Heck reaction with allyl alcohols

Scheme 3-6 Heck reaction with allyl alcohols in the presence of silver salts.

Scheme 5-23. Double Heck reaction with allyl alcohol and subsequent aldol...

Different results were obtained using allylic alcohols as terminating agents. In spite of the expected reactivity of the alcoholic function as hydrogen donor only products deriving from the reaction of the double bond were obtained (23) according to the general pattern previously described for Heck-type reactions with allylic alcohols (24). 

A broad variety of special aldehydes and ketones are easily accessible by Heck-type reactions with allylic alcohols and their homologs [3]. The potential for the synthesis of carbocydic structures is illustrated by the macrocyde 11 [4] which obviously is the product of a fourfold Heck reaction (Scheme 3). A domino process consisting of a double Heck reaction followed by an intramolecular Aldol condensation leads to the annulated ring system 15 [5]. 

Muzart et al. used PdCl2 in [NBu4]Br for the Heck reaction of iodobenzene with various allylic alcohols.30 The Heck reaction of allylic alcohols can lead to the formation of aryl ketones (a- or (3-substituted) as well as the (a- or (S-J arylated allylic alcohols. However, these authors... 

PdCE-catalyzed addition reaction of allyl chloride to alkynes is explained by chloropalladation of a triple bond, followed by insertion of the double bond of allyl chloride to generate 43. No jr-allyl complex is formed from allyl chloride and PdCl2. The final step is elimination of /3-Cl to afford 1-chloro-1,4-diene 44 with regeneration of Pd(ll) [37]. As another example, the Pd(0)-catalyzed Heck reaction of vinyl acetate affords stilbene in this reaction, the primary product is /3-phenylvinyl acetate (45), which reacts again with iodobenzene, and the last step is elimination of /S-OAc to give stilbene. At the same time, Pd(II) is generated, which is reduced to Pd(0) in situ [38]. However, elimination of /3-heteroatoms is not always faster than that of j8-H. For example, the Heck reaction of allyl alcohol with iodobenzene proceeds by preferential elimination of /3-H from the insertion product 46 to afford aldehyde 47, and no elimination of /3-OH from the same carbon occurs to give the alkene 48 [39,40]. 

Similarly, Heck reactions with allylic and homoaUylic alcohols in Scheme 46 lead to intermediary carbonyl compounds, which subsequently undergo heterocyclization either by formation of a hemiacetal (first example) or by cyclocondensation (second ex-ample). f In both cases the palladium catalyst is not involved in the heterocyclization step. 

Jeffery has reported an alternative additive-based solution to yield Hy-abstracted products. Mizoroki-Heck reaction of allylic alcohols with aryl or alkenyl hahdes in the presence of silver salts (AgOAc or Ag2C03) results in selective Hy -abstraction [7]. Similar hydroxy-coordination to the cationic organopalladium intermediates are believed to be involved in this system. In this regard, the use of hypervalent iodonium salts is also effective for generating cationic palladium species [8]. 

A combination of a Heck reaction with an aldol condensation is observed on treatment of aromatic aldehydes or ketones as 6/1-151 with allylic alcohols as 6/1-152, as described by Dyker and coworkers [83]. The Pd-catalyzed reaction led to 6/1-154 via 6/1-153, in 55% yield (Scheme 6/1.40). 

Heck C-C coupling reactions were also facilitated by the presence of a palladium catalyst when Pd was deposited on a tubular membrane of porous glass. Thus, the coupling of iodobenzene with allyl alcohol affording 3-phenylpropionaldehyde in the presence of this Pd catalyst had several advantages - the ease of catalyst manufacture, mechanical strength, thermal stability, and resistance to organic solvents [46],... 

In the presence of additional unsaturation, the intermediate a-palladium bond formed in these transformations can undergo a further Heck process to establish an additional C-C bond. The reactions of allylic alcohols with vinyl ethers proceed along this pathway and lead diastereoselectively to THFs (Equation (112)), with Cu(OAc)2409 and 02410 used as the stoichiometric oxidants. This methodology has been used to good effect in the syntheses of (—)-dihy-droxanthatin,409 fraxinellone limonoids,411 and mycalamide A.412... 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

Mdrour also explored the Heck reactions of indolyl triflates with allylic alcohols [139, 258]. For example, reaction of triflate 227 with allyl alcohol gives the rearranged allylic alcohol 228 [139],... 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

Both 2-bromothiophene and 3-bromothiophene have been coupled with allyl alcohols to make thienylated a, 3-unsaturated ketones [124], Iodothiophenes were more reactive than the corresponding bromides, whereas the chlorothiophenes were unreactive. As expected, 2-bromothiophene was two to three times more reactive than 3-bromothiophene. In addition to the expected Heck adduct 149, the reaction of 2-bromothiophene 148 with l-methylprop-2-en-l-ol also resulted in the regiosmer 150. 

Scheme 8 Heck-type phenylation reaction of allyl alcohol with Ph2BiCl...

A polyethylene glycol-polystyrene graft copolymer palladium catalyst has been used in allylic substitution reactions of allyl acetates with various nucleophiles in aqueous media.58 Another polymer-bound palladium catalyst 40 was developed and used in a Heck coupling of allylic alcohols with hypervalent iodonium salts to afford the substituted allylic alcohols as the sole products under mild conditions with high catalytic efficiency.59 The same polymer-bound palladium catalyst has also been used for Suzuki cross-coupling reactions.60... 

However, the most important of Someis contributions in this area are Heck reactions of haloindoles with allylic alcohols [26, 240, 242-245, 247, 248]. For example, reaction of 4-... 

According to Larock and Kuo the Heck reaction of 2-iodoaniline (20) with allylic alcohols initiates cydocondensation to an imine which finally gives quinolines, in good to moderate yields, by subsequent oxidative aromatization [7]. The analogous reaction with homoallylic alcohols stops at the stage of the imine, thus resulting in benzazepines 23 (Scheme 4) [8]. The result with pyridyl-substituted homoallylic... 

The reaction of allylic alcohols and aryl halides in the presence of a palladium catalyst has been used in the past to prepare various 0-arylal-dehydes. The procedure described here is essentially that of Heck and Melpolder.3 A similar reaction has been carried out with bromobenzene and 2-methyl-2-propen-l-ol in hexamethylphosphoric triamide (HMPT) as solvent with sodium bicarbonate as base. A variety of other bases have also been used.4 2-Methyl-3-phenylpropanal has been prepared by reacting palladium acetate and phenylmercuric acetate with 2-methyl-2-propen-l-ol.5... 

Heck reaction is a diene, trienes are obtained (equation l26). Heck coupling of allylic alcohols and alkenyl iodides has been employed for the synthesis of vitamin A and related compounds (equation A similar double Heck reaction on a Cio-diiodide with... 

However, the most important of Somei s contributions in this area are Heck reactions of haloindoles with allylic alcohols [26, 248a,c-f,h,i]. For example, reaction of 4-iodo-3-indolecarboxaldehyde with 2-methyl-3-buten-2-ol afforded alcohol 231 in high yield. This could be subsequently transformed to ( )-6,7-secoagroclavine (232) [248c]. Interestingly, the one-pot thallation-palladation protocol failed in this case. 

In the last chapter we introduced the Heck reaction as a way to add nucleophiles to electrophilic alkenes. The details of the mechanism are discussed there. The reaction also occurs with allylic alcohols 218 and is a good way to make carbonyl compounds, particularly aldehydes, 219 as the alternative conjugate addition of an organometallic compound to an enal often shows poor regioselectivity (chapter 9). 

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