Iron-Catalyzed Dehydrative Alkylation of Propargyl Alcohol with Alkyl Peroxides to Form Substituted 1,3-Enynes

Article abstract of DOI:10.1021/acs.orglett.8b01043

This paper reports a new method for the generation of substituted 1,3-enynes, whose synthesis by other methods could be a challenge. The dehydrative decarboxylative cascade coupling reaction of propargyl alcohol with alkyl peroxides is enabled by an iron catalyst and alkylating reagents. Primary, secondary, and tertiary alkyl groups can be introduced into 1,3-enynes, affording various substituted 1,3-enynes in moderate to good yields. Mechanistic studies suggest the involvement of a radical-polar crossover pathway.

Full text of DOI:10.1021/acs.orglett.8b01043

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Dehydrative Alkylation of Propargyl Alcohol with
Alkyl Peroxides To Form Substituted 1,3-Enynes
Changqing Ye,†,‡ Bo Qian,† Yajun Li,† Min Su,†,‡ Daliang Li,*,§ and Hongli Bao*,†,‡
†Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Center for Excellence in Molecular Synthesis, Chinese Academy of Sciences, 155
Yangqiao Road West, Fuzhou, Fujian 350002, P. R. China
‡University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
§Biomedical Research Center of South China & College of Life Science, Fujian Normal University, No. 1 Keji Road, Shangjie,
Fuzhou, Fujian 350117, P. R. China
S
* Supporting Information
ABSTRACT: This paper reports a new method for the
generation of substituted 1,3-enynes, whose synthesis by other
methods could be a challenge. The dehydrative decarboxylative
cascade coupling reaction of propargyl alcohol with alkyl
peroxides is enabled by an iron catalyst and alkylating reagents.
Primary, secondary, and tertiary alkyl groups can be introduced
into 1,3-enynes, affording various substituted 1,3-enynes in
moderate to good yields. Mechanistic studies suggest the
involvement of a radical-polar crossover pathway.
(Scheme 1c).7,8 Notwithstanding these established methods,
there is no strategy which can install alkyl groups into existing
motifs to afford polysubstituted 1,3-enynes.
1,3-Enynes are important building blocks in organic synthesis,1
pharmaceutical chemistry,2 and material science.3 Classical
methods to synthesize 1,3-enynes include Wittig olefination of
propargyl aldehyde (Scheme 1a),4 cross-coupling between
alkynes and alkenes,5 metal-catalyzed cross-dimerization of
alkynes (Scheme 1b),6 and dehydration of propargyl alcohols
Redox active esters, derivable from readily available
carboxylic acids, have recently been proven to be useful
reactants, especially as alkylating reagents.9 Alkyl peresters and
alkyl diacyl peroxides are alternative activated carboxylic acids.
Recently, our group demonstrated a series of reactions that use
peresters and diacyl peroxides as efficient alkylation reagents.10
In this work, the iron-catalyzed alkylation of propargyl alcohol
was demonstrated with alkyl peroxide as a general alkylating
reagent, producing structurally diversified polysubstituted 1,3-
enynes under mild reaction conditions (Scheme 1d).
Scheme 1. Previous and Current Work on the Synthesis of
Polysubstituted 1,3-Enynes
Initially, the coupling reaction of 2-phenyl-4-(p-tolyl)but-3-
yn-2-ol (1a) with tert-butyl 2-ethylhexaneperoxoate (2a) was
carried out with metal catalysis (for details, see Supporting
Information (SI), Table S1).
After the comprehensive investigation of the parameters of
the reaction, the optimal reaction conditions were found to be
2 mol % of Fe(OTf)3 in THF at 50 °C for 4 h (eq 1).
With these reaction conditions in hand, the scope of the
propargyl alcohols was explored (Table 1). Both electron-
donating and -withdrawing substituents on the aromatic ring of
R1 are tolerated in this coupling reaction, which produces the
trisubstituted 1,3-enyne products (3a−3i) in yields of 60−83%.
Heterocyclic aryl groups, such as thienyl, are compatible, which
Received: April 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01043
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Letter
a
Table 2. Scope of Alkyl Peroxides
a
Table 1. Scope of Propargyl Alcohol
a
Reaction conditions: 1a (0.50 mmol, 1 equiv), 2 (1 mmol, 2 equiv),
b
Fe(OTf)3 (2 mol %), THF (2 mL), 4 h, 50 °C. Isolated yields. 1a
(0.6 mmol, 1.2 equiv), 5 (0.50 mmol, 1 equiv). tert-Pentyl
c
benzoperoxoate (5c) (0.5 mmol, 1 equiv).
a
Reaction conditions: 1 (0.50 mmol, 1 equiv), 2a (1 mmol, 2 equiv),
b
Fe(OTf)3 (2 mol %), THF (2 mL), 4 h, 50 °C. Isolated yields.
mmol reaction.
2
such as phenyl, benzoyl, esters, chloro, bromo, alkenyl and
alkynyl, also give the corresponding products (6e−6k) in 34−
82% yields.
Preliminary experiments were performed to investigate the
mechanism of the reaction (Scheme 2). A radical trapping
produce 3j in 74% yield. Alkyl groups (R1) deliver products
(3k−3m) with 63−75% yields. The product 3n is obtained in
53% yield when TMS-substituted propargyl alcohol is used.
The presence of various functional groups in R2 was
investigated. Electron-deficient and electron-rich substituents
in an aromatic ring in R2 give the desired products (3o−3w) in
32−78% yields. Product (3x) bearing a fluorenyl group is
formed in 37% yield. Activated 1,4-enediynes and 1,3-dienynes
can be conveniently synthesized with this simple method,
delivering products 3y and 3z in 45% and 62% yields,
respectively. The R2 substituent representing an aliphatic
Scheme 2. Preliminary Mechanism Experiments
t
group is also examined. When R2 is a Bu group (1aa), the
corresponding product 3aa is obtained in 44% yield. While R2
