P-Stereogenic Phosphines as Reagents in the Aza-Wittig Reaction
t
of BuPCl2 (5.6 mL of a 1.25 M solution in THF, 7.0 mmol) at
then DMAP (10 mol %) was added as a single portion and the
mixture redissolved in 1,2-dichloroethane (5 mL). Triethylamine
(0.17 mL, 1.22 mmol) and acetic anhydride (0.06 mL, 0.63 mmol)
were then added, and the mixture was heated at 90 °C over 4 h.
The mixture was then diluted with water and the product extracted
into DCM (2 × 10 mL). The combined organics were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (eluting with 30% acetone/
petroleum ether) to yield enamide 21 as a white solid (56%, 76%
ee ) 84% ee corrected for the ee of the phosphine; a subsequent
run gave 44% yield of material with 74% corrected ee. Measured
on a Chiralpak OJ column, 10% IPA + 0.1%Et2NH/hexanes, 1.0
-78 °C was added, via cannula, a solution of 1-naphthylmagnesium
bromide (30.0 mL of a 0.23 M solution in THF, 7.0 mmol). The
mixture was then allowed to warm to rt over 1 h and cooled to
0 °C, and LiAlH4 (7.0 mL of a 1 M solution in THF, 7.0 mmol)
was added portionwise, followed by BH3‚THF (8.0 mL of a 1 M
solution in THF, 8.0 mmol) and the mixture stirred at room
temperature overnight. The crude mixture was added carefully via
cannula to a slurry of ice, DCM, and HCl and the product extracted
into DCM (3 × 30 mL). The combined organics were dried, filtered,
and concentrated in vacuo. The crude product was then purified
by flash chromatography eluting with 5-10% Et2O/95-90%
petroleum ether to yield the desired product as a white solid (1.4
g, 88%): mp 51-53 °C; νmax/cm-1 3057, 2959, 2899, 2866, 2380
(B-H), 1507, 1473, 1460; 1H NMR (CDCl3) δ 0.40-1.60 (3H, br),
1.23 (9H, d, J ) 15), 5.82 (1H, dq, J ) 366, 6.2), 7.52-7.65 (3H,
m), 7.92 (1H, d, J ) 8.0), 7.75-8.07 (2H, m), 8.30 (1H, d, J )
8.3); 13C NMR (CDCl3) δ 27.7 (d, J) 2.8), 30.6 (d, J ) 31.9),
122.8 (d, J ) 45.8), 125.4 (d, J ) 12.0), 126.2 (d, J ) 4.3), 126.9,
127.7, 129.7, 133.1 (d, J ) 2.8), 134.0 (d, J ) 6.6), 134.4 (d, J )
3.9), 136.0 (d, J ) 11.4); 31P NMR (CDCl3) δ 15.9 (m); MS (CI,
m/z) 248 (M + NH4+, 40), 217 (M - BH3 + H+, 100); HRMS
(ES, m/z) found 248.1738, C14H24BNP (M + NH4+) requires
248.1734.
1
mL/min, retention time ) 40.0 min (major), 22.8 min). H NMR
data as previously reported.15
Alternatively, for longer reactions where the integrity of the inert
gas might become an issue, the reaction can be carried out in a
closed system. (CAUTION! These reactions were carried out
behind a blast shield. Appropriate consideration must be given to
the consequences of pressure build-up from the liberated nitrogen:
in these examples, reaction on a 0.3 mmol scale would liberate ca.
7 mL of nitrogen gas to a head volume in the Schlenk of ca. 90
mL. Any attempt to scale this process must take account of the
increased volume of gas released and hence pressure buildup.)
Following addition of the solution of the azide to the phosphine,
the system was isolated from the manifold and stirred at room
temperature for 1 h. The reaction vessel was then briefly opened
to the manifold to release the pressure buildup and then closed
again. Upon completion of the reaction (IR monitoring), the reaction
was progressed to the N-acetylenamide as before.
