AmericanChemicalSociety.com

The intramolecular hydroamination of carbon-carbon multiple bonds constitutes one of the most atom-economical means for the synthesis of cyclic amines and imines. In the case of alkene, diene, and allene hydroamination, a new stereogenic center is formed during carbon-nitrogen bond construction. This raises an important synthetic opportunity for asymmetric catalysis leading to enantiomerically enriched heterocycles.

During the proceeding grant period, we have successfully synthesized and begun to evaluate two distinct sets of optically active proligands (e.g., 1a-c and 2) that will lead to complexes in which the chelated metal is endowed with enhanced electron density. Proligands 1a-c represent a conceptually new class of axially chiral bis(b-diiminate)s, whereas 2 is noteworthy by possessing external  contact ligand chirality  that will permit the evaluation of this characteristic on enantioselectivity (Scheme 1).

 The above proligands were readily accessible by the following routes. Condensation of [R- (or S-)]-1,1'-binaphthyl-2,2'-diamine (3) with 2 equiv. of the appropriate and readily prepared 2-(arylamino)benzaldehyde 4a-c^1a (Ti(OEt)₄, THF)^1b provided 1a-c with high efficiency. Proligand 2 was derived from acylation of (R,R-)-2,5-dimethylpyrrolidine (5) (that is now readily available by our methodology, vide supra, followed by resolution with mandelic acid^1c) with 2-nitrobenzoyl chloride to give 6. Exhaustive reduction of 6 followed by acylation of the resulting aniline with oxalyl chloride (0.5 equiv, i-Pr₂NEt as an HCl scavenger) and final reduction (LiAlH₄) then delivered 2 (Scheme 2).

 Asymmetric intramolecular hydroaminations involving the aminoalkenes 7a,b, the aminoallenes 8a,b, and the aminodienes 9a,b are currently  being carried out as previously described² and the resulting ee's are  being determined by ¹H NMR  after diastereomeric  salt formation using optically active O-acetylmandelic acid^3a or as a Mosher's amide^3b (Scheme 3). The selection of the E,E-dienes 9a,b with terminal phenyl substitution is based on the known⁴ predisposition of this substrate type to undergo 1,2- (and not 1,4-) N-H addition to the conjugated p-system.

Given the high reactivity exhibited by the Zr(IV)¥NPS chelates in the intramolecular hydroamination of allenes,⁵ a series of  experiments are being performed using precatalysts derived from Zr(NMe₂)₄ and the new chiral proligands described above. A comparison of the ee's obtained with these complexes to those of the corresponding Y, Lu and Sc chelates in the cyclization of aminoallenes 8a and 8b should be mechanistically interesting in that hydroaminations involving group 4 metals proceed via imido complexes⁶ as opposed to amido complexes, as in the case of group 3 metals. In addition, a direct comparison of Sc(III) and Zr(IV) in this context will be revealing as the covalent radii of these two metals are similar. Irrespective of the viability of the Sc(III) complexes generated from 1a-c and 2 as hydroamination catalysts, the use of these proligands as their Y(III) complexes for asymmetric  hydroamination will be revealing in terms of the electronic prerogatives of this metal vis a vis enantiocontrol. The evaluation of various group 3 and Zr(IV) complexes of the above proligands for the asymmetric hydroamination of representative aminoalkenes is currently underway.

The professional impact of this research for me has been a far better appreciation for, and consequently understanding of, those factors that influence the design and synthesis of high-performance ligands for asymmetric catalysis. My collaborator on this project has benefited significantly from learning the specialized techniques of manipulating air and moisture sensitive compounds in synthesis.

References

1(a). Nickel-Catalyzed Transformations of 2,1-Benzisoxazoles with Organozinc Reagents Baum, J. S.; Condon, M. E.; Shook, D. A. J. Org. Chem. 1987, 52, 2983. Bridgehead Nitrogen Heterocycles which Contain the Quinazoline Moiety-Synthesis and Cycloaddition of 1,2-Dihydroquinazoline 3-Oxides. Org. Biomol. Chem. 2005, 3, 4351. (b). Synthesis of Enantiomerically Pure N-tert-Butane Sulfinyl Imines (tert-Butanesulfinimines) by the Direct Condensation of tert-Butanesulfinamide with Aldehydes and Ketones. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (c). Asymmetric Induction. 2.¹ Enantioselective Alkylation of Cyclohexanone via a Chiral Enamine. Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1977, 42, 1663.

2. Enantioselective Intramolecular Alkene Hydroaminations Catalyzed by Yttrium Complexes of Axially Chiral Bis(thiolate) Ligands. Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737.

3(a). Direct ¹H NMR Assay of the Enantiomeric Composition of Amines and b-Amino Alcohols Using O-Acetyl Mandelic Acid as a Chiral Solvating Agent. Parker, D.; Yaylor, R. J. Tetrahedron 1987, 43, 5451. (b). Zirconium catalysed enantioselective hydroamination/cyclisation. Knight, P. D.; Munslow, I.; O'Shaughnessy, P. N.; Scott, P. J. Chem. Soc. Chem. Commun. 2004, 894.

4. Highly Stereoselective Intramolecular Hydroamination/Cyclization of Conjugated Aminodienes Catalyzed by Organolanthanides. Marks, T. J.; Hong, S. J. Am. Chem. Soc. 2002, 124, 7866.

5. Intramolecular Hydroaminations of Aminoalkynes Catalysed by Yttrium Complexes and Aminoallenes Catalyzed by Zirconium complexes. Kim. H.; Livinghouse, T.; Dong, S.; Lee, P. H. Bull. Korean Chem. Soc. 2007, 28, 1127.

6. Development of the Ti-Catalyzed Intramolecular Hydroamination of Alkynes. Doye, S. Synlett. 2004, 1653 and references therein.