Selective Preparation of C _2v -Symmetric Hexaphenylbenzene Derivatives through Sequential Suzuki Coupling

Abstract

We have developed effective reaction conditions for the ­Suzuki cross-coupling of chlorinated hexaphenylbenzene derivatives. A chloro group on a hexaphenylbenzene framework exhibits a low reactivity to Suzuki cross-coupling, and only nickel catalysts bearing alkyl-substituted phosphine ligands achieved the coupling. With this as a key step, we succeeded in the selective preparation of a C _2v -symmetric hexaphenylbenzene derivative containing two kinds of aryl group.

Key words

hexaphenylbenzene - Suzuki coupling - cross-coupling - nickel catalysis - aryl chlorides - regioselectivity

Hexaphenylbenzene (HPB) is a rigid C ₆-symmetric molecular framework that has been adopted as a core structure of various materials.[1] It is also important as a precursor of large polycyclic aromatic hydrocarbon derivatives such as hexa-peri-benzocoronene.[2] To maximize the potential of the HPB framework, it is crucial to introduce appropriate substituents in a desired arrangement. Among the various substitution patterns for HPB, a C _2v -symmetric one with two kinds of substituent in an alternate pattern is interesting for its potential use as a building unit for polyphenylene dendrimers.[3] This C _2v -symmetric pattern has also been used in HPB-based amphiphiles.[4] Despite their utility, C _2v -symmetric HPB derivatives are difficult to prepare by conventional methods[5] or even by modern protocols.[6]

Scheme 1 Selective preparation of a C _2v -symmetric HPB derivative containing two kinds of aryl group through selective alternate trilithiation of HPB derivative 1 and sequential Suzuki coupling

We recently developed a method for the selective alternate trilithiation of brominated HPB derivatives through a thermodynamically controlled halogen dance,[7] and have overcome the synthetic hurdle for C _2v -symmetric HPB derivatives (Scheme [1]). One of the products, with both bromo and chloro groups on the HPB framework, could serve as a common precursor to various C _2v -symmetric HPB derivatives, owing to the different reactivities of aryl bromide and aryl chloride groups in metal-catalyzed cross-coupling ­reactions.[8] [9] However, we encountered a low reactivity of the C–Cl moiety on the HPB framework in the Suzuki cross-coupling reaction. Here, we report an effective method for Suzuki cross-coupling of the chloro group on the HPB framework. By using this condition, we selectively prepared a C _2v -symmetric HPB derivative containing two kinds of aryl group (Scheme [1]).

Table 1 Optimization of a Suzuki Coupling of HPB Derivative 4 ^a

Entry	Catalyst (mol%)	Base	Solvent	Temp (°C)	Time (h)	Yieldb (%)
1c	Pd(OAc)2 (5) SPhos (10)	K3PO4 d	toluene	100	14	0
2e	Pd2(dba)3 (2.5) PCy3·HBF4 (6)	K3PO4	1,4-dioxane	80	22	0
3e	Pd2(dba)3 (2.5)P(t-Bu)3·HBF4 (6)	K3PO4	THF	80	30	0
4	Ni(dppp)Cl2 (5)	K3PO4	1,4-dioxane	100	66	0
5	Ni(dppp)Cl2 (5)	K3PO4	THF	80	42	0
6	Ni(dppp)Cl2 (5)	K3PO4	toluene	100	42	0
7	Ni(PPh3)2Cl2 (10)	K3PO4	THF	80	44	0
8	Ni(dppf)Cl2 (10)	K3PO4	THF	80	62	0
9	Ni(PCy3)2Cl2 (10)	K3PO4	THF	80	60	66
10	Ni(PCy3)2Cl2 (10)	K3PO4	1,4-dioxane	100	51	55
11	Ni(PCy3)2Cl2 (10)	K3PO4	toluene	100	28	0
12	Ni(PCy3)2Cl2 (10)	CsF	THF	80	38	0
13	Ni(dcype)Cl2 (10)	K3PO4	THF	80	75	25

^a Compound 4 (0.10 g) and solvent (1 mL) were used.

^b Determined by ¹H NMR.

^c With 1.1 equivalents of PhB(OH)₂.

^d With 2.0 equivalents of K₃PO₄.

^e With 1.5 equivalents of PhB(OH)₂.

