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Mar 22, 2016 - Abstract: A convenient photochemical flow proto- col for the formation of aryl-carbon bonds via pho- togenerated phenyl cations has been ...
UPDATES DOI: 10.1002/adsc.201600019

Flow Metal-Free Ar¢C Bond Formation via Photogenerated Phenyl Cations Matteo Bergami,a Stefano Protti,a,* Davide Ravelli,a and Maurizio Fagnonia,* a

Photogreen Lab, Department of Chemistry, Viale Taramelli 12, 27100 Pavia, Italy Fax: (+ + 39)-0382-987323; phone: (+ + 39)-0382-987198; e-mail: [email protected] or [email protected]

Received: January 7, 2016; Revised: February 2, 2016; Published online: March 22, 2016 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600019. Abstract: A convenient photochemical flow protocol for the formation of aryl-carbon bonds via photogenerated phenyl cations has been developed. A wide range of phenylated products, including biaryls, allylarenes, 2-arylacetals and benzyl g-lactones, was smoothly synthesized in satisfactory yields under metal-free conditions. The adoption of a flow reactor often allowed us to adopt higher concentrations of substrates and shorter irradiation times compared to those usually employed in batch systems. Keywords: arylation flow chemistry metal-free conditions phenyl cation photochemistry process mass intensity

Introduction The use of continuous-flow processes is currently an enabling technology to realize process intensification of organic reactions for the smooth preparation of natural products or other valuable derivatives.[1,2] Arylation reactions, among others, are becoming an important tool for the construction of different Ar¢Y bonds under flow conditions and most of them deal with transition metal-catalyzed cross-coupling processes for the formation of Ar¢C bonds [e.g., Ar¢ C(sp3) and Ar¢C(sp2)].[3] Examples belonging to the former class are the Pd-catalyzed a-arylation of oxindoles,[4a] the Pd-catalyzed alkyl-aryl Negishi cross-coupling for the synthesis of alkyl-substituted aromatics,[4b] and the Meerwein arylation of olefins by aryldiazonium salts induced by CuBr or CuI.[4c] A large part of the arylations reported in the literature, however, involves the construction of Ar¢C(sp2) bonds, the Heck reaction being the most investigated process. Thus, the Pd-catalyzed Mizoroki–Heck crosscoupling makes use of Ar¢X,[5] Ar¢OTf[6] or Ar¢ 1164

N2+[7] as the aryl coupling partners. Notably, the adoption of flow conditions markedly improved the sustainability of the reaction, as demonstrated in the cross-coupling of a series of aryl iodides with methyl acrylate or styrene (catalyzed by palladium nanoparticles), where the E factor was reduced from 70.4 (batch) down to 4.6 kg kg¢1 (flow).[5d] Moreover, flow conditions allowed us to work under safer conditions when using hazardous aryldiazonium salts, since they could be prepared in situ from the corresponding anilines.[7,8] Flow reactors were also suitable for the synthesis of biaryls via Pd-catalyzed coupling of arylboronic acids with aryl triflates[9a] or aryl halides.[9b] The Rh-catalyzed asymmetric 1,4-addition of organoboranes to a,b-unsaturated compounds has been likewise optimized under flow conditions.[10] The use of gaseous reagents has also been sparsely reported, as in the aminocarbonylation of aryl bromides in the presence of CO, morpholine and Pd(OAc)2 (2 mol%)[11a] and in the preparation of 2,4,5-trifluorobenzoic acid in the presence of CO2 and EtMgBr.[11b] Transition metal-catalyzed reactions were described as well for the construction of Ar¢O,[12] Ar¢S[13] and Ar¢N bonds.[12b,14] In one case, a continuous-flow photochemical reactor was adopted for the synthesis of carbazoles, including the drug carprofen, via consecutive C¢N and C¢C bond formation, where the metalmediated preparation of a diarylamine was followed by a photoinduced electrocyclization.[14b] The latter experiments show that in most cases flow arylations are carried out either under transition metal-mediated catalysis (mostly by Pd-based catalysts) or by using aggressive reagents (e.g., Grignard reagents). In the last years, continuous-flow conditions were extended to photochemical reactions in order to optimize light penetration in the reaction system[15] and resulted in improved chemoselectivity and shorter reaction times.[16] To this aim, both micro-[17] and macroflow[16,18] photoreactors have been developed. As a matter of fact, only sparse examples on the use of

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Scheme 1. Photoinduced Ar¢C bond formation under flow conditions.

flow conditions for photochemical arylations have been reported as yet, and most of them require a metal-based (Ru, Ir, Ti) photocatalyst (Scheme 1).[19–22] Aryl-carbon bond formation has been often reported, but attention has been mostly focused on intramolecular (Scheme 1a)[19] or intermolecular (Scheme 1b)[19–23] processes involving the addition of an electrophilic photogenerated radical onto electron-rich aromatics (pyrroles, indoles, anilines), followed by oxidation of the resulting radical adduct and deprotonation. To the best of our knowledge, photoinduced metal-free arylations under flow conditions have been reported only in a couple of cases, viz. in the photocyanation of pyrene (Scheme 1c)[24] and in the photolysis of in situ generated diaryl diazo anhydrides for the synthesis of (hetero)biaryls.[25] In the last years, our group has developed a metaland catalyst-free approach for the arylation of olefins and (hetero)aromatics (NuE in Scheme 2) via triplet phenyl cations (3Ar+) photogenerated from substituted electron-rich aryl halides (mainly aryl chlorides) and esters (sulfonates, sulfates or phosphates) Ar¢

Scheme 2. Metal-free arylations via phenyl cations. ISC = intersystem crossing. Adv. Synth. Catal. 2016, 358, 1164 – 1172

X.[26,27] The strategy is based on the heterolytic cleavage of the Ar¢X bond in polar (protic) media and on the chemoselective reaction of the resulting 3Ar+ with p nucleophiles (Scheme 2). The reactions were so far carried out under batch conditions by irradiation of the solutions placed in test tubes with a multi-lamp apparatus[28] or, in favorable cases, by exposure of the starting solution to sunlight.[29] However, a low concentration of the substrate (0.05 M) along with a large excess of the nucleophile (typically from 10- to 20-fold amounts) had to be adopted to make the arylation efficient. Furthermore, the irradiation was carried out in a reactor equipped with low power lamps (15 W) and the reaction often required 4–24 h. We envisioned that the use of a photochemical flow reactor assembled by wrapping a tube (made of a polyfluorinated UV-transparent polymer) around a 500 W Hg lamp (Figure S1, Supporting Information) could be a convenient approach to overcome the limitations described above. The same reactor has been recently applied to photocatalyzed alkylation and acylation reactions, leading to a significant reduction of both waste production and energy expenditure.[30] For this aim, we optimized a set of flow metal-free arylations via phenyl cations by using this photoreactor. The effects of both the absolute concentration and the stoichiometric ratio between the reagents, as well as of the nature of the solvent employed have been investigated. Green metrics tools, including mass (process mass intensity – PMI)[31] and energy indexes (specific productivity – SP),[32] have been employed in the evaluation of the greenness of the process, when moving from batch to flow conditions.[33]

Results We initially selected the synthesis of 4-methoxybiphenyl 8 (obtained by irradiation of chloroanisole 1a in the presence of an excess of mesitylene) as a model reaction. Irradiation of a 2,2,2-trifluoroethanol (TFE) solution containing 1a (0.05 M) and mesitylene (0.5 M) in a multi-lamp apparatus (10 × 15 W lamps, l = 310 nm) for 24 h caused the complete consumption of the aryl chloride and compound 8 was formed in 76% yield (Table 1, entry 1). However, in order to avoid the use of such an expensive reaction medium, a 5:1 MeCN-H2O mixture was likewise investigated as a feasible alternative.[28a,c] A higher yield of 8 (86%) was obtained after only 18 h irradiation, along with a small amount (5% yield) of anisole 1H (entry 2). An identical product distribution was observed when the reaction was performed under flow conditions, although the process was completed in less than 3 h (entry 3). In view of these results, we thus doubled the concentration of 1a while maintaining

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[a]

[b]

[c]

[d]

[e] [f]

Isolated yields of compound 8 after silica gel chromatography; 1H has been quantified via a GC calibration curve. Reaction carried out in a multi-lamp apparatus equipped with 10 × 15 W Hg lamps (l = 310 nm) on 200 mL of solution. Reaction carried out in a flow photoreactor equipped with a 500 W medium pressure Hg lamp. Reactor volume: 50 mL (see the Supporting Information for further details). Reaction carried out in an immersion well apparatus equipped with a 125 W medium pressure Hg lamp on 80 mL of solution. Yields based on 80% consumption of 1a. Yields based on 85% consumption of 1a.

