Dehydrative Cross-Coupling of Allylic Alcohols with Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c00108

A highly efficient Pd/Ca catalytic system for the directly dehydrative cross-coupling of allylic alcohols with terminal alkynes was developed. This calcium salt cocatalyst facilitates the oxidative addition of the palladium catalyst (1 mol %) to the C-OH bond. Then, the in situ-generated hydroxide ion deprotonates the terminal alkynes to promote the formation of the allylalkynylpalladium intermediate, liberating water as the only byproduct. This proposed mechanism is also supported by density functional theory calculations. An anticancer agent was prepared from inexpensive starting materials on a 10 g scale.

Full text of DOI:10.1021/acs.orglett.0c00108

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Letter
Dehydrative Cross-Coupling of Allylic Alcohols with Alkynes
Peizhong Xie,* Zuolian Sun, Shuangshuang Li, Lei Zhang, Xinying Cai, Weishan Fu, Xiaobo Yang,
Yanan Liu, Xiangyang Wo, and Teck-Peng Loh*
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ABSTRACT: A highly efficient Pd/Ca catalytic system for the
directly dehydrative cross-coupling of allylic alcohols with terminal
alkynes was developed. This calcium salt cocatalyst facilitates the
oxidative addition of the palladium catalyst (1 mol %) to the C−
OH bond. Then, the in situ-generated hydroxide ion deprotonates
the terminal alkynes to promote the formation of the
allylalkynylpalladium intermediate, liberating water as the only
byproduct. This proposed mechanism is also supported by density
functional theory calculations. An anticancer agent was prepared
from inexpensive starting materials on a 10 g scale.
he 1,4-enyne skeletons are identified as privileged motifs
1
Tin organic synthesis and biologically and pharmaceuti-
cally active molecules2 (such as hypoxoside and rooperol2a,c,g).
In particular, 1,5-aryl-disubstituted 1,4-enynes were found to
have highly potent anticancer activity against human
esophageal carcinoma cell growth in recent pharmacological
investigations.2a,e This moiety is generally prepared from highly
functionalized activated allylic compounds or preactivated
alkynes with the assistance of large quantities of neutralizing
agents/oxidants and thus generates a stoichiometric amount of
metallic salt.1f,3 Undoubtedly, the direct dehydrative cross-
coupling between allylic alcohols and alkynes to access 1,4-
enynes would be the most ideal approach.4,5 However, the
irreconcilable contradiction between acidity activator for C−
OH bond activation and basic environmental condition
required for maintaining the nucleophilic activity of terminal
alkynes1f challenged the development of catalysts. To address
this problem, the groups of Trost,6 Jiang,7 Kimura,8 and Li9
have paid an extensive amount of attention to this area since
the 1990s. Unfortunately, 1,4-dienes, rather than 1,4-enynes,
were delivered as the major products6−8 (Figure 1a). In one
report, 1,4-enynes were obtained by Li and Liu, who found a
strong dependence on high catalyst (10 mol % Pa) and
additive (25 mol % Ti) loadings.9 On the contrary, Cu10a or
Ga10b was also reported in a few cases to catalyze this reaction
toward some special alcohols in a limited substrate scope via a
carbocation mechanism; a rejuvenation of the dehydrative
cross-coupling can still be anticipated via the creation of a new
strategy capable of overcoming issues such as catalytic
efficiency and a strong dependence on well-defined ligands
and highly concentrated additives.9
Figure 1. Development of dehydrative cross-coupling of allylic
alcohols with alkynes.
with terminal alkynes. We envision the directly oxidative
addition of palladium to the C−OH bond might occur, giving
Received: January 14, 2020
In our continuing green chemistry efforts,5a,11 we focused on
the development of a greener and more efficient method for
addressing the dehydrative cross-coupling of allylic alcohols
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© XXXX American Chemical Society
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A

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a
Scheme 1. Dehydrative Cross-Coupling of Allylic Alcohols with Alkynes
a
MBH alcohol (1.0 equiv, 0.2 mmol), ethynyltriisopropylsilane (2.5 equiv), Pd(PPh3)4 (1.0 mol %), Ca(NTf2)2 (5.0 mol %), NH4PF6 (5.0 mol %),
b
H2O (30 mol %), DMA (2.0 mL), Ar, 100 °C (oil bath), isolated yields. TIPS = triisopropylsilyl. Pd(PPh3)4 (1.0 mol %), Ca(NTf2)2 (5.0 mol %),
c
d
N,N,N′,N′,N″,N″-hexamethylphosphoramide (HMPA) (1.2 mol %), triethylamine (1.0 mol %). 3u, a Z/E ratio of 2/1. 3ab, a Z/E ratio of 5/1.
e
f
Pd(PPh3)4 (3.0 mol %), Ca(NTf2)2 (10.0 mol %), HMPA (3.6 mol %), triethylamine (3.0 mol %). α/γ = 2/3. For 3s, ethynyltrimethylsilane (10
equiv) was used. 3a−3av were prepared from 1, and 3ax−3bc were prepared from 1′.
