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Synthesis of bridgehead-functionalized triptycene quinones via Lewis acid–promoted Diels-Alder reaction of 9-acyloxyanthracenes
Accepted Manuscript Synthesis of Bridgehead-Functionalized Triptycene Quinones via Lewis Acid– Promoted Diels-Alder reaction of 9-Acyloxyanthracenes Kenji Matsumoto, Rina Nakano, Tsukasa Hirokane, Masahiro Yoshida PII: DOI: Reference:
S0040-4039(19)30202-3 https://doi.org/10.1016/j.tetlet.2019.03.001 TETL 50642
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
11 January 2019 18 February 2019 1 March 2019
Please cite this article as: Matsumoto, K., Nakano, R., Hirokane, T., Yoshida, M., Synthesis of BridgeheadFunctionalized Triptycene Quinones via Lewis Acid–Promoted Diels-Alder reaction of 9-Acyloxyanthracenes, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis of Bridgehead-Functionalized Triptycene Quinones via Lewis Acid–Promoted Diels-Alder reaction of 9-Acyloxyanthracenes
Kenji Matsumoto1, Rina Nakano, Tsukasa Hirokane, and Masahiro Yoshida
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan
Abstract Herein, we show that bridgehead-functionalized triptycene quinones can be rapidly and conveniently prepared in good to high yields by Lewis acid–catalyzed cycloaddition of 1,4-benzoquinones and 1,4-naphthoquinones to 9-acyloxyanthracenes and probe the substrate scope of this transformation.
Keywords: triptycene, triptycene quinone, Diels-Alder reaction, anthracene, Lewis acid
Triptycene and triptycene quinone are structurally unique compounds comprising three benzene rings fused into a rigid barrelene framework (Figure 1). The propeller-like shape and high molecular symmetry of triptycene have inspired numerous studies in the fields of materials chemistry and supramolecular chemistry [1], while triptycene quinone is used to synthesize functionalized iptycenes [2] and exhibits promising antitumor and antimalarial activities [3]. Generally, triptycene quinones are prepared by the Diels-Alder reaction of anthracenes with p-benzoquinones, and numerous substituted triptycene quinone analogues have been synthesized to date [4, 5]. Since the Diels-Alder reaction is the key step in the synthesis of functionalized triptycenes and other iptycenes, the scope of its synthetic applications needs to be further extended.
1
Corresponding author. E-mail: [email protected]
3
Figure 1. Structures of triptycene and triptycene quinone. Recently, we have achieved direct oxidative acyloxylation of aromatic C−H bonds under mild conditions using a recyclable heterogeneous metal catalyst and molecular oxygen as a terminal oxidant (Scheme 1) [6, 7] and realized smooth trifluoroacetoxylation and dichloroacetoxylation at the 9-position of anthracene to obtain 9-trifluoroacetoxy- and 9-dichloroacetoxyanthracenes with exclusive regioselectivity. Although 9-substituted anthracenes can be utilized as versatile precursors for the Diels-Alder reaction with benzoquinones to synthesize bridgehead carbon–functionalized triptycene quinones, this approach has not been extensively explored, probably because the weakly dienophilic nature of benzoquinones makes the above reaction sensitive to the steric effects of substituents at the 9-position of anthracene [8, 9]. Furthermore, the Diels-Alder reaction of 9-acyloxyanthracenes has not been explored because of the limitation of a synthetic route to these species [10]. These limitations prompted us to study the Diels-Alder reaction of 9-acyloxyanthracenes with benzoquinones and naphthoquinones, which should theoretically provide easy access to bridgehead-modified triptycene quinones.
Scheme 1. Rh/C-catalyzed oxidative acyloxylation of anthracene.
