Indoles with imines

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

Scheme 11.20 Asymmetric Friedel-Crafts reaction of imines with indoles.

In 2007, two groups independently described asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylations of indoles. While You et al. chose the conventional approach and employed imines as substrates (Scheme 11), Terada and coworkers came up with a different concept and used electron-rich alkenes as precursors (Scheme 49) [73]. Enecarbamates 125 reacted with indoles 29 in the presence of BINOL phosphate (R)-io (5 mol%, R = bearing 2,4,6-triisopropyl-... 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

Applications of the Vilsmeier-type reaction to the synthesis of a variety of imine-substituted indoles have been reported. The scope appears to be very wide and further examples will undoubtedly be forthcoming. Perhaps the most important development is the use of triflic anhydride in combination with amides to generate highly reactive imino-triflate reagents in situ, and this general area of reagent modification is also likely to develop. 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

Simple, neutral electron-rich imines are generally not useful dienophiles unless q>propriately reactive dienes are used. Thus it is possible to effect cycloadditions of neutral imines with some electron-deficient dienes. - In a series of p rs, Langlois and coworkers have described Diels-Alder reactions of cyclic imines and methyl 2,4-pentadienoate to afford adducts used in alkaloid synthesis. For example, the cycloadditicMi shown in equation (IS) was used in a total synthesis of the indole alkaloid vincamine (45). 

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

Catalytic AFC reactions of indoles have attracted considerable attention, and there has been significant progress in this area since 2009. Catalytic AFC reactions of aromatic and heteroaromatic compounds with a-imino esters provide a direct approach to optically pure aryl and heteroaryl glycines. In 2009, You and co-workers realized the AFC reaction of indoles with ethyl glyoxylate imine with 10 mol% of chiral phosphoric acid (S)-13b, affording (3-indolyl)glycine derivatives 28 in excellent yields (85-93%) with up to 87% ee (Scheme 6.11). ... 

The AFC reaction of indoles with less reaetive aryl aldimines catalyzed by organocatalystwas reported by the group of Deng in 2006. Bifunctional cinchona alkaloid-derived thioureas were utilized to promote the AFC reaetion of indoles with N-Ts- or AT-Bs-protected imines. With 10 mol% of eatalyst 29, 3-indolyl methanamine derivatives 30 were obtained in high yields with up to 97% ee for both aryl and alkyl imines (Scheme 6.12). 

An alternative discotmection involves the coupling of 2-haloanilines with vinyl bromides. Barluenga has shown that this approach can lead to either simple imines, or indoles, depending upon the ligand employed, with bulky phosphines allowing ecdusive indole synthesis (Scheme 6.57) [78]. 

A similar dehydrogenation of an amine (primary or secondary amine) to imine with catalyst 1 was used by Beller to alkylate indoles (9) [50]. The imine reacts with the indole to give an aminoalkylated intermediate, which undergoes elimination of ammonia or amine to give an oxidized indole intermediate. The hydrogens removed from the amine are now added back to the latter intermediate to give the indole product so in this case the overall reaction is not an oxidation. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

N-Boc-protected ethyl trifluoropyruvate imine was effectively used in a F-C reaction with indole derivatives for synthesizing, in high selectivities, quaternary a-amino acids via catalysis with chiral phosphoric acid 26e [64]. A binaphthyl-based chiral sulfonimide [42c] and a chiral squaramide-based hydrogen bond donor [42a] were used as effective catalysts for promoting F-C reaction of indoles with imines. Recently, the F-C alkylation of arenes with glyoxylate imine was described via a chiral phosphoric add (Scheme 35.11) [34]. 

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