Petasis reaction

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Petasis reaction
Named after Nicos A. Petasis
Reaction type Coupling reaction
Organic Chemistry Portal petasis-reaction
RSC ontology ID RXNO:0000232

The Petasis reaction (alternatively called the Petasis borono–Mannich (PBM) reaction) is the chemical reaction of an amine, aldehyde, and vinyl- or aryl-boronic acid to form substituted amines.

The Petasis reaction

Reported in 1993 by Nicos Petasis as a practical method towards the synthesis of a geometrically pure antifungal agent, naftifine, the Petasis reaction can be described as a variation of the Mannich reaction.[1] Rather than generating an enolate to form the substituted amine product, in the Petasis reaction, the vinyl group of the organoboronic acid serves as the nucleophile. In comparison to other methods of generating allyl amines, the Petasis reaction tolerates a multifunctional scaffold, with a variety of amines and organoboronic acids as potential starting materials. Additionally, the reaction does not require anhydrous or inert conditions. As a mild, selective synthesis, the Petasis reaction is useful in generating α-amino acids, and is utilized in combinatorial chemistry and drug discovery.[1][2][3][4][5][6]

Reaction mechanism[edit]

The mechanism of the Petasis reaction is not fully understood; however, it is similar to the Mannich reaction at its early stage. In the Mannich reaction, an imine or iminium salt serves as the electrophile to which the nucleophile adds; however, in the Petasis reaction it is not clear which intermediate serves as the electrophile. Petasis proposes that the reaction is characterized by a complex equilibrium among the three starting materials and various intermediates, and the final product is formed via a rate-determining and irreversible C-C bond formation step. The condensation between amine 1 and carbonyl 2 forms hemiaminal 4, which is in a complex equilibrium with iminium ion 3 and aminal 5. Boronic acid 6 react with hemiaminal 4 and aminal 5 in a reversible fashion via intermediate 7 and 8 respectively, forming again electrophilic iminium ion 3, this time accompanied by nucleophilic boronate 3’. Note that there are no evidences suggesting that boronic acid alone can directly react with iminium ions: In addition to needing acid for an appreciable amount of iminium salt to be generated, it has been shown that vinyl boronic acids do not react efficiently with preformed iminium salts (like Eschenmoser’s salt). The irreversible C-C bond migration between 3 and 3’then follows, furnishing desired product 9 with loss of boric acid. All intermediates will ultimately lead to the final product, as the reaction between 3 and 3’ is irreversible, pulling the equilibrium of the entire system towards the final product.[7]

Petasis reaction with equilibrium relationships

Density functional theory (DFT) studies have been performed to study the mechanism of Petasis reaction. Starting with the Petasis reaction between glyoxylic acid, dimethylamine and phenylboronic acid, Gois et al. reported that the migration of the boronic acid substituent (phenyl group) of the "ate complex" A incurs an energy barrier of 10kcal/mol and a five-membered transition state B.[8] Formation of quaternary boron salts during the reaction has been experimentally confirmed by Hansen and coworkers. They reported that, in the absence of amine, an upfield 11B shift is observed after the addition of glyoxylic acid to a solution of phenylboronic acid. This is presumably due to the formation of electron rich boronate species.[9]

Petasis Mechanism_transition state and energy barrier


The Petasis reaction proceeds under mild conditions, without the use of strong acids, bases, or metals. Unlike the Strecker and Ugi syntheses, the Petasis reaction avoids the use of cyanide and isocyanide reagents. The amine is mixed with the carbonyl substrate using either dioxane or toluene as a solvent at 90 °C for 10 minutes. Subsequently, the boronic acid is added to the mixture and product is generated, either after 30 minutes at 90 °C, or after several hours at 25 °C. In α-amino acid synthesis, α-keto acids, such as glyoxylic and pyruvic acid, are stirred in ethanol, toluene, or dichloromethane with amines and vinyl boronic acids at 25–50 °C for 12–48 h to give the corresponding β,γ-unsaturated compounds.[1]

Alpha amino acid synthesis

One of the most attractive features of the Petasis reaction is its use of boronic acids as a nucleophilic source. Unlike most vinyl substrates, vinyl boronic acids are stable to air and water and can be removed during workup with a simple extraction. Many boronic acid derivatives are easy to prepare and with the advent of the Suzuki coupling, a larger number of them are now commercially available. In the seminal report of the reaction, the organoboronic acids were prepared by hydroboration of terminal alkynes with catecholborane.[1]

organoboronic acid synthesis

Other methods of generating boronic acids were also reported.[10][11]

Reaction scope and synthetic applications[edit]

