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. Author manuscript; available in PMC: 2020 Dec 15.
Published in final edited form as: Nat Chem. 2020 Jun 15;12(8):725–731. doi: 10.1038/s41557-020-0470-z

A site-selective amination catalyst discriminates between nearly identical C–H bonds of unsymmetrical disubstituted alkenes

Honghui Lei 1, Tomislav Rovis 1
PMCID: PMC7428077  NIHMSID: NIHMS1586796  PMID: 32541949

Abstract

C–H activation reactions enable chemists to unveil new retrosynthetic disconnections and streamline conventional synthetic approaches. A longstanding challenge in C–H activation is the inability to distinguish electronically and sterically similar C–H bonds. Although numerous synergistic combinations of transition-metal complexes and chelating directing groups have been utilized to distinguish C–H bonds, undirected regioselective C–H functionalization strategies remain elusive. Herein, we report a regioselective C–H activation/amination reaction of various unsymmetrical dialkyl-substituted alkenes. The regioselectivity of C–H activation is correlated to the electronic properties of allylic C–H bonds indicated by the corresponding 1JCH coupling constants. A linear relationship between the difference of 1JCH coupling constants of the two competing allylic C–H bonds (Δ1JCH) and the C–H activation barriers (ΔΔG‡) has also been determined.

The development of synthetic strategies to diversify molecular frameworks through site-selective functionalization of ubiquitous C–H bonds has been an overarching goal in synthetic chemistry1,2,3,4 However, C–H bonds with nearly identical chemical environments give rise to an enormous challenge for achieving site-selectivity (Fig. 1a). The inherently difficult discrimination of these C–H bonds has been achieved by the synergistic combination of transition-metal complexes and chelating directing groups5,6,7,8, which exploits the differences in conformational energies of the in-situ generated metallacycles in the transition state, so that a particular C–H bond is favored. However, its synthetic applications are limited to substrates with preinstalled directing groups, which mandate additional synthetic steps for removal or further manipulation. A more direct and versatile approach may involve a catalyst system that recognizes the subtle differences in C–H bond strengths, ultimately enabling a site-selective C–H bond activation9,10,11. Electronic effects have been utilized as a powerful tool for the site-selective functionalization of arenes12,13,14. Nevertheless, the application of electronic factors in a broader context of C(sp3)–H functionalizations is extremely challenging as the inductive effect gets weakened significantly through saturated bonds15,16,17.

Figure 1. Site-selective allylic C–H amination.

Figure 1.

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a, Distinguishing electronically and sterically similar C–H bonds has been a longstanding challenge. b, Previous examples of intermolecular regioselective allylic C–H amination of alkenes possessing two sets of allylic protons. c, A summary of this work, illustrating successful regioselective C–H activation/amination for 1,1- and trans-1,2-disubstituted alkenes as well as a linear correlation between Δ1JCH coupling constants of the two competing C–H bonds and the difference of C–H activation barriers (ΔΔG‡) [Ir], iridium complex; [N], nitrogen source.

Selective allylic C–H functionalizations provide a platform for the construction of valuable building blocks from chemical feedstocks18,19,20,21,22. Currently, intermolecular allylic C–H amination reactions are mostly limited to alkenes with only one distinct set of allylic protons23,24,25,26,27,28,29, due to the lack of methods to distinguish similar allylic positions. Two important exceptions are Dauban’s work30,31 of Rh(II)-catalyzed outer-sphere nitrene insertion preferring methylene over methyl C–H bonds and Tambar’s two-step protocol32 where an asymmetric ene-type transformation of cis-olefins was demonstrated to distinguish between two allylic positions (Fig. 1b). In complementary work, Katsuki has described a Ru-salen catalyst capable of discriminating benzylic and allylic positions on the basis of size, with the consequence that it aminates only methyl and ethyl groups33. However, selective C–H activation/amination of alkenes possessing two similar sets of allylic protons has yet to be disclosed, presumably due to the following two issues: 1) two similar allylic C–H bonds are competing for C–H activation; and 2) two marginally distinguishable reactive sites of the resulting metal-allyl species could potentially lead to a mixture of four regioisomers, especially for substrates containing trans-1,2-disubstituted alkenes (Fig. 1c). Herein, we report a regioselective C–H activation/amination reaction of unsymmetrical 1,1- and trans-1,2-disubstituted alkenes. We further demonstrate that the exquisite selectivity is electronically controlled through the inherent inductive effect of a remote electron-withdrawing group. We propose that C–H activation selectivity can be predicted using 1JCH coupling constants at the allylic positions, based on a linear relationship between the difference of 1JCH coupling constants (Δ1JCH) and C–H activation barriers (ΔΔG‡).

