Amine-Catalyzed Direct Aldol Addition

Link: JACS ASAP

Morris Markert, Michael Mulzer, Bernd Schetter, and Rainer Mahrwald*

Institut für Chemie der Humboldt-Universität zu Berlin, Brook-Taylor Strasse 2, 12 489 Berlin, Germany

A new method emerged for tertiary amine-catalyzed cross aldol reaction between aldehydes and hydroxyl acetone. This method is different from previous method where tertiary amine was used in conjunction with LiClO4. The initial results are as seen in Scheme 1 of the reactions catalyzed by DBU.In the subsequent scheme, further utilities of the reaction is illustrated, using Hunig's base as catalyst. In some of these reactions, cyclic acetal was obtained along with the expected aldol adduct.As is readily seen, the reaction predominantly afforded syn-aldol product. The selectivity was probably stemed from the effect of hydrogen-bonding - a welcome complement to the previously known anti-selectivity.

The method is applicable to enolizable aldehyde. The reaction is also regioselective with regards to enolate counterpart, namely only alpha-carbon bearing OH group was observed to add to the aldehyde. In the scheme below, the method was used effectively in the synthesis of furanose 8 and sorbose 9.In addition to DBU and Hunig's base, alkaloid such as cinchonine was also found to be an effective catalyst as demonstrated in the example below.

Enantioselective Organocatalytic Singly Occupied Molecular Orbital Activation: The Enantioselective alpha-Enolation of Aldehydes

Link: JACS ASAP

Hye-Young Jang, Jun-Bae Hong, and David W. C. MacMillan*

Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

In continuing their investigation in the newly discovered mode of organocatalysis - the singly occupied molecular orbital, or SOMO activation - MacMillan group presented a new reaction. In the original contribution, alpha-allylation of aldehyde using allylsilane was recently reported.

This time alpha-enolation of aldehyde and enolsilane using the same catalyst system was reported for the first time. The mode of activation is through a single-electron activation with CAN, as shown in the scheme below, to give the corresponding electron-deficient radical cation.

Based on a DFT calculation, the enolsilane or the "SOMOphile" would approach the "SOMO-catalyst" on the si-face to avoid the bulky t-Bu group of 1, establishing the enantioselectivity of the reaction.

Thus, using enolsilane 3 as a somophile, reactions with various aldehydes proceeded in good yields and ees as shown in Table 1.

In addition, several somophiles were used to react with octanal to give the expected products in good to excellent yields and excellent ees (Table 2).

In addition, the reaction was found to be very mild and chemoselective as illustrated in Eqs 5 and 6. In a normally difficult-to-control intramolecular radical cyclization of 4, when reaction was conducted in the presence of enolsilane, the corresponding alpha-enolation product was obtained selectively in excellent yield and ee.

SOMO-activation has become more important in the field of organocatalysis. One could expect to see much more of this in the near future.

A Vaulted Biaryl Phosphoric Acid-Catalyzed Reduction of alpha-Imino Esters: The Highly Enantioselective Preparation of alpha-Amino Esters

Link: JACS ASAP

Guilong Li, Yuxue Liang, and Jon C. Antilla*

Department of Chemistry, University of South Florida, 4202 East Fowler Avenue CHE205A, Tampa, Florida 33620

This is a new organocatalytic method for enantioselective reduction of acyclic alpha-imino esters to form the corresponding alpha-amino esters (and subsequently alpha-amino acids). The method employed sterically hindrance chiral biaryl phosphoric acid as a ligand and Hantzsche ester as hydrogen source in a transfer hydrogenation process. Several biaryl phosphoric acids were initally considered.

In the initial studies, imino esters 2a-c were screened in the reaction using using phosphoric acid (PA) 1e to investigate the effect of solvents and it was found that non-polar, non-coordinating solvents such as benzene and toluene gave the best results, especially with imino ester 2a-b while ester 2c did not work too well presumably due to its steric hindrance.

Next, all PAs in Figure 1 were screened using 2a as a test substrate and PA 1e was found to be the most optimal acid for the reaction.

Generality of the reaction was established in the following table, where several alpha-imino esters were subjected to the optimal reaction conditions. In all cases, the reactions proceeded in excellent yields to give products in excellent ees.

In general, the imino esters were pre-formed before subjecting to the reactions. When the imino esters were formed in situ before the reductions, yields were lower (10-20%). However, in the cases of the alkyl-substituted imino esters (Table 3, entries 9-11), yields were found to be good to excellent, indicating that this reduction could be performed with an alpha-imino ester generated in situ in one pot.

Highly Stereoselective Formal [3 + 3] Cycloaddition of Enals and Azomethine Imines Catalyzed by N-Heterocyclic Carbenes

Link: JACS ASAP

Audrey Chan and Karl A. Scheidt*

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208

A method for polarity reversal (umpolung) applied to alpha,beta-unsaturated aldehydes (1) using NHC catalyst and reaction of the resulting intermediate with azomethine imines (2) in a formal [3+3] cycloaddition to form pyridazinones (3). NHC catalyst effectively generated homoenolate species in the process.The mechanism was proposed to involve addition of NHC to aldehyde to form the extended Breslow intermediate I, followed by reaction of this intemediate with azomethine imine to give intermediate II. This intermediate then tautomerized to give III which intramolecularly acylated to give product 3.

