Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives

Article abstract of DOI:10.14233/ajchem.2020.22565

Novel thiazolidine-2,4-dione (TZD) based pyrimidine derivatives have been synthesized by Knoevenagel condensation reaction between thiazolidine-2,4-dione and amino pyrimidinyl aliphatic aldehydes followed by heterogeneous metal reduction. Synthetic strate

Full text of DOI:10.14233/ajchem.2020.22565

Asian Journal of Chemistry; Vol. 32, No. 5 (2020), 1101-1108
A
SIAN
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OURNAL OF HEMISTRY
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https://doi.org/10.14233/ajchem.2020.22565
Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives
1,2
1,*
VIJAY KUMAR SHARMA , ANUP BARDE2,* and SUNITA RATTAN
1Amity Institute of Applied Sciences, Amity University Uttar Pradesh, Noida-201313, India
2Integral Bio Sciences Pvt. Ltd. C-64, Hosiery Complex, Phase-II, Noida-201306, India
*Corresponding authors: E-mail: srattan@amity.edu; anup.barde@ibs.net.in
Received: 1 December 2019;
Accepted: 11 January 2020;
Published online: 29 April 2020;
AJC-19842
Novel thiazolidine-2,4-dione (TZD) based pyrimidine derivatives have been synthesized by Knoevenagel condensation reaction between
thiazolidine-2,4-dione and amino pyrimidinyl aliphatic aldehydes followed by heterogeneous metal reduction. Synthetic strategy involved
nucleophillic substitution of hydroxyl protected six membered aliphatic chain on 4,6-dichloropyrimidine followed by Suzuki coupling.
This approach is regioselective, efficient and versatile for synthesis of such analogs.
Keywords: Thiazolidine-2,4-dione, Suzuki coupling, Knoevenagel condensation.
diverse chemical reactivities along with broad spectrum of
biological activities [10-14]. Literature provides ample indica-
tions that varying the substitutions on the thiazolidine ring
results in modulation of the biological activities [15].
2,4-Thiazolidinedione derivatives with aliphatic chain up
to five carbon chain was reported as insulin sensitizers with
antidiabetic activities [16]. Keeping in mind further scope for
thiazolidinedione, a series of pyrimidine based thiazolidine-
dione with C-linked aromatic substituents and amine substi-
tuted six membered aliphatic chain with terminal thiazolidine-
2,4-dione group were designed. Suzuki partners for C-C bond
formation are chosen based on their potential to influence the
SAR.
INTRODUCTION
Design and synthesis of molecules possessing value as
human therapeutic agents is one of the main objectives of drug
discovery. Compounds containing heterocyclic ring systems
have being receiving great attention as they belong to a class
of compounds with proven beneficial in medicinal chemistry
[1]. Thiazolidine-2,4-dione (TZD) is a derivative from thia-
zolidine which belongs to an important heterocyclic group.
Thiazolidinedione possesses different types of biological
activities like anticonvulsant activity, hypnotic activity,
antitubercular activity, antibacterial activity antimicrobial,
antidiabetic, anticancer and anti-inflammatory, etc. [2-5].Anti-
diabetic activity of this moiety is very well established and
numbers of drugs are available in market based on this moiety
(Fig. 1). In 1980’s, antihyper glycaemia activity of thiazolidine-
2,4-diones were studied extensively. Ciglitazone was the first
active compound of this class, whereas other derivatives viz.
pioglitazone, troglitazone, englitazone and rosiglitazone (Fig.
1) were reported soon after this. Various derivatives of thiazo-
lidinedione have been reported for their diverse biological
activities apart from synthetic interests [6-8]. Biological/thera-
peutically activities such as hypoglycaemic, cardiovascular,
antibacterial, anti-inflammatory, antilipidimic and various
other activities have been reported [9]. Thiazolidine-2,4-dione
derivatives have been studied extensively and found to have
EXPERIMENTAL
1H and 13C NMR spectra were recorded at 400 and 101
MHz instruments, respectively and spectral data were reported
in ppm relative to tetramethylsilane (TMS) as the internal
standard. UPLC-LCMS were recorded in UPLC coupled with
Single quadruple mass spectrometer using electrospray
ionization (ESI).
Step-1: Synthesis of compound 3: To a solution of
6-aminohexanol (1) (1 eq.) in DCM (500 mL) was added DMAP
(0.1 eq.) at ambient temperature and reaction mixture was
cooled to 0 °C. Triethyl amine (1.5 eq.) and tert-butyldimethyl-
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1102 Sharma et al.
Asian J. Chem.
O
O
O
O
O
N
O
O
HN
HN
HN
O
O
O
O
S
S
OH
S
Ciglitazone
Troglitazone
Pioglitazone
O
N
N
O
O
O
O
HN
O
HN
O
N
N
HN
N
O
O
O
S
S
S
Rosigliazone
Englitazone
Lobeglitazone
Fig. 1. Structures of some commercial drugs containing 1,3-thiazolidine-2,4-dione moiety
silyl chloride (1.2 eq) were added sequentially. Reaction mix-
ture was allowed to come to ambient temperature and stirred
at same temperature for 18 h. TLC (10 % methanol in DCM,
stain visualization-ninhydrin) showed that starting material was
consumed.After completion, reaction mixture was concentrated
under vacuum and suspension was filtered off. Filterate was
concentrated under reduced pressure to afford 6-((tert-butyl-
dimethylsilyl)oxy)hexan-1-amine (3). Yield: 99.3 %; colour-
less oil which was used as such for further reactions LC-MS
(ESI) m/z calculated for C16H30N30SiCl (M + H)+: 231.20. 1H
NMR (400 MHz, chloroform-d1): δ 5.80-5.60 (s, b, 2H), 3.60
(s, 2H), 2.83-2.88 (m, 2H), 1.66 (m, 2H), 1.28-1.54 (m, 6H),
0.83 (br, s, 9H), 0.00 (s, 6 H); 13C NMR (101 MHz, DMSO-
d6): δ 63.0, 41.5, 32.7, 32.5, 25.9, 25.9, 25.5, 18.2, 18.2, 18.2,
5.4, 5.4; Anal. calcd. (%) for C12H29NOSi: C, 62.27; H, 12.63;
N, 6.05; found (%): C, 62.39; H, 12.56; N, 6.07.
Step-2: Synthesis of compound 5:To a solution of 6-((tert-
butyldimethylsilyl)oxy)hexan-1-amine (3) (1 eq.) was charged
in ethanol (50 mL). Reaction mixture was cooled to 0 °C. DIPEA
(1 eq.) was added drop-wise into it. 2,4-Dichloropyrimidine
(4) (1 eq.) was added portion wise at same temperature. Reaction
mixture was allowed to room temperature and stirred at
ambient temperature for 18 h. TLC (40 % ethyl acetate:hexane,
stain visualization–UV active) showed that starting material
was consumed. After completion, reaction mixture was
concentrated under reduced pressure and ice water (100 mL)
was added in to this. Organic phase was extracted with ethyl
acetate (2 × 250 mL). Combined organic layers were washed
with water (2 × 50 mL), dried over anhydrous sodium sulphate
and concentrated under reduced pressure to get the crude pro-
duct. Crude product was purified by Combi-Flash {(Teledyne
Isco) using Hi-Purit flash column silica (NP) 80 g, 60 Å, max
pressure: 350 psi (24 bar)-using 0-70 % ethyl acetate: hexane
to afford N-(6-((tert-butyldimethylsilyl)oxy)hexyl)-6-chloro-
pyrimidin-4-amine (5).Yield: 70.3 %; transparent liquid which
solidifies on freezing; LC-MS (ESI) m/z calculated for
C16H30N3OSiCl (M + H)+: 344.18; found (%): 344.30, 1H NMR
(400 MHz, chloroform-d1): δ 8.32 (s, 1H), 6.32 (s, 1H), 5.16
(br, s, 1H), 3.60 (t, J = 6.36 Hz, 2H), 3.28 (br, m, 2H), 1.32-
1.70 (m, 8H), 0.89 (s, 9H), 0.04 (s, 6 H); 13C NMR (101 MHz,
DMSO-d6): δ 165.1, 163.9, 154.1, 104.1, 64.2, 51.5, 34.1, 32.2,
25.9, 25.9, 24.1, 18.5, 18.5, 18.5, 5.4, 5.4;Anal. calcd. (%) for
C16H30N30SiCl: C, 55.87; H, 8.79; Cl, 10.31; N, 12.22; found
(%): C, 55.80; H, 8.79; Cl, 10.36; N, 12.24.
