Palladium-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes with Hydrazones

Article abstract of DOI:10.1002/anie.202005132

We have developed an unprecedented Pd-catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio- and stereoselectivity to form (Z)-alkenes, which are more difficult to generate compared to (E)-alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, late-stage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd-hydride intermediates.

Full text of DOI:10.1002/anie.202005132

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Pd-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes
with Hydrazones
Authors: Lin Yu, Leiyang Lv, Zihang Qiu, Zhangpei Chen, Ze Tan, Yu-
Feng Liang, and Chao-Jun Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005132
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Pd-Catalyzed Formal Hydroalkylation ofAryl-Substituted Alkynes
with Hydrazones
Lin Yu,[a],[b],‡ Leiyang Lv,[a],‡ Zihang Qiu,[a] Zhangpei Chen,[a] Ze Tan,[b] Yu-Feng Liang,[a] Chao-Jun Li*[a]
Dedication ((optional))
[a]
[b]
L. Yu, Dr. L. Lv, Dr. Z. Qiu, Dr. Z. Chen, Dr. Y.-F. Liang, Prof. Dr. C.-J. Li
Department of Chemistry and FRQNT Center for Green Chemistry and Catalysis
McGill University
801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
E-mail: cj.li@mcgill.ca
L. Yu, Prof. Dr. Z. Tan
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering
Hunan University
Changsha 410082, P. R. China
‡These authors contributed equally to this work
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: We have developed an unprecedented Pd-catalyzed
formal hydroalkylation of alkynes with hydrazones, which are
generated in situ from naturally abundant aldehydes, as both
alkylation reagents and hydrogen donors. The hydroalkylation
proceeds with high regio- and stereoselectivity to form (Z)-alkenes,
which are more difficult to generate, instead of (E)-alkenes. The
reaction is compatible with a wide range of functional groups,
including hydroxyl, ester, ketone, nitrile, boronic ester, amine and
halide. Furthermore, late-stage modifications of natural products and
pharmaceutical derivatives exemplify its unique chemoselectivity,
regioselectivity and synthetic applicability. The mechanistic studies
indicate the possible involvement of palladium-hydride intermediates.
methods require the stoichiometric reductant/organometallic
reagents, oxidants or directing groups, and the alkyl donors are
limited to alkyl halides, pseudohalides, boranes, carboxylic acids
and compounds with activated C(sp3)–H bonds. As the synthetic
community is placing increasing emphasis on more sustainable,
versatile and operationally simple chemical syntheses, the
development of new alkylation reagents that readily derived from
naturally abundant chemical feedstocks with harmless byproducts
would be highly desirable.
Alkenes are basic functionalities and highly desirable building
blocks. They are not only frequently used as versatile synthetic
intermediates but are also prevalent among organic molecules
with a wide range of applications.1 Therefore, the exploration of
efficient methods for their synthesis has been a continuous pursuit
throughout the history of organic chemistry.2 Among the many
efforts for alkene syntheses, the transition-metal-catalyzed
“formal” hydrofunctionalization of simple and readily available
alkynes is considered as one of the most straightforward and
versatile stereo-controlled approaches to access various
alkenes.3-4
Despite requiring a stoichiometric amount of reductant or
organometallic reagent, transition-metal-catalyzed “formal”
hydroalkylation reaction between alkynes and alkyl halides,
pseudohalides or boranes has been considered as an attractive
strategy in this field and has attracted great interests (Scheme
1a).5-8 Without using halides and other functional groups, the
C(sp3)–H bond alkenylation represented another promising
method for conversion of alkynes to alkenes, and some elegant
examples have been disclosed involving the direct C-H activation9
and radical processes (Scheme 1b).10 Very recently, MacMillan
and Rueping independently developed the iridium and nickel
dual-catalytic photoredox decarboxylative hydroalkylation
reactions with carboxylic acids as the alkyl donors (Scheme 1c).11
Despite much progress having been made, a number of
challenges still remain unsettled in this field. For example, most
Scheme 1. Catalytic (formal) hydroalkylation of alkynes.
