Synthetic studies on novel 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylic acid esters and their tautomers

Article abstract of DOI:10.1248/cpb.59.1458

A mixture of alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1 and its tautomeric isomer, alkyl 1,6-dihydro-2- methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate 2 is synthesized by the Atwal - Biginelli cyclocondensatio

Full text of DOI:10.1248/cpb.59.1458

1458
Regular Article
Chem. Pharm. Bull. 59(12) 1458—1466 (2011)
Vol. 59, No. 12
Synthetic Studies on Novel 1,4-Dihydro-2-methylthio-4,4,6-trisubstituted
Pyrimidine-5-carboxylic Acid Esters and Their Tautomers
a
Yoshio NISHIMURA, ,a Yasuko OKAMOTO,b Masaya IKUNAKA,a and Yoshihiko OHYAMA
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yasuda Women’s University; 6–13–1 Yasuhigashi,
Asaminami-ku, Hiroshima 731–0153, Japan: and b Faculty of Pharmaceutical Sciences, Tokushima Bunri University;
Yamashiro-cho, Tokushima 770–8514, Japan.
Received June 22, 2011; accepted September 22, 2011; published online October 4, 2011
A mixture of alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1 and its tau-
tomeric isomer, alkyl 1,6-dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate 2 is synthesized by
the Atwal–-Biginelli cyclocondensation reaction of S-methylisothiourea hemisulfate salt 3 with 2-(gem-disubsti-
tuted)methylene-3-oxoesters 4 that can be accessed by the Lehnert procedure for the Knoevenagel-type conden-
sation. The structures of the tautomeric products of the Atwal–Biginelli cyclocondensation reaction, 1 and 2,
which are inseparable from each other, are determined unambiguously by 1H-NMR spectroscopy at various tem-
peratures and nuclear Overhauser enhancement spectroscopy (NOESY) experiment. Because these dihydro-
pyrimidine products are otherwise inaccessible and thus hitherto unavailable, the synthetic methods established
in this study will help to expand the molecular diversity of their related derivatives.
Key words Atwal–Biginelli reaction; 2-(gem-disubstituted methylene)-3-oxoester; tautomer; alkyl 1,4-dihydro-2-methylthio-
4,4,6-trisubstituted pyrimidine-5-carboxylate; alkyl 1,6-dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate
This article deals with a general approach to synthesizing to explore alkyl 3,4-dihydro-2-oxo-3,4,4,6-tetrasubstituted
alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimi- pyrimidine-5-carboxylates 5a and their 2-thioxo congeners
dine-5-carboxylate 1 and its tautomeric isomer, alkyl 1,6- 5b for novel therapeutic agents,6) which was inspired by the
dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-car- two track records with the related 1,4-dihydro-4-monoaryl-6-
boxylate 2, which was achieved by applying the Atwal–Bigi- methylpyrimidine derivatives that follow: (R)-SQ 32926 6,7)
nelli cyclocondensation reaction1—3) of S-methylisothiourea a calcium channel blocker developed as an orally active anti-
hemisulfate salt 3 to 2-(gem-disubstituted)methylene-3-oxo- hypertensive agent, and monastrol 7,8—10) a possible anti-
esters 4 available by the Lehnert procedure4,5) for the Kno- cancer agent that inhibits mitotic cell division by blocking
evenagel-type condensation (Fig. 1). This synthetic study the activity of kinesin Eg 5, a motor protein causing spindle
was conducted as part of our medicinal chemistry program bipolarity.
Fig. 1. Synthetic Approach to Alkyl 1,4-Dihydro-2-methylthio-4,4,6-trisubstituted Pyrimidine-5-carboxylate 1 and Its Tautomeric Isomer 2 and Structures
of Related 2-Oxo and 2-Thioxo Analogs
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: nishimura-y@yasuda-u.ac.jp

December 2011
1459
Chart 1. Three-Component Biginelli Reaction
Chart 2. Typical Atwal–Biginelli Cyclocondensation Reaction to Afford Alkyl 1,4-Dihydro-2-methylthio-4,6-disubstituted Pyrimidine-5-carboxylate 15
and Its Tautomeric Isomer 16
Results and Discussion
[3 (1.2 eq), NaHCO3 (4.0 eq), DMF, 60 °C for 5 h], the cyclo-
One of the ultimate synthetic targets being 3,4-dihydro- condensation reaction proceeded uneventfully to provide
4,4,6-trisubstituted-2-thioxopyrimidine 5b (R5ꢀH), a three- ethyl 1,4-dihydro-2-methylthio-4,6-disubstituted pyrimidine-
component Biginelli reaction was first attempted, in which 5-carboxylate 15 and its tautomeric isomer 16 as an insepara-
ethyl acetoacetate (10 1.0 eq) was treated with thiourea 8 ble mixture [15/16 (2.2 : 1)] in a combined yield of 67%
(1.2 eq) and acetone 9 (3—10 eq) in dimethylformamide (Chart 2).16,17) Structural assignments for 15 and 16 were
(DMF) at 65 °C for 12 h in the presence of a Brønsted acid made by the following nuclear Overhauser enhancement
(1.0 eq), such as HCl, H2SO4, trifluoroacetic acid, 4-toluene- spectroscopy (NOESY) experiment. With the major compo-
sulfonic acid, or methanesulfonic acid (Chart 1).11) However, nent 15, its 6-methyl protons exhibited a significant nuclear
no desired ethyl 3,4-dihydro-4,4,6-trimethyl-2-thioxopyrimi- Overhauser effect (NOE) when the 1-NH proton was irradi-
dine-5-carboxylate 11 was produced, and the starting mate- ated; hence, its structure was determined to be 1,4-dihy-
rial 10 was recovered intact. Furthermore, no such three- dropyrimidine 15 as depicted in Chart 2. Irradiation of the 1-
component reaction took place to afford ethyl 1,4-dihydro- NH proton in the minor component 16 caused the NOE on
4,6,6-trimethyl-2-methylthiopyrimidine-5-carboxylate 12 or the 6-proton, which led to its structure being determined to
its 1,6-dihydro tautomer 13 when 9 (3—10 eq) and 10 be 1,6-dihydropyrimidine 16, a tautomeric isomer of 15
(1.0 eq) were exposed to 3 (1.2 eq) instead of 8 in DMF in (Chart 2): for detail, see Experimental. Hence, it was envi-
the presence of NaHCO3 (4.0 eq) at 65 °C for 12 h.12—14)
sioned that when prefabricated ethyl 3-oxo-2-(2-propyl-
In contrast, when ethyl 2-benzylidene-3-oxobutanoate 14 idene)-butanoate 17 was allowed to react with 8 and 3, the
[E/Z (1 : 3.0)],15) a typical 2-(monosubstituted)methylene-3- cyclocondensation in question should proceed to give 11
oxoester prepared under the conventional Knoevenagel reac- and a mixture of 12 and 13, respectively (Chart 1).
