Recent Advances in the Direct Nucleophilic Substitution of Allylic

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 alcohols are environmentally friendly, since they generate only water as a byproduct, allowing access to new allylic compounds. This reaction 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 methodology 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 asymmetric 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 reactions 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 and, therefore, a carbocationic intermediate is rarely in- An additional attractive application from an environmen- volved when their complexes are used for this reaction.6,12 tal point of view has been developed based on the use of However, Au(III) is not the same, as in this higher oxida- ZnBr2 acting as a catalyst for the solvent-free allylic sub- tion state the gold species are considered oxophilic and stitution reaction of alcohols, using indoles and nitrogen can activate the hydroxyl group generating a carbocation.5 compounds (mainly sulfonamides and electron-poor ani- Thus, the Ohshima and Mashima group took advantage of lines) as nucleophiles under high-speed vibration milling this well-known fact,6 and they reported the use of conditions. Other common Lewis acids employed in this NaAuCl ·2 H O (1 mol%) for the direct allylic amination 4 2 reaction, such as FeCl3, AlCl3, and CuCl2, afforded the reaction of different linear allylic alcohols using highly corresponding products in lower yields under the same functionalized nitrogen nucleophiles (containing other conditions. Unfortunately, a relatively high catalyst load- functional groups such as protected alcohols, carbonyl ing (20 mol%) was necessary to achieve high yields.17 groups, acetals etc.) in refluxing dichloromethane.13 This In addition, a further two processes use zinc salts in a C– group also described the use of aluminum salts, more pre- C bond-forming reaction. The first uses 15 mol% cisely Al(OTf) , which were unexplored as catalysts for 3 Zn(OTf) as the catalyst and TMSCN (4) as the cyanide this type of transformation.14 In this case only 1 mol% of 2 source for the direct cyanation of benzylic and allylic al- catalyst loading in nitromethane as solvent was sufficient cohols, such as (E)-1,3-diphenylprop-2-en-1-ol (3), giv- to achieve high yields within minutes for most examples ing the corresponding nitriles in good yields (Scheme 7).18 described. In both cases, the observed racemization of op- tically enriched substrates during the substitution process OH CN supports an SN1-type mechanism. In addition, in the case Zn(OTf)2 (15 mol%) + TMSCN of Al(OTf) the authors also performed the direct amina- Ph Ph Ph Ph 3 MeNO2, 100 °C tion under microwave irradiation and this shortened the 3 4 6 h 77% reaction times, especially in the most challenging exam- Scheme 7 Cyanation of allylic alcohols catalyzed by zinc triflate ples, and maintained the excellent results.14 The same racemization in the aminated product when The second process, from the Ma group, uses allenes as starting from an enantioenriched allylic alcohol was ob- nucleophiles in the reaction with in situ formed carboca- served by Yamamoto and co-workers for the intermolec- tions derived from allylic alcohols. In this case zinc ha- ular amination of alcohols using sulfamates as lides, although used in stoichiometric amounts, were the nucleophiles and Hg(OTf)2 as catalyst, which, as in the promoters. Depending on the allene structure and the zinc previous gold case, is commonly classified as a soft π- halide employed, different products were isolated Lewis acid. This fact, together with double bond isomer- (Scheme 8). Thus, when the R group was alkyl or aryl and izations, points towards an SN1-type mechanism. Thus, ZnCl2 was employed, the corresponding indene deriva- high yields were obtained at room temperature with only tives were obtained as a consequence of nucleophilic at- 2 mol% catalyst loading. The reaction shows high func- tack of the allene on the transient carbocation followed by This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tional group tolerance, although in some cases higher tem- a Friedel–Crafts-type reaction. However, for monosubsti- peratures were needed. In addition, a supported version of tuted allenes (R = H), the corresponding halopenta-1,4-di- this catalyst was also successfully employed and reused enes were obtained regardless of the zinc salt employed.19 for up to five cycles by simply filtration without apparent metal leaching, for example, in the reaction between cy- clohex-2-enol (1) and methyl sulfamate (2) (Scheme 6).15

R1 OX OX Ph

OH SbCl3 (15 mol%) + (a) R = aryl, alkyl Ph Ph MW, 400 W, 65 °C X = Cl R 25 min R Ph R 3 X = H, Me 61–79% OH

