Hydrogen-Transfer Annulations Forming Heterocycles

Samuel John Thompson

Dong Group Ð UT Austin Wednesday Ð October 7th, 2015 Literature Review This review brought to you by

Angewandte. 560 ACCOUNT Minireviews A. Nandakumar,E.Balaraman et al. Cp*Ir Complex-Catalyzed Hydrogen Transfer Reactions Directed toward International Edition:DOI:10.1002/anie.201503247 Synthetic Methods German Edition:DOI:10.1002/ange.201503247 Environmentally Benign Organic Synthesis Cp*IrKen-ichi Complex-Catalyzed Hydrogen Transfer Reactions Fujita, Ryohei Yamaguchi* Transition-Metal-Catalyzed Hydrogen-Transfer Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan Fax +81(75)7536634; E-mail: [email protected]; E-mail: [email protected] Annulations:Access to Heterocyclic Scaffolds Received 1 October 2004 Avanashiappan Nandakumar,* Siba Prasad Midya, Vinod Gokulkrishna Landge, and Ekambaram Balaraman* The stability of organoiridium complexes was advanta- Abstract: Catalytic activity of Cp*Ir complexes toward hydrogen geous for the studies on stoichiometric reactions in detail; annulations ·heterocycles ·hydrogen transfer · transfer reactions are discussed. Three different types of reactions thus the oxidative addition reaction, which is one of the synthetic methods ·transition metal catalysis have been developed. The first is Oppenauer-type oxidation of alco- hols. This reaction proceeds under quite mild conditions (room tem- most fundamental and important process in organo-

perature in acetone) catalyzed by [Cp*IrCl2]2/K2CO3, and both metallic chemistry, has been studied using Vaska’s com- primary and secondary alcohols can be used as substrates. Introduc- 2 he ability of hydrogen-transfer transition-metal catalysts,whichen- plex IrCl(CO)(PPh3)2. T tion of a N-heterocyclic carbene ligand to the catalyst considerably able increasingly rapid access to important structural scaffolds from enhances the catalytic activity, and a very high turnover number of The catalytic chemistry of iridium started with the discov- simple starting materials,has led to aplethora of researchefforts on the 950 has been obtained in the oxidation of 1-phenylethanol. The ery of a highly efficient catalyst, [Ir(cod)(PCy3)(py)]PF6, 3 construction of heterocyclic scaffolds.Transition-metal-catalyzed second is the N-alkylation of amines with alcohols. A new effective for hydrogenation of olefin by Crabtree et al. in 1977. catalytic system consisting of [Cp*IrCl2]2/K2CO3 for the N-alkyla- Thereafter, a number of iridium-catalyzed hydrogenation hydrogen-transfer annulations are environmentally benign and highly tion of primary amines with alcohols has been developed. Synthesis systems including enantioselective reactions have been atom-economical as they release of water and hydrogen as by-product of indoles and 1,2,3,4-tetrahydroquinolines via intramolecular N- disclosed.4 In recent years, iridium complexes were found alkylation of amino alcohols and synthesis of nitrogen heterocycles and utilize renewable feedstock alcohols as starting materials.Recent to be effective as catalysts for hydrosilylation,5 carbon- via intermolecular N-alkylation of primary amines with diols cata- 6,7 8,9 advances in this field with respect to the annulations of alcohols with lyzed by a Cp*Ir complex have been also achieved. The third is the carbon and carbon-heteroatom bond formation, hy- transfer strategy involves utilization of drogen transfer reaction,10 functionalization of C-H various nucleophilic partners,thus leading to the formation of hetero- regio- and chemoselective transfer hydrogenation of quinolines. An the initially extracted hydrogen gas for efficient method for the transfer hydrogenation of quinolines cata- bonds,11Ð13 and the catalytic chemistry of iridium has been cyclic scaffolds,are highlighted herein. the hydrogenation of an intermediate lyzed by [Cp*IrCl2]2/HClO4 using 2-propanol as a hydrogen source attracting quite a lot of interest. Most of these interesting (derived from the reaction of the has been realized. A variety of 1,2,3,4-tetrahydroquinoline deriva- reactions were achieved using low-valent iridium com- tives can be synthesized by this method. These results show that dehydrogenated precursor with nucle- plexes coordinated with olefin, CO, halogen, or phospho- Cp*Ir complexes can be useful catalysts for hydrogen transfer 1. Introduction ophilic partners) in the final step of the reactions from the viewpoint of developing environmentally benign rous ligands (e.g. [IrCl(cod)]2) as a catalyst precursor. reaction, thus leading to the net release of water as the only organic synthesis. On the other hand, a trivalent iridium complex bearing [2g] 1.1. Scope and Organization of Review by-product. Despite reports on several transition-metal- 5 1Introduction an h -pentamethylcyclopentadienyl (Cp*) ligand, catalyzed (Cu, Ni, Zn, Pd, etc.)hydrogen-transfer reactions,[3] 2Hydrogen Transfer Oxidation of Primary and Secondary [Cp*IrCl2]2 (Figure 1), is another well-known stable com- Heterocycles constitute the largest and most diverse Ru-, Ir-, and rare examples of Fe-based catalytic systems have Alcohols (Oppenauer-Type Oxidation) plex of iridium. The first synthesis of [Cp*IrCl2]2 was re- family of organic compounds and have been mostly identified shown excellent activity and selectivity in hydrogen-transfer 3N-Alkylation of Amines with Alcohols 14 ported by Maitlis et al. in 1969. At first, [Cp*IrCl2]2 was by their profound application in synthetic biology and annulations to deliver heterocyclic compounds.In2010, 4Synthesis of N-Heterocyclic Compounds prepared by the reaction of IrCl áxH O with hexamethyl [1] 3 2 materials science. Theextent to which they can be utilized Yamaguchi et al. reported areview article focusing on the 4.1 Intramolecular N-Heterocyclization of Amino Alcohols 14a,c 4.2 Intermolecular N-Heterocyclization of Primary Amines Dewar benzene, however, a convenient preparation by in these endeavors depends on the selective and efficient construction of nitrogen-based heterocycles by transition- the reaction of IrCl áxH O with pentamethylcyclopentadi- [4] with Diols 3 2 synthetic methods for their synthesis from simple,and metal-catalyzed hydrogen-transfer annulations. In recent 5Transfer Hydrogenation of Quinolines ene was reported later.15 Now we can purchase it from the abundant starting materials.Hence,the development of an years,this field has evolved in terms of catalyst and ligand 6Conclusion reagent market. The chemistry of Cp*Ir complex has been efficient strategy for the construction of heterocycles is akey design, and reaction conditions,thus taking the place of Key words: iridium, catalysis, hydrogen transfer, alcohols, amines mainly focused on the stoichiometric reactions, and their motivation in contemporary science. conventional synthetic processes and receiving an over- ability toward C-H bond activation of hydrocarbon mole- In the past few decades,the transition-metal-catalyzed whelming amount of attention. In this respect, there is need cules was revealed by Bergman et al. and others.16,17 How- hydrogen-transfer strategy has attracted much interest from for areview article focused on the potential of catalytic ever, catalytic utilizations of Cp*Ir complexes have been [2] the synthetic and organometallic community. Transfer of H2 hydrogen-transfer annulation strategies for the formation of 1 Introduction relatively unexplored. Only a few examples of Cp*Ir plays acrucial role in activating the substrate for further heterocyclic scaffolds.Herein we highlight recent advance- complex-catalyzed reactions for organic synthesis other transformation through C X(C, N, and O) bond-forming ments in hydrogen-transfer annulations of alcohols with In the field of homogeneous catalytic organic synthesis, ˇ than simple hydrogenation reactions had been reported annulations with the liberation of H2Oand H2.The hydrogen- various nucleophilic partners,thus leading to the formation relatively little attention have been paid to the utilization 11a,18

when we started our investigation in 1999. Downloaded by: IP-Proxy University of Texas at Austin, Austin Libraries. Copyrighted material. of heterocyclic scaffolds.This review material is organized of iridium as catalyst for a long time, while its family [*] Dr.A.Nandakumar,S.P.Midya, V. G. Landge,Dr. E. Balaraman into four different categories:a)N-alkylation of amines by member, rhodium and cobalt, have seen extensive use as Catalysis Division alcohols,b)dehydrogenative amide formation from amines 1 catalysts including industrial processes. This difference Cl Cl CSIR-National Chemical Laboratory (CSIR-NCL) and alcohols,c)oxidative cyclization of alcohols,and d) an- would be probably due to the scarcity of iridium as well as Ir Dr.Homi Bhabha Road, Pune, 411008 (India) nulation of unsaturated systems. the preconceived idea that organoiridium complexes are Ir E-mail:[email protected] too stable to be used as catalysts for organic synthesis. Cl Cl [email protected] Dr.A.Nandakumar 1.2. N-Alkylation of Amines by Alcohols SYNLETT 2005, No. 4, pp 0560Ð0571 04.03.2005 Organic Chemistry Division Figure 1 Advanced online publication: 22.02.2005 Central Leather Research Institute (CSIR-CLRI) DOI: 10.1055/s-2005-862381; Art ID: A36504ST Adyar,Chennai, 600 020 (India) Catalytic N-alkylation of amines is apromising atom- © Georg Thieme Verlag Stuttgart á New York E-mail:[email protected] economical and eco-benign approach for the selective con-

11022 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034

Nandakumar & Balaraman et al.! Fujita & Yamaguchi. Fujita, Yamaguchi, & Zhu. Angew. Chem. Int. Ed. 2015, 54, 11022. Synlett. 2005, 560. Heterocycles 2010, 1093. Two Major Catalyst Metals

Ru Ir

Other metals are used, but are not as widely explored!

Cu, Ni, Zn, Pd, Fe, Rh, & more ! ! Hydrogen-Transfer Reaction

§ Transfer of H2 between a substrate (H-donor) to an H-acceptor: § Oxidation of alcohols or amines § Reduction of ketones or imines

View Article Online § Inspiration comes from Oppenhauer Oxidation / Meerwein-Ponndorf- Verley Reduction (hydride transfer)

Scheme 2 MPV reduction and Oppenauer oxidation. § Used Industrially to make morphine, codeine, progesterone, etc § Ran on ton scales for production of chemicals

Fig. 1 Examples of metal hydrides. catalyst and substrate. The classical pathway involves a metal The hydridic route alkoxide as intermediate. More recently, this pathway has been questioned for certain catalysts that contain both the metal Transition metal catalysts generally operate through a hydridic hydride and an acidic proton. Noyori has proposed a metal route. A common feature of these catalysts is that a metal ligand bifunctional pathway where the hydrogen transfer hydride is involved as a key intermediate in the hydrogen 1,5 occurs simultaneously outside the coordination sphere of the transfer. Such hydrides have indeed been isolated from metal. An ionic mechanism has been proposed for hydrogena- transition metal-catalyzed hydrogen transfer reactions in some tion of ketones (aldehydes) and imines. cases (Fig. 1). An early example of a transition metal-catalyzed hydrogen Direct hydrogen transfer transfer with moderate rates and turnovers was reported by Henbest in the 1960s.6 Sasson and Blum7 found in 1971 that

The pathway through a ‘‘direct hydrogen transfer’’ was RuCl2(PPh3)3 (2a) can be used at high temperature with proposed for the Meerwein–Ponndorf–Verley (MPV) reduc- moderate turnover frequency.8 In 1991 the effect of base on the 2 9 tion (Scheme 2). In the original version, of the MPV RuCl2(PPh3)3-catalyzed transfer hydrogenation was reported. reduction, aluminum isopropoxide was used to promote The presence of small amounts of base led to a dramatic rate transfer of hydrogen from isopropanol to a ketone.3 The enhancement (103–104 times faster). It was later shown that the reaction can also be run in the opposite direction, using rate enhancement is due to formation of a highly active 9b acetone as hydrogen acceptor, and this was studied by RuH2(PPh3)3 (2). Also in the reversed reaction, the Oppenauer.4 Thus, for the MPV reduction of a ketone, i.e. Oppenauer-type oxidation, a spectacular effect by the base transfer hydrogenation, isopropanol is employed in excess. For with the use of 2a as catalyst was observed (Scheme 3).10 These Published on 23 January 2006. Downloaded by University of Texas Libraries 02/10/2015 17:00:21. the Oppenauer oxidation acetone is used in excess. reactions proceed under very mild conditions with low loading The mechanism is proposed to proceed through a six- of catalyst. The promoting effect of base had been observed membered transition state, without involvement of metal previously for Ir- and Rh-catalyzed reactions, but not of this hydride intermediates (Scheme 2).2 order.11

Pher G. Andersson was born Peter Brandt is a research 1963 in Va¨xjo¨, Sweden. He was computational chemist and educated at Uppsala University Chemistry Team Leader at where he received his BSc in Biovitrum—one of the largest 1988 and his PhD in 1991. After biotech companies in Europe. postdoctoral research at Scripps The skills in computer-aided Research Institute with Prof. drug design were received at K. B. Sharpless, he returned to KaroBio working with nuclear Uppsala where he became receptors. He obtained his docent 1994 and full professor PhD in organic chemistry at 1999. His main research inter- the Royal Institute of ests involve organometallic Technology, Stockholm, chemistry, steroselective synthe- Sweden. After this, he contin- sis, and asymmetric catalysis. ued the study of reaction mechanisms and expanded the Pher G. Andersson Peter Brandt work to cover enantioselective reactions as a postdoc at the Royal Danish School of Pharmacy, Copenhagen.

238 | Chem. Soc. Rev., 2006, 35, 237–248 This journal is ß The Royal Society of Chemistry 2006 H-Transfer with Catalysis

Traditional synthetic strategies ¥ Amine alkylation (halides) ¥ Reductive amination

¥ SN2 displacement

§ Major advantages for complex molecule synthesis § Environmentally benign and atom economical § Water as only byproduct § No stoichiometric waste § Avoids toxic alkyl/aryl halides § Avoids carbonyl precursors which decrease efficiency of transformations! Heterocylic Bond Disconnection

Key Players

§ Ryohei Yamaguchi § Robert Madsen Kyoto University University of Denmark

§ David Milstein § Krische Weizmann Institute of Science Overview

§ Synthesis of N-Heterocyclesß 1. N-alkylation of amines by alcohols 2. Dehydrogenative amide formation from amines and alcohols 3. Oxidative cyclization of alcohols 4. Annulation of unsaturated systems (alkene/alkyne) § Synthesis of O- / S-Heterocycles

N-Alkylation of Amines

§ Usually performed with alkyl halides § Difficult to control and predict reactivity § Via amide reduction a § Toxic and expensive wastes . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

asingle operation, thus enabling environmentally benign and efficient protocols.

2.1. Annulation by N-Alkylation of Amines by Alcohols

N-AlkylationSaturated nitrogen-containing of Aminesheteroc yclic scaffolds are found in many natural products and biologically important compounds.The first example of the N-alkylation of an amine Figure 2. Dehydrogenative amide formation from alcohols and amines.§ Usuallyby an alcoholperformedthrough withah ydrogen-transferalkyl halidesannulation was reported§ Difficultby Grigg to etcontrolal. in 1981. andTh predictus pyrrolidines reactivitywere formed by the intramolecular reaction of N-substituted § Via amide reduction a 4-aminobutan-1-ols in the presence of 5mol%[RhH(PPh3)4] as the§ Toxiccatalyst andin boiling expensive1,4-dioxane wastes.The cascade reaction consists of dehydrogenative oxidation of the alcohol to an aldehyde,imine formation with an amine,and hydrogenative reduction of the imine to afford the N-substituted pyrroli- dines 1a and 1b in 56 and 82%yields,respectively [Eq. (1)]. Similar catalytic conditions were used to synthesize 1bby the amination of butane-1,4-diol with benzylamine in aratio of Figure 3. Dehydrogenative coupling of alcohols with nucleophiles.§ First example of N-alkylation cyclization by Grigg in 1981 10:1 to yield 1b in 31%[Eq. (2)].[12]

1.4. Oxidative Cyclization of Alcohols

Transition-metal-catalyzed dehydrogenative coupling of Side: Methanol as alkylation reagent alcohols with various nucleophilic partners has resulted in the formation of C X(C, N, and O) bonds with the liberation of 5 mol% [RhH(PPh3)4] N ˇ [9] N Methanol, reflux, 4 h H2 and H2Oasby-products (Figure 3). Inter-and intra- H Me molecular hydrogen-transfer annulations of alcohols with 97% yield various coupling partners enable the formation of function- alized saturated and aromatic heterocyclic compounds.This methodology has provided direct and rapid access to avariety of heterocyclic frameworks.

Grigg. J. Chem. Soc. Chem. Commun. 1981, 611. Direct coupling of adiol with an amine through aborrow- 1.5. Annulation of Unsaturated Systems (Alkenes and Alkynes) ing-hydrogen strategy is the most promising protocol for the construction of N-heterocyclic compounds since diol deriva-

Unsaturated systems such as alkenes and alkynes are tives can be easily accessed. [{Ru(p-cymene)Cl2}2]combined important building blocks in the chemical sciences.Their with the bidendate DPEphos ligand provided access to utility in organic synthesis have increased because of the saturated five-, six-, and seven-membered N-heterocyclic development of newer synthetic methodologies based on compounds by the N-alkylation of diols with amines [Eq. (3); transition-metal catalysts.[10] Transition-metal-catalyzed hy- drogen-transfer annulations of these building blocks provide novel heterocyclic frameworks.[11]

2. Synthesis of N-Heterocycles

Nitrogen-containing heterocycles are omnipresent in DPEphos = bis(2-diphenylphosphinophenyl)ether].Thus, nature and biologically active compounds,including nucleo- 1,4-butanediol reacted with various anilines and aliphatic bases within RNA, DNA, nucleotides,nucleosides,and amines to provide N-substituted pyrrolidines in the presence haemoglobin. They also have applications in avariety of of trimethylamine as an additive in refluxing toluene.Other fields such as agrochemicals and pharmaceuticals,aswell as in diols such as 1,5-pentanediol and 1,6-hexanediol were also the preparation of foods,dyes,detergents,and surfactants.[1] converted into the corresponding N-substituted piperidine Hence,there is aplethora of methods for the preparation of and azepane derivatives under similar catalytic conditions.[13] novel nitrogen-based heterocycles for various applications. Significantly,Enyong et al. used the simple,inexpensive,and Transition-metal-catalyzed hydrogen-transfer annulations readily accessible (S)-2-hydroxy-N,3-diphenylpropanamide have provided aplatform to synthesize the basic skeletons (3)ligand in combination with [{Ru(p-cymene)Cl2}2]for the for complex nitrogen-containing heterocyclic compounds in N-alkylation of diols with aliphatic amines under mild

11024 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Borrowing Hydrogen Methodology ARTICLES

Scheme 9. Reaction of Diols with Amines to Form N-Heterocycles Scheme 10. N-Alkylation Reactions of Sulfonamides

Table 5. N-Heterocyclization of Amines with Diols catalyzed borrowing hydrogen approach, a process which has Modern N-Alkylation through H-Transfer not been reported previously, although Lewis acid catalysts have recently been reported to effect this transformation (Scheme 10).29 We chose to examine the alkylation of p-toluenesulfona- Borrowing§ Hydrogen Methodology mide with oneARTICLES equivalent of benzyl alcohol as a model reaction. Jump ahead to 2009 – Williams et al. published very mild conditionsUsing 2.5 mol% [Ru(p-cymene)Cl2]2 with 5 mol% DPEphos Scheme 9. Reaction of Diols with Amines to Form N-Heterocycles Scheme 10. N-Alkylation Reactions of Sulfonamideswe only observed a 32% conversion into the alkylated product, Borrowing Hydrogen Methodology ARTICLES N-benzyltoluenesulfonamide, when the reaction was performed Scheme 9. Reaction of Diols with Amines to Form N-Heterocycles Scheme¥ Bidentate 10. N-Alkylation ligand Reactions ofsuppresses Sulfonamidesat 110 °esterC for 24 formation h in toluene in the absence of base. However, by performing the reactions in p-xylene at 150 °C the reaction O proceeded to 44% conversion (in the absence of base) and to R 95% conversion (in the presence of 10 mol% K2CO3) after 6 h. R O After 24 h at 150 °C, these reactions had essentially gone to Table 5. N-Heterocyclization of Amines with Diols completion whether base was present or not. The results of these ¥ Cycliccatalyzed amine borrowing ring hydrogen sizes approach, =reactions 5, a6, process areand given which7 in has Table 6, where the reaction of benzyl Table 5. N-Heterocyclization of Amines with Diols not been reported previously, althoughalcohol Lewis withacid catalysts arylsulfonamides have (entries 1-6) led to the corre- recently been reported to effect thissponding transformation secondary (Scheme sulfonamides in good yields. The p-methoxy catalyzed borrowing29 hydrogen approach, a process which has not been reported10). We previously, chose to although examine Lewis the alkylation acidsubstrate catalysts of p (entry-toluenesulfona have 4) provided- the highest conversion and yield, recently beenmide reported with one to equivalent effect¥ this ofAryl benzyltransformation and alcoholwhile aliphatic the as (Scheme ap-nitro model substrate reaction. amines (entry 5) was the least reactive. The 10).29 WeUsing chose to 2.5 examine mol% [Ru( the alkylationp-cymene)Cl of p2alkylation]-toluenesulfona2 with 5 mol% of methanesulfonamide- DPEphos with benzyl alcohol was also mide withwe one only equivalent observed of benzyla 32% conversionalcohol as asuccessful into model the reaction. alkylated (entry 7). product, Other benzylic alcohols could be used to N-benzyltoluenesulfonamide, when thealkylate reactionp-toluenesulfonamide was performed (entries 8-10), and the aliphatic Using 2.5 mol% [Ru(p-cymene)Cl2]2 with 5 mol% DPEphos we only observedat 110 °C a 32% for 24 conversion h in toluene into in the the alkylated absencealcohols ofproduct, tryptophol base. However, (entry 11) and cyclohexylmethanol (entry N-benzyltoluenesulfonamide,by performing the reactions when the in reactionp-xylene12) was and at performed 150 cyclopropylmethanol°C the reaction (entry 13) were also effective. Since the use of higher temperatures was effective in the at 110 °Cproceeded for 24 h in to toluene 44% conversion in the absence (in ofthe base. absence However, of base) and to N-alkylation reactions of sulfonamides, we chose to use the same by performing95% the conversion reactions (in in thep-xylene presence at of150 10°C mol% the reaction K2CO3) after 6 h. proceededAfter to 44% 24 conversion h at 150 °C, (in these the absence reactionsapproach of had base) essentially for and the to reactions gone to of secondary alcohols 40 with amines 95% conversioncompletion (in the whether presence base of was 10 mol% present K41 orCOto not. give) TheafterN-alkylation results 6 h. of these products 42.Preliminaryresultsobtained at2 1103 C had been unsatisfactory, with low conversions under After 24 hreactions at 150 °C, are these given reactions in Table had 6, where essentially the° reaction gone to of benzyl completionalcohol whether with base arylsulfonamides was present or not. (entries Thethese results 1- conditions.6) of led these to the For corre- example, the reaction of cyclohexanol with reactions aresponding given secondary in Table sulfonamides 6, where the in reaction goodmorpholine yields. of benzyl The usingp-methoxy 2.5 mol% Ru(p-cymene)Cl2]2 with 5 mol% alcohol withsubstrate arylsulfonamides (entry 4) provided (entries the 1- highest6) ledDPEphos to conversion the corre-in toluene and yield, at 110 °C for 24 h only gave 51% sponding secondarywhile the sulfonamidesp-nitro substrate in good (entry yields. 5)conversion, was The thep-methoxy least but reactive. when The this reaction was repeated in xylene at substrate (entryalkylation 4) provided of methanesulfonamide the highest conversion with150 benzyl°C, and 100% alcohol yield, conversion was also was achieved. successful (entry 7). Other benzylic alcoholsCyclic aminescould be were used alkylated to with cyclohexanol under these while the p-nitro substrate (entry 5) was theWatson least reactive. et al. JACS The 2009, 131, 1766. alkylationalkylate of methanesulfonamidep-toluenesulfonamide with benzyl (entriesconditions alcohol 8-10), was and to also give the aliphatic the products with good conversions (Table a Reactions were performedsuccessful using 1alcohols (entry mmol of 7). tryptophol amine Other and benzylic 1.2 (entry mmol alcohols 11) of and cyclohexylmethanolcould7, entries be used 1-4). to Primary (entry amines were also successful (entries b diol using DPEphos as thealkylate ligand. pValues-toluenesulfonamide12) and given cyclopropylmethanol are conversions (entries with 8- (entry10),5 and 13)-6), the were although aliphatic also effective. in the case of t-butylamine, which was easily respect to unreacted alcohol, as determinedSince by analysis the use of of the higher1H NMR temperaturesalkylated was by effective primary in alcohols, the the reaction proceeded with low spectra. Figures in parenthesesalcohols are isolated tryptophol yields. (entry 11) and cyclohexylmethanol (entry 12) and cyclopropylmethanolN-alkylation reactions (entry of sulfonamides, 13) wereconversion also we effective.chose towith use cyclohexanol, the same presumably for steric reasons. Aniline was reacted withSince 1,4-butanediol theapproach use of to for higher give the reactionsN temperatures-phenylpyr- of secondary was effectiveOur alcohols attention in40 thewith turned amines to the use of other secondary alcohols rolidine (entry 1, TableN 5),-alkylation and other41 reactionsto substituted give N of-alkylation sulfonamides, anilines products were we chose42.Preliminaryresultsobtainedas to alkylating use the same agents for amines, and these results are summarized also found to be effectiveapproach (entries forat 110 the 2- reactions°7),C had although been of secondary unsatisfactory, the more alcohols within40 Table lowwith conversions amines8. We chose under 1-phenylethanol (R ) Ph, R′ ) Me), electron poor anilines (entries41 to give 6 andtheseN-alkylation 7) conditions. gave lower products For conversions example,42.Preliminaryresultsobtained the reaction1-phenylpropan-2-ol of cyclohexanol (R with) PhCH2,R′ ) Me) and pentan-2-ol under these conditions.at Aliphatic 110 °C primarymorpholine had been amines unsatisfactory, using (entries 2.5 mol% 8- with11) Ru( lowp-cymene)Cl conversions(R ) CH2CH] under2 with2Me, 5 R mol%′ ) Me) as representative alcohols. The were also effective, includingthese conditions. theDPEphos branched For primary example,in toluene amine the at reaction used 110 ° ofC cyclohexanol forbenzylic 24 h alcohol, only with gave 1-phenylethanol, 51% was the least reactive of these conversion, but when this reactionalcohols, was repeated providing in xylene only at moderate yields of the tertiary amine for entry 9. The use ofmorpholine alternative diolsusing also 2.5 ledmol% to cyclization Ru(p-cymene)Cl2]2 with 5 mol% to the corresponding DPEphosN-heterocycle,150 in toluene°C, with 100% atthe conversion 110 use°C of for 1,5- was 24 achieved. hproduct only gave under 51% these conditions (Scheme 11). However, the non- pentanediol and 1,6-hexanediolconversion, leading butCyclic when to amines the this products werereaction alkylated given was repeated withbenzylic cyclohexanol in xylene alcohols at under both these showed higher reactivity and the products in entries 12-13. 150 °C, 100%conditions conversion to give was the achieved. products withwere good obtained conversions with higher (Table conversion. To examine whether the a Reactions were performed using 1 mmolSulfonamides of amine and 1.2 are mmol found ofCyclic in many amines7, entriespharmaceutical were 1- alkylated4). Primary drugs with (e.g., amines cyclohexanol were also under successful these (entries b diol using DPEphos as the ligand. ValuesSumatripan, given are conversions Viagra, Furosemide) with 5- and6), have although also in been the used case as of t-butylamine,(28) Quaal, which K. S.; was Ji, S.; easily Kim, Y. M.; Closson, W. D.; Zubieta, J. A. J. 1 conditions to give the products with good conversions (Table respect to unreacted alcohol, as determined by analysis of the H NMR 28 Org. Chem. 1978, 43, 1311. a protecting groups for nitrogen. alkylatedWe were by interested primary in alcohols, inves- the reaction proceeded with low Reactionsspectra. were Figuresperformed in parentheses using 1 mmol are of isolated amine yields. and 1.2 mmol of 7, entries 1-4). Primary amines were also successful(29) (a) Qin, (entries H.; Yoaagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. b conversion with cyclohexanol, presumably for steric reasons. diol using DPEphos as the ligand. Values given aretigating conversions whether with primary5-6), sulfonamides although in38 thewould case of reactt-butylamine, with whichChem., was easily Int. Ed. 2007, 46, 409. (b) Sreedhar, B.; Reddy, P. S.; Reddy, respect to unreactedAniline alcohol, was reacted as determined with 1,4-butanediol by analysisalcohols of the to to1 giveH give NMRN-phenylpyr-N-alkylatedalkylated sulfonamides byOur primary attention39 using alcohols, the turned ruthenium- the to reaction the use proceeded of otherM. secondaryA.; with Neelima, low alcohols B.; Arundhathi, R. Tetrahedron Lett. 2007, 48,8174. spectra. Figuresrolidine in parentheses (entry 1, are Table isolated 5), yields. and other substituted anilines wereconversionas with alkylating cyclohexanol, agents for presumably amines, and for these steric results reasons. are summarized in Table 8. We chose 1-phenylethanol (R ) Ph, R′J.) AM.Me), CHEM. SOC. 9 VOL. 131, NO. 5, 2009 1771 Aniline wasalso reacted found towith be 1,4-butanediol effective (entries to give 2-N7),-phenylpyr- although the moreOur attention turned to the use of other secondary alcohols 1-phenylpropan-2-ol (R ) PhCH2,R′ ) Me) and pentan-2-ol rolidine (entryelectron 1, Table poor 5),anilines and other (entries substituted 6 and 7) anilinesgave lower were conversionsas alkylating agents for amines, and these results are summarized under these conditions. Aliphatic primary amines (entries 8-in11) Table 8.(R We) CH chose2CH 1-phenylethanol2Me, R′ ) Me) (Ras representative) Ph, R′ ) Me), alcohols. The also found to be effective (entries 2-7), although the more benzylic alcohol, 1-phenylethanol, was the least reactive of these were also effective, including the branched primary amine used1-phenylpropan-2-ol (R ) PhCH2,R′ ) Me) and pentan-2-ol electron poor anilines (entries 6 and 7) gave lower conversions alcohols, providing only moderate yields of the tertiary amine for entry 9. The use of alternative diols also led to cyclization(R ) CH2CH2Me, R′ ) Me) as representative alcohols. The under these conditions. Aliphatic primary amines (entries 8-11) product under these conditions (Scheme 11). However, the non- were also effective,to the corresponding including the branchedN-heterocycle, primary with amine the used use ofbenzylic 1,5- alcohol, 1-phenylethanol, was the least reactive of these pentanediol and 1,6-hexanediol leading to the products givenalcohols, providingbenzylic alcohols only moderate both showed yields higher of the reactivity tertiary amineand the products for entry 9. The use of alternative diols also led to cyclization were obtained with higher conversion. To examine whether the to the correspondingin entries 12-N13.-heterocycle, with the use of 1,5- product under these conditions (Scheme 11). However, the non- pentanediol andSulfonamides 1,6-hexanediol are found leading in many to the pharmaceutical products given drugs (e.g.,benzylic alcohols both showed higher reactivity and the products in entries 12Sumatripan,-13. Viagra, Furosemide) and have also been usedwere as obtained(28) withQuaal, higher K. S.;conversion. Ji, S.; Kim, Y. To M.; examine Closson, whether W. D.; Zubieta, the J. A. J. protecting groups for nitrogen.28 We were interested in inves- Org. Chem. 1978, 43, 1311. Sulfonamides are found in many pharmaceutical drugs (e.g., (29) (a) Qin, H.; Yoaagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Sumatripan,tigating Viagra, whether Furosemide) primary and sulfonamides have also been38 usedwould as react with(28) Quaal, K. S.;Chem., Ji, S.; Int. Kim, Ed. Y.2007 M.;, 46 Closson,, 409. (b) W. Sreedhar, D.; Zubieta, B.; Reddy, J. A. J. P. S.; Reddy, protectingalcohols groups for to give nitrogen.N-alkylated28 We sulfonamides were interested39 using in inves the- ruthenium- Org. Chem.M.1978 A.;, 43 Neelima,, 1311. B.; Arundhathi, R. Tetrahedron Lett. 2007, 48,8174. (29) (a) Qin, H.; Yoaagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. tigating whether primary sulfonamides 38 would react with Chem., Int. Ed. 2007, 46, 409.J. AM. (b) Sreedhar, CHEM. SOC. B.; Reddy,9 VOL. P. 131, S.; NO.Reddy, 5, 2009 1771 alcohols to give N-alkylated sulfonamides 39 using the ruthenium- M. A.; Neelima, B.; Arundhathi, R. Tetrahedron Lett. 2007, 48,8174.

J. AM. CHEM. SOC. 9 VOL. 131, NO. 5, 2009 1771 Borrowing Hydrogen Methodology ARTICLES

Scheme 12. N-Alkylation Reactions Involving Enantiomerically Scheme 13. Hydrogen/Deuterium Crossover Study in Morpholine Pure Substrates Alkylation

Modern N-Alkylation through H-Transfer Scheme 14. Mechanistic Proposal for the N-Alkylation of Alcohols with Amines

Borrowing Hydrogen Methodology § Insight into mechanism ARTICLES

Scheme 12. N-Alkylation Reactions Involving Enantiomerically Scheme§ Does 13. Hydrogen/Deuterium imine formation Crossover Studyform in Morpholineat metal center? Pure Substrates Alkylation

C13 labeled

Scheme 14. Mechanistic Proposal for the N-Alkylation of Alcohols with Amines observation is consistent with the necessary loss of stereochem- istry in the conversion of alcohol into achiral ketone in theIn our case, oxidation step. The reaction of enantiomerically pureThis diol is η452 iminium complex with dimethylamine occurs selectively with the primary alcoholor via enamine to give the racemic amino alcohol 49 as product. This is consistent with reversible oxidation of the secondary alcohol to the achiral ketone, as noted in racemization reactions of secondary alcohols in the presence of appropriate ruthenium catalysts.31 Racemization of the intermediate aldehyde or iminium species may also be responsible. In the case of the that there is crossover of the deuterium to the 13Clabeledbenzyl amination of enantiomerically pure alcohol 46, the majority of Watson et al. JACS 2009, 131, 1766. observation is consistent with the necessary lossthe of stereochemicalstereochem- integrity is lost in the formation of the group implies that the intermediate aldehyde can dissociate from istry in the conversion of alcohol into achiralproduct ketone50 in,andthisobservationisconsistentwithracemization the the ruthenium and that imine formation does not necessarily oxidation step. The reaction of enantiomericallyoccurring pure diol by45 enolization of the intermediate aldehyde or iminium take place while coordinated. However, since water is formed with dimethylamine occurs selectively with the primary32 alcohol in the oxidation process, either as H2O or HOD, a mechanism to give the racemic amino alcohol 49 asspecies. product. ThisPresumably, is stereochemistry positioned further away consistent with reversible oxidation of the secondaryfrom the alcohol alcohol would be stereochemically stable, although involving H/D exchange of the water with the starting alcohols to the achiral ketone, as noted in racemizationthis reactions has not ofbeen investigated. 52 and 53 cannot be entirely ruled out. The higher deuterium secondary alcohols in the presence of appropriateIn rutheniumthe borrowing hydrogen mechanism, the intermediate incorporation in compound 53 is consistent with the fact that catalysts.31 Racemization of the intermediate aldehyde or only one of the two C-D bonds needs to be broken in order iminium species may also be responsible. Inaldehyde the case of could the either remain complexed to the metal during 13 for the reaction to take place. amination of enantiomerically pure alcohol 46the, the imine-forming majority of processthat there is or crossover it could of dissociate the deuterium and to the formClabeledbenzyl the the stereochemical integrity is lost in the formationimine/iminium of the awaygroup from implies the that metal the intermediate center. We aldehyde performed can dissociate a from Aplausiblemechanismforthealkylationofanamineby product 50,andthisobservationisconsistentwithracemizationcrossover experimentthe rutheniumin order and to gain that imine evidence formation for does either not of necessarilyalcohol using the [Ru(p-cymene)Cl2]2 /diphosphine combination occurring by enolization of the intermediate aldehyde or iminium take place while coordinated. However, since water is formedis given in Scheme 14. Complexation of a diphosphine with 32 these possible mechanisms. Thus, the deuterated alcohol 51 and species. Presumably, stereochemistry positioned further away in the oxidation process, either as H2O or HOD, a mechanism the 13Clabeledalcohol52 were reacted with morpholine to the ruthenium would lead to the formation of the cationic 18 from the alcohol would be stereochemically stable, although involving H/D exchange of the water with the starting alcohols 33 this has not been investigated. provide the N-benzylated52 and 53 cannot morpholine be entirely adducts ruled out.53 Theand higher54 deuteriumelectron complex [Ru(P-P)(p-cymene)Cl]Cl which needs to In the borrowing hydrogen mechanism,(Scheme the intermediate 13). Deuteriumincorporation incorporation in compound was53 is observed consistent in with both the fact thatgenerate a free co-ordination site to become catalytically active. 34 aldehyde could either remain complexed tothe the metal unlabeled during productonly53 oneand of the the two labeled C-D bonds product needs54 to. The be broken fact in orderWe have previously shown that the reaction of [Ru(p- for the reaction to take place. the imine-forming process or it could dissociate and form the cymene)Cl2]2 with BINAP and the diamine DPEN leads to the imine/iminium away from the metal center. We performed a Aplausiblemechanismforthealkylationofanamineby 35 formation of the Noyori complex Ru(BINAP)(DPEN)Cl2 and crossover experiment in order to gain evidence(30) for (a) either Samec, of J. S. M.;alcohol Ell, usingA. H.; the Ba¬ckvall, [Ru(p-cymene)Cl J.-E. Chem.2]2 /diphosphine-Eur. J. 2005 combination, these possible mechanisms. Thus, the deuterated alcohol11, 2327.51 and (b) Blacker,is given A. in J.; Scheme Stirling, 14. M. Complexation J.; Page, M. I. ofOrg. a diphosphine Proc. withwe believe that p-cymene is dissociated in the active complex. 1 the 13Clabeledalcohol52 were reacted with morpholineRes. DeV. to2007, 11the, 642 ruthenium. would lead to the formation of the cationic 18p-Cymene is also observed in the crude H NMR spectra at the 33 provide the N-benzylated morpholine adducts(31)53 Ahn,and Y.;54 Ko, S.-B.;electron Kim, complex M.-J.; Park, [Ru(P J.-P)(Coord.p-cymene)Cl]Cl Chem. ReV. 2008which, needsend to of N-alkylation reactions. We therefore believe that complex (Scheme 13). Deuterium incorporation was observed252, in 647 both. generate a free co-ordination site to become catalytically active. 34 the unlabeled product 53 and the labeled product(32)54 (a). The Atuu, fact M. R.;We Hossain, have M. previously M. Tetrahedron shown Lett.that2007 the, reaction48, 3875. of [Ru(p- (b) Stru¬bing, D.; Krumlinde,cymene)Cl2] P.;2 with Piera, BINAP J.; Ba¬ckvall, and the diamine J.-E. AdV DPEN. Synth. leads to the(33) Mashima, K.; Nakamura, T.; Matsuo, Y.; Tani, K. J. Organomet. Catal. 2007, 349,formation 1577. of the Noyori complex Ru(BINAP)(DPEN)Cl 35 and Chem. 2000, 607, 51. (30) (a) Samec, J. S. M.; Ell, A. H.; Ba¬ckvall, J.-E. Chem.-Eur. J. 2005, 2 we believe that p-cymene is dissociated in the active complex. 11, 2327. (b) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Proc. J. AM. CHEM. SOC. 9 VOL. 131, NO. 5, 2009 1773 Res. DeV. 2007, 11, 642. p-Cymene is also observed in the crude 1H NMR spectra at the (31) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. ReV. 2008, end of N-alkylation reactions. We therefore believe that complex 252, 647. (32) (a) Atuu, M. R.; Hossain, M. M. Tetrahedron Lett. 2007, 48, 3875. (b) Stru¬bing, D.; Krumlinde, P.; Piera, J.; Ba¬ckvall, J.-E. AdV. Synth. (33) Mashima, K.; Nakamura, T.; Matsuo, Y.; Tani, K. J. Organomet. Catal. 2007, 349, 1577. Chem. 2000, 607, 51.

J. AM. CHEM. SOC. 9 VOL. 131, NO. 5, 2009 1773 Angewandte Heterocycle Synthesis Chemie Angewandte Chemie HeterocyclereactionSynthesisconditions where the diol acts as both asubstrate and reaction medium, thus affording N-alkylated pyrrolidines and Modernreaction conditionspiperidines N-Alkylationwherein the99diol%yacts throughieldsas both[Eq.as(4)ubstrate ;MH-Transfer.Sand. = molecular [14] reaction medium,sieves]. thus affording N-alkylated pyrrolidines and The Journal of Organic Chemistry Article § piperidines in 99%yields [Eq. (4);M.S. = molecular Enyong[14] expaned in 2014 this reaction to lower temperaturesScheme 2. Aminoamide Ligand Synthesis therefore, the need for more active catalysts that span a wider sieves]. range of amines. Here, we report the first ruthenium-catalyzed alkylation of primary and secondary amines under mild conditions using the alcohol as the solvent or cosolvent of the reaction. We also present, to the best of our knowledge, the first examples of this chemistry at room temperature using a ruthenium catalyst. Catalysis can also be carried out at higher temperatures with near-stoichiometric amounts of alcohol. All catalytic reactions were performed using the inexpensive Thesame ruthenium complex was used along with and readily accessible amino amide ligand 3 or its TFA salt (2), whose synthesis is shown in Scheme 2. Boc-Phe-OH was Xantphos for the construction of the benzodiazepine core, coupled to aniline using DCC and subsequently deprotected with trifluoroacetic acid in methylene chloride. Ligand 3 is which hasEnyongmany etapplications al. JOC 2014,in 79medicinal, 7553. chemistry3,t – hroughdecomposes above -20 oC unstable under ambient conditions and has to be stored at Thesame ruthenium complex was used along with −20 °C. On the other hand, the TFA salt of the ligand, 2, is Xantphosconsecutivefor the constructionhydrogen-borrowingof the benzodiazepinesteps using 2-aminobenzyl-core■ ,RESULTS AND DISCUSSION indefinitely stable on the benchtop and was thus a more § Used foralcohols benzodiazepineand 1,2-amino corealcohols (show(Scheme how normally1). BasedMost alcoholmade?)on alkylationsthe of amines through borrowing convenient alternative to 3. Use of either 2 or 3 in combination which has many applications in medicinal chemistry,throughhydrogen are carried out at high temperatures with only one with the ruthenium precursor, Ru[(p-cymene)Cl2]2, resulted in example of room temperature alkylation of anilines. There is, identical catalytic performance. consecutive§ Isolatedhydrogen-borrowing intermediates 6steps and using7 2-aminobenzyl- Scheme 2. Synthesis of C2-substituted pyrrolidines by hydroaminoalky- a alcohols and 1,2-amino alcohols (Scheme 1). Based on theTable 3. Alkylation of Primarylation Aliphaticof amino Amines alcohols with dienes. DMAP=4-(N,N-dimethylamino)- pyridine, dCypp= 1,3-bis(dicyclohexylphosphino)propane, Ts = 4-tolue- Scheme 2. Synthesnesulfonylis of. C2-substituted pyrrolidines by hydroaminoalky- lation of amino alcohols with dienes. DMAP=4-(N,N-dimethylamino)- pyridine, dCypp=Cheap1,3-bis(di startingcyclohexyl phosphino)propane, Ts = 4-tolue- nesulfonyl. materials standard reaction conditions.Significantly,deuterium incor- poration was observed at all vinylic positions,allyl positions, standard reactionand in theconditionsmethyl.Significantlygroup (R =,dH)euteriumof theincorproduct,- thus poration wasconfirmingobservedtheat allreversibilityvinylic positionsof the,allylhydrometalationpositions, step. Complete retention of deuterium ( 95) at the methine and in the methyl group (R = H) of the product,> thus Taddei et al. Eur.position J. Org.adjacent 2015, 2015to, 1068.the nitrogen atom confirmed the non- Scheme 1. Synthesis of benzodiazepines (8). Xantphos= 9,9-dimethyl-confirming the reversibility of the hydrometalation step. 4,5-bis(diphenylphosphino)xanthene. Completereversibilityretention ofof alcoholdeuteriumdehydrogenation(> 95) at theformethineimine formation. position adjacentTheintermediateto the nitrogen12 wasatomproposedconfirmedfor thetheantinon--diastereose- Scheme 1. Synthesis of benzodiazepines (8). Xantphos= 9,9-dimethyl- [16] reversibilitylectivityof alcoholof thedehydrogenationproduct. for imine formation. 4,5-bis(diphenylphospidentificationhino)xanthenof thee.intermediates and in the reaction Fujita and co-workers developed the first iridium-cata- 6 7 Theintermediate 12 was proposed for the anti-diastereose- mixture,the tandem reaction starts with the oxidation lectivityof the oflyzedthe product.intramolecular[16] annulation reaction of 3-(2-aminophe- more reactive benzyl alcohol to an aldehyde through abor- nyl)propanol to yield 1,2,3,4-tetrahydroisoquinolines in mod- identification of the intermediates 6 and 7 in the reaction Fujita and co-workers developed the first iridium-cata- mixture,therowing-hydrogentandem reactionprocessstarts.Swithubsequentthe oxidationimine offormationthe lyzedwithintramolecularerate to highannulationyields.Treactionhe reactionof 3-(2-aminophe-proceeded by an initial more reactivethe morebenzylreactivealcohol1,2-aminoto an aldehydealcohol throughleads to theaborN-alkylation- nyl)propanolcatalyticto yielddehydrogenative1,2,3,4-tetrahydroisoquinolinesoxidation of theinalcoholmod- by using of the benzyl alcohol. Then intramolecular N-alkylation of the 2mol%of[{Cp*IrCl } ]asthe catalyst. Aromatic substrates rowing-hydrogen process.Subsequent imine formation with erate to high yields.The reaction2 2 proceeded by an initial alcohol with an aromatic amine affords the benzodiazepine.[15] having different substituents were converted into the corre- the more reactive 1,2-amino alcohol leads to the N-alkylation catalytic dehydrogenative oxidation of the alcohol by using Recently,Krische and co-workers reported amethod for sponding 1,2,3,4-tetrahydroquinolines in moderate to excel- of the benzyl alcohol. Then intramolecular N-alkylation of the 2mol%of[{Cp*IrCl2}2]asthe catalyst. Aromatic substrates the synthesis of C2-substituted pyrrolidines ( [15])through lent yields and 2,3,4,5-tetrahydro-1-benzazepine was also alcohol with an aromatic amine affords the benzodiazepine.14 having different substituents were converted into the corre- a hydrogen-transfer hydroaminoalkylation of aminoReactionalcohols conditions: amine (1 mmol),synthesized alcohol (solvent),from ligand 3 (4-(2-aminophenyl)butanolx mol %), [Ru(p-cymeneCl2]2 (x/2 mol %), t-BuOKusing (2 equiv wrtthe3), 45−same65 °C, 3 Å molecular sieves. bYield calculated by GCMS using N,N-dimethylbenzylamine as the internal standard. Recently,Krische and co-workers reported amethod for sponding 1,2,3,4-tetrahydroquinolines in moderate[17]to excel- with dienes (Scheme 2). Thereaction proceeds with complete iridium catalyst [Eq. (5);Cp* = C5Me5]. Thesuccess of the the synthesis of C2-substituted pyrrolidines (14)through lent yields and 2,3,4,5-tetrahydro-1-benza7555 zepinedx.doi.org/10.1021/jo501273twas | J.also Org. Chem. 2014, 79, 7553−7563 branch selectivity and good to excellent levels of anti- Cp*Ir complex was extended to the synthesis of piperazines hydrogen-transfer hydroaminoalkylation of amino alcohols synthesized from 4-(2-aminophenyl)butanol using the same diastereoselectivity.Optimization of the reaction conditions with dienes (Scheme 2). Thereaction proceeds with complete iridium catalyst [Eq. (5);Cp* = C Me ].[17] Thesuccess of the and catalyst identified in situ generated catalysts,derived 5 5 branch selectivity and good to excellent levels of anti- Cp*Ir complex was extended to the synthesis of piperazines from [HClRu(CO)(PPh ) ]and various phosphine ligands,for diastereoselectivity.Optimization3 of3 the reaction conditions delivery of 2-substituted pyrrolidines in high yield and with and catalyst identified in situ generated catalysts,derived maximum diastereoselectivity.Mechanistically,alcohol dehy- from [HClRu(CO)(PPh ) ]and various phosphine ligands,for drogenation triggers3 3 generation of an electrophilic imine,3,4- delivery of 2-substituted pyrrolidines in high yield and with dihydro-2H-pyrrole (9), and ruthenium hydride.The latter from 1,2-diamines and 1,2-diols by using an intermolecular maximum diastereoselectivity.Mechanistically,alcohol dehy- undergoes hydrometalation with the diene to form the borrowing-hydrogen N-alkylation strategy with aweak base, drogenation triggers generation of an electrophilic imine,3,4- nucleophilically less-stable disubstituted p-allylruthenium such as NaHCO ,asanadditive,ineither water or toluene dihydro-2H-pyrrole (9), and ruthenium hydride.The latter from 1,2-diamines and 1,2-diols3 by using an intermolecular complex 10.The complex 10 undergoes reversible isomer- [Eq. (6)].Additionally,piperazine (17)formation was also undergoes hydrometalation with the diene to form the borrowing-hydrogen N-alkylation strategy with aweak base, ization to form the more-stable isomeric monosubstituted p- derived from aprimary benzyl amine and 1,2-diol through the nucleophilically less-stable disubstituted p-allylruthenium such as NaHCO ,asanadditive,ineither water or toluene allylruthenium complex 11 which is involved in imine addition 3 complex 10.The complex 10 undergoes reversible isomer- [Eq. (6)].Additionally,piperazine (17)formation was also via the (E)-s-allylruthenium haptomer to afford C2-substi- ization to form the more-stable isomeric monosubstituted p- derived from aprimary benzyl amine and 1,2-diol through the tuted pyrrolidines.The reversibility of the hydrometallation allylruthenium complex 11 which is involved in imine addition step was studied for the coupling reaction of adeuterated via the (E)-s-allylruthenium haptomer to afford C2-substi- amino alcohol [HOCD (CH ) NH ]with butadiene under tuted pyrrolidines.The reversibility2 of 2the3 hydrometallation2 step was studied for the coupling reaction of adeuterated Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11025 amino alcohol [HOCD2(CH2)3NH2]with butadiene under

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11025 Journal of the American Chemical Society Communication

Table 1. Selected Optimization Experiments in the the coupling of 1,3-pentadiene (1d), C−C coupling occurs at the Ruthenium-Catalyzed Coupling of Butadiene (1a) with 4- diene 2-position to furnish the adduct 4d with complete levels of Aminobutanol (2a)a anti-diastereoselectivity. Similarly, the 1-cyclohexyl-substituted diene 1e and 1-(4-tetrahydropyranyl)-substituted diene 1f engage in C−C coupling at the diene 2-position to furnish adducts 4e and 4f, respectively, with complete levels of anti- diastereoselectivity. As will be discussed (vide infra), coupling to the diene 2-position, exemplified by the formation of 4d−4f, suggests reversible diene hydrometalation in advance of imine addition. Reversible hydrometalation enables nonconjugated dienes, such as 1,4-pentadiene (1g), to serve as conjugated diene equivalents, as shown in the formation of 4d (eq 1). Whereas

a b Yields are of material isolated by silica gel chromatography. PCy3 (10 mol%). cAverage isolated yield from four experiments. See the Supporting Information for further details.

variation of temperature and reaction time, optimal conditions for the highly diastereoselective (>20:1 dr) coupling of 1a with Hydroaminoalkylation 2a to form 4a in 75% yield were identified (Table 1, entry 13). With these conditions in hand, the coupling of 2a with various conjugated dienes 1a−1f was explored (Table 2). As illustrated attempted reactions of 1a with 5-aminopentanol failed to provide § Krische – hydroaminoalkylation in the couplings of 1a, isoprene (1b), and myrcene (1c), a the corresponding 2-substituted piperidine, it was found that the gradual decline in anti-diastereoselectivity with increasing size of more highly substituted 4-aminobutanols 2b and 2c participate § Branch selective the diene 2-substituent due to allylic 1,2-strain is observed.8c In in redox-triggered imine addition to form adducts 4g (eq 2) and § Anti-diastereoselectivity Angewandte 4h (eq 3), respectively, with complete levels of anti- Heterocycle Synthesis TableChe 2.mi Regio-e and Diastereoselective Ruthenium-Catalyzed diastereoselectivity, as determined by 1H NMR spectroscopy. a C−C Coupling of Conjugated Dienes 1a−1f with 2a Functionalized dienes, such as chloroprene or alkoxy-substituted dienes, do not participate in C−C coupling under these reaction conditions where the diol acts as both asubstrate and conditions. reaction medium, thus affording N-alkylated pyrrolidines and In the couplings of 2a with conjugated dienes 1a−1f, alcohol piperidines in 99%yields [Eq. (4);M.S. = molecular dehydrogenation triggers pairwise generation of an imine sieves].[14] electrophile, 3,4-dihydro-2H-pyrrole, and a ruthenium hydride that hydrometalates the diene to form a nucleophilic allylruthenium complex. It was reasoned that such nucleo- phile−electrophile pairs could be generated through the redox- triggered coupling of dienes with pyrrolidine itself, constituting a rare example of late transition metal-catalyzed hydroaminoalky- lation in the absence of a directing group.2,3 However, as observed empirically in the present couplings of 2a, alcohol dehydrogenation occurs in preference to amine dehydrogen- Thesame ruthenium complex was used along with ation, suggesting that such processes would pose significant Xantphos for the construction of the benzodiazepine core, challenges, which proved to be the case. Nevertheless, after which has many applications in medicinal chemistry,through screening of various ruthenium complexes, it was found that the consecutive hydrogen-borrowing steps using 2-aminobenzyl- catalyst generated in situ through the acid−base reaction of alcohols and 1,2-amino alcohols (Scheme 1). Based on the H2Ru(CO)(PPh3)(dppp) and ferrocene carboxylic acid or C7F15CO2H promotes the hydroaminoalkylation of conjugated Scheme 2. Synthesis of C2-substituted pyrrolidines by hydroaminoalky- dienes 1a and 1b with pyrrolidine (3a) to form adducts 4a and lation of amino alcohols with dienes. DMAP=4-(N,N-dimethylamino)-a Krische et al. JACS 2015, 137, 1798.b 4b, respectively, in good yields with good levels of anti- Yields are of material isolated by silica gel chromatography. 1a (500 pyridine, dCypp= 1,3-bis(dicyclohexylphosphino)propane, Ts = 4-tolue- mol%). cdCype was used as the ligand. Diastereoselectivities were diastereoselectivity (Scheme 1, eq 4). Finally, with the trimeric nesulfonyl. determined by 1H NMR analysis of crude reaction mixtures. See the imine derived from pyrrolidine, dehydro-3a, 2-propanol-medi- Supporting Information for further details. ated reductive coupling to form N-Cbz-4a could be achieved,

1799 DOI: 10.1021/ja5130258 standard reaction conditions.Significantly,deuterium incor- J. Am. Chem. Soc. 2015, 137, 1798−1801 poration was observed at all vinylic positions,allyl positions, and in the methyl group (R = H) of the product, thus confirming the reversibility of the hydrometalation step. Complete retention of deuterium (> 95) at the methine position adjacent to the nitrogen atom confirmed the non- Scheme 1. Synthesis of benzodiazepines (8). Xantphos=9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene. reversibility of alcohol dehydrogenation for imine formation. Theintermediate 12 was proposed for the anti-diastereose- lectivity of the product.[16] identification of the intermediates 6 and 7 in the reaction Fujita and co-workers developed the first iridium-cata- mixture,the tandem reaction starts with the oxidation of the lyzed intramolecular annulation reaction of 3-(2-aminophe- more reactive benzyl alcohol to an aldehyde through abor- nyl)propanol to yield 1,2,3,4-tetrahydroisoquinolines in mod- rowing-hydrogen process.Subsequent imine formation with erate to high yields.The reaction proceeded by an initial the more reactive 1,2-amino alcohol leads to the N-alkylation catalytic dehydrogenative oxidation of the alcohol by using of the benzyl alcohol. Then intramolecular N-alkylation of the 2mol%of[{Cp*IrCl2}2]asthe catalyst. Aromatic substrates alcohol with an aromatic amine affords the benzodiazepine.[15] having different substituents were converted into the corre- Recently,Krische and co-workers reported amethod for sponding 1,2,3,4-tetrahydroquinolines in moderate to excel- the synthesis of C2-substituted pyrrolidines (14)through lent yields and 2,3,4,5-tetrahydro-1-benzazepine was also hydrogen-transfer hydroaminoalkylation of amino alcohols synthesized from 4-(2-aminophenyl)butanol using the same [17] with dienes (Scheme 2). Thereaction proceeds with complete iridium catalyst [Eq. (5);Cp* = C5Me5]. Thesuccess of the branch selectivity and good to excellent levels of anti- Cp*Ir complex was extended to the synthesis of piperazines diastereoselectivity.Optimization of the reaction conditions and catalyst identified in situ generated catalysts,derived from [HClRu(CO)(PPh3)3]and various phosphine ligands,for delivery of 2-substituted pyrrolidines in high yield and with maximum diastereoselectivity.Mechanistically,alcohol dehy- drogenation triggers generation of an electrophilic imine,3,4- dihydro-2H-pyrrole (9), and ruthenium hydride.The latter from 1,2-diamines and 1,2-diols by using an intermolecular undergoes hydrometalation with the diene to form the borrowing-hydrogen N-alkylation strategy with aweak base, nucleophilically less-stable disubstituted p-allylruthenium such as NaHCO3,asanadditive,ineither water or toluene complex 10.The complex 10 undergoes reversible isomer- [Eq. (6)].Additionally,piperazine (17)formation was also ization to form the more-stable isomeric monosubstituted p- derived from aprimary benzyl amine and 1,2-diol through the allylruthenium complex 11 which is involved in imine addition via the (E)-s-allylruthenium haptomer to afford C2-substi- tuted pyrrolidines.The reversibility of the hydrometallation step was studied for the coupling reaction of adeuterated amino alcohol [HOCD2(CH2)3NH2]with butadiene under

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11025 hardly explored.6 During the course of our investigation on catalytic activity (entries 8-10), but the optimum result was the chemistry of pentamethylcyclopentadienyl (Cp*) iridium obtained in the reaction with K2CO3.Toluenewasthesolvent 7 complexes, we found a catalytic activity of [Cp*IrCl2]2 of choice, since the reactions in other solvents (dioxane or toward hydrogen-transfer reactions between organic mol- acetonitrile) gave lower yields of 2 (entries 11 and 12). ecules and reported Oppenauer-type oxidation of primary and The present oxidative N-heterocyclization could be ap- secondary alcohols giving rise to the corresponding carbonyl plicable to various amino alcohols, affording indole deriva- compounds.7 In this paper, we wish to report a Cp*Ir tives. The results are summarized in Table 2.8 2-Aminophen- complex-catalyzed synthesis of indoles, 1,2,3,4-tetrahydro- quinolines, and 2,3,4,5-tetrahydro-1-benzazepine by oxidative N-heterocyclization of amino alcohols. ORGANIC Table 2. Synthesis of Indoles from Various Amino Alcohols At first, we investigated Cp*Ir-catalyzed oxidative N- LETTERS Catalyzed by the [Cp*IrCl ] /K CO Systema heterocyclization of 2-aminophenethyl alcohol (1) under 2 2 2 3 various conditions. The reactions were performed in the 2002 presence of severalOxidative iridium complexes Cyclization and bases in toluene of Amino Alcohols Vol. 4, No. 16 as a solvent. TheCatalyzed results are summarized by in Table a Cp*Ir 1. Indole Complex. 2691-2694 Synthesis of Indoles, Table 1. Synthesis of Indole (2) from 2-Aminophenethyl Alcohol (1) by Various1,2,3,4-Tetrahydroquinolines, Catalytic Systemsa and 2,3,4,5-Tetrahydro-1-benzazepine

Ken-ichi Fujita,*,† Kazunari Yamamoto,‡ and Ryohei Yamaguchi*,‡ entry catalyst base yieldb (%) Department of Natural Resources, Graduate School of Global EnVironmental Studies, 1 [Cp*IrCl2]2 K2CO3 70 c and Graduate School of Human and EnVironmental Studies, Kyoto UniVersity, 2 [Cp*IrCl2]2 K2CO3 90 Kyoto 606-8501, Japan 3 [Cp*IrHCl]2 K2CO3 55 4 [Cp*Ir(MeCN)[email protected]][OTf]2 K2CO3 20 5 [IrCl(COD)]2 K2CO3 22 6 none K CO 2 Received May 17, 2002 2 3 7 [Cp*IrCl2]2 none 31 Modern N-Alkylationa through H-Transfer 8 [Cp*IrCl2]2 Li2CO3 42 The reaction was carried out at reflux temperature (111 °C) for 20 h 9 [Cp*IrCl ] tBuOK 62 with amino alcohol (1.0 mmol), [Cp*IrCl2]2 (5.0 mol %/Ir) and K2CO3 (0.10 2 2 mmol) in toluene (2 mL). b Isolated yield. c Reaction time was 17 h. 10 [Cp*IrCl2]2 Et3N57 d 11 [Cp*IrCl2]2 K§2CO 3 Ir-catalyzed50 formation of indoles, tetrahydroquinolines, and benzapines e 12 [Cp*IrCl2]2 K2CO3 24 ABSTRACT ethyl alcohols bearing a substituent on the aromatic ring were a The reaction was carried out at 100 °C for 17 h with 1 (1.0 mmol), catalyst (5.0 mol %/Ir), and base (0.10 mmol) in toluene (2 mL). converted into the corresponding indoles in moderate to high b Determined by GC. c The reaction was carried out at reflux temperature yields (entries 2-4). Indoles bearing a substituent on the (111 °C). d The reaction was carried out in dioxane. e The reaction was N-heterocyclic ring could be also synthesized68-99% yield in good to carried out in acetonitrile at reflux temperature (81 °C). excellent yields by the reaction of 2-aminophenethyl alcohols with a substituent on the methylene chain58-96% yield (entries 5 and 6). (2) was formed in a yield of 70% when the reaction was In the synthesis of indoles, the reaction proceeded with high selectivity and no indoline product was detected. performed at 100 °C for 17 h with use of [Cp*IrCl2]2 (5.0 Since the complex [Cp*IrCl2]2 exhibits a catalytic activity mol %/Ir) and KAnewiridium-catalyzedoxidativecyclizationofaminoalcoholshasbeenrevealed.Indolederivativesaresynthesizedingoodtoexcellent2CO3 (10 mol %) (entry 1). The yield of 2 increased up toyields 90% when from 2-aminophenethyl the reaction was alcohols performed by means at of a [Cp*IrCltoward2] the2/K2CO reduction3 catalytic of system. the nitro The group present to catalytic an amino system group is also effective for 9 reflux temperaturesyntheses (111 ° ofC) 1,2,3,4-tetrahydroquinolines (entry 2).§ Other They iridium found from com- 3-(2-aminophenyl)propanols that withthis usecatalyst of alcohols and with 2,3,4,5-tetrahydro-1-benzazepine as 2-propanol a hydrogen source, couldwe frombe examined 4-(2-aminophenyl)buused to reducetanol. 2+ the synthesis of indole from 2-nitrophenethyl alcohol (3)(eq plexes, [Cp*IrHCl]2,[Cp*Ir(MeCN)3] ,or[IrCl(COD)]nitrobenzene2, to analine (their own unpublished results) showed some catalytic activity (entries 3-5), but the yields 1). Indole (2) was obtained in the yield of 69% by the 3-5 3d,4a,5b,c,e,g of 2 were lowerN-Heterocyclic than that in compounds the reaction have catalyzed attracted by considerable at- cyclization. Catalytic systems with palladium, 3a,b,4b,5a,f 3c,5d 2 [Cp*IrCl ] .Wenextexaminedtheeffectofbase.Whenthetention owing to their functionality in pharmaceutical ruthenium, rhodium, and other metals have been 2 2 chemistry, material chemistry, synthetic organic chemistry, applied for the synthesis of indoles. On the other hand, the reaction was performed without1 any base, the yield of 2 declined to 31%and (entry dyes. 7). AdditionIn particular, of other the alkali synthesis metal of benzo-fused catalytic synthesis of 1,2,3,4-tetrahydroquinolines or 2,3,4,5- N-heterocyclic compounds, such as indoles, quinolines, tetrahydro-1-benzazepines via N-heterocyclization has been bases (Li CO , tBuOK) or organic base (Et N) improved the 2 3 benzazepines, and their saturated3 derivatives, is very impor-

(6) (a) Katritzky,tant A. R.; because Rachwal, their S.; Rachwal, skeletons B. areTetrahedron found in1996 a variety, of natural (3) Inter- or intramolecular addition of NH2 to alkyne: (a) Tokunaga, 52, 15031 and referencesproducts, therein. which (b) Larock exert R. physiological C.; Berrios-Pena, activities. N. G.; A numberreaction of of 3 inM.; 2-propanol Ota, M.; Haga, at 120 M.; Wakatsuki,°C for 40 Y. hTetrahedron in a heavy- Lett. 2001, 42, 3865. Fried, C. A.; Yum, E. K.; Tu, C.; Leong, W. J. Org. Chem. 1993, 58,4509. (b) Kondo, T.; Okada, T.; Suzuki, T.; Mitsudo, T. J. Organomet. Chem. (7) Fujita, K.; Furukawa,methods S.; Yamaguchi, for synthesis R. J. of Organomet. indoles Chem have. 2002 been, developedwalled and glass reactor.2001, 622 A, small 149. (c) amount Burling,of S.; 2-aminophenethylField, L. D.; Messerle, B. A. Organome- 649, 289. reviewed.2 Recently, much attention has focusedalcohol on the (1)wasdetectedbyGCanalysis(6%)asabyproduct.tallics 2000, 19,87.(d)Iritani,K.;Matsubara,S.;Utimoto,K.Tetrahedron synthesis of indoles by transition-metal-catalyzed N-hetero- Lett. 1988, 29, 1799. 2692 (4) Intramolecular oxidativeOrg. Lett., cyclizationVol. 4,Fujita No. of amino 16, & 2002Yamaguchi. alcohol: (a) Org. Aoyagi, Lett. 2002, 4, 2691. Y.; Mizusaki, T.; Ohta, A. Tetrahedron Lett. 1996, 37, 9203. (b) Tsuji, Y.; † Graduate School of Global Environmental Studies. Kotachi, S.; Huh, K.-T.; Watanabe, Y. J. Org. Chem. 1990, 55, 580. ‡ Graduate School of Human and Environmental Studies. (5) Via other routes: (a) Cho, C. S.; Kim, J. H.; Kim, T.-J.; Shim, S. C. (1) ComprehensiVe Heterocyclic Chemistry II; Bird, C. W., Ed.; Perga- Tetrahedron 2001, 57, 3321. (b) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. mon: Oxford, 1996. Am. Chem. Soc. 2000, 122, 5662. (c) Larock, R. C.; Yum, E. K.; Refvik, (2) (a) Sundberg, R. J. In ComprehensiVeHeterocyclicChemistryII;Bird, M. D. J. Org. Chem. 1998, 63, 7652. (d) Dong, Y.; Busacca, C. A. J. Org. C. W., Ed.; Pergamon: Oxford, 1996; Vol. 2, pp 119-206. (b) Gribble, G. Chem. 1997, 62, 6464. (e) So¬derberg, B. C.; Shriver, J. A. J. Org. Chem. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (c) Gilchrist, T. L. J. Chem. 1997, 62,5838.(f)Hsu,G.C.;Kosar,W.P.;Jones,W.D.Organometallics Soc., Perkin Trans. 1 1999, 2849. (d) Hegedus, L. S. Angew. Chem., Int. 1994, 13, 385. (g) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, Ed. Engl. 1988, 27, 1113. 5291.

