Radical C?H-Amination of Heteroarenes using Dual Initiation by Visible Light and Iodine

Article abstract of DOI:10.1002/adsc.201800677

A novel light-induced C?H amination of heteroarenes can be accomplished with preformed iodine(III) reagents as the combined oxidant and nitrogen source. The reaction requires the use of a small amount of molecular iodine, which under photochemical activation generates in situ an iodine(I) reagent as the initiator of the radical amination reaction. A total of 32 examples exemplify the broad scope of the transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.201800677

Title: Radical C-H-Amination of Heteroarenes using Dual Initiation by
Visible Light and Iodine
Authors: Nicola Lucchetti, Anastasia Tkacheva, Serena Fantasia, and
Kilian Muniz
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800677
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Radical C-H-Amination of Heteroarenes using Dual Initiation
by Visible Light and Iodine
a
a
Nicola Lucchetti, Anastasia Tkacheva, Serena Fantasia,b and Kilian Muñiza,c*
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, 16 Avgda.
Països Catalans, 43007 Tarragona, Spain. Email: kmuniz@iciq.es
F. Hoffmann-La Roche Ltd. Process Research & Development, Grenzacherstrasse 124,ꢀ 4070 Basel, Switzerland.
ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
nitrogen-centered radicals have been involved in
heteroarenes can be accomplished with preformed many useful organic transformations.[8] When
Abstract. A novel light-induced C─H amination of
iodine(III) reagents as the combined oxidant and nitrogen
source. The reaction requires the use of a small amount of
molecular iodine, which under photochemical activation
generates in situ an iodine(I) reagent as the initiator of the
radical amination reaction. A total of 32 examples
exemplify the broad scope of the transformation.
compared to carbon-centered radicals, the synthetic
utility of N-centered radical species, including neutral
N-radicals and N-radical ions, remains conceptually
underdeveloped.[8] Visible-light photocatalysis has
proven to be a mild tool for the conversion of N-
containing compounds into their corresponding
highly reactive N-radical species,[9] and photoredox
catalysis has provided an entry to nitrogen radicals by
the cleavage of weak N-heteroatom bonds.[10,11] As an
alternative, the direct oxidation of activated N−H
bonds can involve stoichiometric reagents.[12] We
here report on a novel dual light and iodine induced
amidoyl radical formation and its application to the
position-selective C−H amination of heteroarenes.
Keywords: Amination; Amidoyl Radicals; C─H
Functionalization; Iodine; Photochemistry
Aminated heteroarenes constitute an important class
of compounds in biological and medicinal chemistry.
An appealing general synthetic strategy to the class of
aminated heteroarenes consists in the direct C−H
amination of the free arene precursor.[1] Despite
significant progress, predictable regioselectivity still
constitutes
a
major
challenge
in
C−H
functionalization. With respect to indoles as
privileged scaffolds of prominent biological and
medicinal importance, selective C2−H amination of
this particular substrate has been a domain of
transition metal catalysis.[2] In previous exploration of
benign metal-free methodology, we could
demonstrate that isolated hypervalent iodine reagents
ArI[N(SO2R)2]2 allow for selective C3-amination of
2,3-unsubstituted indoles,[3,4] while the corresponding
C2-position is not accessed (Figure 1). Pursuing a
change in regioselectivity to encounter the
corresponding C−H amination, (radical) catalysis was
envisaged. Pioneering work by Maruoka and Studer
has explored iodine(III) reagents as precursors for
heteroatom-centered radicals.[5,6] Notably, except the
special case of azido[6a] and sulfoximine[6c]
derivatives there is only a single previous literature
example on nitrogen-containing iodine(III) reagents
affording amination reactions under photochemical
conditions, which refers to elegant work on N-
Figure 1. Indole C3 vs. C2 amination with iodine(III)
reagents.
N-Boc-indole 1a was selected as the substrate and
saccharin as the nitrogen source. Saccharin
constitutes an interesting pharmaceutical entity in its
own right due to its capability for DNA
intercalation.[13] Stable iodine(III) reagents have been
formed from this heterocycle in the past,[14] and three
reagents were considered at the outset. The
bis(saccharinato)iodane (2a) could readily be
prepared from (diacetoxyiodo)benzene and saccharin
on a 31 mmol scale in 88% yield. The bench stable
compound 2a can be stored without decomposition
for months and is characterized here for the first time
acylimidoiodinanes
by
Takemoto.[6d]
The
photochemical functionalization of inert C(sp2)−H
bonds has recently been explored.[7] Highly reactive
1
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
in its solid state displaying the characteristic T-
shaped structure.[15,16] The results obtained for the
amidation of N-Boc indole (1a) proved to follow a
concise trend. In dichloromethane as solvent,
catalytic amounts of molecular iodine initiate the
selective C2-amination of 1a to product 3a in the
presence of iodine(III) reagent 2a as the combined
terminal oxidant and nitrogen source. High amounts
of iodine are detrimental for the photochemical
activation and 8 mol% was encountered as optimum
(entries 1-4). Without iodine, no reaction takes place
(entry 5), and alternative iodine sources such as
NBu4I, potassium and sodium iodide give inferior
results.[15] Alternative solvents provided lower yields
(entries 6-8). Under black LEDs irradiation (entry 9),
the same isolated yield as with visible-light (upon
exposure to ambient light) was observed. In the latter
case 3a was already formed in 54% yield after 1 h
(entry 10). Also for black LEDs irradiation, the
iodine catalyst is required (entry 11). The known
cyclic iodine(III) reagent 2b and its counterpart 2c
