Xanthate-mediated intermolecular alkylation of pyrazines

Article abstract of DOI:10.1016/j.tet.2018.08.040

An expedient approach for the intermolecular C-H functionalization of pyrazines and other heteroarenes by the radical chemistry of xanthates is reported. Incorporation of a multitude of functional alkyl groups onto these heteroarenes proceeds in good yiel

Full text of DOI:10.1016/j.tet.2018.08.040

Accepted Manuscript
Xanthate-mediated intermolecular alkylation of pyrazines
Qi Huang, Ling Qin, Samir Z. Zard
PII:
S0040-4020(18)31006-8
10.1016/j.tet.2018.08.040
TET 29760
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 July 2018
Revised Date: 21 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Huang Q, Qin L, Zard SZ, Xanthate-mediated intermolecular alkylation of
pyrazines, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.040.
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ACCEPTED MANUSCRIPT
Xanthate-mediated intermolecular alkylation of pyrazines
Qi Huang,* Ling Qin and Samir Z. Zard*
Graphical abstract
1

ACCEPTED MANUSCRIPT
Xanthate-mediated intermolecular alkylation of pyrazines
Qi Huang,* Ling Qin and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au C. N. R. S., UMR 7652, Ecole
Polytechnique, 91128 Palaiseau Cedex, France.
Fax: +33 169335972; Tel: +33 169335971 (S. Z. Z.)
E-mail: qi.huang@polytechnique.edu
E-mail: samir.zard@polytechnique.edu
†
This paper is dedicated with respect and admiration to Professor Léon Ghosez.
Graphical abstract
Abstract: An expedient approach for the intermolecular C-H functionalization of
pyrazines and other heteroarenes by the radical chemistry of xanthates is reported.
Incorporation of a multitude of functional alkyl groups onto these heteroarenes
proceeds in good yield and good to excellent regioselectivity, leading to highly
functionalized heteroaromatics.
Keywords: Minisci reaction; xanthates; pyrazines; C-H functionalization of
heteroaromatics
1
. Introduction
Pyrazines constitute an important member of the class of diazines due to their wide
1
2
ranging applications as flavoring agents, in material sciences, and in medicines.
For example, disubstituted 2-sec-butyl-3-methoxypyrazine is present in
2

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Cabernet-Sauvignon wine. 2,5-Dimethyl-3-(pentan-3-yl)-pyrazine serves as an ant
alarm pheromone. As for drugs, amiloride, a potassium-sparing diuretic, is used in the
management of hypertension and congestive heart failure. After more than two
decades’ efforts, a potent small molecule named SHP099 containing a pyrazine core
was finally found as inhibitor of SHP2 phosphatase, a stimulator of cancer growth
3
(Figure 1).
Figure 1. Selected examples of biologically active pyrazines
4
Conventional methods for the preparation of pyrazines include cyclocondensation,
5
modification of pyrazinones, transition metal catalyzed cross-coupling with
6
7
halogenopyrazines and metalation. These pathways, however, suffer from various
limitations, such as inaccessible substitution patterns, harsh reaction conditions,
prefunctionalized substrates, etc. These disadvantages limit the exploitation of the
potential of pyrazines.
Recently, radical chemistry has arisen to prominence due to its high promise in the
8
early- and late-stage C-H functionalization of pharmaceutical leads. This demand
from industry has resulted in the revival of Minisci-type reactions as powerful tools
for the modification of heteroaromatics. Since the seminal work by Minisci et al., in
which the radicals were generated from carboxylic acids by silver-catalyzed oxidative
9
10
decarboxylation or from alkyl iodides with H O and Fe(II)SO •7H O in DMSO,
2
2
4
2
the toolkits for the generation of radicals useful in this context have considerably
expanded. For example, alkyl radicals generated by decarboxylation can now be
1
1
12
accessed via Barton’s esters, amino acids or from acid chlorides and anhydrides
3

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1
3
under photoredox conditions. Starting from alkyl halides, alkyl radicals can be
1
4
15
produced through palladium catalysis or by photoredox. A multitude of other
radical precursors suitable for Minisci reactions have been developed, including:
1
6
17
18
19
20
alkanes, alkyltrifluoroborates, organoboronic acids , peracetates, aldehydes,
2
1
22
23
24
25
alcohols, sulfonyl halides, sulfones, sulfinates, 1,4-dihydropyridines and
2
6
olefins, among others. The alkyl groups introduced, however, are mostly scarcely
functionalized.
For over two decades, the unique degenerate addition-fragmentation of xanthates has
2
7
evolved into a powerful method in the creation of carbon-carbon bonds. Its
adoption in the intermolecular functionalization of heteroaromatics, however, dates
back to 1992, when Minisci et al. reported in a sole paper the cyclohexylation of
2
8
heteroarenes via a Barton-McCombie-type dithiocarbonate.
Employment of
alternative cleavage of the carbon-sulfur bond in xanthates for the intermolecular C-H
2
9
alkylation of heteroarenes is more recent. For our part, we have developed for
2
9f
29g
example the trifluoroethylamination
and tert-butylation
of a wide array of
electron-rich and electron-poor heteroaromatics, demonstrating also a high tolerance
towards polar functional groups. Moreover, methyl and related alkyl groups were
incorporated into heteroarenes by the intermolecular addition of carboxylic acid
2
9h
xanthates, followed by spontaneous or thermal-induced decarboxylation.
These
methods provide an expedient inexpensive alternative for the functionalization of
heteroaromatics.
Herein, we would like to report further progress in the introduction of highly
functionalized alkyl groups into pyrazines and other heteroaromatics mediated by
xanthates under mild reaction conditions (Scheme 1).
4

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Scheme 1. Previous work on the xanthate-mediated Minisci-type alkylations
2
. Results and Discussion
Our investigation commenced with 2-chloro-6-methylaminopyrazine 1a, which was
2
9g
previously examined in the tert-butylation process. We were pleased to find that
exposure of pyrazine 1a and 2.0 equivalents of mildly nucleophilic
phthalimidomethyl xanthate 2 to portionwise addition of stoichiometric dilauroyl
peroxide (DLP) in refluxing 1,2-dichloroethane (DCE) afforded readily
aminomethylated product 3a in 73% yield, together with 5% of double alkylation
product 4a, displaying therefore good regioselectivity.
Scheme 2. First example of pyrazine alkylation
This inspiring result encouraged us to explore the scope of pyrazine substrates. Our
observations are summarized in Scheme 3 (brsm = based on recovered starting
5

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material). Compound 3b containing a methylamino group was obtained in 67% yield,
while chlorine-bearing product 3c was obtained in 35% yield, with part of the starting
pyrazine recovered. Electron-donating methylamino group is therefore a better
activating group than chlorine. Variation from the electron-donating methylamino
group to other groups was then investigated, including phenoxy, methoxy, amino,
tert-butylamino. The corresponding desired products 3d-g were indeed isolated in
good yield. It is worth noting that the tert-butylamino group can serve as a protected
amino group in the place of Boc, since the protection of the amino group with Boc
failed under standard conditions. By changing the relative equivalents of
2
,6-dimethoxypyrazine and xanthate 2, mono-substituted product 3i and double
substituted product 4c could be obtained in variable ratio and in good combined yields.
-Methylthiopyrazine was also successfully involved in the alkylation to afford
2
pyrazine 3j in moderate yield (40%). Alkylation of methyl pyrazine-2-carboxylate
containing an electron-withdrawing group gave exclusively the para-substituted
product 3k in a moderate yield of 39%. As for the reaction involving
2
,6-dichloropyrazine and alkylpyrazines, activation of the ring with trifluoroacetic
acid (TFA) proved necessary and the corresponding monoalkylated products 3l-n and
double alkylated products 4d-f were obtained in good combined yields. The other two
regioisomers of pyrazine 1a, namely 2-chloro-5-methylaminopyrazine and
2
-chloro-3-methylaminopyrazine, were exposed to the same reaction conditions to
further confirm the ortho-activation of electron-donating group. Starting from the
former and its non-methylated analog, mono-addition products 3o-p were isolated in
2
9% and 39% yield, respectively. While the yield of 4g was not determined due to
difficulties in purification, double-addition compound 4h was isolated in 25% yield, a
comparatively higher yield than that of product 4a. This is probably due to the
meta-deactivating ortho-activating chlorine atom. As for the alkylation of the
2
,3-disubstituted pyrazine, only traces of the desired product 4q were observed.
6

