SHORT REVIEW ▌25 Recentshort review Advances in the Direct Nucleophilic Substitution of Allylic Alcohols through SN1-Type Reactions AlejandroSN1 Reactions of Allylic Alcohols Baeza,* Carmen Nájera* Departamento de Química Orgánica and Instituto de Síntesis Orgánica, University of Alicante, Apdo.99, 03080 Alicante, Spain Fax +34(965)903549; E-mail: [email protected]; E-mail: [email protected] Received: 03.10.2013; Accepted after revision: 06.11.2013 Abstract: Direct nucleophilic substitution reactions of allylic alco- hols are environmentally friendly, since they generate only water as a byproduct, allowing access to new allylic compounds. This reac- tion has, thus, attracted the interest of the chemical community and several strategies have been developed for its successful accom- plishment. This review gathers the latest advances in this methodol- ogy involving SN1-type reactions. 1 Introduction 2SN1-Type Direct Nucleophilic Substitution Reactions of Allylic Alcohols 2.1 Lewis Acids as Catalysts Alejandro Baeza was born in Alicante (Spain) in 1979. He studied 2.2 Brønsted Acids as Catalysts chemistry at the University of Alicante and he received his M.Sc. (2003) and Ph. D. degrees (2006) from here under the supervision of 2.3 Other Promoters Prof. José Miguel Sansano and Prof. Carmen Nájera. He was a post- 3 Conclusions and Outlook doctoral researcher in Prof. Pfaltz’s research group (2007–2010). In 2010 he returned to Alicante and joined the research group of Prof. Key words: S 1 reaction, allylic substitution, carbocations, allylic N Carmen Nájera. His main research interests focus on the development alcohols, green chemistry of new environmentally friendly methodologies, especially in asym- metric synthesis. Carmen Nájera was born in Nájera (La Rioja). She graduated from the University of Zaragoza in 1973, and obtained her doctorate in chemistry from the University of Oviedo in 1979. This 1 Introduction was followed by postdoctoral positions at ETH (Zurich), Dyson Per- rins Laboratory (Oxford), Harvard University, and Uppsala Universi- The need to save resources and concerns about our envi- ty. She became an Associate Professor in 1985 at the University of ronment have led to the development of new strategies in Oviedo and a Full Professor in 1993 at the University of Alicante. organic synthesis that are able to fulfill these require- Prof. Carmen Nájera is the co-author of more than 300 papers and 1 book chapters, and she has been a visiting professor at the University ments. Thus, new environmentally friendly processes of Arizona (Tucson, USA), Universidad Nacional del Sur (Bahia have been established that minimize waste production by Blanca, Argentina), Université Louis Pasteur (Strasbourg, France), applying the atom-economy concept2 and avoiding the and Ecole Nationale Superiéure de Chimie de Paris (France). She was use of toxic or expensive reagents and/or catalysts. awarded the ‘Organic Chemistry Prize’ from Real Sociedad Española de Química (2006), ‘Rosalind Franklin International Lectureship’ The allylic substitution reaction is a widespread method- from the Royal Society of Chemistry (2006), and the SCF 2010 ology that is successfully employed in organic synthesis French-Spanish Prize from the Société Chimique de France. In 2012 to obtain new allylic compounds.3 Traditionally, this pro- she was named a Member of the Real Academia de Ciencias Exactas, cess employs alcohol derivatives, such as allylic carbon- Físicas y Naturales, and she was appointed a Member of the European ates, acetates, phosphates, and halides as substrates, and Academy of Sciences and Arts. this generates a stoichiometric amount of waste in their preparation and on their reaction with the corresponding indirect route This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. nucleophile. Therefore, a more attractive strategy from X both a practical and environmentally point of view would preactivation cat., NuH be the direct use of allylic alcohols in this transformation, R R since they are readily available compounds and water OH waste HX Nu would be the only byproduct formed (Scheme 1).1 R R R R cat., NuH H2O SYNTHESIS 2014, 46, 0025–0034 direct route Advanced online publication: 25.11.20130039-78811437-210X DOI: 10.1055/s-0033-1340316; Art ID: SS-2013-M0658-SR Scheme 1 Direct and indirect routes for allylic substitution reactions © Georg Thieme Verlag Stuttgart · New York 26 A. Baeza, C. Nájera SHORT REVIEW 2SN1-Type Direct Nucleophilic Substitution OH Reactions of Allylic Alcohols R R H2O The advantages of free alcohols in allylic substitution re- actions have the attention of organic chemists, and numer- LA ous procedures have been devised to accomplish this + [LA–OH]– NuH purpose. However, free