Syntheses and bioactivity of o- or p-trifluoromethylphenyl phosphates

Article abstract of DOI:10.1080/10426500802253090

o- and p-Trifluoromethylphenyl phosphates designed as mechanism-based phosphotyrosine phosphatase inactivators have been prepared. Some of them show herbicidal activities.

Full text of DOI:10.1080/10426500802253090

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Syntheses and Bioactivity of
o- or p-Trifluoromethylphenyl
Phosphates
Xinming Zhou a , Yantao He a , Miao Wang a & Yixiang
Ding a
a Shanghai Institute of Organic Chemistry, Chinese
Academic of Science, Shanghai, China
Version of record first published: 19 Feb 2009.
To cite this article: Xinming Zhou , Yantao He , Miao Wang & Yixiang Ding (2009):
Syntheses and Bioactivity of o- or p-Trifluoromethylphenyl Phosphates, Phosphorus,
Sulfur, and Silicon and the Related Elements, 184:3, 651-659
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Phosphorus, Sulfur, and Silicon, 184:651–659, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802253090
Syntheses and Bioactivity of o- or
p-Trifluoromethylphenyl Phosphates
Xinming Zhou, Yantao He, Miao Wang, and Yixiang Ding
Shanghai Institute of Organic Chemistry, Chinese Academic of Science,
Shanghai, China
o- and p-Trifluoromethylphenyl phosphates designed as mechanism-based phos-
photyrosine phosphatase inactivators have been prepared. Some of them show her-
bicidal activities.
Keywords Herbicidal activities; phosphotyrosine phosphatase inactivator; trifluo-
romethylphenyl phosphates
INTRODUCTION
Protein phosphatases play important roles in the regulation of cell
growth and metabolism. Recently,1 Widlanski designed and synthe-
sized 4-(fluoromethyl)phenyl phosphate, which is likely to function
as a mechanism-based phosphotyrosine phosphatase inactivator. 4-
(Fluoromethyl)phenyl phosphate undergoes a phosphatase-catalyzed
hydrolytic reaction to give a reactive intermediate quinone methide
that could irreversibly inactivate the phosphatase by forming a cova-
lent bond to an active site residue (i.e., OH, SH, and NH2 groups) shown
in Scheme 1.
One can anticipate that trifluoromethylphenyl phosphates could ex-
hibit bioactivity similar to 4-(fluoromethyl)phenyl phosphate. Some
substituted trifluoromethylphenyl phosphates with insecticidal activ-
ity have been reported.2 We are interested in the synthesis and
Received 14 November 2007; accepted 4 June 2008.
We thank the National Natural Science Foundation of China (Grant No. 20572123)
for financial support, the State Key Laboratory of Elemento-organic Chemistry NanKai
University for their testing of the herbicidal activity of the experimental compounds, and
the National Center for Drug Screening for their testing of the inhibition rates against
Protein Tyrosine Phoshatase 1B (PTP1B).
Address correspondence to Yixiang Ding, Shanghai Institute of Organic Chemistry,
Chinese Academic of Science, 200032 Shanghai, China. E-mail: dingyx@mail.sioc.ac.cn
651

652
X. Zhou et al.
SCHEME 1
bioactivity of a series of substituted trifluoromethylphenyl phosphates,
2-X-4-Y-phenol phosphates (X or Y=CF3).
RESULTS AND DISCUSSION
Trifluoromethylation of phenol with trifluoromethyl bromide is not a
satisfactory method for the synthesis of trifluoromethylphenol,3 be-
cause of the low yield and poor regioselectivity. We prepared the
p-substituted trifluoromethylphenols 1a–c, starting from p-chloro-
trifluoromethylbenzenes via nitration, hydrolysis, reduction, and di-
azotisation according to the literature,4 as shown in Scheme 2. The
p-substituted trifluoromethylphenols 1d–f were synthesizied from o-
substituted phenols via iodination4 with high regioselectivity followed
by trifluoromethylation5 as shown in Scheme 3. The o-substituted-
trifluoromethylphenols 1h–m were prepared by the same route from
p-substituted phenols. The results are summarized in Table I.
We have determined the herbicidal activities of the compounds 2
with respect to the growth inhibition of the rape roots under the con-
dition of darkness. The results of the test proved that some of the
compounds exhibited herbicidal activities. At a concentration of 10