Initial studies were conducted between aldehyde 1a and imine 2a to give bicycle 4. Three NHC precursors, A, B, and C, were screened and results are in the table below.

From the table, one could conclude that catalyst C containing a single mesitylene group worked best (entry 8). In all cases, products were obtained in high diastereoselectivity having all syn substituents.

Having identified optimal reaction parameters, scope of the reaction was explored with various aldehydes and azomethine imines. The results are summarized below.The reaction tolerated various R groups on aldehyde including aliphatic (entry 6) and extended olefin (entry 7). However, when R group was eletron-withdrawing group-substituted phenyl ring, the reaction did not yield any product (entry 8).

In term of variation in R1 groups, the reaction tolerated well with both electron-donating and electron-withdrawing aryl groups (entries 9-14), although yield was lower in a more electron-rich system (entry 14). When R1 contained an enolizable alpha-carbon such as entry 15, the reaction was shut down.

The nature of an all-syn selectivity was proposed to be a hydrogen-bond-directed addition of 'homoenolate' to the imine away from phenyl group as shown in the scheme below.Further transformations of pyridazinone 4 were found to be facile both with MeOH and BnNH2 to give the corresponding ester 19 and amide 20 in almost quantitative yields.

Enantioselective Organocatalytic Double Michael Addition Reactions

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070581y.html

From Prof. Wei Wang's group at the University of New Mexico, Albuquerque, NM

The method presented in this paper recently published in Org Lett ASAP detailed the using of chiral organo catalyst in performing domino double Michael additions to form chiral tetrahydrothiophene derivatives.

The reaction seemed to be quite simple to conduct. First, several catalysts (I-IV) were screened for reactivity in the representative reaction using enal 1a. However, the reaction only proceeded and stopped after the first Michael addition to give aldehyde 3. The authors reasoned that the steric hindrance of the benzene ring in the thiophenol framework perhaps prevented the second addition of the enamine intermediate to the ester.

Therefore, the thiol reacting partner was switched to thiol ester 4 and the reaction was screened again with all four organocatalysts and the results are summarized below.

This time, the reaction worked very well with catalysts I-III, while catalyst IV did not give any desired product. The reactions between 1a and 4 were found to be extremely efficient both in terms of yields and selectivities. After optimal conditions were found, the several substrates were screened for scope of the reaction and the results are summarized in Table 2.

The reactions were found to telerate well in a variety of substrates 1, whether it be electron-rich (entries 8 and 9) or electron-deficient aromatic rings (entries 2-7), or both (entry 10). In 2-substituted aromatic rings (entries 3, 7, and 9), the reaction also tolerated well with steric hindrance. Entry 11 demonstrated the tolerance of the reaction with heteroaromatic. Entry 12 showed that extended conjugation in aromatic ring also worked well, as well as with alkyl-substituted enal (entry 13).

A nice method, which can be used to build complex tetrahydrothiophene derivatives quickly with good to excellent yields and excellent enantio- and diastereoselectivities.

A Highly Enantioselective Intramolecular Michael Reaction Catalyzed by N-Heterocyclic Carbenes

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114188063/ABSTRACT?CRETRY=1&SRETRY=0

From Prof. Karl A. Scheidt's group at Northwestern University

I have only skimmed through the paper. But I think this is a neat method demonstrating the use of N-heterocyclic carbenes or NHCs in a basic organic reaction for the formation carbocycles (1 to 2).

The mechanism of this process is proposed as followed.

The reaction conditions were screened with four different NHC compounds. The screening results are summarized below.

Triazolium salt D was found to be the most effective in term of both yield and ee of product 3. The scope of the reaction was explored and the results are in Table 2.

- The use of methanol to quench the reaction avoids the propensity for several of the bicyclic products to undergo hydrolysis when purified on silica gel.

- The optimized reaction conditions allowed both electron-withdrawing and -donating groups on the enone (entries 1–3).

- Additionally, electron-withdrawing and -donating substituents could be placed on the aromatic tether (entries 6 and 7).

- The alpha,beta-unsaturated methyl ketone 1d provided a moderate yield of the cyclopentane product with excellent enantioselectivity (entry 4).

- The bisaldehyde 1e underwent an interesting desymmetrization reaction in which one aldehyde became the nucleophile when exposed to an NHC while the other unsaturated moiety became the conjugate acceptor (entry 5).

- The cyclization of the aliphatic substrate 13 (entry 8) proceeded in good yield after ten hours with a catalyst loading of 20 mol%.

- When the tether length was increased to access six-membered rings, cyclohexene products were afforded but with reduced enantioselectivity and yield (62%ee, 52%; entry 9). Interestingly, product 16 did not open after the addition of methanol, unlike the cyclopentane compound.

The method also allows access to amide-substituted carbocycles when amines, instead of metahnol, were used to open the ring.

Nice chemistry which seems to have practical uses. NHCs have become an efficient and popular tool in organic synthesis. And chemists have started to explore the use of this class of compounds in reactions, other than only as ligands for Grubbs or Hoveyday-Grubbs metathesis catalysts. In fact, recently a book on NHCs in organic synthesis has been published by Wiley.