S. Bolek, J. Ignatowska
JournalofFluorineChemistry217(2019)13–21
4.84–4.90 (m, 1 H), 5.24 (s, 2 H), 5.30 (s, 2 H), 7.27–7.45 (m, 10 H).
13C NMR (125 MHz, CDCl3): δ 57.9, 67.9, 68.7, 69.9, 128.1, 128.4,
128.82, 128.87, 128.89, 128.9, 134.3, 134.4, 149.5, 166.6.
chromatography (Hexane : Ethyl acetate, 7:3). Compound 1a (78 mg,
19%) and compound 8 (128 mg, 48%) were obtained.
3.3.1. 4-Ethoxycarbonyl-2,2-dioxo-1,2,3-oxathiazolidine (8)
1H NMR (500 MHz, CDCl3): δ 1.33 (t, 3JHH = 7.2 Hz, 3 H), 4.34 (qd,
3.1.5. (4S)-4-Ethoxycarbonyl-3-(N-trityl)-2,2-dioxo-1,2,3-oxathiazolidine
4
3JHH = 7.2 Hz, JHH = 0.8 Hz, 2 H), 4.40–4.50 (m, 1 H), 4.59 (dd,
(1e)
3
2
2JHH = 9.0 Hz, JHH = 5.4 Hz, 1 H), 4.76 (dd, JHH = 9.0 Hz,
3JHH = 7.8 Hz, 1 H), 5.29 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ 14.0,
56.2, 63.6, 69.9, 168.3.
Yield 38% (6.34 g). Yellowish solid, mp 112–115 °C.
1H NMR (500 MHz, CDCl3): δ 1.37 (t, JHH = 7.1 Hz, 3 H), 3.54 (t,
3
3JHH = 8.6 Hz, 1 H), 4.27–4.40 (m, 3 H), 4.67 (dd, 2JHH = 8.8 Hz, 3JHH
= 3.0 Hz, 1 H), 7.20–7.35 (m, 10 H), 7.68–7.73 (m, 5 H). 13C NMR
(125 MHz, CDCl3): δ 14.3, 60.1, 62.8, 67.6, 80.1, 127.8, 128.2, 129.3,
141.9, 169.1.
3.4. General procedure for the synthesis of compounds 11a-d
In an argon-flushed flask was placed copper (156 mg, 2.44 mmol),
THF (3 mL) and BrCF2CO2Et (0.16 mL, 1.25 mmol). The flask was he-
ated in 55 °C for 1 h, then cooled to room temperature. TMEDA
(0.08 mL, 0.53 mmol) and compound 1a (304 mg, 1.03 mmol) dissolved
in THF (3 mL) were added. The mixture was stirred overnight in room
temperature (18 h). After that time, the content of flask was poured into
baker containing 10% citric acid (or 1 M NaH2PO4) : AcOEt (1:1,
50 mL) and stirred for few minutes. Copper was quickly removed by
filtration and the phases were separated. Water phase was extracted
twice with ethyl acetate. Combined organic phases were washed by
brine, dried over magnesium sulphate and filtrated. Volatiles were re-
moved under reduced pressure to give liquid, which was purified by
column chromatography (Hexane : Ethyl acetate, 9:1→7:3). Compound
11a was obtained in 46% yield (160 mg) as colorless oil, which soli-
dified upon standing.
3.2. Reaction of compound 1a-e with halogen anions
3.2.1. Ethyl 3-bromo 2-(N-tert-butoxycarbonyl)amino propanoate (6a)
In the flask compound 1a (219 mg, 0.744 mmol), THF (2 mL) and
potassium bromide (139 mg, 1.170 mmol) were placed, then water
(0.5 mL) was added and the mixture was stirred for 2 h at room tem-
perature. The mixture was quenched with 10% citric acid (2 mL) and
extracted three times with Et2O. Combined organic phases were dried
over magnesium sulphate. Volatiles were removed at rotary evaporator
and the residue was purified by column chromatography (Hexane :
Ethyl acetate, 9 : 1) to give 6a in 66% yield (144 mg) and compound 2a
(5.7 mg, 4%).