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Scheme 3. Scope of pyrazine substrates
Apart from xanthate 2, which introduces a useful and conveniently protected
aminomethyl group, this protocol proved applicable to alkylation with various other
xanthates (Scheme 4). For instance, in the addition involving oxazolidinonemethyl
xanthate, the desired product 5a was isolated in 47% yield, while a minor by-product
7
resulting from the ionic attack of the methylamino group on the thermally produced
iminium intermediate was observed in less than 7% yield. When a nucleophilic amino
group was absent, as in pyrazine 5b containing a phenoxy group, the expected adduct
was obtained in 58% yield, without complication from side products arising from
unwanted ionic pathways. Pyrazines arising from alkylation with other alkyl groups,
including
succinimidomethyl
(5c),
phenylacetamidomethyl
(5d),
trifluoroethylacetamido (5e), Weinreb amide (5f) and amide (5g) were delivered
smoothly in moderate to good yields. However, the reaction involving highly
7

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electrophilic cyanomethyl radical furnished the two regioisomers 5h and 8 in 22% and
3
% yield, respectively, together with the double alkylated product 7d in 9% yield. To
our surprise, however, addition of 2-propionitrile xanthate to pyrazine 1a gave adduct
i cleanly in 41% yield, even though some starting pyrazine was recovered. The
5
reason for this divergence in behavior is presently not clear. The sensitive acetal group
also proved compatible, as in compound 5j. Equally noteworthy is the benzylated
product 5k, which was secured in 48% yield. Benzyl radicals tend to be somewhat
unreactive.
8

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Scheme 4. Scope of the xanthate partner
Even more heavily functionalized pyrazines can be readily accessed by performing an
intermolecular addition of a xanthate to an alkene prior to the intermolecular
alkylation of the pyrazines. For example, addition of malonyl xanthate to
3
0
N-vinylphthalimide 10 led to a new xanthate 8a, which in turn added with high
efficiency to pyrazine 1a to deliver product 9a in 65% yield (Scheme 5). Similarly, by
simply varying the starting xanthate, pyrazines containing trifluoromethyloxadiazo
(9b) and cyano (9c) were readily obtained. The minor double addition products were
not isolated, except for compound 11, which was formed in 26% yield.
Scheme 5. Incorporation of substituted aminoalkyl groups into pyrazines
In the same manner, reaction with xanthates 13a and 13b, generated by intermolecular
9

ACCEPTED MANUSCRIPT
addition to N,N-diacetyl imidazolone 12, afforded the corresponding functionalized
pyrazines 14a and 14b containing the protected 1,2-diamine motif in good yield
(Scheme 6). An unusual example is the synthesis of molecule 19 containing both a
pyridine and a pyrazine ring, arising from the addition of the pyridine-bearing
3
1
xanthate 17 to 2-amino-6-chloropyrazine 18. Double addition products 15 and 20
were isolated as minor components in this series.
Scheme 6. Incorporation of highly functional motifs into pyrazines
In the case of pyrazine 23 derived from α-acetoxy substituted xanthate 22a, however,
1
0

ACCEPTED MANUSCRIPT
we noted its tendency to undergo elimination of the acetate group followed by
nucleophilic attack by the lauric acid present in the reaction medium to give
compound 24, isolated in 31% yield (Scheme 7). In contrast, the reaction of
phenoxypyrazine 25 and xanthate 22a did not suffer from such complication and
afforded smoothly the corresponding adduct 26a in 64% yield. The preparation of the
highly complex cortisone derived pyrazine 26b, arising from initial radical adduct 22b
is of particular significance. Finally, the reaction of methoxypyrazine 27 with
pivaloyloxymethyl xanthate 28 furnished readily the corresponding adduct 29, albeit
in moderate yield, probably due to the low stability (and higher and less controllable
3
2
reactivity) of the incoming pivaloyloxymethyl radical generated from 28.
11

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Scheme 7. Incorporation of α-acyloxy substituted fragments into pyrazines
Considering that double alkylated products were sometimes isolated in significant
yield, functionalization of the last position available on the pyrazine ring should be
therefore feasible by treating the mono-alkylated products produced above with a
different xanthate. Indeed, addition of phthalimidomethyl xanthate 2 to pyrazine 14b
gave a new pyrazine 30a in 59% yield (Scheme 8). The sequence of the introduction
of the two alkyl groups can be easily inverted, as demonstrated by the synthesis of
3
0b from addition of xanthate 13b to pyrazine 3a. Tetrasubstituted pyrazines 30c and
1
2

ACCEPTED MANUSCRIPT
3
0d are two further examples. In the latter case, with an electron-donating group
ortho to the last available position, the alkylation turned out to be quite efficient,
furnishing pyrazine 30d in good yield (59%) from pyrazine 3i.
Scheme 8. Access to tetrasubstituted pyrazines
This chemistry is obviously not limited to pyrazines. Even though beyond the scope
of the present study, the few examples, obtained under non-optimized reaction
conditions and assembled in Scheme 9, are included to draw attention to the vast
possibilities offered by this approach. These include pyridine (31a), phthalazine (31b),
caffeine (31c), isoquinoline (31d-e) and indole (31f). In the case of electron-rich
caffeine and indole, no acid was required for the reaction to proceed. Interestingly,
phthalazine was readily doubly aminomethylated (31b) and product 31f was obtained
in 70% by simple evaporation of the solvent and trituration with diethyl ether of the
crude residue followed by recrystallization from ethyl acetate.
1
3

ACCEPTED MANUSCRIPT
Scheme 9. Alkylation of other heteroaromatics
To conclude, we have been able to expand the use of the unique radical chemistry of
xanthates to the functionalization of pyrazines and briefly to other heteroaromatic
systems. This approach involves very inexpensive reagents, mild metal-free reaction
conditions, and remarkably good functional group tolerance. Indeed, most of the
structures described would be very tedious, if not impossible, to obtain by other more
conventional methods. The ability to place together so many different functional
groups in close proximity opens manifold post-modification routes, such as ring
closures by ionic condensation of the latent amino group with other functionalities
present in the structure. Studies along these lines are currently underway.
3
3
. Experimental section
.1 General experimental methods
All reactions were carried out under dry, oxygen free nitrogen. Thin Layer
Chromatography (TLC) was performed on alumina plates precoated with silica gel
(
Merck silica gel, 60 F ), which were visualized by the quenching of UV
254
fluorescence when applicable (max = 254 nm and/or 366 nm) and/or by staining with
1
4

