Cycloaddition of Nonstabilized Azomethine Ylides an - MDPI

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One-Pot Synthesis of Triazolobenzodiazepines Communication Through Decarboxylative [3 + 2] Cycloaddition of One-Pot Synthesis of Triazolobenzodiazepines Nonstabilized Azomethine and Cu-Free of Click Through Decarboxylative [3Ylides + 2] Cycloaddition Reactions Nonstabilized Azomethine Ylides and Cu-Free Click Reactions Xiaoming Ma , Xiaofeng Zhang , Weiqi Qiu , Wensheng Zhang , Bruce Wan Jason Evans 1,†

2, †

2

3

2,

2

and Wei Zhang * Xiaoming Ma 1,† , Xiaofeng Zhang 2,† , Weiqi Qiu 2 , Wensheng Zhang 3 , Bruce Wan 2 , 1 School of Pharmaceutical 2, * Engineering and Life Science, Changzhou University, Changzhou 213164, China; Jason Evans 2 and Wei Zhang 2,

[email protected] School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China; Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA [email protected] USA. [email protected] (X.Z.); [email protected] (W.Q.); [email protected] 2 02125, Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, (B.W.); [email protected] (J.E.) USA; [email protected] (X.Z.); [email protected] (W.Q.); [email protected] (B.W.); 3 School of Science, Jiaozuo Teachers’ College, 998 Shanyang Road, Jiaozuo 454100, China; [email protected] (J.E.) 3 [email protected] School of Science, Jiaozuo Teachers’ College, 998 Shanyang Road, Jiaozuo 454100, China; [email protected] ** Correspondence: Correspondence:[email protected]; [email protected];Tel.: Tel.:+1-617-287-6147 +1-617-287-6147 † These authors contributed equally to this work. † These authors contributed equally to this work. 1 2

Received: 16 January 2019; Accepted: 5 February 2019; Published: 8 February 2019 Received: 16 January 2019; Accepted: 5 February 2019; Published: 8 February 2019







Abstract: A one-pot synthesis of triazolobenzodiazepine-containing polycyclic compounds is Abstract: one-pot synthesis triazolobenzodiazepine-containing polycyclic is introduced.AThe reaction process of involves a decarboxylative three-component [3 + 2]compounds cycloaddition introduced. The reaction process involves a decarboxylative [3 +reactions. 2] cycloaddition of of nonstabilized azomethine ylides, N-propargylation, and three-component intramolecular click nonstabilized azomethine ylides, N-propargylation, and intramolecular click reactions. Keywords: one-pot synthesis; decarboxylative [3 + 2] cycloaddition; nonstabilized azomethine Keywords: ylides; clickone-pot reactionsynthesis; decarboxylative [3 + 2] cycloaddition; nonstabilized azomethine ylides; click reaction

1. Introduction 1. Introduction Triazolobenzodiazepines and related scaffolds are privileged heterocyclic systems for Triazolobenzodiazepines and related scaffolds are privileged heterocyclic systems for biologically biologically active molecules, such as benzodiazepine-bearing bretazenil [1], midazolam [2]; active molecules, such as benzodiazepine-bearing bretazenil [1], midazolam [2]; protease inhibitors [3], protease inhibitors [3], alprazolam [4], estazolam [5], and triazolam [6] (Figure 1). Due to their alprazolam [4], estazolam [5], and triazolam [6] (Figure 1). Due to their medicinal significance, the medicinal significance, the development of synthetic methods for triazolobenzodiazepine-bearing development of synthetic methods for triazolobenzodiazepine-bearing compounds continuously compounds continuously attracts the attention of organic and medicinal chemists [7–9]. attracts the attention of organic and medicinal chemists [7–9].

Figure 1. Biologically active triazolobenzodiazepine-related molecules. Figure 1. Biologically active triazolobenzodiazepine-related molecules.

Highly efficient and atom economic synthesis such as one-pot reactions and multicomponent Highly efficient atom economic synthesisinsuch as one-pot reactions multicomponent reactions (MCRs) haveand gained increasing popularity the synthesizing of complexand molecules including reactions (MCRs) have gained increasing popularity in the synthesizing of complex molecules triazolobenzodiazepine-type compounds [10–15]. For example, the Martin group reported a cascade including triazolobenzodiazepine-type compounds [10–15]. Forreaction example,sequence the Martin reported reductive amination and intramolecular [3 + 2] cycloaddition forgroup triazole-fused 1,4-benzodiazepines (Scheme 1A) [10,11]. The Djuric group modified the van Leusen imidazole Molecules 2019, 24, x; www.mdpi.com/journal/molecules synthesis to develop an intramolecular azide-alkyne cycloaddition for imidazoleand triazole-fused benzodiazepine compounds (Scheme 1B) [12]. The Kurth group reported a Lewis acid-catalyzed Molecules 2019, 24, 601; doi:10.3390/molecules24030601