allylic alcohols have two main NuH [LA–OH]– + drawbacks: the poor ability of the hydroxyl function as a R R R R leaving group and the formation of a stoichiometric amount of water; this requires the use of a water-tolerant Scheme 3 Activation mode of allylic alcohols by Lewis acids catalyst able to activate the hydroxy group. Thus, three main strategies, based on the catalysts employed, have Our group has reported the use of silver(I) triflate for the been developed to overcome these problems (Scheme 2): direct amination of allylic alcohols; silver salts are readily The use of transition-metal-based catalysts (such as Pd, Ir, available Lewis acids that had not previously been used in Pt, Rh etc.) implying a π-allyl intermediate in a Tsuji– direct intermolecular allylic substitution reactions using Trost-type reaction.4 allylic alcohols.8 The use of silver(I) triflate in low cata- The employment of Brønsted or oxophilic Lewis acids lyst loadings (2–5 mol%) allowed the successful amina- forming the corresponding carbocationic intermediate in tion of various allylic alcohols with sulfonamides, 5 carbamates, and anilines [Scheme 4, (a)]. an SN1-type reaction. The use of soft π-Lewis acids, such as Au(I) or Hg(II), The Che group also used silver(I) triflate for the allylation able to activate the double bond, and hence facilitating the of electron-rich arenes and heteroarenes in a Friedel– 6 Crafts-type reaction that achieved good to excellent re- nucleophilic attack in an SN2′-type reaction. sults [Scheme 4, (b)].9 Che and co-workers also described This review discusses the most relevant recent work pub- the use of Ag3PW12O40 as a heterogeneous catalyst for this lished since 2011 that uses catalysts or promoters, which transformation that gives comparable results; implies the formation of a carbocationic intermediate in Ag3PW12O40 was recyclable by simply filtration for up to an SN1-type reaction, for direct allylic substitution reac- 9 5 five cycles. Rueping and co-workers described the use of tions using free alcohols. silver(I) triflate for the direct azidation of allylic alcohols [Scheme 4, (c)].10 In all cases the regioselectivity of the process was governed by the stability of the carbocation R OH R Nu + NuH + H2O intermediate. R R NHR4 4 R NH2 2 (a) R3 R 1,4-dioxane R1 25–110 °C 4 1–24 h R = RSO2, Cbz, Ar π-allyl intermediates double-bond activation 36–90% π Tsuji–Trost-type reaction soft -Lewis acids OH AgOTf Ar (Pd, Ir, Pt, Rh...) carbocationic intermediates [Au(I) or Hg(II)] (1–5 mol%) ArH or HetArH (b) 2 3 2 3 R SN1-type reaction R R neat R R1 R1 (Lewis and Brønsted acids) 100–140 °C ArH = 40–92% R1, R3 = H, alkyl, aryl 2 h HetArH = 21–96% 2 Scheme 2 Strategies to perform allylic substitution reactions of free R = H, Me N3 alcohols TMSN3 2 (c) toluene, r.t. R3 R R1 4–16 h 2.1 Lewis Acids as Catalysts 45–98% This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. The use of oxophilic Lewis acids as catalysts grows rap- Scheme 4 Nucleophilic substitutions catalyzed by AgOTf idly, despite the great progress already achieved.5 Gener- ally, the Lewis acids employed tend to be readily 7 Another late transition metal that had not previously been available. As depicted in Scheme 3, the mode of activa- frequently employed in this type of transformation is cop- tion of these catalysts consists of the interaction of the per.5 The Wang and Zhang group reported the formation Lewis acid (LA) with the hydroxyl group, forming a of C–C bonds between terminal alkynes and allylic alco- hydroxo–anionic complex and the allylic carbocation in- hols catalyzed by Cu(OTf)2 with low catalyst loadings termediate. After attack of the nucleophile and proton re- (0.5 mol%) and using 1,2-dibromoethane as the solvent. lease, the Lewis acidity is re-established by the loss of a Remarkably, other Lewis and Brønsted acids commonly molecule of water. employed in direct substitution reactions of alcohols failed or, at best, gave poor results for this particular trans- Synthesis 2014, 46, 25–34 © Georg Thieme Verlag Stuttgart · New York SHORT REVIEW SN1 Reactions of Allylic Alcohols 27 formation. This methodology was also applied to benzylic 11 Si HgOTf alcohols (Scheme 5). H OH O O N OMe (10 mol%) S + S O Ph H2N OMe CH2Cl2, r.t., 10 h O 12 90% yield >99% recovered OH Cu(OTf)2 (0.5 mol%) + Ph up to 5 cycles Ar Ar BrCH2CH2Br, 120 °C Ar Ar 12 h 71–84% Scheme 6 A supported mercury(II) salt as a recyclable catalyst Scheme 5 Alkynylation of allylic alcohols catalyzed by Cu(OTf)2 Zinc(II)-based salts efficiently catalyze the direct allylic substitution of alcohols employing 1,3-dicarbonyl com- As discussed, Au(I) is considered as a π-philic Lewis acid, pounds as nucleophiles under microwave irradiation.5,16