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. 2015 Dec 4;17(23):5788-5791.
doi: 10.1021/acs.orglett.5b02898. Epub 2015 Nov 17.

Palladium-Catalyzed Benzylic C-H Arylation of Azaarylmethylamines

Byeong-Seon Kim #  1 , Jacqueline Jiménez #  1   2 , Feng Gao  1   3 , Patrick J Walsh  1
Affiliations

Palladium-Catalyzed Benzylic C-H Arylation of Azaarylmethylamines

Byeong-Seon Kim et al. Org Lett. .

Abstract

A direct C-H functionalization approach to produce aryl(azaaryl)methylamines from azaarylmethylamines without directing groups is described. Under conditions where the azaarylmethylamines' C-H is reversibly deprotonated, a Pd(OAc)(2)/NIXANTPHOS-based catalyst couples the resulting carbanions with various aryl halides to provide aryl(azaaryl)methylamines. This umpolung strategy directly provides tertiary amines without protecting or activating groups.

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Figures

Figure 1
Figure 1
Selected pharmacologically active compounds containing aryl(azaaryl)methylamines.
Figure 2
Figure 2
Representative synthetic intermediates with directing groups (A, B) and activating groups (C–F) employed in metal-catalyzed C–H functionalization adjacent to nitrogen.
Scheme 1
Scheme 1
Palladium-Catalyzed Benzylic C–H Arylation with Azaarylmethylamines
Scheme 2
Scheme 2. Pd-Catalyzed C(sp3)–H Arylation of 2-Pyridylmethylamines 1 with Aryl Bromides 2a
aIsolated yields. bX = Br was used unless noted. c5 mol % of Pd(OAc)2 and 7.5 mol % of NIXANTPHOS and the yields in parentheses with 1 mol % of Pd(OAc)2 and 1.5 mol % of NIXANTPHOS. d4 mol % of Pd(OAc)2 and 6 mol % of NIXANTPHOS.
Scheme 3
Scheme 3. Benzylic Cross-Coupling of 2-(Dialkylaminomethyl)pyridine 1 with Aryl Bromides 2a
aIsolated yields.
Scheme 4
Scheme 4. Benzylic Cross-Coupling of Azaarene Derivatives
aIsolated yields. bX = Br unless noted. c1 mol % of Pd(OAc)2 and 1.5 mol % of NIXANTPHOS and the yields in parentheses with 5 mol % of Pd(OAc)2 and 7.5 mol % of NIXANTPHOS. d5 mol % of Pd(OAc)2 and 10 mol % of NIXANTPHOS. eThe reaction was conducted in THF at 110 °C with KN(SiMe3)2 instead of LiN(SiMe3)2.
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