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Palladium-Catalyzed Direct Intermolecular Amination of Unactivated Methylene C(sp3)-H Bonds with Azodiformates via Bidentate-Chelation Assistance heyuan bai, Zhi-Gang Ma, Min Yi, Jun-Bing Lin, and Shu-Yu Zhang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03621 • Publication Date (Web): 10 Feb 2017 Downloaded from http://pubs.acs.org on February 10, 2017
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ACS Catalysis
Palladium-Catalyzed Direct Intermolecular Amination of Unactivated Methylene C(sp3)−H Bonds with Azodiformates via Bidentate-Chelation Assistance He-Yuan Bai, Zhi-Gang Ma, Min Yi, Jun-Bing Lin and Shu-Yu Zhang* School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
Supporting Information Placeholder R1
H N
H 2
R
O
DG +
R3 N N
Pd(OAc)2 R 3 AmylOH/O2
R3
N H
R3 N
R1
R2
H N O
Cs2 CO 3/MeCN DG
HCl/MeOH
up to 87 % y ield
R3
R1
H N
OMe R2
O
β -amino acid derivatives
Unact iv ated methylene C( sp 3)-H amination DG = N, N-bidentat e dir ect ing gr oup
ABSTRACT: An efficient and convenient method enabling direct amination of unactivated methylene C(sp3)−H bonds to form C-N bonds with azodiformates as amino source is described. This method highlights the emerging strategy of unactivated methylene as versatile functional groups in organic synthesis and provides a strategy to construct functionalized C-N bonds for the synthesis of complex molecules. KEYWORDS: C-H amination, Azodiformates, Palladium-catalyzed, Methylene, β-amino acid derivatives
Nitrogen-containing molecules are very important and widely present in amino acids, alkaloids, and pharmaceutical compounds (Figure 1)1. The development of efficient and novel C-N bond forming methods as an intensively investigated field has been focused by synthetic chemistry. While many classical transformations have been established to form the C-N bond, the direct selectively conversion of an unactivated C-H bond to the corresponding C-N bond is one of the most attractive synthetic approaches.2
palladium-catalyzed intermolecular unactivated C(sp3)−H amination process were individually reported (Scheme 1A). Scheme 1. Synthetic Utilities of the Palladium-Catalyzed Intermolecular Unactivated sp3 C−H Amination. A) Previous work: Intermolecular terminal C(sp3)-H amination
B) This work: Intermolecular methylene C(sp3)-H amination
Figure 1. Biologically active molecules containing β-amino acids or 1,3-diamines derivatives In the past decades, significant advances have been made in the direct conversion of C(sp2)-H or C(sp3)-H bonds to C-N bonds.3-10 However, direct catalytic functionalization of intermolecular unactivated sp3 hybridized C−H amination reaction still remains a great challenge in synthetic chemistry. Since the seminal work of Che and Yu on palladium-catalyzed C(sp3)-H amination of Omethyl oximes has received special attention because of its high regioselectivity and atom efficiency,11a only few examples of this
In 2011, Buchwald reported a monoamination of 1-bromo-tertbutylbenzene derivatives with the formation the C-N bond at the methyl group.11b Recently, Yu reported a palladium-catalyzed βC(sp3)−H amination of methyl group of aliphatic amides for the synthesis of terminal β-amino acids using an electron-deficient triarylphosphine ligand.11c Qin reported a palladium-catalyzed inter-molecular terminal amination with the assistance of the amide derived from 2-aminothioether as a directing group.11d How-
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ever, to date, ligand-controlled palladium-catalyzed intermolecular unactivated methylene direct C(sp3)-H amination process has not been discovered. In continuing efforts and interest to develop efficient and selective unactivated C(sp3)-H functionalization and their applications in the synthesis of natural products,12 herein, we disclosed the first example of a palladium-catalyzed bidentatechelation assistant intermolecular unactivated methylene direct C(sp3)-H amination protocol using azodiformates as a new amino source (Scheme 1B). This unactivated methylene C(sp3)−H amination of aliphatic acid provides a new simple method for synthesis of bioactive multi-substituted primary or secondary β-amino acid derivatives or 1, 3-diamine compounds.
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With an optimized set of conditions in hand, we then probed the scope of different azodiformates (Table 2, 3b-3d). Some commercial available azodiformates, such as DEAD (Diethyl azodicarboxylate), DBAD (Di-t-butyl azodicarboxylate), and Dibenzyl azodicarboxylate, can react with 1a and provide amination products 3b-3d with 19% to 83% yield. It was clear that the reaction was sensitive to steric hindrance of the substituents on the azodiformates, and the azodiformate DEAD with the smallest steric hindrance gave the best isolated yield (83%, Table 2, 3b).
Table 2. Substrate Scope of C-H Amination Reaction a,b Table 1. Optimization of Reaction Condition for Intermolecular Methylene C(sp3)−H Amination with DIADa
Entry
Cat. (10 mol %)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
PdCl2 Pd(PPh3)4 Pd(OTF)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 d
Additives (equiv) /atmosphere
Solvents
Yield (%) b
Ar,110 oC Ar,110 oC Ar,110 oC Ar,110 oC Ar,110 oC Ar,110 oC Ar,110 oC Ar,110 oC Cu(OAc)2 (2), Ar,110 oC BQ(2), Ar,110 oC Ag2CO3 (2), Ar,110 oC O2, 110 oC O2, 80 oC O2, DIAD (3), 110 oC O2, DIAD(1), 110 oC O2, 110 oC
DCE DCE DCE DCE THF MeCN Toluene t-AmylOH t-AmylOH t-AmylOH t-AmylOH t-AmylOH t-AmylOH t-AmylOH t-AmylOH t-AmylOH
