Au(I)-catalyzed highly efficient intermolecular hydroamination of alkynes

Article abstract of DOI:10.1021/ol0353159

Addition of aniline derivatives to aromatic and aliphatic alkynes proceeds efficiently in the presence of a gold(I) catalyst (0.01-1.0 mol %) to afford ketimines in good yields.

Full text of DOI:10.1021/ol0353159

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3349-3352
Au(I)-Catalyzed Highly Efficient
Intermolecular Hydroamination of
Alkynes
,†
,†,‡
Eiichiro Mizushima,† Teruyuki Hayashi,* and Masato Tanaka*
Research Institute for Green Technology, National Institute of
AdVanced Industrial Science and Technology (AIST), Tsukuba Central 5,
Tsukuba, Ibaraki 305-8565, Japan, and Chemical Resources Laboratory,
Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
t.hayashi@aist.go.jp; m.tanaka@res.titech.ac.jp
Received July 16, 2003
ABSTRACT
Addition of aniline derivatives to aromatic and aliphatic alkynes proceeds efficiently in the presence of a gold(I) catalyst (0.01−1.0 mol %) to
afford ketimines in good yields
Although the condensation between carbonyl compounds and
primary amines is a well-established standard method for
synthesizing imines,1 hydroamination of alkynes2-4 attracts
intense interest as an environmentally benign alternative
route. By the development of new catalyst systems, the
intramolecular hydroamination of alkynylamines has made
significant progress.3,4 As for the intermolecular version on
the other hand, the procedure involving aminomercuration
of alkynes followed by demercuration is well-known.2c,d,5
However, the necessity of a stoichiometric amount of toxic
mercury(II) reagents does not meet the contemporary re-
quirement against hazardous reagents. A wide range of metal
catalysts of zinc, cadmium,6 mercury, thallium,7 zirconium,8
titanium,9 lanthanide,10 actinide,11 ruthenium,12 rhodium,13
and palladium14 have been examined for the catalytic
(6) (a) Kruse, C. W.; Kleinschmidt, R. F. J. Am. Chem. Soc. 1961, 83,
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(7) (a) Barluenga, J.; Aznar, F.; Liz, R.; Rodes, R. J. Chem. Soc., Perkin
Trans. 1 1980, 2732. (b) Barluenga, J.; Aznar, F. Synthesis 1977, 195.
(8) (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem.
Soc. 1992, 114, 1708. (b) Baranger, A. M.; Walsh, P. J.; Bergman, R. G.
J. Am. Chem. Soc. 1993, 115, 2753.
(9) (a) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 1999,
38, 3389. (b) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2, 1935.
(c) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305. (d) Johnson,
J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923. (e) Straub, B.
F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001, 40, 4632. (f) Shi, Y.;
Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 3967. (g) Cao,
C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011. (h)
Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853. (i) Tillack, A.;
Castro, I. G.; Hartung, C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41,
2541. (j) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 6, 935.
(10) (a) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770. (b) Li, Y.;
Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771.
(11) (a) Haskel, A.; Straub, T.; Eisen, M. S. Organometallics 1996, 15,
3773. (b) Straub, T.; Haskel, A.; Neyroud, T. G.; Kapon, M.; Botoshansky,
M.; Eisen, M. S. Organometallics 2001, 20, 5017.
(12) (a) Uchimaru, Y. Chem. Commun. 1999, 1133. (b) Tokunaga, M.;
Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999, 38, 3222. (c)
Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Jpn. Kokai Tokkyo Koho JP 2000-
256284; Chem. Abstr. 2000, 133, 237674. (d) Tokunaga, M.; Ota, M.; Haga,
M.; Wakatsuki, Y. Tetrahedron Lett. 2001, 42, 3865. (e) Tokunaga, M.;
Wakatsuki, Y. Jpn. Kokai Tokkyo Koho JP 2002-30069; Chem. Abstr.
2002, 136, 118383.
† National Institute of Advanced Industrial Science and Technology.
‡ Tokyo Institute of Technology.
(1) Layer, R. W. Chem. ReV. 1963, 63, 489.
(2) (a) Chekulaeva, I. A.; Kondrat’eva, L. V. Russ. Chem. ReV. 1965,
34, 669. (b) Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Dekker:
New York, 1969; p 286. (c) Hudrlik, P. F.; Hudrlik, A. M. In The Chemistry
of the Carbon-Carbon Triple Bond; Patai, S. Ed.; Wiley: New York, 1978;
Part 1, p 244. (d) Larock, R. C.; Leong, W. W. In ComprehensiVe Organic
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Press: Oxford, 1991; Vol. 4, p 290. (e) March, J. AdVanced Organic
Chemistry; Wiley: New York, 1992; p 769.
(3) (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (b) Mu¨ller,
T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y.-K.
Organometallics 2000, 19, 170. (c) Nobis, M.; Driessen-Ho¨lscher, B. Angew.
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(4) Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization;
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(5) (a) Larock, R. C. Angew. Chem., Int. Ed. Engl. 1978, 17, 27. (b)
Barluenga, J.; Aznar, F. Synthesis 1975, 704.
10.1021/ol0353159 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/15/2003

