Convergent Synthesis of Dihydropyrans from Catalytic Three-Component Reactions of Vinylcyclopropanes, Diazoesters, and Diphenyl Sulfoxide

Article abstract of DOI:10.1021/acs.orglett.0c01992

A novel Rh(I)/La(III) cocatalytic three-component reaction of vinylcyclopropanes, diazoesters, and diphenyl sulfoxide has been developed. The reaction gives polysubstituted dihydropyrans as the reaction products. Mechanistic studies indicate that isomerization of vinylcyclopropanes gives conjugated dienes, which then undergo [4 + 2]-cycloaddition with vicinal tricarbonyl compounds generated by oxygen atom transfer from diphenyl sulfoxide to diazoesters.

Full text of DOI:10.1021/acs.orglett.0c01992

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Letter
Convergent Synthesis of Dihydropyrans from Catalytic Three-
Component Reactions of Vinylcyclopropanes, Diazoesters, and
Diphenyl Sulfoxide
Ya-Lin Zhang, Rui-Ting Guo, Heng Luo, Xin-Shen Liang, and Xiao-Chen Wang*
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ABSTRACT: A novel Rh(I)/La(III) cocatalytic three-component
reaction of vinylcyclopropanes, diazoesters, and diphenyl sulfoxide
has been developed. The reaction gives polysubstituted dihydropyr-
ans as the reaction products. Mechanistic studies indicate that
isomerization of vinylcyclopropanes gives conjugated dienes, which then undergo [4 + 2]-cycloaddition with vicinal tricarbonyl
compounds generated by oxygen atom transfer from diphenyl sulfoxide to diazoesters.
Scheme 1. Metal-Mediated Ring-Opening of VCPs and
Subsequent Reactions with Diazo Compounds
inylcyclopropanes (VCPs) are highly versatile substrates
Vin transition-metal-catalyzed C−C bond activation
reactions. Their uses in building cyclic, bicyclic, and polycyclic
ring structures have been well documented.1 In particular, as
the pioneer, Wender established rhodium-catalyzed (5 + 2)
cycloadditions of VCPs with various π-systems such as alkynes,
alkenes, and allenes.2 Yu further advanced the field by
developing rhodium-catalyzed (3 + 2) intramolecular cyclo-
additions of unactivated VCPs.3 Moreover, CO as a donor−
acceptor ligand could participate in the cycloadditions to
provide (5 + 2 + 1) and (3 + 2 + 1) products.4 These works
generally utilized VCPs as three-carbon or five-carbon
components for cycloadditions.
Our interest in C−C bond activation reactions5 prompted us
to study the activation reactions of VCPs. Our initial plan was
to achieve the carbene migration insertion to the rhodacyclo-
hexene intermediate obtained from rhodium-mediated C−C
activation of vinylcyclopropanes (Scheme 1a). And upon
reductive elimination, the (5 + 1) cycloaddition product would
be formed.6 However, this proposed reaction did not occur in
our hands. Instead, we accidentally discovered a novel three-
component reaction of VCPs with diazoesters and diphenyl
sulfoxide, which produced polysubstituted dihydropyrans
(Scheme 1b). In this reaction, VCPs have been found to
serve as a four-carbon component for cycloaddition.
Mechanistic studies suggest that VCPs are converted to
conjugated dienes, which then undergo hetero-Diels−Alder
reactions with vicinal tricarbonyl compounds obtained from
the oxygen atom transfer from diphenyl sulfoxide to
diazoesters. Because dihydropyrans are the core structure of
many bioactive molecules and pharmaceuticals, such as
(+)-goniothalamin,7a AC-7954,7b cANA,7c and blasticidin S7d
(Scheme 1c) and the methods for directly accessing such
structures are limited,8 we believe that this reaction would be
particularly attractive for medicinal chemists. Herein, we would
like to elaborate the study of this reaction.
We began our study by reacting 1-(1-cyclopropylvinyl)-
benzene (1a) with dimethyl diazomalonate (2a) in the
presence of [Rh(cod)Cl]2 (5 mol %) in dioxane at 120 °C,
in a hope to get the (5 + 1) cycloaddition product (Table 1).
However, after reacting for 12 h, no cycloaddition product was
formed (entry 1). Interestingly, when we added AgOTf (10
Received: June 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01992
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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a
With the optimal reaction conditions in hand, we first
explored a number of VCPs bearing various α substituents
(Scheme 2). Electron-donating and electron-withdrawing
Table 1. Study of Reaction Conditions
a
Scheme 2. Scope of VCPs Bearing Various α-Substituents
b
entry
catalyst
3
Lewis acid
yield (%)
1
2
3
4
5
6
7
8
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
none
none
none
none
3a
3b
3c
3d
3e
3f
3e
3e
3e
3e
3e
3e
none
AgOTf
AgOTf
none
8
25
22
20
c
c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
none
42
trace
trace
69
30
11
68
63
87 (81 )
79
48
9
10
11
12
13
14
15
16
AgOTf
Sc(OTf)3
La(OTf)3
Yb(OTf)3
TMSOTf
d
a
Unless otherwise specified, all reactions were performed with 0.2
mmol of 1a, 0.4 mmol of 2a, and 0.4 mmol of 3 in 1 mL of dioxane.
