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3884
M. Budesínsky et al. / Tetrahedron 70 (2014) 3871e3886
afford the target N-oxide 5 as a white solid (0.134 g, 0.78 mmol,
98%; Rf 0.15 in H1). 1H and 13C NMR datadsee Fig. 2, 15N NMR data
in Fig. 3. HRMS (ESI): [MþH]þ, found 172.16960. C10H22ON requires
172.16959.
160 ꢀC for 12 h under a steady flow of argon to dilute the emerging
highly pyrophoric bistrimethylsilyl phosphonite (BTSP). The dark-
brown mixture was then cooled to room temperature, the re-
action was quenched by adding 2 M aqueous HCl (50 mL), filtered
through Celite, and the filtration cake was washed with EtOAc
(200 mL). The filtrate was diluted with water (500 mL), and the
product was extracted with EtOAc (4ꢂ200 mL). The combined or-
ganic phase was dried over anhydrous sodium sulfate, filtered
again, and the solvents were removed in vacuo at 80 ꢀC to give the
desired phosphinic acid 8 as a pale yellow semisolid (3.65 g,
19.19 mmol, 54%; 42e55 % in repeated runs, Rf 0.15 in H1). 1H NMR
4.5.4. N-Benzoyl-4-tert-butylpiperidine (6). To a solution of hydro-
chloride 2 (95.57 g, 0.537 mol) in water (500 mL) in a 2 L round-
bottomed flask equipped with a magnetic stirrer and dropping
funnel and cooled in an ice bath a solution of NaOH (49.49 g,
1.23 mol, 2.3 equiv) in water (100 mL) was added. Then, benzoyl
chloride (62.47 mL, 0.537 mol, 1 equiv) diluted with diethyl ether
(100 mL to prevent lumping of crude product) was slowly added
from the dropping funnel to an intensively stirred reaction mixture.
After 12 h at room temperature, the mixture was partitioned be-
tween water and Et2O (500 mL, then 2ꢂ150 mL), and the organic
layer was dried over Na2SO4 and evaporated in vacuo. The crude
product was purified by flash chromatography on silica (elution
with a linear gradient of EtOAc in toluene) to give compound 6 as
white glistening crystals (129.5 g, 528 mmol, 98%; Rf 0.75 in T1). 1H
(600 MHz, CDCl3):
d 0.88 (s, 9H, (CH3)3), 1.03 (tm, 1H, >CHe), 1.54
(m, 2H) and 2.07 (m, 2H) (2ꢂ eCH2e), 1.61 (m, 2H) and 1.98 (m, 2H)
(2ꢂ PeCH2e), 10.15 (br s, 1H, PeOH). 13C NMR (150.9 MHz, CDCl3):
d
24.54 (d, 2J(P,C)¼5.2 Hz, 2ꢂ eCH2e), 27.70 (d, 1J(P,C)¼87.6 Hz, 2ꢂ
PeCH2e), 27.72 ((CH3)3), 32.82 (d, 4J(P,C)¼0.9 Hz, >C<), 48.26 (d,
3J(P,C)¼5.0 Hz, >CHe). HRMS (ESI): [MþH]þ, found 191.11970.
C9H20O2P requires 191.11954.
