Selective synthesis of spirobiindanes, alkenyl chlorides, and monofluoroalkenes from unactivated gem-difluoroalkanes controlled by aluminum-based Lewis acids

The highly selective synthesis of spirobiindanes, alkenyl chlorides, and monofluoroalkenes via the cleavage of inert C(sp3)–F bonds in unactivated gem-difluoroalkanes using readily available and inexpensive aluminum-based Lewis acids of low toxicity is reported. The selectivity of this reaction can be controlled by modifying the substituents on the central aluminum atom of the promoter. An intramolecular cascade Friedel-Crafts alkylation of unactivated gem-difluorocarbons can be achieved using a stoichiometric amount of AlCl3. The subsequent synthesis of alkenyl chlorides via F/Cl exchange followed by an elimination can be accomplished using AlEt2Cl as a fluoride scavenger and halogen source. The defluorinative elimination of acyclic and cyclic gem-difluorocarbons to give monofluoroalkenes can be achieved using AlEt3.

www.nature.com/scientificreports www.nature.com/scientificreports/ carbocation intermediates. Meanwhile, due to their comparatively lower steric congestion, primary monofluoroalkanes have been used for Finkelstein-S N 2-type halogen-exchange reactions 32,33 . However, in spite of recent advances in transition-metal-catalyzed reactions of activated allylic or propargylic gem-difluoroalkanes 34,35 , there are only a few synthetic methods that use classical aluminum-based Lewis acids on gem-difluorocarbon-type substrates. In early examples, the alkylation and chlorodefluorination of benzylic gem-difluorocarbons has been achieved using an excess of AlCl 3 , AlMe 3 , or AlPh 3 28 . Subsequently, the S N 2′-type alkylation of difluorohomoallyl alcohols can be controlled by trialkylaluminum compounds, which can coordinate to fluorine and adjacent oxygen atoms 36,37 . Recently, it has been reported that Al(OTf) 3 enables the defluorinative cycloaddition/aromatization between benzylic 2,2-difluoroethanol and nitriles to afford oxazoles 38 . Nevertheless, breaking C(sp 3 )-F bonds in unactivated gem-difluoroalkanes remains highly challenging [39][40][41] . In 2018, Young and co-workers achieved the selective monodefluorination of benzylic and non-benzylic gem-difluoromethyl compounds using a frustrated Lewis pair approach based on B(C 6 F 5 ) 3 and P(o-Tol) 3 to generate monofluoro phosphonium salts, which were subsequently convert into monofluoroolefins using Wittig protocols (Fig. 1a). Although the activation of benzylic gem-difluoromethyl groups proceeds in good yields (Fig. 1a), the abstraction of fluoride from unactivated 1,1-difluoroalkanes does not proceed well, and the more fluorophilic Lewis acid [Al(C 6 F 5 ) 3 ·(C 7 H 8 )] (2 equiv.) was required for the transformation, which proceeded in lower yields (Fig. 1b) 40 .
The occurrence of "over reactions" and poor reaction selectivity, which are mainly caused by unexpected transformations 32,39 that include hydride shifts, hydrogen fluoride (HF) eliminations, and skeletal rearrangements of unstable fluoro-substituted carbocation intermediates generated from the initial abstraction of fluoride from a gem-difluoromethyl moiety, renders controlled synthetic methods highly desirable. Recently, we have reported the selective synthesis of spirobiindanes and monofluoroalkenes using B(C 6 F 5 ) 3 and hexafluoroisopropanol (HFIP), which exhibits a very high affinity toward fluoride 41 . Although the method is of great importance as a proof-of-concept, the reaction still requires high temperatures and the relatively expensive reagents B(C 6 F 5 ) 3 and HFIP, which are critical for this transformation. Our continued interest in the activation and modification of inert C(sp 3 )-F bonds 41,42 has led us to examine ubiquitous aluminum-based Lewis acids of low cost for the selective synthesis of spirobiindanes (2), alkenyl chlorides (3), and monofluoroalkenes (4) from unactivated gem-difluoroalkanes (1) under mild conditions. Specifically, we used stoichiometric amounts of AlCl 3 , AlEt 2 Cl, or AlEt 3 in this study to induce aluminum-fluorine (Al-F) interactions 29,43,44 for the direct abstraction of fluoride (Fig. 1c).

