Enantioselective synthesis of 3,4-dihydropyran derivatives via organocatalytic Michael reaction of α,β-unsaturated enones

Article abstract of DOI:10.1021/jo3001047

A simple chiral diamine catalyst (1a) was successfully applied in the asymmetric Michael reaction between cyclic dimedone and α,β- unsaturated ketones. Both acyclic enones with aryl or alkyl β-substituents and cyclic enones were tolerated well in the reaction. The desired adducts were obtained in high yields (up to 98%) with excellent enantioselectivities (up to 97% ee). The additives were found to increase the reactivity dramatically. The biologically active 2,4-disubstituted polyhydroquinoline scaffold was conveniently prepared through an ammoniation from the generated 3,4-dihydropyran product.

Full text of DOI:10.1021/jo3001047

Note
pubs.acs.org/joc
Enantioselective Synthesis of 3,4-Dihydropyran Derivatives via
Organocatalytic Michael Reaction of α,β-Unsaturated Enones
Yangbin Liu, Xiaohua Liu,* Min Wang, Peng He, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
S
* Supporting Information
ABSTRACT: A simple chiral diamine catalyst (1a) was success-
fully applied in the asymmetric Michael reaction between cyclic
dimedone and α,β-unsaturated ketones. Both acyclic enones with
aryl or alkyl β-substituents and cyclic enones were tolerated well in
the reaction. The desired adducts were obtained in high yields (up
to 98%) with excellent enantioselectivities (up to 97% ee). The
additives were found to increase the reactivity dramatically. The
biologically active 2,4-disubstituted polyhydroquinoline scaffold
was conveniently prepared through an ammoniation from the generated 3,4-dihydropyran product.
he asymmetric Michael reaction of cyclic 1,3-dicarbonyl
compounds to α,β-unsaturated carbonyl compounds is
asymmetric transformations.8 Chin and Mlynarski utilized
vicinal diamine in the Michael reaction between 4-hydrox-
ycoumarin and trans-4-phenyl-3-buten-2-one.4a,d On the basis
of previous reports,9 we considered that Dpen as a typical
primary amine could activate both α,β-unsaturated enones via
an iminium intermediate and 1,3-diketones via an enamine
intermediate at the same time.10 Herein, we describe the chiral
1,2-diphenylethylenediamine as an efficient catalyst for the
asymmetric Michael cyclization of 1,3-dicarbonyl compounds
with unactivated α,β-unsaturated ketones. The additives could
greatly enhance the reaction activity. Good yields and
enantioselectivities were achieved for aryl and alkyl β-
substituted enones.
T
one of the most powerful tools for the construction of
biologically active compounds and has attracted growing
attention in recent years.1 Since the first example of such an
asymmetric process reported by the Jørgensen group using
chiral bisoxazoline−Cu(II) complexes,2 a series of Michael
acceptors and donors subsequently have been extended by
many research groups.3 Among them, the asymmetric Michael
reaction of cyclic 1,3-dicarbonyl compounds to α,β-unsaturated
enones provides an efficient method to synthesize chiral
compounds possessing considerable bioactivities. For example,
the chiral anticoagulant drug warfarin has been successfully
prepared from the direct asymmetric reaction between 4-
hydroxycoumarin and α,β-unsaturated ketones.3c,4 In addition,
aliphatic cyclic 1,3-diketone is a useful nucleophile to perform
the Michael cyclization reaction. The resulted dihydropyran
derivatives could be conveniently converted into a chiral 2,4-
disubstituted polyhydroquinoline scaffold, which is a common
structure with a number of biological activities such as
antihypertensive, antidyslipidemic, and antidiabetic.5 Recently,
Calter's and our group reported such a procedure of β,γ-
unsaturated α-ketoesters by cinchona alkaloid derived pyr-
imidine organocatalysts and N,N′-dioxide−Cu(OTf)2 complex,
respectively.6 Yu’s group utilized a fluorinated diarylprolinol
silyl ether catalyst for the reaction of α,β-unsaturated
aldehydes.7 Despite good yield and enantioselectivity obtained,
it is worth pointing out that α,β-unsaturated ketones, the
common Michael acceptor, have not been applied in this kind
of reaction as a consequence of the relatively low reactivity.
Therefore, the development of efficient catalysts to realize
asymmetric Michael cyclization of aliphatic cyclic 1,3-diketones
with unactivated α,β-unsaturated enones is still in high demand.
C2-Symmetric 1,2-diphenylethylenediamine (Dpen) is com-
mercially inexpensive and air- and moisture-stable. Dpen as
ligand and organocatalyst has shown high performance in many
The addition of dimedone 3a and cinnamone 2a was used as
a model reaction to screen the optimal conditions in the
presence of chiral diamine catalysts 1a−1f (Figure 1). Initially,
Figure 1. Chiral organocatalysts used for the reaction.
(R,R)-1,2-diphenylethylenediamine (Dpen) 1a was used as the
organocatalyst in toluene, but low yield was obtained (Table 1,
entry 1).11 Then, protonic acid was added to improve the
reaction activity since it may facilitate the formation of the
ketimine cation intermediate from cinnamone 2a. Delightly,
optically active 4a was formed in a slightly improved yield and
enantioselectivity in the presence of Dpen 1a and benzoic acid
Received: February 4, 2012
Published: March 20, 2012
© 2012 American Chemical Society
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Note
Table 1. Screening of Catalysts for the Asymmetric Michael Reaction
a
b
c
entry
catalyst
solvent
additive
PhCO2H
T (°C)
yield (%)
ee (%)
1
1a
1a
1b
1c
1d
1e
1f
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
Et2O
rt
10
80
92
59
nd
80
nd
nd
71
90
82
92
92
90
94
94
93
95
2
rt
30
3
PhCO2H
rt
20
4
PhCO2H
rt
trace
15
5
PhCO2H
rt
6
PhCO2H
rt
trace
trace
15
7
PhCO2H
rt
8
1a
1a
1a
1a
TFA
rt
9
AcOH
rt
24
10
11
12
13
14
15
16
17
PhCO2H
40
0
10
PhCO2H
35
d
1a
PhCO2H
0
52
d
1a
PhCO2H/NaBArF
PhCO2H/NaBArF
PhCO2H/NaBArF
PhCO2H/NaBArF
PhCO2H/NaBArF
0
70
d
1a
−20
−20
−20
−20
72
d
1a
45
d
1a
80
d
1a
PhOMe
94
a
For entries 1−11, the reactions were performed with 2a (0.15 mmol), 3a (0.1 mmol), the indicated catalysts 1 (10 mol %), and additives (10 mol
b
c
d
%) in solvent (1.0 mL) at room temperature for 48 h. Isolated yield. Determined by chiral HPLC analysis. With 1a (20 mol %) and additives (20
mol %) in solvent (0.5 mL) for 96 h. NaBArF = Na[B(3,5-(CF3)2C6H3)4], nd = not detected.
