Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
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 ‡
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S Supporting Information *
ABSTRACT: A photocatalytic active alkyne generation reaction was developed using cyclopropenone as a starting reagent. Visible lightresponsive 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.
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excitation, the technique may not be universally effective for all cyclopropenones. An alternative approach toward using visible light to trigger a reaction that requires UV light is to employ a visible lightresponsive photocatalyst.10 To the best of our knowledge, decarbonylation of cyclopropenones using visible light responsive photocatalysts has yet to be reported. If photodecarbonylation 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).
n alkyne is a versatile functional group that is widely used for 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 cyclization.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 cyclopropenone 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 © XXXX American Chemical Society
Scheme 1. Phototriggered Decarbonylative Active Alkyne Generation Reactions
Received: April 12, 2019
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DOI: 10.1021/acs.orglett.9b01280 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 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 decarbonylation 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 aminocyclopropenone 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 Table 2. Redox Potential of the Photocatalysts 8−14a
a
entry
catalyst
4aa yield (%)a
1a recovery yield (%)a
1 2 3 4 5 6 7 8 9b 10b
none 8 9 10 11 12 13 14 13 14
0 99
catalyst 8 9 10 11 12 13 14
Eox (C•+/C) (V)
Ered (C/C•−) (V)
Eox* (C•+/C*) (V)
Ered* (C*/C•−) (V)
ref
+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
+1.69 +1.69
−0.89 −1.15
a
Previously reported data in the reference literatures. All the potentials are versus the saturated calomel electrode (SCE). Measurements were performed in MeCN. C: ground state catalyst. C*: excited state catalyst. C•+: one electron oxidized catalyst. C•−: one electron reduced catalyst.
b
NMR yield. In dark.
expected, some of the photocatalysts promoted the dehydration 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 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 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
entry
solvent
1a concn (mM)
14 (mol %)
time (h)
4aa yield (%)a
1 2 3 4 5 6 7 8 9 10 11 12
MeCN THF 1,4-dioxane AcOEt toluene CHCl3 1,2-DCE CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
100 100 100 100 100 100 100 100 100 20 20 10
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 degradation of 1a. 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
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. 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 photocatalyst. 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
Scheme 3. Hypothesized Reaction Mechanisms for the Photocatalyst-Promoted Decarbonylation of a Cyclopropenone
C
DOI: 10.1021/acs.orglett.9b01280 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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 photocatalystmediated 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
NMR yield. bIsolated yield. c72% 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
solvent
17 concn (mM)
time (h)
20 yield (%)
Table 4. Phototriggered Dehydration Condensation in the Presence of a UV Light-Sensitive Tetrazole
1 2c 3
MeCN MeCN MeCN/H2O (1/1)
5 5 2
18 18 40
74a (75b) 0a 67a
a
entry 1 2
irradiation conditions UVB (280−350 nm) visible (400−750 nm) + 14 (20 mol %)
time (h)
4ab yield (%)a
16 yield (%)a
15 recovery (%)a
3 20
46 75
46
