Direct, Catalytic Hydroaminoalkylation of Unactivated Olefins with N-Alkyl Arylamines

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1 Current Literature - May 12, 2007 Direct, Catalytic ydroaminoalkylation of Unactivated lefins with -Alkyl ylamines ' '' Ta[ 2 ] 5 (4-8 mol%), o C 24-67h 66-95% ' '' S. B. erzon and J. F. artwig, J. Am. Chem. Soc., ASAP DI: /ja

2 Biological Activation of C Bonds Cytochrome P450, a family of over 60 enzymes, participates in a variety of cellular redox processes P450, 2e - Ability of P450 to transform endogeous and foreign compounds has a tremendous impact on the metabolism of drugs 2 For recent studies on the metabolism of cyclopropylamines, see: Cerny, anzlik J. Am. Chem. Soc. 2006, 128, 3346 Many efforts have been focused on developing a catalytic system mimicking activity of P450. tals such as Pd(0), u(ii), Cu(I) are successful candidates for the catalytic activation of C bonds.

3 Activation of sp 3 C Bonds Adjacent to itrogen Catalytic carbonylation via pyridine-directed activation of pyrrolidine has been achieved using h(i) catalysts hcl(cod) 2 (4 mol%) C, 2 C=C 2, i-pr 160 o C, 60 h, 70% [hcl(c) 2 ] 2 (4 mol%) C, 2 C=C 2, i-pr 160 o C, 60 h, 73% Et =, 40 h, 68% 3-, 60 h, 73% 4-, 60 h, 73% 5-, 40 h, 84% 6-, 60 h, 12% 5-CF 3, 60 h, 15% Et Murai et al. J. Am. Chem. Soc. 2000, 122, Doye Angew. Chem. Int. Ed. 2001, 40, 3351 Similarly, imines are viable substrates in Ir(I) promoted 3 component coupling with alkynes '' ' 2, ', '' = n-pr, i-pr, n-bu, i-bu, s-bu, ex [IrCl(cod)] 2 (10 mol%) TF, 60 o C ' Ishii et al. Angew. Chem. Int. Ed. 2001, 40, 2534 '' 45-74%

4 Activation of sp 3 C Bonds Adjacent to itrogen Aerobic oxidation of alkyl amines using ucl 3 has been successfully applied to dimethyl aryl amines ac, ucl 3 (5 mol%) 2,, Ac 81-88% Murahashi et al. J. Am. Chem. Soc. 2003, 125, C CuBr (5 mol %) TBP, 100 o C, 3 h 12-82% Similarly, Li showed that CuBr can catalyze oxidative coupling of amines in the presence of TBP 2 CuBr (5 mol %) TBP, rt, 6 h Li, Li J. Am. Chem. Soc. 2004, 126, Li, Li J. Am. Chem. Soc. 2004, 126, 3672 =, %

5 Activation of sp 3 C Bonds Adjacent to itrogen Boc Pd(Ac) 2 (10 mol%) C 2 Cl 2, 50 o C, 40 h IAc A. I(Ac) 2 I 2 or B. AgAc I 2 Boc Ac 70-96% = Alkyl, yl itrogen protecting groups are commonly applied as directing moieties in Pd-promoted C activations Yu et al. rg. Lett. 2006, 8, 3387 Imine-directed coupling of boronic esters was carried out in the presence of reducing agent (ketone) in good yields amd modest selectivities Pastine, Gibkov, Sames J. Am. Chem. Soc. 2006, 128, B t-buc (5 eq) u 3 (C) 12 (3.3 mol%) 150 o C, 4-19 h 38-78% dr 1:0 to 3:1 A conceptually different approach was applied by Davis - catalytic C insertion into C bonds afforded pyrrolidines and piperidines in high chemoslectivities, de s, and ee s. Boc 2 C 2 h 2 (S-DSP) 4 Boc C 2 Davis et al. J. Am. Chem. Soc. 2003, 125, 64620

6 Activation of sp 3 C Bonds Adjacent to itrogen [hcl(coe) 2 ] 2 (5 mol%) PCy 3 Cl (15 mol%) TF, 165 o C ent r y alkene time (h) Yield (%) 1 t-bu (linear) 2 n-bu (branched) C 2 i-bu C 2 i-bu Lewis, Bergman, Ellman J. Am. Chem. Soc. 2007, 127, 5332

