Visible-Light-Mediated Synthesis of Pyrazines from Vinyl Azides Utilizing a Photocascade Process

Article abstract of DOI:10.1055/s-0036-1590888

A convenient method for the synthesis of substituted pyrazines from vinyl azides has been developed. This method is enabled by a dual-energy and electron-transfer strategy by visible-light photocatalysis. Initially, vinyl azides are activated by a triplet sensitization process from an excited ruthenium photocatalyst in the presence of water to form dihydropyrazines, followed by a single-electron-transfer (SET) process under oxygen (air) atmosphere that leads to the tetrasubstituted pyrazines in good to excellent yields.

Full text of DOI:10.1055/s-0036-1590888

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–H
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A. Hossain et al.
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Visible-Light-Mediated Synthesis of Pyrazines from Vinyl Azides
Utilizing a Photocascade Process
Asik Hossain
EtOOC
N
Ar(Het)
COOEt
[Ru(bpy)3]Cl2 (1 mol%)
Visible Light
(Het)Ar
Santosh K. Pagire
N3
(Het)Ar
N
COOEt
Oliver Reiser*
0
0
0
0
0-
0
0
3
1-
4
3
0
5-
7
3
X
Vinyl Azides
Pyrazines
H2O then O2 (air)
Institut für Organische Chemie, Universität Regensburg,
Universitätsstraße 31, 93053 Regensburg, Germany
oliver.reiser@chemie.uni-regensburg.de
Energy
Transfer
Electron
Transfer
H
(Het)Ar
EtOOC
N
COOEt
Ar(Het)
[Ru]
H2O
Dedicated to Professor Albert Padwa on the occasion of his
80th birthday
[Ru]
O2
N
H
–H2
–N2
Published as part of the ISHC Conference Special Section
Dihydropyrazines
Received: 30.06.2017
Accepted after revision: 09.08.2017
Published online: 16.08.2017
For example, the synthesis of dragmacidin A12 and 2,5-
bis(6′-bromo-3′-indolyl)piperazine11 (Figure 1) is achieved
from the corresponding symmetrical pyrazines as key inter-
mediates.14
DOI: 10.1055/s-0036-1590888; Art ID: st-2017-b0533-c
Abstract A convenient method for the synthesis of substituted pyra-
zines from vinyl azides has been developed. This method is enabled by a
dual-energy and electron-transfer strategy by visible-light photocataly-
sis. Initially, vinyl azides are activated by a triplet sensitization process
from an excited ruthenium photocatalyst in the presence of water to
form dihydropyrazines, followed by a single-electron-transfer (SET) pro-
cess under oxygen (air) atmosphere that leads to the tetrasubstituted
pyrazines in good to excellent yields.
NH2
O
OH
N
N
Cl
H2N
N
H2N
NH2
N
N
O
Amiloride
O
NH
R
N
Keywords visible-light photocatalysis, pyrazines, synthetic methods,
vinyl azides, photocascade process
HO
Br
Br
N
R
OH
Botryllazine A
(cytotoxicity)
Visible-light photocatalysis has been widely employed
in challenging organic transformations.1,2 In principle, the
photocatalyst gets excited by visible light, which subse-
quently activates a colorless organic substrate either by di-
rect energy transfer (ET)3,4 or by single-electron-transfer
(SET)5,6 processes. By the independent use of these two ac-
tivation modes, a great number of synthetic transforma-
tions have been established from various scientific groups
including our own.7 However, the utilization of ET followed
by SET modes aiming at photocascade processes is not well
established.8,9 A first example was reported by Xiao and co-
workers9 in the reaction between vinyl azides and alkynes
to obtain polysubstituted pyrroles. Similarly, we have also
combined ET- and SET-based pathways for the activation of
vinyl bromides in the presence of oxygen.10 As a further ex-
ample for employing the same photocatalyst in different re-
action modes, we report here the visible-light-photocata-
lyzed transformation of vinyl azides into pyrazines, which
are important nitrogen-containing heterocycles with inter-
esting biological activities and great utility as precursors in
organic synthesis.11–13
HN
R = Me: Dragmacidin A
R = H: 2,5-bis(6'-bromo-3'-indolyl)piperazine
Figure 1 Representative biologically active pyrazine derivatives
Various methods are known for the synthesis of pyra-
zines,15 however, their synthesis from vinyl azides by ther-
mal16 or photochemical17 approaches is not well-explored,
despite the fact that the latter are well-known precursors
for the synthesis of N-containing heterocycles such as in-
doles,16 pyrroles,17 pyridines,18 phenanthridines,19 and iso-
quinolines20 for decades.21
Recently, Yoon and coworkers reported the photocata-
lytic, visible-light sensitization of dienylazides to azirines as
key intermediates, which further rearrange to substituted
pyrroles (Scheme 1a, top).4 In this context, we report here a
conceptually different strategy for the synthesis of pyra-
zines from readily accessible vinyl azides (Scheme 1b, bot-
tom).
