Chemical synthesis of coelenterazine and its analogs: New route by four segment-couplings

Article abstract of DOI:10.3987/COM-12-S(N)85

A novel and improved synthetic route includes four segment-couplings toward coelenterazine and its analogs as luminescent molecules. Regio- and chemo-selective cross coupling reactions using palladium catalysts with 5-iodo-3-bromo-2-aminopyrazine have enabled providing various aminopyrazine derivatives having different substituents. The improved synthesis of coelenterazine and its analogs employed advanced condensation with the aminopyrazines using various keto-acetal segments, which resulted in much higher yields to give the final imidazopyrazinone heterocycles than the previous method using keto-aldehydes.

Full text of DOI:10.3987/COM-12-S(N)85

HETEROCYCLES, Vol. 86, No. 2, 2012
1323
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1323 - 1339. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 1st July, 2012, Accepted, 30th August, 2012, Published online, 11th September, 2012
DOI: 10.3987/COM-12-S(N)85
CHEMICAL SYNTHESIS OF COELENTERAZINE AND ITS ANALOGS:
NEW ROUTE BY FOUR SEGMENT-COUPLINGS
Chun-Ming Chou, Yu-Wen Tung, Meng-I Lin, Diana Chan, Wong
Phakhodee, and Minoru Isobe*
Chemistry Department, National Tsing Hua University, No. 101, Sec. 2, Kuang
Fu Road, Hsinchu, 30013, Taiwan; E-mail: minoru@mx.nthu.edu.tw
Abstract
–
A
novel and improved synthetic route includes four
segment-couplings toward coelenterazine and its analogs as luminescent
molecules. Regio- and chemo-selective cross coupling reactions using palladium
catalysts with 5-iodo-3-bromo-2-aminopyrazine have enabled providing various
aminopyrazine derivatives having different substituents. The improved synthesis
of coelenterazine and its analogs employed advanced condensation with the
aminopyrazines using various keto-acetal segments, which resulted in much
higher yields to give the final imidazopyrazinone heterocycles than the previous
method using keto-aldehydes.
INTRODUCTION
Coelenterazine 1, as shown in Scheme 1, is a well-known chromophore involved in the marine
bioluminescence substrate for the various different photoproteins. It (1) was first isolated and identified in
1960s. Later, Inoue et al. achieved the synthesis of coelenteramine 2 and coelenterazine from the
acid-mediated condensation of two segments between a keto-aldehyde 3 and coelenteramine 2.1 This
method was employed for many years without much improvement in the final step of acid-mediated
condensation, which resulted in fair yields as 40-45%. But some efforts were paid for the segments
synthesis. For example, our group reported that aminopyrazine, the precursor of coelenteramine, can be
obtained from the condensation of N-Boc-glycine and aminonitrile hydrochloride and provided the new
route based on cross-coupling between imino-tosylates and aryl-boronates to give various analogs.2
Maciej Adamczyk’s group developed a route from halogenated aminopyrazine to provide the
______________________________________________________
Decidated to Professor Eiichi Negishi for his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Pd-mediated coupling precursor toward coelenteramine.3 Knochel’s group found the metal-halide
exchange on pyrazine can yield the intermediate of coelenteramine through Negishi coupling reaction.4
Ohashi’s group5 and Knochel’s group4 both modified the Inoue’s method1c to generate α-bromoketone
which can lead to keto-aldehyde. Based on the previous studies, the full method was well developed.
However, we are looking for an even more efficient method to continue and supply modified
chromophoric substrates for our own study on the bioluminescence of symplectin-photoprotein in
Tobi-Ika (meaning flying squid in Japanese), a luminous oceanic squid (Symplectoteuthis oualaniensis).
In our previous research, we found fluorinated analogs showed different performance in bioluminescence,
for which we developed a different synthetic route using large amount of diazomethane.6 This method
may not be suitable nowadays. In this article, we described a new synthetic route toward the
keto-aldehyde-segment equivalents, and new synthetic intermediates of coelenterazine to make the analog
synthesis efficiently.
HO
N
N
NH2
O
R4
6
aminopyrazine, 5
acid mediated
condensation
O
O
O
N
N
NH2
OH
keto-aldehyde,
N
N
OH
R4
3
N
H
HO
HO
O
Pd catalyzed
cross-coupling
1
coelenterazine,
2
coelenteramine,
O
R4
4
keto-ketal,
O
R4
7
Scheme 1. The retro-synthetic route on the basis of four-segment couplings of coelenterazine 1
RESULTS AND DISCUSSION
1. Novel synthetic route toward the keto-acetal
In the previous synthesis, α-bromoketone,1c,4 the precursor to yield ketoaldehyde, was prepared from
diazomethane and phenylacetic acid. Diazomethane is a notorious explosive material in pure gas-form at
room temperature, but it is almost universally used as a solution in diethyl ether. This compound is a

HETEROCYCLES, Vol. 86, No. 2, 2012
1325
popular methylating agent in chemical laboratory, but it is too hazardous to use in technical scales without
special precautions. For the purpose of safety and simple route, we tried to design an alternative route
without diazomethane. So we explored different approach to equivalent of ketoaldehyde 3 as described in
the following sentence.
To obtain the ketoaldehyde 3, we tried several oxidative conditions of acetylene (Table 1) or 1,2-diol
(Table 2), but we failed to obtain the target molecule. The oxidation of the olefinic precursors to
α-hydroxyketone was not reproducible (Table 3). We concluded that uncontrollable over-oxidation or
oxidative C-C bond cleavage is always associated because the enolization of the product ketone.
Table 1. The oxidation of acetylene to ketoaldehyde 3
condition
TMS
8
Entry
condition
Result
RuO2, NaIO4
CH2Cl2/MeCN/H2O
Recovery of SM
Recovery of SM
complex mixture
1
2
3
RuO2, NaIO4
CHCl3/MeCN/H2O
RuCl3, Oxone, NaHCO3
EtOAc/MeCN/H2O
Table 2. The oxidation of 1,2-diol to ketoaldehyde 3
condition
OH
OH
9
Entry
condition
Result
1
2
3
4
PDC, CH2Cl2, 24 h
complex mixture
complex mixture
complex mixture
complex mixture
SO3·py, DMSO, Et3N

