Palladium-Catalyzed Aminomethylation and Cyclization of Enynol to O-Heterocycle Confined 1,3-Dienes

Article abstract of DOI:10.1021/acs.orglett.1c01019

The rational tuning of the electrophilicity of the allylpalladium intermediates enables the regioselectively intramolecular 1,2-addition of enynol in the presence of aminal. This aminomethylation and cyclization reaction via C-N bond activation and intramolecular nucleophilic addition provides a rare example for the synthesis of O-containing heterocycle-confined 1,3-dienes, which is of synthetic potential for further derivatization. The method possesses broad substrate generality as well as functional group compatibility and efficiently affords a wide range of desired products with 5-, 6-, and 8-membered O-containing heterocycles with various functional groups.

Full text of DOI:10.1021/acs.orglett.1c01019

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Letter
Palladium-Catalyzed Aminomethylation and Cyclization of Enynol
to O‑Heterocycle Confined 1,3-Dienes
Houjian Yu, Bangkui Yu, Haocheng Zhang, and Hanmin Huang*
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ABSTRACT: The rational tuning of the electrophilicity of the allylpalladium
intermediates enables the regioselectively intramolecular 1,2-addition of enynol in
the presence of aminal. This aminomethylation and cyclization reaction via C−N
bond activation and intramolecular nucleophilic addition provides a rare example
for the synthesis of O-containing heterocycle-confined 1,3-dienes, which is of
synthetic potential for further derivatization. The method possesses broad substrate
generality as well as functional group compatibility and efficiently affords a wide
range of desired products with 5-, 6-, and 8-membered O-containing heterocycles
with various functional groups.
he conjugated 1,3-dienes have long been recognized as an
important class of organic compounds prevalent in myriad
regioselectivities (Scheme 1A).12 The high regioselectivities
might be attributed to the cationic palladium species formed via
the oxidative addition of aminal to a Pd(0) species, which leads
T
biologically active natural products and artificial synthetic
materials.1 Given unique reactivities, they are also essential
building blocks for the synthesis of diverse carbocycles,
heterocycles, and lactams.2 To further enhance the synthetic
versatility, the installation of additional functionalities to the 1,3-
diene backbone is of importance, whereas to the best of our
knowledge, the synthesis of 1,3-dienes through the olefination of
the carbonyl compounds,3 cross-coupling reactions,4 or meta-
thesis of enynes5 is significantly limited to access the simple
ones. On the other hand, the oxygen-containing heterocycles are
vital structural skeletons,6 and those tethered with 1,3-dienes are
able to serve as reactive synthons and of great importance for
synthetic chemistry.7 However, these synthetically valuable O-
heterocycles confined 1,3-dienes cannot be obtained from the
known methods of synthesizing oxygen heterocycle compounds,
such as the intramolecular insertion of an unsaturated C−C
bond into an O−H bond,8 intramolecular ring-closing meta-
thesis,9 and heterocycloaddition.10 One feasible disconnection
may be enabled by the intramolecular enolate attack toward the
alkyl halide, but only intermolecular examples are reported,
which failed to undergo cyclization to give products comprising
O-heterocycles.11 Therefore, a new method that efficiently
installs the O-containing heterocycles onto 1,3-dienes remains
worth exploring.