π-allylpalladium intermediates and hydroxide ions with the
assistance of a suitable cocatalyst. Subsequently, the in situ-
generated hydroxide ions can serve as the base to deprotonate
the terminal alkynes, delivering water as the only byproduct.
Then, the reaction process could heavily favor the desired π-
allylalkynylpalladium intermediate rather than the competitive
allylvinylpalladium or dialkynylpalladium pathways (Figure
1b). Herein, we report a highly efficient Pd/Ca catalytic system
for the direct dehydrative cross-coupling between allylic
alcohols and alkynes (Figure 1c). The assumed mechanism
was also demonstrated by DFT calculations. (E)-1-Methoxy-4-
(5-phenylpent-4-en-1-yn-1-yl)benzene (an inhibitor of human
esophageal carcinoma cell growth; IC50 = 10 μg/mL; 2.5 times
more active than rooperol)2a can be conveniently prepared on
a 10 g scale from commercially available and ubiquitous
B
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feedstocks, namely, (E)-3-phenylprop-2-en-1-ol and 1-ethynyl-
4-methoxybenzene.
double dehydrative allylalkynyl cross-coupling was also
demonstrated with the generation of 3t in good yield.
Next, secondary and tertiary allylic alcohols other than MBH
derivatives were tested as the allylic coupling partner. As
expected, the desired products (3u) can also be obtained when
the ester group is replaced with a methyl. This result indicated
that the reaction was not limited to electron-deficient allylic
alcohols. A variety of aryl-substituted allylic alcohols were
found to be fully compatible with this method (3v−3aa, 3ad,
and 3ae), regardless of the electron-withdrawing or electron-
donating groups on the phenyl ring. It should be noted that 1-
(pyridin-3-yl)prop-2-en-1-ol could also deliver the desired
product (3z) in high yield. Even a phenolic hydroxyl group was
found to be well tolerated in this reaction; however, the
corresponding 1,3-enyne (3aa) was obtained in a slightly lower
yield. Remarkably, this method also allowed access to 4,6-dien-
1-yne skeletons (3ab) from vinyl-substituted allylic alcohols.
This will increase the opportunities for structural modification
of the products and enhance their synthetic utility. Notably,
tertiary allylic alcohols could undergo intramolecular elimi-
nation processes if they had an adjacent α-C−H bond,
resulting in the desired product in moderate yield (3ad). A
steroid moiety with an active hydroxyl group was also well
tolerated (3ae), which further highlights the utility of this
method in pharmaceutical studies. Moreover, nonconjugated
allylic alcohols were also compatible (3af and 3ag). 3af can be
isolated in high yield, while the sterically demanding 3ag was
obtained in lower yields only due to the competitive
dimerization of 2a (for detail, see the SI).
The reaction of methyl 2-[hydroxy(phenyl)methyl]acrylate
(1a) with ethynyltriisopropylsilane (2a) was selected as a
model. Without other cocatalysts, palladium itself could not
promote the reaction [Supporting Information (SI), Table 1,
entries 1−3]. In searching for a powerful cocatalyst (SI, Table
1, entries 4−7), we paid special attention to alkaline earth
metals,12 which are abundant and exhibited amazing catalytic
activities in many transformations.13 In particular, calcium salts
are powerful catalysts for Friedel−Crafts and related cationic
cycloadditions14−16 developed by the groups of Niggemann,14
Gandon,15 and others16 owing to their high activities toward
alcohols and epoxides. Inspired by these studies and
investigations related to the Trost−Tsuji reaction,17 we
envision the combination of an alkaline earth metal with
palladium might be a solution for this challenging dehydrative
cross-coupling. To our delight, with the assistance of
Ca(NTf2)2 (20 mol %) and Pd(PPh3)4 (10 mol %), the
reaction proceeded smoothly with dioxane as the solvent to
afford the desired product in 69% yield (SI, Table 1, entry 6).
