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DOI: 10.1055/a-1979-6123
Fused λ5-Phosphinines: Design, Syntheses, and Properties
A part of this work was supported by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number JP15K05430, Grant-in-Aid for Scientific Research(C)).
Dedicated to Professor Masahiro Murakami on the occasion of his retirement
Abstract
Synthesis of several heterocycle-fused λ5-phosphinines through intramolecular cyclization is described. The incorporation of a heteroatom affected their photophysical properties through perturbation of the LUMO level, which is in good contrast to the HOMO-based tuning by the C-4 substituent. The C-3-substituent-based property tuning provides a new guide to designing phosphinine-based fluorophores.
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Conjugated heterocycles are attracted much attention because of their features as functional materials, such as fluorophores and electronic materials.[1] Among them, phosphorus-containing heterocycles are a desirable and increasing outcome of research treating the phospholes, the 5-membered phosphorus heterocycles.[2] On the other hand, the 6-membered phosphorus heterocycles attracted relatively less interest due to the absence of versatile and convenient synthetic methods for those heterocycles.[3]
Recently, we have revealed the significant new fluorophore skeleton, λ5-phosphinine 1, along with the newly developed synthesis, multiple derivatization strategies, and highly fluorescent features in both solution and solid state.[4] Since then, the 6-membered phosphorus heterocycles have attracted much attention, and several applications, such as in the field of laser dyes and functional fluorophores, have continuously appeared.[5]
As shown in Figure [1], the distributions of HOMO and LUMO in the phosphinine skeleton are quite unique; the C-4 position significantly contributes to the HOMO, whereas the same C-4 shows no contribution to the LUMO.[4] Therefore, the substituent at the C-4 position can exclusively control the HOMO level of the substituted phosphinine without affecting the LUMO level (Figure S1).[4] On the contrary, the LUMO shows an essential contribution at the adjacent positions (C-3 and C-5), though the HOMO is estimated to contribute little to those positions. Based on these characteristic orbital distributions, a substituent at the C-3 position will exclusively control the LUMO level of the phosphinine, resulting in the tuning of the absorption and emission wavelengths. However, when this study started, there was no method for selective substitution at the C-3 position of the parent phosphinine. The low aromaticity of the λ5-phosphinine ring and the electron-withdrawing cyano group at the C-2 and C-6 positions inspired us to investigate that the conjugate addition to the C-3 position can be available to the cyanoalkene partial structure with an assistance of an acid catalyst. In addition, an intramolecular nucleophilic heteroatom will increase the efficiency of the addition. Thus, we designed the heteroatom-fused phosphinines 2 with a heteroatom substitution at the C-3 position, which will affect the photophysical properties (Figures S2 and S3). The fused-phosphinines 2 can be synthesized from the precursors 3 having an ortho-substituted phenyl group, which can be prepared by a simple Suzuki–Miyaura coupling procedure (Scheme [1]).[4]
The fused phosphinines 2 are expected to have relatively higher quantum emissions yields than the nonfused molecules since the planar-fixed conformation of the fused heterocycle usually showed relatively high quantum yields of the emission because of a decrease of nonemissive transition. In addition, the incorporated heteroatom will affect its emission wavelength through the perturbation of the LUMO level; an electron-donating substituent at the C-3 position will cause a hypsochromic shift in the emission via destabilization of LUMO, whereas an electron-withdrawing substituent will be expected in a bathochromic shift of the emission.
To confirm our hypothesis described above, we tried synthesizing benzofuran-fused phosphinine 2a as a model. The cyclization precursor 3a was synthesized by the Suzuki coupling of 4-iodo-substituted phosphinine 4 (prepared via electrophilic iodination of the parent phosphinine 1) with ortho-methoxyphenylboronic acid 5a, followed by demethylation with BBr3 (Scheme [2]).
Cyclization conditions for 3a were surveyed, and the results are shown in Table [1]. A suitable Lewis acid catalyst should be required for effective intramolecular nucleophilic attack by the phenolic oxygen through the coordination to the cyano group at the C-2 position. After the initial attack of the oxygen to the phosphinine C-3 position, two hydrogens should be removed from the intermediate, i.e., the product should be oxidized to reform the fused phosphinine. Therefore, several Lewis acids and concomitant oxidants were surveyed.