n
is a Bu group (1ab), the reaction is messy. When terminal
propargylic alcohol (1ac) is used, only a trace amount of the
desired product is detected.
The scope of the alkyl groups was studied, and the results are
given in Table 2. Both secondary acyclic and cyclic peresters
can be used in this transformation, affording the trisubstituted
1,3-enyne products (4a−4i) in 38−78% yields. Furthermore,
tertiary peresters (2) couple smoothly with propargyl alcohol
(1a), providing the corresponding products (4j, 4k) in 22% and
61% yields, respectively.
Alkyl peresters derived from primary aliphatic acids do not
perform well in this reaction, and consequently, alkyl diacyl
peroxides are introduced to produce the primary alkyl 1,3-
enyne compounds. General alkyl diacyl peroxides are converted
to the desired products (6a, 6b, 6d) in 65−78% yields.
Reaction of tert-pentyl benzoperoxoate (5c) provides the ethyl
substituted 1,3-enyne (6c) in 61% yield. Functional groups,
experiment with 2 equiv of TEMPO (2,2,6,6-tetramethyl-
piperidine-1-oxyl) under the standard reaction conditions
affords no product (3a) (Scheme 2a), but when 2 equiv of
MeOH are added to the reaction, trace amounts of product 3a
can be detected and 7 is produced in 46% yield (Scheme 2b).
Product 3a can be isolated in 84% yield when the enyne (8) is
used in place of propargyl alcohol (Scheme 2c). The enyne (8)
can be generated from propargyl alcohol (1a) under the
standard reaction conditions in 98% yield, as determined from
B
DOI: 10.1021/acs.orglett.8b01043
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Letter
1H NMR spectra (Scheme 2d). These results suggest that a
radical species and benzylic carbocation intermediates could be
involved in this transformation and that the enyne (8) might be
an intermediate derived from 1a. This coupling reaction can
also be promoted by HOTf, but full conversion of a terminal
1,3-enyne to the alkylated 1,3-enyne needs as much as 40% of
HOTf and produces the alkylated 1,3-enyne in only 60% yield
(SI, Table S2). These results suggest that a catalytic amount of
HOTf, which may generated from Fe(OTf)3, is not responsible
for the high yield of the desired product and that iron is the
actual catalytic species in the reaction.
obtained in 38% yield from the reaction of 1,3-enyne 6a with an
alkyl peroxide (5g) (Scheme 4c).
Further examples of the synthetic applications of this method
are shown in Scheme 5. Compound 13, which is synthesized by
Scheme 5. Synthetic Applications
From these experiments, a plausible mechanism can be
proposed and is shown in Scheme 3. A Lewis acid and single
Scheme 3. Proposed Catalytic Cycle
hydrolysis of product 6g under basic conditions, reacts with N-
bromosuccinimide (NBS) to afford 14 in 60% yield (Scheme
5a).11 Compound 15 is obtained in 48% yield by intramolecular
alkylboration of a tri-substituted 1,3-enyne (6i) under copper
catalysis.12 These products could serve as key building blocks in
pharmaceuticals and natural products.
In conclusion, a novel dehydrative decarboxylative coupling
reaction of propargyl alcohol with alkyl peroxides has been
established. A series of polysubstituted 1,3-enynes are formed
under mild reaction conditions by this iron-catalyzed coupling.
Primary, secondary, and tertiary alkyl peroxides, which can be
easily acquired from alkyl carboxylic acids, are used
simultaneously as both an alkyl reagent and internal oxidant.
Investigation of the mechanism suggests that a radical-polar
crossover pathway might be involved in this reaction. The 1,3-
enyne products can be used in the synthesis of pharmaceuticals
and natural products.
electron transfer catalytic cycle might be involved in this
coupling reaction. First, propargyl alcohol 1a is activated by
Fe(III) to generate water and an intermediate (8). The alkyl
radical formed by a single electron transfer between the alkyl
perester (2a) and Fe(II) attacks 8 to give benzylic radical
species (A). This benzylic radical (A) is oxidized by Fe(III),
affording the benzylic carbocation intermediate (B) and Fe(II).
Finally, the 1,3-enyne product (3a) is obtained by the
deprotonation of the benzylic carbocation intermediate (B).
Based on this strategy of dehydrative decarboxylative
coupling, a series of tetrasubstituted 1,3-enynes can be
synthesized (Scheme 4). When the reaction is treated with
excess primary alkyl peroxide 5a under the standard conditions,
compound 9 is formed in 47% yield (Scheme 4a). Propargyl
alcohol 10 can react with 5a to deliver the desired product (11)
in 52% yield (Scheme 4b). Tetrasubstituted 1,3-enyne 12 is
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.8b01043.
Experimental details and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hlbao@fjirsm.ac.cn.
*E-mail: daliangli@fjnu.edu.cn.
Scheme 4. Synthesis of Tetrasubstituted 1,3-Enynes
ORCID
Hongli Bao: 0000-0003-1030-5089
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key R&D Program of China
(2017YFA0700100), the NSFC (Grant No. 21502191,
21672213), Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000), Haixi
Institute of CAS (CXZX-2017-P01), “the 100 Talents
Program”, “the 1000 Youth Talents Program”, and the
Innovative Research Teams Program II of Fujian Normal
University of China (IRTL1703) for financial support.
C
DOI: 10.1021/acs.orglett.8b01043
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Letter
L.; Chan, P. W. H. J. Org. Chem. 2009, 74, 1740. (c) Mothe, S. R.;
Chan, P. W. H. J. Org. Chem. 2009, 74, 5887.
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