Stereoselective synthesis and fungicidal activities of (E)-α- (methoxyimino)-benzeneacetate derivatives containing 1,3,4-oxadiazole ring

Article abstract of DOI:10.1016/j.bmcl.2006.01.026

Fifteen novel (E)-α-(methoxyimino)-benzeneacetate derivatives, the analogues of strobilurins, which contain two pharmacophoric substructures of (E)-methyl methoxyiminoacetate moiety and 1,3,4-oxadiazole ring were stereoselectively synthesized. It was first found that the coupling reaction could give stereoselectively the key intermediate (E) and (Z)-methyl 2-(hydroxyimino)-2-o-tolylacetate 2 with a ratio of 14:1. The preliminary bioassays indicated that all the compounds 1 showed potent fungicidal activity against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Physalospora piricola and Bipolaris mayclis, and all of the tested compounds 1a-1o had more potent fungicidal activities against R. solani than Kresoxim-methyl.

Full text of DOI:10.1016/j.bmcl.2006.01.026

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2278–2282
Stereoselective synthesis and fungicidal activities of
(E)-a-(methoxyimino)-benzeneacetate derivatives containing
1,3,4-oxadiazole ring
a
a
a
b
Yan Li,a,b, Jie Liu, Hongquan Zhang, Xiangping Yang and Zhaojie Liu
*
aKey Laboratory of Synthesis and Application of Organic Functional Molecules of the Education Ministry,
Hubei University, Wuhan, Hubei 430062,China
bKey Laboratory of Pesticide and Chemical Biology of the Education Ministry, Central China Normal University,
Wuhan, Hubei 430079,China
Received 15 November 2005; revised 27 December 2005; accepted 6 January 2006
Available online 7 February 2006
Abstract—Fifteen novel (E)-a-(methoxyimino)-benzeneacetate derivatives, the analogues of strobilurins, which contain two
pharmacophoric substructures of (E)-methyl methoxyiminoacetate moiety and 1,3,4-oxadiazole ring were stereoselectively synthe-
sized. It was first found that the coupling reaction could give stereoselectively the key intermediate (E) and (Z)-methyl 2-(hydroxy-
imino)-2-o-tolylacetate 2 with a ratio of 14:1. The preliminary bioassays indicated that all the compounds 1 showed potent
fungicidal activity against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Physalospora piricola and Bipolaris mayclis,
and all of the tested compounds 1a–1o had more potent fungicidal activities against R. solani than Kresoxim-methyl.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Strobilurins have been an important class of agricultural
fungicides such as Kresoxim-methyl and Trifloxystrob-
in.1,2 These compounds exhibit strong fungicidal activity
against various fungi by binding to electron transfer at
the ubiquinol-oxidation centre (Qo-site) of the bc1-en-
zyme complex (complex III).1–3 These well-known stro-
bilurins have an (E)-methyl methoxyiminoacetate
moiety as a common pharmacophoric substructure,
isosteric with (E)-methyl b-methoxyacrylate group and
these (E)-configured compounds have been shown to
exhibit biological activity higher than that of the corre-
sponding (Z)-stereoisomers.1 The methods used for the
synthesis of strobilurin fungicides include the lactone
ring opening of phthalide,1 the Pinner reaction of acy-
lcyanides4,5 and the coupling reactions assisted by orga-
nometallic reagents.6 Although the required (E)-isomer
generally predominates, all these approaches tend to
produce mixtures of stereoisomers. On the other hand,
1,3,4-oxadiazole ring derivatives also exhibit a broad
spectrum of biological activities such as fungicidal,7,8
antimicrobial and antibacterial activities,9 and 1,3,4-
oxadiazole ring is a major pharmacophoric substruc-
ture. In view of these facts, we will have developed a
new and efficient method for stereoselective synthesis
of methyl (E)-a-(methoxyimino)-benzeneacetate and
synthesized some novel analogues of strobilurins which
contain both (E)-methyl methoxyiminoacetate and
1,3,4-oxadiazole ring moieties, methyl (E)-a-(methoxyi-
mino)-2-[(5-aryl-1,3,4-oxadiazole-2-mercapto)-methyl]-
benzeneacetates 1, in order to obtain better fungicidal
activities.
According to retro-synthetic analyses and the litera-
ture,2,6 both methyl 2-oxo-2-arylacetate and methyl 2-
hydroxyimino-2-arylacetate 2 are the key intermediates
of the analogues of strobilurins. Our initial goal was
to develop a new method for synthesis of methyl 2-
oxo-2-arylacetate in which the commercially available
and cheap arylamines and glyoxylic acid were used as
starting material based on previous literature.10,11 In
our work, we first found that the coupling reaction
between aryldiazonium salt derived from 2-methylani-
line and methyl 2-(hydroxyimino)-acetate gave stereose-
lectively oxime 2 in 44% yield.12 The E/Z ratio
Keywords: Strobilurins; (E)-a-(methoxyimino)-benzeneacetates; Subs-
tituted 1,3,4-oxadiazoles; Fungicides.
