Asymmetric Pd-Catalyzed Allylic Substitution Reactions
FULL PAPER
overnight. The reaction was quenched with saturated NH4Cl aq (50 mL)
and followed by the addition of additional diethyl ether (40 mL) and
water (40 mL). The organic layer was separated, washed with water,
dried over MgSO4, filtered and the solvent removed in vacuo. The resi-
due was purified by chromatography to give the desired tertiary oxazo-
line alcohols 27–32, 35, 38, 41, 44 (see Supporting Information).
dominantly at the allylic terminal carbon atom located trans
to the phosphite moiety. The study of the Pd–1,3-dipheny-
lallyl and 1,3-cyclohexenylallyl intermediates also indicates
that for enantioselectivities to be high, the substituents at
the alkyl backbone chain and the electronic/steric properties
at the oxazoline substituents need to be correctly combined
in order to form predominantly the isomer that reacts faster
with the nucleophile and also to avoid the formation of spe-
cies with ligands coordinated in monodentated fashion.
However, for the Pd–1,3-methylallyl intermediates the dif-
ference in enantioselectivity observed cannot be explained
by the reactivity of the nucleophile versus the different p-
allyl intermediates. We found a good explanation in the en-
hancement of the steric interaction upon attack of the nucle-
ophile.
General procedure for the preparation of the phosphite–oxazoline and
phosphite–oxazine ligands L1–L15a–h: The corresponding phosphoro-
chloridite (3.0 mmol) produced in situ was dissolved in toluene (12.5 mL)
and pyridine (1.14 mL, 14 mmol) was added. The corresponding hydrox-
yl-oxazoline/oxazine compound (2.8 mmol) was azeotropically dried with
toluene (32 mL) and then dissolved in toluene (12.5 mL) to which pyri-
dine (1.14 mL, 14 mmol) was added. The oxazoline/oxazine solution was
transferred slowly at 08C to the solution of phosphorochloridite. The re-
action mixture was stirred overnight at 808C, and the pyridine salts were
removed by filtration. Evaporation of the solvent gave a white foam,
which was purified by flash chromatography in alumina to produce the
corresponding ligand as a white solid (for characterization see Supporting
Information).
General procedure for the preparation of [Pd
ACHTREUNG
55–62: The corresponding ligand (0.05 mmol) and the complex [PdACHTREUNG
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, 0.5 mmol) was added
after 30 minutes and the mixture was stirred for 30 minutes. The mixture
was then filtered over Celite under argon and the resulting solutions
were analyzed by NMR. After the NMR analysis, the complexes were
precipitated adding hexane as pale yellow solids (for characterization see
Supporting Information).
Experimental Section
General considerations: All reactions were carried out using standard
Schlenk techniques under an atmosphere of argon. Solvents were purified
and dried by standard procedures. Phosphorochloridites are easily pre-
pared in one step from the corresponding biaryls.[23] Compounds 7,[10]
8,[24] 9,[25] 11,[26] 12,[25] 14–15,[24] 16,[25] 19,[25] 20,[27] 21–22,[24] 23,[25] 25,[26]
26,[25] 27,[24] 30–31,[24] 34,[28] 36–40[9b] have been previously prepared. Race-
Study of the reactivity of the [Pd
ACHTREUNG
mic substrates S1–S7 were prepared as previously reported.[29–32] [Pd(h3-
by insitu NMR :[36] A solution of in situ prepared [Pd
AHCTREUNG
[34]
1,3-Ph2-C3H3)
cyclohexenyl)
(m-Cl)]2,[33] [Pd(h3-1,3-Me2-C3H3)
A
and [Pd(h3-
(L=phosphite-oxazoline, 0.05 mmol) in CD2Cl2 (1 mL) was cooled in the
NMR at À808C. At this temperature, a solution of cooled sodium malo-
nate (0.1 mmol) was added. The reaction was then followed by 31P NMR.
The relative reaction rates were calculated using a capillary containing a
solution of triphenylphosphine in CD2Cl2 as external standard.
[35]
(m-Cl)]2
were prepared as previously described. 1H,
13C{1H}, and 31P{1H} NMR spectra were recorded using a 400 MHz spec-
trometer. Chemical shifts are relative to that of SiMe4 (1H and 13C) as in-
ternal standard or H3PO4 (31P) as external standard. 1H, 13C and 31P as-
signments were done based on 1H–1H gCOSY, 1H–13C gHSQC and
1H–31P gHMBC experiments.
