Wheatley and Keay
SCHEME 14. Mechanism of Palladium-Mediated Isomerizations in the Heck Reaction with 2e
Synthesis of 2,2-Dideuterio-2,3-dihydrofuran (2e). LiAlD4 (300
mg, 7.15 mmol) was suspended in THF (25 mL) and refluxed for
30 min. It was then cooled to -55 °C, and a solution of 18 (1.24
g, 12,4 mmol) in THF (20 mL) was added dropwise over 15 min.
The solution was then warmed to rt over 90 min and then cooled
to 0 °C for 10 min and then finally to -15 °C. A solution of HCl
in water (6 M, 5 mL) was added slowly, and the reaction was then
warmed to rt and stirred for 20 min. It was then saturated with
NaCl, and the layers were separated. The aqueous layer was
extracted with Et2O (3 × 50 mL), and the combined organic layers
were dried over MgSO4 and concentrated in Vacuo. The residue
was distilled to give 17e as a clear colorless liquid (548 mg, 6.22
mmol) in 50.2% yield. Bp 65 °C (aspirator) (lit.11 75-76 °C, 5
Torr); IR (film) νmax 2960 (w, CsH), 1771 (s, CdO), 1250 (s),
(CDCl3, 75 MHz) δ 145.5, 143.2, 128.7, 127.8, 125.8, 99.2, 77.3
(three lines equal intensity, J ) 22.8 Hz), 37.9; 2H NMR (CHCl3,
300 MHz) δ 5.51 (br s); MS: m/z 147 (97%, M+), 118 (100%,3,3
-
sigmatropic rearrangement then loss of CHO), 77 (11%, Ph+). NMR
data for 7b: 1H NMR (CDCl3, 300 MHz) δ 7.4-7.3 (5H, m), 6.1
(1H, dt, J ) 6.2, 1.5 Hz), 5.9 (1H, dt, J ) 6.2, 1.5 Hz), 4.9 (1H,
br d, J ) 12.3 Hz), 4.79 (1H, br d, J ) 12.3 Hz); 13C NMR (CDCl3,
75 MHz) δ 142.1, 130.0, 128.6, 128.0, 126.8, 126.5, 87.6 (three
2
lines equal intensity, J ) 22.7 Hz), 76.0; H NMR (CHCl3, 300
MHz) δ 5.86 (br s, D2). MS: m/z 147 (100%, M+), 105 (92%,
PhsCtO+), 77 (29%, Ph+).
General procedure 3 using 2c gave 6c, with 76% deuterium
incorporation, and 7c, with 77% deuterium incorporation, upon
column chromatography. NMR data for 6c: 1H NMR (CDCl3, 300
MHz) δ 7.5-7.3 (5H, m), 6.5 (1H, t, J ) 2.3 Hz), 5.6 (1H, d, J )
1
1185 (s), 978 (s, CsO) cm-1; H NMR (CDCl3, 300 MHz) δ 2.4
(2H, t, J ) 8.1 Hz), 2.1 (2H, t, J ) 8.1 Hz); 13C NMR (CDCl3, 75
MHz) δ 181.1, 71.1 (5 lines with relative intensities of 1:2:3:2:1,
7.7 Hz), 5.0 (1H, t, J ) 2.6 Hz), 2.7 (1H, dt, J ) 7.7, 2.3 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 145.6, 143.3, 128.7, 127.8, 125.8, 99.1,
2
2
J ) 23.2 Hz), 30.8, 25.0; H NMR (CHCl3, 300 MHz) δ 4.38 (br
82.5, 37.7 (three lines equal intensity, J ) 20.6 Hz); H NMR
(CHCl3, 300 MHz) δ 3.1 (br s); MS: m/z 147 (75%, M+), 118
(100%,3,3-sigmatropic rearrangement then loss of CHO), 77 (13%,
Ph+). NMR data for 7c: 1H NMR (CDCl3, 300 MHz) δ 7.4-7.3
(5H, m), 6.1 (1H, br s), 5.8 (1H, m), 4.9 (1H, dd, J ) 12.8, 6.2
Hz), 4.79 (1H, dd, J ) 12.8, 4.1 Hz); 13C NMR (CDCl3, 75 MHz)
δ 142.2, 130.1 (three lines equal intensity, J ) 26.1 Hz), 128.7,
128.0, 126.6, 126.5, 88.0, 76.0; 2H NMR (CHCl3, 300 MHz) δ 6.0
(br s). MS: m/z 147 (61%, M+), 105 (100%, PhsCtO+), 77 (30%,
Ph+).
s); MS: m/z 88 (16%, molecular ion), 56 (20%, loss of DC2dO),
44 (100%, CO2 or C3H4D2); HRMS calcd for C4H4O2D2, 88.049 33;
found, 88.049 03.
Using general procedure 1: lactone 17e (3.91 g, 44.4 mmol) in
DCM (17.3 mL) was cooled for 75 min and then treated with a
solution of DIBALH in DCM (1.0 M, 52.0 mL, 52.0 mmol); the
reaction was quenched with MeOH (3.5 mL) and saturated aqueous
Rochelle salt solution (3.5 mL), and the crude lactol was isolated
and used immediately.