A wide variety of functional groups including alcohols, carboxylic acids, and amines are tolerated in the Petasis Reaction. Known substrates that are compatible with reaction conditions include vinylboronate esters, arylboronate esters, and potassium organotrifluoroborates.[12][13][14] Additionally, a variety of substituted amines can be used other than secondary amines. Tertiary aromatic amines, hydrazines, hydroxylamines, sulfonamides, and indoles have all been reported.[15][16][17][18]

Synthesis of allyl amines
Petasis and coworkers proposed, in their seminal study, that vinyl boronic acids can react with the adducts of secondary amines and paraformaldehyde to give tertiary allylamines. The geometry of the double bond of the starting vinyl boronic acid is completely retained in the final product. Yield is typically in the good to excellent range. The following reaction is particularly effective, hitting a yield of 96%:[1]

geometrically pure allylamines

Petasis and coworkers used this reaction to synthesize naftifine, a very potent topical antimycotic, in one step in 82% yield. Other compounds with related structure include terbinafine and NB598.[1]

synthesis of naftifine

Synthesis of amino acids
β,γ-unsaturated, N-substituted amino acids are conveniently prepared through the condensation of organoboronic acids, boronates, or boronic esters with amines and glyoxylic acids. Yields are typically in the range of 60–80%, and a wide variety of polar or non-polar solvents can be employed (although DCM and MeOH is typically used). Free amino acids that do not have N-substitutions can be prepared by using trityl amine or bis-(4-methoxyphenyl)methyl amine, followed by deprotection under aciic conditions.[2] Piettre and coworkers found out that the usage of highly polar protic solvents like Hexafluoroisopropanol (HFIP) can shorten reaction time and improve yield. Microwave irradiation was also be used to promote the reaction in methanol.[19]

PBM coupling to synthesize amino acid with HFIP solvent

Apart from vinyl boronic acids, aryl boronic acids and other heterocyclic derivatives can also be used in Petasis multicomponent coupling. Possible substrate scope includes thienyl, pyridyl, furyl, and benzofuranyl, 1-naphthyl, and aryl groups with either electron-donating or electron-withdrawing substituent.[12]

PBM coupling to synthesize aryl glycine

Clopidogrel, an antiplatelet agent, was racemically synthesized by Kalinski and coworkers in two steps, using Petasis reaction as the key strategy. Acid-catalyzed esterification immediately following the multicomponent coupling steps to afford Clopidogrel in 44% overall yield.[20]

synthesis of clopidogrel via PBM coupling

The Petasis reaction exhibits high degrees of stereocontrol when a chiral amine or aldehyde is used as a substrate. When certain chiral amines, such as (S)-2-phenylglycinol, are mixed with an α-keto acid and vinyl boronic acid at room temperature, the corresponding allylamine is formed as a single diastereomer. Furthermore, enantiomeric purity can be achieved by hydrogenation of the diastereoselective product. In the reaction with (S)-2-phenylglycinol, (R)-2-phenylglycinol is generated in 76% yield.[1]

stereoselective alpha amino acids

Unconventional synthesis of carboxylic acids
Apart from amino-acids, Petasis borono-Mannich reaction can also be used to prepare carboxylic acids, albeit with unconventional mechanisms. Naskar et al. reported the use of N-substituted indoles as amine equivalent. The mechanism begins with the nucleophilic attack of the 3-position of the "N"-substituted indole to electrophilic aldehyde, followed by formation of "ate complex" 1 via the reaction of boronic acid with the carboxylic acid. The intermediate then undergoes dehydration, followed by migration of boronate-alkyl group to furnish the final carboxylic acid product. The yield is in the moderate to good range (40–70%). A wide range of aryl boronic acids is tolerated, while the usage of vinyl boronic acids is not reported. It is interesting to note that "N"-unsubstituted indoles react very sluggishly under normal reaction conditions, thus confirming the mechanism below.[18]

PBM coupling with N-substituted indole

Naskar et al. also proposed the usage of tertiary aromatic amines in Petasis reaction as another equivalent of amine nucleophile. The mechanism is similar to the N-substituted indole case. The reaction is carried out under harsh conditions (24-hr reflux in 1,4-dioxane), but the resultant carboxylic acid is obtained in reasonable yield (41–54% yield). Note that the usage of α-ketoacids instead of glyoxylic acid does not diminish yields. 1,3,5-trioxygenated benzene derivatives can also be used in lieu of tertiary aromatic amines.[17]

