Intramolecular hydroamination of alkynes catalyzed by Pd(PPh 3)4/triphenylphosphine under neutral conditions

Article abstract of DOI:10.1021/jo050412w

The intramolecular hydroamination of alkynes tethered with amino group 1 in the presence of catalytic amounts of Pd(PPh₃)₄ and PPh₃ in benzene at 100°C proceeded smoothly without the use of any additional acid source to af

Full text of DOI:10.1021/jo050412w

droamination of allenes,4 enynes,5 methylenecyclopro-
panes,6 and cyclopropene7 proceeded smoothly, giving the
corresponding allylic amines in good to high yields. The
presence of a carboxylic acid was needed as an unavoid-
able additive for the Pd-mediated inter- and intramo-
lecular hydroamination of internal alkynes.8 In these
reactions, the presence of carboxylic acid as a cocatalyst
modifies the palladium catalyst to a more active hydri-
dopalladium species via in situ oxidative addition of Pd0
into H-A. We also reported that an asymmetric version
of the intramolecular hydroamination of alkynes pro-
ceeded smoothly by using a Pd2(dba)3‚CHCl3-PhCO2H
catalytic system in the presence of (R,R)-RENORPHOS
as a chiral ligand to give various kinds of optically active
five- and six-membered nitrogen heterocycles (eq 1).8c
Intramolecular Hydroamination of Alkynes
Catalyzed by Pd(PPh3)4/
Triphenylphosphine under Neutral
Conditions
Gan B. Bajracharya, Zhibao Huo, and
Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8578, Japan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received March 3, 2005
The intramolecular hydroamination of alkynes tethered with
amino group 1 in the presence of catalytic amounts of Pd-
(PPh3)4 and PPh3 in benzene at 100 °C proceeded smoothly
without the use of any additional acid source to afford five-
and six-membered nitrogen heterocycles 2 in good to excel-
lent yields. A compulsory addition of carboxylic acid as a
cocatalyst was not needed, and the reaction could be carried
out under essentially neutral conditions.
The use of an stoichiometric amount of an expensive
chiral ligand [(R,R)-RENORPHOS] for obtaining a better
yield and high enatioselectivity was a drawback for this
reaction, and thus we further struggled in this area to
find much milder and more efficient reaction conditions.
While we were searching for an alternative catalytic
system, we found that the intramolecular hydroamina-
tion of alkynes proceeded without using an acid source.
We report that in the presence of 15 mol % Pd(PPh3)4
and 10 mol % PPh3 in benzene at 100 °C the intramo-
lecular hydroamination reaction of alkynes tethered with
amino group 1 proceeded well to give the corresponding
nitrogen heterocycles 2 in good to excellent yields under
essentially neutral conditions.
Nonfunctionalized carbon-carbon multiple bonds are
generally unreactive toward nucleophiles because of their
electron-rich π-orbitals. However, the use of transition
metal catalysts enables the addition of nucleophiles to
such unactivated C-C multiple bonds.1 Nitrogen-con-
taining heterocycles are main building blocks for many
biologically important compounds. The hydroamination
reaction of alkynes using transition metal catalysts is an
attractive route to reach such compounds,2 since the
reaction proceeds in an atom-economical manner. Several
catalytic systems have been explored to promote the
hydroamination of carbon-carbon multiple bonds.3 Re-
cently, we reported that the palladium-mediated hy-
After several attempts, we found that the reaction of
1a in the presence of 15 mol % Pd(PPh3)4 together with
10 mol % PPh3 in benzene at 100 °C for 66 h produced
the corresponding hydroamination product 2a in 86%
(4) (a) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett.
1997, 38, 6071-6074. (b) Meguro, M.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 5421-5424.
(1) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. Rev. 1999, 28,
199-207.
(5) Radhakrishnan, U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 1037-1040.
(2) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198.
(3) (a) Savoia, D. Houben-Weyl; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann E., Eds.; Georg Theime Verlag: Stuttgart,
1995; Vol. E21e, pp 5356-5394. (b) Mu¨ller, T. E.; Beller, M. Chem.
Rev. 1998, 98, 675-703 and references therein. (c) Taube, R. Applied
Homogeneous Catalysis with Organometallic Compounds; Cornils, B.,
Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 1, Applica-
tions; pp 513-524. (d) Schaffrath, H.; Keim, W. J. Mol. Catal. A: Chem.
2001, 168, 9-14. (e) Nobis, M.; Driessen-Ho¨lscher, B. Angew. Chem.,
Int. Ed. 2001, 40, 3983-3985. (f) Minami, T.; Okamoto, H.; Ikeda, S.;
Tanaka, R.; Ozawa, F.; Yoshifuji, M. Angew. Chem., Int. Ed. 2001, 40,
4501-4503. (g) Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed.
2001, 40, 4632-4635. (h) Utsunomiya, M.; Kuwano, R.; Kawatsura,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608-5609. (i) Alonso,
F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079-3160. (j)
Shimada, T.; Bajracharya, G. B.; Yamamoto, Y. Eur. J. Org. Chem.
2005, 59-62 and references therein.
(6) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998,
63, 6458-6459.
(7) Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem.
2003, 68, 2297-2299.
(8) (a) Kadota, I.; Shibuya. A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570-4571. (b) Lutete, L. M.; Kadota, I.; Shibuya,
A.; Yamamoto, Y. Heterocycles 2002, 58, 347-357. (c) Lutete, L. M.;
Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 1622-1623.
(d) Patil, N. T.; Khan, N.; Yamamoto, Y. Tetrahedron Lett. 2004, 45,
8497-8499. (e) Patil, N. T.; Wu, H.; Kadota, I.; Yamamoto, Y. J. Org.
Chem. 2004, 69, 8745-8750. For the other type of reactions using HA-
Pd, see: (f) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110,
2301-2303. (g) Trost, B. M.; Brieden, W.; Baringhaus, K. H. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1335-1336. (h) Trost, B. M.; Michellys,
P. Y.; Gerusz, V. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1750-
1753. Review: (i) Trost, B. M. Chem. Eur. J. 1998, 4, 2405-2412.
10.1021/jo050412w CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/12/2005
J. Org. Chem. 2005, 70, 4883-4886
4883