the concentration of mesitylene at 0.5 M. In this case, the reaction proceeded sluggishly in batch and 45 hours of irradiation were required to reach a complete conversion of the starting chloride. The yield of 1H increased at the expense of the desired 8 (entry 4). Moving to an immersion well batch apparatus with a 125 W mercury lamp was likewise unproductive, since the increased optical path and the competitive absorption by the biaryl formed were detrimental for the process (56% yield of 8, 80% consumption of 1a after 30 h irradiation, entry 5). In contrast, 8 was formed in 74% yield under flow conditions (entry 6) after only 5 h irradiation. The same product was obtained more efficiently (90% yield) in TFE and no anisole 1H was detected (entry 7). When decreasing the concentration of mesitylene to 0.25 M (entries 8 and 9), the yield of 8 halved under both batch (80% consumption of 1a after 50 h) and flow conditions. A similar product distribution was found in flow (ca. 8 h irradiation) when further increasing the concentration of 1a to 0.2 M (in the presence of mesitylene 0.5 M, entry 10). 1166

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These results encouraged us to extend the flow approach to other arylations of mesitylene by using the conditions tested in Table 1, entry 6, as summarized in Table 2. In some cases, TFE was also tested as the solvent, in the aim of minimizing the formation of dechlorinated products 1H–7H. Compound 8 was isolated in a similar yield (compare entries 1 and 3) when using methanesulfonate ester 1b instead of chloride 1a. Irradiation of 4-chlorophenol (2a, 0.1 M) in the presence of mesitylene afforded the corresponding biaryl 9 in 68% yield (entry 4). Gratifyingly, the stoichiometric ratio between 2a and mesitylene could be lowered down to 1:2 (entries 5 and 6), while still maintaining satisfactory arylation yields (65%) along with reasonable irradiation times (3 h 40’). 2-Chlorophenol (3a, 0.1 M) also afforded biaryl 10 in 60% yield (entry 7). Product 11 was formed in 85% yield (entry 8) starting from 5-chloro-1,3-benzodioxole (4a) and the process was still efficient (66% yield) when increasing the concentration of the aryl chloride up to 0.25 M, although a slightly longer irradiation time was required in this case (6 h 15’, entry 9). Similar results were obtained with 4-chloroaniline 5a, that afforded the corresponding 4-aminobiaryl 12 in 60% yield (entry 10). In the case of 4-chloro-N,N-dimethylaniline 6a, however, a significant amount of N,N-dimethylaniline 6H (11%) was formed as by-product (entry 11). Accordingly, in the latter case the use of protic, non-reducing TFE allowed us to minimize photoreduction and gave a satisfactory amount of 13 (58% yield after only 1 h 15’ irradiation; entry 12). Pyrex-filtered radiation was mandatory in the case of amino derivatives 5 and 6 in order to preserve the final product from secondary photodecomposition. Finally, chloroalkylbenzene 7a afforded the corresponding biaryl in discrete yield only in TFE under acetone-sensitized conditions,[26b] when a low concentration of the aromatic substrate was adopted (entry 15). We then moved to other arylations and the results have been resumed in Table 3. The synthesis of allylarenes 15–19 took place efficiently by using a solution of the chosen aromatic in the presence of 0.3 M allyltrimethylsilane (ATMS in Table 3). Estragole 15 was synthesized in good yields from both 1a and 1b in an MeCN-H2O mixture, although a significant yield of anisole 1H (around 10% yield) has been detected under these conditions (entries 1–3). However, when the same process was carried out in TFE, the yield of arylated 15 increased up to 79% and no 1H was observed (entry 4). Chavicol 16 was likewise obtained efficiently from 4-chlorophenol (75% yield, entry 5) after only 2 h 30’ irradiation. Further increasing the concentration of starting 2a (0.2 M) resulted in a lowering of the arylation yield in favor of phenol 2H, and TFE was again required to make the reaction satisfactory (entries 6 and 7). A similar behavior was observed for substrates 4a and 5a, where the best condi-

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Flow Metal-Free Ar¢C Bond Formation via Photogenerated Phenyl Cations Table 2. Synthesis of biaryls 8–14 under flow conditions.[a]

[a]

[b]

[c] [d] [e]

Reaction carried out in a flow photoreactor equipped with a 500 W medium pressure Hg lamp. Reactor volume: 50 mL (see the Supporting Information, Figure S1). Isolated yields after silica gel chromatography for compounds 8–14; 1H, 4H and 6H have been quantified via GC calibration curves. Pyrex-filtered radiation was used. Acetone (20% v/v) used as the sensitizer. Yield based on 80% consumption of 7a.

