Mukaiyama aldol reaction of benzaldehyde

Activities of various metallosilicates for Mukaiyama aldol reaction of benzaldehyde with silyl enol ether... 

Table 19 Bi(OTf)3-catalyzed vinylogous Mukaiyama aldol reaction of benzaldehyde...

Scheme 6.4 Mukaiyama-aldol reaction of benzaldehydes with a ketene silyl acetal catalyzed by thiourea 9.

Although most Lewis acids decompose in water, rare earth triflates (e.g., ScCOTOj, YbCOTOj) can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids). For example, the Mukaiyama aldol reaction of benzaldehyde with silyl enol ether 1 was catalyzed by Yb(OTf)3 in water/THF (1/4) to give the corresponding aldol adduct in high yield (Scheme 15.1). Interestingly, when this reaction was carried out in dry THF (without water), the yield of the aldol adduct was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also activated by water, probably owing to dissociation of the counteranions from the Lewis acidic metal. Furthermore, the catalyst in this example can be easily recovered and reused. 

Kobayashi and coworkers further developed a new immobilizing technique for metal catalysts, a PI method [58-61]. They originally used the technique for palladium catalysts, and then applied it to Lewis acids. The PI method was successfully used for the preparation of immobilized Sc(OTf)3. When copolymer (122) was used for the microencapsulation of Sc(OTf)3, remarkable solvent effects were observed. Random aggregation of copolymer (122)-Sc(OTf)3 was obtained in toluene, which was named as polymer incarcerated (PI) Sc(OTf)3. On the other hand, spherical micelles were formed in THF-cyclohexane, which was named polymer-micelle incarcerated (PMI) Sc(OTf)3.. PMI Sc(OTf)3 worked well in the Mukaiyama-aldol reaction of benzaldehyde with (123) and showed higher catalytic activity compared to that of PI Sc(OTf)3 mainly due to its larger surface area of PMI Sc(OTf)3. This catalyst was also used in other reactions such as Mannich-type (123) and (125) and Michael (127) and (128) reactions. For Michael reactions, inorganic support such as montmorilonite-enwrapped Scandium is also an efficient catalyst [62]. 

SnOTf-MCM-41 ordered mesoporous structure with tetrahedrally coordinated Sn species is another heterogeneous catalyst showing activity in Mukaiyama aldol reaction [118]. It promoted the Mukaiyama aldol reaction of benzaldehyde with 1-trimethylsiloxycyclohexene at room temperature showing greater catalytic activity than untreated Sn-MCM-41 (Equation (8.63)). 

Catalyzed enantioselective Mukaiyama-aldol reactions have been developed extensively [101] and chiral polymer-supported Lewis acids are the catalysts of choice. Polymer-supported chiral A(-sulfonyloxazaborohdinones 86 and 87, prepared by copolymerization of styrene, divinylbenzene, and chiral monomers derived from L-valine and L-glutamic acid, respectively, have been used for aldol reactions [102]. The rates of reaction using the polymeric catalysts were slow and enantioselectivity was lower than was obtained by use of the low-molecular-weight counterpart (88). The best ee obtained by use of the polymeric catalyst was 90 % ee with 28 % isolated yield in the asymmetric aldol reaction of benzaldehyde with 89 (Eq. 27). 

Further, the Mukaiyama aldol reaction of l-(trimethylsiloxy)-l-cyclohexene and benzaldehyde was effected with the bidentate 49, giving the aldol products er -thro/threo= 3) in 87% yield, though its monodentate counterpart 50 showed no evidence of reaction under similar conditions (Scheme 1-17). 

I n 1993, the first cinchona-catalyzed enantioselective Mukaiyama-type aldol reaction of benzaldehyde with the silyl enol ether 2 of 2-methyl-l -tetralone derivatives was achieved by Shioiri and coworkers by using N-benzylcinchomnium fluoride (1, 12 mol%) [2]. However, the observed ee values and diastereoselectivities were low to moderate (66-72% for erythro-3 and 13-30% ee for threo-3) (Scheme 8.1). The observed chiral inductioncan be explained by the dual activation mode ofthe catalyst, that is, the fluoride anion acts as a nucleophilic activator of the silyl enol ethers and the chiral ammonium cation activates the carbonyl group of benzaldehyde. Further investigations on the Mukaiyama-type aldol reaction with the same catalyst were tried later by the same [ 3 ] and another research group [4], but in all cases the enantioselectivities were too low for synthetic applications. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Mukaiyama aldol reaction of an enol silyl ether with benzaldehyde (Scheme 17)7 These reactions were conducted in a neat organic solvent, and the catalyst was precipitated after cooling the reaction mixture to room temperature, hence permitting its easy recovery. The same group also reported on the use of a polystyrene-bounded super Brpnsted acid catalyst in a flow system. ... 