tion conditions, was subjected to Atwal–Biginelli conditions
To test the above-mentioned proposition, 17 was required

1460
Vol. 59, No. 12
Chart 3. Synthesis of Ethyl 1,4-Dihydro-4,4,6-trimethyl-2-methylthiopyrimidine-5-carboxylate 12 and Its 1,6-Dihydro Tautomer 13
in sufficient quantity. To our disappointment, it was obtained combined yield of 89% (Chart 3). The structures of 12 and
in less than 3% yield when ethyl acetoacetate 10 (1.0 eq) and 13 were determined to be as depicted in Chart 3 by the
acetone 9 (2.0 eq) were subjected to the conventional Kno- NOESY experiment similar to that conducted with the tau-
evenagel reaction conditions [piperidine (0.25 eq), molecular tomeric mixture of 15 and 16: for detail, see Experimental.
sieves 4A (34% w/w based on 10), toluene, 50 °C, 24 h]
To see the concentration dependence of the tautomeric
(Chart 3).18) However, literature search in parallel with failed ratio of 12 to 13, their combined concentration was changed
experimentation led to identifying the Lehnert’s report,19—24) from 1.1ꢁ10ꢂ2 to 8.8ꢁ10ꢂ2 M. The tautomeric ratio deter-
which was demonstrated to be the most effective means of mined by H-NMR at 25 °C remained unaffected at 1.5 : 1
1
preparing 17 by the Knoevenagel-type condensation: when throughout the concentrations varied. In contrast, the tau-
10 (1.0 eq) and 9 (2.0 eq) were treated with TiCl4 (1.0 eq) in tomeric ratio changed in a temperature-dependent manner.
1
the presence of pyridine (4.0 eq) in tetrahydrofuran (THF) at When the H-NMR spectra were measured at temperatures
room temperature for 12 h, 17 was obtained in 44% yield increased from 25 to 105 °C, the ratio decreased from 1.5 : 1
(Chart 3).4,5)
to 1.3 : 1. When the mixture was cooled to 25 °C, the ratio
Having secured 17 in quantity, we turned our attention to- was restored to the original value. Although the change in the
wards the synthesis of 11 (Chart 3). When 17 was treated composition was not large over the range of temperatures
with thiourea 8 in the presence of HCl according to the typi- tested, it was such the temperature-dependent interconverti-
cal procedures of the three-component Biginelli reaction, the bility that corroborated the tautomeric relationship between
expected 2-thione product 11 was obtained in a low yield of 12 and 13.
1%. In contrast, the Atwal–Biginelli cyclocondensation reac-
Now that the Knoevenagel-type condensation between the
tion proceeded successfully with 17 and S-methylisothiourea b-oxoester 10 and the ketone 9 had provided 17 in good yield
hemisulfate salt 3 to afford 1,4-dihydro-4,4,6-trimethyl-2- under the Lehnert conditions,4,5) we chose to apply those con-
methylthiopyrimidine-5-carboxylate 12 and its 1,6-dihydro ditions to the synthesis of a range of 2-(gem-disubstituted)-
tautomer 13 as an inseparable mixture [12/13 (1.5 : 1)] in a methylene-3-oxoesters 4. The Lehnert’s procedures worked

December 2011
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Table 1. Synthesis of 2-(gem-Disubstituted)methylene-3-oxoesters 4 under Lehnert Conditions for the Knoevenagel-Type Reactiona)
Entry
R1
R2
R3
R4
Yield (%)
1
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
CH2Ph
Et
47
37
17
16
11
15
7
2
3
4b,c)
5b,c,d)
6b,d,e)
7b,c,d)
Me
Me(CH2)2
Me
Me(CH2)4
Me(CH2)2
Me
Et
Et
Et
g
Ph
Et
Me
Et
8b,d, f)
h
Me
Et
7
a) General conditions: a mixture of 18 (80 mmol), 19 (40 mmol), TiCl4 (40 mmol) and pyridine (160 mmol) in THF (40 ml) was stirred at room temperature for 12 h under an
atmosphere of argon unless otherwise specified. b) For 24 h. c) 18 (1.0 eq) was used. d) TiCl4 (2.0 eq) was used. e) 18 (3.0 eq) and pyridine (6.0 eq) were used at 40 °C.
f) 18 (1.0 eq), 19 (1.5 eq), TiCl4 (3.0 eq) and pyridine (6.0 eq) were used.
for the Knoevenagel-type condensation of the aliphatic ke- ucts 1c/2c and 1e/2e in acceptable yields (entries 3, 5).
tones 18a—f and the aromatic ketones 18g and h to afford When starting from ethyl 2-isopropylidene-3-phenyl-3-oxo-
the expected products 4a—f, as summarized in Table 1.
propanoate 4f, prepared from ethyl benzoylacetate 19f, a
Lehnert reported that ketones could undergo the Knoeve- phenyl group could be installed at the 6-position of 1f/2f al-
nagel-type condensation with dialkyl malonate in the pres- though 3 needed to be used in 3.0 eq to gain an acceptable
ence of TiCl4 and pyridine,4) with the use of 3-oxoester being yield (entry 6). A phenyl group could also be accommodated
limited to the condensation reaction with aldehydes.5) Thus, at the 4-position, as illustrated by 1g/2g (entry 7). Further-
the experimental results in Table 1 are the first successful ex- more, a fluorenylidene group could be appended to the dihy-
pansion of the Lehnert procedures to the Knoevenagel-type dropyrimidine skeleton, as shown by 1h/2h (entry 8).
condensation between 3-oxoesters and ketones.
With a variety of 2-(gem-disubstituted)methylene-3-oxo- Conclusion
esters 4 (17, 4a—h) in hand, the stage was set for assembling
In summary, it was demonstrated that alkyl 1,4-dihydro-2-
1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine 1 methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1
and its 1,6-dihydro tautomeric isomer 2, both of which had (12, 1a—h) and its 1,6-dihydro tautomer 2 (13, 2a—h) could
remained otherwise inaccessible. With all these substrates, be assembled by applying the Atwal–Biginelli cycloconden-
17 and 4a—h, the Atwal–Biginelli cyclocondensation reac- sation reaction to 2-(gem-disubstituted)methylene-3-oxo-
tion [3 (1.2 eq), NaHCO3 (4.0 eq), DMF, 65 °C, 12 h)] pro- esters 4 (17, 4a—h), which, in turn, was prepared from ke-
ceeded uneventfully to give 1,4-dihydro-2-methylthio pyrimi- tones, 9 and 18a—h, and 3-oxoesters, 10 and 19a—h, by re-
dine 1 and its 1,6-dihydro tautomer 2 in a fair to good yield, sorting to the Lehnert conditions for the Knoevenagel-type
as listed in Table 2.