ACCEPTED MANUSCRIPT
anisadehyde in acidic ethanol solution and/or KMnO in basic water followed by
4
heating. Flash chromatography was carried out on Kieselgel 60 (40-63 µm).
Petroleum ether refers to the fraction of petroleum boiling between 40 °C and 60 °C.
Infrared spectra were recorded on a Perkin-Elmer Spectrum Two. Absorption maxima
−
1
(
υmax) are reported in wavenumbers (cm ). Nuclear magnetic resonance spectra were
recorded at ambient temperature on a Bruker Avance DPX 400 instrument. Proton
1
magnetic resonance spectra ( H NMR) were recorded at 400 MHz and coupling
constants (J) are reported to ± 0.5 Hz. The following abbreviations were utilized to
describe peak patterns when appropriate: br = broad, s = singlet, d = doublet, t =
1
3
triplet, q = quartet and m = multiplet. Carbon magnetic resonance spectra ( C NMR)
were recorded at 100 MHz. Chemical shifts (H, C) are quoted in parts per million
(
ppm) and are referenced to the residual solvent peak (CDCl : δ = 7.27 and δ = 77.1).
3 H C
High-resolution mass spectra were recorded by electron impact ionization (EI) on a
JMS-GCmateII mass spectrometer. The quoted masses are accurate to ± 5 ppm.
3
.2 General procedures for the xanthate-mediated alkylation
A magnetically stirred solution of xanthate (2.0 equiv) and pyrazine (1.0 equiv) in 1,
-dichloroethane (1.0 mmol/mL according to the xanthate) was refluxed for 15 min
2
under a flow of nitrogen. Then dilauroyl peroxide (DLP) was added portionwise (20
mol % according to the xanthate) every hour until total consumption of one substrate.
The reaction mixture was then cooled to room temperature and the solvent was
evaporated under reduced pressure. Unless otherwise specified, the crude product was
purified by flash chromatography on silica gel.
3
.2.1 2-((5-Chloro-3-(methylamino)pyrazin-2-yl)methyl)isoindoline-1,3-dione (3a).
3
3
According to the general procedure, the reaction was carried out with xanthate 2
(155 mg, 0.55 mmol) and pyrazine 1a (40 mg, 0.28 mmol) in 0.6 mL DCE and needed
5
h for the reaction to go to completion. Flash chromatography on silica gel (gradient
of petroleum ether/Et O = 1/2 to 0/1) afforded the desired product 3a as a white solid
2
1
(
62 mg, 0.20 mmol, 73% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.92 – 7.84 (m,
3
1
5

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2
4
1
1
H), 7.77 – 7.73 (m, 2H), 7.71 (s, 1H), 6.04 (br, 1H, NH), 4.84 (s, 2H), 3.01 (d, J =
1
3
.7 Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.7 (C=O), 153.2, 147.1, 134.6,
3
-1
33.8, 132.0, 129.2, 123.9, 39.9, 28.6. IR (ν, cm , CDCl ) 3384, 2942, 1771, 1714,
3
582, 1511, 1429, 1392, 1382, 1329, 1235, 1106, 1084. HRMS (EI+) calculated for
C H ClN O : 302.0571; Found: 302.0575. mp: 175-176 °C.
14
11
4
2
3
.2.2 2,2'-((3-Chloro-5-(methylamino)pyrazine-2,6-diyl)bis(methylene))bis
(isoindoline-1,3-dione) (4a). The dialkylated product 4a was isolated as a white solid
1
(
7 mg, 0.01 mmol, 5% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.90 – 7.85 (m,
3
3
H), 7.85 – 7.78 (m, 2H), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (s, 1H), 5.91 (br, J = 4.4
1
3
Hz, 1H, NH), 4.97 (s, 2H), 4.81 (s, 2H), 2.99 (d, J = 4.7 Hz, 3H). C NMR (δ, ppm)
(
101 MHz, CDCl ) 168.3, 168.2, 167.9, 153.1, 143.7, 134.6, 134.5, 133.66, 132.0,
3
-1
1
31.5, 129.2, 124.3, 123.8, 123.7, 41.3, 39.9, 28.5. IR (ν, cm , CDCl ) 3386, 1775,
3
1
719, 1582, 1512, 1394, 1392, 1235, 1105, 1086. HRMS (EI+) calculated for
C H ClN O : 461.0891; Found: 461.0902.
23
16
5
4
3
.2.3 2-((3-(Methylamino)pyrazin-2-yl)methyl)isoindoline-1,3-dione (3b). Following
the general procedure, the reaction was carried out with xanthate 2 (566 mg, 2.01
mmol) and 2-methylaminopyrazine (110 mg, 1.01 mmol) in 2.0 mL DCE and needed
6
h for the reaction to go to completion. Flash chromatography on silica gel (gradient
of petroleum ether/Et O = 1:1 to 0:1) afforded the desired product 3b as a light yellow
2
1
solid (181 mg, 0.67 mmol, 67% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.98 (d,
3
J = 2.7 Hz, 1H), 7.87 (dd, J = 5.4, 3.0 Hz, 2H), 7.74 (ddd, J = 7.3, 4.7, 2.8 Hz, 3H),
13
5
.68 (br, 1H, NH), 4.85 (s, 2H), 3.00 (d, J = 4.7 Hz, 3H). C NMR (δ, ppm) (101
MHz, CDCl ) 168.7, 153.6, 142.0, 136.2, 134.4, 132.2, 131.5, 123.8, 40.4, 28.4. IR (ν,
3
-1
cm , CDCl ) 3398, 2930, 1772, 1714, 1587, 1523, 1422, 1392, 1334, 1205, 1084.
3
HRMS (EI+) calculated for C H N O : 268.0960; Found: 268.0959. mp:
1
4
12
4
2
1
3
68-169 °C.
.2.4 2-((3-Chloropyrazin-2-yl)methyl)isoindoline-1,3-dione (3c). Following the
1
6

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general procedure, the reaction was carried out with xanthate 2 (258 mg, 0.92 mmol)
and 2-chloropyrazine (52 mg, 0.46 mmol) in 0.9 mL DCE and needed 7 h for the
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/EtOAC = 10:1 to 4:1) afforded the desired product 3c as a white solid
(44 mg, 0.16 mmol, 35% yield), and 15 mg 2-chloropyrazine (0.13 mmol) was
1
recovered. H NMR (δ, ppm) (400 MHz, CDCl ) 8.31 (d, J = 2.5 Hz, 1H), 8.26 (d, J
3
=
2.5 Hz, 1H), 7.91 (dd, J = 5.4, 3.1 Hz, 2H), 7.77 (dd, J = 5.4, 3.1 Hz, 2H), 5.14 (s,
1
3
2
H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.1, 149.0, 147.7, 142.8, 142.2, 134.3,
3
-1
1
32.5, 123.8, 40.1. IR (ν, cm , CDCl ) 2930, 1775, 1720, 1602, 1421, 1395, 1331,
3
1
192, 1153, 1115, 1083, 1063. HRMS (EI+) calculated for C H ClN O : 273.0305;
1
3
8
3
2
Found: 273.0309. mp: 137-140 °C.
3
.2.5
Following the general procedure, the reaction was carried out with xanthate 2 (287 mg,
.02 mmol) and pyrazine (105 mg, 0.51 mmol) in 1.0 mL DCE and needed 7 h for the
2-((5-Chloro-3-phenoxypyrazin-2-yl)methyl)isoindoline-1,3-dione
(3d).
1
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 3:1 to 1:1) afforded the desired product 3d as a white solid
2
1
(
130 mg, 0.36 mmol, 70% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 8.06 (s, 1H),
3
7
7
1
3
1
3
.92 (dd, J = 5.4, 3.1 Hz, 2H), 7.79 – 7.75 (m, 2H), 7.47 – 7.41 (m, 2H), 7.28 (d, J =
1
3
.4 Hz, 1H), 7.24 – 7.19 (m, 2H), 5.17 (s, 2H). C NMR (δ, ppm) (101 MHz, CDCl )
3
68.2, 155.9, 152.4, 144.4, 138.5, 136.7, 134.2, 132.4, 129.9, 125.9, 123.7, 121.4,
-1
8.0. IR (ν, cm , CDCl ) 2929, 1775, 1719, 1601, 1542, 1490, 1419, 1396, 1384,
3
219, 1175, 1114. HRMS (EI+) calculated for C H ClN O : 365.0567; Found:
19
12
3
3
65.0576. mp: 170-173 °C.
3
.2.6
2-((5-Chloro-3-methoxypyrazin-2-yl)methyl)isoindoline-1,3-dione
(3e).
Following the general procedure, the reaction was carried out with xanthate 2 (342 mg,
.22 mmol) and pyrazine (88 mg, 0.61 mmol) in 1.2 mL DCE and needed 3 h for the
1
reaction to go to completion. Flash chromatography on silica gel (gradient of
toluene/dichloromethane = 4:1 to 2:1) afforded the desired product 3e as a white solid
1
7

