I
Synthesis
A. Castelló-Micó, P. Knochel
Paper
1
1
H NMR (400 MHz, CDCl ): δ = 8.80 (br s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H),
H NMR (400 MHz, CDCl ): δ = 7.83 (br s, 1 H), 7.78 (d, J = 7.8 Hz, 1 H),
3
3
8
7
7
.17 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 2 H), 7.46 (t, J = 7.8 Hz, 1 H),
.38 (t, J = 7.6 Hz, 2 H), 7.27–7.31 (m, 1 H), 5.78 (br s, 1 H), 4.41 (qd, J =
.1, 1.8 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H), 0.94 (s, 9 H), 0.12 (s, 3 H), 0.05
7.67 (d, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 5.63–5.72 (m, 1 H),
5.21 (d, J = 10.2 Hz, 1 H), 5.13 (d, J = 17.0 Hz, 1 H), 2.78 (dd, J = 13.7, 7.1
Hz, 1 H), 2.66 (dd, J = 13.7, 7.1 Hz, 1 H), 0.95 (s, 9 H), 0.26 (s, 3 H), 0.00
(s, 3 H).
(s, 3 H).
13
13
C NMR (101 MHz, CDCl ): δ = 198.0, 165.8, 138.6, 134.6, 134.0,
C NMR (101 MHz, CDCl ): δ = 142.2, 132.4, 129.7, 129.6, 129.4,
3
3
1
1
33.6, 131.3, 130.6, 128.7, 128.3, 127.9, 125.6, 80.8, 61.2, 25.7, 18.2,
4.3, –5.0, –5.1.
128.9, 121.5, 119.5, 118.1, 112.9, 74.4, 50.1, 25.6, 18.3, –3.8, –3.8.
MS (70 eV, EI): m/z (%) = 297 (1), 271 (25), 255 (26), 228 (100), 130
MS (70 eV, EI): m/z (%) = 383 (5), 341 (55), 221 (100), 177 (5), 73 (78),
9 (8).
(43), 99 (30), 84 (15), 75 (39), 73 (55), 57 (24), 41 (17).
5
HRMS (EI): m/z [M – Me]+ calcd for C18H24N OSi: 297.1423; found:
2
HRMS (EI): m/z [M – CN – Me – H]+ calcd for C22H27O Si: 383.1679;
297.1414.
4
found: 383.1646.
3-[1-(tert-Butyldimethylsilyloxy)-1-cyano-2-phenylethyl]benzo-
Ethyl 3-[(tert-Butyldimethylsilyloxy)dicyanomethyl]benzoate (6f)
nitrile (6h)
According to GP3, compound 1a (128 mg, 0.40 mmol) was dissolved
in anhyd THF (1.6 mL). TMPMgCl·LiCl (3; 0.43 mL, 0.52 mmol, 1.21 M
in THF) was added dropwise at –20 °C and the reaction mixture was
stirred for 2 h. A solution of tosyl cyanide (109 mg, 0.60 mmol) in an-
hyd THF (0.4 mL) was added at –78 °C and the mixture was allowed to
warm up to 25 °C over 12 h. The resulting solution was quenched
According to GP2, compound 1b (82 mg, 0.30 mmol) was dissolved in
anhyd THF (1.2 mL). TMP Zn·2MgCl ·2LiCl (2; 1.03 mL, 0.33 mmol,
2
2
0.32 M in THF) was added dropwise at –20 °C and the reaction mix-
12
ture was stirred for 2 h. CuBr (4 mg, 0.03 mmol) and solid benzyl
bromide (54 mg, 0.32 mmol) were added at –78 °C. The reaction mix-
ture was stirred at –78 °C for 1 h and at 50 °C for 12 h. The resulting
solution was quenched with sat. aq NH Cl/NH solution (8:1, 10 mL),
with sat. aq NH Cl (10 mL), extracted with EtOAc (3 × 30 mL), and the
4
4
3
combined organic phases were dried (anhyd MgSO ). After filtration,
extracted with EtOAc (3 × 30 mL), and dried (anhyd MgSO ). After fil-
4
4
the solvents were evaporated in vacuo. The crude product was puri-
fied by flash column chromatography on silica gel (i-hexane/EtOAc,
tration, the solvents were evaporated in vacuo. The crude product was
purified by flash column chromatography on silica gel (i-hexane/EtOAc,
96:4) yielding 6h as a white solid (80 mg, 74%); mp 97.7–98.7 °C.
9:1) yielding 6f as a colorless oil (69 mg, 50%).
IR (Diamond-ATR, neat): 2934, 2862, 2244, 1723, 1472, 1300, 1268,
IR (Diamond-ATR, neat): 2931, 2859, 2233, 1588, 1472, 1362, 1256,
–1
–1
1190, 1022, 837, 786, 688 cm
.
1112, 1094, 908, 874, 839, 782, 693 cm
.
