Research

Nucleophilic substitution (SN) reactions belong to the most important and frequently applied transformations in chemistry. However, they are typically associated inevitably with the generation of vast waste amounts and are therefore restricted by a poor sustainability and a poor cost-efficiency.[1] To address these major challenges, we are committed towards the development of novel catalytic methods for SN-type bond formations as illustrated in Scheme 1 A.[2,3]

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Research

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Scheme 1. A General concept for Lewis base catalyzed nucleophilic substitutions and B selected natural products and pharmaceuticals potentially accessible through SN-type transformations.

 


Thereby, mild reaction conditions and a good waste balance are realized through the application of weakly electrophilic reagents such as benzoyl,[4,6,7] acetyl[6,7] and cyanuric chloride (TCT, Scheme 2).[5] These inexpensive commodity chemicals furnish only weakly acidic by-products, whereas conventional protocols are often restricted by the formation of strongly acidic hydrogen chloride. Notably, these non-classical agents only provide the desired substitution products in high levels of chemoselectivity in the presence of a suitable Lewis base catalysts. Indeed, we identified simple formamides such as 1-formylpyrrolidine as potent catalysts for the conversion of alcohols into alkyl chlorides by means of benzoyl chloride[4] and TCT in substoichiometric amounts for down to 34 mol% with respect to the starting alcohol[5] (Scheme 2 A).

Scheme 2. Lewis base catalyzed dehydroxyhalogenations of alcohols.[4-7] a. Prepared from corresponding alcohol (98-99% ee) under twofold inversion. Cbz = carbonyloxybenzyl TBDMS = tert-butyldimethylsilyl, MOM = methoxymethyl.

 

In the following, we introduced diethylcyclopropenone catalyzed chlorinations, brominations and iodinations of alcohols with benzoyl chloride and acetyl chloride, respectively, which are distinguished by low catalyst loadings (down to 1 mol%) and high turnover numbers up 100.[6] Finally, out of a rational screening of various sulfinyl compounds (2-methoxyphenyl) methyl sulfoxide emerged as potent catalyst to access benzylic chlorides.[7] Sulfoxide catalysis in regard to nucleopilic substitutions is mainly focused on benzylic substrates, whereas Pummerer rearrangement is the dominant reaction pathway in the case of less reactive aliphatic starting materials.

 

Subsequently, formamide catalysis has been applied towards the activation of carboxylic acids (Scheme 3 A). Transformation into acid chlorides by means of TCT, which is indeed the cheapest reagent for OH group activation (besides phosgene), allowed to access esters and amides in high yields and excellent scalability (Scheme 3 B). Remarkably, even C-N peptide bonds can be formed virtually without epimerization, when phthaloyl protected amino acids are employed as starting materials. Eventually, formamide catalysis also facilitated the synthesis of geminal dichlorides from aldehydes in high efficacy using phthaloyl chloride as stoichiometric promotor (Scheme 3 C).

Scheme 3. Lewis base catalysis promoted synthesis of A acid chlorides, esters and amides,[8] B selected examples and C conversion of aldehydes into geminal dichlorides.[9] Phth = Phthaloyl.


References

[1]: (a) Constable et al., Green Chem. 2007, 9, 411; (b) J. An, R. M. Denton, T. H. Lambert, E. D. Nacsa, Org. Biomol. Chem. 2014, 12, 2993–3003; (c) P. H. Huy, T. Hauch, I. Filbrich, Synlett 2016, 27, 2631-2636.

 

[2]: Selected examples for Lewis-Base catalyzed halogenations of alcohols: (a) R. M. Denton, J. An, B. Adeniran, Chem. Commun. 2010, 46, 3025–3027; (b) R. M. Denton, J. An, B. Adeniran, A. J. Blake, W. Lewis, A. M. Poulton, J. Org. Chem. 2011, 76, 6749–6767; (c) C. M. Vanos, T. H. Lambert, Angew. Chem. Int. Ed. 2011, 50, 12222–12226; Angew. Chem. 2011, 123, 12430-12434; (d) H. A. van Kalkeren, S. H. A. M. Leenders, C. Rianne, A. Hommersom, F. P. J. T. Rutjes, F. L. van Delft, Chem. Eur. J. 2011, 17, 11290–11295; (e) C. Dai, J. M. R. Narayanam, C. R. J. Stephenson, Nature Chem. 2011, 3, 140-145; (f) T. V. Nguyen, A. Bekensir, Org. Lett. 2014, 16, 1720−1723; (g) L. Longwitz, S. Jopp, T. Werner, J. Org. Chem. 2019, 84, 7863-7870; (h)  M. A. Hussein, T. V. Nguyen, Chem. Commun. 2019, 55, 7962-7965.

 

[3]: Catalytic Mitsunobu reactions: (a) T. Y. S. B. But, P. H. Toy, J. Am. Chem. Soc. 2006, 128, 9636-9637. (b) O’Brien, C. J. PCT Int. Appl. WO2010/118042A2, 2010. (c) D. Hirose, T. Taniguchi, H. Ishibashi, Angew. Chem. Int. Ed. 2013, 52, 4613–4617; Angew. Chem. 2013, 125, 4711-4715; (d) J. A. Buonomo, C. C. Aldrich, Angew. Chem. Int. Ed. 2015, 54, 13041–13044; Angew. Chem. 2015, 127, 13233-13236; (e) D. Hirose, M. Gazvoda, J. Kosmrlj, T. Taniguchi, Chem. Sci. 2016, 7, 5148-5159; (f) D. Hirose, M. Gazvoda, J. Kosmrlj, T. Taniguchi, Org. Lett. 2016, 18, 4036−4039.

[4]: P. H. Huy, S. Motsch, S. M. Kappler, Angew. Chem. 2016, 128, 10300-10304; Angew. Chem. Int. Ed. 2016, 55, 10145-10149.

 

[5]: P. H. Huy, I. Filbrich, Chem. Eur. J. 2018, 24, 7410-7416.

 

[6]: T. Stach, J. Dräger, P. H. Huy, Org. Lett. 2018, 20, 2980-2983.

 

[7]: S. Motsch, C. Schütz, P. H. Huy, Eur. J. Org. Chem. 2018, 4541-4547.

 

[8]: P. H. Huy, C. Mbouhom, Chem. Sci. 2019, 10, 7399-7406.

 

[9]: P. H. Huy, Synthesis 2019, 51, 2474-2483.