Palladium-Catalyzed C,N-Cross Coupling Reactions of 3-Halo-2-aminopyridines

Abstract

A simple approach towards N³-substituted-2,3-diaminopyridines is presented, based on Pd-catalyzed C,N-cross coupling. The use of RuPhos- and BrettPhos-precatalysts in combination with LiHMDS allows for C,N-cross coupling reactions of unprotected 3-halo-2-aminopyridines with primary and secondary amines.

In the last decade N³-subsituted 2,3-diaminopyridines have been disclosed as potential therapeutics^1,2,3 for multiple indications. They also serve as versatile intermediates in the synthesis of further elaborated, biologically active heterocycles.^4,5,6,7,8

Despite the emerging utility of N³-substituted 2,3-diaminopyridines, the known synthetic routes remain mostly limited to two-step procedures: S_NAr reactions on 3-halo-2-nitropyridines followed by nitro reduction;^5,9 reductive alkylation^4,8,10 of 2,3-diaminopyridines or amide coupling^6,8 of the aforementioned diamine followed by reduction.¹¹ Additionally, two modestly efficient copper-catalyzed aminations have been described, which are limited to 2-amino-3-iodopyridines⁷ or the corresponding boronic ester.² Most importantly, all methods described to date are limited to the synthesis of N³-alkylated 2,3-diaminopyridines while N³-arylated products remain inaccessible.

Given the potential utility of N³-subsituted 2,3-diaminopyridines we felt that there was a need for a general and convenient synthetic method for their construction. We envisioned that a Pd-catalyzed C,N-cross coupling reaction of 3-bromo-2-aminopyridine might be amenable to the problem, given the maturity of the field and several recent advances.¹²

The potential challenges of 3-bromo-2-aminopyridine as the substrate in a Pd-catalyzed C,N-cross coupling reaction are three-fold: 1) prevention or retardation of oxidative addition due to potential coordination/chelation of palladium by the amidine-like structure; 2) hindrance of transmetallation due to coordination of the proximal amino group to the Pd(II) center after oxidative addition and 3) formation of homocoupling product due to competition of 2-amino-halopyridine as the nucleophilic component. While there are few reports of each of these scenarios (Scheme 1, equations I¹³ and II¹⁴) there is no precedent for a Pd-catalyzed C,N-cross coupling with a substrate that combines all three challenges (Scheme 1, equation III).

Scheme 1.

Proposed Pd-catalyzed Amination Reaction of 3-Bromo-2-aminopyridine and Potential Challenges

^asee reference 13

^bsee reference 14

We decided to react 3-bromo-2-aminopyridine with morpholine under the same conditions as described previously for 5-chloro-2-aminopyridine¹⁴ [Pd₂dba₃ (2 mol %)/XPhos (L1, 8 mol %) and LiHMDS (2.5 equiv) in THF at 65 °C for 16 h]. We were pleased to obtain 40% of the desired product along with unreacted starting material and 2-aminopyridine. Encouraged by this result, we examined structurally related biarylmonophosphine ligands L1-L8 and palladacycles Pre-L1, -L3, -L4, -L8¹⁵ leaving all the other reaction parameters unchanged (Figure 1). As palladium complexes of bidentate phosphine ligands have proven to be competent catalysts in the N-arylation of 2-aminopyridine itself and in the amination of 2-bromoaniline (Scheme 1, equation I), three representative ligands L9-L11 of this class were also included in the catalyst screen.¹⁶

Figure 1.

Ligand screen for C,N-cross coupling of morpholine to 3-bromo-2-aminopyridine. Yields are an average of two runs and were determined by GC analysis using dodecane as an internal standard.

