REVISTA BOLIVIANA DE QUÍMICA (Rev.Bol.Quim.) Vol. 33, No.3, pp. 127-133, Jul./Ago. 2016 Bolivian Journal of Chemistry 33(3) 127-133, Jul./Aug. 2016 Received 08 23 2016 Accepted 09 12 2016 Published 09 15 2016

Bravo et Vila .

SYNTHESIS OF ALKENES: CLAISEN REARRANGEMENT OF ALLYL VINYL ETHERS, PART III; MECHANISTIC VIEWS; THE ORGANIC CHEMISTRY NOTEBOOK SERIES, A DIDACTICAL APPROACH, Nº 11

José A. Bravo1,*, José L. Vila2

1Department of Chemistry, Research Institute of Natural Products IIPN, Laboratory of Phytochemistry, Universidad Mayor de San Andrés UMSA, P.O. Box 303, Calle Andrés Bello s/n, Ciudad Universitaria Cota Cota, Phone 59122792238, La Paz, Bolivia, [email protected]

2Department of Chemistry, Research Institute of Natural Products IIPN, Laboratory of Synthesis and Hemi- synthesis of Natural Products, Universidad Mayor de San Andrés UMSA, P.O. Box 303, Calle Andrés Bello s/n, Ciudad Universitaria Cota Cota, Phone 59122795878, La Paz, Bolivia, [email protected]

Keywords: Organic Chemistry, Alkenes, Allyl vinyl ethers, Claisen rearrangement, Mechanisms of Reactions, W. Carruthers.

ABSTRACT

This is the eleventh theoretical assay in the series: “The Organic Chemistry Notebook Series, a Didactical Approach”. The aim of this series of studies is to help students to have a graphical view of organic synthesis reactions of diverse nature. We have taken a series of reactions compiled by W. Carruthers in ‘Some modern methods of organic synthesis’, and we have proposed didactical and mechanistic views for them. This theme is included in the chapter “Formation of carbon-carbon double bonds” in the mentioned text. In chapter 11, we expose a complementing of Claisen rearrangements of ally-vinyl ethers started two papers ago. Now it’s turn for the use of a variation of the Claisen rearrangement: the ester-enolate variation (also known as the ketene acetal variation). In this sense, the synthesis of the natural product: methyl santolinate is briefly exposed in a mechanistic manner. Also, the mechanism of the synthesis of -unsaturated amino acid derivative and ulterior lactone hydrochloride from the Z-crotyl glicine ester is proposed on the basis of theoretical approaches. The condensation between allylic alcohols and cyclic orthoesters to produce (via Claisen rearrangement) lactones with the inverted allyl group as a  substituent is mechanistically exposed. Vinyl lactones can be converted into cycloalkenes (via Claisen rearrangement of cyclic enol ethers); we’ve analyzed the mechanism.

*Corresponding author: [email protected]

RESUMEN Spanish title: Síntesis de alquenos mediante transposición de Claisen de éteres alil-vinílicos, parte III; vistas mecanicísticas; de la serie: El cuaderno de notas de química orgánica, un enfoque didáctico, Nº11. Este es el décimo ensayo teórico en la serie: “El cuaderno de química orgánica, un enfoque didáctico”. El objetivo de esta serie de estudios es ayudar a los estudiantes a disponer de una visión gráfica de reacciones de síntesis orgánicas de diversa naturaleza. Hemos tomado una serie de reacciones compiladas por W. Carruthers en: ‘Some modern methods of organic synthesis’, para las cuales hemos propuesto vistas mecanicísticas y didácticas. Este tema esta incluido en el capítulo “Formation of carbon-carbon double bonds” del mencionado texto. En el capítulo 11 exponemos un complemento de la transposición de Claisen de éteres alil-vinílicos comenzado hace dos artículos. Ahora es turno del uso de una variación de la Transposición de Claisen: la variación ester-enolato (conocida también como variación ceteno acetal). En este sentido, la síntesis del producto natural santolinato de metilo es expuesta brevemente en una manera mecanicística. También el mecanismo de la síntesis de derivados de amino acido -insaturados y producción del ulterior clorhidrato de lactona a partir de ester de Z-crotyl glicina es propuesto sobre la base de enfoques teóricos. La condensación entre alcoholes alílicos y ortoésteres cíclicos para dar lactonas con un grupo alilo invertido como sustituyente en , se expone mecanicísticamente. Vinil lactonas pueden convertirse en cicloalquenos vía transposición de Claisen de enol éteres; hemos propuesto el mecanismo.

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Bravo et Vila . INTRODUCTION

During master classes of organic chemistry, we noticed that students are confronted with a lack of knowledge with regard to mechanisms. A mechanistic approach about any kind of reaction enhances the capacity of facing new reactions with respect to an understanding of all processes involved in them, and also develops synthetic creativity. As academics we feel concerned with the didactical importance of covering these needs in debutant students in organic synthesis. This, the synthesis of alkenes by Claisen rearrangement of allyl vinyl ethers, part III; mechanistic views; is the eleventh study in the series: “The Organic Chemistry Notebook Series, a Didactical Approach” [1-10].

REACTIONS AND THEIR MECHANISTIC PROPOSALS, DISCUSSION

The variation of the Claisen rearrangement: the ester enolate (known also as the ketene acetal variation) is useful in stereocontrolled synthesis of natural products. Methyl santolinate 25, an irregular monterpene can be synthesized from propionate ester 23, which gives mainly the Z-ketene acetal 24 and this gives 25. The reaction is carried on lithium isopropylcyclohexylamide in THF and after on t-butyldimethylsilyl chloride [11]. The reaction path is: C.R. (Claisen Rearrangement) at 650C followed by hydrolysis and esterification by using diazomethane to give santolinate with high stereoselectivity [11,12]. See Figure 1 for the schematic reaction and its proposed mechanism.

Comments

The propionate ester (23) forms a six membered cycle in the chair form with lithium and nitrogen. The nitrogen extracts a proton from the  carbon of the ester. The formed carbanion establishes an alkene by dispatching the “pi” electrons of the carbonyl over the oxygen atom which after establishes a covalence with Li+ (or at least neutralizes it ionically). The tert-butyldimethylsilyl chloride interchanges its anion (Cl-) with RO-. Thus, with this alkoxy protected (24), the Claisen rearrangement (C.R.) becomes effective to form the -alkene. There follows the separation of the protecting group, the tert-butyldimethylsilyl group from the substrate, and generates a hydroxyl group of an acid function. Final methylation converts the hydroxy group into a methoxy by the action due to diazomethane to afford methyl santolinate (25). Another synthetic pathway employing a C.R. uses the Z-crotyl glycine ester 26 which is converted in the - unsaturated amino acid derivative 27a which at its turn converts into the lactone chloride 28. This is a natural product isolated from Amanita phalloides (Green Death Cap Toadstool), after hydrolysis of - and -amanitin (toxic cyclic peptides) [13,14]. When the transition state is assumed to be a chair-like conformer (29), the stereochemical pathway of the rearrangement implies that the intermediate ketene acetal presents mostly the stereochemistry E (26’) instead of the Z-configuration [13,15]. This is the general case for esters of acids with a heterosubstituent on the - carbon like -amino and -hydroxy acids [15,16]. See Figure 2 for the reaction scheme and Figure 3 for the corresponding mechanistic proposal.

Comments

- The ester 26 is submitted to the alkali action of LiN(iso-pr)2 to afford the anion N . A charge transfer occurs from nitrogen to oxygen. Every negative charge is neutralized at any moment by Li+. In this condition, the interaction of the lithiated substrate and another equivalent of LiN(iso-pr)2 takes place under the form of the six membered cycle in the chair form conformed by the adduct of 26-Li + LiN(iso-pr)2. The nitrogen of LiN(iso-pr)2 takes a hydrogen from the substrate currently under the form of a chair six membered cycle, generating thus a carbanion in the substrate. + The tetravalent nitrogen positively charged [LiN H(iso-pr)2] recovers neutrality and its tri-valence by excision of its covalence to Li. The Li cation thus formed makes ionic pair with the negative charge now situated on the oxygen of carbonyl after charge transfer from the carbanion; a new carbon-carbon double bond has formed. Lithium stabilizer is replaced by silicon of trimethylsilyl chloride through a nucleophilic attack of the enol oxygen of substrate to silicon of TMS chloride to expel Cl-. The same happens to the other Li+O- couple in the substrate. This substrate with two protected enol groups (26’) suffers the Claisen rearrangement to afford the -alkene. Acid hydrolysis withdraws the protecting group trimethylsilyl at the carbonyl adjacent position. The second protecting group (OSiMe3) is withdrawn by methanolysis after protonation. Follows a deprotonation of the methoxy group and protonation of the nitrogen. This protic catalysis promotes the elimination of the methyl of the methoxy group and formation of a + – carbonyl group. The carbocation Me establishes a bond with the anion OSiMe3 to give MeOSiMe3, we´ve reached the intermediate 27a (Fig. 3).

