One-pot synthesis of unsymmetrical benzils and N-heteroarenes through nucleophilic aroylation catalyzed by N-heterocyclic carbene

Article abstract of DOI:10.1016/j.tet.2012.11.039

An efficient one-pot synthesis of various unsymmetrical benzils via N-heterocyclic carbene (NHC)-catalyzed aroylation of N-phenylimidoyl chlorides with aromatic aldehydes followed by acidic hydrolysis has been developed. The one-pot procedure was extended to synthesis of quinoxalines and pyrazines by condensation/annulation of unsymmetrical benzils generated in situ with diamines.

Full text of DOI:10.1016/j.tet.2012.11.039

Tetrahedron 69 (2013) 470e473
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One-pot synthesis of unsymmetrical benzils and N-heteroarenes
through nucleophilic aroylation catalyzed by N-heterocyclic carbene
,
b
b
Yumiko Suzuki a , Mai Murofushi , Kei Manabe
*
a Department of Materials & Life Sciences, Faculty of Science & Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
b School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of various unsymmetrical benzils via N-heterocyclic carbene (NHC)-cat-
alyzed aroylation of N-phenylimidoyl chlorides with aromatic aldehydes followed by acidic hydrolysis
has been developed. The one-pot procedure was extended to synthesis of quinoxalines and pyrazines by
condensation/annulation of unsymmetrical benzils generated in situ with diamines.
Received 11 September 2012
Received in revised form 7 November 2012
Accepted 8 November 2012
Available online 15 November 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
N-Heterocyclic carbene
Unsymmetrical benzil
Quinoxaline
Pyrazine
I
N
N
H3C
1. Introduction
CH3
Ph
Ph
3 (3 mol%)
O
N
N
10% HCl
NaH
OHC R2
Unsymmetricalbenzils arenotonlyvaluableintermediates butare
also key synthetic targets in organic synthesis, since they are pre-
cursors to biologically active heterocyclic compounds such as
qunoxalines, pyrazines, and imidazoles1e3 as well as inhibitors of
carboxylesterase.4 However, of the several known methods to syn-
thesize these compounds, few can be considered environmentally
friendly, versatile, and facile. For example, one of the most common
methods is the oxidation of alkynes;5 however, that the oxidation
processes often require severe conditions and rare or expensive ma-
terials. An alternative method involves oxidizing unsymmetrical
benzoin prepared by the addition reaction between cyanohydrin
anions and aldehydes;3,6 unfortunately, this method requires toxic
cyanation reagents, which makes it problematic for commercial ap-
plication. Another route is oxidation of the products of the Frie-
deleCrafts reaction between benzenes and 2-phenylacetyl
chlorides;6,7 in this case, the method is not always applicable owing
to the directing and activating effects of the substituents.
R2
R2
+
R1
R1
R1
THF
THF
rt, 3 h
Cl
5
reflux, 6 h
1
4
2
O
O
Scheme 1. Synthesis of unsymmetrical benzils via NHC-catalyzed nucleophilic ar-
oylation followed by hydrolysis.
4, which was synthesized from N-phenylbenzimidoyl chlorides 1
and aromatic aldehyde 2 by NHC-catalyzed aroylation (The mech-
anism of the NHC-catalyzed reaction is shown in Scheme 2.).
However, although efficient, the procedure can be further simpli-
fied by performing successive hydrolysis after the first reaction
without isolation of 4.
Herein, we report one-pot synthesis of unsymmetrical benzils
by NHC-catalyzed aroylation of N-phenylbenzimidoyl chlorides
with aromatic aldehydes followed by hydrolysis of the aroylated
productsdi.e., a-iminoketones. We also report one-pot synthesis of
N-heteroarenes through subsequent/simultaneous annulations of
the resulting unsymmetrical benzils with diamines.
