An efficient synthesis of a class of novel N-alkyl-N-aryl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-3- quinolinecarbothioamides

Article abstract of DOI:10.1002/jhet.5570390427

The novel title compounds have been prepared in high yield by an optimized amide coupling followed by a Dieckmann cyclization. Additionally, this new route is amenable to preparative scale synthesis.

Full text of DOI:10.1002/jhet.5570390427

Jul-Aug 2002
An Efficient Synthesis of a Class of Novel N-Alkyl-N-aryl-4-hydroxy-
799
1-methyl-2-oxo-1,2-dihydro-3-quinolinecarbothioamides
*
Glen W. Spears, Kiyoshi Tsuji, Takashi Tojo, Hiroaki Nishimura and Takashi Ogino
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.,
1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan
Received January 30, 2002
The novel title compounds have been prepared in high yield by an optimized amide coupling followed by
a Dieckmann cyclization. Additionally, this new route is amenable to preparative scale synthesis.
J. Heterocyclic Chem., 39, 799 (2002).
Introduction.
because of the high reactivity in the cyclization step of the
thioamide compared to the ester of 4, a mixture of products
was obtained with the desired 1a as the minor compound.
The product 1a could be easily separated from the by-
product 5 by taking advantage of the relatively high acidity
of 5 compared to 1a (see experimental) and several ana-
logues of 1a were conveniently and quickly synthesized by
Method A as a first approach.
However, when 1a was chosen for further biological
evaluation, we needed access to larger amounts of 1a than
could be synthesized by this convenient albeit low yield
route. We thought it unlikely that the 2:3 ratio of the prod-
ucts could be changed significantly by simply changing
the reaction parameters. A number of different approaches
were considered. Thiolation of the easily obtainable
amides did not appear promising due to competing other
reactive functional groups. Acylation with N-methyl-N-
phenylthiocarbamoyl chloride looked problematic.
Alkylation of the easily obtained 4-hydroxy-1-methyl-6-
(methylthio)-2-oxo-N-phenyl-1,2-dihydro-3-quinolinecar-
bothioamide (6, Equation 3) with methyl iodide did not
provide the desired 1a but the S-methylated 7.
Recently we have been investigating a series of com-
pounds based on the structure of the known immunomodu-
lator, linomide [1] (Figure 1), in order to find a new com-
pound with an improved pharmacological profile (i.e.,
more potent, less toxic). We identified such a compound,
FR142107 (1a, Figure 1), in which linomide has been sub-
stituted in the 6 position by a methylthio moiety and the
exo amide changed to a thioamide [2]. Compound 1a
belongs to a class of newly synthesized compounds, which
is the subject of this paper.
Initially 1a was synthesized using the same procedure as
for linomide except using the thioamide 4 instead of mal-
onamide 2 (Method A, Equations 1 and 2) [3]. However,
Finally we decided to use a stepwise procedure starting
with the anthranilic ester 8a (Method B, Scheme 1).

800
G. W. Spears, K. Tsuji, T. Tojo, H. Nishimura and T. Ogino
Vol. 39
Amide coupling with the appropriate acid 9a followed by
Dieckmann cyclization would provide the desired material
without any regiochemical problems. This method looked
appealing because of the many known methods for amide
coupling [4], and the many examples of similar
Dieckmann cyclizations [5].
(Table 1; entries 1,2). However, using the more reactive
pivaloyl chloride provided a 55% yield on the first
attempt (entry 3). Increasing the equivalents of the acid
9a and reagent relative to the amine 8a increased the
yield, but not in a linear fashion (entry 4). Use of only
pyridine instead of pyridine plus triethylamine gave
another increase in the yield (entry 5), but the use of luti-
dine instead of pyridine (entry 6) or inverse addition
(activated acid added to 8a, entry 7) was not beneficial.
Results and Discussion.
The known isatoic anhydride 3 [6] was converted to the
amine 8a (Scheme 1) in nearly quantitative yield with cat-
alytic sodium ethoxide in refluxing ethanol for 30 minutes
[7]. The preparation of acid 9a has been previously
described by us [8] and proceeds in 93% yield by hydroly-
sis of 4 with aqueous sodium hydroxide in methanol. The
coupling reaction proved more difficult than anticipated.