(30% yield, 92% ee; Table 1, entry 1 vs entry 2). However,
diamine catalyst 1b and 1c, formed by modification of the
primary diamine, proved to be inferior to the precursor 1a
(Table 1, entries 3 and 4 vs entry 2). It indicated the
importance of the primary diamine subunits on the catalytic
reaction. Next, chiral primary diamine catalysts bearing different
backbones were investigated. The dihedral angle of the catalyst
seemed to be another linchpin. Neither axial chiral binaphthyl
diamine 1d nor cyclohexylenediamine 1e afforded satisfactory
results (Table 1, entries 5 and 6). The use of chiral amino
alcohol 1f as the catalyst resulted in a trace amount of the
product (Table 1, entry 7), which indicated the activation of
both the enone and dimedone of concern was crucial for the
yield and enantioselectivity of the reaction. To further improve
the reactivity of the reaction, a series of additives was
investigated. Acids, such as TFA, AcOH, had no improvement
on the yield (Table 1, entries 8 and 9).12 The catalyst loading of
1a and the reaction temperature were also adjusted to
enhancing the yield. Lowering the reaction temperature to 0
°C was more suitable for this process compared with raising the
temperature to 40 °C (Table 1, entries 10 and 11). When the
loading of the catalyst 1a was increased to 20 mol % at 0 °C,
the yield of the reaction was smoothly improved (Table 1, entry
12). Strikingly, adding 20 mol % of PhCO2H/NaBArF at the
same time achieved a 70% yield with little loss of the
enantioselectivity (Table 1, entry 13).13 In addition, the
enantioselectivity was further raised to 94% ee at −20 °C
with maintained yield (Table 1, entry 14). Solvent investigation
showed that the enantioselectivity and yield increased in
PhOMe (Table 1, entries 15−17). Hence, the optimal
conditions were 20 mol % of 1a with equivalent catalyst
amounts of PhCO2H and NaBArF in PhOMe at −20 °C, which
afforded the product 4a with 94% yield and 95% ee.
The organocatalytic asymmetric Michael cyclization reaction
under the optimal conditions was extended to various α,β-
unsaturated enones, and the results are given in Table 2. A
number of acyclic α,β-unsaturated enones with either various
aryl substituents or alkyl substituents at the β-position of the
enone 2 proceeded smoothly with dimedone 3a, delivering the
corresponding product 4 in high yields and enantioselectivities.
The electronic properties and steric hindrance of the
substituents at the aromatic ring had no apparent effect on
the enantioselectivity (Table 2, entries 1−14). In general,
cinnamone derivatives with electron-withdrawing substituents
on the aromatic ring showed higher reactivity than the
substrates with electron-donating substituents. Especially,
hydroxyl substituted enone 2o, which was rarely investigated,
also was well tolerated in this reaction. Although the yield of
the Michael adduct 4o was slightly reduced, excellent
enantioselectivity was maintained (66% yield, 94% ee; Table
2, entry 15). In the case of o-methoxyl substituted enone 2p,
relatively lower yield was obtained as a consequence of 1,2-
addition side reaction (Table 2, entry 16).7 The disubstituted
aromatic α,β-unsaturated ketones could also be successfully
extended, affording the products in moderate yields with 94−
95% ee (Table 2, entries 17 and 18). Fused-ring enone 2s and
heteroaromatic enone 2t were suitable substrates to give the
corresponding products 4s and 4t with 95% ee and 94% ee,
respectively (Table 2, entries 19 and 20). In addition, β-alkyl
substituted enones 2u and 2v were also investigated and well
tolerated (Table 2, entries 21 and 22). Notably, the best
enantioselectivity (97% ee) was achieved in the case of (E)-1-
phenylpent-1-en-3-one 2w (Table 2, entry 23).
Moreover, we successfully achieved the asymmetric Michael
reaction of 2-cyclohexen-1-one 2x to synthesize bridged-ring
compound 4x (Scheme 1a, 70% yield, 90% ee). Gratifyingly,
optically active anticoagulant warfarin 4y was formed by one
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Note
step in 95% yield and 96% ee in the presence of catalytic
amounts of additives (Scheme 1b).4
Table 2. Substrate Scope for the Catalytic Asymmetric
Michael Cyclization Reaction
In order to show the synthetic utility of the catalyst system, a
gram-scale synthesis of the chiral dihydropyran derivative 4a
was performed. As shown in Scheme 2, by treatment of 1.1 g of
Scheme 2. Scaled-Up Version of the Michael Reaction and
Conversion into 2,4-Disubstituted Polyhydroquinoline
2a (7.5 mmol) and 0.7 g of 3a (5.0 mmol) under the optimal
reaction conditions, the desired product 4a was obtained in
90% yield with 95% ee (Scheme 2a). Notably, through a simple
ammoniation, product 4a was successfully converted into 2,4-
disubstituted polyhydroquinoline scaffold 5a in 93% yield
without any loss of enantioselectivity (Scheme 2b).
The absolute configuration of the product 4c was determined
to be R by utilizing single-crystal X-ray diffraction (Figure 2).14
Figure 2. X-ray crystallographic structure of 4c and proposed catalytic
model.
Considering the influence of the catalyst structure on the
reaction outcomes, we proposed a possible catalytic model as
shown in Figure 2. For the chiral primary diamine catalyst 1a,
an iminium ion generated from enone 2c and an enamine
intermediate from dimedone 3a can be envisaged in the
process. The combined action of benzoic acid and NaBArF is
the generation of sterically hindered BArF− anion around the
iminium ion (see Supporting Information for details), and the
α,β-unsaturated iminium ion adopts such an arrangement that
facilitates the attack of the neighboring enamine from its β-re
face. Therefore, the desired R-configured product 4c was
generated. The model can also be used to explain the best
enantioselectivity obtained from enone 2w with a bulky
carbonyl substituent (Table 2, entry 23).
a
Unless otherwise noted, the reaction was performed with 2 (0.15
mmol), 3a (0.1 mmol), and catalyst 1a/ PhCO2H/NaBArF (20 mol
b
%, 1/1/1) in PhOMe (0.5 mL) at −20 °C for 96 h. Isolated yield.
c
d
Determined by chiral HPLC analysis. The absolute configuration of
e
4c was R as determined by X-ray analysis. With catalyst 1a/PhCO2H/
NaBArF (30 mol %, 1:1:1)
Scheme 1. Michael Cyclization Reaction between Cyclic 1,3-
Dicarbonyl Compounds and α,β-Unsaturated Ketones
In conclusion, we have successfully demonstrated that simple
unmodified chiral (R,R)-diphenylethylenediamine was an
excellent organocatalyst for the enantioselective Michael
reaction of aliphatic cyclic dimedone with unactivated α,β-
unsaturated ketones under mild conditions. A variety of
substituted α,β-unsaturated ketones were tolerated well in the
presence of combined additives, delivering the products with
high yields and excellent enantioselectivities. Further expan-
sions of other nucleophiles and electrophiles using this catalyic
system are under way.
