Dual nickel- and photoredox-catalyzed reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides

Article abstract of DOI:10.1039/c9cc00768g

A novel reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides has been realized via photoredox/nickel dual catalysis to produce vinyl arene derivatives bearing all-carbon quaternary centers with excellent E-selectivity. A stoichiometric metal reductant could be avoided by employing commercially available N,N,N′,N′-tetramethylethylenediamine (TMEDA) as the terminal reductant.

Full text of DOI:10.1039/c9cc00768g

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DOI: 10.1039/C9CC00768G
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Dual Nickel- and Photoredox-Catalyzed Reductive Cross-coupling
of Aryl Vinyl Halides and Unactivated Tertiary Alkyl Bromides
Weijie Yu,a Long Chen,a Jiasi Tao,a Tao Wang,*a and Junkai Fu*b,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
novel reductive cross-coupling of aryl vinyl halides and bromides (Figure 1C). Considering the significance of
unactivated tertiary alkyl bromides has been realized via the constructing quaternary carbon centers in organic scaffolds,
photoredox/nickel dual catalysis to produce vinyl arene searching for a complementary and practical pathway to
derivatives bearing all-carbon quaternary centers with excellent E- realize the reductive cross-coupling of vinyl electrophiles with
selectivity. A stoichiometric metal reductant could be avoided by tertiary alkyl electrophiles is highly desirable.
employing
commercially
available
N,N,N',N'-
(A) Transition metal-catalyzed reductive alkenylation of 1° and 2° alkyl halides (ref. 5-9)
tetramethylethylenediamine (TMEDA) as the terminal reductant.
[Ni], [Pd], [Co]
X
R2
R2
Y
R1
X = Cl, Br, I, OAc, etc.
R1 = aryl (het), alkyl; R2 = 1° or 2° alkyl
(B) Reductive cross-coupling of gem-difluoroalkenes with tertiary alkyl electrophiles (ref. 10)
R1
Zn(0) or Mn(0)
The reductive cross-coupling of two organic electrophiles has
emerged as a powerful tool for the construction of C−C bond
in modern organic synthesis.1 When tertiary alkyl electrophiles
are employed, this protocol provides an efficient access to the
construction of quaternary carbon centers,2 which are
frequently encountered moieties in biologically active natural
products and pharmaceutical compounds.3 Although aryl
electrophiles have proven to be suitable partners to be
coupled with tertiary alkyl electrophiles by Gong and
MacMillan,4 the coupling of tertiary alkyl electrophiles with
vinyl electrophiles has been far less studied. Transition metal-
catalyzed reductive cross-coupling of vinyl electrophiles with
primary or secondary alkyl halides has been successively
achieved by Lipshutz5, Reisman6, Gong7, Wiex8 and Gosmini9
with the assistance of metal reductants (Figure 1A). Until very
recently, Fu’s group10a and Sun’s group10b independently
disclosed the reductive cross-coupling of gem-difluoroalkenes
with unactivated tertiary, secondary and primary alkyl halides
or N-hydroxyphthalimide (NHP) esters by using (Bpin)2/K3PO4
or Zinc as the final reductant (Figure 1B). Xiao and co-workers
developed a visible-light driven alkenylation of unactivated
alkyl bromides with vinyl phenyl sulfones or vinyl bromides, in
which (TMS)3SiH was utilized as the atom transfer reagent.4b,11
The reaction mainly focused on primary and secondary alkyl
bromides, and only three cases were provided for tertiary alkyl
Y = Cl, Br, I
F
R
conditions
Ar
Ar
R
Y
F
F
R = 1° , 2° or 3° alkyl
Fu's group:
Sun's group:
Zn, Y = NHP esters
Ni(cod)2, ligand, (Bpin)2/K3PO4, Y = Br, I;
(C) Photocatalysis driven reductive alkenylation of unactivated alkyl bromides (ref. 4b, 11)
R2
R2
[Ir], blue LEDs
(TMS)3SiH
R
Br
X
R
R1
R1
R = 1° , 2° alkyl
Ph
X = SO2Ph, without [Ni]
X = Br, with [Ni]
Ph
X = SO2Ph, 68%
Ph X = Br, 79%
R1, R2 = aryl, H, alkyl
Ph
X = SO2Ph, 51%
(this work)
Ar
(D) Photoredox and nickel-catalyzed alkenylation of tertiary alkyl halides
R1
R1
R3
Ir
Ni
Br
X
R2
R2
Ar
Blue LEDs
NHC, MgCl2, TMEDA
R3
unactivated tertiary
alkyl bromides
24 examples
up to 85% yield
X = Br, I
quaternary carbon centers
excellent E selectivity
metal reductant free



Figure 1. Reductive cross-coupling of the vinyl electrophiles.