Initially, we followed the synthetic protocol reported by Bartlett et al. and examined the thermally induced Diels-Alder reaction of 9-dichloroacetoxyanthracene (1) with 1,4-naphthoquinone in xylene (Table 1, entry 1) [11]. However, the reaction did not proceed at all under these conditions. In the presence of 1 equiv. of AlCl3, which is known to promote Diels-Alder reactions [12], the expected
4
cycloadduct 2a was produced in 82% yield (entry 2), with similar yields achieved for FeCl3 and Sc(OTf)3 (91% (entry 3) and 87% (entry 4), respectively) [13]. In contrast, no cycloadduct was obtained in the presence of the less Lewis-acidic Y(OTf)3 (entry 5). When 1,1,2,3,3,3-hexafluoroisopropanol (HFIP) was used a solvent, the loading of Sc(OTf)3 could be reduced to 0.5 equiv., and 2a was obtained in good yield, even though a prolonged reaction time was needed (entry 6). The Lewis acid loading could be further decreased to 0.1 equiv. for Hf(OTf)4, in which case 2a was obtained in 69% yield (entry 7) [14]. These experiments revealed that Lewis-acidic FeCl3 and Sc(OTf)3 effectively promoted the Diels-Alder reactions of 9-acyloxyanthracene.
Table 1. Diels-Alder reactions of 1 with 1,4-naphthoquinone.
Entry
Lewis acid
1
none
2
AlCl3
3 4
Equiv.
Conditions
Time (h)
Yield (%)
xylene, reflux
72
No reaction
1.0
CH2Cl2, 0 °C
1.5
82
FeCl3
1.2
CH2Cl2, 0 °C
1.5
91
Sc(OTf)3
1.0
CH2Cl2, 0 °C to rt
2
87
5
Y(OTf)3
1.0
CH2Cl2, 0 °C to rt
24
No reaction
6
Sc(OTf)3
0.5
HFIP, 45 °C
19
70
7
Hf(OTf)4
0.1
HFIP, 45 °C
23
69
With the optimized conditions in hand, we examined the reactions of 1 with substituted 1,4-benzoquinones (Table 2). When non-substituted 1,4-benzoquinone and FeCl3 were employed, 3a was obtained in low yield, probably because the enone group of 3a reacted with chloride ions generated in situ from FeCl3 (entry 1). In support of this hypothesis, the yield of 3a could be improved by using Sc(OTf)3 (entry 2) [15]. Similarly, the Sc(OTf)3-mediated reaction of 2-chloro-1,4-benzoquinone afforded higher yields of two regioisomers, 3b and 4b, than the corresponding FeCl3-mediated reaction (entries 3 and 4). In the case of 2-tert-butyl-1,4-benzoquinone, which is less reactive than other benzoquinones, reactions mediated by FeCl3 and Sc(OTf)3 afford mixtures of 3c and 4c in 87 and 61%
5
yields, respectively (entries 5 and 6), although heating was required in both cases. The structure of regioisomer 4c was confirmed by X-ray crystallographic analysis (Figure 2). Table 2. Diels-Alder reactions of 1 with 1,4-benzoquinones.
Entry
R
Lewis acid
Conditions
3/ 4
Yield (%)
3:4
1
H
FeCl3
CH2Cl2, 0 °C
3a
30
–
2
H
Sc(OTf)3
HFIP, 0 °C
3a
72
–
3
Cl
FeCl3
CH2Cl2, 0 °C
3b/ 4b
57
1 : 6.1
4
Cl
Sc(OTf)3
HFIP, rt
3b/ 4b
79
1 : 1.5
5
tert-Bu
FeCl3
CH2Cl2, reflux
3c/ 4c
87
1 : 0.9
6
tert-Bu
Sc(OTf)3
HFIP, 50 °C
3c/ 4c
61
1 : 1.4
Figure 2. Crystal structure of 3c determined by X-ray diffraction analysis.
Subsequently, we explored the effect of anthracene substituents at 9-position (Table 3), showing that both 9-dichloroacetoxy- and 9-trifluoroacetoxyanthracenes efficiently reacted with naphthoquinone in the presence of FeCl3 to afford 2b in excellent yields (entry 1). The FeCl3-promoted reaction of 9,10-dimethylanthracene afforded 2c in 93% yield (entry 2), and the FeCl3-promoted reactions of both 9-methylanthracene and anthracene were more efficient than those promoted by heating (entries 3 and 4). The 9-bromo group was tolerated in the presence of FeCl3, and 2f was obtained in moderate yield (entry
6
5), while the reactions of phenyl- and cyano-substituted anthracenes did not afford the desired products (entries 6 and 7). Therefore, it was concluded that electron-donating substituents (such as methyl) in the 9 and 10 positions increased the reactivity of anthracene, while an opposite effect was observed for electron-withdrawing groups. Since the Diels-Alder reaction is generally affected by both electronic and steric effects of substituents, the sterically bulky acyloxy group probably hampered the above reaction under thermal conditions. On the other hand, Lewis acids were found to strongly facilitate the Diels-Alder reactions of 9-acyloxyanthracenes. Table 3. Diels-Alder reactions of 9,10-substituted anthracenes with 1,4-naphthoquinone.