Ar Ar Ar Ar OH 61–96% NHPG ZnX2 1 3 (1 equiv) R R 3 + R2 R1 R R2 CH2Cl2 0 °C, N Re2O7 (1.5 mol%) • 2 Ar Ar OH + H NPG (b) 2 NHPG CH2Cl2, r.t. R R = H H X X = Cl, Br, I 1 R 33–60% n n

R1, R2 = H, alkyl, aryl PG = Cbz, Boc, Ts, Ns 61–99% R1 = H, Me, Cl, OMe 3 R1 R = H, Me n = 0, 1, 2 Scheme 8 Allenes as nucleophiles in zinc(II)-mediated reactions Scheme 10 Antimony(III)- and rhenium(VII)-catalyzed allylic sub- with allylic alcohols stitution

Bismuth(III) triflate is an excellent catalyst for the direct The use of tin as a catalyst for this transformation has re- allylic substitution of free alcohols.5,20 However, a new ceived scant study. However, the Roy group has reported protocol by the Laali group uses ionic liquids as environ- the use of heterobimetallics Sn–Pd and Sn–Ir complexes, mentally friendly and reusable reaction media in combi- PdCl(COD)–SnCl3 and [Ir(μ-Cl)(COD)Cl(SnCl3)]2, re- nation with 10 mol% of Bi(OTf)3 as the catalyst. Under spectively, for direct nucleophilic substitution through these conditions silyl-based nucleophiles were successful- dual activation of allylic alcohols.24 Under these condi- ly introduced in short reaction times affording the corre- tions a wide variety of nucleophiles, such carbon nucleo- sponding products in high yields (Scheme 9). The ionic philes, e.g. 1,3-dicarbonyl compounds and arenes, liquid [BMIN][BF4] was recovered for up to six cycles organosilanes, nitrogen-based nucleophiles, alcohols, and without affecting the chemical yield.21a A similar strategy, thiols, have been successfully introduced even using less but using Bi(NO3)3·5 H2O as the catalyst, was followed by reactive allylic alcohols such as cinnamyl alcohol. The the same group when using 1,3-dicarbonyl compounds as dual activation, which was corroborated by 1H and 13C nucleophiles.21b NMR, of the hydroxy group by the Lewis acid and the double bond by the transition metal (Pd or Ir), respective- Nu OH Bi(OTf)3 (10 mol%) ly, is thought to be responsible for the good yields ob- 24 + (alkyl)3SiNu tained (Figure 1). 1 R3 1 R3 R Me F4B R 2 R2 N R N C H 4 9 85–94% [Sn] [BMIN][BF ] [M] Nu = H, , 4 OH Ph r.t., 15–60 min R H Scheme 9 Bismuth(III)-catalyzed allylic substitution of alcohols in H ionic liquids NuH

Other metal species that act as Lewis acids which are able Figure 1 Proposed activation mode of heterobimetallics Sn–Pd and to catalyze the direct allylic substitution of alcohols that Sn–Ir complexes had not previously been explored are SbCl3 and Re2O7.

The alkaline-earth metals have attracted much less atten- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Nayak et al. used SbCl3 as a catalyst for the allylation (and alkylation using benzylic alcohols) of electron-rich arenes tion as Lewis acids that are able to activate the hydroxy and heteroarenes with (E)-1,3-diphenylprop-2-en-1-ol (3) group and, hence, promote this transformation. The as the substrate in a microwave-accelerated reaction that Niggemann group has studied the use of calcium salts as achieved good yields in short reaction times, although a catalysts for the direct substitution of alcohols in an SN1- relatively large amount of catalyst (15 mol%) was needed type reaction. Concretely, they have successfully utilized 22 calcium triflimide in combination with an ammonium salt [Scheme 10, (a)]. In contrast, Re2O7 showed excellent activity as a catalyst for the amination of allylic alcohols for the nucleophilic substitution reactions of various allyl- with different nitrogen-containing nucleophiles; only 1.5 ic alcohols. Thus, depending on the nucleophile employed the direct amination, Friedel–Crafts-type arylation, and mol% of Re2O7 was required at room temperature to reach high yields [Scheme 10, (b)].23 allylation/alkenylation reaction were achieved (Scheme 11).25

Synthesis 2014, 46, 25–34 © Georg Thieme Verlag Stuttgart · New York SHORT REVIEW SN1 Reactions of Allylic Alcohols 29