CH2Cl2, 0 C
NaOCl, TEMPO, KBr
CH2Cl2/H2O
(COCl)2, DMSO, Et3N

CH2Cl2, -78 C

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HETEROCYCLES, Vol. 86, No. 2, 2012
Table 3. The oxidation of olefin to α-hydroxyketone
condition
OH
O
MeO
MeO
10
11
Entry
condition
Result
KMnO4
acetone/H2O/AcOH
complex mixture
29%
1
RuCl3, Oxone, NaHCO3
EA/CAN/H2O
2a
a) the reaction isn't reproducible.
To avoid such enolization, we implemented different sequences to keto-acetal by addition to a carbonyl
equivalent group rather than by oxidation. The Umpolung nucleophile 13 was prepared by the
1,3-propanedithiol protection of phenylacetaldehyde 12. The prepared nucleophile 13 can undergo
Bouveault’s aldehyde formation7 together with the 2-benzyl-1,3-dithiane-2-carbaldehyde 14. Followed by
acetal formation and deprotection of dithiane, the keto-acetal 4 was obtained in about 60% in total yield
(Scheme 3). However, another target keto-acetal was not formed through the same pathway, but
benzaldehyde 13e was obtained instead. Even a dianion nucleophile also led to the same result. To
achieve our purpose, we change the method from aldehyde formation to ketone formation. We started the
Weinreb amide 16b for the ketone formation from 2,4-difluorophenylacetic acid 6b rather than aldehyde
or acyl halide to avoid oxidation or 2-times additions. The Umpolung nucleophile, precursor of aldehyde,
underwent the ketone formation with amide 16c (Table 4).
1. n-BuLi, -20 oC
O
2. DMF, 6 h
SH SH
S
S
.
a: 87%
OMe
BF3 OEt2, CH2Cl2, 12 h
a: 91%
OMe
12a
13a
OH
O
OH, pTSA
O
NCS, AgNO3
S
S
O
S
S
PhMe, reflux, 12 h
a: 82%
MeCN/H2O, 5 min
a: 91%
OMe
OMe
14a
15a
O
O
O
OMe
4a
Scheme 2. The route toward keto-acetal

HETEROCYCLES, Vol. 86, No. 2, 2012
1327
F
F
F
1. n-BuLi (1.2 equiv.), -20 o
C
SH SH
O
O
S
S
S
S
S
.
2. DMF (1.0 or 5.0 equiv.)
-20 °C->rt
BF3 OEt2, CH2Cl2, 12h
85%
F
F
F
6 h, 82%
12b
13b
13e
F
7%
D
82%
D
F
S
F
1. n-BuLi (2.2 equiv.), -20 °C->0 °C
O
S
S
S
2. DMF (1.0 equiv.), -20 °C, 6 h
F
13e
F
73%
D
D 90%
F
S
Scheme 3. The route toward diF-keto-acetal
As the result shown in Table 4, we can obtain various ketone 17b, 18b, 19b in 26~95% chemical yield.
Two kinds of sulfide cleavage methods were applied to transform the dithioacetal 17b and 18b as well as
the hemithioacetal 19b to dimethylacetal (Table 5). However, only the hemithioacetal 19b could be
transformed to acetal 20b in the presence of copper(II) chloride and copper oxide in anhydrous methanol
under reflux condition with 61% chemical yield. On the other hand, the acetal formation was not
successful for other substrates (Scheme 4).
Table 4. The ketone formation from various thioacetal/hemithioacetal anions as the nucleophile
F
OMe
N
F
1. CDI, THF, 30 min
Nu-Li+
HO
Me
2. MeNHOMe HCl
DMF, DIPEA, 24 h, 95%
condition
O
O
F
F
6b
16c
Product (yield %)
F
Nu
condition
Entry
1a
S
THF (460 mM)
-20 oC->28 oC, 3 h
(1.1 equiv.)
(1.1 equiv.)
(46%)
S
S
S
S
S
O
F
17b
SMe
F
F
THF (230 mM)
-20 oC->25 oC, 3 h
2a
(26%)
MeS
O
F
18b
THF (46 mM)
-78 oC, 0.5 h
3b,c
(1.2 equiv.)
(3.0 equiv.)
(42%)
(95%)
OMe
MeO
MeO
SPh
SPh
PhS
THF (46 mM)
-78 oC, 0.5 h
4c
O
F
19b
a) Nu was prepared at -20 oC for 0.5 h.
b) Nu was prepared at -30 oC for 1 h.
c) Nu was prepared at -78 oC for 1 h.

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HETEROCYCLES, Vol. 86, No. 2, 2012
R2
R4
R6
SPh
O
R2
OMe
O
R2
CuCl2, CuO
a
b
H
F
OMe
F
H
H
MeO
MeO
MeOH, reflux, 2 h
b: 61%
R6
19b,c
R4
R6
20b,c
R4
c: trace
c
F
H
F
Scheme 4. Acetal formation from various hemithioacetals
R2
SO2Ph
R2
NaHCO3, CH2Cl2
mCPBA (4 equiv.)
SPh
MeO
MeO
-10 °C, 2 h
b: 82%
c: 90%
O
O
R6
R4
R6
R4
19b,c
24b,c
Scheme 5. Conversion of sulfide to sulfonyl group
Table 5. The transformation of the nucleophilic groups into hemithioacetal or dimethyl acetal
F
OMe
F
condition
R
MeO
O
O
F
F
17b, 18b, 19b
20b
Product (yield %)
Entry
1
R
condition
OMe
F
A, 1.5 h
B, 1.5 h
A, 1.5 h
HS
S
(32%)
O
21b
O
F
S
S
S
F
(62%)
2
3
MeO
OMe
F
22b
O
F
SMe
F
S
MeO
MeO
OMe
22b
OMe
F
F
23b
MeO
MeO
SPh
SPh
4
5
A, 3 h
B, 2 h
Recovery of SM
OMe
MeO
F
(61%)
O
20b
F
condition A: AgNO3 (5.0 equiv.), NCS (5.0 equiv.), 2,6-lutidine (5.0 equiv.),
MeOH/THF (1:1, 54 mM), 0 oC.
condition B: CuCl2 (1.5 equiv.), CuO(3.0 equiv.), MeOH (100 mM), reflux.

