Scope of the reaction

The interaction of amino acids and sugars falls into two general types. The first is the simple, controlled condensation of the reactants this leads 

Aldoses have been condensed with a number of amino acids and their esters to yield V-substituted glycosylamines. For example, D-glucose has 

Although much work has been done in an attempt to elucidate the structure of iV-substituted glycosylamines, rigid proof of their structures has not yet been achieved.43 Spectroscopic evidence is inconclusive,69 whilst chemical methods are of limited value because equilibrium between open-chain, pyranose, and furanose forms is possible. However, all such derivatives as ethers and esters so far prepared directly from A-glycosylamines have been shown to be pyranoid, and periodate oxidation of some N-glycosylamines has confirmed this conclusion.70 71 

The Maillard reaction has been studied from several viewpoints and these differing approaches have sometimes been reflected in the particular molecular proportions of sugar and amino acid which were used in the experiments. Thus, the reaction has been regarded as the decomposition or polymerization of the carbohydrate by a small molecular-proportion of amino acid.20, 72 77 

When an amino acid is heated with D-glucose in a stream of oxygen at 130°, decarboxylation and deamination occur according to the following equation. Very little free ammonia can be detected, since it quickly com- 

For many years the activation of unfunctionalized alkanes has been the Holy Grail of organic synthesis and, indeed, it has only been during the past few years that catalysts have evolved which allow an alkane C—H bond to be selectively 

The results of some initial experiments indicated that the catalytic activity of 1 is strongly temperature-dependent. For instance, at 100 °C, the rates are relatively low but there is an appreciable turnover [turnover frequency (TOE) = 20.5 h j. Increasing the reaction temperature to 200 °C increases the TOE to 720 h hence, the thermal robustness of the iridium catalyst is pivotal for optimal catalyst performance. The tridentate pincer-type ligands provide a particularly stable platform for metal confinement through covalent Ir—C bonding combined with the terden-tate chelating coordination. 

A variety of alkanes can be dehydrogenated with catalysts such as 1. Whilst COA dehydrogenation usually stops at the COE stage, cyclohexane dehydrogenation affords benzene in good yields [7]. Substituted cyclohexanes are dehydrogenated at both exocycHc and endocyclic positions for example, ethylcyclohexane dehydrogenation produces styrene as the major product (Equation 12.1). 

Linear alkanes have been successfully dehydrogenated under similar conditions. Initially, selective activation of the terminal position has been observed, leading 

Accordingly, catalyhc dehydrogenahon with complexes such as 1 must be performed under an atmosphere of argon that is devoid of traces of N2. Similarly, alkenes exert an inhibitory effect, and high concentrahons of either the product olefin or the hydrogen acceptor TBE inhibit catalyst achvity. 

The addition of HF to alkenes is practicable, but the addition reaction is slow and the handling of anhydrous HF is challenging. With anhydrous HF, alkene polymerization is a major 

FIGURE 11.9 Addition of HX to alkenes is not regioselective when the intermediate cations are of comparable stability. 

FIGURE 11.10 Acid-catalyzed addition of water to an aikene. 

we protonate the double bond to give the more stable tertiary carbocation then this is attacked by water. The final step is loss of a proton to give the alcohol. 

The addition of HCl at 0 °C to 3-methyl-l-butene gave a 40 60 mixture of 2-chloro-3-methylbutane and 2-chloro-2-methylbutane. Explain, writing a complete mechanism. 

SCHEME 19.13 Regioselectivity of Heck reactions with dppp as ligand in DMF. 

The complexation of the alkene to the cationic [PhPd(dppp)S] (1+) may generate the two isomers 2 and 2 and then complexes 3 and 3 in a reversible insertion step. If I or AcO is present at high concentrations, the cationic complexes 3 and 3 can be reversibly qnenched by the anions to form the neutral 4 and 4, respectively. 

TRANSITION METAL-CATALYZED CARBON-CARBON CROSS-COUPLING 

SCHEME 19.14 (i - and P -hydride elimination and enantioselective Heck reactions. 