1
determined in the crude mixture by H NMR spectros-
copy was ca. 14:1. After further column chromatogra-
phy purification, the purity of E-2 could exceed 99% in
*
Corresponding author. Tel.: +86 27 50865369; fax: +86 27
88663043; e-mail: liyanok@hotmail.com
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.026

Y. Li et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2278–2282
2279
41% yield. The compound E-2 was methylated by sodi-
um hydride-dimethyl sulfate in 91% yield and succes-
sively brominated with NBS to afford oxime ether 4 in
81% yield.
figurations of compounds 1 were assigned on the basis of
their 2D-NOESY spectra of 1H NMR, and the 2D-
NOESY experiments all showed the absence of the
cross-peak between the resonance of the NOCH3 pro-
tons and that of 6-ArH.
The designed compounds were synthesized according to
Scheme 1.The starting hydrazide 5 was obtained by pro-
longed heating of benzoic acid ethyl ester with hydrazine
hydrate in methanol. Hydrazide 5 was reacted with car-
bon disulfide and potassium hydroxide, in ethanol,
followed by acidification to yield 5-aryl-2-mercapto-
1,3,4-oxadiazoles 6a–6o (56–89%).13 The targeted prod-
ucts 1a–1o were synthesized by reaction of oxime ether
5 with different oxadiazoles 6a–6o in the presence of
NaOCH3 in dry DMF (49–85%). The structures of
1a–1o were confirmed by element analyses, IR, 1H
NMR, 13C NMR and EI-MS spectral data.14 The (E)-con-
The fungicidal activities of the title compounds 1 were
tested at a concentration of 50 lg/ml by the modified
method from the literature.15 The five fungi used, Rhi-
zoctonia solani, Botrytis cinereapers, Gibberella zeae,
Physalospora piricola and Bipolaris mayclis, belong to
the group of field fungi and were isolated from corre-
sponding crops. The results of preliminary bioassays
were compared with that of commercial agricultural
fungicide, Kresoxim-methyl. As indicated in Table 1,
all the compounds 1a–1o showed potent fungicidal
activities against all of the fungi tested, and the fluori-
Scheme 1. Stereoselective synthesis of (E)-a-(methoxyimino)-benzeneacetate derivatives 1. Reagents and conditions: (a) MeO2C–CH@NOH,
CuSO4–Na2SO3, pH 6–7; (b) NaH, Me2SO4; (c) NBS, CCl4, reflux; (d) NH2NH2ÆH2O, reflux 6 h; (e) CS2, KOH, reflux 8 h; (f) CH3ONa /DMF,
overnight.
Table 1. Fungicidal activities of (E)-a-(methoxyimino)-benzeneacetate derivatives 1a–1o (50 lg/ml, inhibition %)
Compound
R
Inhibition %
Rhizoctonia solani
Botrytis cinereapers
Gibberella zeae
Physalospora piricola
Bipolaris mayclis
1a
1b
1c
1d
1e
1f
H
92.4
91.8
98.0
94.4
91.6
92.6
97.0
97.8
92.6
97.9
97.9
100
97.6
94.2
90.6
85.4
83.3
98.8
88.5
98.8
97.6
100
79.4
85.7
89.2
96.9
84.3
74.3
90.6
88.6
98.0
98.6
85.7
98.6
93.8
98.4
92.5
96.8
94.9
93.8
96.9
92.6
96.7
88.9
100
88.0
92.5
95.0
90.9
84.0
85.7
82.7
81.6
92.3
91.7
92.9
96.4
81.8
86.4
86.4
90.6
4-MeO
4-C6H5-CH2O
3-Cl
2,3-Cl2
2,4-Cl2
2,5-Cl2
2,4-Cl2-5-F
2-F
1g
1h
1i
100
100
1j
4-F
100
100
1k
1l
2-F-4-Br
2,3-F2
4-CF3
2-I
100
100
100
100
1m
1n
1o
95.6
90.2
85.9
66.1
84.6
96.2
88.5
97.2
96.3
96.3
98.5
4-NO2
Kresoxim-methyl

2280
Y. Li et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2278–2282
solution was completed, the stirring was continued for an
additional hour. Then the mixture was stirred at 10–20 ꢁC
for 2 h, the reaction mixture was extracted with ether.
