Efficient proline and prolinol ether mediated 3-component synthesis of 3- and 3,4-substituted chromenone derivatives

Article abstract of DOI:10.1039/c2ob25443c

A highly efficient route for the synthesis of valuable 3,4-substituted chromenone derivatives by the reaction of 1,3-diketones with aldehydes in the presence of l-proline was developed. The reactions take advantage of readily available starting materials and follow a Knoevenagel condensation/Michael addition/hemiacetalization domino process. Chiral 3-substituted chromenones are obtained with high enantioselectivities when a chiral diarylprolinol TMS-ether is applied in the reaction.

Full text of DOI:10.1039/c2ob25443c

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
This article is part of the
OBC 10th anniversary
themed issue
All articles in this issue will be gathered together
online at
www.rsc.org/OBC10

Dynamic Article Links
Organic &
View Article Online
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 6201
www.rsc.org/obc
PAPER
Efficient proline and prolinol ether mediated 3-component synthesis of 3- and
3,4-substituted chromenone derivatives†
Magnus Rueping,*a Estíbaliz Merinoa and Michael Bolteb
Received 29th February 2012, Accepted 19th April 2012
DOI: 10.1039/c2ob25443c
A highly efficient route for the synthesis of valuable 3,4-substituted chromenone derivatives by the
reaction of 1,3-diketones with aldehydes in the presence of L-proline was developed. The reactions take
advantage of readily available starting materials and follow a Knoevenagel condensation/Michael
addition/hemiacetalization domino process. Chiral 3-substituted chromenones are obtained with high
enantioselectivities when a chiral diarylprolinol TMS-ether is applied in the reaction.
Previously, we described an organocatalytic enantioselective
addition–cyclization cascade reaction of 2-hydroxynaphthoqui-
Introduction
The development of multicomponent reactions has attracted con-
siderable attention due to the significant advantages this method-
ology offers to combinatorial and medicinal chemistry in the
formation of complex structures in a few reaction steps.1 Nowa-
days, the high atom-economy, the improvement of the reaction
efficiency,2 the reduction of waste and the high enantioselectivity
represent important challenges in organic chemistry. In this
respect, multicomponent metal-free domino reactions have the
potential to address and fulfil all these aspects.3–5
1,3-Dicarbonyl compounds have been widely employed in the
synthesis of natural products and biologically active compounds
through multicomponent reactions.6 Commonly, these transform-
ations employ, beside simple 1,3-dicarbonyl compounds, ali-
phatic aldehydes as electrophiles and further nucleophilic
partners and give rise to structurally different heterocyclic com-
pounds by domino reactions.6
none with α,β-unsaturated aldehydes. The diarylprolinol silyl
ether catalyzed reaction provided 1,4-pyranonaphthoquinones in
good yields and excellent enantioselectivities.8 Following this
methodology, a very efficient and highly enantioselective orga-
nocatalytic synthesis of pyranocoumarins, quinolinones and pyr-
anones was also reported starting from commercially available
cyclic 1,3-dicarbonyl compounds and α,β-unsaturated alde-
hydes.9 In addition, we have studied the reaction of 1,3-cyclo-
hexanedione and 5,5-dimethyl-1,3-cyclohexanedione with alkyl
and aryl substituted α,β-unsaturated aldehydes. This reaction
provides 4-substituted chromenes with excellent enantioselectiv-
ities starting from commercially available compounds using dia-
rylprolinol TMS ether derivatives as catalysts (Scheme 1a).10–12
The usefulness of this class of compounds was subsequently evi-
denced in the synthesis of more complex fused polycyclic
heterocycles.13
Chromenes or benzopyrans are an important group of hetero-
cyclic compounds with various biological and pharmacological
activities such as spasmolytic, diuretic, antiviral, antitumoral and
antianaphylactic, among others.7 Furthermore, the chromene
skeleton is present in numerous natural products which can be
used as pigments, photoactive compounds and biodegradable
agrochemicals (Fig. 1).7 Hence, their synthesis holds a special
place and considerable efforts are devoted to the development of
efficient methods for their synthesis.
aRWTH Aachen University, Institute of Organic Chemistry, Landoltweg
1, D-52074 Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.
de; Fax: +49 241 8092665
bDepartment of Inorganic and Analytical Chemistry, Goethe University,
Max-von-Laue Strasse 7, 60438 Frankfurt am Main, Germany
†Electronic supplementary information (ESI) available: NMR spectra
and HPLC chromatograms. CCDC 876877 and 876878. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob25443c
Fig. 1 Natural products with a chromene core.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6201–6210 | 6201

View Article Online
Table 2 Scope of the domino process
Entrya
1
6
R1, R2
R3
8
d.r.b
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
6a
6b
6c
6a
6b
6d
6e
6f
H
H
H
C2H5
C6H13
CH2Ph
C2H5
C6H13
CH3
C3H7
C9H19
Ph
8ad
8bd
8c
8d
8e
8f
8g
8h
8i
4.6 : 1
4 : 1
—
47
65
69
82
90
69
80
99
87
48
e
Scheme 1 Reaction of cyclic 1,3-diketones with aldehydes.
CH3
CH3
CH3
CH3
CH3
CH3
H,furyl
4 : 1
4 : 1
3 : 1
4 : 1
2 : 1
Table 1 Screening of solvents in the reaction of 1,3-cyclohexanedione
(1a) and butanal (6a)
e
6g
6a
—
—
e
C2H5
8j
a Reaction conditions: 1 (0.5 mmol), 6 (2 mmol) and L-proline
(0.5 mmol) in acetonitrile (1 mL) at room temperature (40 h). The
oxidation was carried out after column chromatography of the lactol
intermediate 7. b Diastereomeric ratio determined by 1H NMR
spectroscopy of the crude mixture. c Overall yield of both
diastereoisomers after column chromatography. d Oxidation with TPAP/
NMO. e Diastereoisomeric ratio could not be determined by 1H NMR.
Entrya
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CHCl3
DMF
DMSO
Toluene
MeCN
THF
H2O
Et2O
MeOH
46
55
72
64
58
86
72
28
65
80
Having established that acetonitrile is the best solvent for the
reaction of 1,3-cyclohexanedienone (1a) with butanal (6a), we
decided to explore the scope of this transformation by employing
differently substituted cyclohexanediones and various aliphatic
aldehydes (Table 2). In order to determine the diastereoselectiv-
ity, the hemiacetals 7 were converted into the corresponding lac-
tones 8 by oxidation with TPAP/NMO or PCC.
a Reaction conditions: 1a (1 equiv.), 6a (4 equiv.) and L-proline (1
The reaction of 1,3-cyclohexanedione (1a) with butanal and
octanal and subsequent oxidation with TPAP/NMO afforded the
corresponding chromenones 8a and 8b in 47 and 65% yield,
with a diastereoisomeric ratio of 4.6 : 1 and 4 : 1 respectively
(Table 2, entries 1 and 2). When 3-phenyl-propionaldehyde (6c)
was used, the product 8c was isolated in 69% overall yield. The
reaction of 5,5-dimethyl-1,3-cyclohexanedione (1b) with ali-
phatic and aromatic aldehydes provided the chromenones 8d–i
in good to excellent yields (69–99%) and diastereoisomeric
ratios in the range of 2 : 1 to 4 : 1 (Table 2, entries 4–9). In the
case of 5-furyl-1,3-cyclohexanedione (1c) reaction with butanal
(6a) afforded chromenone 8j in 48% yield (Table 2, entry 10).
Next, we decided to explore the scope of the reaction with
respect to other 1,3-diketones. The reaction of 1,3-cyclopentane-
dione (9) with butanal afforded, after oxidation, the product 14
in 53% overall yield (Table 3, entry 1). In the case of 2-hydroxy-
naphthoquinone (10), reaction with butanal and subsequent oxi-
dation afforded the product 15 in 64% yield and 8 : 1
diastereomeric ratio (Table 3, entry 2). A similar result was
obtained with the 4-hydroxy-6-methyl-2-pyrone 11. In this case
we isolated the product 16 in 65% yield and 7 : 1 diastereomeric
ratio (Table 3, entry 3). Furthermore, 4-hydroxycoumarin (12)
and its lactam analog 13 reacted with butanal (6a) giving the
products 17 and 18 in 57 and 99% yield, respectively (Table 3,
entries 4 and 5).
equiv.), 0.5 M.