With this motivation, we developed a new efficient synthetic
method using N-heterocyclic carbene (NHC) catalysis.8,9 As shown
in Scheme 1, unsymmetrical benzils 5 were prepared by hydrolysis
under acidic conditions from 1,2-diaryl-(2-phenyl)iminoethanone
2. Results and discussion
2.1. One-pot synthesis of unsymmetrical benzils 5
Based on the procedure we previously reported,8 NHC-catalyzed
aroylation and subsequent hydrolysis were carried out using a one-
* Corresponding author. Tel.: þ81 3 3238 3089; fax: þ81 3 3238 3361; e-mail
address: yumiko_suzuki@sophia.ac.jp (Y. Suzuki).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.039

Y. Suzuki et al. / Tetrahedron 69 (2013) 470e473
471
CH3
in organic synthesis, in 1 was examined: the results showed that
a 2,6-disubstituted substrate is unfavorable for aroylation (entry 9).
Overall, the substrates with monochloro groups and 2,4-dichloro
groups afforded benzils (entries 1e8). The advantage of this one-
pot method is that benzils can be obtained efficiently without
work-up and purification of the intermediates after aroylation.
N
I
N
CH3
H2
NaH
Ph
O
2.2. One-pot synthesis of 2,3-diarylquinoxalines 7
N
CH3
N
R2
R2
OHC
R1
Next, we attempted to extend this procedure to one-pot syn-
thesis of 2,3-diarylquinoxalines. As mentioned above, un-
symmetrical benzils are an important precursor to heterocyclic
compounds. For example, condensation of benzils with o-phenyl-
enediamine 6 and ethylenediamine 8 affords 2,3-diarylquinoxalines
7 and 2,3-diaryl-5,6-dihydropyradines, respectively. Derivatives of
these diarylheterocyclic compounds have been reported to have
useful bioactivities such as anti-inflammatory effects.7,9 Huang and
4
N
CH3
N
CH3
NHC
R2
NaH
H2
Ph
N
CH3
O
CH3
N
N
R1
R2
co-workers
reported
the
synthesis
of
a-phenyl-3-
trifluoromethylquinoxaline 7 (R1¼CF3, R2¼phenyl) by reacting
N
Cl
HO
CH3
CH3
N
-iminoketone 4 (R1¼CF3, R2¼phenyl) with 6 under acidic condi-
R2
a
tions (6 N HCl in methanol).10 Following their work, we constructed
a quinoxaline framework in a one-pot method by adding concd HCl
and 6 after aroylation of 1a,b with 2a,e to afford the corresponding 7
(Table 2, entries 1, 2, and 4). The use of concd H2SO4 instead of HCl
increased the reaction yield (entries 3 and 5). Note that annulation
also proceeded without acids, although the yield was lower (entry
6). Moreover, a large excess of 6 slightly increased the product yield
(entries 7 and 8) (Table 2).
Ph
N
OH
N
1
CH3
Bresow intermediate
R1
Cl
(acyl anion equivalent)
Scheme 2. Plausible mechanism for aroylation.
pot method. A mixture of 1a, 2e (1.5 equiv), NaH (1.3 equiv), and
3 mol % of 1,3-dimethylimidazolium iodide 3 in THF was refluxed for
6 h and the resulting 4ae was confirmed by thin-layer chromatog-
raphy. Although benzoin condensation can be considered to be
a potential side reaction, the formation of benzoinwas not observed.
After cooling, 10% HCl was added: the mixture was then stirred at
room temperature for 3 h to afford 5ae in 70% yield (Table 1, entry 1).
The reaction of 1a with aldehydes 2f,g afforded benzils 5af,ag in
good yields, respectively (entries 2 and 3). However, the yield of
5ahdprepared from 1a and 2-anisaldehyde 2hdwas low (entry 4).
