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Communication

One-Pot Synthesis of Triazolobenzodiazepines Through Decarboxylative [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides and Cu-Free Click Reactions

by
Xiaoming Ma
1,†,
Xiaofeng Zhang
2,†,
Weiqi Qiu
2,
Wensheng Zhang
3,
Bruce Wan
2,
Jason Evans
2 and
Wei Zhang
2,*
1
School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China
2
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
3
School of Science, Jiaozuo Teachers’ College, 998 Shanyang Road, Jiaozuo 454100, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2019, 24(3), 601; https://doi.org/10.3390/molecules24030601
Submission received: 16 January 2019 / Revised: 3 February 2019 / Accepted: 5 February 2019 / Published: 8 February 2019
(This article belongs to the Special Issue Sustainable Synthesis)
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Abstract

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

Graphical Abstract

1. Introduction

Triazolobenzodiazepines and related scaffolds are privileged heterocyclic systems for biologically active molecules, such as benzodiazepine-bearing bretazenil [1], midazolam [2]; protease inhibitors [3], alprazolam [4], estazolam [5], and triazolam [6] (Figure 1). Due to their medicinal significance, the development of synthetic methods for triazolobenzodiazepine-bearing compounds continuously attracts the attention of organic and medicinal chemists [7,8,9].
Highly efficient and atom economic synthesis such as one-pot reactions and multicomponent reactions (MCRs) have gained increasing popularity in the synthesizing of complex molecules including triazolobenzodiazepine-type compounds [10,11,12,13,14,15]. For example, the Martin group reported a cascade reductive amination and intramolecular [3 + 2] cycloaddition reaction sequence for triazole-fused 1,4-benzodiazepines (Scheme 1A) [10,11]. The Djuric group modified the van Leusen imidazole synthesis to develop an intramolecular azide-alkyne cycloaddition for imidazole- and triazole-fused benzodiazepine compounds (Scheme 1B) [12]. The Kurth group reported a Lewis 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 sequence involving decarboxylative intermolecular [3 + 2] cycloaddition of nonstabilized azomethine ylides followed by N-propargylation and intramolecular [3 + 2] cycloaddition for triazolobenzodiazepines (Scheme 1D).
1,3-Dipolar cycloaddition of primary amino esters, aldehydes, and activated alkenes is a well-established three-component reaction [16,17,18,19,20,21]. The azomethine ylides derived from deprotonation of iminium ions are CO2R-stabilized ylides A (Figure 2A) [22,23,24,25,26,27,28,29,30]. In recent years, our lab has reported a series of azomethine ylides A-based [3 + 2] cycloadditions for diverse heterocyclic scaffolds [31,32,33,34,35], including one-pot [3 + 2] and click reactions for triazolobenzodiazepines [32]. Compared to the reactions of stabilized ylides A, cycloadditions of nonstabilized ylides B are less explored (Figure 2B) [36,37,38,39,40,41,42]. We have recently reported the synthesis of α-trifluoromethyl pyrrolidines through decarboxylative [3 + 2] cycloaddition of nonstabilized azomethine ylides B derived from α-amino acids [43]. Presented in this paper is a new application of nonstabilized azomethine ylides in the one-pot [3 + 2] and click reactions for triazolobenzodiazepines.

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 solvents including 2-methyltetrahydrofuran, toluene, EtOH and CH3CN as well as reaction time and temperature, it was found that a reaction using CH3CN as a solvent at 110 °C for 6 h afforded 4a in 93% LC (liquid chromatography) yield with a dr (diastereomer) of 6:1 (Table 1, entry 6). The stereochemistry of 4a was determined according to the literature report [38].
Decarboxylative [3 + 2] cycloaddition product 4a was then used for the development of conditions for the N-propargylation and sequential click reaction for the synthesis of triazolobenzodiazepine 6a. In the presence of K2CO3, 4a reacted with propargyl bromide in CH3CN at 80 °C for 2 h to give 5a in 94% LC yield (Table 2, entries 2–5). Without separation, the reaction mixture was used for intramolecular click reaction at 100 °C under the catalysis of Cu salts (Table 2, entries 2–4). The CuI-catalyzed click reaction gave 6a in 89% LC yield, which is better than the reactions catalyzed with CuCl or CuBr. In our previous work, the intramolecular click reaction was accomplished under microwave heating and Cu-free conditions [32]. In this work, N-propargylation compound 5a generated under the microwave heating was continuously heated at 150 °C for 1 h to give 6a in 88% LC yield without CuI catalyst (Table 2, entry 6). A Cu-free control reaction of 5a under conventional heating at 100 °C for 3 h only gave 5% of 6a (Table 2, entry 5).
After establishing the three-component [3 + 2] cycloaddition, N-propargylation, and sequential click reactions for 6a shown in Table 1 and Table 2, we then aimed to combine these three reactions in one pot. After modification of the conditions shown in Table 1 and Table 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 4).
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 the azidobenzaldehyde with the strong electron-withdrawing group NO2 gave no product of 6m. The reactions of glycine and leucine with azidobenzaldehydes (R1 = H, Br, Cl) and maleimides (R4 = Me, Et) gave 6h–l in 44–55% yields. The stereochemistry of product 6 was established during the step of the decarboxylative [3 + 2] cycloaddition, which was determined according to the literature report [38].
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 under Cu-free conditions [10,15,32,45,46].