Scheme 1. Evolution of Intermediates Following the
Insertion of Enynes
The transition metal-catalyzed conjugated 1,2-addition of
element−element linkages to the triple bond of enynes is one of
the most straightforward approaches to the functionalized 1,3-
dienes. However, without substrate control, the achievement of
the corresponding 1,3-dienes is challenging since the every-
moment competition with the corresponding 1,4-addition leads
to lower regioselectivities. In this context, we have reported a
palladium-catalyzed 1,4-addition of C−N linkages of aminals to
enynes, which led to 1,5-allenic diamines with excellent
Received: March 24, 2021
Published: May 10, 2021
https://doi.org/10.1021/acs.orglett.1c01019
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3891−3896
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to the formation of the electrophilic cationic allylpalladium
complex. These results enlightened us to envisage that the O-
heterocycle confined 1,3-diene might be formed once the π-
allylpalladium complex was intercepted by an intramolecular
oxygen nucleophile (Scheme 1B). However, the reaction mode
may still suffer from the competition of other intermolecular
nucleophiles such as the aminal or the amine released due to the
comparatively weak nucleophilicity of the alcohol. Herein, we
describe a facile aminomethylative cyclization of enynols with
aminals under the catalysis of palladium, which delivers a diverse
set of polysubstituted 1,3-dienes confined in O-heterocycles
with different ring sizes.
Our attempts began with the optimization of the reaction
parameters by using hept-6-en-4-yn-1-ol (1a) and N,N,N′,N′-
tetrabenzylmethanediamine (2a) as the model substrates. To
our delight, the reaction performed well at 100 °C when PdBr2
was used as the catalyst precursor with Xantphos as the ligand in
the presence of a catalytic amount of AgOTf, delivering the
desired product 3aa in 52% yield (Table 1, entry 1). However,
the undesired 1,5-allenic diamine 4aa was detected as byproduct
in 33% yield, which probably resulted from the intermolecularly
nucleophilic attack of the aminal to the π-allylpalladium
intermediate.12 Subsequent screening of the Pd precursors and
ligands revealed that [Pd(allyl)Cl]2 together with Xantphos gave
the best result (Table 1, entries 2−6). To our surprise, almost no
corresponding product was detected in the absence of AgOTf
(Table 1, entry 7), which demonstrated the significance of TfO−
as the counteranion for the cationic palladium species.
Inevitably, a higher yield (81%) of 3aa was obtained when the
cationic Pd(Xantphos)(CH3CN)2(OTf)2 served as the catalyst
(Table 1, entry 8). In addition, the reactivity was diminished by
either increasing or decreasing the reaction temperature (Table
1, entries 9−11). Among the solvents tested, DME performed as
the best, while others were detrimental to the reaction (Table 1,
entries 12−18). Control experiments with typical Lewis acids
including AgOTf, Zn(OTf)2, and Sc(OTf)3 as catalyst for this
reaction resulted in no conversion. Moreover, the HOTf alone
could not catalyze the reaction at all. These results disclosed that
the reaction is neither Lewis acid- nor Bronsted acid-catalyzed
(see the Supporting Information).
The scope of enynols was investigated as shown in Scheme 2.
Various enynol substrates with substituents on the vinyl carbons
a
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope of Enynols
3aa yield
4aa yield
b
b
entry
catalyst
solvent
DME
DME
DME
DME
(%)
(%)
c
1
PdBr2/Xantphos/AgOTf
Pd(CH3CN)2Cl2/
Xantphos/AgOTf
[Pd(allyl)Cl]2/Xantphos/
AgOTf
[Pd(allyl)Cl]2/dppb/
AgOTf
[Pd(allyl)Cl]2/L1/AgOTf
[Pd(allyl)Cl]2/TrixiePhos/
AgOTf
52
52
33
31
c
2
3
4
72
trace
ND
ND
d
5
DME
DME
34
38
ND
trace
e
6
7
8
[Pd(allyl)Cl]2/Xantphos
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
Pd(Xantphos)
(CH3CN)2(OTf)2
DME
DME
ND
81
ND
trace
f
9
DME
76
38
28
70
40
63
67
31
23
trace
trace
53
g
10
DME
h
11
DME
57
12
13
14
15
16
17
18
THF
13
CH2Cl2
p-xylene
mesitylene
DMSO
DMF
26
trace
trace
trace
trace
61
a
Reaction conditions: 1 (0.30 mmol), 2a (0.36 mmol), Pd-
(Xantphos)(CH3CN)2(OTf)2 (5 mol %), DME (1.0 mL), 100 °C,
b
c
12 h, isolated yield. 60 °C. 80 °C.