NHR4 ing a wide range of allylic alcohols as alkylating agents 4 R NH2 3 (a) through a SN1-type reaction under mild reaction condi- R1 R 1–24 h R2 tions (25–50 °C) and using a relatively low catalyst load- 4 R = RSO2, Cbz, aryl ing (normally 5–10 mol% of FeCl3·6 H2O) with dioxane 36–90% as the solvent. The SN1 reaction mechanism was con- OH Ca(NTf2)2/Bu4NX Ar ArH or HetArH firmed not only by the detected racemization of enantio- (5 mol%) (b) 1 R3 1 R3 enriched allylic (E)-1-phenylpent-1-en-3-ol (5) [Scheme R R 2 R2 CH2Cl2, r.t. 2 h R 13, (a)] after the reaction took place, but also because the 40–92% use of isomeric alcohols 6, 7, and 8 produced the same TMS amination product [Scheme 13, (b)]. This fact, which gov- n n = 0,1 n erns the regiochemistry of the process, suggest a common (c) R1, R2 = H, alkyl, aryl 1 R3 carbocationic allylic intermediate that leads to the most 4–16 h R 2 R3 = H, Me R stable, from a thermodynamic point of view, double bond 45–98% X = PF6, BF4 prior to the amination. In addition other carbonucleophiles such as silyl-based, aromatics, and malonates were also Scheme 11 Calcium triflimide catalyzed allylic substitution with 29 free alcohols successfully allylated employing this methodology.

OH FeCl3⋅6H2O (10 mol%) NHTs Iodine efficiently catalyzes the direct allylic substitution + TsNH2 (a) ∗ reaction of alcohols under mild conditions giving satisfac- Ph Et 1,4-dioxane, 50 °C Ph Et 5 24 h tory results with different nucleophiles. The Liu group 5 90% took advantage of this fact and applied this methodology 65% ee racemic to the allylation of a wide variety of nucleophiles, such as Ph arenes, nitrogen nucleophiles, and 1,3-dicarbonyl com- 8 pounds, achieving excellent results.26 HO standard The Ji group used the combination of Fe/I2/NaI in stoi- TsNH2 conditions chiometric amounts for the synthesis of alkenyl iodides in good yields and diastereoselectivities through the reaction OH NHTs OH of alkynes with allylic and benzylic alcohols (a represen- TsNH2 TsNH2 (b) tative example is shown in Scheme 12).27 Although the Ph standard Ph standard Ph exact mechanism remains unclear, it is proposed that a conditions conditions carbocation derived from the corresponding alcohol is 6787–95% formed by reaction either with iodine or iron. standard conditions: FeCl3⋅6H2O (5 mol%), 50 °C, 1,4-dioxane, 24 h

I Scheme 13 Experiments carried out to confirm carbocationic inter- I H mediates under FeCl3·6 H2O catalysis H Ph Ph 1 or 3 or Ph We have also developed a greener strategy using this Fe/I2/NaI (1:1:2 equiv) Ph Ph BrCH CH Br, 55 °C, 8–12 h 2 2 methodology; the catalyst FeCl3·6 H2O is used with water 72% 81% as the solvent.30 This protocol is the first example of the E/Z 82:18 E/Z 80:20 use of a Lewis acid in direct nucleophilic substitution re- Scheme 12 Iodoalkenylation of allylic alcohols actions with free allylic alcohols in pure water in an SN1- type reaction. As expected, harsher conditions were nec- Iron(III) chloride has already shown its effectiveness as a essary to reach satisfactory results; using 10 mol% catalyst for this synthetic transformation in its inter- and FeCl3·6 H2O at a temperature of 90 °C gave similar or intramolecular versions.5,28 However, our research group slightly inferior results to those obtained in organic solvents (Scheme 14). However, it is remarkable that some This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. used FeCl3·6 H2O, which, in contrast to anhydrous FeCl3 which had been used previously, is more economic and carbon nucleophiles, such as TMSCN (4), which failed can be used in an open-air flask using technical grade sol- completely when the reaction was carried out in organic vents. Our work focused on direct allylic amination reac- solvents, produced the desired product in water, although in a modest 45% yield. The need for the use of more forc- tions with free alcohols using FeCl3·6 H2O or TfOH as a representative, readily available Brønsted acid (see Sec- ing conditions can be easily understood from a solubility tion 2.2 for further details) in a comparative study.29 In point of view, but also can be ascribed to the formation of +3–n 30 this way sulfonamides, anilines, carbamates, amides, and less Lewis acidic species [Fe(H2O)6–n(OH)n] Cl3–n. even triazoles were allylated, generally in high yields, us-

