Abstract
We report a copper-catalyzed aminoheteroarylation of unactivated alkenes to access valuable heteroarylethylamine motif. The developed reaction features a copper-catalyzed intermolecular electrophilic amination of the alkenes followed by a migratory heteroarylation. The method applies on alcohol-, amide-, and ether-containing alkenes, overcoming the common requirement of a hydroxyl motif in previous migratory difunctionalization reactions. This reaction is effective for the introduction of diverse aliphatic amines and has good functional group tolerance, which is particularly useful for richly functionalized heteroarenes. This migration-involved reaction was found well suited as a powerful ring expansion approach for the construction of medium-sized rings that are in great demand in medicinal chemistry.
Keywords: unactivated olefin, copper, heteroaryl migration, N-centered radical, aminoheteroarylation
Graphical Abstract
The heteroarylethylamine core is an important structural motif found prevalently in bioactive molecules and pharmaceuticals, such as conserved in many opioid receptor ligands (Figure 1).1 Their importance as medicinally privileged functionality has motivated the development of effective methods to access this structural motif in a rapid and diverse manner. Toward this end, an appealing strategy is 1,2-aminoheteroarylation of alkenes as a straightforward approach that enables direct installation of an amino group and a heteroaryl group on the alkenes.2,3 Particularly, the intermolecular aminoheteroarylation of unactivated alkenes presents a general, most desirable manner rapid and modular construction of molecular diversity and complexity. Series methods have been developed on nitrogen-tethered unactivated alkenes to afford the azacyclic skeletons bearing different aryl group, by an elegant amino cyclization and a subsequent intermolecular C–C bond formation.4 Yet for the flexible installation of diverse amino functionality, especially aliphatic amines that feature attractive biological activities, few aminoheteroarylation reactions that involved an intermolecular C–N bond formation have been achieved (Scheme 1).5 A photo-catalyzed alkene aminopyridylation reaction was reported to install secondary amides and 2-pyridyl groups (Scheme 1a).5a The palladium-catalyzed aminoarylation reaction reported by the Engle’s group was successful for an intermolecular installation of amide, sulfonamides, and imidazole (Scheme 1b).5b Zhu’s group has developed a nickel-catalyzed reductive aminoarylation for the installation of aliphatic amines, yet only on iodoarenetethered alkenes (Scheme 1c).5e The versatile assembly of diverse heteroarylethylamine motifs remains a challenge for catalytic alkene aminoheteroarylation. To address this problem, we envisioned an alkene amino migratory heteroarylation strategy by leveraging a temporary installation of a heteroaryl group onto the remote carbonyl or iminyl group (Scheme 1d). This paper reports the development of a copper-catalyzed migratory aminoheteroarylation reaction for the creation of diverse heteroarylethylamines motifs.
Figure 1.
Heteroarylethylamines as an important motif commonly found in bioactive natural products and molecules
Scheme 1.
Aminoheteroarylation reactions of unactivated alkenes via intermolecular C–N bond formation
Key to the development in new catalytic protocol is use of O-benzoyl-N-hydroxylamines electrophilic aminating reagents8 in the copper-catalyzed amination step. This intermolecular C–N bond formation not only enables installation of diverse electron-rich aliphatic amines that were problematic in most existing methods but also positions the formation of carbon-radical intermediates that are expected to undergo a distal migration for the assembly of the heteroarene. Our work was inspired by radical-based functional group migration-involved transformations, particularly alcohol-assisted alkene migratory functionalization.6,7 Different from previous migratory reactions, the catalytic protocol described here is effective on alcohol-, amide-, and even ether-containing alkenes, overcoming a common limitation for the requirement of a hydroxyl moiety and presenting synthetic potential for broader applications. Furthermore, our method is well suited for a rapid approach to access medium-sized rings via the form of ring expansion, particularly for heteroarene-bearing medium-sized ketones that are highly valued in medicinal chemistry yet would be difficult to access otherwise.
