Regiodivergent Visible Light-Induced C–H Functionalization of Quinolines at C-5 and C-8 under Metal-, Photosensitizer- and Oxidant-Free Conditions

Article abstract of DOI:10.1002/adsc.201700471

A general strategy towards the selective perfluoroalkylation of quinoline derivatives at C-5 and C-8 is described. This exceptionally mild radical transformation, compatible with a large panel of substrates, does not require any transition metal catalysts or oxidants. Outstandingly, visible light photoinduction using simple household bulbs, in the absence of a photosensitizer, is the unique activation mode. Further importance of this reaction relies on its capacity to functionalize selectively both C-5 and C-8 positions of quinolines. This transformation, perfectly fulfilling green chemistry requirements, allows a truly practical and straightforward access to a variety of unprecedented functionalized amino- and amidoquinoline skeletons, presenting attractive features for medicinal and agrochemical industry. (Figure presented.).

Full text of DOI:10.1002/adsc.201700471

Title: Regiodivergent C5 & C8- visible light induced C-H
functionalisation of quinolines under metal-, photosensitizer- and
oxidant-free conditions
Authors: Percia Arockiam, Lucas Guillemard, and joanna Wencel-
delord
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700471
Link to VoR: http://dx.doi.org/10.1002/adsc.201700471

10.1002/adsc.201700471
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regiodivergent C5 & C8- visible light induced C-H
functionalisation of quinolines under metal-, photosensitizer-
and oxidant-free conditions
Percia Beatrice Arockiama, Lucas Guillemarda and Joanna Wencel-Delorda*
a
Laboratoire de Chimie Moléculaire (UMR CNRS 7509), Université de Strasbourg, ECPM, 25 rue Becquerel, 67087,
Strasbourg, France; Tel.: + 33 3 68 85 26 43; E-mail: wenceldelord@unistra.fr
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))
recently received a great deal of attention. In
particular, over the last two years, many research
groups focused on selective C5 functionalisation of 8-
Abstract. A general strategy towards C5 and C8 selective
perfluoroalkylation of quinoline derivatives is described.
This exceptionally mild radical transformation, compatible
with a large panel of substrates, does not require any amidoquinolines (Figure 1B). Commonly, transition
transition metal catalysts or oxidants. Outstandingly, visible
metals such as copper,[7] nickel[8] or iron[9] have been
employed to perform various C-X couplings,[10] under
light photoinduction using simple household bulbs, in
absence of a photosensitizer, is a unique activation mode.
Further importance of this reaction relays on its capacity to
functionalise selectively both C5 and C8-quinoline
positions. This transformation, perfectly fulfilling green-
chemistry requirements, allows truly practical and
straightforward access to a variety of unprecedented
functionalised amino- and amidoquinolines skeletons,
presenting attractive features for medicinal and
agrochemical industry.
frequently harsh reaction conditions (high
temperature, use of strong oxidants). Very recently, a
few
additional
examples
of
metal-free
transformations have been disclosed and
a
comparable reactivity can be achieved in the presence
of strong oxidants like PIDA, PIFA or oxone,
hampering their synthetic utility and versatility.[11]
Indeed, the bicoordinating capacity of 8-
amidoquinoline renders this substrate perfectly suited
for remote C5-functionalisation but the same reaction
using synthetically more attractive unprotected 8-
aminoquinolines is much more challenging.
Furthermore, direct couplings at C8-position are
elusive. The rare selective transformations require
expensive Ir- or Rh-based catalysts (Figure 1C)[12]
and very sporadic radical couplings are low yielding
and unselective.[13]
Keywords: quinoline; C-H functionalisation; visible light;
perfluoroalkylation; photocatalysis
Quinoline, one of the most important N-heterocyclic
aromatic compounds, is present in numerous natural
products[1] and is largely exploited in both
pharmaceutical
and
agrochemical
industry.
