Additions to non-activated alkenes: Recent advances

1 Introduction

The carbon-carbon (C—C) bonds are the main feature of all skeleton of organic molecules. Hence, the development of new methods for C—C bond formation represent an important advance in the field of organic synthesis, providing improved routes to valuable compounds ranging from pharmaceutical agents to functional polymers (Corey and Cheng, 1989). Alkenes are among the most abundant classes of organic molecules, available in bulk quantities from petrochemical feedstocks and renewable resources (Yang et al., 2016). The widespread availability of alkenes combined with their unique reactivity profile has made alkene functionalization reactions essential in organic synthesis (Yang et al., 2016).

Therefore, some unique transition metal catalyst systems can activate the olefin double bonds leading to highly elegant as well as useful reactions. Famous examples include the Wacker process (Takacs and Jiang, 2003), olefin metathesis (Hoveyda and Zhugralin, 2007; Connon and Blechert, 2003), olefin hydroformylation (Evans, 2005) and Heck reaction (Corey and Cheng, 1995) that have been extensively used in the preparation of complex organic molecules both in laboratory and in industry. These reactions establish the central role of olefins in modern synthetic organic chemistry as well as chemical industry.

More recently, non-activated alkenes have been used directly as chemical input in some novel functionalization reactions (Lu et al., 2016). As it will be demonstrated later in this review, different and elegant methods have been used, in recent years, for the construction of C—C bonds (Dao et al., 2015; Yang et al. 2016), and more interesting, C-heteroatom bond building (such as carbon-halogen (Kindt and Heinrich, 2014; Thomoson et al., 2015) –nitrogen (Shigehisa et al., 2014; Gui et al., 2015), –phosphorous (Troupa et al., 2015; Espinal-Viguri et al., 2016)) and others) using these alkene types as a subtracts.

First of all, it is important to define the terms “non-activated” and “unactivated” alkenes. Therefore, conventionally, the organic chemical community defines an alkene (also known as an olefin) as an unsaturated chemical compound containing at least one carbon-carbon double bond (Wade, 2006). Therefore, in this present review, the term “non-activated alkene” and “unactivated alkene” refers to an alkene without electron-withdrawing groups (EWG) directly attached to the double bond.

For among all of the presented examples, it could be expected different reactivity’s between them. For instance, as will be seen in this review exomethylenes (1,1-disubstituted and trisubstituted) demonstrated a significantly higher reactivity than terminal variants (the extreme case of “non-activated alkenes”). Terminal olefin appears to need more activation energy than exomethylenes (Lenardão et al., 2013; Dao et al., 2015).

Non-activated alkenes are inexpensive starting materials for synthesis. As substrates, non-activated alkenes, especially terminal alkenes, are among the most attractive synthons for chemical synthesis since a wide array of them are stable and readily available from several sources in low-cost. In addition, compounds with an unactivated olefin are relatively inert and thus resistant to the conditions of several synthetic transformations (Xu and Negishi, 2016).

As it will be showed in this review, non-activated alkenes, despite their lower reactivity can participate in several types of organic addition reactions in order to create a wide variety of carbon skeletons (Dao et al., 2015; von Delius et al. 2012; Wang et al., 2012; Hewitt et al., 2013). Actually, their lack of reactivity is a useful tool, because that could means an improvement of selectivity and more resistance to several reaction conditions and compatible with different substituent groups (no collateral reactions observed).

2 Synthesis of fluoro-, chloro- and bromo- compounds

It is well documented in the literature that the incorporation of a fluorine atom into drugs often leads to a significant improvement of their medicinal properties, which has resulted in a revolution in the pharmaceutical industry in the past decades (Filler and Kobayashi, 1982). Fluoroalkylated compounds are considered important in pharmaceutical industry because of their superior lipophilicity, binding selectivity, metabolic stability, and bioavailability to those of their nonfluoroalkylated analogues (Chatterjee et al., 2016).

In the last few years, several methods have been reported for the insertion of one, two or even three fluorine atoms into carbon-carbon bond of non-activated alkenes. In the first section of this review, a list of these recent studies will be described.

In 2012, Barker and Boger (2012) reported a powerful Fe(III)/NaBH₄-mediated free radical hydrofluorination of non-activated alkenes using Selectfluor® as a source of fluorine resulting in an exclusive Markovnikov addition of one fluorine atom (Scheme 1). This method of hydrofluorination with alkenes 1a-d was conducted under mild reaction conditions (0 °C, 5 min, CH₃CN/H₂O) in an open flask, in the presence of air and water as a co-solvent. The method can be applied to several substrates having different functional groups. In Scheme 1 are represented several monofluorinated derivatives prepared from alcohol 1a, ester 1b, epoxide 1c and even from ester derivative 1d in good to excellent yields.

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Scheme 1 Fe(III)/NaBH4-mediated free radical hydrofluorination of non-activated alkenes 1a-d.

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One year later, Shigehisa et al. (2013) developed a catalytic hydrofluorination of olefins using a cobalt catalyst. The exclusive Markovnikov selectivity, functional group tolerance, and scalability of this reaction makes it an attractive protocol for the hydrofluorination of unactivated olefins. A preliminary investigation of the mechanism revealed the involvement of a radical intermediate. By using this method several monofluorinated alkanes 6a-d were prepared in good yields (Scheme 2).

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Scheme 2 Hydrofluorination of olefins 4a-e, using a cobalt catalyst.

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Li et al. (2013) also used SelectFluor®s 2 as fluorine transfer reagent to develop a mild and catalytic intramolecular aminofluorination of unactivated alkenes 7a-f. The best catalyst for these reactions was AgNO₃, which efficiently produced various 5-fluoromethyl- γ-lactams 8 (Scheme 3). It should be noted that substrates with different substitution on the alkenyl chain also underwent smooth 5-exo cyclization. In addition, amides and ureas could also be used in this transformation, as exemplified by the synthesis of 8e and 8f from the corresponding substrates 7e and 7f, with 84% and 68% yield, respectively.

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Scheme 3 Catalytic intramolecular aminofluorination of unactivated alkenes 7.

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Wu et al. (2013a,b) developed a regioselective intramolecular aminofluorination of unactivated alkenes 9 and 10 catalysed by Pd, in which a primary Csp³—Pd bond was selectively fluorinated by AgF/PhI(OPiv)₂ in the presence of hexafluoroisopropyl alcohol (HFIP). This method allowed the preparation of monofluoromethylated nitrogen-containing heterocycles 11 and 12, respectively, in good yields (Scheme 4).

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Scheme 4 Intramolecular aminofluorination of unactivated alkenes 9 and 10.

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Kong et al. (2013) reported the first regioselective application of an intramolecular metal-free aminofluorination of unactivated alkenes by using difluoroiodonium salts. Styrenes derivatives 13a-d were transformed into 2-fluoro-2-phenylethanamines 15a-d in high yields (Scheme 5).

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Scheme 5 Intramolecular, metal-free aminofluorination of unactivated alkenes 13.

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Other methods to obtain mono-fluorinated compounds are the phosphonofluorination and the carbofluorination reactions. Zhang et al. (2013a,b) developed a catalytic radical phosphonofluorination reaction of unactivated alkenes 16 via condensation with diethyl phosphite and SelectFluor®, synthetizing β-fluorinated alkylphosphonates 17a-d (Scheme 6). These reactions proceeded under mild conditions in aqueous media and were applied to a broad range of substrates (16a-d) (Scheme 6).

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Scheme 6 Phosphonofluorination reaction of unactivated alkenes 16a-d via condensation with diethyl phosphite and SelectFluor®.

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One year later, Kindt and Heinrich (2014) described the first metal-free intermolecular Meerwein-type carbofluorination reaction (Scheme 7). Alkenes 18a-g were evaluated as suitable for carbofluorination using the arylhydrazines 19a-c and Selectfluor®, as fluorinating and oxidant agent. The aryl carbofluorine derivatives 20a-i were obtained in yields ranging from 11% to 45% (Scheme 7).

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Scheme 7 Intermolecular Meerwein-type carbofluorination reaction metal-free of the 18a-d.

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Another big step in the fluorine addition to unactivated olefins was the preparation difluorinated compounds.

In 2013, Sumino et al. (2013) explored photoirradiation conditions using a low-pressure mercury lamp, to prepared difluorinated compounds from non-activated alkenes 22 and 23, using α-Bromo ester 21 (Scheme 8). The reaction was conducted in hexane/H₂O (10 mL/100 μL) for 6 h and the corresponding addition/reduction products 24 and 25 was obtain with 46% and 59%, respectively.

