With Carboxylic Acid Derivatives

A promising method for the synthesis of unsymmetrical diorgano tellurium compounds uses carboxylic acid derivatives and diaryl ditellurium as starting materials. The carboxylic acid chloride, prepared in quantitative yield from the acid and oxalyl chloride is added slowly to a mixture of a diaryl ditellurium and the sodium salt of 2-mercaptopyridine N-oxide in toluene at 35 . Under normal laboratory light the aryl tellurium radicals 

This sequence of reactions transfers the alkyl group of a carboxylic acid to the tellurium atoms of a diaryl ditellurium. Because many carboxylic acids are commercially available at prices much lower than the corresponding alkyl halides, this reaction is a very useful alternative route to unsymmetrical diorgano tellurium compounds. 

The following alkyl aryl tellurium compounds were prepared in this manner  

Upon treatment with lithium triethylborohydride in tetrahydrofuran, 2-benzoyl-1-ethenyl tellurium trichlorides produced did not produce the expected ditellurium compounds but bis[2-benzoylethenyl] telluriums.  

Irgolic Organo TeJlurium Compounds with 2 Te —C Bonds or 1 Te = C Bond 

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Nonclassical Wittig reaction, olefination by phosphoranes interaction with carboxylic acid derivatives, in transformation of heterocycles 99JCS(P1)3049. 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

The most widely used method for the preparation of [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 85 employs 4-amino-5-thio-4/7-[l,2,4]triazoles 83 or 4-amino[l,2,4]-triazole-5(47T)-thiones 84 as starting materials. The reaction of the triazoles 83 or 84 with carbonic acid derivatives furnishes [l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles with a heteroatom substituent (N, O, S) at position 6 the O- and S-functions are formulated as 6-hydroxy and 6-thio derivatives 85a or as thiadiazol-(5/7)6-ones and -thiadiazole-(577)6-thiones 85b, respectively reaction with carboxylic acid derivatives provides the 6-substituted-[l,2,4]triazolo[3,4-4][l,3,4]-thiadiazoles 85c (Equation 20 Table 3). 

Thiols undergo the same types of nucleophilic reaction with carboxylic acid derivatives as do alcohols. However, reactivity tends to be increased for two reasons. First, sulfur, because of its larger size, is a better nucleophile than oxygen (see... 

The reaction of carbon nucleophiles derived from organometallics with carboxylic acid derivatives follows closely the reactions we have already encountered in Sections 6.3.2 and 7.6.2. Organometallics... 

Acylation is one of the most fundamental and useful reactions in organic synthesis and is normally achieved by the reaction either with carboxylic acid derivatives and organometallic compounds or with masked acyl anions and aUcyl halides. 

The cyclocondensation of l,3-amino alcohols with carboxylic acid derivatives is a method often applied for the synthesis of 5,6-dihydro-4/7-l,3-oxazines <1996CHEC-II(6)301 >. Ebsorb-4, a weakly acidic zeolite-type adsorbent with 4 A pore size, proved an efficient catalyst of the cyclization of benzoic acid and 3-aminopropanol <2002TL3985>. In the presence of zinc chloride as a catalyst, the expulsion of ammonia drove the reactions of 3-aminopropanol with nitriles to completion, affording 2-substituted 5,6-dihydro-47f-l,3-oxazines in good yields... 

As shown above, 3-acyltetramic acids (pKa about 3) form anions whose reactivity toward alkylating agents is low. Successful reaction of 3-acylte-tramic acids with carboxylic acid derivatives are scarce in the literature... 

A nucleophile is an electron rich species that reacts with an electrophile. The term electrophile literally means electron-loving , and is an electron-deficient species that can accept an electron pair. A number of nucleophilic substitution reactions can occur with alkyl halides, alcohols and epoxides. However, it can also take place with carboxylic acid derivatives, and is called nucleophilic acyl substitution. 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

Carboxy terminal amino acid or peptide thiols are prepared from various p-amino alcohols by conversion into a thioacetate (R2NHCHR1CH2SAc) via a tosylate followed by saponification.Several methods have been used to prepare N-terminal peptide thiols, the most common procedure is the coupling of (acetylsulfanyl)- or (benzoylsulfanyl)alkanoic acids or add chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 16 Other synthetic methods include deprotection of (trit-ylsulfanyl)alkanoyl peptides, 1718 alkaline treatment of the thiolactones from protected a-sulfanyl acids, 19 and preparation of P-sulfanylamides (HSCH2CHR1NHCOR2, retro-thior-phan derivatives) from N-protected amino acids by reaction of P-amine disulfides with carboxylic acid derivatives, followed by reduction. 20,21 In many cases, the amino acid or peptide thiols are synthesized as the disulfides and reduced to the corresponding thiols by the addition of dithiothreitol prior to use. 

