Synthesis of chromanes by sequential '[3+3]-cyclization/Williamson' reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes

Article abstract of DOI:10.1016/j.tet.2006.05.076

Functionalized chromanes were prepared by sequential '[3+3]-cyclization/Williamson' reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes with 1,1,3,3-tetramethoxypropane, 3-silyloxyalk-2-en-1-ones, and 1,1-diacetylcyclopropane. The first step

Full text of DOI:10.1016/j.tet.2006.05.076

Tetrahedron 62 (2006) 7674–7686
Synthesis of chromanes by sequential ‘[3D3]-cyclization/
Williamson’ reactions of 1,3-bis(trimethylsilyloxy)-
7-chlorohepta-1,3-dienes
Van Thi Hong Nguyen,a Bettina Appela and Peter Langerb,c,
*
aInstitut fu€r Biochemie, Universita€t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
bInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
cLeibniz-Institut fu€r Katalyse e. V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 17 April 2006; revised 24 May 2006; accepted 29 May 2006
Available online 16 June 2006
Abstract—Functionalized chromanes were prepared by sequential ‘[3+3]-cyclization/Williamson’ reactions of 1,3-bis(trimethylsilyloxy)-7-
chlorohepta-1,3-dienes with 1,1,3,3-tetramethoxypropane, 3-silyloxyalk-2-en-1-ones, and 1,1-diacetylcyclopropane. The first step of the
sequence involves [3+3] cyclizations of the starting materials to give 2-(3-chloropropyl)phenols. The subsequent cyclization proceeds by intra-
molecular nucleophilic substitution. 6-(2-Hydroxybenzoyl)chromanes were prepared based on sequential ‘[3+3]-cyclization/Williamson’
reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes with 3-formylchromones.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(a-tocopherol) exhibits anti-androgen properties. Many syn-
thetic approaches to 3,4-dihydro-2H-chromenes are based
on intramolecular Friedel–Crafts alkylations.2 Finn et al.
have prepared chromanes from salicylic aldehydes and
vinylboronic acids in the presence of catalytic amounts of
dibenzylamine.3 Jones et al. reported the synthesis of chro-
manes by Diels–Alder reactions of o-quinone methides,
which were generated from salicylic aldehydes and
alcohols.4
3,4-Dihydro-2H-chromenes (chromanes) represent pharma-
cologically relevant heterocycles, which occur in a variety
of natural products (Scheme 1).1,2 For example, bavachro-
manol has been isolated from leaves of Maclura tinctoria
L. (Venezuela).2a The chromanol moiety of vitamin E
OH
OH
OH
OH
Chan and co-workers reported an efficient one-pot synthesis
of salicylates based on [3+3] cyclizations of 1,3-bis-silyl
enol ethers5 with 3-silyloxyalk-2-en-1-ones or 1,1,3,3-tetra-
methoxypropane.6 Recently, we have reported7 an extension
of this method by the first use of 1,3-bis-(trimethylsilyloxy)-
7-chlorohepta-1,3-dienes (chloro-substituted 1,3-bis-silyl
enol ethers)8 in [3+3] cyclizations. The combination of these
[3+3] cyclizations with subsequent intramolecular William-
son reactions allows for the synthesis of functionalized chro-
manes. Herein, we report full details of these studies. With
regard to our preliminary communication in this field,7 we
herein report, for the first time, the synthesis of 6-(2-hydroxy-
benzoyl)-3,4-dihydro-2H-chromenes based on sequential
‘[3+3]-cyclization/Williamson’ reactions of 1,3-bis(tri-
methylsilyloxy)-7-chlorohepta-1,3-dieneswith3-formylchro-
mones. The general strategy reported herein allows for a
convenient synthesis of a variety functionalized chromanes.
Notably, the substitution patterns of these products are not
readily available by other methods.
O
HO
O
O
O
HO
Bavachromanol
Flemistrictin F
O
OH
Vitamin E (alpha-tocopherol)
Scheme 1. Chromane natural products.
Keywords: Benzopyrans; Cyclizations; Ethers; Lewis acids; Silyl enol
ethers.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.076

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7675
2. Results and discussion
explained, following the mechanism proposed by Chan,6
by initial attack of carbon atom C-4 of 1a,b onto the carbon
atom attached to the silyloxy group of 5a–d, cyclization by
attack of carbon C-2 onto the carbonyl group and subsequent
aromatization.
2.1. [3D3] Cyclization of 1,1,3,3-tetramethoxypropane
The key substrates of this study—1,3-bis(trimethylsilyloxy)-
7-chlorohepta-1,3-dienes 1a,b—were prepared in three steps
from ethyl acetoacetate as previously reported.7,9 The TiCl4-
mediated [3+3] cyclization of 1a with 1,1,3,3-tetramethoxy-
propane (2) afforded the 2-(3-chloropropyl)phenol 3a. The
formation of 3a proceeds by attack of carbon atom C-4 of
1a onto 2, cyclization via carbon C-2, and finally aromatiza-
tion. Notably, the chloride functionality remained unattacked
during the reaction. Treatment of a THF solution of 3a with
sodium hydride (NaH), in the presence of tetrabutylammo-
nium iodide (TBAI), afforded chromane 4a (Scheme 2).
Cl
Cl Me3SiO
OSiMe3
OEt
R3
OH
O
R3
OEt
1a,b
i
R1
R1
Me3SiO
O
[3+3]
R2
3b-h
+
R1
R1
R3
R2
5a-d
ii
Williamson
O
O
OEt
Cl
OSiMe3
Me3SiO
R1
R1
Cl
OEt
R2
OH
O
1a
i
4b-h
OEt
[3+3]
OMe OMe
OMe
+
MeO
Scheme 4. Synthesis of chromanes 4b–h. Reagents and conditions: (i)
TiCl4, CH2Cl2, ꢀ78/20 ꢁC; (ii) NaH, TBAI, THF, 20 ꢁC.
2
3a (42%)
Williamson
ii
Table 1. Synthesis of chromanes 4b–h
O
O
5
3,4
R1
R2
R3
% (3)a
% (4)a
OEt
a
b
c
d
a
b
c
b
c
d
e
f
Me
Me
Me
Et
Me
Me
Et
Me
H
Et
H
Me
H
H
H
H
H
H
Me
Me
Me
52
46
43
42
44
46
53
90
70
82
65
94
80
97
4a (64%)
Scheme 2. Synthesis of chromane 4a. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78/20 ꢁC; (ii) NaH, TBAI, THF, 20 ꢁC.
g
h
2.2. [3D3] Cyclizations of 3-silyloxyalk-2-en-1-ones
a
Yields of isolated products.
The [3+3] cyclization of 1,3-bis-silyl enol ether 6a with
3-silyloxyalk-2-en-1-one 5a has been reported to give sali-
cylate 7.6 The cyclization proceeds by TiCl4-mediated con-
jugate addition of the terminal carbon atom of the bis-silyl
enol ether onto 5a, cyclization, extrusion of siloxane, and
aromatization (Scheme 3).
The [3+3] cyclization of 1,3-bis(trimethylsilyloxy)-7-chloro-
hepta-1,3-diene 1a with 3-silyloxyalk-2-en-1-one 5e, pre-
pared from 2-(hydroxymethylidene)cyclohexan-1-one,
furnished tetrahydronaphthalene 3i (Scheme 5). In contrast
to 3b–h, the formation of regioisomers is theoretically possi-
ble in case of 3i. The regioselective formation of 3i can be ex-
plained by the same mechanism as described for 3b–h, i.e. by
initial attack of carbon atom C-4 of 1a onto the carbon
attached to the silyloxy group of 5e. Treatment of 3i with
NaH/TBAI afforded the tricyclic benzopyran 4i. The struc-
ture of 4i was established by H,H-COSY, C,H-COSY,
Me3SiO
OSiMe3
OH
O
Me3SiO
Me
O
OMe
OMe
Me
6a
Me
Me
Me
5a
i
Me
7 (55%)
HMBC, and NOESY experiments.
Cl
TiCl4
Me3SiCl
_
OH
O
1a
Me3SiO
O
OEt
i
O
O
O
Me3SiO
OMe
[3+3]
OMe
Me
5e
_
3i (33%)
Williamson
Me
Me
(Me3Si)2O
Me
OTiCl3
O
O
O
ii
Me
Me3SiO
Me TiCl3
OEt
A
B
Scheme 3. Synthesis of salicylate 7 by Chan et al. Reagents and conditions:
(i) TiCl4, CH2Cl2, ꢀ78/20 ꢁC.
4i (70%)
The [3+3] cyclization of 1,3-bis(trimethylsilyloxy)-7-chloro-
hepta-1,3-dienes 1a,b with 3-silyloxyalk-2-en-1-ones 5a–d
affordedthe2-(3-chloropropyl)phenols3b–h.Thelatterwere
transformed (by NaH and TBAI) into chromanes 4b–h
(Scheme 4, Table 1). The formation of 3b–h can be
Scheme 5. Synthesis of chromane 4i. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78/20 ꢁC; (ii) NaH, TBAI, THF, 20 ꢁC.
The [3+3] cyclization of 1a with 3-silyloxyalk-2-en-
1-one 5f, available by silylation of 2-acetylcyclohexanone,

7676
V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
Cl
regioselectively afforded 3j, which was transformed into the
tricyclic chromane 4j (Scheme 6, Table 2). The formation of
3j can be explained by TiCl4-mediated isomerization of 5f
into iso-5f and subsequent attack of carbon C-4 of 1a onto
the carbon attached to the silyloxy group of iso-5e. The
structure of 4j was established by H,H-COSY, C,H-COSY,
HMBC, and NOESY experiments. The cyclization of 1a
with 3-silyloxyalk-2-en-1-one 5g, prepared from 2-acetyl-
tetralone, regioselectively afforded 3k, which was trans-
formed into the tetracyclic chromane 4k. The formation
of 3k presumably follows the mechanism as discussed for
3j. The structure of 4k was established by H,H-COSY,
C,H-COSY, HMBC, and NOESY experiments. Notably, the
structures of 3j,k and 4j,k have to be revised with respect to
our preliminary communication.
Cl
OSiMe3
OEt
Me3SiO
OH
O
TiX4
i
1a
OEt
O
O
[3+3]
Me
Me
X
+
Me
Me
3l (X = Cl): 53%
3m (X = Br): 35%
ii
Williamson
O
O
OEt
Me
Me
X
4l (X = Cl): 77%
4m (X = Br): 60%
Scheme 7. Synthesis of chromanes 4l,m. Reagents and conditions: (i) TiX4
(X¼Cl, Br, 2 equiv), CH2Cl2, ꢀ78/20 ꢁC; (ii) NaH, TBAI, THF, 20 ꢁC.
O
OSiMe3
R2
O
Me3SiO
Me
TiCl4
R2
Me
R1
5f,g
R1
report the reaction of formylchromones with 1,3-bis(tri-
methylsilyloxy)-7-chlorohepta-1,3-dienes,whichallowforan
efficient synthesis of 6-(2-hydroxybenzoyl)-3,4-chromanes.
iso-5f,g
1a
[3+3]
Cl
O
O
Me3SiO
O
i
i
H
H
activation
+
_
O
O
O
O
OTf
OH
O
ii
8a
A
OEt
OEt
R2
Me
R2
Me
Williamson
Me3SiO
OSiMe3
R1
R1
ii
OEt
Michael
4j,k
3j,k
6b
Scheme 6. Synthesis of chromanes 4j,k. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78/20 ꢁC; (ii) NaH, TBAI, THF, 20 ꢁC.
_
+
SiMe3
OTf
O
H
O
Me3SiO
O
O
O
O
O
Table 2. Products and yields
retro-
H
Michael
OEt
R1
R2
% (3)a
% (4)a
OEt
3,4
OSiMe3
OSiMe3
j
k
–(CH2)4–
–(CH2)2C6H4–
34
27
87
88
SiMe3
C
a
B
Isolated yields.
_
Me3SiOTf
Aldol
2.3. [3D3] Cyclizations of 1,1-diacetylcyclopropane
SiMe3
O
We have recently reported9 the synthesis of 2-(3-chloro-
propyl)-4-(2-chloroethyl)phenol 3l by TiCl4-mediated cycli-
zation of 1a with 1,1-diacetylcyclopropane (6) (Scheme 7).
The formation of 3l can be explained by initial [3+3] cycliza-
tion to give a spirocyclopropane, which is cleaved by attack
of TiCl4 (homo-Michael reaction).10 Likewise, theTiBr4-me-
diated cyclization of 1a with 6 furnished 2-(3-chloropropyl)-
4-(2-bromoethyl)phenol 3m. Treatment of 3l,m with NaH/
TBAI afforded the novel functionalized chromanes 4l,m.
O
OH
O
OEt
O
O
OEt
OH
O
+ H2O
_
OH
(Me3Si)2O
SiMe3
D
9
Scheme 8. Mechanism of the cyclization of 1,3-bis-silyl enol ethers with
3-formylchromones (Ref. 11). Reagents and conditions: (i) Me3SiOTf
(0.3 equiv), 20 ꢁC, 10 min; (ii) (1) 2a (1.3 equiv), CH2Cl2, 0/20 ꢁC,
12 h; (2) HCl (10%).
2.4. [3D3] Cyclizations of 3-formylchromones
The TMSOTf catalyzed reaction of 1,3-bis(trimethylsilyl-
oxy)-7-chlorohepta-1,3-dienes 1a,b with 3-formylchromones
8a–e afforded the 4-(2-hydroxybenzoyl)salicylates 10a–h
containing a remote chloride group (Scheme 9, Table 3).
The mechanism of these reactions can be explained analo-
gously to the formation of 9 (Scheme 8). Treatment of
10a–h with NaH/TBAI afforded the 6-(2-hydroxybenzoyl)-
3,4-dihydro-2H-chromenes 11a,b,e–h by intramolecular
Williamson reaction. These products were isolated in the
We have recently reported the reaction of 1,3-bis-silyl enol
etherswith3-formylchromonestogivefunctionalizedbenzo-
phenones.11 The formation of the products can be explained
byadomino‘Michael/Retro-Michael/Aldol’reactionfollow-
ing the mechanism as given in Scheme 8. The reaction can be
formally regarded as a [3+3] cyclization of an activated enal
andresemblethe[3+3]cyclizationsof1,3-bis-silyl enol ethers
with 3-silyloxyalk-2-en-1-ones discussed above. Herein, we

