Synthesis of a versatile 2 (1H)-pyrazinone core for the preparation of Tissue Factor-Factor VIIa inhibitors

Article abstract of DOI:10.1016/j.tet.2010.02.026

A new, general synthetic route to 2(1H)-pyrazinones 11 is described. The four-step synthesis is accomplished utilizing a regioselective hydrolysis and N-alkylation. These compounds efficiently undergo metal-catalyzed cross-coupling reactions to install P2 diversity groups in the 6-position, which can be used to refine the SAR of the S2 pocket of the Tissue Factor/Factor VIIa (TF/VIIa) complex.

Full text of DOI:10.1016/j.tet.2010.02.026

Tetrahedron 66 (2010) 2570–2581
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Synthesis of a versatile 2 (1H)-pyrazinone core for the preparation of Tissue
Factor-Factor VIIa inhibitors
,
b
Darin E. Jones a , Michael S. South
*
a Pfizer Global Research and Development, St. Louis Laboratories, Department of Medicinal Chemistry, 700 Chesterfield Pkwy. St. Louis, Mail Zone AA2G, MO 63017, USA
b Monsanto Company, 800 North Lindburg Boulevard, St. Louis, MO 63167, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, general synthetic route to 2(1H)-pyrazinones 11 is described. The four-step synthesis is accom-
plished utilizing a regioselective hydrolysis and N-alkylation. These compounds efficiently undergo
metal-catalyzed cross-coupling reactions to install P2 diversity groups in the 6-position, which can be
used to refine the SAR of the S2 pocket of the Tissue Factor/Factor VIIa (TF/VIIa) complex.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 24 November 2009
Received in revised form
28 January 2010
Accepted 2 February 2010
Available online 8 February 2010
1. Introduction
Cardiovascular disease, which is characterized by acute coronary
syndromes (ACS) such as unstable angina and myocardial in-
farction, is the leading cause of death in the western world.1,2
A
common cause for ACS is the occlusion of coronary arteries by
a thrombus. This thrombus formation is triggered by vascular in-
jury when the plasma serine protease Factor VIIa (VIIa) comes in
contact with its cofactor Tissue Factor (TF), which is an integral
membrane protein not normally in contact with blood. Formation
of the TF/VIIa complex is the first step in an enzymatic cascade that
ultimately leads to the formation of a potentially life threatening
fibrin clot.3 The development of safe and efficacious antith-
rombotics is needed to combat these diseases. Most research has
centered on inhibition of enzymes found down stream in the co-
agulation cascade such Factor Xa and thrombin.4 However there is
growing evidence, including from our own laboratories, that small
molecule inhibitors of the TF/VIIa complex may provide effective
anticoagulation while minimizing the risk of bleeding side effects.4
As a result there has been increased interest in the development of
a small molecule inhibitor of TF/VIIa.5 We therefore believed TF/
VIIa to be an attractive target to address this large unmet medical
need for safe and efficacious orally available antithrombotics.6
Our group recently reported the design, synthesis and structure–
activity relationship (SAR) of a series of pyrazinone antithrombotics
of the general structure shown in Figure 1.7 These compounds had
nanomolar potency against TF/VIIa and exhibited excellent selec-
tivity over other serine proteases such as thrombin and Factor Xa.
Importantly, the pyrazinone core orients the constituents in the
Figure 1. Pyrazinone core structure.
correct spatial arrangement to probe the S1, S2, and S3 pockets of the
TF/VIIa complex. The pyrazinone cores for this study were prepared
according to literature procedures to provide templates for library
synthesis. The approach involved a modified Strecker reaction be-
tween glycine benzyl ester, trimethylsilylcyanide, and an aldehyde
to give the a-cyanoamine. This intermediatewas then cyclized tothe
pyrazinone core with oxalyl chloride (Scheme 1).8 Most notably this
approach installs the P2 diversity element at the 6-position from the
aldehyde very early in the synthesis. This P2 moiety was found to be
crucial for both potency and selectivity.7b Unfortunately, many al-
dehydes completely failed this reaction sequence or gave low yields
of pyrazinone. In many cases the aldehyde failed to form the imi-
nium ion intermediate of the Strecker reaction. Other times the
Cl
O
P2
N
i, ii
NH2
O
N
Cl
O
CO2Bn
2
3
* Corresponding author. Fax: þ1 636 247 0250.
Scheme 1. Pyrazinone Synthesis. Reagents: (i) TMSCN, P2CHO; (ii) (ClCO)2.
E-mail address: darin.e.jones@pfizer.com (D.E. Jones).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.026

D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
2571
a
-cyanoamine intermediate was unstable to the harsh conditions of
The synthesis of the pyrazinone core is shown in Scheme 3.
The P3 inputs were restricted to small aliphatic amines, iso-
propylamine, and cyclobutylamine, based on the reported SAR.7b
There are many reports of nucleophilic substitution of chloro-
pyrazine 7 with amines.10 Most of these methods require long
reaction times and give low to moderate yields of the desired
product. The initial attempt to perform this substitution reaction
was also disappointing employing these methods. Refluxing a so-
lution of 7 and 5 equiv of amine in acetonitrile, toluene or 2-
propanol gave only meager yields of 8 (2–18%). It appeared that
the poor yields of 8 were related to the volatility of the amines,
which may have been lost during heating. We found that heating
a neat solution of chloropyrazine 7 in the presence of 2 equiv of
amine in a sealed tube resulted in good to excellent yields of N-
alkylaminopyrazine 8. With 8 in hand, aminopyrazine 8 and N-
bromosuccinimde were stirred in an aqueous solution of DMSO to
give the dibromopyrazine 9.11 Regioselective hydrolysis of 9 was
readily accomplished by refluxing in aqueous KOH to give
hydroxypyrazine 10.11b,e,12 In order to confirm the regiochemistry
of hydrolysis, a solution of 10 was heated in the presence of
carbonyldiimidazole (CDI) in tetrahydrofuran, which resulted in
the formation of benzoxazolinone 13.13 This product can only be
formed from regioisomer 10.
cyclization to the pyrazinone core. In order to further refine the SAR
in this pyrazinone series we set out to develop a new scalable route
to a pyrazinone core that will be more amenable to the introduction
of a P2 diversity element.
2. Results and discussion
The strategy to a more versatile pyrazinone intermediate is
outlined in Scheme 2. We believed that installation of the P2 moiety
via a metal-catalyzed process from compound 5 would be mild, ef-
ficient and easily scalable. This would allow the installation of di-
verseand complex moietiesrequiredtofullyexplore the S2 pocketof
the enzyme. This intermediate could also serve to explore diversity
in the S1 and S3 pockets as well. Intermediate 5 can be derived from
selective alkylation of hydroxypyrazine 6. There are many reports in
the literature for the preparationof hydroxypyrazines.9 Most involve
the condensation of an
a-aminoacid amide and a 1,2-dicarbonyl
compound or the cyclization of a dipeptide. Regiochemical issues
plague the latter route when unsymmetrical 1,2-dicarbonyl com-
pounds are used. Conversely, the dipeptide route does not offer the
required diversity. We surmised that preparing intermediate 6 from
an intact pyrazine ring would avoid the harsh conditions of forming
the heterocyclic nucleus and potential regiochemical problems,
while maintain the versatility we require. So we envisioned the
general structure 5 being ultimately derived from commercially
available chloropyrazine 7. Therefore, we set out to prepare com-
pound 5.
The alkylation of hydroxypyrazines, such as 10, reported in the
literature tend to be non-selective as both the N- and O- alkylated
products are formed.14 The alkylation of intermediate 10 to the
targeted molecule 11 was also problematic. Heating a solution of
10a with tert-butyl bromoacetate in the presence of potassium
carbonate gave a 1:4.5 ratio of isomers 11a and 12a respectively,
in a combined yield of 91%. The structures of the isomers were
determined by 1-D and 2-D NMR experiments since the 1H NMR
spectra of the isomers were indistinguishable. Structural assign-
ment of these compounds was accomplished with 2-D HMBC and
1-D APT experiments. The assignment of the methylene carbon of
the acetate group in both isomers was accomplished by 1-D APT
experiments, which in turn ultimately lead to the structural as-
signment of the isomers. In compound 12a, this appeared at
P2
P2
Br
N
N
N
P3
N
O
P3
N
O
P3
N
O
N
H
N
H
N
H
O
O
O
P1
OR
OR
4
5
1
d
63.7, which is characteristic of an oxygen bearing carbon.15
Conversely, the methylene group in 11a appeared at
d 49.7,
which is common for nitrogen bearing carbons.15 Long-range
carbon–hydrogen couplings observed in the 2-D HMBC further
confirmed these assignments (Scheme 4). For example, the
Br
N
N
P3
N
N
N
H
Cl
OH
methylene singlet at
ester carbonyl carbon at
the pyrazine ring found at
d
4.74 for 12a exhibited a cross peak to the
167.2 and the oxygen bearing carbon of
135.7. For compound 11a, cross peaks
d
6
7
d
Scheme 2. Retrosynthetic plan.
