Synthesis of deuterated herbicidal ZJ0273, ZJ0702, ZJ0777, and SIOC0163

Article abstract of DOI:10.1002/jlcr.1749

ZJ0273 (propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate), ZJ0702 (isopropyl 4-(2-(4,6-dimethoxy pyrimidin-2-yloxy)benzylamino)benzoate), ZJ0777 (2-bromo-N-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl)aniline), and SIOC0163 (5-bromo-N-(2-(4,6

Full text of DOI:10.1002/jlcr.1749

Research Article
Received 20 October 2009,
Revised 24 January 2010,
Accepted 26 January 2010
Published online 23 March 2010 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1749
Synthesis of deuterated herbicidal ZJ0273,
ZJ0702, ZJ0777, and SIOC0163
Ã
Zheng-Min Yang and Long Lu
ZJ0273 (propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate), ZJ0702 (isopropyl 4-(2-(4,6-dimethoxy
pyrimidin-2-yloxy)benzylamino)benzoate), ZJ0777 (2-bromo-N-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl)aniline), and
SIOC0163 (5-bromo-N-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl)pyridin-2-amine) are active ingredients in oilseed rape
herbicides. The middle aromatic ring-deuterated form of ZJ0273 was synthesized from (2H6)phenol and have been
successfully used as tracer in its metabolism and degradation study. The methoxyl-deuterated forms of four ingredients
were synthesized from (2H4)methanol, respectively, and they could be used as internal standards in quantitation of
herbicide residue in rapeseed and its downstream foodstuff by using HPLC-MS/MS.
Keywords: propyl 4-(2-(4, 6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate; isopropyl 4-(2-(4, 6-dimethoxypyrimidin-2-yloxy)
benzylamino)benzoate; 2-bromo-N-(2-(4, 6-dimethoxypyrimidin-2-yloxy)benzyl)aniline; 5-bromo-N-(2-(4, 6-dimethoxypyrimidin-2-
yloxy)benzyl)pyridin-2-amine; deuterated compounds; synthesis; rape herbicide
activity and similar herbicidal spectrum as ZJ0273, and its
tradename is Youda (EC) and Youhuan (SC). ZJ0777 and
Introduction
ZJ0273 (propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl
amino)benzoate), ZJ0702 (isopropyl 4-(2-(4,6-dimethoxy
pyrimidin-2-yloxy)benzylamino)benzoate), ZJ0777 (2-bromo-N-
(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl)aniline), and SIOC0163
(5-bromo-N-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzyl)pyridin-
2-amine) are active ingredients in oilseed rape herbicides of
2-pyrimidinyloxy-N-arylbenzylamines (Figure 1) co-developed
by Shanghai Institute of Organic Chemistry and Zhejiang
Institute of Chemical Industry in China.1,2
ZJ0273 is a pre-herbicidal ingredient and converts to 2-(4,6-
dimethoxypyrimidin-2-yloxy)benzoic acid to work. The ingredi-
ent acts on ALS enzyme and belongs to the family of the
ALS-inhibitors.3,4 It is formulated as herbicide under the trade-
name of Youli (EC) and Youli No.2 (SC) employed on the field.2
The extractable residues, bound residues, and mineralization of
the herbicide in soils meet the non-accumulative criteria of the
Commission of the European Communities.5–7 The only residue
of the herbicide in rapeseed is ZJ0273. The residue in rapeseed
(1 kg) ranges from 16.97–19.17 mg under simulated field condi-
tions when ZJ0273 is applied at the recommended rate,
determined by employing the hyphenated techniques of
radioisotope tracing and HPLC-MS.4 ZJ0702 has equivalent
SIOC0163, two herbicidal ingredients with low mammalian
toxicity and favorable environmental profile, can control many
grass weed species as well as broadleaf weeds on rape field.