The screening study revealed that the ligands RuPhos (L3), SPhos (L4) and BINAP (L9) performed similarly, affording the desired product in high yield (71%, 76% and 71%, respectively) after 16 h (Figure 1). The yields obtained with the precatalysts were slightly lower in comparison to the corresponding Pd₂dba₃/ligand catalyst system, except for the RuPhos–precatalyst (Pre-L3), which exhibited a ~10% increase resulting in the highest yield (83%). Notably, at no point did we observe formation of “homocoupling product” due to 2-amino-halopyridine competing as the nucleophilic component nor the formation of 2,3-diaminopyridine as a consequence of LiHMDS functioning as an ammonia surrogate.

The superior performance of the RuPhos-precatalyst (Pre-L3, Table 1, entry 2) compared to the catalyst system Pd₂dba₃/BINAP (L9, Table 1, entry 3) was further demonstrated by its ability to effectively catalyze the reaction at room temperature (Table 1, entries 4 and 5) and to even couple 3-chloro-2-aminopyridine (Table 1, entries 6 and 7) at 65 °C. Replacing THF with dioxane and increasing the reaction temperature from 65 to 90 °C delivered comparable results (Table 1, entries 1 and 8), though no product formation was observed in toluene (Table 1, entry 9). When initiating the reaction with a Pd-source in a higher oxidation state, only 51% yield was obtained [Pd(OAc)_2, Table 1, entry 10].¹⁷ Alternative bases, such as NaOtBu, K₃PO₄, Cs₂CO₃, K₂CO₃ or Na₂CO₃ proved to be ineffective in the coupling reaction and 2.5 equivalents of LiHMDS were determined to be optimal.¹⁸

Table 1.

Variation of Reaction Parameters for the Coupling of Morpholine to 3-Halo-2-aminopyridine.^a

entry	X	catalyst	temp [°C]	solvent	yieldb
1	Br	Pd2dba3/L3	65	THF	71
2	Br	Pre-L3	65	THF	83 (85)c
3	Br	Pd2dba3/L9	65	THF	71
4	Br	Pre-L3	rt	THF	68
5	Br	Pd2dba3/L9	rt	THF	11
6	Cl	Pre-L3	65	THF	76
7	Cl	Pd2dba3/L9	65	THF	0
8	Br	Pd2dba3/L3	90	dioxane	82
9	Br	Pd2dba3/L3	90	toluene	0
10	Br	Pd(OAc)2/L3d	65	THF	51

^aReaction conditions: 3-halo-2-aminopyridine (1 mmol), morpholine (1.5 mmol), Pd₂dba₃ (2 mol %)/ligand (8 mol %), LiHMDS (2.5 mmol), solvent (2.5 mL) or 3-halo-2-aminopyridine (1 mmol), morpholine (1.5 mmol), Pre-L3 (4 mol %), LiHMDS (2.5 mmol), solvent (2.5 mL);

^bYields [%] were determined by GC analysis using dodecane as an internal standard;

^cReaction was analyzed after 5 h reaction time;

^d4 mol % Pd(OAc)₂ was used.

With these optimized reaction conditions in hand we set out to investigate the scope of the reaction with regard to the secondary cyclic amine coupling partner. High yields were obtained for a range of substituted morpholines (Table 2, entries 1–4) and piperidines (Table 2, entries 8–11); pyrrolidines were coupled in moderate yields (Table 2, entries 6–7). The ability to perform the reaction at room temperature proved important in the case of the Boc-protected piperazine as the yield was increased from 39 to 65% by lowering the reaction temperature (Table 2, entry 5). Substituents in positions 5 and 6 on the 3-bromo-2-aminopyridine were well tolerated, whereas substitution in position 4 was deleterious (Figure 2).

Table 2.

Cross-coupling of 3-Bromo-2-aminopyridine with Secondary Cyclic Amines^a

entry	HNR1R2	Yieldb	entry	HNR1R2	Yieldb
1		79 (76)c 3a	6		53 3f
2		76	7		53 (3g)
		3b	8		79 (3h)
3		85 3c	9		65 3i
4		70 3d	10		65 3j
5		65d (39) 3e	11		81 3k

^aReaction conditions: 3- bromo-2-amino pyridine (1 mmol), amine (1.5 mmol), Pre-L3 (4 mol %), LiHMDS (2.5 mmol, 1 M in THF), 65 °C, 12 h;

^bIsolated yields [%] are an average of two runs;

^c3-chloro-2-aminopyridine was used;

^dReaction was run at room temperature.

