Metal-free Bronsted acid catalyzed formal [3 + 3] annulation. Straightforward synthesis of dihydro-2H-chromenones, pyranones, and tetrahydroquinolinones

Article abstract of DOI:10.1021/jo901238y

(Chemical Equation Presented) Bronsted acids catalyze the addition of enolizable β-diketones, β-ketoesters, and vinylogous amides to α,β-unsaturated aldehydes to lead to substituted chromenones, pyranones, and tetrahydroquinolinones in good yields under mild reaction conditions via a formal [3 + 3] cycloaddition.

Full text of DOI:10.1021/jo901238y

pubs.acs.org/joc
Metal-Free Brønsted Acid Catalyzed Formal [3 þ 3] Annulation.
Straightforward Synthesis of Dihydro-2H-Chromenones, Pyranones,
and Tetrahydroquinolinones
Julie Moreau,† Claudie Hubert,† Jessika Batany,† Loic Toupet,‡ Thierry Roisnel,§
Jean-Pierre Hurvois,† and Jean-Luc Renaud*,^
†
‡
Sciences Chimiques de Rennes, Catalyse et Organometalliques, UMR 6226, Institut de Physique de Rennes,
ꢀ
Groupe Matiere Condensee et Materiaux, UMR 6626, Sciences Chimiques de Rennes, Diffraction
§
ꢁ
ꢀ
ꢀ
Rayons-X, UMR 6226, CNRS-Universite de Rennes 1, Campus de Beaulieu-35042 Rennes Cedex, France,
ꢀ
^
ꢀ
and Laboratoire de Chimie Moleculaire et Thioorganique, UMR 6507, INC3M, FR 3038,
ꢀ
ENSICAEN-Universite de Caen, 14050 Caen, France
jean-luc.renaud@ensicaen.fr
Received June 17, 2009
Brønsted acids catalyze the addition of enolizable β-diketones, β-ketoesters, and vinylogous amides
to R,β-unsaturated aldehydes to lead to substituted chromenones, pyranones, and tetrahydroqui-
nolinones in good yields under mild reaction conditions via a formal [3 þ 3] cycloaddition.
Introduction
fused to a six-membered ring. These fundamental structural moi-
eties represent a dominant heterocycle core for several organic
transformations and are embedded in several natural products,1
such as arisugacins2 and pyripyropenes3 which contain a chro-
manone subunit, cordipyridones,4 hongoquercins,5 forskolin,6
and rhododaurichromanic acids7 (Figure 1). Elegant approaches
to these intermediates and their use in synthesis have already
Oxadecalins, chromanes, and pyranocoumarins contain a te-
trahydropyran or a pyran core in which the pyranyl moiety is
*To whom correspondence should be addressed. Fax: 33(0)231452877.
Phone: 33(0)231452842.
(1) For recent reviews, see: (a) Larrosa, I.; Romea, P.; Urpı, F. Tetra-
hedron 2008, 64, 2683. (b) Tang, Y.; Oppenheimer, J.; Song, Z.; You, L.;
Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785.
(4) Isaka, M.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y.
J. Org. Chem. 2001, 66, 4803.
~
(2) For isolation and biological activities of arisugacin, see: (a) Omura,
S.; Kuno, F.; Otoguro, K.; Sunazuka, T.; Shiomi, K.; Masuma, R.; Iwai, Y.
J. Antibiot. 1995, 48, 745. (b) Kuno, F.; Otoguro, K.; Shiomi, K.; Iwai, Y.;
(5) Roll, D. M.; Manning, J. K.; Carter, G. T. J. Antibiot. 1998, 51, 635.
(6) (a) Bhat, S. V; Bajwa, B. S.; Dornauer, H.; de Souza, N. J.; Fehlhaber,
H.-W. Tetrahedron Lett. 1977, 18, 1669. (b) Bhat, S. V; Bajwa, B. S.;
Dornauer, H.; de Souza, N. J. J. Chem. Soc., Perkin Trans. 1 1982, 767.
(7) Kashiwada, Y.; Yamzaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioko,
T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-Natschke,
S. L.; Lee, K.-H. Tetrahedron 2001, 57, 1559.
~
Omura, S. J. Antibiot. 1996, 49, 742. (c) Kuno, F.; Shiomi, K.; Otoguro, K.;
~
Sunazuka, T.; Omura, S. J. Antibiot. 1996, 49, 748. (d) Otoguro, K.; Kuno,
~
F.; Omura, S. Pharmacol. Ther. 1997, 76, 45. For C-H, see: (e) Otoguro, K.;
Shiomi, K.; Yamaguchi, Y.; Arai, N.; Sunazuka, T.; Masuma, R.; Iwai, Y.;
~
Omura, S. J. Antibiot. 2000, 53, 50.
DOI: 10.1021/jo901238y
r
Published on Web 11/12/2009
J. Org. Chem. 2009, 74, 8963–8973 8963
2009 American Chemical Society

Moreau et al.
JOCArticle
SCHEME 1. General Brønsted Acid Catalyzed Synthesis of
7,8-Dihydro-2H-Chromen-5(6H)-ones, Pyrano[3,2-c]chromen-
5(2H)-ones, and 1,2,7,8-Tetrahydroquinolin-5(6H)-ones
reactions have been described using such organocatalysts.17,18
These catalysts do not contain any metals; they are stable under a
large set of reaction conditions and are moisture insensitive.
Among the known carbonyl activators, Brønsted acids have
appeared as catalysts of choice in a large variety of synthetically
useful reactions in organic chemistry.
FIGURE 1. Natural compounds containing a pyran core.
been described by several groups using either R,β-unsaturated
iminium salts as activated electrophiles,8 Lewis acids as cata-
lysts,9 or a tandem Stille-oxo-electrocyclization reaction.10-13
1,3-Dicarbonyl derivatives constitute important synthetic
intermediates as they incorporate electrophilic and nucleo-
philic functionalities.14 These derivatives can be condensed
to R,β-unsaturated aldehydes to form a 2H-pyran motif via a
formal [3 þ 3] cycloaddition (Scheme 1).15 From a synthetic
point of view, this type of approach allows the formation of
multiple bonds, rings, and new stereogenic centers. Cycload-
ditions and related reactions are commonly promoted by
heat, light, high pressure, sonication, or by the use of
transition metal and Lewis acids as catalysts.16 More re-
cently, activation by small organic molecules has emerged as
an important tool in catalysis, and a large number of
Several groups have already described the synthesis of
2H-pyran-containing derivatives from cyclic β-diketones
and R,β-unsaturated aldehydes in the presence of Lewis
acids. In 2002, Lee et al. reported the use of InCl3 (50 mol%)
as the best Lewis acid. The condensation was carried out in
refluxing acetonitrile, and yields ranged from 40 to 70%.19
Later, Hsung et al. reported a similar reaction in dichlor-
omethane at room temperature, in the presence of 1 equiv of
BF3 Et2O,20 affording the expected heterocycles in moder-
3
ate to high yields. In a complementary approach, the same
group developed a catalyst-free addition of 1,3-dicarbonyl
compounds on R,β-unsaturated iminium salts.21 These imi-
nium salts reacted in sealed tubes with 1,3-diketones at
temperatures ranging from 80 to 150 ꢀC and provided
the desired 2H-chromenones in moderate to good yields.
Although successful, this approach suffered from several
drawbacks such as the use of moisture sensitive iminium salts
and harsh reaction conditions.
(8) (a) Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C.
D.; Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn,
J. M.; Liu, J.; Sklenicka, H. M.; Wei, L.-L.; Zehnder, L. R.; Zificsak, C. A.
J. Org. Chem. 2003, 68, 1729. (b) Cole, K. P.; Hsung, R. P. Chem. Commun.
2005, 5784. (c) Cravotto, G.; Nano, G. M.; Tagliapietra, S.Synthesis 2001, 1, 49.
(9) (a) Kurdyumov, A. V.; Lin, N.; Hsung, R. P.; Gullickson, G. C.; Cole,
K. P.; Sydorenko, N.; Swidorski, J. J. Org. Lett. 2006, 8, 191. (b) Lee, Y. R.;
Kim, D. H.; Shim, J.-J.; Kim, S. K.; Park, J. H.; Cha, J. S.; Lee, C.-S. Bull.
Korean Chem. Soc. 2002, 23, 998. (c) Appendino, G.; Cravotto, G.;
Giovenzana, G. B.; Palmisano, G. J. Nat. Prod. 1999, 62, 1627.
(10) Tambar, U. K.; Kano, T.; Zepernick, J. F.; Stoltz, B. M. Tetrahedron
Lett. 2007, 48, 345.
Organocatalyzed approaches were also reported in the
literature. Following the pioneering work of Hua et al.
devoted to proline-mediated pyran synthesis,22 several
groups introduced ethylenediamine diacetate as organoca-
talyst for the synthesis of tetrahydropyrans.23 Thus, Lee and
collaborators described the synthesis of one chromenone
derivative catalyzed by ethylenediamine diacetate.24 They
also reported the reaction of R,β-unsaturated aldehydes with
(11) (a) Li, C.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2000, 122,
10484. (b) Li, C.; Johnson, R. P.; Porco, J. A. J. Am. Chem. Soc. 2003, 125, 5095.
(12) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y
Angew. Chem., Int. Ed. 2002, 41, 3192.
(13) (a) Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003, 125, 9554.
(b) Malerich, J. P.; Maimone, T. J.; Elliott, G. I.; Trauner, D. J. Am. Chem.
Soc. 2005, 127, 6276.
(14) For recent reviews on the reactivity of 1,3-dicarbonyl compounds,
see: (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
4957. (b) Rodriguez, J. Synlett 1999, 505. (c) Filippini, M.-H.; Rodriguez, J.
Chem. Rev. 1999, 99, 27.
(15) For a recent review, see: Hsung, R. P.; Kurdyumov, A. V.;
Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(16) For reviews on cycloaddition, see: (a) Lautens, M.; Klute, W.; Tam,
W. Chem. Rev. 1996, 96, 49. (b) Yamamoto, H.; Futatsugi, K. Angew. Chem.,
Int. Ed. 2005, 44, 1924.
(17) (a) Taylor, M. S.;Jacobsen,E.N. Angew. Chem., Int. Ed.2006, 45, 1520.
(b) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418. (c) de Figueiredo, R. M.;
Christmann, M. Eur. J. Org. Chem. 2007, 2575. (d) List, B. Chem. Rev. 2007,
107, 5413. (e) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(18) For a review on organocatalyzed cycloadditions, see: Shen, J.; Tan,
C.-H. Org. Biomol. Chem. 2007, 3229.
(19) Lee, Y. R.; Kim, D. H.; Shim, J.-J.; Kim, S. K.; Park, J. H.; Cha, J. S.;
Lee, C.-S. Bull. Korean Chem. Soc. 2002, 23, 998.
(20) Kurdyumov, A. V.; Lin, N.; Hsung, R. P.; Gullickson, G. C.; Cole,
K. P.; Sydorenko, N; Swidorski, J. J. Org. Lett. 2006, 8, 191.
(21) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen,
S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690. (b) Shen, H. C.; Wang, J.; Cole,
K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.; Hsung, R. P.;
Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Sklenicka, H. M.;
Wei, L.-L.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68, 1733.
(22) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J.; Robinson, P. D.;
Newell, S. W.; Perchellet, E. M.; Ladesich, J. B.; Freeman, J. A.; Perchellet,
J.-P.; Chiang, P. K. J. Org. Chem. 1997, 62, 6888.
(23) (a) Huang, C.-N.; Kuo, P.-Y.; Lin, C.-H.; Yang, D.-Y. Tetrahedron
2007, 63, 10025. (b) Hu, H.; Harrison, T. J.; Wilson, P. D. J. Org. Chem. 2004,
69, 3782. (c) Tietze, L. F.; Kiedrowski, G. V.; Berger, B. Synthesis 1982, 683.
(24) Lee, Y. R.; Kim, D. H. Synthesis 2006, 603.
8964 J. Org. Chem. Vol. 74, No. 23, 2009

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resorcinol derivatives25 or with 4-hydroxy-2-quinolones26
catalyzed by this diammonium salt. More recently, Rueping
et al. showed that the condensation of β-diketones with
R,β-unsaturated aldehydes, in the presence of diarylproline
derivatives as catalysts, yielded the unexpected 2-hydroxy-4-
substituted chromane derivatives. The latter may come from
a 1,4-addition of the keto-enolic functions to the in situ
generated iminium salts.27 Interestingly, in the presence of
L-proline, the catalytic process followed another pathway
and provided, as major product, the conjugated dienone
resulting from a Knoevenagel condensation between the
unsaturated aldehyde and the diketone.28
SCHEME 2. Synthesis of 1,4-Dihydropyridines Catalyzed by
Phosphoric Acid 6 or 7
When we started our studies,29,30 little was known on the
activation of unsaturated carbonyl compounds by phospho-
ric acid derivatives and no general studies on the synthesis of
pyran-containing derivatives were proposed in the litera-
ture.31,32 We report here our contribution to the synthesis of
several 7,8-dihydro-2H-chromen-5(6H)-one and pyrano-
[3,2-c]chromen-5(2H)-one derivatives from β-diketones
and conjugated enals in the presence of a catalytic amount
of Brønsted acid under mild reaction conditions (Scheme 1).
This new methodology is then extended further to the
synthesis of some substituted 1,2,7,8-tetrahydroquinolin-
5(6H)-ones and octahydrochromanones.
TABLE 1. Brønsted Acids Comparison for the Synthesis of 7,8-Dihy-
dro-2H-Chromen-5(6H)-one 1aa
entry
catalyst
conversion (%)c
yield (%)d
1
2
3
4
5
6
-
6
0
100
96
96
97
60
0
70
73
70
66
59
7
HBF4
b
Results and Discussion
PTSAb
PPTSb
We have recently reported a simple and efficient prepara-
tion of several 1,4-dihydropyridines 8 from the enaminoe-
sters 9 and R,β-unsaturated aldehydes 3, catalyzed by the
phosphoric acids 6 and 7 (Scheme 2).29 These catalysts
activated the unsaturated aldehydes and allowed the addi-
tion of the enaminoesters 9. We were also pleased to find that
the same organocatalysts opened a rapid access to some
7,8-dihydro-2H-chromen-5(6H)-ones 1.30
aWith 0.5 mmol of β-diketone 2a, 0.75 mmol of R,β-unsaturated
aldehyde 3a, 0.025 mmol of catalyst (5 mol%), 5 mL of CH2Cl2, 150 mg
of Na2SO4 (1.05 mmol). bReaction was performed with 15 mol% of
catalyst. cAs determined by 1H NMR spectroscopy. dIsolated yield after
purification on silica gel.
outlined. The use of the bulkier catalyst 7 had a slight effect
on the reactivity (entry 3, Table 1). A higher catalyst loading
(15 mol%) was required with Brønsted acids such as HBF4,
PTSA, or PPTS to ensure a complete conversion. Then, in
these conditions, 1a was isolated in yields ranging from 59 to
70% (entries 4-6, Table 1). In view of these preliminary
results, the study has been carried on with 7 as catalyst.
To extend the scope of the reaction, the condensation of
various R,β-unsaturated aldehydes 3 with the β-diketone 2a
was investigated (Table 2). Reactive aldehydes such as
2-methylbutenal 3a, 3-methylbutenal 3b, and citral 3c led
to the corresponding chromenone derivatives 1a-c in high
yields (entries 1-3, Table 2). This is an exceedingly mild
method for such an annulation reaction. Aldehydes such as
crotonaldehyde 3d and pentenal 3e led to the expected
adducts 1d and 1e but in lower yields (16 and 15%,
respectively). To improve the yields and the reaction rates,
several experimental conditions were evaluated. High con-
versions and yields were then obtained by heating at 60 ꢀC in
toluene. Compounds 1d and 1e were isolated in 78 and 81%
yields, respectively (entries 8 and 10, Table 2). With aromatic
aldehydes such as cinnamaldehyde 3f and p-nitrocinnamal-
dehyde 3g, a catalyst loading of 15 mol % was necessary to
ensure the completion of the reaction in dichloromethane at
room temperature. The chromenone derivatives 1f,g were
then obtained in 72 and 61% yields, respectively (entries 11
and 12, Table 2).
