Improved Phosphotriester Formation
loss of the methyl ester resonace signal and less than 30% of
the combined characteristic signal intensity remained for
presumed lactonized trialkyl phosphate 5′ and benzyl alcohol
1-(4-Hydroxy-3-methyl-phenyl)-ethanone 9′. 11.3 g, 76%;
mp 106-109 °C; 1H NMR δ 7.79 (s, 1H), 7.74 (d, J ) 8.41 Hz,
1H), 7.39 (s, 1H), 6.88 (d, J ) 8.41 Hz, 1H), 2.57 (s, 3H), 2.29
(s, 3H); 13C NMR δ 198.7, 159.6, 132.1, 129.6, 128.8, 124.6,
114.9, 26.4, 16.0; IR (NaCl) 3252, 1652, 1591, 1281 cm-1. Anal.
Calcd for C9H10O2: C, 71.98; H, 6.66. Found: C, 72.14; H, 6.80.
2-Bromo-1-(4-hydroxy-3-methyl-phenyl)-ethanone 10′.
3.44 g, 72%; mp 118-20 °C; 1H NMR δ 7.80 (s, 1H), 7.76
(d, J ) 8.41 Hz, 1H), 6.85 (d, J ) 8.41 Hz, 1H), 5.95 (s, 1H),
4.39 (s, 2H), 2.29 (s, 3H); 13C NMR δ 190.7, 159.4, 132.6, 129.4,
126.9, 124.7, 115.2, 30.8, 15.9; IR (NaCl) 3386, 1670, 1587.
Anal. Calcd for C9H9BrO2: C, 47.19; H, 3.93; Br, 34.88.
Found: C, 47.30; H, 4.03; Br, 34.64.
4-(2-Bromo-ethyl)-2-methyl-phenol 11′. 2.27 g, 79%;
1H NMR δ 6.95 (s, 1H), 6.90 (d, J ) 8.41 Hz, 1H), 6.69
(d, J ) 8.41 Hz, 1H), 4.39 (b, 1H), 3.51 (t, J ) 7.67 Hz, 2H),
3.05 (t, J ) 7.67 Hz, 2H), 2.23 (s, 3H); 13C NMR δ 152.8, 131.4,
131.2, 127.3, 124.2, 115.1, 38.7, 33.6, 15.9; IR (NaCl) 3415,
1510, 1261 cm-1. Anal. Calcd for C9H11BrO: C, 50.25; H, 5.11;
Br, 37.15. Found: C, 50.10; H, 5.18; Br, 36.94.
4-(2-Azido-ethyl)-2-methyl-phenol 12′. 1.57 g, 89%;
1H NMR δ 6.96 (s, 1H), 6.90 (d, J ) 8.16 Hz, 1H), 6.70
(d, J ) 8.16 Hz, 1H), 4.85 (s, 1H), 3.45 (t, J ) 7.18 Hz, 2H),
2.79 (t, J ) 7.18 Hz, 2H), 2.23 (s, 3H); 13C NMR δ 152.7, 131.5,
130.2, 127.3, 124.1, 115.2, 52.8, 34.6, 15.9; IR (NaCl) 3407,
2102, 1509 cm-1. Anal. Calcd for C9H11N3O: C, 61.00; H, 6.21;
N, 23.71. Found: C, 61.20; H, 6.33; N, 23.58.
1
6′ (based on their close H NMR correspondence to 5 and 6).
The scale of the reaction and limited observable material
prevented isolation and definitive characterization of lacton-
ized trialkyl phosphate 5′ and benzyl alcohol 6′. Additional,
unidentified resonance signals were observed in the final
1H NMR spectrum.
The conversion of trialkyl phosphate 3 to lactonized trialkyl
phosphate 5 was monitored by comparison of the relative
integration of the resonance signal consistent with the methyl
ester at 3.68 ppm (s, 3H) to a resonance signal for the internal
standard of mesitilyene (Ar-H, 6.79 ppm, 3H) at 35 °C in
CDCl3 in five min. intervals for 120 min. During the first hour
of lactonization monitoring, the triplet of doublets at 5.52 ppm
(JH-P ) 3.24 Hz, 1H) from 3 began to overlap with the
emerging triplet of doublets at 5.57 ppm (td, JP-H ) 3.24, 1H),
characteristic of lactonized trialkyl phosphate 5. Concurrent
with the formation of the triplet of doublets at 5.57 ppm for 5
was the disappearance of the resonance signal for the aromatic
proton at 7.07 (s, 1H) of 3 and subsequent emergence of a
resonance signal of an aromatic proton at 7.18 (s, 1H)
consistent with the formation of 5. Additionally, during the
first hour of lactonization monitoring, the slight appearance
of a resonance signal at 5.04 ppm and a singlet at 7.28 ppm
was observed consistent with the formation of benzyl alcohol
6. After 2 h, based on analysis of the already described
resonance signals, complete conversion of quinone methide 2
to lactonized trialkyl phosphate 5 and lactonized benzyl alcohol
6 was observed in a 3.0:1.0 ratio favoring trialkyl phosphate
5. The reaction conditions (CDCl3, 35 °C) were maintained for
an additional 10 h. No measurable change was detected in the
ratio of lactonized trialkyl phosphate 5 and benzyl alcohol 6
following the completion of the lactonization reaction in the
initial 2 h. This was determined by comparison of the relative
integration of the aromatic proton of trialkyl phosphate 5 at
7.18 with the aromatic proton of benzyl alcohol 6 at 7.28 ppm
and the triplet of doublets of trialkyl phosphate 5 at 5.57 ppm
with the multiplet of benzyl alcohol 6 at 5.04 to an internal
standard of mesitilyene (Ar-H, 6.79 ppm, 3H). The rate of
lactonization was calculated as the slope of concentration of
methyl ester (mM) vs time (min.) for the first 60% of methyl
ester resonance signal loss. All experiments were performed
in triplicate.
2-(4-Hydroxy-3-methyl-phenyl)-ethylammonium Chlo-
ride 13′. 1.19 g, 72%; mp 178-181 °C; 1H NMR δ 6.97 (s, 1H),
6.89 (d, J ) 8.16, 1H), 6.71 (d, J ) 8.16 Hz, 1H), 3.10 (t, J )
15.09 Hz, 2H), 2.82 (t, J ) 15.09 Hz, 2H), 2.17 (s, 3H);
13C NMR δ 154.2, 130.8, 126.9, 126.7, 124.8, 114.7, 41.0, 32.5,
14.9. Anal. Calcd for C9H14ClNO: C, 57.60; H, 7.46; Cl, 18.89.
Found: C, 57.45; H, 7.27; Cl, 19.03.
[2-(4-Hydroxy-3-methyl-phenyl)-ethyl]-carbamic Acid
1
tert-Butyl Ester 14′. 1.69 g, 70%; mp 126-129 °C; H NMR
δ 6.91 (s, 1H), 6.87 (d, J ) 8.16 Hz, 1H), 6.69 (d, J ) 8.16 Hz,
1H), 3.30 (q, J ) 6.93 Hz, 2H), 2.67 (t, J ) 6.93 Hz, 2H), 2.21
(s, 3H), 1.43 (s, 9H); 13C NMR δ 156.2, 152.8, 131.4, 130.6,
127.2, 124.1, 115.1, 79.5, 42.1, 35.3, 28.5, 15.9; IR (NaCl) 3347,
1685, 1611, 1512 cm-1. Anal. Calcd for C14H21NO3: C, 66.90;
H, 8.36. Found: C, 67.00; H, 8.19.
[2-(4-Hydroxy-3-iodo-5-methyl-phenyl)-ethyl]-carbam-
Lactonized Trialkyl Phosphate 5. A 22 mM solution of
phenol 1 (5.0 mg phenol/0.65 mL CHCl3) was stirred with lead-
(II) oxide for 20 min. The suspension was filtered as described
above to yield a yellow solution of quinone methide. To the
resulting quinone methide solution was added 2 equiv of
dibutyl phosphate (5.3 µL, 28.6 µmol), and the resulting
solution was stirred at 35°C for 2 h. The mixture was
concentrated in vacuo to yield a crude oil. The desired product
was isolated via preparative TLC (3:1 EtOAc/hexanes) to yield
a semi-white solid (4.8 mg, 61%): 1H NMR δ 7.18 (s, 1H), 5.57
(td, JP-H ) 3.24, 1H), 3.96 (m, 4H), 3.53-3.44 (bm, 1H), 3.31-
3.19 (bm, 1H), 2.94 (t, J ) 6.91, 2H), 2.73 (t, J ) 6.91, 2H),
2.27 (s, 3H), 2.26 (s, 3H), 1.62 (m, 4H), 1.44 (s, 9H), 1.31
(m, 4H), 0.89 (m, 6H); 13C NMR δ 171.3, 156.0, 148.2, 135.7,
134.0, 132.6, 129.2, 126.4, 79.3, 74.2, 63.8, 47.3, 32.1, 29.7, 28.5,
21.4, 18.7, 16.3, 15.0, 13.1. Anal. Calcd for C26H42NO8P: C,
59.19; H, 8.02; N, 2.65. Found: C, 59.41; H, 8.22; N, 2.83.