In all of the reactions with carboxylic acid derivatives, the carbonyl carbon is acting as the substrate in nucleophilic substitution. Rather than memorize all these reactions, you should remember that carboxylic acids and their derivatives undergo nucleophilic substitution aldehydes and ketones prefer nucleophilic addition. 

Pyrazolotroponehydrazones like 580a, on treatment with carboxylic acid derivatives or aliphatic carbonyl compounds, are cyclized to fused [l,2,4]tri-azine derivatives (e.g., 580b,c) with aromatic carbonyl compounds, they form azines (79BCJ1972 80JHC1057, 80S331). 

The methoxide ion uses of its lone pairs of electrons to form a bond to the electrophilic carbonyl carbon of the acid chloride. Simultaneously, the relatively weak n bond of the carbonyl group breaks and both of the n electrons move onto the carbonyl oxygen to give it a third lone pair of electrons and a negative charge. This is exactly the same first step involved in nucleophilic addition to aldehydes and ketones. However, with an aldehyde or a ketone, the tetrahedral structure is the final product. With carboxylic acid derivatives, the lone pair of electrons on oxygen return to reform the carbonyl n bond (Step 2). As this happens, the C-Cl o bond breaks with both electrons moving onto the chlorine to form a chloride ion that departs the molecule. 

When Do Pure Acylations Succeed with Carboxylic Acid (Derivative)s, and When Are Alcohols Produced ... 

Chemoselective SN reactions of nucleophiles with carboxylic acid derivatives are guaranteed to take place without the risk of an overreaction when the substitution mechanism of Figure 6.4 applies. This is because as long as the nucleophile is present, only one reaction step is possible the formation of the negatively charged tetrahedral intermediate. Figure 6.40 summarizes this addition in the top line as Reaction 1 (— B). 

Fig. 6.41. Three strategies for the chemoselective acylation of hydride donors, organometallics and heteroatom-stabilized "carbanions" with carboxylic acid derivatives.

Acylation of Organometallic Compounds and Heteroatom-Stabilized Carbanions With Carboxylic Acid (Derivative)s Synthesis of Ketones... 

In Figure 6.41, the reaction of certain heteroatom-stabilized carbanions with carboxylic acid derivatives is presented as strategy 3 of Figure 6.32 for achieving chemoselective acylations. This strategy can be used to convert esters into /i-ketophosphomc acid esters with... 

Following strategy 2 from Figure 6.32, chemoselective SN reactions of hydride-donors with carboxylic acid derivatives also succeed starting from carboxylic chlorides. For the reasons mentioned further above, weakly nucleophilic hydride donors are used for this purpose preferentially and should be added dropwise to the acylating agent in order to achieve success ... 

He reacted water with carboxylic acid derivatives RCOX that had been labelled with an isotope of oxygen, 180. 

REACTIONS WITH CARBOXYLIC ACID DERIVATIVES TRANSACYLATIONS... 

Substitution and Addition Reactions with Carboxylic Acid Derivatives... 

Compounds such as 543 and 545 were prepared either from 5-hydrazino-1,4-benzodiazepines (e.g. 542), by cyclization (78JHC1127) with carboxylic acid derivatives, or from 1,4-benzodiazepine-5-imidates (e.g. 544, Z = OMe) (7ITL1609), 5-thioimidates (e.g. 544, Z = SMe) (78JHC1127), or 5-imidoyl chlorides (e.g. 544 Z = Cl) (76TL1931 77TL1699) with carboxylic acid hydrazides. 

Reaction of organometallic reagents with carboxylic acid derivatives... 

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