Syntheses of 3,7-Dimethyl-8-hydroxy-6-methoxyisochroman, the 3,7-Dimethyl-6-hydroxy-8-methoxy Isomer, and Their Ester and Ether Derivatives: Plant Growth Regulatory Activity

Article abstract of DOI:10.1021/jf960618l

A systematic invesitgation of ester and ether derivatives of 3,7-dimethyl-8-hydroxy-6-methoxyisochroman and 3,7-dimethyl-6-hydroxy-8-methoxyisochroman has established that all of the derivatives synthesized exhibited activity in the wheat coleoptile assay, with several of the compounds being more active than the parent systems.

Full text of DOI:10.1021/jf960618l

1422
J. Agric. Food Chem. 1997, 45, 1422−1429
Syn th eses of 3,7-Dim eth yl-8-h yd r oxy-6-m eth oxyisoch r om a n , th e
3,7-Dim eth yl-6-h yd r oxy-8-m eth oxy Isom er , a n d Th eir Ester a n d
Eth er Der iva tives: P la n t Gr ow th Regu la tor y Activity
Horace G. Cutler*
Natural Products Discovery Group, Southern School of Pharmacy, Mercer University,
3001 Mercer University Drive, Atlanta, Georgia 30341
George Majetich,* Xinrong Tian, and Paul Spearing
Box 218, Department of Chemistry, The University of Georgia, Athens, Georgia 30602
A systematic invesitgation of ester and ether derivatives of 3,7-dimethyl-8-hydroxy-6-methoxyiso-
chroman and 3,7-dimethyl-6-hydroxy-8-methoxyisochroman has established that all of the derivatives
synthesized exhibited activity in the wheat coleoptile assay, with several of the compounds being
more active than the parent systems.
Keyw or d s: Esters and ethers of isochroman; plant growth regulatory activity
We earlier reported the isolation of 3,7-dimethyl-8-
hydroxy-6-methoxyisochroman (1) from Penicillium cory-
lophilum and demonstrated that it inhibited etiolated
wheat coleoptiles at 10-3 and 10-4 M, as did the acetoxy
and methoxy synthetic derivatives (Cutler et al., 1989).
The parent compound had originally been isolated from
moldy millet hay implicated in the death of cattle (Cox
et al., 1979), but the metabolite had not been tested in
plants. Because of the results obtained in the wheat
coleoptile bioassay, isochroman 1 and two derivatives
were assayed on greenhouse-grown bean, corn, and
tobacco plants. The methyl ether exhibited the most
herbicidal activity in all of the plants treated, while the
parent and its acetoxy derivative were only active
against corn.
(1)
Because it was surprising that the acetoxy and
methoxy synthetic derivatives exhibited herbicidal ac-
tivity, we were curious whether other esters and ether
treatment of bromide 7 with vinylmagnesium bromide
in the presence of a catalytic amount of copper(I) iodide
produced olefin 8 in 68% yield. Oxymercuration-
demercuration of 8 gave secondary alcohol 9 in 68%
yield, along with some unreacted starting material.
Upon treatment with sodium hydride and chloromethyl
methyl ether in refluxing tetrahydrofuran, alcohol 9
generated the methoxymethyl ether in situ (cf. 10),
which cyclized under these reaction conditions to pro-
duce isochroman 3 in 91% yield. While Lewis acid-
catalyzed cyclialkylations (Brunson and Kroeger, 1940)
have been used to synthesize chroman (Deady et al.,
1963) and ochratoxin A37 (Steyn et al., 1967), the
cyclization of 10 to 3 occurred under thermal conditions
without a Lewis acid catalyst.
With a practical synthesis of isochroman 3 in hand,
its demethylation was then attempted. Methyl phenyl
ethers can be easily deprotected using strong mineral
acid (Greene and Wuts, 1991) or TMS-I (J ung and
Lyster, 1977). We were concerned, however, that acidic
reagents known to effect demethylation might compro-
mise the “A” ring of the isochroman. This concern led
us to employ nucleophilic reagents, such as sodium ethyl
thiolate, to effect deprotection (Feutrill and Mirrington,
1970). We were pleased to discover that treatment of
3 with excess NaSEt in hot DMF (150 °C) gave only
derivatives of 1 and its isomer, 3,7-dimethyl-6-hydroxy-
8-methoxyisochroman (2), would also exhibit significant
plant growth regulatory activity. We reasoned that 3,7-
dimethyl-6,8-dimethoxyisochroman (3) represents a logi-
cal precursor for the systematic preparation of the
desired ester and ether analogues of isochromans 1 and
2. To test this hypothesis, we needed both an efficient
synthesis of compound 3 and a practical way to selec-
tively demethylate the C(6) or C(8) ethers (eq 1).
While numerous synthetic routes are known for the
preparation of the isochroman skeleton (Macchia et al.,
1993; Saeed and Rama, 1995), we instead chose to
modify the synthetic strategy reported by Deady and
Steyn (Deady et al., 1963; Steyn et al., 1967). Our
synthesis of isochroman 3 begins with commerically
available 3,5-hydroxy-4-methylbenzoic acid (4) (Aldrich),
which was exhaustively methylated to provide ester 5
(Scheme 1). Reduction of ester 5 with LiAlH4, followed
by bromination of the benzylic alcohol (i.e., 6) with PBr3,
furnished bromide 7 in 91% overall yield. Subsequent
* Authors to whom correspondence should be ad-
dressed [(H.G.C.) fax (770) 986-3423; cutler_hg@
mercer.edu; (G.M.) fax (706) 542-9454; majetich@
sunchem.chem.uga.edu].
S0021-8561(96)00618-8 CCC: $14.00
© 1997 American Chemical Society

Syntheses of Isochroman Esters and Ethers
J. Agric. Food Chem., Vol. 45, No. 4, 1997 1423
Sch em e 1
isochroman 2 in 72% yield in which the less sterically
hindered C(6) methoxy group was selectively demethyl-
ated. With a practical synthesis of isochroman 2 in
hand, we were able to prepare the ether and ester
derivatives 12-27 without any complications using a
DCC-based esterification procedure (Ziegler and Berger,
1979). DCC-based esterifications are simple to conduct
but are notorious for having difficult to remove urea
byproducts or unreacted carbodiimide. However, we
found these difficulties could be avoided during ethereal
workup by washing the crude reaction mixture with
dilute aqueous acid. Although not used in this study,
an improved DCC-based esterification procedure has
been developed (Boden and Keck, 1985).
Surprisingly, neither prolonged heating nor a large
excess of ethyl thiolate was able to effect the further
deprotection of 2 to provide resorcinol derivative 11.
Efforts were therefore made to remove the C(8) protec-
tive group prior to the cyclialkylation. Toward this end,
substrates 28 and 29 were prepared (Figure 1); unfor-
tunately, both compounds failed to cyclize under a
variety of conditions, including the use of Lewis acid
catalysts.
F igu r e 1.
C(6) phenylthiomethyl ether intact (cf. 31). Desulfur-
ization of 31 with W-6 Raney nickel (Fieser and Fieser,
1967) converted the phenylthiomethyl ether protecting
group into a methoxy ether, thereby furnishing iso-
chroman 1. While the conversion of 1 into the ethers
32-39 could be achieved using standard Williamson
ether synthesis conditions, these ethers could be pre-
pared in higher overall yield if isochroman 31 was
alkylated prior to desulfurization of the phenylthio-
methyl ether group, i.e., 31 f 32 f 33-40. In theory,
esters 42-49 could be prepared from either 41 or 1 as
shown in Scheme 2. In practice, however, the sequence
31 f 1 f 42-49 was employed because it required the
preparation of fewer intermediates. Finally, hydrolysis
of 31 using vigorous conditions (mercuric chloride in
refluxing 4:1, acetonitrile/water) generated 6,8-dihydro-
Aryl phenylthiomethyl ethers are stable to most
nucleophiles (Holton and Nelson, 1980). This led us to
protect isochroman 2 with a phenylthiomethyl ether
(Scheme 2). Treatment of 30 with sodium ethyl thiolate
selectively removed the C(8) methyl ether, leaving the

1424 J. Agric. Food Chem., Vol. 45, No. 4, 1997
Cutler et al.
