Inter- and intramolecular Mitsunobu reaction based approaches to 2-substituted chromans and chroman-4-ones

Article abstract of DOI:10.1016/j.tet.2005.04.047

Two approaches to optically active 2-substituted chromans and chroman-4-ones are described. The first utilized an intermolecular Mitsunobu reaction of a homochiral halopropanol and 2-bromophenol followed by cyclization to the 2-substituted chroman. In addition, a double lithiation procedure was developed to introduce additional functionality to the chroman. The second approach utilized an intramolecular Mitsunobu cyclization to give the 2-substituted chroman-4-one nucleus. The methodologies were applied to the syntheses of several biologically active natural and synthetic products.

Full text of DOI:10.1016/j.tet.2005.04.047

Tetrahedron 61 (2005) 6860–6870
Inter- and intramolecular Mitsunobu reaction based approaches
to 2-substituted chromans and chroman-4-ones
*
Kevin J. Hodgetts
Department of Chemistry, University College Dublin, Dublin 4, Ireland
Received 16 February 2005; revised 5 April 2005; accepted 21 April 2005
Abstract—Two approaches to optically active 2-substituted chromans and chroman-4-ones are described. The first utilized an
intermolecular Mitsunobu reaction of a homochiral halopropanol and 2-bromophenol followed by cyclization to the 2-substituted chroman.
In addition, a double lithiation procedure was developed to introduce additional functionality to the chroman. The second approach utilized
an intramolecular Mitsunobu cyclization to give the 2-substituted chroman-4-one nucleus. The methodologies were applied to the syntheses
of several biologically active natural and synthetic products.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
While there is extensive literature precedent for the
synthesis of chromans and chroman-4-ones, few are
amenable to the synthesis of single enantiomers. Knight6a
has reported an approach to 2-substituted chromans based
on the intramolecular trapping by alcohols of benzynes
generated from 7-substituted-1-aminobenzotriazoles and
Sames has developed a method based on a Ruthenium
catalyzed cyclization of an arene–alkene substrate.6b Routes
to 2-substituted chroman-4-ones include the diastereo-
selective conjugate addition of cuprates to homochiral
3-(p-tolylsulfinyl)chromanones described by Wallace7 and
an approach based on the Houben–Hoesch reaction.8 The
synthesis of related 2-substituted chromenes9 and chroma-
nols10 has also been reported. Notwithstanding these
examples, the preparation and manipulation of substituted
chroman-4-ones can be problematic, due in part to the ease
with which they undergo racemization via the ring-opening
equilibrium shown in Scheme 1.11
2-Substituted chromans (benzopyrans) are widely distri-
buted in nature and many show significant biological
activity.1 Examples include a-tocopherol (vitamin E) (1),2
the antibiotic LLD253a (2)3 and the aromatase inhibitor
pinostrobin (3).4 In addition, chromans are valued as targets
in their own right and several biologically active synthetic
chromans have been reported. For example, racemic
40,6-dichloroflavan (BW683C) (4) is a potent in vitro
inhibitor of rhinovirus replication (Fig. 1).5
Scheme 1.
With this in mind, we have evaluated two approaches to
2-substituted chromans and chromanones in which inter-
and intramolecular Mitsunobu reactions are key steps
(Scheme 2).12 In the first, halogen–metal exchange of the
aryl bromide 6 and subsequent cyclization, should give the
chroman 5.13 The stereocenter to be located at the 2-position
could be installed by a Mitsunobu14 inversion reaction
Figure 1.
Keywords: Mitsunobu; Cyclization; Chroman; Chromanone.
*
Present address: Neurogen Corporation, 35 Northeast Industrial Road,
Branford, CT 06405 USA. Tel: C1 203 488 820; fax: C1 203 483 7027;
e-mail: khodgetts@nrgn.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.047

K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
6861
Scheme 2.
between the 2-bromophenol 7 and the appropriately
substituted chiral halopropanol 8. Alternatively, inter-
molecular Mitsunobu cyclization of the chiral hydroxy-
phenol 10 should give the chromanone 9. The hydroxy-
phenol 10 should be accessible from the 2-bromophenol 7
and the appropriately substituted Weinreb amide 11. In this
paper, we report our results in full detail.12
of n-butyllithium in THF at K50 8C and allowing the
reaction to warm to room temperature. Under these
conditions, (2S)-phenylchroman (15a), [a]DZK15 (c 3.0
in CHCl3) [lit17 [a]DZK15.3 (c 3.48 in CHCl3)] was
obtained in 83% yield. The sign and magnitude of rotation
confirmed that the Mitsunobu reaction occurred with
inversion and the cyclization without significant racemiza-
tion. A single recrystallization from methanol gave
enantiomerically pure material by HPLC analysis.18
Commercially available (R)-3-chloro-1-phenyl-1-propanol
(13a)15 was treated with 2-bromophenol (12) under standard
Mitsunobu14 inversion conditions and gave, following
chromatography, the (S)-phenyl ether 14a in 78% yield
(Scheme 3). Initially 14a was subjected to the cyclization
conditions originally described by Parham, but these lead
to only moderate yields of the 2-phenylchroman (15a).
Optimal conditions for the Parham cyclization were found
to be a modified version of those recently described by
Spoors16 for the cyclization of 2-(o-bromophenoxy)ethyl
bromides to benzodihydrofurans; addition of 14a to 1 equiv
In order to investigate the utility of the methodology, a
variety of commercially available substituted bromophenols
12a–f were studied in the reaction with (R)-3-chloro-1-
phenyl-1-propanol (13a) (Table 1). The Mitsunobu reaction
and cyclization all proceeded in good yields to furnish the
(2S)-phenyl chromans 15b, 15c, 15d, and 15f, respectively.
Tephrowatsin E (15f) was previously isolated from the
aerial parts of Tephrosia watsoniana.19 The spectral
properties of the synthetic sample were in close agreement
with the reported spectral data.19 The phenyl substituent at
the 2-position could be replaced by an alkyl group. For
example, repeating the sequence with 2-bromophenol (12)
and (S)-4-bromobutane-2-ol (13e)20 gave (2R)-methyl-
chroman (15e) in 54% yield and 97% e.e.18 over the two
steps (entry e).
To extend the synthetic utility of the methodology a one-pot
cyclization and in situ functionalization of the chroman ring
was investigated.21 The 2,4-dibromo ether 16 was prepared
by Mitsunobu reaction as described previously. Halogen–
metal exchange was expected to be selective for the bromide
adjacent to the ether and this proved to be the case. Addition
of 16 to 1 equiv of n-butyllithium, in THF at K50 8C and
allowing the reaction to warm to room temperature gave
the cyclized product, 6-bromo-2-phenylchroman (17a)
in 84% yield, thereby confirming the selectivity for the
ortho-bromide. The reaction was repeated, but when the
cyclization was judged to be complete, the reaction mixture
was re-cooled to K50 8C and the second bromide was
exchanged by further addition of n-butyllithium. The
resultant chromanyl lithium was then quenched by the
addition of an excess of an electrophile. A range of
electrophiles were screened in the process (entries b, c, d,
Scheme 3. Reaction conditions: (i) PPh3, DEAD, THF, RT, 18 h, (78%)
(ii) nBuLi, THF, K50 8C to RT (83%).

