4.5.1. Chiral Amine Epimerisation. Racemic sertraline (88
g) with the composition described above and 0.25 g (85 µmol)
bis-diiodoiridiumpentamethylcyclopentadiene (SCRAM catalyst
1) were charged to the mother liquors from the previous stage.
The mixture was heated at 80 °C for 8 h then cooled to ambient.
In-situ HPLC monitoring showed a composition of (1S,4S)
11.7%, (1R,4R) 41.2%, (1R,4S) 8.5%, (1S,4R) 24.7%, ketone
7.9%, imine 5.9%. Gaseous ammonia was bubbled through the
solution for 6 h during which a fine precipitate formed. The
solid recovered was screened and reused in the next cycle whilst
the reaction mass was used directly in the next stage.
mL). The combined ether layers were washed with water (2 ×
100 mL) and dried over Na2SO4, and solvent was removed to
give an orange/brown oil. Purification by eluting through a large
plug of silica (heptane/EtOAc 10:1 as eluent) gave the product
as a pale-yellow oil (25.8 g, 45%). HPLC Retention time 8.0
1
min; H NMR (300 MHz, CDCl3) 3.63 (t, J ) 6.6 Hz, 2 H,
CH2OH), 2.21 (m, 2 H, CH2), 1.81 (s, 6 H, 2 × CH3), 1.78 (s,
3 H, CH3), 1.59 (m, 2 H, CH2), 1.38 (m, 5 H, 2 × CH2 and
allyl CH), 1.01 (dd, J ) 7.2, 3.3, 3 H, CH3); GC/MS
(Trimethylsilyl chloride added) 280.0 (M+ + TMS) 7.49 min,
83%.
4.5.2. Benzylic Epimerisation. Potassium tert-butoxide [9.5
g (0.085 mol)] was charged to the toluene solution and heated
to reflux for 1 h. The solution turned dark and was cooled to
ambient. Norit ROX 0.8 charcoal was added and the solution
screened before adding an equal volume of water, stirring,
settling and separating. After a further aqueous wash the solution
was dried azeotropically. HPLC analysis of the isomer com-
position showed (1S,4S) 21.2%, (1R,4R) 34.1%, (1R,4S) 18.4%,
(1S,4R) 18.5%, ketone 1.4%, imine 6.4%.
Iridium trichloride hydrate (1.50 g, 4.25 mmol) and sodium
bicarbonate (0.39 g, 4.68 mmol) were added to degassed
methanol (10 mL) in a 20 mL capacity microwave tube, and
the suspension was purged with nitrogen for 10 min. 1-(5-
Hydroxypentyl)-2,3,4,5-tetramethylcyclopentadiene (1.77 g, 8.5
mmol) was added, and the purge continued for 5 min. The tube
was sealed, and microwave heating was applied with a set
temperature of 150 °C for 10 min. After cooling, a nitrogen
balloon was attached via a needle through the reaction tube lid
septum which resulted in effervescence from the solution. Once
this had subsided, the tube was opened, and the reaction mixture
was diluted with DCM (20 mL), then washed with water (15
mL), extracting the aqueous layer with DCM (2 × 10 mL).
The combined DCM layers were washed with brine and dried
over Na2SO4, and solvent was removed. The oily red residue
was taken up in DCM (3-5 mL) and product precipitated with
heptane. An orange powdery solid was obtained (1.87 g, 93%).
4.6. Recovered Catalyst. The solid recovered after am-
monia precipitation was washed with toluene and dried. The
1
product was characterised: HNMR (CD2Cl2) CpMe5 1.84 (s,
15H); NH3 3.27 (b, 3H); 13CNMR (CD2Cl2) CpMe5 10.7, 86.9;
MS 605, 472; Microanalysis % theory (% actual): C 20.08
(20.17); H 3.03 (2.97); N 2.34 (2.23); other 74.55 (74.63);
UV-vis (CHCl3) (nm, M-1 cm-1) 232 (1.6 × 104), 336 (4.3
× 103), 384 (4.2 × 103); IR (cm-1): 2923 (m), 2959 (m), 2904
(m),1459 (l), 1412 (m), 1380 (l),1356 (m), 1155 (m), 1076 (m),
1022 (l), 951 (m), 609 (m), 533 (m), 422 (m). Single crystal
X-ray diffraction: Ir-I1 2.7166(4) Å, Ir-I2 2.7140(4) Å, Ir-N
2.133(4) Å, Cp(cent)-Ir 1.783(3) Å; I1-Ir-I2 91.46°(1),
N-Ir-I1 85.37°(14), N-Ir-I2 83.51°(14).
