Selective Syntheses of Z-Alkenes via Photocatalyzed Decarboxylative Coupling of N-Hydroxyphthalimide Esters with Terminal Arylalkynes

Article abstract of DOI:10.1021/acs.orglett.9b00558

A novel, efficient Z-alkene synthesis via photocatalyzed decarboxylative couplings between terminal aryl alkynes and alkyl N-hydroxyphthalimide (NHPI) esters, which are derived from aliphatic carboxylic acids, is described. A wide range of primary, secondary, and tertiary carboxylates as well as α-amino acid and α-oxyacid-derived esters were employed as suitable substrates. The mild reaction conditions, broad substrate scope, functional group tolerance, and operational simplicity make this decarboxylative coupling reaction a valuable method in organic syntheses.

Full text of DOI:10.1021/acs.orglett.9b00558

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Syntheses of Z‑Alkenes via Photocatalyzed
Decarboxylative Coupling of N‑Hydroxyphthalimide Esters with
Terminal Arylalkynes
Guo-Li Dai,‡ Shu-Zhen Lai,‡ Zhuangzhu Luo,*,† and Zhen-Yu Tang*,†,‡
†School of Chemical Engineering and Technology, Sun Yat-Sen University, Zhuhai 519082, China
‡Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha
410083, China
S
* Supporting Information
ABSTRACT: A novel, efficient Z-alkene synthesis via photo-
catalyzed decarboxylative couplings between terminal aryl
alkynes and alkyl N-hydroxyphthalimide (NHPI) esters,
which are derived from aliphatic carboxylic acids, is described.
A wide range of primary, secondary, and tertiary carboxylates as
well as α-amino acid and α-oxyacid-derived esters were
employed as suitable substrates. The mild reaction conditions, broad substrate scope, functional group tolerance, and
operational simplicity make this decarboxylative coupling reaction a valuable method in organic syntheses.
Scheme 1. Hydroalkylation of Alkynes with Alkyl
Electrophiles
lkenes are among the most important structural motifs
that frequently appear in chemical, material, natural
A
product, and pharmaceutical fields.1 While compared with the
synthesis of more stable E-alkene, there were few reports on
the preparation of Z-alkene. The most general method of Z-
alkene synthesis is the Wittig-type reaction, which is non-
catalytic and generates a stoichiometric amount of phosphine
oxide waste.2 As nontoxic, abundant, stable, and inexpensive
substrates, carboxylic acids are highly useful starting materials
in coupling reactions. Macmillan and co-workers reported the
selective intermolecular addition of nucleophilic radicals to
alkynes via Ir- and Ni-catalyzed decarboxylative hydro-
alkylation of alkynes.3 As aliphatic carboxylic acids derivatives,
N-hydroxyphthalimide (NHPI) esters have attracted consid-
erable attention and were usually used as efficient alkyl
electrophiles in alkyl coupling reactions, such as with
organometallic reagents,4 aryl iodides,5 α,β-unsaturated
acids,6 alkynes,7 alkenes,8 boron reagents,9 and other
substrates.10 In recent years, several methods were reported
to access Z-alkenes by coupling of terminal alkynes with alkyl
electrophiles (Scheme 1). For example, in 2015, Hu and co-
workers developed the first Z-selective olefin synthesis via iron-
catalyzed reductive coupling of terminal alkynes with alkyl
iodides and alkyl tosylates as electrophiles.11 Bao and co-
workers have reported the Z-preferred olefin syntheses via Ru-
and Ni-catalyzed hydroalkylation of terminal aryl alkynes with
alkyl diacyl peroxides as electrophiles.12 Li and co-workers
disclosed a radical-mediated oxidative decarbonylative hydro-
alkylation of alkynes with alkyl aldehydes using di-tert-butyl
peroxide (DTBP) as oxidant.13 In organic chemistry, visible
light as a safe, renewable, and inexpensive source of chemical
energy to facilitate the construction of complex organic
molecules has always been harnessed. With those advantages,
we wondered if NHPI esters could be also used to react with
terminal aryl alkynes to access Z-alkene via a photocatalyzed
decarboxylative coupling strategy, and herein we report our
results.