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K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
Table 1. Reaction conditions: (i) PPh3, DEAD, THF, RT, 8–36 h; (ii) nBuLi, THF, K50 8C to RT
Entry
R1
R2
R3
R4
R
X
Yield 14 (%)
Yield 15 (%)
a
b
c
d
e
f
H
H
H
H
Me
Cl
H
H
H
H
H
MeO
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Me
Ph
Cl
Cl
Cl
Cl
Br
Cl
78
82
81
64
67
76
83
77
78
74
81
78
–(CH)4–
H
MeO
H
H
and e, Table 2) and gave moderated to good yields of the
corresponding 6-carbaldehyde 17b, 6-carboxylic acid 17c,
6-hydroxymethyl 17d, and 6-methyl 15b analogues.
gave the expected 8-bromo-2-phenylchroman (19) in 79%
yield. Repeating the reaction, but when the cyclization was
judged to be complete, the reaction mixture was re-cooled to
K50 8C and n-butyllithium was added followed by an
excess of DMF. This time 8-carbaldehyde-2-phenyl-
chroman (20) was isolated in 76% yield (Scheme 4). The
double lithiation procedure allows the introduction of a
variety of functional groups to the chroman that would not
normally be compatible with the conditions of the original
cyclization.
The sequence outlined in Table 2 was repeated with the
2,6-dibromoether 18. Treatment of the dibromide 18 with
1 equiv of n-butyllithium followed by aqueous work-up
Table 2. Reagents and conditions: (i) nBuLi, THF, K50 8C to RT, 2 h;
(ii) K50 8C, BuLi, 30 min; (iii) electrophile (4–6 equiv), K50 8C to RT
n
The range of potential substituents located at the chroman
2-position can be extended by taking advantage of the
asymmetric reduction of suitable prochiral ketones,22 as
exemplified by the synthesis of enantiomerically pure (R)-
40,6-dichloroflavan (4) (Scheme 5). Catalytic asymmetric
reduction of 3,40-dichloropropiophenone (21) with (R)-
oxazaborolidine and borane, under the conditions described
by Corey,23 gave (S)-3-chloro-1-(4-chlorophenyl)-1-propa-
Entry
Electrophile Product
R
Yield (%)
1
a
b
c
d
e
None
DMF
17a
17b
17c
17d
15b
Br
84
81
78
57
80
nol (22) in 91% yield and 94% ee as judged by H NMR
analysis of the MTPA (Mosher) ester.24 Mitsunobu reac-
tion of 22 with 2-bromo-4-chlorophenol followed by
treatment with 1 equiv of n-butyllithium under the standard
cyclization conditions gave, following recrystallization
from methanol, enantiomerically pure BW683C (4).18
Racemic BW683C (4) is a potent in vitro inhibitor of
rhinovirus replication and was previously isolated in
enantiomerically pure form following preparative HPLC
using the chiral stationary phase cellulose tris(3,5-dimethyl-
phenylcarba-mate).25
CHO
CO2H
CH2OH
Me
CO2 (g)
(CH2O)n
MeI
2-Substituted chroman-4-ones such as LLD253a (2)3 and
pinostrobin (3)4 were also targets for our work. The most
direct route appeared to be the oxidation of a chiral
2-substituted chroman to the corresponding chroman-4-one.
Several methods for benzylic oxidation are known in the
Scheme 4. Reagents and conditions: (i) nBuLi, THF, K50 8C to RT, 2 h;
(ii) K50 8C, BuLi, 30 min; (iii) electrophile (4–6 equiv), K50 8C to RT.
n
Scheme 5. Reaction conditions: (i) BH3, (R)-oxazaborolidine, THF, 0 8C, 91%; (ii) 2-bromo-4-chlorophenol, PPh3, DEAD, THF, RT, 16 h (85%); (iii) nBuLi,
THF, K50 8C to RT (78%).

K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
6863
Scheme 6. Reaction conditions: (i) H5IO6, CrO3 (cat), CH3CN, RT.
literature, these include (i) catalytic chromium(VI) oxide in
the presence of periodic acid,26 (ii) copper sulfate and
peroxydisulfate,27 and (iii) cerium ammonium nitrate in
acetic acid.28 (2S)-Phenyl chroman (15a)29 was subjected to
the above sets of conditions, but unfortunately yields of the
desired 2-phenyl chroman-4-one (23)30 were low and
complicated by competing processes. For example, treat-
ment of 15a with 2 equiv of periodic acid and 5 mol%
chromium(VI) oxide in acetonitrile at room temperature
gave the desired (2S)-phenyl chroman-4-one (23) in a
moderate 43% yield accompanied by a significant amount of
the quinone 24. The magnitude of rotation of 23 indicated
that the oxidation had proceeded without significant
racemization. The quinone 24 was presumably formed by
competing oxidation at the benzylic chroman-2-position,
ring-opening to the phenol 26, and finally oxidation to the
quinone 24 (Scheme 6). The moderate isolated yields in the
oxidation step prompted the investigation of an alternative
route to 2-substituted chroman-4-ones.
respectively.32 This mode of action could prevent the
development of estrogen related tumors such as breast and
prostate cancer.33 In addition, pinostrobin (3) has been
isolated from T. graveolens, a plant used in traditional
Mexican medicine for the treatment of gastrointestinal
ailments such as diarrhea and stomach pain.34 It was
recently demonstrated that pinostrobrin (3) was an active
ingredient in T. graveolens and inhibited intestinal smooth
muscle contractions by a calcium-mediated mechanism.35
The interesting biological activity made pinostrobin (3) an
attractive target for synthesis.
The key fragments, Weinreb amide 28 and the methoxy-
methyl (MOM) protected phenol 30, were readily prepared
from commercially available starting materials. Ethyl (R)-3-
hydroxy-3-phenylpropanoate (27)36 was protected as the
tert-butyldimethylsilyl (TBS) ether and then converted into
the Weinreb amide 28 (Scheme 7).37 3,5-Dimethoxyphenol
(29) was protected as the MOM ether 30 using standard
conditions. The MOM ether 30 was ortho-lithiated by
treatment with tert-butyllithium31c in toluene at K78 8C and
the Weinreb amide 28 then added to produce the ketone 31
in 72% yield (based on the amide 28).
We next investigated an approach to 2-substituted chroman-
4-ones based on an intermolecular Mitsunobu cyclization31
(Scheme 2) and pinostrobin (3) was chosen as the target.
Pinostrobin (3) has been isolated from several natural
sources4 and has also been shown to inhibit aromatase, a
cytochrome P450 enzyme converting C19 androgens such
as androstenedione and testosterone to estrone and estradiol,
The protecting groups on 31 were conveniently cleaved by
treatment with 10% pZvia-TsOH in aqueous THF, which
gave the hydroxyphenol 32 (Scheme 8). Intramolecular
Scheme 7. Reaction conditions: (i) TBSCl, imidazole, CH2Cl2 (94%); (ii) MeONHMe$HCl, Me3Al, CH2Cl2 (82%); (iii) CH3OCH2Cl, K2CO3, DMF (94%);
(iv) tBuLi, PhMe, K78 8C then 28 (0.5 equiv) (72%).

6864
K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
Scheme 8. Reaction conditions (i) p-TsOH (10%), THF/H2O (9:1), 55 8C (86%); (ii) PPh3, DEAD, THF, 0 8C (88%); (iii) AlCl3, CH3CN, reflux (79%).
Mitsunobu cyclization of 32 gave an 88% yield of
dimethylpinocembrin 33.38 The intramolecular Mitsunobu
reaction has been used by several groups to prepare 6- and
7-membered cyclic ethers, but we believe this to be the first
example of the formation of an optically active 2-substituted
chroman-4-one via such an approach.31 Regioselective
demethylation of 33 with aluminum chloride gave, follow-
ing chromatography, (K)-pinostrobin (3) [a]DZK48 (cZ1
in CHCl3) [lit.4a [a]DZK52.7 (cZ1 in CHCl3)].
Compositions of solvent mixtures are quoted as ratios of
volume.
2.1.1. (S)-1-Bromo-2-(3-chloro-1-phenylpropoxy)-ben-
zene (14a). To a stirred solution of triphenylphosphine
(1.52 g, 5.8 mmol) and diethyl azodicarboxylate (1.02 g,
5.8 mmol) in THF (10 mL) at 0 8C was added a solution of
2-bromophenol (12) (1.0 g, 5.8 mmol) and (R)-3-chloro-1-
phenyl-1-propanol (13) (1.0 g, 5.8 mmol) in THF (5 mL).
