A General Strategy Toward Aromatic 1,2-Ambiphilic Synthons: Palladium-Catalyzed ortho-Halogenation of PyDipSi-Arenes

Ambiphilic aromatic synthons—compounds possessing both electrophilic and nucleophilic centers in the same molecule—are important building blocks that are widely used for a modular construction of complex molecules in organic synthesis, medicinal chemistry, and materials science.^[1] Traditionally, they are accessed through multistep syntheses. One of the most efficient strategies toward 1,2-ambiphilic structures involves directed ortho-metalation (DOM) approach.^[2] Our research group has recently developed the palladium-catalyzed directed ortho-acyloxylation of pyridyldiisopropylsilyl (PyDipSi) arenes B^[3] [Eq. (1)] based on a C–H activation process.^[4] Most importantly, we have shown that the PyDipSi directing group^[5] could efficiently participate in a variety of reactions as a nucleophilic entity. Because the acyloxy group is known to serve as an electrophilic coupling partner,^[6] the o-acyloxylated PyDipSi-arenes can be formally considered as 1,2-ambiphiles. Taking into account the immense synthetic potential of aryl halides as electrophilic reagents, we aimed at the development of a general strategy for the synthesis of ortho-halogenated aryl silanes C, which are much more powerful 1,2-ambiphiles. Herein, we report the palladium-catalyzed ortho-halogenation reaction of easily accessible PyDipSi-arenes B into 1,2-ambiphiles C and their further transformations to a variety of valuable building blocks.

(1)

First, we tested PyDipSi-arene 1a under a variety of halogenation reaction conditions in the presence of 10 mol% of Pd(OAc)₂ (Table 1).^[4a,7] Initially, the palladium-catalyzed bromination with 2 equivalents of NBS (N-bromosuccinimide) in PrCN at 80°C afforded 50% of the desired product 2 (Table 1, entry 1; Hal =Br). Further increase of temperature to 100°C led to a slight improvement of the reaction outcome (Table 1, entry 2). Addition of 50 equivalents of acetic acid^[7a,b] resulted in significant decrease of the reaction yield (Table 1, entry 3). The employment of a stoichiometric amount of Cu(OAc)₂ additive gave only traces of brominated product (Table 1, entry 4). Remarkably, addition of 1.5 equivalents of PhI(OAc)₂ dramatically improved the reaction, and provided the bromination product in 80% yield (Table 1, entry 5). Performing the reaction at the elevated temperature (100°C), however, gave a lower yield of 2 (Table 1, entry 6). Gratifyingly, switching solvent to 1,2-dichloroethane allowed for a better reaction yield (85%) at lower temperature (60°C; Table 1, entry 7). Employment of NIS (N-iodosuccinimide) as a halogen source under these reaction conditions produced iodinated aryl silane 2 in 95% yield (Table 1, entry 8; Hal =I). On the other hand, employment of NCS (N-chlorosuccinimide) gave the chlorinated product in a moderate yield only (Table 1, entry 9; Hal =Cl).

Table 1.

Optimization of ortho-halogenation reaction. X =halide.

Entry	Additive (equiv)	Hal	Solvent	T [8C]	Yield [%][a]
1	none	Br	PrCN	80	50
2	none	Br	PrCN	100	65
3	AcOH (50)	Br	PrCN	80	15
4	Cu(OAc)2 (1)	Br	PrCN	100	trace
5	PhI(OAc)2 (1.5)	Br	PrCN	80	80
6	PhI(OAc)2 (1.5)	Br	PrCN	100	65
7	PhI(OAc)2 (1.5)	Br	C2H4Cl2	60	85
8	PhI(OAc)2 (1.5)	I	C2H4Cl2	65	95
9	PhI(OAc)2 (1.5)	Cl	C2H4Cl2	65	42

^[a]Yield determined by NMR spectroscopy.

Next, the generality of the palladium-catalyzed ortho-halogenation of PyDipSi-arenes 1 was examined. The iodination reaction with NIS in the presence of 1.5 equivalents of PhI(OAc)₂ was studied first. We found this transformation to be efficient for a wide range of substrates, which allowed for the synthesis of monoiodinated aryl silanes 2a–w in good to excellent yields (Scheme 1). It was found that a variety of groups, including OMe (2b, 2k), F (2d, 2n), Cl (2e), Br (2 f, 2l), ester (2g), and amide (2h) were perfectly tolerated under the halogenation reaction conditions. Iodination of para-substituted aryl silanes possessing both electron-donating (2b) and electron-withdrawing (2d–h) substituents proceeded with equal efficiency. meta-Substituted substrates displayed excellent site selectivity in the iodination reaction, and provided monoiodinated compounds as single regioisomers (2i–l). In addition, ortho-iodination of m-, p-disubstituted aryl silanes (2m,n), and 2-naphthyl derivative (2o) occurred uneventfully and furnished the desired products as sole regioisomers in high yields. Next, the bromination reaction of 1 allowed for efficient synthesis of o-bromo aryl silanes 2p–r. Notably, chlorination of electron-rich aryl silane, possessing an OMe group para to the functionalization site, was found to be more efficient than that of electron-neutral 1a (Table 1, entry 9), thus producing chloro-derivative 2s in 69% yield. Finally, PyDipSi derivatives of various heterocycles, such as benzofuran (2t), carbazole (2u), indole (2v), and benzoxazole (2w), were monoiodinated in good yields. We find these results remarkable, as 6-halo derivatives of most of these heterocycles are not readily available and require multistep preparation. These derivatives now can be accessed from the 5-haloprecursors of the corresponding PyDipSi-heterocycles, which are either commercially available or can be easily synthesized in one step.

Scheme 1.

Palladium-catalyzed ortho-halogenation of aryl silanes. [a] Yield of isolated product. [b] See Supporting Information for experimental details. [c] Reaction was performed in PrCN at 100°C. [d] Reaction was performed without PhI(OAc)₂ and with 1 equivalent of NIS. Boc = tert-butoxycarbonyl.

Naturally, after the development of efficient palladium-catalyzed halogenation of aryl silanes, we investigated possible transformations of the PyDipSi directing group (Scheme 2).^[8] First, the reaction of 2c with AgF/H₂O (2:3) in THF resulted in efficient removal of the directing group, thus affording m-iodobiphenyl (6) in 97% yield.^[9] Interestingly, the overall three-step transformation of p-bromobi-phenyl into m-iodobiphenyl constitutes an example of a formal Finkelstein/“1,2-halogen dance” reaction. Next, the iododesilylation reaction of chlorobromoaryl silane 2e with NIS in the presence of AgF in THF allowed for efficient preparation of 1-cloro-3-bromo-4-iodobenzene (3), which is a synthetically useful and versatile building block for modular functionalization of the benzene ring. Furthermore, iodoaryl silane 2i was efficiently converted into o-iodoaryl boronate 4,^[10] which is another powerful 1,2-ambiphile, in 87% yield by a one-pot sequence involving borodesilylation with BCl₃, and subsequent protection with pinacol.^[11,12] Furthermore, borodesilylation of 2i and subsequent oxidation with H₂O₂/NaOH afforded o-iodophenol 5 in 80% yield.

Scheme 2.

Transformations of the PyDipSi group in haloarene derivatives. Reagents and conditions: a) AgF (4 equiv), H₂O (6 equiv), THF, RT, 12 h; b) AgF (4 equiv), NIS (4 equiv), THF, RT, 12 h; c) 1. BCl₃ (4.4 equiv), DCM, 0 °C, RT, 6 h; 2. 30 wt% H₂O₂/3 wt % NaOH (excess), H₂O, RT, 12 h; d) 1. BCl₃ (4.4 equiv), DCM, 0 °C, RT, 6 h; 2. pinacol (excess), Et₃N/DCM (1:1), RT, 12 h. THF = tetrahydrofuran.