Our studies began with the aminoheteroarylation reaction of 1-phenyl-1-(benzothiazolyl)pentenol 1a using O-benzoyl-N-hydroxylmorpholine 2 as an amine precursor (Table 1). With Cu(OTf)2 as the catalyst and in the presence of TsOH∙H2O as additive, the reaction at 80 ºC readily proceeded to afford the desired product 3a (entry 1). Yet significant amounts of cyclization and elimination byproducts were formed (see SI). To minimize these side reactions, shorter reaction time and lower temperature were tested (entries 2–4). When the reaction was run at 60 ºC for 20 min, the formation of 3a was improved to 73% yield (entry 3). We also tested the reaction of 1-phenyl-1-(thiazolyl)pentenol 1b at different temperatures (entries 5–7). The desired 1,2-aminothiazole product 3b was formed in 77% yield most effectively when the reaction was run at 80 ºC for 5 min (entry 5). Control experiments showed that both copper catalyst and the acid additive are imperative in this reaction (entries 8–9). Although we chose Cu(OTf)2 as standard conditions, the reactions were also effective with other Cu(I) and Cu(II) salts as the catalyst (see SI).
Table 1.
Optimization of aminoheteroarylation of alkenea
| ||||
|---|---|---|---|---|
| entry | 1a/1b | T (°C) | time | 3a/3b (%)b |
| 1 | 1a | 80 | 1 h | 20 |
| 2 | 1a | 80 | 5 min | 66 |
| 3 | 1a | 60 | 20 min | 70 (73) c |
| 4 | 1a | 40 | 4.5 h | 65 |
| 5 | 1b | 80 | 5 min | 72 (77)c (72)c,d |
| 6 | 1b | 60 | 20 min | 65 |
| 7 | 1b | 40 | 5 h | 66 |
| 8e | 1a | 60 | 20 h | Trace |
| 9f | 1a | 60 | 72 h | ND |
Reaction conditions: 1a or 1b (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE (1 mL).
Yields determined by 1H NMR spectroscopy with CH2Br2 as an internal standard.
Isolated yields in parentheses.
Run on 2.0 mmol scale.
No acid was added.
No copper catalyst was added.
With effective conditions established, we studied the scope of O-benzoylhydroxylamines for the aminoheteroarylation of alkene (Table 2). Starting from 1a or 1b, the reactions using piperidine and 3-methylpiperidine derived hydroxylamines as the amine precursors smoothly afforded benzothiazole- and thiazole-containing amine products (5a–5b and 6a–6b), respectively. Other six-membered cyclic amine precursors bearing different functional groups were well tolerated, providing a diverse range of β-aminoethyl thiazole derivatives from the reactions of 1b, such as ester-containing piperidine (6c), N-Bz- (6d), N-Cbz- (6e), and N-Boc-(6f) piperazines, bridged bicyclic morpholine (6g) as well as thiomorpholine (6h). Five- and seven-membered cyclic amine precursors, specifically pyrrolidine and azepane, also participated in this reaction, affording 6i and 6j in 20% and 45% yield, respectively. The aminoheteroarylation reactions with N-Cbz and N-Boc protected 1,4-diazepane precursors successfully delivered 6k and 6l. The reaction was also applicable to acyclic amine precursors, demonstrated in the formation of diethylamine 6m and methylphenethylamine 6n in moderate yields. Noticeably, primary amine was also successfully installed on the alkene to give 6o in 69% yield.
Table 2.
Generality of amine precursors in aminoheteroarylation reactions
|
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 4 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE (1 mL), 80 °C. Isolated yields shown.
Run with 4f (3.0 equiv).
Run at 40 °C.
Run with 4j (4.0 equiv) and TsOH∙H2O (3.0 equiv) at 60 °C.
Run at 40 °C.
Run with 4n (3.0 equiv) and TsOH∙H2O (2.25 equiv) at 60 °C.