Quinoline-based compounds exhibit indeed anti-
malarial, anti-bacterial, anti-fungal, anti-asthmatic,
anti-hypertensive, anti-inflammatory, anti-tumoral
and immune depressing properties.[2] Their
applications as food colorants, pH indicators, OLED
phosphorescent complexes and conjugate polymers,
further underline their unique features. Thus the
synthesis of complex quinoline-derived scaffolds by
means of a late-stage functionalisation of simple,
commercially available and inexpensive precursors is
particularly tempting.[3] Due to the intrinsic reactivity
of the heterocyclic moiety, a large panel of methods
allowing C2, C3 and C4-quinoline functionalisation
has been intensively studied (Figure 1A). Indeed,
amongst others, C2-functionalisaton is commonly
achieved via radical Minisci reaction,[4] while C3[5]
and C4[6] diversification may account from metal-
catalyzed transformations. In contrast, regioselective
modifications of the carbocyclic ring have only
1
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
when employing other acetate source (entry 3).
Despite its effectiveness, the use of a stoichiometric
amount of silver salt obviously hampers the synthetic
value of the reaction. Targeting, hence, a more eco-
compatible transformation, we assumed that
generation of the quinoline radicals should also be
feasible via a photocatalytic process while using only
a trace amount of a photosensitizer. Accordingly, the
potency of an Ir-based photocatalyst (PC1:
[Ir{dF(CF3)ppy}2(dtbbpy]PF6) and an organic
photocatalyst (PC2: Fukuzumi reagent: 9-mesityl-10-
methylacridiniumperchlorate) to fulfil this role was
investigated. A moderately efficient synthesis of 3Aa
was achieved when using PC1 together with K2HPO4
in MeOH or acetone but the desired product was
isolated in 91% yields in mixed solvents (entries 4-6).
The less expensive and more reliable organic
photosensitizer (PC2) also performed quite well in
combination with K2CO3 base and MeOH/acetone
medium (entry 7). Unexpectedly, the reaction
conducted in the absence of photosensitizer delivered
3Aa in 82% yield (entry 8), but omission of the base
or light irradiation (reaction in dark) completely
suppressed the reactivity. Further improvement was
reached with acetone as solvent. Noteworthy,
unchanged outcome of the reaction in presence of
extra pure K2CO3 supports the truly metal-free nature
of this coupling (entry 9). Finally, the impact of the
light source was investigated.[21] Only trace amount
of the product was formed while using blue LED as a
light source (entry 10) and a significantly lower
efficiency of the coupling was observed while
irradiating the reaction mixture with a single
household bulb (entry 11). Furthermore, while using
single light household bulb equipped with a cutoff λ
> 455 nm filter, no reactivity was observed, whereas
using λ > 370 nm filter, 3Aa was delivered in 34%
yield (entries 12-13).[22] Finally, high conversion of
the starting material into the desired product could
also be achieved while using UV-A irradiation
although some degradation of the product was
detected (entry 14, for details see SI).
Figure 1. Selective C-H functionalisation of quinolines.
Following this analysis, we endeavored on
designing an alternative, general approach, based on
radical-type reactivity and suitable for both C5 and
C8-selective C-H functionalisation of quinolines,
under eco-compatible reaction conditions. The major
challenge to undertake while targeting such
transformation is therefore to overcome the intrinsic
reactivity of the quinoline scaffold, orientating radical
couplings at C2 position. Our working hypothesis
surmised that a radical functionalisation of quinolines
might be triggered towards carbocyclic ring by
introducing
a
relevant substituent. Regardless
position of the substituent, a similar type quinoline
radical intermediate would be accessed and a
subsequent oxidation would deliver the expected,
regiosiomeric products. Regarding, on one hand, the
・
relative stability of perfluoalkyl radicals (RF ) and
their convenient generation under visible-light
irradiation, and on the other hand, unique biological
properties of the fluorinated molecules, we have
therefore chosen a perfluoroalkylation as a test
reaction to develop the desired poly-regioselective
functionalisation of quinolines.
We report herein an original synthetic route
towards C5- and C8-perfluoroalkylated quinoline
derivatives, unique molecular scaffolds with
appealing features for pharmaceutical and
agrochemical industry (Figure 1D).[14] This method
implies exclusively visible-light photoactivation
using simple household bulbs (simple “home-made”
setup with commercially available two bulbs to insure
convenience of this work), in absence of not only
transition metals and oxidants but also
a
photosensitizer. Importantly, although several
different strategies are already known to prepare
fluorinated quinolines bearing the fluorine motifs at
C2, C3 or C4 positions,[15] only very few pathways
For reasons of convenience and targeting a truly
synthetically useful transformation, the following
work was pursued using the standard setup with two
26W household bulbs.
enabling installation of RF motifs at C5 position has
[11e],[16]-[19]
been described up to now.
