Access to 2-alkyl chromanones via a conjugate addition approach

Article abstract of DOI:10.1016/j.tet.2012.05.115

The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the chromenones via acylation of the corresponding β-diketo-compounds are also described.

Full text of DOI:10.1016/j.tet.2012.05.115

Tetrahedron 68 (2012) 6948e6956
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Access to 2-alkyl chromanones via a conjugate addition approach
*
Louise A. Stubbing, Freda F. Li, Daniel P. Furkert, Vittorio E. Caprio, Margaret A. Brimble
School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to
a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good
yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to
chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the
Received 20 March 2012
Received in revised form 8 May 2012
Accepted 28 May 2012
Available online 7 June 2012
chromenones via acylation of the corresponding
b
-diketo-compounds are also described.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chromenones
Chromanones
Conjugate addition
1. Introduction
The chromanone scaffold 1 is represented in a large number
of natural products, exhibiting wide variety of biological
a
activities.1e3 The synthesis of flavanones (e.g., pinostrobin 2) that
possess aromatic substituents at C-2 is well represented in the
literature.4 The corresponding chromanones bearing aliphatic
substituents at C-2 are less well described, though naturally oc-
curring examples such as gonytolide A 3 and microdiplodiasone 4
exhibit interesting immunogenic and antimicrobial activity.5,6 In
addition, methods for the enantioselective synthesis of these
chromanones are rare (Fig. 1).
Two main strategies for the enantioselective synthesis of 2-
substituted chromanones of type 5 are well documented, namely
the intramolecular oxa-Michael cyclisation of an appropriately
substituted phenol 6, and the conjugate addition of varying nucle-
ophiles to chromenones 7 (Fig. 2).4 The former strategy has been
employed by several research groups,7e12 while asymmetric con-
jugate addition of aromatic nucleophiles for flavanone synthesis has
been reported.13e15
Fig. 1. Chromanone-based natural products.
Somewhat surprisingly, only two examples of enantioselective
methods for the introduction of simple aliphatic substituents at C-2
have been described.16,17
Our group has developed a number of approaches for the
asymmetric synthesis of pyronaphthoquinone natural products18
and we became interested in investigating the related chroma-
none natural products such as 3 and 4. We envisaged it should be
possible to introduce alkyl substituents at C-2 of chromanones via
an asymmetric conjugate addition to a chromenone (Fig. 3).19
Towards this end, an efficient method for the introduction of an
alkyl group onto the chromenone scaffold using silyl enol ether
nucleophiles was initially undertaken, albeit racemically. Further-
more, we decided to investigate the asymmetric addition of silyl
enol ethers to a range of chromenones 7 using Cu(II)ebox or
Cu(II)epybox catalysts. In order to pursue this aim we also re-
quired practical and scalable methodology to access the necessary
chromenone substrates to study the proposed conjugate addition
chemistry.
* Corresponding author. E-mail address: m.brimble@auckland.ac.nz (M.A.
Brimble).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.115

L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
6949
Fig. 2. Reported asymmetric approaches to 2-substituted chromanones.
Table 1
Preparation of b-dicarbonyl-phenols 11
Fig. 3. Proposed conjugate addition of silyl enol ethers to chromenones.
2. Results and discussion
Entry
R1
R2
Methoda
Product
Yield (%)
1
2
3
H
OMe
H
Ac
A
A
B
11a
11b
11c
87
77
79
2.1. Synthesis of chromenones
Ac
COt2Bu
Initial attention focused on the synthesis of the required chro-
menones 7aeh. Despite the number of publications involving
chromenone synthesis in the literature,20 we were disappointed to
find that many reported methods performed poorly in our hands
and characterisation in many cases was cursory or absent
altogether.21,22
The desired 3-substituted chromanones 7eeh could be accessed
via KostaneckieRobinson acylation of the corresponding phenols
11. These, in turn, were synthesised in high yield from the corre-
sponding 20-hydroxyacetophenones 10a and 10b.
Although several methods for the synthesis of diketone 11a are
reported in the literature, in our hands attempts to obtain 11a via
BakereVenkataraman rearrangement of 2-acetylphenyl acetate
were low yielding.23e25 The only procedure that provided 11a in
satisfactory yield was that reported recently by Patonay et al.26
Thus, Claisen condensation of 10a with ethyl acetate using so-
dium hydride as base afforded 11a in high yield.
a
Method A: NaH (4 equiv), EtOAc (2.5 equiv), THF, rt, 15 min; method B: LiHMDS
(3 equiv), Boc2O (1.1 equiv), THF, ꢀ78 ꢁC to rt, 18 h.
some experimentation, the optimal reaction conditions (TMSOTf
1 equiv, CH2Cl2, rt) provided the desired chromanone 9a in only
20% yield. Other Lewis acids (BF3$OEt2, TiCl4, SnCl2) failed to pro-
mote the addition. Hoping that the acetyl group in 7e would confer
greater reactivity to the chromenone, we applied the same reaction
conditions to chromenone 7e (entry 2), but the yield of 9b was still
unsatisfactory (21%). In addition, the ketoeenol tautomerism of 9b
afforded complex spectra making identification and separation via
HPLC of the possible diastereomers difficult.
Chromenone 7g appeared to be a good candidate to improve the
conjugate addition, hoping that its enhanced reactivity due to the
presence of the electron-withdrawing COt2Bu group at C-3 would
facilitate the conjugate addition. The C-3 group could then be
removed under mild conditions to afford chromanone 9a. With this
in mind, the same reaction conditions used for 7e were applied to
7g (entry 3).
Reaction of 7g with 8a afforded an inseparable mixture of
unreacted chromenone 7g and chromanone 9a rather than the
expected chromanone. Compound 9a could arise either from
TMSOTf-promoted in situ decarboxylation of the expected product,
or in situ decarboxylation of chromenone 7a with subsequent
addition of the silyl enol ether. Treatment of a solution of 7g with
TMSOTf, however, did not provide 7a, suggesting that the first
possibility is most likely.
Reports by Wallace et al.27 and later Scheidt et al.7 have dem-
onstrated that 3-ester substituents on chromanones can be re-
moved by simple decarboxylation under mildly acidic conditions. It
was hoped that an ester substituent at the 3-position would in-
crease the reactivity of the chromenone electrophile in conjugate
additions, and importantly, it would be readily removed or deri-
vatised in subsequent steps. The 3-tert-butyl ester substituted
chromenone 7g was derived from the corresponding b-keto ester
11c. In turn,11c was synthesised in 79% yield from 10a using lithium
bis(trimethylsilyl)amide and di-tert-butyl dicarbonate (Table 1).
