Thesis
Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions
LINDER, David
Abstract
La combinaison du précatalyseur stable à l'air [CpRu(η⁶-C₁₀H₈)] [PF₆] avec des ligands de type pyridine-monooxazoline a permis de développer une nouvelle stratégie pour effectuer des réactions de substitution allyliques avec des conditions expérimentales simples. Cette famille de ligands est apparue particulièrement appropriée pour effectuer l'étude de réactions du type réarrangement de Carroll. Le mécanisme de cette réaction a été étudié et un cycle catalytique raisonnable en a découlé. Une stratégie de double activation par co-catalyse a donc été développée: l'utilisation synergique de sels de magnésium a permis d'effectuer ces réactions à température ambiante et donc de manière plus sélective.
Reference
LINDER, David. Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions. Thèse de doctorat : Univ. Genève, 2008, no. Sc. 4033
URN : urn:nbn:ch:unige-14791 DOI : 10.13097/archive-ouverte/unige:1479
Available at: http://archive-ouverte.unige.ch/unige:1479
Disclaimer: layout of this document may differ from the published version.
1 / 1 UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES Section de Chimie et Biochimie Département de chimie organique Professeur J. Lacour
Enantioselective CpRu-Catalyzed Decarboxylative C-C Bond Forming Reactions
THÈSE
présentée à la Faculté des sciences de l'Université de Genève
pour obtenir le grade de Docteur ès sciences, mention chimie
par
David LINDER
de
Copenhague (Danemark)
Thèse N° 4033
GENÈVE
Atelier d'impression ReproMail
2008
Dedicated to Dr. Pierre Mangeney. On the occasion of his retirement.
We want the observed facts to follow logically from our concept of reality. Without the belief that it is possible to grasp the reality with our theoretical constructions, without the belief in the inner harmony of our world, there could be no science. This belief is and always will remain the fundamental motive for all scientific creation. Throughout all our efforts, in every dramatic struggle between old and new views, we recognize the eternal longing for understanding, […] continually strengthened by the increasing obstacles to comprehension. Albert Einstein (1879-1955), Leopold Infeld (1898-1968) The Evolution of Physics, 1938 , Cambridge University Press
Remerciements
You can get much farther with a kind word and a gun than you can with a kind word alone. Al Capone (1899-1947)
Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé au sein du laboratoire du Professeur Jérôme Lacour, dans le département de chimie organique de l’Université de Genève, du 01 octobre 2004 au 31 octobre 2008.
Je voudrais d’abord exprimer toute ma gratitude au Professeur Jérôme Lacour, pour m’avoir donné l’opportunité de réaliser ce travail de thèse dans son laboratoire, pour la confiance et l’autonomie qu’il m’a accordées ainsi que pour sa patience pendant toutes ces années.
Je désire ensuite remercier le Professeur Antonio Togni (Eidgenössische Technische Hochschule Zürich) et le Docteur Clément Mazet (Université de Genève) pour avoir eu l’amabilité de bien vouloir juger les travaux de thèse rapportés ci-après.
J’exprime aussi toute ma gratitude aux équipes de service d’analyse : RMN (Dr. Damien Jeannerat, André Pinto and Bruno Vitorge), SM (Philippe Perottet and Eliane Sandmeier) et SM-HR (Prof. Gérard Hopfgardner and Nathalie Oudry) pour leur indispensable contribution.
Je voudrais chaleureusement saluer mes collègues, passés et présents, et de tout le département participation active et leur alcophilie partagée. Dans un ordre parfaitement chaotique, j’exprime ma gratitude à Richard, Sam-arche, Benoit, Jej and Simone pour de si nombreuses raisons que je ne peux les détailler ici. Un grand merci à Cédric (a.k.a. Boubou) et à Michael pour leur participation efficace à ces travaux. Le « réfugié politique » remercie Reno, Chloé, Stéphane (x2), Fran et les autres pour leur accueil. Un grand, grand merci à Phan (je suis pas encore devenu comme Niko Brevic…) et à la bande de gros lourds pour les gaming-sessions interminables et les sessions pizza sponsorisées par Feldschlösschen. “Gracie mille ” pour “little V” et à l’autre petite terroriste pour tout et plus encore.
Il me reste à remercier Ankit Sharma, Andrei Badoiù et le Dr. Chloé Bournaud pour leur participation active à la correction de ce manuscrit.
Finalement je tiens à remercier chaleureusement Pierre et Manu qui m’ont tout deux transmis leur enthousiasme pour la recherche et leur saine vision du milieu…
- i - Abbreviations, Symbols and Units
Abbreviations Cp*: pentamethyl cyclopentadienyl br(s): broad (singlet) Cp’: substituted cyclopentadienyl s: singlet phen: 2,2’-phenantroline d: doublet bpy: 2,2’-bipyridine dd: doublet of doublet cod: 1,4-cyclooctadiene t: triplet BSA: N,O-bis(trimethylsilyl)amide dt: doublet of triplet Tol.: toluene q: quartet TMS: trimethyl silyl sept: septet TBDMS: tert -butyl dimethyl silyl m: multiplet TIPS: triisopropyl silyl TLC: Thin layer chromatography n-Pr: propyl Rf: retardation factor i-Pr: iso -propyl cat.: catalytic amount t-Bu: tert -butyl equiv.: equivalent BDU: Diaza(1,3)bicyclo[5.4.0]undecane conv.: conversion Ts: Tosyl C: concentration Symbols litt.: literature δ: chemical shift ref.: reference λ: wave length maj.: major J: coupling constant min.: minor l: length
M.p.: melting point tR: retention time ppm: part per million T: temperature rac : racemic Units ent : opposite enantiomer of °C: degree Celsius Y.: yield K: Kelvin ee : enantiomeric excess g: gram dr.: diastereomeric ratio mg: miligram R.T.: room temperature l: microliter b: branched regioisomer mL: milliliter l: linear regioisomer mmol: millimole Ar: aryl M: molarity napht: naphthalene min: minute Cp: cyclopentadienyl h: hour
- ii - Résumé en français
Formation énantiosélective de liaisons C-C par décarboxylation catalysée par des complexes CpRu
L’objectif des travaux de cette thèse est de développer une version asymétrique du réarrangement de Carroll, une réaction qui peut être catalysé par des complexes de ruthénium (Schéma 1 ) comme décrit par Tunge 1 puis par Lacour. 2 Bien que le domaine de la substitution allylique soit extrêmement étendu, ce type de réactions catalysées par des complexes de ruthénium est globalement peu décrit dans la littérature.
O O O O 6 [CpRu(η -C10H8)][PF6] (10 mol%) N O L18f (10 mol%) N
THF, 60 °C O b l L18f R R R b:l jusqu'à 99:1 ee jusqu'à 87 % Schéma 1: Réarrangement de Carroll catalysé par un complexe du type CpRu.
Les expériences décrites dans ce manuscrit montrent que la famille des pyridine- monooxazolines est une classe de ligand appropriée pour l’étude du réarrangement de Carroll catalysé par des complexes de type Cp-ruthenium. En particulier le ligand L18f a permis d’obtenir de bonnes réactivités (jusqu’à 20 fois supérieure qu’avec les pyridine-imines), de bonnes régiosélectivités (jusqu’à > 99:1) et de bonnes énantiosélectivités (jusqu’à > 80 %).
O O Le mécanisme de la réaction a été O O R O étudié en détail. Même s’il n’a été R O
Ar [Ru*] possible de caractériser précisément les
Ar espèces intermédiaires, les nombreuses
[Ru*] expériences ont permis de rassembler CO2 O suffisamment d’indices non équivoques
R pour pouvoir proposer un cycle O O [Ru*] catalytique raisonnable très proche de R R Ar celui décrit dans la littérature dans le Ar Ar b l cas des réactions catalysées au Schéma 2: Cycle catalytique postulé. palladium ( Schéma 2 ).
1 Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603-2605. Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835-2837. 2 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082-2085. Constant, S.; Tortoioli, S.; Muller, J.; Linder, D.; Buron, F.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 8979-8982.
- iii - Résumé en français
Ces résultats mécanistiques ont par ailleurs permis de développer une stratégie de co-catalyse basée sur l’utilisation synergique de sels de magnésium. De meilleures réactivités ont ainsi été obtenues ; permettant de réaliser la réaction à température ambiante et par conséquent d’améliorer sensiblement les sélectivités.
Dans un second temps, le système catalytique développé a été testé dans le cadre de réactions de substitutions allyliques classiques (Schéma 3 ). Il est apparu dans ces cas que l’utilisation de sels de lithium donne de bons résultats en termes de régiosélectivité (généralement 9:1) pour des réactions de substitutions allyliques sans ajout de base avec une grande variété de prénucléophiles activés. L’ensemble de ces expériences souffre malheureusement du fait que la diastéréosélectivité obtenue pour les produits branchés est médiocre (généralement 1:1) et aucune piste prometteuse ne peut être proposée à ce jour pour contourner ce problème.
O Z X Z X 6 O R' [CpRu(η -Napht)][PF6] (2 mol%) O O L18f (2.4 mol%) Z R'' O LiOMe (1 mol%)
X THF, 60 °C b l R R R b:l jusqu'à 92:8 r d. de 45:55 à 56:44 Schéma 3: Réactions de substitution allylique dîtes classiques .
Il a aussi été montré que la même stratégie pouvait être appliquée au réarrangement décarboxylatif de carbonates et carbamates dérivés de l’alcool cinnamique. Le cas des nucléophiles azotés demeure relativement problématique puisque ni la chimiosélectivité (réactions de double alkylation) ni la régiosélectivité n’ont pu être contrôlées de manière satisfaisante. Au contraire, le cas de nucléophiles oxygénés est apparu comme bien plus prometteur puisque de bonnes sélectivités ont pu être obtenues.
6 La combinaison du précatalyseur stable à l’air [CpRu( η -C10 H8)][PF 6] avec le ligand L18f a permis de développer une nouvelle stratégie pour effectuer des réactions de substitutions allyliques avec des conditions expérimentales relativement simples. Le ligand L18f est par ailleurs apparu comme particulièrement intéressant non seulement à cause de sa synthèse extrêmement directe, mais aussi du fait que les deux énantiomères de l’aminoalcool dont il est issu sont commerciaux sous forme énantiopure pour un prix relativement modéré ((+)- or (–)- aminoindanol 5g ~ 200 CHF).
De nombreux développements sont actuellement en cours au laboratoire pour évaluer la généralité de ce type de catalyseurs dans le cadre de la substitution allylique.
- iv - Table of Contents
Enantioselective CpRu-Catalyzed Decarboxylative C-C Bond Forming Reactions
1. GENERAL INTRODUCTION - 1 -
1.1. PREAMBLE - 1 -
1.2. ASYMMETRIC CATALYSIS - 4 - 1.2.1. Birth of the Catalytic Concept - 4 - 1.2.2. Industrial Developments - 4 -
1.3. MODERN APPLICATIONS OF ASYMMETRIC CATALYSIS - 5 - 1.3.1. Asymmetric Organocatalysis - 5 - 1.3.2. Asymmetric Organometallic Catalysis - 6 -
2. METAL CATALYZED ALLYLIC SUBSTITUTIONS - 7 -
2.1. PREAMBLE - 7 -
2.2. PALLADIUM CATALYZED ALLYLIC SUBSTITUTIONS - 8 - 2.2.1. General Mechanism - 8 - 2.2.2. Structure of Metal-Allyl Complexes - 9 - 2.2.3. Enantiodiscriminating Steps - 11 -
2.3. OTHER METAL -CATALYZED ALLYLIC SUBSTITUTIONS - 18 - 2.3.1. Copper - 18 - 2.3.2. Molybdenum - 19 - 2.3.3. Tungsten - 19 - 2.3.4. Rhodium - 20 - 2.3.5. Iridium - 20 -
2.4. RUTHENIUM -CATALYZED ALLYLIC SUBSTITUTIONS - 23 - 2.4.1. Early-Stage Developments - 23 - 2.4.2. Ru-Catalysts for Regioselective Allylation of Nucleophiles - 24 - 2.4.3. Asymmetric Allylation of Nucleophiles - 27 - 2.4.4. Ru-catalyzed “Carroll rearrangement” - 28 -
2.5. AIM AND SCOPE OF THE WORK - 30 -
- v - Table of Contents
3. CATALYTIC SYSTEM OPTIMIZATION - 31 -
3.1. PREAMBLE - 31 -
3.2. OPTIMIZATION OF THE LIGAND - 33 - 3.2.1. Use and Synthesis of Pymox Ligands - 33 - 3.2.2. Ligand Structure Screening - 34 -
3.3. OPTIMIZATION OF THE REACTION CONDITIONS - 36 - 3.3.1. Reaction Conditions Screening - 36 - 3.3.2. Synthesis of the Substrates - 37 - 3.3.3. Scope of the Reaction - 38 - 3.3.4. Metal Source Optimization - 40 -
3.4. CONCLUSION - 44 -
4. MECHANISTIC INSIGHT - 45 -
4.1. PREAMBLE - 45 - 3 4.2. MO ANALYSIS OF [C PRUL2(η -ALLYL )] COMPLEXES - 45 -
4.3. REGIOSELECTIVITY OF THE REACTION IN THE CASE OF UNSYMMETRICALLY
SUBSTITUTED SUBSTRATES - 48 - 4.7.1. Analysis in Terms of Molecular Orbitals - 48 - 4.7.2. Substituent effect: linear free-energy relations - 50 -
4.4. ENANTIOSELECTIVITY OF THE REACTION - 51 - 4.7.1. Stereoselectivity at the Ru-centre - 51 - 4.7.2. Rationalization of the enantioselectivity - 55 -
4.5. NATURE OF THE NUCLEOPHILE - 59 -
4.6. APPROACHES TO CO-CATALYSIS / DUAL -ACTIVATION - 65 -
4.7. MECHANISTIC RATIONAL - 71 - 4.7.1. Kinetic Isotope Effects - 71 -
4.7.2. Effect of CO 2 - 73 - 4.8. CONCLUSION - 74 -
5. APPLICATIONS TO “ CLASSICAL ” ALLYLIC SUBSTITUTION - 76 -
5.1. PREAMBLE - 76 -
5.2. ACTIVATED C-NUCLEOPHILES - 76 - 5.2.1. 1,3-Dicarbonyl Prenucleophiles - 76 -
vi Table of Contents
5.2.2. Application of Co-Catalysis - 79 -
5.3. PREFORMED C-NUCLEOPHILES - 84 -
5.4. UNSTABILIZED NUCLEOPHILES - 85 - 5.4.1. Unstabilized Ketones - 85 - 5.4.2. Unstabilized Alkynes - 86 -
5.5. HETEROATOMIC NUCLEOPHILES - 88 - 5.5.1. N-Nucleophiles - 88 - 5.5.2. O-Nucleophiles - 89 -
5.6. CONCLUSION - 91 -
6. GENERAL CONCLUSION & OUTLOOK - 92 -
6.1. CONCLUSION - 92 -
6.2. OUTLOOK - 93 -
7. EXPERIMENTAL PART - 97 -
7.1. GENERALITIES - 97 -
7.2. SYNTHESIS OF SUBSTRATES OF TYPE 1. - 98 -
7.3. SYNTHESIS OF PRODUCTS OF TYPE 2. - 100 -
7.4. CSP-SEPARATION OF PRODUCTS OF TYPE 2. - 106 -
7.5. GC-SEPARATION OF PRODUCTS OF TYPE 2 AND 3. - 107 -
7.6. SYNTHESIS OF METAL PRECATALYSTS OF TYPE 4. - 107 -
7.7. SYNTHESIS OF LIGANDS OF TYPE L18. - 108 -
7.8. SYNTHESIS OF PRODUCTS OF TYPE 15. - 110 -
7.9. GC-SEPARATION OF REGIOISOMERS OF 15. - 111 -
7.10. SYNTHESIS OF CARBAMATES OF TYPE 23. - 111 -
7.11. SYNTHESIS AND REACTIVITY OF SUBSTRATE 25. - 111 -
7.12. SYNTHESIS AND REACTIVITY OF CARBONATES 27. - 112 -
- vii - Chap. 1: General Introduction
1. General Introduction
How would you like to live in Looking-glass House, Kitty? I wonder if they'd give you milk in there? Perhaps Looking-glass milk isn't good to drink. Lewis Carroll, Through the Looking-Glass (1871)
1.1. Preamble
The concept of "chirality" is known in chemistry since the 1870's although it took nearly a hundred years before chemists began using this term. In fact, in the first edition of Eliel's "Stereochemistry of Carbon Compounds" in 1962, 1 the word chiral was not even mentioned, it became prominent in later editions. 2 In extremely simple terms, chirality corresponds to "handedness" - that is, the existence of a left / right opposition. For example, left and right hands are mirror images of each other which cannot be superposed and therefore are "chiral". The term chiral is derived from the Greek name kheir meaning "hand" (Scheme 1 1) and apparently was coined by Lord Kelvin in 1904 when he stated: "I call any geometrical figure, or group of points, chiral, and say it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself". In more modern phrasing, any object or molecule which has no improper axis of symmetry (Sn, n > 0) is thus defined as chiral.
Scheme 1 1: Illustration of chirality with the hands.
The first observation of the macroscopic effects of chirality was made by the French physicist Jean-Baptiste Biot in 1835. He noticed that the plane of polarization of a beam of planar polarized light could be rotated by passing through sugar solutions. In 1848 the French chemist Louis Pasteur provided a new milestone by solving the problems concerning the
1 (a) Eliel, E. L. Stereochemistry of carbon compounds ; McGraw-Hill: New York, 1962 . (b) Eliel, E. L. Stereochemistry of Carbon Compounds , 1962 2 Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds , 1994 .
- 1 - Chap. 1: General Introduction nature of tartaric acid. Contrary to samples of the synthetic molecule, which exhibited no optical activity, “natural” tartaric acid, obtained from wine lees, were deviating the plane of polarization of light in one specific direction. By crystallizing sodium ammonium tartrate in the right conditions, Pasteur discovered that some of the obtained crystals were non- superimposable mirror images and that solutions of these exhibited opposite rotations of the plane of polarization. Pasteur correctly deduced that the molecule in question was chiral and could “exist in two different forms that resemble one another as would left- and right-hand gloves”, and the biological source of the compound provided only one type. 3
Following Kekule's 1858 postulate that carbon has a valence of four,4 van’t Hoff 5 and Le Bel 6 independently recognized that four different groups attached to the same carbon atom, arrayed at the corners of a tetrahedron, lead to two different configurations A and Ā called enantiomers ( Scheme 1 2).
a a CO2H CO2H (S) (R) d d H H NH2 H2N c b b c H3C CH3 mirror plane mirror plane Scheme 1 2: Models of asymmetric molecules made by van’t Hoff (left), schematic representation of two enantiomeric tetrahedrons (middle) and representation of the two enantiomers of alanine (right).
Many building blocks (amino acids, sugars …), constituting the important families of biologically active molecules (proteins, nucleic acids …), are usually found in nature as a single enantiomer and transfer their properties of chirality to the whole superstructure. These matrices thus have complex three-dimensional structures which are liable to interact differently with the two enantiomers of a molecule. The different interactions can subsequently induce different physiological activities which are particularly important for pharmacologically active molecules ( Scheme 1 3).
Due to the constantly growing demand for non-racemic compounds as drugs, agrochemicals, flavours, fragrances and synthetic materials, many efforts have been devoted to developing efficient methods to yield the desired enantioenriched / enantiopure synthetic intermediates. 7
3 L. Pasteur, Two lectures delivered to the Société Chimique de Paris , Jan. 20 th & Feb. 3 rd , 1860 . 4 Kekule, A. Ann. 1858 , 154. 5 van't Hoff, J. H. Bull. Soc. Chim. Fr. 1875 , 295. 6 Le Bel, J. A. Bull. Soc. Chim. Fr. 1874 , 337. 7 (a) Halpern, J.; Trost, B. M. Proc. Nat. Acad. Sci. U.S.A. 2004 , 101 , 5347-5347. (b) Trost, B. M. Proc. Nat. Acad. Sci. U.S.A. 2004 , 101 , 5348-5355.
- 2 - Chap. 1: General Introduction
O OH H effective against (S) N N (S) O N (S) treats tuberculosis morning sickness NH H OH O O O O OH NH H N (R) teratogenic N (R) O (R) N causes blindness H OH O Thalidomide Ethambutol
OH OH H (S) N O treats arthritis pain (R) local anesthetic O MeO MeO O causes liver poisoning (S) (R) N O adrenoceptor antagonist OH H OH local anesthetic Naproxen Propanolol
Scheme 1 3: Both enantiomers of selected drugs and their respective physiological effects.
Historically, enantioenriched compounds were synthesized by manipulating, through successive chemical transformations, an optically active precursor often generated from nature’s chiral pool or by separating the two enantiomers of a racemic mixture by the use of an enantiopure agent. Both these approaches suffer from potentially severe drawbacks: the former requires stoichiometric amounts of a suitable precursor and often leads to tortuous synthetic routes to overcome nature’s rather specific structural scaffold, while the yield of the desired enantiomer for the latter is limited to a maximum of 50 %, unless a suitable epimerization reaction is simultaneously at play.
The strategy consisting in using a chiral auxiliary (generally derived from the chiral pool) as asymmetry inducing agent also suffers from the same drawbacks. However, one must notice the importance of this strategy in total synthesis, since certain functions, with already established configurations, can act as intramolecular asymmetry inducers (diastereoselective synthesis). On the other hand, asymmetric catalysis, in which each molecule of chiral catalyst, by virtue of being continually regenerated, can yield many molecules of chiral product, has significant potential advantages over these older procedures. Nature is the biggest user of asymmetric catalysis: living systems use enzymes to perform the stereoselective synthesis of their building blocks with very high fidelity. Enzymes exploit hydrogen bonding between the active site and substrate, together with non-bonding dipole-dipole, electrostatic, and steric interactions, to orient the substrate and stabilize the transition state, leading to high levels of stereoselectivity.
- 3 - Chap. 1: General Introduction
1.2. Asymmetric Catalysis
Catalysis is the process by which the rate of a chemical reaction is increased by the action of a substance (catalyst) which remains unchanged in nature at the end of the reaction.
1.2.1. Birth of the Catalytic Concept
It is the Swedish chemist Jöns Jacob Berzelius who first described the concept of “ catalytic power ” in 1835. 8 This he defined as follows: “The catalytic force actually appears to consist in the ability of substances to arouse the affinities dormant at this temperature by their mere presence and not by their affinity and so as a result in a compound substance [where] the elements become arranged in another way such that a greater electrochemical neutralization is brought about ”. Though he was not the first to use the word catalysis , as it was already in use in Andreas Livbavius’s Alchemy in 1597, he was the first to crystallize the concept with help of the separate experiments of Kirchhoff, Thénard, Davy, Döbereiner and Mitscherlich (1811-1834). Most of these early catalytic experiments dealt with the reaction of gaseous reagents at the surface of noble metal wires. In 1909 Ostwald received a Nobel Prize in recognition of his work on catalysis and for his investigations into the fundamental principles governing chemical equilibria and rates of reaction leading to a new definition: “ catalysts are substances which change the velocity of a reaction without modification of the energy factors of the reaction ”. 9 This year, Ertl recived the Nobel Prize “ for his studies of chemical processes on solid surfaces ” showing the on-going validity of the concept.
1.2.2. Industrial Developments
Prior to the Second World War the chemical industry was mainly coal-based with a strong emphasis on production of ammonia, nitric acid, hardened fat and methanol synthesis. In the 50s the rapid expansion of the petrochemical industry (based on oil and natural gas) resulted in the production of new fuels and synthetic materials and to the growing significance of catalyzed processes as selective oxidations and hydroformylations. Major advances have been made among which one can focus on the Ziegler-Natta catalysis, steam reforming with
NiK 2Al 2O3, catalytic cracking with zeolites, low pressure methanol synthesis and metallocene catalysis among many others. 10 Today some 80 % of chemical processes use catalysts whose whole sell price corresponds to less than 1 % of their generated revenue. However, despite the
8 Roberts, M.W. Catalysis Lett. 2000, 67 , 1-4. 9 Nobel Lectures, Chemistry 1901-1921 , Elsevier Publishing Company, Amsterdam, 1966 . 10 Roberts, M.W. Catalysis Lett .2000, 67 , 67-72.
- 4 - Chap. 1: General Introduction wide investments by both governments and industry, catalytic enantioselective industrial processes remain quite rare compared to other processes yielding achiral or racemic products.
1.3. Modern Applications of Asymmetric Catalysis
In this section only selected examples of applications for asymmetric catalysis will be briefly discussed in an attempt to show the width of the scope of synthetic catalytic methodologies.
1.3.1. Asymmetric Organocatalysis
The first example of an asymmetric organocatalyzed reaction 11 dates back to 1912 with the report of Bredig of the effect of alkaloids on the addition of HCN onto benzaldehyde. 12 The yield was modest but the product was optically active and its optical activity of opposite sign when using quinine or quinidine as catalyst.
O OH
H O OH O NHAr H Intermolecular cross-aldol reaction H C OBn OBn up to 97% ee 3 OH α-oxyaldehyde NO dimerization 2 up to 99 % ee Mannich reaction up to > 99 % ee
As catalyst N CO2H H
O CO2Bn N CO2Bn O Ph H N H H NO2 O O NHPh 1 2 α-amination Intermolecular R R up to 96 % ee Michael reaction up to 23 % ee α-aminooxylation up to > 99 % ee Scheme 1 4: Selected ( S)-proline catalyzed reactions.
However the field did not really develop until the 70s and the Hajos-Parrish-Eder-Sauer- Weichert reaction: a proline catalyzed intramolecular aldol reaction. 13 Since that time, proline (and its derivatives) has become a versatile and widely used catalyst providing the desired products with high selectivity ( Scheme 1 4). 14
11 For recent reviews on organocatalysis see : (a) Shi, Y . Acc. Chem. Res. 2004 , 37, 488-496 . (b) Chem. Rev 2007 , 107 , (whole issue 12). (c) Enantioselective Organocatalysis, Dalko, P.I. Ed.; Wiley-VCH: Weinheim Germany, 2007 . 12 (a) Bredig Ber. 1908 , 41 , 752. (b) Bredig Biochem. Zeit. 1913 , 46 , 7. 13 (a) Eder Angew. Chem. Int. Ed. Engl. 1971, 10 , 496-497. (b) Hajos J. Org. Chem. 1974 , 39 , 1615-1621. 14 (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002 , 124 , 827-833. (b) α- Amination: List, B. J. Am. Chem. Soc. 2002 , 124 , 5656-5657. (c) α-Aminoxylation: Zhong, G. Angew. Chem. Int. Ed. 2003 , 42 , 4247-4250; Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C . J. Am. Chem. Soc. 2003 , 125 , 10808-10809; Bøgevig, A.; Sunden, H.; Córdova. A. Angew. Chem. Int. Ed. 2004 , 43 , 1109-1112. (d) Michael addition: List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001 , 3, 2423-2425. (e) α-Oxyaldehyde dimerization: Northrup, A. B.; Mangion, I. K.; Hettche,
- 5 - Chap. 1: General Introduction
1.3.2. Asymmetric Organometallic Catalysis
The major advantage of asymmetric organometallic catalysis resides in the use of the reactivity of organometallic species in order to obtain reactions that are sometimes not accessible via classical organic chemistry. In addition, in the case of homogeneous catalysis, the use of soluble catalysts, by their easier synthesis, opens up perspectives for “ rational ” structural modifications of both ligand and metal to reach improved activity and selectivity.
The first example of an enantioselective reaction catalyzed by an organometallic complex was reported by Nozaki and Noyori for styrene cyclopropanation with a phenol-imine/copper complex.15 In the last 40 years tremendous advances in this field have been made and which can be emphasized by the Nobel prizes in 2001 of Knowles and Noyori 16 “ for their work on chirally catalyzed hydrogenation reactions ” and of Sharpless 17 “ for his work on chirally catalyzed oxidation reactions ”. Asymmetric homogeneous catalysis has now become a versatile tool for the modern chemist as exemplified by the synthesis of (–)-salicylihamlamide by Fürstner which is strongly based on organometallic catalysis for several key steps. 18 The field has also expanded to industrial applications ( Scheme 1 5).19 For instance, Novartis has developed the synthesis of ( S)-metolachlor by an asymmetric iridium catalyzed hydrogenation process (herbicide, 10000 tons/year) 20 and Takasago uses an enantioselective rhodium catalyzed allylic amine isomerization for the synthesis of (–)-menthol (2000 tons/year). 21
O O H [Pd] cat. N H2, [Ir-xyliphos] N acid, I [Cu] cat. 2
[Cr] HN 80% ee, ton >1000000, tof 180000 h-1 O Ciba-Geigy/Novartis (S)-metolachlor synthesis OH [Ru] cat. OH O NEt2 + [Ru] cat. [Rh-(S)-BINAP]
NEt2 OH [Pd] cat.
[Ru] cat. 97.6% ee (-)-menthol Fürstner's synthesys of (-)-salicylihalamide ton 400000 tof 1300 h-1 Takasago (-)-menthol synthesis Scheme 1 5: Fürstner’s synthesis of ( –)-salicylihamlamide and selected industrial catalytic processes.
F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004 , 43 , 2152-2154. (f) Cross-aldol reaction: Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002 , 124 , 6798-6799. 15 (a) H. Nosaki, H. Takaya, S. Moriuti, R. Noyori, Tetrahedron 1968 , 24 , 3655-3669. (b) H. Nosaki, S. Moriuti, H. Takaya, R. Noyori, Tetrahedron Lett. 1966 , 22 , 5239-5243. 16 (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998-2007. (b) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008- 2022. 17 Sharpless, K. B., Angew. Chem. Int. Ed. 2002, 41, 2024-2032. 18 A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J. 2001 , 7, 5286-5298. 19 Blaser, H. U.; Studer, M. Chirality 1999 , 11 , 459-464. Blaser, H. U. Chem. Commun. 2003 , 293-296. 20 (a) Spindler, F.; Pugin, B. (Ciba-Geigy A.-G., Switzerland). (b) Pat. 87-810435256982, 1988 . Spindler, F.; Pugin, B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.; Blaser, H.-U. Chemical Industries (Dekker) 1996, 68, 153. 21 (a) Noyori, R.; Takaya, H., Acc. Chem. Res. 1990, 23, 345-350. (b) Noyori, R. Science 1990, 248, 1194-1199.
- 6 - Chap. 2: Metal-Catalyzed Allylic Substitutions
2. Metal Catalyzed Allylic Substitutions
If knowledge can create problems, it is not through ignorance that we can solve them. Isaac Asimov (1920-1992)
Enantioselective metal catalyzed allylic substitution and rearrangement reactions constitute too wide a field to be exhaustively described in this chapter. This introduction will thus mainly focus on enantioselective metal catalyzed reactions of non symmetrically substituted substrates with an emphasis on palladium and ruthenium as metal sources. It will only highlight a few selected historical results or important breakthroughs. The addition of carbon nucleophiles will be primarily stressed but can not be exclusively treated in this overview. However, many more detailed reviews have been published in the recent years with a much broader scope of substrates, metal sources and nucleophiles.1,2,3
2.1. Preamble
Transition metal catalyzed allylic substitutions are widely used in organic synthesis. 4 Indeed, the allylic moiety combined with a stereogenic center is an important intermediate in many organic syntheses as the remaining carbon carbon double bond allows a large variety of functionalisations. 5 Starting either from branched or linear substrates, a common π allyl (or σ,π ) metal complex is formed (Scheme 2-1) onto which a nucleophile is liable to add in the 1 The enantioselective allylic substitutions have been widely studied. For reviews, see: (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992 , 3, 1089 1122. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996 , 96 , 395 422. (c) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998 , 98 , 1689 1708. (d) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis , Vol 2; Jacobsen, E. N.; Pfaltz, A.;Yamamoto, H., Eds.; Springer: Berlin Germany, 1999 , 833–884. (e) Trost, B. M.; Lee, C. B. In Catalytic Asymmetric Synthesis II ; Ojima, I., Ed.; Wiley VCH: Weinheim Germany, 2000 , 593 650. (f) Trost, B. M. Chem. Pharm. Bull. 2002 , 50 , 1. (g) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003 , 103 , 2921 2944. (h) Lu, Z.; Ma, S. M. Angew. Chem. Int. Ed. 2008 , 47 , 258 297. 2 For reviews on ligands see: (a) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003 , 36 , 659 667. Hayashi, T. Acc. Chem. Res. 2000 , 33 , 354 362. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000 , 33 , 336 345. McManus, H. A.; Guiry, P. J. Chem. Rev. 2004 , 104 , 4151 4202. Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006 , 106 , 3561 3651. Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006 , 39 , 747 760. 3 For reviews on applications see: (a) Braun, M.; Meier, T. Angew. Chem. Int. Ed. 2006 , 45 , 6952 6955. Graening, T.; Bette, V.; Neudorfl, J.; Lex, J.; Schmalz, H. G. Org. Lett. 2005 , 7, 4317 4320. Trost, B. M. J. Org. Chem. 2004 , 69 , 5813 5837. Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005 , 1715 1726. 4 (a) B. M. Trost and C. Lee, in Catalytic Asymmetric Synthesis , ed. I. Ojima, Wiley VCH, New York, 2nd Ed, 2000 , 593–649; (b) A. Pfaltz and M. Lautens, in Comprehensive Asymmetric Catalysis I-III , ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999 , 833–884. 5 (a) Söll, H. In Houben-Weyl , 4th ed. Vol. V, 1b; Thieme: Stuttgart, 1972 , 946. (b) Comprehensive Organic Synthesis, Vol. 4 ; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991 , Chap. 4. (c) Comprehensive Organic Synthesis, Vol. 7 ; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991 , Chap. 3.
7 Chap. 2: Metal-Catalyzed Allylic Substitutions least substituted position, yielding in the linear regioisomer ( l), or the more substituted position, giving the branched regioisomer ( b). Mono substituted allylic substrates have drawn attention the last years because the control of the regioselectivity of the reaction in favor of the branched chiral product remained challenging. Recent developments have provided methodologies where the substitution of the substrate, the nature of the metal and its ligands play a crucial role: the fact that only catalytic amounts of the transition metal are required and the possibility of tuning the reactivity by means of suitable ligands have definitely contributed to the success of this methodology.
LG Nu Nu- b b [M] R [M] R LG R Nu l l R LG- R π-allyl intermediate Scheme 2-1: General scheme for transition metal catalyzed allylic substitutions.
2.2. Palladium catalyzed allylic substitutions
One of the most documented,1,6 and historically the first, metal used for allylic substitutions is palladium. This reactivity was discovered by Tsuji 7 and thoroughly developed by the group of Trost since the seventies. 8 This paragraph will thus set the basis for the analysis of mechanistic issues which are common to most of the metal catalyzed allylic substitutions.
2.2.1. General Mechanism
The reaction, which general course is outlined in Scheme 2-2, starts with the complexation of the allylic substrate onto an unsaturated Pd(0) species. Allylic acetates and carbonates are the most widely used substrates due to the ease of the ionisation that allows the formation of a π allyl complex through oxidative addition . These Pd(II) π allyl complexes can then isomerize via a π−σ−π rearrangement before the addition of the nucleophile and finally decomplexation of the product to regenerate the active Pd(0) species. The general catalytic cycle of the Pd catalyzed asymmetric allylic substitution thus offers at least four opportunities for
6 (a) Tenaglia, A.; Heumann, A. Angew. Chem. Int. Ed. 1999 , 38 , 2180 2184. Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003 , 103 , 1875 1916. 7 (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org. Chem. 1985 , 50 , 1523 1529. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965 , 4387. 8 (a) Trost, B. M. Tetrahedron 1977 , 33 , 2615 2649. Trost, B. M. Acc. Chem. Res. 1980 , 13 , 385 393. Trost, B. M.; Murphy, D. J. Organometallics 1985 , 4, 1143 1145. Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977 , 99 , 1649 1651. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980 , 102 , 4730 4743.
8 Chap. 2: Metal-Catalyzed Allylic Substitutions enantiodiscrimination (see section 2.2.3). In some instances, the stereochemistry of the incoming nucleophile can also be set in the same step providing a fifth possibility.
R ∗ R' R ∗ R' R LG or L L' Nu Nu R' Pd
Decoordination Coordination
[Pd] [Pd] [Pd] R ∗ R' or R ∗ R' R LG
Nu Nu R'
[Pd+] R Nucleophilic Oxidative Addition R' Addition LG- Nu- [Pd+] R R'
Isomerization Scheme 2-2: General scheme for transition metal catalyzed allylic substitutions.