After pioneering work on the Lewis base-catalysed Mukaiyama aldol reaction, Mukaiyama-Michael reaction, and Mukaiyama-Mannich-type reaction with the use of lithium acetate, Mukaiyama also demonstrated the same reactions using simple sodium salts (Scheme 2.28). For example, a catalytic Mukaiyama aldol reaction between benzaldehyde and trimethylsilyl enolate using sodium methoxide in DMF proceeded smoothly under mild conditions. Moreover, the Mukaiyama-Michael reaction between chalcone and trimethylsilyl enolates using sodium acetate in DMF provided the desired Michael adduct as the major product in 92% yield along with the 1,2-adduct in 8% yield. ... 

The first use of rare earth metals in the aldol reaction began in the case of cerium enolate (198). Subsequently, Kagan and Kobayashi groups reported systematically the use of rare earth metalscatalyzed for the Mukaiyama aldol-type reaction of silyl enol ethers with aqueous formaldehyde solution (199,200). The efficiency of rare earth metals in a Mukaiyama aldol reaction of 1-trimethylsiloxycyclohexene with benzaldehyde was examined in aqueous THF (Scheme 52). Of the rare earth metal trifiates screened, catalytic efficiency was increased in the order of Yb (91%) > Gd (89%) > Lu (88%) > Nd (83%) > Dy (73%) > Er (52%) > Ho(47%) > Sm (46%) > Eu (34%) > Tm (20%) > La (8%) > Y (trace) (201,202). For different aldol or aldol-type reactions, every rare earth metal occupied its special position in the aldol reaction with distinctive catalytic activity. There were several reviews concerning the rare earth metals catalyzed aldol reactions (203,204). New progress in this context will be discussed herein according to rare earth metals catalysis especially for the past 10 years. 

Scandium tris(perfluorooctanesulfonyl)methide complex was immobilized in a fluorous phase as a recyclable catalyst for Mukaiyama aldol reaction (2). On the other hand, the catalytic activity of scandium could be significantly increased by the use of a continuous flow system compared with a batch system. For example, in per-fluoromethylcyclohexane, the aldol reaction of benzaldehyde withthe trimethylsilyl enol ether derived from methyl 2-methylpropannoate was completed within seconds in the presence of less than 0.1 mol% of Sc(N(S02CgFi7)2]3 [3]. 

Maruoka and Ooi reported that a significant activation of carbonyl reactivity can be realized through the double coordination of carbonyl compounds by appropriate bidentate Lewis acids such as aluminum Lewis acid (17) prepared by treatment of the biphenylenediol (18) with Me3Al (2 equivalent) in CH2CI2 at room temperature for 30 minutes. The Mukaiyama aldol reaction of l-(trimethylsilyloxy)- -cyclohexene with benzaldehyde is effected by this bidentate Lewis acid (17) to give the aldol products in 87% yield (erythro/threo = 1 3). On the other hand, the use of its monodentate counterpart (19) did not produce the aldol products under similar conditions (Scheme 6.19). [26] Another examples of the carbonyl activation by bidentate aluminum Lewis acids are summarized in Section 6.6. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

Another SBU with open metal sites is the tri-p-oxo carboxylate cluster (see Section 4.2.2 and Figure 4.2). The tri-p-oxo Fe " clusters in MIL-100 are able to catalyze Friedel-Crafts benzylation reactions [44]. The tri-p-oxo Cr " clusters of MIL-101 are active for the cyanosilylation of benzaldehyde. This reaction is a popular test reaction in the MOF Hterature as a probe for catalytic activity an example has already been given above for [Cu3(BTC)2] [15]. In fact, the very first demonstration of the catalytic potential of MOFs had aheady been given in 1994 for a two-dimensional Cd bipyridine lattice that catalyzes the cyanosilylation of aldehydes [56]. A continuation of this work in 2004 for reactions with imines showed that the hydrophobic surroundings of the framework enhance the reaction in comparison with homogeneous Cd(pyridine) complexes [57]. The activity of MIL-lOl(Cr) is much higher than that of the Cd lattices, but in subsequent reaction rans the activity decreases [58]. A MOF with two different types of open Mn sites with pores of 7 and 10 A catalyzes the cyanosilylation of aromatic aldehydes and ketones with a remarkable reactant shape selectivity. This MOF also catalyzes the more demanding Mukaiyama-aldol reaction [59]. 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

The 9-catalyzed Mukaiyama-aldol reaction [74] of benzaldehyde and 1,2-dimethoxy benzaldehyde with a ketene silyl acetal in the presence of 10mol% thiourea 9 furnished the target product in low yield (36%), while the same reaction... 

In 1995 Carreira et al. [19] reported a catalytic variant of the asymmetric carbonyl-ene reaction (Scheme Ha). By treatment of the aldehyde 60 with 2 mol % of titanium catalyst 35, already used in the Mukaiyama aldol reaction, the / -hy-droxyketone 61 is formed in quantitative yield and with an excellent ee value. Here, the ene-compound, 2-methoxypropene, is used simultaneously as solvent in a large excess. The high en-antioselectivity is still limited to aldehydes similar to 60 benzaldehyde for instance is converted with an ee of only 66 %. 