Combined organic layers were washed with an aqueous
10% sodium bicarbonate solution then with brine, dried
over anhydrous magnesium sulfate, filtered and concen-
trated. The residue was subjected to column chromatog-
raphy using a mixture of n-hexane and ethyl acetate (4:1)
as an eluent to obtain the compound 2. (Z)-isomer (upper
spot) yield: oil, 0.22 g, 3%, IR (KBr): 3353, 1728, 1620,
nated compounds such as 1j and 1l showed activity high-
er than that of Kresoxim-methyl. In particular, all of the
tested compounds 1a–1o had more potent fungicidal
activities against R. solani than Kresoxim-methyl. These
results also demonstrated that the introduction of 1,3,4-
oxadiazole rings to the strobilurin fungicides might im-
prove their fungicidal activities.
In conclusion, 15 novel (E)-a-(methoxyimino)-benze-
neacetate derivatives were stereoselectively synthesized,
and their activities were tested. All of the tested com-
pounds showed potent fungicidal activity against all of
the fungi tested, especially it was found that compounds
1a–1o had higher fungicidal activities against R. solani
than Kresoxim-methyl.
1445, 1314, 1032, 930, 757, 732, 670 cmꢀ1 1H NMR
.
(600 MHz, CDCl3) d = 2.36 (3H, s, Ar-CH3), 3.88 (3H, s,
–COOMe),7.27–7.22 (3H, m, 3 · Ar-H), 7.32 (1H, d,
J = 7.8 Hz, 6-Ar-H). (E)-isomer (down spot) yield: oil,
3.01 g, 41%, IR (KBr): 3349, 1732, 1622, 1443, 1310, 1034,
930, 757, 730, 696 cmꢀ1 1H NMR (600 MHz, CDCl3)
.
d = 2.23 (3H, s, Ar-CH3), 3.83 (3H, s, –COOMe), 7.15
(1H, d, J = 7.8 Hz, 3-Ar-H), 7.25–7.28 (2H, m, 2 · Ar-H),
7.33 (1H, t, J = 7.2 Hz, 4-Ar-H), 10.15 (1H, s, –OH).
13. Abdou, N. A.; Amin, F. M.; Mansoura, A. J. Pharm. Sci.
1990, 6, 25.
Acknowledgment
14. General procedure for synthesis of (E)-a-(methoxyimino)-
benzeneacetate derivatives 1a–1o: compounds 6a–6o
(4.6 mmol) were added to a solution of MeONa 0.25 g
(4.6 mmol) in 10 ml absolute methanol and then refluxed
for 0.5 h. After the methanol was removed under reduced
pressure, to the residue were added dry DMF (30 ml) and
1.20 g (4.2 mmol) of compound (E)-4 and then stirred at
room temperature overnight. The mixture was mixed with
water and extracted with ethyl ether, combined organic
layers were washed with an aqueous 5% NaOH solution
then with brine, dried over anhydrous magnesium sulfate,
filtered and concentrated. The residue was subjected to
column chromatography using a mixture of benzene and
ethyl acetate (8:1) as an eluent or crystallized from
absolute ether to obtain compound (E)-1.
This work was financially supported by the Natural
Science Foundation of Hubei Provincial Department
of Science and Technology (2002AB091).
References and notes
1. Sauter, H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1328, and references cited therein.
2. Bartlett, D. W.; Clough, J. M.; Godwin, J. R. Pest.
Manag. Sci. 2002, 58, 649.
3. Becker, W. F.; von Jagow, G.; Anke, T.; Steglich, W.
FEBS Lett. 1981, 132, 329.
4. (a) Kuhnt, D.; Heinemann, U.; Gayer, H.; Gerdes, P.;
Stetter, J.; Tiemann, R.; Stenzel, K.; Dutzmann, S. DE
19,508,513, 1996; (b) U.S. 6,194,464, 2001.
Compound 1a: 80%; mp 242.1–243.3 ꢁC. IR (KBr) m: 3050,
1
2963, 1727, 1602, 1068, 1017 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.90 (s, 3H, COOMe), 4.09 (s, 2H, NOCH3),
4.41 (s, 3H, SCH2–), 7.18 (d, J = 7.2 Hz, 2H, 6-ArH),
7.37–7.43 (m, 5H, 30, 40, 50 and 4, 5-ArH), 7.63 (d, 2H,
J = 7.2 Hz, 3-ArH), 7.98 (d, J = 7.2 Hz, 2H, 20and 60-
ArH). 13C NMR (150 MHz, CDCl3) d = 35.2, 53.7, 64.4,
124.1, 127.1, 128.6, 129.1, 129.5, 130.4, 130.7, 131.0, 132.1,
134.5, 149.5, 163.7, 164.4, 166.3. MS (70 eV) m/z (%): 351
5. Clough, J. M.; Godfrey, C. R. A.; Fraine, D. J. DE
472,300, 1991.