In the last decade, visible-light-driven photoredox catalysis
has been utilized as a powerful technique in the carbon-carbon
and carbon-heteroatom bond formation.12 Recent advance has
demonstrated that the generation of alkyl carbon radical13
from non-activated primary, secondary or even tertiary alkyl
electrophiles could be achieved by the cooperative
photoredox catalysis and transition metal catalysts14,15 under
mild conditions via a single electron transfer (SET) process to
construct a variety of C(sp2)−C(sp3) and C(sp3)−C(sp3) bonds. In
this context, we envisaged that the visible-light photoredox
catalysis might be a potential solution to introduce a tertiary
alkyl radical16 for the reductive cross-coupling of aryl vinyl
electrophiles. This idea ultimately led to the discovery of a dual
a. National Research Center for Carbohydrate Synthesis and Key Laboratory of
Chemical Biology, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R.
China. wangtao@jxnu.edu.cn
b. Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024,
China. fujk109@nenu.edu.cn
c. Key Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055,
China
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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nickel- and photoredox-catalyzed reductive cross-coupling of react with 2d to afford the desired products 3bViaewndArt3iccle Ownilitnhe
aryl vinyl halides and unactivated tertiary alkyl bromides for excellent E-selectivities in good yields. Interestingly, when (Z)-
DOI: 10.1039/C9CC00768G
the synthesis of vinyl arene derivatives bearing all-carbon (2-bromoethenyl)benzene was employed as the partner, E-
quaternary centers (Figure 1D).
configured 3b was isolated in 70% yield as a single isomer. The
electron-donating group-substituted 2-aryl vinyl bromides
including mono-methoxyl (3a), di-alkoxy (3d) and tri-methoxyl
(3e) groups could all be well tolerated, and the hindered ortho-
methoxyl substituent on the phenyl ring had a slight effect on
the outcome to produce 3f in only 50% yield. This reaction was
also compatible with 2-aryl vinyl bromides bearing electron-
withdrawing groups (F−, Cl−, CF3− and CO2Me−) to deliver the
products 3g-3j. Additionally, vinyl bromides with diverse
functionalities, such as naphthalene and hetero-aromatic ring
were all suitable for this reaction, and coupled products 3k and
3l were obtained in 62% and 70% yields, respectively.
Unfortunately, tri- or tetra-substituted olefins, such as 2-
bromo-1,1-diphenylethylene and bromotriphenylethylene all
failed to give any desired products.
Table 1. Effects of Reaction Parametersa
Ni(TMHD)2 (10 mol%)
[Ir]
A1
(20 mol%)
(1 mol%),
Br
Br
Ar
N
N
I
Ar
TMEDA (3.0 equiv)
MgCl2 (1.0 equiv)
N,N-dimethylaniline
blue LEDs, r.t.
1a
Ar = 4-OMe-Ph
2a
3a
A1
entry
variation of standard conditions
yield/%b
E/Z c
1
2
3
4
5
6
7
8
9
none
Ir(ppy)3 instead of [Ir]
Ru(bpy)3Cl2·6H2O instead of [Ir]
Ni(cod)2 instead of Ni(TMHD)2
NiBr2 instead of Ni(TMHD)2
CH3CN instead of N,N-dimethylaniline
20W CFL lamp instead of blue LEDs
Et3N instead of TMEDA
no MgCl2
73
0
0
> 20:1
--
--
58
69
55
<5
0
17
40
0
8:1
> 20:1
> 20:1
--
Scheme 1. Substrate Scope of Aryl Vinyl Bromidesa, b
--
> 20:1
> 20:1
--
R2
R2
R1
Ni(TMHD)2 (10 mol%)
Br
10
11
12
13
14
no A1
no Ni(TMHD)2
no [Ir]
no light
no TMEDA
R1
[Ir]
A1
(20 mol%)
(1 mol%),
Br
R3
R3
R4
TMEDA (3.0 equiv)
MgCl2 (1.0 equiv)
N,N-dimethylaniline
blue LEDs, r.t.