ACCEPTED MANUSCRIPT
1
(
119 mg, 0.39 mmol, 64% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.93 (s, 1H),
3
7
3
1
1
.89 (dd, J = 5.5, 3.0 Hz, 2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 4.97 (s, 2H), 4.06 (s,
1
3
H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.2, 156.8, 144.3, 138.2, 134.4, 134.2,
3
-1
32.4, 123.7, 54.8, 37.9. IR (ν, cm , CDCl ) 3422, 3360, 2944, 1686, 1580, 1541,
3
508, 1447, 1376, 1328, 1278, 1259, 1214, 1177, 1124. HRMS (EI+) calculated for
C H ClN O : 303.0411; Found: 303.0405. mp: 185-186 °C.
14
10
3
3
3
.2.7 2-((3-Amino-5-chloropyrazin-2-yl)methyl)isoindoline-1,3-dione (3f). Following
the general procedure, the reaction was carried out with xanthate 2 (434 mg, 1.54
mmol) and pyrazine (100 mg, 0.78 mmol) in 1.5 mL DCE and needed 5 h for the
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 2:3 to 0:1) afforded the desired compound 3f as a white solid
2
1
(
114 mg, 0.39 mmol, 51% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.89 (dd, J =
3
5
.5, 3.0 Hz, 2H), 7.87 (s, 1H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 5.45 (s, 2H, NH ), 4.89
2
1
3
(
s, 2H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.6, 152.8, 146.7, 134.6, 133.4,
3
-
1
1
1
2
32.1, 132.0, 123.9, 39.9. IR (ν, cm , CDCl ) 3481, 3363, 1771, 1714, 1624, 1536,
3
439, 1423, 1392, 1327, 1234, 1208, 1083. HRMS (EI+) calculated for C H ClN O :
1
3
9
4
2
88.0414; Found: 288.0412. mp: 220-221 °C.
3
.2.8 2-((3-(tert-Butylamino)-5-chloropyrazin-2-yl)methyl)isoindoline-1,3-dione (3g).
Following the general procedure, the reaction was carried out with xanthate 2 (579 mg,
.06 mmol) and pyrazine (191 mg, 1.03 mmol) in 2.1 mL DCE and needed 4 h for the
2
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 2:1 to 1:2) afforded the single addition product 3g as a white
2
1
solid (234 mg, 0.68 mmol, 66% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.89
3
(dd, J = 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 7.68 (s, 1H), 5.74 (br, 1H,
13
NH), 4.80 (s, 2H), 1.48 (s, 9H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.6, 152.0,
3
-
1
1
2
1
46.1, 134.5, 133.7, 132.0, 128.7, 123.8, 52.6, 40.0, 28.7. IR (ν, cm , CDCl ) 3374,
3
968, 1772, 1714, 1575, 1545, 1457, 1429, 1392, 1366, 1328, 1256, 1233, 1213, 1117,
079, 987. HRMS (EI+) calculated for C H ClN O : 344.1040; Found: 344.1042.
1
7
17
4
2
1
8

ACCEPTED MANUSCRIPT
mp: 158-159 °C.
3
.2.9 2,2'-((3-(tert-Butylamino)-5-chloropyrazine-2,6-diyl)bis(methylene))bis-
(isoindoline-1,3-dione) (4b). The dialkylated product 4b was isolated as a white solid
1
(
128 mg, 0.25 mmol, 25% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.74 (dd, J =
3
5
2
1
2
1
.5, 3.1 Hz, 2H), 7.69 (q, J = 3.1, 2.4 Hz, 2H), 7.66 (m, 4H), 5.25 (s, 1H, NH), 4.89 (s,
1
3
H), 4.57 (s, 2H), 1.46 (s, 9H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.2, 167.9,
3
50.9, 143.2, 134.1, 133.8, 133.2, 132.40, 131.9, 131.5, 123.5, 123.3, 52.6, 39.2, 39.1,
-1
8.8. IR (ν, cm , CDCl ) 3373, 2968, 1775, 1718, 1576, 1503, 1469, 1456, 1428,
3
396, 1365, 1322, 1213, 1187, 1112, 1087, 1036. HRMS (EI+) calculated for
C H ClN O : 503.1360; Found: 503.1355. mp: 242-244 °C.
26
22
5
4
3
.2.10 2-((3-Methoxypyrazin-2-yl)methyl)isoindoline-1,3-dione (3h). Following the
general procedure, the reaction was carried out with xanthate 2 (331 mg, 1.18 mmol)
and pyrazine (65 mg, 0.59 mmol) in 1.2 mL DCE and needed 3 h for the reaction to
go to completion. Flash chromatography on silica gel (gradient of petroleum
ether/Et O = 3:1 to 2:1) afforded the desired product 3h as a white solid (96 mg, 0.36
2
1
mmol, 61% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.96 (d, J = 2.7 Hz, 1H),
3
7
5
1
1
.92 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.4, 3.1 Hz, 2H),
13
.01 (s, 2H), 4.03 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.4, 157.9, 140.4,
3
-1
39.5, 135.8, 134.1, 132.5, 123.6, 53.8, 38.4. IR (ν, cm , CDCl ) 2952, 1774, 1718,
3
602, 1548, 1462, 1424, 1395, 1360, 1172, 1144, 1011. HRMS (EI+) calculated for
C H N O : 269.0800; Found: 269.0796. mp: 158-160 °C.
14
11
3
3
3
.2.11 2-((3,5-Dimethoxypyrazin-2-yl)methyl)isoindoline-1,3-dione (3i). Entry 1: A
magnetically stirred solution of xanthate 2 (281 mg, 1.00 mmol, 1.0 equiv) and
,6-dimethoxypyrazine (283 mg, 2.00 mmol, 2.0 equiv) in 1 mL DCE was refluxed
2
for 15 min under a flow of nitrogen. 20 mol % of DLP was then added every hour
until the total consumption of one substrate. After 6 h, the reaction mixture was
cooled to room temperature and the solvent was then evaporated. The crude product
1
9

ACCEPTED MANUSCRIPT
was purified by flash chromatography on silica gel (toluene/EtOAc = 5:1) to give the
mono addition product 3i as a white solid (166 mg, 0.55 mmol, 55% yield). Entry 2:
A magnetically stirred solution of xanthate 2 (452 mg, 1.61 mmol, 3.0 equiv) and
2
,6-dimethoxypyrazine (75 mg, 0.54 mmol, 1.0 equiv) in 1 mL DCE was refluxed for
5 min under a flow of nitrogen. 20 mol % of DLP was then added every hour until
1
the total consumption of one substrate. After 6 h, the reaction mixture was cooled to
room temperature and the solvent was then evaporated. The crude product was
purified by flash chromatography on silica gel (toluene/EtOAc = 5:1) to give the
1
mono addition product 3i as a white solid (41 mg, 0.17 mmol, 25% yield). H NMR
(
δ, ppm) (400 MHz, CDCl ) 7.87 (dd, J = 5.4, 3.0 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.60
3
1
3
(
s, 1H), 4.94 (s, 2H), 4.00 (s, 3H), 3.91 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl )
3
-1
1
68.4, 158.7, 155.9, 134.0, 132.6, 129.5, 123.5, 123.2, 53.9, 53.7, 37.8. IR (ν, cm ,
CDCl ) 2849, 1774, 1717, 1584, 1547, 1485, 1456, 1423, 1398, 1380, 1365, 1313,
3
1176, 1112, 1047, 1013. HRMS (EI+) calculated for C H N O : 299.0906; Found:
15 13 3 4
2
99.0906. mp: 197-198 °C.
3
1
0
.2.12 2,2'-((3,5-Dimethoxypyrazine-2,6-diyl)bis(methylene))bis(isoindoline-
,3-dione) (4c). Entry 1: Dialkylated product 4c was isolated as a white solid (42 mg,
.09 mmol, 9% yield). Entry 2: Dialkylated product 4c was isolated as a white solid
1
(
123 mg, 0.27 mmol, 50% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.58 (dt, J =
3
1
3
7
.1, 3.5 Hz, 4H), 7.55 – 7.48 (m, 4H), 4.78 (s, 4H), 3.99 (s, 6H). C NMR (δ, ppm)
-1
(
101 MHz, CDCl ) 167.8, 155.2, 133.6, 132.1, 128.0, 123.1, 53.9, 37.2. IR (ν, cm ,
3
CDCl ) 2988, 2946, 1775, 1721, 1479, 1455, 1430, 1419, 1396, 1353, 1199, 1184,
3
1
112, 1014. HRMS (EI+) calculated for C H N O : 458.1226; Found: 458.1235.
2
4
18
4
6
mp: 318-319°C.
3
.2.13 2-((3-(Methylthio)pyrazin-2-yl)methyl)isoindoline-1,3-dione (3j). Following
the general procedure, the reaction was carried out with xanthate 2 (332 mg, 1.18
mmol) and pyrazine (74 mg, 0.59 mmol) in 1.2 mL DCE and needed 7 h for the
reaction to go to completion. Flash chromatography on silica gel (gradient of
2
0

