Stereocontrolled synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.bmcl.2018.04.004

A general procedure for the stereocontrolled synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (E)-2-phenylethenylboronic acid pinacol ester with aryl bromides was investigated. (E)-2-Phenylethenylboronic acid pinacol ester was prepared by 9-BBN-catalyzed hydroboration of phenylacetylene with pinacolborane. This reagent undergoes facile palladium-catalyzed cross-coupling with a diverse set of aryl bromides to provide the corresponding (E)-stilbene derivatives in moderate to good yield. The use of the sterically bulky t-Bu₃PHBF₄ ligand was crucial to the successful coupling of electron-rich and electron-poor aryl bromides. Complete stereochemical retention of the (E)-2-phenylethenylboronic acid pinacol ester alkene geometry was observed in all of the (E)-stilbene derivatives synthesized.

Full text of DOI:10.1016/j.bmcl.2018.04.004

Accepted Manuscript
Stereospecific synthesis of (E)-stilbene derivatives by palladium-catalyzed Su-
zuki-Miyaura cross-coupling reaction
Hailee H. Rau, Nathan S. Werner
PII:
S0960-894X(18)30302-0
https://doi.org/10.1016/j.bmcl.2018.04.004
BMCL 25751
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
2 February 2018
31 March 2018
2 April 2018
Please cite this article as: Rau, H.H., Werner, N.S., Stereospecific synthesis of (E)-stilbene derivatives by palladium-
catalyzed Suzuki-Miyaura cross-coupling reaction, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://
doi.org/10.1016/j.bmcl.2018.04.004
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Stereospecific synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction
Hailee H. Raua and Nathan S. Wernera,*
Department of Physical Science, Southern Utah University, 351 W University Blvd, Cedar City, UT 84720, USA
*nathanwerner@suu.edu
Abstract
A general procedure for the stereospecific synthesis of (E)-stilbene derivatives by palladium-catalyzed
Suzuki-Miyaura cross-coupling reaction of (E)-2-phenylethenylboronic acid pinacol ester with aryl bromides
was investigated. (E)-2-phenylethenylboronic acid pinacol ester was prepared by 9-BBN-catalyzed
hydroboration of phenylacetylene with pinacolborane. This reagent undergoes facile palladium-catalyzed cross-
coupling with a diverse set of aryl bromides to provide the corresponding (E)-stilbene derivatives in moderate to
good yield. The use of the sterically bulky t-Bu3PHBF4 ligand was crucial to the successful coupling of
electron-rich and electron-poor aryl bromides.

(E)-Stilbene derivatives are known to exhibit a variety of interesting biological activity.1 In particular, the
natural product resveratrol, found in red wine, has been widely studied after it was associated with the low
incidence of cardiovascular disease in a French population with a diet that is relatively high in saturated fat.2
Simple, synthetic (E)-stilbene derivatives have also been identified to have value as potential therapeutics.1b–d
The stilbene alkene geometry fundamentally changes the overall structure of the molecule and can affect the
biological activity.1e–h Therefore, it is important that synthetic methods are developed for the preparation of
stilbene derivatives with high geometrical selectivity.
The Suzuki-Miyaura cross-coupling reaction provides a mild and selective method for the construction of
bonds between all hybridizations of the carbon atom.3 Increasingly, the study of the Suzuki-Miyaura cross-
coupling reaction has provided a number of solutions for the synthesis of complex organic molecules4, and has
elucidated many of the mechanistic details of this important reaction.5 Surprisingly, a review of the literature
provided very few examples of the general preparation of simple (E)-stilbene derivatives by Suzuki-Miyaura
reaction.6,7 Therefore, a general method for the synthesis of (E)-stilbene derivatives by palladium-catalyzed
Suzuki-Miyaura cross-coupling reaction was investigated.
Initially, two polar disconnections were entertained for the synthesis of (E)-stilbene derivatives by
palladium-catalyzed Suzuki-Miyaura cross-coupling: (A) an aryl organometallic donor with a 2-phenylethenyl
(styrenyl) organic electrophile, or (B) an aryl organic electrophile and a styrenyl organometallic donor (Scheme
1). Couplings of type A were recently studied by Lipshutz et. al and the effect of ligands on the geometrical
selectivity of the couplings was reported.8 It was found in these studies that the ligand additive had the greatest
effect on the E/Z composition of the product when (E)-1-iodooctene was used as the organic electrophile. The
ligand dependent mixtures of isomeric alkene products led us to investigate couplings of type B for a general
preparation of geometrically pure (E)-stilbene derivatives.

