Ruthenium(II)-catalyzed C–H activation/C–N bond formation via in situ generated iminophosphorane as the directing group: construction of annulated pyridin-2(1H)-ones

Abstract

We describe an efficient and straightforward synthesis of annulated pyridin-2(1H)-ones following condensation of acyl azides with internal alkynes via the ruthenium-catalyzed ortho C–H bond activation. The reaction in DCE proceeds via in situ generation of iminophosphoranes as directing group-coordination of Ru with N-atom-ortho cyclometallation-insertion of an alkyne into the Ru–C bond-protonation-reductive elimination in a domino sequence. The role and stability of in situ generated iminophosphorane and ruling out the possibility for the benzamide involvement was established using ¹H and ³¹P NMR experiments.

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In recent years, the directing group (DG) concept¹ for the ortho C–H activation/functionalization has emerged as a powerful approach for de novo construction of a wide variety of annulated heterocycles of medicinal significance. The directing groups generally comprise functional groups (FG) with abilities to act as versatile ligands to transition metals and form ortho-cyclo-metallated complexes for smooth functionalization at the ortho C–H position. Interestingly, in organic chemistry, besides recent application of functional groups as DGs, they traditionally remained in use for a wide variety of selective transformations. Report exploiting the dual ability of FG, by transforming a non-directing functional group into an in situ DG is scarce.² Such a strategy would provide options to proceed with a selective transformation of a functional group either into other functionalities or into a DG for the ortho C–H activation.

Among plethora of applications reported for the synthesis of heterocycles utilizing the DG concept, synthesis of 1-(2H)-isoquinolones in a single step from arenes bearing a directing group attracted our attention. The core structure has drawn much attention owing to its ubiquity in plant alkaloids,³ and many biologically active natural products⁴ and due to its remarkable pharmacological importance ranging from anticancer, antihypertensive,⁵ to topoisomerase I inhibitor activities.⁶ A careful literature survey revealed synthesis of 1-(2H)-isoquinolones via oxidative insertion of internal alkyne across arenes with directing groups comprising oximes (CONHOMe, CONHOPiv, CONHOH, CONMeSOPh) and nitriles (CN) in the presence of Rh-, Ru-assisted catalysts (Fig. 1).⁷

Fig. 1 Ours, and literature strategies for the synthesis of 1-(2H)-isoquinolones via ortho C–H activation/functionalization from arenes bearing DGs and internal alkynes.

Ironically, investigations leading to the direct synthesis of 1-(2H)-isoquinolones from primary aryl carboxamides either failed to undergo oxidative annulation with internal alkynes or furnished undesired tricyclic amides via double oxidative insertion of internal alkynes.^7a,8a,b Pursuing our interest in heterocycles based on privileged structures,⁹ we were interested in the application of in situ generated iminophosphoranes as a DG using less expensive Ru catalyzed oxidative conditions. The motivation for the use of iminophosphoranes as DG stemmed from several reports¹⁰ demonstrating regioselective palladation of keto-stabilized iminophosphoranes [Ph₃P=NC(O)Ar] via ortho C–H activation. For the in situ generation of iminophosphoranes as a DG under mild reaction conditions, we envisioned that aryl acyl azides with poor directing group abilities could be the ideal choice as the precursor (Fig. 2a).

Fig. 2 Dual application of acyl azides for in situ generation of DGs and for functionalization of molecules via ortho C–H activation.

Recently, acyl azides has been employed as FG for the ortho functionalization of a DG carrying arene affording N-substituted amides via either C–N or C–O bond formation¹¹ (Fig. 2b). Other application includes transformation to a heterocycle¹² without employing DG concept. To the best of our knowledge, application of in situ generated iminophosphoranes as DG leading to ortho C–H activation/functionalization has not been reported. In this communication, we report Ru-catalyzed C–H activation/C–N bond formation involving aryl acyl azides and internal alkynes to afford 1-(2H)-isoquinolones in one pot.

We commenced our studies by treating benzoyl azide 1a with unactivated internal alkyne 3a in the presence of (1.0 equiv.) TPP (triphenylphosphine) in DCE without the addition of Ru catalyst (Table 1). The reaction failed to give the desired product 4aa instead resulted in a corresponding iminophosphorane 2a as the only product following the Staudinger reaction¹³ (entry 1). Next, we carried out the same reaction in the presence of [Ru(p-cymene)Cl₂]₂/AgSbF₆/Cu(OAc)₂·H₂O mixture which resulted in the formation of a desired product 4aa albeit in 32% isolated yield (entry 2) with recovery of 2a in 26% isolated yield. Removing AgSbF₆ as an additive raised the isolated yield of 4aa to 42% (entry 3) while raising the loading of the oxidant Cu(OAc)₂·H₂O from 20 mol% to 100 mol% selectively afforded 4aa in 86% isolated yield (entry 4). Carrying out control experiment in the absence of Cu-salt resulted in the recovery of 2a with no formation of 4aa (entry 5). Replacing Cu(OAc)₂·H₂O with other oxidants like K₂S₂O₈, t-BuOOH and CuBr₂ reactions failed to give 4aa (entry 6–8). Similarly, replacing Ru- with Rh- and Pd-catalysts failed to initiate the reaction with the recovery of 2a (entry 9–12).

