Solid phase synthesis of benzothiazole and thiophene derivatives based on resin-bound cyclic malonic acid ester

Article abstract of DOI:10.1016/S0040-4020(03)00688-4

A new method for the solid phase synthesis of benzothiazoles and 2-arylamino-3-carboxyl-4-hydroxy-5-arylthiophenes is described. Resin bound cyclic malonic acid ester was reacted with aryl isothiocyanates and then with bromine or α-bromoketones, followed by treatment with perchloric acid or sodium methoxide to afford substituted 2-methylbenzothiazoles or 2-arylamino-3-carboxyl-4-hydroxy-5-arylthiophenes, respectively, in high yields and purities.

Full text of DOI:10.1016/S0040-4020(03)00688-4

Tetrahedron 59 (2003) 4851–4856
Solid phase synthesis of benzothiazole and thiophene derivatives
based on resin-bound cyclic malonic acid ester
a
Xian Huanga,b and Jing Tang
,
*
aDepartment of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
bLaboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
Received 21 October 2002; revised 2 April 2003; accepted 28 April 2003
Abstract—A new method for the solid phase synthesis of benzothiazoles and 2-arylamino-3-carboxyl-4-hydroxy-5-arylthiophenes is
described. Resin bound cyclic malonic acid ester was reacted with aryl isothiocyanates and then with bromine or a-bromoketones, followed
by treatment with perchloric acid or sodium methoxide to afford substituted 2-methylbenzothiazoles or 2-arylamino-3-carboxyl-4-hydroxy-
5-arylthiophenes, respectively, in high yields and purities. q 2003 Published by Elsevier Science Ltd.
1. Introduction
Meldrum’s acid derivatives could be cleaved by milder
methods. For example, the alkylthiomethylene derivative of
Meldrum’s acid, which is an important intermediate, can
react with various reagents and subsequently cyclise to
afford heterocyclic compounds under milder conditions.5
Meanwhile, benzothiazole derivatives are of particular
interest within the realm of medicinal chemistry.6 For
example, many useful therapeutic agents containing the
benzothiazole moiety possess selective antitumor activities
and antimicrobial properities.7a–e Compounds containing a
thiophene moiety also possess a wide range of biological
activities.8 As part of our research on the solid-phase
synthesis of heterocyclic compounds by resin-bound
malonic acid ester, we wish to report in this paper a suitable
method for the preparation of resin-bound functionalized
alkylthiomethylene cyclic malonic acid esters and their
applications in the synthesis of substituted benzothiazoles
and multisubstituted thiophenes based on the resin-bound
cyclic malonic acid ester under milder cleavage conditions.
Combinatorial organic synthesis has developed into an
important tool for the generation of libraries of pharmaco-
logically attractive molecules. Solid-phase organic syn-
thesis (SPOS) has been regarded as one of the important
new fields in synthetic organic chemistry.1 SPOS techniques
offers a powerful strategy for the discovery and generation
of drug lead heterocyclic compounds. In addition, a solid-
phase approach is interesting since the reaction can be
driven to completion by using excess reagents, which are
subsequently removed by simple filtration. The work-up is
therefore easy and can be automated.
We have previously reported the synthesis of a variety of
heterocyclic compounds from the derivatives of Meldrum’s
acid (2,2-dimethyl-1,3-dioxane-4,6-dione) in solution.2
Recently, we reported the preparation of resin-bound cyclic
malonic acid ester and its application in the synthesis of
heterocyclic compounds.3 The reaction of the resin-bound
cyclic malonic acid ester with triethyl orthoformate and
subsequent double substitution with nucleophilic reagents,
followed by thermal cyclization at 220–2508C gave a series
of heterocyclic compounds.3 However, as the last step needs
high temperature, this methodology may be limited to
thermally stable heterocyclic compounds.
2. Results and discussion
2.1. Preparation of the resin-bound cyclic malonic acid
ester 43
The resin-bound cyclic malonic acid ester 4 was prepared
from the Merrifield resin, as outlined in Scheme 1.
Merrifield resin was reacted with sodium ethyl acetoacetate
in DMF to give the b-keto ester resin 2. Decarboxylation of
resin 2 afforded the ketone resin 3. The resin 3 was reacted
with malonic acid and acetic anhydride in the presence of
concentrated H2SO4 to give the resin-bound cyclic malonic
acid ester 4.
Meldrum’s acid is a versatile intermediate in organic
synthesis due to nucleophilic on it along with the unique
ring-opening reaction.4 In view of this, it is anticipated that
Keywords: benzothiazole; thiophene; resin-bound; cyclic malonic acid ester.
