Cross-Coupling Reactions of Alkenyl Halides with 4-Benzyl-1,4- Dihydropyridines Associated with E to Z Isomerization under Nickel and Photoredox Catalysis

Article abstract of DOI:10.1002/asia.201801542

Cross-coupling reactions of alkenyl halides with 4-alkyl-1,4-dihydropyridines as alkylation reagents have been achieved by combination of nickel and photoredox catalysts. Alkenyl halides bearing alkyl and aryl substituents are available. Particularly, in

Full text of DOI:10.1002/asia.201801542

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Cross-Coupling Reactions of Alkenyl Halides with 4-Benzyl-1,4-
Dihydropyridines Associated with E to Z Isomerization under
Nickel- and Photoredox-Catalysis
Authors: Kazunari Nakajima, Xifeng Guo, and Yoshiaki Nishibayashi
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To be cited as: Chem. Asian J. 10.1002/asia.201801542
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Chemistry - An Asian Journal
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Cross-Coupling
Cross-Coupling Reactions of Alkenyl Halides with 4-Benzyl-1,4-
Dihydropyridines Associated with E to Z Isomerization under Nickel-
and Photoredox-Catalysis**
Kazunari Nakajima,* Xifeng Guo, and Yoshiaki Nishibayashi*
Abstract: Cross-coupling reactions of alkenyl halides with 4-alkyl-
1,4-dihydropyridines as alkylation reagents have been achieved by
combination of nickel and photoredox catalysts. Alkenyl halides
bearing alkyl and aryl substituents are available. Particularly, in
the use of aryl-substituted alkenyl halides, cross-coupling reactions
are associated with E to Z isomerization of alkenes. Thus, Z-isomers
of the products are obtained as major products. The present strategy
provides a novel synthetic method to control the stereochemistry
around alkenes.
Recently, our group and others have reported the synthetic
utilization of dihydropyridine skeletons as formal nucleophilic
alkylation
reagents
in
photoredox-catalyzed
molecular
transformations.[7-9] We have succeeded in the nickel- and
photoredox-catalyzed cross-coupling reactions of aryl halides with
4-alkyl-1,4-dihydropyridines.[7b,8d,8g,8j] In the course of our study to
expand the utility of dihydropyridines, herein, we have developed
cross-coupling reactions of alkenyl halides with 4-alkyl-1,4-
dihydropyridines, where not only alkyl-substituted alkenyl halides
but also aryl-substituted alkenyl halides were applicable (Scheme
1b). Furthermore, in reactions of aryl-substituted alkenyl halides, the
corresponding Z-isomers were obtained as major products, and the
preferential formation of the Z-isomer is independent from the
stereochemistry of the starting alkenyl halides. In this paper, the
experimental results on this reaction system are described.
A
lkene is a fundamental molecular skeleton found in various
natural products, pharmaceuticals and other useful molecules.[1] In
the synthesis of alkenyl compounds, controlling the formation of E-
and Z-isomers is generally unavoidable concern. Among the vast
range of methods to synthesize alkenyl compounds, transition metal-
catalyzed cross-coupling reactions of alkenyl halides with
nucleophilic reagents have been one of the most powerful strategies
in the last decades.[2] In this strategy, control of the stereochemistry
around alkenes is premised of retention of the starting E- or Z-
isomer, that is, the stereochemistry around the alkenes is usually
retained throughout the transformation.[2,3]
(a) Previous work
R2
CO2H
R1
Ni-/photoredox-
R1
catalysts
or
+
X
R2
–
visible light
R2
Si(OR)4
R1 = alkyl or aryl
(E)-isomer
(E)-isomer
Besides the classical cross-coupling reactions under thermal
conditions, recently, combination of a nickel catalyst and a
photoredox catalyst has emerged as a new method to achieve cross-
coupling reactions, where generation of alkyl radicals via single
electron transfer is a key step.[4] Actually, reactions of alkenyl
halides with alkylation reagents such as aliphatic carboxylic acids
and alkyl silicates have been reported to date (Scheme 1a).[5] In
previously reported nickel- and photoredox-catalyzed cross-
coupling reactions of alkenyl halides,[5,6] limited attention has been
paid to the use of aryl-substituted alkenyl halides.
R1
(b) This work
R1
R2
R2
Ni-/photoredox-
catalysts
R1 = alkyl: (E)-isomer
E
E
+
X
visible light
R1
R2
R1 = alkyl or aryl
N
H
(E)-isomer
R1 = aryl: (Z)-isomer
Scheme 1. Cross-coupling reactions of alkenyl halides with alkylation reagents.