Table 1 Optimization of reaction condition for the annulation of acyl azide 1a with unactivated internal alkyne 3a^a

Entry	Catalyst (3.0 mol%)	Oxidant (mol%)	Solvent	Yield^d 2a/4aa (%)
a Reaction conditions: 1a (1.0 equiv.), 3a (0.8 equiv.), PPh3 (1.0 equiv.), [Ru(p-cymene)Cl2]2 (3.0 mol%), and Cu(OAc)2·H2O (100 mol%), in 5 mL DCE, 80 °C, 6 h.b In the absence of PPh3 benzoyl azide underwent degradation under standard condition (with no detectable formation of 4aa).c 5.0 mol% AgSbF6 were used.d Yield of isolated products.e Reaction stirred for 10 h.f A yellow colored byproduct in ∼10% yield.g Byproducts: benzamide in 15% yield and a yellow colored spot in 23% yield.
1		Cu(OAc)2 (20)	DCE	65/—
2^c	[RuCl2(p-cymene)]2	Cu(OAc)2 (20)	DCE	26/32
3	[RuCl2(p-cymene)]2	Cu(OAc)2 (20)	DCE	22/42
4	[RuCl2(p-cymene)]2	Cu(OAc)2 (100)	DCE	—/86
5	[RuCl2(p-cymene)]2	—	DCE	78/—
6	[RuCl2(p-cymene)]2	K2S2O8 (100)	DCE	63/NR
7	[RuCl2(p-cymene)]2	t-BuOOH (100)	DCE	65/NR
8	[RuCl2(p-cymene)]2	CuBr2 (100)	DCE	68/NR
9	Rh(PPh3)3Cl	Cu(OAc)2 (100)	DCE	55/NR
10	Pd(OAc)2	Cu(OAc)2 (100)	DCE	58/NR
11	Pd(OAc)2	K2S2O8 (100)	DCE	52/NR
12	Pd(OAc)2	t-BuOOH (100)	DCE	38/NR
13	[RuCl2(p-cymene)]2	Cu(OAc)2 (100)	Toluene	45/28
14	[RuCl2(p-cymene)]2	Cu(OAc)2 (100)	THF,ACN	35/trace
15	[RuCl2(p-cymene)]2	Cu(OAc)2 (100)	MeOH	63^e^,^f
16	[RuCl2(p-cymene)]2	Cu(OAc)2 (100)	t-AmOH	38^g

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Next, we studied the affect of polar and nonpolar solvents on the outcome of the reaction. While replacing DCE with toluene furnished a mixture of 4aa and an iminophosphorane intermediate 2a in 28% and 45% yields respectively (entry 13), use of THF and acetonitrile afforded 4aa in traces (entry 14) with the recovery of 2a in 35% yield. Indeed, introducing polar solvents had a dramatic effect and led to interesting findings. Carrying out reaction in MeOH, although made the reaction sluggish, transformation of 1a initially afforded 2a along with an additional intermediate on tlc. Prolonged stirring led to gradual disappearance of both the intermediates affording 4aa along with a yellow colored byproduct 6 in 63% and ∼10% isolated yields respectively (entry 15). For the characterization of the new intermediate observed in MeOH, we quenched the reaction after 5 h that resulted in the isolation of two intermediates iminophosphorane 2a (32%) and benzamide 5 (36%) and the byproduct 6 in traces.¹⁴

Replacing MeOH with yet another polar solvent t-AmOH afforded 4aa in reduced yield (38%) along with the isolation of benzamide 5 in 15% and the byproduct 6 in 23% yield (entry 16). Literature precedence report formation of iminophosphoranes and benzamides in polar solvents from acyl azides.¹⁵ The yellow coloured byproduct 6 observed in polar solvents was characterized as a tricyclic compound¹⁴ and as reported by Miura et al.^8a and Xingwei Li et al.^8b has been reported to be formed following the reaction of 4aa with another molecule of internal alkyne.

Thus, it is evident from the optimization studies that transformation of acyl azides 1a to 4aa is highly favored in DCE and proceeds via in situ generated iminophosphoranes with no formation of byproduct 6. On the contrary, in polar solvent both iminophosphorane and benzamide are generated in situ and formation of 4aa is accompanied by formation of the yellow coloured tricyclic byproduct 6 in 10–23% isolated yields (Table 1).

The involvement of intermediates 2a and 5 in the transformation was further confirmed by treating presynthesized benzamide 5 (Scheme 1) and iminophosphorane 2a (Scheme 2) separately with 3a in MeOH/DCE. As is evident, selective transformation of 2a to 4aa occurred in higher yields in DCE, whereas formation of byproduct 6 was observed from benzamide 5 both in MeOH and DCE. The findings suggest acyl azides 1 as the best option for the synthesis of pyridin-2(1H)-ones over that of benzamide 5.

