Vinylethylene Carbonates as α,β-Unsaturated Aldehyde Surrogates for Regioselective [3 + 3] Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.9b02266

Herein, we report a novel stepwise addition-controlled ring size method, to access tetrahydropyrimidines through an operationally simple [3 + 3] cycloaddition of vinylethylene carbonates with triazinanes. Interestingly, we could also use this method for a [3 + 3] oxidative cycloaddition, which allows the facile synthesis of polysubstituted terphenyls under mild conditions. Mechanistic studies suggest that vinylethylene carbonates could generate α,β-unsaturated aldehydes as 3-carbon synthons for cycloaddition via a combination process of Pd-catalyzed decarboxylation and β-H elimination.

Full text of DOI:10.1021/acs.orglett.9b02266

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Vinylethylene Carbonates as α,β-Unsaturated Aldehyde Surrogates
for Regioselective [3 + 3] Cycloaddition
Yi Xu,†,‡,§,⊥ Lu Chen,†,‡,§,⊥ Yu-wen Yang,†,‡,§ Zhiqiang Zhang,∥ and Weibo Yang*,†,‡,§,∥
†Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese
Academy of Sciences, Shanghai, China
‡Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
§University of Chinese Academy of Sciences, Beijing 100049, China
∥Key Laboratory for Functional Material, Educational Department of Liaoning Province, University of Science and Technology
Liaoning, Anshan 114051, China
S
* Supporting Information
ABSTRACT: Herein, we report a novel stepwise addition-controlled ring size method,
to access tetrahydropyrimidines through an operationally simple [3 + 3] cycloaddition of
vinylethylene carbonates with triazinanes. Interestingly, we could also use this method for
a [3 + 3] oxidative cycloaddition, which allows the facile synthesis of polysubstituted
terphenyls under mild conditions. Mechanistic studies suggest that vinylethylene
carbonates could generate α,β-unsaturated aldehydes as 3-carbon synthons for
cycloaddition via a combination process of Pd-catalyzed decarboxylation and β-H
elimination.
he divergent cycloaddition of identical starting material
by judicious choice of parameters, such as catalysts,
T
ligands, solvents, etc., is a powerful approach to generate
diverse molecular scaffolds and to expand the chemical space.1
Despite the significant recent advances in divergent cyclo-
addition, the development of a new method to realize
divergent cycloaddition still represents an important goal in
organic synthesis and is highly appealing. As part of an
overarching goal to develop new modes for divergent
cycloaddition, we questioned whether the different intermedi-
ate species could be captured under stepwise addition.
However, one fundamental challenge would be associated
with the development of such a method. If intermediates
species are thermodynamically unstable and reversible under
stepwise addition mode, they could easily return to the starting
state.2
Recently, vinylethylene carbonates (VECs) have emerged as
promising dipole precursors to generate zwitterionic π-allyl
palladium intermediates,3 and they have been successfully used
for various cycloadditions (Figure 1a). Seminal works from
Zhang and co-workers took advantage of VECs as a 3-atom
(3C, 5O) synthon to engage in asymmetric [3 + 2]
cycloadditions and constructed a series of useful five-
membered heterocycles.4 Subsequently, the group of Zhao,5
Glorious,6 Xiao/Lu,7 Guo,8 and others3e,9 reported that VECs
could serve as a 5-atom (1C, 5O) synthon for forming
heterocyclic compounds with a challenging larger ring or
medium-sized ring. Notably, all these reported synthons were
exclusively generated via a single decarboxylation process.
Figure 1. Evolution of VECs and our new discovery.
More recently, increasing attention has been devoted to
explore VECs as novel synthons for cycloaddition through a
combination process of decarboxylation and β-H elimination,
thus enabling a diverse range of compound libraries to build.
Received: July 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02266
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Letter
Until now, only one elegant formal [4 + 2] cycloaddition of
VECs by the utilization of a (1C, 4C) synthon formed via
decarboxylation and β-H elimination was disclosed by Zhao.10
However, to the best of our knowledge, the formal cyclo-
addition by utilizing VECs as a 3-atom (2C, 4C) synthon via
decarboxylation and β-H elimination has not yet been
demonstrated. Undoubtedly, generating the intermediate
with the reactivity of a 3-atom synthon (2C, 4C) synthon via
stepwise addition would be a challenging issue because a 2-atom
(1C, 2C) synthon or 5-atom (1C, 5O) synthon might become
the predominant intermediate in the reaction.5a,9c Herein, we
demonstrate how this method can be translated into the novel
[3 + 3] cycloaddition between VECs and 1,3,5-triazinane-
s1e,9c,11 or allylic sulfones that would be difficult to implement
with other strategies (Figure 1b). Specifically, these reactions
provide efficient and environmentally benign methods to
synthesize tetrahydropyrimidines12 and polysubstituted ter-
phenyls13 which represent two classes of therapeutic agents
with multiple biological activities.