Treatment of the dicarbonyl compounds 11a and 11c with acetic
formic anhydride28 and sodium formate in THF then afforded the
desired chromenones 7e and 7g as crystalline solids in moderate
yield (Table 2).29 Alternatively, the 2-methyl derivatives 7f and 7h
could be synthesised in an analogous manner from the same dicar-
bonyl compounds 11a and 11c using acetic anhydride and sodium
acetate, providing the chromenones in moderate yield. 5-Methoxy-
substituted chromenones 7b and 7d were also synthesised in good
yields from 10b and 11b, respectively. 3,30 Known chromenones 7a
and 7c31 were also prepared from phenols 10a and 11a for the pur-
pose of comparison with their C-3 and C-5 substituted counterparts.
The presence of the electron-withdrawing COt2Bu substituent at
C-3 in 7g afforded no increase in reactivity of the chromenone.
Hoping to improve the efficiency of the conjugate addition process
before attempting an asymmetric variant, we next turned to the use
of the morereactive silyl ketene acetal 8b. The improved reactivityof
8b was immediately apparent, with the known chromanone 9c
isolated in highyield upon reactionwith 7a using TMSOTf as catalyst
in CH2Cl2 for 4 h. The reaction of 8b with an array of chromenones
7bef was then examined to investigate the effect of substituents at
both C-2 and C-3 on the conjugate addition reaction.
As expected, substitution at C-2 using 7c, 7d, and 7f led to de-
creased efficiency of the reaction (entries 6, 7, and 9), an important
consideration for the future synthesis of more complex natural
product frameworks using this approach. Furthermore, the pres-
ence of increased electron density in the benzene ring (methoxy-
group at C-5) and C-2 substitution in 7d resulted in reduced yields
2.2. Conjugate addition of silyl enol ethers to chromenones
Acetophenone-derived silyl enol ether 8a was first selected to
probe the conjugate addition to chromenone 7a (Table 3). After

6950
L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
Table 2
Table 3
Summary of practical methods for preparation of chromenones 7aeh
Conjugate addition of silyl enol ethers 8aec to chromenones 7aef
Entry
1
Phenol
Methoda
A
Product
Yield (%)
92
10a
7a
7b
7c
7d
7e
7f
Entry Chrome Silyl
Methoda
Product
Yield (%)
none
enol
ether
2
3
4
5
6
7
10b
11a
11b
11a
11a
A
B
B
C
D
81
92
93
73
48
1
7a
8a
A
9a 26
21b
dr, n.d.
9a 20
2
3
7e
7g
8a
8a
A
A
9b
4
5
6
7a
7b
7c
8b
8b
8b
B
B
B
9c 80
9d >99
9e 71
11c
11c
C
7g
7h
55
22
7
8
7d
8b
8b
B
B
9f 18
8
D
10b
dr, n.d.
a
Method A: NaH, ethyl formate, then HCl; method B: HCl, MeOH; method C:
HCO2Na, acetic formic anhydride, THF; method D: NaOAc, Ac2O, reflux.
7e
9g
of chromanone (entry 7). Unfortunately, reactions with chrome-
nones 7g and 7h were unsuccessful and did not provide the
expected chromanones.
16b
dr, n.d.
Use of 2-(trimethylsilyloxy)furan 8c as the nucleophile in the
conjugate addition was also examined. Porco et al.32 had earlier
reported a similar addition of 8c to a related chromenone, utilising
stoichiometric benzopyrylium ion methodology. In the present
work, employing a 2-fold excess of 8c in the reaction afforded good
yields of adducts 9iek, which were obtained as diastereomeric
mixtures (entries 10e12). Again, C-2 substitution resulted in lower
reactivity in the conjugate addition (entry 13).
9
7f
8b
8c
8c
B
C
C
9h
9i
77
dr, 3:2
10
11
7a
7e
2.3. Asymmetric conjugate addition study
77
dr, 77:23
Cu(II)ebox catalysts have been successfully used to effect a vari-
ety of asymmetric reactions, including the MukaiyamaeMichael
addition of 2-(trimethylsilyloxy)furan to (E)-3-crotonoyl-1,3-
oxazolidin-2-one.33,34
9j

L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
6951
Table 3 (continued )
Entry Chrome Silyl
Methoda
Product
Yield (%)
none
enol
ether
76
dr, 73:27
12
7b
8c
8c
C
9k
9
dr, n.d.
13
7c
C
9l
Fig. 4. Chiral catalysts screened in the MukaiyamaeMichael reaction.
a
Method A: 8a (1.5 equiv), TMSOTf (1 equiv), CH2Cl2, ꢀ78 ꢁC to rt, 4 h; method B:
8b (1.2 equiv), TMSOTf (1 equiv), CH2Cl2, rt, 4 h; method C: 8c (2.2 equiv), TMSOTf
(1.1 equiv), CH2Cl2, ꢀ78 ꢁC, 2 h. n.d.¼not determined.
adduct 9g in lower yield than its unsubstituted counterpart 9c
(entries 5e7). Changing the counterion to the less coordinating
SbFꢀ6 (entry 6) had little effect, resulting in a small increase in yield
only. Reasoning that the low yields were a result of irreversible
binding of the Lewis acid complex to the substrate, we attempted to
increase turnover of the metal centre by adding TMSCl to the
mixture (entry 7).36 This did improve the yield slightly, but not to
a synthetically useful extent.
Unfortunately, in each case the products 9cei obtained were
racemic. The lack of stereocontrol may be due to several factors, and
further work is underway to identify ligand classes that will suc-
cessfully effect enantioselective conjugate addition to these het-
erocyclic systems.
b
Diastereomeric ratios for these compounds were unable to be determined due
to overlapping of signals in the 1H NMR spectra.
Given that silyl enol ethers 8b and 8c and chromenones 7a and
7e gave the highest yields in the racemic conjugate addition re-
actions, these compounds were selected to investigate an asym-
metric variant of this reaction (Table 4).
Table 4
Cu(II)ebox and Cu(II)epybox promoted conjugate addition of silyl enol ethers 8b
and 8c to chromenones 7a and 7e
3. Conclusion
In summary, we herein report the conjugate addition of silyl
enol ethers to a variety of substituted chromenones. In most cases
the 2-alkyl chromanones were obtained in good yield in the pres-
ence of TMSOTf. The presence of electron-withdrawing sub-
stituents at C-3 did not increase the reactivity of the chromenones
towards conjugate addition, and C-2 substitution reduced the yield
of products obtained. The copper(II)-promoted conjugate addition
of silyl enol ethers to chromenones was also carried out, albeit in
low yield. Investigations into an asymmetric variant of this reaction
have not been successful to date and further work to achieve this
goal is currently underway.
