Photoredox Propargylation of Aldehydes Catalytic in Titanium

A practical and effective photoredox propargylation of aldehydes promoted by 10 mol % of [Cp2TiCl2] is presented. No stoichiometric metals or scavengers are used for the process. A catalytic amount of the cheap and simply prepared organic dye 3DPAFIPN is used as the reductant for titanium. The reaction displayed a broad scope, and no traces of allenyl isomers were detected for simple propargyl bromide, whereas mixtures of propargyl and allenyl isomers were observed for substituted propargyl bromides.

I n just a few years, photoredox catalysis has reached an extraordinary level of advancement, introducing new and exciting methodologies in organic chemistry. 1 Besides electron transfer, many interesting reactions can also be promoted by photocatalytic methodologies using energy transfer (EnT) to reach a reactive transition state in molecules or complexes. 2 Now, dual photoredox catalysis, 3 that is the combination of metal-promoted processes with photoredox cycles, is in continuous development. 4 From the application of synergistic dual photoredox catalysis to cross-coupling reactions, metalcatalyzed processes were addressed to radical to polar crossover reactions (RPC), 5 with the aim of developing important C−C bond-forming reactions. 6 In this context, allylation methodologies were introduced with chromium, 7 nickel, 8 and titanium. 9 Particularly, the earth-abundant titanium can give important advantages in terms of sustainability and ecofriendliness of the process, 10 and its use in combination with photoredox catalysis was first explored by Gansaüer. 11 In addition, the interesting photophysical properties of titanium complexes make the further exploration of their chemistry in the excited state even more intriguing. 12 We recently have reported the allylation reaction of aldehydes, employing 10 mol % of the inexpensive [Cp 2 TiCl 2 ], in the presence of an organic dye, 3DPAFIPN, 13 and Hantzsch's ester as the stoichiometric reductant. 9 Quite recently, Glorius has reported an interesting carbonyl propargylation 14 via dual chromium/photoredox catalysis, taking advantage of a catalytic radical three components coupling of 1,3-enynes, aldehydes, and radical precursors, in the presence of CrCl 3 and visible light. 15 However, the direct use of propargylic halides or alkynes for the generation of propargyl chromium species is still not reported by means of the emerging dual photoredox catalytic system.
Preliminarily, we have also mentioned that the propargylation reaction of aldehydes was also accessible by the dual photoredox-mediated catalysis with titanium, 9, 16 and herein we illustrate the potentiality, cleanness, and simplicity of the propargylation reaction conducted under photoredox conditions by the use of propargyl bromide.
Starting by employing hydrocinnamic aldehyde 1a, we have optimized the model propargylation reaction using propargyl bromide, and in general, it was found that the reaction was promoted by the organic dyes 3DPAFIPN, affording the product 3a in good yields. 4CzIPN 17 and 3CzClIPN 18 were also tested in the model reactions and gave inferior results (Table 1, entries 3 and 4, respectively). All reactions were performed with the cheap and commercially available [Cp 2 TiCl 2 ]. As reported in our allylation reaction, 9a the use of THF, with a substrate concentration of 0.05 M, was important to allow the desired transformation due to the strong overlap in the absorbance of the photocatalyst and the titanium complex. The optimized conditions are in line with the photophysical observation because the concentration of the red titanium complex (ε 455nm ≈ 250 M −1 cm −1 ) allows a significant absorption of the blue photons by 3DPAFIPN (ε 455nm ≈ 2900 M −1 cm −1 ) to promote the photoinduced electron transfer. Hantzsch's ester was found to be the best choice as the stoichiometric reductant since various sacrificial reductants (i.e., different amines) were proved to be not suited for the propargylation reaction. This is in part related to the lack of stability of [Cp 2 TiCl 2 ] in the presence of different amines under irradiation. 16 The propargylation reaction was quite sensitive to traces of oxygen and water, and low yields were isolated, performing the reaction in the presence of oxygen (Table 1, entry 8). 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.
It was possible to scale the reaction up to 1.0 mmol, increasing the reaction time to 48 h without observing an appreciable decrease of the yield (Table 1, entry 2).
The selected reaction conditions were employed to test the scope of the reaction with aromatic and aliphatic aldehydes. As evident by the data reported in Scheme 1, aromatic and heteroaromatic aldehydes are suitable substrates for the reaction. Yields are, in general, from good to moderate. The presence of electron-withdrawing groups on the aromatic ring reduced the yield of the reaction. Sterical hindrance in the ortho-position does not hamper the reactivity, with either activating or deactivating groups. Although the oxidized product of Hantzsch's ester (the corresponding protonated pyridinium) is strongly acidic and could favor undesired reaction pathways involving the indole ring, indole substrates are reactive in the propargylation reaction, giving much better yields compared to what was observed for the allylation reaction. 9a Variously substituted thiophene carboxaldehydes are suitable substrates for the transformation. As already noted in the allylation reaction, no additives or scavengers are required for the release of the desired homopropargylic alcohol with the concomitant restoration of the titanium complex from homopropargylic alkoxide. As a matter of fact, the protonated pyridine derivative obtained by the oxidation of the Hantzsch's ester behaves as a scavenger for the reaction, enabling the desired turnover of the employed titanium complex. As was observed for the allylation reaction, also in the photoredox propargylation reaction, 10 mol % of the [Cp 2 TiCl 2 ] complex gave the optimal catalyst concentration. In all reported examples with aromatic aldehydes, no traces of the possible allenylic product were detected by 1 H NMR analysis of the crude reaction mixture. The reaction is also quite effective with aliphatic aldehydes (3q−v), and excellent results were obtained (Scheme 2). Branched aliphatic aldehydes were found to be reactive substrates, furnishing the respective homopropargylic alcohols in good yields. In addition, aliphatic aldehydes with acidic protons, whose propargylation products can suffer from undesired water elimination pathways, are suitable substrates. No modifications in the conditions were made to perform the reaction with aliphatic aldehydes with respect to aromatic substrates.
