Copper-catalyzed synthesis of β-boryl cyclopropanes via 1,2-borocyclopropanation of aryl olefins with CO as the C1 source

Cyclopropane represents one of the most critical rings and has been found present in various bioactive compounds, especially in clinical medicines. It can be synthesized by the reaction of olefins with diazo-derived carbenoids which are potentially hazardous. Carbonylation is a powerful tool for synthesizing carbonylated or carbon-extended compounds. In this communication, we describe a straightforward approach for synthesizing β-boryl cyclopropane derivatives catalyzed by an inexpensive copper catalyst with CO as the C1 source. This reaction was mediated by an in situ generated carbene intermediate and afforded a wide range of cyclopropane-containing organoboron compounds in moderate to good yields.

compounds. 22,23 However, this cyclopropanation method was limited in that the carbene species were generated from the decomposition of diazo compounds which are potentially hazardous. 24 The carbonylation reactions represent one of the essential industrial methods for synthesizing carbonyl-containing compounds using CO as an inexpensive C1 source. 25,26 Furthermore, the carbonylation reactions can be unitized in the carbon extension of their parent compounds. Noble metal catalyzed carbonylation reactions have been well developed, such as carbonylative cross-coupling reactions catalyzed by palladium. 26 Considering the high price of these noble metals, more attention has focused on developing remarkable, inexpensive, and non-toxic catalyst systems for carbonylative reactions.
As a representation of base metals, copper is attractive due to its low price, low toxicity, and ready availability. Copper catalysts were highly active for many synthetic transformations, including C-C, C-B, C-N, and C-Si bond formations. 27 Over the past few years, many synthetic methods have been reported by utilizing copper-boryl complexes as the reactive intermediates. 28 Among them, Cu-catalyzed borofunctionalization was approved as a powerfully synthetic tool in that the borylation reagents obtained from this reaction could be used in further transformations such as C-C coupling reactions. 29 In borocarbonylation, high-value b-boryl acyl compounds can be obtained to undergo a similar reaction mechanism. As shown in Fig. 1c, in the reaction of copper-boryl complexes with alkenes, the b-borylalkylcopper intermediate could be formed by the addition of a copper-boryl complex into the C]C bond. Aer the coordination and insertion of CO, acyl copper species were formed. In the presence of an electrophile, the nal carbonylated products could be formed by the oxidative addition of acyl-copper species with the electrophile and then reductive elimination steps. 30,31 In our recent studies on copper-boryl complex-mediated carbonylation reactions, we found that the acyl-copper intermediate could isomerize to carbene species in the absence of electrophilic reagents, which was different from the reported achievements in the borocarbonylation of alkenes (Fig. 1d). We could obtain a range of different products through the transformations of the in situ generated carbene intermediates including a-C-H insertion, 32 b-C-H insertion, 33,34 CO insertion, 35 and N-H/O-H insertion of carbene. 36 With our continued interest in copper-catalyzed borocarbonylation of olens, we speculate that the carbene intermediates can be captured by C]C double bonds to generate cyclopropanes. In this communication, we describe a straightforward approach to synthesis b-boryl cyclopropanes via coppercatalyzed 1,2-borocyclopropanation of aryl olens with CO as the C1 source (Fig. 1e).
We began our investigation by using styrene and bis(pinacolato)diboron (B 2 pin 2 ) as the model substrates (for details, see the ESI †). Throughout the optimization process (Table 1), the hydroboration reaction provided the major by-product 3a. We could also detect trace amounts of 4a and 5a which may indicate the pathway of this reaction. To establish suitable reaction conditions, we initially screened different ligands (Table 1, entries 1-4, for details, see the ESI †). We found that only bidentate phosphines could give access to the b-boryl cyclopropane product. Among these ligands, the reaction with DPPB was inuential in obtaining the target product (Table 1, entry 4). Moreover, no signicant hydroboration by-product was observed. Then various parameters of this copper-catalyzed carbonylation, such as bases and solvent, were explored (for details, see the ESI †). In our testing of copper pre-catalysts, the results showed no signicant difference between Cu(II) and  With the optimized reaction conditions in hand, we turned to examine the scope of aryl olens for this copper-catalyzed 1,2borocyclopropanation reaction. As shown in Fig. 2, a broad spectrum of aryl olens underwent the desired reaction and were transformed into the corresponding b-boryl cyclopropanes in moderate to good yields (2a-y). Aryl olens bearing either electron-donating groups (e.g., -Me, -MeO, -MeS, and -PhO) or electron-withdrawing (e.g., -OCF 3 and -SCF 3 ) at the para position of the phenyl ring were all well reacted and provided the corresponding b-boryl cyclopropane products in moderate to good yields. Notably, 39% yield of product (2h) was produced from Bpin-substituted styrene. The reaction was not sensitive to the substitution pattern of the benzene ring. There was no signicant difference in the reactivity of vinyl benzene substituted with uorine atoms at the para, meta, or ortho positions, respectively (2i-k). The electron-withdrawing group (SCF 3 ) and the electron-donating group were also applied at the meta-position of vinyl benzene, and good yields of the corresponding products were obtained (2l and 2m). Styrene decorated with sulfonyl (2n) and triuoromethyl (2o) was also suitable for this carbonylative reaction to deliver the desired products in moderate yields. The adamantyl group substituted styrene provided the desired product 2p in 36% yield. Considering that heterocycles play an essential role in drug design due to their widespread presence in biologically active structures, we prepared cyclopropane products with various heterocycles. Heterocycles such as indole (2q), pyrrole (2r), furan (2s), morpholine (2t), and thiophene (2u) on the phenyl rings of styrenes could be successfully applied in the reaction and deliver the corresponding cyclopropane-containing products. Meanwhile, heterocyclic substituents containing two heteroatoms provided 2v and 2w in 47% and 53% yields, respectively. In addition, valid substrates containing complex-molecule-derived substrates, such as diacetone fructose-and citronellol-derived aryl olens, can also be converted into products 2x and 2y in 44% and 43% yields, correspondingly.
We also depicted a possible mechanism for this carbonylation process (Fig. 3). In this transformation, the initiated copper catalyst reacted with the ligand, NaO t Bu, and B 2 pin 2 to produce the (L)CuBpin complex. Then, aer the addition of (L)CuBpin to styrene 1a and then the subsequent insertion of CO, the acylcopper species II was delivered. 28 Aerwards, the acyl-copper II species will isomerize to the carbene intermediate III. Next, the complex III will be captured by unsaturated C-C double bonds to give the cyclopropane-containing structure IV. In the presence of another equivalent of B 2 pin 2 , the complex IV afforded -OBpin substituted compound V. 37 The OBpin group acted as a leaving group that activates the C-O bond of compound V. In the presence of an adequate amount of B 2 pin 2 and base, compound V will be converted into compound VI, which could be detected by GC-MS during the optimization process. Finally, the nal b-boryl substituted cyclopropanes could be eliminated aer protodeborylation with a trace amount of water from reagents as the proton source. 38 To support our mechanism, we applied 13 CO in the reaction to obtain the 13 C-labelled cyclopropane 2ae which demonstrates that CO was the source of one of the carbons in cyclopropane (Fig. 3B). In our performed reaction with a-deuterated styrene under the standard conditions 2af was obtained in 56% yield (Fig. 3C). The deuterium position in 2af indicated that there was no intramolecular hydrogen transfer.
To demonstrate the utility of this 1,2-borocyclopropanation of aryl olens, we conducted several diversication reactions of 2a (Fig. 4). As we expected, 2a can be oxidized by NaBO 3 $H 2 O to alcohol 2aa in 65% yield with a cis conguration. 39 Zweifel-Olenation converts b-boryl substituted cyclopropane 2a to 2ab when the Grignard reagent is employed. Moreover, transformation to the triuoroborate salt 2ac occurred in 77% yield. The further Suzuki-Miyaura reaction of 2ac can be successfully applied to deliver the desired product 2ad in 70% yield.
In conclusion, we have discovered a copper-catalyzed straightforward method for synthesizing cyclopropanecontaining organoboron compounds. Taking advantage of the in situ carbene intermediate generation from the isomerization of the acyl-copper species, we can access the nal b-boryl substituted cyclopropane structures by capturing the carbene intermediate with C]C bonds in another equivalent of aryl olens. Various b-boryl cyclopropane derivatives were produced in moderate to good yields. Further synthetic applications of the  formed b-boryl cyclopropane were successfully performed as well to demonstrate the value of this borocarbonylation process.

Data availability
All data supporting the ndings of this study are available within the article and its ESI le. †