6052 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Yu et al.
N-(2-(5-Chloro-2-methoxyphenylamino)-4,5′-bithiazol-2′-yl)piv-
alamide 22. A suspension of 21 (0.73 g, 2.3 mmol) and N-(5-chloro-
2-methoxyphenyl)thiourea (0.73 g, 2.53 mmol) in EtOH (25 mL)
was refuxed for 30 min. When the mixture was cooled, the product
was collected by filtration and washed with cold ethanol to yield
22 as a pale-yellow solid (0.40 g, 84%). Mp decomposition at 216
°C. 1H NMR (600 MHz, DMSO-d6): δ 11.86 (br s, 1H) 9.93 (br s,
1H), 8.64 (d, J ) 2.4 Hz, 1H), 7.83 (s, 1H), 7.18 (s, 1H), 7.02 (d,
J ) 8.4 Hz, 1H), 6.98 (dd, J ) 8.4 Hz, 2.4 Hz, 1H), 3.86 (s, 3H),
1.25 (s, 9H). 13C NMR (150 MHz, DMSO-d6): δ 176.7, 162.1,
158.9, 146.6, 140.2, 136.4, 130.5, 124.7, 124.2, 121.3, 117.3, 112.1,
91.0, 56.1, 38.8, 26.6. HRMS m/z (ESI) calcd for C18H19ClN4O2S2
(M + H)+ 423.0711, found 423.0713.
N-(5-Propionylthiazol-2-yl)pivalamide 23. Following the protocol
outlined for 20 gave 23 as an off-white powder (0.78 g, 52%). Mp
decomposition at 126 °C. 1H NMR (400 MHz, CDCl3), δ 9.23 (br
s, 1H), 8.03 (s,1H), 2.88 (q, J ) 8 Hz, 2H), 1.34 (s, 9H), 1.23 (t,
J ) 8 Hz, 3H). MS (ESI) m/z 241.07 [M + 1]+.
N-(5-(2-Bromopropanoyl)thiazol-2-yl)pivalamide 24. Following
the protocol outlined for 21 gave 24 (0.73 g, 71%) as an off-white
powder. Mp decomposition at 192 °C. 1H NMR (400 MHz, CDCl3):
δ 8.25 (s, 1H), 5.02 (q, J ) 6.8 Hz, 1H), 1.87 (d, J ) 6.8 Hz, 3H),
1.35 (s, 9H). MS m/z (ESI) 319.04 [M + H]+, 321.00 [(M + 2) +
H]+.
pressure and the residue was recrystallized from EtOH to yield 28
(2.1 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.19
(s, 2H), 8.44 (d, J ) 2.4 Hz, 1H), 7.00 (d, J ) 8.4 Hz, 1H), 6.92
(dd, J ) 8.4 Hz, 2.4 Hz, 1H), 3.83 (s, 3H), 2.91-2.87 (m, 4H),
1.98 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 167.6, 160.8,
147.0, 135.5, 131.7, 124.9, 122.0, 121.3, 117.2, 114.5, 112.6, 56.7,
28.9, 25.9, 21.9, 19.2. MS (ESI) m/z 378.88 [M + 1]+.
N-(2-(5-Chloro-2-methoxyphenylamino)-7,8-dihydro-6H-cyclo-
hepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide 29. Compound 28
(1.73 g, 3.75 mmol) and dry DCM (40 mL) under N2 was treated
sequentially with TEA (1.32 mL, 9.38 mmol) and 2,2-dimethyl-
propionyl chloride (598 µL, 4.86 mmol). The suspension became
light-brown within 2 min and DCM was removed in vacuo at room
temperature. The residue was purified by flash chromatographic
column (hexane/ethyl acetate ) 4:1 and then 1:1 eluent) to afford
29 (1.46 g. 84%) with 99.0% purity. Mp decomposition at 197 °C.
1H NMR (400 MHz, DMSO-d6): δ 11.60 (s, 1H), 9.65 (s, 1H),
8.58 (d, J ) 0.8 Hz, 1H), 6.99-6.92 (m, 2H), 3.84 (s, 3H), 3.01 (t,
J ) 4 Hz, 2H), 1.91 (t, J ) 4 Hz, 2H), 1.99 (m, 2H), 1.21 (s, 9H).
