Photocatalytic Annulation-Alkynyl Migration Strategy for Multiple Functionalization of Dual Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b04018

A novel photoredox catalysis for multiple functionalization of two different types of unactivated alkenes in a single operation was reported through a conceptually new mode of annulation-alkynyl migration. A wide array of cyclopentane carboxylates were sy

Full text of DOI:10.1021/acs.orglett.9b04018

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic Annulation−Alkynyl Migration Strategy for Multiple
Functionalization of Dual Unactivated Alkenes
Qi Zhao, Wen-Juan Hao,* Hao-Nan Shi, Ting Xu, Shu-Jiang Tu,* and Bo Jiang*
School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu
Normal University, Xuzhou 221116, P. R. China
S
* Supporting Information
ABSTRACT: A novel photoredox catalysis for multiple
functionalization of two different types of unactivated alkenes
in a single operation was reported through a conceptually new
mode of annulation−alkynyl migration. A wide array of
cyclopentane carboxylates were synthesized in a highly
selective and functional-group-compatible manner via C-
centered radical induced cascade 5-exo-trig/5-exo-dig bicycliza-
tion and C−C bond cleavage process. This methodology might open a new entry for designing annulation−functional group
migration to create structurally applicable cyclic ring systems.
methods generally focus on activated alkenes, because the
nascent alkyl radical needs to be stabilized by adjacent
functional groups (e.g., aryl, carbonyl, heteroatom) via the
p−π conjugate effect. In very recent years, many chemists have
turned their attention to developing radical induced intra-
molecular cyclization and difunctionalization of unactivated
alkenes, providing powerful strategic tools for the collection of
substantial significant cyclic molecules and thereby enriching
the type of alkene difunctionalization.6 However, these state-
of-the-art radical transformations are highly dependent upon
the use of monomolecular unactivated alkenes. Accordingly,
the development of radical synergistic transformation of two
different unactivated alkenes in one pot remains a formidable
challenge because of the tremendous difficulty in the control of
regio- and chemoselectivities.
lkenes are omnipresent in natural products, pharmaceut-
1
Aical science, and organic materials.
Besides, as inex-
pensive and readily available feedstocks, alkenes possess a
unique reactivity profile and thus have been extensively applied
in synthetic chemistry.2 In this context, radical-triggered
difunctionalization of alkenes provides a valuable synthetic
strategy for their high utilization by incorporating two
functional groups across the CC π system (Scheme 1,
pathway i).3 Very recently, Stephenson4 and Zhu5 independ-
ently established seminal strategies for radical alkene
difunctionalization by using sulfone-linked difunctionalized
reagents (Scheme 1, pathway ii). Despite the great achieve-
ments gained in this field, the vast majority of well-developed
Scheme 1. Profiles of Radical-Mediated Functionalization of
Meanwhile, radical functionality migration, standing at the
intersection of both radical and rearrangement transforma-
tions, constitutes a unique reaction category that enables
reconstruction of the molecular structures and assembly of
significant compounds in a highly efficient way that are difficult
to obtain through other methods.7 This kind of strategy
provides new synthetic protocols to radical difunctionalization
of unactivated alkenes.8 Numerous elegant works for
developing intramolecular functionality migration strategies,
such as arylation,9 cyanation,10 imidization,11 formylation,12
heteroarylation,13 alkenylation,14 and alkynylation,15 have been
well documented (Scheme 1, pathway iii). Generally, this type
of migration reaction refers to a functional group from a
carbon or heteroatom to a radical center by means of the
formation of an annular transition state. In contrast,
annulation−functionality migration for alkene functionaliza-
tion remains elusive, as the giant challenge lies in how to build
Alkenes
Received: November 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04018
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
suitable transition states between distinct molecules for
functionality migration. To overcome the obstacle and given
the difference in reactive behaviors of terminal and internal
olefins, we design a new radical reaction mode by the
interactions between terminal and internal ones to transport
radical species across each other, by which an applicable 5-
membered transition state could be constructed to complete
annulation−functionality migration (Scheme 1, pathway iv).