2.2.2. Structure of Metal-Allyl Complexes
Furthermore, to gain insight into the nature of the stereodetermining event, one needs to determine the structure of the lowest energy diastereomeric transition states. However, this is not experimentally easy since only the ground state metal olefin or metal π allyl complexes can, in some cases, conveniently be observed by X ray crystallography 9, mass spectrometry 10 or NMR spectroscopy.11 Though information concerning the structure of olefin complexes remains scarce, 12 many X ray structures of metal π allyl complexes have been studied. 9 However the influence of the ligands on the environment of the metal and more importantly its changes during the course of the reaction remain difficult to predict with certainty. Thus the crucial information about the exact structure of the lowest energy transition state is most
9 (a) Allured, V. S.; Kelly, C. M.; Landis, C. R. J. Am. Chem. Soc. 1991 , 113 , 1 12. Chan, A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem. Soc. 1980 , 102 , 5952 5954. Fiaud, J. C.; Aribizouioueche, L. J. Chem. Soc. Chem. Commun. 1986 , 390 392. Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am. Chem. Soc. 1989 , 111 , 6301 6311. Lloyd Jones, G. C.; Pfaltz, A. Zeit. Naturforsch. 1995 , 50b , 361 367. Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W. A.; Skiff, W. M. J. Am. Chem. Soc. 1992 , 114 , 10024 10035. Togni, A.; Rihs, G.; Pregosin, P. S.; Ammann, C. Helv. Chim. Acta 1990 , 73 , 723 732. Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W. Angew. Chem. Int. Ed. Engl. 1995 , 34 , 2386 2388. Von Matt, P.; Lloyd Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.; Ruegger, H.; Pregosin, P. S. Helv. Chim. Acta 1995 , 78 , 265 284. 10 Muller, C. A.; Pfaltz, A. Angew. Chem. Int. Ed. 2008 , 47 , 3363 3366. 11 Zalubovskis, R.; Bouet, A.; Fjellander, E.; Constant, S.; Linder, D.; Fischer, A.; Lacour, J.; Privalov, T.; Moberg, C. J. Am. Chem. Soc. 2008 , 130 , 1845 1855. 12 Hodgson, M.; Parker, D.; Taylor, R. J.; Ferguson, G. J. Chem. Soc. Chem. Commun. 1987 , 1309 1311.
9 Chap. 2: Metal-Catalyzed Allylic Substitutions often only postulated. Still, much information can be gathered to rationalize the different mechanistic theories.
2.2.2.1. ηηη3-ηηη1-ηηη3 isomerization One crucial aspect of palladium catalyzed allylic substitution reactions is that, during the course of the reaction, ligands may dissociate, re associate, exchange and/or change in conformation and geometry. This state of dynamic equilibrium is key to the selectivities observed.
syn syn A B A B R' H H 3 R H A B η3-η1 C-C rotation η3-η1 A B R R' R' R R 1 3 1 3 1 3 1 H H R' path a anti H H H H H H syn syn,syn-endo anti,syn-exo Pd-C rotation path b
A B H H η3-η1 A B : Metal H H R' 3 1 R A,B : ligands H R' 3 1 R H syn,syn-exo Scheme 2-3: η3 η1 η3 isomerization and nomenclature of a π allyl complex.
An important nomenclature needs to be introduced at this point: (i) the substituents of a π allyl are named anti and syn according to their position respective to the central allylic substituent ( Scheme 2-3), (ii) the π allyl is named exo or endo when the central allylic substituent is pointing respectively opposite or towards the concave face of the metal complex. On the time scale of a typical alkylation reaction, the syn and anti substituents in a palladium π allyl complex can exchange hundreds of times faster than the alkylation.
Two possible isomerization pathways have been shown. In the first case (path a) the ligands of the palladium and the substituents of the π allyl fragment keep the same relative configuration (bold substituents remain on the same side). This has two consequences: the bold R group exchanges position from syn to anti and the conformation of the π allyl changes from endo to exo but C1 and C3 globally remain at the same position. The stereospecificity of this isomerization was shown by Togni and collaborators in the case of an allyl palladium Josiphos complex. 13 On the time scale of the nOe experiments, the carbon trans to the dicyclohexylphosphino group (C 1) always remains in the same position ( Scheme 2-4).
13 Breutel, C.; Pregosin, P. S.; Salzmann, R.; Togni, A. J. Am. Chem. Soc. 1994 , 116 , 4067 4068.
10 Chap. 2: Metal-Catalyzed Allylic Substitutions
PCy 2 ηηη3-ηηη1 PCy2 ηηη1-ηηη3 PCy Fe P 2 Pd Fe P 3 P Ph 1 Pd Fe Pd 2 3 Ph2 Ph2 3 1 nOe 1 Rotation around C-C bond nOe Scheme 2-4: Dynamics of a Josiphos palladium π allyl complex.
Another type of isomerization is an apparent rotation of the π allyl which involves a rotation around the metal carbon single bond in the η1 complex. In this case there is no anti /syn isomerization of the allyl substituents but an overall rotation of the allyl fragment occurs (bold substituents on opposite sides – Scheme 2-2, path b). Helmchen has shown that this mechanism takes place in the isomerization of (phosphinoaryl)oxazoline (Phox) palladium diphenylallyl complexes ( Scheme 2-5). 14
ηηη3-ηηη1 1 3 O PPh2 O PPh2 ηηη -ηηη O PPh2 N N N Pd Ph Pd Ph Pd 1 Ph 3 Ph 3 Ph 3 1 1 Ph Rotation around Pd-C bond Scheme 2-5: Dynamics Phox palladium π allyl complex.
This isomerization can also occur through pseudorotation of the ligands with the participation of a coordinating counterion 15 or by decoordination of one of the other ligands of the metal. 16
2.2.3. Enantiodiscriminating Steps
M M M M M M
LG LG Nu- LG -O Coordination on Oxidative addition Isomerization to Addition of nucleophile Allylation enantiotopic faces on enantiotopic enantiotopic faces on enantiotopic termini on enantiotopic faces of the olefin leaving groups of the π-allyl of the π-allyl of the nucleophile I II III IV V Scheme 2-6: Sources for Enantiodiscrimination in metal catalyzed allylic substitutions.
2.2.3.1. Enantiofacial Complexation and Ionization (I) The complexation of the olefin to the metal is the first potential source of stereoselection. Indeed, unless the olefin is symmetrically substituted, the complexation of the olefin to the 14 Sprinz, J.; Kiefer, M.; Helmchen, G.; Huttner, G.; Walter, O.; Zsolnai, L.; Reggelin, M. Tetrahedron Lett. 1994 , 35 , 1523 1526. 15 (a) Andersson, P. G.; Harden, A.; Tanner, D.; Norrby, P. O. Chem. Eur. J. 1995 , 1, 12 16. (b) Gogoll, A.; Ornebro, J.; Grennberg, H.; Bäckvall, J. E. J. Am. Chem. Soc. 1994 , 116 , 3631 3632. (c) Hansson, S.; Norrby, P. O.; Sjogren, M. P. T.; Akermark, B.; Cucciolito, M. E.; Giordano, F.; Vitagliano, A. Organometallics 1993 , 12 , 4940 4948. 16 (a) Albinati, A.; Kunz, R. W.; Ammann, C. J.; Pregosin, P. S. Organometallics 1991 , 10 , 1800 1806. (b) Churchil, M. R.; O'Brien, T. A. J. Chem. Soc. A 1970 , 206.
11 Chap. 2: Metal-Catalyzed Allylic Substitutions metal will yield a planar chiral complex. The stability of such metal complexes is very much depending on the electronic and steric properties of the olefin. 17 For example electron withdrawing groups on the olefin will enhance the stability of the complex (due to better π back bonding from the metal into the lower LUMO of the allylic ligand) whereas bulky groups will destabilize the complex via unfavorable steric interactions.
MeO2C CO2Me R % ee σ CO2Me OR CO2Me 4 O2N PhCO 22 0.78 NaCH(CO2Me)2
4 mol% Pd(dba)2 4 CN PhCO 60 0.63 4 mol% (R)-BINAP dioxane, RT PhCO 76 0.00 t-Bu t-Bu t-Bu 4 H3C PhCO 80 0.17 major minor 4 H3CO PhCO 90 0.27
Table 2-1: Examples of enantioselective complexation and ionization.
This question was investigated by Fiaud et al. (Table 2-1) for the palladium catalyzed allylic alkylation of esters using BINAP as chiral ligand. 18 The selectivity of the process was found to be very sensitive to the reaction conditions and the nature of the leaving group in particular: enantioselectivities in this system were found to approximately linearly correlate with the electronic properties of the leaving benzoate group (Hammett σ value). There is no direct evidence for selective complexation as direct source of enantioselection in metal catalyzed allylic substitutions; but since the olefin complex serves as precursor to the ionization step, these two sources of selectivity cannot be considered separately.
2.2.3.2. Ionisation of Enantiotopic Leaving Groups (II) Type II asymmetric induction depends on the ability of the catalyst to promote differential ionization of enantiotopic leaving groups. As shown in Scheme 2-6 (II), the metal coordinates to the face of the olefin opposite to the leaving groups and the oxidative addition can then occur with departure of one of the two enantiotopic leaving groups. Many ligands have been used but the most successful family is based on a combination of 2 (diphenylphosphino)benzoic acid (DPPBA) 19 and enantiopure diols or diamines possessing a
C2 symmetry; this allows many straightforward variations ( Scheme 2-7). Two cases can be
17 (a) Tolman, C. A. J. Am. Chem. Soc. 1974 , 96 , 2780 2789. (b) White, D.; Coville, N. J. Adv. Organomet. Chem. 1994 , 36, 95. 18 (a) Fiaud, J. C.; Legros, J. Y. J. Org. Chem. 1990 , 55 , 4840 4846. (b) Legros, J. Y.; Fiaud, J. C. Tetrahedron 1994 , 50 , 465 474. 19 (a) Hoots, J. E.; Rauchfuss, T. B.; Wrobleski, D. A. Inorg. Synth. 1982 , 21 , 175 179. (b) Jeffery, J. C.; Rauchfuss, T. B.; Tucker, P. A. Inorg. Chem. 1980 , 19 , 3306 3316. (c) Rauchfuss, T. B. J. Organomet. Chem. 1978 , 162 , C19 C22.
12 Chap. 2: Metal-Catalyzed Allylic Substitutions distinguished: (a) asymmetric induction onto symmetrically 1,3 disubstituted olefins (Table 2-2)20 or (b) asymmetric induction onto symmetrically 1,1 disubstituted olefins ( Table 2-3).21
O O X X X O O O O Ph Ph Ph Ph = P P H2N NH2 NH Ph Ph H2N NH2 2 X O O H2N L* L1 L2 L3 L4 Scheme 2-7: DPPBA based chiral ligands for Pd catalyzed asymmetric allylic substitutions.
n Ligand % yield % ee
1 L1 100 (+) 64 2.5 mol% (dba)3Pd2 CHCl3 O O 7.5 mol% L* n O O n O 1 L2 97 (+) 78 THF R.T. O TsHN NHTs N 1 L3 91 (–) 79 Ts 1 L4 94 (–) 88 2 L1 82 97 3 L1 82 95
Table 2-2: Examples of intramolecular asymmetric induction onto symmetrically 1,3 disubstituted olefins.
R R’ NaNu % yield % ee
2.5 mol% (dba)3Pd2 CHCl3 Ph CH 3 NaCH 3C(CO 2CH 3)2 92 95 H 7.5 mol% 2 H NaNu Nu i Pr CH 3 NaCH 3C(CO 2CH 3)2 93 95 R OCOR' R OCOR' THF R.T. OCOR' CH 3 CH 3 NaCH 3C(CO 2CH 3)2 99 92
CH 3 C2H5 NaCH 3C(CO 2CH 3)2 99 92
CH 3 CH 3 NaCH 3C(SO 2Ph) 2 99 67
Table 2-3: Examples of asymmetric induction onto symmetrically 1,1 disubstituted olefins.
20 (a) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987 , 109 , 3792 3794. (b) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1988 , 110 , 7933 7935. (c) Trost, B. M.; Vanvranken, D. L. J. Am. Chem. Soc. 1990 , 112 , 1261 1263. 21 (a) Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995 , 117 , 7247 7248. (b) Trost, B. M.; Vercauteren, J. Tetrahedron Lett. 1985 , 26 , 131 134.
13 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.2.3.3. Enantiofacial Isomerization of πππ-Allyl Complexes (III)
LG LG B A or
C1-symmetric
Nu A B A B Nu A B Nu endo H H H H H H
Nu A B Nu A B Nu A B
Nu B A B A Nu B A Nu
exo H H H H H H
Nu B A Nu B A Nu B A syn,syn syn,syn anti,syn anti,syn anti,anti anti,anti Scheme 2-8: Some of the possible complexes of unsymmetrical π allyl systems and nucleophile attacks.
If both terminal positions of the allyl fragment are disymmetrically substituted and the ligands 22 are not C2 symmetric, a complex situation with up to 16 equilibrating π allyl complexes occurs ( Fig 2-8). In addition for each case, two different trajectories of the nucleophile can be envisaged depending on the terminus of attack as shown in Scheme 2-9.23
O O
MeO OMe MeO OAc OH MeO N NaCH(CO2Me)2 56 % yield; 80 % ee 3 Fe PPh2 [{η -C3H5Pd(dba)}2] L10 O O THF 40°C PPh2 OH MeO OMe MeO L10
44 % yield; 95 % ee Scheme 2-9: Example of dissymmetrically substituted diaryl allylic acetate.
In this case, the result implies that each enantiomer of the starting material is the precursor of one of the regioisomeric products and that racemization of neither starting material nor the reactive intermediate is occurring. This example is however misleading since the regiocontrol remains a general problem for Pd catalyzed allylic substitution with dissymmetrical substrates since the more hindered position is generally inaccessible for nucleophilic attack as shown in
22 With C2 symmetric ligands or symmetrically substituted allylic subtrates the situation becomes much simpler. 23 Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron Lett. 1986 , 27 , 191 194.
14 Chap. 2: Metal-Catalyzed Allylic Substitutions the two following examples ( Scheme 2-10 ). 24 This issue is still difficult to overcome with Pd 25 but some ligands have been developed to circumvent this problem. 26
TMS OAc TMS CH(CO2Me)2 NaCH(CO2Me)2 TMS 3 [{η -C3H5PdCl}2] TMS L2
69 % yield; 86 % ee
Ph OAc
NaCH(CO2Me)2 Ph CH(CO2Me)2 Ph 3 [{η -C3H5PdCl}2] L2 Ph
74 % yield; 96 % ee Scheme 2-10: Regioselectivity for dissymmetrically substituted allylic acetate.
2.2.3.4. Attack at Diastereotopic Termini of the πππ-Allyl Complex (IV) The 1,3 diphenylallyl fragment was introduced as a model substrate for the metal catalyzed allylic alkylations because of the transient formation of a meso π allyl complex ( Scheme 2- 11) and has become a standard for comparing the activity of new ligands. 27 Numerous ligands have been developed for this transformation; a few examples are shown in Scheme 2-12.28 In this case the nucleophile is directly involved in the stereodetermining step; its nature thus has a crucial role on the enantioselectivity ( Table 2-4).
24 (a) R = TMS: Romero, D. L.; Fritzen, E. L. Tetrahedron Lett. 1997 , 38 , 8659 8662. (b) R = Ph: Martin, C. J.; Rawson, D. J.; Williams, J. M. J. Tetrahedron: Asymmetry 1998 , 9, 3723 3730. 25 (a) Bernardinelli, G. H.; Kündig, E. P.; Meier, P.; Pfaltz, A.; Radkowski, K.; Zimmermann, N.; Neuburger Zehnder, M. Helv. Chim. Acta 2001 , 84 , 3233 3246. (b) Cozzi, P. G.; Zimmermann, N.; Hilgraf, R.; Schaffner, S.; Pfaltz, A. Adv. Synth. Cat. 2001 , 343 , 450 454. (c) Fernandez, F.; Gomez, M.; Jansat, S.; Muller, G.; Martin, E.; Flores Santos, L.; Garcia, P. X.; Acosta, A.; Aghmiz, A.; Gimenez Pedros, M.; Masdeu Bulto, A. M.; Dieguez, M.; Claver, C.; Maestro, M. A. Organometallics 2005 , 24 , 3946 3956. (d) Polosukhin, A. I.; Bondarev, O. G.; Korostylev, A. V.; Hilgraf, R.; Davankov, V. A.; Gavrilov, K. N. Inorg. Chim. Acta 2001 , 323 , 55 61. (e) Powell, M. T.; Porte, A. M.; Reibenspies, J.; Burgess, K. Tetrahedron 2001 , 57 , 5027 5038. 26 (a) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997 , 561 562. (b) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am. Chem. Soc. 1998 , 120 , 1681 1687. (c) Hilgraf, R.; Pfaltz, A. Synlett 1999 , 1814 1816. (d) Pretot, R.; Pfaltz, A. Angew. Chem. Int. Ed. 1998 , 37 , 323 325. (e) You, S. L.; Zhu, X. Z.; Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001 , 123 , 7471 7472. 27 Trost, B. M.; Murphy, D. J. Organometallics 1985 , 4, 1143 1145. 28 (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991 , 113 , 726 728. (b) Dawson, G. J.; Frost, C. G.; Williams, J. M. J. Tetrahedron Lett. 1993 , 34 , 3149 3150. (c) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993 , 34 , 1769 1772. Vonmatt, P.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1993 , 32 , 566 568. (d) Allen, J. V.; Coote, S. J.; Dawson, G. J.; Frost, C. G.; Martin, C. J.; Williams, J. M. J. J. Chem. Soc.- Perkin Trans. 1 1994 , 2065 2072. (e) Sprinz, J.; Kiefer, M.; Helmchen, G.; Huttner, G.; Walter, O.; Zsolnai, L.; Reggelin, M. Tetrahedron Lett. 1994 , 35 , 1523 1526. (f) Abbenhuis, H. C. L.; Burckhardt, U.; Gramlich, V.; Kollner, C.; Pregosin, P. S.; Salzmann, R.; Togni, A. Organometallics 1995 , 14 , 759 766. (g) Pregosin, P. S.; Ruegger, H.; Salzmann, R.; Albinati, A.; Lianza, F.; Kunz, R. W. Organometallics 1994 , 13 , 83 90. (h) Trost, B. M.; Murphy, D. J. Organometallics 1985 , 4, 1143 1145. For more recent reports see references cited in 1h.
15 Chap. 2: Metal-Catalyzed Allylic Substitutions
Formal plane of symmetry Nu
R R LG
R R R R Nu - - Nu Nu R R Scheme 2-11: Desymmetrization of meso π allyl complexes.
The case of cyclic substrates will not be discussed here since their selectivity resembles the one detailed above to the exception of their impossibility to isomerize via a π−σ−π mechanism. The substrates remain however important in the assessment of the scope of new catalytic systems.29
O O O O PCy2 PPh2 Fe PPh N N 2 PPh2 N PPh2 N XPh R R R t-Bu L5a R = t-Bu L6a R = i-Pr L7a X = S Josiphos (S)-BINAP L5b R = Bn L6b R = Ph L7b X = SO L8 L6c R = t-Bu L7c X = P-Np L9 L7d X = P-2-Biphenylyl L7e X = Se Scheme 2-12: Classical ligands.
29 (a) Bergner, E. J.; Helmchen, G. Eur. J. Org. Chem. 2000 , 419 423. (b) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000 , 122 , 7905 7920. (c) Kudis, S.; Helmchen, G. Angew. Chem. Int. Ed. 1998 , 37 , 3047 3050. (d) Mori, K.; Watanabe, H.; Fujiwhara, M.; Kuwahara, S. Liebigs Ann. Chem. 1990 , 1257 1259. (e) Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994 , 35 , 8595 8598. (f) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994 , 116 , 4089 4090. (g) Trost, B. M.; Dudash, J.; Dirat, O. Chem. Eur. J. 2002 , 8, 259 268. (h) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991 , 32 , 1613 1616. (i) Trost, B. M.; Organ, M. G. J. Am. Chem. Soc. 1994 , 116 , 10320 10321. (j) Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000 , 65 , 1569 1573.
16 Chap. 2: Metal-Catalyzed Allylic Substitutions
Ligand Nu Pd source % yield % ee Ref(s)
L9 a [C 3H5PdCl] 2 80 34 30 OAc Nu L* cat. Pd(0), L6b b [C 3H5PdCl] 2 99 99 28b Nu, Solvent L6a b [C 3H5PdCl] 2 98 98 28b,28d
L7a b [C 3H5PdCl] 2 92 96 28c,31 Nucleophile: L7e b [C 3H5PdCl] 2 50 84 95 28d Na O O O OH (a) (b) + BSA L8 b [C 3H5PdOTf] nd 93 28e,32 MeO OMe MeO OMe L7b b [C 3H5PdCl] 2 100 92 31 Na O OH O (c)+ BSA (d) O L9 b [C 3H5PdCl] 2 85 90 33
L5b b [C 3H5PdCl] 2 97 88 34 O L7c b [C 3H5PdCl] 2 98 78 28d (f) (PhSO2)2CH2 + BSA (e) + BSA L6b d [C H PdCl] 98 97 28b (g) (PhSO2)2CHNa 3 5 2
O L9 d [C 3H5PdCl] 2 92 95 30
L5a e [C 3H5PdCl] 2 87 88 28c
L5a f [C 3H5PdCl] 2 78 93 28c
Table 2-4: Examples of allylic alkylation of 1,3 diphenylprop 2 enyl acetate.
2.2.3.5. Allylation of Enantiotopic Faces of the Nucleophile (V)
N OMe H AcO OAc 5 steps N OMe N O O Pd(0), L O CO2Me NH2 CO2Me ee up to 90 % (_)-Hupersine A
O H O N OAc CO2Et CO Et 4 steps 2 3 0.5 mol% [{η -C3H5PdCl}2] OH 1.5 mol% L2 TNG, Toluene, 0 °C 81 % yield,86 % ee (_)-Nitramine Scheme 2-13: Allylation of prochiral nucleophiles. 35
Two methodologies have been developed to efficiently overrun this regioselectivity problem of Pd ( Scheme 2-13): (i) intramolecular reactions (formation of a 5 or 6 membered cycle is
30 Yamaguchi, M.; Shima, T.; Yamagishi, T.; Hida, M. Tetrahedron Lett. 1990 , 31 , 5049 5052. 31 Allen, J. V.; Bower, J. F.; Williams, J. M. J. Tetrahedron: Asymmetry 1994 , 5, 1895 1898. 32 Pregosin, P. S.; Salzmann, R.; Togni, A. Organometallics 1995 , 14 , 842 847. 33 Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994 , 50 , 4493 4506. 34 Pfaltz, A. Acc. Chem. Res. 1993 , 26 , 339 345. 35 Hurpersine A: (a) He, X. C.; Wang, B.; Bai, D. L. Tetrahedron Lett. 1998 , 39 , 411 414. (b) He, X. C.; Wang , B.; Yu, G. L.; Bai, D. L. Tetrahedron: Asymmetry 2001 , 12 , 3213 3216. (c) Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron: Asymmetry 1997 , 8, 829 832. (d) Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron 1998 , 54 , 5471 5484. Nitramine: (e) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997 , 119 , 7879 7880.
17 Chap. 2: Metal-Catalyzed Allylic Substitutions the driving force), 36 (ii) the use of a prochiral nucleophile (the facial attack being controlled by the ligand). The latter case has received a lot of interest.37,1b,1g,1h Indeed enantioselection can occur when the π allyl complex differentiates the two prochiral faces of the nucleophile and can thus, despite the intrinsic linear selectivity of palladium, yield a chiral product with high enantioselectivity. To better circumvent this drawback, other metals have been used and will be detailed in the next paragraphs.
2.3. Other Metal-Catalyzed Allylic Substitutions
2.3.1. Copper
Copper tolerates the use of non stabilized hard nucleophiles such as non delocalized carbanions. This reaction has been thoroughly studied and many reviews are dealing with this 38 subject. In general, copper catalyzed allylic substitutions proceed though a S N2’ mechanism (Scheme 2-14 ), which, contrary to palladium, makes the reaction regiospecific. 39 Both Grignard and organo zinc reagents have been successfully used in this transformation in conjunction with among others enantiopure aminoacids, 40 diaminocarbenes, 41 diphosphines 42 and phosphoramidites43 as ligands.
LG R RMgX or R2Zn SN2' mechanism R1 R2 Cu(I), L R1 R2 Scheme 2-14: Cu catalyzed allylation.
36 (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani Ronchi, A. J. Am. Chem. Soc. 2006 , 128 , 1424 1425. (b) Bandini, M.; Melloni, A.; Tommasi, S.; Umani Ronchi, A. Synlett 2005 , 1199 1222. (c) Bian, J. W.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc. 2006 , 128 , 7428 7429. (d) Koch, G.; Pfaltz, A. Tetrahedron: Asymmetry 1996 , 7, 2213 2216. (e) Trost, B. M.; Sacchi, K. L.; Schroeder, G. M.; Asakawa, N. Org. Lett. 2002 , 4, 3427 3430. 37 For reviews on the addition of preformed enolates onto π allyl complexes see: (a) Braun, M.; Meier, T. Angew. Chem. Int. Ed. 2006 , 45 , 6952 6955. (b) Braun, M.; Meier, T. Synlett 2006 , 661 676. 38 For recent reviews see: (a) Yorimitsu, H.; Oshima, K. Angew. Chem. Int. Ed. 2005 , 44 , 4435 4439. (b) Kar, A.; Argade, N. P. Synthesis 2005 , 2995 3022. (c) Alexakis, A.; Malan, C.; Lea, L.; Tissot Croset, K.; Polet, D.; Falciola, C. Chimia 2006 , 60 , 124 130. (d) Falciola, C.; Alexakis, A. Eur. J. Org. Chem. 2008 , 2008 , 3755. (e) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008 , 108 , 2796 2823. (f) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008 , 108 , 2824 2852. 39 The term regiospecificity is not defined in the 1996 IUPAC recommendations. 40 Murphy, K. E.; Hoveyda, A. H. Org. Lett. 2005 , 7, 1255 1258. 41 Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005 , 127 , 6877 6882. 42 Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006 , 128 , 15572 15573. 43 Falciola, C. A.; Tissot Croset, K.; Alexakis, A. Angew. Chem. Int. Ed. 2006 , 45 , 5995 5998.
18 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.3.2. Molybdenum
Molybdenum catalyzed allylic substitutions are very similar to Pd catalyzed reaction to the key difference that, without any electronic bias, the nucleophile preferentially attacks onto the more substituted terminus of the π allyl. 44 Mechanistic studies have provided conclusive evidence that the Mo catalyzed allylic alkylations proceeds with an overall retention of configuration through a mechanism involving an oxidative addition and subsequent nucleophilic attack onto the resulting π allyl complex. 44 Many examples have been detailed in the litterature 1b,1g,1h and can be exemplified by the following reaction (Scheme 2-15) in which two stereocentres are introduced in a single step.45
Ph OCO2Me 10 mol% [Mo(C7H8)(CO)3] N 15 mol% L9 O 70-89 % yield, LiHMDS O Ph R b:l 5.5:1-24:1 O O N d.r. 7.4:1-24:1 up to >99 % ee NH HN O O N L9 N R R = Me, n-Bu, s-Bu, Allyl, i-Pr, c-Hex, Ph Ar = Ph, 2-thienyl, 2-Br-Ph, 2,4-(MeO)2-Ph Scheme 2-15: Mo catalyzed allylic substitution.
2.3.3. Tungsten
The case of tungsten is very similar in terms of selectivity to the one of Mo; notably in this case the tungsten π allyl complexes are not subject to anti / syn isomerization and apparent rotation processes contrary to the case for Pd catalyzed reactions. Mechanistic insight into this reaction has been provided by Kočovský. 46 One example is given below ( Scheme 2- 16).47,1b,1g
O O 10 mol% [W*] 89 % yield OPO(OEt) NaHC(CO2Me)2 MeO OMe 2 b:l 3:1 O PPh2 96 % ee N W(CO)2(NCMe) [W*] Scheme 2-16: Mo catalyzed allylic substitution.
44 Belda, O.; Moberg, C. Acc. Chem. Res. 2004 , 37 , 159 167. 45 Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004 , 126 , 1944 1945. 46 Malkov, A. V.; Baxendale, I. R.; Dvorak, D.; Mansfield, D. J.; Kočovský, P. J. Org. Chem. 1999 , 64 , 2737 2750. 47 (a) Lloyd Jones, G. C.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1995 , 34 , 462 464. (b) Lloyd Jones, G. C.; Pfaltz, A. Zeit. Naturforsch. 1995 , 50b , 361 367.
19 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.3.4. Rhodium
Rhodium is even less prone to isomerization than tungsten, leading to the possibility to develop regio and stereospecific reactions.48,1h As shown by A. Evans, the Rh catalyzed allylic substitution of cinnamyl carbonates with Cu enolates can be fully regio and stereospecific ( Scheme 2-17 ). 49 Enantioselective versions of this reaction 50 have also been developed as shown in Scheme 2-18 .51 O i. n-BuLi, ClCO2Me OH ii. 4-MeOC6H4COMe LiHMDS, CuI 4-MeO-Ph 80 % yield b:l > 99:1
iii. 5 mol% RhCl(PPh3)3 99 % cee MeO 20 mol% P(OEt)3 MeO Scheme 2-17: Regio and stereospecific Rh catalyzed allylic substitution.
O O H2C(CO2Me)2 O OAc Cs2CO3 MeO OMe 93-97 % yield b:l 88:12-99:1 Ar 5 mol% [Rh(dpm)(C2H4)2] N 5 mol% L10 94-97 % ee Ar Ph2P Toluene, 40 °C
Ar = Ph, 4-Me-Ph, 4-CF3-Ph, 4-Cl-Ph (S,S)-L10 Scheme 2-18: Enantioselective Rh catalyzed allylic substitution.
2.3.5. Iridium
Ir catalysts were first probed for allylic substitution by Takeuchi 52 and have received the most attention in the context of allylic substitution in the latest years. 1g,1h,53 The focus will only be made on carbon carbon bond forming reactions, for heteroatomic nucleophiles see the above 1g,1h,52,53 mentioned reviews. Using [Ir(cod)Cl]2, as precatalyst, fine tuning with ligands and comparison of isomeric substrates uncovered the following trends: (i) reaction rate and regioselectivity are increased by electron poor ligands and decreased by electron rich ligands; (ii) a ligand to Ir ratio of 1 gives optimal results; additional ligand leads to decrease in rate but not in regioselectivity; (iii) the reaction rate is significantly higher for the branched than for the linear substrates; (iv) there are distinct memory effects concerning the allylic substrate in 48 Leahy, D. K.; Evans, P. A. In Modern Rhodium-Catalyzed Organic Reactions ; ed Evans, P. A., Wiley VCH: Weinheim, Germany, 2005 , 191 214 and references therein. 49 Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003 , 125 , 8974 8975 and references therein. 50 Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens, M. Org. Lett. 2006 , 8, 4569 4572. 51 Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003 , 5, 1713 1715. 52 (a) Takeuchi, R.; Akiyama, Y. J. Organomet. Chem. 2002 , 651 , 137 145. (b) Takeuchi, R.; Kashio, M. Angew. Chem. Int. Ed. Engl. 1997 , 36 , 263 265. (c) Takeuchi, R.; Kezuka, S. Synthesis 2006 , 3349 3366.. 53 (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007 , 675 691. (b) Miyabe, H.; Takemoto, Y. Synlett 2005 , 1641 1655.
20 Chap. 2: Metal-Catalyzed Allylic Substitutions that branched substrates give branched products with high selectivity and linear substrates tend to give mixtures; (v) substrates with ( Z) configuration of the double bond preferentially yield linear products with conservation of the ( Z) configuration. A few representative examples of Ir catalyzed allylation of stabilized carbanions are given in Table 2-5.
R R' cat. [Ir(cod)Cl] ,L* Nu or 2 Ar Ar Nu- Ar
L Ar = R = R’ = Pronucleophile % yield % ee Ref
L13 (CH 2)2Ph OAc NaHC(CO 2Me) 2 99 93 54
L11 4 MeO Ph OAc NaHC(CO 2Me) 2 98 95 55
L12 4 MeO Ph OCO 2Me H2C(CO2Me) 2 99 96 56
L14 Ph OCO 2Me NaHC(CO 2Me) 2 88 96 57
L14 Ph OCO 2Me NaHC(CO 2Me) 2 82 82 58
L15 Ph OCO 2Me CH3CH 2NO 2 85 (dr 1:1) 98, 96 59
L15 Ph OCO 2Me CH 2(CO 2Et)NO 2 90 98 59
Ligands: OMe Ph O O O O O P O P N P N P N N P(4-CF -Ph) 3 2 O Ph O O O Ph OMe L11 L12 L13a L13b L13c Table 2-5: Examples of allylic alkylation of cinnamyl derived acetates and stereotypical ligands. The three following examples of Ir catalyzed allylic substitutions with carbon carbon bond formation have been chosen due to their strong resemblance with the reaction subsequently detailed in this manuscript. The first example is the enantioselective α allylation of ketone enolates, generated in situ by the addition of fluoride anion to silyl enol ethers, yielding branched γ,δ unsaturated ketones as the major product from silyl enol ethers and Boc protected allylic alcohols ( Scheme 2-19 ).60
54 Bartels, B.; Helmchen, G. Chem. Commun. 1999 , 741 742.. 55 (a) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997 , 38 , 8025 8026. (b) Garcia Yebra, C.; Janssen, J. P.; Rominger, F.; Helmchen, G. Organometallics 2004 , 23 , 5459 5470.. 56 (a) Fuji, K.; Kinoshita, N.; Tanaka, K.; Kawabata, T. Chem. Commun. 1999 , 2289 2290. (b) Kinoshita, N.; Marx, K. H.; Tanaka, K.; Tsubaki, K.; Kawabata, T.; Yoshikai, N.; Nakamura, E.; Fuji, K. J. Org. Chem. 2004 , 69 , 7960 7964. 57 Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem. Int. Ed. 2004 , 43 , 4595 4597. 58 (a) Alexakis, A.; Polet, D. Org. Lett. 2004 , 6, 3529 3532. (b) Polet, D.; Alexakis, A.; Tissot Croset, K.; Corminboeuf, C.; Ditrich, K. Chem. Eur. J. 2006 , 12 , 3596 3609. (c) Polet, D.; Alexakis, A. Org. Lett. 2005 , 7, 1621 1624. 59 Dahnz, A.; Helmchen, G. Synlett 2006 , 697 700. 60 Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005 , 127 , 17192 17193.
21 Chap. 2: Metal-Catalyzed Allylic Substitutions
OTMS O R' 2 mol% [Ir(cod)Cl]2 L13b 4 mol% ent- R' 46-94 % yield b:l 87:13-99:1 CsF 0.4 equiv. R OBoc R 91-96 % ee ZnF2 1.5 equiv
R = 4-anisyl, 4-CF3-Ph, 2-furyl, i-Pr, n-Pr,1-propenyl, Ph R' = Ph, 2-anisyl, i-Pr, phenethyl Scheme 2-19: Ir catalyzed regio and enantioselective allylation of preformed silyl enol ethers.
The second example is the Ir catalyzed allylation of ketamines to give, after acidic hydrolysis, similar γ,δ unsaturated ketones with high regioselectivity in preference for the branched position and good enantioselectivity (Scheme 2-20). 61
N O i. 2 mol% [Ir(cod)Cl]2 R' 4 mol% ent-L13b R' 64-91 % yield b:l 85:15 - >99:1 77-97 % ee ZnCl2 0.5 equiv R Toluene R OCO2i-Pr ii. NaOAc/NaOH, H2O
R = Ph, 4-anisyl, 4-CF3-Ph, 2-furyl, 2-anisyl, Me, n-Pr R' = Ph, i-Pr, 2-anisyl, i-Bu Scheme 2-20: Regioselective and enantioselective Ir catalyzed allylation of preformed enamines.
This last example of Ir catalyzed allylic substitution deals with the regio and enantioselective decarboxylative alkylation of γ substituted allylic β aryloylacetates in the presence of a stoichiometric amount of base ( Scheme 2-21). 62 The same reaction, though catalyzed by a Ru complex, will be the basis for this manuscript.
O O O 2 mol% [Ir(cod)Cl]2 Ar O 4 mol% ent-L13b Ar 62-83 % yield b:l 80:20 - >99:1 DBU 2 equiv. 89-96 % ee R R CH2Cl2, 40 °C
R = Ph, 4-Me-Ph, 4-MeO-Ph, 3-MeO-Ph, 4-CF3-Ph, 4-F-Ph, 2-furyl, Me, n-C5H11 Ar = Ph, 4-MeO-Ph, 4-Me-Ph, 2-naphthyl Scheme 2-21: Ir catalyzed regio and enantioselective decarboxylative allylic alkylations.
Several other metals have been used as catalysts in allylic substitution such as Ni, 63 Pt 64 and Fe 65 but will not be detailed in this manuscript.
61 Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007 , 129 , 7720 7721. 62 He, H.; Zheng, X. J.; Yi, U.; Dai, L. X.; You, S. L. Org. Lett. 2007 , 9, 4339 4341. 63 (a) Consiglio, G.; Piccolo, O.; Roncetti, L.; Morandini, F. Tetrahedron 1986 , 42 , 2043 2053. (b) Consiglio, G.; Indolese, A. Organometallics 1991 , 10 , 3425 3427. (c) Indolese, A. F.; Consiglio, G. Organometallics 1994 , 13 , 2230 2234. (d) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008 , 130 , 2756 2757. (e) Gomez Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1998 , 120 , 7649 7650. 64 (a) Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Humphries, M. E.; Williams, J. M. J. Chem. Eur. J. 2000 , 6, 353 360. (b) Blacker, A. J.; Clark, M. L.; Loft, M. S.; Williams, J. M. J. Chem. Commun. 1999 , 913 914.