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Table 3. Synthesis of arylated derivates 15–28 under flow metal-free conditions.[a]

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Table 3. (Continued)

[a]

[b] [c] [d]

Reaction carried out in a flow photoreactor equipped with a 500 W medium pressure Hg lamp. Reactor volume: 50 mL (see the Supporting Information, Figure S1). ATMS = allyltrimethylsilane; EVE = ethyl vinyl ether; PA = 4-pentenoic acid; PE = 4-pentenol; HE = 1-hexyne. Isolated yields after silica gel chromatography; 1H, 2H, 4H and 6H have been quantified via GC calibration curves. Acetone (20% v/v) used as the sensitizer. Pyrex-filtered radiation was used.

tions involved the irradiation of a 0.05 M solution of the aromatic substrate in the presence of 6 equiv. of ATMS (entries 8–10). Photoreduction was a competing path also in the case of 4-chloro-N,N-dimethylaniline 6a in acetonitrile-water mixture, whereas exclusive arylation took place in TFE (entries 11 and 12). Flow reactions of aromatic derivatives (0.1 M) with ethyl vinyl ether (EVE; 0.5 M) in alcohols afforded a-aryl aldehydes protected as acetals (20–24, 2 to 3 h 20’ irradiation; entries 13–17). The structure of the end products obviously depended on the alcohol employed, and the best yields were obtained when using TFE (compare, as an example, the results for 2a in methanol and TFE, entries 14 and 15). In contrast, when 4pentenoic acid (PA) was used, no significant improvement of the results obtained for the batch process was observed, and g-benzyllactones 25 and 26 were formed in discrete yields from 4-chloroanisole and 4chlorophenol, respectively (entries 18–21). Interestingly, 26 was synthesized in a higher yield when 4-fluorophenol 2d was used in place of the corresponding chloride (entry 22). Irradiation of 6a in the presence of 4-pentenol (PE) afforded g-benzyltetrahydrofuran 27 by using either an acetonitrile-water 5:1 mixture or TFE as the solvent (entries 23 and 24). Finally, 4-(1hexynyl)anisole 28 was prepared in 50% yield from the photochemical coupling of 1a and 1-hexyne (HE; entry 25).

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Discussion The advantages of applying a flow approach in organic synthesis (including arylation processes) have been highlighted in several reviews[1,2,34] and include: (i) a significant shortening of the reaction time;[4b] (ii) an improvement of the space time yield value (STY = the amount of the desired product per unit volume of the reactor per unit time); (iii) an optimization of energetic and economic costs; (iv) safety improvement; (v) easy scalability;[4b] and (vi) waste reduction. Sometimes, an increase in the reaction yield was also observed, as reported in the case of Meerwein coupling reactions.[4c] As for waste minimization, the adoption of a flow procedure based on a “release and catch” approach for Suzuki[35] and Heck[5d] couplings was found to reduce by more than 99% the production of exhaust chemicals with respect to the traditional batch protocols (from ca. 3000–5000 kg kg¢1 down to 3.5 kg kg¢1 in the case of Suzuki coupling when the solvent was recovered).[35] A comparison between flow and batch reactors in photochemistry and photocatalysis has been frequently carried out, but not yet for the case of photochemical/photocatalytic arylation processes. In terms of reaction times, the adoption of flow photoreactors often allowed a dramatic shortening of this parameter,[21] leading to higher STY values.[30,33,36] Conversely, a significant difference between photochemical and photocatalytic reactions has

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Table 4. Environmental performance of selected arylation processes.

