Cycloaddition reaction with acrolein

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

Examples with 2-vinylindoles are also found. Thus, the reaction of N-methyl-2-(2-methoxyvinyl)indole, as a cis-trans mixture, with acrylonitrile and ethyl and methyl acrylate gives the corresponding Diels-Alder compounds [83IJC(B)846]. With N-methyl-2-(2-nitrovinyl)indole as diene, similar reactions occur with methyl acrylate, acrylonitrile, and acrolein acetal but in these cases, the fully aromatic compounds were isolated. The cycloaddition reaction with acrolein acetal was nonregioselective and the isolated adducts had a CHO group, indicating that the acetal had been hydrolyzed (presumably during work-up). 

A substituted a,/3-unsaturated aldehyde, cinnamaldehyde, has been observed to undergo the same type of two-step 1,3-cycloaddition reaction with a cyclohexanone enamine as acrolein does, forming in this case a stereo-isomeric mixture of substituted bicycloaminoketones in excellent yield (29a,31a,31b). 

In an investigation by Yamabe et al. [9] of the fine tuning of the [4-1-2] and [2-1-4] cycloaddition reaction of acrolein with butadiene catalyzed by BF3 and AICI3 using a larger basis set and more sophisticated calculations, the different reaction paths were also studied. The activation energy for the uncatalyzed reaction were calculated to be 17.52 and 16.80 kcal mol for the exo and endo transition states, respectively, and is close to the experimental values for s-trans-acrolein. For the BF3-catalyzed reaction the transition-state energies were calculated to be 10.87 and 6.09 kcal mol , for the exo- and endo-reaction paths, respectively [9]. The calculated transition-state structures for this reaction are very asynchronous and similar to those obtained by Houk et al. The endo-reaction path for the BF3-catalyzed reaction indicates that an inverse electron-demand C3-0 bond formation (2.635 A... 

The same catalytic effect imparted by the empty capsule was observed changing the diazoacetate ester in the reaction with acrolein. In fact, with the t-butyl derivative the reaction with the capsule led to 97% yield, and with benzyl diazoacetate 54% yield of the corresponding cycloaddition product was observed. In both cases, the presence of the capsule occupied by the ammonium inhibitor led to a marked decrease of product formation. The higher conversions obtained in the presence of t-butyl diazoacetate as substrate were probably due to the good affinity with the cavity by means of CH-ji interactions. 

It was thought that a new type of analog that does not contain the endocyclic double bond could be synthesized in almost exactly the same manner. Instead of the mono-esterified pimelic acid undergoing the aldol reaction with acrolein, an allyl group could be installed via a simple enolate alkylation reaction. Subsequent methylation, elimination, decarboxylation, cycloaddition, and cross-metathesis steps could be performed in the same manner as before with the result being a more saturated analog (76 Scheme 15). The synthesis to generate diester 73 proceeded as planned however, numerous decarboxylation conditions failed. 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Monodentate dipolarophiles such as acrolein, methacrolein, and a-bromoacrolein could be successfully utilized in the l ,J -DBFOX/Ph-transition metal complex-catalyzed asymmetric nitrone cycloadditions [76]. The reactions of N-benzylideneani-line N-oxide with acrolein in the presence of the nickel(II) aqua complex R,R-DBF0X/Ph-Ni(C104)2 3H20 (10mol%) and MS 4 A produced a mixture of two regioisomers (5-formyl/4-formyl regioisomers ca 3 1). However, enantio-... 

The Lewis acid-catalyzed 1,3-dipolar cycloaddition reaction of nitrones to a,/ -un-saturated carbonyl compound in the presence of Lewis acids has been investigated by Tanaka et al. [31]. Ab-initio calculations were performed in a model reaction of the simple nitrone 18 reacting with acrolein 1 to give the two cycloadducts 19 and 20 (Scheme 8.7). 

Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a, S-unsaturated aldehydes with several dienes. It has been prepared from (ri -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels-Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. 

Indium trichloride [30] and methylrhenium trioxide [31] catalyze the aqueous Diels-Alder reaction of acrolein and acrylates with cyclic and open-chain dienes. Some examples of the cycloaddition of methyl vinyl ketone with 1,3-cyclohexadiene are reported in Scheme 6.18. MeReOs does not give satisfactory yields for acroleins and methyl vinyl ketones with substituents at the jS-position and favors the self-Diels-Alder reaction of diene. 

In reactions in which methyl acrylate is used as the dienophile (Scheme 6.33), cycloadditions occur with lower levels of enantioselection (23% ee, as compared to 53 % observed for acrolein), but with significantly higher degrees of diastereoselectivity (17 1, endo-.exo). Improved levels of endo selectivity are observed in the case of the methyl ester (Scheme 6.33) this is perhaps because, at least in part, the dienophile p-system is oriented towards the t-butoxy ligand, where the steric influence of the bulky substituent is expected to be more pronounced. As before, formation of the endo isomer may occur to a greater extent, since the transition structure that leads to the exo isomer would involve energetically unfavorable interactions between the diene... 

Two other applications of catalyst 364, i.e. in cycloaddition reactions of a-substituted acroleins with dienes 374 and 376, have been depicted in equations 110 and 111237. Cycloadducts 375 and 377 have been used as precursors in the syntheses of cassiol and gibberellic acid, respectively. The use of catalysts 364 and 369b in cycloadditions with acrolein resulted in low enantioselectivities with opposite face selectivities. 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

This and other similar cycloadditions, however, when unactivated hydrocarbons without heteroatom substituents participate in Diels-Alder reaction, are rarely efficient, requiring forcing conditions (high temperature, high pressure, prolonged reaction time) and giving the addition product in low yield. Diels-Alder reactions work well if electron-poor dienophiles (a, p-un saturated carbonyl compounds, esters, nitriles, nitro compounds, etc.) react with electron-rich dienes. For example, compared to the reaction in Eq. (6.86), 1,3-butadiene reacts with acrolein at 100°C to give formy 1-3-cyclohexene in 100% yield. 

