Ruthenium-catalyzed intramolecular hydroamination of aminoalkynes

Article abstract of DOI:10.1016/S0022-328X(00)00869-X

Low-valent ruthenium complexes with a π-acidic ligand, such as Ru(η⁶-cot)(dmfm)₂ [cot=1,3,5-cyclooctatriene, dmfm=dimethyl fumarate] and Ru₃(CO)₁₂, showed high catalytic activity for the intramolecular hydroamination of aminoalkynes. The reaction is highly regioselective, in which a nitrogen atom is selectively attached to an internal carbon of alkynes to give five-, six-, and seven-membered nitrogen heterocycles as well as indoles in good to high yields.

Full text of DOI:10.1016/S0022-328X(00)00869-X

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 622 (2001) 149–154
Ruthenium-catalyzed intramolecular hydroamination of
aminoalkynes
Teruyuki Kondo, Takumi Okada, Toshiaki Suzuki, Take-aki Mitsudo *
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto Uni6ersity, Sakyo-ku, Kyoto 606-8501, Japan
Received 4 September 2000; received in revised form 27 October 2000; accepted 4 November 2000
Abstract
Low-valent ruthenium complexes with a p-acidic ligand, such as Ru(h6-cot)(dmfm)2 [cot=1,3,5-cyclooctatriene, dmfm=
dimethyl fumarate] and Ru3(CO)12, showed high catalytic activity for the intramolecular hydroamination of aminoalkynes. The
reaction is highly regioselective, in which a nitrogen atom is selectively attached to an internal carbon of alkynes to give five-, six-,
and seven-membered nitrogen heterocycles as well as indoles in good to high yields. © 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Ruthenium catalyst; Aminoalkynes; Hydroamination; Cyclization
used Ru3(CO)12 as a catalyst for intramolecular hy-
droamination of 6-aminohex-1-yne, however, the yield
of the product, 2-methyl-1,2-dehydropiperidine, was
only 21% [9]. Therefore, there is a considerable interest
in new catalytic approaches as well as reinvestigation of
the catalytic activity of the ruthenium catalyst. In the
course of our study on ruthenium catalysis [10], we
previously found the first ruthenium-catalyzed inter-
molecular hydroamination of alkynes with N-aryl-sub-
stituted amides via catalytic activation of NꢀH bond,
which offers a novel synthesis of enamides [11a]. Fur-
ther study on the synthesis of novel amine-coordinated
zero-valent ruthenium complexes [12] prompted us to
investigate the catalytic activity of low-valent ruthe-
nium complexes for the intramolecular hydroamination
reaction via NꢀH bond activation. We report here the
practically useful ruthenium-catalyzed intramolecular
hydroamination of aminoalkynes.
1. Introduction
Among the various addition reactions across CꢀC
multiple bonds, the direct addition of NꢀH bonds in
amines to alkenes and/or alkynes mediated and cata-
lyzed by transition metal complexes is of fundamental
importance in organic chemistry, and is both a chal-
lenging and highly desirable transformation [1]. To
catalyze the hydroamination of alkenes and/or alkynes,
two basic approaches have been used; i.e. activation of
either the amine by low-valent transition metal com-
plexes or the unsaturated bond by high-valent com-
plexes [2]. In comparison to the intermolecular
hydroamination reaction [3], intramolecular hydroami-
nation, especially of aminoalkynes, has been consider-
ably developed using several transition metal catalysts
[4–7] as well as lanthanide catalysts [8], since this
reaction is a direct and easy way to preparation of
various biologically important nitrogen heterocycles.
However, the catalyst systems reported so far have
serious drawbacks: the catalysts (generally air- and
moisture-sensitive) are unwieldy and short catalyst life-
times lead to low turnover frequencies. As for the
ruthenium complex catalyst, Mu¨ller et al. have first
2. Results and discussion
Recently, we reported the synthesis of novel zero-va-
lent ruthenium mono- [12a] and bidentate [12b] amine
complexes by reacting Ru(h6-cot)(dmfm)2 [cot=1,3,5-
cyclooctatriene, dmfm=dimethyl fumarate] [13] with
the corresponding amines. As expected, Ru(h6-
* Corresponding author. Fax: +81-75-7534976.
E-mail address: mitsudo@scl.kyoto-u.ac.jp (T.-a. Mitsudo).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00869-X

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
150
T. Kondo et al. / Journal of Organometallic Chemistry 622 (2001) 149–154
Table 1
cot)(dmfm)2 showed high catalytic activity for the facile
intramolecular hydroamination of general aminoalky-
nes. For example, treatment of 5-phenyl-4-pentynyl-1-
amine (1a) with 4.0 mol% Ru(h6-cot)(dmfm)2 in
diglyme at 150°C for 6 h under an argon atmosphere
gave 2-benzyl-1-pyrroline (2a) in 88% yield without any
byproducts which can be detected by GLC (Eq (1)).