The mixture was allowed to return to room temperature and
stirred overnight or until the reaction was complete by TLC.
The THF was removed by evaporation, the residue triturated
with hexane (3!50 mL) and the combined hexane fractions
concentrated. Flash chromatography of the residue, eluting
with hexane, gave the title compound (1.48 g, 78%) as a
colorless oil: [a]2D2C73 (c 3.0, CHCl3); dH (400 MHz) 2.25–
2.33 (1H, m), 2.54–2.62 (1H, m), 3.70 (1H, quintet, JZ
5.5 Hz), 3.92–3.99 (1H, m), 5.48 (1H, dd, JZ4.5, 9.0 Hz),
6.74–6.81 (2H, m), 7.09 (1H, t, JZ8 Hz), 7.32–7.45 (5H,
m), 7.55 (1H, d, JZ7.5 Hz); dC (100 MHz) 41.27, 41.31,
77.79, 112.63, 115.01, 122.01, 125.80, 128.02, 128.19,
128.79, 133.25, 140.15, 154.08; EI-LRMS m/z (relative
In conclusion, we have developed a two-step synthesis
of 2-substituted chromans utilizing an intermolecular
Mitsunobu reaction and an aryl lithium cyclization as key
steps. In addition, a double lithiation procedure was
developed to introduce additional functionality into the
chroman. Oxidation of 2-phenyl chroman to the correspond-
ing chroman-4-one was possible, but complicated by
competing reactions at the benzylic 2-positon. A route to
2-substituted chroman-4-ones was also developed that
featured an intramolecular Mitsunobu reaction as the key
step. The methodologies were applied to the synthesis of the
natural products tephrowatsin E (15f) and pinostrobin (3)
and a biologically active synthetic compound BW683 (4).
intensity) 326 and 324 (5%), 153 (95), 117 (48), 91 (100);
EI-HRMS calcd. for C15H BrClO 325.9896, found
81
14
325.9893.
2. Experimental
2.1.2. (S)-2-Bromo-1-(3-chloro-1-phenylpropoxy)-4-
methyl-benzene (14b). The ether 14b was prepared using
the same procedure and scale as described for 14a but using
2-bromo-4-methylphenol. Flash chromatography of the
residue, eluting with hexane, gave the title compound
(82%) as a colorless oil: [a]2D2C22 (c 1.0, CHCl3); dH
(400 MHz) 2.23 (3H, s), 2.25–2.32 (1H, m), 2.52–2.61 (1H,
m), 3.69 (1H, quintet, JZ5.5 Hz), 3.92–3.98 (1H, m), 5.43
(1H, dd, JZ4.0, 8.5 Hz), 6.64 (1H, d, JZ8.5 Hz), 6.88 (1H,
d, JZ8.5 Hz), 7.30–7.44 (6H, m); dC (100 MHz) 20.05,
41.29, 77.92, 112.92, 114.95, 125.87, 127.95, 128.60,
128.73, 131.71, 133.61, 140.33, 151.92 (one signal
obscured, 41.29); Anal. C16H16BrClO requires: C, 56.58;
H, 4.75. Found: C, 56.79; H, 4.90%.
2.1. General methods
Melting points were determined using a Thomas–Hoover
capillary melting apparatus and are uncorrected. Elemental
analyses were performed at Robertson Microlabs, Madison,
NJ, USA, and are within 0.4% of theoretical C, H, and N. 1H
and 13C NMR spectra were recorded in deuteriochloroform
(unless otherwise noted) with tetramethylsilane as the
internal standard on a Varian Unity 400 MHz spectrometer.
Coupling constants (J values) are quoted to the nearest
0.5 Hz. Mass spectra were recorded on a VG 70SE magnetic
sector mass spectrometer. Chiral HPLC analyses were
recorded on a CHIRALCELwOJ-R (4.6 mm!150 mm)
column with methanol as the mobile phase and a flow rate
of 0.6 mL/min.
2.1.3. (S)-2-Bromo-4-chloro-1-(3-chloro-1-phenylpro-
poxy)-benzene (14c). The ether 14c was prepared using
the same procedure and scale as described for 14a but using
2-bromo-4-chlorophenol. Flash chromatography of the
residue, eluting with hexane, gave the title compound
(81%) as a colorless oil: [a]2D2 K34 (c 1.0, CHCl3); dH
(400 MHz) 2.22–2.30 (1H, m), 2.51–2.60 (1H, m), 3.66 (1H,
quintet, JZ5.5 Hz), 3.88–3.94 (1H, m), 5.41 (1H, dd, JZ
4.0, 8.5 Hz), 6.64 (1H, d, JZ9.0 Hz), 7.03 (1H, dd, JZ2.5,
9.5 Hz), 7.31–7.33 (1H, m), 7.37–7.38 (4H, M), 7.52 (1H, d,
JZ2.5 Hz); dC (100 MHz) 41.17, 78.23, 113.12, 115.63,
125.82, 126.25, 128.05, 128.25, 128.91, 132.74, 139.65,
Starting materials and solvents were routinely purified by
conventional techniques39 and most reactions were carried
out under a nitrogen atmosphere. Organic solutions were
dried using anhydrous magnesium sulfate and concentrated
by rotary evaporation. Analytical thin layer chromatography
(TLC) was carried out on Camlab Polygram SIL G/UV254
plates. The chromatograms were visualized by UV light or
suitable developing agent. Unless otherwise stated, pre-
parative column chromatography was carried out on 60H
silica gel (Merck 9385) using the flash technique.40

K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
6865
152.93 (one signal obscured, 41.17); Anal. C15H13BrCl2O
requires: C, 50.03; H, 3.64. Found: C, 49.81; H, 3.79%.
chloride (40 mL). The mixture was extracted with ethyl
acetate (3!75 mL), and the combined extracts washed with
water (50 mL), brine (50 mL), dried and evaporated. Flash
chromatography of the residue, eluting with hexane, gave
the title compound (1.6 g, 83%) as a white solid, mp 52 8C
(MeOH): [a]2D2 K15 (c 3.0, CHCl3); dH (400 MHz) 2.10–
2.20 (1H, m), 2.24–2.30 (1H, m), 2.85 (1H, dt, JZ2.5,
16.5 Hz), 3.01–3.09 (1H, m), 5.12 (1H, dd, JZ2.5,
10.0 Hz), 6.92–7.00 (2H, m), 7.14–7.21 (2H, m), 7.38–
7.40 (1H, m), 7.43–7.50 (4H, m); dC (100 MHz) 25.09,
29.90, 77.68, 116.88, 120.27, 121.77, 125.94, 127.29,
127.76, 128.46, 129.48, 141.70, 155.08; FAB-LRMS 210
(100%), 117 (30); FAB-HRMS calcd. for C15H14O
210.1044, found 210.1042; Anal. C15H14O requires: C,
85.68; H, 6.71. Found: C, 85.41; H, 6.66%.