22 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.4. Ruthenium-Catalyzed Allylic Substitutions
Since ruthenium is the metal of choice for this work, 66 a wider scope of reactions will be discussed but keeping a focus on CpRu type catalysts. Ru catalyzed reactions cannot be fully covered here but one cannot omit to cite olefin metathesis 67 or enyne cyclisation reactions. 68
2.4.1. Early-Stage Developments
Historically, the first use of Ru based catalyst for allylic substitution was reported by Tsuji in
1985 using [RuH 2(PPh 3)4] as catalyst, cinnamyl carbonates as substrate and activated β ketoesters as prenucleophile.69 Several other Ru based catalysts were subsequently proposed for allylic substitution, however none of the following afforded a reaction with a satisfying 70 71 regioselectivity in favour of the branched product: [Ru(cod)(cot)], [CpRuCl(PPh 3)2], 72 73 74 [CpRuCl(cod)], [CpRu(PPh 3)(MeCN)2][PF 6], and [CpRu(MeCN)3][PF 6] ( 4a ). This latter example allowed however the reactions to take place under much milder conditions. 75 The first breakthrough in terms of regioselectivity, but also in terms of reactivity, came with the use of Cp*Ru complexes; the five methyl groups offering to the metal simultaneously enhanced steric shielding and electron density. The first successful catalyst described is [Cp*RuCl(cod)] which afforded good selectivities in favor of the branched product mainly for cinnamyl substrates; alkyl substituted substrates remaining however problematic. 76 A lot of efforts were made to develop new catalytic combinations and the use of N based ligands 77 was particularly investigated. 78 65 (a) Plietker, B.; Dieskau, A.; Mows, K.; Jatsch, A. Angew. Chem. Int. Ed. 2008 , 47 , 198 201. (b) Fukuzawa, S.; Yamamoto, M.; Hosaka, M.; Kikuchi, S. Eur. J. Org. Chem. 2007 , 5540 5545. 66 Ru catalyzed « Carroll rearrangements » will be studied separately at the end of this section. 67 (a) Grubbs, R. H.; Trnka, T. M in Ruthenium in Organic Synthesis , ed Murahashi, S. I. Wiley VCH, Weinheim, 2004 , 153 177. (b) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P. Angew. Chem. Int. Ed. 2007 , 46 , 6786 6801. (c) Hoveyda, A. H.; Schrock, R. R. Comprehensive Asymmetric Catalysis 2004 , 1, 207 233. 68 Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem. Int. Ed. 2005 , 44 , 6630 6666. 69 Minami, I.; Shimizu, I.; Tsuji, J. J. Organomet. Chem. 1985 , 296 , 269 280. 70 (a) Zhang, S. W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1993 , 450 , 197 207. (b) Kondo, T.; Mitsudo, T. in Ruthenium in Organic Synthesis , ed Murahashi, S. I. Wiley VCH, Weinheim, 2004 , 129 –151. 71 Kang, S. K.; Kim, D. Y.; Hong, R. K.; Ho, P. S. Synthetic Commun. 1996 , 26 , 3225 3235. 72 Morisaki, Y.; Kondo, T.; Mitsudo, T. A. Organometallics 1999 , 18 , 4742 4746. 73 Kitamura, M.; Tanaka, S.; Yoshimura, M. Journal of Organic Chemistry 2002 , 67 , 4975 4977. 74 Tanaka, S.; Saburi, H.; Ishibashi, Y.; Kitamura, M. Org. Lett. 2004 , 6, 1873 1875. 75 Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed. 2002 , 41 , 1059 1061. 76 (a) Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.; Watanabe, Y. Organometallics 1995 , 14 , 1945 1953. (b) Kondo, T.; Morisaki, Y.; Uenoyama, S.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 1999 , 121 , 8657 8658. (c) Renaud, J. L.; Bruneau, C.; Demerseman, B. Synlett 2003 , 408 410. 77 Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000 , 100 , 2159 2231. 78 Bruneau, C.; Renaud, J. L.; Demerseman, B. Chem. Eur. J. 2006 , 12 , 5178 5187 and references therein.
23 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.4.2. Ru-Catalysts for Regioselective Allylation of Nucleophiles
2.4.2.1. Structures of ηηη3-Allyl Cp*Ru(IV) Complexes Initial studies indicated that, as for palladium, the mechanism of Cp*Ru catalyzed allylic substitutions proceed through the formation of a π allyl Ru(IV) complex obtained by the oxidative addition of a 16 electron Ru(II) complex onto an allylic subtrate. 76a The study of the structure of η3 allyl Ru(IV) complexes has then received a lot of attention since they are believed to be a crucial reaction intermediate and thus closely related to the transition state.
All the isolated complexes have a pseudo tetrahedral (Td) geometry bearing an endo syn-η3 allyl ligand with a clear dissymmetry in the bond length between the Ru atom and the allyl termini ( (Ru C) up to 0.27 Å, Table 2-6). This difference in bond lengths is commonly referred to when rationalizing the regioselectivity of the reaction: the nucleophile attacks preferentially onto the most hindered position due to the weaker metal carbon bond at this site (longer bond length). 78 This dissymmetry (more important for aryl than alkyl R groups) is believed to mainly arise from a worse MO overlap α to the substituent because of conjugation or hyperconjugation. However, in solution, additional species have been observed by NMR, and are assumed to either arise from an endo-exo isomerism of the π allyl ligand (nOe 79 crosspeak between the central allylic proton and the Cp*), or from L/X exchanges for non 13 symmetrical ligands (two sets of signals in C NMR for each terminal allyl carbon).
Cplx Ru (CH 2) Ru (CHR) Ref
5a 2.18 2.35 76a 5b 2.19 2.35 79 Ru Ru Ru L O N 5c 2.21 2.28 80 X R O R N Ph 2.18 2.45 81 5a R=Ph L=Cl X=Cl t-BuO 5d 5b R=Ph L=NCMe X=Cl 5f R = 4-MeO-Ph 5g N-N= o-phenantroline 5e 2.19 2.34 81 5c R=Me L=NCMe X=Br 5d R = Ph L = Ph2(MeO)P X = Cl 5f 2.16 2.30 82 5e R = n-Pr L = Ph2(MeO)P X = Cl 5g 2.19 2.40 83
Table 2-6: Examples of Cp*Ru(IV) π allyl complexes and selected bond lengths in the X ray structures.
79 Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Watson, E. J.; Albinati, A.; Rizzato, S.; Veiros, L. F.; Calhorda, M. J. Organometallics 2005 , 24 , 1809 1812. 80 Mbaye, M. D.; Demerseman, B.; Renaud, J. L.; Toupet, L.; Bruneau, C. Adv. Synth. Catal. 2004 , 346 , 835 841. 81 Demerseman, B.; Renaud, J. L.; Toupet, L.; Hubert, C.; Bruneau, C. Eur. J. Inorg. Chem. 2006 , 1371 1380. 82 Hermatschweiler, R.; Fernandez, I.; Breher, F.; Pregosin, P. S.; Veiros, L. F.; Calhorda, M. J. Angew. Chem. Int. Ed. 2005 , 44, 4397 4400. 83 Mbaye, M. D.; Demerseman, B.; Renaud, J. L.; Toupet, L.; Bruneau, C. Angew. Chem. Int. Ed. 2003 , 42 , 5066 5068.
24 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.4.2.2. Regioselective Allylation of Oxygen-Nucleophiles One of the most studied regioselective Cp*Ru catalyzed allylic substitution reaction is the allylation of phenol derivatives starting from allyl chlorides ( Table 2-7). 80,81 These reactions smoothly provide the branched O allylated phenols with good regioselectivity in the case of phenyl or benzyl derivatives. One noticeable exception is the report by Pregosin of the C allylation, by a Friedel and Craft reaction, of electron rich phenols or aromatic nucleophiles. 84
Cl [Ru] OAr ArOH R R 1.2 equiv. K2CO3
[Ru] Solv. R Ar b:l Ref
[Cp*Ru(MeCN)3][PF 6] MeCN Ph Ph 98:02 80
[Cp*Ru(MeCN)3][PF 6] MeCN Ph 4 MeOPh 98:02 80
[Cp*Ru(MeCN)3][PF 6] MeCN Ph 4 MePh 97:03 80
[Cp*Ru(MeCN)2(PPh 2OMe)][PF 6] THF PhCH 2 Ph 92:08 81
[Cp*Ru(MeCN)2(PPh 2OMe)][PF 6] THF PhCH 2 4 MeOPh 96:04 81
[Cp*Ru(MeCN)3][PF 6] MeCN n Pr Ph 63:37 80
[Cp*Ru(MeCN)3][PF 6] Me 2CO n Pr Ph 70:30 80
Table 2-7: Examples of regioselective Cp*Ru catalyzed O allylation of phenols.
2.4.2.3. Regioselective allylation of nitrogen-nucleophiles The first example of regioselective Ru catalyzed allylic amination reaction was reported by Kondo and Nagashima using a CpRu catalyst and piperidine as nucleophile but the regioselectivity was clearly in favour of the less substituted position ( Table 2-8 (a) ). 85
H N [RuCl2(cod)]x 5 mol% (a) NH PF 10 mol% OCO Me 4 6 N 2 decane 100°C N 2 equiv. 77 % 37 %
L HNR 2 b:l Ref OCO Et [Cp*Ru(MeCN)3][PF6] 2 NR2 Phen piperidine 96:04 83 3 mol% HNR2 Ph L Ph Phen Et 2NH 89:11 83 Phen pyrrolidine 98:02 83 (b) R N N R cod Et 2NH 0:100 86
L14a R = i-Pr L14a Et 2NH 05:95 86 L14b R = Mes L14b Et 2NH 02:98 86
Table 2-8: Examples of regioselective Cp*Ru catalyzed N allylation of secondary amines.
84 Fernandez, I.; Hermatschweiler, R.; Breher, F.; Pregosin, P. S.; Veiros, L. F.; Calhorda, M. J. Angew. Chem. Int. Ed. 2006 , 45 , 6386 6391. 85 Morisaki, Y.; Kondo, T.; Mitsudo, T. A. Organometallics 1999 , 18 , 4742 4746.
25 Chap. 2: Metal-Catalyzed Allylic Substitutions
Later Bruneau and Demerseman obtained much better regioselectivities (up to b/l 96:4) with an in situ generated Cp* phenantroline Ru catalyst. 83 The crucial role of the N,N ligand was shown in a later publication ( Table 2-8 (b) ). 86
2.4.2.4. Regioselective allylation of carbon-nucleophiles Stabilized carbon nucleophiles are the most common in carbon carbon bond forming allylic substitution reactions and are usually generated by deprotonation of gem dicarbonyl compounds (ketones and/or esters) using NaH as base.76a Trost has shown that cationic 87 trisnitrile complexes as [CpRu(MeCN)3][PF 6] are efficient catalysts to perform the reaction shown in Table 2-9 and that the preferred leaving group are carbonates.75 In contrast to rhodium and copper, the Ru catalyzed allylic substitution is not regiospecific as the same products are obtained from the corresponding branched or linear substrates; showing that the reaction most probably proceeds through a π allyl Ru intermediate.
O O 2 O O OCO2R [Ru] MeO OMe MeO OMe R X Y R1 Entry [Ru] X, Y Solv. R1 R2 b:l Ref
1 [CpRu(MeCN)3][PF 6] Na, H DMF OMe t Bu 55:45 88
2 [CpRu(MeCN) 3][PF 6] Na, H DMF H t Bu 33:67 88
3 [CpRu(MeCN) 3][PF 6] Na, H DMF Cl t Bu 30:70 88
4 [Cp*Ru(MeCN) 3][PF 6] Na, H DMF OMe t Bu 95:05 88
5 [Cp*Ru(MeCN) 3][PF 6] Na, H DMF H t Bu 90:10 88
6 [Cp*Ru(MeCN) 3][PF 6] Na, H DMF Cl t Bu 90:10 88
7 [Cp*Ru(MeCN) 3][PF 6] Na, H DMF H t Bu 92:8 75
8 [Cp*Ru(MeCN) 3][PF 6] Na, OMOM DMF H t Bu 90:10 75
9 [Cp*Ru(MeCN) 3][PF 6] Na, NHBoc DMF H t Bu 82 :18 75
10 [Cp*Ru(MeCN)2(4,4’ diMe bipy)][PF 6] H, H MeCN H Et 96:04 83
Table 2-9: Examples of regioselective Cp*Ru catalyzed C allylation of dimethylmalonate.
Once again, the superior efficiency of Cp*Ru based catalysts is clear both in terms of reactivity and of regioselectivity ( Table 2-9 entries 2, 3 vs. 5, 6).88 The effect of the ligands on the Cp*Ru moiety again proved to be crucial. In some cases the use of an additional base could be avoided by using the alkoxide liberated by decarboxylation of the carbonate leaving group ( Table 2-9 entry 10).83 86 Mbaye, M. D.; Demerseman, B.; Renaud, J. L.; Bruneau, C. J. Organomet. Chem. 2005 , 690 , 2149 2158. 87 Trost, B. M.; Older, C. M. Organometallics 2002 , 21 , 2544 2546. 88 Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Breher, F. Organometallics 2006 , 25 , 1440 1447.
26 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.4.3. Asymmetric Allylation of Nucleophiles
Although many studies of Ru catalyzed allylic substitution reactions have been communicated, asymmetric examples of this reaction remain rare.
2.4.3.1. Stereospecific Nucleophilic Substitutions
Having established the involvement of a functional equivalent to a π allyl Ru complex, Trost envisaged a stereoselective version of the above described reaction. The treatment of an enantioenriched branched cinnamyl carbonate with [Cp*Ru(MeCN)3][PF 6] and a carbon nucleophile yielded the desired product with a full transfer of the initial stereogenic information: a complete retention of the absolute configuration of the branched carbon was achieved ( Scheme 2-22 (a) ).75 Thus, the nucleophilic attack proceeds faster than the possible equilibration of the transient π allyl Ru complex and the addition exclusively takes place from the side opposite to the metal coordination; globally resulting in a retention of configuration. This was also shown for phenoxy nucleophiles. 75 In addition, Onitsuka showed the very efficient kinetic resolution of racemic allylic carbonates with sodium dimethylmalonate using an enantiopure Cp’Ru based catalyst (Scheme 2-22 (b) ). 89
MeO2C CO Me OCO2Me 1 mol% [Cp*Ru(MeCN)3][PF6] 2 MeO2C CO2Me 1 equiv. NaH BocHN (R) (a) NHBoc DMF, R.T. (R) 99 % ee 99 % ee
- O O t-Bu O PF6 OCO2Et MeO OMe Ru O 90-94 % ee MeCN R R NaH MeCN P 2.5 mol% Ar2 (b) THF, R.T. OCO2Et O O R R MeO OMe 92-99 % ee
R = Me, Et Ar = Ph, 2-MeO-Ph, 3,5-Me2-Ph R R Scheme 2-22: Ru catalyzed stereospecific substitution of enantiopure allylic carbonates.
2.4.3.2. Enantioselective nucleophilic substitutions Although enantioselective allylic substitution is a powerful synthetic tool very few examples of Ru catalyzed reactions had been reported at the beginning of this work. Still today only three reports, independent from our group, are available in the literature. The first example was reported by Takahashi in 2001 using enantiopure Cp’Ru planar chiral complexes with C
89 Onitsuka, K.; Matsushima, Y.; Takahashi, S. Organometallics 2005 , 24 , 6472 6474.
27 Chap. 2: Metal-Catalyzed Allylic Substitutions or N nucleophiles ( Scheme 2-23 (a) ). 89,90 Since in this example the substrate was symmetrically 1,3 disubstituted, the reaction did not suffer from a regioselectivity problem.
On the other hand, Bruneau showed in 2004 that [Cp*Ru(MeCN) 3][PF 6] in conjunction with enantiopure bisoxazoline ligands could effect the enantioselective O allylation of phenols starting from cinnamyl chloride albeit with low regioselectivity ( Scheme 2-23 (b) ). 91 Recently Onitsuka described the use of Cp’Ru catalysts to effect the same reaction and obtained excellent regio and enantioselectivities ( Scheme 2-23 (c) ). 92
- R O PF6
Ru O MeCN P 5 mol% Nu OCO2Et MeCN Ar NuNa 2 63-97 % ee (a) Ph Ph THF, R.T. Ph Ph
NuNa = NaCH(CO2Me)2, NaCH(CO2Et)2, NaCMe(CO2Me)2 R = Me, Ph, t-Bu ; Ar = Ph, 2-MeO-Ph, 3,5-Me2-Ph O O Ph Ph N N Ph Ph 10 mol% Cl 10 mol% [Cp*Ru(MeCN) ][PF ] Ar OH 3 6 O b:l 1.6:1 - 3:1 52-82 % ee (b) Ar K CO , acetone, R.T. Ph 2 3 Ph Ar = 4-MeO-Ph, 4-Cl-Ph, 4-Me-Ph
- t-Bu O PF6
Ru O MeCN 2 Cl MeCN P 2.5 mol% R OH Ar2 O b:l > 95:5 2 (c) R 1 80-95 % ee R K2CO3,THF, R.T. R1
1 R = Ph, 4-CF3-Ph, 4-Cl-Ph, 2-MeO-Ph, 1-naphtyl, Me 2 R = Ph, 2-MeO-Ph, 3-Me-Ph, 4-Me-Ph, 2-t-Bu-Ph, 2-Ph-Ph, 4-CF3-Ph, Bn, Me Scheme 2-23: Ru catalyzed enantioselective substitution of allylic subtrates.
2.4.4. Ru-catalyzed “Carroll rearrangement”
The “ Carroll rearrangement” 93 is a decarboxylative [3,3] sigmatropic rearrangement of allylic β ketoesters, to yield γ,δ unsaturated ketones, which proceeds at high temperatures (typically 140 180 °C). 94 This reaction has however found several useful synthetic applications. 95
90 Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem. Soc. 2001 , 123 , 10405 10406. 91 Mbaye, M. D.; Renaud, J. L.; Demerseman, B.; Bruneau, C. Chem. Commun. 2004 , 1870 1871. 92 Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008 , 47 , 1454 1457. 93 For clarity, the improper term “ Carroll rearrangement” will be used throughout this manuscript to name the Ru catalyzed version of the reaction although it does not proceed trough a sigmatropic rearrangement. 94 (a) Carroll, M. F. J. Chem. Soc. 1940 , 1266 1268. (b) Carroll, M. F. J. Chem. Soc. 1940 , 704 706. (c) Carroll, M. F. J. Chem. Soc. 1941 , 507 511. 95 (a) Bonrath, W.; Netscher, T. Appl. Catal., A 2005 , 280 , 55 73. (b) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. Org. Lett. 2003 , 5, 4037 4040. (c) Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004 , 45 , 107 109. and refferences therein.
28 Chap. 2: Metal-Catalyzed Allylic Substitutions
2.4.4.1. Cp*Ru-Catalyzed Carroll Rearrangement The first Ru catalyzed Carroll rearrangement was reported by Nagashima using Cp*Ru based catalysts, but only moderate selectivities were obtained. 96 Recently Tunge reported that the in- situ obtained [Cp*RuCl(bpy)] moiety could transform allyl β ketoesters almost exclusively into the corresponding branched ketones. 97a b In addition Tunge also reported that the reaction could be stereospecific when starting from enantioenriched branched allylic substrates (Scheme 2-24 ).97c
O O O O O 2.5 mol% [{Cp*RuCl}4] 10 mol% bipy R or b:l > 98:2 R O R O rac or cee 45-98% CH2Cl2, R.T. Ar Ar Ar
R = Me, Bn, i-Pr ; Ar = Ph, 4-MeO-Ph, 4-Me-Ph, 4-Cl-Ph, 4-NO2-Ph,4-CF3-Ph Scheme 2-24: CpRu catalyzed (enantioselective or stereospecific) Carroll rearrangement.
2.4.4.2. CpRu-catalyzed Enantioselective Carroll rearrangement The development of a Ru catalyzed enantioselective version of the Carroll rearrangement of cinnamyl derived substrates was achieved by our group using a combination of 98 [CpRu(MeCN)3][PF 6] and enantiopure pyridine imine ligands ( Scheme 2-25 ). Branched β ketoesters were obtained with good regio and enantioselectivities (up to b:l > 99:1 and 80 % ee for linear substrate and 92 % ee for branched substrate). Interestingly, in this particular case, the Cp*Ru derived catalyst proved to be less efficient than their CpRu counterparts. Unfortunately, these conditions require rather large amounts of metal precursor (10 mol%), long reaction times (20 h to several days) and suffer from an acute sensitivity to reaction parameters.
R2 O R1 O O O O 10 mol% [CpRu(MeCN) ][PF ] 3 6 3 10 mol% L* N R O or O N THF, 60 °C Ar L* Ar Ar 1 R = H, 4-NMe2, 6-Me 2 Ar = Ph, 4-MeO-Ph, 4-Cl-Ph up to b:l > 98:2 R = Ph, 2-MeO-Ph upto80or 92% ee R3 = Et, n-Pr, Bn, t-Bu Scheme 2-25: CpRu catalyzed (enantioselective or stereospecific) Carroll rearrangement.
96 Kondo, H.; Kageyama, A.; Yamaguchi, Y.; Haga, M.; Kirchner, K.; Nagashima, H. Bull. Chem. Soc. Jpn 2001 , 74 , 1927 1937. 97 (a) Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603 2605. (b) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005 , 1715 1726. (c) Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835 2837. 98 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082 2085..
29 Chap. 2: Metal-Catalyzed Allylic Substitutions
An alternative methodology based on the use of TRISPHAT N99 coordinating anion allowed the recycling of the precatalyst Y (> 85 %). In addition, since these complexes could be easily purified by chromatography, more selective reactions were obtained ( Scheme 2-26 ). 100
2 PF6
[CpRu(MeCN)3][PF6] [Bu3NH][TTN] 2 equiv. 2 equiv. N N Ru N N Ru Ru N N Ru
CH2Cl2 CH2Cl2 N N MeCN N N NCMe 43 % TTN N N TTN
X Y
Cl Cl Cl
O Cl Cl O O P N O O O Cl TRISPHAT-N (TTN) Cl Cl Cl
Enantioselectivity of branched product as a function of time in the reactions catalyzed by Y ( ) and X () Scheme 2-26: Use of TRISPHAT N ligand for the CpRu catalyzed Carroll rearrangement. 2.5. Aim and scope of the work
The aim of this PhD was to further develop the CpRu catalyzed Carroll rearrangement methodology to make it synthetically applicable and to better understand the mechanism of the reaction. In order to solve some of the issues related to the preliminary work, new catalytic combinations were developed and used in the context of the Carroll rearrangement. This led to the use of the pymox ligand family which exhibited greater reactivity and/or selectivity and to the use of a less air and moisture sensitive metal source. Different mechanistic aspects of the reaction were studied and attempts to rationalize most experimental observations have been made. The use of co catalysts was subsequently envisaged and the scope of the catalytic systems finally probed with different “classical ” allylic substitution reactions. All these results are reported in the following chapters.
99 Constant, S.; Frantz, R.; Muller, J.; Bernardinelli, G.; Lacour, J. Organometallics 2007 , 26 , 2141 2143. 100 Constant, S.; Tortoioli, S.; Muller, J.; Linder, D.; Buron, F.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 8979 8982.
30 Chap. 3: Catalytic System Optimization
3. Catalytic System Optimization
There is no such thing as ligand design. At best one can copy features that are present in “privileged” ligands, that is, ligands that have been successful in other cases. Johannes G. de Vries 1 3.1. Preamble
The introduction to this chapter will be entirely devoted to the understanding of the detailed scientific background to this work as it was initiated and the different issues that remained unsolved at that time. The initial reports by Tunge dealing with the Cp*Ru catalyzed Carroll rearrangement 2 set the basis for the work of our group . ( Scheme 3-1). 3
O O O O
[CpRu(MeCN)3][PF6] O (10 mol%) Ligand (10 mol%) * + THF, 60 °C 1 2 3 R R R
R = 4-OMe, H, Cl R'' For R = 4-OMe L11a R'=MeR''=H 56% ee N R' L11b R' = tBu R'' = H 72 % ee N L11c R' = tBu R'' = OMe 80 % ee Ligand Scheme 3-1: CpRu catalyzed rearrangement of primary esters with ligands L.
In our hands, and in contrast to the report of Tunge, using 2,2’ bipy as ligand, precatalyst
[Cp*RuCl]4 did not afford satisfactory reactivity and selectivity with all tested chiral N,N ligands. However, [CpRu(MeCN)3][PF 6] (4a ) was found to be an efficient precatalyst which, in the conjunction with pyridine imine ligands, afforded the smooth rearrangement of cinnamyl derived acetoacetates ( Fig 3-1). The pyridine imine ligand family allowed a very easy and straightforward screening due to the ease of synthesis and the availability of the vast number of aldehyde and amine fragments. As such, ligand L11c appeared as the most selective: the branched isomer 2 was obtained selectively ( b:l up to > 99:1) with a good level of enantioselectivity (up to 80 % ee with L11c ); the presence of pyridine imine ligands allowing a reversal of the preferential “linear” regioselectivity induced by 4a as catalyst. 4 Unfortunately, these reported conditions require rather large amounts of metal precursor (10 1 de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006 , 12 , 4722 4734, also see: Yoon, T. P.; Jacobsen, E. N. Science 2003 , 299 , 1691 1693. 2 (a) Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603 2605. (b) Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835 2837. (c) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005 , 1715 1726. 3 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082 2085. 4 (a) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed. 2002 , 41 , 1059 1061. (b) Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Breher, F. Organometallics 2006 , 25 , 1440 1447.
31 Chap. 3: Catalytic System Optimization mol% of 4a ). Long reaction times are also needed (20 h to several days) especially with substrates bearing electron withdrawing substituents ( e.g. a 4-Cl: 5 days). 4b An acute sensitivity to several reaction parameters, including temperature and solvent, was noticed diminishing somewhat the scope of this process. A second issue came up when the rearrangement of branched cinnamyl acetoacetates, first described by Tunge, 2b was effected. Using secondary allylic esters ( R) and ( S) 5c ( ee > 99 %) and L11c as ligand, a complicated “matched/mismatched” situation was observed ( Scheme 3-2).
O O O O
[CpRu(MeCN)3][PF6] O (10 mol%) * Ligand (10 mol%) + THF, 60 °C 5c 2c 3c
OMe
tBu Ph Ph
N N At full conversion : L11c L11d (R)-5c L11c 6h (_)-70 % ee 5c L11c N N (S)- 10h (+)-92 % ee (S)-5c L11d 6h (+)-70 % ee Scheme 3-2: CpRu catalyzed rearrangement of secondary esters with ligands L
Compared to the use of achiral ligand L11d (70 % ee ), ( S) 5c and L11c gave a “matched” situation (92 % ee ). But this “matched” reaction was quite slower than the “mismatched” (( R) 5c and L11c: 70 % ee ) situation and little effect on the ee was seen in the latter case in comparison with the reaction with achiral L11d . Reasoning that blocking the rotation around the C N single bond of the imine moiety would restrain the conformational flexibility of the ligand, the use of the more rigid 2 pyridine monooxazoline (pymox) structural scaffold was considered. In addition, the relatively moderate enantioselectivity, obtained with ligands of type L11 , possibly was a consequence of this conformational flexibility. A new generation of ligands was obviously needed to overcome the limitations associated with the use of pyridine imine ligands L11 and the use of a more rigid structural scaffold would ease up the rationalization of the reaction’s stereochemical outcome.
32 Chap. 3: Catalytic System Optimization
3.2. Optimization of the Ligand
3.2.1. Use and Synthesis of Pymox Ligands
N,N-ligands 5 have received a lot of attention in the context of asymmetric metal catalyzed reactions and more particularly ligands incorporating heteroaromatic fragments such as pyridines.6 Though pymox ligands were introduced in the late 80s by Brunner, they have only received limited attention in other fields than coordination chemistry and their application to highly enantioselective reactions remains rare. Historically, pymox ligands were prepared by converting 2 cyanopyridine to the corresponding imidate by addition of methanol followed by addition of the corresponding optically active amino alcohol.7 Later Bolm described the direct 8 ZnCl 2 condensation of aminoalcohol onto 2 cyanopyridine ( Scheme 3-3).
R 1) cat NaOMe MeOH R 2) aminoalcohol
Aminoalcohol O R4 N CN cat ZnCl N or 2 R3 PhCl, 60 °C N R2 R1
O N Ph O N O Ph N N N H OH N L12 L13 L14 Ph
RO O O O N N N Ph N N N L15Ph L16Ph L17 Scheme 3-3: Syntheses of pymox ligands and chosen examples.
Ligand L12 was used in the Rh catalyzed enantioselective hydrosilylation of ketones with diphenylsilane.9 Ligands L13 and L14 , bearing additional stereogenic elements on the pyridine moiety, were used in the Rh catalyzed enantioselective hydrosilylation 10 and the Pd catalyzed asymmetric allylic alkylation of 1,3 diphenylprop 2 enyl pivalate with dimethyl malonate, respectively.11 Ligands L15 and L16, prepared with similar strategies, were active
5 Togni, A.; Venanzi, L. M. Angew. Chem. Int. Ed. Engl. 1994 , 33 , 497 526. 6 (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000 , 100 , 2159 2231. (b) Kwong, H. L.; Yeung, H. L.; Yeung, C. T.; Lee, W. S.; Lee, C. S.; Wong, W. L. Coord. Chem. Rev. 2007, 251, 2188 2222. 7 Brunner, H.; Obermann, U.; Wimmer, P. J. Organomet. Chem. 1986 , 316 , C1 C3. 8 Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991 , 124 , 1173 1180. 9 Brunner, H.; Henrichs, C. Tetrahedron-Asymmetry 1995 , 6, 653 656. 10 Brunner, H.; Storiko, R.; Nuber, B. Tetrahedron-Asymmetry 1998 , 9, 407 422. 11 Nordström, K.; Macedo, E.; Moberg, C. J. Org. Chem. 1997 , 62 , 1604 1609.
33 Chap. 3: Catalytic System Optimization in Pd catalyzed asymmetric allylic alkylation.12 Ligand L17, with a remote chiral substituent, was obtained from ( S) mandelic acid and was used in the Rh catalyzed hydrosilylation of 4 methylacetophenone with trichlorosilane.13
3.2.2. Ligand Structure Screening
Several pymox ligands were thus synthesized following the procedure of Bolm 8 and were subjected to the standard allylation reaction conditions developed for the pyridine imine ligands. 3 The results are summarized in Table 3-1.14
O O O O
[CpRu(MeCN)3][PF6] (10 mol%) O L18 (10 mol%)
THF, 60 °C
1a 2a 3a MeO MeO MeO Ph b c O O Ph Entry Ligand Time Conv. % ee Conf. b:l Ph N N 1 - 48 h < 3 %
N L18aN L18b 2 L18a 2 h > 97 % 53 (–) > 97:3 3 L18b 2 h > 97 % 56 (–) > 97:3 O O 4 L18c 2 h > 97 % 63 (+) > 97:3 N N 5 L18d 2 h > 97 % 72 (+) > 97:3 N L18cN L18d 6 L18e 48 h < 3 % 7 L18f 2 h > 97 % 80 (–) > 97:3 O O a N N Fresh 4a (10 mol%), ligand L18 (10 mol%), THF, 60 °C, c(1a ) 0.5 M; the results being the average of at least two runs; b sign of optical rotation N L18eN L18f of 2a ; c ratios of branched ( 2) to linear (3) products were determined by 1H NMR (400 MHz). Table 3-1: Ligand screening, oxazoline part.a
Ligand L18a, bearing the same oxazoline than the most selective ligand of Bruneau,15 proved to be already quite efficient in our case: the Carroll rearrangement of substrate 1a yielded the expected product 2a with full conversion and perfect b:l ratio in less than 2 h with a decent ee value of 53 % (entry 2). A gradual increase of the bulk of the substituent α to the N atom improved the enantiomeric excess up to 72 % with the valinol derived pymox L18d without any loss of regioselectivity (entries 3 5). Surprisingly, ligand L18e derived from tert leucinol
12 Bremberg, U.; Rahm, F.; Moberg, C. Tetrahedron-Asymmetry 1998 , 9, 3437 3443.. 13 Malkov, A. V.; Liddon, A. J. P. S.; Ramirez Lopez, P.; Bendova, L.; Haigh, D.; Kočovský, P. Angew. Chem. Int. Ed. 2006 , 45 , 1432 1435. 14 Conversions are given (but not isolated yields) since it was possible to isolate the mixtures of 2a and 3a in yields above 95 % each time. The yields are thus considered to be virtually quantitative in all cases. 15 In the context of O allylation of phenols: Mbaye, M. D.; Renaud, J. L.; Demerseman, B.; Bruneau, C. Chem. Commun. 2004 , 1870 1871.
34 Chap. 3: Catalytic System Optimization displayed no catalytic activity whatsoever (entry 6). The completely rigid ligand L18f, derived from (1 R,2 S) cis 1 amino 2 indanol, afforded solely the desired branched product 2a with an enantioselectivity of 80 % at full conversion (entry 7). Ligand L18f performed thus as regio and enantioselectively as the most efficient pyridine imine ligand L11c but with a much higher catalytic activity (2 h vs. 24 h for L18f and L11c respectively). In order to further optimize the structure of the ligand, variations on the substitution pattern of the pyridine part were undertaken and a few other structures were synthesized using the above mentioned methods. 7,8
O O O O
[CpRu(MeCN)3][PF6] (10 mol%) O L18 (10 mol%)
THF, 60 °C
1a 2a 3a MeO MeO MeO
O O N N N N N L18g N L18h b c Entry Ester Ligand Time Conv. % ee Conf. b:l 1 1a L18g 3.5 h > 97 % 78 (–) > 97:3 O O 2 1a L18h 3.5 h > 97 % 78 (–) > 97:3 N N 3 1a L18i 1.5 h > 97 % 73 (–) > 97:3 N L18i N L18j 4 1a L18j 4 h > 97 % 76 (–) > 97:3 5 1a L18k 16 h > 97 % 58 (–) > 97:3 O O H Bn 6 1a L18l 14 h > 97 % 64 (–) > 97:3 N N N N 7 1a L18m 5 h > 97 % 69 (–) > 97:3 N L18k N L18l 8 1a L18n 48 h < 3 %
a Fresh 4a (10 mol%), ligand L18 (10 mol%), THF, 60 °C, c(1a ) 0.5 M; O O the results being the average of at least two runs; b sign of optical rotation Li c N O of 2a ; ratios of branched ( 2) to linear ( 3) products were determined by N N 1H NMR (400 MHz). N L18m N L18n
Table 3-2: Ligand screening, heteroaromatic part.a
Electron poor pyrimidine and pyrazine derived ligands ( L18g and L18h respectively) were thus synthesized in a similar manner to L18f. These two ligands afforded solely the branched product 2a with the same ee value of 78 %. However, for these two electron poor ligands, the reactions were noticeably slower than for the unsubstituted pyridine ligand L18f (Table 3-2, entries 1 and 2). On the other hand, ligand L18i (entry 3), bearing an electron donating methyl group para to the N-atom of the pyridine, afforded a faster reaction with excellent regioselectivity but a lower enantioselectivity (73 % ee in 1.5 h for L18i, vs . 80 % ee in 2 h for L18f). Electronic factors on the pyridine side of the ligand seem to play a crucial role on
35 Chap. 3: Catalytic System Optimization the kinetics of the reaction (electron poor ligands affording slower reactions) but accelerating the reaction seems detrimental to the enantioselectivity of the process.3 In addition, the 5 methyl substituted pyridine ligand L18j (entry 4) allowed reaching full conversion of 1a into 2a but with a strongly detrimental effect on the kinetics of the reaction (76 % ee in 4 h for L18j, vs . 80 % ee in 2 h for L18f). The additional methyl group, in the latter cases, is probably sterically interacting with the π allyl fragment and overall slowing down the reaction. Replacing the pyridine moiety by a NH or NBn benzimidazole ( L18k and L18l) proved to have a detrimental effect on both reaction kinetics and enantioselectivities (entries 5 and 6). However the deprotonated benzimidazole oxazoline ligand L18m afforded a much faster reaction than its NH equivalent (entry 7). This effect is not likely due to the Li cation since the addition of LiPF 6 to the reaction of 1a with ligands L18f of L18k did not have any measurable effect on the outcome of the reaction. Ligand L18n (entry 8) did not show any catalytic activity at all; probably due to the always present disfavored steric interaction between the Cp and the indenyl moieties.
A “naked” pyridine moiety combined with an indanyl oxazoline on the ligand thus seems to be the best compromise to fulfill the stereoelectronic requirements for the reaction to proceed. Ligand L18f thus appeared as the most suitable candidate for further reaction optimization.
