Nitrile masked

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

TV-aluminum imines are another example of masked inline derivatives of ammonia. They are easily synthesized by partial reduction of nitriles with diisobutylaluminum hydride (D1BAL-H)6. Addition of lithium organic reagents to /V-aluminum iniines 7 derived from O-protected cyanohydrins 6 provides a-amino alcohols 8a and 8b in moderate yields and low to good diastereo-selectivities n 12. 

Gloves, nitrile and latex Tyvek spray suit Respirator or dust mask Protective eye wear, goggles or glasses... 

The Stille coupling reaction is very versatile with respect to the functionality that can be carried in both the halide and the tin reagent. Groups such as ester, nitrile, nitro, cyano, and formyl can be present, which permits applications involving masked functionality. For example, when the coupling reaction is applied to l-alkoxy-2-butenylstannanes, the double-bond shift leads to a vinyl ether that can be hydrolyzed to an aldehyde. 

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

A variety of functional groups resist reduction arene rings, N02, COOMe, CONH2, sulfones, nitrile, and ArHal. Nitriles can bind to the metal, and the N lone pair is not effectively masked by acid addition so lower rates can be encountered if this group is present. Alkynes, alkenes, and imines are the best-studied substrates for which reduction is efficient. 

In contrast, the 5-phenyliminothiatriazoline (323) reacts as a masked 1,3-dipole with a variety of electrophilic nitriles. Tosyl cyanide and ethyl cyanoformate both react with (323) in refluxing chloroform to give initially (324) which then isomerizes to (325) as the reaction proceeds (Scheme 71) <91JHC333>. When the solvent is changed to acetone the reaction with the nitriles proceeds faster due to the formation of the adduct (326) which is capable of undergoing cycloaddition/elimination reactions at 20 °C. Trichloroacetonitrile does not react with (323) in chloroform solution in acetone,... 

A representative sample of terpolymers was exposed to a variety of etchants for polysilicon and silicon dioxide, and the results are given in Table V. The ratio of the etch rate of the substrate to the etch rate of the resist must be at least 2 1 for the resist to be a viable etch mask. Inspection of Table V, shows that the materials examined are unacceptable for only the QFj — CF3CI (4 1) plasma. The etch rates are comparable to those for PMMA the a-keto-oxime exhibits essentially no effect on that rate and the nitrile affords a slight decrease in the plasma etch rate. The etch rates of some commercially available materials are shown for comparison. 

Reaction kinetics for the interaction of 5-alkyliminothiatriazoles 52 or 58 with heterocumulenes, nitriles, ketones, imines, or other dipolarophiles a=b show that the decomposition of the thiatriazole is bimolecular, and new heterocyclic five-membered rings 71 are formed (Scheme 15). The term masked 1,3-dipolar cycloaddition was used by L abbe and co-workers for this type of reaction <1978JOC4951>, the thioimidate function being the masked 1,3-dipole. The reaction is thought to involve a thiapentalenic intermediate 70 with hypervalent sulfur. The product 71 is itself a masked dipole and often further reactions take place. 

Electron-poor nitriles react with compound 87 and its derivatives to form the 5-amino-l,2,4-thiadiazole derivatives 104 <1985JOC1295>. Therefore, the formation of product 94 (see Scheme 21) may be explained alternatively by the addition of amidonitrile 93 to compound 90. The mechanism of the formation of product 104 was discussed in detail in CHEC-II(1996) <1996CHEC-II(4)691> but most probably the steps involved are (1) reaction of the electrophilic nitrile with the exocyclic nitrogen of compound 87 or its derivatives (2) loss of nitrogen similarly to the previous reactions and formation of an imine 103 (3) masked 1,3-dipolar cycloaddition/elimination reaction of the nitrile to the imine 103. Since the same nitrile is expelled in the elimination step, only 1 equiv of reagent is needed (Scheme 24). 

Much of the more recent work using isoxazolines involves ste-reocontrolled synthesis. Kozikowski and Ghosh (84JOC2762) used nitrile oxide cycloaddition to prepare the /8-hydroxyester (143) and the jS-hydroxyketone (145) from the dioxolane (S)-(48b) (Schemes 63 and 64). The ester (143) and ketone (145) are masked triols, suitable for use in the synthesis of sugars, as shown through the elaboration of the ester (143)... 

RCHO to a ketone RCOR (for other methods, see 10-71, 16-82, and 18-9). In this procedure the normal mode of reaction of a carbonyl carbon is reversed. The C atom of an aldehyde molecule is normally electrophilic and is attacked by nucleophiles (Chapter 16), but by conversion to the protected cyanohydrin this carbon atom has been induced to perform as a nucleophile. The German word Umpolung is used to describe this kind of reversal (another example is found in 10-71). Since the ion 166 serves as a substitute for the unavailable R— C=0 anion, it is often called a masked R( C=0) ion. This method fads for formaldehyde (R = H), but other masked formaldehydes have proved successful. In an interesting variation of nitrile alkylation, a quaternary bromide [PhC(Br)(Me)CN] reacted with allyl bromide, in the presence of a Grignard reagent, to give the alkylated product [PhC(CN)(Me)CH2CH=CH2]. ... 

The most systematically investigated acyl anion equivalents have been the IMS ethers of aromatic and heteroaromatic aldehyde cyanohydrins, TBDMS-protected cyanohydrins, - benzoyl-protected cyanohydrins, alkoxycaibonyl-protected cyanohydrins, THP-protected cyanohydrins, ethoxyethyl-protect cyanohydrins, a-(dialkylamino)nitriles, cyanophosphates, diethyl l-(trimethylsiloxy)-phenyimethyl phosphonate and dithioacetals. Deprotonation di these masked acyl anions under the action of strong basie, usually LDA, followed by treatment with a wide varies of electrophiles is of great synthetic value. If the electrophUe is another aldehyde, a-hydroxy ketones or benzoins are formed. More recently, the acyl caibanion equivalents formed by electroreduction of oxazolium salts were found to be useful for the formation of ketones, aldehydes or a-hydroxy ketones (Scheme 4). a-Methoxyvinyl-lithium also can act as an acyl anion equivalent and can be used for the formation of a-hydroxy ketones, a-diketones, ketones, y-diketones and silyl ketones. - - ... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

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