Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C-H Activation

Abstract

α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp²)-H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields. Catalytic hydrogenation was then used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.

Graphical Abstract

Nitrogen heterocycles are among the most abundant structural components of pharmaceuticals.¹ Due to their omnipresence in biologically active molecules, the synthesis of nitrogen heterocycles has attracted considerable attention in the synthetic community. Pyridines represent one of the most prevalent scaffolds encountered in medicinal chemistry.^1b,c Removal of one unsaturation from a pyridine ring affords dihydropyridines.² These molecules come as three double-bond isomers: 1,4-dihydropyridine 1, 2,3-dihydropyridine 2, and 1,2-dihydropyridine 3 (Figure 1). The first synthesis of a 1,4-dihydropyridine is attributed to Arthur Hantzsch for work done over a century ago.³ The importance of this motif is highlighted by its presence in nicotinamide adenine dinucleotide (NADH), a universal biological reducing agent. Interest in 1,4-dihydropyridines has been further stimulated after their incorporation into Ca-channel blockers.⁴

Figure 1.

Structures of Dihydropyridines

In stark contrast to 1,4-dihydropyridines, which are stable structures, the 2,3- and 1,2-congeners are kinetically labile and thus not found in bioactive molecules as such. Nevertheless, they have been implicated as versatile intermediates in biosynthetic pathways leading to alkaloid natural products. Recent examples include the proposed biosynthesis of the marine natural product Symbioimine,⁵ as well as isoquinuclidine alkaloids Keramaphidin B and Manzamine A.⁶

While N-alkyl 2,3-dihydropyridinium salts are well-documented and even isolable,⁷ there is scarce information on the synthesis of N-unprotected 2,3-dihydropyridines.⁸ This constitutes a handicap to the synthetic community, given the potential number of transformations that such intermediates can engage in.

In recent years, Rh(III)-catalyzed C-H activation has become a method of choice for constructing nitrogen heterocycles.^9,10 In particular, coupling of α,β-unsaturated imines and oximes with alkynes represents a useful approach to pyridines.¹¹ We have recently demonstrated that high regioselectivities are obtainable when electronically-biased alkenes are used in place of alkynes as coupling partners (Scheme 1, eq 1).^11a Furthermore, substituted acrylic acids were shown to give the complementary regioisomer of the pyridine products, where the carboxylate acts as a traceless directing group (eq 2).^11b In a conceptually distinct approach, Bergman and Ellman have shown that a Rh(I) catalyst can couple unsaturated imines with internal alkynes followed by imminium formation and reduction to deliver complementary tetrahydropyridines depending on nature of the acid (eq 3).^11c This latter reaction was proposed to proceed through dihydropyridine intermediates.

Scheme 1.

Rh(III)-Catalyzed Synthesis of 2,3-Dihydropyridines

In our initial work (eq 1), we never observed the presumed intermediate dihydropyridine adducts even in the absence of external oxidants. We speculated that the instability of the 2,3-dihydropyridine was responsible, and rapid in situ oxidation to the pyridine was faster than the initial annulation.¹² We speculated that the use of 1,1-disubstituted alkenes would prevent oxidation and deliver 2,3-dihydropyridines as isolable outcomes of the reaction (eq 4). Herein we disclose our results.

We commenced our investigation by subjecting α,β-unsaturated oxime pivalate 1a and alkene 2a to catalytic amounts of various CpRh(III) diacetates¹³ in HFIP at 60 °C (Table 1). As can be seen from the Table, replacing the Cp* ligand (A₁) with its more sterically congested tert-butyl-substituted congener (A₂) increases the yield of the 2,3-dihydropyridine product (3aa) from 81% to 91%. Product yield is further enhanced when electron-deficient Cp-ligand A₃ bearing a trifluoromethyl^10b substituent is used. Provided that CsOAc was employed as an additive, product 3aa was isolated in 99% yield when 5 mol % of A₃ was used.

Table 1.

Optimization of the Reaction Conditions^a

entry	Rh(III)	additive	yield (%)d
1	[Cp*RhCl2]2	AgOAcb	<12c
2	A1	none	55
3	A1	p-TsOHb	72
4	A1	CsOAc	81
5	A2	CsOAc	91
6	A3	CsOAc	99
7	A4	CsOAc	92
8	B3	CsOAc	99
9e	B3	CsOAc	99

^aReaction Conditions: 1a (1.0 equiv), 2a (1.2 equiv), additive (2.0 equiv), Rh(III) catalyst (5 mol %) in HFIP (0.3 M), at 60 °C for 16 h.

^b10 mol % of additive was used.

^cDetermined by ¹H NMR.

^dYield of isolated product.

^eCatalyst loading was decreased to 2 mol %, reaction temperature was decreased to 50 °C.

The use of Rh(III) diacetates is problematic for some Cp-ligands due to their hygroscopicity. Fortunately, use of the more easily handled cationic tris(acetonitrile) Rh(III) precatalyst B₃, bearing a trifluoromethyl-substituted Cp*-ligand, did not deteriorate the yield of the 2,3-dihydropyridine. Interestingly, the dinuclear [Cp*RhCl₂]₂ complex did not promote the title transformation with either CsOAc or AgOAc as additives.

With the optimal conditions in hand, we examined the scope of the reaction. α,β-Unsaturated oxime pivalates 1 bearing various linear or branched alkyl substituents at positions 2 and 3 are tolerated (Scheme 2, 3aa-3da). Substrates bearing an aromatic ring at position 3 are also competent (3ha-3na), as well as functional groups like silylated alcohols (3fa) and halides (3ga, 3la).

Scheme 2.

α,β-Unsaturated Oxime Pivalate Scope

Turning our attention to the scope of the alkenes, we found that various 1,1-disubstituted olefins are competent substrates for 2,3-dihydropyridine synthesis (Scheme 3). Functional groups including esters (3ab), ketones (3ac), ethers (3ad), and protected amines (3am) are tolerated. With methylene cyclopentanes and cyclohexanes as substrates, spiro-bicyclic 2,3-dihydropyridines are obtained in good yields (3dj-3ao). Finally, exo-methylene cyclohexanes bearing a prostereogenic carbon at the 4-position furnished the corresponding 2,3-dihydropyridines (3an and 3ao) with high levels of diastereocontrol (up to 10:1 dr).

Scheme 3.

Alkene Scope

To demonstrate the synthetic utility of the 2,3-dihydropyridines, we turned our attention to derivation of the products. Stimulated by the wide abundance of piperidines in biologically active copounds,^1a attention was placed on the reduction of C-C and C-N double bonds. We successfully developed a single-pot protocol wherein the Rh(III)-catalyzed coupling of imines and alkenes was sequenced with Pd-catalyzed hydrogenation (Scheme 4) to deliver high overall yield of piperidine products. Surprisingly, the major diastereomer formed proved to have the trans relationship between the substituents at the 2 and 3 positions, although the level of selectivity seems to be modestly substrate dependent (compare 6mi vs 6hi). The relative configuration of products 6am and 6ao was unambiguously assigned by X-ray crystallography.¹³

Scheme 4. One-Pot Synthesis of Piperidines.

^*numbers in parantheses denoted yields and dr’s after recrystallization.

Labeling studies provided valuable insight into the mechanism of the reaction. A small primary kinetic isotopic effect (KIE = 1.41) was observed when deuterated oxime pivalate d₅-1j was used (Scheme 5). This observation may be explained by evoking a reversible C-H activation event and incorporation of deuterium from solvent rather than a direct indicator of rate difference.¹⁴ A rather large inverse KIE (0.74) was observed with deuterated alkene d₂-2f, which is consistent with rate-determining olefin insertion.

Scheme 5.

Observation of KIE Effects

A Hammett study provided further support for olefin insertion being the slow step.¹³ A large and negative value of the reaction constant (ρ = −1.2) indicates that positive charge builds up at the reaction site during the rate-limiting step. Preliminary kinetic analysis¹⁵ of the reaction revealed a first order dependence of rate on both catalyst and oxime. Furthermore, first order dependence on alkene was also seen at low concentrations; higher concentrations demonstrated some evidence of an inhibitory effect.¹⁴

In order to account for the observed mechanistic data, the following catalytic cycle is proposed (Scheme 6). Following the formation of the active Rh(III) diacetate complex, C-H activation takes place reversibly through a concerted metallation deprotonation mechanism. The resultant five-membered metallacycle II then undergoes rate-limiting migratory insertion to give the seven-membered metallacycle IV. Reductive elimination/N-O bond cleavage furnishes the 2,3-dihydropyridine and regenerates the catalyst.

Scheme 6.

Postulated Catalytic Cycle

In conclusion, we have described an efficient Rh(III)-catalyzed synthesis of semi-saturated nitrogen heterocycles. A significant ligand effect on reactivity was observed, the electron-deficient trifluoromethyl-substituted Cp*^CF3 being optimal. The scope of the transformation is large¹⁶ and many of the obtained 2,3-dihydropyridines were successfully reduced to piperidines with good levels of diastereocontrol. Mechanistically, it was established that the reaction follows overall second-order kinetics, migratory insertion being the turnover-limiting step.