Using general procedure 2: the isolated lactol 16e was treated
with a solution of TsOH‚H2O (15 mg, 0.080 mmol) in quinoline
(1.8 mL), and the distillate was trapped in a receiving flask
containing aqueous NaOH (2 M, 3 mL) to give 2e (740 mg, 10.3
mmol) in 23.1% yield over two steps. Bp 54 °C; 1H NMR (CDCl3,
300 MHz) δ 6.3 (1H, q, J ) 2.6 Hz), 5.0 (1H, q, J ) 2.6 Hz), 2.60
(2H, pentet, J ) 2.57 Hz); 13C NMR (CDCl3, 75 MHz) δ 145.8,
99.6, 68.9 (five lines with relative intensities of 1:2:3:2:1, J ) 22.4
Hz), 29.0.
General procedure 3 using 2d gave 6d, with 96% and 86%
deuterium incorporation at the 3- and 4-positions, respectively, and
7d, with 84% deuterium incorporation, upon column chromatog-
raphy. NMR data for 6d: 1H NMR (CDCl3, 300 MHz) δ 7.5-7.3
(5H, m), 6.5 (1H, d, J ) 2.0 Hz), 5.6 (1H, d, J ) 10.8 Hz), 3.1
(1H, dq, J ) 10.8, 2.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 145.5,
143.2, 128.7, 127.8, 125.8, 98.9 (three lines equal intensity, J )
26.7 Hz), 82.5, 37.6 (three lines equal intensity, J ) 20.3 Hz); 2H
NMR (CHCl3, 300 MHz) δ 4.9 (1D, br s), 2.54 (1D, br s). MS:
m/z 148 (45%, M+), 119 (100%,3,3-sigmatropic rearrangement then
loss of CHO), 77 (8.3%, Ph+). NMR data for 7d: 1H NMR (CDCl3,
300 MHz) δ 7.4-7.2 (5H, m), 5.9 (1H, br s), 5.8 (1H, t, J ) 4.9
Hz), 4.9 (1H, ddd, J ) 12.7, 6.0, 2.5 Hz), 4.8 (1H, ddd, J ) 12.7,
4.9, 2.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 142.2, 130.0, 128.6,
127.9, 126.5, 88.1, 75.9, one signal was lost in the baseline of the
NMR; 2H NMR (CHCl3, 300 MHz) δ 6.0 (1D, br s). MS: m/z 147
(73%, M+), 105 (100%, PhsCtO+), 77 (31%, Ph+).
NMR Data for 2-Phenyl-2,3-dihydrofuran (6a): 1H NMR
(CDCl3, 300 MHz) δ 7.5-7.3 (5H, m), 6.5 (1H, q, J ) 2.4 Hz),
5.6 (1H, dd, J ) 10.8, 8.2 Hz), 5.0 (1H, q, J ) 2.4 Hz), 3.1 (1H,
ddt, J ) 14.9, 10.8, 2.3 Hz), 2.67 (1H, ddt, J ) 14.9, 8.2, 2.3 Hz);
13C NMR (CDCl3, 75 MHz) δ 145.5, 143.3, 128.7, 127.8, 125.8,
99.2, 82.5, 38.1. MS: m/z 146 (34%, M+), 117 (100%,3,3
-
sigmatropic rearrangement then loss of CHO), 77 (12%, Ph+).
NMR Data for 2-Phenyl-2,5-dihydrofuran (7a): 1H NMR
(CDCl3, 300 MHz) δ 7.4-7.2 (5H, m), 6.1 (1H, dq, J ) 6.0, 2.0
Hz), 5.9 (1H, dq, J ) 6.0, 2.0 Hz), 5.8 (1H, ddt, J ) 5.8, 4.1, 2.1
Hz), 4.9 (1H, ddt, J ) 12.8, 6.0, 2.1 Hz), 4.8 (1H, ddt, J ) 12.8,
4.1, 2.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 142.2, 130.1, 128.6,
127.9, 126.8, 126.5, 88.0, 76.0. MS: m/z 146 (42%, M+), 105
(100%, PhsCtO+), 77 (43%, Ph+).
General procedure 3 using 2e gave 6e and 7e upon column
chromatography. NMR data for 6e: 1H NMR (CDCl3, 300 MHz)
δ 7.5-7.3 (5H, m), 5.6 (1H, dd, J ) 10.8, 8.2 Hz), 5.0 (1H, t, J )
2.3 Hz), 3.1 (1H, ddd, J ) 15.1, 10.8, 2.3 Hz), 2.6 (1H, ddd, J )
15.1, 8.2, 2.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 145.3 (three lines
equal intensity, J ) 29.1 Hz), 143.2, 128.7, 127.8, 125.7, 99.0 (three
2
General procedure 3 using 2b gave 6b and 7b upon column
chromatography. NMR data for 6b: 1H NMR (CDCl3, 300 MHz)
δ 7.5-7.3 (m), 6.5 (1H, q, J ) 2.6 Hz), 5.0 (1H, q, J ) 2.6 Hz),
3.1 (1H, br d, J ) 15.4 Hz), 2.7 (1H, br d, J ) 15.4 Hz); 13C NMR
lines equal intensity, J ) 1.8 Hz), 82.5, 38.0; H NMR (CHCl3,
300 MHz) δ 6.5 (1D, br s). MS: m/z 147 (63%, M+), 117 (100%,3,3
-
sigmatropic rearrangement then loss of CDO), 77 (12%, Ph+). NMR
data for 7e: 1H NMR (CDCl3, 300 MHz) δ 7.4-7.2 (5H, m), 6.0
7258 J. Org. Chem., Vol. 72, No. 19, 2007