Palladium-catalyzed picolinamide-directed iodination of remote ortho-C−H bonds of arenes: Synthesis of tetrahydroquinolines

Abstract

A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ε-C(sp²)−H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp³)−H arylation, Pd-catalyzed ε-C(sp²)−H iodination, and Cu-catalyzed C−N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

Introduction

Tetrahydroquinoline (THQ) is an important N-heterocyclic scaffold found in many natural products and pharmaceutical agents [1–2]. Efficient and generally applicable methods for the synthesis of THQs with complex substitution patterns are still in great demand [3–7]. Recently, we reported a synthetic strategy for THQs based on picolinamide (PA)-directed sequential C−H functionalization reactions starting from readily accessible aryl iodide and alkylamine precursors (Scheme 1) [8]. Alkylpicolinamides were first subjected to Pd-catalyzed γ-C(sp³)−H arylation with aryl iodides to form γ-arylpropylpicolinamides [9–20]. These γ-arylpropylpicolinamides were then selectively iodinated at the remote ε-C(sp²)−H position via a rarely precedented PA-directed electrophilic aromatic substitution (S_EAr) reaction (Scheme 1, reaction 2) [21–22]. Copper-catalyzed intramolecular C−N cyclization of these ortho-iodinated intermediates provided PA-coupled THQ products in good yields.

Scheme 1.

New synthetic strategy for THQs via PA-directed C−H functionalization.

Although ε-C−H iodination via directed S_EAr proceeds with excellent yield and mono-selectivity for many γ-arylpropylpicolinamides, the scope of these PA-directed S_EAr reactions is limited to arenes bearing moderate electron-donating or withdrawing groups. Arene substrates bearing strongly electron-donating substituents typically gave substantial amounts of undesired iodinated side products via competing innate S_EAr processes, and arene substrates bearing strongly electron-withdrawing substituents were often unreactive. Herein, we report our development of a Pd-catalyzed PA-directed iodination reaction of ε-C(sp²)−H bonds of γ-arylpropylpicolinamides. This Pd-catalyzed reaction is complementary in scope to the directed S_EAr iodination approach and allows for the efficient synthesis of a broad range of THQs with diverse substitution patterns.

Results and Discussion

Methods for metal-catalyzed halogenation of ortho C−H bonds at the more remote ε position are scarce, in contrast to the large number of ortho C−H halogenation reactions of arenes effected by more proximal directing groups [23–33]. Fundamentally, it is challenging to achieve efficient reactions through kinetically unfavorable seven-membered palladacycle intermediates. Furthermore, the electrophilic reagents used for C–H halogenation can often react with arenes through undirected S_EAr pathways, which need to be suppressed for regioselectivity. To address this issue upfront, we commenced our study of Pd-catalyzed ε-C−H halogenation with 3-arylpropylpicolinamide 5 bearing a strongly electron-donating OMe group (Table 1, see Supporting Information File 1 for the preparation of 5). Iodination of 5 under our previous S_EAr protocol gave undirected iodination product 7 as the major product; only a trace amount of ortho-iodination product 6 was detected (Table 1, entries 1 and 2). Iodination of 5 under a variety of Pd-catalyzed oxidative conditions gave either low conversion or poor regioselectivity (Table 1, entries 3–5). To our delight, the use of a combination of 2 equiv of I₂ and 2 equiv of PhI(OAc)₂ in DMF at 110 °C gave the desired product 6 in good yield and moderate selectivity. Similar conditions were reported by Yu to effect the Pd-catalyzed NHTf-directed iodination of δ-C(sp²)−H bonds of β-phenylethyl triflamides [33]. IOAc generated in situ is believed to be the active iodinating species. DMF was found to be the best solvent for this reaction (Table 1, entry 9 vs 11 and 12). Moreover, we found that the choice of alkali carbonate base was important: replacing K₂CO₃ with KHCO₃ or Na₂CO₃ gave notably improved yields and ortho selectivity (Table 1, entries 9 and 10) [34–35]. By analogy with similar Pd-catalyzed directed C–H halogenation reactions, we speculate that the catalytic cycle follows a sequence of C−H palladation, oxidative addition and reductive elimination [36–37].

