Reichwein and Pagenkopf
with 10% aqueous HCl (2×), aqueous saturated NaHCO3, and
brine, dried (MgSO4), and concentrated in vacuo. Purification
of the residue by flash chromatography afforded 9b as a
SCHEME 7
1
colorless oil in 82% yield: Rf 0.70 (EtOAc); H NMR (CDCl3,
300 MHz) δ 0.89 (t, J ) 6.8 Hz, 3H), 1.26-1.36 (m, 10H), 1.54-
1.80 (m, 4H), 3.68 (d, J ) 10.8 Hz, 3H), 5.09 (d, J ) 8.4 Hz,
2H), 7.28-7.42 (m, 5H); 13C NMR (CDCl3, 75.5 MHz) δ 14.3
(CH3), 22.5 (CH2), 22.6 (CH2), 22.9 (CH2), 24.7 (CH2), 26.6
(CH2), 29.2 (CH2), 30.7 (CH2), 30.9 (CH2), 32.1 (CH2), 52.3
(CH3), 67.3 (CH2), 67.4 (CH2), 128.1 (CH), 128.6 (CH), 128.8
(CH), 136.8 (C), 136.9 (C); 31P NMR (CDCl3, 121.5 MHz) δ 35.7;
MS (CI) m/z 299 [M + H]+; HRMS (CI) calcd for C16H27O3P
[M + H]+ 299.1776, found 299.1773.
â-Hyd r oxy P h osp h on a tes 10a fr om 9a . To a cooled (-78
°C) solution of 9a (0.80 mmol) in THF (2.5 mL) was added
n-BuLi in hexanes (0.80 mmol). After the mixture was stirred
at -78 °C for 15 min, the aldehyde (0.80 mmol) in THF (1
mL) was added. After 60 min at -78 °C, aqueous NH4Cl was
added to the cold mixture. After being warmed to room
temperature, the mixture was extracted with EtOAc, and the
organic layer was washed with brine and dried (MgSO4).
Purification by flash chromatography afforded 10a as a
phonate coupling reactions with aldehydes and ketones.
The overall sequence detailed herein can be routinely
executed on multigram scales in ∼45% overall yield from
starting olefin 21 through to coupled product 22 (Scheme
7). The transesterification of pinacol phosphonates pro-
vides a new and efficient method for accessing phosphonic
acid mono methyl esters.
1
colorless oil in 60% yield: Rf 0.65 (EtOAc); H NMR (CDCl3,
300 MHz) δ 0.80-0.87 (m, 9H), 1.15-1.68 (m, 16 H), 1.97-
2.09 (m, 1H), 3.65-3.73 (m, 6H); 13C NMR (CDCl3, 75.5 MHz)
δ 7.5 (CH3), 7.6 (CH3), 14.2 (CH3), 22.8 (CH2), 26.5 (CH2), 28.6
(CH2), 28.7 (CH2), 29.2 (CH2), 30.0 (CH2), 30.5 (CH2), 30.6
(CH2), 32.0 (CH2), 43.6 (CH), 52.2 (CH3), 52.3 (CH3), 52.4 (CH3),
75.3 (C); 31P NMR (CDCl3, 121.5 MHz) δ 39.1; MS (CI) m/z
309 [M + H]+, 291 [M - H2O + H]+.
Olefin s 12b fr om 10b. A solution of 10b (1.1 mmol) in
EtOH (5 mL) containing a catalytic amount of Pd/C was
shaken at room temperature for 16 h under an H2 atmosphere
(250 psi), and the resulting mixture was concentrated in vacuo
to afford crude 11. Without further purification, 11 was
dissolved in CHCl3 (5 mL) and DIC (2.2 mmol) was added.
After being stirred at room temperature for 4 h, the reaction
mixture was concentrated in vacuo, and the residue was
purified by flash chromatography to give 12b as a colorless
oil in 68% yield: Rf 0.73 (hexane/EtOAc); 1H NMR (CDCl3, 300
MHz) δ 1.13 (t, J ) 7.5 Hz, 6H), 2.18 (q, J ) 7.5 Hz, 2H), 2.26
(q, J ) 7.5 Hz, 2H), 3.48 (d, J ) 7.2 Hz, 2H), 5.39 (t, J ) 7.2
Hz, 2H), 7.25-7.41 (m, 5H); 13C NMR (CDCl3, 75.5 MHz) δ
12.8 (CH3), 13.2 (CH3), 23.3 (CH2), 29.2 (CH2), 33.8 (CH2), 121.1
(CH), 125.7 (CH), 128.3 (CH × 2), 141.9 (C), 143.8 (C).
