Light-Promoted Copper-Catalyzed Enantioselective Alkylation of Azoles

Article abstract of DOI:10.1002/anie.202009323

A catalytic asymmetric alkylation of azoles with secondary 1-arylalkyl bromides through direct C?H functionalization is reported. Under blue-light photoexcitation, a copper(I)/carbazole-based bisoxazoline (CbzBox) catalytic system exhibits good reactivity and high stereoselectivity, thus offering an efficient strategy for the construction of chiral alkyl azoles. These reactions proceed at low temperature and are compatible with a wide range of azoles.

Full text of DOI:10.1002/anie.202009323

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Accepted Article
Title: Photo-Promoted Copper-Catalyzed Enantioselective Alkylation of
Azoles
Authors: Chen Li, Bin Chen, Xiaodong Ma, Xueling Mo, and Guozhu
Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009323
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Photo-Promoted Copper-Catalyzed Enantioselective Alkylation of
Azoles
Chen Li+, Bin Chen+, Xiaodong Ma, Xueling Mo, Guozhu Zhang*
asymmetric alkylation of azoles through C–H functionalization
would be highly desired.
Abstract: A catalytic asymmetric alkylation of azoles with secondary
1-arylalkyl bromides through direct C–H functionalization is reported.
Under blue light photoexcitation, copper(I)/carbazole-based
bisoxazoline (CbzBox) catalytic system exhibits good reactivity and
high stereoselectivity, thus offering an efficient strategy for
constructing chiral alkyl azoles
Alkylated heteroaromatics are important organic molecules
because they often possess useful biological, pharmaceutical,
and material properties.[1] Friedel–Crafts alkylation,[2] Minisci-
type
radical
additions,[3]
and
metal-catalyzed
hydroheteroarylation of olefins[4] are traditional methods to
construct alkylated heteroaromatics. In recent years, significant
progress has been made in direct arylation, alkenylation, and
alkynylation of acidic C-H bond of heterocycles using readily
available carbohalides.[5] Direct alkylation using alkyl halides,
however, proves to be more challenging, especially if the alkyl
groups contain β-hydrogens. Besides β-H elimination,
protodehalogenation and homocoupling are also major side
Scheme 1. Alkylation of azoles
[6-7]
reactions in the alkylation of heteroaromatics.
Asymmetric
alkylation of aromatic heterocycles is also a challenging task.
To address the above problems, the transition-metal-
catalyzed cross-coupling approaches have recently been
developed. One important strategy to ensure high levels of
reactivity and selectivity is based on the introduction of a
directing group, allowing selective alkylation of a single C–H
bond of heteroaromatics.[8] A notable alternative is the direct
alkylation of heteroaromatics involving acidic C–H bond. In the
past decade, Miura[9a], Huang[9b], Zhou[10a] and Fu[10b] have
reported the coupling reactions between heteroaromatics and
alkyl hallides under palladium catalysis. In 2012, the Hu group
first reported the coupling of azoles with benzyl bromide using
copper catalysts (Scheme 1, eq 1).[11] In 2016, Ohmiya
pioneered the copper-catalyzed enantioselective allylic alkylation
of azoles with ,-disubstituted primary allylic phosphates under
mild conditions (Scheme 1, eq 2).[12a] However, copper-catalyzed
enantioselective alkylation of azoles by benzylic bromides has
not been reported.[12b] The corresponding chiral alkylated azoles
was obtained by chiral column resolution in a literature report.[13]
In addition, enantioselective C–H functionalization is a highly
atom- and step-economic method toward the facile synthesis of
value-added optically active molecules and has drawn extensive
research interests.[14] Thus, new strategies for achieving the
Photoredox catalysis has become a powerful synthetic tool,
with notable feature of forming reactive radical species under
mild reaction conditions for controllable transformation.[15]
Stephenson and co-workers reported photocatalytic alkylation of
indoles, pyrroles and furans with brominated malonates at room
temperatures.[16a,b] The very first photo-induced copper-catalyzed
enantioselective cross-coupling reaction was established by Fu
et al. in the C–N bond formation by a copper(I) catalyst
containing a chiral phosphine ligand.[17a] Inspired by these
pioneering works, in line with our ongoing interest in copper
catalysis,[18] we report in this manuscript an efficient photo-
promoted, copper-catalyzed direct asymmetric alkylation of
azoles. The reaction involves radicals generated from secondary
benzylic bromides (Scheme 1, eq 3).
