Functional groups transformations

The current practical alternatives for preparing each functional group include many classical reactions with relatively known mechanisms, plus many modern ones with complex or often unknown mechanisms. The introductory texts favor conceptually simple methods applied to small monofunctional molecules. A broader selection of methods is chosen here and new methods are published regularly. Online sources can be the most readily accessed and up to date[l]. The functional group syntheses that involve carbon-carbon bond forming reactions are presented in Chapter 7. 

Intermediate Organic Chemistry, Third Edition. Ann M. Fabirkiewicz and John C. Stowell. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

In the previous few chapters, we developed several synthesis strategies that enable us to move the location of a functional group or change its identity. Let s briefly review these techniques, as they will be extremely helpful when solving multistep synthesis problems. 

In Chapter 9, we developed a technique for changing the position of a halogen by performing an elimination reaction followed by an addition reaction. For example  

In this two-step process, the halogen is removed and then reinstalled at a diflferent location. The regiochemical outcome of each step must be carefully controlled. The choice of base in the elimination step determines whether the more substituted or the less substituted alkene is formed. In the addition step, the decision whether or not to use peroxides will determine whether a Markovnikov addition or an ij wri-Markovnikov addition occurs. 

As we saw in Chapter 9, this technique must be shghtly modified when the functional group is a hydroxyl group (OH). In such a case, the hydroxyl group must first be converted into a tosylate (a better leaving group), and only then can the technique be employed (elimination followed by addition) OTs 

After converting the hydroxyl group into a tosylate, the regiochemical outcome for elimination and addition can be carefully controlled, as summarized below  

Jeffrey C. PeUetier of Wyeth Research, Collegeville, PA has developed (Tetrahedron Lett. 2007, 48,7745) a easy work-up Mitsunobu procedure for the conversion of a primary alcohol such as 1 to the corresponding primary amine 2. Shlomo Rozen of Tel-Aviv University has taken advantage (J. Org. Chem. 2007, 72, 6500) of his own method for oxidation of aprimary amine to the nitro compound to effect net conversion of an amino ester 3 to the alkylated amino ester 5. Note that the free amine of 3 or 5 would react immediately with methyl iodide. Keith A. Woerpel of the University of California, Irvine has uncovered (J. Am. Chem. Soc. 2007,129,12602) a Cu catalyst that, with 7, effected direct conversion of sUyl ethers such as 6 to the aUyl silane 8. An Ag catalyst gave 9, which also shows arllyl silane reactivity. Biswanath Das of the Indian Institute of Chemical Technology, Hyderabad has established (Tetrahedron Lett. 2007, 48, 6681) a compact procedure for the direct conversion of an aromatic aldehyde such as 10 to the benzylic halide 11. This will be especially useful for directly generating benzyhc hahdes that are particularly reactive. 

Y asuharu Yoshimi and Minoru Hatanaka of the University of Fukui have described (Chem. Comm. 2007, 5244) a convenient procedure for the reductive decarboxylation of acids such as 21 to the corresponding alkane 22. Teruaki Mukaiyamaofthe Kitasato Institute, Tokyo has developed (Chemistry Lett. 2007, 36,1456) a simple protocol for the activation of carboxylic acids for amide formation. DMAP-mediated coupling of the acid with 25 gave the mixed anhydride, which combined efficiently with the amine 24 to give the amide 26. 

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It IS convenient m equations such as this to represent generic alcohols and alkyl halides as ROH and RX respectively where R stands for an alkyl group In addition to con venience this notation lets us focus more clearly on the functional group transformation that occurs the OH functional group of an alcohol is replaced as a substituent on car bon by a halogen usually chlorine (X = Cl) or bromine (X = Br)... 

Thionyl chloride and phosphorus tribromide are specialized reagents used to bring about particular functional group transformations For this reason we won t present the mechanisms by which they convert alcohols to alkyl halides but instead will limit our selves to those mechanisms that have broad applicability and enhance our knowledge of fundamental principles In those instances you will find that a mechanistic understand mg IS of great help m organizing the reaction types of organic chemistry... 

Chemical reactivity and functional group transformations involving the preparation of alkyl halides from alcohols and from alkanes are the mam themes of this chapter Although the conversions of an alcohol or an alkane to an alkyl halide are both classi tied as substitutions they proceed by very different mechanisms... 

This concludes discussion of our second functional group transformation mvolv mg alcohols the first was the conversion of alcohols to alkyl halides (Chapter 4) and the second the conversion of alcohols to alkenes In the remaining sections of the chap ter the conversion of alkyl halides to alkenes by dehydrohalogenation is described... 

Predict the major organic product of each of the following reactions In spite of the struc tural complexity of some of the starting matenals the functional group transformations are all of the type described in this chapter... 