Sch em e 2
(Triticum aestivum L. cv. Wakeland) was germinated on
vermiculite at 22 ( 1 °C for 4 days in the dark. The seedling
were individually picked and fed into a Van der Weij guillotine,
the apical 2 mm was cut and discarded, and the next 4 mm
from each coleoptile was saved for bioassay. Ten 4 mm
sections were placed in each test tube with phosphate-citrate
buffer at pH 5.6 containing 2% sucrose and the compound to
be tested, in a dilution series, from 10-3 to 10-6 M. Ten
microliters of acetone was added to each test tube prior to
addition of the sucrose buffer to aid in formulating the
materials, and controls were treated in the same manner. The
test tubes were placed in a roller tube apparatus for 18 h at
22 °C, and then the coleoptiles were removed from the tubes
and blotted dry; their images were magnified (×3) and
recorded (Cutler, 1984). All data were statistically analzyed
(Kurtz et al., 1965), and experiments were duplicated.
3,7-dimethylisochroman (11), which decomposed under
the reaction conditions.
We were delighted to find that all of the synthetic
derivatives of isochromans 1 and 2 exhibited activity
in the wheat coleoptile assay up to C8, with some of the
compounds being more active than the parent. These
results are summarized in Tables 1 and 2.
EXPERIMENTAL PROCEDURES
Gen er a l. All reactions were run under an inert atmosphere
of nitrogen and monitored by TLC analysis until the starting
material was completely consumed. Unless otherwise indi-
cated, all ethereal workups consisted of the following proce-
dure: The reaction was quenched at room temperature with
saturated aqueous ammonium chloride and diluted with ether.
The resulting phases were separated, and the aqueous phase
was extracted with ether (three times). The combined ethereal
phases were washed with brine and dried over anhydrous
MgSO4. Filtration, followed by concentration at reduced
pressure on a rotary evaporator and at 1 Torr to a constant
weight, afforded a crude residue which was purified by flash
chromatography using NM silica gel 60 (230-400 mesh ASTM)
and distilled reagent grade solvents. All spectra were obtained
using CDCl3 as the solvent. Proton NMR spectra were
calibrated using trace CHCl3 present (δ 7.26) as an internal
reference.
Meth yl 3,5-Dim eth oxy-4-m eth ylben zoa te (5). To a so-
lution of benzoic acid 4 (3.9 g, 22.0 mmol) in acetone (50 mL)
was added K2CO3 (21.3 g, 155 mmol) and dimethyl sulfate (15.6
mL, 165 mmol). The mixture was refluxed for 18 h and then
acidified with 10% aqueous HCl. Standard ethereal workup
provided ester 5 as a light brown solid (4.40 g, 95%) which
was homogeneous on the basis of TLC analysis (hexanes/ether,
5:1, Rf 5 ) 0.44): mp 100.5-102 °C; 1H NMR (250 MHz) δ
2.13 (s, 3 H), 3.88 (s, 6 H), 3.92 (s, 3 H), 7.23 (s, 2 H); 13C NMR
(62.5 MHz) 178.1, 157.9, 128.1, 120.2, 104.5, 55.7, 52.0, 8.5
ppm; IR (neat) 1713, 1142 cm-1; ESI-MS, m/z 211 (MH+).
Bioa ssa y. Etiolated wheat coleoptiles were used to deter-
mine the biological activity of the compounds. Wheat seed
3,5-Dim eth oxy-4-m eth ylp h en ylm eth yl Alcoh ol (6). Li-
AlH4 (1.0 g, 26.4 mmol) was slowly added to a solution of ester

Syntheses of Isochroman Esters and Ethers
J. Agric. Food Chem., Vol. 45, No. 4, 1997 1425
Ta ble 1. Effects of th e Eth er a n d Ester Der iva tives of
3,7-Dim eth yl-6-h yd r oxy-8-m eth oxyisoch r om a n on th e
Gr ow th of Etiola ted Wh ea t Coleop tiles (T. a estivu m L.
Cv. Wa k ela n d )
NMR (62.5 MHz) 158.3, 139.3, 113.6, 102.1, 65.7, 55.6, 8.0
ppm; IR (neat) 3250-3600, 1590, 1138 cm-1; ESI-MS, m/z 183
(MH+).
3,5-Dim eth oxy-4-m eth ylp h en ylm eth yl Br om id e (7). To
a solution of alcohol 6 (3.60 g, 19.8 mmol) in ether (60 mL)
was added PBr3 (2.25 mL, 23.7 mmol) at 0 °C. After 2 h, the
reaction was quenched with ice. Standard ethereal workup,
followed by chromatography of the residue (elution with
hexanes/ether, 4:1), gave 4.60 g of benzyl bromide 7 as a white
crystalline solid (95%), which was homogeneous on the bais
of TLC analysis (hexanes/ether, 2:1, Rf 7 ) 0.86): mp 88-90
1
°C; H NMR (250 MHz) δ 2.08 (s, 3 H), 3.84 (s, 6 H), 4.50 (s,
2 H), 6.57 (s, 2 H); 13C NMR (62.5 MHz) 158.2, 135.8, 114.9,
104.1, 55.6, 34.6, 8.1 ppm; IR (neat) 1591, 1142 cm-1; EI-MS,
m/z (relative intensity) 246 (10), 244 (10), 165 (100), 150 (10),
120 (11), 105 (8), 91 (22), 77 (20), 51 (15).
wheat coleoptile assay (mm ×3)
R
10-3
M
10-4
M
10-5
M
10-6
M
1,3-Dim eth oxy-2-m eth yl-5-(2-pr open yl)ben zen e (8). Vin-
ylmagnesium bromide (1.0 M solution in THF, 28.2 mL) was
added to a stirred suspension of CuI (0.53 g, 2.8 mmol) in THF
(40 mL) at -40 °C and stirred for 10 min. Bromide 7 (2.3 g,
9.4 mmol) was then added, and the mixture was stirred at -25
°C for 2.5 h. Standard ethereal workup, followed by chroma-
tography of the residue (elution with hexanes), gave 1.23 g of
adduct 8 as a yellow oil (68%), which was homogeneous on
the basis ofTLC analysis (hexanes/ether, 10:1, Rf 8 ) 0.82):
1H NMR (250 MHz) δ 2.09 (s, 3 H), 3.38 (d, 2 H, J ) 6.7 Hz),
3.83 (s, 6 H), 5.08-5.18 (m, 2 H), 5.91-6.05 (m, 1 H), 6.40 (s,
2 H); 13C NMR (62.5 MHz) 158.2, 138.4, 137.4, 125.5, 115.7,
103.8, 55.6, 30.2, 7.9 ppm; IR (neat) 1588, 1109 cm-1; ESI-
MS, m/z 193 (MH+).
ethyl (12)
propyl (13)
butyl (14)
pentyl (15)
hexyl (16)
heptyl (17)
octyl (18)
nonyl (19)
13.0*
13.1*
12.0*
12.0*
15.1*
15.0*
15.9*
17.1
14.5*
14.5*
14.1*
13.1*
15.1*
17.0
17.0
17.1
17.2
17.0
17.1
17.0
17.1
17.1
17.1
17.2
17.1
17.1
17.1
17.1
17.1
17.1
17.0
17.1
acetate (20)
12.0*
12.0*
12.0*
12.1*
13.2*
13.0*
13.1*
17.0
14.5
17.1
17.0
17.1
17.1
17.1
17.1
17.0
17.1
17.1
17.2
17.1
17.1
17.0
17.1
17.1
17.1
propanoate (21)
butanoate (22)
pentanoate (23)
hexanoate (24)
heptanoate (25)
octanoate (26)
nonanoate (27)
15.1*
14.0*
14.0*
14.5*
15.8*
13.9*
17.0
1-(3,5-Dim eth oxy-4-m eth ylp h en yl)p r op a n -2-ol (9). To
a solution of Hg(OAc)2 (2.04 g, 6.4 mmol) in THF (30 mL)/
H2O (15 mL) was added 8 (1.23 g, 6.4 mmol) in THF (10 mL)
at room temperature. The mixture was stirred until the yellow
color faded (approximatly 20 min) and then cooled to 0 °C.
NaBH4 (0.63 g, 16.7 mmol) in THF (10 mL) was added, and
after 20 min, the solution was saturated with NaCl. Standard
ethereal workup furnished 1.79 g of a crude oil. Chromatog-
raphy of this residue (elution with hexane/ether, 3:2) gave 0.92
g of alcohol 9 as a white crystalline solid (86% yield, based on
recovery of 0.25 g of 8), which was homogeneous on the basis
of TLC analysis (hexanes/ether, 1:1, Rf 9 ) 0.31): mp 68-69
Ta ble 2. Effects of th e Eth er a n d Ester Der iva tives of
3,7-Dim eth yl-8-h yd r oxy-6-m eth oxyisoch r om a n on th e
Gr ow th of Etiola ted Wh ea t Coleop tiles (T. a estivu m L.