chloropyrimidin-4-amine (5) (1 eq.), boronic acid/ester (1.5
eq.) and Cs2CO3 (3 eq.) were charged in dioxane:water (3:1)
(20 vol.) and nitrogen was purged for 10 min. [1,1'-Bis(diphenyl
phosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane (0.15 eq.) was added and nitrogen was again
purged for 5 min. Reaction mixture was allowed to stir at 100 °C
for 3 h. TLC (40 % ethyl acetate/hexane, stain visualization-
UV active) showed that starting material was consumed. The
reaction mixture was allowed to come at ambient temperature
and concentrated under reduced pressure. Water was added
into reaction mixture and organic phase was extracted in DCM
(2 times). Combined organic layers were washed with water,
dried over anhydrous sodium sulphate and concentrated under
reduced pressure to get the crude product. Crude product was
purified by Combi-Flash {(Teledyne Isco) using Hi-Purit flash
column silica (NP), 60 Å, max pressure: 350 psi (24 bar)} using
0-30 % ethyl acetate:hexane) to afford the desired compound.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-phenyl-
pyrimidin-4-amine (6a): Yield: 87.0 %; transparent oil
which solidifies on freezing; LC-MS (ESI) m/z calculated for
C22H35N3OSi(M + H)+: 386.25; found (%): 386.90; 1H NMR
(400 MHz, chloroform-d1): δ 8.64 (s, 1H), 7.97 (m, 2H), 7.46
(m, 3H), 6.68 (s, 1H), 4.97 (br, s, 1H), 3.60 (m, 2H), 3.35 (br,
m, 2H), 1.31-1.73 (m, 8H), 0.89 (s, 9H), 0.05 (s, 6 H); 13C NMR
(101 MHz, DMSO-d6): δ 165.2, 163.8, 154.2, 134.2, 129.1,
129.1, 128.2, 128.2, 126.1, 104.1, 64.1, 51.6, 34.1, 32.2, 25.9,
25.9, 24.1, 18.5, 18.5, 18.5, 5.4, 5.4; Anal. calcd. (%) for
C22H35N3OSi: C, 68.52; H, 9.15; N, 10.90; found (%): C, 68.50;
H, 9.17; N, 10.92.
tert-Butyl 4-(6-((6-((tert-butyldimethylsilyl)oxy)hexyl)-
amino)pyrimidin-4-yl)benzoate (6b): Yield: 68.6 %; trans-
parent oil which solidifies on freezing; LC-MS (ESI) m/z calcu-
lated for C27H43N3O3Si(M + H)+: 486.31; found (%): 486.40;
1H NMR (400 MHz, chloroform-d1): δ 8.65 (s, 1H), 7.91-8.13
(m, 4H), 6.71 (s, 1H), 5.01 (br, s, 1H), 3.60 (m, 2H), 3.38 (m,
2H), 1.33-1.73 (m, 26H), 0.05 (s, 6H); 13C NMR (101 MHz,
DMSO-d6): δ 165.2, 163.8, 161.9, 157.9, 157.9, 156.1, 150.2,
150.2, 134.3, 128.2, 104.1, 64.1, 62.1, 51.6, 34.1, 32.2, 28.3,
28.3, 28.3, 25.9, 25.9, 24.1, 18.5, 18.5, 18.5, 5.4, 5.4; Anal.
calcd. (%) for C27H43N3O3Si: C, 66.76; H, 8.92; N, 8.65; found
(%): C, 66.70; H, 8.96; N, 8.62.
6-(2-(tert-Butyl)pyridin-4-yl)-N-(6-((tert-butyldimethyl-
silyl)oxy)hexyl)pyrimidin-4-amine (6c): Yield: 67.1 %; white
solid; LC-MS (ESI) m/z calculated for C25H42N4OSi(M + H)+:
443.31; found (%): 443.40; 1H NMR (400 MHz, chloroform-
d1): δ 8.67 (m, 2H), 7.91 (s, 1H), 7.56 (dd, J = 1.53, 5.04 Hz,
Step-3: Synthesis of compounds (6a-i): In a sealed tube,
a mixture of N-(6-((tert-butyldimethylsilyl)oxy)hexyl)-6-

Vol. 32, No. 5 (2020)
Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives 1103
1H), 6.70 (s, 1H), 5.05 (br, s, 1H), 3.61 (t, J = 6.36 Hz, 2H),
3.39 (br, m, 2H), 1.33-1.73 (m, 17H), 0.89 (s, 9H), 0.04 (s, 6
H); 13C NMR (101 MHz, DMSO-d6): δ 169.4, 162.3, 159.1,
157.7, 149.2, 145.1, 117.4, 115.6, 102.0, 64.2, 51.5, 37.4, 34.1,
32.2, 29.9, 29.9, 29.9, 25.9, 25.9, 24.1, 18.5, 18.5, 18.5, 5.4,
5.4; Anal. calcd. (%) for C25H42N4OSi: C, 67.82; H, 9.56; N,
12.66; found (%): C, 67.80; H, 9.58; N, 12.65.
Hz, 1H), 5.03-5.16 (br, s, 1H), 3.61 (t, J = 6.36 Hz, 2H), 3.40
(br, m, 2H), 2.65 (s, 3H), 1.35-1.71 (m, 8H), 0.89 (s, 9H),
0.00 (s, 6H); 13C NMR (101 MHz, DMSO-d6): δ 169.5, 162.4,
159.2, 157.6, 149.3, 145.2, 117.5, 115.7, 102.1, 64.2, 51.5,
34.1, 32.3, 28.1, 25.9, 25.9, 24.1, 18.5, 18.5, 18.5, 5.4, 5.4;
Anal. calcd. (%) for C22H36N4OSi: C, 65.95; H, 9.06; N, 13.98;
found (%): C, 65.98; H, 9.076; N, 13.95.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-(o-tolyl)-
pyrimidin-4-amine (6d):Yield: 62.0 %; transparent oil; LC-
MS (ESI) m/z calculated for C23H37N3OSi (M + H)+: 400.27;
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-(2,6-
dimethylphenylpyrimidin-4-amine (6i): Yield: 62.0 %;
transparent oil; LC-MS (ESI) m/z calculated for C24H39N3OSi
1
1
found (%): 400.40; H NMR (400 MHz, chloroform-d1): δ
(M + H)+: 414.29; found (%): 414.80 and 415.40; H NMR
8.61 (s, 1H), 7.33 (m, 4H), 6.37 (s, 1H), 4.97 (br, s, 1H), 3.61
(t, J = 6.36 Hz, 2H), 3.32 (br, m, 2H), 2.38 (m, 3H), 1.28-1.73
(m, 8H), 0.89 (s, 9H), 0.00 (s, 6H); 13C NMR (101 MHz,
DMSO-d6): δ 163.8, 158.3, 158.2, 135.9, 133.1, 129.9, 129.5,
128.7, 126.5, 102.1, 64.2, 51.6, 34.1, 32.2, 25.9, 25.9, 24.1,
20.0, 18.6, 18.6, 18.6, 5.4, 5.4;Anal. calcd. (%) for C23H37N3OSi:
C, 69.12; H, 9.33; N, 10.51; found (%): C, 69.15; H, 9.34; N,
10.53.