In all the tested case, the solvent DMA (N,N-dimethylaceta-
mide) give the best yield (SI, Table 2). The temperature and
reaction time had substantial influences on the outcome of this
reaction (SI, Table 3, entries 1−5). NH4PF6 was identified as a
powerful additive for accelerating the transformation (SI, Table
3, entries 6−10). In sharp contrast with the previous study,9 in
which a high palladium loading (10 mol %) combined with a
well-defined ligand was vital to the success of the cross-
coupling reaction, Pd(PPh3)4 (1 mol %) in cooperation with
Ca(NTf2)2 (5 mol %) exhibited excellent catalytic activity in
our developed method (SI, Table 3, entries 11−18). Even
Pd(PPh3)4 (0.5 mol %) combined with Ca(NTf2)2 (10 mol %)
can promote this transformation, albeit with a lower yield (SI,
Table 3, entries 19 and 20). Further investigations revealed
that water (SI, Table 3, entries 21−25) and the counterions
also play an important role in this reaction. Ca(NTf2)2 and
Ca(OTf)2 worked well, whereas CaCl2 was ineffective in this
transformation (SI, Table 3, entries 26 and 27).
Under the optimized reaction conditions, we examined the
reactions between Morita−Baylis−Hillman (MBH) alcohols 1
and ethynyltriisopropylsilane (2a). As shown in Scheme 1, a
variety of MBH alcohols were amenable to this protocol. The
electronic properties (3a−h) and position (3b, 3i, and 3j) of
the phenyl substituents on the MBH alcohols have little effect
on the yield. Even allylic alcohols bearing highly active groups
such as nitryl (3d), cyano (3e), and trifluoromethyl (3h) could
furnish the desired products in good yields. Monosubstituted
and polysubstituted (3k) as well as fused-aromatic (3l) MBH
alcohols smoothly reacted with ethynyltriisopropylsilane (2a)
under the identified conditions. MBH alcohols bearing
heteroaryl substituents, such as pyridien-2-yl (3m), thiophen-
2-yl (3n), and furan-2-yl (3o), were also well tolerated.
Moreover, a cinnamoyl group was tolerated, delivering a
synthetically useful 2,4-dienoate skeleton with an alkyne
moiety (3p). Sterically demanding allylic alcohols can also
proceed smoothly (3f and 3q), but in some cases, the yields
were lower. A comparable result was obtained even when the
ester group was replaced with a cyano group (3r).
Ethynyltrimethylsilane was also compatible with the reaction
conditions (3s), and the convenient deprotonation of the TMS
(trimethylsilyl) group will facilitate further elaboration. A
Having established the scope of the reaction with respect to
allylic alcohols, we investigated the suitability of various
terminal alkynes for this reaction. We varied the aryl acetylene
in an attempt to prepare 1,5-diaryl-substituted 1,4-enyne
skeletons, which are common in biologically and pharmaceuti-
cally active molecules in addition to being a privileged motif in
organic synthesis.
To improve the overall performance, N,N,N′,N′,N″,N″-
hexamethylphosphoramide (HMPA) (1.2 mol %) and triethyl-
amine (TEA) (1.0 mol %) were introduced to replace
NH4PF6. We found that the reaction was very sensitive to
the acidity of the C(alkynyl)−H bond (3ah and 3ak−3ap).
Electron-deficient aryl acetylenes, to some extent, disfavored
the transformation (3ak, 3am, and 3ao). The position of the
substituents (para, ortho, and meta) on the phenyl ring has a
limited effect on the transformation (3ak, 3an, and 3ao).
Notably, a tert-butyl substituent at the phenyl ring could
effectively participate in this transformation (3ap). Moreover,
allylic alcohols with adjacent C−H bonds, which favored the
self-dehydration process with the generation of conjugated 1,3-
dienes, can also react with aryl acetylene to give the
corresponding products (3ai and 3aj) in moderate to high
yields. In our preliminary investigation, alkyl acetylenes such as
ethynylcyclopropane were found to be suitable substrates for
this reaction (3aq and 3ar). Allylic alcohols without ester
substituents were also suitable substrates when reacted with
aryl acetylene (3ar−3av). In the tested case, the reaction of
nonconjugated allylic alcohols with aryl-substituted terminal
alkynes was sluggish and thus gave the desired product in
moderate yield (for details, see the SI). Finally, the reactions
between ubiquitous feedstock cinnamyl alcohol and commer-
cially available aryl acetylenes were investigated. The
extensively investigated biologically active 1,5-diaryl-substi-
tuted 1,4-enynes (derivatives of natural products such as
C
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hypoxoside and rooperol, which exhibit good anticancer
bioactivities) were obtained in moderate to high yields under
our developed catalytic system (3ax−3bc).