FeCl3⋅6H2O (5 mol%) (a) SiZr5 (30 mg) 1,4-dioxane, 25–50 °C, 24 h Ph OH Ph p-anisole (5 mL), 110 °C OH 78–93% 15 h MeO 3 1 NHR 9, 1 mmol 73% Ph Ph 1:5 (ortho/para) + Ph Ph 1 (b) R NH2 OH SiZr5 (30 mg) FeCl3⋅6H2O (10 mol%) + Ph Ph BnOH (5 mL), 110 °C Ph Ph Ph Ph H O, 90 °C, 24 h 15 h 2 3, 1 mmol 11 63% 12 18% 47–90% Ph 1 2 R = R SO2, Cbz, Ar, PhC(O) Scheme 14 Direct allylic substitution of alcohols in water catalyzed 10, expected (trace) by FeCl3·6 H2O

Scheme 16 Mixed oxide SiO2–ZrO2 catalyzed Friedel–Crafts reac- The Wang and Sun group used FeCl3·6 H2O in the synthe- tions using allylic alcohols sis of dihydroquinolines through an intramolecular direct amination (Scheme 15); high yields were obtained under had not been considered as potential catalysts for this mild reaction conditions and using low catalyst loadings. transformation, with the exception of some sulfonic acids.5 In addition, the obtained dihydroquinolines were readily The mode of action is simple, as depicted in Scheme 17. transformed in almost quantitatively yields into the corre- Thus, the protonation of the hydroxyl group by the Brøn- sponding quinolines following basic treatment.31 sted acid affords, after dehydration, the corresponding sta- Finally, the Kaper group used ZrO2, which to the best of bilized allyl carbocation that reacts with the nucleophile our knowledge has not previously been used for this type regenerating the Brønsted acid after proton release. of transformation, acting as a supported Lewis acid in a SiO2–ZrO2 mixed oxide structure, in the Friedel–Crafts OH alkylation of anisole with cinnamyl alcohol (9) [Scheme R R 16, (a)]. The best results were achieved when molar ratio BH of SiO2–ZrO2 was 95:5 (named SiZr5). Of particular inter- ested is the result obtained when (E)-1,3-diphenylprop-2- BA H en-1-ol (3) was reacted at 110 °C with benzyl alcohol as B– NuH the solvent. The desired result was an intramolecular NuH Friedel–Crafts reaction and subsequent transfer hydroge- R R R R nation (MPV-type) of the double bond to obtain the prod- + uct 10, but instead the major product was the H2O cyclopropane derivative 11, the result of the hydrogena- Scheme 17 Activation mode of allylic alcohols by Brønsted acids tion of cyclopropene 12 [Scheme 16, (b)].32 Sulfonic acids have been the most successful Brønsted 2.2. Brønsted Acids as Catalysts acids employed so far as catalysts for this type of transformation. This success prompted our research group, among The use of Brønsted acids (BA) as catalysts for the direct others, to explore TfOH as a potential catalyst. Thus, we nucleophilic substitution of allylic alcohols has experi- chose this strong acid for the direct amination of allylic al- enced significant growth as, despite their simplicity and cohols in a comparative study with FeCl3·6 H2O as both availability, they were previously unexploited and they are readily available catalysts.29 In this case, we observed This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

2 2 R2 OH R R

3 R FeCl3⋅6H2O (2 mol%) NaOH

1 CH2Cl2, r.t., 1 h 3 reflux 3 R NHY 1 N R 1 N R R Y R Y = Ts, Ms, Bz up to 96% up to 93% R1 = H, Hal R2 = H, aryl, Me R3 = H, aryl, heteroaryl

Scheme 15 Synthesis of dihydroquinolines catalyzed by FeCl3·6 H2O by an intramolecular amination of allylic alcohols

