C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
73
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-((S)-1-oxo-2,3-dihy-
dro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (14). White
solid (5 mmol scale: 1.44 g, 86% yield, 25 mmol scale: 6.58 g,
THF (100 mL). The reaction flask was cooled to ꢀ78 8C and LDA
(2 M in THF, 19.1 mL) was added dropwise with stirring. After 1 h at
ꢀ78 8C, sulfinylimine 6 (5.03 g, 25.0 mmol) dissolved in anhydrous
THF (50 mL) was added dropwise. Stirring was continued at ꢀ78 8C
for 3 h, then the reaction was quenched with saturated NH4Cl
(50 mL) followed by H2O (75 mL) and the mixture was brought to
room temperature. The organic layer was taken and the aqueous
layer was extracted with EtOAc (2 ꢂ 100 mL). The combined organic
layers were washed with H2O (2 ꢂ 200 mL) and brine solution
(1 ꢂ 200 mL) and dried with anhydrous Na2SO4, filtered and the
solvent was removed to give the crude product (90:10 dr,
determined by 19F NMR analysis of the crude product), which
was purified by column chromatography (hexanes/EtOAc = 2:1) to
afford the corresponding product 17 as a white solid in 65% isolated
yield with virtually complete diastereoselectivity.
79% yield), mp 193–195 8C. ½a D25
ꢃ
ꢀ 104.3 (c = 1.21, CHCl3). 1H NMR
(CDCl3, 400 MHz):
d = 7.76 (d, J = 7.7 Hz, 1H), 7.65 (td, J = 7.6,
1.1 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H),
4.72 ꢀ 4.61 (m, 1H), 3.44 ꢀ 3.29 (m, 2H), 3.15 ꢀ 3.05 (m, 2H),
0.93 (s, 9H), 13C NMR (CDCl3, 101 MHz):
d = 203.6, 153.4, 136.1,
135.7, 128.0, 126.7, 125.3 (q, J = 282.9 Hz), 124.1, 58.1 (q,
J = 30.5 Hz), 57.2, 47.0, 27.2, 22.3, 19F NMR (CDCl3, 376 MHz):
d
= ꢀ73.1. HRMS [M + Na+]: calcd for C15H18F3NO2SNa+: 356.0908,
found: 356.0906.
4.7. Procedure for the addition of indanone-derivative enolates to
sulfinylimine (S)-6 (25 mmol scale)
(S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(3-methyl-6-phenyli-
midazo[2,1-b]thiazol-2-yl)ethyl)propane-2-sulfinamide (17).
Into an oven-dried round-bottom flask flushed with N2 were
taken 1-indanone 13 (3.63 g, 27.5 mmol) and anhydrous THF
(125 mL). The reaction flask was cooled to ꢀ78 8C and LDA (2 M in
THF, 2.75 mL) was added dropwise with stirring. After 40 min at
ꢀ78 8C, sulfinylimine 6 (5.03 g, 25.0 mmol) dissolved in anhydrous
THF (50 mL) was pre-cooled to ꢀ78 8C, then added dropwise to the
reaction mixture. Stirring was continued at ꢀ78 8C for 6 h, then the
reaction was quenched with saturated NH4Cl (50 mL), followed by
H2O (100 mL) and the mixture was brought to room temperature.
The organic layers were taken and the aqueous layer was extracted
with EtOAc (2 ꢂ 100 mL). The combined organic layers were
washed with H2O (2 ꢂ 200 mL) and brine solution (1 ꢂ 200 mL)
and dried over anhydrous Na2SO4. The solvent was evaporated, and
the crude mixture was co-concentrated with hexane (94:6 dr,
determined by 19F NMR analysis of the crude product). The solid
product was washed with a minimum amount of hexane/ethyl
acetate mixture (4:1) to afford pure product 14 in 79% isolated
yield with virtually complete diastereoselectivity.
White solid (6.74 g, 65% yield), mp 182–183 8C. ½a D25
ꢃ
+ 153.1
= 7.86 ꢀ 7.82 (m,
(c = 1.04, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
2H), 7.64 (s, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 5.19
(qd, J = 6.5, 2.1 Hz, 1H), 3.84 (s, 1H), 2.53 (s, 3H), 1.28 (s, 9H), 13C
NMR (CDCl3, 101 MHz):
d = 148.6, 147.7, 133.8, 129.7, 128.7, 127.6,
125.3, 123.9 (q, J = 282.0 Hz), 114.4, 106.2, 56.7, 54.0 (q,
J = 32.6 Hz), 22.4, 12.1, 19F NMR (CDCl3, 376 MHz):
d
= ꢀ74.0.