Table 1.

Optimization of Pd-catalyzed ortho C−H iodination of 5.^a

entry	reagents (equiv)	solvent	temperature (°C)	yield (%)b
				6	7
1	NIS (1.5), HBF4·EtO2 (4.0)	T/Dc	0	<2	68
2	NIS (1.5)	T/D	0	<2	82
3	Pd(OAc)2 (10 mol %), NIS (1.5)	chlorobenzene	110	<2	74
4	Pd(OAc)2 (10 mol %), NaI (1.5), NaIO3 (1.5), K2S2O8 (2.0)	n-BuOH	110	<2	<2
5	Pd(OAc)2 (10 mol %), I2 (2.0), K2S2O8 (2)	DMF	110	<2	60
6	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0)	DMF	110	43	25
7	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), K2CO3 (1.0)	DMF	110	14	11
8	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (2.0)	DMF	110	45	12
9	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (1.0)	DMF	110	75 (72)d	9 (5)d
10	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), Na2CO3 (1.0)	DMF	110	80	8
11	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (1.0)	dichloroethane	110	16	58
12	Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (1.0)	dioxane	110	13	65
13	I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (1.0)	DMF	110	<2	64

^aAll screening reactions were carried out in a 10 mL glass vial on a 0.2 mmol scale: ^bYields are based on ¹H NMR analysis of the reaction mixture using CH₂Br₂ as internal standard; ^cT/D: TFA (T)/CH₂Cl₂ (D); ^disolated yield.

With the best conditions in hand (Table 1, entries 9 and 10), we then examined the substrate scope of this Pd-catalyzed iodination of γ-arylpropylpicolinamides (Table 2). The γ-arylpropylpicolinamides were prepared from the corresponding N-alkylpicolinamides and aryl iodides under our (BnO)₂PO₂H-promoted Pd-catalyzed γ-C(sp³)−H arylation conditions (see Supporting Information File 1 for details). The substrate scope was chosen to complement the S_EAr method, which is notably incompatible with NO₂, F and OMe substituents. In contrast to the mono-selectivity of the directed S_EAr approach (reaction 2, Scheme 1), iodination of γ-phenylpropylpicolinamide 2 bearing two equivalent ortho C−H bonds under Pd-catalyzed conditions A gave a mixture of mono-iodinated 3 and ortho diiodinated product 4. However, no para-iodinated side product was formed. With 4 equiv of PhI(OAc)₂/I₂ and 1 equiv of KHCO₃, 4 can be formed as the major product in 69% yield.

Table 2.

Substrate scope of Pd-catalyzed ε-C−H iodination and Cu-catalyzed C−N cyclization to form THQs^a.

C–H arylationb	iodination		C–N cyclization
	Pd catalyzed	directed SEAr
2 (67%)	3 (mono-I, 47%) + 4 (di-I, 25%)c	3 (76%) + 4 (6%)	8 (93%)
9 (81%)	10 (75%)	10 (60%) (o/x = 5:3)c	11 (96%)
12 (81%)	13 (68%)	13 (50%) (o/x = 5:4)c	14 (94%)
15 (28%)	16 (68%)	NR	17 (47%)
18 (60%)	19 (56%)	19 (20%) (o/x = 1:4)c	20 (85%)
21 (95%)	22 (53% or 85%d)	23 (90%) X-ray	24 (78%)

^aYields are based on isolated product on a 0.2 mmol scale; ^bsee reaction 1 in Scheme 1B for conditions for Pd-catalyzed C−H arylation; ^cdi: ortho-diiodinated isomer, x: mixture of other iodinated isomers; ^dconditions B: I₂ (2 equiv), PhI(OAc)₂ (2 equiv), Pd(OAc)₂ (10 mol %), Na₂CO₃ (1 equiv), DMF, 110 °C, 24 h.

