Synthesis of Triazolodiazepinium Salts: Sequential [3++2

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Synthesis of Triazolodiazepium Salts: Sequential [3++2] Cycloaddition-rearrangement Reaction of 1-Aza-2-azoniaallenium Cation Intermediates Generated from Piperidin-4-ones Lin-Bo Luan, Zi-jie Song, Zhi-Ming Li, Quan-Rui Wang, and Jing-Mei Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02742 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 2, 2018

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The Journal of Organic Chemistry

Synthesis of Triazolodiazepium Salts: Sequential [3++2] Cycloaddition-rearrangement Reaction of 1-Aza-2-azoniaallenium Cation Intermediates Generated from Piperidin-4-ones Lin-bo Luan,† Zi-jie Song,† Zhi-ming Li,† Quan-rui Wang,*,† Jing-mei Wang*,‡ †

Department of Chemistry, Fudan University, 220 Handan Road, Fudan University, Shanghai 200433, People’s Republic of China ‡

Research Centre for Analysis and Measurement, 220 Handan Road, Fudan University, Shanghai 200433, People’s Republic of China

ABSTRACT: The bicyclic 1-aza-2-azoniaallenium salt intermediates, generated from the azoester species upon treatment with a Lewis acid, have been demonstrated to participate in Huisgen-type cycloaddition with nitriles to result in the formation of fused 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinum salts. This transformation is interpreted as a regular [3++2] cycloaddition between intermediates as the reactive 1,3-monopole reactants and nitriles as the nucleophilic reagents followed by spontaneous [1,2]-cationic rearrangement. The azoester precursors were easily accessible via oxidation of the corresponding hydrazones using hypervalent iodine oxidant PhI(OAc)2 under mild conditions. The [1,2,4]triazolodiazepine compounds represent a class of N-containing biologically important heterocycles with a new type of scaffold.

■

INTRODUCTION

[1,4]-Diazepines fused with an additional five-membered heterocycle such as triazole constitute privileged building blocks which illustrate a wide range of biological activities and have drawn considerable attention in the past decades (Figure 1. I).1-6 For example, 5H-[1,2,4]triazolo[4,3-d][1,4]diazepines (Figure 1. II) have been introduced in N-heteroaryl sulfonamides series as inhibitors of Bcl-2 family for a large and important class of potential therapeutic areas like cancer.7,8 In a particular case, compound II-A comprising the core II showed potent Bcl-2 inhibitor with an IC50 of 25 nM. However, this compound had a cell potency of LD50 3.47 µM.7 Compounds carrying a core II were also designed as 11β-hydroxysteroid dehydrogenase inhibitor for the treatment of diabetes, obesity and dyslipidemia.9 Recently, new members of this family comprising a 6,7,8,9-tetrahydro-5H[1,2,4]triazolo[1,5-d][1,4]diazepine (Figure 1. III) core have been explored for use as autotaxin (ATX) and lysophosphatidic acid (LPA) inhibitors to treat different pathophysiological conditions related to the ATX/LPA axis.10 An example for III (III-A) is also presented in Figure 1. The inhibitory activities (IC50) against ATX for III-A was found to be 0.006 µM. Although valuable pharmaceutical activities have been connected to the structure III, few reports can be found in the literature describing the construction of them. To the best of our knowledge, the published strategy for the construction of the bicyclic heterocycles III, presented only in a patent.10 A schematic illustration of this strategy is given in Scheme 1. It starts with condensation of 2-hydroxyethylhydrazine and alkyl 2-amino-2-thioxoacetates to give the (2Z)-2-amino-2-(2hydroxyethylhydrazono)acetates, which are further converted to the [1,2,4]triazole intermediates by treatment with N-protected β-aminopropanoyl chloride. Final build-up of the [1,4]-diazepine ring is based upon the intramolecular substitution of the pendent amino and the hydroxyl moieties. However, this protocol gave low overall yield, requires multiple steps, and structural diversification seems to be inconvenient. In order to achieve structural modulation, to enhance activities, to modify profiles, or to expand into new intellectual property space in drug R&D, the development of a general and facile synthesis to provide structural diversity from readily available starting materials is highly desirable. In the 1990s, one of us and Jochims et al. first described 1-aza-2-azoniaalene salts as a type of positively charged monopoles with three-center and 4π-electron in character, and exploited these as useful synthetic blocks for the preparation of [1,2,4]triazolium salts by reaction with nitriles.11 Later, Wang and coworkers expanded this strategy to the synthesis of trifluoromethyl-containing [1,2,4]triazolo[1,5-a]azepine derivatives.12 Recently, Brewer’s group have developed an

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intramolecular version of 1,3-dipolar cycloaddition of 1-aza-2-azoniaalene salts tethered to an olefin moiety.13 They have shown that cationic 1-aza-2-azoniaallene salts react intramolecularly with pendent alkenes by a variety of mechanistically distinct pathways leading to novel classes of N-containing heterocycles. For example, bicyclic diazenium salt products by intramolecular + [3++2] cycloaddition and 1,2,3,4-tetrahydrocinnoline products by polar [4 +2] cycloaddition have been reported. Quite recently, evidence of the nitrenium-like character of 1-aza-2-azoniaallene salts from the [2+1]-cycloaddition with the alkene followed by ring opening has also been disclosed.14

Figure 1. General structure of diazepines fused with aromatic five-membered heterocycles (I) and triazolodiazepines (II, III) and selected examples Scheme 1. The Reported Strategy for Construction of 6,7,8,9-Tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepines

Given the potential value of the [1,2,4]triazolo[1,5-d][1,4]diazepine framework in drug research, we decided to develop new strategy to synthesize the closely related isomeric triazolodiazepines, i.e. 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5d][1,4]diazepines (Figure 1. III). We envisioned that these novel bicyclic diazepine derivatives could be obtained and diversified from easily available piperidin-4-ones via the [3++2] cycloaddition followed by a spontaneous ring expansion via a [1,2]-alkyl shift. The synthesis route is shown in Scheme 2.


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Scheme 2. Route for Preparation of Bicyclic [1,2,4]Triazolo[1,4]diazepinium Salts

■ RESULTS AND DISCUSSION To date, geminal chloroazo compounds have been employed frequently as precursors of cationic intermediate 5 for use in the [3++2] cycloaddition.11,15 Thus, as an initial trial, we successfully prepared the required piperidone arylhydrazones 3 by condensation of the N-substituted piperidin-4-ones 1 with arylhydrazines 2 under catalysis of acetic acid, which were to serve as substrates for oxidation. In view of the fact that tert-butyl hypochlorite is stable, easy to prepare, and a very useful oxidizing reagent,11-16 at the offset of this work, the various hydrazones 3 containing different blocking group at the N-4 atom, including acyl and alkyl substituents, were allowed to react with tert-butyl hypochlorite to create the respective chloroazo compounds. However, all these attempts were unsuccessful. The reaction always produced a complex product mixture. This may be due to the instability of the expected chloroazo derivatives. As a consequent, we were unable to obtain sufficiently pure chloroazo intermediates for a satisfied cycloaddition reactions. The anomalous behavior of piperidone arylhydrazones has also documented in several other transformations.17 To solve this problem, we modified the precursors to α-acetoxyazo species.18 To access the α-acetoxy-azo species, we chose to use the commercially available hypervalent iodine compound PhI(OAc)2 as the oxidizing agent which has been well documented.19 It should also be noted that oxadiazole and oxadiazoline derivatives may be produced when ketone and aldehyde N-acylhydrazones were subjected to reaction with PhI(OAc)2 in alcohol.20 Taking into account these reports, we initiated our investigation on reaction condition screening with 1-acetylpiperidin-4-oneꞌs hydrazone 3a as the model substrate. We found that 3a could be converted to the corresponding azoester compound 4a in the presence of a slight access of PhI(OAc)2 (1.2 eq.) upon reaction for 0.5 h in CH2Cl2, however, in a low yield of 31%. An appreciably better yield of 36% was obtained when prolonging the reaction time to 8 h. A literature survey suggested that acetic acid might be capable of accelerating the oxidation process of hydrazones.21 Therefore, we decided to perform the reaction in neat acetic acid. To our delight, the reaction proceeded much faster and reached completion in 15 min, affording the α-acetoxylation product 4a in high yield of 91%. Thus, the optimal oxidation condition for preparation of the azoester compounds 4 was identified (Scheme 3).The dramatic rate acceleration and yield increase may be due to the high local concentration of acetic acid, which serves as a nucleophile and facilitates the dissociation process of the common oxidation intermediates, i.e. (1-phenylhydrazinyl)(phenyl)-λ3-iodanyl acetate in α-acetoxylation. As a consequence, the plausible regeneration to the hydrazones is outcompeted.



