Chinese Chemical Letters  2019, Vol. 30 Issue (5): 1059-1062   PDF    
Preparation of pyrido[1, 2-c][1, 2, 4]triazole-based π-conjugated triazene as a Fe3+ ion fluorescent sensor
Dong Yia,1, Yaping Wua,1, Changyou Chena, Li Wanga, Qin Wanga,*, Lin Pua,b,*, Siping Weia,*     
a Department of Medicinal Chemistry, School of Pharmacy, Southwest Medical University, Luzhou 646000, China;
b Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
Abstract: A highly efficient coupling reaction of N-heterocyclic carbene precursors with sulfonyl azides has been developed, affording a variety of pyrido[1, 2-c][1, 2, 4]triazole-based π-conjugated triazenes. The present reaction proceeds under very mild conditions with good functional group tolerance. The resulting triazenes exhibit selective and sensitive fluorescent response toward Fe3+ ion.
Keywords: Triazene     Sulfonyl azide     Fluorescence     Iron ion     Sensor    

Triazenes are a class of versatile and unique compounds with three nitrogen atoms in a linear arrangement and a double bond between two nitrogen atoms [1]. They have found extensive applications in many areas such as protecting groups for diazonium salts and amines [2], intermediates for the synthesis of diverse heterocyclic compounds [3], masking groups [4], alkylating agents for DNA [5], photoactive materials [6], and so on. As shown in Fig. 1, most triazenes are of Type Ⅰ (linear or cyclic aliphatic) or Ⅱ (π-conjugated). The first example of a triazene originally documented was reported by Martius and Griess in 1866, fitting into the Type Ⅰ triazenes category. Whereas the Type Ⅱ triazenes were reported by Winberg and Coffman until 1965 [7]. Both types of triazenes can be easily prepared from readily available organic azides and investigated extensively [8].

Download:
Fig. 1. Types of triazenes and 1.

It was known that N-heterocyclic carbenes can react with azides to form Type Ⅱ triazenes [8]. Previously, we reported a very efficient method to make the pyrido-annulated triazolium salts 1 (Fig. 1) as precursors to a new class of N-heterocyclic carbenes [9]. The N-heterocyclic carbenes derived from 1 have exhibited diverse reactivity in the synthesis of functional organic compounds [9, 10]. Recently, we have found that in the presence of base, compounds 1 reacts with tosyl azides to form new Type Ⅱ triazenes containing the annulated pyrido unit. One of such triazenes is further found to have high selectivitiy in the fluorescent detection of Fe3+. Herein, these results are reported.

As shown in Table 1, we studied the coupling reaction of 1a with tosyl azide 2a in the presence of base in order to generate a p-conjugated triazene product. As shown in entry 1, in DMF solution, 1a reacted with 2a to give the desired triazene product 3a in 35% yield when KOtBu was used as the base after 2 h at 50 ℃. Encouraged by this result, we further explored the reaction conditions. The yield increased to 52% by lowering the reaction temperature to 20 ℃ or 0 ℃ (entries 2–3). A range of reaction solvents besides DMF were then screened (entries 4–12), with acetone being identified as the best solvent to give 3a in 92% yield. Other bases such as LiOtBu, KOH, K2CO3, DBU (1, 8-diazabicyclo [5.4.0]undec-7-ene) and Et3N were tested which were all less effective than KOtBu (entries 13–17). The reactions in entries 1–17 were all conducted under an argon atmosphere. When the reaction of entry 12 was carried out in air, it gave significantly reduced yield (entry 18).

Table 1
Optimization of conditions for the reaction of pyrido-annulated triazolium salt 1a with tosyl azide 2a.a

Subsequently, we applied the conditions of entry 12 in Table 1 for the coupling reaction of the triazolium salts 1a-c with various sulfonyl azides 2a-p to synthesize the π-conjugated triazenes 3a-r. As the results summarized in Scheme 1 demonstrated, very good to excellent yields of the expected products were obtained for the reaction of triazolium salts with benzenesulfonyl azides bearing a range of electron-rich or electron-poor groups at the ortho-, meta-or para-positions of the phenyl rings. Additionally, the naphthalene-1-sulfonyl azide, pyridine-3-sulfonyl azide and methanesulfonyl azide could also be compatible with this protocol, affording the corresponding products 3n-p with isolated yields of 90%, 87% and 95% respectively. In terms of the triazolium salts, we were delighted to find that not only the pyrido-annulated triazolium salt, but also pyrrolidin-annulated triazolium salt, could be used for this transformation to give the corresponding triazenes 3q-r in satisfactory yields.

Download:
Scheme 1. Synthesis of triazenes from the triazolium salts and the sulfonyl azides. Reaction conditions were used unless otherwise noted: triazolium salts 1a–c (0.2 μmol), sulfonyl azides 2a–p (0.22 μmol), and KOtBu (0.22 μmol) in acetone (2.0 mL) at 20 ℃ for 2 h under an Ar atmosphere. Isolated yields based on the triazolium salts 1a–c after the chromatographic purification.

NMR spectra of the above newly prepared triazenes show that only one stereoisomer is obtained although the C=N and N=N doubles are expected to have both E and Z configurations. That is, the reactions of pyrido-annulated triazolium salts with the azides are highly stereoselective. In order to determine the stereostructure of these π-conjugated triazenes, the solid-state structures of 3a and 3b were established by single-crystal X-ray diffraction analysis. As shown in Fig. 2, both compounds contain an E, E-configuration for the C=N and N=N bonds with a transoid conformation. This structure is expected to have minimum steric interaction among the substituents on the triazine unit. By analogy, we expect that other π-conjugated triazines should have structures similar to 3a and 3b.

Download:
Fig. 2. ORTEP drawings of the molecular structures of 3a (left) and 3b (right).

We then conducted a preliminary study on the optical properties of the π-conjugated triazenes (Fig. 3), and details were deposited in the Supporting information. The compound 3a absorbs at λmax = 343 nm in CH2Cl2 solution and gives an emission signal at λem = 432 nm in Britton-Robinson buffer solution (pH 7.4)/ CH3CN (95:5, v/v). Normally, the fluorescence intensities of the triazenes with electron-donor groups on the phenyl rings of benzenesulfonyl azides are stronger than that with electronwithdrawing groups (Fig. 3B and Fig. S2 in Supporting information). Consequently, the triazene 3a was chosen to examine its fluorescence response toward a variety of metal ions. As shown in Fig. 3A, 3a could give selective fluorescence quenching response to Fe3+ ions, while the addition of other tested metal ions, namely, Fe2+, Ag+, Ca2+, Co2+, Cu2+, K+, Mn2+, Ni2+, Pb2+ and Zn2+ ions, did not lead to a significant fluorescence quenching of 3a. Furthermore, the fluorescence response of several more π-conjugated triazenes bearing typical electron-donating or electron-withdrawing groups were tested with Fe3+ under the same conditions. As shown in Fig. 3B, the fluorescence quenching ratios are not obviously affected by the electronic effect of the substituents on the phenyl rings of benzenesulfonyl azides, such as 4-MeO (3b, 86%), 4-tBu (3c, 93%), 2, 4, 6-trimethyl (3d, 87%), 4-Cl (3f, 91%), 4-Br (3g, 91%), 4-CF3 (3j, 95%), 4-Ac (3k, 96%), and 4-NO2 (3 m, 96%). Moreover, 3p and 3q could also display different extents of fluorescence quenching upon the addition of Fe3+ with moderate fluorescence quenching ratios.

Download:
Fig. 3. (A) Relative fluorescence intensities of 3a (25 μmol/L) at 432 nm with Fe3+, Fe2+, Ag+, Ca2+, Co2+, Cu2+, K+, Mn2+, Ni2+, Pb2+ and Zn2+ ions (500 μmol/L) in the BrittonRobinson buffer solution (pH 7.4)/CH3CN (95:5, v/v); I and I0 are the fluorescence intensities of 3a in the presence and absence of metal ions, respectively. (B) The fluorescence intensities of 3a, 3b, 3c, 3d, 3f, 3g, 3j, 3k, 3m, 3p and 3q; the corresponding fluorescence quenching ratios ((I0-I)/I0×100%) are given in parentheses and marked in green. (C) UV–vis absorption spectra of 3a (50 μmol/L) in CH2Cl2. Fluorescence spectra of 3a (25 μmol/L) in the presence of different concentrations of Fe3+ (from top to bottom 0, 25, 75, 150, 225, 300, 375, 450, 525 and 600 μmol/L) in the Britton-Robinson buffer solution (pH 7.4)/CH3CN (95:5, v/v), inset indicates a linear range within 0–450 μmol/L.

In addition, Fig. 3C shows that as the concentration of Fe3+ was gradually changed from 0 to 600 μmol/L (0–24 equiv.) in the solution of 3a (25 μmol/L), the emission of 3a in Britton-Robinson buffer solution (pH 7.4)/CH3CN (95:5, v/v) was gradually quenched. According to the Stern Volmer plot obtained plotting I0/I values versus the concentrations of Fe3+ in the range of 0– 450 μmol/L, a linear correction was obtained. The value of the Ksv was found as 13, 360 L/mol from the linear fit data y = 0.55305 + 0.01336x. The detection limit of Fe3+ was estimated to be 2.1 μmol/L based on 3s/slope (s is the standard deviation of blank sample), which was lower than the maximal contaminant level (0.3 mg/L, 5.4 μmol/L) of Fe3+ permitted in drinking water [11]. Thus, one of the resulting π-conjugated triazenes could serve as a potential fluorescent sensor for selectively and sensitively detecting Fe3+ ion [12].

In summary, a highly efficient method has been successfully developed for the synthesis of structurally diverse π-conjugated triazenes. Under basic conditions, a broad range of pyrido[1, 2-c] [1, 2, 4]triazole-based π-conjugated triazenes could be obtained in moderate to excellent yields from the readily available triazolium salts 1 and sulfonyl azides. In addition, this approach has led to the discovery of a library of triazenes as potential fluorescent sensors for the selective detection of Fe3+ ion. Further studies on the mechanism of Fe3+ ions quenching of fluorescence from the triazenes and their potential application are ongoing.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 21302081), the Scientific Fund of Sichuan Province, China (No. 2014JQ0052). We give thanks to Professor Xiaoqi Yu (Department of Chemistry, Sichuan University) for assistance in HR-MS and X-ray crystallographic analyses.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.cclet.2019.01.013.

References
[1]
(a) S. Patil, A. Bugarin, Eur. J. Org. Chem. 5 (2016) 860-870;
(b) D.B. Kimball, M.M. Haley, Angew. Chem. Int. Ed. 18 (2002) 3338-3351.
[2]
(a) H. Jian, J.M. Tour, J. Org. Chem. 9(2005) 3396-3424;
(b) M.L. Gross, D.H. Blank, W.M. Welch, J. Org. Chem. 8 (1993) 2104-2109;
(c) E.B. Merkushev, Synthesis 12 (1988) 923-937;
(d) G. Lunn, E.B. Sansone, L.K. Keefer, Synthesis 12 (1985) 1104-1108.
[3]
(a) M.E.P. Lormann, C.H. Walker, M. Es-Sayed, et al., Chem. Commun. 12 (2002) 1296-1297;
(b) D.B. Kimball, A.G. Hayes, M.M. Haley, Org. Lett. 24 (2000) 3825-3827;
(c) S. Bräse, S. Dahmen, J. Heuts, Tetrahedron Lett. 34 (1999) 6201-6203.
[4]
(a) K.C. Nicolaou, C.N.C. Boddy, H. Li, et al., Chem.-Eur. J. 9 (1999) 2602-2621;
(b) W. Wirschun, G.M. Maier, J.C. Jochims, Tetrahedron 16 (1997) 5755-5766;
(c) J.S. Moore, Acc. Chem. Res. 10 (1997) 402-413.
[5]
(a) C. Hejesen, L.K. Petersen, N.J.V. Hansen, et al., Org. Biomol. Chem. 15 (2013) 2493-2497;
(b) F. Marchesi, M. Turriziani, G. Tortorelli, et al., Pharmacol. Res. 4 (2007) 275-287.
[6]
(a) E.C. Buruiana, A.L. Chibac, V. Melinte, et al., J. Chem. Sci. 1 (2013) 193-202;
(b) E.C. Buruiana, L. Stroea, T. Buruiana, Polym. J. 41 (2009) 694;
(c) J. Stebani, O. Nuyken, T. Lippert, et al., Die Makromol. Chem. Rapid Commun. 6 (1993) 365-369.
[7]
H.E. Winberg, D.D. Coffman, J. Am. Chem. Soc. 12 (1965) 2776-2777.
[8]
(a) S. Patil, K. White, A. Bugarin, Tetrahedron Lett. 34 (2014) 4826-4829;
(b) D. Jishkariani, C.D. Hall, A. Demircan, et al., J. Org. Chem. 7 (2013) 3349-3354;
(c) D.M. Khramov, C.W. Bielawski, Chem. Commun. 39 (2005) 4958-4960.
[9]
(a) Y. Ma, S. Wei, J. Lan, et al., J. Org. Chem. 73 (2008) 8256-8264;
(b) S. Wei, B. Liu, D. Zhao, et al., Org. Biomol. Chem. 7 (2009) 4241-4247.
[10]
S. Wei, S. Li, C. Chen, et al., Adv. Synth. Catal. 11 (2017) 1825-1830.
[11]
S. Mirlohi, A.M. Dietrich, S.E. Duncan, Environ. Sci. Technol. 45 (2011) 6575-6583. DOI:10.1021/es200633p
[12]
(a) L. Yu, Y. Qiao, L. Miao, et al., Chin. Chem. Lett. 29 (2018) 1545-1559;
(b) T. Wang, Q. Liu, Y. Gao, et al., Chin. Chem. Lett. 27 (2016) 497-501.