(400 MHz, chloroform-d1): δ 8.63 (s, 1H), 7.17 (m, 1H), 7.08
(d, J = 7.45 Hz, 2H), 6.24 (s, 1H), 4.91-5.10 (br, s, 1H), 3.60
(t, J = 6.58 Hz, 2H), 3.30 (br, s, 2H), 2.12 (s, 6H), 1.25-1.70
(m, 8H), 0.89 (s, 9H), 0.00 (s, 6H); 13C NMR (101 MHz,
DMSO-d6): δ 163.8, 158.3, 136.3, 136.3, 133.5, 129.8, 129.8,
128.9, 104.2, 64.2, 51. 5, 34.1, 34.1, 32.1, 25.8, 25.8, 24.1,
20.1, 20.1, 18.5, 18.5, 18.5, 5.3, 5.3; Anal. calcd. (%) for
C24H39N3OSi: C, 69.68; H, 9.50; N, 10.16; found (%): C, 69.69;
H, 9.51; N, 10.15.
Step-4: Synthesis of compounds (7a-i): In a round bottom
flask, Suzuki product (6a-i) (1 eq.) was charged in THF (10
vol.). Solution was cooled to 0 °C and 1 M TBAF in THF (3
eq.) was added in to this drop-wise with constant stirring.
Reaction mixture was allowed to come to ambient temperature
and stirred at same temperature for 16 h. TLC (40 % ethyl
acetate/hexane, stain visualization-UV active) showed that
starting material was consumed. Reaction mixture was concen-
trated under reduced pressure and water was added into reaction
mixture. Organic phase was extracted in DCM (2 times).
Combined organic layers were washed with water, dried over
anhydrous sodium sulphate and concentrated under reduced
pressure to afford desired compound (7a-i) which was used
as such for further reaction.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-(quinolin-
4-yl)pyrimidin-4-amine (6e):Yield: 78.1 %; off white solid;
LC-MS (ESI) m/z calculated for C25H36N4OSi(M + H)+: 437.27;
1
found (%): 437.40; H NMR (400 MHz, chloroform-d1): δ
9.00 (d, J = 4.38 Hz, 1H), 8.73 (s, 1H), 8.17 (m, 2H), 7.70-
7.84 (t, 1H), 7.57 (t, J = 7.45 Hz, 1H), 7.49 (d, 1H), 6.58 (s,
1H), 5.12 (br, s, 1H), 3.61 (t, J = 6.36 Hz, 2H), 3.36 (br, s,
2H), 1.32-1.76 (m, 8H), 0.88 (s, 9H), 0.00 (s, 6H); 13C NMR
(101 MHz, DMSO-d6): δ 164.5, 160.4, 158.2, 150.9, 147.9,
144.3, 129.5, 129.3, 127.4, 127.1, 126.1, 121.2, 104.1, 64.2,
51.5, 34.1, 32.2, 25.9, 25.9, 24.1, 18.5, 18.5, 18.5, 5.4, 5.4;
Anal. calcd. (%) for C25H36N4OSi: C, 68.76; H, 8.31; N, 12.83;
found (%): C, 68.74; H, 8.31; N, 12.84.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-(3-methoxy-
phenyl)pyrimidin-4-amine (6f): Yield: 73.8 %; transparent
oil which solidifies on freezing; LC-MS (ESI) m/z calculated
for C23H37N3O2Si (M + H)+: 416.27; found (%): 416.70 and
417.40; 1H NMR (400 MHz, chloroform-d1): δ 8.47 (s, 1H),
7.54 (br, s, 2H), 7.40 (t, J = 7.89 Hz, 2H), 7.03 (m, 1H), 6.90 (s,
1H), 3.82 (s, 3H), 3.55 (m, 2H), 3.32 (br, m, 2H) 1.28-1.61 (m,
8H), 0.85 (s, 9H) 0.00 (s, 6H); 13C NMR (101 MHz, DMSO-
d6): δ 163.4, 159.9, 159.7, 157.9, 138.5, 129.6, 118.4, 115.5,
111.1, 100.1, 64.2, 56.0, 51.4, 34.1, 32.2, 25.9, 25.9, 24.1, 18.5,
18.5, 18.5, 5.4, 5.4;Anal. calcd. (%) for C23H37N3O2Si: C, 66.46;
H, 8.97; N, 10.11; found (%): C, 66.42; H, 8.95; N, 10.10.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-[4,5'-
bipyrimidin]-6-amine (6g): Yield: 84.1 %; off white solid;
LC-MS (ESI) m/z calculated for C20H33N5OSi(M + H)+: 387.25;
6-((6-Phenylpyrimidin-4-yl)amino)hexan-1-ol (7a):
Yield: 100 %; transparent oil; LC-MS (ESI) m/z calculated
for C16H21N3O(M + H)+: 272.17; found (%): 272.30; 1H NMR
(400 MHz, chloroform-d1): δ 8.66 (s, 1H), 7.97 (m, 2H), 7.46
(m, 3H), 6.70 (s, 1H), 5.15 (br, s, 1H), 3.66 (t, J = 6.58 Hz,
2H), 3.33 (t, 2H), 1.33-1.86 (m, 8H).
tert-Butyl 4-(6-((6-hydroxyhexyl)amino)pyrimidin-4-
yl)benzoate (7b): Yield: 63.8 %; brown oil; LC-MS(ESI): m/z
calculated for C16H21N3O(M + H)+: 372.22; found (%): 372.30.
6-((6-(2-(tert-Butyl)pyridin-4-yl)pyrimidin-4-yl)-
amino)hexan-1-ol (7c): Yield: 69.2 %; light yellow oil; LC-
MS (ESI) m/z calculated for C19H28N4O (M + H)+: 329.23;
1
found (%): 329.40; H NMR (400 MHz, chloroform-d1): δ
1
found (%): 388.40; H NMR (400 MHz, chloroform-d1): δ
8.67 (m, 2H), 7.91 (s, 1H), 7.56 (dd, J = 1.32, 5.26 Hz, 1H),
6.71 (s, 1H), 5.06 (br, s, 1H), 3.67 (t, J = 6.36 Hz, 2H), 3.20-
3.48 (m, 2H), 1.17-1.77 (m, 17H).
9.29 (s, 3H), 8.66 (s, 1H), 6.69 (s, 1H), 5.07 (br, s, 1H), 3.60
(m, 2H), 3.40 (br, s, 2H), 1.30-1.76 (m, 8H), 0.89 (s, 9H),
0.00 (s, 6H); Anal. calcd. (%) for C20H33N5OSi: C, 61.98; H,
8.58; N, 18.07; found (%): C, 61.99; H, 8.60; N, 18.05.
N-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-6-(2-
methylpyridin-4-yl)pyrimidin-4-amine (6h):Yield: 86.2 %;
white solid; LC-MS (ESI) m/z calculated for C22H36N4OSi(M
6-((6-(o-Tolyl)pyrimidin-4-yl)amino)hexan-1-ol (7d):
Yield: 77.8 %; transparent oil; LC-MS (ESI) m/z calculated
for C17H23N3O(M + H)+: 286.18; found (%): 286.30.; 1H NMR
(400 MHz, chloroform-d1): δ 8.62 (s, 1H), 7.20-7.45 (m, 4H),
6.38 (s, 1H), 5.03 (br, s, 1H), 3.65 (t, J = 6.36 Hz, 2H), 3.34
(br, s, 2H), 2.40 (s, 3H), 1.23-1.77 (m, 8H).
1
+ H)+: 401.27; found (%): 401.7 and 402.4; H NMR (400
MHz, chloroform-d1): δ 8.64 (d, J = 14.91 Hz, 1H), 8.61 (s,
1H), 7.74 (s, 1H), 7.60 (d, J = 5.26 Hz, 1H), 6.71 (d, J = 0.88
6-((6-(Quinolin-4-yl)pyrimidin-4-yl)amino)hexan-1-ol
(7e): Yield: 73.7 %; transparent oil; LC-MS (ESI) m/z calcu-

1104 Sharma et al.
Asian J. Chem.
lated for C19H22N4O(M + H)+: 323.18; found (%): 323.20; 1H
NMR (400 MHz, chloroform-d1): δ 8.99 (d, J = 3.95 Hz, 1H),
8.59 (br, s, 1H), 8.20 (d, J = 8.33 Hz, 1H), 8.10 (m, 1H), 7.81
(t, J = 7.45 Hz, 1H), 7.54-7.68 (m, 2H), 6.75 (s, 1H), 5.45 (br,
s, 1H), 3.38 (br, m, 4H), 1.16-1.64 (m, 8H).