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cascade reductive reductive amination amination and and intramolecular intramolecular [3 [3 ++ 2] 2] cycloaddition cycloaddition reaction reaction sequence sequence for for aa cascade triazole-fused 1,4-benzodiazepines (Scheme 1A) [10,11]. The Djuric group modified the van Leusen triazole-fused 1,4-benzodiazepines (Scheme 1A) [10,11]. The Djuric group modified the van Leusen imidazole synthesis synthesis to to develop develop an an intramolecular intramolecular azide-alkyne azide-alkyne cycloaddition cycloaddition for for imidazoleimidazole- and and imidazole triazole-fused benzodiazepine compounds (Scheme (Scheme 1B) 1B) [12]. [12]. The The Kurth Kurth group group reported reported aa Lewis Lewis Molecules 2019, 24,benzodiazepine 601 2 of 7 triazole-fused compounds acid-catalyzed MCR for imidazoleand triazole-fused benzodiazepines through sequential [3 2] acid-catalyzed MCR for imidazole- and triazole-fused benzodiazepines through sequential [3 ++ 2] cycloaddition and cycloaddition reactions (Scheme 1C) [13]. Introduced in this paper is a new cycloaddition and cycloaddition reactions (Scheme 1C) [13]. Introduced in this paper is a new MCR for imidazoletriazole-fused intermolecular benzodiazepines sequential [3 +of2] cycloaddition sequence involving and decarboxylative [3through 2] cycloaddition cycloaddition nonstabilized sequence involving decarboxylative intermolecular [3 ++ 2] of nonstabilized and cycloaddition reactions (Scheme 1C) [13]. Introduced in this paper is [3 a new sequence involving azomethine ylides followed by N-propargylation and intramolecular + 2] cycloaddition for azomethine ylides followed by N-propargylation and intramolecular [3 + 2] cycloaddition for decarboxylative intermolecular [3 1D). + 2] cycloaddition of nonstabilized azomethine ylides followed by triazolobenzodiazepines (Scheme triazolobenzodiazepines (Scheme 1D). N-propargylation and intramolecular [3 + 2] cycloaddition for triazolobenzodiazepines (Scheme 1D).

Scheme1.1.Atom Atom economic synthesis oftriazolobenzodiazepines. triazolobenzodiazepines. Atomeconomic economicsynthesis synthesisof Scheme

1,3-Dipolar cycloaddition cycloaddition of of primary primary amino amino esters, esters, aldehydes, aldehydes, and and activated activated alkenes alkenes isis is aaa 1,3-Dipolar cycloaddition of primary amino esters, aldehydes, and activated alkenes 1,3-Dipolar well-established three-component reaction [16–21]. The azomethine ylides derived from deprotonation well-established three-component reaction [16–21]. The azomethine ylides derived from well-established three-component reaction [16–21]. The azomethine ylides derived from of iminium ions CO2 R-stabilized ylides A (Figureylides 2A) [22–30]. In recent years, our lab hasyears, reported deprotonation ofare iminium ionsare areCO CO 2R-stabilized A (Figure 2A) [22–30]. In recent our deprotonation of iminium ions 2R-stabilized ylides A (Figure 2A) [22–30]. In recent years, our a series of azomethine ylides A-based [3 + 2] cycloadditions for diverse heterocyclic scaffolds [31–35], lab has reported a series of azomethine ylides A-based [3 + 2] cycloadditions for diverse heterocyclic lab has reported a series of azomethine ylides A-based [3 + 2] cycloadditions for diverse heterocyclic including[31–35], one-pot [3 + 2] and click reactions for triazolobenzodiazepines [32]. Compared to the reactions scaffolds [31–35], including one-pot [3 ++ 2] 2] and and click click reactions reactions for for triazolobenzodiazepines triazolobenzodiazepines [32]. scaffolds including one-pot [3 [32]. of stabilized ylides A, cycloadditions of nonstabilized ylides B are less explored (Figure 2B) [36–42]. We Compared to the reactions of stabilized ylides A, cycloadditions of nonstabilized ylides B are less Compared to the reactions of stabilized ylides A, cycloadditions of nonstabilized ylides B are less have recently reported the synthesis of α-trifluoromethyl pyrrolidines through decarboxylative [3 + 2] explored (Figure 2B) [36–42]. We have recently reported the synthesis of α-trifluoromethyl explored (Figure 2B) [36–42]. We have recently reported the synthesis of α-trifluoromethyl cycloadditionthrough of nonstabilized azomethine B derived from α-amino acids azomethine [43]. Presented in this pyrrolidines through decarboxylative [3 ++ylides 2] cycloaddition cycloaddition of nonstabilized nonstabilized azomethine ylides pyrrolidines decarboxylative [3 2] of ylides BB paper is a new application of nonstabilized azomethine ylides in the one-pot [3 + 2] and click reactions derived from α-amino acids [43]. Presented in this paper is a new application of nonstabilized derived from α-amino acids [43]. Presented in this paper is a new application of nonstabilized for triazolobenzodiazepines. azomethine ylidesin inthe theone-pot one-pot[3 [3++2] 2]and andclick clickreactions reactionsfor fortriazolobenzodiazepines. triazolobenzodiazepines. azomethine ylides

Figure 2. Azomethine ylides from amino esters or amino acid. Figure2.2.Azomethine Azomethineylides ylidesfrom fromamino aminoesters estersor oramino aminoacid. acid. Figure

2. Results and Discussions

Reaction conditions for the synthesis of proline 4a through one-pot [3 + 2] cycloaddition were developed using 1:1.2:1 of 2-azidebenzaldehyde 1a, 2-aminoisobutyric acid 2a, and N-ethylmaleimide 3a in the presence of 0.3 equiv. of AcOH for decarboxylation [43] (Table 1). After screening

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2. Results and Discussions Reaction conditions for the synthesis of proline 4a through one-pot [3 + 2] cycloaddition were of 7 1:1.2:1 of 2-azidebenzaldehyde 1a, 2-aminoisobutyric acid 2a, 3and N-ethylmaleimide 3a in the presence of 0.3 equiv. of AcOH for decarboxylation [43] (Table 1). After screening solvents including 2-methyltetrahydrofuran, toluene, EtOH and CH3CN as well as solvents including 2-methyltetrahydrofuran, toluene, EtOH and CH3 CN as well as reaction time and reaction time and temperature, it was found that a reaction using CH3CN as a solvent at 110 °C for 6 temperature, it was found that a reaction using CH3 CN as a solvent at 110 ◦ C for 6 h afforded 4a in 93% h afforded 4a in 93% LC (liquid chromatography) yield with a dr (diastereomer) of 6:1 (Table 1, entry LC (liquid chromatography) yield with a dr (diastereomer) of 6:1 (Table 1, entry 6). The stereochemistry 6). The stereochemistry of 4a was determined according to the literature report [38]. of 4a was determined according to the literature report [38]. Molecules 2019, 24, 601 developed using

Table 1. Three-component decarboxylative [3 + 2] cycloaddition a. Table 1. Three-component decarboxylative [3 + 2] cycloaddition a . CHO N3 CO2H +

+ H 2N

1a

Entry 1 2 3 4 5 6 7 a

O

Et

2a

O

N

AcOH (0.3 eq)

O

Et N

solvent T, t

N3

O

3a

ntry Solvent Solvent 2-Me THF 1 2-Me THF MePh MePh 2 3 EtOH EtOH 4 EtOH EtOH 5 CH3 CN CH3CN 6 CH3 CN CH3CN 7 CH CN CH3CN 3

NH

4a

(◦ C) TT(°C) 8080 110 110 8080 110 110 110 110 110 110 125 125

t (h) t (h) 4 4 4 6 4 6 12

4 4 4 6 4 6 12

4a (%)4ab (%) b dr (%) c dr (%) c — trace trace — — trace trace — 82 82 5:1 5:1 93 93 6:1 6:1 92 92 6:1 6:1 93 93 6:1 6:1 88 6:1 88 6:1

b Detected by LC-MS. c Determined 1H NMR. a Reaction Reaction conditions: 1:1.2:1 1a:2a:3a conditions: 1:1.2:1 1a:2a:3afor for[3 [3 ++ 2] 2] cycloaddition. cycloaddition. b Detected by LC-MS. c Determined by 1 Hby NMR.

Decarboxylative[3[3+ 2] + cycloaddition 2] cycloaddition product 4athen wasused then for the development of Decarboxylative product 4a was forused the development of conditions conditions for the N-propargylation andreaction sequential reaction for the synthesis 6a. of for the N-propargylation and sequential click for theclick synthesis of triazolobenzodiazepine triazolobenzodiazepine 6a. In the presence of K 2CO3, 4a reacted with propargyl bromide in CH 3CN ◦ In the presence of K2 CO3 , 4a reacted with propargyl bromide in CH3 CN at 80 C for 2 h to give 5a in 94% at 80 °C (Table for 2 h2,toentries give 5a in 94% LC yield (Tablethe 2, entries Without separation, the reaction LC yield 2–5). Without separation, reaction2–5). mixture was used for intramolecular mixture was used click reaction at 100 °C under the2–4). catalysis Cu salts (Table 2, ◦ Cintramolecular click reaction at 100for under the catalysis of Cu salts (Table 2, entries The of CuI-catalyzed click entries 2–4). The CuI-catalyzed click reaction gave 6a in 89% LC yield, which is better than the reaction gave 6a in 89% LC yield, which is better than the reactions catalyzed with CuCl or CuBr. In our reactions work, catalyzed with CuCl or CuBr. our previous work, the intramolecular click reaction was previous the intramolecular click In reaction was accomplished under microwave heating and accomplished under microwave heating and Cu-free conditions In this work, N-propargylation Cu-free conditions [32]. In this work, N-propargylation compound[32]. 5a generated under the microwave compound 5a generated under the microwave heating was continuously heated at 150 CuI °C for 1 h to ◦ heating was continuously heated at 150 C for 1 h to give 6a in 88% LC yield without catalyst Molecules 2019, 24, x 4 of 8 give 6a2,inentry 88% 6). LCA yield without CuIreaction catalyst (Table 2, entry 6). A Cu-free control of 5a (Table Cu-free control of 5a under conventional heating atreaction 100 ◦ C for 3 hunder only conventional 100 °C gave 5% of 6a heating (Table 2,atentry 5).for 3 h only gave 5% of 6a (Table 2, entry 5). Table 2. One-pot N-propargylation and click reaction a. Table 2. One-pot N-propargylation and click reaction a . O Et N

