Cp2TiCl2-Catalyzed Photoredox Allylation of Aldehydes with Visible Light

A Barbier-type Cp2TiCl2-mediated (10 mol %) photoredox allylation of aldehydes under irradiation with visible light (blue light-emitting diodes (LEDs), 450 nm) and in the presence of an organic dye (3DPAFIPN, 5 mol %) with allylbromides is described.

A llylation of carbonyls is a key strategy for the preparation of functionalized building blocks in the total synthesis of natural products. 1 In particular, allylation reaction realized under Barbier conditions can give access to transient organometallic reactive allylating species. 2 Normally, an overstoichiometric amount of the sacrificial reductant such as metallic manganese or zinc in the presence of an active redox metal complex is necessary. In the Barbier-type allylation performed with a catalytic amount of titanium 3 or chromium 4 (Nozaki−Hiyama−Kishi reaction), 5 the use of a scavenger able to liberate the active metal from the organic product is mandatory for sustaining the catalytic cycle. Pioneering studies reported by Fuerstner 6 and Gansaüer 7 have introduced the practice of catalytic redox cycle in organic synthesis, further developed into interesting stereoselective variants. 8 Photoredox catalysis, by the use of metal complexes, dyes, or semiconductors, can give interesting approaches to radical species by electron transfer (ET) or energy transfer. 9 The combination of the photoredox catalytic cycle with other catalytic cycles, working cooperatively, makes way to new reaction pathways. 10 Metallaphotoredox catalysis, i.e., metal catalysis merged with photoredox catalysis, is a new and rapidly growing research area. 11 Now, photoredox catalysis is starting to explore the possibility of using clean and rapid access to radicals for generating nucleophilic reagents. 12 This concept that combines radical and polar chemistry in a so-called reductive radical-polar crossover (RRPC) was recently reviewed. 13 In this approach, a suitable alkyl radical is converted into a nucleophile by reduction or by the capture with a suitable transition metal complex. These so formed nucleophilic species can then react with electrophiles such as carbonyls or imines.
Glorius and Kanai have recently reported RRPC photoredox allylation methodologies based on chromium ( Figure 1). 14 In these radical reactions, photogenerated allyl radicals are converted into traditional nucleophilic Cr(III)allyl reagents by means of a single electron reduction carried out by the Cr(II) present in the reaction mixture. The Cr(II) used in catalytic amount was regenerated by the photocatalytic cycle. Importantly, these new transformations are still in their infancy, although high enantiomeric excesses can be obtained. 14b,c In this article, we report a practical and straightforward radical-polar crossover photoredox allylation of aldehydes mediated by titanium complexes that give access to a wide range of homoallylic alcohols in high yields. Moreover, the reaction uses 1,3-dicyano-5-fluoro-2,4,6-tris(diphenylamino)benzene (3DPAFIPN) as the photocatalyst, 15 a cheap and easily prepared organic dye, in the presence of the readily available Hantzsch's ester as the sacrificial reductant and scavenger for the titanium complexes.
Recently, we have reported a nickel-based dual photoredox approach in the allylation of aldehydes, with a broad scope and functional group compatibility, by the use of commercially available or easily prepared allylacetates. 16 However, we want to explore the use of affordable green metals and mild reaction conditions. In particular, the use of Cp 2 Ti(III)Cl, the Nugent− Rajanbabu reagent, 17 in Barbier-type allylation reactions 18 is particularly attractive, as titanium is considered nontoxic, environmentally friendly, and abundant. 19 Methodologies based on the employment of Cp 2 (III)TiCl in catalytic conditions in the presence of stoichiometric amounts of active metals (Mn) and in combination with 2,4,6-collidine and Me 3 SiCl added more interest in this chemistry, leading to the discovery of new transformations. 20 In addition, recently, Gansaüer reported an interesting study on the photoredox titanium mediated reactions of epoxides, combining Cp 2 Ti-(III)Cl catalysis with photoredox catalysis and bypassing the requirement of metallic reductants and stoichiometric acidic additives. 21 Shi and co-workers have recently reported another synergistic utilization of titanocene/photoredox dual catalysis in the radical opening/spirocyclization of epoxyalkynes in the presence of 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst and Hantzsch's ester. 22 Based on Gansaüer's, Shi's, and our studies, we have settled a new photoredox allylation of aldehydes mediated by catalytic amount of titanium complex, and in Table 1 some key observations about the reaction conditions are reported.
Hydrocinnamic aldehyde (1a) was used in the model reaction, and in general, it was found that the reaction was promoted by various photocatalysts (entries 5−6 Table 1 and  Table S7) and light-emitting diode (LED) sources (entries 1− 2, Table 1), with the organic dyes 3DPAFIPN 15 affording good conversions and extremely clean reactions. Other organic dyes were found to be less efficient in promoting the transformation.
Different titanium complexes and salts were employed (see Table S3), demonstrating their inferior ability to promote the reaction compared to the cheap and available Cp 2 TiCl 2 . Reaction conditions were carefully optimized bringing out that tetrahydrofuran (THF) with a substrate concentration of 0.05 M was crucial. The role played by the Hantzsch's ester is also important since a series of different sacrificial reductants were found not suitable for the reaction (see Table S5). In this regard, we first checked the stability of Cp 2 TiCl 2 in the presence of different amines (See Figure S15). The addition of 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole (BIH), quinuclidine, and other aliphatic amines to a millimolar solution of Cp 2 TiCl 2 causes changes in the absorption spectrum attributable to ligand exchange. The bulky triphenylamine (TPA) did not interact with the titanium complex in the ground state, but absorption changes have been observed under visible light irradiation. However, the addition of amines was found deleterious, giving practically no conversion (see Table S6). From a practical point of view, the reaction was quite sensitive to traces of oxygen and water. It is worth noting that the photocatalyst does not decompose during the photoreaction and can be easily recovered at the end of the reaction by flash chromatography. By the use of a Kessil LED lamp at 456 nm (40 W, for 6 h, Table 1 entry 2), it was possible to considerably reduce the reaction time and to scale the reaction up to 5 mmol without observing lower conversion and yield (Table 1 entries 3 and 4).
The wide applicability of our initial finding was confirmed with a variety of aromatic and aliphatic aldehydes, and Schemes 1,2 illustrate the salient results obtained. As is evident by the data reported in Scheme 1, aromatic and  heteroaromatic aldehydes are suitable substrates for the reaction. Yields are good to moderate as a function of the presence of electron-withdrawing groups that have an impact on the isolated yields. As the Hantzsch's ester is oxidized under the reaction conditions to the corresponding protonated pyridinium salt, with concomitant formation of H + , acidsensitive substrates such as pyrrole or indole gave lower yields due to decomposition promoted by the presence of Brønsted acids. Hindered aromatic substrates were found less reactive. In comparison to the published titanium mediated allylation reaction, a minor percentage of titanium (10 vs 20 mol %) is necessary. No further scavengers or bases are necessary for the titanium as the proton derived from the oxidation of the Hantzsch's ester is able to restore the catalytic cycle acting as a scavenger. Differently substituted linear aliphatic aldehydes are quite suitable substrates as illustrated in Scheme 2 (see Scheme S2 for further substrates studied).
Hindered aromatic substrates were found less reactive. Irradiation with powerful Kessil lamp is necessary for hindered Research Article cyclohexane carboxaldehyde. In the case of pyvalic aldehyde, the reaction gave only low yields (see Scheme S2). Reaction with chiral aldehydes 1y gave quite a moderate diastereoisomeric ratio, in favor of a Felkin-controlled allylation product. The reaction is quite tolerant to functional groups including halides, CF 3 , esters, nitriles, and ethers. Interestingly, acidic NH groups were also tolerated although aliphatic or aromatic amines cannot be used. Allyl bromide bearing substituents in three positions can be employed with good regioselectivity in favor of the branched products and with moderate to good yields (Scheme 3).
Allyl substituted reagents are in general less reactive with respect to allyl bromide under our photoredox condition, as indicated by the preliminary results obtained (Scheme 4) with cinnamyl bromide (2c) and in the presence of prenyl bromide (2d).
Ketones showed quite a reduced reactivity in this reaction compared to aldehydes, and the corresponding products were isolated in low yields, even using Kessil lamp (see Scheme S2).