For this reason, we considered using α-allyl-α-bromomalonates
as both the radical donor and acceptor to generate an
electrophilic C-centered radical through visible-light photo-
redox catalysis that could add to alkenes to initiate the
addition−cyclization pathway.16 If an alkynyl alcohol was
introduced into the alkenes to construct strategically located
tertiary alcohols, hydroxymethyl radical was formed upon 5-
exo-trig cyclization and subsequent 5-exo-dig cyclization and
alkynyl migration could yield the desired α-cyclopentyl
ketones, with both cyclization processes occurring in a
regioselective manner (see proposed mechanism discussion).
Herein we report a conceptually new annulation−alkynyl
migration mode in which photoinduced multiple functionaliza-
tion of dual unactivated alkenes was successfully implemented.
Our initial investigations were conducted with 1,4-enyne 1a
and ethyl α-allyl-α-bromomalonate 2a as the model substrates
under blue LED irradiation. In the presence K2CO3 as the
base, the reaction catalyzed by fac-Ir(ppy)3 (Er1e/d2[IrIV/*IrIII] =
−1.73 V vs SCE),17 proceeded in acetonitrile at 30 °C, and the
desired alkynyl migration product 3a was obtained, albeit with
27% yield (Table 1, entry 1). This preliminary result supported
the feasibility of intermolecular alkynyl migration mode and
thus prompted us to further search the optimal conditions for
accessing product 3a. The reaction efficiency was found to
show an important solvent dependence. For example, the use
of DCE, toluene, and EtOH as the reaction media all led to a
slightly lower conversion of 1a into 3a as compared with
acetonitrile (entry 1 vs entries 2−4). In another case with
hexafluoroisopropanol (HFIP), remarkably increased yield of
3a was observed (46%, entry 5). HFIP was selected as reaction
media to investigate the effect of other reaction parameters.
Increasing the amount of 2a to 2.0 equiv did not show any
improvement on the obtainable yield of 3a (entry 6). Next, a
Table 1. Optimization of the Reaction Conditions for
Product 3a
a
b
c
entry
photocatalyst (mol %)
base
solvent yield (%)
1
2
3
4
5
6
7
8
9
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
fac-Ir(ppy)3 (1.0)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
K3PO4
MeCN
DCE
27
23
19
21
46
42
h
21
44
51
51
46
h
toluene
EtOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
d
tBuOK
10
11
12
13
K2HPO4
K2HPO4
K2HPO4
K2HPO4
e
f
[Ir{dF(CF3)ppy}2(bpy)] PF6
(1.0)
14
15
16
17
18
[Ir(dtbbpy)(ppy)2]PF6 (1.0)
Ir(dFppy)3 (1.0)
Ir(dFppy)3 (2.0)
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
53
63
55
51
i
Ir(dFppy)3 (3.0)
g
19
Ir(dFppy)3 (1.0)
i
a
Reaction conditions: 1,4-enyne 1a (0.1 mmol, 1.0 equiv), 2a (0.15
mmol, 1.5 equiv), photocatalyst (1 mol %), base (0.2 mmol, 2.0
b
equiv), 1.5 mL of HFIP, 30 °C, under argon conditions. dF(CF3)ppy
= 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridyl; dtbbpy = 4,4′-di-
tert-butyl-2,2′-dipyridyl; dFppy = 2-(2′,4′-difluorophenyl)pyridyl.
c
d
e
f
Isolated yield based on 1a. 2a (0.2 mmol, 2.0 equiv). 40 °C. 25
g
h
i
°C. In the dark. Trace. No reaction.
With these optimal reaction conditions in hand, we
evaluated the substrate generality using a broad range of 1,4-
enynes and α-allyl-α-bromomalonate derivatives. Overall, all
tested substrates could enable the photocatalytic annulation−
alkynyl migration process to access the desired α-cyclopentyl
ketones 3 in synthetically useful yields and diastereoselectiv-
ities, which were hardly attainable via a conventional
annulation process (Schemes 2−4). At the outset, a variety
of functional groups such as methyl, ethyl, tert-butyl, methoxy,
fluoro, chloro, and bromo were introduced into the different
positions of phenyl ring relative to arylalkynyl moiety of
substrates 1, and in all the cases, the desired products 3b−3k
were obtained in acceptable yields and high diasereoselectivity
(>8:1 dr, Scheme 2). Among them, 1,4-enyne 1e bearing tert-
butyl functionality seemed reluctant to undergo this photo-
catalytic process, as the product 3e was generated in 34% yield,
but with a complete diastereoselectivity. In contrast, the
presence of sterically more demanding substituents on the
alkyne moiety, for example, the o-chlorophenyl groups, could
show a highly reactive profile, furnishing the corresponding
product 3j with 55% yield, albeit with an obvious decline of the
diastereoselectivity (8:1 dr). Notably, swapping the aryl moiety
on the alkyne with a tert-butyl group provided the product 3l
in a highly diastereoselective pathway, but with a low yield,
which may be caused by the instability of in situ generation of
vinyl radical D (see mechanism discussion).