6-((6-(3-Methoxyphenyl)pyrimidin-4-yl)amino)hexan-
1-ol (7f): Yield: 99%; Brown oil; LC-MS (ESI) m/z calculated
for C17H23N3O2 (M + H)+: 302.3; 1H NMR (400 MHz, chloro-
form-d1): δ 8.62 (s, 1H), 7.45-7.61 (m, 2H), 7.37 (t, J = 7.89
Hz, 1H), 7.00 (dd, J = 1.75, 7.89 Hz, 1H), 6.67 (s, 1H), 5.09
(br, s, 1H), 3.89 (s, 3H), 3.66 (t, J = 6.58 Hz, 2H), 3.37 (m,
2H), 1.49-1.44 (m, 8H).
1H NMR (400 MHz, chloroform-d1): δ 9.79 (s, 1H), 8.68 (m,
2H), 7.91 (s, 1H), 7.56 (dd, J = 1.53, 5.04 Hz, 2H), 6.71 (s,
1H), 5.04 (br, s, 1H), 3.43 (br, m, 2H), 2.43-2.55 (m, 2H),
1.29-1.82 (m, 15 H).
6-((6-(o-Tolyl)pyrimidin-4-yl)amino)hexanal (8d):
Yield: 50.0 %; transparent oil which solidifies on freezing;
LC-MS (ESI) m/z calculated for C17H21N3O(M + H)+: 284.17;
1
found (%): 284.20; H NMR (400 MHz, chloroform-d1): δ
9.78 (d, J = 1.32 Hz, 1H), 8.62 (s, 1H), 7.33-7.27 (m, 4H),
6.38 (s, 1H), 4.91-5.17 (br, s, 1H), 3.33 (br, m, 2H), 2.48 (m,
2H), 2.40 (s, 3H), 1.23-1.77 (m, 8H).
6-((6-(3-Methoxyphenyl)pyrimidin-4-yl)amino)hexanal
(8f): Yield 22.8 %; white solid; LC-MS (ESI) m/z calculated
for C17H21N3O2 (M + H)+: 300.16; found (%): 300.20; 1H NMR
(400 MHz, chloroform-d1): δ 9.78 (s, 1H), 8.63 (s, 1H), 7.43-
7.60 (m, 3H), 7.37 (t, 1H), 7.01 (dd, J = 1.97, 8.11 Hz, 1H),
6.63 (s, 1H), 5.02 (br, s, 2H), 3.39 (br, m, 2H), 2.48 (t, J = 7.02
Hz, 2H), 1.58-1.80 (m, 4H), 1.36-1.51 (m, 2H), 1.20-1.32 (m,
2H).
6-([4,5'-Bipyrimidin]-6-ylamino)hexan-1-ol (7g): Yield:
99%; Yellow oil; LC-MS (ESI) m/z calculated for C14H19N5O
1
(M + H)+: 274.16; found (%): 274.30; H NMR (400 MHz,
chloroform-d1): δ 9.30 (s, 3H), 8.64 (s, 1H), 6.70 (s, 1H), 3.67
(t, J = 6.36 Hz, 2H), 3.40 (br, m, 2H), 1.32-1.83 (m, 8H).
6-((6-(2-Methylpyridin-4-yl)pyrimidin-4-yl)amino)-
hexan-1-ol (7h): Yield: 99%; Yellow oil; LC-MS (ESI) m/z
calculated for C16H22N4O (M + H)+: 287.18; found (%): 287.20;
1H NMR (400 MHz, chloroform-d1): δ 8.53-8.69 (m, 2H), 7.74
(s, 1H), 7.60 (d, J = 4.82 Hz, 1H), 6.73 (s, 1H), 5.19 (br, s,
1H), 3.66 (t, J = 6.36 Hz, 2H), 3.40 (br, s, 2H), 2.64 (s, 3H),
1.33-1.76 (m, 8H).
6-((6-(2,6-Dimethylphenyl)pyrimidin-4-yl)amino)-
hexan-1-ol (7i): Yield: 99%; brown oil; LC-MS (ESI) m/z
calculated for C18H25N3O (M + H)+: 300.20; found (%): 300.40.
Step-5: Synthesis of compounds (8a-d,8f): To a solution
of alchol (7a-d,f) (1 eq.) in DCM (50 vol.), added triethylamine
(7 eq.). Resultant mixture was stirred at 0 °C for 15 min. DMSO
(7 eq.) and sulfur trioxide-pyridine complex (5 eq.) were added
in to the suspension at same temperature. Resultant mixture
was allowed to stir at room temperature for 3 h. TLC (40 %
ethyl acetate/hexane, stain visualization-UV active) showed
that starting material was consumed. Water was added in to this
and organic phase was extracted.Aqueous layer was extracted
with DCM (2 times). Combined organic layers were washed
with water (3 times), dried over anhydrous sodium sulphate
and evaporated under reduced pressure to get crude product.
Crude product was purified by Combi-Flash {(Teledyne Isco)
using Hi-Purit flash column silica (NP) 40 g, 60 Å, max
pressure: 350 psi (24 bar)} using 0-40 % ethyl acetate:hexane)
to afford desired aldehyde (8a-d,8f).
6-((6-Phenylpyrimidin-4-yl)amino)hexanal (8a): Yield:
36.4 %; off white solid; LC-MS (ESI) m/z calculated for
C16H19N3O(M + H)+: 270.15; found (%): 270.20; 1H NMR (400
MHz, chloroform-d1): δ 9.79 (s, 1H), 8.64 (s, 1H), 7.96 (m,
2H), 7.44 (m, 3H), 6.69 (s, 1H), 4.93 (br, s, 1H), 3.40 (br, s,
2H), 2.48 (s, 2H), 1.20-1.73 (m, 6 H).
tert-Butyl-4-(6-((6-oxohexyl)amino)pyrimidin-4-yl)-
benzoate (8b): Yield: 11.2 %; yellow solid; LC-MS (ESI) m/z
calculated for C21H27N3O3 (M + H)+: 370.21; found (%): 370.30;
1H NMR (400 MHz, chloroform-d1): δ 9.79 (s, 1H), 8.66 (s,
1H), 7.96-8.12 (m, 4H), 6.72 (s, 1H), 5.04 (br, s, 1H), 3.42
(m, 2H), 2.47 (m, 2H), 1.38-1.79 (m, 15H).
Step-6: Synthesis of compounds (8e,8g-i): To an alcoholic
solution of (7e,g-i) (1 eq.) in DCM (50 vol) and the resulting
solution was cooled to 0 °C. Dess martin (3 eq.) was added
into this and resultant mixture was stirred for 0.5 h at 0 °C.
Resultant mixture was allowed to stir at room temperature for
3 h. TLC (60 % ethyl acetate/hexane, stain visualization-UV
active) showed that starting material was consumed. Water
was added in to this and organic phase was extracted.Aqueous
layer was extracted with DCM (2 times). Combined organic
layers were washed with water (3 times), dried over anhydrous
sodium sulphate and evaporated under reduced pressure to
get crude product. Crude product was purified by Combi-Flash
{(Teledyne Isco) using Hi-Purit flash column silica (NP) 40 g,
60 Å, max pressure: 350 psi (24 bar)} using 0-70 % ethyl
acetate:hexane) to afford the desired aldehyde (8e,8g-i).
6-((6-(Quinolin-4-yl)pyrimidin-4-yl)amino)hexanal
(8e): Yield: 27.9 %; yellow solid; LC-MS (ESI) m/z calculated
for C19H20N4O(M + H)+: 321.16; found (%): 321.20; 1H NMR
(400 MHz, chloroform-d1): δ 9.79 (s, 1H), 8.99 (d, 1H), 8.74
(s, 1H), 8.17 (t, J = 7.24 Hz, 2H), 7.74-7.80 (m, 1H), 7.57 (t,
J = 8.11 Hz, 1H), 7.48 (d, 1H), 6.59 (s, 1H), 5.17 (br, s, 1H) 3.40
(br, m, 2H), 2.49 (t, J = 6.58 Hz, 2H), 1.41-1.74 (m, 6H).