Our studies were commenced with the model reaction
between N-acyloxyphthalimide (1b) and phenylacetylene (1a)
(Table 1). Previous reports indicated that fac-Ir(ppy)3 and
diisopropylethylamine (DIPEA) played important roles in
styrene’s (E)- to (Z)-isomerization.14 Inspired by this result,
we discovered that simply mixing 1a (0.2 mmol), 1b (0.5
mmol, 2.5 equiv), DIPEA (3 equiv), and fac-Ir(ppy)3 (1 mol
%) in DMA for 18 h afforded 29% (Z/E = 67:33) of product 1
after irradiation by 36 W blue LED lamps under Ar. This initial
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope with Respect to Terminal
a
(Hetero)arylalkynes
entry
1
change from standard condition
yield % (Z/E)
no change
no Ir(ppy)3
no blue LEDs
no DIPEA
DABCO instead of DIPEA
TMEDA instead of DIPEA
Et3N instead of DIPEA
DMAP instead of DIPEA
DBU instead of DIPEA
CH3COOLi instead of DIPEA
K2CO3 instead of DIPEA
20 equiv of DIPEA
77 (79:21)
0
0
b
2
3
4
5
6
7
8
9
b
b
0
b
18 (50:50)
20 (57:43)
17 (57:43)
13 (56:44)
15 (58:42)
0
b
b
b
b
b
10
11
12
13
14
15
16
17
b
0
c
34 (74:26)
56 (89:11)
31 (86:14)
37 (73:27)
40 (86:14)
0
c
70 equiv of DIPEA
d
DMSO instead of DMA
THF instead of DMA
MeCN instead of DMA
Cy-COOH instead of 1b
d
d
d
a
Conditions: 1a (0.2 mmol), 1b (1.2 mmol), and Ir(ppy)3 (1−2 mol
%) in a mixture of DIPEA/DMA (2.4 mL/1.6 mL) were irradiated by
36 W blue LEDs for 18 h under Ar. Isolated yields. The Z/E ratio was
b
determined by 1H NMR. 1b (2.5 equiv), Ir(ppy)3 (1−2 mol %), and
c
d
DIPEA (3 equiv) in DMA (2 mL). 1b (2.5 equiv). 1b (2.5 equiv)
and DIPEA (70 equiv) in DMA (2 mL).
result promoted us to improve both yield and Z/E ratio of this
reaction. The control experiments indicated that photocatalyst,
blue LED, and DIPEA were essential for the transformation to
occur (entries 2−4). When DIPEA was replaced by other
organic bases such as DABCO, TMEDA, Et3N, DMAP, and
DBU, both yields and Z/E ratios decreased significantly
(entries 5−9). There was no product formed when replacing
DIPEA with inorganic bases(CH3COOLi, K2CO3) (entries 10
and 11). Increasing the amount of DIPEA significantly
improved both yield and selectivity. Different ratios (see the
Supporting Information for details) of DIPEA were tested for
this condition. The best selectivity was observed when 70
equiv of DIPEA was added (entries 12 and 13). Next, different
solvents (DMSO, THF, MeCN, DCM, dioxane, DCE, acetone,
ethyl acetate) were screened. DMA was established as the best
solvent (entries 14−16). It should be noted that no product
was formed when cyclohexanecarboxylic acid was employed
instead of its NHPI ester 1b, probably because of the lower
oxidation capacity of the photocatalyst (entry 17).15 Finally,
lowering concentration to 0.05 mmol/mL and increasing the
amount of 1b to 6 equiv (see the Supporting Information for
details) produced coupling product 1 with 77% yield and Z/E
selectivity of 79:21. Overall, optimal choice of solvent and
equivalents of base were the keys for this transformation.
With the optimized reaction conditions in hand, we explored
the substrate scope with various aryl alkynes (Scheme 2). A
wide range of alkynyl arenes with either electron-withdrawing
or electron-donating functional groups at the para-, meta-, and
ortho-positions were converted to Z-alkenes with good yields
and Z/E selectivities. The tolerance to the reactive functional
groups like halogen (3, 5, 7, 11, 12, and 13), ester (15), and
cyano (16) groups further broadens the application of this
a
Conditions: Terminal (hetero)arylalkynes (0.2 mmol), NHPI esters
(1.2 mmol), and Ir(ppy)3 (1−2 mol %) in a mixture of DIPEA/DMA
(2.4 mL/1.6 mL) were irradiated by 36 W blue LEDs for 18 h under
Ar. Isolated yields of Z/E mixtures and the Z/E ratio were determined
1
by H NMR.