The steric effect of chloro groups, which are versatile substituents
Table 2
One-pot synthesis of 2,3-diarylquinoxalines 7
H2N
I
N
N
H3C
CH3
3 (3 mol%)
H2N
Ph
Cl
R1
R2
N
N
(1 mmol)
6
N
acid
NaH
THF
OHC R2
+
R1
reflux, 24 h
reflux, 6 h
7
2
1
(1 mmol)
Entry
1
2
Acid
7
Yield (%)
1
2
3
4
5
6
1a
1b
1b
1b
1b
1b
1b
1b
2e
2e
2e
2a
2a
2a
2a
2a
Concd HCl 2 mL
Concd HCl 2 mL
Concd H2SO4 0.6 mL
Concd HCl 2 mL
Concd H2SO4 0.6 mL
None
7ae
7be
7be
7ab
7ab
7ab
7ab
7ab
65
48
63
65
75
40
73
80
Table 1
One-pot synthesis of unsymmetrical benzils 5
I
N
N
H3C
CH3
7a,b
8a,c
Concd H2SO4 0.6 mL
concd H2SO4 0.6 mL
Ph
Cl
3 (3 mol%)
NaH
O
N
10% HCl
rt, 3 h
OHC R2
+
R2
a
R1
R1
The reaction mixture was refluxed for 9 h for aroylation.
2 mmol of 6 was used.
10 mmol of 6 was used.
THF
reflux, 6 h
b
c
2
5
1
O
Entry
1
2
5
Yield (%)
2.3. One-pot synthesis of 2,3-diarylpyrazines 10
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1c
1c
1d
2e
2f
5ae
5af
70
72
75
28
96
68
72
70
d
Next, the feasibility of completing four successive reactions with
this one-pot method to synthesize 2,3-diarylpyrazines 10 was ex-
amined (Table 3). After aroylation and acidic hydrolysis, the re-
action mixture containing 5 was refluxed with 8 (12 equiv) to
promote condensation/annulation. Oxidation of the resulting 9
using sulfur powder (2 equiv) as an oxidant was carried out at
reflux temperature. The reaction sequence was started with aroy-
lation of 1a,b with 2a,f,g,i to afford the corresponding 10 in good-
to-moderate yields.
2g
2h
2a
2f
2a
2e
2e
5ag
5ah
5ab
5bf
5ac
5ce
5de
3. Summary
We described the one-pot synthesis of benzils, 2,3-
diarylquinoxalines, and 2,3-diarylpyrazines in sequences of 2e4

472
Y. Suzuki et al. / Tetrahedron 69 (2013) 470e473
Table 3
(1H, t, J¼8.0 Hz), 7.56e7.67 (3H, m), 7.89e8.01 (4H, m), 8.03 (1H, t,
One-pot synthesis of 2,3-diarypyrazines 10
J¼2.0 Hz), 8.09 (1H, dd, J¼8.0, 2.0 Hz), 8.40 (1H, s).
I
H2N
H2N
N
N
H3C
CH3
4.1.4. 1-(4-Chlorophenyl)-2-(2-methoxyphenyl)ethane-1,2-dione
(5ah). Yellowish solid, 28%; mp 108e110 ꢀC; IR (ATR, cmꢁ1): 1585
(C]O), 1662 (C]O); HRMS (FAB) calcd for C15H12O3Cl (Mþ1)þ:
Ph
Cl
3 (3 mol%)
N
conc. H2SO4
rt, 3 h
8
NaH
THF
reflux, 6 h
OHC R2
+
R1
275.0475, found: 275.0447; 1H NMR (500 MHz) CDCl3
d: 3.90 (3H,
reflux, 12 h
2
1
s), 6.88 (1H, d, J¼8.8 Hz), 7.08 (1H, t, J¼8.8 Hz), 7.41 (2H, d,
R1
R2
N
R1
R2
N
J¼8.5 Hz), 7.54 (1H, t, J¼8.8 Hz), 7.81 (2H, d, J¼8.5 Hz), 7.94 (1H, d,
J¼8.8 Hz); 13C NMR (125 MHz) CDCl3
d: 55.5, 112.3, 121.6, 123.6,
129.1, 130.5, 130.6, 131.2, 136.6, 140.2, 160.3, 192.1, 194.2.
