Pinner reaction

Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine. 

aryl R = Me, Et, 1° and 2° alkyl, aryl HX = HCI, HBr solvent CHCI3, benzne, nitrobenzene, dioxane, (EtOH, 

MeOH) base NaHCOs, Na2COs acid HCI, H2SO4 

The first stereoselective total synthesis of AI-77B, a gastroprotective substance, was accomplished by Y. Hamada and co-workers. In the final stages of the synthetic effort, the intramolecular Pinner reaction was utilized to convert the cyano group into the corresponding carboxylic acid. The nitrile substrate was dissolved in 5% HCI in methanol, and excess trimethyl orthoformate was added at 5 °C and the reaction mixture was stirred at this temperature for almost two days. Next, the cyclic imino ether hydrochloride salt was treated with water at room temperature followed by basic hydrolysis. Finally, the pH was adjusted with HCI to obtain the natural product. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 203, Springer-Verlag Berlin Heidelberg 2009 

Racane, L. TraUc-Kulenovic, V. MihaUc, Z. Pavlovic, G. Karminsld-Zaniola, G. Tetrahedron 2008, 64,11594-11602. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 217, Springer International Publishing Switzerland 2014 

---

Furthermore, macro-azo-initiators have also been synthesized by direct condensation of AIBN with diols (Pinner reaction, [42,43]) or formaldehyde [44,45]. The... 

In the first step, (R)-2-chlorobenzaldehyde cyanohydrin is prepared by the almond meal-catalyzed addition of HCN to 2-chlorobenzaldehyde. The cyanohydrin is then transformed into the corresponding 2-hydroxy ester by Pinner reaction. Subsequently, the hydroxy group is activated by sulfonylafion and reacted with tetrahydrothieno[3.2-c]pyridine to give, under complete inversion of configuration, the (5 ) — a-amino acid derivative CLOPIDOGREL. ... 

The first synthesis of acylglycine dithioester derivatives was described by Storer et al.[86l Their synthesis begins with the Pinner reaction 86 88 89 of the corresponding aminoacyl nitrile 39 in the presence of ethanethiol and HC1 gas to produce a thioimidoester hydrochloride 40. Use of an alcohol instead of a thiol gives the thionoesterJ90 The thioimidoester 40 was then treated with H2S gas in the presence of pyridine to yield the dithioester 41 (Scheme 18).[861... 

This approach eliminates the problem of the low solubility of TV-acylaminonitriles in HC1 saturated CH2C12 used in the classical Pinner reaction. Overall yields were greatly improved with more reactions in the 60-70% range. The only limitation of this method is the incompatibility of some N-protecting groups with HF. 

PINNER REACTION. Formation of imino esters (alkyl imidates) by addition of dry hydrogen chloride to a mixture of a nitrile and an alcohol. Treatment of alkyl imidates with ammonia or primary or secondary amines affords amidines. while treatment with alcohols yields ortho-esters. 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

The most common method for synthesizing peptide dithioesters is based on the Pinner reaction. N-Protected peptide nitriles react with thiols in the presence of HQ to give imi-dothioic acid ester hydrochlorides that are treated with H2S (Section 15.1.11.1). 1 61 A modification of this procedure is made by dissolving the nitriles in liquid HF and reacting with thiols to form imidothioic acid ester hydrofluorides, followed by thiolysis with H2S (Section 15.1.11.1.1). 7 The second approach is to synthesize the thiopiperidide derivative using Lawesson s reagent, followed by S-methylation with iodomethane and thiolysis with H2S (Section 15.1.11.2). 4 A modification of the Lawesson s procedure via a thioamide is also used to prepare amino acid dithioesters (Section 15.1.11.2.1). 8 ... 

Reaction of Nitriles with Thiols via Imidothioic Acid Ester Hydrochlorides (Pinner Reaction)... 