were observed between the methylene singlet found at
d 4.79 and
Br
N
N
i
ii
N
N
R
N
R
N
Cl
N
H
N
H
Br
7
9a: R = cyclobutyl, 73%
9b: R= i-Pr, 85%
8a: R = cyclobutyl, 95%
8b: R= i-Pr, 79%
iii
Br
Br
Br
Br
N
N
N
N
iv
N
N
v
R
N
+
R
N
R
R
N
O
N
H
N
N
O
H
H
OH
O
CO2t-Bu
O
CO2t-Bu
12a: R = cyclobutyl
11a: R = cyclobutyl, 87%
11b: R= i-Pr, 90%
10a: R = cyclobutyl, 87%
10b: R= i-Pr, 87%
13a: R = cyclobutyl, 95%
13b: R = i-Pr, 91%
12b
: R= i-Pr
Scheme 3. Synthesis of 2(1H)-pyrazinones. Reagents and conditions: (i) 2 equiv of RNH2; (ii) 2 equiv NBS, DMSO/H2O; (iii) KOH, H2O, reflux; (iv) 1.1 equiv tert-butyl bromoacetate,
2 equiv CaH2, THF, reflux; (v) CDI, THF.

2572
D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
Table 2
the ester carbonyl carbon at
d 165.8, the oxygen bearing carbon of
Suzuki Cross-coupling of 11a
the pyrazine found at
d 152.5, and the bromine bearing carbon
Br
N
Ar
found at 105.1. By analogy, similar shifts were observed for
11b and 12b. This allowed structural assignment of the isomers 11
and 12.
d
N
Ar-B(OR)2
R
R
N
N
N
H
N
H
5% Pd(PPh3)4
O
CO2t-Bu
O
CO2t-Bu
THF or dioxane
Na2CO3 or Cs2CO3
14
11a: R = cyclobutyl
11b: R= i-pr
Br
Br
N
N
N
O
H
N
H
N
H
N
H
Ot-Bu
O
Entry Bromide
Ar-B(OR)2
Product
Yield (%)
O
O
Ot-Bu
N
N
B(OH)2
1
11a
82
11a
12a
N
H
O
CO2t-Bu
CO2t-Bu
Scheme 4. 2D-HMBC long-range carbon–hydrogen couplings observed for 11a
and 12a.
14a
Since the O-alkylation product 12a was formed as the major
product, we decided to perform a small alkylation study in hope of
reversing the regiochemisty. The results are summarized in Table 1.
The use of bromoacetate decreased the ratio of 12a:11a relative to
chloroacetate (entries 1 and 2). Carbonate bases all gave the O-al-
kylation product 12a as the major product (entries 1–4). However,
increasing the equivalence of base did slightly decrease the ratio
(entries 3 and 4). The use of a strong kinetic base, lithium hexam-
ethyldisilylazide, resulted in nearly the exclusive formation of 12a
in the ratio of approximately 25:1 (entry 6). The use of a stronger
thermodynamic base, 1 equiv of calcium hydride resulted in a 3:1
ratio of 11a to 12a (entry 7). We found that refluxing a solution of
10a and tert-butyl bromoacetate in the presence of 2 equiv of cal-
cium hydride gave the desired N-alkylation product 11a in a ratio of
12:1 in an isolated yield of 87% (entry 8). Application of these
conditions to the alkylation of 10b resulted in a 10:1 ratio also fa-
voring the desired product 11b in an isolated yield of 90% (entry 9).
It is important to note, this route allows the introduction of base
labile acetates, such as methyl acetate, which can be utilized for
orthogonal protecting group strategies.
N
B(OH)2
N
N
2
11b
80
H
O
14b
Cl
N
Cl
N
B(OH)2
3
4
11b
11b
59
74
N
H
O
CO2t-Bu
14c
Cl
N
Cl
B(OH)2
N
N
H
O
CO2t-Bu
14d
Table 1
Alkylation study of 10
Cl
Br
Br
Br
B(OH)2
X
CO2tBu
N
N
N
N
5
11b
86
R
N
R
N
+
R
N
N
N
H
N
H
N
H
N
H
Base/solvent
Cl
OH
O
CO2t-Bu
O
CO2t-Bu
O
CO2t-Bu
11a: R = cyclobutyl
11b: R= i-pr
12a: R = cyclobutyl
12b: R= i-pr
10a: R = cyclobutyl
10b: R= i-pr
14e
Entry
Pyrazine
Base/Solvent
X
Time (h)
Ratio 11:12a
CN
N
NC
B(OH)2
B(OH)2
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10a
10a
10b
K2CO3 (1 equiv)/DMSO
K2CO3 (1 equiv)/DMSO
K2CO3 (2 equiv)/DMSO
Cs2CO3 (2 equiv)/DMSO
DBU (2 equiv)/THF
LHMDS (1 equiv)/THF
CaH2 (1 equiv)/THF
CaH2 (2 equiv)/THF
CaH2 (2 equiv)/THF
Br
Cl
3
3
1
1.5
14
3
24
24
24
1:4.5
1:6
6
7
8
11b
11b
11b
73
57
70
N
N
H
O
CO2t-Bu
Br
Br
Br
Br
Br
Br
Br
1:2.8
1:2.9
1:4.7
1:24.7
3:1
14f
CN
12:1
10:1
N
N
N
H
a
NC
Ratios were determined by LC-MS on crude reaction mixtures.
O
CO2t-Bu
14g
Pyrazines have been extensively utilized in various metal-
catalyzed cross-coupling reactions.10b,11d,16–19 However, there are
only a limited number of reports involving 2(1H)-pyrazinones in
such processes. Nearly all of these reports involve metal-catalyzed
cross-coupling at the C3 or C5-position of 2(1H)-pyrazinones.14h,20
Now with the targeted pyrazinone in hand, we set out to examine
the use of various metal-catalyzed reactions to introduce P2 di-
versity groups at the C6-position. As shown in Table 2, compounds
OCH3
N
H3CO
B(OH)2
N
N
H
O
CO2t-Bu
14h
(continued on next page)

D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
2573
Table 2 (continued)
Table 2 (continued)
Entry Bromide
Ar-B(OR)2
Product
Yield (%)
Entry Bromide
Ar-B(OR)2
Product
Yield (%)
OCH3
NH2
B(OH)2
N
CF3
9
11b
85
N
N
H
CF3
H3CO
N
O
CO2t-Bu
N
17
11b
11a
11b
93
88
18
O
N
H
B
O
NH2
14i
O
CO2t-Bu
NH2
16
14q
CH3
N
B(OH)2
N
N
H
10
11b
75
CF3
H3C
O
CO2t-Bu
CF3
N
14j
N
18
O
N
B
O
NH2
H
O
CO2t-Bu
O2N
16
14r
N
NO2
CHO
N
B(OH)2
11
11a
71
N
H
S
O
CO2t-Bu
NO2
N
14k
S
OHC
B(OH)2
19
N
N
H
O
14s
CO2t-Bu
B(OH)2
N
12
11a
53
N
N
a
O2N
Reagents and conditions: 1.1 equiv Aryl boronate, 2.0 equiv Na2CO3 (aq), 5 mol %
H
O
CO2t-Bu
Pd(PPh3)4.
14l
11 readily undergo the Suzuki Cross-Coupling reaction in moderate
to good yield (entries 1–18).21 Due to the established SAR, which
suggests that aryl groups at P2 are optimal, only arylboronic acids
and esters were used.7b This reaction is not optimized, and the
conditions used were typical for the Suzuki Cross-Coupling re-
action.21 Diminished yields are due to typical cross-coupling by-
products such as homo-coupling of the bromide and the arylbor-
onic acid, reductive debromination, and protolytic deborolation.21
As shown in Table 2, substitution on the aryl boronate can be tol-
erated in the othro, meta, and para positions with a minimal impact
on yield (entries 3–5). The othro substituted boronic acid gave the
lowest yield of product as expected (entry 3).21 Compounds 11 also
readily undergo cross-coupling with boronic esters in good yield
(entries 17 and18). The boronic ester 16 was prepared from the
corresponding bromide 15 as shown in Scheme 5.22 Importantly,
many compounds were prepared in good to moderate yield that
were previously not accessible via the Strecker route (entries
6,7,11,12).23
O
B(OH)2
N
13
11b
55
N
N
H
O
CO2t-Bu
NO2
O
14m
O2N
B(OH)2
CO2Me
N
N
14
11b
59
N
H
O
CO2t-Bu
CO2CH3
14n
NO2
O
O
O
O
B
B
O2N
B(OH)2
CF3
CF3
CO2Me
62
N
15
11a
5% Pd(dppf)Cl2
N
N
O
CO2CH3
H
Br
NH2
B
O
NH2
KOAc, DMSO
69%
O
CO2t-Bu
NH2
14o
15
16
Scheme 5. Preparation of boronate 16.