R4
3
, E/Z > 20:1
0
0
0
--
--
--
1
2
a
Standard reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
Ni(TMHD)2 (10 mol%), Ir[(dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol%), (ppy = 2-
phenylpyridine, dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyridine), A1 (20
mol%), TMEDA (3.0 equiv), MgCl2 (1.0 equiv) in N,N-dimethylaniline
Ph
d
tBu
Ph
MeO
3a
c
3b
3c
, 66%
, 73% (65%)
, 73% (70%)
MeO
MeO
b
c
(3.0 mL) at r.t. under 20W blue LEDs for 24 h. Isolated yield. E/Z
O
O
ratios are determined by 1H NMR. TMEDA
tetramethylethylenediamine.
=
N,N,N',N'-
Ph
OMe
OMe
3d
3g
3e
3f
3i
, 67%
, 71%
, 85%
, 50%
The investigation was initiated by employing (E)-1-(2-
bromovinyl)-4-methoxybenzene 1a and 2-bromo-2-
methylpropane 2a as the model substrates. The combination
of Ni(TMHD)2, Ir[(dF(CF3)ppy)]2(dtbbpy)PF6 (identified as [Ir] in
above text), NHC A1 as additive,17 TMEDA and MgCl2 in N,N-
dimethylaniline at room temperature under 20W blue LEDs for
24 h led to the best result to give the desired product 3a in
73% yield as a single E isomer (Table 1, entry 1). When
photocatalysis was changed to Ir(ppy)3 or Ru(bpy)3Cl2·6H2O, 3a
was not detected (entries 2, 3), while replacement of
Ni(TMHD)2 with Ni(cod)2 or NiBr2 led to a slight decrease in the
yield (entries 4, 5). Other additives, including a series of
imidazole salts and nitrogen-containing ligands (see Table S1 in
SI) would result in dramatically decreased yields. Using CH3CN
as the solvent could provide 3a in 55% yield (entry 6, for more
details of solvent effect see Table S2 in SI). When blue LEDs
was replaced with CFL lamp, only trace amount of desired
product could be detected (entry 7). In addition, other amine,
such as triethylamine has shown to be ineffective as a
reductant in the current reaction system (entry 8). Without
F
Ph
Cl
Ph
Ph
F3C
Ph
3h
, 63%
, 60%
O
Ph
N
Ph
O
e
3k
3l
, 62%
, 70%
3j
, 70%
a Standard reaction conditions. b Isolated yields. c 1.0 mmol scale. d (Z)-
(2-bromoethenyl)benzene was used. CH3CN (3.0 mL) was used to
replace N,N-dimethylaniline as the solvent.
e
Next, various unactivated tertiary alkyl bromides were
subjected to the reductive cross-coupling with (E)-1-(2-
bromovinyl)-4-methoxybenzene 1a (Scheme 2). Both the
acyclic and cyclic tertiary alkyl bromides could suffer the
reaction conditions to give desired products 4a and 4b in 63%
and 71% yields, respectively. This reductive cross-coupling
reaction was operative with a variety of tertiary alkyl bromides
bearing different functional groups including phenyl ring (4c),
methyl ketone (4d), benzoate (4e) and phthalimide (4f) in a
highly stereoselective manner. It should be noted that when
the substrates containing both tertiary alkyl bromide and
primary or secondary alkyl bromide moieties, the reductive
cross-coupling could be chemoselectively carried out with the
tertiary alkyl bromide to give 4g and 4h, albeit in moderate
yields. The remaining halides allow further functional group
manipulation. Unfortunately, the frequently used 1-
bromoadamantane, which is considered as a less sterically
hindered tertiary alkyl halide failed in this reaction, and only
trace amount of desired product was detected by GC-MS (EI).
18
MgCl2 or A14a, the yield of 3a would drop to 17% and 40%,
respectively (entries 9, 10). Further control experiments
indicated that all of the photocatalysis, nickel catalyst, light
and organic amine reductant were crucial for this
transformation (entries 11-14).
