Asymmetric Rh-Catalyzed Synthesis of Dihydronicotinamides

Abstract

We report a rhodium-catalyzed enantioselective dearomatization of nicotinamide-derived pyridinium salts to access primary, secondary, and tertiary dihydropyridine carboxamides, with high regio- and enantioselectivity (up to 99% ee). Employing aryl-boronic pinacol esters and Rh/(R)-Xyl-BINAP, the reaction tolerates diverse functional groups, enabling a versatile approach for synthesizing chiral azaheterocycles with pharmaceutical relevance.

Saturated or partially saturated analogues of nicotinamide are common structural motifs in FDA approved drugs and natural products (Figure 1).^1–8 Such widespread presence of these nitrogen heterocycles has driven chemists to develop various synthetic strategies for their synthesis. These efforts have included amide bond formation reactions from corresponding nipecotic acid derivative and various cyclization reactions.^{3–6, 8} Despite these efforts, methods that allow asymmetric synthesis of saturated analogues of substituted nicotinamide are rare.

Figure 1.

Examples of alkaloids and bioactive molecules with C3-carboxamide containing piperidines.

Enantioselective nucleophilic dearomatization of pyridinium salts have recently gained attention as a method of choice for the preparation of saturated and partially saturated six-membered nitrogen heterocycles.^9–16 Our research group and others have investigated Rh-catalyzed arylation of heteroarenium salts including regiodivergent dearomatization of nicotinic acid ester derived pyridinium salts, using Ar-Bpin and Ar-B(OH)₂ reagents as nucleophiles (Figure 2A).

Figure 2.

(A) Dearomatization of pyridinium salts with nucleophiles for the synthesis of nicotinate-ester substituted DHPs. (B) Dearomatization of pyridinium salts with nucleophiles for the synthesis of nicotinamide substituted DHPs.

Despite the broad scope of nicotinic acid-ester-derived pyridinium salt dearomatization, a catalytic asymmetric method for nicotinamide-derived pyridinium salts remain underdeveloped. Our lone attempt at asymmetric dearomative arylation of a nicotinamide derivative using the reaction conditions developed for dearomatization of nicotinic acid ester derivatives yielded the corresponding dihydronicotinamide 9 in low yield and ee (Figure 2B).¹⁸ Considering the importance of 3-carboxamide piperidines and related nitrogen heterocycles we studied dearomatization of nicotinamide derived pyridinium salts. Herein we report results of these dearomatization studies.

Our optimization studies commenced using pyridinium carboxamide salt 11, with PhBpin as coupling partner and [Rh(COD)₂BF₄]/(S)-BINAP as a catalyst in a 10:3 dioxane/water mixture at 75 °C resulting in a 21% yield of the dearomatization product 12a (Table 1, entry 1). The choice of boron nucleophile significantly influenced the reaction yield. Replacing PhBpin with quaternary cyclic triolborate 13, led to a high yield (80%) and excellent enantioselectivity (96% ee) (Table 1, entry 2). Preparation of cyclic triolborate 13 in situ from PhBpin, trimethylolethane (TME) and tetramethylammonium chloride (TMA-Cl) as phase transfer catalysts resulted in comparable yield to those achieved with premade cyclic triolborate (Table 1, entry 3).²³ This is significant as this in situ preparation protocol improves overall efficiency, and operational simplicity of this methodology. Using [Rh(C₂H₄)₂Cl]₂ as the rhodium source instead of [Rh(COD)₂]BF₄ resulted in slightly lower yield (Table 1, entry 4). An assessment of over 15 ligands revealed that axially chiral bis-phosphines were the most effective, delivering dihydropyridine 12a with higher enantioselectivity compared to that of other ligands tested (entries 5–8, see Supporting Information for full list of ligands). Among these, (R)-XylBINAP stood out, providing the best results in terms of both reactivity and enantioselectivity, with an 84% yield and 92% ee. No C-4 or C-2 addition products were observed (Table 1, entry 8). Lowering the reaction temperature to 60 °C resulted in improved enantioselectivity (Table 1, entry 9). Enantiomeric excess (ee) of the reaction product was further improved at 50 °C, however the yield of the reaction decreased noticeably. (Table 1, entry 10).

Table 1.

Optimization of the reaction conditions. ^[a]

Entry	Ligand	Deviation from standard conditions	Yield	ee
1	L2	no TME or TMA-Cl added	21%	ND
2	L2	13 instead of PhBpin, no TME or TMA-Cl	80%	96%
3	L2	none	99%	82%
4	L2	[Rh(C2H4)2Cl]2 instead of [Rh(COD)2]BF4	97%	82%
5	L3	none	96%	88%
6	L4	none	70%	85%
7	L5	none	97%	86%
8	L1	none	84%	92%
9	L1	60 °C instead of 75 °C	84%	96%
10	L1	50 °C instead of 75 °C	76%	98%

^[a]Reaction conditions: pyridinium salt 11 (1 equiv.), PhBpin (2.5 equiv.), catalyst (5 mol%), ligand (10 mol %), Na₂CO₃ (2.5 equiv.), TME (5.0 equiv.) and TMA-Cl (3.75 equiv.) were reacted in 0.5 mL of dioxane: H₂O (10:3) at 75 °C unless otherwise noted. Enantiomeric excess (ee) of the reaction product was determined by chiral HPLC analysis. The yield of the reaction was determined by ¹H NMR analysis of crude reaction using dimethyl terephthalate as an internal standard. TME = trimethylolethane; TMA-Cl = tetramethylammonium chloride; ND = not determined.

