Facile synthesis of tetrahydroquinolines and julolidines through multicomponent reaction

Article abstract of DOI:10.1055/s-2006-947360

Aldehydes, anilines and enol ethers react in trifluoroethanol (TFE) through an aza-Diels-Alder reaction (Povarov reaction) to afford the corresponding substituted tetrahydroquinolines. This reaction occurs, without any catalyst, under sequential three-com

Full text of DOI:10.1055/s-2006-947360

LETTER
1899
Facile Synthesis of Tetrahydroquinolines and Julolidines through
Multicomponent Reaction
Synthesis
u
of
T
etrahydr
l
oquino
i
lines an
e
d Julolidin
n
es Legros,* Benoit Crousse,* Michèle Ourévitch, Danièle Bonnet-Delpon
Laboratoire BioCIS-CNRS, Faculté de Pharmacie-Paris Sud, rue J. B. Clément, 92296 Châtenay-Malabry, France
Fax +33(1)46835740; E-mail: benoit.crousse@cep.u-psud.fr; E-mail: julien.legros@cep.u-psud.fr
Received 18 May 2006
enophiles.3b,3c We now found that the reaction gives also
nice results under domino conditions with alkyl alde-
hydes. By mixing the aldehyde with the dienophile in
TFE, then followed by the slow addition of the aniline, the
Abstract: Aldehydes, anilines and enol ethers react in trifluoro-
ethanol (TFE) through an aza-Diels–Alder reaction (Povarov reac-
tion) to afford the corresponding substituted tetrahydroquinolines.
This reaction occurs, without any catalyst, under sequential three-
component conditions, allowing thus the use of aliphatic aldehydes. expected reaction occurs, affording thus tetrahydroquino-
In the presence of formaldehyde and an excess of dienophile, the
lines in good to very good yields (56–88%, Scheme 1).
product undergoes a second Povarov reaction affording new
julolidine derivatives.
R1
Key words: domino reaction, cycloaddition, fluorous alcohols,
heterocycles, solvent effect
HN
ArNH2
R1CHO
+
R2
TFE
R2
r.t., 2 h
56–88%
R
Multicomponent reactions (MCRs) constitute a very
attractive way to synthesize complex molecules due to
their numerous advantages (atom economy, simplicity to
implement, etc.).1 In this connection, the aza-Diels–Alder
reaction (also called imino-Diels–Alder or Povarov reac-
tion) is a useful transformation that offers an easy entry to
the tetrahydroquinoline family (Figure 1). This reaction is
formally a [4+2] cycloaddition between a Schiff base (as
diene) and an electron-rich olefin (as dienophile) in the
presence of a Lewis or Brønsted acid as promoter.2 The
Schiff base can be either preformed or formed in the pot
under three-component conditions. However, in the case
of unstable alkyl aldimines their in situ generation is re-
quired, and there are only rare reports dealing with such
substrates.2c,2e In connection with our studies on the use of
fluorinated alcohols (trifluoroethanol, TFE and hexa-
fluoroisopropanol, HFIP) as reaction medium,3a–d,4 we
now report herein the facile synthesis of tetrahydroquino-
lines under multicomponent conditions by using TFE as
solvent.3e,3f
1a–f
Scheme 1
The results reported in Table 1 show that the use of eno-
lizable aldehydes such as isobutyraldehyde (entry 2), iso-
valeraldehyde (entries 3–5) and hexanal (entry 6) gives
satisfactory to very good results. In all cases, the products
are obtained with the cis-configuration for the major iso-
mer. It is worth mentioning that the reaction conditions
are attractive: they are mild (neutral conditions and at r.t.
in open vessels for 2 h), no other effluent than water is re-
leased and only a slight excess of reagents is required (1.2
equiv). Thus this process could be interesting for large-
scale synthesis. However, one of the limitation of the re-
action stems from the dienophile: only electron-rich ole-
fins (vinyl ethers) are able to react in the reaction.5 This
method offers thus a simple alternative to access to 3-
alkyl substituted tetrahydroquinolines, whose access was
rather limited (see Figure 1 for the tetrahydroquinoline
numbering).
