Two-Group C-X Disconnections

Background Needed for this Chapter References to Clayden, Organic Chemistry Chapter 10 Conjugate Addition. 

Asked to make the sulfide 1 you would not hesitate to disconnect a C-S bond, choosing the one between the sulfur and the aliphatic part of the molecule to ensure a good S 2 reaction. There 

If you were asked to make the sulfide 4 you might very reasonably take the same decisions, proposing the same sulfur compound 2 as nucleophile and the alkyl bromide 5 as electrophile. 

Organic Synthesis The Disconnection Approach. Second Edition Stuart Warren and Paul Wyatt 2008 John Wiley Sons, Ltd 

The idea with two-group disconnections is that we recruit the other functional group to help us discover a better reagent. Here the carbonyl group can make the cationic centre in 6 electrophilic if we simply add a double bond to the structure. 

---

Salbutamol has three hydroxyl groups and an amine but the only two-group C-X disconnection is of the C-N bond 64a revealing the epoxide 66 as a starting material. This approach is successful but it involves chemistry we encounter in chapter 30 so we shall discuss it there. 

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 . 

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 used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

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. 

Before we leave C-X disconnections and go on to look at OC disconnections we should just review some important points. We suggested three guidelines for choosing disconnections and now that you have met the principle of two-group disconnections, we can add a fourth ... 

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. 

Disconnect structural C-X bonds first and try to use two-group disconnections. 

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. 

Disconnect C-X bonds, especially two-group disconnections. This includes RCO-X. 

---