An unprecedented approach to the single-step synthesis of 3,4-fused pyrimidi-2-one and pyrimidin-2-thione derivatives by a [3+2+1] annulation

Article abstract of DOI:10.1002/ejoc.200900639

An unprecedented three-component coupling reaction was developed for the synthesis of 3,4-fused. pyrimidin-2-one and pyrimidin-2-thione derivatives from an α-acidic imine compound, a nitrile, and triphosgene or carbon disulfide. This method can be used to

Full text of DOI:10.1002/ejoc.200900639

FULL PAPER
DOI: 10.1002/ejoc.200900639
An Unprecedented Approach to the Single-Step Synthesis of 3,4-Fused
Pyrimidin-2-one and Pyrimidin-2-thione Derivatives by a [3+2+1] Annulation
Toshiaki Sasada,[a] Masato Moriuchi,[a] Norio Sakai,[a] and Takeo Konakahara*[a]
Keywords: Multicomponent reactions / Nitrogen heterocycles / Pyrimidin-2-ones / Pyrimidin-2-thiones / Annulation
An unprecedented three-component coupling reaction was
developed for the synthesis of 3,4-fused pyrimidin-2-one and
pyrimidin-2-thione derivatives from an α-acidic imine com-
pound, a nitrile, and triphosgene or carbon disulfide. This
method can be used to easily prepare a variety of pyrimidines
from commercially available reagents in a single step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
3,4-Fused pyrimidin-2-one and pyrimidin-2-thione deriv-
atives[1] are ubiquitous in natural products and biologically
active substances[2] and are useful synthetic intermediates.[3]
Currently, a number of methods for the efficient and practi-
cal synthesis of pyrimidine derivatives are available;[4,5]
however, synthesis of the 3,4-fused pyrimidine skeleton is
limited to the following general methods (Scheme 1): (i)
intermolecular annulation and intramolecular cyclization of
3- or 4-substituted pyrimidine derivatives (route a);[6] (ii)
[3+3] annulation of a C–C–N fragment, such as an α-acidic
imine derivative, with a C–N–C fragment, such as an acyl
heterocumulene derivative (route b);[7] and (iii) [5+1] annu-
lation of an N–C–C–C–N fragment with a C-1 unit, such
as a carbonyl compound or a heterocumulene (route c).[8]
Moreover, these methods often require the isolation of
intermediates, the synthesis of starting materials, high reac-
tion temperatures, and a prolonged reaction time, which de-
creases product yield. Hence, development of a novel pro-
cedure that allows for a facile, efficient, single-step synthesis
of 3,4-fused pyrimidine derivatives using commercially
available reagents is highly desirable.
We previously reported that intermolecular annulation of
a 1-azaallylic anion,[9] which was generated from an α-
acidic methylene compound and a nitrile in the presence of
a base, and its synthetic equivalent, a functionalized en-
amine,[10] selectively produced a variety of nitrogen-contain-
ing heterocyclic compounds.[11] During our ongoing devel-
opment of novel synthetic methods for multifunctionalized
nitrogen-containing heterocycles using 1-azaallylic anions,
we identified a practical three-component coupling reaction
Scheme 1. New approach to the synthesis of 3,4-fused pyrimidines.
using a picoline derivative, a nitrile, and triphosgene or car-
bon disulfide as a C-1 unit that produced 3,4-fused pyrim-
idin-2-one or pyrimidin-2-thione derivatives in a direct,
one-pot synthesis. To the best of our knowledge, this ap-
proach to the synthesis of a 3,4-fused pyrimidine skeleton
through a [3+2+1] annulation is rare (Scheme 1, route d).
In this paper, we describe the preparation of pyrimidine de-
rivatives using this unprecedented method.
Results and Discussion
On the basis of our previous studies, when the reaction
mixture of 2-picoline (1a) and benzonitrile (2a) was initially
treated with LDA in THF at –70 °C for 1 h, followed by the
addition of triphosgene (3), the desired bicyclic pyrimidine
derivative 4a was obtained in 63% yield (Table 1, run 1).
The structure of isolated pyrimidine 4a was determined
from spectroscopic data, elemental analysis, and X-ray crys-
tallographic structural analysis. When triethylamine (Et3N,
[a] Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
Fax: +81-4-7123-9326
E-mail: konaka@rs.noda.tus.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900639.
