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7 The reagent, 3-bromo-3,3-difluoropropene,
is available from the TCI Company, although we obtained it as a
gift from Professors G. Zhao and F.-L. Qing of the Shanghai Institute of
Organic Chemistry (see also Acknowledgment).
12 The acetal deprotection proceeded
much faster when the acid used was switched from oxalic acid to
TsOH×H2O.
15
Preparation of
New Compounds
Compound 5
Indium
powder (67 mg, 0.58 mmol) and 3-bromo-3,3-difluoropropene (70 µL,
0.72 mmol) were added sequen-tially to a solution of 4 (94
mg, 0.45 mmol) in DMF (3 mL). The mixture was then sonicated for
3 h. After evaporation of DMF under reduced pressure, sat. aq NaHCO3 soln
and EtOAc were added. The two layers were separated, and
the
aqueous layer was further extracted with EtOAc. The combined organic
layers were dried (Na2SO4), filtered, and concentrated
to give a residue, which was chromatographed (EtOAc-PE,
1:5) to afford 5 (100 mg, 78%)
as a colorless oil: ¹H NMR (300 MHz, CDCl3): δ = 1.16
(t, J = 9.2
Hz, 3 H), 1.27 (t, J = 9.9
Hz, 3 H), 3.36-3.50 (m, 2 H), 3.54-3.65 (m, 1
H), 3.74-3.82 (m, 1 H), 4.99 (d, J = 9.6
Hz, 1 H), 5.36-5.45 (m, 1 H), 5.49 (d, J = 11.1
Hz, 1 H), 5.61-5.69 (m, 1 H), 5.88 (s, 1 H), 5.92-6.02
(m, 1 H), 7.31 (dd, J = 7.8,
4.5 Hz, 1 H), 8.04 (dd, J = 7.8,
1.5 Hz, 1 H), 8.53 (dd, J = 4.7,
1.7 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 15.0,
15.0, 60.2, 63.2, 70.4 (t, J = 31.1
Hz), 97.7 (t, J = 4.6
Hz), 120.1 (t, J = 244.8
Hz), 121.1 (t, J = 9.6
Hz), 123.4, 129.8 (t, J = 25.4 Hz),
133.7, 135.6, 147.7, 152.3 (d, J = 5.4
Hz). ¹9F NMR (282 MHz, CDCl3): δ = -109.59
(dm, J = 249.2
Hz, 1 F), -104.12 (dm, J = 248.7
Hz, 1 F). MS (MALDI): m/z = 310.1 [M + Na],
289.1 [M + 2H], 288.1
[M + H].
HRMS (MALDI): m/z calcd for
C14H19NO3F2 + H: 288.1411;
found: 288.1414.
Compounds 6a,b
To
a soln of 5 (108 mg, 0.38 mmol) in acetone
and H2O (1:1, 8 mL) was added PTSA˙H2O
(143 mg, 0.75 mmol). The mixture was heated at reflux for 2 h, cooled
to r.t., neutralized with sat. aq NaHCO3 soln, and extracted
with EtOAc. The combined organic layers were dried (MgSO4), filtered,
and concentrated. The residue was chromatog-raphed (EtOAc-PE,
1:1) to give a mixture of 6a and 6b (9:1, 71 mg, 89%) as a colorless
oil. ¹H NMR [300 MHz, CDCl3, three
compounds (two hemiacetals and one aldehyde), 0.49:0.42:0.09]: δ = 3.68
(d, J = 9.6
Hz, 0.42 H, 0.42 OH), 4.46 (d, J = 7.2
Hz, 0.49 H, 0.49 OH), 5.18-5.26 (m, 0.42 H), 5.26-5.29
(m, 0.09 H), 5.38-5.44 (m, 0.49 H), 5.48-2.62 (m,
1 H), 5.82-5.70 (m, 1 H), 5.93-6.07 (m, 0.49 H),
6.12-6.25 (m, 0.42 H), 6.49 (d, J = 9.9
Hz, 0.42 H), 6.65 (d, J = 5.7
Hz, 0.49 H), 7.35-7.39 (m, 0.91 H), 7.56 (dd, J = 7.7, 5.0
Hz, 0.09 H), 7.80-7.84 (m, 0.91 H), 8.28 (d, J = 8.1 Hz, 0.09
H), 8.66-8.69 (m, 0.91 H), 8.80 (d, J = 4.2
Hz, 0.09 H), 10.30 (s, 0.1 H) [0.1 H missing (0.1 OH)].
¹9F
NMR (282 MHz, CDCl3): δ = -111.29
(dt, J = 251.4, 11.8
Hz, 0.09 F), -110.33 (dt, J = 251.5,
10.9 Hz, 0.49 F),
-110.13 (dt, J = 251.3,
11.8 Hz, 0.42 F), -108.22 (dt, J = 251.5,
12.4 Hz, 0.42 F), -107.89 (dt, J = 251.3,
9.6 Hz, 0.49 F), -105.58 (dm, J = 251.4
Hz, 0.09 F). MS (EI): m/z (%) = 213 [M+],
136 (100). Anal. Calcd for C10H9F2NO2:
C, 56.34; H, 4.26; N, 6.57. Found: C, 56.44; H, 4.48; N, 6.70.
