3640
M. Kurosu, K. Li
PAPER
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 8.8 Hz, 1 H), 7.35–
7.18 (m, 7 H), 6.83 (s, 2 H), 6.25 (s, 1 H), 4.56 (dd, J = 11.2, 21.2
Hz, 2 H), 3.76 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.7, 138.1, 137.5, 136.5, 133.8,
133.2, 131.7, 129.4, 128.5, 128.0, 127.9, 126.3, 125.7, 115.5, 76.2,
71.2, 55.9.
In conclusion, we have developed the novel reagent 4 for
the protection of alcohols. The trichloroacetimidate 4 can
efficiently protect primary, secondary, and phenolic alco-
hols to furnish the corresponding ethers in excellent yields
without sophisticated reaction procedures, and the gener-
ated ethers are efficiently deprotected with 30–50% TFA
in CH2Cl2. Notably, the trichloroacetimidate 4 can be used
as a selective ether-forming reagent for primary alcohols.
Due to the quantitative formation of trifluoro(2,6-dichlo-
ro-4-methoxyphenyl)-(2,4-dichlorophenyl)methyl ester
(7) during deprotection of the ethers 6 with TFA, (2,6-
dichloro-4-methoxyphenyl)-(2,4-dichlorophenyl)metha-
nol (3) can be readily regenerated by saponification of 7.
Similarly, the trichloroimidate resin 10 is a useful linker
that can be used to immobilize alcohols and carboxylic ac-
ids. Utility of 4 and 10 in the synthesis of complex mole-
cules both in solution and on polymer support will be
reported eleswhere.
Anal. Calcd for C21H16Cl4O2: C, 57.04; H, 3.65. Found: C, 57.20; H,
3.50.
Protection of Alcohols with 4 on a Small Scale; Typical Proce-
dure
To a stirred suspension of 5e (10 mg, 0.018 mmol), 4 (13.0 mg,
0.026 mmol), and 3 Å MS (20 mg) in CH2Cl2 (0.5 mL), was added
TMSOTf (0.58 mg, 0.0026 mmol in CH2Cl2) at r.t. The workup pro-
cedure was the same as for a larger scale reaction. Purification by
silica gel chromatography (hexanes–EtOAc, 10:1) gave 6e (16.0
mg, 99%) as a white powder. A mixture of the diastereomers 6e (10
mg) were separated by PTLC (hexanes–EtOAc, 4:1) to afford a 1:1
ratio of diastereomers (4 mg each).13
Lower Rf Diastereomer of 6e
Rf = 0.4 (hexanes–EtOAc, 4:1); [a]20D +21 (c 0.4, CHCl3).
IR (film): 2929, 1715, 1666, 1455 cm–1.
IR absorption measurements on NaCl plates were run on a Perkin–
Elmer FT-IR 1600. H NMR spectral data were obtained using
1
1H NMR (400 MHz, CDCl3): d = 7.93 (d, J = 8.4 Hz, 1 H), 7.51 (d,
J = 8.4 Hz, 1 H), 7.36 (m, 3 H), 7.32 (t, J = 8.0 Hz, 2 H), 7.27 (m,
2 H), 6.90 (s, 2 H), 6.28 (s, 1 H), 5.74 (s, 1 H), 5.46 (s, 2 H), 5.27
(d, J = 8.4 Hz, 1 H), 4.70 (s, 2 H), 4.28 (m, 2 H), 4.27 (d, J = 8.4 Hz,
1 H), 3.98 (d, J = 10.8 Hz, 1 H), 3.87 (dd, J = 4.0, 11.2 Hz, 1 H),
3.82 (s, 3 H), 3.45 (s, 3 H), 0.92 (s, 9 H), 0.18 (s, 3 H), 0.14 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.0 160.0, 151.0, 139.1, 138.2,
137.0 135.5, 134.4, 133.4, 130.5, 129.9, 128.5, 127.9, 127.8, 126.5,
125.0, 115.7, 101.0, 91.0, 80.8, 78.1, 77.7, 74.4, 72.3, 70.3, 67.8,
58.6, 56.1, 25.8, 18.3, –4.3, –5.0.
Varian 300 or 400 MHz instruments; the residual solvent signal was
utilized as an internal reference. 13C NMR spectral data were ob-
tained using a Varian 87 or 100 MHz spectrometer. Chemical shifts
(d) are reported in parts per million (ppm) downfield from TMS, us-
ing the central resonance of CDCl3 (d = 77.0 ppm) as an internal
standard; J values are given in Hz. Mass spectra were obtained at
Colorado State University’s Central Instrument Facility. Reagents
and solvents are commercial grade and were used as supplied. Re-
action vessels were flame-dried or oven-dried and cooled under an
inert atmosphere when necessary.