Cv. Wa k ela n d )
1
°C; H NMR (250 MHz) δ 1.26 (d, 3 H, J ) 6.0 Hz), 1.76 (s, 1
H), 2.07 (s, 3 H), 2.57-2.81 (m, 2 H), 3.82 (s, 6 H), 3.98-4.08
(m, 1 H), 6.40 (s, 2 H); 13C NMR (62.5 MHz) 158.2, 136.7, 112.4,
104.4, 68.8, 55.6, 46.2, 22.7, 7.9 ppm; IR (neat) 3300-3550,
1587, 1101 cm-1; ESI-MS, m/z 211 (MH+).
6,8-Dim eth oxy-3,7-d im eth ylisoch r om a n (3). Alcohol 9
(3.89 g, 18.5 mmol) in THF (50 mL) was added to a stirred
suspension of NaH (1.85 g, 46.3 mmol of a 60% dispersion in
mineral oil) at room temperature and was stirred for 45 min.
Chloromethyl methyl ether (3.52 mL, 46.3 mmol) was added,
and the solution was heated to 65 °C for 2 h. Standard
ethereal workup, followed by chromatography (elution with
hexane/ether, 5:1), gave 3.74 g of isochroman 3 as a white
crystalline solid (91%), which was homogeneous on the basis
of TLC analysis (hexanes/ether, 4:1, Rf 3 ) 0.51): mp 52.5-
54 °C; 1H NMR (250 MHz) δ 1.35 (d, 3 H, J ) 6.0 Hz), 2.12 (s,
3 H), 2.65 (d, 2 H, J ) 6.7 Hz), 3.69 (s, 3 H), 3.80 (s, 6 H), 4.70
(d, 1 H, J ) 15.1 Hz), 4.93 (d, 1 H, J ) 15.1 Hz), 6.39 (s, 1 H);
13C NMR (62.5 MHz) 154.7, 133.8, 132.2, 119.9, 116.9, 106.0,
70.5, 64.5, 60.1, 55.5, 35.8, 21.5, 8.5 ppm; IR (neat) 1608, 1456,
1121 cm-1; ESI-MS, m/z 223 (MH+).
wheat coleoptile assay (mm ×3)
R
10-3
M
10-4
M
10-5
M
10-6
M
ethyl (33)
propyl (34)
butyl (35)
pentyl (36)
hexyl (37)
heptyl (38)
octyl (39)
nonyl (40)
12.0*
12.0*
12.0*
12.0*
15.2*
15.0*
17.1
13.7*
13.5*
13.5*
15.2*
17.0
17.0
17.0
17.0
17.0
17.2
17.1
17.0
17.1
17.1
17.0
17.1
17.1
17.0
17.0
17.0
17.1
17.1
17.1
17.1
14.7*
acetate (42)
12.0*
12.08*
12.0*
12.0*
13.0*
17.0
15.1
17.0
17.1
17.1
17.0
17.0
17.1
17.1
17.1
17.1
17.0
17.1
17.1
17.0
17.0
17.1
17.1
propanoate (43)
butanoate (44)
pentanoate (45)
hexanoate (46)
heptanoate (47)
octanoate (48)
nonanoate (49)
14.3*
14.8*
13.2*
14.3*
17.0
3,7-Dim et h yl-6-h yd r oxy-8-m et h oxyisoch r om a n
(2).
17.1
17.0
17.1
17.1
Ethanethiol (21.0 mL, 285 mmol) was added to a stirred
suspension of NaH (17.0 g, 425 mmol of a 60% dispersion in
mineral oil) in DMF (150 mL) at 0 °C and then stirred for 1 h
at room temperature. Isochroman 3 (3.15 g, 14.2 mmol) was
added to the reaction mixture, and the resulting mixture was
heated to 130 °C for 6 h. The reaction was quenched with
saturated aqueous NH4Cl, acidified with 10% aqueous HCl,
saturated with NaCl, and then extracted with ether (5 × 40
mL). The combined organic layers were washed with brine
and then stirred vigorously with CuSO4 (50.0 g) for 1 h. The
solids were filtered and the filtrate concentrated. The result-
ing residue was chromatographed (elution with hexanes/ether,
5 (4.40 g, 20.8 mmol) in ether (150 mL) at 0 °C. The mixture
was stirred for 2 h and then quenched with saturated aqueous
NH4Cl. Standard ethereal workup, followed by chromatogra-
phy (elution with hexanes/ether, 4:1), gave 3.63 g of alcohol 6
as a white solid (96%), which was homogeneous on the basis
of TLC analysis (hexanes/ether, 1:1, Rf 6 ) 0.26): mp 67.5-
69 °C; 1H NMR (250 MHz) δ 1.77 (t, 1 H, J ) 5.9 Hz), 2.09 (s,
3 H), 3.83 (s, 6 H), 4.65 (d, 2 H, J ) 5.9 Hz), 6.56 (s, 2 H); 13
C

1426 J. Agric. Food Chem., Vol. 45, No. 4, 1997
Cutler et al.
2:1) to yield 2.12 g of phenol 2 as a white crystalline solid
(72%), which was homogeneous on the basis of TLC analysis
(hexanes/ether, 1:1, Rf 2 ) 0.56): mp 149.5-151 °C; 1H NMR
(250 MHz) δ 1.34 (d, 3 H, J ) 6.0 Hz), 2.07 (s, 3 H), 2.63 (d, 2
H, J ) 5.9 Hz), 3.71-3.82 (m, 1 H), 3.79 (s, 3 H), 4.65 (d, 2 H,
J ) 14.8 Hz), 4.67 (s, 1 H), 4.92 (d, 1 H, J ) 14.8 Hz), 6.23 (s,
1 H); 13C NMR (62.5 MHz) 156.4, 149.9, 132.2, 114.1, 108.3,
102.7, 70.4, 64.3, 55.5, 35.8, 21.4, 7.5 ppm; IR (neat) 3150-
3500, 1591, 1126 cm-1; ESI-MS, m/z 209 (MH+).
3,7-Dim eth yl-6-eth oxy-8-m eth oxyisoch r om a n (12). Iso-
chroman 2 (80 mg, 0.38 mmol) was added to a stirred
suspension of NaH (18 mg, 0.46 mmol of a 60% dispersion in
mineral oil) in DMF (0.5 mL) at 0 °C. After 30 min of stirring
at room temperature, iodoethane (37 µL, 0.46 mmol) was added
and the mixture stirred for 90 min. The reaction was
quenched with saturated aqueous NH4Cl and extracted with
ether (3 × 5 mL). The combined ethereal extracts were
washed with 10% aqueous CuSO4 and brine, then dried over
anhydrous MgSO4, and concentrated. The residue was chro-
matographed (elution with hexanes/ether, 5:1) to yield 79 mg
of ether 12 (87%) as a white crystalline solid: Rf 12 ) 0.80
(hexanes/ether, 1:1); mp 75-76.5 °C; 1H NMR (250 MHz) δ
1.34 (d, 3 H, J ) 6.1 Hz), 1.39 (t, 3 H, J ) 7.2 Hz), 2.11 (s, 3
H), 2.64 (d, 2 H, J ) 6.7 Hz), 3.68-3.85 (m, 3 H), 3.79 (s, 3 H),
4.69 (d, 1 H, J ) 15.1 Hz), 4.94 (d, 1 H, J ) 15.1 Hz), 6.38 (s,
1 H); 13C NMR (62.5 MHz) 157.0, 153.9, 132.0, 120.1, 117.1,
105.8, 70.5, 68.3, 64.7, 55.4, 35.8, 21.5, 15.6, 8.8 ppm; IR (neat)
1609, 1124 cm-1; ESI-MS, m/z 237 (MH+).
3,7-Dim et h yl-8-m et h oxy-6-p r op oxyisoch r om a n (13).
The alkylation of isochroman 2 with 1-bromopropane (cf. the
preparation of 12) produced ether 13 in 76% yield as a white
crystalline solid: Rf 13 ) 0.80 (hexanes/ether, 1:1); mp 53-
54 °C; 1H NMR (250 MHz) δ 1.05 (t, 3 H, J ) 7.4 Hz), 1.34 (d,
3 H, J ) 6.4 Hz), 1.79 (sextet, 2 H, J ) 7.0 Hz), 2.10 (s, 3 H),
2.65 (d, 2 H, J ) 6.8 Hz), 3.69 (t, 2 H, J ) 6.6 Hz), 3.69-3.80
(m, 1 H), 3.79 (s, 3 H), 4.69 (d, 1 H, J ) 14.9 Hz), 4.95 (d, 1 H,
J ) 14.9 Hz), 6.38 (s, 1 H); 13C NMR (62.5 MHz) 157.1, 153.9,
132.0, 120.0, 117.1, 105.8, 74.3, 70.5, 64.7, 55.4, 35.8, 23.5, 21.5,
10.5, 8.8 ppm; IR (neat) 1609, 1122 cm-1; ESI-MS, m/z 251
(MH+).