o- or p-Trifluoromethylphenyl Phosphates
653
SCHEME 2 Method A.
µg/ml, the rape roots growth inhibition rates (%) of compounds 2a, 2e,
2i, 2n, and 2o were respectively 63.6, 67.8, 73.6, 73.6, and 45.4. Other
compounds were inactive or exhibited low activity. Under the same ex-
perimental conditions, the commercial herbicide methsulfuron-methyl
DPX-T6376 is 77.5% and Miekuotin DUS-06 is 19.5%. The compari-
son of 2c with 2e indicated that the hydrolysis of the phosphate would
affect the herbicidal activity. The activity of the isopropyl phosphate
SCHEME 3 Method B.

654
X. Zhou et al.
TABLE I Synthesis of Trifluoromethylphenyl Phosphates 2
No.
R
X
Y
Method
Phosphorylation Yield
2a
2b
2c
2d
2e
i-Pr
i-Pr
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
NO2
NHAc
Cl
CH3
Cl
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
Cl
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
70
65
76
45
35
77
57
73
87
90
43
62
56
50
77
2f
Ph
H
2g*
2h
2i
2j
2k
2l
2m**
2n*
2o*
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
F
t-Bu
H
Naphthol-2
∗Commercial material.
∗∗Pyrimidine compound.
2c, which was inactive, was obviously lower compared with the methyl
phosphate 2e. The possible reason is that isopropyl phosphate is more
difficult to hydrolyze to form the electrophilic quinone methide interme-
diates. When an electron-withdrawing group, such as Cl, NO2,is present
in the benzene ring of the phenol, the herbicidal activity is higher.
The same effect was observed for 4-(fluoromethyl) phenyl phosphate,
which required an electron-withdrawing group as a better phosphatase
inactivator.6
In order to test the inhibition activity against phosphatases,
dimethyl p-trifluoromethylphenyl phosphates were hydrolyzed to the
corresponding o- or p-trifluoromethylphenyl phosphoric acid mo-
noesters by the TMSBr/H2O sequence according to the reference
methods.7 We have preliminarily tested their inhibition rates against
protein tyrosine phoshatase 1B (PTP1B). At a concentration of 500 µM,
inhibition rates (%) of compounds 2g, 2i, 2k, and 2l are respectively
54.0, 57.2, 63.2, and 89.1. Further biochemical evaluation of these com-
pounds is underway.
EXPERIMENTAL
1
All melting points are uncorrected. HNMR spectra were recorded on
a Bruker AM-300 spectrometer using TMS as internal standard and
CDCl3 as solvent. Mass and HRMS spectra were taken on a Finni-
gan GC-MS-4021 spectrometer. Elemental analyses were done by the