TABLE 1. Optimization of Reaction Conditions for the Pd/Phosphine Additive Catalyzed Intramolecular
Hydroamination of Alkynesa
phosphine additive
(10 mol %)
additional additive
(10 mol %)
entry
catalyst (15 mol %)
Pd(PPh3)4
time (h)
1b yield (%)b
2b yield (%)b
1
PPh3
PPh3
37
0
98 (87)
0
2
37
100
84
18
5
3
Pd(PPh3)4
37
trace
41
4
Pd(PPh3)4
P(O)Ph3
P(o-tolyl)3
dppp
41
5
Pd(PPh3)4
41
49
6
Pd(PPh3)4
41
13
22
trace
0
63
7
Pd(PPh3)4
dppf
41
55
8
Pd(PPh3)4
PPh3
CH3CO2H
PhCO2H
PhCO2H
16
55
9
Pd(PPh3)4
PPh3
9
28
10c
11
12
13
14
15d
Pd(PPh3)4
overnight
0
94
Pd2dba3.CHCl3
PdCl2(PPh3)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
37
37
37
37
37
37
88
88
80
0
trace
0
0
0
77
[(η3-C3H5)PdCl]2
Pd(PPh3)4
a The reaction of 1b (0.1 mmol) was carried out in the presence of 15 mol % palladium catalyst and 10 mol % phosphine additive in
benzene (0.1 M) at 100 °C under argon unless otherwise noted. b Yield was calculated from 1H NMR integration using CH2Br2 as an
internal standard; isolated yield is in parentheses. c 15 mol % PhCO2H was used. d The reaction temperature was 120 °C.
use of an acid additive.9 In their report, Pd(PPh3)4 was
generated in situ from [(η3-C3H5)PdCl]2 and PPh3, and
in general the use of a catalytic amount of trifluoroacetic
acid was needed as a cocatalyst for the other examples.
To the best of our knowledge, the Pd(PPh3)4/PPh3 cata-
lytic system for the catalytic hydroamination of alkynes
has not been reported in the past.
We observed that the reaction of trifluoromethane-
sulfonyl (Tf)-substituted substrate 1b was faster than
that of 1a having the nonafluorobutanesulfonyl (Nf)
group. Hence, for further optimization of the reaction
conditions, we chose 1b as a model substrate (eq 3), and
the results are summarized in Table 1. The substrate 1b
was cyclized in the presence of both 15 mol % Pd(PPh3)4
FIGURE 1. Time profile of the cyclization of 1a (0.1 mmol)
in the presence of 15 mol % Pd(PPh3)4 and 10 mol % PPh3 in
benzene (0.1 M) at 100 °C.
and 10 mol % PPh3 to afford the pyrrolidine 2b within
37 h with excellent yield (87%) (entry 1). In the absence
of either Pd(PPh3)4 or PPh3, essentially no reaction was
observed, indicating the importance of the combination
of both Pd(PPh3)4 and PPh3 (entries 2 and 3). The use of
other monodentate [P(O)Ph3, P(o-tolyl)3] and bidentate
ligands [dppp ) 1,3-bis(diphenylphosphino)-propane,
dppf ) 1,1′-bis(diphenylphosphino)-ferrocene] afforded
the product in moderate yields (entries 4-7). The use of
additional carboxylic acids was not essential for this
transformation, resulting in poor chemical yields (entries
8 and 9). Although the intramolecular hydroamination
using the Pd(PPh3)4-PhCO2H catalytic system without
additional PPh3 gave a high chemical yield in rather short
reaction time (entry 10), we were motivated to carry out
the present reaction under essentially neutral conditions.
Other palladium catalysts such as Pd2dba3‚CHCl3, PdCl2-
(PPh3)2, Pd(OAc)2, [(η3-C3H5)PdCl]2, etc. were completely
not effective (entries 11-14). Increasing reaction tem-
perature up to 120 °C led to a moderate yield (entry 15).
The scope of the intramolecular hydroamination of
alkynes is summarized in Table 2. Substrates 1c and 1d
yield (99% NMR yield) (eq 2). As shown in Figure 1, the
time profile of the reaction of 1a monitoring by NMR
indicated that the complete conversion of the substrate
occurred within 66 h. In contrast, the reaction of 1a in
the presence of 15 mol % Pd(PPh3)4 only without the
presence of additional PPh3 afforded only trace amounts
of the product 2a with the recovery of significant amounts
of the starting material even after prolonged heating. The
reaction of 1a in the presence of 10 mol % PPh3 only did
not proceed at all, and the substrate was recovered. These
results clearly indicate that combined use of Pd(PPh3)4
and PPh3 is the key for cyclization of 1a. Hartwig et al.
apparently reported two examples of the Pd-catalyzed
intermolecular hydroamination of cyclohexadiene without
(9) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 4366-4367.
4884 J. Org. Chem., Vol. 70, No. 12, 2005

