Metal-Free Three-Component Oxyalkynylation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.8b02954

An unprecedented (NH₄)₂S₂O₈ mediated metal-free three-component alkene oxyalkynylation using H₂O or alcohol as oxygenation agent is described. Mechanistic studies suggested that the reversed regiosele

Full text of DOI:10.1021/acs.orglett.8b02954

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Three-Component Oxyalkynylation of Alkenes
Yangshan Li,†,§ Ran Lu,†,§ Shutao Sun,† and Lei Liu*,†,‡
†School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
‡School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
S
* Supporting Information
ABSTRACT: An unprecedented (NH4)2S2O8 mediated
metal-free three-component alkene oxyalkynylation using
H2O or alcohol as oxygenation agent is described. Mechanistic
studies suggested that the reversed regioselectivity should be
dictated by an alkene radical cation intermediate.
ue to their prevalence, selective difunctionalization of
alkenes to prepare value-added building blocks of
oxyalkylation of alkenes, which often requires an excess of
metal reagents such as trialkylaluminum, organotin, and
Grignard reagents.6 Therefore, developing a general and
practical protocol for direct three-component alkene carboox-
ygenation with reversed regioselectivity is highly desirable.
In seminal work, Arnold disclosed isolated examples of
direct three-component oxyarylation of alkenes with reversed
regioselectivity through an alkene radical cation-mediated
photochemical nucleophile-olefin combination, aromatic sub-
stitution (photo-NOCAS) reaction (Figure 1b).7 Despite the
extremely limited scopes of both alkenes and arenes, reversed
regioselectivity was observed in modest efficiency. We
envisioned that a general and practical carbooxygenation
protocol with such regioselectivity might be enabled by a
single-electron chemical oxidant promoted generation of the
alkene radical cation intermediate. Herein, we report an
unprecedented (NH4)2S2O8-mediated metal-free three-compo-
nent oxyalkynylation of alkenes using H2O or alcohols as the
oxygenation agent (Figure 1c).
D
medicinal relevance is a broad goal in chemistry.1 In this
context, three-component carbooxygenation of alkenes is
particularly attractive as it allows a one-step introduction of a
C−C bond and a C−O bond. Impressive advances have been
achieved in this area during the past decade either through a
radical-mediated2 or through a cationic metal species-catalyzed
process (Figure 1a).3 Because of the innate alkene polarization,
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. An efficient hydroxyalkynylation to
synchronously introduce both alkyne and hydroxyl groups
into alkene moieties would be highly desirable. However, to
our knowledge, direct three-component oxyalkynylation of
alkenes has not been reported to date.8,9 Therefore, the three-
component hydroxyalkynylation of styrene 1a with phenyl-
ethynylbenziodoxolone 2a and H2O was initially investigation
(Scheme 1a; also see the Supporting Information (SI)).10
Common single electron chemical oxidants such as (NH4)2Ce-
(NO3)6 and Mn(OAc)3 did not give any expected 3a.
Delightedly, peroxydisulfate salts promoted the reaction, and
(NH4)2S2O8 was identified to be optimal. Other electrophilic
alkynylating agents such as phenyl phenylethynyl sulfone and
Figure 1. Overview of the regioselectivity in three-component
carbooxygenation of alkenes.
the carbooxygenation outcome follows Markovnikov’s rule, in
which the oxygen bonds to more substituted olefinic carbon. In
contrast, direct three-component carbooxygenation to achieve
the opposite regioisomer by reversing the alkene polarity has
remained a formidable challenge.4 Known methods, each
including only isolated examples, suffer from significantly
limited scope and require either stoichiometric palladium
species or a large excess of alkenes (up to 80 equiv).5 Instead,
such adducts are customarily accessed by indirect one-pot
Received: September 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b,c
Scheme 1. Scope of Styrenes
Scheme 2. Scope of Aliphatic Alkenes and Complex
Molecules
a
Reaction condition: 1 (0.3 mmol), 2a (0.1 mmol), and (NH4)2S2O8
(0.2 mmol) in CH3CN/H2O (1.0 mL, v:v = 1:1) at 90 °C in 1 h.