Results and discussion

1,1-disubstituted alkene 1a was selected as the model substrate to initiate our study. We postulated that the homoallylic trifluoromethyl group could electronically differentiate between potentially reactive β and δ allylic C–H bonds through the inductive effect. Following the selective C–H activation, the resultant π-allyl-metal species may undergo selective C–N bond formation at the internal position. At the outset, we first tested the reaction with [Cp*MCl2]2 (M = Co, Rh, Ir; Cp* = pentamethylcyclopentadienyl) as the precatalyst, silver tetrafluoroborate (AgBF4) as the additive, lithium acetate (LiOAc) as the base, and p-toluenesulfonyl azide (TsN3) as the nitrene precursor. Although no amination products were detected with either [Cp*CoCl2]2 or [Cp*RhCl2]2, we realized the formation of δ amination 2a as a major product with [Cp*IrCl2]2 in moderate yield. In line with our proposal, the reaction proceeds through the selective C–H activation of the distal δ C–H bond, followed by C–N bond formation at the internal position of the corresponding π-allyl-Ir species. After an extensive evaluation of the reaction conditions, the optimal conditions were achieved by making three crucial changes: 1) switching the ligand from Cp* to Cp™ (Cp™ = tetramethylcyclopentadienyl), which significantly improves the yield; 2) replacing lithium acetate with silver trifluoroacetate (AgTFA); 3) adding cesium carbonate (Cs2CO3) as a co-base (see Supplementary Section 4 for details). Control experiments further revealed that both [Cp™IrCl2]2 and AgBF4 are necessary components for the reaction. Moreover, [Cp™Ir(TFA)2] was also tested as a replacement for [Cp*IrCl2]2 and AgTFA, which leads to a comparable yield and regioselectivity, but no reactivity is observed in the absence of AgBF4.

Having established the optimal conditions, we investigated the scope of the reaction by examining a diverse array of unsymmetrical 1,1-dialkylsubstituted alkenes (Table 1). Various electron-withdrawing groups (EWG) are tolerated providing excellent yields and regioselectivities (2a–2e). Notably, when a suitably placed toluenesulfonate group (OTs) is present, a pyrrolidine ring is formed in situ from the corresponding amination product (2e). High selectivity is also observed with a weakly electron-withdrawing phenyl group, and the electron density of the arene affects the regioselectivity (2f–2h). With respect to the distance between the EWG and olefin, this method tolerates tethers ranging from one to four methylene units while maintaining good reactivity and regioselectivity (2i–2l). Surprisingly, a substrate bearing marginally different allylic C–H bonds, which are remotely influenced by OTs vs OTBDPS, reacts with measurable selectivity (2m). Moreover, the reaction is exquisitely selective for secondary C–H bonds over methyl groups under the standard conditions, and the regioselectivity increases as the EWG moves away from the reactive center (2n–2q). In terms of trisubstituted olefins, citronellyl acetate provides the allylic amine with migration of the double bond to the terminal position (2r). p-Nitrobenzene-sulfonyl azide can also be employed, which allows facile deprotection (2s). Besides sulfonyl azides, a variety of dioxazolones were utilized under slightly modified conditions. Various amides, possessing substitutions that include phenyl, cyclopropyl, α-fluoro, or α-amino groups, are effectively incorporated in the distal allylic position (2t–2x).

