Palladium-catalyzed intermolecular hydroamination of alkynes: A dramatic rate-enhancement effect of o-aminophenol

Article abstract of DOI:10.1021/ja027683y

The hydroamination of alkynes using o-aminophenol proceeds in very high to good yields in the presence of Pd(NO₃)₂ catalyst. Remarkable rate enhancement with o-aminophenol is presumably due to the chelation effect of the ortho OH group to palladium. Copyright

Full text of DOI:10.1021/ja027683y

Published on Web 10/02/2002
Palladium-Catalyzed Intermolecular Hydroamination of Alkynes: A Dramatic
Rate-Enhancement Effect of o-Aminophenol
Tomohiro Shimada and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received July 13, 2002
Table 1. Palladium-Catalyzed Hydroamination of Various Alkynesa
The addition of ammonia or primary and secondary amines to
alkenes and alkynes, known as hydroamination,1 is one of the most
reaction
time, h
yield,
%
R1
R2
1
3:4
efficient approaches for the synthesis of higher substituted amines
and their derivatives which are important bulk and fine chemicals
or building blocks in organic chemistry. A variety of metals are
known as efficient catalysts for the intermolecular hydroamination
of alkynes, but almost all reactions are restricted to terminal
alkynes,2 and only a few efficient methods are applicable to internal
alkynes.3,4 Among the metals utilized for internal alkynes, titanium
catalysts are the most effective and efficient,4 although they are
air- or light-sensitive and care should be taken in handling them.
In the course of the palladium-catalyzed addition of phenols to
diynes,5 we have discovered that the intermolecular hydroamination
of internal alkynes 1 with o-aminophenol 2a proceeds very smoothly
in the presence of Pd(NO3)2 catalyst (eq 1). The palladium catalyst
is easy to handle, the hydroamination proceeds in very high-to-
good yields, and the use of 2a as an amine substrate dramatically
enhances the reaction rate of the palladium-catalyzed hydroami-
nation.6
entry
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
nPent
nPent
Ph
nPent
nPent
Ph
Me
nBu
H
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
12
10
7
5
5
5
5
5
5
5
20
5
3
5
76
93
81
65
>99
54
40
>99
94
95
58
95
95
-
-
-
Ph
2:1
1:1
Ph
nDec
Ph
1:ndd
1:ndd
1:1
H
Ph
Ph
Ph
Ph
(CH2)4OMe
(CH2)4OBn
(CH2)4OAc
(CH2)4OTBS
(CH2)4Cl
nBu
1:1
1:1
2:1
Ph
1:1e
3:1
4-MeOC6H4
4-MeC6H4
4-FC6H4
nBu
99
99
62
2:1
2:1
1:2
nBu
5
20
4-CF3C6H4
nBu
a Reaction conditions: 0.5 mmol amine, 0.75 mmol alkyne, 15 mol %
Pd(NO3)2, 1,4-dioxane, 120 °C. b Isolated yields. c The ratio of amine:alkyne
was 1.0:1.2. d The corresponding aldehyde and its derivatives were not
detected. e The ratio of 3k:5.
3f, respectively, in lower yields (entries 6 and 7), due to competitive
cyclotrimerization of the terminal alkynes under the palladium
catalyst. Since the aldehydes 4e and 4f or their derivatives were
not detected, the hydroamination of the terminal alkynes was very
regioselective. Various protecting groups of alcohol were tolerated
under the reaction conditions (entries 8-11). When the chloro-
substituted alkyne 1k was used, a 50:50 mixture of 3k and 5 was
obtained in 95% yield (entry 12, eq 2). The regioisomeric
hydroamination product of 1k, an enamine precursor of 4k, would
undergo the intramolecular replacement of the chlorine atom to
produce a six-membered enamine and subsequently an imine
derivative, and the intramolecular reaction of the resulting imine
with phenolic OH would give 5. The arylalkynes 1l and 1m, bearing
an electron-donating group at the para position, gave the hydroami-
nation products, with the predominant formation of 3 over 4, in
very high yields (entries 13 and 14). However, the reaction of 1o
having an electron-withdrawing group at the para position was
sluggish, and the predominant formation of 4o over 3o was
observed.
The results are summarized in Table 1. The reaction of
6-dodecyne 1a (1.2 equiv) with 2a (1 equiv) in the presence of 15
mol % Pd(NO3)2 catalyst in 1,4-dioxane at 120 °C for 12 h, followed
by hydrolysis of the reaction mixture and subsequent purification
of the product gave 6-dodecanone 3a in 76% yield (entry 1). We
tested various kinds of palladium catalysts in the reaction of 1a
with 2a under the conditions similar to those of entry 1. The use
of Pd2(dba)3‚CHCl3, PdCl2, Pd(acac)2, [(η3-C3H5)PdCl]2, and Na2-
PdCl4 gave 3a in the range of 62-68% yields, while that of PdCl2-
(dppf) and PdCl2(CH3CN)2 afforded 3a in 47-51% yields. Among
n
the solvents examined, 1,4-dioxane gave the best result. BuOH,
DMF, DMSO, toluene, and octane were less effective. Accordingly,
the use of strongly coordinating phosphine ligands or solvents is
not desirable for the palladium-catalyzed hydroamination. The use
of 1.5 equiv of alkyne 1a gave 3a in 93% yield (entry 2). The
reaction of diphenylacetylene 1b gave 3b in 81% yield (entry 3).
The hydroamination of the unsymmetrical alkynes 1c and 1d
afforded a mixture of the regioisomeric products (entries 4 and 5).
The hydroamination of the terminal alkynes 1e and 1f gave 3e and
The hydroamination of 1a with 2a is representative. To a 1,4-
dioxane suspension (0.05 mL) of 2-aminophenol 2a (54.6 mg, 0.5
mmol) and Pd(NO3)2 (17.3 mg, 0.075 mmol) in the reaction vial
was added 6-dodecyne 1a (124.7 mg, 0.75 mmol) under an argon
* To whom correspondence should be addressed. E-mail: yoshi@