Scheme 3. Optimized Conditions for the Preparation of Azoesters 4 from Hydrazones 3 by PhI(OAc)2

Analogously, the N-benzoyl-substituted α-acetoxy-phenylazo substrate 4b was prepared in 94% yield by reaction of the hydrazone 3b with PhI(OAc)2 in the medium of acetic acid. We were pleased to discover that the prerequisite α-acetoxyazo compounds 4 were sufficiently stable under ambient conditions, and general work-up via silica gel chromatography can be carried out to furnish pure and characterizable products. Thus, from these stable α-acetoxy-azo species, a robust domino [3++2] cycloaddition/rearrangement reaction sequence has been established providing the bicyclic of 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium salts. With the azoester compounds 4 in hand, we tried to synthesize the targeted bicyclic heterocycles 7. The synthesis of 7a is representative and is shown in Scheme 4. An equimolar amount of 4a was added into an ice-cooled suspension of AlCl3 and 1.4 equivalents of MeCN in CH2Cl2. Under the action of AlCl3, the 1-aza-2-azoniaallene salt 5a was generated upon departure of the acetoxy group. After stirring the mixture for 2 h at 0 °C, cycloaddition of the ionic intermediate 5a to the C≡N triple bond of MeCN gave the 3-spiro-substituted 1,2,4-triazolium salt 6a. The reaction mixture was allowed to warm to 35 °C and stirred further for another one hour, subsequent [1,2]-alkyl shift from C-3 to the electron-deficient N-2 in intermediate 6a resulted in ring expansion with insertion of one of the hydrazone nitrogen atoms into the carbon skeleton to provide 7a. This rearrangement is one of uncommon examples of migration of a substituent from carbon to electron-deficient nitrogen22. Finally, the 6,7,8,9tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate 7a was obtained as a colorless oil in 91% isolated yield. It should be noted that the counter ion in the salt had been changed from trichloro(acetoxy)aluminate to trifluoroacetate after usual aqueous work-up and chromatography on C18-column using CF3CO2H-containing mobile phase. Isolation of the target heterocycle salt as trifluoroacetate is more advantageous in terms of reducing the hygroscopicity and enhancing its storage stability. In an analogous manner, the N-benzoyl-substituted compound 7b was prepared in comparable yield through the similar approach (Scheme 3). Scheme 4. Sequential [3++2] Cycloaddition/rearrangement Reaction of Azoesters 4a,b with MeCN

Encouraged by these results and interested in the potential utility of this framework in pharmaceuticals, we then explored the scope of nitriles (Table 1) with 4a as the substrate. In the majority of cases the expected products were obtained with high yields (Table 1). Both aliphatic and aromatic nitriles participated smoothly in the reaction sequence leading to the formation of 2substituted 7-acetyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium salts 8a-r. It should be noted that the


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counter ion can be either trifluoroacetate or chloride depending upon the work-up procedure. In place of trifluoroacetic acid, the hydrochloric acid-containing mobile phase offered the chloride salts 8a-c. Like acetonitrile, cyclopropanecarbonitrile worked well in the reaction to give 8a with 87% yield. However, the reaction with fluoro- or chloroacetonitriles gave low yields of the products 8b and 8c due to the decreased nucleophilicity of the nitrile moiety. On the other hand, using phenylacetonitrile provided the 2-benzyl substituted 8d in 81% yield. For aromatic nitriles, the steric and electronic influences of substituents attached to the benzene ring on the yields of the reaction were investigated by application of differently substituted nitrile molecules. It has been found that the substitution at the para-position had little influence regardless of the electronic character, and high yields of compounds 8 were produced. The nucleophilicity of N atom of aromatic nitriles should be lower than that of aliphatic ones owing to the conjugation of the triple bond with benzene ring. Thus, it is not possible to make a definite conclusion about the impact of N-atom nucleophilicity of the employed nitriles. The influence of steric effects were also investigated. It was observed that, while facial reaction with o-, m- and p-tolunitrile resulted in the formation of the corresponding products 8l-n, the yield for o-tolyl substituted 8l was the lowest, however, the difference was small. A similar pattern was observed when 4-chloro-2-methylbenzonitrile was applied. 8o was prepared with good yield of 83%, only slightly lower than that for 8h. The reaction of compound 4a with 2,6-dimethylbenzonitrile and 2-cyano4'-methylbiphenyl gave much lower yields of the products 8q and respectively 8r. Obviously, this should be attributed to the great steric hindrance. Thus, the reaction is not so insensitive to steric effects of nitriles judging by the yields Table 1. Substrate Scope for the Synthesis of Bicyclic [1,2,4]Triazolo[1,4]diazepinium Salts 8 with Different Nitrilesa,b



a Reaction conditions: (1) 4a (1.74 mmol), R3CN (2.44 mmol), AlCl3 (2.78 mmol), anhydrous CH2Cl2 (6 mL), 0 °C , 2 h; (2) 35 °C, 1 h. bIsolated yield.

The final product 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium salts were fully characterized by appropriate spectroscopic methods. Mechanistically, the rearrangemnt of the initial adducts like 6, which bear a diazenium function, might occur in two directions: the migration to N(2) as the reported precedents and to N(4) leading to ring isomeric products. To indisputably prove the structure assigned, an X-ray crystallography analysis was carried out for the picrate of 8i′′, which was prepared by treatment of the trifluoroacetate 8i with picric acid for the sake of facilitating the cultivation of suitable single crystal. The X-ray structure 8i′′ is shown in Figure 2, which unambiguously comfirmed the structure assighment.23


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Figure 2. Crystal structure of the picrate 8i′. The displacement ellipsoids are drawn at the 30% probability level. The scope of the protocol was expanded to include several other substituted phenylhydrazones of N-protected piperidin-4-ones (Table 2). Under the standard reaction condition described above, the azoesters 4c-g were prepared in decent to moderate yields. Using acetonitrile and benzonitrile respectively as model reaction partners, the expected bicyclic [1,2,4]triazolium salts 9-13 were synthesized in general good to high yields. Again, the results were in agreement with the above observations: both aliphatic and aromatic nitriles behaves comparably good in the reaction, and the yields were satisfying without sharp difference in the electronic effect from electron-donating group like methoxy group (9a, 9b) to electron-withdrawing groups like chloro (10a, 10b) and trifluoromethyl (11a,11b). Reaction with 4g bearing a methyl group at para position provided good yields (12a, 12b), while a methyl group at ortho position exhibited a decreased reactivity (13a, 13b). Thus, the efficiency of this methodology mainly depended on the inherent steric factors of the nitrile molecules. Table 2. The Prepared [1,2,4]Triazolo[1,4]diazepinium Salts 9-13 from Substituted Phenylhydrazones 3c-ga R2 O

R2

O

N

O N N

N NH

N

N +N

Cl R3

N 9a, R3 = CH3, 88% 9b, R3 = C6H5, 83%

9-13

52% 90% 88% 84% 74%

CF3

Cl

− Cl

O N

N +N

R3

R2 4c, 4d, 4e, 4f, 4g,

−

Cl−

N +N N

3c, R2 = 4-OCH3 3d, R2 = 4-Cl 3e, R2 = 4-CF3 3f, R2 = 4-CH3 3g, R2 = 2-CH3

O

O N

Acetic acid rt, 2 h

OMe

o

(1) AlCl3, R CN, CH2Cl2, 0-35 C (2) HCl

N

PhI(OAc)2

O

3

R3

Cl

O N

N +N

−

R3

O

N

N 10a, R3 = CH3, 87% 10b, R3 = C6H5, 91%

11a, R3 = CH 3, 93% 11b, R3 = C6H5, 94%


N

N +N

Cl

Cl

−

R3

N 12a, R3 = CH3, 82% 12b, R3 = C6H5, 79%

O N

− N +N

R3

N 13a, R3 = CH3, 71% 13b, R 3 = C6H5, 67%


a b

Reaction conditions: azoesters 4 (1.10 mmol), R3CN (1.54 mmol), AlCl3 (1.76 mmol), anhydrous CH2Cl2 (6 mL), 0 °C, 2 h; (2) 35 °C, 1 h. Isolated yield.

With a reliable route to the N-acyl substituted bicyclic [1,2,4]triazolo[1,4]diazepinium salts in hand, the N-diversification was undertaken with 7a as a model point of embarkation to afford N-alkyl analogues. Although the use of N-alkyl substituted piperidin-4-ones are straightforward, the oxidation of the hydrazones had proved to be ineffective, which led to very complicated product mixture. We were gratified to find that the de-acetyl reaction was readily achieved by acidic hydrolysis in refluxing ethanol to afford the de-blocked salt 14, obtained in 87% yield. Reductive amination using formaldehyde or butyraldehyde was performed on 14, leading to the desired N-alkyl substituted products 15 in good yields (83% for 15a and 86% for 15b) (Scheme 5).

Scheme 5. Diversification of 7a to Give N-Alkyl Bicyclic [1,2,4]Triazolo[1,4]diazepinium Salts

In all cases, the products were obtained as triazolo[1,5-d][1,4]diazepinium chloride or trifluoroacetate salts according to our protocol. Although neutral free base of N-heterocycles are usually examined in the drug screening study, cationic species are also known to exhibit significant pharmaceutical properties.24 For example, imidazolium and triazolium salts have been synthesized and evaluated as Plasmodium inhibitors.24a The salts were found to be highly potent with active concentrations in the nanomolar range. To explore the mechanistic pathway, a theoretical investigation on the reaction between α-acetoxy-phenylazo compound 4a and acetonitrile was also carried out. The calculation was performed using density functional theory at the B3LYP/6-31++G(d,p) level of Gaussian03 program package with continuum solvent model.25,26 The transition states (TS) were optimized using the Berny algorithm, whereas harmonic frequency calculations were carried out to verify the nature of the stationary points. Only one possible pathway was obtained. As shown in Figure 3, the results postulated a three-step reaction mechanism. According to this proposed mechanism, the key intermediate 1-aza-2-azoniaallene cation 5a was generated from the complex 16 via TS1 (Transition state 1), which was derived from α-acetoxy-phenylazo compound 4a by coordination with AlCl3. Then the isolated electron pair on N atom of acetonitrile firstly attacks the carbon atom of the carbocation center in 5a, leading to the formation of complex 17, which cyclizes via TS2 by a concerted but asynchronous pathway to furnish the initial adduct, i.e. the 3-spirosubstituted 1,2,4-triazolium salt 6a. Subsequent [1,2]-shift at C via TS3 to the electron-deficient N of [1,2,4]triazolium salt forms the isolated [1,2,4]triazolo[1,4]diazepinium salts 7a. Considering the huge difference of global electrophilicity (∆ω) between azocarbenium ions and nitriles, this asynchronous concerted cyclization should be classified as a “[1,3]-dipolar cycloaddition with reverse electron demand” (“Type III” according to Sustmann’s classification), and governed by the HOMOnitriles-LUMOazocarbenium ion interaction.27 From the reduced density gradient (RDG) analysis,28 the weakly electrostatic attraction is expected due to the lower electron density surface area between nitriles and azocarbenium in 17 (Figure 4a). The lengths of the two forming bonds in 17 are 3.483 Å and 4.143 Å, respectively. The angle of the skeleton atoms (N-N-C) of azocarbenium ion turns to be 163.0° from the original 178.8°. With the reaction progression, in the TS2, the azocarbenium bend its skeleton atoms (N-N-C) in order to approach nitriles more closely. The angle of N-N-C is 129.0°, the distance of two forming bonds are 1.916 Å and 2.724 Å, respectively, which is very close to 6a. It is in agreement with RDG analysis, the density of isosurface which lies between nitriles and azocarbenium raised and another weak density surface reveals (Figure 4b). It indicated that the interactions between two fragments in TS2 are strongly electrostatic attractive and the weakly repulsion near the ring center. This suggests that in the concerted process, one C-N bond forming is more advanced than another bond C-N. Hence, the transition state is in-between a concerted and a stepwise process which can be described generally as asynchronous concerted pathway.


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O N O N

O

N N

− O

+ O

N

0.0 O

4a

N

−

N

Al

Cl

N+

Cl

Cl

O Cl Cl

N

Al

O

−

+ N

Cl

O

N

-14.69

Cl

TS2 O

N

O

Cl

-26.28

TS1

-27.98

-31.01

17

16 N

Al Cl

-22.95

N

Relative Energy (kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O

TS3

-38.21 O

O

5a AlCl3(OAc)

N

N

AlCl3 O N

O

-45.03

−

O N

N

N

− AlCl3 (OAc)

N

+

6a

N

N

+

AlCl3 (OAc)

O

−

N

N N N

+ N

-74.92 7a AlCl3 (OAc)

O N

N N

+ N

Figure 3. The relative energies (using the sum of electronic and zero-point energies in kcal· mol-1) for the title reaction in nitriles


−


Figure 4. Optimized geometries and gradient isosurfaces (s = 1/2 a.u.) for (a) 17, (b) TS2. The surfaces are colored on a bluegreen-red scale according to values of sign(λ2)ρ, ranging from −0.04 to 0.02 au. Blue indicates strong attractive interactions, and red indicates strong non-bonded overlap. It should be pointed out that charge separation usually requires to explicitly consider solvent molecules. However, the present investigation employed dichloromethane as the solvent, which has a low coordination ability. The coordination of this solvent molecule is almost negligible. Continuum solvent model has thus been successfully applied in the theoretical studies on the similar reaction of 1-aza-2-azoniaalene salts, and the simulation results are in good agreement with the experimental findings.29,30

■ CONCLUSION In summary, we have developed a facial pathway for construction of various 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5d][1,4]diazepine derivatives by sequential [3++2] cycloaddition/rearrangement reactions of 1-aza-2-azoniaallenium cation intermediates which are generated from piperidin-4-one arylhydrazones. This strategy is applicable to a broad range of nitrile substrates. The N-acetyl functionality present in the diazepine moiety can be exploited for further diversification of the Nsubstitution, as demonstrated by facile de-acetylation and reductive amination. Our method provides synthetic access to a novel class of [1,2,4]triazolodiazepines, yet currently with limited representation in the literature. This structure is expected to be useful in lead compounds exploration for drug discovery applications.10

■ EXPERIENTAL SCETION General. All Reactions were carried out in oven-dried glassware under a nitrogen atmosphere. All the solvents and reagents were ordered from Sinopharm Chemical Reagent Co.. Ltd (SCRC). Commercial available reagents were used without purification. For the sequential [3++2] cycloaddition/rearrangement reactions, the solvent of anhydrous CH2Cl2 was prepared via the distillation of commercial CH2Cl2 from CaH2. 1H NMR (400 MHz) and 13C NMR (101MHz) spectra were obtained as solutions in chloroform-d (CDCl3), dimethylsulfoxide-d6 (DMSO-d6) or deuterium oixde-d2 (D2O) from a Bruker spectrometer using tetramethylsilane as an internal standard. High resolution mass spectra (HRMS) were obtained with a Bruker Micro TOF 11 spectrometer using the positive electrospray ionization (ESI) mode. Column chromatography was performed on Biotage using a pre-packed silica gel column, a detector with UV wavelength at 214 nm and 254 nm. There were two amide rotamers for aryl hydrazones, α-acetoxy-phenylazo and the final N-acyl protected products (confirmed via 1H NMR of 7a at 100 °C, see the Supporting Information) because the synthesis was started from rotamers of the acyl protected piperidin-4-one 1. The ratio of the two rotamers can be deduced from 1H NMR. General procedure for the synthesis of aryl hydrazones 3. I. Synthesis of aryl hydrazones 3a and 3b. Anhydrous sodium acetate (35.4 mmol, 1.0 equiv) was added into a mixture of N-protected piperidin-4-one 1 (35.42 mmol, 1.0 equiv) and phenylhydrazine hydrochloride 2 (35.4 mmol, 1.0 equiv) in anhydrous ethanol (80 mL) at rt. The reaction was stirred under reflux in an atmosphere of nitrogen for 3 h. Then the mixture was filtered and the filter-cake was washed with anhydrous ethanol (3 × 5 mL). The combined filtrates were concentrated and recrystallized from hot ethanol to give the desired hydrazone. In all manipulations care was taken to minimize the exposure time of the hydrazone to air. 1-Acetylpiperidin-4-one phenylhydrazone (3a). A white powder. 7.45 g, 91%. Mp 119-120 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.17 – 7.11 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 3.64 – 3.51 (m, 4H), 2.56 (t, J = 6.0 Hz, 1H), 2.47 (t, J = 5.8 Hz, 2H), 2.37 (t, J = 6.1 Hz, 1H), 2.07 (s, 1.4H), 2.03 (s, 1.6H). 13C NMR (101 MHz, DMSO-d6) δ 169.1, 168.9, 148.0, 147.0, 145.1, 129.2, 118.6, 112.7, 112.7, 46.0, 43.8, 42.1, 39.1, 33.8, 33.3, 27.4, 26.8, 21.9, 21.8. HRMS (ESI) m/z [M + H]+ calcd for C13H18N3O 232.1450, found 232.1461. 1-Benzoylpiperidin-4-one phenylhydrazone (3b). A white needle solid. 6.70 g, 93%. Mp 131-132 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (br, s, 0.5H), 8.88 (br, s, 0.5H), 7.50 – 7.41 (m, 5H), 7.17 – 7.10 (m, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 3.81 – 3.63 (m, 2H), 3.54 – 3.39 (m, 2H), 2.71 – 2.50 (m, 3H), 2.44 – 2.29 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.9, 146.9, 144.8, 136.7, 130.0, 129.2, 128.9, 127.2, 118.6, 112.7, 47.8, 45.1, 42.8, 34.5, 33.1, 27.5, 26.5. HRMS (ESI) m/z [M + H]+ calcd for C18H20N3O 294.1606, found 294.1602. II. Synthesis of arylhydrazones 3c-g. As described for the preparation of 3a and 3b. 1-Acetylpiperidin-4-one (4-methoxyphenyl)hydrazone (3c). A brown oil. 1.67 g. It was difficult to obtain the pure product and the crude residue was used for next step directly. 1-Acetylpiperidin-4-one (4-chlorophenyl)hydrazone (3d). A white powder. 1.51 g, 89%. Mp 196-197 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.21 – 7.13 (m, 1H), 7.06 – 7.01 (m, 1H), 3.62 – 3.52 (m, 4H), 2.55 (t, J = 6.0 Hz, 1H), 2.48 – 2.44 (m, 2H), 2.39 – 2.35 (m, 1H), 2.06 (s, 1.3H), 2.03 (s, 1.7H). 13C NMR (101 MHz, DMSO-d6) δ 169.1, 168.9, 146.1, 145.9, 129.0, 121.8, 114.1, 46.0, 43.8, 42.0, 39.1, 33.9, 33.3, 27.5, 27.0, 21.9, 21.8. HRMS (ESI) m/z [M + H]+ calcd for C13H17ClN3O 266.1055, found 266.1051. 1-Acetylpiperidin-4-one (4-trifluoromethylphenyl)hydrazone (3e). A white powder. 1.74 g, 91%. Mp 200-201 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 3.63 – 3.54 (m, 4H), 2.59 (t, J = 6.0 Hz, 1H), 2.49 – 2.46 (m, 2H), 2.40 (t, J = 6.1 Hz, 1H), 2.07 (s, 1.4H), 2.04 (s, 1.6H). 13C NMR (101 MHz, DMSO-d6) δ 169.1, 168.9, 149.8, 147.8, 126.6 (q, J = 3.6 Hz), 125.6 (q, J = 270.2 Hz), 118.3 (q, J = 31.8 Hz), 112.2, 45.9, 43.8, 41.9, 39.1, 33.9, 33.4, 27.7, 27.1, 21.9, 21.8. HRMS (ESI) m/z [M + H]+ calcd for C14H17F3N3O 300.1318, found 300.1315.


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1-Acetylpiperidin-4-one (4-methylphenyl)hydrazone (3f). A gray powder. 1.35 g, 86%. Mp 205-206 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.98 – 6.89 (m, 4H), 3.62 – 3.50 (m, 4H), 2.56 – 2.52 (m, 1H), 2.47 – 2.42 (m, 2H), 2.38 – 2.34 (m, 1H), 2.18 (s, 3H), 2.06 (s, 1.4H), 2.03 (s, 1.6H). 13C NMR (101 MHz, DMSO-d6) δ 169.1, 168.9, 144.8, 144.5, 129.6, 127.0, 112.8, 46.0, 43.8, 42.1, 39.1, 33.8, 33.3, 27.3, 26.8, 22.0, 21.83, 20.7. HRMS (ESI) m/z [M + H]+ calcd for C14H20N3O 246.1601, found 246.1601. 1-Acetylpiperidin-4-one (2-methylphenyl)hydrazone (3g). A brown oil. 1.57 g. It was difficult to obtain the pure product and the crude residue was used for next step directly.

General procedure for the synthesis of azoesters compound 4. I. Synthesis of azoesters compound 4a and 4b. Hydrazone 3 (21.6 mmol, 1.0 equiv) was added in portions into a mixture of iodobenzene diacetate (25.9 mmol, 1.2 equiv) in acetic acid (10 mL) at rt (exothermic). The reaction turned from colorless to yellow during stirring. After the reaction was stirred at rt for 15 min, the solution was poured into stirring ice water (20 mL) and sat. aq. NaHCO3 was added dropwise into the stirring solution under ice bath until free from acetic acid. Then the mixture was extracted with ethyl acetate (3 × 30 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (boiling point range 60-90 °C) = 1 : 1, 0.5% triethylamine in petroleum ether) to give the desired α-acetoxy-phenylazo compounds 4. 1-Acetyl-4-acetoxy-4-(phenylazo)-piperidine (4a). A light yellow oil. 5.69 g, 91%. 1H NMR (400 MHz, CDCl3) δ = 7.71 – 7.65 (m, 2H), 7.48 – 7.43 (m, 3H), 4.48 – 4.40 (m, 1H), 3.87 – 3.79 (m, 1H), 3.54 – 3.43 (m, 1H), 3.25 – 3.15 (m, 1H), 2.40 – 2.33 (m, 1H), 2.28 – 2.17 (m, 2H), 2.16 (s, 3H), , 2.05 (s, 3H), 2.08 – 1.98 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.4, 169.0, 151.2, 131.3, 129.0, 122.6, 100.0, 77.2, 42.7, 37.8, 33.3, 33.1, 21.91, 21.5. HRMS (ESI): m/z [M + Na]+ calcd for C15H19NaN3O3 312.1324, found 312.1315. 1-Benzoyl-4-acetoxy-4-(phenylazo)-piperidine (4b). A light yellow solid. 6.76 g, 94%. Mp 170-171 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.69 – 7.63 (m, 2H), 7.58 – 7.52 (m, 3H), 7.49 – 7.43 (m, 5H), 4.36 (m, 1H), 3.65 (m, 1H), 3.39 (m, 2H), 2.28 (m, 1H), 2.17 (s, 3H), 2.12 – 1.96 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.72, 169.4, 151.1, 136.4, 132.0, 130.1, 129.9, 128.9, 127.3, 122.7, 100.1, 43.9, 38.2, 33.5, 32.9, 22.0. HRMS (ESI) m/z [M + Na]+ calcd for C20H21NaN3O3 374.1480, found 374.1476. II. Synthesis of α-acetoxyazo compounds 4c-g. As described for the preparation of 4a and 4b. 1-Acetyl-4-acetoxy-4-(4-methoxyphenylazo)-piperidine (4c). A light yellow oil. 0.83 g, 52%. 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.65 (m, 2H), 6.98 – 6.91 (m, 2H), 4.46 – 4.37 (m, 1H), 3.90 – 3.76 (m, 1H), 3.86 (s, 3H), 3.53 – 3.42 (m, 1H), 3.24 – 3.14 (m, 1H), 2.40 – 2.30 (m, 1H), 2.27 – 2.10 (m, 2H), 2.15 (s, 3H), 2.06 – 1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.4, 169.0, 162.2, 145.4, 124.6, 114.1, 99.7, 55.6, 42.8, 37.8, 33.4, 33.1, 22.0, 21.5. HRMS (ESI) m/z [M + Na]+ calcd for C16H21NaN3O4 342.1424, found 342.1428. 1-Acetyl-4-acetoxy-4-(4-chlorophenylazo)-piperidine (4d). A light yellow oil. 1.46 g, 90%. 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.61 (m, 2H), 7.45 – 7.40 (m, 2H), 4.45 (dt, J = 13.5, 4.0 Hz, 1H), 3.83 (dt, J = 13.7, 3.6 Hz, 1H), 3.53 – 3.42 (m, 1H), 3.23 – 3.12 (m, 1H), 2.40 – 2.32 (m, 1H), 2.27 – 2.10 (m, 2H), 2.16 (s, 3H), 2.02 (s, 3H), 2.06 – 1.94 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.4, 169.0, 149.5, 137.3, 129.3, 124.0, 100.03, 99.99, 42.7, 37.7, 33.3, 33.0, 21.9, 21.5. HRMS (ESI) m/z [M + Na]+ calcd for C15H18NaClN3O3 346.0929, found 346.0933. 1-Acetyl-4-acetoxy-4-(trifluoromethylphenylazo)-piperidine (4e). A light yellow oil. 1.57 g, 88%. 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.70 (m, 4H), 4.57 – 4.43 (m, 1H), 3.89 – 3.80 (m, 1H), 3.54 – 3.44 (m, 1H), 3.22 – 3.13 (m, 1H), 2.42 – 2.33 (m, 1H), 2.29 – 2.12 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 2.05 – 1.97 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.5, 169.1, 153.1, 132.7 (q, J = 32.5 Hz), 126.4 (q, J = 3.7 Hz), 122.9, 123.8 (q, J = 272.4 Hz), 100.4, 42.7, 37.8, 33.3, 33.1, 21.9, 21.5. HRMS (ESI) m/z [M + Na]+ calcd for C16H18NaF3N3O3 380.1192, found 380.1190. 1-Acetyl-4-acetoxy-4-(4-methylphenylazo)-piperidine (4f). A light yellow oil. 1.27 g, 84%. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 9.8 Hz, 2H), 4.49 – 4.35 (m, 1H), 3.87 – 3.77 (m, 1H), 3.52 – 3.41 (m, 1H), 3.25 – 3.14 (m, 1H), 2.43 – 2.30 (m, 1H), 2.40 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.28 – 2.10 (m, 2H), 2.07 – 1.95 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.4, 169.0, 149.3, 141.8, 129.6, 122.6, 99.9, 42.7, 37.8, 33.3, 33.9, 21.9, 21.9, 21.5, 21.4, 21.4. HRMS (ESI) m/z [M + Na]+ calcd for C16H21NaN3O3 326.1475, found 326.1474. 1-Acetyl-4-acetoxy-4-(2-methylphenylazo)-piperidine (4g). A light yellow oil. 1.12 g, 74%. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.20 (dd, J = 7.2 Hz, 1H), 4.44 – 4.37 (m, 1H), 3.87 – 3.80 (m, 1H), 3.54 – 3.46 (m, 1H), 3.29 – 3.22 (m, 1H), 2.56 (s, 3H), 2.37 (d, J = 13.7 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 2.26 – 2.13 (m, 2H), 2.09 – 2.02 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.4, 169.0, 149.5, 137.1, 131.13, 131.09, 126.5, 115.9, 100.3, 42.7, 37.8, 33.6, 33.3, 21.9, 21.5, 17.3. HRMS (ESI) m/z [M + Na]+ calcd for C16H21NaN3O3 326.1475, found 326.1480.

General procedure for the preparation of [1,2,4]-triazolo[1,5-d][1,4]diazepiniums 7, 8, 9-13. I. Synthesis of [1,2,4]-triazolo[1,5-d] [1,4] diazepiniums 7 and 8. A solution of aryl α-acetoxy-phenylazo compound 4 (1.74 mmol, 1.0 equiv) in anhydrous CH2Cl2 (1 mL) was added dropwise slowly to a mixture of MeCN (2.44 mmol, 1.4 equiv) and AlCl3 (2.78 mmol, 1.6 equiv) in CH2Cl2 (5 mL) at 0 °C under an atmosphere of nitrogen (exothermic). After stirring at 0 °C for 2 h and 35 °C for another 1 h, the reaction was cooled to 0 °C and extracted with H2O (4 × 2 mL). The aqueous phase was concentrated and purified via reverse flash column chromatography (C18, acetonitrile/H2O = 0 to 1: 3, 0.5% CF3COOH or HCl in H2O). The collected fractions were dried via lyophilizator to afford the title compound as a colorless oil. 7-Acetyl-2-Methyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (7a). A colorless oil. 0.61 g, 91%. 1H NMR (400 MHz, DMSO-d6) δ 7.88 – 7.79 (m, 3H), 7.77 – 7.71 (m, 2H), 4.19 – 4.09 (m, 2H), 3.94 – 3.88 (m, 2H), 3.86 – 3.79 (m, 2H), 3.47 – 3.31 (m, 2H), 2.43 (d, J = 3.8 Hz, 3H), 2.15 (s, 1.5H), 2.06 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 167.0, 160.9, 160.5, 158.5 (q, J = 34.0 Hz), 157.8, 157.7, 133.7, 133.6, 131.3, 131.3, 129.6, 129.5, 129.2, 129.1, 116.8 (q, J = 295.4 Hz), 51.4, 50.7, 45.8, 44.7, 41.8, 40.8, 33.2, 32.2, 29.5, 28.4, 22.1, 22.0, 13.4. HRMS (ESI) m/z [M]+ calcd for C15H19N4O+ 271.1559, found 271.1575. 7-Benzoyl-2-Methyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (7b). A colorless oil. 0.72 g, 93%. 1H NMR (400 MHz, DMSO-d6) δ 7.87 – 7.68 (m, 5H), 7.54 – 7.38 (m, 5H), 4.32 – 4.14 (m, 2H), 4.08 – 3.97 (m, 2H), 3.81 – 3.66 (m, 2H), 3.53 – 3.32 (m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 170.9, 160.9, 160.4, 158.8 (q, J = 35.1 Hz), 157.9, 136.1, 133.6, 131.3,



130.2, 129.5, 129.1, 129.0, 127.1, 116.5 (q, J = 293.3 Hz), 50.9, 50.2, 46.9, 45.7, 42.3, 41.0, 29.3, 28.0, 13.4. HRMS (ESI) m/z [M]+ calcd for C20H21N4O+ 333.1715, found 333.1718. 7-Acetyl-2-cyclopropyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (8a). A colorless oil. 0.50 g, 87%. 1H NMR (400 MHz, DMSO-d6) δ 7.87 – 7.77 (m, 5H), 4.19 – 4.02 (m, 2H), 4.01 – 3.94 (m, 2H), 3.84 – 3.71 (m, 2H), 3.41 – 3.21 (m, 2H), 2.13 (s, 1.5H), 2.05 (s, 1.5H), 1.79 – 1.68 (m, 1H), 1.29 – 1.14 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 170.0, 169.9, 162.1, 162.0, 161.0, 160.7, 133.7, 133.6, 131.4, 131.4, 129.6, 129.5, 129.39, 129.37, 51.1, 50.4, 45.8, 44.6, 41.7, 29.6, 28.5, 22.1, 22.0, 11.0, 7.9. HRMS (ESI) m/z [M]+ calcd for C17H21N4O+ 297.1715, found 297.1717. 7-Acetyl-2-(fluoromethyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (8b). A colorless oil. 0.28 g, 49%. 1H NMR (400 MHz, DMSO-d6) δ 7.92 – 7.72 (m, 5H), 5.66 – 5.53 (m, 2H), 4.28 – 4.15 (m, 2H), 4.00 – 3.80 (m, 4H), 3.58 – 3.47 (m, 2H), 2.16 (s, 1.5H), 2.07 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.2, 170.1, 161.6, 161.3, 154.2, 154.1, 154.0, 154.0, 134.1, 134.0, 131.2, 131.2, 129.2, 129.1, 128.9, 128.9, 75.5, 74.3, 51.6, 51.0, 45.6, 44.6, 41.6, 40.7, 29.6, 28.6, 22.1, 21.9. HRMS (ESI) m/z [M]+ calcd for C15H18FN4O+ 289.1464, found 289.1457. 7-Acetyl-2-(chloromethyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (8c). A colorless oil. 0.39 g, 66%. 1H NMR (400 MHz, D2O) δ 7.83 – 7.76 (m, 1H), 7.73 – 7.67 (m, 2H), 7.59 – 7.53 (m, 2H), 4.62 (s, 2H), 4.38 – 4.19 (m, 2H), 3.98 – 3.82 (m, 4H), 3.51 – 3.33 (m, 2H), 2.15 (s, 1.8H), 2.07 (s, 1.2H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 161.9, 161.3, 156.6, 156.5, 134.5, 134.2, 131.2, 131.1, 128.3, 127.5, 127.5, 51.0, 50.5, 46.2, 44.8, 42.3, 41.1, 33.2, 28.9, 28.1, 20.8, 20.7. HRMS (ESI) m/z [M]+ calcd for C15H18ClN4O+ 305.1169, found 305.1169. 7-Acetyl-2-benzyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8d). A colorless oil. 0.65 g, 81%. 1H NMR (400 MHz, DMSO-d6) δ 7.88 – 7.74 (m, 3H), 7.74 – 7.65 (m, 2H), 7.35 – 7.23 (m, 3H), 7.17 – 7.09 (m, 2H), 4.20 – 4.03 (m, 4H), 3.97 – 3.87 (m, 2H), 3.87 – 3.73 (m, 2H), 3.49 – 3.27 (m, 2H), 2.14 (s, 1.5H), 2.05 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.0, 167.0, 161.1, 160.8, 159.0, 156.0, 158.6 (q, J = 31.2 Hz), 133.8, 133.8, 133.8, 131.3, 131.3, 129.7, 129.6, 129.4, 129.3, 129.3, 129.1, 127.9, 116.6 (q, J = 294.1 Hz), 51.6, 50.8, 45.6, 44.7, 41.7, 40.8, 32.6, 29.6, 28.5, 22.1, 21.9. HRMS (ESI) m/z [M]+ calcd for C21H23N4O+ 347.1872, found 347.1883. 7-Acetyl-2,3-diphenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8e). A colorless oil. 0.71 g, 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 – 7.74 (m, 5H), 7.64 – 7.56 (m, 1H), 7.55 – 7.44 (m, 4H), 4.29 – 4.12 (m, 2H), 4.05 – 3.94 (m, 2H), 3.94 – 3.83 (m, 2H), 3.61 – 3.40 (m, 2H), 2.17 (s, 1.5H), 2.08 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.2, 160.9, 158.7 (q, J = 34.6 Hz), 156.2, 156.1, 1340, 133.9, 133.2, 131.6, 131.6, 130.7, 130.7, 129.8, 129.8, 129.7, 129.4, 124.4, 116.6 (q, J = 294.3 Hz), 45.7, 44.7, 41.6, 40.7, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C20H21N4O+ 333.1715, found 333.1720. 7-Acetyl-2-(4-methoxyphenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8f). A colorless oil. 0.77 g, 93%. 1H NMR (400 MHz, DMSO-d6) δ 7.90 – 7.78 (m, 5H), 7.48 – 7.41 (m, 2H), 7.06 – 7.00 (m, 2H), 4.23 – 4.09 (m, 2H), 3.99 – 3.84 (m, 4H), 3.79 (s, 3H), 3.57 – 3.37 (m, 2H), 2.16 (s, 1.5H), 2.07 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 163.1, 161.0, 160.6, 158.6 (q, J = 34.5 Hz), 155.9, 155.9, 134.0, 133.9, 131.8, 131.7, 131.2, 130.98, 130.95, 129.9, 129.8, 116.6 (q, J = 294.2 Hz), 116.2, 115.3, 56.1, 50.9, 50.3, 45.7, 44.7, 41.6, 40.7, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C21H23N4O2+: 363.1821, found 363.1829. 7-Acetyl-2-(4-fluorophenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8g). A colorless oil. 0.74 g, 92%. 1H NMR (400 MHz, DMSO-d6) δ 7.89 – 7.74 (m, 5H), 7.62 – 7.53 (m, 2H), 7.41 – 7.30 (m, 2H), 4.30 – 4.11 (m, 2H), 4.03 – 3.94 (m, 2H), 3.93 – 3.81 (m, 2H), 3.61 – 3.37 (m, 2H), 2.17 (s, 1.5H), 2.08 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 164.79 (d, J = 252.7 Hz), 164.78 (d, J = 252.9 Hz), 161.2, 160.8, 158.7 (q, J = 34.3 Hz), 155.38, 155.35, 134.0, 134.0, 132.3, 132.2, 131.7, 131.6, 130.6, 130.5, 129.8, 129.7, 121.0, 120.97, 117.1 (d, J = 22.5 Hz), 117.1 (d, J = 22.5 Hz), 116.7 (q, J = 294.8 Hz), 51.1, 50.6, 45.7, 44.6, 41.6, 40.6, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C20H20FN4O+ 351.1621, found 351.1624. 7-Acetyl-2-(4-chlorophenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8h). A colorless oil. 0.74 g, 89%. 1H NMR (400 MHz, DMSO-d6) δ 7.89 – 7.75 (m, 5H), 7.63 – 7.56 (m, 2H), 7.54 – 7.47 (m, 2H), 4.30 – 4.11 (m, 2H), 4.01 – 3.81 (m, 4H), 3.62 – 3.40 (m, 2H), 2.17 (s, 1.5H), 2.08 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.2, 160.9, 158.5 (q, J = 33.6 Hz), 155.30, 155.27, 138.3, 134.1, 134.0, 131.70, 131.65, 131.2, 130.48, 130.45, 130.0, 129.8, 129.7, 123.3, 117.1 (q, J = 296.5 Hz), 51.2, 50.6, 45.7, 44.6, 41.6, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C20H20ClN4O+ 367.1325, found 367.1328. 7-Acetyl-2-(4-bromophenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8i). A colorless oil. 0.85 g, 93%. 1H NMR (400 MHz, DMSO-d6) δ 7.90 – 7.70 (m, 7H), 7.46 – 7.37 (m, 2H), 4.27 – 4.11 (m, 2H), 4.01 – 3.76 (m, 4H), 3.60 – 3.38 (m, 2H), 2.17 (s, 1.5H), 2.07 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.2, 160.9, 158.5 (q, J = 33.6 Hz), 155.42, 155.39, 134.1, 134.0, 132.9, 131.70, 131.65, 131.3, 130.5, 130.4, 129.73, 129.66, 127.4, 127.3, 123.6, 116.9 (q, J = 296.0 Hz), 51.2, 50.6, 45.7, 44.6, 41.56, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C20H20BrN4O+ 411.0820, found 411.0831. 7-Acetyl-2-(4-iodophenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8j). A colorless oil. 0.90 g, 90%. 1H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.87 (m, 2H), 7.87 – 7.83 (m, 1H), 7.82 – 7.79 (m, 2H), 7.79 – 7.77 (m, 2H), 7.27 – 7.22 (m, 2H), 4.27 – 4.11 (m, 2H), 4.02 – 3.79 (m, 4H), 3.58 – 3.39 (m, 2H), 2.17 (s, 1.5H), 2.08 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.2, 160.9, 158.5 (q, J = 33.7 Hz), 155.7, 155.6, 138.7, 134.1, 134.0, 131.7, 131.7, 130.9, 130.49, 130.45, 129.7, 129.6, 123.8, 116.9 (q, J = 295.9 Hz), 101.9, 101.8, 51.1, 50.6, 45.7, 44.6, 41.6, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C20H20IN4O+ 459.0682, found 459.0680. 7-Acetyl-2-(4-trifluoromethylphenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8k). A colorless oil. 0.82 g, 92%. 1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.76 (m, 7H), 7.75 – 7.68 (m, 2H), 4.33 – 4.18 (m, 2H), 4.03 – 3.84 (m, 4H), 3.64 – 3.43 (m, 2H), 2.18 (s, 1.5H), 2.09 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.4, 161.1, 158.3 (q, J = 31.5 Hz), 154.99, 154.96, 134.13, 134.09, 132.7 (q, J = 33.9 Hz), 131.7, 131.6, 130.5, 130.28, 130.25, 129.74, 129.68, 128.4, 126.69, 126.66, 123.9 (q, J = 272.9 Hz), 117.5 (q, J = 299.3 Hz), 51.3, 50.73, 45.7, 44.6, 41.6, 29.5, 28.5, 22.1, 22.0. HRMS (ESI) m/z [M]+ calcd for C21H20F3N4O+ 401.1589, found 401.1635.


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7-Acetyl-2-(o-tolyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8l). A colorless oil. 0.69 g, 86%. 1H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.60 (m, 5H), 7.45 – 7.31 (m, 2H), 7.31 – 7.16 (m, 2H), 4.34 – 4.16 (m, 2H), 4.11 – 3.83 (m, 4H), 3.62 – 3.35 (m, 2H), 2.34 (s, 3H), 2.19 (s, 1.5H), 2.10 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.0, 160.6, 158.6 (q, J = 34.0 Hz), 157.2, 157.1, 138.7, 138.6, 133.4, 133.4, 132.2, 131.3, 131.00, 130.95, 130.5, 130.1, 130.0, 129.54, 129.46, 126.3, 124.23, 124.20, 116.8 (q, J = 295.2 Hz) 51.9, 51.2, 45.6, 44.7, 41.7, 40.9, 29.7, 28.6, 22.1, 22.0, 19.8. HRMS (ESI) m/z [M]+ calcd for C21H23N4O+ 347.1872, found 347.1881. 7-Acetyl-2-(m-tolyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8m). A colorless oil. 0.75 g, 94%. 1H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.75 (m, 5H), 7.48 – 7.28 (m, 3H), 7.26 – 7.07 (m, 1H), 4.32 – 4.09 (m, 2H), 4.04 – 3.79 (m, 4H), 3.61 – 3.35 (m, 2H), 2.26 (s, 3H), 2.17 (s, 1.5H), 2.08 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.1, 160.9, 158.7 (q, J = 34.5 Hz), 156.19, 156.15, 139.3, 133.94, 133.89, 131.60, 131.55, 130.8, 130.7, 129.9, 129.83, 129.76, 129.5, 126.3, 124.3, 116.7 (q, J = 294.4 Hz), 51.11, 50.53, 45.69, 44.65, 41.57, 40.67, 29.54, 28.52, 22.10, 22.00, 21.21. HRMS (ESI) m/z [M]+ calcd for C21H23N4O+ 347.1872, found 347.1884. 7-Acetyl-2-(p-tolyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8n). A colorless oil. 0.73 g, 91%. 1H NMR (400 MHz, DMSO-d6) δ 7.88 – 7.75 (m, 5H), 7.41 – 7.35 (m, 2H), 7.32 – 7.25 (m, 2H), 4.25 – 4.09 (m, 2H), 4.00 – 3.83 (m, 4H), 3.58 – 3.38 (m, 2H), 2.32 (s, 3H), 2.17 (s, 1.5H), 2.07 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.1, 160.8, 158.6 (q, J = 34.5 Hz), 156.18, 156.16, 143.8, 143.8, 134.0, 133.9, 131.7, 131.6, 130.81, 130.77, 130.3, 129.82, 129.75, 129.3, 121.5, 116.7 (q, J = 294.6 Hz), 51.0, 50.5, 45.7, 44.7, 41.6, 40.7, 29.5, 28.5, 22.1, 22.0, 21.2. HRMS (ESI) m/z [M]+ calcd for C21H23N4O+ 347.1872, found 347.1882. 7-Acetyl-2-(4-chloro-2-methylphenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8o). A colorless oil. 0.71 g, 83%. 1H NMR (400 MHz, DMSO-d6) δ 7.80 – 7.61 (m, 5H), 7.51 (s, 1H), 7.37 – 7.21 (m, 2H), 4.32 – 4.15 (m, 2H), 4.07 – 3.83 (m, 4H), 3.60 – 3.38 (m, 2H), 2.35 (s, 3H), 2.19 (s, 1.5H), 2.10 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.1, 160.7, 158.6 (q, J = 34.1 Hz), 156.19, 156.15, 141.4, 141.3, 137.0, 133.6, 133.5, 132.3, 131.2, 131.1, 131.2, 129.9, 129.9, 129.5, 129.4, 126.6, 123.1, 123.1, 116.8 (q, J = 295.3 Hz), 51.90, 51.17, 45.57, 44.66, 41.66, 40.85, 29.69, 28.55, 22.12, 22.00, 19.59. HRMS (ESI) m/z [M]+ calcd for C21H22ClN4O+ 381.1482, found 381.1489. 7-Acetyl-2-(2-fluoro-5-methylphenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8p). A colorless oil. 0.73 g, 88%. 1H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.64 (m, 5H), 7.50 – 7.42 (m, 1H), 7.42 – 7.34 (m, 1H), 7.22 (t, J = 9.2 Hz, 1H), 4.34 – 4.20 (m, 2H), 4.09 – 3.82 (m, 4H), 3.63 – 3.38 (m, 2H), 2.27 (s, 3H), 2.18 (s, 1.5H), 2.09 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.6, 161.3, 158.6 (q, J = 34.2 Hz), 157.6 (d, J = 251.2 Hz), 153.28, 153.26, 136.1, 136.0, 135.12, 135.09, 133.62, 133.57, 132.2, 131.00, 130.95, 130.1, 129.4, 129.3, 116.80 (d, J = 21.0 Hz), 116.78 (q, J = 289.6 Hz), 112.5, 112.3, 51.9, 51.3, 45.5, 44.6, 41.5, 40.7, 29.7, 28.6, 22.1, 22.0, 20.3. HRMS (ESI) m/z [M]+ calcd for C21H22FN4O+ 365.1777, found 365.1789. 7-Acetyl-2-(2,6-dimethylphenyl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8q). A colorless oil. 0.24 g, 29%. 1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.54 (m, 5H), 7.31 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 4.30 – 4.19 (m, 2H), 4.15 – 4.01 (m, 2H), 3.97 – 3.86 (m, 2H), 3.58 – 3.41 (m, 2H), 2.19 (s, 1.5H), 2.11 (s, 1.5H), 2.15 (s, 3H), 2.14 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 170.2, 170.0, 161.8, 161.4, 158.4 (q, J = 33.6 Hz), 157.1, 157.1, 138.1, 133.2, 133.5, 132.0, 131.01, 130.96, 129.73, 129.71, 128.33, 128.27, 128.1, 124.21, 124.18, 116.9 (d, J = 296.1 Hz), 53.0, 52.0, 45.3, 44.8, 41.7, 41.3, 30.0, 28.7, 22.1, 22.0, 20.0. HRMS (ESI) m/z [M]+ calcd for C22H25N4O+ 361.2028, found 361.2031. 7-Acetyl-2-(4'-methyl-[1,1'-biphenyl]-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (8r). A colorless oil. 0.38 g, 41%. 1H NMR (400 MHz, DMSO-d6) δ 7.72 – 7.62 (m, 2H), 7.60 – 7.52 (m, 2H), 7.48 – 7.37 (m, 3H), 7.18 – 7.10 (m, 2H), 6.89 – 6.81 (m, 2H), 6.77 (m, 2H), 4.22 – 4.06 (m, 2H), 3.96 – 3.77 (m, 4H), 3.59 – 3.37 (m, 2H), 2.36 (s, 3H), 2.16 (s, 1.5H), 2.06 (s, 1.5H). 13 C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.6, 161.2, 158.4 (q, J = 33.6 Hz), 157.9, 157.8, 141.5, 137.9, 137.9, 135.60, 135.57, 133.0, 132.8, 132.7, 132.3, 130.7, 130.6, 130.5, 130.0, 129.3, 129.2, 128.71, 128.67, 128.5, 128.4, 128.1, 122.9, 116.8 (q, J = 295.3 Hz), 52.0, 51.2, 45.7, 44.7, 42.0, 41.1, 29.7, 28.6, 22.1, 22.0, 21.2. HRMS (ESI) m/z [M]+ calcd for C27H27N4O+ 423.2185, found 423.2189. II. The synthesis of of 1,2,4-triazolo[1,5-d][1,4]diazepinium 9-13. As described for the preparation of 7 and 8. 7-Acetyl-3-(4-methoxyphenyl)-2-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (9a). A colorless oil. 0.31 g, 88%. 1H NMR (400 MHz, D2O) δ 7.44 – 7.39 (m, 2H), 7.22 – 7.16 (m, 2H), 4.29 – 4.14 (m, 2H), 3.95 – 3.80 (m, 7H), 3.43 – 3.27 (m, 2H), 2.37 (s, 3H), 2.15 (s, 1.8H), 2.08 (s, 1.2H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 162.8, 162.7, 160.7, 160.2, 159.2, 159.1, 129.9, 120.53, 120.48, 116.2, 56.0, 55.9, 50.3, 49.8, 46.4, 45.0, 42.5, 41.2, 28.7, 27.9, 20.8, 20.8, 20.7, 20.7, 12.5, 12.4. HRMS (ESI) m/z [M]+ calcd for C16H21N4O2 301.1659, found 301.1664. 7-Acetyl-3-(4-methoxyphenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (9b). A colorless oil. 0.29 g, 83%. 1H NMR (400 MHz, D2O) δ 7.64 – 7.51 (m, 5H), 7.45 (t, J = 7.9 Hz, 2H), 7.28 – 7.21 (m, 2H), 4.48 – 4.32 (m, 2H), 4.10 – 3.95 (m, 4H), 3.95 – 3.88 (m, 3H), 3.66 – 3.46 (m, 2H), 2.27 (s, 1.8H), 2.20 (s, 1.2H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 162.84, 162.8, 161.1, 160.6, 157.7, 157.6, 133.1, 130.4, 129.3, 129.2, 123.1, 121.62, 121.57, 116.4, 116.3, 55.9, 50.1, 49.7, 46.3, 45.0, 42.4, 41.3, 28.9, 28.0, 20.8, 20.7. HRMS (ESI) m/z [M]+ calcd for C21H23N4O2 363.1816, found 363.1822. 7-Acetyl-3-(4-chlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (10a). A colorless oil. 0.31 g, 87%. 1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.87 (m, 1H), 7.86 – 7.78 (m, 1H), 4.23 – 4.09 (m, 2H), 3.95 – 3.75 (m, 4H), 3.40 – 3.27 (m, 2H), 2.42 (s, 3H), 2.14 (s, 1.5H), 2.05 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.04, 169.95, 160.9, 160.7, 158.0, 157.9, 138.6, 138.5, 131.5, 131.4, 131.3, 131.2, 128.3, 51.4, 50.8, 45.8, 44.7, 41.8, 40.7, 29.5, 28.3, 22.1, 22.0, 13.4. HRMS (ESI) m/z [M]+ calcd for C15H18ClN4O 305.1164, found 305.1179. 7-Acetyl-3-(4-chlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (10b). A colorless oil. 0.32 g, 91%. 1H NMR (400 MHz, D2O) δ 7.78 – 7.72 (m, 2H), 7.65 – 7.58 (m, 3H), 7.57 – 7.52 (m, 2H), 7.45 (t, 2H), 4.51 – 4.34 (m, 2H), 4.13 – 3.95 (m, 4H), 3.67 – 3.48 (m, 2H), 2.26 (s, 1.8H), 2.19 (s, 1.2H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 161.6, 161.1, 157.84, 157.75, 139.8,



139.7, 133.2, 131.54, 131.50, 130.4, 129.4, 129.2, 127.89, 127.85, 122.9, 50.6, 50.1, 46.2, 44.9, 42.3, 41.2, 28.8, 28.0, 20.9, 20.8. HRMS (ESI) m/z [M]+ calcd for C20H20ClN4O 367.1320, found 367.1342. 7-Acetyl-2-methyl-3-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (11a). A colorless oil. 0.37 g, 93%. 1H NMR (400 MHz, D2O) δ 8.04 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 7.9 Hz, 2H), 4.36 – 4.17 (m, 2H), 4.00 – 3.82 (m, 4H), 3.52 – 3.31 (m, 2H), 2.41 (s, 3H), 2.16 (s, 1.8 H), 2.09 (s, 1.2 H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 161.7, 161.1, 159.3, 159.1, 134.7 (q, J = 33.3 Hz), 134.7 (q, J = 33.3 Hz), 131.3, 129.3, 128.6 – 128.4 (m), 123.1 (q, J = 272.5 Hz), 50.9, 50.5, 46.3, 44.9, 42.4, 41.2, 28.7, 27.9, 20.8, 20.7, 12.5, 12.5. HRMS (ESI) m/z [M]+ calcd for C16H18F3N4O 339.1427, found 339.1447. 7-Acetyl-2-phenyl-3-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (11b). A colorless oil. 0.37 g, 94%. 1H NMR (400 MHz, D2O) δ 8.04 – 8.00 (m, 1H), 7.81 – 7.76 (m, 1H), 7.59 – 7.54 (m, 1H), 7.49 – 7.46 (m, 1H), 7.43 – 7.38 (m, 1H), 4.45 – 4.27 (m, 2H), 4.08 – 3.92 (m, 4H), 3.64 – 3.46 (m, 2H), 2.22 (s, 1.8H), 2.14 (s, 1.2H).13C NMR (101 MHz, D2O) δ 173.8, 173.6, 162.0, 161.4, 158.0, 157.9, 134.7 (q, J = 33.2 Hz), 134.7 (q, J = 33.3 Hz), 133.4, 132.61, 132.58, 130.01, 129.99, 129.5, 129.3, 128.7 – 128.5 (m), 123.0 (q, J = 272.7 Hz), 122.8, 50.9, 50.5, 46.2, 44.9, 42.2, 41.2, 28.9, 28.0, 20.96, 20.94, 20.81, 20.79. HRMS (ESI) m/z [M]+ calcd for C21H20F3N4O 401.1584, found 401.1594. 7-Acetyl-2-methyl-3-(p-tolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (12a). A colorless oil. 0.27 g, 82%. 1 H NMR (400 MHz, D2O) δ 7.53 – 7.47 (m, 2H), 7.37 – 7.32 (m, 2H), 4.30 – 4.13 (m, 2H), 3.95 – 3.80 (m, 4H), 3.44 – 3.26 (m, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.15 (s, 1.8H), 2.07 (s, 1.2H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 160.9, 160.3, 158.9, 158.8, 145.13, 145.08, 131.52, 131.49, 127.9, 125.52, 125.48, 50.4, 50.0, 46.4, 44.9, 42.5, 41.2, 28.7, 27.8, 20.8, 20.64, 20.60, 12.43, 12.41. HRMS (ESI) m/z [M]+ calcd for C16H21N4O1 285.1710, found 285.1719. 7-Acetyl-2-phenyl-3-(p-tolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepin-3-ium chloride (12b). A colorless oil. 0.26 g, 79%. 1H NMR (400 MHz, DMSO-d6) δ 7.75 – 7.67 (m, 2H), 7.63 – 7.56 (m, 3H), 7.55 – 7.46 (m, 4H), 4.23 – 4.13 (m, 2H), 4.01 – 3.83 (m, 4H), 3.58 – 3.39 (m, 2H), 2.48 – 2.44 (m, 2H), 2.16 (s, 1.5H), 2.07 (s, 1.5H). 13C NMR (101 MHz, DMSO-d6) δ 170.1, 170.0, 161.0, 160.7, 156.1, 144.3, 144.2, 133.2, 132.0, 131.9, 129.7, 129.63, 129.55, 129.4, 128.2, 128.1, 124.5, 51.0, 50.4, 45.6, 44.6, 41.4, 29.6, 28.6, 22.2, 22.1, 21.5. HRMS (ESI) m/z [M]+ calcd for C21H23N4O 347.1866, found 347.1878. 7-Acetyl-2-methyl-3-(o-tolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride (13a). A colorless oil. 0.24 g, 71%. 1 H NMR (400 MHz, D2O) δ 7.70 – 7.63 (m, 1H), 7.59 – 7.54 (m, 1H), 7.52 – 7.45 (m, 1H), 7.41 – 7.36 (m, 1H), 4.29 – 4.13 (m, 2H), 3.98 – 3.81 (m, 4H), 3.48 – 3.31 (m, 2H), 2.37 (s, 3H), 2.16 (s, 1.8H), 2.08 (s, 1.2H), 2.04 (s, 1.2H), 2.03 (s, 1.8H). 13C NMR (101 MHz, D2O) δ 173.6, 173.5, 161.7, 161.1, 159.2, 159.1, 137.62, 137.58, 134.1, 134.0, 132.6, 132.5, 128.64, 128.57, 128.5, 127.21, 127.16, 50.1, 49.6, 46.7, 44.9, 42.7, 41.2, 28.9, 28.1, 20.82, 20.80, 20.67, 20.65, 16.1, 12.21, 12.17. HRMS (ESI) m/z [M]+ calcd for C16H21N4O 285.1710, found 285.1719. 7-Acetyl-2-phenyl-3-(o-tolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepin-3-ium chloride (13b). A colorless oil. 0.22 g, 67%. 1H NMR (400 MHz, D2O) δ 7.68 – 7.61 (m, 1H), 7.56 – 7.49 (m, 1H), 7.49 – 7.44 (m, 4H), 7.41 - 7.32 (m, 2H), 4.36 – 4.20 (m, 2H), 4.03 – 3.83 (m, 4H), 3.58 – 3.41 (m, 2H), 2.18 (s, 1.8H), 2.09 (s, 1.2H), 2.00 – 1.95 (m, 3H). 13C NMR (101 MHz, D2O) δ 173.7, 173.5, 162.1, 161.5, 157.6, 157.5, 137.62, 137.57, 134.2, 134.1, 133.5, 132.8, 132.8, 129.3, 129.2, 128.9, 128.82, 128.79, 128.54, 128.50, 122.8, 49.9, 49.5, 46.7, 44.9, 42.7, 41.2, 29.1, 28.3, 20.9, 20.71, 20.69, 16.3. HRMS (ESI) m/z [M]+ calcd for C21H23N4O 347.1866, found 347.1880.

Procedure for the preparation of 2-methyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium chloride hydrochloride 14. Hydrochloric acid (1.50 mL, 18.00 mmol) was added dropwise into a mixture of 7a (0.58 g, 1.50 mmol) in ethanol (6.00 mL) at rt. The reaction was stirred under reflux overnight. After the mixture was concentrated to remove most of the solvent, the residue was filtered off and the filtered-cake was washed via ethanol (2 × 0.5 mL). Then the filtered cake was collected and dried via oil pump to give 14 (0.39 g, 87%) as a brown solid. Mp 238-239 °C. 1H NMR (400 MHz, D2O) δ 7.91 – 7.85 (m, 1H), 7.84 – 7.77 (m, 2H), 7.66 – 7.60 (m, 2H), 4.68 – 4.60 (m, 2H), 3.79 – 3.67 (m, 6H), 2.54 (s, 3H). 13C NMR (101 MHz, D2O) δ 159.7, 159.6, 134.0, 131.2, 128.2, 127.8, 45.2, 43.3, 41.6, 24.1, 12.6. HRMS (ESI) m/z [M]+ calcd for C13H17N4+ 229.1453, found 229.1449. Procedure for the preparation of N-alkyl 1,2,4-triazolo[1,5-d][1,4]diazepiniums 15. Pd(OH)2 (10.0% mmol) was added in a mixture of 14 (0.50 mmol, 1.0 equiv) and an aldehyde (1.00 mmol, 2.0 equiv) in H2O (5 mL) at rt. The reaction was stirred at the atmosphere of hydrogen balloon for 2 h. Then the mixture was filtered via diatomite and the filtrate was purified via reverse flash column chromatography (H2O, 0.5% CF3CO2H in H2O). The collected fractions were dried via lyophilizer to afford the N-alkyl substituted [1,2,4]-triazolo[1,5-d][1,4] diazepinium 15. 2,7-Dimethyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (15a). By using formaldehyde to give 15a as a colorless oil. 0.15 g, 83%. 1H NMR (400 MHz, DMSO-d6) δ 7.88 – 7.78 (m, 3H), 7.76 – 7.71 (m, 2H), 4.45 – 4.33 (m, 2H), 3.65 – 3.38 (m, 6H), 2.85 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.4, 159.0 (q, J = 32.6 Hz), 158.1, 133.7, 131.3, 129.14, 129.08, 117.4 (q, J = 297.7 Hz), 52.0, 50.6, 45.0, 43.9, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.3, 23.8, 13.4. HRMS (ESI) m/z [M]+ calcd for C14H19N4+ 243.1604, found 243.1614. 7-Butyl-2-methyl-3-phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepinium trifluoroacetate (15b). By using butyraldehyde to give a colorless oil. 0.17 g, 86%. 1H NMR (400 MHz, DMSO-d6) δ 7.89 – 7.74 (m, 5H), 4.56 – 4.45 (m, 2H), 3.83 – 3.73 (m, 2H), 3.73 – 3.55 (m, 4H), 3.30 – 3.16 (m, 2H), 2.46 (s, 3H), 1.72 – 1.57 (m, 2H), 1.33 (q, J = 14.2, 7.1 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.1, 159.0 (q, J = 34.9 Hz), 158.1, 133.8, 131.3, 129.11, 129.07, 116.4 (q, J = 293.0 Hz), 55.9, 49.6, 48.6, 44.4, 25.7, 23.2, 19.8, 13.9, 13.3. HRMS (ESI) m/z [M]+ calcd for C17H25N4+ 285.2074, found 285.2088.

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ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxxx Copies of the NMR spectra for all products (PDF)


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X-ray crystallographic data for 8i′′ (CIF)

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AUTHOR INFORMATION

Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. ■ ORCID Quan-rui Wang: 0000-0001-7593-9176 Notes The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

Financial support from the National Natural Science Foundation of China (NNSFC) under Grant 21372045 is gratefully acknowledged. We thank also Dr. Yue-jian Lin for structural confirmation of 8i′′ by single-crystal X-ray analysis.

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Synthesis of Triazolodiazepinium Salts: Sequential [3++2

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