HRMS (ESI): m/z [M+ + Na] calcd for C38H44Cl4N2NaO8Si:
847.1518; found: 847.1513.
(2,6-Dichloro-4-methoxyphenyl)-(2,4-dichlorophenyl)methyl
Trichloroacetimidate (4)
To a stirred solution of alcohol 3 (350 mg, 1.0 mmol) and CCl3CN
(0.5 mL, 5.0 mmol) in toluene (5 mL), was added DBU (15 mg, 0.1
mmol) at r.t. After 3 h at r.t., the reaction mixture was concentrated
in vacuo and the residue was purified by silica gel chromatography
(petroleum ether–EtOAc, 40:1) to give 4.
Higher Rf Diastereomer of 6e
Rf = 0.45 (hexanes–EtOAc, 4:1); [a]20D +38 (c 0.4, CHCl3).
IR (film): 2929, 1714, 1666, 1455 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 8.0 Hz, 1 H), 7.51 (d,
J = 8.4 Hz, 1 H), 7.37 (m, 3 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.27 (m,
2 H), 6.89 (s, 2 H), 6.28 (s, 1 H), 5.75 (d, J = 2.0 Hz, 1 H), 5.47 (s,
2 H), 5.39 (d, J = 8.0 Hz, 1 H), 4.71 (s, 2 H), 4.23 (m, 2 H), 4.18
(dd, J = 1.6, 6.8 Hz, 1 H), 3.81 (s, 3 H), 3.74 (dd, J = 4.0, 7.6 Hz,
1 H), 3.62 (d, J = 8.8 Hz, 1 H), 3.31 (s, 3 H), 0.89 (s, 9 H), 0.16 (s,
3 H), 0.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.1, 160.0, 151.0, 139.1, 138.2,
137.1, 135.2134.6, 133.8, 131.0, 129.9, 128.5, 127.9, 127.8, 126.5,
124.9, 115.6, 101.1, 91.3, 80.9, 77.9, 77.6, 74.3, 72.3, 70.3, 67.4,
58.4, 56.0, 25.8, 18.3, –4.3, –5.1.
Yield: 483 mg (99%); amorphous solid; mp 155 °C.
IR (film): 1665, 1230 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.52 (s, 1 H), 7.66 (s, 1 H), 7.44
(d, J = 8.4 Hz, 1 H), 7.41 (d, J = 2.0 Hz, 1 H), 7.23 (dd, J = 2.0, 8.4
Hz, 1 H), 6.91 (s, 2 H), 3.81 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.4, 160.1, 137.3, 134.9, 134.3,
133.4, 131.1, 130.0, 126.7, 124.1, 115.5, 75.7, 55.9.
Anal. Calcd for C16H10Cl7NO2: C, 38.71; H, 2.03; N, 2.82. Found:
C, 38.82; H, 2.10; N, 2.89.
HRMS (ESI): m/z [M+ + Na] calcd for C38H44Cl4N2NaO8Si:
847.1518; found: 847.1510.
Protection of Alcohols with 4; Typical Procedure
To a stirred solution of benzyl alcohol (5b; 50 mg, 0.46 mmol) and
4 (342 mg, 0.69 mmol) in CH2Cl2 (2.5 mL), was added TMSOTf
(15.3 mg, 0.069 mmol) at r.t. After 10 min, the reaction mixture was
quenched with sat. aq NaHCO3 (5 mL) and the aqueous phase was
extracted with CH2Cl2 (5 × 3 mL). The combined organic phase was
dried over Na2SO4, and evaporated in vacuo. Purification by silica
gel chromatography (hexanes–EtOAc, 20:1) gave 6b.
Typical Deprotection Procedure
The ether 6l was dissolved in 30% TFA in CH2Cl2 (0.1 M) and kept
for 4 h at r.t. All volatiles were evaporated in vacuo to provide the
crude mixture, then the alcohol 5l was separated from 6 by silica gel
chromatography (hexanes–EtOAc, 15:1). To a solution of (2,6-
dichloro-4-methoxyphenyl)-(2,4-dichlorophenyl)methyl 2,2,2-tri-
fluoroacetate (6; 100 mg, 0.22 mmol) in MeOH (3 mL), was intro-
duced NH3. After 12 h at r.t., all volatile material was evaporated in
vacuo and the crude material was pass through a silica gel plug
(CH2Cl2–hexanes–EtOAc, 4:1:1) to provide 3 (69.0 mg, 99%).
Yield: 200 mg (99%); oil.
IR (film): 1450, 1235 cm–1.
Synthesis 2009, No. 21, 3633–3641 © Thieme Stuttgart · New York