Convergent and Functional-Group-Tolerant Synthesis of B‑Organo

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Convergent and Functional-Group-Tolerant Synthesis of B‑Organo BODIPYs Taka Sawazaki, Yusuke Shimizu, Kounosuke Oisaki, Youhei Sohma,* and Motomu Kanai* Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

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S Supporting Information *

ABSTRACT: Boron-dipyrromethenes (BODIPYs) are one of the most important fluorescent materials. Despite their potential unique properties, however, B,B-fluoro-organo BODIPYs (BFR-BODIPYs) possessing an organo group (R) on the boron center have not been studied in detail, due in part to challenges related to their synthesis. In this paper, a convergent synthesis of BFR-BODIPYs operative under mild conditions is reported. Conversions of the thus-synthesized functionalized BFR-BODIPYs by cross-coupling, condensation, and SN2 reactions at the R group are also demonstrated.

F

luorescent materials are essential for a variety of fields relevant to chemical sensors,1 biologic imaging,2 poly-

Table 1. Optimization for the Convergent Synthesis of 3a

Lewis acid

X (equiv/borate salt)

solventa

yield [%]b

1 2 3 4 5 6 7 8 9 10 11 12

BF3·OEt2 AlCl3 TMSCN TMSCl TMSOTf TMSCl TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf TMSOTf

1 1 1 1 1 2 2 2 2 2 2 2

MeCN MeCN MeCN MeCN MeCN MeCN MeCN THF Et2O acetone DCM toluene

71c 36 0d 70 47 71 79 44 60 0d 49 36

a

Solvent/DCM (1:4). bIsolated yield. cBF2-BODIPY was produced as a byproduct. dNo reaction.

Figure 1. Synthetic methods of BFR-BODIPYs possessing an organo substituent (R) at the boron center. (a) Nucleophilic substitution of BF 2-BODIPY by carbanion R−. (b) Successive nucleophilic substitutions of BCl2R by dipyrromethene and fluoride. (c) Convergent coupling (this work).

high absorbance coefficient and fluorescence quantum yield, emission of sharp fluorescence peaks, and high biocompatibility due to its neutral charge and insensitivity to the polarity and pH of the media.6

meric materials,3 organic electroluminescence,4 and organic photovoltaic devices.5 Specifically, organic dye molecules are noteworthy because they are inexpensive and highly flexible with regard to structure modifications. Boron-dipyrromethene (BODIPY) is a highly attractive structural motif because of its © XXXX American Chemical Society

entry

Received: October 1, 2018

A

DOI: 10.1021/acs.orglett.8b03138 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Substrate Scopea,b

a Isolated yield is shown. bDipyrromethene as a TFA salt was used for 3. cIn situ generated 5-phenyldipyrromethene through oxidation of corresponding dipyrromethane by DDQ was directly used.

Numerous types of BODIPY have been reported, most of which possess two fluorine atoms at the boron center (BF2BODIPY). B,B-Fluoro-organo BODIPYs (BFR-BODIPYs) possessing an organo group (R) instead of a fluorine atom at the boron center exhibit unique properties, such as high fluorescence quantum yield7 and solid-state fluorescence intensity.8 Previous synthetic methods of BFR-BODIPYs, however, involved multiple steps with a linear fashion, which deters structural optimization at the R group. As a typical example, organo group R was introduced via nucleophilic substitution of fluoride at the boron atom in BF2-BODIPY by carbanion R− (Figure 1a).9 Many functional groups, however, were not tolerated in this method. Alternatively, successive substitution reactions of organo dichloroboron BCl2R by a dipyrromethene10 and fluoride produced BFR-BODIPY (Figure 1b), although BFPh-BODIPY is the sole example synthesized by this method. Here, we disclose a versatile