Arenes bearing meta-substituents (e.g., 12) were selectively iodinated at the less hindered ortho position. Pd-catalyzed iodination of substrate 15 bearing a strongly electron-withdrawing NO₂ group also proceeded smoothly to give 16; this substrate is unreactive to directed S_EAr. The rigid arylnorbornane scaffold 18 is incompatible with directed S_EAr, but was iodinated selectively at the ortho position under Pd-catalyzed conditions without the formation of regioisomeric side products. The strong para-directing effect exerted by aryl fluoride substituents overrides directed S_EAr selectivity [38–39]. Thus, we observed only para-iodinated compound 23 when 21 was subjected to the directed S_EAr protocol. In contrast, using our Pd-catalyzed iodination (conditions B), ortho-iodinated product 22 was obtained via Pd-catalyzed iodination as the only product in excellent yield. The iodinated intermediates could be readily cyclized under our previously reported Cu-catalyzed conditions to give PA-coupled THQ products with various substitution patterns in good yields (Scheme 2) [8].

Scheme 2.

Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)₂ (10 mol %), (BnO)₂PO₂H (20 mol %), Ag₂CO₃ (1.5 equiv), t-AmylOH, 110 °C, 24h; b) Pd(OAc)₂ (10 mol %), I₂ (4 equiv), PhI(OAc)₂ (4 equiv), KHCO₃ (1 equiv), 130 °C, DMF, 24 h; c) NIS (1.1 equiv), HBF₄^.OEt₂ (4), TFA/DCM (1:9), 2.5 mM, 0 °C, 4 h; d) CuI (10 mol %), CsOAc (2.5 equiv), DMSO, Ar, 90 °C, 20 h; e) NIS (1.1 equiv), TFA/DCM (1:9), 2.5 mM, rt, 16 h; f) Pd(OAc)₂ (15 mol %), NIS (2.5 equiv), α,α,α-trifluorotoluene, Ar, 100 °C, 24 h.

As shown in Scheme 2, Pd-catalyzed PA-directed ε-C−H iodination can be used in concert with PA-directed γ-C−H arylation, PA-directed S_EAr iodination, and undirected S_EAr iodination to quickly access THQs 27–30 bearing iodo groups at different positions on the arene ring [40–42]. Ortho-diiodinated product 4 was obtained from 2 in 69% yield using optimized Pd-catalyzed ε-C–H iodination conditions, and Cu-catalyzed C–N cyclization of 4 gave 5-iodo-THQ 27. PA-THQ 8 was susceptible to iodination at two positions. Under undirected S_EAr conditions, 6-iodo-THQ 28 was produced in excellent yield and regioselectivity. Alternatively, a Pd-catalyzed C–H iodination reaction of 8 was developed which provides 8-iodo-THQ 29. Pd-catalyzed C−H arylation of 1 with para-diiodobenzene under the standard arylation conditions gave 25 in moderate yield. Iodination of 25 via PA-directed S_EAr gave diiodinated compound 26, which was cyclized under Cu catalysis to give 7-iodo-THQ 30 in good yield. The PA group of 8-iodo-THQ 29 was readily removed with LiBHEt₃ to give 31 (Scheme 3) [10].

Scheme 3.

Removal of PA auxiliary from THQ product.

Conclusion

In summary, we have developed a new palladium-catalyzed picolinamide (PA)-directed iodination reaction of ε-C(sp²)−H bonds of γ-arylpropylamine substrates. This method works well for arenes with a broad range of substituents and offers a complementary scope to our previously reported PA-directed S_EAr approach. This Pd-catalyzed PA-directed ε-C−H iodination can be used in concert with the PA-directed γ-C−H arylation, PA-directed S_EAr iodination, undirected S_EAr iodination, and Cu-catalyzed C−N cyclization to quickly access tetrahydroquinolines bearing diverse substitution patterns from readily accessible starting materials.

Supporting Information

File 1

Detailed synthetic procedures and characterizations of all new compounds.

This article is part of the Thematic Series "C–H Functionalization/activation in organic synthesis".