Phototriggered Active Alkyne Generation from Cyclopropenones with Visible Light-Responsive Photocatalysts

Article abstract of DOI:10.1021/acs.orglett.9b01280

A photocatalytic active alkyne generation reaction was developed using cyclopropenone as a starting reagent. Visible light-responsive photocatalysts induced cyclopropenone decarbonylation. The resulting highly reactive alkyne could be used directly, witho

Full text of DOI:10.1021/acs.orglett.9b01280

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phototriggered Active Alkyne Generation from Cyclopropenones
with Visible Light-Responsive Photocatalysts
Kenji Mishiro,*,† Takeshi Kimura,‡ Taniyuki Furuyama,§,∥ and Munetaka Kunishima*,‡
†Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
‡Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
§Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
∥Japan Science and Technology Agency (JST)-PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: A photocatalytic active alkyne generation reaction was
developed using cyclopropenone as a starting reagent. Visible light-
responsive photocatalysts induced cyclopropenone decarbonylation.
The resulting highly reactive alkyne could be used directly, without
isolation, for further reactions, such as in a dehydration condensation
reaction and alkyne−azide click chemistry.
excitation, the technique may not be universally effective for all
cyclopropenones.
n alkyne is a versatile functional group that is widely used
Afor C−C and C−heteroatom bond formation in synthetic
organic chemistry and biological chemistry.1 A cyclopropenone
can be photolyzed to yield one molecule of carbon monoxide
and an alkyne; hence, it can be regarded as a “photocaged
alkyne.”2 The phototriggered alkyne generation reaction is
especially useful for generating a highly reactive alkyne because
of the following features: (i) the highly reactive and unstable
alkyne can be utilized for chemical reactions without isolation,
and (ii) the location and the timing of the alkyne-involving
reaction can be controlled through localized light irradiation
and timing.
Popik et al. have developed a phototriggered cyclooctyne
generation reaction3 and applied it to strain-promoted alkyne−
azide click chemistry.4 They also developed a phototriggered
ene−diyne formation reaction5 followed by Bergman cycliza-
tion.6 Inspired by their work, we recently developed a
phototriggered amidation7 and a phototriggered ketone
formation8 using aminocyclopropenones. In previous reports,
mainly UV light has been used for the cyclopropenone
decarbonylation. When UV sensitive molecules or UV
absorbing molecules coexist with the cyclopropenones, the
uncaging reaction should be performed with longer wavelength
light, such as visible light. Although it would be possible to
develop a visible-light-labile cyclopropenone, such a cyclo-
propenone would be impractical because it could undergo
undesired decomposition under ambient light conditions.
Popik et al. have reported a photodecarbonylation of a
cyclopropenone by two-photon excitation with a near-infrared
laser.9 The two-photon excitation technique is useful due to its
low invasivity and high permeability. However, because there
are strict structural requirements for efficient two-photon
An alternative approach toward using visible light to trigger a
reaction that requires UV light is to employ a visible light-
responsive photocatalyst.10 To the best of our knowledge,
decarbonylation of cyclopropenones using visible light
responsive photocatalysts has yet to be reported. If photo-
decarbonylation of visible-light-stable cyclopropenones can be
executed with visible light sources in the presence of a
photocatalyst, the versatility of the phototriggered alkyne
generation reaction would be expanded greatly. In this letter,
we demonstrate the possibility of the photocatalyst-promoted
active alkyne generation reaction and applications of the in situ
generated active alkynes to further reactions (Scheme 1).
Scheme 1. Phototriggered Decarbonylative Active Alkyne
Generation Reactions
Received: April 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We selected the phototriggered dehydration condensation
reaction we reported previously as a model reaction (Scheme
2). In this system, photolysis of the aminocyclopropenone 1
5a was also obtained in a stoichiometric ratio to 4aa (entries 7
and 8). Under dark conditions, the catalysts 13 and 14 did not
promote the decarbonylation of 1a and the dehydration
condensation of 2a and 3a was not observed (entries 9 and
10). These results indicated that the photocatalyst 13 and 14
were excited by the visible light and induced the decarbon-
ylation of the aminocyclopropenone, yielding the ynamine
which worked as a dehydration condensation agent.
Scheme 2. Phototriggered Dehydration Condensation
forms highly reactive ynamine 6. This is then followed by
formation of acyloxyenamine 7 from the ynamine and
carboxylic acid 2. Aminolysis of 7 with 3 furnishes amide 4
and the hydrated ynamine-derived product 5. When the R
substituent of 1 is phenyl or naphthyl, 1 has an absorption
around 200−350 nm, and the reaction proceeds efficiently
under UVA−UVB (300−400 nm) conditions.
We began by screening several commercially available visible
light-responsive photocatalysts. A solution of aminocyclopro-
penone 1a, carboxylic acid 2a, amine 3a, and a photocatalyst
(8−14) in MeCN was irradiated with a household
fluorescence lamp (400−750 nm) for 48 h (Table 1). As
Table 1. Catalyst Screening for the Photocatalytic
Dehydration Condensation
The redox potential of the catalysts 8−14 are listed in Table
2. Catalysts 8−10, which do not effectively induce 4aa
a
Table 2. Redox Potential of the Photocatalysts 8−14
a
a
Eox
(C•+/C)
(V)
Ered
(C/C•−
(V)
Eox*
(C•+/C*)
(V)
Ered*
entry
catalyst
4aa yield (%)
1a recovery yield (%)
)
(C*/C•−
)
1
2
3
4
5
6
7
8
none
8
9
10
11
12
13
14
13
0
<1
<1
<1
4
>99
85
89
87
30
42
6
7
>99
>99
catalyst
(V)
ref
8
9
+0.77
+1.29
+1.26
+1.86
−2.19
−1.33
−1.36
−0.80
−0.57
−1.37
−1.62
−1.73
−0.81
−0.87
−0.26
+0.31
+0.77
+0.82
+1.45
+2.06
+1.21
+1.22
11
12
13
12
14
11
15
10
11
12
13
14
6
35
44
0
+1.69
+1.69
−0.89
−1.15
b
9
a
Previously reported data in the reference literatures. All the
b
10
14
b
0
potentials are versus the saturated calomel electrode (SCE).
Measurements were performed in MeCN. C: ground state catalyst.
a
NMR yield. In dark.
C*: excited state catalyst. C•+: one electron oxidized catalyst. C•−
:
one electron reduced catalyst.
expected, some of the photocatalysts promoted the dehy-
dration condensation reaction. Under catalyst-free conditions,
amide 4aa was not obtained and 1a was recovered
quantitatively (entry 1). The reactions in the presence of
catalysts 8−10 afforded only trace amounts of 4aa and most of
1a was recovered (entries 2−4). For catalysts 11 and 12,
although more than half of 1a was consumed, the 4aa yield was
only 4−6% (entries 5 and 6). For catalysts 13 and 14, more
than 90% of 1a was consumed and 4aa was obtained in 35−
44% yield. Under these conditions, ynamine-derived product
formation and did not decompose 1a significantly, exhibit a
relatively low excited state reduction potential [Ered* = +0.31
to +0.82 V]. Catalysts 11 and 12 which resulted in
nonconstructive decomposition of 1a exhibit relatively high
excited state reduction potential [Ered* = +1.45 and +2.06 V]
and relatively low first reduction potential [Ered = −0.80 and
−0.57 V]. Catalyst 13 and 14, which resulted in >90%
consumption of 1a and moderate 4aa yield exhibit relatively
B
DOI: 10.1021/acs.orglett.9b01280
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Organic Letters
Letter
high excited state reduction potential [Ered* = +1.21 and +1.22
V] and relatively high first reduction potential [Ered = −1.37
and −1.62 V].
Considering the relationship between the catalyst redox
potential and the results in Table 1, the redox potential of the
photocatalyst is critically important to the success of the
decarbonylation of aminocyclopropenone 1a. The redox
potentials of 1a were estimated with cyclic voltammetry
(Figure 1). Aminocyclopropenone 1a exhibited one reversible
cation C. C then receives one electron from the catalyst to
form zwitter ion D. Decarbonylation of D occurs thereafter to
produce the desired alkyne E. It might be also possible that the
radical cation C first releases CO to produce an alkyne radical
cation and it receives one electron from the catalyst to produce
the desired alkyne. To explore the proposed mechanism in
greater detail, more specialized analyses are required, such as
flash photolysis/ultrafast time-resolved spectroscopy.
Further optimization of the condition was performed with
catalyst 14 (Table 3). Solvent screening studies found that
Table 3. Optimization of the Conditions for the
Photocatalyst-Promoted Dehydration Condensation
Reaction
1a concn
14
time
(h)
4aa yield
a
entry
solvent
MeCN
THF
1,4-dioxane
AcOEt
toluene
CHCl3
1,2-DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(mM)
(mol %)
(%)
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
100
100
100
20
10
10
10
10
10
10
10
10
20
10
20
20
48
48
48
48
48
48
48
48
48
41
24
24
39
51
52
31
42
56
61
57
56
61
66
76
Figure 1. Cyclic voltammogram of 1a.
reduction couple at −0.81 V and an irreversible oxidation wave
at >+1.4 V (its anodic peak potential was +1.67 V). Therefore,
one electron oxidation of the aminocyclopropenone by a
photocatalyst could produce an unstable radical cation that can
decompose to another species. The decomposition may lead to
the ynamine generation or a nonynamine-mediated degrada-
tion of 1a.