Br

NH N3

O

4a

Entry Entry 1 1 2 2 3 3 4 4 5 5c 6 6c

O

O

K2CO3 T1, t1

Et N

click

N N3

O

5a

cat. (0.5 eq) T2, t2

Et N O

N N

N

N

6a

b b Solvent T1 (°C) T1 (◦ C) t1 (h) t1 (h) 5a (%) T2 (◦ C)t2 (h)t2 (h) 6a (%) 5a (%) 6a (%) b b Solvent Cat.Cat. T2 (°C) EtOH 80 80 2 2 trace EtOH trace CN 80 2 94 CHCH 3CN 80 2 94 CuClCuCl 100 100 3 3 35 35 3 CH CN 80 2 94 CuBr 100 3 3 CH3CN 80 2 94 CuBr 100 3 60 60 CH CN 80 2 94 CuI 100 3 3 80 2 94 CuI 100 3 89 89 CH3CN CH CN 80 2 94 — 100 3 3 80 2 94 — 100 3 5 5 CH3CN CH3 CN 110 0.5 93 — 150 1 88 (dr 6:1) CH3CN 110 0.5 93 — 150 1 88 (dr 6:1)

a

Reaction conditions:K2KCO 2CO 3 (2.5 equiv.) propargyl bromide (5.0 under equiv.) under conventional or Reaction conditions: equiv.) and and propargyl bromide (5.0 equiv.) conventional or microwave 3 (2.5 c Microwave heating b Detected heating. b Detected by LC-MS. for both N-propargylation andN-propargylation click reactions. by LC-MS. c Microwave heating for both and click microwave heating. reactions.

After establishing the three-component [3 + 2] cycloaddition, N-propargylation, and sequential establishing the three-component + 2] cycloaddition, N-propargylation, and sequential click After reactions for 6a shown in Tables 1 and 2,[3we then aimed to combine these three reactions in one click reactions for 6a shown in Tables 1 and 2, we then aimed to combine these three reactions in one pot. After modification of the conditions shown in Tables 1 and 2, the best conditions for the one-pot pot. After modification of the conditions shown in Tables 1 and 2, the best conditions for the one-pot synthesis was to conduct the decarboxylative [3 + 2] cycloaddition in MeCN under conventional heating at 110 °C for 6 h, then to perform the N-propargylation and spontaneous Cu-free click reaction under microwave heating at 150 °C for 1 h to give 6a in 76% LC yield (Table 3, entry 3). A control reaction using CuI as a catalyst for the click reaction didn’t give a better yield (Table 3, entry

2.1. Immunofluorescence Analysis of the Rat Liver Following Intraperitoneal Injection of GdCl3 or Zymosan Immunofluorescence double staining showed increased numbers of myeloperoxidase positive (MPO+ ) cells (recruited granulocytes) as early as 3 h (hours) after GdCl3 administration (Figure 1B) compared to untreated animals (Figure 1A) while the number of MPO+ cells decreased at 24 h after + treatment Molecules 2019, 24, 601 (Figure 1C). MPO cells were mainly located near the portal vessel and in close vicinity to 4 of 7 the liver macrophages. The same liver sections showed a progressive reduction of ED-1 positivity after GdCl3 administration, mainly near the portal vessel (Figure 1) while ED-2 positivity remained unchanged (Figure 2). Double immunofluorescence staining showed few ED-1+ and MPO+ , and ED-2+ synthesis was to conduct the decarboxylative [3 + 2] cycloaddition in MeCN under conventional and MPO+ cells in close contact to each other near the portal area (Figures 1 and 2). heating at 110 ◦ CDouble for 6 immunofluorescence h, then to perform the N-propargylation and spontaneous staining of liver sections after Zymosan treatment withCu-free antibodiesclick reaction + cells at 3 h (Figure 3B,D), ◦ against ED-1, ED-2 and MPO showed an increased number of MPO under microwave heating at 150 C for 1 h to give 6a in 76% LC yield (Table 3, entry 3). A control which were located near the portal vessels but also through the liver parenchyma, compared to reaction using CuI as a catalyst for the click reaction didn’t give a better yield (Table 3, entry 4). controls (Figure 3A). Double immunofluorescence staining showed few MPO+ /ED-1+ as well as MPO+ /ED-2+ cells near the portal area (Figure 3A–D).

