Catalytic synthesis of tricyclic quinoline derivatives from the regioselective hydroamination and C-H bond activation reaction of benzocyclic amines and alkynes

Article abstract of DOI:10.1021/ja042318n

The cationic ruthenium-hydride complex [(PCy₃)₂(CO)(CH₃CN)₂RuH]⁺BF₄^- (1) was found to be an effective catalyst for the regioselective coupling reaction of benzocyclic amines and

Full text of DOI:10.1021/ja042318n

Published on Web 04/05/2005
Catalytic Synthesis of Tricyclic Quinoline Derivatives from the Regioselective
Hydroamination and C-H Bond Activation Reaction of Benzocyclic Amines
and Alkynes
Chae S. Yi,*,† Sang Young Yun,† and Ilia A. Guzei‡
Department of Chemistry, Marquette UniVersity, Milwaukee, Wisconsin 53201-1881, and Molecular Structure
Laboratory, Department of Chemistry, UniVersity of Wisconsin-Madison, Madison, Wisconsin 53706-1396
Received December 21, 2004; E-mail: chae.yi@marquette.edu
Table 1. Coupling Reaction of Benzocyclic Amines and Terminal
Catalytic C-H bond activation reaction is a highly attractive
Alkynesa
method in organic synthesis since it can give the products directly
from readily available and unreactive starting materials without
forming copious amount of byproducts.1 In particular, considerable
efforts have been devoted to the development of effective C-H
bond activation methods for forming biologically important quino-
lines, indoles, and related polycyclic alkaloids.2-7 Selected recent
examples include: Heck-type coupling reaction involving 1,4-metal
migration,3 intramolecular C-H bond oxidative annulation of
indoles,4 combinatorial synthesis of quinoline derivatives from
Lewis acid-catalyzed Mannich-like coupling reaction of arylamines,
aldehydes, and alkenes,5 and intramolecular alkylation and car-
boxylation of alkenylindoles.6 A remarkably regioselective chelate-
directed C-H bond activation methodology has also been developed
and subsequently applied to the synthesis of quinoline-containing
teleocidin B4 core.7 A significantly more challenging task is to
design an intermolecular version of the reaction since most of the
reported examples involve intramolecular C-H bond activation
methods. We recently reported a catalytic intermolecular C-H bond
coupling reaction of cyclic amines and alkenes by using a
ruthenium-hydride complex (PCy3)2(CO)RuHCl.8 Here we report
an effective catalytic method for the synthesis of tricyclic quinoline
derivatives from the hydroamination and C-H bond activation
reaction of benzocyclic amines and alkynes.
We initially discovered that the cationic ruthenium-hydride
-
complex [(PCy3)2(CO)(CH3CN)2RuH]+BF4 (1)9 is an effective
catalyst for the coupling reaction of benzocyclic amines and terminal
alkynes. For example, the treatment of indoline (30 mg, 0.25 mmol)
with excess propyne (20 equiv) in the presence of 1 (5 mol %) in
benzene at 95 °C for 24 h cleanly produced the tricyclic products
2a and 3a (15:1) in 81% combined yield (eq 1). The catalytic
reaction produced tricyclic hydroquinoline structure directly from
the regioselective coupling reaction of indoline and 2 equiv of
propyne.
a Reaction conditions: amine (1.5 mmol), alkyne (10-20 mmol), [Ru]
) Ru3(CO)3/NH4PF6 (1:3), benzene (2-5 mL), 95 °C. b Isolated yields.
tive yield of 2a and 3a (20:1, 99%) in less than 12 h for the reaction
described in eq 1. Previously, the catalytic system Ru3(CO)12/NH4-
PF6 has been utilized for hydroamination and C-C bond activation
reactions.11
The scope of the coupling reaction was explored by using the
Ru3(CO)12/NH4PF6 catalytic system (Table 1). Both five- and six-
membered benzocyclic amines were found to readily undergo the
regioselective coupling reaction with terminal alkynes to give the
cyclized products 2 and trace amounts of the isomerization products
3 (<5%). No coupling product was formed with sterically demand-
ing terminal alkynes such as with 3-methyl-1-butyne and internal
alkynes. Analytically pure organic products were isolated after a
simple column chromatography on silica gel, and their structure
was completely established by spectroscopic methods.
The complex 1 was found to be less effective for electron-
deficient terminal alkynes; for example, the analogous reaction of
indoline with phenylacetylene predominantly gave a simple hy-
droamination product. The search for a more effective ruthenium
catalyst was ensued, and Ru3(CO)12/NH4PF6 (1:3 molar ratio) was
found to be the most effective catalyst among the selected ruthenium
complexes.10 Thus, 1 mol % of Ru3(CO)12/NH4PF6 gave a quantita-
† Marquette University.
‡ University of Wisconsin-Madison.
9
5782
J. AM. CHEM. SOC. 2005, 127, 5782-5783
10.1021/ja042318n CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
observation of ruthenium-vinyl complex 4 along with the formation
of styrene. The hydroamination reaction of the acetylide species 6
via an initial N-H bond activation and intramolecular migratory
insertion of the amine substrate would form the cationic vinyl
species.14 The subsequent ortho-C-H arene bond activation, the
second alkyne insertion, and the regioselective migratory insertion/
cyclization sequences would yield the cationic alkyl species 7. Since
7 does not have any â-hydrogens, either oxidative addition/reductive
elimination or σ-bond metathesis of the terminal alkyne must be
invoked for the formation of 2 and the regeneration of the acetylide
species 6.