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Scheme 8 Difluorination procedure of non-activated alkenes 22 and 23.

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In this study, the authors proposed a nonchain radical mechanism involving C—Br homolysis and rapid conversion of the resulting bromine radical to HBr by H-abstraction of alkenes. A mechanistic proposal is illustrated in the Scheme 9.

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Scheme 9 Mechanistic proposal to the synthesis of derivatives 24 and 25.

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Ma et al. (2014) reported a mild and efficient procedure to hydrodifluoromethylation of unactivated alkenes mediated by a silver catalyst. This reaction led to hydro-(ethoxycarbonyl)difluoromethylation of the vicinal C⚌C bond to construct the moiety Csp³–CF₂ (Scheme 10).

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Scheme 10 Silver-mediated hydrodifluoromethylation of unactivated alkenes 26a-e.

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After protocol’s optimization, the authors examined a range of unactivated terminal monosubstituted alkenes that were capable of undergo silver(I)-mediated hydrodifluoromethylation with TMSCF₂CO₂Et. In addition, these mild reaction conditions of hydrodifluoromethylation of alkenes allowed the preparation of a wide range of substrates and functional groups, including esters, sulfonic esters, ethers, amides, imides, (hetero)arenes, ketones, and protected amines. The reactions were regioselective and afforded the desired products in good to high yields (Scheme 10). In all the cases, the hydrodifluoromethylated compounds 27a-e were the major products. Moreover, terminal alkenes derived from coumarin 26b, 3-hydroxyflavone 26c and 4-methyl-umbelliferone 26a, which contained two inequivalent alkenyl groups, showed excellent chemoselectivity. The method was extended to 1,1-disubstituted alkene 26e which under the same reaction conditions was converted into the product 27e in 76% yield (Scheme 10). This study did not show significantly different reactivity for 1,1-disubstituted alkene 26e comparing to other mono-substituted substrates.

In 2015 Thomoson et al. (2015) developed a method for metal-free carbomethoxydifluoromethylation of a variety of unactivated alkenes 28, using sulfonyl chlorides CF₂HSO₂Cl 29a and MeO₂CCF₂SO₂Cl 29b as the radical precursors (Scheme 11). This mild protocol enables the addition of HCF₂ or MeO₂CCF₂ groups to alkenes in a highly regioselective way. Some selected examples are presented in the Scheme 11.

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Scheme 11 Metal-free carbomethoxydifluoromethylation of unactivated alkenes 28a-c.

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Recently, Yu et al. (2016) reported a method of carbomethoxydifluoromethylating using methyl fluorosulfonyldifluoroacetate reagent (FO₂SCF₂CO₂Me, Chen’s reagent) under visible light irradiation producing a variety of carbomethoxydifluoromethylated products (Scheme 12). Various unactivated alkenes were transformed into the corresponding saturated products in moderate to excellent yields. This reaction tolerates a variety of functional groups present in some unactivated olefin, such as 31c and 31d. Interestingly, estrone-derived terminal olefin 31e was also a very good subtract to this protocol (Scheme 12).

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Scheme 12 Carbomethoxydifluoromethylation of unactivated alkenes 33a-e under visible light.

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A further method of light-dependent difluorination was developed by Yoshioka et al. (2016) (Scheme 13). This method demonstrated that a water-soluble organic dye, rhodamine B, was capable to induce the carbon-carbon bond-forming radical reactions in aqueous media. Alkenes 34 and 35 was submitted to an addition−cyclization−trapping reaction using perfluoroalkyl iodide 36, in the presence of Rhodamine B and (i-Pr)₂NEt as a reductive quencher, yielding the compounds 37 and 38 with 73% and 47%, respectively (Scheme 13).

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Scheme 13 Light-dependent difluorination of alkenes 34 and 35.

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Parsons and Buchwald (2011) developed an allylic trifluoromethylation of unactivated terminal olefins 39, using Togni reagent I (40) and a copper complex as catalysts (Scheme 14). The mild conditions for this transformation enabled the trifluoromethylation of a range of substrates 39 with several different functional groups. Some selected examples (e.g. 39a-d) are represented in Scheme 14. It is noteworthy that this trifluormethylation occurred with the migration of the double bond.

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Scheme 14 Allylic trifluoromethylation of unactivated terminal olefins 39a-d.

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Zu and Buchwald (2012) reported another mild and versatile method for the oxytrifluoromethylation of unactivated alkenes 42a-d based on a copper(I)/2,2′-biquinoline catalytic system (Scheme 15) allowing the preparation of a range of synthetically useful building blocks such as CF₃-containing lactones, cyclic ethers, and epoxides. Hybrid olefins having carboxylic acids, alcohols and phenols served as suitable nucleophiles in this intramolecular process. Additionally, this process is also compatible with a range of functional groups including amides 42a, β-lactones 42c, epoxides 42d and aryl bromides 42b. All the reactions were carried out using simple bench-top set-up (Scheme 15).

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Scheme 15 Oxytrifluoromethylation of unactivated alkenes 42a-d.

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Zu and Buchwald (2013) proposed a mechanism for this process, as depicted in Scheme 16. The mechanism is consistent with a single-electron transfer between 40 and the Cu(I) catalyst, which generates a CF₃ radical and a Cu(II) complex. Then, the CF₃ radical adds to the alkene, giving the intermediate D, which undergoes enantioselective C—O bond formation mediated by the Cu(II) species, thus affording the lactone product while regenerating the Cu(I) catalyst.

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Scheme 16 Mechanistic proposal to the synthesis of derivatives 43.

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Recent advances in the carbofluorination were described by Wang et al. (2014). An intermolecular trifluoromethylazidation protocol of unactivated alkenes under mild reaction conditions using Togni reagent II and catalysed by a copper complex afforded a range of new compounds containing CF₃- and azide groups, such as 44 and 48 (Scheme 17).

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Scheme 17 Intermolecular trifluoromethylazidation of alkenes 44a-c and 48a-d.

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These products can be easily transformed into the corresponding amine derivatives vicinal to CF₃ groups. They evaluated the scope of cyclic 47a-c and acyclic 44a-c alkenes, and they prepared more complex products, such as compound 48d, employing the less reactive Togni reagent II (46), as an oxidant as well as CF₃ source under mild reaction conditions (Scheme 17).

In addition to the previously method, Lin et al. (2014) reported a mild intramolecular aminotrifluoromethylation process of unactivated alkenes, which has high step economy and tolerate a variety of nitrogen-based nucleophiles in the presence of a simple copper salt catalyst (Scheme 18). Many different nitrogenated nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulphonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction as shown in the Scheme 18.

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Scheme 18 Intramolecular aminotrifluoromethylation of unactivated alkenes 49a-f.

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The authors, also evaluated the scope of this reaction using unactivated alkenes with sulphonamides or free amines using the following optimized conditions: CuI (10 mol% for free amines 49d-f and 25 mol% of sulphonamide derivatives 49a-c), Togni reagent (40, 1.5 equiv.), in dichloroethane (DCE), at 75 °C for different periods, obtaining the derivatives 50a-f with good to excellent yields (Scheme 18).

Chen et al. (2015) also reported a catalytic trifluoromethoxylation of unactivated alkenes 51 using Pd(CH₃CN)₂Cl₂ as catalyst, AgOCF₃ as trifluoromethoxide source and Selectfluor-BF₄ as oxidant. Appling this procedure a variety of 3-OCF₃ substituted piperidines 52a-d were selectively obtained in good yields (Scheme 19).

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Scheme 19 Catalytic trifluoromethoxylation of unactivated alkenes 51a-d.

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Another approach for the derivatization of unactivated alkenes is the reductive intermolecular process. With this aim in mind and as a further extension of this field, Mizuta et al. (2013) have prepared several products by reductive intermolecular hydrotrifluoromethylation that consists of regioselective addition of CF₃ to alkenes 53a-e (Scheme 20). The authors used in this hydrotrifluoromethylation the Umemoto reagent 54 as the CF₃ source, methanol as the hydrogen donor and 5 mol% of Ru(bpy)₃Cl₂ as the catalyst at room temperature (Scheme 20).

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Scheme 20 Regioselective addition of CF₃ onto alkenes 53a-e.

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Wu et al. (2013a,b) developed another method of hydrotrifluoromethylation of simple alkenes 56a-c catalysed silver using nucleophilic CF₃SiMe₃ in the presence of PhI(OAc)₂. This mild reaction allowed the synthesis of a series of trifluoromethylated alkanes 57a-c bearing a wide range of functional groups (Scheme 21).

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Scheme 21 Hydrotrifluoromethylation of simple alkenes 56a-c.

