Ru-catalyzed activation of sp³ C–O bonds: O- to N-alkyl migratory rearrangement in pyridines and related heterocycles

Abstract

We report a novel strategy for the formal activation of sp³ C–O bonds under Ru catalysis. In this reaction, an O-alkylpyridine undergoes migratory rearrangement to its corresponding N-alkylpyridone via coordination of the Lewis basic N atom. This transformation represents the first generalcatalytic approach to O- to N-alkyl migration in N-containing heterocycles. Extension of this methodology to other heterocycles, including O-alkylpyridazines and O-alkylazoles, was achieved.

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Introduction

The transition metal catalyzed activation of σ bonds provides a general strategy to build molecular complexity from simple starting materials. Oxidative addition of electron-deficient bonds, such as C–X, C–N₂, and C–OSO₂R, is well known;¹ however, direct insertion into electron-rich bonds, such as C–H, C–C, and C–OR, remains a significant challenge.^2–4 Notably, ethereal C–O bonds are typically inert, unlike the C–O bonds of sulfates, esters, carbonates, and carbamates, which are active in cross-couplings⁵ and π-allyl chemistry.⁶ Ethereal variants of these reactions are quite rare.⁴ To this end, Kakiuchi and co-workers reported a unique strategy for sp² C–O bond activation in ethers using a ketone directing group.⁷ Herein, we report a complementary method for sp³ ethereal C–O bond activation in alkoxypyridines and related heterocycles (Fig. 1).

Fig. 1 Proposed sp³ C–O bond activation strategy for N-alkylated heterocycle synthesis.

A brief survey of the literature reveals a lack of general methods for the preparation of N-alkylated heterocycles (e.g., N-alkylpyridones),⁸ important structural motifs found in natural products⁹ and medicinal targets.¹⁰ Direct alkylation of aromatic imidates is not ideal due to competing O- and N-alkylation because of their ambivalent character.¹¹ One attractive solution to this problem is the O- to N-alkyl migratory rearrangement reaction, a practical approach because O-alkyl heterocycles can be easily synthesized via nucleophilic aromatic substitution. Current methods for O- to N-alkyl migration use stoichiometric amounts of LiI¹² or NaCl;¹³catalytic variants are limited to rearrangements of O-allylN-heterocycles promoted by Pd and Pt salts.¹⁴ We propose a complementary strategy involving two distinct mechanistic steps: 1) oxidative addition of an sp³ C–O bond to generate a metal imidate, and 2) reductive elimination to furnish an sp³ C–N bond.

Results and discussion

Initial studies

Our initial studies confirmed that most transition metals, including Pd, Ni, Rh, and Fe were ineffective in promoting the desired O- to N-alkyl migration reaction in 2-benzoxypyridine (1a) (Table 1, entries 1–4).‡ Surprisingly, Rucatalysts known to undergo oxidative addition into C–O bonds⁷ were unreactive (entries 5–6); to our delight, [Ru(p-cymene)Cl₂]₂ catalyzed the rearrangement efficiently (entry 7). The difference in reactivity may be attributed to the presence of the CO ligand. Substitution of the solvent by THF was tolerated, although DCE resulted in decreased reaction yields (entries 8–9), as did the use of other ligands (entries 10–13). The use of strong bases (e.g., NaO^tBu, entry 15) or organic bases (e.g., NEt₃) led to decreased reactivity.

Table 1 Reaction optimization

Entry^a	Cat. [M]/ligand^b	Base	Solv.	Yield (%)^c
a Reaction conditions: Substrate, 0.1 mmol; catalyst, 10 mol% [M], ligand, 10 mol%, base, 0.11 mmol, solvent, 1 mL, 80 °C, 24 h. b Arene = p-cymene. c Conversion by ^1H NMR; isolated yield in parenthesis. d Ligand, 5 mol%.
1	Pd(PPh3)4	K2CO3	PhMe	0
2	Ni(COD)2	K2CO3	PhMe	0
3	Fe(CO)5	K2CO3	PhMe	0
4	RhCl(PPh3)3	K2CO3	PhMe	0
5	Ru3(CO)12	K2CO3	PhMe	0
6	RuH2(CO)(PPh3)3	K2CO3	PhMe	0
7	[Ru(arene)Cl2]2/PPh3	K2CO3	PhMe	100 (91)
8	[Ru(arene)Cl2]2/PPh3	K2CO3	THF	100
9	[Ru(arene)Cl2]2/PPh3	K2CO3	DCE	19
10	[Ru(arene)Cl2]2/PCy3	K2CO3	PhMe	1
11	[Ru(arene)Cl2]2/P(OPh)3	K2CO3	PhMe	0
12	[Ru(arene)Cl2]2/dppp^d	K2CO3	PhMe	4
13	[Ru(arene)Cl2]2/bpy^d	K2CO3	PhMe	0
14	[Ru(arene)Cl2]2/PPh3	K3PO4	PhMe	85
15	[Ru(arene)Cl2]2/PPh3	NaO^tBu	PhMe	0
16	[Ru(arene)Cl2]2/PPh3	NEt3	PhMe	5