o- or p-Trifluoromethylphenyl Phosphates
655
Elemental Analyses Group of the Shanghai Institute of Organic Chem-
istry (SIOC). The known compounds were identified in agreement with
the literature data, and only the NMR data are reported here. The
starting materials 1g, 1n, and 1o are commercially available from J&K
Chemical Co.
Typical Procedure for the Preparation of Substituted
Trifluoromethylphenols: Method A (Scheme 1)
2-Nitro-4-(trifluoromethyl)phenol (1a)8
Compound 1a was prepared from 4-trifluoromethyl-chlorobenzene
via nitration followed by hydrolysis. The nitration yield was 73.2%,
and the hydrolysis yield was 85.7%.
2-Acetamino-4-(trifluoromethyl)phenol (1b)9
2-Nitro-4-(trifluoromethyl)phenol (1) was reduced by catalytic hydro-
genation in anhydrous methanol with 10%Pd/C as catalyst at 1 atm H2
to give 2-amino-4-(trifluoromethyl)phenol in 93% yield. To a solution of
2-amino-4-(trifluoromethyl)phenol (1.0 g) in absolute ethyl acetate (20
mL), acetic anhydride (1.2 mL) was added dropwise at 0–5◦C, and white
crystals formed slowly. After 10 min, the solvent was evaporated in vac-
uum. Recrystallization from a mixture of petroleum ether (60–90◦C)
and ethyl acetate gave pure 2-acetoamino-4-(trifluoromethyl)phenol
(1b), yield 81%.
2-Chloro-4-(trifluoromethyl)phenol (1c)
2-Chloro-4-(trifluoromethyl)phenol (1c) was prepared via diazota-
tion of 2-amino-4-(trifluoromethyl)phenol according to the reference
methods.8
Method B (Scheme 2)
Typical Procedure of Iodination4
2-Methylphenol (50 mmol) was dissolved in 100 mL of methanol.
Sodium iodide (7.5 g, 50 mmol) and sodium hydroxide (2.0 g, 50mmol)
were added, and the solution was cooled to 0◦C. Aqueous sodium
hypochlorite (61.5mL, 5.2% NaOCl) was added dropwise over 90 min
at 0–3◦C. The resulting slurry was stirred for 2h at 0–2◦C and then
was treated with 20 mL of 10% aqueous sodium thiosulfate. The mix-
ture was neutralized using 5% aqueous HCl. Then ether (75 mL) was
added. The organic layer was washed with brine (70 mL) and dried over
Na2SO4. Filtration and rotary evaporation at 40◦C afforded 10.63 g of

656
X. Zhou et al.
2-iodo-4-methylphenol (4h), colorless liquid, yield 91%. 1H-NMR δ 7.46
(d, 1H, J = 2 Hz, H-3), 7.02 (dd, 1H, J1 = 8 Hz, J2 = 2 Hz, H-5), 6.86
(d, 1H, J = 8 Hz, H-6), 5.28 (s, 1H, OH), 2.23 (s, 3H, CH3); MS (m/e,
%): 235 (M++1, 11.70), 234 (M+, 100.00), 108 (12.52), 107 (47.49), 79
(11.84), 78 (18.01), 77 (39.40), 51 (17.37).
Typical Procedure of Benzyl Protection
A mixture of 4h (10 mmol), benzyl bromide (15 mmol), K2CO3(15
mmol), and DMF (20 mL) was stirred at 40–50◦C for 12 h under an
anhydrous atmosphere. The mixture was cooled, neutralized using 5%
HCl, then diluted with 100 mL of water and extracted with ether. The
organic layer was washed with water and brine, dried over Na2SO4,
and filtrated.Evaporation of the solvent gave a crude product that was
purified by flash column chromatography to afford benzyl 2-iodo-4-
1
methylphenyl ether (5h), yield 88%. H-NMR δ 7.58 (d, 1H, J = 1.5
Hz), 7.45 (d, 2H, J = 7.3 Hz), 7.34 (t, 2H, J = 7.3 Hz), 7.28 (t, 1H, J =
7.3 Hz), 7.01 (dd, 1H, J1 = 8 Hz, J2 = 1.5 Hz), 6.70 (d, 1H, J = 8 Hz),
5.07 (s, 2H), 2.20 (s, 3H); MS (m/e, %): 324 (M+, 34.35), 288 (17.60), 197
(8.03), 180 (6.70), 91 (100.00), 78 (5.65), 65 (9.63), 51 (6.21).
Typical Procedure of Trifluoromethylation5
5h (8 mmol) was treated with FO2SCF2COOMe (32 mmol) in
dimethylformamide (DMF) in the presence of catalytic amounts of
CuI (24 mmol) at 80◦C for 24 h. The solution was washed with sat-
urated aqueous NH4Cl, filtered, and extracted with ether. The organic
layer was washed with water and brine, dried over Na2SO4, and fil-
trated. Evaporation of the solvent gave a crude product that was pu-
rified by flash column chromatographyto obtain benzyl 4-methyl-2-
trifluroromethylphenyl ether (6h), yield 74%. 1H-NMR δ 7.72∼7.50 (m,
7H), 7.19 (d, 1H, J = 8.4 Hz), 5.42 (s, 2H), 2.58 (s, 3H); MS (m/e, %):
266(M+, 14.39), 265 (M+-1, 8.13), 181 (6.64), 127 (8.80), 92 (4.55), 91
(100.00), 65 (9.31), 63 (3.13).
Typical Procedure for the Hydrogenolytic Debenzylation
A solution of 6h (6 mmol) and HCOONH4(90 mmol) in methanol (7
mL) with 10% (mol) Pd/C as catalyst was refluxed for 1.5 h, filtrated,
and evaporated. The product was used directly in the next reaction
without purification.
Typical Procedure of Phosphorylation
4.8 mmol of ClPO(OCH3)2 was added dropwise to a mixture of the
trifluoromethylphenol (4 mmol), MeCN (8 mL), and Et3N (4.8 mmol) at
room temperature, followed by TLC. After the reaction was finished and