Exp er im en ta l Section 23
Compounds 3,3 and 43 were prepared according to literature
procedures. Compounds 8, 9b-e, 10, and 12 were prepared
by one of the following general methods:
P h osp h on ic Acid Mon om eth yl Ester 8a fr om 4. To a
solution of 4 (9.1 mmol) and BHT (3.0 mmol) in MeOH (10
mL) was added 4 M HCl in dioxane (10 mL). The solution was
stirred at 50 °C for 3 h and concentrated in vacuo to yield crude
8a , which was used in the next step without further purifica-
tion: 1H NMR (CD3CN, 300 MHz) δ 0.90 (t, J ) 6.5 Hz, 3H),
1.30-1.53 (m, 10H), 1.53-1.77 (m, 4H), 3.67 (d, J ) 10.8 Hz,
1
3H); H NMR (CD3OD, 300 MHz) δ 0.92 (t, J ) 6.0 Hz, 3H),
1.32-1.42 (m, 10H), 1.56-1.81 (m, 4H), 3.70 (d, J ) 10.5 Hz,
3H); 13C NMR (CD3CN, 75.5 MHz) δ 14.5 (CH3), 23.5 (CH2),
23.6 (CH2), 23.7 (CH2), 23.9 (CH2), 25.3 (CH2), 27.2 (CH2), 20.2
(CH2), 31.5 (CH2), 31.8 (CH2), 31.9 (CH2), 33.0 (CH2), 52.1
(CH3); 13C NMR (CD3OD, 75.5 MHz) δ 17.3 (CH3), 26.3 (CH2),
26.4 (CH2), 26.5 (CH2), 28.1 (CH2), 29.6 (CH2), 29.9 (CH2), 33.1
(CH2), 34.4 (CH2), 34.6 (CH2), 35.8 (CH2), 55.0 (CH3), 55.1
(CH3); 31P NMR (CD3OD, 121.5 MHz) δ 34.3; 31P NMR
(CD3Cl, 121.5 MHz) δ 38.2; MS (EI) m/z 209 [M + H]+.
P h osp h on ic Acid Dim eth yl Ester 9a fr om 8a . To a
solution of crude 8a and Cs2CO3 (10 mmol) in MeCN (15 mL)
was added MeI (26 mmol). The resulting suspension was
stirred at 50 °C for 48 h. The reaction mixture was diluted
with EtOAc and washed with 10% aqueous HCl (2×), aqueous
saturated NaHCO3, and brine, dried (MgSO4), and concen-
trated in vacuo. Purification by flash chromatography gave 9a
as a colorless oil in 73% yield: Rf 0.47 (EtOAc); 1H NMR
(CDCl3, 300 MHz) δ 0.80 (t, J ) 6.6 Hz, 3H), 1.19-1.31 (m,
8H), 1.47-1.72 (m, 4H), 3.66 (d, J ) 10.8 Hz, 6H); 13C NMR
(CDCl3, 75.5 MHz) δ 14.2 (CH3), 22.4 (CH2), 22.5 (CH2), 22.8
(CH2), 23.9 (CH2), 25.7 (CH2), 29.2 (CH2), 30.6 (CH2), 30.8
(CH2), 31.9 (CH2), 52.3 (CH3), 52.4 (CH3); 31P NMR (CDCl3,
121.5 MHz) δ 36.2; MS (EI) m/z 223 [M + H]+; HRMS (EI)
calcd for C10H23O3P [M + H]+ 223.1463, found 223.1462.
P h osp h on ic Acid Ben zyl Ester Meth yl Ester 9b fr om
8b. To a solution of crude 8b (10 mmol) and Cs2CO3 (10 mmol)
in MeCN (15 mL) was added BnBr (26 mmol). The resulting
suspension was heated at reflux for 48 h, allowed to cool, and
then diluted with EtOAc. The organic solution was washed
P h osp h on ic Acid ter t-Bu tyl Ester Meth yl Ester 9d
fr om 8b. To a solution of crude 8b (4.3 mmol) in CH2Cl2 (10
mL) and cyclohexane (10 mL) was added tert-butyl 2,2,2-
trichloroimidate (43 mmol) portionwise. The resulting slurry
was stirred for 16 h and then concentrated in vacuo. Purifica-
tion of the residue by flash chromatography afforded 9d as a
colorless oil in 62% yield: Rf 0.30 (EtOAc/hexane 1:1); 1H NMR
(CDCl3, 300 MHz) δ 1.52 (s, 9H), 1.98-2.10 (m, 2H), 2.87-
2.95 (m, 2H), 3.71 (d, J ) 11.1 Hz, 3H), 7.23-7.36 (m, 5H);
13C NMR (CDCl3, 75.5 MHz) δ 28.69 (d, J ) 143 Hz, CH2),
28.72 (d, J ) 4.4 Hz, CH2), 30.24 (d, J ) 3.9 Hz, CH3), 51.79
(d, J ) 6.6 Hz, CH3), 82.26 (d, J ) 9.4 Hz, C), 126.1 (CH),
127.9 (CH), 128.4 (CH), 141.02 (d, J ) 17.6 Hz, C); 31P
NMR (CDCl3, 121.5 MHz) δ 39.1; MS (CI) m/z 401 [M + H]+;
HRMS (CI) calcd for C13H21O3P [M + H]+ 257.1307, found
257.1317.
Olefin s 12e fr om 10e. To a solution of 10e (0.68 mmol) in
MeOH (2.5 mL) was added 4 M HCl in dioxane (2.5 mL). The
reaction mixture was stirred for 2 h and then concentrated in
vacuo. The residue was dissolved in CHCl3, and DIC (1.36
mmol) was added. The reaction mixture was stirred for 2 d
and then concentrated in vacuo. Purification of the residue by
flash chromatography afforded 12e as a colorless oil in 42%
1
yield: Rf 0.31 (hexane/EtOAc); H NMR (CDCl3, 300 MHz) δ
2.42-2.49 (m, 1H), 2.55-2.62 (m, 1H), 2.77-2.84 (m, 2H), 3.42
(t, J ) 5.1 Hz, 2H), 5.64-5.69 (m, 2H), 7.18-7.41 (m, 10H);
13C NMR (CDCl3, 75.5 MHz) δ 29.6 (CH2), 33.8 (CH2), 34.7
(23) For general experimental details, see: Reichwein, J . F.; Iacono,
S. T.; Pagenkopf, B. L. Tetrahedron 2002, 58, 3813-3822.
1462 J . Org. Chem., Vol. 68, No. 4, 2003