synthesis of BFR-BODIPY through convergent coupling between BF2R and dipyrromethene that proceeded under mild conditions with high functional group tolerance (Figure 1c). For the generation of unstable BF2R,11 we referred to Vedejs’ report; that is, the reaction of organotrifluoroborate salts (KBF3R, 1) with a Lewis acid.12 Because KBF3R is airand moisture-stable, and easily prepared from potassium bifluoride and boronic acids possessing a wide range of R groups, we hypothesized that various BFR-BODIPYs would be accessible through coupling between BF2R generated from KBF3R and dipyrrolomethenes.13 On the basis of this idea, we started the optimization study with the coupling of potassium phenyltrifluoroborate (KBF3Ph, 1a) and tetramethyldipyrrolomethene salt 2 (Table 1). A mixture of 1a and a Lewis acid stirred at room temperature (rt) for 20 min was added to a dichloromethane B

DOI: 10.1021/acs.orglett.8b03138 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

afforded the corresponding BFR-BODIPY (3b, 3c) in good yield (63%, 74%). In contrast, the use of KBF3(2-BrC6H4) failed to give the desired product, probably due to steric hindrance. Products bearing a cyano (3d) or an ester (3e) group at the 4-position of the phenyl ring were successfully obtained in good yields (82%, 76%). Synthesis of a 3,5disubstituted phenyl group-containing product was also possible (3f, 71%). The reaction from KBF3(2-thienyl) afforded 3g in moderate yield (40%). KBF3(3-thienyl) afforded the desired product in only trace amounts, however, possibly because coordination of the sulfur atom to the boron center interfered with the formation of the boron-dipyrromethene complex. Notably, aliphatic substituents as R were also accessible using the present method (3h, 3i, 3j). Synthesis of BFR-BODIPYs 3b−3e, 3h, and 3i have not been reported before because preparing the corresponding carbanion nucleophiles is difficult or impossible.15,16 In addition, a previous synthesis of 3j required multiple steps due to an acidic proton at the ethynyl position.17 We further investigated the scope of the dipyrromethene side (Scheme 1). Dipyrromethenes containing a phenyl or a 4bromophenyl substituent at the meso position18,19 were successfully converted to the corresponding BF(4-CNC6H4)BODIPY (4d) and BF(CH2Br)-BODIPY (4i, 5i) in good yields (4d: 58%, 4i: 56%, 5i: 85%). Single crystals of 5i were obtained from ethyl acetate, and the three-dimensional structure of this novel BODIPY analogue was determined by X-ray diffraction.20 Dipyrromethenes without substituents at the 1- and 9-positions (R1 = H) were too unstable to isolate. In such cases, the one-pot procedure involving DDQ-oxidation of the stable dipyrromethane precursor to dipyrromethene,18 followed by coupling with a boron reagent was adopted (4d, 4i). AzaBODIPY22 and π-extended BODIPY23 furnished hypsochromic shift properties. The corresponding BFRBODIPYs possessing a 3-bromophenyl (6b) or a bromomethyl (6i and 7i) group at the R group were also synthesized in good yields (6b: 87%, 6i: 61%, 7i: 83%). Moreover, we demonstrated postmodifications of the organo group at the boron center for further diversifications of the BODIPY structure (Figure 2). Compound 3b containing a 3bromophenyl group was successfully coupled with phenylboronic acid under Suzuki−Miyaura cross-coupling conditions (Figure 2, eq 1). The benzyl ester moiety of 3e was converted to a carboxylic acid functional group through catalytic hydrogenolysis, and subsequent condensation with isobutylamine by EDCI and HOBt gave 9 in 84% yield (2 steps; eq 2). Moreover, 3i bearing a bromomethyl group was converted to thioethers 10 and 11 through SN2 reaction with the corresponding thiolates (eq 3 and 4). The B−F bond of 3i can be further activated by TMSOTf, and selectively converted to a B−phenoxide bond (12, eq 5). Finally, we studied photophysical properties of BFRBODIPYs, such as absorption, fluorescence emission, and quantum yield, relative to those of the corresponding BF2BODIPYs (Table S1). It is noteworthy that many BFRBODIPYs (3a, 3c−h, 3j, 4d, 7i) exhibited higher fluorescence quantum yields than those of the corresponding BF2BODIPYs. In addition, we compared the photostability of a series of tetramethyldipyrrolomethene-type BODIPYs (Figure S1). As a result, all BFR-BODIPYs (3a−3j) were more photostable than the BF2-BODIPY. Those results demonstrate that photophysical properties of BFR-BODIPYs can be superior to BF2-BODIPYs.