6-([4,5'-Bipyrimidin]-6-ylamino)hexanal (8g): Yield:
11.3 %; white solid; LC-MS (ESI) m/z calculated for C14H17N5O
1
(M + H)+: 272.14; found (%): 272.20; H NMR (400 MHz,
chloroform-d1): δ 9.79 (s, 1H), 9.29 (s, 3H), 8.67 (s, 1H), 6.70
(s, 1H), 5.14 (br, s, 1H), 3.36-3.52 (br, m, 2H), 2.46-2.56 (m,
2H), 1.39-1.74 (m, 8H).
6-((6-(2-Methylpyridin-4-yl)pyrimidin-4-yl)amino)-
hexanal (8h): Yield: 25.2 %; off white solid; LC-MS (ESI) m/z
calculated for C16H20N4O(M + H)+: 285.16; found (%): 285.30
1H NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 8.41-8.62 (m,
3H), 7.56 (m, 1H), 7.00 (m, 1H), 3.32 (br, m, 2H), 2.36-2.49
(m, 2H), 1.16-1.61 (m, 8H).
6-((6-(2,6-Dimethylphenyl)pyrimidin-4-yl)amino)-
hexanal (8i): Yield: 59.5 %; white solid; LC-MS (ESI) m/z
calculated for C18H23N3O(M + H)+ 298.18; found (%): 298.30;
1H NMR (400 MHz, chloroform-d1): δ 9.78 (d, J = 1.32 Hz,
1H), 8.64 (s, 1H), 6.94-7.23 (m, 4H), 6.25 (s, 1H), 5.04-5.27
6-((6-(2-(tert-Butyl)pyridin-4-yl)pyrimidin-4-yl)amino)-
hexanal (8c): Yield: 90.5 %; white solid; LC-MS (ESI) m/z
calculated for C19H26N4O(M + H)+: 327.21; found (%): 327.30;

Vol. 32, No. 5 (2020)
Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives 1105
(br, s, 1H), 3.33 (br, m, 2H), 2.47 (m, 2H), 2.18 (m, 6H), 1.61-
1.70 (m, 4H), 1.35-1.51 (m, 2H), 1.16-1.32 (m, 2H).
104.2, 40.2, 38.0, 32.2, 28.3, 26.4, 26.4, 22.1; Anal. calcd.
(%) for C20H22N4O2S: C, 62.81; H, 5.80; N, 14.65; found (%):
C, 62.79; H, 5.81; N, 14.63.
Step-6: A mixture of aldehyde (8a-i) (1 eq.), 2,4-thiazoli-
dinedione (1.5 eq.), piperidine (0.15 eq.) were charged in acetic
acid for 2 h. TLC (60 % ethyl acetate/hexane, stain visuali-
zation-UV active) and LCMS showed that starting material
was consumed.After completion, reaction mixture was concen-
trated under reduced pressure. Residue was diluted with DCM
and washed with saturated aqueous sodium bicarbonate
(2 times) and water (1 time). The organic layer was dried over
anhydrous sodium sulphate and concentrated under reduced
pressure to get the crude product. Crude product was purified
by Combi-Flash {(Teledyne Isco) using Hi-Purit flash column
silica (NP) 12 g, 60 Å, max pressure: 350 psi (24 bar)} using
0-70 % ethyl acetate:hexane) to afford desired product (9a-i).
5-(6-((6-Phenylpyrimidin-4-yl)amino)hexylidene)-
thiazolidine-2,4-dione (9a): Yield: 50.6 %; off white solid;
LC-MS (ESI) m/z calculated for C19H20N4O2S(M + H)+: 369.13;
found (%): 369.30; 1H NMR (400 MHz, chloroform-d1), 3.40
(br, s, 2H), 2.19-2.31 (m, 2H), 2.10 (br, s, 2H), 1.32-1.76 (m,
5-(6-((6-(Quinolin-4-yl)pyrimidin-4-yl)amino)hexyli-
dene)thiazolidine-2,4-dione (9e): Yield: 24.8 %; light yellow
solid; LC-MS (ESI) m/z calculated for C22H21N5O2S(M + H)+:
420.14; found (%): 420.20; 1H NMR (400 MHz, chloroform-
d1): δ 12.37 (br, s, 1H), 8.99 (d, J = 4.38 Hz, 1H), 8.59 (br, s,
1H), 8.19 (d, J = 8.77 Hz, 1H), 8.10 (d, J = 8.33 Hz, 1H), 7.81
(t, J = 7.02 Hz, 1H), 7.55-7.70 (m, 3H), 6.91 (m, 1H), 6.74 (s,
1H), 3.38 (br, m, 2H), 2.20 (d, J = 7.45 Hz, 2H), 1.57-1.38
(br, m, 6H); 13C NMR (101 MHz, DMSO-d6): δ 172.2, 167.9,
161.9, 159.8, 157.7, 149.8, 147.6, 146.6, 143.9, 129.2, 128.9,
127.8, 127.3, 124.8, 120.2,116.2, 106.3, 40.2, 32.5, 29.4,26.7,
26.6; Anal. calcd. (%) for C22H21N5O2S: C, 62.99; H, 5.05; N;
found (%): C, 62.95; H, 5.07; N, 16.70.
5-(6-((6-(3-Methoxyphenyl)pyrimidin-4-yl)amino)-
hexylidene)thiazolidine-2,4-dione (9f): Yield: 60.2 %; off
white solid; LC-MS (ESI) m/z calculated for C20H22N4O3S(M
1
+ H)+: 399.15; found (%): 399.30; H NMR (400 MHz,
1
6 H). H NMR (400 MHz, DMSO-d6): δ 12.36 (br, s, 1H),
chloroform-d1): δ 8.64 (s, 1H), 7.49-7.59 (m, 2H), 7.37 (t, 1H),
7.01 (m, 2H), 6.63 (s, 1H), 3.89 (s, 3H), 3.33-3.49 (m, 2H),
2.24 (m, 2H), 1.17-1.74 (m, 8 H); 13C NMR (101 MHz, DMSO-
d6): δ 176.6, 172.1, 163.2, 159.8, 159.7, 157.9, 145.0 138.7,
129.8, 126.5 118.6, 115.7, 111.3, 100.7, 55.1, 40.1 32.2, 29.2,
26.6, 26.4; Anal. calcd. (%) for C20H22N4O3S: C, 60.28; H,
5.57; N, 14.06; found (%): C, 60.30; H, 5.55; N, 14.07.
5-(6-([4,5'-Bipyrimidin]-6-ylamino)hexylidene)thiazo-
lidine-2,4-dione (9g): Yield: 58.4 %; white solid; LC-MS (ESI)
m/z calculated for C17H18N6O2S(M + H)+: 371.12; found (%):
371.20; 1H NMR (400 MHz, chloroform-d1): δ 9.30 (s, 3H),
8.67 (s, 1H), 6.96 (m, 1H), 6.70 (s, 1H), 3.40 (br, m, 2H), 2.24
(m, 2H), 1.36-1.73 (m, 6H).1H NMR (400 MHz, methanol-
d4): δ 9.30 (br, s, 2H), 9.23 (s, 1H), 8.51 (s, 1H), 6.93 (m, 2H),
3.45 (br, m, 2H), 2.29 (m, 2H), 1.13-1.72 (m, 6H); 13C NMR
(101 MHz, DMSO-d6): δ 177.9, 173.0, 159.4, 159.1, 155.5,
155.3, 145.7, 134.0, 130.7, 127.2 101.9, 98.2, 59.3, 31.9, 28.5,
26.0, 25.6; Anal. calcd. (%) for C17H18N6O2S: C, 55.12; H,
4.90; N, 22.69; found (%): C, 55.15; H, 4.91; N, 22.64;
5-(6-((6-(2-Methylpyridin-4-yl)pyrimidin-4-yl)amino)-
hexylidene)thiazolidine-2,4-dione (9h): Yield: 22.3 %; beige
solid; LC-MS (ESI) m/z calculated for C19H21N5O2S(M + H)+:
384.14; found (%): 384.30; 1H NMR (400 MHz, DMSO-d6):
δ 12.30-12.45 (m, 1H), 8.43-8.61 (m, 3H), 7.53-7.60 (m, 1H),
6.95-7.06 (m, 1H), 6.81-6.94 (m, 1H), 3.32 (m, 2H), 2.55 (m,
2H), 2.20-2.22 (m, 2H), 1.24-1.62 (m, 4H);); 13C NMR (101
MHz, DMSO-d6): δ 177.1, 172.7, 171.3, 164.5, 160.7, 159.2,
158.8, 146.0, 139.8, 130.9, 127.4 117.1, 111.2, 52.2, 50.7,
32.4, 29.8, 29.4, 27.0; Anal. calcd. (%) for C19H21N5O2S: C,
59.51; H, 5.52; N, 18.26; found (%): C, 59.50; H, 5.54; N,
18.25.