Synthesis 2014, 46, 25–34 © Georg Thieme Verlag Stuttgart · New York SHORT REVIEW SN1 Reactions of Allylic Alcohols 31 that generally TfOH performed slightly better than the – TfO – SO3H TfO Fe(III) salt and as little as 1 mol% of catalyst was suffi- HN C H 14 29 N N cient to effectively promote the direct amination of a wide Me Me SO3H variety of allylic alcohols using dioxane as solvent at 25 N N °C in most cases. Remarkably, good yields (although Me Me higher temperatures were required) were achieved even Figure 2 Sulfonic acid functionalized ionic liquids when more challenging substrates, such as linear primary allylic alcohols cinnamyl alcohol (9) and (E)-but-2-en-1- ol (13) were used; utilizing FeCl3·6 H2O with the same substrate with high temperatures and catalyst loadings Ph gave the corresponding products in low yields (Scheme OH 18). However, it is important to note that the reaction with Ph Ph Ph Ph TfOH failed completely using water as the solvent, this is 3 TfOH (7.5 mol%) 87% in contrast to FeCl3·6 H2O. + Ph BrCH2CH2Br 60 °C, 4–24 h 9, R = Ph OH Ph NHTs 50 °C Ph 83% 1 33% R OH TfOH (1 mol%) + 3 2 1,4-dioxane Scheme 19 Csp –Csp Bond formation catalyzed by TfOH TsNH2 NHTs 13, R = Me + 90 °C Although the effectiveness of 4-toluenesulfonic acid NHTs (PTSA) as the catalyst in this type of transformation has been clearly demonstrated, especially by the Sanz 70% group,35 remarkable work has now been published on the 2:1 linear/branched use of PTSA as a catalyst in SN1-type reactions (Scheme Scheme 18 Direct amination of linear primary allylic alcohols cata- 20). Reddy et al. described a highly stereoselective C5-al- lyzed by TfOH kylation of oxoindoles with different alcohols. Interest- ingly, the alkylation occurs at C5 and not at C3 (α- This direct amination reaction has been also described us- alkylation) as happens when Lewis acids or basic media ing sulfonic acid functionalized ionic liquids as catalysts are employed [Scheme 20, (a)].36 In contrast, the α-alkyl- (Figure 2). The reaction proceeds well in terms of yield ation of carbonyl compounds, such as aldehydes, was ob- for different sulfonamides, amides, and anilines, when 10 tained using PTSA under mild reaction conditions with mol% of the ionic liquids was used in dioxane at 80 °C excellent results especially for (E)-1,3-diphenylprop-2- and with (E)-1,3-diphenylprop-2-en-1-ol (3) as the sub- en-1-ol (3) [Scheme 20, (b)].37,38 strate of choice. The catalyst can be recovered by simply The α-alkylation of various aldehydes using alcohol 3 has aqueous extraction from the reaction crude and reused up 33 been also reported using PTSA (20 mol%) with acetoni- to six times without significant loss of activity. trile as the solvent in combination with a polysiloxane (10 Jin et al. described an interesting transformation also cat- mol%) bearing a secondary amine in the structure in a alyzed by TfOH and leading to Csp3–Csp2 bond forma- dual activation strategy. Thus, whereas PTSA activates tion. The reaction of allylic (and benzylic) alcohols with the allylic alcohol forming the corresponding carbocation, styrene and other alkenes (Scheme 19), gave particularly the amine forms the corresponding enamine, therefore ac- high yields for alcohol 3.34 tivating the aldehyde. The yields obtained were moderate

R OH PTSA (5 mol%) (a)

O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. + Ph R O N MeNO2 Me 90 °C, 7 h Ph N Me R = H, 91% R = Ph, 92%

Ph (b) O OH PTSA (20 mol%) O R H + Ph Ph MeCl or PhMe H Ph 1 R 3 t-BuOH (1 equiv) 1 r.t. to 50 °C, 5–40 h R R 77–93%

Scheme 20 Alkylation employing allylic alcohols catalyzed by PTSA

to high; the polysiloxane can be easily separated and re- X B(OH)2 X used at least in 10 cycles without detriment to the results n F F n 39 (Figure 3). F F Ph F Ph (10–20 mol%) R OH R MeNO2, r.t. to 50 °C up to 97% HN 16–60 h OH Ph Nu NuH Me Ph R n R n TMS Si O Si TMS m n R = Ph, H up to 99% Me Me n = 1, 2, 3 X = O, CH Figure 3 Recyclable polysiloxane for the α-alkylation of aldehydes 2 NuH = OH, NHTs