Entry Chromenone Silyl enol ether Ligand Methoda Product Yieldb (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7e
7e
7e
7e
7a
8b
8b
8b
8b
8b
8b
8b
8c
8c
12
14
15
13
12
12
12
12
12
A
A
A
A
A
B
C
D
D
9c
9c
9c
9c
9g
9g
9g
9i
20
<10
23
20
11
16
22
<10
48
Furthermore, a number of the chromenone substrates, though
previously reported, were not supported by detailed experimental
procedures or characterisation data. Reliable syntheses of these
9i
a
Method A: 20 mol % ligand 12e15, 20 mol % Cu(OTf)2, CH2Cl2, rt, 4 h; method B:
20 mol % 12, 20 mol % CuCl2, 20 mol % AgSbF6, CH2Cl2, rt, 4 h; method C: 20 mol % 12,
20 mol % Cu(OTf)2, 1 equiv TMSCl, CH2Cl2, rt, 4 h; method D: 20 mol % 12, 20 mol %
Cu(OTf)2, CH2Cl2, ꢀ78 ꢁC to rt, 1 h.
compounds via acylation of the corresponding
b-diketo-com-
pounds have been carried out, and these detailed experimental
procedures have been provided together with full spectroscopic
characterisation data.
b
Diastereomeric ratio of products identical to material prepared in the TMSOTf-
promoted conjugate additions (Table 3).
4. Experimental
The chiral complexes were generated in situ, followed by addi-
tion of the chromenone 7a or 7e, then silyl enol ether 8b or 8c.
Several ligands were screened for this transformation, including
diPhBOX 12, PyBOX 14, IndaBOX 13, and IndaPyBOX 15 (Fig. 4).35
The yields of chromanones 9c, 9g, and 9i obtained using these
chiral catalysts were significantly lower than those promoted by
TMSOTf. This is likely due to the reaction taking place via a Lewis
acid-catalysed mechanism, rather than through a benzopyrylium
ion as in the case of TMSOTf-promoted additions. To date, most
reported examples of conjugate addition to chromenones have
required stoichiometric generation of benzopyrylium salts.
4.1. General information and materials
Reagents purchased from commercial sources were used as re-
ceived. All reactions were carried out under an inert atmosphere of
N2. THF was distilled from sodium/benzophenone immediately
prior to use. Dichloromethane was distilled from CaH2. Melting
points were recorded on a hot-stage apparatus and are uncorrected.
1H and 13C NMR spectra were recorded on a Bruker Avance-300 or
DRX-400 at the frequencies stated, and are referenced to tetrame-
thylsilane at 0.00 ppm for 1H in CDCl3 and residual solvent signals
at 77.0 ppm for 13C in CDCl3. IR spectra were obtained using a Per-
kinElmer Spectrum100 UATR FT-IR spectrometer, using either
Again, attempts to improve the yield through addition of an
electron-withdrawing group at C-3 proved futile, providing the

6952
L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
a solid or thin film of the compound to be analysed. High-resolution
mass spectra were obtained by electron spray ionisation (ESI) using
a microTOF-Q mass spectrometer. HPLC was performed on a Daicel
ChiralpakÔ IC column using Dionex Ultimate 3000Ô HPLC kit with
Chromeleon software.
4.6. 1-Ethoxy-1-(tert-butyldimethylsilyloxy)ethene (8b)
Prepared according to the procedure reported by Jacobsen and
Wenzel.39 1H NMR (300 MHz, CDCl3)
(d, J¼2.3 Hz, 1H), 3.05 (d, J¼2.3 Hz, 1H), 1.29 (t, J¼7.0 Hz, 3H), 0.92
(s, 9H), 0.17 (s, 6H). Spectral data are in agreement with literature
values.39
d
3.74 (q, J¼7.0 Hz, 2H), 3.21
4.2. General procedure A: preparation of chromanones 9ael
via TMSOTf-catalysed conjugate addition of 8a, 8b, or 8c
4.7. 1-(2-Hydroxyphenyl)butane-1,3-dione (11a)
TMSOTf (1 equiv) was added to a solution of the chromenone
(1 equiv) in dichloromethane (1 mL/0.1 mmol chromenone) at
room temperature, and the mixture allowed to stir for 15 min. A
solution of silyl enol ether 8a (1.5 equiv), silyl ketene acetal 8b
(1.2 equiv), or 8c (2.2 equiv) in dichloromethane (1 mL/0.1 mmol)
was then added dropwise, and the resulting mixture allowed to stir
for an additional 4e6 h. Satd aq NaHCO3 was added, and the
mixture extracted with dichloromethane three times. The com-
bined organic extracts were washed with brine, dried over MgSO4,
and concentrated under reduced pressure to afford the crude
adducts.
Prepared according to the procedure reported by Patonay et al.26
Sodium hydride (60% dispersion in mineral oil, 3.53 g, 88.2 mmol)
was rinsed three times with hexanes, then suspended in THF
(9 mL).
A
mixture of 20-hydroxyacetophenone 10a (2.65 mL,
22.0 mmol) and EtOAc (5.42 mL, 55.1 mmol) in THF (2.5 mL) was
added dropwise to the above suspension at room temperature. A
vigorous reaction was observed, and the temperature rose to reflux.
After complete addition, the reaction mixture was stirred for a fur-
ther 5 min, then quenched by pouring onto ice, then acidified to pH
6 with 6 M aq HCl. The resulting precipitate was collected via fil-
tration, washed with water, and dried under high vacuum to afford
the title compound 11a (3.41 g, 87%) as a crystalline white solid as
4.3. General procedure B: asymmetric Lewis acid-catalysed
conjugate addition of silyl enol ether 8b or 8c to chromenones
7a and 7e
a
1:4 mixture of keto/enol tautomers: mp 90e92 ꢁC (lit.26
93e96 ꢁC). Rf (hexanes/EtOAc 7:3): 0.47. IR: 3361, 2920, 1674,
1608, 1327, 1115, 1087, 891, 775 cmꢀ1 1H NMR (400 MHz, CDCl3)
14.97 (s, 1H), 12.06 (s, 1H), 11.93 (s, 0.25H), 7.90
(dd, J¼1.7, 7.8 Hz,
0.25H), 7.63 (dd, J¼1.5, 8.2 Hz,1H), 7.53e7.47 (m, 0.25H), 7.44 (ddd,
J¼1.5, 7.0, 8.5 Hz, 1H), 7.06e6.98 (m, 0.25H), 6.97 (dd, J¼1.0, 8.5 Hz,
1H), 6.94e6.90
(m, 0.25H), 6.88 (ddd, J¼1.0, 7.0, 8.2 Hz, 1H), 6.18
(s, 1H), 4.10 (s, 0.5H), 2.32
(s, 0.75H), 2.15 (s, 3H). 13C NMR
(100 MHz, CDCl3) 195.6, 190.9 , 186.2 , 183.1, 162.7, 160.4 , 137.4
135.9, 128.6, 126.8 , 119.5 , 119.2 , 118.3, 95.6,
.
d
*
*
Cu(OTf)2 (0.2 equiv) was added to a solution of the ligand
(0.2 equiv) in dichloromethane (5 mL) and the resulting brightly
coloured solution allowed to stir at room temperature for 10 min. A
solution of the chromenone (1 equiv) in dichloromethane (0.5 mL/
0.1 mmol) was then added dropwise, and the mixture allowed to
stir for 30 min. A solution of silyl ketene acetal 8b (1.2 equiv) or silyl
enol ether 8c (3 equiv) in dichloromethane (1 mL/0.1 mmol) was
then added dropwise, and the mixture allowed to stir for a further
4e6 h. Water (10 mL) was added, and the mixture extracted with
dichloromethane three times. The combined organic extracts were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure to afford the crude adducts.