Yield (%) 1
2
2
FeCl3 a
thermal b
H
2b
93
–
Me
Me
2c
93
85
Me
H
2d
77
57
4
H
H
2e
61
33
5
Br
H
2f
48
11
6
Ph
H
–
Complex mixture
No reaction
7
CN
H
–
No reaction
No reaction
Entry
R
1
OCOCF3
2 3
a
R
b
Conditions: FeCl3 (1.2 eq.), CH2Cl2. Conditions: xylene, reflux.
Subsequently, we attempted to prepare 9-acyloxytriptycene quinone from 2a, revealing that HBr-mediated tautomerization of the latter adduct followed by oxidation with PhI(OAc)2 afforded triptycene quinone 5 in 83% overall yield (Scheme 2). Importantly, the above transformations provide easy access to 9-acyloxytriptycene quinone, which cannot be obtained via usual acylation, since the acylation of sterically hindered tertiary alcohols is often challenging [16].
7
Scheme 2. Synthesis of 9-dichloroacetoxytriptycene quinone 5.
In conclusion, Lewis acids such as Sc(OTf)3 and FeCl3 were found to remarkably enhance the reactivity of 9-acyloxyanthracenes in Diels-Alder reactions with benzoquinones. The above acyloxyanthracenes could be easily prepared from anthracenes via previously developed direct C–H oxygenation protocols, and the cycloaddition reaction with benzoquinones followed by oxidation was demonstrated to provide rapid access to bridgehead-acyloxylated triptycene quinones and diverse triptycene analogues. These novel bridgehead-substituted triptycenes can be employed as new building blocks and lead compounds for material and pharmaceutical sciences in further studies.
Acknowledgments We thank Prof. Dr. H. Imagawa and Prof. Dr. H. Kaku (Tokushima Bunri University) for X-ray diffractive analysis. This study was partly supported in part by JSPS KAKENHI Grant No. 17K15430 from MEXT, the Research Foundation for Pharmaceutical Sciences, and the Cooperative Research Program of the Network Joint Research Center for Materials and Devices.
Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/
8
References 1. a) Swager TM. Acc. Chem. Res. 2008; 41:1181-1189; b) Chong JH, MacLachlan MJ. Chem. Soc. Rev. 2009; 38:3301-3315; c) Chen C-F. Chem. Commun. 2011; 47:1674-1688. 2. a) Long TM, Swager TM. J. Am. Chem. Soc. 2003; 125:14113-14119; b) Zhu X-Z, Chen C-F. J. Org. Chem. 2005; 70:917-924; c) Zhao Y, Rocha SV, Swager TM. J. Am. Chem. Soc. 2016; 138:13834-13837. 3. a) Hua DH, Tamura M, Huang X, Stephany HA, Helfrich BA, Perchellet EM, Sperfslage BJ, Perchellet J-PH, Jiang S, Kyle DE, Chiang P. J. Org. Chem. 2002; 67:2907; b) Perchellet EM, Wang Y, Lou K, Zhao H, Battina SK, Hua DH, Perchellet J-PH. Anticancer Res. 2007; 27:3259-3272. 4. a) Bartlett PD, Ryan JM, Cohen SG. J. Am. Chem. Soc. 1942; 64:2649-2653; b) Wiehe A, Senge MO, Kurreck H. Liebigs Ann. 1997; 1997:1951-1963. c) Zhao L, Li Z, Wirth T. Chem. Lett. 2010; 39:658-667. 5. Triptycenes can also be prepared by reacting anthracenes with benzynes, see: a) Wittig G, Ludwig R. Angew. Chem. 1956; 68:40; b) Luo J, Hart H. J. Org. Chem. 1987; 52:3631-3636; c) Umezu S, dos Passos Gomes G, Yoshinaga T, Sakae M, Matsumoto K, Iwata T, Alabugin I, Shindo M. Angew. Chem., Int. Ed. 2017; 56:1298-1302. 