H2N
B(OH)2
CO2Me
N
N
We also decided to examine the use of 11 in other metal-
catalyzed processes in order to assess the versatility of this
intermediate. These results are summarized in Table 3. These in-
termediates do serve as substrates in Sonogashira24 (entries 1 and
2), Heck25 (entries 3 and 4) and Buchwald–Hartwig cross-coupling
16
11a
52
N
H
O
CO2t-Bu
CO2CH3
14p

2574
D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
Table 3
Metal-catalyzed cross-coupling reactions of 11a
Br
R
N
N
R-X
R
R
N
N
N
H
N
H
PdLx
O
CO2t-Bu
O
CO2t-Bu
17
11a: R = cyclobutyl
11b: R= i-pr
Entry
Bromide
R-X
Product
Yield (%)
N
1
11b
59
N
N
H
O
CO2t-Bu
17a
CO2Bn
N
CO2Bn
N
2
11a
47
N
H
O
CO2t-Bu
17b
CO2Me
N
N
N
3
11a
42
CO2CH3
H
O
CO2t-Bu
17c
CO2Et
N
N
N
4
11b
39
H
CO2Et
O
CO2t-Bu
17d
O
N
N
N
N
O
5
11b
28
N
HN
H
O
CO2t-Bu
17e
N
N
HN
6
11b
N
H
32
O
CO2t-Bu
17f
a
Reagents and conditions: 1.1 equiv Aryl boronate, 2.0 equiv Na2CO3 (aq), 5 mol % Pd(PPh3)4.

D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
2575
reactions26 (entries 5 and 6). While the yields of these reactions are
moderate at best, these reactions were not optimized. More im-
portantly, these products would not be easily obtainable, if at all,
via the Strecker route.
7.50 g (65.5 mmol) chloropyrazine 7 and 14.0 g (238 mmol) iso-
propylamine. The autoclave was sealed, purged with nitrogen
(2ꢁ3 bar), and pressurized with nitrogen to about 7.7 bar
(100 psig). The reactor was stirred and heated to 130 ꢀC for 24 h.
The maximum pressure reached during the reaction was about
13 bar (180 psig). After cooling to room temperature, the mixture
was diluted with 150 mL of water and extracted with ethyl acetate
(3ꢁ75 mL). The combined organic solutions were washed with
saturated sodium hydrogen carbonate (1ꢁ100 mL) and brine
(1ꢁ100 mL). The organic solution was then dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude product was
then filtered through a silica gel plug (ethyl acetate). Removal of
solvents under reduced pressure afforded a yellow oil. Addition of
about 30 mL of pentane to the oil and cooling to 0 ꢀC afforded, after
washing with cold pentane and drying, 79% of 8b as light tan
3. Conclusion
A new route to 2(1H)-pyrazinones, designed for the preparation
of novel antithrombotics, has been developed. The route is very
scalable and has been performed on a kilogram scale. To the best of
our knowledge, this work represents the first metal-catalyzed
cross-coupling reactions at the C6-position of 2(1H)-pyrazinones.
These processes provide a mild and efficient method for the in-
troduction of a P2 input on the core 11. Most notably, compounds
that were not assessable via the Strecker route are now obtainable
in moderate to excellent yield. Utilization of the chemistry de-
veloped by Miyaura and others for the preparation of arylboronic
esters and the extremely large number of commercially available
aryl bromides and aryl chlorides results in a large pool of potential
P2 diversity elements.22 This can be used to fully develop the SAR
around the S2 pocket of the TF/VIIa complex. Just as importantly,
this methodology can also be used to explore the SAR of the S1 and
S3 pockets of the enzyme by simple substitution of amines at P3
and P1. The application of this chemistry to the preparation of TF/
VIIa antithrombotic inhibitors will be reported in due course.
crystals. Mp 48–49 ꢀC: 1H NMR (400 MHz, CDCl3)
d
7.97 (dd, J¼1.3,
2.8 Hz, 1H), 7.85 (d, J¼1.3 Hz, 1H), 7.75 (d, J¼2.8 Hz, 1H), 4.96 (br d,
J¼5.1 Hz, 1H), 4.09–3.97 (m, 1H), 1.25 (d, J¼6.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3)
d 154.0, 141.8, 132.02, 131.86, 42.4, 22.6; HRMS
(ES) calcd for C7H12N3 (MþHþ) 138.1031, found 138.0990.
4.1.3. 3,5-Dibromo-N-cyclobutylpyrazin-2-amine (9a). To a solution
of 30.36 g (203.5 mmol) 8a in 407.0 mL dimethyl sulfoxide (0.5 M)
and 10.0 mL (20 M) water was added 79.17 g (444.8 mmol) N-bromo-
succinimide over a 30 min period with the temperature being kept
below 15 ꢀC with an ice water bath. After the addition was com-
pleted the ice bath was removed and the reaction mixture was
allowed to warm to room temperature and stirred for 5 h. The re-
action mixture was then poured into 1.0 L of ice water and the
aqueous solution was extracted with ethyl acetate (5ꢁ250 mL). The
combined organic solutions were washed with 5% sodium car-
bonate (2ꢁ250 mL), water (1ꢁ250 mL), and brine (1ꢁ250 mL). The
organic solution was dried (MgSO4), filtered, and concentrated to
a yellow solid. Purification of the crude product by MPLC (20% ethyl
acetate in hexanes) gave pure 9a in 73% yield as a light yellow solid:
4. Experimental section
4.1. General
Solvents and chemicals were reagent grade or better and were
obtained from commercial sources. Air and moisture sensitive re-
actions were carried out in oven dried (at 120 ꢀC) glassware. 1H, 13C,
19F NMR spectra were recorded using a 300 or 400 MHz NMR
spectrometer. Sample purities were determined by HPLC analysis
equipped with a mass spectrometric detector using a C18 3.5 um,
30ꢁ2.1 mm column, eluting with a gradient system of 5:95 to 95:5
acetonitrile/water with a buffer consisting of 0.1% TFA over 4.5 min
at 1 mL/min and detected by DAD. Analytical Thin Layer Chroma-
tography (TLC) was performed on Merck silica gel plates (Merck
Kieselgel 60, 0.25 mm thickness) with F254 indicator. Compounds
were visualized under UV lamp or by developing in iodine. Medium
pressure liquid chromatography (MPLC) separations were carried
out using commercially available columns using technical grade
solvents. Compound 8b has been reported in the literature, but
with limited spectroscopic data.11a,c
1H NMR (400 MHz, CDCl3)
4.39–4.30 (m, 1H), 2.44–2.37 (m, 2H), 1.95–1.85 (m, 2H), 1.83–1.70
d
7.98 (s, 1H), 5.31 (br d, J¼4.8 Hz, 1H),
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 150.5, 143.0, 125.0, 121.6, 47.2,
31.4, 15.4; HRMS (ES) calcd for C8H10Br2N3 (MþHþ) 307.9221, found
307.9214.
4.1.4. 3,5-Dibromo-N-isopropylpyrazin-2-amine (9b). To a solution
of 22.95 g (167.3 mmol) 8b in 330.0 mL dimethyl sulfoxide (0.5 M)
and 8.0 mL water (20 M) was added 75.24 g (422.7 mmol) N-bromo-
succinimide over a 30 min period with the temperature being kept
below 15 ꢀC with an ice water bath. After the addition was com-
pleted the ice bath was removed and the reaction mixture was
allowed to warm to room temperature and stirred for approxi-
mately 18 h. The reaction was protected from light as a pre-
cautionary measure. The reaction mixture was then poured into
1.0 L of ice water and the aqueous solution was extracted with ethyl
acetate (4ꢁ250 mL). The combined organic solutions were washed
with 1 N NaOH (1ꢁ250 mL), water, and brine (2ꢁ250 mL). The or-
ganic solution was dried (MgSO4), filtered, and concentrated to
a yellow solid. Purification of the crude product by MPLC (20% ethyl
acetate in hexanes) gave pure 9b in 85% yield as a light yellow
4.1.1. N-Cyclobutylpyrazin-2-amine (8a). A solution of 26.12 g
(228.0 mmol) chloropyrazine 7 and 40.00 mL (468.5 mmol) cyclo-
butylamine was heated in a pressure reaction flask with stirring to
110 ꢀC for 16 h. The brown reaction mixture was allowed to cool to
room temperature and was diluted with water (750 mL). The
aqueous solution was extracted with ethyl acetate (2ꢁ250 mL). The
combined organic solutions were washed with water (1ꢁ250 mL),
saturated sodium hydrogen carbonate (1ꢁ250 mL), and brine
(2ꢁ250 mL). The organic solution was dried (MgSO4), filtered, and
solvents removed under reduced pressure. The crude product was
purified by MPLC (20% ethyl acetate in hexanes to 40% ethyl acetate
in hexanes) to afford 8a in 95% yield as a light yellow solid: 1H NMR
liquid: 1H NMR (400 MHz, CDCl3)
d 7.99 (s, 1H), 6.50 (br s, 1H), 4.12–
4.04 (m, 1H), 1.23 (d, J¼6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
150.5, 142.7, 125.0, 120.9, 43.6, 22.5; HRMS (ES) calcd for
(300 MHz, DMSO)
d
7.97–7.96 (m, 1H), 7.82–7.79 (m, 2H), 5.12 (br s,
C9H10Br2N3 (MþHþ) 295.9221, found 295.9186.