The weakly basic and hindered secondary amine 8a,
strongly hydrogen bonded to the adjacent ester group, and
the unstable acid 9a provided challenging criteria that
many coupling conditions could not meet. For instance,
although carbodiimide reagents gave some desired cou-
pling product 10a, the main product was 11, probably
obtained by the path shown in Scheme 2. A large amount
of decarboxylation product 12 was also obtained, which
demonstrated the short half-life of the acid 9a in solution.
The Mukaiyama reagent [9] and N,N'-disuccinimidyl car-
bonate (DSC) [10] were also unsatisfactory (63% and 10%
maximum yield respectively).
Finally a modified mixed anhydride method was found
to be acceptable. Using the standard procedure as for
peptide synthesis [11] in which isobutyl chloroformate
was used as the activating reagent, did not perform well
The final improvements came by increasing the equiva-
lents of 9a and pivaloyl chloride to 1.5, and the use of
powdered molecular sieves (4A) (entry 8). The use of
molecular sieves was especially useful for maintaining

Jul-Aug 2002
N-Alkyl-N-aryl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinecarbothioamides
801
consistency between experiments, notably during the hot
and humid summer months in Japan.
Conclusion.
Ethyl N-methylanthranilates 8 were condensed with
thiocarbamoylacetic acids 9 activated by the mixed anhy-
dride method using pivaloyl chloride, followed by
Dieckmann cyclization to give various N-alkyl-N-aryl-4-
hydroxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinecarboth-
ioamides 1. According to this new route (Method B), the
overall yield of 1a from the readily available isatoic anhy-
dride 3 was improved to 80% from 25% (by Method A).
This route is applicable to a variety of related compounds
and is also amenable to preparative scale synthesis.
With the synthesis of intermediate 10a completed we
turned our attention to the cyclization. We were gratified to
find that the cyclization proceeds smoothly with 1.1 equiv-
alents sodium ethoxide in absolute ethanol at 5 °C for 30
minutes. Simple dilution with water followed by neutral-
ization with 1.2 equivalents hydrochloric acid yielded
beautiful, light yellow crystals of the desired 1a in 97%
yield and 98% purity.
We have now conducted this reaction reproducibly
under these optimized conditions and found it to give uni-
formly high yields and clean reactions. We have also
applied it to a number of other substrates as shown in
Table 2 and Scheme 3. As can be seen, the reaction pro-
ceeds smoothly with a variety of substituents. When the
acid 9 aryl moiety is unsubstituted or substituted with an
electron releasing substituent, the yields are generally
good (entries 1 to 4). When 9 is substituted with an elec-
EXPERIMENTAL
Melting points were measured on a Mitamura capillary melt-
ing point apparatus and are uncorrected. IR spectra were
recorded on a Shimadzu IR-408 spectrophotometer. H-nmr
1
spectra were taken with a Bruker AC-200 (200 MHz) instrument
using tetramethylsilane as an internal standard. Electron impact
ms were obtained with a Hitachi M80 mass spectrometer.
Atmospheric pressure chemical ionization ms were obtained with
a Hitachi M-1000 LC/QMS spectrometer. Solvents used for
anhydrous reactions were dried over molecular sieves (4A).
Organic extracts were dried over anhydrous magnesium sulfate.
Column chromatography was performed using Kieselgel 60 (70-
230 mesh, E. Merck). The purity of 1a was determined by high
performance liquid chromatography on a TSK gel ODS-80Tm
(5µm) column (10 cm x 4.6 mm) eluting with phosphate buffer
tron withdrawing aryl moiety (CF or Cl) and when the
3
amine 8 is activated (entries 5, 6) yields are high but
decrease when 8 is deactivated with electron withdrawing
substituents (entries 7 to 9). Even in the case of the steri-
cally hindered amine in entry 8 the reaction proceeds in
good yield. The especially demanding cases using the
unstable acids found in entries 10 and 11 show the versa-
tility of this procedure.

802
G. W. Spears, K. Tsuji, T. Tojo, H. Nishimura and T. Ogino
Vol. 39
(pH=3):acetonitrile (3:2) using a UV detector (254 nm) and a
flow rate of 1 ml/min.
The Following Compounds (1a to 1k) were Prepared According
to Method B, Reaction 2.
