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3
sulting mixture was heated to 1208C by microwave irradiation. Sol-
vents were removed under reduced pressure and the residue was
purified by flash chromatography on silica gel.
CH), 4.06 (d, J(H,H)=13.0 Hz, 1H; NCH Ph), 3.82 (s, 1H; CHOH),
2
3
3.59–3.53 (m, 2H; CH OH), 3.37 (d, J(H,H)=13.0 Hz, 1H; NCH Ph),
3.24 (t, J(H,H)=9.0 Hz, 1H; CH N), 2.73 (s, 1H; CH), 2.56 (d,
J(H,H)=9.0 Hz, 1H; CHN), 2.26–2.20 (m, 3H; CH N, CH), 1.80–1.77
2
2
3
2
3
2
(
m, 1H; CH ), 1.66–1.55 (m, 2H; CH ), 1.50–1.45 (m, 1H; CH ), 1.38
2
2
2
Gram-scale preparation of perhydroisoindole 25a
3
(
s, 3H; CH ), 1.14 (q, J(H,H)=12.0 Hz, 1H; CH ), 0.93 ppm (t,
2
2
3
13
Diallylamine 5 (1.23 mL, 10.0 mmol, 2.0 equiv) and boronic acid 21
J(H,H)=7.0 Hz, 3H; CH3); C NMR (75 MHz, CDCl , 258C): d=
3
(
640 mg, 5.00 mmol, 1.0 equiv) were added to a stirred solution of
139.45 (CqAr), 130.47 (HC=CH), 129.35 (HC=CH), 128.71 (Ar), 128.57
aldehyde 4a (1.30 g, 10.0 mmol, 2.0 equiv) in 1:1 CH Cl /HFIP
(Ar), 127.24 (Ar), 73.14 (CHN), 69.08 (CHOH), 67.14 (CH OH), 60.17
2
2
2
(
25 mL). The resulting mixture was heated at 508C for 16 h. Solvent
(CH N), 59.23 (NCH Ph), 38.11 (CH), 37.54 (CH), 35.72 (CH), 33.04
2
2
evaporation and purification afforded perhydroisoindole 25a
(CH ), 30.35 (CH ), 29.32 (CH ), 23.06 (CH ), 14.27 ppm (CH ); IR: n˜ =
3395, 2927, 1453, 1071, 1029 cm ; HRMS (ESI): m/z calcd for
2
2
2
2
3
[13]
À1
(
1.32 g, 4.50 mmol, 90%) as a yellow oil.
C H NO : 330.2433; found: 330.2433.
21
32
2
Hexahydroisoindole 13
General procedure a was followed by using 4a (32 mg, 0.25 mmol),
Hexahydroisoindole 31a
1
0 (25 mL, 0.20 mmol), and 1 (14 mg, 0.13 mmol) in 9:1 CH Cl /HFIP
2 2
General procedure a was followed by using 4a (40 mg, 0.31 mmol),
(
(
0.6 mL), 30 min. After purification (AcOEt/heptane 5:95–15:85), 13
32 mg, 0.10 mmol, 78%) was obtained as a yellow oil. [a] =
5
(38 mL, 0.31 mmol), and 23 (17 mg, 0.15 mmol) in 9:1 CH Cl /HFIP
2 2
25
D
(0.8 mL) for 30 min. After purification (AcOEt/heptane/Et N 1:9:0–
3
1
+
86.0 (c=0.80 in CHCl ); H NMR (300 MHz, CDCl , 258C): d=7.31–
3 3
3
5
0:49.5:0.5), 31a (37 mg, 0.13 mmol, 88%) was obtained as
7
.18 (m, 5H; H ), 5.16 (s, 1H; CH=C), 3.95 (d, J(H,H)=13.0 Hz, 1H;
25
1
Ar
a yellow oil. [a] =+37 (c=0.78 in CHCl ); H NMR (500 MHz,
3
D
3
NCH Ph), 3.73–3.68 (m, 1H; CHOH), 3.25 (d, J(H,H)=13.0 Hz, 1H;
NCH Ph), 2.77 (s, 1H; CH N), 2.67 (s, 1H; CH), 2.24 (s, 1H; CHN),
3
2
CDCl , 258C): d=6.72 (d, J(H,H)=6.0 Hz, 1H; HC=CH), 6.19 (d,
3
2
2
3
J(H,H)=6.0 Hz, 1H; HC=CH), 5.91–5.83 (m, 1H; HC=CH ), 5.19 (d,
2
2
.20–2.13 (m, 2H; CH, CH N), 1.86–1.75 (m, 2H; CH ), 1.63 (s, 3H;
3
3
2
2
J(H,H)=17.0 Hz, 1H; HC=CH ), 5.11 (d, J(H,H)=10.0 Hz, 1H; HC=
2
CH ), 1.58–1.49 (m, 4H; CH ), 1.42–1.36 (m, 2H; CH ), 1.32–1.30 (m,