yamamoto1.chem.tohoku.ac.jp.
9
12670
J. AM. CHEM. SOC. 2002, 124, 12670-12671
10.1021/ja027683y CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Palladium-Catalyzed Hydroamination of 1a with
Arylamines 2a
(2) oxidative addition of N-H bond to MLn (with lower oxidation
state) followed by the hydrometalation of alkenes and alkynes with
the resulting M-H species (amine activation).1b Since the dramatic
rate enhancement was observed in the case of 2a and a phenolic
OH was essential for this enhancement, a chelation effect of
o-aminophenol is operative. Accordingly, it is most probable that
an o-aminophenoxide palladium(II) complex and HX would be
generated by the reaction of Pd(II) with 2-aminophenol, leading to
an equiliblium with the o-hydroxyamido tautomer, and subsequent
1,2-insertion of an alkyne into the amido tautomer would give the
product.8 However, there is an alternative possibility that H-Pd-
(2-aminophenoxide) species, generated by the reaction of 2-ami-
nophenol with Pd(0), would react with an alkyne to produce a
vinylpalladium intermediate, which would undergo tautomerization
to give an amidopalladium species, and subsequent reductive
elimination would afford the hydroamination product and Pd(0).9
Now, we are in a position to carry out the hydroamination of alkynes
very smoothly with high chemical yields in the presence of Pd-
(NO3)2 catalyst and o-aminophenol. Further extension of this
palladium chemistry is continuing.
b
entry
R of 2
reaction time, h
yield of 3, %
1
2
3
4
5
6
7
2-OH (2a)
3-OH (2b)
4-OH (2c)
2-CH2OH (2d)
2-OMe (2e)
3-OMe (2f)
H (2g)
10
10
20
20
20
20
20
96
48
30
12
11
18
13
a Reaction conditions: 0.5 mmol amine, 0.75 mmol alkyne, 15 mol %
Pd(NO3)2, 1,4-dioxane, 120 °C. b 1H NMR yields, dibromomethane was
used as an internal standard.
atmosphere. The suspension was heated at 120 °C for 10 h. The
reaction mixture was cooled to room temperature and filtered
through a short Al2O3 pad using diethyl ether as an eluent, and the
resulting filtrate was concentrated. The residue was purified by
column chromatography (silica gel, hexanes-ethyl acetate 50/1 to
10/1) to afford 6-dodecanone 3a in 93% yield (86.0 mg).
The rate enhancement effect of o-aminophenol in the palladium-
catalyzed hydroamination was investigated. The addition of aliphatic
amines, such as ethanolamine and 2-aminomethylphenol, to 1a in
the presence of representative palladium catalysts including Pd-
(NO3)2 did not take place at all under various reaction conditions.
The results of the hydroamination of 1a with arylamines 2 in the
presence of Pd(NO3)2 are summarized in Table 2.
Supporting Information Available: Spectroscopic and analytical
data of synthesized compounds and information on procedures (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Among the three-regioisomeric aminophenols 2a-c, o-ami-
nophenol 2a was the most effective and efficient, and the hy-
droamination with m-aminophenol 2b was faster than that with the
para isomer 2c (entries 1-3). These results suggest that the rate
enhancement of 2a is most probably due to the chelation effect of
the ortho hydroxy group to the palladium atom. The hydroamination
with o-hydroxymethylaniline 2d was sluggish (entry 4); perhaps
the chelation (and protonation ability to Pd) of this amino alcohol
would be less effective. Interestingly, the addition of the methoxy-
substituted amines 2e and 2f was also sluggish, despite ortho and
meta substitution (entries 5 and 6). Accordingly, the presence of
OH at the ortho position is essential to dramatically enhance the
rate of hydroamination.7 As expected, the hydroamination of aniline
2g was sluggish, and the addition rates of 2d-g were approximately
of similar level.
(3) (a) Zr: Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.
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For the purpose of obtaining an amine adduct, the reaction
product of the hydroamination of 1a with 2a was reduced prior to
hydrolyzing the reaction mixture (eq 3).4h Treatment with NaBH3-
CN and ZnCl2 in MeOH gave o-N-(1-pentylheptyl)aminophenol 6
in 62% isolated yield.
(5) Camacho, D. H.; Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2002, 1085-
1088.
(6) For palladium-catalyzed intramolecular hydroamination, see: (a) Muller,
T. E.; Pleier, A.-K. J. Chem. Soc., Dalton Trans. 1999, 575-587. (b)
Muller, T. E.; Berger, M.; Grosche, M.; Herdtweck, E.; Schmidtchen, F.
P. Organometallics 2001, 20, 4384-3493.
(7) It is conceivable that not only the chelation effect of OH but also the
other factor, such as an acidity of phenol, is responsible for the rate
enhancement.
(8) We appreciate very much one of the reviewers who suggested this
mechanism.
(9) Recently, Hartwig et al. proposed palladium hydride intermediate in the
palladium-catalyzed intermolecular hydroamination of vinylarenes, see:
(a) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166-
1167. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
9546-9547.
Two major mechanisms have been proposed for the transition
metal-catalyzed hydroamination of C-C multiple bonds: (1)
activation of C-C multiple bonds through the coordination of MLn
followed by the nucleophilic attack of amines to the electron-
deficient alkenes and alkynes (C-C multiple bond activation) and
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