Substituent effect of imino-o-arenesulfonates, a coupling partner in Suzuki-Miyaura reaction for substitution of the pyrazine ring: A study for the synthesis of coelenterazine analogs

Article abstract of DOI:10.1246/bcsj.82.870

Amino(aryl)pyrazines, a key intermediate in the synthesis of coelenterazine and its analogs, can be prepared in excellent yields by utilizing imino-O-tosylates in the SuzukiMiyaura reaction. These imino-O-tosylates serve as a substitute for the corresponding imino-O-triflates, which are sometimes too unstable to be stored during the optimization of the reaction conditions. Aryltrifluoroborates, a coupling partner, worked well when arylboronic acids or arylboronate esters were less reactive. Aryltrifluoroborates also worked well when containing an electron-donating group attached to the aromatic ring. The study of the substituent effect of imino-O-arenesulfonates demonstrated a major difference in the rate of the reactions when changing from electron-donating groups to electron-withdrawing groups at the para position of arenesulfonates. Imino-O-arenesulfonate containing a para-bromo substituent only gave the desired coupling product leaving the para substituent of arenesulfonate untouched.

Full text of DOI:10.1246/bcsj.82.870

870
Bull. Chem. Soc. Jpn. Vol. 82, No. 7, 870–878 (2009)
© 2009 The Chemical Society of Japan
Substituent Effect of Imino-O-arenesulfonates, a Coupling Partner in
Suzuki-Miyaura Reaction for Substitution of the Pyrazine Ring:
A Study for the Synthesis of Coelenterazine Analogs
Arthit Makarasen,1 Masaki Kuse,2 Toshio Nishikawa,1 and Minoru Isobe*1,3
1Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa-ku, Nagoya 464-8601
2Institute of Material Science, Nagoya University, Chikusa-ku, Nagoya 464-8601
3Institute for Advanced Research, Nagoya University, Chikusa-ku, Nagoya 464-8601
Received February 13, 2009; E-mail: minoru@mx.nthu.edu.tw
Amino(aryl)pyrazines, a key intermediate in the synthesis of coelenterazine and its analogs, can be prepared in
excellent yields by utilizing imino-O-tosylates in the Suzuki-Miyaura reaction. These imino-O-tosylates serve as a
substitute for the corresponding imino-O-triflates, which are sometimes too unstable to be stored during the optimization
of the reaction conditions. Aryltrifluoroborates, a coupling partner, worked well when arylboronic acids or arylboronate
esters were less reactive. Aryltrifluoroborates also worked well when containing an electron-donating group attached to
the aromatic ring. The study of the substituent effect of imino-O-arenesulfonates demonstrated a major difference in the
rate of the reactions when changing from electron-donating groups to electron-withdrawing groups at the para position of
arenesulfonates. Imino-O-arenesulfonate containing a para-bromo substituent only gave the desired coupling product
leaving the para substituent of arenesulfonate untouched.
Palladium-mediated cross-coupling reactions are one of the
and organoborons containing an electron-donating group
attached to the aromatic ring.4 Herein, we demonstrate the
successful utilization of imino-O-tosylates in the Suzuki-
Miyaura cross-coupling to access various substituents into
amino(aryl)pyrazines, which is the key intermediate in the
synthesis of unstable coelenterazine and its derivatives,6
together with the study of substituent effect of imino-O-
arenesulfonates at the para position in the cross-coupling
reactions.
useful methods employed to form carbon-carbon bonds in
organic synthesis.1 High functional group tolerance, easily
separable and nontoxic by-products, and commercial avail-
ability of boron coupling partners have provided the Suzuki-
Miyaura cross-coupling both a popular and effective tool in
organic synthesis. Suzuki-Miyaura reaction involves the
palladium-mediated cross-coupling between organoboron com-
pounds and aryl/alkenyl halides/triflates in the presence of
a base.2 Using aryltrifluoroborates and arylboronate esters
as alternatives to arylboronic acids have been examined to
determine their usefulness in the Suzuki-Miyaura cross-
coupling reaction, because of their high stability, availability
of purified sample, and in order to avoid the formation of
trimeric anhydride boroxime.3 Instead of aryl, vinyl triflates,
or halides, aryl tosylates were recently reported in Suzuki-
Miyaura cross-coupling reaction.4 Although these tosylates are
more stable, their reactivity becomes relatively lower than the
corresponding triflates or halides. Due to the lower reactivity,
less expensive, more stable and easier to handle than the
corresponding triflates it is therefore a challenge to develop a
general protocol for the coupling between imino-O-tosylates
and organoborons. In 1994, we reported Heck reaction of
various imino-O-triflates with acetylenes.5 However, there has
only been incidental reporting of palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction of imino-O-tosylate with
organoboron.4c We have found that some imino-O-triflates are
unstable for purification or decompose during storage. In the
previous report, a low yield of coupling products was obtained
when the two coupling partners have the same electronic
properties, such as imino-O-triflates6a or heteroaryl tosylates4b
Results and Discussion
Chemical biology studies have identified a requirement for
new ways to supply new classes of analogs of these N-
heterocycles.7 The core skeleton of coelenterazine is amino-
pyrazine which has found only limited use due to unstability.
The imino-O-tosylates 1a-1g and the homologs 2a-2g were
prepared for this study from amino nitriles using our reported
procedure as shown in Scheme 1.6b
The Suzuki-Miyaura reaction of imino-O-tosylates 1a or 2a
and arylboronic acid 3, arylboronate ester 4, or aryltrifluoro-
borate 5 was examined in polar solvents in the presence of PdII,
phosphine ligand, and base. All reactions were monitored in the
same time scale as 5 h for the reaction time. The results are
summarized in Table 1. Combination of Pd(OAc)2 and a bulky
and electron-rich phosphines 6 was found to be useful for the
current coupling system. This combination was also used in the
screening to optimize the cross-coupling condition. In case
of imino-O-tosylate 1a, the excellent yields of the coupling
products were obtained when organoboron accompanied with a
suitable base and solvent were used (Table 1, Entries 1, 6, and
9). However, for imino-O-tosylate 2a, the coupling could only
Published on the web July 10, 2009; doi:10.1246/bcsj.82.870

A. Makarasen et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
871
N
N
NHTs
R
R
arylsulfonyl
chloride
NH2
CN
N
NHTs
R
CN
X
Ph
CH2-Ph
O
ClH3N
R
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
CH3
H
O
N
R
O
N
H
O S O
H
OCH3
Cl
R = Ph,
-CH2Ph
Br
F
1g
2g
NO2
X
Scheme 1. Synthesis of imino-O-tosylates 1a-1g and the homologs 2a-2g.
