Heck reaction syntheses

Zhou, L. and Wang, L. (2006) Functionalized Ionic Liquid as an Efficient and Recyclable Reaction Medium for Phosphine-Free Palladium-Catalyzed Heck Reaction. Synthesis, 2653-2658, DOI 10.1055/S-2006-942466. 

Figure 9.36 Ligand libraries for the catalyzed Heck reaction synthesis of reagents 9.92 in solution and 9.93 on SP.

Scheme 3-42 Example of a twofold Heck reaction synthesis and reactions of ,Z, )-l,3,5-hexatrienes 159 [141, 194b,c].

Scope and limitations of the Heck reaction synthesis of dienes The Heck reaction with electron-rich alkenes A synthesis of strychnine Recent developments in the Heck reaction Sp2-sp2 Cross-Coupling Reactions by Transmetallation Stille coupling... 

Scope and limitations of the Heck reaction synthesis of dienes... 

A series of new phosphinooxazoline ligands have been recently prepared and tested in the asymmetric Heck reaction. Synthesis of the ligands involved the aromatic nucleophilic substitution of aryl fluorides with phosphide nucleophile generated from the corresponding phosphine and KHMDS (eq 49). The reaction proceeded in good yields, but proved to be more sluggish with electron-rich aryl fluorides and failed completely when the addition of electron-deficient phosphines was attempted. 

Schultz, T. and Pfaltz, A. (2005) Palladium(II) complexes with chelating P,0-ligands as catalysts for the Heck reaction. Synthesis, 1(X)5-11. 

Joseph, B., Cornec, O. and Merour, J.-Y. (1998) Intramolecular Heck reaction synthesis of benzo[4,5]cyclohepta[6]indole derivatives. Tetrahedron, 54, 7765-76. 

Clique, B., Fabritius, C.-H., Couturier, C. et al. (2003) Unexpected isolation, and structural characterization, of a -hydrogen-containing halide complex in the course of an intermolecular Heck reaction. Synthesis of fwlycyclic isoquinoline derivatives. Chem. Commun., 272-3. 

Tietze, L.R and Schimpf, R. (1993) Efficient synthesis of 2,3,4,5-tetrahydro-l//-3-benzazepines by intramolecular Heck reaction. Synthesis, 876 0. 

Heck reaction synthesis of P(PV) derivatives. After Reference [519], reproduced with permission. 

A novel intramolecular, Heck reaction synthesis of a cholesterol-baccatin III hybrid, Angew. Chem. Int. Ed. Engl, 34, 452, 1995. 

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

Asymmetric Heck reaction in synthesis of heterocycles 97T7371. 

Synthesis of heterocycles using the intramolecular Heck reaction involving a formal nnd-elimination process 99H(51)1957. 

Legros et al. (2001T2507) carried out the synthesis of acetylquinolines (e.g. 130) via Heck reaction of 3-bromoquinoline (70) and -butyl vinyl ether (Scheme 16) employing either Pd(dba)2 or Pd(OAc)a as the catalyst. In each case it was found that the Heck reaction for this synthesis gave better overall yields than using the Stille reaction (see Section IV.C). Another advantageous point in favor of the Heck is that it avoids the use of toxic stannane. 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

In a six-step synthesis of (5)-camptothecin (20010L4255), the final step involved a C-ring closure using the Heck reaction. As shown in Scheme 17, 2-chloroquinoline 146 was treated with 15% (PPh3)2Pd(OAc)2 and two equivalents KOAc in CH3CN at 100 °C, affording (5)-campotothecin (147) in 64% yield. 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

The Heck reaction and other related transformations for selective C-C couplings are receiving a great deal of attention among synthetic chemists, due to their versatility for fine chemical synthesis. However, these reactions suffer in many cases from the instability of the Pd-catalysts used, resulting in high catalyst consumption and difficult processing. 

The synthetic strategy towards the copolymers is shown in Figure 16-3. The use of bifunctional monomers in a Heck reaction allows the synthesis of polymers, and the great potential of this approach has been demonstrated previously [53-55]. The syntheses have been described in detail by Hilberer el al. [16],... 

To illustrate the utility of the Heck reaction in organic synthesis, we will address a few of the many spectacular achievements reported thus far. For a much more thorough treatment of this important subject, we direct the reader s attention to a recent review by de Meijere and Meyer.12a... 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

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