hydroamination. In terms of the yield, catalytic efficiency,
and simplicity of the procedure, however, the intermolecular
hydroamination in the presence of these catalyst systems is
not yet satisfactory for practical exploitation. Thus, the
development of new catalyst systems remains an intriguing
challenge.
Homogeneous catalysis by gold complexes has not been
extensively explored.15 However, in 1987, Utimoto and co-
workers reported the intramolecular hydroamination cata-
lyzed by NaAuCl4.16 Highly efficient gold(I)-catalyzed
hydration of alkynes was also found by us recently.17
Continued research on gold-catalyzed reactions has uncov-
ered that (Ph3P)AuCH3 in conjunction with acidic promoters,
heteropoly acids in particular catalyze the intermolecular
hydroamination far more efficiently than the foregoing metal-
containing catalysts (Scheme 1). Preliminary observations
are disclosed in this communication.
Table 1. Hydroamination of Phenylacetylene with
4-Bromoanilinea
entry
promoter
yield of ketimine 3 (%)b
1
2
3
4
5
6
7
8
9
none
0
97
95
97
88
72
26
56
7
H3PW12O40
H3MoW12O40
H4SiW12O40
CF3SO3H
C12H25C6H4SO3H
CH3SO3H
NH4PF6
NH4BF4
10c
Nafion-SAC13
19
a Reaction conditions: 0.002 mmol of (Ph3P)AuCH3, 0.01 mmol of
promoter, 1 mmol of PhCtCH, 1.1 mmol of 4-BrC6H4NH2, 70 °C, 2 h.
b Determined by 500 MHz 1H NMR spectroscopy. c Performed with 0.013
g of Nafion-SAC13.
NH4Cl, NEt4Cl, NEt4PF6, H2WO4, and CH3COOH were
totally ineffective. Finally, it is interesting from the practical
viewpoint to note that Nafion-SAC13, a polymer-supported
sulfonic acid, does promote the gold-catalyzed reaction (entry
10), though the efficacy remains to be further enhanced.
The present hydroamination procedure has proved to be
applicable to substituted anilines with various alkynes, both
aromatic and aliphatic, inclusive of internal ones, as shown
in Table 2. All the reactions were run under solvent-free
conditions, using H3PW12O40 as the acidic promoter in most
cases.18
The reaction of aniline and phenylacetylene, using 0.2 mol
% (Ph3P)AuCH3 and 1 mol % H3PW12O40, proceeded to give
N-(R-methylbenzylidene)aniline in 98% yield (Table 2, entry
1). However, when the precatalyst and promoter loadings
were decreased to 0.01 and 0.05 mol %, respectively (20
mmol scale reaction), the yield of the ketimine dropped to
28%, although the TON reached 2800/Au (entry 2). 4-Bromo-
aniline reacted more smoothly even at lower loadings of the
precatalyst and the promoter, resulting in high yields and
TONs (entry 3, 94%, TON 940/Au; entry 4, 86%, TON 8600/
Au). Other anilines having electron-withdrawing substituents
such as 4-cyanoaniline and 4-nitroaniline reacted as well
(entries 5-7, near 90% yields, TON 9000/Au in entry 6).
In these reactions, the products were obtained as a mixture
of the corresponding imine and enamine,19 the former being
the major component. Steric hindrance in the aniline deriva-
tives does not hamper the addition seriously, as the high-
Scheme 1. Gold(I)-Catalyzed Intermolecular Hydroamination
As the reaction of phenylacetylene with p-bromoaniline
indicates (Table 1), use of both (Ph3P)AuCH3 and an acidic
promoter is an indispensable prerequisite for the hydro-
amination to take place. Thus, an attempted reaction using
NH4PF6 or H3PW12O40 alone without the gold precatalyst
complex did not proceed at all. Another attempted reaction
using the gold precatalyst in the absence of an acidic
promoter did not work either (entry 1). However, the addition
of acidic promoters activates the precatalyst to afford
4-bromo-N-(R-methylbenzylidene)aniline, though the ef-
ficiency depends on the nature of the promoter. Heteropoly
acids are particularly effective (entries 2-4), resulting in near
quantitative yields, the turnover numbers (TONs) being
approximately 500/Au. Trifluoromethanesulfonic acid and
dodecylbenzenesulfonic acid also serve as powerful promot-
ers (entries 5 and 6), while methanesulfonic acid is inferior
(entry 7). Ammonium hexafluorophosphate and tetrafluoro-
borate are able to activate, but only modestly or marginally
(entries 8 and 9). Other ammonium salts and acids such as
(18) Typical Experimental Procedure. Synthesis of 4-Bromo-N-(R-
methylbenzylidene)aniline. Under a nitrogen atmosphere, a mixture of
phenylacetylene (2.17 g, 21 mmol), 4-bromoaniline (3.61 g, 21 mmol),
(Ph3P)AuCH3 (1.0 mg, 0.0021 mmol), and H3PW12O40 (30 mg, 0.01 mmol)
was stirred at 70 °C for 14 h. After the mixture was cooled, hexane (25
mL) was added to the reaction mixture to precipitate out a white powder.
The powder was recrystallized from hexane-dichloromethane to give
4-bromo-N-(R-methylbenzylidene)aniline (4.9 g, 18 mmol, 85% isolated
yield).
(13) (a) Hartung, C. G.; Tillack, A.; Trauthwein, H.; Beller, M. J. Org.
Chem. 2001, 66, 6339. (b) Beller, M.; Breindl C.; Eichberger, M.; Hartung,
C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002,
10, 1579.
(14) (a) Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570. (b) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12670.
(15) (a) Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237. (b) Teles, J.
H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415.
(16) Fukuda, Y.; Utimoto, K.; Nozaki, H. Heterocycles 1987, 25, 297.
(17) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563.
(19) Presence of a tautomeric enamine component in the product was
substantiated by the olefinic proton signals at 4.8 and 5.1 ppm for the product
from p-cyanoaniline and 4.9 and 5.2 ppm for that from p-nitroaniline. In
the reactions of other aniline derivatives, signals arising from enamines
were not evident.
3350
Org. Lett., Vol. 5, No. 18, 2003

