DOI: 10.1002/chem.201403275

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Photoorganocatalytic Hydroacylation of Dialkyl Azodicarboxylates by Utilising Activated Ketones as Photocatalysts Giorgos N. Papadopoulos, Dimitris Limnios, and Christoforos G. Kokotos*[a]

Abstract: A fast and efficient visible-light metal-free hydroacylation of dialkyl azodicarboxylates is described. Among a variety of activated ketones, phenyl glyoxylic acid and its

ethyl ester were identified as suitable photoorganocatalysts. A range of aliphatic and aromatic aldehydes were employed, thus leading to products in high to excellent yields.

Introduction

expensive Xe lamp (300 W) had to be applied (the authors state that the same transformation can be carried out efficiently in a solar box).[10]

C N bond-forming methodologies have received wide attention, since there is a plethora of natural and non-natural bioactive molecules that require the development of simple and convenient methods for their construction.[1] Dialkyl azodicarboxylates have been recognised as extremely useful reagents owing to their strong electron-withdrawing character and their vacant orbital, thus rendering them good nucleophilic acceptors.[2] Except for their role in Mitsunobu reactions, azodicarboxylates have been employed successfully in electrophilic a-aminations,[3] C H derivatisation at the a position of heteroatoms[4] and the ene-type reaction with olefins.[5] Another interesting reaction of dialkyl azodicarboxylates constitutes their hydroacylation, which leads to hydrazine imides.[6–10] These are versatile compounds for the synthesis of various products. Although early attempts under photocatalytic and thermal conditions led to low yields and rather narrow substrate scope,[6, 7] the use of transition-metal-catalysed processes appeared to provide elegant solutions to this transformation.[8] Lee and Otte were among the first to highlight that, although the reaction in the absence of solvent requires two weeks to reach completion, the use of low Rh catalyst loadings could significantly accelerate the reaction in just a few days (usually 24– 48 h).[8a] Recently it has been demonstrated that the use of ionic liquids or water as the reaction medium can lead to a significant acceleration of the reaction;[9] yet narrow substrate scope, high excess amounts of reagents or reaction time over 24 hours were still required to obtain the products in high yields. A partial solution to this problem has been given recently through the use of metal tetrabutylammonium decatungstate[11] in a photocatalytic reaction, in which high yields were obtained in just two hours (21–98 % yield).[10] Although this methodology utilised an equimolar reagent ratio, a rather

Results and Discussion We have recently turned our attention to the use of activated ketones for a number of chemical processes,[12, 13] and coupled with our own experience in organocatalysis,[14] we speculated that activated ketones could be excellent candidates to be used as metal-free catalysts for photochemical reactions.[15] This hypothesis was tested in the hydroacylation reaction between heptanal and diisopropyl azodicarboxylate (DIAD) (Scheme 1). Cheap and common household lamps were utilised and the reaction could be also monitored by decolourisa-

Scheme 1. Catalyst optimisation for the photoorganocatalytic reaction of diisopropyl azodicarboxylate with heptanal.

tion of the reaction mixture (for details on the reaction, see the Supporting Information). Initially, 2,2,2-trifluoromethylacetophenone was employed, since it has been previously shown to be the catalyst of choice for oxidation reactions.[12] The reaction did not reach completion after two hours and the yield of the product was 52 %. Phenylglyoxylic acid was then employed, which led to quantitative yield. A slight decrease in the activation of the ketone,

[a] G. N. Papadopoulos, Dr. D. Limnios, Prof. Dr. C. G. Kokotos Department of Chemistry, University of Athens Panepistimiopolis 15771, Athens (Greece) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403275 or from the author. Chem. Eur. J. 2014, 20, 1 – 5