3.3. Optimization of the Reaction Conditions
3.3.1. Reaction Conditions Screening
Reaction conditions were then screened again with ligand L18f. Surprisingly, little solvent effect could be observed with a variety of media ( Table 3-3) to the exception of acetonitrile and benzonitrile 16 which completely inhibited the reaction. Probably, these two latter strongly coordinating solvents compete efficiently with the pymox ligand for an access to the first coordination sphere of the metal and thus inhibit the ligand accelerated catalysis. 17 Due to the higher reactivity of the catalytic system derived from ligand L18f , a lowering of the catalyst loading towards a more synthetically applicable level was deemed feasible. Several experiments were performed and it was observed that the amount of metal could be decreased
16 6 4+ The isolation of a stable [CpRu{CpRu(η p CH 3C6H4CN)} 3] complex has been described by Pregosin and coworkers see Ref 4b. 17 [CpRu(MeCN)3][PF 6] cannot catalyze the Carroll rearrangement of allylic esters of type 1 without a suitable ligand: no reaction is observed in the absence of a proper ligand (see Table 3-1 entry 1).
36 Chap. 3: Catalytic System Optimization to 2.5 mol% without any noticeable loss of regio or enantioselectivity ( Table 3-4). To keep conveniently short reaction times, the concentration of the substrate was gradually increased from 0.5 to 2 M with again no obvious effect on the stereochemical outcome of the reaction or the conversion.
O O O O
[CpRu(MeCN)3][PF6] (10 mol%) O L18f (10 mol%)
THF, 60 °C
1a 2a 3a MeO MeO MeO
Entry Ester Solvent Time Conv. % ee Conf. b b:l c
1 1a Acetone 2 h > 97 % 78 (–) > 97 : 3 2 1a DME 2 h > 97 % 77 (–) > 97 : 3 3 1a DMF 2 h > 97 % 77 (–) > 97 : 3 4 1a THF 2 h > 97 % 80 (–) > 97 : 3 5 1a MeCN 48 h < 3 % 6 1a PhCN 48 h < 3 %
a Fresh 4a (10 mol%), ligand L18f (10 mol%), 60 °C, c(1a ) 0.5 M; the results being the average of at least two runs; b sign of optical rotation of 2a ; c ratios of branched (2) to linear ( 3) products were determined by 1H NMR (400 MHz). Table 3-3: Solvent screening CpRu catalyzed rearrangement of allylic ester 1a .a
O O O O
[CpRu(MeCN)3][PF6] (x mol%) O L18f (x mol%)
THF, 60 °C
1a 2a 3a MeO MeO MeO
Entry c ( 1a ) mol% Time Conv. % ee Conf. b b:l c
1 0.5 M 10 2 h > 97 % 80 (–) > 97 : 3 2 0.5 M 5 4 h > 97 % 79 (–) > 97 : 3 3 2 M 5 2 h > 97 % 80 (–) > 97 : 3 4 2 M 2.5 6 h > 97 % 79 (–) > 97 : 3
a Fresh 4a (x mol%), ligand L18f (x mol%), 60 °C; the results being the average of at least two runs; b sign of optical rotation of 2a ; c ratios of branched ( 2) to linear ( 3) products were determined by 1H NMR (400 MHz). Table 3-4: Catalyst loading screening a
3.3.2. Synthesis of the Substrates
The cinnamyl acetoacetates 1a , 1b , 1d , 1e , 1f , 1i , 1j , 1k ( Table 3-5) were synthesized in high yield from the corresponding commercially available cinnamic acids ( Scheme 3-4). The first step is the acid catalyzed formation of the corresponding methyl esters which is subsequently reduced to the allylic alcohol using DIBAL H. The resulting alcohol is then esterified using diketene 6a in THF or commercially available 2,2,6 trimethyl 4H 1,3 dioxin 4 one 6b in
37 Chap. 3: Catalytic System Optimization toluene (DMAP catalysis). Substrates 1c and 1h (Table 3-5) were synthesized in a similar manner directly from the commercially available allylic alcohol. Compound 1g (Table 3-5) was prepared by a palladium catalyzed Sonogashira coupling of 4 iodo anisole and propargylic alcohol. The triple bond was subsequently selectively hydrogenated to the Z
olefin using Pd/BaSO 4 as catalyst, the allylic alcohol being then esterified as described before.
O O O O OH 1.5 equiv. 6a R cat HCl, MeOH R 3 equiv. DIBAL-H R Reflux 2 h THF -78 °C THFreflux 2 h O OH OMe R 94 - 99 % 97 - 99 % or 0.95 equiv. 6b R' R' R' cat DMAP Tol. 100°C 87 - 95 % R' 1 [PdCl2(PPh3)2] 2.5 mol% OH CuI 5 mol%, I OH H , Pd/BaSO 10% 1.1 equiv. NEt3 2 4 MeO O MeOH, R.T. MeO MeCN, R.T., 2h MeO OH 0.95 equiv. 6b 88 % 95% cat DMAP Tol. 100°C 1 equiv. 1.2 equiv. MeO 92 % O O
R = 4-MeO, 2-MeO, 4-Cl, 4-NO , 3,4-OCH O,H O 2 2 6a O O 6b R' = Me, Ph O O Scheme 3-4: Synthesis of cinnamyl acetoacetates.
3.3.3. Scope of the Reaction
To assess the scope of this catalytic combination, 10 mol% of catalyst appeared as a good compromise to keep constant conditions for fast but also slow reacting substrates. Using ligand L18f and “classical” conditions 18 (THF, 60 °C, 0.5 M of substrate 1, 4a and L18f 10 mol% each), the scope of the reaction was investigated with the variety of substrates detailed in Table 3-5 (compounds 1a to 1g ).
The regioisomeric anisyl derivatives 1a and 1b ( o or p-OMe) and 1f bearing a 3,4 methylidene dioxy group reacted equally well when submitted to the reaction conditions yielding the corresponding branched products with ca . 80 % ee in all cases. As observed with the pyridine imine ligands, 3 with the more challenging substrates bearing no substituent or an electron withdrawing group ( 1c to 1e ), the reactions were slower. However with L18f as
ligand, reactions occurred within a few days even with 1e bearing a p NO 2 group. A much lower b:l ratio of 76:24 was only obtained for this particular substrate; this being in good agreement with the previously described reactivity of such electron poor substrates. 4b Contrary to what had been previously observed using L11c as ligand for which the enantioselectivity was lower when longer reaction times were needed (80, 74 and 66 % ee for 1a, 1c and 1d respectively), 3 only the b:l ratio was significantly influenced by the electronic 18 The “non optimized” conditions were applied to allow the use of a single set of conditions for all substrates.
38 Chap. 3: Catalytic System Optimization properties of the cinnamyl fragment ( Table 3-3, entries 1, 4 and 5). No important effect on the enantioselectivity of the reaction was observed along this series. This observation indicates that the enantio and the regiodetermining steps of this reaction are probably distinct and independent.
The configuration of the olefin is also important. For instance, compound 1g, the Z isomer of 1a , reacted to form 2a as the major product. The reaction was nevertheless significantly slower (7 h vs . 2 h) and much less selective (15 vs. 80 % ee ); the same levorotatory enantiomer of 2a being however predominant in both cases. Further substrate limitations for the catalytic system at play could be uncovered as allylic substrates 1h to 1k did not react at all. The reasons for the lack of reactivity of alkyl derived substrate 1i and of cinnamyl substrates bearing a trisubstituted alkene moiety 1j to 1k remains to be clarified but the results show the crucial importance of the stereoelectronic properties of the substrates for this type of transformation to occur.
O O O O O O O O
O O O O n-Pr
1f 1h R O R O O 1i R = Me 1a R = 4-OMe 1j R = Ph 1b R = 2-OMe O 1c R = H 1d R = 4-Cl O O 1e R = 4-NO2 MeO O O 1g 1k
Entry Ester Time Conv. % ee Conf. b b:l c
1 1a 2 h > 97 % 80 (–) > 97:3 2 1b 3 h > 97 % 78 (–) > 97:3 3 1c 7 h > 97 % 77 (–) (R) 95:5 4 1d 24 h > 97 % 77 (–) 93:7 5 1e 120 h > 97 % 75 (–) 76:24 6 1f 1.5 h > 97 % 77 (–) > 97:03 7 1g 7 h > 97 % 15 (–) 95:05 8 1h 48 h < 3 % 9 1i 48 h < 3 % 10 1j 48 h < 3 % 11 1k 48 h < 3 %
a Fresh 4a (10 mol%), ligand L18f (10 mol%), THF, 60 °C, c(1) 0.5 M; the results being the average of at least two runs; b sign of optical rotation of 2 and absolute configuration when known; c ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz). Table 3-5: CpRu catalyzed rearrangement of allylic esters 1.a
39 Chap. 3: Catalytic System Optimization 3.3.4. Metal Source Optimization
However, importantly, we observed during the initial screening process that the enantioselectivity of the reaction of 1a could vary from one reaction to the next under the same conditions ( Table 3-6). After extensive investigation of reaction parameters, this 19 phenomenon could be correlated to a change of aspect of the [CpRu(MeCN)3][PF 6] salt and to the shelving time of 4a in the freezer in particular. Indeed, the color of this precatalyst, although kept under argon atmosphere at –20 °C, gradually changed from bright yellow (when fresh) to brown orange after a few weeks. Then, using older and older samples of 4a , a gradual decrease of the enantioselectivity was noticed, from 80 % ee with freshly prepared 4a to 69 % with a five weeks old sample. Interestingly, neither the b:l ratio nor the conversion after two hours was affected by the condition of 4a . Needless to say that all previously detailed experiments have then been carried out with freshly prepared precatalyst 4a (less than one week old).
O O O O
[CpRu(MeCN)3][PF6] (10 mol%) O L18f (10 mol%)
THF, 60 °C
1a 2a 3a MeO MeO MeO
Entry Ester 4a age Time Conv. % ee Conf. b b:l c
1 1a < 1 week 2 h > 97 % 80 (–) > 97 : 3 2 1a 2 weeks 2 h > 97 % 76 (–) > 97 : 3 3 1a 3 weeks 2 h > 97 % 72 (–) > 97 : 3 4 1a 5 weeks 2 h > 97 % 69 (–) > 97 : 3
a 4a (10 mol%), ligand L18f (10 mol%), 60 °C, c(1a ) 0.5 M; the results being the average of at least two runs; b sign of optical rotation of 2a ; c ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz). Table 3-6: Effect of the aging of precatalyst 4a .a
In addition, the synthesis of 4a requires several days and the final product is almost impossible to purify. In addition, out of the numerous batches of 4a synthesized during this work, two gave rise to a parasite reaction ( Scheme 3-5): 5 10 % of O allylated product was obtained.20 Unfortunately, no experimental conditions were found to neither promote, nor prevent this side reaction using these two precatalyst batches.
19 Kündig, E. P.; Monnier, F. R. Adv. Synth. Catal. 2004 , 346 , 901 904. 20 Product ratios were mesured by GC MS and ee was determined by CSP GC.
40 Chap. 3: Catalytic System Optimization
O O O
[CpRu(MeCN)3][PF6] (10 mol%) O L18f (10 mol%) O
THF, 60 °C
MeO MeO 90-95 % MeO 5-10 % 80 % ee 81 % ee Scheme 3-5: Side reaction using 4a as catalyst.
To circumvent these problems, the use of a different source of metal precursor was envisaged 6 19 – and [CpRu( η naphthalene)][PF 6] complex 4b in particular ( Table 3-5). As reported recently by Hintermann and Bolm, 21 this air stable complex can be used as a precatalyst for hydration of terminal alkynes. Initial experiments validated this choice as salt 4b was indeed able, in the presence of ligand L18f, to yield the desired product 2a with excellent regioselectivity. However, in the experiments performed under standard conditions, a quite lower ee value was obtained (71 % ee with 4b , Table 3-4, entry 2 vs . 80 % ee with 4a Table 3-3, entry 1). We reasoned that the presence of the substrate during the displacement of the η6 naphthalene by the pymox ligand was perturbing the outcome of the reaction. This problem was then overcome by treating complex 4b with the ligand prior to the addition of the substrate.
To determine the optimal induction period, reactions were performed with an initiation time of 30, 60 or 90 minutes before introducing the allylic ester. In the latter two cases, the enantioselectivity was essentially restored (79 % ee , Table 3-7, entries 3 and 4).
O O O O 4b (10 mol%) O L18f (10 mol%) THF, 60 °C
1a 2a 3a MeO MeO MeO
b c Entry Ligand Initiation Time Conv. % ee Conf. b:l PF6 PF6 1 0 min 48 h < 3 % Ru Ru 2 0 min 6 h > 97 % 71 (–) > 97:3 MeCN NCMe L18f NCMe 3 L18f 30 min 6 h > 97 % 74 (–) > 97:3 4a 4b 4 L18f 60 min 6 h > 97 % 79 (–) > 97:3 5 L18f 90 min 6 h > 97 % 79 (–) > 97:3 a 4b (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1a ) 2 M; the results being the average of at least two runs; b sign of optical rotation of 2; c ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz). Table 3-7: Initiation time effect with 4b .a
21 (a) Labonne, A.; Kribber, T.; Hintermann, L. Org. Lett. 2006 , 8, 5853 5856. (b) Kribber, T.; Labonne, A.; Hintermann, L. Synthesis 2007 , 2809 2818. (c) Labonne, A.; Zani, L.; Hintermann, L.; Bolm, C. J. Org. Chem. 2007 , 72 , 5704 5708.
41 Chap. 3: Catalytic System Optimization Whether the liberated naphthalene moiety is involved in the reaction after its displacement is debatable, however, it is almost quantitatively recovered unchanged at the end of the reaction and thus provides an internal reference for GC yield calculations. 22
To probe the influence of the metal’s counterion in the catalytic process, salts of type [CpRu( η6 naphthalene)][X] were synthesized following the procedure by Kündig ( 4c X = 19 SbF 6, 4d X = BPh 4, 4e X = BF 4). Whereas the SbF 6 salt was obtained in good yield (60 %) 23 and high purity, the BPh 4 (46 %) and the BF 4 (74 %) salts were obtained in unsatisfactory purity. When used as catalyst, all these salts proved to be potent catalysts in the standard conditions detailed above ( Table 3-8), but the enantioselectivity and the regioselectivity of the reaction were once again dependant on the purity of the metal source. Overall, PF 6 salt 4b appears as the best choice of catalyst for further studies.
O O O O [CpRu(η6-napht)][X] (2.5 mol%) O L18f (3 mol%)
THF, 60 °C 1a 2a 3a MeO MeO MeO
b c d Entry [Ru] X Time Conv. % ee Conf. b:l
1 4b PF 6 6 h > 97 % 79 (–) > 97:3
2 4c SbF 6 6 h > 97 % 79 (–) 95:5
e 3 4d BPh 4 6 h > 97 % 74 (–) 93:7
4 4e BF 4 6 h > 97 % 73 (–) 79:21
a 4 (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1a ) 2 M; the results being the average of at least two runs; b reaction time without 1 h induction time; c sign of optical rotation of 2; d ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz); e 12 h initiation time was necessary to solubilize the complex. Table 3-8: CpRu catalyzed rearrangement of allylic esters 1a with 4.a
The generality of this catalytic combination was then tested using some of the substrates described previously. The results are detailed in Table 3-9. For all tested substrates, the catalyst generated in-situ from 4b performed as selectively as the one derived from 4a . In the particular case of the less active substrates (entries 3 and 4), regio and enantioselectivities 6 were even slightly better. Importantly, complex [CpRu( η naphthalene)][PF 6] could be stored at ambient temperature under regular atmosphere in a screw cap vial for over 6 months without any noticeable erosion of reactivity or selectivity. However, due to the
22 The intensity of the signal being not sufficient for accurate measurements. 23 6 6 This complex was obtained as a 60:40 mixture of [CpRu( η naphtalene)][BPh 4] and [CpRu( η BPh 4)].
42 Chap. 3: Catalytic System Optimization
6 24 photosensitivity of [CpRu( η naphthalene)][PF 6], care must nevertheless be taken to store 4b in the dark.
O O O O 6 [CpRu(η -napht)][PF6] (2.5 mol%) O L18f (3 mol%)
THF, 60 °C 1 2 3 R R R
b c d Entry Ester R Time Conv. % ee Conf. b:l 1 1a 4 MeO 6 h > 97 % 79 (–) > 97:3 2 1c H 25 h > 97 % 77 (–) 95:5 3 1d 4 Cl 120 h > 97 % 81 (–) 93:7
4 1e 4 NO 2 400 h > 97 % 79 (–) 79:21
a 4b (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1) 2 M; the results being the average of at least two runs; b reaction time without 1 h induction time; c sign of optical rotation of 2; d ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz). Table 3-9: CpRu catalyzed rearrangement of allylic esters 1 with 4b .a
The robustness of this catalytic system was further assessed by performing the rearrangement of allylic ester 1a in non anhydrous conditions. The results of the reactions performed with various amounts of water are reported in Table 3-10 . No effect on the regioselectivity (> 97 : 3) and only a very small effect on the enantioselectivity (78 vs. 79 % ee ) of the process was noticed with 10, 300 and 2100 ppm of water in THF (entries 1 to 3, Table 9). However if the amount of water is raised to approximately 0.3 % (volume), the branched product is still the only obtained but with a slightly lower enantioselectivity (75 vs. 79 % ee ). This reaction can thus also be performed under non anhydrous conditions using standard bottled solvent (typically less than 50 ppm of water for commercially available analytical grade THF) with virtually no effect on the stereochemical outcome of the reaction.
24 For leading references on the photolability of arene ligands in CpRu( η6 arene) complexes, see (a) McNair, A. M.; Mann, K. R. Inorg. Chem. 1986 , 25 , 2519 2527. (b) Trost, B. M.; Older, C. M. Organometallics 2002 , 21 , 2544 2546.
43 Chap. 3: Catalytic System Optimization
O O O O 6 [CpRu(η -napht)][PF6] (2.5 mol%) O L18f (3 mol%)
THF, 60 °C 1 2 3 R R R
b c d e Entry Water (ppm) Time Conv. % ee Conf. b:l 1 10 8 h > 97 % 79 (–) 99:1 2 300 8 h > 97 % 78 (–) 98:2 3 2100 8 h > 97 % 78 (–) 98:2 4 11600 8 h > 97 % 75 (–) 97:3
a 4b (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1) 2 M; the results being the average of at least two runs; b measured using a Karl-Fisher apparatus; c reaction time without 1 h induction time; d sign of optical rotation of 2; e ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by 1H NMR (400 MHz). Table 3-10: CpRu catalyzed rearrangement of allylic ester 1a with 4b in non dry THF.a
3.4. Conclusion
Herein, we have reported that the conjunction of simple to make and readily available enantiopure pymox ligands (one step from commercially available sources) and a CpRu precatalyst provides an efficient catalytic system which allows Carroll rearrangements of allyl β ketoesters of type 1 with good to perfect regioselectivity and good enantiomeric excess. Even challenging substrates bearing electron withdrawing atoms or groups could react with catalyst loadings as low as 2 mol%. In addition, to avoid the phenomenon of catalyst aging detrimental to the selectivity of the reaction, an alternative catalytic combination was 6 developed combining air stable [CpRu( η naphthalene)][PF 6] 4b and indanyl pymox ligand L18f, reproducibly allowing high selectivities.
44 Chap. 4: Mechanistic Insight
4. Mechanistic Insight
There are two possible outcomes: if the result confirms the hypothesis, then you've made a discovery. If the result is contrary to the hypothesis, then you've made a discovery. Enrico Fermi (1901-1954)
4.1. Preamble
At this stage, it thus appeared important to better understand the mechanism of the reaction. As an initial working hypothesis, it was considered that the Ru catalyzed Carroll rearrangement proceeds through intermediates similar to Pd catalyzed allylic substitution reactions ( Scheme 2-2). As such, understanding the precise structure of [CpRu(LL’)( η3 allyl)] 2+ seemed crucial to comprehend the regio and stereochemical outcome of the reaction.
3 4.2. MO Analysis of [CpRuL 2(ηηη -allyl)] Complexes
The first step for this purpose is to consider, on a theoretical point of view, the [CpRu] fragment’s molecular orbitals (MOs). A simplified MO interaction diagram is given in Scheme 4-1 and explained in the subsequent paragraphs.1
e2"
Metal spn hybrid dxz
Metal 4d orbitals
e1"
d yz d z2
a2" dx2-y2 dxy
spn Ru2+: (4d4 5s2) Ru 4 n Scheme 4-1: Simplified interaction diagram between Cp and d Ru(II) fragments (only the pz based sp molecular hybrid shown and 5s electrons omitted for clarity since not interacting with the Cp molecular orbitals).
1 Rauk, A. Orbital interaction theory of organic chemistry ; 2nd ed.; Wiley Interscience: New York, 2001 .
45 Chap. 4: Mechanistic Insight
Two types of interactions are important: only the Cp π orbitals overlap efficiently with the d and sp n hybrid MOs of the metal. Considering the pseudo tetrahedral geometry of the metal complex, the sp n MO has an hybridization close to sp 3. It appears that only one strongly bonding interaction exists between the Cp frontier MOs with the sp 3 MO of the 4d4 Ru(II) fragment (only the MO arising from the overlap of the pz is shown): a stabilizing interaction n occurs upon overlap of the Cp a2” MO with the sp hybrid on the metal. Due to non equivalent symmetries between the Cp e2” MO with the d orbitals of the metal, the interactions are globally weak and non bonding. The e1” MO efficiently interacts with the degenerate dxy and dx2-y2 but much less overlap with the dxz and dyz is possible due to different
MOs symmetry. In the case of a Ru(II) complex, the dz2 globally has a non bonding interaction with the e1” MO due to their different symmetry: it is only slightly more stabilized than in the case of the dxz and dyz .
If one considers that, as for palladium, the catalytically active species is a 16 electron unsaturated metal species, it is also important to describe its structure ( Scheme 4-2). This two legged piano stool metal complex has C2v symmetry if ligands L and L’ are identical and has an empty p orbital (T shaped complex with sp 2 hybridized metal). Upon interaction with a ligand this p orbital progressively hybridizes to sp 3 (2 nd order Jahn Teller distortion) thus yielding a chiral pseudo tetrahedral three legged piano stool (L ≠ L’ ≠ L”). This is the geometry of a [CpRu(LL’)(C=C)] + olefin complex which could be a reaction intermediate for the studied reaction.
2nd order Jahn-T eller distortion M L M L' L L' M L' M ϕ ϕ L' 2θ L L L'' Scheme 4-2: Jahn-Teller distortion for 16 electron [CpMLL’] +.
The interactions between the CpRu(II) and the η3 allyl fragments are primarily based on the overlap of the π orbitals of the allyl moiety with the populated e2 and 1a 1 MOs of the metal 2 (Scheme 4-3). Repulsive interactions occur through the π1 MO which however can overlap n with the empty sp hybrid MO. On the other hand the metal dxy has the correct symmetry to efficiently overlap with the π2 MO of the allyl fragment. In addition, metal to allyl stabilizing back bonding interactions are symmetry allowed between the dz2 and d x2-y2 of the metal and the
2 Pruchnik, F. P. Organometallic chemistry of the transition elements; Plenum Press: New York, 1990 , 427 475.
46 Chap. 4: Mechanistic Insight
π3 MO of the allyl fragment. As discussed in Chapter 2 , the allyl ligand can adopt two configurations ( endo and exo ) for which the overlap with the d MOs is unequally efficient.
The dxy π2 interaction is stabilizing and an endo arrangement of the allyl ligand is favored 3 because of better orbital overlap ( Scheme 4-4). Indeed, in the d π3 back bonding interaction, both the dz2 and d x2-y2 MOs are participating ( Scheme 4-5). In the case of an endo arrangement, the overlap between dz2 and π3 is more efficient than in the exo arrangement; on the other hand, the dx2-y2 π3 interaction is stronger in the exo case than in the endo case. 4 However, since the dz2 has a higher orbital energy ( Scheme 4-3), it has a greater back 5 bonding ability than the d x2-y2 MO. The endo arrangement is also sterically favored as, in the exo arrangement, the C C C allylic moiety eclipses the two M L bonds giving significant repulsive interactions. In addition, the proximity of the central allylic substituent with the Cp “roof” also provides, in the exo arrangement, higher steric repulsion for Cp’ or Cp* ligands.
3 sp 2a1
Anti bonding MOs
e1 dyz d xz metal(d) to η3-allyl(π ) π or 3 3 back-bonding interactions
dx2-y2 dxy 1a1
metal(d) to η3-allyl(π ) π or 2 2 bonding interactions
dz2 e2
π or repulsive 1 interactions
4 d -CpRu(II) cationic η3-allyl Scheme 4-3: Interactions between d4 CpRu(II) and η3 allyl fragments.
dxy dxy
L L L L endo exo
Scheme 4-4: Bonding interactions between dxy and π2. 3 Bi, S. W.; Ariafard, A.; Jia, G. C.; Lin, Z. Y. Organometallics 2005 , 24 , 680 686. 4 3 In [CpML 2(η allyl)] structures, the dx2-y2 MO does not have any σ* antibonding character with the two L ligands residing on the nodal planes. For this is the reason dx2-y2 is lower in energy than dz2 in a four legged piano stool complex. 5 (a) Kubacek, P.; Hoffmann, R.; Havlas, Z. Organometallics 1982 , 1, 180 188. (b) Poli, R. Organometallics 1990 , 9, 1892 1900. Lin, Z. Y.; Hall, M. B. Organometallics 1993 , 12 , 19 23. (c) Ward, T. R. Organometallics 1996 , 15 , 2836 2838.
47 Chap. 4: Mechanistic Insight
dx2-y2 dz2 dx2-y2 dz2
L L L L L L L L
endo exo Scheme 4-5: Metal( d) to η3 allyl( π3) back bonding.
4 3 Overall, the endo arrangement in d [CpRuL 2(η allyl)] complexes is intrinsically both electronically and sterically more stable than its exo counterpart. For example, an energy difference of 14.3 kcal.mol 1 between endo and exo isomers was calculated for the 3 3 [CpRuCl 2(η allyl)] complex.
4.3. Regioselectivity of the Reaction in the Case of Unsymmetrically Substituted Substrates
Another field of application of the MOs theory is the rationalization of the regioselectivity of the addition of a nucleophile onto an unsymmetrcally substituted π allyl fragment. Indeed, the addition of a [CpML 2] fragment onto prochiral allylic substrates creates stereoisomeric situations which can be governed by both steric and electronic requirements; and thus can be analyzed in terms of frontier molecular orbitals.
4.7.1. Analysis in Terms of Molecular Orbitals
The dissymmetrically substituted π allyl complex is chiral and possibly exists in several isomeric forms (Scheme 2-24 ) due to steric and electronic reasons; the two allylic termini are as such non equivalent towards nucleophilic addition since the nucleophile can select one or the other terminus. The effect of the electronic asymmetry of a bidentate ligand onto such metal π allyl complexes has been widely studied in the case of several other metals. 6 However the through metal electronic effects of the ligands remain difficult to predict, even qualitatively, without extensive computational calculations. From an electronic point of view, and in first approximation, the nucleophile will attack into the π 2 MO of the allyl fragment.
The allylic π2 MO has a nodal plane on the central allylic carbon; this is why only products resulting from the attack of the nucleophile onto one of the termini of the allyl moiety are 6 (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem. Soc. 1993 , 115 , 7033 7034. (b) Lloyd Jones, G. C.; Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1995 , 34 , 462 464. (c) Burckhardt, U.; Hintermann, L.; Schnyder, A.; Togni, A. Organometallics 1995 , 14 , 5415 5425. (d) Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. Engl. 1995 , 34 , 931 933.
48 Chap. 4: Mechanistic Insight obtained. In addition the antisymmetrical nature of this MO implies an approach of the nucleophile anti to the metal. In case of a dissymmetrically substituted allylic substrate, the two lobes centred on the terminal carbons are of different size and thus orienting the nucleophilic attack mainly onto one of the two possible termini ( Scheme 4-6).
In the case of an electron rich substituent (Electron Donating Group, EDG case 3), the positive charge in the π2 MO is better cancelled α to the substituent due to stronger overlap. This results in a smaller coefficient and, as such, a smaller lobe on the most substituted C(3) carbon. The overlap with the dxy MO of the metal fragment is thus lower for C(3) than for C(1) resulting in a longer Ru C(3) bond and as such a favoured attack of the nucleophile at this position. The opposite case is to be expected with electron poor substituent (Electron
Withdrawing Group, EWG case 2). However, as the π2 MO is involved in interaction with the metal d orbitals, the effect of the metal should be taken into account for a more accurate description of the reaction. Still, the results shown in Table 3-6 are in good agreement with the previous analysis as far as aromatic substituents are considered.
1/2 1/2
(1) (2) (3) 13 1 3 EWG 1 3 EDG
Scheme 4-6: Schematic representation of electronic effects on the π2 MO of the π allyl.
Importantly, the previous analysis of the π allyl MOs is not sufficient in itself: there are several other elements to take into account to be able to rationalize the regioselectivity directing properties of the metal complex; and the early or late transition state of the nucleophilic addition in particular (Scheme 4-7). The structure of an early transition state, being more similar to the structure of the reactants, will resemble to the CpRu π allyl complex. The most electrophilic site on the allylic fragment will thus control the regioselectivity. For a late transition state, the formation of the most stable η2 olefin complex, produced after nucleophilic addition, will be the determining factor. In the case of monosubstituted allylic substrates, both the most stable final olefin complex (due to less steric hindrance) and the attack of the nucleophile at the most electrophilic (branched) site provide the same regioselectivity. Consequently, this does not allow drawing any conclusion on the early or late nature of the transition state of the nucleophilic attack.
49 Chap. 4: Mechanistic Insight
Early transition state Late transition state reactant like product like
2 L L' L L' Ru Ru Nu- Ar Ar Nu Most electrophilic Most stable η2-olefin- site metal complex Scheme 4-7: Schematic reaction profile.
4.7.2. Substituent effect: linear free-energy relations
As mentioned before, the electronic properties of the allylic fragment’s substituent should have an impact on the regioselectivity. The data collected in Table 3-9 indeed shows an evolution towards more linear product with the increasing electron withdrawing effect of the substituent (Scheme 4-8). In view of this collection of results, a more in depth analysis was done to determine a possible linear free energy relation between the electronic properties of the allylic fragment and the regioselectivity of the nucleophilic addition. The regioselectivity results ( log(( b/l)/( bH/lH)) ) were thus plotted against different Hammett coefficient σ values + 7 (σp, σp and σp in particular).
0.8 OMe sigma sigma+ 0.6 sigma - Linear (sigma+) 0.4 y = -0.8977x Me 2 0.2 R = 0.9947 )) H
/l H H 0 -1 -0.5 0Cl 0.5 1 1.5
log((b/l)/(b -0.2
-0.4
-0.6 NO 2
-0.8 Sigma Scheme 4-8: Hammett plot and ρ constant calculation for para substituents.
+ 2 Only in the case of the σp scale, a good linear correlation was obtained (, R > 0.99). Since a single slope was obtained throughout the scale of electronegativity of the para-substituents, + a single mechanism is most probably at play. In addition, by definition of the σp values, this 7 Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991 , 91 , 165 195.
50 Chap. 4: Mechanistic Insight shows that the through conjugation mesomerical effect is the predominant regiodetermining factor. Considering a linear correlation passing through the origin of the graph, a negative + Hammett constant (or sensitivity constant) is obtained by linear regression of the series of σp data, affording a ρ value of 0.9. These data thus lead to the conclusion that there is some amount of positive charge on the benzylic carbon which is stabilized (or destabilized) by resonance during the formation of the transition state that sets the regiochemistry. 8 This is coherent with the proposed mechanism involving ionization by oxidative addition yielding a cationic π allyl complex onto which is subsequently added a nucleophile. Since the results show a reduction of the electron density on the allylic fragment in the transition state of the nucleophilic addition step, it is most probably an early transition state. As such its structure resembles more to the π allyl complex, confirming the validity of the previous MO analysis.
4.4. Enantioselectivity of the reaction
As discussed for palladium in section 2.2.3, there can be several enantiodetermining events for the considered allylic substitution reaction ( Carroll rearrangement). In the case of CpRu chemistry, there is one more element to be considered: the stereogenicity of the metal atom.
4.7.1. Stereoselectivity at the Ru-centre
If one reasons that the catalytically active species is an unsaturated 16 electron Cp ruthenium complex ( Scheme 4-2), two diastereomeric forms can be obtained with an enantiopure C1 symmetrical ligand upon coordination of a third ligand. Indeed, due to the pseudo tetrahedral geometry in an 18 electron piano stool shaped complex of the Ru atom. In the presence of four different ligands, two RRu or SRu diastereomeric complexes arise. This has been thoroughly studied by Brunner 9 and Davies 10 with (among others) pymox ligands and Cp or 6 η arene ruthenium piano stool complexes respectively. With a bidentate enantiopure C1 symmetrical ligand, the two possible orientations of the ligand provide two different isomeric complexes as show in Scheme 4-9. In the first case, the proximity of the indanyl arene moiety of L18f with the Cp ring results in important steric repulsion ( Scheme 4-9 (a)). Case (b) seems like the most liable complex to form a labile olefin complex that will allow the reaction
8 Lehmann, J.; Lloyd Jones, G. C. Tetrahedron 1995 , 51 , 8863 8874. 9 Brunner, H.; Klankermayer, J.; Zabel, M. Organometallics 2002 , 21 , 5746 5756.. 10 (a) Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Organometallics 2001 , 20 , 3029 3034. (b) Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Dalton Trans. 2004 , 3629 3634..
51 Chap. 4: Mechanistic Insight to proceed further. In this case, the ligand delimits the environment in such a way that only one relative orientation of the cinnamyl fragment is possible ( Scheme 4-9 (c) ).
(a)
(b) (c) Scheme 4-9: 3D drawings of the two diastereomeric forms of the alleged catalytically active species with L18f (a) and (b) (third ligand omitted for clarity) and of the postulated most stable π allyl complex (c).
It can however not be excluded that form (a) participates in the reaction and thus accounts for a part of the imperfect enantiomeric excess ( ee < 100 %). Another more plausible explanation is that form (b) solely reacts and that a perfect orientation of the cinnamyl fragment is obtained (allylic CH 2 pointing towards the indanyl moiety, Scheme 4-9 (c) ) but that the endo / exo isomerism is imperfectly controlled (the endo and exo isomers show a different face for 11 the nucleophilic attack). To assess this issue, [Cp*Ru(MeCN)3][PF 6] was tried as metal source for the Carroll rearrangement of ester 1a in the standard conditions. The more bulky Cp* ligand is believed to promote a better control of the endo / exo isomerism by enhanced steric interactions with the central allylic substituent. However, using L18f as ligand, the reaction was very irreproducible in terms of enantioselectivity ( ee 45 75 %, (–) enantiomer still being major as with 4a ) and the reaction was much slower than with
[CpRu(MeCN)3][PF 6] ( 4a ) as metal source. This slower reaction rate is quite surprising knowing the traditionally accepted stronger oxidative addition efficiency of Cp* complexes. 12 11 Mbaye, M. D.; Demerseman, B.; Renaud, J. L.; Toupet, L.; Bruneau, C. Adv. Synth. Catal. 2004 , 346 , 835 841. 12 (a) Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Breher, F. Organometallics 2006 , 25 , 1440 1447. (b) Trost, B. M.; Older, C. M. Organometallics 2002 , 21 , 2544 2546.
52 Chap. 4: Mechanistic Insight
It appeared that this reaction is sensitive to the metal ligand stoichiometry with the Cp*Ru based catalyst. This is probably due to the fact that, contrary to the CpRu species, the Cp*Ru species are catalytically active even when the bidentate ligand is not or only partially coordinated to the metal centre.
Starting from [CpRu(COD)I] (generous gift from the Kündig group) and 1 equivalent of ligand L18f in dry CH 2Cl 2, complex [CpRu( L18f)I] ( 7a) was obtained in 75 % yield after column chromatography. The analysis of the 1H NMR (500 MHz) spectrum of 7a showed that it was composed of a 67:33 mixture of two isomeric complexes (ratio of H α and H Cp protons).
13 When starting from [CpRu(MeCN)3][PF 6], obtained by the method of Kündig, and 1 equivalent of ligand L18f in dry CD 2Cl 2, the transient complex [CpRu( L18f)(MeCN)][PF 6] (7b) was obtained as a single visible species (one set of signals for each proton). The coordination of the ligand was shown by a clear upfield shift of the 1H NMR signals of the coordinated ligand (especially for H α) compared to free L18f and by the appearance of a signal for free MeCN accounting for 2 equivalents. Complex 7b was thus obtained as a single isomer or an on the NMR time scale rapidly isomerizing mixture of stereoisomers. Upon bubbling of CO into the reaction mixture, the signal for the free MeCN accounted for 3 equivalents and all 1H signals were split into two sets. Each group of peaks, accounting for two diastereomeric species of complex [CpRu( L18f)(CO)][PF 6] ( 7c), was obtained with a 64:36 ratio. The coordination of CO to the complex being irreversible in the reaction conditions, this result could account for the kinetic ratio of the two isomers. Unfortunately the different isomers could not be separated for catalytic activity studies. As such the stereoisomeric mixtures of complexes 7a and 7c were separately tried as catalysts for the Carroll rearrangement but none of these two catalytic combinations afforded any reaction in the standard conditions (THF, 60 °C …).