PBM coupling with trisubstituted aromatic amine

Synthesis of iminodicarboxylic acid derivatives
When used as nitrogen nucleophiles, amino acids can furnish various iminodicarboxylic acid derivatives. High diastereoselectivity is usually observed, and the newly formed stereocenter usually share the same configuration with the starting amino acid. This reaction works well in highly polar solvents (ex. water, ethanol, etc.). Peptides with unprotected nitrogen terminal can also be used as a nitrogen nucleophile equivalent. Petasis and coworkers prepared Enalaprilat, an ACE inhibitor, with this method.[7]

synthesis of Enalaprilat via PBM coupling

Synthesis of peptidomimetic heterocycles
When diamines are used in PBM reactions, heterocycles of various structures, such as piperazinones, benzopiperazinones, and benzodiazepinones, are efficiently prepared. Lactamization reactions are commonly employed to form the heterocycles, usually under strongly acidic conditions.[7]

preparation of Piperazinones, benzopiperazinones, and benzodiazepinones via PBM coupling

Synthesis of amino alcohols
When a α-hydroxy aldehyde is used as a substrate in the synthesis of β-amino alcohols, a single diastereomer is generated. This reaction forms exclusively anti-product, confirmed by 1H NMR spectroscopy. The product does not undergo racemization, and when enantiomerically pure α-hydroxy aldehydes are used, enantiomeric excess can be achieved. It is believed that the boronic acid first reacted with the chiral hydroxyl group, furnishing a nucleophilic alkenyl boronate, followed by face selective, intramolecular migration of the alkenyl group into the electrophilic iminium carbon, forming the desired C-C bond irreversibly. In the reaction of enantiomerically pure glyceraldehydes, the corresponding 3-amino 1,2-diol product is formed in 70% yield and greater than 99% ee.[3]

Stereoselective B amino alcohols

Pyne and coworkers suggested that diastereoselectivity arises from the reaction of the more stable (and, in this case, more reactive) conformation of the ate complex, where 1,3 allylic strain is minimized.[21][22][23]

diastereoselectivity of amino synthesis_mechanism and transition state

Using dihydroxyacetone, a somewhat unconventional aldehyde equivalent, Sugiyama et al. is able to use Petasis reaction to assemble the core structure of FTY720 (a potent immunosuppressive agent) in 40% yield. A straightforward hydrogenation then follows to afford the product via a one-step benzyl-group removal and C-C double bond hydrogenation.[24]

synthesis of FTY720

Synthesis of amino polyols and amino sugars
Petasis and coworkers reported the usage of unprotected carbohydrates as the carbonyl component in PBM reactions. It is used as the equivalent of α-hydroxyl aldehydes with pre-existing chirality, and the aminopolyol product is usually furnished with moderate to good yield, with excellent selectivity. A wide variety of carbohydrates, as well as nitrogen nucleophiles (ex. amino acids), can be used to furnish highly stereochemically-enriched products. The aminopolyol products can then undergo further reactions to prepare aminosugars. Petasis used this reaction to prepare Boc-protected mannosamine from D-arabinose.[7]

synthesis of Boc-protected Mannosammine

Applications in enantioselective synthesis[edit]

With chiral amine nucleophile
Generally speaking, when chiral amine is used in Petasis coupling, the stereochemical outcome of Petasis reaction is strongly correlated to the chirality of the amine, and high to excellent diastereoselectivity is observed even without the usage of bulky chiral inducing groups. Chiral benzyl amines,[25] 2-substituted pyrrolidines,[26] and 5-substituted 2-morpholinones[27][28] have been shown to induce good to excellent diastereomeric excess under different Petasis reaction conditions.

diastereoselective PBM coupling with chiral amine

With chiral N-acyliminium ions
Chiral N-acyliminium ion "starting materials" are generally prepared by in-situ dehydration of cyclic hemiaminal. They also carry a chiral hydroxyl group that is in proximity with the iminium carbon; boronic acids react with such chiral hydroxyl groups to form a chiral and electron-rich boronate species, followed by side-selective and intramolecular boronate vinyl/aryl transfer into the iminium carbon. Hence, the reaction is highly diastereoselective, with cis- boronate aryl/vinyl transfer being the predominant pathway. Hydroxypyrrolidines[29] and Hydroxy-γ- and δ-lactams[30] have been shown to react very diastereoselectively, with good to excellent yield. However, such procedures are limited to the usage of vinyl- or electron-rich aryl- boronic acids only.

diastereoselective PBM coupling with chiral N-acyliminium ion

Batey and coworkers take advantage of the high diastereoselectivity of this reaction to prepare (±)-6-deoxycastanospermine in 7 steps, with an impressive overall yield of 32% (from the vinyl boronic ester). The key acyclic precursor to deoxycastanospermine (A) is formed first by condensing vinyl boronic ester 1 with Cbz-protected hydroxy-pyrrolidine 2 with a PBM coupling, followed by dihydroxylation and TBS protetction. A then undergo intramolecular cyclization via a one-pot imine formation and reduction sequel, followed by TBS deprotection, to afford (±)-6-deoxycastanospermine.[31]

Deoxycastanospermine synthesis (Batey et al.)

