Intramolecular C-N bond addition of amides to alkynes using platinum catalyst

Article abstract of DOI:10.1021/ja047542r

The intramolecular aminoacylation of alkynes using ortho-alkynylacetanilides proceeds in very high yields in the presence of PtCl₂ catalyst. This reaction provides not only a useful procedure for synthesizing 2,3-disubstituted indoles at once from ortho-alkynylaniline derivatives, but also an interesting mechanistic aspect; the intramolecular C-N bond addition of amides to alkynes takes place readily in the presence of Pt(II) catalyst. Copyright

Full text of DOI:10.1021/ja047542r

Published on Web 08/06/2004
Intramolecular C-N Bond Addition of Amides to Alkynes Using Platinum
Catalyst
Tomohiro Shimada, Itaru Nakamura, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received April 27, 2004; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Table 1. Catalyst Activity in the Intramolecular Aminoacylation of
Catalytic additions of H-H, C-H, C-M, and H-X (X ) N,
t
the Alkyne of ortho-Alkynylanilide 1a (R1 ) Bu, R2 ) Me)a
O, halides and S, P...) to carbon-carbon unsaturated bonds have
b
entry
catalyst
solvent
time, h
yield, %
2a:3a
been well investigated as atom-economical transformations to
construct carbon-carbon and -heteroatom bonds (eq 1).1 However,
the direct addition of a carbon-nitrogen bond (carboamination) to
alkenes and alkynes is rare due to lack of reactivity and still
considered as a challenging subject.2,3 We report here that the C-N
bond of ortho-alkynylanilides adds to the alkynyl bond intramo-
lecularly in the presence of platinum catalyst (eq 2).
1
2
3
4
5
6
7
8
9
PtCl2
PtCl2(CH3CN)2
PtBr2
Pt(PPh3)4
PtCl4
PtCl2
PtCl2
PtCl2
PtCl2
Pd(PPh3)4
PdCl2
anisole
anisole
anisole
anisole
anisole
benzene
toluene
p-xylene
mesitylene
anisole
anisole
3
8
5
94
80
79
0
80
33
99
92
93
0
2:1
2:1
2:1
-
12
1
24
14
7
14
12
12
2:1
2:1
3:1
2:1
2:1
-
10
11
18
1:7
a Reaction conditions: 0.5 mmol of substrate 1a, 10 mol % catalyst,
solvent (0.5 M), 80 °C. b Combined 1H NMR yields; dibromomethane was
used as an internal standard.
The transition metal-catalyzed reaction of the ortho-alkynyl
amides 1 gave the 3-acylindoles 2 along with deacylated indoles 3
(eq 3).4,5 First, the catalytic activity of metals was investigated using
reactions completed within 1 h (entries 8 and 9). The ratio of 2/3
was not affected by the electronic factor of the substituents of aryl
group, giving a similar level of selectivity. Not only the methyl
amides 1a-h but also the other amides 1i-m can be used. When
the formamide 1i was used, the formylindole 2i was obtained in
high yield (entry 10). The ratio of 2/3 was strongly influenced by
the acyl moiety, and the benzamide 1j gave 2j in higher selectivity
(entry 11). Phenylacetamide 1k and trifluoroacetamide 1m gave
the acyl products 2k and 2m, respectively, as sole products (entries
12 and 14). Furthermore, phenyl-substituted amide 1l also gave 2l
in good selectivity compared with the reaction using 1f (entry 13).