5738
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Eur. J. Org. Chem. 2009, 5738–5743

Single-Step Synthesis of 3,4-Fused Pyrimidin-2-one and -2-thione Derivatives
2 equiv.) was then added to the reaction mixture as a base, Table 2. Single-step synthesis of pyrimidin-2-one derivatives 4.
the yield increased to 83% yield (Table 1, run 2). Moreover,
a prolongation of the reaction time to 2 h improved the
yield of isolated product to nearly quantitative yield
(Table 1, run 3). In contrast, reduction of the amount of
added base to 1 equivalent resulted in a slight decrease in
product yield compared with the addition of 2 equivalents
(Table 1, run 4). Moreover, addition of pyridine did not en-
hance the product yield (Table 1, run 5). Thus, the reaction
conditions used during run 3 (Table 1) were optimal for the
three-component coupling reaction.
Table 1. Examination of the one-pot, three-component coupling re-
action.
Run
Base (equiv.)
Time [h]
Yield [%][a]
1
2
3
4
5
none
0.5
0.5
2
2
2
63
83
(95)
80
Et3N (2)
Et3N (2)
Et3N (1)
pyridine (2)
70
[a] NMR yield (Isolated yield).
To extend the generality of the reaction, the annulation
reaction was then conducted with the use of various pico-
line derivatives, related nitrogen-containing compounds,
and nitriles. The results are summarized in Table 2. When
nitriles 2b,c, which had a methoxy group and a halogen
group on the benzene ring, respectively, were treated with
compounds 1a and 3 under optimal reaction conditions,
corresponding pyrimidine derivatives 4b,c were obtained in
excellent yields (Table 2, runs 2 and 3).
[a] Isolated yield.
In addition, this method was successfully applied to the
reaction with a nitrile, consisting of a heterocyclic ring or
an aliphatic chain, producing expected products 4d,e in
moderate to good yields (Table 2, runs 4 and 5). When 2-
ethylpyridine (1b) and 2,3-lutidine (1c) were then used in-
stead of 1a, the corresponding pyrimidine derivatives 4f,g
were produced, respectively, in good yields (Table 2, runs 6
and 7). Also, heterocycles containing more than one hetero-
Scheme 2. Double annulation from 2,3-dimethylpyrazine.
We next attempted the synthesis of pyrimidin-2-thione
atom, such as 2-methylthiazoline (1d) and 1,2-dimethyl- derivatives by using carbon disulfide (CS2) as a C-1 unit
imidazole (1e), afforded the desired five-membered-ring- (Table 3). The desired annulation of compound 1a, benzo-
fused pyrimidines 4h,i in good yields (Table 2, runs 8 and nitrile (2a), and carbon disulfide (5) gave expected product
9). Moreover, employment of 2-methylqunoline (1f) pro- 6a in 37% yield. However, addition of pyridine improved
vided tricyclic pyrimidine derivatives 4j in 91% yield the yield to 70% (Table 3, run 1).
(Table 2, run 10).
Thus, under these reaction conditions, we examined the
To further explore the scope of this chemistry, a double preparation of pyrimidin-2-thione derivatives from hetero-
annulation reaction with the use of 2,3-dimethylpyrazine cycle 1, nitrile 2, and CS2. All reactions resulted in success-
(1g), nitrile 2a, and 3 was examined (Scheme 2). As ex- ful intermolecular annulation, producing the corresponding
pected, the desired reaction proceeded to produce polycy- pyridine-2-thione derivatives 6a–g in moderate to good
clic pyrimidine derivative 4k in 52% yield.
yields (Table 3, runs 1–7).
Eur. J. Org. Chem. 2009, 5738–5743
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T. Sasada, M. Moriuchi, N. Sakai, T. Konakahara
FULL PAPER
Table 3. Single-step synthesis of pyrimidin-2-thione derivatives 6.
A plausible mechanism for the synthesis of pyrimidin-2-
one derivatives using the novel method described in this
study is shown in Scheme 3. First, azaallyl anion 7, gener-
ated in situ from an α-acidic imine derivative and a nitrile
in the presence of LDA, reacts with triphosgene to produce
intermediate 8 with concurrent elimination of lithium chlo-
ride and phosgene. Then, intermediate 8 generates isocyan-
ate 9 with liberation of hydrogen chloride and phosgene.
