Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines†

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.


III. Optimization of the 4-Selective Etherification of 3-Bromopyridine (a) Evaluation of changes in optimal base, solvent, temperature, and concentration
Preliminary experiments varying base and solvent suggested KOH with 18-crown-6 in DMAc could promote a 4-selective etherification reaction between 3-bromopyridine and 2-ethyl-1hexanol. The optimal conditions were identified using pyridine:alcohol stoichiometry studies and KBr additive experiments that are described below in Section IIIb and IIIc, respectively. The optimized conditions are provided in the table below in comparison to specific changes of reagents or conditions used.

S 19
Results: A significant increase in yield of the 4-ether product and 4:3 selectivity were observed as the equivalents of KBr increased up to 0.5 equiv (see Table S3).

IV. Description of Mechanistic Studies on 3-Bromopyridine Isomerization (a) Furan cycloaddition experiment under optimized basic conditions
Purpose: A known trap for 3,4-pyridyne is a cycloaddition reaction with furan. 1

(b) Effect of the addition of KCl and KI on product yield and selectivity
Purpose: After observing that KBr improved the product yield and selectivity for the model etherification reaction (see Table S3), we next investigated how addition of potassium iodide (KI) and potassium chloride (KCl) impacts the yield and selectivity of the reaction.
Results: Addition of KCl or KI had a negligible effect on the yield and 4-selectivity of the reaction. The yield and 4-selectivity under either condition was comparable to a control in which no halide salt was included. Addition of KBr to the reaction improved the yield of the 4-alkoxylated product and the 4-selectivity of the reaction.

(c) Determination of the reaction profile
Purpose: This experiment was performed to analyze components of the reaction solution at different time points to observe the formation and consumption of potential reaction intermediates.
Procedure: An oven-dried 25 mL round bottom flask was charged with a magnetic stir bar, 3bromopyridine (237 mg, 1.5 mmol, 1.5 equiv), and dibenzyl ether (99.2 mg, 0.5 mmol, 0.5 equiv, used as internal standard). The flask was then brought into a N2 filled glovebox and 2-ethyl-1hexanol (130.2 mg, 1 mmol, 1.0 equiv), DMAc (6.0 mL, 0.17 M), KBr (59.5 mg, 0.5 mmol, 0.5 equiv), 18-crown-6 (1.19g, 4.5 mmol, 4.5 equiv), and KOH (224.4 mg, 4.0 mmol, 4.0 equiv) were added to the flask in successive order. The flask was sealed with a Fisherbrand® red septum stopper (Cat. No. FB57875) and the edges of the septum were lined with Parafilm®. The flask was put under positive pressure using a balloon filled with N2, and then placed into a preheated 80 °C silicon oil bath. At the given time intervals (see Table S5), a small aliquot (ca. 25 µl) of the reaction solution was removed using a syringe, injected into an NMR tube, and constituted in CDCl3 (0.6 mL). The mass balance, selectivity, and amount of 4-bromopyridine, 10, and 11 was then    Figure S11. Reaction profile obtained for the model etherification reaction of 3-bromopyridine.
Result: Upon monitoring the reaction over time, we observed a buildup of 4-bromopyridine that is ultimately consumed by the end of the reaction. No other discernable intermediates were observed.

(d) Conversion of 3-iodopyridine to 4-and 3-bromopyridine with KBr additive
Purpose: A possible explanation for the positive effect of KBr on the yield and selectivity of the etherification reaction is addition of bromide to a 3,4-pyridyne intermediate. We sought to investigate if there is a yield of 3-or 4-bromopyridine when 3-iodopyridine is stirred under the basic reaction conditions in the presence of KBr.
Figure S12: 1 H NMR spectrum of the crude reaction solution of the base-catalyzed substitution of 3-iodopyridine with KBr; 17% yield of 3-bromopyridine (marked in red), 17% yield of 4bromopyridine (marked in blue), and 14% yield of pyridine (marked in green). Note: To support the identity that corresponds to each 1 H NMR signal above, we mixed authentic 3-bromopyridine, 4-bromopyridine, 3-iodopyridine, and 4-iodopyridine into 4 separate 1 H NMR samples of the crude solution. Only in the cases of 3-iodopyridine and 4-iodopyridine were new signals observed.

Supplementary Experiments and Notes:
To corroborate that 3,4-pyridyne is generated under the reaction conditions for 3-iodopyridine, we performed a trapping experiment with furan analogous to Section IVa. Additionally, we stirred 3-iodopyridine under the conditions above with exclusion of KOH; under these conditions we observed no conversion of 3-iodopyridine.
Procedure: An oven-dried 4 mL vial (ThermoFisher, C4015-1) was charged with a magnetic stir bar. Inside a N2 filled glovebox, the vial was charged with 3-iodopyridine (20.5 mg, 0. sealed with a PTFE-lined screw cap (ThermoFisher, C4015-1A), removed from the glovebox, and placed into a preheated 80 °C aluminum reaction block. The solution was stirred at 80 °C for 18 h, at which point the solution was removed from the aluminum reaction block and allowed to cool to rt. 1,3,5-Trimethoxybenzene internal standard (8.8 mg, 0.052 mmol) was then added to the solution, and the yield of 13 was determined by 1 H NMR spectroscopy (400 MHz, CDCl3, 24% yield). The 1 H NMR of 13 is consistent with that in Section IVa.
(d) Observation of the isomerization of 3-bromopyridine substrates from Table 1 Purpose: To demonstrate that 3-bromopyridines from Table 1 isomerize to 4-bromopyridines under the optimal reaction conditions, we subjected several substrates to the basic conditions in the absence of alcohol nucleophile.
Procedure: An oven-dried 4 mL vial (ThermoFisher, C4015-1) was charged with a magnetic stir bar. Inside a N2 filled glovebox, the vial was charged with the appropriate 3-or 5-bromopyridine substrate (0.1 mmol, 1.0 equiv), DMAc (0.6 mL, 0.17 M), KBr (6.0 mg, 0.05 mmol, 0.5 equiv), 18-crown-6 (1.0-1.5 equiv), and KOH (5.6 mg, 0.1 mmol, 0.1 equiv) in successive order. The vial was sealed with a PTFE lined screw cap (ThermoFisher, C4015-1A), removed from the glovebox, and placed into a preheated 80 °C aluminum reaction block. The reaction solutions were stirred at 80 °C for 4 h. The reaction solutions were removed from the aluminum reaction block and allowed to cool to rt. 1,3,5-Trimethoxybenzene internal standard was then measured into each solution, and the yield of the starting material and the corresponding 4-bromopyridine was determined via analysis of the crude solutions by 1 H NMR spectroscopy (400 MHz, CDCl3). Note: the structure of the corresponding 4-bromopyridine was confirmed by 1 H NMR analysis of authentic samples of the appropriate 4-bromopyridine or by direct isolation and 1 H NMR characterization of the 4bromopyridine from the reaction solution. An overlay of the 1 H NMR spectra of the authentic 3bromopyridine and 4-bromopyridine isomer for each substrate is provided above the 1 H NMR spectrum of each crude reaction solution. the reaction was run according to the general procedure using 1.5 equiv of KOH (8.4 mg, 0.15 mmol) and 1.5 equiv of 18-crown-6 (39.6 mg, 0.15 mmol); 12.7 mg (0.076 mmol) of 1,3,5-trimethoxybenzene was added as internal standard: 33% 3-bromo-2-(cyclopentyloxy)pyridine and 14% 4-bromo-2-(cyclopentyloxy)pyridine.  1 H NMR spectrum of the crude reaction solution of 3-bromo-5-methylpyridine base-catalyzed isomerization with a small quantity of authentic 4-bromo-3-methylpyridine spiked into it. We note that the spectrum of 4-bromo-3-methylpyridine from (a) above does not overlay onto the 1 H NMR spectrum of the crude solution. When authentic 4-bromo-3-methylpyridine was spiked into the 1 H NMR sample of the crude solution, we observed an increase in the signals we labeled as corresponding to the 4-bromo-3-methylpyridine isomer. This is shown in spectrum (c).

(e) Control test for the decomposition of 3-((2-ethylhexyl)oxy)pyridine (11) under reaction conditions
Purpose: To determine if the 3-alkoxypyridines are stable under the reaction conditions in Table  1.
Procedure: An oven-dried 4 mL vial (ThermoFisher, C4015-1) was charged with a magnetic stir bar. Inside a N2 filled glovebox, the vial was charged with 3- ( Figure S17: 1 H NMR spectrum for the subjection of 11 to the standard reaction conditions. 13.9 mg (0.083 mmol) of 1,3,5-trimethoxybenzene was added to reaction solution as internal standard. 100% of 11 can be accounted for in the 1 H NMR spectrum with no observable decomposition products.

V. General Procedure for the 4-Selective Substitution of 3/5-Bromopyridines
General procedure for 1 mmol scale reactions: KOH, KBr, and 18-crown-6 were stored in a N2 filled glovebox at rt and used immediately upon removal from the glovebox. Outside of the glovebox, an oven-dried 25 or 50 mL round bottom flask was charged with a magnetic stir bar, 18-crown-6 (925.1 mg, 3.5 mmol, 3.5 equiv), KBr (59.5 mg, 0.5 mmol, 0.5 equiv), and KOH (168.3 mg, 3.0 mmol, 3.0 equiv). The flask was then sealed with a Fisherbrand® red septum stopper (Cat. No. FB57875) and the edges of the septum were then sealed with Parafilm®. The flask was evacuated and backfilled three times with N2 and left under positive pressure using either a N2 balloon or a Schlenk line. DMAc (4.0 mL) was then added via syringe under N2 and the solution was stirred at rt (Note: there is usually some insoluble solid that remains in the bottom of the flask). The 3/5-bromopyridine substrate (1.0-1.5 mmol, 1.0-1.5 equiv) and the alcohol substrate (1.0 mmol, 1.0 equiv) were measured into a separate vessel and constituted in DMAc (2.0 mL). This substrate solution was then sparged with N2 for 3 min and then transferred into the reaction flask via a syringe under N2. The reaction solution was then placed into a preheated 80 °C silicon oil bath and stirred for 15 h. The solution was then allowed to cool to rt, and 1,3,5trimethoxybenzene internal standard was measured into the solution. 1 H NMR spectroscopy of the crude reaction solution was used to determine the selectivity of the reaction (see discussion below). The solution was then poured into a 250 mL separatory funnel containing water (60 mL). The product was extracted with ethyl acetate (3 x 40 mL) and the organic layers were dried over Na2SO4. The Na2SO4 was filtered off and the organic layer was concentrated in vacuo. All substrates were purified by silica gel chromatography using the given conditions. Note: in some cases, residual DMAc co-eluted with the desired product; this can be removed by extended drying in vacuo. The results below are reported in the format: (mass of isolated product, percent isolated yield, 4:3 substitution selectivity of crude reaction mixture).
Determining the selectivity of the reaction: The selectivity of each reaction was determined by analyzing the crude reaction solutions by 1 H NMR spectroscopy and determining the yield of both 4-and 3-isomeric products. If the identity of the 3-isomeric product was ambiguous in the 1 H NMR spectrum, an authentic sample was synthesized, or the 3-isomeric product was purified from the reaction mixture to ensure the correct peaks were used for the analysis.

3-bromo-2-(cyclopentyloxy)pyridine:
NaH (60% dispersion, 800 mg, 20.0 mmol, 2.0 equiv) was weighed into an oven-dried 100 mL round bottom flask. The flask was sealed with a septum stopper (VWR, Cat. No. 89097-544). The flask was evacuated and backfilled three times with N2 and then left under positive pressure with a N2 balloon. The flask was cooled to 0 °C, and then DMAc (20 mL) was added. Cyclopentanol (1.29 g, 15.0 mmol, 1.5 equiv) was then added dropwise to the slurry. The solution was allowed to stir at 0 °C for 10 min, then 3-bromo-2-chloropyridine (1.92g, 10.0 mmol, 1.0 equiv) constituted in DMAc (20 mL) was added dropwise. Upon completion of the addition, the solution was allowed to warm to rt and was then placed into a 40 °C preheated silicon oil bath. The solution was stirred at 40 °C for 4 h. The solution was then allowed to cool to rt and was quenched dropwise with H2O (ca. 1.0 mL). The mixture was then poured into H2O (100 mL) in a separatory funnel and the product was extracted with EtOAc (3 x 80 mL). The organic layers were dried over Na2SO4. The Na2SO4 was filtered off and the organic layer was concentrated in vacuo. Purification of the resultant residue by silica gel chromatography (5% EtOAc/hexanes) yielded the title compound as a clear oil (2.23   No. 89097-544) and removed from the glovebox. The system was put under positive pressure with a N2 balloon, then H2O (7 mL) was then added via syringe. The flask was then placed into a preheated 80 °C silicon oil bath and stirred for 16 h. The solution was then allowed to cool to rt and was poured into a separatory funnel containing H2O (70 mL). The product was extracted with EtOAc (3 x 60 mL). The organic layers were dried over Na2SO4. The Na2SO4 was filtered out and the organic layer was concentrated in vacuo.

(b) Preparation of 3-bromopyridines where corresponding 4-halopyridine is less available
Note on the commercial availability of 3-bromopyridines vs. 4-halopyridines: For the substrates below, the 3-bromopyridine derivative is more readily available and/or cheaper than a corresponding 4-halogenated derivative. For these substrates, a comparison of the cheapest price for 1 gram of both the 3-bromopyridine and a 4-halopyridine (as reported in the online www.emolecules.com database accessed March 2, 2020) starting material is provided in Figure  S26 below. The obtained estimated times of delivery are also included. The comparison is meant to provide a general idea of the relative cost and availability of these substrates compared to their 4-halogenated or 4-hydroxylated derivatives.
An oven-dried 25 mL round bottom flask was charged with a magnetic stir bar, tert-butyl ((5bromopyridin-3-yl)methyl) (213.8 mg, 0.75 mmol, 1.0 equiv) and anhydrous THF (4.0 mL, 0.19 M). The solution was cooled to 0 °C and then NaH (60% dispersion, 36.0 mg, 0.9 mmol, 1.2 equiv) and iodomethane (51 µl, 0.83 mmol, 1.1 equiv) were added. The reaction solution was warmed to rt and stirred for 4 h. The solution was then slowly quenched with H2O (ca. 1 mL) and then transferred to a separatory funnel containing H2O (30 mL). The product was extracted with EtOAc (3 x 30 mL) and the organic layers were pooled and dried over Na2SO4. The Na2SO4 was filtered out and the organic layer was concentrated in vacuo. Silica gel chromatography (30% EtOAc/hexanes) yielded the title compound as an off-white solid (166.2 mg, 0.55 mmol, 77% step yield, 55% overall yield).