General Procedure for Asymmetric Synthesis of Tertiary
Phosphine-Boranes: (RP)-tert-Butylmethyl(2-methylphenyl)-
phosphine-Borane 15. This procedure was adapted from the
method of Livinghouse.13 To a solution of secondary phosphine-
borane 6 (658 mg, 3.4 mmol) and (-)-sparteine (1.0 mL, 4.4 mmol)
in diethyl ether (25 mL) at -78 °C was added n-butyllithium (1.4
M in THF, 2.7 mL, 3.8 mmol) dropwise. The mixture was then
allowed to warm to rt over 1 h, and the formation of a thick
precipitate was seen. The mixture was recooled to -78 °C,
iodomethane (0.32 mL, 5.1 mmol) added dropwise, and the mixture
allowed to warm to rt overnight. A 5% solution of H2SO4 (aq) was
then added and the product extracted into Et2O (3 × 20 mL). The
combined organics were dried (MgSO4), filtered, and concentrated
in vacuo to yield the crude product which was purified by flash
chromatography (eluting with 5% Et2O/95% petroleum ether) to
yield the desired phosphine-borane 15 as a white solid (584 mg,
83%, 92% ee measured on a Chiralcel OD-RH column, gradient
40-51% MeCN/H2O over 30 min, 1.0 mL/min, retention time )
24.9 min (major), 26.3 min)): [R]25D +28.0 (c 0.02, CH2Cl2); mp
88-90 °C; νmax/cm-1 3057, 2974, 2947, 2903, 2869, 2372 (B-H),
1475, 1461; 1H NMR (CDCl3) δ 0.44-1.37 (3H, br), 1.14 (9H, d,
J ) 14.0), 1.64 (3H, d, J ) 9.2), 2.66 (3H, s), 7.22-7.27 (2H, m),
7.35-7.40 (1H, m), 7.52-7.58 (1H, m); 13C NMR (CDCl3) δ 9.2
(d, J ) 39.0), 23.8 (d, J ) 3.4), 25.8 (d, J ) 2.4), 31.1 (d, J )
31.8), 125.7 (d, J ) 8.2), 126.1 (d, J ) 46.4), 131.5 (d, J ) 2.1),
General Procedure for the One-Pot Aza-Wittig Reaction
(Method B). To a solution of phosphine-borane 10 (65 mg, 0.34
mmol) in degassed Et2O (2 mL) in a 100 mL Schlenk tube was
added via cannula a solution of azide 20 (57 mg, 0.20 mmol) and
DABCO (152 mg, 1.35 mmol) in degassed Et2O (5 mL) and the
reaction stirred at room temperature and monitored by IR. On
completion of the reaction, the Et2O was removed in vacuo, and
then DMAP (10 mol %) was added as a single portion and the
mixture redissolved in 1,2-dichloroethane (5 mL). Triethylamine
(0.28 mL, 2.0 mmol) and acetic anhydride (94 µL, 1.0 mmol) were
then added, and the mixture was heated at 90 °C over 4 h. The
mixture was then diluted with water, and the product was extracted
into DCM (2 × 10 mL). The combined organics were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (eluting with 30% acetone/
petroleum ether) to yield 22 as a white solid (53% of material with
64% ee ) 77% ee corrected for the ee of the phosphine. A
subsequent run gave 59% of material with 77% corrected ee.
Measured on a Chiralcel OD-H column, 20% IPA/hexanes, 1.0 mL/
1
min, retention time ) 18.5 min (major), 25.0 min). H NMR data
132.5 (d, J ) 9.1), 134.4 (d, J ) 6.3), 144.5 (d, J ) 10.2); 31P
as previously reported.15
+
NMR (CDCl3) δ 25.9 (q, J ) 49); MS (CI, m/z) 226 (M + NH4
,
General Procedure for Two-Pot Aza-Wittig Using MTO
Catalyst (Method C). As for method A, except methyltrioxorhe-
nium (5 mol %) was added to the phosphine solution prior to the
addition of the solution of the azide. Reaction of azide 19 with
phosphine-borane 10 gave 21 (36% yield of material with 33%
ee ) 40% ee corrected for the ee of the phosphine).
70), 195 (M - BH3 + H+, 45); HRMS (ES, m/z) found 226.1892,
C12H26BNP (M + NH4+) requires 226.1890.
General Procedure for Two-Pot Aza-Wittig Reaction (Method
A). CAUTION: All reactions with azides were carried out behind
blast shields in glassware which was kept clean of any contamina-
tion by transition metals.
Acknowledgment. This work was supported by the EPSRC
(GR/S44181/01). We thank the EPSRC Mass Spectrometry
Service at Swansea for an allocation and Mr. Jim Titchmarsh
(Leeds) for chiral HPLC.
To a 100 mL Schlenk tube charged with DABCO (200 mg, 1.78
mmol) was added a solution of phosphine-borane 10 (120 mg,
0.63 mmol) in degassed toluene (5 mL), and the mixture was heated
at 50 °C over 16 h. On completion of the reaction, the solution
was filtered into another 100 mL Schlenk tube through basic
alumina and the alumina washed with 5% Et2O/petroleum ether.
The solvent was removed and the free phosphine then dried in vacuo
over 4 h. To this phosphine was added via cannula a solution of
azide 19 (64 mg, 0.31 mmol) in degassed Et2O (5 mL) and the
reaction stirred at room temperature and monitored by IR. On
completion of the reaction, the Et2O was removed in vacuo, and
Supporting Information Available: Characterization data for
the remaining compounds, 1H NMR spectra for compounds 3-18
and 21/22, 13C NMR spectra for all novel compounds, and ee data
for the individual experiments comprising Table 3. This material
JO0709908
J. Org. Chem, Vol. 72, No. 19, 2007 7189