As shown in Table [1], typical Lewis acids gave the desired cyclized phosphinine 2a in moderate yields by using DDQ or MnO2 as an oxidant. Especially, BF3 etherate gave better results using MnO2. The solvent used dramatically affected yields; 1,4-dioxane gave the best result, and 2a was isolated in 83% yield.[6] Similarly, indol-type and benzothiophene-type fused phosphinine 2b and 2c were synthesized.[6]
Amino-substituted precursor 3b was prepared through the reduction of nitrophenylphosphinine 3b′, which was synthesized by the Suzuki coupling of iodo-phosphinine 4 with ortho-nitrophenylborate ester shown in Scheme [3].
a p-BQ: p-benzoquinone.
b Isolated yield is shown in parentheses.
Cyclization of 3b was initially tried by applying the conditions for cyclization of 3a. However, the desired cyclized product 2b was formed only in 28% (Table [2], entry 1). The increase of 2b during acidic workup suggested that the desired cyclization efficiently proceeded by Brønsted acid instead of Lewis acid. Actually, the use of 1 N HCl aq. instead of BF3 etherate dramatically accelerated the desired cyclization; more than 90% of the cyclization proceeded in only 3 min (Table [2], entry 2). After optimization of the reaction conditions, the cyclized product 2b was formed (96% 31P NMR ratio) and isolated in 77% yield (Table [2], entry 4).[6]
a Isolated yield is shown in parentheses.
Synthesis of the thiol precursor of benzothiophene-fused phosphinine 2c was started from bromobenzene 6 having THP-protected thiol at the ortho position (Scheme [4]). Bromobenzene 6 was converted into the corresponding bromophenyl pinacol borate ester 5c by lithiation with n-BuLi, followed by the reaction with B(OMe)3. The intermediate pinacol borate 5c was used in the subsequent coupling without isolation. The Suzuki coupling with iodo-phosphinine 4 gave the S-protected precursor 3c′′ in 81% yield. Deprotection of the S-THP thioether was conducted by the reaction with silver nitrate. Although the deprotection has proceeded appropriately, the corresponding silver salt of the thiol could not be purified (the product mixture had too much mass, probably due to contamination of excess silver salt). Therefore, the mixture was subjected to the next cyclization step without isolation (Scheme [4]).
Palladium-catalyzed cyclization of 3c′ was conducted according to the literature procedure,[7] and the ring-fused phosphinine 2c was successfully formed in 83% 31P NMR ratio in the reaction mixture (Table [3], entry 1). The addition of the silver salt as an oxidant accelerated the reaction; optimization of the reaction conditions increased the ratio of the product up to 96% (31P NMR), and finally, the benzothiophene-fused phosphinine 2c was isolated in 64% in 2 steps from the S-THP-protected precursor 3c′′ (entry 6).[6]
a Isolated yield (from 3c′′) is shown in parentheses.
a 31P NMR ratio (%) of each compound. Isolated yields are shown in parentheses.
Benzofuran-fused 2a, indol-fused 2b, and benzothiophene-fused 2c phosphinines were successfully synthesized as described above. In all these cases, an electron-donating atom was incorporated at the C-3 position. An electron-withdrawing substituent at the C-3 position may clarify the electronic effects on the photophysical properties. Thus, an electron-donating thioether part was converted into electron-withdrawing substituents, such as sulfoxide or sulfone, by the oxidation of the sulfur atom. Thus, oxidation of 2c was attempted by several oxidants; the results are shown in Table [4]. Unfortunately, selective oxidation to each oxidation state (sulfoxide or sulfone) failed. However, the separable mixture of two compounds was formed in acceptable yields; finally, the corresponding fused phosphinine sulfoxide 2d and sulfone 2e were isolated in 31% and 38% yields, respectively.[6]
All fused-phosphinines provided reasonable NMR (1H, 13C, and 31P) and HRMS spectra. The structures of all fused phosphinines were determined by X-ray crystallographic analyses.[8] ORTEP drawings of the products are shown in Figure [2].