b
c
d
NMR yields. Used 40 mol % of Lewis acids. Isolated yield.
a
Unless otherwise specified, all reactions were performed with 0.2
mmol of VCPs, 0.4 mmol of 2a, and 0.4 mmol of 3e in 1 mL of
b
dioxane. When the reaction was run at 2.0 mmol scale.
mol %) as an additive in order to in situ generate cationic
[Rh(cod)2]OTf, a cyclic compound 4a, which was determined
to be a polysubstituted dihydropyran, was produced in 8%
yield (entry 2). We suspected that the oxygen atom in 4a came
from AgOTf, so we increased the loading of AgOTf to 40 mol
%. Indeed, the yield of 4a was enhanced to 25% (entry 3). Use
of Cu(OTf)2 (40 mol %) instead of Ag(OTf)2 was also able to
afford 4a (22% yield, entry 4). However, further increasing the
loading of Ag(OTf)2 or Cu(OTf)2 failed to improve the yield,
only resulting in decompositions of the starting materials.
Then, we reconsidered the reaction mechanism. We speculated
that the OTf anion had transferred its oxgen atom to the
diazoester to provide the C−O fragment in the ring. Actually,
metal-catalyzed oxygen atom transfer from an oxidant to a
metal carbene is a known reaction, which was studied in detail
by Doyle and co-workers.9 Dimethyldioxirane, dimethyl
sulfoxide, and pyridine N-oxides are suitable oxidants for this
transfer reaction. Therefore, we tested the addition of an
oxidant to our reaction. When 2,6-dimethylpyridine N-oxide
(3a) was used in the presence of 10 mol % of Cu(OTf)2, 4a
was obtained in 20% yield (entry 5). Encouragingly, when 3,5-
dibromopyridine N-oxide (3b) was used, the yield was
improved to 42% (entry 6). Further screening of oxidants
revealed that diphenyl sulfoxide (3e) was optimal, which
afforded 4a in 69% yield (entry 9). Furthermore, the Lewis
acid was found to be very important for the reactivity because
the yield dropped to only 11% when the reaction was run in
the absence of any Lewis acids (entry 11). Additional tests of
other Lewis acids, including AgOTf, Sc(OTf)3, La(OTf)3,
Yb(OTf)3, and TMSOTf, showed that La(OTf)3 gave the
highest yield (87%, entry 14).
t
groups, including butyl (4b), bromo (4c), phenyl (4d),
methoxy (4e), trifluoromethyl (4f), and methoxycarbonyl
(4g), at the para position of the α phenyl ring were tolerated;
the cycloaddition products were obtained in 62−82% isolated
yields. In these reactions, we also obtained an isomerization
product, which has the olefin unit migrating to the adjacent
C−C bond (b′ in each structure). Substrates bearing electron-
donating groups tend to produce more of this isomer.
Especially, for the para-methoxy-substituted substrate, the
isomerization product became the major product (4e, a′:b′ =
1:2). Disubstituted phenyls (4h−4j) were also compatible.
Moreover, other aryl rings, including 2-naphthyl (4k), 2-
thienyl (4l), and 3-indolyl (4m), at the α position were also
acceptable; the cycloaddition products were isolated in 35−
69% yields. Furthermore, reactions of VCPs bearing phenethyl
(4n) and aminomethyl (4o) were feasible. When the reaction
of 1a was performed at 2.0 mmol scale, product 4a was isolated
in 71% yield. Therefore, this reaction can be scaled up.
VCPs bearing substituents at other locations were next
investigated (Scheme 3). When the cyclopropane ring was
substituted with a methyl group at a carbon adjacent to the
vinyl-substituted carbon (1p), the bond cleavage occurred at
both proximal C−C bonds (bonds A and B), providing two
isomeric products (4p) in a ratio of 1.5:1. When the same
carbon was substituted with a phenyl group (1q), the ratio of
the two isomers (4q) became 2:1. A 1,1-disubstituted
cyclopropane (1r) gave a single product (4r) in 47% yield.
And the reaction of bicyclic VCP 1s selectively cleaved the less
B
https://dx.doi.org/10.1021/acs.orglett.0c01992
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Scheme 3. Scope of VCPs Bearing Substituents at Other
Locations
Scheme 5. Transformations of 4a
a
We then performed several control experiments to look into
the reaction mechanism (Scheme 6). First, VCP 1a was heated
a
Unless otherwise specified, all reactions were performed with 0.2
Scheme 6. Mechanistic Experiments
mmol of substrates, 0.4 mmol of 2a, and 0.4 mmol of 3e in 1 mL of
dioxane. Reaction time: 20 h.
b
hindered C−C bond, affording a single product (4s) in 38%
yield.
