s for Chapter 40 40 PBLEM 1 Suggest mechanisms for these reactions, explaining the role of palladium in the first step. Ac Et Et BS () 4 2 1. 2. K 2 C 3 evision of enol ethers and bromination, the Wittig reaction, and, of course, first steps in palladium chemistry. The first step is a reaction of an enol with an allylic acetate catalysed by palladium(0) via an η 3 allyl cation. There is no regiochemistry to worry about as the diketone and allylic acetate are both symmetrical. Ac Et () 4 Ac L n Et L n Et You might have drawn the η 3 allyl cation complex in various satisfactory ways some are mentioned on p. 1089 of the textbook. L n Et Et BS in aqueous solution is a polar brominating agent, ideal for reaction with an enol ether. The intermediate is hydrolysed to the ketone by the usual acetal style mechanism.
2 Solutions Manual to accompany rganic Chemistry 2e Et Et 2 This process is a general way to make 5,5 fused systems devised by B. M. Trost and D. P. Curran, J. Am. Chem. Soc., 1980, 102, 5699. Finally, an intramolecular Wittig reaction. This is a slightly unusual way to do what amounts to an aldol reaction but the 5,5 fused enone system is strained and the Wittig went under very mild conditions (K 2C 3 in aqueous solution). The stereochemistry of the new double bond is the only one possible and Wittig reactions with stabilised ylids generally give the most stable of the possible alkene. P 3 K 2 C 3 2 P 3 Wittig PBLEM 2 This eck- style reaction does not lead to regeneration of the alkene. Why not? What is the purpose of the formic acid (C2) in the reaction mixture? I, cat. () 2 (Ac) 2 C 2, 2, DMF Making sure you understand the steps in the mechanism of the eck reaction. The reaction must start with the oxidative addition of (0) into the I bond. The reagent added is (II) so one of the reduction methods on page 1081 of the textbook must provide enough (0) to start the reaction going. The oxidative addition gives I and this does the eck reaction on the alkene. Addition occurs on the less hindered top (exo- ) face and the phenyl group is transferred to the same face.
Solutions for Chapter 40 rganometallic chemistry 3 I (0) oxidative insertion I I I ormally now the alkyl palladium(ii) species would lose palladium by β- elimination. This is impossible in this example as there is no hydrogen atom syn to the I group. Instead, an external reducing agent is needed and that is the role of the formate anion: it provides a hydride equivalent by transfer hydrogenation when it loses C 2. A heterocyclic version of this reaction was part of a synthesis of the natural analgesic epibatdine by S. C. Clayton and A. C. egan, Tetrahedron Lett., 1993, 34, 7493. I 2 C 2 PBLEM 3 Cyclization of this unsaturated amine with catalytic (II) under an atmosphere of oxygen gives a cyclic unsaturated amine in 95% yield. ow does the reaction work? Why is the atmosphere of oxygen necessary? Explain the stereochemistry and regiochemistry of the reaction. ow would you remove the C2Bn group from the product? C 2 Bn cat. (II) 2 C 2 Bn Introducing you to aminopalladation : like oxypalladation, nucleophilic attack on a palladium π- complex. The π- complex between the alkene and (II) permits nucleophilic attack by the amide on its nearer end and in a cis fashion because the nucleophile is tethered by a short chain of only two carbon atoms. ucleophilic attack and elimination of (0) occur in the usual way. The removal of the C 2Bn group would normally be done by hydrogenolysis but in this case ester hydrolysis by, say, would be preferred to
4 Solutions Manual to accompany rganic Chemistry 2e This general synthesis of heterocycles was introduced by J.- E. Bëckvall and group, Tetrahedron Lett., 1995, 36, 7749. avoid reduction of the alkene. The free acid decarboxylates spontaneously. X X C 2 Bn (0) X C 2 Bn C 2 Bn + X PBLEM 4 Suggest a mechanism for this lactone synthesis. C, Bu 3 cat. (Ac) 2 Introducing you to carbonyl insertion into a palladium (II) σ- complex. M. Moru et al., eterocycles, 1979, 12, 921. xidative insertion into the aryl bromide, carbonylation, and nucleophilic attack on the carbonyl group with elimination of (0) form the catalytic cycle. o doubt the palladium has a number (1 or 2?) of phosphine ligands complexed to it during the reaction and these keep the (0) in solution between cycles. (0) L n C
Solutions for Chapter 40 rganometallic chemistry 5 PBLEM 5 Explain why enantiomerically pure lactone gives syn but racemic product in this palladium- catalysed reaction. C 2 Me 2 C C 2 Me ( )-lactone () 4 syn but racemic C 2 Me C 2 Me elping you to understand the details of palladium- catalyzed allylation. Following the usual mechanism, the palladium complexes to the face of the alkene opposite the bridge. The ester leaves to give an allyl cation complex. This is attacked by the malonate anion from the opposite face to the palladium. So the overal result is retention of configuration, the syn starting material giving the syn product. C 2 C 2 C 2 L n L n C 2 Me C 2 Me L n C 2 Me C 2 Me C 2 Me C 2 Me The racemization comes from the structure of the allyl cation complex. It is symmetrical with a plane of symmetry running vertically through the complex as drawn. Attack by the malonate anion occurs equally at either side of the plane giving the two enantiomers of the syn diasterereoisomer in equal amounts. This investigation helped to establish the mechanism of these reactions: B. M. Trost and.. Schmuff, Tetrahedron Lett., 1981, 22, 2999. C 2 C 2 C 2 Me 2 C Me 2 C C 2 Me C 2 Me C 2 Me Me 2 C L n C 2 Me C 2 Me
6 Solutions Manual to accompany rganic Chemistry 2e PBLEM 6 Explain the reactions in this sequence, commenting on the regioselectivity of the organometallic steps. SiMe 3 Mg C (0) C, 2 work-up Cu(I), 2 3 evision of allylic Grignard reagents, the synthesis of pyridines, and the mechanism of the Wacker oxidation. The allylic Grignard reagent does direct addition from the end remote to the magnesium atom, as often happens. ydrolysis of the silyl enol ether reveals an aldehyde. Mg SiMe 3 Mg SiMe 3, 2 SiMe 3 2 SiMe 3 2 SiMe 3 C ow the Wacker oxidation, by whatever detailed mechanism you prefer, must involve the addition of water to a (II) π- complex of the alkene and β- elimination of palladium to give (0) which is recycled by oxidation with oxygen mediated by copper.