1H), 4.30–4.18 (m, 1H), 2.51–2.39 (m, 2H), 1.97–1.73 (m, 4H); 13C
NMR (75 MHz, DMSO)
d
149.3, 137.6, 128.3, 126.9, 42.2, 26.7, 10.7;
4.1.5. 6-Bromo-3-(cyclobutylamino)pyrazin-2-ol (10a). To a suspen-
sion of 25.03 g (81.53 mmol) 9a in 500.0 mL water (0.16 M) was
added 22.90 g (408.1 mmol) potassium hydroxide in 480.0 mL water
(0.85 M). The resulting suspension was heated to reflux for ap-
proximately 18 h. The reaction mixture was then added charcoal and
HRMS (ES) calcd for C8H12N3 (MþHþ) 150.1031, found 150.0992.
4.1.2. N-Isopropylpyrazin-2-amine (8b)10a. A 50-mL stainless steel
stirred Parr autoclave equipped with a glass liner, was charged with

2576
D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
refluxed for an additional 15 min. The mixture was then allowed to
cool for 5 min and was filtered through Celite 545Ò. The filtrate was
cooled in an ice bath and was acidified with concentrated hydro-
chloric acid to a pH of approximately 5 (litmus paper) upon which
a white precipitate forms. The precipitate was collected by filtration,
washed twice with water and dried under vacuum to afford pure 10a
90% yield as a white solid: 1H NMR (400 MHz, CDCl3)
d 7.02 (s, 1H),
5.97 (br d, J¼7.5 Hz, 1H), 4.84 (s, 2H), 4.12–4.03 (m, 1H), 1.49 (s, 9H),
1.24 (d, J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 165.5, 152.3,
148.9, 124.2, 104.3, 82.9, 49.3, 42.4, 27.8, 22.1; HRMS (ES) calcd for
C13H20BrN3O3 (MþHþ) 346.0766, found 346.0753.
in 87% yield: 1H NMR (400 MHz, DMSO-d6)
d
12.43 (s, 1H), 7.18 (br d,
4.1.9. tert-Butyl
{[6-bromo-3-(cyclobutylamino)pyrazin-2-yl]oxy}
J¼5.1 Hz,1H), 6.87 (s,1H), 4.29–4.19 (m,1H), 2.16–2.09 (m, 2H), 2.03–
acetate (12a). To a solution of 2.0668 g (8.467 mmol) of 10a in
30.0 mL dimethyl sulfoxide (0.2 M) was added 1.4017 g (10.14 mmol)
potassium carbonate and heated to 45 ꢀC. The resulting suspension
was stirred for approximately 15 min. The mixture was then added
1.40 mL (9.481 mmol) tert-butyl bromoacetate in 13.0 mL in dimethyl
sulfoxide (0.73 M) drop wise over a 10 min period. After stirring for
approximately 3 h, the reaction was quenched by the addition of
water (250 mL). The aqueous solution was extracted with ethyl ace-
tate (4ꢁ50 mL). The combined organic solutions were washed with
brine (2ꢁ50 mL), dried (MgSO4), filtered, and solvents removed un-
der reduced pressure. The crude reaction mixture was purified by
MPLC (10% ethyl ether in hexanes to 25% ethyl ether in hexanes)
afforded pure 12a in 75% yield and pure 11a in 16% yield. Data for 12a:
1.93 (m, 2H), 1.63–1.51 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d
147.0, 144.2, 119.9, 41.3, 26.0, 10.8; HRMS (EI) calcd for C8H11BrN3O
(MþHþ) 244.0085, found 244.0086.
4.1.6. 6-Bromo-3-(isopropylamino)pyrazin-2-ol (10b). To a suspen-
sion of 38.58 g (130.79 mmol) 9b in 820.0 mL water (0.16 M) was
added 36.74 g (654.79 mmol) potassium hydroxide in 750.0 mL
water (0.87 M). The resulting suspension was heated to reflux for
approximately 20 h. The clear, yellow, homogeneous reaction
mixture was then added charcoal and refluxed for an additional
15 min. The mixture was then allowed to cool for 5 min and was
filtered through Celite 545Ò. The filtrate was cooled in an ice bath
and was acidified with concentrated hydrochloric acid to a pH of
approximately 4 (litmus paper) upon which a white precipitate
forms. The precipitate was collected by filtration, washed twice
with water and dried under vacuum to afford pure 10b in 87% yield:
1H NMR (400 MHz, CDCl3)
(s, 2H), 4.44–4.35 (m,1H), 2.43–2.36 (m, 2H),1.91–1.83 (m, 2H),1.78–
1.69 (m, 2H) 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3)
167.2, 145.6,
d
7.64 (s,1H), 5.22 (br d, J¼7.3 Hz,1H), 4.74
d
143.3,135.7,118.5, 82.8, 63.7, 46.4, 31.5, 28.2,15.5; HRMS (ES) calcd for
1H NMR (400 MHz, DMF-d7)
d
12.49 (br s, 1H), 6.96 (s, 1H), 6.57 (br
C14H21N3O3 (MþHþ) 358.0766, found 358.0754.
d, J¼7.5 Hz, 1H), 4.14–4.02 (m, 1H), 1.21 (d, J¼6.5 Hz, 6H); 13C NMR
(100 MHz, DMF-d7)
d
152.1, 149.6, 124.6,103.7, 42.6, 22.2; HRMS (EI)
4.1.10. tert-Butyl {[6-bromo-3-(isopropylamino)pyrazin-2-yl]oxy}
acetate (12b). Following the procedure for the preparation of 12a,
pure 12b was obtained in 77% yield and pure 11b in 12% yield after
purification by MPLC (hexanes to 16% ethyl acetate in hexanes).
calcd for C7H11BrN3O (MþHþ) 232.0080, found 232.0078.
4.1.7. tert-Butyl [6-bromo-3-(cyclobutylamino)-2-oxopyrazin-1(2H)-
yl]acetate (11a). To a suspension of 1.7246 g (40.96 mmol) calcium
hydride in 80.0 mL tetrahydrofuran (0.50 M) was added 5.0477 g
(20.68 mmol) 10a in 50.0 mL tetrahydrofuran (0.41 M) drop wise via
an addition funnel. The resulting suspension was heated to reflux for
30 min. To this mixture was then added a solution of 3.40 mL
(23.03 mmol) tert-butyl bromoacetate in tetrahydrofuran (2.3 M).
Refluxing of the mixture was continued for 18 h. The reaction mix-
ture was allowed to cool to room temperature, and then cautiously
poured in to a stirred ice water mixture (600.0 mL). The aqueous
layer was extracted with ethyl acetate (4ꢁ250 mL). The combined
organic solutions were washed with saturated sodium hydrogen
carbonate (1ꢁ250 mL) and brine (2ꢁ250 mL). The organic solution
was dried (MgSO4), filtered, and solvents removed under reduced
pressure. Purification of the crude product by MPLC (20% ethyl ac-
etate in hexanes) afforded pure 11a in 87% yield as an off white solid:
Data for 12b: 1H NMR (400 MHz, CDCl3)
d 7.68 (s, 1H), 4.94 (br d,
J¼7.4 Hz, 1H), 4.77 (s, 2H), 4.20–4.08 (m, 1H), 1.49 (s, 9H), 1.25 (d,
J¼6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 166.9, 145.4, 143.3,
135.3, 117.8, 82.4, 63.4, 42.4, 28.0, 22.6; HRMS (ES) calcd for
C13H21BrN3O3 (MþHþ) 346.0761, found 346.0756.
4.1.11. 6-Bromo-3-cyclobutyl[1,3]oxazolo[4,5-b]pyrazin-2(3H)-one
(13a). A solution of 6.0129 g (24.63 mmol) of 10a in 125.0 mL dry
tetrahydrofuran (0.2 M) was added 6.0221 g (37.14 mmol) 1,10-car-
bonyldiimidazole in one portion. The resulting solution was then
heated to reflux over night. The reaction mixture was allowed to
cool to room temperature and diluted with ethyl acetate (500 mL).