Remarkably,
synthesis of C8-perfluoroalkylated quinolines has
been an uncharted field till this work. Finally, the use
of polyfluoroalkane iodides further highlights the
synthetic value of this reaction as such coupling
partners bring not only the versatility (access to an
array of scaffolds) but are also largely available and
inexpensive fluorinated building blocks considered as
raw materials.[20]
Table 1. Optimisation of C5-functionalisation of 1A.a)
C4F9
base (x equiv)
PC (2 mol%)
N
N
C4F9-I
+
solvent
HN
R
HN
R
Our experimental work debuted by performing a
light, r.t., 20 h
coupling
between
N-(quinolin-8-
O
O
yl)cyclopentanecarboxamide (1A) and nonafluoro-4-
iodobutane (2a), in the presence of Ag2CO3 used as
mild oxidant and iodine scavenger in DMAc and
under irradiation with two household bulbs (Table 1,
entry 1). The desired product was obtained albeit in
low, 18% yield. Replacing Ag2CO3 by AgOAc and
performing the reaction in DCM resulted in full
conversion of 1A with 85% yield of 3Aa (entry 2),
but significantly lower productivity was observed
2a
1A (R = cyclopentane)
1B (R = Ph)
3Aa / 3Ba
Base (x
equiv)
Yield
Entry
1
Solvent
PC
(%)[b]
1
2
3
4
1A
Ag2CO3 (1)
1A AgOAc (1.5)
DMAc
DCM
DCM
-
-
-
18
85
24
66
1A
1A
KOAc (1)
K2HPO4 (2)
MeOH
PC1
2
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
5
6
1A
1A
K2HPO4 (2)
K2HPO4 (2)
Acetone PC1
79
91
regioisomers (C5 and C7). To further delimitate the
scope of this methodology and regarding a limited
number of C5-selective functionalisations of
quinolines bearing diverse directing motifs, we
pursued by examining the impact of the nature of the
C8-substituents on the reaction. Remarkably, 8-
aminoquinoline (1G) and ester-derived 1I substrates,
Acetone/
MeOH
PC1
Acetone/
MeOH
7
8
9
1A
1A
1A
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
PC2
71
Acetone/
MeOH
-
82, 6c)
89, 0,d)
93e)
traces
22
0
34
generally
inefficient
in
C5-functionalisation,
Acetone
-
performed quite well under our basic protocol (71
and 45% yield respectively) whereas diminished
yields were obtained under conditions A. These
results demonstrate the outstanding potential and real
synthetic value of our photocatalytic and green
transformation. Secondary amine substrate 1H turned
out to be more challenging, as 3Ha was isolated in
only 29% yield along with diperfluoroalkylated
derivative (43% yield) under conditions B. No
selective functionalisation could be performed while
using 8-hydroxy and 8-bromoquinolines, as well as
unsubstituted quinoline and isoquinoline substrates.
10f)
11g)
12h)
13i)
14j)
1B
1B
1B
1B
1B
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
Acetone
Acetone
Acetone
Acetone
Acetone
-
-
-
-
-
50
[a) reaction Conditions: 1A (0.1 mmol), 2a (5 equiv), base
(x equiv), PC (2 mol%), solvent (0.2 M), r.t., Ar2, 2 × 26
W CFL for 20 h; GC yield with dodecane as internal
standard; absence of base; reaction performed in dark
b)
c)
d)
e)
f)
at 37 °C; reaction performed with extra pure K2CO3;
g)
reaction performed using 23W Blue Led strips; reaction
performed using 1 x 26W CFL; h) reaction performed using
1 x 26W CFL with filter λ > 455 nm; i) reaction performed
Table 2. Substrate scope for 8-quinoline derivatives 1(A-
I).a)
j)
using 1 x 26W CFL with filter λ > 370 nm; reaction
C4F9
Conditions A:
performed using UV-A pen (λ = 315-400 nm; λmax = 365
nm).
