Metal- and Reagent-Free Intramolecular Oxidative Amination of Tri- and Tetrasubstituted Alkenes

Article abstract of DOI:10.1021/jacs.7b01016

A metal- and reagent-free, electrochemical intramolecular oxidative amination reaction of tri- and tetrasubstituted alkenes has been developed. The electrosynthetic method proceeds through radical cyclization to form the key C-N bond, allowing a variety of hindered tri- and tetrasubstituted olefins to participate in the amination reaction. The result is the efficient synthesis of a host of alkene-bearing cyclic carbamates and ureas and lactams.

Full text of DOI:10.1021/jacs.7b01016

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Communication
Metal- and Reagent-Free Intramolecular Oxidative
Amination of Tri- and Tetrasubstituted Alkenes
Peng Xiong, He-Huan Xu, and Hai-Chao Xu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01016 • Publication Date (Web): 15 Feb 2017
Downloaded from http://pubs.acs.org on February 15, 2017
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Metal- and Reagent-Free Intramolecular Oxidative Amination
of Tri- and Tetrasubstituted Alkenes
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Peng Xiong,† He-Huan Xu,† Hai-Chao Xu†*
†iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian
Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
Supporting Information Placeholder
tive/undesired proton elimination.12 Herein, we report the success-
ful development of an intramolecular oxidative amination of the
ABSTRACT: A metal- and reagent-free, electrochemical intra-
molecular oxidative amination reaction of tri- and tetrasubstituted
challenging tri- and tetrasubstituted alkenes through electrochem-
alkenes has been developed. The electrosynthetic method pro-
ical oxidation (Scheme 1b).13 Advantageously, this process pro-
ceeds through radical cyclization to form the key C–N bond, al-
lowing a variety of hindered tri- and tetrasubstituted olefins to
ceeds in a metal-14 and reagent-free15 fashion to provide function-
alized cyclic carbamates and ureas and lactams.
participate in the amination reaction. The result is the efficient
synthesis of a host of alkene-bearing cyclic carbamates and ureas
and lactams.
Scheme 1. Intramolecular Oxidative Amination of Alkenes
Allylic amines are important synthetic building blocks that can
be converted into a diverse range of products through the manipu-
lation of the amino as well as alkenyl moieties.1 Recently, there
has been considerable interest in preparing these compounds
through the cross-coupling between a N–H bond and an allylic C–
H bond, which allows for an efficient route from easily available
starting materials.2 Particularly, the aza-Wacker type cyclizations,
which is often catalyzed by a palladium species, allows the easy
access to alkene-containing N-heterocycles (Scheme 1a).3 A num-
ber of excellent recent studies have reported successful aza-
Wacker cyclizations under mild conditions and with molecular
oxygen as the terminal oxidant.4 Despite this progress, reported
methods are generally not efficient with multisubstituted alkenes
and oxidative amination of tri- and tetrasubstituted olefins re-
mains challenging.
We first identified the optimal reaction conditions for the cy-
clization of carbamate 1 bearing a trisubstituted olefin, which
involved constant-current electrolysis using a reticulated vitreous
carbon (RVC) anode and a Pt plate cathode, in an undivided cell
containing a mixed electrolyte solution of Et4NPF6 in dimethyla-
cetamide (DMA) and acetic acid (40:1). Under these conditions,
the desired cyclic carbamate 2 was isolated in 82% yield (Table 1,
entry 1). Particularly noteworthy is the fact that the regeneration
of the C–C double bond occurred regioselectively at the terminus,
instead of favoring the formation of the more thermodynamically
stable enamine derivative (a tetrasubstituted alkene). Despite that
the redox potentials (Ep/2 vs SCE in MeCN) of 1 (1.23 V) and 2
(1.39 V) were close to each other, over-oxidation was not ob-
served. Conducting the electrolysis without AcOH (entry 2),16 or
in other solvents such as DMF (entry 3) or MeCN (entry 4), dra-
matically decreased product formation. In comparison, slightly
reduced but still acceptable yields were obtained when the reac-
tion conditions were modified in one of the following manners:
lowering the concentration of Et4NPF6, changing the electrolyte to
nBu4NBF4 or Et4NOTs(entry 5), switching to a platinum plate
anode (entry 6) with a surface
Nitrogen-centered radical (NCR) intermediates have attracted
considerable interest from organic chemists due to their ability to
cyclize with alkenes of diverse steric properties, leading to the
formation of new C–N bonds.5 The synthetic utility of these reac-
tive species has been further boosted by the emergence of various
new methodologies, particularly those involving single electron
transfers, that greatly facilitated their preparation.5b,c We have
been involved in developing sustainable C–N bond-forming reac-
tions by employing electrochemically generated NCRs.6,7 Based
on these results, we envisioned an electrochemical amination
reaction (Scheme 1b).8 The anodic activation of the amidyl N–H
bond in an alkene-tethered amide could lead to the generation of a
