Synthesis of substituted 1,2-dihydroquinolines and quinolines from aromatic amines and alkynes by gold(I)-catalyzed tandem hydroamination-hydroarylation under microwave-assisted conditions

Article abstract of DOI:10.1021/ol070814l

Equation Presented A method to efficiently prepare substituted 1,2-dihydroquinolines and quinolines by Au(I)-catalyzed tandem hydroamination-hydroarylation under microwave irradiation was developed. This method requires short reaction time (10-70 min) and

Full text of DOI:10.1021/ol070814l

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2645-2648
Synthesis of Substituted
1,2-Dihydroquinolines and Quinolines
from Aromatic Amines and Alkynes by
Gold(I)-Catalyzed Tandem
Hydroamination−Hydroarylation under
Microwave-Assisted Conditions
Xin-Yuan Liu, Pan Ding, Jie-Sheng Huang, and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong, People’s Republic of China
cmche@hku.hk
Received April 5, 2007
ABSTRACT
A method to efficiently prepare substituted 1,2-dihydroquinolines and quinolines by Au(I)-catalyzed tandem hydroamination
−hydroarylation
under microwave irradiation was developed. This method requires short reaction time (10 70 min) and has a broad substrate scope.
−
Compounds containing a partially hydrogenated quinoline
moiety are potential therapeutics such as inhibitors for lipid
peroxidation, HMG-CoA reductase, and progesterone ago-
nists and antagonists.1 Many synthetic methods including
transition metal catalysis have been developed to generate
dihydroquinoline compounds.2,3 As inter- and intramolecular
formation of dihydroquinolines usually requires high tem-
perature and/or prolonged reaction time, and most of the
reported catalysts for dihydroquinoline synthesis showed
limited scope of substrates and modest selectivity, a mild
and efficient protocol for the synthesis of this class of
compounds would be highly desirable.
Au(I) and Au(III) complexes have increasingly been used
as catalysts for a variety of organic transformations,4,5 and
gold-catalyzed intermolecular hydroamination of alkynes3c,6
(2) (a) Hennion, G. F.; Hanzel, R. S. J. Am. Chem. Soc. 1960, 82, 4908.
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N. M.; Ward, A. D. Tetrahedron 2005, 61, 155.
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D. P.; Roth, B. J. Med. Chem. 1989, 32, 1942. (c) Carling, R. W.; Leeson,
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10.1021/ol070814l CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/12/2007

