Gold-catalyzed hydroarylation of allenes: A highly regioselective carbon-carbon bond formation producing six-membered rings

Article abstract of DOI:10.1021/ol702179n

(Chemical Equation Presented) Gold-catalyzed intramolecular hydroarylation of allenic anilines and phenols offers an efficient route to dihydroquinoline and chromene derivatives under mild reaction conditions. The hydroarylation takes place at the terminal or central allenic carbon depending on the substrate structure, leading to a highly selective formation of six-membered rings.

Full text of DOI:10.1021/ol702179n

ORGANIC
LETTERS
2
007
Vol. 9, No. 23
821-4824
Gold-Catalyzed Hydroarylation of
Allenes: A Highly Regioselective
4
Carbon−Carbon Bond Formation
Producing Six-Membered Rings
Toshiaki Watanabe, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received September 5, 2007
ABSTRACT
Gold-catalyzed intramolecular hydroarylation of allenic anilines and phenols offers an efficient route to dihydroquinoline and chromene derivatives
under mild reaction conditions. The hydroarylation takes place at the terminal or central allenic carbon depending on the substrate structure,
leading to a highly selective formation of six-membered rings.
Transition-metal-catalyzed cycloisomerization of allenes has
received considerable attention as an atom-economical
transformation. Compared to the well-documented cycliza-
ethers mediated by a stoichiometric amount of mercury(II)
trifluoroacetate to form regioisomeric six-membered rings
has also been shown.
1
3-5
tion reactions with a highly nucleophilic functionality such
as nitrogen, oxygen, or active methylene (Scheme 1, eq 1),
cycloisomerization through functionalization of an aromatic
C-H bond (hydroarylation; eq 2) has scarcely been inves-
tigated. Nagao and co-workers reported endo-mode hy-
Scheme 1. Transition-Metal-Catalyzed Reaction of Allenic
Compounds
droarylation of allenic ketones promoted by Lewis acids such
2
as BF
3
‚OEt
2
or TiCl
4
. Cycloisomerization of aryl allenic
(1) For recent reviews, see: (a) Zimmer, R.; Dinesh, C. U.; Nandanan,
E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (b) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2000, 39, 3590. (c) Yamamoto, Y.; Radhakrishnan, U. Chem.
Soc. ReV. 1999, 28, 199. (d) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV.
2
002, 31, 12. (e) Hashmi, A. S. K. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol.
, pp 877-923.
2) (a) Nagao, Y.; Lee, W.-S.; Kim, K. Chem. Lett. 1994, 389. (b) Nagao,
2
(
Y.; Lee, W. S.; Komaki, Y.; Sano, S.; Shiro, M. Chem. Lett. 1994, 597. (c)
Nagao, Y.; Lee, W. S.; Jeong, I.-Y.; Shiro, M. Tetrahedron Lett. 1995, 36,
As a part of a program directed toward the development
of novel methods for cyclization of allenic compounds, we
2
799. (d) Lee, W. S.; Jeong, I.-Y.; Shiro, M.; Sano, S.; Nagao, Y.
Tetrahedron Lett. 1997, 38, 611.
3) Balasubramanian, T.; Balasubramanian, K. K. Tetrahedron Lett. 1991,
2, 6641.
4) For related intermolecular reactions, see: (a) De Renzi, A.; Panunzi,
A.; Saporito, A.; Vitagliano, A. J. Chem. Soc., Perkin Trans. 2 1983, 993.
b) Kido, Y.; Yonehara, F.; Yamaguchi, M. Tetrahedron 2001, 57, 827.
6
(
3
(5) For related electrocyclization, see: (a) Turnbull, P.; Moore, H. W.
J. Org. Chem. 1995, 60, 3274. (b) Brandsma, L.; Nedolya, N. A.;
Verkruijsse, H. D.; Owen, N. L.; Li, D.; Trofimov, B. A. Tetrahedron Lett.
1997, 38, 6905. (c) Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 5295.
(
(
1
0.1021/ol702179n CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/09/2007

planned to investigate the catalytic hydroarylation of allenes
in the presence of a gold salt. Gold-catalyzed reaction is of
Table 1. Screening of Transition-Metal Catalystsa
7
current interest for various transformations including nu-
cleophilic cyclization of allenes shown in eq 1.8 Although
-10
6
-exo cyclization of allenes with a highly nucleophilic
11a
11b
indole or pyrrole ring and 5-endo indene formation from
12
acetoxy-substituted allenes have been already reported,
there have been no precedents for gold-catalyzed 6-endo
hydroarylation of allenes that can be applied to a variety of
allenes and aromatic rings. Herein we report hydroarylation
of allenes derived from anilines and phenols, leading to
dihydroquinolines and chromenes, which are widely found
yieldb
catalyst
(mol %)
temp
(°C)
time
(min)
13
entry
2
3
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (5)
CuBr2 (5)
AgOTf (5)
AuCl (5)
AuCl3 (5)
PtCl2 (5)
4/P(p-CF3C6H4)3 (5)
(Ph3P)AuCl/AgOTf (5)
5/AgOTf (5)
6/AgOTf (5)
6/AgOTf (1)
80
80
25
80
25
80
25
25
25
25
25
360
60
720
90
30
360
5
10
10
5
14
12
as core structures of natural products and other biologically
trace
29
d
active compounds.14,15
58
77
57
56
86
98
96
First, screening of transition-metal catalysts for the hy-
droarylation of allenes was performed by use of N-allenyl-
aniline 1, which was easily prepared by propargylation of
N-protected 3,5-dimethoxyaniline followed by t-BuOK-
mediated isomerization.1 Results are summarized in Table
6,17
10
11
5
(
6) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka,
a
b
Reactions were carried out in dioxane at room temperature. Yields
Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992. (b) Ohno, H.; Anzai,
M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J.
Org. Chem. 2001, 66, 4904. (c) Ohno, H.; Ando, K.; Hamaguchi, H.;
Takeoka, Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255. (d) Ohno,
H.; Miyamura, K.; Takeoka, Y.; Tanaka, T. Angew. Chem., Int. Ed. 2003,
1
c
based on H NMR. 13% of 1 was recovered.
4
2, 2647. (e) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew.
Chem., Int. Ed. 2003, 42, 1749. (f) Ohno, H.; Hamaguchi, H.; Ohata, M.;
Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744. (g) Ohno, H.;
Mizutani, T.; Kadoh, Y.; Miyamura, K.; Tanaka, T. Angew. Chem., Int.
Ed. 2005, 44, 5113.
(
7) For recent reviews, see: (a) Gorin, D. J.; Toste, F. D. Nature 2007,
4
46, 395. (b) F u¨ rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
1
(for more details, see Supporting Information). Whereas
Pd(OAc) , CuBr , and AgOTf afforded a mixture of un-
desired products such as 3 as well as the recovered starting
material (entries 1-3), AuCl, AuCl , and PtCl gave the
desired cyclization product 2 in low to good yields (29-
3410. (c) Nevado, C.; Echavarren, A. M. Synthesis 2005, 2, 167. (d) Hashmi,
2
2
3
2
7
7%, entries 4-6). The reaction with a platinum complex
1
1a
4
/p-(CF
3
C
6
4
H )
3
P
completed in only 5 min, affording 2 in
P)AuCl/
AgOTf gave 2 in moderate yield (56%, entry 8), a gold
57% yield (entry 7). While the reaction with (Ph
3
18
complex 5 in the presence of AgOTf gave a more promising
result (86% yield, entry 9). Among the catalysts investigated,
1
8
gold complex 6 with AgOTf was most effective in
producing the desired product 2 in 98% yields (entry 10).
By lowering the catalyst loading to 1 mol %, a comparable
result was obtained (96% yield, entry 11). Considering that
combination of the gold and silver salts is important (compare
entries 3 and 11), a cationic gold complex would be the
reactive species for this transformation.
We next investigated the cyclization of various N-
allenylaniline derivatives based on the optimized conditions
(Table 1, entry 11) for the allenylaniline 1. Results are
summarized in Table 2. Disubstituted electron-rich aniline
derivatives 7 and 9 gave the desired products 8 and 10,
respectively (both in 88% yield after hydrogenation; entries
2 and 3). While the reaction of monomethoxyaniline deriva-
tive 11 provided 12 as the sole product (90% yield after
(
16) (a) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
(17) Unfortunately, synthesis of internal allenes by this approach was
difficult.
(18) Complexes 5 and 6 were prepared according to Lopez, S.; Nieto-
Oberhuber, C.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178.
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (b) Huang, J.; Xiong, H.;
Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett.
002, 4, 2417.
2
4822
Org. Lett., Vol. 9, No. 23, 2007