ACCEPTED MANUSCRIPT
petroleum ether/Et O = 4:1 to 2:1) afforded the desired product 3j as a white solid (67
2
1
mg, 0.23 mmol, 40% yield) and 4 mg (0.05 mmol) pyrazine was recovered. H NMR
(δ, ppm) (400 MHz, CDCl ) 8.25 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.89
3
1
3
(
dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 4.94 (s, 2H), 2.62 (s, 3H). C
NMR (δ, ppm) (101 MHz, CDCl ) 168.2, 154.8, 147.3, 142.4, 138.1, 134.1, 132.5,
3
-
1
1
1
2
23.6, 39.4, 12.7. IR (ν, cm , CDCl ) 3055, 2932, 1775, 1718, 1520, 1470, 1422,
3
396, 1324, 1192, 1154, 1114, 1088, 1066. HRMS (EI+) calculated for C H N O S:
1
4
11
3
2
85.0572; Found: 285.0579. mp: 172-173 °C.
3
.2.14 Methyl 5-((1,3-dioxoisoindolin-2-yl)methyl)pyrazine-2-carboxylate (3k).
Following the general procedure, the reaction was carried out with xanthate 2 (416 mg,
.48 mmol) and methyl 2-pyrazinecarboxylate (102 mg, 0.74 mmol) in 1.5 mL DCE
1
and needed 7 h for the reaction to go to completion. Flash chromatography on silica
gel (gradient of petroleum ether/EtOAc = 3/1 to 1/2) afforded the desired product 3k
as a white solid (84 mg, 0.28 mmol, 38% yield), and 36 mg pyrazine (0.26 mmol) was
1
recovered. H NMR (δ, ppm) (400 MHz, CDCl ) 9.17 (d, J = 1.4 Hz, 1H), 8.75 (d, J
3
=
1.4 Hz, 1H), 7.90 (dd, J = 5.4, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 5.12 (s,
1
3
2
1
1
2
H), 4.01 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 167.9, 164.4, 154.4, 145.7,
3
-1
43.1, 142.3, 134.4, 132.2, 123.8, 53.2, 40.8. IR (ν, cm , CDCl ) 2929, 1776, 1721,
3
602, 1423, 1395, 1316, 1273, 1135, 1032. HRMS (EI+) calculated for C H N O :
15
11
3
4
97.0750; Found: 297.0759. mp: 167-170 °C.
3
.2.15 2-((3,5-Dichloropyrazin-2-yl)methyl)isoindoline-1,3-dione (3l). Following the
general procedure, the reaction was carried out with xanthate 2 (281 mg, 1.00 mmol,
.0 equiv), 2,6-dichloropyrazine (74 mg, 0.50 mmol, 1.0 equiv) and TFA (68 mg, 48
2
µL, 0.6 mmol, 1.2 equiv) in 1.0 mL DCE and needed 6 h for the reaction to go to
completion. Flash chromatography on silica gel (gradient of petroleum
ether/dichloromethane = 1:1 to 2:3, then ethyl acetate/petroleum ether = 1:1) afforded
1
the desired product 3l as a white solid (78 mg, 0.25 mmol, 51% yield). H NMR (δ,
ppm) (400 MHz, CDCl ) 8.31 (s, 1H), 7.91 (dd, J = 5.5, 3.1 Hz, 2H), 7.77 (dd, J = 5.5,
3
2
1

ACCEPTED MANUSCRIPT
1
3
3
1
1
.1 Hz, 2H), 5.10 (s, 2H). C NMR (δ, ppm) (101 MHz, CDCl ) 167.9, 146.9, 146.5,
3
-1
45.6, 141.9, 134.4, 132.2, 123.8, 39.5. IR (ν, cm , CDCl ) 1776, 1722, 1520, 1470,
3
424, 1415, 1395, 1322, 1290, 1258, 1195, 1174, 1156, 1116, 1072. HRMS (EI+)
calculated for C H Cl N O : 306.9915; Found: 306.9906. mp: 175-176 °C.
1
3
7
2
3
2
3
.2.16 2,2'-((3,5-Dichloropyrazine-2,6-diyl)bis(methylene))bis(isoindoline-1,3-dione)
1
(
4d). Product 4d was isolated as a white solid (36 mg, 0.08 mmol, 15% yield). H
NMR (δ, ppm) (400 MHz, CDCl )7.62 – 7.57 (m, 4H), 7.53 – 7.48 (m, 4H), 4.96 (s,
3
1
3
4
H). C NMR (δ, ppm) (101 MHz, CDCl ) 167.2, 146.5, 144.1, 134.0, 131.7, 123.4,
3
-1
3
9.1. IR (ν, cm , CDCl ) 1777, 1726, 1602, 1470, 1422, 1404, 1381, 1310, 1194,
3
1
163, 1104. HRMS (EI+) calculated for C H Cl N O : 466.0236; Found: 466.0241.
2
2
12
2
4
4
mp: 303-304 °C.
3
.2.17 2-((3,5-Dimethylpyrazin-2-yl)methyl)isoindoline-1,3-dione (3m). Following the
general procedure, the reaction was carried out with xanthate 2 (563 mg, 2.00 mmol,
2
.0 equiv), 2,6-dimethylpyrazine (108 mg, 1.00 mmol, 1.0 equiv) and TFA (137 mg,
9
2 µL, 1.20 mmol, 1.2 equiv) in 1.0 mL DCE and needed 6 h for the reaction to go to
completion. Flash chromatography on silica gel (gradient of petroleum ether/diethyl
ether = 1:1 to 2:3, then ethyl acetate/petroleum ether = 1:1 to 2:1) afforded product
1
3
m (120 mg, 0.45 mmol, 45% yield) as a white solid. H NMR (δ, ppm) (400 MHz,
CDCl ) 8.08 (s, 1H, H ), 7.91 – 7.84 (m, 2H), 7.76 – 7.70 (m, 2H), 4.97 (s, 2H), 2.63
3
1
1
3
(
s, 3H), 2.45 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.4, 151.6, 150.1,
3
-1
1
45.1, 141.2, 134.1, 132.4, 123.6, 39.8, 21.2. IR (ν, cm , CDCl ) 3052, 2928, 1774,
3
1
716, 1469, 1420, 1396, 1345, 1324, 1276, 1194, 1175, 1133, 1111, 1089. HRMS
(
EI+) calculated for C H N O : 267.1008; Found: 267.1000. mp: 137-138 °C.
15 13 3 2
3
.2.18 2,2'-((3,5-Dimethylpyrazine-2,6-diyl)bis(methylene))bis(isoindoline-1,3-dione)
1
(
4e). Product 4e was isolated as a white solid (26 mg, 0.08 mmol, 6% yield). H
NMR (δ, ppm) (400 MHz, CDCl ) 7.64 – 7.58 (m, 4H), 7.56 – 7.49 (m, 4H), 4.81 (s,
3
1
3
4
H), 2.59 (s, 6H). C NMR (δ, ppm) (101 MHz, CDCl ) 167.7, 148.7, 144.7, 133.7,
3
2
2