The alkylation of isochroman 2 with 1-bromoheptane (cf. the
preparation of 12) produced ether 17 in 81% yield as a colorless
oil: Rf 17 ) 0.87 (hexanes/ether, 1:1); H NMR (250 MHz) δ
1
0.91 (t, 3 H, J ) 6.8 Hz), 1.27-1.55 (m, 11 H), 1.71-1.82 (m,
2 H), 2.11 (s, 3 H), 2.65 (d, 2 H, J ) 6.6 Hz), 3.72 (t, 2 H, J )
8.1 Hz), 3.68-3.80 (m, 1 H), 3.79 (s, 3 H), 4.70 (d, 1 H, J )
15.1 Hz), 4.95 (d, 1 H, J ) 15.1 Hz), 6.38 (s, 1 H); 13C NMR
(62.5 MHz) 157.1, 153.9, 132.0, 120.0, 117.1, 105.8, 72.8, 70.5,
64.7, 55.4, 35.8, 31.7, 30.3, 29.1, 22.5, 21.5, 14.0, 8.8 ppm; IR
(neat) 1610, 1465, 1125 cm-1; ESI-MS, m/z 307 (MH+).
3,7-Dim et h yl-8-m et h oxy-6-oct a n oxyisoch r om a n (18).
The alkylation of isochroman 2 with 1-bromooctane (cf. the
preparation of 12) produced ether 18 in 89% yield as a colorless
1
oil: Rf 18 ) 0.88 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.91 (t, 3 H, J ) 6.7 Hz), 1.28-1.53 (m, 13 H), 1.71-1.80 (m,
2 H), 2.11 (s, 3 H), 2.65 (d, 2 H, J ) 6.5 Hz), 3.72 (t, 2 H, J )
6.6 Hz), 3.68-3.80 (m, 1 H), 3.80 (s, 3 H), 4.69 (d, 1 H, J )
15.1 Hz), 4.95 (d, 1 H, J ) 15.1 Hz), 6.38 (s, 1 H); 13C NMR
(62.5 MHz) 157.0, 153.9, 132.0, 120.0, 117.1, 105.8, 72.8, 70.5,
64.7, 55.4, 35.8, 31.7, 30.2, 29.4, 29.2, 26.1, 22.6, 21.5, 14.0,
8.8 ppm; IR (neat) 1610, 1465, 1125 cm-1; ESI-MS, m/z 321
(MH+).
3,7-Dim eth yl-8-m eth oxy-6-n on a n oxyisoch r om a n (19).
The alkylation of isochroman 2 with 1-bromononane (cf. the
preparation of 12) produced ether 19 in 84% yield as a colorless
1
oil: Rf 19 ) 0.90 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.90 (t, 3 H, J ) 7.0 Hz), 1.28-1.51 (m, 15 H), 171-1.82 (m,
2 H), 2.11 (s, 3 H), 2.65 (d, 2 H, J ) 6.6 Hz), 3.72 (t, 2 H, J )
6.6 Hz), 3.69-3.81 (m, 1 H), 3.79 (s, 3 H), 4.69 (d, 1 H, J )
15.0 Hz), 4.94 (d, 1 H, J ) 15.0 Hz), 6.37 (s, 1 H); 13C NMR
(62.5 MHz) 157.1, 153.9, 132.0, 120.0, 117.1, 105.8, 72.8, 70.5,
64.7, 55.4, 35.8, 31.7, 30.2, 29.4, 29.2, 26.0, 22.6, 21.5, 14.0,
8.8 ppm; IR (neat) 1610, 1465, 1125 cm-1; ESI-MS, m/z 335
(MH+).
6-Acetoxy-3,7-dim eth yl-8-m eth oxyisoch r om an (20). Iso-
chroman 2 (84 mg, 0.40 mmol) was added to a mixture of DCC
(92 mg, 0.45 mmol), DMAP (5 mg, 0.04 mmol), and acetic acid
(23 µL, 0.45 mmol) in CH2Cl2 (2.0 mL) and stirred at room
temperature for 2 h. The solution was filtered and the filtrate
washed with 5% aqueous HCl and saturated aqueous NaHCO3,
dried over anhydrous MgSO4, and concentrated. (The aqueous
acid wash serves to hydrolyze any unreacted DCC.) The
residue was chromatographed (elution with hexane/ether, 2:1)
to yield 85 mg of acetate 20 as a white crystalline solid (85%),
which was homogeneous by TLC analysis (hexanes/ether, 1:1,
Rf 20 ) 0.66): mp 60.5-62 °C; 1H NMR (300 MHz) δ 1.33 (d,
3 H, J ) 6.1 Hz), 1.97 (s, 3 H), 2.31 (s, 3 H), 2.65 (d, 2 H, J )
6.7 Hz), 3.69-3.80 (m, 1 H), 3.79 (s, 3 H), 4.52 (d, 1 H, J )
14.9 Hz), 4.70 (d, 1 H, J ) 14.9 Hz), 6.49 (s, 1 H); 13C NMR
(75.5 MHz) 168.8, 155.9, 145.8, 132.4, 118.9, 116.9, 108.1, 70.5,
63.9, 55.6, 35.6, 21.4, 20.3, 8.8 ppm; IR (neat) 1765, 1622, 1203,
1116 cm-1; ESI-MS, m/z 251 (MH+).
6-Bu toxy-3,7-dim eth yl-8-m eth oxyisoch r om an (14). The
alkylation of isochroman 2 with 1-bromobutane (cf. the prepa-
ration of 12) produced ether 14 in 86% yield as a colorless oil:
1
Rf 14 ) 0.82 (hexanes/ether, 1:1); H NMR (250 MHz) δ 1.00
(t, 3 H, J ) 7.3 Hz), 1.35 (d, 3 H, J ) 6.0 Hz), 1.47-1.56 (m,
2 H), 1.70-1.78 (m, 2 H), 2.11 (s, 3 H), 2.65 (d, 2 H, J ) 6.6
Hz), 3.73 (t, 2 H, J ) 6.5 Hz), 3.68-3.80 (m, 1 H), 3.79 (s, 3
H), 4.69 (d, 1 H, J ) 15.4 Hz), 4.95 (d, 1 H, J ) 15.4 Hz), 6.38
(s, 1 H); 13C NMR (62.5 MHz) 157.1, 153.9, 132.0, 120.0, 117.1,
105.8, 72.5, 70.5, 64.7, 55.4, 35.8, 32.3, 21.5, 19.2, 13.9, 8.8
ppm; IR (neat) 1609, 1125 cm-1; ESI-MS, m/z 265 (MH+).
3,7-Dim eth yl-8-m eth oxy-6-p en ta n oxyisoch r om a n (15).
The alkylation of isochroman 2 with 1-bromopentane (cf. the
preparation of 12) produced ether 15 in 89% yield as a colorless
3,7-Dim et h yl-8-m et h oxy-6-p r op a n oyloxyisoch r om a n
(21). The condensation of isochroman 2 with propionic acid
(cf. the preparation of 20) produced ester 21 in 75% yield as a
white crystalline solid: Rf 21 ) 0.67 (hexanes/ether, 1:1); mp
1
oil: Rf 15 ) 0.85 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.95 (t, 3 H, J ) 7.0 Hz), 1.35 (d, 3 H, J ) 6.0 Hz), 1.37-1.45
(m, 4 H), 1.71-1.80 (m, 2 H), 2.11 (s, 3 H), 2.64 (d, 2 H, J )
6.6 Hz), 3.70 (t, 2 H, J ) 6.6 Hz), 3.69-3.80 (m, 1 H), 3.79 (s,
3 H), 4.69 (d,1 H, J ) 15.0 Hz), 4.95 (d, 1 H, J ) 15.0 Hz),
6.37 (s, 1 H); 13C NMR (62.5 MHz) 157.1, 153.9, 132.0, 120.0,
117.1, 105.8, 72.8, 70.5, 64.7, 55.4, 35.8, 29.9, 28.1, 22.5, 21.5,
14.0, 8.8 ppm; IR (neat) 1609, 1465, 1125 cm-1; ESI-MS, m/z
279 (MH+).
