Heck reaction allylic alcohols

Related reactions, that have been catalysed by NHC/Pd systems, are the intramolecular Mizoroki-Heck using catalysts formed in situ from imidazolium salts and a Pd(0) source [69], and the arylation of allylic alcohols by a benzothiazole-Pd complex [70,71] (Scheme 6.14). 

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 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). 

The selectivity in the Heck reaction of allylic alcohol 111 is interesting, and the factors that lead to the observed preference for (3-hydride elimination toward nitrogen in this system are unclear, although a combination of steric effects and stereoelectronic factors (i.e., alignment of C-H and C-Pd bonds, nN a c H interactions) is likely involved. Examination of related examples from the literature (Scheme 4.20) reveals no clear trend. Rawal and Michoud examined substrate 115, which lacks the influence of both the amine and hydroxyl substituents and also seems to favor (3-hydride elimination within the six-membered ring over formation of the exocyclic olefin under standard Heck conditions [18a]. However, under... 

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],... 

Suitably positioned vinyl halide can undergo Heck-type intramolecular coupling to generate dienes (equations 124 and 125)216,217. When one of the reacting partners in the Heck reaction is a diene, trienes are obtained (equation 126)218. Heck coupling of ally lie alcohols and alkenyl iodides has been employed for the synthesis of vitamin A and related compounds (equation 127)219,220. A similar double Heck reaction on a Cio-diiodide with a Cis-allylic alcohol leads to -carotene as a mixture of isomers (equation 128)209e. 

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...

Heck-type phenylation of allyl alcohol with Ph2BiCl proceeded in the presence of Pd(OAc)2 to afford an isomerized product, 3-phenylpropanal, in 61% yield together with biphenyl (Scheme 8) [23]. The reaction required air (or oxygen) for catalytic conversion. A similar reaction with Ph2SbCl was more efficient and afforded 3-phenylpropanal in 94% yield. 

Bienayme and Yezeguelian [63] described a new synthesis of retinal via a Heck vinylation of a C15 tertiary allylic alcohol with a C5 iodoacetal. Thus, the bromo acetal was prepared by a known procedure [64], by a bromination-dehydrobromination reaction sequence (E and Z isomers 40/60). 

Unlike 4-19, the Heck reaction is not limited to activated substrates. The substrate can be a simple olefin, or it can contain a variety of functional groups, such as ester, ether,319 carboxyl, phenolic, or cyano groups.320 Primary and secondary allylic alcohols (and even nonallylic unsaturated alcohols321) give aldehydes or ketones that are products of doublebond migration,322 e.g.,... 

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... 

Benzamido-cinnamic acid, 20, 38, 353 Benzofuran polymerization, 181 Benzoin condensation, 326 Benzomorphans, 37 Benzycinchoninium bromide, 334 Benzycinchoninium chloride, 334, 338 Bifiinctional catalysts, 328 Bifiinctional ketones, enantioselectivity, 66 BINAP allylation, 194 allylic alcohols, 46 axial chirality, 18 complex catalysts, 47 cyclic substrates, 115, 117 double hydrogenation, 72 Heck reaction, 191 hydrogen incorporation, 51 hydrogen shift, 100 hydrogenation, 18, 28, 57, 309 hydrosilylation, 126 inclusion complexes, oxides, 97 ligands, 19, 105 molecular structure, 50, 115 mono- and bis-complexes, 106 NMR spectra, 105 olefin isomerization, 96... 

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-... 

The rate of the palladium-catalysed Heck-type phenylation of allylic alcohols has been found to be markedly enhanced by addition of tertiary amines454. Regioselectivity can be increased, in some cases, by adding E NCl or employing a Wilkinson Rh catalyst (rather than pd)455 456. Another Heck-type reaction involves addition of arenediazonium tetraflu-oroborates to a-silylstyrenes to give (Z )-PhCH=CHAr. A BF4 -mediated vyw-elimination of silicon and palladium has been suggested to account for the stereochemistry457. 

Since 1,4 addition of a variety of appropriate aryl caibanions to 36 failed, an intramolecular version of the Heck reaction was examined. With this end in view, the ketone 36 was reduced stereospecifically to the corresponding allyl alcohol which was then protected as its p-methoxybenzyl ether 37. The amine, obtained on reduction of the azide 37, was condensed with 6-bromopiperonylic acid to furnish the amide 38. 

Several commercial products have been produced via Heck reactions on a scale in excess of one ton year"1 [43]. The sunscreen agent 2-ethylhexyl-p-methoxycinna-mate has been synthesized on a pilot scale by using Pd/C as the catalyst [44]. Albermarle produces Naproxen via a Heck reaction of 2-bromo-6-methoxy-naphthalene with ethylene, followed by carbonylation of the product [45]. A key step in the production of Singulair (montelukast sodium), a leukotriene receptor antagonist for treatment of asthma, is Heck reaction of methyl 2-iodobenzoate with an allylic alcohol to give a ketone [43]. 

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]. 

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 first example was described in the mid-1980s independently by Jeffery, Hallberg, and others in their work on Heck coupling. The former demonstrated the beneficial role of silver salts in the formation of dienols from allylic alcohols and vinyl iodides, as well as the role of counterion or phase transfer conditions (Scheme 10.28).50 The latter found that silver salts accelerated the reaction between aryl iodide and allyl or vinyl silanes, reinforcing regioselectivity and avoiding desilylation (Scheme 10.29).51... 

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... 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

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... 

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