[*]
Prof. Dr. K. Nakajima
Frontier Research Center for Energy and Resources, School of
Engineering, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8656
(Japan)
At the onset of this research, we carried out reactions of (E)-1-
iodooct-1-ene (E-1a) with 4-benzyl-3,5-bis(ethoxycarbonyl)-2,6-
dimethyl-1,4-dihydropyridine (2a) to investigate detailed reaction
conditions (Table 1).[10] In the presence of fac-Ir(ppy)3 (1 mol%),
anhydrous NiCl2 (10 mol%), 4,4'-di-tert-butyl-2,2'-bipyridyl
(dtbbpy; 15 mol%), and sodium acetate (1.5 equiv), the reaction of
1a (1 equiv) with 2a (3 equiv) was carried out in various solvents
under visible light illumination. When the reaction was performed in
N,N-dimethylimidazolidinone (DMI) as solvent, which was the best
solvent in our previous reaction system,[7b] the desired (E)-1-
phenylnon-2-ene (3a) was obtained in 61% yield without formation
of the corresponding Z-isomer (Table 1, Entry 1). After
investigation of other solvents such as dimethylsulfoxide (DMSO),
acetonitrile, tetrahydrofuran (THF), and toluene, we found that THF
E-mail: nakajima@sys.t.u-tokyo.ac.jp,
X. Guo, Prof. Dr. Y. Nishibayashi
Department of Systems Innovation, School of Engineering, The
University of Tokyo, Bunkyo-ku, Tokyo, 113-8656 (Japan)
E-mail: ynishiba@sys.t.u-tokyo.ac.jp.
[**] The present project is supported by CREST, JST (JPMJCR1541).
We thank JSPS KAKENHI Grant Numbers 16K05767, 16KT0160,
15H05798, 17H01201, and 18K19093 from the JSPS and the
MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.((Please delete if not
appropriate))
1
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10.1002/asia.201801542
Chemistry - An Asian Journal
heteroatom-substituted alkyl group afforded the products in
moderate yields (3k-l).
Reactions of a variety of alkyl-substituted alkenyl iodides with
4-(4-methoxybenzyl)-3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-
dihydropyridine (2b) were also examined. Alkenyl iodides with
acyclic and cyclic alkyl groups were successfully converted into the
corresponding products (3m-q). The reaction of (Z)-4-iodooct-4-ene
(Z-1g) with 2b afforded the tri-substituted alkene derivative (3r) in
30% yield.
was the best solvent (Table 1, Entries 2-5). Changing NiCl2 to
Ni(acac)2 (acac = acetylacetonato) gave the product in only a lower
yield (Table 1, Entry 6). Reducing the amount of 2a to 2 equiv was
successful to obtain 3a in a comparable yield, but further reduction
to 1.5 equiv. gave 3a in a lower yield (Table 1, Entries 4, 7, and 8).
We confirmed that photoredox catalyst such as nickel catalyst and
visible light are inevitable to this reaction system (Table 1, Entries
9-11). Both dtbbpy as a ligand and sodium acetate as a base were
also necessary to obtain the product in high yields (Table 1, Entries
12 and 13). It is noteworthy that the aromatized pyridine derivative
2a' was observed in 92% yield under the optimized conditions
(Table 1, Entry 7).