6. (a) Rossi, R.; Carpita, A. Tetrahedron 1999, 55, 11343(b)
Ziegler, H.; Neff, D.; Stutz, W. W.O. 9,520,569, 1995.; (c)
Hayase, H.; Kataoka, T.; Takenana, H.; Ichinari, M.;
Masoko, M.; Takahashi, T.; Tanimoto, N. EP-A 398,692
1989.
7. Chen, H.; Li, Z.; Han, Y. Agric. Food Chem. 2000, 48, 5312.
8. Zou, X.-J.; Lai, L.-H.; Jin, G.-Y.; Zhang, Z.-X. Agric.
Food Chem. 2002, 50, 3757.
9. (a) Vossoghi, M.; Akbarzadeh, T.; Fallah, A.; Fazeli, M.
R.; Jamalifar, H.; Shafiee, A. J. Sci. I. R. Iran. 2005, 16,
146; (b) Ali, A. E.; Omar, A. A.; Mohamed, A.; Jochen, L.
Bioorg. Med. Chem. 2004, 12, 5107; (c) Fliur, M.;
Ghenadie, R.; Serghei, P.; Alexandru, G.; Eugenia, S.;
Ludmila, V.; Nathaly, S.; Fatma, K.; Anatholy, D.;
Robert, R. Bioorg. Med. Chem. 2005, 13, 4842; (d) Miara,
H. K. Arch. Pharm. 1983, 316, 487.
10. (a) Beech, W. F. J. Chem. Soc. 1954, 1297(b) Jolad S. D.;
Rajagopalan S. Org. Synth., Coll. Vol. 5, 139.
11. Herr, R. J.; Fairfax, D. J.; Meckler, H. Org. Process Res.
Dev. 2002, 6, 67.
(MꢀCH3O+,
0.1),
206
(M–HetS+,
3.7),
116
(N„CArCH2+, 4.2), 105 (ArC„N+, 100), 77 (59.8), 40
(50.0). Anal. Calcd for C19H17N3O4S: C, 59.52; H, 4.47;
N, 10.96. Found: C, 59.63; H, 4.26; N, 10.77.
Compound 1b: 76%, mp 111.2–111.9 ꢁC. IR (KBr) m: 3051,
1
2958, 1728, 1605, 1065, 1017 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.87 (s, 3H, COOMe), 3.90 (s, 3H, OCH3),
4.09 (s, 2H, NOCH3), 4.39 (s, 3H, SCH2–), 6.81 (d,
J = 8.4 Hz, 2H, 30 and 50-ArH), 7.18 (d, J = 8.4 Hz, 2H, 20
and 60-ArH), 7.37–7.42 (m, 2H, 4 and 5-ArH), 7.63 (d, 2H,
J = 7.2 Hz, 3-ArH). 13C NMR (150 MHz, CDCl3)
d = 35.2, 53.7, 55.9, 64.4, 115.4, 128.7, 129.1, 130.3,
130.7, 130.9, 134.6, 149.5, 162.7, 163.6, 163.7, 166.3. MS
(70 eV) m/z (%): 413 (M+, 6.5), 382 (MꢀCH3O+, 18.2), 367
(MꢀHCOOCH3+), 206 (MꢀHetS+, 76.4), 131 (43.4),116
(N„CC6H4CH2+, 95.2), 89 (33.5), 59 (48.1). Anal. Calcd
12. Methyl
2-hydroxyimino-2-o-tolylacetate
2:
3.92 g
for C21H19F3N O3S: C, 58.10; H, 4.63; N, 10.16. Found:
(38 mmol) methyl 2-hydroxyiminoacetate and 17 ml water
were placed in a flask. To it were added 0.65 g (2.6 mmol)
of cupric sulfate hydrate, 0.1 g (0. 79 mmol) of sodium
sulfite, and a solution of 16 g of sodium acetate hydrate in
18 ml water. The solution is maintained at 5–10 ꢁC and
stirred vigorously. The fresh neutral diazonium salt
(38 mmol) solution was then slowly introduced into the
oxime solution. After the addition of the diazonium salt
4
C, 58.14; H, 4.59; N, 10.19.
Compound 1c: 71%; mp151.9–152.1 ꢁC. IR (KBr) m: 1040,
2949, 1727, 1601, 1060, 1011 cmꢀ1
.
