Balancing Reactivity, Regioselectivity, and Product Stability in Ir-Catalyzed Ortho-C–H Borylations of Anilines by Modulating the Diboron Partner

Ir-catalyzed arene C–H borylations (CHB) of anilines can be highly ortho selective by using a small B2eg2 (eg = ethane-1,2-diol) as the borylating reagent. Unfortunately, the products are prone to decomposition, and transesterification with pinacol is required prior to isolation. This work offers a solution by adjusting the size of the diboron reagent. Based on our evaluation, we conclude that B2bg2 (bg = butane-1,2-diol) achieves an optimal balance between CHB regioselectivity and stability for the borylated products.

S elective replacement of ubiquitous C−H bonds with Bpin opens the door to diverse compound modifications.For example, Suzuki−Miyaura cross-couplings enable the substitution of Bpin with alkyl and aryl groups, while Chan−Lam couplings facilitate the exchange of C−Bpin groups with C−O or C−N functionalities. 1 Iridium-catalyzed C−H borylation (CHB) stands as a reliable and established method for introducing Bpin groups, with regioselectivity highly governed by steric factors. 2−5 CHB of 1,3-disubstituted arenes exhibits remarkable selectivity for the C5-borylated products, regardless of the electronic nature of the substituents present.However, it is possible to switch the CHB regioselectivity to the less sterically accessible ortho position by modifying the ligand or employing different directing groups. 6−9 Despite these successes, methods that bypass the need for preinstalled directing groups would be highly advantageous.
Previously, in collaboration with the Singleton group, we discovered the preference of N-(Boc)-anilines to yield the ortho-borylated product under standard CHB conditions. 10he unexpected selectivity was attributed to an N−H•••O hydrogen bonding interaction between the hydrogen of the aniline and one of the Bpin ligands on the iridium catalyst.One year later, we reported a method for the ortho-borylation of anilines without a preinstallation of a directing group by using HBpin as the boron partner (Figure 1, Method A). 11 The proposed mechanism suggests the initial formation of ArNH− Bpin, succeeded by ortho-C−H borylation controlled by a hydrogen bond interaction (N−H•••O) akin to that suggested for N-(Boc)-anilines.Unfortunately, this method worked well exclusively on substrates with substituents para to the NH 2 group, and selectivities were considerably diminished without that substitution.
In 2017, our research revealed that phenols have a propensity to form ortho-borylated products, albeit with low selectivity in the presence of other sterically available C−H bonds.The formation of the ortho-borylated product was attributed to an electrostatic interaction between the partial negatively charged OBpin group formed in situ and the partial positively charged bipyridine ligand.Remarkably, the utilization of a small diboron partner B 2 eg 2 led to high regioselectivity for the ortho-borylation without detectable formation of the meta and para borylated products. 12Inspired by this work, we and the Chattopadhyay group showed that using B 2 eg 2 as the boron reagent during the borylation of anilines also gives high ortho regioselectivity without the necessity of a para substituent (Figure 1, Method B). 13 This enhanced selectivity is a result of the reduced steric hindrance of the Beg group, which provides stability to the transition state.However, the (2-Beg)ArNH 2 product must be converted to the more stable (2-Bpin)ArNH 2 , by treatment with pinacol prior to purification.Eliminating the need for the final transesterification step while retaining the regioselectivity of the reaction mixture would be highly desirable and advantageous.Recently, the Yan group discovered that employing mesoionic carbene-Ir catalysts enables high regioselectivities in the ortho CHB of anilines with B 2 pin 2 . 14Traditionally, the focus in achieving high selectivities in CHB reactions has centered on extensive ligand screening, while the influence of the diboron reagent employed has been a less-explored facet. 12,13,15,16e proposed that using boronic partners with larger substituents than B 2 eg 2 could lead to more stable orthoborylated anilines, possibly enabling direct isolation of the product. 17However, there is a risk of reducing the regioselectivity of ortho CHB in the process.Thus, our objective was to strike a balance between maintaining high regioselectivity and achieving increased stability of the borylated product by careful optimization of the diboron partner.
A diversity of diboron partners can be imagined with a range of sizes between those of B 2 pin 2 and B 2 eg 2 .We began this investigation with the most straightforward choice, B 2 pg 2 (pg = propane-1,2-diol), which presents a single methyl group in each glycolate group of B 2 eg 2 and for which there are examples where arenes bearing a Bpg group afford higher yields than the corresponding Bpin bearing substrates in Suzuki−Miyaura cross-couplings. 18We were pleased when the initial CHBs (Scheme 1) on aniline with B 2 pg 2 afforded the ortho product, albeit with slightly lower conversions when compared to reactions with B 2 eg 2 . 13 improve this result, we first decided to explore different amine additives.In earlier studies, 12,13 the presence of triethyl amine improved the ortho selectivity in the CHB of phenols and anilines with B 2 eg 2 .It was proposed that the H−Beg side product formed a stabilizing complex with the amine, 19,20 which in turn retarded undesirable reactions.Thus, to assess the effect of the amine, diisopropylethylamine (Hunig base), DBU, and DABCO were tested as potential alternatives to triethylamine using B 2 pg 2 the boron source on the ortho-CHB of aniline.As seen in Scheme 1, a lower reactivity was observed with these amines.Thinking that counter to our original idea the poor results might be due to the HBpg•amine complex being destabilized by sterics, we proceeded to test diethylmethyl amine and ethyldimethyl amine.Despite the improved conversions, triethylamine remained to be the most effective, yielding the highest conversion and selectively at producing the ortho-monoborylated product.
The impact of triethylamine stoichiometry on the orthoborylation of anilines was evaluated next, and the results are depicted in Figure 2. Conversions leading to the ortho monoborylated aniline are represented by the blue bars, while the orange bars illustrate the diborylated product.Unexpectedly, lowering the amount of Et 3 N improved conversions with 0.25 equiv being optimal.Though the reasons for improved conversions are unclear, perhaps it is the excess equivalents of base break the N−B bond of the intermediate PhN(H)Bpg causing loss of reactivity.Using less than 0.25 equiv of Et 3 N was met with negative results, but we note that the CHB proceeded when no amine was present.
After the optimized equivalents of the amine were determined, our focus shifted to evaluating various diboron partners to identify the optimal balance between ortho Before moving beyond B 2 pg 2 , we conducted experiments to compare the selectivity induced by each stereoisomer of B 2 pg 2 with that of the mixture of stereoisomers (Scheme 2).Pure (S,S)-B 2 pg 2 was synthesized from (S)-propylene glycol and subjected to CHB conditions.Interestingly, the reactivity and regioselectivity with (S,S)-B 2 pg 2 were comparable to those seen with the stereoisomer mixture.This suggests that all diastereomers present in the B 2 pg 2 mixture react similarly during ortho-CHB of aniline.Unfortunately, the use of B 2 pg 2 did not solve the stability issues seen with B 2 eg 2 as deborylation occurred during purification of the crude reaction products.
The trouble encountered during the isolation of ArBpg products heightened the desire to test additional boron partners.Therefore, three larger diboron partners, B 2 bg 2 with its ethyl pendant group, the gem-dimethyl bearing B 2 mpg 2 , and B 2 ((2R,3R)bg) 2 , were synthesized from the corresponding glycol and B 2 (OH) 4 .These diboron reagents were used in the CHB of unsubstituted aniline with 0.0, 0.25, and 2.0 equiv of triethylamine (Figure 3).As observed with B 2 pg 2 , the highest reactivity in each case was achieved with 0.25 equiv of the base.The high regioselectivity for ortho-CHB of aniline remained with the diboron partners having only one pendant alkyl group (B 2 pg 2 and B 2 bg 2 ), but it was reduced when additional methyls were introduced (B 2 mpg 2 and B 2 ((2R,3R)bg) 2 ).