Results
Optimization study. The results of the screening of Al-based Lewis acids for the cleavage of C(sp 3 )-F bonds are summarized in Table 1. Initially, we selected the simple unactivated aliphatic difluoroalkane 3,3-difluoropentane-1,5-diyl)dibenzene (1a) as a substrate. When 2.2 equiv. of AlCl 3 was used to initiate an intramolecular Friedel-Crafts cyclizations, the targeted 2,2′,3,3′-tetrahydro-1,1′-spirobi[indene] (2a) was formed in 72% yield ( Table 1, entry 1), albeit under heterogeneous conditions. Attempts to render the reaction catalytic were unsuccessful, i.e., the formation of 2a was observed in <10% yield when 0.2 equiv. of AlCl 3 were used (entry 3). However, when 1.1 equiv. of AlCl 3 were used for the degradation of fluorinated 1a, the defluorinative chlorination/elimination product (3-chloropent-2-ene-1,5-diyl)dibenzene (3a) was formed in 24% yield, together with 2a in 39% yield (entry 2). As alkenyl chlorides represent useful building blocks for the formation of complex organic architectures [45][46][47][48] , establishing control by preventing such "over reactions" in favor of alkenyl chlorides 3 would most likely be as attractive as it would be challenging. To solve this problem, we aimed at decelerating the heterolysis of C(sp 3 )-F bonds in gem-difluoroalkanes 1 by tuning the Lewis acidity of the aluminum reagents, which could potentially establish control over the reaction selectivity and exclusively afford alkenyl chlorides 3. Therefore, we focused our attention on organoaluminum reagents with reduced Lewis acidity by adding electron-rich alkyl substituents to the central aluminum atom (entries 4-7).
Recently, it has been reported that an equimolar amount of AlEtCl 2 promotes an intermolecular S N 1′-type substitution in 2-trifluoromethyl-1-alkenes 29 . However, when we treated 1a with 2.2 equiv. of AlEtCl 2 , we obtained only a tar-like complex mixture (entry 4). Yet, when using the weaker Lewis acid AlEt 2 Cl, alkenyl chlorides 3 formed exclusively, i.e., the desired 3a was obtained in 92% yield and the formation of side products was not observed (entry 5; for more details, see also Supplementary Fig. 76 in SI). AlEt 2 Cl has already been reported to facilitate F/Cl exchange reactions in aliphatic monofluoroalkanes at −78 °C via S N 1-or S N 2-type mechanisms, albeit that these reactions exhibit a very limited substrate scope 32 . Using AlEt 3 under otherwise identical reaction conditions afforded monofluoroalkene 4a in 51% yield without producing any Friedel-Crafts alkylation products (2a). Further improvement of the yield of 4a to 85% was observed upon conducting the reaction in n-hexane, using 1.5 equiv. of AlEt 3 , and prolonging the reaction time (entry 7; for more details, see also Supplementary Table 1 in SI). However, it should be noted here that the AlEt 3 -mediated defluorinative elimination of 1,1-difluorocyclopentane has already been reported by Ozerov, albeit only in one special case 39 . Specifically, the formal HF-abstraction product 1-fluorocyclopent-1-ene was observed in 24% 19 F NMR yield after a C 6 D 12 solution of 1,1-difluorocyclopentane (1.5 M) in a J. Young tube had been treated for 24 h with AlEt 3 (2.0 equiv.) at room temperature 39 . Modifying the substituents on the central aluminum atom (AlCl 3 , AlEt 2 Cl, and AlEt 3 ) allowed tuning the reaction selectivity for the heterolysis of the C(sp 3 )-F bonds in unactivated gem-difluoroalkanes 1. Fig. 2, aliphatic gem-difluoroalkanes substituted with alkyl groups (1a-f) afford moderate to high yields (up to 85%) of the corresponding spirobiindanes, whereby C2-substituted substrates (1a,b) perform slightly better than C4-substituted substrates (1c-e). Interestingly, when using methoxy-substituted gem-difluoride 1 g, alkenyl chloride 2,2′-(3-chloropent-2-ene-1,5-diyl)bis(methoxybenzene) (3 g) was formed in 38% yield, and the desired Friedel-Crafts alkylation product (2 g) was not observed. Consistent with our strategy that a modification of the Lewis acidity could potentially control the reaction selectivity, the oxygen atom in 1 g probably coordinates to the aluminum center of AlCl 3 and thus reduces its Lewis acidity, which would hamper the fluoride-abstraction process, and thus switch the reaction pathway from the expected Friedel-Crafts alkylation to a chlorination/elimination process. The presence of halogen substituents in the gem-difluoroalkanes (1h-l) was well tolerated when using AlCl 3 , and the corresponding products were generated in acceptable yield (42-64%). Moreover, naphthyl-type 2 m, mixed product 2n, and the six-membered spiro-compound 2o were also obtained in good yield.