1H NMR
(600 MHz,CDCl1) d = 1.90(s, 1H, COOMe), 4.09 (s, 2H,
NOCH1), 5.11 (s, 1H, OCH2Ar), 4.19(s, 2H, SCH2), 7.06
(d, J = 8.4 Hz, 2H, 10 and 50-ArH), 7.18 (d, J = 7.2 Hz,
1H, 6-ArH), 7.18–7.45 (m, 6H, J = 8.4 Hz, 5 · Ar00H and

Y. Li et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2278–2282
2281
5-ArH), 7.41 (t, J = 7.2 Hz, 1H, 4-ArH), 7.61 (d, 2H,
J = 7.2 Hz, 3-ArH); 7.91 (d, J = 7.2 Hz, 2H, 20 and 60-
ArH). 13C NMR (150 MHz, CDCl3) d = 35.0, 53.4, 64.2,
70.6, 115.5, 127.7, 128.3, 128.5, 128.7, 128.9, 130.1, 130.5,
130.7, 134.4, 136.4, 149.2, 161.6, 163.4, 163.5, 166.0. MS
(70 eV) m/z (%): 490 (M+, 15.8), 489 (M+, 13.0), 443 (62.0),
206 (MꢀHetS+, 99.7), 146 (50.7), 131 (98.1), 116
(NCC6H4CH2+, 100), 89 (97.9), 59 (48.3). Anal. Calcd
for C26H23N3O5S: C, 63.79; H, 4.74; N, 8.58. Found: C,
63.82; H, 4.71; N, 8.64.
(30.3), 173 (39.5), 147 (35.5), 116 (N„CC6H4CH2+, 42.5),
89 (17.1), 59 (16.7). Anal. Calcd for C19H15Cl2N3O4S: C,
50.45; H, 3.34; N, 9.29. Found: C, 50.39; H, 3.40; N, 9.33.
Compound 1h: 77%, mp 101.5–102.4 ꢁC, IR (KBr) m: 3043,
1
2957, 1725, 1601, 1067, 1016 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.92 (s, 3H, COOMe), 4.09 (s, 3H, N–OCH3),
4.32 (s, 2H, SCH2), 7.19 (d, J = 7.2 Hz, 1H, 6-ArH), 7.34
(t, J = 7.8 Hz, 1H, 4-ArH), 7.40 (t, J = 8.1 Hz, 1H, 5-
ArH), 7.61 (d, J = 6.6 Hz, 1H, 30-ArH), 7.64 (d, 1H, 3-
ArH), 7.75 (d, J = 7.2 Hz, 1H, 50-ArH). 13C NMR
(150 MHz, CDCl3) d = 35.3, 53.7, 64.4, 118.4, 118.6,
125.9, 129.2, 130.4, 130.7, 131.0, 131.2, 132.1, 132.7,
133.0, 134.3, 149.5, 157.6, 163.7, 165.7. MS (70 eV) m/z
(%): 470 (M+1+, 1.7), 449 (9.5), 438 (MꢀMeO+, 12.4), 425
(83.7), 423 (100), 407 (32.1), 405 (38.5), 206 (MꢀHetS+,
11.5), 193 (13.9), 191 (diClFC6H3C„O+, 22.7), 146 (10.8),
131 (4.0), 116 (NCC6H4CH2+, 26.9), 89 (13.3), 59 (15.6).
Anal. Calcd for C19H14Cl2FN3O4S: C, 48.52; H, 3.00; N,
8.93. Found: C, 48.56; H, 3.06; N, 8.86.
Compound 1d: 78%, mp 126.2–126.7 ꢁC. IR (KBr) m: 3055,
1
2965, 1725, 1601, 1065, 1017 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.91 (s, 3H, COOMe), 4.09 (s, 3H, N–OCH3),
4.41 (s, 2H, –SCH2), 7.19 (d, J = 7.2 Hz, 1H, 6-ArH), 7.39
(t, 1H, 5-ArH), 7.41 (d, 1H,J = 6.6 Hz, 3-ArH), 7.43 (t,
1H, J = 6.9 Hz, 4-ArH), 7.49 (t, 1H, J = 7.2 Hz, 50-ArH),
7.63 (d, 1H, J = 7.2 Hz, 40-ArH), 7.95 (s, 1H, 20-ArH). 13C
NMR (150 MHz, CDCl3) d = 35.2, 53.7, 64.4, 125.2,
125.6, 127.1, 128.6, 129.2, 130.7, 130.9, 131.0, 132.1,
134.1, 135.6, 149.5, 163.7, 164.9, 165.1. MS (70 eV) m/z
(%): 418 (M+, 2.4), 389 (13.7), 387 (MꢀCH3O+, 40.7), 373
(35.7), 371(100), 206 (MꢀHetS+, 69.1), 146 (20.6),
139(27.3), 116 (N„CC6H4CH2+, 20.0). Anal. Calcd for
C19H16ClN3O4S: C,54.61; H, 3.86; N, 8.23. Found: C,
54.65; H, 3.82; N, 8.27.