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Note
4-(2-Hydroxy-2,7,7-trimethyl-5-oxo-3,4,5,6,7,8-hexahydro-
2H-chromen-4-yl)benzonitrile (4e). Yield 28.1 mg, 90%; colorless
oil; [α]20D = −24.0 (c 0.50, CH2Cl2); HPLC Daicel chiralcel OD-H, n-
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 9.99 min, tR(minor) 7.47
min; 1H NMR δ 7.51 (dd, J = 11.3, 8.3 Hz, 2H), 7.25 (dd, J = 16.7, 8.1
Hz, 2H), 5.16 (s, 0.55H), 4.73 (s, 0.35H), 3.86 (dd, J = 12.5, 6.9 Hz,
1H), 3.49 (q, J = 7.0 Hz, 0.1H), 2.40−2.00 (m, 6H), 1.43 (d, J = 13.3
Hz, 3H), 1.15 (d, J = 12.5 Hz, 3H), 1.08 (d, J = 11.6 Hz, 3H); 13C
NMR δ 208.8, 197.5, 197.2, 170.7, 170.1, 151.6, 150.6, 132.1, 131.8,
128.4, 127.9, 119.1, 112.2, 110.2, 109.1, 99.6, 98.1, 65.8, 50.6, 50.5,
42.9, 42.4, 40.4, 34.6, 34.5, 32.0, 31.5, 29.5, 28.5, 28.3, 27.6, 27.3, 26.7,
22.6, 15.2, 14.1; ESI-HRMS calcd for [C19H21NO3 + H+]: 312.1594,
found 312.1602.
2-Hydroxy-2,7,7-trimethyl-4-(4-nitrophenyl)-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one (4f). Yield 28.4 mg, 86%; colorless oil;
[α]20D = −40.3 (c 0.52, CH2Cl2); HPLC Daicel chiralcel IA, n-hexane/
i-PrOH 80/20, 1.0 mL/min, tR(major) 13.84 min, tR(minor) 26.06 min; 1H
NMR δ 8.11 (dd, J = 11.8, 8.7 Hz, 2H), 7.32−7.28 (m, 2H), 3.99 (t, J
= 5.7 Hz, 0.4H), 3.93 (dd, J = 11.5, 6.7 Hz, 0.6H), 3.75 (t, J = 6.5 Hz,
0.55H), 3.19 (s, 0.45H), 2.39−2.17 (m, 6H), 1.55 (s, 2H), 1.51 (s,
1H), 1.19 (s, 1H), 1.15 (s, 2H), 1.11 (s, 1H), 1.09 (s, 2H); 13C NMR
δ 197.0, 196.5, 169.6, 168.9, 153.4, 152.3, 146.1, 128.3, 127.7, 123.8,
123.5, 112.4, 110.3, 99.2, 97.8, 67.9, 65.8, 50.7, 50.6, 42.9, 42.8, 42.0,
39.9, 34.4, 33.8, 32.0, 31.6, 30.3, 29.4, 28.7, 28.3, 28.2, 27.5, 27.4, 25.6,
15.2; ESI-HRMS calcd for [C18H21NO5 + H+]: 332.1492, found
332.1497.
EXPERIMENTAL SECTION
■
General Details. Unless otherwise noted, 1H and 13C NMR
spectra are internally referenced to residual solvent signals (1H, 600
MHz, CDCl3; 13C 150 MHz, CDCl3). Spectra were reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet). Enantiomeric excesses (ee) were
determined by HPLC analysis using chiralpak columns. Optical
rotations were reported as follows: [α]20 (c g/100 mL, CH2Cl2).
D
HRMS was recorded on a commercial apparatus (ESI Source).
General Procedure for Asymmetric Michael Cyclization
Reaction. The α,β-unsaturated ketones 2 (0.15 mmol, 1.5 equiv),
cyclic 1,3-diketones 3 (0.1 mmol), catalyst 1a (20 mol %, 4.2 mg),
PhCO2H (20 mol %, 2.4 mg), and NaBArF (20 mol %, 17.7 mg) were
added into a test tube. Then, PhOMe (0.5 mL) was added under
nitrogen, and the mixture was stirred for 96 h at −20 °C. The product
4 was isolated via column chromatography (1/1/2.5, EtOAc/CH2Cl2/
petroleum ether).
2-Hydroxy-2,7,7-trimethyl-4-phenyl-3,4,7,8-tetrahydro-2H-
chromen-5(6H)-one (4a). Yield 27.0 mg, 94%; white solid, mp 114−
116 °C; [α]20D = +17.1 (c 0.54, CH2Cl2); HPLC Daicel chiralpack IA,
n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 5.93 min, tR(minor) 8.41
1
min; H NMR (600 MHz, DMSO) δ 7.17−7.28 (m, 3H), 7.12−7.08
(m, 2H), 4.69 (t, J = 7.6 Hz, 0.3H), 3.73 (dd, J = 19.3, 9.1 Hz, 0.7H),
3.42−3.36 (m, 0.4H), 3.23−3.14 (m, 0.6H), 2.39−2.05 (m, 6H), 1.69
(dd, J = 13.3, 11.1 Hz, 0.54H), 1.42 (s, 2.45H), 1.13 (d, J = 3.5 Hz,
2H), 1.04 (s, 2.2H), 0.95 (s, 1.8H); 13C NMR (150 MHz, DMSO) δ
207.9, 195.7, 195.5, 169.4, 168.5, 146.2, 146.0, 145.0, 128.4, 128.1,
127.8, 127.6, 127.3, 125.6, 125.5, 115.9, 112.5, 111.3, 100.3, 98.5, 65.4,
50.9, 46.3, 43.8, 42.8, 35.5, 34.4, 34.3, 31.9, 31.7, 30.1, 29.4, 28.8, 28.2,
28.1, 27.9, 27.6, 25.9, 15.6; ESI-HRMS calcd for [C18H22O3 + Na+]:
309.1461, found 309.1471.
2-Hydroxy-4-(4-methoxyphenyl)-2,7,7-trimethyl-3,4,7,8-tet-
rahydro-2H-chromen-5(6H)-one (4g). Yield 24.6 mg, 78%; color-
less oil; [α]20 = +8.2 (c 0.49, CH2Cl2); HPLC Daicel chiralcel IA, n-
D
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 7.72 min, tR(minor) 12.61
min; 1H NMR δ 7.08 (dd, J = 29.8, 8.6 Hz, 2H), 6.81 (dd, J = 19.5, 8.6
Hz, 2H), 4.00 (s, 0.6H), 3.82−3.78 (m, 0.4H), 3.76 (d, J = 2.2 Hz,
3H), 3.40 (t, J = 9.8 Hz, 0.4H), 3.25 (s, 0.6H), 2.42−2.10 (m, 6H),
1.48 (s, 3H), 1.20 (s, 1.8H), 1.15 (s, 1.2H), 1.11 (s, 1.8H), 1.07 (s,
1.2H); 13C NMR δ 197.1, 196.7, 169.1, 167.8, 158.3, 157.6, 136.8,
134.4, 128.0, 127.9, 114.5, 113.8, 113.3, 110.5, 99.7, 98.1, 55.2, 55.1,
50.8, 43.0, 42.8, 42.7, 40.1, 33.2, 32.0, 31.6, 31.5, 31.4, 29.5, 28.9, 28.3,
28.0, 27.5, 22.6, 14.1; ESI-HRMS calcd for [C19H24O4 + H+]:
317.1747, found 317.1746.
4-(4-Fluorophenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (4b). Yield 29.2 mg, 96%; colorless
oil; [α]20D = +15.9 (c 0.58, CH2Cl2); HPLC Daicel chiralcel OD-H, n-
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 6.34 min, tR(minor) 5.68
min; 1H NMR δ 7.12 (dd, J = 8.4, 5.4 Hz, 0.88H), 7.07 (d, J = 3.0 Hz,
1.12H), 6.90−6.96 (m, 2H), 4.09 (s, 0.5H), 3.93 (t, J = 5.3 Hz,
0.41H), 3.80 (dd, J = 27.5, 18.7 Hz, 0.5H), 3.56 (s, 0.38H), 3.53−3.46
(m, 0.21H), 2.04−2.38 (m, 6H), 1.46 (d, J = 7.5 Hz, 3H), 1.17 (s,
1.3H), 1.14 (s, 1.7H), 1.09 (s, 1.3H), 1.07 (s, 1.7H); 13C NMR δ
210.5, 197.3, 197.0, 169.6, 168.7, 162.1, 161.8, 160.5, 160.2, 140.6,
139.1, 139.0, 129.2, 128.6, 128.5, 128.3, 115.5, 115.3, 115.1, 115.0,
114.6, 114.5, 113.0, 110.7, 99.7, 98.1, 65.8, 50.7, 46.1, 42.9, 42.8, 40.6,
33.6, 33.4, 32.6, 32.0, 31.5, 31.4, 30.0, 29.7, 29.5, 28.6, 28.4, 27.9, 27.4,
27.1, 15.2; ESI-HRMS calcd for [C18H21FO3 + H+]: 305.1547, found
305.1560.
4-(4-(Benzyloxy)phenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-
tetrahydro-2H-chromen-5(6H)-one (4h). Yield 30.0 mg, 80%;
yellow solid, mp 126−128 °C; [α]20D = −0.5 (c 0.60, CH2Cl2); HPLC
Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 9.83
1
min, tR(minor) 16.92 min; H NMR δ 7.39 (dt, J = 14.7, 7.6 Hz, 4H),
7.31 (t, J = 7.1 Hz, 1H), 7.08 (dd, J = 27.3, 8.5 Hz, 2H), 6.91−6.87 (m,
2H), 5.00 (s, 2H), 4.01 (d, J = 4.1 Hz, 0.5H), 3.80 (d, J = 9.0 Hz,
0.3H), 3.70 (s, 0.4H), 3.24−3.13 (m, 0.8H), 2.45−1.98 (m, 6H), 1.48
(s, 3H), 1.17 (d, J = 26.0 Hz, 3H), 1.09 (d, J = 19.0 Hz, 3H); 13C
NMR δ 197.0, 196.7, 196.6, 169.1, 157.6, 157.0, 137.3, 137.0, 128.6,
128.5, 128.0, 127.9,127.8, 127.5, 127.4, 115.5, 114.7, 113.3, 100.0, 99.7,
98.1, 70.0, 69.9, 67.1, 50.8, 42.9, 42.8, 40.0, 33.2, 32.0, 31.5, 31.3, 29.5,
28.9, 28.3, 28.0, 27.6, 27.5, 22.6, 15.6; ESI-HRMS calcd for [C25H28O4
+ Na+]: 415.1880, found 415.1878.
4-(4-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (4c). Yield 30.7 mg, 95%; white
solid, mp 123−124 °C; [α]20D = −3.4 (c 0.61, CH2Cl2); HPLC Daicel
chiralcel OD-H, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 7.49
min, tR(minor) 5.49 min; 1H NMR δ 7.16−7.22 (m, 2H), 7.02−7.09 (m,
2H), 4.28−4.40 (m, 0.6H), 3.96−3.75 (m, 1.4H), 2.39−2.12 (m, 6H),
1.51−1.40 (m, 3H), 1.17 (s, 1.2H), 1.13 (s, 1.8H), 1.09 (s, 1.2H), 1.06
(s, 1.8H); 13C NMR δ 197.4, 197.1, 169.9, 169.1, 143.7, 142.3, 131.7,
131.2, 129.2, 128.6, 128.4, 128.3, 127.9, 115.4, 115.3, 115.1, 115.0,
112.8, 110.6, 99.7, 98.1, 50.7, 50.6, 42.9, 42.6, 40.6, 33.6, 33.4, 33.1,
32.7, 32.0, 31.5, 29.5, 28.6, 28.4, 27.9, 27.4, 27.0, 26.9, 22.6, 14.1; ESI-
HRMS calcd for [C18H2135ClO3 + H+]: 321.1252, found 321.1254.
4-(4-Bromophenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (4d). Yield 33.4 mg, 91%; colorless
oil; [α]20D = −8.5 (c 0.66, CH2Cl2); HPLC Daicel chiralcel OD-H, n-
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 8.19 min, tR(minor) 5.58
4-(Biphenyl-4-yl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one (4i). Yield 32.2 mg, 89%; colorless oil;
[α]20D = −24.0 (c 0.60, CH2Cl2); HPLC Daicel chiralcel IA, n-hexane/
1
i-PrOH 80/20, 1.0 mL/min, tR(major) 7.86 min, tR(minor) 12.46 min; H
NMR δ 7.51 (ddd, J = 27.9, 15.3, 8.0 Hz, 4H), 7.40 (td, J = 7.6, 3.6 Hz,
2H), 7.34−7.28 (m, 1H), 7.26−7.24 (m, 1.12H), 7.20 (d, J = 8.1 Hz,
0.88H), 4.07 (s, 0.48H), 3.91−3.87 (m, 0.40H), 3.75 (t, J = 6.4 Hz,
0.28H), 3.48 (q, J = 7.0 Hz, 0.43H), 3.27 (s, 0.42H), 2.40−2.19 (m,
6H), 1.50 (s, 3H), 1.21 (s, 1.69H), 1.17 (s, 1.29H), 1.11 (s, 1.56H),
1.08 (s, 1.43H); 13C NMR δ 197.1, 196.8, 169.3, 168.3, 144.1, 142.0,
141.2, 140.8, 139.6, 138.7, 135.8, 128.7, 128.6, 127.7, 127.4, 127.2,
127.1, 127.0, 126.8, 125.5, 113.1, 110.5, 99.7, 98.1, 68.0, 65.8, 50.8,
43.0, 42.9, 42.7, 40.3, 34.2, 33.8, 32.3, 32.0, 31.5, 30.3, 29.5, 28.8, 28.3,
28.1, 27.5, 27.4, 25.6, 15.2; ESI-HRMS calcd for [C24H26O3 + Na+]:
385.1774, found 385.1779.