*
Corresponding author. Fax: þ86-571-88807077;
e-mail: huangx@mail.hz.zj.cn
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00688-4

4852
X. Huang, J. Tang / Tetrahedron 59 (2003) 4851–4856
same purity as the first time even after five runs (entry 9,
Table 1).
The multi-step synthesis from resin 4 to final product was
monitored by FT-IR. The resin-bound cyclic malonic acid
ester 4 showed carbonyl peaks at 1767 and 1794 cm21 in the
IR spectrum. When the cyclic malonic acid ester resin was
converted into the resins 6, the IR carbonyl peaks shifted to
1738 and 1684 cm21 with new peaks at 1545 cm21 (CvC)
and 2552 cm21 (S–H). Disappearance of the 2552 cm21
indicated complete transformation of resin 6 into resin 7.
After cleavage, the recovered resin possessed the same IR
spectrum as that of the resin 3.
Scheme 1. Reagents and conditions: (i) sodium ethyl acetoacetate, DMF,
808C, 16 h; (ii) DMSO, NaCl, 1408C, 48 h; (iii) malonic acid, acetic
anhydride, conc. H2SO4.
Scheme 2. Reagents and conditions: (i) (a) Et3N, DMF, rt, 1 h; (b) R–C6H4NCS, 458C, 18 h; (ii) 2 M HCl; (iii) Br2, AcOH, rt, 2 h; (iv) HClO4, CH3CN, reflux,
4 h.
2.2. Solid-phase synthesis of 2-methyl benzothiazoles 8
2.3. Solid-phase synthesis of 2-arylamino-3-carboxyl-4-
hydroxy-5-arylthiophenes 10
Because aryl isothiocyanates are highly reactive towards
activated methylene compounds, aryl isothiocyanates can
react with resin-bound cyclic malonic ester smoothly
(Scheme 2).
The potential utility of intermediate 5 for the synthesis of
other heterocyclic compounds makes the solid-phase
approach even more attractive. So, we further investigated
the reaction of intermediate 5 with a-bromoketones, which
provides an efficient method for the synthesis of
2-arylamino-3-carboxyl-4-hydroxy-5-arylthiophenes
(Scheme 3).
Initially, we investigated the synthesis of resin 6 by using
various bases. When sodium hydride was used as base at
room temperature, the yield and purity of product 8 were
unsatisfactory. Due to the stronger acidity of the methylene
of resin-bound cyclic malonic acid ester 4, triethylamine
was used to deprotonate the methylene of the resin-bound
cyclic malonic acid ester 4 to form the anion at room
temperature. The formed anion was reacted with the aryl
isothiocyanates in anhydrous DMF at 458C, and after 18 h,
was treated with 2 M HCl to generate resin 6. Excess
reagents were removed by simple washing with solvents
(EtOH, CH2Cl2). The resin 6 was then treated with bromine
at room temperature to give the corresponding resin 7. We
further examined cleavage conditions of the resin 7, but
when 50% TFA/CH2Cl2 and 100% TFA were adopted,
cleavage did not take place. However, the desired product 8
was obtained in good yield and excellent purity when the
resin 7 was treated with perchloric acid (70–72%) in
refluxing CH3CN. The results are summarized in Table 1.
Finally, we verified that the released ketone resin 3 was
reusable. Resin 4 was thus prepared from the recovered
ketone resin 3 and the corresponding reactions were
repeated. After cleavage, 8a was obtained in nearly the
The polymer-bound cyclic malonic acid ester 4 was treated
with aryl isothiocyanates in the presence of Et3N in dry
DMF at 458C to afford intermediates 5, then an
Table 1. Yields and purities of benzothiazoles 8
Entry
R
Product
Yielda
Purityb
1
2
3
4
5
6
7
8
9
H
5-Cl
4-Br-6-CH3O
4-CH3
6-CH3
6-Cl
6-Br
6-F
H
8a
8b
8c
8d
8e
8f
8g
8h
8a
79
75
80
80
82
81
77
76
76
.95
.95
.95
.95
.95
.95
.95
.95
.95c
a
The yields are based on the loading of the cyclic malonic acid ester resin
4.9
Determined by H NMR spectroscopy.
