Enantiomerically pure diarylmethylamines are important intermediates in the synthesis of biologically active compounds. [1] Cetirizine hydrochloride (1) stands out from several drug candidates as a commercially important nonsedating antihistamine agent. Binding studies indicate that the R enantiomer displays a better pharmacological profile than the racemate. [2] Despite the importance of enantiopure diarylmethylamines, synthetic accesses and especially asymmetric (catalytic) processes for their synthesis are rather limited. [3] While there are several synthetic routes to, for example, enantiopure cetirizine that utilize resolution techniques, [4] stoichiometric amounts of chromium complexes, [5] or diastereoselective approaches with chiral auxiliaries, [6] to the best of our knowledge there is only a single report on an asymmetric catalytic addition of an organometallic arylation agent to an imine derivative. Hayashi and Ishigedani described a highly enantioselective rhodium-catalyzed process for the arylation of N-sulfonylimines with aryl stannanes (up to 96 % ee). [7] For quite some time we have been engaged in the asymmetric transfer of a phenyl group from organozinc reagents and have developed a protocol for the highly enantioselective transfer of a phenyl group to aldehydes using ferrocene (R p ,S)-2 and cyrhetrene (R p ,S)-3. [8] However, a major difficulty in the development of asymmetric processes for the transfer of a phenyl group remains the much higher reactivity of diphenylzinc relative to dialkylzinc and the concomitant rapid uncatalyzed background reaction.Recently, we developed a catalytic procedure for the enantioselective addition of diethylzinc to masked N-formylimines by employing catalytic amounts of [2.2]paracyclophane-based ketimines. [9,10] We now report on the combination of both methods, which leads to the first highly enantioselective addition of phenylzinc to imines and gives rise to optically active diarylmethylamines in very high enantiomeric excesses.At the outset of our study we examined the use of different N,O-ligands (Scheme 1) in the phenylation of N-[p-tolylmethyl-(toluene-4-sulfonyl)]formamide (7 a, Table 1). This class of N-acylimine precursors is readily available in a one-pot synthesis from benzaldehyde, amide, and p-tolylsulfinic acid. [11] The addition to the imine then proceeds by deprotonation of amide 7 a, followed by elimination of the sulfinate to form N-formylimine 8 a. Addition of the zinc reagent gives rise to the N-formylamine 9 a. We started out by employing the reaction conditions developed for the enantioselective transfer of a phenyl group to aldehydes using a mixed zinc reagent formed in situ from diphenylzinc and diethylzinc. This reagent selectively transfers only the phenyl moiety to the substrate to afford N-formylamine 9 a in very high yield without formation of the corresponding ethylation product. [12] The ligand screening (Table 1) showed that ferrocene (R p ,S)-2 and cyrhetrene 3, which represent the best ligands for the enantioselective transfe...

The first highly enantioselective dialkylzinc addition to imines in the presence of catalytic amounts of N,O-ligands is reported. N-formyl-alpha-(p-tolysulfonyl)benzylamines are the readily available starting materials easily obtained in a one-pot synthesis from benzaldehydes, formamide, and p-tolylsulfinic acid. Upon deprotonation, the sulfinate is eliminated to give the acyl imine. The acyl imines further react with alkylzinc reagents in the presence of catalytic amounts of [2.2]paracyclophane-based N,O-ligands L yielding the alkylated N-(1-phenylpropyl)formamides with excellent yields and enantioselectivities.

[reaction: see text] The application of planar and central chiral [2,2]paracyclophane-based N,O-ligands in asymmetric alkenylzinc additions to various aldehydes is described, which gives rise to very high ee's especially for difficult substrates. A fine-tuning of the alkenylzinc species by employing different transmetalation reagents is reported, allowing control of the steric bulk of the alkenylzinc species and thus the selectivity of the catalysis.

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.

Traceless linkers, which enable the attachment of arenes and alkanes to a polymeric support, have received increased attention in recent years. These anchoring groups allow chemical transformations on the polymer-bound molecules, which can be cleaved from the resin leaving no residual functionality to bias the library. Various approaches based on different Group 14 to Group 16 heteroatoms have been developed in the past and used in new syntheses of diverse compound libraries.

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[reaction: see text] [2.2]Paracyclophane-based ketimine ligands were evaluated as catalysts for the enantioselective addition of in situ-prepared alkynylzinc reagents to aldehydes. The initial high activity and enantioselectivity of these ligands could be improved by an additive screening. The final protocol gives chiral propargyl alcohols in up to >98% ee.

A s y m m e t r i c A d d i t i o n R e a c t i o n s i n t h e P r e s e n c e o f [ 2 . 2 ] P a r a c y c l o p h a n e L i g a n d s Abstract: Planar and central chiral [2.2]paracyclophane ligands have been designed and used in the highly enantioselective addition of alkyl, alkenyl, alkynyl and aryl zinc reagents to aldehydes and imines.