ACCEPTED MANUSCRIPT
-
1
1
1
4
32.0, 123.2, 39.4, 20.6. IR (ν, cm , CDCl ) 1775, 1721, 1469, 1428, 1397, 1343,
3
323, 1198, 1178, 1112. HRMS (EI+) calculated for C H N O : 426.1328; Found:
2
4
18
4
4
26.1324. mp: 282-283 °C.
3
.2.19 2-((3-Ethylpyrazin-2-yl)methyl)isoindoline-1,3-dione (3n). Following the
general procedure, the reaction was carried out with xanthate 2 (563 mg, 2.00 mmol,
2
.0 equiv), 2-ethylpyrazine (108 mg, 1.00 mmol, 1.0 equiv) and TFA (137 mg, 92 µL,
1
.20 mmol, 1.2 equiv) in 1.0 mL DCE and needed 5 h for the reaction to go to
completion. Flash chromatography on silica gel (gradient of petroleum ether/diethyl
ether = 3:2 to 1:2) afforded product 3n (43 mg, 0.16 mmol, 16% yield) as a white
1
solid. H NMR (δ, ppm) (400 MHz, CDCl ) 8.37 (d, J = 2.6 Hz, 1H), 8.21 (d, J = 2.5
3
Hz, 1H), 7.93 – 7.87 (m, 2H), 7.79 – 7.72 (m, 2H), 5.04 (s, 2H), 2.97 (q, J = 7.5 Hz,
1
3
2
H), 1.40 (t, J = 7.5 Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.4, 155.8,
3
-1
1
48.0, 142.8, 141.5, 134.2, 132.5, 123.6, 39.7, 27.3, 12.1. IR (ν, cm , CDCl ) 3056,
3
2
978, 2939, 2879, 1774, 1718, 1602, 1469, 1426, 1410, 1395, 1351, 1325, 1193, 1161,
1
112, 1089. HRMS (EI+) calculated for C H N O : 267.1008; Found: 267.1019.
1
5
13
3
2
mp: 142-143 °C.
3
.2.20 2,2'-((3-Ethylpyrazine-2,6-diyl)bis(methylene))bis(isoindoline-1,3-dione) and
,2'-((3-ethylpyrazine-2,5-diyl)bis(methylene))bis(isoindoline-1,3-dione) (4f).
2
Products 4f was isolated in 1:1 mixture as a white solid (48 mg, 0.11 mmol, 11%
1
yield). H NMR (δ, ppm) (400 MHz, CDCl ) 8.20 (s, 1H), 8.15 (s, 1H), 7.88 (dddd, J
3
=
12.7, 4.5, 3.7, 2.3 Hz, 8H), 7.74 (qd, J = 5.4, 3.0 Hz, 8H), 5.20 (s, 2H), 5.14 (s, 2H),
4
7
1
1
3
4
.98 (d, J = 1.9 Hz, 4H), 2.87 (q, J = 7.5 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H), 1.23 (t, J =
1
3
.5 Hz, 3H), 1.01 (t, J = 7.5 Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.34,
3
68.31, 168.2, 168.0, 156.8, 154.9, 148.6, 146.7, 146.4, 144.7, 142.0, 139.4, 134.23,
34.16, 134.13, 134.11, 132.5, 132.44, 132.40, 132.2, 123.7, 123.60, 123.58, 40.6,
9.7, 39.4, 39.3, 28.0, 26.9, 12.6, 11.7. HRMS (EI+) calculated for C H N O :
24
18
4
4
26.1328; Found: 426.1338.
2
3

ACCEPTED MANUSCRIPT
3
.2.21 2-((6-Chloro-3-(methylamino)pyrazin-2-yl)methyl)isoindoline-1,3-dione (3o).
Following the general procedure, the reaction was carried out with xanthate 2 (231 mg,
.82 mmol) and pyrazine (59 mg, 0.41 mmol) in 0.8 mL DCE and needed 5 h for the
0
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 3:2 to 1:3) afforded the desired product 3o as a light yellow
2
1
solid (36 mg, 0.12 mmol, 29% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 8.00 (s,
3
1
4
1
2
H), 7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 5.74 (br, 1H, NH),
13
.83 (s, 2H), 2.99 (d, J = 4.7 Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.5,
3
-1
52.3, 141.2, 134.9, 134.5, 134.4, 132.0, 123.9, 40.0, 28.8. IR (ν, cm , CDCl ) 3392,
3
944, 1773, 1714, 1582, 1511, 1427, 1389, 1370, 1327, 1210, 1083. HRMS (EI+)
calculated for C H ClN O : 302.0571; Found: 302.0559. mp: 185-186 °C.
1
4
11
4
2
3
.2.22
Following the general procedure, the reaction was carried out with xanthate 2 (563 mg,
.00 mmol) and pyrazine (130 mg, 1.00 mmol) in 2.0 mL DCE and needed 6 h for the
2-((3-Amino-6-chloropyrazin-2-yl)methyl)isoindoline-1,3-dione
(3p).
2
reaction to go to completion. Flash chromatography on silica gel (gradient of
EtOAc/petroleum ether = 1:4 to 1:0) afforded product 3p as a white solid (112 mg,
1
0
.39 mmol, 39% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.96 (s, 1H, H ), 7.88
3
4
(
dd, J = 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 5.25 (s, 2H, NH ), 4.86 (s,
2
1
3
2
1
1
2
H). C NMR (δ, ppm) (101 MHz, CDCl ) 168.5, 151.9, 141.7, 136.6, 134.6, 131.9,
3
-1
23.9, 40.1. IR (ν, cm , CDCl ) 3485, 3372, 1774, 1715, 1623, 1448, 1428, 1399,
3
387, 1352, 1325, 1201, 1171, 1079. HRMS (EI+) calculated for C H ClN O :
1
3
9
4
2
88.0414; Found: 288.0426. mp: 199-200 °C.
3
.2.23 2,2'-((3-Amino-6-chloropyrazine-2,5-diyl)bis(methylene))bis(isoindoline-
1
,3-dione) (4h). Product 4h was isolated as a white solid (112 mg, 0.25 mmol, 25%
1
yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.89-7.85 (m, 4H), 7.77-7.73 (m, 4H),
3
1
3
5
1
3
.12 (s, 2H, NH ), 4.94 (s, 2H), 4.82 (s, 2H). C NMR (δ, ppm) (101 MHz, CDCl )
2
3
68.4, 168.1, 151.7, 145.7, 134.5, 134.2, 133.7, 133.3, 132.4, 131.9, 123.8, 123.6,
-1
9.7, 39.6. IR (ν, cm , CDCl ) 3484, 3368, 1775, 1718, 1622, 1470, 1418, 1392, 1321,
3
2
4