condensation. In view of the fact that all the dihydropyrimi-
What is worth making comments with respect to the tabu- dine derivatives reported in this article are new in spite of
lated results are as follows. In addition to ethyl ester 17 their existence as inseparable tautomeric mixtures, the syn-
(Chart 3), the methyl and benzyl esters 4a and 4b, respec- thetic procedures developed in our laboratory should help to
tively, were tolerated in the reaction, and the corresponding expand the dihydropyrimidine-based molecular diversity,
products 1a/2a and 1b/2b could be obtained without incident which would impact the drug discovery program.6)
(entries 1, 2). Their alkylidene substituents being sterically
Experimental
demanding, 4c and 4e underwent olefin isomerization to-
wards deconjunction under the basic conditions applied so
that steric congestion can be relieved; however, when 3
was used in excess amounts, the cyclocondensation could
compete with the isomerization to afford the respective prod-
All melting points were determined with an AS ONE melting point appa-
ratus ATM-02 without correction. IR spectra were measured on a JASCO
FT/IR-6100. 1H-NMR spectra were recorded on a Bruker AVANCETM III
600 (600 MHz) with tetramethylsilane (0 ppm) or dimethylsulfoxide (2.49
ppm) as an internal standard. 13C-NMR spectra were recorded on a Bruker

1462
Vol. 59, No. 12
Table 2. Synthesis of Alkyl 1,4-Dihydro-2-methylthio-4,4,6-trisubstituted Pyrimidine-5-carboxylate 1 and Its 1,6-Dihydro Tautomer 2 under Atwal–
Biginelli Conditionsa)
Entry
R1
R2
R3
R4
Yieldb) (%)
1/2c)
1
a
b
c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2Ph
Et
84
68
63
80
63
1.5 : 1
1.6 : 1
8.4 : 1
1.7 : 1
1.8 : 1
2
3d)
4e)
5d)
d
e
Me
Me(CH2)4
Me(CH2)2
Et
Me(CH2)2
Et
6d)
7 f)
f
Me
Ph
Me
Et
Ph
Et
Et
73
63
1 : 3.7
3.0 : 1
g
Me
8
h
Me
Et
40
6.0 : 1
a) General conditions: a mixture of 3 (0.6 mmol), 4 (0.5 mmol), NaHCO3 (2.0 mmol) and DMF (1.0 ml) was stirred and heated at 65 °C for 12 h under an atmosphere of argon
1
unless otherwise specified. b) A combined yield of 1 and 2. c) Determined by H-NMR spectroscopy featuring NOE experiment. d) 3 (3.0 eq) was used. e) With 4d was
used a (2.5 : 1) mixture of the E/Z isomers. f) With 4g was used a single geometric isomer although its configuration was unidentified.
Fig. 2. NOE and HSQC Observed with 15 and 16
AVANCETM III 600 (150 MHz) with chloroform (77.0 ppm) or dimethylsul- signment was made unambiguously by NOESY experiment: With the major
foxide (39.7 ppm) as an internal standard. Mass spectra were recorded on a component, the significant NOE was observed between 1-NH proton (d
JEOL JMS-700. High-resolution mass spectroscopy (HRMS) was performed
using a JEOL JMS-700. Column chromatography was performed on silica
gel 60 (nacalai tesque, 70—230 mesh) using the indicated solvents. TLC
9.58) and 6-methyl protons (d 2.21) and as such, its structure was deter-
mined to be 15 (Fig. 2). With the minor component, the significant NOE was
observed between 1-NH proton (d 9.06) and 6-proton (d 5.24) and as such,
was performed using pre-coated silica gel 60 F254 plates (Merck KGaA) its structure was determined to be 16 (Fig. 2). 13C-NMR (150 MHz, DMSO-
using the indicated solvents.
d6) d: 12.7 (unresolved), 14.3 (unresolved), 17.7, 23.3, 53.3, 59.0, 59.2,
Ethyl 1,4-Dihydro-6-methyl-2-methylthio-4-phenyl Pyrimidine-5-car- 59.3, 98.4, 103.4, 126.4, 126.7, 126.8, 127.7, 128.3, 128.6, 145.0, 145.9,
boxylate (15) and Ethyl 1,6-Dihydro-4-methyl-2-methylthio-6-phenyl
Pyrimidine-5-carboxylate (16) Under an atmosphere of argon, a mixture
of S-methylisothiourea hemisulfate (3; 84 mg, 0.6 mmol), 14 [109 mg,
0.5 mmol, E/Z (1 : 3.0)],15) NaHCO3 (168 mg, 2.0 mmol), and dry DMF
(1.0 ml) was heated at 60 °C for 5 h. To the reaction mixture was added
EtOAc (20 ml) followed by water (10 ml), and the organic layer was sepa-
rated. The aqueous layer was extracted with EtOAc (20 mlꢁ2), and the com-
bined organic layer and extracts were washed with water, brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified
by flash column chromatography [n-hexane–EtOAc (2 : 1)] to give 15 and 16
as an inseparable mixture (97 mg, 0.33 mmol, 67%) in a ratio of 2.2 : 1 in
favor of 15. Colorless crystals. Melting point (mp) 168—171 °C (chloro-
146.2, 150.6, 155.2, 160.9, 166.36, 166.43. The unresolved signals, d 12.7
and d 14.3, were further analyzed by heteronuclear single-quantum coher-
ence (HSQC) experiment, which revealed that the signal at dC 12.7 was due
to the S-CH3 of 15 and 16 because of its correlation to the signals at dH 2.27
(s, 15) and dH 2.38 (s, 16) and that dC 14.3 was due to the OCH2CH3 of 15
and 16 because of its correlation to attached to the signals dH 1.11 (t, 15)
and dH 1.10 (t, 16) (Fig. 2). IR (KBr) cmꢂ1: 3320, 1657, 1470, 1281, 1155,
1109. Electron ionization (EI)-MS m/z: 290.1083 (Calcd for C15H18N2O2S:
290.1089). MS m/z: 290 (Mꢃ), 261, 213, 185.