5
3
3
4
N
4
HN
6
2
1
2
1
Having in hand a straightforward and simple method to
synthesize tetrahydroquinolines, we decided to further ex-
plore its potential in view to access to structurally more
complex structures. In 1988, it was reported by Grieco
and Bahsas that the Povarov reaction between form-
aldehyde (in excess), aniline, and an electron-rich olefin
(in excess) under strong acidic conditions (CF3CO2H,
1 equiv), afforded tricyclic compounds related to the
benzoquinolizine family (julolidines, Figure 1).7 Juloli-
dine and its derivatives have found various applications:
fluorescent probes,8 photoconductive materials, potential
antidepressants and tranquilizers.9 The classical ways to
prepare julolidines involve the N-alkylation of tetrahydro-
quinolines or anilines followed by intramolecular electro-
7
8
10
9
tetrahydroquinoline
julolidine
Figure 1
Previously, we showed that TFE and HFIP were able to
promote, without any catalyst, the Povarov reaction be-
tween Schiff bases (aryl aldimines) and electron-rich di-
SYNLETT 2006, No. 12, pp 1899–1902
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947360; Art ID: G15306ST
© Georg Thieme Verlag Stuttgart · New York

1900
J. Legros et al.
LETTER
Table 1 Synthesis of Tetrahydroquinolines through Three-Component Reactiona
Entry
1
R1
Ph
Dienophile
Ar
Ph
Product
cis:transb
Yield (%)
Ph
HN
85:15
85
78
56
70
OEt
OEt
1a
i-Pr
HN
2
3
4
i-Pr
Ph
Ph
Ph
85:15
80:20
85:15
OEt
OEt
1b
i-Bu
HN
i-Bu
i-Bu
O
O
1c
i-Bu
HN
OEt
OEt
OEt
OEt
1d
i-Bu
HN
5
6
i-Bu
4-MeO-C6H4
70:30
85:15
60
88
OEt
OMe
1e
n-C5H11
HN
n-C5H11
Ph
OEt
1f
a According to Scheme 1.6
b Measured by 1H NMR.
philic cyclization.10 However, both these methods offer tetrahydroquinolines 1b and 1f according to our condi-
only few possibilities to introduce substituents on the tions (see Table 1) and, without isolating the product, a
skeleton. Later on, some other synthetic paths have been solution of formaldehyde (35% aq) and of olefin was
used, allowing the synthesis of few julolidines with sub- added in the medium. After only 1 hour reaction time, we
stituents on 3- and 1-positions.11
were delighted to see that the reaction was completed and
that the julolidines were formed (Scheme 2).12
According to Grieco’s report and to our work, we rea-
soned that we could use our method to prepare 1,3,7- By this protocol we obtained three new substituted julol-
trisubstituted julolidines (see Figure 1 for the julolidine idines 2, 3 and 4. Products 2 and 4 (with the same substit-
numbering). Indeed, by adding formaldehyde and a dieno- uent on the positions 1 and 7) were obtained in good yields
phile to a crude tetrahydroquinoline in TFE, the fluorous (72% and 80%, respectively) while the compound 3 (with
alcohol could also promote the second aza-Diels–Alder two different substituents) was obtained in low yield
reaction. In order to check our hypothesis, we prepared (35%). However, considering that the product is the result
Synlett 2006, No. 12, 1899–1902 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrahydroquinolines and Julolidines
1901
R1
Delpon, D.; Bégué, J.-P. Tetrahedron Lett. 2003, 44, 217.
(c) Di Salvo, A.; Spanedda, M. V.; Ourévitch, M.; Crousse,
B.; Bonnet-Delpon, D. Synthesis 2003, 2231. (d) Magueur,
G.; Crousse, B.; Ourévitch, M.; Bégué, J.-P.; Bonnet-
Delpon, D. J. Org. Chem. 2003, 68, 9763.
1. PhNH2
TFE, r.t., 1.5 h
N
R1CHO
+
R2
R3
R2
2. 35% aq HCHO
R3
1 h
TFE has already been used as a superior solvent in other
MCR’s: (e) Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.;
Kim, Y.; Lee, D. H. Tetrahedron Lett. 1998, 39, 7109.
(f) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett 2001, 3, 4079.