With the optimized reaction conditions secured, we
explored the substrate scope with a variety of aryl vinyl
bromides 1 and tertiary alkyl bromide 2a or 2d. As shown in
Scheme 1, both the 2-phenyl vinyl bromide and 2-aryl vinyl
bromide bearing electrically neutral tert-butyl group could
2 | J. Name., 2012, 00, 1-3
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Moreover, the primary or secondary alkyl halides could also Scheme 4. Mechanistic Investigation
View Article Online
proceed smoothly to produce 4j and 4k, albeit in low yields.
DOI: 10.1039/C9CC00768G
standard
conditions
Br
(1)
Scheme 2. Substrate Scope of Tertiary Alkyl Bromidesa, b
Br
2.0 equiv
TEMPO or BHT
MeO
MeO
MeO
R2
(0%)
R2
Ni(TMHD)2 (10 mol%)
[Ir] A1
1a
1a
2a
2a
3a
(1 mol%),
(20 mol%)
Br
Br
R3
R4
R3
Ar
standard
conditions
Br
Br
TMEDA (3.0 equiv)
MgCl2 (1.0 equiv)
N,N-dimethylaniline
blue LEDs, r.t.
Ar
Ph
R4
(2)
(3)
3a
Ar = 4-OMe-Ph
Br
2.0 equiv
1,1-diphenylethylene
Ph
6a
1a
2
4
, E/Z> 20:1
trace
(58%)
tertiary alkyl bromides
standard
conditions
Ar
Ph
MeO
0%
Ar
Ar
Br
4a
4b
4c
, 68%
, 63%
, 71%
MeO
O
1a
MeO
6b
(15%)
O
O
Ar
N
Ar
Ar
O
Ph
Based on the experimental results and previous literature15,
a plausible mechanism involving a combined photoredox
catalytic cycle and nickel catalytic cycle is proposed for this
reductive cross-coupling. As shown in Figure 2, this reaction is
initiated by the oxidative addition of aryl vinyl bromide 1 or 5
with Ni(0). The formed Ni(II) species B could then combine
with a tertiary alkyl radical to afford the Ni(III) complex C.4b,19
Herein the tertiary alkyl radical was proposed to be generated
through a single electron transfer (SET) of the tertiary alkyl
bromide 2 with either low-valent Ni(0) (path a) or the
photoredox system (path b).20 Reductive elimination of the
O
c
c
4d
4g
, 67%
, 53%
4e
4f
4i
, 61%
, 56%
Ar
Br
Ar
Br
Ar
4h
, 64%
, trace
1
and 2 alkyl bromides


O
O
Ar
O
Ar
4k
d
4j
, 23%
, 17% (40%)
a Standard reaction conditions. b Isolated yields. c CH3CN (3.0 mL) was
used to replace N,N-dimethylaniline as the solvent. 4.0 equiv alkyl
bromides was used.
d
organonickel(III)
C
would forge the new C−C bond
simultaneously delivering the coupling product 3 or 4 along
with Ni(І) intermediate D. The Ni(І) D undergoes another SET
process with iridium redox catalysis [Ir(II) to Ir(III)] to
regenerate the Ni(0) species A and completes the nickel
catalytic cycle. Meanwhile, the Ir(III) photocatalysis could be
transformed to excited state Ir(ІІІ)* through the irradiation of
blue LEDs, and the photoredox catalytic cycle is completed by
the reduction of excited Ir(ІІІ)* to Ir(ІІ) species with TMEDA.
In addition, this protocol could be extended to aryl vinyl
iodides, a frequently engaged moieties in organic synthesis. As
shown in Scheme 3, several aryl vinyl iodides including these
with electron-withdrawing (F-) and -donating (MeO-) groups
on the phenyl ring and 2-naphthyl vinyl iodide were
successfully tested to afford the coupled products 3b, 3g, 3j
and 4c, despite resulting in relatively lower yields compared to
the corresponding aryl vinyl bromides.
TMEDA
Ni0Ln
Ir(II)
1
5
or
Scheme 3. Substrate Scope of Aryl Vinyl Iodidesa, b
A
Photoredox
Catalytic
Cycle
TMEDA
R1
R1
Ni(TMHD)2 (10 mol%)
[Ir] A1
Nickel
Catalytic
Cycle
Ir(III)*
I
(1 mol%),
(20 mol%)
Br
NiIILnX
SET
TMEDA (3.0 equiv)
MgCl2 (1.0 equiv)
N,N-dimethylaniline
blue LEDs, r.t.