6. a) Matsumoto K, Tachikawa S, Hashimoto N, Nakano R, Yoshida M, Shindo M. J. Org. Chem. 2017; 82:4305-4316; b) Matsumoto K. J. Pharm. Soc. Jpn. 2018; 138:1353-1361. 7. a) Matsumoto K, Dougomori K, Tachikawa S, Ishii T, Shindo M. Org. Lett. 2014; 16:4754–4757; b) Matsumoto K, Yoshida M, Shindo M. Angew. Chem., Int. Ed. 2016; 55:5272–5276; c) Fujimoto S, Matsumoto K, Shindo M. Adv. Synth. Catal. 2016; 358:3057–3061; d) Fujimoto S, Matsumoto K, Iwata T, Shindo M. Tetrahedron Lett. 2017; 58:973–976; e) Shindo, M.; Matsumoto, K. In New Horizon of Process Chemistry by Scalable Reactions and Technologies; Tomioka, K., Shioiri, T., Sajiki, H., Eds.; Springer: Singapore, 2017; pp 11-27. 8. For a recent review on Diels-Alder reactions of 9-substituted anthracenes, see: Atherton JCC, Jones S. Tetrahedron 2003; 59:9039-9057. 9. a) Bartlett PD, Cohen SG, Cotman Jr JD, Kornblum N, Landry JR, Lewis ES. J. Am. Chem. Soc. 1950; 72:1003-1004; b) Bartlett PD, Greene FD. J. Am. Chem. Soc. 1954; 76:1088-1096; c) Nakamura N, Kohno M, Oki M. Chem. Lett. 1982; 11:1809-1810; d) Gung BW, Xue X, Reich HJ. J. Org. Chem. 2005; 70:3641-3644. 10. a) Fuson RC, Brasure DE. J. Am. Chem. Soc. 1955; 77:3131-3132; b) Meek JS, Monroe PA,
9
Bouboulis CJ. J. Org. Chem. 1963; 28:2572-2577; c) Lehr RE, Kole PL, Singh M, Tschappat KD. J. Org. Chem. 1989; 54:850-857; d) Damme JV, Vlaminck L, Assche GV, Mele BV, van den Berg O, Du Prez F. Tetrahedron 2016; 72:4303-4311. 11. Bartlett PD, Ryan JM, Cohen SG. J. Am. Chem. Soc. 1942; 64:2649-2653. 12. a) Yates P, Eaton P. J. Am. Chem. Soc. 1960; 82:4436-4437; b) Patney HK. Synthesis 1991; 1991:694-696; c) Fukuzumi S, Okamoto T. J. Am. Chem. Soc. 1993; 115:11600-11601; d) Fukuzumi S, Ohkubo K, Okamoto T. J. Am. Chem. Soc. 2002; 124:14147. 13. Typical reaction procedure: To a solution of 9-dichloroacetoxyanthracene (1; 100 mg, 0.33 mmol) in CH2Cl2 (10 mL), cooled to 0 °C under argon, were added 1,4-naphthoquinone (78 mg, 0.49 mmol, 1.5 equiv.) and FeCl3 (64 mg, 0.39 mmol, 1.2 equiv.) and then stirred at 0 °C for 1.5 h. Subsequently, saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (20 to 50% AcOEt/hexane) to afford 2a (138 mg, 91%). 14. Ishitani H, Suzuki H, Saito Y, Yamashita Y, Kobayashi S. Eur. J. Org. Chem. 2015; 2015:5485-5499. 15. As a solvent, HFIP was used because the reaction using HFIP proceeded faster than that using CH2Cl2. 16. Yoon I, Suh S-E, Barros SA, Chenoweth DM. Org. Lett. 2016; 18:1096-1099.
10
Graphical Abstract
Synthesis of Bridgehead-Functionalized Triptycene Quinones via Lewis Acid–Promoted Diels–Alder Reactions of 9-Acyloxyanthracenes Kenji Matsumoto, Rina Nakano, Tsukasa Hirokane, and Masahiro Yoshida
11
Highlights • Successful synthesis of the bridgehead-functionalized triptycene quinones. • 9-Acyloxyanthracenes reacted with 1,4-benzoquinones and 1,4-naphthoquinones efficiently. • Sc(OTf)3 and FeCl3 remarkably enhanced the reactivity of 9-acylanthracenes in the Diels-Alder reactions. • The 9-acylanthracenes were easily prepared by the direct oxidative acyloxylation of aromatic C−H bonds.
11
S0040-4039(19)30202-3 https://doi.org/10.1016/j.tetlet.2019.03.001 TETL 50642
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
11 January 2019 18 February 2019 1 March 2019
Please cite this article as: Matsumoto, K., Nakano, R., Hirokane, T., Yoshida, M., Synthesis of BridgeheadFunctionalized Triptycene Quinones via Lewis Acid–Promoted Diels-Alder reaction of 9-Acyloxyanthracenes, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis of Bridgehead-Functionalized Triptycene Quinones via Lewis Acid–Promoted Diels-Alder reaction of 9-Acyloxyanthracenes
Kenji Matsumoto1, Rina Nakano, Tsukasa Hirokane, and Masahiro Yoshida
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama, Yamashiro-cho, Tokushima 770-8514, Japan
Abstract Herein, we show that bridgehead-functionalized triptycene quinones can be rapidly and conveniently prepared in good to high yields by Lewis acid–catalyzed cycloaddition of 1,4-benzoquinones and 1,4-naphthoquinones to 9-acyloxyanthracenes and probe the substrate scope of this transformation.
Keywords: triptycene, triptycene quinone, Diels-Alder reaction, anthracene, Lewis acid
Triptycene and triptycene quinone are structurally unique compounds comprising three benzene rings fused into a rigid barrelene framework (Figure 1). The propeller-like shape and high molecular symmetry of triptycene have inspired numerous studies in the fields of materials chemistry and supramolecular chemistry [1], while triptycene quinone is used to synthesize functionalized iptycenes [2] and exhibits promising antitumor and antimalarial activities [3]. Generally, triptycene quinones are prepared by the Diels-Alder reaction of anthracenes with p-benzoquinones, and numerous substituted triptycene quinone analogues have been synthesized to date [4, 5]. Since the Diels-Alder reaction is the key step in the synthesis of functionalized triptycenes and other iptycenes, the scope of its synthetic applications needs to be further extended.
1
Corresponding author. E-mail: [email protected]
3
Figure 1. Structures of triptycene and triptycene quinone. Recently, we have achieved direct oxidative acyloxylation of aromatic C−H bonds under mild conditions using a recyclable heterogeneous metal catalyst and molecular oxygen as a terminal oxidant (Scheme 1) [6, 7] and realized smooth trifluoroacetoxylation and dichloroacetoxylation at the 9-position of anthracene to obtain 9-trifluoroacetoxy- and 9-dichloroacetoxyanthracenes with exclusive regioselectivity. Although 9-substituted anthracenes can be utilized as versatile precursors for the Diels-Alder reaction with benzoquinones to synthesize bridgehead carbon–functionalized triptycene quinones, this approach has not been extensively explored, probably because the weakly dienophilic nature of benzoquinones makes the above reaction sensitive to the steric effects of substituents at the 9-position of anthracene [8, 9]. Furthermore, the Diels-Alder reaction of 9-acyloxyanthracenes has not been explored because of the limitation of a synthetic route to these species [10]. These limitations prompted us to study the Diels-Alder reaction of 9-acyloxyanthracenes with benzoquinones and naphthoquinones, which should theoretically provide easy access to bridgehead-modified triptycene quinones.
Scheme 1. Rh/C-catalyzed oxidative acyloxylation of anthracene.
Initially, we followed the synthetic protocol reported by Bartlett et al. and examined the thermally induced Diels-Alder reaction of 9-dichloroacetoxyanthracene (1) with 1,4-naphthoquinone in xylene (Table 1, entry 1) [11]. However, the reaction did not proceed at all under these conditions. In the presence of 1 equiv. of AlCl3, which is known to promote Diels-Alder reactions [12], the expected
4
cycloadduct 2a was produced in 82% yield (entry 2), with similar yields achieved for FeCl3 and Sc(OTf)3 (91% (entry 3) and 87% (entry 4), respectively) [13]. In contrast, no cycloadduct was obtained in the presence of the less Lewis-acidic Y(OTf)3 (entry 5). When 1,1,2,3,3,3-hexafluoroisopropanol (HFIP) was used a solvent, the loading of Sc(OTf)3 could be reduced to 0.5 equiv., and 2a was obtained in good yield, even though a prolonged reaction time was needed (entry 6). The Lewis acid loading could be further decreased to 0.1 equiv. for Hf(OTf)4, in which case 2a was obtained in 69% yield (entry 7) [14]. These experiments revealed that Lewis-acidic FeCl3 and Sc(OTf)3 effectively promoted the Diels-Alder reactions of 9-acyloxyanthracene.
