Synthesis of heterocycle substituted 1-aryl-4-piperidones

Article abstract of DOI:10.3987/COM-02-9447

A series of heterocycle substituted 1-aryl-4-piperidones were prepared via Knoevenagel condensations between nitrogen-containing 5-membered heterocycles and benzaldehyde (1) followed by reduction or amination. The oxadiazolidinedione ring was formed by reacting the N-hydroxyurea (10) with methyl chloroformate and sodium hydride.

Full text of DOI:10.3987/COM-02-9447

HETEROCYCLES, Vol. 57, No. 5, 2002, pp. 857-870, Received, 28th January , 2002
SYNTHESIS OF HETEROCYCLE SUBSTITUTED 1-ARYL-4-
PIPERIDONES
Baihua Hu*, Michael Malamas, and John Ellingboe
Wyeth Research, Chemical Sciences, Collegeville, PA 19426, U.S.A.
hub@wyeth.com
Abstract – A series of heterocycle substituted 1-aryl-4-pipeidones were prepared
via Knoevenagel condensations between nitrogen-containing 5-membered
heterocycles and benzaldehyde (1) followed by reduction or amination. The
oxadiazolidinedione ring was formed by reacting the N-hydroxyurea (10) with
methyl chloroformate and sodium hydride.
As part of a research program directed at the development of human β agonists, a series of 1-aryl-4-
3
piperidones with various heterocyclic acid equivalents were required in the hope of obtaining potent and
1, 2
selective β agonists with good pharmacokinetic properities.
Herein, we report the synthesis of 1-aryl-
3
4-piperidones with nitrogen-containing 5-membered heterocycles as surrogates for the carboxylic acid
3
functionality. The heterocycles reported here are thiazolidinedione, pseudothiohydantoin, hydantoin,
rhodanine, oxadiazolidinedione, and thiazolidinone.
The thiazolidineone, pseudothiohydantoin, hydantoin or rhodanine substituted 1-aryl-4-piperidones (4a-d
4
and 6a-d) were prepared according to Scheme 1. Knoevenagel condensations between benzaldehyde (1)
and 2,4-thiazolidinedione, hydantoin, pseudothiohydantoin, or rhodanine (2a-d) followed by acidic
hydrolysis provided the olefinic piperidones (4a-d). The condensations were usually effected in refluxing
ethanol in the presence of piperidine. It was found more satisfactory to condense benzaldehyde (1) with
2d (rhodanine) in the presence of β-alanine in refluxing acetic acid. The reduced alkylpiperidone (6a)
5
was obtained by a hydrogen transfer reaction (5% Na-Hg in wet THF) followed by an acidic ketal
hydrolysis. A much slower reaction was observed on reduction of thiazolidinedione (3a) under catalytic
hydrogenation due to the presence of sulfur in the molecule. Similarly, the reduced pseudothiohydantoin
(6b) and hydantoin (6c) analogues were obtained by 5% Na-Hg reduction and acidic hydrolysis.
However, treatment of rhodanine (3d) with 5% Na-Hg resulted in the formation of a partially hydrolyzed
6
dimeric compound (5). The reduced rhodanine (6d) was successfully prepared by reduction of 3d with

7
lithium borohydride in pyridine/THF followed by acidic hydrolysis.
b
a
O
O
O
O
Z
O
O
O
N
O
N
CHO
N
+
NH
NH
Y
4 a-d
2a-d
1
3a-d
NH
Z
Z
Y
Y
c or d, b
c for 3d
O
H
N
SH
O
NH
O
Ar
a, Y = O, Z = S;
b, Y = NH, Z = S;
c, Y = NH, Z = NH;
d, Y = S, Z = S.
O
Y
Ar =
N
Ar
O
S
NH2
O
Y, Z =
N
Z
5
6a-d
Scheme 1. (a) piperidine/EtOH or β-alanine/HOAc; (b) concentrated hydrochloric acid; (c) 5% Na/Hg, THF/H2O; (d)
LiBH4/pyridine/THF.
Oxadiazolidinedione substituted 1-aryl-4-piperidone (11) was prepared as outlined in Scheme 2.
Reductive amination of benzaldehyde (1) with hydroxylamine produced 8, which was treated with N-TMS
isocyanate and ketal hydrolysis to afford hydroxyurea (10). The oxadiazolidinedione ring was formed by
8
reacting the N-hydroxyurea (10) with methyl chloroformate and sodium hydride.
O
O
O
O
O
O
O
O
N
a
N
N
b
c
N
O
N
OH
NH2
NHOH
8
NHOH
7
9
CHO
1
d
e, f
N
O
O
N
HO N
H2N
O
N
O
O
10
O
N
11
H
Scheme 2. (a) NH2OH HCl salt, NaOAc, 90%; (b) NaCNBH3, MeOH, 78%; (c) Me3SiNCO, THF/dioxane (1: 1), 73%; (d)
concentrated hydrochloric acid, 98%; (e) ClCO2Me, NaH, THF; (f) NaH, DMF, 85%.
Synthesis of thiazolidinone substituted 1-aryl-4-piperidone (14a-j) was achieved as illustrated in Scheme
3. The thiazolidinone (14f) was obtained by condensation of rhodanine (3d) with piperidine in refluxing
ethanol followed by ketal hydrolysis. Alternatively, alkylation of rhodanine (3d) with methyl iodide
provided the methylmercapto compound (12). Reaction of compound (12) with various amines such as 4-

amino-1-benzylpiperidine, N,N-dimethylguanidine or cyanamide followed by ketal hydrolysis gave the
desired piperidones (14a-e) and (14g-j).
O
O
a
N
N
O
O
O
O
S
S
12
N
NH
3d
b
b
SMe
S
O
c
O
N
N
O
O
O
S
N
S
14 a-j
N
13 a-j
NR1R2
NR1R2
NH
NHMe
NHnHex
NHCH2CH2NMe2
NHCN
N
N
H
d
c
b
a
e
NR1R2 =
H
N
N
N
O
N
NMe
HN
j
N
O
i
h
g
N
f
Bn
Scheme 3. (a) MeI, N,N-diisopropylethylamine, EtOH, 99%; (b) NHR1R2, EtOH; (c) concentrated hydrochloric acid.
7, 9-11
In all cases, the Knoevenagel condensations only afforded the Z isomers.
In conclusion, thiazolidinedione, pseudothiohydantoin, hydantoin, rhodanine, and thiazolidinone
substituted 1-aryl-4-piperidones have been prepared by Knoevenagel condensations between nitrogen-
containing 5-membered heterocycles and benzaldehyde (1) followed by reduction or amination. The
oxadiazolidinedione substituted 1-aryl-4-piperidone (11) was synthesized by reacting the N-hydroxyurea
(10) with methyl chloroformate.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Meltemp melting point apparatus and are
1
uncorrected. H NMR spectra were determined with a Bruker DPX-300 spectrometer at 300 MHz.
Chemical shifts δ are expressed in ppm relative to the internal standard tetramethylsilane and J (coupling
constant) in Hz. ESMS spectra were recorded in positive or negative mode on a Micromass Platform
spectrometer. HRMS spectra were obtained on a Finnigan MAT-90 spectrometer. Combustion analyses
were obtained using a Perkin-Elmer Series II 2400 CHNS/O analyzer. Chromatographic purifications

were performed by flash chromatography using Baker 40 µm silica gel. Thin-layer chromatography
(TLC) was performed on Analtech silica gel GHLF 250 M prescored plates.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]thiazolidine-2,4-dione (3a)
4
A mixture of benzaldehyde (1) (15.0 g, 60 mmol), 2,4-thiazolidinedione (7.0 g, 60 mmol) and piperidine
(8.0 mL, 81.2 mmol) in 450 mL of ethanol was refluxed for 6 h. The solid which was formed on cooling
the solution was collected and washed with a small amount of ethanol to give the title compound as an
1
orange solid (20.5 g, 99%); mp 255-257 °C; H NMR (DMSO-d ) δ 1.67 (t, J = 5.6 Hz, 4 H), 3.47 (t, J =
6
5.6 Hz, 4 H), 3.92 (s, 4 H), 7.07 (d, J = 9.0 Hz, 2 H), 7.43 (d, J = 9.0 Hz, 2 H), 7.67 (s, 1 H), 12.40 (br s, 1
+
+
H); MS (ES) m/z: 346.8 (MH ); HRMS Calcd for C17H19N2O4S(MH ): 346.0987. Found: 346.0994.
Anal. Calcd for C17H18N2O4S: C, 58.94; H, 5.24; N, 8.09. Found: C, 58.92; H, 5.11; N, 7.96.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-iminothiazolidin-4-one (3b)
4
The same procedure described above for 3a was employed with 5.0 g (20.2 mmol) of benzaldehyde (1),
2 mL of piperidine and 2.78 g (24 mmol) of pseudothiohydantoin to afforded 6.50 g (94%) of the title
1
compound as an orange solid; mp >300 °C (decomp); H NMR (DMSO-d ) δ 1.68 (t, J = 5.6 Hz, 4 H),
6
3.43 (t, J = 5.6 Hz, 4 H), 3.91 (s, 4 H), 7.06 (d, J = 8.9 Hz, 2 H), 7.41 (d, J = 8.9 Hz, 2 H), 7.48 (s, 1 H),
+
+
8.99 (br s, 1 H), 9.33 (br s, 1 H); MS (ES) m/z: 345.9 (MH ); HRMS Calcd for C17H20N3O3S (MH ):
346.1226. Found: 346.1205. Anal. Calcd for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.16. Found: C, 58.80;
H, 5.71; N, 12.38.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]imidazolizolidine-2,4-dione (3c)
4
The same procedure described above for 3a was employed with 5.0 g (20.2 mmol) of benzaldehyde (1),
4 mL of piperidine and 3.0 g (30.0 mmol) of hydantoin to afforded 5.90 g (90%) of the title compound as
1
an orange solid; mp 265-267 °C; H NMR (DMSO-d ) δ 1.68 (t, J = 5.8 Hz, 4 H), 3.38 (t, J = 5.8 Hz, 4
6
H), 3.91 (s, 4 H), 6.34 (s, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 10.33 (br s, 1 H), 11.05
+
+
(br s, 1 H); MS (ES) m/z: 330.0 (MH ); HRMS Calcd for C17H20N3O4(MH ): 330.1454. Found:
330.1477.
5-[4(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-thioxothiazolidin-4-one (3d)
4
A mixture of benzaldehyde (1) (4.96 g, 20.0 mmol), rhodanine (2.66 g, 20.0 mmol), and β-alanine (2.0 g,
22.5 mmol) in 50 mL of acetic acid was refluxed for 2 h. The solid which was formed on cooling the
solution was collected and washed with a small amount of acetic acid to give the title compound as a red

1
solid (4.8 g, 66%); mp >240 °C (decomp); H NMR (CDCl ) δ 1.81 (t, J = 5.5 Hz, 4 H), 3.55 (t, J = 5.5
3
Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J = 8.9 Hz, 2 H), 7.58 (d, J = 8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z:
+
+
362.8 (MH ); HRMS Calcd for C17H19N2O3S2(MH ): 363.0837. Found: 363.0852. Anal. Calcd for
C17H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N, 7.73.
5-[4-(Oxopiperidin-1-yl)benzylidene]thiazolidine-2,4-dione (4a)
Compound (3a) (1.60 g, 4.6 mmol) was treated with concentrated hydrochloric acid (150 mL) at rt. After
4 h ~28% ammonium hydroxide was added dropwise and the precipitate was collected by filtration,
washed with water, and dried over phosphorus pentoxide to give 1.30 g (93%) of the title compound as an
1
orange solid; mp >255 °C (decomp); H NMR (DMSO-d ) δ 2.45 (t, J = 6.0 Hz, 4 H), 3.76 (d, J = 6.0 Hz,
6
4 H), 7.10 (d, J = 9.0 Hz, 2 H), 7.48 (d, J = 9.0 Hz, 2 H), 7.70 (s, 1 H), 12.41 (br s, 1 H); MS (ES) m/z:
-
+
301.0 (M-H) ; HRMS Calcd for C15H14N2O3S(M ): 302.0726. Found: 302.0731.
1-[4-(2-Imino-4-oxothiazolidin-5-ylidenemethyl)phenyl]piperidin-4-one (4b)
The same procedure described above for 4a was employed with 1.50 g (4.3 mmol) of 3b and 150 mL of
concentrated hydrochloric acid to afforded 1.25 g (96%) of the title compound as a yellowish solid; mp
1
>260 °C (decomp); H NMR (DMSO-d ) δ 2.44 (t, J = 6.0 Hz, 4 H), 3.74 (t, J = 6.0 Hz, 4 H), 7.14 (d, J =
6
6.7 Hz, 2 H), 7.46 (d, J = 6.7 Hz, 2 H), 7.50 (s, 1 H), 9.00 (br s, 1 H), 9.24 (br s, 1 H); MS (ES) m/z: 301.9
+
+
(MH ); HRMS Calcd for C15H16N3O2S (MH ): 302.0961. Found: 302.0957.
5-[4-(4-Oxopiperidin-1-yl)benzylidene]imidazolidine-2,4-dione (4c)
The same procedure described above for 4a was employed with 0.99 g (3.0 mmol) of 3c and 50 mL of
concentrated hydrochloric acid to afforded 0.65 g (76%) of the title compound as a yellowish solid; mp
1
>240 °C (decomp); H NMR (DMSO-d ) δ 2.43 (t, J = 6.0 Hz, 4 H), 3.70 (t, J = 6.0 Hz, 4 H), 6.36 (s, 1
6
H), 7.01 (d, J = 9.0 Hz, 2 H), 7.53 (d, J = 9.0 Hz, 2 H), 10.35 (br s, 1 H), 11.10 (br s, 1 H); MS (ES) m/z:
+
+
285.9 (MH ); HRMS Calcd for C15H16N3O3 (MH ): 286.1192. Found: 286.1169.
1-[4-(4-Oxo-2-thioxothiazolidin-5-ylidenemethyl)phenyl]piperidin-4-one (4d)
The same procedure described above for 4a was employed with 0.90 g (2.5 mmol) of 3d and 25 mL of
concentrated hydrochloric acid to afforded 0.71 g (89%) of the title compound as a red solid; mp >250 °C
1
(decomp); H NMR (DMSO-d ) δ 2.46 (t, J = 6.1 Hz, 4 H), 3.79 (t, J = 6.1 Hz, 4 H), 7.11 (d, J = 9.0 Hz,
6
-
2 H), 7.48 (d, J = 9.0 Hz, 2 H), 7.56 (s, 1 H); MS (ES) m/z: 316.9 (M-H) ; HRMS Calcd for
+
C15H14N2O2S2(M ): 318.0497. Found: 318.0502.

2-{5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzyl]-4-oxothiazolidin-2-yl}-3-[4-(1,4-dioxa-8-aza-
spiro[4.5]dec-8-yl)phenyl]-2-mercaptopropionamide (5)
A mixture of 3d (3.62 g, 10.0 mmol) and 5% Na-Hg (23.0 g, 50.0 mmol) in water (30 mL) and THF (100
mL) was stirred at rt overnight. The organic layer was decanted from mercury and water. The solvent was
evaporated and the residue was purified by flash chromatography (hexanes/ethyl acetate 2/5) followed by
recrystalization from methylene chloride/hexanes to afforded 0.75 g (23%) of the title compound as a
1
white solid; mp 138°C (decomp); H NMR (DMSO-d ) δ 1.65-1.75 (m, 8 H), 2.50-3.00 (m, 4 H), 3.10-
6
3.30 (m, 8 H), 3.89 (s, 4 H), 3.91 (s, 4 H), 4.07 (br d, J = 9.0 Hz, 1 H), 4.80 (s, 1 H), 6.81 (d, J = 8.4 Hz, 2
H), 6.89 (d, J = 8.4 Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.50 (s, 1 H), 7.54 (s, 1
2+
+
H), 8.23 (s, 1 H); MS (ES) m/z: 328.0 ((M + 2H) , 100%), 655.1 (MH , 25%); HRMS Calcd for
+
C33H43N4O6S2 (MH ): 655.2624. Found: 655.2588. Anal. Calcd for C33H42N4O6S2: C, 60.53; H, 6.46; N,
8.56. Found: C, 60.65; H, 6.60; N, 8.47.
5-[4-(4-Oxopiperidin-1-yl)benzyl]thiazolidine-2,4-dione (6a)
A mixture of 3a (2.20 g, 6.3 mmol) and 5% Na-Hg (16.0 g, 34.8 mmol) in water (20 mL) and THF (60
mL) was stirred at rt overnight. The organic layer was decanted from mercury and water. The solvent was
evaporated and the residue was treated with 100 mL of concentrated hydrochloric acid. After 3 h ~28%
ammonium hydroxide was added dropwise and the precipitate was collected by filtration, washed with
water, and dried over phosphorus pentoxide to give 1.20 g (63%) of the title compound as an off-white
1
solid; mp 152-154 °C; H NMR (DMSO-d ) δ 2.40 (t, J = 5.9 Hz, 4 H), 3.01 (dd, J = 14.1, 9.2 Hz, 1 H),
6
3.29 (dd, J = 14.1, 4.2 Hz, 1 H), 3.57 (t, J = 5.9 Hz, 4 H), 4.86 (dd, J = 9.2, 4.2 Hz, 1 H), 6.96 (d, J = 8.6
+
+
Hz, 2 H), 7.10 (d, J = 8.6 Hz, 2 H); MS (ES) m/z: 304.8 (MH , 100%), 609.0 (2MH , 100%), 914.1
+
+
(3MH , 10%); HRMS Calcd for C15H16N2O3S(M ): 304.0881. Found: 304.0905. Anal. Calcd for
C15H16N2O3S: C, 59.19; H, 5.36; N, 9.20. Found: C, 58.96; H, 5.16; N, 8.91.
1-[4-(2-Imino-4-oxothiazolidin-5-yl-methyl)phenyl]piperidin-4-one (6b)
The same procedure described above for 6a was employed with 4.0 g (11.6 mmol) of 4b, 21.3 g (46.4
mmol) of 5% Na-Hg and 250 mL of concentrated hydrochloric acid to afforded 2.51 g (71%) of the title
1
compound as a yellowish solid; mp >260 °C (decomp); H NMR (DMSO-d ) δ 2.40 (t, J = 5.9 Hz, 4 H),
6
2.79 (dd, J = 14.2, 9.7 Hz, 1 H), 3.28 (dd, J = 14.2, 4.0 Hz, 1 H), 3.56 (t, J = 5.9 Hz, 4 H), 4.54 (dd, J =
9.7, 4.0 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 2 H), 7.10 (d, J = 8.6 Hz, 2 H), 8.68 (br s, 1 H), 8.90 (br s, 1 H); MS
+
+
(ES) m/z: 303.9 (MH ); HRMS Calcd for C15H18N3O2S (MH ): 304.1119. Found: 304.1113.

5-[4-(4-Oxo-piperidin-1-yl)benzyl]imidazolidine-2,4-dione (6c)
The same procedure described above for 6a was employed with 1.80 g (5.4 mmol) of 4c, 10.0 g (21.7
mmol) of 5% Na-Hg and 150 mL of concentrated hydrochloric acid to afforded 1.20 g (77%) of the title
1
compound as an off-white solid; mp >165 °C (decomp); H NMR (DMSO-d ) δ 2.39 (t, J = 6.0 Hz, 4 H),
6
2.83 (d, J = 4.8 Hz, 2 H), 3.55 (t, J = 6.0 Hz, 4 H), 4.25 (t, J = 4.8 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 7.05
+
+
(d, J = 8.7 Hz, 2 H), 7.91 (s, 1 H); MS (ES) m/z: 287.9 (MH ); HRMS Calcd for C15H18N3O3(MH ):
288.1348. Found: 288.1396.
1-[4-(4-Oxo-2-thioxothiazolidin-5-ylmethyl)phenyl]piperidin-4-one (6d)
Lithium borohydride (0.17 g, 6.3 mmol) was added in portions to a stirred solution of 3d (0.90 g, 2.5
mmol) in pyridine (2.5 mL) and THF (12 mL) at rt under nitrogen. The mixture was heated to reflux and
stirred for 3 h. The cooled mixture was carefully added to a stirred solution of hydrochloric acid (3 mL)
and iced water (~50 mL). Extracted into ethyl acetate, the combined organic extracts were washed with
water, dried (MgSO4) and the solvent was removed in vacuo. The resulting residue was treated with 100
mL of concentrated hydrochloric acid. After 16 h ~28% ammonium hydroxide was added dropwise until
pH about 7, and extracted with methylene chloride. The organic extracts were dried over MgSO4.
Evaporation and purification by flash chromatography (hexanes/ethyl acetate 1/1) gave 0.40 g (50%) of
1
the title compound as a yellow solid; mp 152-154 °C; H NMR (CDCl ) δ 2.55 (t, J = 6.0 Hz, 4 H), 3.15
3
(dd, J = 14.2, 9.7 Hz, 1 H), 3.34 (dd, J = 14.2, 4.1 Hz, 1 H), 3.60 (t, J = 6.0 Hz, 4 H), 4.58 (dd, J = 9.7, 4.1
+
Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 9.05 (br s, 1 H); MS (ES) m/z: 321 (MH ,
+
100%); HRMS Calcd for C15H17N2O2S2(MH ): 321.0730. Found: 321.0732. Anal. Calcd for
C15H16N2O2S2: C, 56.22; H, 5.03; N, 8.74. Found: C, 56.20; H, 4.91; N, 8.34.
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde oxime (7)
A solution of sodium acetate (6.64 g, 60.7 mmol) in water (10 mL) was added into a mixture of
benzaldehyde (1) (5.0 g, 20.2 mmol), hydroxylamine hydrochloride (4.22 g, 60.7 mmol), ethyl alcohol
(300 mL), and water (50 mL). The mixture was stirred at 70 °C for 10 h, then poured into water and
extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by
flash chromatography (hexanes/ethyl acetate 2/1) gave a white solid (6.3 g, 90% yield); mp 151-152 °C;
1
H NMR (DMSO-d ) δ 1.63 (m, 4 H), 3.35 (m, 4 H), 3.90 (s, 4 H), 6.96 (m, 2 H), 7.40 (m, 2 H), 7.96 (s, 1
6
+
H), 10.75 (s, 1 H); MS (ES) m/z: 263 (MH ); Anal. Calcd for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68.
Found: C, 64.24; H, 6.81; N, 10.64.

8-{4-[(Hydroxyamino)methyl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane (8)
Hydrochloric acid (4N, in dioxane) was added dropwise into a mixture of 7 (5.3 g, 20.2 mmol), sodium
cyanoborohydride (6.3 g, 101.2 mmol), methyl alcohol (200 mL) and methyl orange (10 mg) until an
acidic solution (pH about 4) was achieved. The mixture was then stirred for 1 h, poured into water,
neutralized with NaOH (2N) and extracted with ethyl acetate. The organic extracts were dried over
MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate/methyl alcohol
1
10/5/1) gave a white solid (4.2 g, 78% yield); mp 107-109 °C; H NMR (DMSO-d ) δ 1.64 (m, 4 H), 3.20
6
(m, 4 H), 3.74 (s, 2 H), 3.90 (s, 4 H), 5.84 (br s, 1 H), 6.86 (m, 2 H), 7.14 (m, 2 H), 7.19 (br s, 1 H); MS
+
(ES) m/z: 265 (MH ).
N-[4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-N-hydroxyurea (9)
Trimethylsilyl isocyanate (2.1 mL, 14.9 mmol) was added dropwise into a mixture of 8 (2.61 g, 9.9
mmol), THF (20 mL) and dioxane (20 mL). The mixture was stirred at rt for 24 h, poured into water and
extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification
by flash chromatography (hexanes/ethyl acetate/methyl alcohol 10/5/1) gave a white solid (2.20 g, 73%);
1
mp 153-154 °C; H NMR (DMSO-d ) δ 1.70 (m, 4 H), 3.21 (m, 4 H), 3.89 (s, 4 H), 4.37 (s, 2H), 6.23 (br
6
+
s, 2 H), 6.86 (m, 2 H), 7.10 (m, 2 H), 9.19 (s, 1 H); MS (ES) m/z: 308 (MH ); Anal. Calcd for
C15H21N3O4: C, 58.62; H, 6.89; N, 13.67. Found: C, 58.37; H, 6.78; N, 13.47.
N-Hydroxy-N-[4-(4-oxo-1-piperidinyl)benzyl]urea (10)
A mixture of 9 (2.20 g, 7.2 mmol) and 10 mL of concentrated hydrochloric acid was stirred at rt for three
days. The mixture was then neutralized with ammonium hydroxide, and extracted with ethyl acetate. The
organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl
1
acetate) gave a white solid (1.86 g, 98%); mp 138-140 °C; H NMR (DMSO-d ) δ 2.41 (m, 4 H), 3.60 (m,
6
+
4 H), 4.43 (s, 2 H), 6.37 (br s, 2 H), 7.03 (m, 2 H), 7.21 (m, 2 H), 9.31 (s, 1 H); MS (ES) m/z: 264 (MH ).
2-[4-(4-Oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione (11)
Sodium hydride (60% in mineral oil, 0.46 g, 11.4 mmol) was added into a mixture of 10 (1.50 g, 5.7
mmol) and THF (10 mL). The mixture was stirred at rt for 2 h and then methyl chloroformate (2.0 mL,
22.8 mmol) was added. The new mixture was stirred for 2 h, poured into water, acidified with
hydrochloric acid (2 N) to pH about 6, and extracted with ethyl acetate. The organic extracts were dried
over MgSO4. Evaporation gave a yellow solid (1.58 g). Part of that material (0.46 g, 1.43 mmol) was
dissolved in DMF (4 mL) and treated with sodium hydride (60% in mineral oil, 0.057 g, 1.43 mmol). The
mixture was stirred for 1 h, poured into water, acidified with hydrochloric acid (2N) and extracted with

ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash
1
chromatography (hexanes/ethyl acetate 1/1) gave the title compound as a yellow solid (0.35 g, 85%); H
NMR (DMSO-d ) δ 2.42 (m, 4 H), 3.62 (m, 4 H), 4.76 (s, 2 H), 7.10 (m, 2 H), 7.23 (m, 2 H), 12.43 (br s,
6
+
1 H); MS (ES) m/z: 290 (MH ).
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylsulfanylthiazo-4-one (12)
A mixture of 3d (1.50 g, 4.14 mmol), N,N-diisopropylethylamine (0.65 g, 5 mmol), methyl iodide (1.13 g,
8 mmol) in ethanol (50 mL) was stirred at rt overnight. Water (300 mL) was then added and the mixture
was stirred for 1 h. The solid which was formed was collected, washed with water, and dried over MgSO4
1
to give the title compound as a red solid; mp 163-165 °C; H NMR (CDCl ) δ 1.80 (t, J = 5.8 Hz, 4 H),
3
2.88 (s, 3 H), 3.50 (t, J = 5.8 Hz, 4 H), 4.00 (s, 4 H), 6.90 (d, J = 9.0 Hz, 2 H), 7.45 (d, J = 9.0 Hz, 2 H),
+
+
7.80 (s, 1 H); MS (ES) m/z: 376.9 (MH , 100%), 752.9 ((2M + H) , 5%); HRMS Calcd for C18H20N2O3S2
+
(M ): 376.0915. Found: 376.0888. Anal. Calcd for C18H20N2O3S2: C, 57.42; H, 5.35; N, 7.44. Found: C,
57.34; H, 5.18; N, 7.34.
5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylaminothiazo-4-one (13a)
A mixture of 12 (0.56 g, 1.5 mmol) and methylamine (7.5 mL, 2.0 M solution in tetrahydrofuran) in
ethanol (100 mL) was refluxed overnight. After cooling to rt hexanes (70 mL) was added and the solid
which was formed was collected and washed with hexanes to give 0.31 g (58%) of the title compound as a
1
yellowish solid; mp 250-252 °C; H NMR (CDCl ) δ 1.75-1.85 (m, 4 H), 3.19 (s, 3 H), 3.40-3.50 (m, 4
3
H), 4.00 (s, 4 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.46 (d, J = 9.0 Hz, 2 H), 7.71 (s, 1 H); MS (ES) m/z: 359.9
+
+
+
(MH , 100%), 719.0 ((2M+H) , 10%); HRMS Calcd for C18H21N3O3S (M ): 359.1304. Found:
359.1307.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-hexylaminothiazol-4-one (13b)
The same procedure described above for 13a was employed with 3.76 g (10.0 mmol) of 12 and 5.06 g
(50.0 mmol) of hexylamine to afforded 3.20 g (75%) of the title compound as a yellowish solid; mp 185-
1
187 °C; H NMR (DMSO-d ) δ 0.87 (t, J = 6.6 Hz, 3 H), 1.20-1.40 (m, 6 H), 1.50-1.60 (m, 2 H), 1.66 (br
6
t, J = 5.6 Hz, 4 H), 3.40-3.60 (m, 6 H), 3.92 (s, 4 H), 7.06 (d, J = 8.9 Hz, 2 H), 7.39 (d, J = 8.9 Hz, 2 H),
+
+
7.48 (s, 1 H), 9.50 (br s, 1 H); MS (ES) m/z: 430.0 (MH , 100%); HRMS Calcd for C23H31N3O3S (M ):
429.2086. Found: 429.2081.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-4-oxo-4,5-dihydrothiazol-2-ylcyanamide (13c)

A solution of cyanamide (0.25 g, 6.0 mmol) in ethanol (50 mL) was treated in portions with potassium
tert-butoxide (0.62 g, 5.5 mmol) at 0~5 °C. The mixture was stirred for 15 min and then 12 (1.70 g, 4.52
mmol) in ethanol (50 mL) was added. The reaction mixture was refluxed for 3 h. Upon cooling with
1
addition of 40 mL of hexanes the precipitated solid was collected as a red solid; mp >300 °C (decomp); H
NMR (DMSO-d ) δ 1.68 (br t, J = 5.6 Hz, 4 H), 3.45 (br t, J = 5.6 Hz, 4 H), 3.92 (s, 4 H), 7.05 (d, J = 9.0
6
+
Hz, 2 H), 7.33 (s, 1 H), 7.39 (d, J = 9.0 Hz, 2 H); MS (ES) m/z: 370.9 (MH , 100%); HRMS Calcd for
+
C18H19N4O3S (MH ): 371.1172. Found: 371.1172.
2-(3-Dimethylaminopropylamino)-5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]thiazol-4-
one (13d)
The same procedure described above for 13a was employed with 3.76 g (10.0 mmol) of 12 and 5.11 g (50
mmol) of 3-dimethylaminopropylamine to afforded 3.60 g (84%) of the title compound as a yellowish
1
solid; mp 230-232°C; H NMR (DMSO-d ) δ 1.60-1.70 (m, 6 H), 2.10 (s, 6 H), 2.25 (t, J = 7.0 Hz, 2 H),
6
3.30-3.50 (m, 6 H), 3.85 (s, 4 H), 7.07 (d, J = 9.0 Hz, 2 H), 7.40 (d, J = 9.0 Hz, 2 H), 7.48 (s, 1 H), 9.50
+
+
(br s, 1 H); MS (ES) m/z: 431.1 (MH , 100%); HRMS Calcd for C22H30N4O3S (M ): 430.2038. Found:
430.2040.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-morpholin-4-ylthiazol-4-one (13g)
The same procedure described above for 13a was employed with 3.76 g (10.0 mmol) of 12 and 8.70 g
(100 mmol) of morpholine to afforded 4.01 g (78%) of the title compound as a yellowish solid; mp 228-
1
230 °C; H NMR (DMSO-d ) δ 1.68 (br t, J = 5.6 Hz, 4 H), 3.45 (br t, J = 5.6 Hz, 4 H), 3.60-3.70 (m,
6
2H), 3.70-3.80 (m, 4 H), 3.90-3.92 (m, 2 H), 3.92 (s, 4 H), 7.05 (d, J = 7.6 Hz, 2 H), 7.49 (d, J = 7.6 Hz, 2
+
+
H), 7.52 (s, 1 H); MS (ES) m/z: 416.0 (MH , 100%); HRMS Calcd for C21H25N3O4S (M ): 415.1565.
Found: 415.1570.
5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-(4-methylpiperazin-1-yl)thiazol-4-one (13h)
The same procedure described above for 13a was employed with 1.88 g (5.0 mmol) of 12 and 5.0 g (50.0
mmol) of 4-methylpiperazine to afforded 2.1 g (98%) of the title compound as a yellowish solid; mp 240-
1
242 °C; H NMR (DMSO-d ) δ 1.68 (br t, J = 5.6 Hz, 4 H), 2.22 (s, 3 H), 2.40-2.50 (m, 4 H), 3.41 (br t, J
6
= 5.6 Hz, 4 H), 3.60-3.65 (m, 2 H), 3.90-4.05 (m, 2 H), 4.05 (s, 4 H), 7.05 (d, J = 8.7 Hz, 2 H), 7.46 (d, J
+
+
= 8.7 Hz, 2 H), 7.53 (s, 1 H); MS (ES) m/z: 429.0 (MH , 100%); HRMS Calcd for C22H28N4O3S (M ):
428.1882. Found: 428.1869.

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-(2-morpholin-4-yl-ethylamino)thiazo-4-one
(13j)
The same procedure described above for 13a was employed with 0.39 g (1.0 mmol) of 12 and 1.30 g (10.0
mmol) of 2-morpholin-4-yl-ethylamine to afforded 0.37 g (78%) of the title compound as a yellowish
1
solid; mp 265-267 °C; H NMR (DMSO-d ) δ 1.68 (t, J = 5.5 Hz, 4 H), 2.35-2.55 (m, 6 H), 3.44 (t, J =
6
5.5 Hz, 4 H), 3.55-3.65 (m, 6 H), 3.92 (s, 4 H), 7.07 (d, J = 8.9 Hz, 2 H), 7.40 (d, J = 8.9 Hz, 2 H), 7.47 (s,
2+
+
+
1 H), 9.43 (br s, 1 H); MS (ES) m/z: 229.9 ((M+2H) , 40%), 458.9 (MH , 100%), 917.2 ((2M+H) , 3%);
+
HRMS Calcd for C23H30N4O4S (M ): 458.1988. Found: 458.1979.
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)phenyl]piperidin-4-one (14a)The same
procedure described above for 4a was employed with 0.25 g (0.7 mmol) of 13a and 18 mL of
concentrated hydrochloric acid to afforded 0.20 g (91%) of the title compound as a yellowish solid; mp
1
254-256 °C; H NMR (DMSO-d ) δ 2.43 (t, J = 5.9 Hz, 4 H), 3.05 (s, 3 H), 3.73 (t, J = 5.9 Hz, 4 H), 7.13
6
+
(d, J = 7.3 Hz, 2 H), 7.46 (d, J = 7.3 Hz, 2 H), 7.50 (s, 1 H), 9.41 (br s, 1 H); MS (ES) m/z: 315.8 (MH ,
+
+
100%), 631.0 ((2M+H) , 10%); HRMS Calcd for C16H17N3O2S (M ): 315.1041. Found: 315.1057.
1-[4-(2-Hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)phenyl]piperidin-4-one (14b)
The same procedure described above for 4a was employed with 2.30 g (5.4 mmol) of 13b and 150 mL of
concentrated hydrochloric acid to afforded 1.50 g (73%) of the title compound as a yellowish solid; mp
1
>180 °C (decomp); H NMR (DMSO-d ) δ 0.87 (t, J = 6.5 Hz, 3 H), 1.20-1.40 (m, 6 H), 1.50-1.75 (m, 2
6
H), 2.43 (t, J = 5.9 Hz, 4 H), 3.40-3.55 (m, 2 H), 3.74 (t, J = 5.9 Hz, 4 H), 7.12 (d, J = 8.9 Hz, 2 H), 7.44
+
(d, J = 8.9 Hz, 2 H), 7.50 (s, 1 H), 9.47 (t, J = 5.3 Hz, 1 H); MS (ES) m/z: 386.0 (MH , 100%); HRMS
+
Calcd for C21H27N3O2S (M ): 385.1824. Found: 385.1809.
4-Oxo-5-[4-(4-oxopiperidin-1-yl)benzylidene]-4,5-dihydrothiazol-2-yl-cyanamide (14c)
The same procedure described above for 4a was employed with 1.60 g (3.9 mmol) of 13c and 50 mL of
concentrated hydrochloric acid to afforded 0.51 g (40%) of the title compound as a red solid; mp >250 °C
1
(decomp); H NMR (DMSO-d ) δ 2.43 (t, J = 6.0 Hz, 4 H), 3.76 (t, J = 6.0 Hz, 4 H), 7.12 (d, J = 9.0 Hz, 2
6
+
H), 7.36 (s, 1 H), 7.47 (d, J = 9.0 Hz, 2 H); MS (ES) m/z: 326.7 (MH , 100%); HRMS Calcd for
+
C16H15N4O2S (MH ): 327.0910. Found: 327.0909.
1-{4-[2-(3-Dimethylaminopropylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]phenyl}piperidin-4-one
(14d)

The same procedure described above for 4a was employed with 2.50 g (5.8 mmol) of 13d and 150 mL of
concentrated hydrochloric acid to afforded 1.02 g (45%) of the title compound as a yellowish solid; mp
1
>190 °C (decomp); H NMR (DMSO-d ) δ 1.60-1.80 (m, 2 H), 2.24 (s, 6 H), 2.30-2.45 (m, 6 H), 3.51 (t,
6
J = 6.9 Hz, 2 H), 3.74 (t, J = 5.9 Hz, 4 H), 7.12 (d, J = 9.0 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.53 (s, 1
+
+
H); MS (ES) m/z: 387.0 (MH , 100%); HRMS Calcd for C20H26N4O2S (M ): 386.1776. Found:
386.1768.
N,N-Dimethyl-N’-{4-oxo-5-[4-(4-oxopiperidin-1-yl)benzylidene]-4,5-dihydrothiazol-2-yl}guanidine
(14e)
A solution of 1,1-dimethylguanidine sulfate (2.05 g, 7.5 mmol) in ethanol (50 mL) was treated in portions
with potassium tert-butoxide (1.44 g, 12.9 mmol). The mixture was stirred for 40 min and then rapidly
filtered into a suspension of 12 (1.88 g, 5 mmol) in ethanol (20 mL). The reaction mixture was refluxed
for 2 h. Upon cooling with addition of a small amount of hexanes the precipitated solid was collected and
dissolved in 25 mL of concentrated hydrochloric acid. After 30 min ~28% ammonium hydroxide was
added dropwise and the precipitate was collected by filtration, washed with water, and dried over
1
phosphorus pentoxide to give 1.80 g (97%) of the title compound as a yellowish solid; mp 218-220 °C; H
NMR (DMSO-d ) δ 2.49 (t, J = 6.0 Hz, 4 H), 2.90-3.20 (m, 6 H), 3.73 (t, J = 6.0 Hz, 4 H), 7.10 (d, J = 9.0
6
+
Hz, 2 H), 7.47 (d, J = 9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 372.0 (MH ); HRMS Calcd for
+
C18H22N5O2S (MH ): 372.1416. Found: 372.1404.
1-[4-(4-Oxo-2-piperidin-1-yl -4H-thiazol-5-ylidenemethyl)phenyl]piperidin-4-one (14f)
A solution of 12 (1.69 g, 4.5 mmol) and piperidine (4.25 g, 50 mmol) in 100 mL of ethanol was refluxed
for 2 h. The excess piperidine and the solvent were removed and the residue was dissolved in 200 mL of
concentrated hydrochloric acid. After 30 min ~28% ammonium hydroxide was added dropwise and the
precipitate was collected by filtration, washed with water, and dried over phosphorus pentoxide to give
1
1.60 g (97%) of the title compound as a yellowish solid; mp >70 °C (decomp); H NMR (DMSO-d ) δ
6
1.50-1.75 (m, 6 H), 2.43 (t, J = 5.9 Hz, 4 H), 3.55-3.70 (m, 2 H), 3.74 (t, J = 5.9 Hz, 4 H), 3.80-3.95 (m, 2
+
H), 7.10 (d, J = 8.9 Hz, 2 H), 7.51 (d, J = 8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 370.0 (MH , 100%),
+
+
739.1 ((2M+H) , 5%); HRMS Calcd for C20H23N3O2S (M ): 369.1511. Found: 369.1518.
1-[4-(2-Morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)phenyl]piperidin-4-one (14g)
The same procedure described above for 4a was employed with 3.80 g (9.2 mmol) of 13g and 150 mL of
concentrated hydrochloric acid to afforded 2.9 g (85%) of the title compound as a yellowish solid; mp

1
250-252 °C; H NMR (DMSO-d ) δ 2.44 (t, J = 6.0 Hz, 4 H), 3.60-3.80 (m, 10 H), 3.85-3.95 (m, 2 H),
6
+
7.10 (d, J = 8.9 Hz, 2 H), 7.51 (d, J = 8.9 Hz, 2 H), 7.57 (s, 1 H); MS (ES) m/z: 372.0 (MH , 100%);
+
HRMS Calcd for C19H21N3O3S (M ): 371.1303. Found: 371.1310.
1-{4-[2-(4-Methylpiperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]phenyl}piperidin-4-one (14h)
The same procedure described above for 4a was employed with 1.90 g (4.4 mmol) of 13h and 100 mL of
concentrated hydrochloric acid to afforded 1.60 g (94%) of the title compound as a yellowish solid; mp
1
>200 °C (decomp); H NMR (DMSO-d ) δ 2.24 (s, 3 H), 2.40-2.60 (m, 8 H), 3.60-3.70 (m, 2 H), 3.74 (t,
6
J = 6.0 Hz, 4 H), 3.85-3.95 (m, 2 H), 7.10 (d, J = 8.9 Hz, 2 H), 7.51 (d, J = 8.9 Hz, 2 H), 7.55 (s, 1 H); MS
+
+
(ES) m/z: 385.0 (MH , 100%); HRMS Calcd for C20H24N4O2S (M ): 384.1620. Found: 384.1616.
1-{4-[2-(1-Benzylpiperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]phenyl}piperidin-4-one
(14i)
The same procedures described above for 13a and 4a were employed to afforded 66% of the title
1
compound as a yellowish solid; mp 95-97 °C; H NMR (DMSO-d ) δ 1.50-4.00 (m, 9 H), 2.43 (t, J = 5.9
6
Hz, 4 H), 3.33 (s, 2 H), 3.74 (t, J = 5.9 Hz, 4 H), 7.12 (d, J = 8.7 Hz, 2 H), 7.20-7.50 (m, 5 H), 7.44 (d, J =
+
+
8.7 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 475.0 (MH , 100%), 949.3 ((2M+H) , 2%); HRMS Calcd for
+
C27H30N4O2S (M ): 474.2089. Found: 474.2085.
1-{4-[2-(2-Morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl] phenyl}piperidin-4-one
(14j)
The same procedure described above for 4a was employed with 0.18 g (0.39 mmol) of 13j and 12 mL of
concentrated hydrochloric acid to afforded 0.14 g (86%) of the title compound as a yellowish solid; mp
1
243-245 °C; H NMR (DMSO-d ) δ 2.30-2.55 (m, 10 H), 3.50-3.70 (m, 6 H), 3.74 (t, J = 5.9 Hz, 4 H),
6
7.11 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H), 7.50 (s, 1 H), 9.46 (br s, 1 H); MS (ES) m/z: 414.9
+
+
+
(MH , 100%), 829.1 ((2M+H) , 2%); HRMS Calcd for C21H26N4O3S (M ): 414.1726. Found: 414.1734.
ACKNOWLEDGEMENTS
The authors acknowledge the members of the Wyeth Research Discovery Analytical Chemistry group for
analytical and spectral determinations.
REFERENCES AND NOTES

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