Solutions for Chapter 40 rganometallic chemistry 7 C 2 (II) Cl C Cl C Cl C Finally, the pyridine synthesis is simply a double enamine/imine formation between ammonia and the two carbonyl groups. Probably the aldehyde reacts first. C 3 2 M. A. Tius, Tetrahedron Lett., 1982, 23, 2819 PBLEM 7 Give a mechanism for this carbonylation reaction. Comment on the stereochemistry and explain why the yield is higher if the reaction is carried out under a carbon monoxide atmosphere. Cl C 2 CCl ence explain this synthesis of part of the antifungal compound pyrenophorin. Bn AIB Bn Cl C 2 CCl Si 2 t-bu Si 2 t-bu Bn More carbonylation with a Stille coupling.
8 Solutions Manual to accompany rganic Chemistry 2e The tin- palladium exchange (transmetallation) occurs with retention of configuration at the alkene. The exchange of the benzyl group for the benzoyl group is necessary to get the reaction started. Cl + C 2 + Cl + CCl + C 2 Cl ow the coupling can take place on the palladium atom producing the product and (0) which can insert oxidatively into the C Cl bond. Transmetallation sets up a sustainable cycle of reactions. It is better to have an atmosphere of carbon monoxide because the acyl palladium complex can give off C and leave a σ- complex. The atmosphere of C reverses this reaction. Cl + 3P + 3 P CCl + C 2 Cl Cl The second sequence starts with a radical hydrostannylation (chapter 37) giving the E- vinyl stannane preferentially if a slight excess of Bu 3Sn is used. Bn SnBu 3 Bn SnBu 3 C 2 Bn C 2 Bn ow the coupling with the acid chloride takes place as before though this time we have an aliphatic carbonyl complex. There is no problem with β- elimination as that would give a ketene. Again, the stereochemistry of the vinyl stannane is retained in the product.
Solutions for Chapter 40 rganometallic chemistry 9 Si 2 t-bu CCl + C 2 Bn ( 3 ) 2 ClBn Si 2 t-bu C 2 Bn Si 2 t-bu Bn PBLEM 8 The synthesis of an antifungal drug was completed by this palladium- catalysed reaction. Give a mechanism, explaining the regio- and stereochemistry. Me Me t-bu Ac () 4 A simple example of amine synthesis using palladium. The palladium forms the usual allyl cation complex and the nitrogen nucleophile attacks the less hindered end thus also retaining the conjugation. Attack at the triple bond would give an allene. The E stereochemistry of the palladium complex is retained in the product. () 4 product Ac Me L 2
10 Solutions Manual to accompany rganic Chemistry 2e PBLEM 9 Work out the structures of the compounds in this sequence and suggest mechanisms for the reactions, explaining any selectivity. C heat with catalyitc acid A C (II) CuCl, 2 B K 2, TF C B has I: 1730, 1710 cm 1, δ 9.4 (1, s), 2.6 (2, s), 2.0 (3, s), and 1.0 (6, s). C has I: 1710 cm 1, δ 7.3 (1, d, J 5.5 z), 6.8 (1, d, J 5.5 z), 2.1 (2, s), and 1.15 (6, s). An intramolecular aldol reaction (p. 636) and a Wacker oxidation (p. 1096). B clearly has aldehyde and ketone functional groups with nothing but singlets in the M. n the other hand C has a cis disubstituted alkene with a small (and therefore cis) J value and is a cyclpentenone. (II) K A C CuCl, 2 B C 2, TF C
Solutions for Chapter 40 rganometallic chemistry 11 PBLEM 10 A synthesis of the istol- Meyers Squibb anti- migraine drug Avitriptan (a 5- T receptor antagonist) involves this palladium- catalysed indole synthesis. Suggest a mechanism and comment on the regioselectivity of the alkyne attachment. S Me I + 2 SiEt 3 Me cat. (Ac) 2, LiCl, a 2 C 3 2, MeC S Me SiEt 3 Me A new reaction for you to try a palladium- catalysed indole synthesis. Although palladium(ii) is added to the solution, the aryl iodide tells you that this is an oxidative insertion of (0) produced by one of the methods described on p. 1081 of the textbook. The resulting (II) species complexes to the alkyne and the amine can now attack the triple bond. This gives a heterocycle with the (II) in the ring. Coupling of the two organic fragments extrudes (0) to start a new cycle. The nitrogen attacks the more hindered end of the alkyne so that the palladium can occupy the less hindered end.
12 Solutions Manual to accompany rganic Chemistry 2e S Me I 2 (0) S Me I 2 SiEt 3 S Me SiEt 3 (0) S Me SiEt 3 This is the Larock indole synthesis (. C.Larock and E. K. Yum, J. Am. Chem. Soc., 1991, 113, 6689) and its usedin the synthesis of Avitriptan is described in P. D. od fuehrer et al, J. rg. Chem., 1997, 62, 9192).