Table 1. Relative Reactivity of Imino-O-tosylates and Organoboronsa)
B(OH)2
N
N
NHTs
R1
R2
3a R2 = OMe
N
N
NHTs
R1
Pd(OAc)2 (4 mol%)
6 (8 mol%)
O
S
or
Base (3.0 equiv)
O
O
solvent, bath temp 80 o
C
O
B
+
H3CO
O
R2
R2
4a R2 = OMe
7a R1 = Ph
8a R1 = -CH2-Ph
CH3
PCy2
BF3K
H3CO
OCH3
1a R1 = Ph
2a R1 = -CH2-Ph
6
5a R2 = OMe
Organoboron
R2 = OMe (equiv)
Product
(% Yield)b)
Entry
Aryl tosylate
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
3a (2.0)
3a (1.1)
3a (2.0)
4a (2.0)
4a (2.0)
4a (2.0)
4a (1.3)
5a (2.0)
5a (2.0)
5a (1.3)
3a (2.0)
4a (2.0)
4a (1.3)
5a (1.1)
5a (1.1)
5a (2.0)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
KOH
K3PO4
KOH
KOH
K3PO4
KOH
KOH
KOH
THF
THF
Dioxane
THF
THF
MeOH
MeOH
THF
MeOH
MeOH
THF
MeOH
MeOH
MeOH
Ethanol
MeOH
7a (91)
7a (27)
7a (nr)c)
7a (15)d)
7a (21)
7a (91)
7a (85)
7a (nr)e)
7a (92)
7a (28)
8a (11)
8a (87)
8a (73)
8a (5)
Et3N
KOH
8a (9)
8a (22)
a) Reaction condition: imino-O-tosylate 1a and 2a (0.10 mmol), organoboron, Pd(OAc)2 (4 mol %), ligand
6 (8 mol %), base (3.0 equiv), solvent (5.0 mL), bath temp 80 °C, 5 h. b) Isolated yield. c) PPh3 was used as
ligand in the reaction. d) [PdCl2(dppf)] was used as catalyst. e) nr = no reaction.
be accomplished when arylboronate ester 4a (R = OMe) and
KOH in MeOH were employed (Table 1, Entries 12 and 13).
This result implied that imino-O-tosylate 2a is less reactive
than 1a.
product was obtained when arylboronic acid or aryltrifluoro-
borate was used lower than 1.3 equivalent (Table 1, Entries 2
and 10).
Under the optimum condition obtained as above, the
coupling reactions of 1a and 2a were further examined with
various arylboronate esters 4 under the condition [Pd(OAc)2
(4 mol %), 6 (8 mol %), 4 (2.0 equiv), KOH (3.0 equiv), MeOH,
bath temp 80 °C]. The results are shown in Table 2. We found
that the coupling products between imino-O-tosylates 1a or 2a
and arylboronate esters 4b, 4c, and 4e were obtained in good
yields. Less than 20% yield of products were observed,
however, when arylboronate esters 4d and 4f were used having
an electron-donating substituent at the para position of the
aromatic ring (Table 2, Entries 3 and 5). The cross-coupling
In the previous efforts to couple aryl tosylate with various
organoborons in the Suzuki-Miyaura cross-coupling engen-
dered significant stoichiometric inefficiencies as well; reported
procedures required either 1.5 or 2.04f equivalent of arylboronic
acid or 1.0,4b 1.1,4b and 1.53e equivalent of arylboronate ester
or aryltrifluoroborate.3,4 In the Table 1, we found that two
equivalents of organoborons provided the best yields of
the coupling products. A slightly lower yield was obtained
when 1.3 equivalent of arylboronate ester was used for the
reaction (Table 1, Entries 7 and 13). Less than 30% yield of

872
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
Imino-O-arenesulfonates for Suzuki-Miyaura Reaction
Table 2. Reaction of Imino-O-tosylates 1a or 2a with
Arylboronate Esters 4b-4f under Optimum Condition
from Table 1a)
Table 3. Reaction of Imino-O-tosylates 1a or 2a with
Aryltrifluoroborates 5b-5f under Optimum Condition from
Table 1a)
N
NHTs
N
NHTs
O
BF3K
B
O
N
R1
O
O
N
R1
R2
SO2
5b-f
SO2
R2
4b-f
Pd(OAc)2 (4 mol%)
6 (8 mol%)
Cs2CO3 (1.0 equiv)
MeOH, refluxing
Pd(OAc)2 (4 mol%)
6 (8 mol%)
1a R1 = Ph
2a R1 = -CH2-Ph
H3C
1a R1 = Ph
KOH (3.0 equiv)
H3C
2a R1 = -CH2-Ph MeOH, refluxing
R1
N
N
NHTs
R1
R1
N
NHTs
R1
R2
Ph
CH2-Ph
R2
Ph
CH2-Ph
7b
7c
7d
7e
7f
8b
8c
8d
8e
8f
H
F
N
7b
7c
7d
7e
7f
8b
8c
8d
8e
8f
H
F
N(CH3)2
O-Ph
OH
R2
N(CH3)2
O-Ph
OH
R2
Aryl
tosylate
R2 of
aryltrifluoroborates 5
Product
Aryl
tosylate
R2 of arylboronate
ester 4
Product
Entry
Entry
(% Yield)b)
(% Yield)b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
5b; H
5c; F
5d; N(CH3)2
5d; N(CH3)2
5e; O-Phenyl
5f; OH
5f; OH
5b; H
5c; F
5d; N(CH3)2
5d; N(CH3)2
5e; O-Phenyl
5f; OH
7b (90)
7c (99)
7d (78)c)
7d (100)
7e (84)
7f (98)c)
7f (97)
8b (93)
8c (84)
8d (13)c)
8d (93)
8e (100)
8f (95)c)
8f (100)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
2a
2a
2a
4b; H
4c; F
7b (89)
7c (85)
7d (17)
7e (74)
7f (nr)c)
8b (82)
8c (79)
8e (83)
4d; N(CH3)2
4e; O-Phenyl
¹
4f; OH (O )
4b; H
4c; F
4e; O-Phenyl
a) Reaction condition: imino-O-tosylate 1a and 2a (0.10 mmol),
arylboronate ester 4b-4f (2.0 equiv), Pd(OAc)2 (4 mol %),
ligand 6 (8 mol %), KOH (3.0 equiv), MeOH (5.0 mL), bath
temp 80 °C, 5 h. b) Isolated yield. c) nr = no reaction.
5f; OH
a) Reaction condition: imino-O-tosylate 1a and 2a
(0.10 mmol), aryltrifluoroborate 5b-5f (2.0 equiv), Pd(OAc)2
(4 mol %), ligand 6 (8 mol %), Cs2CO3 (1.0 equiv), MeOH
(5.0 mL), bath temp 80 °C, 5 h. b) Isolated yield. c) KOH (3.0
equiv) was used as a base in the reaction.
reactions between imino-O-tosylate 2a and arylboronate esters
4d and 4f did not observe because of less reactive than 1a.
In 2002, Miyaura has suggested that the transmetalation step
is often faster with more nucleophilic/electron-rich organic
fragments, and is inhibited by the steric bulk of the coupling
partners.8 Moreover, Hartwig et al. have found that reductive
elimination can often be facilitated by the use of catalysts
having a bulky substituent and it is believed that the reaction
occurs most rapidly when the two coupling partners have
opposite electronic properties, such as one electron-rich and
one electron-poor.9 This, together with the fact that cross-
coupling reactions of imino-O-tosylate with arylboronate esters
containing an electron-donating group attached to the aromatic
ring under certain condition do not proceed well (Table 2,
Entries 3 and 5), suggests that the reaction rate of the
transmetalation step was retarded because of the same
electronic property in the two coupling partners (Scheme 2;
Cycle 1). Moreover, two equivalents of organoboron is
necessary to use in these cross-coupling reactions in order that
the rate of reaction in the transmetalation step was accelerated
to accomplish the corresponded product in excellent yield
within 5 h.
Addition of inexpensive, aqueous KHF2 to either an
arylboronic acid or arylboronate ester will also afford the
potassium organotrifluoroborate directly.3 We examined the
coupling reactions between 1a or 2a and various potassium
aryltrifluoroborates 5b-5f under similar optimized conditions.