Figure 2. Postmodifications at the R group on the boron center.

(DCM) solution of 2 and ethyl diisopropyl amine (DIPEA) premixed for 10 min. The coupling reaction was conducted for 3 h at rt. First, BF2Ph generated from 1a and an equimolar amount of BF3·OEt2 in MeCN was used for the coupling reaction (entry 1), and BFPh-BODIPY 3a was obtained in 71% yield. A byproduct, BF2-BODIPY, however, was observed in trace amounts on 1H NMR. Therefore, we examined other Lewis acids to improve the reaction. The use of a stronger Lewis acid, AlCl3, resulted in a lower yield (36%, entry 2). We therefore used trimethylsilyl compounds because the removal of trimethylsilylfluoride (TMSF) with a low boiling point (16 °C) shifts the equilibrium to favor the generation of BF2R. The use of TMSCN did not afford 3a at all, however, probably due to insufficient Lewis acidity (entry 3). TMSCl and TMSOTf gave 3a in 70% and 47% yields, respectively (entries 4 and 5). The byproduct formation of BF2-BODIPY was not detected in these entries. Aggarwal et al. reported that BF2(OTf), generated by treating BF3 with TMSOTf, possesses stronger Lewis acidity than BF3.14 This report prompted us to investigate the addition of 2 equiv TMSOTf to 1a to generate presumably more electrophilic BF(OTf)Ph species than BF2Ph. As a result, the yield improved to 79% (entry 7 vs entry 5). The yield remained unchanged, however, when using 2 equiv of TMSCl (entry 6 vs entry 4). The solvent screening studies revealed MeCN to be optimal (entries 7−12). Thus, entry 7 was determined to be the optimal condition. We next studied the substrate scope under the optimized conditions (Scheme 1). The use of KBF3Ar possessing a bromine substituent at the 3- or 4-position of the phenyl ring C

DOI: 10.1021/acs.orglett.8b03138 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(7) (a) Goze, C.; Ulrich, G.; Mallon, L. J.; Allen, B. D.; Harriman, A.; Ziessel, R. J. Am. Chem. Soc. 2006, 128, 10231−10239. (b) Ehrenschwender, T.; Wagenknecht, H. A. Synthesis 2008, 22, 3657−3662. (c) Brizet, B.; Bernhard, C.; Volkova, Y.; Rousselin, Y.; Harvey, P. D.; Goze, C.; Denat, F. Org. Biomol. Chem. 2013, 11, 7729−7737. (d) Yu, Y.; Bogliotti, N.; Tang, J.; Xie, J. Eur. J. Org. Chem. 2013, 34, 7749−7760. (8) (a) Kubota, Y.; Uehara, J.; Funabiki, K.; Ebihara, M.; Matsui, M. Tetrahedron Lett. 2010, 51, 6195−6198. (b) Yamane, H.; Tanaka, K.; Chujo, Y. Tetrahedron Lett. 2015, 56, 6786−6790. (9) For a review, see: Boens, N.; Verbelen, B.; Dehaen, W. Eur. J. Org. Chem. 2015, 2015, 6577−6595. (10) (a) Hudnall, T. W.; Lin, T. P.; Gabbaï, F. P. J. Fluorine Chem. 2010, 131, 1182−1186. (b) Nguyen, A. L.; Fronczek, F. R.; Smith, K. M.; Vicente, M. G. H. Tetrahedron Lett. 2015, 56, 6348−6351. (11) McCusker, P. A.; Makowski, H. S. J. Am. Chem. Soc. 1957, 79, 5185−5188. (12) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020−3027. (13) A related approach was previously reported for the synthesis of BFC6F5-BODIPY using isolated BF2C6F5, which is exceptionally stable. The generality of this approach, however, was not studied. See: Bonnier, C.; Piers, W. E.; Ali, A. A. S.; Thompson, A.; Parvez, M. Organometallics 2009, 28, 4845−4851. (14) Myers, E. L.; Butts, C. P.; Aggarwal, V. K. Chem. Commun. 2006, 4434−4436. (15) Synthesis of subporphyrins bearing functional groups (R in the figure below) was previously reported using arylzinc reagents. The synthesis, however, required multiple steps in a linear fashion. See:

In conclusion, we developed a convergent synthesis of BFRBODIPYs. The method enabled installation of a variety of functionalized carbon substituents at the boron center, whose introduction by previous methods was difficult or unfeasible. The substrate scope of the dipyrromethene ligand was also broad. This study will facilitate the identification of new BODIPYs with improved properties. Moreover, this synthetic method may offer an alternative site for introducing functional molecules to BODIPYs via the boron center, in addition to the conventional sites such as the meso-position. Therefore, this method will contribute to the production of sophisticated BODIPY analogues, such as multifunctionalized BODIPYs.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03138. General experimental procedure and characterization of the products (PDF) Accession Codes

CCDC 1870954 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

Kotani, R.; Yoshida, K.; Tsurumaki, E.; Osuka, A. Chem. - Eur. J. 2016, 22, 3320−3326. (16) When BF2-BODIPY was reacted with TMSCF3, the abstraction of fluorine from BF2-BODIPY took place. However, no CF3 anion underwent nucleophilic addition. BF(OH)-BODIPY was observed by mass-spectrometry instead of the formation of 3h. (17) Ziessel, R.; Goze, C.; Ulrich, G. Synthesis 2007, 6, 936−949. (18) Yu, C.; Jiao, L.; Yin, H.; Zhou, J.; Pan, W.; Wu, Y.; Wang, Z.; Yang, G.; Hao, E. Eur. J. Org. Chem. 2011, 28, 5460−5468. (19) Li, L.; Nguyen, B.; Burgess, K. Bioorg. Med. Chem. Lett. 2008, 18, 3112−3116. (20) The B−F bond length observed in 5i was slightly longer (1.394(5) Å) than that of the corresponding BF2-BODIPY (1.36 Å),21 while average B−N bond length was similar in both compounds (5i: 1.576(5) Å; BF2-BODIPY: 1.56 Å). (21) Rihn, S.; Retailleau, P.; Bugsaliewicz, N.; De Nicola, A.; Ziessel, R. Tetrahedron Lett. 2009, 50, 7008−7013. (22) (a) Killoran, J.; Allen, L.; Gallagher, J. F.; Gallagher, W. M.; O’Shea, D. F. Chem. Commun. 2002, 1862−1863. (b) Gorman, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2004, 126, 10619−10631. (23) Ulrich, G.; Goeb, S.; Nicola, A. D.; Retailleau, P.; Ziessel, R. J. Org. Chem. 2011, 76, 4489−4505.

ORCID

Motomu Kanai: 0000-0003-1977-7648 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI Grant Numbers JP17H06442 (M.K.) (Hybrid Catalysis), 17H01522 (M.K.), 17K19479 (M.K.), and JP16H06216 (Y.S.), and the Asahi Glass Foundation (Y.S.). We are grateful to Prof. Y. Kuninobu (Kyushu University) and Dr. T. Komatsu (University of Tokyo) for fruitful discussions.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03138 Org. Lett. XXXX, XXX, XXX−XXX