Substrate scope. As shown in
Subsequently, we examined the synthesis of tri-substituted alkenyl chlorides (3) using AlEt 2 Cl both as an activator and a chloro source (Fig. 3). High yields and good Z/E stereocontrol were observed in most cases; specifically, long-chain acyclic substrates, independent of their substitution pattern on the benzene ring, afforded the desired alkenyl chlorides (3a,b, 3p, 3d, 3h-k, 3q), including halogen-substituted products, in good to high yield (up to 96%) with good Z/E stereoselectivity (up to 21.4:1). In addition, moderate regioselectivity was observed for the defluorinative chlorination/elimination to provide the inner alkene product (3-chlorobut-2-en-1-yl)benzene (3 s), and only ~10% of the corresponding terminal alkene was formed. It should also be noted here that cyclic gem-difluoroalkanes (1t-v) are also well tolerated under the AlEt 2 Cl-mediated conditions, furnishing the targeted cyclic alkenyl chlorides (3t-3v) in acceptable yield (67-75%). www.nature.com/scientificreports www.nature.com/scientificreports/  www.nature.com/scientificreports www.nature.com/scientificreports/ Monofluoroalkenes 4 were obtained via a defluorination/elimination process (Fig. 4). As expected, long-chain acyclic substrates, independent of their substitution pattern on the benzene ring, furnished the desired monofluoroalkenes (4a-b, 4d, 4i,j, 4f, and 4q in moderate to good yield (up to 77%) with good Z/E stereocontrol (up to 12:1). In particular, dialkyl-substituted substrates 1 f and 1q generated the corresponding monofluoroalkenes (4 f and 4q) in 72% and 74% yield, respectively. Furthermore, the defluorination of cyclic substrates including large-ring-type gem-difluoroalkanes proceeded smoothly to afford the corresponding cyclic monofluoroalkenes (4t, 4 u, and 4w) in moderate yield (40-50%) 39,49,50 . Mechanistic investigations. In order to avoid "over reactions" during the modification of inert C(sp 3 )-F bonds in saturated gem-difluoroalkanes (1), we reduced the Lewis acidity of the Al-based promoters. We observed that such "controllable reactions" stopped at the defluorinative elimination or F-Cl exchange/elimination stage, while further Friedel-Crafts alkylations did not occur. Indeed, using methoxyl-substituted fluorocarbon 1 g and AlCl 3 (Fig. 2) represents a special case, as it does not generate the desired spiro product 2 g, but alkenyl chloride 3 g in 38% yield. Accordingly, the vital importance of the Lewis acidity of the aluminum promotors for the reaction selectivity can feasibly be rationalized under consideration of two points: 1. The abstraction of a fluoride anion from the C(sp 3 )-F bonds is facilitated with increasing strength of the Lewis acidity of the main-group promoter, as the fluorine moiety is neither a good Lewis base nor a good leaving group 13 [54][55][56][57] , as well as due to the heterogeneous reaction conditions when using aluminum trichloride 58,59 , control experiments were conducted (Fig. 5) and a feasible reaction mechanism that would explain the high reaction selectivity is outlined in Fig. 6.
Initially, the strong Al-F interaction could promote the cleavage of one C(sp 3 )-F bond in gem-difluoroalkanes to give one tight ion pair (A) between a fluorinated carbocation and a conjugated Lewis base [LA-F] − counter ion. Then, the reaction could proceed via three competitive reaction pathways: 1. Direct elimination of the acidic α-proton of the fluorinated carbocation intermediate to give monofluoroalkenes 4, which is favored in the presence of AlEt 3 ; 2. Twofold intramolecular Friedel-Crafts alkylation in the presence of AlCl 3 ; 3. F-Cl exchange reaction via S N 1-type substitutions 32 in the presence of AlCl 3 or AlEt 2 Cl. Subsequently, the second abstraction of a fluoride anion could generate the tight ion pair C, which bears a chlorinated carbocation. In a similar fashion, the direct Friedel-Crafts alkylation, the F-Cl exchange, and the E1-type elimination represent three competitive reaction pathways. As mentioned above, when 1.1 equiv. of AlCl 3 were used, the trisubstituted alkenyl chloride was detected in 24% yield (Table 1, entry 2). Using alkenyl chloride 3a as the chlorinated carbocation precursor furnished the intramolecular Friedel-Crafts type product 2a in 51% yield in the presence of 1.1 equiv. of AlCl 3 , while 31% yield were observed when using monofluorinated olefin 4a as the precursor for the fluorinated carbocation intermediate under otherwise identical reaction conditions (Fig. 5). Meanwhile, the F-Cl-exchange-type product 3,3-dichloropentane-1,5-diyl)dibenzene (5) also generated spirobiindane 2a in 52% yield. These results indicate that the cascade intramolecular Friedel-Crafts cyclization is a complex transformation that involves fluorinated carbocations and chlorinated carbocation intermediates, as well as competitive F-Cl exchange reaction pathways. Although we were unable to capture any F-Cl exchange products such as gem-chlorofluoroalkane 6 when using www.nature.com/scientificreports www.nature.com/scientificreports/  www.nature.com/scientificreports www.nature.com/scientificreports/ 0.5 equiv. or 1.0 equiv. of AlEt 2 Cl, the double F-Cl exchange product gem-dichloroalkane 5 was observed in 13% and 21% yield, respectively ( Fig. 5; for more details, see the NMR study in Supplementary Figs. 78-85 in SI). Thus, alkenyl chloride 3 is probably generated from the double F-Cl exchange product gem-dichloroalkane 5, which may serve as a reservoir for the chlorinated carbocation intermediate in the tight ion pair C.