10.1021/ol026200s CCC: $22.00 © 2002 American Chemical Society Published on Web 07/13/2002 Angewandte Heterocycle Synthesis Chemie reaction conditions where the diol acts as both asubstrate and reaction medium, thus affording N-alkylated pyrrolidines and piperidines in 99%yields [Eq. (4);M.S. = molecular sieves].[14]

Thesame ruthenium complex was used along with Xantphos for the construction of the benzodiazepine core, which has many applications in medicinal chemistry,through consecutive hydrogen-borrowing steps using 2-aminobenzyl- alcohols and 1,2-amino alcohols (Scheme 1). Based on the

Scheme 2. Synthesis of C2-substituted pyrrolidines by hydroaminoalky- lation of amino alcohols with dienes. DMAP=4-(N,N-dimethylamino)- pyridine, dCypp= 1,3-bis(dicyclohexylphosphino)propane, Ts = 4-tolue- nesulfonyl. Iridium-Catalyzed Synthesis of Substituted Piperazines

standard reaction conditions.Significantly,deuterium incor- quired for full conversion, which is higher than that for the trisubstituted piperazine was isolated in 63 % yield, whereas poration was observed at all vinylic positions,allyl positions, same reaction with ethylene and propylene glycol (Tables 1 an improved selectivity was observed with phenylethylene and in the methyl group (R = H) of the product, thus and 3, Entries 1 and 2). glycol, for which the product was obtained in 90% yield. confirming the reversibility of the hydrometalation step. In all, the substrate screening summarized in Tables 1, 2, Complete retention of deuterium (> 95) at the methine and 3 illustrates that a number of 1,2-diamines and 1,2- position adjacent to the nitrogen atom confirmed the non- Scheme 1. Synthesis of benzodiazepinesdiols(8). canXantphos be employed=9,9-dimethyl- in the cyclization. The most reactive reversibility of alcohol dehydrogenation for imine formation. 4,5-bis(diphenylphosphino)xanthene. diamine is 1,2-diaminocyclohexane, whereas ethylene and Theintermediate 12 was proposed for the anti-diastereose- propylene glycol are the most efficient diols. N-Substituted lectivity of the product.[16] View Article Online diamines, i.e., secondary amines, are less reactive substrates, identification of the intermediates 6 and 7 in the reaction Fujita and co-workers developed the first iridium-cata- and the same is observed with more substituted diols. Sub- mixture,the tandem reaction starts with the oxidation of the lyzed intramolecular annulation reaction of 3-(2-aminophe- stituents, however, are required for the cyclization to pro- more reactive benzyl alcohol to an aldehyde through abor- nyl)propanol to yield 1,2,3,4-tetrahydroisoquinolinesScheme 3. Synthesis ofin 2-substitutedmod- 1,4-dibenzylpiperazine. ceed, because the parent piperazine could not be prepared rowing-hydrogen process.Subsequent imine formation with erate to high yields.The reaction proceeded by an initial from ethylenediamine and ethylene glycol. When a substitu- Similar reactions may be possible with ammonia as the the more reactive 1,2-amino alcohol leads to the N-alkylation catalytic dehydrogenative oxidation of the alcohol by using ent gives rise to a new stereocenter in the product, the ther- amine component. N-Alkylation of ammonium salts with of the benzyl alcohol. Then intramolecular N-alkylation of the 2mol%of[{Cp*IrCl2}2]asthe catalyst.primaryAromatic and secondarysubstrates alcohols has previously been carried alcohol with an aromatic amine affordsmodynamicallythe benzodiazepine most stable.[15] isomerhaving different is usuallysubstituents preferred.were converted into the corre- Interestingly, no notable difference in reactivity was ob- out in the absence of solvent with [Cp*IrCl2]2 as the precat- Recently,Krische and co-workers reported amethod for sponding 1,2,3,4-tetrahydroquinolinesalyst.[22]in moderateUnder theseto excel- conditions, however, we observed no the synthesis of C2-substitutedservedpyrrolidines when the(14)t reactionshrough werelent conductedyields and in2,3,4,5-tetrahydro-1-benza toluene or zepine was also water. piperazine formation from ethylene glycol and ammonium hydrogen-transfer hydroaminoalkylation of amino alcohols synthesized from 4-(2-aminophenyl)butanoltetrafluoroborate.using the Thissame may not be surprising, because the Piperazine formation can also be envisioned from sub- [17] with dienes (Scheme 2). Thereaction proceeds with complete iridium catalyst [Eq. (5);Cp* = Clack5Me5 of]. aTh substituentesuccess mayof the hinder the synthesis of the unsub- branch selectivity and good tostratesexcellent otherlevels than 1,2-diaminesof anti- Cp*Ir andcomplex 1,2-diols.was First,extended it was to the synthesis of piperazines investigated whether a single primary amine could be used stituted piperazine. The transformation was therefore re- diastereoselectivity.Optimization of the reaction conditions peated with both 2,3-butylene glycol and cyclohexane-1,2- and catalyst identified in situ generatedinstead ofcatalysts a 1,2-diamine.,derived Accordingly, the condensation of benzylamine with ethylene glycol was studied under dif- diol. In both cases, a mixture of three products was formed, from [HClRu(CO)(PPh3)3]and various phosphine ligands,for which – according to GC–MS analysis – were believed to delivery of 2-substituted pyrrolidinesferentin conditionshigh yield inand a closedwith vial (Scheme 2). In toluene at 140 °C the reaction only afforded a moderate yield of 1,4- be the corresponding piperazine, pyrazine, and morpholine. maximum diastereoselectivity.Mechanistically,alcohol dehy- The reaction with cyclohexane-1,2-diol was further opti- drogenation triggers generation ofdibenzylpiperazinean electrophilic imine (45,3 %).,4- However, when the transforma- tion was repeated at 160 °C in the absence of a solvent the mized, but it was not possible to obtain the piperazine as dihydro-2H-pyrrole (9), and ruthenium hydride.The latter from 1,2-diamines and 1,2-diols theby using majoran product.intermolecular Instead, the morpholine adduct could undergoes hydrometalation withyieldtheModern increaseddiene to toform 94% N-Alkylationthe (Schemeborrowing-hydrogen 2). The high through temperatureN-alkylation H-Transferstrategy with aweak base, was necessary under the neat conditions, because the trans- be isolated in 63% yield when the condensation was carried nucleophilically less-stable disubstituted p-allylruthenium such as NaHCO3,asanadditive,ioutneither withwater trifluoroaceticor toluene acid in mesitylene at 180 °C complex 10.The complex 10 undergoesformationreversible at 110 °Cisomer only- afforded[Eq. (6)] 30.A %dditionally yield after,p 18iperazine h. (17)formation was also Aniline was also examined as a substrate under the same (Scheme 4). Presumably, this transformation proceeds by a ization to form the more-stable isomeric§ monosubstitutedMadsen usedp -Cp*derivedIr complexfrom ap torimary synthesizebenzyl amine piperazinesdoubleand alkylation1,2-diol through of ammoniathe with the diol to form bis(2- allylruthenium complex 11 whichconditionsis involved in atimine 160 °C,addition but only trace amounts of 1,4-di- phenylpiperazine were obtained in this case, presumably hydroxycyclohexyl)amine, which then cyclizes to the via the (E)-s-allylruthenium haptomer to afford C2-substi- morpholine. The synthesis of morpholine derivatives from tuted pyrrolidines.The reversibilitydueof tothe thehydrometallation lower nucleophilicity compared to benzylamine. Two other diols were also studied in the reaction with ben- di(ethanol)amines has previously been described in the step was studied for the coupling reaction of adeuterated presence of RuCl and PPh .[23] zylamine.Fig. 10 Overview However, ofwith the entire both reaction phenylethylene pathway from glycol benzyl and alcohol cy- complex 1a to benzyl3 amine complex3 1h. amino alcohol [HOCD2(CH2)3NH2]with butadiene under clohexane-1,2-diol the reaction stopped at the amino alcohol stage, and no dimerization to the corresponding Angew.Chem. Int.Ed. 2015, 54,11022 –11034 § Additionally,⌫ 2015 Wiley-VCH throughVerlag GmbH 1,2-diols&Co. KGaA, andWeinheim a primary aminewww .angewandte.org 11025 symmetric piperazines were observed. This illustrates once more that the§ 4 cyclization new C-N is hamperedbonds, neat by additional conditions substit- uents. Iridium-Catalyzed Synthesis of Substituted Piperazines Scheme 4. Synthesis of dodecahydro-1H-phenoxazine. quired for full conversion, which is higher than that for the trisubstituted piperazine was isolated in 63 % yield, whereas Ethanolamine is also a potential substrate that may form same reaction with ethylene and propylene glycol (Tables 1 an improved selectivity was observed with phenylethylene a piperazine with the iridium catalyst. It was quickly discov- and 3, Entries 1 and 2). glycol, for which the product was obtained in 90% yield. ered that this reaction did not afford the parent piperazine, In all, the substrate screening summarized in Tables 1, 2, but instead two substituted analogues were generated. After Scheme 2. Synthesis of 1,4-dibenzylpiperazine. and 3 illustrates that a number of 1,2-diamines and 1,2- some optimization, 1-(2-hydroxyethyl)piperazine and 1,4- diols can be employed in the cyclization. The most reactive bis(2-hydroxyethyl)piperazine were isolated in 30 and 27 % diamine is 1,2-diaminocyclohexane, whereas ethylene and Published on 11 January 2012. Downloaded by University of Texas Libraries 02/10/2015 22:28:07. yield, respectively (Scheme 5). The transformation required Fig. 11 Iridium–amine complex 1h formed after imine reduction. propylene glycol are the most efficient diols. N-Substituted It may, however, be possible to use two different diolsScheme in 5 aRevised rather longcatalytic reaction cycle for time iridium-catalysed for full conversion, alkylation and of it was diamines, i.e., secondary amines, are less reactive substrates, DFT Study the reaction with benzylamine if one is ethylene glycol.amines To withnot alcohols. possible toAldehyde alter the does ratio not between leave catalyst the two products. and the same is observed with more substituted diols. Sub- avoid 1,4-dibenzylpiperazine formation the substituted diol The exact pathway leading to the substituted piperazines With amines present in large excess under experimental con- stituents, however, are required for the cyclization to pro- shouldScheme first 3. Synthesis be allowed of 2-substituted to react with 1,4-dibenzylpiperazine. 2 equiv. of benzyla- could not be identified, but 2-[(2-aminoethyl)amino]ethanol ditions we do not favour the direct coordination of carbonate to Madsen. Eur. J. Org. Chem. 2012, 2012, 6752. ceed, because the parent piperazine could not be prepared mine, and – upon completion of this reaction – ethylenevibrationalmight analysis be with a potentialT = 110 intermediate. °C results in To a calculated probe this KIE question iridium proposed bySimilar Crabtree, reactions Eisenstein may and be co-workers. possible with14 Fur- ammonia as the from ethylenediamine and ethylene glycol. When a substitu- glycol should be added to the mixture (Scheme 3).of It 2.70 was whichthe diamino is in good alcohol agreement was also with subjected the experimental to the iridium value. cata- amine component. N-Alkylation of ammonium salts with ent gives rise to a new stereocenter in the product,thermore, the ther- the reactionfound can that be this performed one-pot with protocol a variety could of differ- be achieved at lyst (Scheme 6). Interestingly, this afforded exclusively the modynamically most stable isomer is usuallyent basespreferred. withoutprimary large andvariations secondary in reactivity alcohols has as previouslyshown by been carried 140 °C in aqueous3g solution. With 1,2-propylene glycol, the unsubstituted piperazine, which was isolated in 79% yield Interestingly, no notable difference in reactivityYamaguchi was ob- and co-workers.out in the absence of solvent with [Cp*IrCl2]2 as the precat- alyst.[22] Under these conditions, however, we observed no served when the reactions were conducted in toluene or Eur. J. Org. Chem. 2012, 6752–6759 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 6755 water. piperazine formation from ethylene glycol and ammoniumConclusion Piperazine formation can also be envisioned from sub- tetrafluoroborate. This may not be surprising, because the Both experimental and theoretical studies suggest a catalytic strates other than 1,2-diamines and 1,2-diols.Determination First, it was oflack theoretical of a substituent KIE may hinder the synthesis of the unsub- cycle where the intermediate aldehyde does not leave the cata- investigated whether a single primary amine could be used stituted piperazine. The transformation was therefore re- instead of a 1,2-diamine. Accordingly, the condensationIf we assume of thepeated C–H(D) with bond both is fully 2,3-butylene broken in glycol the transition and cyclohexane-1,2-lyst, but instead is attacked by the amine resulting in an iridium- benzylamine with ethylene glycol was studiedstate, under one should dif- diol. expect In a both KIE cases, of 4.5 a at mixture 110 °C of based three solely products on washemiaminal formed, intermediate (Scheme 5). This hemiaminal can then −1 ferent conditions in a closed vial (Scheme 2).the In differences toluene at inwhich stretching – according frequencies to (C GC–MS–H: 2900 analysis cm ,C – were–D: believeddehydrate to to the imine, which is subsequently reduced to the −1 36 140 °C the reaction only afforded a moderate2100 yield cm of 1,4-). Thebe the value corresponding obtained by piperazine, the competition pyrazine, exper- and morpholine.amine, both steps taking place without breaking the coordination dibenzylpiperazine (45 %). However, when theiment transforma- was significantlyThe reaction lower (2.48), with suggesting cyclohexane-1,2-diol that the C– wasH–D furtherto the opti- metal. The absence of conventional solution-phase imine tion was repeated at 160 °C in the absence ofbond a solvent indeed theis brokenmized, in but the it wasselectivity-determining not possible to obtain step, the but piperazineformation as may not have large implications for the model systems yield increased to 94% (Scheme 2). The highthat temperature there is signifithecant major stabilisation product. of Instead, the formed the hydride. morpholine With adductinvestigated could here, but can be important when extending the reac- was necessary under the neat conditions, becausethe calculated the trans- intermediatesbe isolated and in 63% transition yield when states the for condensation the reaction wastion carried to more complicated substrates. The increased understanding formation at 110 °C only afforded 30 % yieldsequence after 18 it is h. alsoout possible with to trifluoroacetic determine the KIE acid using in mesitylene transition atof 180 the °C mechanism will be valuable in order to further optimise Aniline was also examined as a substrate understate the theory. same For(Scheme the initial 4). Presumably,β-hydride this elimination transformation a full proceedsand byfine-tune a this catalyst system. conditions at 160 °C, but only trace amounts of 1,4-di- double alkylation of ammonia with the diol to form bis(2- phenylpiperazine were obtained in this case,This presumably journal is © Thehydroxycyclohexyl)amine, Royal Society of Chemistry which 2012 then cyclizes to the Org. Biomol. Chem., 2012, 10, 2569–2577 | 2575 due to the lower nucleophilicity compared to benzylamine. morpholine. The synthesis of morpholine derivatives from Two other diols were also studied in the reaction with ben- di(ethanol)amines has previously been described in the [23] zylamine. However, with both phenylethylene glycol and cy- presence of RuCl3 and PPh3. clohexane-1,2-diol the reaction stopped at the amino alcohol stage, and no dimerization to the corresponding symmetric piperazines were observed. This illustrates once more that the cyclization is hampered by additional substit- uents. Scheme 4. Synthesis of dodecahydro-1H-phenoxazine.

Ethanolamine is also a potential substrate that may form a piperazine with the iridium catalyst. It was quickly discov- ered that this reaction did not afford the parent piperazine, but instead two substituted analogues were generated. After Scheme 2. Synthesis of 1,4-dibenzylpiperazine. some optimization, 1-(2-hydroxyethyl)piperazine and 1,4- bis(2-hydroxyethyl)piperazine were isolated in 30 and 27 % yield, respectively (Scheme 5). The transformation required It may, however, be possible to use two different diols in a rather long reaction time for full conversion, and it was the reaction with benzylamine if one is ethylene glycol. To not possible to alter the ratio between the two products. avoid 1,4-dibenzylpiperazine formation the substituted diol The exact pathway leading to the substituted piperazines should first be allowed to react with 2 equiv. of benzyla- could not be identified, but 2-[(2-aminoethyl)amino]ethanol mine, and – upon completion of this reaction – ethylene might be a potential intermediate. To probe this question glycol should be added to the mixture (Scheme 3). It was the diamino alcohol was also subjected to the iridium cata- found that this one-pot protocol could be achieved at lyst (Scheme 6). Interestingly, this afforded exclusively the 140 °C in aqueous solution. With 1,2-propylene glycol, the unsubstituted piperazine, which was isolated in 79% yield

Eur. J. Org. Chem. 2012, 6752–6759 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 6755 . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

formation of four new C Nbonds resulting from ahydrogen- ˇ transfer annulation using neat conditions at 1608C [Eq. (7)].[18,19]

Impressed by the catalytic performance of the Cp*Ir complex in hydrogen-transfer N-alkylations,new ionic and

Published on Web 10/08/2010water-soluble Cp*Ir complexes having an amine ligand were synthesized for the N-alkylation of alcohols in aqueous Multialkylation of Aqueous Ammonia withmedium. AlcoholsNotably Catalyzed,the by1,5,9-nonanetriol was successfully Water-Soluble Cp*Ir-Ammine Complexes transformed into the N-bridged heterocycle quinolizidine 19 Ryoko Kawahara,† Ken-ichi Fujita,*,†,‡ and Ryohei Yamaguchi*,† using the water-soluble 18 as acatalyst and aqueous ammonia Graduate School of Human and EnVironmental Studies, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan, and [20] Graduate School of Global EnVironmental Studies, Kyoto UniasVersity,the Sakyo-ku,nitrogen Kyotosource 606-8501,[Eq. Japan(8)]. Theapplication of 18 was Received June 19, 2010; E-mail: [email protected]; [email protected]

Creatingcomplex having amminebetter ligands, Ir [Cp*Ir(NH catalysts) ][Cl] (1) in 94% Abstract: Novel water-soluble Cp*Ir ammine complexes have 3 3 2 - yield (eq 1). A similar procedure starting with [Cp*IrBr ] and been synthesized, and a new and highly atom-economical system 2 2 Scheme 3. Three-component tandem reaction for C3-functionalized [Cp*IrI ] also gave [Cp*Ir(NH ) ][X] (2:X) Br, 3:X) I) in for the synthesis of organic amines using aqueous ammonia as 2 2 3 3 2 91 and 87% yield, respectively (eq 1).15 The structures of 1-3 piperidines.CSA= d-(+)-camphor sulfonic acid. anitrogensourcehasbeendeveloped.Withawater-solubleand § Syntheticwere elucidated Challenge: by their spectroscopic use dataaqueous (see the Supporting ammonia as N-source, however [Ru] and air-stable Cp*Ir-ammine catalyst, [Cp*Ir(NH ) ][I] , a variety of 3 3 2 Information). The complexes 1-3 were highly soluble in water tertiary and secondary amines were synthesized by the multi- [Ir] catalysts have poor solubility in aqueous conditions and stable in air for months without decomposition. Single-crystal alkylation of aqueous ammonia with theoretical equivalents of X-ray analysis of 3 demonstrates that three ammine ligands are piperidine derivatives with high regio- and diastereoselective primary and secondary alcohols. The catalyst could be recycled attached to the iridium center, and its geometry could be described [22] by a facile procedure maintaining high activity. A one-flask control. synthesis of quinolizidine starting with 1,5,9-nonanetriol was also demonstrated. This new catalytic system would provide a practical and environmentally benign methodology for the synthesis of various organic amines. extended to the annulation reaction of diols with amines in 2.2. Annulation by Dehydrogenative Amide Formation

water and open to air. Thus,the reaction ofCOMMUNICATIONSbenzyl amine with Recently, much attention has been focused on the use of ammonia 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol provided Benzo-fused lactams,such as oxindoles,dihydroquinoli- § Sealed vessel as a nitrogen source for organic synthesis because of its abundance as a three-leggedthe five-, pianosix-, stool,and whichseven-membered is common in Cp*IrheterocIII yclic compounds nones,and tetrahydrobenzazepinonesReferences are found in many and low price.1 To date, there have been many reports on § complexes Works (see with Figure stoichiometric S1 in the Supporting NH3 & Information). scalable (1) (a) Roundhill, D. M. Chem. ReV. 1992, 92, 1. (b) Willis, M. C. Angew. homogeneous transition-metal-catalyzed systems for the synthesis § WithCan(20 a be series), recycledrespectively of new water-soluble ,ing Cp*Irood complexesyields1-3 [Eq.in (9)].Furthermore, natural products and drug candidatesChem., Int. Ed. 2007.E,co-benign46, 3402. and atom- of organic amines using gaseous (or liquid) ammonia2 and its hand, we next examined their catalytic activity for the N-alkylation (2) (a) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2e,3 N-benzyl morpholine was also derived successfully with the economical methods for the2001synthesis, 42, 3251. (b) Shen,of Q.;such Hartwig,heteroc J. F. J. Am.yclic Chem. Soc. 2006, 128, solution in an organic solvent. Aqueous ammonia must be even of aqueous ammonia (28%) with benzyl alcohol (4a)undervarious [21] 10028. (c) Lavallo, V.; Frey, G. D.; Donnadieu, B.; Soleihavoup, M.; more attractive as a substrate considering its advantages in terms conditions.aid Theof diethylene results are shownglycol in Tableas 1.the Thediol reactionprecursor of . compounds are highly desirableBertrand, G..FAngew.ujita Chem., Int.and Ed. 2008co-workers, 47, 5224. (d) Gunanathan, C.; of safety and handling. Some systems utilizing aqueous ammonia Milstein, D. Angew. Chem., Int. Ed. 2008, 47,8661.(e)Vo,G.D.;Hartwig, § Toleratedaqueous ammonia open with 4aairnever in occurslater in report the absence for of catalystother amines reported aCp*-based rhodiumJ. F. J. Am. Chem.complex Soc. 2009, 131in, 11049.acetone as as a substrate for the synthesis of organic amines, such as Rh- (entry 1). When the reaction of aqueous ammonia with 3 equiv of (3) (a) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354. (b) 4 Based on the mechanisms proposedaselective for the Cp*Ir-catalyzedcatalyst for thePouy,synthesis M. J.; Leitner,of A.; Weix,benzo-fused D. J.; Ueno, S.; Hartwig,five-, J. F. Org. Lett. catalyzed reductive amination of aldehydes, Rh- and Ir-catalyzed 4a was carried out at 140 °Cfor20hinthepresenceof[Cp*IrCl2]2 10 5 6 N-alkylation of amines, a plausible mechanism for the first 2007, 9, 3949. (c) Schulz, T.; Torborg, C.; Enthaler, S.; Scha¬ffner, B.; hydroaminomethylation of olefins, Pd-catalyzed allylic amination, (1.0 mol % Ir), tribenzylamine (5a) and dibenzylamine (6a) were six-, and seven-membered lactamsDumrath, A.;( Spannenberg,27), through A.; Neumann,adehydro- H.; Bo¬rner, A.; Beller, M. Pd-catalyzed telomerization with butadiene,7 Cu-catalyzed coupling monoalkylation cycle transiently affording primary amine is Chem.sEur. J. 2009, 15, 4528. obtained in low yields of 29% and 21%, respectively (entry 2). 19 8 9 depicted in Scheme 1. The secondgenative and thirdamide N-alkylationsformation to (4)reaction Gross, T.; Seayad,[Eq. A.(10)] M.; Ahmad,.T M.;he Beller,change M. Org. Lett.to 2002, 4, 2055. with aryl halides, and Cu-catalyzed coupling with aryl boronic acids, The reaction was considerably accelerated by using the water- (5) Zimmermann, B.; Herwig, J.; Beller, M. Angew. Chem., Int. Ed. 1999, 38, have been reported. However, most such systems require the employ- soluble catalysts (entries 3-5). When the reaction was carried out produce secondary and tertiary amines,other respectively,solvents would,s proceeduch as toluene2372.,resulted in the formation of ment of harmful organic halides as a reagent and/or the use of ammonia in the presence of 1 (1.0 mol % Ir), 5a (70%) and 6a (18%) were through similar sequential processes. (6) Nagano, T.; Kobayashi, S. J. Am. Chem. Soc. 2009, 131, 4200. 1,2,3,4-tetrahydroisoquinol(7)ine Prinz,(15 T.; Driessen-Ho)from¬lscher,3-(2-aminophenyl)- B. Chem.sEur. J. 1999, 5, 2069. in excess amounts. Thus, an environmentally benign catalytic system Scheme 1. A Plausible Mechanism for the N-Alkylation of Aqueous (8) (a) Kim, J.; Chang, S. Chem. Commun. 2008, 3052. (b) Wu, X.-F.; Darcel, Table 1. N-Alkylation of Aqueous Ammonia with Benzyl Alcohol C. Eur. J. Org. Chem. 2009,4753.(c)Xia,N.;Taillefer,M.Angew. Chem., that enables atom-economical synthesis of organic amines using a Ammonia withFujita an Alcohol & Yamaguchi. JACS 2010, 132, 15108. (4a) CatalyzedTh byree-component Cp*Ir Complexes undertandem Various Conditionsreactions for the construction 1-propanol, thus confirmingInt.that Ed. 2009acetone, 48, 337. (d)plays Wang, D.;ak Cai,ey Q.; Ding,role K.asAdV. Synth. Catal. aqueous ammonia has not been developed so far. Adv. Synth. Catal. 2011, 353, 1161. 2009, 351, 1722. (e) Wu, Z.; Jiang, Z.; Wu, D.; Xiang, H.; Zhou, X. Eur. Meanwhile, we have revealed the high catalytic performance of of C3-functionlized piperidines were developed and em- ahydrogen acceptor.Afive-memberedJ. Org. Chem. 2010, 1854.benzo-fused lactam, (9) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Amgew. Chem., Int. Ed. 2009, 48, Cp*Ir complexes in hydrogen transfer reactions and developed ployed easily accessible anilines,diols,and aldehydes and that is,oxindoles,were synthesized1114. in moderate to excellent catalytic systems for the N-alkylation of amines and ammonium (10) (a) Fujita, K.; Yamaguchi, R. Synlett 2005,560.(b)Fujita,K.;Yamaguchi, salts with alcohols.10-12 However, utilization of aqueous ammonia phosphanesulfonate-chelated iridium complex 21 (Scheme 3). yields with lower catalytic loadingR. In Iridium(3 Complexesmol%) in Organicin acetone Synthesis;Oro,L.A.,Claver,C.,Eds.;under yield (%)b [23] Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, Germany, 2009; as a nitrogen source in the N-alkylation with alcohols catalyzed by Thekey step is the endo dehydrogenation leading to C3- reflux for 8hours. Chapter 5, pp 107-143. (c) Fujita, K.; Li, Z.; Ozeki, N.; Yamaguchi, R. entry catalyst temp (°C) time (h) 5a 6a [Cp*IrCl2]2 has been most unsatisfactory (vide infra), probably Tetrahedron Lett. 2003, 44, 2687. (d) Fujita, K.; Fujii, T.; Yamaguchi, R. 13 functionalization of piperidines (26). Theoverall reaction Org. Lett. 2004, 6, 3525. (e) Fujita, K.; Enoki, Y.; Yamaguchi, R. because the catalyst is insoluble in aqueous conditions. Here, we 1 none 140 20 0 0 Tetrahedron 2008, 64, 1943. (f) Yamaguchi, R.; Kawagoe, S.; Asai, C.; report a synthesis of novel water-soluble Cp*Ir complexes having 2involves [Cp*IrCl2]double2 140N-alkylation 20 29of an 21 aniline with adiol and Fujita, K. Org. Lett. 2008, 10,181.(g)Yamaguchi,R.;Zhu,M.;Kawagoe, ammine ligands and their high catalytic performance in the 3 1 140 20 70 18 S.; Asai, C.; Fujita, K. Synthesis 2009, 1220. (h) Fujita, K.; Komatsubara, 4 2 140 20 49 23 A.; Yamaguchi, R. Tetrahedron 2009, 65, 3624. (i) Zhu, M.; Fujita, K.; 14 subsequent endo dehydrogenation of piperidine,thus ena- multialkylation of aqueous ammonia with alcohols. 5 3 140 20 82 7 Yamaguchi, R. Org. Lett. 2010, 12, 1336. First, we focused on preparing a new catalyst that is soluble and 6 3 120 20 79 6 (11) N-Alkylation reactions of amines with alcohols using ruthenium, iridium, bling ahighly regioselective C3-functionalization process. and other transition metals as catalyst have also been reported by other 7c 3 140 20 76 3 stable in water. Treatment of a suspension of [Cp*IrCl2]2 in research groups. (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; methanol with aqueous ammonia (28%) gave a new dicationic 8 When3 this three-component140 24reaction 100 0 is run in the presence of Tongpenyai, N. J. Chem. Soc., Chem. Commun. 1981, 611. (b) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. ReV. 1998, 98, 2599, and references a the ruthenium complex 22 the N-alkylated compound 23 is The reaction was carried out with NH3 (1.0 mmol, 28% aqueous The superiority of catalyst 3 having iodide (I-)asacounteranion cited therein. (c) Hollmann, D.; Tillack, A.; Michalik, D.; Jackstell, R.; † Graduate School of Human and Environmental Studies. solution), Cp*Ir catalyst (1.0 mol % Ir), and benzyl alcohol (4a, 3.0 Beller, M. Chem. Asian J. 2007, 2, 403. (d) Hamid, M. H. S. A.; Williams, ‡ Graduate School of Global Environmental Studies. mmol).theb Determinedmajor by GC.product.c Catalyst 3 (0.50Other mol %commercially Ir) was used. amongavailable the water-solublecatalysts catalysts 1-3 could be attributed to the J. M. J. Tetrahedron Lett. 2007, 48, 8263. (e) Tillack, A.; Hollmann, D.; differences of activities for the hydrogenation of the iminic Mevius, K.; Michalik, D.; Ba¬hn, S.; Beller, M. Eur. J. Org. Chem. 2008, p 4745. (f) Balcells, D.; Nova, A.; Clot, E.; Gnanamgari, D.; Crabtree, R. H.; 15108 9 J. AM. CHEM. SOC. 2010, 132, 15108Ð15111 such as [{Ru(10.1021/ja107274w-cymene)Cl© 2010 American2}2 Chemical]and Society[{Cp*IrCl2}2]were not Milstein and co-workers developed well-defined pyridine- intermediate. When the transfer hydrogenations of N-benzylideneben-II Eisenstein, O. Organometallics 2008, 27, 2529. (g) Hamid, M. H. S. A.; effective for the above reaction. Based on zylaminethe overall (11)werecarriedoutinthepresenceofcatalytic based PNN/Ru1-3 as catalysts,pincer complexAllen, C. L.;for Lamb,the G.direct W.; Maxwell,synthesis A. C.; Maytum,of H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766. (h) Blank, the highest yield of the dibenzylamine (6a) was obtained in the B.; Michlik, S.; Kempe, R. Chem.sEur. J. 2009, 15,3790.(i)Nixon,T.D.; cycle, 21 is the sole catalyst for the N- and C-alkylation amides from alcohols and amines with the release of H2,thus reaction using 3 (eq 4). There have been many examples that iodide Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009, 753, and process which results from two C Nand one C Cbond- enabling base-free,additive-freereferences,a citednd therein.acceptorless (j) Dobereiner, G. E.; Crabtree,amide R. H. Chem. ReV. ˇ often exhibitsˇ a positive effect in the transition-metal-catalyzed 2010, 110,681,andreferencescitedtherein.(k)Guillena,G.;Ramo«n, D. J.; hydrogenation of imines.20 [9b] Yus, M. Chem. ReV. 2010, 110, 1611, and references cited therein. forming hydrogen transfer in asingle operation. Substituted formation. b-amino alcohols(12) N-Alkylationwere of amineseffectively with alcohols orconverted diols in aqueous media catalyzed by Cp*Ir complexes has been reported by Madsen and Williams, diols were also successfully converted into the corresponding into the cyclic dipeptides 29respectively.in the However,presence none ofof the reactionthe dearom- using ammonia as a nitrogen source was reported in these publications. (a) Nordstr¿m, L. U.; Madsen, R. Chem. Commun. 2007,5034.(b)Saidi,O.;Blacker,A.J.;Farah,M.M.; Marsden, S. P.; Williams, J. M. J. Chem. Commun. 2010, 1541. (c) Saidi, 11026 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim AngewO.; Blacker,.Chem. A. J.;Int. Lamb,Ed. G.2015 W.; Marsden,, 54,11022 S. P.;–1 Taylor,1034 J. E.; Williams, J. M. J. Org. Process Res. DeV. 2010, 14, 1046. (13) Reductive amination of R-keto acids with aqueous ammonia leading to R-amino acids catalyzed by a Cp*Ir complex has been reported by Ogo In summary, novel water-soluble Cp*Ir-ammine complexes have and Fukuzumi et al. Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi, S. J. Am. been synthesized and a new and highly atom-economical system Chem. Soc. 2004, 126, 3020. (14) Very recently, Mizuno et al. reported an efficient system for the synthesis for the synthesis of organic amines using aqueous ammonia as a of tertiary and secondary amines by the reaction of alcohols with urea, nitrogen source has been developed. With a water-soluble and air- aqueous ammonia, or ammonium salt catalyzed by ruthenium hydroxide supported on titanium dioxide in organic solvent. (a) He, J.; Kim, J. W.; stable Cp*Ir-ammine catalyst, [Cp*Ir(NH3)3][I]2 (3), a variety of Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009, 48, 9888. (b) tertiary and secondary amines were synthesized by the multialkyl- Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem.sEur. J. 2010, 16, ation of aqueous ammonia with theoretical equivalents of primary 7199. (15) The Cp*Ir monoammine complex, Cp*Ir(NH3)I2, has previously been and secondary alcohols. A one-flask synthesis of quinolizidine reported by Blacker et al. Blacker, A. J.; Brown, S.; Cligue, B.; Gourlay, B.; Headley, C. E.; Ingham, S.; Ritson, D.; Screen, T.; Stirling, M. J.; Taylor, starting with triol was also demonstrated. This new catalytic system D.; Thompson, G. Org. Process Res. DeV. 2009, 13, 1370. would provide a practical and environmentally benign methodology (16) There are several examples of the transition-metal-catalyzed multialkylation of ammonia equivalent (aqueous ammonia, ammonium salt, and urea) with for the synthesis of various organic amines. alcohols (refs 10f, 11d, 14a, and 14b and this work). A summary and comparison of these catalytic systems are shown in Table S1 in the Acknowledgment. This research was supported financially in Supporting Information. See also ruthenium-catalyzed monoalkylation of part by the Mitsubishi Chemical Corporation Fund. We also thank ammonia with alcohol (ref 2d). (17) Secondary amines were selectively obtained even in the reactions using Johnson Matthey, Inc., for a generous loan of iridium trichloride. excess amounts of the secondary alcohol. (18) The synthesis of quinolizidines usually requires noncatalytic multistep Supporting Information Available: Experimental procedures, reactions. (a) Comins, D. L.; O’Connor, S. Tetrahedron Lett. 1987, 28, 1843. (b) Ojima, I.; Iula, D. M.; Tzamarioudaki, M. Tetrahedron Lett. 1998, characterization data of the products, and X-ray data for 3.Thismaterial 39, 4599. (c) Tehrani, K. A.; D’hooghe, M.; De Kimpe, N. Tetrahedron is available free of charge via the Internet at http://pubs.acs.org. 2003, 59, 3099.

