Synthetic approaches to multifunctional indenes

Article abstract of DOI:10.3762/bjoc.7.204

The synthesis of multifunctional indenes with at least two different functional groups has not yet been extensively explored. Among the plausible synthetic routes to 3,5-disubstituted indenes bearing two different functional groups, such as the [3-(aminoethyl)inden-5-yl)]amines, a reasonable pathway involves the (5-nitro-3-indenyl)acetamides as key intermediates. Although several multistep synthetic approaches can be applied to obtain these advanced intermediates, we describe herein their preparation by an aldol-type reaction between 5-nitroindan-1-ones and the lithium salt of N,N-disubstituted acetamides, followed immediately by dehydration with acid. This classical condensation process, which is neither simple nor trivial despite its apparent directness, permits an efficient entry to a variety of indene-based molecular modules, which could be adapted to a range of functionalized indanones.

Full text of DOI:10.3762/bjoc.7.204

Synthetic approaches to multifunctional indenes
Neus Mesquida*, Sara López-Pérez, Immaculada Dinarès
and Ermitas Alcalde*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1739–1744.
Laboratori de Química Orgànica, Departament de Farmacologia i
Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona,
Avda. Joan XXIII s/n, 08028 Barcelona, Spain
doi:10.3762/bjoc.7.204
Received: 06 October 2011
Accepted: 10 December 2011
Published: 29 December 2011
Email:
Neus Mesquida* - neusmesquida@ub.edu; Ermitas Alcalde* -
ealcalde@ub.edu
Associate Editor: M. S. Sherburn
* Corresponding author
© 2011 Mesquida et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aldol reaction; amides; indanones; indenes; organometallic reagents
Abstract
The synthesis of multifunctional indenes with at least two different functional groups has not yet been extensively explored. Among
the plausible synthetic routes to 3,5-disubstituted indenes bearing two different functional groups, such as the [3-(aminoethyl)inden-
5-yl)]amines, a reasonable pathway involves the (5-nitro-3-indenyl)acetamides as key intermediates. Although several multistep
synthetic approaches can be applied to obtain these advanced intermediates, we describe herein their preparation by an aldol-type
reaction between 5-nitroindan-1-ones and the lithium salt of N,N-disubstituted acetamides, followed immediately by dehydration
with acid. This classical condensation process, which is neither simple nor trivial despite its apparent directness, permits an effi-
cient entry to a variety of indene-based molecular modules, which could be adapted to a range of functionalized indanones.
Introduction
Compounds with an indene core are of great interest as precur- mation by indenes, which could permit rapid access to different
sors of metallocene complexes for catalytic polymerization substitution patterns, is rather cumbersome owing to the
processes, as well as being present in N-heterocyclic carbene complexity of the indene chemistry, especially of those
ligands and functional materials [1-9]. In addition, indene-based processes that could be modulated by the aromatic character of
structures are a source of bioactive compounds in drug a resulting indenyl anion species. Indeed, indene is an unusu-
discovery and development [10-18]. The routes to access ally acidic nonaromatic carbocyclic system and, although struc-
multiply substituted indenes with at least two different func- turally different, indene and indole show similar pKa values of
tional groups (FGs) are generally complex, and the synthetic 20.1 and 21.0 in dimethylsulfoxide solution, respectively
approaches leading to these compounds lag behind those for [23,24].
heteroaromatic systems, e.g., indoles, being limited as it is by
the scarce knowledge of indene chemistry in comparison with During the course of our studies on indene-based ligands of
heterocyclic chemistry [3,17-22]. Moreover, chemical transfor- general type 1 with biological effects on the central nervous
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system, we found that different stepwise synthetic routes could which should be favored with the presence of a methyl group at
be applied to inden-5-amines 2 bearing a disubstituted N,N- the indene 2-position.
aminoethyl side arm at the indene 3-position [17,18]. After
analyzing reasonable synthetic routes to the [3-(amino- Results and Discussion
ethyl)inden-5-yl)]amine intermediates 2 starting from substi- We recently reported that the reaction of 2-methylindanone 6
tuted indan-1-one 5, route A was chosen as the most suitable with the lithium salt of ethyl acetate (generated in situ by the
way of functionalizing the 5-position of the indene, e.g., by reaction of lithium hexamethyldisilazide with ethyl acetate),
changing the aryl(heteroaryl) structural motif of a sulfonamide immediately followed by dehydration and hydrolysis/isomeriza-
moiety (Scheme 1). This route proceeded in three steps, and tion, afforded the acetic acid 7 with an improved yield of 74%.
allowed the representative (3-indenyl)acetic acids 4 to be Compound 7 was then conveniently transformed to the corres-
conveniently prepared from nitroindanones 5 and the lithium ponding acetamide 8. The reduction of the amide group with
salt of ethyl acetate [18].
AlH3·NMe2Et was the critical step for the preparation of the
key inden-5-amine 9 due to the particularly troublesome isola-
The present work deals with the alternative synthetic route B, tion process [18].
which relies on the direct formation of the advanced
(3-indenyl)acetamides 3 from nitroindanone 5 and shortens the Thus, a different synthetic option was examined in which the
synthetic sequence to two steps. The aldol-type reaction of (3-indenyl)acetic acid 7 was reduced to the corresponding
indanone 5 with the lithium salts of different N,N-disubstituted alcohol 10 and transformed to tosylate 11. However, an attempt
acetamides, followed immediately by dehydration afforded the to convert the (3-indenyl)ethylsulfonate 11 into the advanced
(3-indenyl)acetamides 3. The success of this route, however, inden-5-amine 9 was ineffective, resulting in the formation of
depends on two main factors: (i) The nature of the lithiated base the spiro indene 12 instead, and hence this route was not studied
used to deprotonate acetamides in order to form lithium further (Scheme 2 and Supporting Information File 1). It should
enolates, which needs to be considered when adjusting the reac- be mention that the propensity of several 3-substituted indenes,
tion conditions [25]; and (ii) the chemical response of indanoles appropriately fitted with leaving groups, to undergo spirocy-
towards dehydration [6,18] to give the desired endo-olefin 3, clization has been previously reported [26,27].
Scheme 1: Retrosynthetic pathways to 3,5-disubstituted indenes bearing two functional groups: Indenylsulfonamides 1.
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Scheme 2: Reagents and conditions: (i) (a) EtOAc, LHMDS, THF, −78 °C, (b) H2SO4, H2O, 60 °C [18]; (ii) (a) SOCl2, CH2Cl2, reflux, (b) Me2NH, rt
[18]; (iii) (a) AlH3·NMe2Et, THF, 0 °C, (b) Zn, AcOH, rt [18]; (iv) AlH3·NMe2Et, THF, 0 °C; (v) TsCl, Py, CH2Cl2, rt; (vi) Me2NH, DMF, rt; (vii) (a) N,N-di-
methylacetamide, LDA, THF, −78 °C, (b) TFA, CH2Cl2, rt, 2 h.
To shorten the multistep route A, an alternative preparation of experimental conditions to indanone 13, the yield of indenyl-
the acetamide 8 was examined, based on an aldol-type reaction acetamide 15 was improved from 37% [18] to 65% (Scheme 2
between nitroindanone 6 and the lithium salt of N,N-dimethyl- and Supporting Information File 1).
acetamide. After various reaction conditions and lithiated bases
were examined, the condensation of 6 with the α-lithio-N,N-di- We next studied the utility of this aldol-type reaction protocol
methylacetamide (prepared in turn from N,N-dimethylacet- by using other disubstituted acetamides, such as N-acetylpyrrol-
amide and an excess of lithium diisopropylamide), immediately idine and N-acetylpiperidine, as shown in Scheme 3. When the
followed by dehydration with trifluoroacetic acid, afforded reaction conditions used to prepare N,N-dimethyl-(3-
indenylacetamide 8 in 70% yield, which was 14% higher indenyl)acetamide 8 were applied, 2-methylindanone 6 failed to
than the previously reported result obtained with the give the (3-indenyl)acetamide 16, and did not progress beyond
(3-indenyl)acetic acid 7 [18]. Upon application of the same the corresponding indanol (Supporting Information File 1).
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Beilstein J. Org. Chem. 2011, 7, 1739–1744.
When the dehydration process was prolonged to 17 h at room employing a different nitration method [28]. In our recently
temperature, conversion of indanone 6 to the desired acetamide reported preliminary experiments, the conversion of 21 to the
16 proceeded in 74% yield, which was 14% higher than that corresponding (3-indenyl)acetic acid 22 resulted in a fairly low
previously reported for a two-step procedure with the yield of 27%, and the transformation to N,N-dimethyl-(3-
(3-indenyl)acetic acid 7 [18]. Following this modified proce- indenyl)acetamide 23 was not carried out [18]. However, after
dure, the reaction between indanones 6 or 13 and the lithium the synthetic approach was changed from route A to route B,
salt of N-acetylpiperidine or N-acetylpyrrolidine afforded the indenylacetamide 23 was prepared by aldol-type conden-
indenylacetamides 17–19 in good yield (≥67%).
sation between indanone 21 and the lithium salt of N,N-di-
methylacetamide, in 57% yield (Scheme 4).
Finally, to broaden the scope of this aldol-type reaction, we
examined the synthesis of (1,1-dimethyl-3-indenyl)acetamides. We thus successfully optimized the synthesis of (3-indenyl)-
Following a standard nitration protocol applied to different acetamides 3, obtaining higher yields with a shorter procedure.
indanones [17], the 3,3-dimethylindanone 20 was efficiently
transformed into the corresponding 6-nitroindan-1-one 21 in The crude reaction products of the aldol-type reaction between
97% yield and no traces of the isomer 4-nitroindanone were nitroindanones and α-lithioacetamides often contained minor
detected, probably due to the presence of the dimethyl moiety at amounts of exo-olefins. Pure indenylacetamides were isolated
the indanone 3-position in 20. This was a marked improvement after careful column chromatography, and sometimes a high-
on a previously reported 62% yield of nitroindanone 21 throughput flash purification system was necessary.
Scheme 3: Reagents and conditions: (i) (a) EtOAc, LHMDS, THF, −78 °C, (b) H2SO4, H2O, 60 °C [18]; (ii) (a) SOCl2, CH2Cl2, reflux, (b) pyrrolidine or
piperidine, rt [7]; (iii) (a) N-acetylpyrrolidine or N-acetylpiperidine, LDA, −78 °C; (b) TFA, CH2Cl2, rt, 17 h.
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Conclusion
Among different synthetic routes that could lead to disubsti-
tuted indenes 1 bearing two functional groups, such as the
indenamines 2, a feasible path explored here required the use of
(5-nitro-3-indenyl)acetamides 3, prepared either from (5-nitro-
3-indenyl)acetic acid (4) or 5-nitroindan-1-one (5). The best
option to prepare the advanced indenylacetamides 3 was based
on an aldol-type reaction between nitroindanone 5 and the
lithium salt of N,N-disubstituted acetamides, followed immedi-
ately by dehydration with acid. Although apparently direct, the
classical aldol-type condensation process is neither simple nor
rudimentary when applied to members of the indene family.
Particularly significant aspects of the reported transformation
are (i) the nature of the lithiated base used to form the lithium
enolate, and (ii) the dehydration process to obtain the desired
endo-olefin 3. The optimal experimental results were achieved
with lithium diisopropylamide as the base and by employing a
long dehydration reaction time, which provided the targeted
indenylacetamides 3 in good yield. This synthetic protocol can
be exploited for the elaboration of a variety of indene-based
molecular modules with applications in fields as diverse as
Scheme 4: Reagents and conditions: (i) KNO3, H2SO4, −5 °C; (ii) (a)
EtOAc, LHMDS, THF, −78 °C, (b) H2SO4, H2O, 60 °C, 7 h [18]; (iii) (a)
N,N-dimethylacetamide, LDA, THF, −78 °C, (b) TFA, CH2Cl2, rt, 17 h.
The structures of the new compounds were confirmed by spec- bioactive compounds, ligand precursors for metallocene cata-
troscopic methods, and their 1H NMR and 13C NMR chemical lyst systems, and functional materials.
shifts and physical data are gathered in the experimental
description (Supporting Information File 1). The constitution of
Supporting Information
the acetamides 17, 19 and 23 was determined by 1D NOESY
experiments in CDCl3 at 500 MHz. Thus, for each compound,
Supporting Information File 1
irradiation at the H-2 proton of the indene core revealed a NOE
for the methylene protons H-1 and H-a. For compound 23, an
additional NOE was observed at the methyl protons of the
acetamide group (Figure 1).
Assays related to the preparation of 8, 10, 11 and 16,
experimental details, characterization data and copies of
NMR and ESI-HRMS spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-204-S1.pdf]
Acknowledgements
This research was supported by Vicerrectorat de Recerca,
Universitat de Barcelona and by the D. G. I. (MICINN) Projects
CTQ2006-1182/BQU and CTQ2010-15251/BQU. Thanks are
also due to the AGAUR (Generalitat de Catalunya), Grup de
Recerca Consolidat 2009SGR562. S. L.-P. is grateful to the
Agaur for a 2008-F.I. fellowship.
References
1. Chirik, P. J. Organometallics 2010, 29, 1500–1517.
doi:10.1021/om100016p
2. Zhang, C.; Luo, F.; Cheng, B.; Li, B.; Song, H.; Xu, S.; Wang, B.
Dalton Trans. 2009, 7230–7235. doi:10.1039/b906933j
3. Guo, S.; Liu, Y. Org. Biomol. Chem. 2008, 6, 2064–2070.
doi:10.1039/b804888f
And references therein.
Figure 1: Key NMR responses for compounds 17, 19 and 23:
1D NOESY experiments.
4. Guan, Z.-H.; Ren, Z.-H.; Zhao, L.-B.; Liang, Y.-M. Org. Biomol. Chem.
2008, 6, 1040–1045. doi:10.1039/b719957k
1743

Beilstein J. Org. Chem. 2011, 7, 1739–1744.
5. Enders, M.; Baker, R. W. Curr. Org. Chem. 2006, 10, 937–953.
doi:10.2174/138527206777435508
License and Terms
6. Silver, S.; Leppänen, A.-S.; Sjöholm, R.; Penninkangas, A.; Leino, R.
Eur. J. Org. Chem. 2005, 1058–1081. doi:10.1002/ejoc.200400789
7. Leino, R.; Lehmus, P.; Lehtonen, A. Eur. J. Inorg. Chem. 2004,
3201–3222. doi:10.1002/ejic.200400214
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
8. Zargarian, D. Coord. Chem. Rev. 2002, 233–234, 157–176.
doi:10.1016/S0010-8545(02)00201-1
9. Hummel, S.; Kirsch, S. F. Beilstein J. Org. Chem. 2011, 7, 847–859.
doi:10.3762/bjoc.7.97
10.Waldmann, H.; Karaguni, I.-M.; Carpintero, M.; Gourzoulidou, E.;
Herrmann, C.; Brockmann, C.; Oschkinat, H.; Müller, O.
Angew. Chem., Int. Ed. 2004, 43, 454–458.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
doi:10.1002/anie.200353089
11.Karaguni, I.-M.; Glüsenkamp, K.-H.; Langerak, A.; Geisen, C.;
Ullrich, V.; Winde, G.; Möröy, T.; Müller, O. Bioorg. Med. Chem. Lett.
2002, 12, 709–713. doi:10.1016/S0960-894X(01)00839-3
12.Li, B.-F.; Moree, W. J.; Yu, J.; Coon, T.; Zamani-Kord, S.; Malany, S.;
Jalali, K.; Wen, J.; Wang, H.; Yang, C.; Hoare, S. R. J.; Petroski, R. E.;
Madan, A.; Crowe, P. D.; Beaton, G. Bioorg. Med. Chem. Lett. 2010,
20, 2629–2633. doi:10.1016/j.bmcl.2010.02.055
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.204
13.Moree, W. J.; Li, B.-F.; Jovic, F.; Coon, T.; Yu, J.; Gross, R. S.;
Tucci, F.; Marinkovic, D.; Zamani-Kord, S.; Malany, S.; Bradbury, M. J.;
Hernandez, L. M.; O’Brien, Z.; Wen, J.; Wang, H.; Hoare, S. R. J.;
Petroski, R. E.; Sacaan, A.; Madan, A.; Crowe, P. D.; Beaton, G.
J. Med. Chem. 2009, 52, 5307–5310. doi:10.1021/jm900933k
14.Hodgson, D. M.; Winning, L. H. Beilstein J. Org. Chem. 2008, 4,
No. 38. doi:10.3762/bjoc.4.38
15.Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12,
1395–1411. doi:10.2174/0929867054020864
16.Böhme, T. M.; Keim, C.; Kreutzmann, K.; Linder, M.; Dingermann, T.;
Dannhardt, G.; Mutschler, E.; Lambrecht, G. J. Med. Chem. 2003, 46,
856–867. doi:10.1021/jm020895l
17.Alcalde, E.; Mesquida, N.; Frigola, J.; López-Pérez, S.; Mercè, R.
Org. Biomol. Chem. 2008, 6, 3795–3810. doi:10.1039/b808641a
And references cited therein.
18.Alcalde, E.; Mesquida, N.; López-Pérez, S.; Frigola, J.; Mercè, R.
J. Med. Chem. 2009, 52, 675–687. doi:10.1021/jm8009469
19.Wang, J.; Zhang, L.; Jing, Y.; Huang, W.; Zhou, X. Tetrahedron Lett.
2009, 50, 4978–4982. doi:10.1016/j.tetlet.2009.06.070
20.Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007, 9, 3033–3036.
doi:10.1021/ol071107v
21.Ivchenko, P. V.; Nifant’ev, I. E.; Luzikov, Yu. N.; Mkoyan, S. G.
Synthesis 2007, 1038–1046. doi:10.1055/s-2007-965957
22.Nishikata, T.; Kobayashi, Y.; Kobayshi, K.; Yamamoto, Y.; Miyaura, N.
Synlett 2007, 3055–3057. doi:10.1055/s-2007-990964
23.Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46,
632–635. doi:10.1021/jo00316a032
24.Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218–4223.
doi:10.1021/jo00013a027
25.Rathman, T. L.; Bailey, W. F. Org. Process Res. Dev. 2009, 13,
144–151. doi:10.1021/op800246z
26.Kelly, P. A.; Berger, G. O.; Wyatt, J. K.; Nantz, M. H. J. Org. Chem.
2003, 68, 8447–8452. doi:10.1021/jo034975o
And references therein.
27.Resconi, L.; Piemontesi, F.; Camurati, I.; Balboni, D.; Sironi, A.;
Moret, M.; Rychlicki, H.; Zeigler, R. Organometallics 1996, 15,
5046–5059. doi:10.1021/om9604233
28.Koelsch, C. F.; LeClaire, C. D. J. Org. Chem. 1941, 6, 516–533.
doi:10.1021/jo01204a005
1744