(4) Reviews on fluorous alcohols: (a) Bégué, J.-P.; Bonnet-
Delpon, D.; Crousse, B. Synlett 2004, 18. (b) Bégué, J.-P.;
Bonnet-Delpon, D.; Crousse, B. In Handbook of Fluorous
Chemistry; Gladysz, J. A.; Curran, D. P.; Horvath, I. T.,
Eds.; Wiley-VCH: Weinheim, 2004, 341.
i-Pr
i-Pr
N
N
O
EtO
OEt
OEt
2 (72%)
3 (35%)
(5) In the presence of styrene or N-vinyl pyrrolidine as
dienophile, no reaction occurred over 24 h, while the alkyl
aldimine decomposed in the medium.
n-C5H11
N
(6) Typical Procedure for the Synthesis of cis-4-Ethoxy-
1,2,3,4-tetrahydro-2-isopropylquinoline (1b).
EtO
OEt
Isobutyraldehyde (1.2 mmol, 86 mg) and ethyl vinyl ether
(1.2 mmol, 86 mg) were dissolved in TFE (1 mL) in a 5 mL
test tube. A solution of aniline (1 mmol, 93 mg) in TFE (1
mL) was then slowly added over 15 min to the previous
mixture under stirring. After stirring for 2 h, the solvent was
evaporated in vacuo. The crude product was then purified by
chromatography on florisil (cyclohexane–EtOAc, 9:1) to
afford 1b as yellow crystals (171 mg, 78%); mp 74–76 °C.
1H NMR (300 MHz, CDCl3): d = 1.02 (d, 3 H, J = 6.7 Hz),
1.03 (d, 3 H, J = 6.7 Hz), 1.33 (t, 3 H, J = 7.0 Hz), 1.75 (m,
2 H), 2.24 (ddd, 1 H, J = 2.5, 5.5, 12.1 Hz), 3.23 (ddd, 1 H,
J = 2.5, 5.3, 11.2 Hz), 3.63 (m, 1 H), 3.79 (m, 1 H), 4.68 (dd,
1 H, J = 5.6, 10.2 Hz), 6.51 (d, 1 H, J = 7.8 Hz), 6.71 (t, 1 H,
J = 7.4 Hz), 7.04 (t, 1 H, J = 7.6 Hz), 7.36 (d, 1 H, J = 7.6
Hz), NH not observed. 13C NMR (300 MHz, CDCl3):
d = 15.6, 18.0, 18.3, 30.3, 32.4, 56.1, 63.4, 74.1, 113.8,
117.1, 122.8, 126.9, 127.91, 144.6. Anal. Calcd for
C14H21NO (219.32): C, 76.67; H, 9.65; N, 6.39. Found: C,
76.33; H, 9.99; N, 6.35.
4 (80%)
Scheme 2
of four reaction steps, a 35% yield means more than 75%
yield per step. Concerning the relative configuration of
the julolidines, the last reaction step always afforded a sin-
gle stereomer, which had the groups in 3- and 7-positions
of the cis-configuration.13
In conclusion, we have reported a useful method to syn-
thesize tetrahydroquinolines with alkyl substituents in the
position 3 through three-component Povarov reaction, by
using TFE as solvent. Such compounds are still challeng-
ing to synthesize by this path. In the presence of aqueous
formaldehyde and of a dienophile these tetrahydroquino-
lines undergo a second reaction in the pot to yield new
cis,cis-trisubstituted julolidines as major isomers. The
reaction conditions are mild (no catalyst) and very simple
to implement.
(7) (a) Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29,
5855. (b) See also: Mellor, J. M.; Derryman, G. D.
Tetrahedron 1995, 21, 6115.
(8) Haidekker, M. A.; Brady, T. P.; Lichlyter, D.; Theodorakis,
E. A. Bioorg. Chem. 2005, 33, 415; and references therein.
(9) Vejdelek, Z.; Protiva, M. Collect. Czech. Chem. Commun.
1990, 55, 1290.
(10) (a) Glass, D. B.; Weissberger, A. Org. Synth., Coll. Vol. III;
Wiley: New York, 1955, 504. (b) Katayama, H.; Abe, E.;
Kaneko, K. J. Heterocycl. Chem. 1982, 19, 925. See also:
(c) Palma, A.; Carrillo, C.; Stashenko, E.; Kouznetsov, V.;
Bahsas, A.; Amaro-Luis, J. Tetrahedron Lett. 2001, 42,
6247. (d) Palma, A.; Agredo, J. S.; Carrillo, C.; Kouznetsov,
V.; Stashenko, E.; Bahsas, A.; Amaro-Luis, J. Tetrahedron
2002, 58, 8719.
References and Notes
(1) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Orru, R. V. A.; de Greef,
M. Synthesis 2003, 1471. (c) Bienaymé, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
(2) For leading references, see: (a) Povarov, L. S.; Makhailov,
B. M. Izv. Akad. Nauk. SSSR 1963, 955. (b) Narasaka, K.;
Shibata, T. Heterocycles 1993, 35, 1039. (c) Kobayashi, S.;
Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977.
(d) Crousse, B.; Bégué, J.-P.; Bonnet-Delpon, D. J. Org.
Chem. 2000, 65, 5009. (e) Cheng, D.; Zhou, J.; Saiah, E.;
Beaton, G. Org. Lett. 2002, 4, 4411. (f) Zhou, Y.; Jia, X.;
Li, R.; Liu, Z.; Liu, Z.; Wu, L. Tetrahedron Lett. 2005, 46,
8937. (g) Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron
Lett. 2006, 47, 3127. (h) See also: Jiménez, O.; de la Rosa,
G.; Lavilla, R. Angew. Chem. Int. Ed. 2005, 44, 6521.
(3) For some representative examples of the use of fluorous
alcohols in organic synthesis, see: (a) Ravikumar, K. S.;
Kesavan, V.; Crousse, B.; Bonnet-Delpon, D.; Bégué, J.-P.
Organic Syntheses, Vol. 80; Wiley: New York, 2003, 184.
(b) Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-
(11) (a) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem.
1996, 61, 3117. (b) Katritzky, A. R.; Luo, Z.; Cui, X.-L. J.
Org. Chem. 1999, 64, 3328.
(12) Typical Procedure for the Synthesis of cis,cis-1,7-
Diethoxy-3-isopropyljulolidine (2).
Isobutyraldehyde (1.2 mmol, 103 mg) and ethyl vinyl ether
(1.2 mmol, 86 mg) were dissolved in TFE (0.5 mL) in a 5 mL
test tube. A solution of aniline (1 mmol, 93 mg) in TFE (0.5
mL) was then slowly added over 15 min to the previous
mixture under stirring. After stirring for 2 h, a solution of
formaldehyde (35% aq; 2 mmol, 172 mg) and ethyl vinyl
ether (1.2 mmol, 86 mg) in TFE (1 mL) was added to the
reaction mixture. After further stirring for 1 h, the solvent
was evaporated in vacuo. The crude product was then
Synlett 2006, No. 12, 1899–1902 © Thieme Stuttgart · New York

1902
J. Legros et al.
LETTER
purified by filtration on florisil (cyclohexane–EtOAc, 7:3) to
afford 2 as an orange oil (218 mg, 72%). 1H NMR (400
MHz, CDCl3): d = 0.88 (d, 3 H, J = 6.7 Hz), 1.00 (d, 3 H,
J = 6.8 Hz), 1.25 (q, 6 H, J = 7.5 Hz), 2.00 (m, 4 H), 2.23
(oct, 1 H, J = 6.8 Hz), 3.00 (m, 1 H), 3.20 (m, 2 H), 3.60 (m,
2 H), 3.70 (m, 2 H), 4.26 (t, 1 H, J = 3.6 Hz), 4.42 (t, 1 H,
J = 5.7 Hz), 6.60 (t, 1 H, J = 7.4 Hz), 7.09 (d, 1 H, J = 7.7
Hz), 7.20 (d, 1 H, J = 7.4 Hz). 13C NMR (400 MHz, CDCl3):
d = 15.6, 15.7, 17.2, 20.5, 27.0, 27.5, 29.0, 42.6, 62.0, 63.3,
63.7, 73.0, 73.9, 114.9, 121.7, 122.6, 128.2, 129.5, 142.1.
H
H
ax Heq
Hax
3
5
N
Hax
7
1
O
OEt
H
Figure 2
(13) The cis-configuration was established by means of NOE
experiments (NOESY) on product 3. The correlations are
shown on the under drawing. Relative configurations of
products 2 and 4 have been deduced by analogy (Figure 2).
Synlett 2006, No. 12, 1899–1902 © Thieme Stuttgart · New York