Ethyl 2-Acetyl-3-methylbut-2-enoate (17) According to the proce-
dures reported by Lernert,4,5) a solution of ethyl acetoacetate (10; 5.2 g,
40 mmol), acetone (9; 5.8 ml, 80 mmol), and pyridine (12.6 g, 160 mmol) in
form). 1H-NMR [dimethyl sulfoxide (DMSO)-d6] d: 1.10 (0.94H, t, Jꢀ dry THF (15 ml) was added to an ice-cooled solution of TiCl4 (4.4 ml, d
7.2 Hz, 16), 1.11 (2.06H, t, Jꢀ7.2 Hz, 15), 2.21 (2.06H, s, 15), 2.26 (0.94H, 1.73, 40 mmol) in dry THF (25 ml) at 0 °C under an atmosphere of argon.
s, 16), 2.27 (2.06H, s, 15), 2.38 (0.94H, s, 16), 3.94—4.05 (2H, m, 15ꢃ16), The reaction mixture was stirred at room temperature for 12 h, and EtOAc
5.24 (0.31H, d, Jꢀ3.0 Hz, 16), 5.50 (0.69H, s, 15), 7.15—7.35 (5H, m, (150 ml) and water (30 ml) were added. The organic layer was separated, and
15ꢃ16), 9.06 (0.31H, d, Jꢀ3.0 Hz, 16), 9.58 (0.69H, s, 15). Structural as- the aqueous layer was extracted with EtOAc (50 mlꢁ2). The combined or-

December 2011
1463
Fig. 3. NOE and HSQC Observed with 12 and 13
ganic layer and extracts were washed with saturated NaHCO3 aqueous solu-
tion, water, brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography [n-
Ethyl 1,4-Dihydro-4,4,6-trimethyl-2-methylthio Pyrimidine-5-car-
boxylate (12) and Ethyl 1,6-Dihydro-4,6,6-trimethyl-2-methylthio Py-
rimidine-5-carboxylate (13) Under an atmosphere of argon, a mixture of
hexane–EtOAc (20 : 1)] to give 17 (3.0 g, 17.6 mmol, 44%), the 1H-NMR S-methylisothiourea hemisulfate (3; 84 mg, 0.6 mmol), 17 (85 mg,
spectral data of which were identical to those reported ones.25)
0.5 mmol), and NaHCO3 (168 mg, 2.0 mmol) in dry DMF (1.0 ml) was
heated at 65 °C for 12 h. To the reaction mixture was added EtOAc (20 ml)
followed by water (10 ml), and the organic layer was separated. The aqueous
layer was extracted with EtOAc (20 mlꢁ2), and the combined organic layer
and extracts were washed with water, brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by flash column
chromatography [n-hexane–EtOAc (4 : 1)] to give 12 and 13 as an insepara-
ble mixture (108 mg, 0.45 mmol, 89%) in a ratio of 1.5 : 1 in favor of 12.
2-(gem-Disubstituted)methylene-3-oxoester (4a—h) The 2-(gem-di-
substituted)methylene-3-oxoesters 4a—h, were all assembled under the
conditions similar to those described for the synthesis of 17,4,5) and below
recorded are their isolated yield and their physicochemical and spectral data
while the spectral data of 4c (yield: 17%) and 4f (yield: 15%) were identical
to those reported ones.25) Analysis and identification of the unresolved signal
in the 13C-NMR spectrum of 4h were made based on HSQC experiment.
Methyl 2-Acetyl-3-methylbut-2-enoate (4a): Colorless oil. Yield: 47%.
1
Colorless crystals. mp 93—94 °C (n-hexane–EtOAc). H-NMR (DMSO-d6)
1H-NMR (CDCl3) d: 1.95 (3H, s), 2.11 (3H, s), 2.29 (3H, s), 3.77 (3H, s). d: 1.18 (1.8H, t, Jꢀ7.2 Hz, 12), 1.19 (1.2H, t, Jꢀ7.2 Hz, 13), 1.26 (3.6H, s,
13C-NMR (CDCl3) d: 22.9, 23.2, 30.6, 51.7, 131.8, 153.6, 166.0, 200.6. IR
(neat) cmꢂ1: 2953, 1727, 1698, 1632, 1233. Chemical ionization (CI)-MS
m/z: 156.1764 (Calcd for C8H12O3: 156.0787). MS m/z: 156 (Mꢃ), 125.
Benzyl 2-Acetyl-3-methylbut-2-enoate (4b): Colorless oil. Yield: 37%.
12), 1.28 (2.4H, s, 13), 1.90 (1.8H, s, 12), 1.94 (1.2H, s, 13), 2.24 (1.8H, s,
12), 2.32 (1.2H, s, 13), 4.05 (1.2H, q, Jꢀ7.2 Hz, 12), 4.07 (0.8H, q,
Jꢀ7.2 Hz, 13), 8.07 (0.4H, s, 13), 9.13 (0.6H, s, 12). Structural assignment
was made unambiguously by NOESY experiment: With the major compo-
1H-NMR (CDCl3) d: 1.95 (3H, s), 2.10 (3H, s), 2.23 (3H, s), 5.22 (2H, s), nent, the significant NOE was observed between 1-NH proton (d 9.13) and
7.30—7.42 (5H, m). 13C-NMR (CDCl3) d: 23.0, 23.3, 30.7, 66.5, 128.2, 6-methyl protons (d 1.90) and as such, its structure was determined to be 12
128.3, 128.5, 131.8, 135.3, 154.0, 165.4, 200.3. IR (neat) cmꢂ1: 1723, 1698, (Fig. 3). With the minor component, the significant NOE was observed be-
1224, 1198. CI-MS m/z: 233.1189 (Calcd for C14H17O3: 233.1177). MS m/z: tween 1-NH (d 8.07) and 6,6-dimethyl protons (d 1.28) and as such, its
233 (MꢃꢃH), 125, 91.
Ethyl 2-Acetyl-3-methyloct-2-enoate (4d): Colorless oil. Yield: 16%. An
structure was determined to be 13 (Fig. 3). 13C-NMR (DMSO-d6) d: 12.4,
12.5, 14.3 (unresolved), 17.8, 23.2, 29.1, 31.0, 53.3, 55.8, 59.27, 59.33,
inseparable (2.5 : 1) mixture of the E/Z isomers with theie structural assign- 105.0, 110.2, 141.7, 147.4, 150.2, 159.7, 167.0, 167.2. The unresolved sig-
ment being impossible by the ordinary spectroscopic methods. 1H-NMR nal, d 14.3, was further analyzed by HSQC experiment, which revealed that
(CDCl3) d: 0.89 (0.86H, t, Jꢀ7.2 Hz), 0.90 (2.14H, t, Jꢀ7.2 Hz), 1.25—1.37 the signal at dC 14.3 was due to the OCH2CH3 of 12 and 13 because of its
(7H, m), 1.45—1.53 (2H, m), 1.95 (2.14H, s), 2.09 (0.86H, s), 2.18 (0.57H, correlation to the signals at dH 1.18 (t, 12) and dH 1.19 (S, 13) (Fig. 3). IR
t, Jꢀ7.8 Hz), 2.28 (2.14H, s), 2.29 (0.86H, s), 2.38 (1.43H, t, Jꢀ7.8 Hz), (KBr) cmꢂ1: 3154, 2929, 1698, 1643, 1609, 1485, 1311, 1171. EI-MS m/z:
4.23 (0.57H, q, Jꢀ7.2 Hz), 4.24 (1.43H, q, Jꢀ7.2 Hz). 13C-NMR (CDCl3) d: 242.1088 (Calcd for C11H18N2O2S: 242.1089). MS m/z: 242 (Mꢃ), 227, 199.