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7677
form of their carboxylic acids (except for 11a); the hydrolysis
3. Conclusions
of the ester group presumably occurred during the aqueous
work-up using hydrochloric acid (10%). Notably, the
employment of the latter proved to be mandatory for a suc-
cessful isolation of any type of product of this reaction.
We have reported the synthesis of functionalized chromanes
by double-annulation reactions of 1,3-bis(trimethylsilyloxy)-
7-chlorohepta-1,3-dienes with 1,1,3,3-tetramethoxypropane,
3-silyloxyalk-2-en-1-ones, and 1,1-diacetylcyclopropane.
The products were formed by [3+3] cyclization of the starting
materials to give 2-(3-chloropropyl)phenols and subsequent
cyclization by intramolecular nucleophilic substitution.
6-(2-Hydroxybenzoyl)chromanes were prepared based on
double-annulationreactionsof3-formylchromones; an anthra-
quinone derived chromane was prepared from 2-bromonaph-
thoquinone. The general strategy reported herein allows for
a convenient synthesis of a variety of functionalized chro-
manes. Notably, the substitution patterns of these products
are not readily available by other methods.
O
OEt
OSiMe3
OEt
R1
R2
O
O
O
O
R1
R2
i
OH
OH
Cl
OSiMe3
Cl
[3+3]
R3
R3
10a-h
8a-e
1a,b
ii
Williamson
O
OR4
O
R1
R2
OH
O
R3
11a-h
4. Experimental
4.1. General
Scheme 9. Synthesis of 11a–h. Reagents and conditions: (i) (1) Me3SiOTf
(0.3 equiv), 0 ꢁC, 10 min; (2) 1a,b (1.3 equiv), CH2Cl2, 20 ꢁC, 12 h; (3)
HCl (10%); (ii) NaH (1.5 equiv), TBAI (2.0 equiv), THF, 20 ꢁC, 20 h; for
11b,e–h: HCl (10%).
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For H
1
Table 3. Products and yields
and 13C NMR spectra, the deuterated solvents indicated were
used. Mass spectrometric data (MS) were obtained by elec-
tron ionization (EI, 70 eV), chemical ionization (CI, H2O),
or electrospray ionization (ESI). For preparative scale chro-
matography, silica gel (60–200 mesh) was used. Melting
points are uncorrected.
8
1
10/11
R1
R2
R3
R4
% (10)
% (11)a
a
b
c
d
e
a
b
d
a
a
a
a
a
b
b
b
a
b
c
d
e
f
H
H
H
H
H
Me
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
41
54
48
51
47
43
41
38
68
94
Me
Et
Cl
Cl
H
b
—
—
b
H
70
71
86
73
Me
Me
Me
g
h
Me
Cl
4.2. General procedure for the synthesis of salicylates
3a–k
H
a
Isolated yields.
Experiment not carried out.
b
To a CH2Cl2 solution of 1a,b and 2 or 5a–g was dropwise
added TiCl4 at ꢀ78 ꢁC under argon atmosphere. The solu-
tion was stirred at ꢀ78 ꢁC for 30 min and was subsequently
warmed to 20 ꢁC within 18 h. To the solution was added
a saturated aqueous solution of NaHCO3. The organic and
the aqueous layer were separated and the latter was extracted
with ether. The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated invacuo.
The residue was purified by chromatography (silica gel,
n-hexane/EtOAc).
2.5. [4D2] Cyclization of 2-bromonaphthalene-1,4-dione
Some years ago, Brassard et al. reported the [4+2] cyclo-
addition of 1,3-bis-silyl enol ethers with bromoquinones to
give anthraquinones.12 The reaction of 1a with 2-bromo-
naphthalene-1,4-dione (12) afforded the functionalized
anthraquinone 13. Surprisingly, the product contained a
bromide group located at the benzene moiety formed during
the reaction. Treatment of 13 with NaH/TBAI afforded
chromane 14 (Scheme 10). The formation of 13 can be
explained by a radical mechanism.
4.2.1. Ethyl 3-(3-chloropropyl)-2-hydroxybenzoate (3a).
Starting with 1a (1.75 g, 5.0 mmol), 2 (0.8 g, 5.0 mmol),
and TiCl4 (0.94 g, 5.0 mmol) in CH2Cl2 (15 mL), 3a was
isolated after chromatography (silica gel, n-hexane/
Cl
Cl
O
O
1
EtOAc ¼ 30:1) as a colorless oil (0.5 g, 42%). H NMR
OH
Br
i
(CDCl3, 300 MHz): d¼1.41 (t, J¼7.1 Hz, 3H, CH3), 2.11
(quint, J¼6.5 Hz, 2H, CH2), 2.82 (t, J¼7.1 Hz, 2H, CH2),
3.54 (t, J¼6.6 Hz, 2H, CH2–Cl), 4.41 (q, J¼7.1 Hz, 2H,
OCH2), 6.18 (m, 1H, CH of Ar), 7.32–7.35 (m, 1H, CH of
Ar), 7.75 (d, 1H, CH of Ar), 11.13 (s, 1H, OH). 13C NMR
(CDCl3, 75 MHz): dC¼14.2 (CH3), 21.2, 31.9, 44.6, 61.4
(CH2), 112.3, 118.6, 128.0, 128.9 (C), 135.9 (CH), 159.9,
170.6 (C). IR (neat, cmꢀ1): ~n ¼ 3140 ðmÞ, 2986 (m), 1671
(s), 1615 (s), 1449 (s), 1401 (s), 1374 (s), 1297 (s), 1249
(s), 1178 (s), 1152 (s), 1087 (m), 1026 (m), 761 (s), 725
(m). UV–vis (CH3CN, nm): lmax (log 3)¼212 (4.42), 242
(3.92), 310 (3.55) nm. MS (EI, 70 eV): m/z (%)¼244
(M+[37Cl], 11), 242 (M+[35Cl], 34), 196 (19), 161 (100),
Br
OSiMe3
OSiMe3
1a
O
O
OH
EtO
13 (30%)
12
ii
O
O
Br
O
OH
14 (73%)
Scheme 10. Synthesis of 14. Reagents and conditions: (i) (1) THF, 1 h,
ꢀ78 ꢁC, (2) 14 h, ꢀ78/20 ꢁC, (3) HCl (10%); (ii) NaH, TBAI, THF, 20 ꢁC.

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V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
134 (44), 105 (21), 77 (24), 51 (9), 27 (10). HRMS (ESI):
calcd for C12H16ClO3 ([M+1]+): 245.07584 [37Cl],
243.07879 [35Cl]; found: 245.07565 [37Cl], 243.0787
[35Cl]. Anal. Calcd for C12H15ClO3 (242.699): C, 59.39;
H, 6.23. Found: C, 60.88; H, 6.36.
(15 mL), 3e was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 30:1) as a colorless oil (0.62 g, 41%).
1H NMR (CDCl3, 300 MHz): d¼1.21 (t, J¼7.5 Hz, 6H,
2ꢂCH3), 1.42 (t, J¼7.2 Hz, 3H, CH3), 2.02 (quint,
J¼7.2 Hz, 2H, CH2), 2.62 (q, J¼7.6 Hz, 2H, CH2), 2.79
(m, J¼6.0 Hz, 2H, CH2), 2.91 (q, J¼7.5 Hz, 2H, CH2),
3.61 (t, J¼6.6 Hz, 2H, CH2–Cl), 4.44 (q, J¼7.2 Hz, 2H,
OCH2), 6.58 (s, 1H, CH), 11.68 (s, 1H, OH). IR (neat,
cmꢀ1): ~n ¼ 2969 ðmÞ, 1654 (s), 1614 (m), 1453 (m), 1401
(s), 1317 (m), 1264 (s), 1171 (s), 1073 (m), 1024 (m), 816
(m). UV–vis (CH3CN, nm): lmax (log 3)¼217 (4.44), 254
(4.04), 316 (3.64) nm. MS (EI, 70 eV): m/z (%)¼300
(M+[37Cl], 3), 298 (M+[35Cl], 11), 252 (15), 217 (100),
189 (14), 133 (9), 70 (10), 28 (29). Anal. Calcd for
C16H23ClO3 (298.805): C, 64.31; H, 7.76. Found: C,
64.24; H, 9.30.
4.2.2. Ethyl 3-(3-chloropropyl)-2-hydroxy-4,5,6-tri-
methylbenzoate (3b). The synthesis of 3b has been previ-
ously reported.9 Starting with 1a (1.23 g, 3.5 mmol), 5a
(0.61 g, 3.5 mmol), and TiCl4 (0.66 g, 3.5 mmol) in CH2Cl2
(10 mL), 3b was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 30:1) as a colorless oil (0.516 g, 52%).
4.2.3. Ethyl 3-(3-chloropropyl)-2-hydroxy-4,6-dimethyl-
benzoate (3c). Starting with 1a (2.90 g, 8.2 mmol), 5b
(1.42 g, 8.2 mmol), and TiCl4 (1.55 g, 8.2 mmol) in CH2Cl2
(15 mL), 3c was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 30:1) as a colorless oil (1.02 g, 46%).
1H NMR (CDCl3, 300 MHz): d¼1.42 (t, J¼7.1 Hz, 3H,
CH3), 2.00 (quint, J¼6.6 Hz, 2H, CH2), 2.25 (s, 3H, CH3),
2.49 (s, 3H, CH3), 2.78 (t, J¼7.7 Hz, 2H, CH2), 3.61 (t,
J¼6.7 Hz, 2H, CH2–Cl), 4.42 (q, J¼7.1 Hz, 2H, OCH2),
6.54 (s, 1H, CH), 11.76 (s, 1H, OH). 13C NMR (CDCl3,
75 MHz): dC¼14.2, 19.8 (CH3), 23.6, 23.9, 31.8, 45.3,
61.4 (CH2), 109.7 (C), 124.8 (CH), 125.2, 138.4, 143.1,
161.1, 172.2 (C). IR (neat, cmꢀ1): ~n ¼ 2977 ðsÞ, 2937 (s),
1938 (w), 1653 (s), 1563 (m), 1447 (s), 1396 (s), 1376
(s), 1349 (s), 1311 (s), 1273 (s), 1232 (s), 1175 (s), 1037
(s), 848 (s), 811 (s). UV–vis (CH3CN, nm): lmax (log 3)¼
216 (4.45), 253 (4.00), 316 (3.60) nm. MS (EI, 70 eV):
m/z (%)¼272 (M+[37Cl], 6), 270 (M+[35Cl], 21), 224 (20),
189 (100), 162 (25), 133 (7), 105 (5), 91 (10), 27 (5.3).
HRMS (ESI): calcd for C14H20ClO3 ([M+1]+): 273.10714
[37Cl], 271.11009 [35Cl]; found: 273.10647 [37Cl],
271.10950 [35Cl]. Anal. Calcd for C14H19ClO3 (270.752):
C, 62.11; H, 7.10. Found: C, 61.20; H, 7.80.
4.2.6. Ethyl 3-(30-chloroisobutyl)-2-hydroxy-4,5,6-tri-
methylbenzoate (3f). The synthesis of 3f has been previ-
ously reported.9 Starting with 1b (1.09 g, 3.0 mmol), 5a
(0.56 g, 3.0 mmol), and TiCl4 (0.56 g, 3.0 mmol) in CH2Cl2
(10 mL), 3f was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 30:1) as a colorless oil (0.398 g, 44%).
4.2.7. Ethyl 3-(3-chloro-2-methylpropyl)-2-hydroxy-
4,6-dimethylbenzoate (3g). Starting with 1b (1.46 g,
4.0 mmol), TiCl4 (0.75 g, 4.0 mmol), and 5b (0.69 g,
4.0 mmol) in CH2Cl2 (10 mL), 3g was isolated after chroma-
tography (silica gel, n-hexane/EtOAc ¼ 30:1) as a colorless
1
oil (520 mg, 46%). H NMR (CDCl3, 300 MHz): d¼1.05
(d, J¼6.7 Hz, 3H, CH3), 1.42 (t, J¼7.1 Hz, 3H, CH3),
2.23 (m, 1H, CH), 2.27 (s, 3H, CH3), 2.49 (s, 3H, CH3),
2.59–2.79 (m, J¼24, 6.9 Hz, 2H, CH2), 3.42–3.56 (dq,
J¼7.0 Hz, 2H, CH2–Cl), 4.43 (q, J¼7.2 Hz, 2H, OCH2),
6.55 (s, 1H, CH), 11.78 (s, 1H, OH). 13C NMR (CDCl3,
75 MHz): dC¼15.3, 18.9, 21.2, 24.9 (CH3), 31.8, 36.8
(CH), 52.5, 62.5 (CH2), 109.8, 124.6 (C), 125.9 (CH),
138.4, 143.6, 161.4, 172.3 (C). IR (neat, cmꢀ1):
~n ¼ 2959 ðmÞ, 2933 (m), 1654 (s), 1618 (m), 1449 (m),
1397 (m), 1268 (s), 1174 (m), 1097 (m), 1042 (m), 846
(m), 808 (m). UV–vis (CH3CN, nm): lmax (log 3)¼216
(4.45), 254 (4.02), 315 (3.62) nm. MS (EI, 70 eV): m/z
(%)¼286 (M+[37Cl], 1.4), 284 (M+[35Cl], 8), 203 (57), 194
(22), 161 (40), 148 (32), 147 (76), 120 (20), 91 (20), 32
(23), 28 (100). Anal. Calcd for C15H21ClO3 (284.778): C,
63.25; H, 7.14. Found: C, 62.62; H, 7.49.
4.2.4. Ethyl 3-(3-chloropropyl)-5-ethyl-2-hydroxy-4,6-di-
methylbenzoate (3d). Starting with 1a (1.75 g, 5.0 mmol),
5c (1.42 g, 5.0 mmol), and TiCl4 (0.94 g, 5.0 mmol) in
CH2Cl2 (15 mL), 3d was isolated after chromatography
(silica gel, n-hexane/EtOAc ¼ 30:1) as a colorless oil
1
(0.630 g, 43%). H NMR (CDCl3, 300 MHz): dC¼1.10 (t,
J¼7.2 Hz, 3H, CH3), 1.39 (t, J¼7.1 Hz, 3H, CH3), 1.99
(quint, J¼6.7 Hz, 2H, CH2), 2.30 (s, 3H, CH3), 2.46 (s,
3H, CH3), 2.65 (q, J¼7.5 Hz, 2H, CH2), 2.85 (m,
J¼6.0 Hz, 2H, CH2), 3.61 (t, J¼6.7 Hz, 2H, CH2–Cl), 4.43
(q, J¼7.1 Hz, 2H, OCH2), 10.83 (s, 1H, OH). 13C NMR
(CDCl3, 75 MHz): d¼13.7, 14.2, 15.9, 18.3 (CH3), 22.8,
24.1, 30.1, 45.3, 61.4 (CH2), 111.5, 125.3, 133.1, 135.1,
141.3, 157.3, 172.1 (C). IR (neat, cmꢀ1): ~n ¼ 2967 ðsÞ,
2874 (m), 1726 (m), 1651 (s), 1599 (s), 1448 (s), 1701 (s),
1375 (s), 1322 (s), 1269 (s), 1195 (s), 1090 (s), 1037 (s),
806 (s), 768 (m). UV–vis (CH3CN, nm): lmax (log 3)¼218
(4.42), 256 (3.95), 320 (3.58) nm. MS (EI, 70 eV): m/z
(%)¼300 (M+[37Cl], 3), 298 (M+[35Cl], 14), 252 (20), 217
(100), 189 (16), 176 (40), 161 (30), 91 (8), 28 (44). Anal.
Calcd for C16H23ClO3 (298.805): C, 64.31; H, 7.76. Found:
C, 64.35; H, 8.10.
4.2.8. Ethyl 3-(3-chloro-2-methylpropyl)-4,6-diethyl-2-
hydroxybenzoate (3h). Starting with 1b (1.82 g, 5.0 mmol),
TiCl4 (0.95 g, 5.0 mmol), and 5d (1.0 g, 5.0 mmol) in CH2Cl2
(10 mL), 3h was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 30:1) as a colorless oil (0.820 g, 53%).
1H NMR (CDCl3, 300 MHz): d¼1.07 (d, J¼6.8 Hz,
3H, CH3), 1.19 (m, J¼7.1 Hz, 6H, 2ꢂCH3), 1.45 (t, J¼
7.1 Hz, 3H, CH3), 2.28 (m, J¼4.5 Hz, 1H, CH), 2.62 (m,
J¼7.0 Hz, 2H, CH2), 2.75 (q, J¼7.0 Hz, 2H, CH2), 2.91 (q,
J¼7.3 Hz, 2H, CH2), 3.51 (dq, J¼6.8, 5.0 Hz, 2H, CH2–
Cl), 4.44 (q, J¼7.1 Hz, 2H, OCH2), 10.77 (s, 1H, OH). 13C
NMR (CDCl3, 75 MHz): dC¼14.4, 15.5, 16.7, 18.3 (CH3),
26.6, 30.1, 31.8 (CH2), 36.5 (CH), 51.9, 61.8 (CH2), 109.1
(C), 121.9 (CH), 123.9, 144.9, 149.7, 161.3, 172.1 (C). IR
(neat, cmꢀ1): ~n ¼ 2972 ðsÞ, 2877 (s), 1654 (s), 1613 (m),
1564 (m), 1460 (s), 1399 (s), 1376 (s), 1315 (s), 1267 (s),
4.2.5. Ethyl 3-(3-chloropropyl)-4,6-diethyl-2-hydroxy-
benzoate (3e). Starting with 1a (1.75 g, 5.0 mmol), 5d
(1.00 g, 5.0 mmol), and TiCl4 (0.94 g, 5.0 mmol) in CH2Cl2

