ARTICLES
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emerging synthetic tools for natural products and pharmaceuticals. Angew.
Chem. Int. Ed. 51, 8960–9009 (2012).
11. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C–C bond
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12. Daugulis, O., Roane, J. & Tran, L. D. Bidentate, monoanionic auxiliary-directed
functionalization of carbon–hydrogen bonds. Acc. Chem. Res. 48, 1053–1064 (2015).
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functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
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by AgTFA (refs 40,41) provides the α-imino acid VI, which releases
final product 2 or 3 and 2-oxoacetic acid, a process facilitated by
water. It should be mentioned that the reaction of 1a failed to
provide any of product 2a in the absence of a silver salt, implying
that AgTFA may play other roles besides iodide abstraction in this
catalytic circle.
During the review of this manuscript, a related work on C(sp3)–H
arylation of free primary amines was reported by Dong and colleagues42.
Conclusions
In summary, palladium-catalysed direct arylation of primary ali-
phatic amines was achieved via an sp3 C–H bond functionalization
process with the assistance of a catalytic directing group. This reac-
tion demonstrates high site selectivity by favouring the γ-C–H bond
of the methyl group, as well as good functional group compatibility.
This newly developed method using a catalytic transient directing
group is inherently superior to previously reported protocols for the
site-selective C–H bond functionalization of primary aliphatic
amines due to the avoidance of the pre-installation and subsequent
removal of a directing group. Considering the importance of
primary aliphatic amines in medicines, the transformation reported
here should find broad applications in drug development and
discovery processes. Detailed mechanistic studies of this reaction
and expansion of the substrate scope are currently ongoing in
our laboratory.
15. Chen, Z. et al. Transition metal-catalyzed C–H bond functionalizations by the
use of diverse directing groups. Org. Chem. Front. 2, 1107–1295 (2015).
16. He, G., Wang, B., Nack, W. A. & Chen, G. Syntheses and transformations of α-
amino acids via palladium-catalyzed auxiliary-directed sp3 C–H
functionalization. Acc. Chem. Res. 49, 635–645 (2016).
17. Yoo, W.-J. & Li, C.-J. Cross-dehydrogenative coupling reactions of
sp3-hybridized C–H bonds. Top. Curr. Chem. 292, 281–302 (2010).
18. Yeung, C. S. & Dong, V. M. Catalytic dehydrogenative cross-coupling: forming
carbon–carbon bonds by oxidizing two carbon–hydrogen bonds. Chem. Rev.
111, 1215–1292 (2011).
19. Zhang, C., Tang, C. & Jiao, N. Recent advances in copper-catalyzed
dehydrogenative functionalization via single electron transfer (SET) process.
Chem. Soc. Rev. 41, 3464–3484 (2012).
20. Girard, S. A., Knauber, T. & Li, C.-J. The cross-dehydrogenative coupling of
Csp3–H bonds: a versatile strategy for C–C bond formations. Angew. Chem. Int.
Ed. 53, 74–100 (2014).
21. Spangler, J. E., Kobayashi, Y., Verma, P., Wang, D.-H. & Yu, J.-Q. α-Arylation of
saturated azacycles and N-methylamines via palladium(II)-catalyzed C(sp3)–H
coupling. J. Am. Chem. Soc. 137, 11876–11879 (2015).
Methods
22. Pastine, S. J., Gribkov, D. V. & Sames, D. sp3 C–H bond arylation directed by
amidine protecting group: α-arylation of pyrrolidines and piperidines. J. Am.
Chem. Soc. 128, 14220–14221 (2006).
Typical procedure for palladium-catalysed C–H arylation of primary aliphatic
amines. To a 35 ml reaction tube were added Pd(OAc)2 (6.7 mg, 0.03 mmol),
glyoxylic acid monohydrate (5.5 mg, 0.06 mmol), AgTFA (99.4 mg, 0.45 mmol),
HOAc (2 ml), tert-amylamine (1a, 26.1 mg, 0.3 mmol), iodobenzene (91.8 mg,
0.45 mmol) and H2O (21.6 µl, 1.2 mmol). The tube was then sealed and the reaction
mixture was stirred at room temperature for 15 min before being heated to 100 °C
for 15 h. The mixture was cooled to room temperature and concentrated under
reduced pressure. The resulting residue was treated with Et2O (10 ml) and
hydrochloric acid (0.5 M, 8 ml) and then filtered. The aqueous phase was separated
from the filtrate, and the organic layer was extracted with hydrochloric acid (0.5 M,
3 × 8 ml). The combined aqueous phase was basified (pH > 12) with saturated
aqueous NaOH solution and extracted with CH2Cl2 (3 × 15 ml). The combined
organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to provide the desired arylated product 2-methyl-4-phenylbutan-
2-amine (2a) as a pale yellow oil (36.3 mg; yield 74%).
23. Chatani, N. et al. Carbonylation at sp3 C–H bonds adjacent to a nitrogen atom in
alkylamines catalyzed by rhodium complexes. J. Am. Chem. Soc. 122,
12882–12883 (2000).
24. McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed
C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature
510, 129–133 (2014).
25. Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed
transannular C–H functionalization of alicyclic amines. Nature 531,
220–224 (2016).
26. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of
sp3 C−H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127,
13154–13155 (2005).
27. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of
azetidines, pyrrolidines and indolines via palladium-catalyzed intramolecular
amination of C(sp3) and C(sp2)–H bonds at γ and δ positions. J. Am. Chem. Soc.
134, 3–6 (2012).
28. Zhang, S.-Y. et al. Efficient alkyl ether synthesis via palladium-catalyzed,
picolinamide-directed alkoxylation of unactivated C(sp3)–H and C(sp2)–H
bonds at remote positions. J. Am. Chem. Soc. 134, 7313–7316 (2012).
29. Zhang, S.-Y. et al. Palladium-catalyzed picolinamide-directed alkylation of unactivated
C(sp3)–H bonds with alkyl iodides. J. Am. Chem. Soc. 135, 2124–2127 (2013).
30. Rodríguez, N., Romero-Revilla, J. A., Fernández-Ibáñez, M. Á. & Carretero, J. C.
Palladium-catalyzed N-(2-pyridyl)sulfonyl-directed C(sp3)–H γ-arylation of
amino acid derivatives. Chem. Sci. 4, 175–179 (2013).
Data availability. The crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) as CCDC 1491489 (6 at 100 K) and can be
Received 12 April 2016; accepted 1 August 2016;
published online 12 September 2016
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