Photocatalyzed Carbon−Carbon Bond Formation Between Glycerol and Electron‐Deficient Olefins

Glycerol is produced in large quantities as a co‐product in the manufacturing of biodiesel and has received relatively little attention as a substrate for carbon−carbon bond‐forming reactions. In this work, the photocatalyzed reaction between glycerol and electron‐deficient olefins is investigated to regioselectively insert an alkyl group at C2 in the triol. The results show that the transformation is highly dependent on the nature of the photocatalyst and the olefin. In the presence of an iridium catalyst and quinuclidine, glycerol can be coupled at C2 with sterically unhindered acrylates. In the presence of tetrabutylammonium decatungstate, glycerol can be reacted with fumaronitrile, N‐methyl maleimide, methyl acrylate and itaconic anhydride where the latter two substrates require the additional presence of potassium persulfate as an oxidant. These findings give rise to several new carbon−carbon bond‐forming reactions with glycerol that allow the triol to be converted into more elaborate structures.


Introduction
Biodiesel is an ester of fatty acids, which is obtained from vegetable oils or animal fats by transesterification with methanol or ethanol.It constitutes an important biofuel with a global annual production of about 30 million tons. [1]The cost of biodiesel, however, is 1.5-3.0times higher than that of petroleum-derived diesel fuel. [1]The main reason is the large amount of glycerol (propane-1,2,3-triol), which is produced as a co-product in the manufacturing of biodiesel.The global production of crude glycerol from this process is about 3 million tons, which is estimated to be about six times higher than the current demand. [1]For biodiesel to emerge as a competitive alternative to petroleum-based diesel, it is crucial to identify valuable applications of this stoichiometric co-product.
The main use of glycerol is as an additive in food and beverages, personal care products, and pharmaceutical formulations, but human applications require a rather vigorous and cost ineffective purification of the crude co-product. [2]The main chemical transformations of glycerol involve hydrogenolysis to propane-1,3-diol, dehydration to acrolein, oxidation to hydroxy acids, steam reforming to syngas and formation of glycerol carbonate and isopropylidene acetal. [1]In addition, propane-1,3diol can be prepared from glycerol by microbial fermentation, which can also be employed to prepare succinic acid and nbutanol. [2]Furthermore, glycerol can be converted into a mixture of various alkylated aromatic compounds over different zeolite catalysts. [3]Besides the biochemical and heterogeneously catalyzed procedures, methods for forming carbonÀ carbon bonds on glycerol are rare.
Since glycerol is a triol, it is intriguing to examine carbonÀ carbon bond-forming reactions with alcohols and carbohydrates.Without protecting the alcohol, an α-hydroxy carbon-centered radical can be generated, which constitutes an electron-rich radical that can react with electron-deficient olefins. [4][8] Suitable photocatalysts for hydrogen atom transfer (HAT) from alcohols are benzophenone derivatives, [6] tetrabutylammonium decatungstate, [7] and a dual catalyst system consisting of quinuclidine and iridium complex 1 (Figure 1). [8]In the latter arrangement, photocatalyst 1 is excited by visible light irradiation followed by single-electron transfer (SET) from quinuclidine to generate the corresponding iridium(II) complex.The ensuing radical cation of quinuclidine then performs the HAT from the alcohol. [8]The transformation is aided by catalysts that bind to hydroxy groups and weaken the α-hydroxy CÀ H bond.These catalysts are tavaborole, [8a] tetrabutylammonium dihydrogen phosphate [8g] and a special spirosilane [8d] for the activation of single hydroxy groups while diphenylborinic acid [8e] and diphenyltin dichloride [8b] have been employed for diols.8e] Previously, photocatalytic reactions on glycerol have mainly been carried out with heterogeneous catalysts where either photoreforming (to produce hydrogen gas) or aerobic oxidation of the triol have been performed. [9]ased on these observations, we decided to investigate the radical-mediated carbonÀ carbon bond formation with glycerol in further detail.Herein, we report the photocatalyzed reaction between glycerol and electron-deficient olefins to introduce a carbonÀ carbon bond at C2 in the triol.