Noteworthy is that the fused rings were essentially flat compared with precyclized phenylphosphinine, which has a dihedral angle of about 35 deg (3a′) between the phosphinine and phenyl rings (Figure S4).[8] Bond lengths between the heteroatoms and C-3 carbon of phosphinines 2a–c are relatively short compared to those of the heteroatoms and benzene carbon atom, which is attributed to the electron-donating nature of the heteroatom substituent. Substitution at the C-3 position makes the phosphinine ring unsymmetric, so two ylidic P–C bond lengths in the fused phosphinines showed a slight difference. However, phosphinine rings of those fused phosphinines are substantially unchanged through the ring fusion. The photophysical properties of the synthesized fused phosphinines are summarized in Table [5] and Figure [3].
a Absorption and emission spectra were measured in CHCl3 solution at 2.5x10–5 M and 2.5x10–6 M, respectively.
As we designed, all phosphinines showed the expected tendency of the photophysical properties; electron-donating substituents incorporated at the C-3 position caused slightly blue-shifted absorption (3–12 nm) and emission (10–19 nm), whereas electron-withdrawing substituents resulted in dramatically red-shifted spectra (2d and 2e) compared to 4-phenylphosphinine (λmax abs: 480 nm, λmax emi: 525 nm). Thus, these results clearly indicated that the electronic perturbation to the HOMO through the phenyl ring at the C-4 position is less significant than that of the direct effect of the C-3 substituent (Figures S2 and S3). Ring-fused phosphinines 2a and 2b showed higher quantum yields (79% and 67%) than the corresponding precyclized precursors 3a and 3b (67% and 37%), respectively. The effective fluorescence of the fused phosphinines may attribute to the fixed conformation of the fused ring, as designed.
In conclusion, we have designed new heteroatom-fused phosphinines and synthesized them through newly developed intramolecular cyclizations. A comparison of the photophysical properties of the synthesized fused phosphinines revealed that the electronic feature of the C-3 substituent dramatically affected the photophysical properties of fused phosphinines through perturbation of the LUMO level. Fixation of the conformation through the ring fusion resulted in higher fluorescence quantum yields. Those findings provide significant guides for designing new phosphinine-based fluorophores, in addition to the C-4 substituent tuning that we have previously reported.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank Division of Applied Protein Research (APR), the Advanced Research Support Center (ADRES), Ehime University for the measurements of NMR, HRMS spectra and X-ray crystallographic analyses.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1979-6123.
- Supporting Information
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References and Notes
- 1a Lavis LD, Raines RT. ACS Chem. Biol. 2014; 9: 855
- 1b Li X, Gao X, Shi W, Ma H. Chem. Rev. 2014; 114: 590
- 1c Kobayashi H, Ogawa M, Alford R, Choyke PL, Urano Y. Chem. Rev. 2010; 110: 2620
- 2a Mathey F. Chem. Rev. 1988; 88: 429
- 2b Matano Y, Imahori H. Org. Biomol. Chem. 2009; 7: 1258
