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Journal of the American Chemical Society
Table 2. Difference in ꢁG (T.S.) for a range of trialkylamine sub-
strates with different HAT agents and experimental selectivity
1
2
3
4
5
6
7
8
9
Notes
HAT reaction
ꢁꢁG (T.S.) N-CH3 : N-CH2
The authors declare no competing financial interests.
N-methylmorpholine/DABCO+
12.1
12.7
1.3
>30:1
•
ACKNOWLEDGMENTS
N-methylmorpholine/Me3N+
-
-
•
We thank GlaxoSmithKline and the University of Strathclyde for
funding. We thank Dr. Colin M. Edge (GlaxoSmithKline) for guid-
ance with computational chemistry, Dr. Leonard E. A. Berlouis
(University of Strathclyde) for advice on cyclic voltammetry, Prof.
John C. Walton (University of St. Andrews) for assistance with EPR
spectrometry and Dr. David Hulcoop for helpful discussions
N-methylmorpholine/Me•
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
dextromethorphan (6a)/DABCO+
2.7
10:1
6:1
-
•
N-methyldioctylamine/DABCO+
3.3
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1.8
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N-methyl THIQ/DABCO+
-2.6b
1:10
•
6,7-dimethoxy-N-methyl
-3.8b
<1:30
THIQ/DABCO+
•
(4)
(5)
(6)
All starting materials, products and transition state energies calcu-
lated using density functional theory (DFT) calculations in Gaussi-
an09 using an unrestricted B3LYP functional with a 6-31+G(d,p)
basis set and C-PCM implicit solvent model.45 aAll energies are in
kcal mol-1. bThe transition state for N-CH2R HAT is lower energy
than N-CH3 HAT.
(7)
(8)
(9)
An important steric factor is the structure of DABCO+•,46 which
sees the radical cation delocalized between the two nitrogen p-
orbitals. As well as imparting stability to enhance lifetime,47,48
this results in a steric ‘cage’ around the radical cation element,
allowing DABCO+• to be uniquely selective in its reactions.
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
Conclusion: DABCO radical cation, generated in situ through
the use of stable, rechargeable radical cation salts, engages in
contra-thermodynamic HAT reactions with trialkylamines with
exquisite regioselectivity for N-CH3 groups. The least stable,
primary α-amino radicals are captured as metastable DABCO-
adduct intermediates which can be readily intercepted with hard
nucleophiles (organometallics or water), facilitating N-
functionalization in a single pot. The transformation is rapid,
scalable and benefits from recyclable TPTA-PF6. We foresee
applications of this direct N-functionalization methodology in
medicinal chemistry; in the late-stage functionalization of mole-
cules or the investigation of structure-activity relationships.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: ..
Experimental procedures including the synthesis of substrates,
key NMR spectra, characterization data of novel compounds,
cyclic voltammetry, EPR studies and computational coordinates
(PDF)
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Xie, J.; Shi, S.; Zhang, T.; Mehrkens, N.; Rudolph, M.;
Hashmi, A. S. K. Angew. Chem. Int. Ed. 2015, 54, 6046–
6050.
AUTHOR INFORMATION
Corresponding Author
Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S.
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