13.8, 13.9, 14.0, 20.5, 21.1, 22.3, 22.4, 27.65, 27.67, 30.5, 30.9, 31.75,
31.83, 36.5, 36.8, 60.6, 60.7, 131.86, 131.89, 157.1, 165.6, 166.0, 200.0,
200.7. IR (neat) cmꢂ1: 2958, 2933, 1725, 1703, 1626, 1227. EI-MS m/z:
226.1578 (Calcd for C13H22O3: 226.1569). MS m/z: 226 (Mꢃ), 151, 43.
Ethyl 2-Acetyl-3-propylhex-2-enoate (4e): Colorless oil. Yield: 11%.
1H-NMR (CDCl3) d: 0.94 (3H, t, Jꢀ7.2 Hz), 0.96 (3H, t, Jꢀ7.2 Hz), 1.30
(3H, t, Jꢀ7.2 Hz), 1.45—1.55 (6H, m), 2.17 (2H, t, Jꢀ7.8 Hz), 2.28 (3H, s),
1,4-Dihydro-2-methylthio-4,4,6-trisubstituted Pyrimidine-5-carboxy-
lates and 1,4-Dihydro-2-methylthio-4,6,6-trisubstituted Pyrimidine-5-
carboxylates (1a—h/2a—h) A tautomeric mixture of 1a—h/2a—h were
synthesized according to the same procedures as described for the synthesis
of the mixture of 12 and 13; below listed are their isolated yield and their
physicochemical and spectral data for 1a—h/2a—h. Analysis and identifica-
tion of the unresolved signals in the 13C-NMR spectra of 1a—b/2a—b,
2.38 (2H, t, Jꢀ7.8 Hz), 4.23 (2H, q, Jꢀ7.2 Hz). 13C-NMR (CDCl3) d: 14.1, 1d—e/2d—e and 1g/2g were made based on HSQC experiment.
14.3, 14.4, 21.86, 21.93, 30.9, 35.7, 36.4, 60.7, 132.0, 160.8, 165.8, 200.5. Methyl 1,4-Dihydro-4,4,6-trimethyl-2-methylthio Pyrimidine-5-car-
IR (neat) cmꢂ1: 2964, 1724, 1698, 1615, 1205. CI-MS m/z: 227.1638 (Calcd boxylate (1a) and Methyl 1,6-Dihydro-4,6,6-trimethyl-2-methylthio
for C13H23O3: 227.1647). MS m/z: 227 (MꢃꢃH), 185, 153.
Pyrimidine-5-carboxylate (2a): Colorless crystals. Yield: 84%. 1a/2aꢀ
1.5 : 1. mp 85—86 °C (n-hexane). 1H-NMR (DMSO-d6) d: 1.26 (3.6H, s,
1a), 1.28 (2.4H, s, 2a), 1.90 (1.8H, s, 1a), 1.95 (1.2H, s, 2a), 2.25 (1.8H, s,
1a), 2.33 (1.2H, s, 2a), 3.59 (1.8H, s, 1a), 3.60 (1.2H, s, 2a), 8.10 (0.4H, s,
Ethyl 2-Acetyl-3-phenylpent-2-enoate (4g): Colorless oil. Yield: 7%. A
1
single geometric isomer with its configuration being unidentified. H-NMR
(CDCl3) d: 1.01 (3H, t, Jꢀ7.2 Hz), 1.32 (3H, t, Jꢀ7.2 Hz), 1.83 (3H, s),
2.73 (2H, q, Jꢀ7.2 Hz), 4.28 (2H, t, Jꢀ7.2 Hz), 7.17—7.21 (2H, m), 7.35— 2a), 9.16 (0.6H, s, 1a). Exact structural assignment was made using NOESY
7.40 (3H, m). 13C-NMR (CDCl3) d: 12.4, 14.0, 29.5, 30.8, 61.0, 127.8, experiment: With the major component, the significant NOE was observed
128.5, 128.7, 133.7, 139.2, 157.3, 165.5, 201.5. IR (neat) cmꢂ1: 2979, 1723, between 1-NH proton (d 9.16) and 6-methyl protons (d 1.90) and as such,
1703, 1233, 1204. EI-MS m/z: 246.1255 (Calcd for C15H18O3: 246.1256).
its structure was determined to be 1a (Fig. 4). With the minor component,
the significant NOE was observed between 1-NH (d 8.10) and 6,6-dimethyl
protons (d 1.28) and as such, its structure was determined to be 2a (Fig. 4).
MS m/z: 246 (Mꢃ), 200, 134, 105, 77.
Ethyl 2-Fluoren-9-ylidene-3-oxobutanoate (4h): Yellow crystals. Yield:
7%. mp 62—63 °C (n-hexane). 1H-NMR (CDCl3) d: 1.40 (3H, t, Jꢀ7.2 Hz), 13C-NMR (DMSO-d6) d: 12.5 (unresolved), 17.8, 23.3, 29.1, 31.0, 50.7 (un-
2.62 (3H, s), 4.44 (2H, q, Jꢀ7.2 Hz), 7.19 (1H, dt, Jꢀ1.2, 7.8 Hz), 7.23 (1H,
resolved), 53.3, 55.8, 104.8, 110.0, 142.0, 147.3, 150.5, 159.9, 167.7. The
dt, Jꢀ1.2, 7.8 Hz), 7.38 (1H, dt, Jꢀ1.2, 7.8 Hz), 7.39 (1H, dt, Jꢀ1.2, unresolved signals, d 12.5 and d 50.7, were further analyzed by HSQC ex-
7.8 Hz), 7.49 (1H, d, Jꢀ7.8 Hz), 7.631 (1H, d, Jꢀ7.8 Hz), 7.632 (1H, d, periment, which revealed that the signal at dC 12.5 was due to the S-CH3 of
Jꢀ7.8 Hz), 7.83 (1H, d, Jꢀ7.8 Hz). 13C-NMR (CDCl3) d: 14.0, 31.1, 62.2,
1a and 2a because of its correlation to the signals at dH 2.25 (s, 1a) and dH
119.7, 119.9, 125.4, 125.7, 127.6, 127.7, 130.6 (unresolved), 131.8, 135.45, 2.33 (s, 2a) and that dC 50.7 was due to the OCH3 of 1a and 2a because of
135.50, 140.1, 141.4, 141.5, 165.2, 201.2. The unresolved signal, d 130.6 its correlation to attached to the signals dH 3.59 (s, 1a) and dH 3.60 (s, 2a)
was further analyzed by HSQC experiment, which revealed that its correla-
(Fig. 4). IR (KBr) cmꢂ1: 2929, 1708, 1649, 1609, 1486, 1316, 1173. EI-MS
tion to the signals at dH 7.38 (dt) and dH 7.39 (dt). IR (KBr) cmꢂ1: 1721, m/z: 228.0939 (Calcd for C10H16N2O2S: 228.0933). MS m/z: 228 (Mꢃ), 213,
1688, 1584, 1226, 1210. EI-MS m/z: 292.1092 (Calcd for C19H16O3: 181.