The scope of alkyne moieties was next explored (Scheme
3a). A variety of electronically varied aryl and heteroaryl
b
c
d
Yield of isolated product. 5.0 mmol scale. d.r. was determined by
e
f
g
1H NMR spectroscopy. (E)-1k used. (Z)-1k used. Mixture of (E)-
and (Z)-alkenes used.
Scheme 3. Scope of Alkyne and Oxygenation Components
phenylethynyl phenyliodonium triflate were ineffective compo-
nents. The optimized procedure is very simple: 1a (3.0 equiv)
and 2a (1.0 equiv) in H2O/CH3CN (1:1 v:v) were treated
with (NH4)2S2O8 (2.0 equiv) at 90 °C for 1 h, predominantly
delivering β-hydroxyalkyne 3a in 81% yield. No regioisomeric
3a′ was detected. The operationally simple protocol does not
require an inert atmosphere, is scalable (entry 1, Scheme 1a),
and is affordable due to the incredibly low cost of the sole
reagent (NH4)2S2O8 (< $0.04 per gram).
The reaction proved fairly general for a wide range of
electronically varied terminal styrenes with different sub-
stituent patterns, providing β-hydroxyalkynes 3a−3i in high
efficiency (Scheme 1a). 1,1-Disubstituted styrene 1j was
tolerated, delivering 3j bearing a quaternary carbon center in
70% yield. The reactions of electronically varied internal
styrenes (3k−3p) also proceeded smoothly, exhibiting
complete regioselectivity in high efficiency (Scheme 1b). The
configuration of internal styrenes proved to have trivial
influence on the reaction as (E)-1k and (Z)-1k were converted
to 3k with comparable d.r. and efficiency. Cyclic styrenes 1q
and 1r were also competent substrates.
Simple acyclic 1,1-dialkyl substituted alkenes bearing diverse
functional groups were suitable substrates for the reaction,
affording 5a−5g bearing a quaternary carbon center in
moderate to good yields (Scheme 2a). Monoalkyl-substituted
4h was also tolerated, albeit in a diminished yield. Cyclic 1,1-
dialkyl substituted alkenes such as 4i and 4j together with
piperidine-based 4k were suitable substrates. Cyclic trialkyl
substituted 4l also exhibited the expected selectivity in 82%
yield. The potential capacity of the method in late-stage
functionalization of complex molecules of biological interest
was further demonstrated (Scheme 2b). The reaction of
estrone-based styrene 4m proceeded, providing 5m in 83%
yield. Lithocholic acid-derived 4n was also tolerated, affording
5n bearing a quaternary carbon center in 62% yield.
acetylenes with different substituent patterns were well
tolerated, affording expected 7a−7i in high efficiency.
Trimethylsilyl-substituted 7j and simple alkyl-substituted 7k
were suitable components. The scope of oxygenation agents
also proved to be expansive (Scheme 3b). Aside from H2O for
hydroxylation reaction, common primary methanol, ethanol,
and n-butanol together with secondary isopropanol were found
to be suitable components for respective ether formation (7l−
7o), though the more sterically encumbered tert-butyl alcohol
and acetic acid did not give any of the expected product.
The synthetic utilities of three-component oxyalkynylation
of alkenes were then examined (Scheme 4). Alkyne in 3a was
selectively reduced, furnishing respective β-oxyalkane 8a and β-
oxyalkenes 8b and 8c (Scheme 4a). Hydroxyl motif can be
readily converted to other synthetically valuable groups, such
as azide 8d, chloride 8e, and cyanide 8f. The versatility of
hydroxyl and alkyne groups also allowed alkenes to function as
a latent “linker” by quickly integrating multiple scaffolds of
B
DOI: 10.1021/acs.orglett.8b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthetic Applications
a
b
c
Pd/C in MeOH under H2. LiAlH4, THF, 60 °C. Lindlar catalyst,
d
e
MeOH, rt. TsCl, Et3N then NaN3, DMF, 75 °C. Triphosgene,
pyridine. TsCl, Et3N, then NaCN.
f
biological importance together in the late-stage functionaliza-
tion (Scheme 4b). For example, 1,2,3-triazole and Boc-L-
analine moieties were regioselectively integrated into 1a, giving
9 in 35% yield over four steps involving alkene oxyalkynylation,
desilylation, click reaction, and acylation.
Mechanistic studies by electron paramagnetic resonance
(EPR) spectroscopy were performed (Figure 2). When free
Figure 3. Mechanistic studies.
two pathways were proposed for the generation of β-oxyl
radical 11: (1) hydrogen atom abstraction from H2O to sulfate
radical anion (SO4−•) giving a hydroxyl radical that adds onto
−•
alkene 1 (eq 2, Figure 3b); (2) oxidation of 1 by SO4
affording alkene radical cation 15 followed by attack of H2O
(eq 3).13 Second, radical clock experiments were performed to
differentiate the two possibilities (Figure 3c). The reaction of
cyclopropyl alkene 16 gave hydroxyalkyne 17, and its
regioisomer 18 was not detected, suggesting that the hydroxyl
radical addition pathway might not be viable (eq 4, Figure
3c).14 The observed regioselectivity, however, could be well
explained by the alkene radical cation -mediated nucleophilic
substitution by H2O.15 The radical cation probe β-pinene 19
was applied to further verify the hypothesis (eq 5, Figure 3d).7a
The reaction exhibited the same regioselectivity as radical
cation-mediated photo-NOCAS process, giving 20 in 35%
yield, and the opposite regioisomer 21 was likewise not
detected, further implying the intermediacy of alkene radical
cation. Third, the reduction potential of S2O82− and SO4−• are
2.01 and 2.44 V, respectively;13 one-electron oxidation
potentials of alkenes in this work ranges from 1.8 to 2.2 V vs
Figure 2. Identification of β-oxyl radical via EPR spectra (X band, 9.1
GHz, room temperature) and mass spectrometry analysis.
radical spin trapping agent 2-methyl-2-nitrosopropane (MNP)
was added to the reaction of 1a and Na2S2O8 with H2O or
MeOH, a respective EPR signal with a triplet of doublets
pattern was observed.11 The EPR spectra suggest the
generation of two similar nitroxide radicals containing one β-
hydrogen.12 The mass spectrometry analysis of two reaction
mixtures indicates that the two nitroxide radicals might be 10a
and 10b, thus implying the generation of β-oxyl radical 11.
Comparison of the simulation (green line) with the
experimental data (purple line) indicated good agreement of
the overall line shape, hyperfine peak positions, and intensities
of the simulated spectra.
SCE.16 Accordingly, SO4 might be the species oxidizing
−•
alkenes 1 to give radical cation 15 (Figure 3e). According to
the DFT calculations by Arnold, H2O might react with 15
affording a nonclassical, bridged radical cation complex
22.4b−e,7c The regiochemistry was dictated by the relative
stabilities of two possible distonic radical cations 23 and 24.
Control experiments were conducted to understand how β-
oxyl radical 11 is generated (Figure 3). First, H218O isotopic
labeling experiments suggested that the hydroxyl moiety
should originate from H2O (eq 1, Figure 3a). Accordingly,
C
DOI: 10.1021/acs.orglett.8b02954
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Int. Ed. 2017, 56, 3708. (m) Yasu, Y.; Koike, T.; Akita, M. Angew.
Chem., Int. Ed. 2012, 51, 9567. (n) Jiang, X.-Y.; Qing, F.-L. Angew.
Chem., Int. Ed. 2013, 52, 14177. (o) Deb, A.; Manna, S.; Modak, A.;
Patra, T.; Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747.
(p) Daniel, M.; Dagousset, G.; Diter, P.; Klein, P.-A.; Tuccio, B.;
Goncalves, A.-M.; Masson, G.; Magnier, E. Angew. Chem., Int. Ed.
2017, 56, 3997.
(3) (a) Melhado, A. D.; Brenzovich, W. E., Jr.; Lackner, A. D.; Toste,
F. D. J. Am. Chem. Soc. 2010, 132, 8885. (b) Xie, Y.; Hu, J.; Xie, P.;
Qian, B.; Huang, H. J. Am. Chem. Soc. 2013, 135, 18327.
(4) For selected examples on anti-Markovnikov oxygenation of
alkenes, see: (a) Dong, G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H.
Science 2011, 333, 1609. (b) Hamilton, D. S.; Nicewicz, D. A. J. Am.
Chem. Soc. 2012, 134, 18577. (c) Perkowski, A. J.; Nicewicz, D. A. J.
Am. Chem. Soc. 2013, 135, 10334. (d) Wilger, D. J.; Grandjean, J.-M.
M.; Lammert, T. R.; Nicewicz, D. A. Nat. Chem. 2014, 6, 720.
(e) Zhang, G.; Hu, X.; Chiang, C.-W.; Yi, H.; Pei, P.; Singh, A. K.; Lei,
A. J. Am. Chem. Soc. 2016, 138, 12037. (f) Luo, C.; Bandar, J. S. J. Am.
Chem. Soc. 2018, 140, 3547. (g) Barthelemy, A.-L.; Tuccio, B.;
Magnier, E.; Dagousset, G. Angew. Chem., Int. Ed. 2018, 57, 13790.
(5) (a) Hallgren, J. E.; Matthews, R. O. J. Organomet. Chem. 1980,
192, C12. (b) Jang, Y.; Wu, J.; Lin, Y.; Yao, C. Tetrahedron 2004, 60,
6565.
The more stable 22 undergoes deprotonation giving radical 14.
The addition of 14 to 2a followed by a β-elimination,
providing β-hydroxyalkyne 3 along with a benziodoxolonyl
radical.10
In summary, a practical (NH4)2S2O8-mediated metal-free,
direct three-component oxyalkynylation of alkenes with
reversed regioselectivity to current studies using H2O or
alcohol as the oxygenation agent has been reported. The
operationally simple and practical protocol features excellent
regiospecificity, a broad substrate scope, inexpensive system,
and good functional group tolerance. Mechanistic studies
suggested that the regioselectivity was dictated by an alkene
radical cation intermediate generated through a single electron
oxidation of alkenes by SO4−•. We envision that the method
would provide a platform to design other anti-Markovnikov
oxygenation reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02954.
(6) (a) Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079.
(b) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771.
(c) Singleton, D. A.; Waller, S. C.; Zhang, Z.; Frantz, D. E.; Leung, S.-
W. J. Am. Chem. Soc. 1996, 118, 9986.
(7) (a) Arnold, D. R.; Du, X. J. Am. Chem. Soc. 1989, 111, 7666.
(b) Mangion, D.; Arnold, D. R. Acc. Chem. Res. 2002, 35, 297.
(c) Arnold, D. R.; Chan, M. S. W.; McManus, K. A. Can. J. Chem.
1996, 74, 2143.
Experimental details and spectral data for new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leiliu@sdu.edu.cn.
ORCID
(8) Three-component oxyalkynylation of allylic amines, see: Orcel,
U.; Waser, J. Angew. Chem., Int. Ed. 2015, 54, 5250.
(9) Two-component alkene oxyalkynylation, see: (a) Nicolai, S.;
́
Erard, S.; Gonzalez, D. F.; Waser, J. Org. Lett. 2010, 12, 384.
Lei Liu: 0000-0002-0839-373X
Author Contributions
§These authors contributed equally.
