Nucleophilic C–H Etherification of Heteroarenes Enabled by Base-Catalyzed Halogen Transfer

Abstract

We report a general protocol for the direct C–H etherification of N-heteroarenes. Potassium tert-butoxide catalyzes halogen transfer from 2-halothiophenes to N-heteroarenes to form N-heteroaryl halide intermediates that undergo tandem base-promoted alcohol substitution. Thus, the simple inclusion of inexpensive 2-halothiophenes enables regioselective oxidative coupling of alcohols with 1,3-azoles, pyridines, diazines and polyazines under basic reaction conditions.

Graphical Abstract

The oxidative coupling of aryl C–H bonds with alcohols is an ideal synthetic approach to aromatic ethers that eliminates the need for preinstalled functional groups.¹ Such methodology can facilitate late-stage derivatization of complex arenes and resource-efficient large-scale syntheses.² While significant progress has been made for the C–H etherification of benzene derivatives, there are no direct protocols applicable to a broad range of N-heteroaryl substrates, such as 1,3-azoles and (di)azines.^1,3–5 A method that addresses this limitation would streamline access to N-heteroaryl ethers that have wide value, especially in pharmaceuticals and agrochemicals.⁶

A key challenge for direct C–H etherification is the incompatibility of combining a C–H oxidative process with nucleophilic alcohol coupling partners.⁷ Thus, existing routes for N-heteroaryl C–H etherification require independent synthesis of a functionalized arene followed by an alcohol substitution reaction. A common strategy in this regard involves heteroaryl N-oxide or N-triflyl formation en route to nitro-, cyano- or phosphonium-substituted azines.^8–10 Alternatively, a two-step metalation/halogenation sequence provides heteroaryl halides; however, this often requires irreversible metalation and a directing group for good selectivity.^11–13 Thus, a new activation strategy is likely required if N-heteroaryl C–H etherification is to be achieved in a single operation. In addition to increased synthetic efficiency, a new oxidative coupling method could complement the scope, selectivity and practicality of existing routes to aromatic ethers.

In 1951, Nord disclosed the unexpected observation that 2-bromothiophene disproportionates in the presence of strong base (Figure 1a).¹⁴ This report represents the first known example of base-catalyzed aromatic halogen transfer, a mechanistic process now widely used in the context of halogen dance methodology.^15,16 We realized the intermolecular nature of aromatic halogen transfer could be exploited in a new C–H functionalization strategy as shown in Figure 1b. Here, base-catalyzed halogen transfer from a sacrificial aryl halide (Ar–X) to an N-heteroarene (HetAr–H) is sequenced with a substitution reaction of the N-heteroaryl halide intermediate.

Figure 1.

The use of base-catalyzed halogen transfer (X-transfer) for a new heteroarene C–H etherification reaction.

Merging halogen transfer with a substitution reaction is a critical design feature for an overall high-yielding and selective C–H functionalization reaction.¹⁷ In the absence of a thermodynamic driving force, aromatic halogen transfer is expected to be reversible and unselective while generating N-heteroaryl halides prone to undesired side reactions.^18–20 A separate challenge for the proposed method is identification of an aryl halide that efficiently transfers a halogen to transient N-heteroaryl anions but does not decompose or undergo nucleophilic substitution under basic conditions. Inspired by Nord’s seminal report, we herein disclose that 2-halothiophenes fulfill this role to enable regioselective N-heteroarene C–H etherification (Figure 1b, bottom).

We first targeted the 2-selective C–H etherification of 1,3-azoles for development as there is currently no general protocol for this coupling process.^21,22 Optimization of a model reaction between thiazole (1) and 2-ethyl-1-hexanol (2) is shown in Scheme 1a using KO-t-Bu as base.²³ We began by examining 2-bromothiophenes as potential oxidants, which are inert towards nucleophilic aromatic substitution.²⁴ Use of 2-bromothiophene (4) provides 16% etherification yield and a small polybromothiophene screen found that inexpensive 2,5-dibromothiophene (7, <$40 per mole) increases the yield to 74%. Use of common halogenating reagents (e.g. CBr₄ and NBS) as oxidants results in no product formation, demonstrating the unique efficacy of 2-bromothiophene reagents under these conditions.²⁵

Scheme 1. Optimization of halogen transfer reagents for the C–H etherification of (a) thiazole and (b) 3-bromopyridine.^a.

^aFor all reactions, 1 equiv of heteroarene and 1.5 equiv of alcohol used. Yields determined by ¹H NMR spectroscopy of the crude reaction mixture. See Supporting Information for full optimization details. ^b65% yield without 18-crown-6 additive.

We reasoned this functionalization strategy could operate on other distinct classes of N-heteroarenes, including pyridine derivatives (Scheme 1b). Targeting the C–H etherification of 3-bromopyridine (8) as a model reaction, use of 2,5-dibromothiophene (7) provides low yields under the previously optimized conditions (12% at 60 °C and 8% at 25 °C). Since pyridines are less acidic than 1,3-azoles, we speculated the lower concentration of pyridyl anions in this reaction would require faster halogen transfer for efficient reactivity.²³ In this regard, we expected iodothiophenes to be more active halogen transfer reagents due to iodine’s increased polarizability and decreased electronegativity.²⁶ While 2,5-diiodothiophene (10) does increase the yield to 82% at 25 °C, we also found inexpensive 2-iodothiophene (11, <$100 per mole) to be equally effective (84% yield).^27,28 When 2-iodothiophene (11) is used, 3-iodothiophene is observed as a major byproduct that likely forms via disproportionation processes. This led us to develop 2,3-diiodobenzothiophene (12, prepared in three steps on 100 mmol scale)²⁹ as an alternative oxidant that is stable to the reaction conditions but still enables high C–H etherification yield (86%).³⁰ We note 18-crown-6 is used as an additive for reactions in Scheme 1b, although useful yields are obtained without it (65% of 9) and many azine substrates reported below do not require its use.

Table 1 provides a scope of heteroaryl ethers that can be accessed using the three 2-halothiophene reagents identified in our optimization studies. High regio- and chemoselectivity is observed for C–H etherification (>10:1 for shown product, unless noted) as judged by examination of crude reaction mixtures. Primary, secondary and benzylic alcohols are effective coupling partners, including amino-alcohols, alkenols and complex alcohols such as the pharmaceutical perphenazine (36).

Table 1.

Substrate scope for heteroarene C–H etherification using optimized halogen transfer reagents.^a

^aReactions conducted on 0.5 to 1 mmol scale of heteroarene; yields are of isolated products; reaction conducted at 60 °C for 3 h for Table 1a and at 25 °C for 20 h for Table 1b and 1c.

^b18-crown-6 (1.5 equiv) additive used.

^cSide products (20% total) from 2-substitution of the starting material observed.

^d2 equiv of alcohol used.

^eDMF used as solvent.

^fReaction conducted at 60 °C.

^gReaction conducted with 2 equiv pyridazine and 1 equiv alcohol; product forms in 4:1 ratio to other aryl ethers.

^hProduct forms in 6:1 ratio to other aryl ethers. See Supporting Information for full details.

Table 1a shows the use of 2,5-dibromothiophene (7) for the 2-etherification of 1,3-azole compounds, including thiazoles, oxazoles, imidazoles and benzofused variants (13–21). 4,5-Dimethylthiazole (13) undergoes 2-etherification without competing methyl oxidation. Substrates with halogen substituents (15, 18) and additional aryl groups (15, 17, 21) favor 1,3-azole etherification over potential substitution or unselective halogenation side reactions.

Table 1b shows the use of 2-iodothiophene (11) for the etherification of 6-membered N-heteroarenes.³¹ 3-Halopyridines (9, 24, 36), including 3,5-dichloropyridine (22), produce 4-etherified products without competing 2-etherification or 3-substitution. The selective etherification of 5-bromo-2-iodopyridine (23) and 2-chloro-5-methoxypyridine (25) illustrates the preferred 4-selectivity over 2-halogen substitution.³² 3-(Phenylthio)pyridine (26) reacts smoothly as do pyridines without electron-withdrawing groups in the 3-position, including 2,6-disubstituted pyridines (27, 28) and pyridine 29 that contains two acidic difluoromethyl groups.³³

Structurally diverse azines and diazines also participate in this method. Selective etherification of a furo[3,2-b]pyridine (30), quinoline (31) and pyrazolo[1,5-a]pyrimidine (35) occurs without competing halogenation of other positions. Pyridazine (32) and derivatives with 3,6-dialkoxy (33) and amide (34) substituents undergo 4-selective C–H etherification.

