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

Article abstract of DOI:10.3762/bjoc.12.119

A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ?-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 ? -C(sp² )-H iodination, and Cu-catalyzed C-N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

Full text of DOI:10.3762/bjoc.12.119

Palladium-catalyzed picolinamide-directed iodination of
remote ortho-C−H bonds of arenes:
Synthesis of tetrahydroquinolines
William A. Nack1, Xinmou Wang2, Bo Wang3, Gang He*1 and Gong Chen*1,2,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1243–1249.
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 and 3Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Tianjin
300071, China
doi:10.3762/bjoc.12.119
Received: 24 March 2016
Accepted: 05 June 2016
Published: 17 June 2016
This article is part of the Thematic Series "C–H
Functionalization/activation in organic synthesis".
Email:
Gang He* - hegang@nankai.eud.cn; Gong Chen* -
gongchen@nankai.edu.cn
Guest Editor: R. Sarpong
* Corresponding author
© 2016 Nack et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
iodination; palladium; remote C–H activation; tetrahydroquinoline
Abstract
A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ε-C(sp2)−H bonds of γ-arylpropylamine sub-
strates 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 iodi-
nation, and Cu-catalyzed C−N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution
patterns.
Introduction
Tetrahydroquinoline (THQ) is an important N-heterocyclic scaf- amides were first subjected to Pd-catalyzed γ-C(sp3)−H aryl-
fold found in many natural products and pharmaceutical agents ation with aryl iodides to form γ-arylpropylpicolinamides
[1,2]. Efficient and generally applicable methods for the synthe- [9-20]. These γ-arylpropylpicolinamides were then selectively
sis of THQs with complex substitution patterns are still in great iodinated at the remote ε-C(sp2)−H position via a rarely prece-
demand [3-7]. Recently, we reported a synthetic strategy for dented PA-directed electrophilic aromatic substitution (SEAr)
THQs based on picolinamide (PA)-directed sequential C−H reaction (Scheme 1, reaction 2) [21,22]. Copper-catalyzed intra-
functionalization reactions starting from readily accessible aryl molecular C−N cyclization of these ortho-iodinated intermedi-
iodide and alkylamine precursors (Scheme 1) [8]. Alkylpicolin- ates provided PA-coupled THQ products in good yields.
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Scheme 1: New synthetic strategy for THQs via PA-directed C−H functionalization.
Although ε-C−H iodination via directed SEAr proceeds with Results and Discussion
excellent yield and mono-selectivity for many γ-arylpropylpi- Methods for metal-catalyzed halogenation of ortho C−H bonds
colinamides, the scope of these PA-directed SEAr reactions is at the more remote ε position are scarce, in contrast to the large
limited to arenes bearing moderate electron-donating or with- number of ortho C−H halogenation reactions of arenes effected
drawing groups. Arene substrates bearing strongly electron-do- by more proximal directing groups [23-33]. Fundamentally, it is
nating substituents typically gave substantial amounts of unde- challenging to achieve efficient reactions through kinetically
sired iodinated side products via competing innate SEAr pro- unfavorable seven-membered palladacycle intermediates.
cesses, and arene substrates bearing strongly electron-with- Furthermore, the electrophilic reagents used for C–H halogena-
drawing substituents were often unreactive. Herein, we report tion can often react with arenes through undirected SEAr path-
our development of a Pd-catalyzed PA-directed iodination reac- ways, which need to be suppressed for regioselectivity. To
tion of ε-C(sp2)−H bonds of γ-arylpropylpicolinamides. This address this issue upfront, we commenced our study of Pd-cata-
Pd-catalyzed reaction is complementary in scope to the directed lyzed ε-C−H halogenation with 3-arylpropylpicolinamide 5
SEAr iodination approach and allows for the efficient synthesis bearing a strongly electron-donating OMe group (Table 1, see
of a broad range of THQs with diverse substitution patterns.
Supporting Information File 1 for the preparation of 5). Iodina-
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Beilstein J. Org. Chem. 2016, 12, 1243–1249.
Table 1: Optimization of Pd-catalyzed ortho C−H iodination of 5.a
entry
reagents (equiv)
solvent
temperature (°C)
yield (%)b
6
7
1
2
3
4
NIS (1.5), HBF4·EtO2 (4.0)
NIS (1.5)
T/Dc
0
<2
<2
<2
<2
68
82
74
<2
T/D
0
Pd(OAc)2 (10 mol %), NIS (1.5)
chlorobenzene
n-BuOH
110
110
Pd(OAc)2 (10 mol %), NaI (1.5), NaIO3 (1.5),
K2S2O8 (2.0)
5
6
7
Pd(OAc)2 (10 mol %), I2 (2.0), K2S2O8 (2)
DMF
DMF
DMF
110
110
110
<2
43
14
60
25
11
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0)
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
K2CO3 (1.0)
8
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
KHCO3 (2.0)
DMF
110
110
110
110
110
110
45
12
9
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
KHCO3 (1.0)
DMF
75
(72)d
9
(5)d
10
11
12
13
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
Na2CO3 (1.0)
DMF
80
16
13
<2
8
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
KHCO3 (1.0)
dichloroethane
dioxane
DMF
58
65
64
Pd(OAc)2 (10 mol %), I2 (2.0), PhI(OAc)2 (2.0),
KHCO3 (1.0)
I2 (2.0), PhI(OAc)2 (2.0), KHCO3 (1.0)
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.
tion of 5 under our previous SEAr protocol gave undirected With the best conditions in hand (Table 1, entries 9 and 10), we
iodination product 7 as the major product; only a trace amount then examined the substrate scope of this Pd-catalyzed iodina-
of ortho-iodination product 6 was detected (Table 1, entries 1 tion of γ-arylpropylpicolinamides (Table 2). The γ-arylpropylpi-
and 2). Iodination of 5 under a variety of Pd-catalyzed oxida- colinamides were prepared from the corresponding N-alkyl-
tive conditions gave either low conversion or poor regioselec- picolinamides and aryl iodides under our (BnO)2PO2H-
tivity (Table 1, entries 3–5). To our delight, the use of a combi- promoted Pd-catalyzed γ-C(sp3)−H arylation conditions (see
nation of 2 equiv of I2 and 2 equiv of PhI(OAc)2 in DMF at Supporting Information File 1 for details). The substrate scope
110 °C gave the desired product 6 in good yield and moderate was chosen to complement the SEAr method, which is notably
selectivity. Similar conditions were reported by Yu to effect the incompatible with NO2, F and OMe substituents. In contrast to
Pd-catalyzed NHTf-directed iodination of δ-C(sp2)−H bonds of the mono-selectivity of the directed SEAr approach (reaction 2,
β-phenylethyl triflamides [33]. IOAc generated in situ is Scheme 1), iodination of γ-phenylpropylpicolinamide 2 bearing
believed to be the active iodinating species. DMF was found to two equivalent ortho C−H bonds under Pd-catalyzed conditions
be the best solvent for this reaction (Table 1, entry 9 vs 11 and A gave a mixture of mono-iodinated 3 and ortho diiodinated
12). Moreover, we found that the choice of alkali carbonate product 4. However, no para-iodinated side product was
base was important: replacing K2CO3 with KHCO3 or Na2CO3 formed. With 4 equiv of PhI(OAc)2/I2 and 1 equiv of KHCO3, 4
gave notably improved yields and ortho selectivity (Table 1, can be formed as the major product in 69% yield.
entries 9 and 10) [34,35]. By analogy with similar Pd-catalyzed
directed C–H halogenation reactions, we speculate that the cata- Arenes bearing meta-substituents (e.g., 12) were selectively
lytic cycle follows a sequence of C−H palladation, oxidative ad- iodinated at the less hindered ortho position. Pd-catalyzed iodi-
dition and reductive elimination [36,37].
nation of substrate 15 bearing a strongly electron-withdrawing
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Table 2: Substrate scope of Pd-catalyzed ε-C−H iodination and Cu-catalyzed C−N cyclization to form THQsa.
C–H arylationb
iodination
C–N cyclization
Pd catalyzed
directed SEAr
3 (76%)
+ 4 (6%)
2 (67%)
3 (mono-I, 47%)
+ 4 (di-I, 25%)c
8 (93%)
10 (60%)
(o/x = 5:3)c
9 (81%)
10 (75%)
13 (68%)
11 (96%)
14 (94%)
13 (50%)
(o/x = 5:4)c
12 (81%)
NR
15 (28%)
18 (60%)
21 (95%)
16 (68%)
19 (56%)
17 (47%)
20 (85%)
19 (20%)
(o/x = 1:4)c
23 (90%)
X-ray
22 (53% or 85%d)
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.
NO2 group also proceeded smoothly to give 16; this substrate is para-directing effect exerted by aryl fluoride substituents over-
unreactive to directed SEAr. The rigid arylnorbornane scaffold rides directed SEAr selectivity [38,39]. Thus, we observed only
18 is incompatible with directed SEAr, but was iodinated selec- para-iodinated compound 23 when 21 was subjected to the
tively at the ortho position under Pd-catalyzed conditions with- directed SEAr protocol. In contrast, using our Pd-catalyzed iodi-
out the formation of regioisomeric side products. The strong nation (conditions B), ortho-iodinated product 22 was obtained
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via Pd-catalyzed iodination as the only product in excellent was obtained from 2 in 69% yield using optimized Pd-cata-
yield. The iodinated intermediates could be readily cyclized lyzed ε-C–H iodination conditions, and Cu-catalyzed C–N
under our previously reported Cu-catalyzed conditions to give cyclization of 4 gave 5-iodo-THQ 27. PA-THQ 8 was suscep-
PA-coupled THQ products with various substitution patterns in tible to iodination at two positions. Under undirected SEAr
good yields (Scheme 2) [8].
conditions, 6-iodo-THQ 28 was produced in excellent yield and
regioselectivity. Alternatively, a Pd-catalyzed C–H iodination
As shown in Scheme 2, Pd-catalyzed PA-directed ε-C−H iodi- reaction of 8 was developed which provides 8-iodo-THQ 29.
nation can be used in concert with PA-directed γ-C−H arylation, Pd-catalyzed C−H arylation of 1 with para-diiodobenzene
PA-directed SEAr iodination, and undirected SEAr iodination to under the standard arylation conditions gave 25 in moderate
quickly access THQs 27–30 bearing iodo groups at different po- yield. Iodination of 25 via PA-directed SEAr gave diiodinated
sitions on the arene ring [40-42]. Ortho-diiodinated product 4 compound 26, which was cyclized under Cu catalysis to give
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.
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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 com-
plementary scope to our previously reported PA-directed SEAr
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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 tetrahydro-
quinolines bearing diverse substitution patterns from readily
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Supporting Information
Supporting Information File 1
Detailed synthetic procedures and characterizations of all
new compounds.
See for our recent report on Pd-catalyzed PA-directed ortho C−H
halogenation of benzylamine substrates.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-119-S1.pdf]
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Acknowledgements
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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