4
CDCl , 258C): d=139.74 (Cq; Ar), 132.32 (C=CH), 128.90 (Ar), 128.55
3
3
2
2
CH ), 4.94 (d, J(H,H)=4.0 Hz, 1H; CHO), 3.81 (m, 1H; CHOH), 3.45
3
13
2
H; CH ), 0.88 ppm (t, J(H,H)=6.5 Hz, 3H; CH ); C NMR (75 MHz,
3
3
2
3
(dd, J(H,H)=13.5, 4.5 Hz, 1H; NCH Ph), 3.30 (t, J(H,H)=7.5 Hz, 1H;
2
3
3
CH N), 3.04 (dd, J(H,H)=13.5, 7.5 Hz, 1H; NCH Ph), 2.70 (s, 1H;
CHN), 2.12 (t, J(H,H)=9.5 Hz, 1H; CH N), 1.87–1.77 (m, 2H; CH,
CH ), 1.62 (dt, J(H,H)=11.0, 4.0 Hz, 1H; CH ),1.59–1.51 (m, 2H;
2
2
(
Ar), 127.25 (Ar), 124.41 (C=CH), 75.82 (CHN), 69.62 (CHOH), 59.02
3
2
(CH Ph), 56.17 (CH N), 37.17 (CH), 35.05 (CH), 33.03 (CH ), 32.29
3
2
2
2
2
2
(CH ), 26.48 (CH ), 25.95 (CH ), 24.35 (CH ), 22.85 (CH ), 22.67 (CH ),
3
2
2
2
3
2
À1
2
CH ), 1.31 (m, 6H; H-3, CH ), 0.88 ppm (t, J(H,H)=6.0 Hz, 3H; CH );
2
2
3
1
4.29 ppm (CH ); IR: n˜ =3478, 2922, 1452, 1071 cm ; HRMS (ESI):
13
3
C NMR (75 MHz, CDCl , 258C): d=136.54 (HC=CH), 134.74 (HC=
3
m/z calcd for C H NO: 328.2640; found: 328.2635.
2
2
34
CH ), 133.87 (HC=CH), 117.34 (HC=CH ), 97.79 (CHO), 79.03 (CHOH),
2
2
7
0.32 (CHN), 69.33 (CH N), 58.12 (CH C=), 56.82 (CH), 43.29 (CH ),
2
2
2
Hexahydroisoindole 14
32.09 (CH
2
), 29.86 (CH
2
), 26.69 (CH
2
), 22.82 (CH
2
), 14.25 ppm (CH
3
);
À1
IR: n˜ =3458, 2934, 2858, 1319, 1050, 967, 917 cm ; HRMS (ESI): m/
z calcd for C H NO : 278.2120; found: 278.2121.
General procedure a was followed by using 4a (49 mg, 0.38 mmol),
17
28
2
11 (66 mg, 0.38 mmol), and 1 (21 mg, 0.19 mmol) in 9:1 CH Cl /
2 2
HFIP (0.9 mL) for 1.5 h. After purification (AcOEt/heptane 5:95–2:8),
2
D
0
1
+
7
4 (52 mg, 0.15 mmol, 78%) was obtained as a yellow oil. [a] =
Hexahydroisoindole 31e1 and 31e2
1
56.4 (c=0.70 in CHCl ); H NMR (500 MHz, CDCl , 258C): d=7.33–
.24 (m, 5H; H ), 5.18 (s, 1H; CH=C), 3.99 (d, J(H,H)=13 Hz, 1H;
NCH Ph), 3.77–3.75 (m, 1H; CHOH), 3.26 (d, J(H,H)=13 Hz, 1H;
NCH Ph), 2.86 (dd, J(H,H)=8.5, 6.5 Hz, 1H; CH N), 2.67 (s, 1H; CH),
.29 (s, 1H; CHN), 2.20 (dd, J(H,H)=8.5, 10.5 Hz, 1H; CH N), 2.04–
.95 (m, 2H; CH, CH ), 1.66 (s, 4H; CH , CH ), 1.61–1.56 (m, 1H;
3
3
3
General procedure a was followed by using 4e (54 mg, 0.36 mmol),
Ar
3
5
(44 mL, 0.36 mmol), and 23 (20 mg, 0.18 mmol) in 1:1 CH Cl /HFIP
2 2
2
3
(0.9 mL) for 30 min. After purification (CH Cl /iPrOH/NH OH 1:0:0–
2 2 4
2
2
3
7
8:20:2), 31e1 and 31e2 (87 mg, 0.25 mmol, 83%) were obtained
2
1
2
as a mixture of two diastereomers (7:3, 47 mg, 0.16 mmol, 89%),
which were separated by flash chromatography on silica gel
2
2
3
CH ), 1.45–1.39 (m, 3H; CH , CH ), 1.35–1.21 (m, 8H; CH ), 0.92 (t,
2
2
3
2
3
3
(
AcOEt/iPrOH/H O/NH OH 91:4:2:5–78:12:5:5) to afford major prod-
J(H,H)=6.5 Hz, 3H; CH ), 0.85 ppm (t, J(H,H)=7.5 Hz, 3H; CH3);
2 4
3
1
3
uct 31e1 as a brown oil and minor product 31e2 as a brown oil.