The results from these studies are shown in Table 3. We found
that the coupling products could be obtained in excellent yields
even in the cases of aryltrifluoroborates containing an electron-
donating group attached at the para position of the aromatic
ring. Moreover, yields of the coupling products were improved
when Cs2CO3 was employed as a base instead of KOH.
Together with our previous report,6 this procedure can be
applied to synthesize various coelenterazine analogs for
chemical biology studies.
Stille et al. have reported the reactivity relationships of
aryl triflates and halides such as bromide and chloride.10a The
order of halide reactivity in oxidative addition processes is:
I > Br µ OTf º Cl.10 The relative rate of oxidative addition
of various aromatic halides is roughly proportional to the
relative rate of SNAr transformations of these substrates.8,11 In
the current report, we have focused on the relative reactivity of
In addition to their air and moisture stability, the greater
nucleophilicity of the potassium aryltrifluoroborates makes the
organotrifluoroborates valuable coupling partner for palladium-
catalyzed cross-coupling. Potassium aryltrifluoroborates can be
easily prepared by various methods.

A. Makarasen et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
873
N
N
NHTs
N
N
NHTs
N
N
NHTs
(CH2)n
O
O
L
X
S
O
(CH2)n
L
(CH2)n
Y
Pd(0)
L
Pd(0)
L
Y
X = CH3, H, OCH3,
Cl, Br, F, NO2
n = 0, 1
Reductive
Elimination
Reductive
Elimination
Oxidative
Addition
Oxidative
Addition
N
NHTs
N
N
NHTs
N
N
NHTs
(II)
Pd
O
(II)
Pd
L2
N
(CH2)n
(II)
Y
1
2
(CH2)n
(CH2)n
Y
X
S O Pd
L2
L2
O
Y = OCH3, H, F,
N(CH3)2, O-Ph,
OH
KOH
Transmetalation
via A or B
Transmetalation
K
N
N
NHTs
O
O
(II)
HO Pd
(CH2)n
K
S O
X
L2
O
Y
BF3
X
S
OK
O
+BF3
+Cs2CO3
Cs2CO3
N
N
NHTs
N
N
NHTs
N
N
NHTs
L2
O
O
L2
O
O
(II)
Pd
L2
HO BF3
K
(CH2)n
Ph
(CH2)n
B
OH
(CH2)n
Ph
X
S
O
HO Pd
(II)
HO Pd
(II)
F
O
B
Y
F
F
B
K
F
Y
F
B
K
Y
O
F
A
C
B
Scheme 2. Mechanism of Suzuki-Miyaura cross-coupling between imino-O-arenesulfonates and organoborons.
imino-O-arenesulfonates containing various substituents at the
para position 1a-1g and 2a-2g.
ing 7a or 8a. After these experiments, the results were carefully
examined. None of the cross-coupling products were resulted
from any further reaction at the halide substituent attached to
the arenesulfonate (such as 9 or 10 in Scheme 3). The absence
of these side products was also confirmed by the mass
spectrometric analysis. These results indicated that the sulfo-
nate group of the imino-O-tosylate is more reactive than the Cl
and Br substituents on arenesulfonate.
The reactivity relationships of these compounds were
studied in the Suzuki-Miyaura cross-coupling reaction with
4-methoxyphenylboronate ester under the condition [Pd(OAc)2
(4 mol %), 6 (8 mol %), 4a (1.0 equiv), KOH (1.5 equiv),
MeOH, bath temp 80 °C]. These competitive reaction processes
were monitored by means of HPLC in terms of consumption of
the starting materials and increasing of product. Due to the
separation capacity in HPLC retention times, we implemented
measures in the four-compound groups of imino-O-arenesul-
fonates for determining the relative rates in the cross-coupling
reactions under the similar condition. However, the concen-
tration of arylboronate esters against the concentration of
imino-O-arenesulfonates cannot be controlled in the same
amount for all groups due to small scale of the reactions
(Figure 1).
After the HPLC monitoring the substituent effects at
the X position in imino-O-arenesulfonates 1a-1g and 2a-2g
for the cross-coupling reactions, the order of reactivity is
as follows: Br > Cl > NO2 µ CH3 > OCH3 µ F > H (from
Scheme 3, Figure 1). Having an electron-withdrawing group
at the para position may activate the arenesulfonate so that it
practically becomes a facile leaving group expected to result in
the reaction proceeding faster. This implied that the oxidative
addition step is the most important in the palladium-catalyzed
Suzuki-Miyaura cross-coupling reaction (Scheme 2).
The catalytic cycle of the palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction is thought to follow a
sequence involving the oxidative addition of imino-O-arene-
sulfonate to a Pd0 complex to form heteroarylpalladium(II)
arenesulfonate intermediate. The order of reactivity of imino-
O-arenesulfonates containing various substituents at the para
position was found that there is a major difference in the
rates of the reactions when changing from electron-donating
groups to electron-withdrawing groups at the para position
of arenesulfonates. Transmetalation with arylboronic acid,
arylboronate ester, or aryltrifluoroborate and reductive elimi-
nation from the resulting diarylpalladium complex affords
the corresponding biaryl and regenerates the Pd0 complex
(Scheme 2).12 At present, the selection of bases in Suzuki-
Miyaura cross-coupling reaction is still empirical, and no
general rule for their selection has been reported. The base
in these reactions is to replace the arenesulfonate in the
coordination sphere of the palladium complex and to facilitate
an intramolecular transmetalation (Scheme 2; Cycle 1).8 Alter-
natively, it has also been facilitated the otherwise slow trans-
metalation of the arylboronic acid by forming a more reactive
In the case of Br or Cl substituent on arenesulfonates 1d, 1e
and 2d, 2e, the reaction might furnish possibly the correspond-

874
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
Imino-O-arenesulfonates for Suzuki-Miyaura Reaction
Figure 1. Relative reactivity of imino-O-arenesulfonates containing various substituents at the para position 1a-1g and 2a-2g in
Suzuki-Miyaura cross-coupling reaction.
N
N
NHTs
N
N
NHTs
R1
Pd(II) (4% mol)
6 (8% mol)
Base (3.0 equiv)
O
(CH2)n
solvent, bath temp 80 oC
SO2
H3CO
7a R1 = Ph
8a R1 = -CH2-Ph
O
1a-g
2a-g
B
X
O
X = CH3, H, OCH ,
Cl, Br, F, NO23
n = 0, 1
not found
4a
H3CO
H3CO
Ts
Reactivity relationships
competitive reaction of 1a-g
entry 1) Br > Cl > CH3 > F
entry 2) Br > Cl > NO2 > OCH3
competitive reaction of 2a-g
entry 3) Br > NO2 > F > H
entry 4) Cl > CH3 > OCH3
N
N
NH
O
S
9
R1 = Ph
O
R1
O
10 R1 = -CH2-Ph
Scheme 3. Reactivity relationships of imino-O-arenesulfonates 1a-1g and 2a-2g.
arylboronate species that can react with the Pd center and
transmetalate in an intramolecular reaction.13 In the case of
aryltrifluoroborate, the base is to facilitate transmetalation
step that can react to form diarylpalladium complex and to
neutralize the boron trifluoride, a residue from the reaction
(Scheme 2; Cycle 2). The cross-coupling reactions of aryl-
boronate ester, a coupling partner, containing an electron-
donating group attached to the aromatic ring were demonstrated
quite low yield because boron atom was reduced electro-
philicity for interaction with OH in the transmetalation step. On
the other hand, arylboronate esters containing an electron-
withdrawing group Y attached to the aromatic ring were
observed in good yield because of the higher electrophilicity
of boron atom (Scheme 2; Part A). However, the electro-
philicity of boron atom of aryltrifluoroborate is the highest
when compare with arylboronate ester and arylboronic acid. A
facile transmetalation in the Suzuki-Miyaura cross-coupling
reaction was occurred when aryltrifluoroborate was employed
in the reaction. KOH is to facilitate transmetalation step by
replacing the arenesulfonate to form the active form of Pd
complex which is ready to react with aryltrifluoroborate
(Scheme 2; Part B). However, Cs2CO3 is to facilitate trans-

A. Makarasen et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
8.48%. Found: C, 57.95; H, 4.26; N, 8.33%.
875
metalation step by activation the cleavage in B-C bond of
aryltrifluoroborate and to neutralize the boron trifluoride
(Scheme 2; Part C). The results indicate that there are highly
dependent on organoboron reagents, bases, and presumably
also electron-donating or electron-withdrawing group and the
functionality therein.
Compound 1b: Yield 75%; Melting point: 165-166 °C; IR
1
(NaCl film): ¯max 3429, 1639, 1434, 1378, 1168 cm¹1; H NMR
(CDCl3, 400 MHz): ¤ 2.44 (s, 3H), 7.32 (d, J = 8.2 Hz, 2H), 7.40-
7.56 (m, 8H), 7.64-7.70 (m, 1H), 7.93-8.00 (m, 4H), 8.08 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 128.3, 128.6, 128.7, 129.1,
129.5, 130.4, 133.4, 133.5, 134.4, 136.3, 140.0, 143.5, 144.7,
148.8; HRMS (FAB+) calcd for C23H20N3O5S2+: 482.084, found:
482.083; Elemental analysis calcd for C23H19N3O5S2: C, 57.37; H,
3.98; N, 8.73%. Found: C, 57.22; H, 3.96; N, 8.74%.
Conclusion
We have accomplished the Suzuki-Miyaura cross-coupling
of imino-O-tosylates with organoborons using electron-donat-
ing and electron-withdrawing groups attached to the aromatic
ring. Aryltrifluoroborate is more reactive than arylboronate
ester and arylboronic acid in these cross-coupling reactions.
This study is also the first report regarding the effect of the
relative reactivity of the para substituent in arenesulfonates in
Suzuki-Miyaura cross-coupling.
Compound 1c:
Yield 74%; Melting point: 53-54 °C; IR
¹1
(NaCl film): ¯max 3437, 1639, 1597, 1497, 1434, 1376, 1166 cm
;
1H NMR (CDCl3, 400 MHz): ¤ 2.43 (s, 3H), 3.87 (s, 3H), 6.95 (d,
J = 9.0 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.42-7.54 (m, 6H),
7.84-7.90 (m, 2H), 7.96 (d, J = 8.3 Hz, 2H), 8.06 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 55.8, 114.3, 127.4, 128.4,
128.5, 129.4, 129.5, 130.4, 131.1, 133.5, 133.6, 136.3, 140.0,
143.3, 144.7, 148.9, 164.3; HRMS (FAB+) calcd for C24H22-
N3O6S2+: 512.095, found: 512.092; Elemental analysis calcd for
C24H21N3O6S2: C, 56.35; H, 4.14; N, 8.21%. Found: C, 56.20; H,
3.97; N, 8.27%.
Experimental
General Procedure. Melting points were determined by using
a Yanaco MP-S3 and uncorrected. Infrared (IR) spectra were
recorded in cm¹1 and determined in NaCl cells by using a JASCO
FT/IR-6100 FT-IR spectrometer. Proton NMR spectra were
recorded on a Bruker AMX-400 for 400 MHz and Carbon NMR
were recorded on a Bruker AMX-400 for 100 MHz. Chemical
shifts (¤) were reported in parts per million (ppm) relative to
tetramethylsilane (TMS). Deuterochloroform (CDCl3) were used
as solvent. The following abbreviations were used for multiplicity:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
brs = broad singlet, brt = broad triplet, dd = double of doublet,
and ddd = double of double of doublet. Coupling constants (J)
were reported in hertz (Hz). EI mass spectra and FAB mass spectra
were performed with a JEOL JMS-700. High-resolution (HR) mass
spectra were measured with JEOL JMS-700. All experiments were
performed in the positive ion mode. Elemental analyses were
performed by Analytical Laboratory. High-performance liquid
chromatography (or High-pressure liquid chromatography, HPLC)
was performed on a JASCO Gulliver system composed of two
PU-980 pumps, and UV-970 UV/VIS detector and an 807-IT
integrator. The system was equipped with a Devolosil ODS-5
column (4.6 © 250 mm2). Analytical thin-layer chromatography
(tlc) was conducted on precoated tlc plates: silica gel 60 F-254,
layer thickness 0.25 mm. Silica gel column chromatography
utilized Silica Gel 60 (spherical) 40-50 ¯m. The components were
detected by visualization under ultraviolet light at - of 254 and
315 nm. The organic solvents utilized in extraction, and eluent for
column chromatography were of commercial grade. The organic
solvents utilized for crystallization were of analytical grade.
Synthesis of the Imino-O-tosylates 1a-1g and the Homologs
2a-2g. The imino-O-tosylates 1a-1g and the homologs 2a-2g
were synthesized by following the reference 6b. The information
of the imino-O-tosylates 1a-1g and homologs 2a-2g were shown
as below.
Compound 1d:
Yield 76%; Melting point: 57-58 °C; IR
(NaCl film): ¯max 3428, 1639, 1439, 1090 cm¹1; 1H NMR (CDCl3,
400 MHz): ¤ 2.44 (s, 3H), 7.28-7.35 (m, 2H), 7.39-7.57 (m, 8H),
7.89 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 8.08 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 128.3, 128.6, 129.4, 129.5,
129.6, 130.3, 130.5, 133.3, 133.4, 134.8, 136.2, 140.0, 141.2,
143.6, 144.7, 148.7; HRMS (FAB+) calcd for C23H19ClN3O5S2
516.046, found: 516.041; Elemental analysis calcd for C23H18-
ClN3O5S2: C, 53.54; H, 3.52; N, 8.14%. Found: C, 53.35; H, 3.72;
N, 8.02%.
+
:
Compound 1e: Yield 70%; Melting point: 169-170 °C; IR
(NaCl film): ¯max 3402, 2958, 1726, 1638, 1576, 1433, 1382,
1
1168 cm¹1; H NMR (CDCl3, 400 MHz): ¤ 2.43 (s, 3H), 7.32 (d,
J = 8.2 Hz, 2H), 7.38-7.45 (m, 2H), 7.47-7.56 (m, 4H), 7.61-7.68
(m, 2H), 7.77-7.85 (m, 2H), 7.97 (d, J = 8.3 Hz, 2H), 8.07 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 128.3, 128.5, 129.4, 129.6,
129.8, 130.3, 130.5, 132.4, 133.3, 135.4, 136.2, 140.0, 143.6,
144.7, 148.7; HRMS (FAB+) calcd for C23H19BrN3O5S2
559.995, found: 559.993; Elemental analysis calcd for C23H18-
BrN3O5S2: C, 49.29; H, 3.24; N, 7.50%. Found: C, 49.17; H, 3.09;
N, 7.47%.