AgOAc (1.5 equiv)
DCM, r.t., 2 x CFL, 20 h
C4F9-I
+
N
N
Conditions B:
K2CO3 (2 equiv)
DG
DG
Acetone, r.t., 2 x CFL, 20 h
2a
3(A-I)a
1(A - I)
This optimisation study hence allowed us to
define two types of reaction conditions to perform the
desired coupling; conditions A implying use of the
silver salt (AgOAc, 1.5 equivalent) in DCM and eco-
C4F9
C4F9
C4F9
N
N
N
compatible basic conditions
B
(K2CO3,
2
HN
HN
tBu
HN
Ph
equivalents) in acetone. In both cases irradiation with
two household bulbs is required. Although the
O
O
O
3Aa: A: 83% yield
3Ba: A: 90% yield
3Ca: A: 82% yield
superiority of conditions
B
fulfilling “green
B: 63% yield
B: 81% yield
B: 67% yield
chemistry” principles over conditions A, the initial
study of the reaction scope was undertaken using
both protocols. As C5-functionalisation of quinolines
is mainly limited to C8-amido-substituted compounds
our aim was to establish a truly versatile system,
prompt to tolerate an array of different directing
group, both electron donating but also electron-
withdrawing. We estimated therefore that comparison
C4F9
C4F9
C4F9
C4F9
N
N
N
N
N
O
Ph
HN
nBu
HN
NH2
Boc
O
3Fa: A: 49% yieldb)
3Ga: A: 15% yieldc),d)
3Da: A: 60% yield
3Ea: A: 62% yield
B: 71% yield
B: 71% yield
B: 47% yieldb)
B: 71% yieldd)
of
both
reaction
conditions
(Ag-mediated
C4F9
C4F9
C4F9
transformation and metal-free protocol) is crucial to
delimitate their effectiveness for a panel of differently
substituted quinoline derivatives.
+
N
C4F9
N
N
Accordingly, the tolerance of the reaction
towards various DG was explored (Table 2). The
same regioselectivity was observed when using N-
NHMe
CO2Ph
NHMe
3Ha: A: 70/ 58:12:0c),d)
3I a: A: 19% yieldb)
B: 100/ 54:0:46e)
B: 45% yieldb)
(quinolin-8-yl)benzamide
(1B)
and
no
B: 29% yield
B: 43% yield
functionalisation of the phenyl ring was evidenced[23]
as confirmed by x-Ray analysis.[24] High yielding
reactions and excellent C5-selectivity were also
observed for tert-butyl (1C) and n-butyl (1D)-
substituted amides. Functionalisation of the N-Boc
protected 8-aminoquinoline (1E) occurred smoothly,
delivering 3Ea in 62% and 71% yield (under
conditions A and B respectively). The secondary
amide 1F proved to be more challenging and
regardless the conditions used 3Fa was obtained in
modest yield and as an inseparable mixture of
a) reaction conditions: Conditions A: 1(A-I) (0.25 mmol),
2a (5 equiv), AgOAc (1.5 equiv), DCM (0.2 M), r.t, Ar2, 2
× 26 W CFL for 20 h; Condition B: 1(A-I) (0.25 mmol),
2a (5 equiv), K2CO3 (2 equiv), Acetone (0.2 M), r.t, Ar2, 2
× 26 W CFL for 20 h; b) total yield of C and C for 40 h;
5
7
c) GC yield; d) 1.2 equiv of 2a; e) 5 equiv of 2a.
3
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
Subsequently,
the
tolerance
of
this
functionalised at C5 position with 65:6:1
(C5:C7:difunctionalisation) selectivity and the desired
product was isolated in 46% yield. Although a
slightly lower C5-selectivity was achieved for the
transformation towards various perfluoroiodoalkanes
2 was explored (Table 3). The length of the
polyfluorinated chain seems to have rather low
impact on the reactivity, regardless reaction
conditions used. Slightly lower yields were obtained
while using C3F7-I (2c), probably due to its volatility.
The more sterically demanding coupling partners
corresponding
2-methylquinolin-8-amine
1K
(64:21:10), almost full conversion of the starting
material was achieved in the presence of 1.2
equivalent of C4F9-I, hence delivering the
regioisomerically pure 3Ka in a comparable yield of
41%. Substitution of both 8-aminoquinoline and the
corresponding amide in the positions 3 or 4 by a
chlorine atom decreased the efficiency of the reaction.