The regenerated resin was used (fifth run).
b
c
1

X. Huang, J. Tang / Tetrahedron 59 (2003) 4851–4856
4853
Scheme 3. Reagents and conditions: (i) a-bromo-ketones, rt, 6 h; (ii) CH3OH, CH3ONa, reflux, 4 h.
a-bromoketone was added and stirred at room temperature
for 6 h to provide resin 9.5 Excess reagents were removed by
simple washing with the solvents (EtOH, CH2Cl2). The
cyclization cleavage of resin 9 was carried out using
CH3ONa in refluxing methanol. 2-Arylamino-3-carboxyl-4-
hydroxyl-5-arylthiophenes was obtained in good yields and
excellent purities (Table 2). The multisubstituted thiophenes
are potentially useful building blocks for further transform-
ations. Furthermore, the regenerated resin 3 was reusable.
This method has attractive features such as the cyclisation
with concomitant cleavage from the resin in one-step and
under mild reaction conditions. For each resin-bound
intermediate, the structure was also verified by FT-IR
spectra. When the cyclic malonic acid ester resin 4 was
converted into the resin 9, the IR carbonyl peak shifted to
1738, 1684 cm21 from 1794, 1768 cm21, respectively, and
two new peaks appeared at 1545 cm21 (CvC) and
1680 cm21 (CvO) attributed to the additional ketone
carbonyl group. After cleavage, the recovered resin
possessed the same IR spectra as that of the resin 3.
conditions, the practicality and the excellent yields and
purities. Moreover, we have described a new traceless
cleavage SPOS route for the synthesis of heterocyclic
compounds and the polymer bound ketone could be
regenerated easily for reuse after cleavage. We are
extending this methodology to the synthesis of other
heterocyclic templates, and we will continue to report on
this work in future disclosures.
4. Experimental
1
The melting points were uncorrected. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Bruker
Avance 400 spectrometer in CDCl3 with TMS as the
internal standard; chemical shifts were quoted in ppm and J
values were given in Hz. IR spectra were recorded on a
Bruker Vector 22 spectrometer. EIMS was run on a HP
5989B mass spectrometer. The resin was prepared accord-
ing to a literature procedure.3 Aryl isothiocyanates were
prepared according to the standard methodologies.10 DMF
(AR) and methanol (AR) were obtained commercially and
dried before used.
Table 2. Yields and purities of 2-amino-3-carboxyl-4-hydroxy-5-arylthio-
phenes 10
Entry
R
R1
Product
Yielda
Purityb
4.1. General procedure for the preparation of the resin
bound cyclic malonic acid ester 4
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
2-CH3C6H4
2-CH3C6H4
3-ClC6H4
C6H5
10a
10b
10c
10d
10e
10f
10g
10h
10i
68
66
72
63
60
62
71
54
68
58
64
95
92
90
91
90
93
92
94
90
88
91c
4-CH3C6H4
4-ClC6H4
C6H5
4-ClC6H4
4-CH3C6H4
4-ClC6H4
C6H5
4-ClC6H4
4-ClC6H4
4-CH3C6H4
To a solution of sodium ethyl acetoacetate (39.2 mmol,
5.96 g) in 30 mL of DMF was added Merrifield resin (2.0 g,
1% cross-linked, 200–400 mesh, loading¼1.96
mequiv. Cl/g) and the mixture was stirred at 808C for 16 h
and filtered. After washing successively with DMF, EtOH
and CH2Cl2, the b-keto ester resin 2 was obtained (IR 1749,
1715 cm21). The b-keto ester resin 2 (2.0 g) was suspended
in a mixture of DMSO (30 mL), NaCl (40 mmol) and H2O
(120 mmol) and the mixture was refluxed for 48 h. The
mixture was filtered and washed with H2O, DMF, EtOH and
CH2Cl2, The ketone resin 3 (IR, 1717 cm21) was obtained
(loading¼1.88 mmol/g, the loading of resin 3 was deter-
mined by titration with sodium hydroxide after the reaction
of resin 3 with hydroxylamine hydrochloride.3,11). A
solution of malonic acid (38 mmol, 3.95 g), concentrated
sulfuric acid (0.1 mL) and acetic anhydride (117 mmol,
11.90 g) was allowed to stand for 24 h at room temperature
and was then concentrated at 408C under reduced pressure.
The resin 3 (2 g, pre-swelled in 17 mL dry CH2Cl2 for 12 h)
was added to the residue at 08C. Then the mixture was
stirred at 158C for 24 h and filtered. After washing with
9
10
11
3-CH3C6H4
4-CH3OC6H4
C6H5
10j
10b
a
The yields were based on the loading of the cyclic malonic acid ester resin
4.9
Determined by 1H NMR spectroscopy.