Compound 1i: 73%, mp 160.1–160.4 ꢁC, IR (KBr) m:3050,
1
2949, 1727, 1602, 1066, 1018 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.91 (s, 3H, COOCH3), 4.01 (s, 3H, N–
OCH3), 4.42 (s, 2H, SCH2–), 7.19 (d, J = 6.6 Hz, 1H, 6-
ArH), 7.23 (t, J = 9.0 Hz, 1H, 5-ArH), 7.28 (t, J = 7.8 Hz,
1H, 4-ArH), 7.40 (d, J = 7.8 Hz, 1H, 30-ArH), 7.41 (d,
J = 7.2 Hz, 1H, 3-ArH), 7.52 (t, J = 6.6 Hz, 1H, 50-ArH),
7.64 (d, J = 7.2 Hz, 1H, 60-ArH), 7.98 (t, J = 6.6 Hz, 1H,
40-ArH). 13C NMR (150 MHz, CDCl3) d = 35.2, 53.7, 64.4
(NOCH3), 125.1, 128.6, 129.1, 130.3, 130.8, 131.1, 133.8,
133.9, 134.5, 149.5, 159.4, 161.1, 163.0, 163.7, 165.2 (Ar0–
C@N). MS (70 eV) m/z (%): 401 (M+, 4.81), 206
(MꢀArCH@NO+, 100), 146 (20.5), 131 (14.0), 116
(N„CC6H4CH2+, 32.8), 89 (13.1), 59 (12.2). Anal. Calcd
for C19H16FN3O4S: C, 56.85; H, 4.02; N, 10.47. Found: C,
56.79; H, 4.10; N, 10.52.
Compound 1e: 80%, mp 123.2–124.3 ꢁC. IR (KBr) m: 3040,
1
2973, 1727, 1601, 1067, 1015 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.91 (s, 3H, COOMe), 4.10 (s, 3H, N-OCH3),
4.42 (s, 2H, -CH2-), 7.19 (d, J = 7.2 Hz, 1H, 6-ArH), 7.33
(t, 1H, 5-ArH), 7.38 (d, 1H, 3-ArH), 7.38–7.42 (m, 3H,
40,4 and 50-ArH), 7.68 (dd, 1H, J = 7.8 and 1.8 Hz, 40-
ArH), 7.89 (d,J = 7.8 Hz, 1H, 60-ArH). 13C NMR
(150 MHz, CDCl3) d = 35.2, 53.7, 64.4, 125.4, 128.1,
128.6, 129.1, 129.7, 130.3, 130.7, 130.9, 131.9, 133.6,
134.3, 135.5, 149.5, 163.7 (N@C–S), 164.1, 165.5
(COOMe). MS (70 eV) m/z (%): 452 (M+, 5.2), 422
(11.8), 420 (MꢀMeOH+, 14.2), 407 (83.5), 405
(MꢀCOOMe+, 100), 205 (15.4), 206 (MꢀHetS+, 9.6),
173 (diClC6H3C„O+, 18.3), 116 (N„CC6H4CH2+, 21.1),
89 (9.8), 59 (10.9). Anal. Calcd for C19H15Cl2N3O4S: C,
50.45; H, 3.34; N, 9.29. Found: C, 50.48; H, 3.43; N, 9.17.
Compound 1f: 75%, mp 108.7–109.5 ꢁC, IR (KBr) m: 3065,
Compound 1j: 85%, mp 93.3–93.9 ꢁC, IR (KBr) m: 3230,
1
2984, 1727, 1600, 1064, 1014 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.90 (s, 3H, COOCH3), 4.09 (s, 3H, N–
OCH3), 4.45 (s, 2H, SCH2–), 7.19 (m, 3H, 20, 60 and 6-
ArH), 7.39 (t, 1H, J = 5.7 Hz, 4-ArH), 7.40 (t, 1H,
J = 5.7 Hz, 5-ArH), 7.62 (d, 1H, J = 7.2 Hz, 3-ArH),
7.98 (dd, 2H, J = 9.0Hz and J = 5.40 Hz, 30 and 50-
ArH). 13C NMR (150 MHz, CDCl3) d = 35.3, 53.7, 64.4,
116.8, 116.9, 120.4, 128.6, 129.2, 129.4, 129.5, 130.4, 130.7,
130.9, 134.5, 149.5, 164.3, 164.4 (Ar06-C), 165.5
(COOMe), 166.0 (Ar0–C@N). Anal. Calcd for
C19H16FN3O4S: C, 56.85; H, 4.02; N, 10.47. Found: C,
56.88; H, 4.08; N, 10.41.