Scheme 1 Treatment of presynthesized benzamide 5 with unactivated internal alkyne 3a in MeOH and DCE.

Scheme 2 Treatment of presynthesized iminophosphorane 2a with unactivated internal alkyne 3a in MeOH and DCE.

Although several literature reports^7a,8a,8b involving reaction of pre-synthesized 5 with the internal alkyne demonstrate formation of either a yellow colored tricyclic compound 6 as the major product or a benzannulated derivative¹⁴ as a minor product with the recovery of 5, a single report by Jeganmohan et al.^7g describes formation of 4aa from benzonitrile via the in situ benzamide (5) intermediacy. This is in accordance to our observation involving transformation of 1a to 4aa in MeOH via in situ benzamide intermediacy. Furthermore, the role and stability of iminophosphoranes during the transformation in DCE and also ruling out involvement of benzamide was confirmed by ¹H and ³¹P NMR experiments.¹⁴

With optimized conditions in hand, we then proceeded to study the scope and limitation of the transformation in DCE. Initially, a series of benzoyl azides (1a–j) bearing electron-donating and -withdrawing groups (R³) were subjected to oxidative annulation with both aliphatic and aromatic internal alkynes (3a–h) in DCE (Table 2).

In all nineteen 1-(2H)-isoquinolones based on 4 were synthesized in 66–88% isolated yields. As is evident, the presence of a single electron-donating and -withdrawing groups in 1 at position 4 of the aromatic ring furnished products in >80% isolated yield with minimal variations. However, introduction of two electron-donating substituents in the aromatic ring at position 3 and 4 reduced the isolated yield to 68–70%. Among symmetrical internal alkynes replacement of R¹ and R² with aromatic ring bearing electron-donating groups produced corresponding 4 in relatively higher yield (4ad) than aliphatic chain (4af, 4ae).

Employing unsymmetrical internal alkynes bearing-aliphatic/aromatic and, aromatic/COOEt moieties as R¹/R² furnished 4ah and 4ag in good to moderate yields with high regioselectivity (Table 2). Terminal alkyne failed to facilitate annulations. The versatility of methodology was demonstrated by replacing benzoyl azides with thiophene and indole-based acyl azides (1k–n). Treating with a variety of internal alkynes furnished 8 examples of corresponding 4 in moderate to good isolated yields (Table 3).

Table 2 Scope of the ruthenium-catalyzed C–H activation of acylazides with internal alkynes^a

a Reaction condition: (1.0 equiv.) of 1, (0.8 equiv.) of 3, (100.0 mol%) of PPh₃, (3.0 mol%) [Ru(p-cymene)Cl₂]₂, (100 mol%) of Cu(OAc)₂·H₂O in 5 mL of DCE at 80 °C.

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Table 3 Scope of the various heterocycles using the same strategy^a

a Reaction condition: (1.0 equiv.) of 1, (0.8 equiv.) of 3, (100.0 mol%) of PPh₃, (3.0 mol%) [Ru(p-cymene)Cl₂]₂, (1.0 equiv.) of Cu(OAc)₂·H₂O in 5 mL of DCE at 80 °C.

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Based on the literature reports,^{7c,7f,7g,10a,b,16} a plausible mechanism for the formation of 4aa is depicted in Scheme 3. The ruthenium dimer precatalyst undergoes dissociation into the coordinatively unsaturated monomer in solution, which exchanges ligand with Cu(OAc)₂·H₂O to form an acetate-ligated species. This metal upon coordination with N-atom of the iminophosphorane 2a (derived from 1a) followed by ortho cyclometallation afforded a five membered ruthenacycle I with the loss of acetic acid through an acetate-assisted mechanism. This is then accompanied by the insertion of an alkyne into the Ru–C bond to afford a seven membered ruthenacycle intermediate II. Finally the protonation of II followed by reductive elimination affords 4aa with the dissociation of triphenyl phosphine by the in situ generated acetic acid¹⁶ and reduction of the ruthenium from Ru(II) to Ru(0). Latter undergoes oxidation to regenerate the catalytically active Ru(II) complex with the aid of copper oxidant.

Scheme 3 A plausible mechanism for the formation of 4aa via iminophosphorane.

In summary we have described a Ru-catalyzed ortho C–H activation and intramolecular C–N bond formation via in situ generated iminophosphoranes as a directing group. The synthetic protocol involves one pot condensation of acyl azides with internal alkynes leading to straightforward and efficient synthesis of a variety of annulated pyridin-2(1H)-ones. The salient feature of the reaction in DCE involves in situ generation of iminophosphorane-coordination of Ru with N-atom-ortho cyclometallation-insertion of an alkyne into the Ru–C bond-protonation-reductive elimination domino sequence. Further studies are in progress with application of other in situ generated DGs for the synthesis of heterocycles via de novo routes.

Acknowledgements

R. K. A., R. K., T. J. and R. M. are thankful to CSIR, and UGC New Delhi, India for fellowships. The authors would like to thank SAIF, CDRI, India for providing NMR data. CDRI Communication no. 8834.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra10105g

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