1
1
H NMR (400 MHz, CDCl ): δ = 8.38 (br s, 1 H), 8.20 (d, J = 7.8 Hz, 1 H),
H NMR (400 MHz, CDCl ): δ = 7.73 (br s, 1 H), 7.64 (d, J = 7.8 Hz, 1 H),
3
3
7
.87 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H),
7.66 (d, J = 7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.23–7.27 (m, 3 H),
7.07 (d, J = 6.6 Hz, 2 H), 3.22 (d, J = 13.4 Hz, 1 H), 3.11 (d, J = 13.4 Hz, 1
H), 0.91 (s, 9 H), 0.01 (s, 3 H), –0.08 (s, 3 H).
1.42 (t, J = 7.1 Hz, 3 H), 1.00 (s, 9 H), 0.41 (s, 6 H).
13
C NMR (101 MHz, CDCl ): δ = 165.1, 135.3, 132.0, 132.0, 129.7,
3
13
129.3, 126.3, 114.8, 64.7, 61.6, 25.2, 18.2, 14.2, –4.4.
C NMR (101 MHz, CDCl ): δ = 142.4, 133.0, 132.4, 130.9, 129.7,
3
1
–
29.3, 129.0, 128.1, 127.8, 119.5, 118.1, 112.7, 75.4, 52.1, 25.7, 18.3,
3.8, –4.2.
MS (70 eV, EI): m/z (%) = 344 (1), 299 (19), 287 (100), 242 (15), 232
23), 177 (96), 149 (11), 75 (10).
HRMS (EI): m/z [M+] calcd for C18H24N O Si: 344.1556; found:
(
MS (70 eV, EI): m/z (%) = 362 (1), 305 (31), 271 (100), 265 (29), 255
10), 130 (32), 90 (22), 84 (19), 75 (39), 73 (56), 41 (11).
HRMS (EI): m/z [M+] calcd for C22H26N OSi: 362.1814; found:
2
3
(
344.1551.
2
362.1817.
3-[1-(tert-Butyldimethylsilyloxy)-1-cyanobut-3-enyl]benzoni-
trile (6g)
3
-[1-(tert-Butyldimethylsilyloxy)-1-cyano-3,3-dimethyl-2-oxobu-
According to GP2, 3-[(tert-butyldimethylsilyloxy)(cyano)methyl]ben-
zonitrile (1b; 136 mg, 0.50 mmol) was dissolved in anhyd THF (2 mL).
TMP Zn·2MgCl ·2LiCl (2, 1.57 mL, 0.55 mmol, 0.35 M in THF) was
tyl]benzonitrile (6i)
According to GP2, compound 1b (136 mg, 0.50 mmol) was dissolved
in anhyd THF (2 mL). TMP Zn·2MgCl ·2LiCl (2; 1.93 mL, 0.55 mmol,
0.28 M in THF) was added dropwise at –20 °C and the reaction mix-
ture was stirred for 2 h. CuCN·2LiCl solution (0.10 mL, 0.10 mmol,
1.0 M in THF) was added at –40 °C and stirred for 5 min. Pivaloyl chlo-
ride (72 mg, 0.60 mmol) was added and the mixture was stirred at
–40 °C and allowed to warm up to 25 °C over 12 h. The resulting solu-
tion was quenched with sat. aq. NH Cl/NH solution (8:1, 10 mL), ex-
2
2
added dropwise at –20 °C and the reaction mixture was stirred for
2
2
11
2
h. CuCN·2LiCl solution (0.10 mL, 0.10 mmol, 1.0 M in THF) was
11
added at –40 °C and stirred for 5 min. Allyl bromide (91 mg, 0.75
mmol) was added and the reaction mixture was stirred at –40 °C and
the mixture was allowed to warm up to 25 °C over 12 h. The resulting
solution was quenched with sat. aq NH Cl/NH solution (8:1, 10 mL),
4
3
extracted with EtOAc (3 × 30 mL), and the combined organic phases
4
3
were dried (anhyd MgSO ). After filtration, the solvents were evapo-
tracted with EtOAc (3 × 30 mL), and the combined organic phases
4
rated in vacuo. The crude product was purified by flash column chro-
matography on silica gel (i-hexane/EtOAc, 96:4) yielding 6g as a col-
orless oil (105 mg, 67%).
were dried (anhyd MgSO ). After filtration, the solvents were evapo-
4
rated in vacuo. The crude product was purified by flash column chro-
matography on silica gel (i-hexane/EtOAc, 95:5) yielding 6i as a light
yellow solid (131 mg, 74%); mp 59.1–60.9 °C.
IR (Diamond-ATR, neat): 2931, 2859, 2233, 1644, 1584, 1472, 1362,
–1
1257, 1108, 1096, 920, 837, 781 cm
.
IR (Diamond-ATR, neat): 2933, 2861, 2233, 1719, 1472, 1363, 1258,
–1
1
151, 1095, 911, 840, 783, 688 cm .
1
H NMR (400 MHz, CDCl ): δ = 7.85 (br s, 1 H), 7.80 (d, J = 7.8 Hz, 1 H),
3
7.71 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 1.28 (s, 9 H), 1.01 (s, 9
H), 0.33 (s, 3 H), 0.02 (s, 3 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O