A few a-acylamino dithioesters were successfully synthesized by the Pinner reaction in the early 1970s. 6 9 However, many amino acid and peptide dithioesters have now been prepared by this procedure and used for the synthesis of endothiopeptides 10 and spectroscopic studies of dithioesters. 1 ... 

A modification of the Pinner reaction using liquid HF has been used to improve the yields of the dithioester products. The N-protected amino acid and peptide nitriles 6 dissolve in liquid HF at temperatures below 0°C and react with thiols to form the imidothioic acid ester hydrofluorides 7 that further react with H2S in pyridine at 0°C to form the dithioesters 8 (Scheme 2)J71 Several isotopic dithioesters have been synthesized by this method with improved yield (Table 2). The use of liquid HF at low temperature helps to dissolve the amino acid nitriles that are not very soluble under Pinner conditions (HCl-saturated CH2C12). 

Amino acid dithioesters have been used as building blocks for the synthesis of en-dothiopeptides, the dithioesters will condense with a-amino groups of N-unprotected amino acids to form thioamides. Preparation of optically active amino acid dithioesters and subsequent formation of thioamide bonds without racemization are two problems that need to be addressed when using this approach to prepare endothiopeptides. The Pinner reaction (Section 15.1.11.1) 1 and Lawesson s procedure (Section 15.1.11.2)M have been successfully used to prepare optically active amino acid dithioesters a modification of Lawesson s procedure via thioamides is also successful.[81... 

When dinitrile 19 was subjected to Pinner reaction conditions, and the imidate was then hydrolyzed, the desired 7 was obtained quantitatively and as a single diastereomer (Scheme 7). Only the equatorial CN group of 19 underwent the Pinner reaction the axial CN group remained complete-... 

The Pinner Reaction is the partial solvolysis of a nitrile to yield an iminoether. Treatment of the nitrile with gaseouc HC1 in a mixture of anhydrous chloroform and an alcohol produces the imino ether hydrochloride. These salts are known as Pinner Salts, and may react further with various nucleophiles. 

This reaction is known as the Pinner synthesis. The salt formed may be converted to the free imino ester by treatment with a weak base. It may also be converted to the corresponding ester by an aqueous acid catalyzed hydrolysis. The Pinner reaction is of a general nature and is applicable to aliphatic, aromatic and heterocyclic alcohols. 

The right side of Figure 7.13 shows the details of the different variants of the Pinner reaction described above. The addition of methanol to the C=N triple bond follows the mechanism of the nitrile hydrolysis under acidic conditions (cf. Figure 7.8). 

An alternative method for preparing the Step 5 product is described by Cozzi (1), which uses Pinner reaction conditions with V-methyl-4-[(lV -methyl-4-nitro-pyrrolyl-2-yl)carbonylamino]-pyrrole-2-carboxylic acid-2-cyanoethylene, (II). 

The Pinner reaction is a standard method for preparing orthoesters that involves treatment of a nitrile with an alcohol in the presence of anhydrous HCL Voss and Gerlach236 used a Pinner reaction to prepare a robust orthoester from cfr-cyclohexane-l,3,5-triol [Scheme 2.114]. The method is obviously limited to substrates that can withstand the harsh acidic conditions required in the first step. 

Other iminocarboxylic carboxylic acid derivatives have been prepared by reacting an hydroxyimino derivative with 2-coumaranone followed by the Pinner reaction of the Step 1 product (2,3) as illustrated in Eq. 4 ... 

The Pinner reaction is the standard method of preparing imidate salts (the free imidate is obtained upon basification with weak bases) by alcoholysis of nitriles in the presence of mineral acids. However, this method is not suitable for the synthesis of allylic imidates since, under these reaction conditions, allylic amides, the product of the Ritter reaction, are formed. The acetimidates are easily prepared by condensation of the sodium or potassium alcoholate with trichloro- or trifluoroacetonitrile in high yield. For the rearrangement reaction the crude imidates can be used. 

---