8.47 (m, 2H), 7.98 (m, 2H), 7.47 (m, 3H), 6.84-6.88 (m, 2H),
2.13-2.25 (m, 2H), 1.29-1.63 (m, 6H); 13C NMR (101 MHz,
DMSO-d6): δ 171.9, 169.8, 163.8, 158.3, 158.2, 147.9, 133.1,
131.6, 129.9, 129.5, 128.7, 126.5, 126.4, 98.1, 42.5, 32.1, 28.7,
26.7, 26.6; Anal. calcd. (%) for C19H20N4O2S: C, 61.94; H,
5.47; N, 15.21; found (%): C, 61.87; H, 5.45; N, 15.24.
4-(6-((6-(2,4-Dioxothiazolidin-5-ylidene)hexyl)amino)-
pyrimidin-4-yl)benzoate (9b): Yield: 39.4 %; white solid; LC-
MS(ESI) m/z calculated for C24H28N4O4S (M + H)+: 469.18;
1
found (%): 469.30; H NMR (400 MHz, chloroform-d1): δ
8.65 (s, 1H), 7.94-8.12 (m, 4H), 7.03 (m, 1H), 6.70 (s, 1H),
3.38 (m, 2H), 1.99-2.15 (m, 2H), 1.33-1.82 (m, 15H); 13C NMR
(101 MHz, DMSO-d6): δ 172.0, 169.7, 162.9, 160.0, 158.9,
158.8, 158.7, 155.4, 155.3, 145.1, 133.5, 130.2, 128.1, 101.6,
55.4, 51.5, 32.1, 28.7,28.7, 28.7, 28.6, 26.7, 26.6, 26.0; Anal.
calcd. (%) for C24H28N4O4S: C, 61.52; H, 6.02; N, 11.96; found
(%): C, 61.56; H, 6.01; N, 11.98.
5-(6-((6-(2-(tert-Butyl)pyridin-4-yl)pyrimidin-4-yl)-
amino)hexylidene)thiazolidine-2,4-dione (9c): Yield: 28.5 %;
off white solid; LC-MS (ESI) m/z calculated for C22H27N5O2S
1
(M + H)+: 426.19; found (%): 426.30; H NMR (400 MHz,
chloroform-d1): δ 8.68 (m, 2H), 7.92 (s, 1H), 7.57 (d, J = 5.26
Hz, 1H), 7.03 (t, J = 7.89 Hz, 1H), 6.71 (s, 1H), 5.22 (br, s,
1H), 3.43 (br, m, 2H), 2.26 (q, J = 7.31 Hz, 2H), 1.38-1.74
(m, 15H); 13C NMR (101 MHz, DMSO-d6): δ 172.2, 170.9,
169.4, 162.5, 159.1, 157.7, 149.1, 146.4, 145.0, 130.0, 117.4,
115.5, 101.8, 40.2, 38.0, 32.2, 30.4, 30.4, 30.4, 28.3, 26.5,
26.4; Anal. calcd. (%) for C22H27N5O2S: C, 62.09; H, 6.40; N,
16.46; found (%): C, 62.12; H, 6.41; N, 16.42.
5-(6-((6-(o-Tolyl)pyrimidin-4-yl)amino)hexylidene)-
thiazolidine-2,4-dione (9d): Yield: 22.2 %; light orange solid;
LC-MS (ESI) m/z calculated for C20H22N4O2S (M + H)+: 383.15;
found (%): 384.30; 1H NMR (400 MHz, chloroform-d1): δ 8.61
(s, 1H), 7.24-7.46 (m, 4H), 7.02 (t, J = 7.67 Hz, 1H), 6.38 (s,
1H), 4.02 (s, 2H), 3.35 (br, s, 2H), 2.39 (s, 3H), 1.30-1.86 (m,
8H); 13C NMR (101 MHz, DMSO-d6): δ 172.2, 170.9, 169.4,
155.9, 145.0, 135.9, 133.1, 130.0, 129.9, 129.5, 128.7, 126.5,
5-(6-((6-(2,6-Dimethylphenyl)pyrimidin-4-yl)amino)-
hexylidene)thiazolidine-2,4-dione (9i): Yield: 28.9 %; light
yellow solid; LC-MS (ESI) m/z calculated for C21H24N4O2S
1
(M + H)+: 397.16; found (%): 397.30; H NMR (400 MHz,
chloroform-d1): δ 8.65 (s, 1H), 6.97-7.21 (m, 4H), 6.26 (s, 1H),
3.29 (br, m, 2H), 2.15 (m, 6H), 1.39-1.74 (m, 8H) 13C NMR
(101 MHz, DMSO-d6): δ 163.8, 158.3, 136.3, 136.3, 133.5,

1106 Sharma et al.
Asian J. Chem.
129.8, 129.8, 128.9, 104.2, 64.2, 51. 5, 34.1, 34.1, 32.1, 25.8,
25.8, 24.1, 20.1, 20.1, 18.5, 18.5, 18.5, 5.3, 5.3; Anal. calcd.
(%) for C21H24N4O2S: C, 63.61; H, 6.10; N; S, 8.09; found
(%): C, 63.63; H, 6.11; N, 14.10.
5-(6-((6-(o-Tolyl)pyrimidin-4-yl)amino)hexyl)thiazo-
lidine-2,4-dione (10d): Yield: 45.1 %; transparent oil which
was further lyophilized to get white solid; LC-MS (ESI) m/z
calculated for C20H24N4O2S (M + H)+ = 385.16; found (%):
386.30; 1H NMR (400 MHz, DMSO-d6): δ 12.03 (br. s), 8.45
(s, 1H), 7.20-7.44 (m, 5H), 6.49 (s, 1H), 4.48-4.61 (m, 1H),
2.32 (s, 3H), 2.01 (m, 1H), 1.76 (m, 1H), 1.24-1.63 (m, 8H);
1H NMR (400 MHz, DMSO-d6 + D2O): δ 8.43 (br, s, 1H),
7.19-7.38 (m, 4H), 6.48 (s, 1H), 4.48-4.56 (m, 1H), 3.32 (br,
m, 2H), 2.31 (s, 3H), 1.97 (m, 1H), 1.76 (m, 1H), 1.19-1.56
(m, 8H); 1H NMR (400 MHz, chloroform-d1): δ 8.62 (s, 1H),
7.27-7.40 (m, 4H), 6.38 (s, 1H), 4.28 (dd, J = 4.38, 8.77 Hz,
1H), 3.32 (m, 2H), 2.38 (s, 3H), 2.09 (m, 1H), 1.94 (m, 1H),
1.29-1.80 (m, 8H); 13C (101 MHz, DMSO-d6): δ 176.4, 171.9,
163.8, 158.3, 158.2, 135.9, 133.1, 129.9, 129.5, 128.7, 126.5,
98.1, 52.0, 40.2, 31.7, 28.3, 28.0, 26.3, 26.2,20.0;Anal. calcd.
(%) for C20H24N4O2S: C, 62.48; H, 6.29; N, 14.57; found (%):
C, 62.47; H, 6.29; N, 14.56.
Step-7: Synthesis of compounds (10a-i): In an autoclave,
Knoevenagel product (9a-i) (1 eq.) was charged in methanol:
water (10:1) (50 vol). 10 % Pd/C (0.1 mol %) was added at
room temperature. The reaction mixture was stirred at 80 °C
under hydrogen at 40 psi for 2h. 1H NMR showed that starting
material was consumed. After completion, reaction mixture
was cooled to room temperature and passed through a celite
bed. Celite bed was washed with methanol (20 mL × 2) and
filtrate was concentrated under reduced pressure. Crude product
was purified by Combi-Flash {(Teledyne Isco) using Hi-Purit
flash column silica (NP) 4 g, 60 Å, max pressure: 350 psi (24
bar)} using 0-100 % ethyl acetate:hexane) to afford desired
compound.
5-(6-((6-Phenylpyrimidin-4-yl)amino)hexyl)thiazoli-
dine-2,4-dione (10a): Yield: 38.2 %; white solid; LC-MS (ESI)
m/z calculated for C19H22N4O2S (M + H)+: 370.15; found (%):
371.30;. 1H NMR (400 MHz, DMSO-d6): δ 12.03 (br, s, 1H),
8.45 (s, 1H), 7.98 (m, 2H), 7.36-7.53 (m, 4H), 6.90 (s, 1H),
4.55 (dd, J=8.33, 3.95 Hz, 1H), 3.30 (m, 2H) 1.98 (m, 1H),
1.77 (m, 1H), 1.18-1.59 (m, 8H). 1H NMR (400 MHz, DMSO-
d6 + D2O): δ 8.40 (s, 1H), 7.92 (m, 2H), 7.46 (m, 3H), 6.88 (s,
1H), 4.45 (m, 1H), 3.28 (m, 2H), 1.98 (m, 1H), 1.72 (m, 1H),
1.07-1.56 (m, 8 H); 13C NMR (101 MHz, DMSO-d6): δ 176.4,
171.9, 163.8, 158.3, 158.2, 133.1, 129.9, 129.5, 128.7, 126.5,
126.4, 98.1, 52.0, 40.2, 31.7, 28.3, 28.0, 26.3, 26.2;Anal. calcd.
(%) for C19H22N4O2S: C, 61.60; H, 5.99; N, 15.12; found (%):
C, 61.62; H, 5.95; N, 15.15.
tert-Butyl 4-(6-((6-(2,4-dioxothiazolidin-5-yl)hexyl)-
amino)pyrimidin-4-yl)benzoate (10b):Yield: 30 %; transparent
oil which was further lyophilized to get white solid; LC-MS
(ESI) m/z calculated for C24H30N4O4S (M + H)+: 471.20; found
(%): 471.40; 1H NMR (400 MHz, chloroform-d1): δ 9.36 (br,
s, 1H), 8.65 (s, 1H), 7.95-8.16 (m, 4H), 6.72 (s, 1H), 4.33 (m,
1H), 3.38 (m, 2H), 1.87-2.21 (m, 2H), 1.12-1.82 (m, 17H).
13C NMR (101 MHz, DMSO-d6): δ 177.1, 172.3, 162.9, 158.4,
158.3, 158.2, 158.1, 154.8, 154.7,133.5, 130.2, 101.6, 60.4,
55.4, 51.5, 31.7, 28.4,28.4, 28.4, 28.3, 28.0, 26.3, 26.2, 25.9;
Anal. calcd. (%) for C24H30N4O4S: C, 61.26; H, 6.43; N, 11.91;
found (%): C, 61.24; H, 6.44; N, 11.93.
5-(6-((6-(Quinolin-4-yl)pyrimidin-4-yl)amino)hexyl)-
thiazolidine-2,4-dione (10e): Yield: 41.5 %, off white solid;
LC-MS (ESI) m/z calculated for C22H23N5O2S (M + H)+: 422.16;
found (%): 422.20; 1H NMR (400 MHz, DMSO-d6): δ 12.03
(br, s, 1H), 8.98 (br, m, 1H), 8.59 (br, m, 1H), 8.00-8.27 (m,
2H), 7.54-7.89 (m, 4H), 6.75 (s, 1H), 4.56 (m, 1H), 3.17 (m,
1
2H), 1.12-2.07 (m, 10H); H NMR (400 MHz, DMSO-d6 +
D2O): δ 8.97 (br, s, 1H), 8.56 (br, m, 1H), 8.05-8.22 (m, 2H),
7.80 (br, m, 1H), 7.59 (m, 3H), 6.74 (m, 2H), 4.46 (m, 1H),
1
3.30 (br, m, 2H), 1.15-2.04 (m, 10H); H NMR (400 MHz,
MeOD-d4): δ 8.94 (s, 1H), 8.55 (br, s, 1H), 8.07-8.15 (m, 1H),
7.83 (t, J = 7.02 Hz, 1H), 7.56-7.69 (m, 2H), 6.75 (s, 1H),
4.42 (m, 1H), 3.45 (br, m, 2H), 2.15 (br, m, 1H), 1.86 (br, m,
1H), 1.24-1.70 (m, 6H); 13C NMR (101 MHz, DMSO-d6): δ
177.12, 177.1, 173.0, 162.6, 160.5, 158.4, 151.1, 147.8, 144.4,
129.5, 129.4, 127.3, 127.2, 126.0, 126.5, 121.2, 106.3, 51.4,
40.2, 31.8, 28.8, 28.7,26.0, 25.9; Anal. calcd. (%) for
C22H23N5O2S: C, 62.69; H, 5.50; N; found (%): C, 62.67; H,
5.52; N, 16.65.
5-(6-((6-(3-Methoxyphenyl)pyrimidin-4-yl)amino)-
hexyl)thiazolidine-2,4-dione (10f): Yield: 37.3 %; white solid;
LC-MS (ESI) m/z calculated for C20H24N4O3S (M + H)+: 401.16;
found (%): 401.30; 1H NMR (400 MHz, methanol-d4): δ 8.43
(s, 1H), 7.35-7.48 (m, 3H), 7.04 (d, J = 6.14 Hz, 1H), 6.84 (s,
1H), 4.43 (dd, J = 4.39, 8.77 Hz, 1H), 3.86 (s, 2H), 2.13 (br, s,
1H), 1.93 (br, s, 1H), 1.21-1.70 (m, 8H). 13C NMR (101 MHz,
DMSO-d6): δ 176.6, 172.1, 163.2, 159.8, 159.7, 157.9, 138.7,
129.8, 118.6, 115.7, 111.3, 100.7, 55.1, 51.4, 40.1 31.8, 28.8,
28.4, 26.2, 26.1; Anal. calcd. (%) for C20H24N4O3: C, 59.98;
H, 6.04; N, 13.99; found (%): C, 59.99; H, 6.05; N, 14.02.
5-(6-([4,5'-Bipyrimidin]-6-ylamino)hexyl)thiazolidine-
2,4-dione (10g): Yield: 33.3 %; transparent oil which was further
lyophilized to get white solid; LC-MS (ESI) m/z calculated
5-(6-((6-(2-(tert-Butyl)pyridin-4-yl)pyrimidin-4-yl)-
amino)hexylidene)thiazolidine-2,4-dione (10c): Yield: 40%;
white solid; LC-MS (ESI) m/z calculated for C22H29N5O2S
1
(M + H)+: 428.20; found (%): 428.40; H NMR (400 MHz,
DMSO-d6): δ 12.05 (br, s, 1H), 8.48-8.67 (m, 2H), 7.94 (br, s,
1H), 7.63-7.72 (m, 1H), 7.56 (br, m, 1H), 7.02 (s, 1H), 4.56
(dd, J = 4.38, 8.77 Hz, 1H), 1.74-2.07 (m, 4H), 1.21-1.62 (m,
15H); 1H NMR (400 MHz, DMSO-d6 + D2O): δ 8.42-8.68 (m,
2H), 7.86-8.01 (br, m, 1H), 7.66 (br, m, 1H), 6.93 (s, 1H),
4.46-4.58 (dd, J = 4.38, 8.77 Hz, 1H), 3.32 (br, m, 2H), 1.91-
2.04 (m, 2H), 1.72-1.35 (m, 17H). 13C NMR (101 MHz, DMSO-
d6): δ 176.4, 171.9, 169.3, 162.6, 159.0, 157.8, 149.1, 145.0,
117.4, 115.5, 101.8, 51.4, 40.2, 37.4, 31.8, 30.0, 30.0, 30.0,
28.3, 28.1, 26.2, 26.1; Anal. calcd. (%) for C22H29N5O2S: C,
61.80; H, 6.84; N, 16.38; found (%): C, 61.82; H, 6.85; N, 16.38.