Table 2. Au-Catalyzed Cyclization of N-Allenylaniline
Derivativesa
Table 3. Au-Catalyzed Cyclization of
N-(Buta-2,3-dienyl)aniline Derivatives and Their Phenol
Analogues
a
Solvent, loading of 6/AgOTf, reaction temperature, and reaction time.
b
Isolated yield. Isolated yield after hydrogenation. d Ratios were deter-
mined by H NMR.
c
a
Conditions: 1 mol % of 6/AgOTf in dioxane. b Isolated yields after
1
hydrogenation since most of the cyclized products with a 1,4-dihydroquino-
line moiety were relatively unstable and gradually decomposed during
isolation. Ratio was determined by H NMR. 3 mol % of 6/AgOTf was
c
1
d
reactivity in dioxane, affording 22 in 98% yield (after
hydrogenation) with 1 mol % of the catalyst (entry 6). These
are remarkable examples of transition-metal-catalyzed hy-
droarylation of unactivated allenes at the central carbon.20
Interestingly, the reaction of phenol-derived methylated
allene 23 in dioxane slightly favors seven-membered ring
formation to give dihydrobenzo[b]oxepine derivative 24,
produced by hydroarylation at the terminal allenic carbon,
as well as the six-membered ring 25 (24:25 ) 59:41, entry
used.
hydrogenation) by regioselective cyclization at the less
hindered aromatic carbon (entry 4), 3-methylaniline deriva-
tive 13 afforded 14 as a mixture of regioisomers (14a:14b
)
61:39, entry 5). As anticipated, unsubstituted derivative
5 showed lower reactivity; however, ca. 40% yield of the
desired product 16 was obtained by refluxing in dioxane with
mol % of the catalyst. In all cases examined, reaction at
1
7
). Although the reaction of 23 in AcOH as the sole solvent
3
gave a mixture of unidentified products, addition of a small
amount of AcOH to dioxane gave 24 and 25 in 99%
combined yield (entry 8).
the terminal allenic carbon resulted solely in formation of a
six-membered ring.
We proceeded to explore the scope of this cyclization
Table 3). Although the reactivity of N-(buta-2,3-dienyl)-
A proposed mechanism for the hydroarylation of allenes
is shown in Scheme 2. The allene is activated by coordination
to cationic gold and undergoes electrophilic aromatic sub-
stitution with the electron-rich arene to give vinyl-gold
complex B, which is deprotonated to produce the neutral
vinyl-gold intermediate C. Cleavage of the gold-carbon
(
aniline derivative 17 was relatively low even with 3 mol %
8d
of the catalyst at 60 °C (entry 1), use of AcOH instead of
dioxane dramatically enhanced its reactivity to afford 18 in
19
8
2% yield at room temperature (entry 2). When the reaction
was performed in AcOH at 60 °C, 85% yield of 18 was
obtained with 1 mol % of the catalyst (entry 3). A similar
result was obtained with disubstituted allene derivative 19
(19) The reaction did not proceed in AcOH without using the gold
catalyst.
(20) Such reactions with Hg(II) reagent have already been reported; see
(entries 4 and 5). Phenol derivative 21 has a sufficient
ref 3. For the reactions of activated allenes, see refs 2 and 4b.
Org. Lett., Vol. 9, No. 23, 2007
4823

Finally, one-pot synthesis of quinoline was investigated
2
1
(
Scheme 4). When the reaction of the allenylaniline 1 was
Scheme 2. Proposed Mechanism
Scheme 4. Synthesis of Quinoline by One-Pot Reaction
conducted in the presence of a catalytic amount of Pd/C
under O , the desired quinoline 26 was obtained in 86% yield.
2
This one-pot reaction clearly demonstrates the utility of the
present hydroarylation of allenes as a convenient tool for
construction of heterocycles.
In conclusion, we have developed a novel efficient route
from allenic compounds to dihydroquinolines and chromenes
by means of gold-catalyzed intramolecular hydroarylation.
We are now exploring ways to broaden the scope of the
reaction, for example, to include various arenes.
bond by the proton generated in the previous step affords 2
and regenerates the cationic gold catalyst.
In order to reveal the role of AcOH as the activator of
8d
hydroarylation, we conducted deuterium experiments using
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Encouragement of Young Scientists (A)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, 21st Century COE Program “Knowl-
edge Information Infrastructure for Genome Science”, and
the Program for Promotion of Fundamental Studies in Health
Sciences of the National Institute of Biomedical Innovation
AcOD (Scheme 3). As expected, the reaction of N-allenyl-
Scheme 3. Deuterium Experiment Using AcOD
(NIBIO).
Supporting Information Available: Representative ex-
1
13
perimental procedure, as well as H and C NMR spectra
for the novel compounds. This material is available free of
charge via Internet at http://pubs.acs.org.
aniline 1 in AcOD gave 2-d (83%-d) in quantitative yield
OL702179N
(Scheme 3). This result strongly suggests that the high
reactivity in AcOH is attributed to acceleration of the
(21) For a related reaction, see: Bennasar, M. L.; Roca, T.; Monerris,
protonation step from C (Scheme 2).
M.; Garc ´ı a-D ´ı az, D. J. Org. Chem. 2006, 71, 7028.
4824
Org. Lett., Vol. 9, No. 23, 2007