Diels-Alder approach to tetra-ortho-substituted biaryls employing propargylic tertiary alcohols as dienophiles

The efficient synthesis of a series of tetra-ortho-substituted biaryls is described utilizing a Diels-Alder reaction between propargylic tertiary alcohols and cyclic oxygenated dienes. The successful resolution of one of the biaryls is achieved through derivatization with menthyl chloroformate followed by crystallization. The menthyl carbamate is cleaved under basic conditions to reveal enantiomerically pure biaryl compounds.     

Enantioselective Synthesis of Tetra-ortho-Substituted Axially Chiral Biaryls through Rhodium-Catalyzed Double [2 + 2 + 2] Cycloaddition

[reaction: see text] We have established an enantioselective synthesis of both C2 symmetric and unsymmetric tetra-ortho-substituted axially chiral biaryls through rhodium-catalyzed double [2 + 2 + 2] cycloaddition (up to >99% ee). This method serves as an attractive new route to enantioenriched tetra-ortho-substituted axially chiral biaryls in view of the one-step access to substrate diynes and tetraynes starting from readily available alkynes.     

Synthesis and computational analysis of densely functionalized triazoles using o-nitrophenylalkynes

Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regioselectivity of these cycloadditions. Several new substrates were predicted that would either give enhanced regiocontrol or invert the regiochemical preference. Experimentally, the alkynes were screened in the [3 + 2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition process and their subsequent orthogonal modification was demonstrated.     

Chiral diphosphites derived from D-glucose: new highly modular ligands for the asymmetric catalytic hydrogenation

A series of novel diphosphite ligands derived from readily available D-(+)-glucose have been synthesized. These ligands were screened in the Rh-catalyzed hydrogenation of a series of alpha,beta-unsaturated carboxylic acid derivatives. Both excellent enantioselectivities (ee up to >99%) and activities were achieved. The advantage of these ligands is that their modular nature allows an easy systematic variation in the configuration of the stereocenters (C-3, C-5) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in asymmetric hydrogenation can be determined. Results show that enantiomeric excesses depend strongly on the absolute configuration of C-3 and slightly on the stereocenter carbon C-5, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryls at the phosphite moieties. Moreover, the presence of bulky substituents at the ortho-positions of the biaryl diphosphite moieties has a positive effect on enantioselectivity.     

Characteristics of the two frontier orbital interactions in the Diels-Alder cycloaddition

Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the roles played by the two frontier orbital interactions emerged. It was demonstrated that in the case of normal Diels-Alder cycloadditions, the FMO theory could predict the relative reactivities between dienophiles, while in the case of inverse-electron demand Diels-Alder reactions, it could not. It was shown that the dissymmetry in electron-rich dienophiles increases their reactivities.     

Dual behavior of masked o-benzoquinones in intermolecular Diels-Alder reactions with acyclic dienes: a rapid entry to polyfunctionalized bicyclo[2.2.2]oct-5-en-2-ones and cis-decalins

The potentiality of the masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclohexadienones 5-8, to react both as dienes and dienophiles in their intermolecular reactions has been demonstrated. The masked o-benzoquinones (MOBs) 5-8 generated in situ from 2-methoxyphenols 1-4 underwent intermolecular Diels-Alder cycloadditions with acyclic 1,3-dienes 9a-e to provide bicyclo[2.2.2]octenones 10a-f-13a-f along with cis-decalin derivatives 14a-f-17a-f with regio- and stereoselectivity, except in the case of MOB 8. The formation of cis-decalins in these Diels-Alder reactions illustrates the dienophilic character of MOBs, in addition to their general behavior as dienes. The ratio of the two cycloadducts obtained in each reaction as a result of the dual character of MOBs depends on the nature and/or position of the substituents on both the cyclohexadienone moiety and the added conjugated acyclic diene. All of the cycloadducts resulted from the diene property of MOBs in intermolecular Diels-Alder reactions smoothly underwent Cope rearrangement to furnish cis-decalins as sole products in excellent to quantitative yields.     

Sensitized photo-oxygenation of acyclic conjugated dienes

Sensitized photo-oxygenation of a wide variety of acyclic 1,3-dienes was investigated. The 1,4-cycloaddition of singlet oxygen to acyclic conjugated dienes was closely related to the thermal Diels-Alder reaction in stereospecificity, and steric and electronic effects of substituents. Reactivity order of singlet oxygen toward conjugated dienes and isolated C—C double bonds was exhibited as follows: trisubstituted mono-olefins > 2-substituted 1,3-dienes > disubstituted mono-olefins.     

