2 For an excellent overview on the preparation and biological
activity of 1,2,3,4-tetrahydroquinolines, see: A. R. Katritzky,
S. Rachwal and B. Rachwal, Tetrahedron, 1996, 52, 15031. See
also ref. 1c.
3 Reviews on aza-Diels–Alder cycloadditions: (a) P. Buonora,
J.-C. Olsen and T. Oh, Tetrahedron, 2001, 57, 6099;
(b) S. Kobayashi, in Cycloaddition Reactions in Organic Synthesis,
ed. S. Kobayashi and K. A. Jørgensen, WILEY-VCH, Weinheim,
2002, pp. 187–210.
4 (a) H. Ishitani and S. Kobayashi, Tetrahedron Lett., 1996, 37, 7357;
(b) G. Sundarajan, N. Prabagaran and B. Varghese, Org. Lett.,
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Chem. Soc., 2006, 128, 13070; (d) H. Liu, G. Dagousset, G. Masson,
P. Retailleau and J. Zhu, J. Am. Chem. Soc., 2009, 131, 4598.
5 In a review, unpublished work was mentioned describing an
enantioselective Povarov reaction with cyclic vinylethers catalysed
by a urea–TfOH system: A. G. Doyle and E. N. Jacobsen, Chem.
Rev., 2007, 107, 5713.
6 P. A. Grieco and A. Bahsas, Tetrahedron Lett., 1988, 29, 5855.
7 For reviews on vinylindoles Diels–Alder reactions, see:
(a) U. Pindur, Heterocycles, 1988, 27, 1253; (b) R. J. Sundberg,
Indoles, Academic Press, London, 1996, p. 156.
8 (a) C. Gioia, A. Hauville, L. Bernardi, F. Fini and A. Ricci, Angew.
Chem., Int. Ed., 2008, 47, 9236; (b) C. Gioia, L. Bernardi and
A. Ricci, Synthesis, 2000, DOI: 10.1055/s-0029.1217046. Iminium
ion catalysed [4 + 2] cycloaddition of a 2-vinylindole derivative;
(c) S. B. Jones, B. Simmons and D. W. C. MacMillan, J. Am.
Chem. Soc., 2009, 131, 13606.
9 Inverse-electron demand cycloaddition of 2-vinylindoles with
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate: U. Pindur and
M.-H. Kim, Tetrahedron Lett., 1988, 29, 3927.
Scheme 2 Nucleophilic interception of Povarov intermediate A.
TFAA = trifluoroacetic anhydride; PMP = 4-methoxyphenyl.
2,3-disubstituted indole derivative 6 [eqn (1)]. Despite the
moderate yield, calculated over two steps, the present one
pot transformation is able to afford very rapidly a rather
complex 2,3-disubstituted indole.
10 (a) Catalytic Asymmetric Friedel-Crafts Alkylations, ed. M. Bandini
and A. Umani-Ronchi, WILEY-VCH, 2009; (b) T. B. Poulsen and
K. A. Jørgensen, Chem. Rev., 2008, 108, 2903; (c) S. L. You, Q. Cai
and M. Zeng, Chem. Soc. Rev., 2009, 38, 2190.
11 As do many aza-Diels–Alder cycloadditions, Povarov reactions
occur following a non-concerted pathway: (a) S. Hermitage,
D. A. Jay and A. Whiting, Tetrahedron Lett., 2002, 43, 9633;
(b) O. Jimenez, G. de la Rosa and R. Lavilla, Angew. Chem., Int.
Ed., 2005, 44, 6521.
ð1Þ
12 (a) D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126,
5356; (b) T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew.
Chem., Int. Ed., 2004, 43, 1566.
13 Reviews: (a) T. Akiyama, Chem. Rev., 2007, 107, 5744; (b) M. Terada,
Chem. Commun., 2008, 4097; (c) G. Adair, S. Mukherjee and B. List,
Aldrichimica Acta, 2008, 41, 31; (d) M. S. Taylor and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2006, 45, 1520; (e) X. Yu and W. Wang,
Chem.–Asian J., 2008, 3, 516.
14 S. Hoffmann, A. M. Seayad and B. List, Angew. Chem., Int. Ed.,
2005, 44, 7424.
15 J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed., 2006,
45, 4796.
Conversely, the high degree of stabilisation of the intermediate
A in the reactions with 3-vinylindole 3 rendered possible its
nucleophilic interception (Scheme 2).11,18 To favour the inter-
molecular trapping of A against the intramolecular ring closure
leading to the Povarov cycloadduct, reactions were performed at
higher concentration. Under these conditions, using 4-methoxy-
aniline as the nucleophilic trapping component, the 1,3-diamine 7
could be isolated in good yield, after derivatisation with trifluoro-
acetic anhydride (Scheme 2). We also found that 3-vinylindole 3
itself could be employed as the intercepting agent, if added in
excess (5 equiv.). In this latter case, the reaction afforded piperidine
8 resulting from intramolecular ring closure of the amine nitrogen
to the second indol-3-yl stabilised cationic intermediate B.19
In conclusion, a reaction manifold was developed based on
the Povarov reactivity of 2- and 3-vinylindoles with N-aryl-
imines, in the presence of (S)-TRIP as catalyst. Taken
together, the results presented here give a versatile synthetic
platform for the construction of enantioenriched compounds
containing an indole moiety, a very common structure in
natural and bioactive molecules.
16 G. Bringmann, T. Bruhn, K. Maksimenka and Y. Hemberger, Eur.
J. Org. Chem., 2009, 2717.
17 N-Tosyl benzylidene imine gives indeed a Friedel–Crafts type
reaction with 2-vinylindole 2, in the presence of phosphoric acids.
18 For examples of the use of indol-3-yl stabilized carbocations in
organocatalysis, see: (a) D. Enders, A. A. Narine, F. Toulgoat and
T. Bisschops, Angew. Chem., Int. Ed., 2008, 47, 5661; (b) M. Rueping,
B. J. Nachtsheim, S. A. Moreth and M. Bolte, Angew. Chem., Int. Ed.,
2008, 47, 593; (c) R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli and
P. Melchiorre, Angew. Chem., Int. Ed., 2008, 47, 8707; (d) Q.-X. Guo,
Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng and L.-Z. Gong, Org.
Lett., 2009, 11, 4620; (e) Q.-L. He, F.-L. Sun, X.-J. Zheng and
S.-L. You, Synlett., 2009, 1111; see also: ; (f) P. G. Cozzi, F. Benfatti
and L. Zoli, Angew. Chem., Int. Ed., 2009, 48, 1313; (g) F. Benfatti,
M. Guiteras Capdevila, L. Zoli, E. Benedetto and P. G. Cozzi, Chem.
Commun., 2009, 5919; (h) S. Shirakawa and S. Kobayashi, Org. Lett.,
2006, 8, 4939; (i) J. Esquivias, R. Gomes Arrayas and J. C. Carretero,
Angew. Chem., Int. Ed., 2006, 45, 629.
We acknowledge financial support from ‘Stereoselezione in
Sintesi Organica Metodologie e Applicazioni’ 2007.
19 Enecarbamates have shown similar behaviour to 3-vinylindole 3 in
Brønsted acid cataysed Mannich reactions with N-Boc imines:
(a) M. Terada, K. Machioka and K. Sorimachi, Angew. Chem.,
Int. Ed., 2009, 48, 2553; (b) M. Terada, K. Machioka and
K. Sorimachi, J. Am. Chem. Soc., 2007, 129, 10336.
Notes and references
1 (a) L. S. Povarov and B. M. Mikhailov, Izv. Akad. Nauk SSR, Ser.
Khim., 1963, 953; (b) L. S. Povarov, Russ. Chem. Rev., 1967, 36,
656; (c) V. V. Kouznetsov, Tetrahedron, 2009, 65, 2721.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 327–329 | 329