O. Pꢀmies, M. Diꢁguez and J. Mazuela
The layers were separated and the organic phase further extracted with
diethyl ether (3ꢅ50 mL). The organic extracts were combined, washed
with brine, dried (MgSO4) and concentrated to a crude oil. The resulting
oil was purified by chromatography on silica (petroleum ether/ethyl ace-
tate 70:30, Rf =0.3) to afford the (rac)-7 as a white solid. The racemate
was separated into its enantiomers by chiral semi-preparative HPLC
using a (250ꢅ20 mm) Chiracel OD column (1% isopropanol in hexanes,
4 mLminÀ1, 31 min (S), 33 min (R)) to yield (S)-7 in>99% ee. 1H NMR
(400 MHz, CDCl3): d=0.9 (s, 9H, tBu), 2.55 (s, 3H, CH3), 4.32 (b, 1H,
extracted with Et2O (3ꢅ10 mL) and the extract dried over MgSO4. The
solvent was removed and the conversion and regioselectivity were meas-
ured by 1H NMR spectroscopy. The enantiomeric excess was determined
by HPLC (Chiralcel OJ, 13% 2-propanol/hexane, flow 0.5 mLminÀ1). A
sample was filtered over basic alumina using dichloromethane as the
eluent.[25c,43]
Typical procedure for the allylic amination of disubstituted linear sub-
strates S1 and S2: A degassed solution of [PdClACTHNUTRGNEUNG
(h3-C3H5)]2 (0.9 mg,
0.0025 mmol) and the corresponding phosphite-pyridine (0.0055 mmol) in
dichloromethane (0.5 mL) was stirred for 30 min. Subsequently, a solu-
tion of the corresponding substrate (0.5 mmol) in dichloromethane
(1.5 mL) and benzylamine (131 mL, 1.5 mmol) were added. The reaction
mixture was stirred at room temperature. After the desired reaction time,
the reaction mixture was diluted with Et2O (5 mL) and saturated NH4Cl
(aq, 25 mL) was added. The mixture was extracted with Et2O (3ꢅ10 mL)
and the extract dried over MgSO4. For substrate S1, solvent was removed
and conversion was measured by 1H NMR spectroscopy. To determine
the ee value by HPLC (Chiralcel OJ, 13% 2-propanol/hexane, flow
0.5 mLminÀ1), a sample was filtered over silica using 10% Et2O/hexane
mixture as the eluent.[42] For substrate S2, conversion and enantiomeric
excess was determined by GC.[25b]
À
OH), 4.35 (s, 1H, CH O), 7.0–7.6 ppm (m, 3H, CH=).
General procedure for the preparation of phosphite-pyridine ligands L1–
L12a–g: Phosphorochloridite (1.1 mmol) produced in situ was dissolved
in toluene (5 mL) and pyridine (0.18 mL, 2.3 mmol) was added. Hydrox-
yl-pyridine (1 mmol) was azeotropically dried with toluene (3ꢅ1 mL)
and then dissolved in toluene (5 mL), to which pyridine (0.18 mL,
2.3 mmol) was added. The alcohol solution was transferred slowly at 08C
to the solution of phosphorochloridite. The reaction mixture was warmed
to 808C and stirred for 2 h, and the pyridine salts were removed by filtra-
tion. Evaporation of the solvent gave a white foam, which was purified
by flash chromatography (toluene/hexane/NEt3) to produce the corre-
sponding ligand as white solid (for characterization details see the Sup-
porting Information).
Typical procedure for the allylic etherification of disubstituted linear sub-
strate S1: A degassed solution of [PdClACTHNUTRGNEUNG
(h3-C3H5)]2 (0.9 mg, 0.0025 mmol)
General procedure for the preparation of [Pd
39–46: The corresponding ligand (0.05 mmol) and the complex [PdAHCTUNTGRENNUNG
(h3-allyl)(L)]BF4 complexes
and the corresponding phosphite-pyridine (0.0055 mmol) in dichlorome-
thane (0.5 mL) was stirred for 30 min. Subsequently, a solution of the cor-
responding substrate (31.5 mg, 0.125 mmol) in dichloromethane (1.5 mL)
was added. After 10 min, Cs2CO3 (122 mg, 0.375 mmol) and alkyl alcohol
(0.375 mmol) were added. The reaction mixture was stirred at room tem-
perature. After the desired reaction time, the reaction mixture was dilut-
ed with Et2O (5 mL) and saturated NH4Cl (aq., 25 mL) was added. The
mixture was extracted with Et2O (3ꢅ10 mL) and the extract dried over
(m-
Cl)(h3-1,3-allyl)]2 (0.025 mmol) were dissolved in CD2Cl2 (1.5 mL) at
room temperature under argon. AgBF4 (9.8 mg, 0.05 mmol) was added
after 30 min and the mixture was stirred for 30 min. The mixture was
then filtered over celite under argon and the resulting solutions were an-
alyzed by NMR spectroscopy. After the NMR analysis, the complexes
were precipitated as pale yellow solids by adding hexane (for characteri-
zation details see the Supporting Information).