Synthesis of 7,8-Dihydro-2H-Chromen-5(6H)-ones 1. As a
model reaction, we chose the reaction between 2a and the
enal 3a. Only starting materials were isolated from the
reaction mixture when a blank reaction was carried out
(entry 1, Table 1). As shown in Table 1, several Brønsted
acids were investigated. The addition of 5 mol% of 6 in the
reaction medium promoted the formation of 7,8-dihydro-
2H-chromen-5(6H)-one 1a, which was then isolated in 70%
yield (entry 2, Table 1). It is worth mentioning that the use of
ethylenediamine diacetate as catalyst led to 1a in a compar-
able yield.24 Nevertheless, in this work, the scope and
limitations of this synthetic transformation were not
(25) (a) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46,
7539. (b) Lee, Y. R.; Xia, L. Synthesis 2007, 3240. (c) Lee, Y. R.; Kim, J. H.
Synlett 2007, 2232. (d) Lee, Y. R.; Xia, L. Tetrahedron Lett. 2008, 49, 3283.
(e) Park, B. H.; Lee, Y. R.; Lyoo, W. S. Synthesis 2009, 2146.
(26) Lee, Y. R.; Choi, J. H.; Trinh, D. T. L.; Kim, N. W. Synthesis 2005,
3026.
(27) (a) Rueping, M.; Sugiono, E.; Merino, E. Chem.;Eur. J. 2008, 14,
6329. (b) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal. 2008, 350,
2127.
(28) Goswami, P; Das, B. Tetrahedron Lett. 2009, 50, 897.
(29) Moreau, J.; Duboc, A.; Hubert, C.; Hurvois, J.-P.; Renaud, J.-L.
Tetrahedron Lett. 2007, 48, 8647.
(30) Hubert, C.; Moreau, J.; Batany, J.; Duboc, A.; Hurvois, J.-P.;
Renaud, J.-L. Adv. Synth. Catal. 2008, 350, 40.
(31) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem., Int. Ed. 2007, 46, 2097.
(32) For recent works, see: (a) Rueping, M.; Nachtsheim, B. J.; Moreth,
S. M.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593. (b) Rueping, M.;
Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47, 5836. (c) Rueping, M.;
Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78.
Under these optimized reaction conditions, several analo-
gues were synthesized starting from 2b and aldehydes 3a-e
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TABLE 2. Synthesis of 7,8-Dihydro-2H-Chromen-5(6H)-ones 1a-ga
aWith 0.5 mmol of β-diketone 2a, 0.75 mmol of R,β-unsaturated aldehyde, 0.025 mmol of 7 (5 mol%), 5 mL of CH2Cl2, 150 mg of Na2SO4
(1.05 mmol). bIsolated yield after purification on silica gel. cToluene, 60 ꢀC. dReaction was performed with 15 mol% of catalyst.
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TABLE 3. Synthesis of Compounds 10a-fa
aWith 0.5 mmol of β-diketone 2b, 0.75 mmol of R,β-unsaturated aldehyde, 0.025 mmol of 7 (5 mol%), 5 mL of toluene, 60 ꢀC, 150 mg of Na2SO4
(1.05 mmol). bIsolated yield after purification on silica gel.
FIGURE 2. 2H-Chromenones 10f (see Table 1 in the Supporting
Information for an ORTEP drawing).
FIGURE 3. β-Diketones 2c and 2d.
(Table 3). Compared with 2a, the reactivity was lower. For
example, aldehydes 3b and 3d furnished the corresponding
structure of one crystal confirmed the regioselectivity of
this reaction (Figure 4).
products 10b and 10d in low to moderate yields (entries 2 and
4, Table 3). All other yields were good, and the 2-substituted
7,8-dihydro-2H-chromen-5(6H)-ones 10 were isolated in up
to 90% yield.
10f was isolated in 50% yield and in high diastereoselec-
tivity (de = 96%) from the optically active (-)-myrtenal 3h
and the β-diketone 2b. A slow crystallization of 10f in ether
allowed the formation of suitable crystals for X-ray analysis.
The structure showed the relative configuration of the newly
formed stereogenic center C-10 (Figure 2).
Thus, this protocol proved to be general for the prepara-
tion of several 2-substituted 7,8-dihydro-2H-chromen-
5(6H)-ones. It is worth mentioning that the use of Brønsted
acid 7 led to the same 2H-chromenones obtained with
iminium salts8 and Lewis acids,9 but in milder reaction
conditions (lower catalyst loading, lower temperature).
Synthesis of Pyrano[3,2-c]chromen-5(2H)-ones 11 and
7-Methyl Pyrano[4,3-b]pyran-5(2H)-ones 12. Having estab-
lished the scope of this reaction with cyclic β-diketones, we
extended it to more sterically hindered β-ketolactones such
as 4-hydroxycoumarin 2c and 6-methyl-4-hydroxy-2-pyrone
2d (Figure 3).
In the optimized reaction conditions (toluene, 60 ꢀC, 5
mol % of catalyst 7), we were pleased to note that the
reactivity of these β-ketolactones was excellent and led
cleanly to the corresponding heterocycles. Except with the
aromatic aldehyde 3f, yields greater than 88% were
obtained from the aldehydes 3a-e and 3i (entries 1-5,
Table 4). Starting from the methyl pyrone 2d, almost all
compounds were obtained in quantitative yields (entries
8-15, Table 4). Whereas most of these substrates were
isolated as oils, 11a crystallized in diethyl ether. An X-ray
The reaction of 2d with (-)-myrtenal 3h afforded the
corresponding tricyclic compound in a moderate 52% yield
(entry 14, Table 4), but with a gratifying diastereoisomeric
excess of 88% (as determined by NMR analysis). A nuclear
Overhauser effect analysis provided us the relative config-
uration of compound 12g as shown in Table 4 (entry 14). The
proton of the newly formed stereogenic center and the
methylene bridge of the myrtenal moiety are in a syn config-
uration.
Synthesis of Tetrahydroquinolinones 14. Tetrahydroquino-
linones 14 could also be prepared from vinylogous amide 13
via this phosphoric acid catalyzed formal [3 þ 3] cycloaddi-
tion (Scheme 3).
Following our ongoing work on Lewis acid catalyzed
synthesis of functionalized β-enaminoesters and β-enami-
nones,33 we were able to isolate at room temperature in
dichloromethane the N-benzylamide 13 in 75% yield
(Scheme 4).
At room temperature, in the presence of 5 mol% of
phosphoric acid 7, no reaction occurred between 13 and 3j
(entry 1, Table 5). An increase of the temperature led to an
improvement of the reactivity. At 60 ꢀC, the catalytic formal
[3 þ 3] cycloaddition between 13 and pentenal 3j provided
not only the desired compound 14a in a moderate conversion
of 50% but also numerous side products. However, at 90 ꢀC,
the tetrahydroquinolinone 14a was isolated cleanly as a
(33) (a) Kaur Vohra, R.; Renaud, J.-L.; Bruneau, C. Collect. Czech.
Chem. Commun. 2005, 70, 1943. (b) Kaur Vohra, R.; Renaud, J.-L.; Bruneau,
C. Synthesis 2007, 731. (c) Hebbache, H.; Hank, Z.; Boutamine, S.; Meklati,
M.; Bruneau, C.; Renaud, J.-L. C. R. Chimie 2008, 612.
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TABLE 4. Synthesis of 2H-Pyrans 11 and 12a
aWith 0.5 mmol of β-diketone 2c or 2d, 0.75 mmol of a R,β-unsaturated aldehyde, 0.025 mmol of 7 (5 mol%), 5 mL of toluene, 60 ꢀC, 150 mg of
Na2SO4 (1.05 mmol). bIsolated yield after purification on silica gel.