2.1.4. 2-((1S)-3-Chloro-1-phenylpropoxyl)-1-bromo-
naphthalene (14d). The ether 14d was prepared using the
same procedure and scale as described for 14a but using
2-bromo-1-naphthol. Flash chromatography of the residue,
eluting with hexane, gave the title compound (64%) as a
white solid, mp 101 8C: [a]2D2 K120 (c 1.0, CHCl3); dH
(400 MHz) 2.29–2.37 (1H, m), 2.59–2.68 (1H, m), 3.71 (1H,
quintet, JZ5.5 Hz), 3.96–4.02 (1H, m), 5.60 (1H, dd, JZ
4.0, 8.5 Hz), 7.06 (1H, d, JZ9.0 Hz), 7.29 (1H, d, JZ
8.0 Hz), 7.34–7.39 (3H, m), 7.44–7.46 (2H, M), 7.55 (1H, t,
JZ8.0 Hz), 7.61 (1H, d, JZ9 Hz), 7.70 (1H, d, JZ8 Hz),
8.23 (1H, d, JZ8.5 Hz); dC (100 MHz) 41.33, 41.39, 78.59,
109.91, 116.07, 124.46, 126.08, 126.19, 127.62, 127.96,
128.16, 128.60, 128.85, 129.89, 133.12, 140.26, 152.14;
2.1.8. (S)-3,4-Dihydro-6-methyl-2-phenyl-2H-1-benzo-
pyran (15b). The benzopyran 15b was prepared using the
same procedure and scale as described for 15a but using
(S)-2-bromo-1-(3-chloro-1-phenylpropoxy)-4-methyl-ben-
zene (14b) and gave the title compound as a colorless oil
(77%), [a]2D2 K18 (c 3.0, CHCl3); dH (400 MHz) 2.07–2.16
(1H, m), 2.20–2.26 (1H, m), 2.31 (3H, s), 2.76 (1H, dt, JZ
4.5, 16.5 Hz), 2.95–3.04 (1H, m), 5.12 (1H, dd, JZ2.0,
10.0 Hz), 6.86 (1H, d, JZ8.0 Hz), 6.94–6.98 (2H, m), 7.35–
7.37 (1H, m), 7.40–7.47 (4H, m); dC (100 MHz) 20.47,
25.02, 30.03, 77.65, 116.63, 121.43, 125.96, 127.72, 127.92,
128.46, 129.41, 129.83, 141.86, 152.90; FAB-LRMS 224
(100%), 117 (24); FAB-HRMS calcd. for C16H16O
224.1201, found 224.1197.
EI-LRMS 376 and 374 (4%), 222 (86), 193 (10), 153 (22),
117 (20), 91 (100); EI-HRMS calcd. for C19H BrClO
79
16
374.0072, found 374.0069; Anal. C19H16BrClO requires: C,
60.74; H, 4.29. Found: C, 60.70; H, 4.10%.
2.1.5. (R)-1-Bromo-2-(3-bromo-1-methylpropoxy)-ben-
zene (14e). The ether 14e was prepared using the same
procedure and scale as described for 14a but using
2-bromophenol and (S)-4-bromobutane-2-ol. Flash chroma-
tography of the residue, eluting with hexane, gave the title
compound (67%) as a colorless oil: [a]2D2 K102 (c 1.0,
CHCl3); dH (400 MHz) 1.37 (3H, d, JZ6 Hz), 2.10–2.18
(1H, m), 2.34–2.43 (1H, m), 3.56–3.69 (2H, m), 4.61–4.66
(1H, m), 6.84 (1H, d, JZ8 Hz), 6.98 (1H, d, JZ8 Hz), 7.26
(1H, t, JZ8 Hz), 7.54 (1H, d, JZ8 Hz); dC (100 MHz)
19.45, 29.81, 39.60, 73.68, 113.57, 115.52, 122.21, 128.41,
2.1.9. (S)-6-Chloro-3,4-dihydro-2-phenyl-2H-1-benzo-
pyran (15c). The benzopyran 15c was prepared using the
same procedure and scale as described for 15a but using
(S)-2-bromo-4-chloro-1-(3-chloro-1-phenylpropoxy)-ben-
zene (14c) and gave the title compound as white crystals
(78%), mp 54 8C; [a]D22 K12 (c 1.0, CHCl3); dH (400 MHz)
2.03–2.13 (1H, m), 2.19–2.26 (1H, m), 2.77 (1H, dt, JZ4.5,
16.5 Hz), 2.93–3.01 (1H, m), 5.06 (1H, d, JZ10.0 Hz), 6.85
(1H, d, JZ8.0 Hz), 7.08–7.10 (2H, m), 7.34–7.39 (1H, m),
7.40–7.42 (4H, m); dC (100 MHz) 24.90, 29.44, 77.83,
118.22, 123.38, 124.97, 125.91, 127.30, 127.94, 128.55,
129.03, 141.25, 153.72; FAB-LRMS 244 (100%), 209 (20),
117 (26); FAB-HRMS calcd. for C15H13ClO 244.0655,
found 244.6419; Anal. C15H13ClO requires: C, 73.62; H,
5.35. Found: C, 73.75; H, 5.39%.
133.50, 154.35; EI-LRMS 310, 308 and 306 (48%), 174
(100), 55 (50); EI-HRMS calcd. for C10H Br2O 305.9255,
79
12
found 305.9252.
2.1.6. (S)-2-Bromo-1-(3-chloro-1-phenylpropoxy)-3,5-
dimethoxy-benzene (14f). The ether 14f was prepared
using the same procedure and scale as described for 14a but
using 2-bromo-3,5-dimethoxyphenol. Flash chromato-
graphy, eluting with hexane–ether (4:1), gave the title
compound (76%) as a white solid, mp 66–67 8C: [a]2D2C56
(c 1.0, CHCl3); dH (400 MHz) 2.21–2.27 (1H, m), 2.51–2.57
(1H, m), 3.62 (3H, s), 3.63–3.69 (1H, m), 3.84 (3H, s), 3.87–
3.95 (1H, m), 5.40 (1H, dd, JZ4.5, 8.5 Hz), 5.99 (1H, d, JZ
2.5 Hz), 6.10 (1H, d, JZ2.5 Hz), 7.26–7.30 (1H, m), 7.33–
7.40 (4H, m); dC (100 MHz) 41.19, 41.30, 55.24, 56.23,
78.00, 92.09, 93.11, 94.33, 125.80, 128.01, 128.78, 140.26,
155.62, 157.34, 159.98; EI-LRMS 386 and 384 (10%),
2.1.10. (S)-3,4-Dihydro-2-phenyl-2H-naphtho[1,2-b]-
pyran (15d). The benzopyran 15d was prepared using the
same procedure and scale as described for 15a but using
2-((1S)-3-chloro-1-phenylpropoxyl)-1-bromonaphthalene
(14d) and gave the title compound as a white solid (74%),
mp 73 8C; [a]2D2C34 (c 1.0, CHCl3); dH (400 MHz) 2.26–
2.34 (1H, m), 2.41–2.47 (1H, m), 3.19–3.23 (2H, m), 5.18
(1H, d, JZ10.0 Hz), 7.26 (1H, d, JZ9 Hz), 7.42–7.51 (4H,
m), 7.55–7.60 (3H, m), 7.73 (1H, d, JZ9 Hz), 7.88 (2H, t,
JZ9.5 Hz); dC (100 MHz) 21.62, 29.62, 77.38, 113.52,
119.14, 121.90, 123.22, 126.00, 126.28, 127.72, 127.80,
128.38, 128.47, 128.95, 132.97, 141.49, 152.62; FAB-
LRMS 260 (100%), 157 (26), 117 (85), 91 (26); FAB-
HRMS calcd. for C19H16O 260.1201, found 260.1204; Anal.
C19H16O requires: C, 87.66; H, 6.19. Found C, 87.34; H,
5.94%.
234 (75), 153 (20), 117 (15), 91 (100); EI-HRMS calcd.
for C17H BrClO3 384.0127, found 384.0130; Anal.
79
18
C17H18BrClO3 requires: C, 52.94; H, 4.70. Found: C,
53.11; H, 4.55%.
2.1.7. (S)-3,4-Dihydro-2-phenyl-2H-1-benzopyran (15a).
To a stirred solution of n-butyllithium in hexane (2.5 M,
4.0 mL, 10.0 mmol) in THF (30 mL) at K50 8C was added
dropwise a solution of (S)-1-bromo-2-(3-chloro-1-phenyl-
propoxy)-benzene (14a) (3.0 g, 9.2 mmol) in THF (8 mL).