Table 1. Diels-Alder reactions of 1 with 1,4-naphthoquinone.
Entry
Lewis acid
1
none
2
AlCl3
3 4
Equiv.
Conditions
Time (h)
Yield (%)
xylene, reflux
72
No reaction
1.0
CH2Cl2, 0 °C
1.5
82
FeCl3
1.2
CH2Cl2, 0 °C
1.5
91
Sc(OTf)3
1.0
CH2Cl2, 0 °C to rt
2
87
5
Y(OTf)3
1.0
CH2Cl2, 0 °C to rt
24
No reaction
6
Sc(OTf)3
0.5
HFIP, 45 °C
19
70
7
Hf(OTf)4
0.1
HFIP, 45 °C
23
69
With the optimized conditions in hand, we examined the reactions of 1 with substituted 1,4-benzoquinones (Table 2). When non-substituted 1,4-benzoquinone and FeCl3 were employed, 3a was obtained in low yield, probably because the enone group of 3a reacted with chloride ions generated in situ from FeCl3 (entry 1). In support of this hypothesis, the yield of 3a could be improved by using Sc(OTf)3 (entry 2) [15]. Similarly, the Sc(OTf)3-mediated reaction of 2-chloro-1,4-benzoquinone afforded higher yields of two regioisomers, 3b and 4b, than the corresponding FeCl3-mediated reaction (entries 3 and 4). In the case of 2-tert-butyl-1,4-benzoquinone, which is less reactive than other benzoquinones, reactions mediated by FeCl3 and Sc(OTf)3 afford mixtures of 3c and 4c in 87 and 61%
5
yields, respectively (entries 5 and 6), although heating was required in both cases. The structure of regioisomer 4c was confirmed by X-ray crystallographic analysis (Figure 2). Table 2. Diels-Alder reactions of 1 with 1,4-benzoquinones.
Entry
R
Lewis acid
Conditions
3/ 4
Yield (%)
3:4
1
H
FeCl3
CH2Cl2, 0 °C
3a
30
–
2
H
Sc(OTf)3
HFIP, 0 °C
3a
72
–
3
Cl
FeCl3
CH2Cl2, 0 °C
3b/ 4b
57
1 : 6.1
4
Cl
Sc(OTf)3
HFIP, rt
3b/ 4b
79
1 : 1.5
5
tert-Bu
FeCl3
CH2Cl2, reflux
3c/ 4c
87
1 : 0.9
6
tert-Bu
Sc(OTf)3
HFIP, 50 °C
3c/ 4c
61
1 : 1.4
Figure 2. Crystal structure of 3c determined by X-ray diffraction analysis.
Subsequently, we explored the effect of anthracene substituents at 9-position (Table 3), showing that both 9-dichloroacetoxy- and 9-trifluoroacetoxyanthracenes efficiently reacted with naphthoquinone in the presence of FeCl3 to afford 2b in excellent yields (entry 1). The FeCl3-promoted reaction of 9,10-dimethylanthracene afforded 2c in 93% yield (entry 2), and the FeCl3-promoted reactions of both 9-methylanthracene and anthracene were more efficient than those promoted by heating (entries 3 and 4). The 9-bromo group was tolerated in the presence of FeCl3, and 2f was obtained in moderate yield (entry
6
5), while the reactions of phenyl- and cyano-substituted anthracenes did not afford the desired products (entries 6 and 7). Therefore, it was concluded that electron-donating substituents (such as methyl) in the 9 and 10 positions increased the reactivity of anthracene, while an opposite effect was observed for electron-withdrawing groups. Since the Diels-Alder reaction is generally affected by both electronic and steric effects of substituents, the sterically bulky acyloxy group probably hampered the above reaction under thermal conditions. On the other hand, Lewis acids were found to strongly facilitate the Diels-Alder reactions of 9-acyloxyanthracenes. Table 3. Diels-Alder reactions of 9,10-substituted anthracenes with 1,4-naphthoquinone.