The organic solution was washed with 1 N HCl (2ꢁ150 mL),
saturated sodium hydrogen carbonate (1ꢁ150 mL), and brine
(1ꢁ150 mL). The organic solution is then dried (MgSO4), filtered,
and solvents removed under reduced pressure. Purification by
MPLC (20% ethyl acetate in hexanes) afforded pure 13 in 95% yield as
1H NMR (400 MHz, CDCl3)
(s, 2H), 4.39–4.29 (m,1H), 2.41–2.34 (m, 2H),1.96–1.86 (m, 2H),1.79–
1.68 (m, 2H) 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
165.8, 152.5,
d
6.97 (s,1H), 6.18 (br d, J¼7.5 Hz,1H), 4.79
d
a white solid. 1H NMR (400 MHz, CDCl3)
1H), 3.05–2.94 (m, 2H), 2.41–2.33 (m, 2H), 2.04–1.96 (m, 2H), 1.92–
d 8.19 (s, 1H), 4.90–4.81 (m,
149.0, 124.6, 105.1, 83.3, 49.7, 46.3, 31.3, 28.2, 15.6; HRMS (ES) calcd
for C14H21N3O3 (MþHþ) 358.0766, found 358.0746.
1.80 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 150.0, 145.6, 139.5, 129.1,
47.9, 27.1, 15.2; HRMS (ES) calcd for C9H8BrN3O2 (MþNHþ4 )
4.1.8. tert-Butyl [6-bromo-3-(isopropylamino)-2-oxopyrazin-1(2H)-
yl]acetate (11b). To a suspension of 8.92 g (211.9 mmol) calcium
hydride in 350 mL tetrahydrofuran (0.60 M) was added 20.21 g
(87.08 mmol) 10b in one portion as a solid. The resulting suspension
was heated to reflux for 30 min. The mixture was then added a so-
lution of 15.40 mL (104.3 mmol) tert-butyl bromoacetate in 85.0 mL
tetrahydrofuran (1.2 M) drop wise over a 30 min period via an ad-
dition funnel. Refluxing of the mixture was continued for 18 h. The
reaction mixturewas allowed to cool to room temperature, and then
cautiously poured in to a stirred ice water mixture. The aqueous
layer was extracted with ethyl acetate (5ꢁ250 mL). The combined
organic solutions were washed with 1 N HCl (2ꢁ500 mL) and brine
(2ꢁ500 mL). The organic solution was dried (MgSO4), filtered, and
solvents removed under reduced pressure. Purification of the crude
product by MPLC (20% ethyl acetate in hexanes) afforded pure 11b in
269.9878, found 269.9825.
4.1.12. 6-Bromo-3-isopropyl[1,3]oxazolo[4,5-b]pyrazin-2(3H)-one
(13b). Following the procedure for the preparation of 13a, pure 13b
was obtained in 91% yield after MPLC purification (15% ethyl ether
in hexanes). 1H NMR (400 MHz, CDCl3)
d 8.18 (s, 1H), 4.72–4.62 (m,
1H),1.61 (d, J¼6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 149.9,145.7,
139.4, 139.2, 128.9, 47.4, 19.5; HRMS (ES) calcd for C8H8BrN3O2
(MþNHþ4 ) 275.0144, found 275.0119.
4.2. General procedure for the Suzuki Cross-coupling reaction
of 11 with boronates
To a two-neck flask equipped with stirring bar, septum, and
argon line was charged with 11 and boronate (1.1 equiv), was

D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
2577
purged with argon for approximately 10 min. The flask was then
added tetrahydrofuran to give a 0.15 M solution followed by
aqueous sodium carbonate (2.0 equiv of 2.0 M solution) and
5 mol % of tetrakis(triphenylphosphine) palladium (0). The result-
ing mixture was allowed to reflux for approximately 18 h. The
crude reaction mixture was allowed to cool to room temperature
and was diluted with ethyl acetate. The organic solution was
washed with saturated sodium hydrogen carbonate (1ꢁ), and brine
(2ꢁ), dried (MgSO4), filtered, and solvent removed under reduced
pressure. Hereafter this is designated as method A.
product was purified by MPLC (hexanes to 33% ethyl acetate in
hexanes) to give a 73% yield of pure 14f as a white solid. 1H NMR
(400 MHz, CDCl3)
d 7.74–7.54 (m, 4H), 6.79 (s, 1H), 6.14 (br d,
J¼7.8 Hz, 1H), 4.37 (s, 2H), 4.21–4.11 (m, 1H), 1.45 (s, 9H), 1.29 (d,
J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 166.3, 151.6, 149.7,
134.01, 133.89, 132.95, 132.21, 129.6, 125.4, 123.2, 117.8, 113.0, 82.9,
47.6, 42.4, 27.8, 22.3; HRMS (ES) calcd for C20H25N4O3 (MþHþ)
369.1921, found 369.1909.
4.2.7. tert-Butyl [6-(4-cyanophenyl)-3-(isopropylamino)-2-oxo
pyrazin-1(2H)-yl]acetate (14g). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 33% ethyl acetate in
hexanes) to give a 57% yield of pure 14g as a white solid. 1H NMR
4.2.1. tert-Butyl [3-(cyclobutylamino)-2-oxo-6-phenylpyrazin-1(2H)-
yl]acetate (14a). Method A, from 11a. The crude product was pu-
rified by MPLC (20% ethyl acetate in hexanes) to give an 82% yield of
(400 MHz, CDCl3)
d
7.72 (d, J¼8.2 Hz, 2H), 7.50 (d, J¼8.2 Hz, 2H),
pure 14a as a light yellow solid. 1H NMR (300 MHz, CDCl3)
d
7.43–
6.81 (s, 1H), 6.15 (br d, J¼7.7 Hz, 1H), 4.38 (s, 2H), 4.21–4.12 (m, 1H),
7.30 (m, 5H), 6.79 (s, 1H), 6.31 (d, J¼7.7 Hz, 1H), 4.54–4.31 (m, 1H),
1.44 (s, 9H), 1.28 (d, J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
4.39 (s, 2H), 2.49–2.40 (m, 2H), 2.04–1.91 (m, 2H),1.85–1.73 (m, 2H),
d 166.3, 151.7, 149.7, 137.2, 132.3, 130.0, 126.1, 123.4, 118.1, 112.5, 82.8,
1.42 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
166.8, 152.0, 149.5, 132.9,
47.8, 42.4, 27.8, 22.3; HRMS (ES) calcd for C20H25N4O3 (MþHþ)
130.0, 129.2, 128.90, 128.55, 122.7, 82.7, 48.0, 46.2, 31.5, 28.1, 15.6;
369.1921, found 369.1945.
HRMS (ES) calcd for C20H26N3O3 (MþHþ) 356.1974, found 356.1992.
4.2.8. tert-Butyl [3-(isopropylamino)-6-(3-methoxyphenyl)-2-oxo-
pyrazin-1(2H)-yl]acetate (14h). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 16% ethyl acetate in
hexanes) to give a 70% yield of pure 14h as a white solid. 1H NMR
4.2.2. tert-Butyl [3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-
yl]acetate (14b). Method A, from 11b. The crude product was pu-
rified by MPLC (hexanes to 16% ethyl acetate in hexanes) to give an
80% yield of pure 14b as a white solid. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d 7.33–7.29 (m, 1H), 6.97–6.89 (m, 3H), 6.82 (s,
d
7.41–7.33 (m, 5H), 6.81 (s, 1H), 6.04 (br d, J¼7.7 Hz, 1H), 4.40 (s,
1H), 6.03 (br d, J¼7.8 Hz, 1H), 4.40 (s, 2H), 4.20–4.12 (m, 1H), 3.80 (s,
2H), 4.21–4.12 (m, 1H), 1.42 (s, 9H), 1.28 (d, J¼6.5 Hz, 6H); 13C NMR
3H), 1.44 (s, 9H), 1.28 (d, J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d
166.5, 151.8, 149.3, 132.06, 129.7, 128.79, 128.54,
d 166.6,159.5,151.8,149.3,133.8,127.7,122.3,121.9,115.1,114.6, 82.4,
127.8, 122.4, 82.3, 47.6, 42.3, 27.8, 22.4; HRMS (ES) calcd for
55.2, 47.8, 42.3, 27.8, 22.4; HRMS (ES) calcd for C20H28N3O4 (MþHþ)
C19H26N3O3 (MþHþ) 344.1969, found 344.1996.
374.2074, found 374.2062.