15110 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 Angewandte Chemie

Table 1: Tandem N,N,C-trialkylation reaction from aniline 2a.[a] phosphinesulfonate ligand with an Ir O bond of 2.140 ß.[17] ß The catalyst B was successfully involved in the tandem process under the reaction conditions used for A, thus affording the trialkylated amine 7a as the major product (entries 4–7). This result demonstrated that B was active for the base-free N,N-dialkylation of 2a with 3a to give 6, and that catalytic activity was maintained for the oxidant-free direct dehydrogenation of 6, thus leading to a reactive [c] Entry Catalyst Conc. 2a/3a/4a 5/6/7a Yield nucleophilic enamine. It is noteworthy that [{IrCl Cp*} ] [m][b] 7a[%][d] 2 2 was totally inactive toward C alkylation but led to 5 as a major 1 [{Ru(p-cymene)Cl2}2] 0.6 1.1:1:1.2 1:0:0 n.d. compound (entry 3). With B, increasing the concentration 2 A 0.6 1.1:1:1.2 7:83:10 5 resulted in lower conversion and higher relative amount of 6, 3 [{Ir(Cp*)Cl } ] 0.6 1.1:1:1.2 82:13:5 1 2 2 and the best result was obtained at 0.4m (entries 4 and 5). A 4 B 0.9 1.1:1:1 3:45:52 42 5 B 0.4 1.1:1:1 4:33:63 50 slight excess of 4a ensured better selectivity for 7a (entry 6). 6 B 0.6 1:1:1.2 1:22:77 50 Finally, the presence of 1 mol% of camphorsulfonic acid 7 B 0.4 1.2:1.1:1 3:27:70 58 (CSA) as a Brønsted acid was required to reach complete 8[e] B 0.4 1:1:1.1 2:10:88 70(55) conversion and optimized reaction conditions, which afforded [a] All reactions were carried in toluene. Step 1 was run for 16 h, step 2 a 70% yield of compound 7a as determined by GC analysis for 19h, and step 3 for 2 h under inert an atmosphere using (entry 8). The tedious separation of the piperidines 7a and 6 a thermostated oil bath (1508C). [b] Molar concentration of the limiting by column chromatography using silica gel led to the isolation substrate; see column 4. [c] Ratio of the products. [d] Yield of 7a of pure 7a in 55% yield. determined by GC analysis using tetradecane as an internal standard. The overall transformation corresponds to three dehy- Value in parentheses is the yield of the isolated product. [e] 1 mol% of drogenation and three hydrogenation steps, thus six formal CSA was added in step 2. n.d. = not determined. catalytic hydrogen-transfer processes, and also two conden- sations of the intermediate aldehyde with aniline and one condensation reaction between an enamine and an aldehyde. for 16 hours, and after cooling benzaldehyde (4a) was added If we assume that the organic reactions proceed quantita- and the reaction was heated for an additional 19 hours at tively, each individual catalytic step presents an excellent 1508C (Table 1). Based on our previous results obtained with yield (> 90%). These results show that only one organome- ruthenium catalysts for C3 functionalization of cyclic amines tallic precatalyst is sufficient for the overall transformation. with aldehydes, formic acid was added as a reducing agent at Moreover, the reaction allows the first oxidant-free direct Angewandte. the last stage (step 3; 1508C for 2 h) of the procedure to endo dehydrogenation of the cyclic saturated 6, and does not Communications ensure complete reduction of the unsaturated intermediates. require more-reactive substrates (i.e. containing activated The expected formation of 3-benzyl-N-phenylpiperidine (7a) benzylic positions as in N-benzyl amines or tetrahydroisoqui- [14] for the formation of 6. In contrast, the reaction with B was undergo dehydrogenation or hydrolysis and reaction withwas observed, but N-benzylaniline (5) and N-phenylpiper- nolines), for dehydrogenation and thus highlights the more efficient and quantitative formation of 6 was obtained piperonal led to 49% of 7h. As previously observed withidine the (6) were also detected. The {ruthenium(II)(p-cymene)} improved activity of this new iridium precatalyst B. within 16 hours. These results clearly demonstrate that A is an ruthenium catalytic systems we used for C3 alkylationdimer of did not afford the C-alkylated piperidine 7a but the To clarify the difference of reactivity between the efficient. catalyst for mono N alkylation of aniline with diols, cyclic amines, no dehalogenation occurred with halogenatedpresence of 5, arising from N-alkylation of 2a by 4a, was ruthenium catalyst A and the iridium catalyst B, their Angewandteand explains why the formation of 7a could not take place aromatic aldehydes and the alkylated anilines 7jand 7kwere Communications observed as the main product (entry 1). Surprisingly, our efficiencies in the first step were evaluated. Thus, 2a was efficiently with this catalyst precursor. obtained in 53 and 54% yield, respectively. The electron-richpreviously reported ruthenium(II) catalyst A, which exhib- reacted with 3a in the presence of 3 mol% of catalyst A at With our optimized reaction conditions in hand (Table 1, anilines 2b,c, substituted by a methyl or a methoxy group, ited a high efficiency for N or C alkylation of N-benzylpiper- 1508C for 16 hours. A 50% conversion of 2a into the forentry the 8),formation we next of 6 investigated. In contrast, the the scope reaction of with thisB tandemwas undergoafforded dehydrogenation the products 7l,m orin hydrolysis 54 and 49% and yield, reaction respectively. with idine, showed very low activity for the tandem protocol, thus monoalkylated amine 8 as the major product was observed moretransformation efficient and quantitative(Scheme 4). formation The reactions of 6 was obtained proceeded piperonalFinally, the led aliphaticto 49% of formylcyclohexane7h. As previously4i observedwas also with reactive the withinsmoothly 16 hours. from These a variety results of clearly aromatic demonstrate aldehydes that (4b–Ae),is anthus rutheniumand gave catalytic7i in 47% systems yield. The we used tandem for process C3 alkylation can alsoaffording of be less than 50% conversion of the diol 3aand leading (Scheme 3). Addition of 4a, which also acts as hydrogen efficientaffording catalyst the N,N,C-trialkylated for mono N alkylation products of aniline7b–e in with yields diols, of up cyclicapplied amines, to substituted no dehalogenation pentan-1,5-diols occurred (Schemes with halogenated 5 andmainly 6). to the piperidine derivative 6 and only 5% of 7a acceptor, to this mixture enhanced only the cyclization rate and explains why the formation of 7a could not take place aromatic aldehydes and the alkylated anilines 7jand 7kwere(entry 2). We then investigated the reactivity of the new efficiently with this catalyst precursor. obtained in 53 and 54% yield, respectively. The electron-richiridium(III) complex featuring the chelating phosphane With our optimized reaction conditions in hand (Table 1, anilines 2b,c, substituted by a methyl or a methoxy group,sulfonate. The complex B was obtained in good yield upon entry 8), we next investigated the scope of this tandem afforded the products 7l,m in 54 and 49% yield, respectively.treatment of the deprotonated diphenylphosphinobenzene transformation (Scheme 4). The reactions proceeded Finally, the aliphatic formylcyclohexane 4i was also reactive sulfonic acid 1 with the cyclopentadienyl dichloride iridium- smoothly from a variety of aromatic aldehydes (4b–e), thus and gave 7i in 47% yield. The tandem process can also be affording the N,N,C-trialkylated products 7b–e in yields of up applied to substituted pentan-1,5-diols (Schemes 5 and 6).(III) dimer (Scheme 2). The solid-state structure of B Creating better Ir catalystsrevealed a piano-stool geometry around the iridium center and a six-membered ring arising from the chelation of the

Scheme 3. Monoalkylation of 2a using the catalyst A versus dialkyla- Scheme 2. Preparation of the catalyst B. tion with the catalyst B.

Angew. Chem.§ P,O-ligand Int. Ed. 2012, 51, 8876 found –8880 to facilitateß C3-2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 8877 alkylation of piperidines with Ir § Ru cat. Has no C3-alkylation Scheme 5. 3,5-disubstituted piperidines made by the tandem N,N,C3- § Ru(cymene) or Cp*Ir catalysts alkylation reactions. The yield is that for the product 7 (3 steps) isolated by column chromatography. All reactions were carried in also failed

toluene with 2/3b/4/B/HCO2H in a 1:1:1.1:0.03:2 molar ratio. Step 1 was run for 16 h, step 2 for 20h, and step 3 for 2 h under inert an atmosphere using a thermostated oil bath (1508C). § Have much larger table with unsubstituted diols Scheme 5. 3,5-disubstituted piperidines made by the tandem N,N,C3- alkylation reactions. The yield is that for the product 7 (3 steps) isolated by column chromatography. All reactions were carried in

toluene with 2/3b/4/B/HCO2H in a 1:1:1.1:0.03:2 molar ratio. Step 1 was run for 16 h, step 2 for 20h, and step 3 for 2 h under inert an Scheme 4. Scope of the direct, tandem trialkylation. The yield is that atmosphere using a thermostated oil bath (1508C). for the isolated product 7 (3 steps) after purification by column chromatography. All reactions were carried in toluene with 2/3a/4/B/

HCO2H in a 1:1:1.1:0.03:2 molar ratio. Step 1 was run for 16 h, step 2 for 20h, and step 3 for 2 h under inert an atmosphere using Bruneau et al. ACIE 2012, 51, 8876. a thermostated oil bath (1508C). Scheme 6. Regioselective formation of 2,5-disubstituted piperidine 7t

Schemeto 59% 4. Scope after of purification the direct, tandem by column trialkylation. chromatography. The yield is that Inter- The treatment of 3b with 2a and subsequent reaction with forestingly, the isolated the product dimethylamino7 (3 steps) group after purification of 7d remained by column intact and various aldehydes afforded a better yield as compared to chromatography. All reactions were carried in toluene with 2/3a/4/B/ no dealkylation/alkylation[7b] processes occurred under our those obtained from 3a (Scheme 5). The formation of two HCO2H in a 1:1:1.1:0.03:2 molar ratio. Step 1 was run for 16 h, step 2 forreaction 20h, and conditions, step 3 for 2 h thus under leading inert an atmosphereto 7d in 50% using yield upon diastereoisomers resulting from the reduction of the enamine/ a thermostatedpurification. oil The bath more (1508 challengingC). heteroaromatic aldehydes Schemeiminium 6. Regioselective intermediates formation by the of 2,5-disubstituted iridium hydride piperidine species7t was were compatible with the experimental conditions and the observed. Diastereoselectivities of up to 3:2 were obtained best yield, 66%, was obtained for compound 7g having a 2- even in refluxing toluene when less-hindered, unsubstituted tothiophene 59% after carboxaldehyde.purification by column The chromatography.acetal moiety did Inter- not Thebenzaldehyde treatment of and3b thiophenewith 2a and carboxaldehyde subsequent werereaction used, with thus estingly, the dimethylamino group of 7d remained intact and various aldehydes afforded a better yield as compared to [7b] 8878 nowww.angewandte.org dealkylation/alkylation processesß 2012 occurred Wiley-VCH under Verlag GmbH our &those Co. KGaA, obtained Weinheim from 3a (SchemeAngew. 5). Chem. The Int. formation Ed. 2012, 51, of8876 two –8880 reaction conditions, thus leading to 7d in 50% yield upon diastereoisomers resulting from the reduction of the enamine/ purification. The more challenging heteroaromatic aldehydes iminium intermediates by the iridium hydride species was were compatible with the experimental conditions and the observed. Diastereoselectivities of up to 3:2 were obtained best yield, 66%, was obtained for compound 7g having a 2- even in refluxing toluene when less-hindered, unsubstituted thiophene carboxaldehyde. The acetal moiety did not benzaldehyde and thiophene carboxaldehyde were used, thus

8878 www.angewandte.org ß 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012, 51, 8876 –8880 Dehydrogenative Amide Formation

§ Dehydrogenative amide formation from alcohols and amines § Applicable for Amide/peptide bonds § Usual formation occurs through activation of acid derivatives or acid/base rearrangement reactions

§ Development of acceptorless dehydrogenative amide formation with . Angewandteliberation of H2 as byproduct à gas extrusion (capture) drives reaction A. Nandakumar,E.Balaraman et al. Minireviews

asingle operation, thus enabling environmentally benign and efficient protocols.

2.1. Annulation by N-Alkylation of Amines by Alcohols

Saturated nitrogen-containing heterocyclic scaffolds are found in many natural products and biologically important compounds.The first example of the N-alkylation of an amine Figure 2. Dehydrogenative amide formation from alcohols and amines. by an alcohol through ahydrogen-transfer annulation was reported by Grigg et al. in 1981. Thus pyrrolidines were formed by the intramolecular reaction of N-substituted

4-aminobutan-1-ols in the presence of 5mol%[RhH(PPh3)4] as the catalyst in boiling 1,4-dioxane.The cascade reaction consists of dehydrogenative oxidation of the alcohol to an aldehyde,imine formation with an amine,and hydrogenative reduction of the imine to afford the N-substituted pyrroli- dines 1a and 1b in 56 and 82%yields,respectively [Eq. (1)]. Similar catalytic conditions were used to synthesize 1bby the amination of butane-1,4-diol with benzylamine in aratio of Figure 3. Dehydrogenative coupling of alcohols with nucleophiles. 10:1 to yield 1b in 31%[Eq. (2)].[12]

1.4. Oxidative Cyclization of Alcohols

Transition-metal-catalyzed dehydrogenative coupling of alcohols with various nucleophilic partners has resulted in the formation of C X(C, N, and O) bonds with the liberation of ˇ [9] H2 and H2Oasby-products (Figure 3). Inter-and intra- molecular hydrogen-transfer annulations of alcohols with various coupling partners enable the formation of function- alized saturated and aromatic heterocyclic compounds.This methodology has provided direct and rapid access to avariety of heterocyclic frameworks.

Direct coupling of adiol with an amine through aborrow- 1.5. Annulation of Unsaturated Systems (Alkenes and Alkynes) ing-hydrogen strategy is the most promising protocol for the construction of N-heterocyclic compounds since diol deriva-

Unsaturated systems such as alkenes and alkynes are tives can be easily accessed. [{Ru(p-cymene)Cl2}2]combined important building blocks in the chemical sciences.Their with the bidendate DPEphos ligand provided access to utility in organic synthesis have increased because of the saturated five-, six-, and seven-membered N-heterocyclic development of newer synthetic methodologies based on compounds by the N-alkylation of diols with amines [Eq. (3); transition-metal catalysts.[10] Transition-metal-catalyzed hy- drogen-transfer annulations of these building blocks provide novel heterocyclic frameworks.[11]

2. Synthesis of N-Heterocycles

Nitrogen-containing heterocycles are omnipresent in DPEphos = bis(2-diphenylphosphinophenyl)ether].Thus, nature and biologically active compounds,including nucleo- 1,4-butanediol reacted with various anilines and aliphatic bases within RNA, DNA, nucleotides,nucleosides,and amines to provide N-substituted pyrrolidines in the presence haemoglobin. They also have applications in avariety of of trimethylamine as an additive in refluxing toluene.Other fields such as agrochemicals and pharmaceuticals,aswell as in diols such as 1,5-pentanediol and 1,6-hexanediol were also the preparation of foods,dyes,detergents,and surfactants.[1] converted into the corresponding N-substituted piperidine Hence,there is aplethora of methods for the preparation of and azepane derivatives under similar catalytic conditions.[13] novel nitrogen-based heterocycles for various applications. Significantly,Enyong et al. used the simple,inexpensive,and Transition-metal-catalyzed hydrogen-transfer annulations readily accessible (S)-2-hydroxy-N,3-diphenylpropanamide

have provided aplatform to synthesize the basic skeletons (3)ligand in combination with [{Ru(p-cymene)Cl2}2]for the for complex nitrogen-containing heterocyclic compounds in N-alkylation of diols with aliphatic amines under mild

11024 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews formation of four new C Nbonds resulting from ahydrogen- ˇ transfer annulation using neat conditions at 1608C [Eq. (7)].[18,19]

Impressed by the catalytic performance of the Cp*Ir complex in hydrogen-transfer N-alkylations,new ionic and water-soluble Cp*Ir complexes having an amine ligand were synthesized for the N-alkylation of alcohols in aqueous medium. Notably,the 1,5,9-nonanetriol was successfully transformed into the N-bridged heterocycle quinolizidine 19 using the water-soluble 18 as acatalyst and aqueous ammonia as the nitrogen source [Eq. (8)].[20] Theapplication of 18 was

Scheme 3. Three-component tandem reaction for C3-functionalized piperidines.CSA= d-(+)-camphor sulfonic acid.

piperidine derivatives with high regio- and diastereoselective control.[22] extended to the annulation reaction of diols with amines in 2.2. Annulation by Dehydrogenative Amide Formation water and open to air. Thus,the reaction of benzyl amine with 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol provided Benzo-fused lactams,such as oxindoles,dihydroquinoli- the five-, six-, and seven-membered heterocyclic compounds nones,and tetrahydrobenzazepinones are found in many (20), respectively,ingood yields [Eq. (9)].Furthermore, natural products and drug candidates.Eco-benign and atom- N-benzyl morpholine was also derived successfully with the economical methods for the synthesis of such heterocyclic aid of diethylene glycol as the diol precursor.[21] compounds are highly desirable.Fujita and co-workers reported aCp*-based rhodium complex in acetone as aselective catalyst for the synthesis of benzo-fused five-, six-, and seven-membered lactams (27), through adehydro- genative amide formation reaction [Eq. (10)].The change to other solvents,such as toluene,resulted in the formation of 1,2,3,4-tetrahydroisoquinoline (15)from 3-(2-aminophenyl)- Three-component tandem reactions for the construction 1-propanol, thus confirming that acetone plays akey role as of C3-functionlized piperidines were developed and em- ahydrogen acceptor.Afive-membered benzo-fused lactam, ployed easily accessible anilines,dDehydrogenativeiols,and aldehydes and that Amideis,oxindoles,w Formationere synthesized in moderate to excellent phosphanesulfonate-chelated iridium complex 21 (Scheme 3). yields with lower catalytic loading (3 mol%) in acetone under endo [23] Thekey step is the dehydrogenation§ 2004 -leading Benzoto-fusedC3- five,reflux size,for 8h andours .seven membered lactams functionalization of piperidines (26). Theoverall reaction involves double N-alkylation of an aniline with adiol and subsequent endo dehydrogenation of piperidine,thus ena- bling ahighly regioselective C3-functionalization process. When this three-component reaction is run in the presence of the ruthenium complex 22 the N-alkylated compound 23 is the major product. Other commercially available catalysts such as [{Ru(p-cymene)Cl2}2]and [{Cp*IrCl§ When2}2]w usingere othernot solvents,Milstein majorand co-workersproduct isdeveloped cyclized well-definedamines (notpyridine- amide) – showing effective for the above reaction. Based on theacetoneoverall catalyticis key for hydrogenbased PNN/Ru acceptingII pincer complex for the direct synthesis of cycle, 21 is the sole catalyst for the N- and C-alkylation amides from alcohols and amines with theFujitarelease & Yamaguchiof H2,t. Org.hus Lett. 2004, 6, 2785. process which results from two C Nand one C Cbond- enabling base-free,additive-free,and acceptorless amide ˇ ˇ forming hydrogen transfer in asingle operation. Substituted formation.[9b] b-amino alcohols were effectively converted diols were also successfully converted into the corresponding into the cyclic dipeptides 29 in the presence of the dearom-

11026 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Dehydrogenative Amide Formation

§ Mechanism

Scheme 1

g)bearingasubstituentonthearomaticringwereconverted moderate (63%) even with a higher catalyst loading (9.8% into the corresponding 3,4-dihydro-2(1H)-quinolinones (2b- Rh) (entry 6). It should be noted that the present catalytic g)inmoderatetoexcellentyields,respectively(entries2-7). system was applicable to the synthesis of 1,3,4,5-tetrahydro- With substrates bearing an electron-withdrawing substituent 2H-1-benzazepin-2-one (2h) using 4-(2-aminophenyl)-1- Fujita & Yamaguchi. Org. Lett. 2004, 6, 2785. (Cl, CO2Me, and COMe), the yields of the products were butanol (1h) as a starting material (entry 8). excellent (entries 2-4). In the case of the substrate 1e bearing Synthesis of five-membered benzo-fused lactams (oxin- a CN substituent, the yield of the product 2e was relatively doles) was also examined. The results are summarized in low (71%) even with a longer reaction time (30 h), which is Table 3. 2-Aminophenethyl alcohols (3a-d) bearing a possibly due to the deactivation of the catalyst by the substituent on the aromatic ring, the methylene chain, and coordination of CN substituent to the rhodium center (entry the nitrogen atom were converted into the corresponding 5). In the case of the substrate 1f bearing the electron- oxindoles (4a-d) in moderate to high yields, respectively. donating OMe substituent, the yield of the product 2f was In contrast to the synthesis of dihydroquinolinones and tetrahydrobenzazepinone, the synthesis of oxindoles could be carried out at a lower temperature (acetone reflux) with a lower catalyst loading (3.0% Rh). Reaction of 2-ami- Table 3. Synthesis of Oxindoles from Amino Alcohols a nophenethyl alcohol (3a)inthepresenceof[Cp*RhCl2]2 Catalyzed by the [Cp*RhCl2]2/K2CO3 System (3.0% Rh) and K2CO3 (10%) in acetone (20 mL) under reflux for 8 h gave oxindole (4a) in 74% yield (entry 1). In this reaction, a small amount of indole (10%) was also formed. Reaction of 2-(2-aminophenyl)-1-propanol (3b)gave3-me- thyloxindole (4b) in good yield (80%) (entry 2). Oxindoles bearing a substituent at the aromatic ring or the nitrogen atom could be also synthesized; however, the yields were relatively low (entries 3 and 4). Although the mechanism for the present reaction is not completely clear yet, a possible one is shown in Scheme 1.12 The first step of the reaction would involve the coordination of amino alcohol to the rhodium center to give an intermedi- ate A. Then, ß-hydrogen elimination would occur to give

(10) Ruthenium-catalyzed oxidative N-heterocyclizations of amino al- cohols to lactams have been reported. In these reactions, a higher reaction temperature (140 °C) and addition of excess benzalacetone as a hydrogen a Reaction was carried under reflux for8hwithaminoalcohol(1.0 acceptor are required, and applicable amino alcohols are highly restricted. b mmol), [Cp*RhCl2]2,andK2CO3 (10%) in acetone (20 mL). Isolated yield. Naota, T.; Murahashi, S.-I. Synlett 1991, 693. c Reaction was carried out in 0.50 mmol scale. d Reaction time was 20 h. (11) Reaction of 1a (0.50 mmol) at 100 °C for 20 h in the presence of [Cp*IrCl2]2 (0.0127 mmol, 5.1% Ir) and K2CO3 (0.050 mmol, 10%) in acetone (12.5 mL) gave 2a in 59% yield.

Org. Lett., Vol. 6, No. 16, 2004 2787 . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews formation of four new C Nbonds resulting from ahydrogen- ˇ transfer annulation using neat conditions at 1608C [Eq. (7)].[18,19]

Impressed by the catalytic performance of the Cp*Ir complex in hydrogen-transfer N-alkylations,new ionic and water-soluble Cp*Ir complexes having an amine ligand were synthesized for the N-alkylation of alcohols in aqueous medium. Notably,the 1,5,9-nonanetriol was successfully transformed into the N-bridged heterocycle quinolizidine 19 using the water-soluble 18 as acatalyst and aqueous ammonia as the nitrogen source [Eq. (8)].[20] Theapplication of 18 was

Scheme 3. Three-component tandem reaction for C3-functionalized piperidines.CSA= d-(+)-camphor sulfonic acid.

piperidine derivatives with high regio- and diastereoselective control.[22]

REPORTS extended to the annulation reaction of4.diols L. J. Richter,with T. P. Petralli-Mallow,amines J. P.in Stephenson,2.2. Annulation13. J. E. Patterson, A.by S. Lagutchev,Dehydrogenative W. Huang, D. D. Dlott, AmidereflectanceFo measurementsrmation were carried out in the Opt. Lett. 23, 1594 (1998). Phys. Rev. Lett. 94, 015501 (2005). Frederick Seitz Materials Research Laboratory Central water and open to air. Thus,the reaction5.of A. S.benzyl Lagutchev, J. E.amine Patterson, W.with Huang, D. D. Dlott, 14. H. K. Lyeo, D. G. Cahill, Phys. Rev. B 73, 144301 Facilities, University of Illinois, which are partially J. Phys. Chem. B 109, 5033 (2005). (2006). supported by the DOE under grant DEFG02-91-ER45439. 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol6. S. D. Brorson, J. G. Fujimoto,provided E. P. Ippen, Phys. Rev. Lett. Benzo-fused15. Z. Ge, D. G. Cahill, P.lactams V. Braun, J. Phys.,s Chem.uch B 108as, oxindolesD.D.D. acknowledges,dihydroquinoli- additional support from the 59, 1962 (1987). 18870 (2004). National Science Foundation under award DMR 0504038 the five-, six-, and seven-membered heteroc7. D. G. Cahill,yclicRev. Sci.compounds Instrum. 75, 5119 (2004). nones16.,a Z. B.nd Ge, D. G.tetrahydrobenzazepinones Cahill, P. V. Braun, Phys. Rev. Lett. 96, and fromare the Air Forcefound Office of Scientificin many Research under 8. C. D. Bain, P. B. Davies, T. H. Ong, R. N. Ward, Langmuir 186101 (2006). award FA9550-06-1-0235. (20), respectively,ingood yields [Eq.7,(9)] 1563 (1991)..Furthermore, natural17. R.products Y. Wang, R. A. Segalman,and A. Majumdar,drug Appl.candidates Phys. .Eco-benign and atom- 9. N. Nishida, M. Hara, H. Sasabe, K. Wolfgang, Jpn. J. Lett. 89, 173113 (2006). Supporting Online Material N-benzyl morpholine was also derived successfullyAppl. Phys. 35, 5866 (1996).with the economical18. S. Chen, M. T.methods Seidel, A. H. Zewail,forAngew.the Chem. Int.synthesis Ed. www.sciencemag.org/cgi/content/full/317/5839/787/DC1of such heterocyclic 10. H. Kondoh,[2 C.1] Kodama, H. Sumida, H. Nozoye, J. Chem. 45, 5154 (2006). Materials and Methods aid of diethylene glycol as the diol precursorPhys. 111., 1175 (1999). compounds19. This material isare based uponhighly work supporteddesirable by the U.S. SOM.F Textujita and co-workers 11. C. D. Bain et al., J. Am. Chem. Soc. 111, 321 Department of Energy (DOE), Division of Materials References (1989). reportedSciencesaC under awardp*-based DEFG02-91ER45439,rhodium through the complex in acetone as REPORTS 12. J. E. Patterson, D. D. Dlott, J. Phys. Chem. B 109, 5045 Frederick Seitz Materials Research Laboratory at the 16 May 2007; accepted 27 June 2007 (2005). aseconomyelective andUniversity no stoichiometric ofcatalyst Illinois at Urbana-Champaign.for activatingthe Thermal agents,synthesis(valuable10.1126/science.1145220of inbenzo-fused itself) will shift thefive-, equilibrium and butylphosphinomethyl)pyridine (PNP)–Ru(II) six-,generatingand noseven-membered waste. Although such a reactionlactams is drive(27 the), reaction.through adehydro- and PNN-Ru(II) hydride complexes (19). Where- expected to be thermodynamically uphill, it is We recently reported the dehydrogenation as secondary alcohols lead to ketones (20, 21), genativeenvisioned thatamide the liberatedformation hydrogenreaction gas of[Eq. alcohols(10)] catalyzed.The change by 2,6-bis-(di-to tert- primary alcohols are efficiently converted into other solvents,such as toluene,resultedon activatedin acidthe derivativesformation (acid chloridesof and esters and dihydrogen (19–21). The dearoma- Direct Synthesis of Amides anhydrides) or rearrangement reactions induced tized PNN pincer complex 1 (Fig. 1) is particu- 1,2,3,4-tetrahydroisoquinolTable 1. Direct dehydrogenative acylationine of amines(15)f withrom alcohols3-(2-aminophenyl)- catalyzed by the ruthenium complex 1.Catalyst1 (0.01 mmol), alcohol (10 mmol), amineby (10 an acid mmol), or base, and which toluene often (3 produce ml) were toxic refluxed larly efficient (19, 22); it catalyzes this process chemical waste and involve tedious procedures Three-component tandem reactionsfromfor the Alcoholsconstruction and1-propanol,under Amines Ar flow (33thus). Conversionconfirming of alcoholsthat was 100%acetone [by gasplays chromatographyakey role (GC) analysis].as The in high yields under neutral conditions, in the 1 (5). Transition2 metal1–catalyzed(0.1 mol %) conversion2 of1 absence of acceptors or promoters. We have following reaction illustrates the transformation: R CH2OH + R –NH2 → R NHCOR of C3-functionlized piperidines were developed and em- ahydrogen acceptor.Afive-memberednitriles intobenzo-fused amidesToluene,Reflux,-2H was reportedlactam,2 (6–8). Cata- now discovered that complex 1 catalyzes the with Liberation of H2 lytic acylation of amines by aldehydes in the Dehydrogenative Amide FormationTime Yield* reaction of alcohols with amines to form ployed easily accessible anilines,diols,and aldehydes and thatEntryis,oxindoles R1CH OH,were synthesized R2NH presencein moderate of a stoichiometricAmideto amountexcellent of oxidant Chidambaram Gunanathan, Yehoshoa Ben-David, David Milstein*2 2 (hours) (%) and a base is known (9, 10). Recently, oxidative on October 3, 2015 amides and H2, leading to a variety of amides phosphanesulfonate-chelated iridium complex 21 (Scheme 3). yields with lower catalytic loading (3amidemol synthesis%) in wasacetone achieved fromunder terminal (Table 1). Thekey step is the endo dehydrogenationGiven the widespreadleading importanceto C3- of amidesreflux in biochemicalfor and8h chemicalours.[23] systems, an efficient alkynes (11). Cu(I)-catalyzed reaction of sulfonyl At the outset, when a toluene solution of § synthesis that avoids wasteful use of stoichiometric coupling reagents or corrosive acidic and azides with terminal alkynes is a facile method 2004basic media - isBenzo highly desirable.-fused We report five, a reaction1 size, in which primaryand amines seven are directly membered7 lactams 96 complex 1 (0.2 mole percent) with benzylamine functionalization of piperidines (26). Theoverall reaction for the synthesis of sulfonyl amides (12, 13). A and 1-hexanol (1:1 ratio) was refluxed in a closed acylated by equimolar amounts of alcohols to produce amides and molecular hydrogen (the desirable goal is the direct catalytic conversion of system for 6 hours, 63% conversion of 1-hexanol involves double N-alkylation of an anilineonly products)with in highad yieldsiol andand high turnover numbers. This reaction is catalyzed by a alcohols and amines into amides and dihydrogen subsequent endo dehydrogenation ofrutheniumpiperidine complex,t basedhus on aena- dearomatized PNN-type ligand [where PNN is 2-(di-tert- (Eq. 1) to N-benzylhexanamide was observed. Contin- butylphosphinomethyl)-6-(diethylaminomethyl)pyridine], and no base or acid promoters are uing the reaction up to 40 hours resulted in a required. Use of primary diamines in the reaction leads to bis-amides, whereas with a mixed catalyst, D bling ahighly regioselective C3-functionalization process. www.sciencemag.org mixture of products. In order to facilitate for- 2 R–NH7 2 +RCH2OH → 97 primary-secondary amine substrate, chemoselective acylation of the primary amine group takes R=alkyl,aryl mation of the product amide by hydrogen When this three-component reaction isplace.run Thein proposedthe presence mechanism involvesof dehydrogenation of hemiaminal intermediates formed RNHCOR + 2H2 (1) by the reaction of an aldehyde intermediate with the amine. removal, we heated 1-hexanol and benzylamine the ruthenium complex 22 the N-alkylated compound 23 is with complex 1 (0.1 mol %) under a flow of argon in refluxing toluene for 7 hours. This setup the major product. Other commercially availablemide formationcatalysts is a fundamental reaction amides, preparation under neutral conditions and This unknown, environmentally benign reaction resulted in the formation of N-benzylhexanamide such as [{Ru(p-cymene)Cl } ]and [{Cp*IrCl§ Whenin chemical} ]w using synthesisere (other1not). The impor- solvents,3 Milsteinwithout the major generationand co-workersproduct of waste is a challenging isdeveloped cyclized(14–918)mightleadtoadiverselibraryofamides well-definedamines (notpyridine- amide) – 99showing 2 2 Atance of2 amides2 in chemistry and biology goal (1, 5). Synthesis of amides is mostly based from very simple substrates, with high atom in 96% yield and a trace of N-benzyl-hexyl-1- II effective for the above reaction. Based onis welltheacetone recognizedoverall and catalytic hasis beenkey studied for exten-hydrogenbased PNN/Ru acceptingpincer complex for the direct synthesis of Downloaded from amine (1%). We observed no formation of hexyl sively over the past century (2–4). Although hexanoate, which forms quantitatively in the cycle, 21 is the sole catalyst for theseveralN- methodsand C-alkylation are known for the synthesisamides of Fig. 2.fromProposedalcohols mecha- and amines with theFujitarelease & Yamaguchiof H2,t. Org.hus Lett. 2004, 6, 2785. nism for the direct acyla- absence of amine (Table 1, entry 1). Repeating † process which results from two C Nand one C Cbond- enabling4 tion of aminesbase-free by alcohols,additive-free,a12nd acceptorless amide 70 the reaction with 1-pentanol under identical § ˇ 2007 – Milsteinˇ developed acatalyzed general by[9b complex] amidation1. strategy via a PNN pincer complex conditions led to selective direct amidation, forming hydrogen transfer in asingle Departmentoperation. of OrganicSubstituted Chemistry, Weizmann Instituteformation. of b-amino alcohols were effectively converted Science, Rehovot 76100, Israel. providing N-benzylpentanamide in 97% yield diols were also successfully converted into*To whomthe the correspondencecorresponding should be addressed. E-mail:into the cyclic dipeptides 29 in the presence of the dearom- (Table 1, entry 2). 2-Methoxyethanol underwent [email protected] clean dehydrogenative acylation by reaction with 5 8 78† the primary amines benzylamine, pentylamine, 11026 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 and cyclohexylamine to give methoxy-acetylated amides in almost quantitative yields (Table 1, entries 3, 8, and 10). The amidation reactions are sensitive to steric hindrance at the a positions of either the alcohol 6 8 0† or the amine. Thus, when 2-methyl-1-butanol reacted with benzylamine, the corresponding amide was obtained in 70% yield, with the rest of the alcohol being converted to the ester 2- Fig. 1. Structure of dearomatized PNN pincer methylbutyl 2-methylbutanoate (Table 1, entry complex 1. 7 8 58†

790 10 AUGUST 2007 VOL 317 SCIENCE www.sciencemag.org Milstein et al. Science 2007, 317, 790.