Finally, intramolecular cyclization of intermediate 9 leads
to the formation of the corresponding 3,4-fused pyrimidin-
2-one derivative.
Conclusions
In conclusion, we demonstrated that our unprecedented
[3+2+1] annulation protocol produces 3,4-fused pyrimidine
derivatives by linking three common and commercially
available reagents in a one-pot synthesis. We also found that
the Et3N-promoted reaction between 1-azaallylic anions,
which were generated from α-acidic imines and nitriles, and
triphosgene leads to 3,4-fused pyrimidin-2-one derivatives.
Moreover, annulation of the anion with carbon disulfide in
the presence of pyridine effectively produces a variety of
bicyclic pyrimidin-2-thiones.
Experimental Section
General Methods: Column chromatography was performed by
using NH silica gel. THF was distilled from sodium–benzophenone
and dried with 5 Å MS. 2-Picoline, triethylamine, pyridine, diiso-
propylamine, and benzonitrile were distilled prior to use. Other ma-
terials were commercially available and were used without further
purification. All reactions were carried out under a nitrogen atmo-
sphere, unless otherwise noted. All melting points reported are un-
[a] Isolated yield.
1
corrected values. H NMR spectra were measured at either 500 or
300 MHz by using tetramethylsilane as the internal standard. 13C
NMR spectra were measured at either 125 or 75 MHz by using the
center peak of chloroform (δ = 77.0 ppm) as the internal standard.
High-resolution mass spectra were measured by using NBA (3-ni-
trobenzyl alcohol) as the matrix. Elemental analyses were per-
formed at Tokyo University of Science.
General Procedure for the Synthesis of Pyrimidin-2-ones 4a–j: To a
THF (2 mL) solution of diisopropylamine (1.0 mmol) was added
nBuLi (1.5  in hexane, 1.1 mmol) at –70 °C, and then the mixture
was stirred at the same temperature. After 30 min, α-acidic com-
pound 1 (1.0 mmol) was added dropwise, and the mixture was
stirred for 1 h at –70 °C. Nitrile 2 (1.0 mmol) was gradually added
to the solution at –70 °C, and the mixture was stirred for 1 h at
the same temperature. Triethylamine (2.0 mmol) was added to the
reaction mixture at room temperature, followed by the addition of
a THF (1 mL) solution of triphosgene (3, 1.0 mmol), and the reac-
tion mixture was stirred for 2 h at the same temperature. To quench
the reaction, a 2  aqueous solution (5 mL) of KOH was added to
the reaction mixture. The mixture was extracted several times with
CHCl3. The combined organic extract was then dried with Na2SO4,
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by NH silica gel chromatography (hexane/AcOEt)
to give pyrimidin-2-ones 4a–j.
4a: Yield: 95% (211 mg); yellow solid (CH2Cl2/hexane); m.p. 155.1–
156.3 °C. H NMR (500 MHz, CDCl3): δ = 6.98 (s, 1 H), 7.09 (t,
Scheme 3. A plausible mechanism for the synthesis of pyrimidin-2-
ones.
1
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Single-Step Synthesis of 3,4-Fused Pyrimidin-2-one and -2-thione Derivatives
J = 7.0 Hz, 1 H), 7.67–7.68 (m, 3 H), 7.46 (d, J = 7.0 Hz, 1 H), NMR (125 MHz, CDCl3): δ = 27.5, 51.2, 95.9, 127.7, 128.5, 131.5,
7.61 (t, J = 7.0 Hz, 1 H), 8.06–8.07 (m, 2 H), 9.03 (d, J = 7.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 96.4, 117.3, 124.4,
127.5, 128.4, 130.1, 130.8, 136.2, 136.8, 148.5, 151.8, 163.7 ppm.
MS (FAB): m/z (%) = 223 (100) [M + H]. C14H10N2O (222.24):
calcd. C 75.66, H 4.54, N 12.60; found C 75.98, H 4.94, N 12.71.
135.9, 155.6, 161.9, 170.0 ppm. MS (FAB): m/z (%) = 231 (100) [M
+ H]. C12H10N2OS (230.29): calcd. C 62.59, H 4.38, N 12.16; found
C 62.60, H 4.27, N 12.06.
4i: Yield: 77% (173 mg); colorless solid (CH2Cl2/hexane); m.p.
1
235.8–236.3 °C. H NMR (500 MHz, CDCl3): δ = 3.67 (s, 3 H, N-
Me), 6.47 (s, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 7.35–7.36 (m, 3 H),
7.50 (d, J = 2.0 Hz, 1 H), 7.98–8.00 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 33.0, 81.0, 110.4, 120.9, 127.3, 128.3, 130.1,
137.8, 146.1, 150.8, 162.3 ppm. MS (FAB): m/z (%) = 226 (100) [M
+ H]. C13H11N3O (225.25): calcd. C 69.32, H 4.92, N 18.66; found
C 69.60, H 4.81, N 18.62.
4b: Yield: 85% (214 mg); yellow solid (CH2Cl2/hexane); m.p. 200.8–
201.2 °C. H NMR (500 MHz, CDCl3): δ = 3.80 (s, 1 H, O-Me),
1
6.90 (d, J = 8.0 Hz, 2 H), 6.93 (s, 1 H), 7.04 (t, J = 7.5 Hz, 1 H),
7.41 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 8.08 (d, J =
8.0 Hz, 2 H), 9.02 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 55.3, 95.5, 113.9, 116.7, 124.2, 129.2, 129.3, 130.2,
135.8, 148.5, 151.9, 162.1, 163.4 ppm. MS (FAB): m/z (%) = 253
(100) [M + H]. C15H12N2O2 (252.27): calcd. C 71.42, H 4.79, N
11.10; found C 71.45, H 4.83, N 11.33.
4j: Yield: 91% (248 mg); yellow solid (CH2Cl2/hexane); m.p. 234.7–
1
235.4 °C. H NMR (300 MHz, CDCl3): δ = 6.92 (s, 1 H), 7.11 (d,
J = 8.7 Hz, 1 H), 7.43–7.48 (m, 4 H), 7.56–7.66 (m, 3 H), 8.14–
8.17 (m, 2 H), 9.78 (d, J = 8.7 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 99.0, 121.8, 122.0, 126.2, 126.8, 127.8, 128.1, 128.7,
130.5, 131.5, 135.2, 135.6, 135.9, 149.5, 156.2, 165.5 ppm. MS
(FAB): m/z (%) = 273 (100) [M + H]. C18H12N2O (272.30): calcd.
C 79.39, H 4.44, N 10.29; found C 79.54, H 4.44, N 10.18.
4c: Yield: 99% (254 mg); yellow solid (CH2Cl2/hexane); m.p. 216.7–
1
217.5 °C. H NMR (500 MHz, CDCl3): δ = 6.98 (s, 1 H), 7.16 (t,
J = 7.0 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.49 (d, J = 7.0 Hz, 1
H), 7.68 (t, J = 7.0 Hz, 1 H), 8.03 (d, J = 8.5 Hz, 2 H), 9.09 (d, J
= 7.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 96.2, 117.6,
124.4, 128.8, 128.9, 130.4, 135.3, 136.5, 137.2, 148.7, 151.7,
162.5 ppm. MS (FAB): m/z (%) = 257 (100) [M + H]. C14H9ClN2O
(256.69): calcd. C 65.51, H 3.53, N 10.91; found C 65.52, H 3.42,
N 10.99.
Procedure for the Synthesis of Pyrimidin-2-one 4k: To a THF
(4 mL) solution of diisopropylamine (2.0 mmol) was added nBuLi
(1.5  in hexane, 2.2 mmol) at –70 °C, and then the mixture was
stirred at the same temperature. After 30 min, 2,3-dimethylpyrazine
(1g, 1.0 mmol) was added dropwise, and the mixture was stirred
for 1 h at –70 °C. Benzonitrile (2a, 2.0 mmol) was gradually added
to the solution at –70 °C, and the mixture was stirred for 1 h at the
same temperature. Triethylamine (4.0 mmol) was added at room
temperature, followed by the addition of a THF (2 mL) solution of
triphosgene (3, 2.0 mmol), and the reaction mixture was stirred for
2 h at the same temperature. To quench the reaction, a 2  aqueous
solution (10 mL) of KOH was added to the reaction mixture. The
mixture was extracted several times with CHCl3. The combined
organic extract was then dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
NH silica gel chromatography (hexane/AcOEt) to give pyrimidin-
2-ones 4k (52%, 191 mg) as a yellow solid (CH2Cl2/hexane). M.p.