Cl Cl Cl HCp HCp Ru Ru O Cl Hααα Hααα Cl O O N N N N P H N O O O O X ααα X O Cl TRISPHAT-N (TTN) Cl Cl 7a X = I, 7b X = NCMe/PF6, 7c X = CO/PF6, 7d X = TRISPHAT-N Cl Scheme 4-10: CpRu(indanyl pymox) complexes. 13 Kündig, E. P.; Monnier, F. R. Adv. Synth. Catal. 2004 , 346 , 901 904.
53 Chap. 4: Mechanistic Insight
Recently our group reported the synthesis, resolution and use of TRISPHAT N (TTN), a hexacoordinated phosphate anion able to coordinate to metal centers though the Lewis 14 basicity of the pyridine’s N atom. When [CpRu(MeCN)3][PF 6] was treated with 1 equivalent of L18f and 1 equivalent of enantiopure [ n Bu 4N][ TTN], a red orange complex 1 was obtained after column chromatography (SiO 2, CH 2Cl 2) in 76 % yield. Analysis of H and 31 P NMR spectra showed the formation of two sets of signals and hence the presence of diastereomeric [CpRu( L18f)( TTN)] complexes in a 63:37 ratio ( Scheme 4-11).
Weak NOESY
rac TTN (a) SRu (a)
Strong NOESY
TTN (+ Λ TTN minor)
(b) RRu
1 Scheme 4-11: H α signals of [CpRu( L18f )(TTN)] complexes ( H NMR, CDCl 3, 500 MHz, with integrations); (a) Weak NOESY between H Cp an H 5, (b) Strong NOESY between H Cp an H 5 (TTN anion omitted for clarity).
Some minor signals were also noticed and compound [CpRu( L18f)( rac TTN)] was synthesized to confirm the nature of these minor signals. Indeed, this latter complex consists 1 of four different diastereomers (( RRu , TTN ), (SRu , TTN ), (RRu ,Λ TTN ) and (SRu ,Λ TTN ) whose H and 31 P NMR signals overlap perfectly with the major and minor signals obtained for the TTN as starting material. Thus confirming that the minor signals account for the presence of some Λ TTN in the analyzed sample. Furthermore, the absolute configurations of all stereogenic elements of the four different diastereomers could be deduced by NOESY experiments and the cross peak between the signal of Cp protons (H Cp ) and the ones for the 14 (a) Constant, S.; Frantz, R.; Müller, J.; Bernardinelli, G.; Lacour, J. Organometallics 2007 , 26 , 2141 2143. (b) Constant, S.; Tortoioli, S.; Muller, J.; Linder, D.; Buron, F.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 8979 8982.
54 Chap. 4: Mechanistic Insight two diastereotopic protons α to the N atom of the oxazoline ( Scheme 4-11 ). Unfortunately these TRISPHAT N based CpRu complexes did not display sufficient catalytic activity in the Carroll rearrangement and were not probed further.
The diastereomeric ratios obtained for complexes 7a to 7d are surprisingly low (~ 2:1) when compared to the enantiomeric ratios of the product from the Carroll rearrangement (~ 9:1). However, these results do not contradict the proposed rational since the formation of the olefin complex is most probably reversible, thus providing a Curtin-Hammett situation: one of the two diastereomeric forms of the olefin Ru complex undergoes faster oxidative addition than the other.
4.7.2. Rationalization of the enantioselectivity
The stereochemical analysis of the outcome of the reaction is also dependent of the configurational stability of the π allyl complex. This issue was assessed by two series of experiments: one involving enantiopure secondary cinnamyl acetoacetates ( Table 4-1) as substrate, and the other cinnamyl esters that cannot decarboxylate under standard reaction conditions ( Table 4-2).
First, the rearrangement of the secondary acetoacetate 5c for which no trivial matched / mismatched effect could be observed using L3 as ligand was revisited. 15 In the case of L18f, a clear matched / mismatched situation was observed as (–,R) 2c and (+, S) 2c were obtained with ee values of 45 and 87 % starting from enantiopure (S) 5c and ( R) 5c respectively (Table 4-1). In addition, in the mismatched series, the reaction was slower and the b:l ratio was noticeably lower. When racemic 5c was submitted to the reaction conditions, a slightly enantioenriched product was obtained at 86 % conversion ( ee 15 % in favor of the (–) (R) enantiomer) which is in good accordance with the results obtained in both enantiopure series and the fact that the reaction is globally stereospecific with branched secondary allylic substrates. 16,17 Interestingly, the b:l ratio is lower in the mismatched series; the different regioselectivity show that the reaction in the matched and the mismatched series proceed through different diastereomeric transition states which are not interconverting under the standard reaction conditions.
15 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082 2085. 16 Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed. 2002 , 41 , 1059 1061. 17 Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835 2837.
55 Chap. 4: Mechanistic Insight
To account for the non complete conservation of the enantiomeric excess, Tunge suggested, in his study with Cp*Ru(bpy) catalyst, that the branched esters 5 could isomerize into their linear regioisomer 1 in the presence of the metallic complex, thus resulting in a loss of the initial stereochemical information; 17 but we were not able to verify this explanation. Globally, these results are in good accordance with the above detailed rational but do not allow drawing any definitive conclusion concerning the conformational stability of the alleged transient π allyl complex.
O O O O 4b (10 mol%) O L18f (10 mol%) + 5c 2c 3c
Entry Ester Time Conv. % ee Conf. b b:l c
1 (R) 5c 2.5 h > 97 % 87 (–) R 95: 5
2 (S) 5c 3 h 85 % 45 (+) S 90:10
3 rac 5c 3 h 86 % 23 (–) R 88:12
a 4b (10 mol%), ligand L18f (10 mol%), THF, 60 °C, c(1) 2 M; the results being the average of at least two runs; b sign of optical rotation of 2 and absolute configuration when known; c ratios of branched ( 2) to linear ( 3) products were determined 1H NMR (400 MHz). Table 4-1: CpRu catalyzed rearrangement of allylic esters 5c .a
To verify the validity of Tunge’s isomerization hypothesis, several branched or linear cinnamyl esters ( 8, rac-9 and 10 ) were synthesized from the corresponding cinnamyl alcohols and acyl chlorides and submitted to the reaction conditions. These esters were chosen because of their ability to get ionized and their inability to decarboxylate. Indeed, an isomerization process may occur in the presence of the Ru catalyst upon ionization of the cinnamic ester and recombination of the two generated fragments.
In all cases, in the absence of Ru catalyst ( Table 4-2, entries 1 to 4), no reaction was observed. Linear esters 8a (R = Me) and 8b (R = t-Bu) were not transformed in any visible way when submitted to the standard Ru catalysis conditions (Table 4-2, entries 5 and 6). However, starting from branched 9a and 9b the corresponding linear products ( 8a and 8b respectively) were selectively obtained (Table 4-2, entries 7 and 8). These results show that, upon treatment with the Ru catalyst, the linear esters can, as hypothesized by Tunge, 17 isomerize to the thermodynamically more stable linear isomers. In addition when 10a (Z/E > 99:1), the ( Z) isomer of 8a, was submitted to the reaction conditions: the Z/E ratio progressively diminishes to reach 80:20 after 19 h and 58:42 after 48 h. This shows that the isomerization of the Ru π allyl complex is possible but slow compared to the attack of the carboxy nucleophile. Comparing the kinetics of the Carroll rearrangement with this Z /E
56 Chap. 4: Mechanistic Insight isomerization reaction, it seems reasonable to suppose that the effect of the isomerization of the π allyl complex during the reaction is negligible on the stereochemical outcome of the reaction. In order to more accurately compare these latter experiments with the Carroll rearrangement, two double crossover experiments were conducted starting from approximately 1:1 mixtures of linear 8a/11b and branched 9a/12b (Scheme 4-12). In both cases, GC MS analysis of the resulting crude reaction mixture showed, after 19 hours, the formation of all possible linear products compatible with intermolecular processes. This result indicates that the rearrangement reaction clearly proceeds through a state where the in-situ generated nucleophilic and electrophilic fragments are separated in solution, resulting in a cross over.
O O
O R 4b (2 mol%) O R L18f (2.4 mol%)
8a R = Me THF, 60 °C,19 h 8b R = t-Bu 8a, 8b O O 4b (2 mol%) O R L18f (2.4 mol%) O R'
THF, 60 °C, 19 h r ac-9a R = Me 8a, 8b r ac-9b R = t-Bu O 4b (2 mol%) L18f (2.4 mol%) O O 10a THF, 60 °C O Z/E > 99:1 19 h, Z/E 80:20 48 h, Z/E 58:42
Entry Ester b [Ru] R = Time b:l c
1 8a Me 19 h < 1 : 99
2 8b - t Bu 19 h < 1 : 99
3 rac-9a Me 19 h > 99 : 1
4 rac -9b t Bu 19 h > 99 : 1
5 8a 4b Me 19 h < 1 : 99
6 8b 4b t Bu 19 h < 1 : 99
7 rac -9a 4b Me 19 h < 1 : 99
8 rac -9b 4b t Bu 19 h < 1 : 99
a 4b (2 mol%), ligand L18f (2.4 mol%), THF, 60 °C, c(8/9 ) 1 M; the results being the average of at least two runs; b regiosisomeric purity of linear 6 ( b:l < 1 : 99) and branched 7 ( b:l > 99 : 1) starting materials were determined by GC MS c ratios of branched ( 6) to linear ( 7) products were determined by GC MS. Table 4-2: CpRu catalyzed rearrangement of allylic esters 8 to 10 .a
57 Chap. 4: Mechanistic Insight
O O
O O
O O
O O 4b (2 mol%) 8a 30% 11b 41% L18f (2.4 mol%) O O 11b 8a THF, 60 °C, 19h O O
11a 14% 8b 15%
O O
O O O
O O O 4b (2 mol%) L18f (2.4 mol%) 8a 33% 11b 18%
O O 12b 9a THF, 60 °C, 19h O O
11a 17% 8b 26%
Scheme 4-12: Double crossover experiments (ratios of products determined by GC MS).
With these results (page 55 to 56) confirming the global conformational stability of the Ru π allyl complexes, it is interesting to reconsider the results obtained for the Z and E cinnamyl acetoacetate reported in Table 3-5 (entries 1 and 7, 1a and 1g respectively). The lower ee obtained for the Z isomer should then not be attributed to an isomerization of the resulting anti CpRu π allyl complex but can be explained by a lower control of the endo /exo isomerism during the formation of the π allyl complex in the case of an anti allyl moiety ( Scheme 4-13 ). Indeed the energy difference between the endo,anti and the ( exo,anti ) CpRu π allyl complexes is lower due to destabilizing steric interactions present in both cases (Cp Ph for the endo,anti and Cp CH for the exo,anti ). The fact that the same (–) (R) 2c enantiomer was predominantly obtained is both cases tends to show that the ( exo,anti ) CpRu π allyl complex is slightly more stable. This explanation is however based on the (reasonable) hypothesis that the orientation of the ligand and the allyl fragment remains the same in both cases.
From (E) substrates From (Z) substrates
Ru H Ru Ru H >>Ru <
endo,syn exo,syn endo,anti exo,anti
(R)-2c (S)-2c (S)-2c (R)-2c Scheme 4-13: Rationalization of the E / Z selectivity of the Carroll rearrangement.
58 Chap. 4: Mechanistic Insight
Finally, possible non linear effects were assessed. A series of reactions with substrate 1c were performed with different mixtures of the two enantiomers of ligand L18f . Results are summarized in Table 4-3 and show that the enantioselectivity of the reaction is directly proportional to the enantiomeric purity of the ligand L18f . This indicates that, the metallic complex involved in the enantiodetermining step is probably a monomeric species composed of one single ligand. 18
O O O O 4b (2 mol%) O L18f + ent-L18f (2.4 mol%)
THF, 60 °C, 22 h 1c 2c 3c
Entry ee of L18f b b:l c % ee b,d 80%
1 > (+) 99 % 95 : 5 (–) 76 % [(–) 76 %] 40% 2 (+) 67 % 95 : 5 (–) 47 % [(–) 50 %]
3 (–) 44 % 95 : 5 (+) 35 % [(+) 34 %] 0% 4 > (–) 99 % 95 : 5 (+) 76 % [(+) 76 %] -100% -50% 0% 50% 100% ee L18f of
a 4b (2 mol%), ligand L18f + ent L18f (2.4 mol%), THF, 60 °C, -40% c(1c ) 1 M; the results being the average of at least two runs; b c sign of αD given; ratios of branched ( 2c ) to linear ( 3c ) products were determined by GC MS; d ee measured by CSP GC, sign of -80% ee of 2c αD given and calculated ee given in brackets. Table 4-3: CpRu catalyzed rearrangement of allylic esters 1c; effect of ligand enantiopurity.a
Overall these experimental data are in line with the proposition that the CpRu catalyzed Carroll rearrangement is proceeding through a Ru π allyl complex obtained from the oxidative addition of an unsaturated Ru complex onto an allylic ketoester; this Ru π allyl complex having, in the reaction conditions, a relatively high configurational stability. However the transient allylic species could not be directly observed by spectrometric or spectroscopic methods.
4.5. Nature of the nucleophile
To further backup the “π allyl theory”, a study of the nature of the nucleophile appeared to be crucial. As initial working hypothesis, the mechanistic rational proposed by Tunge for the Cp*Ru catalyzed version of the reaction was envisaged ( Scheme 4-14 ). 17 Oxidative addition of the metal complex onto the substrate leads to the release of a ketoacetate moiety which, upon decarboxylation, generates an “ unstabilized ” enolate. This nucleophilic enolate
18 (a) Bolm, C.; Bienewald, F.; Seger, A. Angew. Chem. Int. Ed. Engl. 1996 , 35 , 1657 1659. (b) Mikami, K.; Yamanaka, M. Chem. Rev. 2003 , 103 , 3369 3400. (c) Kagan, H. B. New Front. Asymmetric Catal. 2007 , 207 219.
59 Chap. 4: Mechanistic Insight subsequently adds to the π allyl complex to regenerate the catalytically active ruthenium complex and furnishes the corresponding γ,δ unsaturated ketone.
O O O O R O R O 2+ Ar [Ru*] 1 Ar
[Ru*]+ CO2 O
R 2+ O O [Ru*] R R Ar Ar Ar 2 3 Scheme 4-14: Mechanistic rational for the Cp*Ru catalyzed Carroll rearrangement proposed by Tunge. 19,20
Since the nucleophilic species could not be observed directly either, attempts to intercept the nucleophilic intermediates were made to confirm their nature. When the reaction of 1c was conducted in the presence of 1 equivalent of dimethylmalonate, 19 no incorporation of the malonate fragment onto the allyl fragment was observed (GC MS). Rather surprisingly, this tends to show that the addition of the alleged “ unstabilized ” enolate onto the allyl fragment is much faster than the deprotonation of the acidic malonic ester. Moreover, in contrast to the observation of Tunge using a Cp*Ru based catalyst, 20 the enolate could not be trapped by a Michael acceptor (typically substituted methylenemalononitriles) in the standard reaction conditions. In view of the lack of interception of the nucleophilic species, it was then debatable whether the reaction proceeded intramolecularly rather than intermolecularly.
To solve this issue, a double crossover experiment was performed using a 1:1 mixture of 1a and 1r ( Scheme 4-15 ). Gas chromatographic and mass spectrometric analysis of the resulting crude reaction mixture showed, after 6 hours, the formation of all possible branched and linear products compatible with intermolecular processes ( 2a , 3a , 2r, 3r and cross over 9a, 10a, 9r, 10r). This result indicates that the alkylation reaction proceeds clearly through a state where in-situ generated nucleophilic and electrophilic fragments are separated in solution
19 Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603 2605. 20 Wang, C.; Tunge, J. A. Org. Lett. 2005 , 7, 2137 2139.
60 Chap. 4: Mechanistic Insight resulting in a cross over. As postulated by Tunge, bimolecular addition of a ruthenium enolate to a ruthenium allyl remains a possibility.19
O O O O
O
MeO 1a 52 % MeO MeO 4b (2 mol%) 2a 32 % 13a 23 % L18f (2.4 mol%) b:l 99 : 1 b:l 99 : 1 O O O THF, 60 °C 6 h O O
1r 48 %
13r 19 % 2r 26 % b:l 97 : 3 b:l 96 : 4 Scheme 4-15: Double cross over experiment, linear products 3 and linear cross over products 13 are omitted for clarity (products distribution and b:l ratios measured by GC MS ).
To further characterize the nucleophilic species and probe the generality of the reaction, several more elaborate cinnamyl ketoesters were synthesized ( 1l to 1q). As some of these substrates react quite slowly, 10 mol% of catalyst were used instead of 2 mol% to afford faster kinetics; their reactions are summarized in Table 4-4. Substrates 1l to 1n bearing an α substituent between the carbonyl moieties reacted with similar kinetics and enantioselectivities to unsubstituted 1c ( Table 3-5, entry 3 vs. Table 4-4, entries 1 to 3). The regiochemistry in favor of the branched adducts was however noticeably lower (down to 81:19 at most). Clearly, the bulkier is the nucleophile, the larger the amount of linear product. It shows that the regioselectivity of the reaction is not only controlled by the electronic factors of the π allyl described in the section 4.3.1. Furthermore, for these particular substrates, the presence of the α substituent leads to the introduction of a novel stereogenic centre and, as a result, four stereoisomers of compounds 2 and two enantiomeric linear adducts 3 were obtained.
For branched derivative 2l, GC analysis indicated that the diastereoselectivity linked to the presence of the new stereocentre was low (ca. 2:1).21 As a similarly low selectivity was also observed for (cyclic) 2m and 2n ( Table 4-4 entries 2 and 3); this is probably not due to a lack of control of the E / Z geometry of a possible enolate intermediate. Interestingly and
21 A similar result (dr 1.9) was observed by Tunge for substrate 1m . See reference 19.
61 Chap. 4: Mechanistic Insight somewhat in contrast with what has just been detailed, the chiral linear products 3l and 3m were obtained with decent enantioselectivities ( ee 67 % and 79 % respectively). It shows that the facial approach of the alleged enolate is better controlled when the attack onto the electrophilic fragment occurs at the unsubstituted allylic terminal position rather than α to the aromatic moiety ( Scheme 4-9 (c) ).22
O O O
O O O O O O
1l 1m 1n
O O O O O
O O O Ph O
1o 1p 1q
b c d d e f Entry Ester Time Conv. b:l dr % ee (b1, b2, l) Conf. 1 1l 9 h > 97 % 81:19 68:32 72, nd ., g 67 (–) 2 1m 9 h > 97 % 87:13 64:36 nd ., g 81, 79 (–) 3 1n 9 h > 97 % 86:14 64:36 77, 77, nd . g (–) 4 1o 9 h > 97 % 83:17 57 (–) 5 1p 9 h > 97 % 85:15 67 (–) 6 1q 5 h > 97 % 92:8 78 (–) 7 1q h 24 h > 97 % 95:5 83 (–) 8 1q i 64 h > 97 % 95:5 86 (–)
a 4b (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1) 2 M; the results being the average of at least two runs; b reaction time without 1 h induction time; c determined by 1H NMR (400 MHz); d ratios of branched ( 2) to linear ( 3) products and diastereomeric ratios among compounds 2 ( dr ) were determined at complete conversion by GC MS; e ee of first and second eluted branched stereoisomers of 2 and of linear 3 respectively; f sign of optical rotation of 2; g not determined due to absence of peak separation; h reaction was performed at 40 °C; i reaction was performed at 25 °C. Table 4-4: CpRu catalyzed rearrangement of allylic esters 1.a
In addition, when substrate 1m was reacted in the presence of 1 equivalent of ethyl 2 oxocyclopentanecarboxylate, in the standard conditions, GC MS analysis of the crude reaction mixture revealed the incorporation of ethyl 2 oxocyclopentanecarboxylate onto the cinnamyl fragment as well as a corresponding amount of cyclopentanone ( Scheme 4-16 ). This tends to show that the bulkier the nucleophile, the slower the nucleophilic addition since
22 (a) Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996 , 96 , 395 422. (b) Trost, B. M. J. Org. Chem. 2004 , 69 , 5813 5837. (c) Lu, Z.; Ma, S. M. Angew. Chem. Int. Ed. 2008 , 47 , 258 297. (d) Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007 , 2, 1476 1491.
62 Chap. 4: Mechanistic Insight the enolate could, this time, be partially intercepted by deprotonation of an activated ketoester.
O O O O O
4b(2.5 mol%) 2m 72 % 3m 18 % L18f (3 mol%) 1m THF, 60°C O O O O EtO C CO2Et EtO 2
8 % 2 % Scheme 4-16: Incorporation of activated ketoesters into rearranged 1m (ratios determined by GC MS).
Substrates 1l, 1o and 1p, designed to probe the existence of enolate intermediates and their regioisomeric stability, reacted smoothly under the reaction conditions ( Table 4-3 entries 1,4 and 5). In the particular case of 1o, as there is no α hydrogen atom in between the two carbonyl groups, the selective formation of 2o indicates that the decarboxylation of the resulting ketoacetate occurs necessarily prior to the attack onto the π allyl complex. In addition, the fact that the new C C bonds in 2l to 2p and 3l to 3p ( Scheme 4-17) result solely from the attack of the carbon previously bearing the carboxylate moiety is compatible with the formation of enolates in which the regiochemistry is preserved throughout the catalytic cycle. 17,19
O O
+ O 2o 87 % 3o 13 % 4b (2.5 mol%) O O L18f (3 mol%)
THF, 60°C O O 1o +
2p 0 % 3p 0 % Not observed Scheme 4-17: Conservation of the enolate regiochemistry for 1o (ratios determined by GC MS).
Finally the benzoyl substituted substrate 1q reacted smoothly with faster kinetics but the same selectivity than 1c in the same conditions ( Table 4-3 entries 6 to 8).23 The faster reaction for this substrate allowed the temperature to be lowered to 25 °C and 2q could be obtained with
23 For Ir catalyzed regio and enantioselective rearrangement of this type of benzoyl derived substrates see: He, H.; Zheng, X. J.; Yi, U.; Dai, L. X.; You, S. L. Org. Lett. 2007 , 9, 4339 4341.
63 Chap. 4: Mechanistic Insight
86 % ee and a b:l ratio of 95:5 within 64 h. This result confirms that better ee values can be obtained if reactions are performed at lower temperature and are in good accordance with the energy selectivity principle (calculated free Gibbs energy). Similar results on substituted cinnamyl benzoylacetates were obtained by Dr. F. Buron using the same catalytic combination and reaction conditions.
To further study the incorporation phenomenon described in Scheme 4-16 , several rearrangement reactions were run using substrates differing only from the ketoester moiety (R, R’ = H or Me) in the presence of activated 1,3 dicarbonyl compounds ( Table 4-5). Since the pK a of an unactivated ketone lies around 26 (DMSO), it should be able to deprotonate ethyl malonate (pK a = 16.4 in DMSO) or ethyl acetoacetate (pK a = 14.2 in DMSO) and as such, the incorporation of substantial amounts of the dicarbonyl fragment into the final allylic substitution product is expected. In the case of substrate 1a (R = R’ = H), no incorporation of the malonate in the product was observed (entry 1). When ethyl acetoacetate was used, 7 % of incorporation product was observed by GC MS (entry 3) but, no incorporation of the cyclohexanone carboxylate moiety could be seen (entry 2). This is surprising since the pK as of the two latter dicarbonyl products is very similar.
O O O O O O O R R2 R 1 O 4b (5 mol%) R OEt R1 OEt L18f (6 mol%) R R' R2 THF, 60 °C,4 h 1.1 equiv. 1 2/3 15/16
(2/3) : (2/3) : Entry R = R’ = R1, R 2 Conv. b Entry R = R’ = R1, R 2 Conv. b (15 /16 ) b (15 /16 ) b
O O O O 1 H H > 99 % 100:0 5 Me H OEt > 99 % 100 :0 EtO OEt O O O O 2 H H OEt > 99 % 100:0 6 Me H > 99 % 94:6 OEt O O O O 3 H H > 99 % 93:7 7 Me Me > 99 % 100:0 OEt EtO OEt O O O O 4 Me H > 99 % 100:0 8 Me Me OEt > 99 % 90:10 EtO OEt O O 9 Me Me > 99 % 40:60 OEt
a 4b (5 mol%), L18f (6 mol%), THF, 60 °C, c 1 M; b conversion, and ratio of Carroll Products ( 2/3) products and allylic substitution cross over products ( 15 /16 ) were determined by GC MS. Table 4-5: Incorporation of activated 1,3 dicarbonyl compounds into Carroll rearrangement products.a
64 Chap. 4: Mechanistic Insight
The same situation occurred in the case of 1l (R = Me, R’ = H; entries 4 to 6): only the ethyl acetoacetate fragment was slightly incorporated in the final product (6 %, entry 6). In the case of 1o (R = R’ = Me; entries 7 to 9), the decarboxylation is necessarily occurring prior to the nucleophilic addition onto the allylic fragment. As such, in this case, it is possible to conclude that the nucleophilic species is a decarboxylated fragment. Again, no incorporation of a malonate fragment was observed (entry 7), but some incorporation (10 %) of the cyclohexanone carboxylate moiety was detected by GC MS. In addition, this time, the product containing the acetoacetate moiety was majorly obtained (60 %). These results do not fit at all with the scale of pK as for the different species showing that the enolates, if formed, are definitely not unstabilized but most probably coordinated to a metal species. In addition, both the bulk of the “ enolate ” and the prenucleophile play a crucial role on the trapping reactions. This is probably due to differences in the kinetics of the nucleophilic addition and the deprotonation of the activated prenucleophiles: the bulkier the “ enolate ” the slower the nucleophilic addition and as such a bigger proportion of deprotonation.
Overall it has not been possible to directly observe any of the intermediate nucleophilic species and intercepting them has proven difficult. However, strong evidence in favour of a transient regiochemically stable enolate has been found.
4.6. Approaches to Co-Catalysis / Dual-Activation
Though the exact mechanism of the Carroll rearrangement reaction remains largely unassigned, the intermediate π allyl complex, separated from an enolate species, appears as the most reasonable working hypothesis. The new catalytic combination, involving a CpRu metal source and pymox ligands, was shown to be able to overcome most of the problems associated with the use of pyridine imine ligands. However, the question of the low reactivity still remained since electron poor subtrates require extensive reaction times (up to 17 days for 1e , Table 3-9 entry 4). One of the reasons for the lack of reactivity of the CpRu core is that, even in an olefin metal complex, it is not electron rich enough to provide efficient oxidative addition. It was thought thus that a Lewis activation of the leaving ketoacetate, making it a better leaving group, would ease this ionisation step. 1,3 Dicarbonyl moieties are very common as ligands for many metal sources and most often have a double coordination to the metal.
The first idea was to activate the ketoesters with alkali metal salts. However this strategy was not successful at first. The addition of LiPF 6 or KPF 6 (1 20 mol%) to the reaction mixtures
65 Chap. 4: Mechanistic Insight did not afford any visible effect on neither the reaction’s kinetics or selectivity. By the fact that magnesium ions have proven to be crucial in both the acetylCoA biotin carboxylation,24 the biosynthesis of fatty acids and malonyl CoA decarboxylation 25 we turned our attention to this divalent metal. From a more synthetic chemistry point of view, one can also highlight the use of magnesium methyl carbonate (MMC) as reagent for the reversible carboxylation of ketones for selective alkylations ( Scheme 4-18 ). 26 Treatment of a ketone in DMF at 110 °C with a stoichiometric amount of MMC allows the formation of the magnesium salt of the corresponding β ketoacid which could subsequently be selectively alkylated. These methods have been applied many times but have the disadvantage to require large amounts of MMC. 27 To replace the use of MMC and to more specifically overcome the high temperatures required, Rathke developed the use of a stoichiometric amount of a mixture of magnesium halide and triethyl amine under carbon dioxide atmosphere. 28
Mg i. 1 equiv. R''X O O 1 equiv. MMC O O + ii. H R'' R' R R DMF 110 °C R O R' R' Scheme 4-18: Use of MMC for ketone alkylation.
Magnesium halide salts have also been used as Lewis acids to catalyze the enantioselective amination of N acyloxazolidinones 29 or the diastereoselective anti aldol reaction of enantiopure N acyloxazolidinones 30 and N acylthiazolidinethiones ( Scheme 4-19 (a) ).31 Bisoxazoline Mg complexes have also proven efficient in asymmetric catalysis. 32 More recently, Kobayashi described the use of MgBr 2 for the activation of 2 picolinoxy group as
24 (a) Dimroth, P.; Guchhait, R. B.; Stoll, E.; Lane, M. D. P. Nat. Acad. Sci. USA 1970 , 67 , 1353 1360. (b) Attwood, P. V.; Graneri, B. D. L. A. Biochem. Soc. Trans. 1991 , 19 , S231 S231.. 25 Scorpio, R. M.; Masoro, E. J. Biochem. J. 1970 , 118 , 391 399.. 26 Stiles, M. J. Am. Chem. Soc. 1959 , 81 , 2598 2599.. 27 (a) Danishefsky, S.; Bryson, T. A.; Puthenpurayil, J. J. Org. Chem. 1975 , 40 , 1846 1848. (b) Parker, R. A.; Kariya, T.; Grisar, J. M.; Petrow, V. J. Med. Chem. 1977 , 20 , 781 791. (c) Hand, E. S.; Johnson, S. C.; Baker, D. C. J. Org. Chem. 1997 , 62 , 1348 1355. 28 (a) Tirpak, R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985 , 50 , 4877 4879. (b) Rathke, M. W.; Nowak, M. A. Synthetic Commun. 1985 , 15 , 1039 1049. (c) Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985 , 50 , 2622 2624. 29 Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997 , 119 , 6452 6453. 30 Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002 , 124 , 392 393. 31 Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002 , 4, 1127 1130. 32 (a) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992 , 33 , 6807 6810. (b) Desimoni, G.; Faita, G.; Righetti, P. P. Tetrahedron Lett. 1996 , 37 , 3027 30. (c) Carbone, P.; Desimoni, G.; Faita, G.; Filippone, S.; Righetti, P. Tetrahedron 1998 , 54 , 6099 6110 and references therein. (d) Takacs, J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R. Tetrahedron: Asymmetry 1997 , 8, 3079 3087. (e) Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem. Commun. 1997 , 1411 1412.
66 Chap. 4: Mechanistic Insight leaving group in the context of Cu catalyzed allylic substitutions ( Scheme 4-19 (b) ).33 With all these precedents, it was to try the effect of Mg salts in our reaction.
[Mg] [Mg] X O OH X O OH N O O X R''CHO "ArCu" Ar N R'' or N R'' O N X X X R R R R R' R R' R' R' X = O X = S (a) (b) R'
Scheme 4-19: Some examples of the use of MgX 2 salts in catalysis.
To assess the feasibility of this co catalysis approach ( Table 4-6), cinnamyl ester 1a was chosen because of its high reactivity and selectivity under the previously described conditions. When MgBr 2•Et 2O (1 mol%) was added to the in-situ prepared catalyst solution, the reaction mixture immediately turned from dark orange to deep purple whether the substrate had already been added or not (entry 1). In both cases, no catalytic activity was observed at room temperature or at 60 °C. It seems that the bromide anions had been trapped by the ruthenium core yielding, as for the iodo complex 7a , a non catalytically active species.
Mg(ClO 4)2, on the other hand, afforded a complete disappearance of the starting material after 24 h (TLC monitoring) but no product was obtained after filtration on silica (entry 2).
O O 4b (2 mol%) O O L18f (2.4 mol%) O MX2 (1 mol%)
THF, R.T. 1a 2a 3a MeO MeO MeO
b c d e Entry MX 2 Time Conv. b:l % ee Conf.
1 MgBr 2•Et 2O 48 h < 3 %
f 2 Mg(ClO 4)2 48 h > 97 % - -
3 Mg(OTf) 2 24 h > 97 % 97:3 84 % (–)
4 Cu(OTf) 2 54 h 95 % 89:11 84 % (–)
5 Zn(OTf) 2 54 h 80 % 94:6 80 % (–) 6 TfOH g 48 h < 3 %
a 4b (2 mol%), ligand L18f (2.4 mol%), THF, 24 °C, c(1a ) 1 M; the results being the average of at least b c 1 two runs; reaction time without 1 h induction time after which is added the MX 2; determined by H NMR (400 MHz); d ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by GC MS; e sign of optical rotation of 2; f no product 2 or 3 obtained; g 2 mol% were used. Table 4-6: CpRu catalyzed rearrangement of allylic ester 1a , co catalyst effect. a
Mg(OTf) 2 afforded a clean reaction at room temperature (entry 3). The rearranged product was obtained with a slightly higher enantiomeric excess ( ee 84 % vs. 79 %) but a lower 33 Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi, Y. Org. Lett. 2008 , 10 , 1719 1722.
67 Chap. 4: Mechanistic Insight regioselectivity ( b:l 97:3 vs. 99:1, GC MS). This result confirmed the viability of such a co catalysis approach. Cu(OTf) 2 and Zn(OTf) 2 (entries 4 and 5) were then tested to study the influence of the co catalytic metal salt. In both cases, the reactions were noticeably slower (incomplete conversion after 54 h) and the regio and/ or enantioselectivity was lower than for
Mg(OTf) 2 which appeared as a good candidate for further screening. Importantly, no reaction was obtained with 2 mol% of triflic acid (entry 5), showing that a Brønsted acid contamination is not playing a role in the catalysis (conjugated acid of the triflate anion).
The next necessary step was to determine the optimal 4b / L18f / Mg(OTf) 2 stoichiometry; the results of this screening are reported in Table 4-7. Clearly all three compounds are indispensable to obtain the desired reaction (entries 1 and 2). It also appeared that the amount of Mg(OTf) 2 had an influence both on the regio and the enantioselectivity of the reaction (entries 3 to 5): enhancing the co catalyst loading had a negative influence on both parameters. However, with the right amount of Mg salt, the reaction proceeds more enantioselectively and under milder conditions.
O O O O 1) 4b (x mol%) O L18f (y mol%)
2) Mg(OTf)2 (z mol%) THF, 25 °C 1a 2a 3a MeO MeO MeO
b c d e Entry 4b L18f Mg(OTf) 2 Time Conv. b:l % ee Conf. 1 2.4 mol% 1 mol% 48 h < 3 % 2 1 mol% 48 h < 3 % 3 2 mol% 2.4 mol% 1 mol% 24 h > 97 % 97:3 84 % (–) 4 2 mol% 2.4 mol% 2 mol% 24 h > 97 % 94:6 83 % (–) 5 2 mol% 2.4 mol% 3 mol% 24 h > 97 % 90:10 78 % (–)
a 4b (x mol%), ligand L18f (y mol%), Mg(OTf) 2 (z mol%), THF, 24 °C, c(1a ) 1 M; the results being the average of at least two runs; b reaction time without 1 h induction time after which is added the c 1 d Mg(OTf) 2; determined by H NMR (400 MHz); ratios of branched ( 2) to linear ( 3) products were determined at by GC MS; e f sign of optical rotation of 2. Table 4-7: CpRu catalyzed rearrangement of allylic ester 1a , effect of co catalyst loading. a
To further test the efficiency of this co catalysis, a more challenging substrate was chosen: namely rac cinnamyl 2 oxocyclohexanecarboxylate 1n . Ester 1n , for which the diastereoselectivity is also an issue, was chosen as model substrate because of the lower regio and enantioselectivities obtained for it under classical conditions (Table 4-8).
For the purpose of the screening, the 4b / Mg(OTf) 2 ratio was fixed at 2:1. Performing the reaction in the standard conditions ( 4b / L18f / Mg(OTf) 2 ratio 2:2.4:2) at 60 °C and 24 °C (entries 1 and 5 respectively) showed that the temperature played a role on all three monitored parameters ( b:l , dr. and ee , GC MS/CSP GC). Lowering the temperature appeared to have a
68 Chap. 4: Mechanistic Insight beneficial effect on the enantioselectivity (from 77 to 87 % ee ), but the branched to linear ratio was only slightly influenced (from b:l 79:21 to 81:19) and more surprisingly a negative effect on the diastereomeric ratio (from dr. 64:36 to 58:42) was noticed. Overall these results are worse in terms of regioselectivity and diastereomeric ratio compared to the reaction of 1n without co catalyst at 60 °C ( Table 4-4 entry 3). Reasoning that these two factors were more depending on the nature of the nucleophile, additional amount of ligand L18f were added to lower the Lewis acidity of the magnesium cation. The 4b / L18f / Mg(OTf) 2 ratio was gradually changed from 2:2.4:2 to 2:5.4:2. At 60 °C, no effect was seen on the dr. or the ee but the b:l ratio could be increased to almost the same level of the reaction without co catalyst (entries 1 to 4). Performing the same screening at 24 °C was more efficient since, though no effect on the ee was visible, both the dr and the b:l ratio could be increased to 90:10 and 62:38 respectively ( vs. 86:14 and 64:36 for the non co catalyzed process, Table 4-4 entry 3).