+
:
Compound 1f: Yield 81%; Melting point: 80-81 °C; IR (NaCl
¹1
film): ¯max 3437, 1638, 1493, 1436, 1381, 1168 cm
;
1H NMR
(CDCl3, 400 MHz): ¤ 2.43 (s, 3H), 7.13-7.23 (m, 2H), 7.28-7.35
(m, 2H), 7.39-7.59 (m, 6H), 7.92-8.03 (m, 4H), 8.07 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 116.3, 116.6, 128.3, 128.5,
129.4, 129.6, 130.5, 131.7, 131.8, 132.3, 133.3, 133.4, 136.2,
140.0, 143.5, 144.7, 148.8, 164.8, 167.4; HRMS (FAB+) calcd for
C23H19FN3O5S2+: 500.075, found: 500.076; Elemental analysis
calcd for C23H18FN3O5S2: C, 55.30; H, 3.63; N, 8.41%. Found: C,
55.20; H, 3.74; N, 8.13%.
Compound 1g:
Yield 87%; Melting point: 69-70 °C; IR
¹1
Compound 1a: Yield 80%; Melting point: 159-160 °C; IR
(NaCl film): ¯max 3436, 1639, 1434, 1377, 1336, 1168 cm
(NaCl film): ¯max 3268, 3106, 1725, 1534, 1436, 1350, 1167 cm
;
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 2.43 (s, 3H), 7.32 (d, J = 8.1 Hz,
2H), 7.37-7.44 (m, 2H), 7.45-7.63 (m, 4H), 7.96 (d, J = 8.2 Hz,
2H), 8.10 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.8 Hz,
2H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 124.1, 128.2, 128.5,
1H NMR (CDCl3, 400 MHz): ¤ 2.43 (s, 3H), 2.44 (s, 3H), 7.27-
7.37 (m, 4H), 7.39-7.60 (m, 6H), 7.83 (d, J = 7.9 Hz, 2H), 7.97 (d,
J = 7.9 Hz, 2H), 8.06 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤
21.6, 21.7, 128.4, 128.5, 128.8, 129.4, 129.5, 129.7, 130.4, 133.2,
133.5, 133.6, 136.3, 140.0, 143.4, 144.7, 145.7, 148.9; HRMS
(FAB+) calcd for C24H22N3O5S2+: 496.100, found: 496.102;
Elemental analysis calcd for C24H21N3O5S2: C, 58.17; H, 4.27; N,
129.4, 129.6, 130.2, 130.7, 133.1, 136.1, 140.0, 142.2, 143.8,
+
144.8, 148.6, 150.9; HRMS (FAB+) calcd for C23H19N4O7S2
:
527.070, found: 527.068; Elemental analysis calcd for C23H18-
N4O7S2: C, 52.46; H, 3.45; N, 10.64%. Found: C, 52.46; H, 3.38;

876
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
Imino-O-arenesulfonates for Suzuki-Miyaura Reaction
N, 10.43%.
133.1, 135.1, 136.0, 144.5, 148.6, 164.7, 167.3; HRMS (FAB+)
calcd for C24H21FN3O5S2+: 514.091, found: 514.091; Elemental
analysis calcd for C24H20FN3O5S2: C, 56.13; H, 3.93; N, 8.18%.
Found: C, 56.26; H, 3.89; N, 8.08%.
Compound 2a: Yield 76%; Melting point: 136-137 °C; IR
(NaCl film): ¯max 3281, 3064, 1597, 1496, 1439, 1377, 1176 cm
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 2.45 (s, 3H), 4.01 (s,
2H), 6.79-7.00 (m, 1H), 7.00-7.09 (m, 2H), 7.22 (d, J = 8.1 Hz,
2H), 7.27-7.70 (m, 5H), 7.67 (d, J = 8.3 Hz, 2H), 7.79 (d,
J = 8.3 Hz, 2H), 7.98 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤
21.6, 21.8, 39.8, 127.7, 128.3, 128.6, 128.7, 129.4, 129.8, 133.1,
133.3, 135.1, 136.0, 144.5, 145.7; HRMS (FAB+) calcd for
C25H24N3O5S2+: 510.116, found: 510.114; Elemental analysis
calcd for C25H23N3O5S2: C, 58.92; H, 4.55; N, 8.25%. Found: C,
58.85; H, 4.41; N, 8.05%.
Compound 2g:
(NaCl film): ¯max 3402, 1638, 1609, 1534, 1439, 1387, 1187 cm
Yield 80%; Melting point: 64-65 °C; IR
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 2.41 (s, 3H), 3.98 (s, 2H), 6.96-
7.04 (m, 2H), 7.22-7.45 (m, 6H), 7.76 (d, J = 8.3 Hz, 2H), 7.96-
8.08 (m, 3H), 8.21-8.29 (m, 2H); 13C NMR (CDCl3, 100 MHz): ¤
21.6, 39.1, 124.2, 127.6, 128.3, 128.9, 129.2, 129.5, 129.9, 133.0,
134.9, 136.0, 141.9, 142.7, 144.7, 144.8, 148.6, 150.8; HRMS
(FAB+) calcd for C24H21N4O7S2+: 541.085, found: 541.086;
Elemental analysis calcd for C24H20N4O7S2: C, 53.32; H, 3.73; N,
10.36%. Found: C, 53.48; H, 3.79; N, 10.13%.
Compound 2b: Yield 75%; Melting point: 128-130 °C; IR
(NaCl film): ¯max 3279, 3064, 1597, 1439, 1378, 1188 cm
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 3.99 (s, 2H), 6.99-
7.06 (m, 2H), 7.07-7.18 (m, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.27-
7.33 (m, 3H), 7.46-7.55 (m, 2H), 7.62-7.73 (m, 3H), 7.90 (d,
J = 7.6 Hz, 2H), 7.98 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤
21.6, 39.5, 127.6, 128.2, 128.6, 128.7, 129.1, 129.3, 129.4, 134.4,
135.1, 136.0, 136.2, 144.5, 148.6; HRMS (FAB+) calcd for
C24H22N3O5S2+: 496.100, found: 496.099; Elemental analysis
calcd for C24H21N3O5S2: C, 58.17; H, 4.27; N, 8.48%. Found: C,
58.27; H, 4.20; N, 8.65%.
Synthesis of Amino(aryl)pyrazines 7a-7f and 8a-8f. Gen-
eral Procedure for Conversion of Arylboronic Acids into
Arylboronate Esters: p-TsOH¢H2O (7 mol %) was added to a
stirred solution of arylboronic acid (1.5 mmol) and pinacol
hexahydrate (5.0 mmol) in toluene (15 mL). The mixture solution
was heated to reflux for 16 h in an apparatus incorporating a Dean-
Stark trap. The reaction mixture was cooled to room temperature
and the solvent was removed under reduced pressure. The residue
was then dissolved with EtOAc (15 mL) before being washed with
water (5 mL © 3) and brine, respectively. The organic phase was
dried over anh. Na2SO4 and concentrated under reduced pressure to
give arylboronate ester.
Compound 2c: Yield 75%; Melting point: 134-135 °C; IR
(NaCl film): ¯max 3437, 1638, 1596, 1578, 1497, 1439, 1376,
1
1169 cm¹1; H NMR (CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 3.87 (s,
3H), 4.02 (s, 2H), 6.90-6.97 (m, 2H), 7.00-7.11 (m, 3H), 7.22 (d,
J = 8.1 Hz, 2H), 7.28-7.35 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H),
7.78-7.85 (m, 2H), 7.98 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤
21.6, 39.6, 55.7, 114.3, 127.2, 127.6, 128.2, 128.7, 129.3, 129.4,
131.0, 133.3, 135.1, 136.0, 142.5, 144.3, 144.5, 148.8, 164.3;
HRMS (FAB+) calcd for C25H24N3O6S2+: 526.111, found:
526.108; Elemental analysis calcd for C25H23N3O6S2: C, 57.13;
H, 4.41; N, 7.99%. Found: C, 57.27; H, 4.34; N, 7.70%.
