Base-catalyzed coupling

Carbamates can be used as protective groups for ammo acids to minimize race-mization in peptide synthesis. Raccmi/ation occurs during the base-catalyzed coupling reaction of an W-protected, catboxyl-uc ivated amino acid, and takes place in the intermediate oxazolone that foro S readily from an N-acyl protected amino... 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

Basazol dyes, 9 489-490 Base-catalyzed coupling, 10 356 Base-catalyzed ketone condensation,... 

Funk s synthesis in 2004 [28] of perophoramidine (Scheme 3), commenced with a base-catalyzed coupling reactiOTi between indole 19 and 3-bromoindolin-2-one 20. Boc protectiOTi of the resulting lactam 21 followed by reduction of the azido functionality led to transamidation and closure of the resulting carbamate upon the indolenine to deliver the aminal 22. Chemoselective chlorination and protection of the lactam followed by a two-step deprotection and conversion of the resulting alcohol to the azide afforded amide 23. A second transamidation reaction followed by selective methylation gave lactam 24. Treatment of lactam 24 with Meerwein s reagent gave imidate 25, which imderwent a Fukuyama deprotection of the sulfur... 

This reaction suffers all the problems outlined above since these routes rely on chlorine to activate the aromatic ring towards nucleophilic attack. It has recently been discovered at Monsanto that the base catalyzed coupling of aniline and nitrobenzene via NASH chemistry is a superior route for the production of intermediates like 2.24 Understanding the mechanism of the coupling reaction,25 and in particular, the oxidation of a-complex intermediate, 4, has allowed for the development of a commercial process based on this chemistry. 

Bisphenol A based liquid epoxy resins are prepared in a two-step reaction sequence from epichlorohydrin and bisphenol A. ITie first step is the base-catalyzed coupling of bisphenol A and epichlorohydrin to yield a chlorohydrin. 

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

Two disadvantages are associated with the use of S-acetyl or 5-benzoyl derivatives in peptide syntheses (a) base-catalyzed hydrolysis of 5-acetyl- and 5-benzoylcys-teine occurs with /S-elimination to give olefinic side products, CH2=C-(NHPG)CO—(b) the yields of peptides formed by coupling an unprotected amino group in an 5-acylcysteine are low because of prior S-N acyl migration. ... 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

More useful for synthetic purposes, however, is the combination of the zinc-copper couple with methylene iodide to generate carbene-zinc iodide complex, which undergoes addition to double bonds exclusively to form cyclopropanes (7). The base-catalyzed generation of halocarbenes from haloforms (2) also provides a general route to 1,1-dihalocyclopropanes via carbene addition, as does the nonbasic generation of dihalocarbenes from phenyl(trihalomethyl)mercury compounds. Details of these reactions are given below. 

In the azo coupling of nitroethane (Machacek et al., 1968 a, 1968 b already discussed in Sec. 12.7) the forward step of Scheme 12-71 corresponds to the formation of the nitroethane anion. This step is a rate-limiting deprotonation and is therefore general base-catalyzed. 

In the azo coupling reaction of acetoacetanilide (Dobas et al., 1969b) the reaction steps of Schemes 12-71 and 12-72 constitute a steady-state system, i.e., Arx [B] < Ar [HB+] == 2[Ar —NJ] A 2 — 0 with a fast subsequent deprotonation (Scheme 12-73). As with nitroethane, this reaction is general base-catalyzed because the ratedetermining step is the formation of the anion of acetoacetanilide (Scheme 12-71). In contrast to the coupling of nitroethane, however, the addition of the diazonium ion (Scheme 12-72) is rate-limiting. The overall kinetics are therefore between zero-order and first-order with respect to diazonium ion and not strictly independent of [ArNJ ] as in the nitroethane coupling reaction. 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the a-carbon. Drueckhammer et al. first demonstrated the feasibility of this approach by performing DKR of a propionate thioester bearing a phenylthiogroup, which also contributes to the acidity of the a-proton (Figure 4.14) [39a]. The enzymatic hydrolysis of the thioester was coupled with a racemization catalyzed by trioctylamine. Owing to the insolubility of the substrate and base in water, they employed a biphasic system (toluene/H2O). Using P. cepacia (Amano PS-30) as the enzyme and a catalytic amount of trioctylamine, they obtained a quantitative yield of the corresponding... 

CK catalyzes the reversible phosphorylation of creatine in the presence of ATP and magnesium. When creatine phosphate is the substrate, the resulting creatine can be measured as the ninhydrin fluorescent compound, as in the continuous flow Auto Analyzer method. Kinetic methods based on coupled enzymatic reactions are also popular. Tanzer and Gilvarg (40) developed a kinetic method using the two exogenous enzymes pyruvate kinase and lactate dehydrogenase to measure the CK rate by following the oxidation of NADH. In this procedure the main reaction is run in a less favorable direction. 

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

The Heck coupling reaction appeared to be a route of choice to achieve the synthesis of the modified-DIOP ligands. We previously studied the palladium-catalyzed coupling of acrolein and acrolein acetals with several polyaromatic and heteroaromatic bromides either in the presence of homogeneous or heterogeneous catalytic systems (6, 7). After optimization of the reaction conditions, high conversions and selectivities were achieved except with anthracenyl derivatives (8). Based on these results, we developed the synthesis of the desired ligands. The... 

The key Pd-catalyzed coupling step to the indole was optimized by judicious choice of the protection group on 3-butyn-l-ol, screening of different reaction parameters such as bases and additives, and implementing a fine-tuned, yet practical work-up procedure. Tryptophol 27 was isolated in 76-82% yield by crystallization. 

The C,0-bis-TES side chain 61 was prepared quantitatively from propargyl alcohol and TESC1 using n-BuLi as a base. Pd-catalyzed coupling of iodoaniline 28 with bis-TES side chain 61 in the presence of 1.5equiv of MgS04 and 5equiv of... 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

---