been reported in terms of productivity, which was improved when flow microreactors were applied to photoredox catalyzed processes.[19,36] By contrast, similar yields and productivities have been measured both in flow and in batch reactors for several photoinduced reactions.[33] Significant improvements in the energetic cost of some organocatalytic photoredox a-alkylations of aldehydes[17d] and of several photocatalytic C¢H functionalizations[30] have been reported when moving from batch to flow conditions. In the latter cases, a reduction in the production of waste was described as feasible only when flow conditions allowed the use of a higher concentration of substrates with respect to the corresponding batch processes.[30] The results reported herein show that a strong decrease of the irradiation time is possible when moving from batch to flow conditions, independently from the substrates used (see Table 1, Table 2 and Table 3). For these reasons, the STY value (that is strictly related to the productivity of a process) was noticeably improved (ca. 10-fold) when passing from batch to flow reactors, thanks to the shortening of the required irradiation time. Selected parameters, such as the process mass intensity (PMI)[31] and the specific productivity (SP),[32] were calculated in order to quantify the amount of chemicals and the energy expenditure involved under the examined reaction conditions (see the Supporting Information for a detailed analysis of each reaction). According to its definition, the measured PMI strongly depends on the amount of solvent used. Thus, similar values (ca. 50 kg kg¢1) have been calculated in the synthesis of biaryl 8, which was obtained in comparable yields by irradiating the same 1170

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solution in either flow or batch conditions (Table 4). The SP parameter was previously used by our group[30] with the aim of quantifying the energetic cost of a photochemical reaction, and depends on both the reactor volume and the (nominal) power of the lamp. The multi-lamp batch reactor (Batch 1 in Table 4) employed in this work efficiently converted a larger volume of solution than that irradiated in the flow reactor (200 vs. 50 mL) while employing a lower lamp power (150 vs. 500 W). As a consequence, despite the longer irradiation time, this batch reactor exhibited the most satisfying value in terms of specific productivity (2.10 mmol W¢1 h¢1). The result was somewhat different when an immersion well apparatus equipped with a 125 W Hg lamp was used (Batch 2 in Table 4). In this case, the conversion of the reacting solution (80 mL) required 30 h irradiation to achieve a satisfactory (yet, incomplete) consumption of the substrates and this strongly affected the performance of the reactor leading to an inefficient energy expenditure (0.95 mmol W¢1 h¢1). In selected entries, we exploited the technical characteristics of flow reactors to further increase the concentration of the substrates without affecting irradiation times (that remained < 10 h). This is the case of 4-chlorophenol 2a, that afforded biaryl 9 and chavicol 16 in good yields, when a 0.2 M solution of the precursor was irradiated in the presence of the desired pbond nucleophile (see Table 4 for the case of 9). Indeed, STY and SP values did not undergo a significant improvement, since the concentration increase involved the adoption of a slower flow rate, in turn requiring a longer irradiation time. In addition, in the

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flow apparatus a more powerful lamp (500 W) than those usually adopted under batch conditions (150 W overall for the multi-lamp reactor labelled Batch 1 in Table 4) was used. This resulted in a higher energy expenditure, which significantly affected the SP value of the process. By contrast, the minimization of the amount of the required solvent led, as predictable, to a significant improvement of the environmental impact of the process, with PMI values reaching ca. 32 kg kg¢1 in the case of 9 (Table 4). An excess of p-bond nucleophiles is usually required to trap the highly reactive triplet phenyl cation intermediates.[26,27] Interestingly, efficient arylations have been obtained under flow conditions by using a lower substrate:nucleophile stoichiometric ratio (down to 1:1.5, see compound 16 in Table 3) than that usually employed in batch processes (around 1:10).[26,27]

Conclusions In conclusion, we have presented herein one of the rare metal- and catalyst-free arylation procedures carried out under flow conditions, that gives access to a wide range of synthetic targets (e.g., biaryls, benzyl g-lactones and allylarenes) arising from the photoinduced formation of new Ar¢C(sp3), Ar¢C(sp2) and Ar¢C(sp) bonds in satisfactory yields. The use of a flow reactor allowed for a shortening of irradiation times (< 10 h) with a dramatic improvement of the STY values. On the other hand, environmental parameters, such as PMI and SP, are comparable to those observed for the corresponding reactions carried out under batch conditions.

Experimental Section Typical Procedure for the Synthesis of Compounds 8– 28 Aryl chlorides (a), sulfonate esters (b), phosphate esters (c) or fluorides (d) 1–7 and p-bond nucleophiles were dissolved in 50 mL of a 5:1 acetonitrile-water mixture or TFE in the presence of the required additives. The solution was charged in a flask and pumped through the apparatus described in the text (see also the Supporting Information, Figure S1). The photolyzed solution was then evaporated and the residue was purified by column chromatography (cyclohexane:ethyl acetate as the eluents).

Acknowledgements We acknowledge Prof. A. Albini (University of Pavia) for fruitful discussions. Adv. Synth. Catal. 2016, 358, 1164 – 1172

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