4d: Yield: 73% (163 mg); yellow solid (CH2Cl2/hexane); m.p. 228.3–
1
229.0 °C. H NMR (500 MHz, CDCl3): δ = 7.09 (s, 1 H) 7.27 (t, J
= 7.5 Hz, 1 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.77 (t, J = 7.5 Hz, 1 H),
7.91 (d, J = 6.0 Hz, 2 H) 8.65 (d, J = 6.0 Hz, 2 H) 9.15 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 96.9, 118.5,
121.2, 124.7, 130.7, 137.2, 144.2, 148.9, 150.3, 151.5, 161.1 ppm.
MS (FAB): m/z (%) = 224 (100) [M + H]. C13H9N3O (223.23):
calcd. C 69.95, H 4.06, N 18.82; found C 70.13, H 4.00, N 18.72.
4e: Yield: 53% (101 mg); yellow solid (CH2Cl2/hexane); m.p. 125.1–
1
125.4 °C. H NMR (500 MHz, CDCl3): δ = 3.43 (s, 3 H, CH2-O-
Me), 4.37 (s, 2 H, CH2-O-Me), 6.77 (s, 1 H), 7.18 (t, J = 8.0 Hz, 1
H), 7.44 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 9.06 (d, J
= 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 59.0, 74.4,
96.2, 117.5, 124.0, 130.3, 136.5, 148.7, 151.3, 168.2 ppm. MS
(FAB): m/z (%) = 191 (100) [M + H]. C10H10N2O2 (190.20): calcd.
C 63.15, H 5.30, N 14.73; found C 65.50, H 5.09, N 14.77.
1
382.9–383.6 °C. H NMR (500 MHz, CDCl3): δ = 7.55–7.63 (m, 8
H), 8.13 (s, 2 H), 8.21–8.23 (m, 4 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 97.3, 114.0, 128.3, 129.0, 132.7, 135.6, 143.3, 151.4,
169.1 ppm. MS (FAB): m/z (%) = 367 (100) [M + H]. HRMS
(FAB): calcd. for C22H14N4O2 [M + H] 367.1195; found 367.1205.
4f: Yield: 93% (220 mg); yellow solid (CH2Cl2/hexane); m.p. 182.5–
1
183.3 °C. H NMR (500 MHz, CDCl3): δ = 2.20 (s, 3 H, Ar-Me),
General Procedure for the Synthesis of Pyrimidin-2-thiones 6a–g: To
a THF (2 mL) solution of diisopropylamine (1.0 mmol) was added
nBuLi (1.5  in hexane, 1.1 mmol) at –70 °C, and then the mixture
was stirred at the same temperature. After 30 min, α-acidic com-
pound 1 (1.0 mmol) was added dropwise, and the mixture was
stirred for 1 h at –70 °C. Nitrile 2 (1.0 mmol) was gradually added
to the solution at –70 °C, and the mixture was stirred for 1 h at the
same temperature. Pyridine (2.0 mmol) was added to the reaction
mixture at room temperature, followed by the addition of carbon
disulfide (5, 2.0 mmol), and the reaction mixture was stirred for
20 h at the same temperature. To quench the reaction, a saturated
aqueous solution (10 mL) of NaHCO3 was added to the reaction
mixture. The mixture was extracted several times with CHCl3. The
combined organic extract was then dried with Na2SO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by NH silica gel chromatography (hexane/AcOEt) to give
pyrimidin-2-thiones 6a–g.
7.16 (t, J = 7.5 Hz, 1 H), 7.27–7.30 (m, 3 H), 7.46–87.47 (m, 2 H),
7.62 (d, J = 7.5 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 9.12 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.8, 103.6,
117.1, 121.4, 127.6, 128.6, 129.0, 130.4, 136.4, 138.9, 147.3, 150.4,
165.3 ppm. MS (FAB): m/z (%) = 237 (100) [M + H]. C15H12N2O
(236.27): calcd. C 76.25, H 5.12, N 11.86; found C 76.51, H 5.05,
N 11.76.
