Letter Cite This: Org. Lett. 2018, 20, 7071−7075
pubs.acs.org/OrgLett
Cascade C−H Annulation Reaction of Benzaldehydes, Anilines, and Alkynes toward Dibenzo[a,f ]quinolizinium Salts: Discovery of Photostable Mitochondrial Trackers at the Nanomolar Level Vilas D. Kadam, Boya Feng, Xingyu Chen, Wenbo Liang, Fulin Zhou, Yanhong Liu, Ge Gao,* and Jingsong You*
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Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China S Supporting Information *
ABSTRACT: Fluorescent mitochondrial trackers with the dibenzo[a,f ]quinolizinium core are unprecedentedly synthesized by a one-pot protocol starting from commercially available benzaldehydes, anilines, and alkynes through a rhodium(III)-catalyzed cascade C−H N- and C-annulation reaction. Among them, 5g is the most prominent and exhibits high specificity, high efficiency at nanomolar level, superior photostability, and low cytotoxicity.
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laborious and suffer from drawbacks such as uneasy attainability of starting materials, narrow substrate scope, as well as multiple steps with poor overall yields. In recent years, transition-metal-catalyzed nitrogen atom directed C−H annulation reactions have emerged as an efficient and remarkable strategy for the synthesis of Nheterocycles.8 Quinolizinium derivatives were synthesized by this strategy starting with 2-vinyl/ethylpyridines and alkynes (Scheme 1a).9 In 2017, we proposed a cascade C−H annulation strategy to easily access tetracyclic dibenzoquinolizinium derivatives, as successfully exemplified by the one-pot synthesis of benz[a]acridizinium salts via a Rh(III)-catalyzed cascade double N-directed C−H N-annulation of aldoximes with alkynes.10 In this process, an O-methyl oxime group first directs the C−H N-annulation to generate 1H-isoquinoline with a prerequisite nitrogen atom, which then directs the second N-annulation to give the expected salts (Scheme 1b). In light of this precedent and our continuous interest in cationic organic functional materials,11 we envisioned that an N-phenylimine group directed C−H N-annulation to generate N-phenylisoquinolinium salts,12 followed by a carbene-directed C-annulation,11d,13 could also deliver dibenzo[a,f ]quinolizium salts.14 Moreover, it would be even more convenient and practical if (E)-N,1-diphenylmethanimine could be generated in situ in the flask from commercially available benzaldehydes and anilines (Scheme 1c). Herein, we report such a one-pot protocol under rhodium catalysis. The living cell imaging experiments suggested that dibenzo[a,f ]quinolizinium salts are
uinolizinium is a cationic isomer of quinoline with a quaternary nitrogen at the bridgehead position.1 Its dibenzo derivatives, for example, benz[a]acridizinium and dibenzo[a,f ]quinolizium salts, structurally belong to polycyclic heteroaromatics (PHAs, Figure 1).2 The significance of these
Figure 1. Core structures of quinolizinium, benz[a]acridizinium, and dibenzo[a,f ]quinolizium.
cationic PHAs is displayed by various potential applications in biology, pharmaceutical, and functional materials, such as biolabeling, DNA intercalators, anticancer agents, fluorescent dyes, nonlinear optical materials, and photoacids.3 While benz[a]acridizinium salts widely exist as core skeletons in numerous natural alkaloids,4 dibenzo[a,f ]quinolizinium derivatives are synthetic and exhibit double- and triple-stranded DNA intercalating properties with large binding constants comparable with that of coralyne, a well-known DNA intercalator.5 The existing synthetic methods for the dibenzo[a,f ]quinolizinium core are mainly based on photochemical cyclization, acid-mediated cyclization, ring-closing metathesis, and radical intramolecular arylation.5b,6 Most recently, for example, a visible-light-mediated gold-catalyzed reaction between quinoline-substituted aryl diazonium salts and silylaryl alkynes has been reported.7 However, these methods are all © 2018 American Chemical Society
Received: September 20, 2018 Published: October 26, 2018 7071
DOI: 10.1021/acs.orglett.8b03015 Org. Lett. 2018, 20, 7071−7075
Letter
Organic Letters
followed by separation on a neutral alumina column to give pure 4a and 5a as the BF4 salts. When 2.0 equiv of NaOAc was employed as a base, the yield of 4a decreased to 23%, while that of 5a increased to 50% (Table 1, entry 2). When 3.0 equiv of Cu(OAc)2·H2O was used, 5a was obtained exclusively in 70% yield (Table 1, entry 3). Switching to anhydrous Cu(OAc)2 helped increase the yield of 5a to 81% (entry 4). Further varying the amounts of silver and copper salts gave the best combination of 0.2 equiv of AgBF4 and 4.0 equiv of Cu(OAc)2, affording 5a as the single product in the highest yield of 85% (Table 1, entries 5 and 6). Interestingly, only the use of Cu(OAc)2 could provide the desired double-annulated product 5a, while the single-annulated product 4a was solely obtained in the absence of a copper salt or even when Cu(OTf)2 or Cu(BF4)2·6H2O was used (Table 1, entries 7− 9). In the absence of a silver salt, 5a was isolated in a lower yield of 70% (Table 1, entry 10). The other silver salt, AgSbF6, gave a mixture of 4a and 5a in 48% and 25% yields, respectively (Table 1, entry 11). The screen of other factors showed that the solvent is critical. While the reaction in MeCN, DMF, or toluene gave 5a as the sole product in low yields, the reaction in MeOH afforded 4a as the sole product (Table S1). Therefore, additive Cu(OAc)2 and solvent DCE are the two vital factors for the success of this cascade annulation reaction. With the optimized reaction conditions in hand (Table 1, entry 6), the scope of substituted benzaldehydes and anilines was investigated (Scheme 2). Reactions of benzaldehydes bearing electron-donating and -withdrawing groups at the para position with 1a and 2a under the optimized conditions provided the corresponding dibenzo[a,f ]quinolizinium salts (5a−f) in moderate to good yields. 4-(Dimethylamino)benzaldehyde was easily converted into 5g in 71% yield. The structure of 5g was further confirmed by single-crystal X-ray analysis. While m-anisaldehyde gave 5h as 1:0.7 mixed regioisomers in 79% combined yield, the reaction of mchlorobenzaldehyde with 2a and 3a provided 5i regioselectively in 58% yield. For an ortho-substituted benzaldehyde, oanisaldehyde (1a′), only single-annulated product 4a′ was obtained in 79% yield (Scheme 3). The double-annulated product 5a′ could not be detected, even when 4a′ was subjected to reaction with 3a due to the substantial steric hindrance. The reaction of a heteroaromatic aldehyde, thiophene-2-carbaldehyde, delivered the double-annulated product 5j in 57% yield. Similarly, anilines with p-methyl, -methoxy, and -ester groups underwent the cascade C−H annulation smoothly (Scheme 2, 5k−m). The halogen-containing substrates pchloroaniline and p-fluoroaniline afforded 5n and 5o in 84% and 80% yields, respectively. For methoxy-substituted anilines, the yields of the desired products were lowered (Scheme 2, 5l and 5p). Interestingly, an inseparable 1:0.2 mixture of regioisomers was obtained for the reaction of m-methoxyaniline, while for methyl-3-aminobenzoate and m-chloroaniline, 5q and 5r were obtained in each case as a single regioisomer in 74% and 77% yields, respectively. The lower regiospecificity caused by a m-methoxy group was also found for manisaldehyde (vide supra), and the reason is not clear yet. Starting from 2-aminonaphthalene, the desired salt 5s was nicely obtained in 84% yield. Another interesting finding is that the desired double-annulation product 5t could not be obtained in one pot. The reaction conducted in the optimal conditions ended up with only the single-annulated product,
Scheme 1. C−H Annulation Strategies toward Quinolizinium Derivatives
efficient fluorescent mitochondrial trackers at concentrations as low as the nanomolar level. To the best of our knowledge, this one-pot protocol from commercially available starting materials directly to efficient fluorescent mitochondrial trackers is unprecedented. The investigation commenced with treating p-anisaldehyde (1a), aniline (2a), and diphenylacetylene (3a) in the presence of [Cp*RhCl2]2 (5 mol %), AgBF4 (1.0 equiv), and Cu(OAc)2·H2O (2.0 equiv) in 1,2-dichloroethane (DCE) under a nitrogen atmosphere at 140 °C for 24 h. Singleannulated product 4a was obtained in 60% yield along with the desired double-annulated product 5a in only 5% yield (Table 1, entry 1). Annulated product 4a was confirmed by comparing its data with those of the reported one,12b and 5a was characterized by the 1H, 13C, and 19F NMR spectroscopy and HRMS. It should be pointed out that due to the presence of both BF4 and OAc counteranions, the reaction mixture needs to be treated with an aqueous solution of saturated NaBF4 Table 1. Optimization of the Reaction Conditionsa,b
entry
Ag salt (equiv)
Cu salt (equiv)
4a (%)
5a (%)
c
AgBF4 (1) AgBF4 (1) AgBF4 (1) AgBF4 (1) AgBF4 (0.2) AgBF4 (0.2) AgBF4 (0.2) AgBF4 (0.2) AgBF4 (4)
Cu(OAc)2·H2O (2) Cu(OAc)2·H2O (2) Cu(OAc)2·H2O (3) Cu(OAc)2 (3) Cu(OAc)2 (3) Cu(OAc)2 (4) Cu(OTf)2 (4) Cu(BF4)2·H2O (4)
60 23 nd nd nd nd 75 78 87 nd 48
5 50 70 81 73 85 nd nd nd 70 25
1 2 3 4 5 6 7 8 9 10 11
AgSbF6 (0.2)
Cu(OAc)2 (4) Cu(OAc)2 (4)
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), 3a (0.2 mmol), [Cp*RhCl2]2 (5.0 mol %), a silver salt, a copper salt, NaOAc (2.0 equiv), and DCE (2 mL) at 140 °C for 24 h under a N2 atmosphere. nd = not detected. bIsolated yield. cWithout NaOAc. 7072
DOI: 10.1021/acs.orglett.8b03015 Org. Lett. 2018, 20, 7071−7075
Letter
Organic Letters
four methoxy groups from the starting alkyne shows orange emission at 607 nm. The quantum yields of these salts are low ranging from