We screened several sets of conditions for the Suzuki cross-coupling of the chlorinated HPB 4 with phenylboronic acid (Table [1]).[10] No cross-coupling reaction of a chloro group on HPB has previously been reported. We found that compound 4 was completely recovered in the presence of palladium catalysts bearing bulky or electron-rich phosphines such as SPhos,[11] PCy₃,[12] [13] or P(t-Bu)₃,[13] which are known to be effective in Suzuki cross-coupling reactions of aryl ­chlorides (Table [1], entries 1–3). Taking successful examples of Suzuki cross-coupling reaction of brominated HPB derivatives[14] into consideration, we attributed this low reactivity to difficult oxidative addition of the C–Cl moiety of compound 4. Our attention then shifted to Ni catalysts, which are known to promote oxidative addition more readily than do Pd catalysts.[15] Whereas Ni catalysts with aryl-substituted phosphine ligands such as DPPP,[16] PPh₃,[17] or DPPF[18] did not work at all (entries 4–8), more-electron-rich Ni catalysts with alkyl-substituted phosphine ligands, such as PCy₃ [19] or 1,2-bis(dicyclohexylphosphino)ethane (DCYPE),[20] afforded the coupled product 5 when an appropriate base and solvent were used (entries 9–13). The optimized conditions involved a combination of Ni(PCy₃)₂Cl₂ and K₃PO₄ in THF or 1,4-dioxane (entries 9 and 10). The moderate yields under these conditions are due to the recovery of the starting ­material 4 (34% for entry 9, 45% for entry 10). Although the reason for this is unclear, no further improvement of the conversion was achieved, even on doubling the amount of the Ni catalyst.

The inertness of compound 4 against oxidative addition of a metal center might be related to the geometrical structure of the HPB framework (Figure [1]). HPB derivatives adopt a propeller conformation because of steric repulsion between the adjacent aryl groups, especially around the central part of the framework.[21] During oxidative addition of a metal center to an aryl halide, the metal center ­approaches the C–X bond, interacting with the π-orbitals of the aryl ring of an aryl halide.[22] In the case of the HPB ­derivatives such as compound 4, both sides of the π-orbitals of the aryl rings are sterically covered by the adjacent aryl groups. This geometrical characteristic of the HPB framework, combined with the intrinsic low reactivity of aryl chlorides, hampers oxidative addition of a metal catalyst, thereby demanding electron-rich Ni catalysts.

Figure 1 Difficult oxidative addition of a metal catalyst to a C–Cl bond on the HPB framework

We selectively prepared a C _2v -symmetric HPB derivative 8 possessing two kinds of aryl group on the HPB framework (Scheme [2]). HPB derivative 1 was selectively trilithiated in an alternate pattern to afford compound 6 containing three TMS groups.[7] The introduction of the TMS groups enabled us to isolate compound 6 by crystallization. The TMS groups in 6 were then protodesilylated under acidic conditions.[23] Though the direct protonation of the trilithio species deriving from compound 1 afforded compound 2 as the main product, it was difficult to separate compound 2 from small amounts of its isomers generated during the lithiation step. Compound 2 was then subjected to sequential ­Suzuki cross-coupling. The first coupling with phenyl­boronic acid in the presence of Pd(PPh₃)₄ as a catalyst ­occurred exclusively at the Br moieties, even with excess phenylboronic acid, and the diarylated HPB derivative 7 was obtained in high yield.[24] The second Suzuki coupling between the C–Cl moiety of compound 7 and 4-methoxyphenylboronic acid afforded the C _2v -symmetric HPB derivative 8 (44%) with 30% recovery of compound 7.[25] This result demonstrates the utility of our protocol in selectively affording C _2v -symmetric HPB derivatives containing two kinds of aryl group, which are difficult to prepare by other protocols.

Scheme 2 Preparation of HPB derivative 8

In conclusion, we have developed effective reaction conditions for the Suzuki cross-coupling of chlorinated HPB ­derivatives. The aryl chloride moiety on the HPB framework exhibits a low reactivity to Suzuki cross-coupling, and only Ni catalysts bearing alkyl-substituted phosphine ligands were capable of inducing this reaction. With this as a key step, we succeeded in the selective introduction of two kinds of aryl group onto the periphery of a HPB skeleton to give a C _2v -symmetric HPB derivative. This protocol should be applicable to the development of new HPB derivatives bearing multiple functional groups or HPB-based large ­carbon clusters.