The recovered resin was used (third run).
b
c
3. Conclusion
In summary, we have developed a new method for the
preparation of resin-bound functionalized alkylthio-
methylene cyclic malonic acid esters and applied them to
the synthesis of substituted 2-methyl-benzothiazoles and
2-arylamino-3-carboxyl-4-hydroxy-5-arylthiophenes using
mild cleavage protocols. The distinct advantages of this
solid-phase synthetic method include the milder cleavage

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X. Huang, J. Tang / Tetrahedron 59 (2003) 4851–4856
H2O, EtOH and CH2Cl2. The cyclic malonic acid ester resin
4 (loading¼1.11 mmol/g, IR, 1794, 1767, 1290 cm21) was
obtained. The loading of resin 4 was determined by reversed
titration with hydrochloric acid after saponification with
excess NaOH in EtOH.3
(Mþ, 100), 148 (10), 130 (8), 121 (52); IR nmax (cm21
)
1604, 1558, 1530, 1452, 1306, 1245.
4.2.5. 2,6-Dimethylbenzothiazole 8e. Yield: 74.1 mg
1
(82%); oil (lit15); H NMR (CDCl3) d 2.41 (3H, s), 2.76
(3H, s), 7.21 (1H, d, J¼8.2 Hz), 7.53 (1H, s), 7.81 (1H, d,
J¼8.3 Hz); MS m/z (relative intensity) 163 (Mþ, 100), 148
(10), 133 (8); IR nmax (cm21) 1604, 1558, 1530, 1452, 1306,
1245.
4.2. General procedure for the syntheses of 2-methyl-
benzothiazoles 8
Resin-bound cyclic malonic acid ester 4 (500 mg,
1.11 mmol/g) was pre-swelled in dry DMF (5 mL) for 5 h,
triethylamine (5.55 mmol, 0.77 mL) was added and then
stirred at room temperature for 1 h, the aryl isothiocyanate
(2.78 mmol) was added dropwise to the suspension. The
mixture was warmed to 458C and stirred for 18 h, cooled to
room temperature, then 2 M HCl solution was added to the
reaction mixture and stirred for 30 min to afford the resin 6
(IR 2552, 1738, 1684, 1545 cm21) after washing with H2O
(3£10 mL), EtOH (3£10 mL), CH2Cl2 (3£10 mL) and
drying under vacuum. Bromine (0.55 mmol, 89 mg) was
added to a suspension of resin 6 in acetic acid and stirred for
2 h at room temperature and filtered. After washing
successively with H2O (3£10 mL), EtOH (3£10 mL),
CH2Cl2 (3£10 mL) and drying under vacuum, the resin 7
was obtained. The resin 7 was swelled in acetonitrile
(5 mL), then treated with 70–72% perchloric acid (0.5 mL)
and heated to reflux for 4 h. When the mixture was cooled to
room temperature, the resin was filtered and washed
thoroughly with water. The filtrates were combined and
neutralized with 2 M NaOH to pH¼7 and extracted with
CH2Cl2 (3£10 mL). The organic layer was washed with
water and dried over MgSO4. The solvent was evaporated
under reduced pressure to give the products 8.
4.2.6. 6-Chloro-2-methylbenzothiazole 8f. Yield: 82.2 mg
(81%); white solid; mp 84–868C (lit 13 84–868C); 1H NMR
(CDCl3) d 2.82 (3H, s), 7.38–7.41 (1H, dd, J1¼2.0 Hz,
J2¼8.6 Hz), 7.79 (1H, d, J¼8.5 Hz), 7.83 (1H, s); MS m/z
(relative intensity) 185 (Mþ, 37Cl, 37), 183 (Mþ, 35Cl, 100),
148 (39), 116 (21); IR nmax (cm21) 1548, 1523, 1446, 1305,
1271.
4.2.7. 6-Bromo-2-methylbenzothiazole 8g. Yield: 97.8 mg
(77%); white solid; mp 87–888C (lit 16 85–878C); 1H NMR
(CDCl3) d 2.82 (1H, s), 7.52 (1H, dd, J1¼2.0 Hz,
J2¼8.6 Hz), 7.78 (1H, d, J¼8.6 Hz), 7.95 (1H, s); MS m/z
(relative intensity) 229 (Mþ, 81Br, 100), 227 (Mþ, 79Br, 98),
148 (40), 133 (40); IR nmax (cm21) 1587, 1517, 1440, 1303,
1268.
4.2.8. 6-Flouro-2-methyl-benzothiazole 8h. Yield:
70.4 mg (76%); white solid; mp 112–1148C; 1H NMR
(CDCl3) d 2.80 (1H, s), 7.14–7.19 (1H, m), 7.47–7.50 (1H,
dd, J1¼2.5 Hz, J2¼8.1 Hz), 7.85–7.89 (1H, m); 13C NMR
19.4, 107.0 (J¼26.2), 113.8 (J¼24.4), 122.6 (J¼9.3), 136.0
(J¼10.9), 149.4, 159.6 (J¼243.2), 166.0 (J¼24.4); Elemen-
tal analysis. Calcd for C8H6FNS, C 57.47%; H 3.62%; N
8.38% Found C 57.33%, H 3.66%, N 8.36%; MS m/z
(relative intensity) 167 (Mþ, 100), 148 (20), 133 (7), 101
(2); IR nmax (cm21) 1603, 1567, 1528, 1453, 1311, 1254.
4.2.1. 2-Methylbenzothiazole 8a. Yield: 65.3 mg (79%);
white solid; mp 12–148C (lit 12 picrate salt 151–1528C); 1H
NMR (CDCl3) d 2.83 (3H, s), 7.26–7.36 (1H, m), 7.42–
7.46 (1H, m), 7.82 (1H, d, J¼8.0 Hz), 7.96 (1H, d,
J¼7.2 Hz); MS m/z (relative intensity) 149 (Mþ, 100),
117 (15), 104 (4); IR nmax (cm21) 1558, 1523, 1456, 1312,
1238.
4.3. General procedure for the syntheses of 2-arylamino-
3-carboxyl-4-hydroxy-5-arylthiophenes 10
Resin-bound cyclic malonic acid ester 4 (500 mg,
1.11 mmol) was pre-swelled in dry DMF (5 mL) for 5 h,
triethylamine (5.55 mmol, 0.77 mL) was added and then
stirred at room temperature for 1 h, the aryl isothiocyanate
(2.78 mmol) was added dropwise to the suspension, the
mixture was allowed to warm 458C and stirred for 18 h.
The suspension was then cooled to room temperature,
a-bromoketone (2.78 mmol) was added and the mixture
was stirred for 6 h to afford the resin 9 (IR 1738, 1684,
1680, 1545 cm21) after washing with H2O (3£10 mL),
EtOH (3£5 mL), CH2Cl2 (3£5 mL) and then drying under
vacuum for 24 h. The resin 9 and sodium methoxide
(2.78 mmol) in methanol (15 mL) were refluxing for 4 h.
Then solvent was evaporation under reduced pressure.
Water was added to the residual, the resin was filtered
and washed with water (3£10 mL). The filtrates were
combined and neutralized with 1 M HCl to pH¼5 to
produce the precipitated. After filtered, washed with water
(3£5 mL) and dried under vacuum, the products 10 were
obtained.
4.2.2. 5-Chloro-2-methylbenzothiazole 8b. Yield: 76.1 mg
(75%); white solid; mp 68–698C (lit 13 67–698C); 1H NMR
(CDCl3) d 2.82 (3H, s), 7.38–7.41 (1H, dd, J1¼2.0 Hz,
J2¼8.6 Hz), 7.79 (1H, s), 7.83 (1H, d, J¼8.6Hz); MS m/z
(relative intensity) 185 (Mþ, 37Cl, 37), 183 (Mþ, 35Cl, 100),
148 (39), 116 (20), 103 (21); IR nmax (cm21) 1546, 1523,
1446, 1305, 1271.
4.2.3. 4-Bromo-6-methoxy-2-methylbenzothiazole 8c.
1
Yield: 114.9 mg (80%); white solid; mp 104–1068C; H
NMR (CDCl3) d 2.79 (3H, s), 3.95 (3H, s), 7.29 (1H, s), 8.11
(1H, s); Elemental analysis Calcd for C9H8BrNOS, C
41.88%; H 3.12%; N 5.43% Found C 41.87%, H 3.14%, N
5.40%; MS m/z (relative intensity) 259 (Mþ, 81Br, 98), 257
(Mþ, 79Br, 100), 242 (64), 212 (32), 133 (15); IR nmax
(cm21) 1604, 1558, 1530, 1452, 1306, 1245, 1203.
4.2.4. 2,4-Dimethylbenzothiazole 8d. Yield: 72.3 mg
1
(80%); white solid; mp 33–348C (lit14 mp 33–348C); H
NMR (CDCl3) d 2.64 (3H, s), 2.75 (3H, s), 7.13–7.17 (2H,
m), 7.54–7.57 (1H, m); MS m/z (relative intensity) 163
4.3.1. 5-Benzoyl-4-hydroxy-2-phenylamino-3-thiophene-
carboxylic acid 10a. Yield: 127.9 mg (68%); yellow solid;

X. Huang, J. Tang / Tetrahedron 59 (2003) 4851–4856
4855
1
mp 169–1708C; H NMR (400 MHz, CDCl3) d 7.34–7.38
369 (29), 343 (50), 306 (26), 91 (100); IR nmax (cm21) 3345,
1717, 1678, 1604, 1592, 1574, 1550, 1448, 1424, 1092.