[α]25 +6.4 (c 0.20, AcOEt). 1H NMR (500 MHz, CDCl3): δ 1.31 (t,
2
3
3JHH = 7.1 Hz, 3 H), 1.46 (s, 9 H), 3.72 (dd, JHH = 10.4 Hz, JHH
=
2
3
3.5 Hz, 1 H), 3.82 (dd, JHH = 10.4 Hz, JHH = 3.1 Hz, 1 H), 4.26 (m,
2 H), 4.71 (m, 1 H), 1.29 (d, JHH = 6.8 Hz, 1 H). 13C NMR (125 MHz,
3
3.4.1. Diethyl N-(tert-butoxycarbonyl)-4,4-difluoroglutamate (11a)
Yield 46% (160 mg). White solid, mp 41–43 °C.
CDCl3): δ 14.3, 28.4, 34.3, 54.0, 62.3, 80.5, 155.1, 169.2. HRMS (ESI)
m/z: calcd. for
C
10H18NO4BrNa+ 318.0317 [M + Na]+
; found
[α]25 -2.1 (c 1.02, MeOH). 1H NMR (500 MHz, CDCl3): δ 1.28 (t,
318.0306.
3
3JHH = 7.1 Hz, 3 H), 1.36 (t, JHH = 7.2 Hz, 3 H), 1.43 (s, 9 H), 2.60
3
3
3
(qd, JHF = 15.3, JHH = 7.2 Hz, 1 H), 2.74 (qd, JHF
= 15.5,
3.2.2. 2-(N-tert-butoxycarbonyl)amino acrylic acid ethyl ester (2a)
3JHH = 4.4 Hz, 1 H), 4.22 (q, JHH = 7.1 Hz, 2 H), 4.26–4.37 (m, 2 H),
3
3
1H NMR (500 MHz, CDCl3): δ 1.32 (t, JHH = 7.1 Hz, 3 H), 1.47 (s,
4.46–4.54 (m, 1 H), 5.11 (d, JHH = 7.0 Hz, 1 H). 13C NMR (125 MHz,
3
3
4
9 H), 4.26 (q, JHH = 7.1 Hz, 2 H), 5.71 (d, JHH = 1.5 Hz, 1 H), 6.12
CDCl3): δ 13.94, 14.08, 28.32, 36.39 (t, 2JCF = 23.5 Hz), 48.84, 62.07,
(bs, 1 H), 7.01 (bs, 1 H).
1
2
3
63.22, 80.38, 114.99 (t, JCF = 251.5 Hz), 155.04, 163.62 (t, JCF
= 32.1 Hz), 170.73. 19F NMR (470 MHz, CDCl3): δ -104.18 (t, JHF
3.2.3. Ethyl 3-chloro-2-(N-tert-butoxycarbonyl)amino propanoate (7a)
In flask was placed compound 1a (308 mg, 1.045 mmol), anhydrous
THF (3 mL), and anhydrous lithium chloride (55 mg, 0.129 mmol). The
mixture was stirred for 2 days at room temperature. Then water was
added and the mixture was extracted three times with Et2O. Combined
organic phases were dried over magnesium sulphate. Volatiles were
removed at rotary evaporator and the residue was purified by column
chromatography (Hexane : Ethyl acetate, 9 : 1) to give 7a in 66% yield
(165 mg), as colorless oil.
+
= 15.7 Hz, 2 F). HRMS (ESI) m/z: calcd. for C14H24NO6F2 340.1572
[M+H]+ ; found 340.1566.
3.4.2. Diethyl N-(benzyloxycarbonyl)-4,4-difluoroglutamate (11b)
Yield 35% (125 mg). White solid, mp 34–35 °C.