Table 3. Conditions for the one-pot synthesis of 6a a .

Figure 1. Double rat liver sections Entry T1 immunofluorescence (◦ C) t1 (h)staining ofCat. T2 (◦(GdCl C) 3 treatment) t2 (h)with antibodies 6a (%) b directed against ED-1 (green) and MPO (red) followed by fluorescence immunodetection. Liver sections 1 different time 110points of study 0.5are shown: control — (A); 3 h150 75 from (B) and 24 h (C).1Results shown are 2 150 0.5 — 150 1 representative pictures of six animals and six slides per time point. (Original magnification 200×). 51

3 4

150 110

1 0.5

— CuI

150 110

1 1

a

Reaction conditions: 1:1.2:1 1a:2a:3a, K2 CO3 (2.5 equiv.), propargyl bromide (5 equiv.). 6:1 dr.

76 (dr 6:1) 70

b

Detected by LC-MS,

Under the optimized conditions for the one-pot synthesis [44], 13 analogues of triazolobenzodiazepines 6a–m were synthesized using different sets of azidobenzaldehydes 1 (R1 = H, CF3 , Br, Cl, NO2 ), amino acids 2 (R2 = H, Me; R3 = Me, Ph, i-Pr), and maleimides 3 (R4 = Me, Et, Ph, Bn, 4-Br-Ph) (Table 4). The reactions of five different maleimides with 2-aminoisobutyric acids and 2-azidebenzaldehyde gave 6a–e in 55–65% isolated yields. The substitution groups on the benzaldehydes had some influence on the product yield. For example, the azidobenzaldehydes bearing electron-withdrawing groups, such as Br and CF3 , gave 6f and 6g in lower yields (59% and 35%), while 2019, 24, x 5 of 8 the Molecules azidobenzaldehyde with the strong electron-withdrawing group NO2 gave no product of 6m. The 1 = H, Br, Cl) and maleimides (R4 = Me, reactions of glycine and leucine with azidobenzaldehydes (R maleimides (R4 = Me, Et) gave 6h–l in 44–55% yields. The stereochemistry of product 6 was Et) established gave 6h–l during in 44–55% yields. The stereochemistry product 6 was established during the step of the step of the decarboxylative [3 + of 2] cycloaddition, which was determined to the literature [38]. the according decarboxylative [3 + 2]report cycloaddition, which was determined according to the literature report [38]. Table synthesis of triazolobenzodiazepines 6 a. Table4.4.One-pot One-pot synthesis of triazolobenzodiazepines 6 a.

a

Reaction conditions, see [44].ab Reaction Isolated yield. conditions, see [44].

b

Isolated yield.

The proposed mechanism for the synthesis of product 6a is outlined in Scheme 2. The condensation of 2-azidebenzaldehyde 1a and 2-aminoisobutyric acid 2a give oxazolidin-5-one I. It then underwent decarboxylation to form the nonstabilized azomethine ylide II for [3 + 2] cycloaddition with 3a to form 4a. Formation of 5a through propargylation followed by continuous heating for intramolecular click reaction affords product 6a. There are several reports in literature which demonstrated that intramolecular click reactions in one-pot synthesis could be achieved

a see [44]. b Isolated yield. MoleculesReaction 2019, 24, conditions, 601

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The proposed mechanism for the synthesis of product 6a is outlined in Scheme 2. The The proposed mechanism for the synthesis product 6a is outlined 2. The condensation condensation of 2-azidebenzaldehyde 1a and of 2-aminoisobutyric acid in 2aScheme give oxazolidin-5-one I. It of 2-azidebenzaldehyde 1a and 2-aminoisobutyric acid 2a give oxazolidin-5-one I. It then underwent then underwent decarboxylation to form the nonstabilized azomethine ylide II for [3 + 2] decarboxylation to form nonstabilized azomethine ylide IIpropargylation for [3 + 2] cycloaddition 3a to form cycloaddition with 3a tothe form 4a. Formation of 5a through followedwith by continuous 4a. Formation of 5a throughclick propargylation followed by continuous heating for intramolecular click heating for intramolecular reaction affords product 6a. There are several reports in literature reaction affords product 6a. There are several reports in literature which demonstrated that intramolecular which demonstrated that intramolecular click reactions in one-pot synthesis could be achieved click one-pot synthesis could be achieved under Cu-free conditions [10,15,32,45,46]. underreactions Cu-free in conditions [10,15,32,45,46].

