Palladium-catalyzed prenylation of (hetero)aryl boronic acids

Article abstract of DOI:10.1016/j.tetlet.2020.152800

Prenyl or dimethylallyl groups are common structural motifs in natural products and small molecule therapeutics. In this report, we describe a palladium-catalyzed method for the cross-coupling of aryl and heteroaryl boronic acids with prenyl alcohol. Catalyst systems based on dialkylbiaryl phosphines were highly active for this transformation. These supporting ligands provided opportunities for tuning the efficiency and regioselectivity of carbon–carbon bond formation. In addition, this method was further extended to the cross-coupling of symmetrical allylic alcohols with aryl boronic acids.

Full text of DOI:10.1016/j.tetlet.2020.152800

Tetrahedron Letters 66 (2021) 152800
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed prenylation of (hetero)aryl boronic acids
⇑
Jeffrey Leister, Darrian Chao, Kelvin L. Billingsley
Department of Chemistry and Biochemistry, California State University Fullerton, 800 N State College Blvd Fullerton, CA 92831, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Prenyl or dimethylallyl groups are common structural motifs in natural products and small molecule
therapeutics. In this report, we describe a palladium-catalyzed method for the cross-coupling of aryl
and heteroaryl boronic acids with prenyl alcohol. Catalyst systems based on dialkylbiaryl phosphines
were highly active for this transformation. These supporting ligands provided opportunities for tuning
the efficiency and regioselectivity of carbon–carbon bond formation. In addition, this method was further
extended to the cross-coupling of symmetrical allylic alcohols with aryl boronic acids.
Ó 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Received 18 November 2020
Revised 16 December 2020
Accepted 21 December 2020
Available online 9 January 2021
Keywords:
Palladium
Cross-coupling
Prenylation
Regioselectivity
Boronic acid
Introduction
prenyl). However, carbon–carbon bond formation almost entirely
favors the linear product versus establishing the quaternary carbon
Prenylation reactions provide a unique method for Nature to
establish molecular complexity. This feature is eloquently show-
cased in transformations that covalently attach hydrophobic iso-
prene units to secondary metabolites [1,2]. In turn, prenyl (3,3-
dimethylallyl) or reverse-prenyl (1,1-dimethylallyl) groups are
found in bioactive terpenes, terpenoids, flavonoids, and related
alkaloids (Fig. 1) [3–5]. Analogous processes can also afford poly-
isoprene chains (e.g. geranyl and farnesyl), and these structural
motifs are accordingly observed in a myriad of natural products
[6].
Guided by our recent synthetic efforts [7–9], we were interested
in developing a palladium-catalyzed method that promoted the
prenylation of aryl boronic acids. These nucleophiles are ideal as
they generally lack toxicity and possess a high degree of functional
group tolerance [10]. Aryl boronic acids have also proven success-
ful as cross-coupling partners in palladium catalysis with symmet-
rical allylic electrophiles including allylic halides, acetates, and
alcohols (Fig. 2A) [11–16]. Despite these advantages, the reaction
of aryl boronic acids with unsymmetrical allylic electrophiles
remains challenging, as two regioisomers may be produced. To cir-
cumvent this issue, previous reports have generally employed aryl-
substituted allylic electrophiles, which bias the transformation to
yield a single product (Fig. 2A) [17–23]. The cross-coupling reac-
tion of prenyl electrophiles with aryl boronic acids can similarly
result in two regioisomers: linear (prenyl) or branched (reverse-
center found in the branched regioisomer [12,20,24–27].
In this study, we sought to define a palladium-based catalyst
system for the cross-coupling of aryl boronic acids with a prenyl
electrophile (Fig. 2B). In addition, given the difficulties associated
with obtaining the reverse-prenyl group, we concurrently wanted
to determine key factors that may overcome the inherent substrate
bias of prenyl electrophiles and thereby increase branched product
formation. This method would offer a complementary approach to
elegant studies employing prenyl organoboranes [28,29]. More-
over, advancing these dual objectives would potentially provide
new synthetic strategies to access prenyl-containing natural
products.
Results and discussion
We examined two nucleophiles for the transformation: 3-meth-
oxyphenyl boronic acid (1a) and 3-methoxyphenyl pinacol boro-
nate ester (1b). These organoboranes were reacted with several
electrophiles including prenyl alcohol (2a), chloride (2b), bromide
(2c), and acetate (2d). However, no cross-coupling product was ini-
tially observed (Table 1, entries 1–8). A supporting ligand can
increase catalyst stability and activity; therefore, each electrophile
was resubjected to the reaction conditions in the presence of
P(2-furyl)3 (Table 1, entries 9–12). In these experiments, 2b-2d
remained ineffective, whereas 2a successfully furnished the
desired carbon–carbon bond. The alcohol-based electrophile pro-
vided a 20% combined yield of the branched (3B) and linear (3L)
products. Consistent with the literature, 3L was favored in this
⇑
Corresponding author.
E-mail address: kbillingsley@fullerton.edu (K.L. Billingsley).
https://doi.org/10.1016/j.tetlet.2020.152800
0040-4039/Ó 2021 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