*
*
*
*
*
d
*
*
*
*
,
*
*
*
, 119.1, 118.8, 118.6
*
47.9
*
, 30.7
*
, 22.9. HRMS (ESI) calcd for C10H11O3 [MH]þ 179.0703;
*
found 179.0699. ¼keto (minor) tautomer. Spectral data are in
agreement with literature values.25
4.8. 1-(2-Hydroxy-6-methoxyphenyl)-1,3-butanedione (11b)
Prepared as for 11a, from 20-hydroxy-60-methoxyacetophenone
10b (1.25 g, 7.52 mmol), as a yellow powder (1.20 g, 77%) and as
a 2:1 mixture of keto/enol tautomers: mp 99e100 ꢁC (lit.40
96e97 ꢁC). Rf (hexanes/EtOAc 7:3): 0.36. 1H NMR (400 MHz,
4.4. Procedure for counterion exchange to SbFL6 (method B,
Table 4)
CDCl3)
(t, J¼8.5 Hz, 1H), 7.30
1H), 6.57
(dd, J¼1.6, 8.5 Hz, 0.5H), 6.40e6.38 (m, 1.5H), 4.07 (s, 2H),
3.89 (s, 1.5H), 3.86 (s, 3H), 2.25 (s, 3H), 2.13
(s, 1.5H). 13C NMR
(100 MHz, CDCl3) 202.2, 200.4 , 194.5, 183.5 , 165.2, 164.0
160.4 , 137.1, 135.1 , 111.3, 111.2 , 111.1, 110.0 , 101.9 , 101.8
60.2, 55.9
d
15.30
*
(s, 0.5H), 12.95 (s, 1H), 12.48
*
(s, 0.5H), 7.38
A
mixture of CuCl2 (4 mg, 0.03 mmol), AgSbF6 (22 mg,
*
(t, J¼8.5 Hz, 0.5H), 6.61 (dd, J¼1.0, 8.5 Hz,
0.06 mmol), and ligand 12 (15 mg, 0.03 mmol) was diluted with
dichloromethane (5 mL) and the mixture allowed to stir at room
temperature for 1 h, becoming yellow-green in colour. A solution of
7e (30 mg, 0.16 mmol) in dichloromethane (1.5 mL) was then added
and the resulting pale blue mixture allowed to stir for 0.5 h. A so-
lution of 8b (39 mg, 0.19 mmol) in dichloromethane (1.5 mL) was
then added dropwise and the resulting green-yellow mixture
allowed to stir for an additional 3.5 h. Water (10 mL) was added, and
the organic layer removed. The aqueous layer was extracted with
dichloromethane (2ꢂ10 mL) and the combined organic extracts
dried over MgSO4 and concentrated under reduced pressure to af-
ford a yellow-brown solid. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 1:9 as
eluent) to give 9g (7 mg, 16%) as a colourless oil. Spectral data were
identical with material prepared according to general procedure A.
*
*
*
d
*
*
*
*
, 160.9,
, 101.3,
*
*
*
*
*
*
, 55.8, 30.3, 23.1
. HRMS (ESI) calcd for C11H13O4 [MH]þ
*
209.0808; found 209.0806. *¼enol (minor) tautomer.
4.9. tert-Butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (11c)
A solution of 20-hydroxyacetophenone 10a (1.77 mL, 14.7 mmol)
in THF (40 mL) was added dropwise via addition funnel to a solu-
tion of LiHMDS (1.0 M in THF, 44.1 mL, 44.1 mmol) at ꢀ78 ꢁC. The
mixture was allowed to stir at this temperature for 2 h, then a so-
lution of di-tert-butyl dicarbonate (3.60 mL, 15.9 mmol) in THF
(15 mL) was added quickly. The mixture was allowed to slowly
warm to room temperature and stirred overnight. The mixture was
then poured onto a mixture of ice (100 mL) and concd HCl (10 mL).
The resulting solution was extracted with dichloromethane
(3ꢂ150 mL) and the combined organic extracts were washed with
water (2ꢂ100 mL), dried over Na2SO4, and concentrated under re-
duced pressure to afford an orange oil. The crude product was
purified via flash column chromatography (silica gel, ethyl acetate/
4.5. 1-Phenyl-1-(trimethylsilyloxy)ethene (8a)
Prepared according to the procedure reported by Watts et al.37
1H NMR (300 MHz, CDCl3)
d 7.62e7.59 (m, 2H), 7.32e7.29 (m, 3H),
5.04 (d, J¼2.2 Hz, 1H), 4.78 (d, J¼2.2 Hz, 1H), 0.16 (s, 9H). Spectral
data are in agreement with literature values.38

L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
6953
hexanes 1:9 as eluent) to give the title compound 11c (2.74 g, 79%)
as a bright yellow oil: Rf (hexanes/EtOAc 7:3): 0.71. 1H NMR
J¼0.8, 8.3 Hz, 1H), 6.78 (d, J¼8.3 Hz, 1H), 6.07 (d, J¼0.8 Hz, 1H), 3.97
(s, 3H), 2.30 (s, 3H). Spectral data are in agreement with literature
values.3
(400 MHz, CDCl3)
d
11.91 (s, 1H), 7.67 (dd, J¼1.6, 8.1 Hz, 1H),
7.52e7.47 (m, 1H), 7.01e6.99 (m, 1H), 6.94e6.90 (m, 1H), 3.91
(s, 2H), 1.46 (s, 9H). Spectral data are in agreement with literature
values.7
4.14. 3-Acetyl-4H-chromen-4-one (7e)
Acetic formic anhydride28 (14.0 mL, 103 mmol) was added to
a solution of 11a (1.50 g, 8.42 mmol) and sodium formate (0.740 g,
10.9 mmol) in THF (15 mL) at room temperature and the mixture
allowed to stir for 24 h. Water (30 mL) was added and the mixture
extracted with ethyl acetate (3ꢂ30 mL). The combined organic
extracts were washed with satd aq NaHCO3 (50 mL), water, (50 mL),
and brine (50 mL) then dried over MgSO4, and concentrated under
reduced pressure to afford a peach solid. The crude product was
recrystallised from ethanol to afford the title compound 7e (1.15 g,
73%) as fluffy white needles: mp 125e128 ꢁC (lit.29 129 ꢁC). Rf
4.10. Chromone (1-benzopyran-4-one, 7a)
Prepared according to the procedure reported by Li et al.30 So-
dium hydride (60% dispersion in mineral oil, 1.06 g, 44.1 mmol,
washed three times with hexanes) was added portion-wise to
a solution of 20-hydroxyacetophenone 10a (0.88 mL, 7.34 mmol) in
ethyl formate (60 mL) at 0 ꢁC over a period of 2 h. The mixture was
allowed to stir for a further 1.5 h, then quenched with methanol
(3.5 mL). Concd HCl (11.5 mL) was added, and the mixture allowed
to warm to room temperature and stirred for another 16 h. Water
(50 mL) was added, and the mixture extracted with dichloro-
methane (3ꢂ50 mL). The combined organic extracts were washed
with brine (100 mL), dried over MgSO4, and concentrated under
reduced pressure to afford a yellow oil. The crude product was
purified via flash column chromatography (silica gel, ethyl acetate/
hexanes 1:9 as eluent) to give the title compound 7a (0.990 g, 92%)
as pale yellow crystals: mp 52e54 ꢁC (lit.41 55e57 ꢁC). Rf (hexanes/
(hexanes/EtOAc 7:3): 0.37. IR: 1992, 1611, 1312, 1080, 745, 627 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
8.61 (s, 1H), 8.29 (dd, J¼1.6, 8.0 Hz, 1H),
7.73 (ddd, J¼1.6, 7.0, 8.6 Hz, 1H), 7.53e7.47 (m, 2H), 2.75 (s, 3H). 13C
NMR (100 MHz, CDCl3)
d 196.7, 175.3, 161.7, 155.8, 134.3, 126.4,
126.3, 125.3, 122.8, 118.2, 31.5. HRMS (ESI) calcd for C11H9O3 [MH]þ
189.0546; found 189.0547.
