Substitution reactions belong to the most important and frequently applied transformations in chemistry. Nevertheless, substitutions are typically associated inevitably with the generation of vast waste amounts and a poor cost-efficiency, because in contrast to addtions and rearrangements at least one stoichiometric waste by-product is formed.[1] To address this major challenge, we are dedicated to the development of novel catalytic methods for nucleophilic substitutions as shown in Scheme 1 A.[2-3]


Scheme 1
Scheme 1. A General concept for Lewis-base catalyzed nucleophilic substitutions of alcohols, 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 (21)[4] and cyanuric chloride (TCT, 22, see Scheme 2).[5] These inexpensive commodity chemicals furnish only weakly acidic by-products, whereas conventional protocols utilizing reagents such as phosgene, thionyl and oxalyl chloride are often restricted by the formation of strongly acidic hydrogen chloride. Notably, these non-classical agents only provide the desired substitution products in the presence of suitable Lewis base catalysts. Indeed, we identified simple formamides such as 1-formylpyrrolidine as potent catalysts for the conversion of alcohols 11 into alkyl chlorides 41.


In the following, we introduced diethylcyclopropenone (32) catalyzed chlorinations, brominations and iodinations of substrates 11 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, rational screening of various sulfinyl compounds delivered sulfoxide 33, as potent catalyst for the conversion of benzylic alcohols.[7] Sulfoxide catalysis in regard to nucleopilic substitutions is mainly focused on benzylic substrates, whereas Pummerer rearrangement of 32 is the dominant reaction pathway in the case of less reactive aliphatic starting materials.


Scheme 2
Scheme 2. Formamide catalyzed chlorinations.[4-7] a. Prepared from corresponding alcohol (98-99% ee) under twofold inversion.


[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. See also: (g) J. G. Lee, K. K. Kang, J. Org. Chem. 1988, 53, 3634-3637. (h) D. C. Snyder, J. Org. Chem. 1995, 60, 2638-2639.


[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.