t
variety of inorganic bases, such as KHCO3, K3PO4, BuOK,
and K2HPO4 were adopted for this photocatalysis (entries 7−
10). Among the inorganic bases tested, K2HPO4 as base was
found to be more effective for this transformation with the
formation of the product 3a in 51% yield (entry 10). The yield
of 3a leveled off when the reaction temperature was raised to
40 °C (entry 11). A decrease of temperature to 25 °C was not
beneficial for the transformation, resulting in a slightly
decreased yield (entry 12). Screening of the photocatalysts,
such as [Ir{dF(CF3)ppy}2(bpy)]PF6,18 [Ir(dtbbpy)(ppy)2]PF6
(E1re/d2[IrIV/*IrIII] = −0.96 V vs SCE),19 and Ir(dFppy)3
(Er1e/d2[IrIV/*IrIII] = −1.44 V vs SCE)20 (entries 13−15),
revealed that Ir(dFppy)3 exhibited the best catalytic activity
with respect to the overall reaction outcome (63%, entry 15),
and a highly oxidizing photocatalyst, [Ir{dF(CF3)ppy}2(bpy)]-
PF6, was ineffective in the current protocol (entry 13).
Increasing the Ir(dFppy)3 loading had a detrimental impact on
the reaction yield (entries 16 and 17). In the control
experiments, the transformation could be completely sup-
pressed with the removal of the photocatalyst or light
irradiation (entries 18 and 19).
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DOI: 10.1021/acs.orglett.9b04018
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Letter
functional groups such as methyl, tert-butyl, methoxy, fluoro,
chloro, and bromo were all suitable for this photoredox
catalysis, in which satisfactory diastereoselectivity was observed
except for 3r and 3v−3y. Linear alkyl groups such as ethyl, n-
hexyl, and dodecyl exhibited good compatibility, as evident by
the corresponding products 3aa−3cc being obtained in
moderate yields and with 3:1 to >19:1 dr.
Scheme 2. Scope of 1,4-Enyne Substrates Regarding Alkyne
Moiety
Subsequently, the generality and limitations of our protocol
were further assessed by changing 1,4-enyne and α-allyl-α-
bromomalonate components to assemble α-cyclopentyl
ketones. 1,4-Enynes 1 bearing two substituents of opposite
electronic properties on the phenyl ring worked smoothly,
delivering products 3dd and 3ee in 48% and 50% yields,
respectively, together with 6:1 and >19:1 dr value (Scheme 4).
Scheme 4. Scope of 1,4-Enyne and α-Allyl-α-
bromomalonate Substrates
Next, a detailed survey of the possible variation in the R2
substituents linked by the tertiary alcohol unit was examined
by adopting ethyl α-allyl-α-bromomalonate 2a as a representa-
tive internal alkene substrate (Scheme 3). Diverse substituents
such as aryl and alkyl can all tolerate this catalytic system,
leading to the diastereoselective formation of the products
3m−3cc in acceptable yields. All tested aryl groups relative to
tertiary alcohol moiety with varied functionalities and
substitution patterns could undergo effective transformations
to access the corresponding products 3m−3z. Various
Scheme 3. Scope of 1,4-Enyne Substrates Regarding
Substituents Linked by Quaternary Carbon
Similarly, two substituents with same electronic nature were
also compatible with the current photocatalytic conditions (3ff
and 3gg). Interestingly, replacing two methyl groups with
hydrogen on the internal olefin unit, ethyl α-allyl-α-
bromomalonate 2b was successfully transformed into the
corresponding product 3hh in 52% yield and 3:1 dr, which
indicates that two different terminal olefins could also tolerate
these photocatalytic conditions, maintaining commendable
chemo- and regioselectivity. Exchanging ethyl α-allyl-α-
bromomalonates for α-allyl-α-bromo-β-ketoester led to the
construction of α-cyclopentyl ketone 3ii in 41% yield. This
chemistry was also well accommodated by naturally derived
tertiary alcohols including estrone (1hh), isopulegol (1ii), and
D-α-tocopherol (1kk), confirming the success of these
transformations and furnishing the corresponding products
3jj−3ll with 37%−48% yields (Scheme 4). Note that this is the
first reported procedure for the assembly of these new α-
cyclopentyl ketones through a conceptually new photocatalytic
annulation−alkynyl migration. Moreover, we carried out an
C
DOI: 10.1021/acs.orglett.9b04018
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Letter
amplification reaction of 1k with 2a under the standard
conditions, and the product 3k was provided in 52% yield on a
1.0 mmol scale. The structures of these resulting α-cyclopentyl
ketones were fully characterized by their NMR spectroscopy
and HRMS data.