The mixture was stirred at K50 8C for 2 h and allowed to
warm to room temperature over 2 h. The reaction was
quenched by pouring into saturated aqueous ammonium

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K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
2.1.11. (R)-3,4-Dihydro-2-methyl-2H-1-benzopyran
(15e). The benzopyran 15e was prepared using the same
procedure and scale as described for 15a but using (R)-1-
bromo-2-(3-bromo-1-methylpropoxy)-benzene (14e) and
gave the title compound as a colorless oil (81%), [a]2D2C
89 (c 1.0, CHCl3); dH (400 MHz) 1.42 (3H, d, JZ6.5 Hz),
1.69–1.79 (1H, m), 1.98–2.04 (1H, m), 2.73–2.79 (1H, m),
2.84–2.93 (1H, m), 4.14–4.18 (1H, m), 6.81–6.87 (2H, m),
7.06–7.12 (2H, m); dC (100 MHz) 21.32, 24.81, 29.20,
72.08, 116.63, 119.91, 121.75, 127.10, 129.48, 154.99;
FAB-LRMS 121 (20%), 107 (55), 89 (66), 77 (75); Anal.
C10H12O requires: C, 81.04; H, 8.16. Found: C, 81.31; H,
8.86%.
carboxaldehyde (17b). To a stirred solution of n-butyl-
lithium in hexane (2.5 M, 0.24 mL, 0.6 mmol) in THF
(3 mL) at K50 8C was added dropwise a solution of (S)-2,4-
dibromo-1-(3-chloro-1-phenylpropoxy)-benzene (16)
(202 mg, 0.5 mmol) in THF (2 mL). After 1 h at K50 8C,
the cooling bath was removed and the solution stirred at
room temperature for 1 h. The solution was re-cooled to
K50 8C and n-butyllithium in hexane (2.5 M, 0.3 mL,
0.75 mmol) added dropwise. After 30 min, DMF (365 mg,
5 mmol) was added and, following stirring for 30 min, the
solution was allowed to return to room temperature. The
reaction was quenched by pouring into saturated aqueous
ammonium chloride (5 mL). The mixture was extracted
with ethyl acetate (3!10 mL), and the combined extracts
washed with water (10 mL), brine (10 mL), dried and
evaporated. Flash chromatography of the residue, eluting
with hexane, gave the title compound (1.6 g, 81%) as a
white solid (81%), mp 82–83 8C: [a]2D2C109 (c 1.0, CHCl3);
dH (400 MHz) 2.07–2.17 (1H, m), 2.25–2.32 (1H, m), 2.87
(1H, dt, JZ4.5, 16.0 Hz), 2.99–3.08 (1H, m), 5.17 (1H, dd,
JZ2.5, 10.0 Hz), 7.01 (1H, d, JZ8.0 Hz), 7.34–7.38 (1H,
m), 7.40–7.42 (4H, m), 7.66–7.68 (2H, m), 9.86 (1H, s); dC
(100 MHz) 24.74, 29.31, 78.52, 117.59, 122.40, 125.86,
128.14, 128.61, 129.59, 129.73, 131.84, 140.65, 160.53,
190.96; FAB-LRMS 239 (100%), 117 (24), 91 (10); FAB-
HRMS calcd. for C16H14O2 239.1072, found 239.1071;
Anal. C16H14O2 requires: C, 80.65; H, 5.92. Found: C,
81.01; H, 5.87%.
2.1.12. (S)-3,4-Dihydro-5,7-dimethoxy-2-phenyl-2H-1-
benzopyran (15f). The benzopyran 15f was prepared
using the same procedure and scale as described for 15a
but using (S)-2-bromo-1-(3-chloro-1-phenylpropoxy)-3,5-
dimethoxy-benzene (14f) and flash chromatography, eluting
with hexane–ether (4:1), gave the title compound as a
colorless oil (78%), [a]2D2 K9 (c 1.0, CHCl3); dH (400 MHz)
2.05–2.14 (1H, m), 2.23–2.29 (1H, m), 2.69–2.77 (1H, m),
2.81–2.87 (1H, m), 3.83 (3H, s), 3.86 (3H s), 5.05 (1H, dd,
JZ2.5, 10.0 Hz), 6.18 (1H, d, JZ2.5 Hz), 6.24 (1H, d, JZ
2.5 Hz), 7.39–7.52 (5H, m); dC (100 MHz) 19.14, 29.46,
55.12, 55.23, 77.64, 91.27, 93.36, 103.26, 125.92, 127.65,
128.35, 141.62, 156.22, 158.46, 159.30; FAB-LRMS 270
(100%), 167 (50), 91 (24); FAB-HRMS calcd. for C17H18O3
270.1256, found 270.1273.
2.1.16. (S)-3,4-Dihydro-2-phenyl-2H-1-benzopyran-6-
carboxylic acid (17c). The benzopyran 17c was prepared
using the same procedure and scale as described for 17b but
using an excess of carbon dioxide gas as the electrophile and
gave the title compound as a white solid (78%), mp 208–
209 8C: [a]2D2C37 (c 1.0, CHCl3); dH (acetone 400 MHz)
2.02–2.12 (1H, m), 2.26–2.32 (1H, m), 2.86 (1H, dt, JZ4.5,
16.5 Hz), 3.02–3.10 (1H, m), 5.22 (1H, dd, JZ2.5,
10.0 Hz), 6.92 (1H, d, JZ9.0 Hz), 7.32–7.36 (1H, m),
7.38–7.43 (2H, m), 7.47–7.49 (2H, m), 7.81–7.49 (2H, m);
dC (100 MHz) 25.47, 30.34, 79.10, 117.55, 123.04, 123.36,
126.91, 128.75, 129.37, 130.13, 132.70, 142.48, 160.14,
167.64; FAB-LRMS 255 (100%), 237 (30), 209 (12), 151
(12), 117 (36), 91 (12); FAB-HRMS calcd. for C16H14O3
255.1021, found 255.1017; Anal. C16H14O3 requires: C,
75.57; H, 5.55. Found: C, 75.50; H, 5.45%.
2.1.13. (S)-2,4-Dibromo-1-(3-chloro-1-phenylpropoxy)-
benzene (16). The ether 16 was prepared using the same
procedure and scale as described for 14a but using
2,4-dibromophenol. Flash chromatography of the residue,
eluting with hexane, gave the title compound (79%) as a
colorless oil: [a]2D2C45 (c 1.0, CHCl3); dH (400 MHz) 2.22–
2.30 (1H, m), 2.51–2.59 (1H, m), 3.67 (1H, quintet, JZ
5.5 Hz), 3.88–3.95 (1H, m), 5.42 (1H, dd, JZ4.5, 10.0 Hz),
6.59 (1H, d, JZ9.0 Hz), 7.17 (1H, dd, JZ2.5, 9.0 Hz),
7.31–7.33 (1H, m), 7.37–7.39 (4H, m), 7.66 (1H, d, JZ
2.5 Hz); dC (100 MHz) 41.15, 41.18, 78.11, 113.23, 113.51,
116.14, 125.79, 128.26, 128.92, 130.98, 135.41, 139.58,
153.37; FAB-LRMS 154 (100%), 136 (35), 91 (24); Anal.
C15H13Br2ClO requires: C, 44.54; H, 3.24. Found: C, 44.36;
H, 3.36%.