The trifluoromethoxy group as a fluorine twin in the Diels-Alder reactions of halogenated quinones

We describe here a study devoted to the comparison of the relative influence of chlorine, fluorine, and trifluoromethoxy substituents on the regiochemical outcome of the Diels-Alder reaction. For this purpose, we examined the behavior of mixed ‘halogenated’ quinones bearing these groups in their cycloadditions with simple dienes. Contrary to the expectation based on its known electronic properties, the trifluoromethoxy group behaves very much more like a fluorine than a chlorine atom in such reactions. On the basis on an endo transition state demonstrated here for these additions, we tentatively suggest that non-bonded interactions are the main factor controlling the regiochemistry.     

Diels-Alder approach for the construction of halogenated, o-nitro biaryl templates and application to the total synthesis of the anti-HIV agent siamenol

A rapid Diels-Alder approach to halogenated biaryl templates is described. These biaryl templates are available in two steps from the corresponding aromatic aldehydes. The scope of subsequent Suzuki couplings on the biaryl chlorides is explored. Good tolerance for both electron-donating and electron-withdrawing groups in the coupling process can be achieved. Further functionalization of the biaryl templates is described. Hydrogenation of the nitro moiety with concomitant removal of the benzyl ether yields the o-anilino, o-phenolic polyaryls. Selective reduction of the nitro group can be accomplished. Alternatively, the benzyl ether can be selectively removed under Lewis acidic conditions. The utilization of the Diels-Alder adducts for the synthesis of a series of chlorinated carbazoles via the Cadogan cyclization is also demonstrated. Finally, application of this technology to the total synthesis of siamenol, an anti-HIV agent, is reported.     

Scandium triflate and secondary amine promoted AA′B 2:1 coupling and formal inverse electron demand Diels-Alder reactions of dienals

Reaction prospecting studies resulted in the discovery of a Sc(OTf)₃ promoted novel AA′B 2:1 coupling of imidazolone or benzofuran substituted enals with morpholine. A related Sc(OTf)₃/morpholine promoted reaction was demonstrated for the coupling of a benzofuran substituted enal with dihydrofuran. The formation of these adducts is consistent with formal inverse electron demand Diels-Alder cycloadditions, most likely in a stepwise manner via a domino Michael-Mannich annulation process, involving iminium ion activation of the diene. A purely amine promoted formal inverse electron demand Diels-Alder cycloaddition approach was also demonstrated in the 2:1 coupling of 2,4-hexadienal with methanol. These reactions demonstrate the concepts of dual metal/amine catalysis and amine promoted formal inverse electron demand Diels-Alder cycloadditions. They differ from known examples of organocatalyzed Diels-Alder reactions, in which iminium ion activation of the dienophiles or enamine activation of the dienes occur.     

Synthesis of 4-aryl- and 4-alkyl-2-silyl-1,3-butadienes and their Diels-Alder/cross-coupling reactions

An ene-yne cross methasis of silyl-substituted alkynes and alkenes has been developed as a route to 4-aryl- and 4-alkyl-2-silyl-substituted 1,3-dienes. The dienes prepared were used to affect highly diastereoselective Diels-Alder reactions and then the silicon-substituted Diels-Alder cycloadducts were used in Hiyama cross-coupling reactions. The cross-coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes one might prepare and need access to. Two of the silicon-substituted Diels-Alder cycloadducts and one of the Hiyama cross-coupling products were also characterized by X-ray crystallography.     

Racemic and asymmetric Diels-Alder reactions of 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes

Achiral and chiral 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes were prepared from readily available starting materials. Although more stable than the parent 1-amino-3-siloxy dienes, the 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes are still very reactive in Diels-Alder reactions, somewhat more than 1,3-dialkoxy-1, 3-butadienes (e.g., Danishefsky's diene). The cycloadditions of the achiral and chiral dienes with several different dienophiles were examined. The reactions proceeded in good yield, with modest to high endo selectivity. The chiral dienes exhibited excellent facial selectivity in cycloadditions with alpha-substituted acroleins, maleic anhydride and N-phenylmaleimide. Upon reduction and hydrolysis of the cycloadducts, substituted cyclohexenones were obtained with ee's ranging from 22% to >98%.     

Metal-free,noncovalent catalysis of diels-alder reactions by neutral hydrogen bond donors in organic solvents and in water

We examined the catalytic activity of substituted thioureas in a series of Diels-Alder reactions and 1,3-dipolar cycloadditions. The kinetic data reveal that the observed accelerations in the relative rates are more dependent on the thiourea substituents than on the reactants or solvent. Although the catalytic effectiveness is the strongest in noncoordinating, nonpolar solvents, such as cyclohexane, it is also present in highly coordinating polar solvents, such as water. In 1,3-dipolar cycloadditions, the thiourea catalysts demonstrate only very moderate selectivity for reactions with inverse electron demand. Our experiments emphasize that both hydrophobic and polar interactions can co-exist, making these catalysts active, even in highly coordinating solvents. This class of catalysts increases the reaction rates and endo-selectivities of Diels-Alder reactions, in a similar manner to weak Lewis acids, without concomitant product inhibition.     