Scheme Scheme 2. 2. Mechanism Mechanism for for one-pot one-pot synthesis synthesis of of 6a. 6a.

3. Summary 3. Summary A one-pot synthesis of fused-triazolobenzodiazepines was developed using readily available amino A one-pot synthesis of fused-triazolobenzodiazepines was developed using readily available acids, maleimides, and 2-azidebenzaldehydes for decarboxylative [3 + 2] cycloaddition of nonstabilized amino acids, maleimides, and 2-azidebenzaldehydes for decarboxylative [3 + 2] cycloaddition of azomethine ylides, followed by N-propargylation and a Cu-free intramolecular click reaction. This is a nonstabilized azomethine ylides, followed by N-propargylation and a Cu-free intramolecular click highly efficient and operational simple reaction process for fused-triazolobenzodiazepines, and only CO2 and H2 O were generated as byproducts. Supplementary Materials: The following are available online. 1 H-NMR, 13 C-NMR, and 19 F-NMR spectra of final products. Author Contributions: X.M. and X.F. developed above reactions; W.Q., W.Z., and B.W. expanded the substrates scope; X.F. and W.Z. conceived the project; W.Z. supervised the project and revised the manuscript. Acknowledgments: X.M. acknowledges the sponsorship of Jiangsu oversea Visiting Scholar Program for University Prominent Youth & Middle-aged Teachers and Presidents. We also acknowledge John Mark Awad and Guoshu Xie’s involvement in this project. Conflicts of Interest: The authors declare no conflict of interest.

References and Notes 1.

2. 3.

4. 5.

6.

Tashma, Z.; Raveh, L.; Liani, H.; Alkalay, D.; Givoni, S.; Kapon, J.; Cohen, G.; Alcalay, M.; Grauer, E. Bretazenil, a benzodiazepine receptor partial agonist, as an adjunct in the prophylactic treatment of OP poisoning. J. Appl. Toxicol. 2001, 21, S115–S119. [CrossRef] [PubMed] Djabri, A.; Guy, R.H.; Begona Delgado-Charro, M. Potential of iontophoresis as a drug delivery method for midazolam in pediatrics. Eur. J. Pharm. Sci. 2019, 128, 137–143. [CrossRef] [PubMed] Mohapatra, D.K.; Maity, P.K.; Shabab, M.; Khan, M.I. Click chemistry based rapid one-pot synthesis and evaluation for protease inhibition of new tetracyclic triazole fused benzodiazepine derivatives. Bioorg. Med. Chem. Lett. 2009, 19, 5241–5245. [CrossRef] [PubMed] Ye, Z.; Ding, M.; Wu, Y.; Li, Y.; Hua, W.; Zhang, F. Electrochemical synthesis of 1,2,4-triazole-fused heterocycles. Green Chem. 2018, 20, 1732–1737. [CrossRef] Ahmad, M.R.; Sajjad, G.; Ardeshiri, L.H.; Nahad, A. New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor. Med. Chem. Res. 2016, 25, 1538–1550. [CrossRef] Santos, F.; Javier, G.; Carlos, P. 1,4-Benzodiazepine N-Nitrosoamidines: Useful Intermediates in the Synthesis of Tricyclic Benzodiazepines. Molecules 2006, 11, 583–588. [CrossRef]

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7. 8. 9. 10. 11.

12. 13. 14.

15.

16. 17. 18. 19. 20.

21. 22.

23. 24. 25. 26.

27. 28. 29.