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Similarly, other known photocatalysts such as fac-
[Ir(ppy)3] (EIr(IV)/Ir(III)* –1.73 V vs. SCE; Τ = 1900 ns; ppy = 2-
phenylpyridine), [Ir(dtbbpy)(ppy)2]PF6 (EIr(IV)/Ir(III)* = –0.96 V
vs. SCE; Τ = 557 ns; ppy = 2-phenylpyridine, dtb-bpy = 4,4′-
di-tert-butyl-2,2′-dipyridyl), [Ru(bpy)3]Cl2 (ERu(III)/Ru(II)* = –0.81
(a) Yoon et al. (Ref. 4):
[Ir(dF-(CF3)ppy)2(dtb-bpy)](PF6)
R2
R2
(1 mol%)
R1
R1
substituted
pyrroles
N
CHCl3 (0.1 M), blue LEDs
rt, 8 h
N3
azirine
R1 = aryl, alkyl
R2 = COOMe
V vs. SCE; Τ = 1100 ns; bpy = 2,2′-bipyridine), Na2-Eosin Y
•+
(EEY
* = –1.11 V vs. SCE, T = 24000 ns),22 also provide com-
/EY
parable yields of 3a′ and 3a (Table 1, entries 2–4), while
[Cu(dap)2]Cl (ECu(II)/Cu(I)* = –1.43 V vs. SCE; Τ= 270 ns; dap =
2,9-bis(p-anisyl)-1,10-phenanthroline, Table 1, entry 5) did
not promote the transformation. This might be due to the
short excited state lifetime (Τ = 270 ns)23 of [Cu(dap)2]Cl
which does not allow an efficient ET from excited state
Cu(I)* to the substrate and makes at the same time the pho-
tocatalytic activation of the vinyl azides by SET unlikely,
given the high efficiency of SET-triggered Atom Transfer
Radical Addition (ATRA) reactions by [Cu(dap)2]Cl.5,24 Final-
ly, a series of control experiments (Table 1, entries 7–9) in-
dicated the necessity of light, photocatalyst, and water.
Aiming at an operationally simple procedure towards
pyrazines 3, we were looking for a suitable oxidant for the
dehydrogenation of dihydropyrazines 3′. Indeed, carrying
out the photoreaction of 2a under oxygen atmosphere
(open to air), thus utilizing oxygen as the terminal oxi-
dant,25 and employing 1 mol% [Ru(bpy)3]Cl2 gave rise to the
desired product 3a in 61% yield (Table 2, entry 1) along with
15% benzaldehyde as a byproduct. In contrast, iridium pho-
tocatalysts (Table 2, entries 3–5) or Na2-Eosin Y (1 mol%, Ta-
ble 2, entry 6) provided 3a in lower amounts, however, the
(b) This work:
[Ru(bpy)3]Cl2 (1 mol%)
LED455
EtOOC
(Het)Ar
N
Ar(Het)
COOEt
(Het)Ar
N3
N
COOEt
H2O then O2 (air)
24 h
15 examples
26–87% yield
Scheme 1 Photochemical activation of vinyl azides
We began our studies by exposing vinyl azide 2a, being
readily available from the corresponding ethyl cinnamate
4a (see Supporting Information) to blue light (λmax = 455
nm) employing 1 mol% of typical photocatalysts:2 Using
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (EIr(IV)/Ir(III)* –0.89 V vs. SCE; Τ =
2300 ns; dF = difluoro, ppy = 2-phenylpyridine, dtb-bpy =
4,4′-di-tert-butyl-2,2′-dipyridyl) in an acetonitrile/water
(4:1) mixture at room temperature under inert atmosphere,
we were pleased to observe the formation of a mixture of
dihydropyrazine 3a′ and the desired pyrazine 3a (3a′/3a =
6:1) in an overall isolated yield of 85% after 24 hours (Table
1, entry 1). Reducing the amount of water resulted in inferi-
or yields (see Supporting Information for details).
Table 1 Reaction Optimization under Nitrogen Atmospherea
H
photocatalyst
solvent(s), 24 h, rt
EtOOC
Ph
N
Ph
EtOOC
Ph
N
Ph
COOEt
Ph
+
LED455
inert atmosphere
N3
2a
N
H
COOEt
N
COOEt
3a'
3a
Entry
Photocatalyst (1 mol%)
Solvent(s)
Yield of 3a′ + 3a (%)b
1
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6
[Ir(ppy)3]
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
dry MeCN
85 (6:1)
77 (7:1)
80 (6:1)
79 (8:1)
NRf
2
3
[Ir(dtbbpy)(ppy)2]PF6
[Ru(bpy)3]Cl2
4
5
[Cu(dap)2]Cl, 535 nm
Na2-Eosin Y, 535 nm
none
6
77 (8:1)
<15
7c
8d
9e
[Ru(bpy)3]Cl2
NR
[Ru(bpy)3]Cl2
NDg
a Reaction conditions: Substrate 2a (0.5 mmol), photocatalyst (1 mol%), N2, MeCN (1.60 mL), H2O (0.40 mL), 24 h, rt, LED455
.
b Isolated yields.
c Without a photocatalyst.
d Dark reaction.
e No water.
f NR: no reaction.
g ND: not detected.
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A. Hossain et al.
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undesired benzaldehyde was obtained in larger quantities.