The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li has been described briefly by Reetz et al. Wirth 5.0 m LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol %) of LiC104 in Et20 (3 mol % LPDE) required a reaction time of 5 days for 86 % conversion. As observed in the hetero-Diels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol % LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113lanti-113) of >96 % (Sch. 55). 

A f/ireo-selective siloxonium (aldol-like) pathway II was favored when BF3 OEt2 was used as catalyst (Sch. 3) [11]. The reaction of benzaldehyde by quenching after 5 min resulted in 48 % yield of the final cyclic products 3 (1 8 cisitrans ratio) and 46 % yield of the Mukaiyama-like aldol products 5 (1 2 threolerythro ratio). When either threo or erythro adduct was re-subjected to trifluoroacetic acid media, each underwent conversion to the corresponding y-pyrones 3. 

A recent notable finding in this field is Mukaiyama aldol reactions in aqueous medium (THF H20 = 9 1) catalyzed by metal salts. Lewis acids based on Fe(II), Cu(II), and Zn(II), and those of some main group metals and lanthanides are stable in water. Remarkably, the aldol reaction shown in Sch. 29 occurs more rapidly than the hydrolysis of the silyl enol ether [137]. In the presence of surfactants (dodecyl sulfates or dodecane sulfonate salts), reactions of thioketene silyl acetals with benzaldehyde can be performed in water [138]. 

Bidentate Lewis acid. This useful catalyst (1) with a high propensity for double coordination of the carbonyl group is prepared from the corresponding phenol and two equivalents of McjAI in CH Clj at room temperature. It catalyzes the reduction of 5-nonanone by BujSnH at -78° in 86% yield, whereas a reaction in the presence of the monodentate 0-dimethylaluminum 2,6-xylenoxide affords 5-nonanol in only 6%.. Accordingly, different catalytic efficiencies are also found in the Mukaiyama aldol reaction (e.g., 87% vs. 0% in the reaction between 1-trimethylsiloxy-l-cyclohexene and benzaldehyde) and the Claisen rearrangement of (fil-cinnamyl vinyl ether (96% vs. 0%). The contrasting ( >Zi-selectivity of the Michael adducts also reflects the different coordination states. 

Scandium triflate-catalyzed aldol reactions of silyl enol ethers with aldehyde were successfully carried out in micellar systems and encapsulating systems. While the reactions proceeded sluggishly in water alone, strong enhancement of the reactivity was observed in the presence of a small amount of a surfactant. The effect of surfactant was attributed to the stabiMzation of enol silyl ether by it. Versatile carbon-carbon bondforming reactions proceeded in water without using any organic solvents. Cross-linked Sc-containing dendrimers were also found to be effective and the catalyst can be readily recycled without any appreciable loss of catalytic activity.Aldol reaction of 1-phenyl-l-(trimethylsilyloxy) ethylene and benzaldehyde was also conducted in a gel medium of fluoroalkyl end-capped 2-acrylamido-2-methylpropanesulfonic acid polymer. A nanostmctured, polymer-supported Sc(III) catalyst (NP-Sc) functions in water at ambient temperature and can be efficiently recycled. It also affords stereoselectivities different from isotropic solution and solid-state scandium catalysts in Mukaiyama aldol and Mannich-type reactions. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Since our group (22) and Hehnchen s (23) independently announced a new class of chiral acyloxyboranes derive from iV-sulfonylamino acids and borane THF, chiral 1,3 -oxazaborolidines, their utility as chiral Lewis acid catalysts in enantioselective synthesis has been convincingly demonstrated (2(5). In particular, Corey s tryptophan-derived chiral oxazaborolidines 10a and 10b are highly effective for not only Mukaiyama aldol reactions (24) but also Diels-Alder reactions (25). More than 20 mol% of 10b is required for the former reaction, however. Actually, the reaction of the trimethylsilyl enol ether derived from cyclopentanone with benzaldehyde afforded the aldoI products in only 71% yield even in the presence of 40 mol%of 10b (24). We recently succeed in renewing 10b as a new and extremely active catalyst lOd using arylboron dichlorides as Lewis acid components (2(5). 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

Tor a study of the rate and equilibrium constants in the reaction between acetone and benzaldehyde, see Guthrie, J.P. Cossar, J. Taylor, K.F. Can. J. Chem. 1984, 62, 1958. For a microwave induced reaction using aqueous NaOH, see Kad, G.L. Kaur, K.P. Singh, V. Singh, J. Synth. Commun. 1999, 29, 2583. " For some other aldol reactions with preformed enol derivatives, see Mukaiyama, T. Isr. J. Chem. 1984, 24, 162 Caine, D., in Augustine, R.L., Carbon-Carbon Bond Formation, Vol. 1, Marcel Dekker, NY, 1979, pp. 264-276. 

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