Photocatalytic Isomerization of Styrenyl Halides: Stereodivergent Synthesis of Functionalized Alkenes

Article abstract of DOI:10.1002/ejoc.201901119

An efficient and general method for the isomerization of styrenyl halides under different photocatalytic conditions (fac-Ir(ppy)₃ in methanol for E to Z isomerization and fluorescein in 1,4-dioxane for Z to E isomerization, respectively) is disclosed. A series of stereospecific transformations constitute preliminary validation of this strategy in the synthesis of functionalized alkenes, including two diaryl alkenes, a styrenyl boronic ester and an enyne. The photocatalytic isomerization and subsequent cross coupling reaction can be run in a one-pot manner. The stereodivergent synthesis of all four isomers of a conjugated diene, as well as the antitumor agent DMU-212 and its (Z)-isomer highlights the synthetic applicability of this method.

Full text of DOI:10.1002/ejoc.201901119

DOI: 10.1002/ejoc.201901119
Communication
Stereodivergent Synthesis | Very Important Paper |
Photocatalytic Isomerization of Styrenyl Halides:
Stereodivergent Synthesis of Functionalized Alkenes
Hao Zhang,[a,b] Qing Xu,*[a] Lei Yu,*[a] and Shouyun Yu*[b]
Abstract: An efficient and general method for the isomeriza- onic ester and an enyne. The photocatalytic isomerization and
tion of styrenyl halides under different photocatalytic condi- subsequent cross coupling reaction can be run in a one-pot
tions (fac-Ir(ppy)3 in methanol for E to Z isomerization and fluo- manner. The stereodivergent synthesis of all four isomers of a
rescein in 1,4-dioxane for Z to E isomerization, respectively) is conjugated diene, as well as the antitumor agent DMU-212 and
disclosed. A series of stereospecific transformations constitute its (Z)-isomer highlights the synthetic applicability of this
preliminary validation of this strategy in the synthesis of func- method.
tionalized alkenes, including two diaryl alkenes, a styrenyl bor-
Introduction
Functionalized alkenes are frequently encountered in natural
compounds, pharmaceuticals[1] and optical materials.[2] They
are also valuable units in chemical synthesis.[3] Since the config-
uration of C=C double bonds affects physical, chemical, biologi-
cal and physiological properties of alkenes significantly, synthe-
sis of the stereochemistry-defined functionalized alkenes is
quite important and highly demanded. One of the most effi-
cient and reliable method for synthesis of functionalized alk-
enes is transition metal-catalyzed cross couplings of vinyl hal-
ides with organometallics (Scheme 1a).[4] Given that these cross
couplings are stereochemistry conservative, stereoselective syn-
thesis of vinyl halides is crucial to preparation of the functional-
ized alkenes. Hence, the development of a controllable and
facile method for synthesizing stereo-defined vinyl halides is of
great value.
The control of the geometry of alkenes is often a challenging
problem in organic synthesis.[5] In particular, there is a paucity
of routes to the thermodynamically less stable Z-alkenes.[6] To
date, E-styrenyl haildes can be stereoselectively obtained by
Hunsdiecker reaction of cinnamic acid derivatives,[7] halogen-
ation of alkynes[8] or dehalogenation of 1,1-dihaloalkenes[9]
while the common ways to access Z-styrenyl haildes have been
largely restricted to Wittig reaction.[10] Despite these significant
[a] School of Chemistry and Chemical Engineering, Yangzhou University,
Yangzhou, Jiangsu 225002, China
E-mail: xuqing@yzu.edu.cn
yulei@yzu.edu.cn
[b] State Key Laboratory of Analytical Chemistry for Life Science,
Scheme 1. Photocatalytic isomerization of functionalized alkenes.
Jiangsu Key Laboratory of Advanced Organic Materials,
School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210023, China
advances, there is a lack of a general strategy for the synthesis
E-mail: yushouyun@nju.edu.cn
of both E and Z-isomers.
http://hysz.nju.edu.cn/yusy/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901119.