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7679
1171 (s), 1071 (m), 946 (m), 867 (m), 813 (m), 725 (m). UV–
vis (CH3CN, nm): lmax (log 3)¼217 (4.48), 255 (4.05), 317
(3.64) nm. MS (EI, 70 eV): m/z (%)¼314 (M+[37Cl], 2),
312 (M+[35Cl], 9), 232 (43), 231 (100), 190 (12), 189 (51),
176 (29), 133 (13), 28 (25). HRMS (ESI): calcd for
C17H25ClO3 ([M+1]+): 315.15410 [37Cl], 313.15705 [35Cl];
found: 315.15432 [37Cl], 313.15664 [35Cl].
300 MHz): d¼1.00 (t, J¼7.1 Hz, 3H, CH3), 2.03 (quint,
7.5 Hz, 2H, CH2), 2.32 (s, 3H, CH3), 2.65 (t, J¼5.6 Hz,
2H, CH2), 2.81 (t, J¼6.7 Hz, 2H, CH2), 2.92 (t, J¼6.2 Hz,
2H, CH2), 3.64 (t, J¼7.7 Hz, 2H, CH2–Cl), 4.16 (q,
J¼7.1 Hz, 2H, OCH2), 7.06–7.09 (dd, 1H, CH of Ar),
7.12–7.18 (m, 2H, 2ꢂCH of Ar), 7.21–7.24 (dd, 1H, CH
of Ar), 9.95 (s, 1H, OH). 13C NMR (CDCl3, 75 MHz):
dC¼13.4, 15.7 (CH3), 24.2, 25.7, 29.2, 31.1, 45.2, 61.3
(CH2), 109.0 (C), 125.4 (CH), 126.7 (C), 126.8, 126.9,
129.2 (CH), 130.6, 134.6 (C), 137.6 (2C), 139.7, 156.5,
172.2 (C). IR (neat, cmꢀ1): ~n ¼ 3293 ðwÞ, 2956 (m), 1662
(s), 1592 (m), 1443 (m), 1397 (m), 1373 (m), 1313 (s),
1246 (s), 1188 (s), 1162 (m), 1071 (m), 1029 (m), 765 (s).
UV–vis (CH3CN, nm): lmax (log 3)¼204 (4.48), 232
(4.40), 280 (3.94), 341 (3.89) nm. MS (EI, 70 eV): m/z
(%)¼358 (M+[35Cl], 6), 344 (6), 312 (5), 277 (16), 263
(32), 242 (24), 196 (13), 161 (100), 134 (41), 105 (19), 77
(22), 28 (39). Anal. Calcd for C21H23ClO3 (358.859): C,
70.28; H, 6.46. Found: C, 70.44; H, 6.11.
4.2.9. Ethyl 3-(3-chloropropyl)-5,6,7,8-tetrahydro-2-
hydroxynaphthalene-1-carboxylate (3i). Starting with 1a
(2.8 g, 8.0 mmol), TiCl4 (1.5 g, 8.0 mmol), and 5e (1.59 g,
8.0 mmol) in CH2Cl2 (20 mL), 3i was isolated after chroma-
tography (silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless
1
solid (0.72 g, 33%). H NMR (CDCl3, 300 MHz): d¼1.42
(t, J¼7.1 Hz, 3H, CH3), 1.74 (m, J¼3.3 Hz, 4H, 2ꢂCH2),
2.11 (quint, J¼6.9 Hz, 2H, CH2), 2.69 (m, 2H, CH2), 2.75
(m, J¼7.0 Hz, 2H, CH2), 2.97 (m, 2H, CH2), 3.55 (t,
J¼6.7 Hz, 2H, CH2–Cl), 4.43 (q, J¼7.1 Hz, 2H, OCH2),
7.01 (s, 1H, CH), 11.18 (s, 1H, OH). 13C NMR (CDCl3,
75 MHz): dC¼14.4 (CH3), 22.5, 23.6, 27.5, 29.6, 29.9,
32.2, 44.9, 61.6 (CH2), 115.3, 126.2, 128.0 (C), 136.4
(CH), 137.2, 155.3, 172.2 (C). IR (KBr, cmꢀ1):
~n ¼ 2934 ðsÞ, 2860 (m), 1653 (s), 1431 (s), 1373 (s), 1316
(s), 1283 (s), 1159 (m), 1023 (m). UV–vis (CH3CN, nm):
lmax (log 3)¼213 (4.41), 252 (3.99), 324 (3.80) nm. MS
(EI, 70 eV): m/z (%)¼298 (M+[37Cl], 7), 296 (M+[35Cl],
25), 250 (56), 215 (100), 188 (42), 160 (10), 114 (9), 91
(10), 28 (7). HRMS (ESI): calcd for C16H22ClO3
([M+1]+): 299.12279 [37Cl], 297.12574 [35Cl]; found:
299.12179 [37Cl], 297.12495 [35Cl]. Anal. Calcd for
C16H22ClO3 (297.797): C, 64.85; H, 7.14. Found: C,
64.58; H, 7.35.
4.3. General procedure for the preparation of salicylates
(3l,m)
The synthesis of 3l,m has been previously reported.9 To
a stirred CH2Cl2 solution (100 mL) of 1,1-diacetylcyclo-
propane (6) (1.1 mmol) and 1,3-bis-silyl enol ether 1a
(1.6 mmol) was added TiCl4 (2.0 mmol in 2 mL CH2Cl2)
at ꢀ78 ꢁC under argon atmosphere in the presence of molec-
˚
ular sieves (4 A, 1.0 g). The temperature of the reaction mix-
ture was allowed to rise to 20 ꢁC during 6 h. The solution
was stirred for additional 6 h at 20 ꢁC. The reaction mixture
was filtered and the filtrate was poured into an aqueous
solution of HCl (10%, 100 mL). The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (3ꢂ
100 mL). The combined organic layers were dried (Na2SO4),
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
n-hexane/EtOAc) to give 3l,m.
4.2.10. Ethyl 3-(3-chloropropyl)-5,6,7,8-tetrahydro-2-
hydroxy-4-methylnaphthalene-1-carboxylate (3j). Start-
ing with 1a (1.40 g, 4.0 mmol), TiCl4 (0.72 g, 4.0 mmol),
and 5f (0.85 g, 4.0 mmol) in CH2Cl2 (15 mL), 3j was iso-
lated after chromatography (silica gel, n-hexane/EtOAc ¼
1
30:1) as a colorless oil (0.42 g, 34%). H NMR (CDCl3,
300 MHz): d¼1.41 (t, J¼7.1 Hz, 3H, CH3), 1.68 (m,
J¼2.5 Hz, 2H, CH2), 1.76 (m, J¼2.0 Hz, 2H, CH2), 1.98
(quint, J¼6.8 Hz, 2H, CH2), 2.21 (s, 3H, CH3), 2.58 (t,
J¼6.5 Hz, 2H, CH2), 2.86 (m, J¼7.0 Hz, 2H, CH2), 2.98
(t, J¼6.2 Hz, 2H, CH2), 3.61 (t, J¼6.7 Hz, 2H, CH2–Cl),
4.42 (q, J¼7.1 Hz, 2H, OCH2), 11.23 (s, 1H, OH). 13C
NMR (CDCl3, 75 MHz): dC¼14.2, 15.7 (CH3), 22.8, 23.0,
23.9, 27.9, 30.3, 32.2, 45.3, 61.4 (CH2), 110.2, 125.2,
127.4, 136.9, 142.4, 158.1, 172.2 (C). IR (neat, cmꢀ1):
~n ¼ 3416 ðwÞ, 2931 (s), 2863 (m), 1650 (s), 1598 (m),
1434 (s), 1401 (s), 1375 (s), 1316 (s), 1275 (s), 1241 (s),
1202 (s), 1149 (m), 1035 (m), 804 (m), 651 (m). UV–vis
(CH3CN, nm): lmax (log 3)¼216.5 (4.36), 257.9 (3.98),
320.7 (3.59) nm. MS (EI, 70 eV): m/z (%)¼312 (M+[37Cl],
5), 310 (M+[35Cl], 17), 264 (27), 230 (16), 229 (100), 202
(15), 28 (13). Anal. Calcd for C17H23ClO3 (310.816): C,
65.69; H, 7.46. Found: C, 65.39; H, 7.78.
4.3.1. Ethyl 5-(2-chloroethyl)-3-(3-chloropropyl)-2-
hydroxy-4,6-dimethylbenzoate (3l). The synthesis of 3l
has been previously reported.9 Starting with CH2Cl2
(250 mL), 6 (0.48 g, 3.8 mmol), 1a (2.0 g, 5.7 mmol), and
TiCl4 (2.16 g, 11.4 mmol), 3l was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 25:1) as a colorless
solid (0.672 g, 53%).
4.3.2. Ethyl 5-(2-bromoethyl)-3-(3-chloropropyl)-2-
hydroxy-4,6-dimethylbenzoate (3m). The synthesis of 3m
has been previously reported.9 Starting with 1a (1.58 g,
4.5 mmol), 6 (0.38 g, 3.0 mmol), TiBr4 (2.21 g, 6.0 mmol),
and CH2Cl2 (200 mL), 3m was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless
solid (0.397 g, 35%).
4.4. General procedure for the synthesis of
5-(2-hydroxybenzoyl)salicylates (10a–h)
4.2.11. Ethyl-2-(3-chloropropyl)-9,10-dihydro-3-
hydroxy-1-methylphenanthrene-4-carboxylate (3k).
Starting with 1a (2.8 g, 8.0 mmol), 5g (2.08 g, 8.0 mmol),
and TiCl4 (1.52 g, 8.0 mmol) in CH2Cl2 (20 mL), 3k was iso-
lated after chromatography (silica gel, n-hexane/EtOAc ¼
To the 3-formylchromone 8a–e (1.0 equiv) was added
Me3SiOTf (0.3 equiv) at 20 ꢁC. After stirring for 10 min,
CH2Cl2 (8 mL) was added, the solution was cooled to
0 ꢁC and the 1,3-bis-silyl enol ether 1a,b (1.3 equiv) was
added. The mixture was stirred for 12 h at 20 ꢁC and was
1
30:1) as a colorless oil (0.78 g, 27%). H NMR (CDCl3,