4.15. 3-Acetyl-2-methyl-4H-chromen-4-one (7f)
EtOAc 1:1): 0.46. 1H NMR (400 MHz, CDCl3)
d
8.21 (dd, J¼1.8, 8.0 Hz,
1H), 7.85 (d, J¼6.0 Hz, 1H), 7.70e7.66 (m, 1H), 7.46 (br d, J¼7.8 Hz,
1H), 7.41 (br t, J¼7.8 Hz, 1H), 6.35 (d, J¼6.0 Hz, 1H). Spectral data are
in agreement with literature values.22
Acetic anhydride (6.00 mL) was added to a mixture of 11a
(0.700 g, 3.93 mmol) and sodium acetate (0.338 g, 4.13 mmol) and
the mixture heated at reflux for 3 h. The mixture was allowed to
cool to room temperature, whereupon it solidified to an orange
mass. The mixture was diluted with toluene (30 mL) and filtered to
remove undissolved salts. The filtrate was stirred with water
(30 mL) for 1.5 h. The organic layer was then removed, dried over
MgSO4, and concentrated under reduced pressure to afford orange
crystals. The crude product was purified via flash column chro-
matography (silica gel, ethyl acetate/hexanes 1:4 as eluent) to give
the title compound 7f (0.382 g, 48%) as white crystals: mp:
84e88 ꢁC (lit.44 89e90 ꢁC). Rf (hexanes/EtOAc 7:3): 0.40. IR: 2923,
4.11. 5-Methoxy-4H-chromen-4-one (7b)
Prepared as for 7a, from 20-hydroxy-60-methoxyacetophenone
10b (0.500 g, 3.01 mmol) as white crystals (0.430 g, 81%): mp
81e84 ꢁC (lit.42 83e84 ꢁC). Rf (hexanes/EtOAc 1:9): 0.40. IR: 3074,
1921, 1637, 1600, 1432, 1083, 741, 686 cmꢀ1 1H NMR (400 MHz,
.
CDCl3)
d
7.67 (d, J¼5.9 Hz, 1H), 7.54 (t, J¼8.4 Hz, 1H), 7.00 (dd, J¼0.7,
8.4 Hz, 1H), 6.82e6.80 (m, 1H), 6.24 (d, J¼5.9 Hz, 1H), 3.98 (s, 3H).
13C NMR (100 MHz, CDCl3)
d
177.3, 159.8, 158.5, 153.0, 133.7, 115.6,
1688, 1635, 1614, 1561, 1463, 1387, 1216, 1124, 1060, 952, 757 cmꢀ1
1H NMR (400 MHz, CDCl3)
8.14 (dd, J¼1.5, 8.0 Hz, 1H), 7.67 (ddd,
J¼1.5, 7.4, 8.8 Hz, 1H), 7.41e7.37 (m, 2H), 2.63 (s, 3H), 2.51 (s, 3H).
13C NMR (100 MHz, CDCl3)
200.1, 175.5, 168.2, 155.0, 133.8, 125.4,
.
114.6, 110.2, 106.4, 56.4. HRMS (ESI) calcd for C10H9O3 [MH]þ
177.0546; found 177.0548.
d
d
4.12. 2-Methyl-4H-chromen-4-one (7c)
125.2, 123.34, 123.26, 117.4, 31.8, 19.5. HRMS (ESI) calcd for
C12H10NaO3 [MNa]þ 225.0522; found 225.0529.
Prepared according to the procedure reported by Shaw et al.3
Concd HCl (1 mL) was added to
a
solution of 11a (2.50 g,
4.16. 3-tert-Butoxycarbonyl-4H-chromen-4-one (7g)
14.0 mmol) in methanol (30 mL), and the mixture allowed to stir at
room temperature for 14 h. The mixture was concentrated under
reduced pressure and the residue diluted with EtOAc (50 mL), then
washed successively with solutions of satd aq NaHCO3 (3ꢂ30 mL),
water (30 mL), and brine (30 mL). The organic layer was then dried
over MgSO4 and concentrated under reduced pressure to afford an
orange solid. The crude product was purified via flash column
chromatography (silica gel, ethyl acetate/hexanes 1:4 as eluent) to
give the title compound 7c (2.07 g, 92%) as a yellow solid: mp
67e70 ꢁC (lit.43 69e70 ꢁC). Rf (hexanes/EtOAc 7:3): 0.33. 1H NMR
Prepared as for 7e, from 11c (1.50 g, 6.35 mmol) to afford a yel-
low solid. The crude product was purified via flash column chro-
matography (silica gel, ethyl acetate/hexanes 3:17 as eluent) to give
the title compound 7g (0.857 g, 55%) as white crystalline flakes: mp
101e105 ꢁC. Rf (hexanes/EtOAc 7:3): 0.71. IR: 2969, 1728, 1648, 1615,
1570, 1562, 1463, 1392, 1289, 1089, 752 cmꢀ1
CDCl3)
7.2, 8.7 Hz, 1H), 7.48e7.42 (m, 2H), 1.60 (s, 9H). 13C NMR (100 MHz,
.
1H NMR (400 MHz,
d
8.58 (s, 1H), 8.28 (dd, J¼1.6, 8.0 Hz, 1H), 7.69 (ddd, J¼1.6,
CDCl3)
d 173.7, 162.2, 161.2, 155.6, 134.0, 126.6, 126.0, 125.3, 118.1,
(400 MHz, CDCl3)
8.6 Hz, 1H), 7.41e7.35 (m, 2H), 6.17 (d, J¼0.8 Hz, 1H), 2.38 (s, 3H).
d
8.17 (dd, J¼1.6, 8.0 Hz, 1H), 7.63 (ddd, J¼1.6, 7.2,
117.5, 82.3, 28.2. HRMS (ESI) calcd for C14H14NaO4 [MNa]þ
269.0784; found 269.0778.