o- or p-Trifluoromethylphenyl Phosphates
657
the solvent was evaporated, the residue was purified by flash column
chromatography to give the phosphate 2.
Diisopropyl 2-Nitro-4-(trifluoromethyl)phenyl phosphate (2a)
1H-NMR δ: 7.8–8.2 (m, 3H, PhH), 4.7–4.85 (m, 2H, CH), 1.35 (dd,
12H, J = 8.4Hz, J = 11Hz, CH3); MS (m/e, %): 352 (M-F, 0.5), 312
(3.86), 288 (10.19), 270 (47.2), 241 (100), 207 (15.99), 190 (18.26); Anal.
Calcd. for C13H17F3NO6P: C, 42.06; H, 4.62. Found: C, 41.84; H, 4.45.
Diisopropyl 2-(N-Acetylamino)-4-(trifluoromethyl)phenyl
phosphate (2b)
1H-NMR δ: 8.63 (s, 1H, PhH), 8.56 (s, 1H, NH), 7.3 (s, 2H, PhH), 4.75
(m, 2H, OCH2), 2.23 (s, 3H, COCH3), 1.34 (dd, 12H, J = 7.5 Hz, J = 32
Hz, CH3); MS (m/e, %): 383 (M+1), 341 (8.17), 299 (11.74), 282 (17.38),
257 (100), 239 (34.93), 177 (26.84); Anal. Calcd. for C15H21F3NO5P: C,
47.00; H, 5.52. Found: C, 47.13; H, 5.27.
Diisopropyl 2-Chloro-4-(trifluoromethyl)phenyl phosphate (2c)
1H-NMR δ: 7.49–7.70 (m, 3H, PhH), 4.8 (m, 2H, OCH2), 1.35 (dd, J =
8.2 Hz, J = 13Hz, 12H, CH3), MS (m/e, %): 360 (M, 1.01), 325 (9.4), 283
(13.52), 277 (12.5), 241 (100), 223 (2.07), 196 (15.30); Anal. Calcd. for
C13H17ClF3O4P: C, 43.29; H, 4.75. Found: C, 43.13; H, 4.47.
Dimethyl 2-Methyl-4-(trifluoromethyl)phenyl phosphate (2d)
1H-NMR δ 7.47–7.35 (m, 3H), 3.88 (d, 6H, J = 11 Hz), 2.34 (s, 3H); MS
(m/e, %): 284 (M+, 29.72), 269 (59.88), 175 (19.02), 172 (100), 127 (22.41),
110 (16.61), 109 (44.80), 79 (23.94); Anal. Calcd. for C10H12F3O4P: C,
42.27; H, 4.26. Found: C, 42.37; H, 4.38.
Dimethyl 2-Chloro-4-(trifluoromethyl)phenyl ester (2e)
1H-NMR δ 7.74–7.52 (m 3H), 3.95 (d, 6H, J = 11.4 Hz); MS (m/e,
%): 307 (M++2, 9.49), 305 (M+, 27.02), 285 (14.90), 270 (13.45), 269
(100.00); Anal. Calcd. for C9H9ClF3O4P: C, 35.49; H, 2.98. Found: C,
35.67; H, 3.11.
Dimethyl 5-(Trifluoromethyl)[1,1’-biphenyl]-2-yl ester (2f)
1H-NMR δ 7.66∼7.38 (m, 8H), 3.62 (d, 6H, J = 11.5Hz); MS (m/e, %):
346 (M+, 100.00), 327 (17.12), 234 (17.21), 233 (17.30), 217 (22.44), 165
(82.92), 109 (35.56); Anal. Calcd. for C15H14F3O4P: C, 52.03; H, 4.08.
Found: C, 51.86; H, 4.00.