To evaluate the photoinduced mechanism of the reaction, we investigated the quenching of the photocatalyst's luminescence by each of the components of the reaction (see the Supporting Information (SI)). As observed for similarly substituted isophthalonitriles, 15,23 3DPAFIPN is particularly suitable for photocatalysis because it possesses a very long emission lifetime in degassed solutions at room temperature (0.130 ms in THF at λ em 520 nm, see the SI for details). Interestingly, no change in the intensity and decay of the 3DPAFIPN emission was observed upon the addition of allyl bromide and hydrocinnamic aldehyde (at the same concentrations used to perform the reaction). On the other hand, the addition of Hantzsch's ester and Cp 2 TiCl 2 induces strong changes in the emission intensity of the photocatalyst. In particular, the quenching constants, determined from Stern−Volmer experiments, are 1.5 × 10 7 M −1 s −1 for the Hantzsch's ester and 5.2 × 10 8 M −1 s −1 for the Ti complex in degassed solutions (as in the employed photoreaction conditions described above). It is worth noting that the two Stern−Volmer plots have been obtained using the ratio of the lifetime (τ 0 /τ) for the quenching relative to Ti because it reabsorbs the light emitted by 3DPAFIPN and the ratio of the emission intensity (I 0 /I) in the case of Hantzsch's ester because of the superposition of its emission with a pulsed laser source at 405 nm (see the SI). To evaluate a possible role of the pyridine produced by the oxidation of the Hantzsch's ester in the photoinduced processes, 24 we also test the quenching of 3DPAFIPN emission by this compound. No quenching of the excited state of 3DPAFIPN was measured at any concentration of the pyridine added ( Figure S20). The optimized reaction conditions are in line with the photophysical observation because the amount of 3DPAFIPN should be enough to absorb significant blue photons to promote the photoinduced electron transfer. However, the cost, availability, and sustainability of these two players make the present approach extremely competitive for large-scale applications. The determination of the quantum yield carried out gave a value of 1.3% (see SI for full details). Based on the results of the photophysical investigation, and although we cannot exclude short radical chains, the tentative catalytic cycle is depicted in Figure 2. The oxidative quenching of 3DPAFIPN induces the formation of Cp 2 Ti(III)Cl. The 3DPAFIPN •+ is a strong oxidant (E 3DPAFIPN •+ / 3DPAFIPN = + 1.30 vs SCE) 15 and is reduced by the Hantzsch's ester (E HE •+ / HE = +1.0 vs SCE). 25 The reaction produces HE •+ that can participate in further electron transfer events 25 and is a strong reductant. As suggested by Cuerva and Oltra, 3 two molecules of Cp 2 Ti-(III)Cl are necessary for the formation of the allyl titanium specie. Two possible scenarios could be envisioned. The two molecules of Cp 2 Ti(III)Cl are generated by two oxidative quenchings of two molecules of *3DPAFIPN. On the other hand, one molecule of Cp 2 TiCl 2 is reduced by *3DPAFIPN and another by the formed HE •+ . In experiments carried out with crotyl, cinnamyl, and prenyl reagents (Schemes 3,4), we have observed a prevalent γ-regioselectivity. It is well known that both crotyl−Ti(IV) and prenyl−Ti(IV) reagents react with carbonyl favoring the γ-position. 26 As is illustrated in Figure 2, the reaction probably proceeds through the radical coupling between allyl radicals and Cp 2 Ti(III)Cl that forms the allylating Ti(IV) reagents. The protonated rearomatized Hantzsch's ester possesses a low pKa (see Scheme S3 for reactions induced by this Brønsted acid) compared to other reagents used as scavengers in the catalytic redox reaction promoted by titanium chemistry (such as collidine and Me 3 SiCl), and it is efficient in restoring the catalytic cycle by protonation of the titanium-alkoxy bond.
In summary, we have reported a novel allylation photoredox methodology based on the use of the Cp 2 TiCl 2 complex. From the point of view of a green chemistry perspective, the abundance and low toxicity of titanium make the procedure attractive for organic synthesis. 20,27 Careful mechanistic studies have shed light on the application of 3DPAFIPN or parent organic dyes in accessing Cp 2 Ti(III)Cl reagent, avoiding the use of stoichiometric metal, such as Mn or Zn. The Hantzsch's ester used as a stoichiometric reductant is unique for titanium(III) chemistry, and its oxidized and protonated form is beneficial for the turnover of the titanium catalyst. Further studies to expand these radical-polar crossover reaction 28 and to use other redox reactive metals are in progress and will be reported in due time.
Reaction optimization studies; synthetic procedures for allylation reaction and preparation of substrates and photocatalysts; spectroscopic data for new compounds, and copies of NMR spectra; photophysical studies for the model reaction and Stern−Volmer plot (PDF)