1
2982, 1726, 1599, 1060, 1010 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.91 (s, 3H, COOMe), 4.09 (s, 3H, N–OCH3),
4.42 (s, 2H, SH2–), 7.19 (d, J = 7.2 Hz, 1H, 6-ArH), 7.37–
7.43 (m, 3H, 50, 4 and 5-ArH), 7.56 (s, 1H, 30-ArH), 7.64
(d, 1H, J = 7.2 Hz, 60-ArH), 7.87 (d, 1H, J = 8.4 Hz, 20-
ArH). 13C NMR (150 MHz, CDCl3) d = 35.2, 53.7, 64.4,
121.8, 128.1, 128.5, 129.1, 130.3, 130.7, 130.9, 131.6, 131.9,
134.2, 134.3, 138.4, 149.47, 163.7, 163.8, 165.3. MS (70 eV)
m/z (%): 454 (M+2+, 2.2), 452 (M+, 3.8), 407 (17.2), 405
(23.6), 389 (13.7), 206 (MꢀHetS+, 100), 175 (23.5), 173
(diClC6H3C„O+, 27.6), 146 (50.2), 131 (60.8), 116
(N„CC6H4CH2+, 65.1), 89 (11.3), 59 (25.1). Anal. Calcd
for C19H15Cl2N3O4S: C, 50.45; H, 3.34; N, 9.29. Found:
C, 50.49; H, 3.28; N, 9.31.
Compound 1k: 64%, mp 91.5–92.5 ꢁC. IR (KBr) m: 3065,
1
2945, 1725, 1601, 1060, 1010 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.90 (s, 3H, COOCH3), 4.08 (s, 3H, N–
OCH3), 4.41 (s, 2H, SCH2–), 7.17 (d, J = 7.2 Hz, 1H, 6-
ArH), 7.37–7.44 (m, 4H, 30, 50, 60 and5-ArH), 7.62 (d, 1H,
J = 7.2 Hz, 3-ArH), 7.86 (d, 1H, J = 8.1 Hz, 4-ArH). 13C
NMR (150 MHz, CDCl3) d = 35.7 (SCH2) 53.7
(COOCH3), 64.4 (NOCH3), 127.0, 127.1, 128.6, 128.7,
129.1, 130.3, 130.7, 131.5, 134.4, 149.5, 160.7, 162.5, 163.7,
165.2. MS (70 eV) m/z (%): 480 (M+, 3.6), 451 (14.8), 449
(MꢀCOOCH3+, 12.0), 435 (11.0), 433 (81.1), 201 (25.3),
146 (12.1), 116 (N„CC6H4CH2+, 25.7), 89 (11.3), 59
(11.9). Anal. Calcd for C19H15BrFN3O4S: C, 47.51; H,
3.15; N, 8.75. Found: C, 47.52; H, 3.18; N, 8.78.
Compound 1g: 84%, mp 106.7–107.8 ꢁC. IR (KBr) m:3040,
1
2952, 1727, 1600, 1067, 1017 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.89 (s, 3H, COOMe), 4.10 (s, 3H, N–OCH3),
4.42 (s, 2H, –CH2–), 7.19 (d, J = 7.2 Hz and 1.2 Hz, 1H, 6-
ArH), 7.65 (d, J = 7.2 Hz, 1H, 3-ArH), 7.38–7.40 (m, 2H,
40 and 50-ArH), 7.42–7.47 (m, 3H, 4 and 5-ArH) 7.91 (d,
1H, J = 2.4 Hz, 60-ArH). 13C NMR (150 MHz, CDCl3)
d = 35.21 (NCH3), 36.17 (SCH2), 53.71 (COOCH3), 64.43
(NOCH3), 124.5, 128.6, 129.2, 130.4, 130.7, 130.9, 140.0,
131.7, 132.9, 133.6, 134.3, 149.5 (Ar-C@N), 163.5 (N@C–
S), 163.7 (Ar0-C@N), 165.5 (COOMe). MS (70 eV) m/z
(%): 452 (M+, 3.8), 422 (11.2), 420 (MꢀCH3O+, 14.8), 407
(86.0), 405 (100), 206 (MꢀHetS+, 63.5), 205 (94.5), 176
Compound 1l: 79%, mp 107.6–108.5 ꢁC. IR (KBr) m: 3050,
1
2955, 1726, 1600, 1066, 1013 cmꢀ1. H NMR (600 MHz,
CDCl3) d = 3.91 (s, 3H, COOCH3), 4.09 (s, 3H, N–
OCH3), 4.40 (s, 2H, SCH2–), 7.19 (d, J = 6.6 Hz, 1H, 6-
ArH), 7.28–7.74 (m, 5H, 30, 40, 50 and 3, 4-ArH), 7.80 (d,
J = 8.4 Hz, 1H, 60-ArH). 13C NMR (150 MHz, CDCl3)
d = 35.3, 53.7, 64.5, 116.6, 118.8, 123.8, 128.7, 129.2,

2282
Y. Li et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2278–2282
129.2, 130.3, 130.7, 131.1, 134.4, 149.5, 159.4, 161.1, 163.7,
2H), 7.43 (t, 1H, J = 7.5 Hz, 4-ArH), 7.61 (d, 1H,
J = 7.5 Hz,3-ArH), 7.77 (d, 1H, J = 7.8 Hz, 60-ArH),
8.04 (d, 1H, 30-ArH). 13C NMR (150 MHz, CDCl3)
d = 35.1, 53.7, 64.4, 94.5 (20-C), 128.6, 128.7, 129.1,
129.2, 130.4, 130.8, 130.9, 131.6, 132.8, 134.4, 141.8,
149.5, 163.7, 165.1, 165.7. MS (70 eV) m/z (%): 509 (M+,
0.1), 463 (8.7), 206 (MꢀHetS+, 100), 131 (100), 116(92.5),
89 (41.3). Anal. Calcd for C19H16IN3O4S: C, 44.81; H,
3.17; N, 8.25. Found: 44.78; H, 3.19; N, 8.19.