4-Hydroxy-N,1-dimethyl-6-(methylthio)-2-oxo-N-phenyl-1,2-
dihydro-3-quinolinecarbothioamide (1a).
4-Hydroxy-N,1-dimethyl-6-(methylthio)-2-oxo-N-phenyl-1,2-
dihydro-3-quinolinecarbothioamide (1a).
This compound was obtained as bright yellow crystals.
Analytical data was identical to that obtained above by Method A.
Method A.
A solution of 2.37 g (10 mmol) of ethyl N-methyl-N-phenylthio-
carbamoylacetate (4) and 20 ml dimethylacetamide under nitrogen
was chilled to 10 °C and 0.42 g (10.5 mmol) of sodium hydride was
added. After 15 minutes the cold bath was removed and the reac-
tion was stirred at room temperature for 45 minutes. Then 2.23 g
(10.0 mmol) of N-methyl-5-(methylthio)isatoic anhydride (3) was
added, and the reaction vessel was placed in a 120 °C oil bath for 30
minutes. After cooling to room temperature the reaction mixture
was poured into ice/water (200 ml) and concentrated hydrochloric
acid (1.9 ml) was added. After 30 minutes the solid was collected
by filtration and washed with 0.1 N hydrochloric acid (20 ml) (the
obtained solid was a 2:3 mixture of 1a and 5). The solid was dis-
solved in methylene chloride (100 ml) and washed with a solution
of water (50 ml) plus 1.0 N sodium hydroxide (5 ml). The organic
phase was dried (magnesium sulfate), filtered, and evaporated to
give a residue (2.2 g) as a 15:1 mixture of 1a and 5. This residue
was purified by column chromatography (silica gel-methylene
chloride:methanol) to give a homogeneous solid (1.42 g, 38.4%)
which was recrystallization from diisopropyl ether:chloroform (10
ml, 1:1) to yield 0.91 g (25%) of 1a of sufficient purity for pharma-
cology testing, mp 178 °C (dec.); ir (nujol): 2500-3000, 1640,
4-Hydroxy-N,1-dimethyl-2-oxo-N-phenyl-6-(1H-pyrrol-1-yl)-
1,2-dihydro-3-quinolinecarbothioamide (1b).
This compound was obtained as yellow crystals (water), mp
-1
1
209 °C (dec.); ir (nujol) 3230, 1630, 1580, 1510 cm ; H nmr
(DMSO-d ): δ 3.46 (s, 3H), 3.75 (s, 3H), 6.27 (t, 2H, J=2.1 Hz),
6
7.17-7.39 (m, 5H), 7.35 (t, 2H, J=2.1 Hz), 7.44 (d, 1H, J=9.1 Hz),
7.78 (dd, 1H, J=9.1, 2.7 Hz), 7.89 (d, 1H, J=2.7 Hz), 11.04 (br s,
1H); ms: m/z 390 (M+1), 108.
Anal. Calcd. for C
H N O S: C, 67.85; H, 4.92; N, 10.79.
22 19 3 2
Found: C, 67.98; H, 4.79; N, 10.49.
6-Chloro-4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-1,2-dihydro-
3-quinolinecarbothioamide (1c).
This compound was obtained as yellow crystals (water), mp
218 °C (dec.); ir (nujol) 3150, 1625, 1590, 1570, 1495, 1195,
-1
1
1095 cm ; H nmr (DMSO-d ): δ 3.42 (s, 3H), 3.74 (s, 3H),
6
7.17-7.49 (m, 6H), 7.55 (dd, 1H, J=9.0, 1.8 Hz), 7.81 (d, 1H,
J=1.8 Hz), 11.15 (br s, 1H); ms: m/z 359 (M+1), 284.
Anal. Calcd. for C
H N ClO S: C, 60.25; H, 4.21; N, 7.81.
18 15 2 2
-1
1
Found: C, 60.64; H, 4.07; N, 7.74.
1600, 1565 cm ; ms: m/z 371 (M+1); H nmr (DMSO-d ): δ
6
2.48 (s, 3H), 3.40 (s, 3H), 3.73 (s, 3H), 7.10-7.40 (m, 6H), 7.46 (dd,
1H, J=8.8, 1.9 Hz), 7.68 (d, 1H, J=1.9 Hz), 10.94 (br s, 1H).