show comparably lower reactivity (entries 12,13) and
were not considered further.
iodine(III) reagent 2a was used, N-protected indoles
were amidated in moderate to very good yields
(products 3a-g). Electron-donating protecting groups
such as methyl (3b, 64%), para-methoxy benzyl (3d,
62%) and benzyl (3f, 73% yield) were superior
compared to electron-withdrawing ones. Finally, the
aniline 3b could be readily synthesized on 7.6 mmol
scale (1.5 g), and the C2-amination outcome was
additionally confirmed by X-ray analysis.[16]
Substituents on the 5-position of the aromatic ring of
the indoles were well tolerated as demonstrated for
products 3h-l (28-67%). The same holds true for the
4-bromo derivative 3m, which would suffer from
selectivity in classical transition-metal-catalyzed
Hartwig-Buchwald approaches, and for the product
3n with a functionalized N-alkyl substituent.
Introducing a methyl group in the 3-position of the
indole does not interfere with C2-amination (product
3o, 65%).
Table 1. Metal-free C−N bond formation from 2a: reaction
optimization for N-Boc indole 1a.
Entry Reagent I2 [mol%] Time Light
[h]
Yield
[%]a)
1
2
3
4
5
6
20.0
15.0
8.0
3.0
-
8.0
8.0
8.0
8.0
8.0
-
19
19
19
19
19
19
19
19
19
1
Vis
Vis
Vis
Vis
Vis
Vis
Vis
Vis
38
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
49
63b)
24
NRc)
12
Scheme 1. Photochemical amination of indoles: reaction
scope. a)Visible-light. b)Reaction on 7.6 mmol scale. c)3.0
equiv. of starting indole derivative.
7d)
8e)
9
22
18
Black LED 58b)
10
11
12
13
Vis
black LED
Vis
54
8
16
27
Compounds with known biological activity such as
the herbacide gramine and tryptamine were cleanly
aminated to afford 3p and 3q in 66 and 76% yield.
Halide and ester functional groups were readily
compatible, as demonstrated by compounds 3r-t. The
formation of a single derivative 3u proved that in the
presence of a phenyl substituent, the protocol
remained fully selective for the indole core.
Interestingly, for the case of 2-methylindole 3v a
19
19
19
8.0
8.0
Vis
a)GC yields using decane as internal standard.
b)Isolated yields after purification. c)NR = no reaction.
d)HFIP as solvent. e)TFE as solvent.
With the optimized conditions in hand, we evaluated
the scope for several indoles (Scheme 1). When the
2
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
mixture of C−N and C−O products with 1/0.8 ratio
was observed. This demonstrates the ambident
character[14c] of the saccharin in the present C−H
functionalization and may expand the current
amination to complimentary oxygenation in future
endeavors. As extension of the approach, we took
into account the possibility to expand the scope of the
reaction to more diversified heterocycles (Scheme 2).
Under the developed conditions, benzimidazole
provided the corresponding aminated compound 5a
in 43% yield. Interestingly, caffeine, the well-known
xanthine alkaloid for stimulation of the central
nervous system, furnished 5b in 56% yield. This
represented a notable enhancement compared to
previously reported amination protocols on the same
class of substrates.[11a]
provided the final compounds 5f-h in excellent
yields, while 2,4-dimethyl pyrrole undergoes
aliphatic C−H amination to 5i. Also, furan 4j as a
challenging substrate furnished 5j as a mixture of
regioisomers in 26% yield. As demonstrated for
caffeine derivative 5b, quantitative deprotection of
the saccharine group to the free amino derivative 6[17]
is accomplished under acidic hydrolysis (Scheme 3).
With the bis(saccharinato) iodine(III) reagent 2a
representing the combined oxidant and nitrogen
source, control experiments were conducted to clarify
why the presence of the molecular iodine was
necessary at the stage of photoinitiation. In absence
of molecular iodine, the amination of 1a was
completely suppressed under visible light, while a
mere 8% product from the background reaction of the
reagent 2a was detected under black LED irradiation
(Table 1, entries 5,11). This fostered the assumption
that the reaction proceeds through radical amination
pathways, which is further aided by the exclusive
C−N formation at C2, overriding conventional
electrophilic amination. A radical close to the lone
pair on the indole nitrogen is more stabilized due to
the orbital overlap. Additional control experiments[15]
with 1a strengthen the assumption of radical
pathways.[18]
a)
Scheme 2. Saccharine deprotection for compound 5b.
b)
CHCl3 as solvent for better solubilization. 3.0 equiv. of
starting heterocyclic compound.
Scheme 3. Deprotection to free amino caffeine 6.
The structurally related drug pentoxifylline for muscle
pain release was equally aminated cleanly to 5c. The
substrate scope also includes azaindoles 5d,e. Pyrrole
derivatives such as the tetrahydroindole 4f, the ethyl
substituted pyrrole 4g and even free pyrrole 4h
Scheme 4. Control experiments and mechanistic proposal.
NISacc = N-iodo saccharin.
3
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
References
Subsequently, we proceeded with the synthesis of
possible intermediary iodine states to gain
understanding on the initiator species. Treatment of
2a with an equimolar amount of tetrabutylammonium
iodide in dichloromethane formed the ionic
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counter ion (Scheme 4).[19] Compound 7 represents a
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
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[15] Details are provided in the Supporting Information.
[16] Details on the X-ray crystallographic data for
compounds 2a, 2c, 3b, 5b and 6 have been deposited
5
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10.1002/adsc.201800677
Advanced Synthesis & Catalysis
COMMUNICATION
Radical C-H-Amination of Heteroarenes using
Dual Initiation by Visible Light and Iodine
Adv. Synth. Catal. Year, Volume, Page – Page
Nicola Lucchetti, Anastasia Tkacheva, Serena
Fantasia, and Kilian Muñiz*
6
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