Palladium-catalyzed tandem N-vinylation and cyclization of anilines and haloenynes: An efficient approach to substituted quinolines

Article abstract of DOI:10.1002/adsc.201100318

The palladium-catalyzed tandem amination of haloenynes and intramolecular cyclization has been developed. The reaction provides a novel route for the synthesis of quinoline derivatives with high yields. Copyright

Full text of DOI:10.1002/adsc.201100318

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DOI: 10.1002/adsc.201100318
Palladium-Catalyzed Tandem N-Vinylation and Cyclization of
Anilines and Haloenynes: An Efficient Approach to Substituted
Quinolines
Yuxing Wang,a Qian Liao,a Peng Zhao,a and Chanjuan Xia,b,*
a
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+86)-10-6261-8239; e-mail: cjxi@tsinghua.edu.cn
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: April 28, 2011; Revised: June 20, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100318.
Abstract: The palladium-catalyzed tandem amina-
tion of haloenynes and intramolecular cyclization
has been developed. The reaction provides a novel
route for the synthesis of quinoline derivatives with
high yields.
represent a fruitful strategy to access indoles[3,4] or
pyrroles and pyrazoles[5] (Scheme 1, right). Based on
an analysis of the possible routes to the key inter-
mediate 1, we wondered whether it would be possible
to effect a transformation by intramolecular hydroar-
ylation of alkynes,[6] to gain access to other important
nitrogen heterocycles, such as quinolines (Scheme 1,
left).
Keywords: coupling reactions; cyclization; halo-
enynes; palladium; quinolines
Quinoline skeletons play important roles as compo-
nents of bioactive compounds.[7] Many methods have
been developed for the construction of quinolines.[8,9]
Among the various synthetic routines, transition
Transition metal-catalyzed tandem reactions have metal-catalyzed processes are highly attractive.[9] De-
emerged as a useful tool for the synthesis of N- spite this progress, the development of novel ap-
heteroACHTUNGTRENNUNGcyclic compounds, since they can directly lead proaches to quinoline derivatives from common
to complicated molecules from readily accessible building blocks is still desired. Herein we report an
starting materials under mild conditions with high ef- efficient approach to substituted quinolines by palla-
ficiency.[1,2] Among the reactions developed, Pd- or dium-catalyzed tandem N-vinylation and cyclization
Cu-catalyzed transformations of o-haloalkynylarenes of anilines and haloenynes.
or haloenynes via amination to form o-alkynylanilines
To identify the optimal reaction conditions for the
or alkynylenamines 1 followed by intramolecular reaction, a number of palladium catalysts, including
hydro
G
N
Pd
A
Pd
A
and
Scheme 1. Design of the synthesis of N-heterocyclic molecules by a tandem reaction.
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Table 1. Optimization of the reaction conditions.[a]
[a]
[b]
All the reactions were performed with 2a (1.1 mmol) and 3a (1.0 mmol) under a nitrogen
atmosphere.
Determined by 1H NMR. NMP=N-methyl-2-pyrrolidone; DMF=N,N-dimethylforma-
mide; DMSO=dimethyl sulfoxide.
PdACHTUNGTRENNUNG(PPh3)4, and several different organic solvents and yield (entry 5). The structure of product 4a was con-
1
bases were examined in a model reaction of para-tol- firmed by H NMR, 13C NMR, COSY, HMQC, and
uidine (2a) with (Z)-4-bromo-3-ethyl-1-phenylhex-3- HMBC.[11] It is noteworthy that no 2-benzyl-3,4-dieth-
en-1-yne (3a). Interesting observations emerged from yl-6-methylquinoline produced by initial intermolecu-
the data in Table 1. We first tried the reaction of 2a lar hydroamidation of the alkyne portion and subse-
(1.1 mmol) with bromoenyne 3a (1.0 mmol), which quent intramolecular ortho-vinylation was obtained
was readily prepared by the direct bromoalkynylation during the reaction. Different bases were also tested
of 3-hexyne,[10] 5 mol% of Pd
2.0 equivalents of t-BuONa in 2.0 mL of NMP at to be the most effective (entry 5).
ACHTUGNTRENUN(GN PPh3)2Cl2, and in this reaction system (entries 5–8), t-BuONa proved
908C for 24 h. The desired product 4a was not ob-
On decreasing the catalyst loading from 5 to
served (entry 1). The screening of various solvents re- 2.5 mol%, the product 4a was obtained in only 37%
vealed that the solvent played an important role in yield (entry 9). We next tested the reaction in the
this reaction (entries 1–4). Toluene was found to be presence of different catalysts. PdACHTNUGTRNEG(UN PPh3)2Cl2, was su-
quite successful for the transformation, and com- perior to any other palladium catalysts so far tested
pound 4a was obtained in 80% yield (entry 2). When (entries 5, 10–17). Notably, the reaction was not effec-