C NMR (75 MHz, CDCl , 258C): d=139.76 (CqAr), 130.35 (C=CH),
3
2
D
0
1
6
3
28.88 (Ar), 128.54 (Ar), 127.22 (Ar), 123.56 (C=CH), 75.33 (CHN),
Compound 31e1 (major product): [a] =À22.2 (c=0.83 in CHCl );
3
1
3
9.60 (CHOH), 58.96 (CH Ph), 57.47 (CH N), 40.05 (CH), 35.27 (CH),
H NMR (500 MHz, MeOD, 258C): d=6.67 (d, J(H,H)=6.0 Hz, 1H;
2
2
3
5.17 (CH ), 33.06 (CH ), 32.32 (CH ), 31.24 (CH ), 27.07 (CH ), 26.54
HC=CH), 6.26 (dd, J(H,H)=6.0, 1.5 Hz, 1H; HC=CH), 5.93–5.85 (m,
1H; HC=CH ), 5.18 (d, J(H,H)=17.0 Hz, 1H; HC=CH ), 5.08 (d,
J(H,H)=10.0 Hz, 1H; HC=CH ), 4.89 (dd, J(H,H)=1.5, 4.5 Hz, 1H;
2
3
2
2
2
2
3
(
3
CH ), 24.57 (CH ), 22.88 (CH ), 14.30 (CH ), 12.46 ppm (CH ); IR: n˜ =
473, 2926, 1454, 1028, 736, 699 cm ; HRMS (ESI): m/z calcd for
2
3
2
3
3
2
2
À1
3
3
C H NO: 356.2953; found: 356.2955.
CHOH), 3.85–3.78 (m, 3H; CHOH), 3.77–3.73 (m, 1H; CH OH), 3.65
2
2
4
38
3
3
(
5
2
dd, J(H,H)=11.5, 6.0 Hz, 1H; CH OH), 3.55 (dd, J(H,H)=13.5,
2
3
.5 Hz, 1H; NCH Ph), 3.27–3.24 (m, 1H; CHN), 3.10 (d, J(H,H)=
2
Hexahydroisoindole 25c
3
.5 Hz, 1H; CHN), 3.03 (dd, J(H,H)=13.5, 8.0 Hz, 1H; NCH Ph), 2.07
2
3
General procedure a was followed by using 4d (78 mg,
(dd, J(H,H)=10.5, 9.0 Hz, 1H; CHN), 1.97–1.91 (m, 1H; CH), 1.61
(dt, J(H,H)=11.5, 4.0 Hz, 1H; CH ), 1.31 ppm (dd, J(H,H)=11.5,
2
7.5 Hz, 1H; CH2); C NMR (125 MHz, MeOD, 258C): d=136.72 (HC=
CH), 136.44 (HC=CH ), 136.34 (HC=CH), 118.32 (HC=CH ), 99.45
3
3
0
1
.67 mmol), 10 (105 mL, 0.67 mmol), and 21 (43 mg, 0.34 mmol) in
13
:1 CH Cl /HFIP (1.6 mL) for 30 min. After purification (CH Cl /
2
2
2
2
MeOH/NH OH 98.8:1:0.2–94.8:5:0.2), 25c (90 mg, 0.27 mmol, 81%)
4
2
2
2
D
0
was obtained as a colorless oil. [a] =+27.2 (c=0.83 in CHCl );
H NMR (500 MHz, CDCl , 258C): d=7.34–7.23 (m, 5H; H ), 5.81 (d,
J(H,H)=10.0 Hz, 1H; HC=CH), 5.71 (d, J(H,H)=10.0 Hz, 1H; HC=
(CO), 80.34 (CHO), 75.08 (CHOH), 74.93 (CHOH), 73.10 (CHOH),
68.42 (CHN), 64.31 (CH OH), 59.52, 59.44 (CH N, NCH Ph), 43.68
3
1
3
Ar
2
2
2
3
3
(CH), 31.39 ppm (CH2); IR: n˜ =3357, 2908, 1066, 1029, 920,
Chem. Eur. J. 2014, 20, 12133 – 12143
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim