Note pubs.acs.org/joc
Transition-Metal-Free [3+2] Cycloaddition of Dehydroaminophosphonates and N‑Tosylhydrazones: Access to Aminocyclopropanephosphonates with Adjacent QuaternaryTetrasubstituted Carbon Centers Wanqing Wu,* Zhiming Lin, Chuanle Zhu, Pengquan Chen, Jiawei Li, and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China S Supporting Information *
ABSTRACT: A novel one-step strategy for the synthesis of aminocyclopropanephosphonates containing adjacent quaternarytetrasubstituted carbon centers under transition-metal-free catalysis via [3+2] cycloaddition process has been developed. A series of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers including spirocyclopropyl adducts were obtained in moderate to excellent yields under mild reaction conditions. This protocol would find the potential applications in biochemistry and medicinal chemistry. he alleged “phosphorus analogues” of the amino acids as a special structure have attracted particular interest in organic synthesis, which serve as indispensable structural units in many bioactive compounds, medicine, and natural products.1 In the field of biochemistry, as the tetrahedral structure of the “phosphorus analogues” performing stability and mimicry,2 carboxylic group has usually taken place of phosphonate analogues to improve the performance of numerous natural products. For example, as one of the inhibitors of HCV-NS3, BINL-2061 exhibits some side-effects, such as cardiactoxicity off the pill. However, when phosphorus group is introduced, these novel inhibitors show more potent pharmacological activities, and the EC50 (concentration for 50% of maximal effect) of phosphorou analogue II is 0.5 μm (Figure 1).3 Therefore, the development of versatile and efficient methods for constructing different phosphorus compounds is highly desirable. In addition, cyclopropane-containing compounds are versatile building blocks in organic chemistry. Up to now, three major types of methods have been developed to build cyclopropanes: (i) Simmons-Smith cyclopropanation;4 (ii) Michael-initiated ring closure (MIRC);5 (iii) transition metalcatalyzed cyclopropanation.6 Though great progress has been made in this field, most of these methods still have some limitations, such as the requirement of preactivating precursors, toxic organometallic catalysts, and narrow substrate scope. Besides, to the best of our knowledge, the synthesis of aminocyclopropanephosphonates is still rarely reported, especially for those containing adjacent quaternary-tetrasub-
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© 2017 American Chemical Society
stituted carbon centers. Most of the reported methods required multistep manipulation or environmentally unfriendly reagents.7 Particularly, compared with the single quaternary carbon stereocenter, adjacent quaternary-tetrasubstituted carbon centers can enhance the conformational constraints and show more advantages in pharmacokinetic profiles, even making further improvement on the biological activity.8 Therefore, the development of one-step and eco-friendly methods for the synthesis of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers is a challenging issue. As our continuing interests in the construction of functionalized strained rings,9 herein, we disclose a convenient and concise method for building diverse aminocyclopropanephosphonates bearing adjacent quaternarytetrasubstituted carbon centers via transition-metal-free catalyzed cyclopropanation reaction of N-tosylhydrazones and dehydroaminophosphonates in a one-pot manner (Scheme 1). This protocol provides an efficient entry to aminocyclopropanephosphonate derivatives bearing adjacent quaternary-tetrasubstituted carbon centers, which should find its potential applications in biochemistry and medicinal chemistry. Initially, we started our investigation by using diethyl(1acetamidovinyl)phosphonate (1a) and N-tosylhydrazone (2a) as model substrates in the presence of 20 mol% of triethylbenzylammonium chloride (TEBAC) and Li2CO3 as Received: July 25, 2017 Published: September 1, 2017 12746
DOI: 10.1021/acs.joc.7b01862 J. Org. Chem. 2017, 82, 12746−12756
Note
The Journal of Organic Chemistry
Figure 1. Phosphorus analogs used in inhibitors of HCV-NS3 protease.
Scheme 1. Synthetic Methods for Aminocyclopropanephosphonates
base at 90 °C for 12 h. Unfortunately, the total yield of the desired products 3aa and 3aa′ was less than 10% (Table 1, entry 1). Then different types of bases were screened (Table 1, entries 1−6). To our delight, the NMR yield of the desired products 3aa′ and 3aa″ was increased to 84% (dr = 1:1) with Cs2CO3 as the base. And the two diastereoisomers could be separated by silica gel chromatography. The studies of the solvent effects revealed that toluene was the most suitable solvent for this cyclopropanation reaction (Table 1, entries 7− 10). Further examination of the additives proved that TEBAC was the optimal choice (Table 1, entries 11−14). Moreover, raising or lowering the reaction temperature just led to a decrease in product yield. Control experiments showed that the transformation did not occur without the addition of base, suggesting that base played a vital role for the success of this chemical process (Table 1, entry 16). In addition, the attempts to employ transition-metal catalysts, such as Pd, Cu, Fe, etc., in this cyclopropanation reaction were not fruitful. Thus, the optimal reaction conditions were confirmed as follows: 20 mol % of TEBAC as the additive, 2.0 equiv of Cs2CO3 as the base in toluene at 90 °C for 12 h. With the optimal conditions established, the generality and limitations of N-tosylhydrazones were then examined, and the results are summarized in Table 2. Gratifyingly, a wide range of
substitution patterns of N-tosylhydrazones were suitable in this cyclopropanation reaction and the desired products could be obtained in moderate to excellent yields. First, para-substituted N-tosylhydrazones with either electron-donating groups (methyl-, methylthio-, phenyl-, etc.) or electron-withdrawing groups (cyano-, ester-, etc.) attached to the benzene ring were able to transfer to the corresponding cycloaddition products in moderate to excellent yields (3ab−3ag). Moreover, the transformations of the ortho- and bis-substituted N-tosylhydrazones afforded the corresponding products in 72−84% yields (3al−3ao). It should be noted that the halo groups, including -Br and -Cl, could also be tolerated in this process, thus allowing for the subsequent functionalization. Interestingly, when N′-(1-(2-fluorophenyl)ethylidene)-4-methylbenzenesulfonohydrazide was subjected to the standard system, product 3ap was formed in relatively low yield but better diastereoselectivity, which might be caused by the dual role of the stronger steric and electronic effects of the substrate. Delightfully, the reactions of heterocyclic substituted and fused ring substituted N-tosylhydrazones, such as 2-naphthyl-, 3pyridyl-, and 3-thienyl-, proceeded smoothly to provide the desired products in 52−88% yields (3aq−3as). Importantly, the cyclic N-tosylhydrazones were also applicable to this transition-metal-free system and converted to the correspond12747
DOI: 10.1021/acs.joc.7b01862 J. Org. Chem. 2017, 82, 12746−12756
Note
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entrya
additives
base
solvent
T (°C)
yield (%)b
c
TEBAC TEBAC TEBAC TEBAC TEBAC TEBAC TEBAC TEBAC TEBAC TEBAC TBABr3 TBAHS TBAI TBAB TEBAC
Li2CO3 Na2CO3 K2CO3 t-BuOK MeONa Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
toluene toluene toluene toluene toluene toluene DCE DMF THF CH3OH toluene toluene toluene toluene toluene toluene
90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90