transformation, as various structural motifs can be accessed by
those functionalities by well-established methods such as cross-
coupling or simple reduction. Alkynyl heteroarene like pyridine
(17) was also a suitable substrate for this transformation. At
last, the alkyl alkyne (18) and aryl internal alkyne were also
tested for this coupling, and no desired products were
observed. A nickel-catalyzed decarboxylative coupling of
NHPI esters with internal alkynes was previously reported by
the other research group.10s
Subsequently, substrate scopes with different NHPI esters
were investigated (Scheme 3). A wide range of redox-active
esters derived from aliphatic carboxylic acids including
primary, secondary, and tertiary alkyl NHPI esters were
subjected to the optimized conditions and afforded the desired
products. Moderate yields were observed for the reactions of
primary alkyl NHPI esters (19, 20, and 21), probably due to
their low efficiencies of decarboxylation and relative instability
of primary alkyl radicals.14c NHPI esters with sensitive
functional groups such as halogen (21), ether (29), and N-
B
DOI: 10.1021/acs.orglett.9b00558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope with Respect to Aliphatic
Carboxylates
Scheme 4. Control Experiments
a
Scheme 5. Proposed Mechanism
a
Conditions: terminal (hetero)arylalkynes (0.2 mmol), NHPI esters
(1.2 mmol), and Ir(ppy)3 (1−2 mol %) in a mixture of DIPEA/DMA
(2.4 mL/1.6 mL) were irradiated by 36 W blue LEDs for 18 h under
Ar. Isolated yields of Z/E mixtures and the Z/E ratio were determined
1
by H NMR.
CH3CN),6a,8i an Ir IV/Ir III redox mechanism is proposed. The
photocatalyst (PC) is excited to a strongly reducing excited
state (PC*) by visible-light irradiation. Radical anion B was
formed by single electron transfer (SET) from PC*. Further,
CO2 and phthalimide anion extrusion produced an alkyl
radical. The coupling of an alkyl radical with alkyne resulted in
the radical intermediate C. Hydrogen atom transfer (HAT)
from DIPEA to intermediate C finished the final product.
Isotope experiments have excluded the hydrogen transfer from
solvent and trace water content in solvents (see the Supporting
Information for details).6a,8i The Z selectivity of the formed
alkene resulted from the isomerization effect of the iridium
catalyst.14a
In conclusion, we successfully developed an efficient strategy
to synthesize Z-selective alkenes with good yields and Z/E
selectivities via visible-light photoredox catalysis. This method
tolerates a wide range of functional groups and demonstrates a
broad scope with regard to both the carboxylic acid and
arylalkyne components. In addition, the reactions can be
carried out under mild conditions without the requirement for
organometallic activation.
Boc (30−33) groups successfully coupled with aryl alkynes to
afford the Z-alkenes with good yields and Z/E selectivities. The
position of the heteroatoms to the NHPI ester functional
group played important roles on this transformation. For
example, N-Boc-piperidine-2-carboxylic acid ester (31)
resulted in better yield than N-Boc-piperidine-4-carboxylic
acid ester (30). This is probably due to the nitrogen atom’s
stabilization ability to the neighboring radicals. Similar results
were observed for the ortho-, chloro-substituted substrate (23),
which produced better Z/E selectivity than the para-
substituted one (24). Finally, a series of amino-acid-derived
NHPI esters (32 and 33) underwent the decarboxylative
coupling with the aryl alkyne to afford highly selective Z-
alkenes.
To investigate the mechanism, a series of control experi-
ments were conducted (Scheme 4). In the presence of iridium
photoredox catalyst and DIPEA, a synthetic pure E isomer of 1
was converted to the Z isomer in 18 h under standard
conditions. Further experiment established the iridium catalyst
as the only essential one for this Z/E conversion. This result
further proved Prof. Weaver’s report and extended this
transformation’s substrate scope.14a
ASSOCIATED CONTENT
* Supporting Information
■
Based on the above mechanistic studies, a possible
mechanism is proposed in Scheme 5. With the redox potential
S
of the Ir-photoredox catalyst fac-Ir(ppy)3 (E1/2
vs SCE, E1/2IV/III = +0.77 V vs SCE), redox active ester (E1/2
−1.26 to −1.37 V vs SCE), and DIPEA (+0.72 V vs SCE in
*
IV/III = −1.73 V
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00558.
=
C
DOI: 10.1021/acs.orglett.9b00558
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
General information, experimental section, general
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procedure and compound characterization, control
experiment and mechanistic studies, and spectroscopic
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: tangzhenyu@mail.sysu.edu.cn (Z.-Y.T.).
*E-mail: luozhzhu@mail.sysu.edu.cn (Z.L.).
ORCID
Zhen-Yu Tang: 0000-0002-3972-5047
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural
Science Foundation of China 21302231, Hunan Provincial
Natural Science Foundation of China 14JJ3021, Ph.D.
Programs Foundation of Ministry of Education of China
20130162120032. We thank the Valuable and Precision
Instruments of Central South University for NMR assistance.
We thank the Sun Yat-Sen University Mass Spectrometry
Facilities for HRMS-ESI assistance.
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