Run with 1b (0.1 mmol, 1.0 equiv), 4o (3.0 equiv) and TsOH∙H2O (6.0 equiv).
We next examined the generality of this alkene migratory difunctionalization strategy on diverse heteroarenes using alkene substrates bearing different heteroaryl groups (Table 3). The reactions of various azoles were found to afford the desired 1,2-amino azole products, including oxazole (8a), benzoxazole (8b), imidazole (8c), benzimidazole (8d) and 4,5-dimethylthiazole (8e). Six-membered aza-heteroaryl groups were found to be effective in the formation of the 2-pyridyl (8f), 4-pyridyl (8g), isoquinolinyl (8h) products, and more electron-deficient pyrimidine 8i. Structurally more complex caffeine-containing product 8j was also formed in good yields. Even the adenosine-derived alkene was compatible with this migration, furnishing the desired product 8k in 38% yield. These examples have demonstrated the generality of this migratory amino heteroarylation strategy on a broad scope of heteroarene, including those structurally complex ones that have been rarely explored but are important such as caffeine and adenosine derivatives. It should be also noted that electron-rich heteroaryl groups was found unsuccessful under the current conditions, as seen in the case of benzofuryl analog 8l.
Table 3.
Heteroaryl groups in aminoheteroarylation reactions
|
Reaction conditions: 7 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE (1 mL), 80 °C. Isolated yields shown.
Run with 2 (3.0 equiv) and TsOH∙H2O (3.0 equiv).
Run with 7h (0.1 mmol, 1.0 equiv) and TsOH∙H2O (3.0 equiv).
Run with 7ka (2.0 equiv), 2 (0.2 mmol, 1.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (0.6 equiv), DCE (2 mL), 80 °C.
We further investigated the alkene substrates bearing two heteroaryl groups in order to evaluate the migration selectivity and the impact of the second heteroaryl group (Table 4). Subjecting bisthiazole containing alkene 9a to standard reaction conditions, led to the desired product 10a in 35% yield, a significant drop in comparison to the formation of analogous product 3b in 77% yield. Selective formation of β-thiazolyl amine products 10b–10d revealed that thiazolyl migration was favored over the migration of thienyl, benzothienyl, and N-tosylindolyl group. Interestingly, benzofuryl and thiazolyl substituted substrate 9e afforded two isomers in a 1:1.3 ratio that slightly favored the migration of benzofuryl (10e’) over thiazolyl (10e). Note that benzofuryl migration in the analogous phenyl substituted product 8l was unsuccessful. Thus, the change from phenyl to thiazolyl would contribute to the viability of benzofuryl migration in forming product 10e’. The reaction of pyridyl thiazole containing alkene 9f also gave two products 10f and 10f’ in 6.3:1 ratio, via the migration of thiazolyl and pyridyl, respectively. Lastly, imidazolyl thiazole containing alkene 9g afforded both thiazole (10g) and imidazole migration product (10g’) in comparable yields. In comparison to the formation of 3b (77%), 8f (43%) and 8c (41%) from mono-azaheteroaryl substrates, the poorer yields observed in the formation of 10a (35%), 10f and 10f’ (9%) as well as 10g and 10g’ (36%) from bis-azaheteroaryl-containing substrates indicated that the electronic nature of non-migratory substituent affects the efficiency of the heteroaryl migration.
Table 4.
Aminoheteroarylation of alkenes bearing two heteroaryl groups
|
Reaction conditions: 9(0.2 mmol, 1.0 equiv), 2(0.4 mmol, 2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (0.3 mmol, 1.5 equiv), DCE (1 mL), 80 °C. Isolated yields shown.