1
68-70 °C; H NMR (300 MHz) δ 1.29 (t, 3 H, J ) 5.5 MHz),
1.33 (d, 3 H, J ) 6.1 Hz), 1.96 (s, 3 H), 2.59 (q, 2 H, J ) 5.5
Hz), 3.69-3.81 (m, 1 H), 3.79 (s, 3 H), 4.52 (d, 1 H, J ) 14.8
Hz), 4.68 (d, 1 H, J ) 14.8 Hz), 6.48 (s, 1 H); 13C NMR (75.5
MHz) 171.9, 156.7, 145.7, 132.3, 118.9, 116.9, 107.9, 70.4, 64.0,
55.6, 35.6, 27.3, 21.4, 9.4, 8.8 ppm; IR (neat) 1758, 1621, 1261,
1121 cm-1; ESI-MS, m/z 265 (MH+).
3,7-Dim eth yl-6-h exa n oxy-8-m eth oxyisoch r om a n (16).
The alkylation of isochroman 2 with 1-bromohexane (cf. the
preparation of 12) produced ether 16 in 83% yield as a colorless
6-Bu tan oyloxy-3,7-dim eth yl-8-m eth oxyisoch r om an (22).
The condensation of isochroman 2 with butanoic acid (cf. the
preparation of 20) produced ester 22 in 83% yield as a white
crystalline solid: Rf 22 ) 0.72 (hexanes/ether, 1:1); mp 56-
58 °C; 1H NMR (300 MHz) δ 1.31-1.40 (m, 8 H), 1.96 (s, 3 H),
2.65 (d, 2 H, J ) 6.7 MHz), 2.83 (m, 2 H), 3.69-3.82 (m, 1 H),
3.79 (s, 3 H), 4.51 (d, 1 H, J ) 14.6 Hz), 4.69 (d, 1 H, J ) 14.6
Hz), 6.48 (s, 1 H); 13C NMR (75.5 MHz) 174.4, 156.7, 145.6,
132.3, 118.9, 116.9, 107.9, 70.5, 64.0, 55.6, 35.6, 34.1, 21.4, 19.1,
8.7 ppm; IR (neat) 1754, 1261, 1115, 1093 cm-1; ESI-MS, m/z
279 (MH+).
1
oil: Rf 16 ) 0.85 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.92 (t, 3 H, J ) 6.4 Hz), 1.35 (d, 3 H, J ) 5.9 Hz), 1.27-1.55
(m, 6 H), 1.69-1.83 (m, 2 H), 2.11 (s, 3 H), 2.65 (d, 2 H, J )
6.6 Hz), 3.72 (t, 2 H, J ) 6.6 Hz), 3.68-3.81 (m, 1 H), 3.79 (s,
3 H), 4.69 (d, 1 H, J ) 15.0 Hz), 4.94 (d, 1 H, J ) 15.0 Hz),
6.37 (s, 1 H); 13C NMR (62.5 MHz) 157.0, 153.9, 132.0, 120.0,
117.1, 105.8, 72.8, 70.5, 64.7, 55.4, 35.8, 31.7, 30.2, 25.7, 22.5,
21.5, 13.9, 8.8 ppm; IR (neat) 1609, 1465, 1125 cm-1; ESI-MS,
m/z 293 (MH+).
3,7-Dim et h yl-8-m et h oxy-6-p en t a n oyloxyisoch r om a n
(23). The condensation of isochroman 2 with pentanoic acid
3,7-Dim eth yl-6-h ep ta n oxy-8-m eth oxyisoch r om a n (17).

Syntheses of Isochroman Esters and Ethers
J. Agric. Food Chem., Vol. 45, No. 4, 1997 1427
(cf. the preparation of 20) produced ester 23 in 86% yield as a
colorless oil: Rf 23 ) 0.75 (hexanes/ether, 1:1); H NMR (250
117.0, 106.8, 77.6, 70.5, 65.2, 55.6, 35.8, 21.6, 9.7 ppm; IR
(neat) 1612, 1582, 1116 cm-1; ESI-MS, m/z 331 (MH+).
3,7-Dim eth yl-8-h yd r oxy-6-p h en ylth iom eth oxyisoch r o-
m a n (31). Ethanethiol (7.0 mL, 94.5 mmol) was added to a
stirred suspension of 5.7 g of NaH (143 mmol of a 60%
dispersion in mineral oil) in DMF (100 mL) at 0 °C. After 1
h, isochroman 30 (1.56 g, 4.7 mmol) was added and the mixture
heated to 120 °C for 18 h. The reaction was quenched with
saturated aqueous NH4Cl, acidified with 10% aqueous HCl,
saturated with NaCl, and extracted with ether (5 × 40 mL).
The combined organic extracts were stirred vigorously with
CuSO4 (50.0 g) for 1 h, and the solids were suction filtered.
The filtrate was concentrated and the residue chromato-
graphed (elution with hexanes/ether, 2:1) to yield 1.19 g of
isochroman 31 (80%) as a white crystalline solid: Rf 31 ) 0.55
(hexanes/ether, 1:1); mp 107.5-109 °C; 1H NMR (250 MHz) δ
1.31 (d, 3 H, J ) 5.1 Hz), 2.10 (s, 3 H), 2.53 (d, 2 H, J ) 5.1
Hz), 3.65-3.76 (m, 1 H), 4.65 (d, 1 H, J ) 12.5 Hz), 4.93 (d, 1
H, J ) 12.5 Hz), 5.27 (s, 2 H), 5.56 (s, 1 H), 6.31 (s, 1 H), 7.21-
7.33 (m, 3 H), 7.49 (d, 2 H, J ) 6.1 Hz); 13C NMR (62.5 MHz)
153.6, 152.9, 135.5, 132.5, 129.9, 129.0, 127.0, 120.1, 115.2,
111.2, 77.6, 70.8, 65.1, 35.3, 21.4, 9.6 ppm; IR (neat) 3500-
3150, 1614, 1066 cm-1; ESI-MS, m/z 317 (MH+).
1
MHz) δ 0.98 (t, 3 H, J ) 7.3 Hz), 1.33 (d, 3 H, J ) 6.0 Hz),
1.38-1.50 (m, 2 H), 1.70-1.82 (m, 2 H), 1.96 (s, 3 H), 2.57 (t,
2 H, J ) 7.7 Hz), 2.65 (d, 2 H, J ) 6.7 Hz), 3.69-3.82 (m, 1
H), 3.79 (s, 3 H), 4.53 (d, 1 H, J ) 14.7 Hz), 4.69 (d,1 H, J )
14.7 Hz), 6.48 (s, 1 H); 13C NMR (62.5 MHz) 171.2, 156.6, 145.5,
132.2, 118.9, 116.8, 107.9, 70.4, 64.0, 55.5, 35.5, 33.6, 27.1, 22.3,
21.4, 13.6, 8.8 ppm; IR (neat) 1755, 1261, 1142, 1116, 1093
cm-1; ESI-MS, m/z 293 (MH+).
3,7-Dim eth yl-6-h exan oyloxy-8-m eth oxyisoch r om an (24).
The condensation of isochroman 2 with hexanoic acid (cf. the
preparation of 20) produced ester 24 in 75% yield as a colorless
1
oil: Rf 24 ) 0.77 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.94 (t, 3 H, J ) 6.7 Hz), 1.33 (d, 3 H, J ) 6.0 Hz), 1.35-1.46
(m, 4 H), 1.71-1.97 (m, 2 H), 2.06 (s, 3 H), 2.56 (t, 2 H, J )
7.7 Hz), 2.65 (d, 2 H, J ) 6.7 Hz), 3.70-3.81 (m, 1 H), 3.79 (s,
3 H), 4.52 (d, 1 H, J ) 14.7 Hz), 4.69 (d, 1 H, J ) 14.7 Hz),
6.49 (s, 1 H); 13C NMR (62.5 MHz) 171.2, 156.6, 145.5, 132.2,
118.9, 116.8, 107.9, 70.4, 64.0, 55.5, 35.5, 33.8, 31.2, 24.7, 22.2,
21.4, 13.8, 8.8 ppm; IR (neat) 1757, 1261, 1142, 1116, 1093
cm-1; ESI-MS, m/z 307 (MH+).
3,7-Dim et h yl-6-h ep t a n oyloxy-8-m et h oxyisoch r om a n
(25). The condensation of isochroman 2 with heptanoic acid
(cf. the preparation of 20) produced ester 25 in 88% yield as a
3,7-Dim eth yl-8-h yd r oxy-6-m eth oxyisoch r om a n (1). A
solution of 31 (0.83 g, 2.6 mmol) in ethanol (20 mL) was added
to W-6 Raney nickel (approximately 1.0 g), and the mixture
was refluxed for a 3 h period. The mixture was filtered on a
bed of Celite and concentrated to yield 0.50 g of phenol 1 (92%),
which was homogeneous by TLC analysis (hexanes/ether, 1:1,
1
colorless oil: Rf 25 ) 0.79 (hexanes/ether, 1:1); H NMR (250
MHz) δ 0.89 (t, 3 H, J ) 5.8 Hz), 1.26-1.41 (m, 9 H), 1.71-
1.82 (m, 2 H), 1.96 (s, 3 H), 2.56 (t, 2 H, J ) 7.6 Hz), 2.65 (d,
2 H, J ) 6.7 Hz), 3.71-3.81 (m, 1 H), 3.79 (s, 3 H), 4.52 (d, 1
H, J ) 14.7 Hz), 4.69 (d, 1 H, J ) 14.7 Hz), 6.48 (s, 1 H); 13C
NMR (62.5 MHz) 171.2, 156.6, 145.5, 132.2, 118.9, 116.8, 107.9,
70.4, 64.0, 55.5, 35.5, 33.9, 31.3, 28.8, 24.9, 22.4, 21.4, 13.9,
8.8, 5.1 ppm; IR (neat) 1757, 1261, 1141, 1115, 1094 cm-1; ESI-
MS, m/z 321 (MH+).
1
Rf 1 ) 0.51) as a white crystalline solid: mp 143-145 °C; H
NMR (250 MHz) δ 1.33 (d, 3 H, J ) 6.0 Hz), 2.14 (s, 3 H), 2.59
(d, 2 H, J ) 6.6 Hz), 3.68 (s, 3 H), 3.67-3.80 (m, 1 H), 4.68 (d,
1 H, J ) 15.1 Hz), 4.93 (d, 1 H, J ) 15.1 Hz), 4.94 (s, 1 H),
6.35 (s, 1 H); 13C NMR (62.5 MHz) 154.9, 153.3, 132.5, 119.8,
114.9, 110.4, 70.6, 64.5, 60.1, 35.3, 21.4, 8.4 ppm; IR (neat)
3500-3150, 1614, 1098 cm-1; ESI-MS, m/z 209 (MH+).
3,7-Dim eth yl-8-eth oxy-6-m eth oxyisoch r om an (33). The
alkylation of isochroman 1 with iodoethane (cf. the preparation
of 12) produced ether 33 in 81% yield as a colorless oil: Rf 33
3,7-Dim eth yl-8-m eth oxy-6-octan oyloxyisoch r om an (26).
The condensation of isochroman 2 with octanoic acid (cf. the
preparation of 20) produced ester 26 in 72% yield as a colorless
1
oil: Rf 26 ) 0.83 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.91 (t, 3 H, J ) 6.9 Hz), 1.30-1.46 (m, 1 H), 1.71-1.83 (m, 2
H), 2.56 (t, 2 H, J ) 7.8 Hz), 2.66 (d, 2 H, J ) 6.7 Hz), 3.71-
3.82 (m, 1 H), 3.79 (s, 3 H), 4.53 (d, 1 H, J ) 14.7 Hz), 4.69
(d,1 H, J ) 14.7 Hz), 6.48 (s, 1 H); 13C NMR (62.5 MHz) 171.2,
156.6, 145.5, 132.2, 118.9, 116.8, 107.9, 70.4, 64.0, 55.5, 35.6,
33.9, 31.5, 29.1, 28.8, 25.0, 22.5, 21.4, 13.9, 12.3, 8.8 ppm; IR
(neat) 1757, 1261, 1141, 1116, 1094 cm-1; ESI-MS, m/z 335
(MH+).
1
) 0.80 (hexanes/ether, 1:1); H NMR (300 MHz) δ 1.34 (d, 3
H, J ) 6.1 Hz), 1.42 (t, 3 H, J ) 7.0 Hz), 2.12 (s, 3 H), 2.63 (d,
2 H, J ) 6.2 Hz), 3.69 (s, 3 H), 3.70-3.82 (m, 1 H), 3.98 (q, 2
H, J ) 7.0 Hz), 4.69 (d, 1 H, J ) 15.2 Hz), 4.93 (d, 1 H, J )
15.2 Hz), 6.37 (s, 1 H); 13C NMR (75.5 MHz) 156.5, 154.8, 132.1,
119.8, 117.3, 107.2, 70.6, 64.5, 63.8, 60.0, 35.8, 21.5, 14.9, 8.6
ppm; IR (neat) 1608, 1261, 1121 cm-1; ESI-MS, m/z 237 (MH+).
3,7-Dim et h yl-6-m et h oxy-8-p r op oxyisoch r om a n (34).
The alkylation of isochroman 1 with 1-bromopropane (cf. the
preparation of 12) produced ether 34 in 63% yield as a colorless
3,7-Dim et h yl-8-m et h oxy-6-n on a n oyloxyisoch r om a n
(27). The condensation of isochroman 2 with nonanoic acid
(cf. the preparation of 20) produced ester 27 in 70% yield as a
1
oil: Rf 34 ) 0.81 (hexanes/ether, 1:1); H NMR (300 MHz) δ
1
colorless oil: Rf 27 ) 0.85 (hexanes/ether, 1:1); H NMR (250
106 (t, 3 H, J ) 7.4 Hz), 1.34 (d, 3 H, J ) 6.1 Hz), 1.76-1.87
(m, 2 H), 2.13 (s, 3 H), 2.63 (d, 2 H, J ) 6.3 Hz) 3.69 (s, 3 H),
3.70-3.80 (m, 1 H), 3.89 (t, 2 H, J ) 6.3 Hz), 4.69 (d, 1 H, J )
15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37 (s, 1 H); 13C NMR
(75.5 MHz) 156.7, 154.8, 132.1, 119.7, 117.3, 107.1, 70.6, 69.7,
64.6, 50.1, 35.8, 22.6, 21.5, 10.6, 8.6 ppm; IR (neat) 1610, 1262,
1120, cm-1; ESI-MS, m/z 251 (MH+).
MHz) δ 0.90 (t, 3 H, J ) 7.0 Hz), 1.29-1.44 (m, 13 H), 1.71-
1.81 (m, 2 H), 2.56 (t, 2 H, J ) 7.6 Hz), 2.66 (d, 2 H, J ) 6.7
Hz), 3.70-3.81 (m, 1 H), 3.79 (s, 3 H), 4.52 (d, 1 H, J ) 14.7
Hz), 4.69 (d, 1 H, J ) 14.7 Hz), 6.49 (s, 1 H); 13C NMR (62.5
MHz) 171.2, 156.6, 145.5, 132.2, 118.9, 116.8, 107.9, 70.4, 64.0,
55.5, 35.5, 33.9, 31.7, 29.1, 29.0, 25.0, 22.5, 21.4, 13.9, 8.8 ppm;
IR (neat) 1757, 1260, 1141, 1117, 1094 cm-1; ESI-MS, m/z 349
(MH+).
8-Bu toxy-3,7-dim eth yl-6-m eth oxyisoch r om an (35). The
alkylation of isochroman 1 with 1-bromobutane (cf. the prepa-
ration of 12) produced ether 35 in 66% yield as a colorless oil:
3,7-Dim eth yl-8-m eth oxy-6-p h en ylth iom eth oxyisoch r o-
m a n (30). Isochroman 2 (1.14 g, 5.5 mmol) was added to a
stirred suspension of NaH (0.33 g, 8.3 mmol of a 60%
dispersion in mineral oil) in HMPA (20 mL) at 0 °C. After 30
min, chloromethyl phenyl sulfide (1.5 mL, 11.0 mmol) and NaI
(1.0 g, 6.7 mmol) were added, and the resulting mixture was
stirred at room temperature for 2 h. Ether (25 mL) and water
(15 mL) were then added, and the aqueous layer was saturated
with NaCl. Standard ethereal workup afforded a crude
residue, which was chromatographed (elution with hexane/
ether, 2:1) to yield 1.36 g of ether 30 (76%) as a pale yellow
solid: Rf 30 ) 0.75 (hexanes/ether, 1:1); mp 102.5-104 °C; 1H
NMR (250 MHz) δ 1.32 (d, 3 H, J ) 6.0 Hz), 2.09 (s, 3 H), 2.64
(d, 2 H, J ) 6.9 Hz), 3.67-3.81 (m, 1 H), 3.79 (s, 3 H), 4.67 (d,
1H, J ) 15.2 Hz), 4.93 (d, 1 H, J ) 15.2 Hz), 5.29 (s, 2 H), 6.41
(s, 1 H) 7.22-7.36 (m, 3 H), 7.50-7.54 (m, 2 H); 13C NMR (62.5
MHz) 157.2, 152.7, 135.7, 132.4, 129.9, 129.0, 126.9, 120.4,
1
Rf 35 ) 0.83 (hexanes/ether, 1:1); H NMR (300 MHz) δ 0.98
(t, 3 H, J ) 7.6 Hz), 1.34 (d, 3 H, J ) 6.1 Hz), 1.45-1.57 (m,
2 H), 1.73-1.82 (m, 2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J ) 6.4
Hz), 3.69 (s, 3 H), 3.69-3.80 (m, 1 H), 3.92 (t, 2 H, J ) 6.4
Hz), 4.69 (d, 1 H, J ) 15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37
(s, 1 H); 13C NMR (75.5 MHz) 156.7, 154.9, 132.1, 119.8, 117.7,
107.1, 70.6, 67.9, 64.6, 60.1, 35.8, 31.4, 21.5, 19.3, 13.8, 8.6
ppm; IR (neat) 1609, 1262, 1119, cm-1; ESI-MS, m/z 265
(MH+).