4g: Yield: 76% (180 mg); yellow solid (CH2Cl2/hexane); m.p. 168.5–
1
169.0 °C. H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H, Ar-Me),
6.91 (s, 1 H), 6.97 (t, J = 6.5 Hz, 1 H), 7.35–7.64 (m, 3 H), 7.42 (d,
J = 6.5 Hz, 1 H), 8.04–8.05 (m, 2 H), 8.93 (d, J = 6.5 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 18.3, 93.2, 116.4, 127.4, 128.3,
128.4, 130.7, 131.8, 135.6, 137.0, 148.4, 152.2, 163.3 ppm. MS
(FAB): m/z (%) = 237 (100) [M + H]. C15H12N2O (236.27): calcd.
C 76.25, H 5.12, N 11.86; found C 76.30, H 5.05, N 11.79.
4h: Yield: 83% (191 mg); colorless solid (CH2Cl2/hexane); m.p.
195.8–196.4 °C. 1H NMR (300 MHz, CDCl3): δ = 3.46 (t, J = 6a: Yield: 70% (167 mg); yellow solid (CH2Cl2/hexane); m.p. 167.9–
1
7.5 Hz, 2 H, N-CH2-CH2-S), 4.53 (t, J = 7.5 Hz, 2 H, N-CH2-CH2-
168.8 °C. H NMR (500 MHz, CDCl3): δ = 7.32 (t, J = 7.5 Hz, 1
S), 6.75 (s, 1 H), 7.40–7.48 (m, 3 H), 8.00–8.03 (m, 2 H) ppm. 13C H), 7.36–7.39 (m, 3 H), 7.41 (s, 1 H), 7.67 (d, J = 7.5 Hz, 1 H),
Eur. J. Org. Chem. 2009, 5738–5743
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Sasada, M. Moriuchi, N. Sakai, T. Konakahara
FULL PAPER
7.77 (t, J = 7.5 Hz, 1 H), 8.09–8.11 (m, 2 H), 10.34 (d, J = 7.5 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 102.7, 119.6, 125.7,
127.8, 128.6, 131.2, 135.1, 135.3, 136.6, 147.1, 156.6, 174.7 ppm.
MS (FAB): m/z (%) = 239 (100) [M + H]. C14H10N2S (238.31):
calcd. C 70.56, H 4.23, N 11.76; found C 70.39, H 4.54, N 11.65.
Acknowledgments
This work was partially supported by a grant from the Japan
Private School Promotion Foundation (2008), a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) (16550148, 2004–2005;
21590025-0001, 2009–2011), and a fund for the “High-Tech
Research Center” Project for Private Universities, which is a match-
ing-fund subsidy from MEXT (2000–2004 and 2005–2007).
6b: Yield: 41% (110 mg); yellow solid (CH2Cl2/hexane); m.p. 269.6–
1
270.4 °C. H NMR (500 MHz, CDCl3): δ = 3.87 (s, 3 H, O-Me),
6.98 (d, J = 9.5 Hz, 2 H), 7.35 (t, J = 7.0 Hz, 1 H), 7.38 (s, 1 H),
7.62 (d, J = 7.0 Hz, 1 H), 7.77 (t, J = 7.0 Hz, 1 H), 8.22 (d, J =
9.5 Hz, 2 H), 10.46 (d, J = 7.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 55.5, 101.6, 114.3, 118.9, 125.4, 128.0, 129.9, 135.6,
136.2, 147.3, 156.8, 162.7, 175.1 ppm. MS (FAB): m/z (%) = 269
(100) [M + H]. C15H12N2OS (268.33): calcd. C 67.14, H 4.51, N
10.44; found C 66.90, H 4.57, N 10.42.
