Synthesis of 1,5-diphenylpent-3-en-1-yne derivatives utilizing an aqueous B-alkyl Suzuki cross coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2013.07.020

1,5-Diphenylpent-3-en-1-yne derivatives were isolated in minor quantities from terrestrial plants and exhibited strong anti-inflammatory activity. A cross coupling reaction between B-benzyl-9-BBN and chloroenynes under mild condition was developed resulti

Full text of DOI:10.1016/j.tetlet.2013.07.020

Tetrahedron Letters 54 (2013) 5162–5166
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,5-diphenylpent-3-en-1-yne derivatives utilizing
an aqueous B-alkyl Suzuki cross coupling reaction
Da-Wei Chuang a, Mohamed El-Shazly a,b, Chin-Chau Chen c, Yu-Ming Chung a, Balaji D. Barve d,
Ming-Jung Wu c, Fang-Rong Chang a, , Yang-Chang Wu a,e,f,g,
⇑
⇑
a Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt
c Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan
d Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan
f Natural Medicinal Products Research Center, China Medical University Hospital, Taichung 404, Taiwan
g Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
1,5-Diphenylpent-3-en-1-yne derivatives were isolated in minor quantities from terrestrial plants and
exhibited strong anti-inflammatory activity. A cross coupling reaction between B-benzyl-9-BBN and chlo-
roenynes under mild condition was developed resulting in the formation of different 1,5-diphenylpent-3-
en-1-yne derivatives with a full control on the E/Z selectivity. Several substrates bearing electron-donat-
ing and electron-withdrawing substituents were tolerable under the reaction conditions affording the
corresponding products in good yields. This is the first study to report the synthesis of a vast array of
novel 1,5-diphenylpent-3-en-1-yne derivatives paving the way for the preparation of tailored derivatives
on mass scale necessary for biological studies and drug development.
Received 13 May 2013
Revised 21 June 2013
Accepted 3 July 2013
Available online 10 July 2013
Keywords:
Henna
Palladium
B-Benzyl-9-BBN
B-Alkyl Suzuki coupling
Aqueous reaction
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
From a retrosynthetic perspective, 1,5-diphenylpent-3-en-1-
ynes can be considered as a combination of enynes and allylated
Human beings’ fascination with natural products and their
curative effect go back to the early days of human history.1 Henna
(Lawsonia inermis) is a perfect example of an ancient and globally
used herb with a myriad of medicinal and cosmetic uses. Several
biologically active components have been isolated from henna
and some of them have been synthetically prepared.1 Our group
has recently reported the isolation of novel 1,5-diphenylpent-3-
en-1-yne derivatives from henna possessing impressive anti-
inflammatory activity (Fig. 1).2 These derivatives are unique from
different perspectives because they were isolated for the first time
from nature and only two reports in the early nineties discussed
the synthesis of a single 1,5-diphenylpent-3-en-1-yne derivative.3
The significant biological activity and limited isolated quantities
encouraged us to envisage the development of a simple and high
yielding methodology for their synthesis.
aromatics. The enyne moiety and allylated aromatics represent
important structural motifs which are found in many synthetic
precursors.4–10 Despite the fact that 1,3-enyne synthesis has been
established through different efficient methodologies,4 the synthe-
allylated aromatics
R4
R3
enyne
R1
R2
1: R1 = R3 = H, R2 = R4 = OH
2: R1 = R2 = R4 = OH, R3 = H
3: R1 = H, R2 = R4 = OH, R3 = OCH3
⇑
Corresponding authors at: Graduate Institute of Natural Products, College of
Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Tel.: +886 7
3121101x2162; fax: +886 7 3114773.
E-mail address: aaronfrc@kmu.edu.tw (F.-R. Chang).
Figure 1. New 1,5-diphenylpent-3-en-1-ynes isolated from henna.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.020

D.-W. Chuang et al. / Tetrahedron Letters 54 (2013) 5162–5166
5163
Nu
3
1
desired pathway
5
Nu
LG
R
R
u
4
n
1,1-substitution
d
e
s
i
r
e
d
LG = Leaving group
p
a
t
h
w
a
y
Nu
Nu
or
R
R
1,5-substitution
1,3-substitution
Scheme 1. Desired and undesired products from SN reaction of organometallic nucleophiles with enynes.
sis of 1,5-diphenylpent-3-en-1-yne derivatives did not receive
such success. Masuyama et al. used a palladium catalyzed dehy-
dration of propynyl alcohols with SnCl2. However, the product
was formed as a mixture of E/Z isomers (20/80) and the yield
was only 53%.3a Yoshimatsu et al. developed a mild dehydration
process using polyphosphoric acid trimethylsilyl ester (PPSE), but
the method also provided 1,5-diphenylpent-3-en-1-yne as a mix-
ture of E/Z isomers (33/67) with mediocre yield (54%).3b
However, the subsequent use of this reagent in related cross cou-
pling reactions is seldom described in the literature.16,17 Based
on the aforementioned structural analysis of 1,5-diphenylpent-3-
en-1-ynes, we developed a versatile synthetic protocol for their
synthesis in which (E)- and (Z)-chloroenynes were utilized for
the first time as the coupling partners with B-benzyl-9-BBN.
Results and discussion
Nucleophilic substitution of an organometallic reagent on the
allylic position of an enyne (4) was proposed as an alternative
route for the preparation of 1,5-diphenylpent-3-en-1-ynes, how-
ever other side reactions such as 1,3-substitution or 1,5-substitu-
tion are inevitable (Scheme 1).11 Additionally, the use of highly
reactive and moisture-sensitive organometallic reagents adds to
the reaction limitations. In order to establish an easy access to
1,5-diphenylpent-3-en-1-yne derivatives, a mild and selective
method must be introduced. The recent advances in C–C bond for-
mation reactions, suggested that B-alkyl Suzuki coupling could of-
fer a solution to this problem.12
The B-alkyl Suzuki reaction differs from the typical Suzuki reac-
tions, in which alkyl boranes are utilized instead of vinyl or aryl
boranes to react with aryl or vinyl halides.13 In the B-alkyl Suzuki
reaction, the hydroboration of an olefin is followed by a metal-cat-
alyzed coupling reaction with the organic halides. However, these
procedures cannot be applied for the synthesis of 1,5-diphenyl-
pent-3-en-1-ynes because it will result in the formation of prod-
ucts with additional methylene bridge.14 Therefore, we proposed
an alternative pathway for the synthesis of 1,5-diphenylpent-3-
en-1-ynes from two synthons, an enyne (5), and B-benzyl-9-BBN
(Scheme 2).
The preparations of (E)- and (Z)-chloroenynes were achieved
through a typical sonogashira coupling reaction.18 With different
chloroenynes in hand, we proceeded to examine the optimum cou-
Table 1
Optimization of the B-alkyl Suzuki cross coupling reactions using water as the sole
solventa
B
Cl
Pd/Base/H2O/Temp/Time
OCH3
OCH3
8c
6c
Entry Catalyst
(3 mol %)
Base
(3 equiv)
Time
(h)
Temp
(°C)
Yieldb
(%)
most of the organometallic coupling reactions. Some studies re-
ported the preparation of benzylboranes using bis(pinacola-
to)diboron and benzyl halides with palladium or other metal
catalysts as well as B-OMe-9-BBN with benzyl metal species.15
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KOH
6
6
6
6
6
6
6
6
6
6
6
6
12
24
12
12
60
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
Trace
Trace
Trace
20
65
68
75
62
75
Trace
68
77
82
79
Trace
45
Pd2(dba)3
PdCl2(dppf)
PdCl2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
9
10
11
12
13
14
15
16c
KF
Et3N
X
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
+
B
B-benzyl-9-BBN
60
a
Conditions: 6c (80 mg), BBN (2 equiv), catalyst (3 mol %), base (3 equiv), H2O
(6 mL).
5
b
Isolated yields.
c
Reaction without nitrogen.
Scheme 2. Retro-synthetic analysis of 1,5-diphenylpent-3-en-1-yne.

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D.-W. Chuang et al. / Tetrahedron Letters 54 (2013) 5162–5166
Table 2
Synthesis of 1,5-diphenylpent-3-en-1-yne derivativesa
Cl
R1
R1
B
8
6
Pd(PPh3)4/Cs2CO3/H2O, 60 °C
12 hour
Cl
R2
R2
9
7
Entry
Product
Entry
Product
1
8
9h (73%)
9i (76%)
b
8a (65%)
2
3
4
9
8b (71%)
10
11
H3CO
H3CO
H3CO
H3CO
8c (82%)
8d (68%)
9j (65%)
9k (83%)
H3CO
H3CO
5
12
13
OCH3
OCH3
8e (72%)
9l (65%)
F
HO
6
7
9m (64 %)
8f (70%)
HO
8g (50%)
a
Conditions: 6 or 7 (80 mg), BBN (2.0 equiv), Pd(PPh3)4 (3.0 mol %), Cs2CO3 (3.0 equiv), H2O (6.0 mL), 60 °C, 12 h.
Isolated yields.
b