7 C activation in the artwig Group Cp*h(! 4 -C 6 6 ) (5 mol%) 150 o C B - B 2 65% artwig et al. Science 2000, 287, 1995 artwig et al. J. Am. Chem. Soc. 2004, 126, [Cp*uCl 2 ] 2 (1-2.5 mol%) C 3 B B B t-bu Bpin t-bu Bpin 70% 94% Bpin Bpin n-c 8 F 17 80% >90% artwig et al. J. Am. Chem. Soc. 2006, 128, SiEt 3 (Tp 2 )Pt() o C, 24 h 86% SiEt 3 Si 3 (Tp 2 )Pt() o C, 72 h Bu 2 Si 80-86% Tsukada, artwig J. Am. Chem. Soc. 2005, 127, 5022

8 Zirconaaziridines Many metal η 2 -imine complexes of early TM and lanthanides are known ' Li '' Cp 2 ZrX X = Cl, Tf ' Cp 2 Zr '' - C 4 L L ' Cp 2 Zr '' L = TF, P 3 Buchwald et al. J. Am. Chem. Soc. 1989, 111, 4486 Cumming et al. Top. Curr. Chem. 2005, 10, 1 ate of methane elimination is dependent on nitrogen substitution ( availability of nitrogen lone pair ) Cp 2 Zr Bu 10 3 times faster than Cp 2 Zr Pr Unlike η 1- complexes, metallaaziridines undergo typical d 0 Ti/Zr (IV) reactions - insertion of multiple bonds and coupling reactions Cp 2 Zr X X X =, TF Cp 2 Zr Cp 2 Zr

9 Group 5 tals Stoichiometric reactions of η 2 -complexes with aldehydes and ketones have been described (umpolung) bcl 3 (DME) ' '' TF '' ' (TF) 2 Cl 2 b = Bn, allyl ', '' =, alkyl Yields: 34-90% oskamp, Pedersen J. Am. Chem. Soc. 1987, 109, 6551 M( 2 ) 5, M = b, Ta have been shown to catalyze alkylation of alkene in low yields ' =, ' =,, -Bu cat.,, 160 or 200 o C ' 13-38% Cleric, Maspero Synthesis 1980, 305 ugent, venall, olmes rganometallics 1983, 2, 161

10 Title Paper - Experiment Design and Initial Studies ( 2 ) 3 M ( 2 ) 3 M 2 ( 2 ) 3 M product 2 catalyst (4 mol%), o C entry catalyst % yield precursor 1.3 h 5.1 h 24 h 1 Ta[ 2 ] Ta[Et 2 ] b[ 2 ] Cp 2 Zr[ 2 ] Zr[ 2 ] none 0 0 0

11 Title Paper - eaction Scope Typically, high selectivity was observed although some olefins give a mixture of linear and branched isomers nly aromatic rings with m- and p- substituents were shown to undergo hydroaminoalkylation 88% 71% 66% TMS n-pentyl 76% 77% 96% dr 3:1 Si 2 and Si 2 50% 28% F t-bu 88% t-bu 93% 90% 72% (single diastereomer) F F 84% 78% 88% dr 1:1

12 Title Paper - chanistic Proposal Exchange of aromatic protons occurs most likely faster than the insertion reaction CD 3 Ta[ 2 ] 5 (4 mol%), o C 46% 45% 12% 27% at 25% conversion: 15% D in ortho position ene activation via [Ta] Ligand exchange Ta[ 2 ] eq -d8 dodecane, 80 o C, 24 h [ 2 ] 4 Ta [ 2 ] 3 Ta 37% 39% 2 with 25 eq of toluidine, 1:1 ratio

13 eactivity of Tantalum Complexes Primary amines form imido complexes with tantalum Ta( 2 ) 5 t-bu 2 ( 2 ) 3 Ta=t-Bu 2 2 ugent, arlow J. Chem. Soc. Chem. Comm. 1978, 579, eutral Ta complexes have been shown to catalyze hydroamination reactions of anilines and alkynes 2 5 mol% [Ta] C 6 D 5 Cl, 135 o C 3:1 ent r y alkene time (h) yield (%) 1 Bn 3 Ta=C > [BnTa=C 3 ] 8 > p 3 Ta=C > (Et 2 ) 3 Ta=C > Ta( 2 ) > Cl 3 Ta=C Anderson, nold, Bergman rg. Lett. 2004, 6, 2519

14 Summary and Future Prospective Catalytic hydroaminoalkylation of alkenes using Ta proceeded in high yields and appreciable selectivities Although electronic properties of amine control the selectivity, typical directing groups (e.g. pyridyl, iminoyl, carbamoyl) are not necessary What needs to be done Improve reaction conditions and scope More mechanistic data is needed to explain the selectivity as well as reactivity of Ta complexes