We also investigated the generality of alkenes in this amino heteroarylation reaction using different thiazole-bearing unsaturated alcohols 11 (Table 5). First, the reactions of 1-phenyl-substiuted tertiary alcohols all provided desired 1,2-amino thiazole-containing products, regardless of the presence of electron-donating or electron-withdrawing groups on the phenyl ring (12a–12e). The alkylsubstituted tertiary alcohols were also capable of delivering thiazole migration products (12f–12j). The substrates bearing more sterically bulky alkyl groups resulted in higher efficiencies, suggesting that the steric bulkiness would facilitate the migration of neighbouring thiazole group. The backbone substituents of the alkenes were found to affect the transformation dramatically, as seen in the cases of 12k–12l wherein the varied gem-dimethyl position resulted in steric interference hindering the migration step. This reaction from 1,1-disubstituted alkene was capable of forming quaternary carbon-containing product 12m in 64% yield. Cyclic alkene substrates were also evaluated. A α-tetralone derived precursor (as a mixture of 1:1 diastereomers) delivered 12n in 69% yield (a mixture of 1:1 diastereomers), which indicated that this migration process could occur via both cis and trans fused (5:6) bicyclic transition states. Cyclic internal alkenes successfully provided 1,2-amino thiazole products 12o and 12p, via fused 5:6 and 5:5 bicyclic transition states, respectively. The diminished yields of 12o–12p resulted from the competing pathways that led to intramolecular aminooxygenation8b and aza-Wacker type9 byproducts.
Table 5.
Generality of alkenes in aminoheteroarylation reactions
|
Reaction conditions: 11 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE (1 mL), 80 °C. Isolated yields shown.
Detected by LC/MS.
We also examined alkenes 11q–11s under the standard reaction conditions to gain more insight on the reactivity of 1,n-migration involved in this amino heteroarylation transformation. The formation of 12q and 12s, presumably via 1,3- and 1,6-migration, was observed in a trace amount by LC/MS, while aza-Wacker type allylic amination products were formed instead. On the other hand, the 1,5-migration product 12r was smoothly formed in 59% yield. These results support that the readily formed five- and six-membered cyclic transition states facilitated the 1,4- and 1,5-migratory amino heteroarylation reactions, while 1,3- and 1,6-migration is hampered by unfavourable four- and seven-membered transition-state ring formation.
During the investigation of these alkene amino heteroarylation reactions, we observed several possible competing reaction pathways (Scheme 2). For example, subjecting styrene-derived substrate 11t to standard reaction conditions led to the formation of thiazolyl-substituted alkene 13 in 46% yield, presumably owing to the elimination-prone ammonium species under acidic conditions. Another common competing pathway is the formation of cyclic ether products by an intramolecular aminooxygenation reaction. For example, the reaction of conjugated diene precursor 11u formed cyclic ether 14 exclusively, with no desired product 12u observed. The reaction of carvone derivative 11v also gave amino oxycyclization product 15, as the migration would involve a conformationally strained bicyclic transition state. Interestingly, the reaction of another carvone derivative 11w provided aza-Wacker type allylic amination product 16 as the major product, when the oxycyclization was conformationally disfavored. The unsuccessful migration of the thiazolyl group placed at the opposite side of the alkene in both substrates 11v and 11w supported the presence of five-membered cyclic transition state for the 1,4-heteroaryl migration.
Scheme 2. Competing reaction pathways.
Reaction conditions: 11 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE (1 mL), 80 °C. Isolated yields shown.
To probe the radical intermediates that may be involved in the migration step, control experiments were performed with 1b and 11r under the standard reaction conditions, in the presence of a radical scavenger (Scheme 3a). When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) present, the reactions of 1b and 11r provided reduced yield of migrated heteroarylation products and resulted in the formation of TEMPO-trapped product 17 and 18 respectively. The addition of 2,6-di-tert-butyl-4-methylphenol (BHT) also deteriorated the formation of β-aminoethyl thiazole product and gave rise to BHT-derivatives 19 and 20. The formation of 17–20 all implied the presence of nitrogen- and carbon-radical species under the reaction conditions. Based on these experimental results, a plausible reaction mechanism is proposed for the aminoheteroarylation reaction (Scheme 3b). The active Cu(I) catalyst can be generated from the Cu(II) precatalyst through disproportionation.10 The oxidative addition of O-benzoylhydroxylamine to Cu(I) catalyst would generate an amide Cu(III) species (A) or a Cu(II) nitrogen-based radical complex (A’). Subsequent intermolecular amination of alkene 1b through either (A) or (A’) would produce the corresponding Cu(III) species (B) or a carbon radical (B’). Note that the electron-rich amine group would be protonated in the presence of TsOH.11 The migration of the heteroaryl group onto the carbon radical may occur either through a cyclic Cu(III) intermediate (C) or via an alkyl radical intermediate (C’). Subsequent C−C σ-bond breaking would provide a hydroxyalkyl Cu(III) intermediate (D) or a hydroxyalkyl radical (D’),12 finally leading to the formation of desired product by an elimination step (from D) or a SET oxidation (from D’), as well as the regeneration of the Cu(I) catalyst.
Scheme 3. Mechanistic studies on the aminoheteroarylation reactions.
aRun under standard conditions with TEMPO (1.0 equiv). bRun under standard conditions with BHT (1.0 equiv). Isolated yields shown.
Based on the mechanistic hypothesis, we expect that this amino heteroarylation strategy was potentially extendable beyond alcohol-containing alkenes in previous migratory difunctionalization reactions. We examined the aminoheteroarylation conditions on alkene-containing α-tertiary amides and ethers derivatives (Scheme 4). Both sultam 21a and phosphinamide 21b were found effective to promote the migration functionalization in a manner analogous to tertiary alcohols. N-sulfonylimine 22 from 21a was successfully isolated in 41% yield, whereas the N-phosphinylimine from 21b was not stable under acidic condition, with ketone product 3b obtained in 52% yield. Furthermore, the reactions of analogous methyl ethers 23a–23b also afforded the desirable products 3b and 8f. These examples demonstrated that this aminoheteroarylation is applicable to the non-alcohol substrates and is not limited by the presence of a hydroxyl moiety which was commonly required in previous migration methods. Excitingly, this reaction was approved to be a viable strategy for the synthesis of cyclic ketone systems. Subjecting 24a and 24b to standard conditions readily constructed eight-membered and nine-membered cyclic amines 25a and 25b, respectively. Such ring-expansion reactions present an attractive, useful approach to rapidly access medium-size nitrogen-containing ring systems known to be synthetically challenging yet highly desirable in medicinal chemistry.13
Scheme 4. Expanding the generality and application of alkene aminoheteroarylation.
Reaction conditions: alkene (1.0 equiv), 2 (2.0 equiv), Cu(OTf)2 (10 mol %), TsOH∙H2O (1.5 equiv), DCE, 80 °C. aRun with 2 (3.0 equiv), TsOH∙H2O (2.0 equiv), DCE, 80 °C. bRun with 2 (5.3 equiv), TsOH∙H2O (4.8 equiv), DCE, 80 °C. Isolated yields shown.
In summary, we have developed copper-catalyzed aminoheteroarylation of alkenes for the synthesis of valuable heteroarylethylamine motifs. This method features selective migration, good tolerance of functional groups, as well as a broad scope of alkenes, heteroarenes, and amines under mild conditions. Mechanistic studies have implied the presence of nitrogen- and carbon-radical species under reaction conditions. Such an alkene migratory aminoheteroarylation reaction is also well suited as a rapid approach to construct medium-sized rings that are of greatly demanded in medicinal chemistry.
Supplementary Material
ACKNOWLEDGMENT
We acknowledge financial support by Duke University and the National Institutes of Health (GM118786). We thank Dr. Peter Silinski (Duke University) for the assistance with high-resolution mass spectrometry data.
Footnotes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Condition optimizations, experimental procedures, compound characterization, and NMR spectra.
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