Lactonized Benzyl Alcohol 6. 1H NMR δ 7.28 (s, 1H), 5.04
(bm, 1H), 3.40 (ddd, J ) 2.97, 1H), 3.12 (m, 1H), 2.93 (t, J )
6.91, 2H), 2.73 (t, J ) 6.91, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.45
(s, 9H).
1
ic Acid tert-Butyl Ester 15′. 2.060 g, 81%; H NMR δ 7.30
(s, 1H), 6.90 (s, 1H), 5.27 (s, 1H), 4.54 (bs, 1H), 3.27 (q, J )
6.93 Hz, 2H), 2.64 (t, J ) 6.93 Hz, 2H), 2.26 (s, 3H), 1.43
(s, 9H); 13C NMR δ 155.9, 151.6, 135.6, 132.8, 132.0, 124.9,
86.0, 79.4, 41.9, 34.9, 28.5, 17.3; IR (NaCl) 3356, 1693 cm-1
.
3-[5-(2-tert-Butoxycarbonylamino-ethyl)-2-hydroxy-3-
methyl-phenyl]-acrylic Acid Methyl Ester 16′. 1.37 g, 75%;
1
mp 138-140 °C; H NMR δ 8.04 (d, J ) 16.08 Hz, 1H), 7.14
(s, 1H), 6.97 (s, 1H), 6.50 (d, J ) 16.08 Hz, 1H), 5.85 (s, 1H),
4.54 (bs, 1H), 3.79 (s, 3H), 3.30 (q, J ) 6.93, 2H), 2.68 (t, J )
6.93 Hz, 2H), 2.25(s, 3H), 1.42 (s, 9H); 13C NMR δ 168.3, 156.0,
152.2, 140.5, 133.3, 130.9, 126.5, 124.4, 121.6, 118.1, 79.5, 51.8,
41.9, 35.3, 28.5, 16.0; IR (NaCl) 3391, 1630 cm-1. Anal. Calcd
for C18H25NO5: C, 64.46; H, 7.45. Found: C, 64.58; H, 7.31.
3-[5-(2-tert-Butoxycarbonylamino-ethyl)-2-hydroxy-3-
methyl-phenyl]-propionic Acid Methyl Ester 1′. 0.052 g,
1
77%; mp 76-79 °C; H NMR δ 7.13 (s, 1H), 6.81 (s, 1H), 6.74
(s, 1H), 4.51 (bs, 1H), 3.68 (s, 3H), 3.27 (q, J ) 6.43, 2H), 2.84
(t, 2H), 2.71 (t, J ) 6.43, 2H), 2.63 (t, 2H), 2.22 (s, 3H), 1.42
(s, 9H); 13C NMR δ 176.2, 156.0, 151.2, 130.6, 129.7, 128.4,
127.0, 125.8, 79.2, 52.3, 42.1, 35.2, 34.9, 28.5, 24.7, 16.4; IR
(NaCl) 3372, 1693, 1169 cm-1. Anal. Calcd for C18H27NO5: C,
64.07; H, 8.00. Found: C, 64.26; H, 8.02.
Acetic Acid o-Tolyl Ester 8′. 14.3 g, 99%; 1H NMR δ 7.18
(m, 3H), 7.03 (d, 1H), 2.32 (s, 3H), 2.20 (s, 3H); 13C NMR
δ 169.3, 149.5, 131.2, 130.2, 127.0, 126.1, 122.0, 20.9, 16.2;
IR (NaCl) 1761, 1213 cm-1. Anal. Calcd for C9H10O2: C, 71.98;
H, 6.66. Found: C, 71.82; H, 6.80.
JO050050S
J. Org. Chem, Vol. 70, No. 11, 2005 4345