European Journal of Organic Chemistry
10.1002/ejoc.201600959
FULL PAPER
6H), 1.46 (m, 2H), 1.24 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 144.7, 143.2, 142.2, 140.0, 135.7, 133.4, 130.0,
129.1, 128.7, 128.1, 126.9, 126.6, 126.2, 124.6, 67.0, 63.2, 53.5, 36.2,
(Z)-1-(4-(2-chloroethoxy)phenyl)-1-(4-(2-carbomethoxyethyl)phenyl)-
2-(4-(tert-butyldimethylsilyloxy)phenyl)-2-(4-(2-cyano-2-
propyl)phenyl)ethene (3f):
31.6, 22.7, 13.8 ppm. HRMS (ESI): Calc. for C27H31NOS [M+H]+
418.2199; Found: 418.2197.
=
Stereoselective synthesis of SERMs
Prepared according to the general procedure starting from phosphate 2g
(0.320 g, 0.50 mmol), 4-(tert-butyldimethylsilyloxy)phenylzinc chloride
[prepared from tert-butyldimethylsilyloxy)phenyl bromide (0.201 mg, 0.7
mmol) nBuLi (0.28 mL, 0.7 mmol), and zinc chloride (0.7 mL of 1M
solution in THF)], PdCl2(SPhos)2 (20 mg, 4 mol %, 0.02 mmol) and AlCl3
(1 mL, 0.7 M solution in THF). The reaction mixture was stirred for 24 h
at 50 °C. Column chromatography (EtOAc/hexane 1:6, Rf = 0.25)
afforded 0.276 g (80%) of the title compound product as a colorless solid,
M.p. 145146 °C; 1H NMR (400 MHz, CDCl3): δ = 7.17 (d, J = 8.4 Hz,
2H), 7.02 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H) overlapping with
6.91 (br s, 4H), 6.81 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 6.56 (d,
J = 8.4 Hz, 2H), 4.16 (t, J = 5.9 Hz, 2H), 3.78 (t, J = 5.9 Hz, 2H), 3.66 (s,
3H), 2.86 (t, J = 8.3 Hz, 2H), 2.56 (t, J = 8.3 Hz, 2H), 1.67 (s, 6H), 0.95 (s,
9H), 0.15 (s, 6H) ppm=. 13C NMR (75 MHz, CDCl3): δ = 173.3, 156.6,
154.2, 143.6, 141.9, 139.8, 139.0, 138.9, 138.5, 136.8, 136.7, 132.6,
132.4, 131.7, 131.4, 127.4, 124.6, 124.3, 119.4, 113.8, 67.8, 51.6, 41.9,
36.8, 35.6, 30.6, 29.0, 25.7, 18.2, -4.5 ppm. IR (ATR): ν = 2956 (m), 2867
(m), 1730 (s), 1605 (m), 1506 (s), 1436 (m), 1363 (m), 1295 (m), 1248 (s),
1167 (s), 1101 (m), 1040 (m). HRMS (ESI): Calc. for C42H48ClNO4Si
[M+Na]+ = 716.2933; Found: 716.2940. Calcd for C42H48ClNO4Si: C,
72.65; H, 6.97; N, 2.02. Found: C, 72.73; H, 7.19; N, 1.97.
(Z)-2-benzyl-1-(4-(2-chloroethoxy)phenyl)-1-phenylbutene (3l)
Benzylmagnesium chloride (0.65 mL, 0.65 mmol) was added to a
solution of AlCl3 (0.086 g, 0.65 mmol) in dry THF (1 mL) cooled to 0 °C.
The reaction mixture was stirred 15 min at ambient temperature, the
solvents were removed under reduce pressure and formed solid was
redissolved in THF (2 mL). Dry diglyme (0.287 g, 2.15 mmol) was added
to the precipitated solution and the mixture was stirred 30 min at ambient
temperature. Precipitated complex of MgCl2 and diglyme has settled
down and supernatant solution of tribenzylaluminum was added to a
solution of the phosphate 2s (0.219 g, 0.50 mmol), PdCl2(SPhos)2 (0.010
g, 2 mol %) in dry THF (2 mL). The reaction was stirred for 24 h at 45 °C.
Then the reaction mixture was quenched with 1M tartaric acid and diluted
with ether. After clear biphasic mixture was formed the separated organic
layer was washed with brine, dried over MgSO4 and concentrated under
reduce pressure. Purification by column chromatography (EtOAc/hexane
1:20, Rf = 0.35) afforded 0.173 g (92%) of the title compound as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ = 7.317.20 (m, 10H), 7.18 (d,
J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.78 (t,
J = 6.3 Hz, 2H), 3.59 (s, 2H), 2.05 (q, J = 7.8 Hz, 2H), 0.98 (t, J = 7.8 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.6 143.3, 140.5, 138.8,
138.6, 136.2, 130.4, 129.2, 128.6, 128.3, 128.0, 126.2, 125.8, 114.3,
67.8, 41.9, 37.1, 24.7, 13.3 ppm. HRMS (ESI): Calc. for C25H25ClO
[M+Na]+ = 399.1486; Found: 399.1487.