1
for C17H20N6O2S (M + H)+: 373.14; found (%): 373.20; H
NMR (400 MHz, DMSO-d6): δ 12.04 (br, s, 1H), 9.13-9.54
(m, 4H), 8.43-8.57 (m, 1H), 7.62 (br, m, 1H), 7.01 (br, m,
1H), 4.49-4.53 (m, 1H), 1.98 (br, m, 1H), 1.77 (br, m, 1H),
1.19-1.60 (m, 8H). 1H NMR (400 MHz, DMSO-d6 + D2O): δ
9.25 (m, 3H), 8.40-8.57 (s, 1H), 6.92-7.14 (s, 1H), 4.41-4.55
(m, 1H), 3.12-3.39 (m, 2H), 1.89-2.07 (m, 1H), 1.66-1.88 (m,

Vol. 32, No. 5 (2020)
Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives 1107
1H), 1.10-1.61 (m, 8H). 13C NMR (101 MHz, DMSO-d6): δ
177.1, 172.3, 158.7, 158.4, 154.8, 154.6 134.0, 130.7, 101.9,
98.2, 59.3, 51.7, 31.9, 28.5, 28.4, 26.0, 25.6; Anal. calcd. (%)
for C17H20N6O2S: C, 54.82; H, 5.41; N, 22.56; found (%): C,
54.85; H, 5.40; N, 22.55.
7.11 (m, 1H), 4.48-4.59 (m, 1H), 3.32 (br, m, 2H), 2.64 (m,
3H), 1.94-2.06 (m, 1H), 1.70-1.85 (m, 1H), 1.16-1.56 (m, 8H)
13C NMR (101 MHz, DMSO-d6): δ 176.8, 172.1, 171.1, 164.1,
160.0, 158.9, 158.6, 139.7, 130.3, 116.7, 111.2, 55.8, 52.2,
51.7, 31.8, 29.5, 28.9, 28.7, 27.0; Anal. calcd. (%) for
C19H23N5O2S: C, 59.20; H, 6.01; N, 18.17; found (%): C, 59.21;
H, 6.03; N, 18.14.
5-(6-((6-(2-Methylpyridin-4-yl)pyrimidin-4-yl)amino)-
hexyl)thiazolidine-2,4-dione (10h): Yield: 66.7 %, off white
solid; LC-MS (ESI) m/z calculated for C19H23N5O2S (M + H)+:
386.16; found (%): 386.30; 1H NMR (400 MHz, DMSO-d6):
δ 11.98-12.08 (br, s, 1H), 8.62-8.71 (m, 1H), 8.51-8.61 (m,
1H), 7.73-7.99 (m, 2H), 7.01-7.16 (m, 1H), 4.51-4.64 (m, 1H),
2.61 (br, m, 2H), 1.92-2.09 (m, 1H), 1.68-1.87 (m, 1H), 1.34
5-(6-((6-(2-Methylpyridin-4-yl)pyrimidin-4-yl)amino)-
hexyl)thiazolidine-2,4-dione (10i): Yield: 32.9 %; transparent
oil which was further lyophilized to get white solid; LC-MS
(ESI) m/z calculated for C21H26N4O2S (M + H)+: 399.18; found
1
(%): 399.6 and 400.3; H NMR (400 MHz, methanol-d4): δ
1
(br, s, 8H). H NMR (400 MHz, DMSO-d6 +D2O): δ 8.48-
8.45 (s, 1H), 7.02-7.24 (m, 3H), 6.38 (s, 1H), 4.43 (m, 1H),
8.67 (m, 1H), 8.45-8.57 (m, 1H), 7.73-7.99 (m, 2H), 6.97-
3.43 (m, 2H), 2.10 (s, 6H), 1.22-1.92 (m, 10H); 13C NMR(101
Cl
N
Cl Si
2
Cl
Cl
N
4
Si
TEA
DIPEA
Si
O
N
N
HO
O
NH2
NH2
DMAP, DCM
RT,16h
99.3%
N
H
N
R
1
Ethanol
3
RT, ON
5
70.3%
Step-1
(HO)2B R
R
N
Step-2
Pd(dppf)Cl2·CH2Cl2
Cs2CO3
Si
O
N
TBAF (1M in THF)
THF, RT, 16 h
HO
N
N
H
N
Dioxane:water (3:1)
100oC, 3h
H
7a-i
6a-i
63-100%
62-87%
Step-4
Step-3
O
R
N
Condition-1(8a-d,f):SO3-pyridine complex
TEA, DMSO, 3h
R
HN
O
O
S
N
HN
N
Condition-2(8e, 8g-i):
O
O
Dess Martin, 3h
N
N
N
S
CH3COOH
reflux, 2h
20-60%
H
DCM, 0oC to RT
8a-i
H
9a-i
11-90%
O
Step-5
Step-6
O
a
b
d
N
c
R
40 psi (Hydrogen gas)
10% Pd/C
CH3OH:H2O (10:1)
O
HN
N
N
R =
O
N
N
H
S
O
f
80oC, 2h
30-67%
Step-7
10a-i
e
N
N
N
g
h
i
Scheme-I: General scheme for synthesis of compounds

1108 Sharma et al.
Asian J. Chem.
MHz, DMSO-d6): δ 176.4, 171.9, 163.8, 158.3, 158.2, 136.1,
136.1, 133.1, 129.9, 129.5, 128.7, 98.1, 52.0, 40.2, 31.7, 28.3,
28.0, 26.3, 26.2, 19.1, 19.1;Anal. calcd. (%) for C21H26N4O2S:
C, 63.29; H, 6.58; N, 14.06; found (%): C, 63.28; H, 6.59; N,
14.07.
ledge Amity Institute of Applied Sciences, Amity University,
Noida, India for other research support.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
RESULTS AND DISCUSSION
REFERENCES
Novel compounds of six membered aliphatic chain with
terminal thiazolidone and pyrimidine based nucleus have been
synthesized. We optimized synthesis (Scheme-I) based on the
literature available for different steps. Some of the steps needed
optimization and the details of the optimization have been dis-
cussed. Aliphatic amine chain (6-aminohexan-1-ol) is substi-
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in usual TBAF method [20]. Parikh-Doering oxidation [21]
worked fine for (8a-d,8i) but product formation was not obser-
ved for others in this condition. Dess martin oxidation was
optimized for (8f, 8h-I) [22].
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TABLE-1
SCREENING OF REACTION CONDITIONS FOR STEP-6
Reagent
(0.015 eq.)
Urea
Thio-urea
Piperidine
Temp.
(°C)
25-100
50-100
100
Yielda
(%)
Entry
Solvent
Time (h)
1
2
3
DMF
DMF
Acetic acid
16
16
3
0b
< 5b
40-70
aConversions by UPLC-LCMS; b Starting material remained unreacted.
https://doi.org/10.1021/acs.jmedchem.7b00282
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Conclusion
Novel class of TZD based pyrimidine analogs have been
designed and synthesized. The synthesis strategy is based on
hydroxyl protection of 6-aminohexan-1-ol to obtain exclu-
sively the amino substituted pyrimidine under mild conditions.
Suzuki coupling at this stage is very facile and gave good yield
with all boronic acids. Steps involved in this synthesis are
reproducible with high level of regio-selectivity. Further scope
of coupling with other Suzuki partners and alterations in the
length of the aliphatic chain as well as the composition of the
linker substitution cannot be undermined.
ACKNOWLEDGEMENTS
The authors are highly grateful to Integral BioSciences
Pvt. Ltd., C-64, Hosiery Complex, Noida-201306, India for
financial and analytical support for this work. We also acknow-
23. J. Fischer, T. Fodor and E. Petenyi, WO Patent 058827A1 (2005).