3-chloro-8-amidoquinoline 1L was converted into
3La in 35% yield and its 4-chlorosubstituted
congener delivered 3Ma in 26% yield. A more
synthetically useful reaction was however observed
for the amine type substrate 1N affording 3Na in
moderate 47% yield. Presence of the methoxy
substituent at C6 position was quite well supported
for the amide substrate 1O (3Oa isolated in 65%
yield). Besides, perfluoroalkylation of C7-methyl
substituted quinolines worked better for the amino-
quinoline delivering 3Ra in high 85% yield.
such
as
2-iodoheptafluoropropane
2e
and
iodoperfluorocyclohexane 2f performed well under
conditions A (3Ae: 66% yield and 3Af: 55% yield)
but surprisingly, in the absence of AgOAc only trace
amounts of products were formed. Rewardingly, a
less activated ester-derived coupling partner 2g
underwent the reaction smoothly, delivering 3Ag in
68% and 75% yield. This result is particularly
attractive as the ester moiety is recognized as a
convenient handle for post-modifications, paving the
way towards several other fluorinated motifs.[25]
Notably, no desired coupling was achieved when
using an iodoalkane with no fluorine atom directly on
the carbon generating the radical species (2h).
Table 3. Substrate scope for polyfluoroalkane iodides 2(a-
h).
Table 4. Functionalised 8-amido and 8-amino quinolines
(1J-R)
Conditions A:
AgOAc (1.5 equiv)
DCM, r.t.,
RF
C4F9
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.
2 x CFL, 20 h
RF-I
N
+
R
R
C4F9-I
N
+
N
N
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.,
HN
R
2 x CFL
24 - 30 h
HN
R
NHR'
NHR'
3(J - R)a
C4F9
O
O
2a
1(J - R)
1A
2(a-h)
3A(a-h)
2 x CFL, 20 h
R = cyclopentane
C4F9
C4F9
C4F9
Cl
N
Cl
N
C4F9
Cl
C4F9
C5F11
C3F7
C8F17
N
N
N
NHCOPh
NHCOPh
NH2
NHCOPh
NH2
3Ja: 46% yield 3Ka: 41% yield
3La: 35% yield
3M a: 26% yield 3Na: 47% yield
N
N
N
N
(28:65:6:1)a)
(5:64:21:10)a)
(37:55:8:0)a)
(68:31:1:0)a)
(5:50:24:21)a)
HN
R
HN
R
HN
R
HN
R
C4F9
C4F9
C4F9
C4F9
OMe
OMe
O
O
O
O
3Aa: A: 83% yield 3Ab: A: 61% yield 3Ac: A: 51% yield 3Ad: A: 59% yield
N
N
N
N
B: 63% yield
B: 81% yield
B: 62% yield
B: 78% yield
NHCOPh
NH2
NHCOPh
NH2
3Oa: 65% yield
(3:79:11:7)a)
3Pa: 38% yield
(13:57:29:1)a)
3Qa: 61% yield
(21:71:7:1)b)
3Ra: 85% yield
(0:89:0:11)b)
C6F11
CF(CF3)2
CH2CH2C6F13
CF2CO2Et
a)
b)
GC conversion (unreacted SM:C5:C7:C5+C7);
GC
N
N
N
N
HN
R
conversion
(unreacted
SM:C5:other
HN
R
HN
R
HN
R
regioisomer:difunctionalisation)
O
O
O
O
3Af: A: 55% yield 3Ag: A: 68% yield
3Ae: A: 66% yield
3Ah: A: nr
B: traces
B: 75% yield
B: traces
B: nr
Regarding high reactivity of aminoquinoline
substrate, we have subsequently accomplished double
functionalisation of 1G with two different
perfluoroiodoalkanes (Scheme 1). Isolation of 4 in
63% yield over two steps further showcases the
potential of this green and convenient synthetic
pathway to build up polyfunctionalised quinoline
scaffolds.
The synthetic value of the newly developed
strategies strongly relies on their compatibility with
more
complex
molecular
scaffolds.
This
transformation occurs under extremely mild reaction
conditions, hence seems perfectly suited for the late-
stage functionalisation of more complex quinolines.
Accordingly, the metal- and oxidant-free couplings of
functionalised 8-amidoquinolines and unprotected 8-
[26]
aminoquinolines were probed (Table 4). Several
substituents present at different positions of the
heterocyclic scaffolds were well tolerated despite
their clear impact on selectivity and efficiency. N-(2-
methylquinoline-8-yl)benzamide
(1J)
was
4
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
a) 5 equiv of 2a.
Conditions B:
K2CO3
(2 equiv)
Acetone, r.t.,
2 x CFL, 24 h
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.,
C4F9
C4F9
2 x CFL, 24 h
Further exceptional versatility of this reaction was
demonstrated by performing the desired C-RF
coupling on C6-aminoquinoline 13, delivering 14 in
62% yield (eq. 1).
N
N
N
C8F17
C4F9-I
(1.2 equiv)
C8F17-I (5 equiv)
NH2
NH2
NH2
4: 89% yield
1G
3Ga: 71% yield
Considering the simplicity of our transformation,
its general effectiveness and tolerance towards
several functionalised groups, this reaction
establishes itself as an ideal tool for a late-stage
diversification of complex molecular scaffolds. To
exemplify this purpose, we embarked on
perfluoroalkylation of Boc-protected (±)-primaquine
derivative 15, commercialised anti-malaria drug (eq.
2). Rewardingly, our methodology worked perfectly
well, converting 15 into the desired product in 78%
NMR yield. However, due to a tedious purification,
16 was isolated in moderate yield (69% yield with
88% purity and 44% yield with purity > 98%).
Scheme 1. Sequential functionalisation of 8-
aminoquinoline (1G).
Following our initial purpose of designing a
transformation allowing both, C5- and C8 couplings,
we next explored the reaction of 5-amidoquinoline 5
and 5-aminoquinoline 6 using the basic protocol
(conditions B). Although unselective coupling was
observed for the amide 5, the non-protected amine 6
underwent efficient C8-perfluoroalkylation using
only 1.2 equivalent of 2a, delivering 8a in high yield
(62%). Notably, minor C6-functionalised product 10a
could also be isolated in 24% yield (both
regioisomers are separable by silica gel column).[27]
10a was crystalized and the X-Ray analysis
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.,
C4F9
NH2
NH2
unambiguously
confirm
the
regioselectivity.
2 x CFL, 40 h
Encouraged by this first example of C8-quinoline
perfluoroalkylation, we further enlarged the scope of
this transformation using a few RF coupling partners.
Several unprecedented perfluoroalkylated quinolines
have hence been prepared in synthetically useful
yields (44 – 66%). Unfortunately, a somehow lower
reactivity was observed while using the ester type
iodoalkane 2g. Likewise 8-aminoquinoline, its 5-
(eq. 1)
C4F9-I (1.2 equiv)
N
N
14: 62% yield
13
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.,
2 x CFL, 40 h
C4F9
OMe
OMe
(eq. 2)
N
N
C4F9-I (1.2 equiv)
substituted
congener
also
undergoes
HN
HN
NHBoc
NHBoc
bifunctionalisation while increasing the amount of the
coupling partner and the reaction time. Accordingly,
diperfluoroakylation of 6 took place and 11aa was
isolated in 68% yield. Notably, this protocol turned
out to be equally compatible with OMe-type directing
group installed at C5 position, hence delivering 5-
OMe-8-perfluoroalkylated quinoline 12a in 45%
yield under basic conditions.
16: 69% yield (purity of 88%)
15: Boc-primaquine
44% yield (purity > 98%)
Finally, several mechanistic studies have been
performed to elucidate the mechanism of this
transformation using conditions B (for details see SI).
The test reactions effectuated during the optimisation
show unambiguously crucial role of the light and the
experiments with cut-off filters (λ > 370 nm and λ >
455 nm) as well as UV-A lamp clearly suggest a
particular importance of UV-A irradiation to allow
the desired coupling. Optical absorption spectra of 1B
and 1G (measured for λ = 330-430 nm for 1B and λ =
330-500 nm for 1G) indicate that both quinoline
derivatives absorb light at λ < 370 nm (1B) and λ <
430 nm (1G). In contrast no absorption was observed
for 2a (for details see SI) and no change in UV-vis
absorption spectra was detected while mixing 1B or
1G with 2a in acetone. Accordingly, homolytic
cleavage pathway of C4F9-I and intermediacy of
Table 5. Scope for the functionnalised 5-amido and 5-
amino quinolines (5, 6)
NHR
NHR
NHR
Conditions B:
RF
K2CO3 (2 equiv)
RF-I
+
+
N
Acetone, r.t.,
2 x CFL, 24 h
N
N
RF
9(a-d, g)
10(a-d, g)
2(a-d, g)
5: R = COPh
6: R = H
7(a-d, g): R = COPh
8(a-d, g): R = H
NHCOPh
NH2
NH2
C4F9
+
N
N
N
C4F9
photoactive
EDA
(electron
donor-acceptor)
C4F9
aggregation between 1 and 2a could be ruled out.[28]
The radical character of this coupling was however
confirmed by performing the standard reaction in the
presence of TEMPO radical scavenger and 1,1-
diphenylethylene (DPE) as a radical trapper (Scheme
2). For the 8-amidoquinoline, 3Aa was not formed in
a presence of both reactants but the adducts of RF
addition to TEMPO and DPE were detected.