To validate the feasibility of aforementioned divergent
cycloaddition via stepwise addition, our initial reaction was
carried out by subjecting 4-phenyl-4-vinyl-1,3-dioxolan-2-one
(1a) to our previous established conditions9c utilizing
Pd(COD)Cl2 as catalyst, Xantphos as ligand, AgTFA as
additive in dichloromethane (DCM) at 80 °C for 2 h. After
then, 1,3,5-triphenyl-1,3,5-triazinane (2a) was added into the
above mixture and was stirred at 80 °C for additional 2 h.
Gratifyingly, when we used this stepwise addition, the
regioselectivity was totally changed and a formal [3 + 3]
cycloaddition product 5aa was obtained in 16% yield under the
other identical conditions (Figure 2). The unexpected result
Table 1. Optimization of Pd-Catalyzed Formal [3 + 3]
Cycloaddition
a
b
entry
catalyst
2a (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
Pd(COD)Cl2
0
DCM
DCM
toluene
THF
1,4-dioxane
−
16
10
15
20
52
40
30
38
55
52
41
58
64
75(71)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2
H2O
THF/H2O (1/2)
THF/H2O (2/1)
DMSO/H2O (1/2)
DMF/H2O (1/2)
EtOH/H2O (1/2)
i-PrOH/H2O (1/2)
MeOH/H2O (1/2)
MeOH/H2O (1/2)
MeOH/H2O (1/2)
9
10
11
12
13
14
15
a
Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), Pd catalyst
(5 mol %), Xantphos (10 mol %), AgTFA (10 mol %), solvent (2
b
mL) at 80 °C for 2 h. Yields were determined by the 1H NMR using
CH2Br2 as the internal standard; isolated yield was given in
parentheses.
entry 13). Additionally, further examining the amounts of 2a
showed that 2 equiv of 2a could give the best result, affording
5aa in 71% isolated yield (Table 1, entry 15).
After establishing the optimal reaction conditions for the
controllable formal [3 + 3] cycloaddition reaction, we next
examined the substrate scope with respect to various VECs and
1,3,5-triazinanes (Scheme 1). This reaction was applicable to
broad functional group substituted VEC substrates, including
methyl (5ca, 5da), methoxy (5fa), ether (5ha), chloro (5na),
bromo (5ma), and ester groups (5qa). It should be noted that
all products were formed through a formal [3 + 3]
cycloaddition process, in which a zwitterionic π-allyl palladium
intermediate as 3-carbon synthon was discovered for the first
time. Inspired by the fact that physical and biological
properties of fluorine atom are central to the function of
many drugs, we treated the monofluoro (5ja, 5ka), difluoro
(5la), and trifluoromethyl (5oa) substituted VECs to the
standard conditions, which provided the corresponding
products in acceptable yields. It is worth mentioning that the
deuterated substrate was effective for this transformation (D-
5aa) as well, providing access to a product of pharmacokinetic
value given the unique properties of the deuterium atom.
Furthermore, triazinane partners bearing different functional
groups were suitable substrates for this cycloaddition to furnish
the desired 5ab−5ae in good isolated yield. To demonstrate
the practicability of this transformation, a gram-scale reaction
was carried out and the corresponding product 5ab was easily
obtained in 51% yield.
Figure 2. Initial discovery of formal [3 + 3] cycloaddition through
stepwise addition mode.
could be attributed to the 2a, which could suppress the key
intermediate formation under previous conditions.9c This
proof-of-principle result obviously demonstrated that using
stepwise addition to control cycloaddition was feasible.
Encouraged by the preliminary results, we further attempted
to increase the yield of the 5aa by tuning reaction parameters
under stepwise addition. It should be noted that the optimized
conditions for the full conversion of 1a in the first step have
been established. Therefore, we only have to improve the
efficiency of this formal [3 + 3] cycloaddition in the addition
step of 2a which is the rate-determining step. As summarized
in Table 1, the reaction was profoundly affected by the solvents
and the commonly used organic solvents including toluene,
THF, and 1,4-dioxane are not suitable for this reaction.