4.2.3. tert-Butyl
[6-(2-chlorophenyl)-3-(isopropylamino)-2-oxo
4.2.9. tert-Butyl [3-(isopropylamino)-6-(4-methoxyphenyl)-2-oxo-
pyrazin-1(2H)-yl]acetate (14i). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 16% ethyl acetate in
hexanes) to give a 85% yield of pure 14i as a white solid. 1H NMR
pyrazin-1(2H)-yl]acetate (14c). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 25% ethyl acetate in
hexanes) to give a 59% yield of pure 14c as a white solid. 1H NMR
(400 MHz, CDCl3)
d
7.49–7.47 (m, 1H), 7.41–7.37 (m, 2H), 7.32–7.28
(400 MHz, CDCl3)
d
7.26 (d, J¼8.7 Hz, 2H), 6.92 (d, J¼8.8 Hz, 2H),
(m,1H), 6.76 (s,1H), 6.09 (br d, J¼7.5 Hz,1H), 4.38 (ABq, Dn¼454.8 Hz,
6.78 (s, 1H), 6.00 (br d, J¼7.6 Hz, 1H), 4.39 (s, 2H), 4.19–4.11 (m, 1H),
JAB¼16.9 Hz, 2H), 4.22–4.13 (m, 1H), 1.34–1.28 (m, 15H); 13C NMR
3.84 (s, 3H), 1.43 (s, 9H), 1.28 (d, J¼6.4 Hz, 6H); 13C NMR (100 MHz,
(100 MHz, CDCl3)
d
166.1, 151.7, 149.7, 135.2, 133.3, 131.2, 130.7, 129.5,
CDCl3) d 166.6, 160.0, 151.9, 149.2, 131.1, 127.5, 124.9, 122.4, 113.9,
126.8, 124.5, 122.9, 82.3, 46.7, 42.4, 27.8, 22.4; HRMS (ES) calcd for
82.3, 55.2, 47.6, 42.3, 27.8, 22.4; HRMS (ES) calcd for C20H28N3O4
C19H25ClN3O3 (MþHþ) 378.1579, found 378.1585.
(MþHþ) 374.2074, found 374.2048.
4.2.4. tert-Butyl
[6-(3-chlorophenyl)-3-(isopropylamino)-2-oxo
4.2.10. tert-Butyl
[3-(isopropylamino)-6-(4-methylphenyl)-2-oxo-
pyrazin-1(2H)-yl]acetate (14d). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 16% ethyl acetate in
hexanes) to give a 74% yield of pure 14d as a white solid. 1H NMR
pyrazin-1(2H)-yl]acetate (14j). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 16% ethyl acetate in
hexanes) to give a 75% yield of pure 14j as a white solid. 1H NMR
(400 MHz, CDCl3)
d
7.41–7.33 (m, 3H), 7.25–7.22 (m, 3H), 6.79 (s,
(400 MHz, CDCl3)
1H), 4.39 (s, 2H), 4.20–4.11 (m, 1H), 1.43 (s, 9H), 1.28 (d, J¼6.5 Hz,
6H); 13C NMR (100 MHz, CDCl3)
166.5, 151.9, 149.2, 138.8, 129.71,
d
7.21 (m, 4H), 6.79 (s, 1H), 6.02 (br d, J¼7.5 Hz,
1H), 6.08 (br d, J¼7.7 Hz, 1H), 4.39 (s, 2H), 4.20–4.11 (m, 1H), 1.45 (s,
9H), 1.28 (d, J¼6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
166.4, 151.7,
d
149.5, 134.49, 134.35, 129.87, 129.71, 129.01, 127.8, 126.4, 122.8, 82.7,
47.7, 42.4, 27.8, 22.4; HRMS (ES) calcd for C19H25ClN3O3 (MþHþ)
378.1579, found 378.1591.
129.58, 129.22, 127.8, 122.3, 82.3, 47.7, 42.3, 27.8, 22.4, 21.2; HRMS
(ES) calcd for C20H28N3O3 (MþHþ) 358.2125, found 358.2139.
4.2.11. tert-Butyl
[3-(cyclobutylamino)-6-(2-nitrophenyl)-2-oxo
4.2.5. tert-Butyl
[6-(4-chlorophenyl)-3-(isopropylamino)-2-oxo
pyrazin-1(2H)-yl]acetate (14k). Method A, from 11a. The crude
product was purified by MPLC (20% ethyl acetate in hexanes to 40%
ethyl acetate in hexanes) to give a 71% yield of pure 14k as a brown
pyrazin-1(2H)-yl]acetate (14e). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 16% ethyl acetate in
hexanes) to give a 86% yield of pure 14e as a white solid. 1H NMR
solid. 1H NMR (400 MHz, CDCl3)
d 8.01–7.99 (m, 1H), 7.60–7.58 (m,
(400 MHz, CDCl3)
d
7.33–7.29 (m, 1H), 6.97–6.89 (m, 3H), 6.82
2H), 7.48–7.46 (m, 1H), 6.54 (s, 1H), 6.34 (d, J¼7.8 Hz, 1H), 4.45–4.35
(m, 1H), 4.30 (ABq, Dn¼503.0 Hz, JAB¼17.2 Hz, 2H), 2.42–2.34 (m,
2H), 1.99–1.89 (m, 2H), 1.78–1.66 (m, 2H), 1.32 (s, 9H); 13C NMR
(s, 1H), 6.03 (br d, J¼7.8 Hz, 1H), 4.40 (s, 2H), 4.20–4.12 (m, 1H), 3.80
(s, 3H), 1.44 (s, 9H), 1.28 (d, J¼6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3)
d
166.6, 159.5, 151.8, 149.3, 133.8, 127.7, 122.3, 121.9, 115.1,
(100 MHz, CDCl3) d 166.6, 151.7, 150.0, 134.5, 133.2, 131.0, 126.9,
114.6, 82.4, 55.2, 47.8, 42.3, 27.8, 22.4; HRMS (ES) calcd for
124.6, 123.3, 121.9, 82.9, 48.0, 46.2, 31.4, 28.1, 15.5; HRMS (ES) calcd
C20H28N3O4 (MþHþ) 374.2074, found 374.2062.
for C20H25N4O5 (MþHþ) 401.1825, found 401.1834.
4.2.6. tert-Butyl [6-(3-cyanophenyl)-3-(isopropylamino)-2-oxo
4.2.12. tert-Butyl
[3-(cyclobutylamino)-6-(4-nitrophenyl)-2-oxo
pyrazin-1(2H)-yl]acetate (14f). Method A, from 11b. The crude
pyrazin-1(2H)-yl]acetate (14l). Method A, from 11a. Purification

2578
D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
by crystallization (ethyl acetate and hexanes) afforded a 53%
(282 MHz, DMF-d7)
d
ꢂ63.1; HRMS (ES) calcd for C20H26F3N4O3
yield of pure 14l as a yellow solid. 1H NMR (400 MHz, DMF-d7)
(MþHþ) 427.1957, found 427.1966.
d
8.50 (dd, J¼1.9, 7.0 Hz, 2H), 7.87 (dd, J¼1.9, 7.0 Hz, 2H), 7.64 (d,
J¼8.1 Hz, 1H), 4.74–4.64 (m, 3H), 2.49–2.29 (m, 4H), 1.91–1.83 (m,
2H), 1.52 (s, 9H); 13C NMR (100 MHz, DMF-d7)
167.4, 151.7,
4.2.18. tert-Butyl [6-[3-amino-5-(trifluoromethyl)phenyl]-3-(cyclo-
butylamino)-2-oxopyrazin-1(2H)-yl]acetate (14r). Method A, from
11a. The crude product was purified by MPLC (10% ethyl acetate in
hexanes to 40% ethyl acetate in hexanes) to give an 88% yield of pure
d
150.2, 148.1, 139.9, 131.1, 127.2, 124.3, 123.6, 82.5, 48.2, 46.3, 30.8,
27.6, 15.3; HRMS (ES) calcd for C20H25N4O5 (MþHþ) 401.1825,
found 401.1846.
14r as a white solid. 1H NMR (400 MHz, CDCl3)
d 6.89–6.88 (m, 2H),
6.73 (s,1H), 6.72 (s,1H), 6.30(d, J¼7.8 Hz,1H), 4.46–4.36 (m,1H), 4.33
4.2.13. tert-Butyl [6-(4-acetylphenyl)-3-(isopropylamino)-2-oxo
pyrazin-1(2H)-yl]acetate (14m). Method A, from 11b. The crude
product was purified by MPLC (hexanes to 25% ethyl acetate in
hexanes) to give a 55% yield of pure 14m as a white solid. 1H NMR
(s, 2H), 4.05 (br s,1H), 2.43–2.35 (m, 2H),1.97–1.87 (m, 2H),1.79–1.67
(m, 2H),1.39 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 166.5,151.6,149.3,
147.3,134.2,132.57,132.25,131.93,131.61,127.3,125.0,122.41,122.28,
118.6, 115.72, 115.69, 115.65, 111.58, 111.54, 111.50, 82.8, 47.8, 46.0,
(400 MHz, CDCl3)
d
8.00 (d, J¼8.2 Hz, 2H), 7.47 (d, J¼8.3 Hz, 2H),
31.1, 27.8, 15.3; 19F NMR (376 MHz, CDCl3)
d
ꢂ63.4; HRMS (ES) calcd
6.83 (s, 1H), 6.11 (br d, J¼7.8 Hz, 1H), 4.40 (s, 2H), 4.21–4.11 (m, 1H),
for C21H26F3N4O3 (MþHþ) 439.1957, found 439.1980.
