Aldehydes as Nucleophiles

Li has reported the water-promoted, gold(I)-catalyzed cascade addition/cyclization of terminal alkynes with o-alkynylbenzaldehyde derivatives to form 1-alkynyl-lH-isochromenes [41]. For example, reaction of l-(2-phenylethynyl)benzaldehyde with phenylacetylene catalyzed by a 1 4 mixture of (PMe3)AuCl and Hunig s base in a water/toluene mixture at 70 °C for 1 day led to isolation of isochromene 29 in 81% yield (Fq. (12.11)). The transformation is presumably initiated by gold-catalyzed addition of acetylide to the C=0 bond of the aldehyde moiety followed by addition of the resulting alkoxide across the pendant C=C triple bond. 

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The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Proline derivatives, such as (2S,4R)-4-hydroxyproline (2), (2S,4R)-4-tert-butoxy-proline, (2S,3S)-3-hydroxyproline [71b] and tetrazole-containing pyrrolidine 9 [75] also catalyzed the Mannich-type reactions using aldehydes as nucleophiles via enamine intermediates, and afforded the syn-isomer as the major diaster-eomer with high enantioselectivity at room temperature. On the other hand,... 

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

Notz W, Tanaka F, Watanabe S, Chaudari NS, Turner JM, Thayumanavan R, Barbas CF 3rd (2003) The direct organocatalytic asymmetric mannich reaction unmodified aldehydes as nucleophiles. J Org Chem 68 9624-9634 Noyori R (2002) Asymmetric catalysis science and opportunities (Nobel lecture). Angew Chem Int Ed Engl 41 2008-2022 Noyori R, Tokunaga M, Kitamura M (1995) Stereoselective organic synthesis via dynamic kinetic resolution. Bull Chem Soc Jpn 68 36-55 Ohkuma T, Kitamura M, Noyori R (2000) Asymmetric hydrogenation. In Ojima I (ed) Catalytic asymmetric synthesis, 2nd edn. Wiley-VCH, New York, p 1-110... 

Scheme 5.12 Asymmetric Mannich reaction with unmodified aldehydes as nucleophiles.

The use of iV-heterocyclic carbene (NHC) as organocatalysts is well-documented [47]. However, it is their ability to render aldehydes as nucleophilic, thus setting up an umpolung reactivity, which is their greatest asset to organocatalysis. This nuclephilic... 

The Michael addition between aldehydes and nitroalkenes (Scheme 2.17) is, by far, the most studied reaction when using aldehydes as nucleophiles due to the importance of chiral nitroaUcanes as highly versatile synthetic intermediates in organic synthesis [48],... 

Some years later, further developments by Alexakis et al. have shown that prolinol derivative 22a (10 mol%) is a better catalysts for the reaction [89]. The results vary from good, for conjugate addition of linear aldehydes to l,l-bis(benzenesulfonyl) ethylene (77-90% yields 76-93% ee), to moderate (12-91% ee) when using a-branched aldehydes as nucleophiles. Catalyst 22a has been also used by Palomo et al. for the enantioselective conjugate addition of linear and 3-branched aldehydes to E-a-ethoxycarbonyl vinyl sulfones and -a-cyano vinyl sulfones [90], derivatives that after further transformations, which usually involve a reductive desulfonylation process [91], have made possible the synthesis of different interesting chiral building blocks. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

Despite the fact that extensive studies have been conducted on secondary-amine-catalyzed Michael addition of unmodified a-monosubstituted aldehydes, there are few reports on the use of a,a-disubstimted aldehydes as nucleophiles, probably due to the high hinderance during the formation of enamine intermediates. By using (5)-l-(2-pyrrolidinylmethyl)pyrrolidme/TFA salt 19 as catalyst, Barbas and co-workers [13] reported the first application of a,a-disubstituted aldehydes in the enantiose-lective Michael reactions with nitroalkenes (Scheme 5.6). The corresponding Michael adducts bearing an all-carbon quaternary stereocenter were obtained in moderate diastereoselectivities and with moderate to good enantioselectivities (up to 91%). 

The selectivity observed with hydroxyacetone (206) in proline-catalyzed aldol additions is particularly remarkable, as the scope includes a wide range of aldehydes to furnish a,/i-ketone diols such as 207 under mild conditions (Equation 19) [102]. The addition reactions of protected derivatives of a-hydrox) aldehydes as nucleophile coupling partners and aldehyde electrophiles in proline-catalyzed aldol reactions have recently been used to provide access to fragments that can be converted into a variety of carbohydrates [103). 

