Molecules 2019, 24, 1141
7 of 10
3
1
(
H, CH CH), 3.40 (dd, J
= 8.3 Hz, J = 17.5 Hz, 1H, CH CH), 1.70 (m, 1H, CH CH , enol), 1.65
(H,H)
2 2 3
2
13
m, 4H, CH CH ), 1.02–0.86 ppm (m, 7.36, CH CH ); C-NMR (101 MHz, [D]CDCl , 298 K, TMS) δ
2 3 2 3 3
=
199.6, 169.0, 153.6, 143.1, 137.0, 135.3, 135.2, 129.1, 127.7, 126.7, 126.5, 124.6, 124.6, 120.6, 102.7, 78.3,
+
7
6.4, 53.6, 32.52, 30.3, 26.6, 26.4, 9.6, 9.4 ppm; HRMS (ESI): (M + Na) Calcd for C H O Na 269.1148;
15
18
3
found 269.1144.
Tert-butyl-5,7-difluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2i): Following the general
procedure, 0.50 g (2.21 mmol, 1 eq) of 1i was allowed to react with tert-butanol (22.1 mmol, 10 eq.)
and ZnO (0.04 g, 0.45 mmol, 0.2 eq.) in 5 mL of toluene for 5 h. After purification by column
chromatography on silica-.gel (hexanes (95): AcOEt (5)) a purple oil was obtained in 64% yield (0.38 g).
−
1 1
IR (ATR)
TMS)
ArH), 3.64 (dd, J
ν
= 2961, 1758 (C=O), 1722, 1617, 1283, 1045 cm ; H-NMR (360 MHz [D]CDCl , 298 K,
3
3
3
δ
= 10.62 (bs, 0.07H, OH, enol), 6.97 (d, J
= 7.3 Hz, 1H, ArH), 6.74 (t, J
= 8.2 Hz, 1H, CH CH), 3.48 (dd, J
= 8.3 Hz, J = 17.6 Hz, 1H, CH CH), 1.47 (s, 9H, C(CH ) ); 19F-NMR
= 9.1 Hz, 1H,
(
H,F)
(H,F)
3
3
3
3
= 3.9 Hz, J
= 4.4 Hz, J
= 16.7
(
H,H)
(H,H)
2
(H,H)
(H,H)
3
Hz, CH CH), 3.30 (dd, J
2
(H,H)
2
3 3
3
3
(
1
1J(
235 MHz [D]CDCl , 298 K, TMS)
F); C-NMR (91 MHz, [D]CDCl , 298 K, TMS)
δ
=
−
99.9 (d, J
= 13.7 Hz, 1F),
−
111.3 ppm (d, J
= 13.7 Hz,
3
(F,F)
(F,F)
13
3
3
δ
= 194.5 (d, J
= 2.2 Hz), 167.8 (dd, J
= 3.9 Hz,
3
(C,F)
(C,F)
3
1
= 259.5 Hz), 167.5 (s), 160.0 (dd, J
= 14.2 Hz, J
= 267.5 Hz), 157.7 (m), 120.1 (m), 109.5
C,F)
4
(C,F)
(C,F)
= 22.7 Hz, J
2
2
2
(dd, J(
= 4.2 Hz, J
= 22.5 Hz), 103.9 (dd, J
= 24.7 Hz), 82.5 (s), 55.0 (s), 27.8
(C,F)
C,F)
(C,F)
(C,F)
+
(
s) ppm; HRMS (ESI): (M + Na) Calcd for C H F O Na 291.0803; found 291.0805.
14
14
2
3
General procedure for the enantioselective electrophilic fluorinations: In a 10 mL Schlenk flask
in presence of 4 Å MS, Ln(OTf) (0.13 eq.) and the desired pybox ligand (0.15 eq.) were dissolved with
3
dry ACN (5 mL). The colorless reaction mixture was left stirring at room temperature under argon
atmosphere overnight. Next, the corresponding indanone derivative
2 (80 mg; 1 eq.) was added to the
reaction mixture and left stirring at room temperature for 1 h. Then, the reaction mixture was cooled
◦
down until
−
30 C and, once at this temperature, NFSI (1.15 eq.) was added to the mixture in one
portion. The reaction mixture was left at this temperature under argon atmosphere until complete
conversion of the reagent. Afterwards, the solvent was removed under reduced pressure and the
product was purified by column chromatography on silica gel, yielding the α-fluorinated compound.
