A route to 2-substituted tetrahydroquinolines via palladium-catalyzed intramolecular hydroamination of anilino-alkynes

Article abstract of DOI:10.1021/jo0708137

(Chemical Equation Presented) The cyclization of amino-alkynes 1 in which an amino group is attached to the aromatic ring, proceeded smoothly using a catalytic amount of Pd(PPh₃)₄ and benzoic acid in toluene at 120°C, leading to the

Full text of DOI:10.1021/jo0708137

synthesis of this class of compounds involves the hydrogenation
of quinolines.5 The transition-metal-catalyzed process that
involves C-N bond formation is desirable because the product
is obtained generally under milder conditions with high atom
economy.6 Moreover, a catalytic asymmetric version of the
process is possible with the help of chiral metal complexes,
generated from metal and chiral ligands.
A Route to 2-Substituted Tetrahydroquinolines
via Palladium-Catalyzed Intramolecular
Hydroamination of Anilino-alkynes
Nitin T. Patil, Huanyou Wu, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku
The transition-metal-catalyzed addition of amines to activated
and nonactivated C-C unsaturated bonds, generally known as
hydroamination,7 has proven to be a valuable route for the
formation of C-N bonds. Particularly noteworthy is the
intramolecular cyclization of amines with tethered C-C bonds,
which leads to the formation of a wide variety of nitrogen
heterocycles. For example, the hydroamination/cyclization of
aminoalkenes,8 aminoallenes,9 aminodienes,10 and aminoalkynes11
using transition metal and lanthanide complexes provides an
UniVersity, Sendai 980-8578, Japan
yoshi@mail.tains.tohoku.ac.jp
ReceiVed April 18, 2007
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Appl. Chem. 2000, 72, 1233-1246.
The cyclization of amino-alkynes 1 in which an amino group
is attached to the aromatic ring, proceeded smoothly using
a catalytic amount of Pd(PPh3)4 and benzoic acid in toluene
at 120 °C, leading to the formation of the 2-substituted
tetrahydroquinolines 2. An asymmetric variant of the reaction
using the chiral palladium catalyst (prepared in situ by mixing
Pd2(dba)3‚CHCl3 and (R,R)-RENORPHOS) was also ex-
plored. The absolute configuration of the enantiomerically
enriched tetrahydroquinolines, obtained in this way, was
determined by converting them to the known compounds
and was found to be R. The alkaloids such as (()-galipinine,
(()-angustureine, and their optically active form were
synthesized by using this reaction as a key step.
(4) For some recent leading examples of the synthesis of 1,2,3,4-
tetrahydroquinolines, see: (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org.
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One of the most challenging topics in modern organic
chemistry is the synthesis of natural products containing a
heterocyclic ring. Despite the considerable exploration to date
within this field, there is still a need for further development of
alternative methods of preparation for biologically active
heterocyclic compounds. Among numerous families of natural
products, tetrahydroquinolines seem to attract considerable
attention due to their abundant presence in plants1 along with
their promising biological activities.2 Therefore their syntheses
via newer and atom economical3 approaches have been the
subject of current research.4 One of the approaches for the
(1) (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.;
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subramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry
II; McKillop, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 5, Chapter 5,
pp 245-300. (c) Kouznetsov, V.; Palma, A.; Ewert, C.; Varlamov, A. J.
Heterocycl. Chem. 1998, 35, 761-785. (d) De Kimpe, N.; Keppens, M.
Tetrahedron 1996, 52, 3705-3718. (e) Padwa, A.; Brodney, M. A.; Liu,
B.; Satake, K.; Wu, T. J. Org. Chem. 1999, 64, 3595-3607. (f) Katritzky,
A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031-15070. (g)
Leeson, P. D.; Carling, R. W.; Moore, K. W.; Moseley, A. M.; Smith, J.
D.; Stevenson, G.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp,
J. A.; Marshall, G. R.; Hoogsteen, K. J. Med. Chem. 1992, 35, 1954-
1968. (h) Nagata, R.; Tanno, N.; Kodo, T.; Ae, N.; Yamaguchi, H.;
Nishimura, T.; Antoku, F.; Tatsuno, T.; Kato, T.; Tanaka, Y.; Nakamura,
M. I. J. Med. Chem. 1994, 37, 3956-3968.
10.1021/jo0708137 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/18/2007
J. Org. Chem. 2007, 72, 6577-6579
6577

TABLE 1. Palladium-Catalyzed Synthesis of
Tetrahydroquinolinesa
efficient way for synthesizing various nitrogen heterocycles.
Recently, we reported12 an entirely new method for the
hydroamination of alkynes using a Pd(PPh3)4/PhCOOH com-
bined catalyst system. The intramolecular catalytic asymmetric
hydroamination of alkynes was also achieved using (R,R)-
RENORPHOS ligand, which enabled us to synthesize the chiral
nitrogen heterocycles (pyrrolidines and piperidines) in good to
moderate yields and ee’s (eq 1).13 Herein we report the
application of our methodology for the synthesis of 2-substituted
tetrahydroquinolines (eq 2).
entry
1
R
R1
time (h)
2
yield (%)b
1
2
3
4
5
1a
1b
1c
1d
1e
1f
Bn
Me
H
Me
H
Ph
Ph
4
12
2
24
24
2
2a
2b
2c
2d
2e
2f
98
63
80
78
79c
0d
Ph
nPr
nPr
tBu
6
H
7
8
9
10
1g
1h
1i
H
H
H
Me
p-CH3-C6H4
p-OCH3-C6H4
p-CF3-C6H4
24
12
6
2g
2h
2i
77
90
71
87
1j
benzo[1,3]dioxole
12
2j
a The reactions of aminoalkynes 1 (0.125 mmol) in the presence of
Pd(PPh3)4(20 mol %) and PhCO2H (50 mol %) were carried out at 120 °C
in toluene (1 M). b Isolated yields. c A mixture of trans and cis isomer in
the ratio of 2:1 was obtained. d Complex mixture obtained.
be noted that an electron-withdrawing group such as Boc, Ts,
or Nf on the amine nitrogen decreased dramatically the reactivity
of the hydroamination and the desired product was not obtained
at all. These results are in contrast to our previous results where
the use of the Ts and Nf group was necessary.12a,b,13
It is clear that the scope and synthetic utility of this process
would be enhanced dramatically if the reaction proceeded in
an asymmetric manner. For this reason we have examined
several nonracemic chiral ligands that were tested previously
for similar reactions.13 Once again, (R,R)-RENORPHOS gave
better results, although the ee’s obtained were not satisfactory.
The reactions of 1a, 1c, and 1d were conducted using Pd2(dba)3‚
CHCl3 and (R,R)-RENORPHOS to give enantiomerically en-
riched tetrahydroquinolines 2a, 2c, and 2d, respectively (eq 3).
First the anilino-alkyne 1a14 was treated with Pd(PPh3)4 (20
mol %)/PhCOOH (50 mol %) in toluene at 120 °C for 4 h. The
starting material completely disappeared in 4 h, giving the
cyclization product 2a in 98% isolated yield as a single
E-stereoisomer (Table 1, entry 1). As anticipated, in the absence
of benzoic acid no reaction took place even after heating at
120 °C for 24 h. The use of a methyl group on the amine
nitrogen also worked well; however, the yield obtained was
somewhat lower (entry 2). The substrate 1c, in which there is
no protecting group on nitrogen, also gave the cyclization
product 2c in 80% yield in just 2 h (entry 3). Not only aromatic
alkynes but also aliphatic alkynes worked well to give 2d in
78% yield (entry 4). Quite surprisingly, in the case of substrate
1e, a mixture of E- and Z-isomers in a ratio of 2:1 was obtained
(entry 5). The substrate 1f, in which alkyne is attached to a tBu
group, proved to be inert under the standard reaction condition
(entry 6). The substrates 1g-j, in which the alkyne is attached
to various aromatic ring, reacted with Pd(PPh3)4 catalyst under
the standard conditions to give the corresponding tetrahydro-
quinolines 2g-j in good to high yields (entries 7-10). It should
Unfortunately, lowering the amount of palladium catalyst as
well as (R,R)-RENORPHOS ligand resulted into lowering of
either yields or enantioselectivities. Although this process gave
2-substituted tetrahydroquinolines in modest yields and ee’s,
these data demonstrate the feasibility of enantioselective induc-
tion.
The absolute configuration of the hydroamination product 2c
(78% ee) was determined by transforming it into the known
compound 3 (eq 4). It has been reported in the literature that
(12) (a) Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570-4571. (b) Lutete, M. L.; Kadota, I.; Shibuya, A.;
Yamamoto, Y. Heterocycles 2002, 58, 347-357. (c) Bajracharya, G. B.;
Huo, Z.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4883-4886. (d) Patil, N.
T.; Wu, H.; Kadota, I.; Yamamoto, Y. J. Org. Chem. 2004, 69, 8745-
8750. (e) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005,
46, 2101-2103. (f) Patil, N. T.; Huo, Z.; Bajracharya, G. B.; Yamamoto,
Y. J. Org. Chem. 2006, 71, 3612-3614. For other references related to
this chemistry, see: (g) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto,
Y. J. Am. Chem. Soc. 1998, 120, 10262-10263. (h) Patil, N. T.; Kadota,
I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. AdV. Synth. Catal. 2004,
346, 800-804. (i) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69,
6478-6481. (j) Kadota, I.; Lutete, L. M.; Shibuya, A.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 6207-6210. (k) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. Can. J. Chem. 2005, 83, 569-573. (l) Patil, N. T.; Khan, F.
N.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 8497-8499. (m) Huo, Z.;
Patil, N. T.; Jin, T.; Pahadi, N. K.; Yamamoto, Y. AdV. Synth. Catal. 2007,
349, 680-684. (n) Zhang, W.; Haight, A. R.; Hsu, M. C. Tetrahedron Lett.
2002, 43, 6575-6578.
(+)-2-phenethyl-1,2,3,4-tetrahydroquinoline [R]23D ) +73.1 (c
1.0, CHCl3) has R configuration.4a Since the optical rotation of
(13) (a) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 1622-1623. (b) Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi, N.
K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270-4279.
(14) The starting materials were prepared from commercially available
2-iodoaniline, and the details are described in Supporting Information.
3 was found to be [R]25 ) +52.3 (c 0.55, CHCl3), it was
D
unequivocally confirmed that the absolute configuration of major
6578 J. Org. Chem., Vol. 72, No. 17, 2007

droquinoline, 2d having 52% ee was subjected to hydrogenation
to afford (-)-angustureine 6 in 75% yield, [R]26 ) -3.5 (c
D
0.50, CHCl3), [lit.15a [R]25 ) -7.16 (c 1.00, CHCl3)] (eq 7).
D
FIGURE 1. Proposed transition state models.
isomer 2c is R. Previously, we reported that the reaction of the
aliphatic amino alkyne 4, in the presence of Pd2(dba)3‚CHCl3/
(R,R)-RENORPHOS catalyst, afforded the pyrrolidine 5 with
S configuration (eq 5).13 Although in the present case the product
having R-configuration was obtained, the direction of chiral
induction is same as that of previous findings.
In conclusion, we have developed a method for the synthesis
of 2-substituted tetrahydroquinolines via the Pd(0)-catalyzed
intramolecular hydroamination of anilino-alkynes. The applica-
tion of this methodology was implemented for the synthesis of
alkaloids such as (()-angustureine and (()-galipinine. The
method reported herein will be applicable for the synthesis of
natural products containing tetrahydroquinoline moiety. We have
also shown the possibility of asymmetric induction, which gave
chiral tetrahydroquinolines. However, the enantioselectivity
obtained in all cases was not very high, and moreover high
catalyst loading was needed. Research directed toward ligand
design, synthesis, and application for the present reaction is now
underway in our laboratories.
The observed enantioselectivity in the intramolecular hy-
droamination of alkyne could be rationalized in terms of
transition state models I and II as shown in Figure 1. In I, the
space at the lower front side of the catalyst allows the alkyl
chain attached to the π-allyl to move freely. In II, a phenyl
ring emanating from the phosphorus atom at the backside of
the catalyst restricts the movement of the tether. Accordingly,
the reaction proceeds through a transition state model I to give
(R)-2c predominantly.
It was envisaged that the hydrogenation of 2d and 2j would
lead to the formation of (()-angustureine and (()-galipinine,
respectively.15 Accordingly, 2d and 2j were independently
subjected to hydrogenation with 10% Pd/C in methanol at room
temperature after 12 h, giving (()-angustureine 6 and (()-
galipinine 7 in 85% and 80% yields, respectively (eqs 6 and
8). In order to synthesize the enantiomerically enriched tetrahy-
Acknowledgment. N.T.P. thanks the Japan Society for the
Promotion of Science (JSPS) for a postdoctoral research
fellowship.
Supporting Information Available: Experimental details and
1
characterization data including H NMR and 13C NMR of com-
pounds 1a-d,g-j, 2a-d,g-j, 3, 6, and 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0708137
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J. Org. Chem, Vol. 72, No. 17, 2007 6579