• References and Notes

• 1a Vij V. Bhalla V. Kumar M. Chem. Rev. 2016; 116: 9565
• 1b Lungerich D. Reger D. Hölzel H. Riedel R. Martin MM. J. C. Hampel F. Jux N. Angew. Chem. Int. Ed. 2016; 55: 5602
• 2a Ito S. Wehmeier M. Brand JD. Kübel C. Epsch R. Rabe JP. Müllen K. Chem. Eur. J. 2000; 6: 4327
• 2b Sadhukhan SK. Viala C. Gourdon A. Synthesis 2003; 1521
• 3a Miller TM. Neenan TX. Zayas R. Bair HE. J. Am. Chem. Soc. 1992; 114: 1018
• 3b Bauer RE. Enkelmann V. Wiesler UM. Berresheim AJ. Müllen K. Chem. Eur. J. 2002; 8: 3858
• 3c Finke AD. Moore JS. Org. Lett. 2008; 10: 4851
• 4 Hiraoka S. Nakamura T. Shiro M. Shinoya M. J. Am. Chem. Soc. 2010; 132: 13223
• 5 Feng X. Pisula W. Müllen K. Pure Appl. Chem. 2009; 81: 2203
• 6 Suzuki S. Segawa Y. Itami K. Yamaguchi J. Nat. Chem. 2015; 7: 227
• 7a Kojima T. Hiraoka S. Org. Lett. 2014; 16: 1024
• 7b Kojima T. Hiraoka S. Chem. Commun. 2014; 50: 10420
• 8 Stanforth SP. Tetrahedron 1998; 54: 263
• 9 A combination of an aryl bromide and an aryl iodide is not applicable for the selective sequential Suzuki coupling because both substrates are reactive in the lithiation step.
• 10 Suzuki Coupling Reactions of Compound 4; General ­Procedure A suspension of compound 4 (0.100 g, 0.176 mmol, 1.0 equiv), the appropriate arylboronic acid, base, and catalyst were stirred in a Schlenk tube under N₂ while the reaction was monitored and the yield was determined by ¹H NMR.
• 11 Barder TE. Walker SD. Martinelli JR. Buchwald SL. J. Am. Chem. Soc. 2005; 127: 4685
• 12 Shen W. Tetrahedron Lett. 1997; 38: 5575
• 13 Littke AF. Dai C. Fu GC. J. Am. Chem. Soc. 2000; 122: 4020
• 14a Shen X. Ho DM. Pascal RA. Jr. Org. Lett. 2003; 5: 369
• 14b Wunderlich K. Grigoriadis C. Zardalidis G. Klapper M. Graf R. Butt H.-J. Müllen K. Floudas G. Macromolecules 2014; 47: 5691
• 15a Han F.-S. Chem. Soc. Rev. 2013; 42: 5270
• 15b Tasker SZ. Standley EA. Jamison TF. Nature 2014; 509: 299
• 16 Zhao Y.-L. Li Y. Li S.-M. Zhou Y.-G. Sun F.-Y. Gao L.-X. Han F.-S. Adv. Synth. Catal. 2011; 353: 1543 ; Corrigendum: ibid. 2011, 353: 2881
• 17 Inada K. Miyaura N. Tetrahedron 2000; 56: 8657
• 18 Indolese AF. Tetrahedron Lett. 1997; 38: 3513
• 19 Ramgren SD. Hie L. Ye Y. Garg NK. Org. Lett. 2013; 15: 3950
• 20 Muto K. Yamaguchi J. Itami K. J. Am. Chem. Soc. 2012; 134: 169
• 21 Gust D. J. Am. Chem. Soc. 1977; 99: 6980
• 22a Sundermann A. Uzan O. Martin JM. L. Chem. Eur. J. 2001; 7: 1703
• 22b Senn HM. Ziegler T. Organometallics 2004; 23: 2980
• 22c Ahlquist M. Fristrup P. Tanner D. Norrby P.-O. Organometallics 2006; 25: 2066
• 22d Barder TE. Biscoe MR. Buchwald SL. Organometallics 2007; 26: 2183
• 22e Li Z. Fu Y. Guo Q.-X. Liu L. Organometallics 2008; 27: 4043
• 22f McMullin CL. Jover J. Harvey JN. Fey N. Dalton Trans. 2010; 39: 10833