With the renaissance of photocatalysis in recent years, a fea-
sible idea for visible-light-mediated selective isomerization of
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alkenes has been provided.[11] Although the rotation of the employed, (Z)-1a was also isolated as the major isomer in 93:7
C=C double bond is usually hindered by the high rotational Z/E ratio (entry 3). Several other solvents, such as Ethanol and
energy barrier in the ground state reaction, photochemical exci- Acetonitrile, were also tested, but none of them gave better
tation at an appropriate wavelength can alleviate this con- results (entries 5 and 6). Interestingly, when organic dyes eosin
straint.[12] As early as the 1950s, Wyman, Hammond and others Y and fluorescein were used as the photosensitizers, Z to E
demonstrated that direct irradiation or sensitized excitation via isomerization was observed and (E)-1a was isolated as the ma-
energy transfer can result in photoisomerization of symmetrical jor product (entries 7 and 8). 1,4-dioxane proved to be optimal
alkenes,[13] which provided a very powerful guiding principle solvent for Z to E isomerization (Z/E = 7:93, entry 9). Thus, both
for the realization of geometric isomerization of alkenes. Re- direction Z/E isomerization was achieved under different photo-
cently, this concept has been applied to more substrate scopes catalytic conditions (fac-Ir(ppy)3 in Methanol for E to Z isomeri-
and reactions, even under visible light irradiation.[14] Weaver zation and fluorescein in 1,4-dioxane for Z to E isomerization,
and co-workers reported a remarkable E to Z photoisomeriza- respectively).
tion of cinnamyl derived amines with fac-Ir(ppy)3 as the triplet
Table 1. Optimization of the isomerization.[a]
sensitizer (Scheme 1b).[15] This mild energy transfer activation
mode enables the thermodynamically unstable Z-isomer to be
generated under kinetic control. Subsequently, Gilmour and co-
workers disclosed the bio-inspired photoisomerization of di-
verse activated alkenes using the flavin derivative (–)-riboflavin
as an energy transfer catalyst (Scheme 1b).[16] More recently,
the same group has demonstrated that styrenyl boron species
could also undergo this contra-thermodynamic isomerization
process.[17] Good functional-group tolerance and application in
contemporary cross-coupling technologies emphasize the syn-
thetic utility of this strategy.
Inspired by these works, and deeply recognized the general
lack of efficient methods for the formation of polysubstituted
Z-configuration styrenyl halides, we have attempted to provide
a strategy for the synthesis of both E- and Z-styrenyl halides
with high stereoselectivity from an E/Z mixture through visible
light-induced isomerization (Scheme 1c). As indicated by Gil-
mour and co-workers,[16,17] in general, the alkenes with a conju-
gated π system can be activated effectively by the excited state
of a photosensitizer via an energy-transfer mechanism.[18] The
formed diradical intermediate can lead to the re-generation of
both the E and Z-isomers through C–C bond rotation. In gen-
eral, the energy gap between the ground state and the excited
state of acyclic styrenoids is the main influencing factor for its
photostationary state. Specifically, this gap is more pronounced
in Z-alkenes due to the allylic strain disrupting conjugation.
Thus, the re-excitation of Z-configured product is inefficient and
only the E-styrenyl halides can be excited. This intrinsic direc-
tionality is in favor of the contra-thermodynamic isomerization,
resulting in gradual accumulation of the Z-styrenyl halides.
[a] Reactions were performed in specified degassed solvents (2.0 mL) on
0.1 mmol scale at ambient temperature under 90 W blue LEDs irradiation in
the presence of 2 mol-% photocatalyst. The Z/E ratio of (Z/E)-1a is 44:56. [b]
The Z/E ratio was determined by 1H NMR spectroscopy. [c] Yield determined
by 1H NMR using dibromomethane as the internal standard. [d] Isolated yield
based on (Z/E)-1a after column chromatography. [e] 100 % of (E)-1a was
used. [f] No light. [g] 100 % of (Z)-1a was used.
Having established a set of general reaction conditions to
achieve the efficient isomerization of styrenyl haildes, the scope
Results and Discussion
A Z/E mixture of 1-(2-bromovinyl)-4-methoxybenzene (Z/E)-1a and limitations of this isomerization were then established. E to
as a model substrate to investigate the optimal reaction condi- Z isomerization was first investigated (Scheme 2). Electronic of
tions of geometric isomerization (for detailed optimization of the aryl ring was found to have a negligible effect on E to Z
isomerization conditions, see the Supporting Information). isomerization. Moreover, the meta-substituent did not hinder
When Methanol was chosen as the solvent, several photocata- the reaction, yielding the isomerization product ((Z)-1d, (Z)-1m
lysts were preferentially explored under 90 W blue LEDs irradia- and (Z)-1r) in good yield. (Z)-1a–1e could be isolated (86:14 to
tion (Table 1). The triplet sensitizer fac-Ir(ppy)3 has been proved 93:7 Z/E ratios) from the corresponding E/Z mixtures. The
to be effective for the geometric isomerization of (E)-1a to the α-substituent (R2) of styrenyl bromides had a positive effect on
contra-thermodynamic product (Z)-1a (Z/E = 93:7) in nearly E to Z isomerization. Increasing the steric hindrance of α-sub-
quantitative yield (entry 2). The Z/E ratio of the mixture did stituent led to higher stereoselectivity (up to 99:1 Z/E ratios).