Enamines as nucleophiles react with butadiene, and a-octadienyl ketones or aldehydes are obtained after hydrolysis[57]. This is a good way of introducing an octadienyl group at the o-position of ketones or aldehydes, because butadiene does not react with ketones or aldehydes directly. The reaction of the pyrrolidine enamine of cyclohexanone gives, after hydrolysis, 2-(2,7-octadie-nyOcyclohe.xanone (58) as the main product, accompanied by a small amount of 2,6-di(2,7-octadienyl)cyclohexanone. The reaction of the optically active enamine 59 with butadiene gave 2-(2,7-octadienyl)cyclohexanone (60) in 72% ce[58]. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Using (31) as the nucleophile, FSA has been shown to accept several aldehydes as acceptor components for preparative synthesis [91]. In addition to (31), it also utilizes hydroxyacetone as an alternative donor to generate 1-deoxysugars such as (66) regioselectively (Figure 10.25). 

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

The hydrosi(ly)lations of alkenes and alkynes are very important catalytic processes for the synthesis of alkyl- and alkenyl-silanes, respectively, which can be further transformed into aldehydes, ketones or alcohols by estabhshed stoichiometric organic transformations, or used as nucleophiles in cross-coupling reactions. Hydrosilylation is also used for the derivatisation of Si containing polymers. The drawbacks of the most widespread hydrosilylation catalysts [the Speier s system, H PtCl/PrOH, and Karstedt s complex [Pt2(divinyl-disiloxane)3] include the formation of side-products, in addition to the desired anh-Markovnikov Si-H addition product. In the hydrosilylation of alkynes, formation of di-silanes (by competing further reaction of the product alkenyl-silane) and of geometrical isomers (a-isomer from the Markovnikov addition and Z-p and -P from the anh-Markovnikov addition. Scheme 2.6) are also possible. 

Scheme 7.4 illustrates some of the important synthetic reactions in which organolithium reagents act as nucleophiles. The range of reactions includes S/v2-(ype alkylation (Entries 1 to 3), epoxide ring opening (Entry 4), and formation of alcohols by additions to aldehydes and ketones (Entries 5 to 10). Note that in Entry 2, alkylation takes place mainly at the 7-carbon of the allylic system. The ratio favoring 7-alkylation... 

Halide ions will also act as nucleophiles towards aldehydes under acid catalysis, but the resultant, for example, 1,1-hydroxychloro compound (35) is highly unstable, the equilibrium lying over in favour of starting material. With HC1 in solution in an alcohol, ROH, the equilibrium is more favourable, and 1,1-alkoxychloro compounds may be prepared, e.g. 1-chloro-l-methoxymethane (36, a-chloromethyl ether ) from CH20 and MeOH (cf. acetal formation, p. 209), provided the reaction mixture is neutralised before isolation is attempted ... 

During the past few years, increasing numbers of reports have been published on the subject of domino reactions initiated by oxidation or reduction processes. This was in stark contrast to the period before our first comprehensive review of this topic was published in 1993 [1], when the use of this type of transformation was indeed rare. The benefits of employing oxidation or reduction processes in domino sequences are clear, as they offer easy access to reactive functionalities such as nucleophiles (e. g., alcohols and amines) or electrophiles (e. g., aldehydes or ketones), with their ability to participate in further reactions. For that reason, apart from combinations with photochemically induced, transition metal-catalyzed and enzymatically induced processes, all other possible constellations have been embedded in the concept of domino synthesis. 

As can be seen in the scheme below, insertion reactions of aldehydes to the C-H bond of aromatic ketimines by using a rhenium catalyst provided benzo[c]furans via a mechanism involving consecutive steps of C-H bond activation, insertion of aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of aniline <06JA12376>. 

Aldol reactions of isocyanides with aldehydes are catalyzed by cationic platinum complexes having P-C-P or N-C-N ligands in the presence of a catalytic amount of an amine base to give 2-oxazolines (Equation (126)) 48S>485a>485b Platinum-coordinated a-isocyano carbanions presumably serve as nucleophiles toward aldehydes. Low to moderate enantioselectivities were obtained by using chiral platinum complexes.485 4853... 

Vinylsilane to copper transmetallation has entered the literature,93 93a,93b and a system suitable for catalytic asymmetric addition of vinylsilanes to aldehydes was developed (Scheme 24).94 A copper(l) fluoride or alkoxide is necessary to initiate transmetallation, and the work employs a copper(ll) fluoride salt as a pre-catalyst, presumably reduced in situ by excess phosphine ligand. The use of a bis-phosphine was found crucial for reactivity of the vinylcopper species, which ordinarily would not be regarded as good nucleophiles for addition to aldehydes. The highly tailored 5,5 -bis(di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino-4,4 -bis(benzodioxolyl) (DTBM-SEGPHOS) (see Scheme 24) was found to provide the best results, and the use of alkoxysilanes is required. Functional group tolerance has not been adequately addressed, but the method does appear encouraging as a way to activate vinylsilanes for use as nucleophiles. 

For use of alkynes as nucleophilic partners in catalytic hydrometallative reductive couplings to aldehydes, see ... 

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