In line with our mechanistic proposal (Figure 2), the addi-
tion of MeOH instead of water does not provide the desired
product (Table 2, entry 6). Moreover, the use of an oxygen
balloon (excess of oxygen) decreases the yield to 34% and
the undesired benzaldehyde is obtained in a major amount
(Table 2, entry 8). Further optimization studies revealed
that the addition of other oxidant such as K2S2O8 does not
provide any product (Table 2, entry 9), indicating the im-
portance of oxygen. Other additives such as Na2CO3 or tri-
fluoroacetic acid, which were assumed to promote the
opening of the azirine intermediate (Figure 2), also have
negative effect on the reaction (Table 2, entries 10 and 11)
and gave complex mixtures.
*
COOEt
COOEt
–N2
COOEt
Ph
Ph
Ph
N3
N
N3
II
I
2a
Cycle 1
*
Ru(II)
Ru(II)
Energy
Transfer
COOEt
Ph
N
III
Blue Light
Ph
H2O
NH2
H
N
EtOOC
Ph
Condensation
–2H2O
COOEt
Ph
IV
O
N
H
COOEt
3a'
Table 2 Reaction Optimization under Oxygen Atmospherea
H
EtOOC
Ph
N
Ph
photocatalyst
solvent(s), 24 h, rt
*
EtOOC
Ar
N
N
Ar
Ru(II)
COOEt
N
H
COOEt
Ar
Ar
O
+
LED455
open to air
V
N3
COOEt
Blue
Light
1
3
2a (Ar = Ph)
Cycle 2
Ru (I)
2e (Ar = o-MeOC6H4)
EtOOC
Ph
N
Ph
Electron Transfer
Entry
Photocatalyst (1 mol%)
Solvent(s)
Yield of 3 +
(1) (%)b
N
COOEt
O2
Ru (II)
3a
H2O2
1
[Ru(bpy)3]Cl2
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/MeOH (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
MeCN/H2O (4:1)
61 (15)c
52 (31)
53 (23)
40 (35)
5 (65)
42 (36)
NDi
2d
3
[Ru(bpy)3]Cl2
O2
[Ir(ppy)3]
Figure 2 Plausible reaction mechanism for pyrazine formation from vi-
4
[Ir(dtbbpy)(ppy)2]PF6
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6
Na2-Eosin Y, 535 nm
[Ru(bpy)3]Cl2
nyl azide
5
6
tion was especially apparent for vinyl azides bearing elec-
tron-donating arene substituents such as 2e (cf. Table 2, en-
try 2 and Scheme 2), giving rise to significantly increased
yield and complete suppression of aldehyde cleavage prod-
ucts. A wide range of functional groups on the aryl moiety
of the vinyl azides 2 are tolerated well, including weak and
strong electron-donating and electron-withdrawing
groups, ortho and extended π-substituents (Scheme 2). In
only two cases aldehyde byproducts (1a (15%) and 1d (18%)
were observed in significant amounts. It should be pointed
out that all our attempts to separate the two reaction steps,
that is, running the transformation of 2a/d to 3a/d′ under
nitrogen atmosphere, followed by irradiation of 3a/d′ under
aerobic atmosphere did not suppress the formation of 1a or
1d. Switching the aryl group to thiophene (3m) was met
with only limited success, and the replacement of the ester
by keto groups did not result in any product formation (3n
and 3o).
7
8e
9f
[Ru(bpy)3]Cl2
34 (45)
ND
[Ru(bpy)3]Cl2
10g
11h
[Ru(bpy)3]Cl2
ND
[Ru(bpy)3]Cl2
ND
a Reaction conditions: Substrate 2a (0.5 mmol), photocatalyst (1 mol%), N2,
MeCN (1.60 mL), H2O/MeOH (0.40 mL), 24 h, rt, LED455
.
b Isolated yields.
c Yield of aldehyde in parenthesis.
d 2e was employed instead of 2a.
e With additional oxygen balloon.
f K2S2O8(1 equiv).
g Na2CO3(1 equiv).
h Trifluoroacetic acid (1 equiv).
i ND: not detected. For detailed optimization, see Supporting Information.
Employing the optimized reaction conditions (Table 2,
entry 1) we explored the scope of the reaction. Since
[Ru(bpy)3]Cl2 gave rise to comparatively low amounts of the
undesired aldehyde-cleavage products under aerobic condi-
tions, we modified slightly the protocol by simply degassing
the reaction mixture via nitrogen bubbling, but then run-
ning the reaction open to air. The benefit of this modifica-
Moreover, the dimerization reaction by employing two
different vinyl azides in equimolar amounts (Scheme 3) is
possible. However, the homo- and cross-coupled products
are all formed with a slight preference for the sterically less
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

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A. Hossain et al.
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Scheme 2 Substrate scope: substrate 2 (0.50 mmol), [Ru(bpy)3]Cl2 (1 mol%), MeCN (1.60 mL), water (0.40 mL), rt, LED455, 24 h
F
Following the mechanistic rationale put forward by
Yoon and co-workers for the photochemical activation of
dienylazides,4 the reaction sequence to 1,4-pyrazines devel-
oped here starts with an ET from the excited Ru(II)* photo-
catalyst to vinyl azide 2 (Figure 2). As a result, 2 is converted
into the triplet energy state I, which upon loss of nitrogen
forms a reactive nitrene intermediate II that further rear-
ranges to the highly reactive azirine III. This azirine III may
undergo ring opening by water, leading to the formation of
α-amino ketone IV. The condensation of IV to form dihy-
dropyrazine26 species 3a′ concludes the first transformation
of the process.