O O 1) 4b (2 mol%) O L18f (2.4 mol%) O O
2) Mg(OTf)2 (1 mol%) L18f (x mol%) 1n 2n 3n
b c d d e f Entry L18f Temp Time Conv. b:l dr % ee (b1, b2, l) Conf. 1 60 °C 14 h > 97 % 79:21 64:36 77, 77, nd . g (–) 2 1 mol% 60 °C 14 h > 97 % 85:15 64:36 76, 77, nd . g (–) 3 2 mol% 60 °C 14 h > 97 % 87:13 64:36 77, 78, nd . g (–) 4 3 mol% 60 °C 14 h > 97 % 87:13 64:36 77, 77, nd . g (–) 5 24 °C 24 h > 97 % 81:19 58:42 87, 87, nd . g (–) 6 1 mol% 24 °C 24 h > 97 % 85:15 59:41 86, 86, nd . g (–) 7 2 mol% 24 °C 24 h > 97 % 91:9 61:39 87, 88, nd . g (–) 8 3 mol% 24 °C 24 h > 97 % 90:10 62:38 86, 87, nd . g (–)
a 4b (2 mol%), ligand L18f (2.4 + x mol%), Mg(OTf) 2 (1 mol%), THF, c(1n ) 1 M; the results being the average b c of at least two runs; reaction time without 1 h induction time after which is added the Mg(OTf) 2; determined by 1H NMR (400 MHz); d ratios of branched ( 2n ) to linear ( 3n ) products and diastereomeric ratios among compounds 2n ( dr ) were determined at complete conversion by GC MS; e ee of first and second eluted branched stereoisomers of 2 and of linear 3 respectively; f sign of optical rotation of 2n ; g not determined due to absence of peak separation. Table 4-8: CpRu catalyzed rearrangement of allylic esters 1n , co catalyst loading effect. a
The magnesium complex has an influence on the nucleophilic species and thus on the stereochemical outcome of the reaction. In an attempt to determine the modus operandi of the magnesium cation in the activation of the reaction, stoichiometric amount of allylic ester 1a and Mg(OTf) 2 were mixed together and analyzed by IR spectroscopy. Contrary to what was expected, no visible difference with a sample of 1a in the wave numbers, corresponding to the two C=O double bonds vibrations (ketone 1714 cm 1 and ester 1738 cm 1), were obtained. This could mean that the magnesium does not activate the substrate from the beginning but
69 Chap. 4: Mechanistic Insight only plays a role in a later step in the mechanism: by transmetallation of a ruthenium enolate for example. To confirm this hypothesis, subtrates that did not afford any reaction without co catalyst were submitted to the new co catalytic conditions ( Table 4-9).
Interestingly, the use of Mg(OTf) 2 as co catalyst allowed the rearrangement of some of the substrates that did not afford any reaction otherwise (see Table 3-3). For instance 1i or 1s yielded, at 60 °C, the corresponding branched product 2 with some control of the regioselectivity (entries 1 and 4). However aliphatic 1r provided a reaction where the linear product was the major (entry 3) and substrates 1j and 1t (entries 2 and 4 respectively) still did not undergo any reaction at all. In view of these disappointing results in terms of regioselectivity, the enantiomeric excess of the branched products was not measured.
O O O O O O
O O O 1i Ph 1j 1r
O O O O O O
1t 1s S O2
Entry Ester Time b Conv. c b:l d
1 1i 24 h > 97 % 70:30 2 1j 24 h < 3 % 3 1r 24 h 40 % 9:91 4 1s 24 h > 97 % 71:29 5 1t 24 h < 3 %
a b 4b (10 mol%), ligand L18f (13 mol%), Mg(OTf) 2 (5 mol%), THF, c(1) 1 M; reaction time c 1 without 1 h induction time after which is added the Mg(OTf) 2; determined by H NMR (400 MHz); d ratios of branched ( 2) to linear ( 3) products were determined by GC MS. Table 4-9: CpRu catalyzed rearrangement of challenging allylic esters 1.a
To assess the importance of the ketoester moiety, cinnamyl isopropenyl carbonate was synthesized from the corresponding alcohol and the commercially available chloroformate (Scheme 4-21 ). No reaction was obtained in the standard co catalysis reaction conditions and only an extremely slow reaction was obtained in the standard non co catalyzed conditions (< 15 % conv. after 24 h); once again showing the importance of the ketoester moiety.
O
co-catalysis conditions OH O O O No reaction 1.1 equiv. Pyr. Cl O DCM, 0 °C to R.T. standard conditions Slow reaction 95 % Scheme 4-20: Synthesis of constitutional isomer of 1a and rearrangement reactions.
70 Chap. 4: Mechanistic Insight
Overall, the use of Mg(OTf) 2 as co catalyst allows to use a wider scope of substrates but this catalytic combination still suffers from restrictions in the stereoelectronic properties of the possible allylic ketoesters. On the other hand, these results tend to show that the magnesium cation plays a role in the activation of one of the intermediates prior to the decarboxylation. The magnesium could also play a role in the decarboxylation step; however it is most unlikely that the substitution pattern of the allylic fragment plays such a crucial role on the decarboxylation of the separated ketoacetate. The action of the Mg salt remains unclear, but the most likely hypothesis is that the Mg cation activates the ketoacetate leaving group in a similar manner to what was described by Kobayashi (Scheme 4-19 (b) ). 33
4.7. Mechanistic Rational
4.7.1. Kinetic Isotope Effects
In order to analyze possible secondary α isotope effects for the Carroll rearrangement, several isotopologues of 1a were synthesized ( Scheme 4-21). The deuterated ketoester 1u was obtained by the reduction of the corresponding cinnamyl methyl ester using in situ generated AlD 3 followed by standard esterification. The two protons between the ketone and the ester moieties of 1a are prone to proton deuterium exchange: treating 1a in a 1:1 miture of
D2O and acetone d6 in the presence of a catalytic amount of DCl afforded quantitatively the bis deuterated product 1v . The deuterated ketoester 1w was obtained by the regioselective reduction of the corresponding propargylic alcohol by LiAlH 4 and subsequent quench with
D2O followed by standard esterification.
O O O 1 equiv. LiAlD4 OH 0.95 equiv. 6b 3 equiv. AlCl3 cat DMAP O OMe D D Et2O, 0 °C Tol. 100°C D 87 % 80 % D MeO MeO 1u D/H > 97 % O O O O
O cat DCl O D D D2O/Acetone-d6 (1:1) 98 % 1v MeO 1a MeO D/H > 97 % O O OH 1) 1.2 equiv. LiAlH4 0.95 equiv. 6b THF,0 °C to R.T.,24 h D OD cat DMAP D O
2) 50 equiv. D2O Tol. 100°C 85% 82 % 1w MeO MeO MeO D/H > 97 % Scheme 4-21: Synthesis of isotopologues of 1a ( 1u , 1v and 1w ).
71 Chap. 4: Mechanistic Insight
Secondary α isotope effects occur when the atom bearing the associated isotope undergoes a change of hybridization during the rate determining step. 34 Secondary isotope effects arise from the difference of frequency of bending vibrations ( Scheme 4-22). For normal isotope effect, the transition state is developing a sp 2 character at the sp 3 carbon where the isotopic substitution is located; the difference in energy is thus lower at the transition state than for the reactants. The reaction is then slower for the substrate bearing a deuterium on the carbon undergoing a change in hybridization (kH/k D > 1, A). The opposite case is observed for inverse isotope effect where the carbon bearing a deuterium rehybridizes from sp 2 to sp 3 in the transition state (kH/k D < 1, B). Substrates 1u to 1w were chosen for this study since they are respectively bearing deuterium substitution at all three carbons that are liable to change hybridization during the reaction. As such, comparing the conversions of the reactions of the different isotopologues should allow to identify the rate determining step.
Scheme 4-22: Diagrams showing normal ( A) and inverse ( B) secondary kinetic isotope effects.34
The deuterium labeled compounds were thus submitted to the reaction conditions and were quenched by the addition of an excess of lithium bromide (formation of a catalytically inactive [CpRu(L18f )Br] species of deep purple color) and subsequent precipitation of the metal salts with pentane. The crude reaction mixture was subsequently filtered though a plug of silica (elution with ether) and the conversion was measured by 1H NMR (400 MHz).
34 Anslyn, E. V.; Dougherty, D. A. Modern physical organic chemistry ; University Science: Sausalito, CA, 2004 .
72 Chap. 4: Mechanistic Insight
Results are reported in Table 4-10 . Since the methodology used here is obviously imprecise, only gross tendencies can be provided for a qualitative analysis. A more suitable and precise method should be found for quantitative analysis of the isotope effects.
Overall these results show that the reactions are globally much faster than what had been deduced from TLC monitoring of the conversion: almost a full conversion is reached within an hour (only traces of starting material can be seen by 1H NMR after 1 h). Only in the case of isotopologue 1u , the kinetics are clearly different to the others. The fact that the reaction of deuterium labeled 1u is slower than 1a tends to show a normal isotope effect which implies a building up of a sp 2 character at the terminal allylic carbon. This observation is consistent with the oxidative addition being the rate limiting step and corroborates the mechanistic hypothesis formulated in the context of the co catalysis approach.
O O O O O O O O
O O O D O D D D D MeO 1a MeO 1u MeO 1v MeO 1w
Entry Ester Time b Conv. c b:l d ee Entry Ester Time b Conv. c b:l d ee
1 1a 10 min 80 % 99:1 79 % 9 1a 30 min 97 % 99:1 79 % 2 1u 10 min 75 % 99:1 79 % 10 1u 30 min 93 % 99:1 79 % 3 1v 10 min 79 % e 97:3 79 % 11 1v 30 min 97 % e 98:2 78 % 4 1w 10 min 81 % 99:1 78 % 12 1w 30 min 98 % 99:1 79 % 5 1a 20 min 92 % 98:2 80 % 13 1a 60 min > 97 % 99:1 80 % 6 1u 20 min 87 % 99:1 79 % 14 1u 60 min > 97 % 99:1 79 % 7 1v 20 min 92 % e 98:2 79 % 15 1v 60 min > 97 % e 98:2 78 % 8 1w 20 min 93 % 99:1 79 % 16 1w 60 min > 97 % 99:1 79 %
a 4b (5 mol%), ligand L18f (6 mol%), THF, c(1) 1 M; b reaction time without 1 h induction time after which is added ketoesters 1; c determined by 1H NMR (400 MHz); d ratios of branched ( 2) to linear ( 3) products were determined at complete conversion by GC MS. e some scrambling (~5 10 %) of the deuterium atoms could be 1 seen by H NMR in CDCl 3 of the final product. Table 4-10: CpRu catalyzed rearrangement of isotopologues of 1a.a
4.7.2. Effect of CO 2
It was also attempted to analyze the effect of CO 2 onto the kinetics of the reaction by performing reactions that would lead to different molar pressures of CO 2. Vials of the same volume were used with different amounts of a bulk solution of catalyst and substrate to allow the different build up of the increasing internal CO 2 pressure. However, using the previously described methodology, only very low differences in conversion were measured (< 2 %). As such it is not suitable to use these results in a rationalization of the mechanism of the reaction. Once again a more accurate method to follow the reaction should be developed. Qualitatively,
73 Chap. 4: Mechanistic Insight when adding a lump of dry ice in the vial along with the reaction mixture, the reaction proceeded clearly faster but a slight negative effect on the enantioselectivity was observed ( ee 75 % vs. 79 % Table 3-9, entry 1). This negative effect on the selectivity is most probably due to the addition of water along with the dry ice piece ( Table 3-10 ). On the other hand, absorbing the released CO 2 with a calcium hydroxide “cartridge” appeared to have a negative effect on the kinetics of the reaction. This order is surprising from an entropic point of view, but a more precise measurement of the effect of CO 2 might lead to the development of a more efficient process and should consequently be further and more accurately assessed.
4.8. Conclusion
Experimental evidence which sheds some light on the mechanism of the reaction have been gathered in this chapter. In addition it has been possible to develop a new methodology involving a magnesium co catalyst that allows performing the reactions at room temperature resulting in a slightly enhanced enantioselectivity. Some of the mechanistic elements described in this chapter still remain imprecise; however a reasonable mechanistic rational taking all the disclosed elements into account can still be proposed ( Scheme 4-23).
Since the CpRu catalyzed Carroll rearrangements are not regiospecific, the reactions most probably proceed though a π allyl ruthenium intermediate formed upon oxidative addition of the Ru catalyst onto the substrate. Deuterium labeling experiments tend to show that the oxidative addition is the rate limiting step. It was show that the intermediate Ru complexes are slowly isomerizing in the reaction conditions; as such the stereogenic information set at the oxidative addition stage is conserved throughout the catalytic cycle. The ketoacetate generated by the formation of the π allyl complex subsequently undergoes decarboxylation to yield an unstabilized enolate. Double crossover experiments showed that nucleophilic and electrophilic fragments are freely diffusing in solution under the reaction conditions. Since it was difficult to trap the enolate species this latter step is most probably very fast. The generated enolate consequently adds onto the allyl fragment to yield the desired product.
The use of a Mg cocatalyst allowed to perform the reactions at lower temperatures and thus obtain better regio and enantioselectivities. It appeared that the Mg cation was playing a role both in the enantio and the regiodetermining steps since both of these selectivities were perturbed by the use of the co catalyst.
74 Chap. 4: Mechanistic Insight
Scheme 4-23: Proposed catalytic cycle and effect of magnesium co catalyst on reaction.
75 Chap. 5: Applications to “Classical”Allylic Substitution
5. Applications to “Classical ” Allylic Substitution
No amount of experimentation can ever prove me right; a single experiment can prove me wrong. Albert Einstein (1879-1955)
5.1. Preamble
The most common C nucleophiles used in Ru catalyzed allylic substitutions are deprotonated 1,3 dicarbonyl derivatives. 1 When starting from allylic carbonates as substrates, the in-situ generation of alkoxides allow the deprotonation of the activated prenucleophiles, generating the corresponding reactive species. This “base free” possibility was shown by Bruneau in the context of Ru catalyzed regioselective allylic substitution,2 but remains, to the best of our knowledge, the only report using a Ru based catalyst. It thus appeared interesting to apply the previously described protocol to such intermolecular processes.
O EtO- NuH Nu [Ru] [Ru] b EtO O Ph Nu Ph Ph l CO2 EtOH Ph π-allyl intermediate Scheme 5-1: Base free regioselective Cp Ru catalyzed allylic substitution reactions. 2
5.2. Activated C-nucleophiles
5.2.1. 1,3-Dicarbonyl Prenucleophiles
Cinnamyl carbonates 14a to 14d (R = Me, Et, i Pr and t-Bu), synthesized from the corresponding commercially available chloroformates, were treated with 1.1 equivalent of a ketoacetate ester in the presence of the in situ generated Ru catalyst (from 4b and bipyridine). Results are reported in Table 5-1. The reaction proceeds with good to very low conversions only. At first sight, the kinetics of the reaction is clearly influenced by the bulk of the alkyloxy part of substrate 14 . The bulkier is the alkoxide, the slower the reaction. In addition, the same remark is valid, but to a lesser extent, for the bulk of the alkoxy moiety of the 1,3
1 See Chapter 2.4 and references cited therein. 2 Mbaye, M. D.; Demerseman, B.; Renaud, J. L.; Toupet, L.; Bruneau, C. Angew. Chem. Int. Ed. 2003 , 42 , 5066 5068.
76 Chap. 5: Applications to “Classical”Allylic Substitution ketoester. Interestingly, no product corresponding to the attack of the alkoxide directly onto the π allyl moiety could be detected in any of the reactions. Clearly in this case, and contrary to the case of the Carroll rearrangement case, the deprotonation by the alkoxide of the activated prenucleophile is faster than its addition onto the π allyl fragment. In all cases, the branched to linear ratio remained high (from 9:1 to 20:1, entry 9 and 1 respectively). As for the Carroll rearrangement, a bulkier nucleophile resulted in a less regioselective process and the diastereoselectivity for branched product 15 was low (from 47:53 to 55:45, entries 1 and 7 respectively).
O O O O O O OR 4b (2.5 mol%) O O bpy (3 mol%) OR OR
14a R = Me OR' THF,60 °C, 24 h 14b R = Et 1.1 equiv. 14c R = i-Pr 14d R = t-Bu R' = Me, Et, i-Pr, t-Bu 15 16
Entry 15 R = R’ = Conv. b b:l b dr. b
1 a Me Me 93 % 95:5 47:53
2 b Me Et 95 % 93:7 50:50
3 c Me i Pr 87 % 92:8 52:48
4 d Me t Bu 82 % 90:10 53:43 c
5 a Et Me 81 % 92:8 48:52
6 b Et Et 79 % 91:9 50:50 7 c Et i Pr 72 % 90:10 55:45
8 a i Pr Me 21 % 90:10 48:52
9 a t Bu Me 19 % 89:11 47:53
10 c t Bu i Pr 10 % 90:10 54:46
11 d t Bu t Bu 8 % nc. nc.
a 4b (2.5 mol%), bpy (3 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS; c with 15 % of Me transesterified product. Table 5-1: Base free regioselective Cp Ru catalyzed allylation of acetoacetate derivatives.a
To verify the influence of the geometry of the enolate on the diastereoselectivity, secondary ketoesters were used with the most active substrate 14a (Table 5-2). Once again, the same trends in terms of regio and diastereoselectivity were observed; thus ruling out the possibility of lack of control of the E / Z geometry of the in situ generated nucleophile.
77 Chap. 5: Applications to “Classical”Allylic Substitution
O O O O O O O O O 4b (2.5 mol%) OEt bpy (3 mol%) RO RO n n 14a n THF, 60 °C, 24 h 1.1 equiv. 15 16
Entry 15 n Conv. b b:l b dr. b
O O 1 e > 99 % 82:18 51:49 OEt
O O 2 f > 99 % 87:13 nd . c OEt O O
3 g OEt > 99 % 82:18 52:48
a 4b (2.5 mol%), bpy (3 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’) to linear ( 16) products and dr. of branched (15 and 15’) products were determined by GC MS; c not determined due to absence of peak separation. Table 5-2: Base free regioselective Cp Ru catalyzed allylation of acetoacetate derivatives; enolate geometry.a
The generality of the procedure was then assessed with different activated prenucleophiles; results are reported in Table 5-3. For more elaborate ketoesters (entries 1 and 2), the results are in line with what had been obtained for ethyl acetoacetate both in term of regio and diastereoselectivity. For malonate diester derivatives (entries 3 to 5), results were similar and the same trend for the bulk dependency of the regioselectivity and the kinetics was observed. However, in all three cases GC MS analysis of the crude reaction mixture revealed small amounts (< 2 %) of bis allylated products 17 . Ethyl cyanoacetate afforded a very regioselective reaction (97:3 entry 6) but almost 60 % of bis allylated products were obtained. On the other hand, Ethyl nitroacetate reacted slowly (entry 7) but with a good regioselectivity. No bis allylated products 17 could be seen by GC MS but, once again, the diastereoselectivity was very low.
Even though the regioselectivity could be nicely controlled using the same protocol than for the Carroll rearrangement, the same problems observed in terms of reactivity and diastereomeric ratio remained. It was thus envisaged to apply a co catalysis strategy in order to try to overcome these problems.
78 Chap. 5: Applications to “Classical”Allylic Substitution
O OR' O O Ph O O 4b (2.5 mol%) R R O O bpy (3 mol%) OR' OR' R R Ph 14a OR' THF, 60 °C, 24 h + different 1.1 equiv. regioisomers 15 16 17
Entry 15 R = R’ = Conv. b b:l b dr. b 17 b
1 h F3CCO Et > 99 % 91:9 56:44 < 1 % 2 i PhCO Et > 99 % 94:6 52:48 < 1 %
3 j MeOCO Me > 99 % 91:9 1 %
4 k EtOCO Et > 99 % 92:8 1 % 5 l t BuOCO t Bu 86 % 80:20 2 %
6 m NC Et > 99 % 97:3 nd. 57 % c
7 n O2N Et 46 % 97:3 55:45 < 1 %
a 4b (2.5 mol%), bpy (3 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’) to linear ( 16) products, dr. of branched (15 and 15’) products and ratio of 17 were determined by GC MS; c three diasteroisomers of 17 were obtained in a ratio of 72 %, 14 %, 14% (GC MS). Table 5-3: Base free regioselective Cp Ru catalyzed allylation of activated ester derivatives.a
5.2.2. Application of Co-Catalysis
As a first try, addition of Mg(OTf) 2, which had been successful in the context of the Carroll rearrangement, was tried in allylation reactions of ketoacetates ( Table 5-4). The addition of the magnesium salt (4 mol%) proved to be very beneficial on the reaction kinetics, but the regioselectivity was clearly lower than without Mg salt. In addition, no effect on the diastereoselectivity was obtained but the trend in the bulk dependency of the regioselectivity (R ↑, dr. ↓) was preserved.
O 1) 4b (2 mol%) O O O O O O bpy (2.4 mol%) O O 2) Mg(OTf)2 (4 mol%) OR OR
14a OR THF, 60 °C, 12 h 1.1 equiv. R' = Me, Et, i-Pr, t-Bu 15 16
Entry 15 R = Conv. b b:l b dr. b
1 a Me > 99 % 67:33 48:52
2 b Et > 99 % 66:34 50:50
3 c i Pr > 99 % 63:48 52:48
4 d t Bu > 99 % 56:44 55:45
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-4: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; magnesium co catalyst.a
The effect of the co catalyst loading was further assessed by running the reactions with various amounts of Mg Salt and results are summarized in Table 5-5. Overall the effect of the
79 Chap. 5: Applications to “Classical”Allylic Substitution amount of Mg salt used was only very subtle on the regioselectivity and completely inexistent in terms of diastereoselectivity.
O 1) 4b (2 mol%) O O O O O O bpy (2.4 mol%) O O 2) Mg(OTf)2 (x mol%) OR OR
14a OR THF, 60 °C, 12 h 1.1 equiv. R = Me, Et 15 16
b b b Entry 15 R = Mg(OTf) 2 Conv. b:l dr.
1 a Me 1 mol% > 99 % 67:33 48:52
2 a Me 2 mol% > 99 % 68:32 48:52
3 a Me 4 mol% > 99 % 68:32 48:52
4 b Et 1 mol% > 99 % 70:30 50:50
5 b Et 2 mol% > 99 % 68:32 50:50
6 b Et 4 mol% > 99 % 66:34 50:50
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-5: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; magnesium co catalyst loading.a
As in the case of the Carroll rearrangement, additional amounts of ligand were introduced but no effect on the outcome of the reaction was seen in this case ( Table 5-6).
O O O O O 1) 4b (2 mol%) O O bpy (2.4 mol%) O O OR OR 2) Mg(OTf)2 (1 mol%) bpy (y mol%) 14a OR 1.1 equiv. THF,60 °C, 14 h R = Me, Et 15 16
Entry 15 R = bpy Conv. b b:l b dr. b
1 a Me 1 mol% > 99 % 72:28 48:52
2 a Me 2 mol% > 99 % 70:30 48:52
3 a Me 3 mol% > 99 % 71:29 48:52
4 b Et 1 mol% > 99 % 72:38 50:50
5 b Et 2 mol% > 99 % 73:27 50:50
6 b Et 3 mol% > 99 % 73:27 50:50
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-6: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; bpy loading.a
Finally, no temperature effect on the selectivities was noticed as shown in Table 5-7.
80 Chap. 5: Applications to “Classical”Allylic Substitution
O O O O O 1) 4b (2 mol%) O O bpy (2.4 mol%) O O OR OR 2) Mg(OTf)2 (1 mol%) bpy (y mol%) 14a OR 1.1 equiv. THF, 14 h R = Me, Et 15 16
Entry 15 R = bpy T = Conv. b b:l b dr. b
1 a Me 1 mol% 20 °C 7 % n.d. n.d.
2 a Me 2 mol% 20 °C 5 % n.d. n.d.
3 a Me 1 mol% 40 °C 80 % 70:30 46:54
4 a Me 2 mol% 40 °C 82 % 71:29 46:54
5 a Me 1 mol% 60 °C > 99 % 72:28 48:52
6 a Me 2 mol% 60 °C > 99 % 70:30 48:52
7 b Et 1 mol% 20 °C 7 % n.d. n.d.
8 b Et 2 mol% 20 °C 8 % n.d. n.d.
9 b Et 1 mol% 40 °C 79 % 75:25 50:50
10 b Et 2 mol% 40 °C 78 % 73:27 50:50
11 b Et 1 mol% 60 °C > 99 % 72:38 50:50
12 b Et 2 mol% 60 °C > 99 % 73:27 50:50
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-7: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; temperature effect.a
Clearly the choice of a magnesium salt as co catalyst was not successful except in terms of reactivity. Our attention then turned to mono cationic metal salts in order to better mimic the classical sodio malonate nucleophiles. The influence of several metal salts as co catalysts was thus assessed and the results are reported in Table 5-8. The first tests with silver hexafluorophosphate (entries 1 and 5) proved to be encouraging in terms of regioselectivity of the reaction. However linear allylic ether 18 , resulting from the attack of the methoxide anion onto the π allyl fragment, was obtained as the major product. Alkali metal salts were subsequently tried and experiments the nucleophilic attack of the methoxide could be completely suppressed (entries 2 4 and 6 8). With potassium hexafluorophosphate, the regioselectivity of the reaction was globally recovered (entries 2 and 6) but the reactivity problem remained (conv. < 40%). Sodium hexafluorophosphate provided a much faster and as selective reaction (entries 3 and 7). Overall the best results were obtained using lithium hexafluorophosphate as co catalyst (entries 4 and 8).
81 Chap. 5: Applications to “Classical”Allylic Substitution
O O O O O O O 1) 4b (2 mol%) O O bpy (2.4 mol%) OR OR OMe OR 2) [M][PF6] (1 mol%) 1.1 equiv. THF, 60 °C, 14 h 14a R = Me, Et 15 16 18
b b b Entry 15 R = [M][PF 6] Conv. b:l dr. 18
1 a Me [Ag][PF 6] > 99 % 86:14 49:51 85 %
2 a Me [K][PF 6] 38 % 91:9 48:52 < 1%
3 a Me [Na][PF 6] 92 % 91:9 47:53 < 1%
4 a Me [Li][PF 6] > 99 % 93:7 46:54 < 1%
5 b Et [Ag][PF 6] > 99 % 87:13 50:50 87 %
6 b Et [K][PF 6] 40 % 91:9 49:51 < 1%
7 b Et [Na][PF 6] 91 % 91:9 49:51 < 1%
8 b Et [Li][PF 6] > 99 % 92:8 49:51 < 1%
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. a Table 5-8: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; [M][PF 6] co catalysts.
OMe O O O O O O O 1) 4b (2 mol%) O O bpy (2.4 mol%) OR OR 18 OR 2) [Li][Z] (1 mol%) 1.1 equiv. MeO THF,60 °C,14 h 14a R = Me, Et 15 16 19
b b b Entry 15 R = [M][PF 6] Conv. b:l dr. 18 19
1 a Me LiHMDS 49 % 92:8 45:55 11 % 3 %
2 a Me [Li][NTf 2] > 99 % 93:7 48:52 < 1% < 1%
3 a Me [Li][BF 4] > 99 % 93:7 48:52 < 1% < 1%
4 a Me LiO t Bu > 99 % 92:8 48:52 < 1% < 1%
5 a Me LiOMe > 99 % 93:7 48:52 < 1% < 1%
6 b Et LiHMDS 62 % 90:10 46:54 18 % 5 %
7 b Et [Li][NTf 2] > 99 % 89:11 50:50 < 1% < 1%
8 b Et [Li][BF 4] > 99 % 89:11 50:50 < 1% < 1%
9 b Et LiO t Bu 97 % 90:10 50:50 < 1% < 1%
10 b Et LiOMe > 99 % 89:11 50:50 < 1% < 1%
a 4b (2 mol%), bpy (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-9: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; [Li][Z] co catalysts.a
Further screening of the anionic part of the lithium salt was performed and results are reported in Table 5-9. The use of lithium hexamethyldisylazane, a strong base, did not provide the expected results in terms of reactivity (entries 1 and 6). However, the use of [Li][NTf 2]or
[Li][BF 4] afforded similar results to [Li][PF 6] (entries 2, 3 and 7, 8); showing that the anionic
82 Chap. 5: Applications to “Classical”Allylic Substitution counterpart only plays a little role on the outcome of the reaction. The use of inexpensive lithium alkoxides was thus envisaged and commercially available lithium tert butoxide and methoxide were tried as co catalysts in the reaction (entries 4, 5 and 9, 10). The latter reactions proceeded smoothly and good results in terms of reactivity and regioselectivity were obtained. Unfortunately the problem of the diastereoselectivity of the branched product remains to be solved. Lithium methoxide consequently appeared as a good choice for further reaction screening. With optimized conditions in hand ( 4b , LiOMe …) the co catalytic methodology was used with ligand L18f and a variety of activated carbonyl compounds: results are reported in Table 5-10 . Clearly ligand L18f is suitable for this transformation since only ethyl nitroacetate (low reactivity, entry 6) appeared to be problematic. For different 1,3 ketoesters (entries 1 to 5), the reactions were complete. Good regioselectivities above 9:1 were obtained; the relative selectivities being the same than when using 2,2’ bipyridine ( Table5-3). In addition the same problem of low diastereoselectivity remained unsolved in all cases. The more bulky N,N diethyl acetylacetamide reacted efficiently but the regioselectivity was noticeably lower (entry 7). Symmetrical acetylacetone (entry 8) did not afford an efficient reaction whereas diethyl malonate (entry 9) afforded a full conversion with good regioselectivity.
O O O O O 1) 4b (2 mol%) O L18f (2.4 mol%) R R 2) LiOMe (1 mol%) R' R' R 14a R' THF,60 °C,14 h 1.1 equiv. R = Me, Et 15 16
Entry 15 R = R’ = Conv. b b:l b dr. b
1 b MeCO OEt > 99 % 92:8 50:50
2 i PhCO OEt > 99 % 96:4 50:50
3 h CF 3CO OEt > 99 % 87:13 55:45
O O 4 f > 99 % 95:5 n.d. OEt O O
5 g OEt > 99 % 91:9 60:40
6 n O2N OEt 9 % n.d. n.d.
7 o MeCO NEt 2 89 % 70:30 45:55 8 j MeCO Me 10 % n.d.
9 k EtOCO OEt > 99 % 90:10
a 4b (2 mol%), L18f (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-10: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; chiral ligand L18f .a
83 Chap. 5: Applications to “Classical”Allylic Substitution The enantioselectivity aspect of this reaction was not investigated due to time restrictions but overall, the catalytic combination of 4b and L18f , in conjunction with a lithium salt like lithium methoxide, proved to be efficient both on the reactivity and regioselectivity points of view. This methodology efficiently competes with the literature procedures and should be further developed.
5.3. Preformed C-Nucleophiles
Following the report of Hartwig et al concerning the Ir catalyzed allylation of silylenolethers derived from ketones, 3 the newly developed co catalytic combination was tried for this particular reaction. Results are summarized in Table 5-11 . Two commercially available trimethylsilyl enol ethers, respectively derived from cyclohexanone and acetophenone, were used in this study. In this case, the released methoxide should be able to attack the TMS enol ether and release the ketone enolate which could then add to the π allyl complex yielding the same products than the Carroll rearrangement of corresponding ketoesters.
Disappointingly, in both cases the conversion was low after 14 hours of reaction. In the case of 1 (trimethylsilyloxy)cyclohexene (entry 1) only 54 % conversion were reached, but more importantly the regioselectivity was clearly lower than the corresponding Carroll rearrangement reaction ( b:l 54:55 vs. 86:14, Table 4-4, entry 3). In addition, large amounts of product corresponding to the nucleophilic attack of the methoxide were detected (38 %) with, in this case, a 1:1 ratio of branched 19 and linear 18 . Interestingly the diastereoselectivity of branched product 2 was inversed compared to the Carroll rearrangement of 1n ( dr. 40:60 vs. 64:36 Table 4-4 entry 3). A similar situation is obtained with 1 penyl 1 trimethylsilyloxy ethylene (entry 2): medium conversion (74 %), low regioselectivity (20:80 vs. 95:5 Table 4-4 entry 6) and some cinnamyl methyl ether was detected (8 % with a b:l ratio of 1:1).
Obviously, the situation in this case is different from the corresponding Carroll rearrangement. The nucleophilic species in the two cases have very different chemoselectivities; especially the regioselectivity of the reaction is strongly influenced. One plausible explanation for the lower b:l ratio could be that the enolate moiety is not (or only partially) decoordinated from the silicon atom. This bulkier nucleophile will, according to the previously observed empirical relation between nucleophile bulk and regioselectivity, provide
3 Graening, T.; Hartwig, J. F. J. Am. Chem.Soc. 2005 , 127 , 17192 17193.
84 Chap. 5: Applications to “Classical”Allylic Substitution a less regioselective nucleophilic attack. This should be further assessed by varying the bulk of the non transferable alkyl groups on the silicon (TMS, TBDMS, TBDPS, TIPS …).
O O R R R' R' O
O O 1) 4b (2 mol%) OTMS L18f (2.4 mol%) 2 3 2) LiOMe (1 mol%) R 14a R' THF, 60 °C, 14 h 1.1 equiv. OMe OMe
19 18
Entry 2 R = R’ = Conv. b b:l b dr. b 18 19 OTMS
1 n 54 % 45:55 40:60 19 % 19 %
OTMS 2 q 74 % 20:80 4 % 4 %
a 4b (2 mol%), L18f (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-11: Base free regioselective Cp Ru catalyzed allylation of acetoacetates; chiral ligand L18f .a
One other similar possibility would be, as described by Hartwig, to use isolated enamines as nucleophile;4 this methodology yields the same products but the major issue resides in the regioselective synthesis of the starting enamines.
5.4. Unstabilized Nucleophiles
5.4.1. Unstabilized Ketones
5 Reasoning in terms of pK a (DMSO) the released alkoxide should be able to deprotonate also unactivated ketones. The previously described methodology was then tried with cyclohexanone and acetophenone as prenucleophile ( Table 5-13 ). Unfortunately, when using reactant 14a (R = Me), only the attack of the alkoxide onto the π allyl fragment was detected by GC MS. The branched to linear ratio of the obtained product was close to 1:1.5 whatever the ketone used. Once again, 14d (R = t Bu) only afforded a very slow reaction; the
4 Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007 , 129 , 7720 7721. 5 In DMSO: pk a(MeOH) = 29.0; pk a(t BuOH) = 32.2; pk a(cyclohexanone) = 26.4; pk a(acetophenone) = 24.7.
85 Chap. 5: Applications to “Classical”Allylic Substitution distribution of products was thus not determined. Overall these results show the need for activated prenucleophiles in order to achieve the desired reactivity.
O O R R R' R' O R O O 1) 4b (2 mol%) O L18f (2.4 mol%) 2 3 2) LiOR (1 mol%)
14 R'' R' THF, 60 °C, 24 h 1.1 equiv. OR OR
19 18
Entry 2 R = R’ = R’’ = Conv. b b:l b dr. b 18 19 O
1 n Me 60 % nd. nd. 36 % 24 %
O 2 q Me 58 % nd. nd. 34 % 24 %
O
3 n t-Bu < 5% nd. nd. nd. nd.
O 4 q t-Bu < 5% nd. nd. nd. nd.
a 4b (2 mol%), L18f (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion, ratios of branched ( 15 and 15’ ) to linear ( 16 ) products and dr. of branched (15 and 15’ ) products were determined by GC MS. Table 5-13: Regioselective Cp Ru catalyzed allylation of inactivated ketones; chiral ligand L18f .a
5.4.2. Unstabilized Alkynes
In addition to the Carroll rearrangement, Tunge also described the Pd catalyzed decarboxylative sp sp 3 couplings,6 the acetylide being generated in-situ by decarboxylation of a propiolate moiety. This reaction appeared to us as a possible application for the previously described CpRu protocol. The synthesis of branched 20a and linear 20b allylic phenylpropiolic esters is described in Scheme 5-1. Phenyl acetylene was deprotonated with n
BuLi and quenched with dry CO 2; subsequent acidic workup afforded the corresponding carboxylic acid. The final substrates were obtained in high yield by DCC mediated esterification (DMAP was used as catalyst) with the corresponding allylic alcohol.
6 Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005 , 127 , 13510 13511.
86 Chap. 5: Applications to “Classical”Allylic Substitution
O O 1) n-BuLi (0.95 equiv.) DCC (0.95 equiv.) O 2) dry CO2 DMAP (0.1 equiv.) ROH (1 equiv.) O O 3) HClaq or Ph OH Ph Ph Ph Ph THF,0 °C, 5 min Ph THF,0 °C, 5 min 20a 90 % (2 steps) 20b 84 % (2 steps) Scheme 5-1: Synthesis of allylic phenylpropiolic esters 20 . Substrate 20a was then submitted to the standard reaction conditions ( Table 5-14). Using only the Ru based catalyst ( 4b + L18f ), no reaction was obtained. The starting material was completely recovered (entry 1). In order to achieve some reactivity the use of co catalysts was envisaged. However, even metals known to interact with alkyne moieties as copper (I and II) or silver salts did not help in getting a reactivity.
O Ph Ph 1) 4b (2 mol%) O L18f (2.4 mol%) 2) MX (1 mol%) Ph n Ph THF, 60 °C, 14 h Ph Ph 20a 21a 22a
b Entry MX n Conv.
