Oxidative C–H alkynylation of 3,6-dihydro-2H-pyrans

Article abstract of DOI:10.1016/j.cclet.2019.03.027

Current synthesis of α-substituted 3,6-dihydro-2H-pyrans dominantly relies on functional group transformation. Herein, a direct and practical oxidative C–H alkynylation and alkenylation of 3,6-dihydro-2H-pyran skeletons with a range of potassium trifluoro

Full text of DOI:10.1016/j.cclet.2019.03.027

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CCLET 4863 No. of Pages 3
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Oxidative CÀÀH alkynylation of 3,6-dihydro-2H-pyrans
Ran Zhaoa, Guidong Fengb, Xiaodong Xinc, Honghao Guanc, Jing Huad, Renzhong Wanb,
,
*
c,
Wei Lia, , Lei Liu
*
*
a
Department of Pharmaceutical Analysis, School of Pharmacy, Shandong University of Traditional Chinese Medicine, Ji'nan 250355, China
College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
School of Chemistry and Chemical Engineering, Shandong University, Ji'nan 250100, China
b
c
d
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal
University, Guilin, 541004, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Current synthesis of α-substituted 3,6-dihydro-2H-pyrans dominantly relies on functional group
transformation. Herein, a direct and practical oxidative CÀÀH alkynylation and alkenylation of 3,6-
dihydro-2H-pyran skeletons with a range of potassium trifluoroborates is developed. The metal-free
process is well tolerated with a wide variety of 3,6-dihydro-2H-pyrans, rapidly providing a library of 2,4-
disubstituted 3,6-dihydro-2H-pyrans with diverse patterns of α-functionalities for further diversification
and bioactive small molecule identification.
Received 23 February 2019
Received in revised form 12 March 2019
Accepted 18 March 2019
Available online xxx
Keywords:
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
3,6-Dihydro-2H-pyrans
CÀÀH Functionalization
Alkynylation
Oxidation
Organoborane
α-Substituted 3,6-dihydro-2H-pyrans (DHPs) are common
structural motifs in a number of biologically active natural
products and synthetic pharmaceuticals [1]. Their current
synthesis predominantly relies on four types of oxygen-heterocy-
cle construction approaches: (1) Prins-type cyclization of homo-
propargylic alcohols and aldehydes [2]; (2) [4 + 2] cycloaddition of
dienes and aldehydes [3]; (3) ring-closing metathesis [4]; (4)
intramolecular alkene alkoxylation [5]. Despite wide synthetic
applications, these methods rely heavily on the functional group
transformations. On the other hand, a great number of methods
have been established for the facile access to the DHP skeletons
with diverse substituent patterns. Accordingly, direct manipula-
tion of the DHP skeletons with a multitude of readily available
coupling components through the structural-core diversification
strategy represents an attractive alternative to traditional
oxygen-heterocycle construction strategy. Pallidium-catalyzed
Heck reaction of 3,4-dihydro-2H-pyrans represents a practical
protocol for α-substituted DHP synthesis. However, the method is
only suitable for the access to α-aryl substituted DHPs [6]. In this
context, the Ferrier reaction involving the substitution of CÀÀO
bonds with CÀÀC bonds at C1 position of DHP-based acetals is the
most widely adopted approach [6,7]. However, the method suffers
from extra steps for pre-installation of the acetal functionality.
Direct CÀÀH functionalization of DHPs represents an ideal
approachtoaccessthetargetwithaminimalamountofintermediary
refunctionalizations and with high atom economy [8–10]. Magnus
has reported an isolated example of one-pot allylation of DHP-based
triisopropylsilyl enol ethers with allyl tri-n-butylstannane and
Me2AlCl (Scheme 1a) [11]. Wu disclosed one elegant example of
photoredoxinducedCÀÀHalkylationofDHPwithelectron-deficient
benzylidenemalononitrile (Scheme 1b) [12]. Our group docu-
mented a Ph3CClO4 mediated CÀÀH functionalization of DHP with
potassium (phenylethynyl)boronate (Scheme 1c) [13]. Albeit great
innovation, these studies still suffer from the employment of toxic
organotin, limited DHP scope and α-substituent pattern, or
expensive oxidative reagent. On the other hand, alkynes are
common structural elements pervading the realms of biology,
chemistry, material science, and medicine and serve as valuable
building blocks due to their versatile chemical reactivities [14].
Given the importance of 2,4-disubstituted DHPs in pharmaceutical
science [1eÀg], a systematic study on the CÀÀH alkynylation of
4-substituted DHPs using readily available oxidant would be a
highly attractive project to pursue (Scheme 1d).
Initially, the CÀÀH alkynylation of 4-phenyl substituted DHP 1a
with boronate 2a was selected for the optimization of suitable
oxidant (Table 1)À. Common oxidants, including tBuOOH, PhI(OAc)2,
and TEMPO+BF4 (TEMPO = 2,2,6,6-tetramethylpiperidin-1-oxyl)
* Corresponding authors.
E-mail addresses: wrzh63@163.com (R. Wan), liwei6911@163.com (W. Li),
leiliu@sdu.edu.cn (L. Liu).
https://doi.org/10.1016/j.cclet.2019.03.027
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: R. Zhao, et al., Oxidative CÀÀH alkynylation of 3,6-dihydro-2H-pyrans, Chin. Chem. Lett. (2019), https://doi.
org/10.1016/j.cclet.2019.03.027