1
MgSO4. Conversion was measured by H NMR. HPLC was used to deter-
Study of the reactivity of the [Pd
ACHTUNGTRENNUNG
mine the ee value. A sample was filtered over silica using 10% Et2O/
by in situ NMR spectroscopy:[42] A solution of in situ prepared [Pd
AHCTUNGTRENNUNG
hexane mixture as the eluent.[21i]
lyl)(L)]BF4 (L=phosphite-pyridine, 0.05 mmol) in CD2Cl2 (1 mL) was
cooled in the NMR machine at À808C. At this temperature, a solution of
cooled sodium malonate (0.1 mmol) was added. The reaction was then
followed by 31P NMR spectroscopy. The relative reaction rates were cal-
culated using a capillary containing a solution of triphenylphosphine in
CD2Cl2 as external standard.
Typical procedure for the preparation of carbocyclic compounds 35 and
36: A solution of Grubbs II catalyst (5 mg, 0.006 mmol) and the corre-
sponding alkylated product (0.12 mmol) in CH2Cl2 (3 mL) was stirred for
16 h. The solution was directly purified by flash chromatography (95:5;
Hex/EtOAc) to obtained the desired carbocycle compounds.
(R)-35. Yield: 27 mg (86%). For characterization details and details for
ee determination see Refs. [23] and [44]
Typical procedure for the allylic alkylation of disubstituted linear (S1 and
S2) and cyclic (S3–S5) substrates: A degassed solution of [PdClACHTNUTGRNEUNG
(h3-
(À)-36. Yield: 21 mg (88%). Enantiomeric excess determined by HPLC
using Chiralcel OJ-H column (98% hexane/2-propanol, flow
0.5 mLminÀ1, l=220 nm). Rt =15.6 min (À); Rt =16.7 min (+).1H NMR
(400 MHz, CDCl3): d=0.93 (d, 3H, CH3, J=7.6 Hz), 2.72 (d, 1H, H-5,
2J5À5’ =16.8 Hz), 3.28 (dd, 1H, H-5’, 2J5’À5 =16.8 Hz, 3J5’À4 =2.8 Hz), 3.61
(m, 1H, H-2), 3.72 (s, 6H, CO2Me), 5.57 ppm (m, 2H, H-3 and H-4);
13C NMR (100 MHz, CDCl3), d: 15.8 (CH3), 39.7 (C-5), 45.3 (C-2), 52.2
(CO2Me), 52.6 (CO2Me), 63.1 (C-1), 126.2 (C-3 or C-4), 134.4 (C-4 or C-
3), 172.7 ppm (CO2Me).
C3H5)]2 (0.9 mg, 0.0025 mmol) and the corresponding phosphite-pyridine
(0.0055 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Sub-
sequently, a solution of the corresponding substrate (0.5 mmol) in di-
chloromethane (1.5 mL), nucleophile (1.5 mmol), N,O-bis(trimethylsilyl)-
acetamide (370 mL, 1.5 mmol) and a pinch of the corresponding base
were added. The reaction mixture was stirred at room temperature. After
the desired reaction time the reaction mixture was diluted with Et2O
(5 mL) and saturated NH4Cl (aq., 25 mL) was added. The mixture was
extracted with Et2O (3ꢅ10 mL) and the extract dried over MgSO4. For
compound 9, solvent was removed and conversion was measured by
1H NMR spectroscopy. To determine the ee value by HPLC (Chiralcel
OD, 0.5% 2-propanol/hexane, flow 0.5 mLminÀ1), a sample was filtered
over basic alumina using dichloromethane as the eluent.[42] For com-
pounds 21, 27, and 34, the conversion and enantiomeric excess were de-
termined by GC.[35] For compound 33, the conversion was measured by
1H NMR spectroscopy. To determine the ee value by 1H NMR spectro-
Acknowledgements
We would like to thank the Spanish Government for providing grant
CTQ2010-15835, the Catalan Government for grant 2009SGR116, and
the ICREA Foundation for providing M. Diꢁguez and O. Pꢀmies with fi-
nancial support through the ICREA Academia awards.
scopy [EuACHTUNGTRENNUNG
(hfc)3] was used.[25b] For characterization and ee determination
of the rest of products see the Supporting Information.
Typical procedure for the allylic alkylation of 1,3,3-trisubstituted sub-
strates (S6 and S7): A degassed solution of [PdClACTHNUTRGNEUNG
(h3-C3H5)]2 (1.8 mg,
0.005 mmol) and the corresponding phosphite-pyridine (0.011 mmol) in
dichloromethane (0.5 mL) was stirred for 30 min at room temperature.
Subsequently, a solution of substrate (0.5 mmol) in dichloromethane
(1.5 mL), dimethyl malonate (171 mL, 1.5 mmol), N,O-bis(trimethylsilyl)-
acetamide (370 mL, 1.5 mmol) and a pinch of KOAc were added. After
2 h at room temperature, the reaction mixture was diluted with Et2O
(5 mL) and saturated NH4Cl (aq., 25 mL) was added. The mixture was
[1] a) Asymmetric Catalysis in Industrial Scale: Challenges, Approaches
and Solutions (Eds.: H. U. Blaser, E. Schmidt), Wiley-VCH, Wein-
heim, 2003; b) Comprehensive Asymmetric Catalysis (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999; c) Asym-
metric Catalysis in Organic Synthesis (Ed. R. Noyori), Wiley, New
York, 1994; d) Applied Homogeneous Catalysis with Organometal-
lics Compounds, 2nd ed. (Eds.: B. Cornils, W. A. Hermann), Wiley-
2430
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2416 – 2432