6 of 7

Dömling, A.; Ugi, I. Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168–3210. [CrossRef] Dömling, A. Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006, 106, 17–89. [CrossRef] Dömling, A.; Wang, W.; Wang, K. Chemistry and Biology of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083–3135. [CrossRef] Donald, J.R.; Martin, S.F. Synthesis and Diversification of 1,2,3-Triazole-Fused 1,4-Benzodiazepine Scaffolds. Org. Lett. 2011, 13, 852–855. [CrossRef] Donald, J.R.; Wood, R.R.; Martin, S.F. Application of a Sequential Multicomponent Assembly Process/Huisgen Cycloaddition Strategy to the Preparation of Libraries of 1,2,3-Triazole-Fused 1,4-Benzodiazepines. ACS Comb. Sci. 2012, 14, 135–143. [CrossRef] [PubMed] Gracias, V.; Darczak, D.; Gasiecki, A.F.; Djuric, S.W. Synthesis of fused triazolo-imidazole derivatives by sequential van Leusen/alkyne–azide cycloaddition reactions. Tetrahedron Lett. 2005, 46, 9053–9056. [CrossRef] Nguyen, H.H.; Palazzo, T.A.; Kurth, M.J. Facile One-Pot Assembly of Imidazotriazolobenzodiazepines via Indium(III)-Catalyzed Multicomponent Reactions. Org. Lett. 2013, 15, 4492–4495. [CrossRef] [PubMed] Kosychova, L.; Karalius, A.; Staniulyte, Z.; Sirutkaitis, R.A.; Palaima, A.; Laurynenas, A.; Anusevicius, Z. New 1-(3-nitrophenyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines: synthesis and computational study. Molecules 2015, 20, 5392–5408. [CrossRef] [PubMed] Vroemans, R.; Bamba, F.; Winters, J.; Thomas, J.; Jacobs, J.; Meervelt, L.V.; John, J.; Dehaen, W. Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins. Beilstein J. Org. Chem. 2018, 14, 626–633. [CrossRef] [PubMed] Padwa, A.; Pearson, W.H. (Eds.) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley: Hoboken, NJ, USA, 2003. [CrossRef] Kantorowski, E.J.; Kurth, M.J. Dipolar cycloadditions in solid-phase organic synthesis (SPOS). Mol. Divers. 1997, 2, 207–216. [CrossRef] [PubMed] Nájera, C.; Sansano, J.M. Azomethine Ylides in Organic Synthesis. Curr. Org. Chem. 2003, 7, 1105–1150. [CrossRef] Coldham, I.; Hufton, R. Intramolecular Dipolar Cycloaddition Reactions of Azomethine Ylides. Chem. Rev. 2005, 105, 2765–2810. [CrossRef] Rück-Braun, K.; Freysoldt, T.H.E.; Wierschem, F. 1,3-Dipolar cycloaddition on solid supports: nitrone approach towards isoxazolidines and isoxazolines and subsequent transformations. Chem. Soc. Rev. 2005, 34, 507–516. [CrossRef] Harju, K.; Yli-Kauhaluoma, J. Recent advances in 1,3-dipolar cycloaddition reactions on solid supports. Mol. Divers 2005, 9, 187–207. [CrossRef] Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. exo- and Enantioselective Cycloaddition of Azomethine Ylides Generated from N-Alkylidene Glycine Esters Using Chiral Phosphine−Copper Complexes. Org. Lett. 2003, 5, 5043–5046. [CrossRef] [PubMed] Pandey, G.; Banerjee, P.; Gadre, S.R. Construction of Enantiopure Pyrrolidine Ring System via Asymmetric [3+2]-Cycloaddition of Azomethine Ylides. Chem. Rev. 2006, 106, 4484–4517. [CrossRef] [PubMed] Potowski, M.; Bauer, J.O.; Strohmann, C.; Antonchick, A.P.; Waldmann, H. Highly Enantioselective Catalytic [6+3] Cycloadditions of Azomethine Ylides. Angew. Chem. Int. Ed. 2012, 51, 9512–9516. [CrossRef] [PubMed] Adrio, J.; Carretero, J.C. Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Chem. Commun. 2014, 50, 12434–12446. [CrossRef] [PubMed] Narayan, R.; Potowski, M.; Jia, Z.J.; Antonchick, A.P.; Waldmann, H. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Azomethine Ylides for Biology-Oriented Synthesis. Acc. Chem. Res. 2014, 47, 1296–1310. [CrossRef] [PubMed] Hashimoto, T.; Maruoka, K. Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions. Chem. Rev. 2015, 115, 5366–5412. [CrossRef] Singh, M.S.; Chowdhury, S.; Koley, S. Progress in 1,3-dipolar cycloadditions in the recent decade: an update to strategic development towards the arsenal of organic synthesis. Tetrahedron 2016, 72, 1603–1644. [CrossRef] Zhang, J.X.; Wang, H.Y.; Jin, Q.W.; Zheng, C.W.; Zhao, G.; Shang, Y.J. Thiourea–Quaternary Ammonium Salt Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Imino Esters to Construct Spiro[pyrrolidin-3,30 oxindoles]. Org. Lett. 2016, 18, 4774–4777. [CrossRef]

Molecules 2019, 24, 601

30.

31. 32.

33. 34.

35.

36.

37. 38.

39. 40.

41. 42. 43.

44.

45. 46.