D.-W. Chuang et al. / Tetrahedron Letters 54 (2013) 5162–5166
5165
+
+
Base
Base
B
RL2Pd
RL2Pd
B
Base
B
X
Ph
Ph
9
10
Ph
Ph
Base
Base
B
B
L
Ph
R
Pd
L
R-PdXL2
PdL2
R
Ph
R-X
R = chloroenynes
Scheme 3. Plausible mechanism of B-alkyl Suzuki cross coupling reactions.
pling condition with B-benzyl-9-BBN.19 Initially, we used (Z)-chlo-
roenynes 6c (1.0 equiv) as a model substrate with 2.0 equiv of B-
benzyl-9-BBN, 3.0 mol % of Pd(PPh3)4, and 3.0 equiv of K3PO4 in
dry THF at 60 °C for 6 h. Under this condition, the desired (Z)-prod-
uct 8c was obtained in 65% yield without the formation of the
opposite geometrical isomer. Higher yield (78%) was obtained
upon using a mixture of THF and water (3:1). This improvement
in the product yield encouraged us to examine the use of water
as the sole solvent, which to our delight resulted in similar yield
(75%).
Optimizing the reaction time was the final step in the screening
experiments, which was achieved through comparing product
yields after 6, 12, and 24 h. After 12 h the yield increased to 82%
(Table 1, entry 13) compared to 77% yield obtained after 6 h (Ta-
ble 1, entry 12), however after 24 h it dropped slightly (79%, Ta-
ble 1, entry 14) indicating that the optimum reaction time is
12 h. This finding was supported by a time-course NMR experi-
ment (see Supplementary data). Based on the aforementioned
screening results, entry 13 was selected as the most optimum
condition.
After selecting water as the coupling reaction solvent, we exam-
ined the effect of changing other reaction conditions on the prod-
uct yield. Different palladium salts were tested aiming to select
the optimum catalyst for the coupling reaction. The use of
Pd(OAc)2, PdCl2, and Pd2(dba)3, failed to provide any product (Ta-
ble 1, entries 1–3). PdCl2(dppf) resulted in poor yield (20%, Table 1,
entry 4). However, the use of PdCl2(PPh3)2 improved the yield sig-
nificantly (65%, Table 1, entry 5), and Pd(OAc)2(PPh3)2 also resulted
in a similar outcome (68%, Table 1, entry 6). The most commonly
utilized palladium catalyst in organic synthesis, Pd(PPh3)4 afforded
the best result (75%, Table 1, entry 7). These screening reactions
suggested that PPh3 is the ideal ligand compared to other ligands
such as dppf or dba; and Pd(0) is the optimum catalyst compared
to Pd(II). Following the catalyst optimization, we examined the ef-
fect of using different bases on the reaction yield. The use of K3PO4
and KOH resulted in similar yields (75%, Table 1, entry 7 and 9),
while K2CO3 provided slightly a lower yield (62%, Table 1, entry
8). KF, another base used frequently in Suzuki coupling reactions,
failed to yield the desired compound (Table 1, entry 10). Interest-
ingly, the organic base Et3N afforded the product in 68% yield (Ta-
ble 1, entry 11), providing an additional evidence of the versatility
of B-alkyl-Suzuki coupling, since organic amines are not frequently
used in Suzuki cross coupling reactions.20
The optimized cross coupling conditions were applied for the
preparation of different 1,5-diphenylpent-3-en-1-yne derivatives.
Several (Z)-chloroenynes bearing alkoxy groups (Table 2, entries
3–5) reacted selectively and smoothly yielding the corresponding
(Z)-1,5-diphenylpent-3-en-1-ynes without the formation of the
(E)-isomers. This strict stereoselectivity was also achieved for the
(E)-chloroenynes (Table 2, entries 8–13). Interestingly, chloroeny-
nes bearing a free hydroxy group were tolerable under this basic
aqueous condition and afforded the products with moderate yields
(Table 2, entries 7 and 13).
From a mechanistic point of view, the B-alkyl-Suzuki reaction is
slightly different from the typical Suzuki coupling reaction. Soder-
quist and Matos have reported a pioneer investigation on the
mechanism of cross coupling reaction involving B-alkyl-9-BBN
derivatives.22 The base used in the reaction plays a critical role in
the whole mechanistic cycle, especially in the conversion of the
B-alkyl-9-BBN into a more reactive species (9) (Scheme 3). They
suggested a formation of four-centered hydroxo-l2-bridged transi-
tion state (10) which collapses facilitating the transfer of an alkyl
group to the palladium catalyst. Finally through the reductive
elimination step, the desired product is generated. The use of water
in our condition improved base solubility pushing the conversion
of B-benzyl-9-BBN to the corresponding active species (9).
However, the highest yield was obtained using Cs2CO3, which
was selected as the optimum base (77%, Table 1, entry 12).21 The
effect of running the reaction under inert or ambient atmosphere
on the product yield was also studied. Under ambient atmo-
sphere, the reaction mixture turned black and the yield decreased
to 45% (Table 1, entry 16); suggesting the necessity of inert con-
dition for the optimal yield. The effect of temperature was also
examined showing that conducting the reaction at room temper-
ature led to the formation of the product in trace amounts
(Table 1, entry 15).
Conclusion
A mild and selective B-alkyl Suzuki cross coupling protocol for
the synthesis of 1,5-diphenylpent-3-en-1-yne derivatives was
developed. In this study, we present not only the first cross cou-
pling reaction between B-benzyl-9-BBN and chloroenynes, but also
the use of pure water as the reaction solvent for this type of reac-
tions. A number of 1,5-diphenylpent-3-en-1-yne derivatives were
synthesized successfully under this condition with moderate to

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Acknowledgments
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This study was supported by NSC grants (NSC 102-2911-I-002-
303 and NSC 101-2325-B-039-004 to Y.C. Wu), and a grant from
the Department of Health, Executive Yuan, R.O.C. (Taiwan)
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Supplementary data
Supplementary data (1H and 13C NMR copies of all the com-
pounds are available, time-course NMR experiment) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.07.020.
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