Scheme 3. Synthesis of the Anticancer Bioactive Molecule
1,4-Dienyne Moiety and Related Modification
Using our developed method, the same product, (E)-1-
methoxy-4-(5-phenylpent-4-en-1-yn-1-yl)benzene (3aw), was
obtained from both 1-phenylprop-2-en-1-ol and cinnamyl
alcohol upon reaction with ethynyltriisopropylsilane (Scheme
2). These results indicate that the same π-allylpalladium
a
Scheme 2. Control Experiments
a
(i) Pd(PPh3)4 (1.0 mol %), Ca(NTf2)2 (5.0 mol %), NH4PF6 (5.0
mol %), 100 °C for 12 h; (ii) Pd(PPh3)4 (1.0 mol %), Ca(NTf2)2 (5.0
mol %), NH4PF6 (5.0 mol %), 100 °C for 20 h; (iii) Pd(PPh3)4 (1.0
mol %), Bronsted acids [p-TsOH (5 mol %) or PhCO2H (5 mol %)],
100 °C for 24 h.
allylpalladium intermediate. However, the high free energy
barrier (TS0 = 43.2 kcal/mol; for details, see the SI) of the
corresponding transition state indicates that the process might
not be readily accessible. With the assistance of Ca(NTf2)2, the
transition from CAT-R to pre-COM occurred spontaneously
with the release of 14.1 kcal/mol of free energy. Furthermore,
the subsequent oxidative addition involving C−OH bond
cleavage could be facilitated by Ca(NTf2)2 due to the
formation of the Ca−OH bond. The traditional mechanism,
loss of the leaving group from the face of the double bond
opposite palladium (TS1′) to form the Pd(II)-complex INT-1,
cannot completely be ruled out by control experiments (for
details, see the SI). To account for the mechanism, a more
reasonable pathway was proposed on the basis of the related
investigation and our DFT calculations (TS-1 vs TS-1′). The
existence of the interaction between OH and Pd18 in addition
to the coordination effect of electron-rich oxygen atoms
(NTf2) on palladium enabled the elimination of OH from the
face of palladium in a neighborhood participation manner. The
free energy barrier associated with TS-1 is only 12.3 kcal/mol,
and the much more stable Pd(II) complex, INT-1, with an η3-
allyl ligand was delivered. Subsequently, the combination of
INT-1 with alkyne 2 via a palladium−triple bond interaction
affords INT-1-yne. The in situ-generated hydroxide ion then
deprotonates the terminal alkyne through kinetically favored
transition state TS-2 with a low free energy barrier (4.8 kcal/
mol), promoting the formation of allylalkynylpalladium
intermediates INT-2 and INT-2′. Finally, allyl−alkynyl bond
formation via a reductive elimination (TS-3, with a free energy
barrier of 24.2 kcal/mol for the elementary step) gives 1,4-
enynes 3 (INT-3). The cocatalyst can be regenerated in the
presence of an allylic alcohol. For the proposed multistep
pathway, the rate-determining free energy barrier can be
derived from the energetic span model,19 which leads to a total
barrier height of 29.6 kcal/mol, the free energy difference
between INT-1 and TS-3, in line with the experimental
temperature used.
intermediate was generated from the two isomeric allylic
alcohols. Moreover, no reaction occurred in the absence of
Ca(NTf2)2 or even when Bronsted acids, such as 4-
methylbenzenesulfonic acid or benzoic acid, were used under
the identified conditions (for details, see the SI).
Among the reported derivatives, (E)-1-methoxy-4-(5-
phenylpent-4-en-1-yn-1-yl)benzene (3bd) was identified as
having the highest bioactivity in the inhibition of human
esophageal carcinoma cell growth (IC50 = 10 μg/mL; 2.5 times
more active than rooperol).2a With our developed method,
(E)-1-methoxy-4-(5-phenylpent-4-en-1-yn-1-yl)benzene (3bd)
could be conveniently obtained on a gram scale (77% yield, 1.9
g) from 1-phenylprop-2-en-1-ol upon reaction with 1-ethynyl-
4-methoxybenzene. Moreover, the high efficiency of the
catalytic system was further supported by a 10 g scale reaction,
which was conducted at a higher concentration (0.67 M).
More than 10 g of desired anticancer agent 3bd can be
isolated, corresponding to a moderate yield (Scheme 3a). The
1,4-enynes obtained using our protocol are amenable to further
synthetic transformations. Under mild conditions, the triple
bond could be selectively bifunctionalized to afford 4 (Scheme
3b). The TMS moiety can be conveniently removed by
treatment with TBAF in aqueous media (compound 5),
allowing further elaboration by click chemistry (compound 6,
CCDC 1883149) (Scheme 3c).
