Suzuki Cross-Coupling on Enantiomerically Pure Epoxides
Ethyl 3-(3,5-Dibromophenyl)propenoate: 3,5-Dibromobenzal-
dehyde (16 g, 60 mmol) was dissolved in DCM (50 mL) and added
at 0 °C into a solution of carboethoxymethylene triphenylphos-
phorane (23.3 g, 67 mmol) in DCM (50 mL). The mixture was
refluxed overnight then cooled to rt. After concentration, the residue
was filtered over silica eluting with a 9:1 mixture of hexanes and
ethyl acetate. The product was recrystallized from hot hexanes,
yielding the cinnamyl ester as white needles (12.2 g, 60%). 1H NMR
(400 MHz): δ ) 1.35 (t, J ) 7.1 Hz, 3 H), 4.28 (q, J ) 7.1 Hz,
2 H), 6.44 (d, J ) 16.0 Hz, 1 H), 7.53 (d, J ) 16.0 Hz, 1 H), 7.59
(d, J ) 1.8 Hz, 1 H), 7.68 (t, J ) 1.8 Hz, 2 H). 13C NMR (100
MHz): δ ) 14.3 (CH3), 60.9 (CH2), 121.2 (CH), 123.4 (C), 129.5
(CH), 135.2 (CH), 138.0 (C), 141.3 (CH), 166.1 (C).
Ethyl acetate was added, and the mixture was filtered over a pad
of Celite. After concentration, the epoxide (3) was purified by flash
chromatography (hexanes/ethyl acetate 95/5).
1
Epoxyether 8aa: Reaction time: 2 h. Yield: 93%. H NMR
(400 MHz): δ ) 3.33 (m, 1 H), 3.50 (s, 3 H), 3.62 (dd, J ) 5.1
and 11.5 Hz, 1 H), 3.85 (dd, J ) 3.0 and 11.5 Hz, 1 H), 3.97 (d,
J ) 2.1 Hz, 1 H), 7.41 (m, 2 H), 7.50 (m, 4 H), 7.51 (d, J ) 1.7
Hz, 2 H), 7.66 (m, 4 H), 7.77 (t, J ) 1.7 Hz, 1 H). 13C NMR (100
MHz): δ ) 55.8 (CH), 59.4 (CH3), 61.1 (CH), 72.1 (CH2), 123.4
(CH), 126.1 (CH), 127.3 (CH), 127.6 (CH), 128.9 (CH), 138.1 (C),
140.7 (C), 142.2 (C). Mp 80-81 °C. [R]20D -38.9 (c 0.90, CHCl3).
HRMS: calcd for C22H20O2Na, 339.1361; found, 339.1361.
3-(3,5-Dibromophenyl)prop-2-en-1-ol: To a solution of ethyl
3-(3,5-dibromophenyl)propenoate (12.2 g, 36.5 mmol) in anhydrous
ether (50 mL) at 0 °C was added dropwise a solution of DIBALH
(25 wt % in toluene, 53 mL, 80 mmol). Upon completion of the
addition, the reaction mixture was allowed to warm to rt over 1 h
and then carefully added to a stirred mixture of 2 N HCl and ice.
Ethyl acetate was added, and the phases were separated.
The aqueous phase was extracted with ethyl acetate, and the
combined organic phases were washed with water and brine. After
drying over sodium sulfate, the solution was concentrated,
yielding an off white solid which was used in the next step
without purification (10.3 g, 96%). 1H NMR (400 MHz): δ ) 4.36
(dd, J ) 1.4 and 5.1 Hz, 2 H), 6.38 (dt, J ) 16.0 and 5.1 Hz, 1 H),
6.51 (dt, J ) 16.0 and 1.4 Hz, 1 H), 7.45 (d, J ) 1.8 Hz, 2 H),
7.54 (t, J ) 1.8 Hz, 1 H). 13C NMR (100 MHz): δ ) 63.1 (CH2),
123.1 (C), 127.8 (CH), 128.1 (CH), 131.7 (CH), 132.8 (CH),
140.4 (C).