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R. Zhao et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 1. Overview of CÀÀH functionalization of DHPs.
Scheme 2. Scope of DHP components. Reaction conditions: 1a (0.1 mmol), 2a
(0.12 mmol), and DDQ (0.11 mmol) in DCE (1.0 mL) at rt for 3 h. The yield refers to
isolated yield.
Table 1
Reaction condition optimization.a
Entry
Oxidant
Yieldb (%)
1
2
3
4
5
tBuOOH
PhI(OAc)2
TEMPO+BF4
Ph3CClO4
DDQ
< 5
< 5
< 5
32
À
90
a
General conditions: 1a (0.1 mmol), oxidant (0.12 mmol) in solvent (1.0 mL) at
r.t. for 0.5 h followed by 2a (0.15 mmol) at r.t. for 3 h.
b
Isolated yield.
Scheme 3. Scope of alkynyl boronates. aReaction in a 1.0 g scale.
failed to effect the coupling (entries 1–3). Ph3CClO4 promoted the
reaction, and expected 3a was isolated in 32% yield (entry 4). When
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was used, the
reaction proceeded smoothly, affording 3a in 90% yield.
benzyl ether was well tolerated for further manipulation. A gram-
scale CÀÀH alkynylation of 1a proceeded in 83% yield, thus
indicating the practicability of the method.
Besides the alkynylation process, CÀÀH alkenylation of DHP 1a
with 5 was well tolerated under the standard oxidation condition,
furnishing the expected 6 in 85% yield (Scheme 4). No expected
CÀÀH arylation or allylation product was observed when respective
aryl or allyl potassium trifluoroborate was used as the coupling
component.
The synthetic utilities of the protocol were next examined
(Scheme 5). The alkene moiety in DHPs can act as a reactive handle
for diverse functionalization, as exemplified by the efficient hydrogena-
tion of 4c and diastereoselective epoxidation of 3a, giving respective
tetrahydropyrans 7 and 8 with diverse substituent patterns.
According to the mechanistic studies on DDQ-mediated benzylic
ether oxidation [15], a mechanism for C–H alkynylation of DHPs was
suggested (Scheme 6). DHPs 1a proceeded through a single electron
transfer (SET) to DDQ provided radical cation 9 together with DDQ
radical anion 10. The radical cation 9 might either undergo a proton
abstraction by 10 followed by another SET or a hydrogen atom
transfer (HAT) to 10, furnishing α,β-unsaturated oxocarbenium ion
11. Subsequent nucleophilic attack of potassium trifluoroborates
onto 11 afforded the expected product 12.
The substituent effect on DHPs 1 was explored (Scheme 2). DHPs
bearing either electron-donating (1b-1d) or -withdrawing aryl
moieties (1e) at the C4-position were found to be well compatible
with the oxidation condition, providing corresponding 3b-3e in
high efficiency. DHP 1f with a meta-methylsubstitutedarylgroupat
the C4-position proved to be a suitable substrate for the CÀÀH
alkynylation process, and 3f was obtained in 91% yield. DHP 1g
having a heteroaryl moiety at the C4-position was well tolerated,
and 2-thiophenyl substituted 3g was isolated in 82% yield. DHPs
bearing a spirocycle at α positionwere also competent components,
as demonstratedbytheformationofmultiple-substituted3hin80%
yield. Noreactionwas observedfor DHP 1i, which might be ascribed
to the increased oxidation potential of the substrate.
The scope of alkynyl boronates 2 was next investigated
(Scheme 3). Electronically varied potassium (arylethynyl) boro-
nates 2b-2f participated in the oxidative coupling with DHP 1a
smoothly, affording corresponding 4b-4f in good yields. Hetero-
arylacetylenes were competent components for the process, as
demonstrated by the efficient generation of 4g in 83% yield.
Alkylacetylene 2h also proved to be a suitable component, and
expected 4h was obtained in 80% yield. Alkylacetylene 2i bearing
Please cite this article in press as: R. Zhao, et al., Oxidative CÀÀH alkynylation of 3,6-dihydro-2H-pyrans, Chin. Chem. Lett. (2019), https://doi.
org/10.1016/j.cclet.2019.03.027

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3
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.03.027.
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Acknowledgments
This work was financial supported by the National Natural
Science Foundation of China (No. 21722204), Fok Ying Tung
Education Foundation (No. 151035), the Key Laboratory for
Chemistry and Molecular Engineering of Medicinal Resources
(Guangxi Normal University) (No. CHEMR2016-B09), and Guangxi
Funds for Distinguished expert.
Please cite this article in press as: R. Zhao, et al., Oxidative CÀÀH alkynylation of 3,6-dihydro-2H-pyrans, Chin. Chem. Lett. (2019), https://doi.
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