EtOOC
N
N
2f (0.25 mmol)
Standard
Conditions
COOEt
+
3fh (37% yield) [cross]
3h (20% yield) [homo]
3f (24% yield) [homo]
2h (0.25 mmol)
MeO
Cl
OMe
Me
EtOOC
N
2f (0.25 mmol)
+
Standard
Conditions
N
COOEt
3fb (31% yield) [cross]
3b (40% yield) [homo]
3f (22% yield) [homo]
MeO
Cl
2b (0.25 mmol)
OMe
The formation of 3′ from 2 is considerably faster (ap-
prox. 3 h) under the reaction conditions employed then the
subsequent oxidation of 3′ to 3 (21 h). In line with control
(light on/off) experiments (Scheme 4), nevertheless, the
second step should also be a photocatalytic one, that is, be-
ing initiated by excited state Ru(II)* which may reductively
quench 3′ acting as an electron donor. This results in the
Scheme 3 Cross-coupling between two vinyl azides
encumbered pyrazines. Hence this method allows to ac-
cessing unsymmetrical pyrazines from readily available vi-
nyl azides, but only in moderate yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

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generation of Ru(I) and the N-centered radical cation V,
which can be oxidized by superoxide anion radical O2•–, be-
ing in turn generated from Ru(I) and molecular oxygen.
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Control experiment:
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(a) Light ON-OFF experiment:
[Ru(bpy)3]Cl2 (1 mol%)
MeCN:H2O (4:1)
COOEt
Light OFF (dark)
Ph
3a'
3a (traces)
LED455, 3 h, N2, rt
open to air
21 h
N3
2a
Scheme 4 Control experiment
To summarize, we have developed a visible light medi-
ated cascade to 1,4-pyrazines, combining energy and elec-
tron-transfer-initiated reaction steps operated by the same
photocatalyst.27
Funding Information
This work was supported by the German Science Foundation (DFG)
(GRK 1626, Chemical Photocatalysis)
D
e
ustch
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Acknowledgment
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2017, DOI: 10.1002/anie.201702953.
We gratefully acknowledge Birgit Hischa and Dr. Uttam Chakraborty
for carrying out the X-ray crystal structure analysis. We also thank
Prof. Huw M. L. Davies (Emory University, USA) for helpful discus-
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https://doi.org/10.1055/s-0036-1590888.
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B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc.
Chem. Res. 2016, 49, 1429. (f) Shaw, M. H.; Twilton, J.;
MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. (g) Zeitler, K.
Angew. Chem. Int. Ed. 2009, 48, 9785.
(2) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322.
(3) (a) Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329.
(b) Welin, E. R.; Le, C.; Arias-Rotondo, D. M.; McCusker, J. K.;
MacMillan, D. W. C. Science 2017, 355, 380. (c) Brachet, E.;
Ghosh, T.; Ghosh, I.; König, B. Chem. Sci. 2015, 6, 987. (d) Heitz,
D. R.; Tellis, J. C.; Molander, G. A. J. Am. Chem. Soc. 2016, 138,
12715.
(4) Farney, E. P.; Yoon, T. P. Angew. Chem. Int. Ed. 2014, 53, 793.
(5) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B.
M.; Reiser, O. Angew. Chem. Int. Ed. 2015, 54, 6999.
(17) (a) Suresh, R.; Muthusubramanian, S.; Nagaraj, M.; Manickam,
G. Tetrahedron Lett. 2013, 54, 1779. (b) Wang, Y.-F.; Toh, K. K.;
Chiba, S.; Narasaka, K. Org. Lett. 2008, 10, 5019. (c) Chiba, S.;
Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313.
(d) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

F
A. Hossain et al.
Cluster
Synlett
(18) (a) Chen, Z.-B.; Hong, D.; Wang, Y.-G. J. Org. Chem. 2009, 74, 903.
(b) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570.
(19) Sun, X.; Yu, S. Chem. Commun. 2016, 52, 10898.
for C24H24N2O4 [M + H]+: 405.1736; found: 405.1814. IR (neat):
2986, 2871, 1723, 1609, 1462, 1442, 1408, 1292, 1247, 1174,
1137, 1095, 1057, 1012, 853, 828, 775, 700 cm–1
.
(20) (a) Yang, Y.-Y.; Shou, W.-G.; Chen, Z.-B.; Hong, D.; Wang, Y.-G.
J. Org. Chem. 2008, 73, 3928. (b) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.;
Chiba, S. Angew. Chem. Int. Ed. 2011, 50, 5927.
(21) (a) Hu, B.; DiMagno, S. G. Org. Biomol. Chem. 2015, 13, 3844.
(b) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831.
Diethyl 3,6-Di(naphthalen-2-yl)pyrazine-2,5-dicarboxylate
(3c)
Following the general procedure, 3c was prepared from ethyl
(Z)-2-azido-3-(naphthalen-2-yl)acrylate (2c, 134 mg, 0.50
mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1
mol%). The crude product was purified by column chromatogra-
phy (silica gel, hexanes–EtOAc = 4:1, Rf = 0.30) to afford 3c as a
white solid (81 mg, 70% yield).
(22) Hari, D. P.; König, B. Chem. Commun. 2014, 50, 6688.
(23) Reiser, O. Acc. Chem. Res. 2016, 49, 1990.
