Rh(I)-Catalyzed Direct Arylation of Pyridines and Quinolines

Abstract

A Rh(I)-catalyzed direct arylation of pyridine and quinoline heterocycles has been developed. The method provides rapid entry into an important class of bis(hetero)aryl products employing inexpensive and readily available starting materials.

The pyridine and quinoline nuclei are privileged scaffolds that occupy a central role in many medicinally relevant compounds.¹ Consequently, methods for their expeditious functionalization are of immediate interest. However, despite the immense importance of transition-metal catalyzed cross-coupling for the functionalization of aromatic scaffolds, general solutions for coupling 2-pyridyl organometallics with aryl halides have only recently been presented.² Direct arylation at the ortho position of pyridine would constitute an even more efficient approach because it eliminates the need for the stoichiometric preparation and isolation of 2-pyridyl organometallics.^3,4 Progress towards this goal has been achieved by activation of the pyridine nucleus for arylation via conversion to the corresponding pyridine N-oxide⁵ or N-iminopyridinium ylide.⁶ However, this approach necessitates two additional steps: activation of the pyridine or quinoline starting material, and then unmasking the arylated product. The use of pyridines directly would clearly represent the ideal situation both in terms of cost and simplicity. We now wish to document our efforts in this vein, culminating in an operationally simple Rh(I)-catalyzed direct arylation of pyridines and quinolines.

We recently developed an electron-rich Rh(I) system for catalytic alkylation at the ortho position of pyridines and quinolines with alkenes.^7,8 Therefore, we initially focused our attention on the use of similarly electron-rich Rh(I) catalysts for the proposed direct arylation. After screening an array of electron-rich phosphine ligands and Rh(I) salts, only marginal yields (<20%) of the desired product were obtained. Much more efficient was an electron-poor Rh(I) system with [RhCl(CO)₂]₂ as precatalyst (Table 1).^9,10 For the direct arylation of picoline with 3,5-dimethyl-bromobenzene, addition of P(OⁱPr)₃ afforded a promising 40% yield of the cross coupled product 1a (entry 1). The exclusion of phosphite additive proved even more effective, with the yield of 1a improving to 61% (entry 2). Further enhancement in yield was not observed upon the inclusion of other additives such as MgO (entry 3), various organic bases (entries 4, 5) and inorganic bases (entry 6), or a protic acid source (entry 7). Absolute concentration proved very important, with the best results being obtained at relatively high concentrations of the aryl bromide (compare entries 8 and 9). A marginal improvement was observed upon running the reaction with 6 equivalents of 2-methyl pyridine (entry 10).^11,12 The reaction temperature could also be increased to 175 or 190 °C while maintaining reaction yield, to enable the reaction time to be reduced to 24 h (entries 11 and 12).

Table 1.

Direct Arylation of 2-Methyl Pyridine

entry	additive (equiv)	conc. (M)a	temp (°C)	% yieldb,c
1	P(OiPr)3 (0.30)	0.8	165	40
2	None	0.8	165	61
3	MgO (3.0)	0.8	165	33
4	NiPr2iBu (3.0)	0.8	165	0
5	2,6-lutidine (3.0)	0.8	165	47
6	K2CO3 (3.0)	0.8	165	0
7	2,6-lut HCl(0.25)	0.8	165	55
8	none	0.15	165	34
9	none	1.1	165	61
10	none	0.8	165	63d
11	none	0.8	175	60d,e
12	none	0.8	190	62d,e

^aRefers to the absolute concentration in aryl bromide;

^bdetermined by GC analysis with hexamethylbenzene as an internal standard;

^cthe reaction time was 48 h unless otherwise indicated;

^d6.0 equiv of 2-methyl pyridine was employed;

^ethe reaction time was 24 h.

With a set of optimized conditions in hand, we next set out to investigate the generality of the catalytic direct arylation with a variety of substituted pyridine derivatives (Table 2). Good arylation yields were observed for pyridine derivatives with straight chain (entries 1 and 2), β-branched (entry 3), and α-branched (entry 4) substituents at the C-2 position. Tetrahydroquinoline also provided the arylated product in good yield (entry 5) as did 2,4-dimethylpyridine (entry 6). In contrast, when a substituent at the C-2 position is not present, arylation does not occur (entry 7). This result parallels our previous studies on Rh-catalyzed pyridine alkylation.^7,13 The steric interactions provided by a substituent at this position may reduce the energy difference between the N-bound complex and the C-H activation intermediate. Consistent with the requirement for C-2 substitution, quinoline is also a highly effective substrate for direct arylation (entry 8). As illustrated in entry 9, the compatibility of the reaction conditions to chloro substitution should enable efficient further elaboration of the arylation product by standard cross coupling methods. However, no arylation was observed for 2- and 2-choropyridine.

Table 2.

Investigation of Scope in Heterocycle

entry	heterocycle	product	% yielda
1		1a	53
2		1b	51
3		1c	78
4		1d	70
5		1e	76
6		1f	67
7		1g	0
8		1h	86b
9		1i	65b

^aIsolated yield of analytically pure product; 0.4 mmol scale in ArBr; 0.8 M absolute concentration in ArBr;

^breaction run at 175 °C and 0.3 M absolute concentration in ArBr.

The substrate scope in aryl bromide was also evaluated with quinoline as the coupling partner (Table 3). Both electron-rich and electron-poor aryl bromides are accommodated with equal efficiency (compare for example entries 4 and 11). A variety of useful functional groups are tolerated, including aryl and alkyl ethers (entries 3, 4), chloride (entry 8), fluoride (entry 9), and ketone functionality (entry 10). While cross coupling proceeds smoothly with meta substitution on the aryl bromide ring (see for example entry 1), attempted cross coupling with 2-methyl-bromobenzene failed to afford product, with only unreacted starting material recovered.

Table 3.

Investigation of Scope in Aryl Bromide

entry	ArBr	product	% yielda
1		1h	86
2		1j	74
3		1k	62
4		1l	70
5		1m	73
6		1n	77
7		1o	69
8		1p	68
9		1q	69
10		1r	70
11		1s	65
12		1t	45

^aIsolated yield of analytically pure product; 0.4 mmol scale in ArBr; 0.3 M absolute concentration in ArBr.

Studies exploring reaction scope were conducted using 5 mol% of the Rh(I) catalyst. However, the reaction can be performed with comparable efficiency employing only 1 mol% of the catalyst. In this case, the reaction was run neat, resulting in complete consumption of the aryl bromide after 24 h and a 68% isolated yield of the arylated product 1e (eq 1).

(1)

In summary, we have developed a Rh(I)-catalyzed strategy for the direct arylation of pyridines and quinolines. The heterocycle is used without the need for prefunctionalization, and all reaction components are inexpensive and readily available. The strategy represents an expeditious route to an important class of bis(hetero)aryls and should be of broad utility.¹⁴

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures and analytical data for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.