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More interestingly, Wilger et al. (2013) developed a direct method for the metal-free hydrotrifluoromethylation of alkenes (Scheme 22). The method relies on the single electron oxidation of a commercially available sodium trifluoromethanesulfinate salt (CF₃SO₂Na, Langlois reagent) intermediated by N-Me-9-mesityl acridinium 60 as a photoredox catalyst. Methyl thiosalicylate 59b is used as a stoichiometric H-atom donor for aliphatic alkenes 58a-b, and thiophenol 59a is used as a stoichiometric H-atom donor for styrenyl substrates 58c.

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Scheme 22 Metal-free hydrotrifluoromethylation of alkenes 58a-c.

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Deb et al. (2013) disclosed a direct, efficient, and general method to access α-substituted ketones with CF₃ group (Li and Studer, 2012) from trisubstituted alkenes 62a-d (Scheme 23). This oxidative trifluoromethylation were conducted in CF₃SO₂Na as the CF₃ source for the synthesis of α-CF₃-substituted ketones 63a-d, in moderate to good yields.

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Scheme 23 Preparation of α-CF₃-substituted ketones 62a-d.

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In a continuing effort to find new methods of insertion of three fluorine atoms into organic compounds with non-activated alkenes could be achieved using thio-fluorinated or methoxy-fluorinated reagents. Yang et al. (2015) reported an iron-mediated hydrotrifluoromethylthiolation of unactivated olefins 64a-d under mild conditions. This reaction occurred to full conversion within 30 min at 0 °C and tolerates a variety of functional groups (Scheme 24).

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Scheme 24 Iron-mediated hydro-trifluoromethylthiolation of unactivated olefins 64a-d.

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The authors showed that terminal olefins have excellent Markovnikov selectivity, while the internal olefin provided the addition product with a ratio of 1:1. The reactions of sterically hindered trisubstituted alkenes with trifluoromethylthiolating reagent 65 generated only trace amount of the addition product. To clarify some aspects of this matter, they used the trifluoromethylthiolated phthalimide 66 as the radical trap, which allowed to obtain the hydrotrifluoromethylthiolation products with good yields. In the Scheme 24 has shown some of these studied examples.

In 2017, Wu et al. (2017) reported, by the first time, a general method for —CF₃ unit insertion on unactivated alkenes by difunctionalization reaction with distal heteroaryl ipso-migration (Scheme 25).

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Scheme 25 Synthesis of derivatives 69a-f, by difunctionalization reaction with distal heteroaryl ipso-migration.

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According to this procedure, a variety of five- and six membered heteroaryl groups on tertiary alcohol migrate selectively in the presence of an aryl group. This migration reaction could be induced by fluoroalkylation under mild reaction conditions (room temperature), readily affording a variety of fluoroalkyl functionalized heteroarenes 69a-f, in 65–87% yields (Scheme 25).

In addition, the same group (Xu et al., 2017) have described an approach for the radical-mediated alkynylation of unactivated olefins 70a-d by means of intramolecular distal alkynyl migration (Scheme 26). According to their study, alkynyl migration is induced by the addition of a trifluoromethyl radical, which is readily generated by use of the Umemoto’s reagent under visible light irradiation. This mild condition’s procedure provided for the first time, by olefin difunctionalization with concurrent distal alkynyl migration, useful trifluoroethylated linear alkynes 71a-d in 50–78% yields (Scheme 26).

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Scheme 26 Radical-mediated alkynylation of unactivated olefins 70a-d.

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Another challenging reaction in organic synthesis is the functionalization of non-activated C—H bonds to prepare chloro-derivatives with biological interest (Naumann, 2003). As further expansion of this plentiful area of research, Kamijo et al. (2012a) developed a chemo- and regioselective protocol for attachment of various cyano functionalities onto unactivated olefins 72 (Scheme 27). In this procedure, the atom transfers radical reactions of Cl₃CCN 73a and Cl₂C(CN)₂ 73b were all promoted efficiently by a catalytic amount of CuCl and 1,10-bis(diphenylphosphino)ferrocene to introduce chloromethylcyanide and chloride units to the C⚌C double bonds.

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Scheme 27 Chemo- and regioselective synthesis of compounds 74a-b.

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The same group (Kamijo et al., 2012b) reported an improved metal-free atom transfer radical reaction (ATRA) protocol using microwaves radiation to accelerate the reaction. By using this process reacted polychlorinated compounds with unactivated terminal olefin 75a to generate 1,3-dichlorinated adducts under microwave irradiation in the presence of silicon carbide (SiC) as a heating element (Scheme 28). This microwave-assisted ATRA proceeds under essentially neutral conditions (Scheme 28).

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Scheme 28 Synthesis of the chlorinated compounds 78a-d and 76.

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Also in 2012, Wallentin et al. (2012), reported a visible light-mediated ATRA of haloalkanes onto alkenes (Scheme 29).

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Scheme 29 Reductive coupling and cyclization reactions of terminal alkenes 79.

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The authors optimized the reaction conditions for reductive coupling and cyclization reactions with tertiary amines as stoichiometric electron donors. They employed [Ir{dF(CF₃)ppy}2(dtbbpy)]PF₆, as a catalyst, in the photocatalytic ATRA between various activated halides and alkenes, in the Scheme 29 it is illustrated for terminal alkene 79.

This protocol proved to be efficient when it was used terminal alkene 79 and activated alkyl bromides 80, but it is not applied to activated alkyl chlorides, 1,2-disubstituted alkenes, or styrene derivatives (Scheme 29). However, the authors solved this limitation by utilizing [Ru(bpy)₃]Cl₂ or [Ir{dF(CF₃)ppy}₂(dtbbpy)]PF₆ in DMSO instead of a DMF/H₂O mixture (data not shown).

Franz et al. (2015) also using the ATRA strategy prepared the carbon-chlorine addition product 76 from ω-hydroxy alkene 75b in excellent yield and selectivity comparable to catalyst mediated processes (Scheme 28).

3 Synthesis of alkyl/vinyl/aryl/heteroaryl compounds

Olefins are a platform for the synthesis of alkylated, vinylated, arylated or heteroarylated products via activation of π-bonds toward nucleophilic attack. In this regards, gold-catalysts have been extensively used in hydrofunctionalization from simple starting materials.

Xiao et al. (2011) developed the first protocol for direct hydroalkylation of unactivated alkenes with simple α-ketone, using gold(I) complexes as catalysts in the absence of additives (Scheme 30). This method is very efficient for the synthesis of substituted cyclic compounds in high yields and good diastereoselectivity.

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Scheme 30 Intramolecular hydroalkylation of unactivated alkenes with α-ketones 82a-e.

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Several conditions were tested to find the optimal conditions, which are 0.025 mmol of substrate 82, 5 mol% of [IPrAuCl]/AgClO₄, in toluene at 90 °C. Using these conditions, they explored the scope of the protocol with respect to other alkenyl α-ketone substrates (Scheme 30). The changing of the alkenyl alkyl ketone to alkenyl aryl ketones 82a–e did not have a significant influence on the product yield and diastereoselectivity. In all cases, the trans diastereomer was favoured with good to excellent selectivity.

Recently Dao et al. (2015) reported a chemoselective hydromethylation reaction, which tolerates labile and reactive chemical functionalities (a classic and recurrent problem), using simple reagents (Scheme 31).

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Scheme 31 Chemoselective hydromethylation reaction of alkenes 84a-d.

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Therefore, a selection of olefins, including mono-, di-, and trisubstituted olefins, are all hydromethylated. This protocol allowed simplifying the synthesis of a specific target or for direct functionalization of complex natural products and other advanced materials. With this method, the authors opened the possibility to the simple installation of radioactive and stable labeled methyl groups.

Yang et al. (2016) reported a method to construct C—C bonds from two classes of alkenes and carbon−hydrogen (C—H) bonds (Scheme 32). Palladium(II) catalyst was used with several alkenes and masked 8-aminoquinoline (AQ) amide, and several nucleophiles allowed preparing the hydroalkylation product 87. The reaction mixture was heated to 120 °C in a sealed tube with 10 mol% Pd(OAc)₂, AcOH or 4-methoxybenzoic acid as a co-catalyst, and acetonitrile as a solvent. Under these conditions, the authors find that a wide array of different derivatives were prepared in good yields with anti-Markovnikov hydroalkylated products 87a-e. Additionally, they could demonstrate the scale up possibility of this method, 830 mg of 87e was synthesized under the standard reaction conditions (Scheme 32).

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Scheme 32 Synthesis of the hydroalkylated compounds 87a-e.

