Regioselective Synthesis of α-Functional Stilbenes via Precise Control of Rapid cis- trans Isomerization in Flow

Article abstract of DOI:10.1021/acs.orglett.1c00538

The rapid cis-trans isomerization of α-anionic stilbene was regioselectively controlled by using flow microreactors, and its reaction with various electrophiles was conducted. The reaction time was precisely controlled within milliseconds to seconds at -50 °C to selectively give the cis- or trans-isomer in high yields. This synthetic method in flow was well-applied to synthesize precursors of commercial drug compound, (E)- and (Z)-tamoxifen with high regioselectivity and productivity.

Full text of DOI:10.1021/acs.orglett.1c00538

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Letter
Regioselective Synthesis of α‑Functional Stilbenes via Precise
Control of Rapid cis−trans Isomerization in Flow
Hyune-Jea Lee,∇ Yuya Yonekura,∇ Nayoung Kim, Jun-ichi Yoshida,* and Heejin Kim*
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ABSTRACT: The rapid cis−trans isomerization of α-anionic
stilbene was regioselectively controlled by using flow micro-
reactors, and its reaction with various electrophiles was conducted.
The reaction time was precisely controlled within milliseconds to
seconds at −50 °C to selectively give the cis- or trans-isomer in
high yields. This synthetic method in flow was well-applied to
synthesize precursors of commercial drug compound, (E)- and
(Z)-tamoxifen with high regioselectivity and productivity.
Scheme 1. Synthetic Methodology for the Functionalization
of α-Anionic Stilbenes
tilbene is a well-known subunit occurring naturally in
1
Spolyphenols of various plants. Advances in spectroscopic
techniques facilitate the analysis of not only the intricate
structures of stilbenes but also the elucidation of their
biological efficacy. Stilbene derivatives have been at the
forefront of pharmaceutical research and development, because
of their potential therapeutic or preventive applications,
exemplified by tamoxifen,2 resveratrol,3 and combretastatin
A-4.4 Furthermore, they have been often used in material
applications as dye precursors, optical brighteners, phosphors,
and scintillators.5
The widespread applications of stilbene derivatives in
various research fields led the development of synthetic
method for regioselective functionalization of the stilbenes;6
however, the reactions are restricted, because of their rapid
isomerization. The geometry of the trans-stilbene is slightly
lower in energy than cis-stilbene by ∼4.6 kcal/mol, with an
isomerization barrier of 48.3 kcal/mol,7 because the steric
interactions force the aromatic rings out-of-plane and prevent
conjugation.8 Therefore, the formation of trans-isomer is
preferred in nature and the cis-isomer is sensitive to
isomerization, even to mild conditions, such as minor light
irradiation9 and exposure to heat.10 The preference for the
trans-isomer also strongly dominates the product conforma-
tion. The α-functionalization of stilbene through vinylic metal
species is difficult, because of the its rapid transformation from
cis to trans (Scheme 1a), as reported.11 A directing group for
high regioselectivity is required in order to control the olefin
geometry as part of a general synthetic methodology.
Figure 1. Vinyl C−H metalation of cis-stilbene to result in the
formation of the trans-isomer in the flow.
Received: February 15, 2021
Published: April 2, 2021
The carbolithiation of diphenylethylene and selective α-
lithiation of stilbene, one of the simplest and direct
functionalization methods12 is challenging, because the
formation of the trans-isomer cannot be prevented, even
under extremely low temperature conditions, because of the
rapid isomerization. The regioselective synthesis of α-function-
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Figure 2. Generation of α-lithiated stilbene and the control of
isomerization by changing the residence time in R1 in a flow
microreactor: (a) the Br−Li exchange reaction of cis-α-bromo stilbene
(1) and subsequent reaction with benzaldehyde in flow, (b) the
reaction using n-BuLi as a lithiating reagent, and (c) the reaction
using s-BuLi as a lithiating reagent.
alized cis- and trans-stilbene derivatives is an ongoing
challenging issue using transition-metal catalysts.13
Flow chemistry based on microfluidics has been developed
and widely applied in the field of organic chemistry,
pharmaceutical chemistry, and materials science in the last
two decades.14 The flow reactor has emerged as a fascinating
alternative to conventional flask, especially as a safe and
environmentally friendly synthetic tool.15 Continuous flow
chemistry is increasingly recognized as a cutting-edge synthetic
technique that can be combined with artificial intelligence and
autonomous reaction system.16 Flow microreactors contrib-
uted advance in organic synthesis due to fast mixing, effective
control of reaction conditions, and time.17 Based on the precise
control of short reaction time (milliseconds or less) in the flow
reactor, our research group has reported several studies
involving rapid reaction control including rearrangement and
decomposition of intermediates,18 and this concept is referred
to as “flash chemistry”.19
Figure 3. Investigation of the relationship between cationic species
and the isomerization rate: (a) the flow scheme for the reaction with
the cationic species, (b) the reaction with t-BuONa as an additive (the
reaction without an additive was represented by black dashed lines),
(c) the reaction using t-BuOK as an additive, and (d) the reaction
using 12-crown-4-ether as an additive.
lithiated stilbene including cis-stilbenyl borate, which could be
used in various synthetic reactions such as Pd-catalyzed cross-
coupling. The flash synthesis method is illustrated by the
synthesis of the precursors of the well-known pharmaceutical
compounds (E)- and (Z)-tamoxifen.