6-Chloro-4-hydroxy-N-(4-methoxyphenyl)-N,1-dimethyl-2-oxo-
1,2-dihydro-3-quinolinecarbothioamide (1d).
Anal. Calcd. for C
H N O S : C, 61.60; H, 4.90; N, 7.56.
19 18 2 2 2
This compound was obtained as yellow-green crystals (water),
Found: C, 61.82; H, 4.83; N, 7.51.
-1 1
mp 191 °C (dec.), ir (nujol) 3120, 1630, 1605, 1565 cm , H nmr
General Procedure for the Preparation of N-Alkyl-N-aryl-4-
hydroxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinecarbo-
thioamides 1.
(DMSO-d ): δ 3.43 (s, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 6.78 (d,
6
2H, J=8.9 Hz), 7.28 (d, 2H, J=8.9 Hz), 7.38 (d, 1H, J=9.1 Hz),
7.57 (dd, 1H, J=9.1, 2.4 Hz), 7.82 (d, 1H, J=2.4 Hz), 11.12 (s,
1H); ms: m/z 389 (M+1), 284, 138.
Method B.
Anal. Calcd. for C
H ClN O S: C, 58.69; H, 4.41; N, 7.20.
19 17 2 3
All of these reactions were carried out under a nitrogen atmos-
phere. A suspension of N-alkyl-N-arylthiocarbamoylacetic acid
9 (15 mmol), powdered molecular sieves (4A, 3.0 g), methylene
chloride (50 ml) and pyridine (2.43 ml, 30 mmol) was stirred at
room temperature for 30 minutes. Then the solution was chilled
to –20 °C and pivaloyl chloride (1.84 ml, 15 mmol) was added all
at once. After stirring for 10 minutes at -20 to –25 °C (a precipi-
tate usually appears after a few minutes), the amine 8 (10 mmol)
was added. After stirring for 1 minute at –20 °C, and then at 0 °C
for one hour the reaction was allowed to proceed overnight at
room temperature (about 20 hours). The next day the reaction
solution was diluted with ethyl acetate (100 ml), washed succes-
sively with 0.1 N hydrochloric acid (three times, 50 ml each
time), brine (50 ml), saturated aqueous sodium bicarbonate (three
times, 50 ml each time) and brine (50 ml), dried (magnesium sul-
fate), filtered and evaporated. Purification by column chro-
matography (silica gel-diethyl ether:hexane) provided 10.
Found: C, 59.06; H, 4.35; N, 7.21.
N-(4-Chlorophenyl)-4-hydroxy-6-methoxy-N-1-dimethyl-2-oxo-
1,2-dihydro-3-quinolinecarbothioamide (1e).
This compound was obtained as yellow crystals (water), mp
>290 °C, ir (nujol) 3350, 1620, 1580, 1305, 1220 cm , H nmr
-1
1
(CDCl ): δ 3.31 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 6.98-7.30 (m,
3
6H), 7.50 (d, 1H, J=2.5 Hz), 9.69 (s, 1H); ms: m/z 389(M+1),
280, 142.
Anal. Calcd. for C
H ClN O S: C, 58.69; H, 4.41; N, 7.20.
19 17 2 3
Due to water traces, we were unable to obtain a better elemental
analysis than the following: Found: C, 58.33; H, 4.55; N, 6.73.
4-Hydroxy-6-methoxy-N,1-dimethyl-2-oxo-N-[3-(trifluoro-
methyl)phenyl]-1,2-dihydro-3-quinolinecarbothioamide (1f).
This compound was obtained as yellow crystals (water), mp
193-195 °C, ir (nujol) 3150, 1615, 1580 cm , H nmr (DMSO-d ):
δ 3.39 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 7.17 (dd, 1H, J=10.0, 2.6
Hz), 7.20-7.30 (m, 2H), 7.40-7.54 (m, 2H), 7.60-7.70 (m, 1H), 7.76
(s, 1H), 10.93 (br s, 1H); ms: m/z 423 (M+1), 280, 176.
-1 1
To 10 (5 mmol) dissolved in dry ethanol (25 ml) at 5 °C was
added sodium ethoxide (0.37 g, 5.5 mmol). After 30 minutes
water (100 ml) was slowly added followed by dropwise addition
of 1.0 N hydrochloric acid (6 ml) with good stirring. After 30
minutes at 5 °C, the crystals were collected by filtration, washed
with water, and dried at 40 °C under vacuum to give 1.