They are individually formulated as herbicides and applied at
the rate of 15–90 g of active ingredient/ha at the stage of
postemergence.8,9
With the increase of application amount of these herbicides,
growing attentions are paid to the security of rapeseed and its
downstream foodstuff, and herbicide residue in rapeseed and its
downstream foodstuff gradually become a focused issue on
these herbicides. So, it is urgent to develop a method to
quantify the residue of these herbicides. Because of high
specificity, selectivity, and accuracy, high performance liquid
chromatography combined with tandem mass spectrography
(HPLC-MS/MS) is a preferable method for this task. A stable
isotope-substituted compound is the most ideal internal
standard for HPLC-MS/MS analysis.10 To study the metabolism
and degradation of ZJ0273 and to quantify the residue of these
herbicides, certain isotope-substituted forms of the herbicidal
ingredients are required.
In this paper, we report the synthesis of the middle
aromatic ring- and methoxyl-deuterated forms of four herbicidal
ingredients.
MeO
X
OMe
N
N
Q
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academic of Sciences, Shanghai 210032, China
H
N
R1
Y
*Correspondence to: Long Lu, Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No. 345,
Lingling Road, Shanghai 200032, China.
R2
Figure 1. Structures of 2-pyrimidinyloxy-N-arylbenzylamines.
J. Label Compd. Radiopharm 2010, 53 192–197
E-mail: lulong@mail.sioc.ac.cn
Copyright r 2010 John Wiley & Sons, Ltd.

Z.-M. Yang and L. Lu
(9d), and (9e) individually shift 6 units from those of their natural
forms. These reveal that two trideuteromethoxyl groups present
in the molecules of (9b), (9c), (9d), and (9e), respectively.
For a deuterated compound used as internal standard in MS
analysis, at least three deuterium atoms should be introduced to
avoid the possible interference of the isotopic peaks from the
natural form of the compound. The deuterium substitution must
locate on the specific positions in the compound and deuterium
atoms cannot be exchanged in the subsequent study. Moreover,
the isotopic purity should be as high as possible.10
In the molecule of (9a), four deuterium atoms were
introduced on the middle aromatic ring. In our previous study
on the metabolism and degradation of ZJ0273, the mixture of
(9a) and ZJ0273 labeled with carbon-14 on the middle ring was
employed as a tracer, and the study demonstrated that this
deuterated form of ZJ0273 is stable (data not shown). The major
metabolites and degradation products of ZJ0273 are 4-(2-(4,6-
dimethoxypyrimidin-2-yloxy)benzylamino)benzoic acid and 2-
(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid, as means the
methoxyl groups are stable.4 Hence, ZJ0273 was substituted
with deuterium atoms on the methoxyl groups, and so were
ZJ0702, ZJ0777, and SIOC0163 due to the structural similarities
between these three ingredients and ZJ0273. Chemical purities of
these deuterated compounds are all greater than 99%, which
were determined by HPLC under the conditions as described,
employing the natural form of the corresponding standard
compounds as external standard, respectively.11 The mass spectra
of the deuterated compounds demonstrates that the isotopic
purities are all greater than 99%. Therefore, the methoxyl-
deuterated compounds (9b), (9c), (9d), and (9e) can be used as
internal standards in quantitation of herbicide residue in rapeseed
and its downstream foodstuff by employing HPLC-MS/MS.
Results and discussion
Five deuterated forms of 2-pyrimidinyloxy-N-arylbenzylamine
herbicidal ingredients were synthesized from (2H6)phenol in a
four-step yield of 44% (9a) and from (2H4)methanol in three-step
yields of 49% (9b), 51%(9c), 46%(9d), and 51%(9e), respectively,
1
followed by identification by H and 13C NMR, MS(EI), HRMS(EI),
UV, and IR.