Results and Discussion
Glycerol can form carbon-centered radicals at two positions where the radical at C2 is slightly more stable than the radical at C1. [10] However, both radical species can potentially be generated and are known to eliminate water to form the corresponding α-carbonyl radicals. [11]For the exploratory experiments, glycerol was therefore reacted with various hydrogenabstracting reagents in the presence of an acrylate.First, glycerol (10 equiv.)and ethyl acrylate (1 equiv.)were treated with 5 equiv. of a peroxide (tert-butyl hydroperoxide, di-tertbutyl peroxide, dicumyl peroxide or tert-butyl peracetate) in the absence of a solvent at temperatures between 100 and 140 °C.
Potassium fluoride [5b] or copper(II) acetate [6a] was sometimes added in an attempt to favor the desired carbonÀ carbon bond formation.However, all the reactions gave complex mixtures of products, which could not be further analyzed in detail.Possibly, the carbon-centered radicals are formed, but rearrange with the elimination of water at the elevated temperature.Consequently, it was decided to perform the transformation under photocatalytic conditions, since the temperature in this case would be near room temperature.Nevertheless, when glycerol and ethyl acrylate were reacted with benzophenone (20 %) under UV light (~365 nm) at 30 °C, [6a] none of the desired coupling product could be detected.The same result was observed when 2 % of Cu(OAc) 2 was added to the reaction in order to suppress a competing polymerization of the acrylate.
Accordingly, the approach shifted towards the use of photocatalyst 1 with a blue LED light source (Table 1).Repeating the previously reported [8e] experiment with 1 equiv. of quinuclidine and 10 % of diphenylborinic acid (added as the anhydride) gave 40 % isolated yield of γ-bis(hydroxymethyl)-γbutyrolactone (2) after silica gel (15-40 μm) chromatography (entry 1).The yield increased slightly to 44 % when only 10 % of quinuclidine was employed while 40 % yield was obtained with a 1 : 1 ratio of the two reactants (entries 2 and 3).These observations gave rise to a number experiments with catalytic amounts of various HAT and CÀ H bond-weakening catalysts in order to further optimize the transformation.Replacing quinuclidine with the less expensive 3-quinuclidinol gave very little product formation while 3-acetoxyquinuclidine [12] furnished the same yield as the parent HAT catalyst (entries 4 and 5).Omitting the CÀ H bond-weakening catalyst afforded butyrolactone 2 in only 9 % yield illustrating the requirement for this additional hydroxy-binding compound (entry 6).Interestingly, a boronic acid could also serve as bond-weakening catalyst [8c] where phenylboronic acid gave 50 % yield of the lactone while 3nitrophenyl-and 4-pyridinylboronic acid afforded 18 % and 44 % yield, respectively (entries 7-9).With phenylboronic acid, a lower yield of 28 % was obtained when the ratio between glycerol and methyl acrylate was changed to 2 : 3 (entry 10).
Tetrabutylammonium dihydrogen phosphate was also included in the study and in this case the product 2 could be isolated in 52 % yield (entry 11).With 0.5 % of photocatalyst 1, the yield decreased to 43 % (entry 12).In all, the results indicate that the optimal conditions for the transformation use a 2 : 1 ratio of the reactants, quinuclidine as the HAT catalyst and tetrabutylammonium dihydrogen phosphate as the CÀ H bond-weakening catalyst.
The substrate scope of the transformation was then investigated by reacting glycerol with a variety of electrondeficient olefins (Table 2 and Figure 2).First, other esters of acrylic acid were subjected to the reaction where the ethyl and the n-butyl ester gave lactone 2 in 31 and 25 % isolated yield, respectively, while the tert-butyl ester afforded 2 in 12 % yield (Table 2, entries 1-3).Phenyl acrylate, on the other hand, only furnished transesterification with glycerol.Several methyl acrylates with α or β substituents were then submitted to the transformation where methyl 2-fluoro-and 2-methylacrylate afforded 41 % and 37 % yield of lactones 3 and 4, respectively (entries 4 and 5).Surprisingly, methyl acrylates with phenyl and phthalimide substituents in the two positions (i.e. 5-8, Figure 2) failed to react with glycerol and the same was observed with methyl 2-(trifluoromethyl)acrylate (9), methyl (E)-3-(acetylthio)acrylate (10), ethyl crotonate (11), N-isopropyl acrylamide (12) and N,N-diphenyl acrylamide (13).Thus, only sterically unhindered acrylates will undergo the desired transformation with glycerol, i. e. acrylates with no substituents in the β position and small substituents in the α position.Attempts were also made to react vinyl phosphonate 14, vinyl sulfones 15 and 16 as well as ketones 17 and 18 (Figure 2) with glycerol under the optimized conditions, but mostly complex mixtures of products were obtained.Likewise, fumaronitrile, diethyl maleate and N-phenyl maleimide failed to give a well-defined coupling product with glycerol.
