University of Groningen Oxa-Michael Addition to alpha,beta-Unsaturated Nitriles Guo, Beibei; Zijlstra, Douwe S.; de Vries, Johannes G.; Otten, Edwin Published in: ChemCatChem DOI: 10.1002/cctc.201800509 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Guo, B., Zijlstra, D. S., de Vries, J. G., & Otten, E. (2018). Oxa-Michael Addition to alpha,beta-Unsaturated Nitriles: An Expedient Route to gamma-Amino Alcohols and Derivatives. 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For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 30-09-2021 DOI:10.1002/cctc.201800509 Full Papers Oxa-Michael Addition to a,b-Unsaturated Nitriles:An Expedient Route to g-Amino Alcohols and Derivatives BeibeiGuo,[a] Douwe S. Zijlstra,[a] Johannes G. de Vries,*[a, b] and Edwin Otten*[a] Water addition to a,b-unsaturated nitriles would give facile loxy-alkylnitriles obtained from oxa-Michael addition also could access to the b-hydroxy-nitriles, which in turn can be hydro- be hydrogenated directly in the presence of acid to give the genatedtothe g-aminoalcohols. We have previously shown amino alcohols as their HCl salts in excellent yields. Hydroge- that alcohols readily add in 1,4-fashion to these substrates nation under neutralconditions gave amixture of the secon- using Milstein’s Ru(PNN) pincer complex as catalyst. However, dary and tertiary amines. Hydrogenation in the presence of attempted water addition to a,b-unsaturated nitrilesgave the base and Boc-anhydride gave the orthogonally bis-protected 3-hydroxynitriles in mediocre yields. On the otherhand, addi- amino alcohols, in which the benzyl ether can subsequently be tion of benzylalcohol proceeded in excellent yields for avarie- cleaved to yield Boc-protected amino alcohols. Thus, avariety ty of b-substituted unsaturated nitriles. Subsequenttreatment of molecular scaffolds with a1,3-relationship between O-and of the benzylalcohol addition products with TMSCl/FeCl3 re- N-functional group is accessible startingfrom oxa-Michael ad- sulted in the formation of 3-hydroxy-alkylnitriles. The 3-benzy- dition of benzyl alcohol to a,b-unsaturated nitriles. Introduction Amino alcohols are an important class of organic molecules with diverseapplications, ranging from bulk chemicals to phar- maceuticals. Most commonly,these compounds present a b- hydroxy-amine motif (with aC2 spacer between the O-and N- moieties), and severalsynthesis routes to 1,2-amino alcohol buildingblocks are known.[1] This structural motif is present in avariety of biologically active compounds such as b-blockers (propranolol and derivatives), hormones (norepinephrine), and antihistamines (carbinoxamine). The related g-aminoalcohols are also presentinpharmaceuticals, for example in the antide- pressantFluoxetine (Prozac). In addition, both b-and g-amino Scheme1.Examples of applications of g-amino alcohols. alcohols have been used extensively in synthetic chemistry as ligandsin(asymmetric) organic synthesis.[2] Some examples of b-hydroxysulfinylimines,[4] nitrene insertion into C Hbonds,[5] À g-aminoalcohol-containing compounds are shownin reductivehydration of propargylic amines,[6] and asymmetric Scheme 1. Several elegant methods for the synthesis of (ster- hydrogenation.[7] An alternative, atom-economical approach eodefined) g-amino alcohols have been reported;recent exam- would be via oxa-Michael addition of water to unsaturated ni- ples include aldol reactions of benzylic nitriles,[3] reduction of triles, followed by hydrogenation.However,only the unsubsti- tuted parentcompound, acrylonitrile, has been shown to un- dergo oxa-Michael addition (‘cyanoethylation’)[8] in afacile [a] B. Guo, D. S. Zijlstra, Prof. Dr.J.G.deVries, Prof. Dr.E.Otten StratinghInstitute for Chemistry manner;the decreased reactivity of b-substituted derivatives [9] University of Groningen poses significant problems in this regard. Nijenborgh 4, 9747AG Groningen (The Netherlands) We recently reported the use of Milstein’s Ru(PNN)-pincer as E-mail:[email protected] catalystfor the oxa-Michael addition to a,b-unsaturated ni- [email protected] triles.