Scheme 1. Analysis of the polar disconnection of palladium-catalyzed cross-coupling reagents.
Couplings of type B that employed (E)-2-phenylethenylboronic acid were reported to be stereospecific.6
Product yields are higher when (E)-2-phenylethenylboronic acid rather than the corresponding catechol boronic
ester is used as the organometallic donor.6b However, the boronic acid is typically synthesized by hydrolysis of
the corresponding catechol boronic ester, and its isolation can be tedious.7 Moreover, the catechol boronic ester
is air-sensitive.6b Therefore, it was encouraging that (E)-2-phenylethenylboronic acid pinacol ester (E)-3 was
found to be the preferred organometallic donor in a stereospecific cross-coupling with aryl nonaflates.7 Yet, in
this report the pinacol boronic ester (E)-3 was also synthesized from the sensitive catechol derivative. Thus, the
focus of this work was broadened to include a streamlined synthesis of (E)-3 by direct hydroboration reaction
with commercially available pinacolborane 2.
The synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction
required the preparation of (E)-3. It was proposed that (E)-3 could be prepared by direct hydroboration of
pinacolborane. However, the hydroboration reaction of phenylacetylene 1 with pinacolborane 2 is sluggish and
only trace product was observed after 7 h in refluxing THF (65 °C). Gratifyingly, 10 mol % of 9-
borobicyclo[3.3.1]nonane (9-BBN) could be used to catalyze the hydroboration reaction (Scheme 1).9,10 The
reaction produces only the (E)-3 isomer, is complete within 20 min, and no alkylborane products were observed
after a simple aqueous work-up. In addition, (E)-3 was purified by flash chromatography and isolated in good
yield.
Scheme 2. Synthesis of (E)-3 by 9-BBN catalyzed hydroboration of phenylacetylene with pinacolborane.

The pinacol boronic ester (E)-3 was found to cleanly couple with 4a to provide the desired product (E)-5a
(Table 1, entry 1). The effect of reaction parameters on product yield was then studied. Increasing the amount of
(E)-3 from 1.0 to 1.2 equiv increased the yield of (E)-5a (entries 1 and 2). Decreasing the reaction temperature
from 90 °C to 70 °C decreased the yield of (E)-5a (entries 2 and 3). The use of Pd(OAc)2 provided a superior
yield than Pd2(dba)3 (entries 2 and 4). Lower yields were observed when Cs2CO3 and t-BuOK were used as the
base (entries 2, 5 and 6). Interestingly, the combination of Cs2CO3 as base and dioxane as solvent provided a
very low yield of (E)-5a (entry 7). The use of DMF as reaction solvent was found to provide the best product
yield (entries 2, 8–10). The highest yield of (E)-5a was obtained when Ph3P was used as the ligand (entries 2,
11–13).
Table 1. Optimization of the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (E)-3 and 4a.
entry
1b
2
ligand, %
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
Ph3P, 20
JohnPhos, 10
SPhos, 10
base, equiv solvent yield,a %
K2CO3, 1.1
K2CO3, 1.1
K2CO3, 1.1
K2CO3, 1.1
DMF
DMF
DMF
DMF
75
79
62
43
73
73
25
77
66
NRe
53
56
69
3c
4d
5
KOt-Bu, 1.1 DMF
Cs2CO3, 1.1 DMF
Cs2CO3, 1.1 dioxane
K2CO3, 1.1 dioxane
K2CO3, 1.1 DMSO
K2CO3, 1.1 toluene
6
7
8
9
10
11
12
13
K2CO3, 1.1
K2CO3, 1.1
DMF
DMF
DMF
t-Bu3PHBF4, 10 K2CO3, 1.2
aYield of isolated, purified product.
b1.0 equiv of (E)-3 was used.
cReaction temperature of 70 °C.
dPd2(dba)3 (5 mol %) was used as the palladium source.
ePalladium black and no cross-coupling reaction was observed.