1 < 1 %
2 LiPF 6 < 1 %
3 AgPF 6 < 1 % 4 CuTc < 1 %
5 (CuOTf) 2Tol < 1 %
6 Cu(Otf) 2 < 1 %
a 4b (2 mol%), L18f (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion determined by GC MS (ratio of 20a /20b ). Table 5-14: Rearrangement of phenylpropiolic ester 20a.a
Once again, to assess the apparent lack of reactivity, branched 20b was submitted to the reaction conditions ( Table 5-15). In this case, and whatever the co catalyst used, the branched 20b was fully isomerized to linear 20a . This shows that the Ru catalyst is able to react with substrate 20b and that the apparent lack of reactivity of 20a is most probably due to (i) an inability of the phenylpropiolate fragment to undergo decarboxylation or (ii) a very fast return reaction (re)forming 20a after ionization.
87 Chap. 5: Applications to “Classical”Allylic Substitution
O O 1) 4b (2 mol%) O L18f (2.4 mol%) O 2) MX (1 mol%) Ph n Ph Ph Ph THF, 60 °C, 14 h 20b 20a
b Entry MX n Conv.
1 Cu(OTf) 2 > 99 %
2 (CuOTf) 2Tol > 99 %
3 AgPF6 > 99 % 4 > 99 %
a 4b (2 mol%), L18f (2.4 mol%), THF, 60 °C, c 1 M; the results being the average of at least two runs; b conversion determined by GC MS (ratio of 20a /20b ). Table 5-15: Rearrangement of phenylpropiolic ester 20b .a 5.5. Heteroatomic Nucleophiles
Since the applicability of the asymmetric protocol would be greatly benefit from a broadening of the scope of nucleophiles to heteroatomic fragments, some reactions towards this goal were performed with a few chosen substrates.
5.5.1. N-Nucleophiles
For N nucleophiles, carbamates appeared as a possible family of substrates. 7 Cinnamyl carbamates 23a to 23d were easily synthesized from the corresponding commercially available carbamoyl chlorides ( Scheme 5-2). Tertiary carbamates 23a and 23b did not show any reactivity when submitted to the reaction conditions. The situation for carbamates 23c and 23d was significantly different since the reaction proceeded well but only linear product was obtained from 23c after 24 hours and a very non selective process took place from 23d : large amounts of linear product and of diallylated aniline were obtained ( Scheme 5-3).
O O O O Ph Ph O N O N O N O N H O Ph
23a 23b 23c 23d Scheme 5-2: Synthesized cinnamyl carbamates 23.
O NHPh NHPh NHPh 4b (2.5 mol%) N O NHPh L18f (3 mol%)
THF, 60 °C, 24 h Conv. > 97 % 24a 31 % 24b 34 % 23d 24d 35 % Scheme 5-3: Rearrangement reaction of carbamate 23d. 7 Bruneau, C.; Renaud, J. L.; Demerseman, B. Chem. Eur. J. 2006 , 12 , 5178 5187.
88 Chap. 5: Applications to “Classical”Allylic Substitution With this result in hand, we turned our attention to another class of substrate. The methodology of Overmann 8 and Peters 9 for the rearrangement of allylic trichloroacetimidates into allylic amides was then considered. Cinnamyl trichloroacetimidate 25 was synthesized from commercially available trichloroacetonitrile and the corresponding alcohol. 8 When submitted to the standard reaction conditions, the rearrangement indeed took place; GC MS as well as 1H and 13 C NMR and GC MS spectral analyses allowed to determine the nature and the ratios of the obtained products ( Scheme 5-4). The branched product 26a was obtained in a 50 % proportion and with an enantiomeric excess of 65 %. However 30 % of linear product 26b was also obtained along with 15 % of branched linear doubly allylated 26c and 5 % of doubly linear 26d. These results are obviously much worse than the published procedures and clearly, the reaction is not a standard intramolecular rearrangement as for the palladium catalyzed version of this transformation.8,9
O O
HN CCl3 HN CCl3
NH
4b (2.5 mol%) 26a 50 % 26b 30 % O CCl3 L18f (3 mol%) 65 % ee O THF,60 °C,24 h O Conv. > 97 % N CCl 25 3 N CCl3
26c 15 % 26d 5 % Scheme 5-3: Rearrangement of trichloroacetimidates of type 25. Overall the proposed catalytic system does not seem to be well suited for the use of N nucleophiles.
5.5.2. O-Nucleophiles
O nucleophiles also represent an important class of reactive fragments. As such, many methods have been disclosed in the literature, but only very few examples Ru catalyzed
8 (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003 , 125 , 12412 12413. (b) Anderson, C. E.; Donde, Y.; Douglas, C. J.; Overman, L. E. J. Org. Chem. 2005 , 70 , 648 657. Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007 , 129 , 5031 5044. 9 (a) Weiss, M. E.; Fischer, D. F.; Xin, Z. Q.; Jautze, S.; Schweizer, W. B.; Peters, R. Angew. Chem. Int. Ed. 2006 , 45 , 5694 5698. Fischer, D. E.; Xin, Z. Q.; Peters, R. Angew. Chem. Int. Ed. 2007 , 46 , 7704 7707. Jautze, S.; Seiler, P.; Peters, R. Angew. Chem. Int. Ed. 2007 , 46 , 1260 1264.
89 Chap. 5: Applications to “Classical”Allylic Substitution enantioselective allylic substitutions of linear unsymmetrical substrates have been reported.10 Both examples describe the etherification of allyl chlorides with phenols in the presence of stoichiometric amounts of base. It was thought that the previously developed catalytic protocol could be efficient in performing the decarboxylative rearrangement of cinnamyl aryl carbonates: This process would allow the base free addition of a phenoxide nucleophile onto the π allyl moiety. This project was carried out by Martina Austeri (PhD student of the group) and is described here only as a further example of application of the catalytic combination. As such only few selected examples will be described. 11 All the substrates of type 27 were obtained from commercially available aryl chloroformates and corresponding cinnamyl alcohol. When submitted to the catalyst combination, the aryl carbonates proved to be very reactive substrates (see Table 5-16) yielding the desired branched allylic ethers with high selectivity. A similar effect of the electronegativity of the substituents on the cinnamyl fragment on the regioselectivity of the process was observed as for the Carroll rearrangement (Table 3-5). Since the substrates were very reactive, the reactions could be performed at room temperature (25 °C) and enantioselectivities around 85 % were obtained in all cases which is similar to the Mg co catalyzed Carroll rearrangement ( Table 4-6).
R' R' R' O 4a (10 mol%) O O L18f (10 mol%) O O
THF, R.T.
R 27 R 28 R 29
Entry Carbonate R = R’= Time Conv. % ee Conf. b b:l c
1 27a H H 2 h > 97 % 84 % (+) > 97:3
2 27b Cl H 2.5 h 92 % 87 % (+) > 97:3
3 27c NO 2 H 7 h 87 % 85 % (–) 75:25
4 27d H Me 2.5 h 90 % 84 % (–) 90:10
a 4a (10 mol%), L18f (10 mol%), THF, R.T., c 0.5 M; the results being the average of at least two runs; b conversion, ratios of branched ( 27 ) to linear ( 28 ) products were determined by 1H NMR (400 MHz). Table 5-16: Base free regioselective CpRu catalyzed etherification of allyl carbonates.a
In addition, it has been shown in previous experiments that the alkoxide anion (originating from a carbonate) is liable to add to the π allyl fragment. Consequently, this type of
10 (a) Mbaye, M. D.; Renaud, J. L.; Demerseman, B.; Bruneau, C. Chem. Commun. 2004 , 1870 1871.. (b) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008 , 47 , 1454 1457. (c) Ueno, S.; Hartwig, J. F. Angew. Chem. Int. Ed. 2008 , 47 , 1928 1931. 11 Austeri, M.; Linder, D.; Lacour, J. Chem. Eur. J. 2008 , 14 , 5737 5741.
90 Chap. 5: Applications to “Classical”Allylic Substitution transformations with O nucleophiles deserves further studies and work is currently going on in the group to broaden the scope of this methodology in the context of O nucleophiles.
5.6. Conclusion
The catalytic combination described in the previous chapter (4b + L18f ) appears to have a scope wider than the Carroll rearrangement. In order for the reactions to proceed satisfyingly, an alternative co catalyst based on lithium salts had to be used. Using lithium methoxide as co catalyst, the scope of nucleophiles could be broadened to the field of activated prenucleophiles but several limitations still remain. The combination of 4b and L18f also proved to be efficient with carbamates and carbonates; the latter class of molecules being much more suitable for the described strategy. As such further work on the “rearrangement” of carbonates is currently being undertaken in the laboratory.
91 Chap. 6: General Conclusion & Outlook
6. General Conclusion & Outlook
Before I came here I was confused about this subject. Having listened to your lecture I am still confused. But on a higher level… Enrico Fermi (1901-1954)
6.1. Conclusion
The objective of this work was to further develop the chemistry of ruthenium-catalyzed Carroll rearrangement reactions previously reported by Tunge 1 and by our group.2 As shown in the introductory chapter 2, the field of allylic substitution reactions is extremely varied, but ruthenium catalyzed reactions remain little studied.
In the third chapter, we have shown that readily-accessible pyridine mono-oxazolines were ligands very well suited for the CpRu-catalyzed Carroll rearrangement reactions. Ligand L18f appeared especially appropriate for this transformation since excellent regioselectivities (up to > 99:1) good enantioselectivities (up to ca. 80 %) and improved reactivities (up to 20 times faster than the first-generation pyridine imine ligands) could be obtained.
The aim of the fourth chapter was to better understand the transformation and especially its mechanism. Many reactions were performed in an attempt to characterize the different steps of the mechanism. It was unfortunately not possible to directly prove the nature of the different intermediates but mechanistic evidence were gathered and analyzed, sufficient to afford a plausible mechanistic rational. The reaction seems to proceed following a pathway very similar to what is described for palladium catalyzed allylic alkylation reactions.
As a follow-up to this mechanistic rational, a co-catalytic strategy based on magnesium salts was developed and successfully applied to the Carroll rearrangement. Enhanced reactivities were achieved allowing the reaction to be performed at lower temperature (room temperature) and with consequently better enantioselectivity.
The fifth chapter describes the application of the catalytic combinations to intermolecular allylic substitution reactions. They appeared well suited, when used in conjunction with a lithium salt, for “base free” alkylation reactions. Good regioselectivities (generally around 9:1
1 (a) Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603-2605. (b) Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835-2837. 2 (a) Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082-2085. (b) Constant, S.; Tortoioli, S.; Muller, J.; Linder, D.; Buron, F.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 8979-8982.
- 92 - Chap. 6: General Conclusion & Outlook in favour of the branched regioisomer) were obtained for a wide variety of classical activated prenucleophiles. The problem of low diastereoselectivity (generally around 1:1) of the branched product still remains largely unsolved.
The same asymmetric protocol could also be applied to the decarboxylative “rearrangement” of cinnamyl carbamates and carbonates. The reactions of N-based substrates are problematic since neither chemoselectivity (double alkylation reactions) nor regioselectivity could be controlled satisfyingly. The cinnamyl aryl carbonates were much better substrates and good regio and enantioselectivities were obtained.
6 Overall the straightforward combination of air-stable [CpRu( η -napht)][PF 6] with simple-to- make ligand L18f allowed the reactions to be performed under easy experimental conditions. Ligand L18f appeared to be very interesting due to the simplicity in its synthesis but more interestingly due to the fact that both enantiomers of the starting indenyl aminoalcohol are commercially available for a moderate price ((+)- or (–)-aminoindanol 5g ~ 200 CHF). 3
6.2. Outlook
As shown in the different parts of this manuscript, the catalytic combinations described herein still suffers from a few limitations mainly in terms of reactivity and enantioselectivity. Due to simplicity of the catalytic system there still remain a lot of room for structural improvements.
Firstly, except for the unsuccessful attempts to use Cp*Ru complexes, no structural variations have been made to the roof of the half sandwich precatalytic complex. Firstly, as a more electron rich roof seems to be beneficial for the reactivity and selectivity (especially in the endo / exo isomerism of the π-allyl complex) of allylation reactions as reported by Pregosin 4 and by Trost,5 it seems appropriate to substitute the Cp moiety with some electron donating groups ( Scheme 6-1 (a) ). The Cp* appeared too bulky for a combination with L18f , as such di- or tri-substituted Cp’ moieties could be appropriate ( C2 symmetrical Cp’ should be privileged to avoid planar chirality of subsequent complex).
Another strategy could be to substitute the Cp ring with a group able to activate the ketoester moiety in a similar way to the co-catalytic approach. For example structures similar to
3 Senanayake, C. H. Aldrichim. Acta 1998 , 31 , 3-15. 4 Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Breher, F. Organometallics 2006 , 25 , 1440-1447. 5 Trost, B. M.; Older, C. M. Organometallics 2002 , 21 , 2544-2546.
- 93 - Chap. 6: General Conclusion & Outlook
Shvo’s 6 catalyst, bearing a hydroxy group on the Cp Scheme 6-1 (b) , could serve as a useful structural scaffold in this context. Many different variations have been published and successfully applied in the context of chemoenzymatic dynamic kinetic resolutions of amines and alcohols. 7
H O O O Ru Ru Ru Ru O (a) Ar (b) Scheme 6-1: Possible structural variations on the roof of the ruthenium half sandwich complex.
The other straightforward modifications concern the N,N-ligand. Indeed, since the chirality at the metal centre was only poorly controlled by ligand L18f in many CpRu(N,N’)X complexes, it would be interesting to enhance the steric hindrance between the Cp ring and the ortho -substituent of the indenyl moiety ( Scheme 6-2). Two feasible strategies emerge: (a) introduce a more bulky R group and (b) vary the distance between the Cp and the R group by making a bigger middle ring (n = 1, 2 or 3).
R R
N N N N
O O n (a) (b) Scheme 6-2: Possible structural variations on the N,N-pymox ligand.
Cl O O O O Cl Cl
[CpRu(MeCN)3][PF6] (10 mol%) O Cl O L (10 mol%) N O O P THF, 60 °C N O O O Cl 1a 2a 3a MeO MeO MeO PHENPHAT Cl Cl Cl
Entry Ligand Time Conv. b:l c
1 bpy 2 h > 97 % > 97:3 2 phen 1h30 > 97 % > 97:3 3 PHENPHAT 45 min > 97 % > 97:3
a Fresh 4a (10 mol%), ligand L18 (10 mol%), THF, 60 °C, c(1a ) 0.5 M; the results being the average of at least two runs; b ratios of branched ( 2) to linear (3) products were determined at complete conversion by 1H NMR (400 MHz). Table 6-1: Ligand screening. a
6 Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J. Am. Chem. Soc. 1986 , 108 , 7400-7402. 7 (a) Paetzold, J.; Bäckvall, J. E. J. Am. Chem. Soc. 2005 , 127 , 17620-17621. (b) Prabhakaran, R. Synlett 2004 , 2048-2049. (c) Samec, J. S. M.; Ell, A. H.; Aberg, J. B.; Privalov, T.; Eriksson, L.; Bäckvall, J. E. J. Am. Chem. Soc. 2006 , 128 , 14293-14305.
- 94 - Chap. 6: General Conclusion & Outlook
Finally, early screening reactions were performed to determine the optimal geometry of the ligand ( Table 6-1). It appeared that 1,10-phenantroline (phen) was performing quite faster than 2,2’-bypyridine (bpy); probably because of the better planarity of the phenantroline. The use of anionic ligands like PHENPHAT, a hexacoordinated phosphate anion bearing a phenantroline, seemed to be very beneficial to the kinetics of the reaction. Several structural modifications of the N,N-ligand thus seem promising ( Scheme 6-3): (a) oxazines from homologation of natural amino acids or different phenol derived amines, 8 (b) flatening the ligand as for example in a bridged imidazole structure or (c) using a pymox ligand bearing and anionic moiety like a hexacoordinated phosphate for instance.
Cl Cl N N R R Cl O O N N N N O Cl O P O N n O O O (b) (c) (a) Cl Cl
Cl Cl Scheme 6-3: Possible structural variations on the N,N-ligand.
In addition, Kitamura has shown that pyridine or quinoline carboxylates represent a family of ligands ( Scheme 6-4 (a) ), which, in conjunction with a CpRu source, provide very active catalysts for the deallylation of allylic ethers to provide the corresponding free alcohols. 9 Recently Bruneau showed that this class of ligands were, in conjunction with a Cp*Ru source, providing efficient catalysts for classical allylic substitution reactions. 10 As such oxazoline- carboxylates as in case (b) or oxazoline-alkoxides as in case (c) (Scheme 6-4) seem to have a strong potential since they combine similar structural features to the pymox ligands with inherent anionic properties. Work is currently being carried out in the laboratory to assess the scope of such ligands in the context of Carroll rearrangement and more classical allylic substitution. In addition, since the carboxylic acid can also be used, it seems possible to apply this family of chiral ligands to allylic substitution under acidic conditions as described by Pregosin. 11
8 Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.; Ripa, A.; Schupfer, P.; Treptow, B.; Kündig, E. P. Chirality 2000 , 12 , 529-539. 9 (a) Saburi, H.; Tanaka, S.; Kitamura, M. Angew. Chem. Int. Ed. 2005 , 44 , 1730-1732. (b) Tanaka, S.; Saburi, H.; Ishibashi, Y.; Kitamura, M. Org. Lett. 2004 , 6, 1873-1875. (c) Tanaka, S.; Saburi, H.; Kitamura, M. Adv. Synth. Cat. 2006 , 348 , 375-378. 10 Zhang, H. J.; Demersernan, B.; Toupet, L.; Xi, Z. F.; Bruneau, C. Adv. Synth. Cat. 2008 , 350 , 1601-1609. 11 Zaitsev, A. B.; Gruber, S.; Pluss, P. A.; Pregosin, P. S.; Veiros, L. F.; Worle, M. J. Am. Chem. Soc. 2008 , 130 , 11604-11605.
- 95 - Chap. 6: General Conclusion & Outlook
N O R N O R N O or R' O O O O R' (a) (b) (c) Scheme 6-4: Possible structural scaffold for new N,O-ligand.
During his postdoctoral stay, Dr. Simone Tortoioli developed an enantioselective decarboxylative rearrangement of activated cinnamyl esters thus proving that the strategy used in the Carroll rearrangement can be widened to other transferable groups ( Scheme 6-2). A careful study of these reactivities should allow determining the scope of Ru-catalyzed enantioselective decarboxylative allylations of nucleophiles, but the preliminary results are promising as far as activated esters are concerned.
O
X [CpRu(MeCN)3][PF6] (10 mol%) X X O L* (10 mol%) OMe
THF, 60 °C N N L*
Entry Ligand Time Conv. ee
1 Ts b,c 24 h 53 % 25 % d 2 CN c 17 h > 97 % 60 % e
e 3 NO 2 4 h > 97 % 72 %
a Fresh 4a (10 mol%), ligand L* (10 mol%), THF, 60 °C, c(1a ) 0.5 M; the results being the average of at least two runs; b 10 mol% of DBU were used as co- catalyst; c bis-allylated product was also obtained in a 1:1 ratio; d Chiralpak IA (Hexane / iPrOH 90/10, 0.5 mL.min -1, 23 °C; e Chiralpak IB (Hexane / iPrOH 95/5, 0.5 mL.min -1, 23 °C. Table 6-2: Transferable groups.a
- 96 - Chap. 7: Experimental Part
7. Experimental Part
A tidy laboratory means a lazy chemist. Jöns Jacob Berzelius
7.1. Generalities
All reactions were carried out under dry N 2 or Ar by means of an inert gas/vacuum double manifold line and standard Schlenk techniques with magnetic stirring, unless otherwise stated. Dry toluene, dichloromethane, hexane, diethylether and tetrahydrofuran were obtained by filtration through appropriate activated alumina drying columns. Analytical thin layer chromatography (TLC) was performed with Merck SIL G/UV 254 plates. Unless otherwise stated, column chromatography (Fluka silicagel 60, 40 m or Fluka basic alumina type 5016A) was performed in air and under pressure (0.1 0.3 bar). NMR spectra were recorded on Bruker ARX 300 or AMX 400 or ARX 500 at room temperature unless otherwise stated. 1H
NMR: chemical shifts are given in ppm relative to Me 4Si with the solvent resonance used as 31 13 the internal standard. P NMR: chemical shifts were reported in ppm relative to H 3PO 4. C
NMR: chemical shifts were given in ppm relative to Me 4Si, with the solvent resonance used as the internal standard. Assignments may have been achieved using DEPT, COSY and/or NOESY experiments. IR spectra were recorded with a Perkin Elmer 1650 FT IR spectrometer using a diamond ATR Golden Gate sampling. Melting points (M.p.) were measured in open capillary tubes on a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Electrospray mass spectra (ESI MS) were obtained on a Finnigan SSQ 7000 spectrometer. GC MS were obtained spectra on a Hewlett Packard 6890 GC chromatograph coupled with an Agilent 5973 Network mass selective detector. HPLC analyses were performed on an Agilent 1100 apparatus (binary pump, auto sampler, column thermostat and diode array detector). Chiral stationary phase (CSP) chromatography was performed on a Hewlett Packard 6890 GC chromatograph using a Hydrodex β column (25m x 0.25 mm, He) with an auto sampler and a FID detector. Retention times ( tR) are given in minutes (min). Unless otherwise stated, all chemicals were obtained from Fluka, Aldrich, Pressure Chemicals or Acros and used as received or purified according to standard literature procedures. 1
rd 1 D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals , 3 ed., Pergamon Press: Oxford, 1988 .
97 Chap. 7: Experimental Part 7.2. Synthesis of substrates of type 1.
General procedure for the synthesis of cinnamyl acetoacetates of type 1 β ketoesters 1a to 1l were prepared by DMAP catalyzed addition of the corresponding allylic alcohols to diketene;2 compounds 1a ,3 1b,3 1c,3 1d,3 1f,3 1h ,4 1i ,5 1j,6 1l ,7 1m ,8 1n,3 1q 9 having spectral characteristics identical to those described already in the literature.
(E)-3-(4-nitrophenyl)allyl 3-oxobutanoate or 1e: pale yellow solid (86 %); 1H NMR (CDCl , 400 MHz): δ = 8.19 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 O O 3 Hz, 2H), 6.74 (d, J = 16.0 Hz, 1H), 6.45 (dt, J = 16.0 Hz, J = 6.0 O Hz,1H), 4.85 (d, J = 6.0 Hz, 2H), 3.55 (s, 2H), 2.30 (s, 3H); 13 1 C{ H} NMR (CDCl 3, 100 MHz): δ = 200.3 (C), 166.7 (C), 147.3
O2N (C), 142.5 (C), 131.8 (CH), 127.5 (CH), 127.2 (CH), 124.1 (CH),
65.1 (CH 2), 50.0 (CH 2), 30.3 (CH 3); M.p. : 54 56 °C. HR-MS (ESI): m/z calculated for
C13 H13 NO 45 Na 286.0685, found 286.0675.
1 (Z)-4-methoxycinnamyl 3-oxobutanoate or 1g: colourless oil (79 %); H NMR (CDCl 3, 400 MHz):7.21 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 8.7 Hz, J = 2.1 Hz,1H), 6.68 (d, J = 11.8 Hz, 1H), 5.76 (dt, J = 11.8 Hz, J = 6.7 Hz, MeO O 1H), 4.96 (d, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.54 (s, 2H), 2.33 (s, 3H ); O 13 1 C{ H} NMR (CDCl 3, 100 MHz): δ = 200.5 (C), 167.0 (C), 159.1 O (C), 133.2 (CH), 1130.1(CH), 128.5 (C), 123.3(C), 113.9 (CH), 62.4
(CH 2), 55.3 (CH 3), 50.1 (CH 2), 30.2 (CH 3). HR-MS (ESI): m/ z calculated for C14 H16 O4Na 271.0946, found 271.0940 .
2 Collado, I.; Pedregal, C.; Mazon, A.; Espinosa, J. F.; Blanco Urgoiti, J.; Schoepp, D. D.; Wright, R. A.; Johnson, B. G.; Kingston, A. E. J. Med. Chem. 2002 , 45 , 3619 3629 3 Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603 2605. 4 Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q. L.; Martin, S. F. J. Am. Chem. Soc. 1995 , 117 , 5763 5775. 5 Uneyama, H.; Niwa, S.; Onishi, T. Wo9849144, 1998 . 6 Nalesnik, T. E.; Fish, J. G.; Horgan, S. W.; Orchin, M. J. Org. Chem. 1981 , 46 , 1987 1990. 7 Gilchrist, T. L.; Sanchez Romero, O. A.; Wasson, R. C. J. Chem. Soc., Perkin Trans. 1 1989 , 353 359. 8 Balaji, B. S.; Sasidharan, M.; Kumar, R.; Chanda, B. Chem. Commun. 1996 , 707 708. 9 Galliford, C. V.; Scheidt, K. A. Chem. Commun. 2008 , 1926 1928.
98 Chap. 7: Experimental Part 1 Cinnamyl-2,2-dimethyl-3-oxobutanoate or 1o: pale yellow oil, H NMR (CDCl 3, 500 O O MHz): δ = 7.40 (m, 2H), 7.33 (m, 2H), 7.28 (m, 1H), 6.67 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 15.8 Hz, J = 6.5 Hz, 1H), 4.79 O (d, J = 6.5 Hz, 2H), 2.18 (s, 3H), 1.40 (s, 6H ); 13 C{1H} NMR
(CDCl 3, 125 MHz): δ = 205.7 (C), 173.4 (C), 136.0 (C), 134.8 (CH), 128.6 (CH), 128.2 (CH), 126.6 (CH), 122.4 (CH), 65.8
(CH 2), 55.8 (C), 25.8 (CH 3), 21.9 (CH 3). HR-MS (ESI): m/ z calculated for C15H18O3Na 269.1148, found 269.1156 .
1 Cinnamyl-4-methyl-3-oxopentanoate or 1p: pale yellow oil, H NMR (CDCl 3, 500 MHz): O O δ = 7.39 (m, 2H), 7.34 (m, 2H), 7.28 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.29 (dt, J = 15.9 Hz, J = 6.3 Hz, 1H), 4.80 O (d, J = 6.3 Hz, 2H), 3.56 (s, 2H), 2.74 (h, J = 6.8 Hz, 1H ), 13 1 1.15 (d, J = 6.8 Hz, 1H ); C{ H} NMR (CDCl 3, 125 MHz): δ = 206.6(C), 167.4 (C), 136.3 (C), 134.9 (C), 128.8 (CH),
128.4 (CH), 126.9 (CH), 122.8 (CH), 66.1 (CH 3), 47.26 (CH 2), 41.5 (CH), 18.2 (CH 3). HR-
MS (ESI): m/ z calculated for C15H18O3Na 269.1158, found 269.1151 .
1 (E)-3-methyl-3-phenylallyl 3-oxobutanoate or 1k: pale yellow oil, H NMR (CDCl 3, 400 O O MHz): δ = 7.35 (m, 5H), 5.95 (t, J = 7.0 Hz, 1H), 4.91 (d, J = 7.0 Hz, 2H), 3.53 (s, 2H), 2.32 (s, 3H), 2.17 (s, 3H ); 13 C{1H} O NMR (CDCl 3, 100 MHz): δ = 200.6 (C), 167.2 (C), 142.4 (C), 141.0 (C), 128.4 (CH), 127.7 (CH), 125.9 (CH), 120.6 (CH),
62.5 (CH 2), 50.1 (CH 3), 30.2 (CH 3), 16.3 (CH 3). HR-MS (ESI): m/ z calculated for C14 H16 O3Na 255.0991, found 255.0987 .
(E)-1,1-dideutero-3-(4-methoxyphenyl)allyl 3-oxobutanoate or 1u: pale yellow oil, 1H O O NMR (CDCl 3, 400 MHz): δ = 7.43 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 15.9 Hz, 1H), O 6.23 (d, J = 15.9 Hz, 1H), 3.81 (s, 3H), 2.25 (s, 3H), D 13 1 D 1.66 (s, 2H); C{ H} NMR (CDCl 3, 100 MHz): δ = MeO 200.8 (C), 167.2 (C), 159.9 (C), 135.1 (CH), 128.9 (C),
128.1 (CH), 120.1 (CH), 114.2 (CH), 66.1 (CD 2), 55.5 (CH 3), 50.3 (CH 2), 30.5 (CH 3). HR-
MS (ESI): m/ z calculated for C14 H14 D2O4Na 273.1066, found 273.1177 .
99 Chap. 7: Experimental Part (E)-3-methyl-3-phenylallyl 2,2-dideutero-3-oxobutanoate or 1v: pale yellow oil, 1H NMR O O (CDCl 3, 400 MHz): δ = 7.43 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 15.9 Hz, 1H), 6.23 (td, O D D J = 15.9 Hz, J = 6.6 Hz, 1H), 4.75 (d, J = 6.6 Hz, 1H), 13 1 3.82 (s, 3H), 2.25 (s, 3H); C{ H} NMR (CDCl 3, 100 MeO MHz): δ = 200.8 (C), 167.2 (C), 159.9 (C), 135.0 (CH),
128.9 (C), 128.1 (CH), 120.2 (CH), 114.3 (CH), 66.5 (CH 2), 55.5 (CH 3), 50.3 10 (CD 2/CHD/CH 2), 30.5 (CH 3). HR-MS (ESI): m/ z calculated for C14 H14 D2O4Na 273.1066, found 273.1055; m/ z calculated for C14 H15 DO 4Na 272.1003, found 272.1010; m/ z calculated for C14 H16 DO 4Na 271.0940, found 271.0953 .
(E)-3-deutero-3-methyl-3-phenylallyl 3-oxobutanoate or 1w: pale yellow oil, 1H NMR O O (CDCl 3, 400 MHz): δ = 7.43 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.23 (m, 1H), 4.77 (d, J = 6.6 Hz, DO 1H), 3.82 (s, 3H), 2.25 (s, 3H), 1.66 (s, 2H); 13 C{1H} NMR (CDCl 3, 100 MHz): δ = 200.8 (C), 167.2 (C), MeO 159.9 (C), 134.6 (CD), 128.9 (C), 128.2 (CH), 120.1
(CH), 114.1 (CH), 66.5 (CH 2), 55.5 (CH 3), 50.3 (CH 2), 30.5 (CH 3). HR-MS (ESI): m/ z calculated for C14 H15 DO 4Na 272.1003, found 272.1000 .
7.3. Synthesis of products of type 2.
CpRu-catalyzed Carroll rearrangement – Improved procedure . Typical procedure. In a 2 mL screw cap vial equipped with a magnetic stirring bar, [CpRu( η6 naphthalene)][PF 6] (6.6 mg, 0.015 mmol, 2.5 mol%) and L18f (4.3 mg, 0.018 mmol, 3 mol%) were dissolved in 0.3 mL dry THF. The vial was flushed with argon and capped. After a 1h heating at 60 °C, allyl β ketoester 1a (150 mg, 0.6 mmol) was added in one portion and heating was continued for 6 h. The cooled reaction mixture was diluted with 1.5 mL of a mixture of ether and pentane (60:40). After precipitation, the metal salts were filtered off on a short SiO 2 column (0.5 cm x 4 cm, elution ether : pentane 60 : 40); the solvents being then evaporated under reduced pressure to afford the crude reaction mixture as a pale yellow oil.
10 The eluent used in ESI HRMS is acidic (acetic acid) and as such induces a proton/deuterium scrambling at the enolizable deuterated position.
100 Chap. 7: Experimental Part CpRu-catalyzed Carroll rearrangement – Co-catalytic procedure .
Typical procedure. In a 2 mL screw cap vial equipped with a magnetic stirring bar, [CpRu( η6 naphthalene)][PF 6] (5.3 mg, 0.012 mmol, 2 mol%) and L18f (3.3 mg, 0.014 mmol, 2.4 mol%) were dissolved in 0.3 mL dry THF. The vial was flushed with argon and capped. After a 1h heating at 60 °C, the solution was cooled down to R.T. and allyl β ketoester 1a (150 mg, 0.6 mmol) was added in one portion followed by Mg(OTf) 2 (1.9 mg, 0.006 mmol, 1 mol%) and stirring was continued for 24 h. The reaction mixture was diluted with 1.5 mL of a mixture of ether and pentane (60 : 40). After precipitation, the metal salts were filtered off on a short
SiO 2 column (0.5 cm x 4 cm, elution ether : pentane 60 : 40); the solvents being then evaporated under reduced pressure to afford the crude reaction mixture as a pale yellow oil.
Compounds 2a ,11 2b,11 2c,11 2d,11 2e,12 2f,11 2l ,13 2m ,14 2n ,11 2o ,15 2p ,16 2q ,1716 are identical to those described already in the literature.
1 4-(4-methoxyphenyl)- hex-5-en-2-one or 2a: pale yellow oil, H NMR (400 MHz, CDCl 3):
O δ = 7.14 (d, J = 6.5 Hz, 2H), 6.87 (d, J = 6.5 Hz, 2H), 5.97 (ddd, J = 17 Hz, J = 10.3 Hz, J = 7 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 5.02 (d, J = 17 Hz, 1H), 3.88 (q, J = 7 Hz, 1H), 3.80 (s, 3H), 2.87 (dd, J = 16 Hz, J = 7 Hz, 1H), 2.81 (dd, J = 7 Hz, 16 Hz, 1H), 2.10 (s, 3H); MeO 13 C{1H} NMR (100 MHz): δ = 207.7 (C), 158.6 (C), 141.3 (CH),
135.2 (CH) 129.0 (CH), 114.7 (CH2), 114.4 (CH), 55.7 (CH 3), 49.5 (CH 2), 44.2 (CH), 31.1
(CH 3); Low Res GC-MS : m/ z calculated for C16H16O2 204, found 204.
11 Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603 2605. 12 Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835 2837. 13 Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A. J. Org. Chem. 1997 , 62 , 1976 1985. 14 Daub, G. W.; Griffith, D. A. Tetrahedron Lett. 1986 , 27 , 6311 6314. 15 Daub, G. W.; McCoy, M. A.; Sanchez, M. G.; Carter, J. S. J. Org. Chem. 1983 , 48 , 3876 3883. 16 Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007 , 129 , 7720 7721. 17 Graening, T.; Hartwig, J. F. J. Am. Chem.Soc. 2005 , 127 , 17192 17193.
101 Chap. 7: Experimental Part 1 4-(2-methoxyphenyl)- hex-5-en-2-one or 2b: pale yellow oil, H NMR (400 MHz, CDCl 3):
O δ = 7.19 (m, 2H), 6.90 (d, 2H), 6.04 (ddd, J = 17 Hz, 11 Hz, 7 Hz, 1H), 5.07 (d, J = 11 Hz, 1H), 5.04 (d, J = 17 Hz, 1H), 4.32 (q, J = 7 Hz, 1H), 3.86 (s, 3H), 2.89 (dd, J = 16 Hz, 7 Hz, 1H), 2.83 (dd, J = 16 Hz, 7 Hz, 1H) 2.14 (s, 3H); 13 C{1H} NMR (100 MHz): δ = 208.1 (C), 157.1 (C), 140.2 ( CH),
OMe 131.5 (CH)128.5 (CH), 128.1 (CH), 121.1 (CH), 115.0 (CH 2), 111.2 (CH),
55.8 (CH 3), 48.6 (CH 2), 38.9 (CH), 30.6 (CH 3); Low Res GC-MS : m/ z calculated for
C16H16O2 204, found 204.
1 4-phenyl-hex-5-en-2-one or 2c: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = 7.28 (m,
O 5H), 5.99 (ddd, J = 17 Hz, J = 11 Hz, J = 7 Hz, 1H), 5.08 (d, J = 11 Hz, 1H), 5.04 (d, J = 17 Hz, 1H), 3.94 (q, J = 7 Hz, 1H), 2.91 (dd, J = 16 Hz, 7 Hz, 1H), 2.84 (dd, J = 16 Hz, J = 7 Hz, 1H) 2.12 (s, 3H); 13 C{1H} NMR
(100 MHz, CDCl 3): δ = 207.50 (C), 143.19 (C), 140.94 (CH), 129.04 (CH),
128.01 (CH), 127.03 (CH), 115.04 (CH 2), 49.40 (CH 2), 44.95 (CH), 31.10
(CH 3); Low Res GC-MS : m/ z calculated for C12H14O 174, found 174.
1 4-(4-chlorophenyl)- hex-5-en-2-one or 2d: pale yellow oil, H NMR (400 MHz, CDCl 3): δ
O = 7.28 (d, J = 8 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 5.94 (ddd, J = 17 Hz, J = 10.3 Hz, J = 7 Hz, 1H), 5.09 (d, J =10.3 Hz, 1H), 5.02 (d, J = 17 Hz, 1H), 3.92 (q, J = 7 Hz, 1H), 2.89 (dd, J = 16 Hz, J = 7 Hz, 1H), 2.81 (dd, J = 16 Hz, J = 7 Hz, 1H), 2.12 (s, 3H); 13 C{1H} NMR (100
Cl MHz, CDCl 3): δ = 207.0 (C), 141.7 (C), 140.5 (CH), 132.7 (C) 129.5
(CH), 129.1 (CH), 115.4 (CH 2), 49.2 (CH 2), 44.1 (CH), 31.1 (CH 3); Low Res GC-MS : m/ z calculated for C12H13ClO 208, found 208.
1 4-(4-nitrophenyl)- hex-5-en-2-one or 2e: pale yellow oil, H NMR (400 MHz, CDCl 3): δ =
O 8.10 (d, J = 9 Hz, 2H), 7.31 (d, J = 9 Hz, 2H), 5.87 (ddd, J = 17 Hz, J = 10 Hz, J = 7 Hz, 1H), 5.07 (d, J = 10 Hz, 1H), 4.98 (d, J = 17 Hz, 1H), 3.98 (q, J = 7 Hz, 1H), 2.88 (dd, J = 17 Hz, J = 7 Hz, 1H), 2.80 (dd, J = 13 1 17 Hz, J = 7 Hz, 1H), 2.05 (s, 3H). C{ H} NMR (100 MHz, CDCl 3):
O2N δ = 205.76 (C), 150.6 (C), 146.7 (C), 139.1 (CH), 128.6 (CH), 124.1
(CH), 116.0 (CH 2), 48.52 (CH 2), 43.94 (CH), 30.63 (CH 3); Low Res GC-MS : m/ z calculated for
C12H13NO 3 219, found 219 .
102 Chap. 7: Experimental Part 4-(benzo[ d][1,3]dioxol-5-yl)hex-5-en-2-one or 2f: pale yellow oil, 1H NMR (400 MHz,
O CDCl 3): δ = 6.72 (m, 3H), 5.95 (ddd, J = 17 Hz, J = 10 Hz, J = 7 Hz, 1H), 5.96 (s, 2H) 5.06 (d, J = 10 Hz, 1H), 5.02 (d, J = 17 Hz, 1H), 3.85 (q, J = 7 Hz, 1H), 2.85 (dd, J = 7 Hz, J = 16 Hz, 1H), 2.79 (dd, J = 16 13 1 Hz, J = 7 Hz, 1H), 2.11 (s, 3H); C{ H} NMR (100 MHz, CDCl 3): δ = O 207.5 (C), 148.2 (C), 146.5 (C), 141.0 (CH), 137.0 (C) 121.0 (CH), O 114.8 (CH 2), 108.7 (CH), 108.4 (CH), 101.3 (CH 2), 49.4 (CH 2), 44.6
(CH), 31.1 (CH 3); Low Res GC-MS : m/ z calculated for C13H14O3 218, found 218.
1 3-methyl-4-phenylhex-5-en-2-one or 2l: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = O 7.25 (m, 5 H), 5.95 (ddd, J = 17 Hz, J = 10 Hz, J = 7 Hz, 1H), 5.10 (d, J = 10 Hz, 1H), 5.00 (d, J = 17 Hz, 1H), 3.45 (q, J = 7 Hz, 1H), 2.95 (m, 1 H), 2.18/1.90 (s/s, 3 H), 1.10/0.87 (d/d, 3 H, J = 7 Hz); 13 C{1H} NMR was not
measured; Low Res GC-MS : m/ z calculated for C13H16O 188, found 188.
1 2-(1-phenylallyl)cyclopentanone or 2m: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = 6.72 (m, 3H), 5.95 (ddd, J = 17 Hz, 10 Hz, 7 Hz, 1H), 5.96 (s, 2H) 5.06 (d, O J = 10 Hz, 1H), 5.02 (d, J = 17 Hz, 1H), 3.85 (q, J = 7 Hz, 1H), 2.85 (dd, J = 7 Hz, 16 Hz, 1H), 2.79 (dd, J = 7 Hz, 16 Hz, 1H), 2.11 (s, 3H); 13 C{1H}
NMR (100 MHz, CDCl 3): δ = 207.5 (C), 148.2 (C), 146.5 (C), 141.0 (CH),
137.0 (C) 121.0 (CH), 114.8 (CH 2), 108.7 (CH), 108.4 (CH), 101.3 (CH 2),
49.4 (CH 2), 44.6 (CH), 31.1 (CH 3); Low Res GC-MS : m/ z calculated for C14H16O 200, found 200.
1 2-(1-phenylallyl)cyclohexanone or 2n: pale yellow oil, H NMR (400 MHz, CDCl 3): Major
Diastereomer: δ = 7.27 (m, 5H maj ), 6.07 (ddd, J = 7 Hz, J = 10 Hz, J = 17
Hz, 1H maj ), 5.06 (m, 2H maj ), 3.75 (t, J = 9 Hz, 1H maj ), 2.82 (bm, 1H maj ) 2.46 O 1.24 (m, 6H maj ); Minor Diastereomer: δ = 7.27 (m, 5H min ), 5.99 (ddd, J = 7
Hz, J = 10 Hz, 17 Hz, 1H min ), 5.06 (m, 2H min), 3.83 (t, J = 9 Hz, 1H min ), 13 1 2.82 (bm, 1H min ) 1.84 (bm, 6H min ). C{ H} NMR (100 MHz, CDCl 3): Major and Minor δ = 213.15; 212.17 (C), 143.67/142.07 (C), 140.52/139.64 (CH),
128.98/128.85 (CH), 128.24 (CH), 126.94/126.66 (CH), 116.65/115.34 (CH 2), 55.80/55.65
(CH), 49.76/49.44 (CH), 42.76/42.51 (CH 2), 32.35/32.03 (CH 2), 28.96/28.80 (CH 2),
24.80/24.14 (CH 2); Low Res GC-MS : m/ z calculated for C15H18O 214, found 214.
103 Chap. 7: Experimental Part 1 3,3-dimethyl-4-phenylhex-5-en-2-one or 2o: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = 7.27 (m, 5 H), 6.12 (ddd, J = 17 Hz, 10 Hz, 7 Hz, 1H), 5.12 (dd, J = 16 O Hz, J = 10 Hz, 1 H), 5.06 (dd, J = 16 Hz, J = 10 Hz, 1 H), 3.60 (d, 1 H, J = 10 Hz), 2.05 (s, 3 H), 1.13 (s, 3 H), 1.08 (s, 3 H); 13 C{1H} NMR was not
measured; Low Res GC-MS : m/ z calculated for C14H18O 202, found 202.
1 2-methyl-5-phenylhept-6-en-3-one or 2p: pale yellow oil, H NMR (400 MHz, CDCl 3): δ =
O 7.31 7.28 (m, 2H), 7.22 7.19 (m, 3H), 5.98 (ddd, J = 17 Hz, J = 10.5 Hz, J = 7 Hz, 1H), 5.00 5.06 (m, 2H), 3.96 (q, J = 7 Hz, 1H), 2.90 (dd, J = 17, J = 7 Hz, 1H), 2.84 (dd, J = 17, 7 Hz, 1H), 2.50 (sept, J = 7 Hz, 1H), 1.05 (d, J = 7 Hz, 3H), 0.98 (d, J = 7 Hz, 3H); 13 C{1H} NMR (100
MHz, CDCl 3): δ = 212.7 (C), 143.1 (C), 140.7 (CH), 128.5 (CH), 127.6
(CH), 126.5 (CH), 114.5 (CH 2), 45.8 (CH 2), 44.2 (CH), 41.3 (CH), 17.9 (CH 3), 17.7 (CH 3);
Low Res GC-MS : m/ z calculated for C14H18O 202, found 202.
1 1,3-diphenylpent-4-en-1-one or 2q: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = 7.94
O (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.34 7.18 (m, 5H), 6.06 (ddd, J = 17.2 Hz, J = 10.4 Hz, J = 6.8 Hz, 1H), 5.14 (dt, J = 10.4 Hz, J = 1.3 Hz, 1H), 5.04 ( dt, J = 17.2 Hz, J = 1.3 Hz, 1H), 4.15 (q, J = 6.8 Hz, 1H), 3.44 (dd, J = 16.7 Hz, J = 7.6 Hz, 1H), 3.38 (dd, J = 16.7 Hz, J 13 1 = 6.6 Hz, 1H); C{ H} NMR (100 MHz, CDCl 3): δ = 198.2 (C), 143.1 (C), 140.6 (CH), 137.1 (C), 133.0 (CH), 128.6 (CH), 128.5 (CH), 128.0 (CH), 127.7
(CH), 126.5 (CH), 114.7 (CH 2), 44.5 (CH), 44.0 (CH 2); Low Res GC-MS : m/ z calculated for
C17H16O 236, found 236.
4-(4-methoxyphenyl)-6,6-dideutero-hex-5-en-2-one or 2u: pale yellow oil, 1H NMR O (CDCl 3, 400 MHz): δ = 7.13 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.95 (m, 1H), 3.85 (q, J = 7.3 Hz, 1H), 3.79 (s, D 3H), 2.86 (dd, J = 16.0 Hz, J = 7.3 Hz, 1H), 2.78 (dd, J = 16.0 D 13 1 Hz, J = 7.3 Hz, 1H), 2.08 (s, 3H ); C{ H} NMR (CDCl 3, 100 MeO MHz): δ = 207.6 (C), 158.4 (C), 140.9 (CH), 135.0 (C), 128.8
(CH), 114.2 (CH), 113.9 (CD2), 55.5 (CH 3), 49.3 (CH 2), 43.9 (CH), 30.9 (CH 3). Low Res
GC-MS : m/ z calculated for C13 H14 D2O2 206, found 206 .
104 Chap. 7: Experimental Part 3,3-dideutoro-4-(4-methoxyphenyl)hex-5-en-2-one or 2v: pale yellow oil, 1H NMR O (CDCl 3, 400 MHz): δ = 7.13 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 D Hz, 2H), 5.95 (ddd, J = 18.3 Hz, J = 9.0 Hz, J = 6.7 Hz, 1H), 5.05 D (td, J = 9.3 Hz, J = 1.3 Hz, 1H), 4.98 (td, J = 18.3 Hz, J = 1.3 Hz, 1H), 3.85 (d, J = 6.7 Hz, 1H), 3.79 (s, 3H), 2.08 (s, 3H ); 13 C{1H} MeO NMR (CDCl 3, 100 MHz): δ = 207.6 (C), 158.5 (C), 141.1 (CH),
135.0 (C), 128.8 (CH), 114.5 (CH 2), 114.2 (CH), 55.5 (CH 3), 49.4 (CD 2/CHD/CH 2), 44.0
(CH), 30.9 (CH 3). Low Res GC-MS : m/ z calculated for C13 H14 D2O2 206, found 206 .
1 4-deutoro-4-(4-methoxyphenyl)hex-5-en-2-one or 2w: pale yellow oil, H NMR (CDCl 3, O 400 MHz): δ = 7.11 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.93 (dd, J = 17.0 Hz, J = 10.3 Hz, 1H), 5.03 (td, J = 10.3 Hz, J = D 1.3 Hz, 1H), 4.98 (td, J = 17.0 Hz, J = 1.3 Hz, 1H), 3.78 (s, 3H), 2.85 (d, J = 21.4 Hz, 1H), 2.76 (d, J = 21.4 Hz, 1H), 2.08 (s, 3H); 13 1 MeO C{ H} NMR (CDCl 3, 100 MHz): δ = 207.6 (C), 158.4 (C), 141.1
(CH), 134.9 (C), 128.8 (CH), 114.5 (CH 2), 114.2 (CH), 55.5 (CH 3), 49.3 (CH 2), 43.6 (CD),
30.9 (CH 3). Low Res GC-MS : m/ z calculated for C13 H15 DO 2 205, found 205.
105 Chap. 7: Experimental Part 7.4. CSP-separation of products of type 2.
a Entry Product tR (min) tR (min) Method
1 2a 55.9 57.6 A 2 2b 16.7 17.9 B 3 2c 11.0 11.3 A 4 2d 41.9 43.5 A 5 2e 27.2 5.89 C 6 2f 15.3 16.2 D 7 2l b 32.9 33.6 A 8 2l c 37.9 38.1 A 9 3ld 50.9 53.4 A
10 2m b 70.6 71.1 A 11 2m c 81.6 85.8 A 12 3md 125.0 126.2 A 13 2n b 77.5 82.2 A 14 2n c 86.0 87.1 A 15 3nd 73.0 80.1 A 16 2o 19.6 20.1 A 17 2p 10.0 18.1 E 18 2q 16.2 17.7 F 19 2u 55.9 57.6 A 20 2v 55.9 57.6 A 21 2w 55.9 57.6 A
a A: CSP GC (Chiraldex Hydrodex β–3P), Tinj 250 °C, P = 0.596 bar; 130 °C, isotherm; B: CSP HPLC (Chiralcel OD H), Hexane : i PrOH, 97 : 3, 0.8 mL.min 1, 23 °C; C: CSP HPLC (Chiralpak IA), Hexane : i PrOH, 96 : 04, 0.5 mL.min 1, 23 °C; D: CSP HPLC (Chiralpak IB), Hexane : THF, 85 : 15, 0.4 mL.min 1, 23 °C; E: CSP HPLC (Chiralcel OD H), Hexane : i PrOH, 99 : 1, 0.6 mL.min 1, 23 °C. F: CSP HPLC (Chiralcel OD H), Hexane : i PrOH, 98 : 2, 0.5 mL.min 1, 23 °C. b first eluted branched isomer of 2. c second eluted branched isomer of 2. c linear regioisomer of 2. Table 7-1: Chiral stationary phase separation of enantiomers of type 2.
106 Chap. 7: Experimental Part 7.5. GC-separation of products of type 2 and 3.
a Entry Product tR(2) (min) tR(3) (min) Method
1 a 17.7 19.9 A 2 b 17.5 28.4 A 3 c 18.0 22.5 A 4 d 22.9 27.0 A 5 e 20.1 22.1 A 6 f 18.9 28.6 A 7 l 18.9 b 19.2 c 23.5 A
8 m 17.9 b 18.1 c 19.9 A 9 n 19.1 b 19.3 c 21.3 A 10 o 21.2 24.6 A 11 p 21.3 25.8 A 12 q 31.3 35.4 A 13 u 17.8 26.9 A 14 v 17.8 26.9 A 15 w 17.8 26.9 A
a 1 A: GC MS: (HP 5MS), T inj 250 °C, P = 0.48 bar; 60 °C, isotherm 5 min then temperature gradient 10 °C.min until 320 °C, isotherm 5 min. b first eluted branched isomer of 2. c second eluted branched isomer of 2. Table 7-2: GC MS separation of regioisomers of type 2 and 3.
7.6. Synthesis of metal precatalysts of type 4.
Both complexes 4a and 4b were prepared according to the method of Kündig. 18 Synthesis of 4b – purification procedure .
Typical procedure. 3 g of crude [CpRuNapht][PF 6] were dissolved in 60 mL of technical
CH 2Cl 2 (dark orange solution) and filtered through a plug of well packed celite (4 x 5 cm) which was washed with CH 2Cl 2 until washings become colorless. The DCM solution was concentrated to c.a. 10 mL and subsequently dropped in 100 mL technical diethyl ether under vigorous stirring to yield a light tan colored precipitate which was filtered of on a Büchner filter and washed with pentane (3 x 20 mL). The light cream solid obtained is dried under high vacuum and stored in a dark glass vial for weeks (2.95 g nearly quantitative).
18 Kündig, E. P.; Monnier, F. R. Adv. Synth. Catal. 2004 , 346 , 901 904.
107 Chap. 7: Experimental Part 5 6 1 [Ru( ηηη -C5H5)( ηηη -C10 H8)][PF 6] or 4b: pale yellow solid; H NMR PF6 (acetone d6, 400 MHz): δ = 7.92–7.89 (m, 2H), 7.73–7.70 (m, 2H), Ru 7.25–7.24 (m, 2H), 6.48–6.47 (m, 2H), 5.15 (s, 5H); 13 C{1H} NMR
(acetone d6, 100 MHz): δ = 131.5, 129.3, 97.2, 85.9, 83.9, 79.7 31 1 P{ H} NMR (162 MHz, acetone d6): δ = 144.1 (sept, PF 6); Low Res MS (ESI) : m/z = 295; M.p. : 155–160 °C (dec.).
PF6 5 1 [Ru( ηηη -C5H5)(CH 3CN) 3][PF 6] or 4a: yellow solid; H NMR 13 1 Ru (acetone d6, 400 MHz): δ = 4.25 (s, 5H), 2.44 (s, 9H); C{ H} NMR NCMe (acetone d , 100 MHz): δ = 125.9, 68.6, 2.4. MeCN NCMe 6
7.7. Synthesis of ligands of type L18.
General procedure for the synthesis of ligands of type L18 Oxazoline based ligands L18a to L18j were prepared by condensing the appropriate aminoalcohol onto the corresponding nitrile;19 compounds L18a, L18b, L18c, L18d, L18e, L18f and L18n have spectral characteristics identical to those described already in the literature. 20
Alternative synthesis of ligands of type L18 .
Typical procedure. In a 50 mL round bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a rubber septum, 2 cyano pyridine (1040 mg, 10 mmol, 1 equiv.) and sodium methoxide (54 mg, 1 mmol, 10 mol%) were dissolved in 25 mL methanol. The flask was flushed with argon and capped. After a 3h heating at reflux, the solution was cooled down to R.T. and the solvent was removed under reduced pressure by rotatory evaporation and then under high vacuum. The solid residue was diluted with 2 mL of glacial acetic acid. (1 R,2 S) 1 amino 2,3 dihydro 1H inden 2 ol (1492 mg, 1equiv.) was added portion wise to allow progressive solubilization of the amino alcohol. The reaction was capped and stirring at
19 Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991 , 124 , 1173 1180. 20 Brunner, H.; Klankermayer, J.; Zabel, M. Organometallics 2002 , 21 , 5746 5756. Brunner, H.; Obermann, U. Chem. Ber. 1989 , 122 , 499 507. Brunner, H.; Obermann, U.; Wimmer, P. Organometallics 1989 , 8, 821 826. Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Organometallics 2001 , 20 , 3029 3034. Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Dalton Trans. 2004 , 3629 3634.Takeuchi, D.; Yasuda, A.; Okada, T.; Kuwabara, J.; Osakada, K.; Tomooka, K. Helv. Chim. Acta 2006 , 89 , 1574 1588
108 Chap. 7: Experimental Part R.T. was allowed for 24 h. The reaction mixture was poured into 15 mL of water to afford precipitation which was filtered off and washed with 2x5 mL of water (white solid, 1890 mg, 80 %). In case of contamination with remaining amino alcohol column chromatography can be performed to obtain analytically pure product (SiO 2, EtOAc).
(3a R,8a S)-2-(pyrazin-2-yl)-8,8a-dihydro-3aH-indeno[1,2-d]oxazole or L18g: white solid; 1 H NMR (CDCl 3, 400 MHz): δ = 9.26 (bs, 1H), 8.65 (bs, 2H), O 7.60 (bs, 1H), 7.27 (m, 4H), 5.86 (d, J = 7.5 Hz, 2H), 5.62 (dt, J N N = 7.5 Hz, J = 6.6 Hz, 1H), 5.62 (dd, J = 7.5 Hz, J = 6.6 Hz, 1H), N 3.58 (dd, J = 6.6 Hz, J = 18.1 Hz, 1H), 3.47 (d, J = 18.1 Hz, 1H ); 13 1 C{ H} NMR (CDCl 3, 100 MHz): δ = 161.6 (C), 146.5 (CH), 145.6 (CH), 144.3 (CH), 142.8 (C), 141.3 (C), 139.8 (C), 129.0 (CH), 127.9 (CH), 126.0 (CH), 125.6 (CH), 84.4 (CH) 77.5
(CH), 39.9 (CH 2); M.p.: 121 123 °C; HR-MS (ESI): m/ z calculated for C14 H12 N3O
20 238.0974, found 238.0979; [α]D = +232 (CH 2Cl 2, C = 0.10). (3a R,8a S)-2-(pyrimidin-2-yl)-8,8a-dihydro-3aH-indeno[1,2- O d]oxazole or L18h: white solid; 1H NMR (CDCl , 400 MHz): δ = N 3 N 8.87 (d, J = 4.8 Hz, 2H), 7.63 (bs, 1H), 7.38 (t, J = 4.8 Hz, 1H), N 7.27 (m, 4H), 5.89 (d, J = 7.8 Hz, 2H), 5.66 (m, 1H), 3.58 (m, 13 1 2H); C{ H} NMR (CDCl 3, 100 MHz): δ = 162.1 (C), 157.8 (CH), 156.2 (C), 141.2 (C), 139.9 (C), 129.0 (CH), 127.8 (CH), 126.2 (CH), 125.5 (CH), 122.3 (CH), 84.9 (CH) 77.5
(CH), 39.9 (CH 2); M.p.: 163 164 °C; HR-MS (ESI): m/ z calculated for C14 H12 N3O
20 238.0974, found 238.0970; [α]D = +244 (CH 2Cl 2, C = 0.10). (3a R,8a S)-2-(4-methylpyridin-2-yl)-8,8a-dihydro-3aH- O 1 indeno[1,2-d]oxazole or L18i: white solid; H NMR (CDCl 3, N 400 MHz): δ = 8.54 (d, J = 5.0 Hz, 1H), 7.91 (bs, 1H), 7.60 N (bs, 1H), 7.27 (m, 4H), 7.18 (d, J = 4.5 Hz, 1H), 5.80 (d, J = 13 1 7.8 Hz, 1H), 5.60 (m, 1H), 3.50 (m, 2H), 2.38 (s, 3H ); C{ H} NMR (CDCl 3, 100 MHz): δ = 163.7 (C), 149.7 (CH), 148.2 (C), 146.8 (C), 141.7 (C), 140.0 (C), 128.8 (CH), 127.7 (CH),
126.7 (CH), 125.9 (CH), 125.6 (CH), 125.2 (CH), 84.2 (CH) 77.2 (CH), 39.9 (CH 2), 21.2
(CH 3); M.p.: 109 110 °C; HR-MS (ESI): m/ z calculated for C 16 H15 N3O 251.1158, found
α 20 251.1170; [ ]D = +187 (CH 2Cl 2, C = 0.10).
109 Chap. 7: Experimental Part (3a R,8a S)-2-(5-methylpyridin-2-yl)-8,8a-dihydro-3aH- O 1 indeno[1,2-d]oxazole or L18j: white solid; H NMR (CDCl 3, N 400 MHz): δ = 8.51 (bs, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.60 N (bs, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.28 (m, 4H), 5.80(d, J = 13 1 7.7 Hz, 2H), 5.60 (m, 1H), 3.50 (m, 2H), 2.37 (s, 3H ); C{ H} NMR (CDCl 3, 100 MHz): δ = 163.6 (C), 150.38 (CH), 144.3 (C), 141.7 (C), 140.0 (C), 137.2 (CH), 136.1 (C), 128.8 (CH),
127.7 (CH), 126.0 (CH), 125.6 (CH),124.0 (C), 84.2 (CH) 77.1 (CH), 39.9 (CH 2), 18.8 (CH 3);
M.p.: 124 125 °C; HR-MS (ESI): m/ z calculated for C16 H15 N3O 251.1178, found 251.1170;
α 20 [ ]D = +226 (CH 2Cl 2, C = 0.10).
7.8. Synthesis of products of type 15.
CpRu-catalyzed allylic alkylation – Co-catalytic procedure . Typical procedure. In a 2 mL screw cap vial equipped with a magnetic stirring bar, [CpRu( η6 naphthalene)][PF 6] (5.3 mg, 0.012 mmol, 2 mol%) and L18f (3.6 mg, 0.014 mmol, 2.4 mol%) were dissolved in 0.6 mL dry THF. The vial was flushed with argon and capped. After a 1h heating at 60 °C, the solution was cooled down to R.T. and cinnamyl carbonate 1a (115 mg, 0.6 mmol) was added in one portion followed by lithium methoxide (0.25 mg, 0.006 mmol, 1 mol%) and ethyl acetoacetate (84 L, 0.66 mmol, 1.1 equiv.) and stirring was continued for 24 h at 60 °C. The cooled reaction mixture was diluted with 1.5 mL of a mixture of ether and pentane (60 : 40). After precipitation, the metal salts were filtered on a short SiO 2 column (0.5 cm x 4 cm, elution ether : pentane 60 : 40); the solvents being then evaporated under reduced pressure to afford the crude reaction mixture as a pale yellow oil.
Compounds 15a,21 15b,22 15c, 15d,23 15e,22 15f,23 15g , 15h ,24 15i ,25 15j ,26 15k,27 15l , 15m, 15n and 15o were obtained as mixtures of isomers that could not be separated by column chromatography. As such the 1H NMR spectra signals could not be assigned accurately and are consequently not reported. The mass spectrum obtained in each case allowed however the
21 Polet, D.; Alexakis, A.; Tissot Croset, K.; Corminboeuf, C.; Ditrich, K. Chem. Eur. J. 2006 , 12 , 3596 3609. 22 Zhang, S. W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1993 , 450 , 197 207. 23 Renaud, J. L.; Bruneau, C.; Demerseman, B. Synlett 2003 , 408 410. 24 Luo, B. H.; Guan, H. P.; Hu, C. M. J. Org. Chem. 1997 , 62, 4174 4175. 25 Antonioletti, R.; Bovicelli, P.; Malancona, S. Tetrahedron 2002 , 58 , 589 596. 26 Faller, J. W.; Lambert, C.; Mazzieri, M. R. J. Organomet. Chem. 1990 , 383 , 161 177. 27 He, H.; Zheng, X. J.; Yi, U.; Dai, L. X.; You, S. L. Org. Lett. 2007 , 9, 4339 4341.
110 Chap. 7: Experimental Part unequivocal structure attribution (through fragmentation pattern analysis) and isomeric ratio measurements.
7.9. GC-separation of regioisomers of 15.
a Entry Product tR(15 ) (min) tR(16 ) (min) tR(17) (min) Method 1 a 17.5 b 17.7 c 19.9 nd. A 2 b 18.2 b 18.4 c 20.5 nd. A 3 c 18.5 b 18.7 c 20.8 nd. A 4 d 18.7 b 19.1 c 21.1 nd. A 5 e 21.8 b 21.9 c 23.7 nd. A 6 f 20.8 d 22.8 nd. A 7 g 19.1 b 19.1 c 20.8 nd. A 8 h 15.6 b 15.8 c 18.0 nd. A 9 i 23.6 b 23.8 c 25.7 nd. A 10 j 18.1 20.2 26.4 A 11 k 19.4 21.5 27.1 A 12 l 20.5 22.6 nd. A
13 m 18.4 d 20.4 24.7 e 26.5 f 26.6 g A 14 n 18.7 b 18.9 c 20.9 nd. A 15 o 20.6 b 21.0 c 23.3 nd. A
a 1 A: GC MS: (HP 5MS), T inj 250 °C, P = 0.48 bar; 60 °C, isotherm 5 min then temperature gradient 10 °C.min until 320 °C, isotherm 5 min. b first eluted branched isomer of 15 . c second eluted branched isomer of 15 . d absence of peak separation for branched isomers of 15 . e first eluted branched isomer of 17 . f second eluted branched isomer of 15. g third eluted branched isomer of 15 . Table 7-2: GC MS separation of regioisomers of type 15 , 16 and 17. 7.10. Synthesis of carbamates of type 23.
Compounds 23a ,28 23b ,29 23c and 23d were synthesized according to literature procedures starting from commercially available cinnamyl alcohol and carbamoyl chlorides.
7.11. Synthesis and reactivity of substrate 25.
Substrate 24 was synthesized according to a literature procedure from commercially available cinnamyl alcohol and trichloroacetonitrile. 30 Substrate 25 was reacted in the presence of a ruthenium catalyst under “standard Carroll rearrangement conditions” (see § 7.3). ratios of the isomeric products 25 31 were determined by integration of non overlapping signals of the
28 Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am. Chem. Soc. 1978 , 100 , 4822 4834. 29 Mellegaard Waetzig, S. R.; Rayabarapu, D. K.; Tunge, J. A. Synlett 2005 , 2759 2762. 30 Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Ploypradith, P.; Xie, S. J.; Shapiro, T. A.; Posner, G. H. J. Med. Chem. 2003 , 46 , 2516 2533. 31 Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007 , 129 , 5031 5044.
111 Chap. 7: Experimental Part 1H NMR spectrum. An analytically pure sample of branched 24a was obtained by preparative 32 TLC purification (SiO 2, CH 2Cl 2) for CSP HPLC separation.
7.12. Synthesis and reactivity of carbonates 27.
Synthesis of cinnamyl aryl carbonates of type 27.33
Typical procedure: phenyl chloroformate (1.5 mL, 12 mmol) was added dropwise to a solution of cinnamyl alcohol (1340 mg, 10 mmol) dissolved in dichloromethane (10 mL) and pyridine (2 mL) at 0 °C. The reaction mixture was allowed to warm at room temperature and it was stirred until all the allylic alcohol was consumed (TLC monitoring). Typically, the reactions took more than 12 hours. The crude reaction mixture was then treated with an saturated aqueous ammonium chloride solution (10 mL). The organic layer was separated, and the aqueous layer extracted with diethyl ether (2 x 10 mL). The combined organic layers were washed with water, separated, and dried over sodium sulfate. Concentration under reduced pressure followed by purification by flash column chromatography (SiO 2) gave the desired product 26a .
1 cinnamyl phenyl carbonate or 27a: colorless oil, H NMR (400 MHz, CDCl 3): δ = 7.44
O 7.16 (m, 10H), 6.75 (d, J = 16 Hz, 1H), 6.35 (td, J = 16 Hz, J = 6.5 Hz, 1H), 4.89 (bd, J = 6.5 Hz, 2H); 13 C{1H} NMR (100 MHz) δ = 153.5 (C), O O 151.1 (C), 135.8 (C), 135.3 (CH), 129.5 (CH), 129.4 (CH), 128.6 (CH),
128.2 (CH), 126.7 (CH), 125.4 (CH), 121.8 (CH), 120.9 (CH), 69 (CH 2).
1 4-chlorocinnamyl phenyl carbonate or 27b: colorless oil, H NMR (400 MHz, CDCl 3): δ =
7.5 7.35 (m, 7H), 7.25 7.2 (m, 2H), 6.75 (d, J = 15 Hz, 1H), 6.4 (td, J O 13 1 = 15 Hz, J = 7 Hz, 1H), 4.9 (d, J = 7 Hz, 2H); C{ H} NMR (100 O O MHz, CDCl 3) δ = 154.7 (C), 152.2 (C), 135.3 (C), 135.1 (C), 130.5 (CH), 129.8 (CH), 128.9 (CH), 127.3(CH), 127.1 (CH), 123.5(CH),
Cl 122.0 (CH), 69.5 (CH 2); HR-MS (ESI) m/z calculated for
C16 H13 O3ClNa 311.0451, found 311.0450.
32 65 % ee measured by CSP HPLC (Chiralcel OD H), Hexane : i PrOH, 99.5 : 0.5, 0.8 mL/min, 23 °C. 33 Inspired by Matsuhashi, H.; Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 1997 , 70 , 1943 1952
112 Chap. 7: Experimental Part 1 3-(4-nitrophenyl)allyl phenyl carbonate or 27c: colorless oil. H NMR (400 MHz, CDCl 3): δ = 8.30 8.20 (m, 2H), 7.65 7.60 (m, 2H), 7.5 7.40 (m, 3H), 7.25 O 3 7.20 (m, 2H), 6.85 (d, J = 17 Hz, 1H), 6.55 (td, J = 17 Hz, J(H H) = 7 O O 13 1 Hz, 1H), 5.0 (dd, J = 7 Hz, J = 1 Hz, 2H); C{ H} NMR (100
MHz, CDCl 3) δ = 154.0 (C), 152.1 (C), 148.5 (C), 143.4 (C), 133.4
O2N (CH), 130.6 (CH), 128.3 (CH), 127.8 (CH), 127.3(CH), 125.0 (CH),
121.9(CH), 68.8 (CH 2); HR-MS (ESI) m/z calculated for C 16 H13 O5NNa 322.0691, found 322.0679.
1 cinnamyl p-tolyl carbonate or 27d: colorless oil. H NMR (400 MHz, CDCl 3): δ = 7.55 7.48 (m, 2H), 7.45 7.35 (m, 3H), 7.25 7.20 (m, 2H), 7.15 7.05 (m, H3C O 2H), 6.80 (d, J = 16 Hz, 1H), 6.40 (td, J = 16 Hz, J = 6 Hz, 1H), 13 1 O O 4.95 (dd, J = 16 Hz, J = 1 Hz, 2H); C{ H} NMR (100 MHz,
CDCl 3): δ = 154.9 (C), 150.1 (C), 136.8 (C), 136.5 (C), 131.0 (CH), 129.7 (CH), 129.4 (CH), 127.8 (CH), 122.9 (CH), 121.7 (CH), 69.7
(CH 2), 21.2 (CH 3); HR-MS (ESI) m/z calculated for C 17 H16 O3Na 291.0999 found 291.0997.
CpRu catalyzed catalytic etherification of the allyl carbonates 27.34
General procedure: in a 2 mL vial under dinitrogen atmosphere, [RuCp(MeCN) 3][PF 6] 1a (6.3 mg, 14.4 mol, 10 mol %) and pymox ligand L18f (3.4 mg, 10 mol%) were dissolved in 300 L of anhydrous THF. The resulting deep red solution was stirred for 5 minutes at room temperature before the addition of the allyl aryl carbonates 27 (0.144 mmol). The reaction was stirred under N 2 at 25 °C until no trace of the starting material could be seen on TLC
(SiO 2, Et 2O : Pentane, 8 : 2). The reaction mixture was diluted with 1.5 mL of a 8 : 2 mixture of ether and pentane. The precipitated metal salts were filtered on a short SiO 2 column (0.5 cm x 4 cm, elution ether : pentane, 8 : 2): The solvents were evaporated under reduced pressure to afford the crude reaction mixture as a pale yellow oil which was analyzed by 1H NMR and CSP HPLC.
Compounds 28a,35 28b,35 28c36 and 28d35 were identical to those described already in the literature.
34 Austeri, M.; Linder, D.; Lacour, J. Chem. Eur. J. 2008 , 14 , 5737 5741. 35 Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008 , 47 , 1454 1457.
113 Chap. 7: Experimental Part 1 (1-phenoxyallyl)benzene or 28a: pale yellow oil, H NMR (400 MHz, CDCl 3): δ = 7.41 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 7.20 (m, 3H), 6.95 6.89 (m, 3H), 6.10 (ddd, J = 17.2, J = 10.4, J = 6 Hz, 1H), 5.63 (d, J = 6 Hz, 1H), O 5.34 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H); 13 C{1H} NMR (100
MHz, CDCl 3) δ = 157.9 (C), 140.1 (C), 138.0 (CH), 129.3 (CH), 128.6
(CH), 127.8 (CH), 126.6 (CH), 121.0 (CH), 116.5 (CH2), 116.2 (CH), 80.8 (CH).
1 1-chloro-4-(1-phenoxyallyl)benzene or 28b: pale yellow oil, H NMR (400 MHz, CDCl 3): 7.36 7.30 (m, 4H), 7.26 7.20 (m, 2H), 6.97 6.89 (m, 3H), 6.04 (ddd, J = 17.2 Hz, J = 10.4 Hz, J = 5.9 Hz, 1H), 5.61 (d, J = 5.9 Hz, 1H), 5.34 O (dt, J = 17.2 Hz, J = 1.3 Hz, 1H), 5.27 (dt, J = 10.4 Hz, J = 1.3 Hz, 13 1 1H); C{ H} NMR (100 MHz, CDCl 3) δ = 157.7 (C), 138.7 (C),
Cl 137.6 (C), 133.6, 129.4 (CH), 128.8 (CH), 128.0 (CH), 121.2 (CH)
116.9 (CH 2), 116.2 (CH), 80.1 (CH).
1 1-nitro-4-(1-phenoxyallyl)benzene or 28c: pale yellow oil. H NMR (400 MHz, CDCl 3): δ = 8.25 8.20 (m, 2H), 7.62 7.58 (m, 2H), 7.29 7.22 (m, 2H), 6.98 6.89 (m, 3H), 6.06 (ddd, J = 17.1 Hz, J = 10.3 Hz, J = 5.9 Hz, 1H), 5.73 O (d, J = 5.9 Hz, 1H), 5.38 (ddm, J = 10.3, J = 17.1 Hz, 2H); 13 C{1H}
NMR (100 MHz, CDCl 3) δ = 157.1 (C), 147.3 (C), 136.6 (C), 129.4
O2N (CH), 127.2 (CH), 123.8 (CH), 121.5 (CH), 117.9 (CH2), 116.0 (CH), 79.9 (CH).
1-methyl-4-(1-phenylallyloxy)benzene or 28d: pale yellow oil. 1H NMR (400 MHz,
CDCl 3): δ 7.35 7.32 (m, 2H), 7.30 7.25 (m, 2H), 7.22 7.18 (m, 2H), H3C 7.95 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.03 (ddd, J = 17.2 O Hz, J = 10.4 Hz, J = 6.0 Hz, 1H), 5.53 (d, J = 6.0 Hz, 1H), 5.28 (dt, J = 17.2 Hz, J = 1.3 Hz, 1H), 5.19 (dt, J = 10.4 Hz, J = 1.3 Hz, 1H), 13 1 2.22 (s, 3H); C{ H} NMR (100 MHz, CDCl 3): δ = 155.8 (C), 140.3 (C), 138.1 (C), 130.2 (CH), 129.8 (CH), 128.6 (CH), 127.8 (CH), 126.6 (CH), 116.4
(CH 2), 116.1 (CH), 81.0 (CH), 20.5 (CH3).
36 Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004 , 126 , 1628 1629.
114