• 23 Compound 2 A suspension of compound 6 (0.500 g, 0.530 mmol) and TsOH (604 mg, 3.18 mmol) in AcOH (5 mL) was refluxed for 1.5 h. H₂O (5 mL) was then poured into the mixture and the resulting precipitate was collected by filtration and washed with MeOH to afford compound 2 as a colorless solid; yield: 0.346 g (90%); mp >300 °C.¹H NMR (500 MHz, CDCl₃, 298 K): δ = 6.98 (d, J = 8.8 Hz, 4 H), 6.92–6.89 (m, 9 H), 6.83 (d, J = 8.6 Hz, 2 H), 6.78–6.75 (m, 6 H), 6.71 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 8.6 Hz, 4 H). ¹³C NMR (125 MHz, CDCl₃, 298 K): δ = 140.66, 140.57, 139.91, 139.89, 139.48, 139.43, 139.39, 138.90, 132.98, 132.61, 131.45, 131.25, 130.00, 127.21, 127.08, 125.90, 119.75. HRMS (ESI-TOF): m/z [M]⁺ calcd for C₄₂H₂₇ ⁷⁹Br₂ ³⁵Cl: 724.0182; found: 724.0168.
• 24 Compound 7 A solution of compound 2 (0.200 g, 0.275 mmol, 1.0 equiv), PhB(OH)₂ (0.101 g, 0.825 mmol, 3.0 equiv), K₂CO₃ (0.228 g, 1.65 mmol, 6.0 equiv), and Pd(PPh₃)₄ (31.8 mg, 27.5 µmol, 10 mol%) in THF (2 mL) and H₂O (2 mL) was stirred at 80 °C for 6 h under N₂. The mixture was then extracted with EtOAc (3 × 5mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography [silica gel, hexane to hexane–EtOAc (20:1)] to give a colorless solid; yield: 0.186 g (93%); mp 284–286 °C. ¹H NMR (500 MHz, CDCl₃, 298 K): δ = 7.44 (d, J = 7.2 Hz, 4 H), 7.33 (t, J = 7.5 Hz, 4 H), 7.24 (t, J = 7.4 Hz, 2 H), 7.13 (d, J = 8.4 Hz, 4 H), 6.90–6.80 (m, 21 H), 6.77 (d, J = 8.6 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃, 298 K): δ = 140.91, 140.80, 140.55, 140.49, 140.40, 140.31, 139.69, 139.33, 139.27, 137.56, 132.80, 131.90, 131.51, 131.47, 131.29, 128.68, 127.03, 126.92, 126.81, 125.62, 125.50, 125.29. HRMS (ESI-TOF): m/z [M]⁺ calcd for C₅₄H₃₇ ³⁵Cl: 720.2576; found: 724.2584.
• 25 Compound 8 A solution of compound 7 (0.100 g, 0.139 mmol, 1.0 equiv), 4-methoxyphenylboronic acid (42.2 mg, 0.278 mmol, 2.0 equiv), K₃PO₄ (0.118 g, 0.556 mmol, 4.0 equiv), and Ni(PCy₃)₂Cl₂ (9.60 mg, 13.9 µmol, 10 mol%) in THF (1 mL) was stirred at 80 °C for one week under N₂. The mixture was then extracted with EtOAc (3 × 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography [silica gel, hexane to hexane–EtOAc (10:1)] to give a colorless solid [yield: 48 mg (44%)], together with a mixture of compound 7 and 4,4′-dimethoxybiphenyl. Compound 7 [yield: 30 mg (30%); mp 252–253 °C] was recovered after washing this mixture with hexane. ¹H NMR (500 MHz, CDCl₃, 298 K): δ = 7.45 (d, J = 7.4 Hz, 4 H), 7.38 (d, J = 9.0 Hz, 2 H), 7.33 (t, J = 7.8 Hz, 4 H), 7.24 (t, J = 7.4 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 4 H), 7.09 (d, J = 8.5 Hz, 2 H), 6.90–6.80 (m, 23 H), 3.80 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃, 298 K): δ = 158.97, 140.88, 140.71, 140.69, 140.67, 140.60, 140.30, 140.22, 139.94, 139.21, 137.47, 137.09, 133.45, 132.00, 131.97, 131.61, 128.68, 127.82, 127.01, 126.89, 126.82, 125.40, 125.26, 124.79, 114.11, 55.47. HRMS (ESI-TOF): m/z [M]⁺ calcd for C₆₁H₄₄O: 792.3392; found: 792.3395.