Liu and co-workers reported that other strong acids such Scheme 21 Intramolecular carbo- and heterocyclization of allylic al- as sulfuric40a and tetrafluoroboric acid40b effectively ac- cohols catalyzed by pentafluorophenylboronic acid complish the direct substitution of alcohols with 1,3-dicarbonyl compounds under conventional or microwave- acids cannot be discounted), for the cyanation of various assisted heating. Only a few examples of allylic substitu- allylic alcohols. It is claimed that the presence of these tion were given using alcohol 3 as the substrate, however, metals enhances the Brønsted acidity of montmorillonites, the corresponding products were obtained in high yields. since their absence, or the presence of others metals, pro- In both cases employed 5 mol% of catalyst loading with duced poor results at best. The reaction proceeds under nitromethane as the solvent. mild conditions (r.t.) and high yields (63–98%) are obtained within short reaction periods (normally less than 1 The Aoyama group employed NaHSO4 supported on sili- h) even with low catalyst loadings (<3 mol%) using di- ca gel (2.1 mmol NaHSO4/g silica gel) in a heterogeneous allylation of dicarbonyl and arenes compounds with free chloromethane as the solvent for a wide variety of linear 44 alcohols; good yields were obtained when 3 was the allyl- allylic alcohols. ic alcohol employed. The use of less activated alcohols result in lower yields and, for example, the reaction of 2.3 Other Promoters cinnamyl alcohol failed completely under these conditions. The reaction was generally performed at 80 °C with In the search for a simple and metal-free strategy and low- 1,2-dichloroethane as the solvent of choice. However, it is er acidic conditions for the direct nucleophilic substitution remarkable that the catalyst can be recycled up to nine of allylic alcohols and, due to their unique properties, such times if it is separated from the reaction media and dried as high hydrogen bond donor ability, high polarity, and 45 under vacuum prior to reuse.41 ionizing power along with low nucleophilicity, we en- visaged fluorinated alcohols as a reaction medium that The McCubbin group described the use of pentafluoro- would be able to mediate this transformation. Particularly, phenylboronic acid in intermolecular, Friedel–Crafts- 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro- type, allylic substitution reactions of alcohols using differ- 5,42 propan-2-ol (HFIP) were used as solvents and promoters ent arenes and heteroarenes. From this precedent, the of allylic substitution reactions of various alcohols using Hall group reported an intramolecular carbo- and hetero- a wide variety of nitrogen and carbon nucleophiles cyclization reaction employing this catalyst (Scheme 21) 46 43 (Scheme 22). The reaction is simple, works under mild to obtain a wide variety of heterocycles. The reaction reaction conditions (r.t. to 70 °C), and affords the corre- generally affords high yields and diastereoselectivities sponding products in high yields. HFIP generally per- and, according to some experiments, which were carried forms better than TFE, and, for example, HFIP enables the out in order to elucidate the mechanism, proceeds through use of basic amines (such as benzylamine or butanamine) a carbocationic intermediate rather than an SN2′ pathway, as nucleophiles with good results; these reactions general- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. which is the alternative suggested in other papers by the 43 42 ly fail under Lewis or Brønsted acid catalysis. Particularly same authors and also by the McCubbin group. interesting are the results obtained with rather electron- Finally, montmorillonites are excellent solid Brønsted rich anilines, such as 4-chloroaniline (14), which can be- acids that are able to accomplish direct nucleophilic sub- have as a nitrogen or carbon nucleophiles depending on stitution of free alcohols,5 Onaka and co-workers have re- the solvent employed. This was studied and it was shown ported the use of highly active Sn- and Ti-based to be a consequence of the reversibility of the amination montmorillonites, acting as heterogeneous Brønsted acids reaction when HFIP was used as the solvent (Scheme (although a secondary role of the metals acting as Lewis 23).46