Whereas ArBeg and ArBpg decomposed, ArBbg and ArBmpg survived product purification by silica gel chromatography.As stated previously, B 2 bg 2 exhibited higher regioselectivity for the ortho-borylated product compared to B 2 mpg 2 .As a result, B 2 bg 2 exhibits the best balance of regioselectivity, stability, and reactivity.
Gratifyingly, the high selectivity induced by B 2 bg 2 and the stability conferred by the Bbg group could be extended to other substituted anilines (Scheme 3).Halide (Cl, Br, I) substituents at the para position were tolerated to make anilines 4−6 with good conversions, albeit moderate yields were obtained after isolation.Notably, minor amounts of the 2,6-diborylated byproducts were observed during the synthesis of 4−6.Anilines containing EWG and EDG groups like trifluoromethyl, chloro, methyl, and methoxy at the meta position had no significant adverse effect and yielded 7−10 successfully.In the case of 3-fluoroaniline, CHB was observed on both ortho positions, obtaining a mixture of the 2-and 6borylated aniline 11 in an equal ratio.Small quantities of 2,6diborylated-3-fluoroaniline were detected, as well during the synthesis of 11.CHB next to a small substituent as fluorine is not surprising and is commonly observed in iridium-catalyzed borylations. 21,22Notably, perfect ortho-CHB regioselectivity was observed for compound 12 in the presence of sterically available C(sp 2 )−H bonds on the phenyl substituent at the meta position.Unfortunately, the reactivity was attenuated in the presence of ortho substituents on the aniline, leading to the isolation of 13 in a low yield.Yan's group reported a similar limitation in their approach where ortho-substituted anilines did not yield to any product. 14Furthermore, attempts to borylate 2,5-substituted anilines did not afford 6-borylated products in any appreciable yield even under forcing conditions (see Supporting Information for details).Notably, neutral alumina was used for the isolation of compoundss 10 and 11, as deborylation occurred when attempting isolation through silica column chromatography.Overall, this method eliminates the previously required transesterification step with pinacol and is applicable to various substituted anilines.
Upon reconsideration of B 2 pg 2 , we were intrigued by a previous study that demonstrated the slower hydrolysis of ortho-borylated acetamide containing a Beg group compared to the meta or para borylated acetamides. 23We asked if the acetamide of 2.1 would impart a similar stability on the Bpg group by blocking any potential side reaction at boron.To test this hypothesis, we synthesized amide 2.3 (Scheme 4), which was found to be a stable crystalline solid even after 1 year, as evidenced by 1 H NMR analysis.The observed 11 B NMR chemical shift of 10.3 ppm for the C−Bgly group illustrates notable shielding compared to the typical range of 25−30 ppm for this type of boron.We interpret these data to suggest coordination of the boron atom with the Lewis basic acetamide.
To summarize, this report shows the high selectivities and other practical benefits that can be achieved by employing diboron reagents not commonly screened during the develop-ment of CHB reactions.The use of B 2 bg 2 as the diboron partner enables ortho-CHB of anilines to proceed with the high regioselectivity observed with B 2 eg 2 and where the products can be isolated without the need for a transesterification step.Diboron partners that possess a single pendant alkyl group in the glycolate backbone, such as B 2 pg 2 and B 2 bg 2 , demonstrate excellent regioselectivity in ortho-CHB reactions of aniline.However, the bulkier boron partners, such as B 2 mpg 2 and B 2 (2R,3R)bg 2 , negatively impact the regioselectivity.Independent of the boron source, reactions run with 0.25 equiv of triethyl amine gave the best conversions.Deviating from this amount, by using either higher or lower amounts of base, proved to have a negative impact on the formation of ortho-borylated aniline.When subjected to silica gel chromatography ArBeg and ArBpg decompose, but ArBbg and ArBmpg survive.It is possible for undesired reactions to take place during the chromatography, where nucleophilic attack on the boron can occur.Specifically, for the product arising from the ortho-borylation of acetamide with Bpg, a putative intramolecular Lewis acid−base interaction aids in stabilizing the molecule.