General Procedure for Conversion of Arylboronic Acids
into Potassium Aryltrifluoroborates:
Arylboronic acid (ca.
0.3 g) was dissolved in 1 mL of methanol. Excess saturated KHF2
(ca. 1 mL) was slowly added with vigorous stirring. After 15 min,
the precipitated product was obtained. The mixture was filtrated
and the residue was washed with cool methanol and then dried
under reduced pressure. The product was used further without any
purification.
Compound 2d:
(NaCl film): ¯max 3284, 3090, 1586, 1439, 1382, 1188 cm
Yield 75%; Melting point: 57-58 °C; IR
General Procedure for the Palladium-Catalyzed Cross-
Coupling Reactions of Imino-O-tosylates with Organo Borons:
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 4.00 (s, 2H), 6.97-
7.06 (m, 2H), 7.18-7.35 (m, 6H), 7.44 (d, J = 8.6 Hz, 2H), 7.69-
7.76 (m, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.99 (s, 1H); 13C NMR
(CDCl3, 100 MHz): ¤ 21.6, 39.3, 127.6, 128.3, 128.7, 129.3, 129.4,
130.0, 133.0, 134.6, 135.0, 136.0, 141.1, 142.6, 144.5, 144.6,
148.6; HRMS (FAB+) calcd for C24H21ClN3O5S2+: 530.061,
found: 530.059; Elemental analysis calcd for C24H20ClN3O5S2: C,
54.39; H, 3.80; N, 7.93%. Found: C, 54.48; H, 3.66; N, 7.79%.
Under
a Argon atmosphere, imino-O-tosylates (0.10 mmol),
organo boron (2.0 equiv), Pd(OAc)2 (4 mol %), ligand
6
(8 mol %), and KOH (3.0 equiv) (or Cs2CO3 (1.0 equiv)) in
MeOH (5.0 mL) as a solvent was refluxed at 80 °C for a period
of time. After 5 h, the reaction mixture was cooled to room
temperature. The solvent was removed under reduced pressure.
The residue was then dissolved with EtOAc (15 mL) before being
washed with water (5 mL © 2) and brine, respectively. The organic
phase was then dried over anh. Na2SO4 and concentrated to
dryness under reduced pressure to give crude product, which was
purified by silica gel column chromatography to provide the
corresponding product.
Compound 2e: Yield 71%; Melting point: 52-54 °C; IR (NaCl
¹1
film): ¯max 3431, 1639, 1575, 1439, 1393, 1188 cm
;
1H NMR
(CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 4.00 (s, 2H), 6.98-7.07 (m,
2H), 7.15-7.28 (m, 3H), 7.28-7.36 (m, 3H), 7.58-7.64 (m, 2H),
7.72 (d, J = 8.5 Hz, 4H), 7.99 (s, 1H); 13C NMR (CDCl3,
100 MHz): ¤ 21.6, 39.4, 127.6, 128.3, 128.7, 129.3, 129.4,
The information of amino(aryl)pyrazines 7a-7f and 8a-8f were
shown as below.
129.8, 130.1, 132.5, 133.1, 135.0, 135.2, 136.0, 142.6, 144.5,
Compound 7a:
Melting point: 181.5-182.5 °C; IR (NaCl
+
¹1
144.6, 148.7; HRMS (FAB+) calcd for C24H21BrN3O5S2
:
film): ¯max 3429, 1638, 1609, 1515, 1456, 1435, 1169 cm ;
574.011, found: 574.010; Elemental analysis calcd for C24H20-
BrN3O5S2: C, 50.18; H, 3.51; N, 7.31%. Found: C, 50.33; H, 3.37;
N, 7.12%.
1H NMR (CDCl3, 400 MHz): ¤ 2.38-2.45 (m, 3H), 3.82-3.86 (m,
3H), 6.93-7.00 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.44 (bs, 1H),
7.49-7.60 (m, 3H), 7.64-7.72 (m, 2H), 7.90 (d, J = 8.9 Hz, 2H),
8.02 (d, J = 8.3 Hz, 2H), 8.55 (s, 1H); 13C NMR (CDCl3, 100
MHz): ¤ 21.6, 55.3, 114.3, 127.7, 128.5, 129.3, 129.5, 129.8,
135.4, 136.8, 141.7, 142.9, 144.3, 146.8, 160.6; HRMS (FAB+)
calcd for C24H22N3O3S+: 432.138, found: 432.143; Elemental
analysis calcd for C24H21N3O3S: C, 66.80; H, 4.91; N, 9.74%.
Found: C, 66.81; H, 5.02; N, 9.58%.
Compound 2f: Yield 76%; Melting point: 39-40 °C; IR (NaCl
¹1
film): ¯max 3421, 1592, 1495, 1439, 1381, 1187 cm
;
1H NMR
(CDCl3, 400 MHz): ¤ 2.40 (s, 3H), 4.00 (s, 2H), 6.99-7.06 (m,
2H), 7.09-7.17 (m, 2H), 7.20-7.27 (m, 2H), 7.27-7.34 (m, 3H),
7.35-7.54 (m, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.82-7.91 (m, 2H),
7.98 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 39.2, 116.4,
116.6, 127.5, 128.2, 128.8, 129.2, 129.4, 131.5, 131.6, 132.1,
Compound 7b: Melting point: 132-133 °C; IR (NaCl film):

A. Makarasen et al.
3250, 1595, 1451, 1437, 1149 cm
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
877
¹1
1
¯
;
1H NMR (CDCl3,
¯
3236, 1589, 1496, 1451, 1166 cm¹1; H NMR (CDCl3, 400
max
max
400 MHz): ¤ 2.42 (s, 3H), 7.32 (d, J = 8.2 Hz, 2H), 7.37-7.48
(m, 4H), 7.50-7.61 (m, 3H), 7.66-7.73 (m, 2H), 7.94 (d,
J = 7.0 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 8.61 (s, 1H); 13C NMR
(CDCl3, 100 MHz): ¤ 21.6, 126.4, 128.6, 128.9, 129.2, 129.4,
129.6, 130.0, 134.7, 135.3, 136.0, 136.7, 137.5, 141.8, 143.6,
144.4, 146.9; HRMS (FAB+) calcd for C23H20N3O2S+: 402.128,
found: 402.130; Elemental analysis calcd for C23H19N3O2S: C,
68.81; H, 4.77; N, 10.47%. Found: C, 68.79; H, 4.85; N, 10.29%.
MHz): ¤ 2.38 (s, 3H), 4.26 (s, 2H), 6.99-7.15 (m, 1H), 7.16-7.50
(m, 10H), 7.71 (d, J = 8.3 Hz, 2H), 7.81-8.01 (m, 2H), 8.52 (s,
1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 40.6, 126.3, 127.5,
128.2, 128.7, 128.9, 129.2, 129.3, 136.1, 136.4, 137.2, 143.4,
144.2, 144.5, 146.8; HRMS (FAB+) calcd for C24H22N3O2S+:
416.143, found: 416.141; Elemental analysis calcd for C24H21-
N3O2S: C, 69.37; H, 5.09; N, 10.11%. Found: C, 69.35; H, 5.22;
N, 9.85%.
Compound 7c: Melting point: 74-75 °C; IR (NaCl film): ¯max
Compound 8c: Melting point: 181-182 °C; IR (NaCl film):
¹1
1
3378, 1603, 1510, 1456, 1438, 1149 cm
;
1H NMR (CDCl3,
¯
3235, 1602, 1511, 1449, 1158 cm¹1; H NMR (CDCl3, 400
max
400 MHz): ¤ 2.42 (s, 3H), 7.08-7.17 (m, 2H), 7.32 (d, J = 8.18 Hz,
2H), 7.45-7.50 (m, 1H), 7.50-7.61 (m, 3H), 7.68 (d, J = 6.9 Hz,
2H), 7.89-7.97 (m, 2H), 8.03 (d, J = 8.3 Hz, 2H), 8.56 (s, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 115.8, 116.0, 128.1, 128.2,
128.5, 129.4, 129.6, 130.0, 132.1, 135.2, 136.7, 137.1, 141.8,
143.5, 144.4, 145.9, 162.4, 164.8; HRMS (FAB+) calcd for
C23H19FN3O2S+: 420.118, found: 420.122; Elemental analysis
calcd for C23H18FN3O2S: C, 65.86; H, 4.33; N, 10.02%. Found: C,
65.80; H, 4.41; N, 10.21%.
MHz): ¤ 2.38 (s, 3H), 4.24 (s, 2H), 7.06-7.25 (m, 7H), 7.27-7.39
(m, 3H), 7.72 (d, J = 8.3 Hz, 2H), 7.81-7.97 (m, 2H), 8.33-8.61
(bs, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 40.5, 115.8, 116.0,
127.4, 127.5, 128.1, 128.2, 128.3, 128.7, 129.3, 129.4, 132.2,
136.0, 136.9, 144.5, 145.9, 162.4; HRMS (FAB+) calcd for
C24H21FN3O2S+: 434.134, found: 434.135; Elemental analysis
calcd for C24H20FN3O2S: C, 66.50; H, 4.65; N, 9.69%. Found: C,
66.51; H, 4.80; N, 9.46%.
Compound 8d: Melting point: 193-194 °C; IR (NaCl film):
¹1
Compound 7d:
film): ¯max 3248, 1609, 1526, 1456, 1434, 1150 cm
Melting point: 175.5-176.5 °C; IR (NaCl
¯
3248, 1609, 1525, 1440, 1363, 1325, 1164 cm ;
1H NMR
max
¹1
;
1H NMR
(CDCl3, 400 MHz): ¤ 2.37 (s, 3H), 3.01 (s, 6H), 4.23 (s, 2H), 6.76
(d, J = 9.0 Hz, 2H), 6.79-6.89 (m, 1H), 7.14-7.41 (m, 7H), 7.69
(d, J = 8.3 Hz, 2H), 7.74-7.92 (m, 2H), 8.31-8.58 (m, 1H);
13C NMR (CDCl3, 100 MHz): ¤ 21.6, 40.3, 112.3, 127.2, 128.0,
128.1, 128.8, 129.1, 129.2, 136.1, 136.2, 136.6, 143.0, 143.8,
143.9, 151.2; HRMS (FAB+) calcd for C26H27N4O2S+: 459.186,
found: 459.187; Elemental analysis calcd for C26H26N4O2S: C,
68.10; H, 5.71; N, 12.22%. Found: C, 68.13; H, 5.60; N, 12.09%.
(CDCl3, 400 MHz): ¤ 2.41 (s, 3H), 3.00 (s, 6H), 6.75 (d,
J = 9.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.32-7.41 (m, 1H),
7.47-7.59 (m, 3H), 7.68 (d, J = 6.9 Hz, 2H), 7.85 (d, J = 8.9 Hz,
2H), 8.00 (d, J = 8.3 Hz, 2H), 8.52 (s, 1H); 13C NMR (CDCl3,
100 MHz): ¤ 21.6, 40.3, 112.2, 123.7, 127.3, 128.4, 128.6, 129.3,
129.4, 129.7, 135.8, 136.3, 137.0, 142.1, 144.1, 144.9, 151.2;
HRMS (FAB+) calcd for C25H25N4O2S+: 445.170, found:
445.173; Elemental analysis calcd for C25H24N4O2S: C, 67.54;
H, 5.44; N, 12.60%. Found: C, 67.37; H, 5.47; N, 12.72%.
Compound 8e: Melting point: 155-156 °C; IR (NaCl film):
¹1
¯
3227, 3061, 1589, 1490, 1449, 1400, 1168 cm ;
1H NMR
max
Compound 7e: Melting point: 177-178 °C; IR (NaCl film):
(CDCl3, 400 MHz): ¤ 2.37 (s, 3H), 4.24 (s, 2H), 7.00-7.17 (m,
6H), 7.17-7.39 (m, 9H), 7.72 (d, J = 8.3 Hz, 2H), 7.79-7.97 (m,
2H), 8.47 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.55, 40.53,
118.8, 119.3, 123.7, 127.8, 128.2, 128.7, 129.3, 129.8, 136.8,
144.2, 156.6, 158.6; HRMS (FAB+) calcd for C30H26N3O3S+:
508.170, found: 508.170; Elemental analysis calcd for C30H25-
N3O3S: C, 70.98; H, 4.96; N, 8.28%. Found: C, 70.99; H, 5.19; N,
7.99%.
¹1
¯
3274, 3255, 1588, 1489, 1455, 1438, 1168 cm ;
1H NMR
max
(CDCl3, 400 MHz): ¤ 2.42 (s, 3H), 7.00-7.09 (m, 4H), 7.09-7.17
(m, 1H), 7.28-7.39 (m, 4H), 7.42-7.48 (m, 1H), 7.49-7.60 (m,
3H), 7.65-7.72 (m, 2H), 7.88-7.94 (m, 2H), 7.98-8.06 (m, 2H),
8.56 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 116.3, 117.6,
118.8, 119.3, 121.0, 123.7, 127.9, 128.5, 129.4, 129.5, 129.8,
129.9, 135.3, 137.1, 143.3, 144.3, 156.6, 158.6; HRMS (FAB+)
calcd for C29H24N3O3S+: 494.154, found: 494.155.
Compound 7f: Melting point: 80-81 °C; IR (NaCl film): ¯max
3415, 1611, 1436, 1148 cm¹1; 1H NMR (CDCl3, 400 MHz): ¤ 2.42
(s, 3H), 5.09-5.40 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.31 (d,
J = 8.2 Hz, 2H), 7.37-7.45 (m, 1H), 7.49-7.59 (m, 3H), 7.68 (d,
J = 6.8 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.2 Hz,
2H), 8.51 (s, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 115.8,
127.9, 128.5, 128.6, 129.4, 129.5, 129.9, 135.4, 136.8, 142.9,
144.3, 156.9; HRMS (FAB+) calcd for C23H20N3O3S+: 418.123,
found: 418.120; Elemental analysis calcd for C23H19N3O3S: C,
66.17; H, 4.59; N, 10.07%. Found: C, 66.18; H, 4.75; N, 9.83%.