In the mass spectrum of (9a), the m/z values of the typical ion
fractions (10a, 12, 13, 14, Figure 2) are 249, 229, 288, 212
instead of 245, 225, 284, 198 in the spectrum of ZJ0273.11,12 In
the NMR spectrum of (9a), the peaks (d 7.15, 7.31, 7.20, 7.40)
corresponding to four hydrogen atoms on the middle aromatic
ring of the molecule of ZJ0273 are not observed, and four peaks
(d 122.64, 125.46, 128.12, 128.58) corresponding to four carbon
atoms individually split into triple peaks instead of singlet peaks
in the NMR spectrum of ZJ0273.13 These indicate that four
deuterium atoms occur on the middle aromatic ring in the
molecule of (9a). In our downstream study on the metabolism
and degradation of ZJ0273 (data not shown), the mixture of
ZJ0273, the middle aromatic ring-deuterated form of ZJ0273
(9a), and propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)[phenyl-
3,4,5,6-3H4]benzylamino)benzoate (tridium-labeled ZJ0273) was
used as a tracer.14 The tridium-labeled ZJ0273 can effectively
discriminate the metabolites and degradation products from the
complicated matrix on the basis of radioactivity while it cannot
afford molecular structure information. However, (9a) in the
tracer can provide more molecular structure information based
on the relevant isotopic peaks in mass spectrum, which can
further validate the structures of the metabolites and degrada-
tion products of ZJ0273.
In the NMR spectra of (9b), (9c), (9d), and (9e), the peaks (ca. d
3.79) corresponding to three hydrogen atoms on methoxyl
groups in the natural forms of four ingredients all disappear.11,12
Meanwhile, the peaks (d 53.63, 53.52, 53.62, 53.65) individually
split into heptet peaks due to the C-2H coupling, compared with
the singlet peaks corresponding to carbon atoms on the
Experimental
Materials and instruments
methoxyl groups in the natural forms of the ingredients. In (2H6)phenol (D, 99.8%) was purchased from Cambridge Isotope
the mass spectra, the m/z values of the typical ion fractions Laboratories (Massachusetts, USA). Anhydrous magnesium
(10b, 11, Figure 2) and accurate molecular weight of (9b), (9c), dichloride, paraformaldehyde, and (2H4)methanol (2H, 99.6%)
Z3CO
OCZ3
2H
2H
2H3CO
OC2H3
NH+
N
N
2H
2H
O
X
X
X
N
OH+
O
OH
N
H
X
10a: X = 2H, Z = H, m/z 249
10b: X = H, Z = 2H, m/z 251
12: m/z 229
11: m/z 163
2H
2H
2H
O
2H
2H
H
N
2H
2H
2H
O
N
O
Pr-n
O
13
: m/z 288
14
: m/z 212
Figure 2. The typical ion fractions of the deuterated compounds in MS (EI).
J. Label Compd. Radiopharm 2010, 53 192–197
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

Z.-M. Yang and L. Lu
were obtained from Acros Organics (NJ, USA), and methanol for (CDCl3) d: 2.52 (s, 3H, SCH3), 5.70 (s, 1H, CH). HPLC-MS (ESI) m/z:
1
UV spectrum from Fisher Scientific (NJ, USA). Regents were of 193[M11]1; 13C NMR (CDCl3) d: 14.14, 53.40 (hept, J = 22.2 Hz,
analytical grade and purchased on market, unless otherwise OC2H3), 85.53, 171.06, 171.30. MS (EI, 70 eV) m/z (%): 192 (M1,
stated. Flash chromatography was conducted on silica gel 100), 146(29), 128(21), 174(18), 69(8), 145(8), 57(6), 194(6). HRMS
(300–400 mesh, Yantai Institute of Chemical Industry, Shandong, (EI) calcd for C7H24H N2O2S 192.0840, found 192.0837.
