The first aza Diels-Alder reaction involving an α,β-unsaturated hydrazone as the dienophile: Stereoselective synthesis of C-4 functionalized 1,2,3,4-tetrahydroquinolines containing a quaternary stereocenter

Article abstract of DOI:10.1039/b703083e

The reaction between aromatic imines and methacrolein dimethylhydrazone in the presence of 10% indium trichloride affords in good to excellent yields biologically and synthetically relevant 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C-4 in a one-pot process that involves the formation of two C-C bonds and the stereoselective generation of two stereocenters, one of them quaternary, and this constitutes the first example of an α,β-unsaturated dimethylhydrazone behaving as a dienophile in a hetero Diels-Alder reaction and the first vinylogous aza-Povarov reaction. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b703083e

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The first aza Diels–Alder reaction involving an a,b-unsaturated hydrazone as
the dienophile: stereoselective synthesis of C-4 functionalized
1
,2,3,4-tetrahydroquinolines containing a quaternary stereocenter†
Vellaisamy Sridharan, Paramasivan T. Perumal,‡ Carmen Avenda n˜ o and J. Carlos Men e´ ndez*
Received 28th February 2007, Accepted 26th March 2007
First published as an Advance Article on the web 4th April 2007
DOI: 10.1039/b703083e
The reaction between aromatic imines and methacrolein
dimethylhydrazone in the presence of 10% indium trichlo-
ride affords in good to excellent yields biologically and
synthetically relevant 1,2,3,4-tetrahydroquinolines bearing a
hydrazone function at C-4 in a one-pot process that involves
the formation of two C–C bonds and the stereoselective
generation of two stereocenters, one of them quaternary,
and this constitutes the first example of an a,b-unsaturated
dimethylhydrazone behaving as a dienophile in a hetero
Diels–Alder reaction and the first vinylogous aza-Povarov
reaction.
The 1,2,3,4-tetrahydroquinoline moiety is a structural fragment of
several natural products, including the well-known enedyine anti-
tumour drug dynemycin, alkaloids of the benzastatin-virantmycin
1
family, some of which possess potent antiviral activity, and the
2
3
marine alkaloids discorhabdin and martinelline. Furthermore,
many unnatural tetrahydroquinoline derivatives exhibit a broad
4
range of biological activities, which has prompted the selection
Scheme 1 The imino Diels–Alder (Povarov) reaction and two proposed
vinylogous versions thereof.
of tetrahydroquinoline-derived targets in programs aimed at the
solid-phase library generation of natural product-like scaffolds
5
with privileged substructures. Tetrahydroquinolines are also im-
literature. The use of 1,3-butadienes as dienophiles would provide
access to tetrahydroquinoline derivatives bearing a two-carbon
substituent at C-4 [Scheme 1(b)]. A similar reaction involving an
aza derivative of an electron-rich diene [Scheme 1(c)] would also
be very interesting in that it would yield tetrahydroquinolines with
a carbon functional group directly attached to C-4, which is the
substitution pattern found in many relevant tetrahydroquinolines,
including some natural products. In spite of the synthetic potential
of these transformations, only two cases of the Scheme 1(b)
situation have been reported and the strategy summarized in
Scheme 1(c) is unknown, to our knowledge. We present here
the first implementation of the formal cycloaddition between
aromatic imines and 1-azadienes where the imine acts as the diene
portant as synthetic intermediates, especially in the preparation of
6
quinoline derivatives. The interest in these compounds has stim-
7
ulated the development of a large number of synthetic methods,
among which one of the most efficient is the so-called imino
Diels–Alder reaction, i.e. the reaction between imines derived from
aromatic aldehydes and electron-rich alkenes [Scheme 1(a)], which
8
was discovered by Povarov in the 1960s and has experienced
a resurgence in the last 10 years following the discovery that
9
lanthanide triflates were efficient catalysts for this transformation.
11
In spite of its interest, many aspects of the Povarov reaction have
received little attention; for example, the range of dienophiles so
far employed is relatively small, since most attention has been
directed to enol ethers, particularly cyclic ones like dihydrofuran
=
10
and the C C portion of the azadiene behaves as the dienophile.
and dihydropyran. Vinylogous versions of the Povarov reaction,
i.e. cycloadditions of arylimines where one of the double bonds
of an open-chain diene-type structure acts as the dienophile,
would be synthetically very useful, but are almost unknown in the
This transformation involves a vinylogous aza-Povarov reaction
according to Scheme 1(c).
a,b-Unsaturated hydrazones have long been known to behave
as the diene component in hetero Diels–Alder reactions leading
12
to pyridine and fused pyridine derivatives. Due to the electron-
C double bond
Departamento de Qu ´ı mica Org a´ nica y Farmac e´ utica, Facultad de Farma-
cia. Universidad Complutense, 28040, Madrid, Spain. E-mail: josecm@
farm.ucm.es; Fax: +34-91-3941822; Tel: +34-91-3941840
withdrawing effect of the nitrogen atom, the C
=
of these 1-azadienes can be considered as an electron-poor alkene
and therefore unsuitable as a partner for the imino Diels–Alder
reaction. However, the introduction of electron-releasing groups
†
Electronic supplementary information (ESI) available: Analytical and
spectral characterization data and representative spectra. See DOI:
1
‡
0.1039/b703083e
13
14
on nitrogen such as dimethylamino, acetylamino or 1-tert-
butyldimethylsilyloxy substituents reverses this situation and
Permanent address: Organic Chemistry Division, Central Leather Re-
15
search Institute, Chennai 600 020, India
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Org. Biomol. Chem., 2007, 5, 1351–1353 | 1351

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allows the use of a,b-unsaturated hydrazones as dienes in normal
electron demand Diels–Alder reactions. With this precedent in
mind, we undertook the study of the reaction between aromatic
imines 1, and methacrolein dimethylhydrazone 2, hoping to
be able to use for the first time the latter compound as the
dienophile component, rather than the diene, in an imino Diels–
Alder reaction. Gratifyingly, we discovered that the use of 10%
indium trichloride as a catalyst allowed us to carry out the ex-
pected transformation, furnishing the C-4 functionalized 1,2,3,4-
tetrahydroquinolines 3 in good to excellent yields (Scheme 2
imine complex 5 is expected under our conditions. The final
cyclization step should take place through a chair-like transition
state, leading to a preference for an equatorial arrangement of
the bulky dimethylhydrazono and aryl substituents and hence
to the observed stereochemistry for compounds 4 (Scheme 3).
The generation with complete control of the stereocenter at
the tetrahydroquinoline C-4 position is noteworthy, since the
stereoselective installation of quaternary stereocenters is one of
19
the most challenging tasks for synthetic organic chemistry.
16
and Table 1). It is noteworthy that the reaction tolerates well
the presence of both electron-withdrawing and electron-releasing
groups at both aromatic rings of the starting imine. Small amounts
3
of 4-(R -aryl)dimethylhydrazones, arising from a transimination
17
reaction between compounds 1 and 2, were also observed in the
crude reaction mixtures.
Scheme 2 Three-component reaction between anilines, aromatic aldehy-
des and an a,b-unsaturated hydrazone.
The vinylogous aza-Povarov reaction thus developed was
stereoselective and afforded exclusively compounds 3 with a cis
relationship between the C-2 hydrogen and the C-4 methyl. This
structure was established by NOESY studies, which showed a cor-
Scheme 3 Rationale for the stereoselectivity of the vinylogous imino
Diels–Alder reaction.
relation peak between the H-2 and C
4
-CH
3
signals, which is only
In conclusion, we have developed a new domino reaction that
involves the creation of two C–C bonds and the generation of two
stereocenters, one of them quaternary, with complete diastereos-
electivity and in a single synthetic operation. Furthermore, this
method affords synthetically valuable C-4 functionalized 1,2,3,4-
tetrahydroquinolines in good to excellent yields using simple and
readily available starting materials and a non-toxic and inexpensive
catalyst. This transformation can be considered as a new type of
vinylogous aza-Povarov reaction, and constitutes the first example
of an a, b-unsaturated hydrazone behaving as the dienophile
component in an aza Diels–Alder reaction.