J. Leister, D. Chao and K.L. Billingsley
Tetrahedron Letters 66 (2021) 152800
Table 1
Optimization of reaction conditions Pd-catalyzed prenylation reaction.a
GC Yield (%)b
3B:3Ld
Fig. 1. Representative examples of bioactive natural products that integrate prenyl
Entry
Nuc
Elec
Ligand
(blue) and/or reverse prenyl (red) groups.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
—
—
—
—
—
—
—
—
0
0
0
0
0
0
0
0
20
0
—
—
—
—
—
—
—
—
35:65
—
—
—
33:67
—
—
9
P(2-furyl)3
P(2-furyl)3
P(2-furyl)3
P(2-furyl)3
P(OPh)3
P(o-tolyl)3
PtBu2Me
PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
0
0
21
<5
<5
17
0
0
0
0
7
<5
31
17
42
24
29
17
89
48
60c
77c
53:47
e
BINAP
DPPF
—
—
—
—
e
e
DPEphos
XantPhos
JohnPhos
TrixiePhos
tBu-XPhos
CyJohnPhos
DavePhos
CPhos
RuPhos
BrettPhos
XPhos
SPhos
SPhos
Fig. 2. (A) Brief overview of literature reports for the Pd-catalyzed allylation of aryl
boronic acids. (B) General reaction for this study on the prenylation of aryl boronic
acids.
e
57:43
—
34:66
66:34
57:43
62:38
58:42
45:55
34:66
52:48
52:48f
60:40f,g
initial reaction. Interestingly, the 3B:3L ratio of 35:65 provided
greater selectivity for the branched product than described in pre-
vious reports with prenyl alcohol, where 0–8% reverse-prenyl was
observed [26,27]. These preliminary results suggested that (1) a
supporting ligand would increase catalyst activity as well as reac-
tion efficiency and (2) the ligand may influence the product
distribution.
SPhos
aReaction Conditions: nucleophile (1.0 equiv), electrophile (10 equiv), KF (2.0
equiv), 1,4-dioxane (2 mL/mmol nucleophile), Pd2dba3 (0.025 equiv), Ligand:Pd =
2:1. bCombined GC yield of 3B and 3L; average of two experiments. cCombined
isolated yield of 3B and 3L; average of two experiments. dRatio of 3B:3L. eReaction
conducted with Ligand:Pd = 1:1. fReaction performed in toluene instead of 1,4-
dioxane. gReaction conducted at 80 °C instead of 100 °C.
A focused library of monophosphine and diphosphine ligands
was examined in the cross-coupling reaction of 1a with 2a
(Table 1). Monophosphine ligands were more successful than their
diphosphine counterparts. Specifically, no product was detected in
reactions employing BINAP, DPPF, DPEphos, or XantPhos (Table 1,
entries 17–20). In contrast, P(OPh)3 displayed a comparable yield
and product ratio as P(2-furyl)3 (Table 1, entry 13). P(o-tolyl)3
and PtBu2Me resulted in < 5% of the cross-coupling product
(Table 1, entries 14–15). Interestingly, PPh3 favored 3B over 3L,
demonstrating a significant reversal of regioselectivity typically
found for prenyl electrophiles (Table 1, entry 16). The reaction with
PPh3 remained low yielding (17%) though; therefore, a series of
monophosphines were examined to determine whether branched
selectivity could be maintained, while increasing reaction
efficiency.
Dialkylbiaryl phosphines have proven highly effective in cross-
coupling reactions employing aryl boronic acids [30–32]. In this
study, we investigated a variety of these ligands for the cross-cou-
pling reaction of 1a with 2a (Table 1) [33]. Several di-tert-butyl-
derived ligands (i.e., JohnPhos, TrixiePhos, tBuXPhos) were initially
examined, but minimal improvements to reaction yield or 3B:3L
ratio was observed (Table 1, entries 21–23). In contrast, catalyst
systems based upon dicyclohexylbiaryl phosphines provided
appreciable levels of the cross-coupling product (Table 1, entries
24–30). For example, DavePhos afforded a 42% yield with a 3B:3L
ratio of 57:43. Moreover, the nature of the ligand was found to sub-
stantially adjust the reaction efficiency and product distribution, as
the use of XPhos resulted in an 89% yield with selectivity for the
linear product (Table 1, entry 29).
From these initial optimized conditions, Pd2dba3 with SPhos
provided the highest activity among all catalyst systems that
favored 3B (Table 1, entry 30). In addition, an increase in yield to
60% was observed when the reaction was conducted with toluene
as the solvent (Table 1, entry 31). The transformation was further
found to be sensitive to temperature. At lower temperatures, Pd2-
dba3/SPhos resulted in an increased selectivity for 3B but with con-
comitant loss of overall yield. Specifically, a 6% yield with a 3B:3L
ratio of 66:34 was observed at 60 °C. In contrast, elevated temper-
ature (120 °C) resulted in a 75% yield but with opposing regioselec-
tivity (3B:3L ratio of 43:57). Through further optimizations of
reaction temperature and time, we determined that conducting
the reaction at 80 °C for 72 h provided the highest yield (77%),
while still favoring 3B (Table 1, entry 32). These results with the
Pd2dba3/SPhos catalyst system represent a promising advance-
ment for overcoming the substrate bias found in the cross-coupling
of prenyl electrophiles.
2