sulfur
reflux, 12 h
N
N
10
9
4.1.5. 1-(4-Chlorophenyl)-2-(3-chlorophenyl)ethane-1,2-dione
(5ab). Yellowish solid, 96%; mp 111e113 ꢀC; IR (ATR, cmꢁ1): 1585
(C]O), 1662 (C]O); HRMS (ESI) calcd for C14H9O2Cl2 (Mþ1)þ:
278.9980, found: 279.0018; 1H NMR (400 MHz) CDCl3 d: 7.47 (1H, t,
J¼7.8 Hz), 7.51 (2H, d, 7.8 Hz), 7.64 (1H, ddd, J¼7.8, 1.7, 1.1 Hz), 7.84
(1H, dt, J¼7.8, 1.7 Hz), 7.92 (2H, d, J¼7.8 Hz), 7.97 (1H, t, J¼1.7 Hz);
13C NMR (125 MHz) CDCl3 d: 128.8, 129.6, 130.4, 131.0, 131.2, 134.2,
134.5, 134.9, 135.4, 141.8, 192.0, 192.2.
Entry
1
2
10
Yield (%)
1
2
3
4
5
1a
1a
1a
1b
1b
2f
2g
2i
2a
2f
10af
10ag
10ai
10ab
10bf
56
61
57
75
55
4.1.6. 1-(3-Chlorophenyl)-2-(4-methoxyphenyl)ethane-1,2-dione
(5bf). Yellowish solid, 68%; mp 78e80 ꢀC; IR (ATR, cmꢁ1): 1593
(C]O), 1654 (C]O); HRMS (FAB) calcd for C15H12O3Cl (Mþ1)þ:
275.0475, found: 275.0511; 1H NMR (400 MHz) CDCl3
d: 3.83 (3H,
reactions starting with NHC-catalyzed aroylation of N-phenyl-
benzimidoyl chlorides with aromatic aldehydes. The substrates of
the catalytic reactiondN-phenylbenzimidoyl chloridesdare easily
obtained by chlorination of benzanilides. By combining N-phenyl-
arenecarboxamides and aldehydes appropriately, our method
makes it possible to prepare various unsymmetrical benzils, 2,3-
diarylquinoxalines, and 2,3-diarylpyrazines. The products of the
catalytic reactionda-iminoketonesdare versatile intermediates.
The development of novel synthetic routes to other heterocyclic
compounds such as imidazoles, thiazoles, pyrroles, and pyridines
s), 6.98 (2H, d, J¼8.4 Hz), 7.44 (1H, t, J¼8.0 Hz), 7.60 (1H, ddd,
J¼8.0, 1.5, 1.1 Hz), 7.83 (1H, dt, J¼8.0, 1.5 Hz), 7.92 (2H, d,
J¼8.4 Hz), 7.96 (1H, t, J¼1.5 Hz); 13C NMR (125 MHz) CDCl3
d:
55.6, 114.4, 125.6, 128.0, 129.4, 130.2, 132.4, 134.5, 134.6, 135.2,
165.1, 192.1, 193.2.
4.1.7. 1-(2,4-Dichlorophenyl)-2-(3-chlorophenyl)ethane-1,2-dione
(5ac). Yellowish solid, 72%; mp 82e85 ꢀC; IR (ATR, cmꢁ1): 1625
(C]O), 1682 (C]O); HRMS (FAB) calcd for C14H8O2Cl3 (Mþ1)þ:
312.9590, found: 312.9613; 1H NMR (500 MHz) CDCl3
d: 7.38 (1H,
via these a-iminoketones is currently underway in our laboratory.
dd, J¼8.5, 2.0 Hz), 7.41 (1H, d, J¼2.0 Hz), 7.47 (2H, d, J¼8.7 Hz), 7.87
(1H, d, J¼8.5 Hz), 7.92 (1H, d, J¼8.7 Hz); 13C NMR (125 MHz) CDCl3
d: 127.9, 129.3, 129.5, 130.3, 131.6, 132.2, 132.9, 134.7, 140.6, 141.3,
4. Experimental section
190.2, 192.2.