Recently, our group developed the easily available umpolung
carbonyls as nucleophiles in a series of transformations with
unsaturated compounds, including carbonyls,12 imines,13 carbon
dioxide14 and activated alkenes,15 as well as 1,3-dienes.16
Furthermore, the reactions between umpolung carbonyls and
several relatively polar compounds involving carbon-heteroatom
bonds cleavage were also achieved by us17 and others.18
Although the reaction of carbonyl compounds with alkynes have
1
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10.1002/anie.202005132
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well developed,19 the reaction of umpolung nucleophiles with
unactivated alkyne remains an un-resolved challenge. The main
obstacles may be ascribed to the following aspects: a) easy
oligomerization or polymerization of alkyne, b) the difficult direct-
addition of the nucleophile to unactivated alkyne, c) issues
associated with the regio- and stereoselectivity of the addition.
Considering the synthetic importance of hydroalkylation of
alkynes together with our continuous investigation on hydrazone
chemistry, herein, we wish to report a novel Pd-catalyzed formal
syn-hydroalkylation of alkynes using umpolung carbonyls as both
the alkylation reagents and hydrogen donors, with nitrogen gas
as “traceless” byproduct (Scheme 1d).
We selected the simple hydrazone 1a and easily available
alkyne 2a as model substrates. Bis(1,5-cyclooctadiene)nickel(0),
which demonstrated high catalytic efficiency in the reaction of
alkenes,15-16 was evaluated in this hydroalkylation; however, the
desired product was not observed (Table 1, entry 1). Systematic
studies have shown that other nickel catalytic systems were also
inefficient, generating a complex mixture and low stereoselectivity
(Table1, entries 1-4, please see Table S1, in Supporting
Information for details). Therefore, it is necessary to develop a
new catalytic system to realize the hydroalkylation of alkynes. In
view of the inherent difference of alkyne and alkene in binding
affinity and reactivity,20 we investigated other transition-metals,
including Cu, Ni and Pd (entries 5-7). Much to our delight, we
found that the desired product 4aa was formed in 44% yield with
77:23 of Z:E ratio with Pd(OAc)2/ (tBu)2PMe as catalyst and DBU
as base in 1,4-dioxane at 110 °C for 16 h under nitrogen
atmosphere (entry 7). Notably, the major product was switched
from (E)-alkene to (Z)-alkene. Encouraged by this result, various
Table 1. Optimization of the reaction conditions.a,b
entry
1
catalyst
ligand
ICy.HCl
dmpe
base
tBuOLi
tBuOLi
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
-
yield(%)/(Z:E)
Ni(cod)2
0
2
Ni(cod)2
0
3
Ni(cod)2
PMe3
trace
4
Ni(cod)2
(tBu)2PMe
(tBu)2PMe
(tBu)2PMe
(tBu)2PMe
PMe3
25 (32:68)c
5
Cu(OAc)2
CoCl2
0
6
0
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
[Pd(allyl)Cl]2
-
44 (77:23)
8
<10
9
dcype
PCy3
<10
10
11
12
13
14
15
16
17
18
19
55 (86:14)
IPr.HCl
PCy3
0
23 (84:16)
PCy3
32 (80:20)
PCy3
86 (90:10)
PCy3
0
mono-
and
bidentate-phosphine
ligands
such
as
trimethylphosphine
(PMe3), 1,2-bis(dicyclohexylphosphino)
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
PCy3
0
ethane (dcype), tricyclohexylphosphine (PCy3) and 1,3-bis(2,6-
diisopropylphenyl)imidazolium chloride (IPr.HCl) were examined,
and we found that the sterically hindered, strong σ-donor mono
alkylphosphine ligand, PCy3 was the best ligand for this
transformation, and the desired product 4aa could be isolated in
55% yield with 86:14 of Z:E ratio (entry 10). We subsequently
explored other palladium catalysts and found that allylpalladium
chloride dimer not only gave the best yield of 4aa (86%) but also
showed high stereoselectivity (Z:E = 90:10, entry 14). Control
experiments showed that no product was produced in absence of
palladium catalyst or base (entries 15-16). Replacing the base
DBU with TEA, K3PO4 or tBuOLi, the reactions were found to be
unreactive (entries 17-19).