The scope of diazoesters was subsequently investigated
(Scheme 4). Diethyl and diisopropyl diazomalonates (2b and
a
Scheme 4. Scope of Diazoesters
at 120 °C in dioxane in the presence of [Rh(cod)Cl]2 (5 mol
%) for 16 h; diene 9 was produced in 95% yield (Scheme
6a).10 We then reacted ethyl diazomalonate (2b) with
diphenyl sulfoxide under rhodium catalysis; vicinal tricarbonyl
compound 10 was formed in 10% yield via the oxygen atom
transfer reaction. At the same time, the majority of the diazo
compound underwent dimerization (Scheme 6b). By compar-
ison, when we tested the same reaction with the addition of
La(OTf)3 (10 mol %), the yield of 10 improved to 50%
(Scheme 6c). Therefore, the oxygen atom transfer reaction is
promoted by the Lewis acid. We then subjected 9 and 10 to
the standard reaction conditions; cycloadduct 5b was obtained
in 40% yield, with formation of another cycloaddition product
11 in 46% yield (Scheme 6d). Apparently, 5b was generated by
hetero-Diels−Alder reaction11 of 10 with a conjugated diene
isomerized from diene 9; 11 was generated by a cascade
process of the addition of 9 to 10 (Prins reaction12), followed
by hetero-Diels−Alder reaction of the resulting adduct with
another molecule of 10. When 9 and 10 were reacted in the
absence of La(OTf)3, no cycloadducts were formed (Scheme
6e), demonstrating the importance of the Lewis acid for
cycloaddition. Finally, when diene 9 was reacted with ethyl
diazomalonate (2b) and diphenyl sulfoxide (3e), product 5b
was obtained in 66% yield with only 7% of 11 coproduced
(Scheme 6f). This result shows that the in situ generation of
a
Unless otherwise specified, all reactions were performed with 0.2
mmol of 1a, 0.4 mmol of diazoesters, and 0.4 mmol of 3e in 1 mL of
dioxane.
2c) were reactive; the yields dropped with the increase of the
steric bulk. Methyl diazoacetoacetate (2d) was reactive, but the
diastereoselectivity (5d) was very poor. The reaction was also
compatible with dicarbonyl-stabilized diazo compounds
bearing aryl and heteroaryl substituents (5e−5h). However,
this reaction is not feasible with diazo compounds stabilized by
only one carbonyl group (e.g., ethyl diazoacetate and methyl
phenyldiazoacetate; for limitations of the reaction, see the
Supporting Information).
To demonstrate the utility of this cycloaddition reaction, we
studied the transformations of product 4a (Scheme 5).
Treatment of 4a with LiCl and water at 150 °C gave the
decarboxylation product 6 in 68% yield (d.r. = 3:1). Reduction
of the diesters by excess LiAlH4 gave diol 7 in 62% yield.
Finally, hydrolysis of 4a followed by oxidation with Pb(OAc)4
delivered lactone 8 in 45% yield. It is worth mentioning that
these obtained structures exist in many bioactive molecules
(e.g., examples shown in Scheme 1c).
C
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10 from the oxygen atom transfer reaction is better than direct
use of 10 for inhibition of byproduct formation perhaps
because of the kinetics of the coexisting processes.
Based on the results of the control experiments, we propose
a reaction mechanism shown in Scheme 7. In the cycle for
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Xiao-Chen Wang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-0001-
5863-0804; Email: xcwang@nankai.edu.cn
Scheme 7. Proposed Reaction Mechanism
Authors
Ya-Lin Zhang − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Rui-Ting Guo − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Heng Luo − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Xin-Shen Liang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01992
Notes
VCP isomerization, oxidative addition of VCP 1a to rhodium-
(I) gave the rhodacyclohexene intermediate, which then
underwent β-H elimination and reductive elimination to give
diene 9. In the cycle of oxygen atom transfer, rhodium(I)
reacted with the diazo compound to give the metal carbene.
The Lewis-acid-activated metal carbene was subsequently
trapped by diphenyl sulfoxide to give the oxonium ylide.
Elimination of diphenyl sulfide gave vicinal tricarbonyl
compound 10. Metal-catalyzed10,13 1,5-hydrogen transfer in
diene 9 would give diene 12, which underwent [4 + 2]
cycloaddition with the Lewis-acid-activated tricarbonyl com-
pound to give the observed product.
In summary, we have developed a new three-component
reaction of VCPs, diazoesters, and diphenyl sulfoxide. The
reaction features several coexisting reaction pathways, includ-
ing VCP isomerization, oxygen atom transfer, 1,5-hydrogen
transfer, and [4 + 2] cycloaddition, all occurring in one pot.
Moreover, the reaction is suitable to scale up and the obtained
polysubstituted dihydropyrans can be converted to other useful
scaffolds by simple transformations. The application of this
reaction toward natural product synthesis is currently being
explored in our laboratory.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21871147, 91956106,
21602114) and the Fundamental Research Funds for Central
Universities. X.-C.W. thanks the Tencent Foundation for the
support via the Xplorer Prize.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01992.
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CCDC 1985208−1985209 contain the supplementary crys-
tallographic 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
D
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E
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Letter
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(12) The proposed reaction mechanism for the formation of 11 is
given in the Supporting Information.
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