2.1.14. (S)-6-Bromo-3,4-dihydro-2-phenyl-2H-1-benzo-
pyran (17a). The benzopyran 17a was prepared using the
same procedure and scale as described for 15a but using
(S)-2,4-dibromo-1-(3-chloro-1-phenylpropoxy)-benzene
(16) and gave the title compound as a white solid (84%), mp
67 8C: [a]2D2C3 (c 3.0, CHCl3); dH (400 MHz) 2.06–2.13
(1H, m), 2.19–2.26 (1H, m), 2.77 (1H, dt, JZ4.5, 16.5 Hz),
2.93–3.02 (1H, m), 5.06 (1H, dd, JZ2.5, 10.0 Hz), 6.82
(1H, d, JZ9.0 Hz), 7.24 (2H, brs), 7.35–7.43 (5H, m); dC
(100 MHz) 24.80, 29.36, 77.77, 112.26, 118.66, 123.95,
125.87, 127.97, 128.51, 130.15, 131.94, 141.16, 154.19;
2.1.17. (S)-3,4-Dihydro-2-phenyl-2H-1-benzopyran-6-
methanol (17d). The benzopyran 17d was prepared using
the same procedure and scale as described for 17b but using
an excess of paraformaldehyde powder as the electrophile
and gave the title compound as a colorless oil (57%):
[a]2D2C2 (c 1.0, CHCl3); dH (400 MHz) 2.04–2.14 (1H, m),
2.20–2.26 (1H, m), 2.79 (1H, dt, JZ4.0, 16.5 Hz), 2.95–
3.03 (1H, m), 4.59 (2H, s), 5.07 (1H, dd, JZ2.0, 10.0 Hz),
6.91 (1H, d, JZ8.0 Hz), 7.11 (1H, s), 7.33–7.44 (6H, m); dC
(100 MHz) 25.24, 30.06, 51.81, 65.39, 78.05, 117.27,
122.13, 126.19, 126.83, 128.09, 128.76, 133.04, 141.82,
154.99; FAB-LRMS 240 (92%), 223 (100), 209 (25), 117
(38), 91 (52); FAB-HRMS calcd. for C16H14O2 240.1155,
found 240.1155.
FAB-LRMS 290 and 288 (92%), 209 (34), 149 (40), 117
(90), 91 (100); FAB-HRMS calcd. for C15H BrO
79
13
288.0150, found 288.0161; Anal. C15H13BrO requires: C,
62.30; H, 4.53. Found: C, 62.57; H, 4.71%.
2.1.18. (S)-1,3-Dibromo-2-(3-chloro-1-phenylpropoxy)-
benzene (18). The ether 18 was prepared using the same
2.1.15. (S)-3,4-Dihydro-2-phenyl-2H-1-benzopyran-6-

K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
6867
procedure and scale as described for 14a but using
2,6-dibromophenol. Flash chromatography of the residue,
eluting with hexane, gave the title compound (77%) as a
colorless oil: [a]D22 K78 (c 1.0, CHCl3); dH (400 MHz)
2.45–2.53 (1H, m), 2.70–2.79 (1H, m), 3.39–3.45 (1H, m),
3.68–3.74 (1H, m), 5.77 (1H, t, JZ7.0 Hz), 6.78 (1H, t, JZ
8.0 Hz), 7.33–7.35 (3H, m), 7.44–7.48 (4H, m); dC
(100 MHz) 38.51, 41.16, 82.30, 118.61, 125.76, 128.06,
128.27, 128.75, 132.93, 137.90, 151.59; EI-LRMS 252
(18%), 153 (78), 117 (50), 91 (100); Anal. C15H13Br2ClO
requires: C, 44.54; H, 3.24. Found: C, 44.78; H, 3.59%.
70.54, 127.09, 128.72, 133.47, 142.08; FAB-LRMS
208, 206 and 204 (12%), 187 (100), 141 (70), 125 (60);
35
FAB-HRMS calcd. for C9H Cl2O 204.0105, found
204.0106.
10
2.1.22. (R)-6-Chloro-3,4-dihydro-2-(4-chlorophenyl)-
2H-1-benzopyran (4). Following the same procedure and
scale as described for the preparation of 14a but using (S)-3-
chloro-1-(4-chlorophenyl)-1-propanol (22) and 2-bromo-4-
chlorophenol (12c) gave (R)-2-bromo-4-chloro-1-[3-chloro-
1-(4-chlorophenyl)propoxy]-benzene (85%) as a colorless
oil: [a]2D2C85 (c 1.0, CHCl3); dH (400 MHz) 2.17–2.25 (1H,
m), 2.47–2.56 (1H, m), 3.63 (1H, quintet, JZ5.5 Hz), 3.85–
3.91 (1H, m), 5.38 (1H, dd, JZ4.5, 9.0 Hz), 6.60 (1H, d, JZ
9.0 Hz), 7.05 (1H, dd, JZ2.5, 9.0 Hz), 7.29–7.35 (4H, m),
7.51 (1H, d, JZ2.5 Hz); dC (100 MHz) 40.96, 41.00, 77.67,
113.25, 115.68, 126.65, 127.29, 128.12, 129.18, 132.90,
134.13, 138.20, 152.73 which was used in the next step:
using the same procedure and scale as described for 15a
but using (R)-2-bromo-4-chloro-1-[3-chloro-1-(4-chloro-
phenyl)propoxy]-benzene gave the title compound (78%)
as a white solid, mp 107 8C; dH (400 MHz) 1.98–2.06 (1H,
m), 2.15–2.22 (1H, m), 2.72–2.99 (1H, m), 2.75 (1H, dt, JZ
4.5, 16.0 Hz), 5.01 (1H, dd, JZ2.5, 10.0 Hz), 6.83 (1H, d,
JZ8.5 Hz), 7.07–7.09 (2H, m), 7.33–7.35 (4H, m); dC
(100 MHz) 24.72, 29.39, 77.31, 118.15, 123.18, 125.12,
127.26, 127.33, 128.66, 129.01, 133.62, 139.72, 153.39;
2.1.19. (S)-8-Bromo-3,4-dihydro-2-phenyl-2H-1-benzo-
pyran (19). The benzopyran 19 was prepared using the
same procedure described for 15a but using (S)-1,3-
dibromo-2-(3-chloro-1-phenylpropoxy)-benzene (18) and
gave the title compound as a colorless oil (79%): [a]D22
K143 (c 1.0, CHCl3); dH (400 MHz) 2.02–2.12 (1H, m),
2.28–2.34 (1H, m), 2.79 (1H, dt, JZ5.0, 16.5 Hz), 2.96–
3.04 (1H, m), 5.23 (1H, d, JZ9.0 Hz), 6.77 (1H, dt, JZ1.0,
8.0 Hz), 7.04 (1H, d, JZ8.0 Hz), 7.35 (1H, d, JZ8.0 Hz),
7.40–7.44 (3H, m), 7.47–7.49 (2H, m); dC (100 MHz) 24.92,
29.54, 77.99, 111.08, 120.89, 123.63, 125.51, 127.62,
128.44, 128.53, 131.02, 141.10, 151.35; FAB-LRMS 288
(58%), 185 (26), 117 (100), 91 (56); FAB-HRMS calcd. for
C15H BrO 288.0150, found 288.0188.
79
13
2.1.20. (S)-3,4-Dihydro-2-phenyl-2H-1-benzopyran-8-
carboxaldehyde (20). The benzopyran 20 was prepared
using the same procedure described for 17b but using (S)-
1,3-dibromo-2-(3-chloro-1-phenylpropoxy)-benzene (18)
and gave the title compound as colorless needles following
recrystallization from ethanol (76%), mp 94–95 8C (EtOH):
[a]2D2 K287 (c 1.0, CHCl3); dH (400 MHz) 2.08–2.17 (1H,
m), 2.28–2.34 (1H, m), 2.85 (1H, dt, JZ4.5, 16.5 Hz), 2.99–
3.07 (1H, m), 5.20 (1H, dd, JZ2.5, 10.0 Hz), 6.94 (1H, t,
JZ7.5 Hz), 7.31 (1H, d, JZ8.0 Hz), 7.35–7.43 (5H, m),
7.70 (1H, d, JZ8.0 Hz), 10.52 (1H, s); dC (100 MHz) 24.76,
29.31, 78.18, 120.10, 123.15, 124.28, 125.65, 126.19,
128.01, 128.58, 135.77, 140.79, 157.71, 189.83; FAB-
LRMS 239 (100%), 135 (62), 117 (15), 91 (24); FAB-
HRMS calcd. for C16H14O2 239.1072, found 239.1071;
Anal. C16H14O2 requires: C, 80.65; H, 5.92. Found: C,
81.05; H, 6.02%.