292.1100). MS m/z: 292 (Mꢃ), 263, 205, 176.
Benzyl 1,4-Dihydro-4,4,6-trimethyl-2-methylthio Pyrimidine-5-car-

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Vol. 59, No. 12
Fig. 4. NOE and HSQC Observed with 1a and 2a
Fig. 5. NOE and HSQC Observed with 1b and 2b
carboxylate (1d) and Ethyl 1,6-Dihydro-4,6-dimethyl-2-methylthio-6-
pentyl Pyrimidine-5-carboxylate (2d): Colorless oil. Yield: 80%.
1
1d/2dꢀ1.7 : 1. H-NMR (DMSO-d6) d: 0.81 (1.89H, t, Jꢀ7.2 Hz, 1d), 0.82
(1.11H, t, Jꢀ7.2 Hz, 2d), 1.00—1.38 (7H, m, 1dꢃ2d), 1.175 (1.89H, t,
Jꢀ7.2 Hz, 1d), 1.178 (1.11H, t, Jꢀ7.2 Hz, 2d), 1.22 (1.89H, s, 1d), 1.25
(1.11H, s, 2d), 1.82—1.94 (1H, m, 1dꢃ2d), 1.92 (1.89H, s, 1d), 1.97
(1.11H, s, 2d), 2.24 (1.89H, s, 1d), 2.32 (1.11H, s, 2d), 4.00—4.09 (2H, m,
1dꢃ2d), 7.93 (0.37H, s, 2d), 9.03 (0.63H, s, 1d). Exact structural assign-
ment was made using NOESY experiment: with the major component, the
significant NOE was observed between 1-NH proton (d 9.03) and 6-methyl
protons (d 1.92) and as such, its structure was determined to be 1d (Fig. 7).
With the minor component, the significant NOE was observed between 1-
NH (d 7.93) and 6-methyl protons (d 1.25) and as such, its structure was de-
termined to be 2d (Fig. 7). 13C-NMR (DMSO-d6) d: 12.4, 12.5, 14.1 (unre-
solved), 14.3 (unresolved), 17.9, 22.3, 23.5, 24.2, 24.7, 29.6, 30.9, 31.7,
31.8, 40.9, 42.5, 56.9, 59.1, 59.2, 59.3, 102.9, 107.8, 142.8, 147.3, 151.5,
160.0, 167.2, 167.4. The unresolved signals, d 14.1 and d 14.3, were further
analyzed by HSQC experiment, which revealed that the signal at dC 14.1
was due to the CH2CH2CH2CH2CH3 of 1d and 2d because of its correlation
to the signals at dH 0.81 (t, 1d) and dH 0.82 (t, 2d) and that dC 14.3 was due
to the OCH2CH3 of 1d and 2d because of its correlation to attached to the
signals dH 1.175 (t, 1d) and dH 1.178 (t, 2d) (Fig. 7). IR (neat) cmꢂ1: 3313,
2927, 1674, 1487, 1138. EI-MS m/z: 298.1720 (Calcd for C15H26N2O2S:
298.1715). MS m/z: 298 (Mꢃ), 227, 199.
Fig. 6. NOE Observed with 1c
boxylate (1b) and Benzyl 1,6-Dihydro-4,6,6-trimethyl-2-methylthio
Pyrimidine-5-carboxylate (2b): Colorless oil. Yield: 68%. 1b/2bꢀ1.6 : 1.
1H-NMR (DMSO-d6) d: 1.27 (3.69H, s, 1b), 1.28 (2.31H, s, 2b), 1.91
(1.85H, s, 1b), 1.96 (1.15H, s, 2b), 2.25 (1.85H, s, 1b), 2.33 (1.15H, s, 2b),
5.09 (1.23H, s, 1b), 5.11 (0.77H, s, 2b), 7.28—7.41 (5H, m, 1bꢃ2b), 8.13
(0.38H, s, 2b), 9.20 (0.62H, s, 1b). Exact structural assignment was made
using NOESY experiment: with the major component, the significant NOE
was observed between 1-NH proton (d 9.20) and 6-methyl protons (d 1.91)
and as such, its structure was determined to be 1b (Fig. 5). With the minor
component, the significant NOE was observed between 1-NH (d 8.13) and
6,6-dimethyl protons (d 1.28) and as such, its structure was determined to be
2b (Fig. 5). 13C-NMR (DMSO-d6) d: 12.5 (unresolved), 18.0, 23.4, 29.2,
31.1, 53.4, 55.9, 65.4 (unresolved), 104.6, 109.9, 128.2, 128.4, 128.7, 136.6,
142.6, 147.4, 151.1, 160.1, 167.0, 167.1. The unresolved signals, d 12.5 and
d 65.4, were further analyzed by HSQC experiment, which revealed that the
signal at dC 12.5 was due to the S-CH3 of 1b and 2b because of its correla-
tion to the signals at dH 2.25 (s, 1b) and dH 2.33 (s, 2b) and that dC 65.4 was
due to the OCH2Ph of 1b and 2b because of its correlation to attached to the
signals dH 5.09 (s, 1b) and dH 5.11 (s, 2b) (Fig. 5). IR (neat) cmꢂ1: 3322,
1685, 1522, 1489, 1313, 1131. EI-MS m/z: 304.1249 (Calcd for
C16H20N2O2S: 304.1245). MS m/z: 304 (Mꢃ), 289, 91.
Ethyl 1,4-Dihydro-6-methyl-2-methylthio-4,4-dipropyl Pyrimidine-5-
carboxylate (1e) and Ethyl 1,6-Dihydro-4-methyl-2-methylthio-6,6-
dipropyl Pyrimidine-5-carboxylate (2e): Colorless oil. Yield: 63%.