3,7-Dim eth yl-6-m eth oxy-8-p en ta n oxyisoch r om a n (36).
The alkylation of isochroman 1 with 1-bromopentane (cf. the
preparation of 12) produced ether 36 in 75% yield as a colorless
1
oil: Rf 36 ) 0.83 (hexanes/ether, 1:1); H NMR (300 MHz) δ
0.94 (t, 3 H, J ) 7.0 Hz), 1.34 (d, 3 H, J ) 6.1 Hz), 1.35-1.50
(m, 4 H), 1.74-1.84 (m, 2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J )
6.4 Hz), 3.69 (s, 3 H), 3.70-3.79 (m, 1 H), 3.91 (t, 2 H, J ) 6.3

1428 J. Agric. Food Chem., Vol. 45, No. 4, 1997
Cutler et al.
Hz), 4.69 (d,1 H, J ) 15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37
(s, 1 H); 13C NMR (75.5 MHz) 162.9, 156.7, 154.8, 132.1, 119.7,
117.3, 107.1, 70.6, 68.2, 64.6, 60.0, 35.8, 29.0, 28.3, 22.4, 21.5,
14.0, 8.6 ppm; IR (neat) 1609, 1262, 1091 cm-1; ESI-MS, m/z
279 (MH+).
2.64 (d, 2 H, J ) 6.8 Hz), 2.77-2.88 (m, 2 H), 3.69 (s, 3 H),
3.70-3.79 (m, 1 H), 4.70 (d, 1 H, J ) 15.5 Hz), 4.97 (d, 1 H, J
) 15.5 Hz), 6.56 (s, 1 H); 13C NMR (62.5 MHz) 175.3, 154.7,
148.4, 132.8, 125.4, 121.1, 117.4, 70.4, 64.4, 60.1, 35.2, 34.0,
21.4, 18.9, 9.1 ppm; IR (neat) 1754, 1358, 1120, 1084 cm-1
;
ESI-MS, m/z 279 (MH+).
3,7-Dim eth yl-8-h exa n oxy-6-m eth oxyisoch r om a n (37).
The alkylation of isochroman 1 with 1-bromohexane (cf. the
preparation of 12) produced ether 37 in 71% yield as a colorless
3,7-Dim et h yl-6-m et h oxy-8-p en t a n oyloxyisoch r om a n
(45). The condensation of isochroman 1 with pentanoic acid
(cf. the preparation of 20) produced ester 45 in 83% yield as a
1
oil: Rf 37 ) 0.85 (hexanes/ether, 1:1); H NMR (300 MHz) δ
0.92 (t, 3 H, J ) 6.9 Hz), 1.34 (d, 3 H, J ) 6.1 Hz), 1.31-1.54
(m, 6 H), 1.73-1.82 (m, 2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J )
6.3 Hz), 3.69 (s, 3 H), 3.70-3.79 (m, 1 H), 3.92 (t, 2 H, J ) 6.6
Hz), 4.69 (d, 1 H, J ) 15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37
(s, 1 H); 13C NMR (75.5 MHz) 156.7, 154.8, 132.1, 119.7, 117.3,
107.1, 70.6, 68.2, 64.6, 60.0, 35.8, 31.5, 29.3, 25.8, 22.6, 21.5,
13.9, 8.6 ppm; IR (neat) 1609, 1262, 1118, 1091 cm-1; ESI-
MS, m/z 293 (MH+).
1
colorless oil: Rf 45 ) 0.70 (hexanes/ether, 1:1); H NMR (300
MHz) δ 0.97 (t, 3 H, J ) 7.1 Hz), 1.33 (d, 3 H, J ) 6.1 Hz),
1.41-1.49 (m, 2 H), 1.71-1.80 (m, 2 H), 2.05 (s, 3 H), 2.57 (t,
2 H, J ) 7.4 Hz), 2.64 (d, 2 H, J ) 6.7 Hz), 3.70 (s, 3 H), 3.67-
3.80 (m, 1 H), 4.70 (d, 1 H, J ) 15.6 Hz), 4.97 (d, 1 H, J ) 15.6
Hz), 6.57 (s, 1 H); 13C NMR (75.5 MHz) 172.3, 154.8, 148.7,
132.8, 125.7, 121.1, 117.5, 70.4, 64.6, 60.1, 35.3, 33.9, 27.1, 22.3,
21.5, 13.7, 9.2 ppm; IR (neat) 1756, 1358, 1142, 1086 cm-1
;
3,7-Dim eth yl-8-h ep ta n oxy-6-m eth oxyisoch r om a n (38).
The alkylation of isochroman 1 with 1-bromoheptane (cf. the
preparation of 12) produced ether 38 in 70% yield as a colorless
ESI-MS, m/z 293 (MH+).
3,7-Dim eth yl-8-h exan oyloxy-6-m eth oxyisoch r om an (46).
The condensation of isochroman 1 with hexanoic acid (cf. the
preparation of 20) produced ester 46 in 79% yield as a colorless
1
oil: Rf 38 ) 0.86 (hexanes/ether, 1:1); H NMR (300 MHz) δ
0.90 (t, 3 H, J ) 6.9 Hz), 1.34 (d, 3 H, J ) 6.1 Hz), 1.29-1.51
(m, 8 H), 1.72-1.83 (m, 2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J )
6.4 Hz), 3.69 (s, 3 H), 3.69-3.79 (m, 1 H), 3.91 (t, 2 H, J ) 6.3
Hz), 4.69 (d, 1 H, J ) 15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37
(s, 1 H); 13C NMR (75.5 MHz) 156.7, 154.8, 132.1, 119.7, 117.3,
107.1, 70.6, 68.2, 64.6, 60.1, 35.8, 31.8, 29.3, 29.0, 26.1, 22.6,
1
oil: Rf 46 ) 0.73 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.94 (t, 3 H, J ) 6.8 Hz), 1.33 (d, 3 H, J ) 6.3 Hz), 1.34-1.43
(m, 4 H), 1.71-1.81 (m, 2 H), 2.05 (s, 3 H), 2.56 (t, 2 H, J )
7.4 Hz), 2.64 (d, 2 H, J ) 6.8 Hz), 3.70 (s, 3 H), 3.69-3.81 (m,
1 H), 4.70 (d, 1 H, J ) 15.7 Hz), 4.97 (d, 1 H, J ) 15.7 Hz),
6.58 (s, 1 H); 13C NMR (62.5 MHz) 172.0, 154.8, 148.4, 132.8,
125.5, 121.0, 117.5, 70.4, 64.5, 60.1, 35.2, 34.1, 31.2, 24.6, 22.2,
21.5, 14.0, 8.6 ppm; IR (neat) 1609, 1262, 1118, 1092 cm-1
;
ESI-MS, m/z 307 (MH+).
21.4, 13.8, 9.2 ppm; IR (neat) 1757, 1357, 1142, 1086 cm-1
;
3,7-Dim et h yl-6-m et h oxy-8-oct a n oxyisoch r om a n (39).
The alkylation of isochroman 1 with 1-bromoctane (cf. the
preparation of 12) produced ether 39 in 72% yield as a colorless
ESI-MS, m/z 307 (MH+).