OH Nu Another field that is still undeveloped is the use of allylic R R alcohols in enantioselective transformations through a R R 48 R TFE or HFIP (1 M) R SN1-type reaction. In this regard, some advances, mainly + NuX focused on organocatalytic transformations, have been re- r.t. to 70 °C, 24 h ported. However, the scope of allylic alcohols is still lim- OH Nu ited and only those that generate a highly stable carbocationic intermediate have been employed so far. 1 Therefore, new methodologies that would allow a broader 1 NuX = R NH2, R3SiNu, ArH, 1,3-dicarbonyl compounds substrate scope are required. R = H, alkyl, aryl 1 R = alkyl, aryl, Ts, Cbz, Boc, PhC(O) Acknowledgment Scheme 22 Fluorinated alcohols as promoters of the direct allylic Spanish Ministerio de Ciencia e Innovación (MICINN) (projects substitution of free alcohols CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006), FEDER, the Generalitat Valenciana (PROMETEO 2009/039) and OH the University of Alicante are gratefully acknowledged for financial Cl support. A.B. would also like to thank MICINN for a Juan de la Ph Ph Cl Cierva contract (JCI-2009-03710) and the University of Alicante 3 (Project GRE12-03). NH TFE HFIP + H2N Ph Ph 70 °C Cl 50 °C 24 h 24 h Ph Ph References 92% 90% NH2 (1) For recent reviews about the principles of green chemistry, 14 see: (a) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437. (b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, Scheme 23 Different nucleophilicity behavior of aniline 14 depend- G. R.; Leazer, J. L. Jr; Linderman, R. J.; Lorenz, K.; ing on the solvent Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411; and references therein. Studies of the elucidation of the mechanism have also (2) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. been reported, confirming the existence of carbocationic (3) For example, see: (a) Paquin, J.-F.; Lautens, M. In Comprehensive Asymmetric Catalysis, Supplement 2; intermediates, obtained through hydrogen bonding inter- Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: actions, and two working reaction pathways were pro- Heidelberg, 2004, 73. (b) Palladium Reagents and posed to give the allylic substitution product: the direct Catalysis; Tsuji, J., Ed.; Wiley: Chichester, 2004. amination of the alcohol-derived carbocation and the indi- (c) Handbook of Organopalladium Chemistry for Organic rect allylic substitution of the carbocation derived from Systems; Vol. II; Negishi, E., Ed.; Wiley: New York, 2002, the corresponding fluorinated ethers.46 Chap. V.2, 1669. For reviews about asymmetric allylic substitutions for example, see: (d) Trost, B. M.; Zhang, T.; Another procedure, although mainly focused on benzylic Sieber, J. D. Chem. Sci. 2010, 1, 427. (e) Miyabe, H.; alcohols, employs the solvent as promoter in a strategy for Takemoto, Y. Synlett 2005, 1641. (f) Trost, B. M.; Crawley, this transformation reported by Wang et al. A Zn(II)- M. L. Chem. Rev. 2003, 103, 2921; and references therein. based ionic liquid, obtained mixing choline chloride and (4) For recent reviews on transition-metal-catalyzed allylic ZnCl in a 1:2 ratio was used as a recoverable promoter substitution reactions of alcohols, see: (a) Sundararaju, B.; 2 Achard, M.; Bruneau, C. Chem. Soc. Rev. 2012, 41, 4467. (up to 5 times) of this SN1-type allylic substitution reac- (b) Muzart, J. Eur. J. Org. Chem. 2007, 3077. tion using carbon and nitrogen nucleophiles.47 (5) For recent review on SN1-type direct nucleophilic substitution of free alcohols, see: Emer, E.; Sinisi, R.; Guiteras-Capdevila, M.; Petruzziello, D.; De Vincentiis, F.; 3 Conclusions and Outlook Cozzi, P. G. Eur. J. Org. Chem. 2011, 647. (6) For recent reviews about the use of gold as catalyst in transformations involving alcohols, see: (a) Cera, G.;

In conclusion, it can be asserted that great progress has This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Chiarucci, M.; Bandini, M. Pure Appl. Chem. 2012, 84, been already achieved in the last decade in the SN1-type 1673. (b) Biannic, B.; Aponick, A. Eur. J. Org. Chem. 2011, direct allylic nucleophilic substitution reactions of free al- 6605. (c) Muzart, J. Tetrahedron 2008, 64, 5815. cohols and a number of methods are available to success- (7) Biswas, S.; Samec, J. S. M. Chem. Asian. J. 2013, 8, 974. fully perform this transformation.5 However, there is still (8) Giner, X.; Trillo, P.; Nájera, C. J. Organomet. Chem. 2011, room for improvement in various aspects of this transfor- 696, 357. mation. (9) Chen, G.-Q.; Xu, Z.-J.; Cahn, S. L.-F.; Zhou, C.-Y.; Che, C.-M. Synlett 2011, 2713. One point is the use of organic solvents. In this sense, ef- (10) Rueping, M.; Vila, C.; Uria, U. Org. Lett. 2012, 14, 768. forts are now focused on the use of environmentally be- (11) Ren, K.; Li, P.; Wang, L.; Zhang, X. Tetrahedron 2011, 67, nign or recoverable solvents, such as water or ionic 2753. liquids. (12) Our group, among others, reported the use of cationic gold(I) complexes for the direct amination reaction onto free allylic alcohols (see refs. 6 and 8).

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