1
HPLC retention time 5.0 min; H NMR (300 MHz, CDCl3)
3.65 (t, 2 H, CH2OH), 2.16 (m, 2 H, CH2), 1.86 (m, 2 H, CH2),
1.62 (s, 6 H, 2 × CH3), 1.58 (s, 6 H, 2 × CH3), 1.45 (m, 4 H,
2 × CH2).
Iridium chloro complex (1.00 g, 1.0 mmol) and sodium
iodide (1.59 g, 10.6 mmol) were heated at reflux in degassed
acetone (40 mL) under a nitrogen atmosphere. After 18 h, the
solution was cooled, concentrated to approximately 10 mL on
a rotary evaporater, and diluted with chloroform (40 mL). This
solution was washed with water (2 × 40 mL) and then brine.
The organic layer was dried over MgSO4, and the solvent was
removed. Product was precipitated with heptane after dissolution
in a minimum volume of DCM to give a brick-red solid, 1.19 g
4.7. Tethered Iridium Catalyst. An oven-dried three-
necked 1 L round-bottom flask with reflux condenser and
dropping funnel attached was placed under a nitrogen atmo-
sphere and then charged with anhydrous diethyl ether (130 mL).
Lithium wire (7.92 g, 1.14 mmol, 3.2 mm diameter, 0.5-1%
sodium) was washed with hexane, cut into small pieces, and
added to the reaction flask. 2-Bromo-2-butene (80.0 g, 0.59
mmol, mixture of cis and trans isomers) was placed in the
dropping funnel and a small portion added to the vigorously
stirred lithium suspension. Once reaction had initiated, evi-
denced by refluxing of the solvent, the remaining 2-bromo-2-
butene was diluted with diethyl ether (70 mL), the reaction
mixture diluted with ether (80 mL), and addition continued at
a rate to maintain a gentle reflux. After complete addition, the
reaction mixture was stirred for 2 h at rt. Caprolactone (29.0
mL, 0.27 mmol) in diethyl ether (50 mL) was then added
dropwise. After stirring for a further 1 h, the reaction mixture
was poured into sat. NH4Cl aq (600 mL), the ether layer
separated, and the aqueous layer extracted with tert-butyl methyl
ether (3 × 100 mL). The combined ether layers were washed
with brine, dried over MgSO4, and concentrated to ap-
proximately 100 mL. Aqueous hydrochloric acid (10%, 300
mL) was added to the concentrate, and the two-phase mixture
stirred for 3 h at rt. The organic layer was separated and the
aqueous layer extracted with tert-butyl methyl ether (3 × 50
1
(87%). H NMR (300 MHz, CDCl3) 3.65 (t, 2 H, CH2OH),
2.26 (m, 2 H, CH2), 1.85 (s, 6 H, 2 × CH3), 1.80 (s, 6 H, 2 ×
CH3), 1.58 (m, 4 H, 2 × CH2), 1.42 (m, 4 H, 2 × CH2). Single
crystal X-ray diffraction confirmed the identity of this structure:
Ir-I1 2.740 Å, Ir-I2 2.714 Å, Cp(cent)-Ir 1.841 Å, I1-Ir-I2
90.1°.
1-(5-Hydroxypentyl)-2,3,4,5-tetramethylcyclopentadiene (2.0
g, 9.6 mmol) was dissolved in anhydrous DCM (25 mL) and
triethylamine (3.2 mL, 23.0 mmol), and DMAP (12 mg, 0.1
mmol) was added to the stirred solution which was cooled to
0 °C. Tosyl chloride (2.4 g, 12.6 mol) in DCM (20 mL) was
added dropwise and then the reaction mixture stirred at rt for
20 h until TLC showed completion. The reaction mixture was
washed with sat. NaHCO3 aq (2 × 50 mL), then water (2 ×
50 mL), and finally brine (50 mL). The organic phase was dried
over MgSO4, and solvent was evaporated to give a dark-yellow
oil (3.3 g, 95%).
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