Further utility of o-halogenated PyDipSi-arene derivatives was demonstrated by a convergent synthesis of unsymmetrically substituted benzo[b]silole 10 and dibenzosilole 15 (Scheme 3). First, treatment of 2i with HF at room temperature led to selective substitution of the pyridine group with fluoride,^[13] thus providing fluorosilane 7 in excellent yield. Next, o-iodoaryl fluorosilane 7 was alkynylated with potassium phenylethynyltrifluoroborate under Suzuki reaction conditions^[14] and produced 8 in 66% yield. Alternatively, alkynylated aryl silane 8 can be accessed from 2i through a sequence involving Sonogashira reaction^[15] with phenylacetylene and subsequent substitution of the pyridine group with fluoride. A subsequent reduction of silylfluoride 8 with LiAlH₄ furnished silylhydride 9. 5-Endo-dig cyclization of the latter in the presence of KH in DME^[16] provided 10 in 72% yield. En route to dibenzosilole derivative 15, o-iodoaryl silane 2i was subjected to Suzuki coupling^[17] with 4-methoxyphenylboronic acid and gave biphenylsilane 12 in 89% yield. Next, substitution of the pyridine group in 12 with fluoride produced silylfluoride 13 quantitatively. Smooth reduction of 13 into hydride 14 and its subsequent electrophilic cyclization reaction with trityl tetrakis(pentafluorophenyl)borate^[18] resulted in formation of dibenzosilole 15 in 71% yield (Scheme 3).

Scheme 3.

Synthesis of benzannulated siloles 10 and 15. Reagents and conditions: a) HF, THF, RT, 1 h; b) PhCCH, [{Pd(CH₃CN)₂}Cl₂] (3 mol%), tBu₃P (6 mol%), CuI (2 mol%), iPr₂NH, 1,2-dioxane, 60 °C, 12 h; c) PhCCBF₃K, [{Pd(dppf)}Cl₂]·DCM (10 mol%), Cs₂CO₃, THF, reflux, 48 h; d) LiAlH₄ (2.5 equiv), THF, reflux, 12 h; e) KH (1.4 equiv), DME, 5 h; f) 4-MeO-C₆H₄B(OH)₂ (1.2 equiv), [Pd₂(dba)₃] (5 mol%), tBu₃P (10 mol%), K₃PO₄, 1,2-dioxane, 70°C, 12 h; g) Ph₃CB(C₆F₅)₄, 1,6-lutidine, CH₂Cl₂, RT, 1 h. dba = trans,trans-dibenzylideneacetone, DME = 1,2-dimethoxyethane, dppf =1,1′-bis(diphenylphosphanyl)ferrocene, Py =pyridine.

Definitely, o-benzyne is one of the most synthetically attractive 1,2-ambiphiles.^[19] Because o-silylphenyliodonium triflates are known to efficiently generate benzynes in the presence of TBAF,^[20,21] we decided to convert the iodide functionality in PyDipSi-arenes 2 into a better leaving iodonium group. Accordingly, substrate 2e, after exchange of the pyridine group to fluoride, was smoothly converted into the corresponding iodonium tetrafluoroborate 16 (Scheme 4).^[22] Treatment of the latter with TBAF in CH₂Cl₂ allowed for the efficient generation of benzyne 17, trapping of which with furan provided 1,4-epoxydihydronaphthalene 18 in 89% yield. To the best of our knowledge, the above sequence, taken together with the o-iodination of PyDipSi-arenes, represents the first example of benzyne synthesis featuring C–H activation strategy.

Scheme 4.

Conversion of PyDipSi-iodoarenes into benzyne. Reagents and conditions: a) 1. 48 wt % HF (excess), THF, RT, 1 h; 2. m-CPBA (1.2 equiv), DCM, then BF₃·Et₂O (2.5 equiv), RT, 1 h; 3. PhB(OH)₂ (1.1 equiv), 0°C, RT, 30 min ; b) TBAF (1.2 equiv), furan (5 equiv), DCM, RT, 1 h. m-CPBA =meta-chloroperbenzoic acid, TBAF =tetra-n-butylammonium fluoride.

In conclusion, we have developed a general and efficient strategy for the synthesis of 1,2-ambiphilic aromatic and heteroannulated aromatic synthons. This method features installation of the removable/modifiable PyDipSi directing group on haloarenes and subsequent palladium-catalyzed directed ortho-halogenation reaction to give the o-halogenated PyDipSi-arene derivatives. Synthetic usefulness of these 1,2-ambiphilic building blocks was demonstrated in a variety of transformations, involving participation of both nucleophilic aryl silane and electrophilic aryl iodide moieties. These transformations include protio-, halo-, borodesilylations, and conversion of the PyDipSi group into the OH functionality, as well as Suzuki and Sonogashira cross-coupling reactions of the aryl iodide unit. Finally, the unique reactivity of these 1,2-ambiphiles was illustrated in convergent syntheses of benzannulated silole derivatives, as well as in the efficient generation of o-benzyne.