Yield (%) 1
2
2
FeCl3 a
thermal b
H
2b
93
–
Me
Me
2c
93
85
Me
H
2d
77
57
4
H
H
2e
61
33
5
Br
H
2f
48
11
6
Ph
H
–
Complex mixture
No reaction
7
CN
H
–
No reaction
No reaction
Entry
R
1
OCOCF3
2 3
a
R
b
Conditions: FeCl3 (1.2 eq.), CH2Cl2. Conditions: xylene, reflux.
Subsequently, we attempted to prepare 9-acyloxytriptycene quinone from 2a, revealing that HBr-mediated tautomerization of the latter adduct followed by oxidation with PhI(OAc)2 afforded triptycene quinone 5 in 83% overall yield (Scheme 2). Importantly, the above transformations provide easy access to 9-acyloxytriptycene quinone, which cannot be obtained via usual acylation, since the acylation of sterically hindered tertiary alcohols is often challenging [16].
7
Scheme 2. Synthesis of 9-dichloroacetoxytriptycene quinone 5.
In conclusion, Lewis acids such as Sc(OTf)3 and FeCl3 were found to remarkably enhance the reactivity of 9-acyloxyanthracenes in Diels-Alder reactions with benzoquinones. The above acyloxyanthracenes could be easily prepared from anthracenes via previously developed direct C–H oxygenation protocols, and the cycloaddition reaction with benzoquinones followed by oxidation was demonstrated to provide rapid access to bridgehead-acyloxylated triptycene quinones and diverse triptycene analogues. These novel bridgehead-substituted triptycenes can be employed as new building blocks and lead compounds for material and pharmaceutical sciences in further studies.
Acknowledgments We thank Prof. Dr. H. Imagawa and Prof. Dr. H. Kaku (Tokushima Bunri University) for X-ray diffractive analysis. This study was partly supported in part by JSPS KAKENHI Grant No. 17K15430 from MEXT, the Research Foundation for Pharmaceutical Sciences, and the Cooperative Research Program of the Network Joint Research Center for Materials and Devices.
Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/
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References 1. a) Swager TM. Acc. Chem. Res. 2008; 41:1181-1189; b) Chong JH, MacLachlan MJ. Chem. Soc. Rev. 2009; 38:3301-3315; c) Chen C-F. Chem. Commun. 2011; 47:1674-1688. 2. a) Long TM, Swager TM. J. Am. Chem. Soc. 2003; 125:14113-14119; b) Zhu X-Z, Chen C-F. J. Org. Chem. 2005; 70:917-924; c) Zhao Y, Rocha SV, Swager TM. J. Am. Chem. Soc. 2016; 138:13834-13837. 3. a) Hua DH, Tamura M, Huang X, Stephany HA, Helfrich BA, Perchellet EM, Sperfslage BJ, Perchellet J-PH, Jiang S, Kyle DE, Chiang P. J. Org. Chem. 2002; 67:2907; b) Perchellet EM, Wang Y, Lou K, Zhao H, Battina SK, Hua DH, Perchellet J-PH. Anticancer Res. 2007; 27:3259-3272. 4. a) Bartlett PD, Ryan JM, Cohen SG. J. Am. Chem. Soc. 1942; 64:2649-2653; b) Wiehe A, Senge MO, Kurreck H. Liebigs Ann. 1997; 1997:1951-1963. c) Zhao L, Li Z, Wirth T. Chem. Lett. 2010; 39:658-667. 5. Triptycenes can also be prepared by reacting anthracenes with benzynes, see: a) Wittig G, Ludwig R. Angew. Chem. 1956; 68:40; b) Luo J, Hart H. J. Org. Chem. 1987; 52:3631-3636; c) Umezu S, dos Passos Gomes G, Yoshinaga T, Sakae M, Matsumoto K, Iwata T, Alabugin I, Shindo M. Angew. Chem., Int. Ed. 2017; 56:1298-1302. 6. a) Matsumoto K, Tachikawa S, Hashimoto N, Nakano R, Yoshida M, Shindo M. J. Org. Chem. 2017; 82:4305-4316; b) Matsumoto K. J. Pharm. Soc. Jpn. 2018; 138:1353-1361. 