3,7-Dim et h yl-8-h ep t a n oyloxy-6-m et h oxyisoch r om a n
(47). The condensation of isochroman 1 with heptanoic acid
(cf. the preparation of 20) produced ester 47 in 74% yield as a
1
oil: Rf 39 ) 0.89 (hexanes/ether, 1:1); H NMR (300 MHz) δ
0.89 (t, 3 H, J ) 6.7 Hz), 1.29-1.51 (m, 13 H), 1.74-1.83 (m,
2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J ) 6.4 Hz), 3.69 (s, 3 H),
3.68-3.79 (m, 1 H), 3.91 (t, 2 H, J ) 6.4 Hz), 4.69 (d, 1 H, J )
15.0 Hz), 4.93 (d, 1 H, J ) 15.0 Hz), 6.37 (s, 1 H); 13C NMR
(75.5 MHz) 156.8, 155.2, 132.1, 119.7, 117.6, 107.1, 70.6, 68.2,
64.6, 60.1, 35.8, 31.8, 29.3, 29.2, 26.1, 22.6, 21.6, 14.1, 8.6 ppm;
IR (neat) 1610, 1262, 1118, 1092 cm-1; ESI-MS, m/z 321 (MH+).
3,7-Dim eth yl-6-m eth oxy-8-n on a n oxyisoch r om a n (40).
The alkylation of isochroman 1 with 1-bromononane (cf. the
preparation of 12) produced ether 40 in 62% yield as a colorless
1
colorless oil: Rf 47 ) 0.78 (hexanes/ether, 1:1); H NMR (300
MHz) δ 0.89 (t, 3 H, J ) 6.0 Hz), 1.29-1.52 (m, 9 H), 1.70-
1.81 (m, 2 H), 2.05 (s, 3 H), 2.56 (t, 2 H, J ) 7.6 Hz), 2.64 (d,
2 H, J ) 6.8 Hz), 3.69 (s, 3 H), 3.68-3.80 (m, 1 H), 4.70 (d, 1
H, J ) 15.6 Hz), 4.97 (d, 1 H, J ) 15.6 Hz), 6.57 (s, 1 H); 13C
NMR (75.5 MHz) 172.1, 154.8, 148.5, 132.9, 125.6, 121.1, 117.6,
70.4, 64.6, 60.1, 35.3, 34.2, 31.7, 29.1, 25.0, 22.6, 21.5, 14.1,
9.2 ppm; IR (neat) 1757, 1357, 1140, 1086 cm-1; ESI-MS, m/z
321 (MH+).
1
oil: Rf 40 ) 0.91 (hexanes/ether, 1:1); H NMR (250 MHz) δ
0.89 (t, 3 H, J ) 6.3 Hz), 1.28-1.51 (m, 15 H), 1.73-1.83 (m,
2 H), 2.12 (s, 3 H), 2.63 (d, 2 H, J ) 6.6 Hz), 3.69 (s, 3 H),
3.69-3.80 (m, 1 H), 3.91 (t, 2 H, J ) 6.2 Hz), 4.70 (d, 1 H, J )
15.0 Hz), 4.94 (d, 1 H, J ) 15.0 Hz), 6.37 (s, 1 H); 13C NMR
(62.5 MHz) 156.7, 154.7, 132.0, 119.6, 117.2, 107.0, 70.5, 68.2,
64.5, 60.0, 35.8, 31.8, 29.4, 29.3, 26.0, 22.6, 21.5, 14.0, 8.6 ppm;
IR (neat) 1609, 1262, 1118, 1091 cm-1; ESI-MS, m/z 335 (MH+).
8-Acetoxy-3,7-dim eth yl-6-m eth oxyisoch r om an (42). The
condensation of isochroman 1 with acetic acid (cf. the prepara-
tion of 20) produced ester 42 in 72% yield as a white crystalline
solid: Rf 42 ) 0.61 (hexanes/ether, 1:1); mp 83-84 °C; 1H NMR
(250 MHz) δ 1.33 (d, 3 H, J ) 6.1 Hz), 2.06 (s, 3 H), 2.31 (s, 3
H), 2.64 (d, 2 H, J ) 6.8 Hz), 3.70 (s, 3 H), 3.68-3.80 (m, 1 H),
4.70 (d, 1 H, J ) 15.6 Hz), 4.97 (d, 1 H, J ) 15.6 Hz), 6.59 (s,
1 H); 13C NMR (62.5 MHz) 169.2, 154.8, 148.4, 132.9, 125.7,
121.0, 117.5, 70.4, 64.5, 60.1, 35.2, 21.4, 20.7, 14.6, 9.1 ppm;
IR (neat) 1761, 1206, 1119, 1085 cm-1; ESI-MS, m/z 251 (MH+).
3,7-Dim et h yl-6-m et h oxy-8-p r op a n oyloxyisoch r om a n
(43). The condensation of isochroman 1 with propionic acid
(cf. the preparation of 20) produced ester 43 in 74% yield as a
white crystalline solid: Rf 43 ) 0.64 (hexanes/ether, 1:1); mp
3,7-Dim eth yl-6-m eth oxy-8-octan oyloxyisoch r om an (48).
The condensation of isochroman 1 with octanoic acid (cf. the
preparation of 20) produced ester 48 in 80% yield as a colorless
1
oil: Rf 48 ) 0.79 (hexanes/ether, 1:1); H NMR (300 MHz) δ
0.90 (t, 3 H, J ) 6.8 Hz), 1.31-1.51 (m, 11 H), 1.71-1.81 (m,
2 H), 2.05 (s, 3 H), 2.56 (t, 2 H, J ) 7.5 Hz), 2.64 (d, 2 H, J )
6.8 Hz), 3.69 (s, 3 H), 3.68-3.80 (m, 1 H), 4.70 (d, 1 H, J )
15.5 Hz), 4.97 (d, 1 H, J ) 15.5 Hz), 6.57 (s, 1 H); 13C NMR
(75.5 MHz) 172.1, 154.9, 148.3, 133.2, 125.8, 121.1, 117.5, 70.4,
64.6, 60.1, 35.3, 34.2, 31.6, 29.1, 28.9, 25.0, 22.5, 21.5, 14.0,
9.2 ppm; IR (neat) 1757, 1358, 1141, 1086 cm-1; ESI-MS, m/z
335 (MH+).
3,7-Dim et h yl-6-m et h oxy-8-n on a n oyloxyisoch r om a n
(49). The condensation of isochroman 1 with nonanoic acid
(cf. the preparation of 20) produced ester 49 in 78% yield as a
1
colorless oil: Rf 49 ) 0.84 (hexanes/ether, 1:1); H NMR (300
MHz) δ 0.90 (t, 3 H, J ) 6.8 Hz), 1.28-1.49 (m, 13 H), 1.71-
1.81 (m, 2 H), 2.05 (s, 3 H), 2.57 (t, 2 H, J ) 7.6 Hz), 2.65 (d,
2 H, J ) 6.7 Hz), 3.69 (s, 3 H), 3.68-3.79 (m, 1 H), 4.70 (d, 1
H, J ) 15.5 Hz), 4.97 (d, 1 H, J ) 15.5 Hz), 6.57 (s, 1 H); 13C
NMR (75.5 MHz) 172.1, 154.9, 148.4, 132.9, 125.6, 121.1, 117.5,
70.4, 64.6, 60.1, 35.3, 34.1, 31.4, 28.8, 24.9, 22.4, 21.5, 13.9,
9.2 ppm; IR (neat) 1757, 1358, 1141, 1095 cm-1; ESI-MS, m/z
349 (MH+).
1
58-59 °C; H NMR (300 MHz) δ 1.25-1.34 (m, 6 H), 2.05 (s,
3 H), 2.55-2.65 (m, 4 H), 3.70 (s, 3 H), 3.64-3.78 (m, 1 H),
4.70 (d, 1 H, J ) 15.2 Hz), 4.97 (d, 1 H, J ) 15.2 Hz), 6.58 (s,
1 H); 13C NMR (75.5 MHz) 172.8, 154.9, 148.5, 132.9, 125.6,
121.1, 117.5, 70.4, 64.6, 60.1, 35.3, 27.5, 21.5, 9.2 ppm; IR
(neat) 1758, 1357, 1142, 1088 cm-1; ESI-MS, m/z 265 (MH+).
8-Bu tan oyloxy-3,7-dim eth yl-6-m eth oxyisoch r om an (44).
The condensation of isochroman 1 with butanoic acid (cf. the
preparation of 20) produced ester 44 in 77% yield as a white
crystalline solid: Rf 44 ) 0.65 (hexanes/ether, 1:1); mp 59-
60 °C; 1H NMR (250 MHz) δ 1.25-1.40 (m, 8 H), 2.05 (s, 3 H),
ACKNOWLEDGMENT
This work was supported by a joint USDA/UGA
Cooperative Agreement (58-6612-5-018), and a patent
application has been filed (08/667,749).

Syntheses of Isochroman Esters and Ethers
J. Agric. Food Chem., Vol. 45, No. 4, 1997 1429
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