With the optimized conditions identified (Table 1, entry 14), we
investigated the scope of hydrazone 1. As shown in Table 2,
hydrazone 1 bearing a variety of functional groups including both
electron-donating and electron-withdrawing groups reacted
smoothly with diphenylacetylene 2a to provide the hydroalkylation
of alkynes products in moderate to good yields with high ratios of
Z:E (generally > 90:10) (Table 2). The functional groups,
regardless of the ortho-, meta-, para-, or multiple substitutions,
were all tolerated to generate the corresponding products 4aa-
4av in modest to excellent yields under the standard conditions.
It is worthwhile to mention that even the reaction of a 3-
nicotinaldehyde and 3-thiophenecarboxaldehyde derived
hydrazones were smoothly tansformed into the corresponding
desired products 4an in 82% and 4at in 80% yields, respectively.
Gratifyingly, the boronic ester
PCy3
TEA
0
PCy3
K3PO4
tBuOLi
0
PCy3
trace
a Reaction conditions: phenyl hydrazone 1a (0.5 mmol, 1.0 M generated in situ
from benzaldehyde and hydrazine), diphenylacetylene 2a (0.2 mmol), catalyst
(0.01 mmol), ligand (10 mol% for monodentate, 5 mol% for bidentate and
carbene ligand) and base (0.2 mmol) in 1,4-dioxane (0.5 mL) at 110 oC for 16
hr under N2; b NMR yields were determined by 1H NMR; Along with further
c
hydroalkylation products of obtained alkenes, namely the alkane products.
substituent on the phenyl ring of hydrazone is well compatible,
which can be utilized for further transformations (4ap). Notably,
aliphatic hydrazones such as 3-phenylpropionaldehyde and
phenylacetaldehyde derived hydrazones were also found to be
applicable substrates, albeit furnishing the desired products in
lower yields (4ax, 4ay). It is noteworthy that the target product
4aw was obtained in 50% yield when a hydrazone derived from
acetophenone was subjected to our standard conditions.
However, for other types of ketones, such as cyclohexanone and
acetone, only trace amounts of desired products were detected.
Subsequently, the scope of alkynes was examined, as
summarized in Table 3. Notably, the reactivity was higher when
trifluoromethyl benzaldehyde was used as the substrate, which
allows the reaction to proceed at 100 oC with a better Z/E
selectivity (Table 2 vs Table 3). In general, moderate to good
yields with high stereoselectivities and regioselectivities
(generally >95:5) were obtained with a wide
2
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Table 2. Evaluation of hydrazones.a,b
a Reaction conditions: hydrazone 1 (0.5 mmol, 1.0 M generated in situ from aldehyde and hydrazine), diphenylacetylene 2a (0.2 mmol), [Pd(allyl)Cl]2 (0.005
mmol), PCy3 (0.02 mmol) and DBU (0.2 mmol) in 1,4-dioxane (0.5 mL) at 110 oC for 5-18 hr under N2; b isolated yields; c yield was based on recovered alkyne
(35%); d yield was based on recovered alkyne (35%); e yield was based on recovered alkyne (32%).
Table 3. Evaluation of alkynes.a,b
a Reaction conditions: hydrazone 1 (0.25 mmol, 1.0 M generated in situ from aldehyde and hydrazine), alkyne 2 (0.1 mmol), ), [Pd(allyl)Cl]2 (0.0025 mmol),
PCy3 (0.01 mmol) and DBU (0.1 mmol) in 1,4-dioxane (0.25 mL) at 100 oC for 7-8 hr under N2; b isolated yields; Z/E ratios and regioselectivity were determined
by 1H NMR.
3
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range of symmetrical and non-symmetrical alkynes (Table 3). A
number of functional groups, including chloro (4bb), fluoro (4bl),
methoxyl (4bi, 4bn, 4bv), nitrile (4bn), alkylester (4bf), arylester
(4bo), hydroxyl (4bm) and protected amino groups (4bc, 4bs)
were all viable in this transformation. Heteroaromatic alkynes
containing pyridine (4be), thiophenes (4bd, 4bj), and
benzothiophene (4bt) were also effective as coupling partners.