10
11
12
The mechanistic study of direct cyclopropenone photolysis
has already been reported.16 The decarbonylation takes place
via a two-step bond cleavage. Additionally, the spin multiplicity
of the reactant remains in the singlet state throughout the
decarbonylation process. Because the visible light responsive
photocatalyst normally cannot excite a nonvisible light
absorbing substrate from the singlet ground state to the singlet
excited state, the photocatalyst-supported decarbonylation of
the cyclopropenone would proceed via a different mechanism
than in the case of direct photolysis. We hypothesized the
following photoredox mechanisms shown in Scheme 3. The
excited catalyst removes one electron from the cyclopropenone
A to produce radical cation B. Then, the ring opening of the
radical intermediate B, which would be driven by the strain
release of the three membered ring,17 occurs to produce radical
20
10
a
NMR yield.
chlorinated solvents worked best and provided relatively good
yields (entries 1−8). This tendency was consistent with the
direct UV irradiation conditions we reported previously. Next
the reaction concentrations and the catalyst amounts were
optimized (entries 9−12). Although the reason is still unclear,
reaction conditions with lower substrate concentrations
exhibited faster reaction rates and better yields. Under the
conditions of 10 mM substrates with 20 mol % catalyst, the
product was obtained in 76% yield after 24 h.
We investigated the substrate scope of our visible light
promoted reaction with the optimized conditions. As shown in
Scheme 4, the reaction could be applied to various substrates.
However, in the reaction of 3-phenylpropionic acid and aniline,
the photolysis of 1a was sluggish. Even after 24 h irradiation,
72% of 1a was recovered and the amide 4af was obtained in
only 12% yield.
Scheme 3. Hypothesized Reaction Mechanisms for the
Photocatalyst-Promoted Decarbonylation of a
Cyclopropenone
In general, an amine is prone to oxidation and can be
oxidized under photoredox conditions.11,18 Therefore, there is
concern about oxidative decomposition of the amine and
quenching of the excited catalyst. In our reaction, an alkyl
amine can be used for the amide formation probably because
most of the amine is being protonated by the coexisting
carboxylic acid and tolerates the oxidation by the photo-
catalyst. In fact, in the reaction using aniline, most of which
should not be being protonated by a carboxylic acid, the
photocatalytic decarbonylation of the cyclopropenone was
significantly disturbed. It would be because the excited catalyst
C
DOI: 10.1021/acs.orglett.9b01280
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Organic Letters
Letter
photocatalyst 14, aminocyclopropenone 1a was selectively
decomposed. After 20 h irradiation, the amide 4ab was
obtained in 75% yield, and most of the tetrazole 15 remained
intact (entry 2). These results indicated that the photocatalyst-
mediated method can be applied to UV light-sensitive
substrates that cannot tolerate the direct excitation conditions.
We envisioned that our reaction might be applicable to
photoclick chemistry using a cyclopropenone reported by
Popik et al.3,4 Cyclopropenone 17 was used as a model
substrate. Although 17 had no absorption near the >400 nm
region, 17 was decomposed slightly by household fluorescence
lamp irradiation even in conditions without a photocatalyst.
Perhaps the fluorescence lamp contained a weak UV range
light that was absorbed by 17. Therefore, a blue LED (450−
500 nm) that did not decompose 17 was used for the reaction.
A mixture of 17 and azide 18 was irradiated by blue LED-light
in the presence of photocatalyst 13. Catalyst 13 promoted the
decarbonylation of 17, and the in situ generated cyclooctyne
19 was efficiently trapped as stable triazole 20 (Table 5). In
Scheme 4. Substrate Scope
Table 5. Photocatalyst-Promoted Alkyne−Azide Click
Chemistry
a
b
c
NMR yield. Isolated yield. 72% of 1a was recovered.
was quenched by the nonprotonated aniline. Therefore, for the
success of the photocatalyst mediated alkyne generation, the
reaction conditions need to be appropriately arranged so that
undesired substrate decomposition or the quenching of the
excited catalyst does not occur.
