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

  1. 1 ,
  2. 2 ,
  3. 3 ,
  4. 1 and
  5. 1,2,3
1Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
2State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
3Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
  1. Corresponding author email
Guest Editor: R. Sarpong
Beilstein J. Org. Chem. 2016, 12, 1243–1249.
Received 24 Mar 2016, Accepted 05 Jun 2016, Published 17 Jun 2016
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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.


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 (SEAr) 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 SEAr proceeds with excellent yield and mono-selectivity for many γ-arylpropylpicolinamides, the scope of these PA-directed SEAr 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 SEAr 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 SEAr 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 SEAr 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 SEAr 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

[Graphic 1]
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
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 SEAr method, which is notably incompatible with NO2, F and OMe substituents. In contrast to the mono-selectivity of the directed SEAr 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 THQsa.

[Graphic 2]
C–H arylationb iodination C–N cyclization
Pd catalyzed directed SEAr
[Graphic 3]
2 (67%)
[Graphic 4]
3 (mono-I, 47%)
+ 4 (di-I, 25%)c
3 (76%)
+ 4 (6%)
[Graphic 5]
8 (93%)
[Graphic 6]
9 (81%)
[Graphic 7]
10 (75%)
10 (60%)
(o/x = 5:3)c
[Graphic 8]
11 (96%)
[Graphic 9]
12 (81%)
[Graphic 10]
13 (68%)
13 (50%)
(o/x = 5:4)c
[Graphic 11]
14 (94%)
[Graphic 12]
15 (28%)
[Graphic 13]
16 (68%)
NR [Graphic 14]
17 (47%)
[Graphic 15]
18 (60%)
[Graphic 16]
19 (56%)
19 (20%)
(o/x = 1:4)c
[Graphic 17]
20 (85%)
[Graphic 18]
21 (95%)
[Graphic 19]
22 (53% or 85%d)
[Graphic 20]
23 (90%)
[Graphic 21]
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 SEAr. The rigid arylnorbornane scaffold 18 is incompatible with directed SEAr, 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 SEAr selectivity [38,39]. Thus, we observed only para-iodinated compound 23 when 21 was subjected to the directed SEAr 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 SEAr iodination, and undirected SEAr iodination to quickly access THQs 2730 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 SEAr 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 SEAr 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.


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 SEAr 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 SEAr iodination, undirected SEAr iodination, and Cu-catalyzed C−N cyclization to quickly access tetrahydroquinolines bearing diverse substitution patterns from readily accessible starting materials.

Supporting Information

Supporting Information File 1: Detailed synthetic procedures and characterizations of all new compounds.
Format: PDF Size: 5.6 MB Download


We gratefully acknowledge financial support from the State Key Laboratory of Elemento-Organic Chemistry at Nankai University and the Pennsylvania State University.


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