(Z)-4-(2-thienyl)-5-(4-methoxyphenyl)-5-(1-toluenesulphonylindol-3-
yl)-pent-4-enyl pivalate (3g):
Prepared according to the general procedure starting from phosphate 2h
(0.363 g, 0.50 mmol), 2-thienylzinc chloride [prepared from thiophene
(0.056 mL, 0.7 mmol) nBuLi (0.28 mL, 0.7 mmol), and zinc chloride (0.7
mL of 1 M solution in THF)], PdCl2(SPhos)2 (20 mg, 4 mol %, 0.02 mmol)
and AlCl3 (1 mL, 0.7M solution in THF). The reaction mixture was stirred
for 24 h at 50 °C. Column chromatography (EtOAc/hexane 1:6, Rf = 0.25)
afforded 0.284 g (91%) of the title compound product as an amorphous
solid; 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 1H), 7.60 (d, J
= 8.4 Hz, 2H), 7.26 (s, 1H), 7.197.16 (m, 5H), 7.036.95 (m, 3H), 6.81
(d, J = 8.4 Hz, 2H), 6.736.66 (m, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.80 (s,
3H), 2.67 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 1.86 (m, 2H), 1.15 (s, 9H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 179.5, 158.7, 144.6, 144.0, 135.4,
134.9, 134.2, 134.1, 131.3, 130.4, 129.9, 129.7, 126.8, 126.5, 126.4,
125.9, 125.1, 124.8, 124.3, 123.1, 120.7, 113.7, 113.4, 64.1, 55.2, 38.7,
32.8, 28.8, 27.1, 21.5 ppm. IR (ATR): ν = 2957 (m), 1721 (s), 1606 (m),
1507 (m), 1445 (m), 1368 (m), 1283 (m), 1243 (m), 1171 (s), 1120 (s),
1034 (m). HRMS (ESI): Calc. for C36H37NO5S2 [M+Na]+ = 620.2005;
Found: 650.2003.
(Z)-(1-(4-(2-chloroethoxy)phenyl)-1-(4-(tert-
butyldimethylsilyloxy)phenyl-2-phenyl) butane (3m):
Prepared according to the general procedure starting from phosphate 2t
(0.284 g, 0.50 mmol), phenylzinc chloride [prepared from bromobenzene
(0.110 g, 0.70 mmol), nBuLi (0.28 mL, 0.7 mmol), and zinc chloride (0.7
mL of 1 M in THF) in THF (1 mL)], PdCl2(SPhos)2 (20 mg, 4 mol %) and
AlCl3 (1 mL, 0.7M solution in THF). The reaction mixture was stirred for
24 h at 50 °C. Column chromatography (EtOAc/hexane 1:10, Rf = 0.25)
afforded 0.204 g (83%) of the title compound as a colorless glass; 1H
NMR (300 MHz, CDCl3): δ = 7.207.09 (m, 7H), 6.846.78 (m, 4H), 6.56
(d, J = 8.7 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.50
(q, J = 7.5 Hz, 2H), 1.02 (s, 9H), 0.94 (t, J = 7.5 Hz, 3H), 0.24 (s, 6H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 156.0, 154.3, 142.6, 141.2, 137.8,
136.7, 136.5, 132.0, 130.5, 129.7, 127.8, 125.9, 119.5, 113.4, 67.7, 41.9,
29.0, 25.7, 18.2, 13.6, -4.4 ppm. HRMS (APCI): Calc. for C30H37ClO2Si
[M+H]+ = 493.2324; Found: 493.2323.
(Z)-1-phenyl-1-(4-(1-morpholinomethyl)phenyl)-2-(2-thienyl)hexene
(3h):
(Z)-1-(4-(2-chloroethoxy)phenyl)-2-ferrocenyl-1-phenylbutene (3n):
Prepared according to the general procedure starting from phosphate 2i
(0.250 g, 0.50 mmol), 2-thienylzinc chloride [prepared from thiophene
(0.056 mL, 0.7 mmol) nBuLi (0.28 mL, 0.7 mmol), and zinc chloride (0.7
mL of 1 M solution in THF)], PdCl2(SPhos)2 (20 mg, 4 mol %, 0.02 mmol)
and AlCl3 (1 mL, 0.7M solution in THF). The reaction mixture was stirred
for 24 h at 50 °C. Column chromatography (EtOAc/hexane 1:3, Rf = 0.25)
afforded 0.186 g (90%) of the title compound product as a colorless solid,
M.p. 102-103 °C; 1H NMR (400 MHz, CDCl3): δ = 7.387.19 (m, 5H Ph +
1H thiophene), 7.11 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.79 (m,
1H), 6.68 (m, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.42 (s, 2H), 2.492.34 (m,
Prepared according to the general procedure starting from phosphate 2s
(0.219 g, 0.50 mmol), ferrocenylzinc chloride [prepared from
bromoferrocene (0.185 g, 0.70 mmol), nBuLi (0.28 mL, 0.7 mmol), zinc
chloride (0.7 mL, 1M solution in THF), and THF (1 mL)], PdCl2(SPhos)2
(20 mg, 4 mol %) and AlCl3 (1.0 mL, 0.7M solution in THF). The reaction
mixture was stirred for 24
h at 50 °C. Column chromatography
(DCM/hexane 1:4, Rf = 0.25) afforded 0.139 g (59%) of the title
compound as a rusty red solid, M.p. 118120 °C; 1H NMR (300 MHz,
CDCl3): δ = 7.367.17 (m, 5H), 6.99 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.7
Hz, 2H), 4.19 (t, J = 5.7 Hz, 2H), 4.11 (s, 5H), 4.094.08 (br s, 2H),
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