Spectral data are in agreement with literature values.3
4.17. 3-tert-Butoxycarbonyl-2-methyl-4H-chromen-4-one
4.13. 5-Methoxy-2-methyl-4H-chromen-4-one (7d)
(7h)
Prepared as for 7c from 11b (1.20 g, 5.76 mmol). Purified via
flash column chromatography (silica gel, ethyl acetate/hexanes 1:1
as eluent) to give the title compound 7d (1.02 g, 93%) as a pale
yellow solid: mp 95e97 ꢁC (lit.3 97e98 ꢁC). Rf (hexanes/EtOAc 1:1):
Sodium acetate (anhydrous, 182 mg, 2.22 mmol) was added to
a solution of 11c (500 mg, 2.11 mmol) in acetic anhydride (2.80 mL)
and the mixture heated at 100e110 ꢁC for 3 h. The mixture was
allowed to cool and diluted with toluene (5 mL). The mixture was
filtered through cotton wool to remove the salt and the filtrate
0.11. 1H NMR (400 MHz, CDCl3)
d
7.51 (t, J¼8.3 Hz, 1H), 6.97 (dd,

6954
L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
stirred with water (30 mL) for 3 h. The organic layer was removed,
dried over MgSO4, and concentrated under reduced pressure to
afford an orange oil. The crude product was purified via flash col-
umn chromatography (silica gel, ethyl acetate/hexanes 1:9 as elu-
ent) to give the title compound 7h (122 mg, 22%) as white needles:
mp 70e76 ꢁC. Rf (hexanes/EtOAc 7:3): 0.59. IR: 2978, 1769, 1723,
1647, 1575, 1464, 1400, 1366, 1254, 1222, 1129, 1073, 762 cmꢀ1. 1H
4.21. Ethyl 2-(5-methoxy-4-oxochroman-2-yl)acetate (9d)
Prepared according to general procedure A from chromenone 7b
(50 mg, 0.28 mmol) and silyl ketene acetal 8b (69 mg, 0.34 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 3:7 as
eluent) to give the title compound 9d (75 mg, >99%) as a yellow oil:
NMR (400 MHz, CDCl3)
7.2, 8.8 Hz, 1H), 7.41e7.36 (m, 2H), 2.48 (s, 3H), 1.61 (s, 9H). 13C NMR
(100 MHz, CDCl3) 174.4, 165.2, 164.3, 155.7, 133.7, 126.0, 125.3,
d
8.18 (dd, J¼1.6, 7.8 Hz, 1H), 7.64 (ddd, 1.6,
Rf (hexanes/EtOAc 7:3): 0.10. 1H NMR (400 MHz, CDCl3)
d 7.36
(t, J¼8.4 Hz, 1H), 6.57e6.51 (m, 2H), 4.90e4.83 (m, 1H), 4.21
(q, J¼7.0 Hz, 2H), 3.91 (s, 3H), 2.87 (dd, J¼7.4, 15.8 Hz, 1H), 2.74
(d, J¼7.6 Hz, 2H), 2.69 (dd, J¼5.6, 15.8 Hz, 1H), 1.29 (t, J¼7.0 Hz, 3H).
Spectral data are in agreement with literature values.45
d
123.5, 119.7, 117.7, 82.7, 28.1, 19.1. HRMS (ESI) calcd for C15H16NaO4
[MNa]þ 283.0941; found 283.0938.
4.22. Ethyl 2-(2-methyl-4-oxochroman-2-yl)acetate (9e)
4.18. 2-(2-Oxo-2-phenylethyl)chroman-4-one (9a)
Prepared according to general procedure A from chromenone 7c
(50 mg, 0.31 mmol) and silyl ketene acetal 8b (76 mg, 0.37 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 1:9 as
eluent) to give the title compound 9e (55 mg, 71%) as a colourless
oil: Rf (hexanes/EtOAc 7:3): 0.42. IR: 2940, 1733, 1693, 1609, 1581,
1464, 1375, 1309, 1115, 1030, 765 cmꢀ1. 1H NMR (400 MHz, CDCl3)
Prepared according to general procedure A from chromenone 7a
(50 mg, 0.34 mmol) and silyl enol ether 8a (99 mg, 0.51 mmol) to
afford an orange oil. The crude product was purified via flash col-
umn chromatography (silica gel, ethyl acetate/hexanes 1:9 as elu-
ent) to give the title compound 9a (24 mg, 26%) as yellow crystals:
mp: 85e92 ꢁC (lit.45 99e102 ꢁC). Rf (hexanes/EtOAc 7:3): 0.56. 1H
NMR (400 MHz, CDCl3)
d
8.00e7.98 (m, 2H), 7.90 (dd, J¼1.7, 7.9 Hz,
d
7.86 (dd, J¼1.8, 7.8 Hz, 1H), 7.50e7.45 (m, 1H), 7.02e6.98 (m, 1H),
1H), 7.63e7.59 (m, 1H), 7.52e7.44 (m, 3H), 7.03 (td, J¼0.7, 7.9 Hz,
1H), 6.93 (d, J¼8.3 Hz, 1H), 5.21e5.14 (m, 1H), 3.70 (dd, J¼6.4,
17.0 Hz, 1H), 3.29 (dd, J¼6.0, 17.0 Hz, 1H), 2.92 (dd, J¼3.3, 16.8 Hz,
1H), 2.80 (dd, J¼12.2, 16.8 Hz, 1H). Spectral data are in agreement
with literature values.45
6.94e6.92 (m, 1H), 4.15 (q, J¼7.3 Hz, 2H), 3.08 (d, J¼16.7 Hz, 1H),
2.82e2.72 (m, 3H), 1.56 (s, 3H), 1.26 (t, J¼7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d 191.5, 169.2, 159.1, 136.2, 126.4, 121.1, 120.1,
118.3, 79.1, 60.7, 46.8, 43.9, 24.5, 14.1. HRMS (ESI) calcd for
C14H16NaO4 [MNa]þ 271.0941; found 271.0941.
