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. 2020 Dec 9;1(1):13–22. doi: 10.1021/jacsau.0c00003

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines

Vinod G Landge †, Justin M Maxwell †, Pratibha Chand-Thakuri †, Mohit Kapoor †, Evan T Diemler †, Michael C Young †,*
PMCID: PMC8395680  PMID: 34467268

Abstract

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Palladium-catalyzed organometallic transformations of free amines are often unsuccessful due to side reactions, such as oxidation, that can occur. However, the ability to furnish the free amine products from these reactions is important for improving the utility and sustainability of these processes, especially for accessing their potential as medicinal and agrochemical agents. Notably, the 3,3-diarylallylamine motif is prevalent in a variety of biologically relevant structures, yet there are few catalytic approaches to their synthesis, and none involving the free amine. Herein, we describe a simple protocol for the arylation of cinnamylamines and the diarylation of terminal allylamines to generate a diverse group of 3,3-diarylallylamine products using a PdII precatalyst. Key features of the method are the ability to access relatively mild conditions that facilitate a broad substrate scope as well as direct diarylation of terminal allylamine substrates. In addition, several complex and therapeutically relevant molecules are included to demonstrate the utility of the transformation.

Keywords: amines, organometallics, carbon dioxide, catalysis, directing group, nanoparticles

Allylamines are an important class of compounds that have seen use as antifungals,1 antihistimines,2 antidepressants,3 and even as a treatment for male sexual dysfunction.4 They have also served as useful building blocks in complex molecule synthesis.5−9 As a result, there are numerous approaches to their synthesis.10−13 A powerful approach for the arylation of olefins is the Mizoroki–Heck (MH) reaction,14,15 though internal olefin substrates often require directing groups to achieve reasonable regioselectivity.16−19 In the case of allylamine substrates, protection of the amine has been required (Scheme 1a) to achieve these reactions,20−24 and the reactions are limited to a single arylation except in a few circumstances (Scheme 1b).25−27 We therefore decided that the direct arylation of unprotected or free cinnamylamines, and subsequently diarylation of terminal allylamines, would provide rapid access to new therapeutic targets which had previously been challenging to directly access via conventional methods. Moreover, by omitting the need for a protection and deprotection step, the transformations could be achieved with improved step and atom economy.

Scheme 1. Approaches for the Mizoroki–Heck Arylation of Allylamine Substrates.

Scheme 1

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One challenge in using free amines as substrates is that amines are typically poor directing groups on their own,28−31 unless steric bulk, substitution, or exogenous ligands are used to inhibit decomposition pathways or formation of unreactive intermediates.32,33 Recent advances have been made with the use of free amines as native directing groups, typically using acidic media to help protect the amine from oxidation.34−37 However, the most common workaround is to convert the amine in situ to a better, transient directing group.38−41 Based on this precedent, our group recently explored the use of CO2 as a transient directing group and simultaneously transient protecting group for C–H arylation of aliphatic42 and benzylic substrates.43 We wondered whether or not a similar approach could be applied to the functionalization of allylamine substrates (Scheme 1c) without the need for additional protection/deprotection steps.

There were numerous potential pitfalls to achieving regioselective MH arylation of unprotected allylamines or in situ-formed carbamates, the first being the possibility for allylic deamination.44 While allylamines are unlikely to undergo the intramolecular amination reactions of amino olefins with longer chains,45 conversion to the carbamate could lead to undesirable cyclization in the presence of a transition metal.46−48 This is especially true in the case of internal allylamines where there is no strong steric or electronic bias to drive regioselectivity, and so the coordination will be critical to achieve high regioselectivity. Because of the presence of a γ-C(sp2)–H bond, we reasoned that competitive C–H activation might also occur,49−51 which would give the undesired stereoisomer. Finally, the presence of both the free amine and carbamate might also erode the regioselectivity, as both sides of the olefin can potentially become functionalized.52,53