Table 1.

Scope of unsymmetrical 1,1-disubstituted alkenes and nitrene precursors

graphic file with name nihms-1586796-t0004.jpg
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Based on the success of selective C–H activation of 1,1-disubstituted alkenes, we envisioned that similar selectivity could also be achieved with unsymmetrical trans-1,2-disubstituted alkenes containing a remote electron-withdrawing group (EWG). However, the π-allyl-metal intermediates derived from C–H activation of 1,2-dialkylsubstituted alkenes bearing two similar internal positions have rarely been differentiated34. We speculated that the electronic difference between the two reactive sites, produced by the inductive effect, could also lead to regioselective nitrene insertion. To set the stage, we examined the Ir-catalyzed C–H activation/amination of trans-3-hexene, a symmetrical substrate that would lead to an unsymmetrical π-allyl-Ir intermediate. In the event, under standard reaction conditions, amination occurs unselectively to give two products (Fig. 2a). In contrast, reaction of substrate 3a bearing p-toluenesulfonate (OTs) as the EWG leads to a moderate selectivity favoring the more electron-rich side of the π-allyl-Ir intermediate, which results from C–H activation of the distal allylic C–H bond (Fig. 2b). Regioisomers derived from C–H activation of the proximal C–H bonds were not detected.

Figure 2. Study of regioselectivities in C–H amination of unsymmetrical trans-1,2-disubstituted alkenes.

Figure 2.

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a, Non-selective C–H amination of trans-3-hexene. b, Remote electronically controlled C–H activation and amination. c, Electronic and steric effects of Cp ligands with substrate 3a. d, Scope of unsymmetrical trans-1,2-disubstituted alkenes catalyzed by Ir-9. Unless otherwise noted, all reactions were conducted on a 0.1 mmol scale using alkene (1.0 equiv.), TsN3 (1.5 equiv.), [Ir-n] (15 mol% of monomer), AgBF4 (60 mol%), LiOAc (1.0 equiv.). Yields were determined after column chromatography. Yields* and r.r. values (β/α) were collected from 1H NMR spectrum of unpurified reaction mixutre with mesitylene as the internal standard. a5 mol% [Cp™IrCl2]2 (Ir-6) was used. bReaction was conducted at 50 °C.

The electronic effect of the Cp ligand35,36 was investigated by comparing catalysts Ir-2, Ir-3, and Ir-4, bearing electronically variant aryl rings on the Cp core. These catalysts all lead to inferior regioselectivities, suggesting that the electron density of the Cp ligand has little effect on the regioselectivity while the steric properties seem to have a profound influence (Fig. 2c). Indeed, when the Cp ligand contains fewer methyl groups, the regioselectivity is dramatically improved (Ir-6, Ir-7, and Ir-8). Additionally, by comparing the outcomes of Ir-5 and Ir-8, both mono-alkyl Cp derivatives, the same steric effect on the regioselectivity is observed. Eventually, an electron-donating hyperconjugative interaction was found to improve the productive reactivity, which delivers Ir-9 as the optimal catalyst.

The scope of trans-1,2-disubstituted alkenes was then explored (Fig. 2d). Substrate 3b bearing an n-butyl group is tolerated, indicating that the regioselectivity is not related to the steric bias between two sides of the π-allyl-Ir intermediate. Other electron-withdrawing groups may be used, including one with chloride substitution (4c–4e). Allylic substitutions that are known to deactivate the alkene also perform well (4f, 4g). Even those substrates with conjugated carbonyl groups are reactive at elevated temperature, leading to the desired amination products (4h, 4i). Additionally, β-alkyl styrene 3j was found to give the conjugated amination product 4j selectively, which is complementary to Blakey’s report using Cp*Rh-catalyst and tert-butyldioxazolone29.

To gain further insight into the origin of the observed regioselectivities, we conducted several studies probing the mechanism and the impact of substrate electronics. Several experiments proved particularly enlightening. On the basis of a deuterium labeling experiments, we conclude that the allylic C–H activation step is irreversible for both alkene classes (see Supplementary Section 7 for details). 1JCH coupling constants37, which are closely correlated with the s character of the C–H bonding orbital and also influenced by the nature of substituents, were utilized to understand the electronic properties of allylic C–H bonds. Inspired by a previous study where a positive linear correlation between 1JCH and Hammett σ constants was unveiled38, we propose that the electronic difference between two allylic C–H bonds could be indicated by the corresponding difference of 1JCH (Δ1JCH). It’s worth noting that most allylic C–H bonds of the substrates investigated in Figure 2 have very similar steric environment and are electronically influenced by a remote (non-α-substitution) EWG, which excludes the influence of angular distortion effects and α-substitution effects. Therefore, the differences of 1JCH between two allylic positions are mainly induced by the substituent inductive effect. Comparing the data of substrates 1a, 1j, and 1y, we noticed that the Δ1JCH coupling constant between two sides of the olefin decreases as the CF3 group becomes more distal to the double bond, in line with our hypothesis (Fig. 3a). Additionally, as the electron density of the aromatic ring two methylenes away from the alkene is varied, the Δ1JCH between two sides of the olefin also varies accordingly. Moreover, we found that the electronic differences indicated by Δ1JCH likely correlates to the regioselectivities. Indeed, we graphed the results for twelve substrates involving a methylene vs methylene competition chosen from Table 1, and found a linear relationship between Δ1JCH coupling constant and the difference of C–H activation barriers (ΔΔG‡) (Fig. 3b). Namely, the regioselectivity of C–H activation could be quantitatively predicted by calculating the difference of 1JCH coupling constants of two allylic C–H bonds (Δ1JCH).

Figure 3. Study of the origin of regioselectivities.

Figure 3.

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a, Inductive effect induced changes in 1JCH coupling constants and regioselectivities. b, The analysis of twelve substrates involving a methylene vs methylene competition and identification of a linear relationship between Δ1JCH coupling constants of the two competing C–H bonds and the difference of C–H activation barriers (ΔΔG‡). Error bars indicate a ±0.1 Hz error in the Δ1JCH and ±0.058 kcal/mol in the ΔΔG‡.

In all these cases, C–H abstraction occurs selectively at the carbon bearing the lower 1JCH coupling which corresponds to greater p-character at that position, and a weaker C–H bond. Given that C–H activation is irreversible as evidence by the isotope labelling experiment, this effect is almost certainly kinetic in nature. It is also worth noting that an outlier 1c was found probably due to the interfering chelation to the Ir by Lewis basic carbonyl, which suggests potential limitation of the correlation in some special cases. In general, we believe that the electronic difference between allylic C–H bonds, which is introduced by the inductive effect, is the primary factor contributing to regioselectivity.

Besides the selectivities between two sets of allylic C–H bonds or two positions of the π-allyl-Ir intermediates, intermolecular competition reactions were studied (Table 2). For example, a competition reaction between 1:1 ratio of substrates 1c and 1i-2 produces 2c as the major product, which suggests the preference of the allylic C–H bonds with the smallest 1JCH coupling constant among total four sets of allylic protons. Moreover, β-alkyl styrene 3j and 1,2-trans-alkene 3a are more reactive than α,β-unsaturated ester 3i because of the electronic deactivation by the conjugated carbonyl group (1JCHa < 1JCHb). Additionally, accessibility of the alkene plays an important role in the intermolecular competition reactions. For instance, 1-decene undergoes allylic amination completely selectively over either 1,1- or 1,2-disubstituted alkenes, regardless of the electronic properties of the allylic C–H bonds.

Table 2.

