4
Tetrahedron Letters
Conclusion
designed ,addition of 2.0 equivalents free radical scavengers ,
such as 2,2,6,6-tetramethylpiperidine oxynitride (TEMPO) or
2,6-di-tert-butyl-4 Methylphenol (BHT), there was no
In summary, we have reported a novel metal-free approach to
-
the synthesis of 1,3,5-triazine derivatives in moderate to good
yields by using elemental sulfur to promote the cyclization of
benzyl chlorides and amidines. By changing the stoichiometry of
benzyl chlorides, amidines, elemental sulfur and base, an
effectively alternative approach to access 1,2,4-thiadiazoles has
also been developed (Scheme 4). Detailed mechanistic studies
and extension to other heteroaromatic substrates of this protocol
are under way in our laboratory.
significant decrease in the yield of 1,3,5-triazine product 3aa or
1,2,4-thiadiazole 4aa, which confirmed that the reaction process
does not include free radical step (Scheme 2, eq 3 and eq 4 ).
NH·HCl
NH2
S
N
1
S
8(0.75eq), KOH, DMSO
2, 130 oC, 24 h
Cl
N
+
N
N
+
N
N
1a
2a
4aa
, trace
3aa
, 42%
NH·HCl
NH2
S
N
N
2
S
8(5eq), Na2CO3, DMSO
2, 120 oC, 24 h
NH·HCl
NH2
Cl
+
N
N
+
S
S
8 (0.75 equiv)
N
Cl
S
8 (5.0 equiv)
N
N
N
+
N
N
KOH, DMSO
Na2CO3, DMSO
N
4aa
, 53%
2a
1a
3aa
, 13%
60%
82%
NH·HCl
NH2
S
8(0.75eq), KOH, DMSO
Cl
+
N
N
3
N
2, 130 oC, 24 h
Scheme 4 The synthesis of 1,3,5-triazine and 1,2,4-
N
1a
2a
3aa
thiadiazole.
TEMPO (2 equiv)
BHT (2 equiv)
78%
80%
Acknowledgments
NH·HCl
NH2
S
N
4
S
8(5eq), Na2CO3, DMSO
2, 120 oC, 24 h
Cl
N
We thank Major National Science and Technology Program of
China for Innovation Drug (2017ZX09101002-001-004), the Six
Talent Peaks Project in Jiangsu Province (No. 2015-SWYY-016)
and Postgraduate Research & Practice Innovation Program of
Jiangsu Province (Grant No. SJCX17_0287) for supporting this
research.
+
N
N
+
N
N
2a
1a
4aa
3aa
14%
15%
58%
59%
TEMPO (2 equiv)
BHT (2 equiv)
Scheme 2. Control experiments.
Based on the above findings, a plausible mechanism is
proposed (Scheme 3).11,
Initially, the amidine 1a’ is
16, 17
References and notes
neutralized by base from its hydrochloride salt. 1a’ and benzyl
chloride form intermediate 5 which undergoes an elimination
reaction to give intermediate 6. The subsequent nucleophilic
addition of the amino group to the electrophilic carbon center
would afford intermediate 7 and racemic aminals 8. Finally, the
thermodynamically favourable deamination may release
ammonia and dihydrotriazine 9, followed by dehydrogenative
aromatization to afford the product 3aa. On the other hand, the
intermediate 5 undergoes an isomerization reaction and reacts
with elemental sulfur, generating intermediate 10. Then,
intermediate 10 undergoes imine isomerization reaction to give
intermediate 11, and 4H-thiadiazole 12 is obtained via
intramolecular cyclization of 11 with a new C-S bond formed.
Finally, dehydrogenation of 12 forms the desired product 4aa.
1
2
(a) Lim, J.; Pyun, J.; Char, K. Angew. Chem. Int. Ed. 2015, 54, 3249;
(b) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2013,
15, 4218; (c) Liu, H.; Jiang, X. Chem. Asian J. 2013, 8, 2546; (d) Gan,
H.; Miao, D.; Pan, Q.; Hu, R.; Li X.; Han, S. Chem. Asian J. 2016, 47,
1770.
(a) Talapaneni, S. N.; Hwang, T. H.; Je, S. H.; Buyukcakir, O.; Choi J.