In the course of time it appeared that many olefinic substrates could undergo this reaction in the presence of a transition metal compound, such as substituted alkenes, dienes, polyenes, and cyclic alkenes, and even alkynes. Calderon et al. were the first to realize that the ring-opening polymerization of cycloalkenes, which they observed with their tungsten-based catalyst system [4], and the disproportionation of acyclic olefins are, in fact, the same type of reaction. They introduced the more general name metathesis [2], The metathesis reaction has now become a common tool for the conversion of unsaturated compounds. In view of the limited space this intriguing reaction is reviewed only briefly more information can be found in a detailed and extensive monograph [5]. 

The metathesis of acyclic alkadienes and polyenes may follow an inter- or intramolecular pathway. The intramolecular metathesis of an a,tfi-diene yields ethylene and a cyclic alkene, while the intermolecular reaction results primarily in the formation of ethylene and a symmetric triene (eq. (2)). The loss of a small molecule like ethylene serves to drive the equilibrium to the product side. 

Whether the inter- or intramolecular pathway dominates depends on the relative stability of the cyclic vs. the linear products and to some extent on the dilution of 

Polymers with carbon-carbon double bonds in their backbone can undergo two types of metathesis, both leading to degradation. In an intramolecular reaction cyclic oligomers are formed, while many unsaturated polymers can be degraded by intermolecular cross-metathesis with low-molecular-weight olefins. Identification of the degradation products provides valuable information on the microstructure of the polymer [7] (cf Section 3.3.10.1). 

3 Cross-Metathesis Between a Cyclic and an Acyclic Alkene 

Once we determined the best reaction conditions, the scope was explored. Products I-16a-h of [2-I-2-I-2] cycloaddition were isolated from enyne I-15a in 21-85 % yield, along with 1,3-dienes I-17a-h (Table 2.4). The reaction proceeded readily with electron-rich aldehydes. Conversely, in the reaction of I-15a with o-nitro-benzaldehyde, no adduct was formed (Table 2.4, entry 17), which is in contrast with the previously reported results for 1,6-enynes bearing a terminal aUcene moiety 1-9 [Refs. 226, 228 in Chap. 1]. 

Skeletal rearrangement product was also formed (10-50 % yield) 

The metathesis-type products I-17a-c and I-17g were the major products observed with benzaldehyde, 4-methylbenzaldehyde, 2,4-dimethylbenzaldehyde, and 2,4,6-trimethoxy-benzaldehyde using phosphite complex 20 as catalyst (Table 2.4, entries 3, 5, 7, and 16). In contrast, with 2,4-dimethylbenzaldehyde, 2,4,6-trimethylbenzaldehyde, 4-methoxybenz-aldehyde, and 2,4-dimethoxybenz-aldehyde, the major products were the dihydropyran I-16c-f using IPr NHC complex 16 (Table 2.4, entries 6, 8, 11 and 13). 

In general, we observed an increase in the yield of the dihydropyran products 1-16 using IPr gold(I) complex 16 (Table 2.4, entries 4,6,8,13,16 and 18). On the other hand, using phosphite complex 20, the metathesis product 1-17 is favored (Table 2.4, entries 3, 5, 7 and 16). 

On the other hand, complete selectivity toward 1,6-dienes 1-17 was obtained with 1,6-enynes I-15b-c, which only differ from I-15a in the heteroatom in the 

This very rich chemistry has been the subject of several comprehensive reviews, including recent ones sp carbon centres, general (Kornblum, 1975, 1982 Russell, 1970, 1987), photochemically induced reactions (Bowman, 1988a), substituted aliphatic nitro-compounds (Bowman, 1988b), alkyl mercurials (Russell, 1989) sp carbon centres, general (Norris, 1983 Rossi and 

light-induced and solvated-electron-induced reactions (Bun-nett, 1978), electrochemical induction (Saveant, 1980a), synthetic aspects (Beugelmans, 1984 Norris, 1990 Wolfe and Carver, 1978), photochemical induction of the reaction at heteroaromatic carbon centres (Lablache-Combier, 1988). There is no point in repeating here the extensive lists of reactions contained in these review articles. We shall just underline a few points and report recently available findings. 