The reactions of the substrates 1n and 1o, which had a methoxy
group at the 4 or 5 position of the aromatic ring, selectively
produced the methoxyindole derivatives 2n and 2o in 89 and 99%
yield, respectively (eq 4).
t
1a (R1 ) Bu, R2 ) Me) as a substrate (Table 1). Among various
metals examined, PtCl2 gave the best result and gave the products
almost quantitatively (entry 1). The other Pt(II) catalysts, such as
PtCl2(CH3CN)2 and PtBr2, gave the products in slightly lower yields
(entries 2 and 3). Very interestingly, Pt(PPh3)4 did not give the
products at all, even after a prolonged reaction time (entry 4),
although PtCl4 afforded the products in good yield in a very short
time (entry 5). This reaction was strongly influenced by the solvents
used. Among the solvents examined, aromatic solvents are suitable
for this transformation, and an electron-donating substituent on the
aromatic ring dramatically enhanced the reaction rate (entries 1 and
6-9).6 Interestingly, only platinum complexes catalyzed the reaction
efficiently, and other transition metals such as palladium complexes
did not exhibit useful catalytic activity (entries 10 and 11).
A proposed mechanism is shown in Scheme 1. The coordination
of the alkyne moiety of 1 to PtCl2 gives the π-complex A. The
intramolecular nucleophilic attack of the ortho-nitrogen atom to
the electron-deficient alkyne leads to the zwitterionic intermediate
B. An intramolecular [1,3]-migration of acyl moiety then yields
the intermediate C, which produces 2 and PtCl2. The substrates,
bearing an acidic proton at the R-position of amide, gave the
corresponding 3-deacylated indoles 3 as byproducts; presumably
the deacylation takes place through protonolysis of the C-Pt bond
of B, although it is highly speculative.
Next, we investigated the scope of this reaction using various
substrates 1 (Table 2). The substrates 1b,c, which had sterically
less bulky groups, afforded the products within 1 h with high
selectivities of 2 over 3 (entries 1 and 3), and the reaction also
proceeded almost quantitatively even at room temperature (entry
2). However, the substrate having tert-butyl group 1a proceeded
sluggishly, and the ratio of 2/3 became lower (entry 4). The electron-
donating groups of arylalkynes reduced the reaction rate, and
methoxy substituent required slightly higher loadings of the catalyst
compared to the other aryl derivatives (entries 5-7). On the other
hand, the electron-withdrawing groups enhanced the rate and the
To confirm the proposed mechanism, we carried out the
deuterium-labeling experiments. As shown in eq 5, the deuterium-
9
10546
J. AM. CHEM. SOC. 2004, 126, 10546-10547
10.1021/ja047542r CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Platinum-Catalyzed Intramolecular Aminoacylation of
Alkynes 1a-ma
Cacchi and co-workers, although the trifluoroacetamide moiety is
needed (eq 8).2
1
2
b
entry
R
R
1
time, h
yield, %
2:3
1
2c
3
nPr
nPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
1b
1b
1c
1a
1d
1e
1f
1g
1h
1i
0.3
10
0.5
3
0.3
3
96
93
98
91
81
97
94
88
93
74
75
99
87
9:1
8:1
13:1
2:1
3:1
2:1
3:1
3:1
4:1
5:1
Cyclohexyl
4d
5d
6
tBu
4-MeO-C6H4
4-Me-C6H4
Ph
7
8
9
1
4-F-C6H4
0.5
0.7
24
16
0.5
2
4-CF3-C6H4
10d,e
11
12
13
14
nPr
nPr
nPr
Ph
Ph
1j
1k
1l
13:1
Bn
Bn
CF3
1:-f
We are now in a position to synthesize 2,3-disubstituted indoles
very easily from ortho-alkynylanilides. Further mechanistic inves-
tigation on the catalytic C-N bond addition is in progress.
4:1
nPr
1m
3
>99
1:-g
a Reaction conditions: 0.5 mmol of substrate 1, 5 mol % PtCl2, anisole
(0.5 M), 80 °C. b Combined isolated yields. c Reaction was performed at
30 °C. d 10 mol % of catalyst was used. e Reaction was achieved at 100
°C. f A trace amount of 3k was detected (<1%). g 3m was not detected.
