Electron-rich aldehydes

A Hammett plot for para-substituted benzaldehydes showed that electron-rich aldehydes gave higher ees (r = -0.4). As in Shibuya s related results (Section 5.3.3.1 above), this indicates that aldehyde coordination is important in enantiodifferentia-tion, but the lower rvalue (compared to Shibuya s r = -1.30) suggests a weaker electronic influence, probably due to the relative Lewis acidities of A1 and La. For ortho-substituted aldehydes, lower ees were observed, presumably due to steric effects. Although Al-Cl and Al-triflate complexes 29-30a-b did not catalyze the reaction, they... 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

Applying (S)-102 in the asymmetric benzoin condensation hS i-ben-zoin (6, R = Ph) was produced in very good enantioselectivity (90% ee, 83% yield) (Enders and Kallfass 2002). The condensation of numerous other aromatic aldehydes 6 yielded the corresponding a-hydroxy ketones 85 with excellent enantiomeric excesses up to 99%. As previously observed, electron-rich aldehydes gave higher asymmetric inductions than the electron-deficient ones. Lower reaction temperatures (0°C instead of room temperature) or lower amounts of catalyst caused decreased yields but slightly enhanced enantiomeric excesses (Scheme 27). 

Dihydropyrans. Either by cycloaddition of dienes with aldehydes (electron-rich aldehydes not suitable) or by sequential oxo-ene reaction, the synthesis is catalyzed by TfOH. 

Condensation of triamine (171) with arylaldehydes in dimethylformamide at room temperature affords 4-amino-6-aryl-l,5-dihydroimidazo[4,5-c][l,2,6]thiadiazine 2,2-dioxides (177) in 63-95% yield. The reaction is also successful with ethanal, but proceeds in lower yield (45%) <87H(26)3123). Studies in the late 1980s, revealed that under anhydrous conditions and with electron rich aldehydes, mixtures of the imidazo[4,5-c]-thiadiazine dioxides (177) and pyrazino[2,3-c]thiadiazine dioxides (180) are produced <88JHC89i, 89MI616-01). The latter products arise by electrocyclization of the bis-anils (178), formed by condensation of the triamine with two equivalents of aldehyde, followed by... 

Evans-Tishchenko reduction of ent-26 with cither p-nitrobenzaldehyde or benzaldehyde itself afforded benzoates 84 and 85, respectively, in good yield and with complete diastereoselectivity in each case. Interestingly, the same reaction, when attempted with / -anisaldehyde, gave none of the expected p-methoxybenzoate 86. Failure of this reaction may reflect the lower propensity of p-anisaldehyde to form hemiacetals owing to its poor electrophilicity. Alternatively, the in situ generation of a Sm(lll) "pinacolate" catalyst from Sml2 and p-anisaldehyde may be hampered by the relatively high reduction potential of this electron rich aldehyde. 

In 1996, great efforts were made by Enders et al. [16] using chiral triazolium salts as catalysts. The most effictive catalyst 2 provided benzoin with up to 86% ee using only 1.25 mol% of catalyst. In addition, the scope of the reaction was successfully expanded to electron-rich aldehydes affording benzoins with moderate to good enantioselectivities (Scheme 7.2). However, the asymmetric inductions with electron-deficient aldehydes were somewhat lower. 

Interestingly, Murry et al. [34] successfully applied acylimines 23 as a suitable coupling partner for crossed coupling condensation, giving a number of a-ketoamides 24 in good yields. The reaction is tolerable for both electron-deficient and electron-rich aldehydes (Scheme 7.16). Mattson and Scheldt [35] found that thioazolium carbene... 

Electronic and steric effects play an important role in this transformation and some limitations have been observed. Also, the scope was limited to electron-rich aldehyde precursors with regards to f-alkenyl halide formation, in which the best additive was MgBt2/Et20 instead of HMPA. 

Alumina sulfuric acid (ASA) was found to be an effective catalyst for the solvent-free one pot Beckmann rearrangement of several alkyl and aryl aldehydes and ketones 1. It has been reported that the electron rich aldehydes and ketones require shorter reaction times than the electron poor aldehydes. Cyclic ketones require longer reaction time than the aryl ketones ascribable to the steric factors. ... 

A variety of 2-acyloxylquinoline N-oxides, which is a valuable template for psychiatric medications, were prepared by condensation of quinoline N-oxides with aldehydes in the presence ofTBHP as an oxidant and a copper catalyst (Scheme 72) (13CC6900). Acetoxylation occurred regioselec-tively at C-2. A number of electron-rich aldehydes could be added to the quinoline N-oxides. Quinoline N-oxides with methyl or methoxy groups also worked well under these conditions. Other aryl aldehydes (pyridinecar-boxyaldehde and furfural) failed to provide the desired product. 