Scheme 3. An (E)-5a by-product was observed in reactions that used the Ph3P ligand and an electron-rich aryl
bromide substrate.
aGC peak area ratio.
The reaction conditions of (E)-3 (1.2 equiv), aryl bromide (1.0 equiv), Pd(OAc)2 (5%), Ph3P (20%), K2CO3
(1.1 equiv), DMF, and a 90 °C reaction temperature were then used to evaluate the scope of compatible aryl
bromides (Scheme 3). Surprisingly, an (E)-5a by-product, presumably the result of phenyl group transfer from
Ph3P,11 was observed under these reaction conditions when electron-rich aryl bromides were used as substrates.
Specifically, the reaction of (E)-3 with 4c provided an 86:14, (E)-5c/(E)-5a which increased to 20:80 favoring
the (E)-5a by-product when the more electron-rich aryl bromide 4e was used. The (E)-5a by-product was not
observed in reactions that used t-Bu3PHBF4 as the ligand.12 Therefore, t-Bu3PHBF4 was used as the ligand to
evaluate other aryl bromide substrates.
The scope of compatible aryl bromides in the cross-coupling reaction with (E)-3 when t-Bu3PHBF4 was
used as the ligand was studied (Table 2).13 The electronically neutral aryl bromides 4a and 4b were found to be
good substrates in this reaction (entries 1–2). The sterically hindered aryl bromides 4d and 4h successfully
coupled under these conditions (entries 4 and 8). Importantly, the electron-rich substrates 4e and 4c provided
clean conversion (GC) to the desired (E)-stilbene derivative. (entries 3 and 5). Substrates bearing electron-poor
groups (e.g. 4g, 4f, 4i, 4j, and 4k) coupled well under these reaction conditions (entries 7, 9–11). The
heterocyclic aryl bromides 4l and 4m provided the corresponding (E)-stilbene derivative in good isolated yield.
In addition, GC analysis of crude reaction aliquots showed complete stereochemical retention of (E)-3 in all
cases studied.
In conclusion, (E)-stilbene derivatives can be readily prepared by the stereospecific palladium-catalyzed
Suzuki-Miyaura cross-coupling reaction of (E)-3 and aryl bromides. The reagent (E)-3 is easily prepared by 9-
BBN catalyzed hydroboration reaction of 1 and 2. This circumvents the use of the air-sensitive catechol boronic

ester intermediate. The use of t-Bu3PHBF4 as the ligand was found to be crucial to the successful coupling of
(E)-3 with a variety of electronically and sterically diverse substrates. Moderate to good yield of the (E)-stilbene
derivatives 5a–m were obtained. Complete retention of the stereochemistry of the boronic ester (E)-3 was
observed in all cases studied.

Table 2. Scope of trans-stilbene derivatives synthesized by palladium-catalyzed Suzuki-Miyaura cross-
coupling reaction.a
entry
1
product
yield,b %
69
2
3
4
5
73
52
53
54
6
7
8
9
73
66
44
76
10
63
11
12
13
67
67
83
aReactions were performed on at least 0.5 mmol scale.
bYield of isolated, purified product.

Acknowledgments
We are grateful to Southern Utah University for a Faculty Project Fund Grant (N.S.W.), a Walter Maxwell
Gibson Research Fellowship (H.H.R.), and a L. S. and Aline W. Skaggs Research Grant (H.H.R.) to generously
support this work.
References and Notes
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Chem. Rev. 1995, 95, 2457−2483.

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9. Preparation of (E)-3. To an oven-dried, 250 mL round-bottomed flask, containing a magnetic stir-bar,
equipped with a reflux condenser capped with septum, purged with Ar, and under a balloon of Ar was
added THF (70 mL), phenylacetylene (1.65 mL, 15 mmol, 1.0 equiv), pinacolborane (2.18 mL, 15
mmol, 1.0 equiv), and 9-BBN (3.00 mL, 1.5 mmol, 0.1 equiv). An additional volume of THF (5 mL)
was used to wash all of the reagents into the flask. The flask was then placed in a preheated oil bath (80
°C) and allowed to reflux for 20 min. The reaction was then cooled to rt, and purified by aqueous work-
up and flash chromatography (15 g silica gel, 20 mm column diameter, 5% EtOAc/hexane eluent) to
provide 2.54 g (74%) of (E)-3 as a clear, colorless oil. 1H NMR (400 MHz, CDCl3):  7.48–7.45 (m, 2
13
H), 7.40 (d, J = 18.5, 1 H), 7.33–7.23 (m, 3 H), 6.17 (d, J = 18.5, 1 H), 1.29 (s, 12 H); C NMR (101
MHz, CDCl3): ; IR (neat): 3080 (w), 3054 (w), 3018 (w),
2978 (w), 2928 (w), 1623 (m), 1577 (w), 1495 (w), 1450 (m), 1391 (m), 1371 (m), 1346 (s), 1322 (s),
1271 (m), 1237 (m), 1210 (m), 1142 (s), 1109 (w), 997 (m), 969 (m), 899 (m), 851 (m), 748 (m), 692
(m), 660 (w), 641 (w); MS (EI, 70 eV) 230 ([M], 49), 229 (12), 215 (24), 157 (11), 145 (38), 144 (69),

