One-Group C-X Disconnections

Background Needed for this Chapter References to Clayden, Organic Chemistry Chapter 12 Nucleophilic Substitution at the Carbonyl (C=0) Group. 

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. 

The corresponding reactions are mostly ionic involving nucleophilic displacement by SnI, Sn2 or carbonyl substitution with amines, alcohols and thiols on carbon electrophiles. The normal polarity of the disconnection 1 will be a cationic carbon synthon 2 and an anionic heteroatom synthon 3 represented by acyl or alkyl halides 4 as electrophiles and amines, alcohol or thiols 5 as nucleophiles. 

It is possible to use the reverse polarity with a nucleophilic carbon synthon 6 and an electrophilic heteroatom synthon 7 but only with second or third row elements such as S, Si, P and Se. These synthons are represented by organometallic compounds 8 or 9 and compounds 10 such as RSC1, MesSiCl and PI12PCI and we shall consider these later. 

We start with acid derivatives since we almost always choose to disconnect the bond between the heteroatom and the carbonyl group. So we make esters 11 and amides 13 from acid (acyl) chlorides 12 and alcohols or amines. 

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In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

We now leave disconnections of bonds between carbon and other atoms (C-X disconnections) and turn to the more challenging C-C disconnections. These are more challenging because organic compounds contain many C-C bonds and it is not clear at first which ones should be disconnected. There is some very good news the synthons that we met in chapter 6 for two-group C-X disconnections are the ones we shall use for one-group C-C disconnections. We start with an introduction to the three main types. In each case we shall replace one of the heteroatoms by a carbon unit R . 

If disconnection back to available starting materials is impossible in one step, disconnection to give compounds whose synthesis will be easy is often possible. Fragments like (11) or (12) can easily be made by two group C-X disconnections so a disconnection leading to (11) or (12) is good strategy. 

Amine synthesis needs a separate chapter because the C-X disconnection la used for ethers, sulfides and the like in chapter 4 is not suitable for amines. The problem is that the product of the first alkylation 2 is at least as nucleophilic as the starting material 1 (if not more so because of the electron-donating effect of each alkyl group) and further alkylation occurs giving the tertiary amine 3 or even the quaternary ammonium salt 4. It is no use adding just one equivalent of Mel as the first formed product 1 will compete with the starting material 2 for Mel. 

The. synthesis of the minor tranquilliser Oxanamide (31) illustrates how C-X disconnections and FGl can be added to this general plan. The molecule has amide and epoxide FGs. We know of one way to put in each of these groups—by C-N and C 0 disconnection—so we must start here and decide the order of events later. This gives us an , -unsaturated acid, so we can disconnect at the double bond. 

If the target molecule is monofunctional, the disconnection process is classified as a one-group disconnection. The bond initially considered for cleavage would be, if present, the a-carbon-heteroatom single bond (i.e. the C—O, C—X, C—N, C—S bonds) as would be found in, for example, alcohols (Section 5.4), alkyl halides (Section 5.5), ethers (Section 5.6), nitroalkanes (Section 5.15), amines (Section 5.16), thiols and thioethers (Section 5.17). 

If the two heteroatoms are the same, it is usually best to disconnect both C-X bonds, choosing the ones to the same carbon atom, and write a carbonyl group at that atom. The heterocycle 72 has two C-N bonds to the same carbon atom. If we disconnect both, we get cyclohexanone and a very unstable looking imine 73. We know how to make imines combine a carbonyl group with an amine so disconnecting both imines we end up with the diketone 74 and two molecules of ammonia. 

We promised in chapter 1 that a synthesis of the elm bark beetle would appear and here it is. It has four chiral centres but one of them (marked as a hidden carbonyl group) is unimportant. Disconnecting the acetal reveals keto-diol 33. If we make 33 it must cyclise to 3—-no other stereochemistry is possible. Further C-C disconnection with alkylation of an enolate in mind reveals symmetrical ketone 34 and a diol 35 with a leaving group (X) at one end and the two chiral centres (marked with circles) adjacent. 

The analgesic Flupirtine 23 is a simple pyridine with three substituents at the 2, 3, and 6 positions. Removal of the amide shows the core 24. The 4-fluorobenzylamine 25 could be added by nucleophilic substitution (easier in pyridines than in benzenes) and we shall delay the choice of the leaving group (X in 26) for the moment. The only amino group we could conceivably add by nitration is the one in the 3-position so we might continue by FGI (reduction) and C—N disconnection 27. 

The first disconnection to be considered is breaking all the C-X bonds in the ring. This is an obvious strategy for a pyrazole since one C-N bond is part of an enamine and the other is an imine 23. Both functional groups are made from amines and carbonyl compounds. Here hydrazine is the diamine that emerges from an easily made 1,3-dicarbonyl compound 24. 

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