and inter- or intramolecular hydroarylation of alkynes7 have
been reported. Since catalytic dual activation is of interest
from the perspective of atom economy, we are interested to
explore gold-catalyzed tandem hydroamination-hydroary-
lation as a possible synthetic strategy for substituted 1,2-
dihydroquinolines, particularly under microwave-assisted
conditions to shorten the reaction time.5l
Scheme 1
The gold complexes 1a,8 1b,9 1c,10 and 1d10 employed in
this work were prepared by literature methods. We examined
2A-K with alkynes 3a-i to give dihydroquinoline deriva-
tives 4 and/or 4′ (Scheme 1) in 42-94% yields (Table 1; a
control experiment with AgOTf/NH4PF6 as catalyst afforded
4Aa in 2% NMR yield).
Table 1. Gold(I)-Catalyzed Reactions between Primary
Arylamines 2A-K and Alkynes under Microwave Irradiationa
the reaction of m-anisidine (2A) with phenylacetylene (3a)
at 80-100 °C in the presence of 5 mol % of these gold
catalysts, which gave 1,2-dihydroquinoline derivative 4Aa
in up to 80% yields after 12-24 h (Table S1 in the
Supporting Information). Upon microwave irradiation, the
reaction time considerably shortened to 25 min, with the best
result obtained for the Au(I) catalyst 1c/AgOTf with
CH3CN as solvent in the presence of additive NH4PF6 (Table
S2 in the Supporting Information). Under these conditions,
1c/AgOTf catalyzed the reactions of primary arylamines
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J. Am. Chem. Soc. 2006, 128, 9705. (h) Horino, Y.; Luzung, M. R.; Toste,
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entry substrates
product(s)
4Aa
2A + 3b 4Ab
2A + 3c 4Ac
2A + 3d 4Ad
time (min)/P (W) yieldb (%)
1
2
2A + 3a
25/26
30/25
40/24
40/30
60/26
60/40
70/47
60/43
60/28
35/19
45/20
40/23
40/25
40/26
70/21
70/29
40/21
40/26
30/28
82
81
73
83
89
71
42
64
3
4
5
6
7
2A + 3e
2A + 3f
2A + 3g
4Ae
4Af
4Ag
8
9
2A + 3h 4Ah
2A + 3i 4Ai
52
78
10
11
12
13
14
15
16
17
18
19
2B + 3a 4′Ba
2C + 3a 4Ca + 4′Ca
2D + 3a 4Da
2E + 3a
2F + 3a
2G + 3a 4Ga
2H + 3a 4Ha
2I + 3a
2J + 3a
2K + 3a 4Ka + 4′Ka
84 (11:10)
71
4Ea + 4′′Ea
4Fa
85 (8:7)
74
62;c 71d
54c
4Ia
4Ja
69c
65
94 (27:67)
(8) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178.
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C. L.; Ketring, A. R.; Jurisson, S. S. Inorg. Chem. 2001, 40, 972.
(10) de Fre´mont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411.
a Reaction conditions: 2 (0.5 mmol), 3 (2.5 mmol), 1c/AgOTf (0.025
mmol), NH4PF6 (0.075 mmol), CH3CN (1 mL), 150 °C with microwave
irradiation. b Isolated yield based on arylamine. c A 20-40% yield of imine
was obtained. d 1a/AgOTf was used as catalyst.
2646
Org. Lett., Vol. 9, No. 14, 2007