FAB-LRMS 282, 280 and 278 (100%), 243 (20), 217 (85),
176 (55); FAB-HRMS calcd. for C15H Cl2O 278.0265,
found 278.0264; Anal. C15H12Cl2O requires: C, 64.54; H,
4.33. Found: C, 64.67; H, 4.60%.
35
12
2.2. Oxidation of (S)-3,4-dihydro-2-phenyl-2H-1-benzo-
pyran (15) with periodic acid and chromium(VI) oxide
Periodic acid (455 mg, 2.0 mmol) was dissolved in
acetonitrile by vigorous stirring followed by the addition
of chromium(VI) oxide (5 mg, 0.05 mmol). (S)-3,4-Dihydro-
2-phenyl-2H-1-benzopyran (15) (210 mg, 1.0 mmol) was
added and an exotherm and white precipitate were
immediately observed. The mixture was stirred for 1 h,
filtered through Celitew, and the volatiles evaporated. The
residue was dissolved in dichloromethane (10 mL), washed
with saturated aqueous sodium bicarbonate (10 mL), brine
(10 mL), dried and evaporated. Flash chromatography of the
residue, eluting with hexane–ether (3:1 then 1:1), gave first
(S)-2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one (23)
(96 mg, 43%) as a white solid: [a]2D2 K63 (c 1.0, CHCl3);
dH (400 MHz) 2.90 (1H, dd, JZ3.0, 1.0 Hz), 3.10 (1H, dd,
JZ3.5, 17.0 Hz), 5.49 (1H, dd, JZ3.0, 13.5 Hz), 7.05–7.08
(2H, m), 7.39–7.54 (6H, m), 7.94 (1H, dd, JZ2.0, 8.0 Hz);
IR 1684 cmK1. Later fractions contained 2-(3-oxo-3-
phenylpropyl)cyclohexa-2,5-diene-1,4-dione (24) (74 mg,
31%). Recrystallization from hexane/ethyl acetate gave
yellow needles mp 127 8C: dH (400 MHz) 2.87 (2H, t, JZ
7.0 Hz), 3.25 (2H, d, JZ7.0 Hz), 6.64 (1H, s), 6.70–6.78
(2H, m), 7.46 (2H, t, JZ8.0 Hz), 7.57 (1H, t, JZ8.0 Hz),
7.94 (2H, JZ8.0 Hz); dC (100 MHz) 23.95, 36.39, 127.98,
128.68, 133.25, 133.35, 136.38, 136.76, 148.17, 187.37,
187.47, 197.78 (one signal obscured); FAB-LRMS 241
(40%), 223 (20), 105 (100); Anal. C15H12O3 requires: C,
74.99; H, 5.03%. Found: C, 74.82; H, 4.93%.
2.1.21. (S)-3-Chloro-1-(4-chlorophenyl)-1-propanol (22).
To (R)-oxazaborolidine (1.0 M in toluene, 1.0 mL,
1.0 mmol) in THF (2 mL) at 0 8C was added dropwise
borane–THF complex (1.0 M, 6 mL, 6 mmol). After 5 min a
solution of 3,40-dichloropropiophenone (21) (2.03 g,
10 mmol) in THF (10 mL) was added dropwise and the
reaction mixture stirred for an additional 1 h. Methanol
(3 mL) was added and after 10 min hydrogen chloride in
ether (1.0 M, 2.0 mL, 2.0 mmol) was added. After 30 min,
the volatiles were removed by evaporation and the residue
triturated with ether and filtered to remove any insoluble
material. The ether solution was washed with brine (10 mL),
saturated aqueous sodium bicarbonate (10 mL), dried
and evaporated to give the title compound as a colorless
oil (1.86 g, 91%); [a]D22 K17 (c 1.0, CHCl3); dH (400 MHz)
1.98–2.06 (1H, m), 2.12–2.19 (1H, m), 2.43 (1H, brs),
3.48–3.54 (1H, m), 3.66–3.73 (1H, m), 4.89 (1H, dd, JZ4.5,
8.5 Hz), 7.25–7.33 (4H, m); dC (100 MHz) 41.28, 41.43,

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K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
2.2.1. (R)-3-(tert-Butyldimethylsily)oxy-N-methoxy-N-
methyl-benzenepropanamide (28). To a stirred solution
of ethyl-(R)-3-hydroxy-3-phenyl propionate (27) (1.94 g,
10 mmol) and imidazole (1.36 g, 20 mmol) in dichloro-
methane (50 mL) was added tert-butyldimethylsilyl
chloride (1.65 g, 11 mmol). The mixture was stirred at
room temperature overnight and the resulting white
precipitate was poured into saturated aqueous ammonium
chloride (150 mL). The mixture was extracted with
dichloromethane (3!50 mL) and the combined extracts
washed with water (50 mL), brine (50 mL), dried and
evaporated. Flash chromatography of the residue, eluting
with hexane–ether (19:1), gave (R)-3-phenyl-3-(tert-butyl-
dimethylsily)oxypropanoate41 as a colorless oil (2.89, 94%);
dH (400 MHz) K0.18 (3H, s), 0.01 (3H, s), 0.87 (9H, s),
1.25 (3H, t, JZ6 Hz), 2.53 (1H, dd, JZ4.0, 14.5 Hz), 2.72
(1H, dd, JZ9.5, 14.5 Hz), 4.13 (2H, q, JZ6 Hz), 5.14 (1H,
dd, JZ4.0, 9.5 Hz), 7.24–7.36 (5H, m).
dropwise tert-butyllithium in pentane (1.7 M, 0.88 mL,
1.5 mmol). The reaction mixture was stirred at K78 8C for
15 min, allowed to warm to 0 8C over 1 h, re-cooled to
K78 8C and (R)-3-(tert-butyldimethylsily)oxy-N-methoxy-
N-methyl-benzenepropanamide (28) (154 mg, 0.5 mmol) in
toluene (2 mL) added dropwise. The solution was allowed
to return to room temperature over 2 h and quenched by the
dropwise addition of saturated aqueous ammonium chloride
(10 mL). The phases were separated and the aqueous layer
extracted with ether (3!10 mL), combined and washed
with water (10 mL), brine (10 mL), dried and evaporated.
Flash chromatography of the residue, eluting with hexane–
ether (3:1), gave the title compound as a colorless oil
(165 mg, 72%): [a]D22C71 (c 1.0, CHCl3) dH (400 MHz)
K0.13 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 3.02 (1H, dd, JZ
4.5, 17.5 Hz), 3.30 (1H, dd, JZ7.5, 17.5 Hz), 3.39 (3H, s),
3.69 (3H, s), 3.77 (3H, s), 5.03 (2H, s), 5.38 (1H, dd, JZ4.5,
7.5 Hz), 6.09 (1H, s), 6.29 (1H, s), 7.20 (1H, t, JZ8.0 Hz),
7.27 (2H, t, JZ7.5 Hz), 7.35 (2H, d, JZ8.0 Hz); dC
(100 MHz) K5.15, K4.73, 18.08, 25.76, 55.29, 55.39,
55.58, 55.89, 56.16, 70.47, 92.11, 93.16, 94.59, 114.42,
126.11, 126.90, 127.94, 145.31, 155.99, 158.16, 162.14,
200.65; FAB-LRMS 483 (MC23, 100%), 221 (26), 73
(100).
To a stirred suspension of N, O-dimethylhydroxylamine
hydrochloride (1.75 g, 18 mmol) in dichloromethane
(45 mL) at 0 8C under nitrogen was added dropwise
trimethylaluminum (2.0 M in toluene, 9 mL, 18 mmol).