658
X. Zhou et al.
Dimethyl 4-(Trifluoromethyl)phenyl phosphate (2g)
1H-NMR δ 7.65–7.28(m 4H), 3.87(d, 6H, J = 11.4); MS (m/e, %): 270
(M+, 73.63), 251 (53.47), 172 (32.31), 162 (46.88), 158 (100.00), 109
(79.91), 96 (51.00), 79 (27.01); Anal. Calcd. for C9H10F3O4P: C, 40.01;
H, 3.73. Found: C, 40.38; H, 3.92.
Dimethyl 4-Methyl-2-(trifluoromethyl)phenyl phosphate (2h)
1H-NMR δ 7.48–7.26 (m, 3H), 3.88 (d, 6H, J = 11 Hz), 2.34 (s, 3H);
MS (m/e, %): 284 (M+, 25.19), 244 (19.91), 191(12.91), 109 (46.19), 127
(28.46), 149 (23.95), 97 (50.70), 71 (57.23), 69 (70.76), 57 (92.85), 55
(65.63), 44(51.79), 43(100.00); Anal. Calcd. for C10H12F3O4P: C, 42.27;
H, 4.26. Found: C, 42.59; H, 4.21.
Dimethyl 4-Chloro-2-(trifluoromethyl)phenyl phosphate (2i)
1H-NMR δ 7.61–47 (m, 3H), 3.88 (d, 6H, J = 11 Hz); MS(m/e, %): 306
(M++2, 19.06), 304 (M+, 55.55), 264 (49.66), 178 (20.21), 176 (60.42),
148 (28.89), 109 (100.00), 79 (25.45); Anal. Calcd. for C9H9ClF3O4P: C,
35.49; H, 2.98. Found: C, 35.50; H, 3.12.
Dimethyl 3-(trifluoromethyl)[1,1’-biphenyl]-4-yl ester (2j)
1H-NMR δ 7.84∼7.39 (m, 8H), 3.92 (d, 6H, J = 11.5 Hz); MS (m/e,
%): 347 (M++1, 16.62), 346 (M+, 100.00), 218 (29.02), 205 (10.68), 190
(14.83), 188 (9.35), 109 (21.40), 43 (9.80); Anal. Calcd. for C15H14F3O4P:
C, 52.03; H, 4.08. Found: C, 52.04; H, 4.29.
Dimethyl 4-Fluoro-2-(trifluoromethyl)phenyl phosphate (2k)
1H-NMR δ 7.60–7.16 (m, 3H), 3.88 (d, 6H, J = 12 Hz); MS (m/e, %):
288 (M+, 84.96), 248 (96.60), 219 (18.51), 205 (23.46), 160 (76.91), 132
(45.56), 109 (100.00), 79 (23.61); Anal. Calcd. for:C9H9F4O4P C, 37.52;
H, 3.15. Found: C, 37.56; H, 3.49.
Dimethyl 4-Tert-butyl-2-(trifluoromethyl)phenyl ester (2l)
1H-NMR δ 7.62∼7.47 (m, 3H), 3.89 (d, 6H, J = 11.42 Hz), 1.32 (s,
9H); MS (m/e, %): 326 (M+, 6.14), 311 (100.00), 183 (7.92), 155 (4.00),
131 (9.89), 109 (7.36), 41 (3.66); Anal. Calcd. for C13H18F3O4P: C, 47.86;
H, 5.56. Found: C, 47.61; H, 5.38.
Dimethyl 6-Methyl-2-phenyl-5-(trifluoromethyl)-4-pyrimidinyl
ester (2m)
1H-NMR δ 8.60–8.51 (m, 2H), 7.62–7.53 (m, 3H), 4.08 (d, 6H, J =
11.7 Hz), 2.85 (q, 3H); MS (m/e, %): 362 (M+, 21.11), 293 (7.77), 267
(14.54) 254 (100.00), 221 (43.17), 151 (10.95), 104 (84.05), 77 (28.59);