Gratifyingly, after the initial optimization, we were able to determine conditions for the arylation of cinnamylamine substrates (see Supporting Information for discussion) using Pd(OAc)2 as catalyst, AgTFA as a stoichiometric additive, aryl iodide as the arene source, acetic acid as solvent, 5 equiv of water, and 10 equiv of carbon dioxide in the form of dry ice.54 Notably, these reactions generally involve full conversion of the starting material with a number of different minor side products observed. The major side products observed by crude NMR and GC-MS were the oxidized imines (both of the starting material and the product) as well as the cinnamaldehydes from subsequent hydrolysis. Other minor side products include alkene hydration, alkene hydrogenation, as well as deamination/cyclization to give indane, indene, and indanone. The arylation product could also undergo degradation to give small amounts of benzophenone. Transition metal precatalysts other than Pd were unsuccessful for this transformation (see Supporting Information for details). It is also worth noting that isolable amounts of the β-arylation product were observed during the optimization as well as what we concluded must be α- and N-arylation in trace amounts by GC-MS, illustrating the competitive nature of other reaction pathways and the sensitivity of the desired process to changes in the reaction conditions.

While the reaction proceeded at a temperature as low as 70 °C in AcOH for the model substrate, the highest and most consistent yields across the scope of substrates were observed when the reaction was heated to 100 °C. Interestingly, the transformation could also be performed at as low as 40 °C when TFA was used as the solvent in conjunction with AgOAc as the silver additive, though 70 °C was required for some substrates. Silver is often invoked in Pd-catalyzed arylation reactions as an iodide scavenger; however, using the alternative iodide scavenger Me4NCl55 was not effective, suggesting that silver plays a greater role such as activating the C–I bond (see Supporting Information for details on the effects of other additives, including bases and oxidants).

We compared the reaction with a variety of other potential amine-based directing groups and gratifyingly found that the best yield and selectivity was observed for the free amine under these conditions (see Supporting Information for details on reactions using other directing groups), obviating the extra steps needed to modify the substrates for the reaction. Much to our surprise, although we found that the addition of CO2 was important for reproducible results, the control reactions gave yields as high as 40% in its absence (though not consistently), suggesting that its role may be solely as a transient protecting group rather than as a directing group.56−59 This is corroborated by the observation that tertiary cinamylamines also give the desired products in lower yields, as a consequence of being unable to form the carbamate and therefore being prone to faster decomposition,60 but still able to direct the reaction. Attempts to isolate potential transient carbamate–Pd complexes under the reaction conditions were not successful.

With these conditions in hand, we found that the scope was very broad for cinnamylamines bearing a variety of branched and linear alkyl substituents off of the nitrogen (Table 1, 1a–1h). Various carbocycle-containing examples also worked well in the reaction (1i–1m), including both N-cyclopropyl (1i) and N-methylcyclopropyl (1m) groups. The same could be said for both saturated (1n) and unsaturated (1o and 1p) heterocycle-containing substrates, though notably, these performed better under alternative conditions where trifluoroacetic acid was employed as solvent at a reduced temperature of 40 °C. These conditions were also preferable for arene containing substituents and allowed electronically neutral, rich, and poor arene-containing substrates to be used (1q–1w). Notably, the reaction could tolerate a pyridine heterocycle (1u) as well as SVI-containing substrates (1v and 1w) and was fully selective for functionalizing the γ-carbon of the allyl group despite the presence of competitive γ-C–H bonds on the side chains.

Table 1. Substrate Scope of the γ-Arylation of Cinnamylaminesa.

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a

All reactions were performed on 0.3 mmol scale with 2 equiv of aryl halide in 1 mL of solvent, in at least duplicate, and the average yield is reported.

b

Reactions performed at 40 °C in TFA (1 mL), AgOAc used instead of AgTFA.

c

Product obtained with concomitant esterification of the free hydroxyl group(s).

d

Product obtained with subsequent lactamization with a pendant ester group.

