Visible-light-mediated Minisci C-H alkylation of heteroarenes with unactivated alkyl halides using O2 as an oxidant

Article abstract of DOI:10.1039/c8sc04892d

Herein, we report a protocol for direct visible-light-mediated Minisci C-H alkylation of heteroarenes with unactivated alkyl halides using molecular oxygen as an oxidant at room temperature. This mild protocol is compatible with a wide array of sensitive

Full text of DOI:10.1039/c8sc04892d

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Visible-light-mediated Minisci C–H alkylation of
heteroarenes with unactivated alkyl halides using
O2 as an oxidant†‡
Cite this: DOI: 10.1039/c8sc04892d
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Jianyang Dong,a Xueli Lyu,a Zhen Wang,a Xiaochen Wang,a Hongjian Song,a Yuxiu Liua
ab
*
and Qingmin Wang
Herein, we report a protocol for direct visible-light-mediated Minisci C–H alkylation of heteroarenes with
unactivated alkyl halides using molecular oxygen as an oxidant at room temperature. This mild protocol is
compatible with a wide array of sensitive functional groups and has a broad substrate scope. Notably,
functionalization of (iso)quinolines, pyridines, phenanthrolines, quinazoline, and other heterocyclic
compounds with unactivated primary, secondary, and tertiary alkyl halides proceeds smoothly under the
standard conditions. The robustness of this protocol is further demonstrated by the late-stage
functionalization of complex nitrogen-containing natural products and drugs.
Received 2nd November 2018
Accepted 26th November 2018
DOI: 10.1039/c8sc04892d
rsc.li/chemical-science
N-heteroarenes by means of an iridium photoredox catalysis
approach.7 Because alkyl bromides are readily available and
Introduction
inexpensive, we wished to expand the substrate scope of C–H
alkylation of heteroarenes with alkyl bromides by developing
a practical, mild protocol with a broader functional group
tolerance. In addition, we wanted the new Minisci reaction
protocol to employ oxygen, which is environmentally benign, as
the only oxidant and to avoid the need for high catalyst loadings
and high-energy UV light. However, we needed to overcome the
Heteroaryl motifs are present in a wide variety of natural prod-
ucts, organic materials, small-molecule drugs, and ligands for
metal catalysts.1 Substituted heteroarenes can be readily accessed
by direct functionalization of the C–H bonds of unsubstituted
heteroarenes.2 A useful tool for this purpose is the Minisci reac-
tion, in which a protonated N-heteroarene is attacked by an alkyl
radical under oxidative conditions.3 Classic Minisci reactions,
which involve carboxylic acids as the alkyl radical sources, oen
require the use of excess oxidant (e.g., peroxide), excess acid, and
high temperature.3,4 Recently, there have been several reports of
visible-light-mediated Minisci C–H alkylation reactions of N-
heteroarenes with alkyl peroxides, primary alcohols, aliphatic
carboxylic acids, boronic acids, alkyltriuoroborates, and alkyl
iodides as the alkyl radical sources (Scheme 1A).5 In addition,
Barriault and co-workers described a protocol for direct alkyl-
ation of heteroarenes with alkyl bromides in the presence of
a gold photoredox catalyst (Scheme 1B).6 However, the protocol
employs a high catalyst loading and high-energy UVA (365 nm)
irradiation, which can narrow the functional group tolerance and
limit the substrate scope.
Our group is interested in visible-light-mediated Minisci
reactions, and we recently achieved a-aminoalkylation of
aState Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People's Republic of China. E-mail: wangqm@nankai.edu.cn
bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, People's Republic of China
† Dedicated to the 100th anniversary of Nankai University.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c8sc04892d
Scheme
heteroarenes.
1 Photoredox-mediated Minisci C–H alkylation of N-
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challenge posed by the fact that Ru- and Ir-based photoredox molecular oxygen as the oxidant, and acetone as the solvent
catalysts cannot undergo efficient excited-state quenching with under irradiation with a 36 W blue LED (see the ESI‡). To our
unactivated alkyl bromides (ca. ꢀ2.0 V vs. SCE) to generate alkyl delight, desired product 3 was obtained in excellent yield when
radicals under standard Minisci conditions (which are acidic TTMS was used as a silyl radical precursor (entry 1). Using the
and oxidative).8
above-described conditions, we then varied the photocatalyst
Halogen abstraction from alkyl bromides by tris(- (entries 2–4). However, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 proved to
trimethylsilyl)silyl radical for thermal generation of alkyl radi- be the most effective catalyst. Other solvents (acetonitrile,
cals has been widely studied, and photomediated processes methanol, and dimethylformamide) gave lower yields (entries
have also been reported.9 However, halogen abstraction by 5–7). Control experiments showed that the reaction failed to
a silyl radical under Minisci reaction conditions has not been proceed in the absence of light, photocatalyst, TTMS, or
explored. In this study, we focused our attention on developing molecular oxygen (entries 8–11).
a practical method for Minisci-type reactions using alkyl
With the optimized reaction conditions in hand, we studied
bromides as the alkyl radical sources and tris(trimethylsilyl) the scope of the reaction with respect to the alkyl bromide
silane (TTMS) as the halogen-abstraction agent under photo- (Table 2). The reaction was found to be amenable to a wide
redox conditions. Specically, we herein report a protocol for range of primary alkyl bromides, which gave the desired prod-
visible-light-mediated Minisci C–H alkylation of heteroarenes ucts in good to excellent yields. For example, linear alkyl
with unactivated primary, secondary, and tertiary alkyl halides bromides afforded the corresponding alkylated heteroarenes
(Scheme 1C). The high efficiency, broad substrate scope, (5–7) in 45–84% yields. Minisci reactions of primary alkyl
excellent functional group tolerance, and mildness of this radicals are more challenging than reactions of secondary alkyl
protocol make it particularly suitable for late-stage functional- radicals, owing to the lower stability and nucleophilicity of the
ization of complex nitrogen-containing natural products and former.10 However, we were pleased to observe that primary
drugs.
alkyl substituents carrying various functional groups (e.g.,
a terminal alkyne, a terminal alkene, an ester, an acetal, or
a phenoxy group; 8–12, respectively) could be incorporated in
good yields. Phenylethyl bromide and benzyl bromide were also
suitable substrates, giving 13 and 14 in 78 and 85% yields.
Alkylation reactions of secondary bromoalkanes also proceeded
under the standard conditions to afford the corresponding
alkylated heteroarenes in moderate to excellent yields (15–20,
22–24). Notably, ether, amine, and tert-butyl carbamate groups
Results and discussion
As a model reaction, we investigated the alkylation of lepidine
(1, 1.0 equiv.) with bromocyclohexane (2, 2.0 equiv.) under
various conditions (Table 1). First, a number of silanes were
screened with 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the
photocatalyst, triuoroacetic acid as the proton source,
were
also
tolerated.
Finally,
tertiary-bromoalkane-
functionalized lepidine derivatives 25 and 26 could be ob-
tained in good to excellent yields, and the protocol was
amenable to scale up; 26 was isolated in 77% yield when the
reaction was carried out on a 6 mmol scale.
Table 1 Optimization of conditions for alkylation of lepidine with
bromocyclohexanea
Next, we explored alkylation reactions with alkyl iodides
(Table 2). Gratifyingly, we found that unactivated primary,
secondary, and tertiary iodoalkanes underwent the desired
reaction, and the corresponding products were obtained in
moderate to good yields. Although in each case the yield was
lower than that obtained with the corresponding alkyl bromide,
the ability to use alkyl iodides broadens the scope of the reac-
tion with respect and would be helpful when the alkyl bromide
is not available. Unfortunately, unactivated primary, secondary,
and tertiary alkyl chlorides showed no reactivity.
Finally, we tested this new alkylation protocol with various N-
heteroarenes (Table 3). Electron-decient heteroarenes were
readily alkylated at the most electrophilic position with bro-
mocyclohexane (2) in fair to excellent yields. Specically, quin-
oline was selectively alkylated with 2 at the C2 position to afford
27 in 45% yield. The use of 4-chloro- and 4-bromo-quinoline
and 2-methyl-quinoline resulted in selective alkylation with 2
at C2 for the halogenated substrates and at C4 for the methyl-
ated substrate (28–30, 41–84% yields). Reactions of 2 with 4-
methoxycarbonyl-substituted isoquinolines afforded products
of selective a-aminoalkylation at C2 position (31, 81% yield).
Alkylation of 2,6-dimethylpyridine afforded a fair yield (50%) of
Entry
Photocatalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir(ppy)3
[Ru(bpy)3](PF6)2
Acetone
Acetone
Acetone
Acetone
CH3CN
MeOH
82
Trace
NR
Trace
68
52
23
NR
NR
NR
12
Eosin-Y
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
—
7
DMF
8c
9
Acetone
Acetone
Acetone
Acetone
10d
11e
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)PF6
a
General conditions, unless otherwise noted: 1 (0.2 mmol), 2 (0.4
mmol), photocatalyst (0.002 mmol), TTMS (0.4 mmol), triuoroacetic
acid (TFA, 0.4 mmol), and acetone (2 mL) under O2 atmosphere. NR ¼
b
c
no reaction. Isolated yields are given. Reaction performed in the
d
absence of light. Reaction performed in the absence of TTMS.
e
Reaction performed under argon atmosphere.
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Table 2 Substrate scope with respect to alkyl halidesa
a
Reactions were performed on a 0.3 mmol scale. Isolated yields are given.