HETEROCYCLES, Vol. 86, No. 2, 2012
1329
Table 6. Attempted transformation from hemithioacetal into dimethyl acetal
SPh
F
OMe
F
condition
MeO
MeO
O
O
F
F
19b
20b
Entry
1
Conditions
Product (yield %)
OMe
MeOH, reflux, 2 h
MeO
Ar
(61%)
O
OMe
O
SO2Ph
1. mCPBA (4 equiv.), NaHCO3
CH2Cl, -10 °C, 1 h
2. MeOH (8 equiv.), K2CO3
17 °C, 3 h
2
MeO
Ar
(trace)
MeO
Ar
(~30%)
O
SO2Ph
O
1. mCPBA (4 equiv.), NaHCO3
CH2Cl2, -10 °C, 1 h
2. MeOH (8 equiv.), pTSA
17 °C, 3h
3
4
MeO
Ar
(~20%)
mCPBA (4 equiv.), MeOH
-10 °C, 1 h
messy
We were not satisfied with this result, so we kept improving the condition (Table 6). However, those
other method did not provide good result. The α-sulfonyl ketone 24b, 24c were synthesized in good yield
as equivalent as keto-acetal 20 (Scheme 5).
2.
A precursor synthesis of coelenteramine analogs.
The synthesis of coelenteramine was reported for many years. There are two kinds of methods to yield
coelenteramine. Kishi and Goto developed the first method in 1972 through the condensation of
keto-oxime and aminonitrile. The other method was developed by Adamczyk et al.3,8 and Nakamura et
al.9 through the palladium-meditated cross coupling on the commercially available 2-aminopyrazine.
However, we would like to obtain the 8-position analogs of coelenterazine for our research interest. The
method of Adamczyk et al. was modified to reach our goal.
We started from 2-aminopyrazine, which is commercially available. In route A, the mono-bromination
product 26 was obtained from bromination of 2-aminopyrazine 25. Through the Suzuki-Miyaura coupling,
the bromination, and further demethylation, the coelenteramine analog precursor 31 was obtained in 31%
in 4 steps. On the other hand, we did iodination, which was immediately followed by bromination.

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HETEROCYCLES, Vol. 86, No. 2, 2012
The halogenation product 29 can undergo selective Suzuki-Miyaura coupling on the 5-position rather than
the 3-position of 2-aminopyrazine. Demethylation of the coupling product resulted in giving the precursor
31 with total yield 31%. The structure of 2-amino-5-iodopyrazine 28 was confirmed from the chemical
shifts of the two protons at δ 7.81 and δ 8.19 ppm with small coupling constant (J = 1.4 Hz) as a long
range coupling. The other evidence was in the fact that the same compound 30 was identified with those
obtained from both routes A and B. The coelenteramine 2, 30, 31, 32 can be yielded through Negishi
coupling8 or Suzuki-Miyaura coupling at the 3-position of the precursor 31.
B(OH)2
N
N
NH2
Route A
N
N
NH2
N
NH2
0.9 equiv. NBS
MeO
DMF, 0 °C, 88%
Pd(PPh3)4, Na2CO3
DMF, reflux, 99%
Br
N
MeO
25
26
27
Route B
1.0 eq. NBS
CH2Cl2, reflux
36%
2.0 eq. NIS
DMF, 28 °C
61%
B(OH)2
N
N
NH2
Br
N
NH2
N
NH2
Br
1.1 equiv. NBS
(1.0 equiv.)
MeO
DMF, 0 °C
75%
Pd(PPh3)4, Na2CO3
DMF, reflux, 67%
I
N
I
N
MeO
28
29
30
BBr3, CH2Cl2
-78 °C for 1 h, then
-30 °C for 5 h, quant
N
N
NH2
Br
HO
31
Scheme 6. Halogenation of aminopyrazine for precursors to coelenterazine analogs

HETEROCYCLES, Vol. 86, No. 2, 2012
1331
Table 7. The acid-mediated condensation between aminopyrazine and ketoacetals to form coelenterazine
R2
O
N
N
NH2
N
N
R6
R4
keto-ketal, HCl, heat
N
H
RO
RO
2 (R=H)
32 (R=Me)
1b, 1c, 33a
Entry
1a,b
2a,b
3a,b
4a,b
SM
32 (86 mM)
keto-ketal
HCl
condition
Result
4a (2.0 equiv.)

3N
3N
3N
3N
80 C, 4 h
33a, 92%
2
20b

(49 mM)
(2.0 equiv.)
1b
80 C, 4 h
, 86%
2
22b
22c

(131 mM)
(52 mM)
(2.0 equiv.)
(2.0 equiv.)
1b
80 C, 4 h
, 79%
2

1c
, 83%
80 C, 4 h
R6
a) degas under reduce pressure in N2(l)
b) work up with reverse phase column
c) 1.0 mL 12N HCl dilute with 3.0 mL EtOH
R
R2
R4
1b
H
H
F
F
F
H
F
1c
H
33a
Me
H
OMe
H
Table 8. The acid-mediated condensation to form coelenterazine analog
F
O
N
N
NH2
R
keto-ketal 20b
N
N
R
F

3N HCl, 80 C, 4 h
N
H
HO
HO
R
Entry
1a,b
SM
Result
2
1b, 86%
2a,b
3a,b
4a,b
30
31
32
33b
, 84%
34b, 60%
OMe
S
35b
, 13%
a) degas under reduce pressure in N2(l)
b) work up with reverse phase column

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HETEROCYCLES, Vol. 86, No. 2, 2012
3.
Synthesis of coelenterazine
Since we developed several routes to yield keto-acetal and coelenteramine, we tried to synthesize
coelenterazine itself by an acid-mediated condensation between keto-acetal and coelenteramine (Table 7).
The obtained result shows that keto-acetal or keto-sulfone can react with coelenteramine 2 as better
precursor to keto-aldehyde. In fact, these conditions have provided much higher yields (79~92%) than
63% (best results, but not repeatable) chemical yield from the condensation of keto-aldehyde and
coelenteramine. And the keto-acetal is also suitable to undergo the condensation with other
coelenteramine analog in good yields (Table 8).
EXPERIMENTAL
General
Proton NMR spectra were recorded on a Varian Mercury-400 for 400 MHz, or a Varian Unityinova-500
for 500 MHz. Chemical shift (δ) are given in parts per million relative to CD3OD (δ 3.30) or CDCl3 (δ
7.24) as internal standard. Coupling constants (J) are given in Hz. Carbon NMR spectra were recorded on
Varian Mercury-400 for 100 MHz, or a Varian Unityinova-500 for 125 MHz. Chemical shifts are (δ)
given in parts per million relative to CDCl3 (δ 77.0) or CD3OD (δ 49.0) as internal standard. Coupling
constants (J) are given in Hz. Fluorine NMR spectra were recorded on a Varian Unityinova-500 for 470
MHz. Chemical shifts are (δ) given in parts per million relative to 1,1,1-trifluorotoluene (δ 0.00) as
external standard. High-resolution (HR) MS spectra were measured with a Finnigan LCQ ion-trap mass
spectrometer (Thermo Finnigan Co., San Jose, CA). All the solvents were of reagent grade. Analytical
thin-layer chromatography (TLC) was conducted on precoated tlc plates: silica gel 60 F-254 [E. Merck
(Art 5715) Darmstadt, Germany], layer thickness 0.25 mm. Silica gel column chromatography utilized
Silica Gel 60 (spherical) 40-50 μm [E. Merck (Art 5715) Darmstadt, Germany].
2-(4-Methoxybenzyl)-1,3-dithiane (13a).
To a solution of 2-(4-methoxyphenyl)acetaldehyde (1.00 g, 6.66 mmol), 4Å MS (6.00 g) and
1,3-propanedithiol (0.80 mL, 7.98 mmol) in anhydrous CH2Cl2 (20.0 mL) under Argon at 0 °C, boron
trifluoride diethyl etherate (3.30 mL, 26.6 mmol) was added. The reaction mixture was stirred for 2 h at
0 °C, and then was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was
quenched by NaHCO3(aq), filtered, and extracted with CH2Cl2 (10 mL × 3). The combined organic layer
was dried over MgSO4 and evaporated under reduced pressure to dryness. The crude was purified by
column chromatography (EtOAc: hexane = 1 : 8 ) to give 2-(4-methoxybenzyl)-1,3-dithiane as a
yellow-green solid (1.455 g, 91%). 1H NMR (CDCl3, 400 MHz): δ 1.75-1.90 (m, 1H), 2.02-2.14 (m, 1H),
2.72-2.83 (m, 4H), 2.95 (d, 2H, J = 7.2 Hz), 3.76 (s, 1H), 4.19 (t, 1H, J = 7.2 Hz), 6.83 (d, 2H, J = 8.6 Hz),

HETEROCYCLES, Vol. 86, No. 2, 2012
1333
7.15 (d, 2H, J = 8.6Hz). 13C NMR (CDCl3, 100 MHz): δ 25.5, 30.2, 40.6, 48.6, 54.8, 113.4, 129.0, 129.9,
158.2. HRMS (APCI) calcd for C12H16OS2 241.0715 (M+H+), found 241.0712 (M+H+).
2-(4-Methoxybenzyl)-1,3-dithiane-2-carbaldehyde (14a)
To a solution of 2-(4-methoxybenzyl)-1,3-dithiane (1.00 g, 4.16 mmol) in anhydrous THF (10.0 mL) at
-20 °C, n-BuLi (2.5 M, 1.70 mL, 4.25 mmol) was added. After 30 min, anhydrous DMF (1.60 mL, 20.8
mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 6 h.
The reaction was quenched by 10% HCl(aq) (30 mL), then extracted with EtOAc (20 mL × 3). The
combined organic layer was dried over MgSO4 and evaporated under reduced pressure to dryness. The
crude was purified by column chromatography (EtOAc : hexane = 1 : 8) to give 2-(4-methoxybenzyl)-
1
1,3-dithiane-2-carbaldehyde as a colorless oil (0.970 g, 87%). H NMR (CDCl3, 400 MHz): δ 1.65-1.81
(m, 1H), 1.98-2.11 (m, 1H), 2.53-2.63 (m, 2H), 2.89-3.02 (m, 2H), 3.08 (s, 2H), 3.75 (s, 3H), 6.80 (d, 2H,
J = 8.8 Hz), 7.11 (d, 2H, J = 8.8 Hz), 9.20 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 24.1, 27.0, 41.5, 55.2,
58.7, 113.8, 125.1, 131.2, 159.1, 189.2. HRMS (APCI) calcd for C13H16O2S2 269.0664 (M+H+), found
269.0669 (M+H+).
2-(2-(4-Methoxybenzyl)-1,3-dithian-2-yl)-1,3-dioxolane (14a)
To a solution of 2-(4-methoxybenzyl)-1,3-dithiane-2-carbaldehyde (1.00 g, 3.73 mmol) in toluene (20.0
mL), ethylene glycol (1.0 mL, 17.9 mmol) and p-toluenesulfonic acid (6 mg, 1 mol%) was added. The
reaction mixture was refluxed for 12 h under Dean-Stark conditions. The reaction was cooled to room
temperature, quenched by NaHCO3(aq), and extracted with EtOAc (20 mL × 3). The combined organic
layer was dried over MgSO4 and evaporated under reduced pressure to dryness. The crude was purified
by column chromatography (EtOAc : hexane = 1 : 8) to give 2-(2-(4-methoxybenzyl)-1,3-dithian-2-yl)-1,
1
3-dioxolane as a colorless oil (0.955 g, 82%). H NMR (CDCl3, 400 MHz): δ 1.70-1.87 (m, 1H),
1.97-2.10 (m, 1H), 2.44-2.55 (m, 2H), 3.02 (s, 2H), 3.14-3.26 (m, 2H), 3.76 (s, 3H), 3.87-3.95 (m, 2H),
4.09-4.18 (m, 2H), 5.00 (s, 1H), 6.79 (d, 2H, J = 8.4 Hz, ArH), 7.27 (d, 2H, J = 8.4 Hz). 13C NMR
(CDCl3, 100 MHz): δ 24.6, 27.1, 43.1, 53.3, 55.1, 65.6, 109.6, 113.1, 126.6, 132.1, 158.5. HRMS (APCI)
calcd for C15H20O3S2 313.0927 (M+H+), found 313.0935 (M+H+).
1-(1,3-Dioxolan-2-yl)-2-(4-methoxyphenyl)ethanone (4a)
To a solution of 2-(2-(4-methoxybenzyl)-1,3-dithian-2-yl)-1,3-dioxolane (1.00 g, 3.20 mmol) in the
mixed solvent of MeCN (100.0 mL) and water (35.0 mL), N-chlorosuccinimide (2.13 g, 16.0 mmol) and
silver nitrate (2.72 g, 16.0 mmol) was added. The reaction solution was stirred for 5 min. The reaction
was quenched by Na2SO3(aq) (40 mL), NaHCO3 (aq) (40 mL), and NaCl (aq) (40 mL), filtered, and extracted

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HETEROCYCLES, Vol. 86, No. 2, 2012
with EtOAc (100 mL × 3). The combined organic layer was dried over MgSO4 and evaporated under
reduced pressure to dryness. The crude was purified by column chromatography (EtOAc : hexane = 1 : 5)
1
to give 1-(1,3-dioxolan-2-yl)-2-(4-methoxyphenyl)ethanone as a colorless oil (0.647 g, 91%). H NMR
(CDCl3, 400 MHz): δ 3.74-3.82 (m, 2H), 3.78 (s, 3H), 3.85-4.05 (m, 2H), 5.10 (s, 1H), 6.83 (d, 2H, J =
13
7.6 Hz, ArH), 7.10 (d, 2H, J = 7.6 Hz). C NMR (CDCl3, 100 MHz): δ 43.0, 55.1, 65.6, 101.5, 114.0,
124.9, 130.6, 158.6, 203.3. HRMS (APCI) calcd for C12H14O4 223.0965 (M+H+), found 223.0968
(M+H+).
2-(2,4-Difluorophenyl)-N-methoxy-N-methylacetamide (16b)
To a solution of 2,4-difluorophenylacetic acid (0.512 g, 2.98 mmol) in THF (5.0 mL) in ice bath under Ar,
1,1'-carbonyldiimidazole (0.580 g, 3.58 mmol) was add in portions and allowed to stir for 1 h.
N,O-Dimethylhydroxylamine hydrochloride (0.32 g, 3.28 mmol) and N,N-diisopropylethylamine (0.55
mL, 3.16 mmol)were dissolved in DMF (2.0 mL). The DMF solution was injected to the solution of
2,4-difluorophenylacetic acid and allowed to stir for 24 h. The crude product was evaporated under
reduced pressure to dryness, dissolved in EtOAc, washed with 1M HCl(aq), sat. NaHCO3(aq), and water,
and then dried over MgSO4. The organic layer was evaporated under reduced pressure to dryness to give
1
2-(2,4-difluorophenyl)-N-methoxy-N-methylacetamide as light yellow liquid (0.609 g, 95%). H NMR
13
(CDCl3, 400 MHz): δ 3.16 (s, 3H), 3.66 (s, 3H), 3.72 (s, 2H), 6.73-6.82 (m, 2H), 7.17-7.25 (m, 1H). C
NMR (CDCl3, 100 MHz): δ 31.5, 32.2, 61.2, 103.5 (t, 2JC-F = 25.6 Hz), 110.0 (dd, 2JC-F = 20.9 Hz, 4JC-F
=
=
2
4
3
1
3.9 Hz), 118.0 (dd, JC-F = 16.2 Hz, JC-F = 3.7 Hz), 132.1 (dd, JC-F = 9.6, 5.9 Hz), 160.8 (dd, JC-F
3
1
3
19
248.0 Hz, JC-F = 11.8 Hz), 161.9 (dd, JC-F = 248.0 Hz, JC-F = 11.8 Hz), 171.0. F NMR (CDCl3, 470
MHz): -112.5, -113.7. HRMS (APCI) calcd for C10H11F2NO2 216.0831 (M+H+), found 216.0834
(M+H+).
2-(2,6-Difluorophenyl)-N-methoxy-N-methylacetamide (16c)
To a solution of 2,6-difluorophenylacetic acid (0.51 g, 2.98 mmol) in THF (5.0 mL) in ice bath under Ar,
1,1'-carbonyldiimidazole (0.58 g, 3.58 mmol) was add in portions and allowed to stir for 1h.
N,O-Dimethylhydroxylamine hydrochloride (0.32 g, 3.28 mmol) and N,N-diisopropylethylamine (0.55
mL, 3.16 mmol) were dissolved in DMF (2.0 mL). The DMF solution was injected to the solution of
2,4-difluorophenylacetic acid and allowed to stir for 24h. The crude product was evaporated under
reduced pressure to dryness, dissolved in EtOAc, washed with 1M HCl(aq), sat. NaHCO3(aq), and water,
and then dried over MgSO4. The organic layer was evaporated under reduced pressure to dryness to give
1
2-(2,6-difluorophenyl)-N-methoxy-N-methylacetamide as colorless liquid (0.590 g, 92%). H NMR
13
(CDCl3, 400 MHz): δ 3.13 (s, 3H), 3.65 (s, 3H), 3.77 (s, 2H), 6.76-6.84 (m, 2H), 7.09-7.17 (m, 1H). C

HETEROCYCLES, Vol. 86, No. 2, 2012
1335
NMR (CDCl3, 100 MHz): δ 25.9, 31.9, 60.8, 110.6 (dd, 2JC-F = 18.9 Hz, 4JC-F = 6.7 Hz), 111.0 (t, 2JC-F
=
20.2 Hz), 128.3 (t, 3JC-F = 10.3 Hz), 161.3 (dd, 1JC-F = 247.5 Hz, 3JC-F = 7.5 Hz), 169.7. 19F NMR (CDCl3,
470 MHz): -115.1. HRMS (APCI) calcd for C10H11F2NO2 216.0831 (M+H+), found 216.0825 (M+H+).
3-(2,4-Difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one (19b)
To the solution of methoxymethyl phenyl sulfide (2.10 mL, 14.3 mmol) in THF (50 mL) at -78 °C,
n-BuLi (5.8 mL, 2.5M, 14.5 mmol) was added and allowed to stir for 1 h. The prepared solution was
added to the solution of 2-(2,4-difluorophenyl)-N-methoxy-N-methylacetamide (0.997 g, 4.64 mmol) in
THF (50 mL) at -78 °C and allowed to stir for 0.5 h. The reaction solution was poured into NH4Cl(aq)
,
extracted with EtOAc. The combined organic layer was dried over MgSO4 and evaporated under reduced
pressure to dryness. The crude was purified by column chromatography (EtOAc : hexane = 1 : 6) to give
1
3-(2,4-difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one as a yellow color oil (1.358 g, 95%). H
NMR (CDCl3, 400 MHz): δ 3.50 (d, J = 17.7 Hz, 1H, ABq), 3.61 (s, 3H), 3.88 (d, J = 17.7 Hz, 1H, ABq),
5.08 (s, 1H), 6.72-6.80 (m, 2H), 6.86-6.94 (m, 1H), 7.27-7.34 (m, 3H), 7.45-7.50 (m, 2H). 13C NMR
2
2
4
(CDCl3, 125 MHz): δ 38.1, 56.2, 91.9, 103.6 (t, JC-F = 25.9 Hz), 111.1 (dd, JC-F = 21.0 Hz, JC-F = 3.8
Hz), 116.6 (dd, 2JC-F = 15.5 Hz, 4JC-F = 3.3 Hz), 128.8, 129.1, 130.5, 132.3 (dd, 3JC-F = 9.4, 6.1 Hz), 134.4,
1
3
1
3
19
161.0 (dd, JC-F = 248.0 Hz, JC-F = 12.2 Hz), 162.1 (dd, JC-F = 248.0 Hz, JC-F = 12.2 Hz), 198.7. F
NMR (CDCl3, 470MHz): -112.6, -111.9. HRMS (APCI) calcd for C16H14F2O2S 309.0755 (M+H+), found
309.0742 (M+H+).
3-(2,6-Difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one (19c)
To the solution of methoxymethyl phenyl sulfide (2.10 mL, 14.3 mmol) in THF (50 mL) at -78 °C,
n-BuLi (5.8 mL, 2.5M, 14.5 mmol) was added and allowed to stir for 1 h. The prepared solution was add
to the solution of 2-(2,6-difluorophenyl)-N-methoxy-N-methylacetamide (0.997 g, 4.64 mmol) in THF
(50 mL) at -78 °C and allowed to stir for 0.5 h. The reaction solution was poured into NH4Cl(aq), extracted
with EtOAc. The combined organic layer was dried over MgSO4 and evaporated under reduced pressure
to dryness. The crude was purified by column chromatography (EtOAc: hexane = 1 : 6 ) to give
1
3-(2,6-difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one as a yellow color oil (0.943 g, 66%). H
NMR (CDCl3, 400 MHz): δ 3.59 (d, J = 18.2 Hz, 1H, ABq), 3.64 (s, 3H), 4.05 (d, J = 18.2 Hz, 1H, ABq),
5.10 (s, 1H), 6.80-6.88 (m, 2H), 7.14-7.23 (m, 1H), 7.28-7.34 (m, 3H), 7.47-7.52 (m, 2H). 13C NMR
2
2
4
(CDCl3, 125 MHz): δ 32.5, 56.2, 91.8, 109.9 (t, JC-F = 20.6 Hz), 110.9 (dd, JC-F = 19.8 Hz, JC-F = 5.5
3
1
3
Hz), 128.7, 128.8 (t, JC-F = 10.3 Hz), 129.0, 130.4, 134.3, 161.4 (dd, JC-F = 247.8 Hz, JC-F = 8.3 Hz),
19
197.7. F NMR (CDCl3, 470 MHz): -114.3. HRMS (APCI) calcd for C16H14F2O2S 309.0755 (M+H+),
found 309.0745 (M+H+).

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HETEROCYCLES, Vol. 86, No. 2, 2012
3-(2,4-Difluorophenyl)-1,1-dimethoxypropan-2-one (20b)
To the solution of 3-(2,4-difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one (1.000 g, 3.23 mmol) in
anhydrous MeOH (30 mL) under Ar, copper(II) chloride (0.653 g, 4.86 mmol) and copper oxide (0.773 g,
9.72 mmol) were added and allowed to stir. The reaction mixture was refluxed for 1.5 h, and then cooled
to room temperature. The reaction crude mixture was filtered, evaporated under reduced pressure to
dryness, dissolved in water, extracted with EtOAc. The combined organic layer was dried over MgSO4
and evaporated under reduced pressure to dryness. The crude was purified by column chromatography
(EtOAc : hexane = 1 : 20) to give 3-(2,4-difluorophenyl)-1,1-dimethoxypropan-2-one as a yellow color
oil (0.453 g, 61%). 1H NMR (CDCl3, 400 MHz): δ 3.43 (s, 6H), 3.86 (s, 2H), 4.54 (s, 1H), 6.76-6.85 (m,
13
2
2H), 7.06-7.14 (m, 1H). C NMR (CDCl3, 125 MHz): δ 36.9, 54.9, 103.7 (t, JC-F = 25.1 Hz), 104.0,
111.1 (dd, 2JC-F = 21.2 Hz, 4JC-F = 3.5 Hz), 116.7 (dd, 2JC-F = 17.0 Hz, 4JC-F = 3.7 Hz), 132.4 (dd, 3JC-F
=
10.3, 5.9 Hz), 161.1 (dd, 1JC-F = 248.0 Hz, 3JC-F = 12.2 Hz), 162.2 (dd, 1JC-F = 248.0 Hz, 3JC-F = 12.2 Hz),
201.2. 19F NMR (CDCl3, 470 MHz): -113.1, -112.0. HRMS (APCI) calcd for C12H12F2O3 231.0827
(M+H+), found 231.0829 (M+H+).
3-(2,6-Difluorophenyl)-1-methoxy-1-(phenylsulfonyl)propan-2-one (24c)
To the solution of 3-(2,6-difluorophenyl)-1-methoxy-1-(phenylthio)propan-2-one (0.301 g, 0.98 mmol) in
CH2Cl2 (9 mL) at -10 °C, meta-chloroperoxybenzoic acid (0.676 g, 3.92 mmol) and NaHCO3 (0.329 g,
3.92 mmol) were added and allowed to stir for 2 h. The reaction crude was poured into water, extracted
with EtOAc. The combined organic layer was dried over MgSO4 and evaporated under reduced pressure
to dryness. The crude was purified by column chromatography (EtOAc : hexane = 1 : 4) to give
3-(2,6-difluorophenyl)-1-methoxy-1-(phenylsulfonyl)propan-2-one as a white color solid (0.300 g, 90%).
1H NMR (CDCl3, 400 MHz): δ 3.71 (d, J = 18.9 Hz, 1H, ABq), 3.79 (s, 3H), 4.15 (d, J = 18.2 Hz, 1H,
ABq), 4.83 (s, 1H), 6.80-6.88 (m, 2H), 7.16-7.25 (m, 1H), 7.53-7.59 (m, 2H), 7.65-7.71 (m, 1H),
7.85-7.90 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 34.1, 62.0, 100.0, 109.0 (t, 2JC-F = 20.6 Hz), 111.0 (dd,
2JC-F = 20.0 Hz, 4JC-F = 5.1 Hz), 128.2, 129.2, 129.7, 134.7 (t, 3JC-F = 220.6 Hz), 161.3 (dd, 1JC-F = 247.8
3
Hz, JC-F = 8.3 Hz), 169.9, 196.1. 19F NMR (CDCl3, 470 MHz): -114.4. HRMS (APCI) calcd for
C16H14F2O4S 341.0654 (M+H+), found 341.3039 (M+H+).
5-Iodopyrazin-2-amine (28)
To a solution of pyrazin-2-amine (3.00 g, 3.16 mmol) in DMF (106 mL), was added NIS (13.6 g, 6.04
mmol). The mixture was stirred overnight. The reaction was diluted by addition of sat. Na2S2O3(aq) (100
mL), then extracted with EtOAc (150 mL × 3). The combined organic layer was washed with brine (150
mL) and dried over Mg2SO4, then concentrated under vacuum. The residual solid was purified by column

HETEROCYCLES, Vol. 86, No. 2, 2012
1337
chromatography (EtOAc : hexane = 1 : 3) to give 5-iodopyrazin-2-amine as a yellow solid (4.3 g, 61%).
13
1H NMR (CDCl3, 400 MHz), δ 4.59 (br s, 2H), 7.81 (d, 1H, J = 1.4 Hz), 8.19 (d, 1H, J = 1.4 Hz). C
NMR (CDCl3, 100 MHz), δ 100.2, 133.5, 149.5, 153.6. HRMS (ESI) calcd for C4H4IN3 220.9450, found
220.9450 (M+).
3-Bromo-5-iodopyrazin-2-amine (29)
To a solution of 5-iodopyrazin-2-amine (2.00 g, 9.05 mmol) in DMF (43 mL), was added NBS (1.93 g,
10.86 mmol). The mixture was stirred for 2 h. Additional of NBS (0.81 g, 4.53 mmol) was added, and the
resulting solution was stirred for 1 h. The reaction extracted with ether (150 mL × 3). The combined
organic layer was washed with brine (150 mL) and dried over Mg2SO4, then concentrated under vacuum.
The residual solid was purified by column chromatography (EtOAc : hexane = 1 : 5) to give 3-bromo-
5-iodopyrazin-2-amine and 3,5-dibromopyrazin-2-amine as a yellow solid in a ratio 5:1 (2.0 g, 75%).
3-Bromo-5-(4-methoxyphenyl)pyrazin-2-amine (30)
To a solution of 3-bromo-5-iodopyrazin-2-amine (200 mg, 0.67 mmol) in degassed DME (3 mL),
4-methoxyphenylboronic acid (102 mg, 0.67 mmol), 10% Na2CO3 aq. (1.42 mL, 1.34 mmol) and
Pd(PPh3)4 (39 mg, 0.034 mmol) were added, then the reaction mixture was refluxed for 1 day under
nitrogen. The solution was cooled to room temperature and extracted with EtOAc (20 mL × 3). The
combined organic layer was washed with brine (10 mL), and dried over MgSO4. After removal of the
solvent, the residual solid was purified by column chromatography (EtOAc : hexane = 1 : 1) to give
1
3-bromo-5-(4-methoxyphenyl)pyrazin-2-amine as a yellow solid (126 mg, 67%). H NMR (CDCl3, 400
MHz), δ 3.53 (s, 3H), 4.99 (br s, 2H), 6.94 (d, 2H, J = 8.8 Hz), 7.78 (d, 2H, J = 8.8 Hz), 8.32 (s, 1H).
4-(5-Amino-6-bromopyrazin-2-yl)phenol (29)
A solution of the 3-bromo-5-(4-methoxyphenyl)pyrazin-2-amine (200mg, 0.71 mmol) in anhydrous
CH2Cl2 (4 mL) was cooled to -78 °C and then BBr3 (0.14 mL, 1.42 mmol) was added. After the mixture
was stirred for 1 h at -78 °C, the temperature was warmed to -30 °C, and then stirred for 5 h. The reaction
was quenched by water (10 mL), and the CH2Cl2 was removed in vacuo. The aqueous solution was
neutralized by NaHCO3 sat. aq., and then extracted with EtOAc (50 mL × 3). The combined organic layer
was washed with brine (50 mL) and dried over MgSO4, then concentrated under vacuum. The residue was
purified by column chromatography (EtOAc : hexane = 1 : 1) to give 19 as a yellow solid (100 mg, 53%).
1H NMR (CDCl3, 400 MHz) 4.98 (br s, 1H), 6.88 (d, 2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.8 Hz), 8.31 (s,
13
1H). C NMR (CD3COCD3, 125 MHz) 116.4, 125.6, 127.5, 128.2, 137.8, 142.8, 152.4, 158.6. HRMS
(EI) calcd for C10H8BrN3O 264.9851, found 264.9846 (M+).

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HETEROCYCLES, Vol. 86, No. 2, 2012
General procedure of synthesis of coelenterazine
To a solution of aminopyrazine (0.258 mmol) and keto-acetal (0.516 mmol) in degassed MeOH (3.0 mL)
under Ar, 12N HCl (1.0 mL) was added and allowed to stir for 5 min. The reaction solution was heat to
80 °C for 4 h, and then cooled to room temperature. The crude product was diluted with water (100 mL),
and filtered through Cosmosil. The collected fraction was purified by the crude mixture was purified by
column chromatography (MeOH : CH2Cl2 = 1 : 20) to give coelenterazine as a solid.
8-Benzyl-2-(4-methoxybenzyl)-6-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one (33a)
1H NMR (400 MHz, CD3OD): δ 3.66 (3H, s), 3.71 (3H, s), 4.04 (2H, s), 4.32 (2H, s), 6.75 (2H, d, J = 8.7
13
Hz), 6.85 (2H, d, J = 8.7 Hz), 7.19-7.22 (5H, m, aromatic), 7.34-7.36 (3H, m), 7.40-7.43 (3H, m). C
NMR (100 MHz, CD3OD): δ 31.59, 40.12, 55.61, 55.82, 108.05, 114.82, 115.31, 128.13, 129.07, 129.71,
129.77, 130.77, 131.74, 132.34, 137.99, 159.70, 162.10. HRMS (ESI) calcd for C28H25N3O3 451.1896,
found 451.1896 (M+).
8-Benzyl-2-(2,4-difluorobenzyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one (1b)
1H NMR (400 MHz, CD3OD): δ 4.16 (2H, s), 4.37 (2H, s), 6.84-6.91 (2H, m), 6.91-6.96 (2H, m),
7.18-7.24 (1H, m), 7.24-7.33 (3H, m), 7.37 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.56 (1H, s).
HRMS (APCI) calcd for C26H20F2N3O2 444.1508 (M+H+), found 444.1528 (M+H+).
8-Benzyl-2-(2,6-difluorobenzyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one (1c)
1H NMR (400 MHz, CD3OD): δ 4.20 (2H, s), 4.28 (2H, s), 6.83-6.87 (2H, m), 6.92-6.99 (2H, m),
7.15-7.24 (3H, m), 7.26-7.27 (1H, m), 7.31 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.47 (1H, s).
HRMS (APCI) calcd for C26H20F2N3O2 444.1518 (M+H+), found 444.1511 (M+H+).
2-(2,4-Difluorobenzyl)-6-(4-hydroxyphenyl)-8-(naphthalen-2-yl)imidazo[1,2-a]pyrazin-3(7H)-one
(33b)
1H NMR (400 MHz, CD3OD): δ 4.18 (2H, s), 6.80-6.96 (3H, m), 7.25-7.33 (1H, m), 7.24-7.33 (3H, m),
7.54-7.65 (2H, m), 7.73 (1H, d, J = 8.1 Hz), 7.84 (1H, s), 7.95 (1H, d, J = 9.2 Hz), 7.99-8.05 (1H, m),
8.17 (2H, d, J = 8.1 Hz), 8.65 (1H, s). HRMS (APCI) calcd for C29H20F2N3O2 480.1500 (M+H+), found
480.1518 (M+H+).
2-(2,4-Difluorobenzyl)-6-(4-hydroxyphenyl)-8-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one
(34b)
1H NMR (400 MHz, CD3OD): δ 3.87 (3H, s), 4.14 (2H, s), 6.82-6.93 (4H, m), 7.07 (2H, d, J = 8.6 Hz),

HETEROCYCLES, Vol. 86, No. 2, 2012
1339
7.27 (1H, q, J = 8.5 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.67 (1H, br s), 8.02 (2H, d, J = 8.6 Hz). HRMS
(APCI): calcd for C26H18F2N3O3 (M-H+) 458.1311; found 458.1302.
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