2.64 (s, 3H), 1.44 (s, 9H), 1.29 (d, J¼6.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3)
d
197.1, 166.4, 151.8, 149.6, 137.21, 136.96, 129.6, 128.5, 126.8,
4.2.19. tert-Butyl [6-(5-formylthien-2-yl)-3-(isopropylamino)-2-oxo-
pyrazin-1(2H)-yl]acetate (14s). Method A, from 11b. The crude
product was purified by MPLC (20% ethyl acetate in hexanes to 60%
ethyl acetate in hexanes) to give an 18% yield of pure 14s as a yellow
123.0, 82.6, 47.9, 42.4, 27.8, 26.6, 22.3; HRMS (ES) calcd for
C21H28N3O4 (MþHþ) 386.2074, found 386.2056.
4.2.14. Methyl 3-[1-(2-tert-butoxy-2-oxoethyl)-5-(isopropylamino)-
6-oxo-1,6-dihydropyrazin-2-yl]-5-nitrobenzoate (14n). Method A,
from 11b. The crude product was purified by MPLC (hexanes to 30%
diethyl ether in hexanes) to give a 59% yield of pure 14n as a light
solid. 1H NMR (300 MHz, CDCl3)
d
9.90 (s, 1H), 7.72 (d, J¼3.8 Hz,1H),
7.14 (d, J¼4.0 Hz, 1H), 6.22 (br d, J¼7.9 Hz, 1H), 4.56 (s, 2H), 4.23–
4.11 (m, 1H), 1.47 (s, 9H), 1.28 (d, J¼6.4 Hz, 6H); 13C NMR (75 MHz,
CDCl3)
d 182.6, 166.4, 151.5, 150.2, 144.5, 143.0, 135.9, 129.6, 125.4,
yellow solid. 1H NMR (400 MHz, CDCl3)
d
8.89–8.88 (m, 1H), 8.45–
119.6, 83.1, 47.6, 42.6, 27.9, 22.3; HRMS (ES) calcd for C18H24N3O4
8.44 (m, 1H), 8.38–8.37 (m, 1H), 6.85 (s, 1H), 6.18 (d, J¼7.9 Hz, 1H),
(MþHþ) 378.1488, found 378.1484.
4.38 (s, 2H), 4.23–4.14 (m, 1H), 4.00 (s, 3H), 1.45 (s, 9H), 1.30 (d,
J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 166.1,164.2,151.6,149.9,
4.2.20. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(tri-
fluoromethyl)aniline (16). To a two-neck, oven dried flask equipped
with stirring bar, septum and argon line was charged with 15.00 g
(62.5 mmol) of 3-bromo-5-(trifluoromethyl)aniline, 19.53 g
(76.92 mmol) bis(pinacolato)diboron, and 18.40 g (187.5 mmol)
potassium acetate was purged with argon for approximately
10 min. The flask was then added 375.0 mL dimethyl sulfoxide
(0.16 M) and 1.54 g (3 mol %) dichloro[1,10-bis(diphenylphosphi-
no)ferrocene]palladium (II) dichloromethane adduct. The resulting
mixture was heated to 80 ꢀC and stirred for approximately 18 h. The
crude reaction mixture was allowed to cool to room temperature
and was diluted with brine (1 L). The aqueous solution was
extracted with ethyl acetate (3ꢁ500 mL). The combined organic
solutions were washed with water (1ꢁ250 mL), brine (2ꢁ250 mL)
dried (MgSO4), filtered, and solvent removed under reduced pres-
sure. Purification by Kugelrohr distillation to gave 69% yield of pure
148.4, 135.9, 134.9, 132.4, 128.0, 124.62, 124.46, 123.91, 83.3, 52.9,
47.9, 42.6, 27.8, 22.3; HRMS (ES) calcd for C21H27N4O7 (MþHþ)
447.1880, found 447.1885.
4.2.15. Methyl 3-[1-(2-tert-butoxy-2-oxoethyl)-5-(cyclobutylamino)-
6-oxo-1,6-dihydropyrazin-2-yl]-5-nitrobenzoate (14o). Method A,
from 11a. The crude product was purified by MPLC (hexanes to
20% diethyl ether in hexanes) to give a 62% yield of pure 14o as
a light yellow solid. 1H NMR (400 MHz, CDCl3)
d 8.83–8.82 (m, 1H),
8.37–8.36 (m, 1H), 8.31–8.30 (m, 1H), 6.77 (s, 1H), 6.39 (d, J¼7.5 Hz,
1H), 4.48–4.38 (m, 1H), 4.31 (s, 2H), 3.93 (s, 3H), 2.44–2.36 (m,
2H), 2.00–1.90 (m, 2H), 1.80–1.71 (m, 2H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 166.4, 164.5, 151.7, 150.0, 148.7, 136.1, 135.1,
132.7, 128.3, 125.3, 124.8, 124.1, 83.6, 53.2, 48.1, 46.3, 31.3, 28.1,
15.6; HRMS (ES) calcd for C22H27N4O7 (MþHþ) 459.1880, found
459.1907.
16. Bp 144–146 ꢀC/0.7 mmHg; 1H NMR (400 MHz, CDCl3)
d 7.43 (s,
1H), 7.25 (m, 1H), 6.97 (s, 1H), 3.99 (s, 2H), 1.32 (s, 12H); 13C NMR
(100 MHz, CDCl3) 145.8, 131.0, 124.3, 122.8, 121.34, 121.31, 114.02,
4.2.16. Methyl
3-amino-5-[1-(2-tert-butoxy-2-oxoethyl)-5-(cyclo-
113.98, 84.2, 24.8; 19F NMR (376 MHz, CDCl3)
d
ꢂ63.2.
butylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoate (14p). Method
A, from 11a. The crude product was purified by MPLC (15% ethyl ac-
etate in hexanes to 30% ethyl acetate in hexanes) to give a 52% yield of
pure 14p. 1H NMR (400 MHz, DMF-d7)
d
7.38–7.37 (m, 1H), 7.19 (d,
4.3. General procedure for the Sonogashira coupling of 11
with acetylenes
J¼8.0 Hz,1H), 7.13–7.12 (m,1H), 6.88–6.87 (m,1H), 6.71 (s,1H), 5.69(s,
2H), 4.54–4.44 (m, 1H), 4.41 (s, 2H), 3.81 (s, 3H), 2.32–2.25 (m, 2H),
2.19–2.09 (m, 2H),1.73–1.65 (m, 2H),1.37 (s, 9H); 13C NMR (100 MHz,
To a two-neck flask equipped with stirring bar, septum and ar-
gon line was charged with 11 and was purged with argon for ap-
proximately 10 min. The flask was then charged with 1,4-dioxane to
give a 0.2 M solution followed by the acetylene (1.1 equiv) and
triethylamine (5.0 equiv) The resulting mixture was then added
trans-dichlorobis(triphenylphosphine) palladium (II) (5 mol %),
copper (I) iodide (1 mol %) and the resulting mixture was heated to
80 ꢀC and stirred for approximately 18 h. The crude reaction mix-
ture was allowed to cool to room temperature and filtered through
a pad of Celite 545Ò. The filtrate was diluted with ethyl acetate. The
organic solution was washed with saturated sodium hydrogen
carbonate (1ꢁ), and brine (2ꢁ), dried (MgSO4), filtered, and solvent
removed under reduced pressure. Hereafter this is designated as
method B.
DMF-d7)
d 167.1, 166.8, 151.5, 150.1, 149.6, 134.0, 131.4, 128.8, 121.7,
119.5,117.9,115.0, 82.2, 51.9, 47.8, 46.1, 30.7, 27.5,15.1;HRMS(ES) calcd
for C22H29N4O5 (MþHþ) 429.2138, found 429.2138.
4.2.17. tert-Butyl [6-[3-amino-5-(trifluoromethyl)phenyl]-3-(isopropyl-
amino)-2-oxopyrazin-1(2H)-yl]acetate (14q). Method A, from 11b.