Notes
(b) Nicolai, S.; Waser, J. Org. Lett. 2011, 13, 6324. (c) Nicolai, S.;
Sedigh-Zadeh, R.; Waser, J. J. Org. Chem. 2013, 78, 3783. (d) Han,
W.-J.; Wang, Y.-R.; Zhang, J.-W.; Chen, F.; Zhou, B.; Han, B. Org.
Lett. 2018, 20, 2960. (e) Tang, S.; Liu, Y.; Gao, X.; Wang, P.; Huang,
P.; Lei, A. J. Am. Chem. Soc. 2018, 140, 6006.
The authors declare no competing financial interest.
(10) Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012, 41, 4165.
(11) Experimental EPR spectra of 10a (g = 2.0032, αN = 15.57 G,
αH = 3.16 G) and simulated one (αN = 15.502 G, αH = 3.162 G);
experimental EPR spectra of 10b (g = 2.0034, αN = 15.04 G, αH
2.32 G) and simulated one (αN = 15.085 G, αH = 2.894 G).
ACKNOWLEDGMENTS
■
=
We gratefully acknowledge the National Science Foundation of
China (21722204, 21472112) and the Fok Ying Tung
Education Foundation (151035) for support.
(12) Rosenthal, I.; Mossoba, M. M.; Riesz, P. Can. J. Chem. 1982, 60,
1486.
(13) House, D. A. Chem. Rev. 1962, 62, 185.
REFERENCES
■
(14) EPR studies and control experiments also imply the pathway of
hydroxyl radical might not be viable. See the SI for details.
(15) (a) Dinnocenzo, J. P.; Lieberman, D. R.; Simpson, T. R. J. Am.
Chem. Soc. 1993, 115, 366. (b) Dinnocenzo, J. P.; Simpson, T. R.;
Zuilhof, H.; Todd, W. P.; Heinrich, T. J. Am. Chem. Soc. 1997, 119,
987.
(1) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Minatti, A.; Mun
36, 1142. (c) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011,
111, 2981. (d) Zhu, Y.; Cornwall, R. G.; Du, H.; Zhao, B.; Shi, Y. Acc.
Chem. Res. 2014, 47, 3665. (e) Yin, G.; Mu, X.; Liu, G. Acc. Chem. Res.
2016, 49, 2413.
̃
iz, K. Chem. Soc. Rev. 2007,
(16) One electron oxidation potentials of olefins in this work were
measured using cyclic voltammetry (see the SI for details).
̈
(2) (a) Kirchberg, S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed.
2010, 49, 6877. (b) Kindt, S.; Wicht, K.; Heinrich, M. R. Angew.
Chem., Int. Ed. 2016, 55, 8744. (c) Taniguchi, T.; Sugiura, Y.;
Zaimoku, H.; Ishibashi, H. Angew. Chem., Int. Ed. 2010, 49, 10154.
(d) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am. Chem. Soc. 2011, 133, 10756.
(e) Li, M.; Yu, F.; Qi, X.; Chen, P.; Liu, G. Angew. Chem., Int. Ed.
2016, 55, 13843. (f) Nobe, Y.; Arayama, K.; Urabe, H. J. Am. Chem.
Soc. 2005, 127, 18006. (g) Wang, Y.; Zhang, L.; Yang, Y.; Zhang, P.;
Du, Z.; Wang, C. J. Am. Chem. Soc. 2013, 135, 18048. (h) Schweitzer-
Chaput, B.; Demaerel, J.; Engler, H.; Klussmann, M. Angew. Chem.,
Int. Ed. 2014, 53, 8737. (i) Cheng, J.-K.; Loh, T.-P. J. Am. Chem. Soc.
2015, 137, 42. (j) Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.;
Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 5443. (k) Jian, W.; Ge, L.;
Jiao, Y.; Qian, B.; Bao, H. Angew. Chem., Int. Ed. 2017, 56, 3650.
(l) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Angew. Chem.,
D
DOI: 10.1021/acs.orglett.8b02954
Org. Lett. XXXX, XXX, XXX−XXX