Figure 2.

Amination of substituted 2-amino-3-bromopyridines; for reaction conditions see Table 2.

In contrast to the cross-coupling of secondary amines, BrettPhos-precatalyst (Pre-L8) outperformed RuPhos-precatalyst (Pre-L3) and Pd₂dba₃/BrettPhos (L8) in the coupling of 3-bromo-2-aminopyridine with a branched primary amine like cyclopentylamine, yielding 8a in 78% (Table 3, entry 1), compared to only 47% and 66%, respectively. Benzylamine and linear primary amines also proved to be competent under these reaction conditions yielding the corresponding products in moderate to good yields (Table 3, entries 3–5).

Table 3.

Cross-coupling of 3-Bromo-2-aminopyridine with Primary Amines^a

entry	RNH2	Yieldb	entry	RNH2	Yieldb
1		78 (69)c 8a	6		66(61)d 8f
2		70 8b	7		73 8g
3	H2N-n-Hex	58 8c	8		75 8h
4		48 8d	9		66 8i
5		70 8e	10		63 8j

^aReaction conditions: 3-bromo-2-aminopyridine (1 mmol), amine (1.5 mmol), Pre-L8 (4 mol %), LiHMDS (2.5 mmol, 1 M in THF), 65 °C, 12 h;

^bIsolated yields [%] are an average of two runs;

^c3-chloro-2-aminopyridine was used.

As mentioned above no synthesis of N³-arylated 2,3-diaminopyridines has been described to date. A new screen of catalysts revealed again BrettPhos-precatalyst (Pre-L8) as the best system delivering 8f up to 66% yield versus 42% when using Pd₂dba₃/BrettPhos (L8) (Table 3, entry 6). Electron-rich anilines were coupled in comparably high yields (Table 3, entries 7 and 8), electron-withdrawing groups were tolerated and in the case of para-chloroaniline no competitive coupling on the chloride was observed (Table 3, entries 9 and 10).

Finally, as N³,N⁵-disubsituted 2,3,5-triaminopyridines have been disclosed as important pharmacophores,³ we set out to synthesize this scaffold using our methodology. First, 3,5-dibromo-2-aminopyridine (9) was reacted with morpholine following the general conditions (Scheme 2). Three different products (10–12) were formed, the major product being 2-morpholine-5-bromo-2-aminopyridine (11)¹⁹ arising from preferred coupling in position 3.^20,21 XPhos-precatalyst (Pre-L1) gave slightly better selectivity than RuPhos-precatalyst (Pre-L3) with respect to the desired product 11 (1:8:1.6, 86% total yield vs. 1:8.5:3, 75% total yield). The ratio of the products was not altered by shortening the reaction time or by performing the reaction at room temperature. After isolating 2-morpholine-5-bromo-2-aminopyridine (11) a second Pd-catalyzed C,N-cross coupling reaction with piperidine was carried out. From all precatalysts tested SPhos-precatalyst (Pre-L4) performed best and provided product 13 in 71% yield.

Scheme 2.

Sequential Pd-catalyzed C,N-cross coupling of 3,5-Dibromo-2-aminopyridine

^a Isolated yields.

In summary, we have identified reaction conditions for the efficient Pd-catalyzed C,N-cross coupling of unprotected 3-halo-2-aminopyridines with a range of primary and secondary amines. Additionally, the method described herein allowed for the synthesis of N³-arylated 2,3-diaminopyridines, which had been unprecedented to date. The precatalysts derived from the ligands RuPhos and BrettPhos were identified as outstanding catalyst systems for secondary amines and primary amines, respectively, which is in accordance with recently identified trends.²²