Visible-Light-Driven Palladium-Catalyzed Radical Alkylation of C?H Bonds with Unactivated Alkyl Bromides

Article abstract of DOI:10.1002/anie.201704513

Reported herein is a novel visible-light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross-coupling of C(sp³)?H bonds in N-aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra- and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)?C(sp³) and C(sp²)?C(sp³) bonds in moderate to excellent yields. These redox-neutral reactions feature broad substrate scope (>60 examples), good functional-group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible-light photocatalyst and radicals are involved in the process.

Full text of DOI:10.1002/anie.201704513

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Visible-Light-Driven Pd-Catalyzed Radical Alkylation of C─H
Bonds with General Unactivated Alkyl Bromides
Authors: Wen-Jun Zhou, Guang-Mei Cao, Guo Shen, Xing-Yong Zhu,
Yong-Yuan Gui, Jian-Heng Ye, Liang Sun, Li-Li Liao, Jing Li,
and Da-Gang Yu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704513
Angew. Chem. 10.1002/ange.201704513
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http://dx.doi.org/10.1002/ange.201704513

10.1002/anie.201704513
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Visible-Light-Driven Pd-Catalyzed Radical Alkylation of C─H
Bonds with General Unactivated Alkyl Bromides
Wen-Jun Zhou,[a,b] Guang-Mei Cao,[a] Guo Shen,[a] Xing-Yong Zhu,[a] Yong-Yuan Gui,[a] Jian-Heng Ye,
[a] Liang Sun,[a] Li-Li Liao,[a] Jing Li,[a] and Da-Gang Yu*[a]
Dedicated to the 150th Anniversary of the Gesellschaft Deutscher Chemiker (GDCh)
sluggish oxidative addition and reductive elimination as well as
the competitive side reactions, such as β-H elimination and
protonation of the resulting alkylpalladium intermediates.[10]
Recently, great breakthrough has been realized that Fu, Zhou,
and Alexanian independently realized Pd-catalyzed radical
alkylation of (hetero)arenes with unactivated alkyl halides.[11,12]
Pd-catalyzed alkylation of C(sp3)─H bonds with unactivated
tertiary and secondary alkyl halides, however, remains
unexplored. We wondered whether it was possible to resolve
such challenges by introducing visible light as an energy source
to activate the Pd-catalyst and facilitate the radical cross-
couplings. Herein, we report the discovery of a unique visible-
light photoredox system with Pd(PPh3)4 as sole catalyst to
realize the first general cross-coupling of C(sp3)─H bonds in N-
aryl tetrahydroisoquinolines with unactivated alkyl halides
(Scheme 1, B). Moreover, alkylation of (hetero)aryl C(sp2)─H
bonds was also realized under mild reaction conditions.
Abstract: Herein, we report a novel visible-light photoredox system
with Pd(PPh3)4 as the sole catalyst to realize the first direct cross-
coupling of C(sp3)─H bonds in N-aryl tetrahydroisoquinolines with
general unactivated alkyl bromides. Moreover, intra- and inter-
molecular alkylations of hetero-arenes were also developed under
mild reaction conditions. A variety of tertiary, secondary and primary
alkyl bromides undergo such reactions to generate C(sp3)─C(sp3)
and C(sp2)─C(sp3) bonds in moderate to excellent yields. These
redox-neutral reactions feature broad substrate scope (>60
examples), good functional group tolerance and facile generation of
quaternary centers. Mechanistic studies indicate that the simple Pd-
complex acts as the visible-light photocatalyst and radicals are
involved in the process.
Over the past decades, visible-light photoredox catalysis has
Table 1: Screening the reaction conditions.[a]
emerged as
a
useful tool to realize novel organic
transformations under mild conditions.[1] Beside organic dyes,[2]
Ru- and Ir-complexes, chemists have applied many other
transition metal complexes as photocatalysts in organic
synthesis (Scheme 1, A).[3,4] Although palladium catalysts have
been widely used in cross-coupling reactions[5] and limited
photophysical properties have been well studied,[6] the use of a
simple and commercially available palladium complex without
any exogenous photosensitizer in the visible-light photoredox
procedure has been less investigated.[7,8]
entry
variation from the standard conditions
yield (%)[b]
98 (90)
89
94 (87)
trace
N.D.
62
N.D.
N.D.
N.D.
1
2
3
4
5
6
7
8
9
None
PdCl2(PPh3)2 as catalyst
PdBr2(PPh3)2 as catalyst
Pd(OAc)2 as catalyst
Pd2(dba)3 as catalyst
Pd2(dba)3, 10 mol% PPh3
no light
no Pd(PPh3)4
110 oC, without light
[a] 1 (0.2 mmol), 2 (0.3 mmol), Pd(PPh3)4 (6 mol%), 2,4,6-collidine (0.4 mmol)
in N, N-dimethyl formamide (DMF) (2 mL) at room temperature (20 oC) for 24 h
under irradiation with 30 W blue LED. [b] GC yields. The isolated yield is given
in parentheses. LED = light-emitting diode. N.D. = Not detected.
With this hypothesis in mind, we started to investigate the
reaction of 2-phenyl-1,2,3,4-tetrahydroisoquinoline 1[13] and tert-
butylbromide 2, in which the catalytic formation of new
quaternary centers[14] would be achieved. After screening a lot of
parameters (Please see more details in SI), we were happy to
get the desired product 3 in 90% isolated yield with Pd(PPh3)4 as
catalyst in the absence of any extra photoinitiators (Table 1,
entry 1). Control experiments demonstrated that phosphorus
Scheme 1. Visible-light photocatalysis.
Pd-catalyzed direct transformations of C─H bonds are highly
useful and attractive methods in organic chemistry.[9] Although
significant progress has been achieved, Pd-catalyzed C─H
functionalization with unactivated alkyl halides, especially tertiary
ones, lags behind due to the challenges associated with
ligand,
Pd-catalyst
and
visible-light
irradiation
were
[a]
[b]
Prof. Dr. W.-J. Zhou, G.-M. Cao, G. Shen, X.-Y. Zhu, Dr. Y.-Y. Gui,
J.-H. Ye, L. Sun, L.-L. Liao, Dr. J. Li, Prof. Dr. D.-G. Yu
Key Laboratory of Green Chemistry & Technology of Ministry of
Education, College of Chemistry, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P. R. China)
E-mail: dgyu@scu.edu.cn
Prof. Dr. W.-J. Zhou,
College of Chemistry and Chemical Engineering, Neijiang Normal
University, Neijiang 641112 (P. R. China)
indispensable for the reaction (Table 1, entries 2-8. See more
details in Table S2 and Figure S14 in SI). Importantly, thermal
reaction without light delivered no product (Table 1, entry 9).
On the basis of these observations, we evaluated the
generality of this reaction with a range of unactivated tertiary
alkyl bromides (Table 2, A). A wide set of other sterically
hindered tert-alkyl bromides were conveniently converted into
the desired products in good to excellent yields, indicating the
high versatility of this catalytic system. Notably, these congested
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201704513
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COMMUNICATION
quaternary centers were generated efficiently with no detection
of isomerization products via this photoredox strategy. Moreover,
carbonyl-containing functional groups (9 and 16) survived the
reaction conditions without complications.
In addition to tertiary alkyl bromides, various unactivated
secondary and primary alkyl bromides were also examined
(Table 2, B and C). For example, the secondary alkyl bromides
(20-28), including cyclic and acyclic ones, all reacted smoothly.
Moreover, a variety of unactivated primary alkyl bromides also
worked well (29-42). Notably, LiBr was helpful to promote the
reactions of benzyl chlorides, indicating that benzyl bromides are
key players in this reaction (40-42). This reaction tolerated many
kinds of functional groups, including alcohol (33), ester (34 and
35), ether (36 and 37), chloro (38 and 42) and fluoro (41), which
may be beneficial for subsequent transformations.
[a] The standard reaction conditions (Table 1, entry 1). Isolated yields are
reported. [b] 48 h.
The catalytic system appears to be general with a variety of N-
aryl tetrahydroisoquinolines (Table 3). The benzene rings on the
nitrogen atom bearing fluoro, chloro, bromo, as well as methoxyl
at the ortho, meta, and para positions can successfully give the
corresponding alkylation products (43-54) in moderate to
excellent yields. The substituent on the benzene ring of
tetrahydroisoquinoline can be varied, as demonstrated by the
selective tert-butylation of 55 in 81% yield. However, alternative
benzyl amines show no reactivity in this transformation (Please
see more details in SI).
Table 2: Direct -alkylation of amines with alkyl halides.[a]
Considering the high importance of functionalization of
heteroarenes, we further applied this catalytic system toward the
intramolecular alkylation of indoles under mild reaction
conditions. With minor alterations of base and solvent, such
cyclization proceeded efficiently to generate the desired
products in good to excellent yields (Table 4). The electronic
nature of the substituents on the indole ring has little effect on
the transformation with slight preference for electron-
withdrawing groups at C-3 position (57-63). This method offers a
mild and safe alternative to indole functionalization avoiding the
use of organostannanes or ultraviolet light.[15]
Table 4: Indole functionalization via intramolecular cyclization.[a]
[a] N-alkylindole (0.2 mmol), Pd(PPh3)4 (10 mol%), Cs2CO3 (0.3 mmol) in THF
(2 mL) at room temperature (20 oC) for 24 h under irradiation with 30 W blue
LED. Isolated yields are reported. [b] Without light or without Pd(PPh3)4.
[a] The standard reaction conditions (Table 1, entry 1). Isolated yields are
reported. [b] 48 h. [c] LiBr (1.5 eq.) was added, 48 h.
Moreover, this photoredox protocol can also be applied to the
intermolecular C─H alkylation of heteroarenes (Table 5).
Benzoxazole (64), furan (65), thiophenes (66-68), and 2-methyl-
pyridine N-oxide (69) all can be alkylated well with 10, delivering
the desired products containing otherwise difficult to obtain
quaternary centers. In all of these cases, C2-selective alkylated
Table 3: Substrate scope of N-aryl tetrahydroisoquinolines.[a]
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10.1002/anie.201704513
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and rearomatization to give the alkylated heteroarene, as well as
regeneration of the Pd(0) catalyst. Further mechanistic studies
and applications of such Pd-complexes in visible-light
photocatalysis are underway in our laboratory.
products were obtained. Notably, electron-withdrawing functional
groups were important for the reactivity and regioselectivity.
Table 5: Coupling of 1-adamantyl bromide and heterocycles.[a]
[a] Heterocycles (0.4 mmol), 10 (0.2 mmol), Pd(PPh3)4 (10 mol%), Cs2CO3
(0.3 mmol) in THF (2 mL) at room temperature (20 oC) for 24 h under
irradiation with 30 W blue LED, unless otherwise noted. Isolated yields are
reported. [b] Without light or without Pd(PPh3)4. [c] 48 h.
To gain more insight into this alkylation reaction, mechanistic
studies were conducted with radical trapping experiments,
competing reactions and radical clock reactions (Scheme 2,
Please see SI for details), which all indicated that this reaction
proceeded through a radical-type mechanism.
Scheme 3. Possible mechanism.
In conclusion, we have developed a unique and general
visible-light-driven Pd-catalyzed process to realize the efficient
radical alkylation of C─H bonds with general alkyl halides under
mild reaction conditions. A variety of unactivated alkyl bromides,
including tertiary, secondary and primary ones, could undergo
such reactions to selectively generate C(sp3)─C(sp3) and
C(sp2)─C(sp3) bonds in moderate to excellent yields. These
redox-neutral reactions feature broad substrate scope (>60
examples), good functional group tolerance, as well as facile
construction of quaternary centers. Key for the success of this
photochemisty is the disclose of simple and commercially
available Pd(PPh3)4 as the sole catalyst.
Scheme 2. Selected mechanistic studies
In order to verify that the Pd(0) catalyst is the photoabsorbing
species, photophysical behaviors including absorption and
emission spectra were performed (Please see SI for more
details). As shown in Figure S5-S10 of SI, fluorescence
quenching experiments and Stern-Volmer studies indicate that
the alkyl bromide quenches the excited state of Pd(PPh3)4,
where it presumably engages in single electron transfer (SET)
with the excited Pd(0) complex.[7]
Based on the obtained results and previous reports,[11,12] we
propose the following mechanism with 1 and 2 as the substrates
(Scheme 3A). Under visible-light irradiation, the active Pd(0)-
complex undergoes SET with 2 to provide tert-butyl radical III
and Pd-complex II, which further reacts with 1 to afford a radical
cation IV and regenerate Pd(0)-complex.[16] The generated IV
undergoes deprotonation in the presence of base to give an α-
amino radical V, which undergoes radical-radical coupling with
III to afford the desired product 3[8c]. At this stage, we could not
exclude other pathways for this catalysis.
Acknowledgements
Financial support is provided by the National Natural Science
Foundation of China (21772129), the “973” Project from the
MOST of China (2015CB856600), the “1000-Youth Talents
Plan”, and the Fundamental Research Funds for the Central
Universities. We also thank Prof. Oliver Reiser, Prof. Aiwen Lei,
Prof. Li-Zhu Wu, Prof. Wen-Jing Xiao, Prof. Yi-Yun Chen, Prof.
Di Wu and Prof. Jason J. Chruma (Sichuan University) for
invaluable help.
Based on previous reports,[11,12] our mechanistic hypothesis
for the alkylation of heterocycles is shown in Scheme 3B. It
starts from the SET from the excited Pd0Ln* to the alkyl halide,
forming an alkyl radical and PdILnBr complex.[7] The carbon-
centered radical then adds to the heteroarene to generate an
cyclic alkyl radical intermediate, followed by SET, deprotonation
Keywords: visible-light photoredox • C─H transformation •
palladium catalysis • unactivated alkyl halides • radical
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Prof. Dr. W.-J. Zhou, G.-M. Cao, G.
Shen, X.-Y. Zhu, Dr. Y.-Y. Gui, J.-H. Ye,
L. Sun, L.-L. Liao, Dr. J. Li, Prof. Dr. D.-
G. Yu*
Page No. – Page No.
Visible-Light-Driven Pd-Catalyzed
Radical Alkylation of C─H Bonds
with General Unactivated Alkyl
Bromides
Pd, just do it! A novel visible-light photoredox system with Pd(PPh3)4 as the sole catalyst is disclosed
to realize the direct alkylation of C─H bonds with general unactivated alkyl bromides under mild
reaction conditions. These redox-neutral reactions feature high yields, broad substrate scope (>60
examples), facile generation of quaternary centers and good functional group tolerance.
This article is protected by copyright. All rights reserved.