(3H, m), 7.46–7.55 (5H, m), 7.79 (2H, d, J¼6.9 Hz), 11.07
(1H, s, NH), 12.33 (1H, br, COOH); 13C NMR (400 MHz,
CDCl3) d 99.2, 102.3, 123.0, 127.9, 128.2, 129.4, 130.4,
132.6, 133.6, 137.5, 166.6, 169.3, 172.4, 187.3; Elemental
analysis. Calcd for C18H13NO4S, C 63.71%; H 3.86%; N
4.13% Found C 63.53%, H 3.77%, N 4.36%; MS m/z
(relative intensity), 339 (Mþ, 24), 321 (23), 295 (23), 105
(35), 77 (100); IR nmax (cm21) 3337, 1715, 1680, 1593,
1549, 1493, 1462, 1438, 1363, 1080.
4.3.6. 5-(4-Methylbenzoyl)-4-hydroxy-2-(2-methyl-
phenylamino)-3-thiophenecarboxylic acid 10f. Yield:
1
126.2 mg (62%); yellow solid; mp 204–2068C; H NMR
(400 MHz, CDCl3) d 2.36 (3H, s), 2.40 (3H, s), 7.28–7.33
(5H, m), 7.39–7.41 (1H, m), 7.68 (2H, d, J¼8.1 Hz), 10.80
(1H, s, NH), 12.34 (1H, br, COOH); 13C NMR (400 MHz,
CDCl3) d 18.5, 22.1, 99.7, 101.7, 121.0, 123.1, 127.9, 128.3,
130.2, 130.7, 131.4, 136.1, 138.7, 143.8, 166.6, 170.4,
171.2, 187.0; Elemental analysis. Calcd for C20H17NO4S, C
65.38%; H 4.66%; N 3.81% Found C 65.38%, H 4.33%, N
3.79%; MS m/z (relative intensity) 367 (Mþ, 17), 349 (12),
323 (21), 308 (41), 293 (27), 91 (100), 77 (16); IR nmax
(cm21) 3400, 1710, 1677, 1609, 1588, 1543, 1440, 1077.
4.3.2. 5-(4-Methylbenzoyl)-4-hydroxy-2-phenylamino-3-
thiophenecarboxylic acid 10b. Yield: 129.3 mg (66%);
yellow solid; mp 218–2208C; 1H NMR (400 MHz, CDCl3)
d 2.42 (3H, s), 7.29–7.38 (5H, m), 7.45 (2H, d, J¼7.8 Hz),
7.69 (2H, d, J¼8.1 Hz), 11.04 (1H, s, NH), 12.40 (1H, br,
COOH); 13C NMR (400 MHz, CDCl3) d 21.1, 98.3, 100.8,
122.0, 126.9, 127.3, 129.2, 129.4, 129.9, 136.6, 142.6,
165.7, 168.8, 171.2, 186.2; Elemental analysis. Calcd for
C19H15NO4S, C 64.58%; H 4.28%; N 3.96% Found C
64.36%, H 4.11%, N 4.03%; MS m/z (relative intensity)
353 (Mþ, 50), 335 (38), 309 (33), 91 (100), 77 (93); IR
nmax (cm21) 3400, 1707, 1677, 1591, 1569, 1544, 1458,
1076.
4.3.7. 5-(4-Chlorobenzoyl)-4-hydroxy-2-(2-methyl-
phenylamino)-3-thiophenecarboxylic acid 10g. Yield:
1
152.4 mg (71%); yellow solid; mp 186–1888C; H NMR
(400 MHz, CDCl3) d 2.36 (3H, s), 7.26–7.34 (3H, m),
7.38–7.41 (1H, m), 7.44 (2H, d, J¼8.5 Hz), 7.69 (2H, d,
J¼8.6 Hz), 10.84 (1H, s, NH), 12.21 (1H, br, COOH); 13C
NMR (400 MHz, CDCl3) d 18.2, 98.5, 102.2, 123.8, 127.4,
128.6, 129.1, 129.3, 131.7, 131.8, 133.2, 135.7, 138.4,
166.1, 167.1, 173.4, 187.1; Elemental analysis. Calcd for
C19H14ClNO4S, C 58.84%; H 3.64%; N 3.61% Found C
58.54%; H 3.31%; N 3.77%; MS m/z (relative intensity) 387
(Mþ, 35Cl, 22), 389 (Mþ, 37Cl, 8), 369 (27), 343 (42), 306
(65), 91 (65), 77 (30); IR nmax (cm21) 3385, 1713, 1680,
1592, 1586, 1544, 1441, 1073.