An electron deficient CF3-containing cinnamylamine was also able to participate in the reaction (1x). Free alcohols did not inhibit the reaction (1y and 1z) and were fortuitously protected as the acetate esters in the presence of the acetic acid solvent. We next explored amino acids and found that a valine-derivative worked well (1aa), while a glutamate ester gave the product with subsequent lactamization with the side chain after the arylation reaction (1ab). A derivative of the dipeptide aspartame was also used in the reaction, in this case giving subsequent lactamization at the C-terminus (1ac). The reaction also worked on terpene-containing examples (1ad and 1ae), including a bulky cedrene-containing cinnamylamine (1af). We could even use the reaction to selectively arylate medicinally relevant substrates such as cinnamylamine derivatives of colchicine (1ag), dehydroabiethylamine (1ah), and podophyllotoxin (1ai). Surprisingly, using β-substituted cinnamylamines failed to give the same products, giving alternative C–H arylation products depending on the substituents (see Supporting Information).

In addition to enjoying a broad substrate scope for amines, the reaction is also amenable to a wide array of aryl iodides (Table 2). Unlike the simple diphenyl substrates, installation of a distinct arene gave mixtures of both possible alkene isomers, though one isomer was favored in most cases. NOESY spectroscopy of the products could be used to confirm that the major isomer was the expected E-stereoisomer. The small amounts of the Z-stereoisomers formed might arise from a competitive C(sp2)–H activation but could just as likely come from Pd-mediated isomerization considering the poor steric discrimination between the aryl groups. To probe this, E-2a was resubjected to the reaction conditions; however, no isomerization was observed, which suggests that the Z-isomer comes from a competitive C–H activation pathway and not isomerization of the product.

Table 2. Substrate Scope of the Aryl Iodide for the γ-Arylation of Cinnamylaminesa.

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a

All reactions were performed on 0.3 mmol scale with 2 equiv of aryl halide in 1 mL of solvent, in at least duplicate, and the average yield was reported, with the E/Z ratio being determined from the crude mixture prior to purification.

b

Reactions were performed at 70 °C in TFA, and AgOAc was used instead of AgTFA (1 mL).

Using N-tert-butylcinnamylamine as a model substrate, we could readily install arenes containing electron deficient substituents (2a–2o), including ketones (2k and 2m), aldehydes (2l), and primary amides (2n) onto the cinnamylamine structure. Notably, the amide came from hydrolysis of an iodobenzonitrile starting material. The amide product 2n was successfully crystallized as its acetic acid salt and was subsequently analyzed by X-ray diffraction, which confirmed the stereochemistry of the product. Electron-rich groups are also tolerated (2p–2w) in the reaction, including an arylthioether that participates in the reaction without concomitant oxidation at the sulfur (2u). Furthermore, iodopyridine can be effectively coupled in good yield (2x), a common challenge in organometallic reactions with weak directing groups,61 though notably with an elevated reaction temperature used. While we have shown a number of examples on complex substrates, we wanted to demonstrate specific synthetic targets of medicinal relevance. By starting from N-methyl-4-bromocinnamylamine, we were able to add a 3-pyridyl group, providing access to the drug norzimelidine (2y) in two steps from commercially available starting materials. We also prepared the alkene-precursor to cinacalcet and demonstrated that the alkene could be readily arylated to access new derivatives (2z and 2aa) bearing the 3,3-diarylmoiety.

While the selective arylation of cinnamylamines was an exciting result, we wondered whether or not the utility of the method could be extended by beginning with terminal allylamines. Notably, most directing group approaches for this transformation only give the monoarylated products with high regioselectivity.20−27 However, if successful, our method could furnish symmetrical γ,γ-diarylallylamines in one pot, dramatically expediting the synthesis of this important class of drug molecules. After some additional optimization, we found that this transformation could also be achieved (Table 3) by using trifluoroacetic acid as solvent, albeit at an increased temperature compared to the reaction on the secondary cinnamylamines. Simple allylamine could be diarylated effectively (3a–3d). We considered that an appropriate diiodide might give rise to an interesting carbocycle, but found perhaps unsurprisingly that under the present conditions, intermolecular diarylation was faster than formation of a 14-membered ring, giving rise to the diarylated tetraester (3e). Secondary allylamines could also participate in the reaction (3f and 3g). When diallylamine was used as the substrate, the reaction could be performed four times simply by increasing the loading of aryl halide and silver (3h–3j). Notably, under the current conditions selective monoarylation was not achieved, and a nearly 1:1 mixture of mono- and diarylation occurred when a threefold excess of amine to aryl iodide was used.

Table 3. Substrate Scope of the γ-Diarylation of Terminal Allylaminesa.

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a

All reactions were performed on 0.3 mmol scale with 4 equiv of aryl halide in 1 mL of solvent, in at least duplicate, and the average yield was reported.

b

Reactions were performed using AgTFA (4 equiv) and organohalide (12 equiv).

The ability to access 3,3-diarylallylamines directly from terminal allylamines inspired us to consider whether or not two separate aryl groups could be introduced in one reaction. Despite the inability to selectively access the monoarylation products under the current conditions, we thought that there might be conditions that would give selective heterodiarylation. We first attempted a competition experiment by combining an electron-poor aryl iodide (4-iodobenzotrifluoride) with an electron-rich aryl iodide (4-(trifluoromethoxy)iodobenzene) under the reaction conditions to see if a selective reaction could be achieved. In this case, a mixture of monoarylation and diarylation products was observed with little selectivity between isomers. We next attempted the sequential addition of aryl iodides, which unfortunately also gave a complex mixture of products (see Supporting Information for details). Future efforts in our lab will focus on controlling the selective monoarylation, which is expected to facilitate a higher-yielding and more selective heterodiarylation protocol.

To ensure the utility of these reactions, we wanted to consider common issues. First, organometallic reactions often have difficulty being scaled-up. To test this, we performed a scale-up of 10× for the synthesis of 3c and found that the desired product could be isolated in 54% yield (Scheme 2a). Another problem with insertion-based mechanisms is that β-hydride elimination can often lead to decreased regioselectivity due to chain walking.62,63 However, we were delighted to find reasonable selectivity for the desired product when an aliphatic allylamine was used instead of a cinnamylamine substrate (Scheme 2b) with less than 10% of possible chain walking products observed in the crude NMR.

Scheme 2. Investigation of Scale-up and Chain Walking.

Scheme 2

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We next turned our attention to better understanding the mechanism. To ensure CO2 did not have a catalytic role, as our previous controls had suggested, we setup the reactions in a glovebox using freshly distilled amine and ampules of TFA-d or AcOD, ensuring no trace CO2 should be present in the reactions. In this case, we saw the same variability in the yields; however, the reaction was still able to occur. Even when the reactions were set up with distilled amine in a glovebox and subjected to three freeze–pump–thaw cycles, product could be observed as high as 40% yield. This again supported that the reaction was amine-directed, rather than by an in situ formed carbamate.

While initial rates were found to be highly variable under the standard reaction conditions, by conducting the reaction in an NMR tube using a decreased loading of palladium on simple allylamine, we were able to compare product formation for the reaction with and without added CO2 (Figure 1). It is worth mentioning that the reaction with CO2 was performed after purging (at approximately 1 atm of CO2), and so the effects are expected to be less pronounced than in our standard reaction conditions which operate under higher pressures. There are two notable takeaways from these experiments, the first being that the total recovery of amines decreases faster in the absence of CO2, consistent with carbon dioxide serving as a protecting group in the reaction. The other notable point is that the formation of both the mono- and subsequently the diarylation products are slower in the presence of CO2, consistent with it actually inhibiting the reaction. These experiments support the role of CO2 as a protecting group and not a directing group. While CO2 inhibits the arylation reaction by protecting the starting material and amine, the overall efficiency of the reaction is increased when CO2 is present.

Figure 1.

Figure 1

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NMR tube kinetics of allylamine arylation.

Having ruled out that CO2 was serving as a transient directing group, the directing effect must come from the amine. For an insertion mechanism using a mononuclear Pd catalyst, however, that would suggest that a relatively rare four-membered palladacycle would be forming, which we considered unlikely given the lack of either a strongly chelating directing group64 or bulky substrate.65,66 As previously mentioned, while trying to probe the role of CO2, we realized that we could not generate meaningful kinetics data using our cinnamylamine substrates: the initial rates were irreproducible. This suggested to us that the reaction may actually be occurring from some particulate instead of a mononuclear complex.

It is known that PdII can readily degrade to nanoparticles under harsh reaction conditions,67,68 and allylamine will reduce PdCl2 at room temperature with a half-life of ∼1 h in dichloromethane.69 To probe the potential for a nanoparticle or heterogeneous Pd catalyst being responsible for the directed MH reaction in our system, we first attempted Hg poisoning of the catalyst. In line with the recent observation that the mercury can exchange for C,N-palladacycles as well as prevent activation of the catalyst,70 we performed the reaction both by addition of Hg at the beginning of the reaction as well as after initiation. In both cases, no product was observed. We also performed a split test: the arylation of N-isopropyl cinnamylamine was allowed to proceed for 4 h, and then the reaction was filtered. Both the filtrate and filtered solids were separately used in a subsequent reaction; notably, the filtrant was not active, while the filtrate gave 18% NMR yield of product after further reaction. We also conducted the arylation of N-isopropyl cinnamylamine starting from solid-supported Pd nanoparticles71 and found 48% NMR yield of product with 86% overall conversion. This allows us to rationalize the regioselectivity, as the amine can coordinate to one metal center, while an adjacent metal center would be responsible for the insertion reaction, obviating the need to invoke a highly strained four-membered metallacycle.

Having established that the insertion reaction was most likely the result of a nanoparticle-catalyzed reaction, we next explored other details of the reaction. When the reactions were performed in deuterated media, no detectable H/D exchange was observed, ruling out the formation of any reversible steps in the mechanism (see Supporting Information for details). To provide more evidence that the E and Z products were the result of different mechanistic pathways, we screened a variety of ligands and found that in every case the E/Z selectivity was degraded (see Supporting Information for details).

Because we could not produce reproducible kinetics data on the cinnamylamine substrates, a kinetic isotope effect study of the initial rates seemed out of reach. However, while the rates could not be determined, we reasoned that if a γ-deuterated substrate were used, and if C–H activation was the rate-determining step for the C–H activation pathway, it would change the product distribution. We therefore performed the reaction under conditions that were found to give a 1:1 distribution of the E and Z isomers with both a proteo and deutero substrate (Scheme 3). The experiment showed a similar yield of the E product in both cases but a reduced amount of the Z product when the deutero substrate was used, consistent with that isomer coming from a C–H activation pathway in which the C–H bond breaking is the rate-determining step.72

Scheme 3. Differentiating Reaction Pathways using Kinetic Isotope Effect.

Scheme 3

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Based on our mechanistic experiments, we propose the following catalytic cycles are operative in this reaction (Figure 2). The amine will be preferentially protonated in the reaction; however, there is also a small equilibrium expected to the free amine and subsequently to the protected carbamate, which will further slow other reactions. For the major reaction, the free amine will degrade palladium to nanoparticles, which are expected to be stabilized by additional amine ligands during the reaction (I). Oxidative addition of the palladium nanoparticle to the aryl iodide is facilitated by silver to give II with concomitant precipitation of silver iodide. The resulting Pd–Ar species will then undergo migratory insertion into the olefin to generate III.