C4-functionalized product 32. When nicotinonitrile was used, either an isopropyl group or a tert-butyl group to afford 41 and
dialkylated product 33 (40%) was the major product. The scope 42 in good yields. Fasudil, which bears a free secondary NH
of the reaction was further extended to phthalazine (34, 46%), 2- group, was selectively alkylated at C1 to give a fair yield of 43.
chloroquinazoline (35, 56%), 6-chloroimidazo[1,2-b]pyridazine Fenarimol, which has a tertiary OH group, could also tolerate
(36, 48%), and benzothiazole (37, 44%). Notably, the reaction the reaction conditions and was selectively monoalkylated to
could be used to modify commercially available phenanthroline afford 44 in 62% yield. Loratadine, which has amide and vinyl
ligands, as demonstrated by the selective monoalkylation with 2 groups, could be alkylated selectively at the C2 position of the
at the C2 position to afford fair to good yields of 38–40. The pyridine ring to give 45. The fungicide quinoxyfen was alkylated
selective monoalkylation of these phenanthroline ligands at C2 of the quinoline ring to give 46 in good yield. Remarkably,
suggests that this protocol may nd applications in the the alkylation of steride also proceeded smoothly, affording
synthesis of ligands for catalysis.
a 71% yield of 47. Considering that alkyl halides are readily
As shown in Table 4, this Minisci C–H alkylation protocol available and inexpensive, this new Minisci protocol may prove
could be readily used to functionalize complex natural products highly useful in drug discovery research.12
and drug molecules.5,11 For instance, quinine and cinchonine,
Having explored the substrate scope and utility of the reac-
both of which have a free OH group as well as amine and vinyl tion, we turned our attention to the mechanism (Scheme 2).
groups, could be selectively alkylated at the C2 position with When a radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy
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Table 3 Scope of the reaction with respect to the N-heteroarenea
product of cyclohexyl radical trapping, benzyl 3-cyclo-
hexylpropanoate (50), was observed by mass spectrometry.9f To
lend additional support to our proposed mechanism, we carried
out a radical clock experiment.6,13 Alkylation of 1 with 6-
bromohex-1-ene (51) resulted in 5-exo trig cyclization prior to
heteroarene addition and afforded a 14 : 1 mixture of 52a and
52b. Alkylation of 1 with (bromomethyl)cyclopropane (53) under
the standard conditions gave ring-opened product 54 in 45%
yield. (Bromomethyl)cyclobutane 55 remained mostly
unopened, affording 56a and 56b in a 14 : 1 ratio. These
experiments clearly point to a radical pathway. Moreover, we
conducted a light/dark experiment, which showed that coupling
product 3 formed only under continuous irradiation (see ESI‡).
This result suggests that radical chain propagation was not
involved in the reaction.
On the basis of our experimental observations and literature
reports, we propose the mechanism depicted in Scheme 3. The
mechanism begins with generation of carbon-based radical A
from an alkyl bromide under photoredox conditions, which has
been explained previously by MacMillan and co-workers in the
context of their cross-electrophile coupling.9e Briey, alkyl
bromide may produce tiny amounts of bromide (Brꢀ) under
irradiation of light, oxidation of bromide (Brꢀ) by the photo-
catalyst generates an electrophilic bromine radical,14 which can
abstract the hydrogen from (Me3Si)3SiH, generating a silyl
radical species [(Me3Si)3Sic].9e Subsequent halogen abstraction
from alkyl bromide 2 provides nucleophilic radical species A
and the bromosilane byproduct. This abstraction step is effec-
tively irreversible owing to the difference in bond dissociation
energy between the Si–Br bond of Me3Si–Br (96 kcal molꢀ1) and
the Csp3–Br bond of bromoethane (69 kcal molꢀ1).15 Radical A
then adds to the protonated electron-decient heteroarene via
a Minisci-type pathway to afford radical cation B. Single-
a
Reactions were performed on a 0.3 mmol scale. Isolated yields are
given.
(TEMPO) or 1,1-diphenylethylene, was present in a reaction
mixture containing 1 and 2, the formation of 3 was completely
inhibited. When benzyl acrylate (48) was used as a radical
scavenger, benzyl 3-(1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)
trisilan-2-yl)propanoate (49) was isolated in 5% yield, which
suggests that a silyl radical was generated.9f In addition, the
Table 4 Use of Minisci C–H alkylation for functionalization of natural products and drug moleculesa
a
b
Reactions were performed on a 0.3 mmol scale. Isolated yields are given. Steride (0.2 mmol) and lepidine (0.4 mmol) were used.
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Scheme 2 Mechanistic experiments.
electron oꢀxidation of Ir2+ by O2 forms the superoxide radical
anion (O2 c) and completes the photoredox cycle.16 O2ꢀc can
abstract a hydrogen atom from B to form the nal alkylated
ꢀ
17
product, along with HO2
.
Conclusions
In conclusion, we have achieved visible-light-mediated Minisci
C–H alkylation of heteroarenes by using readily available,
inexpensive alkyl halides as the alkyl radical sources. A broad
range of cyclic and acyclic unactivated primary, secondary, and
tertiary alkyl groups can be efficiently incorporated into N-
heteroarenes under mild conditions, and the protocol is scal-
able to the gram level. Its high efficiency, broad substrate scope,
excellent functional group tolerance, and mild operation
conditions make it particularly suitable for late-stage func-
tionalization of complex nitrogen-containing natural products
and drugs.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Scheme
heteroarenes.
3 Proposed mechanism for direct C–H alkylation of
We are grateful to the National Natural Science Foundation of
China (21732002, 21672117) and the Tianjin Natural Science
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Foundation (16JCZDJC32400) for generous nancial support for
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