4.1. General procedure for the one-pot synthesis of un-
symmetrical benzils
4.1.8. 1-(2,4-Dichlorophenyl)-2-phenylethane-1,2-dione
(5ce).-
Yellowish solid, 70%; mp 69e72 ꢀC; IR (ATR, cmꢁ1): 1573 (C]O),
1666 (C]O); HRMS (FAB) calcd for C14H9O2Cl2 (Mþ1)þ: 278.9980,
To a mixture of the N-phenylbenzimidoyl chlorides 1 (1.0 mmol),
aromatic aldehyde 2 (1.5 mmol), and 1,3-dimethylimidazolium io-
dide 3 (6.7 mg, 0.03 mol) in THF (20 mL), NaH (60% in oil, 52 mg,
1.3 mmol) was added with stirring underan argonatmosphere. After
refluxing for an appropriate time, the reaction mixture was cooled
and 10% HCl (2 mL) was added. Thereaction mixturewas then stirred
at room temperature for 3 h and poured into water. The products
wereextractedwith diethyl ether, washed withbrine, and dried over
MgSO4. The solvent was evaporated and the residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate) to ob-
tain benzils 5.
found: 278.9993; 1H NMR (500 MHz) CDCl3
d
: 7.43 (1H, dd, J¼8.2,
1.8 Hz), 7.51 (1H, d, J¼1.8 Hz), 7.54 (2H, t, J¼7.4 Hz), 7.67 (1H, t,
J¼7.4 Hz), 7.86 (1H, d, J¼8.2 Hz), 8.01 (2H, d, J¼7.4 Hz); 13C NMR
(125 MHz) CDCl3 d: 128.2, 129.1, 130.3, 130.5, 130.7, 132.2, 132.8,
134.5, 134.8, 140.5, 191.4, 192.3.
4.2. General procedure for the one-pot synthesis of
quinoxalines
To
a
mixture of the N-phenylbenzimidoyl chlorides
1
(1.0 mmol), aromatic aldehyde
2
(1.5 mmol), and 1,3-
4.1.1. 1-(4-Chlorophenyl)-2-phenylethane-1,2-dione
(5ae).8,9
: 7.51 (2H, d,
dimethylimidazolium iodide 3 (6.7 mg, 0.03 mol) in THF (20 mL),
NaH (60% in oil, 52 mg, 1.3 mmol) was added with stirring under an
argon atmosphere. After refluxing for the indicated time, the re-
action mixture was cooled and concd HCl (2.0 mL) or concd H2SO4
(0.6 mL), and o-phenylenediamine (104 mg, 1.0 mmol) were added.
The reaction mixture was then stirred at reflux temperature for
24 h and poured into water. The products were extracted with
diethyl ether, washed with brine, and dried over MgSO4. The sol-
vent was evaporated and the residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate) to obtain qui-
noxalines 7.
Yellowish solid, 70%; 1H NMR (500 MHz) CDCl3
d
J¼8.5 Hz), 7.53 (2H, d, J¼8.5 Hz), 7.68 (1H, t, J¼8.3 Hz), 7.93 (2H, td,
J¼8.3, 1.5 Hz), 7.98 (2H, dd, J¼8.3, 1.5 Hz).
4.1.2. 1-(4-Chlorophenyl)-2-(4-methoxyphenyl)ethane-1,2-dione
(5af).8,9 Yellowish solid, 2%; 1H NMR (500 MHz) CDCl3 d: 3.89 (3H,
s), 6.98 (2H, d, J¼8.5 Hz), 7.48 (2H, d, J¼8.5 Hz), 7.93e7.98 (4H, m).