6
Anal. Calcd. for C
H F N O S: C, 56.87; H, 4.06; N, 6.63.
20 17 3 2 3
Found: C, 56.87; H, 4.14; N, 6.53.

Jul-Aug 2002
N-Alkyl-N-aryl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinecarbothioamides
803
N-(4-Chlorophenyl)-4-hydroxy-N-1-dimethyl-2-oxo-6-(trifluoro-
methoxy)-1,2-dihydro-3-quinolinecarbothioamide (1g).
4.19 (q, 2H, J=7.1 Hz), 7.05 (d, 1H, J=8.3 Hz), 7.10-7.50 (m,
6H), 7.70 (d, 1H, J=2.3 Hz).
This compound was obtained as yellow crystals (water), mp
290 °C (dec.); ir (nujol) 1625, 1580, 1460, 1380, 1250 cm ; H
Ethyl 2-{Methyl-[2-(methyl-phenyl-thiocarbamoyl)-acetyl]-
amino}-5-pyrrol-1-yl-benzoate (10b).
-1
1
nmr (CDCl ): δ 3.33 (s, 3H), 3.89 (s, 3H), 7.07-7.60 (m, 6H),
7.92 (s, 1H), 9.78 (br s, 1H); ms: m/z 443 (M+1).
3
This compound was obtained as a light green foam, ir (nujol)
-1
1
1720, 1710, 1655 cm ; H nmr (DMSO-d ): δ 1.14 (t, 3H, J=7.1
6
Anal. Calcd. for C
H ClF N O S: C, 51.53; H, 3.19; N,
19 14 3 2 3
Hz), 2.99 (s, 3H), 3.24 (d, 1H, J=15.4 Hz), 3.31 (d, 1H, J=15.4
Hz), 3.59 (s, 3H), 4.18 (m, 2H), 6.32 (t, 2H, J=2.2 Hz), 7.07 (d,
1H, J=8.4 Hz), 7.21 (m, 2H), 7.40-7.51 (m, 5H), 7.81-7.92 (m,
2H); ms: m/z 436 (M+1).
6.33. Found: C, 51.71; H, 2.97; N, 5.99.
6-Chloro-N-(4-chlorophenyl)-4-hydroxy-N-1,8-trimethyl-2-oxo-
1,2-dihydro-3-quinolinecarbothioamide (1h).
This compound was obtained as yellow crystals (water), mp
285-290 °C; ir (nujol) 1620, 1570, 1480 cm , H nmr (DMSO-
Ethyl 5-Chloro-2-{methyl-[2-(methyl-phenyl-thiocarbamoyl)-
acetyl]-amino}-benzoate (10c).
-1
1
d ): δ 2.50 (s, 3H), 3.38 (s, 3H), 3.89 (s, 3H), 7.05 (d, 2H, J=8.0
Hz), 7.16 (d, 2H, J=8.0 Hz), 7.26-7.30 (m, 1H), 7.70 (s, 1H),
6
This compound was obtained as a thick, green oil, ir (neat)
-1
1
1720, 1710, 1690 cm ; H nmr (CDCl ): δ 1.20 (t, 3H, J=7.1
3
10.91 (br s, 1H); ms: m/z 407 (M+1).
Hz), 3.12 (s, 3H), 3.35 (s, 2H), 3.71 (s, 3H), 4.20 (m, 2H),
7.15 (d, 1H, J=8.4 Hz), 7.17-7.44 (m, 5H), 7.49 (dd, 1H,
J=8.4, 2.6 Hz), 7.87 (d, 1H, J=2.6 Hz); ms: m/z 405 (M+1),
192, 108.
1
Anal. Calcd. for C
H
Cl N O S• / H O: C, 54.82; H, 4.12;
19 16
2
2
2
2 2
N, 6.73. Found: C, 54.96; H, 4.21; N, 6.39.
6-Chloro-4-hydroxy-N,1-dimethyl-2-oxo-N-[3-(trifluoro-
methyl)phenyl]-1,2-dihydro-3-quinolinecarbothioamide (1i).