J. Leister, D. Chao and K.L. Billingsley
Tetrahedron Letters 66 (2021) 152800
interconversion via a
p
-allyl intermediate was readily occurring
during the catalytic cycle and therefore the outcome of the cross-
coupling reaction was independent of the starting alcohol.
The substrate scope of Pd2dba3/SPhos catalyst system was
examined with a variety of aryl and heteroaryl boronic acids
(Table 2). Shorter reaction times are typically more practical in lab-
oratory settings, so standard conditions of 100 °C for 24 h were
adopted for evaluation of this methodology. The transformation
was effective for aryl boronic acids possessing electronic properties
ranging from electron-rich to -poor. For example, nucleophile 4a,
which possesses an electron-withdrawing ketone, displayed an
enhanced yield of 86% (Table 2, entry 2). In addition, electron-neu-
tral (5a) and -rich (6a) aryl boronic acids provided consistently
high yields of 74% and 73%, respectively (Table 2, entries 3–4).
The process proved to be less efficient for 7a, a nucleophile with
multiple electron-donating groups (Table 2, entry 5). The method
was applicable to aryl boronic acids with reactive functional
groups, and 8a, which has a 2° amide bearing a free NH, success-
Fig. 3. Prenylation of 1a with alcohol 2e.
Our studies identified prenyl alcohol (2a) as a suitable elec-
trophile for the prenylation of aryl boronic acids. However, because
2a is a linear 1° alcohol, this starting material could be partially
biasing the product distribution towards the linear regioisomer
3L. To test this hypothesis, analogous experiments were conducted
with 2-methylbut-3-en-2-ol (2e), a 3° alcohol that could directly
lead to branched regioisomer 3B. The Pd2dba3/SPhos catalyst sys-
tem displayed comparable yields and product distributions with
electrophiles 2a and 2e (Fig. 3). These experiment suggested that
Table 2
Substrate scope of the Pd-catalyzed prenylation reaction.a
Entry
1
Nucleophile
Product
Yield (%)b
60
B:Lc
52:48
2
3
86
74
48:52
56:44
4
5
73
38
46:54
40:60
6
63
45:55
7
8
9
62
69
77
42:58
46:54
22:78
10
32d
21:79
aReaction Conditions: nucleophile (1.0 equiv), 2a (10 equiv), KF (2.0 equiv), toluene (2 mL/mmol nucleophile), Pd2dba3 (0.025 equiv), SPhos:Pd = 2:1. bCombined isolated yield
of B and L; average of two experiments. cRatio of B:L. dReaction conducted with Pd2dba3 (0.05 equiv).
3