7680
V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
subsequently poured into an aqueous solution of hydrochlo-
ric acid (10%). The organic and the aqueous layer were sep-
arated and the latter was extracted with Et2O (3ꢂ80 mL).
The combined organic layers were washed with water, dried
(Na2SO4), filtered, and the filtrate was concentrated invacuo.
The residue was purified by column chromatography (silica
gel, n-hexane/EtOAc ¼ 10:1/3:1).
4.4.3. Ethyl 3-(3-chloropropyl)-2-hydroxy-5-(2-hydroxy-
5-ethylbenzoyl)benzoate (10c). Starting with 8c (505 mg,
2.50 mmol), Me3SiOTf (167 mg, 0.75 mmol), and 1,3-bis-
silyl enol ether 1a (1.147 mg, 3.25 mmol), 10c was isolated
as a yellow solid by column chromatography with n-hexane/
EtOAc ¼ 25:1 (472 mg, 48%). 1H NMR (300 MHz, CDCl3):
d¼1.20 (t, J¼7.6 Hz, 3H, CH3CH2), 1.42 (t, J¼7.2 Hz, 3H,
OCH2CH3), 2.15 (m, J¼6.4 Hz, 2H, CH2CH2CH2Cl), 2.57
(q, J¼7.5 Hz, 2H, CH3CH2), 2.89 (t, J¼7.2 Hz, 2H,
ClCH2CH2CH2), 3.59 (t, J¼6.5 Hz, 2H, CH2CH2CH2Cl),
4.45 (q, J¼7.2 Hz, 2H, OCH2CH3), 7.02 (d, J¼8.4 Hz, 1H,
Ar), 7.35–7.41 (m, J¼2.1 Hz, 2H, Ar), 7.77 (t, J¼1.5 Hz,
1H, Ar), 8.19 (d, J¼2.3 Hz, 1H, Ar), 11.64 (s, 1H, OH),
11.68 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼14.1, 15.9 (CH3), 27.2, 27.9, 31.7, 44.4, 62.0 (CH2),
111.9 (C), 118.3, 118.8 (CH), 128.5, 129.6 (C), 130.8,
131.6 (CH), 134.4 (C), 136.1, 136.7 (CH), 161.1, 163.1,
170.1, 199.1 (C). IR (KBr): ~n ¼ 3167 ðbrÞ, 2961 (m), 1675
(s), 1629 (m), 1588 (s), 1476 (m), 1342 (m), 1290 (m),
4.4.1. Ethyl 3-(3-chloropropyl)-5-(2-hydroxybenzoyl)-
salicylate (10a). Starting with 8a (268 mg, 1.54 mmol),
Me3SiOTf (103 mg, 0.46 mmol), and 1,3-bis-silyl enol ether
1a (703 mg, 2.00 mmol), 10a was isolated as a yellow solid
(229 mg, 41%), mp¼107 ꢁC. 1H NMR (300 MHz, CDCl3):
d¼1.41 (t, J¼7.1 Hz, 3H, OCH2CH3), 2.15 (m, 2H,
CH2CH2CH2), 2.90 (t, J¼7.1 Hz, 2H, ArCH2), 3.58 (t,
J¼6.5 Hz, 2H, CH2–Cl), 4.44 (q, J¼7.2 Hz, 2H, OCH2CH3),
6.92 (m, 1H, Ar), 7.09 (dd, J¼8.4, 1.0 Hz, 1H, Ar), 7.53 (m,
1H, Ar), 7.59 (dd, J¼8.0, 1.5 Hz, 1H, Ar), 7.40 (d, J¼2.3 Hz,
1H, Ar), 8.18 (d, J¼2.3 Hz, 1H, Ar), 11.65 (s, 1H, OH),
11.88 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼14.1 (CH3), 27.2, 31.6 (CH2), 44.4 (CH2Cl), 62.1
(OCH2CH3), 111.9 (C), 118.5, 118.7 (CH), 119.0, 128.4,
129.5 (C), 130.5, 132.9, 136.1, 136.6 (CH), 162.9, 163.0
(C-OH), 169.9, 199.2 (C]O). IR (KBr): ~n ¼ 3329 ðmÞ,
3095 (m), 3070 (m), 2991 (m), 2963 (m), 2938 (m),
1675 (s), 1624 (s), 1590 (s), 1483 (s), 1450 (s), 1407 (s),
1381 (s), 1348 (s), 1328 (s), 1289 (s), 1264 (s), 1237
(s), 1192 (s), 1158 (s), 1134 (w), 1023 (m), 807 (w), 770
(s), 738 (m), 706 (m), 659 (w) cmꢀ1. UV–vis (CH3CN):
lmax (log 3): 316 (3.93), 289 (3.99), 240 (4.28), 214
(4.47) nm. MS (EI, 70 eV): m/z (%)¼362 (M+, 64), 317
(4), 281 (67), 252 (19), 242 (24), 197 (6), 161 (10),
121 (100), 93 (9). HRMS (FT-ICR): calcd for C19H19O5Cl
([M+1]+): 363.09938; found: 363.09970. Anal. Calcd
for C19H19ClO5: C, 62.90; H, 5.28. Found: C, 62.72;
H, 5.51.
1254 (s), 1200 (s), 1166 (m), 1023 (m), 841 (m) cmꢀ1
.
UV–vis (CH3CN): lmax (log 3)¼251.0 (4.42), 239.6 (4.26),
287.9 (3.96), 344.5 (3.71) nm. MS (EI, 70 eV): m/z
(%)¼392 (M+[37Cl], 8), 390 (M+[35Cl], 29), 310 (45), 226
(38), 225 (100), 148 (61), 147 (51), 133 (19), 74 (17), 28
(71). HRMS (ESI): calcd for C21H23O5Cl: 390.12340;
found: 390.12216.
4.4.4. Ethyl 3-(3-chloropropyl)-2-hydroxy-5-(2-hydroxy-
5-chlorobenzoyl)benzoate (10d). Starting with 8d
(522 mg, 2.50 mmol), Me3SiOTf (167 mg, 0.75 mmol),
and 1,3-bis-silyl enol ether 1a (1.147 g, 3.25 mmol), 10d
was isolated as yellow solid by column chromatography
with n-hexane/EtOAc ¼ 25:1 (507 mg, 51%). 1H NMR
(300 MHz, CDCl3): d¼1.42 (t, J¼7.1 Hz, 3H, OCH2CH3),
2.16 (m, J¼6.5 Hz, 2H, CH2CH2CH2Cl), 2.92 (t,
J¼7.0 Hz, 2H, ClCH2CH2CH2), 3.59 (t, J¼6.5 Hz, 2H,
CH2CH2CH2Cl), 4.48 (q, J¼7.2 Hz, 2H, OCH2CH3), 7.05
(d, J¼8.5 Hz, 1H, Ar), 7.35–7.41 (dd, J¼2.6 Hz, 6.2 Hz,
1H, Ar), 7.58 (d, J¼2.6 Hz, 1H, Ar), 7.75 (t, J¼1 Hz, 1H,
Ar), 8.18 (d, J¼2.3 Hz, 1H, Ar), 11.70 (s, 1H, OH), 11.74
(s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼14.1 (CH3), 27.3, 31.6, 44.3, 62.2 (CH2), 112.1, 119.7
(C), 120.1 (CH), 123.5, 127.8, 130.0 (C), 130.7, 131.9,
135.9, 136.4 (CH), 161.4, 163.5, 169.9, 198.2 (C). IR
(KBr): ~n ¼ 3089 ðbrÞ, 2956 (w), 1675 (m), 1630 (m), 1464
(m), 1335 (m), 1256 (m), 1206 (m), 1017 (w), 843
(m) cmꢀ1. UV–vis (CH3CN): lmax (log 3)¼218.9 (4.39),
293.1 (3.84) nm. MS (EI, 70 eV): m/z (%)¼398 (M+[37Cl
35Cl], 4), 390 (M+[35Cl 35Cl], 10), 363 (4), 320 (8), 291
(40), 275 (19), 219 (33), 217 (31), 203 (18), 146 (20), 129
(29), 74 (100), 28 (59). Anal. Calcd for C19H18O5Cl2: C,
57.63; H, 4.58. Found: C, 56.75; H, 5.43.
4.4.2. Ethyl 3-(3-chloropropyl)-2-hydroxy-5-(2-hydroxy-
5-methylbenzoyl)benzoate (10b). Starting with 8b
(376 mg, 2.00 mmol), Me3SiOTf (133 mg, 0.60 mmol),
and 1,3-bis-silyl enol ether 1a (917 mg, 2.60 mmol), 10b
was isolated as a yellow solid by column chromatography
with n-hexane/EtOAc ¼ 25:1 (410 mg, 54%). 1H NMR
(300 MHz, CDCl3): d¼1.43 (t, J¼7.1 Hz, 3H, OCH2CH3),
2.16 (m, J¼6.6 Hz, 2H, CH2CH2CH2Cl), 2.28 (s, 3H,
CH3), 2.90 (t, J¼7.1 Hz, 2H, ClCH2CH2CH2), 3.58 (t,
J¼6.5 Hz, 2H, CH2CH2CH2Cl), 4.46 (q, J¼7.2 Hz, 2H,
OCH2CH3), 7.00 (d, J¼2.3 Hz, 1H, Ar), 7.26 (d,
J¼2.0 Hz, 1H, Ar), 7.36 (dd, J¼1, 2 Hz, 1H, Ar), 7.74 (d,
J¼2.0 Hz, 1H, Ar), 8.19 (d, J¼2.3 Hz, 1H, Ar), 11.63 (s,
1H, OH), 11.68 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz,
CDCl3): d¼14.2, 20.5 (CH3), 27.2, 31.5, 44.3, 62.0 (CH2),
112.1 (C), 118.3 (CH), 118.8, 127.9, 128.6, 129.4 (C),
130.6, 132.7, 136.7, 137.2 (CH), 160.0, 163.0, 170.1,
199.2 (C). MS (EI, 70 eV): m/z (%)¼378 (M+[37Cl 35Cl],
18), 376 (M+[35Cl 35Cl], 55), 340 (34), 295 (55), 206
(31), 135 (100), 44 (72). IR (KBr): ~n ¼ 2990 ðwÞ, 1674
(s), 1631 (s), 1583 (s), 1484 (m), 1406 (s), 1378 (s), 1348
(s), 1290 (s), 1236 (s), 1177 (s), 1023 (m), 786 (m),
705 (m) cmꢀ1. UV–vis (CH3CN): lmax (log 3)¼214.9
(4.45), 240.3 (4.29), 285.3 (3.99), 343.5 (3.74) nm. Anal.
Calcd for C20H21O5Cl: C, 63.74; H, 5.62. Found: C, 63.60;
H, 5.72.
4.4.5. Ethyl 3-(3-chloropropyl)-2-hydroxy-5-(2-hydroxy-
5-chloro-3-methylbenzoyl)benzoate (10e). Starting with
8e (556 mg, 2.50 mmol), Me3SiOTf (167 mg, 0.75 mmol),
and 1,3-bis-silyl enol ether 1a (1.147 mg, 3.25 mmol), 10e
was isolated as yellow solid by column chromatography
with n-hexane/EtOAc ¼ 25:1 (482 mg, 47%). 1H NMR
(300 MHz, CDCl3): d¼1.43 (t, J¼7.2 Hz, 3H, OCH2CH3),
2.16 (m, J¼6.5 Hz, 2H, CH2CH2CH2Cl), 2.42 (s, 3H,
CH3), 2.92 (t, J¼7.3 Hz, 2H, ClCH2CH2CH2), 3.59 (t,
J¼6.5 Hz, 2H, CH2CH2CH2Cl), 4.48 (q, J¼7.1 Hz, 2H,

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7681
OCH2CH3), 6.99 (d, J¼1.0 Hz, 1H, Ar), 7.56 (s, 1H, Ar),
7.73 (dd, J¼1, 2 Hz, 1H, Ar), 8.17 (d, J¼2.3 Hz, 1H, Ar),
11.67 (s, 1H, OH), 11.77 (s, 1H, OH). 13C NMR (DEPT,
75.5 MHz, CDCl3): d¼14.1, 20.8 (CH3), 27.3, 31.6, 44.3,
62.1 (CH2), 112.1, 117.9 (C), 120.5 (CH), 124.1, 127.9,
129.9 (C), 130.5, 132.3, 136.4 (CH), 145.4, 161.4, 163.3,
169.9, 197.9 (C). IR (KBr): ~n ¼ 3110 ðbrÞ, 2957 (m), 1678
(s), 1626 (m), 1587 (s), 1471 (m), 1381 (m), 1340 (s),
1264 (s), 1242 (s), 1181 (s), 1022 (m), 843 (s) cmꢀ1. UV–
vis (CH3CN): lmax (log 3)¼218.9 (4.39), 293.1 (3.84) nm.
MS (EI, 70 eV): m/z (%)¼413 (M+[37Cl 35Cl], 20), 411
(M+[35Cl 35Cl], 36), 371 (11), 329 (26), 219 (35), 217
(39), 169 (49), 129 (24), 74 (100), 29 (19). HRMS (ESI):
calcd for C20H20O5Cl2: 410.06878; found: 410.06721.
163.1, 170.1, 199.3 (C). IR (KBr): ~n ¼ 2962 ðwÞ, 1676 (s),
1630 (s), 1586 (s), 1482 (m), 1349 (s), 1291 (s), 1265 (s),
1204 (s), 1173 (m), 791 (m) cmꢀ1. UV–vis (CH3CN): lmax
(log 3)¼213.3 (4.47), 240.6 (4.29), 287.8 (3.98), 345.1
(3.73) nm. MS (EI, 70 eV): m/z (%)¼326 (M+, 90), 175
(100), 134 (91), 77 (15), 28 (29). HRMS (ESI): calcd for
C21H23O5Cl: 390.12340; found: 390.12286.
4.4.8. Ethyl 3-(3-chloro-2-methylpropyl)-2-hydroxy-5-
(2-hydroxy-5-chlorobenzoyl)benzoate (10h). Starting with
8d (417 mg, 2.00 mmol), Me3SiOTf (133 mg, 0.60 mmol),
and 1,3-bis-silyl enol ether 1b (948 mg, 2.6 mmol),
10h was isolated as yellow solid by column chromato-
graphy with n-hexane/EtOAc¼25:1 (410 mg, 38%). 1H
NMR (300 MHz, CDCl3): d¼1.08 (d, J¼6.7 Hz, 3H,
CH3(CH)CH2), 1.43 (t, J¼7.1 Hz, 3H, OCH2CH3), 2.37
(m, J¼5.4 Hz, 1H, CH3(CH)CH2), 2.69 (q, J¼7.0 Hz, 1H,
CH3(CH)CH2), 2.88 (q, J¼7.0 Hz, 1H, CH3(CH)CH2),
3.44–3.57 (qq, J¼5.4, 8.0 Hz, 2H, CH3(CH)CH2Cl), 4.47
(q, J¼7.2 Hz, 2H, OCH2CH3), 7.06 (d, J¼8.9 Hz, 1H, Ar),
7.44–7.48 (m, J¼2.5, 6.3 Hz, 1H, Ar), 7.57 (d, J¼2.0 Hz,
1H, Ar), 7.71 (d, J¼2.2 Hz, 1H, Ar), 8.19 (d, J¼2.2 Hz,
1H, Ar), 11.69 (s, 1H, OH), 11.73 (s, 1H, OH). 13C NMR
(DEPT, 75.5 MHz, CDCl3): d¼14.1, 17.7 (CH3), 34.4
(CH2), 34.9 (CH), 50.6, 62.2 (CH2), 112.2, 119.7 (C),
120.1 (CH), 123.4, 127.5, 129.1 (C), 130.7, 131.9, 135.9,
137.2 (CH), 161.4, 163.5, 169.9, 198.1 (C). IR (KBr):
~n ¼ 3109 ðbrÞ, 2970 (w), 1674 (s), 1629 (s), 1593 (s), 1464
(s), 1378 (m), 1347 (s), 1320 (s), 1287 (s), 1254 (s), 1231
(s), 1177 (s), 737 (m) cmꢀ1. UV–vis (CH3CN): lmax
(log 3)¼218.6 (4.52), 294.2 (3.95), 343.1 (3.78) nm. MS
(EI, 70 eV): m/z (%)¼413 (M+[37Cl 35Cl], 7), 412 (31),
411 (M+[35Cl 35Cl], 11), 410 (47), 374 (34), 287 (12), 220
(100), 155 (49). HRMS (ESI): calcd for C20H20O5Cl2:
410.06878; found: 410.06794. Anal. Calcd for C20H20O5Cl2:
C, 58.41; H, 4.90. Found: C, 58.45; H, 4.89.
4.4.6. Ethyl 3-(3-chloro-2-methylpropyl)-2-hydroxy-5-
(2-hydroxybenzoyl)benzoate (10f). Starting with formyl-
chromone 8a (348 mg, 2.0 mmol), Me3SiOTf (133 mg,
0.60 mmol), and 1,3-bis-silyl enol ether 1b (949 mg,
2.6 mmol), 10f was isolated by column chromatography
(silica gel, n-hexane/EtOAc ¼ 25:1) as a yellow solid
1
(324 mg, 43%). H NMR (300 MHz, CDCl3): d¼1.08 (d,
J¼6.7 Hz, 3H, CH3(CH)CH2), 1.42 (t, J¼7.2 Hz, 3H,
OCH2CH3), 2.38 (m, J¼5.7 Hz, 1H, CH3(CH)CH2), 2.69
(q, J¼7.2 Hz, 1H, CH3(CH)CH2), 2.87 (q, J¼7.1 Hz, 1H,
CH3(CH)CH2), 3.43–3.57 (qq, J¼5.4, 9.2 Hz, 2H,
CH3(CH)CH2Cl), 4.46 (q, J¼7.1 Hz, 2H, OCH2CH3),
6.89–6.94 (td, J¼6.3, 1.0 Hz, 1H, Ar), 7.08–7.10 (dd, J¼7.6,
1.0 Hz, 1H, Ar), 7.49–7.56 (td, J¼7.0, 2.0 Hz, 1H, Ar),
7.59–7.62 (dd, J¼6.3, 2.0 Hz, 1H, Ar), 7.72 (d, J¼2.2 Hz,
1H, Ar), 8.20 (d, 2.2 Hz, 1H, Ar), 11.66 (s, 1H, OH),
11.89 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼14.2, 17.7 (CH3), 34.4 (CH2), 34.9 (CH), 50.6, 62.1
(CH2), 112.1 (C), 118.5, 118.7 (CH), 119.1, 128.4, 128.8
(C), 130.6, 132.9, 136.2, 137.4 (CH), 163.0, 163.2, 170.1,
199.3 (C). UV–vis (CH3CN): lmax (log 3)¼214.9 (4.46),
240.2 (4.28), 289.6 (3.99), 317.2 (3.94) nm. IR (KBr):
~n ¼ 3418 ðbrÞ, 2960 (w), 1675 (s), 1624 (s), 1587 (s), 1482
(m), 1458 (m), 1348 (s), 1296 (s), 1263 (s), 1240 (s), 1180
(s), 766 (m) cmꢀ1. MS (EI, 70 eV): m/z (%)¼378
(M+[37Cl], 1), 376 (M+[35Cl], 5), 295 (8), 253 (8), 121
(14), 32 (24), 28 (100). Anal. Calcd for C20H21O5Cl: C,
63.75; H, 5.62. Found: C, 63.52; H, 5.65.
4.4.9. 2-Bromo-4-(3-chloropropyl)-1,3-dihydroxyanthra-
cene-9,10-dione (13). A THF solution (50 mL) of 1a
(2.81 g, 8.0 mmol) and 2-bromonaphthalene-1,4-dione (12)
(0.95 g, 4.0 mmol) was stirred at ꢀ78 ꢁC for 1 h. The solu-
tion was allowed to warm to 20 ꢁC during 14 h. To the solu-
tion was added hydrochloric acid (10 mL, 6 M). The THF
was removed in vacuo and the residue was washed with
water and extracted with CH2Cl2 (3ꢂ50 mL). The combined
organic layers were dried over Na2SO4, filtered, and the sol-
vent of the filtrate was removed in vacuo. The residue was
purified by column chromatography (silica gel, n-hexane/
EtOAc ¼ 20:1) to give 13 as a yellowish solid (0.375 g,
4.4.7. Ethyl 3-(3-chloro-2-methylpropyl)-2-hydroxy-5-
(2-hydroxy-5-methylbenzoyl)benzoate(10g).Startingwith
8b (376 mg, 2.0 mmol), Me3SiOTf (133 mg, 0.60 mmol),
and 1,3-bis-silyl enol ether 1b (948 mg, 2.60 mmol),
10g was isolated as yellow solid by column chromato-
graphy with n-hexane/EtOAc ¼ 25:1 (320 mg, 41%). 1H
NMR (300 MHz, CDCl3): d¼1.09 (d, J¼6.7 Hz, 3H,
CH3(CH)CH2), 1.44 (t, J¼7.2 Hz, 3H, CH3CH2O), 2.28
(s, 3H, CH3), 2.38 (m, J¼5.5 Hz, 1H, CH3(CH)CH2), 2.69
(q, J¼6.2 Hz, 1H, CH3(CH)CH2), 2.87 (q, J¼6.5 Hz, 1H,
CH3(CH)CH2), 3.45–3.58 (qq, J¼5.2, 9.0 Hz, 2H,
CH3(CH)CH2Cl), 4.46 (q, J¼7.1 Hz, 2H, CH3CH2O), 7.00
(d, J¼8.3 Hz, 1H, Ar), 7.31–7.38 (m, J¼1.0, 2.0 Hz, 2H,
Ar), 7.71 (d, J¼2.2 Hz, 1H, Ar), 7.74 (d, J¼2.0 Hz, 1H,
Ar), 8.21 (d, J¼2.3 Hz, 1H, Ar), 11.63 (s, 1H, OH), 11.68
(s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼14.2, 17.8, 20.5 (CH3), 30.3 (CH), 34.4 (CH2), 34.9
(CH3), 50.6, 62.1 (CH2), 112.1 (C), 118.3 (CH), 118.8,
127.9, 128.5 (C), 130.6, 132.7, 137.2, 137.5 (CH), 160.9,
1
30%). H NMR (CDCl3, 300 MHz): d¼2.14 (m, J¼6.9,
1.5 Hz, 2H, CH2), 3.36 (m, J¼5.7 Hz, 2H, CH2), 3.74 (t,
J¼6.8 Hz, 2H, CH2–Cl), 6.59 (s, 1H, OH), 7.71–7.83 (m,
2H, 2ꢂCH of Ar), 8.22–8.29 (m, 2H, 2ꢂCH of Ar), 14.44
(s, 1H, OH). 13C NMR (CDCl3, 75 MHz): dC¼25.1, 31.9,
45.3 (CH2), 105.4, 110.6 (C), 126.3, 127.3 (CH), 127.5,
130.4, 132.1 (C), 134.5 (CH), 134.6 (C), 135.2 (CH),
160.5, 161.1, 184.2, 187.1 (C). IR (KBr, cmꢀ1):
~n ¼ 3435 ðsÞ, 1667 (s), 1626 (s), 1586 (s), 1439 (s), 1393
(s), 1358 (s), 1279 (s), 1183 (s), 1150 (s), 1013 (m), 838
(m), 732 (s), 628 (m). UV–vis (CH3CN, nm): lmax
(log 3)¼206.7 (4.32), 248.9 (4.37), 272.5 (4.37), 338.6
(3.51), 408.4 (3.77) nm. MS (EI, 70 eV): m/z (%)¼398
(M+[81Br 37Cl], 20), 397 (12), 396 (M+[81Br 35Cl],