Next, the reaction was performed in the presence of UV
light-sensitive tetrazole 15 (Table 4). A tetrazole is photolyzed
entry
1
2
solvent
MeCN
MeCN
17 concn (mM) time (h) 20 yield (%)
a
b
5
5
2
18
18
40
74 (75 )
0
c
a
Table 4. Phototriggered Dehydration Condensation in the
Presence of a UV Light-Sensitive Tetrazole
a
3
MeCN/H2O (1/1)
67
a
b
c
NMR yield. Isolated yield. Without 13.
MeCN, 20 was obtained in 74% yield (entry 1). The reaction
did not progress without photocatalyst 13 (entry 2).
Remarkably, the reaction proceeded under aqueous conditions
in MeCN/H2O (1/1), and 20 was obtained in 67% yield
(entry 3).
15
time 4ab yield 16 yield recovery
As demonstrated above, we have developed a novel
phototriggered active alkyne generation reaction with a
visible-light-responsive-photocatalyst. The method would be
especially useful when UV light cannot be used for alkyne
generation due to the UV light-sensitivity of other coexisting
substrates. It must be noted that the photocatalyst-mediated
conditions would not always be preferable to the direct UV
irradiation conditions because other side reactions may be
possible, such as the undesired decomposition of other redox-
sensitive substrates. Appropriate selection of the reaction
conditions depending on the situation would be critically
important for the best use of the phototriggered active alkyne
generation reactions.
a
a
a
entry
irradiation conditions
(h)
(%)
(%)
(%)
1
2
UVB (280−350 nm)
3
46
75
46
<1
22
97
visible
20
(400−750 nm) + 14
(20 mol %)
a
Isolated yield.
to produce a highly reactive nitrile imine. A nitrile imine can
react with a carboxylic acid to produce a diacyl hydrazide.19
Under UVB light conditions, decomposition of both of 1a and
15 were observed, and amide 4ab and tetrazole-derived diacyl
hydrazide 16 were obtained in similar yields (entry 1). On the
other hand, under visible light conditions in the presence of
D
DOI: 10.1021/acs.orglett.9b01280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2006, 71 (19), 7417−7421. (c) McNitt, C. D.; Cheng, H.;
Ullrich, S.; Popik, V. V.; Bjerknes, M. J. Am. Chem. Soc. 2017, 139
(40), 14029−14032.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01280.
■
S
(10) (a) Xuan, J.; Xia, X.-D.; Zeng, T.-T.; Feng, Z.-J.; Chen, J.-R.;
Lu, L.-Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 5653−5656.
(b) Denning, D. M.; Pedowitz, N. J.; Thum, M. D.; Falvey, D. E. Org.
Lett. 2015, 17, 5986−5989.
General information, list of abbreviations, procedures for
Tables 1 and 3−5 and Scheme 4, 1.0 mmol scale
reaction of the photocatalyst promoted dehydration
condensation, reaction monitoring by 1H NMR,
synthetic procedure for 15, UV−vis spectra of catalysts
and cyclopropenones, cyclic voltammetry experiment of
(11) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113 (7), 5322−5363.
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1
1a, and H and 13C NMR spectra (PDF)
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(16), 7244−7249.
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AUTHOR INFORMATION
Corresponding Authors
■
(16) Poloukhtine, A.; Popik, V. V. J. Phys. Chem. A 2006, 110 (5),
1749−1757.
*E-mail: mishiro@p.kanazawa-u.ac.jp.
*E-mail: kunisima@p.kanazawa-u.ac.jp.
ORCID
(17) (a) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc.
1976, 98 (22), 7024−7026. (b) Lu, Z.; Shen, M.; Yoon, T. P. J. Am.
Chem. Soc. 2011, 133 (5), 1162−1164. (c) Amador, A. G.; Sherbrook,
E. M.; Lu, Z.; Yoon, T. P. Synthesis 2018, 50 (03), 539−547.
(18) Yates, S. F.; Schuster, G. B. J. Org. Chem. 1984, 49 (18), 3349−
3356.
Kenji Mishiro: 0000-0002-5071-7574
Munetaka Kunishima: 0000-0002-3296-490X
Notes
(19) (a) Li, Z.; Qian, L.; Li, L.; Bernhammer, J. C.; Huynh, H. V.;
Lee, J. S.; Yao, S. Q. Angew. Chem., Int. Ed. 2016, 55 (6), 2002−2006.
(b) Zhao, S.; Dai, J.; Hu, M.; Liu, C.; Meng, R.; Liu, X.; Wang, C.;
Luo, T. Chem. Commun. 2016, 52 (25), 4702−4705.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by MEXT KAKENHI, Grant in
Aid for Early Career Scientists (Grant 18K14864), and
Kanazawa Univerity SAKIGAKE Project 2018. K.M. acknowl-
edges the support from the Program to Disseminate Tenure
Tracking System, MEXT.
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