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Full Paper by replacing the phenyl moiety with ethyl, resulted in a significant decrease in the yield (26 % instead of 100 %). Esters of phenylglyoxylic acid, such as methyl phenyl glyoxylate, have been commercially available as photoinitiators since the 1960s, primarily for polymerisation reactions and rarely as substrates in photochemical transformations.[16] To understand how they initiate the polymerisation, Neckers’ group has published a number of detailed studies.[17] However, phenyl glyoxylates have never been reported as catalysts for C N bond-forming reactions. When ethyl phenylglyoxylate was utilised in our reaction, similar results to phenylglyoxylic acid were observed. A decrease in the activation of the ketone by replacing the carboxylic group with a methyl (acetophenone) or a phenyl group (benzophenone), which are also known photosensitisers,[15] led to low yields (25– 28 %). Isatin, a strained ketoamide, and a 1,2-diketone led to inferior results (41 and 53 %, respectively). It has to be noted that the reaction in the absence of catalyst afforded the product in just 23 % yield in two hours. Caddick and co-workers had previously postulated that acyl radicals can be generated by aldehyde autooxidation in organic solvents and on-water reactions, but usually this process is slow.[9c] Perhaps in the presence of visible-light irradiation (and in the absence of catalyst) this process of generating acyl radicals is occurring and this is the reason why the product is obtained in low yield in the absence of catalyst. After identifying the optimal catalyst for this visible-light metal-free transformation, the reaction conditions were scrutinised (Table 1, see also the Supporting Information). In testing a number of solvents, petroleum ether (PE) afforded the best results (Table 1, entries 1–5). It should be highlighted that water can be also utilised as a reaction medium, since an excellent yield was recorded (Table 1, entry 5). This constitutes a direct improvement to the literature knowledge,[9c] in which a reaction time of at least 24 hours is required to afford the product in slightly lower yield. Also, since water is considered an environmentally friendly solvent, this methodology Scheme 2. Substrate scope of the reaction. can be categorised as a green alternative for the production of such molecules. The reagent ratio can be time has to be increased to afford the product in respectable decreased to stoichiometric quantities, thereby affording the yields (3 c and 3 d). Chains that bear aromatic groups or product in slightly reduced yields, whereas for sensitive and double bonds are also tolerated and no other products were expensive aldehydes a reversed ratio might be preferred observed (3 e and 3 f). Cyclic aliphatic chains of small to (Table 1, entries 6 and 7). A further decrease in the catalyst medium size and secondary aliphatic chains afforded the prodloading led to lower yields (5 mol %, 88 % yield; 2 mol %, 68 % uct in excellent yields in short reaction times, with 2-phenylyield). propanal being the only exception (3 g–3 n). Pivaldehyde, With the optimum reaction conditions in hand, the substrate a substrate known for its steric hindrance, can also be utilised scope of this visible-light metal-free protocol was explored with success (3 o). To our knowledge, the above results are the (Scheme 2). By utilising DIAD, a variety of aliphatic aldehydes best reported so far for these substrates with respect to the rewere tested (3 a–3 o). Long linear aliphatic alkyl chains are tolaction time and yield of the product. a,b-Unsaturated aldeerated well, thus leading to excellent yields (3 a and 3 b). Other hydes can be employed successfully in this protocol; however, functional groups are accepted well, although the reaction &

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Full Paper catalyst or light. Thus, it is clear that this photoorganocatalytic reaction follows a radical mechanism. Furthermore, to investigate the significance of the chain propagation mechanism, an on/off visible-light irradiation experiment was performed (Scheme 4). The graph shows that continuous irradiation with visible light was necessary. Taking these data into account, the following reaction mechanism is proposed (Scheme 5). Initially, visible-light irradiation of activated ketone is required to produce the excited state of the catalyst P*. Reaction of P* with the aldehyde leads to production of acyl radical I and [P H]*. Then the radical adds to azodicarboxylate II to produce radical intermediate III. This intermediate regenerates the catalyst and releases the product of the reaction. To further highlight the importance of this methodology, hydrazine amide 3 e was treated with allylamine to afford amide 4 in high yield (Scheme 6).[9c] Owing to the high importance of amide bond formation,[18] this constitutes a two-step procedure for the formation of an amide bond starting from an aldehyde and an amine.

Table 1. Photoorganocatalytic reaction of heptanal with diisopropyl azodicarboxylate catalysed by phenylglyoxylic acid.[a]

Entry 1 2 3 4 5 6 7

Solvent [c]

PE hexane CH2Cl2 MeCN H2O PE PE

1 a/2 a

Yield [%][b]

1.5:1 1.5:1 1.5:1 1.5:1 1.5:1 1:1 1:1.5

100 (99) 78 82 76 92 76 96

[a] Reactions performed with catalyst (0.05 mmol), 2 a (0.50 mmol) and 1 a (0.75 mmol) in solvent (0.5 mL) at RT. [b] Yield was determined by 1 H NMR spectroscopy. Isolated yield is given in parentheses. [c] Petroleum ether (40–60 8C).

longer reaction times are required and moderate yields are obtained (3 p and 3 q). Since the reaction time for some substrates was prolonged, we performed the same experiments without the use of catalyst for pivaldehyde and (E)-2-decenal. These experiments led to lower yields, thus highlighting the necessity of the catalyst. When switching from aliphatic aldehydes to aromatic aldehydes, prolonged reaction times are required to obtain similar levels of high yields (3 r–3 w). In some cases, a solvent switch from PE to dichloromethane was necessary for solubility purposes. Finally, other dialkyl azodicarboxylates could be utilised, since tert-butyl or ethyl groups can be employed, thus leading again to high yields (3 y and 3 z). It is important to note that freshly distilled aldehydes produced the products in higher yields Scheme 4. Visible-light irradiation on/off experiment. and in shorter reaction times. To probe the reaction mechanism, a number of control experiments were carried out (Scheme 3). The known radical traps (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) and butylhydroxytoluene (BHT) shut down the reaction completely and only starting materials were observed after two hours, whereas the reaction yield was low in the absence of

Scheme 5. Proposed reaction mechanism.