Typical procedure of allylic alkylationof rac-1,3-diphenyl-3-acetoxyprop-
1-ene (S1):
A
(h3-C3H5)]2 (0.9 mg,
degassed solution of [PdClACHTREUNG
General procedure for the preparation of amides: To a solution of the
corresponding acyl chloride (25 mmol) in CH2Cl2 (200 mL) was added in
one portion the corresponding hydroxyl amino acid (25 mmol). A solu-
tion of triethylamine (19.4 mL, 50 mmol) in CH2Cl2 (50 mL) was slowly
added at 08C. The resulting mixture was stirred at room temperature for
3 h. The solvent was removed in vacuo and the residue purified by chro-
matography to afford the corresponding amides 8–14, 33, 36, 39, 42 (see
Supporting Information).
0.0025 mmol) and the corresponding phosphite–oxazoline/oxazine
(0.0055 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Sub-
sequently,
a solution of S1 (126 mg, 0.5 mmol) in dichloromethane
(1.5 mL), dimethyl malonate (171 mL, 1.5 mmol), N,O-bis(trimethylsily-
l)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 (310 mL) and the extract dried over MgSO4. Sol-
vent was removed and conversion was measured by 1H NMR. To deter-
mine the ee by HPLC (Chiralcel OD, 0.5% 2-propanol/hexane, flow
0.5 mLminÀ1), a sample was filtered over basic alumina using dichloro-
methane as the eluent.[37]
General procedure for the preparation of oxazoline/oxazine esters: To a
solution of the corresponding amide (10 mmol) in CH2Cl2 (40 mL) was
added dropwise diethylaminosulfur trifluoride (1.45 mL, 11 mmol) at
À788C. This solution was then stirred at this temperature for 1 h. Anhy-
drous K2CO3 (2.07 g, 15 mmol) was added in one portion and the reac-
tion mixture allowed to warm to room temperature. After 2 h, saturated
NaHCO3 (aq) (50 mL) was added and the organic layer separated, dried
over MgSO4, filtered and the solvent removed in vacuum. The residue
was purified by chromatography to give the desired oxazoline esters 15–
21, 34, 37, 40 and oxazine ester 43 (see Supporting Information).
Typical procedure of allylic alkylationof rac-(E)-ethyl 2,5-dimethyl-3-
hex-4-enylcarbonate (S2):
A degassed solution of [PdClACHTREUNG
(h3-C3H5)]2
(1.8 mg, 0.005 mmol) and the phosphite–oxazoline/oxazine (0.011 mmol)
in dichloromethane (0.5 mL) was stirred for 30 min. Subsequently, a solu-
tion of S2 (107.2 mg, 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. The reaction mixture was
stirred at room temperature. After the desired reaction time, the reaction
mixture was diluted with Et2O (5 mL) and a saturated NH4Cl (aq)
(25 mL) was added. The mixture was extracted with Et2O (310 mL)
General procedure for the reduction of the oxazoline esters with LiAlH4:
To a solution of the corresponding oxazoline ester (10 mmol) in diethyl
ether (50 mL) was added in five portions over ten minutes LiAlH4
(0.42 g, 11 mmol) at 08C. After stirring for 15 min, ethyl acetate (25 mL)
was added then water (40 mL). The organic layer was separated, dried
over MgSO4, filtered and the solvent removed in vacuo. The residue was
purified by chromatography to give the desired oxazoline alcohols 22–26
(see Supporting Information).
and the extract dried over MgSO4. Conversion and enantiomeric excess
1
was determined by H NMR using [Eu
A
Typical procedure of allylic alkylationof rac-1,3-dimethyl-3-acetoxyprop-
1-ene (S3): degassed solution of [PdCl
(h3-C3H5)]2 (0.9 mg,
General procedure for the reduction of the oxazoline esters with
Grignard reagents: To a solution of the corresponding oxazoline ester
(10 mmol) in THF/diethyl ether 1:1 (50 mL) was added dropwise a solu-
tion of the Grignard reagent in THF (11 mmol) at 08C. The mixture was
then stirred for 3 h, allowed to warm to room temperature and stirred
A
ACHTREUNG
0.0025 mmol) and the corresponding phosphite–oxazoline/oxazine
(0.0055 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Sub-
sequently,
a solution of S3 (64 mg, 0.5 mmol) in dichloromethane
(1.5 mL), dimethyl malonate (171 mL, 1.5 mmol), N,O-bis(trimethylsilyl)-
Chem. Eur. J. 2008, 14, 3653 – 3669
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3667
Dieguez, Montserrat