Compounds 7
A soln of 6 (222 mg, 1.04 mmol) and sarcosine (98%,
139 mg, 1.56 mmol) in toluene (18 mL) was heated at reflux under
N2 overnight, cooled to r.t., and concentrated. The residue
was diluted with brine and extracted with EtOAc. The combined organic
layers were dried (MgSO4), filtered, and concentrated.
The residue was chromatographed (EtOAc-PE, 1:1) to give
a pair of diastereomers of 7 (dr = 9:1,
171 mg, 68%) as a white solid: mp 82-83 ˚C (dec.). ¹H
NMR (300 MHz, CDCl3): δ = 2.18 (s,
3 H), 2.11-2.30 (m, 1 H), 2.33-2.42 (m, 1 H),
2.45-2.53 (m, 1 H), 2.93-3.07 (m, 1 H), 3.23-3.29
(m, 2 H), 4.75 (d, J = 7.8
Hz, 0.9 H), 5.17 (d, J = 23.4
Hz, 0.1 H), 6.30 (s, 1 H), 7.30-7.34 (dd, J = 7.8,
5.1 Hz, 1 H), 7.54 (d, J = 8.1
Hz, 0.1 H), 7.60 (d, J = 7.5,
1.2 Hz, 0.9 H), 8.56 (d, J = 4.8
Hz, 0.1 H), 8.61 (dd, J = 5.1,
1.2 Hz, 0.9 H). ¹9F NMR (282 MHz, CDCl3): δ =
-115.82
(d, J = 238.8
Hz, 0.1 F), -111.39 (dm, J = 249.7
Hz, 0.9 F), -109.14 (dm, J = 238.8
Hz, 0.1 F), -88.52 (dm, J = 249.7
Hz, 0.9 F). ESI-MS: m/z = 483.0 [2M + H],
263.0 [M + Na], 240.9 [M + H].
Anal. Calcd for C12H14F2N2O:
C, 59.99; H, 5.87; N, 11.66. Found: C, 59.84.; H, 6.06; N, 11.25.
Compound 2b
To a suspension
of NaH (60% in mineral oil, 34 mg, 0.86 mmol) in dry THF
(10 mL) under N2 was added a soln of 7 (103
mg, 0.43 mmol) in dry THF (2 mL). After the mixture was stirred
at r.t. for 30 min, CS2 (80 µL, 1.29 mmol) was added
and stirring continued for 1 h. Iodomethane (30 µL, 0.47
mmol) was then added. After stirring for another 0.5 h, the reaction
was quenched with sat. aq NaHCO3 soln and the mixture
was extracted with EtOAc. The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The residue
was chromatographed (EtOAc-PE, 1:10) to afford the xanthates
(138 mg, 97%) as a colorless oil. To a solution of above-mentioned
xanthates (138 mg, 0.42 mmol) in anhyd toluene (36 mL) were added n-Bu3SnH (97%, 0.14 mL,
0.50 mmol) and AIBN (14 mg, 0.08 mmol). The mixture was stirred
at reflux overnight, cooled to r.t., concentrated, diluted with
sat. aq NaHCO3 soln, and extracted with EtOAc. The combined
organic extracts were dried (Na2SO4), filtered,
and concentrated. The residue was chromatographed (EtOAc-PE,
1:1) to afford 2b (74 mg, 79%)
as a colorless oil. ¹H NMR (300 MHz, CDCl3): δ = 1.79-2.23
(m, 2 H), 2.29-2.41 (m, 1 H), 2.32 (s, 3 H), 2.96-3.13
(m, 2 H), 3.23-3.34 (m, 2 H), 3.60 (dd, J = 33.9,
15.0 Hz, 1 H), 7.21 (dd, J = 7.2,
4.8 Hz, 1 H), 7.49 (d, J = 7.2
Hz, 1 H), 8.49 (d, J = 4.8
Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 25.3
(t, J = 6.0
Hz), 38.4 (t, J = 26.4
Hz), 40.0, 45.0 (dd, J = 26.1,
26.1 Hz), 56.0, 67.3 (d, J = 7.4
Hz), 121.8, 125.9 (dd, J = 244.9,
205.7 Hz), 130.2, 136.4, 148.6, 153.7 (d, J = 11.2
Hz). ¹9F NMR (282 MHz, CDCl3): δ = -101.41
(d, J = 242.4
Hz, 1 F), -90.0 (dm, J = 242.4
Hz, 1 F). ESI-MS: 225.2 [M + H]. HRMS
(EI): m/z calcd for C12H14N2F2: 224.1125;
found: 224.1118.