Figure 2.

Figure 2

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Proposed catalytic cycles.

The presence of the chelating amine drives the γ-selectivity, while the presence of multiple metal centers circumvents the challenge in achieving a four-membered cyclic intermediate that would be observed if a mononuclear catalyst were responsible for the reaction, as the same metal is not required to be involved in both the N–Pd coordination and C–Pd bond formation during the intermediate step. A β-hydride elimination would generate the product bound to the nanoparticle (IV), and subsequent exchange with an unfunctionalized allylamine would give rise to the major E-isomer. The hydride is presumably lost via reaction with the protic solvent. Meanwhile, the amine product can also be partially stabilized by reaction with CO2. Notably, although the exact role of the added water is not known, it has been postulated to change both the kinetics and enthalpic favorability of carbamate formation and is clearly necessary for reproducibly higher yields (see Supporting Information for more details).73−75

Occurring simultaneously is a process where the allylamine coordinates to Pd(OAc)2 (V), followed by metalation of the γ-C–H bond most likely through a concerted metalation–deprotonation process (VI). This reaction is favored without the use of CO2 or another transient directing group, we hypothesize, because chelation with the allyl group of the amine likely overcomes the formation of less reactive palladium diamine complexes.76 The electron-rich Pd-species can then undergo oxidative addition to the aryl iodide to give VII, followed by reductive elimination to give the 3,3-diarylproduct VIII, which exchanges to give the minor Z-product. Because the reaction is performed with AgI, some Pd0 can be reoxidized to PdII,76 and as a result, both pathways are able to occur with similar rates throughout the reaction, as evidenced by the lack of change in the E/Z ratio throughout the reactions. This also explains why the degradation of PdII occurs throughout the reaction (see Figure 1).

In conclusion, we demonstrated a highly selective γ-arylation of both primary and secondary allylamines through a regio- and stereospecific olefin insertion mechanism to achieve 3,3-diarylallylamines. Due to the lengthy and occasionally difficult syntheses required to access these 3,3-diarylallylamines, we anticipate that this method will open this class of substrates up to further scrutiny by medicinal chemists. This arylation strategy is simple, efficient, and tolerant of various functional groups, including esters, ketones, and heterocyclic motifs. The reaction can be scaled up under relatively mild conditions. Furthermore, the use of CO2 as a transient protecting group under nonsupercritical conditions may prove useful for improving step and atom economy in other amine-based transformations. The potential for directed nanoparticle-catalyzed olefin functionalization reactions to occur is expected to lead to novel approaches for regioselective transformations of these feedstocks.

Acknowledgments

The authors wish to acknowledge start-up funding from the University of Toledo as well as a grant from the ACS Herman Frasch Foundation (830-HF17) in partial support of this work. E.T.D. acknowledges funding from The University of Toledo’s Office of Undergraduate Research (USRCAP). Prof. Wei Li, Prof. Joseph A. R. Schmidt, and Prof. Jianglong Zhu are acknowledged for useful discussions. Ms. Sandhya Adhikari of The University of Toledo and Dr. Kristin Blake and Dr. Ian Riddington of The University of Texas at Austin’s Mass Spectrometry Facility are acknowledged for collection of high resolution mass spectrometry data. The crystal structure for 2n·HOAc has been deposited with the Cambridge Structural Database (CCDC 1990723).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.0c00003.

  • General notes, reaction details, and 1H, 13C, and heteroatom NMR spectral data (PDF)

The authors declare the following competing financial interest(s): M.C.Y. and M.K. hold a patent related to this work (US20190185392).

Dedication

This manuscript is dedicated to the memory of Prof. Thomas H. Morton (1947–2020), whose overwhelming passion for knowledge knew no bounds.

Supplementary Material

au0c00003_si_001.pdf (20.3MB, pdf)

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