The following preliminary results provided supporting evidence
for the reaction mechanism. The reaction of indoline with excess
DCtCPh (10 equiv) and Ru3(CO)12/NH4PF6 (3%) yielded the
product 2c with extensive deuterium incorporation on both vinyl
(85% D) and methyl (81% D) positions as well as on the arene
hydrogen para to the amine group (∼50%) as measured by both
Figure 1. Molecular structure of the cation part of 5.
Scheme 1
2
1H and H NMR. Conversely, ca. 25% of the methyl group and
30% of the vinyl hydrogen of 2c were found to contain the
deuterium when N-deuterated indoline was reacted with 10 equiv
of HCtCPh. These results indicate that both C-H and N-H bond
activation steps are reversible.
In summary, an efficient catalytic C-H bond activation/
hydroamination protocol has been developed for the synthesis for
tricyclic quinoline derivatives. A catalytically active cationic
ruthenium-acetylide complex 5 has been isolated and characterized.
Efforts to establish a detailed mechanism as well as the role of
ruthenium-acetylide species in amination reactions are currently
underway.
Acknowledgment. Financial support from the National Institutes
of Health, General Medical Sciences (R15 GM55987) is gratefully
acknowledged.
In an effort to gain insights on the nature of intermediate species,
the reaction mixture of 1 (30 mg, 34 µmol) and HCtCPh (10 mg,
0.1 mmol) in C6D6 was monitored by NMR. After heating the
reaction tube at 60 °C for 10 min, a set of new peaks due to the
cationic ruthenium-vinyl complex [(PCy3)2(CO)(CH3CN)2RuCHd
Supporting Information Available: Experimental procedure,
characterization data, and crystallographic data of 5 (CIF, PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
-
CHPh]+BF4 (4) appeared as indicated by the characteristic vinyl
References
1
resonances at δ 8.03 and 6.38 (d, J ) 18.3 Hz) by H NMR and
the new phosphorus signal at δ 24.3 by 31P NMR.12 Upon further
heating of the reaction mixture for 10 min at 80 °C, the peaks due
to the cationic ruthenium-acetylide complex 5 appeared at the
expense of the vinyl complex 4. In particular, the complex 5
exhibited two alkynyl carbon signals at δ 111.4 and 103.7 (t, JPC
) 17.3 Hz), of which only the latter peak was coupled with the
phosphorus atoms. The formation of styrene was also observed in
the crude reaction mixture.
(1) Recent reviews: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002,
102, 1731. (b) Kakiuchi, F.; Murai, S. In ActiVation of UnreactiVe Bonds
and Organic Synthesis; Murai, S. Ed.; Springer: New York, 1999.
(2) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
(3) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem.
Soc. 2003, 125, 11506.
(4) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (b)
Matsumoto, M.; Watanabe, N.; Kobayashi, H. Heterocycles 1987, 26,
1479.
(5) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977.
(6) (a) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 3700. (b) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 10250.
(7) (a) Sezen, B.; Franz, R.; Sames, D. J. Am. Chem. Soc. 2002, 124, 13372.
(b) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856.
(8) Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004, 23, 5392.
(9) Yi, C. S.; He, Z.; Guzei, I. A. Organometallics 2001, 20, 3641.
(10) See the Supporting Information for a detailed description.
(11) (a) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999,
38, 3222. (b) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
6646.
(12) A neutral analogue was previously synthesized: Yi, C. S.; Lee, D. W.;
Chen, Y. Organometallics 1999, 18, 2043.
(13) Yi, C. S.; Liu, N.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A.
Organometallics 1997, 16, 3729 and references therein.
The acetylide complex 5 was subsequently isolated in 81% yield
from a preparatory scale reaction of 1 with phenylacetylene in THF,
and its structure was established by X-ray crystallography (Figure
1). The molecular structure of 5 showed an octahedral geometry
with two trans PCy3 ligands and cis arrangement between the
acetylide and CO ligands. The bond distances of the acetylide
ligand, Ru-C(37) ) 2.008(5) Å and C(37)-C(38) ) 1.188(7) Å,
are comparable to the previously reported ruthenium-acetylide
complexes.13 The catalytic activity of isolated complex 5 was found
to be identical to that of 1 for the coupling reaction of indoline
and propyne.
A possible mechanism of the catalytic reaction is shown in
Scheme 1. The successful isolation of the catalytically active
complex 5 implicates a cationic ruthenium-acetylide species as
the key species for the catalytic reaction. The acetylide complex 6
is initially generated from the reaction of a ruthenium-hydride
complex with 2 equiv of a terminal alkyne, as indicated by the
(14) The treatment of 5 with p-MeO-C6H4CtCH (5 equiv) in THF for 3 h at
80 °C produced a ∼1:1 mixture of 5 and the alkyne-exchanged complex
[(PCy3)2(CO)(CH3CN)2RuCtCC6H4-p-OMe]+BF4-. A negligible isotope
effect of kNH/kND ) 1.1 ( 0.1 was measured from the reaction of indoline
and N-deuterated indoline with propyne (THF, 95 °C). Also, the catalytic
reaction by 1 was found to be inhibited by PCy3.10 While these results
are most consistent with an intramolecular insertion mechanism, we still
cannot rigorously rule out a nucleophilic addition mechanism.
JA042318N
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J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5783