Based on our previous results, we now envisioned that it
might be possible to synthesize these compounds in one step by
a multicomponent reaction employing 1,3-diketones and simple
saturated aliphatic aldehydes as electrophiles and nucleophiles
(Scheme 1b, R4 = R3CH2). Furthermore, careful selection of the
electrophilic partner (non-enolizable aldehyde) should allow the
application of two different aldehydes in this process
(Scheme 1b, R4 ≠ R3CH2). Notably, this protocol would circum-
vent the additional purification procedures required in the case of
sensitive α,β-unsaturated aldehyde substrates.8–10
Results and discussion
In order to verify our proposal we first evaluated the effect of
several solvents in the reaction of 1,3-cyclohexanedione (1a)
with butanal (6a) promoted by L-proline (Table 1). The use of
chlorinated solvents such as CH2Cl2 and CHCl3 (Table 1, entries
1 and 2) afforded the desired product 7a in moderate yields
(46–55%). The yield slightly increased when DMSO, DMF or
THF were employed in the reaction (Table 1, entries 3, 4 and 7).
The best results were obtained when the reaction was carried out
in MeCN or MeOH affording the desired product 7a in 86 and
80% yield, respectively (Table 1, entries 6 and 10).
The trans relative configuration of the 3,4-disubstituted chro-
menones was determined by single crystal X-ray analysis of the
6202 | Org. Biomol. Chem., 2012, 10, 6201–6210
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 3 Reaction of different 1,3-diketones with butanal (6a)
Table 4 Scope of the domino process using two different aldehydes
Entrya
6
R
20
d.r.b
Yieldc (%)
Entrya
1d,e
1,3-Diketone
Product
d.r.b
Yieldc (%)
53
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
C2H5
C6H13
CH2Ph
CH3
C3H7
C9H19
20a
20b
20c
20d
20e
20f
1.3 : 1
1.4 : 1
—
71
84
78
50
81
83
—
d
1 : 1
1.4 : 1
2 : 1
2
8 : 1
64
a Reaction conditions: 1b (0.5 mmol), benzaldehyde (2 mmol), 6
(2 mmol) and L-proline (0.5 mmol) in acetonitrile (1 mL) at room
temperature (40 h). The oxidation was carried out after column
chromatography of the lactol intermediate. b Diastereomeric ratio
determined by 1H NMR spectroscopy of the crude mixture. c Overall
yield of both diastereoisomers after column chromatography.
d Diastereoisomeric ratio could not be determined by 1H NMR.
3
4
7 : 1
3 : 1
65
57
5
2 : 1
99
Scheme 2 Organocatalyzed reaction between 1,2-cyclohexanedione
(1a) with formaldehyde and butanal (6a).
a Reaction conditions: 1,3-diketone (0.5 mmol), 6a (2 mmol) and L-
proline (0.5 mmol) in acetonitrile (1 mL) at room temperature (40 h).
The oxidation was carried out after column chromatography of the lactol
intermediate. b Diastereomeric ratio determined by 1H NMR
spectroscopy of the crude mixture. c Overall yield of both
diastereoisomers after column chromatography. d Diastereomeric ratio
could not be determined by 1H NMR. e Oxidation with PCC.
Finally, we were interested in the enantioselective synthesis of
this type of compounds. For this purpose, the reaction between
1,3-cyclohexanedione (1a), formaldehyde and butanal (6a) was
carried out in the presence of diarylprolinol TMS-ether deriva-
tive 3b as catalyst12,14 (20 mol%) and acetic acid (1 equiv.).
After an extended reaction time of 11 days the corresponding
lactol 21a was isolated in 79% yield (Scheme 2).
With the goal to decrease the reaction time, one equivalent of
the prolinol derivative 3b was applied in the reaction. In order to
circumvent the racemization of lactol 21, oxidation to the corre-
sponding lactones 22 was performed.
The reaction of 5,5-dimethyl-1,3-cyclohexanedione (1b) with
formaldehyde and aliphatic aldehydes 6 gave rise, after oxidation
with PCC, to chromenones 22 in moderate yields (49–52%) and
good enantioselectivities (Table 5). The absolute configuration
of the chromenones 22 was determined by single crystal X-ray
analysis of derivative 23. Based on this structure, the configur-
ation of compounds 22 was assigned as (3R) (Fig. 3).
Fig. 2 X-ray crystal structure of 3-ethyl-2-hydroxy-4-propyl-3,4-
dihydro-2H-benzo[g]chromene-5,10-dione 19.
Regarding the mechanism of this transformation, two different
pathways are possible. On one hand proline can mediated the
autocondensation of the aldehyde with the formation of an
iminium ion intermediate A. Attack of the 1,3-dicarbonyl
nucleophile 1 on the iminium ion electrophile A and subsequent
cyclization affords the desired product 7 (Scheme 3, pathway A).
On the other hand, the 1,3-dicarbonyl compound can react with
a molecule of aldehyde in a Knoevenagel condensation affording
product B, which can undergo Michael addition with the
enamine intermediate C formed by the condensation of the
lactol 19 obtained in the reaction of 2-hydroxynaphthoquinone
(10) and butanal (6a) (Fig. 2).
A challenging task consists in the use of two different alde-
hydes. In this case, in order to succeed, the reaction was per-
formed by reacting benzaldehyde with 5,5-dimethyl-1,3-
cyclohexanedione (1b), with subsequent addition of a second
aldehyde 6 after 2 h. The corresponding 3,4-disubstituted chro-
menes 20a–f were obtained in good yields (Table 4).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6201–6210 | 6203

View Article Online
Table 5 Enantioselective synthesis of 3-substituted chromenones
Scheme 4 Reaction of 2-hydroxynaphthoquinone (10) with 2-ethyl-
hexenal (24).
Entrya
6
R
22
Yieldb (%)
Eec (%)
1
2
3
4
6a
6b
6d
6e
C2H5
C6H13
CH3
22a
22b
22d
22e
49
50
51
52
89
87
83
88
Conclusions
C3H7
In summary, we have described a highly efficient one-pot syn-
thesis of 3,4-disubstituted chromenones in very good yields,
under mild conditions starting from 1,3-dicarbonyl compounds
and aldehydes in the presence of L-proline. Notably, the reaction
can be performed either with the same aldehyde as electrophile
and nucleophile or as a three component reaction with two
different aldehydes. The reaction mechanism involves first a
Knoevenagel condensation between the 1,3-dicarbonyl com-
pound and one molecule of aldehyde with subsequent Michael
addition and hemiacetalization. Chiral 3-substituted derivatives
are obtained with high enantioselectivities when (S)-2-[bis-(3,5-
bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine
is applied in the reaction.
a Reaction conditions: 1b (1 equiv.), formaldehyde (4 equiv.), 6 (4
equiv.) and 3b (1 equiv.) in acetonitrile (0.5 M) at room temperature
(40 h). The oxidation was carried out after column chromatography of
the lactol intermediate. b Overall yield of both diastereoisomers after
column chromatography. c Enantiomeric excesses were determined by
HPLC.
Experimental section
General
Fig. 3 X-ray crystal structure of (3R)-3,7,7-trimethyl-5-oxo-
3,4,5,6,7,8-hexahydro-2H-chromen-2-yl-4-bromobenzoate 23.
All commercially available compounds were distilled or recrys-
tallized prior to use. Solvents for chromatography were technical
grade and distilled prior to use. MeCN used in reactions was
analytical grade. Analytical thin-layer chromatography (TLC)
was performed on Merck silica gel aluminium plates with F-254
indicator, visualized by irradiation with UV light. Column
chromatography was performed using silica gel Merck 60 (par-
ticle size 0.040–0.063 mm). Solvent mixtures are understood as
volume/volume. 1H NMR and 13C NMR were recorded on a
Bruker AM 250 spectrometer in CDCl3. Data are reported in the
following order: chemical shift (δ) in ppm; multiplicities are
indicated s (singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet); coupling constants (J) are in Hertz (Hz). Mass spectra
(MS-EI, 70 eV) were conducted on GC-MS Shimadzu QP2010
(column: Equity®-5, length × I.D. 30 m × 0.25 mm, df 0.25 μm,
lot#28089-U, Supelco). IR spectra were recorded on a Jasco FT/
IR-420 spectrometer and are reported in terms of frequency of
absorption (cm−1). The enantiomeric excesses were determined
by HPLC analysis using a chiral stationary phase column. The
chiral HPLC methods were calibrated with the corresponding
racemic mixtures. Optical rotations were measured on a Perkin
Elmer 241 polarimeter.