ACCEPTED MANUSCRIPT
1
4
213, 1193, 1115, 1087. HRMS (EI+) calculated for C H ClN O : 447.0734; Found:
2
2
14
5
4
47.0736. mp: 256-258 °C.
3
.2.24
3-((5-Chloro-3-(methylamino)pyrazin-2-yl)methyl)oxazolidin-2-one
(5a).
3
3
Following the general procedure, the reaction was carried out with xanthate (308 mg,
.39 mmol) and pyrazine 1a (100 mg, 0.70 mmol) in 1.4 mL DCE and needed 6 h for
1
the reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 1:1 to EtOAc/petroleum ether = 2:1) afforded the desired
2
1
product 5a as a white solid (79 mg, 0.33 mmol, 47% yield). H NMR (δ, ppm) (400
MHz, CDCl ) 7.62 (s, 1H), 6.40 (br, 1H, NH), 4.41 (s, 2H), 4.40 – 4.36 (m, 2H), 3.61
3
1
3
–
1
1
3.57 (m, 2H), 2.97 (d, J = 4.7 Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl )159.8,
3
-1
53.8, 147.6, 134.0, 128.1, 62.6, 47.1, 44.7, 28.4. IR (ν, cm , CDCl ) 3361, 2941,
3
732, 1585, 1512, 1444, 1383, 1272, 1237, 1103, 1088, 1037. HRMS (EI+)
calculated for C H ClN O : 242.0571; Found: 242.0580. mp: 167-169 °C.
9
11
4
2
3
.2.25 3-((5-Chloro-3-phenoxypyrazin-2-yl)methyl)oxazolidin-2-one (5b). Following
3
3
the general procedure, the reaction was carried out with xanthate (314 mg, 1.42
mmol) and pyrazine 1a (147 mg, 0.71 mmol) in 1.4 mL DCE and needed 6 h for the
reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 1:2 to 1:0) afforded the desired product 5b as a white solid
2
1
(
125 mg, 0.41 mmol, 58% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 8.21 (s, 1H,
3
H ), 7.48 – 7.39 (m, 2H), 7.29 – 7.26 (m, 1H, H ), 7.17 (dd, J = 5.4, 3.4 Hz, 2H), 4.75
3
8
1
3
(
s, 2H), 4.43 (dd, J = 8.7, 7.3 Hz, 2H), 3.76 (dd, J = 8.7, 7.3 Hz, 2H). C NMR (δ,
ppm) (101 MHz, CDCl ) 159.0, 156.3, 152.4, 144.6, 139.3, 136.8, 129.9, 125.9, 121.3,
3
-
1
6
1
3
2.3, 45.4, 44.4. IR (ν, cm , CDCl ) 2923, 1755, 1600, 1541, 1490, 1426, 1376, 1277,
3
219, 1195, 1184, 1172, 1162, 1114, 1042. HRMS (EI+) calculated for C H ClN O :
1
4
12
3
3
05.0567; Found: 305.0555. mp : 129-131 °C.
3
.2.26 1-((5-Chloro-3-(methylamino)pyrazin-2-yl)methyl)pyrrolidine-2,5-dione (5c).
3
2
Following the general procedure, the reaction was carried out with xanthate (284 mg,
2
5

ACCEPTED MANUSCRIPT
1
.22 mmol) and pyrazine 1a (87 mg, 0.61 mmol) in 1.2 mL DCE and needed 6 h for
the reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/EtOAc = 3:2 to 0:1) afforded the desired product 5c as a white solid
1
(
81 mg, 0.32 mmol, 52% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.69 (s, 1H),
3
1
3
6
.00 (s, 1H, NH), 4.65 (s, 2H), 2.97 (d, J = 4.7 Hz, 3H), 2.79 (s, 4H). C NMR (δ,
ppm) (101 MHz, CDCl ) 177.6, 153.2, 147.0, 133.1, 129.1, 40.6, 28.4, 28.3. IR (ν,
3
-1
cm , CDCl ) 3376, 2944, 1779, 1704, 1583, 1543, 1511, 1430, 1397, 1383, 1337,
3
1
266, 1236, 1217, 1175, 1154, 1102. HRMS (EI+) calculated for C H ClN O :
10 11 4 2
2
54.0571; Found: 254.0578. mp: 139-140 °C.
3
.2.27 1,1'-((3-Chloro-5-(methylamino)pyrazine-2,6-diyl)bis(methylene))bis-
(pyrrolidine-2,5-dione) (7a). Product 7a was isolated as a white solid (64 mg, 0.17
1
mmol, 28% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 5.95 (br, 1H, NH), 4.75 (s,
3
1
3
2
H), 4.52 (s, 2H), 2.96 (d, J = 4.7 Hz, 3H), 2.87 (s, 4H), 2.74 (s, 4H). C NMR (δ,
ppm) (101 MHz, CDCl ) 177.8, 177.5, 152.8, 144.6, 132.9, 131.4, 40.0, 39.4, 28.7,
3
-
1
2
1
3
8.6, 28.4. IR (ν, cm , CDCl ) 3376, 2944, 1778, 1705, 1586, 1514, 1428, 1401, 1359,
3
329, 1294, 1233, 1173, 1153, 1018. HRMS (EI+) calculated for C H ClN O :
1
5
16
5
4
65.0891; Found: 365.0887. mp: 111-114 °C.
3
.2.28 N-((5-Chloro-3-(methylamino)pyrazin-2-yl)methyl)-N-phenylacetamide (5d).
3
4
Following the general procedure, the reaction was carried out with xanthate (345
mg, 1.28 mmol) and pyrazine 1a (92 mg, 0.64 mmol) in 1.3 mL DCE and needed 5 h
for the reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 1:1 to 1:2) afforded the desired product 5d as a white solid
2
1
(
125 mg, 0.43 mmol, 67% yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.43 (s, 1H,
3
H ), 7.40 – 7.33 (m, 3H), 7.13 (br, 1H, NH), 6.95 – 6.93 (m, 2H), 4.91 (s, 2H), 3.01 (d,
3
13
J = 4.7 Hz, 3H), 1.88 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 172.5, 153.8,
3
-
1
1
3
47.1, 141.5, 135.0, 130.1, 128.8, 128.1, 127.7, 51.6, 28.4, 22.7. IR (ν, cm , CDCl )
3
320, 3126, 2944, 1637, 1596, 1516, 1495, 1440, 1385, 1299, 1239, 1198, 1104, 1013.
HRMS (EI+) calculated for C H ClN O: 290.0934; Found: 290.0930. mp:
14
15
4
2
6

ACCEPTED MANUSCRIPT
1
3
33-135 °C.
.2.29
N-(1-(5-chloro-3-(methylamino)pyrazin-2-yl)-2,2,2-trifluoroethyl)acetamide
3
5
(5e). Following the general procedure, the reaction was carried out with xanthate
(522 mg, 2.00 mmol) and pyrazine 1a (143 mg, 1.00 mmol) in 2.0 mL DCE and
needed 5 h for the reaction to go to completion. Flash chromatography on silica gel
(gradient of petroleum ether/EtOAc = 3:1 to 1:1) afforded the desired product 5e as a
1
white solid (208 mg, 0.74 mmol, 74% yield). H NMR (δ, ppm) (400 MHz, CDCl )
3
7
4
1
.74 (s, 1H), 6.97 (br, 1H, NH), 6.08 (br, 1H, NH), 6.01 – 5.92 (m, 1H), 2.99 (d, J =
1
3
.7 Hz, 3H), 2.14 (s, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 170.5, 153.1, 148.1,
3
30.1, 128.5, 124.2 (q, J = 282.1 Hz, CF ), 49.1 (q, J = 31.8 Hz), 28.5, 23.3. IR (ν,
3
-1
cm , CDCl ) 3422, 3360, 2944, 1686, 1580, 1541, 1508, 1447, 1376, 1328, 1278,
3
1
259, 1214, 1177, 1124. HRMS (EI+) calculated for C H ClF N O: 282.0495;
9 10 3 4
Found: 282.0490. mp: 201-202 °C.
3
.2.30 2-(5-Chloro-3-(methylamino)pyrazin-2-yl)-N-methoxy-N-methylacetamide (5f).
3
6
Following the general procedure, the reaction was carried out with xanthate (632
mg, 2.83 mmol) and pyrazine 1a (203 mg, 1.41 mmol) in 2.8 mL DCE and needed 7 h
for the reaction to go to completion. Flash chromatography on silica gel (gradient of
diethyl ether/petroleum ether = 1:1 to 4:1, then diethyl ether/MeOH = 15:1 to 5:1)
afforded the mono addition product 5f as a white solid (169 mg, 0.69 mmol, 49%
1
yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.68 (s, 1H), 6.64 (br, 1H, NH), 3.89 (s,
3
13
2
H), 3.74 (s, 3H), 3.21 (s, 3H), 2.98 (d, J = 4.7 Hz, 3H). C NMR (δ, ppm) (101
-1
MHz, CDCl ) 170.3, 154.9, 146.0, 134.9, 128.9, 62.2, 39.0, 32.3, 28.4. IR (ν, cm ,
3
CDCl ) 3345, 2941, 1637, 1588, 1516, 1443, 1391, 1383, 1286, 1231, 1188, 1108,
3
1
004. HRMS (EI+) calculated for C H ClN O : 244.0727; Found: 244.0731. mp:
9 13 4 2
1
42-143 °C.
3
.2.31 2,2'-(3-Chloro-5-(methylamino)pyrazine-2,6-diyl)bis(N-methoxy-N-methyl-
acetamide) (7b). Product 7b was isolated as a white solid (52 mg, 0.15 mmol, 11%
2
7