Functional group transformations of epoxides rank among the fundamental reactions of organic chemistry and epoxides are commonplace natural products The female gypsy moth for example attracts the male by emittmg an epoxide known as disparlure On detechng the presence of this pheromone the male follows the scent to its ongm and mates with the female... 

Often more than one synthetic route may be available to prepare a particular com pound Indeed it is normal to find m the chemical literature that the same compound has been synthesized m a number of different ways As we proceed through the text and develop a larger inventory of functional group transformations our ability to evaluate alternative synthetic plans will increase In most cases the best synthetic plan is the one with the fewest steps... 

The most frequently encountered nucleophiles in functional group transformations are anions which are used as their lithium sodium or potassium salts If we use M to represent lithium sodium or potassium some representative nucleophilic reagents are... 

Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides... 

Section 8 1 Nucleophilic substitution is an important reaction type m synthetic organic chemistry because it is one of the mam methods for functional group transformations Examples of synthetically useful nucleophilic sub stitutions were given m Table 8 1 It is a good idea to return to that table and review its entries now that the details of nucleophilic substitution have been covered... 

A second strategy for alkyne synthesis involving functional group transformation reactions is described m the following section... 

Chlorination is carried out m a manner similar to brommation and provides a ready route to chlorobenzene and related aryl chlorides Fluormation and lodmation of benzene and other arenes are rarely performed Fluorine is so reactive that its reaction with ben zene is difficult to control lodmation is very slow and has an unfavorable equilibrium constant Syntheses of aryl fluorides and aryl iodides are normally carried out by way of functional group transformations of arylammes these reactions will be described m Chapter 22... 

Both the Clemmensen and the Wolff-Kishner reductions are designed to carry out a specific functional group transformation the reduction of an aldehyde or ketone carbonyl to a methylene group Neither one will reduce the carbonyl group of a carboxylic acid nor... 

The chemistry of carboxylic acids is the central theme of this chapter The impor tance of carboxylic acids is magnified when we realize that they are the parent com pounds of a large group of derivatives that includes acyl chlorides acid anhydrides esters and amides Those classes of compounds will be discussed m Chapter 20 Together this chapter and the next tell the story of some of the most fundamental struc tural types and functional group transformations m organic and biological chemistry... 

In particular we thought it would be useful to include cross-references of functional group transformations and an experimental procedure, so that the reader will be able to evaluate the reaction conditions at a glance for instance is this reaction carried out at room temperature or at 200 C For 1 h or 5 days Are special catalysts required How is the reaction worked up, what yield can be expected ... 

Table 8.1 illustrates an application of each of these to a functional group transformation. The anionic portion of the salt substitutes for the halogen of an alkyl halide. The metal cation portion becomes a lithium, sodium, or potassium halide. 

An ability to fonn caibon-caibon bonds is fundamental to organic synthesis. The addition of Grignaid reagents to aldehydes and ketones is one of the most frequently used reactions in synthetic organic chemistry. Not only does it pennit the extension of caibon chains, but because the product is an alcohol, a wide variety of subsequent functional group transformations is possible. 

Allylic rearrangement (Section 10.2) Functional group transformation in which double-bond migration has converted one allylic structural unit to another, as in ... 

Azaloxan (12) is an antidepressant agent. Its synthesis can be accomplished starting with the reaction of catechol (7) and 3,4-dibromobutyronitrile (obtained by addition of bromine to the olefin) to give l,4-benzodioxan-2-ylacetonitrile (8). A series of functional group transformations ensues [hydrolysis to the acid (9), reduction to the alcohol (10) and conversion to a tosylate (11)] culminating in an SN-2 displacement reaction on tosylate 11 with l-(4-piperidinyl)-2-imidazolidi-none to give azaloxan (12) [3]. 

The 6-substituted 1,4-dioxocins can be used to prepare other 6-substituted derivatives by simple functional group transformations.4,8,9 Especially interesting is the synthesis of the 4/7-4-oxo-2,3-dihydropyran-2-yl-substituted derivative 16 from l,4-dioxocin-6-carbaldehyde (15) by a cyclocondcnsation with Danishefsky s diene.9 Dehydrogenation of 16 yields 2 which can be isomerized to the corresponding isomeric. sr/i-benzene dioxide 3 (X = 4/f-4-oxopyran-2-yl), which is identical with and proved the structure of the naturally occurring antibiotic LL-Z 1220.10... 

Fig. 7 Examples of microwave-assisted reactions and functional group transformations that are covered in Sect. 2...

Farnesyl protein inhibitor 2 Flavones 254 Fluorous phases 112 Fluorous Ugi reactions 115 Functional group transformations 25... 

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