8 8 99

9 8 72†

10 8 99

*Isolated yields. †The remaining alcohol was converted into the corresponding ester. In the reactions involving hexanol and pentanol, trace amounts of the corresponding secondary amines were detected (GC–mass spectrometry). Scheme 1.

www.sciencemag.org SCIENCE VOL 317 10 AUGUST 2007 791 REPORTS

REPORTS economy and no stoichiometric activating agents, (valuable in itself) will shift the equilibrium and butylphosphinomethyl)pyridine (PNP)–Ru(II) generating no waste. Although such a reaction is drive the reaction. and PNN-Ru(II) hydride complexes (19). Where- 4. L. J. Richter, T. P. Petralli-Mallow, J. P. Stephenson, 13. J. E.expected Patterson, toA. S. be Lagutchev, thermodynamically W. Huang, D. D. Dlott,uphill, it is reflectanceWe measurements recently reported were carried the out dehydrogenation in the as secondary alcohols lead to ketones (20, 21), Opt. Lett. 23, 1594 (1998). Phys. Rev. Lett. 94, 015501 (2005). Frederick Seitz Materials Research Laboratory Central 5. A. S. Lagutchev, J. E. Patterson, W. Huang, D. D. Dlott, 14. H.envisioned K. Lyeo, D. G. Cahill, thatPhys. the Rev. liberated B 73, 144301 hydrogen gas Facilities,of alcohols University of catalyzed Illinois, which by are partially 2,6-bis-(di-tert- primary alcohols are efficiently converted into J. Phys. Chem. B 109, 5033 (2005). (2006). supported by the DOE under grant DEFG02-91-ER45439. esters and dihydrogen (19–21). The dearoma- 6. S. D. Brorson, J. G. Fujimoto, E. P. Ippen, Phys. Rev. Lett. 15. Z. Ge, D. G. Cahill, P. V. Braun, J. Phys. Chem. B 108, D.D.D. acknowledges additional support from the Table 1. Direct dehydrogenative acylation of amines with alcohols catalyzed by the ruthenium complex tized PNN pincer complex 1 (Fig. 1) is particu- 59, 1962 (1987). 18870 (2004). National Science Foundation under award DMR 0504038 larly efficient (19, 22); it catalyzes this process 7. D. G. Cahill, Rev. Sci. Instrum. 75, 5119 (2004). 16. Z. B.1.Catalyst Ge, D. G. Cahill,1 (0.01 P. V. Braun,mmol),Phys. alcohol Rev. Lett. (1096 mmol),, amineand from (10 the mmol), Air Force and Office toluene of Scientific (3 Research ml) were under refluxed 8. C. D. Bain, P. B. Davies, T. H. Ong, R. N. Ward, Langmuir 186101under (2006). Ar flow (33). Conversion of alcohols was 100%award FA9550-06-1-0235. [by gas chromatography (GC) analysis]. The in high yields under neutral conditions, in the 1 2 1 (0.1 mol %) 2 1 absence of acceptors or promoters. We have 7, 1563 (1991). 17. R. Y.following Wang, R. reactionA. Segalman, illustrates A. Majumdar, theAppl. transformation: Phys. R CH2OH + R –NH2 → R NHCOR 9. N. Nishida, M. Hara, H. Sasabe, K. Wolfgang, Jpn. J. Lett. 89, 173113 (2006). Supporting Online MaterialToluene,Reflux,-2H2 now discovered that complex 1 catalyzes the Appl. Phys. 35, 5866 (1996). 18. S. Chen, M. T. Seidel, A. H. Zewail, Angew. Chem. Int. Ed. www.sciencemag.org/cgi/content/full/317/5839/787/DC1Time Yield* reaction of alcohols with amines to form Entry R1CH OH R2NH Amide 10. H. Kondoh, C. Kodama, H. Sumida, H. Nozoye, J. Chem. 45, 5154 (2006). 2 2 Materials(hours) and Methods (%) Phys. 111, 1175 (1999). 19. This material is based upon work supported by the U.S. SOM Text amides and H2, leading to a variety of amides 11. C. D. Bain et al., J. Am. Chem. Soc. 111, 321 Department of Energy (DOE), Division of Materials References (Table 1). (1989). Sciences under award DEFG02-91ER45439, through the At the outset, when a toluene solution of 12. J. E. Patterson, D. D. Dlott, J. Phys. Chem. B 109, 5045 Frederick Seitz Materials Research Laboratory at the 16 May 2007; accepted 27 June 2007 1 7 96 complex 1 (0.2 mole percent) with benzylamine (2005). University of Illinois at Urbana-Champaign. Thermal 10.1126/science.1145220 and 1-hexanol (1:1 ratio) was refluxed in a closed system for 6 hours, 63% conversion of 1-hexanol to N-benzylhexanamide was observed. Contin- uing the reaction up to 40 hours resulted in a mixture of products. In order to facilitate for- 2 on activated7 acid derivatives (acid chlorides and 97 mation of the product amide by hydrogen anhydrides) or rearrangement reactions induced Direct Synthesis of Amides removal, we heated 1-hexanol and benzylamine by an acid or base, which often produce toxic with complex 1 (0.1 mol %) under a flow of chemical waste and involve tedious procedures argon in refluxing toluene for 7 hours. This setup from Alcohols and Amines (5). Transition metal–catalyzed conversion of 3 9 99 resulted in the formation of N-benzylhexanamide nitriles into amides was reported (6–8). Cata- in 96% yield and a trace of N-benzyl-hexyl-1- with Liberation of H lytic acylation of amines by aldehydes in the 2 amine (1%). We observed no formation of hexyl presence of a stoichiometric amount of oxidant Chidambaram Gunanathan, Yehoshoa Ben-David, David Milstein* hexanoate, which forms quantitatively in the and a base is known (9, 10). Recently, oxidative on October 3, 2015 absence of amine (Table 1, entry 1). Repeating amide synthesis was achieved from terminal 4 12 70† the reaction with 1-pentanol under identical Given the widespread importance of amides in biochemical and chemical systems, an efficient alkynes (11). Cu(I)-catalyzed reaction of sulfonyl conditions led to selective direct amidation, synthesis that avoids wasteful use of stoichiometric coupling reagents or corrosive acidic and azides with terminal alkynes is a facile method providing N-benzylpentanamide in 97% yield basic media is highly desirable. We report a reaction in which primary amines are directly for the synthesis of sulfonyl amides (12, 13). A (Table 1, entry 2). 2-Methoxyethanol underwent acylated by equimolar amounts of alcohols to produce amides and molecular hydrogen (the desirable goal is the direct catalytic conversion of clean dehydrogenative acylation by reaction with only products) in high yields and high turnover numbers. This reaction is catalyzed by a alcohols and amines into amides and dihydrogen † the primary amines benzylamine, pentylamine, ruthenium complex based on a dearomatized PNN-type ligand5 [where PNN is 2-(di-tert- (Eq. 1) 8 78 butylphosphinomethyl)-6-(diethylaminomethyl)pyridine], and no base or acid promoters are and cyclohexylamine to give methoxy-acetylated amides in almost quantitative yields (Table 1, required. Use of primary diamines in the reaction leads to bis-amides, whereas with a mixed catalyst, D R–NH +RCHOH www.sciencemag.org primary-secondary amine substrate, chemoselective acylation of the primary amine group takes 2 2 R=alkyl,aryl→ entries 3, 8, and 10). place. The proposed mechanism involves dehydrogenation of hemiaminal intermediates formed The amidation reactions are sensitive to steric RNHCOR + 2H2 (1) by the reaction of an aldehyde intermediate with the amine. hindrance at the a positions of either the alcohol 6 8 0† or the amine. Thus, when 2-methyl-1-butanol reacted with benzylamine, the corresponding mide formation is a fundamental reaction amides, preparation under neutral conditions and This unknown, environmentally benign reaction amide was obtained in 70% yield, with the rest in chemical synthesis (1). The impor- without the generation of waste is a challenging (14–18)mightleadtoadiverselibraryofamides of the alcohol being converted to the ester 2- tance of amides in chemistry and biology goal (1, 5). SynthesisDehydrogenative of amides is mostly based from very simpleAmide substrates, withFormation high atom A methylbutyl 2-methylbutanoate (Table 1, entry is well recognized and has been studied exten- Downloaded from † sively over the past century (2–4). Although 7 8 58 several methods are known for the synthesis of Fig. 2. Proposed mecha- Angewandte nism for the direct acyla- Heterocycle Synthesis Chemie tion of amines by alcohols Department of Organic Chemistry, Weizmann Institute of catalyzed by complex 1. Science, Rehovot 76100, Israel. 8 8 99 *To whom the correspondence should be addressed. E-mail: atized PNN/Ru complex 28 in 1,4-dioxane,under argon, [email protected] without racemization of the products [Eq. (11)). Interestingly, large substituents (R H, Me) at the a-position to the amino à6 † 9 group resulted8 in the formation of the cyclic72 dipeptide as the sole product, whereas (S)-(+)-2-amino-1-propanol under the same catalytic conditions gave 72%ofthe polypeptide and aminor amount of the cyclic dipeptide.Aplausible catalytic 10 8 99 cycle involves anew mode of metal–ligand cooperation based on ligand aromatization/dearomatization.[24] It was observed *Isolated yields. †The remaining alcohol wasthat convertedthe intohemilability the corresponding ester.of In thethe reactionsN-arm involvingis hexanolimportant and and plays pentanol, trace amounts of the corresponding secondary amines were detected (GC–mass spectrometry). Scheme 1. Fig. 1. Structure of dearomatized PNN pincer acrucial role in the amide bond formation. In contrast,Milsteinthe et al. Science 2007, 317, 790. complex 1. complementary PNP/RuII complex gave the aromatized www.sciencemag.org SCIENCE VOL 317 10 AUGUST 2007 791 § Relevance for productheterocycles[see Eq., when(16)]. β-amino alcohols with R ≠ H, Me à cyclicScheme dipeptides4. Synthesis of cyclic imides from diols and nitriles. 790 10 AUGUST 2007 VOL 317 SCIENCE www.sciencemag.org

cyclization of a,w-amino alcohols to afford the cyclic amines 41 as well as the cyclic amides 42 [Eq. (13)].The ratio of 41 to 42 depends on the ring size of the product formed. The addition of water or phenol as an additive resulted in acomplete shift of equilibrium towards the amine formation. Milstein etTh al.is ACIEresult 2011might, 50, be12240.due to water or phenol serving as aweak Madsen and co-workers reported the application of acid, which might facilitate the dehydration of acyclic astrongly donating N-heterocyclic carbene (NHC) com- hemiaminal to an imine.Complete selectivity for amide plexed with ruthenium as acatalyst for the selective synthesis formation was achieved using propiophenone as asacrificial of amides from alcohols and amines.Three different NHC/Ru hydrogen acceptor.[27] systems (30–32)were designed and analyzed for their activity in amide formation starting from 1,4- and 1,6-amino alcohols [Eq. (12);cod = 1,5-cyclooctadiene].All three catalytic sys- tems showed similar reactivities and product yields,thus revealing that acommon catalytically active species is involved.[25]

2.3. Annulation by Oxidative Cyclization of Alcohols

Oxidative cyclization of diols with amines provide an alternative protocol for the construction of five- and six- membered heteroaromtic compounds by consecutive hydro- gen-transfer C Cand C Nbond formation. Astraightfor- ˇ ˇ ward, one-pot synthesis of the quinolines 46 from anilines and 1,3-diols was reported to proceed in the presence of acatalytic

An atom-economical strategy for the formation of cyclic amount of [RuCl3·xH2O],PBu3,and MgBr2·OEt2 in mesity- imides (39)from diols and nitriles was developed by Hong lene (Scheme 5). Theaddition of magnesium salt is believed et al. (Scheme 4). They used aruthenium complex in combi- to improve the electrophilic cyclization of 45 to 46 through nation with the NHC 34 as the catalyst. Notably,transfer of aC Cbond-forming process.Substituents on the aniline and ˇ hydrogen from the diol produces the active electrophile 35 diol both played significant roles in the heterocyclization and nucleophile 36 as intermediates through aruthenium- reactions.Interestingly,the regioselectivity of product for- catalyzed redox-neural catalytic cycle.Nitrile precursors act mation reveals that the reaction proceeds with the formation as anitrogen source as well as ahydrogen acceptor in the of the a,b-unsaturated aldehyde 44 from the diol by reaction. Thereaction of 35 and 36 affords the hydroxy amide ruthenium-catalyzed dehydrogenation and subsequent elim- 37 which can be further converted into acyclic imide by ination of water. Aniline then undergoes Michael addition dehydrogenative formation of the hemiaminal 38 as apoten- with 44 followed by electrophilic cyclization to afford either tial intermediate.[26] the 2- or 3-substituted quinolines in moderate to good yields Vogt et al. reported ruthenium catalyst systems,compris- which is similar those of the Doebner–von Miller quinoline [28] ing [Ru3(CO)12]and CataCXiumPCy (40), for intramolecular synthesis.

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11027 Angewandte Heterocycle Synthesis Chemie

atized PNN/Ru complex 28 in 1,4-dioxane,under argon, without racemization of the products [Eq. (11)). Interestingly, large substituents (R H, Me) at the a-position to the amino à6 group resulted in the formation of the cyclic dipeptide as theAngewandte Heterocycle Synthesis sole product, whereas (S)-(+)-2-amino-1-propanol under the Chemie same catalytic conditions gave 72%ofthe polypeptide and aminor amount of the cyclic dipeptide.Aplausible catalytic atized PNN/Ru complex 28 in 1,4-dioxane,under argon,cycle involves anew mode of metal–ligand cooperation based without racemization of the products [Eq. (11)). Interestinglyon ligand, aromatization/dearomatization.[24] It was observed large substituents (R H, Me) at the a-position to the aminothat the hemilability of the N-arm is important and plays à6 group resulted in the formation of the cyclic dipeptide asactherucial role in the amide bond formation. In contrast, the sole product, whereas (S)-(+)-2-amino-1-propanol undercomplementarythe PNP/RuII complex gave the aromatized same catalytic conditions gave 72%ofthe polypeptideproductand [see Eq. (16)]. Scheme 4. Synthesis of cyclic imides from diols and nitriles. aminor amount of the cyclic dipeptide.Aplausible catalytic cycle involves anew mode of metal–ligand cooperation based [24] on ligand aromatization/dearomatization. It was observed cyclization of a,w-amino alcohols to afford the cyclic amines that the hemilability of the N-arm is important and plays 41 as well as the cyclic amides 42 [Eq. (13)].The ratio of 41 to acrucial role in the amide bond formation. In contrast, the 42 depends on the ring size of the product formed. The II complementary PNP/Ru complex gave the aromatized addition of water or phenol as an additive resulted in product [see Eq. (16)]. Scheme 4. Synthesis of cyclic imides from diols and nitriles. acomplete shift of equilibrium towards the amine formation. This result might be due to water or phenol serving as aweak Madsen and co-workers reported the application of acid, which might facilitate the dehydration of acyclic astronglycyclizationdonatingofN-heteroca,w-aminoyclicalcoholscarbeneto afford(NHC)thecom-cyclic amineshemiaminal to an imine.Complete selectivity for amide plexed with41 asrutheniumwell as theascyclicacatalystamidesfor42the[Eq.selective(13)].Tsynthesishe ratio offormation41 to was achieved using propiophenone as asacrificial of amides42fromdependsalcoholsonandtheaminesring .Tsizehreeof differentthe productNHC/Ruformed.hydrogenThe acceptor.[27] systems (addition30–32)wereof designedwater orandphenolanalyzedas foran theiradditiveactivityresulted in in amideacformationompletestartingshift of equilibriumfrom 1,4- andtowards1,6-aminothe aminealcoholsformation. [Eq. (12)Th;cisodresult= 1,5-cyclomightoctadiene]be due to water.All threeor phenolcatalyticservingsys-as aweak Madsen and co-workers reported the applicationtemsof showedacid, similarwhich mightreactivitiesfacilitateand theproductdehydrationyields,thusof acyclic astrongly donating N-heterocyclic carbene (NHC) revealingcom- hemiaminalthat acommonto an iminecatalytically.Completeactiveselectivityspecies foris amide plexedSearchwith ruthenium of Generalas acatalyst for Catalyststhe selective synthesisinvolved. formation[25] was achieved using propiophenone as asacrificial of amides from alcohols and amines.Three different NHC/Ru hydrogen acceptor.[27] systems (30–32)were designed and analyzed for their activity in§ amideMadsenformation - 2010starting from 1,4- and 1,6-amino alcohols [Eq. (12)§ ;cWantedod = 1,5-cyclo to findoctadiene] general.A llstablethree catalyticcatalystssys- for amide formation tems showed similar reactivities and product yields,thus revealing§ Designedthat acommon NHC-catalyticallyRu complexesactive àspecies all showedis great reactivity [25] involved. 2.3. Annulation by Oxidative Cyclization of Alcohols

Oxidative cyclization of diols with amines provide an alternative protocol for the construction of five- and six- membered heteroaromtic compounds by consecutive hydro- gen-transfer C Cand C Nbond formation. Astraightfor- ˇ ˇ Angewandte ward, one-pot synthesis of the quinolines 46 from anilines and Heterocycle Synthesis Chemie 2.3. Annulation by Oxidative Cyclization of Alcohols 1,3-diols was reported to proceed in the presence of acatalytic § Hong – 2014 – Cyclic imide strategy Madsen et al. Eur. J. Chem. 2010,16, 6820. An atom-economical strategy for the formation of cyclic amount of [RuCl3·xH2O],PBu3,and MgBr2·OEt2 in mesity- atized PNN/Ru complex 28 in 1,4-dioxane,under argon, imides (39)fOxidativerom diols cyclizatand nitrilesion ofwasdiolsdevelopedwith aminesby Hongprovidelenean(Scheme 5). Theaddition of magnesium salt is believed without racemization of the products [Eq. (11)). Interestingly, et al. (Schemealternative4). Thprotocoley used arforutheniumthe constructioncomplex inofcombi-five- andtosix-improve the electrophilic cyclization of 45 to 46 through large substituents (R H, Me) at the a-position to the amino nation withmemberedthe NHCheteroaromtic34 as the catalyst.compoundsNotablyby,tconsecutiveransfer of hydro-aC Cbond-forming process.Substituents on the aniline and à6 group resulted in the formation of the cyclic dipeptide as the gen-transfer C Cand C Nbond formation. Astraightforˇ- hydrogen from the diolˇproducesˇthe active electrophile 35 diol both played significant roles in the heterocyclization sole product, whereas (S)-(+)-2-amino-1-propanol under the and nucleophileward, one-pot36 as synthesisintermediatesof thethroughquinolinesar46uthenium-from anilinesreactionsand .Interestingly,the regioselectivity of product for- Nitrile acts as same catalytic conditions gave 72%ofthe polypeptide and catalyzed1,3-diolsredox-neuralwas reportedcatalytictocyproceedcle.Nitrilein theprecursorspresence ofactacatalyticmation reveals that the reaction proceeds with the formation aminor amount of the cyclic dipeptide.Aplausible catalytic N-source and H-acceptor An atom-economical strategy for the formation of cyasclicanitrogenamountsourceof [RuClas well3·xHas2O]ah,PydrogenBu3,andacceptorMgBr2·OEtin the2 in mesity-of the a,b-unsaturated aldehyde 44 from the diol by cycle involves anew mode of metal–ligand cooperation based imides (39)from diols and nitriles was developed by Hongreaction.leneTher(Schemeeaction of5).35Thandea36dditionaffordsof themagnesiumhydroxy amidesalt is believedruthenium-catalyzed dehydrogenation and subsequent elim- on ligand aromatization/dearomatization.[24] It was observed et al. (Scheme 4). They used aruthenium complex in combi-37 whichtocanimprovebe furtherthe electrophilicconverted intocyclizationacyclicofimide45 to by46 throughination of water. Aniline then undergoes Michael addition that the hemilability of the N-arm is important and plays nation with the NHC 34 as the catalyst. Notably,transferdehydrogenativeof aC Cbond-formingformation of processthe hemiaminal.Substituents38 asonaptheoten-anilinewithand44 followed by electrophilic cyclization to afford either acrucial role in the amide bond formation. In contrast, the ˇ hydrogen from the diol produces the active electrophile 35 diol both[26]played significant roles in the heterocyclization complementary PNP/RuII complex gave the aromatized tial intermediate. Hong et al. Org. Lett. 2014,16, 4404. the 2- or 3-substituted quinolines in moderate to good yields and nucleophile 36 as intermediates through aruthenium- reactions.Interestingly,the regioselectivity of product for- product [see Eq. (16)]. Scheme 4. Synthesis of cyclic imides from diols and nitriles. Vogt et al. reported ruthenium catalyst systems,compris- which is similar those of the Doebner–von Miller quinoline catalyzed redox-neural catalytic cycle.Nitrile precursors act mation reveals that the reaction proceeds with the formation [28] ing [Ru3(CO)12]and CataCXiumPCy (40), for intramolecular synthesis. as anitrogen source as well as ahydrogen acceptor in the of the a,b-unsaturated aldehyde 44 from the diol by reaction. Thcyclizationereactionofofa,w35-aminoand 36alcoholsaffordstotheaffordhydroxythe cyamideAngewclic .Camineshem.ruthenium-catalyzedInt.Ed. 2015, 54,11022 –1dehydrogenation1034 ⌫and2015subsequentWiley-VCH Verlagelim-GmbH &Co. KGaA, Weinheim www.angewandte.org 11027 37 which 41canas wellbe furtheras the cyclicconvertedamidesinto42 [Eq.ac(13)]yclic.Timidehe ratiobyof 41inationto of water. Aniline then undergoes Michael addition dehydrogenative42 dependsformationon theofringthe hemiaminalsize of the product38 as apformed.oten- Thwithe 44 followed by electrophilic cyclization to afford either tial intermediateaddition.[26]of water or phenol as an additive resulted thein 2- or 3-substituted quinolines in moderate to good yields Vogt etacal.ompletereportedshiftrutheniumof equilibriumcatalysttowardssystemsthe amine,compris-formation.which is similar those of the Doebner–von Miller quinoline [28] ing [Ru3(CO)This12result]andmightCataCXiumPCybe due to water(40),orforphenolintramolecularserving as aweaksynthesis. Madsen and co-workers reported the application of acid, which might facilitate the dehydration of acyclic astrongly donating N-heterocyclic carbene (NHC)Angewcom-.Chem.hemiaminalInt.Ed. 2015, 54to,11022an –1imine1034 .Complete selectivity⌫ 2015 Wiley-VCHfor amideVerlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11027 plexed with ruthenium as acatalyst for the selective synthesis formation was achieved using propiophenone as asacrificial of amides from alcohols and amines.Three different NHC/Ru hydrogen acceptor.[27] systems (30–32)were designed and analyzed for their activity in amide formation starting from 1,4- and 1,6-amino alcohols [Eq. (12);cod = 1,5-cyclooctadiene].All three catalytic sys- tems showed similar reactivities and product yields,thus revealing that acommon catalytically active species is involved.[25]

2.3. Annulation by Oxidative Cyclization of Alcohols

Oxidative cyclization of diols with amines provide an alternative protocol for the construction of five- and six- membered heteroaromtic compounds by consecutive hydro- gen-transfer C Cand C Nbond formation. Astraightfor- ˇ ˇ ward, one-pot synthesis of the quinolines 46 from anilines and 1,3-diols was reported to proceed in the presence of acatalytic

An atom-economical strategy for the formation of cyclic amount of [RuCl3·xH2O],PBu3,and MgBr2·OEt2 in mesity- imides (39)from diols and nitriles was developed by Hong lene (Scheme 5). Theaddition of magnesium salt is believed et al. (Scheme 4). They used aruthenium complex in combi- to improve the electrophilic cyclization of 45 to 46 through nation with the NHC 34 as the catalyst. Notably,transfer of aC Cbond-forming process.Substituents on the aniline and ˇ hydrogen from the diol produces the active electrophile 35 diol both played significant roles in the heterocyclization and nucleophile 36 as intermediates through aruthenium- reactions.Interestingly,the regioselectivity of product for- catalyzed redox-neural catalytic cycle.Nitrile precursors act mation reveals that the reaction proceeds with the formation as anitrogen source as well as ahydrogen acceptor in the of the a,b-unsaturated aldehyde 44 from the diol by reaction. Thereaction of 35 and 36 affords the hydroxy amide ruthenium-catalyzed dehydrogenation and subsequent elim- 37 which can be further converted into acyclic imide by ination of water. Aniline then undergoes Michael addition dehydrogenative formation of the hemiaminal 38 as apoten- with 44 followed by electrophilic cyclization to afford either tial intermediate.[26] the 2- or 3-substituted quinolines in moderate to good yields Vogt et al. reported ruthenium catalyst systems,compris- which is similar those of the Doebner–von Miller quinoline [28] ing [Ru3(CO)12]and CataCXiumPCy (40), for intramolecular synthesis.

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11027 . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

asingle operation, thus enabling environmentally benign and efficient protocols.

2.1. Annulation by N-Alkylation of Amines by Alcohols

Saturated nitrogen-containing heterocyclic scaffolds are found in many natural products and biologically important Oxidative Cyclization of Alcohols compounds.The first example of the N-alkylation of an amine Figure 2. Dehydrogenative amide formation from alcohols and amines. by an alcohol through ahydrogen-transfer annulation was reported by Grigg et al. in 1981. Thus pyrrolidines were § Substrate does not accept hydrogen formed by the intramolecular reaction of N-substituted

4-aminobutan-1-ols in the presence of 5mol%[RhH(PPh3)4] as the catalyst in boiling 1,4-dioxane.The cascade reaction consists of dehydrogenative oxidation of the alcohol to an aldehyde,imine formation with an amine,and hydrogenative reduction of the imine to afford the N-substituted pyrroli- dines 1a and 1b in 56 and 82%yields,respectively [Eq. (1)]. Similar catalytic conditions were used to synthesize 1bby the amination of butane-1,4-diol with benzylamine in aratio of Figure 3. Dehydrogenative coupling of alcohols with nucleophiles. § Great for quinoline, pyrrole, pyridine, etc… 10:1 to yield 1b in 31%[Eq. (2)].[12]

§ Employing1.4. Oxidative very generalCyclizati conditions,on of Alcohols could be easy to synthesize new ligands using these procedures Transition-metal-catalyzed dehydrogenative coupling of alcohols with various nucleophilic partners has resulted in the formation of C X(C, N, and O) bonds with the liberation of ˇ [9] H2 and H2Oasby-products (Figure 3). Inter-and intra- molecular hydrogen-transfer annulations of alcohols with various coupling partners enable the formation of function- alized saturated and aromatic heterocyclic compounds.This methodology has provided direct and rapid access to avariety of heterocyclic frameworks.

Direct coupling of adiol with an amine through aborrow- 1.5. Annulation of Unsaturated Systems (Alkenes and Alkynes) ing-hydrogen strategy is the most promising protocol for the construction of N-heterocyclic compounds since diol deriva-

Unsaturated systems such as alkenes and alkynes are tives can be easily accessed. [{Ru(p-cymene)Cl2}2]combined important building blocks in the chemical sciences.Their with the bidendate DPEphos ligand provided access to utility in organic synthesis have increased because of the saturated five-, six-, and seven-membered N-heterocyclic development of newer synthetic methodologies based on compounds by the N-alkylation of diols with amines [Eq. (3); transition-metal catalysts.[10] Transition-metal-catalyzed hy- drogen-transfer annulations of these building blocks provide novel heterocyclic frameworks.[11]

2. Synthesis of N-Heterocycles

Nitrogen-containing heterocycles are omnipresent in DPEphos = bis(2-diphenylphosphinophenyl)ether].Thus, nature and biologically active compounds,including nucleo- 1,4-butanediol reacted with various anilines and aliphatic bases within RNA, DNA, nucleotides,nucleosides,and amines to provide N-substituted pyrrolidines in the presence haemoglobin. They also have applications in avariety of of trimethylamine as an additive in refluxing toluene.Other fields such as agrochemicals and pharmaceuticals,aswell as in diols such as 1,5-pentanediol and 1,6-hexanediol were also the preparation of foods,dyes,detergents,and surfactants.[1] converted into the corresponding N-substituted piperidine Hence,there is aplethora of methods for the preparation of and azepane derivatives under similar catalytic conditions.[13] novel nitrogen-based heterocycles for various applications. Significantly,Enyong et al. used the simple,inexpensive,and Transition-metal-catalyzed hydrogen-transfer annulations readily accessible (S)-2-hydroxy-N,3-diphenylpropanamide

have provided aplatform to synthesize the basic skeletons (3)ligand in combination with [{Ru(p-cymene)Cl2}2]for the for complex nitrogen-containing heterocyclic compounds in N-alkylation of diols with aliphatic amines under mild

11024 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Annulation by Oxidative Cyclization View Article Online

§ Quinoline synthesis à One-pot procedure from 1,3 diols & analines View Article Online Table§ 2 ScreenedSynthesis of quinolines Lewis from anilines Acids and 1,3-diols to helpa electrophilicTable 2 (Contd.) cyclization

Table 2 Synthesis of quinolines from anilines and 1,3-diolsa Table 2 (Contd.)

Entry X R R¢ Product Yieldb Entry X R R¢ Product Yieldb

1H HH 20% 16 o-Cl Me H 43% Entry X R R¢ Product Yieldb Entry X R R¢ Product Yieldb

1H HH 20% 16 o-Cl Me H 43% 2H HMe 32%c 17 —h Me H 54% 2H HMe 32%c 3H Hn-Hex 30%d 17 —h Me H 54%

3H Hn-Hex 30%d 18 —i Me H 52%j 4H MeH 47% 18 —i Me H 52%j 4H MeH 47% 5H n-Bu H 48% a See experimental section for reaction procedures. b Isolated yield. c 4-Methylquinoline was also isolated in 4% yield. d Trace amount 5H n-Bu H 48% of 4-hexylquinoline was observed, but not isolated. e 6-methoxy-4- 6H PhH 31% methylquinolinea See experimental was also section isolated for in 3% reaction yield. f procedures.Heated to refluxb Isolated for 24 yield. h. g Isolatedc 4-Methylquinoline as an inseparable was 6: 1 also mixture isolated of 3,7- in and 4% 3,5-dimethylquinoline. yield. d Trace amount h Withof 4-hexylquinoline1-naphthylamine. wasi With observed, 2-naphthylamine. but notj Trace isolated. amounte 6-methoxy-4- of the 6H PhH 31% 6,7-benzomethylquinoline isomer was was observed, also isolated but not in isolated.3% yield. f Heated to reflux for 24 h. g Isolated as an inseparable 6: 1 mixture of 3,7- and 3,5-dimethylquinoline. 7 p-Cl Me H 46% h i j of theWith diol 1-naphthylamine. to the hydroxyWith carbonyl 2-naphthylamine. compoundTrace which amount from of the 6,7-benzo isomer was observed, but not isolated. butane-1,3-diol wouldMadsen lead et to al. either Org. 4-hydroxybutan-2-one Biomol. Chem. 2011 or, 3-9, 610. 7 p-Cl Me H 46% hydroxybutanal. Interestingly, when 4-hydroxybutan-2-one was 8 -Me Me H 61% of the diol to the hydroxy carbonyl compound which from p condensed with aniline and RuCl xH O/PBu /MgBr OEt , butane-1,3-diol would lead to either3· 4-hydroxybutan-2-one2 3 2· or2 3- amixtureof4-anilinobutan-2-oneand4-methylquinolinewashydroxybutanal. Interestingly, when 4-hydroxybutan-2-one was 8 p-Me Me H 61% obtained (Scheme 1). Control experiments showed that the condensed with aniline and RuCl3 xH2O/PBu3/MgBr2 OEt2, 9 -MeO H H 43% · · p formeramixtureof4-anilinobutan-2-oneand4-methylquinolinewas is converted into the latter with the catalyst system orobtained with MgBr (Scheme2 OEt2 alone. 1). Control In fact, experiments reaction between showed aniline, that the Published on 22 November 2010. Downloaded by University of Texas Libraries 05/10/2015 15:36:53. · 9 p-MeO H H 43% 4-hydroxybutan-2-one and MgBr2 OEt2 in the absence of ruthe- former is converted into the· latter with the catalyst system e nium also produced a mixture of 4-anilinobutan-2-one and 10 p-MeO H Me 47% or with MgBr2 OEt2 alone. In fact, reaction between aniline, Published on 22 November 2010. Downloaded by University of Texas Libraries 05/10/2015 15:36:53. 4-methylquinoline.· Attempts to form the imine between ani- 4-hydroxybutan-2-one and MgBr2 OEt2 in the absence of ruthe- line and 4-hydroxybutan-2-one led· to a mixture of the 10 p-MeO H Me 47%e nium also produced a mixture of 4-anilinobutan-2-one and desired4-methylquinoline. hydroxyimine and Attempts 4-anilinobutan-2-one. to form the imine When between this mix- ani- 11 p-MeO Me H 60% ture was treated with MgBr OEt or the ruthenium catalyst only line and 4-hydroxybutan-2-one2· 2 led to a mixture of the desired hydroxyimine and 4-anilinobutan-2-one. When this mix- 11 p-MeO Me H 60% ture was treated with MgBr OEt or the ruthenium catalyst only 2· 2 12 p-MeO n-Bu H 56%f

12 p-MeO n-Bu H 56%f 13 p-MeO Ph H 41%

13 p-MeO Ph H 41% 14 m-Me Me H 43%g

14 m-Me Me H 43%g 15 o-Me Me H 36%

15 o-Me Me H 36% Scheme 1 Condensation between aniline and 4-hydroxybutan-2-one.