General Procedure for the Ring Opening of Epoxides with
Ammonia (Method B): In a 25 mL autoclave were placed
epoxyether 3 (2.3 mmol), lithium perchlorate (0.50 g, 4.7 mmol),
ammonia (30 wt % in water, 10 mL), and THF (5 mL), and the
mixture was heated to 125 °C under stirring for 16 h. After cooling,
the mixture was taken in DCM and water, and the phases were
separated. The aqueous phase was extracted twice with DCM, and
the combined organic phases were washed with water and brine
and then dried over sodium sulfate. The compound was purified
by flash chromatography (DCM/ethyl acetate 1/1 then DCM/MeOH
9/1).
1
Amino Alcohol 9aa: Method B. Yield: 84%. H NMR (400
MHz): δ ) 1.97 (br, 3 H), 3.38 (s, 3 H), 3.46 (m, 2 H), 4.06 (q,
J ) 5.1 Hz, 1 H), 4.31 (d, J ) 5.1 Hz, 1 H), 7.39 (m, 2 H), 7.49
(m, 4 H), 7.61 (d, J ) 1.7 Hz, 2 H), 7.68 (m, 4 H), 7.76 (t, J ) 1.7
Hz, 1 H). 13C NMR (100 MHz): δ ) 58.1 (CH), 59.2 (CH3), 73.6
(CH2), 73.7 (CH), 125.0 (CH), 125.3 (CH), 127.3 (CH), 127.5 (CH),
128.8 (CH), 140.98 (C), 141.01 (C), 142.0 (C). Mp 120-121 °C.
(3,5-Dibromophenyl)glycidol 6: A dry flask equipped with an
addition funnel was charged with 0.12 mL of L-DIPT and 40 mL
of DCM. After the mixture was cooled to -20 °C, 1 g of activated
4 Å molecular sieves, 0.11 mL of Ti(OiPr)4, and 5.2 mL of tert-
butylhydroperoxide in isooctane (3 M) were added sequentially.
The mixture was stirred at -20 °C for 1 h. Freshly activated 3 Å
molecular sieves (powder) were stirred with the cinnamyl alcohol
in 8 mL of DCM for 1 h. The solution was then added dropwise
over 1 h onto the previous mixture, and the sieves were rinsed with
DCM (5 mL). After 3 h at -20 °C, the reaction was quenched by
addition at -20 °C of a 10% NaOH solution saturated with sodium
chloride (1 mL). Ether was added, and the mixture was allowed to
warm to 10 °C. Then, MgSO4 (0.8 g) and Celite (0.1 g) were added.
After an additional 15 min of stirring, the mixture was allowed to
settle, and the clear solution was filtered through a pad of Celite,
washing with ethyl ether. Concentration yielded a white solid. It
was dissolved in a minimum amount of ethyl acetate, filtered
through a short pad of silica gel with ethyl acetate, and recrystallized
from hexane (insoluble, ca. 30 mL)/ethyl acetate (soluble, ca. 6
mL), to give a white solid. The epoxide was recrystallized once
again from hexanes (20 mL)/ethyl acetate (5 mL), yielding pure
[R]20 -18.4 (c 0.83, CHCl3). HRMS: calcd for C22H24O2N,
D
334.1807; found, 334.1817.
Bisoxazoline 10: Amino alcohol 9aa (0.764 g, 2.3 mmol) was
dissolved in DCM (2 mL) and cooled to 0 °C. Triethylamine (0.36
mL, 2.5 mmol) and then a solution of dimethylmalonyl dichloride
(0.15 mL, 1.15 mmol) in DCM (2 mL) were added. The mixture
was stirred for 20 h at rt. The reaction mixture was diluted with
DCM, then washed with 10% HCl (twice), saturated NaHCO3, and
brine. The solution was dried over sodium sulfate and concentrated,
yielding a yellow foam, which was used in the next step without
further purification. Methanesulfonyl chloride (0.20 mL, 2.5 mmol)
was added dropwise onto a solution of the crude bis(amide) and
triethylamine (0.71 mL, 5.0 mmol) in DCM (5 mL) at 0 °C. The
solution was stirred for 2 h at rt, then the reaction mixture was
poured into a saturated NH4Cl solution. The phases were separated,
and the aqueous layer was extracted with DCM. The organic
extracts were washed with brine, dried over sodium sulfate, and
concentrated. The crude bis(mesylate) was then treated over 70 h
with a 5 wt % solution of potassium hydroxide in methanol (25
mL). DCM and water were added, and the phases were separated.
The aqueous layer was extracted twice with DCM, and the
combined organic phases were washed with brine and dried over
sodium sulfate. After concentration, it was purified by flash
chromatography (hexane/AcOEt 100/0 to 70/30), yielding an oil.
A white foam was obtained after addition of toluene and concentra-
1
white crystals (58% yield, 99% ee). H NMR (400 MHz): δ )
1.82 (dd, J ) 8.0 and 5.3 Hz, 1 H), 3.16 (m, 1 H), 3.84 (ddd, J )
3.5, 8.0, and 13.0 Hz, 1 H), 3.91 (d, J ) 2.1 Hz, 1 H), 4.06 (ddd,
J ) 2.3, 5.3, and 13.0 Hz, 1 H), 7.39 (d, J ) 2.0 Hz, 2 H), 7.62 (t,
J ) 2.0 Hz, 1 H). 13C NMR (100 MHz): δ ) 53.9 (CH), 60.7
(CH2), 62.6 (CH), 123.2 (C), 127.5 (CH), 133.9 (CH), 141.0 (C).
Mp 88-89 °C. [R]20 -34.7 (c 1.51, CHCl3). HRMS: calcd for
D
C9H7O2Br2, 304.8813; found, 304.8808. The enantiomeric excess
was determined by HPLC: Chiralcel OD-H column, hexane/IPA
98/2, 1 mL/min, detection at 215 nm, tR (minor) ) 27.3 min (R,R),
tR (major) ) 29.9 min (S,S), ee ) 99%.
1
tion. H NMR (400 MHz): δ ) 1.77 (s, 6 H), 3.41 (s, 6 H), 3.55
(m, 4 H), 4.59 (q, J ) 5.4 Hz, 2 H), 5.10 (d, J ) 5.9 Hz, 2 H),
7.35 (m, 4 H), 7.42 (m, 8 H), 7.49 (d, J ) 1.7 Hz, 4 H), 7.62 (m,
8 H), 7.72 (t, J ) 1.7 Hz, 2 H). 13C NMR (100 MHz): δ ) 24.3
(CH3), 39.0 (C), 59.5 (CH3), 72.0 (CH), 73.4 (CH2), 86.2 (CH),
124.5 (CH), 125.5 (CH), 127.3 (CH), 127.4 (CH), 128.8 (CH), 141.1
General Procedure for the Suzuki Cross-Coupling on Ep-
oxides 7: Epoxide 7 (1.0 mmol) was dissolved in anhydrous,
degassed toluene (2 mL), and the resulting solution was added onto
a mixture of arylboronic acid (2.2 mmol), cesium carbonate (1.34
g, 4 mmol), Pd2(dba)3‚C6H6 (20.4 mg, 0.02 mmol), and S-Phos
(33.0 mg, 0.08 mmol) placed in a Schlenk tube under Ar. The
mixture was stirred at 100 °C for 2-15 h and then cooled to rt.
(C), 142.2 (C), 143.3 (C), 169.9 (C). Mp 71-72 °C. [R]20 173.5
D
(c 2.31, CHCl3). HRMS: calcd for C49H47O4N2, 727.3536; found,
727.3522.
J. Org. Chem, Vol. 72, No. 9, 2007 3257