1
min; H NMR δ 7.31−7.36 (m, 2H), 7.06−6.96 (m, 2H), 4.31−4.40
(m, 0.55H), 3.75−3.89 (m, 1.43H), 2.37−2.08 (m, 6H), 1.44(s, 1.3H),
1.43 (s, 1.7H), 1.16 (s, 1.2H), 1.13 (s, 1.8H), 1.09 (s, 1.2H), 1.06 (s,
1.8H); 13C NMR δ 210.0, 197.4, 197.1, 169.9, 169.1, 144.2, 142.9,
131.5, 131.3, 130.9, 129.7, 129.0, 128.8, 128.6, 128.4, 119.8, 119.3,
112.8, 110.6, 99.7, 98.1, 50.6, 42.9, 42.6, 33.7, 33.2, 32.0, 31.5, 29.5,
28.6, 28.4, 27.9, 27.4, 26.9, 22.6, 14.1; ESI-HRMS calcd for
[C18H2179BrO3 + H+]: 365.0747, found 365.0753.
4-(3-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (4j). Yield 32.0 mg, 98%; white
4139
dx.doi.org/10.1021/jo3001047 | J. Org. Chem. 2012, 77, 4136−4142

The Journal of Organic Chemistry
Note
solid, mp 102−104 °C; [α]20D = +1.3 (c 0.64, CH2Cl2); HPLC Daicel
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 6.39 min,
tR(minor) 9.01 min; 1H NMR (400 MHz, CDCl3) δ 7.17−7.06 (m, 3H),
7.00 (q, J = 7.4 Hz, 1H), 4.61 (s, 0.59H), 3.87 (t, J = 5.5 Hz, 0.40H),
3.82−3.77 (m, 0.51H), 3.73 (d, J = 5.9 Hz, 0.49H), 2.41−2.04 (m,
6H), 1.43 (d, J = 4.2 Hz, 3H), 1.16 (d, J = 9.6 Hz, 3H), 1.07 (d, J = 8.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 197.1, 170.0, 169.3,
147.4, 146.1, 134.2, 134.0, 129.6, 129.5, 129.1, 128.0, 127.5, 127.1,
126.3, 126.0, 125.4, 125.3, 112.6, 110.5, 99.7, 98.2, 67.9, 65.8, 50.7,
50.6, 43.0, 42.9, 42.6, 40.7, 34.0, 33.6, 32.0, 31.6, 30.3, 30.0, 29.7, 29.5,
29.3, 28.6, 28.4, 27.8, 27.4, 26.8, 25.6, 22.7, 15.2; ESI-HRMS calcd for
[C18H2135ClO3 + H+]: 321.1252, found 321.1259.
6H), 1.45 (s, 3H), 1.14 (d, J = 13.3 Hz, 3H), 1.06 (d, J = 22.7 Hz,
3H); 13C NMR δ 211.6, 198.4, 171.4, 170.6, 169.9, 157.0, 156.2, 146.3,
144.5, 130.0, 129.3, 118.0, 117.9, 115.0, 114.5, 114.2, 113.2, 113.0,
110.5, 100.1, 98.5, 65.8, 60.5, 50.6, 50.5, 43.0, 42.9, 42.5, 40.3, 33.8,
32.6, 32.0, 31.5, 29.4, 28.8, 28.1, 27.8, 27.5, 27.1, 21.0, 15.2, 14.1; ESI-
HRMS calcd for [C18H22O4 + H+]: 303.1591, found 303.1602.
2-Hydroxy-4-(2-methoxyphenyl)-2,7,7-trimethyl-3,4,7,8-tet-
rahydro-2H-chromen-5(6H)-one (4p). Yield 22.0 mg, 70%;
colorless oil; [α]20 = +39.1 (c 0.44, CH2Cl2); HPLC Daicel chiralcel
D
OD-H, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 5.96 min,
tR(minor) 8.32 min; 1H NMR δ 7.19−7.10 (m, 1H), 6.98−6.92 (m, 1H),
6.89−6.80 (m, 2H), 4.22−4.28 (m, 0.8H), 3.87 (d, J = 5.8 Hz, 0.7H),
3.86 (s, 2H), 3.82 (s, 1H), 3.55 (s, 0.5H), 2.43−2.00 (m, 6H), 1.45 (s,
2H), 1.42 (s, 1H), 1.19 (s, 2H), 1.16 (s, 1H), 1.10 (s, 2H), 1.06 (s,
1H); 13C NMR δ 209.3, 198.2, 196.8, 196.5, 171.2, 169.3, 157.0, 156.7,
155.4, 132.6, 130.5, 130.4, 129.2, 128.1, 127.3, 126.8, 126.2, 121.3,
120.8, 120.4, 115.0, 113.0, 111.1, 110.6, 110.4, 110.3, 100.0, 99.9, 98.4,
65.8, 55.8, 55.4, 55.2, 51.3, 50.9, 50.8, 45.8, 43.0, 42.9, 40.0, 37.3, 32.0,
31.6, 31.5, 31.1, 30.1, 29.5, 29.06, 28.4, 28.3, 28.2, 27.9, 27.8, 27.7,
27.6, 27.4, 22.6, 15.2, 14.1; ESI-HRMS calcd for [C19H24O4 + H+]:
317.1747, found 317.1756.
2-Hydroxy-2,7,7-trimethyl-4-(3-(trifluoromethyl)phenyl)-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (4k). Yield 34.2 mg,
96%; colorless oil; [α]20 = +7.6 (c 0.68, CH2Cl2); HPLC Daicel
D
chiralcel IA, n-hexane/i-PrOH 90/10, 1.0 mL/min, tR(major) 11.23 min,
1
tR(minor) 18.74 min; H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 15.1
Hz, 2H), 7.32 (d, J = 5.7 Hz, 2H), 4.07 (s, 0.3H), 3.98−3.84 (m, 1H),
3.74 (t, J = 6.1 Hz, 0.4H), 3.54−3.37 (m, 0.3H), 2.37−2.08 (m, 6H),
1.42 (s, 3H), 1.17 (s, 1.2H), 1.14 (s, 1.8H), 1.09 (s, 1.3H), 1.06 (s,
1.7H); 13C NMR (100 MHz, CDCl3) δ 197.3, 197.1, 170.1, 169.4,
146.3, 145.2, 130.8, 130.6, 130.5, 130.3, 130.2, 128.7, 128.6, 125.8,
125.6, 125.5, 124.2, 123.7, 123.6, 123.0, 122.9, 122.6, 112.6, 110.6,
99.7, 98.1, 67.9, 65.8, 50.6, 50.5, 43.0, 42.9, 42.6, 40.7, 34.2, 34.0, 32.0,
31.5, 30.3, 29.7, 29.5, 28.5, 28.2, 27.8, 27.1, 26.8, 25.5, 15.2; ESI-
HRMS calcd for [C19H21F3O3 + Na+]: 377.1335, found 377.1316.