612 | Org. Biomol. Chem.,2011,9,610–615 SchemeThis 1 journalCondensation is © The between Royal aniline Society and 4-hydroxybutan-2-one. of Chemistry 2011

612 | Org. Biomol. Chem.,2011,9,610–615 This journal is © The Royal Society of Chemistry 2011 Communications

DOI: 10.1002/anie.201105876 Homogeneous Catalysis . Angewandte Pyrazine and Pyridine SynthesisA. Nandakumar ,E.Balaraman et al. Minireviews Synthesis of Peptides and Pyrazines from b-Amino Alcohols through

Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes: Ligand- § MilsteinControlled pyrazine synthesis Selectivity** – using PNP ligands instead of PNN . § Angewandte BulkyBoopathy PNP Gnanaprakasam, ligandsA. Nandakumar release,E Ekambaram.B alaramanaldehyde Balaraman,et al. which undergoes Yehoshoa Ben-David, condensation and with Minireviews amineDavid Milstein*

Peptides constitute one of the most important families of compounds in chemistry and biology. Short peptides have found intriguing biological and synthetic applications. For example, the conformational rigidity of cyclic peptides makes them attractive for drugpincer discoverycomplex and biomedical(51)for research.the synthesis[1] of substituted pyridines Several cyclic peptides( that52)t showhrough intriguingacceptorless biological activityhydrogen-transfer annulation of are found in nature.[2] Cyclic peptides have been discovered Scheme 5. Synthesis of quinolines from anilines and 1,3-diols. g-amino alcohols with secondarySchemealcohols 1. PNN- and[Eq. PNP-type(17)] pincer.The ruthenium complexes. that are novel antibiotics,[3] enzyme inhibitors,[4] and receptor dppf= 1,1’-bis(diphenylphosphino)ferrocene. complex 51 in the presence of tBuOK in 4:1mixture of antagonists. Among them are the smallest cyclopeptides, 2,5- Milstein et al. ACIE 2011, 50, 12240. diketopiperazines derivatives,toluene whichand areTHF commonlywas found found asto be optimal for the secondary [5] pincer§ Milsteincomplexnatural (pyridine51)f products.or the synthesisThesealcohol compoundsof initiatedsubstituted exhibitannulation high-affinitypyridines process.Cyclic and acyclic An atom-economical practical method for thebindingsynthesis to a largeof varietysecondary of receptorsalcohols and show awere broad rangesuccessfully incorporated into the (52)through ofacceptorless biological acitivities,hydrogen-transfer[6] including antimicrobial,annulation antitu-of highly substituted/functionalized pyrroles§ (Cyclic47)wmoral,as antiviral,achievedand acyclic and neuroprotectivepyridine secondarycore effects.of the 2,5-diketopiper- alcoholsproducts by couldconsecutive be usedC Na nd C C Scheme 5. Synthesis of quinolines from anilines and 1,3-diols. g-amino alcohols with secondary alcohols [Eq. (17)].The [30] ˇ ˇ by aruthenium-catalyzed three-component azineannulation derivativesof are synthesizedbond-forming in solutionhydrogen-transfer or on the solid steps. dppf= 1,1’-bis(diphenylphosphino)ferrocene. complex§ 51 in the presence of tBuOK in 4:1mixture of ketones,amines,and vicinal diols [Eq. (14)]C-Nphase.[29] andTo fromderive C-C commercially bond available formation and appropriately pro- toluene and THF was found to be optimal for the secondary better catalytic systems,various ruthenium catalyststected chiral,ligandsa-amino, acids in processes that are usually not alcohol initiatedatom-economicalannulation andprocess generate.C considerableyclic and amountsacyclic of and bases were analyzed for the three-component annulation Scheme 2. Reactions of alcohols with amines catalyzed by complexes An atom-economical practical method for the synthesis of secondary alcoholswaste. Largewere librariessuccessfully of cyclic peptidesincorporated are accessibleinto throughthe reaction. Better activity resulted from employingsolid-phase1m split-and-poolol% synthesis,[7] and various methods 1–3. highly substituted/functionalized pyrroles (47)was achieved pyridine core wereof the developedproducts forby theirconsecutive syntheses.[8] VeryC Na recently,nd C theC [{Ru(p-cymene)Cl2}2], 2mol%Xantphos,and 20 mol% [30] ˇ ˇ by aruthenium-catalyzed three-component annulation of bond-formingsynthesishydrogen-transfer of diketopiperazinessteps. from amino acids under tBuOK in tert-amyl alcohol at 1308C. Significantly,less- ketones,amines,and vicinal diols [Eq. (14)].[29] To derive microwave irradiation was reported.[9] Green, atom-econom- dehydrogenative coupling of amines with alcohols appeared reactive ketones and a-functionalized ketonesicalunder methodssame for the generation of peptides are highly later.[18] Unlike complex 1, the analogous PNP complex 2 (or better catalytic systems,various rutheniumcatalytic conditionscatalysts,lyieldedigands,the correspondingdesirable.pyrrole deriv- complex 3 in the presence of an equivalent of base) catalyzes and bases were analyzed for the three-componentatives.Aliphatic andannulationaromatic amines and ammoniaWe haveeffected developed severalBeller reactionset al. catalyzedreported byag PNNeneraltheroute couplingtoMilsteinindoles of amines et (al.56 with Chem.)f alcoholsrom Commun to form. 2013 imines, 49, rather 6632. II [10,11] reaction. Better activity resultedpyrrolefrom synthesisemployingand1mtheollatter% provided the NH-pyrrolesand PNP Ru. pincereasily complexesaccessible based onanilines pyridine, and epoxidesthan amidesby withar liberationuthenium- of H2 and H2O (Scheme 2, bipyridine,[12, 13] and acridine[14] and have discovered a new Eq. (2)).[19] [{Ru(p-cymene)Cl } ], 2mol%Xantphos,and 20 mol% [31] 2 2 mode of metal–ligand cooperationcatalyzed[15]oxidativebased on ligandannulation aroma- processHerein(Scheme we report6). a novelAfter method for peptide synthesis, tBuOK in tert-amyl alcohol at 1308C. Significantly,less- tization–dearomatization.[16] For example, the PNN RuII which involves dehydrogenative coupling of b-amino alcohols reactive ketones and a-functionalized ketones under same pincer complex 1 (Scheme 1) catalyzes the direct synthesis with extrusion of H2 catalyzed by complex 1. This environ- [17] catalytic conditions yielded the corresponding pyrrole deriv- of amides from alcohols and amines with liberation of H2 mentally benign and atom-economical reaction proceeds (Scheme 2, Eq. (1)). Several reports on amide formation by under neutral reaction conditions without the use of toxic atives.Aliphatic and aromatic amines and ammonia effected Beller et al. reported ageneral route to indoles (56)from reagents, activators, condensing agents, or other additives. pyrrole synthesis and the latter provided the NH-pyrroles. easily accessible[*] Dr.anilines B. Gnanaprakasam,and Dr.epoxides E. Balaraman,by Y. Ben-David,aruthenium- With the analogous PNP complex 2, a strikingly different catalyzed oxidativeProf. D.annulation Milstein process (Scheme 6).[31] After reaction takes place, which leads to pyrazines with extrusion Biomass-derived 1,2-diol derivatives were Departmenteffectively of Organic Chemistry of H2 and H2O. Weizmann Institute of Science Initially, we were interested to see whether coupling of b- utilized for the construction of quinoxalines using761002-nitroani- Rehovot, (Israel) amino alcohols with amines can be accomplished and whether lines in aruthenium-catalyzed hydrogen-transferE-mail:reaction [email protected] racemization would be involved. Reaction of (S)-2-amino-3- Homepage: http://www.weizmann.ac.il/Organic_Chemistry/mil- phenylpropan-1-ol (4), benzylamine, and 1 mol% of the wherein the diol and nitroaniline serve as hydrogen donor andstein.shtml catalyst 1 in toluene at reflux for six hours led to (S)-2-amino- hydrogen acceptor,respectively [Eq. (15)].O[**]ptimization This research was supported by the European Research Council [20a] under the FP7 framework, (ERC No 246837), by the Israel Science N-benzyl-3-phenylpropanamide 5 in 58% yield after studies reveal that [Ru3(CO)12]incombination Foundation,with dppp and by the MINERVA Foundation. D.M. is the holder of column chromatography (Scheme 3). The specific rotation served as an active catalyst in the presence ofthe50 Israelmol Matz% ProfessorialScheme Chair6. ofSynthesis Organic Chemistry.of indoles from anilinesof amideand5 obtainedepoxides. from the catalysis is essentially the same Biomass-derived 1,2-diol derivatives were effectively [20b] Supporting information for this article is available on the WWW as reported (+ 16.08). The neutral reaction conditions CsOH·H2Oin t-amyl alcohol at 1508C. Both symmetrical and utilized for the construction of quinoxalines using 2-nitroani- under http://dx.doi.org/10.1002/anie.201105876. likely help to prevent racemization. unsymmetrical diol derivatives were converted into the lines in aruthenium-catalyzed hydrogen-transfer reaction corresponding 2,3-substituted quinoxaline derivatives (48) screening several catalyst systems,the commercially available wherein the diol and nitroaniline serve as hydrogen donor and 12240 ß 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 12240 –12244 and electron-donating and electron-withdrawing substituents [Ru (CO) ]complex and the dppf ligand were found to be hydrogen acceptor,respectively [Eq. (15)].Optimization 3 12 on anilines significantly influenced the product yield.[9e] the optimal catalyst system for the efficient synthesis of studies reveal that [Ru (CO) ]incombination with dppp 3 12 indoles (Scheme 6; 56). Notably,noreaction was observed in served as an active catalyst in the presence of 50 mol% Scheme 6. Synthesis of indoles from anilines and epoxides. the absence of para-toluenesulfonic acid (p-TsOH), which is CsOH·H2Oin t-amyl alcohol at 1508C. Both symmetrical and necessary both for the epoxide ring opening (53)and the unsymmetrical diol derivatives were converted into the electrophilic cyclization reaction (55 56). Various substitu- ! corresponding 2,3-substituted quinoxaline derivatives (48) screening several catalyst systemsents,theoncommerciallyaniline underwentavailablecyclization to provide the corre- and electron-donating and electron-withdrawing substituents [Ru3(CO)12]complex and the dppfspondingligandindoleswereinfoundgoodtoyieldsbe .Initially,the ring opening of [9e] on anilines significantly influenced theMilsteinproductandyield.co-workers reportedthe optimalthe RuIIcatalyst/PNP complexsystem forthe theepoxideefficientwith anilinesynthesisprovidesof 1,2-amino alcohol deriva- 49 to catalyze the synthesis of theindolespyrazines(Scheme50 from6; 56b-amino). Notablytives,nor(eaction53)whichwasadditionallyobserved inundergo oxidative cyclization to alcohols in the presence of abthease absence[Eq. (16)]of.Tparahe -toluenesulfonictoluene form indoleacid (pderivatives-TsOH), which. is solution of a b-amino alcohol wasnecessaryheated tobothrefluxforvigorouslythe epoxide ringAhydrogen-transferopening (53)andstrategythe enabled the use of 1,3-diols, under argon atmosphere for 24 electrophilichours to givecycorrespondingclization reactioninstead(55 of56).potentiallyVarious substitu-unstable carbonyl compounds,for the ! pyrazines,presumably via an intermediateents on aniline1,4-dihydropyra-underwent cyclpreparationization to provideof 1,4-disubstitutedthe corre- pyrazoles [Eq. (18)].An zine.[9b] Thesame group exploredspondingabipyridine-basedindoles in goodRu/yieldsin.Isitunitiallygenerated,the ring openingcatalystof derived from 3mol% Milstein and co-workers reported the RuII/PNP complex the epoxide with aniline provides 1,2-amino alcohol deriva- 49 to catalyze the synthesis11028of thewwwpyrazines.angewandte.org50 from b-amino tives⌫ 2015(53Wiley-V)whichCH VeadditionallyrlagGmbH &Cundergoo. KGaA,Woxidativeeinheim cyclizationAngewto .Chem. Int. Ed. 2015, 54,11022 –11034 alcohols in the presence of abase [Eq. (16)].The toluene form indole derivatives. solution of a b-amino alcohol was heated to reflux vigorously Ahydrogen-transfer strategy enabled the use of 1,3-diols, under argon atmosphere for 24 hours to give corresponding instead of potentially unstable carbonyl compounds,for the pyrazines,presumably via an intermediate 1,4-dihydropyra- preparation of 1,4-disubstituted pyrazoles [Eq. (18)].An zine.[9b] Thesame group explored abipyridine-based Ru/ in situ generated catalyst derived from 3mol%

11028 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Pyrrole Synthesis

Journal of the American Chemical Society Article Journal of the American Chemical Society Article Scheme§ 2.Highly Synthesis substituted of Substituted Pyrrolespyrrole Using synthesisα- – 3-componentScheme 3. Synthesis annulation of N-Nonsubstituted Pyrroles from FunctionalizedScheme 2. Ketones Synthesisa of Substituted Pyrroles Using α- VariousScheme Ketones 3. and Synthesis Ammonia of Na-Nonsubstituted Pyrroles from Functionalized§ Ketone Ketones / aminea / vicinal diols Various Ketones and Ammoniaa

a(a) Isolated yield. (b) Total yield of 6g and 6g′. Reaction conditions: See Tablea(a) S4 Isolated in the Supportingyield. (b) Total Information. yield of 6g and 6g′. Reaction conditions: See Table S4 in the Supporting Information. Scheme 4. Synthesis of SubstitutedBeller et al. PyrrolesJACS 2013 Using, 135, Benzylic 11384. KetonesSchemea 4. Synthesis of Substituted Pyrroles Using Benzylic Ketonesa

a(a) Isolated yield. (b) Total yield of 5d and 5d′. Reaction conditions: sSee Tablea(a) S3 Isolated in the yield. Supporting (b) Total Information. yield of 5d and 5d′. Reaction conditions: sSee Table S3 in the Supporting Information.

Considering the importance of N-nonsubstituted pyrroles widely appliedConsidering in industry the andimportance academic of research,N-nonsubstituted19 we turned pyrroles our attentionwidely applied to this in class industry of compounds and academic by using research, ammonia,19 we turned whichour is a cheapattention but to challenging this class amine of compounds coupling reagent. by using20 ammonia,As shownwhich in Scheme is a cheap 3, the but reactions challenging of various amine ketones coupling including reagent.20 As functionalizedshown in ones Scheme with 3, the diff reactionserent vicinal of various diols ketones gave the including correspondingfunctionalized products ones in moderate with different to high vicinal yields diols (Scheme gave the 3, seecorresponding6a−6k). Simple products cyclohexanone in moderate1g towas high e yieldsfficiently (Scheme transformed3, see into6a− the6k). biologically Simple cyclohexanone interesting tetrahydroindole1g was efficiently skeletontransformed in good yield into (Scheme the biologically 3, see 6c interesting). Notably, tetrahydroindole even the pyridyl-substitutedskeleton in good ketone yield afforded (Scheme the desired 3, see 6c product). Notably, in good even the yield (Schemepyridyl-substituted 3, see 6k). ketone Similar afforded to the the results desired described product in in good Schemeyield 2, (Scheme unsymmetrical 3, see 6k 1-phenylethane-1,2-diol). Similar to the results3b describedand in propane-1,2-diolScheme 2,3e unsymmetricalgave the corresponding 1-phenylethane-1,2-diol products in good3b and yields withpropane-1,2-diol high regioselectivity3e gave (Scheme the corresponding 3, see 6a−6c products, 6e−6h in, good a(a) Isolated yield. Reaction conditions: See Table S5 in the and 6kyields). with high regioselectivity (Scheme 3, see 6a−6c, 6e−6h, a and 6k). Supporting(a) Information. Isolated yield. Reaction conditions: See Table S5 in the Finally, the generality of our synthetic protocol was further Supporting Information. evaluatedFinally, by testing the generality a number of of our combinations synthetic protocol of reactive was further benzylicevaluated ketones bywith testing vicinal a diols number and 2-phenylethylamine of combinations of2a reactive. substituents were transformed into the desired products As shownbenzylic in Scheme ketones 4, all with of thevicinal reactions diols and proceeded 2-phenylethylamine efficiently 2a.regioselectivelysubstituents in good were yields transformed (Scheme 4, into7b, the7d, and desired7f). products and affAsorded shown the in Schemesubstituted 4, all pyrroles of the reactions in high proceeded yields upon efficiently To gainregioselectively insight into in the good possible yields mechanism (Scheme 4, of7b, the7d, three- and 7f). isolation.and It awasfforded found the that substituted the substituents pyrroles possessing in high diff yieldserent uponcomponentTo coupling gain insight reaction, into the deuterium-labeling possible mechanism experiments of the three- electronicisolation. properties It was on found benzylic that the ketones substituents were tolerated possessing and differentwere carriedcomponent out. Here, coupling instead reaction, of t-amyl deuterium-labeling alcohol, toluene experiments was have littleelectronic influence properties on the formation on benzylic of ketonesproducts. were In addition tolerated andused, andwere the carried reaction out. was Here, interrupted instead of aftert-amyl 3 alcohol, h to observe toluene was to 1-(4-hydroxy-3-methoxyphenyl)propan-2-onehave little influence on the formation of products.1r, also In un- additionintermediates.used, and The the reaction reaction using was hydroxyl-deuterated interrupted after 3 ethylene h to observe symmetricallyto 1-(4-hydroxy-3-methoxyphenyl)propan-2-one functionalized vicinal diols with ester- and1r cyno-, also un-glycol 3aintermediates.′ with 2-phenylacetophenone The reaction using1m hydroxyl-deuteratedand 2-phenylethyl- ethylene symmetrically functionalized vicinal diols with ester- and cyno- glycol 3a′ with 2-phenylacetophenone 1m and 2-phenylethyl- 11386 dx.doi.org/10.1021/ja406666r | J. Am. Chem. Soc. 2013, 135, 11384−11388 11386 dx.doi.org/10.1021/ja406666r | J. Am. Chem. Soc. 2013, 135, 11384−11388 Pyrrole Synthesis

Stopped reaction after 3 hours

Beller et al. JACS 2013, 135, 11384. Pyrrole Synthesis

Beller et al. JACS 2013, 135, 11384. ARTICLES PUBLISHED ONLINE: 20 JANUARY 2013 | DOI: 10.1038/NCHEM.1547

A sustainable catalytic pyrrole synthesis Stefan Michlik and Rhett Kempe*

The pyrrole heterocycle is a prominent chemical motif and is found widely in natural products, drugs, catalysts and advanced materials. Here we introduce a sustainable iridium-catalysed pyrrole synthesis in which secondary alcohols and amino alcohols are deoxygenated and linked selectively via the formation of C–N and C–C bonds. Two equivalents of hydrogen gas are eliminated in the course of the reaction, and alcohols based entirely on renewable resources can be used as starting materials. The catalytic synthesis protocol tolerates a large variety of functional groups, which includes olefins, chlorides, bromides, organometallic moieties, amines and hydroxyl groups. We have developed a catalyst that operates efficiently under mild conditions. windling reserves of crude oil and the resulting price increase would be especially attractive in terms of its applicability in organic of this and other fossil carbon sources combined with synthesis (and industrial production) if it extended significantly the Denvironmental concerns have resulted in a call for the use scope of existing pyrrole syntheses. The known borrowing hydrogen of alternative, preferably renewable, resources. Aside from fuel, ulti- (BH) methodology22,23, also called hydrogen autotransfer (HA)24, mately a wide variety of chemical feedstocks are derived from fossil converts alcohols into imine or olefin functionalities and reduces sources. Renewable lignocellulosic materials are indigestible and them into amines or alkanes (Fig. 1a, black and blue reactions). therefore not useful as food products and can be processed to give Imines or olefins may be accessible if the final reduction or alcohols and polyols1. These rather highly oxidized hydrocarbons hydrogenation step is suppressed (Fig. 1a, black and red reactions) differ drastically in their chemical nature from the cracking products and the hydrogen atoms (originating from the alcohol substrates) of crude oil. Thus, there is a high demand for new reactions that are liberated. The selective linkage of these imine and olefin func- utilize such oxidized hydrocarbons and convert them into tionalities can lead to heteroaromatics. Coupling reactions with key chemicals. the concomitant liberation of H2 developed by the Milstein group Pyrroles are important compounds and present in many natural has attracted considerable attention recently25–34. These very products, drugs, catalysts and materials. Both the blood respiratory useful reactions can also involve condensation steps29,32,33, but pigment haem and the green photosynthesis pigment chlorophyll theyPyrrole have not been used Synthesis to link different alcohols via selective for- are biosynthesized from the pyrrole porphobilinogen2. mations of C–C and C–N bonds. The simultaneous use of different Atorvastatin, the bioactive component of the best-selling drug by alcohols is challenging because homocoupling has to be avoided. value2, is a pyrrole derivative. Polypyrroles are conducting polymers In turn, many classes of heteroaromatic compounds might be acces- used in batteries3 and solar cells4. There are many classic protocols2 sible§ andPyrrole unsymmetrically synthesis functionalized molecules could and catalytic transformations5–7 for the synthesis of pyrroles. The be obtained. surge of catalytic protocols published recently gives proof of the § Renewable secondary alcohols -1,2-amino alcohols (from amino acids) 8–21 vibrant activity in this field . As a result of both the high Results and discussion NATURE CHEMISTRY DOI: 10.1038/NCHEM.1547 demand for new reactions that utilize renewable resources and the Recently,§ we developedWater/air efficient stable catalysts catalyst for the alkylation of ARTICLES importance of pyrroles, a pyrrole synthesis that fully or partially amines35,36 and novel C–C coupling reactions37 that relied on the uses renewable resources is a highly desirable goal. Such a reaction BH/HA mechanism. The selectivity pattern of our catalysts a Table 1 | Synthesis of 2,5-disubstituted pyrroles from Catalyst I Catalyst II secondary alcohols and amino alcohols. Cat. II, H a c Step 1 OH HO NH2 N b N 1.1 equiv. KO-t-Bu R1 R2 N + ÐH 1 Ir cat., N N 1 2 R HO OH O N R R2 Ð2H2 OH R X NH2 + H2N KO-t-Bu H N P N R 2 P N4 P2 Ð2H2O 1 H ÐH + Ir HN NH2 2 Ir Ir1 HO HO P C1 Entry Product Catalyst loading Yield P1 [M]H2 Reduction C2 (mol%) (%) Oxidation [M] Ir cat., ÐHOH NaO-t-Bu Step 2 ÐH2O 1 1a R = Me 0.05 80

+ R1 ÐXH 201b R = Et .05 93 2 R1 Step 3 10% yield of pyrrole I 63% yield of pyrrole I R O R X NH N Ir cat., Condensation HN b H KO-t-Bu OH N NH 301c .1 65 X = N, CÐH; [M] = transition metal catalyst, 2 Ph Ph R = ÐH2 for example Ir or Ru Pyrrole I ÐH2O NN NN OH H N N NH HN N NH N Figure 1 | Alkylation reactions using amino alcohols. a,ThemechanismoftheBH/HA reactions (black and blue schemes). The suppression of the reduction 2 R Ph R 401d R = i-Pr .03 89 (i-Pr) P P(i-Pr) (i-Pr) P P(i-Pr) step (blue) could give rise to imines or olefins. Catalyst recycling can occur via hydrogen elimination (red). b,SelectiveN-alkylation of aromatic amines 2 Ir 2 2 Ir 2 catalysed by an iridium complex. c,Pyrrolesynthesis:step1,oxidationofthesecondaryalcoholviatheliberationofH;step2,imineformation;step3, O 501e R = 1-methylpropyl .05 88 2 H H intramolecular C–C coupling via the loss of hydrogen and water followed by isomerization to the pyrrole. cat catalyst, O-t-Bu t-butoxide. 2 R H 60.1 69 ¼ ¼ 1f R = i-Bu 701g R = Ph .2 86 Lehrstuhl Anorganische Chemie II, Universita¨t Bayreuth, 95440 Bayreuth, Germany. e-mail: [email protected] * 801h R = Bn .05 79 Figure 2 | Catalyst design. a,YieldsofpyrroleI using catalysts I and II.The 140 NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry molecular structure of catalyst II was determined by X-ray crystal structure analysis (right). b,SynthesisofthecatalystrestingstatebyreactingcatalystMichlik & Kempe. Nat. Chem. 2013, 5, 140.9 1i R = Me 0.03 84 II with an excess of alcohol. An iridium(III)trihydridespeciesisformedby 10 1j R = n-Bu 0.03 76 oxidation of the alcohol. R alkyl or aryl substituent. ¼ 11 1k R = n-hexyl 0.03 97 tolerated the presence of aliphatic amines38. Thus, unprotected ali- 12 1l R = n-nonyl 0.05 74 phatic amino alcohols could be employed to alkylate aromatic 13 1m R = 0.1 77 amines (Fig. 1b). A catalytic pyrrole synthesis becomes feasible if such catalysts are able to link selectively secondary alcohols and amino alcohols (Fig. 1c). The secondary alcohol is oxidized to 14 1n R = i-Pr 0.1 73 give a ketone, which undergoes imine formation with the amino 15 1o R = 4-MeOPh 0.05 75 alcohol. Subsequently, ring closure can occur via iridium-catalysed H R N Bn amino alcohol dehydrogenation and condensation. Two equivalents 16 1p R = 4-Cl–Ph 0.05 84 of water and hydrogen are eliminated in the course of the reaction 17 1q R = 4-Br–Ph 0.2 75 (dehydrogenative condensations). To identify a selective catalyst for this process we investigated thoroughly the reaction of 1-phenyl- ethanol with 2-amino-1-butanol. The compound 2-ethyl-5-phenyl- 18 1r R = Fe 0.2 87 1H-pyrrole (pyrrole I, Fig. 1c) is formed in this reaction. The best catalyst known to tolerate amino alcohols (catalyst I, Fig. 2a, 19 1s R = 2-furanyl 0.5 42 38,39 left ) afforded only 10% conversion when a catalyst loading of 20 1t R = 2-thiophenyl 0.5 57 0.01 mol% was applied. Chemically related catalysts that could OH provide more stability because of stabilization by three-dentate 21 1u R = 0.1 70 ligands40 were thus investigated. The iridium catalyst II (Fig. 2a, middle and right) turned out to be the best catalyst and gave 63% conversion under identical conditions. Catalyst II as a crystalline Reaction conditions: THF, 90 C, 24 hours. material can be handled in air (for instance, for refilling, weighing) 8 as it is not sensitive towards oxygen and moisture for weeks. The optimization of the reaction conditions eventually led to an effi- have not been reported previously (Table 1, blue entries). The syn- cient pyrrole synthesis protocol (details in the Supplementary thesis protocol is characterized by a very broad functional group Information and Supplementary Tables S1–S8). tolerance (Table 1). Amines (1c), olefins (1m), chlorides (1p), Having found a suitable catalyst and optimum reaction con- bromides (1q), organometallic moieties (1r) and hydroxyl groups ditions, we addressed the issues of scope and functional group tol- (1u) remain unaffected. Catalyst loadings as low as 0.03 mol% erance. Eight pyrroles were synthesized from different amino were sufficient for selected reactions listed in Table 1. All alcohols (Table 1, entries 1–8, 1a–1h). These examples carry a the reactions proceeded under rather mild thermal conditions phenyl substituent that originates from the secondary alcohol. (90 8C). The methodology is also extendable to 2H-pyrroles Additionally, 13 pyrroles were prepared by varying the secondary (Supplementary Table S10). alcohol (Table 1, entries 9–21, 1i–1u). Here the benzyl substituent As the C-alkylation step (Fig. 1c) can also take place at a second- that stems from 2-amino-3-phenylpropan-1-ol was ‘kept constant’. ary aliphatic carbon atom, this methodology allows for the synthesis By varying both parameters, 8 13 104 different a-substituted of 2,3,5-trisubstituted pyrroles (Table 2). Cyclic secondary alcohols pyrroles should be accessible, which× indicates¼ the versatility of this afford bicyclic pyrroles. None of the compounds listed in Table 2 synthetic protocol. Of the 21 pyrroles we actually prepared, 13 have been reported previously. These examples give further evidence

NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry 141 NATURE CHEMISTRY DOI: 10.1038/NCHEM.1547 ARTICLES

a Table 1 | Synthesis of 2,5-disubstituted pyrroles from Catalyst I Catalyst II secondary alcohols and amino alcohols. OH HO NH Cat. II, H N 2 R1 N R2 N 1.1 equiv. KO-t-Bu N N 1 + R R2 Ð2H2 N P N P N4 P2 Ð2H2O 1 Ir HN Ir Ir1 P C1 Entry Product Catalyst loading Yield P1 C2 (mol%) (%)

1 1a R = Me 0.05 80

10% yield of pyrrole I 63% yield of pyrrole I 201b R = Et .05 93 H b N Ph Ph 301c R = .1 65

NN NN OH H N N NH 2 R HN N NH Ph N R 401d R = i-Pr .03 89 Pyrrole(i-Pr) P SynthesisP(i-Pr) (i -Pr) P P(i-Pr) 2 Ir 2 2 Ir 2 O 501e R = 1-methylpropyl .05 88 H H 2 R H 601f R = i-Bu .1 69

§ Pyrrole synthesis 701g R = Ph .2 86 NATURE CHEMISTRY DOI: 10.1038/NCHEM.1547 ARTICLES § Water/air stable catalyst – very low catalyst80 loadings1h R = Bn .05 79 Figure 2 | Catalyst design. a,YieldsofpyrroleI using catalysts I and II.The molecular structure of catalyst II was determined by X-ray crystal structure a Table 1 | Synthesis of 2,5-disubstituted pyrroles from analysis (right). b,Synthesisofthecatalystrestingstatebyreactingcatalyst 9 1i R = Me 0.03 84 secondary alcohols and amino alcohols. Catalyst I Catalyst II II with an excess of alcohol. An iridium(III)trihydridespeciesisformedby 10 1j R = n-Bu 0.03 76 oxidation ofOH the alcohol.HO R alkylNH or aryl substituent.Cat. II, H N ¼ 2 R1 N R2 N 1.1 equiv. KO-t-Bu 11 1k R = n-hexyl 0.03 97 N N 1 + N R R2 Ð2H2 P N 38 12 1l R = n-nonyl 0.05 74 P N4 P2 tolerated the presence of aliphatic aminesÐ2H2O . Thus, unprotected1 ali- Ir HN Ir1 phatic amino alcohols could be employed to alkylate aromatic Ir 13 1m R = 0.1 77 P C1 Entry Product Catalyst loading Yield P1 C2 amines (Fig. 1b). A catalytic pyrrole synthesis(mol%) becomes feasible(%) if such catalysts are able to link selectively secondary alcohols and amino1 alcohols (Fig. 1c).1a R The= Me secondary0.05 alcohol is oxidized80 to 14 1n R = i-Pr 0.1 73 give20 a ketone, which undergoes1b R = Et imine formation.05 with the amino93 15 1o R = 4-MeOPh 0.05 75 10% yield of pyrrole I 63% yield of pyrrole I H alcohol. Subsequently, ring closure can occur via iridium-catalysed N H 16 R Bn 1p R = 4-Cl–Ph 0.05 84 b amino alcohol dehydrogenationN and condensation. Two equivalents Ph Ph of30 water and hydrogen are1c R eliminated = in the course.1 of the reaction65 17 1q R = 4-Br–Ph 0.2 75 (dehydrogenative condensations). To identify a selective catalyst NN NN OH for this process we investigated thoroughly the reaction of 1-phenyl- H 18 1r R = Fe 0.2 87 N N NH 2 R HN N NH ethanol withPh 2-amino-1-butanol.N R The compound 2-ethyl-5-phenyl- 401d R = i-Pr .03 89 (i-Pr) P P(i-Pr) (i-Pr) P P(i-Pr) 1H-pyrrole (pyrrole I, Fig. 1c) is formed in this reaction. The best 2 Ir 2 2 Ir 2 19 1s R = 2-furanyl 0.5 42 O catalyst50 known to tolerate1e R = amino1-methylpropyl alcohols.0 (catalyst5 I, Fig.88 2a, H H 38,39 2 R H left ) afforded only 10% conversion when a catalyst loading of 20 1t R = 2-thiophenyl 0.5 57 0.0160 mol% was applied.1f R Chemically = i-Bu related.1 catalysts that6 could9 OH provide70 more stability1g because R = Ph of stabilization.2 by three-dentate86 21 1u R = 0.1 70 ligands40 were thus investigated. The iridium catalyst II (Fig. 2a, 801h R = Bn .05 79 Figure 2 | Catalyst design. a,YieldsofpyrroleI using catalysts I and II.The middle and right) turned out to be the best catalyst and gave 63% conversion under identical conditions. Catalyst II as a crystalline molecular structure of catalyst II was determined by X-ray crystal structure Reaction conditions: THF, 90 8C, 24 hours. analysis (right). b,Synthesisofthecatalystrestingstatebyreactingcatalyst material9 can be handled1i in R = air Me (for instance,0.03 for refilling, weighing)84 II with an excess of alcohol. An iridium(III)trihydridespeciesisformedby as it is not sensitive towards oxygen and moisture for weeks. The10 optimization of the1j reaction R = n-Bu conditions eventually0.03 led to an76 effi- have not been reported previously (Table 1, blue entries). The syn- oxidation of the alcohol. R alkyl or aryl substituent. Michlik & Kempe. Nat. Chem. 2013, 5, 140. ¼ cient11 pyrrole synthesis1k protocol R = n-hexyl (details in0.03 the Supplementary97 thesis protocol is characterized by a very broad functional group Information and Supplementary Tables S1–S8). tolerance (Table 1). Amines (1c), olefins (1m), chlorides (1p), 38 12 1l 0.05 74 tolerated the presence of aliphatic amines . Thus, unprotected ali- Having found a suitableR = n catalyst-nonyl and optimum reaction con- bromides (1q), organometallic moieties (1r) and hydroxyl groups phatic amino alcohols could be employed to alkylate aromatic ditions,13 we addressed the1m issues R = of scope and0.1 functional group77 tol- (1u) remain unaffected. Catalyst loadings as low as 0.03 mol% amines (Fig. 1b). A catalytic pyrrole synthesis becomes feasible if erance. Eight pyrroles were synthesized from different amino were sufficient for selected reactions listed in Table 1. All such catalysts are able to link selectively secondary alcohols and alcohols (Table 1, entries 1–8, 1a–1h). These examples carry a the reactions proceeded under rather mild thermal conditions 14 1n R = i-Pr 0.1 73 amino alcohols (Fig. 1c). The secondary alcohol is oxidized to phenyl substituent that originates from the secondary alcohol. (90 8C). The methodology is also extendable to 2H-pyrroles give a ketone, which undergoes imine formation with the amino Additionally,15 13 pyrroles1o wereR = 4-MeOPh prepared by0.05 varying the secondary75 (Supplementary Table S10). H alcohol. Subsequently, ring closure can occur via iridium-catalysed N alcohol16 (TableR 1, entriesBn 1p 9–21, R = 4-Cl–Ph1i–1u). Here0.05 the benzyl substituent84 As the C-alkylation step (Fig. 1c) can also take place at a second- amino alcohol dehydrogenation and condensation. Two equivalents that stems from 2-amino-3-phenylpropan-1-ol was ‘kept constant’. ary aliphatic carbon atom, this methodology allows for the synthesis of water and hydrogen are eliminated in the course of the reaction By17 varying both parameters,1q R = 4-Br–Ph 8 13 1040.2 different a-substituted75 of 2,3,5-trisubstituted pyrroles (Table 2). Cyclic secondary alcohols (dehydrogenative condensations). To identify a selective catalyst pyrroles should be accessible, which× indicates¼ the versatility of this afford bicyclic pyrroles. None of the compounds listed in Table 2 for this process we investigated thoroughly the reaction of 1-phenyl- synthetic protocol. Of the 21 pyrroles we actually prepared, 13 have been reported previously. These examples give further evidence ethanol with 2-amino-1-butanol. The compound 2-ethyl-5-phenyl- 18 1r R = Fe 0.2 87 1H-pyrrole (pyrrole I, Fig. 1c) is formed in this reaction. The best NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry 141 catalyst known to tolerate amino alcohols (catalyst I, Fig. 2a, 19 1s R = 2-furanyl 0.5 42 38,39 left ) afforded only 10% conversion when a catalyst loading of 20 1t R = 2-thiophenyl 0.5 57 0.01 mol% was applied. Chemically related catalysts that could OH provide more stability because of stabilization by three-dentate 21 1u R = 0.1 70 ligands40 were thus investigated. The iridium catalyst II (Fig. 2a, middle and right) turned out to be the best catalyst and gave 63% conversion under identical conditions. Catalyst II as a crystalline Reaction conditions: THF, 90 C, 24 hours. material can be handled in air (for instance, for refilling, weighing) 8 as it is not sensitive towards oxygen and moisture for weeks. The optimization of the reaction conditions eventually led to an effi- have not been reported previously (Table 1, blue entries). The syn- cient pyrrole synthesis protocol (details in the Supplementary thesis protocol is characterized by a very broad functional group Information and Supplementary Tables S1–S8). tolerance (Table 1). Amines (1c), olefins (1m), chlorides (1p), Having found a suitable catalyst and optimum reaction con- bromides (1q), organometallic moieties (1r) and hydroxyl groups ditions, we addressed the issues of scope and functional group tol- (1u) remain unaffected. Catalyst loadings as low as 0.03 mol% erance. Eight pyrroles were synthesized from different amino were sufficient for selected reactions listed in Table 1. All alcohols (Table 1, entries 1–8, 1a–1h). These examples carry a the reactions proceeded under rather mild thermal conditions phenyl substituent that originates from the secondary alcohol. (90 8C). The methodology is also extendable to 2H-pyrroles Additionally, 13 pyrroles were prepared by varying the secondary (Supplementary Table S10). alcohol (Table 1, entries 9–21, 1i–1u). Here the benzyl substituent As the C-alkylation step (Fig. 1c) can also take place at a second- that stems from 2-amino-3-phenylpropan-1-ol was ‘kept constant’. ary aliphatic carbon atom, this methodology allows for the synthesis By varying both parameters, 8 13 104 different a-substituted of 2,3,5-trisubstituted pyrroles (Table 2). Cyclic secondary alcohols pyrroles should be accessible, which× indicates¼ the versatility of this afford bicyclic pyrroles. None of the compounds listed in Table 2 synthetic protocol. Of the 21 pyrroles we actually prepared, 13 have been reported previously. These examples give further evidence

NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry 141 Pyrrole Synthesis

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1547 § 2,3,5-PyrroleARTICLES synthesis

Table 2 | Synthesis of 2,3,5-trisubstituted pyrroles.

OH Ir cat. II, H H H N R" N 2 KO-t-Bu R R" R H + Ð2H R' HO 2 Ð2H2O R' 2 Entry Product Catalyst loading Yield (%) Entry Product Catalyst loading Yield (%) (mol%) (mol%) H N Bn 1 0.5 66 5 2e R” = Me 0.1 78

2a 602f R” = Et .05 88 H H N R" Ph N Bn 702g R” = i-Pr .03 84 2 0.1 63

2b 802h R” = i-Bu .03 79

H N 902i R” = Bn .05 80 C4H9 Bn 3 0.5 52

2c C3H7 2j H 10 n = 1 0.1 51 N H N NH Bn 4 0.5 56 11 2k n = 4 0.05 77

n 12 2l n = 8 0.1 37 2d

Fragments that stem from the amino alcohol are shown in red and those contributed by the secondary alcohol are in black. Reaction conditions: THF, 90 8C, 24 hours.

a R R' + Michlik & Kempe. Nat. Chem. 2013, 5, 140. + Bn NH HO 2 HO NH2 R' OH HN HN OH 0.1 mol% Ir cat. II, 0.1 mol% Ir cat. II, HN KO-t-Bu KO-t-Bu NH Ð2H2 NH Ð2H2 NH OH Ð2H O Ð2H O NH Bn 2 R 2 Bn R 3a 42% 3b 83%

b OH R3 + + Bn Bn Bn H HO R2 HN HN HN HO NH2 R2 N R3 NH2 0.1 mol% Ir cat. II, OH 0.1 mol% Ir cat. II, H C4H9 R1 KO-t-Bu N KO-t-Bu R2 HN N X 1 HN HN HN ÐH2O R Ð2H2 Ph Ph X X = CH, N Ð2H2O X 3c 83% 3d 82% 3e 87% R1

Figure 3 | Pyrrole syntheses involving diols. a, Synthesis of symmetric and unsymmetric dipyrroles. b,Synthesisofaminopyrroles.SeeTable1forthe reaction conditions.

of the potential of this methodology to complement and augment group tolerance and the selectivity of the C–C and C–N bond for- the conventional organic synthesis of pyrroles. mation steps allow access to these compounds. Starting from diols, dipyrroles can be prepared (Fig. 3a). As Mechanistically, we propose at this stage a reaction sequence as intermediates that carry a hydroxyl group can be isolated in good shown in Fig. 1c. Dehydrogenation of the secondary alcohol is sig- yields (Table 1, 1u), a sequential generation of differently substituted nificantly faster than that of the amino alcohol. It affords a ketone, dipyrroles is possible (Fig. 3a). Such dipyrrole syntheses generate a which undergoes a condensation reaction with the amino alcohol to remarkable amount of hydrogen (four equivalents). The synthesis form an imine (Schiff base). Independent synthesis of this imine of one mole of dipyrrole proceeds with the concomitant generation intermediate and its treatment under catalytic conditions gave of about 90 litres of H2. Furthermore, a combination of selective pyrrole I (Supplementary Figs S8 and S11). Alternatively, intermo- BH/HA chemistry and dehydrogenative condensations is possible. lecular b-alkylation of 1-phenylethanol using protected amino alco- The alkylation of aryl amines using diols gives rise to the respective hols (with or without the liberation of H2) does not proceed N-arylated amino alcohol, which can then be linked selectively with significantly under catalytic conditions (Supplementary Figs S12 unprotected amino alcohols. The products, amino pyrroles, were and S13). Kinetic data indicate that the intramolecular C-alkylation obtained in very good isolated yields (Fig. 3b). The amine functional is fast in comparison to the oxidation of the secondary alcohol, as no

142 NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1547

Table 2 | Synthesis of 2,3,5-trisubstituted pyrroles.

OH Ir cat. II, H H H N R" N 2 KO-t-Bu R R" R H + Ð2H R' HO 2 Ð2H2O R' 2 Entry Product Catalyst loading Yield (%) Entry Product Catalyst loading Yield (%) (mol%) (mol%) H N Bn 1 0.5 66 5 2e R” = Me 0.1 78

2a 602f R” = Et .05 88 H H N R" Ph N Bn 702g R” = i-Pr .03 84 2 0.1 63

2b 802h R” = i-Bu .03 79

H N 902i R” = Bn .05 80 C4H9 Bn Pyrrole3 Synthesis0.5 52

2c C3H7 2j H 10 n = 1 0.1 51 N H § Dipyrrole and aminopyrrole syntheses N NH Bn 4 0.5 56 11 2k n = 4 0.05 77 § High H2 production n 12 2l n = 8 0.1 37 § Useful for2d densely functionalized heterocycles

Fragments that stem from the amino alcohol are shown in red and those contributed by the secondary alcohol are in black. Reaction conditions: THF, 90 8C, 24 hours.

a R R' + + Bn NH HO 2 HO NH2 R' OH HN HN OH 0.1 mol% Ir cat. II, 0.1 mol% Ir cat. II, HN KO-t-Bu KO-t-Bu NH Ð2H2 NH Ð2H2 NH OH Ð2H O Ð2H O NH Bn 2 R 2 Bn R 3a 42% 3b 83%

b OH R3 + + Bn Bn Bn H HO R2 HN HN HN HO NH2 R2 N R3 NH2 0.1 mol% Ir cat. II, OH 0.1 mol% Ir cat. II, H C4H9 R1 KO-t-Bu N KO-t-Bu R2 HN N X 1 HN HN HN ÐH2O R Ð2H2 Ph Ph X X = CH, N Ð2H2O X 3c 83% 3d 82% 3e 87% R1

Figure 3 | Pyrrole syntheses involving diols. a, Synthesis of symmetric and unsymmetric dipyrroles. b,Synthesisofaminopyrroles.SeeTable1forthe reaction conditions. of the potential of this methodology to complement and augment group tolerance and the selectivity of the C–C and C–N bond for- the conventional organic synthesis of pyrroles. mation steps allow accessMichlik to & these Kempe compounds.. Nat. Chem. 2013, 5, 140. Starting from diols, dipyrroles can be prepared (Fig. 3a). As Mechanistically, we propose at this stage a reaction sequence as intermediates that carry a hydroxyl group can be isolated in good shown in Fig. 1c. Dehydrogenation of the secondary alcohol is sig- yields (Table 1, 1u), a sequential generation of differently substituted nificantly faster than that of the amino alcohol. It affords a ketone, dipyrroles is possible (Fig. 3a). Such dipyrrole syntheses generate a which undergoes a condensation reaction with the amino alcohol to remarkable amount of hydrogen (four equivalents). The synthesis form an imine (Schiff base). Independent synthesis of this imine of one mole of dipyrrole proceeds with the concomitant generation intermediate and its treatment under catalytic conditions gave of about 90 litres of H2. Furthermore, a combination of selective pyrrole I (Supplementary Figs S8 and S11). Alternatively, intermo- BH/HA chemistry and dehydrogenative condensations is possible. lecular b-alkylation of 1-phenylethanol using protected amino alco- The alkylation of aryl amines using diols gives rise to the respective hols (with or without the liberation of H2) does not proceed N-arylated amino alcohol, which can then be linked selectively with significantly under catalytic conditions (Supplementary Figs S12 unprotected amino alcohols. The products, amino pyrroles, were and S13). Kinetic data indicate that the intramolecular C-alkylation obtained in very good isolated yields (Fig. 3b). The amine functional is fast in comparison to the oxidation of the secondary alcohol, as no

142 NATURE CHEMISTRY | VOL 5 | FEBRUARY 2013 | www.nature.com/naturechemistry . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

pincer complex (51)for the synthesis of substituted pyridines (52)through acceptorless hydrogen-transfer annulation of Scheme 5. Synthesis of quinolines from anilines and 1,3-diols. g-amino alcohols with secondary alcohols [Eq. (17)].The dppf= 1,1’-bis(diphenylphosphino)ferrocene. complex 51 in the presence of tBuOK in 4:1mixture of toluene and THF was found to be optimal for the secondary alcohol initiated annulation process.Cyclic and acyclic An atom-economical practical method for the synthesis of secondary alcohols were successfully incorporated into the highly substituted/functionalized pyrroles (47)was achieved pyridine core of the products by consecutive C Nand C C [30] ˇ ˇ Angewandte by aruthenium-catalyzed three-component annulation of bond-formingHeterocyclehydrogen-transferSynthesis steps. Chemie ketones,amines,and vicinal diols [Eq. (14)].[29] To derive better catalytic systems,various ruthenium catalysts,ligands, and bases were analyzed for the three-component annulation [RuH2(PPh3)3CO] and 3mol%Xantphos was used for the Asustainable approach for the synthesis of pyrroles was reaction. Better activity resulted from employing 1mol% synthesis of pyrazoles (57)from 1,3-diols and alkyl and aryl developed from the condensation of renewable secondary [{Ru(p-cymene)Cl2}2], 2mol%Xantphos,and 20 mol% hydrazines in the presence of crotonitrile as ahydrogen alcohols with 1,2-amino alcohols using moisture- and air- tBuOK in tert-amyl alcohol at 1308C. Significantly,less- acceptor and 15 mol%AcOH as cocatalyst at 1108Cin stable crystalline tridendate ligands with iridium (63; reactive ketones and a-functionalized ketones underIndolesame Formationtoluene.Itcould be observed that the hydrogen acceptor Scheme 8). Acceptorless dehydrogenation initially starts with catalytic conditions yielded the corresponding pyrrole deriv- (crotonitrile) increased the rate of dehydrogenation of the atives.Aliphatic and aromatic amines and ammonia effected Bellerdiol, andet al.thatreportedthe co-catalystageneral route(AcOH)to indolesenhanced(56)ftheromcon- pyrrole synthesis and the latter provided the NH-pyrroles. easilydensationaccessiblereactionanilinesof theandaldehydeepoxideswithbyhydrazinearuthenium-.Thus the [31] § Bellercatalyzed – reactionAnalineoxidativeyield & epoxidedrasticallyannulationdecreased process (Schemein the absence6). Afterof either § TsOHah –ydrogen necessaryacceptor foror epoxideco-catalyst. opening[32] and electrophilic cyclization

Amine must be unprotected -indole anion important Biomass-derived 1,2-diol derivatives were effectively utilized for the construction of quinoxalines using 2-nitroani- Scheme 8. Synthesis of 2,3,5-substituted pyrroles by condensation of lines in aruthenium-catalyzed hydrogen-transfer reaction Aone-pot reaction for the preparation of indoles and secondary alcohols with 1,2-amino alcohols. wherein the diol and nitroaniline serve as hydrogen donor and subsequent C3-alkylation was reported to proceed through hydrogen acceptor,respectively [Eq. (15)].Optimization aCNand C Cbond-forming hydrogen-transfer process ˇ ˇ studies reveal that [Ru3(CO)12]incombination with dppp (Scheme 7). Cp*Ir was efficiently utilized for both intra- secondary alcohol derivatives followed by base-promoted Scheme 6. Synthesis of indoles from anilines and epoxides. Beller et al. Chem. Eur. J. 2014, 20, 1818. served as an active catalyst in the presence of 50§ molTethered% amino/alcohol condensation to afford the imine intermediate 65,which CsOH·H2Oin t-amyl alcohol at 1508C. Both symmetrical and undergoes dehydrogenative electrophilic cyclization to lead unsymmetrical diol derivatives were converted into the to formation of pyrrole derivatives (67), with adiversity of corresponding 2,3-substituted quinoxaline derivatives (48) screening several catalyst systems,the commercially available substituents,under mild reaction conditions and in good and electron-donating and electron-withdrawing substituents [Ru3(CO)12]complex and the dppf ligand were found to be yields.Interestingly, 63 was also successfully utilized for [9e] on anilines significantly influenced the product yield. the optimal catalyst system for the efficient synthesis of N-alkylation of the aniline derivatives 68 through aborrowing indoles (Scheme 6; 56). Notably,noreaction was observed in hydrogen reaction and subsequent hydrogen-transfer con- the absence of para-toluenesulfonic acid (p-TsOH), which is densation with 1,2-amino alcohols to form 3-amino-substi- necessary both for the epoxide ring opening (53)and the tuted pyrroles (69)invery good yields [Eq. (20)].[34] electrophilic cyclization reaction (55 56). Various substitu- ! ents on aniline underwent cyclization to provide the corre- sponding indoles in good yields.Initially,the ring opening of Milstein and co-workers reported the RuII/PNP complex the epoxide with aniline provides 1,2-amino alcohol deriva- Scheme 7. Synthesis of 3-substituted indoles by oxidative cyclization/ Keep et al. Org. Lett. 2007, 9, 3299. 49 to catalyze the synthesis of the pyrazines 50 from b-amino tivesC3-alkylati(53)whichon. additionally undergo oxidative cyclization to alcohols in the presence of abase [Eq. (16)].The toluene form indole derivatives. solution of a b-amino alcohol was heated to reflux vigorously Ahydrogen-transfer strategy enabled the use of 1,3-diols, under argon atmosphere for 24 hours to give corresponding insteadmolecularof potentiallyoxidativeunstablecyclizationcarbonylof 2-aminophenylcompounds,fethylor thealco- pyrazines,presumably via an intermediate 1,4-dihydropyra- preparationhol and consecutiveof 1,4-disubstitutedintermolecularpyrazoleshydrogen[Eq.borrowing(18)].AnC3- [9b] zine. Thesame group explored abipyridine-based Ru/ in situalkylationgeneratedof the indolecatalystby excessderivedof benzylfrom alcohol3mol%in the presence of KOHunder solvent-free conditions at 1108Cfor 11028 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA24,Whourseinheim.The amount ofAngewbase.Chem.playsInt.anEd.important2015, 54,11022role–11034in C3- In situ generation of acarbonyl precursor from an alcohol versus N-alkylation of indole.The analogue of commercially by catalytic dehydrogenation presents many opportunities to available anti-migraine drugs,such as N,N-dimethyltrypt- modify conventional synthetic protocols,wherein the pres- amine (60), was also synthesized by using above methodology. ence of acarbonyl functionality would decrease the efficiency The2,3-disubstituted indole 61 was synthesized by oxidative of synthetic transformations because of the unusual conden- cyclization of the corresponding secondary alcohol derivative. sation with the nucleophilic partner and self-aldol-type Theefficiency of the iridium catalyst was once again proven condensation process.Oxidative cyclization of primary alco- by the reaction of 2-nitrophenyl ethyl alcohol to give the C3- hols with o-aminobenzamides provided anew methodology alkylated indole 62 in the presence of excess of benzyl for the construction of quinazolinones (70), thus enabling alcohol, thereby employing multiple oxidations and reduc- abase-free,acceptorless hydrogen-transfer annulation pro- tions in asingle catalytic cycle [Eq. (19)].[33] cess [Eq. (21)].[35]

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11029 . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

2.4. Annulation of Alcohols with Unsaturated Systems

Organic building blocks such as alkenes and alkynes have been utilized in combination with alcohols,as precursors for carbonyls,to construct heterocyclic compounds by acatalytic hydrogen-transfer annulation process.Ruthenium-catalyzed redox isomerization of propargyl alcohols resulted in the sensitive a,b-unsaturated carbonyl compounds 71,which .undergo an intramolecular acid-catalyzed Michael addition, Angewandte A. Nandakumar,E.Balaraman et al. for Minireviewsthe construction of five- and six-membered N-hetero- cycles (72)inone pot (Scheme 9).[36]

2.4. Annulation of Alcohols with Unsaturated Systems ynyl)anilines through aC Nbond formation/hydrogen-trans- ˇ fer C Cbond formation sequence in one pot.[11b] Organic building blocks such as alkenes and alkynes have ˇ been utilized in combination with alcohols,as precursors for carbonyls,to construct heterocyclic compounds by acatalytic 3. Synthesis of O- and S-Heterocycles hydrogen-transfer annulation process.Ruthenium-catalyzed redox isomerization of propargyl alcohols resulted in the Oxygen- and sulfur-containing heterocycles are frequently sensitive a,b-unsaturated carbonyl compounds 71,which used in materials and biological chemistry.[37] Cyclic carbox- undergo an intramolecular acid-catalyzed Michael addition, Unsaturated Systems in Annulations ylates are present in large number of natural products and for the construction of five- and six-membered N-hetero- biologically important compounds,and it is auseful building cycles (72)inone pot (Scheme 9).[36] block in organic synthesis and polymer synthesis.[38] Over the § Redox isomerization of propargyl alcohols makes sensitive unsaturatedpast decades ,there has been considerable attention focused ynyl)anilines through aC Nbond formation/hydrogen-trans- carbonyl compounds on the asymmetric synthesisˇ of chiral lactones.Transition- Scheme 9. Synthesis of N-heterocycles by isomerization/Michael addi- fer C Cbond formation sequence in one pot.[11b] tion of amide-tethered propargyl alcohols. Boc = tert-butoxycarbonyl, metal-catalyzedˇ hydrogen transfer provides access to lactones Ns = o-nitrobenzenesulfonyl, Tf =trifluoromethanesulfonyl. in an environmentally friendly approach. 3. Synthesis of O- and S-Heterocycles 3.1. Annulation by Oxidative Cyclization of Alcohols Oxygen- and sulfur-containing heterocycles are frequently Selective intermolecular coupling of terminal propargylic used in materials and biological chemistry.[37] Cyclic carbox- amines with allylic alcohols was reported to occur at the Dehydrogenative annulation of diols into lactones is one ylates are present in large number of natural products and cationic ruthenium center for the preparation of piperidine of the most promising protocols for the construction of cyclic Trost et al.biologically JACS 2008,important 130, 16502.compounds ,and it is auseful building derivatives (75), having an exocyclicolefin, with the elimi- esters from easily accessible starting materials,with extrusion block in organic synthesis and polymer synthesis.[38] Over the nation of water as the only side product (Scheme 10). of H as the by-product. Milstein and co-workers developed past decades2 ,there has been considerable attention focused anew catalytic system, the PNN ruthenium dihydrido on the asymmetric synthesis of chiral lactones.Transition- § Advanced piperidineScheme 9. Synthesis intermediatesof N-heteroc ycles by isomerization/Michael addi- borohydride pincer complex 78,toachieve the base-free metal-catalyzed hydrogen transfer provides access to lactones § Cationic [Rh]tion of amide-tethered propargyl alcohols. Boc = tert-butoxycarbonyl, and acceptorless dehydrogenative coupling reaction of alco- Ns = o-nitrobenzenesulfonyl, Tf = trifluoromethanesulfonyl. in an environmentally friendly approach. hols into esters [Eq. (23)].[9c] Various 1,4- and 1,5-diols were transformed into five- and six-membered lactones (79)in refluxing toluene,thus enabling an acceptorless strategy with 3.1. Annulation by Oxidative Cyclization of Alcohols the liberation of H as aby-product. Selective intermolecular coupling of terminal propargylic 2 amines with allylic alcohols was reported to occur at the Dehydrogenative annulation of diols into lactones is one cationic ruthenium center for the preparation of piperidine of the most promising protocols for the construction of cyclic derivatives (75), having an exocyclicolefin, with the elimi- esters from easily accessible starting materials,with extrusion Dérien et al. Chem. Commun. 2012, 48, 6589. nationSchemeof10.waterSynthesasis ofthefunctionalizeonly sidedpiperidproductines from(Schemeunsaturate10).d of H2 as the by-product. Milstein and co-workers developed systems. anew catalytic system, the PNN ruthenium dihydrido borohydride pincer complex 78,toachieve the base-free and acceptorless dehydrogenative coupling reaction of alco- [Cp*Ru]-catalyzed oxidative C Ccoupling of propargylic ˇ hols into esters [Eq. (23)].[9c] Various 1,4- and 1,5-diols were amines and allylic alcohol gives amino aldehyde intermediate Chemo- and enantioselective formation of five- and six- transformed into five- and six-membered lactones (79)in 74 in THF.Insitu enamine formation of 74 provides anew membered lactones (84)were achieved from 1,4-keto alco- refluxing toluene,thus enabling an acceptorless strategy with method for constructing functionalized piperidines (75).[11a] hols using Noyoris transfer-hydrogenation catalyst the liberation of H as aby-product. Messerle et al. reported new pyrazolyl-1,2,3-triazolyl (Scheme 11). 1,4-keto2 alcohols are precursors for 1,4-keto N,N’ bidentate donor ligands for coordination to ruthenium aldehydes,which are sensitive to decomposition through an and iridium for C Cand C Nbond-forming annulations aldol-type pathway.The mechanism consists of Noyoris ˇ ˇ [Eq. (22)].The complex 76,containing electron-withdrawing transfer hydrogenation of the ketone followed by oxidation of Schemesubstituents10. Synthesonis ofthefunctionalizephenyldpring,iperidineswasfromefficientunsaturateford the the primary alcohol, thus leading to formation of alactone via systems.preparation of the tricyclic indole 77 from 2-(hydroxyalk-1- the hemiacetal intermediate 83.[39]

11030[Cp*Ru]-catalyzedwww.angewandte.orgoxidative C Cc⌫oupling2015 Wiley-Vof CHpropargylicVerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 ˇ amines and allylic alcohol gives amino aldehyde intermediate Chemo- and enantioselective formation of five- and six- 74 in THF.Insitu enamine formation of 74 provides anew membered lactones (84)were achieved from 1,4-keto alco- method for constructing functionalized piperidines (75).[11a] hols using Noyoris transfer-hydrogenation catalyst Messerle et al. reported new pyrazolyl-1,2,3-triazolyl (Scheme 11). 1,4-keto alcohols are precursors for 1,4-keto N,N’ bidentate donor ligands for coordination to ruthenium aldehydes,which are sensitive to decomposition through an and iridium for C Cand C Nbond-forming annulations aldol-type pathway.The mechanism consists of Noyoris ˇ ˇ [Eq. (22)].The complex 76,containing electron-withdrawing transfer hydrogenation of the ketone followed by oxidation of substituents on the phenyl ring, was efficient for the the primary alcohol, thus leading to formation of alactone via preparation of the tricyclic indole 77 from 2-(hydroxyalk-1- the hemiacetal intermediate 83.[39]

11030 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Overview

§ Synthesis of N-Heterocyclesß 1. N-alkylation of amines by alcohols 2. Dehydrogenative amide formation from amines and alcohols 3. Oxidative cyclization of alcohols 4. Annulation of unsaturated systems (alkene/alkyne) § Synthesis of O- / S-Heterocycles

. Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

2.4. Annulation of Alcohols with Unsaturated Systems

Organic building blocks such as alkenes and alkynes have been utilized in combination with alcohols,as precursors for carbonyls,to construct heterocyclic compounds by acatalytic hydrogen-transfer annulation process.Ruthenium-catalyzed redox isomerization of propargyl alcohols resulted in the sensitive a,b-unsaturated carbonyl compounds 71,which undergo an intramolecular acid-catalyzed Michael addition, for the construction of five- and six-membered N-hetero- cycles (72)inone pot (Scheme 9).[36]

ynyl)anilines through aC Nbond formation/hydrogen-trans- ˇ fer C Cbond formation sequence in one pot.[11b] ˇ

3. Synthesis of O- and S-Heterocycles

Oxygen- and sulfur-containing heterocycles are frequently used in materials and biological chemistry.[37] Cyclic carbox- ylates are present in large number of natural products and biologically important compounds,and it is auseful building block in organic synthesis and polymer synthesis.[38] Over the past decades,there has been considerable attention focused Scheme 9. Synthesis of N-heterocycles by isomerization/Michael addi- on the asymmetric synthesis of chiral lactones.Transition- tion of amide-tethered propargyl alcohols. Boc = tert-butoxycarbonyl, metal-catalyzed hydrogen transfer provides access to lactones Ns = o-nitrobenzenesulfonyl, Tf =trifluoromethanesulfonyl. in an environmentally friendly approach.