not affect this isomerization significantly. When pure (E)-1a was Styrenyl chloride (1u) and iodide (1v) also underwent this isom-
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Scheme 2. Photocatalytic E to Z isomerization of styrenyl halides. Reactions were performed with 0.1 mmol substrate at ambient temperature in degassed
methanol (2.0 mL) using 2 mol-% fac-Ir(ppy)3 under 90 W blue LEDs irradiation. Z/E ratios were determined by 1H NMR spectroscopy of the crude products
using dibromomethane as the internal standard. Isolated yields based on (Z/E)-1 after silica gel column chromatography. [a] The initial E/Z ratio of the starting
materials. [b] 5.0 mmol scale (1.15 g).
erization smoothly give (Z)-1u and (Z)-1v in 98:2 and > 99:1
Z/E ratios, respectively. This photocatalytic E to Z isomerization
could be easily scaled up to gram scale without influencing
yield and stereoselectivity significantly (1p).
We next investigated the generality of geometric isomeriza-
tion of the Z/E mixtures of styrenyl haildes to (E)-styrenyl
haildes. As shown in Scheme 3, (E)-styrenyl bromides could be
isolated as the major geometric isomers regardless of the elec-
tronic and steric effects when the corresponding Z/E mixtures
were irradiated by blue LEDs in 1,4-dioxane in the presence of
fluorescein. Unfortunately, Z to E isomerization of α-substituted
styrenyl bromides was unsuccessful. The mechanism for this
Z to E isomerization is not clear at this stage.
To understand the conversion between the E and Z configu-
rations in this photocatalytic isomerization reaction, kinetic ex-
periments were carried out under specified conditions (Fig-
ure 1). The relative compositions of substrates and isomeriza-
1
tion products were monitored over time by H NMR under the
standard conditions of 2 mol-% of photosensitizer. In the case
of the substrate (E)-1a, almost complete Z-selective isomeriza-
tion was observed over the course of 10 h, and after that, the
reaction ultimately reached a photostationary state (Figure 1a).
For (Z)-1a, the equilibration was reached within 10 h smoothly
with 97:3 E/Z ratio (Figure 1b). Both (E)-1a and (Z)-1a are stable
under photocatalytic conditions and decomposition of styrenyl
bromides (E)-1a and (Z)-1a was not observed. In addition, the
slow consumption of the α-substituted substrates leads to a
Scheme 3. Photocatalytic Z to E isomerization of styrenyl bromides. Reactions
were performed with 0.1 mmol substrate at ambient temperature in de-
gassed 1,4-dioxane (2.0 mL) using 2 mol-% fluorescein under 90 W blue LEDs
irradiation. Z/E ratios were determined by 1H NMR spectroscopy of the crude
products using dibromomethane as the internal standard. Isolated yields
based on (Z/E)-1 after silica gel column chromatography. [a] The initial E/Z
ratios of the starting materials.
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slight decrease in the rate of photoisomerization (Figure 1c).
The (E)-1p isomer is completely consumed in 24 h. However, the
continuous decline in product yield is caused by competitive
photocatalytic decomposition. In a case of (Z)-1p (Figure 1d), a
short induction period was recorded during which the compo-
sition of (Z)-1p almost stayed the same. Although the E-selecti-
vity will be improved to some degree with the extension of the
reaction time, the yield of the product will also decrease due
to competitive decomposition.
Scheme 4. Stereospecific transformations of (Z)-1p. (i) (Z)-1p (1.0 equiv.), bor-
onic acid (1.2 equiv.), Pd(PtBu3)2 (2 mol-%), an aqueous solution of K2CO3
(3 equiv.), toluene, r.t.; (ii) (Z)-1p (1.0 equiv.), nBuLi (1.1 equiv.), 4 (3.0 equiv.),
THF, r.t.; (iii) (Z)-1p (1.0 equiv.), 6 (1.1 equiv.), Pd(PPh3)4 (3 mol-%), CuI (5 mol-
%), Et2NH.
boronic esters (E)-8a and (Z)-8a, respectively. Except (3Z, 5Z)-9,
the other three stereoisomers were isolated with the retention
of the stereochemistry. (3Z, 5Z)-9 was isolated as the major
product with slightly loss of stereochemistry (90:2:8:0).