Supporting Information Available: Spectroscopic and analytical
data of synthesized compounds and information on procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 1. Proposed Mechanism for the Intramolecular
Aminoacylation of Alkynes 1
References
(1) For reviews on the addition of nucleophiles to carbon-carbon multiple
bonds, see: (a) Science of Synthesis; Trost, B. M., Ed.; Thieme: Stuttgart,
2001; Vol. 1. (b) Tsuji, J. Transition Metal Reagents and Catalysts;
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Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001-1011.
(3) Formal carboamination through the two-component coupling reactions has
been developed. See: (a) Arcadi, A. Synlett 1997, 941-943. (b) Bouyssi,
D.; Marcello, C.; Balme, G. Synlett 1997, 944-946. (c) Cacchi, S.; Fabrizi,
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Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1992, 33, 6835-6838. (f)
Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1799-
1802.
(4) Stoichiometric addition of an amide bond to alkynes was achieved by
using a chromium complex. See: Rudler, H.; Parlier, A.; Bezennine-
Lafolle´e, S.; Vaissermann, J. Eur. J. Org. Chem. 1999, 2825-2833.
(5) Acylindoles are also produced catalytically through the three-component
coupling reactions using carbon monoxide. See: (a) Kondo, Y.; Shiga,
F.; Murata, N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994, 50,
11803-11812. (b) Arcadi, A.; Cacchi, S.; Carnicellli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437-452.
labeled substrate 1f-d3 gave the 3-deuterim-labeled indole 3f-d along
with the 3-acyl product 2f-d3. This observation indicates that the
deuterium at the 3 position of 3f-d comes partially from CD3 of
the acylamide of 1f-d3. Next, we examined the reaction of an
equimolar mixture of 1f-d3 and 1c under similar conditions (eq 6).
Interestingly, mixing of the acyl substituents did not occur at all.8
This result definitely shows that the addition of the C-N bond of
amides proceeds in an intramolecular fashion.
(6) The precise role of the solvent is not clear. However, we presume that
the zwitterionic intermediate would be stabilized in electron-rich aromatics.
(7) We confirmed that deacylation from N-methylacetanilide hardly occurred
under the same conditions (90% recovery, 16 h). This result clearly
indicates that indoles 3 were not generated through the catalytic cyclization
of 2-alkynylanilines that might be yielded via the deprotection of the
starting materials.
(8) We confirmed that the reactions from both of these substrates proceeded
simultaneously by monitoring thin-layer chromatography (TLC) and gas
chromatography (GC-MS) analyses.
(9) (a) Cacchi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994,
475, 289-296. (b) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54,
5856-5966. (c) Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255-
1261. (d) See also ref 3f.
(10) For reviews on the transition metal-catalyzed syntheses of heteroaromatic
compounds, see: (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104,
2127-2198. (b) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27,
1113-1126. (c) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles
1988, 27, 2225-2249. (d) See also ref 12c.
(11) Recently, our group also reported catalytic constructions of highly
substituted indoles. See: Kamijo, S.; Yamamoto. Y. J. Org. Chem. 2003,
68, 4764-4771 and references therein.
(12) For recent reviews on the syntheses of indoles, see: (a) Katritzky, A. R.;
Pozharskii, A. F. Handbook of Heterocyclic Chemistry; Pergamon:
Oxford, 2000; Chapter 4. (b) Joule, J. A. In Science of Synthesis; Thomas,
E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2000; Vol. 10, pp 361-652.
(c) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
From synthetic point of view, the present reaction provides a
useful procedure for synthesizing 2,3-disubstituted indoles directly
from ortho-alkynylanilides. Until now, a mumber of synthetic
procedures for indoles using ortho-alkynylaniline derivatives and
transition metal catalysts have been reported, but most of them are
useful for synthesizing 2-monosubsituted indoles (eq 7).9-12 An
exceptional example is the palladium-catalyzed allylamination by
JA047542R
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J. AM. CHEM. SOC. VOL. 126, NO. 34, 2004 10547