Scheme 3 Proposed mechanistic pathways for the reaction of 1,3-
dicarbonyl compounds with aldehydes.
second molecule of aldehyde with L-proline. Finally, cyclization
provides lactol 7 (Scheme 3, pathway B).
In order to determine the mechanism, the reaction was carried
out employing 2-ethyl-2-hexenal 24 as aldehyde. Condensation
of aldehyde 24 with L-proline gives rise to the intermediate A,
present in pathway A (Scheme 3). After 48 h, no reaction was
observed for the 2-hydroxynaphthoquinone 10 (Scheme 4). In
view of these results we propose pathway B as plausible reaction
mechanism for this transformation.
General procedure A
To a solution of L-proline (1 equiv.) and the corresponding 1,3-
dicarbonyl compound in MeCN (0.5 M) was added the corre-
sponding aldehyde (4 equiv.) at room temperature. The resulting
solution was stirred for 40 h. The crude reaction mixture was
directly charged on silica gel and purified by column
6204 | Org. Biomol. Chem., 2012, 10, 6201–6210
This journal is © The Royal Society of Chemistry 2012

View Article Online
chromatography using hexane–ethyl acetate = 3 : 1 to afford the
corresponding product as a mixture of two diastereomers.
according to the general procedure D; overall yield: 47%; d.r.
(cis/trans) = 1 : 4.6; pale yellow oil. Major diastereoisomer: H
1
NMR (250 MHz, CDCl3): δ = 2.86–2.82 (m, 1H), 2.59–2.49 (m,
3H), 2.45–2.32 (m, 2H), 2.07–1.93 (m, 2H), 1.61–1.40 (m, 2H),
1.34–1.06 (m, 4H), 1.01–0.91 (m, 3H), 0.87–0.82 (m, 3H); 13C
NMR (62.5 MHz, CDCl3): δ = 197.2, 169.1, 165.7, 116.9, 45.9,
36.7, 36.2, 33.4, 27.0, 24.1, 20.7, 19.5, 13.9, 11.7; IR (neat): ν˜ =
2960, 2874, 1774, 1652, 1457, 1381, 1171, 1129, 1065, 1002,
923, 841, 734 cm−1; MS (EI) m/z (%) = 236 (54) [M]+, 218 (9),
207 (24), 193 (54), 179 (26), 166 (88), 151 (16), 137 (100), 125
(21), 109 (17), 95 (12), 70 (16), 55 (35).
General procedure B
To a solution of L-proline (1 equiv.) and the corresponding 1,3-
dicarbonyl compound in MeCN (0.5 M) was added benzal-
dehyde (4 equiv.) at room temperature. The resulting solution
was stirred for 2 h. After this time, the corresponding aliphatic
aldehyde (4 equiv.) was added and the reaction was stirred for
40 h. The crude reaction mixture was directly charged on silica
gel and purified by column chromatography using hexane–ethyl
acetate = 3 : 1 to afford the corresponding product as a mixture
of two diastereomers.
4-Heptyl-3-hexyl-3,4,7,8-tetrahydro-6H-chromene-2,5-dione (8b)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 65%; d.r.
(cis/trans) = 1 : 4; pale yellow oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 2.82–2.78 (m, 1H), 2.68–2.63 (m,
1H), 2.56–2.48 (m, 2H), 2.46–2.36 (m, 2H), 2.08–2.01 (m, 2H),
1.49–1.13 (m, 22H), 0.86–0.81 (m, 6H); 13C NMR (62.5 MHz,
CDCl3): δ = 197.2, 169.3, 165.7, 117.0, 44.1, 36.7, 34.0, 33.7,
31.7, 31.4, 30.7, 29.4, 29.0, 28.7, 27.0, 26.9, 26.3, 22.5, 22.4,
20.7, 14.0, 13.9; IR (neat): ν˜ = 2927, 2856, 1782, 1653, 1457,
1382, 1129, 737 cm−1; MS (EI) m/z (%) = 348 (55) [M]+, 330
(15), 320 (20), 263 (45), 249 (58), 235 (26), 222 (100), 207
(22), 193 (19), 179 (13), 165 (27), 152 (20), 125 (48), 55 (33).
General procedure C
To a solution of 2(S)-[(bis(3,5-bis(trifluoromethyl)phenyl)tri-
methylsilyloxy)methyl]pyrrolidine 3b (1 equiv.) and 5,5-
dimethyl-1,3-cyclohexanedione (1 equiv.) in MeCN (0.5 M) was
added formaldehyde (4 equiv.) and the corresponding aliphatic
aldehyde (4 equiv.) at room temperature. The resulting solution
was stirred for 40 h. The crude reaction mixture was directly
charged on silica gel and purified by column chromatography
using hexane–ethyl acetate = 3 : 1 to afford the corresponding
product.
General procedure D (oxidation with tetrapropylammonium
perruthenate, TPAP, and N-methylmorpholine N-oxide, NMO)
3-Benzyl-4-phenethyl-3,4,7,8-tetrahydro-6H-chromene-2,5-dione
(8c)
Solid TPAP (20 mol%) is added to a stirred mixture of the lactol
obtained according to the general procedure A (1 equiv.), NMO
(1.5 equiv.) and 4 Å molecular sieves (500 mg mmol−1) in
CH2Cl2 or MeCN (0.2 M) at room temperature. The reaction
was followed by TLC until completed (in some cases additional
amounts of TPAP and NMO were necessary). The crude reaction
mixture was directly charged on silica gel and purified by column
chromatography using hexane–ethyl acetate = 3 : 1 to afford the
corresponding product as a mixture of two diastereomers.
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 69%; pale
yellow oil. Mixture of diastereoisomers: 1H NMR (250 MHz,
CDCl3): δ = 7.24–6.96 (m, 10H), 2.96 (ddd, J = 8.3, 5.8 and 1.1
Hz, 1H), 2.89–2.76 (m, 2H), 2.71–2.64 (m, 1H), 2.57–2.16 (m,
6H), 1.96–1.80 (m, 2H), 1.67–1.43 (m, 2H); 13C NMR
(62.5 MHz, CDCl3): δ = 196.8, 168.6, 165.9, 141.0, 136.7,
128.9 (2C), 128.7, 128.7 (2C), 128.3 (2C), 128.1 (2C), 127.1,
125.9, 116.5, 45.9, 37.4, 36.6, 35.6, 32.4, 32.3, 26.9, 20.4; IR
(neat): ν˜ = 3061, 3029, 2948, 1782, 1653, 1456, 1381, 1266,
1112, 737, 701 cm−1; MS (EI) m/z (%) = 360 (87) [M]+, 342
(6), 269 (93), 241 (10), 227 (12), 207 (14), 165 (91), 137 (98),
104 (21), 91 (100).
General procedure E (oxidation with pyridinium
chlorochromate, PCC)
To a solution of the corresponding lactol obtained according to
the general procedure A, B or C was added PCC (10 equiv.).
The resulting solution was stirred at room temperature (in some
cases an additional amount of PCC was necessary). The reaction
was followed by TLC until completed. Celite was added and
filtered. The solvent was removed in vacuo and the residue was
directly charged on silica gel and purified by column chromato-
graphy using hexane–ethyl acetate = 3 : 1 to afford the corre-
sponding product as a mixture of two diastereomers in the case
of lactols obtained according to methods A and B.
3-Ethyl-7,7-dimethyl-4-propyl-3,4,7,8-tetrahydro-6H-chromene-
2,5-dione (8d)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 82%; d.r.