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The transition-metal-catalysed 1,2- or 1,4-hydrovinylation of unactivated alkenes results in an atom-economic transformation in combination with C—H activation in the absence of a directing group (Hilt, 2015).

Arndt et al. (2012) investigated 1,4-hydrovinylation reaction between two unsymmetrical components. They reported a hydrovinylation of terminal alkenes 88 utilizing a cobalt complex with the Ligand (Scheme 33). The authors was obtained very interesting results applying styrene 88c as the alkene component yielding the regioisomer 90c almost exclusively. Many functional groups were accepted and very interesting building blocks were generated 90a-c, in very good yields.

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Scheme 33 1,4-hydrovinylation between 88a-c and 89.

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Unfortunately, this reaction is strongly limited to the substrate 2-methyl-1,3-pentadiene (89) and does not tolerate many other 1,3-dienes of this type.

The application of ethene with two different types of C-H acceptors was reported by Timsina et al. (2014), Carrilho et al. (2014). The products of type 93 and 95 are structurally more bulky compared with the starting materials so that the formation of higher products was unfavorable (Scheme 34).

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Scheme 34 Preparation of compounds 93 and 95, Timsina and Carrilho, respectively.

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In the last year, Movahhed et al. (2016) developed an efficient protocol for the enantioselective cobalt-catalyzed hydrovinylation of styrene 94 with ethene 91 at low (1.2 bar) pressure (Scheme 35). As a precatalyst, stable [LCoCl₂] complexes are employed that are activated in situ with Et₂AlCl. A modular chiral phosphine–phosphite ligand (L) was identified that allows the conversion of 94 with 73% ee (Scheme 35).

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Scheme 35 Enantioselective cobalt-catalyzed hydrovinylation of styrene 94 by Movahhed.

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Another addition reaction type of unactivated olefins is hydroalkenylation. Zargari et al. (2016) reported a hydrokenylation reaction by cross coupling between styrene 94 and cyclopentene 97, providing a coupling product 99, in 95% yield (Scheme 36). The authors used palladium and a BF₃ source which selectively gave rise to a new a new C—C bond. They think that the complex [Pd(PPh₃)₂]⁺BF₄⁻ was responsible to generate palladium hydride (Pd-H), which catalyzes the reaction between styrene 94 and cyclopentene 97 (Scheme 36).

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Scheme 36 Hydrokenylation reaction between styrene 94 and cyclopentene 97.

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Correia et al. (2012) demonstrated for the first time, an enantioselective reaction employing arenediazonium salts (Scheme 37). This method was applied in the enantioselective Heck–Matsuda (HM) reaction using chiral bisoxazolines as ligands. This method of HM arylations is simple, providing good to excellent yields of the adducts 103 (63–96%) in enantiomeric excesses which varied from 54% up to 84% e.e. (Scheme 37).

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Scheme 37 Enantioselective Heck–Matsuda reaction of olefin 100.

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A route in the synthesis of carboxylate-assisted ruthenium-catalysed hydroarylation of unactivated alkenes employing various (hetero)arenes with a large scope was reported by Schinkel et al. (2013) (Scheme 38). The authors employed a different substituted unactivated alkenes and heteroarenes. In the Scheme 26 is shown several selected examples of 105a-d and 103a-b, respectively, to furnish the corresponding products 106a-d in high yields.

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Scheme 38 Carboxylate-assisted ruthenium-catalysed hydroarylation of unactivated alkenes 105a-d.

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Schramm et al. (2015) reported a wide range of anti-Markovnikov hydroheteroarylations of unactivated olefins with heteroarenes catalysed by a nickel-NHC system (Scheme 39). The scope of this reaction includes unactivated terminal alkenes 107 or 108 with indoles 113, pyrroles 109b, benzofurans 113 and furans 109a as the heteroarene. It occurs regioselectively at C2, due to the selectivity of the catalyst. The process is enabled using specific hindered N-heterocyclic carbine ligands and tolerates a series of functional groups (Scheme 39).

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Scheme 39 Anti-Markovnikov hydroheteroarylations of unactivated olefins 107 and 108.

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A strategy based on hydropyridylation reaction was presented by the Ma and Herzon (2016). This method proceeds by hydrogen atom transfer to alkenes (Scheme 40) under mild conditions, compatible with 1,4 carbogenic substituents on the alkene, and leverages the selectivity of hydrogen atom transfer to achieve regiocontrol. The authors prepared a series of N-methoxy-2,6-dimethylpyridinium salts and observed that N-methoxy-2,6-dimethylpyridinium methylsulfate provided excellent yields and selectivities. The authors believed that the counter ion alters the coordination sphere of the cobalt, leading to less efficient hydrogen atom transfer and/or coupling of the alkyl radical.

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Scheme 40 Hydropyridylation reaction of olefins 116a-d.

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After the conditions’ optimization, the alkenes 116a-d, Co(acac)₂ (1.00 equiv.), t-butyl hydroperoxide (TBHP) (1.00 equiv), 117a-d (5.00 equiv) and Et₃SiH (5.00 equiv) in CH₂Cl₂ (0.2 M), 24 °C, 16 h allowed to synthetize the 118a-d derivatives, with 47–81% yield. They also evaluated the effect of other functional groups on the arene precursor; for that it was prepared a series of substituted N-methoxypyridinium salts 118a-d and additional alkenes were employed (Scheme 40).

Wang et al. (2012) described a Rh-catalysed intermolecular C-alkylation of cyclic 1,2-diketones using simple terminal olefins as alkylating agents. In this study, aminopyridine was employed as a recyclable directing group (Scheme 41). With such possibilities in mind, the ketones were reacted with alkenes and aminopyridine to give enamines catalysed by Rh in the one-pot reaction. The authors developed a method for to a broad range of olefins 119, including aliphatic 119a-d and aromatic olefins 119e. The efficiency of this method was also demonstrated in the synthesis of a natural flavouring compound, 3-ethyl-5-methyl-1,2-cyclopentadione 122f (Scheme 41).

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Scheme 41 Rh-catalysed intermolecular C-alkylation of cyclic 1,2-diketones 120a-b.

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Hewitt et al. (2013) developed a versatile catalytic heteroallylation reaction of unactivated alkenes 123 to form heterocycles 125 that are prevalent in a plethora of targets including natural products and bioactive compounds, like as Citalopram 126 (Scheme 42). The process forms a fully substituted carbon centre and a new sp³–sp³ C—C bond in a single step, and occurs using a commercially available catalyst under operationally convenient conditions (e.g. under air) (Scheme 42).

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Scheme 42 Heteroallylation reaction of unactivated alkenes 123a-d.

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4 Synthesis of phospho/sulfur/silyl/cyano- compounds

In this section, it will enumerate the recent available studies of synthetized phospho-, sulfur-, silyl, and cyano- substances originated from non-activated alkenes.

The catalytic addition of phosphines to alkenes is a very attractive process that offers access to phosphines in a 100% atom-economic reaction using readily available and inexpensive materials. The products are potentially useful ligands and organocatalysts (Espinal-Viguri et al., 2016).

Ortial et al. (2013) reported a room-temperature hydrophosphinylation of unactivated monosubstituted alkenes 127 using phosphinates 128 and catalytic NiCl₂ in the presence of Bis(diphenylphosphino)ethane (dppe) (Scheme 43). This reaction allows one-pot conversion to various organophosphorus compounds 129 (Scheme 43). The authors synthetized 28 substances (129) with 28–87% yield, here it is shown some representative examples of this study (129a-e).

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Scheme 43 Hydrophosphinylation of unactivated monosubstituted alkenes 127a-c.

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Troupa et al. (2015) reported a microwave-assisted hydrophosphinylation of unactivated alkenes with phosphinic acid and its derivatives under metal-free and initiator-free conditions (Scheme 44). In this study, high yields were obtained with terminal alkenes ranging from 8 to 16 carbon atoms (130a). However, some limitations were observed when the reaction was attempted with alkenes which are water-soluble to a certain degree (130b and 130c). Special interest was the synthesis of (4-phenylbutyl)phosphinic acid 134d, an intermediate in the preparation procedure of the heart drug Monopril (Scheme 44). The authors extended this protocol to cyclic alkenes and used aqueous hypophosphorous acid 133 and phenyl phosphinic acid 132, with good to excellent yields.

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Scheme 44 Hydrophosphinylation of unactivated alkenes 130a-i.

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Espinal-Viguri et al. (2016) reported a simple β-diketiminate iron(II) complex as an efficient pre-catalyst for the hydrophosphination of non-activated unsaturated C—C bonds (Scheme 45).

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Scheme 45 Hydrophosphination of non-activated 135a-f.