7. a) Matsumoto K, Dougomori K, Tachikawa S, Ishii T, Shindo M. Org. Lett. 2014; 16:4754–4757; b) Matsumoto K, Yoshida M, Shindo M. Angew. Chem., Int. Ed. 2016; 55:5272–5276; c) Fujimoto S, Matsumoto K, Shindo M. Adv. Synth. Catal. 2016; 358:3057–3061; d) Fujimoto S, Matsumoto K, Iwata T, Shindo M. Tetrahedron Lett. 2017; 58:973–976; e) Shindo, M.; Matsumoto, K. In New Horizon of Process Chemistry by Scalable Reactions and Technologies; Tomioka, K., Shioiri, T., Sajiki, H., Eds.; Springer: Singapore, 2017; pp 11-27. 8. For a recent review on Diels-Alder reactions of 9-substituted anthracenes, see: Atherton JCC, Jones S. Tetrahedron 2003; 59:9039-9057. 9. a) Bartlett PD, Cohen SG, Cotman Jr JD, Kornblum N, Landry JR, Lewis ES. J. Am. Chem. Soc. 1950; 72:1003-1004; b) Bartlett PD, Greene FD. J. Am. Chem. Soc. 1954; 76:1088-1096; c) Nakamura N, Kohno M, Oki M. Chem. Lett. 1982; 11:1809-1810; d) Gung BW, Xue X, Reich HJ. J. Org. Chem. 2005; 70:3641-3644. 10. a) Fuson RC, Brasure DE. J. Am. Chem. Soc. 1955; 77:3131-3132; b) Meek JS, Monroe PA,
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Bouboulis CJ. J. Org. Chem. 1963; 28:2572-2577; c) Lehr RE, Kole PL, Singh M, Tschappat KD. J. Org. Chem. 1989; 54:850-857; d) Damme JV, Vlaminck L, Assche GV, Mele BV, van den Berg O, Du Prez F. Tetrahedron 2016; 72:4303-4311. 11. Bartlett PD, Ryan JM, Cohen SG. J. Am. Chem. Soc. 1942; 64:2649-2653. 12. a) Yates P, Eaton P. J. Am. Chem. Soc. 1960; 82:4436-4437; b) Patney HK. Synthesis 1991; 1991:694-696; c) Fukuzumi S, Okamoto T. J. Am. Chem. Soc. 1993; 115:11600-11601; d) Fukuzumi S, Ohkubo K, Okamoto T. J. Am. Chem. Soc. 2002; 124:14147. 13. Typical reaction procedure: To a solution of 9-dichloroacetoxyanthracene (1; 100 mg, 0.33 mmol) in CH2Cl2 (10 mL), cooled to 0 °C under argon, were added 1,4-naphthoquinone (78 mg, 0.49 mmol, 1.5 equiv.) and FeCl3 (64 mg, 0.39 mmol, 1.2 equiv.) and then stirred at 0 °C for 1.5 h. Subsequently, saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (20 to 50% AcOEt/hexane) to afford 2a (138 mg, 91%). 14. Ishitani H, Suzuki H, Saito Y, Yamashita Y, Kobayashi S. Eur. J. Org. Chem. 2015; 2015:5485-5499. 15. As a solvent, HFIP was used because the reaction using HFIP proceeded faster than that using CH2Cl2. 16. Yoon I, Suh S-E, Barros SA, Chenoweth DM. Org. Lett. 2016; 18:1096-1099.
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Graphical Abstract
Synthesis of Bridgehead-Functionalized Triptycene Quinones via Lewis Acid–Promoted Diels–Alder Reactions of 9-Acyloxyanthracenes Kenji Matsumoto, Rina Nakano, Tsukasa Hirokane, and Masahiro Yoshida
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Highlights • Successful synthesis of the bridgehead-functionalized triptycene quinones. • 9-Acyloxyanthracenes reacted with 1,4-benzoquinones and 1,4-naphthoquinones efficiently. • Sc(OTf)3 and FeCl3 remarkably enhanced the reactivity of 9-acylanthracenes in the Diels-Alder reactions. • The 9-acylanthracenes were easily prepared by the direct oxidative acyloxylation of aromatic C−H bonds.
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