were well accommodated, including phenyl, substituted phenyls,
β-naphthyl, α-thienyl, methyl, and halogenated alkyls. All the
corresponding products could be obtained with moderate to
excellent regioselectively yields (3ba−3ma). The solid structure
of 3ga was unambiguously characterized by single crystal X-ray
diffraction. Subsequently, several secondary alcohols with
different substituents at the α-position of the hydroxyl were
tested. Phenyl-, allyl-, or methyl-substituted substrate could
CH3CN
a
Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), [Pd] (5 mol
%), ligand (6 mol %), [Ag] (6 mol %), solvent (1.0 mL), 12 h.
b
c
d
Isolated yield. [Ag] (12 mol %). L1 = 1,2-bis((di-tert-
e
f
g
butylphosphino)methyl)benzene. Ligand (12 mol %). 120 °C. 80
°C. 60 °C.
h
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deliver the corresponding products in moderate yields (3na−
3pa), except for cyanomethylene with which the desired product
was obtained in only 30% yield (3qa). To our delight, the
reaction was successfully extended to enynols with one-carbon
shorter linkages between the hydroxyl and the alkynyl,
generating the desired products with 5-membered rings (3ra−
3ta). Besides, the enynol derivatives with benzos were able to
deliver products with a benzofuran or isochromene moiety or
even 8-membered benzo N,O-containing heterocycles (3ua−
3wa).
functionalized 1,3-dienes 3ba with NIS and TEMPO in CH2Cl2
afforded the unsaturated aldehyde 5 in 60% yield.13
Unexpectedly, the application of the conditions of NIS in
DMSO at 70 °C for 12 h on 3ba led to the replacement of a
dibenzylaminomethyl by the iodine, generating (E)-5-iodo-6-
styryl-3,4-dihydro-2H-pyran 6 in 67% yield.
To shed light on the mechanism, several control experiments
were conducted (Scheme 4). When complex A instead of
Scheme 4. Control Experiments
The scope of aminals was subsequently explored, and the
results are summarized in Table 2. Various aminals derived from
a
Table 2. Substrate Scope of Aminals
b
entry
R
X
3
yield (%)
1
2
3
4
5
6
7
8
C6H5CH2
(C6H5CH2)2N
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
81
68
65
80
73
76
79
84
83
64
75
4-MeOC6H4CH2
4-MeC6H4CH2
4-tBuC6H4CH2
4-FC6H4CH2
3-FC6H4CH2
2-FC6H4CH2
4-ClC6H4CH2
3-ClC6H4CH2
4-CF3C6H4CH2
C6H5CH2
(4-MeOC6H4CH2)2N
(4-MeC6H4CH2)2N
(4-tBuC6H4CH2)2N
(4-FC6H4CH2)2N
(3-FC6H4CH2)2N
(2-FC6H4CH2)2N
(4-ClC6H4CH2)2N
(3-ClC6H4CH2)2N
(4-CF3C6H4CH2)2N
OMe
9
10
11
3aj
3aa
a
Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), Pd-
(Xantphos)(CH3CN)2(OTf)2 (5 mol %), DME (1.0 mL), 100 °C,
Pd(Xantphos)(CH3CN)2(OTf)2 was used, the substrate 1a was
converted to 3aa in 73% yield under the otherwise identical
conditions (Scheme 4a). HRMS analysis of the reaction mixture
showed a peak at m/z 1004.2994, which was consistent with the
mass of [B-OTf]+, indicating the involvement of the
intermediate B in the catalytic process. Furthermore, the
desired product 3aa could be obtained in 34% yield by the
treatment of enynol 1a with stoichiometric complex A (Scheme
4b). These results revealed that the cyclopalladium complex A
was most likely involved in the catalytic cycle. Further control
experiments disclosed that the allenic byproduct 4aa could be
converted to the desired product 3aa in 68% yield under the
standard conditions (Scheme 4c). Moreover, as shown in Figure
1, the reaction profile of the standard reaction showed 4aa was
quickly formed in the first hour and subsequently decayed to
give the desired product 3aa. These results suggested that 3aa
might be produced from 4aa. However, further investigation of
the reaction with phenyl-substituted enyne 1b under the
standard reaction revealed that no similar allenic product 4ba
was detected (Scheme 4d). These results suggested that the
allenic product is not an essential intermediate for this reaction,
but it might be involved as a reservoir for the allylic palladium
species B.