In a series of recent papers, Komblum et at. have systematically investigated various factors of the reaction at saturated carbon, namely, the stereochemistry (Kornblum and Wade, 1987), the effect of light (Wade et ai, 1987), the effect of leaving groups (Kornblum et al., 1988) and the particular reactivity of the p-nitrocumyl system (Kornblum et al, 1987) as well as the conditions under which the cyano-group may replace the nitro-substituent in reactions involving a benzylic carbon (Kornblum and Fifold, 1989). 

P-Dicarbonyl and P-cyanocarbonyl anions, which have been shown to react in an Sr 1 fashion at sp carbon centres, were also found to be active toward aromatic and heteroaromatic carbons under photochemical (Beugelmans et al, 1982) or electrochemical stimulation (Oturan et al, 1989). 

Alkoxide or aryloxide anions are also reputed to be inactive in Sr I reactions. There is, however, one example of such a reaction at an sp carbon the nitro-derivative of 4-nitrocumyl reacts with phenoxide and 1-methyl-2-naphthoxide ions yielding the corresponding ethers (Kornblum et al., 1967). A similar reaction has been reported for halobenzenes in t-butyl alcohol upon stimulation by sodium amalgam (Rajan and Sridaran, 1977). This reaction could not, however, be reproduced (Rossi and Pierini, 1980) and other attempts to make phenoxide ions react at sp carbons have been equally unsuccessful (Ciminale et al, 1978 Rossi and Bunnett, 1973 Semmelhack and Bargar, 1980). It has been found, more recently, that phenoxide ions react with a series of aryl halides under electrochemical induction, but that the coupling occurs at the p- or o-phenolic carbon rather than at the phenolic oxygen (Alam et al, 1988 Amatore et al, 1988). This is 

P(o-tolyl)3, P( Bu)3, Ph5FcP(PBu)2 (Q-phos), heterocyclic carbenes, (BiaryllPRg. -OP(f-Bu)2, and Verkade s proazaphosphatranes L = Chelating bidentate ligands dppf, BINAP, Xantphos, and Josiphos ligands 

Aryl bromides are the most reactive aryl halide, and aryl chlorides are the next most reactive for this catalytic process. For reasons not well understood, aryl iodides tend to be less reactive toward palladium-catalyzed cross-couplings that form C-N bonds. Aryl triflates also couple with amines, - and even the less-reactive aryl tosylates have been shown to couple with amines.  

CHAPTER 19 TRANSITION METAL-CATALYZED COUPLING REACTIONS 

Primary and secondary amines now react with broad scope, but the most effective catalyst for these two classes of amines tends to be different. The most efficient catalysts for reactions of secondary alkylamines possess hindered monodentate 

Base = NaOPh, GS2CO3, or K3PO4 L = dppf, Xantphos, or P(f-Bu)3, (blaryl)PCy2 (X-phos) 

---

Other carbonyl compounds are within the scope of the reaction ketones give amides, and aldehydes yield nitriles and formyl derivatives of amines ... 

The first report of oxidative carbonylation is the reaction of alkenes with CO in benzene in the presence of PdCh to afford the /3-chloroacyl chloride 224[12,206]. The oxidative carbonylation of alkene in alcohol gives the q, f3-unsaturated ester 225 and /3-alkoxy ester 226 by monocarbonylation, and succinate 111 by dicarbonylation depending on the reaction conditions[207-209]. The scope of the reaction has been studied[210]. Succinate formation takes... 

The oxidative homocoupling of benzene with Pd(OAc)2, generated in situ from PdCl2 and. AcONa, affords biphenyl in 81% yield. In the absence of AcONa, no reaction took place. Pd(OAc)2 itself is a good reagent for the coupling[324-326]. The scope of the reaction has been studied[327,328]. 