The crude product was purified by MPLC (hexanes to 30% ethyl ac-
etate in hexanes) to give a 93% yield of pure 14q as a white solid. 1H
NMR (300 MHz, DMF-d7) d 7.26 (s,1H), 7.11 (s,1H), 7.02 (s,1H), 6.97–
6.96 (m,1H), 6.11 (s, 2H), 4.65 (s, 2H), 4.65 (s, 2H), 4.43–4.31 (m,1H),
1.59 (s, 9H), 1.45 (d, J¼6.5 Hz, 6H); 13C NMR (75 MHz, DMF-d7)
d
167.5, 151.8, 150.9, 150.1, 135.0, 131.81, 131.39, 131.00, 130.56, 128.1,
126.8, 123.2, 122.2, 118.8, 113.1, 110.5, 82.4, 42.6, 27.7, 22.1; 19F NMR

D.E. Jones, M.S. South / Tetrahedron 66 (2010) 2570–2581
2579
4.3.1. tert-Butyl [3-(isopropylamino)-2-oxo-6-(phenylethynyl)pyrazin-
1(2H)-yl]acetate (17a). Method B, from 11b. The crude product was
purified by MPLC (hexanes to 25% ethyl acetate in hexanes) to give
a 84% yield of pure 17a as a white solid. 1H NMR (400 MHz, CDCl3)
(20 mol %),
and
tris(dibenzylideneacetone)dipalladium
(0)
(10 mol %), was purged with argon for approximately 10 min. The
flask was then charged with dimethoxyethane to give a 0.5 M so-
lution followed by sodium tert-butoxide (1.4 equiv), and amine
(1.2 equiv). The resulting solution was then heated to 80 ꢀC and
stirred for approximately 18 h. The crude reaction mixture was
allowed to cool to room temperature and filtered through a pad of
Celite 545Ò. The filtrate was diluted with ethyl acetate. The organic
solution was washed with saturated sodium hydrogen carbonate
(1ꢁ), andbrine (2ꢁ), driedover MgSO4, filtered andsolvent removed
under reduced pressure. Hereafter this is designated as method D.
d
7.47–7.45 (m, 2H), 7.35–7.34 (m, 3H), 7.26 (s, 1H), 6.30 (br d,
J¼7.7 Hz, 1H), 4.86 (s, 2H), 4.21–4.11 (m, 1H), 1.44 (s, 9H), 1.27 (d,
J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 166.1, 151.1, 149.9, 131.1,
128.87, 128.69, 128.36, 122.0, 111.4, 95.7, 82.7, 80.7, 47.2, 42.6, 27.9,
22.2; HRMS (ES) calcd for C21H26N3O3 (MþHþ) 368.1969, found
368.1983.
4.3.2. Benzyl 5-[1-(2-tert-butoxy-2-oxoethyl)-5-(cyclobutylamino)-
6-oxo-1,6-dihydropyrazin-2-yl]pent-4-ynoate (17b). Method B,
from 11a. The crude product was purified by MPLC (hexanes to
25% ethyl acetate in hexanes) to give a 47% yield of pure 17b as
4.5.1. tert-Butyl [3-(isopropylamino)-6-morpholin-4-yl-2-oxopyrazin-
1(2H)-yl]acetate (17e). Method D, from 11b. The crude product was
purified by MPLC (28% ethyl acetate in hexanes to 80% ethyl acetate in
hexanes) to give a 28% yield of pure 17e as a tan solid. 1H NMR
a light yellow solid. 1H NMR (400 MHz, CDCl3)
d 7.32–7.27 (m, 5H),
7.02 (s, 1H), 6.43 (br d, J¼7.8 Hz, 1H), 5.12 (s, 2H), 4.65 (s, 2H),
4.45–4.35 (m, 1H), 2.73–2.69 (m, 2H), 2.62–2.59 (m, 2H), 2.42–2.34
(m, 2H), 1.97–1.87 (m, 2H), 1.79–1.67 (m, 2H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
6.73 (s, 1H), 5.87 (d, J¼7.8 Hz, 1H), 4.73 (s, 2H),
4.13–4.05 (m, 1H), 3.89–3.86 (m, 2H), 3.63–3.58 (m, 2H), 2.94–2.83
(m, 4H),1.49 (s, 9H),1.24 (d, J¼6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
CDCl3)
d
171.2 166.0, 151.0, 149.5, 135.5, 128.51, 128.28, 128.21,
d 166.9,152.0,148.4,135.3,115.4, 82.2, 67.0, 53.2, 43.7, 42.2, 27.9, 22.4;
128.13, 111.8, 94.7, 82.6, 72.9, 66.6, 47.2, 45.9, 33.0, 31.0, 27.9, 15.46,
15.26; HRMS (ES) calcd for C26H31N3O5 (MþHþ) 466.2342, found
466.2326.
HRMS (ES) calcd for C17H29N4O4 (MþHþ) 353.2183, found 353.2215.
4.5.2. tert-Butyl
[3-(isopropylamino)-2-oxo-6-pyrrolidin-1-ylpyr-
azin-1(2H)-yl]acetate (17f). Method D, from 11b. The crude product
was purified by MPLC (16% diethyl ether in hexanes to 60% diethyl
ether in hexanes) to give a 32% yield of pure 17f as a tan solid. 1H
4.4. General procedure for Heck Reaction of 11 with acrylates
To a two-neck flask equipped with stirring bar, septum and argon
line was charged with 11 and tri-o-tolylphosphine (5 mol %), was
purged with argon for approximately 10 min. The flask was then
charged with acetonitrile to give a 1.0 M solution followed by acrylate
(1.5 equiv) and triethylamine (2.0 equiv) The resulting suspension
was then added palladium (II) acetate (1.5 mol %) and then heated to
80 ꢀC and stirred for approximately 18 h. The crude reaction mixture
wasallowed tocooltoroomtemperatureandfilteredthroughapad of
Celite 545Ò. The filtrate was diluted with ethyl acetate. The organic
solution was washed with saturated sodium hydrogen carbonate
(1ꢁ), and brine (2ꢁ), dried (MgSO4), filtered, and solvent removed
under reduced pressure. Hereafter this is designated as method C.
NMR (400 MHz, CDCl3)
d
6.75 (s, 1H), 5.77 (d, J¼7.7 Hz, 1H), 4.69 (s,
2H), 4.13–4.02 (m, 1H), 2.99–2.96 (m, 4H), 1.90–1.87 (m, 4H), 1.48 (s,
9H),1.23 (d, J¼6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 166.9, 152.1,
147.6, 134.8, 114.0, 81.9, 53.6, 44.3, 42.1, 27.9, 24.6, 22.5; HRMS (ES)
calcd for C17H29N4O3 (MþHþ) 337.2234, found 337.2248.
Acknowledgements
We wish to thank James P. Doom, David Masters-Moore, and
Ralph C. Scheibel for HRMS analysis, Dr. Thaddeus Franczyk for
experiments performed in an autoclave, and Dr. Claude R. Jones for
thoughtful discussions and help performing 2-D NMR experiments.
4.4.1. Methyl
(2E)-3-[1-(2-tert-butoxy-2-oxoethyl)-5-(cyclobutyl-
Supplementary data
amino)-6-oxo-1,6-dihydropyrazin-2-yl]acrylate (17c). Method C,
from 11a. The crude product was purified by MPLC (hexanes to 20%
ethyl acetate in hexanes) to give a 42% yield of pure 17c as a yellow
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2010.02.026.
solid. 1H NMR (400 MHz, CDCl3)
d 7.27–7.24 (m, 2H), 6.59 (d,
J¼7.8 Hz, 1H) 6.18 (d, J¼15.3 Hz, 1H), 4.71 (s, 2H), 4.50–4.40 (m, 1H),
3.75 (s, 1H), 2.44–2.37 (m, 2H), 2.02–1.91 (m, 2H), 1.82–1.71 (m, 2H)
References and notes
1.47 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 166.6, 165.9, 151.1, 150.1,
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Harrington, R. A.; King, S. B.; Kleiman, N. S.; Theroux, P.; Topol, E. J.; Van de
Werf, F.; White, H. D.; Willerson, J. T. Am. J. Med. 2000, 108, 41–53; (b) Moreno,
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(ES) calcd for C18H26N3O5 (MþHþ) 364.1872, found 364.1883.
4.4.2. Ethyl (2E)-3-[1-(2-tert-butoxy-2-oxoethyl)-5-(isopropylamino)-
6-oxo-1,6-dihydropyrazin-2-yl]acrylate (17d). Method C, from 11b.
The crude product was purified by MPLC (hexanes to 25% ethyl
acetate in hexanes) to give a 39% yield of pure 17a as a yellow solid.
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1H NMR (400 MHz, CDCl3)
d
7.31–7.25 (m, 2H), 6.35 (br d, J¼7.9 Hz,
1H), 6.20 (br d, J¼15.6 Hz, 1H), 4.75 (s, 2H), 4.26–4.14 (m, 1H), 1.50
(s, 9H), 1.31–1.26 (m, 9H); 13C NMR (100 MHz, CDCl3)
166.1, 165.9,
d
151.2, 150.2, 133.9, 125.0, 122.8, 117.7, 83.2, 60.5, 45.8, 42.6, 27.8,
22.2, 14.1; HRMS (ES) calcd for C18H28N3O5 (MþHþ) 366.2023,
found 366.2030.
4.5. General procedure for Buchwald–Hartwig coupling of
11b with amines
To a two-neck flask equipped with stirring bar, septum and argon
line was charged with 11, 2-(di-tert-butylphosphino)biphenyl

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