ACCEPTED MANUSCRIPT
1
yield). H NMR (δ, ppm) (400 MHz, CDCl ) 6.51 (br, 1H, NH), 3.94 (s, 2H), 3.89 (s,
3
13
2
H), 3.74 (s, 3H), 3.70 (s, 3H), 3.20 (s, 3H), 3.18 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H). C
NMR (δ, ppm) (101 MHz, CDCl ) 171.2, 170.4, 153.9, 145.4, 134.5, 133.3, 62.4,
3
-1
6
1.5, 39.0, 37.9, 32.5, 32.3, 28.6. IR (ν, cm , CDCl ) 3345, 2969, 2940, 2903, 1639,
3
1
588, 1517, 1443, 1421, 1387, 1372, 1337, 1283, 1172, 1027, 1003. HRMS (EI+)
calculated for C H ClN O : 345.1204; Found: 345.1218. mp: 141-142 °C.
1
3
20
5
4
3
.2.32
2-(5-Chloro-3-(methylamino)pyrazin-2-yl)-N,N-dimethylacetamide
(5g).
Following the general procedure, the reaction was carried out with xanthate S5 (586
mg, 2.83 mmol) and pyrazine 1a (203 mg, 1.41 mmol) in 2.8 mL DCE and needed 7 h
for the reaction to go to completion. Flash chromatography on silica gel (gradient of
diethyl ether/petroleum ether = 3:2 to 4:1, then diethyl ether/MeOH = 15:1 to 5/1)
afforded the mono addition product 7c as a white solid (179 mg, 0.78 mmol, 56%
1
yield). H NMR (δ, ppm) (400 MHz, CDCl ) 7.63 (s, 1H), 6.87 (s, 1H, NH), 3.78 (s,
3
1
3
2
H), 3.18 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H), 2.94 (s, 3H). C NMR (δ, ppm) (101
-1
MHz, CDCl ) 169.0, 154.8, 146.0, 134.7, 128.2, 41.6, 38.4, 35.9, 28.3. IR (ν, cm ,
3
CDCl ) 3341, 2941, 1631, 1591, 1518, 1441, 1404, 1384, 1287, 1230, 1199, 1189,
3
1116, 1100, 1059, 974. HRMS (EI+) calculated for C H ClN O: 228.0778; Found:
9 13 4
2
28.0768. mp: 149-150 °C.
3
.2.33 2,2'-(3-Chloro-5-(methylamino)pyrazine-2,6-diyl)bis(N,N-dimethylacetamide)
1
(
7c). Product 7c was isolated as a white solid (63 mg, 0.20 mmol, 14% yield). H
NMR (δ, ppm) (400 MHz, CDCl ) 6.65 (q, J = 5.0 Hz, 1H, NH), 3.83 (s, 2H), 3.76 (s,
3
13
2
H), 3.16 (s, 3H), 3.06 (s, 3H), 2.97 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H), 2.91 (s, 3H). C
NMR (δ, ppm) (101 MHz, CDCl ) 169.7, 168.9, 153.8, 145.1, 134.2, 133.2, 41.6,
3
-1
3
9.0, 38.3, 37.6, 35.9, 35.7, 28.5. IR (ν, cm , CDCl ) 3348, 2939, 1633, 1592, 1518,
3
1
402, 1374, 1338, 1288, 1264, 1189, 11134, 1068, 1029. HRMS (EI+) calculated for
C H ClN O : 313.1306; Found: 313.1294. mp: 171-173 °C.
13
20
5
2
3
.2.34 2-(5-Chloro-3-(methylamino)pyrazin-2-yl)acetonitrile (5h). Following the
2
8

ACCEPTED MANUSCRIPT
3
7
general procedure, the reaction was carried out with cyanomethyl xanthate (478 mg,
2
.98 mmol) and pyrazine 1a (214 mg, 1.49 mmol) in 3.0 mL DCE and needed 6 h for
the reaction to go to completion. Flash chromatography on silica gel (gradient of
petroleum ether/Et O = 2:1 to 0:1) gave two portions. The first portion was further
2
purified by flash chromatography on silica gel (gradient of petroleum ether/EtOAc =
1
3
:1 to 1:1) afforded 5h (60 mg, 0.33 mmol, 22% yield) as a white solid. H NMR (δ,
ppm) (400 MHz, CDCl ) 7.79 (s, 1H), 4.56 (br, 1H, NH), 3.75 (s, 2H), 3.07 (d, J = 4.8
3
1
3
Hz, 3H). C NMR (δ, ppm) (101 MHz, CDCl ) 152.3, 147.5, 130.2, 129.0, 114.9,
3
-
1
2
1
1
8.8, 22.9. IR (ν, cm , CDCl ) 3470, 2947, 1577, 1541, 1507, 142, 1408, 1375, 1282,
3
228, 1209, 1181, 1099. HRMS (EI+) calculated for C H ClN : 182.0359; Found:
7
7
4
82.0364. mp: 190-191 °C.
3
.2.35 2-(3-Chloro-5-(methylamino)pyrazin-2-yl)acetonitrile (8). Product 8 was
1
isolated as a light yellow solid (8 mg, 0.04 mmol, 3% yield). H NMR (δ, ppm) (400
MHz, CDCl ) 7.78 (s, 1H), 4.86 (br, 1H, NH), 3.90 (s, 2H), 3.00 (d, J = 5.1 Hz, 3H).
3
1
3
C NMR (δ, ppm) (101 MHz, CDCl ) 154.7, 145.7, 129.8, 129.1, 116.4, 28.7, 23.4.
3
-1
IR (ν, cm , CDCl ) 3459, 2948, 1591, 1519, 1415, 1376, 1329, 1144, 1063. HRMS
3
(
EI+) calculated for C H ClN : 182.0359; Found: 182.0350.
7 7 4
3
.2.36 2,2'-(3-Chloro-5-(methylamino)pyrazine-2,6-diyl)diacetonitrile (7d). Product
1
7
d was isolated as a light yellow solid (31 mg, 0.14 mmol, 9% yield). H NMR (δ,
ppm) (400 MHz, CD CN) 5.66 (br, 1H, NH), 3.93 (s, 2H), 3.78 (s, 2H), 2.89 (d, J =
3
1
3
4
.7 Hz, 3H). C NMR (δ, ppm) (101 MHz, CD CN) 153.1, 145.4, 132.4, 128.9,
3
-1
1
17.6, 116.4, 28.4, 23.5, 23.2. IR (ν, cm , CDCl ) 3468, 1580, 1513, 1411, 1367,
3
1
178, 1025. HRMS (EI+) calculated for C H ClN : 221.0468; Found: 221.0461. mp:
9 8 5
1
85-186 °C.
3
.2.37 2-(5-Chloro-3-(methylamino)pyrazin-2-yl)propanenitrile (5i). Following the
general procedure, the reaction was carried out with xanthate (522 mg, 2.98 mmol)
and pyrazine 1a (214 mg, 1.49 mmol) in 3.0 mL DCE and needed 6 h for the reaction
2
9