NMR (600 MHz, CDCl3):
d
0.87 (s, 9H, (CH3)3), 1.26 (tt, J¼11.8, 2.9 Hz,
4.5.7. 4-tert-Butyl-1-chlorophosphorinane 1-oxide (9). To a solution
of phosphinic acid 8 (4.0 g, 21.0 mmol) and a catalytic amount of
DMF (200 mL) in dichloromethane (60 mL) in a flask equipped with
1H, >CHe), 1.17 (bt, Jw11 Hz, 1H) and 1.63 (bd, Jw11 Hz, 1H)
(eCH2e),1.30 (bt, Jw11 Hz,1H) and 1.82 (bd, Jw11 Hz,1H) (eCH2e),
2.66 (bt, Jw11 Hz, 1H) and 4.81 (bd, Jw11 Hz, 1H) (NeCH2e), 2.93
(bt, Jw11 Hz,1H) and 3.80 (bd, Jw11 Hz,1H) (NeCH2e), 7.40 (m, 5H,
magnetic stirrer and cooled in an ice bath, oxalyl chloride (3.61 mL,
42.1 mmol, 2 equiv) in CH2Cl2 (20 mL) was slowly added from the
dropping funnel with constant stirring. After the addition was
complete, the mixture was allowed to warm to room temperature
and stir for an additional 2 h. The solution was then evaporated in
vacuo to give brown crystalline mass of crude 9 (epimeric mixture,
9a:9b¼80:20 by NMR), which was used in the next step without
further purification. Major epimer 9a: 1H NMR (600 MHz, CDCl3):
C6H5). 13C NMR (150.9 MHz, CDCl3):
d 27.23 ((CH3)3), 26.64
(eCH2e), 27.59 (eCH2e), 32.24 (>C<), 42.99 (NeCH2e), 46.81
(>CHe), 48.59 (NeCH2e), 126.84 (2ꢂ o-ArC), 128.35 (2ꢂ m-ArC),
129.36 (p-ArC), 136.38 (i-ArC), 170.10 (>C]O). HRMS (ESI):
[MþH]þ, found 246.18515. C16H24ON requires 246.18524.
4.5.5. 4-tert-Butyl-1,5-dibromopentane
(7). N-Benzoyl-4-tert-
d 0.91 (s, 9H, (CH3)3), 1.11 (m, 1H, >CHe), 1.59 (m, 2H) and 2.16 (m,
butylpiperidine (6) (129.5 g, 528 mmol) was placed in a three-
necked round-bottomed flask equipped with mechanical stirrer
and addition funnel. Phosphorus tribromide (49.9 mL, 531 mmol,
1 equiv) was added dropwise over a 30-min period at room tem-
perature. After stirring at rt for 2 h, the light yellow liquid was
cooled with an ice bath, followed by dropwise addition of bromine
(27.2 mL, 531 mmol, 1 equiv) over the course of 30 min. After 1 h,
the resulting black viscous oil was heated to 150 ꢀC for 12 h. Upon
cooling to room temperature, a mass of crystalline POBr3 pre-
cipitated; the mixture was diluted with 500 mL of acetonitrile, and
the crystals were quickly filtered off through a fritted filtration
funnel. The black filtrate was extracted with hexane (2ꢂ300 mL,
then 10ꢂ100 mL), the combined organic layers were washed suc-
cessively with water (300 mL) and saturated aq NaHCO3 (300 mL),
and the total volume was reduced to 0.5 L in vacuo. Then, benzo-
nitrile was removed by extracting with conc. H2SO4 (10ꢂ50 mL),
the pale yellow hexane layer was washed with water (200 mL) and
saturated aq NaHCO3 (200 mL), dried over Na2SO4, and evaporated
in vacuo to give 51.85 g of crude product. Distillation under reduced
pressure afforded 41.1 g (144 mmol, 27.2%) of dibromide 7 as
a colorless liquid (bp 85e90 ꢀC/2 Torr, density 1.41 g/mL, Rf 0.8 in
2H) (2ꢂ eCH2e), 2.12 (m, 2H) and 2.38 (m, 2H) (2ꢂ PeCH2e). 13
C
NMR (150.9 MHz, CDCl3):
d
25.04 (d, 2J(P,C)¼5.7 Hz, 2ꢂ eCH2e),
27.59 ((CH3)3), 32.74 (d, 4J(P,C)¼1.2 Hz, >C<), 33.56 (d, 1J(P,C)¼
69.2 Hz, 2ꢂ PeCH2e), 47.80 (d, 3J(P,C)¼5.2 Hz, >CHe). Minor epi-
mer 9b: 1H NMR (600 MHz, CDCl3):
d 0.91 (s, 9H, (CH3)3), 1.20 (m,
1H, >CHe), 1.82 (m, 2H) and 2.13 (m, 2H) (2ꢂ eCH2e), 1.99 (m, 2H)
and 2.50 (m, 2H) (2ꢂ PeCH2e). 13C NMR (150.9 MHz, CDCl3):
d
24.51 (d, 2J(P,C)¼5.8 Hz, 2ꢂ eCH2e), 26.56 ((CH3)3), 32.95 (d,
4J(P,C)¼1.0 Hz, >C<), 34.80 (d, 1J(P,C)¼70.3 Hz, 2ꢂ PeCH2e), 48.22
(d, 3J(P,C)¼4.6 Hz, >CHe).