J. Leister, D. Chao and K.L. Billingsley
Tetrahedron Letters 66 (2021) 152800
Table 3
lations using symmetrical electrophiles. The latter fact is key, as
this methodology could prove generally applicable to a variety of
molecular targets in organic synthesis.
Pd-catalyzed allylation reaction with symmetrical alcohols.a
Conclusion
In summary, we have developed a palladium-based cross-cou-
pling method that allows for the prenylation of aryl and heteroaryl
boronic acids in moderate to good yield (32–86%). Prenyl alcohol
was identified as the ideal electrophile for the transformation. Cat-
alyst systems based upon dicyclohexylbiaryl phosphines were
most effective for promoting carbon–carbon formation, and Pd2-
dba3/SPhos provided increased levels of reverse-prenyl product
relative to previous reports employing prenyl electrophiles. This
method was further demonstrated with symmetrical allylic alco-
hols. Future studies will focus on application of this methodology
to the synthesis of therapeutically relevant natural products.
Entry
1
Electrophile
Product
Yield (%)b
65 (67)c
2
3
40 (29)c
59 (70)c
aReaction Conditions: 6a (1.0 equiv), electrophile (10 equiv), KF (2.0 equiv), toluene
(2 mL/mmol nucleophile), Pd2dba3 (0.025 equiv), SPhos:Pd = 2:1. bIsolated yield;
average of two experiments. cIsolated yield for XPhos shown in parentheses.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
fully furnished the cross-coupling product in 63% yield (Table 2,
entry 6). For these substrates, the branched product consistently
comprised 46–56% of the B:L ratio, which remained higher in
terms of branched regioselectivity than comparable methods for
the coupling of prenyl electrophiles with aryl boronic acids [26,27].
Heterocycles are structures of fundamental importance to the
pharmaceutical industry and natural product synthesis [34]; there-
fore, we explored the applicability of this methodology to several
heteroaryl boronic acids. Electron-rich 5-benzofuran boronic acid
(9a) smoothly furnished the desired cross-coupling product in
62% yield with a 9B:9L ratio of 42:58 (Table 2, entry 7). In addition,
quinoline-6-ylboronic acid (10a) successfully provided a 69% yield
with a similar product distribution (Table 2, entry 8). Indole-based
boronic acids were also examined. The N-protected indole (11a)
provided a high yield (77%), whereas the free-NH substrate (12a)
displayed a decrease in reaction efficiency even with elevated cat-
alyst loadings (Table 2, entries 9–10). Linear selectivity was found
for both of these nucleophiles. This observation could be attributed
to the fact that each substrate possesses ortho-substitution, which
may further shift the product distribution towards the linear
regioisomer. Importantly, the Pd2dba3/SPhos catalyst system
remained highly active for both aryl and heteroaryl boronic acids.
To further illustrate the applications of this methodology, we
also sought to demonstrate that the catalyst remained active for
standard allylic alcohols. Experiments were conducted with 4-phe-
noxyphenylboronic acid (6a) and several symmetrical allylic alco-
hols: 2-methylprop-2-en-1-ol (2f), prop-2-en-1-ol (2 g), and
cyclohex-2-en-1-ol (2 h) (Table 3). The Pd2dba3/SPhos system
maintained consistently high yields (65% and 59%, respectively)
for alcohols 2f and 2 h, whereas electrophile 2 g was less efficient
(Table 3, entries 1–3). The standard conditions require the reaction
to be conducted slightly above the boiling point of alcohol 2 g,
which may contribute to the lower observed yield.
Acknowledgments
This research was financially supported by startup funds
granted by the College of Natural Sciences and Mathematics at Cal-
ifornia State University, Fullerton.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152800.
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5