(24) (a) Paria, S.; Reiser, O. ChemCatChem 2014, 6, 2477. (b) Pirtsch,
M.; Paria, S.; Matsuno, T.; Isobe, H.; Reiser, O. Chem. Eur. J. 2012,
18, 7336. (c) Pagire, S. K.; Paria, S.; Reiser, O. Org. Lett. 2016, 18,
2106. (d) Rawner, T.; Knorn, M.; Lutsker, E.; Hossain, A.; Reiser,
O. J. Org. Chem. 2016, 81, 7139.
(25) Lu, Z.; Yang, Y.-Q.; Li, H.-X. Synthesis 2016, 48, 4221.
(26) (a) Smith, H. E.; Hicks, A. A. J. Org. Chem. 1971, 36, 3659.
(b) Knittel, D. Synthesis 1985, 186. (c) Banert, K.; Meier, B.
Angew. Chem. Int. Ed. 2006, 45, 4015.
1H NMR (400 MHz, CDCl3): δ = 8.28 (s, 2 H), 7.97–7.85 (m, 8 H),
7.59–7.53 (m, 4 H), 4.33 (d, J = 7.1 Hz, 4 H), 1.13 (t, J = 7.1 Hz, 6
H). 13C NMR (100 MHz, CDCl3): δ = 166.4, 149.6, 145.1, 134.0,
133.5, 133.2, 129.0, 128.8, 128.6, 127.9, 127.4, 126.8, 125.9,
62.6, 13.9. ESI-HRMS: m/z calcd for C30H24N2O4 [M + H]+:
477.1736; found : 477.1821. IR (neat):3056, 2974, 2927, 2854,
1729, 1686, 1462, 1405, 1381, 1304, 1236, 1169, 1140, 1004,
906, 871, 852, 830, 750 cm–1
.
(27) Photochemical Synthesis of Pyrazines: General Procedure
An oven-dried Schlenk tube (10 mL size) equipped with a stir-
ring bar was charged with [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01
equiv, 1 mol%) followed by 1.60 mL MeCN and 0.40 mL distilled
water. The resulting solution was degassed via nitrogen bub-
bling for 5 min using a syringe needle. Then vinyl azide 2 (0.50
mmol, 1 equiv) was added under nitrogen. Irradiation with a
blue LED (λmax = 455 nm) was carried out for 24 h at rt. The
reaction mixture was transferred to a separatory funnel con-
taining distilled water, and extracted three times with EtOAc.
After drying the combined organic layers (Na2SO4), the resulting
solution was concentrated in vacuo. The pure product was
obtained either by recrystallization from CH2Cl2/pentane or by
silica gel column chromatography using hexanes and EtOAc as
eluents.
Diethyl 3,6-Fis(4-methoxyphenyl)pyrazine-2,5-dicarboxylate
(3d)
Following the general procedure, 3d was prepared from ethyl
(Z)-2-azido-3-(4-methoxyphenyl)acrylate (2d, 124 mg, 0.50
mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1
mol%). The crude product was purified by column chromatogra-
phy (silica gel, hexanes–EtOAc = 3:1, Rf = 0.28) to afford 3d as a
white solid (53 mg, 49% yield).
1H NMR (300 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H), 6.99–6.96 (m,
4 H), 4.33 (q, J = 7.1 Hz, 4 H), 3.85 (s, 6 H), 1.21 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 161.2, 148.5, 144.1, 130.3,
128.5, 114.2, 62.4, 55.5, 13.9. ESI-HRMS: m/z calcd for
C
24H24N2O6 [M + H]+: 437.1634; found: 437.1740. IR (neat):
2980, 2955, 2926, 2851, 1732, 1607, 1580, 1518, 1414, 1295,
1253, 1177, 1148, 1060, 1017, 841, 811, 786, 752 cm–1
.
Diethyl 3,6-Diphenylpyrazine-2,5-dicarboxylate (3a)
Following the general procedure, 3a was prepared from ethyl
(Z)-2-azido-3-phenylacrylate (2a, 109 mg, 0.50 mmol, 1.00
equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The
crude product was purified by column chromatography (silica
gel, hexanes–EtOAc = 9:1, Rf = 0.20) to afford 3a as a white solid
(57 mg, 61% yield).
Diethyl 3,6-Bis(2-methoxyphenyl)pyrazine-2,5-dicarboxyl-
ate (3e)
Following the general procedure, 3e was prepared from ethyl
(Z)-2-azido-3-(2-methoxyphenyl)acrylate (2e, 124 mg, 0.50
mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O(3.7 mg, 0.01 equiv, 1
mol%). The crude product was recrystallized as described for 3b
to afford 3e as white solid (86 mg, 79%).
1H NMR (300 MHz, CDCl3): δ = 7.74–7.71 (m, 4 H), 7.49–7.47 (m,
6 H), 4.31 (q, J = 7.1 Hz, 4 H), 1.16 (t, J = 7.1 Hz, 6 H). 13C NMR (75
MHz, CDCl3): δ = 166.2, 149.9, 144.8, 136.2, 130.0, 128.9, 128.7,
62.5, 13.8. ESI-HRMS: m/z calcd for C22H20N2O4 [M + H]+:
377.1423; found: 377.1502. IR (neat): 3059, 2986, 2925, 2854,
1731, 1449, 1405, 1380, 1293, 1173, 1137, 1094, 1057, 1021,
1H NMR (300 MHz, CDCl3): δ = 7.78 (dd, J1 = 7.5 Hz, J2 = 1.6 Hz, 2
H), 7.44–7.38 (m, 2 H), 7.14–7.09 (m, 2 H), 6.89 (d, J = 8.2 Hz, 2
H), 4.25 (q, J = 7.1 Hz, 4 H), 3.73 (s, 6 H), 1.14 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 165.5, 156.5, 147.6, 145.9, 131.4,
131.2, 126.5, 121.4, 110.1, 61.8, 55.1, 13.9. ESI-HRMS: m/z calcd
for C24H24N2O6 [M + H]+: 437.1634; found: 437.1739. IR (neat):
2968,2924, 2843, 1733, 1601, 1495, 1465, 1439, 1411, 1390,
1280, 1248, 1226, 1182, 1149, 1111, 1061, 1014, 854, 759, 697
856, 766, 705 cm–1
.
Diethyl 3,6-Di-p-tolylpyrazine-2,5-dicarboxylate (3b)
Following the general procedure, 3b was prepared from ethyl
(Z)-2-azido-3-(p-tolyl)acrylate (2b, 115 mg, 0.50 mmol, 1.00
equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The
crude product was dissolved in a minimum amount of CH2Cl2
followed by the addition of n-pentane to initiate crystallization.
After 30 min, the solvent mixture was decanted, and the solid
was washed twice with n-pentane. The residual solvents were
removed in vacuo which afforded 3b as white solid (83 mg,
82%).
cm–1
.
Diethyl 3,6-Bis(2-chloro-3,4-dimethoxyphenyl)pyrazine-2,5-
dicarboxylate (3f)
Following the general procedure, 3f was prepared from ethyl
(Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 156
mg, 0.50 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg,
0.01 equiv, 1 mol%). The crude product was recrystallized as
described for 3b to afford 3f as white solid (122 mg, 87%).
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.5 Hz, 2 H), 6.98 (d,
J = 8.6 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 4 H), 3.94 (s, 6 H), 3.87 (s, 6
H), 1.17 (t, J = 7.1 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 164.6,
154.8, 149.8, 145.5, 145.1, 129.5, 127.8, 126.4, 110.9, 62.5, 60.8,
56.3, 13.9. ESI-HRMS: m/z calcd for C26H26Cl2N2O8 [M + H]+:
1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 8.1 Hz, 4 H), 7.27 (d,
J = 7.9 Hz, 4 H), 4.32 (q, J = 7.1 Hz, 4 H), 2.41 (s, 6 H), 1.19 (t, J =
7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 166.4, 149.4, 144.6,
140.2, 133.3, 129.5, 128.7, 62.4, 21.5, 13.9. ESI-HRMS: m/z calcd
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

G
A. Hossain et al.
Cluster
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565.1066; found: 565.1143. IR (neat): 3090, 2980, 2938, 2841,
1735, 1590, 1490, 1447, 1412, 1392, 1293, 1269, 1220, 1202,
Diethyl 3,6-Bis(4-(trifluoromethyl)phenyl)pyrazine-2,5-dicar-
boxylate (3k)
1099, 1038, 1003, 819, 790, 778 cm–1
.
Following the general procedure, 3k was prepared from ethyl
(Z)-2-azido-3-(4-(trifluoromethyl)phenyl)acrylate (2k, 143 mg,
0.50 mmol, 1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv,
1 mol%). The crude product was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc = 3:1, Rf = 0.30) to afford 3k as
a white solid (48 mg, 38% yield).
Diethyl 3,6-Bis(4-fluorophenyl)pyrazine-2,5-dicarboxylate (3g)
Following the general procedure, 3g was prepared from ethyl
(Z)-2-azido-3-(4-fluorophenyl)acrylate (2g, 118 mg, 0.50 mmol,
1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%).
The crude product was recrystallized as described for 3b to
afford 3g as white solid (87 mg, 85%).
1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.1 Hz, 4 H), 7.76 (d,
J = 8.3 Hz, 4 H), 4.34 (q, J = 7.1 Hz, 4 H), 1.20 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 165.4, 149.4, 144.9, 139.4, 132.1
1H NMR (300 MHz, CDCl3): δ = 7.74–7.70 (m, 4 H), 7.20–7.15 (m,
4 H), 4.33 (q, J = 7.1 Hz, 4 H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (75
MHz, CDCl3): δ = 165.9, 164.1 (d, 1JC–F = 250.6 Hz), 148.8, 144.5,
(q, J = 33.1 Hz), 129.4, 125.7 (q, J = 3.6 Hz), 122.1, 62.9, 13.8. 19
F
132.1 (d, 4JC–F = 3.1 Hz), 130.9 (d, 3JC–F = 8.6 Hz), 116.0 (d, 2JC–F
=
NMR (282 MHz, CDCl3): δ = –63.2. ESI-HRMS: m/z calcd for
24H18F6N2O4 [M + H]+: 513.1171; found: 513.1254. IR (neat):
2982, 2965, 2927, 2856, 1721, 1414, 1324, 1254, 1138, 1105,
1072, 1053, 1016, 858, 832, 790, 717 cm–1
21.8 Hz), 62.7, 13.9. 19F NMR (282 MHz, CDCl3): δ = –110.9. ESI-
HRMS: m/z calcd for C22H18F2N2O4 [M + H]+: 413.1235; found:
413.1320. IR (neat): 3084, 2985, 2925, 2854, 1733, 1599, 1512,
1409, 1383, 1289, 1227, 1179, 1155, 1096, 1053, 1012, 845,
C
.
Diethyl 3,6-Bis(4-nitrophenyl)pyrazine-2,5-dicarboxylate (3l)
Following the general procedure, 3l was prepared from ethyl
(Z)-2-azido-3-(4-nitrophenyl)acrylate (2l, 131 mg, 0.50 mmol,
1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%).
The crude product was recrystallized as described for 3b to
afford 3l as yellow solid (99 mg, 86%).
815, 766 cm–1
.
Diethyl 3,6-Bis(2-fluorophenyl)pyrazine-2,5-dicarboxylate (3h)
Following general procedure, 3h was prepared from ethyl (Z)-2-
azido-3-(2-fluorophenyl)acrylate (2h, 118 mg, 0.50 mmol, 1.00
equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The
crude product was recrystallized as described for 3b to afford
3h as white solid (83 mg, 81%).
1H NMR (300 MHz, CDCl3): δ = 8.38–8.35 (m, 4 H), 7.93–7.90 (m,
4 H), 4.37 (q, J = 7.1 Hz, 4 H), 1.24 (t, J = 7.1 Hz, 6 H). 13C NMR (75
MHz, CDCl3): δ = 164.9, 149.08, 149.00, 144.8, 141.8, 130.1,
124.0, 63.2, 14.0. ESI-HRMS: m/z calcd for C22H18N4O8 [M + H]+:
467.1125; found: 467.1198. IR (neat): 3110, 2985, 2958, 2919,
2851, 1721, 1601, 1516, 1466, 1408, 1344, 1296, 1259, 1144,
1H NMR (300 MHz, CDCl3): δ = 7.86–7.80 (m, 2 H), 7.51–7.44 (m,
2 H), 7.35–7.30 (m, 2 H), 7.16–7.09 (m, 2 H), 4.35 (q, J = 7.1 Hz, 4
H), 1.21 (t, J = 7.1 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 164.7,
1
160.1 (d, JC–F = 248.7 Hz), 146.5, 145.4 (d, J = 1.9 Hz), 132.0 (d,
4
3
3JC–F = 8.5 Hz), 131.7 (d, JC–F = 2.3 Hz), 124.9 (d, JC–F = 3.3 Hz),
1100, 1009, 850, 800, 749, 689 cm–1
.
124.7, 115.4 (d, JC–F = 21.7 Hz), 62.5, 13.9. 19F NMR (282 MHz,
Diethyl 3,6-Di(thiophen-2-yl)pyrazine-2,5-dicarboxylate (3m)
Following the general procedure, 3m was prepared from ethyl
(Z)-2-azido-3-(thiophen-2-yl)acrylate (2m, 112 mg, 0.50 mmol,
1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%).
The crude product was purified by column chromatography
(silica gel, hexanes–EtOAc = 5:1, Rf = 0.52) to afford 3m as a pale
yellow solid (25 mg, 26%).
2
CDCl3): δ = –116.6. ESI-HRMS: m/z calcd for C22H18F2N2O4 [M +
H]+: 413.1235; found: 413.1320. IR (neat): 3071, 2985, 2939,
2906, 1730, 1613, 1581, 1490, 1454, 1399, 1384, 1245, 1172,
1140, 1093, 1059, 1014, 859, 757 cm–1
.
Diethyl 3,6-Bis(4-chlorophenyl)pyrazine-2,5-dicarboxylate (3i)
Following the general procedure, 3i was prepared from ethyl
(Z)-2-azido-3-(4-chlorophenyl)acrylate (2i, 126 mg, 0.50 mmol,
1.00 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%).
The crude product was recrystallized as described for 3b to
afford 3i as white solid (63 mg, 57%).
1H NMR (300 MHz, CDCl3): δ = 7.54–7.50 (m, 4 H), 7.12–7.09 (m,
2 H), 4.48 (q, J = 7.1 Hz, 4 H), 1.37 (t, J = 7.1 Hz, 6 H). 13C NMR (75
MHz, CDCl3): δ = 165.9, 142.5, 141.9, 139.1, 130.4, 128.6, 128.4,
62.8, 14.0. ESI-HRMS: m/z calcd for C18H16N2O4S2 [M + H]+:
389.0551; found: 389.0644. IR (neat): 3097, 2991, 2963, 2924,
2853, 1719, 1531, 1435, 1418, 1381, 1330, 1270, 1145, 1109,
1H NMR (300 MHz, CDCl3): δ = 7.68–7.66 (m, 4 H), 7.47–7.45 (m,
4 H), 4.34 (q, J = 7.1 Hz, 4 H), 1.22 (t, J = 7.1 Hz, 6 H). 13C NMR (75
MHz, CDCl3): δ = 165.8, 148.9, 144.5, 136.7, 134.4, 130.2, 129.1,
62.8, 13.9. ESI-HRMS: m/z calcd for C22H18Cl2N2O4 [M + H]+:
445.0644; found: 445.0713. IR (neat): 2985, 2937, 1728, 1595,
1494, 1426, 1401, 1378, 1277, 1234, 1187, 1158, 1109, 1090,
852, 830, 706 cm–1
.
Diethyl 3-(2-Chloro-3,4-dimethoxyphenyl)-6-(p-tolyl)pyra-
zine-2,5-dicarboxylate (3fb)
Following the general procedure, 3fb was prepared from ethyl
(Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 78
mg, 0.25 mmol, 1 equiv), ethyl (Z)-2-azido-3-(p-tolyl)acrylate
(2b, 57.7 mg, 0.25 mmol, 1.00 equiv) and [Ru(bpy)3]Cl2·6H2O
(3.7 mg, 0.01 equiv, 1 mol%). The crude product was purified by
column chromatography (silica gel, hexanes–EtOAc = 3:1, Rf =
0.25) to afford 3fb as a white solid (37 mg, 31% yield).
1053, 1010, 854, 830, 778, 745 cm–1
.
Diethyl 3,6-Bis(4-bromophenyl)pyrazine-2,5-dicarboxylate (3j)
Following the general procedure, 3j was prepared from ethyl
(Z)-2-azido-3-(4-bromophenyl)acrylate (2j, 148 mg, 0.50 mmol,
1 equiv) and [Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%).
The crude product was purified by column chromatography
(silica gel, hexanes–EtOAc = 3:1, Rf = 0.22) to afford 3j as a white
solid (73 mg, 55% yield).
1H NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 8.1 Hz, 2 H), 7.33–7.27
(m, 3 H), 6.97 (d, J = 8.6 Hz, 1 H), 4.36–4.25 (m, 4 H), 3.93 (s, 3
H), 3.87 (s, 3 H), 2.42 (s, 3 H), 1.22–1.16 (m, 6 H). 13C NMR (75
MHz, CDCl3): δ = 166.2, 164.7, 154.7, 150.5, 148.7, 145.5, 144.9,
144.8, 140.5, 133.2, 129.6, 129.5, 128.9, 127.8, 126.3, 110.8,
62.6, 62.4, 60.8, 56.3, 21.6, 13.97, 13.94. ESI-HRMS: m/z calcd
for C25H25ClN2O6 [M + H]+: 485.1401; found: 485.1494. IR (neat):
2982, 2927, 2854, 1739, 1591, 1487, 1450, 1397, 1291, 1277,
1236, 1224, 1198, 1153, 1120, 1077, 1030, 1013, 964, 809,
1H NMR (300 MHz, CDCl3): δ = 7.64–7.58 (m, 8 H), 4.34 (q, J =
7.2 Hz, 4 H), 1.22 (t, J = 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3):
δ = 165.8, 149.0, 144.5, 134.9, 132.0, 130.4, 125.0, 62.8, 13.9.
ESI-HRMS: m/z calcd for C22H18Br2N2O4 [M + H]+: 532.9633;
found: 532.9708. IR (neat): 2983, 2925, 2854, 1728, 1588, 1474,
1423, 1399, 1376, 1279, 1234, 1186, 1159, 1051, 1006, 854,
826, 776, 734 cm–1
.
755 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

H
A. Hossain et al.
Cluster
Synlett
Diethyl 3-(2-Chloro-3,4-dimethoxyphenyl)-6-(2-fluorophe-
nyl)pyrazine-2,5-dicarboxylate (3fh)
Following the general procedure, 3fh was prepared from ethyl
(Z)-2-azido-3-(2-chloro-3,4-dimethoxyphenyl)acrylate (2f, 78
mg, 0.25 mmol, 1 equiv), ethyl (Z)-2-azido-3-(2-fluorophe-
3 H), 7.16–7.09 (m, 1 H), 6.99–6.97 (m, 1 H), 4.38–4.26 (m, 4 H),
3.93 (s, 3 H), 3.87 (s, 3 H), 1.23–1.16 (m, 6 H). 13C NMR (75 MHz,
CDCl3): δ = 164.8, 164.5, 160.1 (d, 1JC–F = 248.3 Hz), 154.8, 149.7,
3
4
146.5, 145.5, 145.1, 132.0 (d, JC–F = 8.5 Hz), 131.7 (d, JC–F = 2.2
3
Hz), 129.4, 127.7, 126.4, 125.0, 124.9 (d, JC–F = 3.3 Hz), 124.9,
2
nyl)acrylate (2h, 59 mg, 0.25 mmol,
1
equiv) and
115.4 (d, JC–F = 21.6 Hz), 110.9, 62.5 (2×), 60.8, 56.3, 13.95,
[Ru(bpy)3]Cl2·6H2O (3.7 mg, 0.01 equiv, 1 mol%). The crude
product was purified by column chromatography (silica gel,
hexanes–EtOAc = 3:1, Rf = 0.34) to afford 3fh as a white solid (45
mg, 37% yield).
13.92. 19F NMR (282 MHz, CDCl3): δ = –116.6. ESI-HRMS: m/z
calcd for C24H22ClFN2O6 [M + H]+: 489.1150; found: 489.1257. IR
(neat): 2981, 2934, 2843, 1723, 1616, 1558, 1490, 1450, 1408,
1296, 1269, 1248, 1224, 1173, 1142, 1099, 1075, 1040, 1016,
1H NMR (300 MHz, CDCl3): δ = 7.87–7.82 (m, 1 H), 7.59–7.30 (m,
812, 758 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H