Thus, the substrate scope with photocatalyst 1 is essentially limited to simple esters of acrylic acid with no substituents or possibly a sterically undemanding substituent in the α position.These observations gave rise to speculations that a substantially different photocatalyst for the HAT process could alter the scope.Therefore, a number of experiments were also performed with tetrabutylammonium decatungstate (TBADT), which is easily prepared in one step from tetrabutylammonium bromide and sodium tungstate. [13]However, no reaction occurred between glycerol and methyl acrylate when the two substrates were subjected to TBADT and UV light at 365 nm in acetonitrile solution.The outcome was the same when additives such as tetrabutylammonium dihydrogenphosphate and phenylboronic acid were included in the reaction mixture.It should be noted that no coupling between an alcohol and an acrylate has been described in the previous transformations with TBADT. [7]nstead, TBADT has been shown to mediate the carbonÀ carbon bond formation between fumaronitrile and various alcohols. [7]onsequently, glycerol (2 equiv.) was reacted with fumaronitrile (1 equiv.)and 4 % of TBADT under different conditions (Table 3).In the absence of an additive, essentially no coupling took place (entry 1), but with 25 % of tetrabutylammonium dihydrogenphosphate the product 19 could be isolated in 43 % yield (entry 2).A slight increase in the yield was observed when 5 % of phenylboronic acid or methylboronic acid was included as an additive where 50 % yield of 19 was isolated in both cases (entries 3 and 4).Almost the same yield was obtained with a 375 nm lamp while the yield decreased to 41 % with 1.2 equiv. of glycerol (entry 6).Likewise, glycerol could be reacted with Nmethylmaleimide and methyl α-fluoroacrylate to afford 20 and 3 in 43 % and 8 % yield, respectively, in the presence of methylboronic acid (Scheme 1).Unfortunately, the substrate scope again turned out to be very limited since a number of other electron-deficient olefins such as 12, 14, 15, and 18 failed to react in the TBADT-catalyzed reaction with glycerol.
A further change in the conditions was therefore made by including 1 equiv. of potassium persulfate in the transformation.This oxidizing agent has previously been added in TBADTcatalyzed Minisci reactions where it is believed to reoxidize the reduced form of the photocatalyst. [14]Interestingly, when glycerol was reacted with methyl acrylate in the presence of   TBADT, methylboronic acid and potassium persulfate, lactone 2 was now obtained in 33 % yield (Scheme 2).With 5 % of the persulfate, the lactone was only isolated in 8 % yield.Since the persulfate in principle could mediate the reaction on its own, a control experiment was performed in the absence of TBADT, which gave no conversion into lactone 2. When the conditions were applied to fumaronitrile and methyl α-fluoroacrylate, the products 19 and 3 were in both cases isolated in 17 % yield (Table 3, entry 7 and Scheme 1).Notably, the protocol could also be employed for coupling to itaconic anhydride (21) (Scheme 2).Since the product is a carboxylic acid, a methyl esterification with trimethylsilyl diazomethane [15] was included in the workup to afford ester 22 in 38 % isolated yield.This transformation constitutes an interesting carbonÀ carbon bond formation between two compounds, which both appear on the list of platform molecules from the U.S. Department of Energy. [16]Itaconic acid is produced on large commercial scale by fermentation [17] and has previously been subjected to a photocatalytic coupling to isopropanol and cyclohexanol with benzophenone as the photosensitizer, [18] but no reaction with glycerol has been described before.
Other electron-deficient olefins such as 7, diethyl maleate and maleic anhydride were also reacted with TBADT in the presence of potassium persulfate, but without giving rise to a carbonÀ carbon bond with glycerol.Nothing indicates that any of the transformations are troubled by poor regioselectivity since only coupling products at C2 in glycerol were isolated and no coupling to C1 in the triol was ever detected.The mechanism for the iridium-catalyzed procedure is believed to follow the previously proposed pathway [8g] where the radical cation of quinuclidine performs the HAT at C2 in glycerol.7b] There is no clear explanation for the difference in substrate scope between the iridium-and the tungstencatalyzed protocol.However, it should be noted that the previous procedures with these two catalyst systems have often shown a rather limited scope in the electron-deficient olefin, [7,8] which is presumably due to side reactions caused by the photocatalyst.

Conclusions
In summary, the photocatalyzed coupling between glycerol and a variety of electron-deficient olefins has been investigated under different conditions.A regioselective carbonÀ carbon bond formation can be achieved at C2 in the triol, but the transformation is highly dependent on the structure of the photocatalyst and the olefin.With photocatalyst 1 and quinuclidine, coupling to several sterically undemanding acrylates can be achieved.With TBADT as the photocatalyst, coupling to fumaronitrile, N-methylmaleimide, methyl acrylate and itaconic anhydride can be performed where the latter two substrates require the additional presence of potassium persulfate.The results illustrate several new reactions between glycerol and electron-deficient olefins to form more advanced structures, but also the challenge in developing photocatalytic transformations on the triol with a broad substrate scope.

General procedure for iridium-catalyzed couplings
To an oven dried 4 mL vial equipped with a stir bar was added glycerol (2.0 equiv., 1.20 mmol), quinuclidine (0.1 equiv., 0.60 mmol), tetrabutylammonium dihydrogen phosphate (0.25 equiv., 0.145 mmol), and iridium complex 1 (0.01 equiv., 0.006 mmol).The vial was placed under an argon atmosphere, and anhydrous CH 3 CN (1.2 mL) followed by the Michael acceptor (1.0 equiv., 0.60 mmol) were added to the reaction mixture.The resulting suspension was degassed under a positive pressure of argon gas for 5 minutes.The vial was sealed with parafilm, and subsequently irradiated for 18 hours by using a Kessil A160WE Tuna Blue, LED lighting (40 W).During the irradiation, the reaction was cooled with a strong flow of air from a hose pointing towards the vial to maintain a temperature of 30 °C.The reaction mixture was diluted with a small amount of EtOAc and acetone and purified directly by flash column chromatography (silica gel 15-40 μm).

General procedure for TBADT-catalyzed couplings
To an oven dried 4 mL Pyrex vial equipped with a stir bar was added glycerol (2.0 equiv., 1.30 mmol), methyl boronic acid (0.05 equiv., 0.032 mmol), Michael acceptor (1.0 equiv., 0.64 mmol), possibly K 2 S 2 O 8 (1 equiv., 0.58 mmol), and TBADT (0.04 equiv., 0.026 mmol).The vial was placed under an argon atmosphere, and anhydrous CH 3 CN (1.2 mL) was added by via a syringe to the vial.The resulting suspension was degassed under a positive pressure of argon gas for 5 minutes.The vial was sealed with parafilm, and subsequently irradiated for 24 hours by using a THORLABS M365L3-C1, 365 nm LED lighting (520 mW).The reaction mixture was diluted with a small amount of EtOAc and acetone and purified directly by flash column chromatography (silica gel 15-40 μm).

Figure 2 .
Figure 2. Structures of electron-deficient olefins unable to participate in the coupling with glycerol.

Table 2 .
Coupling between glycerol and various acrylates.