Synthesis of extended triphenylenes by palladium-catalyzed [2+2+2] cycloaddition of triphenylynes

The synthesis of ortho-(trimethylsilyl)triphenylenyl triflates 7 is described. Fluoride-induced decomposition of these triflates leads to the generation of didehydrotriphenylenes (triphenylynes) 6. These arynes undergo [4+2] cycloadditions with dienes to afford the corresponding Diels-Alder adducts or palladium-catalyzed formal [2+2+2] cycloadditions to afford extended triphenylenes.     

Micellar Catalysis TT45 + TT2S Cycloaddition in Aqueous Media

Micelle catalyzed Diels-Alder reaction of cyclic dienes with various quinones in aqueous media is described. Micellar cycloadditions are remarkably faster and give better yields of the adducts compared to the conventional reaction.     

Hetero [4 + 2] cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of alpha,beta-unsaturated delta-valerolactones and -lactams

[formula: see text] Hetero Diels-Alder reactions of (trialkylsilyl)vinylketenes (TAS-vinylketenes) with carbonyl and imino dienophiles are described. TAS-vinylketenes participate as electron-rich dienes in [4 + 2] cycloadditions with diethyl ketomalonate to afford alpha,beta-unsaturated delta-valerolactones in good yield. Nonenolizable N-alkyl- and N-(trimethylsilyl)imines combine with TAS-vinylketenes to furnish alpha,beta-unsaturated delta-valerolactams. In contrast to most Diels-Alder reactions involving unactivated imines, these cycloadditions do not require promotion by Lewis acids and in general proceed with a high degree of stereoselectivity.     

Novel chiral 1-phosphono-1,3-butadiene for asymmetric hetero Diels-Alder cycloadditions with nitroso and azodicarboxylate dienophiles

Chiral 1-phosphonodienes bearing a bicyclic (R,R)-1,3,2-dioxaphospholane or a (R,R)-1,3,2-diazaphospholidine auxiliary are potent dienes for asymmetric hetero Diels-Alder reactions. Their reactivity towards model nitroso and azodicarboxylate dienophiles has been studied by means of theoretical chemistry at the B3LYP/6-31G∗∗ level. This model, taking solvent effects into account, allowed us to identify parameters governing the stereoselectivity of this reaction. Our study emphasizes a synergy effect when increasing the steric hindrance of substituents of both partners. This led us to predict high levels of diastereoselectivity for one diene. Accordingly, we have hereby illustrated a convenient and original synthesis of this diene and its cycloadditions with commercially available nitroso and azodicarboxylate dienophiles.     

Alkyne hydrosilylation catalyzed by a cationic ruthenium complex: efficient and general trans addition

The complex [Cp*Ru(MeCN)3]PF6 is shown to catalyze the hydrosilylation of a wide range of alkynes. Terminal alkynes afford access to alpha-vinylsilane products with good regioselectivity. Deuterium labeling studies indicate a clean trans addition process is at work. The same complex is active in internal alkyne hydrosilylation, where absolute selectivity for the trans addition process is maintained. Several internal alkyne substrate classes, including propargylic alcohols and alpha,beta-alkynyl carbonyl compounds, allow regioselective vinylsilane formation. The tolerance of a wide range of silanes is noteworthy, including alkyl-, aryl-, alkoxy-, and halosilanes. This advantage is demonstrated in the direct synthesis of triene substrates for silicon-tethered intramolecular Diels-Alder cycloadditions.     

Functionalization of single-wall carbon nanotubes by tandem high-pressure/Cr(CO)6 activation of Diels-Alder cycloaddition

An original method to induce Diels-Alder cycloadditions on carbon nanotubes is reported. The process is based on the double activation of the nanotube surface by combining high pressure and Cr(CO)6. This allows the efficient functionalization of carbon nanotubes by electron-rich dienes.     

Intermolecular enol ether-alkyne metathesis

[reaction: see text] A new intermolecular metathesis between a variety of alkynes and alkyl enol ethers is described. The best results were obtained with the second generation Grubbs' precatalysts. The reaction occurred with a high degree of regioselectivity and provided electron-rich dienes, which underwent a variety of [4 + 2] cycloadditions.