Table 2. Reactions of alkyl-substituted alkenyl iodides (1) with 4-alkyl-1,4-
dihydropyridines (2).[a]
fac-Ir(ppy)3 (1mol%)
NiCl2 (10 mol%)
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
R
E
E
Alkyl
Alkyl
+
N
H
Table 1. Reactions of (E)-1-iodooct-1-ene (1a) with 4-benzyl-3,5-
bis(ethoxycarbonly)-2,6-dimethyl-1,4-dihydropyridine (2a).[a]
THF
25 °C, 18 h
visible light
I
R
E-1
3
2 (E = CO2Et)
2 equiv
isolated yield
fac-Ir(ppy)3 (1mol%)
NiX2 (10 mol%)
nHex
nHex
nHex
Me
Ph
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
E
E
nHex
nHex
OMe
Me
+
3b: 82%
3c: 80%
3d: 80%
3g: 90%
solvent
25 °C, 18 h
visible light
I
Ph
N
E-1a
3a
H
nHex
Me
nHex
nHex
tBu
2a (E = CO2Et)
Ph
Entry
2a (equiv)
NiX2
solvent
yield (%)[b]
3e: 50%
3h: 70%
3f: 64%
3i: 63%
1
3
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
Ni(acac)2
NiCl2
NiCl2
NiCl2
NiCl2
–
DMI
61
22
3
2
3
DMSO
MeCN
THF
nHex
nHex
nHex
3
3
F
Cl
4
3
90
16
60
87
77
trace
0
3j: 74%
5
3
toluene
THF
6
3
nHex
nC5H11
nHex
7
2
THF
Ph
OMe
OMe
NBn2
8
1.5
2
THF
Cl
3k: 32%[b,c]
3l: 30%
3m: 53%
3p: 75%
9[c]
10[d]
11
12[e]
13[f]
THF
nC8H17
Ph
2
THF
2
THF
trace
6
OMe
OMe
2
NiCl2
NiCl2
THF
3n: 86%
3o: 81%
2
THF
24
Cy
nPr
OMe nPr
OMe
N
Ir
EtO2C
CO2Et
3q: 64%
3r:[d] 30% (Z/E = 92/8)
N
N
N
[a] All reactions of 1 (0.25 mmol) with 2 (0.50 mmol) were carried out in the
presence of fac-Ir(ppy)3 (0.0025 mmol), anhydrous NiCl2 (0.025 mmol), dtbbpy
(0.038 mmol) and NaOAc (0.38 mmol) in THF (2.5 mL) with 14 W white LED
illumination at 25 °C for 18 h. [b] For 72 h. [c] NMR yield. [d] From (Z)-4-iodooct-
4-ene (Z-1g).
2a’
fac-Ir(ppy)3
[a] Reactions of 1a (0.25 mmol) with 2a (0.75 or 0.50 mmol) were carried out in
the presence of fac-Ir(ppy)3 (0.0025 mmol), NiX2 (0.025 mmol), dtbbpy (0.038
mmol), and NaOAc (0.38 mmol) in solvent (2.5 mL) with 14 W white LED
illumination at 25 °C for 18 h. [b] Isolated yield. [c] In the absence of fac-Ir(ppy)3.
[d] No light. [e] In the absence of dtbbpy. [f] In the absence of NaOAc.
In previously reported nickel- and photoredox-catalyzed cross-
coupling reactions of alkenyl halides,[5,6] limited attention has been
paid to the use of aryl-substituted alkenyl halides. Contrary to these
reports, we found the present reaction system is applicable toward
the transformation of alkenyl iodides bearing aromatic substituents.
Furthermore, in this case, Z-alkenes were obtained as major
products (Table 3). The reaction of (E)-β-iodostyrene (E-4a) with 2b
was carried out under the typical reaction conditions. The
corresponding alkylated product (5a) was obtained in 89% yield as a
mixture of Z- and E-isomers with the ratio of Z/E = 72/28. Despite
the use of E-alkene as the starting material, the Z-alkene was
obtained as a major isomer after the reaction.
With the optimized reaction conditions in hand, we investigated
reactions of alkenyl iodides bearing alkyl substituents with
dihydropyridines (Table 2). As for the dihydropyridines,
transformations with benzylic type alkyl groups bearing a variety of
substituents were successful to give the corresponding products (3b-
3j). Introduction of a methyl group into the para-, meta-, and ortho-
positions of the benzene ring was also successful (3c-e). The
transformations with a secondary alkyl-type benzylic group and a
2
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10.1002/asia.201801542
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reaction conditions (Scheme 3). In both reactions, the corresponding
Z-isomers were obtained as major products. It is noteworthy that the
yields of the cross-coupling products were lower than those in the
corresponding reactions of the E-isomers. This is presumably due to
steric hindrance around the reaction center.
Reactions of other alkenyl iodides with 2b afforded the
corresponding products in good yields with similar Z/E ratios (5b-e).
Various dihydropyridines bearing a benzylic-type alkyl group were
successfully transformed to give the Z-isomers selectively (5f-i).
fac-Ir(ppy)3 (1mol%)
Ph
Ph
I
THF
25 °C, 18 h
visible light
Table 3. Reactions of alkenyl iodides bearing aromatic substituents with 4-alkyl-
1,4-dihydropyridines (2).[a]
I
4a
95% yield
Z/E = 89/11
E-4a
fac-Ir(ppy)3 (1mol%)
NiCl2 (10 mol%)
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
R
Ph
E
E
fac-Ir(ppy)3 (1mol%)
Aryl
Aryl
R
Ph
OMe
OMe
+
THF
25 °C, 18 h
visible light
N
THF
25 °C, 18 h
visible light
I
5
H
2 (E = CO2Et)
2 equiv
5a
E-4
isolated yield
Z/E ratio
E-5a
94% yield
Z/E = 86/14
Me
MeO
Scheme 2. Photoredox-catalyzed E to Z isomerization of E-4a and E-5a.