1
1e/2eꢀ1.8 : 1. H-NMR (DMSO-d6) d: 0.79 (3.86H, t, Jꢀ7.2 Hz, 1e), 0.82
(2.14H, t, Jꢀ7.2 Hz, 2e), 1.09—1.34 (9H, m, 1eꢃ2e), 1.75—1.87 (2H, m,
1eꢃ2e), 1.93 (1.93H, s, 1e), 1.99 (1.07H, s, 2e), 2.24 (1.93H, s, 1e), 2.31
(1.07H, s, 2e), 4.04 (1.29H, q, Jꢀ7.2 Hz, 1e), 4.05 (0.71H, q, Jꢀ7.2 Hz, 2e),
7.77 (0.36H, s, 2e), 8.90 (0.64H, s, 1e). Exact structural assignment was
made using NOESY experiment: with the major component, the significant
NOE was observed between 1-NH proton (d 8.90) and 6-methyl protons (d
1.93) and as such, its structure was determined to be 1e (Fig. 8). With the
minor component, the significant NOE was observed between 1-NH (d 7.77)
and 6-methylene protons (d 1.75—1.87) and as such, its structure was deter-
mined to be 2e (Fig. 8). 13C-NMR (DMSO-d6) d: 12.2, 12.3, 14.3, 14.4, 14.6
(unresolved), 17.8, 18.01, 18.03, 23.8, 44.1, 45.3, 59.06, 59.13, 60.7, 63.0,
100.4, 105.0, 143.7, 147.2, 152.8, 160.3, 167.4, 167.5. The unresolved sig-
nal, d 14.6, was further analyzed by HSQC experiment, which revealed that
the signal at dC 14.6 was due to the CH2CH2CH3 of 1e and 2e because of its
correlation to the signals at dH 0.79 (t, 1e) and dH 0.82 (t, 2e) (Fig. 8). IR
(neat) cmꢂ1: 2958, 1689, 1668, 1658, 1499, 1279, 1139. EI-MS m/z:
298.1714 (Calcd for C15H26N2O2S: 298.1715). MS m/z: 298 (Mꢃ), 255, 227.
Ethyl 1,4-Dihydro-4,4-dimethyl-2-methylthio-6-phenyl Pyrimidine-5-
carboxylate (1f) and Ethyl 1,6-Dihydro-6,6-dimethyl-2-methylthio-4-
phenyl Pyrimidine-5-carboxylate (2f): Colorless crystals. Yield: 73%.
Ethyl 4-Methyl-2-methylthio-1,3-diazaspiro[5,5]undeca-2,5-diene 5-
Carboxylate (1c) and Ethyl 4-Methyl-2-methylthio-1,3-diazaspiro[5,5]
undeca-2,4-diene 5-Carboxylate (2c): Colorless crystals. Yield: 63%.
1
1c/2cꢀ8.4:1. mp 111—112 °C (n-hexane). H-NMR (DMSO-d6) d: 1.10—
1.90 (13.32H, m, 1cꢃ2c), 1.83 (2.68H, s, 1c), 2.31 (2.68H, s, 1c), 2.32
(0.32H, s, 2c), 4.06 (1.79H, q, Jꢀ7.2 Hz, 1c), 4.09 (0.21H, q, Jꢀ7.2 Hz, 2c),
7.75 (0.11H, s, 2c), 9.10 (0.89H, s, 1c). Exact structural assignment was
made using NOESY experiment: with the major component, the significant
NOE was observed between 1-NH proton (d 9.10) and 6-methyl protons (d
1.83) and as such, its structure was determined to be 1c (Fig. 6). 13C-NMR
(DMSO-d6) d: 12.6, 12.8, 14.3, 17.5, 19.8, 21.0, 22.3, 25.0, 25.9, 34.4, 36.9,
54.9, 57.6, 59.4, 59.6, 106.1, 112.0, 140.3, 146.9, 147.2, 159.4, 167.5. IR
(KBr) cmꢂ1: 3293, 2944, 2922, 1686, 1656, 1618, 1482, 1141. EI-MS m/z:
282.1408 (Calcd for C14H22N2O2S: 282.1402). MS m/z: 282 (Mꢃ), 239, 209,
154.
1
1f/2fꢀ1 : 3.7. mp 132—134 °C (n-hexane–EtOAc). H-NMR (DMSO-d6) d:
Ethyl 1,4-Dihydro-4,6-dimethyl-2-methylthio-4-pentyl Pyrimidine-5-
0.67 (0.64H, t, Jꢀ7.2 Hz, 1f), 0.77 (2.36H, t, Jꢀ7.2 Hz, 2f), 1.33 (1.28H, s,

December 2011
1465
Fig. 7. NOE and HSQC Observed with 1d and 2d
Fig. 8. NOE and HSQC Observed with 1e and 2e
Fig. 9. NOE Observed with 1f and 2f
Fig. 10. NOE and HSQC Observed with 1g and 2g
1f), 1.34 (4.72H, s, 2f), 2.29 (0.64H, s, 1f), 2.38 (2.36H, s, 2f), 3.70 (0.43H,
q, Jꢀ7.2 Hz, 1f), 3.79 (1.57H, q, Jꢀ7.2 Hz, 2f), 7.21 (0.43H, dd, Jꢀ1.8,
7.8 Hz, 1f), 7.25—7.34 (3.93H, m, 2f), 7.35—7.45 (0.64H, m, 1f), 8.28
(0.79H, s, 2f), 9.52 (0.21H, s, 1f). Exact structural assignment was made
using NOESY experiment: with the major component, the significant NOE
was observed between 1-NH proton (d 8.28) and 6,6-methyl protons (d
1.34) and as such, its structure was determined to be 2f (Fig. 9). With the
minor component, the significant NOE was observed between 1-NH (d 9.52)
and 6-phenyl protons (d 7.21) and as such, its structure was determined to
be 1f (Fig. 9). 13C-NMR (DMSO-d6) d: 12.7, 12.8, 13.46, 13.53, 28.6, 30.2,
53.2, 55.8, 59.3, 59.6, 107.0, 110.9, 127.7, 127.9, 128.0, 128.2, 128.3,
129.1, 135.3, 140.8, 141.4, 147.8, 148.9, 159.7, 167.5, 167.9. IR (KBr)
cmꢂ1: 2976, 1702, 1535, 1499, 1326, 1194, 1051. EI-MS (EI) m/z: 304.1250
(Calcd for C16H20N2O2S: 304.1245). MS (EI) m/z: 304 (Mꢃ), 289, 261.