2-Hydroxy-2,7,7-trimethyl-4-(3-nitrophenyl)-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one (4l). Yield 29.8 mg, 90%; colorless oil;
[α]20D = −11.1 (c 0.54, CH2Cl2); HPLC Daicel chiralcel IA, n-hexane/
i-PrOH 80/20, 1.0 mL/min, tR(major) 11.68 min, tR(minor) 14.80 min; 1H
NMR δ 8.04−7.96 (m, 2H), 7.50 (s, 1H), 7.40 (dt, J = 12.4, 7.8 Hz,
1H), 4.02−3.90 (m, 1H), 3.74 (s, 0.6H), 3.15 (s, 0.4H), 2.43−2.13 (m,
6H), 1.52 (d, J = 18.2 Hz, 3H), 1.19 (d, J = 23.2 Hz, 3H), 1.10 (d, J =
14.8 Hz, 3H); 13C NMR δ 197.1, 196.6, 181.9, 169.7, 169.1, 148.4,
147.5, 146.4, 140.2, 134.0, 133.7, 129.1, 128.9, 125.5, 122.6, 121.6,
121.0, 112.4, 110.3, 99.2, 97.9, 67.9, 50.6, 42.9, 42.3, 40.0, 34.2, 33.4,
32.0, 31.6, 30.3, 29.5, 28.6, 28.3, 28.1, 27.6, 27.4, 25.5, 18.8; ESI-
HRMS calcd for [C18H21NO5 + H+]: 332.1492, found 332.1495.
2-Hydroxy-4-(3-methoxyphenyl)-2,7,7-trimethyl-3,4,7,8-tet-
rahydro-2H-chromen-5(6H)-one (4m). Yield 28.5 mg, 90%;
4-(2,3-Dimethoxyphenyl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-
tetrahydro-2H-chromen-5(6H)-one (4q). Yield 24.0 mg, 70%;
colorless oil; [α]20D = −17.9 (c 0.48, CH2Cl2); HPLC Daicel chiralcel
IB, n-hexane/i-PrOH = 80/20, 1.0 mL/min, tR(major) 8.19 min, tR(minor)
1
6.53 min; H NMR (400 MHz, CDCl3) δ 6.91 (td, J = 8.0, 5.4 Hz,
1H), 6.79−6.70 (m, 1H), 6.61 (d, J = 7.7 Hz, 0.55H), 6.53 (d, J = 7.8
Hz, 0.45H), 4.26 (t, J = 8.7 Hz, 1H), 4.07 (s, 0.55H), 3.94 (d, J = 3.8
Hz, 3H), 3.84 (d, J = 3.3 Hz, 3H), 3.71 (s, 0.45H), 2.35−2.11 (m,
6H), 1.47 (d, J = 10.3 Hz, 3H), 1.17 (d, J = 10.0 Hz, 3H), 1.08 (d, J =
10.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 208.5, 198.4, 196.8,
196.5, 171.8, 169.3, 168.1, 153.2, 152.6, 152.0, 146.8, 146.4, 144.3,
138.9, 137.0, 136.4, 125.0, 124.3, 124.0, 120.3, 118.5, 118.0, 115.4,
113.4, 111.1, 110.6, 110.3, 109.8, 99.9, 98.1, 65.8, 61.4, 60.4, 55.7, 55.6,
51.5, 50.8, 46.4, 43.1, 43.0, 42.9, 41.3, 38.9, 32.0, 31.6, 31.1, 30.3, 29.5,
29.2, 29.0, 28.5, 28.2, 28.0, 27.7, 27.6, 27.4, 27.0, 22.6, 15.2, 14.1; ESI-
HRMS calcd for [C20H26O5 + H+]: 347.1853, found 347.1862.
4-(Benzo[d][1,3]dioxol-4-yl)-2-hydroxy-2,7,7-trimethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (4r). Yield 26.4 mg,
80%; colorless oil; [α]20 = +2.5 (c 0.52, CH2Cl2); HPLC Daicel
D
colorless oil; [α]20 = +6.5 (c 0.57, CH2Cl2); HPLC Daicel chiralcel
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 8.92 min,
tR(minor) 13.23 min; 1H NMR δ 6.70 (dd, J = 8.0, 3.4 Hz, 1.6H), 6.64−
6.60 (m, 1.4H), 5.90 (d, J = 12.9 Hz, 2H), 3.96 (s, 0.5H), 3.79−3.74
(m, 0.4H), 3.55−3.44 (m, 0.6H), 3.38 (d, J = 9.4 Hz, 0.5H), 2.41−2.00
(m, 6H), 1.49 (d, J = 3.7 Hz, 3H), 1.19 (s, 1.7H), 1.15 (s, 1.3H), 1.10
(s, 1.7H), 1.07 (s, 1.3H); 13C NMR δ 197.1, 196.8, 169.2, 168.1, 148.3,
147.5, 146.4, 145.5, 138.9, 136.9, 120.0, 119.4, 113.2, 110.5, 108.6,
108.2, 107.8, 107.3, 101.0, 100.7, 99.7, 98.1, 65.8, 50.8, 43.0, 42.8, 40.2,
33.8, 32.1, 32.0, 31.6, 31.5, 29.4, 29.0, 28.2, 28.0, 27.6, 27.5, 22.6, 15.2,
14.1; ESI-HRMS calcd for [C19H22O5 + H+]: 331.1540, found
331.1551.
D
IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 7.66 min, tR(minor)
10.69 min; 1H NMR δ 7.18 (dt, J = 24.6, 7.8 Hz, 1H), 6.79−6.67 (m,
3H), 4.00 (s, 0.56H), 3.94−3.77 (m, 1H), 3.75 (s, 3H), 3.48 (dd, J =
14.0, 7.0 Hz, 0.45H), 2.43−2.01 (m, 6H), 1.46 (d, J = 9.1 Hz, 3H),
1.18 (d, J = 20.9 Hz, 3H), 1.09 (d, J = 19.6 Hz, 3H); 13C NMR δ
197.1, 169.4, 160.1, 146.7, 144.7, 130.1, 129.2, 119.5, 119.0, 113.0,
112.8, 112.0, 111.1, 110.3, 99.7, 98.1, 55.1, 50.7, 42.8, 40.3, 34.1, 32.5,
32.0, 31.6, 31.5, 29.5, 28.8, 28.4, 28.0, 27.3, 22.6, 14.1; ESI-HRMS
calcd for [C19H24O4 + Na+]: 339.1567, found 339.1571.