b
12 h. Isolated yield.
dibenzylamines containing either electron-withdrawing (−F,
−Cl, or −CF3) or electron-donating (−CH3, −t-Bu, or −OMe)
groups on the phenyl proceeded well in the reaction, affording
the corresponding products in good yields (3ab−3aj). Never-
theless, no conspicuous electronic effect was observed.
Satisfyingly, the reaction could smoothly take place when
N,O-acetals were employed instead of N,N-aminals, which
considerably improved the atomic economy of the reaction
(Table 2, entry 11).
The gram-scale experiments were carried out to expand the
synthetic potential of this catalytic protocol (Scheme 3). In the
presence of 5 mol % catalyst, the reaction of the substrate 1b and
aminal 2a proceeded well on a 10 mmol scale, delivering the
corresponding product 3ba (3.4 g) in 86% isolated yield. To
further highlight the practicality and utility, the functional group
transformations were also performed. The treatment of the
Scheme 3. Gram-Scale Reaction and Transformation
A plausible reaction pathway can be proposed on the basis of
the previous reports and our observations (Figure 2).14 With the
assistance of the enynol 1, the reduction of the Pd(II) precatalyst
first takes place to generate the active catalyst Pd(0) species as
well as a catalytic amount of acid.15 The oxidative addition of the
protonated aminal to Pd(0) offers the cyclopalladium complex
A. Through the migratory insertion of the enynol 1 into the C−
Pd bond of complex A, the intermediate B is generated, which is
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Accession Codes
CCDC 2048261 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hanmin Huang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, P. R. China; State Key Laboratory for Oxo Synthesis
and Selective Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Lanzhou, Gansu
730000, P. R. China; orcid.org/0000-0002-0108-6542;
Email: hanmin@ustc.edu.cn
Figure 1. Reaction profile of the standard reaction.
Authors
Houjian Yu − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
Bangkui Yu − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
Haocheng Zhang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, P. R. China
Figure 2. Plausible reaction mechanism.
directly intercepted by the intramolecular oxygen-nucleophile to
give the desired product 3 in the case of the enynols with a
substituent at the terminal of the alkene moiety (R′ ≠ H).
However, when there is no terminal substitution on the alkene
moiety, the 1,5-allenic diamine 4 is formed quickly via the
intermolecular nucleophilic addition of aminal to the π-
allylpalladium B, due to the higher nucleophilicity of the
aminal.14k The 1,5-allenic diamine 4 serves as a reservoir as it can
be reversibly converted into the intermediate B in the presence
of Pd catalyst (R′ = H). The cyclization of intermediate B can
further drive the 1,5-allenic diamine 4 to generate intermediate
B at a higher temperature. Finally, the desired product 3 is
produced via reductive elimination of B, together with the
regeneration of the Pd(0) complex to accomplish the catalytic
cycle.
In summary, we have successfully developed a novel strategy
to realize an intermolecular aminomethylation and intra-
molecular cyclization of enynols and aminals via the
palladium-catalyzed C−N bond activation in which the 1,5-
allenic diamine 4 is formed as a reservoir of the π-allylpalladium
species. This protocol provides effective access to 1,3-dienes
confined in O-heterocycles with different ring sizes, which shows
great appeal in synthetic chemistry.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01019
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the National Natural Science
Foundation of China (21925111 and 21790333).
■
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The Supporting Information is available free of charge at
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Experimental procedures and characterization data
(PDF)
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