HRMS [M + Na+]: calcd for C18H20F3N3OS2Na+: 438.0892, found:
438.0894.
4.10. Procedure for the deprotection of product 17 (10 mmol scale) to
free amine 18
The product 17 (4.15 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 1:1) to afford the corresponding deprotection
product 18 as a white solid in 87% isolated yield.
4.8. Procedure for the deprotection of product 14 (10 mmol scale) to
free
b-amino-ketone 15
The product 14 (3.33 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 2:1) to afford the corresponding deprotection
product 15 as a white solid in 82% isolated yield.
(R)-2,2,2-trifluoro-1-(3-methyl-6-phenylimidazo[2,1-
b]thiazol-2-yl)ethanamine (18). White solid (2.70 g, 87% yield),
mp 121–122 8C. ½a D25
ꢃ
+ 35.0 (c = 1.14, CHCl3). 1H NMR (CDCl3,
= 7.85 ꢀ 7.80 (m, 2H), 7.58 (s, 1H), 7.40 (t, J = 7.6 Hz,
400 MHz):
d
2H), 7.29 (t, J = 7.4 Hz, 1H), 4.75 (q, J = 6.7 Hz, 1H), 2.43 (s, 3H), 1.98
(br, 2H), 13C NMR (CDCl3, 101 MHz):
= 148.2, 146.9, 133.9, 128.6,
127.4, 126.6, 125.0, 124.9 (q, J = 281.9 Hz), 118.8, 105.8, 51.9 (q,
J = 32.0 Hz), 11.8, 19F NMR (CDCl3, 376 MHz):
[M + H+]: calcd for C14H13F3N3S+: 312.0777, found: 312.0769.
d
d
= ꢀ76.7. HRMS
(S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-2,3-dihydro-1H-
inden-1-one (15). White solid (1.89 g, 82% yield), mp 76–77 8C.
½
a 2D5
ꢃ
ꢀ 58.1 (c = 1.58, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
= 7.75
4.11. Procedure for the addition of thiazolo[3,2-b] [1,2,4]triazole-
derived nucleophiles to sulfinylimine (S)-6 (25 mmol scale)
(d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.6, 1.1 Hz, 1H), 7.49 (d, J = 7.7 Hz,
1H), 7.37 (t, J = 7.2 Hz, 1H), 4.16 ꢀ 4.05 (m, 1H), 3.23 ꢀ 3.18 (m,
2H), 3.04 ꢀ 2.97 (m, 1H), 1.33 (s, 2H), 13C NMR (CDCl3, 101 MHz):
Into an oven-dried round-bottom flask flushed with N2 were
taken thiazolo[3,2-b][1,2,4]triazole 19 (8.55 g, 42.5 mmol) and
anhydrous THF (100 mL). The reaction flask was cooled to ꢀ78 8C
and LDA (2 M in THF, 23.4 mL) was added dropwise with stirring.
After 1 h at ꢀ78 8C, sulfinylimine (5.03 g, 25.0 mmol) dissolved in
anhydrous THF (50 mL) was added dropwise. Stirring was
continued at ꢀ78 8C for 3 h, then the reaction was quenched with
saturated NH4Cl (50 mL) followed by H2O (75 mL) and the mixture
was brought to room temperature. The organic layer was taken and
the aqueous layer was extracted with EtOAc (2 ꢂ 100 mL). The
combined organic layers were washed with H2O (2 ꢂ 200 mL) and
d
= 204.9, 154.1, 136.3, 135.3, 127.7, 126.7, 126.7 (q, J = 281.5 Hz),
124.1, 52.6 (q, J = 29.4 Hz), 47.3, 26.4 (d, J = 0.7 Hz), 19F NMR
(CDCl3, 376 MHz):
C
d
= ꢀ76.2. HRMS [M + H+]: calcd for
11H11F3NO+: 230.0793, found: 230.0778.
4.9. Procedure for the addition of imidazo[2,1-b]-thiazole-derived
nucleophiles to sulfinylimine (S)-6 (25 mmol scale)
Into an oven-dried round-bottom flask flushed with N2 were taken
imidazo[2,1-b]-thiazole 16 (9.11 g, 42.5 mmol) and anhydrous