In general, the reactions ran smoothly without any significant inconveniences. Also, with aliphatic aldehydes, the reactions favored the propargylic derivatives in all examined cases.
We have briefly investigated the outcome of the reaction in the case of different propargylic bromides (Scheme 3). Interestingly, the presence of aliphatic or aromatic substituents on the propargylic moiety favors the allenylic product, probably due to the major sterical hindrance of the allenylic titanium intermediate, compared to the propargylic. The synthesis and structural characterizations of allenyl titanocene-(IV) and propargyl titanocene(IV) were reported in literature. 19 These compounds are involved in fast metallotropic allenyl−propargyl equilibria in solution prior to the electrophilic quenching, 20 as confirmed by DFT calculations. Therefore, the reactivity of differently substituted propargylic halides are controlled by the different energy barriers in transition states relative to the reaction of the propargyl and allenyl titanium(IV) precursors with carbonyls via S E 2 mechanism and not by the metallotropic equilibria. 19 The reaction with secondary propargyl bromides gave unsatisfactory simple diastereoselection; in this case, the result could be imputable to the absence of control in the formation of the allenyl titanium intermediate. We have conducted the Stern−Volmer analysis of the reaction, similarity to our previous study of allylation, by simply varying the concentration of propargyl bromide added to the 3DPAFIPN. As illustrated in Figure S3B (see Supporting Information), in airequilibrated solution, the emission intensity of 3DPAFIPN is barely decreasing upon increasing the concentration of propargyl bromide, thus highlighting a slow diffusional quenching (k q 1.0 × 10 8 M −1 s −1 ).
The same conclusions can be drawn by observing the negligible changes in the emission lifetime in the presence of propargyl bromide at concentrations up to ca. 0.13 M ( Figure  S3C). In degassed solutions, the long-excited state lifetime of pristine 3DPAFIPN (172 μs) is decreasing to 41 μs upon the addition of propargyl bromide at high concentrations (ca. 0.11 M). The estimated quenching constant is 3 orders of magnitude lower than that determined for [Cp 2 TiCl 2 ] in the same experimental conditions (k q ≈ 10 5 and 5.2 × 10 8 M −1 s −1 , respectively; 8 see Figure S4B), pointing out that a photoinduced electron transfer is more likely to occur to the latter.
We have already reported 9 that Hantzsch's ester and [Cp 2 TiCl 2 ] are effective quenchers of the photocatalyst. It is also worth mentioning that we have also established that the pyridine salt formed in the reaction is not a quencher at any concentration. In the case of propargylation, the absence of quenching with propargylic bromide suggests the mechanism illustrated in Figure 1. The oxidative quenching of *3DPAFIPN is responsible for the formation of [Cp 2 TiCl] and 3DPAFIPN •+ . The latter is a strong oxidant (E(PC •+ /PC) = +1.30 vs SCE), 13 and the photoredox cycle is closed by the Hantzsch's ester (E(HE •+ /HE) = +1.0 vs SCE), which reduces the 3DPAFIPN •+ back to 3DPAFIPN. The reaction produces the strong reductant HE •+ that can participate in further electron transfer events, 21 generating the rearomatized Hantzsch's ester, in the form of its pyridinium salt. Furthermore, the oxidative quenching of the photocatalyst in its excited state by the titanium complex [Cp 2 TiCl 2 ] generates the [Cp 2 TiCl] species. A radical-mediated addition 22 of [Cp 2 TiCl] to the propargyl bromide gave the corresponding allenylic/propargylic titanium reagents. Subsequent reaction of the allenylic species with aldehydes gave the titanium-alkoxy derivatives that are transformed into the corresponding alcohols by acidic protons available from the oxidized Hantzsch's ester pyridinium salt. In fact, the latter is an acidic compound, and it features a low pK a compared to other reagents used as scavengers in the catalytic redox reaction promoted by titanium chemistry (such as collidine·HCl). 23 In summary, we have described a direct photoredox propargylation reaction mediated by a cheap and not toxic titanium complex that affords the desired homopropargylic alcohols in good yields with both aromatic and aliphatic aldehydes. Further studies about metal photoredox-mediated reactions 24 are in progress in our laboratory.

■ EXPERIMENTAL SECTION
General Methods and Materials. 1 H NMR, 13 C NMR, and 19 F NMR spectra were recorded on a Varian Mercury 400 spectrometer. The residual protic signal of the solvent for the 1 H and 13 CDCl 3 signals for 13 C were used as references for spectra recorded in CDCl 3 (7.26 and 77.16 ppm, respectively). The trifluoroacetic acid signal (−76.55 ppm) was used as a reference for 19 F NMR spectra. Chemical shifts are reported in parts per million (ppm) of the δ scale relative to TMS for 1 H and 13 C NMR spectra and CFCl 3 for 19 F NMR spectra. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublet, ddd =   25 The reaction vessel was placed 10 cm approximately from the lamp, and the temperature was maintained at room temperature by cooling with a PR160 ring w/fan kit. 26 3DPAFIPN, 13 4CzIPN, 13 3CzClIPN, 13 and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (Hantzsch's Ester) 27 were prepared following literature procedures.
Photos of reaction setup, copies of NMR spectra, and photophysical study results (PDF)