2-Hydroxy-2,7,7-trimethyl-4-m-tolyl-3,4,7,8-tetrahydro-2H-
chromen-5(6H)-one (4n). Yield 27.6 mg, 92%; colorless oil; [α]20
=
2-Hydroxy-2,7,7-trimethyl-4-(naphthalen-2-yl)-3,4,7,8-tetra-
D
+19.2 (c 0.59, CH2Cl2); HPLC Daicel chiralcel IA, n-hexane/i-PrOH
hydro-2H-chromen-5(6H)-one (4s). Yield 31.3 mg, 93%; colorless
1
80/20, 1.0 mL/min, tR(major) 7.66 min, tR(minor) 10.69 min; H NMR
oil; [α]20 = −29.7 (c 0.62, CH2Cl2); HPLC Daicel chiralcel IA, n-
D
(400 MHz, CDCl3) δ 7.15 (dd, J = 14.5, 7.4 Hz, 1H), 7.01−6.89 (m,
3H), 4.00 (s, 0.5H), 3.85−3.76 (m, 0.6H), 3.48 (q, J = 7.0 Hz, 0.5H),
3.42 (s, 0.4H), 2.42−2.12 (m, 9H), 1.46 (d, J = 7.7 Hz, 3H), 1.18 (d, J
= 16.8 Hz, 3H), 1.09 (d, J = 14.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.1, 196.8, 169.3, 168.1, 144.9, 142.8, 138.7, 137.7, 129.0,
128.2, 127.8, 127.6, 126.6, 124.0, 123.7, 113.2, 110.4, 99.8, 98.1, 67.0,
65.8, 50.8, 43.0, 42.9, 40.4, 34.0, 32.4, 32.0, 31.5, 29.6, 28.8, 28.4, 28.0,
27.4, 27.3, 21.5, 15.2; ESI-HRMS calcd for [C19H24O3 + H+]:
301.1798, found 301.1809.
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 8.25 min, tR(minor) 13.38
min; 1H NMR δ 7.78−7.69 (m, 3H), 7.55 (d, J = 20.3 Hz, 1H), 7.44−
7.32 (m, 3H), 4.15 (s, 0.55H), 4.01−3.97 (m, 0.45H), 3.79−3.54 (m,
0.5H), 3.37 (t, J = 45.0 Hz, 0.5H), 2.44−2.08 (m, 6H), 1.44 (d, J =
21.8 Hz, 3H), 1.24 (s, 1.6H), 1.18 (s, 1.4H), 1.12 (s, 1.6H), 1.06 (s,
1.4H); 13C NMR δ 214.5, 197.2, 169.6, 140.6, 133.6, 133.5, 132.4,
132.1, 129.0, 128.0, 127.7, 127.6, 126.2, 125.8, 125.7, 125.6, 125.5,
125.0, 124.9, 113.1, 110.5, 99.8, 98.2, 50.8, 43.0, 42.9, 42.6, 40.0, 34.2,
32.9, 32.1, 31.6, 31.5, 29.5, 28.8, 28.4, 28.0, 27.5, 27.3, 22.6, 14.1; ESI-
HRMS calcd for [C22H24O3 + H+]: 337.1798, found 337.1803.
4-(Furan-2-yl)-2-hydroxy-2,7,7-trimethyl-3,4,7,8-tetrahydro-
2H-chromen-5(6H)-one (4t). Yield 23.7 mg, 86%; colorless oil;
2-Hydroxy-4-(3-hydroxyphenyl)-2,7,7-trimethyl-3,4,7,8-tet-
rahydro-2H-chromen-5(6H)-one (4o). Yield 20.0 mg, 66%; color-
less oil; [α]20D = +36.1 (c 0.40, CH2Cl2); HPLC Daicel chiralcel IA, n-
hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 6.76 min, tR(minor) 9.13
[α]20 = +20.9 (c 0.47, CH2Cl2); HPLC Daicel chiralcel AD-H, n-
D
1
min; H NMR δ 7.02 (dt, J = 11.5, 7.9 Hz, 1H), 6.66−6.49 (m, 3H),
hexane/i-PrOH 95/5, 1.0 mL/min, tR(major) 30.75 min, tR(minor) 38.48
1
4.68 (s, 0.33H), 4.12 (d, J = 7.1 Hz, 0.3H), 3.89 (d, J = 30.2 Hz, 0.7H),
3.78−3.73 (m, 0.45H), 3.49 (q, J = 7.0 Hz, 0.56H), 2.37−2.04 (m,
min; H NMR δ 7.33 (s, 0.68H), 7.25 (s, 0.32H), 6.27 (m, 1H), 5.99
(dd, J = 10.9, 2.7 Hz, 0.86H), 5.94 (d, J = 2.9 Hz, 0.21H), 4.12 (dd, J =
4140
dx.doi.org/10.1021/jo3001047 | J. Org. Chem. 2012, 77, 4136−4142

The Journal of Organic Chemistry
Note
8.4, 6.1 Hz, 1H), 4.04 (m, 0.9H), 2.26 (m, 6H), 1.53 (s, 2.34H), 1.40
(s, 0.64H), 1.14 (d, J = 5.8 Hz, 3H), 1.08 (d, J = 9.2 Hz, 3H); 13C
NMR δ 196.7, 169.0, 155.5, 142.0, 140.4, 130.0, 128.4, 110.6, 110.3,
108.4, 106.1, 105.3, 98.9, 60.4, 50.7, 42.9, 36.0, 32.1, 28.6, 28.2, 27.9,
27.7, 26.1; ESI-HRMS calcd for [C16H20O4 + Na+]: 299.1254, found
299.1248.
mL) was added ammonium acetate (115.6 mg, 10 equiv). Then, the
reaction was refluxed for 1.5 h. The solvent was evaporated, and the
mixture was subjected to silica gel chromatography (1/1/2.5, EtOAc/
CH2Cl2/petroleum ether) to provide a yellow solid 5a (37.7 mg, 93%
yield, mp 106−108 °C). [α]20 = +358.1 (c 0.13, CH2Cl2); HPLC
D
Daicel chiralcel IA, n-hexane/i-PrOH 90/10, 1.0 mL/min, tR(major)
13.70 min, tR(minor) 12.25 min; 1H NMR δ 7.28−7.22 (m, 4H), 7.11 (t,
J = 7.0 Hz, 1H), 6.04 (s, 1H), 4.74 (d, J = 4.1 Hz, 1H), 4.54 (d, J = 4.6
Hz, 1H), 2.27−2.12 (m, 4H), 1.75 (s, 3H), 1.06 (s, 3H), 1.00 (s, 3H);
13C NMR δ 195.4, 151.4, 148.3, 129.6, 128.1, 127.6, 125.8, 107.8,
105.7, 50.8, 41.7, 37.7, 32.4, 29.4, 27.4, 18.8; ESI-HRMS calcd for
[C18H21NO + Na+]: 290.1515, found 290.1512.
2-Hydroxy-2,7,7-trimethyl-4-propyl-3,4,7,8-tetrahydro-2H-
chromen-5(6H)-one (4u). Yield 18.3 mg, 73%; colorless oil; [α]20
=
D
+16.1 (c 0.25, CH2Cl2); HPLC Daicel chiralcel IC, n-hexane/i-PrOH
1
80/20, 1.0 mL/min, tR(major) 6.12 min, tR(minor) 12.08 min; H NMR δ
3.68 (d, J = 35.1 Hz, 0.47H), 3.18−3.09 (m, 0.39H), 3.00 (s, 0.35H),
2.63 (d, J = 19.2 Hz, 0.8H), 2.42−2.01 (m, 6H), 1.62−1.35 (m, 4H),
1.22 (d, J = 48.2 Hz, 3H), 1.08−1.00 (m, 6H), 0.88 (d, J = 32.5 Hz,
3H); 13C NMR δ 213.5, 198.7, 198.0, 171.7, 167.4, 167.1, 125.5, 115.6,
114.3, 113.9, 99.5, 98.1, 51.2, 48.2, 43.3, 43.0, 42.9, 38.3, 35.3, 34.7,
34.4, 31.8, 31.3, 31.0, 30.3, 29.8, 29.7, 29.5, 28.4, 28.2, 28.1, 28.0, 27.9,
27.1, 26.7, 21.3, 20.2, 19.5, 14.3, 14.1, 13.9; ESI-HRMS calcd for
[C15H24O3 + Na+]: 275.1618, found 275.1615.