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Synthetic scope

With our optimized reaction conditions, we synthesized a number of N-alkyl pyridones by catalyticO- to N-migratory rearrangement reaction. Electron-neutral, electron-deficient, and electron-rich benzyl groups were tolerated in this transformation (Table 2, entries 1–14, 2a–n, 66–99%). Halide and ester functionalities remained unchanged under our reaction conditions (entries 5–9, 11). Importantly, other ether linkages present in the molecule are preserved and the pyridine N directs selective sp³ C–O bond activation (entries 12–14). Furthermore, the presence of a bulky substituent at the ortho-position did not inhibit catalysis, although elevated temperatures were required (entry 8). Substitution on the backbone of the pyridine ring with electron-donating and electron-withdrawing groups had minimal effect on the reaction efficiency (entries 15–25, 2o–y, 85–99%). Pyridines bearing substituents at the 6-position, however, rendered the reaction unproductive—a steric effect, since both electron-donating (entry 21) and electron-withdrawing (entry 24) substituents were not tolerated. Additionally, substrates bearing secondary O-alkyl groups were completely unreactive even at higher temperatures (entry 26).

Table 2 O- to N-Migratory rearrangement of 2-benzoxypyridines

Entry^a	Substrate	Product	Yield (%)^b	Entry^a	Substrate	Product	Yield (%)^b
a Reaction conditions: Substrate, 0.2 mmol; [Ru(p-cymene)Cl2]2, 5 mol%; PPh3, 20 mol%; K2CO3, 0.22 mmol; PhMe, 2 mL; 24 h. b Isolated yields. c No desired product could be detected by ^1H NMR spectroscopy.
1			91 (80 °C)	14			88 (90 °C)
2			76 (80 °C)	15			90 (80 °C)
3			99 (90 °C)	16			90 (80 °C)
4			99 (90 °C)	17			85 (80 °C)
5			95 (80 °C)	18			92 (80 °C)
6			89 (80 °C)	19			94 (80 °C)
7			88 (90 °C)	20			98 (100 °C)
8			66 (120 °C)	21			—^c (80–110 °C)
9			83 (100 °C)	22			99 (90 °C)
10			96 (100 °C)	23			87 (110 °C)
11			99 (90 °C)	24			—^c (80–110 °C)
12			78 (80 °C)	25			99 (100 °C)
13			99 (90 °C)	26			—^c (80–120 °C)

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Pyridines bearing larger aryl- and heteroaryloxy substituents, such as naphthyl, benzodioxolyl, furyl and benzofuryl at the 2-position underwent the desired O- to N-alkyl migration efficiently (Table 3, entries 1–6, 2aa–ff, 81–99%). Simple alkoxy chains could also undergo the migratory rearrangement, although higher temperatures were required (entries 7–9). A silyl ether was tolerated in our catalytic reaction (entry 9), although other ether and thioether functionalities led to loss of reactivity (entries 10–11), presumably because chelation renders the catalyst inactive.

Table 3 O- to N-Migratory rearrangement of 2-alkoxypyridines

Entry^a	Substrate	Product	Yield (%)^b	Entry^a	Substrate	Product	Yield (%)^b
a Reaction conditions: Substrate, 0.2 mmol; [Ru(p-cymene)Cl2]2, 5 mol%; PPh3, 20 mol%; K2CO3, 0.22 mmol; PhMe, 2 mL; 24 h. b Isolated yields. c No desired product could be detected by ^1H NMR spectroscopy.
1			99 (80 °C)	7			64 (110 °C)
2			92 (90 °C)	8			92 (110 °C)
3			99 (90 °C)	9			65 (120 °C)
4			95 (90 °C)	10			—^c (80–120 °C)
5			81 (90 °C)	11			—^c (120 °C)
6			96 (90 °C)

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During the course of our studies, we found that pyridazines could direct the desired sp³ C–O bond activation (Table 4, entries 1–7, 4a–g, 60–94%). A number of 3-alkoxypyridazines were successfully transformed to the corresponding 2-alkylpyridazones. Electron-neutral and electron-deficient benzyloxy substituents migrated efficiently (entries 1 and 2), although migratory rearrangement of an electron-rich benzyl group and an aliphatic silyl ether required elevated temperatures (entries 3 and 4). With pyridazines bearing two O-alkyl groups (entries 5–7), only one alkyl migration occurred. Presumably, either the electronic nature of the resulting 2-alkylpyridazone is not sufficient to direct the Rucatalyst to activate the second C–O bond or the increased steric bulk on the 2-position hinders the approach of the Rucatalyst.