consistent with a cis arrangement for these substituents, both being
equatorial. The observed stereoselectivity can be explained by
taking into account that the Povarov reaction is known to proceed
in a stepwise manner, as proved by the trapping of the intermediate
iminium species when the reaction is carried out in the presence
18
of nucleophiles. Therefore, the generation of intermediates 6
from the reaction between dimethylhydrazone 2 and indium–
Table 1 Results obtained in the indium-catalyzed reaction between
anilines, aromatic aldehydes and methacrolein dimethylhydrazone
1
2
3
Entry Compound
R
R
R
Time/h Yield (%)
Acknowledgements
1
2
3
4
5
6
7
8
9
0
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
OCH
H
OCH
3
H
H
2
2
2
3
2
3
2
2
3
3
5
3
90
71
76
87
93
70
72
80
79
83
81
80
CH
CH
3
The stay of PTP in Madrid was supported by a grant from
the Santander-UCM “Programa de Visitantes Distinguidos”.
Financial support from MEC (grant CTQ2006-10930), UCM–
CAM (Grupos de Investigaci o´ n, grant 920234) is also gratefully
acknowledged.
3
Cl
Cl
CH
Cl
OCH
OCH
Cl
OCH
CH
Br
OCH
OCH
H
3
3
3
3
CH
OCH
3
3
H
3
3
CH
CH
CH
CH
3
3
3
3
CH
CH
CH
CH
3
3
3
3
1
1
1
3j
3k
3l
3
Notes and references
3
1
(a) S. Omura and A. Nakagawa, Tetrahedron Lett., 1981, 22, 2199;
(
b) W. G. Kim, J. P. Kim and I. D. Yoo, J. Antibiot., 1996, 49, 26.
1
352 | Org. Biomol. Chem., 2007, 5, 1351–1353
This journal is © The Royal Society of Chemistry 2007

View Online
2
B. R. Copp, K. F. Fulton, N. B. Perry, J. W. Blunt and M. H. G. Munro,
J. Org. Chem., 1994, 59, 8233.
14 J. M. P e´ rez, C. Avenda n˜ o and J. C. Men e´ ndez, Tetrahedron, 1995, 51,
6573.
3
4
For a review, see: M. Nyerges, Heterocycles, 2004, 63, 1685.
See, for instance: (a) R. W. Celing, P. D. Leeson, A. M. Moseley, R.
Baker, A. C. Foster, S. Grimwood, J. A. Kemp and G. R. Marshall,
J. Med. Chem., 1992, 35, 1942; (b) R. W. Carling, P. D. Leeson, A. M.
Moseley, J. D. Smith, K. Saywell, M. D. Trickelbank, J. A. Kemp, G. R.
Marshall, A. C. Foster and S. Grimwood, Bioorg. Med. Chem. Lett.,
15 (a) M. Behforouz, Z. Gu, W. Cai, M. A. Horn and M. Ahmadiam,
J. Org. Chem., 1993, 58, 7089; (b) M. Behforouz, Z. Gu, L. S. Stelzer,
M. Ahmadian and J. A. Scherschel, Tetrahedron Lett., 1997, 38, 2211.
16 General procedure: Imines 1 were prepared by the standard procedure
of refluxing equimolecular amounts of the suitable aniline and aldehyde
in ethanol for 3 h and filtering the solid that precipitated after
cooling. The suitable imine 1 (2 mmol) was dissolved in acetonitrile
(15 ml). To this stirred solution was added 1.2 eq. of methacrolein
dimethylhydrazone 2 (270 mg, 2.4 mmol) and indium trichloride
(45 mg, 10 mol%), and stirring was continued for the time period
specified in Table 1. After completion of the reaction, as indicated by
TLC, the reaction mixture was diluted with water (10 ml), extracted
1
993, 3, 65; (c) D. Paris, M. Cottin, P. Demonchaux, G. Augert, P.
Dupassieux, P. Lenoir, M. J. Peck and D. Jasserand, J. Med. Chem.,
1
and N. Nagata, PCT Int. Appl. 2001, WO 0127086; K. Hanada, K.
995, 38, 669; (d) K. Hanada, K. Furuya, K. Inoguchi, M. Miyakawa,
Furuya, K. Inoguchi, M. Miyakawa and N. Nagata, Chem. Abstr.,
2
001, 134, 295752.
5
For two recent reviews, see: (a) P. Abreu and P. S. Branco, J. Braz. Chem.
Soc., 2003, 14, 675; (b) P. Arya, S. Quevillon, R. Joseph, C.-Q. Wei, Z.
Gan, M. Parisien, E. Sesmilo, P. T. Reddy, Z.-X. Chen, P. Durieux, D.
Laforce, L.-C. Campeau, S. Khadem, S. Couve-Bonnaire, R. Kumar,
U. Sharma, D. M. Leek, M. Daroszewska and M. L. Barnes, Pure Appl.
Chem., 2005, 77, 163.
with CH
2
Cl
2
(4 × 10 ml), dried and evaporated. Purification was
achieved through silica gel column chromatography, using petroleum
ether–ethyl acetate (95 : 5, v/v) as eluent. Characterization data for one
representative example (compound 3a) follow. Data for all other com-
pounds, together with copies of representative spectra, can be found
in the Electronic Supporting Information†. (± )-(2S*,4S*)-4-Methyl-
6-methoxy-2-phenyl-1,2,3,4-tetrahydro-quinoline-4-carbaldehyde N,N-
dimethylhydrazone (3a): Viscous liquid. IR (neat) 3389.3, 2914.4,
6
7
(a) G. A. Kraus and N. Selvakumar, J. Org. Chem., 1998, 63, 9846;
(
6
b) V. Sridharan, C. Avenda n˜ o and J. C. Men e´ ndez, Tetrahedron, 2007,
−
1 1
3, 673.
A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996, 48,
5031.
3
2852.5, 1603.9, 1486.0, 1316.3, 1262.6, 1016.2 cm . H-NMR (CDCl ,
250 MHz) d 1.61 (s, 3H), 1.86 (dd, J = 12.9, 2.3 Hz, 1H), 2.08 (dd, J
= 12.9, 12.0 Hz, 1H), 2.15 (s, 3H), 2.25 (s, 3H), 2.78 (s, 6H), 3.89 (bs,
1H), 4.59 (dd, J = 12.0, 2.3 Hz, 1H), 6.70 (s, 1H), 6.81–8.83 (m, 2H),
1
8
9
L. S. Povarov, Russ. Chem. Rev., 1967, 36, 656.
S. Kobayashi, H. Ishitani and S. Nakagawa, Synthesis, 1995, 1195.
13
3
7.33–7.55 (m, 5H). C-NMR (CDCl , 62.9 MHz) d 18.0, 21.0, 28.4,
1
1
0 See, for instance: R. Nagarajan, S. Chitra and P. T. Perumal, Tetrahe-
dron, 2001, 57, 3419.
1 (a) S. Hermitage, J. A. K. Howard, D. J. R. G. Prichard, M. R. Probert
and A. Whiting, Org. Biomol. Chem., 2004, 2, 2451; (b) M. J. Alves,
N. A. Azoia and A. Gil-Fortes, Tetrahedron, 2007, 73, 727.
2 For reviews, see: (a) M. Behforouz and M. Ahmadian, Tetrahedron,
41.4, 44.0, 44.8, 53.7, 122.1, 126.5, 126.6, 127.2, 127.4, 128.2, 129.2,
130.0, 140.4, 145.0, 145.8. Anal. Calcd for C21 : C, 78.46; H, 8.47;
N, 13.07. Found: C, 78.23; H, 8.30; N, 12.78%.
27 3
H N
17 For precedent of a similar transimination promoted by indium
trichloride, see: G. Babu and P. T. Perumal, Tetrahedron, 1999, 55,
4793.
18 For a recent example, see: O. Jim e´ nez, G. de la Rosa and R. Lavilla,
Angew. Chem., Int. Ed., 2005, 44, 6521.
19 For a recent monograph on this subject, see: Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis, ed. J. Christoffers and
A. Baro, Wiley-VCH,Weinheim, 2005.
1
1
2
000, 56, 5259; (b) S. Jayakumar, M. P. S. Ishar and M. P. Mahajan,
Tetrahedron, 2002, 58, 379.
3 B. Serckx-Poncin, A.-M. Hesbain-Frisque and L. Ghosez, Tetrahedron
Lett., 1982, 23, 3261. For a review, see: F. Pautet, P. Nebois, Z. Bouaziz
and H. Fillion, Heterocycles, 2001, 54, 1095.
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1351–1353 | 1353