Palladium(O)-catalyzed regioselective and multicomponent synthesis of 1,2,3-trisubstituted 1H-indenes

Article abstract of DOI:10.1021/ol071107v

A multicomponent synthesis of biologically important indenes bearing three substituent groups at the 1-, 2-, and 3-positions from available o-ethynylbenzaldehyde derivatives and organoboron reagents under pailadium(O) catalysis is described. A two-component coupling reaction in methanol provides 1H-indenols, whereas a three-component reaction involving secondary aliphatic amines as the third component in DMF affords 1H-indenamines. This method allows combinatorial preparation of unsymmetrically substituted 1H-indenes that cannot be prepared via previous synthetic routes.

Full text of DOI:10.1021/ol071107v

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3033-3036
Palladium(0)-Catalyzed Regioselective
and Multicomponent Synthesis of
1,2,3-Trisubstituted 1H-Indenes
Hirokazu Tsukamoto,* Tatsuhiko Ueno, and Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aramaki-aza aoba
6-3, Aoba-ku, Sendai 980-8578, Japan
hirokazu@mail.pharm.tohoku.ac.jp
Received May 12, 2007
ABSTRACT
A multicomponent synthesis of biologically important indenes bearing three substituent groups at the 1-, 2-, and 3-positions from available
o-ethynylbenzaldehyde derivatives and organoboron reagents under palladium(0) catalysis is described. A two-component coupling reaction
in methanol provides 1H-indenols, whereas a three-component reaction involving secondary aliphatic amines as the third component in DMF
affords 1H-indenamines. This method allows combinatorial preparation of unsymmetrically substituted 1H-indenes that cannot be prepared via
previous synthetic routes.
The increasing significance of combinatorial chemistry in
pharmaceutical and material sciences demands the develop-
ment of new strategies to synthesize a collection of analogues
of interesting compounds.1 Indenes are an important class
of carbocyclic compounds that are biologically active,
functional materials and structural constituents of metal-
locene-based catalysts for olefin polymerization.2-4 Despite
their utility, their preparative methods are fewer5-11 than
those for structurally related heterocycles such as indoles
and benzofurans. For 1H-indenols 1,2a-e most of their
synthetic routes belong to carboannulation of internal alkynes
4 with o-(metalated)benzaldehydes generated in situ (Scheme
1, route A).5-9 However, they cannot generate the opposite
(3) (a) Akbulut, U.; Khurshid, A.; Hacioglu, B.; Toppare, L. Polymer
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Coord. Chem. ReV. 1999, 193-195, 147-205. (d) Zargarian, D. Coord.
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tallics 1996, 15, 3509-3519. (b) Vicente, J.; Abad, J.-A.; Lo´pez-Pela´ez,
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10.1021/ol071107v CCC: $37.00
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indenol synthesis based on the alkylative cyclization of
4-alkynal 5, easily prepared by Sonogashira reaction of
o-bromobenzaldehydes 3 and terminal alkynes, with orga-
noboron reagents. Furthermore, we have also developed a
three-component coupling reaction employing secondary
aliphatic amines as the third component to provide inde-
namines 2 selectively.
Scheme 1. Pd0-Catalyzed Synthesis of 1, 2, 7, and 8
Recently, we discovered that the novel alkylative cycliza-
tion of 5-alkynal 12 with organoboron reagents is effective
in the formation of 2-cyclohexen-1-ol 14 (Scheme 2).14
Scheme 2. Pd0-Catalyzed Arylative Cyclization of 12 and 13
regioisomer (regiochemical diversity) because the regio-
selectivity of the carbocyclization using unsymmetrical
alkynes 4 is under a powerful substrate control.
