Synthesis and fungicidal activity of novel 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines

Article abstract of DOI:10.1016/j.bmcl.2015.05.010

Abstract A class of novel 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines was prepared by reactions of 2-methyl-6-((1,3,4-thiadiazolylamino)methyl)phenols or 4-methyl-2-((1,3,4-thiadiazolylamino)methyl)phenols and 2- or 4-nitrobenzaldehyde in t

Full text of DOI:10.1016/j.bmcl.2015.05.010

Accepted Manuscript
Synthesis and fungicidal activity of novel 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-
methyl-1,3-benzoxazines
Zi-long Tang, Zan-wen Xia, Shu-hong Chang, Zhao-xu Wang
PII:
S0960-894X(15)00460-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.010
BMCL 22700
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 November 2014
21 April 2015
6 May 2015
Please cite this article as: Tang, Z-l., Xia, Z-w., Chang, S-h., Wang, Z-x., Synthesis and fungicidal activity of novel
2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines, Bioorganic & Medicinal Chemistry Letters (2015),
doi: http://dx.doi.org/10.1016/j.bmcl.2015.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis and fungicidal activity of novel
2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines
Zi-long Tang, a, b * Zan-wen Xia,a Shu-hong Chang,a Zhao-xu Wang,a, b
a School of Chemistry and Chemical Engineering, Hunan University of Science and Technology，
Xiangtan 411201, China
b Key Laboratory of Theoretical Organic Chemistry and Function Molecule of Ministry of
Education, Hunan University of Science and Technology, Xiangtan 411201, China
*Corresponding author. Tel/fax: +86 731 58291379. E-mail address: zltang67@aliyun.com (Z. Tang)
Abstract : A class of novel 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines was
prepared by reactions of 2-methyl-6-((1,3,4-thiadiazolylamino)methyl)phenols or
4-methyl-2-((1,3,4-thiadiazolylamino)methyl)phenols and 2- or 4-nitrobenzaldehyde in the
presence of TMSCl in refluxing toluene. The electron-donating methyl group on the benzene
ring played an essential role on the reactivity of the substituted phenols, which was proved by
DFT calculation. The fungicidal activity of the resultant products were also preliminarily
evaluated, most of which displayed moderate to good fungicidal activity. Especially,
compound 6f showed 98.0％ activity against Sclerotonia sclerotiorum and Botrytis cinerea
at concentration of 25 µg/mL.
Keywords: (1,3,4-thiadiazolyl)-1,3-benzoxazines; synthesis; TMSCl; fungicidal activity
The importance of 1,3-benzoxazine derivatives in biological systems has received much
attention because of their broad biological activities, such as analgesic1, anticancer2-4,
antitumour5, antiplatelet6, antibacterial and fungicidal7-9, antituberculosis10, antihypertensive11,
and antithromobotic activities12. Particularly, some 1,3-benzoxazines are potential and orally
bioavailable CCR2 and CCR5 dual antagonist13, epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors4, anticancer agents14 and HCV NS5a inhibitor15. In addition,
2-unsubstituted 1,3-benzoxazine derivatives are important materials to prepare
phenol-formaldehyde resins16-18. Consequently, the synthesis of new 1,3-benzoxazine
derivatives with special character attracts great interests from organic chemists. Therefore,
- 1 -