The procedure was largely ignored until the 1950s when interest in melanin-related substances and recognition of serotonin as a 5-hydroxy derivative stimulated exploration of the scope of the reaction. Nowadays, the Nenitzescu reaction is one of the most efficient processes for the preparation of 5-hydroxyindoles. 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

In the previous review (91YGK205, 99H1157), we reported that l-hydroxy-4-nitroindole forms active ester derivatives by reaction with carboxylic acids, which can be applied to acylation of various nucleophiles. To expand the scope of the reaction and obtain novel fungicidal compounds, an attempt has been made to prepare derivatives of wasabi phytoalexin 109 (98P1959). 

This reaction pathway explains well the applicability of amines as catalysts. There is evidence for each one of the mechanisms outlined above. Because of the wide scope of the reaction, there may be no uniform mechanism that would apply to all cases. 

The scope of the reaction depends on the availability of the starting aldehyde (or ketone). A drawback is the toxicity of the hydrogen cyanide used as reactant. ... 

The chemical yield of the classical Henry reaction is not always good and depends on steric factors thus, highest yields are obtained when nitromethane is used. Performing the reaction under high pressure (9 kbar, 30 °C) with tetrabutylammonium fluoride catalysis19 enlarges the scope of the reaction dramatically. Thus, addition of nitropropane to 2-methylcyclohexanone, which is not reactive under the classical conditions, was achieved in 40 % yield. Improved yields... 

The scope of the reaction can be extended from aminomei7 v7ation to aminoci/A j7ation. bnantioselective13 and diastereoselective14,15 aininoalkylation can easily be achieved. 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

Subsequently, the scope of the reaction was extended to N-nucleophiles 82. Because the inherent basicity of the substitution products 83 imposed some problems concerning catalyst decomposition, the addition of catalytic amoimts of piperidine hydrochloride (pip-HCl) proved to be necessary. Under optimized reaction conditions different aromatic amines 82 were allylated with almost exclusive regioselectivites in favor of the ipso substitution products 83 (eq. 1 in Scheme 20) [64]. 

The scope of the reactions of phosphazenes with alkyl halides and, subsequently, water, as a preparative route to secondary amines (as their hydrohalides) has been investigated ... 

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

Rovis and co-workers further extended the scope of the reaction to the enantio-and diastereoselective cyclisation of a,P-disubstituted Michael acceptors 137. The high diastereoselectivity of the process relies on selective protonation of the resnltant enolate after conjugate addition. It was found that HMDS (formed dnring deprotonation of the triazolium salt pre-catalyst) was detrimental to the... 

In order to extend the scope of the reaction, and with the aim of designing a greener approach to the above set of reactions, we preformed the acylation of the same substrates with different acylation agents, such as maleic anhydride, p-methoxybenzoic acid and acetic acid (Scheme 48.4). Table 48.3 shows the results for acylation of benzenesulfonamide. 

The scope of the reaction of Ph3P-Cl3CCOCCl3 with allylic alcohols has been studied. Primary and some secondary alcohols, such as 14A and 14B, give good... 

Aryltrimethylsilanes has been found to be a useful complement to direct thallation in the preparation of arylthallium(III) intermediates. The thallium(III) replaces the silyl substituent and the scope of the reaction is expanded to include some EWGs, such as trifluoromethyl. How does the silyl group function in these systems ... 

The scope and limitations were briefly studied. Unfortunately the scope of the reaction was rather narrow, as shown in Table 1.4. The Emit of generality may originate from differences in aggregation of each individual lithium acetylide. For instance, changing 2-pyridyl to 3-pyridyl, the ee dropped to 36%. Furthermore, changing to 4-pyridyl, the ee further decreased to 13%. Fortunately, asymmetric addition of a TMS protected acetylide provided the desired adduct in 82% ee. Since... 

At the time of this work the palladium-mediated amidation of enol triflates had not been described, and, hence, the scope of the reaction was evaluated with a range of other enol triflates and amides (Scheme 9.20) [22, 23], A number of key observations were made, some of which were to prove important during further development. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

---