4.1.3. 1-(4-Chlorophenyl)-2-(naphthalen-2-yl)ethane-1, 2-dione
(5ag).8 Yellowish solid, 75%; 1H NMR (500 MHz) CDCl3
d: 7.46

Y. Suzuki et al. / Tetrahedron 69 (2013) 470e473
473
4.2.1. 2-(4-Chlorophenyl)-3-phenylquinoxaline
(7ae). Colorless
(Mþ1)þ: 297.0795, found: 297.0791; 1H NMR (400 MHz) CDCl3
d:
powder, 65%; mp 142e143 ꢀC; HRMS (FAB) calcd for C20H14N2Cl
3.73 (3H, s), 6.90 (1H, dd, J¼8.3, 2.2 Hz), 6.96 (1H, d, J¼8.3 Hz), 7.02
(Mþ1)þ: 317.0846, found: 317.0862; 1H NMR (400 MHz) CDCl3
d:
(1H, t, J¼2.2 Hz), 7.20 (1H, t, J¼8.3 Hz), 7.28(2H, d, J¼8.3 Hz), 7.41
7.30e7.38 (5H, m), 7.46e7.52 (4H, m), 7.75e7.79 (2H, m), 8.15e8.19
(2H, d, J¼8.3 Hz), 8.59 (1H, d, J¼2.4 Hz), 8.60 (1H, d, J¼2.2 Hz); 13
C
(2H, m); 13C NMR (125 MHz) CDCl3
d: 128.5, 128.6, 129.0, 129.1,
NMR (125 MHz) CDCl3 d: 55.3, 114.7, 115.2, 122.2, 128.7, 129.6, 130.1,
129.8, 129.9, 130.1, 130.2, 131.3, 135.1, 137.7, 138.8, 141.2, 141.3, 152.1,
153.2.
131.1, 135.0, 137.0, 139.6, 142.3, 151.6, 152.7, 159.7.
4.3.4. 2-(4-Chlorophenyl)-3-(3-chlorophenyl)pyrazine
(10ab). Yellow oil, 75%; HRMS (FAB) calcd for C16H11Cl2N2 (Mþ1)þ:
301.0299, found: 301.0325; 1H NMR (400 MHz) CDCl3 d: 7.18e7.23
(2H, m), 7.27e7.34 (3H, m), 7.40 (2H, d, J¼8.8 Hz), 7.58 (1H, t,
J¼1.2 Hz), 8.60 (1H, d, J¼2.4 Hz), 8.61 (1H, d, J¼2.4 Hz); 13C NMR
4.2.2. 2-(3-Chlorophenyl)-3-phenylquinoxaline
(7be). Colorless
powder, 48%; mp 112e113 ꢀC; HRMS (FAB) calcd for C20H14N2Cl
(Mþ1)þ: 317.0846, found: 317.0872; 1H NMR (500 MHz) CDCl3
d:
7.17e7.37 (6H, m), 7.50e7.52 (2H, m), 7.32 (1H, s), 7.76e7.79 (2H,
m), 8.16e8.18 (2H, m); 13C NMR (125 MHz) CDCl3
d: 128.0, 128.6,
(125 MHz) CDCl3 d: 127.9, 128.7, 129.1, 129.6, 129.7, 131.0, 134.7,
128.8,129.0,129.1,129.2,129.5,129.7,130.1,130.4,131.1,134.6,135.3,
137.0, 140.5, 141.1, 151.4, 151.6.
135.3, 136.6, 140.1, 142.4, 142.6, 151.3, 151.7.
4.3.5. 2-(3-Chlorophenyl)-3-(4-methoxyphenyl)pyrazine
4.2.3. 2-(3-Chlorophenyl)-3-(4-chlorophenyl)quinoxaline
(10bf). Yellow oil, 55%; HRMS (ESI) calcd for C17H14OClN2 (Mþ1)þ:
(7ab). Colorless powder, 65%; mp 95e97 ꢀC; HRMS (FAB) calcd for
297.0795, found: 297.0799; 1H NMR (400 MHz) CDCl3
d: 3.80 (3H,
C
20H13N2Cl2 (Mþ1)þ: 351.0456, found: 351.0455; 1H NMR
s), 6.84 (2H, d, J¼8.8 Hz), 7.16e7.32 (3H, m), 7.39 (2H, d, J¼8.8 Hz),
(500 MHz) CDCl3 d: 7.09e7.48 (5H, m), 7.47e7.49 (2H, m), 7.62 (1H,
7.58 (1H, t, J¼1.7 Hz), 8.54 (1H, d, J¼2.4 Hz), 8.57 (1H, d, J¼2.4 Hz);
s), 7.75e7.79 (2H, m), 8.14e8.22 (2H, m); 13C NMR (125 MHz) CDCl3
13C NMR (125 MHz) CDCl3
d: 55.8, 113.8, 128.8, 129.5, 129.6, 130.4,
d: 128.0, 128.3, 128.4, 128.8, 128.9, 129.0, 129.1, 129.2, 129.6, 129.7,
131.0, 131.1, 134.5, 140.8, 141.6, 142.6, 151.0, 125.6, 160.3.
129.8, 130.1, 130.2, 134.3, 138.5, 140.7, 140.9, 141.2, 151.7, 153.1.
4.3. General procedure for the one-pot synthesis of pyrazines
Acknowledgements
To
a
mixture of the N-phenylbenzimidoyl chlorides
1
We are very appreciative of the funding received via a Grant-in-
Aid for Scientific Research (C) and a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Advanced Molecular Trans-
formations by Organocatalysts’ from the Japan Society for the
Promotion of Science and MEXT, Japan.
(1.0 mmol), aromatic aldehyde
2
(1.5 mmol), and 1,3-
dimethylimidazolium iodide 3 (6.7 mg, 0.03 mol) in THF (20 mL),
NaH (60% in oil, 52 mg, 1.3 mmol) was added with stirring under an
argon atmosphere. The reaction mixture was refluxed for 6 h, and
cooled. After the addition of concd H2SO4 (0.6 mL), the reaction
mixture was stirred at room temperature for 3 h, and then ethyl-
enediamine (104 mg, 1.0 mmol) was added. The reaction mixture
was refluxed for 12 h, and then sulfur (63 mg, 2.0 mmol) was added.
The reaction mixture was refluxed for another 12 h, and then
poured into water. The products were extracted with diethyl ether,
washed with brine, and dried over MgSO4. The solvent was evap-
orated and the residue was purified by silica gel column chroma-
tography (n-hexane/ethyl acetate) to obtain pyrazines 10.
References and notes
1. (a) Bostrom, J.; Berggren, K.; Elebring, T.; Greasley, P. J.; Wilstermann, M. Bioorg.
Med. Chem. 2007, 15, 4077e4084; (b) Singh, S. K.; Saibaba, V.; Ravikumar, V.;
Rudrawar, S. V.; Daga, P.; Rao, C. S.; Akhila, V.; Hegde, P.; Rao, Y. K. Bioorg. Med.
Chem. 2004, 12, 1881e1884; (c) Wilsterman, J. M.; Berggren, A. I. K. PCT Int.
Appl. WO 2003052850, 2003.
2. (a) Shipe, W. D.; Yang, F.; Zhao, Z.; Wolkenberg, S. E.; Nolt, M. B.; Lindsley, C. W.
Heterocycles 2006, 70, 655e689; (b) Katritzky, A. R.; Zhang, D.; Kirichenko, K. J.
Org. Chem. 2005, 70, 3271e3274.
4.3.1. 2-(4-Chlorophenyl)-3-(4-methoxyphenyl)pyrazine
3. Barta, T. E.; Stealey, M. A.; Collins, P. W.; Weier, R. M. Bioorg. Med. Chem. Lett.
1998, 8, 3443e3448.
(10af). Brown oil, 56%; HRMS (FAB) m/z calcd for C17H14OClN2
(Mþ1)þ: 297.0795, found: 297.0779; 1H NMR (500 MHz) CDCl3
d:
4. (a) Harada, T.; Nakagawa, Y.; Wadkins, R. M.; Potter, P. M.; Wheelock, C. E. Bi-
oorg. Med. Chem. 2009, 17, 149e164; (b) Edwards, C. C.; Hyatt, J. L.; Tsurkan, L.;
Bai, F.; Fraga, C.; Morton, C. L.; Howard-Williams, E. L.; Potter, P. M.; Redinbo, M.
R. J. Mol. Biol. 2005, 352, 165e177; (c) Wadkins, R. M.; Hyatt, J. L.; Wei, X.; Yoon,
K. J. P.; Wierdl, M.; Edwards, C. C.; Morton, C. L.; Obenauer, J. C.; Damodaran, K.;
Beroza, P.; Danks, M. K.; Potter, P. M. J. Med. Chem. 2005, 48, 2906e2915; (d)
Mousset, C.; Giraud, A.; Provot, O.; Hamze, A.; Bignon, J.; Liu, J.-M.; Thoret, S.;
Dubois, J.; Brion, J.-D.; Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 3266e3271.
5. (a) Sawama, Y.; Takubo, M.; Mori, S.; Monguchi, Y.; Sajiki, H. Eur. J. Org. Chem.
2011, 3361e3367; (b) Nobuta, T.; Tada, N.; Hattori, K.; Hirashima, S.; Miura, T.;
Itoh, A. Tetrahedron Lett. 2011, 52, 875e877; (c) Ren, W.; Xia, Y.; Ji, S.-J.; Zhang,
Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841e1844.
6. Deuchert, K.; Hertenstein, U.; Huenig, S.; Wehner, G. Chem. Ber. 1979, 112,
2045e2061.
7. Fuson, R. C.; Hoch, P. E. J. Am. Chem. Soc. 1949, 71, 1585e1586.
8. Suzuki, Y.; Md, A. B.; Tanoi, T.; Nomura, N.; Sato, M. Tetrahedron 2011, 67,
4710e4715.
3.81 (3H, s), 6.84 (2H, d, J¼8.5 Hz), 7.28 (2H, d, J¼8.3 Hz), 7.37 (2H, d,
J¼8.5 Hz), 7.40 (2H, d, J¼8.3 Hz), 8.57 (1H, d, J¼2.2 Hz), 8.62 (1H, d,
J¼2.2 Hz); 13C NMR (125 MHz) CDCl3
d: 55.4, 114.0, 128.7, 130.6,
131.0, 131.2, 134.9, 137.4, 141.7, 142.4, 151.3, 152.5, 160.3.
4.3.2. 2-(4-Chlorophenyl)-3-(2-naphthyl)prazine (10ag). Yellow oil,
61%; HRMS (ESI) calcd for C20H14ClN2 (Mþ1)þ: 317.0846, found:
317.0871; 1H NMR (500 MHz) CDCl3
d: 7.25 (2H, d, J¼8.9 Hz),
7.40e7.52 (6H, m), 7.76 (1H, d, J¼8.9 Hz), 7.78e7.80 (2H, m), 8.10
(1H, s), 8.61 (1H, d, J¼2.3 Hz), 8.64 (1H, d, J¼2.3 Hz); 13C NMR
(125 MHz) CDCl3 d: 126.5, 126.8, 127.0, 127.1, 127.7, 128.1, 128.7,
128.8, 129.6, 131.1, 133.4, 135.1, 135.8, 137.0, 142.2, 142.6, 151.7, 152.7.
9. Our former co-workers Miyashita and co-workers reported the first example of
NHC-catalyzed aroylation of N-phenylbenzimidoyl chloride 1, see Miyashita, A.;
Matsuda, H.; Higashino, T. Chem. Pharm. Bull. 1992, 40, 2627e2631.
10. Huang, W.-S.; Yuan, C.-Y.; Wang, Z.-Q. J. Fluorine Chem. 1995, 74, 247e250.
4.3.3. 2-(4-Chlorophenyl)-3-(3-methoxyphenyl)pyrazine
(10ai). Yellow oil, 57%; HRMS (FAB) m/z calcd for C17H14OClN2