Benzoin, reaction with

Benzoin, reaction with chloroform to give 1,1,3 tnchloro n nonane, 45, 104... 

Scheme 25. Precatalyst 98 for benzoin reactions with aliphatic substrates...

As)rmmetric benzoin reactions with N-heterocyclic carbene catalysts 07Y370. 

Using the camphor-derived triazolium salts initially developed by their own group. You and co-workers developed an enantioselective NHC-catalyzed intramolecular aldehyde-ketone benzoin reaction with N-tethered substrates. Various substituted dihydroquinolinone derivatives were obtained with a quaternary carbon stereogenic center in moderate to good yields and excellent ee (up to 96% yield, 92% ee). The utilization of a weak base (NaOAc) is critical for minimizing the aldol side reaction (Scheme 7.5). 

The You group examined o-camphor derived NHCs to conduct intramolecular A7-tethered aldehyde-ketone benzoin reactions. With 15 mol% of D-camphor-derived triazolium salt G1 and 10 mol% of NaOAc, various substituted dihydroquinolinone derivatives 10 were obtained with a quaternary carbon stereocentre in moderate to good yields and excellent enantiomeric excesses, a weak base is used to minimise the possible aldol side reaction (Scheme 20.7). 

The scope of the NHC-catalyzed reactions is generally excellent, particularly when applied to the cyclopentene-forming annulations, making this chemistry ideal for diversity oriented synthesis. Unfortunately, it can be quite difficult to prepare the starting a,p-unsaturated aldehydes, especially when they contain basic functionalities that interfere with the common methods for their synthesis. In seeking to address this, Bode reported that readily prepared a -hydroxyenones serve as surrogates for most of the NHC-promoted annulation reactions, albeit only with the less hindered achiral triazolium catalysts (Scheme 14.20). In this case the Breslow intermediate is generated via a retro-benzoin reaction with release of a moleeule of acetone. 

Although the catalysis of the dimerization of aldehydes to acyloins by thiazolium ion has been known for some tlrae, the development of procedures using anhydrous solvents which give satisfactory yields of acyloins on a preparative scale was first realized in the submitters laboratories. The mechanism proposed by Breslow - for the thiazolium ion-catalyzed reactions is similar to the Lapworth mechanism for the benzoin condensation with a thiazolium ylide replacing the cyanide ion. Similar mechanisms are involved... 

Triphenylethylene has been prepared by the reaction of phenylmagnesium bromide with benzyl benzoate, with desoxy-benzoin, or with ethyl pheaniylacetate, and by the reaction of diphenylketene-quinoline with benzaldehyde. The above procedure is an adaptation of that described by Hell and Wiegandt. ... 

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). 

It should be pointed out that not all benzoin derivatives (75) are suitable for use as photoinitialors. Benzoin esters (75, R=aeyl) undergo a side reaction leading to furan derivatives. Aryl ethers (75, R=aryl) undergo (3-seission to give a phenoxy radical (an inhibitor) in competition with a-scission (Scheme 3.54). Benzoin derivatives with a-hydrogens (75 R-Il) are readily autoxidized and consequently can have poor shelf lives. 

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

The synthesis of 3-H-oxazol-2-ones was described by Nam et al. [69]. The substituted benzoin 89 was formed from the coupling of 3,4,5-trimethoxy-benzaldehyde 18 with 3-nitro-4-methoxybenzaldehyde, Scheme 22. Reaction with PMB-isocyanate and subsequent cyclization gave the protected oxazolone derivative 90. The PMB group was removed by reflux in TFA and reduction of the nitro-group was performed using Zn to give the combretoxazolone-aniline 91. 

The synthesis and biological testing of the pyrazine compound 123 was described by Wang et al. [34], The same benzoin intermediate 22 was formed as described in Scheme 2. A three-step reaction was then performed to obtain the desired pyrazine 123, shown in Scheme 31 (i) oxidation of Q1SO4 in aqueous pyridine, (ii) reaction with ethylenediamine in EtOH, and (iii) aromatization in the presence of elemental sulfur. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

In concurrent and independent work, Suzuki and Enders found that tethered keto-aldehydes undergo highly enantioselective cross-benzoin reactions using tria-zolium based catalysts [50, 51], The scope includes various aromatic aldehydes with alkyl and aryl ketones (Table 4). Additionally, aliphatic substrate 39a is cyclized in excellent enantioselectivity, albeit in 44% yield. 

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