7682
V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
M+[79Br 37Cl], 100), 395 (8), 394 (M+[79Br 35Cl], 73), 331
(85), 264 (8), 210 (14), 139 (34), 105 (6), 77 (13), 28 (40).
HRMS (ESI): calcd for C17H12BrClO4 ([M+1]+):
396.96562 [81Br 35Cl], 394.96857 [79Br 35Cl]; found:
396.94806 [81Br 35Cl], 394.95052 [79Br 35Cl]. Anal. Calcd
for C17H12BrClO4 (395.632): C, 51.59; H, 3.06. Found: C,
51.86; H, 3.60.
NaH (0.008 g, 0.33 mmol), and TBAI (0.144 g, 0.44
mmol) in THF (5 mL), 4c was isolated after chromatography
(silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless oil
(0.036 g, 70%). 1H NMR (CDCl3, 300 MHz): d¼1.36
(t, J¼7.1 Hz, 3H, CH3), 2.02 (m, J¼4.2, 1.2 Hz, 2H, CH2),
2.16 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.59 (t, J¼6.6 Hz,
2H, CH2), 4.14 (t, J¼5.2 Hz, 2H, CH2), 4.38 (q, J¼7.1 Hz,
2H, OCH2), 6.75 (s, 1H, CH of Ar). 13C NMR (CDCl3,
75 MHz): dC¼14.3, 18.9, 19.0 (CH3), 22.0, 22.2, 60.9,
66.1 (CH2), 118.6, 120.9 (C), 123.1 (CH), 133.1, 138.6,
151.9, 168.7 (C). IR (neat, cmꢀ1): ~n ¼ 3414 ðmÞ, 2977 (s),
2938 (s), 1716 (s), 1612 (m), 1574 (m), 1457 (s), 1369
(m), 1303 (s), 1273 (s), 1151 (s), 1106 (s), 1056 (s), 959
(m). UV–vis (CH3CN, nm): lmax (log 3)¼207 (4.48), 285
(3.34) nm. MS (EI, 70 eV): m/z (%)¼236 ([M+2]+, 1),
235.1 ([M+1]+, 12), 234 (M+, 87), 189 (100), 161 (31),
132 (20), 103 (7), 77 (12), 28 (17). HRMS (ESI): calcd for
C14H19O3 ([M+1]+): 235.13342; found: 235.13286. Anal.
Calcd for C14H18O3 (234.291): C, 71.77; H, 7.74. Found:
C, 70.94; H, 7.37.
4.5. General procedure for the synthesis of chromanes
(4a–m), (11a–h), and (14)
To a THF solution of 3a–m, 10a–h, or 13 and of NaH was
added TBAI. After stirring at 20 ꢁC for 20 h, the mixture
was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, n-hexane/EtOAc) to
give the product.
4.5.1. Ethyl 3,4-dihydro-2H-chromene-8-carboxylate
(4a). Starting with 3a (0.329 g, 1.36 mmol), NaH (0.040 g,
1.66 mmol), and TBAI (0.721 g, 2.21 mmol) in THF
(22 mL), 4a was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 20:1) as a colorless oil (0.230 g, 64%).
1H NMR (CDCl3, 300 MHz): d¼1.37 (t, J¼7.1 Hz, 3H,
CH3), 2.04 (m, J¼5.3 Hz, 2H, CH2), 2.82 (t, J¼6.5 Hz,
2H, CH2), 4.29 (t, J¼5.3 Hz, 2H, CH2), 4.35 (q, J¼7.1 Hz,
2H, OCH2), 6.83 (t, J¼7.6 Hz, 1H, CH of Ar), 7.17 (m,
J¼6.5, 1 Hz, 1H, CH of Ar), 7.61 (dt, J¼7.8, 1 Hz, 1H,
CH of Ar). 13C NMR (CDCl3, 75 MHz): dC¼14.3 (CH3),
21.7, 25.1, 60.6, 66.9 (CH2), 111.1 (CH), 119.6, 123.4 (C),
129.3, 133.7 (CH), 154.9, 166.2 (C). IR (neat, cmꢀ1):
~n ¼ 2979 ðmÞ, 2937 (m), 1726 (s), 1595 (s), 1473 (s), 1454
(s), 1367 (m), 1298 (s), 1265 (s), 1238 (s), 1176 (s), 1138
(s), 1094 (s), 1055 (s), 958 (m), 878 (m), 761 (s). UV–vis
(CH3CN, nm): lmax (log 3)¼209 (4.43), 298 (3.51) nm.
MS (EI, 70 eV): m/z (%)¼207 ([M+1]+, 6), 206 (M+, 46),
161 (100), 133 (34), 105 (31), 77 (27), 51 (18), 29 (8).
HRMS (FT-ICR): calcd for C12H14O3 ([M+1]+):
207.10212; found: 207.10165. Anal. Calcd for C12H14O3
(206.238): C, 69.89; H, 6.84. Found: C, 69.18; H, 6.75.
4.5.4. Ethyl-3,4-dihydro-5,7-dimethyl-6-ethyl-2H-chro-
mene-8-carboxylate (4d). Starting with 3d (0.274 g,
0.92 mmol), NaH (0.033 g, 1.37 mmol), and TBAI
(0.600 g, 1.84 mmol) in THF (20 mL), 4d was isolated after
chromatography (silica gel, n-hexane/EtOAc ¼ 20:1) as a
1
colorless oil (0.198 g, 82%). H NMR (CDCl3, 300 MHz):
d¼1.06 (t, J¼7.5 Hz, 3H, CH3), 1.36 (t, J¼7.2 Hz, 3H,
CH3), 2.01 (m, J¼6.5 Hz, 2H, CH2), 2.15 (s, 3H, CH3),
2.20 (s, 3H, CH3), 2.56–2.64 (m, J¼7.4 Hz, 4H, 2ꢂCH2),
4.09 (t, J¼5.2 Hz, 2H, CH2), 4.37 (q, J¼7.1 Hz, 2H,
OCH2). 13C NMR (CDCl3, 75 MHz): dC¼13.7, 14.1, 14.6,
16.0 (CH3), 22.2, 22.3, 23.0, 60.8, 65.7 (CH2), 118.8,
121.8, 130.2, 132.6, 136.1, 149.2, 169.3 (C). IR (neat,
cmꢀ1): ~n ¼ 3435 ðwÞ, 2968 (s), 2934 (s), 2872 (s), 1728
(s), 1583 (s), 1451 (s), 1372 (m), 1275 (s), 1187 (s), 1115
(s), 1087 (s), 1043 (s), 956 (m), 735 (m). UV–vis (CH3CN,
nm): lmax (log 3)¼207 (4.48), 289 (3.36) nm. MS (EI,
70 eV): m/z (%)¼263 ([M+1]+, 7), 262 (M+, 50), 247 (66),
217 (32), 201 (28), 188 (20), 84 (56), 32 (25), 28 (100).
4.5.2. Ethyl 3,4-dihydro-5,6,7-trimethyl-2H-chromene-8-
carboxylate (4b). Starting with 3b (0.307 g, 1.09 mmol),
NaH (0.039 g, 1.63 mmol), and TBAI (0.771 g, 2.18
mmol) in THF (20 mL), 4b was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless
solid (0.235 g, 90%), mp¼76 ꢁC. 1H NMR (CDCl3,
300 MHz): d¼1.36 (t, J¼7.1 Hz, 3H, CH3), 2.00 (m, 2H,
CH2), 2.13 (s, 6H, 2ꢂCH3), 2.17 (s, 3H, CH3), 2.65 (t,
J¼6.5 Hz, 2H, CH2), 4.11 (t, J¼5.2 Hz, 2H, CH2), 4.39 (q,
J¼7.1 Hz, 2H, OCH2). 13C NMR (CDCl3, 75 MHz):
dC¼14.3, 15.3, 15.5 (CH3), 17.2, 22.5, 23.2, 60.9, 65.8
(CH2), 118.6, 121.6, 126.8, 130.9, 136.8, 149.3, 169.4 (C).
IR (KBr, cmꢀ1): ~n ¼ 2983 ðmÞ, 2936 (m), 1724 (s), 1581
(m), 1455 (m), 1312 (m), 1277 (s), 1184 (s), 1114 (s),
1084 (m), 1046 (s), 964 (m). UV–vis (CH3CN, nm): lmax
(log 3)¼205 (4.49), 289 (3.43) nm. MS (EI, 70 eV):
m/z (%)¼249 ([M+1]+, 14), 248 (M+, 100), 203 (66), 202
(22), 174 (25), 161 (40), 133 (13), 105 (11), 77 (16), 51
(5), 29 (8). HRMS (ESI): calcd for C15H20O3 ([M+1]+):
249.14910; found: 249.14908.
4.5.5. Ethyl 5,7-diethyl-3,4-dihydro-2H-chromene-8-car-
boxylate (4e). Starting with 3 (0.330 g, 1.10 mmol), NaH
(0.040 g, 1.66 mmol), TBAI (0.721 g, 2.21 mmol) in THF
(20 mL), 4e was isolated after chromatography (silica gel,
n-hexane/EtOAc ¼ 20:1) as a colorless oil (0.230 g, 80%).
1H NMR (CDCl3, 300 MHz): d¼1.19 (t, J¼7.5 Hz, 6H,
2ꢂCH3), 1.36 (t, J¼7.1 Hz, 3H, CH3), 2.03 (m, J¼4.4 Hz,
2H, CH2), 2.53 (m, J¼7.5 Hz, 4H, 2ꢂCH2), 2.67 (t,
J¼6.5 Hz, 2H, CH2), 4.15 (t, J¼5.2 Hz, 2H, CH2), 4.38 (q,
J¼7.1 Hz, 2H, OCH2), 6.61 (s, 1H, CH). 13C NMR
(CDCl3, 75 MHz): dC¼14.1, 14.2, 15.6 (CH3), 21.6, 22.0,
25.4, 26.3, 60.8, 66.0 (CH2), 117.8 (C), 119.8 (CH), 120.5,
139.5, 144.4, 151.6, 168.7 (C). IR (neat, cmꢀ1):
~n ¼ 2969 ðsÞ, 2937 (s), 2874 (s), 1728 (s), 1609 (s), 1571
(s), 1463 (s), 1442 (s), 1417 (s), 1370 (m), 1276 (s), 1248
(s), 1150 (s), 1113 (s), 1066 (s), 868 (m). UV–vis
(CH3CN, nm): lmax (log 3)¼207 (4.53), 284 (3.38) nm.
MS (EI, 70 eV): m/z (%)¼263 ([M+1]+, 6), 262 (M+, 50),
217 (73), 216 (100), 215 (34), 189 (15), 188 (15),
187 (17), 159 (9), 91 (13), 28 (36). Anal. Calcd for
C16H22O3 (262.344): C, 73.53; H, 8.10. Found: C, 73.49;
H, 8.94.
4.5.3. Ethyl 5,7-dimethyl-3,4-dihydro-2H-chromene-8-
carboxylate (4c). Starting with 3c (0.059 g, 0.22 mmol),

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7683
4.5.6. Ethyl 3,4-dihydro-3,5,6,7-tetramethyl-2H-chro-
mene-8-carboxylate (4f). Starting with 3f (0.230 g, 0.77
mmol), NaH (0.028 g, 1.15 mmol), and TBAI (0.503 g,
1.54 mmol) in THF (12 mL), 4f was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless
solid (0.190 g, 94%), mp¼111 ꢁC. 1H NMR (CDCl3,
300 MHz): d¼1.05 (d, J¼6.5 Hz, 3H, CH3), 1.34 (t,
J¼7.1 Hz, 3H, CH3), 2.09 (m, 1H, CH), 2.13 (s, 6H,
2ꢂCH3), 2.17 (s, 3H, CH3), 2.22 (m, 1H, CH2), 2.74 (dq,
J¼10.1, 1.8 Hz, 1H, CH2), 3.57 (m, J¼10 Hz, 1H, CH2),
4.12 (m, J¼5.3, 1.8 Hz, 1H, CH2), 4.39 (q, J¼7.1 Hz, 2H,
OCH2). 13C NMR (CDCl3, 75 MHz): dC¼14.3, 15.3, 15.5,
17.1, 17.3 (CH3), 27.3 (CH), 31.9, 60.9, 71.2 (CH2), 118.4,
121.4, 126.9, 130.9, 136.6, 148.8, 169.4 (C). IR (KBr,
cmꢀ1): ~n ¼ 2983 ðmÞ, 1726 (s), 1464 (m), 1268 (s), 1185
(s), 1123 (m), 1042 (s). UV–vis (CH3CN, nm): lmax
(log 3)¼203 (4.57), 288 (3.43) nm. MS (EI, 70 eV): m/z
(%)¼263 ([M+1]+, 16), 262 (M+, 100), 217 (89), 216 (40),
188 (39), 175 (21), 146 (11), 91 (12), 32 (17), 28 (80).
Anal. Calcd for C16H22O3 (262.344): C, 73.25; H, 8.45.
Found: C, 72.85; H, 7.98.
70 eV): m/z (%)¼277.6 ([M+1]+, 21), 276.7 (M+, 100),
231 (39), 230 (64), 229 (16), 189 (8), 188 (7), 29 (6).
HRMS (ESI): calcd for C17H24O3 ([M+1]+): 277.18037,
found: 277.18035.
4.5.9. Ethyl 3,4,6,7,8,9-hexahydro-2H-benzo[g]chro-
mene-10-carboxylate (4i). Starting with 3i (311 mg,
1.05 mmol), NaH (38 mg, 1.58 mmol), and TBAI (685 mg,
2.10 mmol) in THF (20 mL), 4i was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless
1
oil (0.189 g, 70%). H NMR (CDCl3, 300 MHz): d¼1.36
(t, J¼7.2 Hz, 3H, CH3), 1.71–1.76 (m, J¼3.3 Hz, 4H,
2ꢂCH2), 1.97 (m, J¼4.3 Hz, 2H, CH2), 2.65 (m, 6H,
3ꢂCH2), 2.71 (t, J¼6.5 Hz, 2H, CH2), 4.16 (t, J¼5.2 Hz,
2H, CH2), 4.36 (q, J¼7.1 Hz, 2H, OCH2), 6.77 (s, 1H,
CH). 13C NMR (CDCl3, 75 MHz): dC¼14.3 (CH3), 22.2,
22.8, 22.9, 24.5, 26.2, 28.8, 60.9, 66.6 (CH2), 111.9, 122.4,
128.7, 131.1, 132.3, 149.4, 168.7 (C). IR (neat, cmꢀ1):
~n ¼ 2977 ðsÞ, 2931 (s), 2858 (s), 1729 (s), 1582 (s), 1476
(s), 1446 (s), 1367 (s), 1285 (s), 1249 (s), 1179 (s), 1164
(s), 1108 (s), 1061 (s), 961 (s), 866 (s), 724 (m). UV–vis
(CH3CN, nm): lmax (log 3)¼204 (4.41), 294 (3.55) nm.
MS (EI, 70 eV): m/z (%)¼261 ([M+1]+, 6), 260 (M+, 50),
214 (64), 186 (23), 168 (12), 153 (16), 128 (6), 114 (6), 91
(9), 28 (100). HRMS (ESI): calcd for C16H20O3 ([M+1]+):
261.14907; found: 261.14928. Anal. Calcd for C16H20O3
(260.328): C, 73.81; H, 7.74. Found: C, 73.51; H, 8.02.
4.5.7. Ethyl 3,4-dihydro-3,5,7-trimethyl-2H-chromene-8-
carboxylate (4g). Starting with 3g (0.176 g, 0.62 mmol),
NaH (0.039 g, 1.63 mmol), and TBAI (0.771 g, 2.18 mmol)
in THF (12 mL), 4g was isolated after chromatography
(silica gel, n-hexane/EtOAc ¼ 20:1) as a colorless solid
1
(0.123 g, 80%), mp¼71 ꢁC. H NMR (CDCl3, 300 MHz):
d¼1.05 (d, J¼6.3 Hz, 3H, CH3), 1.36 (t, J¼7.1 Hz, 3H,
CH3), 2.10 (m, 1H, CH), 2.16 (s, 3H, CH3), 2.22 (s, 3H,
CH3), 2.18 (m, 1H, CH2), 2.68 (m, 1H, CH2), 3.61 (m,
J¼12 Hz, 1H, CH2), 4.15 (m, J¼5.5 Hz, 1H, CH2), 4.38 (q,
J¼7.1 Hz, 2H, OCH2), 6.57 (s, 1H, CH of Ar). 13C NMR
(CDCl3, 75 MHz): dC¼14.3, 17.2, 18.9, 19.0 (CH3), 26.9
(CH), 30.9, 60.9, 71.5 (CH2), 110.9, 118.4, 120.7 (C),
123.2 (CH), 133.2, 138.5, 151.4, 168.7 (C). IR (KBr,
cmꢀ1): ~n ¼ 3442 ðmÞ, 2978 (s), 1728 (s), 1612 (m), 1574
(m), 1452 (m), 1282 (s), 1265 (s), 1151 (s), 1056 (s), 1042
(s), 862 (m). UV–vis (CH3CN, nm): lmax (log 3)¼206
(4.52), 284 (3.39) nm. MS (EI, 70 eV): m/z (%)¼249
([M+1]+, 8), 248 (M+, 100), 202 (66), 161 (21), 32 (22), 28
(100). Anal. Calcd for C15H20O3 (248.318): C, 72.55; H,
8.12. Found: C, 72.10; H, 8.43.
4.5.10. Ethyl 3,4,6,7,8,9-hexahydro-5-methyl-2H-
benzo[g]chromene-10-carboxylate (4j). Starting with 3j
(0.305 g, 0.98 mmol), NaH (0.035 g, 1.47 mmol), and
TBAI (0.640 g, 1.96 mmol) in THF (18 mL), 4j was isolated
after chromatography (silica gel, n-hexane/EtOAc ¼ 20:1)
1
as a colorless solid (0.234 g, 87%), mp¼74 ꢁC. H NMR
(300 MHz, CDCl3): d¼1.38 (t, J¼7.2 Hz, 3H, CH3), 1.69–
1.79 (m, 4H, 2ꢂCH2), 2.00–2.06 (m, 2H, CH2), 2.10 (s,
3H, CH3), 2.58 (t, J¼6.5 Hz, 2H, CH2), 2.64 (m, 4H, 2
CH2), 4.13 (t, J¼5.2 Hz, 2H, CH2), 4.36 (q, J¼7.1 Hz, 2H,
OCH2). 13C NMR (CDCl3, 75 MHz): dC¼14.2, 14.3
(CH3), 22.4 (2 CH2), 22.9, 23.1, 23.2, 26.9, 60.8, 65.8
(CH2), 118.7, 120.6, 127.1, 131.9, 136.9, 149.3, 168.9 (C).
IR (KBr, cmꢀ1): ~n ¼ 3430 ðwÞ, 2931 (s), 1725 (s), 1579
(m), 1445 (m), 1272 (s), 1188 (s), 1076 (m), 1034 (m).
UV–vis (CH3CN, nm): lmax (log 3)¼206 (4.51), 290
(4.47) nm. MS (EI, 70 eV): m/z (%)¼275 ([M+1]+, 3), 274
(M+, 20), 229 (17), 228 (21), 174 (29), 114 (4), 91 (4), 32
(25), 28 (100). Anal. Calcd for C17H22O3 (274.355): C,
74.42; H, 8.09. Found: C, 74.31; H, 8.18.
4.5.8. Ethyl 5,7-diethyl-3,4-dihydro-3-methyl-2H-chro-
mene-8-carboxylate (4h). Starting with 3h (0.450 g,
1.44 mmol), NaH (0.052 g, 2.16 mmol), and TBAI
(0.941 g, 2.88 mmol) in THF (24 mL), 4h was isolated after
chromatography (silica gel, n-hexane/EtOAc ¼ 20:1) as
a colorless solid (0.385 g, 97%), mp¼42 ꢁC. 1H NMR
(CDCl3, 300 MHz): d¼1.05 (d, J¼6.5 Hz, 3H, CH3), 1.20
(q, J¼7.0 Hz, 6H, 2ꢂCH3), 1.36 (t, J¼7.1 Hz, 3H, CH3),
2.14 (m, 1H, CH2), 2.24 (m, 1H, CH2), 2.53 (m, 4H,
2ꢂCH2), 2.75–2.79 (m, 1H, CH), 3.62 (dd, J¼10 Hz, 1H,
OCH2), 4.15–4.19 (dd, J¼2.4 Hz, 1H, OCH2), 4.38 (q,
J¼7.1 Hz, 2H, OCH2), 6.61 (s, 1H, CH of Ar). 13C NMR
(CDCl3, 75 MHz): dC¼14.6, 14.7, 16.1, 17.7 (CH3), 25.9,
26.7 (CH2), 27.3 (CH), 30.7, 61.3, 71.9 (CH2), 117.7,
119.9 (C), 120.4 (CH), 139.6, 144.4, 151.2, 168.8 (C). IR
(KBr, cmꢀ1): ~n ¼ 2967 ðsÞ, 2933 (s), 2875 (s), 1728 (s),
1610 (m), 1571 (s), 1462 (s), 1417 (s), 1274 (s), 1242 (s),
1150 (s), 1261 (s), 1044 (s), 866 (m). UV–vis (CH3CN,
nm): lmax (log 3)¼208 (4.53), 284 (3.39) nm. MS (EI,
4.5.11. Ethyl 6,8,9,10-tetrahydro-7-methyl-5H-naph-
tho[2,1-g]chromene-12-carboxylate (4k). Starting with
3k (0.353 g, 0.984 mmol), NaH (0.035 g, 1.48 mmol), and
TBAI (0.643 g, 1.97 mmol) in THF (18 mL), 4k was iso-
lated after chromatography (silica gel, n-hexane/EtOAc ¼
1
20:1) as a colorless solid (0.280 g, 88%), mp¼180 ꢁC. H
NMR (CDCl3, 300 MHz): d¼1.18 (t, J¼7.1 Hz, 3H, CH3),
2.09 (m, J¼4.0 Hz, 2H, CH2), 2.21 (s, 3H, CH3), 2.69–
2.77 (m, 6H, 3ꢂCH2), 4.18 (t, J¼5.2 Hz, 2H, CH2), 4.29
(q, J¼7.1 Hz, 2H, OCH2), 7.17–7.23 (m, 3H, 3ꢂCH of
Ar), 7.54–7.57 (m, 1H, CH of Ar). 13C NMR (CDCl3,
75 MHz): dC¼13.7, 15.1 (CH3), 22.3, 23.4, 25.4, 29.4,
61.2, 65.9 (CH2), 118.4, 120.7 (C), 126.2, 126.3, 127.2,
127.3 (CH), 129.5, 131.2, 133.9, 135.7, 138.6, 151.0,

7684
V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
169.7 (C). IR (KBr, cmꢀ1): ~n ¼ 3414 ðwÞ, 2986 (m), 1717
(s), 1558 (m), 1415 (m), 1282 (s), 1188 (m), 1164 (m),
1070 (m), 1033 (m), 757 (m). UV–vis (CH3CN, nm): lmax
(log 3)¼208 (4.49), 225 (4.38), 269 (4.12), 316 (3.87) nm.
MS (EI, 70 eV): m/z (%)¼323 ([M+1]+, 22), 322 (M+,
100), 277 (54), 32 (24), 28 (92). HRMS (ESI): calcd for
C21H22O3 ([M+1]+): 323.16472; found: 323.16431. Anal.
Calcd for C21H22O3 (322.398): C, 78.23; H, 6.88. Found:
C, 77.99; H, 7.29.
separated and the aqueous layer was extracted with Et2O
(5ꢂ10 mL). The layers were separated and the organic layer
was washed with water, dried (Na2SO4), filtered, and the
filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, n-hexane/EtOAc ¼
3:1/1:1) to give 11a as a yellow solid (92 mg, 68%),
mp¼119 ꢁC. 1H NMR (300 MHz, CDCl3) d¼1.36 (t,
J¼7.1 Hz, 3H, OCH2CH3), 2.10 (m, 2H, CH2CH2CH2),
2.90 (t, J¼6.3 Hz, 2H, ArCH2), 4.32–4.42 (m, 4H, CH2Cl,
OCH2CH3), 6.91 (m, 1H, Ar), 7.07 (dd, J¼8.1 Hz,
J¼1.0 Hz, 1H, Ar), 7.51 (m, 1H, Ar), 7.61 (m, 2H, Ar),
7.99 (d, J¼2.3 Hz, 1H, Ar), 11.89 (s, 1H, OH). 13C NMR
(DEPT, 75.5 MHz, CDCl3): d¼14.25 (OCH2CH3), 21.33
(CH2CH2CH2), 25.23 (ArCH2), 61.10 (OCH2CH3),
67.64 (OCH2), 118.41, 118.67 (CH), 119.16, 119.58,
123.76, 128.80 (C), 131.45, 133.08, 134.73, 136.04 (CH),
158.15, 162.96 (C), 165.30, 199.40 (C]O). IR (KBr):
~n ¼ 3070 ðwÞ, 3035 (w), 2941 (w), 1692 (s), 1626 (s),
1622 (s), 1480 (s), 1456 (m), 1335 (m), 1276 (s), 1250 (s),
1216 (s), 1184 (s), 1159 (s), 1135 (m), 1021 (m), 762
(w) cmꢀ1. UV–vis (CH3CN): lmax (log 3): 302 (3.99), 248
(4.07), 214 (4.29) nm. Fluorescence (CH3CN): lEx (Flmax):
340 (379) nm. MS (EI, 70 eV): m/z (%)¼326 (M+, 36), 270
(68), 234 (14), 210 (100), 182 (18), 161 (12), 128 (32), 77
(16). HRMS (FT-ICR): calcd for C19H19O5 ([M+1]+):
327.12270; found: 327.12296.
4.5.12. Ethyl 6-(2-chloroethyl)-5,7-dimethyl-3,4-dihydro-
2H-chromene-8-carboxylate (4l). Starting with 3l (0.308 g,
0.923 mmol), NaH (0.033 g, 1.36 mmol), and TBAI
(0.603 g, 1.85 mmol) in THF (16 mL), 4l was isolated after
chromatography (silica gel, n-hexane/EtOAc ¼ 20:1) as
a colorless solid (0.211 g, 77%), mp¼103 ꢁC. 1H NMR
(CDCl3, 300 MHz): d¼1.37 (t, J¼7.2 Hz, 3H, CH3), 2.02
(m, J¼7.5 Hz, 2H, CH2), 2.18 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 2.63 (t, J¼6.6 Hz, 2H, CH2), 3.10 (m, 2H, CH2),
3.47 (m, 2H, CH2–Cl), 4.12 (t, J¼5.2 Hz, 2H, CH2), 4.37
(q, J¼7.1 Hz, 2H, OCH2). 13C NMR (CDCl3, 75 MHz):
dC¼14.2, 15.2, 16.5 (CH3), 22.3, 23.2, 33.2, 42.3, 61.1,
65.9 (CH2), 119.4, 122.4, 126.5, 131.4, 137.3, 150.4, 168.9
(C). IR (KBr, cmꢀ1): ~n ¼ 2987 ðmÞ, 2939 (m), 1727 (s),
1579 (m), 1453 (s), 1308 (s), 1278 (s), 1244 (s), 1186 (s),
1115 (s), 1042 (s), 722 (w). UV–vis (CH3CN, nm): lmax
(log 3)¼208 (4.58), 288 (4.35) nm. MS (EI, 70 eV): m/z
(%)¼298 (M+[37Cl], 10), 296 (M+[35Cl], 34), 247 (100),
201 (17), 173 (3), 114 (4), 28 (7). HRMS (ESI): calcd for
C16H21ClO3 ([M+1]+): 299.12280 [37Cl], 297.12575
[35Cl]; found: 299.12162 [37Cl], 297.12476 [35Cl]. Anal.
Calcd for C16H21ClO3 (296.789): C, 64.73; H, 7.13. Found:
C, 64.73; H, 7.72.
4.6. General procedure for the synthesis of (11b,e–h)
A THF solution of 10b,e–h (1.0 equiv) was added to a mix-
ture of NaH (1.5 equiv) and TBAI (2 equiv). After stirring
for 20 h at 20 ꢁC, an aqueous solution of hydrochloric acid
(10%) was added. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (5ꢂ10 mL). The
layers were separated and the organic layer was washed
with water, dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/EtOAc ¼ 20:1/
10:1) to give 11b,e–h.
4.5.13. Ethyl 6-(2-bromoethyl)-3,4-dihydro-5,7-di-
methyl-2H-chromene-8-carboxylate (4m). Starting with
3m (0.129 g, 0.34 mmol), NaH (0.012 g, 0.51 mmol), and
TBAI (0.222 g, 0.68 mmol) in THF (6 mL), 4m was isolated
after chromatography (silica gel, n-hexane/EtOAc ¼ 20:1)
as a colorless solid (0.070 g, 60%). 1H NMR (CDCl3,
300 MHz): d¼1.36 (t, J¼7.1 Hz, 3H, CH3), 2.02 (quint,
J¼5.3 Hz, 2H, CH2), 2.17 (s, 3H, CH3), 2.22 (s, 3H, CH3),
2.63 (t, J¼6.6 Hz, 2H, CH2), 3.06–3.19 (m, 2H, CH2),
3.44–3.49 (m, 2H, CH2), 4.12 (t, J¼5.3 Hz, 2H, CH2),
4.36 (q, J¼7.2 Hz, 2H, OCH2). 13C NMR (CDCl3,
75 MHz): dC¼14.3, 15.2, 16.4 (CH3), 22.3, 23.2, 33.2,
33.6, 61.1, 65.9 (CH2), 119.5, 126.5, 131.3, 137.3, 150.4,
219.7 (C). IR (KBr, cmꢀ1): ~n ¼ 3431 ðmÞ, 2981 (m), 2961
(m), 2937 (m), 1726 (s), 1581 (m), 1451 (s), 1305 (s), 1277
(s), 1186 (s), 1115 (s), 1041 (s), 962 (m), 793 (m). UV–vis
(CH3CN, nm): lmax (log 3)¼210 (4.52), 289 (3.38) nm. MS
(EI, 70 eV): m/z (%)¼342 (M+[81Br], 6), 340 (M+[79Br],
5), 296 (23), 260 (33), 247 (100), 215 (30), 153 (9), 114
(10), 84 (88), 41 (29), 28 (78). HRMS (ESI): calcd for
C16H21BrO3 ([M+1]+): 343.07317 [81Br], 341.07522
[79Br]; found: 343.07428 [81Br], 341.07612 [79Br].
4.6.1. 3,4-Dihydro-6-(2-hydroxy-5-methylbenzoyl)-2H-
chromene-8-carboxylic acid (11b). Starting with 10b
(102 mg, 0.27 mmol) in 4 mL THF, NaH (10 mg,
0.405 mmol), and TBAI (176 mg, 0.54 mmol), 11b was iso-
1
lated as a yellow solid (80 mg, 94%). H NMR (300 MHz,
CDCl3): d¼2.18 (quint, J¼5.2 Hz, 2H, CH2), 2.26 (s, 3H,
CH3), 2.97 (t, J¼6.1 Hz, 2H, CH2), 4.55 (t, J¼5.4 Hz, 2H,
CH2), 6.96 (d, J¼7.8 Hz, 1H, Ar), 7.32–7.35 (m, 2H, Ar),
7.69 (d, J¼2.2 Hz, 1H, Ar), 8.30 (d, J¼2.2 Hz, 1H, Ar),
11.62 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz, CDCl3):
d¼20.5 (CH3), 21.2, 24.6, 68.9 (CH2), 116.7 (C), 118.2
(CH), 118.6, 124.1, 128.1, 130.9 (C), 132.7, 133.2, 135.8,
137.5 (CH), 156.5, 160.9, 164.8, 199.2 (C). IR (KBr):
~n ¼ 3225 ðmÞ, 1731 (s), 1630 (m), 1594 (s), 1478 (s), 1427
(s), 1336 (s), 1249 (s), 1205 (s), 788 (m) cmꢀ1. MS (EI,
70 eV): m/z (%)¼312 (M+, 42), 264 (25), 57 (12), 44 (42),
28 (100). Anal. Calcd for C18H16O5: C, 69.22; H, 5.16.
Found: C, 69.64; H, 5.38.
4.5.14. Ethyl 3,4-dihydro-6-(2-hydroxybenzoyl)-2H-
chromene-8-carboxylate (11a). A THF solution (5 mL) of
10a (149 mg, 0.41 mmol) was added to a mixture of NaH
(14.8 mg, 0.61 mmol) and TBAI (304 mg, 0.82 mmol).
After stirring for 20 h at 20 ꢁC, an aqueous solution of
NH3Cl (1 M, 4 mL) was added. The organic layer was
4.6.2. 3,4-Dihydro-6-(5-chloro-2-hydroxy-4-methyl-
benzoyl)-2H-chromene-8-carboxylic acid (11e). Starting
with 10e (102 mg, 0.25 mmol) in 4 mL THF, NaH (9 mg,
375 mmol), and TBAI (163 mg, 0.5 mmol), 11e was isolated

