Aromatic compounds disconnection

Guideline 1 Consider the effects of each functional group on the others. Add first (that is disconnect last) the one that will increase reactivity in a helpful way. So, for aromatic compounds, introduce first that group that helps, by reactivity or direction, the introduction of the others. 

We started with aromatic compounds in chapters 2 and 3 because the position of disconnection needed no decision. We continue with ethers, amides and the like because the position of disconnection is again easily decided we disconnect a bond joining the heteroatom (X) to the rest of the molecule a C-O, C-N or C-S disconnection. We call this a one-group C-X disconnection because we need to recognise only one functional group (ester, ether, amide etc.) to know that we can make the disconnection. 

It turns out that we must protect the phenol as its methyl ether 127 and that 126 is best used as an amidine-ester rather than the double enamine. The synthesis is then quite short. We have barely scratched the surface of aromatic heterocyclic synthesis in this chapter but the encouraging message is that cyclisation is easy and that cyclisations to form aromatic compounds are the easiest of all. Disconnect with confidence ... 

Disconnection of pyridazines reveals a molecule of hydrazine and a 1,4-diketone with the proviso that, just as with pyridines, the product will be a dihydropyrazine and oxidation will be needed to give the aromatic compound. As with pyridines, we prefer to avoid the cis double bond... 

Synthons such as 237 or 238 might appear to be non-productive as the availability of reagents corresponding to these synthons may be questionable. Nevertheless, if one takes into account the options to synthesize p-substituted aromatic compounds and their ease of conversion into ci, s -l,4-disubstituted cyclohexanes via catalytic hydrogenation), the proposed disconnections become immediately feasible. This reasoning leads to routes A and B as realistic pathways for the preparation of 236. 

The first step in the experimental procedure consists of preparative electrolysis of the aromatic compound A to A . The preparative potentiostat is then disconnected and a UME is inserted into the cathodic compartment. The steady-state oxidation current of A is recorded as a function of time for a certain time period to ascertain that the stability of A is high. If this is indeed the case, the alkyl halide RX is added to the solution while it is stirred for a few seconds to assure that homogeneous conditions apply for the reaction of Eq. 90. The recorded current is observed to decay exponentially towards zero. A plot of In / versus t is shown in Figure 16 for four different combinations of aromatic compounds and sterically hindered alkyl halides. From the slopes of the straight lines, -2A etCrx, A et values can readily be obtained. The method is useful for the study of relatively slow reactions with kET < 10 M- s-. ... 

There is no simple way to disconnect the TM shown below (dissonant charge pattern). However, the presence of a 1,6-dioxygenated compound suggests opening of a six-member ring. A variety of cyclohexene precursors are readily available via condensation and Diels-Alder reactions or via Birch reductions of aromatic compounds. 

The HIV protease inhibitor palinavir 13 (from Bio-Mega/Boehringer, Quebec) is a complex molecule that can be disconnected simply to five components. Two of these (14 and 18) are simple achiral aromatic compounds and two can be derived from the chiral pool (chapter 25) the amino acid valine 15 and an epoxide 16 derived from phenylalanine. The fifth 17 is the subject of this section. This compound has two chiral centres so we must first produce the right (syn-) diastereo-isomer and then the right enantiomer. 

We start with aromatic compounds because the bond to be disconnected is almost always the bond joining the aromatic ring to the rest of the molecule all we have to decide is when to make the disconnection and exactly which starting materials to use. We shall use the technical terms disconnection, functional group interconversion (FGI), and synthon in this chapter. 

Musk ambrette (4), a synthetic musk, essential in perfumes to enhance and retain the odour, is an aromatic compound with five substituents on the benzene ring. The nitro groups are by far the most electron-withdrawing so we can disconnect them first. 

This is a long synthesis. Though the yields are good, the overall yield is only A second successful and much shorter synthesis comes from the FGA strategy Chapter 24). Introducing unsaturation throughout the whole skeleton of (34) gives an aromatic compound (38) with an obvious ct, 3-disconnection. 

Dieneones such as (12) are not particularly easy to synthesise, but any method which might form them under acidic conditions usually gives cyclo-pentenones instead. The aromatic compound (13) was needed for the synthesis of steroid analogues. Disconnecting the bond opposite the carbonyl group gives dienone (14), a Friedel-Crafts product from ether (15) and add chloride (16). 

Two substituents which are remote in a saturated compound may be sensibly related in an aromatic compound. The ketone (26) has been used in studies on conformational analysis—we used it as a starting material in Chapter 27. We should obviously like to disconnect bond (a) this is hardly possible in (26), but trivial in the aromatic (27). 

Two remote FGs may similarly be brought into revealing relationship in an aromatic compound. Amine (28) has no obvious disconnections but the synthesis of the aromatic amine (29) is a trivial exercise in substitutions (cf. Chapter 3). 

We have already used this strategy. It was used specifically for aromatic compounds Chapter 3), 1,2- and 1,4-difunctionalised compounds Chapters 23 and 25) and formed one of our earliest guidelines to good disconnections (Chapter 11). In this chapter we look at some less obviously available starting materials and TMs made from them. 

The first problem will prepare 4-bromoaniline (168) from benzene. Syntheses that transform one aromatic compound into another aromatic compound, such as this one, do not lend themselves to the retrosynthetic analysis approach presented in Chapter 25. Most of these syntheses involve functional group transformations. For the sake of continuity, a retrosynthesis is shown in which the amino group is removed to generate bromobenzene, which is obtained directly from benzene. The NH2 unit probably comes from reduction of a nitro group (Section 21.6.2), so the first precursor is 4-bromonitrobenzene (59) and disconnection of the C-N bond leads to the preparation of 59 by reaction of bromobenzene (35) with nitric acid/sulfuric acid. Bromobenzene is prepared directly from benzene as shown in the illustration. 

An obvious retrosynthetic step is retro-F.-C. disconnection, and the decision between two Ar-CO bonds is unambiguous in favor of the bond to the dimethox-yphenyl unit since this substrate is activated for F.-C. acylation (Scheme 2.34). Alternative disconnection leads to nitrobenzene, an unreactive aromatic compound in F.-C. acylation. Its high inertness enables its use as the solvent for this reaction ... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Friedel-Crafts disconnection (38a) Is unambiguous because of the synunetry of (39). Further disconnection requires FGA. A carbonyl group next to the aromatic ring gives a 1,4-dicarbonyl compound (40) and allows disconnection of an acyl anion equivalent to give an enone (41). This can be made by Mannich reaction from (42). 

The disconnection or synthon approach now integrated into the text, and the principles of retrosynthetic analysis applied to relevant aliphatic, aromatic, alieyelic and heterocyclic compounds. 

The Pfizer anti-fungal compound fluconazole 60 is a more advanced example of such disconnections.5 It has two identical 1,2-diX relationships between nitrogen and the OH group. You might think that we can make both the same way, but not so. The first disconnection is easy we want the aromatic amine triazole 62 to combine with the epoxide 61 at its less substituted end. 

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