Scheme 6. Reaction of hydrazine amide 3 e with allylamine to afford amide 4.

Scheme 3. Mechanistic investigations for the reaction. Chem. Eur. J. 2014, 20, 1 – 5

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Full Paper Conclusion

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We have developed a fast photoorganocatalytic hydroacylation of dialkyl azodicarboxylates. Activated ketones—in particular, phenyl glyoxylic acid and its ethyl ester—have been identified as excellent visible-light metal-free catalysts for the above transformation. Although phenyl glyoxylic acid and its aliphatic esters are known to initiate polymer reactions, to our knowledge this is the first time that these compounds have been employed successfully as photocatalysts for the construction of C N bonds. A variety of primary, secondary, tertiary and cyclic aliphatic aldehydes, a,b-unsaturated aldehydes and aromatic aldehydes were employed successfully in the above transformation, thus leading to products in high to excellent yields over short reaction times.

Experimental Section General procedure for the photoorganocatalytic hydroacylation of dialkyl azodicarboxylates Phenyl glyoxylic acid (7.5 mg, 0.05 mmol) was placed in an ordinary glass tube followed by dialkyl azodicarboxylate (0.50 mmol). Freshly distilled or prepared aldehyde (0.75 mmol) and PE 40–60 8C (0.5 mL) were added consecutively. The reaction mixture was left stirring under light irradiation (2  15 W household lamps) at room temperature between 90 min to 48 h depending on the substrate. The crude product was purified using flash column chromatography (PE/AcOEt 8:2) to afford the desired product.

Acknowledgements The authors gratefully acknowledge the “Education and Lifelong Learning” operational program for financial support through the NSRF “ENISCYSH METADIDAKTORWN EREYNHTWN” program (PE 2431)” co-financed by ESF and the Greek State. Keywords: acylation · green organocatalysis · photochemistry

chemistry

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ketones

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[1] For selected reviews and books, see: a) K. P. C. Vollhardt, M. J. Eichberg in Strategies and Tactics in Organic Synthesis, vol. 4 (Ed.: M. Harmata), Academic Press, New York, 2004, p. 365; b) V. Nair, A. T. Biju, S. C. Mathew, B. P. Babu, Chem. Asian J. 2008, 3, 810 – 820; c) A. Vallribera, R. M. Sebastian, A. Shafir, Curr. Org. Chem. 2011, 15, 1539 – 1577. [2] For selected references, see: a) R. Huisgen, F. Jakob, Liebigs Ann. Chem. 1954, 590, 37 – 47; b) V. Nair, A. R. S. Menon, A. R. Sreekanth, N. Abhilash, A. T. Biju, Acc. Chem. Res. 2006, 39, 520 – 530; c) T. Kanzian, H. Mayr, Chem. Eur. J. 2010, 16, 11670 – 11677. [3] For selected examples, see: a) A. Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang, K. A. Jørgensen, Angew. Chem. 2002, 114, 1868 – 1871; Angew. Chem. Int. Ed. 2002, 41, 1790 – 1793; b) B. List, J. Am. Chem. Soc. 2002, 124, 5656 – 5657; c) N. S. Chowdari, C. F. Barbas III, Org. Lett. 2005, 7, 867 – 870; d) T. Mashiko, K. Hara, D. Tanaka, Y. Fujiwara, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2007, 129, 11342 – 11343; e) A. Desmarchelier, H. Yalgin, V. Coeffard, X. Moreau, C. Greck, Tetrahedron Lett. 2011, 52, 4430 – 4432; f) A. Theodorou, G. N. Papadopoulos, C. G. Kokotos, Tetrahedron 2013, 69, 5438 – 5443.

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FULL PAPER & Photoorganocatalysis

Lights on: Visible-light metal-free mediated hydroacylation of dialkyl azodicarboxylates was achieved by utilizing phenyl glyoxylic acid as the photocatalyst (see scheme).

G. N. Papadopoulos, D. Limnios, C. G. Kokotos* && – && Photoorganocatalytic Hydroacylation of Dialkyl Azodicarboxylates by Utilising Activated Ketones as Photocatalysts

Chem. Eur. J. 2014, 20, 1 – 5

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Photoorganocatalytic hydroacylation of dialkyl azodicarboxylates by utilising activated ketones as photocatalysts.

A fast and efficient visible-light metal-free hydroacylation of dialkyl azodicarboxylates is described. Among a variety of activated ketones, phenyl g...
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