V. T. H. Nguyen et al. / Tetrahedron 62 (2006) 7674–7686
7685
1
as yellow viscous oil (60 mg, 70%). H NMR (300 MHz,
2.34 (m, 1H, CH3(CH)), 2.62 (q, J¼9.8, 6.6 Hz, 1H, CH2),
2.99–3.06 (dd, J¼3.2, 13.3 Hz, 1H, CH2), 4.04 (t,
J¼10.1 Hz, 1H, CH2), 4.55–4.60 (qq, J¼2.0, 8.6 Hz, 1H,
CH2), 7.04 (td, J¼1.2, 6.9 Hz, 1H, Ar), 7.06–7.09 (dd,
J¼2.0, 7.6 Hz, 1H, Ar), 7.49–7.58 (m, 2H, Ar), 7.70 (quint,
J¼1.0 Hz, 1H, Ar), 8.34 (d, J¼2.3 Hz, 1H, Ar), 11.82 (s, 1H,
OH). 13C NMR (DEPT, 75.5 MHz, CDCl3): d¼16.5 (CH3),
26.2 (CH), 32.8, 73.8 (CH2), 116.9, 119.6 (C), 120.1 (CH),
123.6, 123.9, 130.3 (C), 131.8, 133.1, 135.7, 136.3 (CH),
156.5, 161.5, 164.6, 198.2 (C). IR (KBr): ~n ¼ 3069 ðwÞ,
2959 (m), 1735 (m), 1706 (m), 1674 (s), 1627 (s), 1596
(s), 1474 (s), 1466 (s), 1330 (s), 1249 (s), 1226 (s), 1185
(s), 1140 (m), 1001 (m), 790 (m) cmꢀ1. UV–vis (CH3CN):
lmax (log 3)¼209.1 (4.49), 291.6 (3.93), 344.8 (3.77) nm.
MS (EI, 70 eV): m/z (%)¼348 (M+[37Cl], 22), 346
(M+[35Cl], 62), 192 (100), 175 (66), 155 (24). Anal. Calcd
for C18H15O5Cl: C, 62.35; H, 4.36. Found: C, 62.11; H, 4.34.
CDCl3): d¼2.19 (quint, J¼5.0 Hz, 2H, CH2), 2.40 (s, 3H,
CH3), 2.98 (t, J¼6.2 Hz, 2H, CH2), 4.56 (t, J¼5.2 Hz, 2H,
CH2), 6.97 (s, 1H, Ar), 7.49 (s, 1H, Ar), 7.65 (t, J¼1 Hz,
1H, Ar), 8.31 (d, J¼2.3 Hz, 1H, Ar), 11.68 (s, 1H, OH).
13C NMR (DEPT, 75.5 MHz, CDCl3): d¼20.8 (CH3), 21.2,
24.6, 68.9 (CH2), 117.1, 117.9 (C), 120.5 (CH), 124.2,
130.5 (C), 132.3, 133.0, 135.6 (CH), 145.9, 156.7, 161.4,
164.5, 190.5, 197.9 (C). MS (EI, 70 eV): m/z (%)¼348
(M+[37Cl], 21), 346 (M+[35Cl], 59), 205 (17), 178 (79),
168 (43), 161 (100), 77 (53).
4.6.3. 3,4-Dihydro-3-methyl-6-(2-hydroxybenzoyl)-2H-
chromene-8-carboxylic acid (11f). Starting with 10f
(94 mg, 0.25 mmol) in 10 mL THF, NaH (9 mg,
0.37 mmol), and TBAI (163 mg, 0.50 mmol), 11f was iso-
lated as a yellow viscous oil (55 mg, 71%). 1H NMR
(300 MHz, CDCl3): d¼1.22 (d, J¼6.5 Hz, 3H, CH3(CH)),
2.34 (m, 1H, CH3(CH)), 2.62 (q, J¼9.8, 6.5 Hz, 1H, CH2),
3.00 (dd, J¼5.0, 9.5 Hz, 1H, CH2), 4.04 (t, J¼10.5 Hz,
1H, CH2), 4.54–4.59 (qq, J¼2.0, 9.0 Hz, 1H, CH2), 6.99
(d, J¼8.1 Hz, 1H, Ar), 7.32 (s, 1H, Ar), 7.35 (d, J¼2.2 Hz,
1H, Ar), 7.68 (t, J¼1.1 Hz, 1H, Ar), 8.32 (d, J¼2.2 Hz,
1H, Ar), 11.63 (s, 1H, OH). 13C NMR (DEPT, 75.5 MHz,
CDCl3): d¼16.5 (CH3), 26.3 (CH), 32.7, 73.8 (CH2), 116.6
(C), 118.5 (CH), 118.8 (C), 119.0 (CH), 123.8, 130.9 (C),
133.0, 133.3, 135.9, 136.4 (CH), 156.1, 163.0, 164.6,
199.1 (C). MS (EI, 70 eV): m/z (%)¼312 (M+, 64), 267
(20), 219 (26), 192 (100), 175 (39), 121 (60). IR (KBr):
~n ¼ 3296 ðbr; mÞ, 2926 (m), 1733 (m), 1625 (s), 1598 (s),
4.6.6. 5-Bromo-2,3-dihydro-6-hydroxy-1H-naphtho-
[2,3-f]chromene-7,12-dione (14). Starting with 13 (0.140 g,
0.44 mmol), NaH (0.016 g, 0.66 mmol), and TBAI (0.287 g,
0.88 mmol) in THF (7 mL), 14 was isolated after chromato-
graphy (silica gel, n-hexane/EtOAc ¼ 20:1) as a yellowish
solid (0.115 g, 73%), mp¼235 ꢁC. 1H NMR (CDCl3,
300 MHz): d¼2.10 (tt, J¼5.5, 6.5 Hz, 2H, CH2), 3.36 (t,
J¼6.7 Hz, 2H, CH2), 4.44 (t, J¼6.2 Hz, 2H, CH2), 7.77–
7.79 (m, 2H, 2ꢂCH of Ar), 8.20–8.28 (m, 2H, 2ꢂCH of
Ar), 14.23 (s, 1H, OH). 13C NMR (CDCl3, 75 MHz):
dC¼21.9, 25.0, 67.9 (CH2), 106.5, 111.4, 121.2 (C),
126.4, 127.2 (CH), 129.9, 132.2 (C), 133.8, 134.3, 134.4
(CH), 159.4, 160.2, 184.3, 187.4 (C). IR (KBr, cmꢀ1):
~n ¼ 2921 ðwÞ, 1661 (m), 1631 (s), 1586 (s), 1556 (m), 1439
(m), 1396 (s), 1355 (s), 1282 (s), 1152 (s), 959 (m), 797
(m), 729 (m). UV–vis (CH3CN, nm): lmax (log 3)¼206
(4.46), 250 (4.42), 277 (4.43), 332 (3.43), 414 (3.89) nm.
MS (EI, 70 eV): m/z (%)¼360 (M+[81Br], 16), 359 (96),
358 (M+[79Br], 21), 357 (100), 342.7 (28), 164.9 (11), 139.0
(12), 77.4 (8), 32.0 (20), 28 (89). Anal. Calcd for
C17H11BrO4 (359.171): C, 56.83; H, 3.09. Found: C, 56.43;
H, 3.64.
1479 (s), 1329 (s), 1249 (s), 1158 (s), 762 (m) cmꢀ1
HRMS (ESI): calcd for C18H16O5: 312.09977; found:
312.09901.
.
4.6.4. 3,4-Dihydro-3-methyl-6-(2-hydroxy-5-methyl-
benzoyl)-2H-chromene-8-carboxylic acid (11g). Starting
with 10g (194 mg, 0.50 mmol) in 10 mL THF, NaH
(18 mg, 0.75 mmol), and TBAI (326 mg, 1.0 mmol), 11g
1
was isolated as a yellow solid (140 mg, 86%). H NMR
(300 MHz, CDCl3): d¼1.15 (d, J¼6.8 Hz, 3H, CH3(CH)),
2.26 (s, 3H, CH3), 2.34 (m, 1H, CH3(CH)), 2.62 (q, J¼9.8,
6.5 Hz, 1H, CH2), 3.00 (dd, J¼5.0, 9.5 Hz, 1H, CH2), 4.04
(t, J¼10.5 Hz, 1H, CH2), 4.54–4.59 (qq, J¼2.0, 9.0 Hz,
1H, CH2), 6.99 (d, J¼8.1 Hz, 1H, Ar), 7.32 (s, 1H, Ar),
7.35 (d, J¼2.2 Hz, 1H, Ar), 7.68 (t, J¼1.1 Hz, 1H, Ar),
8.32 (d, J¼2.2 Hz, 1H, Ar), 11.63 (s, 1H, OH). 13C NMR
(DEPT, 75.5 MHz, CDCl3): d¼16.5, 20.5 (CH3), 26.3
(CH), 32.8, 73.8 (CH2), 116.5 (C), 118.2 (CH), 118.6,
123.8, 128.1, 131.2 (C), 132.7, 133.2, 135.8, 137.5 (CH),
156.0, 160.9, 164.7, 199.2 (C). IR (KBr): ~n ¼ 2956 ðmÞ,
2926 (m), 1670 (s), 1596 (s), 1479 (s), 1336 (s), 1246 (s),
1219 (s), 1173 (s), 792 (m) cmꢀ1. MS (EI, 70 eV): m/z
(%)¼326 (M+, 90), 175 (100), 134 (91), 77 (15), 28 (29).
HRMS (ESI): calcd for C19H18O5: 326.11542; found:
326.11530. Anal. Calcd for C19H18O5: C, 69.93; H, 5.56.
Found: C, 69.51; H, 5.56.
Acknowledgements
We thank Dr. Dirk Michalik for NMR studies. Financial
support by the state of Vietnam (MOET scholarship for
V.T.H.N.), by the Deutsche Forschungsgemeinschaft, and
by the state of Mecklenburg-Vorpommern (Landesfor-
schungsschwerpunkt ‘Neue Wirkstoffe und Screeningver-
fahren’) is gratefully acknowledged.
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