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Bravo et Vila .

OSi(CH3)2C4H9 H O (1) LiN(iso-pr)(C6H11) CH3O2 CH3 THF, -78oC O (1) 65oC (2) CH3CO2H-H2O O (2) t-C4H9(CH3)2SiCl (3) CH2N2 H

23 24 25

Mechanism for 25 OR' OR' O O O O - CH3 .. CH3 (1) LiN(iso-pr)(C6H11) H H O O THF, -78oC Li Li 23 H H N +N OR' OR' -O OLi OSiMe -t-but O - CH3 2 .. CH3 H H R' (2) t-C4H9(CH3)2SiCl + O O Li +Li H CH H N 3 N 24

OSiMe2-t-but OSiMe2-t-but O O O O O C.R.

CH3 Me2BuSiO H Me2BuSiO H OSiMe2-t-but 24 OSiMe -t-but O 2 O CH3

H O H CH COOH/H O H 3 2 Me2BuSiO Me2BuSiO H H O H o H H3C H 180 CH3 OSiMe2-t-but

...... - + O+H OH O-CH -N=N - H OSiMe2-t-but 2 2 : OCH2 OCH3 CH CH CH CH + N + H+ H2O: 3 3 3 3 CH3 2 CH3 CH2 O H O H -H+ O H O H O H O H + H H H N N H H H

25 Figure 1. Claisen rearrangement; synthesis of methyl santolinate (25) from propionate ester (23); reviewed by W. Carruthers [11]. Mechanistic views by the authors

O OSi(CH3)3 H (1) 2 equiv. LiN(iso-pr) t-C4H9OCONH 2 t-C4H9O N t-BocNH CO2H O THF, -75oC O (1) reflux H3C H3C (b) OSiMe (2) CH OH (2) 2(CH3)3SiCl 3 3 H H H CH3 26 26' + 27 O H - + t-BocNH CO2H H Cl H3N O several steps O (a) R1 H C N 3 CH3 H (CH3)3SiO R2 OH 29 28

Figure 2. Claisen rearrangement; synthesis of lactone hydrochloride (28) from Z-crotyl glycine ester (26); reaction passes by ketene acetal intermediate with the E-configuration (26’); reviewed by W. Carruthers [13].

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Bravo et Vila . Mechanism for 27a O H O O O + 1 equiv. LiN(iso-pr)2 - t-C4H9OCONH O N O N Li O N O O THF, -75oC O O H C 3 - O O O Li+ H 26 OR' OR' R' O OR' O O H H O N O N O N - O OR' .. O N H Li Li -.. - + - + - + + O Li O Li O Li - +Li H + H O Li i-pr N i-pr N H i-pr N i-pr i-pr i-pr OR' OR' OSiMe2 OSiMe Me2SiO 2 -O O N H 2Me2SiCl O N H O N O N OR' O Li+ O-Li+ H H H OSiMe2 OSiMe2 OSiMe2 i-pr N 26' i-pr OSiMe 2 H H H O O O N O O C.R. H H Me2SiO Me2SiO Me2SiO OSiMe N OSiMe3 N OSiMe3 N 2 Me

O O OSiMe3 O O H H OSiMe 3 OSiMe3 Me SiO o 3 CH3 Me OSiMe3 H O 180 O H H N O N O N O o N 180 Me OSiMe H O 3 Me3SiO Me OSiMe3 O OSiMe3 H H