Table 2. Gold(I)-Catalyzed Hydroamination of Alkynesa
alkyne 1
amine 2
entry
R1
R2
R3
Au-cat. (mol %)
H3PW12O40 (mol %)
time (h)
yield of 3 (%)b
1
2c
3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
0.2
0.01
0.1
0.01
0.1
0.01
0.1
0.2
0.1
0.1
0.1
0.5
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.0
0.05
0.5
0.05
0.5
0.05
0.5
1.0
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0k
2
24
2
14
1
20
1
2
2
1
0.25
2
2
3
2
2
5
5
10
4
98
28
94
86
4-BrC6H4
4-BrC6H4
4-NCC6H4
4-NCC6H4
4-NO2C6H4
2,4,6-(CH3)3C6H2
4-BrC6H4
4-BrC6H4
4-BrC6H4
C6H5
C6H5
C6H5
4-BrC6H4
4-CH3OC6H4
C6H5
4-BrC6H4
4-BrC6H4
C6H5NH
4c
5
6c
7
8
9
10
11
12
13
14
15
16
17
18
19h
20
88 (+6d)
84 (+6d)
86 (+7d)
93
92
91
90
98f
87
96
96
70
59
72
32i + 29j
99
4-FC6H4
4-BrC6H4
4-CH3OC6H4
1,4-diethynylbenzene
2-C4H3Sg
n-C6H13
n-C6H13
n-C6H13
n-C3H7
n-C3H7
e
H
H
H
H
n-C3H7
n-C3H7
CH3
n-C3H7
C6H5
H
a Reaction conditions: 1.0 mmol of alkyne 1, 1.1 equiv of amine 2 with respect to 1, 70 °C. b Determined by 500 MHz 1H NMR spectroscopy. c Performed
with 21 mmol of the alkyne and the amines. d Value in parentheses is the yield of the corresponding enamine. e Performed with 2.2 equiv of the amine
relative to 1. f Yield of 1,4-[C6H5NdC(CH3)]2C6H4. g 2-Thienyl group. h T ) 60 °C. i Yield of 3. j Yield of 3′. k NH4PF6 was used instead of H3PW12O40.
yielding reaction with 2,4,6-trimethylaniline verifies (entry
8). Other arylacetylenes substituted by either electron-
withdrawing or -donating groups all reacted efficiently
(entries 9-11). In particular, 4-methoxyphenylacetylene
reacted rapidly as compared with other arylacetylenes (vide
infra). 1,4-Diethynylbenzene readily reacted at both of the
triple bonds by using of a 2.2 equiv amount of aniline (entry
12). 2-Ethynylthiophene also underwent the hydroamination,
although it was somewhat less reactive than phenyacetylene,
as judged by the higher catalyst loading (entry 13).
Aliphatic terminal alkynes displayed reactivities similar
to aromatic alkynes as far as the H3PW12O40 promoter was
concerned (entries 14-16). Internal ones, less reactive due
presumably to steric reasons, required longer reaction times
to obtain acceptable yields (entries 17-19).
It is interesting to note that phenylhydrazine also adds to
phenylacetylene, affording a high yield of the corresponding
phenylhydrazone, which is an intermediate in Fischer indole
synthesis (entry 20). Fukumoto and co-workers have recently
reported the reaction of terminal alkynes with hydrazines
catalyzed by a rhodium complex. However, the reaction
proceeds in an entirely different route, forming nitriles
through formal displacement of the terminal hydrogen with
an NH2 group.20 On the other hand, titanium complexes have
been known to catalyze the addition of hydrazines to alkynes,
although the process needs higher catalyst loading.9h
Despite the tremendous effort made, aliphatic amines did
not add to alkynes under conditions similar to the aniline
reactions.
The gold(I)-catalyzed intermolecular hydroamination of
alkynes with aromatic amines appears to involve electrophilic
attack of the amine to alkynes. Experiments to more clearly
reveal the influence of the substituents in the starting
materials were carried out using NH4PF6, which was a
modestly effective and hence more suitable promoter for the
objective than H3PW12O40. As the results summarized in
Table 3 indicate, the reaction proceeds more smoothly when
Table 3. Hydroamination of Phenylacetylene Derivatives with
Aniline Derivativesa
alkynes 1
amines 2
entry
R1
R2
R3
yield of 3 (%)b
1
2
3
4
5
6
7d
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-BrC6H4
4-CH3OC6H4
H
H
H
H
H
H
H
4-NCC6H4
4-BrC6H4
C6H5
4-CH3OC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
92c
91
46
31
24
20
99
a Reaction conditions: 1.0 mmol of alkyne 1, 1.1 equiv of amine 2
relative to 1, 0.2 mol % (PPh3)AuCH3, 1 mol % NH4PF6, 70 °C, 5 h.
b Determined by 500 MHz 1H NMR spectroscopy. c Obtained as a 92:8
mixture of the imine and enamine. d Reaction time ) 3 h.
the amine substituent is more electron-withdrawing (entries
1-4) and the alkyne substituent is more electron-donating
(entries 2, 5-7).
The reactivity trend can be rationalized by the mechanism
(20) Fukumoto, Y.; Dohi, T.; Masaoka, H.; Chatani, N.; Murai. S.
Organometallics 2002, 21, 3845.
illustrated in Scheme 2. Thus, analogously to Teles’s
Org. Lett., Vol. 5, No. 18, 2003
3351