o- or p-Trifluoromethylphenyl Phosphates
659
Anal. Calcd. for C14H14F3N2O4P: C, 46.42; H, 3.90. Found: C, 46.05; H,
4.25.
Dimethyl 2-(Trifluoromethyl)phenyl phosphate (2n)
1H-NMR δ 7.64–7.22(m, 4H), 3.90(d, 6H, J = 11.4 Hz); MS (m/e, %):
270 (M+, 50.49), 251 (78.42), 230 (100.00), 187 (15.94), 158 (16.78), 142
(30.06), 114 (57.63), 109 (22.37); Anal. Calcd. for C9H10F3O4P: C, 40.02;
H, 3.73. Found: C, 40.19; H, 3.85.
Dimethyl 1-(Trifluoromethyl)-2-naphthalenyl ester (2o)
1H-NMR δ 8.32–7.50(m, 4H), 3.83(d, 6H, J = 11.5 Hz); MS (m/e,
%): 321 (M++1, 14.05), 320 (M+, 100.00), 251 (14.39), 208 (7.14),
192 (14.60), 164 (31.23), 133 (13.02), 109 (16.85); Anal. Calcd. for
C13H12F3O4P: C, 48.76; H, 3.78. Found C, 48.68; H, 3.84.
REFERENCES
[1] J. K. Myers and T. S. Widlanski, Science, 262, 1451 (1993).
[2] H. Tetsuo, T. Shuichi, O. Atsuki, H. Tadami, and C. Isao, JP. 57085395, 1982, CA: 98:
72436.
[3] M. Tordeux, B. Langlois, and C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 8, 2293
(1990).
[4] K. J. Edgar and S. N. Falling, J. Org. Chem., 55, 5287 (1990).
[5] Q. Y. Chen and S. W. Wu, J. Chem. Soc., Chem. Commun., 11, 705 (1989).
[6] (a) J. K. Myers, J. D. Cohen, and T. S. Widlanski, J. Am. Chem. Soc., 117, 11049
(1995); (b) J. K. Stowell and T. S. Widlanski, J. Org. Chem., 60, 6930 (1995); (c) J. K.
Stowell and T. S. Widlanski, J. Am. Chem. Soc., 116, 789 (1994).
[7] A. J. Ganzhorn, J. Hoflack, P. D. Pelton, F. Strasser, M.-C. Chanal, and S. R. Piettre,
Bioorg. Med. Chem., 6, 1865 (1998).
[8] X. Luo, X. Huang, and F. Qu, Youji Huaxue, 26, 874 (2006).
[9] X. Liu, T. Jia, J. Chen, Z. Jiang, H. Zhang, and X. Huang, Organic Preparations and
Procedures International, 32, 485 (2000).