Preparation of DPEN·HBArF Salt. DPEN (1.0 mmol), NaBArF
(1.0 mmol), and PhCO2H (1.0 mmol) were added into a round
bottomed flask. Then, CH2Cl2 (20 mL) was added, and the mixture
was stirred for 3 h at rt. A white crystalline solid was smoothly
precipitated. After filtration, the solution was concentrated to provide a
white solid. The structure was conformed as DPEN·HBArF salt by 1H
1
NMR analysis. H NMR (400 MHz, CDCl3) δ 7.71 (s, 8H), 7.52 (s,
2-Hydroxy-4-isopropyl-2,7,7-trimethyl-3,4,7,8-tetrahydro-
2H-chromen-5(6H)-one (4v). Yield 15.5 mg, 62%; colorless oil;
[α]20D = +15.4 (c 0.31, CH2Cl2); HPLC Daicel chiralcel IC, n-hexane/
i-PrOH 90/10, 1.0 mL/min, tR(major) 12.07 min, tR(minor) 14.72 min; 1H
NMR δ 3.20−3.15 (m, 0.39H), 3.05 (s, 0.21H), 2.94 (s, 0.38H), 2.68
(d, J = 8.5 Hz, 0.28H), 2.64−2.59 (m, 0.72H), 2.36−2.04 (m, 6H),
1.98 (ddd, J = 13.1, 11.8, 4.9 Hz, 1H), 1.57 (s, 0.8H), 1.51 (s, 1H),
1.43 (s, 1.2H), 1.26 (s, 6H), 1.05 (d, J = 3.6 Hz, 3H), 0.93−0.87 (m,
3H); 13C NMR δ 213.8, 198.6, 197.8, 171.6, 167.0, 166.6, 125.5, 115.7,
114.2, 113.9, 99.3, 98.0, 51.3, 51.2, 48.2, 43.2, 43.0, 42.8, 38.2, 35.0,
34.7, 34.3, 31.9, 31.8, 30.9, 30.3, 29.8, 29.7, 29.6, 29.4, 29.3, 28.3, 28.2,
28.1, 28.0, 27.8, 27.1, 26.7, 22.6, 21.3, 20.2, 19.4, 14.2, 14.1, 13.8; ESI-
HRMS calcd for [C15H24O3 + Na+]: 275.1618, found 275.1632.
2-Ethyl-2-hydroxy-7,7-dimethyl-4-phenyl-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one (4w). Yield 19.4 mg, 65%; white solid,
4H), 7.32 (m, 6H), 7.10 (dd, J = 6.3, 2.9 Hz, 4H), 4.18 (d, J = 15.1 Hz,
9H). 1H NMR (400 MHz, CDCl3-D2O) δ 7.71 (s, 8H), 7.53 (s, 4H),
7.31 (dd, J = 4.9, 1.5 Hz, 6H), 7.13 (dd, J = 6.6, 2.7 Hz, 4H), 4.20 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 162.42, 161.93, 161.43, 160.94,
135.08, 134.79, 130.06, 129.95, 129.08, 128.80, 128.62, 125.91, 125.82,
123.20, 120.49, 117.60, 59.85.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full optimization details, 1H and 13C NMR spectra, and HPLC
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
mp 124−126 °C; [α]20 = +14.7 (c 0.38, CH2Cl2); HPLC Daicel
D
AUTHOR INFORMATION
Corresponding Author
*E-mail: liuxh@scu.edu.cn; xmfeng@scu.edu.cn.
■
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 5.86 min,
1
tR(minor) 9.60 min; H NMR δ 7.29 (dd, J = 10.8, 4.3 Hz, 1H), 7.26−
7.24 (m, 1H), 7.21−7.13 (m, 3H), 4.05 (s, 0.5H), 3.85−3.81 (m,
0.4H), 3.70 (d, J = 3.9 Hz, 0.1H), 3.24 (s, 0.4H), 3.11 (d, J = 23.4 Hz,
0.6H), 2.45−1.99 (m, 6H), 1.75−1.71 (m, 2H), 1.18 (d, J = 26.6 Hz,
3H), 1.09 (d, J = 20.3 Hz, 3H), 0.97−0.92 (m, 3H); 13C NMR δ 197.0,
196.6, 169.4, 168.1, 145.1, 142.9, 129.0, 128.3, 126.9, 126.7, 125.8,
113.3, 110.5, 101.3, 99.8, 50.8, 42.9, 42.8, 40.3, 38.0, 33.9, 33.6, 33.1,
32.0, 31.5, 29.5, 28.9, 28.3, 27.5, 7.4, 7.3; ESI-HRMS calcd for
[C19H24O3 + Na+]: 323.1618, found 323.1614.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21021001, 21072133) and the National Basic Research
Program of China (973 Program: 2010CB833300) for financial
support. We also thank Sichuan University Analytical & Testing
Center for NMR and X-ray analysis.
4,4-Dimethylbi(cyclohexane)-2,3′,6-trione (4x). Yield 16.5 mg,
70%; white solid, mp 116−118 °C; [α]20 = −20.1 (c 0.33, CH2Cl2);
D
HPLC Daicel chiralcel IC, n-hexane/i-PrOH 90/10, 1.0 mL/min,
tR(major) 16.60 min, tR(minor) 14.82 min; 1H NMR δ 3.74 (s, 1H), 3.19 (s,
1H), 2.32 (d, J = 4.9 Hz, 2H), 2.22 (s, 2H), 2.03 (d, J = 12.8 Hz, 1H),
1.92 (dd, J = 12.5, 2.6 Hz, 1H), 1.76−1.69 (m, 2H), 1.63 (d, J = 12.7
Hz, 2H), 1.46−1.40 (m, 2H), 1.07 (s, 6H); 13C NMR δ 196.5, 170.8,
112.4, 101.2, 50.4, 42.0, 38.8, 36.3, 32.3, 28.5, 28.4, 28.2, 27.0, 19.3;
ESI-HRMS calcd for [C14H20O3 + H+]: 237.1485, found 237.1490.
2-Hydroxy-2-methyl-4-phenyl-3,4-dihydropyrano[3,2-c]-
chromen-5(2H)-one (4y). Yield 30.0 mg, 95%; white solid, mp 156−
158 °C; [α]20D = +9.9 (c 0.46, CH2Cl2); HPLC Daicel chiralcel AD-H,
n-hexane/i-PrOH 80/20, 1.0 mL/min, tR(major) 5.45 min, tR(minor) 8.21
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ac.uk/data_request/cif.
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