Scheme 6. Plausible Reaction Pathway
To understand the mechanism of this reaction, 1.5 equiv of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylhy-
droxytoluene (BHT) was subjected to reaction with 1,4-
enyne 1a and ethyl α-allyl-α-bromomalonate 2a under the
standard conditions (Scheme 5), but no product 3a was
Scheme 5. Control Experiments
intermediate B, which undergoes 5-exo-trig/5-exo-dig bicycliza-
tion to deliver D. Subsequent ring-opening of the cyclopentane
ring of D occurs, giving hydroxyalkyl radical E, which is
oxidized by the Ir(IV) species to yield carbon cation F and
regenerate the Ir(III) catalyst. In presence of the base
K2HPO4, intermediate F loses a proton to produce the target
product 3a.
detected with the substrate 1a being recovered. For the former
reaction, the TEMPO−α-allyl-malonate adduct was detected
by HRMS (MS = 384.2747) analysis, which indicates a
possible radical process. Subsequently, several fluorescence
quenching experiments were performed (Figures 1 and 2). The
In summary, starting from 1,4-enynes and α-allyl-α-
bromomalonates, we discovered a conceptually new mode of
annulation−alkynyl migration by visible light irradiation, in
which a wide range of cyclopentane carboxylates with
moderate to good yields were synthesized under mild
conditions. A C-centered radical induced cascade 5-exo-trig/
5-exo-dig bicyclization and C−C bond cleavage process
enabled direct formation of three C−C bonds to realize
multiple functionalization of dual nonconjugated alkenes in
one step. This method provides a seminal mode for the study
of alkynyl migration.21 Further investigation of radical
annulation−functional group migration is underway in our
laboratory.
Figure 1. Stern−Volmer analysis for Ir(dFppy)3 with 1a.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04018.
Experimental procedures, characterization data for all
products, detailed optimized geometries, and free
energies (PDF)
Figure 2. Stern−Volmer analysis for Ir(dFppy)3 with 2a.
observations indicate that the fluorescence intensity of
Ir(dFppy)3 decreases along with the increasing of concen-
tration of 2a. A linear relationship between I0/I and the
concentrations of 1a showed that the fluorescence intensity of
Ir(dFmppy)3 remains unchanged with increasing concentra-
tions of 1a, and the Ir(dFppy)3* is believed to be quenched by
2a.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wjhao@jsnu.edu.cn.
*E-mail: laotu@jsnu.edu.cn.
*E-mail: jiangchem@jsnu.edu.cn.
ORCID
Based on the above experimental results and previous
reports,7c,16a,d a reasonable mechanism is depicted in Scheme
6. Initially, Ir(III) is transformed into the excited state of
*Ir(III) species under visible light irradiation. Radical
intermediate A is afforded through a single electron transfer
(SET) process from *Ir(III) complex and α-allyl-α-bromo-
malonates 2a, together with Ir(IV) species. Then, radical
addition of intermediate A to 1,4-enyne 1a provides
Bo Jiang: 0000-0003-3878-515X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the NSFC (Nos.
21602087, 21871112, and 21971090).
■
D
DOI: 10.1021/acs.orglett.9b04018
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