+ + OSiMe3 H2O H OSiMe3 H2 O HO O H O H O H O H + + N O H2O, H N O N O -H N O Me3SiO Me Me3SiO Me Me3SiO Me Me3SiO Me H H H H - CH3OH + OSiMe3 HO HO HO O O H O H O H H O H H + N O -H N O +H+ +N O N OH CH O+H Me Me Me Me 3 CH3O H3C O O H H H H 27a + MeOSiMe3 O H- O O O O H H O H H O H H H H H - N O+H N O+H N O+H O H N O+H Me Me Me + Me O O -O H H H H O H2C H H- H2C H2C H2C O O O - H H Cl H + H3N H2N NaOH H2N 2HCl Me O Me O O - + Me H H C Na H C H + NaCl H2C H2C H2C OH OH 28 Figure 3. Claisen rearrangement; synthesis of lactone hydrochloride (28) from Z-crotyl glycine ester (26); reaction passes by ketene acetal intermediate with the E-configuration (26’); reviewed by W. Carruthers [13]. Mechanistic views by the authors

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Bravo et Vila . The -unsaturated carboxylic acid 27a suffers lactonization by means of an intracyclic nucleophilic attack over the alkenic double bond. The -lactone formed incorporates a terminal vinyl group by means of elimination of hydride which attacks the carbonyl group becoming thus a temporary alkoxy group. The alkoxy group regenerates the carbonyl and provokes the excision of the molecule by means of breaking the bond C-N. The -vinyllactone is now protonated. A proton transfer betweenthe positively charged oxygen and the anionic nitrogen gives the substrate electronic stability again. The hydroxyl addition over the vinyl terminal methylene occurs to afford a terminal primary alcohol. The lactone cycle resists against ring rupture and the electronic excess settles now over the quaternary carbon of the terminal vinyl group. This anion forms ionic pair with cation sodium. One of two equivalents of HCl serves to withdraw cationic sodium which makes couples with one Cl- and installs a proton over the carbanion . The other HCl equivalent protonates the nitrogen which makes ionic pair with Cl-. We´ve reached the product 28 (Fig. 3). It’s been established that the C.R. of vinyl ethers of acyclic allylic alcohols happens through T.S. of the chair type [15]. There are other examples where the substrates own a double bond of vinyl ether or of allylic alcohol as part of a cycle [15]. In such case, the T.S. is a well-defined boat conformer [15]. The T.S. in the chair form in these cases implies much strain [15]. For example, let’s see the reaction between allylic alcohols and cyclic orthoesters that through Claisen rearrangement give lactones with the allyl group inverted as an -substituent [15]. The cyclic orthoester 29 reacts with the cyclic allyl alcohol 30; the product is lactone 31. The yield was 80 % and the stereoselectivity complete. The configuration of the chiral center at the cyclohexene is controlled by the configuration in the allylic hydroxyl group which is a leaving group. Regarding the configuration of the chiral center in the lactone, this is determined by the conformation of the chair type or the boat type of the transition state. Thus, the stereochemistry of 31 indicates that the reaction was carried on through a transition state of the boat type [15,16]. See Figure 4.

catalytic CH3CH2CO2H + O O reflux H5C6CO2 1,2-dimethylbenzene H H5C2O OC2H5 O OH H5C6CO2 29 30 31

Mechanism for 31 H H H H

CH3CH2CO2H C.R. Ph O Ph O + EtOH Ph O Ph O H H OH H+O O O H O H O O H O O H O 30 O H5C2O O H+OC H OC2H5 2 5 boat-like T.S. + 29 H OC2H5 Ph O

O   O H H H H O O O H5C6CO2 31 31

Figure 4. Claisen rearrangement; reaction of cyclic orthoester 29 with allylic alcohol 30 to form lactone 31 (-unsaturated lactone); reviewed by W. Carruthers [15]. Mechanistic views by the authors

