Two-Component Approach Toward Fully-Substituted N-Fused Pyrrole Ring

Abstract

An efficient two-component palladium-catalyzed arylation/cyclization cascade approach toward a variety of N-fused pyrroloheterocycles has been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with propargylic esters or ethers followed by the 5-endo-dig cyclization leading to highly functionalized pyrroloheterocycles in good to excellent yield.

Nitrogen-containing heteroaromatic molecules and their analogs are pharmaceutically important scaffolds, broadly present in naturally occuring and synthetic biologically active molecules.¹ For example, molecules containing indolizine and other closely related cores exhibit a wide array of biological activities, including cytotoxicity,² multi-drug resistance (MDR) reversal in some cancer cell lines,³ and imunomodulation.⁴

In this regard, transformations that utilize readily available substrates to provide access to densely substituted pyrroloheterocycles are in high demand.⁵ Previously, our group reported silver-catalyzed cycloisomerization of propargyl heterocycles as a route to 1, 3-disubstituted N-fused heterocycles (Scheme 1, eq 1).⁶ An alternative protocol is based on the the gold-catalyzed migratory cycloisomerization of propargyl ethers into various types of 1, 2-disubstituted N-fused heterocycles (eq 2).⁷ Although these methods are general with respect to the heterocyclic core, these approaches are limited to the synthesis of 1, 3- or 1, 2-disubstituted indolizines, while either the C-2 or C-3 position remain unfunctionalized. This problem was recently mitigated by employing stoichiometric amounts of iodine,5f,g,h followed by cross-coupling steps. Herein, we report a Pd-catalyzed two-component arylation/cyclization cascade approach toward 1, 2, 3-trisubstituted N-fused heterocycles in good to excellent yields (eq 3).⁸

Scheme 1.

Approaches Toward Indolizines with Different Substitution Pattern

We hypothesized that Ar-Pd-X species would undergo carbopalladation of the propargylic moiety of 1 with subsequent 5-endo-dig cyclization to produce 2 (eq 3).

To test this idea, the easily accessible propargyl-containing pyridine 1⁹ was first subjected to the palladium-catalyzed arylation/cyclization reaction. Employing iodobenzene as the electrophilic component led to formation of the desired indolizine 2a in 49 % yield (Table 1, entry 1). Attempts to substitute DMF with other solvents were not particularly successful (entries 2–4). Utilizing different lithium and ammonium salts led to a significant improvement in the reaction yields (entries 5–8). Switching the base from NEt₃ to K₂CO₃ was also beneficial (entry 9).

Table 1.

Optimization of Cascade Approach

entry	X	Pd	base	solvent	additive	yield, %b
1	I	PdCl2(PPh3)2	NEt3	DMF	-	49
2	I	PdCl2(PPh3)2	NEt3	DMA	-	46
3	I	PdCl2(PPh3)2	NEt3	NMP	-	47
4	I	PdCl2(PPh3)2	NEt3	MeCN	-	34c
5	I	PdCl2(PPh3)2	NEt3	DMF	LiCl	54
6	I	PdCl2(PPh3)2	NEt3	DMF	TBAC	57
7	I	PdCl2(PPh3)2	NEt3	DMF	TBAB	60
8	I	PdCl2(PPh3)2	NEt3	DMF	TBAI	62
9	I	PdCl2(PPh3)2	K2CO3	DMF	TBAI	69
10	I	PdCl2(PPh3)2	K2CO3	DMF	TBAId	72
11	Br	PdCl2(PPh3)2	K2CO3	DMF	TBAId	26

^aReactions were run in the precence of 5 mol % of catalyst in appropriate solvent (0.33 M) at 120 °C for 4 hours.

^bGC/MS yields.

^cReaction was performed at 90 °C.

^dReaction was run with additional 40 mol % of PPh₃.

Furthermore, using triphenylphosphine as an additive led to the formation of 2a in 78 % yield (entry 10). Employment of bromo-benzene under these conditions proved to be less efficient producing indolizine 2a in 29 % yield only (entry 11).

Next, under the optimized conditions, the scope of this cascade cyclization was examined (Table 2). Thus, acetyloxy and pivalyloxy-propargylic esters possesing alkyl (entries 1–7), aryl (entries 8, 9), or alkenyl (entry 10) substituents at the triple bond underwent smooth conversion to give the corresponding heterocycles 2a–j in good to excellent yields. To provide a handle for further functonalization, pivalates were chosen over acetates due to their greater potential to participate in Suzuki-Miyaura¹⁰ and Kumada^5e coupling reactions.

Table 2.

Arylation/Cyclization Cascade Reactions of Propargylic Esters 1^a

entry	2	yield, %b
1	2a	72
2	2b	76
3	2c	94
4	2d	77
5	2e	94
6	2f	50
7	2g	94
8	2h	69
9	2i	68
10	2j	96
11	2k	87
12	2l	53
13	2m	70
14	2n	90
15	2o	93
16	2p	88
17	2q	71
18	2r	74
19	2s	78
20	2t	88

^aAll reactions were performed with on 0.5 mmol scale in DMF (0.33 M) at 120 °C.

^bYield of the isolated product after flash chromatography on silica gel.

The generality of this process was expanded by utilization of a variety of functionalized iodobenzenes which uneventfully cyclized into the corresponding indolizines 2k–p (entries 11–16). Notably, this reaction proceeded equally efficiently with other heterocyclic cores; quinoline and isoquinoline propargylic esters were successfully utilized in this transformation providing access to tricyclic cores 2q–t in a highly efficient manner (entries 17–20).

It was also found that propargylic phenylethers 3 could be employed in this transformation (Scheme 2). Interestingly, bromobenzenes performed equally well in this process (4a–c). Similarly, the cascade cyclization of propargylic silylether 3 gave the corresponding indolizine 4e in 73 % yield.

Scheme 2.

Arylation/Cyclization Cascade Reactions of Propargylic Ethers 3

^a Reaction was performed under optimized conditions reported in Table 2.

Presumably, this palladium-catalyzed arylation/-cyclization reaction proceeds through a coordination of the triple bond of an alkyne 1 with ArPdX, triggering the 5-endo-dig cyclization by the nucleophilic attack of the pyridyl nitrogen, leading to the formation of zwitterionic adduct 5. The latter, upon deprotonation/tautomerization and subsequent reductive elimination¹¹ would give product 2.

In summary, we have developed a practical and efficient two-component coupling method toward fully-substituted fused pyrroloheterocycles, including indolizines, pyrroloquinolines, and pyrroloisoquinolines. This method is complementary to the previously developed approaches^6,7,12 toward mono- and disubstituted N-fused pyrroloheterocycles.

Scheme 3.

Proposed Mechanism