- 2c Duffy MP, Delaunay W, Bouit P.-A, Hissler M. Chem. Soc. Rev. 2016; 45: 5296
- 2d Shameem MA, Orthaber A. Chem. Eur. J. 2016; 22: 10718
- 2e Hibner-Kulicka P, Joule JA, Skalik J, Bałczewski P. RSC Adv. 2017; 7: 9194
- 3a Nagahora N, Goto S, Inatomi T, Tokumaru H, Matsubara K, Shioji K, Okuma K. J. Org. Chem. 2018; 83: 6373
- 3b Fukazawa A, Suda S, Taki M, Yamaguchi E, Grzybowski M, Sato Y, Higashiyama T, Yamaguchi S. Chem. Commun. 2016; 52: 1120
- 3c Savateev A, Vlasenko Y, Shtil N, Kostyuk A. Eur. J. Inorg. Chem. 2016; 628
- 3d Matveeva ED, Vinogradov DS, Podrugina TA, Nekipelova TD, Mironov AV, Gleiter R, Zefirov NS. Eur. J. Org. Chem. 2015; 7324
- 3e Heim U, Pritzkow H, Fleischer U, Grützmacher H, Sanchez M, Reáu R, Bertrand G. Chem. Eur. J. 1996; 2: 68
- 4 Hashimoto N, Umano R, Ochi Y, Shimahara K, Nakamura J, Mori S, Ohta H, Watanabe Y, Hayashi M. J. Am. Chem. Soc. 2018; 140: 2046
- 5a Ledos N, Sangchai T, Knysh I, Bousquet MH. E, Manzhi P, Cordier M, Tondelier D, Geffroy B, Jacquemin D, Bouit P.-A, Hissler M. Org. Lett. 2022; 24: 6869
- 5b Delouche T, Caytan E, Cordier M, Roisnel T, Taupier G, Molard Y, Vanthuyne N, Le Guennic B, Hissler M, Jacquemin D, Bouit P.-A. Angew. Chem. Int. Ed. 2022; 61: e202205548
- 5c Tang X, Balijapalli U, Okada D, Karunathilaka BS. B, Senevirathne CA. M, Lee Y.-T, Feng Z, Sandanayaka AS. D, Matsushima T, Adachi C. Adv. Funct. Mater. 2021; 31: 2104529
- 5d Karunathilaka BS. B, Balijapalli U, Senevirathne CA. M, Yoshida S, Esaki Y, Goushi K, Matsushima T, Sandanayaka AS. D, Adachi C. Nat. Commun. 2020; 11: 4926
- 5e Karunathilaka BS. B, Balijapalli U, Senevirathne CA. M, Esaki Y, Goushi K, Matsushima T, Sandanayaka AS. D, Adachi C. Adv. Funct. Mater. 2020; 30: 2001078
- 5f Pfeifer G, Chahdoura F, Papke M, Weber M, Szucs R, Geffroy B, Tondelier D, Nyulaszi L, Hissler M, Mueller C. Chem. Eur. J. 2020; 26: 10534
- 5g Huang J, Tarábek J, Kulkarni R, Wang C, Dračínský M, Smales GJ, Tian Y, Ren S, Pauw BR, Resch-Genger U, Bojdys MJ. Chem. Eur. J. 2019; 25: 12342
- 6 Representative Experimental Procedure for 2b Aminophosphinine 3b (234 mg, 0.60 mmol) was dissolved in EtOH (24 mL), and 1 M HCl aq. (2 mL) and MnO2 (102 mg, 1.20 mmol) were added at r.t. After 5 min, the mixture was filtered and concentrated. The residue was purified by a column chromatography on silica gel (eluent: AcOEt/CHCl3/n-hexane = 1/2/6) to give 2b as a yellow solid (220 mg, 77%). Characterization data for 2b, the other synthetic procedures, and analytical data for each compound including cyclization precursors are available in the Supporting Information.
- 7 Zhang T, Deng G, Li H, Liu B, Tan Q, Xu B. Org. Lett. 2018; 20: 5439
- 8 CCDC 2214502 (2a), 2214503 (2b), 2214506 (2c), 2214506 (2d), 2214509 (2e), and 2214510 (3a′) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
For reviews, see:
For reviews, see:
For selected syntheses of 6-membered phosphorus heterocycles, see:
Corresponding Authors
Publication History
Received: 24 October 2022
Accepted: 15 November 2022
Accepted Manuscript online:
15 November 2022
Article published online:
01 December 2022
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References and Notes