Table 4 O- to N-Migratory rearrangement of 3-alkoxypyridazines

Entry^a	Substrate	Product	Yield (%)^b	Entry^a	Substrate	Product	Yield (%)^b
a Reaction conditions: Substrate, 0.2 mmol; [Ru(p-cymene)Cl2]2, 5 mol%; PPh3, 20 mol%; K2CO3, 0.22 mmol; PhMe, 2 mL; 24 h. b Isolated yields.
1			70 (90 °C)	5			94 (80 °C)
2			92 (90 °C)	6			94 (80 °C)
3			64 (120 °C)	7			64 (110 °C)
4			60 (120 °C)

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To demonstrate the generality of our strategy for sp³ C–O bond activation, several other O-alkyl N-containing heterocycles were examined (Table 5). The synthesis of 2-benzylisoquinolinone (6a) could be achieved in good yield at 80 °C (96%), while the isomeric 2-benzylquinolinone (6b) was not detected via O- to N-alkyl migration, in agreement with the unreactive 6-substituted O-alkoxylpyridines (1u,x). With the successful conversion of alkoxypyridazines (see Table 4), pyrimidine and pyrazine directing groups were also examined. 2-Benzyloxypyrimidine (5c) failed to undergo the desired O- to N-alkyl migration, but 2-benzyloxypyrazine (5d) underwent successful migration, although 120 °C was required (33%). An analogous S- to N-alkyl migratory rearrangement was also examined. However, we found that 2-thiopyridine5e was unreactive under our optimized conditions, in stark contrast to the 2-alkoxy analogue (cf.Table 3, entry 3) where essentially quantitative yield of the substituted pyridine (2cc) was obtained. Migratory rearrangement using 5-membered N-containing heterocycles as directing groups had varying results. Gratifyingly, both benzo[d]imidazole5f and benzo[d]oxazole5g were efficiently rearranged to their respective products (6f, 6g); in comparison, 2-alkoxypyridine substrates bearing substituents at the 6-position (cf.1u,x and 5b) were completely unreactive. Interestingly, benzyloxythiazole5h generated thiocarbamate6h, albeit in a lower yield (55%), contrasting the lack of reactivity of 2-(2-(phenylthio)ethoxy)pyridine (1kk) and 2-((furan-2-ylmethyl)thio)pyridine (5e). In this case, chelation of the substrate to the Rucatalyst is not possible.

Table 5 O- to N-Migratory rearrangement of nitrogen heterocycles

Entry^a	Substrate	Product	Yield (%)^b
a Reaction conditions: Substrate, 0.2 mmol; [Ru(p-cymene)Cl2]2, 5 mol%; PPh3, 20 mol%; K2CO3, 0.22 mmol; PhMe, 2 mL; 24 h. b Isolated yields. c No desired product could be detected by ^1H NMR spectroscopy.
1			96 (80 °C)
2			—^c (80–120 °C)
3			—^c (80–120 °C)
4			33 (120 °C)
5			—^c (80–120 °C)
6			95 (100 °C)
7			70 (100 °C)
8			55 (110 °C)

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Mechanistic discussion

In our reaction design, we hypothesized that oxidative addition of an sp³ C–O bond of 2-alkoxypyridines (and related heterocycles) could generate a metal imidate, similar in structure to known Pd π-allyl complexes.^14a–c This Ru-imidate could undergo subsequent reductive elimination to furnish the new sp³ C–N bond.

To study the reaction mechanism, we first conducted a competition study as depicted in Fig. 2. Combining 2-alkoxypyridines 1m and 1p in equimolar amounts and subjecting the mixture to the optimized catalytic conditions resulted in production of N-alkylpyridones 2m and 2p, respectively. No products arising from intermolecular exchange processes (i.e., 2q, and 2f) were observed. This result suggests that Ru is promoting a selective intramolecular alkyl transfer process. If a metal imidate is formed during the course of the reaction, no exchange between two Ru complexes occurs.