Fig. 11. NOE Observed with 1h
Ethyl 4-Ethyl-1,4-dihydro-6-methyl-2-methylthio-4-phenyl Pyrimi- 147.9, 149.0, 150.3, 153.5, 159.8, 166.95, 167.0. The unresolved signal, d
dine-5-carboxylate (1g) and Ethyl 6-Ethyl-1,6-dihydro-4-methyl-2- 9.8, was further analyzed by HSQC experiment, which revealed that the sig-
methylthio-6-phenyl Pyrimidine-5-carboxylate (2g): Colorless crystals. nal at dC 9.8 was due to the S-CH3 of 1g and 2g because of its correlation to
Yield: 63%. 1g/2gꢀ3.0 : 1. mp 149—150 °C (n-hexane–EtOAc). 1H-NMR the signals at dH 2.23 (s, 1g) and dH 2.34 (s, 2g) (Fig. 10). IR (KBr) cmꢂ1
:
(DMSO-d6) d: 0.80 (2.25H, t, Jꢀ7.2 Hz, 1g), 0.90 (0.75H, t, Jꢀ7.2 Hz, 2g),
0.94 (2.25H, t, Jꢀ7.2 Hz, 1g), 0.95 (0.75H, t, Jꢀ7.2 Hz, 2g), 1.80 (0.25H, (Calcd for C17H22N2O2S: 318.1400). MS m/z: 318 (Mꢃ), 289, 261.
dq, Jꢀ13.8, 7.2 Hz, 2g), 1.87 (0.75H, dq, Jꢀ7.2, 13.2 Hz, 1g), 2.06 (2.25H,
Ethyl 6-Methyl-2-methylthio Spiro[9ꢀH-fluorene-9ꢀ,4-1,4-dihydropy-
s, 1g), 2.13 (0.75H, s, 2g), 2.23 (2.25H, s, 1g), 2.34 (0.75H, s, 2g), 2.36— rimidine] 5-Carboxylate (1h) and Ethyl 4-Methyl-2-methylthio
3264, 2969, 1664, 1583, 1530, 1462, 1314, 1073. EI-MS m/z: 318.1401
2.47 (1H, m, 1gꢃ2g), 3.79—3.92 (2H, m, 1gꢃ2g), 7.11 (0.75H, t,
Jꢀ7.2 Hz, 1g), 7.19 (0.25H, t, Jꢀ7.2 Hz, 2g), 7.23 (1.5H, t, Jꢀ7.2 Hz, 1g),
Spiro[9
ꢄH-fluorene-9ꢄ,6-1,6-dihydropyrimidine] 5-Carboxylate (2h): Yel-
low amorphous solid. Yield: 40%. 1h/2hꢀ6.0 : 1. mp 57—63 °C. H-NMR
1
7.30 (0.5H, t, Jꢀ7.2 Hz, 2g), 7.31 (1.5H, d, Jꢀ7.2 Hz, 1g), 7.37 (0.5H, d, (DMSO-d6) d: 0.35 (2.57H, t, Jꢀ7.2 Hz, 1h), 0.36 (0.43H, t, Jꢀ7.2 Hz, 2h),
Jꢀ7.2 Hz, 2g), 8.45 (0.25H, s, 2g), 9.31 (0.75H, s, 1g). Exact structural as- 2.02 (2.57H, s, 1h), 2.23 (2.57H, s, 1h), 2.27 (0.43H, s, 2h), 2.40 (0.43H, s,
signment was made using NOESY experiment: with the major component,
the significant NOE was observed between 1-NH proton (d 9.31) and 6-
methyl protons (d 2.06) and as such, its structure was determined to be 1g
(Fig. 10). With the minor component, the significant NOE was observed be-
tween 1-NH (d 8.45) and 6-methylene protons (d 1.80) and as such, its
structure was determined to be 2g (Fig. 10). 13C-NMR (DMSO-d6) d: 9.8
(unresolved), 12.4, 12.5, 13.95, 13.98, 18.10, 24.0, 31.3, 32.9, 59.0, 59.1,
62.2, 64.9, 101.0, 105.6, 125.8, 126.4, 126.7, 126.8, 127.5, 127.9, 144.3,
2h), 3.30 (1.71H, q, Jꢀ7.2 Hz, 1h), 3.33 (0.29H, q, Jꢀ7.2 Hz, 2h), 7.19—
7.26 (3.42H, m, 1h), 7.26—7.29 (0.29H, m, 2h), 7.30 (1.71H, dt, Jꢀ1.2,
7.2 Hz, 1h), 7.36 (0.29H, dt, Jꢀ1.2, 7.2 Hz, 2h), 7.40 (0.29H, d, Jꢀ7.8 Hz,
2h), 7.71 (1.71H, d, Jꢀ7.2 Hz, 1h), 7.74 (0.29H, d, Jꢀ7.2 Hz, 2h), 8.75
(0.14H, s, 2h), 9.73 (0.86H, s, 1h). Exact structural assignment was made
using NOESY experiment: with the major component, the significant NOE
was observed between 1-NH proton (d 9.73) and 6-methyl protons (d 2.23)
and as such, its structure was determined to be 1h (Fig. 11). 13C-NMR

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Vol. 59, No. 12
(DMSO-d6) d: 12.4, 12.7, 13.0, 13.1, 18.1, 24.0, 58.4, 58.5, 65.7, 69.4, 99.5,
14) Marzinzik A. L., Felder E. R., J. Org. Chem., 63, 723—727 (1998).
15) Anaç O., Sezer Ö., Candan Ö., Güngör F. S¸., Cansever M. S¸., Tetra-
hedron Lett., 49, 1062—1065 (2008).
105.0, 119.7, 120.0, 124.1, 124.3, 127.7, 127.9, 128.3, 128.8, 139.3, 139.5,
146.6, 150.0, 152.3, 155.0, 155.2, 161.0, 165.8, 165.9. IR (CHCl3) cmꢂ1
:
3298, 1676, 1648, 1483, 1165, 1106. EI-MS m/z: 364.1249 (Calcd for
16) Matloobi M., Kappe C. O., J. Comb. Chem., 9, 275—284 (2007).
17) Kappe C. O., Roschger P., J. Heterocycl. Chem., 26, 55—64 (1989).
18) Tietze L. F., Beifuss U., “Comprehensive Organic Synthesis,” Vol. II,
Chap. 1.11, ed. by Trost B. M., Pergamon Press, Oxford, 1991, pp.
341—394.
C21H20N2O2S: 364.1245). MS m/z: 364 (Mꢃ), 291.
Acknowledgements Y. N. thanks Prof. Hidetsura Cho, Graduate School
of Pharmaceutical Sciences, Graduate School of Sciences, Tohoku Univer-
sity for a helpful discussion in a seminal stage of this work.
19)
According to a literature survey conducted online, there were in-
tramolecular successes of the Knoevenegel-type condensation between
3-oxoesters and ketones, as exemplified by references 20 and 21, while
any of them has no relevance to the present case. As regards an inter-
molecular version of such the condensation reactions, there were few
that could be applied to the transformation in question for the follow-
ing reasons: (1) less availability of the condensation catalysts,22,23) (2)
structural limitation on an electrophile employed.24)
References and Notes
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separately in due course.
20) Kikuchi H., Sasaki K., Sekiya J., Maeda Y., Amagai A., Kubohara Y.,
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of ethyl acetoacetate with acetophenone, which ended in less success
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24) For the condensation of ethyl acetoacetate with an exotic ketone, 21-
dimethylaminomethyleneprogesterone, through the catalytic agency of
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