With the optimized reaction conditions established, we explored the scope of the Aryl-Bpin nucleophiles with nicotinamide salt 11 (Scheme 1). Aryl Bpins with electron-withdrawing groups (CF₃, CO₂Me, OCHF₂, SCF₃, F, Br, Cl, Ac) at the para position underwent cross-coupling, resulting in the corresponding products (Scheme 1, 12b-12h and 12o) with excellent enantioselectivity (96–99%) and high yields (80% to99%). Reactions involving para-substituted boronic esters with electron-donating and electron-neutral groups (Scheme 1, 12a and 12i-12l) gave the corresponding dearomatization products in 50–88% yield and high enantioselectivity (93–98%). The meta-disubstituted nucleophiles also successfully underwent cross-coupling, showing good compatibility (Scheme 1, 12m and 12n). The absolute stereochemistry of 12o was confirmed as (R) using X-ray crystallography. Notably, various functionalized heteroarene boronic esters, including thiophene, benzothiophene, 1,3-benzodioxole, furan and benzofuran, (Scheme 1, 12p-12t), were utilized to produce the corresponding compounds in moderate yields with 76–96% ee. Arene Bpin derivatives such as 3-methyl-isoxazole- and 4-(bromomethyl) phenyl-, indole, alkenyl-Bpins, afforded the desired dihydropyridines 12u-12x in low yield.

Scheme 1.

Scope of the boronic pinacol ester for dearomatization of nicotinamide salt 11.[a]

^[a] Reaction conditions: pyridinium salt 11 (0.2 mmol, 1.0 equiv.), Ar-Bpin (2.5 equiv.), [Rh(COD)₂]BF₄ (5 mol%), L1 (10 mol %), Na₂CO₃ (2.5 equiv.), TME (5 equiv.) and TMA-Cl (3.75 equiv.) were reacted in 1 mL of dioxane: H₂O (10:3) at 60 °C for 4 hours. Enantiomeric excess of the reaction product was determined by chiral HPLC analysis. The qNMR yield of the reaction was determined by 1^H NMR analysis of crude reaction using dimethyl terephthalate or 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown in parenthesis.

After establishing the range of compatible boronic acids, we investigated the scope of nicotinamides in the dearomatization reaction (Scheme 2). Consistently high regio- and enantioselectivity were observed in the synthesis of various C-3-carboxamide dihydropyridine derivatives, including primary, secondary, and tertiary amides. The reaction yielded exclusively C6-substituted products. Secondary benzyl, alkyl and aryl nicotinamide derivatives were obtained in high yield and enantioselectivity. N1-benzyl and N1-methyl containing nicotinamide salts underwent dearomatization to deliver corresponding DHPs in similar yields and ees (Scheme 2, 14a-14c versus 14i-14k) reaching up to 99% ee and 99% yield. Highly sterically hindered nicotinic di-isopropyl carboxamide containing DHP was obtained in 33% yield and 90% ee (Scheme 2, 14m). Successful formation of anilinamide containing DHP 14h was achieved by using (S)-BINAP in place of (R)-Xyl-BINAP, without the presence of quaternary ammonium salt additive.

Scheme 2.

Scope of substituted nicotinamide salts. [a]

^[a]Reaction conditions: pyridinium iodide salts 8 (0.2 mmol, 1.0 equiv.), 4-(CF₃)Ph-Bpin (2.5 equiv.), [Rh(COD)₂]BF₄ (5 mol%), L1 (10 mol %), Na₂CO₃ (2.5 equiv.), TME (5.0 equiv.) and TMA-Cl (3.75 equiv.) were reacted in 1 mL of dioxane: H₂O (10:3) at 60 °C for 4 hours unless otherwise noted. Enantiomeric excess of the reaction product was determined by chiral HPLC analysis. The qNMR yield of the reaction was determined by ¹H NMR analysis of crude reaction using dimethyl terephthalate or 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown in parenthesis. ^[b](S)-BINAP was used as a ligand. ^[c]PhBpin was used as a nucleophile. ^[d]X = Br. ^[e]X = OTf

To demonstrate the applications of the reaction products, we explored further functionalization of the DHP products. The enantioenriched dearomatization products 12a and 15 can be chemo-selectively hydrogenated to form tetrahydropyridines 16 and 17 (Scheme 3). Attempted iodoetherification of the dihydropyridine 15 resulted in unexpected, highly functionalized pyrrole 18 in 30% yield (see Supporting Information for the proposed mechanism for the formation of this product).

Scheme 3.

Derivatization of dearomatization products.

In summary, we have developed a catalytic enantioselective Rh-catalyzed method for the dearomatization of nicotinamide derived pyridinium salts, demonstrating high efficiency and functional group tolerance. Key findings included the superior performance of axial chiral bisphosphines, particularly (R)-XylBINAP, and the essential role of additives. Additionally, we systematically adjusted substituents on the pyridinium ring, establishing tolerated patterns and confirming the method’s broad applicability and consistency for primary, secondary, and tertiary carboxamides substituted at the C-3 position.