many reports have been disclosed to access these chemicals in the past few decades19-26
.
Previously, we reported the synthesis of substituted 1,3-benoxazines by reactions of
2-aminomethylphenols and aromatic aldehydes with SnCl4, (CH3)3SiCl (TMSCl) as
catalysts8,27-29, and most of which showed good fungicidal activity. As a part of our
continuous project aimed at searching for new effective fungicides, we planed to prepare a
series of new 2-aryl-3-(1,3,4-thiadiazolyl)-1,3-benzoxazines. However, under the same
conditions, the reactions of 2-(1,3,4-thiadiazolylaminomethyl)phenols 4a or 4b and aromatic
aldehydes to prepare the target compounds failed. Presumably, the reactivity of
2-((1,3,4-thiadiazolylamino)methyl)phenol might be so low because of the
electron-withdrawing effect of 1,3,4-thiadiazolyl group. Alternatively, we prepared a new
class of 3-(1,3,4-thiadiazolyl)-1,3-benzoxazines by phase transfer catalyzed reactions of
2-((1,3,4-thiadiazolylamino)methyl)phenols and CH2Cl230. Interestingly, we found that
2-methyl-6-((1,3,4-thiadiazolylamino)methyl)phenol formed by introducing a methyl group
on the benzene ring can smoothly react with aromatic aldehydes under the aforementioned
conditions, affording the desired 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines
(Scheme 1). Thus, we present herein the results on the synthesis and fungicidal activity
investigation of these compounds.
Scheme 1 Synthesis of 2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines
According to the synthetic route as shown in Scheme 1, reactions of
2-amino-5-alkyl/aryl-1,3,4-thiadiazloes 2 with salicylaldehyde or substituted salicylaldehydes
with TsOH as catalyst in refluxing anhydrous ethanol smoothly gave out the corresponding
- 2 -

Schiff bases 3, which was reduced by NaBH4 to 2-((1,3,4-thiadiazolylamino)methyl)phenols
4a-4i30,31. We then tried the reaction of 4a (R1 = H, R2 = Me) with 4-nitrobenzaldehyde 5a in
toluene or THF or chloroform/cyclohexane (v:v= 1: 4) with SnCl4 as catalyst27, the reaction
did not occur at all (No. 1-3, Table 1), neither did the reaction with TMSCl as catalyst in
toluene (No. 4)28, 29. It was also observed that the reaction of 4b (R1 = H, R2 = Et) with 5a in
the presence of TMSCl or (CH3)3SiI (TMSI) in toluene or chloroform/cyclohexane (v : v= 1 :
4) failed to yield the desired product (No. 5-7). Likewise, the reaction of 4a with
formaldehyde using TMSCl as catalyst in toluene did not generate the desired product (entry
8). The main reason for these failure is possibly the low reactivity of compound 4a and 4b
caused by the electron-withdrawing nature of 1,3,4-thiadiazolyl group. Of course, the
relatively low solubility of 4a and 4b in the mentioned solvent might also lead to the failure
of the reaction. Considering the relatively higher solubility of 4a in DMF, we then carried out
the reaction of 4a with 5a in DMF with SnCl4 as catalyst. However, this reaction still did not
work (entry 9). By comparison, we considered that the solubility of compound 4a or 4b in
solvent did not play an important role in the failure of the reaction. So, we tried to introduce
an electron-donating group on the benzene ring to increase the nucleophilicity of the phenol
substrate. As expected, compound 4c with a methyl group at 2-position of the benzene ring
reacted with 4-nitrobenzaldehyde 5a in toluene in the presence of SnCl4 (20 mol%)
delivering the desired product 6d in 38 % yield (No. 10), but the reaction yield decreased to
22% in 1,4-dioxane (No. 11), and even only trace of the product was obtained in mixed
solvent of chloroform and cyclohexane (v : v= 1 : 4) (No 12). Therefore, we concluded that
toluene was a suitable solvent for the reaction. To our exciting, the reaction yield increased to
57% with TMSCl as catalyst (No 13). But in contrast, the yield decreased to 30% and 35%
with BF3.OEt2 and Sc(OTf) as catalyst, respectively (No 16, 17). Moreover, the reaction did
not work at all when TsOH was employed as the catalyst (No 15). In addition, the yield
decreased to 37% when the reaction time was shortened to 5 h (No 14). Clearly, the methyl
group on the benzene ring played an essential role on the reaction due to its electron-donating
nature, which increases the nucleophilicity of compound 4c. At the meantime, the
- 3 -