SCHEME 3
FIGURE 4. Compound 11a (see Table 1 in the Supporting Infor-
mation for an ORTEP drawing).
et al.,34 but the reaction conditions were here again more
single regioisomer in a gratifying yield of 70%. More polar
harsh (150 ꢀC in a sealed tube) and moisture sensitive
solvent such as ethanol or dimethylformamide seems to
R,β-unsaturated imminium salts have to be handled. As a
inhibit the reaction as no tetrahydroquinolinone was iso-
consequence, this new procedure opens an easy access to a
lated. The use of such cyclic vinylogous amide 13 in a formal
variety of substituted tetrahydroquinolinones.
[3 þ 3] cycloaddition had already been described by Hsung
Having defined the best reaction conditions, various
aldehydes were engaged with compound 13. With citral 3c,
(34) (a) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.;
McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 3, 509. (b) Wei,
L.-L.; Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem., Int.
Ed. 2001, 40, 1517.
the corresponding tetrahydroquinolinone was obtained in
81% yield (compound 14b, Figure 5). Moreover, the formal
[3 þ 3] cycloaddition in the presence of cinnamaldehyde and
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Moreau et al.
JOCArticle
SCHEME 4. Preparation of the Vinylogous Amide 13
FIGURE 6. Chiral phosphoric acid catalysts 15.
TABLE 5. Solvent and Temperature Studies for the Synthesis of 14aa
enhancement of the enantioselectivity was noticed (entry 6,
Table 6). The use of cyclohexanedione 2b instead of
4-hydroxycoumarin 2d led to 10d in high yield at room
temperature but without any enantioselectivity (entry 7,
Table 6).
Starting from the vinylogous amide 13 and cinnamalde-
hyde 3f, a rapid screening of reaction conditions revealed
that the tetrahydroquinolinone 14c could be obtained in high
yields at 90 ꢀC in toluene but always as a racemic mixture,
whatever the catalyst used (Scheme 5). As far as we know, no
enantioselective reaction of 1,3-diketones or related deriva-
tives with R,β-unsaturated aldehydes catalyzed by phospho-
ric acids has been described in the literature. Similar
approach was indeed described by Rueping, using diaryl-
prolinol ether as catalyst.5 However, as already mentioned,
this catalysis led to the 4-substituted 2H-pyrans and not to
the 2-substituted 2H-pyrans. In our reaction conditions, the
absence of enantioselectivity might be due to the reaction
pathway (vide infra).
entry
solvent
temperature
yield (%)b
1
2
3
4
5
toluene
toluene
toluene
ethanol
DMF
rt
nr
60
90
90
90
50
70
nrc
nrc
aWith 0.5 mmol of 13, 0.75 mmol of R,β-unsaturated aldehyde 3j,
5 mol% of catalyst 7, 150 mg of Na2SO4 (1.05 mmol), 5 mL of toluene.
bIsolated yield after purification on silica gel. cNo reaction.
Synthesis of 3,4,7,8-Tetrahydro-2H-chromen-5(6H)-one 16
and Octahydrochromen-5-one 17. The first approach toward
modification of the pyran core was the hydrogenation of
alkenes to produce either the corresponding 3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-ones or the octahydrochromen-5-
ones. Hydrogenation of the C3-C4 double bound of 10a
has successfully been carried out in acetic acid, in the
presence of 10 mol % of Pd/C, under 10 psi of hydrogen.
16 was produced in 70% yield. In these conditions, the
C5-C6 double bound was not reduced (Scheme 6). An
increase of the pressure to 100 psi allowed the reduction of
both alkenes. The chromanone 17 was then isolated in 52%
yield (Scheme 6). According to the 1H and 13C NMR data,
only one diastereoisomer was obtained. Unfortunately, we
have not been able to crystallize this derivative and cannot
assign the relative and absolute stereochemistry of the new
stereocenters.
FIGURE 5. Extension to different tetrahydroquinolinones.
13 gave rise to the tetrahydroquinolinone 14c in a very good
yield (82%).
A recently emerging direction for organocatalysis has
resulted from the independent initial discoveries by
Akiyama35 and Terada36 that chiral phosphoric acids can
provide excellent enantioselectivities for a broad range
of highly enantioselective addition reactions on imines
which involve chiral contact ion pairs generated in situ.37
As we have already shown that these chiral phosphoric
acids, derived from the optically active (S)-(-)-binaphthol
(Figure 6), could promote the synthesis of enantioenriched
1,4-dihydropyridines,29 we anticipated that the same chiral
catalysts could furnish the desired optically enriched chro-
menones.
The structures of all compounds were assigned on the basis
1
of H NMR, 13C NMR, and mass spectra analysis. The
X-ray diffraction structures of compounds 11a and 10f
(see Supporting Information, Table 1) and NMR analysis
(1H, 13C, HMBC, and HMQC) revealed without any ambi-
guity the formation of the 2-substituted isomers. Two dif-
ferent mechanism pathways might explain the formation of
this regioisomer. On one hand, according to route A (Scheme 7),
a direct Michael addition of the enol to the unsaturated
aldehyde (both activated by the phosphoric acid) might lead
to the intermediate 18. A subsequent aldolization/dehydra-
tation sequence might liberate the expected heterocyclic
derivatives 1, 10-12, or 2-substituted 2H-dihydropyridine
type 14. On the other hand, a Knoevenagel condensation
between the enol derivative of the β-diketone or the vinylo-
gous amide and the electrophilic carbonyl of the enal might
In a first set of experiments, reactions were carried out
between the 4-hydroxycoumarin 2c and crotonaldehyde 3d
at 40 ꢀC in toluene. Whatever the catalyst used, the yields
were high but the enantioselectivities were poor (below 10%,
Table 6). We attempted to improve these results by decreas-
ing the temperature. At room temperature, a low conversion
was obtained even after a long reaction time, and no
(35) For recent reviews, see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999. (b) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(36) For a recent review, see: Terada, M. Chem. Commun. 2008, 4097.
(37) For recent reviews, see: (a) Suzuki, K.; Seno, A.; Tanabe, H.; Ueno,
K. Synth. Met. 2004, 14, 89. (b) You, S.-L. Chem. Asian J. 2007, 2, 820.
(c) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed.
2005, 44, 1758.
J. Org. Chem. Vol. 74, No. 23, 2009 8969

Moreau et al.
JOCArticle
TABLE 6. Attempts at the Enantioselective Synthesis of 11d or 14ca
entry
catalyst
compound
yield (%)b
ee (%)c
1
2
3
4
5
6
7
15a
15b
15c
15d
15e
15b
15b
11d
11d
11d
11d
11d
11d
10d
99
99
99
99
7
8
6
7
7
6
0
99
15d
70d
aWith 0.5 mmol of β-diketone 10d or 11d, 0.75 mmol of R,β-unsaturated aldehyde, 5 mol% of catalyst 15, 150 mg of Na2SO4 (1.05 mmol), 5 mL of
toluene, 40 ꢀC. bIsolated yield after purification on silica gel. cEnantiomeric excesses were measured by chiral HPLC analysis. dReaction was run at room
temperature for 8 days.
SCHEME 5. Enantioselective Attempts for the Synthesis of 14c
triene intermediate. Then, the chiral part of the catalyst
cannot have any influence on the new formed stereogenic
center.
This route B of the proposed mechanism was also pre-
viously favored by Hsung21b and Yang,23a who underlined
the presence of different oxatrienes. In our hands, as men-
tioned above, when aromatic aldehydes and dicarbonyl
derivatives 2c and 2d were engaged in the catalytic process,
we observed by NMR analysis unsaturated compounds and
not the expected cycloadduct (see Supporting Information).
Several attempts to purify them were, however, unsuccessful.
In the nitrogen series, during the optimization studies, triene
compounds were also isolated (in low yields, <15%) when
the reaction was run at 60 ꢀC. Such triene intermediates can
also be obtained as major compounds at room temperature,
but a simple heating at 90 ꢀC led to the cycloadducts. Then,
all of these results/observations provided some clues to favor
route B in this phosphoric acid catalysis.
SCHEME 6. Selective Hydrogenation of 10a and 10f
Conclusion
We have developed the first phosphoric acid catalyzed
formal [3 þ 3] cycloaddition allowing the synthesis of a
variety of substituted chromenones, pyranones, and tetra-
hydroquinolinones from cyclic β-diketones, β-ketolactones,
or vinylogous amides and R,β-unsaturated aldehydes. These
reactions proceeded in mild conditions via carbonyl activa-
tion. Very good yields were obtained in the optimized
reaction conditions, and β-ketolactones offered the awaited
products in quantitative yields with almost all aldehydes.