[10] This reactionoperates via an unusualmetal-ligand co- [b] Prof. Dr.J.G.deVries [11] Leibniz Institute fürKatalyse e. V. an der UniversitätRostock operative activation of the nitrile that involves (reversible) Albert-Einstein-Strasse 29a, 18059Rostock(Germany) C(ligand) C(nitrile)bond formation(Scheme 2). With anew À E-mail:[email protected] catalytic method available, we became interested in expanding Supporting informationand the ORCID identification number(s) for the this chemistry to access g-amino alcohol derivatives via this author(s) of this article can be found under: methodology. https://doi.org/10.1002/cctc.201800509. While it is found that direct conjugate addition of H Otoun- This manuscript is part of aSpecialIssue on the “Portuguese Conference 2 on Catalysis” based on the International Symposium on Synthesisand saturated nitriles with this catalystsystem proceeds with rela- Catalysis (ISySyCat). tively poor yields, the addition of benzyl alcohol followed by ChemCatChem 2018, 10,2868 –2872 2868 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Papers poor yield (13%) and with impurities still present.The in- creasedreactivity of 1 at 70 8Cislikelydue to the reversibility of the reaction between H2Oand 1,resulting in ahigher con- centration of ”free“ 1.[17] We attribute the formation of relative- ly large amounts of dimer 4a to the biphasic nature of these reactions, with only alimited amount of water present in the organic phase. To minimizeformation of dimers 4,weswitched to crotonitrile (2b)which is less prone to isomerization, and carried out the catalysis in homogeneous mixtures of organic solvent/water (THF/H2Oand tBuOH/H2O, both in 3/1 ratio;and t-amyl alcohol/H2Oina30/1 ratio). At ambient temperature, the protic solvents tBuOH and TAAafforded the oxa-Michael addition product according to GC/MS analysisasminor prod- uct (up to 54 %ofthe converted starting material), while in Scheme2.Mechanism of oxa-Michael addition to a,b-unsaturated nitriles. THF only the dimer 4b was observed. At 70 8C, the selectivity to the desired product 3b was increased (upto84% in Pd(OH)2/C-catalyzed hydrogenation leads to the formation of tBuOH/H2O) but conversionsremained low,which could be re- the desired g-amino alcohols in asynthetically useful manner. lated to athermodynamic equilibrium being reached.[12] Oxa-Michaeladdition of benzylalcohol. We next turned our attention to benzylalcohol addition followed by reductive Results and Discussion cleavage of the benzyl group as amethodtoobtain the (formal)water addition products. Aseries of unsaturated ni- Oxa-Michaeladditionusing water as nucleophile. Direct con- triles with differentsteric andelectronic properties was select- jugate addition of water to a,b-unsaturated acceptors is chal- ed to examine the scope of benzyl alcohol addition catalysed lenging due to the poor nucleophilicity of water and the rever- by 1.The substrates examined werecommercially available, or, sibility of the addition reaction.[12] Although enzymes are capa- in the case of 2d,easily synthesized by olefin metathesis be- ble of performing hydration of (activated) olefins with exqui- tween acrylonitrile and methyl oleate using asecond genera- site control and artificial metalloenzymes have been reported tion Hoveyda-Grubbscatalyst. The conditions we previously re- for this reaction,[13] general synthetic methodologies are lack- ported for oxa-Michael addition to unsaturated nitriles by 1 ing. Detoursusing water surrogates (e.g.,oximes or boronic were employed(0.5 mol % 1,[18] at room temperature in THF), acids) have been used, as well as (asymmetric) conjugate addi- and reactionprogress was monitored by TLC(Scheme 4). Upon tion of silyl and boryl nucleophiles.[14] Conjugate additions to completion,the catalyst was quenched by openingthe flask to a,b-unsaturated substrates with anitrile as electron-withdraw- air,and the crude mixture was purified by columnchromatog- ing group have been studied comparatively little due to their raphy (Table 1). Using this procedure, benzylalcohol addition low reactivity as Michael acceptors,[9] but Kobayashi and co- to crotonitrileafforded the product 5b as colourless oil in 71% workers recently reportedCuII-catalyzed borylationofthese