Visible-light-promoted redox neutral C-H amidation of heteroarenes with hydroxylamine derivatives

Article abstract of DOI:10.1021/ol501457s

A room temperature redox neutral direct C-H amidation of heteroarenes has been achieved. Hydroxylamine derivatives, which are easily accessed, have been employed as tunable nitrogen sources. These reactions were enabled by a visible-light-promoted single-electron transfer pathway without a directing group. A variety of heteroarenes, such as indoles, pyrroles, and furans, could go through this amidation with high yields (up to 98%). These reactions are highly regioselective, and all the products were isolated as a single regioisomer.

Full text of DOI:10.1021/ol501457s

Letter
pubs.acs.org/OrgLett
Visible-Light-Promoted Redox Neutral C−H Amidation of
Heteroarenes with Hydroxylamine Derivatives
Qixue Qin and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
S
* Supporting Information
ABSTRACT: A room temperature redox neutral direct C−H
amidation of heteroarenes has been achieved. Hydroxylamine
derivatives, which are easily accessed, have been employed as
tunable nitrogen sources. These reactions were enabled by a
visible-light-promoted single-electron transfer pathway without
a directing group. A variety of heteroarenes, such as indoles,
pyrroles, and furans, could go through this amidation with high
yields (up to 98%). These reactions are highly regioselective,
and all the products were isolated as a single regioisomer.
ryl and heteroarylamines, which widely exist in natural
products, pharmaceuticals, and functional materials, have
attracted increasing attention from synthetic and medicinal
chemists.1 As essential structural fragments, they often exhibit
biological activities. Therefore, synthesis of (hetero)arylamines
is always one of the most important tasks of the synthetic
community.2−6
Scheme 1. Major Strategies for C−N Coupling
A
A conventional method to incorporate an amino group into
organic molecules is aromatic nitration followed by reduction.2
Recently copper-mediated Ullmann-type3 and palladium-
catalyzed Buchwald−Hartwig amination/amidation4 have
emerged as more powerful tools for C−N bond formation
(Scheme 1A). However, prefunctionalized arenes and normally
high temperature are necessary. More recently, oxidative direct
C−H amination of arenes with amines has been achieved
(Scheme 1B).5,6 This atom economical approach usually
requires directing groups and stoichiometric oxidants, which
restrains its applications. This has led us to explore more
efficient C−H amination/amidation under mild conditions.
Nitrogen-centered radicals have been involved in a wide
variety of useful organic transformations, which has received
increasing attention from the synthetic community.7 In 2013,
MacMillan and co-workers reported that a nitrogen-centered
radical generated from a hydroxylamine derivative assisted by
visible light could add to the C−C double bond of an enamine.8
Inspired by this work, as well as our recent research on visible-
light-promoted C−H functionalization of enamides,9 we
envisaged that reductive cleavage of a hydroxylamine derivative
could give a nitrogen-centered radical. The nitrogen-centered
radical could add to a (hetero)arene to generate a C−N bond
and a carbon-centered radical. The resultant carbon-centered
radical could be oxidized to a carbocation followed by
deprotonation to regenerate the aromatic ring (Scheme 1C).
Based on this scenario, we would like to report our efforts in
the photoredox neutral direct C−H amidation of heteroarenes
using hydroxylamine derivatives as nitrogen sources.10
Our efforts toward this hypothesis focused on the use of N-
methylindole (1a) and N, O-ditosyl-N-methylhydroxylamine
(2a) as model substrates. The photocatalyst fac-Ir(ppy)3 (I)
was chosen as the photocatalyst because of its superior
reduction capacity in the excited state.11 When a solution of
1a and 2a in DMSO was irradiated by a white LED strip in the
presence of photocatalyst I and Na2HPO4 for 24 h, the desired
amido indole 3a was isolated in 58% yield as one regioisomer
(Table 1, entry 1). After NMR comparison,12 the structure of
3a was established ambiguously as a 2-amido indole derivative.
Received: May 20, 2014
Published: June 25, 2014
© 2014 American Chemical Society
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Letter
a
a
,b
Table 1. Reaction Condition Optimization
Scheme 2. Optimization of Nitrogen Radical Precursors
b
entry
PC
base
solvent
yield (%)
1
I
I
I
I
I
I
I
I
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
NaHCO3
K3PO4
DMSO
DMA
CH3CN
CH2Cl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
58
a
2
56
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.2 mmol, 2.0
equiv), NaHCO3 (0.12 mmol, 1.2 equiv), and fac-Ir(ppy)3 (0.002
mmol, 2.0 mol %) in dry DMF (1.5 mL) were irradiated by a white
3
32
4
46
b
LED strip. The yields were isolated yields.
5
61
6
66
a
,b
Scheme 3. Substrate Scope
7
59
8
K2HPO4
K2CO3
62
9
54
10
11
12
13
II
NaHCO3
NaHCO3
none
13
III
19
I
56%
no rxn
no rxn
none
NaHCO3
NaHCO3
c
14
I
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.2 mmol, 2.0
equiv), NaHCO3 (0.12 mmol, 1.2 equiv), and photocatalyst (0.002