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They tested three different iron β-diketiminate complexes as pre-catalysts (1-Fe, 2-Fe and 3-Fe) for the cyclization of phosphine 135a (Fig. 1). Pre-catalysts 1-Fe and 3-Fe give poor conversions to the Markovnikov phospholane product 136a, after 24 h at 90 °C with a catalyst loading of 10 mol%, while the 2,6-diisopropyl motif, 2-Fe, gives 100% spectroscopic yield of product after 17 h.

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Fig. 1 Pre-catalysts used for intramolecular hydrophosphination.

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So, they investigated the reactivity of phosphino-alkenes 135a-f, with pre-catalyst 2-Fe (10 mol%, 90 °C) to afford the phosphinanes 136a-f, with conversions between 74% and 100% with 20–86% yields (Scheme 45). It is important to be notice that this method is limited to terminal alkenes, as could be seemed when they used compound 135e, no product was isolated and the yield was only estimated (Scheme 45).

Nizamov et al. (2012) studied a possibility of using zinc chloride as a catalyst for the reaction of alkenes 137a-c with acid 138a-c (Scheme 46). Per the ³¹P NMR data, in the reaction of acid 138a with alkene 137a at 80 °C for 2 h in the absence of additives the conversion calculated on the phosphorus does not exceed 12%. The reactions of dithiophosphoric acids 138a-c with hexadec-1-ene 137a, octadec-1-ene 137b, and oct-1-ene 137c in the presence of zinc chloride (3.0 wt%) at 80 °C, over 2 h led to formation of O,O-dialkyl-S-2-methylalkyldithiophosphates 139a-e as the major products in yields of 63–88%.

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Scheme 46 Synthesis of compounds 139a-e.

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In 2011, Denmark et al. (2011) reported the first catalytic, asymmetric sulfenylation of simple alkenes 140 using a chiral selenophosphoramide catalyst 142 (Scheme 47). Both inter- and intramolecular thiofunctionalizations was achieved for a several olefins’ types.

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Scheme 47 Asymmetric sulfenylation of simple alkenes 140a-d.

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Girijavallabhan et al. (2011) reported a method to synthesize tertiary alkyl/aryl sulphides in a mild and regioselective manner from unactivated alkenes 144 using cobalt catalyst 146 (Scheme 48). The methodology is compatible with sensitive functionalities and several sulphides 145.

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Scheme 48 Synthesis of the tertiary alkyl/aryl sulphides 147-d.

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A green protocol was recently described by Lenardão et al. (2007), Lenardão et al. (2009) to the synthesis of several 3-organylthio citronellal by the Michael-addition of thiol to citral, a natural occurring α,β-unsaturated terpenoid aldehyde (Scheme 49). The thio-functionalized aldehydes were tested for their antimicrobial activity, and they showed activity against Staphylococcus sp. higher than that observed for the parent citral or even for nonfunctionalized citronellal.

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Scheme 49 Synthesis of thio-derivatives 150a-e.

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Considering their previous studies, Lenardão et al. (2013) decided to explore the use of glycerol as a solvent in the reaction of thiophenol 149 with non-activated alkenes 148 (Scheme 49) and to evaluate the antioxidant potential of new eugenol derivatives.

In addition, into the direction of sustainable chemistry, Chawla et al. (2014) reported an environment friendly strategy for the synthesis of β-Keto Sulfones: transition-metal free, using stoichiometrics amounts of reagents and water, as a solvent (Scheme 50). The oxysulfonylation of alkenes 151 was conducted with sodium arenesulfinates 152 (Scheme 50). The β-Keto sulfones 153 were obtained in good to excellent yields, directly from unactivated olefins 151 using sodium arenesulfinate salts as sulfonylating agents and K₂S₂O₈ as a radical initiator in open flasks and aqueous media at room temperature, for 18 h (Scheme 50).

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Scheme 50 Synthesis of β-Keto Sulfones 153a-d.

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In the last year, Tamai et al. (2016) focused on the use of gold catalysts to overcome the limitations of the hydrothiolation of alkenes, they reported a gold-catalysed addition of thiols 155 to unactivated alkenes 154, which proceeds with excellent regioselectivity to afford the corresponding anti-Markovnikov adducts 156 in good yields (Scheme 51).

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Scheme 51 Gold-catalysed hydrothiolation of alkenes 154a-g.

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The authors after the optimizing the reaction conditions for the gold-catalysed hydrothiolation using PPh₃AuNTf₂ as the catalyst, they evaluated the scope and limitations of this hydrothiolation of unactivated alkenes (Scheme 51). For that propose alkenes a-g was reacted with benzenethiol a, 2.0 mol% of PPh₃AuNTf₂ in Tetrahydrofuran (THF), as a solvent, at 45 °C, 20 horas, affording regioselectively, the Anti-Markovnikov adducts with 45–92% yields.

They tested benzene thiols with electrondonating or electron-withdrawing groups, aliphatic cyclic or acyclic thiols and afforded the same result, the desired anti-Markovnikov hydrothiolation products 156a-k, regioselectively, in 31–92% yields.

In addition to the synthesis of organosilicon heterocycles from readily available olefins, the study reported by Bokka et al. (2015) shows fundamental mechanistic insights into the non-metathetical function of Grubbs-type ruthenium catalysts (Scheme 52). They have developed an efficient Grubbs-type ruthenium complex-catalysed intramolecular alkene hydrosilylation of alkenylsilyl ethers 157 to provide cyclic silyl ethers 159, with good to excellent yields (Scheme 52).

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Scheme 52 Grubbs-type ruthenium complex-catalysed intramolecular alkene hydrosilylation of alkenylsilyl ethers 157a-c.

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Bokka’s studies also proposed that the initial stage of the hydrosilylation involves the σ-bond metathesis between Si—H and Ru—Cl and, this alkene hydrosilylation follows the modified Chalk−Harrod mechanism.

Buslov et al. (2016) showed that nickel nanoparticles catalyse hydrosilylation of unactivated alkenes with tertiary silanes. Their results showed that not only terminal alkenes are hydrosilylated with high anti-Markovnikov selectivity, but also internal alkenes are hydrosilylated through a tandem isomerization-hydrosilylation process to give terminal alkyl silanes 162 (Scheme 53). The catalytic system has shown could be applied to synthesize a single terminal alkyl silane from a mixture of internal and terminal alkene isomers, and to remotely functionalize an internal alkene derived from a fatty acid. The reactions were performed with 1–5 mol% of Ni precatalyst in THF at room temperature and many unactivated alkenes 160 was hydrosilylated, with good yields (Scheme 53).

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Scheme 53 Hydrosilylation of unactivated alkenes 160a-e.

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Li et al. (2015) developed an efficient hydrocyanoalkylation of unactivated alkenes with alkyl nitriles. Their method allowed to prepare functionalized nitriles, in large scale, through free-radical initiated selective activation of the α-C(sp³)—H bond of acetonitriles, by an anti-Markovnikov addition of α-cyano C-centered radical to olefins (Scheme 54).

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Scheme 54 Hydrocyanoalkylation of unactivated alkenes 163a-d.

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The authors showed that diverse functional groups such as halogen, ester, sulphonamide, heterocycle, amide, hydroxyl, epoxide could be used. It is noteworthy that cyclic alkenes such as cyclopent-3-en-1-ylmethanol gave moderate yield of the desired product (165a-f).

Hopkinson et al. (2016) reported a dual gold/photoredox-catalyzed difunctionalization of alkenes (Scheme 55) to promote intramolecular oxy- and aminoarylation of non-activated alkenes 166 (Scheme 55).

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Scheme 55 Intramolecular oxy- and aminoarylation of non-activated alkenes 166a-c.

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After optimization reaction conditions’ a range of non-activated alkenes was reacted with aryldiazonium salts 167 in the presence of [Ph₃PAu]NTf₂, as a gold(I) source and [Ru(bpy)₃](PF₆)₂, as a photocatalyst, in degassed methanol. After 6 h period of visible light irradiation from a 23 W household compact fluorescent lamp (CFL), the intramolecular cyclization products 168 was obtained in 58–66% yield, as a single regioisomer.

This procedure demonstrated that of several alkenes 166a-c that containing either an alcohol or an amine nucleophile could be successful employed, while aryldiazonium salts featuring electron-neutral or electron-withdrawing substituents performed best (Scheme 55).

Wu et al. (2016) have described an efficient metal-free approach for the azidocyanation of unactivated alkenes 169 (Scheme 56). Applying this method, the authors were able to prepare a variety of useful alkyl nitriles 170 in good yields, with good regio- and stereo-selectivity. This procedure brought a new insight in the functionalization chemistry of the unactivated alkenes, once it described for the very first time the intramolecular cyano migration strategy combined with alkene difunctionalization.

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Scheme 56 Metal-free approach azidocyanation of unactivated alkenes 169a-d.

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Taking theirs and previous studies Wu and co-workers proposed that the interaction of PhI(OAc)₂ with TMSN₃ generates the highly unstable acyclic azido hypoiodite, which decomposes immediately at room temperature to release an azido radical (Scheme 57). Then, the addition of an azidyl radical to cyanohydrin 169 gives to the metastable alkyl radical I. The intramolecular interception of intermediate I by the cyanohydrin species through a five-membered ring allowed to afford the cyclic iminium radical II. The homolysis of II provides the 1,4-cyano migration and generates a hydroxyalkyl radical III. After that, according to them, there are two possibilities for the conversion of radical III into the product 170: the single-electron oxidation of radical III to the carbonium ion IV by PhI(OAc)₂ followed by deprotonation (A), or the capture of radical III by a PhI(N₃)₂ intermediate followed by the collapse of the azidohydrin V to the final carbonyl (B) (Scheme 57).

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Scheme 57 Mechanistic proposal for azidocyanation of unactivated alkenes 169.

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5 Synthesis of amine/amide/oxygenated compounds

The catalytic hydroamination of alkenes is a practical, economical and sustainable alternative for the preparation of amines and its derivatives. This atom-economic process allows the addition of an N—H bond over an unsaturated C—C bond to yield a large variety of alkylated amines, very important chemicals in industry and every day’s chemistry (Weissermel and Harpe, 1993).

Mckinney and Widenhoefer (2011) reported the stereochemical analysis of the Brønsted acid catalysed intramolecular hydrofunctionalization of a cyclohexene moiety 171 with a sulphonamide, an alcohol, and a carboxylic acid, supported by the kinetic analysis of Brønsted acid catalysed intramolecular hydroamination (Scheme 58). The results of these studies, particularly in the case of intramolecular hydroamination, support a mechanism involving concerted, intermolecular protonation of the alkene coupled with intramolecular anti addition of the pendant nucleophile.

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Scheme 58 Hydrofunctionalization of a cyclohexene moiety 171.

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Zhao et al. (2012) reported a hydrogen bonding promoted Cope-type hydroamination process, which allows the conversion of allylic amines 173a-d into functionalized vicinal diamine 175a-e, with excellent yields (Scheme 59).

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Scheme 59 Synthesis of functionalized vicinal diamines 175a-e.

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In the same year, Kitahara and Sakurai (2012) reported that two different reactions proceeded from N-benzyl secondary amines with 4-pentenyl group catalysed by Au:PVP in EtOH under basic conditions (Scheme 60). One was hydroamination, which occurred in the presence of Cs₂CO₃ as a base with up to 45% yield (Scheme 60, A) and the other was the formation of a γ-lactam compound 178 that proceeded in the presence of CsOAc as a base with up to 46% yield (Scheme 60, B).

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Scheme 60 Hydroamination of N-benzyl 176 (A) and synthesis of a γ-lactam 178 (B).

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Sevov et al. (2012) discovered an example of a catalytic process for the addition of amides and sulphonamides to unactivated alkenes 179 (Scheme 61). This methodology includes Ir-catalysed reactions of alkenes with amides and sulphonamides to form products in high yield and e.e%. The kinetic data indicate that a kinetically detectable reorganization of the species formed by amide dissociation precedes alkene binding and insertion.

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Scheme 61 Ir-catalysed reactions of alkenes 179a-d.

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Rodriguez-Zubiri et al. (2013) reported a study on the Pt-catalysed intermolecular-hydroamination of ethylene and 1-hexene by aniline in the presence of a variety of phosphorus ligands and a potential explanation on the recovery of the catalytic activity upon the addition of I₂ (Scheme 62). They observed that, the inhibiting effect shown by aryl and alkylphosphines disappears in the presence of alkyl phosphites (Scheme 62).

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Scheme 62 Pt-catalysed intermolecular hydroamination of ethylene and 1-hexene by aniline in the presence of PR₃.

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Strom and Hartwig (2013) reported a one-pot anti-Markovnikov hydroamination of several alkenes (Scheme 63). The synthesis of primary and secondary amines from unactivated olefins proceed in the presence of a variety of functional groups. Hydrozirconation, followed by amination with nitrogen electrophiles, provides exclusive anti-Markovnikov selectivity (Scheme 63). Here it was selected the examples of quinine and D-mannose as a substrate for this reaction (Scheme 63). The hydroamination of quinine 186 and D-mannose 187 proceeded very well, allowing to prepare the corresponding hydroaminated derivatives 188 and 189 in 92% and 66% yields, respectively.

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Scheme 63 One-pot anti-Markovnikov hydroamination of quinine 186 and D-mannose 187.

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Ingalls et al. (2013) reported an enantioselective Pd-catalysed vicinal diamination of unactivated alkenes 190 using N-fluorobenzenesulfonimide 191 as both an oxidant and a source of nitrogen (Scheme 64). The use of Ph-pybox and Ph-quinox ligands afforded differentially protected vicinal diamines 192a-c in good yields with high enantioselectivities. The mechanistic experiments of this study revealed that the high enantioselectivity arises from selective formation of only one of four possible diastereomeric aminopalladation products of the chiral Pd complex.

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Scheme 64 Enantioselective Pd-catalysed vicinal diamination of unactivated alkenes 190a-c.

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Recently, Shigehisa et al. (2014) developed the Cobalt catalysed intramolecular hydroamination of olefins using N-fluoro-2,4,6-trimethylpyridinium salt and (Me₂SiH)₂O (Scheme 65). This mild and functional group tolerant reaction has shown to be a tool for the synthesis of diverse substrates via simple and efficient C—N bond formation. Mechanistically, this study showed that this Cobalt catalyst system can selectively activate an olefin moiety to react with not only hydroxyl groups, but also with nitrogen atoms, even though they are weakly nucleophilic.

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Scheme 65 Cobalt-catalysed intramolecular hydroamination of olefins 193a-d.

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The authors investigated the scope of several N-protected aminoalkenes 193, under the optimized reaction conditions: 1.3 mol% of Cobalt Catalyst, 2.0 equivalents of Me₃NFPY · BF₄, 2.0 equivalents of (Me₂SiH)₂O, in toluene (0.10 M), at room temperature under Argon atmosphere, giving the hydroaminated products 195, with good to excellent yields (Scheme 65). Further investigation on the substrate scope indicated that C—O bond formation occurred when the protected aminoalkenes contained an additional oxygen nucleophile at a spatially accessible position. This fact as illustrated with compound 193c, which was selectively transformed into hydroalkoxylated product 195′ without the formation of hydroaminated product 195c (Scheme 65). For the successful hydroamination of the substrates, three types of protecting group were screened, being that the acetate protecting group the best option to obtain preferably hydroaminated product 195d (Scheme 65).

Gui et al. (2015) developed a protocol for olefin hydroamination (Scheme 66). The authors screened more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohol 197g, amines 197a-e, and even boronic acids 197f. In the Scheme 66 are presented some selected examples of this study.

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Scheme 66 Hydroamination of alkenes 196a-g.

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Reznichenko and Hultzsch (2012) reported an intermolecular hydroaminoalkylation reaction of unactivated alkenes 199 with secondary amines 200, in the presence of tantalum and niobium binaphtholate catalysts with high regio- and enantioselectivity (up to 98% e.e.) (Scheme 67).

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Scheme 67 Intermolecular hydroaminoalkylation reaction of unactivated alkenes 199a-d.

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The authors observed that the strong preference to activate primary amine α-C—H bonds originate from steric constrains obstructing alkene insertion, as demonstrated by isotopic labeling experiments. Mechanistic studies suggest that the reaction proceeds via a reversible, non-dissociative formation of a six-coordinate metallaziridine species, which undergoes facile alkene insertion and subsequent intramolecular protonolysis. Kinetic studies are supportive of a monometallic catalytic pathway with either alkene insertion or amide exchange serving as a rate-determining step. The amide exchange step is marked by a primary kinetic isotope effect (KIE), whereas essentially no KIE was observed for the aziridine formation/olefin insertion/protonolysis sequence.

One year later, Zhang et al. (2013a,b) discovered that TaMe₃Cl₂ is an efficient hydroaminoalkylation catalyst that can be used with a broad range of amine and alkene substrates, such as disubstituted terminal alkenes, internal unstrained alkenes, and dialkylamines (Scheme 68). This catalyst system can be used to insert a quaternary-carbon centres β to N, as was illustrated in the efficient preparation of amine derivatives 205a-d (Scheme 68).