Ar
Ph
Ph
Ir(III)
path a
B
5
2b
3
4
or , E/Z> 20:1
blue LEDs
NiILn
R
Br
2
R
D
R
F
MeO
R
R
Ar
NiIIILnX
3b
3g
3j
4c
, 55%
, 59%
, 60%
, 53%
path b
hv, Ir
3
4
Ar
or
TMEDA
C
a Standard reaction conditions. b Isolated yields.
R Br
2
To elucidate the reaction mechanism, we performed
preliminary mechanistic studies (Scheme 4). Addition of 2.0
equivalent of 2,2,6,6-tetramethylpiperidinooxy (TEMPO) or
butylated hydroxytoluene (BHT) into the reaction mixture
would totally suppress the desired reaction (eq. 1). When the
reaction was carried out in the presence of 1,1-
diphenylethylene, the Heck-type coupled compound 6a was
formed in 58% yield, and only trace amount of desired product
3a was obtained (eq. 2). What’s more, by using
(bromomethyl)cyclopropane as the coupling partner, diene 6b
was obtained, which was proposed to be generated through a
sequence of alkyl radical generation, ring-opening and cross-
coupling (eq. 3). All of these experiment results suggested that
this reaction involved a radical process.
Figure 2. Proposed reaction mechanism
In summary, we have developed a dual nickel- and
photoredox-catalyzed reductive cross-coupling of aryl vinyl
halides and unactivated tertiary alkyl bromides under very
mild reaction conditions. This protocol provides an efficient
method for the construction of vinyl arene derivatives bearing
all-carbon quaternary centers as single
E
isomers.
Commercially available TMEDA is successfully employed as the
final reductant which avoids the utilization of environmentally-
unfriendly metal reductant, such as Zn(0) or Mg(0). Control
experiments have shown the generation of tertiary alkyl
radical species in the reaction. Further applications and
mechanistic studies are in progress in our laboratory.
This journal is © The Royal Society of Chemistry 20xx
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Stephenson, Acc. Chem. Res., 2016, 49, 2295; (e) KV. ieLw. SAkrtuicblei,OTn.linRe.
We thank the financial support from the NSFC (21562026,
21762025, 21702027), the Natural Science Foundation of
Jiangxi Province (20161BAB203084) and Science Foundation of
Education Department of Jilin Province (JJKH20180013KJ).
Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035; (f) N. A.
DOI: 10.1039/C9CC00768G
Romero and D. A. Nicewicz, Chem. Rev., 2016, 116, 10075; (g) C.-S.
Wang, P. H. Dixneuf and J.-F. Soulé, Chem. Rev., 2018, 118, 7532;
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Zhou, Y.-Q. Zou, L.-Q. Lu and W.-J. Xiao, Angew. Chem., Int. Ed.,
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Q. Liu, X. W. Gao, H. H. Zhang, T. Lei, Z. J. Li, K. Feng, B. Chen, C. H.
Tung and L. Z. Wu, J. Am. Chem. Soc., 2013, 135, 19052. (k) J. Liu,
Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A. Lei, Angew. Chem.,
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Conflicts of interest
The authors declare no competing financial interest.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC00768G
Table of Contents Entry
Dual Nickel- and Photoredox-Catalyzed Reductive Cross-coupling of
Aryl Vinyl Halides and Unactivated Tertiary Alkyl Bromides
Weijie Yu,a Long Chen,a Jiasi Tao,a Tao Wang,*a and Junkai Fu*b,c
aNational Research Center for Carbohydrate Synthesis and Key Laboratory of Chemical Biology,
Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China.
bJilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024, China.
cKey Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking
University Shenzhen Graduate School, Shenzhen 518055, China.
R1
R3
R1
R3
Ir
Ni
Br
X
R2
R2
Ar
Ar
Blue LEDs
NHC, MgCl2, TMEDA
unactived tertiary
alkyl bromides
X = Br, I
up to 85% yield
quaternary carbon centers
excellent E selectivity
metal reductant free



A reductive cross-coupling via photoredox/nickel dual catalysis produces vinyl
arene derivatives bearing all-carbon quaternary centers with excellent E-selectivity.