4.23. Ethyl 2-(5-methoxy-2-methyl-4-oxochroman-2-yl)
acetate (9f)
4.19. 3-Acetyl-2-(2-oxo-2-phenylethyl)chroman-4-one (9b)
Prepared according to general procedure A from chromenone 7e
(50 mg, 0.27 mmol) and silyl enol ether 8a (77 mg, 0.40 mmol) to
afford an orange oil. The crude product was purified via flash col-
umn chromatography (silica gel, ethyl acetate/hexanes 1:9 as elu-
ent) to give the title compound 9b (8 mg,10%) as a pale yellow oil as
an approximately 1:8 mixture of keto/enol tautomers: Rf (hexanes/
EtOAc 7:3): 0.59. IR: 3065, 2923, 1718, 1682, 1604, 1463, 1448, 1359,
Prepared according to general procedure A from chromenone 7d
(50 mg, 0.26 mmol) and silyl ketene acetal 8b (64 mg, 0.32 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 3:7 as
eluent) to give the title compound 9f (13 mg, 18%) as a brown oil: Rf
(hexanes/EtOAc 7:3): 0.16. IR: 2920, 1732, 1686, 1601, 1576, 1473,
1338, 1256, 1087, 1034, 790 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 7.37
1302, 1216, 1149, 974, 755, 690 cmꢀ1
7.88 (dd, J¼1.6, 7.9 Hz, 1H), 7.85e7.82 (m, 2H), 7.58e7.54 (m, 1H),
7.44e7.36 (m, 3H), 7.06 (td, J¼0.7, 7.9 Hz, 1H), 6.93e6.91 (m,
0.13H), 6.76 (dd, J¼0.7, 8.4 Hz, 1H), 5.99 (dd, J¼4.0, 8.8 Hz, 1H),
5.49e5.44 (m, 0.13H), 4.11
(d, J¼9.9 Hz, 0.13H), 3.79 (dd, J¼8.8,
16.3 Hz, 1H), 3.48e3.37
(m, 0.26H), 2.93 (dd, J¼4.0, 16.3 Hz, 1H),
2.45 207.3
(s, 0.39H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3)
202.7 , 196.7, 189.5 , 188.0, 176.1, 156.7, 156.6 , 136.7 , 136.6, 135.1,
, 133.6 , 133.6, 128.7, 128.7 , 128.3, 128.3 , 126.2, 126.2 , 121.9,
, 119.3, 119.3 , 118.1, 118.1 , 105.5, 74.5 , 72.3, 62.9 , 43.6, 41.0
.
1H NMR (400 MHz, CDCl3)
(t, J¼8.4 Hz, 1H), 6.54e6.49 (m, 2H), 4.15 (q, J¼7.2 Hz, 2H), 3.91
d
(s, 3H), 3.02 (d, J¼16.1 Hz, 1H), 2.77e2.73 (m, 3H), 1.54 (s, 3H), 1.26
*
(t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 190.3, 169.3, 160.8,
160.3, 136.0, 110.6, 110.5, 103.6, 78.6, 60.7, 56.1, 48.4, 44.0, 24.3, 14.1.
*
*
HRMS (ESI) calcd for C15H18NaO5 [MNa]þ 301.1046; found 301.1023.
*
*
d
*
,
*
*
*
*
4.24. Ethyl 2-(3-acetyl-4-oxochroman-2-yl)acetate (9g)
135.1
121.8
*
*
*
*
*
*
*
*
*
*
*
,
Prepared according to general procedure A from chromenone 7e
(50 mg, 0.27 mmol) and silyl ketene acetal 8b (65 mg, 0.32 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 7:93 as
eluent) to give the title compound 9g (7 mg, 10%) as a pale yellow
oil as a 1:9 mixture of keto/enol tautomers: Rf (hexanes/EtOAc 7:3):
0.54. IR: 2980, 1731, 1684, 1606, 1461, 1369, 1302, 1164, 1034,
31.3
, 22.1. HRMS (ESI) calcd for C19H16NaO4 [MNa]þ 331.0941;
*
found 331.0937. *¼keto (minor) tautomer.
4.20. Ethyl 2-(4-oxochroman-2-yl)acetate (9c)
Prepared according to general procedure A from chromenone 7a
(50 mg, 0.34 mmol) and silyl ketene acetal 8b (83 mg, 0.41 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 1:9 as
eluent) to give the title compound 9c (66 mg, 80%) as a colourless
759 cmꢀ1
(dd, J¼1.7, 7.8 Hz, 1H), 7.53e7.48
7.08e7.02 (m, 1H), 6.98
(br d, J¼8.6 Hz, 0.1H), 6.89 (dd, J¼0.8,
8.4 Hz, 1H), 5.72 (dd, J¼4.2, 9.6 Hz, 1H), 5.20e5.15 (m, 0.1H),
.
1H NMR (400 MHz, CDCl3)
d
7.88e7.86
*
(m, 0.1H), 7.84
*
(m, 0.1H), 7.46e7.41 (m, 1H),
*
*
4.24e4.12 (m, 2H), 2.91 (dd, J¼9.6, 15.2 Hz, 1H), 2.47 (dd, J¼4.2,
oil: Rf (hexanes/EtOAc 7:3): 0.53. 1H NMR (400 MHz, CDCl3)
d
7.88
15.2 Hz, 1H), 2.43
*
(s, 0.3H), 2.21 (s, 3H), 1.27 (t, J¼7.1 Hz, 3H). 13
C
(dd, J¼1.7, 7.9 Hz, 1H), 7.49e7.45 (m, 1H), 7.04e7.00 (m, 1H), 6.97
(dd, J¼0.7, 8.5 Hz, 1H), 4.95e4.88 (m, 1H), 4.21 (q, J¼7.2 Hz, 2H),
2.92 (dd, J¼7.3, 15.8 Hz, 1H), 2.80e2.78 (m, 2H), 2.72 (dd, J¼5.6,
15.8 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H). Spectral data are in agreement
with literature values.45
NMR (100 MHz, CDCl3)
156.6, 141.2 , 135.2, 135.2
118.0, 104.9, 74.8 , 72.5, 62.1
d
220.8
*
*
, 203.1
*
*
, 187.9, 176.1, 169.8 , 169.8,
*
*
, 127.2
, 126.1, 122.0, 121.9
*
, 119.2, 118.1
, 32.3 , 30.9
*
,
,
*
*
, 61.0
*
, 60.9, 40.7, 37.7
*
*
*
29.7
*
,
22.0, 14.2. HRMS (ESI) calcd for C15H16NaO5 [MNa]þ
299.0890; found 299.0877. *¼keto (minor) tautomer.

L.A. Stubbing et al. / Tetrahedron 68 (2012) 6948e6956
6955
4.25. Ethyl 2-(3-acetyl-2-methyl-4-oxochroman-2-yl)acetate
(9h)
afford a brown solid. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 3:2 as
eluent) to give the title compound 9k (113 mg, 76%) as a pale orange
solid as a 73:27 mixture of diastereomers: mp 134 ꢁC (dec). Rf
(hexanes/EtOAc 1:9): 0.54. IR: 3081, 2940, 1742, 1470, 1103, 1086,
Prepared according to general procedure A from chromenone 9f
(50 mg, 0.25 mmol) and silyl ketene acetal 8b (60 mg, 0.30 mmol)
to afford an orange oil. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 1:9 as
eluent) to give the title compound 9h (12 mg,16%) as a yellow oil, as
a 3:2 mixture of keto/enol tautomers: Rf (hexanes/EtOAc 7:3): 0.42.
