Synthesis of functionalized indenes via cascade reaction of aziridines and propargyl alcohols

Article abstract of DOI:10.1021/ol901033h

concise synthesis of functionalized indenes via the Lewis acid catalyzed cascade reaction of aziridines and propargylic alcohols has been developed. The methodology offers great potential for the synthesis of biologically active indene derivatives and rel

Full text of DOI:10.1021/ol901033h

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2615-2618
Synthesis of Functionalized Indenes via
Cascade Reaction of Aziridines and
Propargyl Alcohols
Shaoyin Wang, Yuanxun Zhu, Yanguang Wang,* and Ping Lu*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P.R. China
orgwyg@zju.edu.cn; pinglu@zju.edu.cn
Received May 11, 2009
ABSTRACT
A concise synthesis of functionalized indenes via the Lewis acid catalyzed cascade reaction of aziridines and propargylic alcohols has been
developed. The methodology offers great potential for the synthesis of biologically active indene derivatives and related polycyclic compounds.
Indenes are carbocyclic compounds of great interest as
synthetic targets and building blocks for various biologically
active molecules1 and functional materials.2 They can also
be utilized as ligands in tailored metallocene complexes,
especially for group IV metallocenes in the catalysis of olefin
polymerization.3 Consequently, much attention has been paid
to the synthesis of indene derivatives. The most effective
methods for the construction of indenes include Brønsted
acidorLewisacid(LA)catalyzedintramolecularFriedel-Crafts
cyclization,4 the ring expansion of substituted cycloprope-
nes,5 and transition-metal-catalyzed cyclizations6 and cy-
cloadditions of alkynes.7 Despite these methods, their
preparative ways are fewer than those for structurally related
heterocycles such as indoles and benzofurans. We recently
synthesized an indene derivative 3a, which is formed from
2-phenyl-1-tosylaziridine (1a) with 1,1,3-triphenylprop-2-yn-
1-ol (2a) in the presence of a LA catalyst (Table 1). Herein,
we describe the systematic optimization of this reaction and
the applicability of this method to several propynols.
Exhaustive studies of the reaction conditions for the
synthesis of 3a from 2-phenyl-1-tosylaziridine (1a) with
(1) (a) Schneider, M. R.; Ball, H. J. Med. Chem. 1986, 29, 75. (b)
Froimowitz, M.; Wu, K. M.; Moussa, A.; Haidar, R. M.; Jurayj, J.; George,
C.; Gardner, E. L. J. Med. Chem. 2000, 43, 4981. (c) Yu, H.; Kim, I.-J.;
Folk, J. E.; Tian, X.; Rothman, R. B.; Baumann, M. H.; Dersch, C. M.;
Anderson, J. L. F.; Parrish, D.; Jacobson, A. E.; Rice, K. C. J. Med. Chem.
2004, 47, 2624. (d) Antonio, D. S.; Piera, S.; Ivana, C.; Alessandra, C.;
Gianfabio, G.; Barbara, C.; Marina, M.; Antonio, L.; Claudia, M.; Giuseppe,
S.; Francesco, D. P.; Elisabetta, D. M.; Francesco, P. J. Med. Chem. 2005,
48, 2646.
(5) (a) Yoshida, H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50, 1145.
(b) Zhu, Z. B.; Shi, M. Chem.sEur. J. 2008, 14, 10219.
(6) For recent selected examples, see: (a) Bajracharya, G. B.; Pahadi,
N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 6204. (b)
Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007, 9, 3033. (c) Guo,
L. N.; Duan, X. H.; Bi, H. P.; Liu, X. Y.; Liang, Y. M. J. Org. Chem.
2007, 72, 1538. (d) Gou, F. R.; Bi, H. P.; Guo, L. N.; Guan, Z. H.; Liu,
X. Y.; Liang, Y. M. J. Org. Chem. 2008, 73, 3837. (e) Duan, X. H.; Guo,
L. N.; Bi, H. P.; Liu, X. Y.; Liang, Y. M. Org. Lett. 2006, 8, 5777. (f)
Miyamoto, M.; Harada, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2008, 10,
2975. (g) Sanz, R.; Miguel, D.; Rodriguez, F. Angew. Chem., Int. Ed. 2008,
47, 7354. (h) Marion, N.; Diez-Gonzalez, S.; de Fremont, P.; Noble, A. R.;
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (i) Liu, C. C.; Korivi,
R. P.; Cheng, C. H. Chem.sEur. J. 2008, 14, 9503.
(2) (a) Barber, O. J.; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew.
Chem., Int. Ed. 1998, 37, 296. (b) Yang, J.; Lakshmikantham, M. V.; Cava,
M. P.; Lorcy, D.; Bethelot, J. R. J. Org. Chem. 2000, 65, 6739.
(3) (a) Cadierno, V.; Diez, J.; Pilar, G. M.; Gimeno, J.; Lastra, E. Coord.
Chem. ReV. 1999, 193-195, 147. (b) Alt, H. G.; Ko¨ppl, A. Chem. ReV.
2000, 100, 1205. (c) Zargarian, D. Coord. Chem. ReV. 2002, 233-234,
157. (d) Leino, R.; Lehmus, P.; Lehtonen, A. Eur. J. Inorg. Chem. 2004,
3201.
(7) For recent selected examples, see: (a) Chen, W. L.; Cao, J.; Huang,
X. Org. Lett. 2008, 10, 5537. (b) Wu, Y. T.; Kuo, M. Y.; Chang, Y. T.;
Shin, C. C.; Wu, T. C.; Tai, C. C.; Cheng, T. H.; Liu, W. S. Angew. Chem.,
Int. Ed. 2008, 47, 9891. (c) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2005, 127, 13498.
(4) Zhou, X. B.; Zhang, H. M.; Xie, X.; Li, Y. Z. J. Org. Chem. 2008,
73, 3958.
10.1021/ol901033h CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