The 1c/AgOTf-catalyzed reactions of 2A with monoalkynes
3a-e afforded 4Aa-Ae in 73-89% yields (entries 1-5,
Table 1). Interestingly, extension of the reaction to the
substrates bearing multiple alkyne groups (3f-i) gave
4Af-Ai in 42-71% yields (entries 6-9, Table 1); each
molecule of these dihydroquinolines features two or four
terminal alkyne groups.
1c/AgOTf, the yield of 5La remained almost the same upon
decreasing catalyst loading from 5 to 2 mol % (Table S3 in
the Supporting Information). Note that previous synthesis
of 5La and 5Ma has considerably lower product yields12a
or requires a substantially longer reaction time.12b For
example, the formation of 5Ma from the Ru3(CO)12-catalyzed
reaction of 2M with 3a was performed at 150 °C for 12
h.12b In view of the potential therapeutic applications,13 we
developed a gram-scale synthesis of 5La (Scheme S1 in the
Supporting Information). It is interesting that the 1c/AgOTf-
catalyzed reactions of 2L with 3f, 3h, and 3i afforded 5Lf,
5Lh, and 5Li, respectively, each bearing one or two terminal
alkyne groups; such compounds, along with 4Af-Ai, are
potentially useful for constructing supramolecular architec-
tures14 and metal-alkynyl optoelectronic materials.15
Reactions of 3a with arylamines 2B-K catalyzed by
1c/AgOTf afforded 4Ca-Ka, together with 4′Ba, 4′Ca,
4′′Ea, and 4′Ka (entries 10-19, Table 1). p-Anisidine (2B)
was the most reactive, with 4′Ba formed in 78% yield within
35 min (entry 10). For 4-phenoxyaniline (2C), a 11:10
mixture of 4Ca and 4′Ca was obtained in a total of 84%
yield (entry 11). p- and m-methyl-substituted anilines reacted
with 3a to give different products: only 4Da was obtained
(in 71% yield) for p-toluidine (2D, entry 12), but a 8:7
mixture of 4Ea and 4′′Ea (in a total of 85% yield) was
formed for m-toluidine (2E, entry 13). In the case of substrate
2G bearing electron-withdrawing p-Cl substituent, the prod-
uct 4Ga was obtained in 62% yield, and changing the catalyst
to 1a/AgOTf increased the yield to 71% after reaction for 1
h (entry 15). This contrasts with the formation of similar
1,2-dihydroquinoline derivatives in <5% yields for the
arylamines bearing an electron-withdrawing substituent in
ruthenium-catalyzed reactions.3b In the presence of catalyst
1c/AgOTf, disubstituted arylamines 2J and 2K reacted with
3a to afford 4Ja in 65% yield (entry 18) and a 27:67 mixture
of 4Ka and 4′Ka in a total of 94% yield (entry 19).
Under similar conditions, the 1c/AgOTf-catalyzed reac-
tions of alkynes 3a-c and 3e with primary arylamines 2L
and 2M bearing an o-alkylcarbonyl or -arylcarbonyl group
produced 2,4-disubstituted quinolines 5L and 5M in
63-94% yields within 30 min (entries 1-6, Table 2; a
Indoline (2N), a secondary arylamine, was also found to
react with alkynes in the presence of a Au(I) catalyst.
Treatment of 2N with 3a using 5 mol % of 1a/AgOTf in
CH3CN gave 4Na in 91% yield within 10 min under
microwave irradiation (entry 1, Table 3). When the reaction
Table 3. Gold(I)-Catalyzed Reactions between Indoline and
Alkynesa
entry
R1
substrates
product
yieldb (%)
1c
2
3
4
5
6
7
8
Ph
Ph
4-MeC6H4
4-CF3C6H4
n-Bu
n-hexyl
4-MeOC6H4
4-FC6H4
2N + 3a
2N + 3a
2N + 3b
2N + 3c
2N + 3d
2N + 3e
2N + 3j
2N + 3k
4Na
4Na
4Nb
4Nc
4Nd
4Ne
4Nj
91
84
81
95
58
63
68
86
Table 2. Gold(I)-Catalyzed Two-Component Synthesis of
Quinolines under Microwave Irradiation
4Nk
a Reaction conditions: 2N (0.5 mmol), 3 (2.5 mmol), CH3NO2 (1 mL).
b Isolated yield based on 2N. c Reaction performed in CH3CN with catalyst
1a/AgOTf under microwave irradiation for 10 min.
was performed at room temperature, a much longer reaction
time of 23 h was required and the best result was obtained
by using the solvent CH3NO2 and catalyst 1a/AgSbF6. Under
these conditions, reactions of 2N with 3a-e, 3j, and 3k
entry
R1
substrates
product
yield (%)
1
2
3
4
5
6
7
8
9
Ph
2L + 3a
2L + 3b
2L + 3c
2L + 3e
2M + 3a
2M + 3b
2L + 3f
2L + 3h
2L + 3i
5La
5Lb
5Lc
5Le
5Ma
5Mb
5Lf
93
94
83
63
89
91
81
72
65
4-MeC6H4
4-CF3C6H4
n-hexyl
(11) (a) Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Naveenkumar, V.;
Nagaiah, K. Synthesis 2003, 1610. (b) Zhang, J.-M.; Yang, W.; Song, L.-
P.; Cai, X.; Zhu, S.-Z. Tetrahedron Lett. 2004, 45, 5771.
Ph
4-MeC6H4
4-(CHtC)C6H4
3-(CHtC)C6H4
3,5-(CHtC)2C6H3
(12) (a) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37. (b) Tokunaga,
M.; Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999, 38, 3222.
(13) Balasubramanian, M.; Keay, J. G. The ComprehensiVe Heterocyclic
Chemistry II; Elsevier: Oxford, UK, 1996; Vol. 5, pp 246-300.
(14) (a) Fujita, M.; Ogura, K. Coord. Chem. ReV. 1996, 148, 249. (b)
Stang, P. J.; Olenyuk, B. Acc. Chem. Res. 1997, 30, 502. (c) Fujita, M.
Chem. Soc. ReV. 1998, 27, 417. (d) Seidel, S. R.; Stang, P. J. Acc. Chem.
Res. 2002, 35, 972.
(15) (a) Long, N. J. In Optoelectronic Properties of Inorganic Com-
pounds; Roundhill, D. M., Fackler, J. P., Jr., Eds.; Plenum Press: New
York, 1999; Chapter 4. (b) Chao, H.-Y.; Lu, W.; Li, Y.; Chan, M. C. W.;
Che, C.-M.; Cheung, K.-K.; Zhu, N. J. Am. Chem. Soc. 2002, 124, 14696.
(c) Lu, W.; Zhu, N.; Che, C.-M. J. Am. Chem. Soc. 2003, 125, 16081.
5Lh
5Li
control experiment with AgOTf/NH4PF6 as catalyst gave 5La
in 4% NMR yield). These reactions are related to the
syntheses of 2,4-disubstituted quinolines from the Cu(I)-
catalyzed reactions of arylaldehydes, alkynes, and primary
arylamines.11 For the reaction of 2L with 3a catalyzed by
Org. Lett., Vol. 9, No. 14, 2007
2647

afforded 4Na-Ne, 4Nj, and 4Nk, respectively, in 58-95%
yields (entries 2-8, Table 3). A similar yield of 4Na or 4Nb
was previously obtained from Ru3(CO)12-catalyzed reactions
at 95 °C for 16 h.3a
To provide insight into the mechanism of the Au(I)-
catalyzed transformations, we examined the 1a/AgOTf-
catalyzed reaction of 2A with 3a at room temperature and
the 1c/AgOTf-catalyzed reaction of 2M with 3a at 60 °C,
which afforded ketimine 6Aa in 87% yield after 30 min and
6Ma in 90% yield after 15 min, respectively (Scheme 2).
at room temperature for 2 h afforded 4Na in 79% yield
(Scheme 2).
On the basis of these observations and by considering
previous works on gold-catalyzed hydroamination reactions,6
a reaction mechanism for the formation of 4 and 5 from the
Au(I)-catalyzed reactions of 2 with 3 was proposed (Scheme
3), which involves hydroamination of alkynes to generate
Scheme 3
Scheme 2
an enamine intermediate in tautomerization with a ketimine,
and reaction of the enamine or ketimine intermediate with
alkynes3c to form a propargylamine intermediate,5k,16 fol-
lowed by an intramolecular hydroarylation to produce 4.7
The ketimines generated from 2L and 2M could undergo a
condensation/annulation reaction to give 5.
In conclusion, we have developed a method to efficiently
prepare substituted 1,2-dihydroquinolines and quinolines by
Au(I)-catalyzed tandem hydroamination-hydroarylation un-
der microwave irradiation. This method features a short
reaction time and a broad substrate scope, including the
substrates bearing multiple alkyne groups.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (University
Development Fund), Hong Kong Research Grants Council
(HKU 7012/05P), and University Grants Committee of Hong
Kong (Areas of Excellence Scheme AoE/P-10/01).
Subsequent reaction of 6Aa with 3a catalyzed by 1a/AgOTf
at 35 °C for 4 h gave 4Aa in 91% yield, whereas 6Ma was
converted to 5Ma in 97% yield upon treatment with catalyst
1c/AgOTf at 80 °C for 14 h. Monitoring the 1a/AgSbF6-
catalyzed reaction of 2N with 3a at room temperature
revealed the formation of an enamine intermediate (charac-
terized by the vinyl proton resonances at δ 5.37 and 5.24
ppm) within 10 min, which was converted to 4Na and
propargylamine 7Na in 84% and 7% yields, respectively,
after 17 h. Treatment of 7Na with 1a/AgSbF6 in CH3NO2
Supporting Information Available: Experimental pro-
cedures, product characterizations, Tables S1-S3 giving
catalyst activity data, and Scheme S1 showing the gram-
scale synthesis of quinoline derivative 5La. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070814L
(16) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
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Org. Lett., Vol. 9, No. 14, 2007