3.1. Annulation by Oxidative Cyclization of Alcohols Selective intermolecular coupling of terminal propargylic amines with allylic alcohols was reported to occur at the Dehydrogenative annulation of diols into lactones is one cationic ruthenium center for the preparation of piperidine of the most promising protocols for the construction of cyclic derivatives (75), having an exocyclicolefin, with the elimi- esters from easily accessible starting materials,with extrusion nation of water as the only side product (Scheme 10). of H2 as the by-product. Milstein and co-workers developed O/S-Heterocycleanew catalytic Formationsystem, the PNN ruthenium dihydrido borohydride pincer complex 78,toachieve the base-free and acceptorless dehydrogenative coupling reaction of alco- [9c] § Oxidative Cyclizationhols into esters of Alcohols[Eq. (23)]. toVa Lactonesrious 1,4- and 1,5-diols were transformed into five- and six-membered lactones (79)in § Annulationrefluxing of diolstoluene to lactones,thus enabling an acceptorless strategy with the liberation of H as aby-product. § H2 as only byproduct 2

Scheme 10. Synthesis of functionalizedpiperidines from unsaturated systems. Milstein et al. OM 2011, 30, 5716. [Cp*Ru]-catalyzed oxidative C Ccoupling of propargylic ˇ amines and allylic alcohol gives amino aldehyde intermediate Chemo- and enantioselective formation of five- and six- 74 in THF.Insitu enamine formation of 74§ providesChemo-anew & Enantioselectivemembered lactones (Lactonization84)were achieved from 1,4-keto alco- [11a] method for constructing functionalized piperidines§ (75Noyori). H-transferhols using catalystNoyori s transfer-hydrogenation catalyst Messerle et al. reported new pyrazolyl-1,2,3-triazolyl (Scheme 11). 1,4-keto alcohols are precursors for 1,4-keto § Normal synthesis à keto aldehydes are very sensitive moieties N,N’ bidentate donor ligands for coordination to ruthenium aldehydes,which are sensitive to decomposition through an and iridium for C Cand C Nbond-forming annulations aldol-type pathway.The mechanism consists of Noyoris ˇ ˇ [Eq. (22)].The complex 76,containing electron-withdrawing transfer hydrogenation of the ketone followed by oxidation of substituents on the phenyl ring, was efficient for the the primary alcohol, thus leading to formation of alactone via preparation of the tricyclic indole 77 from 2-(hydroxyalk-1- the hemiacetal intermediate 83.[39]

11030 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034

V Dong et al. JACS 2013, 135, 5553. . Angewandte A. Nandakumar,E.Balaraman et al. Minireviews

2.4. Annulation of Alcohols with Unsaturated Systems

Organic building blocks such as alkenes and alkynes have been utilized in combination with alcohols,as precursors for carbonyls,to construct heterocyclic compounds by acatalytic hydrogen-transfer annulation process.Ruthenium-catalyzed redox isomerization of propargyl alcohols resulted in the sensitive a,b-unsaturated carbonyl compounds 71,which undergo an intramolecular acid-catalyzed Michael addition, for the construction of five- and six-membered N-hetero- cycles (72)inone pot (Scheme 9).[36]

ynyl)anilines through aC Nbond formation/hydrogen-trans- ˇ fer C Cbond formation sequence in one pot.[11b] ˇ

3. Synthesis of O- and S-Heterocycles

Oxygen- and sulfur-containing heterocycles are frequently used in materials and biological chemistry.[37] Cyclic carbox- ylates are present in large number of natural products and biologically important compounds,and it is auseful building block in organic synthesis and polymer synthesis.[38] Over the past decades,there has been considerable attention focused Scheme 9. Synthesis of N-heterocycles by isomerization/Michael addi- on the asymmetric synthesis of chiral lactones.Transition- tion of amide-tethered propargyl alcohols. Boc = tert-butoxycarbonyl, metal-catalyzed hydrogen transfer provides Communicationaccess to lactones Ns = o-nitrobenzenesulfonyl, Tf =trifluoromethanesulfonyl. in an environmentally friendly approach. pubs.acs.org/JACS

3.1. Annulation by Oxidative Cyclization of Alcohols Selective intermolecular coupling of terminal propargylic Enantioselectiveamines with allylic alcohols Ketonewas reported Hydroacylationto occur at the Dehydrogenative Using Noyoriannulation’sof Transferdiols into lactones is one cationic ruthenium center for the preparation of piperidine of the most promising protocols for the construction of cyclic Hydrogenationderivatives (75), having Catalystan exocyclicolefin, with the elimi- esters from easily accessible starting materials,with extrusion Stephennation K.of Murphywater as andthe Vyonly M.side Dongproduct* (Scheme 10). of H2 as the by-product. Milstein and co-workers developed O/S-Heterocycleanew catalytic Formationsystem, the PNN ruthenium dihydrido Department of Chemistry, University of California, Irvine, California 92697-2025,borohydride Unitedpincer States,complex and Department78,toachieve of Chemistry,the base-free University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6,and Canadaacceptorless dehydrogenative coupling reaction of alco- [9c] § Oxidative Cyclizationhols into esters of Alcohols[Eq. (23)]. toVa Lactonesrious 1,4- and 1,5-diols were *S Supporting Information transformed into five- and six-membered lactones (79)in § Annulationrefluxing of diolstoluene to lactones,thus enabling an acceptorless strategy with the liberation of H as aby-product. ABSTRACT: An enantioselective ketone hydroacylation§ H2 as only byproduct 2 enables the direct preparation of lactones from keto alcohols. The alcohol is oxidized in situ to an aldehyde, obviating the need to prepare sensitive keto aldehyde substrates.Scheme 10. NoyoriSynthes’sis asymmetricof functionalize transferdpiperid hydrogenationines from unsaturated catalystsystems. was applied to address challenges of reactivity, chemoselectivity, and enantioselectivity. Milstein et al. OM 2011, 30, 5716. [Cp*Ru]-catalyzed oxidative C Ccoupling of propargylic ˇ amines and allylic alcohol gives amino aldehyde intermediate Chemo- and enantioselective formation of five- and six- he γ-butyrolactone core occurs in more§ than Chemo- 15,000 & Enantioselective Lactonization natural74 in THF products,.Insitu1 includingenamine formation antibioticof and74 provides antitumoranew membered lactones (84)were achieved from 1,4-keto alco- T 2 [11a] agents,method and it isfor a usefulconstructing buildingfunctionalized block in organicpiperidines synthesis.§ (75ToNoyori). H-transferhols using catalystNoyori s transfer-hydrogenation catalyst prepare enantioenrichedMesserle et al. lactones,reported ournew laboratorypyrazolyl-1,2,3-triazolyl has been (Scheme 11). 1,4-keto alcohols are precursors for 1,4-keto developingN,N’ rhodium-catalyzedbidentate donor ligands hydroacylation.for coordination3 These rhodiumto ruthenium aldehydes,which are sensitive to decomposition through an and iridium for C Cand C Nbond-forming annulations aldol-type pathway.The mechanism consists of Noyoris catalysts, however, fail to cyclizeˇ 1,4-ketoˇ aldehydes such as 3 to generate[Eq. the(22)] corresponding.The complexγ-butyrolactones76,containing electron-withdrawing (Figure 1a).4,5 transfer hydrogenation of the ketone followed by oxidation of Instead,substituents significant decarbonylationon the phenyl occurs,ring, presumablywas efficient duefor to the the primary alcohol, thus leading to formation of alactone via the conformationalpreparation offlexibilitythe tricy ofclic theseindole substrates.77 from Poor2-(hydroxyalk-1- reactivity the hemiacetal intermediate 83.[39] Compound 6 is prone to aldols, need in low concentration and chemoselectivity have limited the use of other catalysts in 11030this transformation,www.angewandte.org including N-heterocyclic⌫ 2015 Wiley-V carbenesCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 (NHCs),6a,b ruthenium hydrides such as RuHCl(CO)- 6c 6d ffi (PPh3)3, and iridium hydrides. Enantioselectivity is di cult to achieve, and only one moderately enantioselective (43−84% V Dong et al. JACS 2013, 135, 5553. ee) Tishchenko-type cyclization of related 1,5-keto aldehydes, which uses stoichiometric SmI2 and a chiral auxiliary, has been reported.6e These results highlight a need for hydroacylation catalysts that operate by alternative mechanisms. To address these challenges, we considered that a bifunctional ruthenium hydride catalyst could be applied to achieve a novel chemo- and enantioselective hydroacylation of 1,4-dioxygenated substrates Figure 1. Strategies for intramolecular ketone hydroacylation. (Figure 1b).7 Applying an asymmetric transfer hydrogenation (ATH) catalyst8 allows the 1,4-keto aldehyde substrate, which is bond and therefore avoids competing aldehyde decarbon- sensitive to decomposition via aldol-type pathways, to be ylation.14 replaced with a stable 1,4-keto alcohol that undergoes in situ With this mechanism in mind, we chose to apply Noyori’s 8 oxidation to the requisite aldehyde (Figure 1b).9 Krische and ATH catalyst in ketone hydroacylation. To test our hypothesis, co-workers have demonstrated diene and alkyne hydroacylation we combined 4-hydroxybutyrophenone with 5 mol % A and 1.2 from the alcohol oxidation state by applying transfer hydro- equiv of acetone as a hydrogen acceptor (Scheme 1). We 15 genation conditions.10 We envisioned that hydroacylation of evaluated a number of solvents and found that when ethyl 1,4-keto alcohol 4 could occur by initial asymmetric reduction acetate (EtOAc) was used, γ-phenyl-γ-butyrolactone was of the ketone to afford diol 5. Oxidation of the primary isolated in 92% yield with 91% ee in favor of the R 11 stereoisomer.16 In contrast to reports on the use of RuHCl- alcohol would generate 1,4-hydroxy aldehyde 6, which could 6c 6d cyclize to hemiacetal 7. Finally, irreversible oxidation of 7 (CO)(PPh3)3 and iridium hydrides in ketone hydro- would yield the desired γ-butyrolactone 8.12,13 In contrast to our reported rhodium-catalyzed hydroacylations,3 this mecha- Received: March 1, 2013 nistic scenario circumvents activation of the aldehyde C−H Published: April 8, 2013

© 2013 American Chemical Society 5553 dx.doi.org/10.1021/ja4021974 | J. Am. Chem. Soc. 2013, 135, 5553−5556 Journal of the American Chemical Society Communication

Table 1. Selected Optimization Experiments in the C−C Table 3. Enantioselective 2-(Alkoxycarbonyl)allylation via a Coupling of Ester 1 to Alcohol 2b [R = (CH2)2Ph] Iridium-Catalyzed C−C Bond-Forming Transfer Hydrogenationa

aYields are of materials isolated by silica gel chromatography. See the Supporting Information for further details.

Under the optimal conditions identified for the conversion of acrylic ester 1 and alcohol 2b to racemic butyrolactone 3b, catalysts modified by diverse axially chiral chelating phosphine ligands were assayed. The chiral ligands assayed included BINAP, Xylyl-BINAP, SEGPHOS, DM-SEGPHOS, C3-TU- NEPHOS, MeO-BIPHEP, Cl,MeO-BIPHEP, and CTH-P- . PHOS, among others. However, the degree of asymmetric Angewandteinduction was disappointing, with 80% ee or lower in each case. A. Nandakumar,E.Balaraman et al. Minireviews In contrast, the chiral complex modified by (−)-2,2′,5,5′- tetramethyl-3,3′-bis(diphenylphosphine)-4,4′-bithiophene . 15 thiophenols,respectively,were developed using iron(II) Angewandte[(−)-TMBTP], designated as Ir(TMBTP), provided butyr- A. Nandakumar,E.Balaraman et al. Minireviewsolactone 3b in 79% yield with 88% ee (Table 2, entryphthaloc 1). Theyanine (FePc) as the catalyst [Eq. (30)].[45]

Table 2. Selected Optimization Experiments in the aAs described for Table 2. bTHF (0.5 M). cThe cyclometalated thiophenols,respectively,were developed using iron(II) d Enantioselective C−C Coupling of Ester 1 to Alcoholphthaloc 2b [Ryaninecatalyst(FePc) derivedas the catalyst from 4-CN-3-NO[Eq. (30)]2-BzOH.[45] was used. (R)-DM- a SEGPHOS was used as the ligand. See the Supporting Information = (CH2)2Ph] for further details. Chiral Lactones continued 5. Synthesis ofconversionCarbocyclic ofCo aldehydempounds4gbyto butyrolactone 3g,2- Annulation of(alkoxycarbonyl)allylationAlcohols with Unsaturated can be conductedSystems from the aldehyde § α-exo-Methylene γ-butyrolactones – present in 10% of natural products oxidation level using isopropanol as a terminal reductant (Scheme 1). Butyrolactones 3a and 3b were previously 5. SynthesisFurthermoreofprepared,tCaherbocyclicapplication in opticallyCoofmpounds enrichedhydrogen-transfer formby and servedannu- to corroborate Scheme 13. Synthesis of lactones from diols and methyl acrylates. lationsAnnulationhas beenoftheextendedAlcohols assignmenttowiththe of absoluteconstructionUnsaturated stereochemistryof Systemscarbocyclic for butyrolactones dppp = 1,3-bis(diphenylphosphino)propane. compounds from3a−vicinali. diols and dienes.Aruthenium(0) complexFurthermoregenerated,thefromapplication[Ru3(CO)of12]ahydrogen-transfernd BIPHEP wasannu-used to synthesize carbocyclic compounds from diols and dienes Scheme 13. Synthesis of lactones from diols and methyl acrylates. lations has beenSchemeextended 1. Enantioselectiveto the construction 2-(Alkoxycarbonyl)allylationof carbocyclic via through a[4 2] cycloaddition [Eq. (31)].This novel strategy dppp = 1,3-bis(diphenylphosphino)propane. compounds +fromIridium-Catalyzedvicinal diols and Aldehydedienes.A Reductiveruthenium(0) Coupling via a follows oxidative coupling of an in situagenerated dione and Yields are of materials isolated by silicaKrische gel chromatography. et al. JACScomplex 134, 11100.generated Transferfrom Hydrogenation[Ru3(CO)12]and BIPHEP was used § Spirolactones – from C-C couplingEnantiomeric followed excesses wereby lactonization determined by chiral stationarydieneto synthesize phaseto formcarbocthe oxametallacyclic compoundsycle 98from(Schemediols and14),dienesthus HPLC analysis. See the Supporting Information for further details. through a[4+2] cycloaddition [Eq. (31)].This novel strategy follows oxidative coupling of an in situ generated dione and isolated yields and degree of asymmetric induction werediene bothto form the oxametallacycle 98 (Scheme 14), thus of the b,g-unsaturatedhighly solvent-dependent.ketones with substoichiometric Whereas reactionsquan- performed in 2- tities of p-toluenesulfonicMe-THF and dioxaneacid afforded providedthe butyrolactonetetrasubstituted3b in 68% yield furans 95 bywithcyclodehydration. 77% ee and 33% yield with 72% ee, respectively, a 31% aAs described for Table 2. See the Supporting Information for further § Furans – from redox-triggeredyield C-C with 92%coupling ee was of obtained diols in MeCN (Table 2, entries 2− details. of the b,g-unsaturated4). To balanceketones the yieldwith andsubstoichiometric enantioselectivity,quan- reactions were tities of p-toluenesulfonicconducted in THF/MeCNacid afforded mixturesthe tetrasubstituted over 3 days (Table 2, furans 95 byentriescyclodehydration. 5 and 6). To illustrate the potential utility of adducts 3a−i, The optimal conditions identified for the enantioselective butyrolactone 3f was converted into allylic bromide 5, which process were applied to primary aliphatic alcohols 2a−i. The was subjected to zinc-mediated reductive coupling to p- corresponding α-exo-methylene γ-butyrolactones 3a−i were bromobenzaldehyde and 3-phenylpropanal (Scheme 2).17 The produced in good to excellent isolated yieldsKrische with et enantiose-al. ACIE 53, 3232. corresponding adducts 6a and 6b were generated diaster- lectivities ranging from 82 to 95% ee (Table 3). Benzylic eoselectively, thereby establishing entry to disubstituted α-exo- alcohols also participated in the 2-(alkoxycarbonyl)allylation,Scheme 14. Synthesmethyleneis of carbocyγ-butyrolactonesclic compounds by withhydrogen-tra controlnsfer of the relative and 4. Synthesisbutof theN,O- enantioselectivitiesand N,S-Heterocycles were modest.by16 As illustrated[4+ by2] cycloaddi the tion.absolute stereochemistries. Annulations with Phenol and Thiophenol Deriva- tives 11101 dx.doi.org/10.1021/ja303839h | J. Am. Chem. Soc. 2012, 134, 11100−11103 Scheme 14. Synthesis of carbocyclic compounds by hydrogen-transfer 4. Synthesis of N,O- and N,S-Heterocycles by Benzoxazoles and benzothiazoles are commonly encoun- leading[4+2] cycloaddito thetion.allylruthenium complex 99 by protonolytic Annulations with Phenol and Thiophenol Deriva- tered groups in natural products,pharmaceuticals,and agro- cleavage by the diol. Intramolecular allylruthenation of 99 tives chemicals.Transition-metal-catalyzed hydrogen-transfer cou- gives the ruthenium(II) alkoxide 100,which undergoes pling of alcohols with 2-aminophenols and thiophenols b-hydride elimination to form the ruthenium hydride 101. Benzoxazoles and benzothiazoles are commonly encoun- leading to the allylruthenium complex 99 by protonolytic resulted in the sustainable synthesis of benzoxazoles and Reductive elimination of 101 affords the carbocyclic com- tered groups in natural products,pharmaceuticals,and agro- cleavage by the diol. Intramolecular allylruthenation of 99 benzothiazoles,respectively,and displaces the conventional pounds 102 and regenerates the ruthenium(0) complex.[46] chemicals.Transition-metal-catalyzed hydrogen-transfer cou- gives the ruthenium(II) alkoxide 100,which undergoes use of stoichiometric oxidants to effect the aromatizing pling of alcohols with 2-aminophenols and thiophenols b-hydride elimination to form the ruthenium hydride 101. condensation of alcohols or aldehydes with 2-aminophenols. resulted in the sustainable synthesis of benzoxazoles and Reductive elimination of 101 affords the carbocyclic com- Iron-catalyzed formation of benzoxazoles by the reaction of benzothiazoles,respectively,and displaces the conventional pounds 102 and regenerates the ruthenium(0) complex.[46] 2-nitrophenol and primary alcohols was reported to proceed use of stoichiometric oxidants to effect the aromatizing through ahydrogen-transfer reaction. Borrowing hydrogen fromcondensationalcohols ofwasalcoholsused toorreducealdehydesthe nitrowithfunctional2-aminophenolsgroup,. whichIron-catalyzedupon reductionformationundergoesof benzoxazolescondensationby theandreactionoxidationof to2-nitrophenolprovide benzoxazolesand primary[Eq.alcohols(29)].[44]wasInexpensivereported toandproceedeffi- cientthroughcatalyticahydrogen-transfermethods for thereaction.preparationBorrowingof benzoxazoleshydrogen andfrombenzothiazolesalcohols was usedfromtoalcoholsreduce theandnitro2-aminophenolsfunctional groupand, Polycyclic aromatic compounds were efficiently prepared which upon reduction undergoes condensation and oxidation through ruthenium(0)-catalyzed [4+2] cycloaddition of cyclic [44] to provide benzoxazoles [Eq. (29)]. Inexpensive and effi- diols with dienes followed by acid-catalyzed aromatization. cient catalytic methods for the preparation of benzoxazoles This methodology was utilized for the construction of various and benzothiazoles from alcohols and 2-aminophenols and polycPoycliclycycompoundsclic aromaticsuchcompoundsas substitutedwerefluoranthenesefficiently prepared(104) naphthalenesthrough ruthenium(0)-catalyzed(105), indeno[1,2,3-[4cd+]-fluoranthene2] cycloaddition(106of),cyan-clic diols with dienes followed by acid-catalyzed aromatization. This methodology was utilized for the construction of various 11032 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 polycyclic compounds such as substituted fluoranthenes (104) naphthalenes (105), indeno[1,2,3-cd]-fluoranthene (106), an-

11032 www.angewandte.org ⌫ 2015 Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem. Int. Ed. 2015, 54,11022 –11034 Angewandte Heterocycle Synthesis Chemie

3.2. Annulation of Alcohols with Unsaturated Systems Angewandte Heterocycle Synthesis Chemie Williams and co-workers reported the synthesis of 2,5- substituted furans from readily available 1,4-alkynediols by ruthenium-catalyzed3.2. Annulation of Alcoholshydrogen-transferwith Unsaturatedisomerization.Systems [Ru(PPh3)3(CO)H2]inassociation with Xantphos was utilized for isomerizationWilliams andof co-workers1,4-alkynediolsreportedinto 1,4-diketonesthe synthesis(87of) 2,5- whichsubstitutedthen undergofuransacid-catalyzedfrom readily dehydration,available 1,4-alkynediolsthus provid- by [41] ingruthenium-catalyzedarange of 2,5-disubstitutedhydrogen-transferfurans (88;Schemeisomerization.12).

[Ru(PPh3)3(CO)H2]inassociation with Xantphos was utilized for isomerization of 1,4-alkynediols into 1,4-diketones (87) which then undergo acid-catalyzed dehydration, thus provid- Scheme 11. Enantioselective synthesis of lactones. ing arange of 2,5-disubstituted furans (88;Scheme 12).[41] Intramolecular hydrogen-transfer Knoevenagel-type con- densation was also developed using alcohols which act as carbonyl precursors and active methylene groups,thus lead- Schemeing to11.cyEnantioseleclic compoundsctive synthesisthroughof lactones.aCCbond formation ˇ process.Cossy et al. reported the synthesis of chromanes and Intramolecular hydrogen-transfer Knoevenagel-type con- thiochromane (85)byaniridium-catalyzed borrowing-hydro- Scheme 12. Synthesis of 2,5-disubstituted furans. densationgen reactionwas[Eq.also(24)]developed.[40] Iridiumusingcatalyticalcoholssystemswhichsuchactasas

carbonyl[{Cp*IrClprecursors2}2]and [{Ir(cod)Cl}and active2]/PPhmethylene3 weregroupshighly,tefficienthus lead- ingcatalyststo cyunderclic compoundsmicrowave conditionsthrough aC.BothCbcatalyticond formationsystems Krische et al. reported the enantioselective synthesis of ˇ processshowed.Csimilarossy etreactivitiesal. reportedandthecissynthesis/trans selectivitiesof chromanesfor theand a-exo-methylene g-butyrolactones (90)through aC Cbond- ˇ thiochromaneconstruction (of85)bchromanesyaniridium-catalyzed,whereas [{Ir(cod)Cl}borrowing-hydro-2]/PPh3 formingScheme 12.reactionSynthesisof ofacrylic2,5-disubsesterstitutedandfurans.alcohols by using genshowedreactionbetter[Eq.yields(24)]for.[40]theIridiumsynthesiscatalyticof thiochromane-4-systems such as acyclometallated chiral iridium complex (89)under mild

[{Cp*IrClcarbonitrile2}2]a.Thend reaction[{Ir(cod)Cl}path2]/PPhconsists3 wereof initialhighlycatalyticefficient reaction conditions for acarbonyl 2-(alkoxycarbonyl)allyla- catalystsdehydrogenationunder microwaveof an alcoholconditionsto form.Bacotharbonylcatalyticcompoundsystems tion [Eq.Krische(26)]et.Tal.hereportedabove reactionthe enantioselectivein THF providessynthesisthe of showedand subsequentsimilar reactivitiesintramolecularandcondensationcis/trans selectivitiesof the carbonylfor the maximuma-exo-methyleneyield withg-butyrolactonesmoderate ee values(90)t,whroughhereasaCMeCNCbond- with an active methylene group to provide olefin function- provides amoderate yield with high ee values.Tobalanceˇthis construction of chromanes,whereas [{Ir(cod)Cl}2]/PPh3 forming reaction of acrylic esters and alcohols by using showedalities.Fbetterinally yieldshydrogenationfor the synthesisof the condensedof thiochromane-4-product reactionacyclometallatedin terms of yieldchiralandiridiumee valuecomplex,the reactions(89)underweremild [42] carbonitrileutilizing the.Tborrowedhe reactionhydrogenpath consistsaffords theof correspondinginitial catalytic conductedreaction inconditionsa1:1 mixturefor acof THF/MeCNarbonyl 2-(alkoxycarbonyl)allyla-. dehydrogenationO- and S-containingof anheterocalcoholyclictocompoundsform acarbonyl85. compound tion [Eq. (26)].The above reaction in THF provides the and subsequent intramolecular condensation of the carbonyl maximum yield with moderate ee values,whereas MeCN O/S-Heterocyclewith an active Formationmethylene group to provide olefin function- provides amoderate yield with high ee values.Tobalance this alities.Finally hydrogenation of the condensed product reaction in terms of yield and ee value,the reactions were utilizing the borrowed hydrogen affords the corresponding conducted in a1:1 mixture of THF/MeCN.[42] § Knoevenagel-type condensation to form chromanes & thiochromanes O- and S-containing heterocyclic compounds 85. § Olefin intermediate captures [Ir]-H instead of nitrile

Hydrogen-transfer condensation of alcohols with active Hydrogen-transfer C Cbond-forming reactions of vicinal ˇ methylene groups in the presence of ahydrogen acceptor, diols with methyl acrylate,using the ruthenium(0) complex

which suppresses the final hydrogenation step,provides [Ru3(CO)12]and dppp,were reported for the construction of astrategy to construct heteroaromatic compounds.The lactones and spirolactones from acyclic and cyclic diols, diversity of the substituted benzofurans and benzothiophenes respectively.Diversely substituted cyclic diols were converted

86 was achieved by iridium-catalyzed Cossyintramolecular et al. Eur. J. Org.dehy- Chem. into2012, spirolactones2012, 4453. in good to excellent yields [Eq. (27)].The drogenativeHydrogen-transfercondensationcondensationof alcohols ofwithalcoholsactive methylenewith active mechanisticHydrogen-transferpathway for theC formationCbond-formingof the lactonereactionsthroughof vicinal § groups using p-benzoquinone as the hydrogen acceptor C Ccoupling and subsequentˇ lactonization is shown in Active methylenemethylene condensationgroups in the presence of ahydrogen acceptor, ˇdiols with methyl acrylate,using the ruthenium(0) complex [Eq. (25)].[9d] Scheme 13.[11c] § BQ is H-acceptorwhich suppresses the final hydrogenation step,provides [Ru3(CO)12]and dppp,were reported for the construction of Redox-triggered C Ccoupling of diols with alkynes to astrategy to construct heteroaromatic compounds.The lactones and spirolactonesˇ from acyclic and cyclic diols, diversity of the substituted benzofurans and benzothiophenes giverespectivelyb,g-unsaturated.Diverselyketonessubstituted(94)wascyclicreporteddiolstowereproceedconvertedby 86 was achieved by iridium-catalyzed intramolecular dehy- usingintoanspirolactonesin situ generatedin goodrutheniumto excellentcomplexyields[Eq.[Eq.(28)](27)].The.The drogenative condensation of alcohols with active methylene reactionmechanisticinvolvedpathwayhydrohydroxyalkylatiofor the formation ofnwtheithlactonecompletethrough regioselectivity.[43] Theabove coupling reaction was effected groups using p-benzoquinone as the hydrogen acceptor C Ccoupling and subsequent lactonization is shown in withˇ acatalytic amount of [Ru (CO) ], PCy ,and 1- [Eq. (25)].[9d] Scheme 13.[11c] 3 12 3 adamantanecarboxylic acid in m-xylene at 1308C. Treatment Redox-triggered C Ccoupling of diols with alkynes to Cossy et al. Org. Lett. 2013, 15, 3876. ˇ give b,g-unsaturated ketones (94)was reported to proceed by Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11031 using an in situ generated ruthenium complex [Eq. (28)].The reaction involved hydrohydroxyalkylationwith complete regioselectivity.[43] Theabove coupling reaction was effected

with acatalytic amount of [Ru3(CO)12], PCy3,and 1- adamantanecarboxylic acid in m-xylene at 1308C. Treatment

Angew.Chem. Int.Ed. 2015, 54,11022 –11034 ⌫ 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11031 Final

§ H-Transfer annulations are a pretty mild way to synthesize heterocycles

§ Although the substrates are not always the most trivial for these reactions, they can still be cheaper/easier to synthesize than trying to densely functionalize pyrroles, pyridines, etc

§ I think this strategy is a great way to rethink organic synthesis and how to approach synthetic problems Questions

2. Predict the mechanism.

Ph OH 1. Predict the product. 5 mol% [Cp*IrCl2]2 + HO Ph NH2 2.5 mol% KOH N (5 equiv.) o 110 C, N2 H 78% yield

3. Predict the mechanism.

5 mol% RuCl3⋅xH2O Me Me HO 10 mol% PBu3 + NH2 N HO 5 mol% MgBr2⋅OEt2 Cl mesitylene, reflux, 16 h Cl 43% yield Questions 1

5 mol% [Ru(p-cymene)Cl ] OH 2 2 NH Me Me OH 5 mol% Xantphos + NH2 NH o 2 PhMe, 160 C, 12 h N Me 46% yield Me H

5 mol% RuH2(PPh3)4 iPr iPr N N O Ph OH Br (5 mol%) Ph HO + Ph NC N Ph 20 mol% NaH benzene, 80 oC, 18 h O 51% yield

N H N Ru P(tBu)2 OH Cl CO OH (0.5 mol%) +

NH2 PhMe/THF, KOtBu (1 equiv.) reflux, 24 h N (2 equiv.) 71% yield Question 2

§ d Ph OH 5 mol% [Cp*IrCl2]2 + HO Ph NH2 2.5 mol% KOH N (5 equiv.) o 110 C, N2 H 78% yield Scheme 3. Proposed Mechanism for the One-Pot, Tandem Oxidative Cyclization/Alkylation of 2-Aminophenyl Ethyl Alcohol and Primary Alcohols To Afford Substituted Indoles

if any, bis-indolylmethane byproducts were evident, high- utilizing the indirect functionalization of alcohols. These lighting indole concentration as the key factor in the allow one-pot access to a wide range of key building blocks. generation of these species. Work continues on the development and application of this In conclusion, two novel [Cp*IrCl2]2-catalyzed methods methodology. for the synthesis of substituted indoles have been developed, Acknowledgment. This work was a collaboration be- tween the MIDAS Centre, Pfizer Chemical Research and Scheme 4. One-Pot Synthesis of 3-Benzylindole from Development, and Johnson Matthey. 2-Nitrophenyl Ethyl Alcohol and Benzyl Alcohol Supporting Information Available: Full experimental details and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. OL071274V

3302 Org. Lett., Vol. 9, No. 17, 2007 View Article Online

4-methylquinoline was formed. Since the 4-substituted quinoline Varian Mercury 300 instrument. Chemical shifts were measured

is the opposite regioisomer compared to the product in Table 1, relative to the signals of residual CHCl3 (d H 7.26 ppm) and CDCl3

the condensation from 4-hydroxybutan-2-one and butane-1,3-diol (d C 77.16 ppm). Mass spectrometry was performed by direct inlet are clearly not following the same pathway. on a Shimadzu GCMS-QP5000 instrument. High resolution mass If a 1 : 1 mixture of nonane-1,3-diol and 4-hydroxybutan-2- spectra were recorded at the Department of Physics and Chemistry, one are condensed with aniline and the ruthenium catalyst, University of Southern Denmark. the former is converted into 2-n-hexylquinoline as in Table 2, entry 3 while the latter again affords 4-methylquinoline. In General procedure for ruthenium-catalysed preparation of all these experiments 4-hydroxybutan-2-one is believed to react quinolines with aniline by elimination of water followed by a Michael A stirred solution of RuCl3 xH2O (26 mg, 0.10 mmol), addition to produce 4-anilinobutan-2-one and subsequently · MgBr2 OEt2 (26 mg, 0.10 mmol), PBu3 (50 mL, 0.20 mmol), aniline · 4-methylquinoline. It is known that 4-methoxybutan-2-one reacts (2.0 mmol) and diol (2.4 mmol) in anhydrous mesitylene (0.50 mL) 20 with aniline hydrochloride to produce 4-methylquinoline and the was heated to reflux under an argon atmosphere for 16 h. The reaction presumably occurs by elimination of methanol followed reaction mixture was cooled to room temperature and purified 21 Question 2 by a Michael addition. Since the elimination of water and the directly by flash column chromatography (toluene–EtOAc) on following Michael addition are very facile reactions, the present silica gel pretreated with 0.1% of Et3N in toluene. condensation may proceed by initial dehydrogenation of the § Doebner–von Millerdiol to Quinoline the 3-hydroxyaldehyde Synthesis (Scheme 2). It has been shown 2-n-Butyl-1,3-propanediol that certain ruthenium catalysts will selectively dehydrogenate a primary alcohol over a secondary alcohol.22 The generated 3- Prepared from diethyl butylmalonate in 88% yield by reduction 5 mol% RuCl3⋅xH2O Me with LiAlH .25 1HNMR(300MHz,CDCl): 3.83 (dd, 3.8, hydroxyaldehyde willMe then eliminate water, undergo a Michael 4 3 d J = HO 10 mol% PBu3 addition+ followed by electrophilic cyclisation.23 The latter part 10.7 Hz, 2H), 3.66 (dd, J = 7.6, 10.6 Hz, 2H), 2.04 (br s, 2 OH), NH2 N involves theHO same steps as in5 the mol% Doebner–von MgBr2⋅OEt2 Miller quinoline 1.84–1.71 (m, 1H), 1.36–1.19 (m, 6H), 0.90 (t, J = 7.0 Hz, 3H). Cl mesitylene, reflux, 16 h Cl 13 synthesis8b,24 and the regioselectivity with unsymmetric diols are CNMR(75MHz,CDCl3): d 66.8, 42.1, 29.5, 27.5, 23.1, 14.1. 43% yield 1 then determined in the initial dehydrogenation reaction. MS: m/z 96 [M–2H2O]. H NMR data are in accordance with literature values.25

Quinoline

1 Rf 0.22 (toluene–EtOAc, 85 : 15). HNMR(300MHz,CDCl3): d 8.91 (d, J = 4.2 Hz, 1H), 8.13 (t, J = 8.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 13 7.38 (dd, J = 4.2, 8.2 Hz, 1H). CNMR(75MHz,CDCl3): d 150.5, 148.4, 136.1, 129.5, 129.5, 128.4, 127.9, 126.6, 121.2. MS: m/z 129 [M]. NMR data are identical to those from a commercial sample. B

Published on 22 November 2010. Downloaded by University of Texas Libraries 05/10/2015 15:36:53. Scheme 2 Proposed mechanism for quinoline formation from anilines 2-Methylquinoline Mg H B OH and 1,3-diols. O 26 H Rf 0.26 (toluene–EtOAc, 85 : 15). bp 109–111 ◦C/8 mmHg (lit. Me Me Me Me [O] 1 118 ◦C/10 mmHg). HNMR(300MHz,CDCl3): d 8.18 (d, J = H Conclusion 8.5 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.84–7.74 (m, 2H), 7.55 (t, N N N N 8.1 Hz, 1H), 7.30 (d, 8.4 Hz, 1H), 2.84 (s, 3H). 13CNMR Cl H In summary,Cl weH have explored theCl one-stepH synthesis of quinolinesCl H J = J = from anilines and 1,3-diols with RuCl xH O/PBu as the catalyst. (75 MHz, CDCl3): d 158.7, 147.6, 135.8, 129.1, 128.4, 127.3, 126.2, 3· 2 3 The reaction does not require any stoichiometric additives and 125.4, 121.7, 25.1. MS: m/z 143 [M]. NMR data are in accordance Madsen et al. Org. Biomol. Chem. 2011, 9, 610.11h only produces water and dihydrogen as byproducts. Increased with literature values. yields are obtained when a catalytic amount of MgBr OEt is 2· 2 2-n-Hexylquinoline added and the transformation gives easy access to 2- and in 1 particular 3-substituted quinolines from simple starting materials. Rf 0.54 (toluene–EtOAc, 85 : 15). H NMR (300 MHz, CDCl3): d 8.10–8.08 (m, 1H), 8.07–8.05 (m, 1H), 7.78 (dd, J = 1.3, 8.0 Hz, Experimental 1H), 7.69 (ddd, J = 1.4, 6.9, 8.4 Hz, 1H), 7.49 (ddd, J = 1.1, 7.0, Reactions were monitored by GC on a Shimadzu GC2010 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.02–2.95 (m, 2H), 1.87– 13 instrument equipped with an EquityTM 1column(15m¥ 0.1 mm, 1.75 (m, 2H), 1.48–1.24 (m, 6H), 0.92–0.84 (m, 3H). CNMR 0.1 mmfilm).Meltingpointsareuncorrected.Solventsusedfor (75 MHz, CDCl3): d 163.2, 147.7, 136.4, 129.5, 128.8, 127.6, 126.8, chromatography were of HPLC grade. Thin layer chromatography 125.8, 121.5, 39.4, 31.9, 30.2, 29.4, 22.7, 14.2. MS: m/z 213 [M]. 27 was performed on aluminium plates coated with silica gel 60. NMR data are in accordance with literature values. Visualisation was done by UV or by dipping in a solution of 3-Methylquinoline KMnO4 (1%), K2CO3 (6.7%) and NaOH (0.08%) in H2O followed 1 by heating with a heatgun. Flash chromatography was performed Rf 0.24 (toluene–EtOAc, 85 : 15). bp 105–106 ◦C/4 mmHg. H

with silica gel 60 (35–70 mm). NMR spectra were recorded on a NMR (300 MHz, CDCl3): d 8.76 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H),

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