Comments

Although the orthoester tri-oxygenated carbon (29) manifests a lower electrophilicity than the carbonyl carbon of the benzoyl substituent in 30, proved by the fact of the lower chemical shift value of the O3C from orthoester with respect of carbonyl carbon (o3c 114.2 vs. c=o 166.8 of methyl benzoate [17,18 respectively]), the nucleophilic + attack occurs over the H O3C from orthoester instead of the benzoyl carbonyl. The reason is attributable to the protic catalysis from propionic acid, experimented firstly by one of the oxygen atoms of the O3C from orthoester instead of the carbonyl oxygen. By statistic reasons the catalyst interacts firstly with one of the oxygen atoms of the O3C instead of the carbonyl’s oxygen. In this three-oxygen group, the oxygen atoms are closer each other. In contrast, the + benzoate presents only two oxygen atoms. This fact makes of this carbon (H O3C) a preferred nucleophile attack site in the mixture instead of the carbonyl of benzoate (O=C-O with no H+ catalyst, 30). We mean by this that the

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Bravo et Vila . + electrophile is the H O3C of the orthoester (29) and the nucleophile, the hydroxyl oxygen of the allylic alcohol (30). On the contrary, due to the protic catalysis, a nucleophilic attack of the nucleophile oxygen from any of the ethoxy protonated groups of the orthoester (29) over the electrophile carbonyl carbon of the unprotonated benzoate of the + allylic alcohol, is not feasible. The nucleophilic attack over carbonyl or H O3C from ester depends on polar and + steric factors. In spite of the fact that H O3C from ester is tetrahedral and the carbonyl carbon is planar (steric + + factor), the polar factor (generated by the H catalyst) drives the nucleophile (ROH) towards the H O3C from ester. The benzoate-orthoester adduct transfers the catalyst from the recently formed (so far protonated) ether bridge to one of the ethoxy groups of the ester moiety of the adduct. This good leaving group leaves the adduct forming a carbocation (not graphically described in Fig. 4). The presence of the carbocation charge promotes a proton elimination from the vicinal CH2 group to form an alkene. Both moieties are now situated in a transition state in the boat form. This mutual position makes the Claisen rearrangement possible to afford the final product 31. In a series of reactions related to those exposed above, vinyl lactones 32 are converted into cycloalkenes through Claisen rearrangements using cyclic enol ethers 33. Un such reactions, the stereochemistry of the products implies a transition state employing a boat conformation [15,19]. See Figure 5.

H C H3C CO H H3C H 3 2 C H O OSi(CH3)2C4H9-t 2 5 (1) LiN(iso-C3H7)2 (1) Toluene, 105°C H O (2) t-C4H9(CH3)2SiCl O (2) CH3OH

H (71%) C2H5

C2H5 vinyl lactone cyclic enol ether 32 33 34 Mechanism for 34

t-but t-but Me O O O- Me O Si Si Cl H Me .. Me C.R. vinyl lactone O O H H O H O H H H cyclic enol ether H boat-like T.S. H + Cl- N + + + 32 Li N N 33 N Li Li Li

t-but t-but Me Me t-but -O Si HO Si H Me H H H3C CO2H H O Si H + Me H Me C H HOMe O HMe OMe 2 5 Me H O O O H H H 34

Figure 5. Claisen rearrangement; transformation of vinyl lactone 32 via cyclic enol ether 33 to afford 34 (-unsaturated carboxylic acid); reviewed by W. Carruthers [15]. Mechanistic views by the authors

Comments

In step one of the mechanism for 34, the strong base NLi(i-pr)2 extracts the acidic hydrogen in  of carbonyl of the substrate 32. Thus, the just formed carbanion derives into a C-C double bond by p-orbital overlapping, sending thus the “pi” bond of carbonyl over the carbonyl oxygen. The oxygen atom (nucleophile) attacks silicon (electrophile) + and expels chloride (leaving group) which makes ionic pair with the quaternary ammonium: N LiH(i-pr)2. The oxydimethylterbutyl cyclic enol ether suffers the Claisen rearrangement employing a transition state in the boat type. This operation affords the -unsaturated carboxylic acid silylated. Methanolysis gives rise to final product 34.

ACKNOWLEDGEMENT

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Bravo et Vila . The authors express their gratitude to Prof. Eduardo Palenque from the Department of Physics, Universidad Mayor de San Andrés, for his bibliographic support.

REFERENCES

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