For certain azines, use of 2,3-diiodobenzothiophene (12) in place of 2-iodothiophene (11) improves the etherification yield (Table 1c).³⁴ Pyridines with phenylsulfonyl (37) and sulfonamide (38) groups produce 4-substituted ethers in high yield under these conditions. More diverse arenes such as 5-chloro-2-phenylpyrimidine (39), imidazo[1,2-b]pyridazine (40) and phthalazine (41) also react.

This etherification protocol enables several benefits over existing routes to N-heteroaryl ethers. For example, practical alkoxide bases are employed under ambient conditions, requiring no strong directing groups to achieve regioselective C–H etherification in a single step. This contrasts with existing methods for net heteroaryl C–H etherification, including a three-step metalation, halogenation and substitution sequence. We expect these features to be especially valuable for the selective functionalization of polyazines. For example, Scheme 2a shows a regioselective C–H etherification reaction on a bipyridine (42) that lacks directing groups required for a 4-selective metalation/halogenation protocol.³⁵ This selectivity also complements the scope of (pseudo)halogenation methods reliant on pyridine N-activation that typically functionalize the most basic and unencumbered N-heteroarene.³⁶

Scheme 2. Direct C–H etherification of polyazines.^a.

^aIsolated yields using conditions from Table 1b and 1c. ^bShown product forms in 7:1 ratio to other ether side products. ^c18-Crown-6 additive used. See Supporting Information for details.

Scheme 2b shows additional polyazines that exhibit high regioselectivity using conditions from Table 1. Here, a pyridine-containing alcohol selectively couples with a chlorinated 2,3’-bipyridine substrate (44). An imidazo[1,2-b]pyridazine with an 8-quinolinyl substituent undergoes selective etherification on the pyridazine ring (45) while 4-selective etherification of a 3,6-disubstituted pyridazine occurs in the presence of two pendant pyridines (46). In sum, numerous C–H etherification products in Table 1, Scheme 2 and Equation 1 (vide infra) are accessed directly from readily available heteroarenes where a corresponding heteroaryl (pseudo)halide is not commercially available and is challenging to access.

Equation 1 demonstrates how this base-promoted method can be incorporated into cascade substitution sequences to access products of greater complexity. Thus, reaction of 5-bromo-2-(trifluoromethyl)-pyridine (47) with L-prolinol (48) produces morpholine-fused pyridine 49 in 70% yield through tandem C–H etherification and C–Br amination reactions.³⁷

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We next performed studies to gain insight into the mechanism of C–H etherification. When alcohol is excluded from the optimized reaction conditions with the model substrates thiazole (1) and 3-bromopyridine (8), 2-bromothiazole and 3-bromo-4-iodopyridine are observed, respectively (see Supporting Information for details). In these control reactions, only low quantities of N-heteroaryl halides accumulate with the reactions ultimately resulting in low mass balances. These observations are consistent with the need to sequence halogen transfer with a substitution reaction for a high C–H functionalization yield.

Another insightful observation came during our substrate scope studies. When the reaction of 3-fluoropyridine (50) and methanol using 2-iodothiophene (11) was attempted, 4-iodo-3-methoxypyridine (51) was obtained as the major product (Scheme 3a). Subjection of 3-fluoro-4-iodopyridine (52) to methanol and KO-t-Bu results in a 3-selective nucleophilic aromatic substitution reaction (S_NAr, Scheme 3b).³⁸ A control experiment in Scheme 3c shows that 3-methoxypyridine (53) does not undergo 4-iodination under these conditions. These results are consistent with halogen transfer and subsequent S_NAr as the operative mechanism for C–H etherification.^39,40 Studies on the halogen transfer process, including further development of halogen transfer reagents, are ongoing.^41,42

Scheme 3. Observation of a halogen transfer adduct.^a.

^aYields determined by ¹H NMR spectroscopy of crude reaction mixture; see Supporting Information for details.

Key to development of this C–H etherification protocol was the discovery that 2-halothiophenes can serve as base- and nucleophile-tolerant halogen oxidants. Thus, heteroarene C–H etherification can be accomplished using typical S_NAr reaction conditions with the simple inclusion of a 2-halothiophene. The underlying mechanistic steps of this process represent a general framework for C–H functionalization methodology that we are currently expanding upon.