4.3.3. 5-(4-Chlorobenzoyl)-4-hydroxy-2-phenylamino-3-
thiophenecarboxylic acid 10c. Yield: 149.0 mg (72%);
yellow solid; mp 221–2228C; 1H NMR (400 MHz, CDCl3)
d 7.30–7.36 (2H, m), 7.49–7.58 (5H, m), 7.79 (2H, d,
J¼8.3 Hz), 11.07 (1H, s, NH), 12.45 (1H, br, COOH); 13C
NMR (400 MHz, CDCl3) d 99.8, 102.2, 123.0, 127.3, 128.2,
129.2, 130.5, 133.9, 137.6, 141.8, 166.3, 169.5, 171.9,
187.3; Elemental analysis. Calcd for C18H12ClNO4S, C
57.84%; H 3.24%; N 3.75% Found C 57.54%; H 3.40%; N
3.98%; MS m/z (relative intensity) 373 (Mþ, 35Cl, 50), 375
(Mþ, 37Cl, 20), 355 (38), 329 (33), 292 (36), 91 (100), 77
(93); IR nmax (cm21) 3380, 1715, 1678, 1593, 1549, 1462,
1438, 1080.
4.3.8. 5-Benzoyl-4-hydroxy-2-(3-chlorophenylamino)-3-
thiophenecarboxylic acid 10h. Yield: 111.7 mg (54%);
yellow solid; mp 197–1988C; 1H NMR (400 MHz, CDCl3)
d 7.29–7.33 (2H, m), 7.39–7.43 (2H, m), 7.51–7.57 (3H,
m), 7.80 (2H, d, J¼7.0 Hz), 11.09 (1H, s, NH), 12.29 (1H,
br, COOH); 13C NMR (400 MHz, CDCl3) d 99.6, 102.2,
123.2, 127.1, 128.3, 129.4, 130.5, 131.7, 132.2, 133.4,
135.7, 138.1, 166.8, 169.2, 173.3, 187.1; Elemental
analysis. Calcd for C18H12ClNO4S, C 57.84%; H 3.24%;
N 3.75% Found C 57.93%; H 3.29%; N 4.01%; MS m/z
(relative intensity) 373 (Mþ, 35Cl, 15), 375 (Mþ, 37Cl, 5),
355 (21), 329 (12), 77 (100); IR nmax (cm21) 3388, 1711,
1682, 1606, 1588, 1543, 1440, 1077.
4.3.4. 5-Benzoyl-4-hydroxy-2-(4-methylphenylamino)-3-
thiophenecarboxylic acid 10d. Yield: 123.4 mg (63%);
yellow solid; mp 194–1968C; 1H NMR (400 MHz, CDCl3)
d 2.39 (3H, s), 7.13–7.26 (3H, m), 7.44–7.54 (4H, m), 7.77
(2H, d, J¼6.9 Hz), 10.86 (1H, s, NH), 12.41 (1H, br,
COOH); 13C NMR (400 MHz, CDCl3) d 20.2, 98.5, 100.9,
123.2, 127.1, 128.1, 129.4, 129.6, 129.8, 130.4, 142.8,
166.3, 169.1, 171.3, 187.2; Elemental analysis. Calcd for
C19H15NO4S, C 64.58%; H 4.28%; N 3.96% Found 64.59%,
H 4.59%, N 4.01%; MS m/z (relative intensity) 353 (Mþ,
4.3.9. 5-(4-Chlorobenzoyl)-4-hydroxy-2-(3-methyl-
phenylamino)-3-thiophenecarboxylic acid 10i. Yield:
1
146.0 mg (68%); yellow solid; mp 190–1928C; H NMR
51), 335 (30), 309 (25), 91 (100), 77 (68); IR nmax (cm21
3400, 1707, 1680, 1591, 1569, 1544, 1442, 1076.
)
(400 MHz, CDCl3) d 2.36 (3H, s), 7.27–7.29 (3H, m),
7.40–7.44 (3H, m), 7.61 (2H, d, J¼8.6 Hz, ArH), 10.92
(1H, s, NH), 12.30 (1H, br, COOH); 13C NMR (400 MHz,
CDCl3) d 20.4, 99.2, 101.8, 120.6, 122.8, 127.6, 127.8,
129.1, 131.0, 132.4, 133.1, 135.7, 138.2, 166.1, 169.7,
171.7, 186.7; Elemental analysis. Calcd for C19H14ClNO4S,
C 58.84%; H 3.64%; N 3.61% Found C 59.05%; H 3.88%;
N 3.88%; MS m/z (relative intensity), 387 (Mþ, 35Cl, 18),
389 (Mþ, 37Cl, 6), 349 (12), 323 (21), 91(100); IR nmax
(cm21) 3400, 1712, 1680, 1609, 1588, 1543, 1440, 1077.
4.3.5. 5-(4-Chlorobenzoyl)-4-hydroxy-2-(4-methyl-
phenylamino)-3-thiophenecarboxylic acid 10e. Yield:
128.8 mg (60%); yellow solid; mp 214–2168C; H NMR
1
(400 MHz, CDCl3) d 2.40 (3H, s), 7.44 (4H, m), 7.71 (2H, d,
J¼8.5 Hz), 8.02 (2H, d, J¼8.4 Hz), 10.94 (1H, s, NH),
12.21 (1H, br, COOH); 13C NMR (400 MHz, CDCl3) d
20.1, 98.5, 101.9, 123.5, 127.4, 128.5, 129.2, 131.7, 134.6,
135.6, 137.8, 166.8, 168.3, 171.4, 187.5; Elemental
analysis. Calcd for C19H14ClNO4S, C 58.84%; H 3.64%;
N 3.61% Found C 59.01%, H 3.55%, N 3.79%; MS m/z
(relative intensity 387 (Mþ, 35Cl, 28), 389 (Mþ, 37Cl, 11),
4.3.10. 5-(4-Chlorobenzoyl)-4-hydroxy-2-(4-methoxyl-
phenylamino)-3-thiophenecarboxylic acid 10j. Yield:
1
129.7 mg (58%); yellow solid; mp 199–2018C; H NMR

4856
X. Huang, J. Tang / Tetrahedron 59 (2003) 4851–4856
7655–7657. (b) Huang, X.; Liu, Z. X. J. Org. Chem. 2002,
67, 6731–6737.
(400 MHz, CDCl3) d 3.85 (3H, s), 6.69 (2H, d, J¼8.7 Hz),
7.43–7.46 (2H, m), 7.70 (2H, d, J¼8.5 Hz), 8.01 (2H, d,
J¼8.3 Hz), 10.96 (1H, s, NH), 12.22 (1H, br, COOH); 13C
NMR (400 MHz, CDCl3) d 51.5, 100.8, 102.0, 121.7, 123.2,
126.7, 129.2, 132.1, 134.6, 136.8, 140.9, 166.0, 167.7,
171.2, 180.5; Elemental analysis. Calcd for C19H14ClNO5S,
C 56.51%; H 3.49%; N 3.47% Found C 56.76%; H 3.27%;
N 3.68%; MS m/z (relative intensity) 403 (Mþ, 35Cl, 100),
405 (Mþ, 37Cl, 37), 387 (21), 361 (12), 324 (36), 77 (100);
IR nmax (cm21) 3400, 1717, 1680, 1609, 1588, 1543, 1440,
1077.
4. For reviews on Meldrum’s acid, see: (a) McNab, H. Chem.
Soc. Rev. 1978, 7, 345–358. (b) Chen, B. C. Heterocycles
1991, 32, 529–597. (c) Gaberm, A. M.; McNab, H. Synthesis
2001, 2059–2074.
5. Augustin, M.; Guenther, E.; Wiss, Z. Martin-Luther-Univ.
Halle-Wittenberg, Math-Naturwiss.Reihe 1989, 38(3), 27–36.
6. (a) Bock, M. G.; Dipardo, R. M.; Evans, B. E.; Rittl, K. E.;
Whittner, W. L.; Veber, D. F.; Anderson, P. S.; Freidiger, R. M.
J. Med. Chem. 1989, 13, 16. (b) Kantoci, D.; Murray, E. D.;
Quiggle, D. D.; Wechter, W. J. J. Med. Chem. 1996, 39, 1196.
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Chem. Abstr. 1991, 115, 198515f. (b) Nahed, K. Can. Pat, EP
430036/1991 cited in Chem. Abstr. 1992, 116, 717c.
(c) Geoffrey, W.; Tracey, D. B.; Patrizia, D.; Angela, S.;
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Acknowledgements
We are grateful to the Natural Science Foundation of China
(Project No.20072032).
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