Conversely, the use of pure water or organic solvent with
excess water is likely beneficial for 5aa formation. It was found
that the yield of 5aa was significantly improved to 58% when
the reaction was carried out in aqueous methanol (Table 1,
Given that the polysubstituted terphenyls are prevalent in
bioactive molecules and nature products, we next turned our
attention to the construction of these compounds by using the
same method (Scheme 2). After substrate 1a was completely
converted to the intermediate, the allylic sulfone 6a was added
B
DOI: 10.1021/acs.orglett.9b02266
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Letter
sulfones and VECs, and both substrates regardless of the
electronic properties were tolerated and gave the desired
products 7aa−7ed in moderate to good yields (Scheme 2). A
furan-containing allylic sulfone could also undergo efficient
cycloaddition to produce 7ae in a moderate yield. Next, we
demonstrated the viability of this [3 + 3] oxidative cyclo-
addition in the late-stage modification of a natural product
estrone derivative,14 which was successfully incorporated with
a terphenyl unit in a good isolated yield.
Scheme 1. Substrate Scope of Formal [3 + 3] Cycloaddition
in the Synthesis of Tetrahydropyrimidines
Several experiments were conducted to gain insight into the
possible mechanism of these Pd-catalyzed cycloadditions
(Scheme 3). The above distinct results were observed under
Scheme 3. Control Experiments
a
Isolated yields are indicated below each structure (Supporting
Information gives the experimental details).
Scheme 2. Substrate Scope of Formal [3 + 3] Cycloaddition
in the Synthesis of Polysubstituted Terphenyls
stepwise addition mode, implying a different intermediate
formed in the reactions. Initially, we captured the intermediate
and characterized it as an α,β-unsaturated aldehyde by NMR
spectra. When the intermediate was reacted with 2a under
standard conditions, the desired product 5aa was obtained in
64% yield. By contrast, the yield of 5aa was significantly
decreased to 30% under metal-free conditions. These results
may indicate that the Pd/Ag active species could act not only
as a catalyst to initiate the first step but also as a Lewis acid to
activate the aldehyde in the second step. Second, we
conducted a crossover experiment. The result is consistent
with formal migration [2 + 3] cycloaddition9c and rules out the
direct nucleophilic attack of triazinanes. The exact reason why
formation of α,β-unsaturated aldehyde is favorable under the
stepwise addition mode remains unclear at this stage. However,
we speculated that triazinanes could prevent a π-allyl palladium
intermediate from undergoing β-H elimination.
On the basis of the mechanistic experiments and relevant
reports,3a,15 a plausible mechanism was proposed in Figure 3.
With regard to the stepwise addition cycloaddition mode, the
zwitterionic π-allyl palladium intermediate (A) formed by
decarboxylation could result in unsaturated enol through β-H
elimination and then isomerizes to α,β-unsaturated aldehyde.
Subsequently, it could react with an imine generated from
triazinane (2a) and provide intermediate D via the Michael
addition process, followed by hydrolysis losing one form-
aldehyde together with attack of imine to afford intermediate
a
Isolated yields are indicated below each structure (Supporting
Information gives the experimental details).
and they were simply treated with the common organic base
DBU in one pot. A highly regioselective [3 + 3] oxidative
cycloaddition product 7aa was isolated in 35% yield. This
transformation proceeded smoothly with a range of allylic
C
DOI: 10.1021/acs.orglett.9b02266
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Organic Letters
Letter
ORCID
Weibo Yang: 0000-0003-1633-7655
Author Contributions
⊥Y.X. and L.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the 100 talent program of the
Chinese Academy of Sciences, Chinese NSF (21702217),
“1000-Youth Talents Plan”, Shanghai-Youth Talent, National
Science & Technology Major Project “Key New Drug Creation
and Manufacturing Program”, China (Number:
2018ZX09711002-006), Shanghai-Technology innovation Ac-
tion Plan (18JC1415300), and Shanghai “Phosphor” Science
Foundation (Number: 19QA1410700) for financial support of
this research.
Figure 3. Plausible mechanism.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02266.
■
S
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1852789 and 1937436 contain 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
■
*yweibo@simm.ac.cn
D
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