OMe
Ph
OMe
OMe
OMe
5a: 89%
Z/E = 72/28
5b: 62%
Z/E = 82/18
5c: 84%
Z/E = 79/21
fac-Ir(ppy)3 (1mol%)
NiCl2 (10 mol%)
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
E
E
Me
Cl
nHex
I
nHex
OMe
+
N
H
THF
25 °C, 18 h
visible light
OMe
OMe Ph
Ph
Z-1a
3b
40% yield
Z/E = 79/21
2b
2 equiv
5d: 51%
Z/E = 75/25
5e: 71%
Z/E = 82/18
5f: 66%
Z/E = 83/17
OMe
Me
fac-Ir(ppy)3 (1mol%)
NiCl2 (10 mol%)
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
Ph
Me
Ph
Ph
Ph
E
E
Ph
I
+
Ph
OMe
5g: 52%
Z/E = 82/18
5h: 55%
Z/E = 79/21
5i: 80%
Z/E = 82/18
N
H
THF
25 °C, 18 h
visible light
5a
67% yield
Z/E = 89/11
Z-4a
2b
2 equiv
[a] All reactions of 4 (0.25 mmol) with 2 (0.50 mmol) were carried out in the
presence of fac-Ir(ppy)3 (0.0025 mmol), anhydrous NiCl2 (0.025 mmol), dtbbpy
(0.038 mmol) and NaOAc (0.38 mmol) in THF (2.5 mL) with 14 W white LED
illumination at 25 °C for 18 h.
Scheme 3. Reactions of Z-alkenyl iodides (Z-1a and Z-4a) with 1b.
To reveal the difference in reactivity of E- and Z-alkenyl iodides
toward the cross-coupling process, we determined quantum yields of
cross-coupling reactions of E- and Z-1a with 2b under the typical
reaction conditions. The quantum yields were determined to be Φ =
0.12 for E-1a and Φ = 0.05 for Z-1a. These results clearly indicate
that the cross-coupling reaction of the E-alkenyl iodide is more rapid
than that of the Z-alkenyl iodide.
These observations allow us to assume the following points: (1)
the E/Z isomerization of the alkenyl iodide is the fastest process in
the reaction system; (2) the cross-coupling process from the E-
alkenyl iodide is faster than that from the Z-alkenyl iodide; (3) the
E/Z isomerization of the cross-coupling product proceeds.
To confirm these assumptions, we monitored the time profile of
the reaction of E-4a with 2b to give Z- and E-5a (Figure 1). At early
stage of the reaction, the rapid E- to Z-isomerization of the alkenyl
iodide was observed. Although the E/Z isomerization process is
considered to occur reversibly,[11] apparent concentration of Z-
alkenyl iodide got higher in a short period. Then, after some
induction period probably due to generation of active nickel species,
formation of the cross-coupling products started. Initially the Z/E
ratio of the cross-coupling product was nearly 1:1, but later the ratio
of Z-isomer increased gradually.
Previously, several groups reported photoredox-catalyzed E to Z
isomerization of alkenes.[11] Weaver et al. reported fac-Ir(ppy)3-
catalyzed E to Z isomerization of styrene derivatives under visible
light irradiation, where the observed Z/E ratios were similar to our
present reaction system.[11b] According to these reports, the present
cross-coupling reaction system is assumed to be associated with the
E to Z isomerization process mediated by energy transfer from the
excited Ir complex.
To obtain information on the isomerization process, we
investigated photoredox-catalyzed isomerization reactions of E-
alkenyl iodide E-4a and the cross-coupling product E-5a. As a result,
we found that the isomerization was promoted only by photoredox
catalyst fac-Ir(ppy)3 and visible light irradiation. After treatment of
E-4a and E-5a in the presence of fac-Ir(ppy)3 under visible light
irradiation, the Z-isomers of 4a and 5a were obtained as major
isomers (Scheme 2). In the absence of fac-Ir(ppy)3, small amounts
of the Z-isomers were observed (>99% yield, Z/E = 11/89 for 4a;
>99% yield, Z/E = 1/>99 for 5a). In addition, the quantum yields of
the E to Z isomerization of E-4a and E-5a were determined to be Φ
= 0.22 and 0.09, respectively, indicating the E/Z isomerization of the
alkenyl iodide is faster than that of the cross-coupling product.