Syntheses involving optically pure aldehydes showed good
diastereoisomeric excesses, and hydrogenation tests high-
light the possibility to obtain 1-oxadecalin-type motives with
also a very high level of diastereoselectivity. Oxatriene
compounds, observed by NMR analysis, were proposed as
intermediates of the catalytic cycle. These clues supported a
mechanism involving a sequential Knoevenagel condensa-
tion and a 6π-electron electrocyclization. The low or absence
of enantioselectivity was explained either by too weak inter-
actions between the chiral phosphoric acids and the hetero-
trienes or by noncatalyzed electrocyclization.
furnish the oxa- or azatriene intermediate 21, which might
undergo a [3 þ 3] electrocyclization to form the heterocyclic
compounds (route B, Scheme 7). This condensation/electro-
cyclization might also occur through a double activation of
the catalyst, which can play both the role of a Brønsted acid
(to activate the aldehydes via hydrogen bonding) and the role of
Lewis base (to activate the enol form of the diketone or the
vinylogous amide). Then, the activation of both partners
of this reaction by the same catalyst might explain the greater
reactivity all along the catalytic process. Furthermore,
the almost absence of enantioselectivities, whatever the
catalyst used for the cycloaddition, seems to be a direct
consequence of the electrocyclization approach and might
be explained according to this mechanism. Indeed, even if a
phosphoric acid catalyst is necessary to promote the oxa- or
azatriene synthesis, either the [3 þ 3] electrocyclization does
not require any acid activation to occur or, as depicted
in Scheme 7, the catalyst is not tightly bonded to the
8970 J. Org. Chem. Vol. 74, No. 23, 2009

Moreau et al.
JOCArticle
SCHEME 7. Two Likely Mechanisms for the Formation of 2H-Pyrans and 1,2-Dihydropyridines
Experimental Section
successively added under argon phosphoric acid 6 or 7 (5 mol
%), toluene (5 mL), the β-diketone or β-ketoester (0.5 mmol),
and the appropriate unsaturated aldehyde (0.6 mmol). The
mixture was stirred at 60 ꢀC until completion by TLC analysis.
The solution was then filtered on a plug of Celite and concen-
trated under vacuum. The crude oil was purified on silica gel
by flash chromatography (eluent: petroleum ether/diethyl
ether, 9/1).
General: Purifications by column chromatography were
performed with 70-230 mesh silica gel. TLC analysis was
carried out on alumina sheets precoated with silica gel (60
F254) and visualized with UV light; NMR spectra were recorded
with a Bruker Avance DRX 500 FT spectrometer [200.13 MHz
(1H) and 50.33 MHz (13C)] or a Bruker AH 300 FT spectrometer
[300.13 MHz (1H) and 75.45 MHz (13C)]. Chemical shifts are
expressed in parts per million downfield from TMS. High-
resolution mass spectra were obtained with a Varian Mat 311
double focusing instrument at the CRMPO “Centre de Mesures
Physiques de l’Ouest” with a source temperature of 170 ꢀC. An
ion accelerating potential of 3 kV and ionizing electrons of 70 eV
were used. All commercially available reagents were used as
supplied. Solvents were freshly distilled and kept under argon
flush. Enantioselective excesses were determined by chiral
HPLC analysis using a Chiralpak AD column (eluent: hexane/i-
PrOH 99/1, UV = 254 nm, flow rate = 0.5 mL/min). 6 and 7
were prepared according to Vogt and collaborators.38 Catalysts
15a-f were synthesized according to known procedures.39
General Procedure for the Synthesis of 2H-Chromenones 1, 10,
11, and 12: To previously dried sodium sulfate (150 mg) were
1
1a: H NMR (200.13 MHz, CDCl3) δ ppm = 1.09 (s, 6H,
CH2C(CH3)2), 1.41 (s, 6H, O(CH3)2), 2.28 (d, J = 3.9 Hz, 4H,
CH2), 5.25 (d, J = 9.9 Hz, 1H, C(CH3)2CH), 6.42 (d, J = 9.9 Hz,
1H, CH); 13C NMR (75.45 MHz, CDCl3) δ ppm = 28.4, 32.3,
42.5, 50.4, 79.8, 109.6, 115.8, 122.7, 170.1, 194.6. HRMS (EIþ)
calcd for C13H18O2 206.13068, found m/z 206.1312.
1
1b: H NMR (200.13 MHz, CDCl3) δ ppm = 1.08 (s, 6H,
CH3),1.36 (d, J = 6.4 Hz, 3H, (O)CH(CH3)), 1.75 (s, 3H, CH3),
2.28 (s, 4H, 2 ꢀ CH2), 4.85 (q, J = 6.7 Hz, J = 8.9 Hz, 1H,
(O)CH(CH3)), 6.21 (s, 1H, CHethylenic); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 18.3, 18.7, 27.1, 28.3, 31.8, 49.7, 76.7, 109.0,
110.9, 127.5, 168.1, 194.6; HRMS (EIþ) calcd for C13H18O2
206.13068, found m/z 206.1313.
1c: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.06 ppm (s, 6H,
CH3), 1.35 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.6-1.8 (m, 5H, CH3
þ C H2), 1.92-2.01 (m, 2H, CH2), 2.23 (s, 2H, CH2), 2.25 (s, 2H,
CH2), 5.0-5.2 (m, 2H, CHethylenic), 6.43 (d, J = 10.1 Hz, 1H,
CHethylenic); 13C NMR (75.45 MHz, CDCl3) δ ppm = 16.6, 21.5,
24.6, 26.5, 26.9, 31.2, 40.7, 41.4, 49.3, 81.5, 108.0, 115.2, 120.3,
122.6, 110.8, 169.7, 192.6; HRMS (EIþ) calcd for C18H26O2
274.19328, found m/z 274.1934.
(38) van der Vlugt, J. I.; Hewat, A. C.; Neto, S.; Sablong, R.; Mills, A. M.;
Lutz, M.; Spek, A. L.; Muller, C.; Vogt, D. Adv. Synth. Catal. 2004, 346, 993.
(39) (a) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319. (b) Simonsen,
K. B.; Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1998, 63, 7536.
(c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W.C. J. Am. Chem.
Soc. 2006, 128, 84.
J. Org. Chem. Vol. 74, No. 23, 2009 8971

Moreau et al.
JOCArticle
1
1d: H NMR (200.13 MHz, CDCl3) δ ppm = 1.09 (s, 6H,
27.08, 27.10, 28.02, 36.34, 79.0, 101.5, 106.9, 127.2, 176.9, 196.0;
HRMS (EIþ) calcd for C13H16O2 204.11503, found m/z
204.1156.
CH3), 1.42 (d, J = 6.5 Hz, 3H, CH3) 2.26-2.30 (m, 4H, CH2),
4.97-5.03 (m, 1H, OCH(CH3)), 5.30 (dd, J = 10.1 Hz, J = 2.8
Hz, 1H, CHethylenic), 6.49 (d, J = 10.2 Hz, 1H, CHethylenic); 13
C
10i: H NMR (200.13 MHz, CDCl3) δ ppm = 0.81 (s, 3H,
1
NMR (75.45 MHz, CDCl3) δ ppm = 22.6, 27.6, 28.5, 31.0, 40.7,
49.7, 77.8, 110.6, 117.2, 126.2, 173.4, 194.6; HRMS (EIþ)
calcd for C12H16O2 192.11503, found m/z 193.1235 (MþH,
C12H17O2).
CH3),1.25-1.45 (m, 5H, CH3 þ CH2), 1.90-2.64 (m, 10H, CH2
þ CH), 4.98 (t, 1H, J = 6.9 Hz, OCH), 6.05 (s, 1H, CHethylenic);
13C NMR (75.45 MHz, CDCl3) δ ppm = 21.2, 22.2, 25.8, 28.0,
30.0, 33.4, 37.0, 40.5, 42.2, 48.7, 72.3, 111.2, 114.8, 133.3, 172.4,
195.8; HRMS (EIþ) calcd for C16H20O2 245.1542, found m/z
245.1531 (MþH, C16H22O2), dr 88:22.
1e: 1H NMR (200.13 MHz, CDCl3) δ ppm = 0.88 (t, 3H, J =
6.0 Hz, CH3), 1.05-1.10 (m, 6H, 2CH3), 1.18-1.40 (m, 6H,
3CH2), 1.57-1.67 (m, 2H, CH2), 2.23-2.26 (m, 4H, 2CH2Cy),
4.86-4.89 (m, 1H, OCH(C5H11)), 5.26 (d, 1H, J = 10.0 Hz,
CHethylenic), 6.43 (d, 1H, J = 10.0 Hz, CHethylenic); 13C NMR
(75.45 MHz, CDCl3) δ ppm = 14.4, 22.9, 28.8, 32.5, 32.6, 36.1,
42.5, 50.7, 78.2, 110.7, 117.7, 117.9, 118.1, 171.6, 195; HRMS
(EIþ) calcd for C16H24O2 248.17763, found m/z 248.1757.
1f: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.16 (s, 6H, 2 ꢀ
CH3), 2.43 (s, 2H, CH2), 2.61 (s, 2H, CH2), 5.04 (d, J = 2.6 Hz,
1H, (O)CH(Ph)), 6.42 (d, JAB = 16.8 Hz, 1H, CH(Ph)-
CHethylenic), 6.65 (dd, J = 4 Hz, JAB = 16.8 Hz, 1H, CHethylenic),
7.41-7.93 (m, 5H, HAr); 13C NMR (75.45 MHz, CDCl3) δ
ppm = 20.4, 27.4, 51.2, 52.9, 77.9, 115.4, 125.8, 126.4, 126.7,
127.6, 128.3, 126.1, 150.6, 152.7, 196.6.
11a: 1H NMR (200.13 MHz, DMSO) δ ppm = 1.52 (s, 6H,
CH3), 5.73 (d, J = 10 Hz, 1H, CHethylenic), 6.38 (d, 1H, J = 10
Hz, CHethylenic), 7.39 (d, 2H, J = 7.7 Hz, HAr), 7.60-7.64 (m,
1H, HAr), 7.77 (d, 1H, J = 7.6 Hz, HAr); 13C NMR (75.45 MHz,
DMSO) δ ppm = 33.5, 86.3, 105.3, 120.4, 121.3, 122.1, 128.1,
110.0, 112.8, 118.3, 158.2, 163.6, 165.2; HRMS (EIþ) calcd for
C14H12O3 228.07864, found m/z 228.07888.
1
11b: H NMR (200.13 MHz, DMSO) δ ppm = 1.43 ppm
(d, 3H, J = 6.4 Hz, CH3), 1.86 (s, 3H, CH3), 5.15 (q, 1H, J = 6.1
Hz, CH), 6.19 (s, 1H, CHethylenic), 7.40 (d, 2H, J = 8.0 Hz, HAr),
7.55-7.7 (m, 1H, HAr), 7.77 (d, 1H, J = 7.7 Hz, HAr); HRMS
(EIþ) calcd for C14H12O3 228.07864, found m/z 228.0799. This
compound has been already described by Appendino, G.,
Cravotto, G.; Tagliapietra, S.; Nano, G. M.; Palmissano, G.
Helv. Chim. Acta 1990, 73, 1865.
1
1g: H NMR (200.13 MHz, CDCl3) δ ppm = 1.12 (s, 3H,
CH3), 1.16 (s, 3H, CH3), 2.38 (s, 2H, CH2), 2.56 (s, 2H, CH2),
4.98-4.99 (m, 1H, (O)CH(Ph)), 6.39 (dd, J = 4 Hz, JAB = 15.8
Hz, 1H, C(H)(Ph)CHethylenic), 6.89 (d, JAB = 15.8 Hz, 1H,
CHethylenic), 7.29-8.16 (m, 4H, HAr); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 27.5, 30.4, 45.1, 45.8, 76.2, 114.9, 123.5, 124.4,
126.6, 127.8, 112.0, 113.6, 112.2, 148.1, 188.4, 189.0.
11c: 1H NMR (200.13 MHz, DMSO) δ ppm = 1.09 (s, 3H,
CH3), 1.5 (s, 6H, CH3), 1.75 (m, 2H, CH2), 2.0-2.18 (m, 2H,
CH2), 5.0-5.15 (m, 1H, CHethylenic-alkyl), 5.70 (d, 1H, J = 10.1
Hz, CHethylenic), 6.43 (d, 1H, J = 10.1 Hz, CHethylenic), 7.41 (d,
2H, J = 7.6 Hz, HAr), 7.55-7.7 (m, 1H, HAr), 7.8 (d, 1H, J = 7.6
Hz, HAr); 13C NMR (75.45 MHz, DMSO) δ ppm = 21.9, 26.5,
29.8, 31.4, 42.6, 87.6, 103.6, 119.1, 120.5, 120.8, 126.8, 128.1,
128.8, 130.4, 135.4, 136.9, 156.9, 162.7, 163.9; HRMS (EIþ)
calcd for C19H20O3 296.14124, found m/z 296.1408.
1
10a: H NMR (200.13 MHz, CDCl3) δ ppm = 1.42 (s, 6H,
C(CH3)2), 1.96-2.05 (m, 2H, CH2Cy), 2.37-2.45 (m, 4H,
CH2Cy), 5.26 (d, J = 10.0 Hz, 1H, CHethylenic), 6.43 (d, J =
10.0 Hz, 1H, CHethylenic); 13C NMR (75.45 MHz, CDCl3) δ
ppm = 19.6, 27.4, 27.6, 28.7, 35.4, 78.7, 109.6, 114.8, 121.9,
170.6, 193.9; HRMS (EIþ) calcd for C11H14O2 178.09938, found
m/z 178.1000.
11d: 1H NMR (200.111 MHz, DMSO) δ ppm = 1.48 ppm (d,
3H, J = 6.5 Hz, CH3), 5.30-5.45 (m, 1H, CH), 5.77 (dd, 1H,
J = 3.0 Hz, J = 10.0 Hz, CHethylenic), 6.42 (d, 1H, J = 10.0 Hz,
CHethylenic), 7.40 (d, 2H, J = 8.0 Hz, HAr), 7.60-7.70 (m, 1H,
10b: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.36 (d, J =
6.5 Hz, 3H, OCH(CH3)), 1.74 (s, 3H, CH3), 1.94-2.04 (m, 2H,
CH2), 2.36-2.45 (m, 4H, CH2), 4.83 (q, J = 6.3 Hz, 1H,
OCH(CH3)), 6.21 (s, 1H, CHethylenic); HRMS (EIþ) calcd for
C11H14O2 178.09938, found m/z 178.0900.
H
Ar), 7.77 (d, 1H, J = 8.0 Hz, HAr); 13C NMR (75.45 MHz,
DMSO) δ ppm = 21.2, 75.2, 100.2, 114.6, 116.5, 116.6, 122.4,
123.6, 124.4, 132.6, 152.5, 158.5, 159.5; HRMS (EIþ) calcd for
C13H10O3 214.06299, found m/z 214.0643.
1
10c: H NMR (200.13 MHz, CDCl3) δ ppm = 0.26 (s, 3H,
11e: 1H NMR (200.13 MHz, DMSO) δ ppm = 0.88 (t, 3H,
J = 6.5 Hz, CH3), 1.28-1.60 (m, 6H, CH2), 1.67-1.90 (m, 2H,
CH2), 5.23 -5.30 (m, 1H, CH), 5.78 (dd, 1H, J = 10.1 Hz, J =
3.0 Hz, CHethylenic), 6.31 (d, 1H, J = 10.1 Hz, CHethylenic),
7.35-7,45 (m, 2H, HAr), 7.66-7.79 (m, 2H, HAr); 13C NMR
(75.45 MHz, DMSO) δ ppm = 12.9, 21.5, 22.9, 30.4, 34.7, 77.0,
99.9, 114.2, 115.6, 117.1, 120.4, 121.6, 122.9, 111.0, 152.0, 158.4,
159.7; HRMS (EIþ) calcd for C17H18O3 270.12559, found m/z
270.1256.
OC(CH3)), 0.28-0.29 (m, 8H, C(CH3)2 þ OC(CH3)(CH2)),
0.31-0.32 (m, 4H, CH2Cy þ CH2), 0.35-0.36 (m, 4H, CH2Cy),
5.07 (t, 1H, J = 5.8 Hz, CHC(CH3)2), 5.17 (d, J = 10.1 Hz, 1H,
CHethylenic), 6.44 (d, J = 10.1 Hz, 1H, CHethylenic); 13C NMR
(75.45 MHz, CDCl3) δ ppm = 16.6, 19.6, 21.5, 24.7, 26.4, 27.6,
35.4, 40.7, 81.3, 109.2, 115.4, 120.6, 122.6, 130.9, 171.0, 193.8;
HRMS (EIþ) calcd for C16H22O2 246.16198, found m/z
246.1614.
10d: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.59 (d, J =
6.4 Hz, 3H, CH3), 1.93-2.03 (m, 2H, CH2), 2.38-2.45 (m, 4H,
CH2), 5.01-5.04 (m, 1H, OCH(CH3)), 5.30 (dd, J = 10.3 Hz,
J = 2.6 Hz, 1H, CHethylenic), 6.49 (d, J = 9.5 Hz, 1H, CHethylenic);
HRMS (EIþ) calcd for C10H12O2 164.08373, found m/z
164.0843.
11f: H NMR (200.13 MHz, DMSO) δ ppm = 0.50-2.30
1
(m, 8H, CH2), 5.28-5.42 (m, 1H, CH2CHO), 6.08 (s, 1H,
CHethylenic), 7.32-7.40 (m, 2H, HAr), 7.59-7.74 (m, 2H, HAr);
13C NMR (75.45 MHz, DMSO) δ ppm = 22.79, 25.32, 28.33,
79.20, 99.67, 114.12, 117.45, 115.30, 116.10, 123.10, 124.10,
110.23, 112.43, 150.99, 161.21, 163.41; HRMS (EIþ) calcd for
C16H14O3 254.09492, found m/z 254.09429.
10e: 1H NMR (200.13 MHz, CDCl3) δ ppm = 0.88 (t, J = 6.0
Hz, 3H, CH3) 1.30-1.72 (m, 8H, CH2), 1.92-1.98 (m, 2H,
CH2Cy), 2.37-2.40 (m, 4H, CH2Cy), 4.86-4.90 (m, 1H, OCH-
(C5H11)), 5.27 (d, J = 9.8 Hz, 1H, CHethylenic), 6.44 (d, J = 10.0
Hz, 1H, CHethylenic); 13C NMR (75.45 MHz, CDCl3) δ ppm =
12.9, 19.6, 21.50, 22.92, 27.29, 29.93, 30.57, 34.7, 35.4, 76.7,
116.5, 116.9,171.6,193.9; HRMS (EIþ) calcd for C14H20O2
220.14633, found m/z 220.1477.
1
12a: H NMR (200.13 MHz, CDCl3) δ ppm = 1.46 (s, 6H,
CH3), 2.38 (s, 3H, CH3), 5.39 (d, 1H, J = 10.0 Hz,
(CH3)2C-CHethylenic), 5.80 (s, 1H, (CH3)C(O)-CHethylenic),
6.41 (d, 1H, J =10.1 Hz, CHethylenic); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 19.1, 28.3, 79.1, 96.8, 99.3, 115.2, 123.8, 161.4,
163.1, 163.1; HRMS (EIþ) calcd for C11H12O3 192.07864, found
m/z 192.0780.
10f: 1H NMR (200.13 MHz, CDCl3) δ ppm = 0.88-2.42 (m,
14H, CH2), 4.92-5.00 (m, 1H, OCH), 6.11 (s, 1H, CHethylenic);
13C NMR (75.45 MHz, CDCl3) δ ppm = 19.73, 21.70, 26.83,
12b: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.42 (d, 3H,
J = 6.6 Hz, (O)CH(CH3)), 2.23 (s, 3H, (O)C(CH3)), 2.38 (s, 3H,
CH3), 4.95 (q, 1H, J = 6.6 Hz, CH), 5.82 (s, 1H, CHethylenic),
8972 J. Org. Chem. Vol. 74, No. 23, 2009

Moreau et al.
JOCArticle
6.19 (s, 1H, CHethylenic); 13C NMR (75.45 MHz, CDCl3) δ
ppm =11.1, 21.7, 28.4, 76.1, 97.9, 98.9, 111.4, 128.6, 161.2,
163.3, 163.3; HRMS (EIþ) calcd for C11H12O3 192.07864, found
m/z 192.0795.
vacuum and the crude oil was filtered on a plug of neu-
tral alumina (eluent: dichloromethane/methanol, 90/10). Sol-
vents were then removed, and 13 was obtained as a bright yellow
solid.
1
12c: H NMR (200.13 MHz, CDCl3) δ ppm = 1.38 (s, 3H,
13: 1H NMR (400.16 MHz, CDCl3) δ ppm = 1.90-1.94 (m,
2H, CH2), 2.24 (t, 2H, J = 5.6 Hz, C(NH)CH2), 2.36 (t, 2H, J =
5.6 Hz, C(O)CH2), 4.18 (d, 2H, J = 4.4 Hz, CH2(Ph)), 5.11 (s,
1H, CHethylenic), 5.54 (br d, 1H, NH), 7.22-7.30 (m, 5H, HAr);
13C NMR (50.4 MHz, CDCl3) δ ppm = 21.9, 29.4, 36.4, 46.9,
96.8, 127.5, 127.6, 128.7, 137.0, 165.3, 197.5; HRMS (EIþ) calcd
for C13H15NO 202.1229, found m/z 202.1232 (M þ H,
C13H16NO).
(O)C(CH3)(alkyl)), 1.55 (s, 3H, C(CH3)2), 1.63 (s, 3H, C(CH3)2),
1.76 (t, 2H, J = 7.7 Hz, CH2), 2.04-2.10 (m, 2H, CH2), 2.18
(s, 3H, CH3), 5.10 (t, 1H, J = 7.1 Hz, CHethylenic-alkyl), 5.33 (d,
1H, J = 10.1 Hz, C(alkyl)-CHethylenic), 5.80 (s, 1H, CHethylenic),
6.38 (d, 1H, J = 10.1 Hz, CHethylenic); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 17.6, 20.6, 22.6, 25.7, 37.5, 41.8, 82.7,
97.6, 100.2, 116.8, 123.4, 123.6, 132.2, 162.3, 162.4, 164.5;
HRMS (EIþ) calcd for C16H20O3 260.14124, found m/z
260.1424.
General Procedure for the Synthesis of Tetrahydroquinolinones
14: To previously dried sodium sulfate (150 mg) were succes-
sively added, under argon, phosphoric acid 7 (5 mol%), toluene
(5 mL), 13 (0.5 mmol), and the appropriate unsaturated alde-
hyde (0.6 mmol). The mixture was stirred at 90 ꢀC until
completion by TLC analysis. The solution was then filtered on
a plug of Celite and concentrated under vacuum. The crude oil
was purified on silica gel by flash chromatography (eluent:
petroleum ether/diethyl ether 50/50, then dichloromethane/
methanol 90/10).
12e: 1H NMR (200.13 MHz, CDCl3) δ ppm = 0.88-1.45 (m,
7H, CH3 þ CH2), 2.23 (s, 3H, CH3), 2.23-2.27 (m, 4H, 2CH2Cy),
5.80 (s, 1H, CHethylenic), 4.99-5.03 (m, 1H, OCH(C5H11)), 5.43
(dd, 1H, J = 10.1 Hz, J = 3.2 Hz, CHethylenic), 6.46 (d, 1H,
J = 9.8Hz, CHethylenic); 13C NMR(75.45 MHz, CDCl3) δppm =
14.4, 20.6, 22.9, 24.3, 31.9, 36.2, 58.0, 76.2, 91.1, 100.5, 118.3,
120.4, 163.0, 165.3;HRMS(EIþ) calcdfor [M - C5H11]þ C9H8O3
- Hþ 163.03952, found m/z 163.0379.
12d: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.47 (d, 3H,
J = 6.5 Hz, CH3), 2.23 (s, 3H, CH3), 5.12-5.20 (m, 1H, CH),
5.43 (dd, 1H, J = 10.1 Hz, J = 3.0 Hz, CHethylenic), 5.80 (s, 1H,
CHethylenic), 6.45 (d, 1H, J = 9.9 Hz, CHethylenic); 13C NMR
(75.45 MHz, CDCl3) δ ppm = 21.6, 21.7, 73.1, 99.1, 99.3, 116.6,
119.9, 160.1, 160.3, 165.4; HRMS (EIþ) calcd for C10H10O3
178.06299, found m/z 178.0632.
14a: 1H NMR (200.130 MHz, CDCl3) δ ppm = 0.92 (t, 3H,
J = 7.4 Hz, CH3), 1.69-1.97 (m, 4H, 2CH2), 2.29-2.50 (m, 4H,
2CH2), 3.94-4.00 (m, 1H, CH(ethyl)), 4.60 (AB, 2H, JAB = 17.0
Hz, CH2(Ph)), 5.2 (dd, 1H, J = 5.1 Hz, 9.6 Hz, Hethylenic), 6.78
(d, 1H, J = 9.8 Hz, Hethylenic), 7.21-7.42 (m, 5H, HAr); 13C
NMR (50.4 MHz, CDCl3) δ ppm = 7.1, 20.3, 25.6, 27.0, 34.5,
51.7, 60.2, 107.4, 112.2, 120.0, 124.9, 126.6, 128.0, 135.7, 159.6,
190.7; HRMS (EIþ) calcd for C18H21NO 266.3654 found m/z
266.2249 (M - H, C18H20NO).
12h: 1H NMR (200.13 MHz, CDCl3) δ ppm = 1.11-2.12 (m,
8H, 4 ꢀ CH2), 2.21 (s, 3H, CH3), 5.01-5.09 (m, 1H, CH), 5.73 (s,
1H, CHethylenic), 6.09 (s, 1H, CHethylenic); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 20.1, 24.5, 26.9, 33.1, 35.2, 79.7, 97.3, 99.8,
109.1, 133.1, 161.4, 162.6, 163.3; HRMS (EIþ) calcd for
C13H14O3 218.09429, found m/z 218.0941.
14b: 1H NMR (200.130 MHz, CDCl3) δ ppm = 1.28 (s, 3H,
-NC(R)(CH3)), 1.58 (s, 3H, CH(CH3)2), 1.72 (s, 3H, CH-
(CH3)2), 1.77-2.43 (m, 10H, 5CH2), 4.60 (AB, 2H, JAB
=
18.3 Hz, CH2(Ph)), 4.93 (d, 1H, J = 10.0 Hz, Hethylenic), 5.11
(t, 1H, J = 5.5 Hz, CH(CH3)2), 6.76 (d, 1H, J = 10.0 Hz,
1
12g: H NMR (200.13 MHz, CDCl3) δ ppm = 0.75 (s, 3H,
(CH3)2), 1.26 (s, 3H, (CH3)2), 2.23 (s, 3H, CH3), 1.62-2.62
(m, 6H, 2 ꢀ CH2 þ 2 ꢀ CH), 5.11-5.15 (m, 1H, (O)CH(alkyl)),
5.87 (s, 1H, CHethylenic), 6.12 (s, 1H, CHethylenic); 13C NMR
(75.45 MHz, CDCl3) δ ppm = 11.1, 21.7, 28.3, 28.7, 30.7,39.1,
47.7, 70.9, 98.7, 100.6, 110.4, 134.5, 161.1, 160.7, 163.4; HRMS
(EIþ) calcd for C16H18O3 258.12559, found m/z 258.1257;
dr = 94:6.
H
ethylenic), 7.20-7.42 (m, 5H, HAr); 13C NMR (50.4 MHz,
CDCl3) δ ppm = 18.1, 22.0, 22.9, 26.1, 27.4, 29.7, 31.8,
35.9, 42.4, 48.2, 63.2, 107.5, 119.9, 124.1, 125.7, 127.6,
127.9, 128.0, 129.3, 132.3, 138.8, 162.6, 192.0; HRMS (EIþ)
calcd for C23H29NO 336.2320 found m/z 336.2327 (M þ H,
C23H30NO).
14c: 1H NMR (200.16 MHz, CDCl3) δ ppm = 1.92-1.97 (m,
2H, CH2), 2.37 (t, 2H, J = 6.5 Hz, CH2), 2.50-2.54 (m, 2H,
(O)CCH2), 4.42 (AB, 2H, JAB = 16.8 Hz, CH2(Ph)), 5.07 (d, 1H,
J = 4.4 Hz, NCH(Ph)), 5.23 (dd, 1H, J = 4.6 Hz, J = 9.6 Hz,
1
16: H NMR (300.13 MHz, CDCl3) δ ppm = 1.20 (s, 6H,
2CH3), 1.58 (t, 2H, J = 6.3 Hz, (CH3)2CH2), 1.84-1.88 (m, 2H,
0
CH2), 2.16 (t, 2H, J = 6.6 Hz, (C1 )CH2), 2.20-2.28 (m, 4H,
C(O)CH2 þ C4(CH2)); 13C NMR (75.45 MHz, CDCl3) δ ppm =
15.6, 20.9, 26.5, 29.1, 32.1, 36.7, 53.4, 109.9, 170.4, 198.0; HRMS
(EIþ) calcd for C11H16O2 181.1228, found m/z 181.1229 (M þ H,
C11H171O2).
H
ethylenic), 6.78 (d, 1H, J = 9.6 Hz, Hethylenic), 7.21-7.41 (m,
10H, HAr); 13C NMR (50.4 MHz, CDCl3) δ ppm = 21.7,
27.0, 35.9, 51.9, 64.7, 106.9, 115.8, 119.4, 126.5, 127.4, 128.2,
128.8, 129.4, 129.6, 136.3, 143.1, 160.6, 192.2; HRMS (EIþ)
calcd for C22H21NO 316.1692 found m/z 316.1701 (M þ H,
C22H22NO).
17: H NMR (300.13 MHz, CDCl3) δ ppm = 1.13 (s, 3H,
CH3), 1.20 (s, 3H, CH3), 1.50-1.92 (m, 8H), 2.00-2.37 (m, 8H),
0
3.49-3.56 (m, 2H, OC1H þ OC1 H); 13C NMR (75.45 MHz,
CDCl3) δ ppm = 17.9, 21.8, 25.8, 27.9, 29.6, 31.8, 34.9, 38.5,
38.7, 40.4, 43.3, 45.4, 50.0, 68.9, 74.0, 213.9; HRMS (EIþ) calcd
for C16H24O2 247.3605, found m/z 247.2293 (M - H,
C16H23O2); [R]20D þ3.33 (c 1.08, CHCl3).
Enantioselective Approach: Enantioselective syntheses
were carried out according to the general procedure, using
5 mol% of catalyst 15a-f. Enantiomeric excesses were deter-
mined after purification by HPLC on a Daicel Chiralpackl AD-
H chiral column (heptane/isopropanol 80/20, 1 mL/min,
285 nm).
Procedure for the Synthesis of 3-(Benzylamino)cyclohex-
2-enone 13: One gram (8.9 mmol) of 1,3-cyclohexanedione 2b,
FeCl3 6H2O (5 mol%), and 100 mg of sodium sulfate were
ꢀ
Acknowledgment. The authors thank la Region Bretagne
for a Ph.D. fellowship for J.M.
3
successively added in a dry Schlenk tube under argon. The
solids were then dissolved in 20 mL of dichloromethane and
stirred for 5 min. Benzylamine (0.96 g, 8.9 mmol) was slowly
added, and the dark brown colored mixture was allowed to
stir overnight. After completion, solvents were removed under
Supporting Information Available: Characterization data for
all compounds and X-ray structures of 10f and 11a. Thismaterialis
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 23, 2009 8973