Notably, a gram-scale hydroalkylation of alkyne gave the product
4ba in 69 % yield (1.54 g). Moreover, aliphatic alkynes are also
suitable substrates for this transformation (4bw, 4bx, 4by).
However, the alkynes with triflate or nitro substitutions at the para-
position of phenyl ring were unreactive (4bq, 4br).
To further exploit the practicability of this method, we
performed this hydroalkylation reaction in one-pot. Gratifyingly,
the desired product could be obtained in 61% yield with the ratio
of Z:E = 90:10 (Scheme 2a). The high efficiency and good
functional-group tolerance of this method enabled its application
to the late-stage modification of natural products and
pharmaceutical derivatives. Theobromine, an alkaloid, derivative
5 was investigated under the current catalytic system, and the
expected hydroalkylation product 6 was obtained in good yield
with high regio- and stereoselectivity (Z:E > 95:5) (Scheme 2b,
entry 1). The estrone derivative 7 proceeded smoothly under the
optimized conditions, with the ketone moiety untouched ( entry 2).
In addition, α-Vitamin E derivative 9 was also tested, delivering
the target product 10 ( entry 3). Furthermore, cholic acid derivative
11 with multiple hydroxyl groups was found to be a viable partner,
affording 12 in moderate yield with high ratio of Z:E (95:5) (entry
4). Notably, the Z-configuration of major products (6, 8, 10, 12)
were confirmed by NOESY experiments (Please see SI in details).
To gain preliminary insights into the hydroalkylation reaction
mechanism, several control experiments were subsequently
carried out. Please see SI for details of the following mechanistic
studies. Firstly, N-tosylhydrazones are often used as the carbene
precursors.21 In order to verify whether our reaction went through
the carbene process, we used N-tosylhydrazones as substrates
to react with alkynes under standard conditions; and no desired
product was detected, suggesting the unlikely involvement of a
carbene process in the reaction. When the reaction was ran for 1
hr under the standard conditions, the high ratio of Z:E (99:1) was
obtained, which suggests the generation of E-configuration from
Z-configuration. Moreover, it was found that the reaction time has
a significant effect on the ratio of Z:E, with the shorter reaction
time affording a higher ratio of Z:E. Finally, in deuterium-labelling
experiments, 0.95 deuterium was incorporated into the benzyl
position, and 0.45 deuterium into the alkene position of product,
which implies the hydrogen of hydrazone serving as hydrogen
donors of product. It should be noted that the hydride species was
observed with the in situ 1H NMR, when the reaction was
performed under the standard conditions. However, the hydride
species was not observed in absence of palladium catalyst or
hydrazone (Please see SI for a possible reaction mechanism).
In summary, we have demonstrated an unprecedented Pd-
catalyzed formal hydroalkylation of alkynes with hydrazones,
which were generated in situ from naturally abundant aldehydes
and ketones, as both alkylation reagents and hydrogen donors.
The formal hydroalkylation proceeds with high regio- and
stereoselectivity to form the more difficult (Z)-alkenes instead of
(E)-alkenes. The reaction is compatible with a wide range of
functional groups, including hydroxyl, ester, ketone, nitrile,
boronic ester, amine and halide. Furthermore, late-stage
modifications of natural products and pharmaceutical derivatives
exemplify its synthetic potentials. The preliminary mechanistic
studies indicate that the reaction may proceed via an oxidative
addition of N-H bond, carbopalladation of an alkyne and
denitrogenative alkylation of an alkenyl-palladium intermediate.
Acknowledgements
We are grateful to the Canada Research Chair Foundation (to C.-
J. L.), the Canadian Foundation for Innovation, FRQNT Centre in
Green Chemistry and Catalysis, Killam Fellowship of the
Canadian Council of Arts, and the Natural Science and
Engineering Research Council of Canada. L. Yu is grateful for the
support from China Scholarship Council.
Keywords: Palladium • Hydroalkylation • Alkynes • Aldehydes •
Alkenes
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Scheme 2. One-pot reaction and application to the late-stage modification of
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4
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Entry for the Table of Contents
A Pd-catalyzed formal hydroalkylation of alkynes with hydrazones has been realized. The
reaction proceeded with high regio- and stereoselectivity to form (Z)-alkene through a Pd-H
species.
6
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