introduction of methyl group also improves the solubility of compound 4c.
Table 1 Results of the preparation of compound 6a-6n
No
1
Conditionsa
Product R1
R2
Ar
Yield/%
H
H
H
H
H
H
H
H
H
Me 4’-NO2C6H4
Me 4’-NO2C6H4
Me 4’-NO2C6H4
Me 4’-NO2C6H4
Et 4’-NO2C6H4
Et 4’-NO2C6H4
Et 4’-NO2C6H4
0
0
6a
6a
6a
6a
6b
6b
6b
6c
6a
6d
6d
6d
6d
6d
6d
6d
6d
6e
6f
SnCl4, toluene, 110°C, 13 h
SnCl4, THF, reflux, 13 h
2
3b
4
0
SnCl4, CHCl3/C6H12, 85°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, CHCl3/C6H12, 85°C, 13 h
TMSI, CHCl3/C6H12, 85°C, 13 h
TMSCl, toluene, 110°C, 13 h
SnCl4, DMF, 110°C, 13 h
0
5
0
6b
7b
8c
0
0
Me
/
0
9
Me 4’-NO2C6H4
0
10
11
12b
13
14
15
16
17
18
19
20
21
22
23
24
25
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 4’-NO2C6H4
8-Me Me 2’-NO2C6H4
8-Me Et 2’-NO2C6H4
8-Me Et 4’-NO2C6H4
8-Me n-Pr 2’-NO2C6H4
8-Me n-Pr 4’-NO2C6H4
8-Me i-Pr 2’-NO2C6H4
8-Me i-Pr 4’-NO2C6H4
6-Me Me 2’-NO2C6H4
38
22
trace
57
37
0
SnCl4, toluene, 110°C, 13 h
SnCl4, 1,4-dioxane, reflux, 13 h
SnCl4, CHCl3/C6H12, 85°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 5 h
TsOH, toluene, 110°C, 13 h
BF3.OEt2, toluene, 110°C, 13 h
Sc(OTf)3, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
30%
35%
54
60
62
59
64
58
58
55
6g
6h
6i
6j
6k
6l
- 4 -

26
27
6-Me Et 4’-NO2C6H4
57
52
6m
6n
TMSCl, toluene, 110°C, 13 h
TMSCl, toluene, 110°C, 13 h
6-Me n-Pr 4’-NO2C6H4
a n (4): n (5) = 1 : 1.3. The amount of catalyst is 20 mol% based on substituted phenols 4 for all reactions.
All the reactions were performed with a Dean Stark trap. b C6H12: cyclohexane, CHCl3/C6H12 = 1:4 (v:v). c
Formaldehyde used.
In order to explore the contribution of the methyl group on the benzene ring, we carried
out DFT calculations about the Mulliken charge of some atoms (O, N (NH), S) of compounds
4a and 4c (with a methyl group on the benzene ring) using B3LYP method with the triple-zata
basis set 6-311++G(d, p) in Gaussian03 suite of programs32. The results are summarized in
Table 2. It is clear that the biggest change in Mulliken charge is N (NH) of compound 4c,
which is two times more than that of compound 4a. Second, the Mulliken charge of S atom is
almost two fold than that of compound 4a. But, there is no change for O atom. So, it is true
that the introduction of a methyl group increases the nucleophilicity of the NH group and in
turn increases the reactivity of compound 4c, but it does not impact effect on the O atom. In
fact, the experiment results showed that introduction of a methyl group at 4-position of the
benzene ring also can enhance the nucleophilicity of the NH group.
Table 2 The Mulliken charge of O, N (NH) and S atoms of compounds 4a and 4c
Mulliken charge /au
Compound
O
N(NH)
S
-0.263
0.010
0.019
4a
N
N
N
CH3
S
H
-0.263
0.024
0.037
OH
CH3
4c
In addition, from the mechanistic point of view, it can also be understood that the yield
of the reaction catalyzed by TMSCl is higher than those of the reactions catalyzed by SnCl4
- 5 -