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6c: Yield: 44% (120 mg); brown solid (CH2Cl2/hexane); m.p. 239.3–
240.1 °C. 1H NMR (500 MHz, CDCl3): δ = 7.42–7.45 (m, 4 H),
7.68 (d, J = 7.0 Hz, 1 H), 7.85 (t, J = 7.0 Hz, 1 H), 8.16 (d, J =
9.0 Hz, 2 H), 10.50 (d, J = 7.0 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 102.4, 119.9, 125.6, 129.1, 129.3, 134.0, 135.7, 136.9,
137.8, 147.3, 155.8, 175.2 ppm. MS (FAB): m/z (%) = 273 (100) [M
+ H]. C14H9ClN2S (272.75): calcd. C 61.65, H 3.33, N 10.27; found
C 61.45, H 3.35, N 10.08.
6d: Yield: 80% (202 mg); yellow solid (CH2Cl2/hexane); m.p. 216.8–
1
217.7 °C. H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H, Ar-Me),
7.38–7.40 (m, 3 H), 7.48 (t, J = 7.0 Hz, 1 H), 7.57–7.59 (m, 2 H),
7.92 (d, J = 7.0 Hz, 1 H), 7.97 (t, J = 7.0 Hz, 1 H), 10.57 (d, J =
7.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.6, 111.0,
119.5, 122.4, 128.0, 129.3, 129.7, 136.0, 136.9, 137.9, 146.6, 158.8,
172.4 ppm. MS (FAB): m/z (%) = 253 (100) [M + H]. C15H12N2S
(252.34): calcd. C 71.40, H 4.79, N 11.10; found C 71.02, H 4.78,
N 11.08.
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6e: Yield: 51% (129 mg); yellow solid (CH2Cl2/hexane); m.p. 243.5–
1
244.3 °C. H NMR (500 MHz, CDCl3): δ = 2.63 (s, 3 H, Ar-Me),
7.28 (t, J = 7.0 Hz, 1 H), 7.46–7.48 (m, 4 H), 7.65 (d, J = 7.0 Hz,
1 H), 8.20–8.21 (m, 2 H), 10.42 (d, J = 7.0 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 18.8, 99.3, 118.5, 128.1, 128.8, 131.3,
133.0, 134.0, 136.0, 136.3, 147.3, 156.8, 176.1 ppm. MS (FAB): m/z
(%) = 253 (100) [M + H]. C15H12N2S (252.34): calcd. C 71.40, H
4.79, N 11.10; found C 71.62, H 5.06, N 11.08.
6f: Yield: 51% (126 mg); yellow solid (CH2Cl2/hexane); m.p. 197.8–
1
198.5 °C. H NMR (500 MHz, CDCl3): δ = 3.48 (t, J = 8.0 Hz, 2
H, N-CH2-CH2-S), 4.94 (t, J = 8.0 Hz, 2 H, N-CH2-CH2-S), 7.02
(s, 1 H), 7.43–7.45 (m, 2 H), 7.51 (t, J = 7.0 Hz, 1 H), 8.07 (m, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 26.1, 57.7, 100.9, 128.3,
128.8, 132.2, 135.0, 162.0, 163.9, 180.5 ppm. MS (FAB): m/z (%) =
247 (100) [M + H]. C12H10N2S2 (246.35): calcd. C 58.51, H 4.09,
N 11.37; found C 58.59, H 4.28, N 11.54.
6g: Yield: 57% (138 mg); colorless solid (CH2Cl2/hexane); m.p.
1
295.7–296.5 °C. H NMR (500 MHz, CDCl3): δ = 3.85 (s, 3 H, N-
Me), 7.00 (s, 1 H), 7.11 (d, J = 2.0 Hz, 1 H), 7.43–7.45 (m, 3 H),
8.13–8.14 (m, 2 H), 8.35 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 33.2, 88.9, 113.5, 124.0, 127.1, 128.6,
130.1, 136.8, 142.9, 154.2, 168.4 ppm. MS (FAB): m/z (%) = 242
(100) [M + H]. C13H11N3S (241.31): calcd. C 64.70, H 4.59, N
17.41; found C 64.47, H 4.74, N 17.28.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data
for novel compounds; ORTEP diagram of 4a; copies of the 1H and
13C NMR spectra of novel products.
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5742
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5738–5743

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Received: June 11, 2009
Published Online: October 5, 2009
Eur. J. Org. Chem. 2009, 5738–5743
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5743