Effect of the reaction temperature on Ru(h6-cot)(dmfm)2-catalyzed
intramolecular hydroamination of 1a to 2a a
Run Temperature
(°C)
Conversion of 1a
Yield of 2a
(%) b
(%) b
1
2
3
4
150
140
130
120
100
88
80
88
65
55
35
35
a Compound 1a (2.5 mmol), Ru(h6-cot)(dmfm)2 (0.1 mmol),
diglyme (4.0 ml) for 6 h under an argon atmosphere.
b Determined by GLC.
(1)
The effects of the reaction temperature and the sol-
vent are summarized in Tables 1 and 2. A reaction
temperature over 150°C was required for completion of
the present reaction. The highest selectivity of 2a was
observed at 150°C, and the selectivity of 2a decreased
at lower reaction temperatures (Runs 1–3 in Table 1).
As for the solvent, benzonitrile and nitrobenzene drasti-
cally decreased the yield of 2a, while the conversion of
1a was high, due to the polymerization of 1a to gener-
ate highly viscous intractable mixtures. On the other
hand, both the conversion of 1a and the yield of 2a
were decreased in mesitylene and decane without poly-
merization. Among the solvents examined, diglyme
gave the best result.
Table 2
Effect of the solvent on Ru(h6-cot)(dmfm)2-catalyzed intramolecular
hydroamination of la to 2a a
Run Solvent
Conversion of la
Yield of 2a (%) b
(%) b
1
2
3
4
5
Diglyme
100
88
100
63
83
46
20
37
23
Benzonitrile
Nitrobenzene
Mesitylene
Decane
23
a Compound la (2.5 mmol), Ru(h6-cot)(dmfm)2 (0.10 mmol), sol-
vent (4.0 mL) at 150°C for 4 h under an argon atmosphere.
The time–dependence of the reaction is shown in
Fig. 1. Most of 1a is consumed at the early stage of the
reaction, and the reaction is almost complete within 1
h.
b Determined by GLC.
Several low-valent ruthenium complexes bearing a
p-acidic ligand showed good to high catalytic activity
for the transformation of 1a to 2a (Table 3). Judging
from the results reported by Mu¨ller et al. [9], Ru3(CO)12
was expected to show low catalytic activity. However,
when Ru3(CO)12 was employed under our optimized
reaction conditions, extremely high catalytic activity
was observed. Other ruthenium complexes, such as
(h3-C3H5)RuBr(CO)3, [RuCl2(CO)3]2, and Ru(CO)3-
(PPh3)2, also showed good catalytic activity. On the
other hand, the catalytic activities of zero- and divalent
ruthenium complexes without a p-acidic ligand, such as
Ru(h4-cod)(h6-cot) [cod=1,5-cyclooctadiene], Ru(h5-
cyclooctadienyl)2, Cp*RuCl(cod) [Cp*=pentamethyl-
cyclopentadienyl], [Ru(h6-C6H6)Cl2]2, RuCl2(PPh3)3,
and RuH2(PPh3)4, were moderate to low.
Since Ru3(CO)12 is commercially available and has a
high catalytic activity superior to other ruthenium cata-
lysts, it was used as a catalyst in the following in-
tramolecular hydroamination of several aminoalkynes
(1a–g) (Table 4). The present process regioselectively
Fig. 1. The time-dependence of Ru(h6-cot)(dmfm)2-catalyzed in-
tramolecular hydroamination of 1a to 2a.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
T. Kondo et al. / Journal of Organometallic Chemistry 622 (2001) 149–154
151
Table 3
tion produces a (hydrido)(amido)ruthenium intermedi-
ate. Subsequently, the reaction can take place either at
the RuꢀN or RuꢀH bond. Insertion of an alkyne
moiety into the RuꢀN bond, followed by reductive
elimination/isomerization gives the corresponding cyclic
imine with regeneration of an active ruthenium species.
Alternatively, the (hydrido)(amido)ruthenium complex
might insert the alkyne moiety into the RuꢀH bond.
However, there is evidence that this type of reaction is
unfavorable in comparison with insertion into the
RuꢀN bond. It has been reported that (hy-
drido)(amido)complexes LnMH(NR2) (M=Pd, Pt)
prefer the insertion of an alkene into the MꢀN bond
[17]. In addition, reductive eliminations involving car-
bon-heteroatom bond formation are generally less com-
mon [18] and probably disfavored relative to
carbonꢀcarbon and carbonꢀhydrogen bond formation.
Catalytic activity of several ruthenium complexes on the intramolecu-
lar hydroamination of la to 2a a
Run Ruthenium complex
Conversion of la Yield of 2a
(%) b
(%) b
1
2
3
Ru(h6-cot)(dmfm)2
Ru3(CO)12
100
100
100
100
100
66
83
\99
\99
93
85
30
(h3-C3H5) RuBr(CO)3
[RuCl2(CO)3]2
4
5
6
7
8
Ru(CO)3(PPh3)2
Ru(h4-cod)(h6-cot)
Ru(h5-cyclooctadienyl)2
[Ru(h6-C6H6)Cl2]2
Cp*RuCl(cod)
53
40
84
46
9
100
45
45
22
10
11
RuCl2(PPh3)3
RuH2(PPh3)4
70
13
a Compound la (2.5 mmol), ruthenium complex (0.10 mmol as Ru
atom), diglyme (4.0 mL) at 150°C for 4 h under an argon atmosphere.
b Determined by GLC.
Table 4
Ru3(CO)12-catalyzed
intramolecular
hydroamination
of
aminoalkynesa
gave five-, six-, and seven-membered heterocycles, while
the present ring-size dependence of cyclization rates and
the product yields is 5\6ꢀ7, consistent with those
observed in the lanthanide-catalyzed intramolecular hy-
droamination of aminoalkynes [8f,h]. Furthermore, in
the formation of seven-membered heterocycles such as
2e, a considerable amount of the saturated heterocycles
such as 2e% was obtained by ruthenium-catalyzed hydro-
gen-transfer reaction [14]. The marked substituent ef-
fects of alkynes fall in the order Ph\H\MeꢀMe3Si,
which is completely different from that observed in the
lanthanide catalysis [8f,h]. In particular, no reaction
occurred with Me3Si-substituted aminoalkynes, such as
5-trimethylsilyl-4-pentynyl-1-amine. This result suggests
that the mechanism of the present reaction may be
different from that of a lanthanide-catalyzed reaction.
Although a mechanism involving s-bond metathesis
can not be ruled out completely, the present ruthenium-
catalyzed intramolecular hydroamination of aminoalky-
nes would proceed via NꢀH bond activation [15]. The
substituent effects would strongly influence the inser-
tion of an alkyne into the generated RuꢀN bond. The
present hydroamination reaction is not limited to pri-
mary amines, and secondary amines, such as 1f, also
undergo rapid cyclization to give the corresponding
enamines in an isolated yield of 72%. Ru3(CO)12 also
catalyzes the formation of indoles from 2-alkynylanili-
nes. Specifically, 2-ethynylaniline (1g) is converted into
indole (2g) in an isolated yield of 54%.
One viable mechanism involves the oxidative addi-
tion of an amine functionality in aminoalkynes to a
coordinatively unsaturated active ruthenium center in a
low oxidation state [3c,15,16]. Ru(II) precursors, such
as (h3-C3H5)RuBr(CO)3 and [RuCl2(CO)3]2, should be
reduced first to low-valent catalytically active Ru(0)
species under the present reaction conditions. The reac-

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
152 T. Kondo et al. / Journal of Organometallic Chemistry 622 (2001) 149–154
In conclusion, we developed the first practically
3.3. General procedure for ruthenium-catalyzed
useful ruthenium-catalyzed intramolecular hydroami-
nation of aminoalkynes. These results demonstrate
that organoruthenium centers are suitable for the effi-
cient activation of NꢀH bond, followed by regioselec-
tive insertion of an alkyne into the RuꢀN bond.
These processes provide an effective method for the
catalytic synthesis of nitrogen heterocycles such as
pyrrole and indole derivatives.
intramolecular hydroamination of aminoalkynes
A mixture of aminoalkyne (2.5 mmol), ruthenium
catalyst (0.10 mmol as Ru atom), and solvent (4.0
ml) was placed in a two-necked 20 ml Pyrex flask
equipped with a magnetic stirring bar and a reflux
condenser under an argon atmosphere. The mixture
was then magnetically stirred at 110–150°C for 4–6
h. After cooling, the reaction mixture was analyzed
by GLC, and the products were isolated by Kugel-
rohr distillation and/or recycling preparative HPLC.
3. Experimental
3.1. General
3.4. Characterization of products
GLC analyses were performed on a Shimadzu GC-
8A gas chromatograph with a glass column (3.2 mm
i.d.×3 m) packed with Silicone OV-17 (2% on Chro-
mosorb W(AW-DMCS), 80–100 mesh) and a Shi-
madzu GC-14A gas chromatograph with a capillary
column (Shimadzu capillary column HiCap-CBP10-
M25-025: 0.22 mm i.d.×25 m). Almost all of the
products were isolated by Kugelrohr distillation, and
further purification, if needed, was performed on a
recycling preparative HPLC (Japan Analytical Indus-
try Co. Ltd., model LC-908) equipped with JAIGEL-
1H and 2H columns (GPC) using THF or toluene as
3.4.1. N-Propyl-5-phenyl-4-pentynyl-1-amine (1f)
Colorless liquid: b.p. 130°C (2 mmHg, Kugelrohr).
1H-NMR (CDCl3, 400 MHz) l 0.96 (t, J=7.32 Hz,
3H, CH3), 1.29 (br s, 1H, NH), 1.54 (septet, J=7.32
Hz, 2H, CH2CH3), 1.82 (quintet, J=6.83 Hz, 2H,
NCH2CH2CH2CC), 2.51 (t, J=6.84 Hz, 2H,
CH2CC), 2.62 (t, J=7.32 Hz, 2H, CH2CH2CH3),
2.80 (t, J=6.84 Hz, CH2N), 7.28–7.44 (m, 5H, Ph).
13C-NMR (100 MHz) l 11.7, 17.3, 23.1, 28.9, 48.8,
51.7, 80.8, 89.6, 123.8, 127.4, 128.1, 131.4. MS (EI)
m/z 200 (M+ꢀH). Anal. Calc. for C14H19N: C, 83.53;
H, 9.51. Found: C, 83.55; H, 9.65%.
1
an eluent. The H (400 MHz) and 13C-NMR spectra
(100 MHz) were obtained on a JEOL EX-400 spec-
trometer. Samples were analyzed in CDCl3, and the
chemical shift values are expressed relative to Me4Si
as an internal standard. IR spectra were obtained on
a Nicolet Impact 410 spectrometer. Elemental analy-
ses were performed at the Microanalytical Center of
Kyoto University.
3.4.2. 2-Benzylhexahydroazepine (2e%)
Colorless liquid: b.p. 120°C (1 mmHg, Kugelrohr).
1H-NMR (CDCl3, 400 MHz) l 1.32–1.44 (m, 2H,
CHHCH2N, CHHCHN), 1.53–1.61 (m, 4H, 2CH2),
1.72–1.76 (m, 2H, CHHCH2N, CHHCHN), 2.52–
2.69 (m, 3H, CHHN, CH2Ph), 2.82–2.92 (m, 3H,
CHHN, CH, NH), 7.11–7.24 (m, 5H, Ph). 13C-NMR
(100 MHz) l 25.3, 27.0, 30.0, 36.0, 43.6, 47.4, 60.8,
126.2, 128.2, 129.2, 139.5. MS (EI) m/z 189 (M+).
Anal. Calc. for C13H19N: C, 82.48; H, 10.12. Found:
C, 82.10; H, 10.00%.
3.2. Materials
The reagents used in this study were dried and
purified before use by standard procedures.
Ru3(CO)12 and [RuCl2(CO)3]2 were obtained commer-
cially, and used without further purification. Ru(h6-
cot)(dmfm)2
[13],
(h3-C3H5)RuBr(CO)3
[19],
Ru(CO)3(PPh3)2 [20], Ru(h4-cod)(h6-cot) [21], Ru(h5-
cyclooctadienyl)2
Cp*RuCl(cod)
[22],
[24],
[Ru(h6-C6H6)Cl2]2
RuCl2(PPh3)3 [25],
[23],
and
3.4.3. 2-Benzylidene-1-propylpyrrolidine (2f)
Colorless liquid: b.p. 120°C (1 mmHg, Kugelrohr).
1H-NMR (CDCl3, 400 MHz) l 0.84 (t, J=7.33 Hz,
3H, CH3),, 1.52 (septet, J=7.32 Hz, 2H,
NCH2CH2CH3), 1.78 (quintet, J=6.83 Hz, 2H, CH2),
2.72 (t, J=7.32 Hz, 2H, CH2CN), 2.99 (t, J=7.32
Hz, 2H, NCH2CH2CH3), 3.10 (t, J=6.83 Hz, 2H,
CH2N), 4.97 (s, 1H, CHPh), 6.79–7.14 (m, 5H, Ph).
13C-NMR (100 MHz) l 12.0, 20.0, 22.1, 31.4, 48.8,
51.6, 90.5, 122.1, 126.0, 128.3, 141.1, 149.9. MS (EI)
m/z 201 (M+). Anal. Calc. for C14H19N: C, 83.53; H,
9.51. Found: C, 83.71; H, 9.63%.
RuH2(PPh3)4 [26] were prepared as described in the
literature. Aminoalkynes (1a–e) were prepared as re-
ported previously [8h], and 1f was prepared as de-
scribed in the literature with some modification.
2-Ethynylaniline (1g) was prepared as reported previ-
ously [27]. Compounds 1a–e [8h], 2a–e [8h], and 1g
[27] have already been reported. The spectral and an-
alytical data of 2g were fully consistent with those of
an authentic sample. Characterization data of 1f, 2e%,
and 2f are given below.