Two approaches, based on furan, have found wide application in carbohydrate synthesis. Cycloaddition reactions of furan with 2-substituted acrylonitrile or acrolein lead to oxabicycloheptanes which, in tnm, can be transformed to monosaccharides. On the other hand, furfuryl alcohols can be converted—either by the Clauson-Kaas reaction or by mild oxidation—into 5,6-dihydro-4-pyrones, suitable for easy functionalization to sugars. 

The use of isoxazole derivatives in organic synthesis is of great interest, but little has been done on the utilization of such compounds as a part of a diene system in [4 + 2]-cycloadditions. 3-Methyl-5-vinylisoxazole 236 gave cycloaddition reactions in a sealed tube in benzene solution at 120°C for 3 days. With the dienophiles acrolein and methyl acrylate, aromatiza-tion of the isoxazole ring via a 1,3-proton shift occurs readily under the reaction conditions, allowing the direct isolation of compounds 237, which are also detected in the mass spectrum of the raw reaction material. The reactions are regioselective (85H2019). 

The second major route to tricyclic /3-lactams with a bridgehead nitrogen atom and extra heteroatom(s) is through cycloaddition reactions. Again, these may be of the intermolecular or intramolecular type. Diels-Alder reaction of acrolein and the cephems 420 gave 421 as the major products (Equation 65) <1996TL5967>. 

Chiral dienes have proved to be less popular in asymmetric Diels-Alder reactions than their chiral dienophile counterparts. This is primarily a result of the problem of designing a molecule that incorporates a chiral moiety, such as the formation of a chiral isoprenyl ether or vinyl ketene acetal.187-190 In addition, diastereoselectivities often are not high,54 191-199 as illustrated by the cycloaddition of the chiral butadiene 5 with acrolein (Scheme 26.4). Improved stereoselection is observed through the use of double asymmetric induction, although this is a somewhat wasteful protocol.35,54 177 200... 

Scheme 18). The 1,3-pentadiene derivatives may be formed by an initial [2 + 2]-cycloaddition reaction, while the formation of the l-oxa-6-silacy-clohexene derivative can be explained by a direct [2 + 4]-cycloaddition reaction (98). It has been reported that the reaction of thermally generated silaethene derivatives with acrolein affords products that can be accounted for in terms of initial competing [2 + 2]- and [2 + 4]-cycloaddition reaction between the intermediates and acrolein (99). 

The PEG-supported imidazolidinone 19 (Scheme 7) was later used in 1,3-dipolar cycloadditions (Puglisi et al. 2004). By reacting A-benzyl-C-phenylnitrone with acrolein, it was shown that the outcome of the reaction was strongly dependent on the nature of the acid employed to generate the catalyst, and that only the use of HBF4 as in the case of 19 allowed reproducible results to be obtained. Under the best reaction conditions (20 mol% of catalyst, DCM, -20 °C, 120 h) the product was obtained in 71% yield as a 85 15 trans/cis mixture of isomers, thetrans isomer having 87% ee (equation b, Scheme 7). 

Since the disclosures that the thermal dimerizations of acrolein and methyl vinyl ketone provide the 3,4-dihydro-2//-pyrans (1, 2) derived from 4ir and 2Tt participation of the a,3-unsaturated carbonyl compound in a Diels-Alder reaction, an extensive series of related observations have been detailed. This work has been the subject of several comprehensive reviews - - including the Desimoni and Tacco-ni extensive tabular compilation of work through 1974. Consequently, the prior reviews should be consulted for thorough treatments of the mechanism, scope, and applications of the [4 + 2] cycloaddition reactions of a,3-unsaturated carbonyl compounds. The [4 + 2] cycloaddition reactions of 1-oxa-1,3-butadienes with their 4-it participation in the Diels-Alder reaction exhibit predictable regioselectivity with the preferential or exclusive formation of 2-substituted 3,4-dihydro-2W-pyrans (equation 1). The exceptions to the predicted regioselectivity that have been observed involve the poorly matched [4 + 2] cycloaddition reaction of an electron-deficient l-oxa-l,3-butadiene with an electron-deficient dienophile, e.g. methyl crotonate or methacrolein. - Rigorous or simplified theoretical treatments of the [4 + 2] cycloaddition reaction of 1-oxa-1,3-butadienes predict the preferential formation of 2-substituted 3,4-dihy-dro-2f/-pyrans and accommodate the preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e. a concerted but nonsynchronous [4 + 2] cycloaddition reaction. ... 

The possibility that metallocenes might function as Lewis acids in Diels-Alder reactions was probed with ferrocenium hexafluorophosphate [184]. The answer is affirmative the cycloadditions studied include methacrolein, crotonaldehyde, and methyl vinyl ketone as dienophiles and butadienes and cyclopentadienes as diene components. Yields are in the range 60-80 % with reaction times of 3-36 h at 0 to 20 °C. Fair to good yields were also obtained in reactions of isoprene and cyclopentadiene with acrolein and methyl vinyl ketone in the presence of 1 % [Pd(PPh3)2(MeCN)2](BF4)2 (in CH2CI2, room temperature). Methyl acrylate resulted in low yields, and chiral modification with (5)-BINAP is reported to give the cycloadducts with modest enantioselectivity [164]. 

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