Discussion
In conclusion, we have developed a highly selective synthetic route to spirobiindanes 2, trisubstituted alkenyl chlorides 3, and monofluoroalkenes 4, based on the aluminum-induced cleavage of inert C(sp 3 )-F bonds in unactivated gem-difluoroalkanes 1. The three reaction types can be selectively controlled by using the readily available aluminum-based Lewis acids AlCl 3 , AlEt 2 Cl, or AlEt 3 . Since the reaction can be performed using ubiquitous and cheap aluminum-based Lewis acids at room temperature, these methods should be of high practical utility.

Methods
General procedure for the intramolecular Friedel-Craft reaction of gem-difluoroalkanes. In a flame-dried test tube (10 mL), to the heterogeneous solution of AlCl 3 (29.3 mg, 0.22 mmol, 2.2 equiv.) in dry CH 2 Cl 2 (0.5 mL), gem-difluoroalkanes 1 (0.1 mmol) in dry CH 2 Cl 2 (0.5 mL) was added dropwise by syringe, and the reaction mixture was stirred at room temperature for 2 hours under a positive pressure of argon with a balloon. Then, the resulting mixture was washed with water, extracted with CH 2 Cl 2 , dried over Na 2 SO 4 , filtered, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel using n-hexane as the eluent to afford the desired spirobiindanes 2a-n and spirobitetraline 2o. In addition, alkenyl chloride 3 g, 2,2′-(3-chloropent-2-ene-1,5-diyl)bis(methoxybenzene), was also prepared as one special example. In addition, the gem-difluoroalkanes 1 were prepared based on previous reports via fluorination of corresponding ketones by (diethylamino)sulfur trifluoride or 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead).
General procedure for the synthesis of alkenyl chlorides 3 from gem-difluoroalkanes 1. In a flame-dried test tube (10 mL), diethylaluminum chloride (255 μL, ca. 0.22 mmol, 2.2 equiv., ca. 15% in hexane, ca. 0.87 mol/L) was added slowly to the solution of gem-difluoroalkanes 1 (0.1 mmol) in dry CH 2 Cl 2 (0.1 M, 1.0 mL), and the reaction mixture was stirred at room temperature for 4 hours under a positive pressure of argon with a balloon. Then, the resulting mixture was washed with water, extracted with CH 2 Cl 2 , dried over Na 2 SO 4 , filtered, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel using n-hexane as the eluent to afford the desired alkenyl chloride 3. The ratio for Z/E isomers was determined by 1 H NMR based on previous literature.
General procedure for the synthesis of monofluoroalkene 4 from gem-difluoroalkanes 1. In a flame-dried test tube (10 mL), triethylaluminum (150 μL, ca. 0.15 mmol, 1.5 equiv.,15% in hexane, ca. 1.0 mol/L) was added slowly to the solution of gem-difluoroalkanes 1 (0.1 mmol) in n-hexane (0.1 M, 1.0 mL), and the reaction mixture was stirred at room temperature for 7 hours under a positive pressure of nitrogen with a balloon. Then, the resulting mixture was washed with water, extracted with CH 2 Cl 2 , dried over Na 2 SO 4 , filtered, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford the desired monofluoroalkene 4. The ratio for Z/E isomers was determined by 19 F NMR.

Data availability
The authors declare that all the data supporting the findings of this study are available within the paper and its supplementary information files, and also are available from the corresponding author upon reasonable request.