The detailed mechanism was still unclear; to elucidate the
reaction mechanism, density functional theory (DFT)
calculations were carried out using the Gaussian 09 computa-
tional program. The geometries were optimized in the gas
phase at the B3LYP/DGDZVP level of theory, and then,
single-point energies were determined at the B3LYP+D3-
PCM/Def2TZVPP level of theory (for computational details,
see the SI and SI references 4−10). 1-Phenylprop-2-en-1-ol
and ethynyltriisopropylsilane were selected as the model
reactants for the examination of the mechanism (Figure 2).
Bicoordinate Pd(0) complex CAT-R was initially generated.
Theoretically, the oxidative addition of Pd(0) to the C−OH
bond could be performed directly by delivering the π-
In conclusion, a highly efficient Pd/Ca cocatalytic system
was developed to achieve the direct dehydrative Tsuji−Trost
reaction from ubiquitous allylic alcohol feedstocks with
commercially available terminal alkynes. The DFT calculations
indicated that this cocatalyst enabled the oxidative addition of
the palladium catalyst (1 mol %) to the C−OH bond without
D
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Figure 2. Free energy profile for the dehydrative cross-coupling reaction, at the B3LYP+D3-PCM/Def2TZVPP//B3LYP/DGDZVP level of
theory.
the assistance of an external ligand or Bronsted acid.
Subsequently, the hydroxide ion rather than water (in the
traditional model, with the assistance of a Bronsted acid) was
generated as the base, which can deprotonate the terminal
alkyne to promote the formation of the allylalkynylpalladium
intermediate and then liberate water as the only byproduct. A
variety of 1,4-enynes could be conveniently isolated in high
yields with broad functional group tolerance. Remarkably, the
utility of the methodology has been highlighted by the direct
preparation of anticancer agents (IC50 = 10 μg/mL) on a 10 g
scale from commercially available feedstocks, (E)-3-phenyl-
prop-2-en-1-ol and 1-ethynyl-4-methoxybenzene.
Sciences, Nanyang Technological University, Singapore
637371; orcid.org/0000-0002-2936-337X;
Email: teckpeng@ntu.edu.sg
Authors
Zuolian Sun − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China
Shuangshuang Li − School of Chemistry and Molecular
Engineering, Institute of Advanced Synthesis, Nanjing Tech
University, Nanjing 211816, P. R. China
Lei Zhang − School of Science, Tianjin Chengjian University,
Tianjin 300384, P. R. China
ASSOCIATED CONTENT
* Supporting Information
Xinying Cai − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China
Weishan Fu − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China
Xiaobo Yang − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China
Yanan Liu − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00108.
Experimental procedures, screening reaction conditions,
NMR spectra of products, and DFT calculation methods
and results (PDF)
Accession Codes
CCDC 1883149 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Xiangyang Wo − School of Chemistry and Molecular
Engineering, Institute of Advanced Synthesis, Nanjing Tech
University, Nanjing 211816, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00108
AUTHOR INFORMATION
Corresponding Authors
■
Notes
Peizhong Xie − School of Chemistry and Molecular Engineering,
Institute of Advanced Synthesis, Nanjing Tech University,
Nanjing 211816, P. R. China; orcid.org/0000-0002-6777-
0443; Email: peizhongxie@njtech.edu.cn
Teck-Peng Loh − School of Chemistry and Molecular
Engineering, Institute of Advanced Synthesis, Nanjing Tech
University, Nanjing 211816, P. R. China; Division of Chemistry
and Biological Chemistry, School of Physical and Mathematical
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China
(21702108), the Natural Science Foundation of Jiangsu
Province, China (BK20160977), the Six Talent Peaks Project
E
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X.; Fu, W.; Loh, T.-P. Org. Lett. 2018, 20, 3341. (d) Wo, X.; Xie, P.;
Fu, W.; Gao, C.; Liu, Y.; Sun, Z.; Loh, T.-P. Chem. Commun. 2018, 54,
11132. (e) Xie, P.; Wang, J.; Fan, J.; Liu, Y.; Wo, X.; Loh, T.-P. Green
Chem. 2017, 19, 2135.
in Jiangsu Province (YY-033), the Fundamental Research
Funds for Tianjin Colleges (2018KJ171), a grant from the
Ministry of Education of Singapore MOE2016-T1-002-043
(RG111/16), and Nanjing Tech University (39837101).
(12) (a) Xie, P.; Li, S.; Liu, Y.; Cai, X.; Wang, J.; Yang, X.; Loh, T.-P.
Org. Lett. 2020, 22, 31−35. (b) Xie, P.; Wo, X.; Yang, X.; Cai, X.; Li,
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