alkyne, forming a cationic Au(I)-alkyne complex. Complex
formation should be favored by an electron-donating sub-
stituent in the alkyne molecule, as was indeed observed. Two
reaction pathways for an amine to react with the gold(I)-
alkyne complex can be considered. One is direct inter-
molecular nucleophilic attack of the amine on the alkyne
ligated to the gold center. However, this route is less likely
since an aniline that has a more electron-withdrawing
substituent reacts faster. The other route, involving coordina-
tion of the amine to the gold center prior to the C-N bond
formation, appears more probable.22
Scheme 2. Plausible Reaction Pathway
In conclusion, we have demonstrated that the combination
of (Ph3P)AuCH3 and acidic promoters efficiently catalyzes
hydroamination of alkynes with anilines. The catalytic
activity is much higher than that observed with the other
catalyst systems so far reported. We believe that the new
findings will be useful for developing a practical process.
mechanistic proposal for the methanol addition to alkynes,16b,21
the cationic gold(I) species, Au(PPh3)+, generated by pro-
tonolysis of (Ph3P)AuCH3, is envisaged to interact with an
OL0353159
(22) In the gold(III)-catalyzed intramolecular hydroamination to afford
cyclic imines, direct attack of amine to the coordinated alkyne was
illustrated; see ref 16. On the other hand, in the gold(I)-catalyzed methanol
addition to alkynes, an associative mechanism involving coordination of
methanol to gold was predicted by ab initio calculations; see ref 16b.
(21) Role of ammonium salts derived from the acidic promoters and 2
in the present reaction system remains to be further clarified. A similar
promoting effect of ammonium salts has been reported in the [Ru3(CO)12]-
catalyzed hydroamination; see ref 12b.
3352
Org. Lett., Vol. 5, No. 18, 2003