3. Summary

A one-pot synthesis of fused-triazolobenzodiazepines was developed using readily available amino acids, maleimides, and 2-azidebenzaldehydes for decarboxylative [3 + 2] cycloaddition of nonstabilized azomethine ylides, followed by N-propargylation and a Cu-free intramolecular click reaction. This is a highly efficient and operational simple reaction process for fused-triazolobenzodiazepines, and only CO2 and H2O were generated as byproducts.

Supplementary Materials

The following are available online. 1H-NMR, 13C-NMR, and 19F-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

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Sample Availability: Samples of the compounds are available from the authors.
Molecules 24 00601 g001 550
Figure 1. Biologically active triazolobenzodiazepine-related molecules.
Figure 1. Biologically active triazolobenzodiazepine-related molecules.
Molecules 24 00601 g001
Molecules 24 00601 sch001 550
Scheme 1. Atom economic synthesis of triazolobenzodiazepines.
Scheme 1. Atom economic synthesis of triazolobenzodiazepines.
Molecules 24 00601 sch001
Molecules 24 00601 g002 550
Figure 2. Azomethine ylides from amino esters or amino acid.
Figure 2. Azomethine ylides from amino esters or amino acid.
Molecules 24 00601 g002
Molecules 24 00601 sch002 550
Scheme 2. Mechanism for one-pot synthesis of 6a.
Scheme 2. Mechanism for one-pot synthesis of 6a.
Molecules 24 00601 sch002
Table
Table 1. Three-component decarboxylative [3 + 2] cycloaddition a.
Table 1. Three-component decarboxylative [3 + 2] cycloaddition a.
Molecules 24 00601 i001
ntrySolventT (°C)t (h)4a (%) bdr (%) c
12-Me THF804trace—
2MePh1104trace—
3EtOH804825:1
4EtOH1106936:1
5CH3CN1104926:1
6CH3CN1106936:1
7CH3CN12512886:1
a Reaction conditions: 1:1.2:1 1a:2a:3a for [3 + 2] cycloaddition. b Detected by LC-MS. c Determined by 1H NMR.
Table
Table 2. One-pot N-propargylation and click reaction a.
Table 2. One-pot N-propargylation and click reaction a.
Molecules 24 00601 i002
EntrySolventT1 (°C)t1 (h)5a (%) bCat.T2 (°C)t2 (h)6a (%) b
1EtOH802trace
2CH3CN80294CuCl100335
3CH3CN80294CuBr100360
4CH3CN80294CuI100389
5CH3CN80294—10035
6 cCH3CN1100.593—150188 (dr 6:1)
a Reaction conditions: K2CO3 (2.5 equiv.) and propargyl bromide (5.0 equiv.) under conventional or microwave heating. b Detected by LC-MS. c Microwave heating for both N-propargylation and click reactions.
Table
Table 3. Conditions for the one-pot synthesis of 6a a.
Table 3. Conditions for the one-pot synthesis of 6a a.
Molecules 24 00601 i003
EntryT1 (°C)t1 (h)Cat.T2 (°C)t2 (h)6a (%) b
11100.5—150175
21500.5—150151
31501—150176 (dr 6:1)
41100.5CuI110170
a Reaction conditions: 1:1.2:1 1a:2a:3a, K2CO3 (2.5 equiv.), propargyl bromide (5 equiv.). b Detected by LC-MS, 6:1 dr.
Table
Table 4. One-pot synthesis of triazolobenzodiazepines 6 a.
Table 4. One-pot synthesis of triazolobenzodiazepines 6 a.
Molecules 24 00601 i004
a Reaction conditions, see [44]. b Isolated yield.

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MDPI and ACS Style

Ma, X.; Zhang, X.; Qiu, W.; Zhang, W.; Wan, B.; Evans, J.; Zhang, W. One-Pot Synthesis of Triazolobenzodiazepines Through Decarboxylative [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides and Cu-Free Click Reactions. Molecules 2019, 24, 601. https://doi.org/10.3390/molecules24030601

AMA Style

Ma X, Zhang X, Qiu W, Zhang W, Wan B, Evans J, Zhang W. One-Pot Synthesis of Triazolobenzodiazepines Through Decarboxylative [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides and Cu-Free Click Reactions. Molecules. 2019; 24(3):601. https://doi.org/10.3390/molecules24030601

Chicago/Turabian Style

Ma, Xiaoming, Xiaofeng Zhang, Weiqi Qiu, Wensheng Zhang, Bruce Wan, Jason Evans, and Wei Zhang. 2019. "One-Pot Synthesis of Triazolobenzodiazepines Through Decarboxylative [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides and Cu-Free Click Reactions" Molecules 24, no. 3: 601. https://doi.org/10.3390/molecules24030601

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