(cis/trans) = 1 : 5; gummy white solid. Major diastereoisomer:
1H NMR (250 MHz, CDCl3): δ = 2.83 (t, J = 5.4 Hz, 1H),
2.59–2.53 (m, 1H), 2.37 (s, 2H), 2.28–2.26 (m, 2H), 1.56–1.39
(m, 2H), 1.37–1.16 (m, 4H), 1.07 (s, 6H), 0.94 (t, J = 7.5 Hz,
3H), 0.87–0.81 (m, 3H); 13C NMR (62.5 MHz, CDCl3): δ =
197.0, 169.2, 164.0, 115.7, 50.6, 45.9, 40.7, 36.2, 33.3, 32.5,
3-Ethyl-4-propyl-3,4,7,8-tetrahydro-6H-chromene-2,5-dione (8a)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6201–6210 | 6205

View Article Online
4-Decyl-7,7-dimethyl-3-nonyl-3,4,7,8-tetrahydro-6H-chromene-
2,5-dione (8h)
28.2, 28.1, 24.1, 19.6, 13.9, 11.7; IR (neat): ν˜ = 3057, 2963,
2874, 1772, 1652, 1458, 1377, 1266, 1171, 1124, 1066,
738 cm−1; MS (EI) m/z (%) = 264 (51) [M]+, 246 (9), 235 (30),
221 (50), 207 (29), 194 (100), 179 (15), 165 (73), 151 (17), 137
(8), 123 (9), 109 (12), 95 (10), 83 (17), 69 (11), 55 (25).
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 99%; d.r.
(cis/trans) = 1 : 2; pale yellow oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 2.79–2.75 (m, 1H), 2.66–2.60 (m,
1H), 2.35 (s, 2H), 2.26–2.24 (m, 2H), 1.22–1.14 (m, 34H), 1.05
(s, 6H), 0.84–0.79 (m, 6H); 13C NMR (62.5 MHz, CDCl3): δ =
197.0, 169.4, 164.1, 115.9, 50.7, 44.1, 40.8, 34.1, 33.7, 32.6,
31.8, 31.8, 30.8, 29.5, 29.5, 29.4, 29.3, 29.2, 29.2, 29.2, 29.1,
28.3, 28.1, 26.9, 26.3, 22.6, 14.0; IR (neat): ν˜ = 2926, 2855,
1783, 1653, 1457, 1383, 910, 735 cm−1; MS (EI) m/z (%) = 460
(86) [M]+, 432 (35), 348 (26), 333 (79), 319 (76), 305 (35), 292
(89), 277 (97), 221 (30), 207 (53), 193 (35), 180 (27), 153 (61),
137 (23), 97 (100), 83 (72), 69 (47), 55 (71).
4-Heptyl-3-hexyl-7,7-dimethyl-3-propyl-3,4,7,8-tetrahydro-6H-
chromene-2,5-dione (8e)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 90%; d.r.
(cis/trans) = 1 : 4; pale yellow oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 2.82–2.77 (m, 1H), 2.69–2.63 (m,
1H), 2.37 (s, 2H), 2.28–2.27 (m, 2H), 1.26–1.19 (m, 22H), 1.08
(s, 6H), 0.85–0.80 (m, 6H); 13C NMR (62.5 MHz, CDCl3): δ =
197.0, 169.4, 164.1, 115.8, 50.7, 44.1, 40.7, 34.0, 33.7, 32.5,
31.7, 31.4, 30.7, 29.4, 29.0, 28.7, 28.2, 28.1, 26.9, 26.3, 22.5,
14.0; IR (neat): ν˜ = 2929, 2857, 1782, 1653, 1383, 1128, 910,
735 cm−1; MS (EI) m/z (%) = 376 (74) [M]+, 358 (14), 348
(30), 333 (14), 319 (11), 306 (17), 291 (70), 277 (90), 263 (38),
250 (100), 235 (75), 221 (27), 207 (32), 193 (41), 180 (28), 153
(49), 137 (18), 123 (17), 97 (77), 83 (58), 69 (40), 55 (82).
3-Benzyl-7,7-dimethyl-4-phenethyl-3,4,7,8-tetrahydro-6H-
chromene-2,5-dione (8i)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 87%; pale
yellow oil. Mixture of diastereoisomers: 1H NMR (250 MHz,
CDCl3): δ = 7.34–7.06 (m, 10H), 3.17–3.05 (m, 1H), 3.00–2.89
(m, 2H), 2.85–2.70 (m, 1H), 2.68–2.48 (m, 1H), 2.47–2.41 (m,
1H), 2.37 (s, 2H), 2.33–2.27 (m, 2H), 1.83–1.53 (m, 2H), 1.16
(s, 3H), 1.13 (s, 3H); 13C NMR (62.5 MHz, CDCl3): δ = 196.6,
168.6, 164.3, 140.9, 136.6, 128.8, 128.7, 128.6, 128.3, 128.3,
128.1, 127.0, 125.8, 115.3, 50.5, 46.0, 40.6, 37.1, 35.6, 32.5,
32.2, 32.1, 28.6, 27.8; IR (neat): ν˜ = 2959, 2871, 1782, 1654,
1455, 1381, 1266, 1104, 740, 701 cm−1; MS (EI) m/z (%) = 388
(35) [M]+, 297 (48), 269 (7), 255 (7), 222 (4), 207 (3), 193 (69),
165 (51), 131 (8), 117 (4), 104 (15), 91 (100), 83 (9), 65 (6), 55
(6).
4-Ethyl-3,7,7-trimethyl-3,4,7,8-tetrahydro-6H-chromene-2,5-
dione (8f)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 69%; d.r.
(cis/trans) = 1 : 3; pale yellow oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 2.87–2.77 (m, 1H), 2.71–2.63 (m,
1H), 2.40 (s, 2H), 2.30 (s, 2H), 1.42–1.24 (m, 2H), 1.17 (d, J =
7.3 Hz, 3H), 1.10 (s, 6H), 0.84 (t, J = 7.5 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): δ = 197.2, 170.1, 164.1, 115.1, 50.7, 40.8,
38.2, 37.0, 32.5, 28.3, 28.1, 27.0, 16.8, 10.7; IR (neat): ν˜ =
2963, 2935, 2876, 1783, 1656, 1457, 1379, 1181, 1125, 1055,
991, 915, 734 cm−1; MS (EI) m/z (%) = 236 (44) [M]+, 218 (7),
207 (39), 193 (13), 180 (100), 165 (68), 147 (20), 137 (30), 124
(20), 109 (20), 95 (27), 83 (26), 55 (49).
3-Ethyl-7-(furan-2-yl)-4-propyl-3,4,7,8-tetrahydro-6H-
chromene-2,5-dione (8j)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 48%; d.r.
4-Butyl-7,7-dimethyl-3-propyl-3,4,7,8-tetrahydro-6H-chromene-
2,5-dione (8g)
1
(cis/trans) = 1 : 5; yellow oil. Major diastereoisomer: H NMR
(250 MHz, CDCl3): δ = 7.35–7.33 (m, 1H), 6.32–6.28 (m, 1H),
6.08–6.06 (m, 1H), 3.61–3.45 (m, 1H), 2.93–2.54 (m, 6H),
1.64–1.13 (m, 6H), 1.04–0.81 (m, 6H); 13C NMR (62.5 MHz,
CDCl3): δ = 195.5, 168.9, 164.2, 155.0, 141.8, 117.0, 110.2,
105.2, 45.9, 40.9, 36.4, 33.2, 32.3, 31.8, 23.9, 19.6, 13.9, 11.6;
IR (neat): ν˜ = 2964, 2935, 2875, 1783, 1653, 1386, 1131, 1065,
738 cm−1; MS (EI) m/z (%) = 302 (100) [M]+, 284 (17), 273
(31), 259 (37), 245 (22), 232 (71), 217 (19), 203 (52), 189 (24),
147 (17), 138 (33), 123 (18), 110 (19), 94 (28), 81 (22), 55 (20).
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 80%; d.r.
1
(cis/trans) = 1 : 4; yellow oil. Major diastereoisomer: H NMR
(250 MHz, CDCl3): δ = 2.84–2.79 (m, 1H), 2.74–2.68 (m, 1H),
2.40 (s, 2H), 2.31 (d, J = 1.4 Hz, 2H), 1.51–1.19 (m, 10H), 1.10
(s, 6H), 0.90 (t, J = 6.8 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3): δ = 197.0, 169.3, 164.1, 115.8, 50.6,
43.8, 40.7, 33.7, 33.6, 32.8, 32.5, 28.4, 28.3, 28.1, 22.5, 20.2,
13.8, 13.5; IR (neat): ν˜ = 2958, 2872, 1783, 1654, 1383,
1127 cm−1; MS (EI) m/z (%) = 292 (37) [M]+, 274 (10), 264
(11), 249 (29), 235 (60), 221 (25), 208 (100), 193 (18), 179
(28), 165 (53), 153 (44), 137 (14), 123 (19), 109 (13), 97 (27),
83 (45), 69 (24), 55 (85).
3-Ethyl-4-propyl-3,4,6,7-tetrahydrocyclopenta[b]pyran-2,5-dione
(14)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
6206 | Org. Biomol. Chem., 2012, 10, 6201–6210
This journal is © The Royal Society of Chemistry 2012

View Article Online
according with the general procedure E; overall yield: 53%; pale
yellow oil. Mixture of diastereoisomers: 1H NMR (250 MHz,
CDCl3): δ = 2.71–2.52 (m, 6H), 1.62–1.47 (m, 2H), 1.44–1.14
(m, 4H), 0.97 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3): δ = 202.5, 178.9, 169.1, 120.2, 46.2,
36.4, 34.1, 33.3, 25.1, 24.8, 19.5, 13.9, 11.6; IR (neat): ν˜ =
2960, 2928, 2874, 1792, 1702, 1653, 1558, 1541, 1457, 1393,
1266, 1134, 1056, 734 cm−1; MS (EI) m/z (%) = 222 (32) [M]+,
204 (8), 193 (58), 179 (34), 165 (11), 152 (100), 137 (17), 125
(22), 111 (33), 95 (11), 70 (19), 55 (31).
3H); 13C NMR (62.5 MHz, CDCl3): δ = 168.6, 161.7, 152.2,
138.9, 131.1, 122.6, 122.1, 114.0, 113.5, 111.2, 45.8, 35.9, 35.6,
29.5, 24.1, 19.4, 13.8, 11.6; IR (neat): ν˜ = 2964, 2935, 2874,
1783, 1653, 1600, 1465, 1391, 1150, 1066, 737 cm−1; MS (EI)
m/z (%) = 299 (21) [M]+, 270 (4), 256 (48), 242 (4), 228 (100),
213 (5), 200 (36), 188 (5), 134 (3), 77 (3).
3-Ethyl-7-methyl-4-propyl-3,4-dihydropyrano[4,3-b]pyran-2,5-
dione (18)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 65%; d.r.
(cis/trans) = 1 : 7; colourless oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 5.88 (s, 1H), 2.89 (t, J = 6.6 Hz,
1H), 2.68 (t, J = 7.5 Hz, 1H), 2.24 (s, 3H), 1.63–1.22 (m, 6H),
0.96 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): δ = 167.8, 163.4, 162.6, 160.5, 103.1, 98.6,
45.9, 36.0, 35.1, 24.3, 19.9, 19.4, 13.8, 11.6; IR (neat): ν˜ =
2965, 2935, 2875, 1792, 1716, 1655, 1598, 1397, 1195, 1130,
1064, 991, 737 cm−1; MS (EI) m/z (%) = 250 (23) [M]+, 221
(11), 207 (100), 180 (24), 165 (22), 151 (19), 139 (9), 123 (4),
85 (8), 69 (5), 55 (7).
3-Ethyl-4-propyl-3,7-dihydrobenzo[g]chromene-2,5,10-trione
(15)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 64%; d.r.
(cis/trans) = 1 : 8; yellow solid. Major diastereoisomer: 1H NMR
(250 MHz, CDCl3): δ = 8.13–8.06 (m, 2H), 7.79–7.71 (m, 2H),
3.21 (t, J = 6.2 Hz, 1H), 2.75 (t, J = 7.5 Hz, 1H), 1.73–1.23 (m,
6H), 0.99 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.0 H, 3H); 13C NMR
(62.5 MHz, CDCl3): δ = 183.3, 176.9, 166.9, 150.2, 134.3,
133.9, 131.4, 130.8, 126.6, 126.4, 126.3, 45.2, 35.8, 34.7, 24.0,
19.7, 13.8, 11.6; IR (neat): ν˜ = 2965, 2935, 2875, 1792, 1683,
1655, 1636, 1596, 1458, 1380, 1331, 1299, 1263, 1196, 1173,
1134, 1060, 953, 721 cm−1; MS (EI) m/z (%) = 298 (100) [M]+,
270 (62), 256 (29), 241 (34), 227 (96), 213 (100), 199 (87), 185
(17), 173 (26), 159 (21), 144 (16), 128 (27), 115 (27), 104 (23),
76 (23), 55 (26).
3-Ethyl-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahydro-6H-chromene-
2,5-dione (20a)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 71%; d.r.
(cis/trans) = 1 : 1.3; colourless oil. Mixture of diastereoisomers:
1H NMR (250 MHz, CDCl3): δ = 7.31–7.03 (m, 10H), 4.21 (d,
J = 7.0 Hz, 1H), 4.09 (s, 1H), 2.79–2.68 (m, 2H), 2.63–2.45 (m,
4H), 2.32–2.26 (m, 4H), 1.81–1.64 (m, 3H), 1.31–1.19 (m, 1H),
1.15 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.10–0.99 (m, 9H); 13C
NMR (62.5 MHz, CDCl3): δ = 196.4, 195.7, 169.0, 168.1,
164.8, 164.8, 140.8, 137.5, 129.0, 128.7, 127.8, 127.4, 127.2,
126.5, 117.9, 114.2, 50.6, 50.4, 49.2, 45.7, 40.8, 39.8, 38.0,
32.6, 32.5, 28.4, 28.4, 28.1, 27.9, 25.2, 19.8, 11.7, 11.7; IR
(neat): ν˜ = 2963, 2876, 1782, 1654, 1456, 1374, 1267, 1162,
1121, 1062, 736, 700 cm−1; MS (EI) m/z (%) = 298 (12) [M]+,
270 (59), 255 (4), 241 (100), 227 (26), 185 (3), 171 (8), 165 (7),
153 (4), 128 (14), 115 (18), 102 (19), 91 (14), 83 (11), 69 (7),
55 (22).
3-Ethyl-4-propyl-3,4-dihydropyrano[3,2-c]chromene-2,5-dione
(16)
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 57%; d.r.
(cis/trans) = 1 : 3; gummy white solid. Major diastereoisomer:
1H NMR (250 MHz, CDCl3): δ = 7.85–7.81 (m, 1H), 7.62–7.55
(m, 1H), 7.37–7.30 (m, 2H), 3.09 (m, 1H), 2.80 (m, 1H),
1.77–1.26 (m, 6H), 1.02 (t, J = 7.4 Hz, 3H), 0.96–0.84 (m, 3H);
13C NMR (62.5 MHz, CDCl3): δ = 167.4, 161.5, 155.9, 153.0,
132.5, 124.4, 122.5, 116.7, 113.5, 106.2, 45.8, 36.1, 35.8, 24.4,
19.5, 13.8, 11.7; IR (neat): ν˜ = 2964, 2935, 2875, 1793, 1717,
1647, 1457, 1388, 1145, 1043, 906, 760, 738 cm−1; MS (EI) m/
z (%) = 286 (38) [M]+, 257 (18), 243 (100), 216 (54), 187 (15),
175 (10), 128 (11), 121 (22), 92 (7).
3-Hexyl-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahydro-6H-chromene-
2,5-dione (20b)
3-Ethyl-6-methyl-4-propyl-3,4-dihydro-6H-pyrano[3,2-c]
quinoline-2,5-dione (17)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 84%; d.r.
(cis/trans) = 1 : 1.4; gummy pale yellow solid. Mixture of dia-
The title compound was obtained according to the general pro-
cedure A. The isolated product was subsequently oxidized
according with the general procedure D; overall yield: 99%; d.r.