6
China).13C NMR (75 MHz) and 1H NMR (300 MHz) spectra were
measured on a Varian 300 spectrometer (Varian Inc., CA, USA) 4,6-Di(2H3)methoxy-2-(methylsulfonyl)pyrimidine (5b)
and chemical shifts dwere given in ppm referring to the signal
center using the solvent peaks for reference (CDCl3: 7.26/77.36;
DMSO-d6: 2.49/39.7). MS and HRMS spectra were recorded on a
5973N instrument (Agilent Technologies, CA, USA) and a
The mixture of (4) (4.15 g, 21.8 mmol), sodium tungstate
dihydrate (0.2 g, 0.6 mmol) and percarbamide (5.30 g, 44.9 mmol)
in acetic acid (15 mL) was stirred at 401C for 10 min and 501C for
4 h. To the reaction mixture was added the solution of sodium
Micromass GCT Premier instrument (Waters Co., MA, USA),
bisulfite (0.6 M, 20 mL) followed by filtration. The filter cake was
respectively. UV analysis was carried out on Cary 100 UV-Vis
spectrometer (Varian Inc.) and IR spectra were determined by a
recrystallized from ethanol to afford (5b) (6.80 g, 68%).14 1H NMR
(CDCl3) d: 3.30 (s, 3H, SCH3), 6.15 (s, 1H, CH). 13C NMR (CDCl3) d:
Nicolet Avatar 330 FT-IR spectrometer (Thermo Electron Corp.,
MA, USA). GC-MS analysis was performed on a Varian 4000 GC-
MS/MS instrument (Varian Inc.). The melting points were taken
39.42, 54.82 (hept, 1J = 22.2 Hz, OC2H3), 92.63, 164.91, 173.43.
HPLC-MS (ESI) m/z: 225 (M111). MS (EI, 70 eV) m/z (%): 145(100),
224(29), 209(16), 86(13), 146(10), 222(9), 69(9), 93(8). HRMS (EI)
on a SGW X-4 microscope melting point instrument without
calcd for C7H24H6N2O4S 224.0738, found 224.0739. These data
calibration (Shanghai precise science instruments Co., Shanghai,
China). HPLC purities of the final deuterated compounds were
consisted with those of (5b) in literature.15
analyzed by employing Prominence liquid chromatograph
system, equipped with SIL-20A auto sampler, LCMS-2010EV
General procedure for synthesis of N-arylbenzylideneamines
(7a)–(7e)
mass spectrometer (Shimadzu Co., Kyoto, Japan) and
a
Diamonsil C18 column (5 mm, 4.6 mm ꢀ 250 mm, Dikma Technol-
ogies, CA, USA). The analysis was performed under the
chromatographic conditions as described.11
To the stirred solution of propyl 4-aminobenzoate (6a) (9.89 g,
55.2 mmol) in anhydrous methanol (30 mL) was added
2-hydroxy(phenyl-3,4,5,6-2H4)benzaldehyde (2a) (6.95 g, 55.1 mmol)
at 15–201C and the stirring was continued for 1 h. Yellow
precipitate formed immediately after ca. 30 min. The precipitate
was filtered off under vacuum, washed with methanol (10 mL,
0–51C), and then dried over P2O5 under vacuum to afford yellow
solid (7a). The reaction conditions for the synthesis of (7d) were
different from those of the other four compounds. The reaction
mixture must be refluxed at least 2 h under the catalysis of acetic
acid (2–3 drops). These five intermediates were employed
without further purification.
Synthesis section
The deuterated compounds were synthesized from anhydrous
(2H6)phenol and (2H4)methanol (Scheme 1) according to the
optimized procedures as described, respectively.11,12,14
2-Hydroxy(phenyl-3,4,5,6-2H4)benzaldehyde (2a)
The mixture of (2H6)phenol (1) (10.00 g, 0.10 mol), anhydrous
magnesium dichloride (24.24 g, 0.15 mol), anhydrous triethyla-
mine (52 mL, 0.37 mol), and anhydrous acetonitrile (90 mL) was
stirred under argon at room temperature for 30 min. Parafor-
maldehyde (24.24 g, 0.81 mol) was added to the mixture.12,14
The resulting mixture was refluxed for 4 h and then cooled to
room temperature. To the mixture was added 10% HCl (120 mL),
followed by extraction with ethyl ether. The combined organic
layers were washed with water and saturated brine, dried over
anhydrous MgCl2, and evaporated in vacuo to afford colorless
General procedure for synthesis of N-arylbenzylamines (8a)–(8e)
Sodium borohydride (3.20 g, 84 mmol) was added portionwise to
the stirred suspension of (7a) (12.43 g, 43 mmol) in anhydrous
methanol (50mL) at 0–51C. The mixture was stirred for 30min. To
the resulting solution was added water (20 mL) then stirred for
another 30 min. The solution was concentrated in vacuo to
remove methanol and extracted with ethyl acetate. The combined
organic layers were washed with saturated brine, dried over
anhydrous Na2SO4, and removed solvent under reduced pressure.