The reaction mixture was stirred for 20 min and then treated
with a solution of (R)-3-phenyl-3-(tert-butyldimethyl-
sily)oxypropanoate41 (2.77 g, 9 mmol) in dichloromethane
(15 mL). The mixture was stirred at room temperature
overnight and poured into saturated aqueous ammonium
chloride (150 mL). The resulting precipitate was filtered
through Celitew, the filtrate extracted with dichloromethane
(3!75 mL) and the combined extracts washed with water
(50 mL), brine (50 mL), dried and evaporated. Flash
chromatography of the residue, eluting with hexane–ether
(1:1), gave the title compound as a colorless oil (2.38 g,
82%); [a]2D2C138 (c 1.0, CHCl3); dH (400 MHz) K0.14
(3H, s), 0.08 (3H, s), 0.84 (9H, s), 2.47 (1H, dd, JZ3.5,
14.5 Hz), 3.02–3.07 (1H, brm), 3.17 (3H, s), 3.63 (3H, s),
5.26 (1H, dd, JZ3.5, 9.0 Hz), 7.21–7.26 (1H, m), 7.29–7.32
(2H, m), 7.36–7.38 (2H, m); dC (100 MHz) K4.57, 18.34,
25.99, 32.17, 43.46, 61.53, 72.34, 76.96, 126.07, 127.49,
128.42, 145.05, 171.87; FAB-LRMS 346 (MC23, 100%),
266 (38), 221 (16), 150 (15), 73 (98).
2.3.2. (R)-3-Hydroxy-1-(2-hydroxy-4,6-dimethoxy-
phenyl)-3-phenylpropan-1-one (32). To a stirred solution
of (R)-1-[2,4-dimethoxy-6-(methoxymethoxy)phenyl]-3-
phenyl-3-(tert-butyldimethylsily)oxy-propan-1-one (31)
(230 mg, 0.5 mmol) in THF (9 mL) and water (1 mL) was
added p-toluene sulfonic acid (19 mg, 0.1 mmol). The
solution was heated to 55 8C for 12 h, cooled and poured
onto saturated aqueous sodium bicarbonate (15 mL). The
mixture was extracted with ethyl acetate (3!15 mL) and
the combined extracts washed with brine (25 mL), dried and
evaporated. Flash chromatography of the residue, eluting
with hexane–ether (1:1), gave the title compound (130 mg,
86%) as a white solid, mp 91 8C: [a]2D2C49.5 (c 2.0,
1
CHCl3); dH (400 MHz) 3.33–3.51 (3H, m, H exchanges
with D2O), 3.77 (3H, s), 3.81 (3H, s), 5.27 (1H, dd, JZ4.0,
9.0 Hz), 5.90 (1H, s), 6.07 (1H, s), 7.28 (1H, t, JZ8.0 Hz),
7.27 (2H, t, JZ8.0 Hz), 7.35 (2H, d, JZ7.5 Hz); dC
(100 MHz) 52.58, 55.51, 55.55, 70.07, 90.92, 93.66,
105.81, 125.84, 127.34, 128.37, 143.33, 162.83, 166.43,
167.71, 204.05; FAB-LRMS 303 (15%), 284 (10), 181
(100); FAB-HRMS calcd. for C17H19O5 303.1232, found
303.1232; Anal. C17H18O5 requires: C, 67.54; H, 6.00.
Found: C, 67.31; H, 6.23%.
2.3. 1,5-Dimethoxy-3-(methoxymethoxy)benzene (30)
To a vigorously stirred solution of 3,5-dimethoxyphenol
(10 g, 65 mmol) and potassium bicarbonate (17.94 g,
130 mmol) in DMF (250 mL) was added chloromethyl
methyl ether (6.44 g, 80 mmol). The mixture was stirred
overnight, poured into saturated ammonium chloride
(250 mL) and extracted with ethyl acetate (3!150 mL).
The combined extracts were washed with water (5!
200 mL), 2.0 M sodium hydroxide (200 mL), brine, dried
and evaporated to give the title compound as a colorless oil
(9.9 g, 94%); dH (400 MHz) 3.47 (3H, s), 3.76 (6H, s), 5.14
(2H, s), 6.14 (1H, s), 6.23 (2H, s); dC (100 MHz) 55.31,
56.02, 94.18, 94.45, 94.96, 159.09, 161.43.
2.3.3. (S)-5,7-Dimethoxy-2-phenylchroman-4-one (33).
A solution of triphenylphosphine (131 mg, 0.5 mmol) and
diethyl azodicarboxylate (88 mg, 0.5 mmol) in THF (3 mL)
at 0 8C was stirred for 15 min and then added dropwise to a
solution of (R)-3-hydroxy-1-(2-hydroxy-4,6-dimethoxy-
phenyl)-3-phenylpropan-1-one (32) (130 mg, 0.43 mmol)
in THF (3 mL) at 0 8C. The reaction mixture was stirred for
1 h at 0 8C and the volatiles removed by evaporation. Flash
chromatography of the residue, eluting with hexane–ether
(1:1 and then 1:2), gave the title compound (120 mg, 88%)
as a white solid, mp 159–160 8C; [a]2D2 K28 (c 2.0, MeOH–
CHCl3, 1:1); dH (400 MHz) 2.79 (1H, dd, JZ3.0, 16.5 Hz),
3.01 (1H, dd, JZ13.0, 16.5 Hz), 3.81 (3H, s), 3.88 (3H, s),
5.40 (1H, dd, JZ3.0, 13.0 Hz), 6.09 (1H, d, JZ2.0 Hz),
2.3.1.
(R)-1-[2,4-Dimethoxy-6-(methoxymethoxy)-
phenyl]-3-phenyl-3-(tert-butyldimethylsily)oxy-propan-
1-one (31). To a stirred solution of 1,5-dimethoxy-3-
(methoxymethoxy)benzene (30) (297 mg, 1.5 mmol) in
toluene (5 mL) at K78 8C under nitrogen was added

K. J. Hodgetts / Tetrahedron 61 (2005) 6860–6870
6869
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6.15 (1H, d, JZ2.0 Hz), 7.38–7.46 (5H, m); dC (100 MHz)
45.56, 55.56, 56.13, 79.18, 93.14, 93.52, 105.97, 126.08,
128.63, 128.75, 138.74, 162.26, 164.94, 165.94, 189.13;
Anal. C17H16O4 requires: C, 71.82%; H, 5.67%. Found: C,
71.70%; H, 5.67%.
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2-phenylchroman-4-one (33) (140 mg, 0.5 mmol) in aceto-
nitrile (10 mL) at room temperature was added aluminum
chloride (265 mg, 2.0 mmol). The mixture was heated to
reflux for 3 h, cooled and the volume reduced by
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compound (106 mg, 79%) as a white solid, mp 89–90 8C
(MeOH); [a]2D2 K48 (c 1.0, CHCl3); dH (400 MHz) 2.82
(1H, dd, JZ3.0, 17.0 Hz), 3.09 (1H, dd, JZ13.0, 17.0 Hz),
3.81 (3H, s), 5.43 (1H, dd, JZ3.0, 13.0 Hz), 6.06–6.09 (2H,
m), 7.41–7.46 (5H, m), 12.03 (1H, s); dC (100 MHz) 43.36,
53.41, 55.67, 79.20, 94.24, 95.12, 103.12, 126.11, 128.85,
138.34, 162.76, 164.16, 167.96, 195.73; Anal. C16H14O4
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5.21%.
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Acknowledgements
The University College Dublin and Schering-Plough
(Avondale) are thanked for the funding of this research
under the Newman Fellowship program and the Department
of Chemistry at the University College Dublin are thanked
for the use of facilities during this research. John Hill (Kent
mass spectrometry) is thanked for high-resolution mass
spectra and Robertson analytical for elemental analysis and
optical polarimetry. The author would like to thank Dr.
Dario Doller (Neurogen Corporation) for helpful discus-
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