With thiourea catalyst
Takemoto and coworkers of Kyoto University recently reported an enantioselective Petasis-type reaction to transform quinolines into respective chiral 1,2-dihydroquinolines (product) using alkenyl boronic acids and chiral thiourea catalyst. Good yields (59–78%) and excellent enantioselectivities (82–96%) are reported.[32]

Takemoto et al.

Takemoto and coworkers observed that addition of chloroformates are required as electrophilic activating agents, and the reaction does not proceed without them. Also, a 1,2-amino alcohol functionality is required on the catalyst for the reaction to proceed stereoselectively. They rationalize these findings by suggesting that the chloroformate reagent reacted with the quinoline nitrogen to make an N-acyated quinolinium intermediate B, which is further activated by electrophilic chiral thiourea. They also suggest that the 1,2-amino alcohol functionality of the catalyst is chelating to the alkenyl boronic acids and that such chelation directed the stereochemical outcome.[32]

Takemoto et al. transition state

With chiral biphenols
Schaus and Lou of Boston University reported the following reaction, in which chiral α-amino acids with various functionalities are conveniently furnished by mixing alkenyl diethyl boronates, secondary amines, glyoxylates and chiral biphenol catalyst in toluene in one-pot:[33]

Schaus reaction

This reaction tolerates a wide range of functionalities, both on the sides of alkenyl boronates and the secondary amine: the electron-richness of the substrates does not affect the yield and enantioselectivity, and sterically demanding substrates (dialkylsubstituted alkenyl boronates and amines with α-stereocenter) only compromise enantioselectivity slightly. Reaction rates do vary on a case-by-case basis.[33]
Interestingly, under the reported condition, boronic acids substrates failed to give any enantioselectivity. Also, 3Å molecular sieve is used in the reaction system. While the authors did not provide the reason for such usage in the paper, it was speculated that 3Å molecular sieves act as water scavenger and prevent the decomposition of alkenyl diethyl boronates into their respective boronic acids. The catalyst could be recycled from the reaction and reused without compromising yield or enantioselectivity.[33]
More recently, Yuan with coworkers from Chengdu Institute of Organic Chemistry, Chinese Academy of Science combined both approaches (chiral thiourea catalyst and chiral biphenol) in a single catalyst, reporting for the first time the catalytic system that is capable of performing enantioselective Petasis reaction between salicylaldehydes, cyclic secondary amines and aryl- or alkenylboronic acids:[34]

Yuan reaction

In one application the Petasis reaction is used for quick access to a multifunctional scaffold for divergent synthesis. The reactants are the lactol derived from L-phenyl-lactic acid and acetone, l-phenylalanine methyl ester and a boronic acid. The reaction takes place in ethanol at room temperature to give the product, an anti-1,2-amino alcohol with a diastereomeric excess of 99%.[35]

Petasis reaction example (Kumagai et al.)

Notice that the authors cannot assess syn-1,2-amino alcohol with this method due to intrinsic mechanistic selectivity, and the authors argue that such intrinsic selectivity hampers their ability to access the full matrix of stereoisomeric products for the usage of small molecule screening. In a recent report, Schaus and co-workers reported that syn amino alcohol can be obtained with the following reaction condition, using a chiral dibromo-biphenol catalyst their group developed:[36]


Although the syn vs. anti diastereomeric ratio ranges from mediocre to good (1.5:1 to 7.5:1), the substrate scope for such reactions remain rather limited, and the diastereoselectivity is found to be dependent on the stereogenic center on the amine starting material.[36]

Petasis reaction and total synthesis[edit]

Beau and coworkers assembled the core dihydropyran framework of zanamivir congeners via a combination of PBM reaction and Iron(III)-promoted deprotection-cyclization sequence. A stereochemically-defined α-hydroxyaldehyde 2, diallylamine and a dimethylketal-protected boronic acid 1 is coupled to form the acyclic, stereochemically-defined amino-alcohol 3, which then undergoes an Iron(III)-promoted cyclization to form a bicyclic dihydropyran 4. Selective opening of the oxazoline portion of the dihydropyran intermediate 4 with water or timethylsilyl azide then furnish downstream products that have structures resembling the Zanamivir family members.[37]

zanamivir core_Beau et al.

Wong and coworkers prepared N-acetylneuraminic acid with a PBM coupling, followed by nitrone-[3+2] cycloaddition. Vinylboronic acid is first coupled with L-arabinose 1 and Bis(4-methoxyphenyl)methanamine 2 to form an stereochemically-defined allyl amine 3. Afterwards, the sequence of dipolar cycloaddition, base-mediated N-O bond breakage and hydrolysis then complete the synthesis of N-acetylneuraminic acid.[38]

N-acetylneuraminic acid_Wong et al.

See also[edit]


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