13C NMR (100 MHz, DMSO-d6): δ 176.9, 160.1, 156.2, 146.9,
146.8, 138.1, 132.0, 125.0, 121.8, 120.9, 120.7, 117.2, 112.4, 56.7,
33.0, 27.3, 26.8, 23.0. HRMS m/z (ESI) calcd for C21H23ClN4O2S2
(M + H)+ 463.1024, found 463.1019.
2-(5-Chloro-2-methoxyphenylamino)-4,5,6,7-tetrahydrocyclo-
hepta[d]thiazol-8-one 30. Following the procedure described for 26
by condensing 5-chloro-2-methoxyphenylthiourea gave 30 (light-
brown solid; 26% for two steps). 1H NMR (600 MHz, DMSO-d6):
δ 7.81 (d, J ) 2.4 Hz, 1H), 7.75 (dd, J ) 9 Hz, 2.4 Hz, 1H), 7.42
(d, J ) 9 Hz, 1H), 3.83 (s, 3H), 2.84-2.75 (m, 2H), 2.58-2.52
(m, 1H), 2.33-2.28 (m, 1H), 1.90-1.74 (m, 4H). 13C NMR (150
MHz, DMSO-d6): δ 194.4, 169.8, 154.5, 148.9, 134.1, 130.2, 125.7,
122.6, 121.7, 116.3, 57.6, 42.9, 30.5, 24.4, 21.5.
7-Bromo-2-(5-chloro-2-methoxyphenylamino)-4,5,6,7-tetrahy-
drocyclohepta[d]thiazol-8-one 31. Following the procedure de-
scribed for 27 gave 31 (white powder; 70% yield). MS (ESI) m/z
[M + H]+ 400.87; [(M + 2) + H]+ 402.90.
N-(2-(5-Chloro-2-methoxyphenylamino)-5-methyl-4,5′-bithiazol-
2′-yl)pivalamide 25. Following the protocol outlined for 22 gave
1
25. Mp decomposition at 221 °C. H NMR (600 MHz, DMSO-
d6): δ 11.79 (br s, 1H), 9.73 (br s, 1H), 8.57 (d, J ) 3 Hz, 1H),
7.67 (s, 1H), 7.01 (d, J ) 8.4 Hz, 1H), 6.96 (dd, J ) 8.4 Hz, 3 Hz,
1H), 3.86 (s, 3H), 2.43 (s, 3H), 1.26 (s, 9H). 13C NMR (150 MHz,
DMSO-d6): δ 176.5, 159.6, 157.9, 146.5, 136.7, 134.0, 131.2, 126.4,
124.3, 120.6, 117.0, 116.9, 112.0, 56.1, 38.8, 26.6, 11.7. HRMS
m/z (ESI) calcd for C19H21ClN4O2S2 (M + H)+ 437.0867, found
437.0868.
2-Amino-6,7-dihydro-4H-cyclohepta[d]thiazol-8(5H)-one 26. Fol-
lowing the procedure reported by Ragan26a afforded cycloheptane-
1,3-dione as clear and colorless oil. IR cm-1: 2949, 2870, 1716,
1696 (lit. 1716, 1693). Bp 70 °C at 0.3 mmHg. 1H NMR matches
literature data.25
To a 0 °C biphasic mixture of cycloheptane-1,3-dione (5.7 g,
45.17 mmol) in CCl4/deionized water (1:1; 150 mL) was added
(dropwise) Br2 (2.55 mL, 49.7 mmol) in CCl4 (75 mL). The mixture
was stirred at 0 °C for 1 h and extracted with DCM, and the organic
layer was collected. DCM was removed under reduced pressure at
room temperature to afford 2-bromocycloheptane-1,3-dione which
was used to the next step without further purification.
N2-(5-Chloro-2-methoxyphenyl)-5,6-dihydro-4H-cyclohepta[1,2-
d:3,4-d′]bithiazole-2,2′-diamine 32. Following the procedure outlined
for 28 by condensing with thiourea afforded 32 as a white powder
(32%). 1H NMR (600 MHz, DMSO-d6): δ 9.48 (br s, 1H),
7.89-7.84 (m, 2H), 7.81 (d, J ) 2.4 Hz, 1H), 7.72 (dd, J ) 9 Hz,
2.4 Hz, 1H), 7.40 (d, J ) 9 Hz, 1H), 3.84 (s, 3H), 2.81-2.73 (m,
2H), 2.47-2.42 (m, 1H), 2.28-2.23 (m, 1H), 1.93-1.88 (m, 2H).