IR: 2931, 1723, 1685, 1607, 1584, 1463, 1375, 1357, 1320, 1303, 1234,
827 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
7.66e7.56 (m, 1H), 7.42e7.36
(m, 1H), 6.60e6.53 (m, 2H), 6.32e6.30 (m, 1H), 5.27 (br s, 1H), 4.71
(dt, J¼3.3, 13.3 Hz, 1H), 4.55 (dt, J¼4.2, 12.9 Hz, 0.27H), 3.90 (s, 3H),
2.99e2.66 (m, 2H). 13C NMR (100 MHz, CDCl3)
188.9, 188.6 , 171.9,
171.8 , 161.8, 161.7 , 160.6, 160.6 , 152.0 , 151.8, 136.2 , 136.2, 123.6,
123.3 , 111.1 , 111.0, 109.8, 109.7 , 104.7 , 104.5, 82.7 , 82.5, 76.2
75.2, 56.1, 56.1 , 40.0, 39.9
. HRMS (ESI) calcd for C14H13O5 [MH]þ
*
d
*
*
*
*
*
*
1187, 1128, 1084, 917, 762 cmꢀ1
(dt, J¼2.1, 7.9 Hz, 1.4H), 7.53e7.45 (m, 3H), 7.04e6.98 (m, 1.4H), 6.95
(br d, J¼8.6 Hz, 1.4H), 4.79 (s, 1H), 4.20e4.11 (m, 2.8H), 3.29
(d, J¼15.3 Hz, 0.4H), 2.86 (d, J¼15.3 Hz, 0.4H), 2.82 (d, J¼3.4 Hz,
2H), 2.40 (s, 3H), 2.32 (s, 1.2H), 1.60 (s, 3H), 1.54 (s, 1.2H), 1.30e1.24
(m, 4.2H). 13C NMR (100 MHz, CDCl3)
203.4, 201.8 , 189.8, 187.9
169.8, 169.5 , 158.8 , 158.7, 137.0 , 136.6, 126.9 , 126.5, 121.3 , 121.3,
120.6, 118.9 , 118.5, 118.5 , 98.8 , 81.0, 79.8 , 64.1, 60.8, 60.8 , 43.2,
41.2 , 33.1, 31.9 , 23.9 , 21.2, 14.2, 14.1
.
1H NMR (400 MHz, CDCl3)
d
7.83
*
*
*
*
*
*
,
*
*
*
*
261.0757; found 261.0758. ¼minor diastereomer.
*
*
*
4.29. 2-Methyl-2-(5-oxo-2,5-dihydrofuran-2-yl)chroman-4-
one (9l)
d
*
*
,
*
*
*
*
*
*
*
*
*
*
Prepared according to general procedure A from chromenone 7c
(100 mg, 0.62 mmol) and silyl enol ether 8c (315 mL, 1.86 mmol) to
*
*
*
*
. HRMS (ESI) calcd for
C16H18NaO5 [MNa]þ 313.1046; found 313.1044. ¼enol (minor)
*
afford a brown solid. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 2:3 as
eluent) to give the title compound 9l (14 mg, 9%) as an orange solid:
mp 99e100 ꢁC. Rf (hexanes/EtOAc 3:2): 0.36. IR: 3118, 2919, 1749,
tautomer.
4.26. 2-(5-Oxo-2,5-dihydrofuran-2-yl)chroman-4-one (9i)
1674, 1463, 1099, 891, 771 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d 7.88
Prepared according to general procedure A from chromenone 7a
(100 mg, 0.68 mmol) and silyl enol ether 8c (345 mL, 2.04 mmol) to
(dd, J¼1.7, 7.8 Hz,1H), 7.61 (dd, J¼1.5, 6.0 Hz, 1H), 7.54e7.50 (m, 1H),
7.07e7.03 (m, 1H), 6.98e6.96 (m, 1H), 6.31 (dd, J¼2.0, 6.0 Hz, 1H),
5.21 (t, J¼1.7 Hz, 1H), 3.03 (d, J¼16.5 Hz,1H), 2.80 (d, J¼16.8 Hz, 1H),
afford a brown solid. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 3:7 as
eluent) to give the title compound 9i (121 mg, 77%) as a pale orange
solid as a 3:2 mixture of diastereomers: mp 118 ꢁC (dec). Rf (hex-
anes/EtOAc 1:1): 0.34. IR: 3085, 1751, 1606, 1464, 1305, 1092, 818,
1.33 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 190.0, 171.8, 158.5, 152.3,
136.6, 126.7, 123.8, 121.8, 120.2, 118.0, 85.3, 80.8, 44.7, 19.1. HRMS
(ESI) calcd for C14H12NaO4 [MNa]þ 267.0628; found 267.0616.
767 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
7.86e7.83 (m, 1H), 7.71 (d,
*
Acknowledgements
J¼5.8 Hz, 0.4H), 7.61 (d, J¼5.8 Hz, 1H), 7.53e7.47 (m, 1H), 7.08e6.93
(m, 2H), 6.32e6.29 (m, 1H), 5.31 (br s, 1H), 4.79 (dt, J¼3.4, 13.4 Hz,
(dt, J¼4.7, 12.4 Hz, 0.4H), 3.02e2.72 (m, 2H). 13C NMR
We thank the Maurice Wilkins Centre for Molecular Biodiscovery
for financial support.
1H), 4.61
*
(100 MHz, CDCl3)
152.1 , 152.0, 136.3
121.9, 120.7
d
190.2, 189.9
*
, 171.83, 171.77
*
, 160.2, 160.1
*
*
,
,
*
*
, 136.2, 126.83
*
, 126.77, 123.3, 123.1
*
, 122.0
*
, 120.6, 117.68, 117.66
*
, 82.7
*
, 82.6, 76.7 , 75.4, 38.6,
*
Supplementary data
38.4
*
. HRMS (ESI) calcd for C13H11O4 [MH]þ 231.0652; found
*
Copies of 1H NMR and 13C NMR spectra for 7aeh, 9aei, and
11aec are provided. Supplementary data related to this article can
be found online at doi:10.1016/j.tet.2012.05.115.
231.0653. ¼minor diastereomer.
4.27. 5-(3-Acetyl-4-hydroxy-2H-chromen-2-yl)furan-2(5H)-
one (9j)
References and notes
Prepared according to general procedure A from chromenone 7e
(50 mg, 0.27 mmol) and silyl enol ether 8c (435 mL, 0.81 mmol) to
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afford a brown solid. The crude product was purified via flash
column chromatography (silica gel, ethyl acetate/hexanes 3:7 as
eluent) to give the title compound 9j (57 mg, 77%) as a dark yellow
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*
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, 126.4, 126.3
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*
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*
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, 151.0, 135.8, 135.7
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*
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, 99.3, 84.0
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, 22.1. HRMS (ESI) calcd for C15H12NaO5 [MNa]þ 295.0577;
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