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Journal of the American Chemical Society
using dichloride 36 and amines 37 and 38. Subsequent Miyaura
EPR, electron paramagnetic resonance; HPLC, high performance
1
2
3
4
borylation of 39 gave BPin 40. Application of the developed reacꢀ
tion conditions towards ChanꢀLam amination of 40 gave access to
41 in 67% isolated yield on 0.5 g scale.
liquid chromatography; NMR, nuclear magnetic resonance; Pin,
pinacolato; RT, room temperature.
i) Me
REFERENCES
Me
37
O
‡ Modeled at the B3LYP/def2ꢀTZVP level of theory with solvent
effects included using COSMO. cis/trans isomers were evaluated
but were isoenergetic within the experimental limits. See SI for
full details.
5
6
7
8
Br
NH2
O
Br
N
H
DIPEA, DMF, RT
Cl
ii)
N
38
MeN
NH
36
Cl
39, 89%
(2 steps)
9
N
K2CO3, 50 °C
[1] For a recent review, see: Bariwal, J.; Van der Eycken, E.
Chem. Soc. Rev. 2013, 42, 9283−9303.
[2] For reviews, see: (a) Hassan, J.; Sévignon, M.; Gozzi, C.;
Schulz, E.; Lamaire, M. Chem. Rev. 2002, 102, 1359–1470; (b)
Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.
Chem. Soc. Rev. 2014, 43, 3525–3550.
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B2Pin2, PdCl2dppf (1 mol%)
KOAc, DMSO, 80 °C
Me
Me
O
O
HN
N
PinB
N
H
H
Cu(OAc)2 (20 mol%)
[3] (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933−2936; (b) Evans, D. A.;
Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937−2940;
(c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39,
2941–2944.
[4] For reviews, see: (a) Qiao, J.; Lam, P. Y. S. Synthesis 2011,
829–856; (b) Lam, P. Y. S. Chan–Lam Coupling Reaction: Copꢀ
perꢀpromoted C–Element Bond Oxidative Coupling Reaction with
Boronic Acids In Synthetic Methods in Drug Discovery: Volume
1, Eds.: Blakemore, D. C.; Doyle, P. M.; Fobian, Y. M., Royal
Society of Chemistry: Cambridge, 2016, Chapter 7, p 242–273.
[5] For selected examples, see: (a) Fan, M.; Zhou, W.; Jiang, Y.;
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W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. J. Am. Chem. Soc. 2015,
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[6] Vantourout, J. C.; Law, R. P.; IsidroꢀLlobet, A.; Atkinson, S.
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[7] For examples, see: Hall, D. G. Structure, Properties, and Prepꢀ
aration of Boronic Acid Derivatives In Boronic Acids: Preparaꢀ
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G., Ed., WileyꢀVCH: Weinheim, 2005; Chapter 1, p 1–133.
[8] For selected examples, see: (a) Larsen, M. A.; Wilson, C. V.;
Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 8633–8643; (b)
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4299; (c) Cho, J.ꢀY.; Tse, M. K.; Holmes, D.; Maleczka, R. E.;
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Am. Chem. Soc. 2002, 124, 390–391; (e) Ishiyama, T.; Murata,
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[9] For an authoritative study, see: Cox, P. A.; Leach, A. G.;
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F. Org. Lett. 2007, 9, 761−764; (b) Sueki, S.; Kuninobu, Y. Org.
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[11] For previous discussions of amination mechanisms in several
different contexts, see: (a) Collman, J. P.; Zhong, M. Org. Lett.
2000, 2, 1233–1236; (b) Collman, J. P.; Zhong, M.; Zhang, C.;
Constanzo, S. J. Org. Chem. 2001, 66, 7892–7897; (c) Lam, P. Y.
S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P. Tetrahe-
dron Lett. 2003, 44, 1691–1694; (d) Tromp, M.; van Strijdonck,
G. P. F.; van Berkel, S. S.; van den Hoogenband, A.; Feiters, M.
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Bokhoven, J. A.; van Leeuwen, P. W. N. M.; Koningsberger, D.
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N
N
B(OH)3, MeCN:t-BuOH
4 Å MS, O2, 80 °C
N
N
N
NH2
N
N
Me
Me
41, 67%
(0.5 g scale)
40, 79%
N
N
N
Scheme 23. Synthesis of Imatinib using the B(OH)3ꢀpromoted
catalytic ChanꢀLam amination. Isolated yields.
6. CONCLUSIONS
In summary, investigation of the ChanꢀLam amination has alꢀ
lowed a complete mechanistic description to be assembled. Specꢀ
troscopic analyses have provided insight into the course of the
reaction with a formative identification of key reactive intermediꢀ
ates. This has allowed the origin of three specific issues (BPin
reactivity, aryl amine reactivity, and side reactions (oxidation,
protodeboronation)) to be determined. In addition, synergistic
promotive effects of boric acid were identified and have been
leveraged to overcome these issues, providing the first generally
efficient BPin ChanꢀLam amination conditions proceeding under
nonꢀbasic reaction conditions. We believe these findings will
allow more general uptake and application of this valuable CꢀN
bond forming reaction.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, assay details and spectra, characterizaꢀ
tion data for all compounds. The Supporting Information is availꢀ
able free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* allan.watson.100@strath.ac.uk
Author Contributions
The manuscript was written through contributions of all authors.
ACKNOWLEDGMENT
This work was supported by the EPSRC. We thank the EPSRC
and GlaxoSmithKline (GSK) for a PhD studentship (JCV) and
GlaxoSmithKline for financial support and chemical resources.
We thank the analytical team at GSK for assistance with HRMS
analysis. We thank the Reviewers for helpful advice during the
submission of this manuscript.
ABBREVIATIONS
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