DMF or DMSO was used as a solvent, the reactions tive when only PdACTHUNTGRENNG(U OAc)2 or PdACHTUNTGERN(NUGN CH3CN)2Cl2 was em-
were messy with less than 5% of the desired product ployed (entries 10 and 11). It is noteworthy that in-
(entries 3 and 4). On prolonging the reaction time to creasing the reaction temperature resulted in de-
40 h, the expected product 4a was formed in 95% creased yield of the product (entries 18 and 19).
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Palladium-Catalyzed Tandem N-Vinylation and Cyclization of Anilines and Haloenynes
On the basis of these results, the optimal conditions tions. The reaction was applicable to various aromatic
included the following parameters: PdACHTNUGTRNEG(UN PPh3)2Cl2 as a amines. For example, reaction of 3a with para-me-
catalyst, t-BuONa as a base, and toluene as a solvent thoxyaniline 2b gave 4b in 87% yield (entry 2). When
with a reaction temperature at 908C. Under these op- 1-naphthylamine 2d was used as a substrate, the de-
timized conditions, a study on the substrate scope was sired product 4d was also formed in high yield after
carried out, and the results are summarized in 60 h (entry 4). Furthermore, the reaction of 3a with
Table 2. First, various aromatic amine derivatives 2 para-fluoroaniline 2e and para-chloroaniline 2f gave
were used for the reaction with (Z)-4-bromo-3-ethyl- the desired product 4e and 4f in 97% and 83% yields,
1-phenylhex-3-en-1-yne 3a under the optimized condi- respectively (entries 5 and 6). Notably, much longer
Table 2. Tandem synthesis of diversely substituted quinolines catalyzed by palladium.[a]
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Table 2. (Continued)
[a]
All the reaction were carried out using 1.1 mmol of aniline 2 and 1.0 mmol of haloenyne 3 in the
presence of Pd(PPh3)2Cl2 (5.0 mol%), and t-BuONa (2.0 mmol), in 3 mL toluene at 908C.
Determined by H NMR, isolated yield in parenthese.
AHCTUNGTRENNUNG
[b]
[c]
1
1-(2,5-Dimethylphenyl)-2,3-diethyl-5-phenyl-1H-pyrrole was isolated in 40% yield as by-product.
reaction times were needed for the para-halogen sub- isomer 4i and ortho-cyclization isomer 5i in 30% and
stituted anilines. It is noteworthy that the aniline with 27% yields (entry 9).
a strong electron-withdrawing group, such as CO2Et
On the other hand, different combinations of sub-
and CN group, on the para-position of he ring failed stituents on the alkyne and alkene of bromoenynes
to generate any product and starting materials re- can be used to allow the synthesis of alkyl- and aryl-
mained. When 2,5-dimethylaniline 2g, which has one substituted quinolines (entries 10–13). When alkyl
methyl group at the ortho-position, was used as a sub- substituents were on the end of alkyne, the desired
strate, the desired product 4g was formed in 43% product could not be observed. When a bromoenyne
yield after 72 h (entry 7), along with 40% of 1-(2,5-di- with one substituent on the alkene, such as (Z)-4-
methylphenyl)-2,3-diethyl-5-phenyl-1H-pyrrole as
a
bromo-4-phenyl-1-phenylbut-3-en-1-yne or (Z)-4-
by-product. This may be attributed to the steric hin- bromo-4-butyl-1-phenylbut-3-en-1-yne was used, the
drance of the ortho-methyl group. The regioselectivity desired product could not be observed. It is notewor-
of the reaction has also been investigated. meta-Me- thy that reaction of iodoenynes with aniline afforded
thoxyaniline derivative 2h afforded the para-cycliza- the desired products in moderate yields (entries 14
tion regioisomer 4h and ortho-cyclization isomer 5h in and 15) along with some uncharacterized by-products.
18% and 73% yields, respectively (entry 8). meta- The reaction of 1-bromo-2-(phenylethynyl)benzene
Chloroaniline 2i afforded the para-cyclization regio- with anilines was evaluated under the optimized con-
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Palladium-Catalyzed Tandem N-Vinylation and Cyclization of Anilines and Haloenynes
dure was repeated three times. Haloenyne (1 mmol) and tol-
uene (2 mL) were added by syringe at room temperature.
The tube was then sealed with a Teflon valve and the reac-
tion mixture was stirred at 908C for the indicated time.
Then the mixture was cooled to room temperature. Water
(5 mL) and ethyl acetate (5 mL) were added and stirred for
30 min. The aqueous layer was washed with ethyl acetate
(5 mL) for three times. The organic phase was combined
and the solvent was removed under vacuum and the crude
product was purified by column chromatography on neutral
alumina to get the corresponding quinoline products.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (2097208 and 21032004).
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