Ethyl 5-Chloro-2-({2-[(4-methoxyphenyl)-methyl-thiocar-
bamoyl]-acetyl}-methylamino)-benzoate (10d).
This compound was obtained as yellow crystals (water), mp
-1
1
>290 °C, ir (nujol) 3350, 1607, 1580 cm , H nmr (DMSO-d ):
6
This compound was obtained as a yellow foam, ir (nujol)
δ 3.41 (s, 3H), 3.77 (s, 3H), 7.38-7.82 (m, 7H), 11.29 (s, 1H); ms:
m/z 427 (M+1), 284, 176.
-1
1
1720, 1655, 1605 cm ; H nmr (CDCl ): δ 1.22 (t, 3H, J=7.1
3
Hz), 3.14 (s, 3H), 3.36 (s, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 4.22 (q,
2H, J=7.1 Hz), 6.82-6.99 (m, 2H), 7.01-7.30 (m, 2H), 7.21 (d,
1H, J=8.4 Hz), 7.51 (dd, 1H, J=8.4, 2.5 Hz), 7.88 (d, 1H, J=2.5
Hz); ms: m/z 435 (M+1), 222, 138.
Anal. Calcd. for C
H ClF N O S•H O: C, 51.30; H, 3.63;
19 14 3 2 2 2
N, 6.30. Found: C, 51.29; H, 3.65; N, 6.18.
6-Chloro-4-hydroxy-N,1-dimethyl-2-oxo-N-(2-thienyl)-1,2-
dihydro-3-quinolinecarbothioamide (1j).
Ethyl 2-({2-[(4-Chlorophenyl)-methyl-thiocarbamoyl]-acetyl}-
methylamino)-5-methoxy-benzoate (10e).
This compound was obtained as white crystals (water), mp
199-201 °C, ir (nujol) 3200, 3090, 1620, 1590 cm , H nmr
-1
1
This compound was obtained as a yellow oil, ir (neat) 1720,
(DMSO-d ): δ 3.47 (s, 3H), 3.74 (s, 3H), 6.76 (dd, 1H, J=5.5, 3.7
1
6
1655, 1285, 1220; H nmr (CDCl ): δ 1.25 (t, 3H, J=7.1 Hz),
3
Hz), 6.99 (dd, 1H, J=3.7, 1.4 Hz), 7.24 (dd, 1H, J=5.5, 1.4 Hz),
7.42 (d, 1H, J=9.1 Hz), 7.59 (dd, 1H, J=9.1, 2.4 Hz), 7.85 (d, 1H,
J=2.4 Hz), 11.25 (s, 1H); ms: m/z 365 (M+1), 284, 114.
3.11 (s, 3H), 3.31 (d, 1H, J=15.0 Hz), 3.34 (d, 1H, J=15.0 Hz),
3.69 (s, 3H), 3.85 (s, 3H), 4.20 (q, 2H, J=7.1 Hz), 6.98-7.27 (m,
4H), 7.37-7.49 (m, 3H); ms: m/z 435 (M+1), 142.
Anal. Calcd. for C
H ClN O S : C, 52.67; H, 3.59; N, 7.68.
16 13 2 2 2
Ethyl 5-Methoxy-2-(methyl-{2-[methyl-(3-trifluoromethyl-
phenyl)thiocarbamoyl]-acetyl}-amino)-benzoate (10f).
Found: C, 52.80; H, 3.55; N, 7.51.
N-(tert-Butyl)-6-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-
1,2-dihydro-3-quinolinecarbothioamide (1k).
This compound was obtained as a yellow oil, ir (neat) 1720,
-1
1
1655, 1495, 1330 cm ; H nmr (CDCl ): δ 1.20 (t, 3H, J=7.1
3
This compound was obtained as yellow crystals (water), mp
Hz), 3.09 (s, 3H), 3.37 (s, 2H), 3.71 (s, 3H), 3.84 (s, 3H), 4.18 (q,
2H, J=7.1 Hz), 6.99-7.10 (m, 2H), 7.30-7.61 (m, 5H); ms: m/z
469 (M+1), 176.