(cis/trans) = 1 : 2; colourless oil. Major diastereoisomer: 1H
NMR (250 MHz, CDCl3): δ = 7.98 (dd, J = 8.0 and 1.3 Hz,
1H), 7.64–7.57 (m, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.31–7.25 (m,
1H), 3.74 (s, 3H), 3.28–3.23 (m, 1H), 2.82–2.76 (m, 1H),
1.70–1.26 (m, 6H), 1.00 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.1 Hz,
1
stereoisomers: H NMR (250 MHz, CDCl3): δ = 7.32–7.11 (m,
10H), 4.20 (d, J = 7.0 Hz, 1H), 4.09 (s, 1H), 2.89–2.76 (m, 2H),
2.64–2.47 (m, 4H), 2.34–2.20 (m, 5H), 1.78–1.61 (m, 4H),
1.47–1.23 (m, 15H), 1.17 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H),
1.09–1.06 (m, 4H), 0.93–0.85 (m, 6H); 13C NMR (62.5 MHz,
CDCl3): δ = 196.4, 195.8, 169.2, 168.3, 164.8, 164.8, 140.9,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6201–6210 | 6207

View Article Online
137.6, 129.0 (2C), 128.7 (2C), 127.8 (2C), 127.4, 127.2, 126.5
(2C), 118.0, 114.3, 50.6, 50.4, 47.4, 44.1, 40.8, 39.9, 38.3, 32.6,
32.5, 31.8, 31.4, 31.4, 28.9, 28.7, 28.5, 28.4, 28.1, 27.9, 27.9,
26.9, 26.9, 26.4, 22.4, 22.4, 13.9; IR (neat): ν˜ = 2959, 2930,
2859, 1783, 1653, 1374, 1266, 1161, 1124, 1087, 1070, 737,
700 cm−1; MS (EI) m/z (%) = 354 (17) [M]+, 326 (99), 311 (10),
269 (34), 255 (11), 241 (100), 227 (35), 213 (3), 207 (8), 185
(4), 173 (14), 165 (6), 145 (6), 129 (17), 117 (20), 102 (13), 91
(25), 83 (23), 69 (9), 55 (36).
1H NMR (250 MHz, CDCl3): δ = 7.31–7.20 (m, 6H), 7.13–7.09
(m, 4H), 4.17 (d, J = 7.1 Hz, 1H), 4.07 (s, 1H), 2.89–2.77 (m,
2H), 2.55–2.52 (m, 4H), 2.32 (m, 2H), 2.25 (d, J = 2.9 Hz, 2H),
1.73–1.41 (m, 8H), 1.15–1.12 (m, 9H), 1.04 (s, 3H), 0.95 (t, J =
7.0 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3): δ = 196.4, 195.7, 169.2, 168.3, 164.8, 164.8, 140.8,
137.56, 128.9 (2C), 128.7 (2C), 127.7 (2C), 127.4, 127.2, 126.5
(2C), 117.9, 114.2, 50.5, 50.4, 47.1, 43.7, 40.7, 39.9, 38.3, 33.7,
32.5, 32.5, 28.6, 28.5, 28.3, 28.1, 27.9, 20.2, 20.1, 13.7, 13.4;
IR (neat): ν˜ = 2960, 2872, 1784, 1655, 1374, 1162, 1122, 1083,
737, 699 cm−1; MS (EI) m/z (%) = 312 (15) [M]+, 284 (77), 269
(18), 255 (11), 241 (100), 227 (35), 207 (4), 193 (8), 171 (8),
165 (7), 144 (5), 131 (25), 115 (19), 102 (17), 91 (17), 83 (17),
55 (33).
3-Benzyl-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahydro-6H-
chromene-2,5-dione (20c)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 78%;
1
white solid. Mixture of diastereoisomers: H NMR (250 MHz,
7,7-Dimethyl-3-nonyl-4-phenyl-3,4,7,8-tetrahydro-6H-chromene-
CDCl3): δ = 7.36–6.97 (m, 20H), 4.08–4.05 (m, 2H), 3.25–2.99
(m, 4H), 2.83 (dd, J = 13.4 and 9.1 Hz, 1H), 2.56–2.37 (m, 5H),
2.28–2.20 (m, 4H), 1.15 (s, 3H), 1.10 (s, 6H), 1.00 (s, 3H); 13C
NMR (62.5 MHz, CDCl3): δ = 196.1, 195.6, 168.9, 167.9,
164.9, 164.6, 140.6, 138.1, 137.4, 136.4, 128.9 (2C), 128.9
(2C), 128.9 (2C), 128.8 (2C), 128.8 (2C), 128.5 (2C), 128.2
(2C), 127.6, 127.2, 126.6, 126.5 (2C), 118.0, 114.0, 50.5, 50.4,
49.1, 45.7, 40.8, 38.3, 38.0, 37.9, 32.4, 32.4, 28.5, 28.1, 27.8;
IR (neat): ν˜ = 2961, 1783, 1654, 1373, 1266, 1099, 736,
700 cm−1; MS (EI) m/z (%) = 360 (9) [M]+, 332 (26), 281 (4),
269 (41), 241 (100), 227 (12), 207 (12), 171 (5), 157 (3), 131
(26), 115 (12), 104 (12), 91 (26), 83 (10), 55 (8).
2,5-dione (20f)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 83%; d.r.
(cis/trans) = 1 : 2; gummy pale yellow solid. Mixture of diaster-
eoisomers: 1H NMR (250 MHz, CDCl3): δ = 7.22–7.11 (m, 6H),
7.04–7.01 (m, 4H), 4.10 (d, J = 7.1 Hz, 1H), 3.99 (s, 1H),
2.78–2.66 (m, 2H), 2.47–2.44 (m, 4H), 2.24 (s, 2H), 2.18–2.15
(m, 2H), 1.68–1.50 (m, 4H), 1.18–1.16 (m, 28H), 1.07–1.04 (m,
6H), 0.99 (s, 3H), 0.96 (s, 3H), 0.82–0.77 (m, 6H); 13C NMR
(62.5 MHz, CDCl3): δ = 196.4, 195.8, 169.2, 168.4, 164.8,
164.8, 140.9, 137.6, 129.0 (2C), 128.7 (2C), 127.8 (2C), 127.4,
127.2, 126.5 (2C), 118.0, 114.3, 50.6, 50.4, 47.4, 44.1, 40.8,
39.9, 38.3, 32.6, 32.5, 31.8, 29.3, 29.3, 29.2, 29.1, 29.0, 28.5,
28.4, 28.1, 28.0, 27.9, 27.0, 26.9, 26.4, 22.6, 14.0; IR (neat): ν˜ =
2957, 2927, 2856, 1784, 1655, 1374, 734 cm−1; MS (EI) m/z
(%) = 396 (16) [M]+, 368 (100), 353 (15), 269 (33), 255 (9),
241 (81), 227 (28), 207 (5), 185 (4), 173 (8), 165 (5), 145 (5),
129 (12), 117 (14), 105 (8), 91 (20), 83 (18), 69 (9), 55 (25).
3,7,7-Trimethyl-4-phenyl-3,4,7,8-tetrahydro-6H-chromene-2,5-
dione (20d)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 50%; d.r.
(cis/trans) = 1 : 1; colourless oil. Mixture of diastereoisomers:
1H NMR (250 MHz, CDCl3): δ = 7.31–7.20 (m, 6H), 7.13–7.07
(m, 4H), 4.08 (d, J = 7.2 Hz, 1H), 3.96 (s, 1H), 3.07–2.95 (m,
2H), 2.57–2.47 (m, 4H), 2.33 (s, 2H), 2.27 (d, J = 3.1 Hz, 2H),
1.15 (d, J = 7.3 Hz, 3H), 0.95–0.91 (m, 9H), 0.86–0.82 (m, 6H);
13C NMR (62.5 MHz, CDCl3): δ = 196.6, 195.8, 169.6, 169.1,
165.0, 164.7, 140.8, 137.3, 129.0 (2C), 128.8 (2C), 127.8 (2C),
127.5, 127.3, 126.5 (2C), 117.8, 114.1, 50.6, 50.4, 41.8, 41.7,
40.9, 40.3, 39.0, 32.6, 32.5, 28.5, 28.4, 28.1, 28.0, 17.6, 12.3;
IR (neat): ν˜ = 2961, 2873, 1791, 1653, 1455, 1374, 1165, 1119,
1054, 1035, 735, 701 cm−1; MS (EI) m/z (%) = 284 (21) [M]+,
269 (4), 256 (100), 241 (84), 227 (35), 223 (16), 200 (6), 185
(5), 171 (9), 157 (6), 145 (5), 129 (18), 115 (19), 102 (20), 91
(9), 83 (9), 55 (16).
(3R)-3,7,7-Trimethyl-3,4,7,8-tetrahydro-6H-chromene-2,5-dione
(22a)
The title compound was obtained according to the general pro-
cedure C. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 51%;
1
white solid, m.p. = 82–84 °C. H NMR (250 MHz, CDCl3): δ =
2.85 (ddt, J = 16.3, 7.2 and 1.5 Hz, 1H), 2.73–2.57 (m, 1H),
2.41–2.39 (m, 2H), 2.30 (s, 2H), 2.16 (ddt, J = 16.3, 12.0 and
2.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H), 1.11 (s, 3H), 1.10 (s, 3H);
13C NMR (62.5 MHz, CDCl3): δ = 198.9, 170.2, 165.5, 112.9,
50.4, 40.8, 33.6, 32.5, 28.4, 28.2, 24.2, 15.3; IR (neat): ν˜ =
2962, 1772, 1749, 1653, 1636, 1376, 1114, 1071, 1047, 1015,
738 cm−1; MS (EI) m/z (%) = 208 (21) [M]+, 193 (4), 180
(100), 165 (95), 147 (22), 138 (16), 124 (52), 109 (23), 96 (44),
82 (15), 55 (19); [α]RDT = +11.67 (c = 0.48, CHCl3, 83% ee);
7,7-Dimethyl-4-phenyl-3-propyl-3,4,7,8-tetrahydro-6H-
chromene-2,5-dione (20e)
The title compound was obtained according to the general pro-
cedure B. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 81%; d.r.
(cis/trans) = 1 : 1.4; colourless oil. Mixture of diastereoisomers:
HPLC conditions: AD-H column, n-hexane–2-propanol
80 : 20, flow rate = 0.6 mL min−1, minor enantiomer: tR
12.24 min; major enantiomer: tR = 17.16 min.
=
=
6208 | Org. Biomol. Chem., 2012, 10, 6201–6210
This journal is © The Royal Society of Chemistry 2012

View Article Online
min−1, minor enantiomer: tR = 31.02 min; major enantiomer:
tR = 28.27 min.
(3R)-3-Ethyl-7,7-dimethyl-3,4,7,8-tetrahydro-6H-chromene-2,5-
dione (22b)
The title compound was obtained according to the general pro-
cedure C. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 49%; col-
ourless oil. 1H NMR (250 MHz, CDCl3): δ = 2.81 (ddt, J =
16.4, 6.9 and 1.7 Hz, 1H), 2.54–2.42 (m, 1H), 2.39 (t, J = 2.0
Hz, 2H), 2.29 (s, 2H), 2.28–2.15 (m, 1H), 1.99–1.82 (m, 1H),
1.65–1.48 (m, 1H), 1.11 (s, 3H), 1.09 (s, 3H), 1.01 (t, J = 7.5
Hz, 3H); 13C NMR (62.5 MHz, CDCl3): δ = 196.9, 169.4,
165.2, 112.7, 50.4, 40.7, 39.8, 32.5, 28.4, 28.2, 23.0, 21.5, 11.1;
IR (neat): ν˜ = 2963, 2876, 1782, 1654, 1377, 1165, 1119, 1077,
756 cm−1; MS (EI) m/z (%) = 222 (13) [M]+, 194 (82), 179
(32), 165 (100), 153 (14), 138 (25), 123 (11), 110 (12), 95 (15),
70 (14), 55 (29); [α]RDT = +10.39 (c = 1.03, CHCl3, 89% ee);
(3R)-3,7,7-Trimethyl-5-oxo-3,4,5,6,7,8-hexahydro-2H-chromen-
2-yl-4-bromobenzoate (23)
The title compound was obtained according to the general pro-
cedure C. The isolated product was subsequently dissolved in
pyridine. Dimethylaminopyridine and 4-bromobenzoyl chloride
were dissolved in dichloromethane and the solution added to the
alkaloid solution. The solution was made up to 6 mL with
dichloromethane and stirred at room temperature overnight. The
reaction mixture was poured into 20 mL 1 M NaHCO3 and
extracted with 3 × 10 mL CH2Cl2. The combined extracts
washed with water and dried over Na2SO4. The solvent was
removed in vacuo and the residue was subjected to column
chromatography; overall yield: 27%; white solid, m.p. =
HPLC conditions: AD-H column, n-hexane–2-propanol
80 : 20, flow rate = 0.6 mL min−1, minor enantiomer: tR
10.43 min; major enantiomer: tR = 15.15 min.
=
=
1
181–184 °C; H NMR (250 MHz, CDCl3): δ = 7.88/7.60 (AB
system, J = 8.6 Hz, 4H), 6.26 (d, J = 4.2 Hz, 1H), 2.58–2.49 (m,
1H), 2.33–2.19 (m, 6H), 1.06–1.03 (m, 9H); 13C NMR
(62.5 MHz, CDCl3): δ = 190.1, 165.6, 164.1, 132.0 (2C), 131.4
(2C), 129.0, 128.1, 109.4, 94.6, 50.6, 41.7, 32.3, 28.7, 28.7,
27.9, 20.9, 15.7; IR (neat): ν˜ = 2962, 2878, 1734, 1635, 1590,
1396, 1265, 1079, 1011, 737 cm−1; MS (EI) m/z (%) = 393 (30)
[M]+, 299 (16), 267 (63), 255 (15), 223 (23), 211 (100), 193
(44), 183 (9), 141 (8); [α]RDT = −141.44 (c = 1.18, CHCl3).
(3R)-7,7-Dimethyl-3-propyl-3,4,7,8-tetrahydro-6H-chromene-2,5-
dione (22c)
The title compound was obtained according to the general pro-
cedure C. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 52%; pale
yellow oil. 1H NMR (250 MHz, CDCl3): δ = 2.81 (ddt, J = 16.5,
7.0 and 1.7 Hz, 1H), 2.62–2.50 (m, 1H), 2.39 (t, J = 1.9 Hz,
2H), 2.30 (s, 2H), 2.28–2.15 (m, 1H), 1.93–1.80 (m, 1H),
1.56–1.34 (m, 3H), 1.11 (s, 3H), 1.10 (s, 3H), 0.94 (t, J = 7.2
Hz, 3H); 13C NMR (62.5 MHz, CDCl3): δ = 197.0, 169.6,
165.3, 112.7, 50.5, 40.8, 38.2, 32.6, 32.0, 28.4, 28.2, 21.9, 19.8,
13.8; IR (neat): ν˜ = 2962, 2874, 1771, 1733, 1716, 1455, 1181,
1070, 930, 734 cm−1; MS (EI) m/z (%) = 236 (11) [M]+, 208
(94), 193 (15), 179 (100), 165 (50), 153 (42), 137 (11), 123
(11), 109 (11), 97 (18), 83 (11), 55 (40); [α]RDT = −29.63 (c =
0.27, CHCl3, 88% ee); HPLC conditions: AD-H column, n-
hexane–2-propanol = 80 : 20, flow rate = 1.0 mL min−1, minor
enantiomer: tR = 9.09 min; major enantiomer: tR = 13.29 min.
Acknowledgements
The authors acknowledge Evonik Degussa and the DFG (Priority
Programme Organocatalysis) for financial support as well as the
Ministerio de Ciencia e Innovación of Spain, for a postdoctoral
contract to E.M.
Notes and references
1 (a) D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602;
(b) J. Zhu and H. Benaymé, Multicomponent Reactions, Wiley-VCH,
Weinheim, 2005; (c) D. M. D’Souza and T. J. J. Mueller, Chem. Soc.
Rev., 2007, 36, 1095; (d) L. F. Tietze and A. Modi, Med. Res. Rev., 2000,
20, 304; (e) G. Guillena, D. J. Ramón and M. Yus, Tetrahedron: Asymme-
try, 2007, 18, 693; (f) B. B. Touré and D. G. Hall, Chem. Rev., 2009,
109, 4439.
(3R)-3-Hexyl-7,7-dimethyl-3,4,7,8-tetrahydro-6H-chromene-2,5-
dione (22d)
2 B. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259.
The title compound was obtained according to the general pro-
cedure C. The isolated product was subsequently oxidized
according with the general procedure E; overall yield: 50%.
3 For selected reviews on domino reactions: (a) L. F. Tietze, Chem. Rev.,
1996, 96, 115; (b) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed.
Engl., 1993, 32, 131; (c) L. F. Tietze, G. Brasche and K. Gericke,
Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 2006;
(d) H.-C. Guo and J.-A. Ma, Angew. Chem., Int. Ed., 2006, 45, 354.
4 For reviews on organocatalytic domino reactions see: (a) D. Enders,
C. Grondal and M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
(b) X. Yu and W. Wang, Org. Biomol. Chem., 2008, 6, 2037;
(c) T. Poisson, Synlett, 2008, 147; (d) A.-N. Alba, X. Companyó,
M. Viciano and R. Rios, Curr. Org. Chem., 2009, 13, 1432;
(e) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167.
5 Reviews on organocatalytic synthesis of biologically active molecules:
(a) E. Marqués-López, R. P. Herrera and M. Christmann, Nat. Prod. Rep.,
2010, 27, 1138; (b) R. M. de Figueiredo and M. Christmann, Eur. J. Org.
Chem., 2007, 2575; (c) M. J. Gaunt, C. C. C. Johansson, A. McNally and
N. T. Vo, Drug Discovery Today, 2007, 12, 8.
1
Gummy yellow solid. H NMR (250 MHz, CDCl3): δ = 2.80
(ddt, J = 16.4, 7.0 and 1.7 Hz, 1H), 2.60–2.47 (m, 1H), 2.39 (t,
J = 2.0 Hz, 2H), 2.29 (s, 2H), 2.27–2.15 (m, 1H), 1.94–1.80 (m,
1H), 1.56–1.35 (m, 3H), 1.36–1.27 (m, 6H), 1.11 (s, 3H), 1.09
(s, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
δ = 197.0, 169.6, 165.3, 112.7, 50.5, 40.8, 38.4, 32.5, 31.5,
29.9, 29.0, 28.4, 28.2, 26.6, 22.5, 21.9, 14.0; IR (neat): ν˜ =
2955, 1700, 1653, 1596, 1457, 1388, 1266, 1069, 895,
740 cm−1; MS (EI) m/z (%) = 278 (25) [M]+, 250 (83), 235
(100), 221 (19), 207 (24), 193 (37), 179 (56), 165 (47), 154
(61), 137 (17), 97 (25), 83 (27), 69 (15), 55 (34); [α]DRT
=
6 (a) C. Simon, T. Constantieux and J. Rodriguez, Eur. J. Org. Chem.,
2004, 4957; (b) F. Liéby-Muller, C. Simon, T. Constantieux and
J. Rodriguez, QSAR Comb. Sci., 2006, 25, 432; (c) D. Bonne,
Y. Coquerel, T. Constantieux and J. Rodriguez, Tetrahedron: Asymmetry,
−23.15 (c = 0.42, CHCl3, 87% ee); HPLC conditions: OD-H
column, n-hexane–2-propanol = 90 : 10, flow rate = 0.3 mL
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6201–6210 | 6209

View Article Online
2010, 21, 1085; (d) M. del Mar Sanchez Duque, C. Allais, N. Isambert,
T. Constantieux and J. Rodriguez, β-Diketo Building Blocks for MCRs-
based Syntheses of Heterocycles in Synthesis of Heterocycles via Multi-
component Reactions, ed. R. V. A. Orru and E. Ruijter, Topics in Hetero-
cyclic Chemistry, Springer, Berlin/Heidelberg, 2010, vol. 23,
pp. 227–279.
8 M. Rueping, E. Sugiono and E. Merino, Angew. Chem., Int. Ed., 2008,
47, 3046.
9 M. Rueping, E. Merino and E. Sugiono, Adv. Synth. Catal., 2008, 350,
2127.
10 (a) M. Rueping, E. Sugiono and E. Merino, Chem.–Eur. J., 2008, 14,
6329; (b) M. Rueping, E. Merino and E. Sugiono, ChemCatChem, 2012,
DOI: 10.1002/cctc.201200151.
7 (a) J. D. Hepworth, C. D. Gabbutt and B. M. Heron, Comprehensive
Heterocyclic Chemistry II: Pyrans and their Benzo Derivatives: Syn-
thesis, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon
Press, Oxford, 1996, vol. 5, pp. 351–468; (b) G. R. Geen, J. M. Evans
and A. K. Vong, Comprehensive Heterocyclic Chemistry II: Pyrans and
their Benzo Derivatives: Applications, ed. A. R. Katritzky, C. W. Rees
and E. F. V. Scriven, Pergamon Press, Oxford, 1996, vol. 5, pp. 469–500;
(c) J. P. A. Harrity, M. S. Visser, J. D. Gleason and A. H. Hoveyda,
J. Am. Chem. Soc., 1997, 119, 1488; (d) C. Hardouin, L. Burgaud,
A. Valleix and E. Doris, Tetrahedron Lett., 2003, 44, 435;
(e) R. S. Kenny, U. C. Mashelkar, D. M. Rane and D. K. Bezawada, Tet-
rahedron, 2006, 62, 9280; (f) S. K. Ko, H. J. Jang, E. Kim and
S. B. Park, Chem. Commun., 2006, 2962; (g) G. P. Ellis and
I. M. Lockhart, The Chemistry of Heterocyclic Compounds, Chromenes,
Chromanones and Chromones, ed. G. P. Ellis, Wiley-VCH, 2007, vol.
31; (h) Y.-L. Shi and M. Shi, Org. Biomol. Chem., 2007, 5, 1499;
(i) X.-L. Sun and Y. Tang, Acc. Chem. Res., 2008, 41, 937; Isolation of
diversonol: ( j) W. B. Turner, J. Chem. Soc., Perkin Trans. 1, 1978,
1621; Afzelechin: (k) N. F. Janes and J. W. W. Morgan, J. Chem. Soc.,
1960, 2560; Isolation of lotthanongine: (l) T. Kanchanapoom, R. Kasai,
P. Chumsri, K. Kraisintu and K. Yamasaki, Tetrahedron Lett., 2002, 43,
2941.
11 (a) P. T. Franke, B. Richter and K. A. Jørgensen, Chem.–Eur. J., 2008,
14, 6317; (b) S. Song, L. Song, B. Dai, H. Yi, G. Jin, S. Zhu and
M. Shao, Tetrahedron, 2008, 64, 5728.
12 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2005, 44, 794; (b) Y. Hayashi, H. Gotoh,
T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212;
Reviews on prolinol TMS-ether catalysis: (c) C. Palomo and A. Mielgo,
Angew. Chem., Int. Ed., 2006, 45, 7876; (d) A. Mielgo and C. Palomo,
Chem.–Asian J., 2008, 3, 922.
13 (a) M. Rueping, C. M. R. Volla, M. Bolte and G. Raabe, Adv. Synth.
Catal., 2011, 353, 2853; (b) X. Wu, H. Fang, Q. Liu, L. Nie, J. Chen,
W. Cao and G. Zhao, Tetrahedron, 2011, 67, 7251.
14 For further examples from our group for the applications of prolinol
TMS-ethers as catalysts in domino reactions, see: (a) M. Rueping,
A. Kuenkel, F. Tato and J. W. Bats, Angew. Chem., Int. Ed., 2009, 48,
3699; (b) M. Rueping, K. L. Haack, W. Ieawsuwan, H. Sundén, H.
M. Blanco and F. R. Schoepke, Chem. Commun., 2011, 47, 3828;
(c) M. Rueping, H. Sundén and E. Sugiono, Chem.–Eur. J., 2012, 18,
3649; (d) M. Rueping, H. Sundén, L. Hubener and E. Sugiono, Chem.
Commun., 2012, 48, 2201; (e) M. Rueping, J. Dufor and M. S. Maji,
Chem. Commun., 2012, 48, 3406.
6210 | Org. Biomol. Chem., 2012, 10, 6201–6210
This journal is © The Royal Society of Chemistry 2012