Ng, T. F. Jamison, J. Am. Chem. Soc. 2006, 128, 5362-5363. Nickel-catalyzed, carbonyl-ene-type reactions selective for alpha olefins and more efficient with electron-rich aldehydes, (c) C.-Y. Ho, T. F. Jamison, Angew. Chem. Int. Ed. 2007, 46, 782—785. Highly selective coupling of alkenes and aldehydes catalyzed by [Ni(NHC) P(OPh)j ] synergy between a strong a donor and a strong k acceptor. 

Reaction scope The reaction scope with the heavier group 2 catalysts (M = Ca, Sr, Ba) includes electron-rich and electron-poor aromatic aldehydes along with non-enolizable and enolizable aliphatic aldehydes. A series of aromatic aldehydes may be dimerized with these catalysts and although heteroaromatic aldehydes are not reported the reaction may be conducted in both an inter- and intramolecular fashion and product yields decrease with the increasingly electron-rich aldehydes... 

Once we determined the best reaction conditions, the scope was explored. Products I-16a-h of [2-I-2-I-2] cycloaddition were isolated from enyne I-15a in 21-85 % yield, along with 1,3-dienes I-17a-h (Table 2.4). The reaction proceeded readily with electron-rich aldehydes. Conversely, in the reaction of I-15a with o-nitro-benzaldehyde, no adduct was formed (Table 2.4, entry 17), which is in contrast with the previously reported results for 1,6-enynes bearing a terminal aUcene moiety 1-9 [Refs. 226, 228 in Chap. 1]. 

In addition, enynes I-15d-f with an aryl substituent at the alkene exclusively gave 1,3-dienes 1-17 by intermolecular metathesis with aldehydes in good yields (Table 2.6, entries 1-6) [Ref. 173 in Chap. 1]. Surprisingly, electron-rich aldehydes, such as 4-methoxybenzaldehyde or 3,4-dimethoxy-benzaldehyde, only led to decomposition or low yield using enynes with an aryl substituent at the alkene I-15b-f (Tables 2.5 and 2.6). 

An effective synthesis of 1,2-dihydroquinolines has been devised using a Lewis acid-mediated bicyclization reaction between alkynylanilines and aldehydes (Scheme 3.14 and Example 3.3) [14]. The authors screened a range of Lewis acids for activity toward the reaction, and scandium(III) triflate was the most effective under the reaction conditions. The reaction proceeded under mild conditions and afforded moderate to good yields of the polycyclic compounds when electron-neutral or electron-rich aldehydes were used. Electron-deficient aldehydes were sluggish under the standard conditions however, the authors discovered that the use of benzoic acid as a cocatalyst enabled the use of these substrates in the bicyclization reaction. 

In the aluminum Lewis acid-mediated ene reaction, the most efficient reactants are electron-rich olefins such as 1,1-disubstituted alkenes or 2-methoxypropene and small and/or highly electron-deficient aldehydes such as formaldehyde, chloral, or glyoxylate esters. Few examples of car bony 1-ene reactions of aromatic or sterically demanding aldehydes and equally those of monosubstituted alkenes have been reported. Recently, Jamison and coworkers reported nickel-catalyzed carbony 1-ene type reactions, in which monosubstituted terminal alkenes and electron-rich aldehydes including tert-alkyl aldehydes and p-anisaldehyde are good substrates, and thus, this reaction compliments Lewis acid-catalyzed methods. For example, as shown in Scheme 6.27, when citronellene (41) and benzaldehyde are treated with Me2AlCl, reaction proceeds at only the trisubstituted alkene part to give the... 

Also of interest in comparing the two organometalUc units is the difference in reactivity with alternative electrophiles. The cobalt system reacted well with electron-neutral and electron-poor substrates, but not at all with electron-rich compounds. In contrast, the iron system reacts much better with electron-rich aldehydes. This does not necessarily indicate a complete change in reaction mechanism however, it does indicate a different rate-determining step in the cobalt case, the malonate reaction attack on the aldehyde is more critical, and the more electropositive the aldehyde, the better the yield. For the iron stabilized system, it may be that that the aldehyde actually acts as a nucleophile, attacking the iron-dieneyl system before fast ring closure of the malonate onto the carbon. Taken with the stereochemical arguments... 

Intriguingly, boron trifluoride, the Lewis acid of choice for the cobalt alkyne cyclopropane, did not give any of the cycloaddition product on reaction with an aldehyde. Instead optimization studies showed that a catalytic quantity of scandium triflate induced the reaction. Also, there are marked differences in the reactivity and stereocontrol achieved. In this case, electron-rich aldehydes give better yields and for the first time with a cobalt alkyne, good stereocontrol. Again, no reaction was seen at all without the activating cobalt group. 

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