Intermolecular competition reactions

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Conclusion

In summary, we have developed an intermolecular regioselective allylic C–H amination of unsymmetrical disubstituted alkenes. This method exploits subtle electronic differences induced by remote electron withdrawing groups to effect a selective C–H activation of allylic C–H bonds. The selectivity can be predicted based on the linear relationship between the Δ1JCH coupling constants of two competing C–H bonds and the difference of C–H activation barriers (ΔΔG‡). The key findings also include the successful differentiation of two internal positions of the π-allyl-Ir intermediates with the assistance of the novel monosubstituted Cp ligand. We further provide a rubric by which to understand C–H activation in more complex systems resulting from competition experiments. More broadly, we envision that this protocol could also benefit other allylic C–H functionalizations of unsymmetrical internal olefins.

Methods

General procedure for 1,1-disubstituted alkenes with TsN3

To an oven-dried screw-capped vial with a magnetic stir bar was sequentially added alkene (0.1 mmol, 1.0 equiv.), tosyl azide (23 μl, 1.5 equiv.), [Cp™IrCl2]2 (Ir-6) (3.9 mg, 5.0 mol%), cesium carbonate (16.3 mg, 50 mol%), silver trifluoroacetate (5.5 mg, 25 mol%), silver tetrafluoroborate (11.7 mg, 60 mol%), and 1,2-dichloroethane (200 μl, 0.5 M). The cap was screwed on, and the reaction was stirred at 35 °C for 20 hours. The reaction mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The crude mixture was analyzed via 1H NMR spectroscopy with mesitylene (12.0 mg, 0.1 mmol) as an internal standard. The sample was further purified by column chromatography to give the desired amination product.

General procedure for 1,1-disubstituted alkenes with dioxazolones

To an oven-dried screw-capped vial with a magnetic stir bar was sequentially added alkene (0.1 mmol, 1.0 equiv.), [Cp™IrCl2]2 (Ir-6) (3.9 mg, 5.0 mol%), cesium carbonate (16.3 mg, 50 mol%), silver trifluoroacetate (5.5 mg, 25 mol%), and silver hexafluoroantimonate (20.6 mg, 60 mol%). In a separated vial, dioxazolone (1.5 equiv.) was dissolved in 1,2-dichloroethane (200 μl), which was then transferred to the first vail. The cap was screwed on, and the reaction was stirred at 35 °C for 20 hours. The reaction mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The crude mixture was analyzed via 1H NMR spectroscopy with mesitylene (12.0 mg, 0.1 mmol) as an internal standard. The sample was further purified by column chromatography to give the desired amination product.

General procedure for 1,2-disubstituted alkenes

To an oven-dried screw-capped vial with a magnetic stir bar was sequentially added Ir-9 (9.0 mg, 15 mol% of monomer), lithium acetate (6.6 mg, 1.0 equiv.), and silver tetrafluoroborate (11.7 mg, 60 mol%). In a separated vial alkene (0.1 mmol, 1.0 equiv.) and tosyl azide (23 μl, 1.5 equiv.) were dissolved in 1,2-dichloroethane (200 μl, 0.5 M), and the resultant solution was transferred to the first vial. The cap was screwed on, and the reaction was stirred at 35 °C for 40 hours. The reaction mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The crude mixture was analyzed via 1H NMR spectroscopy with mesitylene (12.0 mg, 0.1 mmol) as an internal standard. The sample was further purified by column chromatography to give the desired amination product.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information file.

Supplementary Material

1

Acknowledgements

We thank NIGMS (GM80442) for support. We thank John Decatur for assistance with determining 1JCH coupling constants. Correspondence and requests for materials should be directed to TR.

Footnotes

Competing interests

The authors declare no competing interests.

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Associated Data

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Supplementary Materials

1
NIHMS1586796-supplement-1.pdf (13.4MB, pdf)

Data Availability Statement

All data generated or analysed during this study are included in this published article and its supplementary information file.

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