Initially, the generation of α-anionic stilbene was attempted
via vinyl C−H metalation of cis-stilbene using Schlosser’s base
(a mixture of BuLi and potassium tert-butoxide)20 in both a
flask and the flow reactor (Figure 1; see the Supporting
Information). In the various reaction conditions, only trans-
isomer 2b was obtained as a sole product, even using a flow
reactor where the time for the metalation was set to
Herein, we report a remarkable control of isomerization of
α-lithiated stilbene using the flow reaction system. To the best
of our knowledge, this is the first report of α-functionalization
of both cis- and trans-stilbene with high regioselectivity
(Scheme 1b). We also established the successful introduction
of various electrophiles into highly controlled cis- and trans-
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Figure 5. Various reactions of flow-synthesized cis-stilbenyl borate
13a.
Figure 6. Flow-assisted synthesis of (E)- and (Z)-tamoxifen precursor
with high regioselectivity.
We next performed the flow reaction expecting better
controllability. The reaction was conducted in the flow reactors
consisting of two micromixers (M1 and M2; 250 μm of inner
diameter) and two tube reactors (R1 and R2), as shown in
Figure 2a. A solution of cis-α-bromo stilbene (1) and BuLi was
mixed and lithiated in M1 and R1, and the resulting solution
was reacted with benzaldehyde in M2 and R2. Because many
previous reports indicate that the Br−Li exchange at −78 °C in
flow reactors results in low conversions,21 the temperature of
flow reaction was maintained at slightly higher than −50 °C
and the residence time in R1 was controlled from 14 ms to 94 s
by changing the diameter and length of the tube reactor. First,
we used n-BuLi as a lithiating reagent (Figure 2b). The yield of
2a was increased by changing the residence time from 14 ms to
3.1 s, because of the incomplete Br−Li exchange at residence
times that are too short under low temperature. However, the
yield of 2a dwindled by further increasing the residence time
(from 3.1 s to 63 s), because of the rapid cis−trans
isomerization. When the residence time was 0.63 s, we
obtained compound 2a in 91% yield, but the isomerized trans-
compound 2b was also detected (2%). We could confirm that
the isomerization began before the complete Br−Li exchange
reaction to result in the formation of a mixture of compound
2a and 2b. Therefore, we changed the lithiating reagent to s-
BuLi for faster Br−Li exchange and resulted in the highest
yield of compound 2a without the formation of isomer 2b at
55 ms of residence time (93% in Figure 2c). At a residence
time of 94 s, compound 2b was obtained as a sole product,
with a yield of 84%. The yield of 2a was decreased by
Figure 4. Regioselective functionalization of stilbene with various
electrophiles.
milliseconds at −78 °C. All of the attempts to get the cis-
isomer 2a failed. The results suggest that the rate of
isomerization was much faster than the rate of metalation by
the Schlosser’s base, which was not possible to control the
isomerization. For this reason, we modified the strategy to
generate the α-anionic stilbene via the rapid halogen−lithium
exchange reaction.
In a preliminary study using cis-α-bromo stilbene (1), the
generation of α-lithiated stilbene, followed by the reaction with
benzaldehyde, was conducted in a flask. A mixture of cis- and
trans-products was obtained in the ratio of 2:1 (63% and 34%,
respectively), although the lithiation time was kept to 1 min at
−78 °C. This result indicates that the regioselective
functionalization of stilbene is difficult to achieve in flask,
because of the rapid isomerization even at −78 °C (See the
Supporting Information).
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increasing the temperature (from −78 °C to 20 °C) at a fixed
residence time (3.1 s; see the Supporting Information).
Next, we investigated the effect of cationic species on the
isomerization rate. The cis-α-lithiated stilbene generated in R1
was mixed with alkali-metal species, and then trapped with
benzaldehyde in the flow microreactors (Figure 3a).
Interestingly, the kinetics of isomerization was dramatically
changed by the cation. Using sodium tert-butoxide (t-BuONa)
as an additive, the rate of isomerization seemed to be slightly
increased (Figure 3b). When the potassium tert-butoxide (t-
BuOK) was added, trans-isomer 2b was only detected at all of
the residence times in R2 (Figure 3c). The reaction rate of
isomerization was increased in the following order of the
cation: Li+ < Na+ < K+, presumably because of a degree of
ionized α-anionic stilbene. The addition of t-BuONa and t-
BuOK can induce the replacement of Li+ with Na+ or K+,
which leads to more ionized anions. We also conducted the
reaction using 12-crown-4-ether as the additive to generate the
more ionized anion by capturing the Li+ and the rate of
isomerization was dramatically accelerated, as shown in Figure
3d. This result indicates that the more ionized anion stilbene
facilitates faster cis−trans isomerization. Based on the results,
we realized that our initial attempt to generate cis-α-lithiated
stilbene using Schlosser’s base most likely failed even in the
flow, because of the effect of potassium accelerating the rate of
isomerization.
Under the optimized residence times (55 ms for cis-stilbene
derivatives and 94 s for trans-stilbene derivatives), we
conducted the regioselective reactions with various electro-
philes (Figure 4). We obtained the desired cis- (2a−5a) and
trans- products (2b−5b) in high yields of 84−99% through the
reactions with benzaldehydes bearing electron-withdrawing or
electron-donating groups and an aliphatic aldehyde.
Various electrophiles including methyl triflate, benzophe-
none, phenyl isocyanate, hexachloroethane, trimethylsilyl
triflate, diethyl malonate, tributyltin chloride, and trimethox-
yborane were effectively trapped the intermediate organo-
metallic to yield the corresponding cis- (3a−13a) and trans-
stilbene derivatives (3b−13b) with high yield and regiose-
lectivity.
To demonstrate the synthetic utility of the cis-stilbenyl
borate compound, we conducted further reactions using
compound 13a (Figure 5). The oxidation reaction was
achieved with hydrogen peroxide and sodium hydroxide,
resulting in 1,2-diphenylethone (14) in 92% isolated yield. The
Pd-catalyzed cross-coupling reaction gave the corresponding
products (15−18) in high yields (87%−94%), using coupling
partners such as allyl, benzyl, aryl, and heteroaryl bromide.
We next conducted the synthesis of precursors of cis- and
trans-tamoxifen (Figure 6). The remedial effect of tamoxifen is
different by the E/Z geometry, which requires the
regioselective synthesis during production of the drug
compound. Whereas cis- or (E)-tamoxifen is a full estrogen
agonist,22 trans- or (Z)-tamoxifen is a therapeutic agent used
for the management of estrogen-dependent breast cancer.23
The cis- or trans-α-lithiated stilbenes were generated under the
optimized conditions, followed by the reaction with ethyl
triflate (EtOTf) in the flow reactors resulting in ethylated
compound 19a or 19b in the isolated yield of 60% and 69%,
respectively. In case of using ethyl iodide as the electrophile,
compound 19a was not obtained as the sole product, because
of low reactivity.
A high-yielding, high-throughput synthesis of 19a (0.83 g)
and 19b (1.04 g) was achieved in 11 and 12 min of operation
time, respectively. The cis-isomer 19a can be converted to (E)-
tamoxifen via epoxidation (see the Supporting Information)
and epoxide olefination,24 and the trans-isomer can be directly
transformed to (Z)-tamoxifen via Heck-type cross-coupling
reaction.25 These results suggest that the flow-assisted
approach is useful for the regioselective synthesis of
pharmaceutical ingredients with high productivity.
In conclusion, we have achieved the flow-assisted precise cis-
trans isomerization of α-anionic stilbene. We generated the α-
lithiated stilbene via rapid Br−Li exchange. Under the
optimized conditions, two isomers can be regioselectively
trapped with various electrophiles to obtain the desired
products in high yields. The cis-stilbenyl-borate that was
obtained using this method could be used for the synthesis of
various cis-stilbene derivatives. Moreover, the synthesis of both
precursors of cis- and trans-tamoxifen with enhanced
productivity in flow demonstrates the power of flow chemistry
in the field of organic synthesis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00538.
Experimental procedures, supplementary figures and
compound characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Jun-ichi Yoshida − Department of Synthetic and Biological
Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-Ku, Kyoto 615-08510, Japan; National Institution
of Technology, Suzuka College, Suzuka, Mie 510-0294,
Japan; Email: j-yoshida@jim.suzuka-ct
Heejin Kim − Department of Chemistry, College of Science,
Korea University, Seongbuk-gu, Seoul 02841, South Korea;
Department of Synthetic and Biological Chemistry, Graduate
School of Engineering, Kyoto University, Nishikyo-Ku, Kyoto
615-08510, Japan; orcid.org/0000-0002-6095-1794;
Email: heejinkim@korea.ac.kr
Authors
Hyune-Jea Lee − Department of Chemistry, College of Science,
Korea University, Seongbuk-gu, Seoul 02841, South Korea
Yuya Yonekura − Department of Synthetic and Biological
Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-Ku, Kyoto 615-08510, Japan
Nayoung Kim − Department of Chemistry, College of Science,
Korea University, Seongbuk-gu, Seoul 02841, South Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00538
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the support from the National
Research Foundation (NRF) of Korea grant funded by the
Korean government (Nos. 2020R1C1C1014408 and
2020R1I1A1A01067730).
DEDICATION
■
Dedicated in memory of Prof. Jun-ichi Yoshida.
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