- 1a Lavis LD, Raines RT. ACS Chem. Biol. 2014; 9: 855
- 1b Li X, Gao X, Shi W, Ma H. Chem. Rev. 2014; 114: 590
- 1c Kobayashi H, Ogawa M, Alford R, Choyke PL, Urano Y. Chem. Rev. 2010; 110: 2620
- 2a Mathey F. Chem. Rev. 1988; 88: 429
- 2b Matano Y, Imahori H. Org. Biomol. Chem. 2009; 7: 1258
- 2c Duffy MP, Delaunay W, Bouit P.-A, Hissler M. Chem. Soc. Rev. 2016; 45: 5296
- 2d Shameem MA, Orthaber A. Chem. Eur. J. 2016; 22: 10718
- 2e Hibner-Kulicka P, Joule JA, Skalik J, Bałczewski P. RSC Adv. 2017; 7: 9194
- 3a Nagahora N, Goto S, Inatomi T, Tokumaru H, Matsubara K, Shioji K, Okuma K. J. Org. Chem. 2018; 83: 6373
- 3b Fukazawa A, Suda S, Taki M, Yamaguchi E, Grzybowski M, Sato Y, Higashiyama T, Yamaguchi S. Chem. Commun. 2016; 52: 1120
- 3c Savateev A, Vlasenko Y, Shtil N, Kostyuk A. Eur. J. Inorg. Chem. 2016; 628
- 3d Matveeva ED, Vinogradov DS, Podrugina TA, Nekipelova TD, Mironov AV, Gleiter R, Zefirov NS. Eur. J. Org. Chem. 2015; 7324
- 3e Heim U, Pritzkow H, Fleischer U, Grützmacher H, Sanchez M, Reáu R, Bertrand G. Chem. Eur. J. 1996; 2: 68
- 4 Hashimoto N, Umano R, Ochi Y, Shimahara K, Nakamura J, Mori S, Ohta H, Watanabe Y, Hayashi M. J. Am. Chem. Soc. 2018; 140: 2046
- 5a Ledos N, Sangchai T, Knysh I, Bousquet MH. E, Manzhi P, Cordier M, Tondelier D, Geffroy B, Jacquemin D, Bouit P.-A, Hissler M. Org. Lett. 2022; 24: 6869
- 5b Delouche T, Caytan E, Cordier M, Roisnel T, Taupier G, Molard Y, Vanthuyne N, Le Guennic B, Hissler M, Jacquemin D, Bouit P.-A. Angew. Chem. Int. Ed. 2022; 61: e202205548
- 5c Tang X, Balijapalli U, Okada D, Karunathilaka BS. B, Senevirathne CA. M, Lee Y.-T, Feng Z, Sandanayaka AS. D, Matsushima T, Adachi C. Adv. Funct. Mater. 2021; 31: 2104529
- 5d Karunathilaka BS. B, Balijapalli U, Senevirathne CA. M, Yoshida S, Esaki Y, Goushi K, Matsushima T, Sandanayaka AS. D, Adachi C. Nat. Commun. 2020; 11: 4926
- 5e Karunathilaka BS. B, Balijapalli U, Senevirathne CA. M, Esaki Y, Goushi K, Matsushima T, Sandanayaka AS. D, Adachi C. Adv. Funct. Mater. 2020; 30: 2001078
- 5f Pfeifer G, Chahdoura F, Papke M, Weber M, Szucs R, Geffroy B, Tondelier D, Nyulaszi L, Hissler M, Mueller C. Chem. Eur. J. 2020; 26: 10534
- 5g Huang J, Tarábek J, Kulkarni R, Wang C, Dračínský M, Smales GJ, Tian Y, Ren S, Pauw BR, Resch-Genger U, Bojdys MJ. Chem. Eur. J. 2019; 25: 12342
- 6 Representative Experimental Procedure for 2b Aminophosphinine 3b (234 mg, 0.60 mmol) was dissolved in EtOH (24 mL), and 1 M HCl aq. (2 mL) and MnO2 (102 mg, 1.20 mmol) were added at r.t. After 5 min, the mixture was filtered and concentrated. The residue was purified by a column chromatography on silica gel (eluent: AcOEt/CHCl3/n-hexane = 1/2/6) to give 2b as a yellow solid (220 mg, 77%). Characterization data for 2b, the other synthetic procedures, and analytical data for each compound including cyclization precursors are available in the Supporting Information.
- 7 Zhang T, Deng G, Li H, Liu B, Tan Q, Xu B. Org. Lett. 2018; 20: 5439
- 8 CCDC 2214502 (2a), 2214503 (2b), 2214506 (2c), 2214506 (2d), 2214509 (2e), and 2214510 (3a′) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
For reviews, see:
For reviews, see:
For selected syntheses of 6-membered phosphorus heterocycles, see:
