An Efficient Solvent-free Synthesis of Spiro-substituted Cyclopropanes by Grinding

Cyclopropane rings are vital structural components in many synthetic and natural compounds. Due to the strain associated with cyclopropane systems, they can be employed as versatile intermediates for construction of more complex compounds that exhibit biological and pharmaceutical activities. Thus, great effort has been devoted to the development of novel and diverse methods for their synthesis. Among the synthetic methods for cyclopropanation reported, the Simmons-Smithtype reaction is probably the most widely used. Metal-catalyzed cyclopropanation of alkenes with diazo compounds has also attracted much attention. In addition, basepromoted cyclopropanations involving ylides and electron-deficient olefins, and Michael-initiated ring closure (MIRC), are also reliable approaches to cyclopropanes. However, these reported procedures often required harsh reaction conditions or heavy metal catalysts. The need for cyclopropanation under simple mild conditions and the need to expand structural diversity remain significant. Improving the efficiency of organic synthesis, lowering the consumption of chemicals, and constructing complex molecules from simple and readily-available starting materials are fundamental goals in organic synthesis. Recently, great strides have been made in solvent-free reactions using grinding conditions. These procedures are characterized by high efficiency, operational simplicity, and low cost. They are regarded as more environmentally benign processes compared to solvent-based standard protocols. The synthesis of spiro-substituted cyclopropane derivatives under grinding conditions, however, has rarely been reported. We now present an environmentally benign approach for the synthesis of spiro-substituted cyclopropane derivatives from 1,3-indandione and electron-deficient alkenes as shown in Scheme 1. We chose phenylidenemalononitrile (1a) and 1,3-indandione (2) as the model substrates to screen the optimal reaction conditions. At first, a mixture of 1a, 2, iodine and K2CO3 in a molar ratio of 1.0: 1.05: 1.0: 2.0 was ground. When starting materials were consumed, as indicated by thin layer chromatography (TLC), the desired product, 10,30-dioxo-3-phenyl-10,30-dihydrospiro(cyclopropane-1,20-indene)-2,2-dicarbonitrile (3a), was obtained in a modest yield of 57%. This interesting initial result prompted us to

optimize the reaction conditions for greater efficiency by screening different bases, reaction times, and halogenating agents. The results are summarized in Table 1.
In the reactions in which K 2 CO 3 was used as base, we found that deeply colored byproducts were easily formed, which increased the difficulty of purification. To overcome this problem, we focused our attention on seeking a proper base. Interestingly, when the reaction was carried out in the presence of KF . 2H 2 O, the reaction time was decreased to 40 min and the yield of 3a was improved to 61% (entry 3). Further optimization by varying the amount of base showed that 3.0 equiv. of KF . 2H 2 O was the best choice (entry 5 vs. entries 3,4). Subsequently, the amount of iodine was also examined, and the results demonstrated that 1.1 equiv. of iodine was optimal to afford the desired product 3a in up to 84% yield (entry 6 vs. entries 5, 7). Only a trace amount of 3a was observed when Na 2 CO 3 and NaHCO 3 were employed (entries 8 and 9). Other organic and inorganic bases including Cs 2 CO 3 , NaOCH 3 , DMAP, TEA and pyridine facilitated the reaction to some extent, but none exceeded the result of KF . 2H 2 O (entries 10 -14). Therefore, this reaction was most efficient when using I 2 (1.1 equiv) and KF . 2H 2 O (3.0 equiv).
With the optimized reaction conditions in hand, the scope and generality of this reaction were then examined. As shown in Table 2, in all cases, the spiro-substituted cyclopropane (3a -u) was obtained as the sole product. Alkenes (1b -g) bearing parasubstituted electron-withdrawing groups reacted smoothly with 2 to provide products (3b -g) in high yields. Alkenes 1 bearing para-substituted electron-donating groups (Me and OMe) also worked well in this reaction system, and afforded the corresponding products in 89% and 83% yield. It is worthy to mention that the alkenes 1 with diverse groups at the meta-or ortho-positions of the phenyl ring proceeded efficiently to give products (3k -t) in 77 -94% yields, indicating that the steric hindrance of the substituents on the phenyl ring did not significantly affect the product yields. Surprisingly, the reactions of aliphatic alkenes and heteroaromatic alkenes were not very successful. For example, heteroaromatic product 3u was obtained in only 56% while the cyclopropanation of aliphatic derivatives did not proceed. Finally, the product structure was unambiguously confirmed by the single-crystal X-ray diffraction analysis of 3b as an example. 27 On the basis of experimental observation and the known literature, a possible reaction mechanism was proposed (Scheme 2). Firstly, the Michael addition of 1,3-indandione to the electron-deficient olefin afforded intermediate A, which existed in an equilibrium between diketo and enol form B. Due to the H-bond interaction between fluoride ion and the acidic proton in the enol isomer, the enol form B should be more stable and favored. Consequently, the enol form B reacted with iodine to give iodide C as the key intermediate. Then, an intramolecular nucleophilic substitution occurred with the elimination of HI, affording the final product. Scheme 1. Solvent-free synthesis of spirocyclopropanes from alkenes and 1,3-indandione under grinding conditions.
In this described process, potassium fluoride showed different properties from conventional bases. It seemed that the formation of the enol isomer was promoted by formation of a hydrogen-bond interaction. Subsequently, the progression of iodination would be accelerated in the presence of potassium fluoride. The success of this reaction was also attributed to the weak basicity of potassium fluoride, reducing the possibility of unwanted side reactions.
In summary, we have achieved a solvent-free protocol for the highly efficient and environmentally benign preparation of spiro-substituted cyclopropane derivatives from arylidenemalononitrile, 1,3-indandione and iodine in the presence of KF . 2H 2 O. Our approach shows its advantages in terms of mild reaction conditions, simple workup, short reaction time and high product yields.

Experimental section
Commercially available reagents were used without further purification other than those detailed below. Organic extracts were always dried with anhydrous Na 2 SO 4 and filtered before evaporation of the solvent under reduced pressure. Column chromatography was done with the flash methodology by using 220-400 mesh silica. NMR spectra were recorded on a Varian MERCURY plus-400 spectrometer. The chemical shifts were reported in ppm downfield from tetramethylsilane (TMS) with the solvent resonance as the internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplicities. Mass spectra were recorded on an HP5989A mass spectrometer, using the ESI technique. X-ray crystal data were collected with a Bruker Smart Apex2 CCD. Elemental analysis was performed on an Elementar Vario EL-III instrument. The course of reaction was monitored through thin-layer chromatography (Solid phase: silica gel. Eluent: petroleum ether/ethyl acetate, 3/1, v/v).