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Scheme 68 Hydroaminoalkylation TaMe₃Cl₂-catalised of alkenes 203a-c.

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Bandini et al. (2011) explored another way to prepare amino compounds from unactivated olefins. This group used a series of (Z)-allylic alcohols 206a-d as alkylating agents in the Au-catalysed enantioselective FC-type reaction of indoles (Scheme 69). Moreover, the transfer of chirality from enantiomerically pure dinuclear gold(I) complexes of general formula [(PP)∗(Au₂X₂)](PP)∗: chiral C2-symmetric biphosphine ligand to the final polycyclic compounds would give access to the elucidation of the stereochemistry.

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Scheme 69 Au-catalysed alkylation of indoles 206a-d.

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In the same year, Taniguchi et al. (2011) developed a one-pot method of formal nitrocyclization for synthesis of heterocycles 209 using a subsequent process involving iron-mediated chloronitration followed by elimination and intramolecular Michael addition under at alkaline conditions (Scheme 70). This reaction provides a practical method for the synthesis of heterocyclic compounds, using low toxic proprieties and inexpensive reagents.

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Scheme 70 Nitrocyclization of compounds 209a-d.

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Neukom et al. (2011) reported a study which their experiments on the conversion of (P-P)Pd(Ar)[N(Ar¹)(CH₂)₃CR=CHR′] complexes 213 to N-aryl-2-benzylpyrrolidine derivatives 212 indicate that these transformations proceed via syn insertion of the alkene into the Pd—N-bond (Scheme 71). Their data suggests that insertion occurs from a four-coordinate alkene complex, rather than a five-coordinate species.

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Scheme 71 Pd-Catalysed Alkene 210 Carboamination.

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Non-activated alkenes also represent a platform to amide or oxygenated compounds’ preparation, as it will be possible to observe in the next presented studies.

Recently, Miller et al. (2015) reported a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives (Scheme 72). This work includes a variety of di-, tri-, and tetrasubstituted olefins with differing substitution patterns. Steric hindrance adjacent to the site of C—N bond formation was also tolerated (214b). In addition to amide substrates, the hydroamidations of carbamates and ureas proceed smoothly under the standard conditions (214a, 214c). Thiolcarbamates could also be cyclized to furnish thiazolidinone products (215). Moreover, these reactions are largely insensitive to the olefin geometry of the substrate as carbamates derived from the isomeric polyolefins nerol and geraniol both cyclized to afford 215e in high yield (Scheme 72).

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Scheme 72 Intramolecular hydroamidation of unactivated olefins 214a-e.

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In 2011, Okada et al. (2011) demonstrated an electron-transfer induced intermolecular [2+2] cycloaddition reactions based on the aromatic “redox tag” strategy (Scheme 73). The anodically generated radical cation of an aliphatic cyclic enol ether 217 was effectively trapped by several unactivated olefins possessing aromatic “redox tag” 216 to construct the corresponding [2+2] cycloadducts. The aromatic “redox tag” was oxidized during the formation of the cyclobutane ring, affording the relatively long-lived aromatic radical cation, which was then reduced to complete the overall reaction (Scheme 73).

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Scheme 73 Intermolecular [2+2] cycloaddition reaction of derivatives 216.

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Chaplin et al. (2012) reported an intermolecular hydroacylation catalysts based upon small-bite-angle ligands which allow for the union of β-S-substituted aldehydes with a wide variety of unactivated alkenes 219 (Scheme 74). Through acetone as a solvent and right catalyst/substrate concentration, the unwanted decarbonylation deactivation pathway is attenuated while the productive hydroacylation reaction is enhanced to such an extent that very low catalyst loadings (0.1 mol%) (Scheme 74).

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Scheme 74 Intermolecular hydroacylation of olefins 219a-c.

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von Delius et al. (2012) developed a method for the linear-selective intermolecular hydroacylation of a wide range of monosubstituted alkenes 222 with salicylaldehyde derivatives 223 (Scheme 75). This catalytic protocol is compatible with water as solvent, as well as neat or biphasic reaction conditions. This catalytic strategy allowed to prepare natural products from the dothiorelone 224a, cytosporone 224, and phomopsin 224c (Scheme 75). Because of easy access to complex alkene building blocks, this method is ideally suited for the preparation of analogues of anticancer drug candidate cytosporone B.

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Scheme 75 Linear-selective intermolecular hydroacylation of monosubstituted alkenes 222a-c.

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Purino et al. (2012) developed an efficient Prins cyclization of bis-homoallylic alcohols 225 with aldehydes 226 catalysed by iron(III) salts (Scheme 76). The reaction provides a direct entry to cis-2,7-disubstituted oxepanes 227 with excellent yields. Using this approach as a key step, the authors performed a short and very efficient total synthesis of (+)-isolaurepan 228, thus demonstrating the value of this methodology, which uses unactivated olefins. The suitable experiments allowed to propose a rational mechanism in the synthesis of 2,7-disubstituted oxepanes. With this method, they also developed a general route to the synthesis of a wide variety of functionalized cis-2,7-disubstituted oxepanes.

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Scheme 76 Prins cyclization of bis-homoallylic alcohols 225.

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Three years later, Pérez et al. (2015) described the different factors that control the alkene Prins cyclization catalysed by iron(III) salts in the presence of SiMe₃X (X = Cl, Br) towards the synthesis of crossed disubstituted tetrahydropyrans (THPs) (Scheme 77). The density functional theory (DFT) calculations support the preference of the classical oxocarbenium ion pathway over the possible [2+2] cycloaddition pathway and explain the origin of the observed product distribution, which depends on the nature of the substituent at the homoallylic alcohol and the iron(III) source.

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Scheme 77 Prins cyclization of bis-homoallylic alcohols 229a-k.

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In this work using stoichiometric amounts of iron(III) chloride, they observed that the distribution of tetrahydropyrans mainly depends on two factors: the bulkiness of the substituent R¹ and the electronic effect of the substituents directly attached to R¹ if R¹ is an aryl group. An increase in the bulkiness of R¹ (methyl, ethyl and cyclohexyl) increased the formation of the desired THP 231 with a subsequent decrease in that of THP 232. This steric control therefore favoured the Prins cyclization to 233 over the 2-oxonia-Cope rearrangement. Moreover, when R¹ was an aromatic ring, the presence of electron-deficient substituents favoured the Prins cyclization, yielding THP 233 as the major product (Scheme 77).

In 2013, a versatile catalytic method for the synthesis of 2-substituted benzofurans 236 through palladium-catalysed intermolecular annulation of phenols 234 and olefins 235 have been disclosed by Sharma et al. (2013) (Scheme 78). They prepared several benzofurans 236 from substituted phenols 234 under air conditions.

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Scheme 78 Synthesis of 2-substituted benzofurans 236a-d.

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The styrene and other non-activated alkenes remained a challenge, for which a solution has been found by Wuensch et al. (2013) by means of enzyme catalysis (Scheme 79).

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Scheme 79 Direct asymmetric catalytic addition of water to non-activated alkenes 237a-c.

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Hydroxybenzoic acid decarboxylases turned out to be suitable for this purpose and enabled the asymmetric addition of water to p-hydroxystyrene (237a) and substituted derivatives with conversions of up to 82% and enantioselectivities of up to 71% e.e. For example, p-hydroxystyrene was transformed into the product (S)-238a with 82% conversion and 43% e.e. (Scheme 79).

Oxygenation of the cyclohexene 239 has been achieved by Pariyar et al. (2013) at room temperature, using 5,10,15-tris(difluorophenyl) iron(IV) corrole complex [FeIV(tdfc)Cl] 240 as catalyst, using the a mild tert-butylhydropeoxide as the terminal oxidant, giving the corresponding oxygenated products 241–242 with satisfactory yields (Scheme 80). The results show that the main role of the iron(IV) corrole complex is the activation of alkyl hydroperoxide rather than oxygen atom transfer (OAT). The results have also demonstrated the involvement of tert-butoxyl radical (t-BuO^•) and organo-hydroperoxides (ROOH) as key intermediates.

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Scheme 80 Oxygenation of the cyclohexene 239.

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Taniguchi et al. (2013) established a multifunctionalization reaction involving direct sp³ C—H oxidation of aliphatic alkenes 244a-c using tert-butyl nitrite and molecular oxygen (Scheme 81). Per this study, the reaction would consist of a sequence of radical processes including oxynitration of the olefin and C—H oxidation via a 1,5-hydrogen shift. In addition, the reaction can be conducted under mild conditions using inexpensive reagents including no metallic compound, and the use of molecular oxygen as an oxygen source.