For benzofuran 7 and indole 8, there are two types of Pd0-
catalyzed synthetic methods. The first method involves
heteroannulation of internal alkyne 4 with o-halophenol or
aniline 9, which cannot increase regiochemical diversity
(route C).12 The second method is based on an intramolecular
nucleophilic addition of the heteroatom in o-ethynylphenol
or aniline 10 to the alkyne coordinated by electron-deficient
R2-PdII-X, which is generated in situ from organic halide 11
and Pd0 (route D).13 The second method has an advantage
of regioselectivity over the first one and inspired us to
develop its counterpart process for indenols 1, namely, an
intramolecular electrophilic addition of the carbonyl group
in o-ethynylbenzaldehyde 5 to the alkyne coordinated by
electron-rich Pd0 and concomitant transmetalation with an
organometallic reagent 6 (route B). Herein, we describe the
However, the cyclization reaction proved to be dramatically
affected by tether length of the alkynals, and 4-alkynal 13
did not cyclize with less σ-donating PPh3 and more σ-donat-
ing P(c-Hex)3 ligated palladium catalysts.
The cyclization of o-ethynylbenzaldehyde (5a) with p-
tolylboronic acid (6A) upon heating at 80 °C in MeOH in
the presence of a catalytic amount of tris(dibenzylidene-
acetone)dipalladium (Pd2dba3) and tricyclohexylphosphine
was unsuccessful (Table 1, entry 1). Next, the effect of
substituents at the terminal alkyne carbon on the cyclization
reaction was investigated.
In contrast to the alkyl group, the aryl group at the terminal
alkyne carbon leads to formation of 2,3-diaryl-1H-indenols
1cA-1gA in high yields (Table 1, entry 2 vs entries 3-7).14
Substituent groups attached to the para position on the
terminal phenyl ring also affect the cyclization, which is
slowed by an electron-donating dimethylamino group and
accelerated by an electron-withdrawing nitro group (entries
4 vs 7). Other sp2-hybridized heteroaryl, alkenyl, and sp-
hybridized alkynyl groups at the terminal alkyne carbon also
prove to be effective for the cyclization (entries 8-11).
During the course of our investigation, (η3-allyl)PdCp15
(8) Preparation of 1 from o-formylphenylboronic acid under Rh cata-
lyst: (a) Shintani, R.; Okamoto, K.; Hayashi, T. Chem. Lett. 2005, 34,
1294-1295. (b) Matsuda, T.; Makino, M.; Murakami, M. Chem. Lett. 2005,
34, 1416-1417.
(9) Preparation of 1 from o-manganated aryl ketones: (a) Liebeskind,
L. S.; Gasdaska, J. R.; McCallum, J. S.; Tremont, S. J. J. Org. Chem. 1989,
54, 669-677. (b) Robinson, N. P.; Main, L.; Nicholson, B. K. J. Organomet.
Chem. 1989, 364, C37-C39.
(10) Preparation of 2 from aromatic aldimines under Re catalysis:
Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc.
2006, 128, 202-209.
(11) Recent synthesis of other indenes: (a) Xi, Z.; Guo, R.; Mito, S.;
Yan, H.; Kanno, K.; Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68,
1252-1257. (b) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69, 4607-
4614. (c) Dong, C.-G.; Yeung, P.; Hu, Q.-S. Org. Lett. 2007, 9, 363-366.
(d) Kuninobu, Y.; Nishina, Y.; Shouho, M.; Takai, K. Angew. Chem., Int.
Ed. 2006, 45, 2766-2768. (e) Kuninobu, Y.; Nishina, Y.; Takai, K. Org.
Lett. 2006, 8, 2891-2893. (f) Nakamura, I.; Bajracharya, G. B.; Wu, H.;
Oishi, K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 15423-15430. (g) Dube´, P.; Toste, F. D. J. Am. Chem.
Soc. 2006, 128, 12062-12063. (h) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.;
Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2006, 71, 3325-3327. (i) Zhang,
D.; Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251-262.
(j) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.;
Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766-5771.
(12) (a) Larock, R. C. J. Organomet. Chem. 1999, 576, 111-124. (b)
Larock, R. C. Pure Appl. Chem. 1999, 71, 1435-1442. (c) Zeni, G.; Larock,
R. C. Chem. ReV. 2006, 106, 4644-4680.
(13) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42-64. (b)
Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671-
2681. (c) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920. (d)
Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198.
16
turned out to be a more effective Pd source than Pd2dba3
(entries 9 vs 10). It is worth noting that chemoselective
hydrogenation of the disubstituted olefin at the 2-position
in the cyclized product 1iA in the existence of tetrasubstituted
alkene affords the 2-alkyl-3-aryl-1H-indenol 15 (Scheme 3),
which could not be prepared by our or any previous
methods5-9 (cf. Table 1, entry 2).
These cyclization reactions also occur with arylboronic
acids 6A-D with electron-donating or -withdrawing groups
(14) Tsukamoto, H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006, 128,
1406-1407.
(15) Tatsuno, Y.; Yoshida, T.; Otsuka, S. Inorg. Synth. 1979, 19, 220-
223.
(16) (a) Amatore, C.; Jutand, A. Coord. Chem. ReV. 1998, 178-180,
511-528. (b) Mace´, Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand, A.
Organometallics 2006, 25, 1795-1800.
3034
Org. Lett., Vol. 9, No. 16, 2007

was also examined, because more electrophilic iminium ion
would be formed in situ (Table 2). Addition of an excess
Table 1. Pd0-Catalyzed Synthesis of 1H-Indenols 1
Table 2. Pd0-Catalyzed Synthesis of 1H-Indenamines 17 and
18
time yield
entry
5
R1
R3
product (h)
(%)
1a
2a
3a
4a
5a
6a
7a
8b
9b
5a
5b Bu
5c Ph
5d p-Me2N-C6H4 6A
5e p-MeO-C6H4 6A
5f p-Ac-C6H4
H
p-Me-C6H4 6A
6A
6A
1aA
1bA
1cA
1dA
1eA
1fA
1gA
1hA
1iA
1iA
1jA
24
24
9
24
9
9
1
5
18
3
1
9
9
9
24
1.5
1
18
0
0
entrya
5
6
16
product time (h) yield (%)
85
80
87
74
68
100
68
88
80
87
76
74
71
81
97
77
0
1b
2b
3b
4b
5
6
7
8
9
10
11
12
13
5c 6A Bn2NH 16A
5c 6A 16A
5c 6A 16A
5c 6A 16A
5c 6A Et2NH 16B
5c 6A pyrrolidine 16C 18cAC
5c 6A morpholine 16D 18cAD
5c 6A i-Pr2NH 16E
5c 6A PhNHMe 16F
5f 6B 16B
18cAA
18cAA
18cAA
18cAA
18cAB
0.5
0.5
1
0.5
1
1
1
6
32c
60
56
86
89
56
100
0
6A
5g p-NO2-C6H4 6A
5h 2-thiophene 6A
5i cis-propenyl 6A
10b,c 5i cis-propenyl 6A
18cAE
18cAF
18fBB
18cDB
17cFB
18lAB
11a,c 5j CCPh
6A
6
0
12a
13a
14a
15a
5c Ph
5c Ph
5c Ph
5c Ph
p-MeO-C6H4 6B 1cB
Ph 6C
p-Ac-C6H4 6D
cis-propenyl 6E
Et 6F
6B
6A
6A
6A
1
1
1
24
94
88
73
0
1cC
1cD
1cE
1cF
1kB
1lA
2mA 24
2nA
2oA
5c 6D 16B
5c 6F 16B
5l 6A 16B
16b,c 5c Ph
17b,c 5k p-Ac-C6H4
a Reactions in MeOH (entry 1), toluene (entry 2), THF (entry 3), and
DMF (entries 4-13). b Reaction with 2 equiv of 6A and 6 equiv of 16A.
c 1cA is also obtained in 53% yield.