The resulting residue was recrystallized from ethyl acetate/
petroleum ether (1/8) to afford white powder (8a).12
1
oil (2a) (10.57 g, 84%). H NMR (CDCl3) d: 9.92 (s, 1H, OH), 11.05
(s, 1H, CHO). GC-MS (EI, 70 eV) m/z (%): 126 (M1, 100), 109(6),
96(27), 69(9).
4,6-Di(2H3Þmethoxy-2-(methylthio)pyrimidine (4)
Propyl 4-(2-hydroxy(phenyl-3,4,5,6-2H4)benzylamino)benzoate (8a)
To a two-neck flask containing anhydrous (2H4)methanol (15 mL)
at 0–51C in an ice bath was added a piece of sodium (1.295 g,
56.3 mmol) under argon. The mixture was stirred until it became
clear, stirred for another 10 min. The resulting solution was
added dropwise to the stirred solution of 4,6-dichloro-2-
(methylthio)pyrimidine (3) (5.46 g, 28.3 mmol) in anhydrous
(2H4)methanol (15 mL) over 10 min and refluxed for 5 h. Water
(10 mL) was added into the vigorously stirred reaction mixture,
followed by extraction with ethyl acetate. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
purified by flash chromatography (ethyl acetate/petroleum
ether 1/200) to afford white powder (4) (9.42 g, 85%).1H NMR
1
Yield (10.30 g, 82%). m.p. 147–1481C. H NMR (DMSO-d6) d: 0.92
(t, J = 7.2 Hz, 3H, CH3), 1.65 (m, 2H, CH2), 4.10 (t, J = 6.9 Hz, 2H,
OCH2), 4.27 (s, 2H, NCH), 6.62 (t, J = 8.7 Hz, 2H, Ar–H), 7.69
(t, J = 8.7 Hz, 2H, Ar–H ), 9.56 (s, 1H, OH). 13C NMR (DMSO-d6)
d: 11.06, 22.48, 41.52, 65.65, 111.86, 115.26 (t, J = 22.3 Hz, C2H),
116.73, 118.98 (t, J = 22.3 Hz, C2H), 125.41, 127.95(m, C2H),
128.50(m, C2H), 131.66, 153.55, 155.68, 166.60. MS (EI, 70 eV)
m/z (%): 120(100), 137(82), 179(52), 289 (M1, 39), 92(20), 82(20),
111(17), 65(15). HRMS (EI) calcd for C17H215H4NO3 289.1616,
found 289.1614. IR (KBr disk, cmꢁ1) v: 3415(s,gN–H), 1660(s,gC = O).
UV (MeOH,lmax): 202, 246 nm.
www.jlcr.org
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 192–197

Z.-M. Yang and L. Lu
2H
2H
2H
2H
O2H
2H
(a) MgCl2, Et3N, CH3CN, Ar
(b) HCOH, reflux
2H
2H
OH
CHO
2H
2H
2a
1
O
N
S
O
S
S
C2H3ONa
C2H3O2H
percarbamide
N
N
N
N
N
HOAc, 40~50oC
2H3CO
OC2H3
2H3CO
OC2H3
Cl
Cl
3
4
5b
X
X
OH
X
X
CHO
H2N
Y
X
X
OH
N
X
R
Y
EtOH
R
X
: X = 2H
: R = 4-CO2Pr-n, X = 2H, Y = C
7a
7b: R = 4-CO2Pr-n, X = H, Y = C
7c: R = 4-CO2Pr-i, X = H, Y = C
6a
6b
: R = 4-CO2Pr-n, Y = C
: R = 4-CO2Pr-i, Y = C
2a
2b: X = H
6c: R = 2-Br, Y = C
6d
: R = 5-Br, Y = N
7d
: R = 2-Br, X = H, Y = C *
7e
: R = 5-Br, X = H, Y = N
*
under the catalysis of acetic acid.