Fig. 2 Crossover experiment. ^a No desired product could be detected by ¹H NMR spectroscopy.

Next, we synthesized deuterated 3-(benzyloxy)-6-chloropyridazine (3a-d₂) and subjected this substrate to the reaction conditions (Fig. 3). Since Lewis basic pyridine rings are known to facilitate sp³ C–H bond functionalization,¹⁵ this experiment should probe the possibility of C–H bond activation at the α protons. We observed loss of the D label in both recovered starting material and isolated product. This observation suggests that reversible sp³ C–H bond activation is taking place.¹⁶

Fig. 3 Competition experiment. Ratios were determined by ESI-MS. For details, see Electronic Supplementary Information.†

Hence, we propose a mechanism involving α-C–H bond metalation to generate a Ru-hydride, α-C–O bond elimination to yield a Ru-methylidene, and finally a 1,2-hydride migration to produce the formal product of an sp³ C–O bond activation (Fig. 4a). This mechanism is based on Krogh-Jespersen and Goldberg's work on stoichiometric studies involving activation of the ethereal C–O bond of anisole with Ir pincer complexes.¹⁷ However, our studies do not rule out a non-productive C–H bond activation event. Indeed, both Kakiuchi's direct oxidative addition of ethereal C–O bonds (Fig. 4b)⁷ and concerted processes such as concerted suprafacial [1,4]-sigmatropic rearrangements (Fig. 4c)^18,19 are possible. Further mechanistic studies are underway.

Fig. 4 Proposed mechanisms for sp³ C–O bond activation (see text for discussion).

Conclusions

A Ru-catalyzed O- to N-alkyl migratory rearrangement reaction has been developed. This is a mechanistically novel and distinct strategy for sp³ ethereal C–O bond activation towards the preparation of N-alkylated-2-pyridones and related heterocycles. Directing groups of differing electronics had little effect on the desired migration; steric bulk, however, hinders catalysis. Numerous 2-benzoxypyridines and a diverse array of other N-containing heterocycles are efficiently transformed.

Acknowledgements

Funding is provided by the University of Toronto, Canada Foundation for Innovation, Ontario Research Fund, Boehringer Ingelheim Ltd. Canada, and the Natural Sciences and Engineering Research Council (NSERC) of Canada. VMD is grateful for an Alfred P. Sloan Fellowship and CSY for an NSERC André Hamer Award and a Canada Graduate Scholarship.

Notes and references

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16. Presumably, the H originates either from the PhMesolvent or p-cymene or adventitious water. Similar results were observed when PhMe was substituted with PhH. When substrate 3a was subjected to stoichiometric amounts of [Ru(p-cymene)Cl₂]₂ and PPh₃, product 4a was formed with complete conversion. No Ru-hydrides could be observed by ¹H NMR spectroscopy. Instead, Ru(3a) and Ru(4a) complexes were detected, suggesting that these species are catalyst resting states. For details, see Electronic Supplementary Information†.
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19. A Fries-type rearrangement involving formation of distinct Ru-imidate and benzyltriphenylphosphonium cations viadealkylation is an alternative mechanism. Alkylation of the N atom of alkoxypyridines is known using activated methylating agents: (a) K. W. C. Poon and G. B. Dudley, J. Org. Chem., 2006, 71, 3923–3927; (b) W. R. Bowman and C. F. Bridge, Synth. Commun., 1999, 29, 4051–4059. Based on our crossover studies (Fig. 2), we favor the mechanisms highlighted in Fig. 4.

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Footnotes

† Electronic Supplementary Information (ESI) available: General procedures for migratory rearrangement, and spectroscopic data. See DOI: 10.1039/c0sc00498g/

‡ General procedure for Ru-catalyzed O- to N-alkyl migration: In a N₂-filled glovebox, in a one-dram vial equipped with a Teflon cap, [Ru(p-cymene)Cl₂]₂ (6.2 mg, 0.01 mmol, 5 mol%) and PPh₃ (10.5 mg, 0.04 mmol, 20 mol%) were dissolved in PhMe (2 mL). The resulting solution was added to the O-alkyl N-containing heterocycle. Subsequently, K₂CO₃ (30.4 mg, 0.22 mmol) was added. The vial was stirred on a heating block at the appropriate temperature for 24 h. The resulting mixture was passed through a pad of Celite, concentrated in vacuo and the resulting residue was purified by preparative thin-layer chromatography (eluent: hexanes/EtOAc or CH₂Cl₂/MeOH) to afford the pure N-alkylheterocyclic migratory rearrangement products.

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