W.; Coskun, A. Angew. Chem. Int. Ed. 2016, 55, 3106; (b) Guntreddi,
T.; Vanjari, R.; Singh, K. N. Org. Lett. 2015, 17, 976; (c) Nguyen, T.
B.; Ermolenko, L.; Retailleau, P.; Al-Mourabit, A. Angew. Chem. Int.
Ed. 2015, 126, 13808; (d) Canfield, D. E.; Rosing, M. T.; Bjerrum, C.
Phil. Trans. R. Soc. B. 2006, 361, 1819; (e) Wang, X.; Li, X.; Hu, R.;
Yang, Z.; Gu, R.; Ding, S.; Li, P.; Han, S. Synlett 2018, 29, 219.
(a) Grande, F.; A. M.; Occhiuzzi.; Ioele, G.; Ragno, G.; Garofalo, A.
Eur. J. Med. Chem. 2018, 151, 121; (b) Fu, X.; Meng, Y.; nLi, X.;
Stepien, M.; Chmielewski, P. J. Chem. Commun. 2018, 54, 2510; (c)
Li, X.; Meng, Y.; Yi, P.; Stępień, M.; Chmielewski, P. J. Angew.
Chem. Int. Ed. 2017, 56, 10810.
(a) Srivastava, J. K.; Pillai, G. G.; Bhat, H. R.; Verma, A.; Singh, U.
P. Sci. Rep. 2017, 7, 5851; (b) Mibu, N.; Yokomizo, K.; Koga, A.;
Honda, M.; Mizokami, K. Chem. Pharm. Bull. 2014, 62, 1032; (c)
Bhat, H. R.; Gupta, S. K.; Singh, U. P. RSC Adv. 2012, 2, 12690.
(a) Lee, C. R.; Faulds, D.; Drugs 1995, 49, 932; (b) Weintraub, P. G.
Ann. Appl. Biol. 2010, 135, 547.
(a) Wheeler, H. L.; Johnson, T. B.; Mcfarland, D. F. J. Am. Chem.
Soc. 1903, 25, 787; (b) Xu, F.; Zhu, X.; Shen, Q.; Lu, J.; Li, J. Chin.
J. Chem. 2002, 20, 1334; (c) Hung, M.; Long, L.; Yang, Z. J. Org.
Chem. 2004, 67, 198; (d) Goettmann, F.; Fischer, A.; Antonietti, M.;
Thomas, A. New J. Chem. 2007, 31, 1448; (e) Dzik, K. R.; Rapta, P.;
Cywinski, P. J.; Beckert, R. Dunsch, L. Electrochim. Acta 2010, 55,
4858.
3
4
NH
H
2N
Ph
Ph
Ph
N
N
Ph
NH
NH
NH2
Ph
N
N
NH
Ph
NH
H
Ph
NH2
6
Ph
8
7
H2S
O2/Sn
NH
Cl
NH3
HN
Ph
Ph
5
6
NH2
Ph
NH
NH
5
1a'
N
Ph
N
Ph
Sn
-H
KOH
9
N
Ph
NH·HCl
NH2
O2/Sn
H2S
Ph
NH
Sn
Ph
N
N
N
10
1a
Ph
Ph
3aa
7
8
Biswas, S.; Batra, S. Eur. J. Org. Chem. 2012, 2012, 3492.
Xie, F.; Chen, M.; Wang, X.; Jiang, H.; Zhang, M. Org. Biomol.
Chem. 2014, 12, 2761.
You, Q.; Wang, F.; Wu, C.; Shi, T.; Min, D.; Chen, H.; Zhang, W.
Org. Biomol. Chem. 2015, 13, 6723.
2 S2- + 4 H+
Ph
S
N
Ph
2 S
Ph
-Sn-1
H+
HN
N
Ph
NH
S
N
Ph
Ph
N
H
9
Sn
4aa
11
12
Scheme 3. Plausible Mechanism.
10 Tiwari, A. R.; Akash, T.; Bhanage, B. M. Org. Biomol. Chem. 2015,
13, 10973.
11 Tiwari, A. R.; Bhanage, B. M. Green Chem. 2016, 18, 144.