-1
1
198-204 °C, ir (nujol) 1620, 1545, 1455, 1370 cm , H nmr
(CDCl ): δ 1.57 (s, 9H), 3.75 (s, 3H), 6.64 (d, 1H, J=9.1 Hz),
3
6.96-7.12 (m, 5H), 7.26-7.33 (m, 1H), 7.59-7.65 (m, 2H); ms:
Ethyl 2-({2-[(4-Chlorophenyl)-methyl-thiocarbamoyl]-acetyl}-
methylamino)-5-trifluoromethoxy-benzoate (10g).
m/z 150 (PhNHtBu+1).
1
Anal. Calcd. for C
H
ClN O S• / H O: C, 61.98; H, 5.37;
21 21
2
2
3 2
1
N, 6.88. Found: C, 62.03; H, 5.35; N, 6.70.
This compound was obtained as a yellow oil, H nmr (CDCl ):
3
δ 1.25 (t, 3H, J=7.1 Hz), 3.15 (s, 3H), 3.36 (s, 2H), 3.68 (s, 3H),
4.21 (q, 2H, J=7.1 Hz), 7.15-7.50 (m, 6H), 7.75 (s, 1H); ms: m/z
489(M+1), 142.
The Following Compounds (10a to 10k) were Prepared
According to Method B, Reaction 1.
These synthetic intermediates were usually oils or amorphous
solids and thus elemental analyses were not obtained.
Ethyl 5-Chloro-2-({2-[(4-chlorophenyl)-methyl-thiocarbamoyl]-
acetyl}-methylamino)-3-methyl-benzoate (10h).
Ethyl 2-{Methyl-[2-(methyl-phenyl-thiocarbamoyl)-acetyl]-
amino}-5-(methylthio)-benzoate (10a).
This compound was obtained as yellow crystals (diethyl
ether/hexane), mp 160-161 °C, ir (nujol) 1725, 1655, 1280, 1175
-1
1
This compound was obtained as a light green oil, ir (nujol):
cm ; H nmr (CDCl ): δ 1.25 (t, 3H, J=7.1 Hz), 2.23 (s, 3H),
3
-1
1
2990, 2940, 1720, 1655, 1595 cm ; ms: m/z 417 (M+1);
H
3.06 (s, 3H), 3.17 (d, 1H, J=15.0 Hz), 3.32 (d, 1H, J=15.0 Hz),
3.71 (s, 3H), 4.09-4.20 (m, 2H), 7.26-7.43 (m, 5H), 7.69 (d, 1H,
J=2.5 Hz); ms: m/z 453 (M+1), 142.
nmr (CDCl ): δ 1.20 (t, 3H, J=7.1 Hz), 2.51 (s, 3H), 3.12 (s, 3H),
3
3.32 (d, 1H, J=15.2 Hz), 3.42 (d, 1H, J=15.2 Hz), 3.71 (s, 3H),

804
G. W. Spears, K. Tsuji, T. Tojo, H. Nishimura and T. Ogino
Vol. 39
[2] M. Matsuo, K. Tsuji, G. W. Spears, T. Ogino, H.
Nishimura, and T. Tojo, PCT Int. Appl. WO95-24395 (1995); Chem.
Abstr., 124, 117102e (1995).
Ethyl 5-Chloro-2-(methyl-{2-[methyl-(3-trifluoromethyl-
phenyl)thiocarbamoyl]-acetyl}-amino)-benzoate (10i).
This compound was obtained as a yellow oil, ir (neat) 2970,
[3] For similar reactions of activated methylene compounds
with isatoic anhydrides see the following: G. M. Coppola and G. E.
Hardtmann, J. Heterocyclic Chem., 16, 1605 (1979); G. M. Coppola,
G. E. Hardtmann, and O. R. Pfister, J. Org. Chem., 41, 825 (1976); S.
R. Khan, A. Mhaka, R. Pili, and J. T. Isaacs, Bioorg. Med. Chem.
Lett., 11, 451 (2001); G. M. Coppola, R. E. Damon, G. E.
Hardtmann, Synthesis, 391 (1981); L. Ismaili, B. Refouvelet, and J.
F. Robert, J. Heterocyclic Chem., 36, 719 (1999).
[4] G. Benz, Comprehensive Organic Synthesis, Vol. 6, B. M.
Trost, Editor-in-Chief, Pergamon Press, Inc., New York, 1991, p 381.
[5] For related examples of Dieckmann reactions see: B. R.
Davis and P. J. Garratt, Comprehensive Organic Synthesis, Vol. 2, B.
M. Trost, Editor-in-Chief, Pergamon Press, Inc., New York, 1991, p
806; W. Chai and W. V. Murray, Tetrahedron Lett., 40, 7185 (1999);
M. J. Ashton, S. J. Hills, C. G. Newton, J. B. Taylor, S. C. D. Todou,
Heterocycles, 28, 1015 (1989); K. Akiba, M. Nakatani, M. Wada, and
Y. Yamamoto, J. Org. Chem., 50, 63 (1985); I. V. Micovic, G. M.
Roglic, M. D. Ivanovic, L. Dosen-Micovic, V. D. Kiricojevic, and J.
B. Popovic, J. Chem. Soc., Perkin Trans. 1, 2041 (1996).
-1
1
1720, 1655, 1592 cm ; H nmr (CDCl ): δ 1.20 (t, 3H, J=7.1
3
Hz), 3.11 (s, 3H), 3.35 (s, 2H), 3.71 (s, 3H), 4.18 (q, 2H, J=7.1
Hz), 7.11-7.19 (m, 1H), 7.47-7.65 (m, 5H), 7.88 (d, 1H, J=2.4
Hz); ms: m/z 473 (M+1).
Ethyl 5-Chloro-2-{methyl-[2-(methyl-thiophen-2-yl-thiocar-
bamoyl)-acetyl]-amino}-benzoate (10j).
This compound was obtained as a yellow-green waxy solid, ir
-1
1
(neat) 3100, 1720, 1670, 1595, 1535 cm ; H nmr (CDCl ): δ
3
1.28 (t, 3H, J=7.1 Hz), 3.15 (s, 3H), 3.50 (s, 2H), 3.71 (s, 3H),
4.25 (q, 2H, J=7.1 Hz), 6.92 (dd, 1H, J=5.4, 3.6 Hz), 6.98 (dd,
1H, J=3.6, 1.4 Hz), 7.17 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=5.4,
1.4 Hz), 7.50 (dd, 1H, J=8.4, 2.5 Hz), 7.91 (d, 1H, J=2.5 Hz); ms:
m/z 411 (M+1), 129.
Ethyl 2-{[2-(tert-Butyl-phenyl-thiocarbamoyl)-acetyl]-methy-
lamino}-5-chlorobenzoate (10k).
1
This compound was obtained as a yellow oil, H nmr (CDCl ):
3
[6] M. Matsuo, K. Tsuji, K. Nakamura and G. W. Spears, PCT
Int. Appl. WO92-18483 (1992); Chem. Abstr., 118, 212903b (1993).
[7] K. Tsuji, G. W. Spears, K. Nakamura, T. Tojo, N. Seki, A.
Sugiyama and M. Matsuo, Bioorg. Med. Chem. Lett., 12, 85 (2002).
[8] G. W. Spears, K. Tsuji, T. Tojo, H. Nishimura and T.
Ogino, Synth. Commun., 30, 565 (2000).
[9] T. Mukaiyama, Angew. Chem. Int. Ed., 18, 707 (1979).
[10] H. Ogura, T. Kobayashi, K. Shimizu, K. Kawabe and K.
Takeda, Tetrahedron Lett., 20, 4745 (1979).
δ 1.25 (t, 3H, J=7.1 Hz), 1.26 (s, 9H), 2.98 (d, 1H, J=16.1 Hz),
3.23 (d, 1H, J=16.1 Hz), 3.71 (s, 3H), 4.20 (q, 2H, J=7.1 Hz),
6.99-7.07 (m, 1H), 7.14-7.53 (m, 5H), 7.58 (dd, 1H, J=8.5, 2.5
Hz), 8.00 (d, 1H, J=2.5 Hz); ms: m/z 447 (M+1).
REFERENCES AND NOTES
*
To whom correspondence should be addressed. email:
Glen_Spears@po.fujisawa.co.jp
[1] C. Robinson and J. Castaner, Drugs of the Future, 20, 19
(1995).
[11] J. Dudash, Jr., J. Jiang, S. C. Mayer and M. M. Joullie,
Synth. Commun., 23, 349 (1993); J. R. Vaughan, Jr. and R. L. Osato,
J. Am. Chem. Soc., 74, 676 (1952).