18b
5l Ph
19b,d 5m Ph
20b,d 5n Ph
21b,d 5o Ph
24
24
0
73
6A
amount of dibenzylamine (16A) over 5c and 6A to the above
reaction conditions resulted in formation of a mixture of 2,3-
diaryl-1H-indenol 1cA and 1,2-diaryl-1H-3-indenamine
18cAA, which should be formed by isomerization of a
thermodynamically unfavored 2,3-diaryl-1H-indenamine
17cAA under basic conditions (entry 1).10,17 Aprotic solvents
prevent the formation of 1cA, and most polar DMF leads to
formation of 18cAA in maximum yield (entries 2-4).
a Reaction at 80 °C. b Reaction at 100 °C. c (η3-Allyl)PdCp is used for
Pd2dba3. d Reaction in t-BuOH.
(entries 3, 12-14). Generally, electron-rich boronic acids
give higher yields than their electron-deficient counterparts.
Alkenylboronic acid 6E and triethylborane (6F) also par-
ticipate in this process (entries 15 and 16).
Both acyclic and cyclic secondary aliphatic amines 16B-D
participate in this process to afford 3-indenamines 18cA-
(B-D) in moderate to excellent yields (entries 5-7).
Unfortunately, sterically hindered aliphatic amine 16E and
N-methylaniline (16F) gave no cyclized products (entries 8
and 9). In contrast to arylboronic acids 6A‚B‚D, triethyl-
borane (6F) provided 1H-1-indenamine 17cFB, in which
electron-donating ethyl group at 3-position decreased acidity
of the proton at 1-position (entries 5, 10, and 11 vs 12). Non-
enolizable ketone 5l did not cyclize under the reaction
conditions (entry 13). The reaction should not proceed
through indenol formation but through iminium formation,
since neither formation of indenol 1cF under amine-free
conditions nor conversion of 1cF to indenamine 17cF was
observed (Scheme 4).
Scheme 3. Chemoselective Hydrogenation of 1iA
Arylative cyclization reactions of phenylketones 5k,l
require higher temperatures but provide tertiary allylic
alcohols in high yields (entries 17 and 18). Preparation of
1H-indenamines 2 from the corresponding aldimines 5m-o
was also explored to generate further diversity. However,
only electron-withdrawing p-toluenesulfonyl substituted al-
dimine 5o gives cyclized product 2oA in good yield with
reaction in t-BuOH to prevent decomposition of the imine
moiety (entries 19 and 20 vs 21).
In summary, we have developed a new synthetic route
for 1H-indenols and indenamines based on the Pd0-catalyzed
For introduction of amine functionality, a three-component
reaction involving secondary amines as the third component
(17) In some cases, mixtures of 17 and 18 were obtained but became
single isomers 18 in CDCl3 within 1 day.
Org. Lett., Vol. 9, No. 16, 2007
3035

philic attack of the Pd0 complex to the opposite alkyne
position and are required for the cyclization of 4-alkynals.
(2) Lewis acidity of the boron reagents would not be essential
for the cyclization because it also goes well in the presence
of secondary amines. (3) Methanol solvent, essential for the
indenol synthesis and not for the indenamine synthesis, would
work as hydrogen donor to activate less electrophilic carbonyl
groups. Further studies probing the detailed mechanism and
expanding the scope of the cyclization process are underway.
Scheme 4. Plausible Mechanism without Indenol Formation
trans-addition specific alkylative cyclization of o-ethynyl-
benzaldehydes with organoboron reagents. In addition to the
functional group compatibility and additive-free conditions,
completely regioselective introduction of aryl, alkenyl, and
alkyl groups into the indene scaffold and availability of all
building blocks make the process highly practical and suitable
for combinatorial synthesis.
This study also gives us important information about the
cyclization reaction as follows. (1) Aryl, alkenyl, and alkynyl
groups at the terminal alkyne carbon would guide nucleo-
Acknowledgment. This work was partly supported by a
Grant-in-Aid from the Japan Society for Promotion of
Sciences (no. 18790003).
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL071107V
3036
Org. Lett., Vol. 9, No. 16, 2007