164.6, 164.9. MS (70 eV) m/z (%): 419 (M+, 1.7), 388
(14.6), 374 (100), 355 (29.3), 206 (53.3), 205 (88.4), 146
(25.7), 116 (N„CC6H4CH2+, 39.3), 89 (14.9), 59 (13.3).
Anal. Calcd for C19H15F2N3O4S: C, 54.41; H, 3.60; N,
10.02. Found: C, 54.43; H, 3.58; N, 10.08.
Compound 1m: 82%, IR (KBr) m: 3055, 2950, 1727, 1600,
1060, 1015 cmꢀ1 1H NMR (600 MHz, CDCl3) d = 3.92
.
(s, 3H, COOMe), 4.10 (s, 3H, N–OCH3), 4.45 (s, 2H,
–CH2–), 7.20 (dd, J = 7.2 Hz and J = 1.2 Hz, 1H, 6-
ArH), 7.39 (t, 1H, J = 7.2 Hz, 4-ArH), 7.42 (t, 1H,
J = 7.2 Hz, 5-ArH), 7.65 (d, J = 7.2 Hz, 1H, 3-ArH), 7.76
(d, 1H, J = 8.4 Hz, 20 and 60-ArH), 8.15 (d,
2H,J = 8.4 Hz, 30 and 50-ArH). 13C NMR (150 MHz,
CDCl3) d = 37.4, 54.2, 64.70, 126.6, 126.7, 127.1, 127.5,
128.7, 129.2, 130.4, 130.7, 130.9, 134.3, 149.8, 162.5,
161.7, 165.59. MS (70 eV) m/z (%): 451 (M+, 1.8), 420
(12.0), 406 (8.2), 173(CF3C6H5C„N+, 100), 206 (76.4),
146 (42.8), 116 (N„CC6H4CH2+, 67.2), 59 (73.1). Anal.
Calcd for C20H16F3N 3O4S: C, 53.21; H, 3.57; N, 9.31.
Found: C, 53.25; H, 3.55; N, 9.34.
Compound 1o: 64%, IR (KBr) m: 3062, 2945, 1726, 1601,
1072, 1018 cmꢀ1 1H NMR (600 MHz, CDCl3) d = 3.89
.
(s, 3H, COOMe), 4.08 (s, 2H, NOCH3), 4.37 (s, 3H, S–
CH2), 6.90–6.95 (d, J = 8.4 Hz, 2H, 30 and 50-ArH), 7.17
(d, J = 7.2 Hz, 1H, 6-ArH), 7.40 (t, 1 H, J = 7.2 Hz, 4-
ArH), 7.37 (t, 1H, J = 7.2 Hz, 5-ArH), 7.62 (d, 1H,
J = 7.2 Hz, 3-ArH), 7.78 (d, J = 8.4 Hz, 2H, 20 and 6-
ArH). 13C NMR (150 MHz, CDCl3) d = 35.3, 53.7, 64.8,
115.1, 128.7, 129.1, 130.3, 130.7, 130.9, 134.7, 149.5,
150.1, 162.6, 163.7, 165.3. MS (70 eV) m/z (%): 400 (M+,
28), 433 (MꢀCH3O+, 27.3), 229 (96.5), 206 (75.0), 171
(CF3C6H5C„N+, 19.0), 131 (100), 116 (99.7), 59 (56.0).
Anal. Calcd for C19H16N4O6S: C, 53.27; H, 3.76; N,
13.08. Found: C, 53.28; H, 3.77; N, 13.09.
Compound 1n: 49%, IR (KBr) m: 3050, 2965, 1727, 1601,
1063, 1015 cmꢀ1 1H NMR (600 MHz, CDCl3) d = 3.92
.
(s, 3H, COOMe), 4.09 (s, 3 H, N–OCH3), 4.42 (s, 2H,
–SCH2), 7.19 (d, J = 7.2 Hz, 1H, 6-ArH), 7.35–7.41 (m,
15. Wang, H.-Q.; Ding, M.-W.; Liu, Z.-J. Heteroat. Chem.
2004, 15, 333, and therein reference.