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Scheme 81 Multifunctionalization reaction of alkenes 244a-c.

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Sevov and Hartwig (2013) reported an example of a metal-catalysed intermolecular addition of an alcohol 246 to an unactivated alkene 247 (Scheme 82). Their results shown that the reaction is not purely acid-catalysed, and it was more likely involved a generation of an Ir(I) intermediate by reductive elimination of the observed allyliridium hydride species, followed by reversible O—H bond oxidative addition, turnover-limiting olefin insertion, and product-releasing reductive elimination.

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Scheme 82 Intermolecular addition of an alcohol to an unactivated alkenes 247a-d.

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Another way to insert the oxygen atom into double C—C bond was developed by Zhu et al. (2014) and it consists in an intramolecular radical oxyazidation process of alkenes (Scheme 83). This reaction occurs under mild conditions with simple handling, and form the azido-substituted isoxazolines 250a-e in good yields (Scheme 83). The preliminary mechanistic study demonstrates that the inorganic base, such as NaOAc and Na₂CO₃, can efficiently catalyse the formation of oxime radicals.

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Scheme 83 Intramolecular radical oxyazidation of alkenes 249a-e.

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Kindt et al. (2014) reported a carbooxygenation-type version of the Meerwein arylation in which the introduction of oxygen is achieved by using dioxygen from the air (Scheme 84). In this way, hydroperoxides 253a-e were obtained from non-activated alkenes 252a-c by oxidizing aryl hydrazines 251a-c with manganese dioxide, in good yields, as shown in Scheme 84. Using this methodology, the authors was noticed that it is crucial that the aryl hydrazine must be added slowly to the reaction mixture to allow sufficient uptake of dioxygen from the air.

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Scheme 84 Carbooxygenation-type version of the Meerwein arylation.

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Lo et al. (2014) developed a practical method for the reductive coupling of olefins that utilizes an inexpensive Fe source, Fe(acac)₃, as a catalyst (Scheme 85). This study reported an operationally simple reaction and with short reactions times (most reactions <1 h), which could be used on gram-scale (Scheme 85). This coupling could be applied to intra- and intermolecular reactions and can produce complex bicyclic systems 256c, and vicinal quaternary centres 256c, with 54–73% yields. With this transformation-type, it will become possible to directly employ olefins in C—C bond-forming, at the cyclase phase of two-phase terpene synthesis.

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Scheme 85 Reductive coupling between olefins 254 and 255a-c.

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In this study, Lo and their group proposed a mechanistic hypothesis where donor olefin 254 would abstract a hydrogen radical from Fe hydride 52-derived from Fe(III) species 257 and PhSiH₃ to generate reduced Fe species 259 and tertiary radical 260 (Scheme 86). Conjugate addition of 260 into Michael acceptor 254, followed by single-electron transfer with 259, would provide intermediate 262 and regenerate 257, which would re-enter the catalytic cycle. According to them, protonation of 262 would give the addition product 256.

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Scheme 86 Mechanistic proposal for reductive coupling between olefins 254 and 255a-c.

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Schlṻter et al. (2015) described a redox-neutral hydroalkoxylation of a non-activated alkene that is catalysed by a chiral titanium–carboxylate complex under thermally forcing conditions (Scheme 87).

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Scheme 87 Redox-neutral hydroalkoxylation of a non-activated alkenes 263a-e.

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The asymmetric catalytic addition of alcohols (phenols) to non-activated alkenes has been realized through the cycloisomerization of 2-allylphenols 263 to 2-methyl-2,3-dihydrobenzofurans 264 (2-methylcoumarans). The reaction was catalysed by a chiral titanium–carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. This thermal catalysis gave various (S)-2-methylcoumarans with yields of up to 90% and in up to 85% enantiomeric excess (e.e.) at 240 °C, and in 87% e.e. at 220 °C (Scheme 87).

In the last year, Mailyan et al. (2016) reported a method for a directed stereoselective cycloguanidinylation of several alkenes. This study allowed to prepare several cyclic guanidines with complete diastereoselectivity, using unactivated alkenes 265 as a template (Scheme 88). The authors examined the reaction scope with a variety of aryl and alkyl substituted substrates derived from homoallylic alcohols. Compounds comprising different linear and branched alkyl substituents readily undergo cyclization, producing expected guanidines 266 in high yields as single diastereomers (Scheme 88).

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Scheme 88 Directed stereoselective cycloguanidinylation of alkenes 265a-d.

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In the last year, Liu et al. (2016) reported an oxidative intra/inter-molecular oxyamination and diamination of unactivated alkenes through copper-catalysed radical reactions of β,γ- and γ,δ-unsaturated ketoximes 267 with electron-rich aryl and aliphatic amines 268 (Scheme 89). These reactions were carried out by employing di-tert-butyl peroxide (DTBP) or air as the terminal oxidant, and a series of useful nitrogen-containing 4,5-dihydroisoxazoles 269 and cyclic nitrones 270 were formed, with good yields (Scheme 89).

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Scheme 89 Oxidative oxyamination and diamination of unactivated alkenes 267a-c.

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6 Synthesis of other functionalized compounds

Unactivated alkenes could be functionalized with other groups which were not included in the previous sections. Hence, the remaining studies will be listed hereinafter.

Kavanagh et al. (2011) developed a free radical hydrostannylations of olefins of differing steric and electronic demand (Scheme 90). This reaction was carried out using the chiral, nonracemic stannanes (1R,2S,5R)-menthyldiphenyltin hydride 272a, bis[(1R,2S,5R)-menthyl]phenyltin hydride 272b, and tris-[(1R,2S,5R)-menthyl]tin hydride 272c. These reactions resulted in adduct yields (273–275) that were found to depend on the nature of the substituents. For alkenes bearing electron-withdrawing groups (activated alkenes), excellent yields of hydrostannylated products (272273–275) were obtained respective of stannane. For alkenes bearing electron-donating groups, the bulkier stannanes (272b and 272c) failed to react, while MenPh₂SnH (272a) reacted with all substrates with good to excellent conversions (Scheme 90).

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Scheme 90 Hydrostannylations of olefins 271a-b.

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In the same year, Müller et al. (2011) reported an enantioselective catalyst system for bromine-induced semipinacol rearrangements at non-activated double bonds in cyclic systems (Scheme 91). Under the optimized reaction conditions using the commercially available Hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQD)₂Pyr] catalyst 277, the products containing all-carbon quaternary chiral centres 278 was prepared in good yields and good enantioselectivities (Scheme 91).

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Scheme 91 Enantioselective bromine-induced semipinacol rearrangements at non-activated alkenes 276a-b.

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Leggans et al. (2012) reported a study employing Fe(III) as a mediated free radical oxidation of the anhydrovinblastine trisubstituted alkenes 279 to introduce the vinblastine C20′ tertiary alcohol, providing a simple method for direct functionalization of unactivated alkenes (Scheme 92).

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Scheme 92 Oxidation of the anhydrovinblastine trisubstituted alkenes 279.

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Kubota et al. (2013) developed a borylative exo-cyclization reaction, which allows for the one-step construction of alkylboronates with complex structures, such as spirocyclic frameworks 285b and 285c, from simple starting materials (Scheme 93). The undesired boryl substitution of the alkyl bromide moiety 284 in the starting materials was suppressed by choosing an appropriate ligand (Xantphos), which enhanced the reactivity of the key borylcopper(I) intermediate toward addition to the carbon-carbon double bonds (Scheme 93).

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Scheme 93 Borylative exo-cyclization reaction of the subtracts 284a-d.

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In 2013, Fenlon et al. (2013) achieved the first synthesis of the Lindenene 288 (Scheme 94). Through this investigation, the authors realized that the intrinsic instability of lindenane ring system was related with its intermediated and its tendency to epimerize at neutral conditions under transition metal catalysis. So, they submitted the Lindenene 287, under dichloromethane (DCM) reflux, 96 h and obtained the respective cycloprane 288 with 89% yield (Scheme 94).

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Scheme 94 Cyclopropanation of Lindenene 287.

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7 Conclusions

In conclusion, non-activated alkenes have been proved, in the last five years, to participate in several different types of addition reactions allowing to synthetized diverse and important substances with all of kind of substituted groups. This platform could be used to prepare cyclic, acyclic, aromatic or aliphatic compounds with halogen atoms and several other interesting functionalities, such as phospho-, sulphur-, thio-, sylil-, cyano- and even boryl- and stannyl- compounds.