[α]25 −1.6 (c 1.04, MeOH). 1H NMR (500 MHz, CDCl3): δ 1.29 (2 x
t, 3JHH = 7.1 Hz, 6 H), 2.64 (qd, 3JHF = 15.4, 3JHH = 7.2 Hz, 1 H), 2.78
3
3
(qd, JHF = 15.7, JHH = 4.5 Hz, 1 H), 4.16–4.30 (m, 4 H), 4.56–4.61
(m, 1 H), 5.11 (s, 1 H), 5.42 (s, 1 H), 7.28–7.39 (m, 5 H). 13C NMR
[α]25 +6.8 (c 0.204, AcOEt). 1H NMR (500 MHz, CDCl3): δ 1.30 (t,
2
2
3
3JHH = 7.1 Hz, 3 H), 1.45 (s, 9 H), 3.85 (dd, JHH = 11.2 Hz, JHH
=
(125 MHz, CDCl3): δ 13.9, 14.1, 36.3 (t, JCF = 23.4 Hz), 49.3, 62.3,
1
2
3
63.3, 67.3, 114.9 (t, JCF = 251.9 Hz), 128.2, 128.4, 128.7, 136.1,
3.3 Hz, 1 H), 3.97 (dd, JHH = 11.2 Hz, JHH = 3.0 Hz, 1 H), 4.26 (m,
155.7, 163.6 (t, JCF = 32 Hz), 170.4. 19F NMR (470 MHz, CDCl3): δ
2
2 H), 4.67 (m, 1 H), 5.43 (d, JHH = 6.9 Hz, 1 H). 13C NMR (125 MHz,
3
3
-104.17 (t, JHF = 15.7 Hz, 2 F). HRMS (ESI) m/z: calcd. for
CDCl3): δ 14.3, 28.4, 45.7, 54.6, 62.3, 80.5; 155.2, 169.2. HRMS (ESI)
+
17H22NO6F2 374.1415 [M+H]+; found 374.1409.
m/z: calcd. for C10H18NO4ClNa+ 274.0822 [M + Na]+
;
found
C
274.0816.
3.4.3. 1-Benzyl-5-ethyl-N-benzyloxycarbonyl-4,4-difluoroglutamate (11d)
Yield 49% (163 mg). White solid, mp 45–46 °C.
3.3. Reaction of compound 1a with BrZnCF2CO2Et
[α]25 -0.8 (c 1.03, MeOH). 1H NMR (500 MHz, CDCl3) δ: 1.29 (t,
3
3
Zinc (180 mg, 2.7 mmol) was placed in an argon-flushed flask, next
anhydrous THF (4 mL) and pinch of iodine was added. The mixture was
heated under reflux and compound 1a (401 mg, 1.36 mmol) dissolved
in 2 mL of anhydrous THF and BrCF2CO2Et (0.26 mL, 2.04 mmol) were
added at the same time. The mixture was heated at reflux for 4 h, then
cooled down, quenched with 10% citric acid and extracted three times
with diethyl ether. Organic phase was washed with water, dried over
magnesium sulphate, and filtrated. Volatiles were removed under re-
duced pressure to give colorless liquid, which was purified by column
3JHH = 7.1 Hz, 3 H); 2.66 (qd, JHF = 15.6, JHH = 6.8 Hz, 1 H); 2.79
3
3
(qd, JHF = 15.6, JHH = 5.5 Hz, 1 H); 4.16–4.29 (m, 2 H); 4.59–4.69
3
(m,1 H); 5.07–5.14 (m, 2 H); 5.19 (m, 2 H); 5.40 (d, JHH = 7.9 Hz,
1 H); 7.27–7.40 (m, 10 H). 13C NMR (125 MHz, CDCl3) δ: 13.9; 36.2 (t,
2JCF = 23.0 Hz); 49.3; 63.4; 67.4; 68.0; 114.9 (t, JCF = 252 Hz);
1
128.3; 128.4; 128.5; 128.7; 128.7; 128.8; 134.9; 136.1; 155.7; 163.6 (t,
2JCF = 32.0 Hz); 170.3. 19F NMR (470 MHz, CDCl3) δ: -104.10 (d, JHF
3
3
= 15.8 Hz, 1 F); -104.18 (d, JHF = 15.8 Hz, 1 F). HRMS (ESI) m/z:
calcd. for C22H24NO6F2 436.1572 [M+H]+; found 436.1566.
+
18