TABLE 2. Pd(PPh3)4/PPh3-Catalyzed Intramolecular Hydroamination of Alkynesa
a The reaction of 1 (0.3 mmol) was carried out in the presence of 15 mol % Pd(PPh3)4 and 10 mol % PPh3 in benzene (0.1 M) at 100 °C
for the indicated reaction time under argon unless otherwise noted. b Isolated yield. c 30 mol % of Pd(Ph3)4 and 20 mol % of PPh3 were
used. d A mixture of trans and cis isomers (1.7:1) was obtained. The ratio was determined by 1H NMR spectral analysis.
SCHEME 1. A Plausible Mechanism
having methoxy and trifluoromethyl groups at the para-
position of aromatic ring afforded the corresponding
cyclized products 2c and 2d, respectively, in good yields,
indicating that the substituents of aromatic ring did not
exert a significant influence upon the cyclization (entries
1 and 2). In both cases, increased amounts of the catalyst
were needed to obtain good chemical yields. The reaction
of 1e, having a pentyl group at the alkyne terminus,
under the standard conditions proceeded smoothly to give
a 1.7:1 mixture of trans and cis isomers of pyrrolidine
2e in a good yield (entry 3). Not only Nf and Tf but also
Bn could be used as a protecting group for the amine; 2f
was obtained from 1f in 61% yield (entry 4). The cycliza-
tion of 1g afforded the six-membered piperidine 2g in a
good yield (entry 5).
A proposed mechanism, which explains the role of
triphenylphosphine as a cocatalyst in the present hy-
droamination reaction, is shown in Scheme 1, although
it is highly speculative. Triphenylphosphine, acting as a
termediate 4 then undergoes â-elimination to give the
allene 5 coordinated with the cationic palladium hydride.
A subsequent hydropalldation of 5 furnishes the π-al-
lylpalladium species 6. Nucleophilic attack of the amine
Brφnsted base, abstracts a proton from the nitrogen
on the resulting π-allyl moiety gives the final product 2
functionality at the early stage, producing 3 and a
along with regeneration of Pd0. In our previous reports
phosphonium ion [HPPh3]+. Hydropalladation of alkyne
on the Pd/carboxylic acid catalyzed analogous reaction,
with the cationic palladium hydride species generated
we proposed the oxidative addition of Pd0 to RCOO-H
from Pd0 and the phosphonium ion produces the vi-
bond of acid as the very first step to generate catalytically
nylpalladium intermediate 4.10 The vinylpalladium in-
active hydridopalladium complex.8a-e In contrast, forma-
tion of a phosphonium ion is the beginning step in the
present transformation.
In summary we have developed a simple and acid free
hydroamination protocol for the synthesis of various
nitrogen heterocycles. This reaction provides a very
(10) In the palladium-catalyzed intramolecular hydrocarbonation of
ꢀ-alkynyl malononitriles, we proposed a rapid intramolecular cycliza-
tion of carbanion to the triple bond of alkyne coordinated with a cationic
palladium hydride generated from Pd(OAc)2 and a carbon pronucleo-
phile; see: Tsukada, N.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl.
1997, 36, 2477-2480.
J. Org. Chem, Vol. 70, No. 12, 2005 4885

mol %), PPh3 (2.6 mg, 0.01 mmol, 10 mol %), and N-trifyl-(6-
phenyl-hex-5-ynyl)-amine 1b (30.5 mg, 0.1 mmol) was added
benzene (1.0 mL, 0.1 M) under argon atmosphere in a Wheaton
microreactor. The mixture was stirred for 10 min at room
temperature then heated at 100 °C. Progress of the reaction was
monitored by TLC (hexane/ethyl acetate; 4/1). After complete
consumption of the starting material, the reaction mixture was
filtered through a short column of SiO2 using diethyl ether as
an eluent, and the resulting filtrate was concentrated. The
residue was purified by column chromatography (silica gel,
hexane/ethyl acetate; 20/1-5/1) to afford N-triflyl-2-[(E)-2-
phenylethenyl)pyrrolidine 2b in 87% yield (26.5 mg).
useful method for a catalytic synthesis of five- and six-
membered nitrogen heterocycles. Now, it is clear that the
catalytic intramolecular hydroamination of alkynes can
be accomplished under essentially neutral conditions
without using any acid source. We are further continuing
our effort to develop a mild and an efficient asymmetric
version of this hydroamination reaction and synthesizing
various natural compounds by utilizing our methodology
as the key step.11
Experimental Section
Representative Procedure for Intramolecular Hydroam-
Supporting Information Available: Starting material
preparation; characterization data for all new compounds; and
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
ination. To a mixture of Pd(PPh3)4 (17.3 mg, 0.015 mmol, 15
(11) Recently we reported the synthesis of indolizidine (-)-209D
based on an intramolecular hydroamination strategy; see: Patil, N.
T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101-
2103.
JO050412W
4886 J. Org. Chem., Vol. 70, No. 12, 2005