143 (10), 131 (56), 130 (100), 129 (92), 118 (16), 114 (14), 105 (31), 104 (15), 103 (16), 85, (10), 78
(12), 77 (21); TLC (hexane/EtOAc, 95:5) Rf 0.53.
10. Shirakawa, K.; Arase, A.; Hoshi, M. Synthesis, 2004, 1814−1820.
11. Parkins, A. W. Coord. Chem. Rev. 2006, 250, 449−467.
12. (a) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295−4298. (b) Denmark, S. E.; Werner, N. S. Org.
Lett. 2011, 13, 4596−4599.
13. Preparation of (E)-5a. To an oven-dried, 25 mL round-bottomed flask, containing a magnetic stir-bar
was added Pd(OAc)2 (5.90 mg, 0.026 mmol, 0.05 equiv), t-Bu3PHBF4 (15.2 mg, 0.52 mmol, 0.10
equiv), and K2CO3 (87.1 mg, 0.63 mmol, 1.2 equiv). (E)-2-phenylethenylboronic acid pinacol ester (145
mg, 0.63 mmol, 1.2 equiv) was weighed, dissolved in DMF (2.63 mL), and then added to the solid
reagents. The flask was capped with a septum, purged with Ar for 10 min, and bromobenzene (55.3 L,
0.52 mmol, 1.0 equiv) was added by syringe. The flask was then placed in a preheated oil bath (90 °C)
and allowed to stir under a balloon of Ar for 2 h. The reaction was then cooled to rt, and purified by
aqueous work-up and flash chromatography (15 g silica gel, 10 mm column diameter, hexane eluent) to
provide 63.0 mg (66%) of (E)-5a as a white solid. 1H NMR (400 MHz, CDCl3):  7.54–7.52 (m, 4 H),
13
7.39–7.35 (m, 4 H), 7.29–7.25 (m, 2 H), 7.13 (s, 2 H); C NMR (101 MHz, CDCl3): 137.4, 128.71,
128.70, 127.6, 126.5; IR (neat): 3076 (w), 3058 (w), 3019 (w), 2997 (w), 1947 (w), 1878 (w), 1817 (w),
1751 (w), 1597 (w), 1577 (w), 1494 (m), 1450 (m), 1389 (w), 1331 (w), 1300 (w), 1220 (w), 1154 (w),
1071 (w), 1028 (w), 983 (w), 960 (m), 909 (w), 761 (m), 690 (m), 619 (w); MS (EI, 70 eV) 181
([M1]+, 14)180 ([M]+, 100), 179 (99), 178 (62), 176 (10), 177 (8), 166 (6), 165 (45), 152 (12), 151 (6),
102 (7), 89 (14), 77 (6), 76 (10), 63 (5), 51 (6); TLC (hexane) Rf 0.31.

Stereospecific synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction
Hailee H. Raua and Nathan S. Wernera,*
Department of Physical Science, Southern Utah University, 351 W University Blvd, Cedar City, UT 84720, USA
*nathanwerner@suu.edu
Highlights
 (E)-stilbene derivatives were synthesized with complete isomeric purity
 9-BBN catalyzed the hydroboration of phenyl acetylene with pinacol borane
 (E)-2-phenylethenylboronic acid pinacol ester was used as the organometallic donor
 Electron-rich, electron-poor, and hetereoaryl bromides were successfully coupled
 Electron-rich aryl bromides required use of the t-Bu3PHBF4 ligand