Compound 8f: Melting point: 177-178 °C; IR (NaCl film):
¯
max 3436, 1638, 1447, 1164 cm¹1; 1H NMR (CDCl3, 400 MHz): ¤
2.37 (s, 3H), 4.23 (s, 2H), 5.43-6.01 (m, 1H), 6.87 (d, J = 8.6 Hz,
2H), 6.93-7.11 (m, 1H), 7.14-7.41 (m, 7H), 7.62-7.87 (m, 4H),
8.23-8.55 (m, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 40.6,
115.9, 127.3, 127.8, 128.7, 128.8, 129.2, 129.3, 136.3, 143.8,
143.9, 144.0, 156.9; HRMS (FAB+) calcd for C24H22N3O3S+:
432.138, found: 432.137.
General Procedure for Competitive Reaction of Imino-O-
arenesulfonates Containing Various Substituents at the Para
Position 1a-1g and 2a-2g in Suzuki-Miyaura Cross-Coupling
Reaction with 4-Methoxyphenylboronate Ester (4; OMe).
Each of imino-O-arenesulfonates (ca. 1 mg) or amino(aryl)pyra-
zines 7a, 8a (ca. 1 mg) was dissolved in 95% methanol/water
0.1% TFA (200 ¯L) at room temperature (25 °C). Each of samples
was analyzed by HPLC on a Develosil C30-UG-5 column
Compound 8a: Melting point: 170-171 °C; IR (NaCl film):
¹1
¯
3437, 1607, 1515, 1451, 1165 cm ;
1H NMR (CDCl3,
max
400 MHz): ¤ 2.38 (s, 3H), 3.86 (s, 3H), 4.25 (s, 2H), 6.85-6.91
(bs, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.17-7.25 (m, 4H), 7.28-7.39
(m, 3H), 7.69 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 8.47
(s, 1H); 13C NMR (CDCl3, 100 MHz): ¤ 21.6, 40.7, 55.4, 114.4,
127.5, 127.7, 128.2, 128.7, 129.3, 129.4, 136.1, 136.5, 136.7,
143.5, 143.8, 144.1, 146.9, 160.7; HRMS (FAB+) calcd for
C25H24N3O3S+: 446.154, found: 446.152; Elemental analysis calcd
for C25H23N3O3S: C, 67.40; H, 5.20; N, 9.43%. Found: C, 67.40;
H, 5.12; N, 9.26%.
(4.6 © 250 mm2) by an isocratic elution 95% methanol/water
¹1
containing 0.1% TFA for 15 min at a flow rate of 0.6 mL min
.
The chromatograms were monitored at 315 nm for imino-O-
arenesulfonates 1a-1g and amino(aryl)pyrazine 7a and at 254 nm
for homologs 2a-2g and amino(aryl)pyrazine 8a, respectively. The
retention time of imino-O-arenesulfonates 1a-1g and homologs
2a-2g are as follows: 1a at 7.175 min, 1b at 6.621 min, 1c at
Compound 8b: Melting point: 163-164 °C; IR (NaCl film):

878
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
Imino-O-arenesulfonates for Suzuki-Miyaura Reaction
6.837 min, 1d at 7.876 min, 1e at 8.126 min, 1f at 6.850 min, 1g at
7.179 min, 7a at 8.479 min, 2a at 7.345 min, 2b at 6.776 min, 2c at
6.956 min, 2d at 8.212 min, 2e at 8.532 min, 2f at 7.119 min, 2g at
7.558 min, and 8a at 8.684 min.
Zhang, Y. Luo, Tetrahedron Lett. 2006, 47, 6747. f) J. Wu, L.
Zhang, H.-G. Xia, Tetrahedron Lett. 2006, 47, 1525. g) R. K.
Arvela, N. E. Leadbeater, T. L. Mack, C. M. Kormos, Tetrahedron
Lett. 2006, 47, 217. h) G. A. Molander, Y. Yokoyama, J. Org.
Chem. 2006, 71, 2493. i) G. A. Molander, E. M. Sommers, S. R.
Baker, J. Org. Chem. 2006, 71, 1563. j) R. Cella, R. L. O. R.
Cunha, A. E. S. Reis, D. C. Pimenta, C. F. Klitzke, H. A. Stefani, J.
Org. Chem. 2006, 71, 244. k) M. G. Banwell, M. O. Sydnes, Aust.
J. Chem. 2004, 57, 537. l) S. Darses, J.-P. Genet, Eur. J. Org.
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Each group of imino-O-arenesulfonates (0.01 mM) was mixed
and dissolved with methanol (5 mL). 0.1 mL of the mixture was
sampled and dried with argon air then diluted with 95% methanol/
water containing 0.1% TFA (0.2 mL) and filtrated before analysis.
After that, under a argon atmosphere, 4-methoxyphenylboronate
ester 4a (1 equiv of each imino-O-arenesulfonate), Pd(OAc)2
(8 mol %), ligand 6 (16 mol %), KOH (1.5 equiv of each imino-
O-arenesulfonate) were added to a stirred solution of mixture of
imino-O-arenesulfonates. Due to the fact that some imino-O-
arenesulfonates have monitored in the same retention time, the
competitive reactions were done with 4 groups of starting material
under the similar reaction condition. However, the concentration of
arylboronate ester cannot be controlled in the same amount for all.
The solution was stirred at 80 °C for a period of time. Each of
aliquot 0.1 mL of this reaction mixture was sampled at 30, 60, and
120 min after refluxing, and was dried with argon air then diluted
with 95% methanol/water containing 0.1% TFA (0.2 mL) and
filtrated before analysis. All samples were analyzed by HPLC on a
Develosil C30-UG-5 column (4.6 © 250 mm2) by an isocratic
elution 95% methanol/water containing 0.1% TFA for 25 min at a
flow rate of 0.3 mL min¹1. The chromatogram was monitored at
315 nm for imino-O-arenesulfonates 1 and 254 nm for homologs 2.
4
a) T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L.
Jensen, T. Skrydstrup, J. Org. Chem. 2008, 73, 3404. b) L. Zhang,
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Angew. Chem., Int. Ed. 2002, 41, 3910.
5
a) T. Okita, M. Isobe, Tetrahedron 1995, 51, 3737. b) T.
Okita, M. Isobe, Synlett 1994, 589. Heck reaction. See also:
c) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945.
d) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 1971, 44,
581. e) R. F. Heck, J. P. Nolley, J. Org. Chem. 1972, 37, 2320.
6
a) N. Kondo, M. Kuse, T. Mutarapat, N. Thasana, M. Isobe,
Heterocycles 2005, 65, 843, and references cited therein. b) M.
Kuse, N. Kondo, Y. Ohyabu, M. Isobe, Tetrahedron 2004, 60, 835.
The authors are grateful for the financial supports
7
Coelenterazine analogs (sulfates or dehydro form) are
by
a
Grant-in-Aid for Specially Promoted Research
found in luminous marine organisms such as jelly fish (Aequorea
aequorea), firefly squid (Watasenia scintillans), and flying squid
(Tobiika; Symplectoteuthis oualaniensis). See also: a) M. Isobe, M.
Kuse, N. Tani, T. Fujii, T. Matsuda, Proc. Jpn. Acad. Ser., B 2008,
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1994, 843. d) H. Takahashi, M. Isobe, Bioorg. Med. Chem. Lett.
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Lett. 1976, 17, 2971.
No. 16002007 from MEXT Japan as well as the generous
scholarship to A. M. during his Ph.D. studies. We are also
grateful for Dr. Magne O. Sydnes, Mr. Jurrien S. Noot and
Dr. Nisachon Khunnawutmanotham to improve this manu-
script. Grateful acknowledgement is also extended to Nagoya
University for supports and assistance during this study.
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