4.5.8. 4-tert-Butyl-1-methylphosphorinane 1-oxide (10). To a solu-
tion of crude chloride 9 (assumed 21 mmol) in diethyl ether (40 mL)
in a flask equipped with a magnetic stirrer, reflux condenser and
argon inlet, CH3MgBr (3 M solution in Et2O; 21.02 mL, 63 mmol,
3 equiv) was added via syringe through a rubber septum with
spontaneous reflux. After the addition was complete, the solution
was heated to reflux for 2 h. The reaction mixture was then diluted
with CH2Cl2 (200 mL) and poured slowly into a vigorously stirred
0.5 M aqueous HCl (200 mL). The dichloromethane layer was sep-
arated, the aqueous layer was extracted with additional dichloro-
methane (2ꢂ100 mL), the combined organic phase was washed
with saturated aq NaHCO3 (100 mL), dried over Na2SO4 and evap-
orated in vacuo. The crude product was recrystallized from hexane-
EtOAc mixture to give phosphinoxide 10 as pale brown needles
(2.02 g, 10.74 mmol, 51% over two steps; Rf 0.5 in H3. Colorless
needles when obtained by oxidation of phosphine 11). 1H and 13C
NMR datadsee Fig. 4; 31P NMR datadsee Fig. 5. HRMS (ESI):
[MþH]þ, found 189.14080. C10H22OP requires 189.14083.
HT). 1H NMR (600 MHz, CDCl3):
d
0.90 (s, 9H, (CH3)3), 1.24 (tt, J¼7.3,
3.7 Hz, 1H, >CHe), 1.62 (dddd, J¼14.5, 8.4, 7.3, 5.6 Hz, 2H) and 2.09
(dddd, J¼14.5, 8.8, 7.3, 3.7 Hz, 2H) (2ꢂ eCH2e), 3.40 (ddd, J¼9.9,
8.4, 5.6 Hz, 2H) and 3.49 (ddd, J¼9.9, 8.8, 5.6 Hz, 2H) (2ꢂ eCH2eBr).
13C NMR (150.9 MHz, CDCl3):
d
27.49 ((CH3)3), 33.15 (2ꢂ eCH2eBr),
33.72 (>C<), 34.95 (2ꢂ eCH2e), 46.52 (>CHe). HRMS (ESI):
[MþH]þ, found 286.98339. C9H19Br2 requires 286.98330.
4.5.6. 4-tert-Butyl-1-hydroxyphosphorinane 1-oxide (8). To a three-
necked round-bottomed flask equipped with magnetic stirrer, ar-
gon inlet and a reflux condenser dibromide 7 (10.0 g, 35 mmol) was
placed, dry ammonium hypophosphite (11.6 g, 140 mmol, 4 equiv),
hexamethyldisilazane (58.4 mL, 280 mmol, 8 equiv) and mesitylene
(120 mL) were added, and the reaction mixture was heated to
4.5.9. 4-tert-Butyl-1-methylphosphorinane (11). To the phosphin-
oxide 10 (1.0 g, 5.31 mmol) in a flask equipped with reflux con-
denser and argon inlet, phenyl silane (0.44 mL, 3.56 mmol,
0.67 equiv) was added via syringe through a rubber septum. The
mixture became homogenous in 5 min, and an exothermic reaction