (81%); yellow oil.
EI-HRMS: m/z calcd for C11H18N2: 178.1470; found: 178.1479.
1H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1 H), 2.66 (t, J = 7.8 Hz,
2 H), 2.45 (s, 3 H), 2.44 (s, 3 H), 1.62 (quint, J = 7.8 Hz, 2 H), 1.34
(sext, J = 7.2 Hz, 2 H), 0.87 (t, J = 7.2 Hz, 3 H).
5-Cyclohexyl-2,3-dimethylpyrazine (5j)
Yield: 137.0 mg (72%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.15 (s, 1 H), 2.73–2.59 (m, 1 H),
2.50 (s, 3 H), 2.49 (s, 3 H), 1.98–1.70 (m, 4 H), 1.62–1.20 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 154.0, 151.4, 149.2, 140.4, 34.9,
13C NMR (75 MHz, CDCl3): δ = 157.9, 151.2, 149.4, 139.1, 43.9,
32.7, 26.5, 26.0, 22.1, 22.0.
31.9, 22.5, 22.0, 21.6, 13.9.
EI-MS: m/z (%) = 164 (M+, 8), 149 (54), 135 (18), 122 (100), 105
EI-MS: m/z (%) = 190 (M+, 40), 161 (15), 149 (19), 135 (100), 122
(14), 97 (14).
(66).
EI-HRMS: m/z calcd for C8H12N2: 164.1310; found: 164.1311.
EI-HRMS: m/z calcd for C12H18N2: 190.1470; found: 190.1467.
Alkyl- and Arylzinc Bromides; General Procedure
In a flame-dried flask under argon, anhyd ZnBr2 (0.45 g, 2 mmol)
was charged and activated using hot gun under high vacuum. The
flask was refilled with argon and the solid was dissolved in anhyd
THF (4 mL) at 0 °C. To this cooled solution was added the respec-
tive Grignard reagent (2 mmol) in THF–Et2O slowly and stirred for
30 min at the same temperature. After 10 min at r.t., the solution was
used for the next coupling reaction.
2,3-Dimethyl-5-phenylpyrazine (5k)
Yield: 156.6 mg (85%); white solid; mp 58–59 °C.
1H NMR (300 MHz, CDCl3): δ = 8.71 (s, 1 H), 7.97 (d, J = 7.1 Hz,
2 H), 7.52–7.39 (m, 3 H), 2.61 (s, 3 H), 2.57 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.8, 150.6, 149.5, 138.4, 136.9,
129.3, 129.0, 126.8, 22.4, 21.9.
EI-MS: m/z (%) = 184 (M+, 89), 169 (8), 143 (5), 114 (5), 102 (100),
76 (10).
Nickel-Catalyzed Cross-Coupling Reactions of Pyrazine Tri-
flate with Organozinc Bromides; 2,3-Dimethyl-5-(2-methylbu-
tyl)pyrazine (5h);3a Typical Procedure
EI-HRMS: m/z calcd for C12H12N2: 184.1000; found: 184.1005.
In a flame-dried flask, the triflate 4 (0.22 g, 1 mmol) and
NiCl2(dppp) (27 mg, 0.05 mmol) was dissolved in THF (3 mL) at
r.t. under argon atmosphere. To this solution was added 2-methyl-
butylzinc bromide solution (0.5 M in THF, 6 mL, 3 mmol) and the
mixture was stirred for 12 h at r.t. During the addition of the zinc
reagent, the reaction mixture turned to black. The mixture was con-
centrated and to this residue was added 5% aq NaHCO3 (5 mL) via
a syringe. The precipitate was filtered off and the mixture was ex-
tracted with Et2O (2 × 10 mL). The combined organic layers were
dried (MgSO4) and concentrated under a gentle stream of N2 or
evaporated under reduced pressure (bath temp below 20 °C). The
residue was subjected to column chromatography on silica gel
(Et2O–hexane, 8:2) and the solvent was evaporated to dryness under
a gentle stream of N2 to afford 148.0 mg (83%) of 5h as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.06 (s, 1 H), 2.68 (dd, J = 5.7,
13.4 Hz, 2 H), 2.46 (s, 3 H), 2.42 (s, 3 H), 1.90–1.73 (m, 1 H), 1.45–
1.29 (m, 1 H), 1.24–1.09 (m, 1 H), 0.91–0.81 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 153.2, 151.4, 149.1, 141.1, 42.2,
33.9, 29.3, 22.1, 21.6, 18.8, 11.3.
5-(4-Methoxyphenyl)-2,3-dimethylpyrazine (5l)
Yield: 156.4 mg (73%); white solid; mp 63–64 °C.
1H NMR (300 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.93 (d, J = 8.2 Hz,
2 H), 7.01 (d, J = 8.9 Hz, 2 H), 3.86 (s, 3 H), 2.58 (s, 3 H), 2.55 (s,
3 H).
13C NMR (75 MHz, CDCl3): δ = 160.8, 151.7, 149.7, 149.3, 137.8,
129.6, 128.1, 114.5, 55.5, 22.4, 21.8.
EI-MS: m/z (%) = 214 (M+, 100), 199 (27), 171 (12), 132 (31), 102
(6), 89 (13).
EI-HRMS: m/z calcd for C13H14N2O: 214.1101; found: 214.1101.
5-(3-Fluorophenyl)-2,3-dimethylpyrazine (5m)
Yield: 157.8 mg (78%); white solid; mp 67–68 °C.
1H NMR (300 MHz, CDCl3): δ = 8.67 (s, 1 H), 7.74–7.69 (m, 2 H),
7.45–7.38 (m, 1 H), 7.12–7.06 (m, 1 H), 2.37 (s, 3 H), 2.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.4 (d, J = 253.1 Hz), 151.9,
151.2, 148.2, 139.3, 138.3, 130.6, 122.2, 116.3, 113.9, 22.4, 21.9.
EI-MS: m/z (%) = 202 (M+, 100), 159 (7), 119 (48).
EI-MS: m/z (%) = 178 (M+, 64), 149 (100), 121 (28), 109 (21).
EI-HRMS: m/z calcd for C11H18N2: 178.1470; found: 178.1475.
EI-HRMS: m/z calcd for C12H11FN2: 202.0906; found: 202.0906.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1631–1636

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A. Pitchaiah et al.
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Yield: 149.0 mg (62%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.67 (s, 1 H), 7.90 (d, J = 8.3 Hz,
2 H), 7.50 (d, J = 8.3 Hz, 2 H), 2.59 (s, 3 H), 2.56 (s, 3 H), 1.35 (s,
9 H).
13C NMR (75 MHz, CDCl3): δ = 152.5, 150.1, 143.0, 138.2, 134.1,
126.5, 125.9, 125.3, 34.8, 31.4, 22.4, 21.8.
EI-MS: m/z (%) = 240 (M+, 34), 225 (100), 197 (11), 115 (14), 102
(6), 66 (4).
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EI-HRMS: m/z calcd for C16H20N2: 240.1626; found: 240.1628.
5-Benzyl-2,3-dimethylpyrazine (5o)
Yield: 162.6 mg (82%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.33–7.14 (m, 5 H),
4.09 (s, 2 H), 2.51 (s, 3 H), 2.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.6, 149.8, 140.9 138.9, 129.1,
128.8, 128.4, 126.7, 41.7, 22.2, 21.7.
EI-MS: m/z (%) = 198 (M+, 61), 197 (100), 115 (42), 104 (13),
91(33).
EI-HRMS: m/z calcd for C16H20N2: 198.1157; found: 198.1159.
2,3-Dimethyl-5-(2-thienyl)pyrazine (5p)
Yield: 140.8 mg (74%); white solid; mp 57–58 °C.
1H NMR (300 MHz, CDCl3): δ = 8.64 (s, 1 H), 7.61 (d, J = 1.2 Hz,
1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.14–7.10 (dd, J = 0.9, 3.0 Hz, 1 H),
2.56 (s, 3 H), 2.54 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.8, 150.2, 145.3, 141.9, 136.7,
128.2, 127.8, 124.8, 22.1, 21.8.
EI-MS: m/z (%) = 190 (M+, 100), 147 (7), 107 (74), 68 (6), 57 (4).
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EI-HRMS: m/z calcd for C10H10N2S: 190.0565; found: 190.0561.
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Acknowledgment
This work was generously supported by the Nanocatalyst Platform
Technology Program (SI-1109) from the Ministry of Knowledge
Economy and the Cooperative R & D Program (B551179-10-03-
00) from the Korea Research Council for Industrial Science and
Technology, Republic of Korea.
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© Georg Thieme Verlag Stuttgart · New York