7 of 7

Esteban, F.; Cieslik, W.; Arpa, E.M.; Guerrero-Corella, A.; Diaz-Tendero, S.; Perles, J.; Fernandez-Salas, J.A.; Fraile, A.; Aleman, J. Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1, 3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes. Acs Catal. 2018, 8, 1884–1890. Zhang, W.; Lu, Y.; Chen, C.H.-T.; Zeng, L.; Kassel, D.B. Fluorous Mixture Synthesis of Two Libraries with Hydantoin-, and Benzodiazepinedione-Fused Heterocyclic Scaffolds. J. Comb. Chem. 2006, 8, 687–695. [CrossRef] Zhang, X.F.; Zhi, S.J.; Wang, W.; Liu, S.; Jasinski, J.P.; Zhang, W. A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines. Green Chem. 2016, 18, 2642–2646. [CrossRef] Zhang, X.F.; Legris, M.; Muthengi, A.; Zhang, W. [3 + 2] Cycloaddition-based one-pot synthesis of 3,9-diazabicyclo[4.2.1]nonane-containing scaffold. Chem. Heterocycl. Com. 2017, 53, 468–473. [CrossRef] Muthengi, A.; Zhang, X.F.; Dhawan, G.; Zhang, W.S.; Corsinia, F.; Zhang, W. Sequential (3 + 2) cycloaddition and (5 + n) annulation for modular synthesis of dihydrobenzoxazines, tetrahydrobenzoxazepines and tetrahydrobenzoxazocines. Green Chem. 2018, 20, 3134–3139. [CrossRef] Zhang, X.F.; Qiu, W.Q.; Ma, X.M.; Evans, J.; Kaur, M.; Jasinski, J.P.; Zhang, W. One-Pot Double [3 + 2] Cycloadditions for Diastereoselective Synthesis of Pyrrolidine-Based Polycyclic Systems. J. Org. Chem. 2018, 83, 13536–13542. [CrossRef] [PubMed] Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Simple Generation of Nonstabilized Azomethine Ylides through Decarboxylative Condensation of α-Amino acids with Carbonyl Compounds via 5- Oxazolidinone Intermediates. Bull. Chem. Soc. Jpn. 1987, 60, 4079–4089. [CrossRef] Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. The Decarboxylative Route to Azomethine Ylides. Mechanism of 1,3-Dipoie Formation. J. Chem. Soc. Chem. Commun. 1987, 2, 49–51. [CrossRef] Aly, M.F.; Grigg, R.; Thianpatanagul, S.; Sridharan, V. X=Y–ZH systems as potential 1,3-dipoles. Part 10. The decarboxylative route to azomethine ylides. Background and relevance to pyridoxal decarboxylases. J. Chem. Soc. Perkin Trans. I 1988, 4, 949–955. [CrossRef] Kanemasa, S. The Chemistry of Azomethine Ylides Developed in the Institute. Rep. Inst. Adv. Mater. Study Kynshu Univ. 1988, 2, 149–177. [CrossRef] Kanemasa, S.; Sakamoto, K.; Tsuge, O. Nonstabilized Azomethine Ylides Generated by Decarboxylative Condensation of α-Amino acids. Structural Variation, Reactivity and Stereoselectivity. Bull. Chem. Soc. Jpn. 1989, 62, 1960–1968. [CrossRef] Rehn, S.; Bergman, J.; Stensland, B. The Three-Component Reaction between Isatin, α-Amino Acids, and Dipolarophiles. Eur. J. Org. Chem. 2004, 413–418. [CrossRef] Kudryavtsev, K.V. Three-component synthesis of tricyclic lactams containing the pyrrolizidin-3-one moiety. Russ. Chem. Bull. 2008, 57, 2364–2372. [CrossRef] Zhang, X.F.; Liu, M.; Zhang, W.S.; Legris, M.; Zhang, W. Synthesis of trifluoromethylated pyrrolidines via decarboxylative [3+2] cycloaddition of non-stabilized N-unsubstituted azomethine ylides. J. Fluorine Chem. 2017, 204, 18–22. [CrossRef] General procedure for the one-pot synthesis: A solution of 2-azidebenzaldehyde 1 (1.0 mmol), amino acid 2 (1.2 mmol) and maleimide 3 (1.0 mmol) in 3.0 mL of CH3 CN was heated at 110 ◦ C for 6 h in a sealed tube. Upon the completion of the reaction as monitored by LC-MS, propargyl bromide solution (80% in toluene, 5.0 mmol) and K2 CO3 (2.5 mmol) were added to the reaction mixture and then heated under microwaves at 150 ◦ C for 1 h. The concentrated reaction mixture was loaded onto a semi-preparative HPLC with a C18 column to afford purified major diastereomer of product 6. Guggenheim, K.G.; Toru, H.; Kurth, M.J. One-Pot, Two-Step Cascade Synthesis of Quinazolinotriazolobenzodiazepines. Org. Lett. 2012, 14, 3732–3735. [CrossRef] [PubMed] De Moliner, F.; Bigatti, M.; Banfi, L.; Riva, R.; Basso, A. OPHA (Oxidation−Passerini−Hydrolysis−Alkylation) Strategy: A Four- Step, One-Pot Improvement of the Alkylative Passerini Reaction. Org. Lett. 2014, 16, 2280–2283. [CrossRef] [PubMed]

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