We recently disclosed a photoinduced copper-catalyzed
asymmetric three-component alkyl/aryl alkynylation of alkenes
using a diphenylamine-based oxazoline (BOPA) ligand.[18b] We
surmised that the photoexcited chiral anionic NNN-copper
complex could promote the generation of alkyl radicals by single
electron reduction of activated alkyl bromides under mild
conditions.[17b-d] These radicals will couple with heteroaromatics
for carbon–carbon bond formation.
We started our attempt by allowing a model substrate
benzoxazole 2a to be reacted with (1-bromoethyl)benzene. After
comprehensive investigation of the reaction conditions, we were
pleased to find that t-BuCbzBox L3 proved to be a suitable chiral
ligand in this coupling reaction.[19] Under the optimized
conditions, 1a provided the desired product 3a in satisfactory
yield and good enantioselectivity (75% yield and 90% ee) after
48 h at -10 oC (Table 1, entry 15)
[*]
Dr. C. Li, B. Chen, X. Ma, X. Mo, Prof. Dr. G. Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Center for Excellence in Molecular
Synthesis, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
China
E-mail: guozhuzhang@sioc.ac.cn
[+]
These authors contributed equally to this work.
Table 1. Evaluation of Chiral Ligands and Other Reaction Parameters
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compound.[20] A phenyl group could be tolerated at different
positions of the alkyl chain (3c and 3d). The coupling of
benzoxazole with benzyl bromides bearing weak electron-
donating substituents furnished the corresponding products in
moderate yields and high ee (3e and 3f). 4-Chloro-bromobenzyl
chlorides was also a suitable halide, providing the product 3g
suitable for further elaboration. A fluoro-functionality could be
successfully incorporated into the products (3h and 3i). Benzyl
bromide with electron-withdrawing group like trifluoromethyl
group in the meta and para positions gave 3j and 3k in lower
yields and moderate ee values.
entry[a]
devision
Yield[b] (%)
ee[c]
82
10
0
1
none
90
63
52
30
73
75
69
0
Table 2. Substrate Scope Studies with (1-Bromoethyl)benzene
Derivatives[a][b]
2
L1
3
L2
4
L4
0
5
L5
9
6
L6
0
7
L7
15
-
8
Without ligand
Without CuI
9
0
-
10
11
12
13
14
15[d]
Without tBuOLi
Without light
Green LED
0
-
10
15
trace
n.o.
75
81
80
n.d.
-
tBuONa instead of tBuOLi
tBuOK instead of tBuOLi
-10 oC instead of r.t.
90
[a] Reaction conditions: benzoxazole (0.1 mmol,
1
equiv), (1-
bromoethyl)benzene (0.3 mmol, 3 equiv), CuI (10 mol%), Ligand (15 mol%),
tBuOLi (0.3 mmol，3 equiv) in DCE at r.t. for 24 h unless noted otherwise. [b]
Yield was determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal
standard [c] Determined by chiral HPLC analysis, the absolute configuration
was assigned by comparison with reported example, 3b. [d] The reactions
were carried out at -10 oC for 48 h.
The impact of various deviations from the standard reaction
conditions deserves some discussion. We have found that
structurally similar ligands with different substitution at the
oxazoline, L1, L2 and L4 gave significantly poorer results in
terms of yields and enantioselectivities (entries 2 - 4) at r.t. for
24 h. The BOPA ligands L5 and L6 were inefficient in this
transformation (entries 5 and 6).[20] The privileged tridentate
ligand such as Pybox was also not effective for this reaction
(entry 7). Control experiment demonstrated that product 3a was
not produced in the absence of copper salt, ligand or base,
suggesting they are all essential for the success of this
chemistry (entries 8-10). Without light, the yield of the reaction
decreased significantly, confirming that light can promote the
reaction, however, the ee value of the product remains
unchanged at r.t. (entry 11). In addition, reaction performed
under green light irradiation provided small amount of product
with a comparable ee (entry 12). Switching of the base from
tBuOLi to tBuONa or tBuOK was detrimental to the reaction, and
no desired product was observed (entries 13 and 14). Variation
in temperature has a profound effect on the reaction outcome:
the reaction performed at -10 oC for 48 h further improved the ee
to 90% (entry 15). Details for various deviations from the
standard reaction conditions were illustrated in the Supporting
Information.
[a]
Reaction conditions: benzoxazole (0.1 mmol, 1 equiv), (1-bromoethyl)benzene
(0.3 mmol, 3 equiv), CuI (10 mol%), Ligand (15 mol%), tBuOLi (0.3 mmol，3
equiv) in DCE at -10 oC for 48 h. [b] Yields of isolated products are given. The
ee values were determined by HPLC analysis on a chiral stationary phase. [c]
L1 was used as chiral ligand.
After the optimal reaction conditions were established (Table 1,
entry 15), the substrate scope with respect to benzyl bromide
was firstly investigated (Table 2). The reactions were insensitive
to the length of the alkyl chains, and (1-bromopropyl)benzene
reacted smoothly to give the product 3b in comparable yield and
ee. The absolute configuration of the 3b was assigned by
comparing its optical rotation with that of the known
A phenyl group could be allowed at the para position of the
benzyl bromide (3l). Beside benzylic halides, 1- or 2-(1-
bromopentyl)naphthalene were suitable substrates as well,
leading to products (3m and 3n) in comparable yields. Again, a
phenyl at the end of carbon chain gave the coupled product in
moderate yield and excellent ee (3o). Benzylic bromides with
ortho substitutions (eg, Me and Cl) were also tested. To our
delight, the former gave the product in 99.4% ee (3p). Reactions
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of bromides bearing heterocycles such as thiophene and
benzothiophene proceeded equally well to provide the desired
products in comparable yields and ee values (3r and 3s). A
chloride at the end of the alkyl side chains was allowed, and 3t
was isolated in 69% yield and with 97% ee value. Besides
benzylic bromides, 3-bromocyclohex-1-ene also underwent
azolation to yield the product 3u in moderate yield and ee.
Unfortunately, benzyl bromide with OMe and CN group on the
para position of the phenyl were not compatible under current
conditions (3v and 3w). OTBDPS and OMe groups on the alkyl
side chains were not tolerated, either (3x and 3y). Unactivated
alkyl bromides and α-bromoketone failed to couple with oxazole
to form 3z or 3u. Pseudohalide such as OMs did not provide the
desired coupling product 3b, either.
Several deuterium-labeling experiments were conducted to
probe the mechanism of the metalation of benzoxazole. First, 1a
was stirred with CuI and L3 at r.t. for 2 h, followed by the
addition of CD3OD (20 equiv).No deuterium incorporation is
observed (Scheme 2, eq 1). When 1a was reacted with tBuOLi
at r.t. for 2 h and then treated with CD3OD, the C2 of 1a has
85
% deuterium, which suggests that the oxazole C2
deprotonation is facile and likely complete (Scheme 2, eq 2).
When 1a was mixed and stirred with tBuOLi, CuI and L3 at r.t.
for 2 h before treatment of CD3OD, the H/D exchange ratios of
1a was about 88%, which suggests the copper ligand complex
does not affect the lithiation step. The transmetallation of
[Li+oxazole-] to form [LCu-oxazole]-Li+ complex is most likely
(Scheme 2, eq 3) [22]. The reaction of benzylic chloride with a
cyclopropyl group afforded ring opening product exclusively,
suggesting a radical intermediate is involved (Scheme 2, eq 4).
Substituted benzoxazoles could also be alkylated in
moderate yields with good ee (Table 3). Electron-donating Me
(4a) and MeO (4b) groups, and electron-withdrawing F (4c) and
COOMe (4d) groups were tolerated. With regard to
benzoxazoles with extended conjugation, both naphtho[2,3-
d]oxazole and naphtho[1,2-d]oxazole reacted well to provide the
products 4e and 4f
in moderate yields with good ees,
respectively. A better result was observed while using 1-(1-
bromopentyl)naphthalenes as the coupling partner, giving 4g in
95% ee. Benzothiazole was a suitable substrate, giving the corr-
Table 3. Substrate Scope Studies with azoles[a][b]
Scheme 2. Deuterium labeling experiments and radical probe.
The UV-vis spectra of individual reagents or complexes were
recorded in DCE. None of the benzoxazole, CuI, or ligand
absorbed at wavelengths over 400 nm. Instead, [LCuI] and
[LCu-oxazole]-Li+ complexes (both should form in situ in the
reaction) absorbed in the range of 400-500 nm (see the
Supporting Information for details).[17]
In addition, the Stern-Volmer experiment indicated that the
excited state of the in-situ-formed [LCuI-oxazole]-Li+ and [LCuI]
complex could be quenched by benzylic bromide with
Stern−Volmer constants of 47 mM−1 and 8.8 mM−1, respectively.
Since [LCuI-oxazole]-Li+ has a larger Stern−Volmer constant
than [LCuI], [LCuI-oxazole]-Li+ is likely the photoactive species
under the BLED irradiation. Moreover, quantum yield (Φ =
0.43%) suggested that a radical-chain process might not be
involved (see the Supporting Information for details).
[a] The reaction conditions were benzoxazole (0.1 mmol,
1 equiv), (1-
bromoethyl)benzene (0.3 mmol, 3 equiv), CuI (10 mol%), Ligand (15 mol%),
tBuOLi (0.3 mmol，3 equiv) in DCE at -10 oC for 48 h. [b] Yields of isolated
products are given. The ee values were determined by HPLC analysis on a
chiral stationary phase. [c] Conducted with CuTc
Based on the literature[10], [22] and these findings, we proposed
the reaction mechanism shown in Figure 3. In the presence of a
base and a ligand, [LCuI] (A) complex is formed in situ, which
undergoes transmetallation with [Li-azole] to generate [LCuI-
azole]−Li+ (B). This complex serves as the photoactive species
to undergo photoexcitation to give [LCu(I)-azole]−*Li+ (C), which
delivers an electron to the alkyl bromide, leading to LiBr and
[LCuII-azole][R·](D).[23] This intermediate is rapidly transformed
into the chiral Cu(III) species intermediate E via enantioselective
radical trapping.[24-25] Eventually, reductive elimination from the
Cu(III) center leads to optically pure benzylic azoles. An
alternative direct SET process from D to product is also viable.
esponding products 4h and 4i in comparable yields and with
good enantioselectivities. Disubstituted oxazoles were also
examined, and they performed equally well in the coupling
reactions to give 4j and 4k. A similar pattern has been observed
that sterically more hindered 1-(1-bromopentyl)naphthalenes led
to a higher product ee. 5-ethoxycarbonyloxazole was a suitable
substrate, as well (4l). The parent oxazole could also be coupled
with (1-bromoethyl)benzene to give the product 4m in a
moderate ee using CuTc as the copper source. Various other
aromatic heterocycles have been tested, however, no desired
products were observed from those reactions (4n to 4p).
Condition optimization and ligand development are needed to
expand this strategy to accommodate more heteroaromatics.
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Figure 3. Proposed reaction mechanism
In summary, this communication has described a mild
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-Acknowledgements
We are grateful to NSFC-21772218, 21821002, XDB20000000,
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
Keywords: Copper-catalysed • Asymmetric C-H functionaliza-
tion •Enantioselective • Alkyl bromides • Azoles
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10.1002/anie.202009323
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Chen Li, Bin Chen, Xiaodong Ma,
Xueling Mo and Guozhu Zhang*
Page No. – Page No.
Photo-Promoted Copper-Catalyzed
Enantioselective Alkylation of Azoles
A catalytic asymmetric alkylation of heteroaromatics such as oxazoles and
benzothiazoles with secondary 1-arylalkyl bromides through direct C-H
functionalization is reported. Under blue light photoexcitation, copper(I)/Carbazole-
based bisoxazoline (CbzBox) catalytic system exhibits good reactivity and high
stereoselectivity, thus offering an efficient strategy for constructing chiral alkyl
azoles
This article is protected by copyright. All rights reserved.