or by TsOH. Although TsOH can activate the carbonyl group of the aromatic aldehyde, it also
lowers the nucleophilicity of the nitrogen atom by protonating the nitrogen atom of the
aminomethylphenol. Hence, the reaction did not work27. In contrast, because of their
oxophilicity TMSCl and SnCl4 are more liable to coordinate with the oxygen atom of the
carbonyl group of the aromatic aldehyde compared to the nitrogen atom, and increase the
reactivity of aldehydes and lead to higher yield. Moreover, due to its relatively higher
oxophilicity than SnCl4, TMSCl is easier to coordinate with the oxygen atom of the carbonyl
group and finally lead to much higher yield.
Under the above optimized conditions, compounds 6e-6n were also prepared in 52-64%
yields (see Table 1). Generally, the yields mainly depended on the position of the nitro group
on the benzene ring connected with the nitrogen atom within the benzoxazine ring in the
order of para > ortho (No 13 vs 15, No 17 vs 16, No 19 vs 18) possibly because of the bigger
steric hindrance present in the latter case. Secondly, the position of the methyl group on the
benzene ring impacted influence on the yield in the order of 8-position > 6-position (No 17 vs
23, No 19 vs 24). When the methyl group is at 8-position, the nitro group at the 4′-position,
alkyl groups on the 1,3,4-thiadiazole ring affected the yields abiding the following order of
n-Pr > Et > Me (No 19 vs 17 vs 13), which corresponds to their electron-donating ability33.
1
13
The structures of all the target products were characterized by IR, H NMR, C NMR
and elemental analysis. All compounds exhibit characteristic signals appropriately (see
experimental section). This can be illustrated with compound 6e. In the IR spectra, an
absorption at 3024 cm-1 relates to the stretching vibration of C–H bond of the benzene ring,
and 1621 cm-1 for ν C=N bond, 1609 cm-1 for ν C=C bond, signal at 1366 cm−1 indicates the
presence of the NO2 group. In 1H NMR, two singlets at 2.39 and 2.29 ppm correspond to two
CH3 protons. The proton’s chemical shift of OCHN moiety of the benzoxazine ring occurs at
7.05 ppm. The downfield shift of this proton is due to the strong electronegativity of the
nitrogen and oxygen atoms. Particularly, the NCH2 proton absorbs at 4.99 and 4.15 ppm as
two doublets instead of a singlet. This fact strongly suggests the formation of the benzoxazine
13
ring, otherwise the NCH2 proton should appear as singlet. In C NMR, the carbons of 2CH3
- 6 -

group show signals at 15.76 and 15.57 ppm, signal at 45.70 for CH2N and signal at 85.54 for
OCHN.
According to SOP procedure developed by Hunan Branch of National Pesticide R&D
South Center of China34, fungicidal activity of the prepared compounds 6d–6n against
Sclerotonia sclerotiorum, Gibberella zeae, Phytophythora capsici, Alternaria alternate,
Botrytis cinerea and Rhizoctorzia solani were evaluated using the mycelium growth rate test
at concentration of 25 µg/mL. The fungicidal activity was expressed as inhibition rate (%)
and summarized in Table 3. In general, most of the compounds displayed moderate to good
activity. Compound 6f showed 98.0％ activity against Sclerotonia sclerotiorum and Botrytis
cinerea, and 61.8% activity against Gibberella zeae. This meant that compound 6f had broad
fungicidal activity. Compound 6g exhibited 70.0％ activity against Alternaria alternate.
When methyl group locates at 8-position and NO2 group at 2′-position, the alkyl group on
1,3,4-thiadiazole ring affects the activity against Sclerotonia sclerotiorum and Botrytis
cinerea following the order of Et > Me > i-Pr > n-Pr. There was no other apparent
structure-activity relationship.
Table 3 Fungicidal activity (inhibitory rate /%) of products 6d-6n*
No Prod. S. sclerotiorum G. zeae P. capsici A. alternata B. cinerea R. solani
1
2
52.0
52.0
98.0
0
20.6
20.6
61.8
0
18.6
18.6
56.0
0
26.0
26.0
26.0
70.0
26.0
26.0
0
43.8
58.4
98.0
46.0
0
0
0
6d
6e
6f
3
0
4
0
6g
6h
6i
5
0
20.6
0
0
0
6
26.0
23.1
21.9
0
18.6
25.9
0
29.2
8.8
0
7
0
31.0
0
6j
8
17.3
18.7
0
12.3
12.7
0
13.6
18.3
14.7
13.6
6k
6l
9
0
0
10
11
34.6
21.9
48.1
0
38.1
0
6m
6n
9.9
0
- 7 -

*: Activity grade: A, inhibitory rate ≥ 90%; B, 70% ≤ inhibitory rate ＜ 90%; C, 50% ≤ inhibitory rate
＜ 70%; D, ＜ 70%.
In summary, we have designed
a
kind of relatively high nucleophilicity
2-methyl-6-((1,3,4-thiadiazolylamino)methyl)phenols
4-methyl-2-((1,3,4-thiadiazolylamino)-methyl)phenols
and
compared
with
2-((1,3,4-thiadiazolylamino)methyl)phenols by introducing electron-donating methyl group
on the benzene ring, and thereby series of novel
a
2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines were prepared by reactions of the
above mentioned methyl substituted (1,3,4-thiadiazolylamino)methylphenols with 2- or
4-nitrobenzaldehyde in the presence of TMSCl. Theory calculations showed that the methyl
group on the benzene ring played an important role on the increasing reactivity of the
substituted phenols. The fungicidal activity assay showed that most of the tested compounds
displayed moderate to good fungicidal activity. Especially, compound 6f showed 98.0％
activity against Sclerotonia sclerotiorum and Botrytis cinerea at concentration of 25 µg/mL.
Acknowledgment
The authors thank the National Natural Science Foundation of China (No. 21042011, No.
21372070), the Sub-project of National Science and Technology Supporting Program of
China (2011BAE06B01) and the Scientific Research Fund of Hunan Provincial Education
Department (No. 13K089) for the financial support of this work.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://.....
References and notes
1. Kurz, T. Tetrahedron, 2005, 61, 3091.
2. Benameur, L.; Bouaziz, Z.; Nebois, P.; Bartoli, M,; Boltard, M.; Fillion, H. Chem. Pharm. Bull.
1996, 44, 605.
3. Wang, S.; Li, Y.; You, Q.; Liu, Y.; Lu, A. Bioorg. Med. Chem. 2008, 18, 4095.
4. Chen, S.; Li, X.; Wan, S.; Jiang, T. Synth. Commun. 2012, 42, 2937.
5. Urbanski, T.; Radzikowski, C. Z.; Ledochowski, Z. Nature, 1956, 178, 1351.
6. Ihmaid, S. K.; Al-Rawi, J. M. A.; Bradley, C. J.; Angove, M. J.; Robertson, M. N. Eur. J. Med.
Chem. 2012, 57, 85.
7. Ujjinamatada, R. K.; Appala, R.S.; Agasimundin, Y. S. J. Heterocyclic Chem. 2006, 43, 437.
8. Tang, Z.; Chen, W.; Zhu, Z.; Liu, H. J. Heterocyclic Chem. 2011, 48, 255.
- 8 -