NCR intermediate I,9 which could then readily undergo intramo-
lecular cyclization with the alkenyl moiety to give the carbon-
centered radical II. Oxidation of this latter C-radical followed by
the loss of a proton would afford the cyclic allylamine product.
The challenge of this approach lies in its requirement for the effi-
cient and regioselective installation of an alkenyl moiety in the
absence of a metal-based catalyst. The C-radical II is prone to
reduction through H-abstraction,7a,10 whereas its derived cation III
can be trapped by a nucleophile,8a,b,11 or participate in nonselec-
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Table 1. Optimization of Reaction Conditionsa
amination at 5 mA (entry 8) or at RT (entry 9) greatly diminished
the yield.
We next explored the substrate scope of the electrolytic amina-
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tion reaction using a host of carbamates carrying various trisubsti-
tuted alkenyl moieties (Scheme 2, 3–18). The reaction was
demonstrated to be compatible with a diverse range of (het-
ero)aryl- (3–12), alkynyl- (13) and alkyl- (14–18) substituted
olefins. The cyclic carbamate products were produced with good
to high diastereoselectivity and proton elimination proceeded
regioselectively at the distal carbon relative to the newly formed
N-heterocycle, leading to an allylamine moiety regardless of the
substitution pattern of the starting alkene. Both terminal and in-
ternal olefins, including a tetrasubstituted one (7), could be
achieved.
Entry Conditions
Yield%b
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Further studies revealed that unsaturated amides (19–25) and
ureas (26–27) were also viable substrates (Scheme 2). Carbamates
bearing less electron-rich N-aryl rings, such as p-Me-Ph (28) and
p-Br-Ph (29), also underwent smooth cyclization with satisfactory
yields, albeit in reduced current efficiency. However, no reaction
occurred when the substrate contained the highly electron-
withdrawing p-CN-Ph group (30). The increased oxidation poten-
tials17 of these substrates tipped the reaction toward solvent de-
composition. Furthermore, a variety of functional groups were
found to be well-tolerated, including ester (5, 24–25), imide (6),
arylbromide (8), thiazole (10), pyridine (11), thiophene (27), al-
aReaction conditions: RVC anode (100 PPI, 1 cm x 1 cm x 1
cm), Pt cathode (1 cm x 1 cm), 1 (0.3 mmol), solvent (4 mL),
argon, 2.4 h (3 F). bYield of the major diastereomer determined by
1H-NMR analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene as the internal standard. cIsolated yield. dReac-
tion time = 1.2 h. eReaction time = 4.8 h. PMP = p-
methoxyphenyl.
kyne
(13),
alcohol
(22)
and
silyl
ether
(23).
area much lower than that of the RVC anode, or adjusting the
current to 20 mA (entry 7). However, performing the electrolytic
Scheme 2. Substrate Scopea
b
c
1
aReaction conditions from Table 1, entry 1 were used unless otherwise noted. Isolated yield. Determined by H NMR analysis of the
crude reaction mixture. dReaction at 130 °C. eE/Z
=
5:1. TBDPS
=
tert-butyldiphenylsilyl. NR
=
no reaction.
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One major advantage of the electrochemical method lies in its
and vicinal diol 46, respectively.20 Compound 46 could be con-
verted to ketoaldehyde 47 through the oxidative cleavage of its
diol moiety, and further to ketoaldehyde 48 by aldol condensa-
tion.21
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efficient amination of sterically demanding tetrasubstituted al-
kenes.18 As summarized in Scheme 2, both acyclic (31–32) and
cyclic (33–37) olefins, including two that contained a steroid-
based core structure (36–37), were shown to readily react to af-
ford desired products with aza-quarternary stereocenters.
In summary, we have successfully developed an efficient in-
tramolecular oxidative amination reaction of challenging tri- and
tetrasubstituted alkenes. Our electrosynthetic method is broadly
compatible with a wide range of carbamate, amide, and urea sub-
strates, can be easily scaled up, and provide access to various
functionalized N-heterocycles with great synthetic values.
The facile preparation of enantioenriched cyclic carbamates
from easily available enantioenriched allylic alcohols19 lent fur-
ther support to the synthetic utility of the intramolecular amina-
tion reaction in the current study (Scheme 3). As examples, sub-
jecting (+)-38 and (−)-40 to the standard electrolysis conditions
resulted in the stereoselective formation of (−)-39 and (−)-3, re-
spectively, without any observable loss of the enantiomeric ratio.
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ASSOCIATED CONTENT
Supporting Information
Scheme 3. Cyclization of Enantioenriched Carbamates
Full experimental details and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*haichao.xu@xmu.edu.cn
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Notes
The authors declare no competing financial interests.
Scheme 4. Gram-Scale Synthesis and Product Transfor-
mations
ACKNOWLEDGMENT
Financial support of this research from MOST (No.
2016YFA0204100), NSFC (No.s, 21672178, 21402164), and the
“Thousand Youth Talents Plan”.
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment