Organocatalytic asymmetric Diels-Alder reactions of 3-vinylindoles

Article abstract of DOI:10.1002/anie.200804275

(Chemical Equation Presented) Diels or no Diels? A bifunctional organic catalyst based on the thiourea motif is able to coordinate both diene and dienophile in an unprecedented asymmetric Diels-Alder reaction of 3-vinylindole derivatives, giving a rapid access to optically active tetra- and hexahydrocarbazoles with excellent results in terms of yields, diastereoselectivities, and enantioselectivities.

Full text of DOI:10.1002/anie.200804275

Communications
DOI: 10.1002/anie.200804275
Asymmetric Catalysis
Organocatalytic Asymmetric Diels–Alder Reactions of
3-Vinylindoles**
Claudio Gioia, Agnꢀs Hauville, Luca Bernardi,* Francesco Fini, and Alfredo Ricci*
Diels–Alder type reactions are amongst the most useful
transformations in organic chemistry for the construction of
cyclohexene structures, often containing multiple stereocen-
ters. Catalytic asymmetric variants of these [4+2] cyclo-
additions have been reported for different diene–dienophile
combinations,[1] showing in several instances outstanding
synthetic utility. Herein, we present the development of an
unprecedented catalytic asymmetric Diels–Alder reaction of
3-vinylindoles 1 with different representative dienophiles 2
(Scheme 1). Our studies were motivated by the stunning
molecular orbital interactions, favoring an endo approach.
However, no catalytic asymmetric variants of these useful
transformations have been reported to date.[4]
To find a suitable catalytic system, we envisioned a
scenario where a bifunctional acid–base organic catalyst
coordinates through hydrogen-bond interactions to both the
diene 1 and the dienophile 2,[5] resulting in a highly organized
transition state, potentially giving rise to the cycloadduct with
good levels of stereoselectivity. The mild acidic nature of
many commonly employed organic catalysts, often based on
urea or thiourea motifs, should be compatible even with the
acid-sensitive 3-vinylindoles. The asymmetric Friedel–Crafts
reactions of 1-H-indole derivatives,[6] wherein the catalysts
operate through a hydrogen-bonding network involving the
À
indole N H, as well as the cycloaddition reaction of 3-
hydroxy-2-pyrones,[7] wherein the double activation of a diene
and a dienophile by an organic catalyst was realized with great
success, were both of great encouragement and inspiration.
We initially investigated the catalytic reaction between 3-
vinylindole 1a and N-phenylmaleimide 2a (Scheme 2). Car-
rying out the reaction at À258C in dichloromethane, screen-
Scheme 1. Diels–Alder reaction of 3-vinylindoles 1.
directness and versatility of this approach for the [b]anella-
À
tion (at the C2 C3 bond) of the indole nucleus, giving
partially saturated, optically active carbazoles 3. Standard
manipulations of these cycloadducts give access to tricyclic
indolines 4 and tetrahydrocarbazoles 5 (Scheme 1), which are
common scaffolds in a variety of natural and/or biologically
active alkaloids.[2] It has long been recognized that 3-vinyl-
indoles can participate in frontier-molecular-orbital-control-
led Diels–Alder reactions with the HOMO of their electron-
rich diene systems.[3] Control of the relative stereochemistry
in the thus-formed hydrogenated carbazoles is often excel-
lent, owing to the concerted mechanism and to secondary
Scheme 2. Selected results from catalyst-optimization screening reac-
tions. TFAA=trifluoroacetic anhydride
ing of bifunctional organic catalysts[8] suggested 6a, derived
from (1S,2R)-1-aminoindanol, and 6b and c, both derived
from quinine,[9] as the most promising structures. Having
identified dichloromethane as the solvent of choice for this
transformation,[8] optimum selectivity (98% ee) was reached
using catalyst 6d, derived from hydroquinine, at À558C
(Scheme 2). Derivatization with trifluoroacetic anhydride
(TFAA) after the reaction gave additional stability to the
cycloadduct, thus facilitating its isolation by chromatography
on silica gel and subsequent HPLC analysis. As expected,
exclusively the endo cycloadduct 3a was obtained in all
experiments, and isomerization of the double bond, restoring
[*] C. Gioia, A. Hauville, Dr. L. Bernardi, Dr. F. Fini, Prof. A. Ricci
Department of Organic Chemistry “A. Mangini”
University of Bologna
V. Risorgimento 4, I-40136, Bologna (Italy)
Fax: (+39)0512093654
E-mail: nacca@ms.fci.unibo.it
ricci@ms.fci.unibo.it
[**] We acknowledge financial support from “Stereoselezione in Sintesi
Organica Metodologie e Applicazioni” 2005. The financial support
by the Merck–ADP grant 2007 is also gratefully recognized.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804275.
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the aromatic indole nucleus, did not occur under these mild
conditions.[10]
1-Tosyl-, 1-tert-butoxycarbonyl- (1-Boc) and 1-methyl-3-
vinylindoles related to 1a were also tested in the reaction with
maleimide 2a, using catalyst 6b. The 1-tosyl and the 1-Boc
derivatives afforded the corresponding products, albeit in
racemic form, at + 48C and À258C, respectively, whereas 1-
methyl-3-vinylindole did not lead to substantial formation of
the expected cycloadduct.[11] These results were tentatively
taken to suggest the requirement of an interaction between
Figure 1. Proposed working model of the reaction transition state.
À
the basic moiety of the catalyst and the N H group of the
diene, alongside activation of the dienophile by the thiourea
moiety (Figure 1).
group at the 5-position of the indole nucleus was well
tolerated (Table 1, entries 2 and 3), as was a methyl substitu-
ent at the exocyclic double bond (Table 1, entries 4 and 5). In
the latter case, although a 1:1 E/Z mixture of diene 1e was
employed, exclusively the E isomer underwent the cyclo-
We then investigated the generality of this transformation
(Table 1), varying first the structure of the 3-vinylindole 1
(Table 1, entries 1–5). An electron-withdrawing or donating
Table 1: Scope of the reaction.[a]
Entry
Diene 1
Dienophile 2
Cycloadduct 3
Yield[b] [%]
ee[c] [%]
98 (95)
90
96
1
1a: R1 =H
3a: R1 =H[d]
91 (86)
86
77
2[e]
3[e]
1b: R1 =Br
3b: R1 =Br
1c: R1 =MeO
3c: R1 =MeO
2a
4
1d
2a
2a
3d
79 (89)
96 (86)
5[e]
1e: E/Z=50:50
3e[d,f]
58
92
6
7
8
9
2b: R3 =Me
3 f: R3 =Me
3g: R3 =Bn
3h: R3 =tBu
3i: R3 =H
89
89
81
72
98
96
88
52
2c: R3 =Bn
2d: R3 =tBu
2e: R3 =H
1a
1a
1a
10
11
2 f
3j
83 (71)
>99 (98)
2g
3k
77
96
[a] Conditions: 2 (0.15 mmol), 6d (0.030 mmol), 1 (0.18 mmol), CH2Cl2 (1.5 mL), À558C, 48 h. Results in parentheses refer to the opposite
enantiomer, obtained using 6e as the catalyst. [b] Yield of product isolated by chromatography on silica gel. [c] Determined by chiral stationary-phase
HPLC. [d] Relative configuration determined by 1H NMR spectroscopy (see the Supporting Information). [e] 2 equiv diene 1 used. [f] d.r.>95:5.
[g] Reaction carried out at À308C for 72 h.
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addition reaction, giving the product 3e as a single diaste-
catalytic transformation and allowing the assignment of the
absolute configuration of the products.
reoisomer. As stirring 1e (E/Z mixture) in the presence of
catalyst 6d in CD2Cl2 at À308C overnight did not lead to any
E/Z isomerization, two equivalents of this diene were used.[12]
With 3-vinylindole 1a, variation in the dienophile counterpart
was then investigated (Table 1, entries 6–11). Maleimides 2b–
d, bearing substituents of different sizes at nitrogen, including
a hindered tert-butyl group, were used in the Diels–Alder
reaction, affording the cycloadducts 3 f–h with excellent
results (Table 1, entries 6–8). We instead attributed the
rather low enantioselectivity in the reaction with 2e
(Table 1, entry 9) to a possible interference by the imide
hydrogen with the H-bond interactions between the catalyst
and the substrates. Quinones, another popular class of
dienophiles for Diels–Alder cycloadditions, could also be
employed, as the cycloadducts 3j and 3k, derived from
benzoquinone 2 f and naphthoquinone 2g, were both
obtained in good yields and excellent enantioselectivities
(Table 1, entries 10 and 11). The quasi-enantiomeric catalyst
6e, derived from hydroquinidine, gave access to the enantio-
meric products ent-3 with comparable results (Table 1, values
in parentheses).
In conclusion, the use of a bifunctional acid–base organo-
catalyst allowed the development of the hitherto elusive
catalytic asymmetric Diels–Alder reaction of 3-vinylindoles,
offering a direct approach to optically active tetrahydrocar-
bazole derivatives. The possibility of activating 3-vinylindoles
À
by interaction of a base with the N H moiety might also serve
as a useful platform for the realization of catalytic asymmetric
Diels–Alder reactions using other classes of 1-amino-substi-
tuted dienes.[15]
Supporting information (including further optimization
results, experimental details, and copies of the 1H and
13C NMR spectra) for this article is available on the WWW
under http://www.angewandte.org or from the author.
Received: August 29, 2008
Published online: October 29, 2008
Keywords: asymmetric synthesis · cycloaddition ·
.
Diels–Alder reaction · hydrogen bonds · organocatalysis
The reduction of the cycloadduct 3a to the indoline 4a
was straightforward, as was the synthesis of the tetrahydro-
carbazole 5a through a 1,3-H shift, by treatment of the
cycloadduct (before TFAA derivatization)[10] with dilute
aqueous HCl (Scheme 3). Use of harsher conditions gave,
besides the 1,3-H shift, hydrolysis of the imide and regiospe-
cific decarboxylation[3i] at the 1-position (Scheme 3). Reduc-
tion of the carboxylic acid of 5b, followed by homologation
with a Mitsunobu reaction,[13] and methanolysis of the cyano
group, afforded 5c, the enantiomer of a synthetic intermedi-
[1] a) H. B. Kagan, O. Riant, Chem. Rev. 1992, 92, 1007; b) Y.
Hayashi in Cycloaddition Reactions in Organic Synthesis (Eds.:
S. Kobayashi, K. A. Jørgensen), Wiley-VCH, 2001, p. 5; c) K.
Maruoka in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I.
Ojima), Wiley-VCH, New York, 2000, p. 467; d) D. A. Evans,
J. S. Johnson in Comprehensive Asymmetric Catalysis, Vol. 3
(Eds: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New
York, 1999, p. 1177; e) E. J. Corey, Angew. Chem. 2002, 114,
1724; Angew. Chem. Int. Ed. 2002, 41, 1650; f) O. Corminboeuf,
L. Quaranta, P. Renaud, M. Liu, C. P. Jasperse, M. Sibi, Chem.
Eur. J. 2003, 9, 28; g) K. Ishihara, M. Fushimi, M. Akakura, Acc.
Chem. Res. 2007, 40, 1049.
[2] a) M. Hesse, Alkaloids, Nature Curse or Blessing?, Wiley-VCH,
New York, 2002; b) J. E. Saxton, Nat. Prod. Rep. 1997, 14, 559;
c) J. Bonjoch, D. Solꢀ, Chem. Rev. 2000, 100, 3455; d) G. Abbiati,
V. Canevari, D. Facoetti, E. Rossi, Eur. J. Org. Chem. 2007, 517,
and references therein.
ate used in the asymmetric synthesis of tubifolidine,[14]
a
Strychnos alkaloid, highlighting the synthetic potential of this
[3] a) W. E. Noland, W. C. Kuryla, R. F. Lange, J. Am. Chem. Soc.
1959, 81, 6010; b) W. E. Noland, R. J. Sundberg, J. Org. Chem.
1963, 28, 884; c) R. Bergamasco, Q. N. Porter, C. Yap, Aust. J.
Chem. 1977, 30, 1531; d) L. Pfeuffer, U. Pindur, Helv. Chim. Acta
1988, 71, 467. For reviews, see: e) U. Pindur, Heterocycles 1998,
27, 1253; f) R. J. Sundberg, in Indoles, Academic Press, London,
1996, p. 156. Recent examples: g) M. Bleile, H.-H. Otto,
Monatsh. Chem. 2005, 136, 1799; h) M. Bleile, T. Wagner, H.-
H. Otto, Helv. Chim. Acta 2005, 88, 2879; i) W. E. Noland, G.-M.
Xia, K. R. Gee, M. J. Konkel, M. J. Wahlstrom, J. J. Condoluci,
D. L. Rieger, Tetrahedron 1996, 52, 4555.
[4] For a chiral auxiliary approach, giving the cycloadducts in
modest (less than 50%) yields, see: U. Pindur, G. Lutz, G.
Fischer, D. Schollmeyer, W. Massa, L. Schrꢁder, Tetrahedron
1993, 49, 2863.
[5] Reviews on catalysis through hydrogen-bonding interactions:
a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289; b) Y. Take-
moto, Org. Biomol. Chem. 2005, 3, 4299; c) M. S. Taylor, E. N.
Jacobsen, Angew. Chem. 2006, 118, 1550; Angew. Chem. Int. Ed.
2006, 45, 1520; d) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007,
107, 5713; e) P. M. Pihko, Angew. Chem. 2004, 116, 2110; Angew.
Chem. Int. Ed. 2004, 43, 2062.
Scheme 3. Elaborations of the cycloadducts. TFA=trifluoroacetic acid;
DEAD=diethyl azodicarboxylate.
[6] a) R. P. Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew.
Chem. 2005, 117, 6734; Angew. Chem. Int. Ed. 2005, 44, 6576;
9238
www.angewandte.org
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Angew. Chem. Int. Ed. 2008, 47, 9236 –9239

Angewandte
Chemie
b) H. Li, Y.-Q. Wang, L. Deng, Org. Lett. 2006, 8, 4063; c) B.
Tꢁrꢁk, M. Abid, G. London, J. Esquibel, M. Tꢁrꢁk, S. C.
Mhadgut, P. Yan, G. K. S. Prakash, Angew. Chem. 2005, 117,
3146; Angew. Chem. Int. Ed. 2005, 44, 3086; d) Y.-Q. Wang, J.
Song, R. Hong, H. Li, L. Deng, J. Am. Chem. Soc. 2006, 128,
8156; e) J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. 2008,
120, 4080; Angew. Chem. Int. Ed. 2008, 47, 4016, and references
therein.
bond shift, which requires double-bond protonation, is highly
disfavored. See ref. [3i].
[11] This acid-sensitive diene underwent extensive decomposition.
[12] The E-isomer can more easily access the s-cis conformation,
which is necessary for the reaction to occur following a Diels–
Alder pathway, thus giving evidence for a concerted [4+2]
mechanism for this cycloaddition. See: U. Pindur, M.-H. Kim, M.
Rogge, W. Massa, M. Molinier, J. Org. Chem. 1992, 57, 910.
[13] T. Tsunoda, K. Uemoto, C. Nagino, M. Kawamura, H. Kaku, S.
Itꢄ, Tetrahedron Lett. 1999, 40, 7355.
[7] a) Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L. Deng, J.
Am. Chem. Soc. 2007, 129, 6364; b) H. Okamura, T. Iwagawa, M.
Nakatani, Tetrahedron Lett. 1995, 36, 5939. For Diels – Alder
reactions of anthrones, see: c) O. Riant, H. B. Kagan, Tetrahe-
dron Lett. 1989, 30, 7403; d) J. Shen, T. T. Nguyen, Y.-P. Goh, W.
Ye, X. Fu, J. Xu, C.-H. Tan, J. Am. Chem. Soc. 2006, 128, 13692.
[8] See the Supporting Information.
[9] a) B. Vakulya, S. Varga, A. Csꢂmpai, T. Soꢃs, Org. Lett. 2005, 7,
1967; b) S. J. Connon, Chem. Commun. 2008, 2499.
[10] The double bond is stabilized at the 3,4-position by conjugation
with the aromatic ring. After trifluoroacetylation the double-
[14] S. Shimizu, K. Ohori, T. Arai, H. Sasai, M. Shibasaki, J. Org.
Chem. 1998, 63, 7547.
[15] See for example: a) P. Wipf, X. Wang, Tetrahedron Lett. 2000, 41,
8747; b) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc.
2002, 124, 2458; c) D. A. Evans, D. M. Barnes, J. S. Johnson, T.
Lectka, P. von Matt, S. J. Miller, J. A. Murry, R. D. Norcross,
E. A. Shaughnessy, K. R. Campos, J. Am. Chem. Soc. 1999, 121,
7582.
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