9. Nemecek, P.; Mocak, J.; Lehotay, J.; Waisser, K. Chem. Papers, 2013, 67, 305.
10. Waisser, K.; Petrlikova, E.; Perina, M.; Klimesova, V.; Kunes, J.; Jr, K. P.; Kaustova, J.; Dahse,
H. M.; Mollmann, U. Eur. J. Med. Chem. 2010, 45, 2719.
11. Kajino, N.; Shibouta, Y.; Nishikawa, K.; Meguro, K. Chem Pharm Bull. 1991, 11, 2896.
12. Buckman, B. O.; Mohab, R.; Koovakkat, S. Bioorg Med Chem Lett. 1998, 8, 2235.
13. Pasternak, A.; Goble, S. D.; Struthers, M.; Vicario, P. P.; Ayala, J. M.; Salvo, J. D.; Kilburn, R.;
Wisniewski, T.; DeMartino, J. A.; Mills, S. G.; Yang, L. ACS Med. Chem. Lett. 2010, 1, 14.
14. Garg, V.; Kumar, A.; Chaudhary, A.; Agrawal, S.; Tomar, P.; Sreenivasan, K. K. Med. Chem. Res.
2013, 22, 5256.
15. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.;
Kargmam, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.;
Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. ChemMedChem. 2013, 8, 1930.
16. Tomasulo, M.; Sortino, S.; White, A. J. P.; Raymo, F. M. J. Org. Chem. 2005, 70, 8180.
17. Baqar, M.; Agag, T.; Huang, R.; Maia, J.; Qutubuddin, S.; H. Ishida, H. Macromolecules, 2012,
45, 8119.
18. Kawaguchi, A. W.; Sudo, A.; Endo, T. ACS Macro Lett. 2013, 2, 1.
19. Burke, W. J.; Murdock, K. C. Ec, G. J. Am. Chem. Soc. 1954, 76, 1677.
20. Tumtin, S.; Phucho, I. T.; Nongpiur, A.; Nongrum, R.; Vishwakarma, J. N.; Myrboh, B.;
Nongkhlaw, R. L. J. Heterocyclic Chem. 2010, 47, 125.
21. Tang, Z.; Xia, Z.; Ma, H.; Liu, H.; Ou, X. Chin. J. Appl. Chem. 2013, 30, 999.
22. Andronescu, C.; Gârea, S. A.; Deleanu, C.; Nicolescu, A.; Iovu, H. Appl. Clay Sci. 2013, 86, 99.
23. McDonagh, A. F.; Smith, H. E. J. Org. Chem. 1968, 33, 1.
24. Szatmari, I.; Martinek, T. A.; Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2004, 2231.
25. Mangion, I. K.; Chen, C.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon, I.;
Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I. Org. Lett. 2014, 16,
2310.
26. Richers, M. T.; Breugst, M.; Platonova, A. Y.; Ullrich, A.; Dieckmann, A.; Houk, K. N.; Seidel,
D. J. Am. Chem. Soc. 2014, 136, 6123.
27. Tang, Z.; Chen, W.; Zhu, Z.; Liu, H. Synth. Commun. 2012, 42, 1372.
28. Tang, Z; Zhu, Z.; Xia, Z.; Liu, H.; Chen, J.; Xiao, W.; Ou, X. Molecules, 2012, 17, 8174.
29. Tang, Z; Zhu, Z.; Yan, L.; Chang, S.; Liu, H. J. Heterocyclic Chem. 2013, 50, 1116.
30. Tang, Z.; Chang, S.; Yan, L.; Cui, M.; Liu, H. Chin. J. Org. Chem. 2012, 32, 1241.
31. Tang, Z.; Chang, S.; Yan, L.; Liu, H. Chin. J. Appl. Chem. 2012, 29, 878.
32. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
- 9 -

Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J.
A. Gaussian 03, Revision C.02; Gaussian, Inc.:Wallingford, CT, 2004.
33. Cao, C. In Substituent Effects in Organic Chemistry, Science Press, Beijin, 2003, pp 37.
34. Liu, A.; Ou, X.; Huang, M.; Wang, X.; Liu, X.; Wang, Y.; Chen, C.; Yao, J. Pest Manag. Sci.
2005, 61, 166.
- 10 -

Graphic abstract:
Synthesis and fungicidal activity of novel
2-aryl-3-(1,3,4-thiadiazolyl)-6(8)-methyl-1,3-benzoxazines
Zi-long Tang * Zan-wen Xia Shu-hong Chang Zhao-xu Wang
14