a-aminoallylation of Aldehydes with Ammonia: Stereoselective Synthesis of Homoallylic Primary Amines

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1 a-aminoallylation of Aldehydes with Ammonia: Stereoselective Synthesis of omoallylic Primary Amines ML n Masaharu Sugiura, Keiichi irano and Shu Kobayashi JACS ASAP ryan Wipf Group 1 6/5/04

2 Uses of omoallylic Amines ing Closing Metathesis Grubbs Cat. s Grubbs 1 cat. ethylene s Chem Comm., 2000, Chem Comm., 2000, In ther Types of eactions n TMS n InCl 3 MeC reflux n n C 2 Me oc Toluene, reflux C 2 Me oc JC, 2003, TDPS =(C 2 ) 5 TDPS TDPS Squalene Synthetase Inhibitors JACS 1999, Me 2 3 P JC 2001, ryan Wipf Group 2 6/5/04

3 Synthesis of omoallylic Amines 1) t-uli Trs then 2. Me-I, MPA 73% CCCLi 2 2 Trs JC 2001, eq (allymgcl/cecl 3 ) TF, -45 o C to r.t % de=86-90% Pb(Ac) 4 C 2 Cl 2 /Me 2 ee=78-92% Tetrahedron Asym. 1997, SiMe 3 1) A 2) 2 or 1) -78 o C, 3h A: 70%, 73% ee o 2 90%, 92% ee w/ 2 : 89%, 92% ee o 2 2 Ts Angew. Chem. Int. Ed. 1999, A ryan Wipf Group 3 6/5/04

4 Important Work on Allylic Amines - 2 C =C 2 87% 2 C 94% 3 C 54% C 2 C 2 82% JACS 1997, r 2 87% r C 2 Me Me C % 84% C 2 C 2 C % 2 ph JACS 1998, ryan Wipf Group 4 6/5/04

5 Kobayashi s Work Toward omoallylic Amine Synthesis Snu 3 cat. Toluene 0 o C =Me 71-84% yield 87-95% ee = 68-85% yield 96-99% ee X cat X Zr tu tu X=Cl or r Angew. Chem. Int. Ed. 2001, z = Me, Ethyl, Propyl 2 1 SiCl A: 1 =Me 2 = : 1 = 2 =Me z 2 1 A: 37-88% yield 7/93-1/99 syn/anti : 46-78% yield 86/14-93/7 syn/anti JC 2002, 67, ryan Wipf Group 5 6/5/04

6 a-aminoallylation of Aldehydes with Ammonia Method 2 Method Yield A p- 2 A 96 <1 p-r A 92 5 p-me A 91 4 o- A 76 <1 (pyridin-2-2yl) A 85 nd (thiophen-2-yl) A (E)-C=C A 75 3 (C 2 ) 2 C 78 3 c - C 6 11 C 80 4 (/ _ )CMe C C Quant nd Method A- Pre-mixing of Aldehyde and liquid ammonia in ethanol for 2hr at -10 o C. Then allylboronate was addedand the reaction was stirred at -10 o C for 3hrs, then at rt for 1hr before work-up. Method - Pre-mixing of Aldehyde and wt% aqueous ammonia in ethanol for 30 min at rt. Then allylboronate was added and the reaction was stirred at rt for 2hr before work-up. Method C- Pre-mixing of allylboronate and liquid ammonia in ethanol for 30 min at rt. Then the aldehyde in ethanol was added and the reaction was stirred at rt for 2hr before work-up ryan Wipf Group 6 6/5/04

7 Possible eaction Pathways Methods A and 3 2 Method C rg. Let.2004, ryan Wipf Group 7 6/5/04

8 Selective a-aminoallylation of Aldehydes with Ammonia Diastereoselective eactions of a-xyaldehydes TS 3, allylboronate Method C 0 o C, 12hr 67% 2 TS 85% syn 95% ee Me TS 3, allylboronate Method A 0 o C, 24hr 51% oc >98% syn a) 3, Me 2 S b) Cl, Me c) Ac 2, pyridine 44% Me Ac Ac Me Stereospecific a-aminocrotylation Method C 2 = 85% yield >99%syn =p- 2 90% >99% syn = p- 2 2 = 79% yield >99%anti =p- 2 92% >92% anti ryan Wipf Group 8 6/5/04

9 Conclusions Kobayashi has reported a direct route to unsubstituted homoallylic amines through the use of ammonia as the itrogen source. The works well with a variety of aromatic aldehydes, though currently the methodology has not been expanded beyond these substrates. The reaction has been shown to be highly selective both in %ee and syn/anti ratio when using a-xyaldehydes.stereospecific a-aminocrotylations have been shown to giive excellent selectives. Currently the reaction has not been shown to be highly stereoselective in the presence of chiral boronate reagentsthough work in this area is on going Method A C 2 Cl 2, -30 o C, 4hr 74% 2 34% ee () ryan Wipf Group 9 6/5/04