Palladium-Catalyzed Carbonylative Cyclization/Arylation Cascade for 2-Aroyl Indolizine Synthesis

Abstract

An efficient synthesis of densely substituted 2-aroyl indolizines via the palladium-catalyzed carbonylative cyclization/arylation is reported. This transformation proceeds via the 5-endo-dig cyclization of 2-propargylpyridine triggered by an aroyl Pd-complex. It produced diversely substituted 2-aroyl indolizines in good-to-excellent yield.

Indolizines have attracted noteworthy attention in recent years due to their profound biological effects.¹ Both naturally-occurring and synthetic indolizines have shown great potential in pharmaceutical research as cytotoxins,² anti-inflammatory agents,³ and 5-HT3 receptor antagonists⁴. In this regard, transformations that utilize readily available substrates to provide access to diversely substituted indolizines, especially those bearing an electron withdrawing group at the C-2 postion⁵, are in high demand. The classic Tschichibabin reaction provides straightforward access to C-2 substituted indolizines via the condensation of picolines and α-bromo-acetophenone derivatives. However, the limited availability of starting materials restricts the substitution pattern of the product.⁶ The [3+2] cycloaddition of pyridinium ylides with alkynes provides another viable route to the indolizine core. However, the regioselectivity issue, as well as the moderate yields caused by necessary oxidation of the formed intermediate, limits its synthetic application.⁷ The Morita-Baylis-Hillman reaction can also be utilized for the preparation of indolizin-2-yl ketone from an appropriate Michael acceptor. However, it suffers from the narrow range of starting materials that can be used and the usually low reactivity of the substrates.⁸ In addition to the traditional condensation methods, transition metal catalysis has been widely used for the construction of diversely functionalized, especially heteroatom-substituted indolizines, under mild conditions.⁹ Nonetheless, the selective introduction of functionality at the C-2 position is still a challenging task.¹⁰ Along this line, our group has recently reported a synthesis of 2-aryl indolizines via the palladium catalyzed arylative 5-endo-dig cyclization of 2-propargylpyridine (Scheme 1, eq. 1).¹¹ Herein, we report a Pd-catalyzed cascade carbonylative cyclization/arylation approach to densely substituted 2-aroyl indolizines that proceeds in good-to-excellent yields (eq. 2).

Scheme 1.

Indolizine Synthesis via Palladium Catalyzed Cyclization

Continuing with our efforts in the synthesis of diversely functionalized indolizines, we thought that the employment of benzoyl chloride instead of an aryl halide as electrophile in this cascade cyclization would provide 2-benzoyl indolizine.¹² However, the reaction of pivaloate 1a with benzoyl chloride in the presence of a Pd catalyst failed to produce even trace amount of 2a (eq. 3).

Thus, we thought of alternative methods to introduce the benzoyl function at the C-2 position of indolizine. Since (1) an acyl palladium species can be formed via a migratory insertion of carbon monoxide into an aryl-palladium bond; and (2) there have been reported examples on synthesis of diaryl ketones via the palladium catalyzed carbonylative cyclization/arylation cascades,¹³ we anticipated that under a CO atmosphere, the in situ formed acyl palladium species might trigger the expected carbonylative cyclization/arylation cascade to obtain 2.

(3)

To test this idea, we examined the carbonylative cyclization of pivaloate 1a and different aryl halides under continuous 10 psi CO supply. Initially we found that the carbonylative cyclization of 1a and iodobenzene in the presence of Pd(PPh₃)Cl₂ catalyst yielded 2a in quantitative yield (Table 1, entry 1). However, aryl halides bearing electron-withdrawing groups, such as methyl p-iodobenzoate, were not competent reactants under these conditions (entry 2).¹⁴ On the contrary, the combination of Pd(OAc)₂ catalyst, PCy₃ ligand and triethylamine base afforded benzoate 2f in 90% yield (entry 3). Under the same conditions, the yield of 2a was only 19% along with a substantial amount of palladium black produced, which implied decomposition of an excessively reactive catalyst (entry 4). The yield of 2a was improved to 51% by switching ligand to PPh₃ (entry 5). The reaction that was performed in a sealed Schlenk tube, which simplified the reaction setup and allowed a higher pressure (20 psi and above), provided 2a in 86% yield at 20 psi CO pressure (entry 6). Finally the screening of different solvents under a reduced temperature revealed that acetonitrile was the optimal choice over DMF and toluene (entries 7–9).

Table 1.

Optimization of Conditions

entry	ligand	base	solvent	temp.	COa	yield (%)b
1	Pd(PPh3)2Cl2/PPh3	K2CO3	DMF	100	A	2a > 99c
2	Pd(PPh3)2Cl2/PPh3	K2CO3	DMF	100	A	2f decomp.c
3	Pd(OAc)2/PCy3	NEt3	DMF	80	A	2f 90
4	Pd(OAc)2/PCy3	NEt3	DMF	80	A	2a 19
5	Pd(OAc)2/PPh3	NEt3	DMF	80	A	2a 51
6	Pd(OAc)2/PPh3	NEt3	DMF	80	B	2a 86
7	Pd(OAc)2/PPh3	NEt3	DMF	70	B	2a 65
8	Pd(OAc)2/PPh3	NEt3	toluene	70	B	2a 45
9	Pd(OAc)2/PPh3	NEt3	MeCN	70	B	2a 95

^aA: Reactions were conducted in flask with continuous 10 psi CO supply. B: Reacitons were conducted in sealed Schlenk tube with 20 psi CO.

^bIsolated yields of 0.5 mmol reactions.

^c1 equivalent of TBAI was added.

With the optimized conditions in hand, the scope of reaction was examined. It was found that a series of iodoarenes bearing different substituents at various positions smoothly underwent this carbonylative cyclization with 1a, yielding indolizines 2a to 2i in moderate to excellent yields (Table 2, entries 1–9). The cyclization of 3-n-hexyl, n-butyl and cyclohexenyl substituted pivaloates also provided the expected products in good yield (entry 10 to 15). Substrates possessing a functionalized pyridine ring at C-5 produced indolizines 2p, 2q and pyrrolo[1,2-a]quinoline 2r in moderate-to-good yields (entries 16–18). On the contrary, cyclization of 3-methyl substituted pyridine provided 8-methyl 2s in a relative low yield (entry 19). In addition to various pivaloates, a TBDMS ether was equally effective in this reaction, yielding 2t in 80% yield (entry 20). More interestingly, the cyclization of 1-(1-pyridin-2-yl-propargyl)morpholine resulted in the 1-morpholin-1-yl indolizine 2u in 71% yield, which provided a convenient access to the C-2 substituted 1-amino-indolizines.¹⁵

Table 2.

Reaction Scope of Carbonylative Cyclization.

entry	2	yield (%) b
1	2a	95
2	2b	77
3	2c	78
4	2d	99
5	2e	59
6	2f	61
7	2g	69
8	2h	64
9	2i	64
10	2j	80
11	2k	80
12	2l	64
13	2m	81
14	2n	67
15	2o	72
16	2p	90
17	2q	85
18	2r	53
19	2s	35
20	2t	80
21	2u	71

^aConditions: Pd(OAc)₂ 5 mol %, PPh₃ 10 mol %, Ar-I 1.5 equiv, triethylamine 2 equiv, MeCN 0.2 M, 70 °C, CO 20 psi in sealed Schlenk tube, 12 h.

^bIsolated yields of 0.5 mmol reactions.

Presumably, this palladium catalyzed carbonylative cyclization starts with the formation of the aroyl palladium species 3 (Scheme 2) via a migratory insertion of CO into the aryl-palladium bond, followed by its coordination of the triple bond of 1 to the palladium center. The 5-endo-dig cyclization leads to the formation of indolizinium intermediate 4, which after a proton loss-aromatization produces heteroaryl palladium species 5. The reductive elimination of 5 releases the product 2-benzoylindolizine 2 to regenerate the Pd catalyst.

Scheme 2.

Proposed Mechanism

In summary, the Pd-catalyzed carbonylative cyclization/arylation approach to 2-aroyl indolizines has been developed. This new method allows for the efficient and selective synthesis of important⁵ 2-aroyl indolizines from readily available propargyl pyridines, iodoarenes under a carbon monoxide atmosphere.