SO2CH3
Z3CO
X
OCZ3
N
N
X
N
N
X
X
OH
Z3CO
OCZ3
NaBH4
EtOH
H
N
X
X
O
Y
H
N
CH3CN, K2CO3
40 ~ 50oC
R
Y
X
R
X
8a: R = 4-CO2Pr-n, X = 2H, Y = C
5a: Z = H
9a: R = 4-CO2Pr-n, X = 2H, Y = C, Z = H
5b: Z = 2
H
2
8b
9b
: R = 4-CO2Pr-n, X = H, Y = C
: R = 4-CO2Pr-n, X = H, Y = C, Z = H
: R = 4-CO2Pr-i, X = H, Y = C, Z = 2H
8c
9c
: R = 4-CO2Pr-i, X = H, Y = C
8d: R = 2-Br, X = H, Y = C
8e: R = 5-Br, X = H, Y = N
9d: R = 2-Br, X = H, Y = C, Z = 2H
9e: R = 5-Br, X = H, Y = N, Z = 2H
Scheme 1. Synthetic routes of the deuterated compounds.
Propyl 4-(2-hydroxybenzylamino)benzoate (8b)
7.14–7.24 (m, 2H, Ar–H). MS (EI, 70 eV) m/z (%):137(100), 120(85),
179(62), 285 (M1, 48), 107(33), 78(19), 121(18), 92(16).
1
Yield (8.28 g, 83%). H NMR (DMSO-d6) d: 1.01 (t, J = 7.2 Hz, 3H,
CH3), 1.77 (m, 2H, CH2, OCH2), 4.23 (t, J = 6.6 Hz, 2H), 4.43 (s, 2H),
7.91 (d, J = 8.1 Hz, 2H, Ar–H), 6.74 (d, J = 8.1 Hz, 2H, Ar–H),
2-((2-Bromophenylamino)methyl)phenol (8d)
7.23–7.16 (m, 2H, Ar–H), 6.93–6.84 (m, 2H, Ar–H). MS (EI, 70 eV) Yield (5.4 g, 89%). 1H NMR (CDCl3) d: 4.48 (s, 2H, NCH2), 6.72–6.81
m/z (%): 120(100), 137(79), 179(43), 285(M1, 29), 107(21), 78(19), (m, 1H, Ar–H), 6.85–7.05 (m, 3H, Ar–H), 7.19–7.31 (m, 3H, Ar–H),
92(19), 65(17).
7.48–7.55 (m, 1H, Ar–H). MS (EI, 70 eV) m/z (%): 171(100), 173(96),
107(27), 77(25), 277 (M1, 23), 279(23), 65(17), 78(16).
Isopropyl 4-(2-hydroxybenzylamino)benzoate (8c)
2-((5-Bromopyridin-2-ylamino)methyl)phenol (8e)
Yield (8.51 g, 87%). 1H NMR (CDCl3) d: 1.34 (d, J = 6.0 Hz, 6H, CH3),
4.42 (s, 2H, CH2), 5.21 (hept, J = 6.0 Hz, 1H, CH), 6.72 (d, J = 8.7 Hz, Yield (4.62 g, 91%). 1H NMR (CDCl3) d: 4.43 (d, 2H, CNH), 5.20 (brs,
2H, Ar–H), 7.89 (d, J = 8.7 Hz, 2H, Ar–H), 6.83–6.93 (m, 2H, Ar–H), 2H, NH), 6.29–6.36 (m, 1H, Ar–H), 6.82–6.97 (m, 2H, Ar–H),
J. Label Compd. Radiopharm 2010, 53 192–197
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

Z.-M. Yang and L. Lu
7.12–7.27 (m, 2H, Ar–H), 7.41–7.46 (m, 1H, Ar–H), 8.09–8.15 (m, 1701(s,gC = O), 1602, 1488, 1455(w, w, w,gC = O). UV
1H, Ar–H). MS (EI, 70 eV) m/z (%): 172(100), 174(99), 278 (M1, 46), (MeOH,lmax): 200, 246, 303 nm. HPLC purity 499%.
280(45), 77(33), 107(30), 122(26), 78(25).
2-Bromo-N-(2-(4,6-di(2H3)methoxypyrimidin-2-yloxy)benzyl)aniline
(9d)
General procedure for synthesis of deuterated 2-pyrimidinyloxy-N-
arylbenzylamines (9a)–(9e)
Yield (1.73 g, 79%). m.p. 100–1021C. 1H NMR (CDCl3) d: 4.43
To the vigorously stirred solution of propyl 4-(2-hydroxy(phenyl- (s, 2H, NCH2), 5.79 (s, 1H, CH), 6.47–6.62 (m, 2H, Ar–H), 7.03–7.47
3,4,5,6-2H4)benzylamino)benzoate (8a) (10.13 g, 35 mmol) and (m, 6H, Ar–H). 13C NMR (CDCl3) d: 173.22, 164.49, 151.24, 144.79,
4,6-dimethoxy-2-(methylsulfonyl)pyrimidine
(5a)
(7.64 g, 132.50, 131.09, 128.42, 128.53, 128.49, 125.96, 123.04, 118.01,
35 mmol) in anhydrous acetonitrile (150 mL) was added 111.82, 109.70, 84.90, 53.62 (hept, 1J = 22.6 Hz, OC2H3),
anhydrous potassium carbonate (14.51 g, 105 mmol) at 43.32. MS (EI, 70 eV) m/z (%): 251(100), 163(38), 260(22),
40–501C. The stirring was continued for 48 h.12,14 The resulting 180(18), 252(18), 261(17), 258(17), 259(17), 421(M1,11). HRMS
2
mixture was filtered and concentrated under vacuum. The (EI) calcd for C19H12H6BrN3O3 421.0908, found 421.0904.
residue was subjected to silica gel flash chromatography (ethyl IR (KBr disk, cmꢁ1): 3415(s,gN–H), 1599(s,gC = C), 1570, 1501,
acetate/hexane, 1/8–1/7) to afford (9a).12.
1515(w, w, w,gC = C). UV (MeOH,lmax): 205, 245, 300 nm. HPLC
purity 4 99%.
Propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)(phenyl-3,4,5,6-2H4)benzyl
amino)benzoate (9a)
5-Bromo-N-(2-(4,6-di(2H3)methoxypyrimidin-2-yloxy)benzyl)
pyridin-2-amine (9e)
Yield (11.89 g, 80%). m.p. 97–981C. 1H NMR (CDCl3) d: 1.00
(t, J = 7.2 Hz, 3H, CH3), 1.74 (m, 2H, CH2), 3.79 (s, 6H, OCH3), 4.20 Yield (1.84 g, 88%). m.p. 108–1091C. 1H NMR (CDCl3) d: 4.45 (s, 2H,
(t, J = 6.9 Hz, 2H, OCH2), 4.39 (d, J = 5.4 Hz, 2H, NCH2), 4.68 (t, NCH2), 5.38 (brs, 1H, NH), 5.75 (s, 1H, CH), 6.16–6.24 (m, 1H, Ar–H),
J = 5.4 Hz, 2H, NH), 5.77 (s, 1H, CH), 6.51 (d, J = 8.7 Hz, 2H, Ar–H), 7.07–7.44 (m, 5H, Ar–H), 7.95–8.07 (m, 1H, Ar–H). 13C NMR
7.81 (d, J = 8.7 Hz, 2H, Ar–H). 13C NMR (CDCl3) d: 10.74, 22.44, (CDCl3) d: 173.19, 164.33, 157.17, 151.22, 148.31, 139.31, 131.17,
43.07, 54.39, 65.99, 84.64, 111.85, 119.11, 122.64 (t, J = 23.9 Hz, 129.19, 128.60, 125.93, 122.89, 106.64, 107.10, 84.76, 53.65 (hept,
C2H), 125.46 (t, J = 23.8 Hz, C2H), 128.18 (t, J = 24.3 Hz, C2H), 1J = 22.5 Hz, OC2H3), 41.68. MS(EI, 70 eV) m/z (%): 422(M1, 100),
128.58 (t, J = 25.1 Hz, C2H), 130.79, 131.55, 151.19, 151.79, 164.44, 424(99), 163(96), 251(91), 261(60), 157(40), 159(39), 259(37).
2
167.06, 173.26. MS (EI, 70 eV) m/z (%): 249(100), 427 (M1, 40), HRMS(EI) calcd for C18H11H6BrN4O3 422.0861, found 422.0862.
229(21), 288(17), 212(16), 271(13), 384(4). HRMS (EI) calcd for IR (KBr disk, cmꢁ1): 3300(s,gN–H), 1596(s,gC = C), 1575, 1480, 1506
C23H221H4O5N3 427.2045, found 427.2057. IR (KBr disk, cmꢁ1) v: (w, w, w,gC = C). UV (MeOH,lmax): 201, 249, 319 nm. HPLC purity
3285(s,gN–H), 1695(s,gC = O), 1595, 1491, 1460(w, w, w,gC = C). UV 4 99%.
(MeOH,lmax): 203, 247, 304 nm. HPLC purity 4 99%.
Acknowledgement
Propyl 4-(2-(4,6-di(2H3)methoxypyrimidin-2-yloxy)benzylamino)
benzoate (9b)
The authors gratefully acknowledge the financial support from
the project of Application of Nuclear Techniques in Agriculture
(200803034), the Key Program of National Natural Science
Foundation of China (20632070), and National Basic Research
Program of China (2010CB126103).
1
Yield (3.25 g, 85%). m.p. 97–981C. H NMR (CDCl3, 300 MHz) d:
0.98 (t, J = 7.2 Hz, 3H, CH3), 1.74 (m, 2H, CH2), 4.18 (t, J = 6.9 Hz,
2H, OCH2), 4.37 (d, J = 5.1 Hz, 2H, NCH), 5.76 (s, 1H, CH), 6.47 (d,
J = 8.4 Hz, 2H, Ar–H), 7.11–7.45 (m, 4H, Ar–H ), 7.81 (d, J = 8.4 Hz,
2H, Ar–H ). 13C NMR (CDCl3) d: 173.26, 167.06, 164.45, 151.73,
151.25, 131.57, 130.85, 129.03, 128.73, 125.99, 123.06, 119.17,
111.87, 84.82, 66.02, 53.63 (hept, 1J = 22.0 Hz, OC2H3), 43.16,
22.44, 10.76. MS (EI, 70 eV) m/z (%): 251(100), 163(38),
429(M1, 25), 179(20), 225(20), 284(19), 252(18), 224(16). HRMS(EI)
calcd for C23H219H6N3O5 429.2171, found 429.2176. IR (KBr
disk, cmꢁ1) v: 3290(s,gN–H), 1696(s,gC = O), 1540, 1597, 1490
(w, w, w,gC = C). UV (MeOH,lmax): 202, 246, 304 nm. HPLC purity
499%.
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Yield (1.95 g, 89%). m.p. 83–851C. H NMR (CDCl3) d: 5.77 (s, 1H,
CH), 7.15 (m, H, Ar–H), 7.31 (m, H, Ar–H), 7.20 (m, H, Ar–H), 7.40
(m, H, Ar–H), 4.39 (s, 2H, NCH), 6.49 (d, J = 9.0 Hz, 2H, Ar–H), 7.80
(d, J = 8.6 Hz, 2H, Ar–H), 5.15 (m, 1H, –CH–); 1.32 (d, J = 6.0 Hz, 6H,
CH3). 13C NMR (CDCl3) d: 53.52 (hept, 1J = 22.3 Hz,OC2H3), 173.08,
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70 eV) m/z (%): 251(100), 163(39), 224(29), 225(29), 179(27),
2
429(M1, 26), 252(19), 370(15). HRMS (EI) calcd for C23H19H6N3O5
429.2171, found 429.2168. IR (KBr disk, cmꢁ1): 3315(s,gN–H),
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