13C NMR (150 MHz, DMSO-d6): δ 166.7, 165.9, 154.0, 134.4,
134.0, 133.0, 129.6, 124.9, 121.7, 119.4, 115.4, 113.8, 56.8, 28.2,
25.3, 21.6. MS (ESI) m/z 379.01 [M + 1]+.
To a solution of 2-bromocycloheptane-1,3-dione (45.17 mmol)
in absolute EtOH (100 mL) was added thiourea (3.61 g, 47.43
mmol). The reaction mixture was stirred at room temperature
overnight at which point the EtOH was removed under reduced
pressure and the resulting dark-orange residue was triturated with
DCM. The residue was recrystallized from EtOH to afford 26 as
an off-white solid (6 g, 50% overall crude yield from cycloheptane-
1,3-dione). 1H NMR (300 MHz, DMSO-d6): δ 8.87 (br s, 2H), 2.87
(t, J ) 6 Hz, 2H), 2.64 (t, J ) 6 Hz, 2H), 1.89-1.85 (m, 2H),
1.81-1.77 (m, 2H).
N-(2-(5-Chloro-2-methoxyphenylamino)-5,6-dihydro-4H-cyclo-
hepta[1,2-d:3,4-d′]bithi-azole-2′-yl)pivalamide 33. Following the
procedure outlined for 29 gave 33 as a yellow powder (36%). H
1
NMR (600 MHz, DMSO-d6): δ 7.64 (d, J ) 2.4 Hz, 1H), 7.62
(dd, J ) 7.2 Hz, 2.4 Hz, 1H), 7.35 (d, J ) 7.2 Hz, 1H), 7.05 (br
s, 2H), 3.82 (s, 3H), 2.87-2.85 (m, 2H), 2.68-2.64 (m, 1H),
2.48-2.44 (m, 1H), 2.02-1.96 (m, 2H), 1.02 (s, 9H). 13C NMR
(150 MHz, DMSO-d6): δ 187.3, 167.0, 165.8, 154.3, 137.4, 133.1,
131.1, 130.3, 127.3, 124.4, 118.5, 115.4, 114.7, 57.0, 40.7, 29.0,
28.3, 26.5, 22.8. HRMS m/z (ESI) calcd for C21H23ClN4O2S2 (M
+ H)+ 463.1024, found 463.1039.
2-Amino-7-bromo-6,7-dihydro-4H-cyclohepta[d]thiazol-8(5H)-
one 27. Compound 26 (1.96 g, 7.45 mmol; HBr salt form) in glacial
acetic acid (70 mL) was treated dropwise with Br2 (421 µL, 8.2
mmol). The reaction mixture was stirred at room temperature for
30 min. The crude product was collected by filtration, washed with
cold acetone, and dried to yield 27 which was used in the next
step without purification (1.98 g, 78%). 1H NMR (600 MHz,
DMSO-d6): δ 8.71 (br s, 2Η), 5.11 (dd, J ) 6.9 Hz, 3.3 Hz, 1H),
3.08-2.90 (m, 2H), 2.47-2.39 (m, 1H), 2.28-2.20 (m, 1H), 2.14
(dd, J ) 10.1 Hz, 2.3 Hz, 1H), 1.98 -1.90 (m, 1H). MS (ESI) m/z
[M + H]+ 260.92; [(M + 2) + H]+ 262.88.
Computational Methods. Model systems of 1, 17, 22, and 29
with the tert-butyl group replaced by a methyl group and the
methoxy and chloro groups on the aniline replaced by hydrogens
were utilized. Preliminary calculations (see Figure S3 in Supporting
Information) suggested that the presence of the methoxy and chloro
functional groups does not significantly affect the relative energies
of the two aniline conformers. In all cases, the lowest energy aniline
and amide conformers (which are also consistent with the crystal
structure of 29; see Chart 2) were utilized.
All calculations were performed with the Gaussian 0327 software
suite. Geometries were optimized without symmetry constraints
using the B3LYP/6-31+G(d,p) method.28 All stationary points were
characterized as either minima or transition state structures via
frequency calculations, and the reported energies include unscaled
N2-(5-Chloro-2-methoxyphenyl)-7,8-dihydro-6H-cyclohepta[1,2-
d:3,4-d′]bithiazole-2,2′-diamine 28. An absolute ethanol (50 mL)
suspension of 27 (1.73 g, 6.64 mmol) and 4 (2.11 g, 7.3 mmol)
was heated at reflux overnight. EtOH was removed under reduced