Pentan-3-yl (R)-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (10b): Following the general
procedure using La(OTf) and (S,R)-ind-pybox, 79 mg (0.29 mmol, 60% yield) of 10b were obtained as a
3
tan oil from 0.37 mmol of 2b. It was purified by column chromatography on silica-gel (hexane/AcOEt
−
1 1
5
:1). IR (ATR)
ν
= 2970, 1760 (C=O), 1607 (C=O), 1464, 1287, 1214, 1191, 1156, 1100 cm ; H-NMR
3
3
(250 MHz [D]CDCl , 298 K, TMS)
δ
= 7.85 (d, J
= 8.1 Hz, 1H, ArH), 7.71 (t, J
= 7.4 Hz,
= 11.4 Hz,
3
(H,H)
(H,H)
3
2
1
H, ArH), 7.57 (m, 2H, ArH), 4.90 (quint, J
= 6.3 Hz, 1H, OCH), 3.78 (dd, J
(H,H)
(H,H)
3J(
= 17.8 Hz, 1H, CH CF), 3.40 (dd, J
2
= 22.8 Hz, J
3
= 25.7 Hz, 1H, CH CF), 1.55 (m, 4H,
= 18.2 Hz), 167.1
= 3.7 Hz), 136.4 (d, J = 3.0 Hz, Ar-C), 133.4 (s), 128.6 (s), 126.5
H,F)
2
3
(H,H)
(H,F)
2
1
2
CH CH ), 0.84 (m, 6H); C-NMR (91 MHz [D]CDCl , 298 K, TMS)
δ
= 195.5 (d, J
2
3
3
(C,F)
2
= 27.8 Hz), 150.9 (d, 3J
(
(
(
d, J
(
C,F)
(H,F)
4
1
2
d, J(C,F) = 1.2 Hz), 125.5, 94.5 (d, J
s), 9.5 (s), 9.3 (s). F-NMR (235 MHz [D]CDCl , 298 K, TMS)
= 201.2 Hz), 79.6 (s), 38.4 (d, J
= 24.1 Hz), 26.4 (s), 26.3
(C,F)
164.8 ppm (s, 1F); HPLC: Daicel
(C,F)
19
δ
=
−
3
i
Chiralpack AD-H, Hexane/ PrOH=99.5:0.5, 0.75 mL/min, 254 nm, t
=
2
r
(minor) = 33.4 min, t
r
(major)
D
+
40.7 min (64% ee); [
87.1054; found 287.1059.
Tert-butyl (R)-2-fluoro-1-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-indene-2-carboxylate (10g): Following
α
]20
:
−
10.3 (c=5.9, CHCl ). HRMS (ESI): (M + Na) Calcd for C H O FNa
3
15 17
3
the general procedure, using Eu(OTf) and (S,R)-ind-pybox, 67 mg (0.21 mmol, 80% yield) of 10g
3
were obtained as a brown oil from 0.31 mmol of the starting material. It was purified by column
chromatography on silica-gel (hexane/AcOEt 7:3). IR (ATR)
ν
= 2916, 2849, 1736 (C=O), 1467, 1330, 1259,
−
1 1
3
1
1
3
179 cm ; H-NMR (360 MHz [D]CDCl , 298 K, TMS)
δ
= 8.11 (s, 1H, ArH), 7.95 (d, J(H,H) = 7.9 Hz
,
3
3
2
3
H, ArH), 7.68 (d, J
= 7.9 Hz, 1H, ArH), 3.82 (dd, J
= 10.7 Hz, J
= 18.5 Hz, 1H, CH CF),
(H,F)
2
(
H,H)
(H,H)
2
3
19
.47 (dd, J(
= 18.2 Hz, J
= 21.8 Hz, 1H, CH CF), 1.45 (s, 9H, OC(CH ) ); F-NMR (235 MHz
H,H)
(H,F)
2 3 3
13
[
2
D]CDCl , 298 K, TMS)
δ
2
=
−
63.2 (s, 3F, CF ), -163.9 pm (s, 1F, CF); C-NMR (91 MHz [D]CDCl3,
3
3
2
= 27.5 Hz), 154.7 (d, 3J(C,F) = 3.6 Hz), 133.9
(C,F)
98 K, TMS)
δ
= 194.7 (d, J
= 18.6 Hz), 165.6 (d, J
(
C,F)