Next, we investigated reactions of Z-isomers of the alkyl and
aryl-substituted alkenyl iodides (Z-1a and Z-4a) under the typical
3
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10.1002/asia.201801542
Chemistry - An Asian Journal
•R2 alkyl radical
visible light
[Ir]
R1 = Ar
LNi0
visible light
*[Ir]
LNiI
R2
OMe
R1
[Ir]
R1
I
A
B
fac-Ir(ppy)3 (1mol%)
NiCl2 (10 mol%)
dtbbpy (15 mol%)
NaOAc (1.5 equiv)
I
E
E
R2
Ph
I
R2
+
[Ir]–
LNiIII
Ph
OMe
LNiI
I
N
H
I
THF
25 °C, 18 h
visible light
E
E
D
E-4a
0.25 mmol
2b
2 equiv
Z- and E-5a
C
R1
N
H
•R2 alkyl radical
+
0.25
visible light
[Ir]
R1
Ph
E
E
R1
R2
0.20
0.15
0.10
0.05
+
Ph
OMe
OMe
R2
I
R1 = Ar
N
E-4a
H
Z-5a
Ph
Z-4a
I
Scheme 4. Plausible reaction pathway.
Ph
E-5a
In summary, we have succeeded in the development of nickel-
and photoredox-catalyzed cross-coupling reactions of alkenyl
halides with dihydropyridines. The stereochemistry around the
alkene was retained when alkyl-substituted alkenyl iodides were
used. On the other hand, the use of aryl-substituted alkenyl iodides
afforded the corresponding Z-products as major isomers. In these
reactions, the Z-selective product formation has been achieved from
the corresponding E-isomers of starting substrates. In general, Z-
alkenes are thermodynamically less stable than the corresponding E-
alkenes, and preparative methods of Z-alkenes have been relatively
limited. The present reaction system provides a new method to
synthesize Z-alkenyl compounds. We believe that the present
findings lead to a new strategy to control the stereochemistry around
alkenes.
0.00
0
2
4
6
8
10
12
14
16
18
reaction time / h
Figure 1. Time profile of reaction of E-1a with 2b to give Z- and E-5a.
We consider that the present cross-coupling reaction proceeds
via a similar pathway to our previous work,[7b] which was similar to
the reaction pathway originally proposed by Molander and
Kozlowski et al. in the nickel- and photoredox-catalyzed Suzuki-
Miyaura-type cross-coupling reactions (Scheme 4).[12] In the
photoredox cycle, excitation of a iridium catalyst ([Ir]) generates the
excited state ([Ir]*). Then, a single electron transfer occurs to afford
Received: ((will be filled in by the editorial staff))
the reduced iridium catalyst ([Ir]–) and
a radical cationic
Published online on ((will be filled in by the editorial staff))
dihydropyridine, which is further converted to an alkyl radical and
an aromatized pyridine derivative via C–C bond cleavage.[7a] In the
nickel cycle, an in situ-generated nickel(0) species (A) captures the
alkyl radical to form a nickel(I)-alkyl complex (B). Then, oxidative
addition with alkenyl iodides and reductive elimination occur to
give the corresponding coupling product along with the nickel(I)-
halide complex (D). Finally, the two catalytic cycles are completed
by a single electron transfer between [Ir]– and D.
The cross-coupling process is assumed to proceed by a stereo-
retentive manner, but in reactions of aryl-substituted alkenyl halides,
E to Z isomerization via energy transfer process[11] is also included
by the dual role of the photoredox catalyst. As discussed above, both
the starting alkenyl iodides and the cross-coupling products undergo
the E/Z isomerization. However, cross-coupling reactions of E-
alkenyl iodides are more rapid than those of Z-alkenyl iodides.
Keywords: dihydropyridine • nickel catalyst • photoredox catalyst •
cross-coupling reaction
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10.1002/asia.201801542
Chemistry - An Asian Journal
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5
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10.1002/asia.201801542
Chemistry - An Asian Journal
Entry for the Table of Contents
Layout 2:
Cross-Coupling
C
✂
CO2Et
Kazunari Nakajima,* Xifeng Guo, and
Yoshiaki Nishibayashi*__________
Page – Page
photoredox catalyst
visible light
EtO2C
Ar
Ar
C
+
N
H
Nickel catalyst
I
Cross-Coupling Reactions of Alkenyl
Halides with 4-Benzyl-1,4-
Dihydropyridines Associated with E to Z
Isomerization under Nickel- and
Photoredox-Catalysis
Photoredox catalyst serves dual roles. In the nickel- and photoredox-catalyzed
cross-coupling reactions of alkenyl halides with dihydropyridines, the E to Z
isomerization proceeds. The photoredox catalyst works not only to generate alkyl
radicals but also to achieve isomerization.
6
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