mmol, 2.0 mol %) in dry solvent (1.5 mL) were irradiated by a white
b
c
LED strip. Isolated yield. No irradiation. PC = photocatalyst.
Other solvents, such as DMA, CH3CN, and CH2Cl2, could not
give improved results (entries 2−4). To our delight, a 61%
yield was achieved when DMF was used as solvent (entry 5). A
variety of bases were then examined (entries 6−9); NaHCO3
turned out to be a better base with a 66% yield (entry 6).
Several other photocatalysts, such as Ir(ppy)2(dtbbpy)PF6 (II)
and Ru(bpy)3(PF6)2 (III), were not superior to fac-Ir(ppy)3 (I)
(entries 10−11). Control experiments verified the necessity of
the base, irradiation, and photocatalyst (entries 12−14).
In order to improve this reaction further, different nitrogen-
centered radical precursors were then investigated, as shown in
Scheme 2. First, activated groups on the hydroxyl group proved
to be very important. An electron-neutral benzenesulfonyl
group (2b) gave a slightly better result (69% yield). Both
electron-rich and -deficient aromatic sulfonyl groups (2c and
2d) gave worse yields. An aliphatic sulfonyl group (2e) was not
as efficient as a tosyl group. The protecting groups of amine
were then examined. When benzenesulfonyl (2f) was used
instead of the tosyl group, the yield could be improved to 71%.
Neither electron-rich (2g) nor -deficient sulfonyl (2h) groups
could give better results. Other types of radical precursors, such
as N-chloride (2i), a N-hydroxyl succinimide derivative (2j),
and a N-Boc hydroxylamine derivative (2k), did not work at all.
We next sought to establish the scope of the heteroarenes
coupling partners in this transformation. A variety of indoles
were tested with the hydroxylamine derivative 2f, as shown in
Scheme 3. It was found that indoles bearing various
substituents at the C4−C7 positions (indole numbering) gave
the amido indole derivatives 4a−i with satisfactory to excellent
a
Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2f (0.2 mmol, 2.0
equiv), NaHCO3 (0.12 mmol, 1.2 equiv), and fac-Ir(ppy)3 (0.002
mmol, 2.0 mol %) in dry DMF (1.5 mL) were irradiated by a white
b
c
LED strip. The yields were isolated yields. Na2HPO4 (1.2 equiv)
was used as a base in DMSO (1.5 mL). 4 equiv of 2f were used.
c
yields (47−94%). Electron-donating groups, such as 4-OBn
(94% yield), worked better than electron-withdrawing groups,
such as 5-Br (47% yield). Substitutions at the C3 position had a
positive influence on this transformation. 3-Methyl and 3-
phenyl indole derivatives could go through this reaction
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perfectly to give amido indoles 4j and 4k with excellent yields
(96% and 98% respectively). More biologically important
indole derivatives, such as indole propanoic acid, tryptamine,
and melatonin derivatives, could also be amidated fluently
under standard conditions to give corresponding amido indoles
4l−n with 96−97% yields. The protecting groups at the N1
position were next explored. Indoles with more easily
removable groups, such as Bn and PMB, worked quite well
to give the desired products 4o and 4p in nearly quantitative
yields. N-Phenyl and Boc indoles could also undergo this
transformation with slightly lower yields (87% for 4q and 57%
for 4r). Pyrrole and furan derivatives could also be amidated
with the hydroxylamine derivative 2f to give the corresponding
amido pyrroles 4s−t and furans 4v−w with good to excellent
yields (47−94%). It is noteworthy that all the desired products
were isolated in a single regioisomer exclusively without other
regioisomers. However, attempts to amidation of benzene,
pyridine, and thiophene derivatives under standard conditions
failed (for the substrates we tried, see Supporting Information).
Several control experiments were then conducted to gain
some insights into the reaction mechanism (Scheme 4). The
Figure 1. Proposed mechanism.
light-promoted radical pathway enabled that these amidations
could be carried out at room temperature. A series of
heteroarenes, including indoles, pyrroles, furans, and benzofur-
ans, could undergo this amidation with high yields (up to 98%).
These reactions are highly regioselective, and all the products
were isolated as a single regioisomer.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Control Experiments
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yushouyun@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the 863 program (2013AA092903), the
National Natural Science Foundation of China (21272113),
and the Natural Science Foundation of Jiangsu Province
(BK20131266).
reaction could be terminated completely if TEMPO was
introduced to the reaction mixture, which suggested a one-
electron transfer pathway. 1,2-Dimethylindole (1x) could not
go through this reaction which implies that nitrogen-centered
radical attacks the C2 position of indoles. Compared to 3-alkyl
or aryl substituted indoles, which can undergo this trans-
formation perfectly, electron-deficient 3-acetyl indole (1y)
could not work at all. This phenomenon could be explained by
the formation of a carbon cation intermediate at the C3
position.
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