Likewise, no desired coupling product was formed
when performing the reaction under “radical chain
10a: 24%
7a: complex
reaction mixture
8a: 62%
NH2
NH2
NH2
NH2
C5F11
C3F7
+
+
N
N
N
N
C5F11
C3F7
8b: 66%
10b: 27%
10c: 22%
8c: 56%
NH2
NH2
O
NH2
NH2
C4F9
C8F17
+
N
N
N
N
N
C4F9
CF2CO2Et
C4F9
C8F17
12a: 45%
8d: 44%
10d: 24%
11aa: 68%[a]
8g: 24%
5
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
・
type conditions” (presence of AIBN, benzoyl
peroxide or triethylborane and heating at 70 °C). For
8-aminoquinoline 1G adding TEMPO or DPE
resulted in a formation of trapped species. In addition,
rather unexpectedly, the reaction was effective while
using three different typed of standard protocols
implying radical chain reactions.
generating radical RF and radical cation A; 3) radical
addition providing intermediate B, followed by
deprotonation yielding the desired product.
In contrast, the presence of the electron-donating
amino group renders the quinoline core more prone to
undergo radical chain reaction. The reaction starts
[29]
by 1) photoexcitation of the amino-quinoline 1G;
followed by 2) SET step between excited state 1G*
and 2a, delivering RF ・ species (initiation of the
process) and radical cation C; 3) addition of the two
radical coupling partners affording D; 4) electron
transfer from D to RF-I to form oxidized cationic
Mechanistic studies
Conditions B:
K2CO3 (2 equiv)
Acetone, r.t.,
C4F9
2 x CFL, 20 h
・
intermediate E together with RF and I- (formation of
N
N
C4F9-I
perfluoroalkyl radical further triggers the chain
sequence); 5) formation of 3Ga upon deprotonation.
These mechanistic scenarios remain however highly
speculative and further studies are currently
undergoing.
NHR
NHR
DPE
AIBN
TEMPO
(PhCOO)2
nr
Et3B
nr
R = COPh
R = H
DPE-C4F9
(43%)
nr
TEMPO-C4F9
TEMPO-C4F9
DPE-C4F9 C5: 52%
C5: 47%
C7: 22%
C5: 23%
C7: 14%
In conclusion, an unprecedented and general
strategy to access both C5- and C8-
(18%)
C7: 24%
Proposed mechanism
perfluoroalkylated
quinolines
is
described.
Remarkably, the reaction does not require any metal
and/or oxidant and operates smoothly under
extremely mild reaction conditions, using simple
visible-light irradiation and green solvent. This
coupling tolerates not only a range of functionalities
on the amide moiety, but contrary to a majority of
literature described protocols, is also compatible with
non-protected amino-quinoline substrates, delivering
an array of products. Consequently, to the best of our
knowledge, it is the first general methodology
allowing C5-perfluoroalkylation of both amido- and
amino-quinolines. Remarkably, the same approach is
also applicable for functionalisation of 5-
aminoquinolines, yielding C8-coupling products.
This protocol paves therefore the way towards a
panel of new compounds with promising features for
medicinal and agrochemical industry, as well as
advanced material science, under truly green, mild
and user-friendly reaction conditions.
8-amidoquinoline
*
hꢀ
RF-I
+
+
I
RF
SET
N
N
N
N
R
N
H
R
N
H
R
H
A
O
O
O
RF
RF
H
base
N
N
N
NHCOR
H
COR
B
8-aminoquinoline
*
hꢀ
RF-I
+
+
I
RF
SET
N
N
N
NH2
NH2
NH2
C
RF
Experimental Section
H
RF
H
RF
RF
RF
I
RF
I
Typical procedure for perfluoroalkylation of quinoline
substrates:
base
N
N
N
NH2
NH2
E
D
NH2
A 5 mL oven dried screw capped reaction tube was filled
with amides (or) amines (1 equiv) and base (1.5 – 2 equiv),
evacuated with vacuum-argon cycle for 5 times followed
by the addition of perfluoroalkyl iodide (1.2 – 5 equiv) and
solvent (0.2 M) under argon. The reaction tube was placed
approximately 2 cm away from each 2*26 W CFL bulbs.
The reaction mixture was stirred for the indicated time (20
– 40 h). After removal of the volatiles, the crude product
was purified by column chromatography on silica gel.
Condition A: Amide or amine (0.25 mmol, 1 equiv), RF -I
(1.25 mmol, 5 equiv for amides) or (0.3 mmol, 1.2 equiv
for amines), AgOAc (0.375 mmol, 1.5 equiv) and DCM
(1.25 mL, 0.2 M). Condition B: Amide or amine (0.25
mmol, 1 equiv), RF -I (1.25 mmol, 5 equiv for amides) or
(0.3 mmol, 1.2 equiv for amines), K2CO3 (0.5 mmol, 2.0
equiv) and Acetone (1.25 mL, 0.2 M).
Scheme 2. Mechanistic studies.
In light of these mechanistic studies and precedents
from the literature, the radical character of this metal-
free transformation can be assumed and a possible
divergent pathway for amide- and amine- substrates
can be expected. In the case of 8-amidoquinoline
derivatives, the presence of electron withdrawing
group seems to render the substrate ineffective under
classical radical-chain conditions and as the amido-
quinoline substrate undergoes photoexcitation under
irradiation,
a
single electron transfer (SET)
mechanism could be envisioned. Such a scenario
would imply: 1) generating of excited state 1B*
species under irradiation; 2) SET with RF-I
6
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
Acknowledgements
Lin, Y. Deng, Z. Ke, H. Jiang, W. Zeng, J. Org. Chem.,
2016, 81, 946; m) L.-K. Jin, G.-P. Lu and C. Cai, Org.
Chem. Front. 2016, 3, 1309; n) J. Chen, T. Wang, T.
Wang, A. Lin, H. Yao, J. Xu, Org. Chem. Front. 2017,
4, 130; o) X. He, Y. Xu, L. Kong, H. Wu, D. Ji, Z.
Wang, Y. Xu, Q. Zhu, Org. Chem. Front. 2017, DOI
10.1039/C6QO00644B; p) J.-M. Li, Y.-H. Wang, Y.
Yu, R. Wu, J. Weng, G. Lu, ACS Catal. 2017, DOI
10.1021/acscatal.6b03671; for a recent example of
heterogenous catalytic system see : q) C. Shen, J. Xu, B.
Ying, P. Zhang, ChemCatChem, 2016, 8, 3560.
We thank the CNRS (Centre National de la Recherche
Scientifique), the “Ministère de l’Education Nationale et de la
Recherche“, ANR (Agence Nationale de la Recherche) France
and USIAS (University of Strasbourg Institute for Advanced
Studies) for financial support. P. B. Arockiam is very grateful to
USIAS for the post-doctoral fellowship and L. Guillemard
acknowledge the ANR (Agence Nationale de la Recherche),
France for a doctoral grant “2al-VisPhot-CH”. We are also very
greatful to Prof. D. Uguen, Dr. F. Leroux and Dr. A. Panossian
for helpful discussions. We thank Dr. L. Karmazin and Dr. C.
Bailly for single crystal X-ray diffraction analysis and J.-M.
Strub for several HRMS analysis.
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Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201700471
Advanced Synthesis & Catalysis
COMMUNICATION
ꢀ
and ꢀ approach
multitude of compounds
Regiodivergent C5 & C8- visible light induced C-H
functionalisation of quinolines under metal-,
photosensitizer- and oxidant-free conditions.
K2CO3
Acetone, r.t.
RF
RF
N
N
NH2
NHCOR
H
Adv. Synth. Catal. Year, Volume, Page – Page
no metal
no oxidant
green solvent
visible light as
activator
DG
R1
NH2
F
N
H
Percia Beatrice Arockiam, Lucas Guillemard and
Joanna Wencel-Delord*
R2
N
N
F
RF
NH2
RF
NH2
N
9
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