Figure 1. Kinetic experiments: reaction progress monitoring starting from the
E and Z isomers of 1a and 1p: (a) (E)-1a with 2 mol-% fac-Ir(ppy)3. (b) (Z)-1a
with 2 mol-% fluorescein. (c) (E)-1p with 2 mol-% fac-Ir(ppy)3. (d) (Z)-1p with
2 mol-% fluorescein.
In order to preliminary demonstrate the synthetic value of
this photocatalytic isomerization strategy, the resultant styrenyl
bromide (Z)-1p was applied to the following experiments of
stereospecific transformation (Scheme 4a). Bromide (Z)-1p
could undergo Suzuki–Miyaura cross coupling[19] and Sonoga-
shira reaction[20] to give diaryl alkenes 3 and enyne 7 in a
stereochemically conservative manner, respectively. The reac-
tion with boronic acid pinacol ester also proceeded smoothly
to generate another important coupling partner 5. What is
more, this photocatalytic isomerization method and Suzuki–
Miyaura cross coupling reaction can be achieved successively
in a one-pot manner without affecting the chemical yield and
stereoselectivity, even in a gram scale (Scheme 4b).
The linear (E)-s-trans-2,4-dienone can provide cyclohexene
derivatives through visible-light-mediated cascade rearrange-
ment reaction, wherein the regioselective E→Z isomerization of
more dienophilic double bond is the key to the success of this
pathway.[21] It can be seen that construction of the stereo-
defined conjugated diene is extremely important. Thus, the suc-
cessful stereodivergent synthesis of all four stereoisomers of
conjugated dienes further emphasizes the synthetic utility of
this photocatalytic isomerization strategy (Scheme 5). The
Suzuki–Miyaura cross couplings of styrenyl bromide (E)-1p with
boronic esters (E)-8a and (Z)-8a, respectively, affording (3E, 5E)-
Scheme 5. Stereodivergent synthesis of conjugated dienes.
Finally, the highly stereoselective synthesis of the antitumor
and (3E, 5Z)-isomers of conjugated diene 9. (3Z, 5E)- and (3Z, agent DMU-212 (11),[22] a synthetic analogue of resveratrol with
5Z)-isomers of conjugated diene 9 could be accessed by the high activity and selectivity against cancer cell,[23] has been
couplings of photocatalytic isomerization product (Z)-1p with achieved through the Suzuki–Miyaura cross coupling of (E)-1a
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of the Z and E-isomer. The Z/E ratio of the mixture was determined
by the 1H NMR spectra and the crude product was purified by flash
chromatography on silica gel to afford the desired product.
with boronic acid 10 (Scheme 6, 80 % yield in single stereoiso-
mer). Its Z-isomer 12, which effectively induces the rapid po-
lymerization of perinuclear mitochondrial and the apoptosis of
p53-independent cells in cancer cells,[24] could also synthesized
in 86 % yield and 94:6 Z/E ratio using (Z)-1a as the coupling
partner.
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (21732003, 21672163), and the Nature Science Foun-
dation of Jiangsu Province (BK20181449) is acknowledged.
Keywords: Alkenes · Styrenyl halides · Isomerization ·
Photocatalysis
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Isomerization leading to (E)-styrenyl halides: A Z/E mixture of
styrenyl halide (0.1 mmol, 1.0 equiv.) and fluorescein (0.7 mg,
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tube was evacuated and backfilled with nitrogen 3 times. Degassed
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the reaction was completed, the residual catalyst was removed by
filtration through a SiO2-plug, subsequent elution of the products
with Et2O (6.0 mL) and concentration in vacuo yielded the mixture
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Received: July 31, 2019
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Communication
Stereodivergent Synthesis
H. Zhang, Q. Xu,* L. Yu,* S. Yu* ..... 1–7
Photocatalytic Isomerization of
Styrenyl Halides: Stereodivergent
Synthesis of Functionalized Alkenes
An efficient and general method for dation of this strategy in the synthesis
the isomerization of styrenyl halides of functionalized alkenes, including
under photocatalytic conditions is re- two diaryl alkenes, a styrenyl boronic
ported. A series of stereospecific trans- ester, and an enyne.
formations constitute preliminary vali-
DOI: 10.1002/ejoc.201901119
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim