Access to racemic and enantioenriched 3-methyl-4-chromanones: Catalysed asymmetric protonation of corresponding enolic species as the key step

Article abstract of DOI:10.1016/j.tet.2003.09.095

Br?nsted acids induced the intramolecular cyclisation of 3-aryloxypropanoic esters affording 3-methyl-4-chromanones, which have been transformed into the corresponding racemic benzyl β-oxoesters. These latter esters, in the presence of hydrogen and cataly

Full text of DOI:10.1016/j.tet.2003.09.095

Tetrahedron 59 (2003) 9641–9648
Access to racemic and enantioenriched 3-methyl-4-chromanones:
catalysed asymmetric protonation of corresponding enolic species
as the key step
*
Olivier Roy, Franc¸ois Loiseau, Abdelkhalek Riahi, Franc¸oise Henin and Jacques Muzart
´
´ ´ ´ ´
Unite Mixte de Recherche ‘Reactions Selectives et Applications’, CNRS-Universite de Reims Champagne-Ardenne, BP 1039,
51687 Reims Cedex 2, France
Received 13 March 2003; revised 2 September 2003; accepted 29 September 2003
Abstract—Brønsted acids induced the intramolecular cyclisation of 3-aryloxypropanoic esters affording 3-methyl-4-chromanones, which
have been transformed into the corresponding racemic benzyl b-oxoesters. These latter esters, in the presence of hydrogen and catalytic
amounts of both palladium and (endo, endo) aminoborneol, led to optically active chromanones with up to 75% ee through a deprotection–
decarboxylation–protonation cascade reaction.
q 2003 Elsevier Ltd. All rights reserved.
The synthesis of chromanones or their derivatives is of high
interest in organic chemistry. In particular, 3-substituted-4-
chromanones constitute the basic structure of natural
products1 possessing biological activities such as anti-
mutagenic2 and anti-inflammatory3 properties. Therefore,
our aim was to prepare optically active chromanones using a
palladium induced cascade reaction analogous to that
previously described for optically active cyclic4 or linear5
ketones (Fig. 1). For that purpose, the preparation of these
chromanones in their racemic form was required. Many
strategies have been proposed to prepare racemic
4-chromanones using disconnections a6, b7 or most
frequently c,8,9 both b and c being possibly carried out
together9,10 (Fig. 1). On the contrary, a few methods are
available for the preparation of the same non racemic
compounds starting from enantiopure synthons,11 by using
an external chiral ligand12 or incorporating an enzymatic
step.13 A few examples of enantioenriched or enantiopure
3-hydroxychromanones have also been described.14 The
recent improvement of the enantioselective catalytic
intramolecular Stetter reaction15a (disconnection d) to
obtain highly enantioenriched chromanones15b incited us
to present our own investigations for their preparation.
1. Preparation of starting racemic 3-methyl-4-
chromanones and corresponding oxo esters
As we have recently disclosed the efficient synthesis of
unsaturated esters 3 from Baylis–Hillman adducts 4,16 we
envisaged to use these compounds to prepare 1 (Scheme 1).
Compound 3a was first subjected to acidic Friedel–Crafts
conditions using trifluoromethane sulfonic acid,8a (TfOH,
2 equiv.) in CH2Cl2 at room temperature. We only observed
a Claisen transposition without any trace of the expected
methylene chromanone; such a rearrangement has already
been described, under more drastic thermal conditions17
(Eq. (1)).
Figure 1. Target and envisaged methodology.
Keywords: 4-chromanones; Friedel–Crafts cyclisation; Brønsted acids; asymmetric catalysis; benzylic cleavage; decarboxylation; protonation; aminoborneol.
*
Corresponding author. Tel.: þ33-3-26-91-33-10; fax: þ33-3-26-91-31-66; e-mail: francoise.henin@univ-reims.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.095

9642
O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
Table 1. Cyclisation of 2 in the presence of Brønsted acids
Entry Substrate
Acid
(equiv.)
T
(8C)
Time Conv. Product Yield
(%)a
(h)
(%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2c
2c
2d
2d
2d
2d
2e
2e
2f
MsOHb
70
3.5
100 1a
69
37
72
77
95
86
50
86
71
37
41
71
89
46
82
34
28
TfOH (0.25)c Reflux 96
TfOH (0.6)c Reflux 24
66
97
1a
1a
TfOH (2)c
TfOH (3)c
TfOH (4)c
MsOHb
Reflux 5.5
Reflux 4.5
Reflux
70
70
100 1a
100 1a
100 1a
100 1b
100 1c
100 1c
100 1d
100 1d
3
4.5
4
15
2
MsOHb
9
TfOH (3)c
MsOHb
100
80
Scheme 1.
10
11
12
13
14
15
16
17
MsOH (15)c Reflux 24
MsOH (5)c
TfOH (3)c
MsOHb
Reflux 72
Reflux 1.3
80
Reflux
80
92
1d
100 1a
100 1e
2
6
5
TfOH (3)c
MsOHb
97
100 1f
71 1f
1e
TfOH (3)c
Reflux 15
ð1Þ
2f
a
Used as solvent (0.5 mL/mmol of 2).
In toluene as solvent (5 mL/mmol of 2).
b
c
Yields of purified compounds, the difference between conversions and
yields corresponding to tarry material.
Hence, the methylenic double bond of 3 was hydrogenated
over palladium leading to 2, and we envisaged to submit the
corresponding acids or acid chlorides to Friedel–Crafts
cyclisation using reported methods.8,9,11a,13,14c However,
the saponification experiments carried out with 2a as the
substrate were complicated by a competitive retro-Michael
reaction, generating ethyl methacrylate beside phenol.
Consequently, we investigate the electrophilic cyclisation
directly from the ester. Actually, such a reaction has never
been reported.
t-butyl group leading to 1a through a reversal Friedel–
Crafts alkylation was observed.19 The retro-reaction did not
occur with MsOH and the amount of this acid had to be
decreased to 5 equiv. to obtain a fair yield of the expected
product (entries 10–12). Starting from 2e, the cyclisation
occurred with a complete para-regioselectivity (entries 14,
15). Finally, starting from 2f the yields of 1f remained low,
whatever the acid used as promoter (entries 16, 17).
Thus, the synthetic scheme developed here is a convenient
route to chromanones, starting from unexpensive, stable,
safe and easily available materials.
ð2Þ
Chromanones 1a–1f have been transformed to correspond-
ing benzyl b-oxoesters 5a–5f by selective C-carboxy-
benzylation of their enolates with benzyl cyanoformate20
(Scheme 2, Table 2).
2. Enantioselective
deprotection/decarboxylation/tautomerization
Preliminary cyclisation experiments using 2a as substrate in
the presence of Lewis acids (AlCl3 and TiCl4) were
unsuccessful. Therefore, we examined Brønsted acids as
promoters. The use of p-toluene sulfonic acid in toluene at
reflux or under microwave activation18 led to low yields
(,30%), the degradation of starting material being mainly
observed. With polyphosphoric acid, the results were also
not satisfying, since only 39% of 1a and degraded materials
were obtained. The reaction became more effective when
performed in methanesulfonic acid (MsOH) as solvent at
708C (Table 1, entry 1). The decrease of the amount of
MsOH and the use of dichloromethane or toluene as solvent
had a large detrimental effect on the yields. Switching from
MsOH to TfOH in refluxing toluene, allowed to reduce the
acid quantity (entries 2–6); the molar ratio 3:1 of TfOH
versus 2a seemed to be optimum in terms of yield and
conversion. The replacement of toluene by dichloromethane
or benzotrifluoride led respectively to no or low conversion
of 2a. The reactivity of 2b–2f was then examined leading to
the expected compounds except from 2d when TfOH was
the promoter (entry 13). In this case, an elimination of the
Compounds 5a–5f were subjected to the cascade reaction
already described elsewhere4,5 by using catalytic amounts
of both palladium on charcoal and a chiral protic source
(Fig. 2), solvent and bubbling or gas bag of dihydrogen
(Eq. (3)). This allowed the reductive cleavage of the
benzyl group, then decarboxylation followed by
asymmetric protonation of the resulting enolic species to
afford 1 in its optically active form. Our investigations
started with chloro-derivative 5c leading to 1c of known
configuration.11a,13
ð3Þ

O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
9643
Scheme 2. Carboxybenzylation of 1.
Table 2. Carboxybenzylation of 1
same order in ethyl acetate or acetonitrile (entries 6 and 10)
and decreased in THF (entry 5), whereas the benzylic
cleavage did not occur in toluene. No selectivity was
observed in ethanol or DMF (entries 8 and 9). Working at
room temperature seems to give the best result, since at
108C, 5c did not react and at 40 or 508C 1c was obtained
with a lower ee (entries 2, 3 or 7). Such temperature effects
have been noticed with linear compounds but differ from the
results with substituted indanones or tetralones, where the
higher ee’s were reached at around 558C.4 As in cyclic
1!5
R1
R2
R3
Yield %
A
B
C
D
E
F
H
Ome
Cl
t-Bu
H
H
H
H
H
H
OMe
H
H
H
H
H
H
OMe
60
54
74
85
88
92
Figure 2. Aminoalcohols used as chiral protic sources.
A rapid screening of different parameters has been carried
out (Table 3). If we compare the results with those observed
starting from other cyclic4 or linear5 substrates, quite similar
solvent effects will be noticed: the ee’s of 1c were of the
series, aminoborneol 7a was a better chiral protic source
(entries 6 or 10) than (2) ephedrine, cinchonine and
cinchonidine (entries 1, 13 and 14). Substituting the amino
group of aminoborneol as in 7b has no beneficial effect on
the ee (entry 12). An amount of 0.3 equiv. of 7a versus the
substrate seemed appropriate since ee decreased by
diminishing the amount of the chiral protic source (entries
10, 11).
Table 3. Cascade reaction from 5c:a influence of the solvent, temperature
and chiral protic source
Entry ApH Solvent T (8C) Time (h)
1c
Yield (%)b ee (%)c (config.)d
Following these results, we extended the procedure to 5b
using 7a as the chiral protic source but we did not notice any
reproducible ee under the above cited conditions. A careful
examination of experimental parameters led us to conclude
that a strong influence of the supporting catalyst was
responsible of this fact, as exemplified in Table 4. The ee’s
of 1b varied from 13 to 69% by simple modification of the
catalyst origin (entries 1–6). Palladium black finally gave us
fair and reproducible results (entry 7). We have already
observed that the selectivities from cyclic substrates were
greatly influenced by the nature of the support21 and this
differs from the linear compounds.5b Such support effect has
been reviewed22 and largely discussed for in the hetero-
geneous enantioselective hydrogenation of a-oxoesters23 or
activated double bonds.24 During selective reactions, an
optimal geometry as an adequate surface coverage are
required for adsorption of the chiral catalyst. The texture of
the support, the surface area and the dispersion correspond
to crucial parameters to obtain an active metal. In our case,
the low surface area of palladium black was advantageous
for the enantioselectivity (entry 7) as observed in isophorone
reduction.25 This was however not a general fact, since closer
ee were reached in presence of palladium on charcoal from
1
2
6
6
6
6
MeCN
MeCN
MeCN
MeCN
THF
MeCN
MeCN
EtOH
DMF
22
40
50
22
22
22
50
22
22
22
22
22
22
22
3
98
98
97
98
93
97
88
89
89
96
99
98
98
98
32 (R)
26 (R)
24 (R)
28 (R)
26 (R)
65 (R)
60 (R)
0
1.1
1.15
1
1
1
1
3
ndf
1
1
1
6
6
3
4e
5
6
6
7
8
9
10
11
12
13
14
7a
7a
7a
7a
7a
0
AcOEt
63 (R)
52 (R)
58 (R)
22 (S)
8 (R)
7ag AcOEt
7b
8
9
MeCN
MeCN
MeCN
a
5% Pd/C Engelhard 5011 (0.0125 equiv.), ApH, 0.3 equiv., substrate,
solvent, H2 (gas bag or bubbling), the reaction time corresponds to the
period required to reach full conversion of the substrate, as indicated by
TLC.
b
c
d
Isolated yields of purified products.
Enantiomeric excess determined by HPLC.
The configuration was attributed by comparison of the optical rotation
with literature values.13
Amount of Pd/C increased to 0.025 equiv.
Not determined.
ApH: 0.1 equiv. instead of 0.3 equiv.
e
f
g

9644
O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
Table 4. Cascade reaction from 5ba in presence of 7: influence of the
heterogeneous support
Entry
Catalyst
(equiv.)
Timeb
(h)
(R) 1b
Yield
(%)c
ee
(%)d
1
2
3
4
5
6
7
5% Pd/C Engelhard 5011 (0.025)
5% Pd/C Engelhard 5067 (0.025)
5% Pd/C Janssen 1950205 (0.025)
10% Pd/C Janssen 1950306 (0.025)
10% Pd/C Johnson Matthey 490 (0.025)
10% Pd/C Acros 19503100 (0.025)
Pd black Janssen (0.1)
1
1
1
99
99
99
78
88
78
94
13–50
28
33
48
67
1
Figure 3. Plot at 228C of log [selectivity] values for 5a–f versus the
corresponding Hammett constant s.
4.5
1.3
8.5
33
69
charge in the transition state, namely the approach of a
proton to the enolic species.
a
Pd catalyst, 7a (0.3 equiv.), 5b, ethyl acetate, H2 (gas bag or bubbling at
room temperature).
Time required to reach full conversion of the substrate, as indicated by
TLC.
Isolated yields of purified products.
b
As shown in Figure 4, the structure of the enolic species has
not been really ascertained. Since ApH is an aminoalcohol
(Fig. 1), the amino group is basic enough to generate
ammonium enolate E–A, starting from enol E–H or the
ketoacid itself produced after deprotection of 5. The
existence of a palladium enolate species E–Pd could not
be excluded, as the benzylic cleavage probably involves
palladium insertion into the O-alkyl bond of the ester group.
We have also observed the great influence of the nature of
the catalyst on the reaction course. The quite elevated slope
value corresponding to the Hammett line (nearly 1) is
consistent with the participation of charged intermediates
and transition states in the determining step. This is in
favour of E–A or E–Pd and also allows to explain the
deviation of the Hammett line starting from 5e. The
donating mesomeric effect of the methoxy group could
destabilize an enolate as E–A or E–Pd before its
protonation and thus induce a change in the rate determining
step.
c
d
Enantiomeric excess determined by HPLC.
Johnson Matthey (entry 5). Furthermore, we did not observe
such erratic results while using 5c,26 which suggests that the
surface effect strongly depends on the substrate.
Afterwards, we used black palladium and 7a to pursue our
investigation and especially to evaluate the electronic effect
due to the substituent pattern on the aryl group (Table 5).
The ee of 1 varied from 60 to 75%, with the same value for
1b and 1f which both bear a methoxy group in meta-position
of the chromanone carbonyle. The enantioselectivity
correlates well with Hammett s-values27 and a linear
Hammett plot was obtained except for 1e28–30 (Fig. 3). The
slope of the line was determined to be 20.97 (R 2¼0.99) and
was slightly lower than that observed during the asymmetric
protonation of enolates derived from Schiff bases.31 As
discussed when starting from open chain substrates,5 one
partial step responsible for the production of selectivity was
favoured in the presence of electron donating groups. It is
reasonable to assume that the faster reaction is also the more
selective one, as pointed out for several selectivity
examples.32 This assertion agrees with the shorter reaction
time (entry 4), corresponding to the more donor t-Bu group.
According to the Hammett equation, our results suggest that
the protonation of the enolic species corresponds to a key
step, since it corresponds to the development of a positive
3. Conclusion
The present paper describes a convenient synthetic route to
various substituted 3-methyl-4-chromanones from cheap
and easily available starting material. It has also been
established that the sequence deprotection, decarboxylation,
asymmetric tautomerization can be successfully applied to
the corresponding benzyl b-oxoesters to deliver the
Table 5. Cascade reaction from 5a–5f in the presence of 7aa
Entry
Substrate
Timeb
(h)
Product
Yield
(%)c
ee
(%)d
(configuratione)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
8
8.5
9
4
7
1a
1b
1c
1d
1e
1f
99
94
97
89
63
78
73 (R)
69 (R)
60 (R)
75 (R)
64 (R)
69 (R)
8
a
Pd black, (0.1 equiv.), 7a (0.3 equiv.), ethyl acetate, H2 (gas bag or
bubbling), room temperature.
Time required to reach full conversion of the substrate, as indicated by
TLC.
Isolated yields of purified products.
Enantiomeric excess determined by HPLC.
Configurations determined by comparison of Cotton effects of
compounds 1a,b, 1d–f with 1c (see Experimental).
b
c
d
e
Figure 4. Possible structures of enolic species5

O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
9645
enantioenriched compounds in high yields. Using catalytic
aminoborneol as the chiral protic source and palladium
black as promoter, enantiomeric excess up to 75% could be
achieved.
115.8, 125.8, 128.8, 157.7, 174.2. Anal. calcd for
C12H16O3Cl: C, 66.09; H, 6.82. Found: C, 65.75; H, 6.77.
4.1.4. Ethyl 2-methyl-3-(p-tertiobutylphenoxy)propano-
ate (2d). Yellow oil (3.20 g, 90%). IR (KBr): 2963; 1737;
.
1610; 1514; 1465 cm21 1H NMR (CDCl3): d 1.27 (m,
15H), 2.92 (sex, J¼6.4 Hz, 1H), 3,99 (dd, J¼8.8, 6.4 Hz,
1H), 4.17 (m, 3H), 6.95 (d, J¼8.7 Hz, 2H), 7.2 (d,
J¼8.7 Hz, 2H). 13C NMR: 14.0, 14.2, 31.5, 34.0, 39.9,
60.6, 69.6, 114.1, 126.6, 143.6, 156.4, 174.3. Anal. calcd for
C16H24O3: C, 72.79; H, 9.15. Found: C, 72.56; H, 9.03.
4. Experimental
4.1. General remarks
NMR Spectra: Bruker AC 250 (1H, 250 or 13C, 62 MHz) or
Bruker AC 500 (1H, 500 MHz or 13C 124 MHz); internal
TMS, CDCl3 as solvent. Infrared spectra: FTIR Spectrafile
IR plus midac. EI mass spectra: JEOL D-300 (70 eV)
recorded at the Faculty of Pharmacy of Reims. Optical
rotations: Perkin–Elmer 241 (0.5-dm cell). Circular
dichroism: Jasco 810. Microanalysis: Perkin–Elmer CHN
2400. HPLC: Shimadzu LC10AS, UV SPD 10A detector
(254 nm). Circular dichroism: JASCO 810. Chromato-
graphy: CCM, Alufolien Merck 5554 silica gel PF254; flash
chromatography, silica gel Merck 9385, 0.04–0.063 mm.
4.1.5. Ethyl 2-methyl-3-(m-methoxyphenoxy)propanoate
(2e). Colourless oil (2.30 g, 77%). IR (KBr): 2980, 1735,
1603, 1493, 1467 cm21. 1H NMR (CDCl3): d 1.28 (m, 6H),
3.00 (sex, J¼6.2 Hz, 1H), 3.79 (s, 3H), 3.99 (dd, J¼6.2,
4.1 Hz, 1H), 4.18 (m, 3H), 6.55 (m, 3H), 7.2 (t, 1H,
J¼8 Hz). 13C NMR: 13.9, 14.1, 39.8, 55.2, 60.1, 69.5,
101.1, 106.6, 106.7, 129.8, 159.9, 160.7, 174.2. Anal. calcd
for C13H18O4: C, 65.55; H, 7.61. Found: C, 65.48; H, 7.54.
4.1.6. Ethyl 2-methyl-3-(o-methoxyphenoxy)propanoate
(2f). Colourless oil (3.21 g, 87%). IR (KBr): 2980, 1735,
1
Purification of the solvents: ether and THF distilled from
Na/benzophenone, dichloromethane, chloroform, ethyl
acetate and toluene distilled over CaH2, DMF over
MgSO4, acetonitrile over P2O5 and then CaH2.
1509, 1466 cm21. H NMR (CDCl3): d 1.30 (m, 6H), 3.02
(sex, J¼6.9 Hz, 1H), 3.84 (s, 3H), 4.01 (dd, J¼9.6, 6.9 Hz,
1H); 4.17 (q, J¼6.9 Hz, 2H), 4.27 (dd, J¼9.6, 6.9 Hz, 2H),
6.94–7.04 (m, 4H). 13C NMR: 14.0, 14.1, 39.8, 55.9, 60.5,
70.9, 112.3, 114.5, 120.8, (CH); 121.6, 148.2, 149.8, 174.4.
Anal. calcd for C13H18O4: C, 65.55; H, 7.61. Found: C,
65.44; H, 7.60.
Compounds 3 have been previously described;16 their
hydrogenation to compounds 2 have been carried out
under magnetic stirring in 2£1024 M acetonitrile solutions,
using 10% palladium on charcoal (Johnson Matthey 490) as
catalyst (0.02 equiv./3) and gaseous hydrogen from a rubber
balloon or a gas bag. After complete reaction (7–24 h, as
indicated by TLC), the mixture is filtered over a pad of silica
and solvent eliminated; the purification by flash chroma-
tography (petroleum ether/ethyl acetate, 95:5) led to
compounds 2.
4.2. Cyclisation reactions, general procedure
The ester 2 was dissolved either in MsOH or in toluene
containing the acid. The reaction mixture was heated as
indicated in Table 1; the solution was poured into a mixture
of ice-cooled water, extracted with dichloromethane,
washed with a saturated aqueous solution of NaHCO3,
brine and dried over MgSO4. After solvent evaporation
the residue was purified by flash chromatography leading to
3-methyl-4-chromanones 1a–f.
4.1.1. Ethyl 2-methyl-3-phenoxypropanoate (2a). Colour-
less oil (2.32 g, 92%). IR (KBr): 2980; 1737; 1601; 1587;
1497 cm21. H NMR (CDCl3): d 1.3 (m, 6H), 2.95 (sex,
J¼6.1 Hz, 1H), 4.02 (dd, J¼9.2, 6.1 Hz, 1H), 4.15 (m, 3H),
6.85–6.97 (m, 3H), 7.24–7.32 (m, 2H). 13C NMR (CDCl3):
14.0, 14.2, 40.1, 60.3, 69.7, 114.0, 120.5, 129.8, 158.3,
174.2. Anal. calcd for C12H16O3: C, 69.21; H: 7.74. Found:
C, 69.73; H, 7.63.
1
Spectral data of 1a,7a 1c,7a,8a 1e,7b 1f,33 are in accord with
those of the literature.
4.2.1. 6-Methoxy-3-methyl-4-chromanone 1b. Yellow
solid, mp¼398C, IR (KBr) 2974, 1690, 1617, 1490, 1456,
1
1429, 1270 cm21. H NMR (250 MHz. CDCl3) d 1.21 (d,
4.1.2. Ethyl 2-methyl-3-(p-methoxyphenoxy)propanoate
(2b). Colourless oil (2.90 g, 95%). IR (KBr): 2980, 1733,
1593, 1506, 1456 cm21. 1H NMR (CDCl3): d 1.27 (m, 6H),
2.91 (sex, J¼6.1 Hz, 1H), 3.76 (s, 3H), 3.94 (dd, J¼9.1,
6.1 Hz, 1H), 4.17 (m, 3H), 6.82 (m, 4H). 13C NMR: 13.9,
14.1, 39.9, 55.6, 60.5, 70.3, 114.5, 115.6, 152.7, 153.9,
174.3. Anal. calcd for C13H18O4: C, 65.55; H, 7.61. Found:
C, 65.21; H, 7.56.
J¼6.9 Hz, 3H), 2.82 (m, 1H), 3.79 (s, 3H), 4.10 (dd, J¼11.2,
10.9 Hz, 1H), 4.45 (dd, J¼11.1, 5.0 Hz, 1H), 6.88 (d,
J¼9.1 Hz, 1H), 7.07 (dd, J¼9.1, 3.1 Hz, 1H), 7.31 (d,
J¼3.1 Hz, 1H). 13C NMR (62 MHz. CDCl3) d 10.8, 40.6,
55.7, 72.3, 107.7, 119.0, 120.3, 124.8, 154.0, 156.4, 194.9.
Anal. calcd for C11H12O3: C, 68.75; H, 6.25. Found: C,
68.58; H, 6. 09.
4.2.2. 6-t-Butyl-3-methyl-4-chromanone 1d. Yellow oil.
1
4.1.3. Ethyl 2-methyl-3-(p-chlorophenoxy)propanoate
(2c). Colourless oil (3.92 g, 97%). IR (KBr): 2981, 1736,
1709, 1656, 1594, 1492 cm21. 1H NMR (CDCl3): d 1.28 (m,
6H), 2.96 (sex, J¼6.7 Hz, 1H), 3.89 (dd, J¼9.2, 6.7 Hz,
1H), 4.18 (m, 3H), 6.75 (d, J¼9.2 Hz, 2H), 7.23 (d,
J¼9.2 Hz, 2H). 13C NMR: 14.0, 14.1, 39.8, 60.3, 69.8,
IR (KBr) 2963, 1694, 1614, 1579, 1493 cm21. H NMR
(250 MHz. CDCl3) d 1.20 (d, J¼7.2 Hz, 3H), 1.30 (s, 9H),
2.76 (m, 1H), 4.12 (t, J¼11.1 Hz, 1H), 4.47 (dd, J¼11.1,
5.0 Hz, 1H), 6.89 (d, J¼8.1 Hz, 1H), 7.53 (dd, J¼8.1,
2.7 Hz, 1H), 7.89 (d, J¼2.7 Hz, 1H). 13C NMR (62 MHz.
CDCl3) d 10.9, 31.5, 34.2, 40.3, 72.1, 117.6, 119.7, 123.2,

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O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
129.7, 133.5, 159.9, 195.7. Anal. calcd for C14H18O2: C,
77.06; H, 8.26. Found: C, 76.85; H, 8.39.
(CDCl3): d 1.31 (s, 9H), 1.48 (s, 3H), 4.19 (d, J¼11.4 Hz,
2H), 4.80 (d, J¼11.4 Hz, 2H), 5.10 (d, J¼12.6 Hz, 2H), 5.23
(d, J¼12.6 Hz, 2H), 6.90 (d, J¼8.8 Hz, 1H), 7.15 (m, 2H),
7.26 (m, 3H), 7.55 (dd, J¼8.8, 2.3 Hz, 1H), 7.93 (d,
J¼2.3 Hz, 1H). 13C NMR (CDCl3): d 16.0, 31.2, 34.3, 53.4,
67.2, 73.7, 117.4, 119.3, 123.7, 127.4, 128.1, 128.4, 133.8,
135.2, 144.8, 159.0, 170.6, 190.5. Anal. calcd for C22H24O4:
C, 74.98; H, 6.86. Found: C, 74.46; H, 7.00.
4.3. Carboxybenzylation of compounds (1), general
procedure20
A solution of lithium hexamethyldisilazane was prepared by
slow addition of n-BuLi (1.6 M in hexane, 1.2 equiv.) to
hexamethyldisilazane (1.2 equiv.) at 2788C in THF (1 mL
per mmol) under argon. After 30 min of stirring, a THF
solution (1 mL per mmol) of chromanone 1 (1 equiv.) was
added dropwise during 20 min. After further 30 min of
stirring the THF solution (0.3 mL per mmol) of benzyl-
cyanoformate (1.2 equiv.) was added. The mixture was
warmed to room temperature and the contents of the flask
poured into 10% aqueous NH4Cl. The aqueous phase was
extracted three times with ether (0.5 mL per mmol). The
combined organic phases were washed with brine and dried
with MgSO4. After removal of the solvents, the residue was
purified by flash chromatography (petroleum ether/ethyl
acetate, 95:5) to afford pure 5.
4.3.5. 3-Benzyloxycarbonyl-7-methoxy-3-methyl-
chroman-4-one (5e). White solid (1.50 g, 88%), Flash
chromatography, petroleum ether/ethyl acetate, 90:10,
mp¼538C. IR: 3004, 1728, 1492, 1460, 1430, 1228 cm21
.
1H NMR (CDCl3): d 1.46 (s, 3H), 3.82 (s, 3H), 4.19 (d,
J¼11.5 Hz, 1H), 4.80 (d, J¼11.5 Hz, 1H), 5.11 (d,
J¼12.6 Hz, 1H), 5.22 (d, J¼12.6 Hz, 1H), 6.38 (d,
J¼2.6 Hz, 1H), 6.61 (dd, J¼8.9, 2.3 Hz, 1H), 7.17 (m,
2H), 7.28 (m, 3H), 7.87 (d, J¼8.9 Hz, 1H). 13C NMR
(CDCl3): d 16.0, 53.0, 55.6, 67.1, 73.9, 100.5, 110.5, 113.8,
127.5, 128.1, 128.3, 129.4, 135.3, 163.0, 166.0, 170.5,
188.7. Anal. calcd for C19H18O5: C, 69.93; H, 5.56. Found:
C, 69.56; H, 5.52.
4.3.1. 3-Benzyloxycarbonyl-3-methylchroman-4-one
(5a). Colourless oil (2.19 g, 60%). IR (KBr): 3034, 2938,
1737, 1697, 1608, 1478, 1465, 1311, 1282, 1221 cm21. 1H
NMR (CDCl3): d 1.48 (s, 3H), 4.22 (d, J¼11.6 Hz, 1H),
4.83 (d, J¼11.6 Hz, 1H), 5.11 (d, J¼12.5 Hz, 1H), 5.22 (d,
J¼12.5 Hz; 1H), 6.96 (d, J¼8.3 Hz, 1H), 7.06 (t, J¼7.8 Hz,
1H); 7.15 (m, 2H), 7.28 (m, 3H), 7.49 (m, 1H), 7.95 (dd,
J¼8.3, 1.7 Hz, 1H). 13C NMR (CDCl3): d 15.9, 53.4, 67.2,
73.7, 117.8, 120.1, 121.8, 127.5, 127.8, 128.1, 128.4, 135.2,
136.0, 161.1, 170.4, 190.2. MS: 296 (Mþ; 12), 162 (74), 120
(100).
4.3.6. 3-Benzyloxycarbonyl-8-methoxy-3-methyl-
chroman-4-one (5f). White solid (1.50 g, 92%), Flash
chromatography, petroleum ether/ethyl acetate, 90:10,
mp¼828C. IR: 2991, 1731, 1687, 1604, 1584, 1487, 1455,
1273, 1206 cm21. 1H NMR (CDCl3): d 1.48 (s, 3H), 3.89(s,
3H), 4.28 (d, J¼11.4 Hz, 2H), 4.91 (d, J¼11.4 Hz, 2H), 5.10
(d, J¼12.6 Hz, 2H), 5.22 (d, J¼12.6 Hz, 2H), 7.04 (m, 2H),
7.17 (m, 2H), 7.29 (m, 3H), 7.54 (dd, J¼7.6, 1.9 Hz, 1H).
13C NMR (CDCl3): d 15.9, 53.3, 56.2, 67.2, 74.1, 116.7,
118.9, 120.7, 121.3, 127.6, 128.1, 128.4, 135.2, 148.5,
151.0, 170.2, 190.1. Anal. calcd for C19H18O5: C, 69.93; H,
5.56. Found: C, 70.05; H, 5.77.
4.3.2. 3-Benzyloxycarbonyl-6-methoxy-3-methyl-
chroman-4-one (5b). White solid (2.02, 54%), Flash
chromatography, petroleum ether/ethyl acetate, 90:10,
mp¼738C. IR (KBr) 2942, 1739, 1679, 1611, 1578,
4.3.7. General procedure for the deprotection, decar-
boxylation. To a round bottom flask containing a solution of
5 (100 mg) in the corresponding solvent (20 mL) were
successively added the aminoalcohol (0.3 equiv.) and
palladium on charcoal (0.025 equiv.). Gaseous hydrogen
was supplied by a ‘gas bag’ or bubbled continuously
through the solution until complete disappearance of
starting material, as indicated by TLC (Tables 3–5). The
crude mixture was filtered over a pad of silica and purified
by chromatography. Yields are reported in Tables 3–5.
Spectral data have been described above and CD spectra of
each compound was similar to that of 1c shown in Figure 5.
For the optical rotation and HPLC analysis: 1a [a]D¼þ20.8
(c¼0.24, CHCl3) [(R) 73% ee]; Regis (S,S) Whelk-O1
isopropanol/hexane 0.1:99.9; flow rate: 2 mL/min; retention
time, (S) 14.6 min, (R) enantiomer: 16.7 min, a¼1.17. 1b
[a]D¼þ105.7 (c¼0.14, CHCl3) [(R) 69% ee]; Regis (S,S)
Whelk-O1 isopropanol/hexane 0.2:98.8; flow rate:
2 mL/min; retention time (S) 15.8 min, (R) 17.5 min,
a¼1.14. 1c [a]D¼þ37.6 (c¼0.24, CHCl3) [(R) 60% ee];
Regis (S,S) Whelk-O1 isopropanol/hexane 0.1:99.9; flow
rate: 2 mL/min; retention time (S) 9.5 min, (R) 11.1 min,
a¼1.24. 1d [a]D¼þ27.7 (c¼0.34, CHCl3) [(R) 75% ee];
Regis (S,S) Whelk-O1 isopropanol/hexane 0.1:99.9; flow
rate: 1.8 mL/min; retention time (S) 11.3 min, (R) 12.9 min,
a¼1.20. 1e [a]D¼þ29 (c¼0.20, CHCl3) [(R) 64% ee];
Regis (S,S) Whelk-O1 isopropanol/hexane 0.8:99.2; flow
1
1259 cm21. H NMR (CDCl3): d 1.47 (s; 3H), 3.80 (s,
3H); 4.17 (d, J¼11.5 Hz, 1H); 4,77 (d, J¼15.5 Hz; 1H),
5.10 (d, J¼12.6 Hz, 1H); 5.22 (d, J¼12.6 Hz, 1H); 6.89 (d,
J¼9.1 Hz, 1H), 6.87–7.19 (m, 3H), 7.28 (m, 3H), 7,35 (d,
J¼3.0 Hz, 1H). 13C NMR (CDCl3): d 15.9, 53.2, 55.7, 67.2,
73.8, 107.9, 119.0, 119.9, 125.2, 127.5, 128.1, 128.4, 135.2,
154.3, 155.7, 170.5, 190.2. Anal. calcd for C19H18O5: C,
69.93; H, 5.56. Found: C, 69.84; H, 5.61.
4.3.3. 3-Benzyloxycarbonyl-6-chloro-3-methylchroman-
4-one (5c). White solid (3.1 g, 74%), mp¼988C. IR: 3069,
1721, 1694, 1604, 1477, 1460, 1419, 1231 cm21 1H
.
NMR (CDCl3): d 1.46 (s, 3H), 4.19 (d, J¼11.9 Hz, 1H),
4.81 (d, J¼11.9 Hz, 1H), 5.09 (d, J¼12.3 Hz, 1H), 5.20
(d, J¼12.3 Hz, 1H), 6.90 (d, J¼8.8 Hz, 1H), 7.15 (m, 2H),
7.28 (m, 3H), 7.41 (ddd, J¼8.8, 2.7, 0.7 Hz, 1H), 7.88
(d, J¼2.6 Hz, 1H). 13C NMR (CDCl3): d 15.7, 53.1,
67.4, 73.8, 119.5, 120.9, 127.0, 127.3, 127.6, 128.2,
128.5, 135.0, 135.8, 159.4, 170.0, 189.0. Anal. calcd
for C18H15O4Cl: C, 65.63; H, 4.57. Found: C, 65.38; H,
4.52.
4.3.4. 3-Benzyloxycarbonyl-6-t-butyl-3-methylchroman-
4-one (5d). White solid (1.86 g, 85%), mp¼658C. IR: 2956,
1730, 1699, 1616, 1495, 1298, 1263 cm21 1H NMR
.

O. Roy et al. / Tetrahedron 59 (2003) 9641–9648
9647
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Asymmetry
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rate: 2 mL/min; retention time (S) 16.6 min, (R) 18.9 min,
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Acknowledgements
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`
We are grateful to the ‘Ministere de la Recherche et de la
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Technologie’ for a PhD studentship to O. R. and to
Engelhard and Johnson Matthey Companies for the gift of
Pd catalysts. We thank Isabel Mondim for a few
experiments, Dr D. K. Mukherjee for help with the text of
the manuscript, Professor A. Alix and G. Moroy (Reims
University) for the facilities in recording CD spectra.
´
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