Table 1. Screening for the Reaction Conditionsa
Scheme 2. Proposed Mechanism for the Cascade Reaction
entry
catalyst
temp (°C)
time
solvent
yield (%)b
1
2
3
4
5
6
7
8
Zn(OTf)2
Sc(OTf)3
BF3·OEt2
Cu(OTf)2
CF3CO2H
AgOTf
80
80
80
80
80
80
80
80
60
80
20
80
12
12
5
12
12
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
toluene
DCE
DCE
trace
35
0
21
0
51
41
63
TfOH
1
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
12
12
12
12
2
9
trace
46
the cascade process to generate 3a-3s in moderate to
excellent yields (41-79%). In cases of R2 ) alkenyl or alkyl,
lower yields were obtained for 3f (45%; Table 2, entry 6),
3g (41%; Table 2, entry 7), and 3o (44%; Table 2, entry
15), respectively. 2-Alkyl-1-tosylaziridines were also exam-
ined for this transformation, but they did not yield the desired
indene products.
10
11
12
0c
30d
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (0.05
mmol), solvent (5 mL). b Isolated yield refers to aziridine. c ꢀ-Alkoxyamine
4 was isolated in 60% yield. d Imine 5 was isolated in 20% yield.
1,1,3-triphenyl prop-2-yn-1-ol (2a) were conducted (Table
1). These results showed that 0.1 equiv of Yb(OTf)3 was
the most efficient catalyst for this transformation among
others, such as Zn(OTf)2, Sc(OTf)3, Cu(OTf)2, AgOTf,
BF3·Et2O, CF3COOH, and TfOH (Table 1, entries 1-8),
whereas dichloroethane (DCE) was the most suitable solvent
(Table 1, entries 8-10). Besides these two key factors, the
reaction products largely depended on the reaction temper-
ature and reaction time. When the reaction was conducted
at room temperature for 12 h, a simple nucleophilic ring-
opening reaction occurred, and ꢀ-alkoxyamine 4 (Scheme
1) was isolated in 60% yield (Table 1, entry 11). It was
Table 2. Synthesis of Indenes 3a
entry
R1
R2/R3
product yield (%)b
1
C6H5 (1a)
C6H5/H (2a)
3a
3b
3c
3d
3e
3f
63
54
62
51
78
45
41
51
50
52
63
62
68
62
44
78
72
79
69
2
1a
1a
1a
1a
1a
1a
1a
4-MeC6H4/H (2b)
3-MeC6H4/H (2c)
4-t-BuC6H4/H (2d)
4-MeOC6H4/H (2e)
1-cyclohexenyl/H (2f)
n-Bu/H (2g)
3
4
5
Scheme 1. Nucleophilic Ring-Opening Reaction of Aziridine 1a
6
7
3g
3h
3i
8
C6H5/Cl (2 h)
9
4-MeC6H4 (1b) 2a
4-t-BuC6H4 (1c) 2a
4-ClC6H4 (1d)
4-BrC6H4 (1e)
1d
1d
1d
1d
1e
1e
1e
10
11
12
13
14
15
16
17
18
19
3j
2a
2a
2b
2e
2g
2h
2b
2h
2e
3k
3L
3m
3n
3o
3p
3q
3r
3s
noteworthy that 4 could also be converted into 3a at 80 °C
in the presence of Yb(OTf)3 which indicated that the
nucleophilic ring-opening reaction is reversible. When the
reaction time was shortened to 2 h at 80 °C, 3a and
intermediate imine 5 (Scheme 2) were isolated in yields of
30% and 20%, respectively (Table 1, entry 12). Thus, the
most suitable reaction conditions for the formation of 3a were
established (Table 1, entry 8).
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Yb(OTf)3 (0.05
mmol). b Isolated yield refers to aziridine.
A proposed mechanism for the present cascade reaction
is shown in Scheme 2. In the presence of LA, the in situ
ring opening of aziridine 1a generates an azomethine ylide
A,8 while propynol 2a is converted to the cationic intermedi-
The scope of the reaction was investigated with a variety
of reactants, and the results were presented in Table 2.
Aziridines 1a-1e and propargyl alcohols 2a-2h underwent
2616
Org. Lett., Vol. 11, No. 12, 2009

ate B via a Meyer-Schuster rearrangement.9 Then, A reacts
with B through a [3 + 2] cycloaddition to form a five-
membered ring carbocation C. Deprotonation along with the
ring opening of C leads to the formation of 5, which is
sequentially transferred into the final indene product 3a via
an intramolecular Friedel-Crafts reaction promoted by LA.
Furthermore, isolated 5 could also be quantitatively converted
into 3a in the presence of Yb(OTf)3, which strongly supports
this postulated mechanism.
using TfOH as the catalyst. Under 0.2 equiv of TfOH, 1a
reacted with 2a at 80 °C for 16 h to afford 6a in 31% yield
(Scheme 4). Using this procedure, 6b and 6c were also
obtained in 28% and 34% yields, respectively.
Scheme 4. Single-Step Synthesis of 6 from 1 and 2
We also investigated the possibility of intramolecular
annulation of 3. When indene 3a was treated with TfOH at
80 °C for 2 h, 6,11b-diphenyl-11bH-benzo[c]fluorene (6a)
was obtained in 45% yield along with a certain amount of
p-methyl-benzenesulfonamide (Scheme 3). This cyclization
Scheme 3. Conversion of Indene 3a to 6a
Transformation of indenes 3 to indenones 8 was also
investigated further. As shown in Scheme 5, 3a, 3h, and 3p
Scheme 5
.
Transformation of Indenes 3 to Indenimines 7 and
Indenones 8
involves an acid-catalyzed isomerization of the CdC bond
and an intramolecular Friedel-Crafts reaction.
Structures of compounds 3a (Figure 1), 4, 5, and 6a were
confirmed by X-ray diffraction analysis, and the results
could be oxidized with I2 in the presence of K2CO3 and
resulted in indenimines 7a10 (80% yield), 7b (82% yield),
and 7c (89% yield), respectively. It is also significant that
hydrolysis of indenimines 7a, 7b, and 7c under acid
conditions yielded the corresponding indenones 8a, 8b, and
8c in excellent yields (Scheme 5). Since the indenone
skeleton has been discovered as a template for peroxisome
Figure 1. Crystal structure of compound 3a.
supported the E configuration of the alkenyl group in the 3a
structure (see Supporting Information).
On the basis of these results, a single-step cascade
synthesis of 6 from 1 and 2 was designed and achieved by
(8) (a) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765. (b) Pinho
e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2873.
(9) (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819. (b)
Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429.
Org. Lett., Vol. 11, No. 12, 2009
2617

proliferator-activated receptor γ agonists,11 which are of
interest as a treatment for diabetes, our strategy provides a
new entry to this important class of compounds.12
In summary, we have developed a novel synthesis of
functionalized indenes via a Lewis acid catalyzed cascade
reaction of aziridines and propargylic alcohols. Since the
substrates are readily available and the products can be
converted to polycyclic indenes, indenimines and indenones,
this approach may prove to be useful for the synthesis of
biologically active indene derivatives and related carbocycles.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20872128; J0830413) for support
of this work.
(10) The structure of compound 7a was unambiguously determined by
X-ray diffraction analysis (see Supporting Information).
(11) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.;
Rhee, S. D.; Jung, W. H.; Yang, S. D.; Kim, S. J.; Woo, J. R.; Lee, J. H.;
Cheon, H. G.; Kim, S. S. J. Med. Chem. 2006, 49, 4781.
Supporting Information Available: Detailed experimen-
1
tal procedures, characterization data, copies of H and 13C
(12) For papers on indenone synthesis, see: (a) Larock, R. C.; Doty,
M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579. (b) Kokubo, K.; Matsumasa,
K.; Miura, M.; Nomura, M. J. Org. Chem. 1996, 61, 6941. (c) Pletnev,
A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. (d) Harada,
Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2007, 129, 5766. (e) Kerr, D. J.; Hamel, E.; Jung, M. K.; Flynn,
B. L. Bioorg. Med. Chem. 2007, 15, 3290.
NMR spectra for all products, and crystallographic informa-
tion files for compounds 3a, 4, 5, 6a, and 7a. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901033H
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